PMID- 23079885 TI - Isolated involvement of the posterior elements in spinal tuberculosis: a review of twenty-four cases. AB - BACKGROUND: The literature on tuberculosis of the posterior spinal elements without involvement of the vertebral body is scarce. In this study we report our experience with twenty-four cases of neural arch tuberculosis that were treated at our center. METHODS: We performed a retrospective review of the clinical and radiographic data of twenty-four consecutive patients who had tuberculosis of the posterior spinal elements with total sparing of the vertebral bodies and intervertebral disc space. We categorized the patients into two groups on the basis of the clinical and radiographic evaluation. The patients who had rapid onset weakness of the lower limbs or pyramidal signs or who showed evidence of epidural abscess underwent emergency decompressive laminectomy (Group A). Patients who had pyomyositis of the posterior spinal muscles without any neurological deficit, pyramidal signs, or epidural abscess were managed with antitubercular therapy alone (Group B). RESULTS: The common presenting features were spastic limb weakness and back pain. The majority of the patients had involvement of the thoracic spine. Epidural abscess, erosion of lamina, and pyomyositis of posterior spinal muscles were common imaging findings. Group A consisted of nineteen patients and Group B consisted of five patients. The mean period of follow-up was 16.9 months (range, nine to sixty months). Patients in Group A had a poorer outcome than those in Group B. Thirteen of the nineteen patients in Group A improved to become independent in the activities of daily living, with complete neurological recovery in eight patients and partial recovery in five patients. Six of the nineteen patients continued to have spastic paraplegia and were wheelchair-dependent. All of the patients in Group B remained neurologically intact during the follow-up period. None of the patients had recurrence of the disease or developed anterior element involvement or kyphotic deformity during the follow-up period. CONCLUSIONS: Neural arch tuberculosis is often missed at the time of initial presentation. In association with epidural abscess, it leads to rapid neurological deterioration. This atypical picture of spinal tuberculosis showed a high rate of neurological deficit at the time of initial presentation for medical care. PMID- 23079886 TI - Plaster: our orthopaedic heritage: AAOS exhibit selection. AB - BACKGROUND: Plaster has been used for centuries as a stiffening agent to treat fractures and other musculoskeletal conditions that require rest, immobilization, or correction of a deformity. Despite modern metallurgy and internal stabilization, plaster casts and splints remain an important means of external stabilization. Casting is a dying art as modern internal and external fixation replace external immobilization. Proper casting technique is paramount. This manuscript outlines the history and chemistry of immobilization materials and techniques as well as the differences among them and the advantages and disadvantages of each. METHODS: Historical references, peer-reviewed journals, textbooks, and primary sources were reviewed to provide data for this review. RESULTS: The history of immobilization reveals a progressive development and refinement of materials that culminated in Mathijsen's plaster bandage in 1851. In 1798, calcium sulfate (plaster of Paris) was introduced. By 1927, crinoline rolls dipped in plaster treated with binding agents facilitated application. Synthetic casting "tapes" (45% polyurethane resin and 55% fiberglass) were introduced in the 1970s. Splinting techniques are ancient, with development spurred by treatment of war wounds. Plaster relies on soft-tissue contact to maintain rigidity. There are well-known advantages, disadvantages, and complications of plaster management. Casting materials all create an exothermic reaction. Burns are associated with water temperatures of >24 degrees C, more than eight layers (ply), and inadequate ventilation. The maximum water temperature must be lower with fiberglass casts. Plaster was the definitive management for most fractures for over 100 years until it was replaced by modern surgical techniques involving internal fixation in the latter part of the twentieth century. CONCLUSIONS: Plaster casts and splints remain an important treatment method for acute and chronic orthopaedic conditions. PMID- 23079887 TI - You have to crawl before you walk: commentary on an article by Bernhard Kessler, MD, et al.: "risk factors for periprosthetic ankle joint infection: a case control study". PMID- 23079888 TI - Two-component gelation and morphology-dependent conductivity of a naphthalene diimide (NDI) pi-system by orthogonal hydrogen bonding. AB - The utility of an external structure-directing agent to induce orthogonal H bonding-mediated programmed supramolecular-assembly and gelation of an n-type NDI chromophore is reported. Further, the effect of pi-stacking and morphology on electrical conductivity of semiconducting NDI building blocks is revealed. PMID- 23079889 TI - Comparative evaluation of pumice stone as an alternative immobilization material for 1,3-propanediol production from waste glycerol by immobilized Klebsiella pneumoniae. AB - In this study, pumice stone (PS), which is a vastly available material in Turkey, was evaluated as an alternative immobilization material in comparison to other commercially available immobilization materials such as glass beads and polyurethane foam. All immobilized bioreactors resulted in much better 1,3 propanediol production from waste glycerol in comparison to the suspended cell culture bioreactor. It was also demonstrated that the locally available PS material is as good as the commercially available immobilization material. The maximum volumetric productivity (8.5 g L(-1) h(-1)) was obtained by the PS material, which is 220 % higher than the suspended cell system. Furthermore, the immobilized bioreactor system was much more robust against cell washout even at very low hydraulic retention time values. PMID- 23079890 TI - Effect of synergistic inducement on the production of laccase by a novel Shiraia bambusicola strain GZ11K2. AB - In this study, an easily detectable method was employed for screening laccase producing microorganisms by using 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonate) as laccase secretion indicator. A novel laccase-producing strain was isolated and identified as Shiraia bambusicola Henn. strain GZ11K2 according to the morphological characteristics and the comparison of internal transcribed spacer ribosomal DNA gene sequences. In further investigation, the production of laccase by S. bambusicola GZ11K2 was greatly enhanced by the nontoxic inducers of copper sulfate and rhodamine B. Copper and rhodamine B were added into the cultivation medium at 24 and 12 h, respectively, and the maximum laccase production was obtained. Under the induction of 2.0 mM copper sulfate and 35 MUM rhodamine B, an increment of about 80 times of laccase activity compared with that in the inducer-free medium and about 20 times compared with that in the single copper-supplemented medium was observed. Compared with other species, S. bambusicola GZ11K2 exhibits better laccase-producing characteristics with an activity of 16,400 U/L after 108 h, suggesting its potential ability for industrial application. PMID- 23079891 TI - Maximum standard uptake value of 18F-fluorodeoxyglucose positron emission tomography is a prognostic factor for progression-free survival of newly diagnosed patients with diffuse large B cell lymphoma. AB - The treatment of patients with diffuse large B cell lymphoma (DLBCL) would be greatly facilitated with a rapid method for determining prognosis that can be performed more easily and earlier than cytological or specific pathological examinations. It has been suggested that newly diagnosed patients with DLBCL who have low maximum standard uptake value (SUV(max)) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are more likely to be successfully treated and remain in remission compared with patients with high SUV(max), but this concept has been poorly studied. We retrospectively analyzed 50 patients with de novo DLBCL to evaluate the relationship between the SUV(max) and disease progression. For patients with low SUV(max) (n = 10) and high SUV(max) (n = 40) (P = 0.255), respectively, the 3-year overall survival rates were 90 and 72 %, and the progression-free survival (PFS) rates were 90 and 39 % (P = 0.012). By multivariate analysis, the revised International Prognostics Index (R-IPI) and SUV(max) at diagnosis were shown to predict longer PFS. The 3-year PFS for patients with low SUV(max) classified into the good prognosis group by R-IPI was 100 vs. 62 % for those with high SUV(max) (P = 0.161), and patients with low SUV(max) classified into the poor prognosis group by R-IPI was 80 vs. 18 % for those with high SUV(max) (P = 0.050). We conclude that the SUV(max) on FDG-PET for newly diagnosed patients with DLBCL is an important predictor of disease progression, especially for patients with poor prognosis by R-IPI. PMID- 23079892 TI - A reduced curcuminoid analog as a novel inducer of fetal hemoglobin. AB - Thalassemia is an inherited disorder of hemoglobin molecules that is characterized by an imbalance of alpha- and beta-globin chain synthesis. Accumulation of unbound alpha-globin chains in erythroid cells is the major cause of pathology in beta-thalassemia. Stimulation of gamma-globin production can ameliorate disease severity as it combines with the alpha-globin to form fetal hemoglobin. We examined gamma-globin-inducing effect of curcuminoids extracted from Curcuma longa L. and their metabolite reduced forms in erythroid leukemia K562 and human primary erythroid precursor cells. The results showed that curcuminoid compounds, especially bisdemethoxycurcumin are potential gamma-globin enhancers. We also demonstrated that its reduced analog, hexahydrobisdemethoxycurcumin (HHBDMC), is most effective and leads to induction of gamma-globin mRNA and HbF in primary erythroid precursor cells for 3.6 +/- 0.4 and 2.0 +/- 0.4-folds, respectively. This suggested that HHBDMC is the potential agent to be developed as a new therapeutic drug for beta-thalassemia and related beta-hemoglobinopathies. PMID- 23079893 TI - Happy with a difference, unhappy with an identity: observers' mood determines processing depth in visual search. AB - Visual search for feature targets was employed to investigate whether the mechanisms underlying visual selective attention are modulated by observers' mood. The effects of induced mood on overall mean reaction times and on changes and repetitions of target-defining features and dimensions across consecutive trials were measured. The results showed that reaction times were significantly slower in the negative than in the positive and neutral mood groups. Furthermore, the results demonstrated that the processing stage that is activated to select visual information in a feature search task is modulated by the observer's mood. In participants with positive or neutral moods, dimension-specific, but no feature-specific, intertrial transition effects were found, suggesting that these observers based their responses on a salience signal coding the most conspicuous display location. Conversely, intertrial effects in observers in a negative mood were feature-specific in nature, suggesting that these participants accessed the feature identity level before responding. PMID- 23079894 TI - Crystal structures and stability of trigonal KLnF4 fluorides (Ln = Y, Ho, Er, Tm, Yb). AB - Crystal structures of pure and doped KLnF(4) (Ln = Y, Ho, Er, Tm, Yb) grown hydrothermally were studied with synchrotron single-crystal and powder diffraction as a function of temperature and pressure. At atmospheric conditions, KHoF(4) and KErF(4) crystallize in space group P3(1), while KTmF(4), Er:KYbF(4), and KYF(4) crystallize in space group P3(2). In both enantiomorphic structures, the K(+) and Ln(3+) cations are completely ordered. The pseudo-symmetry of the structures with respect to the two minimal supergroups k = 3 (P3(1) and P3(2)) and t = 2 (P3(1)12 and P3(2)12) increases with decreasing radius of the Ln(3+) cation, respectively. No phase transition is detected in KYF(4) at low temperatures down to 100 K at atmospheric pressure. Er:KYbF(4) and KYF(4) undergo irreversible pressure-induced phase transitions at about 4 GPa. In each case, the single crystals become fragmented into several crystallites as observed during single-crystal measurements in diamond anvil cells. Up to the phase transitions, both Er:KYbF(4) and KYF(4) are more compressible along the c axis and their bulk compressibility predominantly results from the contraction of the KF(8) polyhedra. The application of pressure does not affect the distribution of the cations in the crystal structures of Er:KYbF(4) and KYF(4) up to the phase transitions at about 4 GPa. PMID- 23079896 TI - Circulating neutrophil dysfunction in acute liver failure. AB - Systemic inflammation and susceptibility to developing sepsis is common in acute liver failure (ALF) resulting in tissue damage and organ failure. This study characterized the function of circulating neutrophils in 25 patients with ALF and subacute liver failure (SALF). ALF (n=15)/SALF (n=10) patients were prospectively studied and compared with 11 healthy (HC) and 6 septic controls (SC). Neutrophils were isolated on admission to intensive care and every 3-4 days until death / liver transplantation / recovery. Neutrophil phenotype was determined using fluorochrome-labeled antibodies to CD16 and CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) was determined using fluorescein isothiocyanate-labeled opsonized Escherichia coli and oxidative burst (OB) was determined by the percentage of neutrophils producing reactive oxygen species (ROS) at rest and after stimulation with opsonized E. coli. Physiological variables, biochemistry, arterial ammonia, microbiology, and outcomes were collected. Plasma pro- and antiinflammatory cytokine profiles were performed by enzyme-linked immunosorbent assay. Neutrophil expression of CD16 which recognizes the FcgammaRIII region of immunoglobulin G was significantly reduced in the ALF cohort (P<0.001) on day 1 compared to HC. NPA was significantly impaired in the SALF cohort compared to HC (P<0.01). Impaired NPA in the ALF and SALF cohorts on admission predicted nonsurvival without liver transplantation (P=0.01). Spontaneous neutrophil production of ROS was not significantly increased in any of the cohorts. E. coli-stimulated OB was preserved in ALF/SALF cohorts but was significantly impaired in the SC group (P<0.05). CONCLUSION: Circulating neutrophils in ALF/SALF have impaired bacteriocidal function similar to that seen in severe sepsis. Neutrophil function indices are important biomarkers in ALF and may be implicated in the development of organ dysfunction and the increased susceptibility to developing sepsis. PMID- 23079895 TI - Substrate competition studies demonstrate oxidative metabolism of glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate in cortical astrocytes from rat brain. AB - It is well established that astrocytes can utilize many substrates to support oxidative energy metabolism; however, use of energy substrates in the presence of other substrates, as would occur in vivo, has not been systematically evaluated. Substrate competition studies were used to determine changes in the rates of (14)CO(2) production since little is known about the interaction of energy substrates in astrocytes. The rates of (14)CO(2) production from 1 mM D-[6 (14)C]glucose, L-[U-(14)C]glutamate, L-[U-(14)C]glutamine, D-3-hydroxy[3 (14)C]butyrate, L-[U-(14)C]lactate and L-[U-(14)C]malate by primary cultures of astrocytes from rat brain were determined to be 1.17 +/- 0.19, 85.30 +/- 12.25, 28.04 +/- 2.84, 13.55 +/- 4.56, 14.84 +/- 2.40 and 5.20 +/- 1.20 nmol/h/mg protein (mean +/- SEM), respectively. The rate of (14)CO(2) production from glutamate oxidation was higher than that of the other substrates Addition of unlabeled glutamate significantly decreased the rates of (14)CO(2) production from all other substrates studied; however, glutamate oxidation was not altered by the addition of any of the other substrates. The rate of (14)CO(2) production of glutamine was decreased by glutamate, but not altered by other substrates. The rate of (14)CO(2) production from glucose was significantly decreased by the addition of unlabeled glutamate, glutamine or lactate, but not by 3 hydroxybutyrate or malate. Addition of unlabeled glucose did not significantly alter the (14)CO(2) production from any other substrate. (14)CO(2) production from lactate was decreased by the addition of unlabeled glutamine or glutamate and increased by addition of malate. The (14)CO(2) production from malate was decreased by the addition of unlabeled glutamate or lactate, but was not altered by the other substrates. The substrate utilization for oxidative energy metabolism in astrocytes is very different than the profile previously reported for synaptic terminals. These studies demonstrate the potential use of multiple substrates including glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate as energy substrates for astrocytes. The data also provide evidence of interactions of substrates and multiple compartments of TCA cycle activity in cultured astrocytes. PMID- 23079897 TI - Combination treatment of localized concurrent chemoradiation therapy and transarterial chemoembolization in locally advanced hepatocellular carcinoma with intrahepatic metastasis. AB - PURPOSE: Although sorafenib has been approved for treating advanced hepatocellular carcinoma (HCC), its high cost, frequent adverse events, and unsatisfactory efficacy remain unresolved. We evaluated the efficacy and safety of the combination treatment of localized concurrent chemoradiation therapy (CCRT) for locally advanced HCC with portal vein thrombosis (PVT) and transarterial chemoembolization (TACE) for intrahepatic metastasis. METHODS: Between January 2006 and June 2011, 30 patients with HCC with portal vein invasion and intrahepatic metastasis were enrolled. After TACE for intrahepatic metastasis, localized CCRT (45 Gy over 5 weeks with conventional fractionation and hepatic artery infusional chemotherapy using 5-fluorouracil as a radiosensitizer, administered during the first and fifth weeks of radiotherapy) was used to treat main HCC with PVT. The modified response evaluation criteria in solid tumors (mRECIST) were used to evaluate tumor response. RESULTS: The median age of the patients (26 men, 4 women) was 51 years. Objective response rates were 30.0% (9/30) and 32.1% (9/28) in the intention-to-treat and per protocol analyses, respectively. The median progression-free survival (PFS) and overall survival (OS) were 4.5 and 9.8 months, respectively. Baseline alpha-fetoprotein (AFP) correlated significantly with PFS (P = 0.008), whereas baseline AFP, completion of the protocol, and overall radiological response influenced OS significantly (all P < 0.05). All adverse events were predictable and manageable with conservative care. CONCLUSIONS: Combination treatment of localized CCRT and TACE was effective and tolerable in patients with locally advanced HCC with PVT and intrahepatic metastasis. This protocol may be an alternative option when sorafenib cannot be prescribed. PMID- 23079898 TI - Personality factors moderate the associations between apolipoprotein genotype and cognitive function as well as late onset Alzheimer disease. AB - OBJECTIVES: We tested the hypothesis that neuroticism moderates the association between APOE (apolipoprotein E) genotype and two major outcomes, cognitive function and Alzheimer disease. We also explored whether other personality dimensions (extraversion, openness to experience, agreeableness, and conscientiousness) moderate the associations of APOE with these outcomes. DESIGN: Primary analyses of existing randomized clinical trial data. SAMPLE: Six-hundred two older adults (mean age of 78 years at baseline). MEASUREMENTS: APOE genotype, the NEO-Five Factor Inventory, the Alzheimer's Disease Assessment Scale Cognitive: measured every 6 months for 6.5 years) and relevant covariates. RESULTS: Fully adjusted multivariate analyses showed that the association between the presence of APOE [Latin Small Letter Open E]-4 allele(s) and both outcomes was evident among individuals with high levels of neuroticism and extraversion but not among persons with low levels of these traits. CONCLUSIONS: Phenotypic personality dimensions, primarily neuroticism and extraversion, moderate the relationship between APOE [Latin Small Letter Open E]-4 genotype and cognitive outcomes among older adults. Future research is needed to elucidate the physiological processes involved in these particular phenotype-genotype interactions. PMID- 23079899 TI - Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. AB - RATIONALE: A major challenge in the pharmacological treatment of psychotic disorders is the effective management of the associated cognitive dysfunctions. Novel concepts emphasize a potential benefit of partial agonists acting upon dopamine D(2)-like receptors in ameliorating these cognitive deficits, and pre clinical studies suggest that D(3)-receptor-preferring compounds can exert pro cognitive effects. OBJECTIVE: The objective of the study was to use acute phencyclidine (PCP) treatment to model the cognitive deficits of schizophrenia in mice, and to test the efficacy of the novel, dopamine D(3)-receptor-preferring drug cariprazine in ameliorating the severity of PCP-triggered cognitive deficits. METHODS: One group of wild-type or D(3)-receptor knockout mice was acutely treated with either saline or phencyclidine (PCP, 1 mg/kg). A separate group of mice was treated with cariprazine prior to PCP administration. Both groups were then tested in three cognitive tasks: social interaction/recognition and recognition memory, spatial working memory, and attention-set-shifting. RESULTS: PCP effectively disrupted social recognition and social recognition memory, spatial working memory, and extradimensional attention set-shifting. Cariprazine pretreatment significantly attenuated the emergence of these cognitive deficits in PCP-treated wild-type mice, but not in PCP-treated D(3) receptor knockout mice. CONCLUSIONS: In an animal model of PCP-induced cognitive impairment, cariprazine pretreatment significantly diminished PCP-triggered cognitive deficits, and studies on knockout mice show that dopamine D(3) receptors contribute to this effect. PMID- 23079900 TI - Activity of ethanol and daptomycin lock on biofilm generated by an in vitro dynamic model using real subcutaneous injection ports. AB - Vancomycin lock solution (LS) is recommended for the conservative treatment of subcutaneous injection port (SIP)-related infections, but may be associated with failure. We used an in vitro dynamic model of biofilm formation in an SIP, based on a continuous flow circulating via a real SIP, to assess the effectiveness of vancomycin (5 mg/ml), daptomycin (5 mg/ml) and ethanol 40 % LS in eradicating a pre-established Staphylococcus epidermidis biofilm. Heparin, Ringer's lactate and enoxaparin sodium LS were used as controls. The logarithmic reductions of colony forming units (CFU) were compared by Student's t-test. After 24 h of exposure, the vancomycin LS did not exert a greater bactericidal effect than the heparin LS control (mean logarithmic reduction: 2.27 +/- 0.58 vs. 1.34 +/- 0.22, respectively, p = 0.3). The mean logarithmic reduction was greater with daptomycin LS (5.45 +/- 0.14 vs. 0.39 +/- 0.12, p < 0.01) and ethanol LS (6.79 +/ 1.03 vs. 1.43 +/- 0.54, p = 0.02). Bacterial revival after exposure to 24 h of LS was assessed. The mean viable bacteria count was significantly higher for vancomycin LS (9.36 +/- 0.10 log(10)CFU) and daptomycin LS (9.16 +/- 0.02 log(10)CFU) than for ethanol LS (2.95 +/- 1.65 log(10)CFU). Ethanol appeared to be the most attractive option to treat SIP-related infection, but its poor ability to entirely disrupt the biofilm structure may require its use in association with a dispersal agent to avoid renewal of the biofilm. PMID- 23079908 TI - Unearthing the naked mole-rat. PMID- 23079909 TI - Amendment submitted; protocol reviewed? PMID- 23079910 TI - Response. Unnecessary delays! PMID- 23079911 TI - A word from OLAW and USDA. PMID- 23079912 TI - Response. Amendment necessitates re-review. PMID- 23079913 TI - Endotracheal intubation in swine. AB - Swine are commonly used as research models for cardiovascular surgery and disease, gastrointestinal disease, organ transplantation and intra-renal surgery. These surgical models require anesthesia and, consequently, endotracheal intubation in order to protect the airway; prevent aspiration of saliva, blood and foreign materials; and maintain positive pressure ventilation of the animal. Successful intubation is vital to the stable maintenance of swine under inhalational anesthesia. Here we discuss key features of swine anatomy that make intubation challenging, equipment necessary for successful intubation and techniques for endotracheal intubation in swine. PMID- 23079915 TI - Current practices in a captive breeding colony of 13-lined ground squirrels (Ictidomys tridecemlineatus). AB - The authors provide an update to their 2006 report on the successful large-scale captive breeding of the 13-lined ground squirrel (TLGS; Ictidomys tridecemlineatus) in their colony, now a single-source supplier of purpose-bred TLGSs for several research institutions. With funding from the National Institutes of Health, the authors have expanded their capacity for breeding pairs and built a dedicated hibernaculum to house torpid animals in the facility. The authors report new information on housing, diet, environmental enrichment, breeding, behavior and health. They also report the findings of several in-house studies on the health, behavior and well-being of their TLGSs. PMID- 23079916 TI - Decontamination and digestion of infectious animal waste using a tissue dissolver in an animal biosafety level 3 facility. AB - Alkaline hydrolysis-based tissue dissolvers (TDs) are commercially available tools for the digestion and decontamination of infectious animal waste. The authors carried out a series of experiments to verify whether the TD in their facility completely digested animal carcasses and inactivated infectious agents. Using the manufacturer's recommended cycle parameters, the TD inactivated a high concentration of chemically resistant bacterial spores used as a surrogate for the infectious agents in use in the facility. Animal tissues were completely digested into a non-infectious liquid effluent that could be disposed of directly to the sanitary sewer. Reducing the cycle time by 50% still inactivated all spores, although a small amount of tissue remained undigested. The authors recommend that each facility carry out its own experiments to verify the efficacy of a TD before use, given that the design and style of TD as well as the composition of the tissue load is likely to vary between facilities. PMID- 23079917 TI - Safety and efficacy of buprenorphine for analgesia in laboratory mice and rats. AB - Buprenorphine is a long-acting opiate with a high therapeutic index. The authors review the pharmacology, toxicity, analgesic effects and delivery of buprenorphine for use in laboratory mice and rats. Buprenorphine-based analgesic therapy has a substantial record of safety, and there is growing evidence of its effectiveness for treating post-operative pain. Nonetheless, more research is needed to determine optimal delivery systems and analgesic regimens for pain therapy in laboratory animals. PMID- 23079918 TI - Working with animals is 'in her blood'. PMID- 23079919 TI - Going back to nature: the benefits of wood enrichment. AB - Environmental enrichment can be defined as altering the living environment of captive animals in order to provide them with opportunities to express more of their natural behavioral repertoire. The challenge of providing effective enrichment in laboratory species is to ensure that it allows for normal behavioral opportunities. For many animals, these behaviors include foraging, sheltering, exploring, nest building and gnawing. In the wild, many species use wood and bark to satisfy these behaviors, thereby maintaining physiological and behavioral health. For laboratory animals, various wood enrichment products are available that will provide appropriate environmental enrichment and satisfy those same needs. PMID- 23079921 TI - Differences and similarities in cross-cultural perceptions of boundaries: a comparison of results from two studies. AB - There has been substantial literature on boundary excursions in clinician-patient relationships; however, very little empirical research exists. Even less information exists on how perceptions of this issue might differ across cultures. Prior to this study, empirical data on various kinds of boundary excursions were collected in different cultural contexts. First, clinicians from the U.S. and Brazil were asked to rate 173 boundary excursions for both their perceived harmfulness and their professional unacceptability (Miller et al., 2006). In a second study, colleagues from Qatar administered a slightly modified version to mental health care professional staff of a hospital in Doha, Qatar (Ghuloum et al., 2011). In this paper, the results of these two separate studies are compared. The results showed some similarities and some differences in perceptions of the boundary behaviors. For example, both sets of cultures seem to agree that certain behaviors are seriously harmful and/or professionally unacceptable. These behaviors include some frankly sexual behavior, such as having sexual intercourse with a patient, as well as behavior related to doing business with the patient, and some disclosing behavior. There are also significant cultural differences in perceptions of how harmful some of the behaviors are. Qatari practitioners seemed to rate certain behaviors that within therapy mix disclosing or personal behavior with therapy as more harmful, but behaviors that involved interacting with patients outside of therapy as less serious. A factor analysis suggested that participants in U.S./Brazil saw a much larger number of behaviors as making up a set of Core Boundary Violations, whereas Qatari respondents separated sexual behaviors from others. Finally, a Rasch analysis showed that both cultures perceived a continuum of boundary behaviors, from those that are least harmful or unprofessional to those that are highly harmful or unprofessional. One interpretation is that cultural factors may be most influential on those kinds of behaviors that are perceived as relatively less serious. Implications for training and supervision are also discussed. PMID- 23079922 TI - Galvanic-cell-induced growth of Ag nanosheet-assembled structures as sensitive and reproducible SERS substrates. AB - SERS up: Ag nanosheet-assembled structures with controlled morphologies were achieved on indium tin oxide substrates by galvanic-cell-induced growth (see figure). These structures exhibit a highly active and homogeneous surface enhanced Raman scattering (SERS) effect, and show promising potential as reliable SERS substrates for detection of trace polychlorinated biphenyls. PMID- 23079923 TI - Rational substrate and enzyme engineering of transketolase for aromatics. AB - The uses of 3-formylbenzoic acid and 4-formylbenzoic acid as molecular probes along with previous and new transketolase mutants revealed the factors governing the rate of reaction between transketolase and aromatic aldehydes. The novel alpha,alpha-dihydroxyketones were produced at 15 to 30-fold higher yields and up to 250-fold higher specific activities with D469T TK when compared to those obtained for benzaldehyde. PMID- 23079924 TI - Introducing Neurosurgery's Journal Club. PMID- 23079926 TI - Journal Club: brain hypoxia is associated with short-term outcome after severe traumatic brain injury independently of intracranial hypertension and low cerebral perfusion pressure. PMID- 23079927 TI - Commentary: journal club: intraoperative confocal microscopy for brain tumors: a feasibility analysis in humans. PMID- 23079930 TI - Surgical management of the lateral neck compartment for metastatic thyroid cancer. AB - PURPOSE OF REVIEW: The lateral neck compartment is the second most frequent target region for metastatic papillary thyroid cancer (PTC) and medullary thyroid cancer (MTC). Lateral lymph node metastases are associated with locoregional recurrence and, when they involve either side of the neck, with mediastinal and distant metastases. RECENT FINDINGS: For tumors originating from the upper thyroid pole, the first nodal basin is not invariably the central compartment (as for primaries arising from the inferior thyroid pole) but often the upper part of the ipsilateral lateral compartment. Lymph node dissection of the first basin may differ depending on the location of the primary tumor. Involvement of the contralateral lateral compartment is seen in PTC with extensive central compartment involvement, and in MTC with preoperative basal calcitonin levels more than 200 pg/ml (normal limit <10 pg/ml). SUMMARY: After lateral lymph node dissection for metastatic thyroid cancer, dysfunction of lateral neck nerves is fairly common. This observation underpins the importance of striking a balance between oncological benefit and surgical risk. Lateral lymph node dissection may be warranted for an upper thyroid pole primary, for a tumor with extensive involvement of the central compartment, and for an MTC with increased basal calcitonin level of 20-200 pg/ml (ipsilateral dissection) or more than 200 pg/ml (bilateral dissection). PMID- 23079931 TI - Radiofrequency and ethanol ablation for the treatment of recurrent thyroid cancers: current status and challenges. AB - PURPOSE OF REVIEW: To review the role and safety of radiofrequency ablation (RFA) and ethanol ablation for the treatment of recurrent thyroid cancers in patients at high risk of surgery. RECENT FINDINGS: RFA and ethanol ablation are currently used as local tumor control methods for the treatment of recurrent thyroid cancers. The therapeutic success rates of RFA and ethanol ablation have been reported to be 75-91.6 and 70.8-98%, respectively. Local tumor recurrence has been reported to be 0-25% following RFA and 3.2-33% following ethanol ablation. Various complications have also been reported, such as discomfort, pain, skin burning, and changes in voice, but not life-threatening complications. All patients with changes in their voice received treatment to the central neck area, and permanent injury has been reported in patients who received RFA. SUMMARY: RFA and ethanol ablation could be considered as nonsurgical treatment options for recurrent thyroid cancers in patients at high risk of surgery. Efficacy seems to be higher for RFA, but complications seem to be lower for ethanol ablation. PMID- 23079933 TI - A Hydrogel Sensing Pathological Urate Concentrations. AB - Metabolite-responsive hydrogels that detect pathological metabolite concentrations and react by releasing a therapeutic stimulus hold high promises in treating metabolic diseases. In this study, a hydrogel is described that discriminates between physiological and pathological concentrations of urate, the causative agent of gouty arthritis. The hydrogel is synthesized by coupling a dimeric variant of the Deinococcus radiodurans-derived urate repressor HucR to linear polyacrylamide. The protein-grafted polymer is crosslinked to form a hydrogel by a multimeric hucO DNA sequence [hucO]n specifically binding HucR. At elevated urate concentrations, HucR dissociates from [hucO]n thereby weakening the hydrogel structure and resulting in its dissolution. PMID- 23079932 TI - Early prediction of hypocalcemia following total thyroidectomy using combined intact parathyroid hormone and serum calcium measurement. AB - BACKGROUNDS: Concomitant intact parathyroid hormone (iPTH) and serum calcium measurement is deemed to be useful in predicting hypocalcemia after total thyroidectomy. This study aimed to prospectively assess the diagnostic accuracy of combined iPTH and serum calcium measurement in predicting early postoperative hypocalcemia. METHODS: From January 2010 to January 2011, 112 patients underwent total thyroidectomy in our department. A prospective study was carried out to search for factors predicting postoperative hypocalcemia. Serum calcium, phosphorus, and iPTH levels have been measured before operation and at 6, 24, and 48 h postoperatively. Hypocalcemia was defined as a serum calcium level less than 8.0 mg/dL. Sensitivity and specificity of different serum measurements have been calculated using the receiver-operator characteristics curve. RESULTS: Thirty three patients (29.5 %) had transient postoperative hypocalcemia. Serum iPTH level showed the highest sensitivity and specificity in predicting hypocalcemia after 6 h (84.8 % and 93.7 %, respectively) for a criterion value <= 12.1 pg/mL. Serum calcium level showed the highest sensitivity and specificity after 24 h (93.9 and 100.0 %, respectively) for a criterion value <= 7.97 mg/dL. Combined cutoffs of 6-h iPTH and 24-h serum calcium showed sensitivity and specificity of 100.0 %. CONCLUSIONS: The combined measurement of 6-h iPTH and 24-h serum calcium are highly predictive of early postoperative hypocalcemia. Patients with serum iPTH and calcium level <= criterion value are at major risk for developing hypocalcemia. These results are important in selecting patients eligible for early discharge and those patients who need calcium and vitamin D supplementation. PMID- 23079935 TI - Reversible freezing of gait caused by dural arteriovenous fistula and congestion of the globus pallidus. AB - BACKGROUND: Freezing of gait (FOG) is defined as an episodic inability to generate effective stepping in the absence of any known cause other than parkinsonism or high-level gait disorders. METHODS: We present a 59-year-old male with acute, progressive episodes of FOG. Imaging studies revealed a dural arteriovenous fistula (DAVF) associated with edema of the globus pallidus interna (GPi). Cerebral angiography confirmed the diagnosis of DAVF and demonstrated an occluded straight sinus and a retrograde blood flow of deep cerebral veins. RESULTS: After endovascular closure of the DAVF, a major improvement of FOG was observed concomitant with striking near resolution of GPi congestion. CONCLUSIONS: This reversal of the clinical course, correlated with changes in imaging studies, suggests a major role of the GPi in the pathology of FOG. PMID- 23079936 TI - High levels of iron status and oxidative stress in patients with metabolic syndrome. AB - Studies concerning oxidative stress (OxE) parameters have increased, mainly because of its important role in cardiovascular diseases and diabetes complications. The main objective of this study was to evaluate iron nutrition status and oxidative stress parameters in subjects that had developed metabolic syndrome (MetS). Subjects from the Research Program of Risk Factors for Cardiovascular Disease (n = 155) were studied (ages ranging from 45 to 65 years old) and classified according to the Adult Treatment Panel III criterion. A blood sample was taken after a 12-h fasting period, and basal glucose, insulin, thiobarbituric acid reactive substances (TBARS), oxidized LDL (oxLDL), heme oxygenase (HO) activity, lipid profile, and iron nutrition status were determined. Eighty-five subjects were classified as MetS, and 70 non-MetS. Individuals with MetS showed higher Fe storage (high levels of ferritin, total body iron and low transferrin receptor), oxLDL, TBARS, and homeostatic model assessment for insulin resistance levels. The MetS group showed high levels of oxidative stress parameters (HO activity, oxLDL, and TBARS). The presence of MetS showed an association with LDL oxidation risk (multiple lineal regression according to sex and age, p < 0.001). High levels of triglycerides (p < 0.001) and waist circumference (p < 0.012) were associated with oxLDL levels, as well as an association between TBARS and oxLDL with ferritin levels. Through logistic regression analyses, the highest quartile of ferritin was associated with a threefold risk of developing MetS compared to the lowest quartile; also, TBARS showed a 21-fold risk for the development of MetS. Finally, elevated levels of oxidative stress parameters such us oxLDL, TBARS, HO, and Fe storage were associated to MetS. PMID- 23079937 TI - The effect of retributive and restorative sentencing on psychological effects of criminal proceedings. AB - Retribution and restoration have been cited as two goals of sentencing for victims. Furthermore, there is a perspective that acknowledges the overlap of these two aims, seeking to obtain restoration through retribution. Achieving these goals may have implications for the victim's psychological well-being. The current study examines 101 victims of serious crime and how different outcomes may impact their perceptions of psychological well-being. Incarceration, community service, compensation from the offender, and compensation from the state, in addition to acquittals, are included as predictors of the dependent variable. After reviewing the literature on retributive and restorative sentencing, also making a distinction between compensation from the offender and compensation from the state, hierarchical regression analysis finds that compensation from the offender is the only sentencing option significantly associated with psychological effects. PMID- 23079938 TI - Occurrence and contribution of alkyl methoxypyrazines in wine tainted by Harmonia axyridis and Coccinella septempunctata. AB - BACKGROUND: Ladybug taint (LBT) is a wine fault caused by the inadvertent incorporation of ladybeetles to the wine during the winemaking process. Harmonia axyridis, also known as the multicolored Asian lady-beetle (MALB), was the only species considered responsible for causing the taint. A second species, Coccinella septempunctata (7 Spot), has recently also been implicated. The main objectives of this study were to identify and quantify the compounds associated with ladybug taint of white and red wine from these two Coccinellidae species (Harmonia axyridis and Coccinella septempunctata), and determine the most odor active compounds in LBT-affected wines. RESULTS: Results show that Coccinellidae can contribute dimethyl, isopropyl, secbutyl and isobutyl methoxypyrazine to wine when they are processed with grapes, and that the methoxypyrazine composition varies between MALB and 7 Spot. Isopropyl methoxypyrazine is the major contributor to LBT in wines produced with these ladybeetle species, although secbutyl and isobutyl methoxypyrazine may contribute in MALB- and 7 Spot-affected wines, respectively. Finally, dimethyl methoxypyrazine is reported for the first time in wines not affected by Coccinellidae; the global significance and prevalence of this compound in wine remains to be determined. CONCLUSION: Both Harmonia axyridis and Coccinella septempunctata can contribute alkyl methoxypyrazines, and particularly isopropyl methoxypyrazine, to wine at concentrations that can have a negative impact on wine quality. These findings will allow grape growers and winemakers to be more aware of the risks posed by 7 Spot beetles, and to take the appropriate preventative and remedial actions. Furthermore, this is the first time dimethyl methoxypyrazine is reported in wine, either as an endogenous or Coccinellidae-derived odorant. PMID- 23079939 TI - Inhibitory mechanism of 10-hydroxy-trans-2-decenoic acid (royal jelly acid) against lipopolysaccharide- and interferon-beta-induced nitric oxide production. AB - Royal jelly acid, 10-hydroxy-trans-2-decenoic acid (10H2DA), is a major lipid component of royal jelly, which is the exclusive diet of queen honeybees. Previously, we showed partial inhibition of lipopolysaccharide (LPS)-induced NF kappaB activation by 10H2DA. In this study, the ability of 10H2DA to inhibit LPS induced nitric oxide (NO) production was investigated. LPS-induced NO production and inducible NO synthase (iNOS) gene transcription were inhibited by 10H2DA. LPS stimulated interferon (IFN)-beta production, IFN regulatory factor-1 induction and IFN-stimulated response element activation, which are required for iNOS induction, were unaffected by 10H2DA. IFN-beta-induced NO production, however, was significantly inhibited by 10H2DA. Furthermore, IFN-beta-induced nuclear factor (NF)-kappaB activation and tumour necrosis factor (TNF)-alpha production were significantly inhibited by 10H2DA, and TNF-alpha-induced NF-kappaB activation was also inhibited by 10H2DA. These results and our previous study suggest that 10H2DA inhibits LPS- and IFN-beta-induced NO production via inhibition of NF-kappaB activation induced by LPS or IFN-beta. PMID- 23079940 TI - A high-fat diet increases IL-1, IL-6, and TNF-alpha production by increasing NF kappaB and attenuating PPAR-gamma expression in bone marrow mesenchymal stem cells. AB - It is well established that a high-fat diet (HFD) can lead to overweight and ultimately to obesity, as well as promoting low-grade chronic inflammation associated with increased levels of such mediators as TNF-alpha, IL-1, and IL-6. Bone marrow mesenchymal stem cells (MSCs), which are involved in hematopoietic niches and microenvironments, can be affected by these cytokines, resulting in induction of NF-kappaB and inhibition of PPAR-gamma. Because this phenomenon could ultimately lead to suppression of bone marrow adipogenesis, we set out to investigate the effect of an HFD on the expression of PPAR-gamma and NF-kappaB, as well as the production of IL-1, IL-6, and TNF-alpha in MSCs. Two-month-old male Wistar rats were fed a HFD diet and evaluated by means of leukograms and myelograms along with blood total cholesterol, triglyceride, and C-reactive protein levels. MSCs were isolated, and PPAR-gamma and NF-kappaB were quantified, as well as IL-1, IL-6, and TNF-alpha production. Animals that were fed a HFD showed higher levels of blood total cholesterol, triglycerides, and C-reactive protein with leukocytosis and bone marrow hyperplasia. MSCs from HFD animals showed increased production of IL-1, IL-6, and TNF-alpha and increased NF-kappaB and reduced PPAR-gamma expression. Therefore, ingestion of an HFD induces alterations in MSCs that may influence modulation of hematopoiesis. PMID- 23079941 TI - The 20th year of Technology and Health Care. PMID- 23079942 TI - Multiscale computational and experimental approaches to elucidate bone and ligament mechanobiology using the ulna-radius-interosseous membrane construct as a model system. AB - An in vivo axial loading model of the rat ulna was developed almost two decades ago. As a minimally invasive model, it lends itself particularly well for the study of functional adaptation in bone and the interosseous membrane, a ligament spanning between the radius and ulna. The objective of this paper is to review computational and experimental approaches to elucidate its applicability for the study of multiscale bone and ligament mechanobiology. Specifically, this review describes approaches, including i) measurement of strains on bone tissue surfaces, ii) development of a three-dimensional finite element (FE) mesh of a skeletally mature rat ulna, iii) parametric study of the relative influence of mechanical constants and materials properties on computational model predictions, iv) comparison of experimental and computational strain distribution data, and analysis of the radius and interosseous membrane (IOM) ligament's effect on axial load distribution through the ulna of the rat, and v) the effect of mechanical loading on transport through the IOM using different molecular weight fluorescent tagged dextrans. In the first stage of the study a computational stress analysis was performed after applying a 20 N single static load at the ulnar extremities, corresponding to values of experimental strain gauge measurements. To account for the anisotropy of the bone matrix, transverse isotraopic, elastic material properties were applied. In a parametric study, we analyzed the qualitative effect of different material properties on the global load and displacement behavior of the computational model. In a second stage, the same ulnar model used in the parametric study was extended to account for the interaction between the ulna, radius and IOM. The three-dimensional FE model of the rat forelimb confirms the influence of ulnar curvature on its deformation and underscores the influence of the radius and IOM on strain distribution through the ulna. The mode of strain, {i.e.} compression or tension, and strain distribution along the bone diaphysis correspond to those measured experimentally in vivo. When the radius and, indirectly, the IOM were loaded, the bone deformation shifted distally with respect to the diaphysis. In a final stage, the aforementioned ulnar model was used to study the permeability of fluorescent tagged dextrans with different molecular weights in the presence and absence of ulnar compression. Small molecular weight dextrans (3,000 Da) were distributed throughout the IOM in the absence of as well as after mechanical loading. Interestingly, no gradient in distribution was observed in either case. In contrast, very high molecular weight dextrans (1,000,000 Da) were observed only within vascular and lymphatic spaces in the bone (as well as periosteum) and IOM, both in the absence of and after the application of mechanical loading via end load compression. Between the two extremes, both 10 and 70 kDa tracers were distributed throughout the IOM after application of compressive loading. Loading appears to dissipate the steep gradient of fluorescent 70 kDa tracer observed along the lateral surface of the unloaded IOM and its insertion into the radius and ulna. Hence, this combined computational and experimental analysis of the ulna compression model provides new insight into multiscale mechanobiology of the ulna-radius-interosseous membrane construct and may provide new avenues for elucidation of ligament's remarkable structure-function relationships. PMID- 23079943 TI - Prevention and diagnosis of retained foreign bodies through the years: past, present, and future technologies. AB - Post operative retained foreign bodies are a rare but recalcitrant problem. We detail reports of interventions over the last two centuries and review the most current interventions using automated data identity capture and computer aided detection. This was one of earliest areas in which multidisciplinary collaboration was achieved in patient safety. This multidisciplinary collaboration was unique because most other initiatives had been internal: among the disciplines working in the OR i.e. surgeons, nurses and anesthesiologists; this collaboration, to achieve optimal patient safety at that point in time was between surgeons and radiologists to ensure a lack of post operative retained foreign bodies. PMID- 23079944 TI - A study of the bioengineered surgical sponge. AB - The postoperatively retained foreign body (PORFB) can induce complications leading to the need for follow-up surgery to ensure its removal, to treat or prevent the formation of an abscess, and to minimize the risk of death for the patient and liability for the surgeon and hospital. The most common cause of PORFB complications is the surgical sponge. Previously, PORFB prevention was focused on improved efficiency in RFB counting; however, because of the inability to entirely eliminate human error, cost, and the potentially unproven patient outcome improvement, new approaches have been sought. We examined the use of a novel bioengineered, biodegradable sponge (BSS) to reduce the risk of complications due to PORFBs, thus potentially improving patient outcomes. PMID- 23079945 TI - On the efficiency of FES cycling: a framework and systematic review. AB - Research and development in the art of cycling using functional electrical stimulation (FES) of the paralysed leg muscles has been going on for around thirty years. A range of physiological benefits has been observed in clinical studies but an outstanding problem with FES-cycling is that efficiency and power output are very low. The present work had the following aims: (i) to provide a tutorial introduction to a novel framework and methods of estimation of metabolic efficiency using example data sets, and to propose benchmark measures for evaluating FES-cycling performance; (ii) to systematically review the literature pertaining specifically to the metabolic efficiency of FES-cycling, to analyse the observations and possible explanations for the low efficiency, and to pose hypotheses for future studies which aim to improve performance. We recommend the following as benchmark measures for assessment of the performance of FES-cycling: (i) total work efficiency, delta efficiency and stimulation cost; (ii) we recommend, further, that these benchmark measures be complemented by mechanical measures of maximum power output, sustainable steady-state power output and endurance. Performance assessments should be carried out at a well-defined operating point, i.e. under conditions of well controlled work rate and cadence, because these variables have a strong effect on energy expenditure. Future work should focus on the two main factors which affect FES-cycling performance, namely: (i) unfavourable biomechanics, i.e. crude recruitment of muscle groups, non-optimal timing of muscle activation, and lack of synergistic and antagonistic joint control; (ii) non-physiological recruitment of muscle fibres, i.e. mixed recruitment of fibres of different type and deterministic constant-frequency stimulation. We hypothesise that the following areas may bring better FES-cycling performance: (i) study of alternative stimulation strategies for muscle activation including irregular stimulation patterns (e.g. doublets, triplets, stochastic patterns) and variable frequency stimulation trains, where it appears that increasing frequency over time may be profitable; (ii) study of better timing parameters for the stimulated muscle groups, and addition of more muscle groups: this path may be approached using EMG studies and constrained numerical optimisation employing dynamic models; (iii) development of optimal stimulation protocols for muscle reconditioning and FES-cycle training. PMID- 23079946 TI - Hierarchy and inhomogeneity in the systematic structure of the mammalian myocardium: towards a comprehensive view of cardiodynamics. AB - In order to visualise the mammalian myocardial structure in its entirety, we distended excised porcine left ventricles by inflating the coronary arteries with compressed air, using rising pressures between 100 and 300 kPa. The ventricular walls became elongated, and left ventricular cavity widened with rising pressure albeit with insignificant changes in their mural thickness. High resolution computed tomographic analysis subsequent to pneumographic distension revealed a hierarchical structure. First, a feathered arrangement of the cardiomyocytes aggregated together mainly within the equatorial area of the ventricle, giving an overall appearance of systematically arranged spatially netted lamellar structures with pronounced local inhomogeneity. Second, histological examination in orthogonal planes, analysing samples dividing the ventricular walls into 18 segments, showed the lamellae themselves to be made up of aggregated chains of myocytes, the alignment of these chains producing the well-recognised change in so-called helical angle when traced through the thickness of the walls. Transmural length sections removed from the same positions in the ventricular walls showed inter-lamellar connections aligned in the direction from the ventricular base to the apex which were definitely longer than those we observed in transmural cross-sections. Electron-microscopy exposed the two compartments of interstitial connective tissue, suggesting the endomysium to bind long chains of myocytes to lamellar aggregates, while the loose perimysium strengthens the structure of the lubricating medium which eases the gliding of the lamellar aggregates relative to one another. PMID- 23079947 TI - Merits and capabilities of helicopter emergency medical service (HEMS) in traumatized patients. AB - Since the introduction of helicopter emergency medical service (HEMS) into the civilian rescue system, there is an ongoing discussion on its potential benefits in terms of time- and cost-effectiveness as well as clinical outcome improvement. Currently, the use of HEMS seems to provide a survival benefit in traumatized patients due to several aspects compared to ground emergency medical service (GEMS). First of all, HEMS facilitate rapid transport from the scene to hospital based on increased transportation velocity. Furthermore, HEMS medical crew members are experienced in trauma management resulting in improved on-scene management and patients' triaging. However, these aspects should be considered carefully as specific circumstances referring to rescue teams, on-scene management as well as preclinical durations, triaging of trauma patients and subsequent treatment at different hospitals have to be attended. In the present review current aspects of HEMS compared to GEMS are discussed. PMID- 23079948 TI - Telehealth and ergonomics: a pilot study. AB - OBJECTIVES: As an emerging model of health care delivery, telehealth has the potential to provide individuals living in remote regions with access to health care services that are otherwise not available. This paper provides a review of the feasibility, comparative effectiveness, cost effectiveness, client and clinician satisfaction, and the barriers to providing telehealth services. A proof-of-concept study that examined the feasibility of telehealth-based ergonomic assessment and intervention is included in this paper to demonstrate the application of telehealth in occupational therapy and ergonomics. METHODS: Ten computer users received a telehealth ergonomic assessment and intervention for their computer workstations via the Telerehabilitation Computer Ergonomics System (tele-CES) - a platform for computer users to access web-based assessments and to communicate with researchers via tele-conferencing. The tele-CES was used to assess participants' computer workstations and pain and comfort levels at baseline and at 4-month follow-up. Ergonomic recommendations were also provided via the tele-CES. RESULTS: Although there was no significant improvement in pain and comfort for participants, a high rate of compliance with ergonomic recommendations - 88% of all recommendations - was observed. CONCLUSION: Further research examining the comparative effectiveness of telehealth ergonomic assessment and intervention relative to in-person ergonomic assessment and intervention is warranted. PMID- 23079949 TI - Mobile economics and pricing of health care services. AB - This paper presents tools and concepts to analyze the business environment of the biopharmaceutical industry. It was presented at MEDETEL 2010. Emerging paradigms appear in that industry and new ways to value life science technologies are developed especially using mobile economics analysis. At a time, mobile computing technologies revolutionize the field of health care, this paper contributes to show how the value chain concept can be useful to analyze the value system in a mobile computing environment. It is also a milestone for the designs of future technology platforms and of health care infrastructure, in order to retain enough value between innovators, new and traditionnal players from life science, IT and other new comers, in a fragmented global competitive environment. PMID- 23079950 TI - New type of price measurement for medical services: interest of a cost sensitivity index for a research agenda on pharmaceutical models. AB - This paper aims to propose a new methodological agenda for new price measurement for medical services; it is based on a cost sensitivity index coming from series of pilot studies on physicians, in order to provide adjustment methods to household surveys for health care expenditure budgets. The use of stated-revealed preference models with inclusion of stated preference studies is proposed with an example on a physician cost sensitivity study in Europe; it could also help the ISPOR task for force best practices in conjoint study designs. PMID- 23079952 TI - An automated method for measurement of methoxetamine in human plasma by use of turbulent flow on-line extraction coupled with liquid chromatography and mass spectrometric detection. AB - Methoxetamine is a new ketamine derivative designer drug which has recently become available via the Internet marketed as "legal ketamine". It is a new dissociative recreational drug, acting as an NMDA receptor antagonist and dopamine reuptake inhibitor. The objective of this study was to develop on-line automated sample preparation using a TurboFlow device coupled with liquid chromatography with ion-trap mass spectrometric detection for measurement of methoxetamine in human plasma. Samples (100 MUL) were vortex mixed with internal standard solution (ketamine-d4 in acetonitrile). After centrifugation, 20 MUL of the supernatant was injected on to a 50 mm * 0.5-mm C18XL Turboflow column. The retained analytes were then back-flushed on to a 50 mm * 3-mm (3 MUm) Hypersil Gold analytical column for chromatographic separation, then eluted with a formate buffer-acetonitrile gradient. Methoxetamine and the IS were ionized by electrospray in positive mode. Parent [M + H](+) ions were m/z 248.1 for methoxetamine and m/z 242.0 for the IS. The most intense product ions from methoxetamine (m/z 203.0) and the IS (m/z 224.0) were used for quantification. The assay was accurate (96.8-108.8% range) and precise (intra and inter-day coefficients of variation <8.8%) over the range of 2.0 (lower limit of quantification) to 1000.0 ng mL(-1) (upper limit of quantification). No matrix effect was observed. This method has been successfully applied to determination of plasma concentrations of methoxetamine in the first French hospitalization case report after acute intoxication; the plasma concentration was 136 ng mL(-1). PMID- 23079951 TI - Opportunities in multidimensional trace metal imaging: taking copper-associated disease research to the next level. AB - Copper plays an important role in numerous biological processes across all living systems predominantly because of its versatile redox behavior. Cellular copper homeostasis is tightly regulated and disturbances lead to severe disorders such as Wilson disease and Menkes disease. Age-related changes of copper metabolism have been implicated in other neurodegenerative disorders such as Alzheimer disease. The role of copper in these diseases has been a topic of mostly bioinorganic research efforts for more than a decade, metal-protein interactions have been characterized, and cellular copper pathways have been described. Despite these efforts, crucial aspects of how copper is associated with Alzheimer disease, for example, are still only poorly understood. To take metal-related disease research to the next level, emerging multidimensional imaging techniques are now revealing the copper metallome as the basis to better understand disease mechanisms. This review describes how recent advances in X-ray fluorescence microscopy and fluorescent copper probes have started to contribute to this field, specifically in Wilson disease and Alzheimer disease. It furthermore provides an overview of current developments and future applications in X-ray microscopic methods. PMID- 23079953 TI - Determination of t,t-muconic acid in urine samples using a molecular imprinted polymer combined with simultaneous ethyl chloroformate derivatization and pre concentration by dispersive liquid-liquid microextraction. AB - The present communication describes the preparation and evaluation of a molecularly imprinted polymer (MIP) as a solid-phase extraction (SPE) sorbent and simultaneous ethyl chloroformate (ECF) derivatization and pre-concentration by dispersive liquid-liquid microextraction (DLLME) for the analysis of t,t-muconic acid (t,t-MA) in urine samples using gas chromatography-mass spectrometry. The imprinting polymer was prepared using methacrylic acid as a functional monomer, ethylene glycol dimethacrylate as a cross-linker, 2,2-azobisisobutyronitrile as the initiator and t,t-MA as a template molecule. The imprinted polymer was evaluated for its use as a SPE sorbent by comparing both imprinted and non imprinted polymers in terms of the recovery of t,t-MA from urine samples. Molecular modelling studies were performed in order to estimate the binding energy and efficiency of the MIP complex formed between the monomer and the t,t MA. Various factors that can affect the extraction efficiency of MIP, such as the loading, washing and eluting conditions, were optimized; other factors that can affect the derivatization and DLLME pre-concentration were also optimized. MIP in combination with ECF derivatization and DLLME pre-concentration for t,t-MA exhibits good linearity, ranging from 0.125 to 2 MUg mL(-1) (R(2) = 0.9971), with limit of detection of 0.037 MUg mL(-1) and limit of quantification of 0.109 MUg mL(-1). Intra- and inter-day precision was found to be <6%. The proposed method has been proven to be effective and sensitive for the selective pre-concentration and determination of t,t-MA in urine samples of cigarette smokers. PMID- 23079954 TI - Mass spectrometric profiling of Bacillus cereus strains and quantitation of the emetic toxin cereulide by means of stable isotope dilution analysis and HEp-2 bioassay. AB - A fast and robust high-throughput ultra-performance liquid chromatography/time-of flight mass spectrometry (UPLC-TOF MS) profiling method was developed and successfully applied to discriminate a total of 78 Bacillus cereus strains into no/low, medium and high producers of the emetic toxin cereulide. The data obtained by UPLC-TOF MS profiling were confirmed by absolute quantitation of cereulide in selected samples by means of high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) and stable isotope dilution assay (SIDA). Interestingly, the B. cereus strains isolated from four vomit samples and five faeces samples from patients showing symptoms of intoxication were among the group of medium or high producers. Comparison of HEp-2 bioassay data with those determined by means of mass spectrometry showed differences, most likely because the HEp-2 bioassay is based on the toxic action of cereulide towards mitochondria of eukaryotic cells rather than on a direct measurement of the toxin. In conclusion, the UPLC-electrospray ionization (ESI)-TOF MS and the HPLC-ESI-MS/MS SIDA analyses seem to be promising tools for the robust high-throughput analysis of cereulide in B. cereus cultures, foods and other biological samples. PMID- 23079955 TI - Invited comment on Kanakala et al.: Comparative study of safety and outcomes of single-port access versus conventional laparoscopic colorectal surgery. PMID- 23079956 TI - External haemorrhoidal thrombosis: evidence for current management. AB - BACKGROUND: External haemorrhoidal thrombosis (EHT) may be managed surgically or conservatively. The optimal treatment is, however, unclear, as is the long-term outcome following treatment. METHODS: A literature search was undertaken to review and grade the evidence available for EHT management, determine the optimal management modality and assess long-term outcome after each treatment. RESULTS: Among 800 articles on haemorrhoids, only two prospective studies encompassing 248 patients and two retrospective studies of 571 patients were found. Excision significantly relieves presenting symptoms by postoperative day 4 compared with incision or topical GTN (Level IB evidence). Symptoms last over 3 weeks with conservative treatment (Level III evidence) and this period may be reduced by combining topical nifedipine and lignocaine rather than using lignocaine alone (Level IB evidence). There is no evidence regarding the optimal time for non surgical options. CONCLUSIONS: There is a remarkable paucity of studies on EHT and few of those available provide high levels of evidence. Surgery may be superior to conservative treatment but there is no evidence regarding the optimal period of initiation of conservative management. Prospective comparative studies are needed. PMID- 23079957 TI - Effect of selective serotonin reuptake inhibitors in Alzheimer's disease with comorbid depression: a meta-analysis of depression and cognitive outcomes. AB - BACKGROUND: Comorbid depression is a leading neuropsychiatric complication in the Alzheimer's disease (AD) syndrome. In 2011, diagnostic criteria for AD were revised to include neuropsychiatric symptoms. It has been proposed that adding an antidepressant to existing treatment for AD could provide relief for not only depressive but also cognitive symptoms. OBJECTIVE: The aim was to quantitatively review published studies to examine the efficacy of selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) therapy for alleviation of comorbid, diagnosed depression as well as cognitive decline in AD. METHODS: A search of electronic databases was performed. Studies were retained for analysis if SSRI/SNRI antidepressant therapy was compared with placebo among AD patients with comorbid depression. Effect-size (ES) estimates (Hedges' g) were calculated using Comprehensive Meta-Analysis software. RESULTS: From 598 examined studies, 12 SSRI studies met the inclusion criteria, and from these, only six met all criteria, among which five reported sufficient and consistent data to be included in the meta-analysis. Within a random effect model, ES estimates of the first and second nested global analyses were non-significant, non-heterogeneous and small to null at the endpoint for depression, favouring SSRIs, -0.06 and -0.10, respectively (p > 0.05). The ES for global cognition as measured by the Mini-Mental State Examination was negligible (ES = 0.001). CONCLUSIONS: Current evidence does not support the efficacy of SSRI treatment for symptoms of comorbid depression in AD. However, studies differed in terms of criteria for diagnosis of depression, the compound tested and outcome measures for depression. These factors could account for the lack of a clear benefit for depression. PMID- 23079958 TI - Tunable high-channel-count bandpass plasmonic filters based on an analogue of electromagnetically induced transparency. AB - We have proposed a novel type of bandpass plasmonic filter consisting of metal insulator-metal bus waveguides coupled with a series of side-coupled cavities and stub waveguides. The theoretical modeling demonstrates that our waveguide resonator system performs a plasmonic analogue of electromagnetically induced transparency (EIT) in atomic systems, as is confirmed by numerical experiments. The plasmonic EIT-like response enables the realization of nanoscale bandpass filters with multiple channels. Additionally, the operating wavelengths and bandwidths of our filters can be efficiently tuned by adjusting the geometric parameters such as the lengths of stub waveguides and the coupling distances between the cavities and stub waveguides. The ultracompact configurations contribute to the achievement of wavelength division multiplexing systems for optical computing and communications in highly integrated optical circuits. PMID- 23079959 TI - Phylogeny of bacteria isolated from Rhabditis sp. (Nematoda) and identification of novel entomopathogenic Serratia marcescens strains. AB - Twenty-five bacterial strains isolated from entomopathogenic nematodes were characterized to the genus level by 16S rRNA phylogeny and BLAST analyses. Bacteria strains isolated could be affiliated with seven genera. Microbacterium like isolates phylogenetically affiliated with M. oxydans while those of Serratia were highly similar to S. marcescens. 16S rRNA sequences of Bacillus isolates matched those of both B. mycoides and B. weihenstephanesis. One isolate each matched Pseudomonas mosselii, Rheinheimera aquimaris, Achromobacter marplatensis, or Staphylococcus hominis. Serratia isolates were examined further for their pathogenicity to Galleria mellonella larvae. All the Serratia isolates exhibited potent pathogenicity toward G. mellonella larvae and possessed a metalloprotease gene encoding for a novel serralysin-like protein. The nucleotide sequence of the metalloprotease gene had 60 synonymous and 8 nonsynonymous substitutions when compared to the closest genBank entry, S. marcescens E-15, with an insertion of a new aspartic acid residue. Tajima's test for equality of evolutionary rate was significant between the metalloprotease gene sequence of S. marcescens strain DOAB 216-82 (this study) and strain E-15. This new insecticidal metalloprotease gene and/or its product could have applications in agricultural biotechnology. PMID- 23079960 TI - Osteopontin promoter polymorphisms at locus -443 significantly affect the metastasis and prognosis of human hepatocellular carcinoma. AB - Osteopontin (OPN) plays a crucial role in hepatocellular carcinoma (HCC) metastasis. However, little is known about the impact of OPN polymorphisms on cancer progression. In this study, we first identified the single nucleotide polymorphisms (SNPs) in the OPN promoter region by direct sequencing in 30 HCCs, and then evaluated the prognostic values of the selected ones in two large cohorts of 826 HCC patients. The identified SNPs were functionally analyzed using in vitro and in vivo assays and their correlations with OPN levels were also evaluated. Only SNP at locus -443 and their related haplotypes (Ht2: -1748A/ 616G/-443T/-155* [*indicates base deletion]; Ht3: -1748A/-616G/-443C/-155*) were significantly associated with overall survival (OS) and time to recurrence (TTR). The patients with the -443TT/TC genotype or Ht2 had a shorter OS and TTR compared with those with -443CC genotype or Ht3. This was further confirmed in the validation cohort. Moreover, this correlation remained significant in patients with small HCCs (<=5 cm). Multivariate analyses indicated that the prognostic performance of the -443 genotypes (OS, P=0.031; TTR, P=0.005) and their related haplotypes (OS, P=0.002; TTR, P=0.001) was independent of other clinicopathological factors. The Ht2 and -443TT genotype could significantly increase the promoter transcriptional activity and expression level of OPN compared with the Ht3 or -443CC genotype, and lead to an obvious increase in both in vitro invasion and in vivo tumor growth and lung metastasis of HCC cells (P<0.05). CONCLUSION: The genetic variation at locus -443 of the OPN promoter plays important roles in the regulation of OPN expression and cancer progression of HCCs, which is a novel determinant and target for HCC metastasis and prognosis. PMID- 23079961 TI - Bone marrow remission status predicts leukemia contamination in ovarian biopsies collected for fertility preservation. PMID- 23079963 TI - Current controversies in prenatal diagnosis 1: screening for fragile X syndrome. PMID- 23079962 TI - Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1. AB - Donor T cells directed at hematopoietic system-specific minor histocompatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the clinical evaluation of the concept of mHag-based immunotherapy and subsequent broad implementation, the identification of more hematopoietic mHags with broad applicability is imperative. Here we describe novel mHag UTA2-1 with ideal characteristics for this purpose. We identified this antigen using genome-wide zygosity-genotype correlation analysis of a mHag-specific CD8(+) cytotoxic T lymphocyte (CTL) clone derived from a multiple myeloma patient who achieved a long-lasting complete remission after donor lymphocyte infusion from an human leukocyte antigen (HLA) matched sibling. UTA2-1 is a polymorphic peptide presented by the common HLA molecule HLA-A*02:01, which is encoded by the bi-allelic hematopoietic-specific gene C12orf35. Tetramer analyses demonstrated an expansion of UTA2-1-directed T cells in patient blood samples after several donor T-cell infusions that mediated clinical GvT responses. More importantly, UTA2-1-specific CTL effectively lysed mHag(+) hematopoietic cells, including patient myeloma cells, without affecting non-hematopoietic cells. Thus, with the capacity to induce relevant immunotherapeutic CTLs, it's HLA-A*02 restriction and equally balanced phenotype frequency, UTA2-1 is a highly valuable mHag to facilitate clinical application of mHag-based immunotherapy. PMID- 23079964 TI - December 3--International Day of Persons with Disabilities: an opportunity to advocate for equal opportunities. PMID- 23079965 TI - Retrospective analysis of live birth prevalence of children with Down syndrome in Denizli, Turkey. AB - Down syndrome (DS) is the most frequent chromosome abnormality among live births. Its prevalence increases with maternal age, and can be diagnosed by antenatal screening. We examined prevalence variations of DS in Denizli, Turkey, through a retrospective study. Sixteen years of survey data were retrieved from the two main state hospital registries from records between 1994 and 2010. We identified 113 DS live births in Denizli for 16 years. The prevalence of DS was 9.07 per 10,000 live births before the year 2000 and 9.90 after 2000. The prevalence did not change significantly. The population in Turkey is still young; the fertility rate is high in women under 35 years old and prenatal screening programs are extensively applied; for these reasons, the prevalence of DS has remained stable during these 16 years. PMID- 23079966 TI - Complete sequence of the mitochondrial genome of the Japanese buff-tip moth, Phalera flavescens (Lepidoptera: Notodontidae). AB - We sequenced the complete mitochondrial genome of Phalera flavescens. The mitogenome is 15,659 bp in length, including 13 protein-coding genes (atp6, atp8, cox1-3, nad1-6, nad4L, cob), two ribosomal RNAs (rrnS and rrnL), 22 transfer RNAs and an AT-rich region, a putative control region (D-loop). Gene order and orientation were found to be identical to those of other completely sequenced lepidopteran mitogenomes. All 13 protein-coding genes start with the common codon ATN, except for the cox1 gene, which uses CGA as the initial codon. Nine of the 13 protein-coding genes stop with codon TAA, while the cox1, cox2, nad5, and nad4 genes stop with the single nucleotide T. All tRNA genes can be folded into canonical cloverleaf secondary structure, except for trnS1, which loses the ''DHU'' arm. Six overlapping sequences totaling 20 bp (1-8 bp for each sequence) and 16 intergenic spacer sequences, totaling 276 bp (1-58 bp for each sequence) are scattered throughout the genome; the largest intergenic spacer is located between the trnQ and nad2 genes. A microsatellite-like structure (AT)(6)ACC(AT)(6) and 16-bp poly-T elements preceded by the ATTTA motif are present in the D-loop region. Additionally, unexpectedly, an extra 190-bp insertion, with unknown function, was found in the small subunit rRNA gene (rrnS); this gene is the longest known (1020 bp) among all of the Lepidoptera. PMID- 23079967 TI - The pollen wall and tapetum are altered in the cytoplasmic male sterile line RC7 of Chinese cabbage (Brassica campestris ssp pekinensis). AB - Cytoplasmic male sterile line RC(7) of Chinese cabbage produces mature anthers without pollen. To understand the mechanisms involved, we examined the ultrastructural changes during development of the microspores. Development of microspores was not affected at the early tetrad stage. During the ring vacuolated period, some large vacuoles appeared in the tapetum cells, making them larger, extending to the anther sac center during the monocyte period. At the same time, the tapetum degenerated as the microspores aborted, resulting in pollen-deficient anthers. As a result, the locules collapsed and the anthers shriveled. The callose was degraded in the pollen walls; abnormal deposits of electrodense material gave rise to irregular spike-shaped structures, rather than the characteristic rod-like shape of the B7 bacula. The internal intine wall of RC(7) was thinner than that of the B7 type. At the mitosis I microspore stage, the tapetum cells contained multiple plastids, with numerous small spherical plastoglobuli, and lipid bodies. Based on these observations, we suggest that RC(7) abortion may be due to mutated genes that normally regulate development of the pollen wall and cell walls in the RC(7) line. PMID- 23079968 TI - Updates and perspectives on the utilization of molecular makers of complex traits in rice. AB - After complete sequencing of its genome and annotation of the majority of its ~32,000 genes, rice genome has become the model genome among the cereal genomes, and the focus has shifted from structural to functional genomics and application of genomic-derived information in rice breeding. During the past 2 decades, intensive worldwide efforts have led to significant improvements in rice. An abundance of molecular markers and information related to many genes/quantitative trait loci that control agronomically important traits such as yield, quality, and biotic and abiotic stress tolerance have been identified. Bridging the application gap between quantitative trait locus identification and marker-assisted selection breeding is an urgent, arduous, and long-term task. Marker development, allele mining, gene discovery, and molecular breeding have progressed to a great extent because of the rapid development of next-generation sequencing, large-scale high-density genotyping, and genome-wide selection strategies. The availability of high-density markers and the rapidly decreasing cost of genotyping have facilitated marker-assisted selection of many traits that were previously not possible. PMID- 23079969 TI - Exogenous abscisic acid increases antioxidant enzymes and related gene expression in pepper (Capsicum annuum) leaves subjected to chilling stress. AB - To elucidate how physiological and biochemical mechanisms of chilling stress are regulated by abscisic acid (ABA) pretreatment, pepper variety (cv. 'P70') seedlings were pretreated with 0.57 mM ABA for 72 h and then subjected to chilling stress at 10 degrees /6 degrees C (day/night). Chilling stress caused severe necrotic lesions on the leaves and increased malondialdehyde and H(2)O(2) levels. Activities of monodehydroascorbate reductase (DHAR), dehydroascorbate reductase, glutathione reductase, guaiacol peroxidase, ascorbate peroxidase, ascorbate, and glutathione increased due to chilling stress during the 72 h, while superoxide dismutase and catalase activities decreased during 24 h, suggesting that chilling stress activates the AsA-GSH cycle under catalase deactivation in pepper leaves. ABA pretreatment induced significant increases in the above-mentioned enzyme activities and progressive decreases in ascorbate and glutathione levels. On the other hand, ABA-pretreated seedlings under chilling stress increased superoxide dismutase and guaiacol peroxidase activities and lowered concentrations of other antioxidants compared with untreated chilling stressed plants. These seedlings showed concomitant decreases in foliage damage symptoms, and levels of malondialdehyde and H(2)O(2). Induction of Mn-SOD and POD was observed in chilling-stressed plants treated with ABA. The expression of DHAR1 and DHAR2 was altered by chilling stress, but it was higher in the presence than in the absence of ABA at 24 h. Overall, the results indicate that exogenous application of ABA increases tolerance of plants to chilling-induced oxidative damage, mainly by enhancing superoxide dismutase and guaiacol peroxidase activities and related gene expression. PMID- 23079970 TI - Cloning and expression of ethylene receptor ERS1 at various developmental and ripening stages of mango fruit. AB - Ethylene induces characteristic ripening reactions in climacteric fruits through its binding to histidine-kinase (HK) receptors, activating the expression of ripening genes. Ethylene receptors have been found in Arabidopsis thaliana (Brassicaceae) and some fruits; number and expression patterns differ among species. In mango, only ethylene receptor ETR1 was known. We cloned ERS1 cDNA from mango, and evaluated the expression of Mi-ERS1 and Mi-ETR1 by qPCR in developmental and ripening stages of this fruit. The Mi-ERS1 coding sequence is 1890 bp long and encodes 629 amino acids, similar to ERS1 from other fruits. Also, the amino acid sequence of ERS1 C-terminal HK domain shows the cognate fold after molecular modeling. Mi-ERS1 expression levels increased as mangoes ripened, showing the highest levels at the climacteric stage, while Mi-ETR1 levels did not change during development and ripening. We conclude that the patterns of expression of Mi-ERS1 and Mi-ETR1 differ in mango fruit. PMID- 23079971 TI - Chromosome number, microsporogenesis, microgametogenesis, and pollen viability in the Brazilian native grass Mesosetum chaseae (Poaceae). AB - The genus Mesosetum is a primarily South American genus with 42 species. Mesosetum chaseae, regionally known as 'grama-do-cerrado', is abundant in the Pantanal Matogrossense (Brazil); it is a valuable resource for livestock and for environmental conservation. We collected specimens from the Nhecolandia sub region of the Brazilian Pantanal, located in Corumba, Mato Grosso do Sul, Brazil. We examined chromosome number, ploidy level, meiotic behavior, microgametogenesis, and pollen viability of 10 accessions. All the accessions were diploid, derived from x = 8, presenting 2n = 2x = 16 chromosomes. Chromosomes paired as bivalents showing, predominantly, two terminal chiasmata. Interstitial chiasmata were rare. Meiosis was quite normal producing only a few abnormal tetrads in some accessions. Microgametogenesis, after two mitotic divisions, produced three-celled pollen grains. Pollen viability was variable among plant and accessions and was not correlated with meiotic abnormalities. PMID- 23079972 TI - Genetic association of UBE2B variants with susceptibility to male infertility in a Northeast Chinese population. AB - The ubiquitin-conjugating enzyme 2B gene (UBE2B) is involved in the regular and symmetric organization of the fibrous sheath of sperm flagella. This study aimed to examine the relationship between single nucleotide polymorphisms (SNPs) in UBE2B and infertility in Northeast Chinese men. We carried out a polymerase chain reaction-restriction fragment length polymorphism analysis for SNPs in 312 fertile males and 388 infertile males in Northeast China. Taking advantage of the high degree of linkage disequilibrium among SNPs surrounding UBE2B (r(2) > 0.90), we selected 2 haplotype-tagging SNPs with a minor allele frequency of 5% or greater (rs17167484: g.-293T>G and rs3777373: g.20016A>G) that captured the majority of the genetic variations in a 40-kbp region of this gene. No significant differences between cases and controls were found in the allelic and genotype distribution of the 2 SNPs. However, the haplotype analysis for the 2 SNPs showed that the GA haplotype was significantly associated with a greater than 3-fold decreased risk of male infertility (P = 0.003). Because the frequency of the GA haplotype (1.1%) is relatively low in Chinese men, such a significant finding may occur by chance, but the results are still significant after multiple comparison adjustments (P = 0.012 after Bonferroni's correction). We conclude that the UBE2B polymorphisms g.-293T>G, g.20016A>G and g.9157A>G are not associated with male infertility, and the GA haplotype is likely a protective factor for male fertility in Northeast Chinese men. PMID- 23079973 TI - NPRL2 gene expression in the progression of colon tumors. AB - Genetic and epigenetic factors affecting DNA methylation and gene expression are known to be involved in the development of colon cancer, but the full range of genetic alterations and many key genes involved in the pathogenesis of colon cancer remain to be identified. NPRL2 is a candidate tumor suppressor gene identified in the human chromosome 3p21.3 region. We evaluated the role of this gene in the pathogenesis of colorectal cancer by investigating NPRL2 mRNA expression in 55 matched normal and tumor colon tissue samples using quantitative RT-PCR analysis. There was significantly decreased NPRL2 expression in 45% of the patients. Lower NPRL2 expression was observed significantly more frequently in poorly differentiated tumor samples than in highly or moderately differentiated tumors. We conclude that expression of NPRL2 contributes to progression of colon cancer. PMID- 23079974 TI - A protocol for high-quality genomic DNA extraction from legumes. AB - Current DNA extraction protocols, which require liquid nitrogen, lyophilization and considerable infrastructure in terms of instrumentation, often impede the application of biotechnological tools in less researched crops in laboratories in developing countries. We modified and optimized the existing CTAB method for plant genomic DNA extraction by avoiding liquid nitrogen usage and lyophilization. DNA was extracted directly from freshly harvested leaves ground in pre-heated CTAB buffer. Chloroform:isoamyl alcohol (24:1) and RNase treatments followed by single-purification step decontaminated the samples thereby paving way for selective extraction of DNA. High molecular weight DNA yield in the range of 328 to 4776 ng/MUL with an average of 1459 ng/MUL was obtained from 45 samples of cultivated and wild Cajanus species. With an absorbance ratio at 260 to 280 nm, a range of 1.66 to 2.20, and a mean of 1.85, very low levels of protein and polysaccharide contamination were recorded. Forty samples can be extracted daily at a cost between 1.8 and US$2.0 per plant sample. This modified method is suitable for most plants especially members of the Leguminosae. Apart from Cajanus, it has been extensively applied in DNA extraction from Cicer and Vigna species. PMID- 23079975 TI - Association of MHC class-III gene polymorphisms with ER-positive breast cancer in Chinese Han population. AB - Polymorphisms of the major histocompatibility complex (MHC) have been linked to many diseases, especially autoimmune disorders. Previous studies have shown that genetic variants in MHC class III are associated with breast cancer. To determine if there is an association between MHC class III and breast cancer risk in the Chinese Han population, we carried out a hospital-based case-control study in Guangdong and Jiangsu Provinces, including 216 histologically confirmed breast cancer patients and 216 healthy controls. Nine SNP markers distributed in the class III-coding region were detected using the Sequenom MassARRAY((r)) iPLEX System. Deviation from Hardy-Weinberg equilibrium was observed for seven SNPs. There was no significant association between these seven SNP variants and breast cancer in these Chinese women (unconditional logistic regression analysis). However, chr6_31697494 at BAT2, one of the seven SNPs, was found to be significantly associated with both ER- and PR-positive breast cancer. In addition, both chr6_31911109 at C6orf48 and chr6_31975605 at ZBTB12, another two of the seven SNPs, show relevance with ER-positive breast cancer. In conclusion, this is the first evidence that genetic polymorphisms in the MHC class III region are significantly associated with ER-positive breast cancer in the Han Chinese population. PMID- 23079976 TI - Conjugated linoleic acid-induced milk fat reduction associated with depressed expression of lipogenic genes in lactating Holstein mammary glands. AB - The efficacy of conjugated linoleic acid (CLA) in diet supplements for milk fat reduction is well documented in several species. However, the mechanisms by which fatty acids regulate mammary lipogenesis remain largely unknown, especially with regard to gene expression of enzyme and regulators. In this study, 8 Holstein dairy cows in their mid-lactation period were randomly divided into 2 groups. Control cows received a Ca salt of palm oil fatty acid dietary supplement, and those in the CLA group were fed Ca salts of CLA (Ca-CLA), all in a dose of approximately 200 g?cow(-1)?day(-1) for 14 days. The milk yield was recorded daily, and protein, lactose, and fat in the milk were quantified every 3 days for 2 weeks. Fatty acids in the milk were analyzed with gas-liquid chromatography. Measurement of messenger RNA levels of the main lipogenic genes of lipoprotein lipase, acetyl-coenzyme A (CoA) carboxylase, fatty acid synthase, stearoyl-CoA desaturase, and transcription factors such as sterol response element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor gamma was performed in biopsy samples of mammary tissue on the last day. The results indicated that dietary Ca-CLA caused a continuous reduction of milk fat (P < 0.01) with no effect on milk yield, milk protein, and lactose. The fatty acid profile in the milk from the CLA group differed from that from controls, and the yield of milk fatty acid decreased (P < 0.01) with Ca-CLA supplementation. The depressed expression of lipogenic genes (lipoprotein lipase, acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase) demonstrated inhibition of fatty acid de novo synthesis and uptake in the mammary gland of the CLA group. Furthermore, the gene expression of transcription factor SREBP1 was also downregulated (P < 0.01), but peroxisome proliferator-activated receptor gamma was unchanged, suggesting that SREBP1 may play a key role in the regulation of lipogenic gene expression in the lactating mammary gland. PMID- 23079977 TI - Development and characterization of DNA microsatellite primers for buriti (Mauritia flexuosa L.f.). AB - Mauritia flexuosa L. (Arecaceae) is a palm tree species known as buriti that occurs in the Cerrado biome. It is characteristic of the vereda, a typical ecosystem of central Brazil. In this phytophysiognomy, M. flexuosa and other groups of arboreal-herbaceous species develop in open fields with very humid soils. M. flexuosa can be found in forest borders and is a palm tree with a wide distribution in South America (Brazil, Colombia, Venezuela, French Guyana Ecuador, Peru, and Bolivia). The main objectives of this study were to develop simple sequence repeat marker-enriched libraries and to characterize these loci in buriti palm to facilitate future population studies. A total of 40 sequences derived from the microsatellite-enriched libraries were selected for primer design. The optimization results showed that 9 primer pairs could successfully amplify polymorphic target fragments of the expected sizes. The data also show that the described primers can be used in population genetic studies in M. flexuosa to obtain information that will inform conservation and management strategies. PMID- 23079978 TI - Candidate genes for production traits in Nelore beef cattle. AB - Meat quality is an important trait for the beef industry. Backfat thickness, ribeye area, and shear force are traits measured late in life, and the investigation of molecular markers associated with these traits can help breeding programs. In cattle, some polymorphisms have been related to production traits. Thus, the purpose of this study was to assess the presence of polymorphisms in the candidate genes insulin-like growth factor 1 (IGF1), fatty acid-binding protein 4 (FABP4), and peroxisome proliferative active receptor gamma coactivator 1 A (PPARGC1A) and associate them with production traits in reference families of Nelore cattle. We used 270 steers descendent from 20 sires that were chosen to represent variability in this breed. The investigation of marker effects on the traits was performed using a mixed model under the restricted maximum likelihood method. A significant allele substitution effect was found for IGF1 and yearling weight (P <= 0.017). The mean allele substitution effect was 6.9 kg, with the 229 allele associated with reduced yearling weight in this Nelore population. PMID- 23079979 TI - Effect of the IGF-1/PTEN/Akt/FoxO signaling pathway in the duodenal mucosa of rats subjected to water immersion and restraint stress. AB - The insulin growth factor 1/phosphatase and tensin homologue deleted on chromosome 10/Akt/forkhead box (IGF-1/PTEN/Akt/FoxO) signaling pathway reportedly exhibits gastroprotective effects by reducing water immersion and restraint stress (WRS)-induced gastric mucosal cell apoptosis. We examined the expression and localization of IGF-1, PTEN, Akt, and FoxO proteins, caspase-3 activity, and the number of apoptotic cells in the duodenal mucosa of rats subjected to WRS to confirm whether the IGF-1/PTEN/Akt/FoxO signaling pathway has a role in the duodenal mucosa. The results indicated that WRS enhanced cell apoptosis in the duodenal mucosa. In addition, in normal rats, PTEN was found mainly in the cellular cytoplasm of the duodenal glands and lamina propria of villi. IGF-1 and total Akt were observed in the cellular cytoplasm of the duodenal glands. In addition, total Akt was found in the cellular cytoplasm of the myenteric plexus. FoxO3a and FoxO4 were primarily concentrated in the cellular cytoplasm of the lamina propria. Specifically, PTEN, FoxO3a and FoxO4 were also localized in the cellular cytoplasm of lamina propria of restituted villi in the duodenal mucosa of rat subjected to WRS. In addition, messenger RNA transcript levels of IGF-1, PTEN, Akt1, Akt2, FoxO3, and FoxO4 were upregulated in the duodenal mucosa, with a peak between the 4th and 8th day after 7 h of WRS. Furthermore, the results also suggested that Akt3 messenger RNA transcript levels in the duodenal mucosa of rats after WRS showed no significant differences compared with those in the non-WRS group. Collectively, our results implied that the IGF-1/ PTEN/Akt/FoxO signaling pathway was effective in regulating cellular apoptosis in the duodenal mucosa of rats after WRS. PMID- 23079981 TI - Isolation and characterization of microsatellite loci from an endangered tree species, Toona ciliata var. pubescens. AB - Toona ciliata var. pubescens is considered an endangered tree species native to China. In order to help develop a conservation program for this species, we evaluated its genetic diversity and population genetics. We isolated microsatellite DNA loci using streptavidin beads. A genomic library, enriched with microsatellites, was constructed and screened by sequencing. We detected 8 polymorphic microsatellite loci from the tree tissue samples. The population of T. ciliata var. pubescens used in this study is located within the Guanshan National Nature Reserve, Jiangxi Province, China. Sixty-five individuals were collected for the study. The Guanshan population was split into two subpopulations due to terrain. The number of alleles per locus ranged from 2 to 6, with expected heterozygosity from 0.2386 to 0.6772. Four of the 8 loci, except loci Tc02, Tc04, Tc05, and Tc07 showed no significant departure from Hardy Weinberg equilibrium. The mean observed heterozygosity was 0.59. The average coefficient of genetic differentiation between the two subpopulations was quite low (F(ST) = 0.0235). The level of gene flow (N(m)) was 10.39, reflecting a high degree of gene flow between the two subpopulations. PMID- 23079980 TI - Molecular cloning and characterization of two novel NAC genes from Mikania micrantha (Asteraceae). AB - NAC proteins, which are plant-specific transcription factors, have been identified to play important roles in plant response to stresses and in plant development. The full-length cDNAs that encode 2 putative NAC proteins, designated as MmATAF1 and MmNAP, respectively, were cloned from Mikania micrantha by rapid amplification of cDNA ends. The full-length cDNAs of MmATAF1 and MmNAP were 1329 and 1072 bp, respectively, and they encoded deduced proteins of 260- and 278-amino acid residues, respectively. The proteins MmATAF1 and MmNAP had a calculated molecular mass of 29.81 and 32.55 kDa and a theoretical isoelectric point of 7.08 and 9.00, respectively. Nucleotide sequence data indicated that both MmATAF1 and MmNAP contained 2 introns and 3 exons and that they shared a conserved genomic organization. Multiple sequence alignments showed that MmATAF1 showed high sequence identity with ATAF1 of Arabidopsis thaliana (61%) and that MmNAP showed high sequence identity with NAP of A. thaliana (67%) and CitNAC of Citrus sinensis Osbeck (62%). Phylogenetic analysis showed that the predicted MmATAF1 and MmNAP proteins were classified into the ATAF and NAP subgroups, respectively. Transient expression analysis of onion epidermal cells indicated nuclear localization of both MmATAF1-GFP and MmNAP-GFP fusion proteins. Semi quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis indicated that MmATAF1 was expressed in all the tissues tested, but in varying abundance, while MmNAP was specifically expressed in stems, petioles, shoots, and leaves, but not in roots. The transcript levels of MmATAF1 and MmNAP in shoots and in infected stems were induced and strengthened by wounding, exogenous ZnSO(4), abscisic acid, salicylic acid, and Cuscuta campestris infection on the basis of semi-quantitative RT-PCR and real-time PCR analyses, respectively. Collectively, these results indicated that MmATAF1 and MmNAP, besides having roles in M. micrantha adaptation to C. campestris infection and abiotic stresses, also integrated signals derived from both C. campestris infection and abiotic stresses. PMID- 23079982 TI - Implications of the progeny x environment interaction in selection index involving characteristics of the common bean. AB - Breeders normally select simultaneously for several traits in various environments. We investigated the effects of the progeny x environment interaction on success in selection for several traits. The population used was obtained from a cross between the CVIII-85-11 line, which has a semi-erect to prostrate plant architecture and a cream with brown streaks bean type, and the BRS-Supremo cultivar, which has an erect plant architecture and black grains. In experiments conducted in the field, 47 progenies F(4:6) and F(4:7) were evaluated for two seasons for grain yield, plant architecture and grain type score. The variables were standardized and we obtained the sum of Z. The components of genetic variance in the average of the two environments were nil due to the progeny x environment interaction, which would hinder successful simultaneous selection of characters. PMID- 23079983 TI - Carcass and meat quality traits of four commercial pig crossbreeds in China. AB - We evaluated carcass and meat quality traits of two Chinese native crossbreeds Landrace x Meishan (LM) and Duroc x (Landrace x Meishan) (DLM) and two foreign crossbreeds Duroc x (Landrace x Yorkshire) (DLY) and PIC (an imported five-way crossbreed). One hundred and twenty weaned pigs (half castrated males and half females) were reared and slaughtered at a predestinated slaughter age. The general carcass and meat quality traits were measured and analyzed. The DLY and PIC crosses had significantly heavier live weights (93.39 and 96.33 kg, P < 0.01), significantly higher dressing percentages (80.65 and 79.39%, P < 0.05), significantly bigger loin areas (42.69 and 43.91 cm(2), P < 0.001), and significantly more lean carcasses (65.78 and 66.40%, P < 0.001) than LM and DLM. On the other hand, LM had a significantly lower live weight (70.29 kg, P < 0.01), significantly thicker back fat (3.54 cm, P < 0.001), significantly less lean carcasses (46.82%, P < 0.001), and significantly less ham and breech (26.53%, P < 0.05) than the other crossbreeds. Among meat quality parameters, LM had the highest intramuscular fat content (5.02%, P < 0.001) and the smallest fiber area (3126.45 MUm(2), P < 0.01). However, PIC showed the lowest pH(1) (5.82, P < 0.01) and pH(2) (5.63, P < 0.01), the highest drip loss (2.89%, P < 0.01), and the lowest intramuscular fat (1.35%, P < 0.001). We concluded that LM and DLM had good meat quality traits but poorer carcass traits than DLY and PIC; DLY had good carcass and meat quality traits; PIC had good carcass traits, but it had less intramuscular fat, lower pH and higher drip loss. PMID- 23079984 TI - Genetic variation based on microsatellite analysis of the oriental river prawn, Macrobrachium nipponense from Qiandao Lake in China. AB - The oriental river prawn (Macrobrachium nipponense) is an important freshwater prawn species in China. We collected 236 oriental river prawns from four wild stocks from Qiandao Lake, Zhejiang, China, and used nine polymorphic microsatellite markers to investigate their genetic diversity and structure, to facilitate the development of a selective breeding program. We found 185 alleles at nine loci in this sample. The observed heterozygosity (H(O)) and expected heterozygosity (H(E)) ranged from 0.43 to 0.89 and 0.56 to 0.95, respectively. The four stocks of M. nipponense displayed high genetic diversity (14.33-15.89 alleles/locus, H(O) = 0.66-0.77 and H(E) = 0.78-0.88). Genetic diversity of the stock from Weiping town was lower than the stocks from the other locations. Mutation-drift equilibrium analysis showed no significant bottleneck effect. F statistics among stocks ranged from 0.03 to 0.07, indicating a moderate level of differentiation. Based on genetic structure analysis, the 236 individuals from the four wild stocks could be divided into two potential populations. Overall, the 09CA, 09AY and 09JJ wild stocks had higher allelic and genetic diversity than the upstream 09WP stock. These three wild stocks could be used as founders for selective breeding. PMID- 23079985 TI - Effect of forest fragmentation on microsporogenesis and pollen viability in Eugenia uniflora, a tree native to the Atlantic Forest. AB - Habitat fragmentation, caused by the expansion of agriculture in natural areas, may be one of the strongest impacts humans have on the ecosystem. These changes can decrease the number of individuals in a population, leading to endogamy. In allogamous species, endogamy can have a negative effect on reproductive capacity. In this study, we analyzed the effects of forest fragmentation on microsporogenesis and pollen viability in Eugenia uniflora L., a tree species native to the Atlantic Forest. We analyzed 4 populations, 3 of which were connected by forest corridors and 1 of which was isolated by agricultural fields on all sides. For microsporogenesis analysis, 9000 meiocytes representing all stages of meiosis were evaluated. To perform the pollen viability test, we evaluated 152,000 pollen grains. Microsporogenesis was stable in plants from populations that were connected by forest corridors (abnormalities, less than 6%), while microsporogenesis in plants from the isolated population showed a higher level of abnormalities (13-29%). Average pollen viability was found to be more than 93% in the non-isolated populations and 82.62% in the isolated population. The chi(2) test showed that, in the isolated population, the meiotic index was significantly lower than that in the non-isolated populations (P = 0.03). The analysis of variance for the percentage of viable pollen grains confirmed the significant difference between the isolated and non-isolated populations. Our data show that forest fragmentation has a direct effect on microsporogenesis and pollen viability in E. uniflora and can directly influence the reproductive capacity of isolated populations of this species. PMID- 23079986 TI - Expression of IL-1beta, IL-6, TNF-alpha, and iNOS in pregnant women with periodontal disease. AB - Periodontal disease is one of the most prevalent oral diseases. An association between this disease and pregnancy has been suggested, but available findings are controversial. We evaluated the expression levels of interleukins (IL-1beta and IL-6), tumor necrosis factor-alpha (TNF-alpha), and inducible nitric oxide synthase (iNOS) in pregnant women with and without periodontal disease in comparison with non-pregnant women with and without periodontal disease since studies have suggested a relationship between periodontitis and the expression levels of these genes. The women in the sample were distributed into four groups: pregnant and non-pregnant women, with or without periodontal disease, a total of 32 women. The periodontal condition was evaluated according to the probing depth, clinical attachment level and bleeding on probing. Analysis of gene expression was performed by real-time PCR. Comparisons were made of the level of gene expression among the four groups. Expression of IL-1beta in the non-pregnant women with periodontal disease was 12.6 times higher than in the non-pregnant women without periodontal disease (P < 0.01), while expression of TNF-alpha in the non-pregnant women without periodontal disease was 3.5 times higher than in the pregnant women with periodontal disease (P < 0.05). Despite these differences, our overall findings indicate no differences in the expression levels of the cytokines IL-1beta, IL-6, TNF-alpha, and iNOS in pregnant women with and without periodontal disease in comparison with expression of the same genes in non-pregnant women with and without periodontal disease, suggesting that periodontal disease is not influenced by pregnancy. PMID- 23079987 TI - Karyotype characterization of two populations of Vernonia geminata (Asteraceae, Vernonieae) using banding and FISH techniques. AB - In order to extend our knowledge concerning karyotypes of the genus Vernonia, we applied various techniques of chromosome banding, including AgNOR and triple staining with the fluorochromes CMA/DA/DAPI (CDD), and of fluorescent in situ hybridization (FISH) for the 45S rDNA probe to specimens of two populations of Vernonia geminata collected from an open-pasture area, in southern Brazil. B chromosomes were observed in one of the populations. Both populations of V. geminata presented a pair of CMA(3)(+) terminal bands and one pair of chromosomes with terminal AgNOR banding. The FISH evidenced, in one population, two pairs of small sites of 45S rDNA; these being two small terminal sites and two centromeric sites. In the other population, there was only one pair of small terminal sites and two sites in two B chromosomes, one in each chromosome. There was coincidence of localization between CMA(+) and NOR bands with one of the small terminal sites of 45S rDNA of one chromosome of the normal complement, but not in B chromosomes. PMID- 23079988 TI - Damaging effects of water-borne cadmium chloride on DNA of lung cells of immature mice. AB - We investigated the effects of cadmium on lung cell DNA in immature mice. The mice were randomly divided into four groups: control group, low-dose group (1/100 LD(50)), middle-dose group (1/50 LD(50)), and high-dose group (1/25 LD(50)); they were supplied with cadmium chloride or control water for 40 days. Lung cells collected from sacrificed mice were used to evaluate the extent of DNA damage by comet assay. The ratio of tailing cells, DNA tail length, DNA comet length, DNA tail moment, DNA olive tail moment, and percentage of DNA in the comet tail were measured. The rate of tailing lung cells exposed to cadmium increased significantly; the low-concentration group had significantly (P < 0.05) higher rates, and the middle- and high-concentration groups had higher (P < 0.01) rates compared to the control. DNA tail length, DNA comet length, DNA tail moment, and DNA olive tail moment all increased with the increase in cadmium doses, but compared with those of the control group, no significant differences in low-dose group were found (P > 0.05), and the differences in middle- and high-dose groups were all highly significant (P < 0.01). The degree of DNA damage also increased with the increase of the cadmium concentrations. We conclude that cadmium significantly increases DNA damage in lung cells of immature mice in a dose-dependent manner. PMID- 23079989 TI - Distinct linear hydrocarbon profiles and chemical strategy of facultative parasitism among Mischocyttarus wasps. AB - Insects use pheromones as a means of chemical communication. Pheromones act on individual receptors and produce specific behavioral or physiological responses that are fundamental to intra- and interspecific recognition. The objective of this study was to evaluate the interspecific differences among the linear hydrocarbon profiles of the cuticles of 3 wasp species of the genus Mischocyttarus. The chemical strategy that permits an interaction among 2 of these species was also examined about their hydrocarbon profiles. The cuticular hydrocarbons present on the abdomen of each individual were extracted with hexane in an ultrasonic bath and analyzed using gas chromatography with a flame ionization detector. The results suggested that the wasp species have distinct chemical signatures as the linear hydrocarbons of their cuticles. However, these signatures are more alike in those with similar morphological and behavioral aspects. These similarities facilitate an interaction of facultative parasitism observed among these species, in which the invaders acquire parts of the chemical signature of the host colony, possibly as a chemical strategy to increase the likelihood that an invader will be accepted by the females of a host colony. Both invader and host have their own chemical signature changed by the first contact between the species. PMID- 23079990 TI - Molecular cloning and functional characterization of a glutathione S-transferase involved in both anthocyanin and proanthocyanidin accumulation in Camelina sativa (Brassicaceae). AB - Recently, we found that the Arabidopsis TT19 protein, a glutathione S transferase, has two functional domains that influence both anthocyanin and proanthocyanidin accumulation. To further understand the function of this protein in the other species, we cloned a cDNA encoding a glutathione S-transferase (namely CMGSTF12) from Camelina sativa, an oil crop that has received renewed interest due to its biofuel value and high omega-3 levels. Southern blot analysis demonstrated one copy of CMGSTF12 in C. sativa. Transformation of the Arabidopsis loss-of-function tt19-1 mutant with CMGSTF12 cDNA complemented accumulation of anthocyanin in vegetative tissues and resulted in the wild-type level of proanthocyanidin (both extractable and unextractable) in seeds. No obvious flavonoid accumulation changes were detected in the transgenic seeds, indicating that CMGSTF12 may only involve the lower flavonoid pathway, further proving that the TT19 protein controls accumulation of unextractable proanthocyanidin. PMID- 23079991 TI - Phenotype characterization and sequence analysis of BMP2 and BMP4 variants in two Mexican families with oligodontia. AB - Both BMP2 and BMP4 are involved in tooth development. We examined phenotypes and BMP2 and BMP4 gene variations in two Mexican oligodontia families. Physical and oral examinations and panoramic radiographs were performed on affected and unaffected members in these two families. The affected members lacked six or more teeth. DNA sequencing was performed to detect BMP2 and BMP4 gene variations. Three single nucleotide polymorphisms (SNPs) in BMP2 and BMP4 genes were identified in the two families, including one synonymous and two missense SNPs: BMP2 c261A>G, pS87S, BMP2 c570A>T, pR190S, and BMP4 c455T>C, pV152A. Among the six affected patients, 67% carried "GG" or "AG" genotype in BMP2 c261A>G and four were "TT" or "AT" genotype in BMP2 c570A>T (pR190S). Polymorphism of BMP4 c455T>C resulted in amino acid changes of Val/Ala (pV152A). BMP2 c261A>G and BMP4 c455T>C affect mRNA stability. This was the first time that BMP2 and BMP4 SNPs were observed in Mexican oligodontia families. PMID- 23079992 TI - Association of DNMT1 and DNMT3B polymorphisms with breast cancer risk in Han Chinese women from South China. AB - Patterns of DNA methylation are established and maintained by a family of DNA methyltransferases (DNMTs). Aberrant promoter DNA methylation of tumor suppressor genes is found in breast cancer. Association studies between DNMT gene polymorphisms and breast cancer in various populations have reported inconsistent results. This study assessed the associations of single nucleotide polymorphisms (SNPs) in DNMT1, DNMT3A, DNMT3B, DNMT3L, and DNMT2 with breast cancer among Han Chinese women from South China. Sixteen SNPs (rs2114724, rs2228611, rs2228612, rs8101866, and rs16999593 in DNMT1; rs13420827, rs11887120, rs13428812, rs1550117, rs11695471, and rs6733301 in DNMT3A; rs2424908, rs2424913, and rs6087990 in DNMT3B; rs113593938 in DNMT3L, and rs11254413 in DNMT2) in 408 women with breast cancer and 469 controls were genotyped using a MassARRAY matrix assisted laser desorption/ionization time-of-flight mass spectrometry platform. Two SNPs, rs16999593 in DNMT1 and rs2424908 in DNMT3B, were significantly associated with breast cancer risk. The heterozygous genotype CT of rs16999593 was associated with increased breast cancer risk [odds ratio (OR) = 1.60; 95% confidence interval (95%CI) = 1.20-2.14; P = 0.0052], whereas rs2424908 was associated with decreased risk (OR = 0.62; 95%CI = 0.46-0.84; P = 0.0061). Other DNMT polymorphisms showed no significant associations with breast cancer risk in the study population. Haplotype CGTC of rs2114724, rs2228611, rs8101866, and rs16999593 in DNMT1 differed significantly as a risk factor between the case and control groups (OR = 1.51; 95%CI = 1.18-1.93; P = 0.0012). The heterozygous genotypes of rs16999593 in DNMT1 and rs2424908 in DNMT3B were strongly associated with breast cancer risk. PMID- 23079993 TI - Novel and recurrent COL2A1 mutations in Chinese patients with spondyloepiphyseal dysplasia. AB - Spondyloepiphyseal dysplasia (SED) is an autosomal dominant skeletal dysplasia characterized by short stature, abnormal epiphyses and flattened vertebral bodies. SED is mainly caused by mutations in the gene encoding the type II procollagen alpha-1 chain (COL2A1). We looked for mutations in COL2A1 in three unrelated Chinese families with SED. Putative mutations were confirmed by RFLP analysis. We identified three missense mutations (p.G504S, p.G801S and p.G1176V) located in the triple-helical domain; p.G801S and p.G1176V are novel mutations. The p.G504S mutation has been associated with diverse phenotypes in previous studies. Our study extends the mutation spectrum of SED and confirms a relationship between mutations in the COL2A1 gene and clinical findings of SED. PMID- 23079994 TI - Assessing genetic divergence in interspecific hybrids of Aechmea gomosepala and A. recurvata var. recurvata using inflorescence characteristics and sequence related amplified polymorphism markers. AB - Conventional hybridization and selection techniques have aided the development of new ornamental crop cultivars. However, little information is available on the genetic divergence of bromeliad hybrids. In the present study, we investigated the genetic variability in interspecific hybrids of Aechmea gomosepala and A. recurvata var. recurvata using inflorescence characteristics and sequence-related amplified polymorphism (SRAP) markers. The morphological analysis showed that the putative hybrids were intermediate between both parental species with respect to inflorescence characteristics. The 16 SRAP primer combinations yield 265 bands, among which 154 (57.72%) were polymorphic. The genetic similarity was an average of 0.59 and ranged from 0.21 to 0.87, indicating moderate genetic divergence among the hybrids. The unweighted pair group method with arithmetic average (UPGMA)-based cluster analysis distinguished the hybrids from their parents with a genetic distance coefficient of 0.54. The cophenetic correlation was 0.93, indicating a good fit between the dendrogram and the original distance matrix. The two-dimensional plot from the principal coordinate analysis showed that the hybrids were intermediately dispersed between both parents, corresponding to the results of the UPGMA cluster and the morphological analysis. These results suggest that SRAP markers could help to identify breeders, characterize F(1) hybrids of bromeliads at an early stage, and expedite genetic improvement of bromeliad cultivars. PMID- 23079995 TI - DNA polymorphisms of the Hu sheep melanocortin-4 receptor gene associated with birth weight and 45-day weaning weight. AB - The melanocortin-4 receptor (MC4R) has important roles in regulating food intake, energy balance, and body weight in mammals. In pigs and cattle, MC4R mutations have been identified as genetic markers for growth and traits. Compared with abundant research conducted on other livestock species, little is known about mutations of the ovine MC4R gene. We investigated the effect of MC4R polymorphisms on birth weight and on 45-day weaning weight in 144 Hu sheep. Four single nucleotide polymorphisms (SNPs; g.1016 G/A, g.1240 T/C, g.1264 G/A, and g.1325 A/G) were identified in the 3?-untranslated region of Hu sheep MC4R by PCR-single-strand conformation polymorphism and DNA sequencing. A haplotype block, containing g.1240 T/C, g.1264 G/A, and g.1325 A/G, was constructed within the Hu sheep MC4R gene. Four SNPs were found to be significantly associated with 45-day weaning weight, while the haplotype block was significantly associated with birth weight. Hu sheep with the genotypes GG in g.1016 G/A or with the genotype CCAAGG in the haplotype block, had higher 45-day weaning weights. We conclude that these 4 SNPs of the MC4R gene have potential as genetic markers for early growth traits in Hu sheep. PMID- 23079996 TI - Evaluation of genetic diversity and population structure in a commercially important freshwater fish Prochilodus costatus (Characiformes, Prochilodontidae) using complex hypervariable repeats. AB - We used complex hypervariable repeats to evaluate the genetic diversity and structure of Prochilodus costatus (Characiformes), an ecologically and economically important species endemic to the Sao Francisco River basin. Hydroelectric dams along the river have led to population fragmentation, which can limit gene flow. Restocking from hatcheries has been used to repopulate declining populations. To determine how fragmentation and hatchery supplementation affect P. costatus population structure, we studied populations from three sites up and downstream of the Gafanhoto Dam (Para River, State of Minas Gerais). High levels of genetic diversity were found within populations (0.926 to 0.873); the three populations showed significant differentiation (F(ST) = 0.16), suggesting that populations from the three sites were affected by fragmentation of the river and by hatchery contributions. These results will be useful for developing a management and conservation plan for fish species in this area. PMID- 23079997 TI - Genetic effect of the prolactin receptor gene on egg production traits in chickens. AB - The identification and utilization of potential candidate genes with significant effects on economically important traits have become increasingly important in poultry breeding programs. The prolactin (PRLR) receptor is a specific receptor for prolactin, which is an anterior pituitary peptide hormone involved in various physiological activities and is essential for reproductive success. In chickens, the PRLR gene resides on the Z chromosome. We used a pooled DNA sequencing approach for identifying SNPs of the PRLR gene. Three hundred and nine-six Erlang Mountainous chicken hens were genotyped for six SNPs using PCR-SSCP and PCR sequencing methods; the association with chicken egg production traits was studied using general linear model procedures. Three linked SNPs (G14952A, A14969C and G14984A) at the P1 locus, two linked SNPs (G17560A and T17626A) at the P2 locus, and one SNP (T20868C) at the P3 locus were identified. Eight haplotypes were reconstructed on the basis of the six SNPs. The general linear model analysis indicated that there were significant associations of certain genotypes and haplotypes with some egg production traits. We conclude that chicken PRLR gene polymorphisms are associated with egg production traits and have potential as molecular markers for chicken breeding. PMID- 23079998 TI - Identification and abundance of miRNA in chicken hypothalamus tissue determined by Solexa sequencing. AB - We used Solexa sequencing technology to identify and determine the abundance of miRNAs and compared the characteristics and expression patterns of miRNA of 1-day old and 36-week-old chicken hypothalamuses. We obtained 17,825,753 and 10,928,745 high-quality reads from 36-week-old and 1-day-old chickens, respectively. Three hundred and seventy-one conserved miRNAs were expressed in both libraries. Among the conserved miRNAs, 22 miRNAs were up-regulated and 157 miRNAs were down regulated in the 36-week-old chicken hypothalamus tissues. The abundance of sRNAs between 1-day-old and 36-week-old chickens differed considerably. KEGG pathway analysis suggested that the target genes of highly expressed miRNAs in the chicken hypothalamus are associated with metabolism and development. This information on differential expression of miRNAs in the hypothalamus of 1-day-old and 36-week-old chickens will help us understand the molecular mechanisms of metabolism and development. PMID- 23080000 TI - Tuning the binding properties of a new heteroditopic salt receptor through embedding in a polymeric system. AB - In this communication, we describe a polymerizable, heteroditopic salt receptor, based on an amino acid scaffold, which is able to bind sodium salts of chloride, acetate and nitrate. A poly(butyl methacrylate) derivative containing receptor was then prepared. In contrast to receptor copolymer is capable of extracting sodium nitrate from aqueous media. PMID- 23079999 TI - Limited gene expression variation in human embryonic stem cell and induced pluripotent stem cell-derived endothelial cells. AB - Recent evidence suggests human embryonic stem cell (hESC) and induced pluripotent stem (iPS) cell lines have differences in their epigenetic marks and transcriptomes, yet the impact of these differences on subsequent terminally differentiated cells is less well understood. Comparison of purified, homogeneous populations of somatic cells derived from multiple independent human iPS and ES lines will be required to address this critical question. Here, we report a differentiation protocol based on embryonic development that consistently yields large numbers of endothelial cells (ECs) derived from multiple hESCs or iPS cells. Mesoderm differentiation of embryoid bodies was maximized, and defined growth factors were used to generate KDR(+) EC progenitors. Magnetic purification of a KDR(+) progenitor subpopulation resulted in an expanding, homogeneous pool of ECs that expressed EC markers and had functional properties of ECs. Comparison of the transcriptomes revealed limited gene expression variability between multiple lines of human iPS-derived ECs or between lines of ES- and iPS-derived ECs. These results demonstrate a method to generate large numbers of pure human EC progenitors and differentiated ECs from pluripotent stem cells and suggest individual lineages derived from human iPS cells may have significantly less variance than their pluripotent founders. PMID- 23080001 TI - Scientific discoveries: swimming with and against the tide. PMID- 23080002 TI - Is high-dose intravenous steroid effective on preserving vision in acute methanol poisoning? PMID- 23080003 TI - Is the debate between "nature vs. nurture" almost over?. PMID- 23080006 TI - Experimental study of hydrogen bonding potentially stabilizing the 5' deoxyadenosyl radical from coenzyme B12. AB - Coenzyme B(12) can assist radical enzymes that accomplish the vicinal interchange of a hydrogen atom with a functional group. It has been proposed that the Co-C bond homolysis of coenzyme B(12) to cob(II)alamin and the 5'-deoxyadenosyl radical is aided by hydrogen bonding of the corrin C19-H to the 3'-O of the ribose moiety of the incipient 5'-deoxyadenosyl radical, which is stabilized by 30 kJ mol(-1) (B. Durbeej et al., Chem. Eur. J. 2009, 15, 8578-8585). The diastereoisomers (R)- and (S)-2,3-dihydroxypropylcobalamin were used as models for coenzyme B(12). A downfield shift of the NMR signal for the C19-H proton was observed for the (R)-isomer (delta=4.45 versus 4.01 ppm for the (S)-isomer) and can be ascribed to an intramolecular hydrogen bond between the C19-H and the oxygen of CHOH. Crystal structures of (R)- and (S)-2,3-dihydroxypropylcobalamin showed C19-H???O distances of 3.214(7) A (R-isomer) and 3.281(11) A (S-isomer), which suggest weak hydrogen-bond interactions (-DeltaG<6 kJ mol(-1)) between the CHOH of the dihydroxypropyl ligand and the C19-H. Exchange of the C19-H, which is dependent on the cobalt redox state, was investigated with cob(I)alamin, cob(II)alamin, and cob(III)alamin by using NMR spectroscopy to monitor the uptake of deuterium from deuterated water in the pH range 3-11. No exchange was found for any of the cobalt oxidation states. 3',5'-Dideoxyadenosylcobalamin, but not the 2',5'-isomer, was found to act as a coenzyme for glutamate mutase, with a 15 fold lower k(cat)/K(M) than 5'-deoxyadenosylcobalamin. This indicates that stabilization of the 5'-deoxyadenosyl radical by a hydrogen bond that involves the C19-H and the 3'-OH group of the cofactor is, at most, 7 kJ mol(-1) ( DeltaG). Examination of the crystal structure of glutamate mutase revealed additional stabilizing factors: hydrogen bonds between both the 2'-OH and 3'-OH groups and glutamate 330. The actual strength of a hydrogen bond between the C19 H and the 3'-O of the ribose moiety of the 5'-deoxyadenosyl group is concluded not to exceed 6 kJ mol(-1) (-DeltaG). PMID- 23080007 TI - Encapsulation of ferritin, ribosomes, and ribo-peptidic complexes inside liposomes: insights into the origin of metabolism. AB - Here we summarize the main results of our latest investigation on the spontaneous encapsulation of proteins (ferritin) and ribosomes inside lipid vesicles. We show that when vesicles form in a solution containing some macromolecules (even at low concentration), in contrast to the expectations, a few but measurable number of vesicles is able to capture a very high number of solutes, up to 60 times the external concentration. We also show preliminary evidences on the encapsulation of additional solutes (ribo-peptidic complexes, fluorescent proteins and enzymes), and shortly present our current approach aimed at exploiting this phenomenon. In particular, we would like to reveal how the formation of compartments can trigger effective intra-vesicle reactions starting from diluted solutions. Although the mechanistic details for this phenomenon are still missing, we claim that these new evidences are highly relevant for the origin of the first functional cells in primitive times. PMID- 23080008 TI - Processes that drove the transition from chemistry to biology: concepts and evidence. PMID- 23080009 TI - Search for the most primitive membranes: some remaining problems. PMID- 23080010 TI - Ionizing radiation: friend or foe of the origins of life? PMID- 23080011 TI - Neutral one-dimensional metal chains consisting of alternating anionic and cationic rhodium complexes. AB - The metallophilic interactions were investigated within chains of oppositely charged rhodium carbonyl complexes. The cationic [Rh(CO)(2)(L)](+) (L = 2,2' bipyridine and 1,10-phenanthroline) and anionic [RhCl(2)(CO)(2)](-) units were self-assembled into one dimensional rhodium chains supported by electrostatic interactions. The array of Rh centers in {[Rh(CO)(2)(2,2' bpy)][RhCl(2)(CO)(2)]}(n) was found to be nearly linear with a Rh...Rh...Rh angle of 170.927(11) degrees and Rh...Rh distances of 3.3174(5) A and 3.4116(5) A. The crystal structure of {[Rh(CO)(2)(1,10-phen)][RhCl(2)(CO)(2)]} consisted of two sets of crystallographically independent chains with slightly different Rh...Rh...Rh angles (170.275(9) degrees and 159.573(9) degrees ). The higher linearity allowed closer packing of the rhodium complexes. The Rh...Rh distances were 3.2734(3) A and 3.3155(3) A for the more linear and 3.3498(3) A and 3.3211(3) A for the less linear system. The existence of metallophilic interactions was confirmed computationally by TD-DFT and QTAIM analysis. The computational results also indicated that the intermolecular charge transfer from the cation to the anion had a significant contribution to the absorption properties of the chain compounds. PMID- 23080012 TI - Intraocular lens as a drug delivery reservoir. AB - PURPOSE OF REVIEW: To describe the development and use of intraocular lenses (IOLs) as drug delivery systems and to review the current literature on their application and efficacy. RECENT FINDINGS: Many drugs have been loaded onto IOLs by coating or by attachment in a separate reservoir. With incorporation of polymeric materials either as a coating or by attachment as a separate reservoir, it is possible to achieve a sustained and controlled release of drugs. Experimental evidence in animal models has shown that IOL drug delivery systems are effective in the prevention and treatment of inflammation, infection and posterior capsule opacification after cataract surgery. SUMMARY: The use of IOLs as drug delivery reservoirs appears to show great promise. Although excellent results with therapeutic potential have been reported in experimental animal studies, further studies are needed to reach clinical use. PMID- 23080013 TI - Glued intraocular lens: a major review on surgical technique and results. AB - PURPOSE OF REVIEW: To review the changes and results of glued intraocular lens (IOL) procedure in eyes with inadequate capsule. RECENT FINDINGS: The recent review of 735 eyes with glued IOL showed 486 rigid glued IOL, 191 foldable IOL, 10 glued iris prosthesis, 16 eyes with glued IOL with pupilloplasty and 32 eyes with glued IOL with penetrating keratoplasty. The postoperative best corrected visual acuity (BCVA) in eyes with the rigid glued IOL was 0.38 +/- 0.27. There was a significant improvement in BCVA (P = 0.000). The mean postoperative BCVA in foldable glued IOL was 0.39 +/- 0.29. IOL optic-related complications included optic capture and decentration. Haptic-related complications seen are haptic extrusion, haptic dislodgement, broken haptic and subconjunctival haptic. Most of the haptic-related problems are due to improper scleral tucking. The second surgeries in rigid glued IOL included IOL repositioning (2.2%), haptic repositioning (1%), conjunctival peritomy closure (0.8%), posterior segment surgery (1.2%) and IOL explantation (0.4%). The surgical modifications included glued IOL scaffold and vertical glued IOL. Glued IOL, which was combined with corneal procedures such as penetrating keratoplasty, Descemet stripping automated endothelial keratoplasty and Descemet's membrane endothelial keratoplasty, showed good visual and anatomical outcome. SUMMARY: Glued IOL and its surgical modifications showed good visual outcome with minimal complications in the recent review of its results and complications profile. However, long-term functional and anatomical outcome has to be observed in future. PMID- 23080014 TI - Role of topical, subconjunctival, intracameral, and irrigative antibiotics in cataract surgery. AB - PURPOSE OF REVIEW: To summarize current understanding of antibiotic prophylaxis in cataract surgery, with particular emphasis on available evidence and change in practice patterns over the past decade. RECENT FINDINGS: Povidone-iodine application prior to cataract surgery remains a universal practice, and is backed by good quality evidence. Subsequent to the results of the European multicenter trial documenting decreased risk of endophthalmitis with intracameral cefuroxime injection at the end of surgery, similar benefit with intracameral antibiotic use has been reported in studies with large sample sizes from multiple centers around the world. There has been a distinct change in practice patterns in many countries, with intracameral antibiotic use becoming part of routine protocol. In the USA, topical fluoroquinolone application remains the most popular mode of antibiotic prophylaxis. A promising approach is the development of novel drug delivery methods like polymeric devices designed for sustained antibiotic release. SUMMARY: Based on current evidence, the recommended measures for endophthalmitis prophylaxis are preoperative topical instillation of povidone iodine and intracameral antibiotic injection at the end of cataract surgery. PMID- 23080015 TI - Influence of constitutive phenolic compounds on the response of grapevine (Vitis vinifera L.) leaves to infection by Plasmopara viticola. AB - Flavonols and hydroxycinnamic acids are known to contribute to plant resistance against pathogens, but there are few reports on the implication of flavonols in the resistance of grapevine against Plasmopara viticola, and none on the involvement of hydroxycinnamic acids. In order to analyze the effect of flavonols on P. viticola infection, variable amounts of flavonols were induced by different light conditions in otherwise phenologically identical leaves. Differences in content of leaf hydroxycinnamic acids were induced at the same time. A non invasive monitoring of flavonols and hydroxycinnamic acids was performed with Dualex leaf-clip optical sensors. Whatever the light condition, there were no significant changes in flavonol or in hydroxycinnamic acid contents for control and inoculated leaves during the development of P. viticola until 6 days after inoculation. The violet-blue autofluorescence of stilbenes, the main phytoalexins of grapevine that accumulate in inoculated leaves, was used as an indicator of infection by P. viticola. The implication of leaf constitutive flavonols and hydroxycinnamic acids in the defence of Vitis vinifera against P. viticola could be investigated in vivo thanks to this indicator. The increase in stilbene violet blue autofluorescence started earlier for leaves with low flavonol content than for leaves with higher content, suggesting that constitutive flavonols are able to slow down the infection by P. viticola. On the contrary, constitutive hydroxycinnamic acids did not seem to play a role in defence against P. viticola. The non-destructive nature of the methods used alleviates the major problem of destructive experiments: the large variability in leaf phenolic contents. PMID- 23080016 TI - The developmental outcomes of P0-mediated ARGONAUTE destabilization in tomato. AB - The plant protein ARGONAUTE1 (AGO1) functions in multiple RNA-silencing pathways, including those of microRNAs, key regulators of growth and development. Genetic analysis of ago1 mutants with informative defects has provided valuable insights into AGO1's biological functions. Tomato encodes two AGO1 homologs (SlAGO1s), but mutants have not been described to date. To analyze SlAGO1s' involvement in development, we confirmed that both undergo decay in the presence of the Polerovirus silencing suppressor P0 and produce a transgenic responder line (OP:P0HA) that, upon transactivation, expresses P0 C-terminally fused to a hemagglutinin (HA) tag (P0HA) and destabilizes SlAGO1s at the site of expression. By crossing OP:P0HA with a battery of driver lines, constitutive as well as organ and stage-specific SlAGO1 downregulation was induced in the F1 progeny. Activated plants exhibited various developmental phenotypes that partially overlapped with those of Arabidopsis ago1 mutants. Plants that constitutively expressed P0HA had reduced SlAGO1 levels and increased accumulation of miRNA targets, indicating compromised SlAGO1-mediated silencing. Consistent with this, they exhibited pleiotropic morphological defects and their growth was arrested post-germination. Transactivation of P0HA in young leaf and floral organ primordia dramatically modified corresponding organ morphology, including the radialization of leaflets, petals and anthers, suggesting that SlAGO1s' activities are required for normal lateral organ development and polarity. Overall, our results suggest that the OP:P0HA responder line can serve as a valuable tool to suppress SlAGO1 silencing pathways in tomato. The suppression of additional SlAGOs by P0HA and its contribution to the observed phenotypes awaits investigation. PMID- 23080017 TI - 3D Photofixation Lithography in Diels-Alder Networks. AB - 3D structures are written and developed in a crosslinked polymer initially formed by a Diels-Alder reaction. Unlike conventional liquid resists, small features cannot sediment, as the reversible crosslinks function as a support, and the modulus of the material is in the MPa range at room temperature. The support structure, however, can be easily removed by heating the material, and depolymerizing the polymer into a mixture of low-viscosity monomers. Complex shapes are written into the polymer network using two-photon techniques to spatially control the photoinitiation and subsequent thiol-ene reaction to selectively convert the Diels-Alder adducts into irreversible crosslinks. PMID- 23080018 TI - Synthesis of 4,6-disubstituted 2-(4-morpholinyl)pyrimidines by cross-coupling reactions using triorganoindium compounds. AB - 4,6-Disubstituted-2-(4-morpholinyl)pyrimidines, an important class of bioactive compounds, have been synthesized from 4,6-dichloro-2-(4-morpholinyl)pyrimidine by selective and sequential palladium-catalyzed cross-coupling reactions using triorganoindium reagents. This methodology, being efficient and versatile, allowed the synthesis of a variety of non-symmetrical pyrimidines functionalized at C-4 and C-6 positions. PMID- 23080019 TI - The impact of magnesium on isometric twitch parameters and resting membrane potential of the skeletal muscle in diabetic rats. AB - To present the relationship between oral magnesium supplementation, blood glucose, and changes in isometric twitch parameters, resting membrane potential (RMP), in the gastrocnemius muscle in diabetic rats. Sixty rats were used in this study. The rats were divided into four groups: control (drinking tap water, Group I, n = 15), control with treated with magnesium sulfate (10 g/L) (Group II, n = 15), diabetic (Group III, n = 15), and diabetic with treated with magnesium sulfate (10 g/L) (Group IV, n = 15). In Group II and IV, the level of plasma magnesium was increased comparing to those of the control group (p < 0.05). Isometric twitch tensions were decreased significantly in the Group III, but Group IV isometric twitch tensions were increased significantly. Group IV RMP values were close to the Group I. Hyperglycemia decreases gastrocnemius muscle isometric twitch tension and increases RMP in diabetic rats. Magnesium treatment can prevent these diabetic complications. PMID- 23080020 TI - Studying single red blood cells under a tunable external force by combining passive microrheology with Raman spectroscopy. AB - The dynamic micromechanical and structural properties of single human red blood cells are studied using a combination of dual trap optical tweezers and confocal Raman spectroscopy. Such a combination permits us to show a direct relationship between the rheological properties and chemical structure conformation. The frequency dependence of the complex stiffness of the cells was measured using both one and two probe response functions under identical experimental conditions. Both the microrheology and Raman measurements were performed at different stretching forces applied to the cell. A detailed analysis of the auto- and cross-correlated probe motions allows exploring the local and overall viscoelastic properties of the cells over a controlled range of the deformations. The observed growth of the cell viscoelasticity with stretching was associated with structural changes in the cell membrane monitored via the Raman spectroscopy. PMID- 23080021 TI - Contribution of mature hepatocytes to small hepatocyte-like progenitor cells in retrorsine-exposed rats with chimeric livers. AB - The potential lineage relationship between hepatic oval cells, small hepatocyte like progenitor cells (SHPCs), and hepatocytes in liver regeneration is debated. To test whether mature hepatocytes can give rise to SHPCs, rats with dipeptidyl peptidase IV (DPPIV) chimeric livers, which harbored endogenous DPPIV-deficient hepatocytes and transplanted DPPIV-positive hepatocytes, were subjected to retrorsine treatment followed by partial hepatectomy (PH). DPPIV-positive hepatocytes comprised about half of the DPPIV chimeric liver mass. Tissues from DPPIV chimeric livers after retrorsine/PH treatment showed large numbers of SHPC clusters. None of the SHPC clusters were stained positive for DPPIV in any analyzed samples. Furthermore, serial sections stained for gamma-glutamyl transpeptidase (GGT, a marker of fetal hepatoblasts) and glucose-6-phosphatase (G6Pase, a marker of mature hepatocytes) showed inverse expression of the two enzymes and a staining pattern consistent with a lineage that begins with GGT(+)/G6Pase(-) to GGT(-)/G6Pase(+) within a single SHPC cluster. Using double immunofluorescence staining for markers specific for hepatic oval cells and hepatocytes in serial sections, oval cell proliferations with CK-19(+)/laminin(+) and OV-6(+)/C/EBP-alpha(-) were shown to extend from periportal areas into the SPHC clusters, differentiating into hepatic lineage by progressive loss of CK 19/laminin expression and appearance of C/EBP-alpha expression towards the cluster side. Cells in the epithelial cell adhesion molecule (EpCAM(+)) SHPC clusters showed membranous EpCAM(+)/HNF-4alpha(+) (hepatocyte nuclear factor 4alpha) staining and were contiguous to the surrounding cytoplasmic EpCAM(+)/HNF 4alpha(-) ductular oval cells. Extensive elimination of oval cell response by repeated administration of 4,4'-methylenedianiline (DAPM) to retrorsine-exposed rats impaired the emergence of SHPC clusters. CONCLUSION: These findings highly suggest the hepatic oval cells but not mature hepatocytes as the origin of SHPC clusters in retrorsine-exposed rats. PMID- 23080022 TI - Molecular phylogeny and morphology reveal three new species of Cantharellus within 20 m of one another in western Wisconsin, USA. AB - Three new species, Cantharellus phasmatis, Cantharellus flavus and Cantharellus spectaculus, all previously considered Cantharellus cibarius, are described in this study. The circumscription of these three species from C. cibarius and other Cantharellus species is supported by morphological differences and nuclear DNA sequence data (nLSU, ITS, TEF1). All were found under Quercus spp. in a small plot in Hixon Forest Park in La Crosse, Wisconsin, emphasizing the need for further taxonomic study of even common and conspicuous genera in North America. In addition, a review of the current state of C. cibarius sensu lato systematics is presented, including a review of the recent elevation of C. cibarius var. roseocanus to the species rank. Taxonomic descriptions and photographs are provided for the newly described species. PMID- 23080023 TI - Two taxonomic novelties in the Sordariomycetidae: Ceratolenta caudata gen. et sp. nov. and Platytrachelon abietis gen. et comb. nov. for Ceratosphaeria abietis. AB - Wood-inhabiting taxa of the Sordariomycetidae comprise several distantly related monotypic or small genera, which lack familial or ordinal affiliation and share a simple and inconspicuous morphology of dark ascomata with carbonaceous walls and long necks, stipitate asci and hyaline ellipsoidal, fusiform to cylindrical ascospores. Recent collections of an undescribed fungus and of Ceratosphaeria abietis reveal two additional evolutionary lineages characterized by this simple and indistinct teleomorph morphology. Phylogenetic analysis of three genes, small and large subunit nuclear ribosomal DNA (nc28S and nc18S rDNA) combined with the second largest subunit of RNA polymerase II (rpb2), supports the recognition of two new genera, Ceratolenta and Platytrachelon for C. abietis. Platytrachelon abietis is redescribed and illustrated based on additional collections. In culture it produced a dematiaceous hyphomycetous anamorph with blastic conidiogenesis and ellipsoidal, septate, pale brown conidia. It was associated with a synanamorph producing cylindrical, strongly curved hyaline conidia. Molecular data suggest a relationship of Platytrachelon with the Papulosaceae, while Ceratolenta forms a monophylum on a separate branch. Both taxonomic novelties possess striking morphological similarities with Ceratosphaeria, Lentomitella and Rhodoveronaea, which recently were reinstated based on DNA sequence data. A key to morphologically similar wood-inhabiting fungi classified in the Sordariomycetidae is provided. PMID- 23080024 TI - New species of Xerocomus (Boletales) from the Guiana Shield, with notes on their mycorrhizal status and fruiting occurrence. AB - Xerocomus cyaneibrunnescens, Xerocomus potaroensis, and Xerocomus parvogracilis (Boletales, Basidiomycota) are described as new species from the Pakaraima Mountains of Guyana, in the central Guiana Shield region. These boletes occur in neotropical forests dominated by ectomycorrhizal (ECM) trees in the genus Dicymbe (Fabaceae subfam. Caesalpinioideae). Each species produced basidiomata during a multi-year plot survey, and each was confirmed as an ECM symbiont with one or more leguminous host plant species in Guyana. PMID- 23080025 TI - New species and new records of freshwater ascomycetes from Brazil and Costa Rica. AB - During independent surveys for freshwater ascomycetes in Brazil and Costa Rica, two new species, Torrentispora pilosa and Vertexicola ascoliberatus, and nine previously described species were recovered. Among the described species, Annulatascus biatriisporus, Anthostomella aquatica, Tamsiniella labiosa and Torrentispora crassiparietis are reported for the first time from the western hemisphere, Aniptodera chesapeakensis, Chaetosphaeria lignomollis and Jahnula seychellensis are new records for South America and Annulatascus velatisporus and Ophioceras venezuelensis are reported for the first time for Brazil. The description of the genus Torrentispora is emended to accommodate T. pilosa. The new species are described and illustrated and a brief description is provided for all new records. PMID- 23080026 TI - [Epithelial-mesenchymal transition in non-small cell lung cancer]. AB - Non-small cell lung carcinoma (NSCLC) is a highly fibrotic malignancy, which exhibits a prominent desmoplastic stroma. Epithelial-mesenchymal transition (EMT) is one of the main modes of carcinoma invasion. We identified the stromal N glycoprotein periostin by mass spectrometry of lung adenocarcinoma pleural effusions. Validation on a NSCLC tissue microarray and on tumor whole sections by immunohistochemistry indicated that periostin is strongly upregulated at the invasive front in both tumor epithelia and the surrounding matricellular space. In comparison to collagen, elastin and vimentin, periostin was found to be most closely associated with parameters of tumor progression such as larger size and higher stage, with the squamous cell histotype, and with decreased survival. An association with decreased survival was also found for the cell adhesion molecule L1CAM. In conclusion, enlargement of NSCLC tumors is associated with an increase of desmoplastic stroma and concomitant upregulation of EMT markers at the invasive front. The tumor-stroma interface may be a candidate topographic region for stroma- or EMT-directed therapy. PMID- 23080027 TI - [Lymph node staging in gastrointestinal cancer. Combination of methylene blue assisted lymph node dissection and ex vivo sentinel lymph node mapping]. AB - The histopathological lymph node staging is of crucial importance for the prognosis estimation and therapy stratification in gastrointestinal cancer. However, the recommended numbers of lymph nodes that should be evaluated are often not reached in routine practice. Methylene blue assisted lymph node dissection was introduced as a new, simple and efficient technique to improve lymph node harvest in gastrointestinal cancer. This method is inexpensive, causes no delay and needs no toxic substances. All studies performed revealed a highly significantly improved lymph node harvest in comparison to the conventional technique. Moreover, this technique can be combined with a new ex vivo sentinel lymph node mapping that for the first time is based on histological sentinel lymph node detection. The success rate of this method is similar to conventional techniques and it enables an efficient application of extended investigation methods, such as immunohistochemistry or the polymerase chain reaction. PMID- 23080028 TI - [Current issues in pulmonary pathology. Report of the working group on pulmonary pathology of the German Society of Pathology]. AB - The working group on pulmonary pathology of the German Society of Pathology (Deutsche Gesellschaft fur Pathologie, DGP) developed very actively in the last year. Apart from the autumn meeting in Heidelberg in 2011 and the sessions at the annual DGP meeting in Berlin it was possible to realize a first publication with support and coauthorship of several members of the working group dealing with the classification of lung adenocarcinoma. In this report the key aspects of the activity related to the following issues are summarized including non-small cell lung carcinoma, neuroendocrine tumors of the lungs, interstitial pulmonary diseases, cell blocks in cytology and banking in thoracic pathology. PMID- 23080029 TI - [Carcinoma in situ of the testis]. PMID- 23080030 TI - External ophthalmomyiasis: a case series. AB - Oestrus ovis or 'sheep botfly' causes common ophthalmomyiasis in warm climates. It is a self-limited infestation with symptoms such as foreign body sensation and/or tearing. The larvae can be observed in the conjunctiva and should be extracted with forceps. The development of larvae beyond the first stage does not occur in healthy humans, although they may penetrate the ocular globe, causing so called internal myiasis. External ophthalmomyiasis is typical of rural areas, but it may be observed occasionally in urban environments. PMID- 23080031 TI - Granulomatous keratic precipitates in birdshot retinochoroiditis. AB - With the purpose of facilitating clinical studies of this infrequent disease, an expert panel published research criteria for birdshot retinochoroiditis (RCBRC). The aim of our study was to investigate the sensitivity of the exclusion criteria of the RCBRC as applied to all patients seen in our center with a diagnosis of BRC. This was a single center retrospective study involving all patients with an ocular inflammatory disease seen at the Centre for Ophthalmic Specialized Care, Lausanne, Switzerland, between 1995 and 2012. The percentage of patients with a diagnosis of BRC was identified. The exclusion criteria of the RCBRC were applied to all patients and the percentage of patients with absence of keratic precipitates (KPs) and absence of posterior synechiae were calculated. Out of 1,504 new patients, 25 patients (1.66 %; 19 female, 6 male) were diagnosed with BRC and 19 patients had sufficient data to be included in the study (1.26 %, 13 female). All patients were positive for HLA-A29 testing. The sensitivity of the RCBRC with respect to the exclusion criteria applied to our patient cohort was 84.2 % due to the exclusion of three patients showing KPs. Our study supports the motion to re-evaluate the RCBRC, since granulomatous KPs can be present and are more frequent than previously estimated and stringent application of the criteria would lead to a substantial loss of study patients. PMID- 23080032 TI - ARID1A loss is prevalent in endometrial hyperplasia with atypia and low-grade endometrioid carcinomas. AB - ARID1A (AT-rich interactive domain 1A) has recently been identified as a tumor suppressor gene in various, predominantly gynecological cancers. We wanted to investigate the distribution of ARID1A in endometrial hyperplasia, carcinomas and metastatic lesions to elucidate the timing of expression loss of its protein ARID1A in the course of endometrial cancer carcinogenesis. In addition, we wanted to assess the relationship between the loss of ARID1A and clinicopathological variables in endometrial cancer in general and the endometrioid subtype in particular. We analyzed a prospectively collected series of 535 primary endometrial cancers, 77 metastatic lesions, as well as 38 retrospectively collected endometrial hyperplasias with evaluable immunohistochemical staining for ARID1A. Fresh frozen tissue was available for mRNA microarray analysis in 122 primary tumors in parallel. Loss of ARID1A protein expression was noted in none of the hyperplasias without atypia, 16% of hyperplasias with atypia, 19% of primary endometrioid tumors and 28% of metastatic lesions. Loss of ARID1A in primary tumor was significantly associated with endometrioid grade 1 or 2 and clear-cell histology, diploid tumor cells, younger patient age and deeper myometrial infiltration, but not survival. ARID1A RNA expression was significantly correlated with ARID1A protein loss. Thus, loss of ARID1A appears to be an early event in the carcinogenesis of endometrioid uterine carcinomas and the association with deep myometrial infiltration may suggest an importance for invasiveness. PMID- 23080033 TI - Endometrium is not the primary site of origin of pelvic high-grade serous carcinoma in BRCA1 or BRCA2 mutation carriers. AB - Serous endometrial intraepithelial carcinoma has been proposed to be a potential precursor lesion of pelvic high-grade serous carcinoma. If true, an increased incidence of uterine papillary serous carcinomas would be expected in BRCA1 and BRCA2 mutation carriers, who are at high-risk of developing pelvic high-grade serous carcinoma. This study explored particularly the occurrence of uterine papillary serous carcinoma, as well as other endometrial cancers, following risk reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 germline mutation attending a tertiary multidisciplinary clinic. A consecutive series of women with a BRCA1 or BRCA2 mutation who had undergone risk-reducing salpingo-oophorectomy without hysterectomy at the University Medical Center Groningen from January 1996 until March 2012 were followed prospectively. They were crossed with the histopathology list of endometrial cancer diagnoses reported by the Dutch nationwide pathology database PALGA. To assess the risk of endometrial cancer, a standardized incidence ratio was calculated comparing the observed with the expected number of endometrial cancer cases. Overall, 201 BRCA1 and 144 BRCA2 mutation carriers at a median age of 50 years (range, 32-78) were analyzed. After a median follow-up period of 6 years, after risk-reducing salpingo-oophorectomy, two cases of endometrial cancer were diagnosed, whereas the expected number was 0.94 cases (standardized incidence ratio 2.13; 95% confidence interval 0.24-7.69; P=0.27). Both endometrial cancer cases were of the endometrioid histological subtype. We showed that the incidence of endometrial cancer following risk reducing salpingo-oophorectomy, especially uterine papillary serous carcinoma, in women at high-risk of developing pelvic high-grade serous carcinoma is not increased. On the basis of our data, the hypothesis of serous endometrial intraepithelial carcinoma being an important precursor lesion of pelvic high grade serous carcinoma seems unlikely. There is no need to add a prophylactic hysterectomy to risk-reducing salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers. PMID- 23080034 TI - Effect of micronisation of pre-conditioned cowpeas on cooking time and sensory properties of cooked cowpeas. AB - BACKGROUND: Cowpea is mostly utilised as cooked whole seeds. This is often achieved only after boiling for up to 2 h, resulting in high energy consumption and a long time for food preparation. Micronisation of pre-conditioned cowpeas reduces their cooking time. Micronisation changes the physicochemical properties of cowpea seeds, which may affect the sensory properties of cooked cowpeas. Consumer acceptance and utilisation of micronised cowpeas depend on their sensory properties. Micronised and unmicronised samples of Blackeye, Bechuana white, Glenda and Dr Saunders cowpeas were subjected to cooking time, descriptive sensory and colour analyses. RESULTS: Micronisation significantly reduced cowpea cooking time by 28-49%. There were significant (P < 0.05) increases in roasted aroma and flavour, mushy texture and splitting in all micronised samples. Bechuana white was more mushy and split than others. There were significant decreases in firmness, mealiness and coarseness after micronisation for all cowpea types. Micronised cowpeas were darker (lower L* values) than unmicronised cooked cowpeas. Darkening was more evident in light-coloured than dark-coloured cowpeas. CONCLUSION: Micronisation reduces cowpea cooking time but also affects sensory properties of cowpeas such as introducing roasted flavours that may not be familiar to consumers. This might have an influence on consumer acceptance of micronised cowpeas. PMID- 23080035 TI - Weak detrusor contractility correlates with motor disorders in Parkinson's disease. AB - Limited attention has been paid to the relationship between urinary symptoms or urodynamic findings and motor disorders in Parkinson's disease (PD). We aimed to correlate pressure-flow urodynamic parameters with video-gait analysis parameters in PD. We recruited 41 patients with PD (25 men and 16 women; age, 70.6 +/- 8.5 years; H & Y motor grading: 2 [range, 1-3]; disease duration: 4 years [range, 1 7]; taking levodopa 300 mg/day [range, 100-400]). All patients underwent pressure flow urodynamics (parameters: first sensation, bladder capacity, detrusor overactivity [noted in 24 patients], and Watts factor [WF]) and video-gait analysis (parameters: time and number of strides for 5-m gait [simple task] and time for timed up and go [complex task]). Statistical analysis was made by Mann Whitney's U-test for analyzing the relation between detrusor overactivity and gait as well as Spearman's rank-correlation coefficient test for analyzing the relation between the remaining parameters and gait. We found no relation between filling-phase urodynamics (detrusor overactivity, first sensation, and bladder capacity) and video-gait analysis parameters. By contrast, we found a significant relation between voiding-phase urodynamics (WF, reflecting detrusor power) and all three video-gait analysis parameters (reflecting lower-half bradykinesia and loss of postural reflex) in our PD patients (P < 0.01). The close relation between the WF and motor disorders in the present study suggests that, though clinically mild, a weak detrusor in PD might have a central origin. We should follow postvoid residual volume carefully in PD patients with advanced gait disorder, because postvoid residual volume might increase in such patients. PMID- 23080036 TI - Robotics in rehabilitation: technology as destiny. AB - Robotic aids for rehabilitation hold considerable promise but have not yet achieved widespread clinical adoption. Barriers to adoption include the limited data on efficacy, the single-purpose design of existing robots, financial considerations, and clinician lack of familiarity with this technology. Although the path forward to clinical adoption may be slow and have several false starts, the labor-saving aspect of robotic technology will ultimately ensure its adoption. PMID- 23080037 TI - Clinical designs of recent robot rehabilitation trials. AB - Rehabilitation robots are increasingly being tested and promoted for clinical neurorehabilitation. Compared with conventional and manual methods, robots allow for a variety of advantages, particularly in the areas of interventional control and the ability to provide a high volume of facilitated movement. Since 1997, there have been more than 60 clinical trials reporting the use of two dozen different robots for neurorehabilitation. Although there are a number of smaller pilot studies, there are only few larger clinical trials. There may be a number of reasons why pilot robot studies do not materialize into larger studies. Beyond devices that failed to perform as intended, what are the clinical design issues that have limited these studies? Some basic considerations include randomization, inclusion of a control group, power calculation based on a clinically meaningful outcome, and finally, reproducible descriptions of the intervention being tested. Although many of these issues are general challenges presented for all rehabilitation studies, there are clinical design features that would likely greatly improve interpretation of results and better position robot devices toward the next clinical trial step. On the other hand, the absence of these elements, even in the setting of a pilot study, may significantly hamper the interpretation of results and not yield sufficient information on treatment effects, adverse event rates, dropout rate, and so on, to allow further testing to proceed to follow-up Food and Drug Administration phase II and III studies. Development of rehabilitation robots for clinical use needs to occur hand in hand with well-conducted clinical trials to provide evidence of efficacy while also taking into account costs. PMID- 23080038 TI - Robotic-assisted gait training and restoration. AB - The past two decades have seen the introduction of and a strong growth in the availability of rehabilitation interventions that are based on the use of robotics. A major driving factor has been the advancement of technology, with faster, more powerful computers, new computational approaches, as well as increased sophistication of motors and other electro mechanical components. These advancements in technology have not been the only factor propelling these new rehabilitation interventions. During the same period, a strong growth in the understanding of neuroplasticity and motor learning has also been witnessed. Although there is still much to learn, comprehension of how new skills are acquired, or old ones are relearned, is evolving at a fast pace. Much of this improved understanding can be linked to the advancement of central nervous system imaging as well as techniques for studying changes at the cellular or molecular level. In this review, the authors present the notion that an ever-advancing understanding of neuroplasticity and motor learning can provide a theoretical basis for the clinical use of rehabilitation robotics as applied to enhancing mobility. Specifically focusing on locomotor training after injury to the central nervous system, these principles can provide guidance to clinicians on how to structure their interventions to potentially promote or accelerate functional recovery in their patients. Several types of existing robotic devices to assist walking that are currently available for use in the clinic, as well as their advantages and limitations, will be discussed. PMID- 23080039 TI - Comparison of three-dimensional, assist-as-needed robotic arm/hand movement training provided with Pneu-WREX to conventional tabletop therapy after chronic stroke. AB - OBJECTIVES: Robot-assisted movement training can help individuals with stroke reduce arm and hand impairment, but robot therapy is typically only about as effective as conventional therapy. Refining the way that robots assist during training may make them more effective than conventional therapy. Here, the authors measured the therapeutic effect of a robot that required individuals with a stroke to achieve virtual tasks in three dimensions against gravity. DESIGN: The robot continuously estimated how much assistance patients needed to perform the tasks and provided slightly less assistance than needed to reduce patient slacking. Individuals with a chronic stroke (n = 26; baseline upper limb Fugl Meyer score, 23 +/- 8) were randomized into two groups and underwent 24 one-hour training sessions over 2 mos. One group received the assist-as-needed robot training and the other received conventional tabletop therapy with the supervision of a physical therapist. RESULTS: Training helped both groups significantly reduce their motor impairment, as measured by the primary outcome measure, the Fugl-Meyer score, but the improvement was small (3.0 +/- 4.9 points for robot therapy vs. 0.9 +/- 1.7 for conventional therapy). There was a trend for greater reduction for the robot-trained group (P = 0.07). The robot group largely sustained this gain at the 3-mo follow-up. The robot-trained group also experienced significant improvements in Box and Blocks score and hand grip strength, whereas the control group did not, but these improvements were not sustained at follow-up. In addition, the robot-trained group showed a trend toward greater improvement in sensory function, as measured by the Nottingham Sensory Test (P = 0.06). CONCLUSIONS: These results suggest that in patients with chronic stroke and moderate-severe deficits, assisting in three-dimensional virtual tasks with an assist-as-needed controller may make robotic training more effective than conventional tabletop training. PMID- 23080040 TI - Robotic approaches for rehabilitation of hand function after stroke. AB - The goal of this review was to discuss the impairments in hand function after stroke and present previous work on robot-assisted approaches to movement neurorehabilitation. Robotic devices offer a unique training environment that may enhance outcomes beyond what is possible with conventional means. Robots apply forces to the hand, allowing completion of movements while preventing inappropriate movement patterns. Evidence from the literature is emerging that certain characteristics of the human-robot interaction are preferable. In light of this evidence, the robotic hand devices that have undergone clinical testing are reviewed, highlighting the authors' work in this area. Finally, suggestions for future work are offered. The ability to deliver therapy doses far higher than what has been previously tested is a potentially key advantage of robotic devices that needs further exploration. In particular, more efforts are needed to develop highly motivating home-based devices, which can increase access to high doses of assisted movement therapy. PMID- 23080041 TI - Robotic assessment of upper limb motor function after stroke. AB - Traditional assessment of a stroke subject's motor ability, carried out by a therapist who observes and rates the subject's motor behavior using ordinal measurements scales, is subjective, time consuming and lacks sensitivity. Rehabilitation robots, which have been the subject of intense inquiry over the last decade, are equipped with sensors that are used to develop objective measures of motor behaviors in a semiautomated way during therapy. This article reviews the current contributions of robot-assisted motor assessment of the upper limb. It summarizes the various measures related to movement performance, the models of motor recovery in stroke subjects and the relationship of robotic measures to standard clinical measures. It analyses the possibilities offered by current robotic assessment techniques and the aspects to address to make robotic assessment a mainstream motor assessment method. PMID- 23080042 TI - Task-oriented rehabilitation robotics. AB - Task-oriented training is emerging as the dominant and most effective approach to motor rehabilitation of upper extremity function after stroke. Here, the authors propose that the task-oriented training framework provides an evidence-based blueprint for the design of task-oriented robots for the rehabilitation of upper extremity function in the form of three design principles: skill acquisition of functional tasks, active participation training, and individualized adaptive training. The previous robotic systems that incorporate elements of task-oriented trainings are then reviewed. Finally, the authors critically analyze their own attempt to design and test the feasibility of a TOR robot, ADAPT (Adaptive and Automatic Presentation of Tasks), which incorporates the three design principles. Because of its task-oriented training-based design, ADAPT departs from most other current rehabilitation robotic systems: it presents realistic functional tasks in which the task goal is constantly adapted, so that the individual actively performs doable but challenging tasks without physical assistance. To maximize efficacy for a large clinical population, the authors propose that future task oriented robots need to incorporate yet-to-be developed adaptive task presentation algorithms that emphasize acquisition of fine motor coordination skills while minimizing compensatory movements. PMID- 23080043 TI - New horizons for robot-assisted therapy in pediatrics. AB - The field of rehabilitation robotics has grown substantially during the past 15 yrs. Studies of upper limb robot-assisted therapy for adults with moderate to severe hemiparesis after stroke have shown significant gains compared with usual care in isolated control, coordination, and strength in the paretic arm (J Rehabil Res Dev 2006;43:171-84; Top Stroke Rehabil 2007;14:22-44; Neurorehabil Neural Repair 2008;22:111-21). While attempts to increase the understanding of the key active ingredients of these interventions continue, researchers have recently extended their focus to children with neurologically based movement disorders arising from cerebral palsy and acquired brain injury or stroke. This study's aim was to provide a narrative review that highlights recent pediatric studies of robot-assisted therapies for the upper and lower limbs. Potential benefits will be discussed, as well as challenges and needs for future development. PMID- 23080044 TI - Robotic therapy: the tipping point. AB - The last two decades have seen a remarkable shift in the neurorehabilitation paradigm. Neuroscientists and clinicians moved away from the perception that the brain is static and hardwired to a new dynamic understanding that plasticity is a fundamental property of the adult human brain and might be harnessed to remap or create new neural pathways. Capitalizing on this innovative understanding, the authors introduced a paradigm shift in the clinical practice in 1989 when they initiated the development of the Massachusetts Institute of Technology-Manus robot for neurorehabilitation and deployed it in the clinic in 1994 (Krebs et al. 1998). Since then, the authors and others have developed and tested a multitude of robotic devices for stroke, spinal cord injury, cerebral palsy, multiple sclerosis, and Parkinson disease. Here, the authors discuss whether robotic therapy has achieved a level of maturity to justify its broad adoption in the clinical realm as a tool for motor recovery. PMID- 23080046 TI - The Olympic Games challenge. PMID- 23080045 TI - Robot therapy tipping point: caveats for post hoc speculation. PMID- 23080047 TI - Solution to standard addition challenge. PMID- 23080048 TI - Performance of GFR equations in Japanese subjects. AB - BACKGROUND: Japanese GFR equations based on serum creatinine (Scr) (Eq(cr)), serum cystatin C (Scys) (Eq(cys)) and average value of Eq(cr) and Eq(cys) (Eq(average)), and coefficient-modified CKD-EPI equations based on Scr (CKD EPI(cr)), Scys (CKD-EPI(cys)) and Scys in combination with Scr (CKD-EPI(cr-cys)) are now available for Japanese subjects. Performance of these equations has not been well evaluated in subjects stratified by GFR. Therefore, the bias, precision and accuracy of the GFR equations were compared in Japanese subjects stratified by measured GFR. METHODS: Three hundred fifty Japanese subjects were included for validation. These subjects were stratified by measured GFR (0-29, 30-59, 60-89, 90-119 ml/min/1.73 m(2) and total). Japanese equations (Eq(cr), Eq(cys) and Eq(average)) were compared with coefficient-modified CKD-EPI equations (0.813 * CKD-EPI(cr), CKD-EPI(cys) and 0.908 * CKD-EPI(cr-cys)), respectively. GFR was measured by inulin renal clearance. Standardized Scr was measured by enzymatic method. Standardized Scys was measured by colloidal gold immunoassay. RESULTS: Bias and accuracy were not significantly different between Japanese GFR equations and coefficient-modified CKD-EPI equations in all mGFR ranges. The precision of Eq(cr) was significantly better in GFR 0-29 ml/min/1.73 m(2) and significantly worse in GFR 60-89 and GFR 90-119 ml/min/1.73 m(2) compared with 0.813 * CKD EPI(cr). The precision of Eq(cys) was significantly better in GFR 30-59 and GFR 60-89 ml/min/1.73 m(2) compared with CKD-EPI(cys). The precision of Eq(average) was significantly better in GFR 30-59 ml/min/1.73 m(2) and significantly worse in GFR 90-119 ml/min/1.73 m(2) compared with 0.908 * CKD-EPI(cr-cys). CONCLUSION: Japanese GFR equations performed well in subjects with GFR under 60 ml/min/1.73 m(2) compared with the coefficient-modified CKD-EPI equations. PMID- 23080049 TI - Plasmon-plasmon interaction: controlling light at nanoscale. AB - This paper investigates the effect of the locally induced bulk plasmon resonance on light guiding of a plasma-like medium. It is demonstrated that, by inducing or suppressing the bulk plasmon resonance, one can manipulate the light propagation. This concept is then employed for a hybrid dielectric-loaded plasmonic waveguide with the aim to efficiently control the surface plasmon polaritons with a highly doped silicon as an active material. The proposed approach is shown to have a high potential for nanoscale light manipulation and development of a fully CMOS compatible electro-optical plasmonic modulator. PMID- 23080050 TI - Aberrant function and differentiation of monocytes in end stage renal disease. AB - Patients with end stage renal disease (ESRD) suffer from many disturbances of the immune system. These immunopathologies are related to the higher failure of vaccination, and increased prevalence of infections and neoplasms. In the presented article, we review the current data regarding the role of monocytes in immune dysfunctions which are observed in terminal renal failure. As monocytes play a pivotal role in regulating the function of the immune system, their dysfunction can have a profound effect on the immune system and may lead to accelerated arteriosclerosis and deteriorating overall health conditions. More specifically, we suggest that peripheral blood monocytes in patients with ESRD are chronically activated, and their functional and phenotypical features resemble those of inflammatory macrophages. This state of chronic inflammation is unfavorable for dendritic cells and consequently, the prevalence of dendritic cells is reduced. As these effects are consistent across different modes of dialysis, they are probably mediated by the uremia itself. PMID- 23080051 TI - Islam and termination of pregnancy for genetic conditions in Pakistan: implications for Pakistani health care providers. PMID- 23080052 TI - Hyaluronic acid and adhesions on polypropylene endoperitoneal mesh: an experimental study. AB - INTRODUCTION: The aim of this study was to verify the effectiveness of hyaluronic acid in preventing adhesion formation after endoperitoneal surgery in which prosthetic polypropylene mesh is placed directly on the viscera. METHODS: Forty albino rats were included in this study and the animals were randomized to the following 4 groups each with 10 rats: polypropylene prosthesis (PP), PP+hyaluronic acid (HA), Hertra prosthesis (HP), HP+HA. A large defect was created in the anterior abdominal wall of each rat and repaired in different ways. In the first group a polypropylene mesh was placed intraperitoneally, while, in the second group the peritoneal surface of the mesh was impregnated with HA. In the third group a Hertra 0 polypropylene rigid mesh was placed intraperitoneally and, in the fourth group, the peritoneal surface of the Hertra 0 mesh was impregnated with HA. Clinical controls on the animals were carried out at 1 month. Each group was divided into two subgroups in which the controls and the prosthetic explantation were randomly carried out at 3 and 6 months. Explanted prostheses were subjected to histological and immunohistochemical analysis, and examined for shrinkage. An assessment of adhesion formation was performed, evaluating the quantity and tenacity of the adhesions. RESULTS: We demonstrated higher levels of adhesions in rats with PP than in those with HP and lower levels in rats with a protective layer of hyaluronic acid. The amount of fibronectin in the periprosthetic fibrotic tissue and the histological score confirmed the previous data. CONCLUSIONS: Hertra 0 mesh with HA provided the best results in terms of physical stability and resistance to adhesion formation. PMID- 23080053 TI - Evaluating quality of life in adults with profound learning difficulties resettled from hospital to supported living in the community. AB - This article describes a longitudinal evaluation of the quality of life of service users with profound learning difficulties who were resettled from hospital accommodation to supported housing in the community. The Trident approach was used for the design of the evaluation with data gathered regarding outcomes, process and stakeholder perspectives. Using a specially designed tool, quality of life was measured in seven domains for 39 service users in the hospital as a base line and at six months, twelve months and eighteen months in supported housing. A statistically significant improvement in quality of life overall and in each of the seven domains was found. Questionnaire surveys of parents/next of kin and support staff confirmed these findings as did a number of qualitative case studies. PMID- 23080054 TI - Eating disorders, substance use disorders, and impulsiveness among disordered gamblers in a community sample. AB - Disordered gambling and many eating disorders (EDs) involve recurrent loss of impulse control. We examined rates of specific EDs, ED psychopathology, substance use disorders, and their interrelationships with impulsiveness among community members with disordered gambling. Community-recruited adults with pathological (n = 95) or problem (n = 9) gambling (N = 104; 51% female) completed structured interviews and questionnaires. We observed high rates of substance dependence, lifetime EDs, and current ED psychopathology; 20.8% of women (vs 1.9% of men) had a DSM-IV ED, and 37.8% (vs 3.9%) had an ED according to proposed DSM-5 criteria. Although disordered gambling severity was not associated with ED diagnosis or severity of ED psychopathology, greater disordered gambling severity and an ED diagnosis were both associated with increased impulsiveness. These findings suggest that impulsiveness might constitute a common personality characteristic that underlies disordered gambling and EDs. PMID- 23080055 TI - Oxidative carbonylation of amines to formamides using NaIO4. AB - Carbonylation of amines in methanol in the presence of NaIO(4) produces formamide derivatives in good to excellent yields without a transition metal catalyst. PMID- 23080056 TI - TiO2 and ZnO mediated photocatalytic degradation of E2 and EE2 estrogens. AB - In this work, the photocatalytic degradation of selected estrogens (E2 and EE2) was evaluated, using bench-scale and continuous treatment systems assisted by artificial UV-A and solar radiation. Processes based on the use of TiO2 permit an efficient degradation of E2 and EE2 estrogens, usually at reaction times lower than 15 min. Especially remarkable is the high degradation efficiency shown by sunlight-assisted processes, which are extremely favored by the high efficiency of compound parabolic collectors. PMID- 23080057 TI - The influence of attentional control on stimulus processing is category specific in Stroop tasks : Attentional control. AB - It is still unclear how attentional control influences stimulus processing. We investigated this issue in four Stroop task experiments utilizing a pretest training-posttest design. Subjects were given extensive training on the Stroop task using typical incongruent Stroop trials. The rates of color naming and word reading, which reflect the efficiency of stimulus processing, were assessed in pretest and posttest. The difference in rates between posttests and pretests reflects the influence of attentional control, acquired during the training phase, on stimulus processing. In Experiment 1, members of color category were used in the training phase; in Experiment 2, members of color category were used, but not in the training phase; in Experiment 3, they were neither in the color category nor were they used in the training. The results consistently showed that the suppression of word reading and the enhancement of color naming were developed in the training phases and they were not due to general training of color-naming task without conflict but to color-naming training with Stroop conflict (Experiment 4). More importantly, both suppression and enhancement affected the members of color category regardless of whether they were trained or not. The present findings suggest that the influence of attentional control on stimulus processing is category specific. We discuss the implications of the present results in terms of existing research on the locus of attentional control in Stroop tasks. PMID- 23080058 TI - The impact of intermittent air exposure on lipid deposition. AB - PURPOSE: To analyze the impact of intermittent air exposure on the in vitro deposition of two radioactive lipids on various contact lens (CL) materials, using a custom-designed model blink cell. METHODS: Six different CL materials (balafilcon A, lotrafilcon B, comfilcon A, senofilcon A, etafilcon A, and omafilcon A) were mounted on the model blink cell pistons, which cycled the lenses in and out of a complex artificial tear solution (ATS) that contained a trace amount of C-cholesterol or C-phosphatidylcholine. For the short-term experiment, air-exposed lenses were continuously cycled in and out of the ATS for 10 h. Longer term incubations for 6 days were tested with lotrafilcon B and balafilcon A materials incubated in C-cholesterol ATS. The air-exposed CLs were cycled for 14 h then submerged for 10 h each day. For both experiments, the control lenses were submerged for the entire test period. After incubation, lenses were processed, and deposited masses were quantified. RESULTS: Exposure to air resulted in increased amounts of cholesterol deposited by 1.6 to 4.3 fold on omafilcon A, balafilcon A, comfilcon A, and senofilcon A (p <= 0.03) compared with submerged lenses. No differences in deposition were observed for etafilcon A and lotrafilcon B (p > 0.05). The longer term incubation of lotrafilcon B and balafilcon A showed statistically significant increases in cholesterol deposition for both air-exposed lens materials (p < 0.02) with the increase in deposition 1.8* and 2.8*, respectively. For phosphatidylcholine, all air-exposed lenses had increased masses of deposition. These deposits were statistically greater by 1.1 to 1.6 times for omafilcon A, comfilcon A, lotrafilcon B, and senofilcon A (p < 0.04), but not statistically different for etafilcon A or balafilcon A (p > 0.05). CONCLUSIONS: This study found that lipid deposition profiles are CL material dependent and that intermittent air exposure can influence the mass of lipid deposited. PMID- 23080059 TI - Predisposing factors for solution-induced corneal staining. AB - PURPOSE: To evaluate predisposing factors in subjects susceptible to solution induced corneal staining (SICS). METHODS: Four hundred forty-six existing soft contact lens wearers were randomly fitted with one of two study lenses (lotrafilcon B, CIBA Vision, or omafilcon A, CooperVision) and used a hydrogen peroxide care system (Clear Care, CIBAVision) for a 1-month period. Each subject was then challenged with the same lenses presoaked in a multipurpose solution (ReNu MultiPlus, Bausch & Lomb) and assessed after approximately 2 h to be categorized as either "stainers" or "non-stainers" based on whether they showed a classic SICS pattern (diffuse punctate corneal staining in three or more peripheral quadrants). RESULTS: Overall, 36% (155 of 425) of eligible subjects were classified as stainers and included a higher proportion of omafilcon wearers: 44% (91 of 205) vs. 29% (64 of 220). After using the peroxide system, the stainers were more likely to show poorer wetting (odds ratio [OR] = 1.76, p = 0.02) compared with the non-stainers. Lens wetting showed a significant negative correlation with film deposits (r = -0.63, p < 0.0001, n = 425). Furthermore, on slit lamp examination, the stainers were more likely to show higher levels of upper- and lower-palpebral hyperemia (OR = 2.18, p = 0.02; OR = 1.93, p = 0.04), tarsal roughness (OR = 1.71, p = 0.01), corneal staining (OR = 17.1, p < 0.0001), and conjunctival staining (OR = 1.94, p = 0.004). Although not exposed to preservatives, twice as many eyes in the stainers group had some level of corneal staining: 51% vs. 25%. There were no significant differences between the stainers and non-stainers with respect to age, sex, refraction, or keratometry (p > 0.05). CONCLUSIONS: This study highlighted some notable trends in patients susceptible to SICS. The findings point toward poor tear quality as a predisposing factor for SICS. PMID- 23080060 TI - Scale and spatial distribution of aberrations associated with tear breakup. AB - PURPOSE: We examined the spatial correlation between tear breakup (TBU) and the associated optical anomalies on multiple spatial scales. METHODS: Five subjects refrained from blinking while the time course and patterns of TBU were sequentially observed using fluorescein, retroillumination, and Shack-Hartmann (SH) aberrometry. Wavefront error maps were developed using Zernike polynomials, as well as local zonal analysis of measured wavefront slopes. The difference between these maps reveals the presence of very high-order aberrations missed by standard modal fitting methods. Size of SH spots was also quantified to estimate optical perturbations on a microscopic scale. The spatial correlation between TBU and optical aberrations was also computed. RESULTS: Degradation of the tear film increased wavefront aberrations over all spatial scales measured. Consistent with tear thinning, blink suppression induced an irregular pattern of phase advances in regions of TBU. SH spot size also increased in regions of TBU, which indicates the presence of optical aberrations on a scale smaller than individual lenslets. CONCLUSIONS: The optical signature of TBU caused by blink suppression is a combination of wavefront aberrations on macroscopic and microscopic scales due to non-uniform tear film thinning and possible exposure of a rough epithelial surface. Localized optical defects correspond temporally and spatially with TBU revealed by fluorescein and retroillumination. In addition to gross wavefront aberrations, scatter develops in areas of TBU that will further contribute to image degradation and visual disturbances after TBU. PMID- 23080061 TI - Hydrogen storage and evolution catalysed by metal hydride complexes. AB - The storage and evolution of hydrogen are catalysed by appropriate metal hydride complexes. Hydrogenation of carbon dioxide by hydrogen is catalysed by a [C,N] cyclometalated organoiridium complex, [Ir(III)(Cp*)(4-(1H-pyrazol-1-yl kappaN(2))benzoic acid-kappaC(3))(OH(2))](2)SO(4) [Ir-OH(2)](2)SO(4), under atmospheric pressure of H(2) and CO(2) in weakly basic water (pH 7.5) at room temperature. The reverse reaction, i.e., hydrogen evolution from formate, is also catalysed by [Ir-OH(2)](+) in acidic water (pH 2.8) at room temperature. Thus, interconversion between hydrogen and formic acid in water at ambient temperature and pressure has been achieved by using [Ir-OH(2)](+) as an efficient catalyst in both directions depending on pH. The Ir complex [Ir-OH(2)](+) also catalyses regioselective hydrogenation of the oxidised form of beta-nicotinamide adenine dinucleotide (NAD(+)) to produce the 1,4-reduced form (NADH) under atmospheric pressure of H(2) at room temperature in weakly basic water. In weakly acidic water, the complex [Ir-OH(2)](+) also catalyses the reverse reaction, i.e., hydrogen evolution from NADH to produce NAD(+) at room temperature. Thus, interconversion between NADH (and H(+)) and NAD(+) (and H(2)) has also been achieved by using [Ir-OH(2)](+) as an efficient catalyst and by changing pH. The iridium hydride complex formed by the reduction of [Ir-OH(2)](+) by H(2) and NADH is responsible for the hydrogen evolution. Photoirradiation (lambda > 330 nm) of an aqueous solution of the Ir-hydride complex produced by the reduction of [Ir OH(2)](+) with alcohols resulted in the quantitative conversion to a unique [C,C] cyclometalated Ir-hydride complex, which can catalyse hydrogen evolution from alcohols in a basic aqueous solution (pH 11.9). The catalytic mechanisms of the hydrogen storage and evolution are discussed by focusing on the reactivity of Ir hydride complexes. PMID- 23080063 TI - Rh-catalyzed C-C cleavage of benzyl/allylic alcohols to produce benzyl/allylic amines or other alcohols by nucleophilic addition of intermediate rhodacycles to aldehydes and imines. AB - We report three transformations: 1) direct transformation from biarylmethanols into biarylmethylamines; 2) direct transformation from one biarylmethanol into another biarylmethanol; 3) direct transformation from allylic alcohols into allylic amines. These transformations are based on pyridyl-directed Rh-catalyzed C-C bond cleavage of secondary alcohols and subsequent addition to C=X (X = N or O) double bonds. The reaction conditions are simple and no additive is required. The driving force of C-C bond cleavage is the formation of the stable rhodacycle intermediate. Other directing groups, such as the pyrazolyl group, can also be used although it is not as efficient as the pyridyl group. We carried out in depth investigations for transformation 1 and found that: 1) the substrate scope was broad and electron-rich alcohols and electron-deficient imines are more efficient; 2) as the leaving group, aldehyde had no significant impact on either the C-C bond cleavage or the whole transformation; 3) mechanistic studies (intermediate isolation, in situ NMR spectroscopic studies, competing reactions, isotopic labeling experiments) implied that: i) The C-C cleavage was very efficient under these conditions; ii) there is an equilibrium between the rhodacycle intermediate and the protonated byproduct phenylpyridine; iii) the addition step of the rhodacycle intermediate to imines was slower than the C-C cleavage and the equilibrium between the rhodacycle and phenylpyridine; iv) the whole transformation was a combination of two sequences of C-C cleavage/nucleophilic addition and C-C cleavage/protonation/C-H activation/nucleophilic addition, with the latter being perhaps the main pathway. We also demonstrated the first example of cleavage of an C(alkenyl)-C(benzyl) bond. These transformations showed the exchange (or substitution) of the alcohol group with either an amine or another alcohol group. Like the "group transplant", this method offers a new concept that can be used to directly synthesize the desired products from other chemicals through reorganization of carbon skeletons. PMID- 23080062 TI - Block copolymer cross-linked nanoassemblies improve particle stability and biocompatibility of superparamagnetic iron oxide nanoparticles. AB - PURPOSE: To develop cross-linked nanoassemblies (CNAs) as carriers for superparamagnetic iron oxide nanoparticles (IONPs). METHODS: Ferric and ferrous ions were co-precipitated inside core-shell type nanoparticles prepared by cross linking poly(ethylene glycol)-poly(aspartate) block copolymers to prepare CNAs entrapping Fe(3)O(4) IONPs (CNA-IONPs). Particle stability and biocompatibility of CNA-IONPs were characterized in comparison to citrate-coated Fe(3)O(4) IONPs (Citrate-IONPs). RESULTS: CNA-IONPs, approximately 30 nm in diameter, showed no precipitation in water, PBS, or a cell culture medium after 3 or 30 h, at 22, 37, and 43 degrees C, and 1, 2.5, and 5 mg/mL, whereas Citrate-IONPs agglomerated rapidly (> 400 nm) in all aqueous media tested. No cytotoxicity was observed in a mouse brain endothelial-derived cell line (bEnd.3) exposed to CNA-IONPs up to 10 mg/mL for 30 h. Citrate-IONPs (> 0.05 mg/mL) reduced cell viability after 3 h. CNA-IONPs retained the superparamagnetic properties of entrapped IONPs, enhancing T2-weighted magnetic resonance images (MRI) at 0.02 mg/mL, and generating heat at a mild hyperthermic level (40 ~ 42 degrees C) with an alternating magnetic field (AMF). CONCLUSION: Compared to citric acid coating, CNAs with a cross-linked anionic core improved particle stability and biocompatibility of IONPs, which would be beneficial for future MRI and AMF-induced remote hyperthermia applications. PMID- 23080064 TI - Biomaterials for stem cell culture and seeding for the generation and delivery of cardiac myocytes. AB - PURPOSE OF REVIEW: Present an overview of last year's advances in stem cell delivery for cardiac tissue engineering. RECENT FINDINGS: Several promising novel biomaterial platforms to improve myocardial tissue repair/regeneration and local neovascularization using cellular therapy have been developed. SUMMARY: Still today, a clear statement on cellular therapy efficacy cannot be made but nonetheless, as we describe in this review, several improved in-vivo applications have already been initiated. The newest tissue engineering platforms have basically two main objectives: to improve low cell engraftment and viability into the hostile environment of the infarcted tissue; and to promote neoformation of functional myocardial tissue. With the idea to solve these issues many groups are presently working on the association of stem cells with novel biomaterials, providing an initial appropriate microenvironment (scaffold) for successful cell transplantation, proper differentiation and improved cardiac function. PMID- 23080065 TI - The pits and pearls in translating operational tolerance biomarkers into clinical practice. AB - PURPOSE OF REVIEW: This review highlights the importance and the role of key biomarker studies in liver and kidney transplant tolerance, discusses the most recent findings with respect to organ-type and cell-type specificity in blood and tissue, and points out the novel research directions in the field of immunological tolerance that involve both adult and pediatric recipients. RECENT FINDINGS: Recent studies indicate that biomarkers for solid organ transplant tolerance are distinct with respect to organ type and cell type, suggesting distinct tolerogenic mechanisms for different organs. In both liver and kidney transplant tolerant recipients, novel cellular mechanisms have been proposed for natural killer cells, B cells, and dendritic cells in the maintenance of stable operational tolerance. SUMMARY: Major advances have been made with respect to the understanding of mechanisms and the process of discovery and early validation of peripheral blood biomarkers for operational transplant tolerance both in kidney and liver transplantation. These studies have shed light on the findings that these tolerance mechanisms may be organ specific, as the peripheral blood transcriptional profiling attempts by microarrays and PCR reveal distinct differences and suggest roles for specific cell types. Although these studies are mostly in adults and limited in children, the first tolerance gene signature for pediatric liver transplant tolerance suggests that there are common mechanisms, yet distinct peripheral biomarkers across age. Prospective trials and organ integrative studies are now needed to further develop these biomarkers for future clinical application in addition to expanding novel approaches such as the investigation of miRNAs to better understand the tolerance mechanisms. PMID- 23080066 TI - Mechanistic target of rapamycin inhibitors in solid organ transplantation: from benchside to clinical use. AB - PURPOSE OF REVIEW: Here, we review recent advances and new insights in mechanistic target of rapamycin (mTOR) biology (signalling pathway, kidney biology and immune system), and recent clinical data on mTOR inhibitors related to solid organ transplantation. RECENT FINDINGS: The mTOR pathway is a major integrator of signals governing protein and lipid biosynthesis and growth factor driven cell cycle progression. Recent findings have emphasized a critical role of mTOR in cellular homeostasis with a crucial role in podocyte function. Beyond CD8(+) and regulatory T-cell control, mTOR protein is involved in critical biological functions of T helper cells or dendritic cells. New specific inhibitors of mTORC1/C2 are available and shed new light on mTOR functions. Finally, clinical trials have better defined the use of mTOR inhibitors and emphasized their role in cancer prevention. SUMMARY: The mTOR pathway is considered as a key integrator of multiple inputs that drives numerous biological processes in cell biology. mTOR inhibitors are potent immunosuppressive drugs for solid organ transplantation. Newly designed specific inhibitors of mTOR complex 1 and 2 offer promising therapeutic effects and a better understanding of the pathway. Many conditions may benefit from mTOR inhibition for a short period, but tolerance of treatment in a chronic setting remains a major concern. PMID- 23080067 TI - Chronic renal allograft damage after transplantation: what are the reasons, what can we do? AB - PURPOSE OF REVIEW: Chronic renal allograft damage is one of the main problems after kidney transplantation. This review enumerates causes, describes available therapeutic options, and discusses options of the future. RECENT FINDINGS: Alloantigen-dependent and alloantigen-independent factors are responsible for allograft damage. Prevention of renal allograft damage starts with interventions that occur surrounding the explantation in cadaveric organs. These include the use of dopamine or machine perfusion systems.Followed by the critical phase of ischemia/reperfusion injury, the LCN2/lipocalin-2, HAVCR1, and p38 MAPK pathway are new players involved in that process. Innate immunity plays a part, too. Cold ischemia time is associated with genes of apoptosis. Nondonor-specific antibodies like antihuman leukocyte antibodies-Ia or angiotensin type 1 receptor may also play a role. Recent research indicates that genetic polymorphism like the Ficolin 2 Ala258Ser polymorphism and the mannose-binding lectin-2 polymorphism are involved in that process. New therapeutic options are rare and in the future. However, there is some evidence that drugs interfering with metalloproteinases, sexual hormones like dihydroandrosterone, and mesenchymal stem cell therapy may be of importance. SUMMARY: Taken together, although the understanding of chronic rejection has improved, the available therapeutic options remain scarce. PMID- 23080068 TI - Are stem cells the teacher or the student? AB - PURPOSE OF REVIEW: Stem cell-based therapies for preventing and treating chronic end-organ dysfunction have captured the imagination of the lay public and spurred scientific and clinical development in multiple disciplines and disease states. The goal of this review is to build a framework around the different approaches being deployed to heal or treat end-organ dysfunction and discuss how within this framework future developments may occur. RECENT FINDINGS: In this review, we divide the development of regenerative therapies into two broad categories. The first 'Stem Cells as the Student' focuses on the fact that we need to coax/teach the stem cells to differentiate in an efficient manner into the cells of interest, then using tissue engineering, we need to integrate them in an appropriate delivery system/matrix, and then generate a blood supply, sufficient to allow for their survival following engraftment. In the second category 'Stem Cells as the Teacher,' we learn from studies on stem cell biology, critical pathways that are dysregulated in tissue repair. By identifying these critical pathways, we can develop drug and biologics that can enhance tissue repair and end-organ function. SUMMARY: Regenerative therapies have exciting potential to improve patient outcomes in a variety of acute and chronic disease states. There is significant excitement in general public, and the scientific and clinical communities. Early studies have been variably successful. As we move forward and understand the biology and engineering principles involved, significant advances with greater chances of success and efficacy will come. PMID- 23080070 TI - Association between PPP1R1B polymorphisms and defense mechanisms in healthy Chinese-Han subjects. AB - Defense mechanisms resulting from the interaction between biological factors and the environment have been established. In genetic studies, dopamine genes have been recognized to play an important role in the determination of defense mechanisms. DARPP-32 (dopamine- and cAMP-regulated phosphoprotein) plays a central role in the biology of dopamine-receptive neurons; its coding gene (PPP1R1B) has been linked to psychological and psychopathological traits. Here, we aimed to explore the association between PPP1R1B polymorphisms and defense mechanisms measured using the 88-item Defense Style Questionnaire in 400 healthy Chinese-Han subjects. Of the three polymorphisms examined, rs12601930 was associated with projection (P = 0.028) and splitting (P = 0.032), while rs3764352 was associated with splitting (P = 0.042). No significant association was found between rs879606 and defenses. When analyzed separately by gender, no significant association between defense mechanisms and PPP1R1B polymorphisms in males was observed. In females, however, rs12601930 was significantly associated with splitting (P = 0.018), and rs879606, with projection (P = 0.015), help-rejecting complaining (P = 0.030), and immature defense style (P = 0.031), while rs3764352 was not associated with any defense. The distribution of genotypes between the low- and high-scoring subgroups for each defense style showed no significant differences. Our results suggest that PPP1R1B polymorphisms are, at least partially, responsible for immature defenses. PMID- 23080069 TI - Protein phosphatase 1gamma isoforms linked interactions in the brain. AB - Posttranslational protein modifications, in particular reversible protein phosphorylation, are important regulatory mechanisms involved in cellular signaling transduction pathways. Thousands of human proteins are phosphorylatable and the tight regulation of phosphorylation states is crucial for cell maintenance and development. Protein phosphorylation occurs primarily on serine, threonine, and tyrosine residues, through the antagonistic actions of protein kinases and phosphatases. The catalytic subunit of protein phosphatase 1 (PP1), a major Ser/Thr-phosphatase, associates with a large variety of regulatory subunits that define substrate specificity and determine specific cellular pathway responses. PP1 has been shown to bind to different proteins in the brain in order to execute key and differential functions. This work reports the identification of proteins expressed in the human brain that interact with PP1gamma1 and PP1gamma2 isoforms by the yeast two-hybrid method. An extensive search of PP1 binding motifs was performed for the proteins identified, revealing already known PP1 regulators but also novel interactors. Moreover, our results were integrated with the data of PP1gamma interacting proteins from several public web databases, permitting the development of physical maps of the novel interactions. The PP1gamma interactome thus obtained allowed for the identification of novel PP1 interacting proteins, supporting novel functions of PP1gamma isoforms in the human brain. PMID- 23080071 TI - Pubo-femoral distance: an easy sonographic screening test to avoid late diagnosis of developmental dysplasia of the hip. AB - OBJECTIVES: To propose an easy and reproducible sonographic screening test able to avoid late presentation of developmental dysplasia of the hip (DDH). METHODS: The pubo-femoral distance (PFD) cut-off point was determined on 980 infants who underwent ultrasonography of the hips in comparison with the final diagnosis, based on clinical, ultrasound data and follow-up. PFD reproducibility was tested on 52 hips by both an experienced and an inexperienced radiologist. After teaching this screening method to general radiologists, its impact was evaluated by analysing the rate of late diagnosis in an entire administrative area. RESULTS: An abnormal PFD threshold above 6 mm gave a sensitivity of 97.4 % for the diagnosis of DDH (271 hips) and a specificity of 84 %. Sensitivity increased to 100 % when taking into consideration children of 1 month or older. The PFD measurement stayed reproducible even in inexperienced hands (k = 0.795). For 3 years, following the extension of screening to all female infants, there was no late diagnosis of DDH in girls in amongst a catchment area of 1 million inhabitants. CONCLUSIONS: PFD measurement with a threshold for abnormality of 6 mm at the age of 1 month, without asymmetry above 1.5 mm, could eradicate DDH late diagnosis. PMID- 23080072 TI - Volumetric MR-guided high-intensity focused ultrasound ablation of uterine fibroids: treatment speed and factors influencing speed. AB - OBJECTIVES: To assess the treatment speed of volumetric magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) ablation of symptomatic uterine fibroids, with a focus on factors affecting treatment speed. METHODS: We received Institutional Review Board approval, and informed consent was obtained from all participants. Among 109 patients referred, 43 women (39.4 %) (mean age, 43.7 years), with 112 fibroids passed the screening. We treated 53 symptomatic uterine fibroids (47.3 %, 53/112) (volume, 341.2 +/- 256.5 ml) using volumetric MR-HIFU ablation. We assessed procedure times, non-perfused volume (NPV) and treatment speed (NPV/treatment time). We statistically analysed the factors affecting treatment speed using multiple logistic regression tests. RESULTS: Technical success was achieved in 42 of 43 cases. MR room time (from entrance to exit) and treatment time (from first to last sonication) were 216.0 +/- 40.6 min and 131.5 +/- 55.9 min, respectively. Immediate NPV was 178.9 +/- 147.3 ml, which was 57.4 +/- 25.5 % of the fibroid volume. Treatment speed was 81.8 +/- 48.0 ml/h. Multivariate analysis showed that a large fibroid volume (P < 0.001), a low signal intensity ratio of fibroid to skeletal muscle on T2-weighted images (P = 0.009) and timing after completion of the learning curve (P < 0.001) significantly increased treatment speed. CONCLUSION: Volumetric MR-HIFU ablation can effectively treat symptomatic uterine fibroids. The treatment speed appeared to improve when treating large and/or dark fibroids as well as upon completion of the learning curve. PMID- 23080074 TI - Parkinson's disease: diagnostic potential of high-resolution phase difference enhanced MR imaging at 3 T. AB - OBJECTIVES: To determine whether it is possible to diagnose patients with Parkinson's disease (PD) on an individual basis using magnetic resonance imaging with phase difference enhanced imaging (PADRE). METHODS: PADRE delineated the crural fibres as a layer of low signal intensity and the substantia nigra as a layer of medium signal intensity in a healthy volunteer, and showed a clear boundary between the crural fibres and the substantia nigra (BCS). Twenty-four PD patients and 24 control subjects were enrolled. Contrast ratios between the substantia nigra and occipital white matter were calculated, and two radiologists independently reviewed the PADRE findings regarding BCS obscuration. RESULTS: Mean contrast ratio in PD patients was significantly higher than in control subjects (0.56 vs 0.39, P < 0.01). The BCS on PADRE was obscured significantly more frequently in any subgroups with PD patients compared with control subjects (P < 0.01). The observation of BCS obscuration had a sensitivity, specificity and accuracy for the diagnosis of PD of 92 %, 88 % and 90 % for radiologist 1 and 83 %, 88 % and 85 % for radiologist 2, respectively. CONCLUSION: PADRE is able to identify PD in patients as a loss of delineation between the crural fibres and the substantia nigra on an individual basis. PMID- 23080073 TI - A method for improving iodine contrast enhancement in abdominal computed tomography: experimental study in a pig model. AB - OBJECTIVES: To investigate the improvement in diagnostic image quality of an iodine contrast enhancement tool in an animal model for computed tomography (CT). METHODS: One pig was examined over several consecutive days with a CT system. The quantity of iodine as contrast medium (0.6-1.2 ml/kg) varied among different acquisitions. The contrast enhancement in the reconstructed slices was improved via a post-processing tool. The post-processing tool is an algorithm designed for enhancement of iodine contrast in CT data. Contrast-to-noise ratio (CNR), the detectability between soft-tissue and vascular structures, and quantitative image analysis were assessed. RESULTS: When reducing the quantity of contrast medium, our subjective image quality assessment revealed that it is visually possible to generate similar enhancement with less iodine. This observation was confirmed quantitatively in our CNR results. While employing the algorithm, the CNR between vascular structures and subcutaneous fat significantly improved. For unenhanced regions, we identified no change in HU values and no significant strengthening of artefacts. CONCLUSIONS: With post-processing there was a significantly improved diagnostic image quality compared with non-processed data. In particular, similar contrast enhancement could be achieved with a reduced quantity of contrast medium injected during the CT acquisition. PMID- 23080075 TI - A comparative study to distinguish the vineyard of origin by NIRS using entire grapes, skins and seeds. AB - BACKGROUND: Interest in high-quality products with a clear geographical origin is increasing. For the wine industry and market sector, identity preservation is of fundamental importance owing to the large number of geographical classifications. Nowadays, there is a growing demand for analytical methods for tracing grapes and wines. In the oenological sector, infrared spectroscopy is becoming an attractive tool allowing simultaneous measurement of several analytical parameters and enabling real-time decision making. RESULTS: Discriminant partial least squares, a supervised pattern recognition technique, was employed to discriminate between vineyards of origin using the near-infrared spectra of intact grapes, skins or seeds. In order to compare the three sample presentations, a receiver operating characteristic curve was used. The best results were obtained using intact grape seeds, with prediction rates of samples correctly classified of about 95%, although the good results obtained with entire grapes (about 93% of samples correctly classified) and the simplicity of use of the fibre optic probe could advise using entire grape presentation for comprehensive studies. CONCLUSION: The procedure reported here seems to have excellent potential for a fast and reasonably inexpensive analysis of the origin of samples. It is noted that such classification can be made at any time of ripening. This paper provides information of interest to develop new and extensive models in the future. PMID- 23080077 TI - Targeting triple-negative breast cancer through the somatostatin receptor with the new cytotoxic somatostatin analogue AN-162 [AEZS-124]. AB - Previously, we have shown that the targeted cytotoxic somatostatin (sst) analogue AN-162 [AZSE-124] inhibits the growth of MDA-MB-231 human breast cancers xenografted into nude mice. In this study, we examined the trafficking of AN-162 into the cell, the expression of the somatostatin receptors (sstr) in specimens of human triple-negative breast cancers (TNBC), and the effect of AN-162 on HCC 1806 human TNBC xenografts. The expression of sstr in TNBC tumor samples was investigated by immunohistochemical staining. The expression of sstr in HCC 1806 was evaluated by reverse transcription PCR. Internalization studies with I labeled AN-162 were carried out and the autofluorescence sign of doxorubicin moiety in the cell nucleus after incubation with AN-162 was measured using a fluorescence assay. The effects of AN-162 on the growth of HCC 1806 xenografted into nude mice were studied. A fluorescence microscopy cytotoxicity assay in vitro to detect cell death after treatment with AN-162 was also carried out. About 28% of TNBC tumor specimens showed a positive staining for sstr subtype 2a. HCC 1806 expresses all five subtypes of sstr. In the fluorescence cytotoxicity assay, dead HCC 1806 cells were found 24 h after incubation with AN-162. The growth of HCC 1806 tumors in nude mice was significantly inhibited by treatment with AN-162. AN-162 was internalized into the HCC 1806 cells and doxorubicin moiety was detected in the cell nuclei. This study is the first to show that the trafficking of the cytotoxic sst analogue AN-162 into the cell is mediated by sstr. Our work shows that the growth of xenografted HCC 1806 TNBCs can be effectively inhibited in vivo with AN-162. This investigation provides information on the mechanism of action and efficacy of this new targeted cytotoxic sst analogue and identifies in this relation the sstr as a favorable therapeutic target in TNBC. PMID- 23080076 TI - Modulation of the biliary expression of arylalkylamine N-acetyltransferase alters the autocrine proliferative responses of cholangiocytes in rats. AB - Secretin stimulates ductal secretion by interacting with secretin receptor (SR) activating cyclic adenosine 3',5'-monophosphate/cystic fibrosis transmembrane conductance regulator/chloride bicarbonate anion exchanger 2 (cAMP=>CFTR=>Cl(-) /HCO 3- AE2) signaling that is elevated by biliary hyperplasia. Cholangiocytes secrete several neuroendocrine factors regulating biliary functions by autocrine mechanisms. Melatonin inhibits biliary growth and secretin-stimulated choleresis in cholestatic bile-duct-ligated (BDL) rats by interaction with melatonin type 1 (MT1) receptor through down-regulation of cAMP-dependent signaling. No data exist regarding the role of melatonin synthesized locally by cholangiocytes in the autocrine regulation of biliary growth and function. In this study, we evaluated the (1) expression of arylalkylamine N-acetyltransferase (AANAT; the rate limiting enzyme for melatonin synthesis from serotonin) in cholangiocytes and (2) effect of local modulation of biliary AANAT expression on the autocrine proliferative/secretory responses of cholangiocytes. In the liver, cholangiocytes (and, to a lesser extent, BDL hepatocytes) expressed AANAT. AANAT expression and melatonin secretion (1) increased in BDL, compared to normal rats and BDL rats treated with melatonin, and (2) decreased in normal and BDL rats treated with AANAT Vivo-Morpholino, compared to controls. The decrease in AANAT expression, and subsequent lower melatonin secretion by cholangiocytes, was associated with increased biliary proliferation and increased SR, CFTR, and Cl(-) /HCO 3- AE2 expression. Overexpression of AANAT in cholangiocyte cell lines decreased the basal proliferative rate and expression of SR, CFTR, and Cl(-) /HCO 3- AE2 and ablated secretin-stimulated biliary secretion in these cells. CONCLUSION: Local modulation of melatonin synthesis may be important for management of the balance between biliary proliferation/damage that is typical of cholangiopathies. (HEPATOLOGY 2013). PMID- 23080078 TI - Relational security moderates the effect of serotonin transporter gene polymorphism (5-HTTLPR) on stress generation and depression among adolescents. AB - Previous research demonstrates that carriers of the short allele of the serotonin transporter gene (5-HTTLPR) show both greater susceptibility to depression in response to stressful life events and higher rates of generation of stressful events in response to depression. The current study examines relational security (i.e., self-reported beliefs about attachment security) as a moderator of these effects, building on emerging research suggesting that the short allele acts as a marker of sensitivity to the social environment. Participants were 354 Caucasian adolescents oversampled for maternal depression (137 male, 217 female), assessed at ages 15 and 20. Results indicated that the short allele predicted increased stress generation at age 20 among those with low age 15 security but decreased stress generation among those with high security, and revealed a three-way interaction between age 15 depression, age 15 security, and genotype, where depression predicted stress generation only among short allele carriers with low security. Further, among boys only, security interacted with genotype to predict longitudinal changes in depression diagnosis, with the s-allele predicting relative increases in probability of depression among boys with low security but decreases among boys with high security. Results support the notion of the short allele as a marker of social reactivity, and suggest that attachment security may buffer against the genetic vulnerability introduced by the short allele, in line with predictions of the differential susceptibility theory. PMID- 23080080 TI - Correlating the structure and localized surface plasmon resonance of single silver right bipyramids. AB - Localized surface plasmon resonances (LSPRs), collective electron oscillations in metal nanoparticles, are being heavily scrutinized for applications in prototype devices and circuits, as well as for chemical and biological sensing. Both the plasmon frequency and linewidth of a LSPR are critical factors for application optimization, for which their dependence on structural factors has been qualitatively unraveled over the past decade. However, quantitative knowledge based on systematic single particle studies has only recently become available for a few particle shapes. We show here that to understand the effect of structure (both size and shape) on plasmonic properties, one must take multiple parameters into account. We have successfully done so for a large data set on silver right bipyramids. By correlating plasmon energy and linewidth with edge length and corner rounding for individual bipyramids, we have found that the corner rounding has a significant effect on the plasmon energy for particles of the same size, and thus corner rounding must be taken into account to accurately describe the dependence of a LSPR on nanoparticle size. A detailed explanation of the phenomena responsible for the observed effects and their relationship to each other is presented. PMID- 23080079 TI - White matter hyperintensities and self-reported depression in a sample of patients with chronic headache. AB - White matter hyperintensities (WMH) have been associated with mood disorders in psychiatric patients. In the present study, we aimed to assess whether WMHs are associated with depressive symptoms and different sensitivity of the behavioral inhibition (BIS), and activation (BAS) systems in patients with chronic headache. Participants were 85 adult outpatients (16 men and 69 women) with a diagnosis of chronic headache. All of the patients underwent brain magnetic resonance imaging (MRI) and were administered the BIS/BAS scales and the Center for Epidemiologic Studies Depression Scale. Above 40 % of patients had periventricular WMHs (PWMHs) and almost 98 % had deep WMHs (DWMHs). Patients with PWMHs reported fewer depressive symptoms than patients without PWMHs. Patients with more severe DWMHs (compared with patients with mild or without DWMH lesions) were older and reported lower scores on the drive dimension of the BIS/BAS scales. In multivariate analyses, patients with PWMHs were 1.06 times more likely to report fewer depressive symptoms than patients without PWMHs. WMH lesions in patients with chronic headache were associated with less depression severity. PMID- 23080081 TI - Decrease of cerebral mast cell degranulation after systemic administration of lipopolysaccharide. AB - INTRODUCTION: The mast cell is an immunocyte, but its functions in the brain remain unclear. MATERIALS AND METHODS: In a rat model of weak inflammation, we analyzed the effect of a gram-negative bacterial lipopolysaccharide injection (100 MUg/kg) on thalamic mast cell (MC) population. CONCLUSION: We demonstrate a significant decrease of their degranulation, which suggests the implication of MC in preventing sepsis on the brain. PMID- 23080083 TI - A theoretical study of closed polyacene structures. AB - The electronic structure of planar molecular edifices obtained by joining polyacene fragments (polyacene stripes) is investigated at tight-binding and ab initio levels. It is shown that the presence of 60 degrees angles in the molecular skeleton induces the formation of singly-occupied molecular orbitals, whose combination gives rise to quasi-degenerate electronic states. The ab initio investigation requires therefore the use of CAS-SCF and MR-PT approaches. The three types of possible convex polygons having a unique side length (hexagons, rhombuses and triangles) have been considered in this work. The spin multiplicity of these quasi-flat molecular structures is found to be in systematical accord with the Ovchinnikov rule. PMID- 23080082 TI - The effect of ionizing radiation on the homeostasis and functional integrity of murine splenic regulatory T cells. AB - OBJECTIVE: Radiotherapy affects antitumor immune responses; therefore, it is important to study radiation effects on various compartments of the immune system. Here we report radiation effects on the homeostasis and function of regulatory T (Treg) cells, which are important in down-regulating antitumor immune responses. METHODS: C57Bl/6 mice were irradiated with 2 Gy and alterations in splenic lymphocyte fractions analyzed at different intervals. RESULTS: Total CD4+ numbers showed stronger decrease after irradiation than CD4+Foxp3+ Tregs. Tregs were less prone to radiation-induced apoptosis than CD4+Foxp3- T cells. The ratio of CD4+Foxp3- and CD4+Foxp3+ fractions within the proliferating CD4+ pool progressively changed from 74:26 in control animals to 59:41 eleven days after irradiation, demonstrating a more dynamic increase in the proliferation and regeneration of the Treg pool. The CD4+Foxp3+ fraction expressing cell-surface CTLA4, an antigen associated with Treg cell activation increased from 5.3 % in unirradiated mice to 10.5 % three days after irradiation. The expression of IL-10 mRNA was moderately upregulated, while TGF-beta expression was not affected. On the other hand, irradiation reduced Treg capacity to suppress effector T cell proliferation by 2.5-fold. CONCLUSION: Tregs are more radioresistant, less prone to radiation-induced apoptosis, and have faster repopulation kinetics than CD4+Foxp3- cells, but irradiated Tregs are functionally compromised, having a reduced suppressive capacity. PMID- 23080084 TI - Forces and moments generated by the human arm: variability and control. AB - This is an exploratory study of the accurate endpoint force vector production by the human arm in isometric conditions. We formulated three common-sense hypotheses and falsified them in the experiment. The subjects (n = 10) exerted static forces on the handle in eight directions in a horizontal plane for 25 s. The forces were of 4 magnitude levels (10, 20, 30 and 40 % of individual maximal voluntary contractions). The torsion moment on the handle (grasp moment) was not specified in the instruction. The two force components and the grasp moment were recorded, and the shoulder, elbow, and wrist joint torques were computed. The following main facts were observed: (a) While the grasp moment was not prescribed by the instruction, it was always produced. The moment magnitude and direction depended on the instructed force magnitude and direction. (b) The within-trial angular variability of the exerted force vector (angular precision) did not depend on the target force magnitude (a small negative correlation was observed). (c) Across the target force directions, the variability of the exerted force magnitude and directional variability exhibited opposite trends: In the directions where the variability of force magnitude was maximal, the directional variability was minimal and vice versa. (d) The time profiles of joint torques in the trials were always positively correlated, even for the force directions where flexion torque was produced at one joint and extension torque was produced at the other joint. (e) The correlations between the grasp moment and the wrist torque were negative across the tasks and positive within the individual trials. (f) In static serial kinematic chains, the pattern of the joint torques distribution could not be explained by an optimization cost function additive with respect to the torques. Plans for several future experiments have been suggested. PMID- 23080085 TI - Safety behaviours in eating disorders: factor structure and clinical validation of the brief safety behaviours scale. AB - This study examined the utility of a transdiagnostic measure of safety behaviours [Brief Safety Behaviours Scale (BSBS)] in eating disorders. Prior to treatment, a group of 102 women with eating disorders completed the BSBS and well-validated measures of eating pathology, anxiety and intolerance of uncertainty. The BSBS had three factors, suggesting that avoidant, checking and social safety behaviours are distinct constructs in the eating disorders. This three-scale scoring system showed greater clinical precision in correlations with eating pathology than the original two-scale version. The pattern of safety behaviours in the eating disorders is more specific than had previously been shown in other clinical samples. While it is important to consider eating-related safety behaviours in the eating disorders (e.g. restriction, body checking), it is also necessary to consider the role of generic safety behaviours when assessing, formulating and treating eating disorders. PMID- 23080086 TI - Axillary lymphadenectomy for breast cancer and fibrin glue. AB - BACKGROUND: Axillary lymphadenectomy or sentinel biopsy is integral part of breast cancer treatment, yet seroma formation occurs in 15-85% of cases. Among methods employed to reduce seroma magnitude and duration, fibrin glue has been proposed in numerous studies with controversial results. METHODS: Eighty patients underwent quadrantectomy or mastectomy with level I/II axillary lymphadenectomy; a suction drain was fitted in all patients. Fibrin glue spray were applied to the axillary fossa in 40 patients; the other 40 patients were treated conventionally. RESULTS: Suction drainage was removed between post-operative Days 3 and 4. Seroma magnitude and duration were significantly reduced (p=0.004 and 0.02, respectively), and there were fewer evacuative punctures, in patients receiving fibrin glue compared with the conventional treatment group. CONCLUSIONS: Use of fibrin glue does not always prevent seroma formation, but does reduce seroma magnitude, duration and necessary evacuative punctures. PMID- 23080087 TI - The determinants of side branch compromise after main vessel stenting in coronary bifurcation lesions. AB - BACKGROUND AND AIM: The purpose of this analysis was to determine the factors responsible for side branch (SB) ostial stenosis after main vessel stent implantation. METHODS: Theoretical and bench-test bifurcation models with different lengths of carina were created. Bench-test experiments with a flexible bifurcation model were performed for the observation of changes in the bifurcation region after stent implantation. An angiographic analysis of 92 bifurcation lesions (84 patients) was performed to determine the role of theoretical parameters on SB compromise in practice. The theoretically predicted and actual SB compromise were compared in these patients. RESULTS: Bench tests revealed a complex change in the bifurcation region with carina displacement, SB lateral walls stretch and main vessel - SB proximal angle decrease after main vessel stent placement. In an angiographic analysis, actually measured SB% diameter stenosis was larger than expected in 35 (38%) lesions and the measured stenosis was smaller than expected in 49 lesions. Independent predictors of difference between theoretically predicted and observed SB stenosis were carina length mismatch (OR = 2.568, CI 1.336-4.896), main branch reference diameter (OR = 0.314, CI 0.101-0.972), and proximal main vessel - SB angle change after stenting (OR = 0.926, CI 0.870-0.985). In a plot comparing the values of carina length mismatch and deviations from the prediction in SB ostial stenosis, 30% (n = 27) of cases were located in a zone with a shorter carina and more SB compromise than expected, suggesting the role of plaque shift in these cases. CONCLUSIONS: The degree of SB jailing seems to be determined by carina deformation, the length of the carina, and plaque shifting. PMID- 23080088 TI - The effect of stent coating on stent deliverability: direct randomised comparison of drug eluting and bare metal stents using the same stent platform. AB - BACKGROUND: There is certain experimental and clinical evidence indicating that the covering of bare metal stents (BMS) with drug eluting polymers to produce drug eluting stents (DES) results in increased stent stiffness and modifies the mechanical properties of the stent platform. In addition, it has been speculated that the mechanical performance of DES, compared to BMS, may be related to the type of polymer used to cover stents. AIM: We aimed at evaluating the deliverability of DES with a lactate based biodegradable polymer and BMS in patients with stable coronary artery disease in a prospective randomised study. METHODS: One hundred eleven consecutive patients (age: 36-77, mean 58.8 years) scheduled for routine angioplasty due to stable coronary disease were randomised to receive BMS (Chopin II(TM), Balton, Poland) or paclitaxel eluting stent (Chopin Luc(TM), Balton, Poland) using the same metal platform. Only patients scheduled for angioplasty using the direct implantation technique of a single stent were randomised. The exclusion criteria included patients > 80 years, multivessel disease and reference diameter of the target vessel > 3.5 mm. RESULTS: In the BMS group (n = 55; 35 males and 20 females), the mean diameter of implanted stents was 3.09 +/- 0.40 and the mean length was 11.37 +/- 2.80, whereas in the DES group (n = 56; 34 males and 22 females) the mean stent sizes were 3.02 +/- 0.34 and 17.90 +/- 7.38 mm, respectively (p > 0.05 for length). The groups did not significantly differ regarding the frequency of stent implantation to particular coronary vessels. The direct stenting technique was attempted and failed, leading to the stents' implantation after predilatation in five patients in the BMS group and six patients in the DES group. Failure of stent implantation and subsequent implantation of another stent type was observed in no BMS patients and in one DES patient (NS). CONCLUSIONS: Although stent covering with lactate based drug eluting polymer may increase its stiffness, it does not affect its deliverability in patients with stable coronary disease. PMID- 23080089 TI - Detection of heart failure at a primary care practice in a small town in Central Poland. AB - BACKGROUND: Heart failure (HF) is commonly misdiagnosed, and the validity of diagnosis in primary care is poor. According to the guidelines, an electrocardiogram, a chest X-ray and a standard echocardiogram should be obtained and the level of B-type natriuretic peptide (BNP) should be determined in every patient with signs and symptoms suggestive of HF. AIM: We performed a community based study to evaluate the diagnostic evaluation of patients with HF and/or HF risk factors carried out by primary care physicians. METHODS: We screened the adult population of a small Polish town (5521 inhabitants). Inclusion criteria were as follows: age >= 55 years and either the diagnosis of HF or presence of at least one of the following HF risk factors: ischaemic heart disease and/or hypertension with complications and/or diabetes mellitus. RESULTS: A total of 218 patients who met the inclusion criteria were invited to participate in the study and 175 of them (80.3%) were evaluated and followed up for 58 +/- 1 months. The diagnosis of HF was established in 38/175 patients (22%) (Group 1). The signs and symptoms of HF without the formal diagnosis of HF were present in 44/175 patients (25%) (Group 2) and 93/175 patients (53%) had neither HF nor its signs or symptoms (Group 3). During the follow-up, in some of patients from Groups 2 and 3, the diagnosis of HF was established and these patients crossed over to Group 1a. In 2009, there were 56 patients in Group 1a, 37 in Group 2a and 82 in Group 3a. At baseline, in years 2004/2005, echocardiograms were available in 37%, 25% and 17% of the patients in Groups 1, 2 and 3, respectively, chest radiograms in 86%, 54%, 58% of the patients, respectively, and BNP measurements in 5%, 5% and 0% of the patients, respectively. At the end of the follow-up we observed an increased number of diagnostic tests performed but the difference was not statistically significant. CONCLUSIONS: Our study showed a considerable discrepancy between the guidelines and primary practice and underscores the need to change the practical approach to diagnostic investigations, especially echocardiography and BNP measurements in HF patients. PMID- 23080090 TI - [Can the quality of care for people with heart failure be improved?]. PMID- 23080091 TI - Clinical, haemodynamic and echocardiographic features of early cardiac graft dysfunction. AB - BACKGROUND: The main cause of early death after heart transplantation (HTx) is so called early primary or secondary graft failure (GF). The risk of profound GF has not declined in the past decade, as the consequence of the liberalisation of donor acceptance criteria because of the scarcity of donors. It is therefore important to try to diagnose graft failure and recognise the mechanisms of early graft dysfunction. AIM: To establish haemodynamic and echocardiographic criteria of early GF to define patients who should be considered for assist device support or re-transplantation. METHODS: Between January 2000 and March 2009, 116 HTx patients were studied. On the basis of echocardiography and continuous invasive monitoring, three groups were identified: (1) The true graft failure group (GF) consisted of 46 patients; (2) The latent right ventricular (RV) dysfunction group (RV-D) consisted of 25 patients with small left ventricular (LV) chamber (< 39 mm) and RV ejection fraction (RVEF) < 50%; (3) The control group consisted of 45 consecutive HTx patients without any haemodynamic complications. RESULTS: Postoperatively, only the GF group required large doses of norepinephrine (> 0.3 MUmg/kg/min) and inhalative NO (40 ppm). Nevertheless, right and left filling pressures were significantly higher than in the controls (right 12 +/- 3.6 vs. 9.0 +/- 2 and left atrial pressure 13.0 +/- 3.2 vs. 9.6 +/- 2 mm Hg, both p < 0.001). Cardiac index was significantly smaller (2.9 +/- 0.7 vs. 3.7 +/- 0.9, p < 0.001) but neither pulmonary artery pressure (29.5 +/- 6 vs. 29.7 +/- 7 mm Hg) nor transpulmonary gradient (6 +/- 5 vs. 5.1 +/- 5 mm Hg) nor pulmonary vascular resistance (273 +/- 97 vs. 287 +/- 144 dyn * s * cm-5) differed significantly from those of the control group. In the GF group, LV end diastolic dimension (LVEDD) was significantly smaller and function poorer than in controls (39.8 +/- 5 vs. 44.4 +/- 5 mm, respectively, p = 0.001). RV function was also significantly worse (RVEF 42.2 +/- 14% vs. 56.0 +/- 9%), respectively, p = 0.001), whereas RV dimension did not differ significantly. Mechanical support after failure of the initial medical treatment was necessary in 37% of patients; 29 (63.0%) patients from the GF group died, the cause of death being sepsis with multi-organ failure. In the RV-D group, remodelling was quite similar but LVEF was excellent and maximal systolic velocity from the posterior wall was significantly higher than in GF. No death occurred. CONCLUSIONS: True early GF represents a grave haemodynamic situation with high mortality. Bedside echocardiography helps to distinguish between latent RV dysfunction and true GF. PMID- 23080092 TI - Association between insulin like growth factor-1 and lipoprotein metabolism in stable angina patients on statin therapy: a pilot study. AB - BACKGROUND AND AIM: The aim of this study was to test whether there was an association between systemic levels of insulin like growth factor-1 (IGF-1), IGF 1 binding protein-3 (IGFBP3) and selected parameters of lipid metabolism depending on the lipid-lowering therapy. This work was conducted in patients described by us previously who had either highly probable, or documented, coronary artery disease, and controlled serum lipids with prolonged statin therapy. METHODS: The study was conducted among 140 patients undergoing coronary angiography. The following parameters were measured: LDL- and HDL-cholesterol levels, TG, TC, apoB-100, apoA1, Lp(a) and IGF-1 and IGFBP3, as well as the level of oxidation products of proteins and lipids. RESULTS AND CONCLUSIONS: In the group of patients with LDL target up to 100 mg/dl and statins use, as well as in the entire population, IGF-1 and IGFBP3 were associated with protein oxidation products and Lp(a). Additionally, in the whole studied group, IGF-1 was associated with TG and LDL. More differences were observed when we used multivariate analysis. Even then, IGF-1 and IGFBP3 in the group with LDL up to 100 mg/dL, as well as in the entire group, were associated with protein oxidation products, Lp(a) and with quantitative arteriosclerosis scale (Gensini score). These results seem to confirm our previous findings, wherein significantly higher levels of systemic IGF-1 were found in patients with advanced coronary atherosclerosis. PMID- 23080093 TI - IgG, IgM and inflammatory markers serum concentration in patients with acute coronary syndrome: a pilot study. AB - BACKGROUND: A number of biomarkers have been found that might help to predict the risk of acute coronary syndrome (ACS) in adults. AIM: To analyse the association between immunoglobulins concentration and other inflammatory markers such as C reactive protein (CRP) and fibrinogen that show correlation with the risk of ACS. METHODS: The study population consists of 52 consecutive patients with ST segment elevation myocardial infarction (STEMI) or unstable angina/non-STEMI. Concentrations of total protein, albumin, alpha-1 globulin, beta globulin, gamma protein, immunoglobulin in class A (IgA), G (IgG), M (IgM) and E (IgE), creatinine kinase (CK), creatinine kinase MB (CK-MB), CRP and fibrinogen were quantified. RESULTS: In the ACS patients, there was a significant increase in gamma globulin, CRP and fibrinogen. IgG was elevated only in the STEMI group and correlated with fibrinogen (R = 0.48, p < 0.01). CONCLUSIONS: 1. IgG appears to be the only immunoglobulin associated with ACS in the STEMI group. 2. Fibrinogen reveals features of a reactive biomarker of ACS. 3. CRP appears to be closely related to the causative process in coronary artery disease patients. PMID- 23080094 TI - [Immunoglobulin E - marker for development of coronary heart disease?]. PMID- 23080095 TI - Attitudes towards healthy lifestyle promotion in mass media in the Polish adult population. AB - BACKGROUND: Healthy lifestyle promotion in mass media is a very important way to diminish cardiovascular diseases morbidity and mortality. Effectiveness of healthy lifestyle promotion can, among others, depend on people's attitudes towards it. AIM: To characterise the Pole's attitudes towards healthy lifestyle promotion in mass media and identify their socio-demographic predictors. METHODS: A research project consisted of qualitative and quantitative studies. Qualitative research containing 30 individual in-depth interviews was carried out from June 2007 to April 2008. A survey on national Polish sample including 934 adults was conducted in November 2008. In the study there was used the scale to estimate the attitudes towards healthy lifestyle promotion in mass media containing four subscales: appraisal of the idea of healthy lifestyle promotion in mass media (regarding a need of healthy lifestyle promotion in mass media), appraisal of its practice (which means credibility as well as effectiveness manifested in the change of people's behaviour), propensity to receive messages and propensity to avoid messages promoting healthy lifestyle. RESULTS: Above 71% of Poles is characterised by a positive attitude towards healthy lifestyle promotion in mass media. As much as 87% of people positively evaluate its idea; about 70% have high propensity to receive messages promoting healthy lifestyle and only 21% is characterised by high propensity to avoid them. On the contrary, only 29% of the respondents positively evaluate the practice of healthy lifestyle promotion in mass media. The results of multivariable linear regression analysis show that being a woman and having higher education are the predictors of relatively positive attitude towards healthy lifestyle promotion in mass media while living in the biggest cities and being executives or intellectuals are related to more negative attitude. CONCLUSIONS: Results indicate the need to enhance credibility of messages promoting healthy lifestyle as well as create ones that would better reach men and low-educated people. PMID- 23080096 TI - [Angiographic and stress echocardiographic evaluation after surgical treatment of Bland-White-Garland syndrome and mitral valve insufficiency]. AB - We report case of 58-year-old male patient with severe mitral insufficiency in whom in preoperative angiography anomalous left anterior descending coronary artery arising from pulmonary artery was revealed. Patient successfully underwent mitral valve replacement, ligation and bypass of left anterior descending artery. Eighteen months after surgery control exercise echocardiography and angiography were performed to evaluate coronary flow, valve prosthesis and left ventricle function. PMID- 23080097 TI - [Severe left main stem stenosis in preoperative cineangiography - acute aortic dissection as intraoperative final diagnosis]. AB - Acute aortic dissection occurs in 0.5-2.95 cases per 100,000 citizens-year. Although the modern diagnostic tools help in more accurate diagnosis, the missleading findings still occure. We present a case of a 72-year-old man who was admitted to cardiology ward due to persistent chest pain. Initial diagnosis of acute coronary syndrome was confirmed by electrocardiography (ST segment depression in V(1)-V(5) leads), transthoracic echocardiography (anterior wall dyskinesis) and laboratory tests (Tn-I: 6.92 MU/L, CK-MB: 226.24 ng/mL). Due to aortic aneurysm history, computer tomography (CT) was performed. Neither CT nor transthoracic echocardiography were negative for aortic dissection. Intraoperatively aortic dissection limited to Valsalva sinuses was found. Left main orifice was blindly closed followed by Bentall procedure and coronary artery revascularisation. PMID- 23080098 TI - [Heart failure in female patient in peripartum period - how to determine the aetiology?]. AB - Peripartum cardiomyopathy (PPM) is an acquired disease of increasing incidence. Its diagnosis and treatment is often problematic. We report a case of 31-year old woman who was diagnosed with PPM three weeks after delivery and died nine months later despite proper therapy. PMID- 23080099 TI - [Assessment of left atrial size and function]. PMID- 23080101 TI - [Current opinions on mechanisms of energetic abnormalities in heart. Significance of the PPARalpha expression and therapeutic objects]. PMID- 23080100 TI - [New oral anticoagulants - sunset for warfarin in therapy of atrial fibrillation]. PMID- 23080102 TI - [Abnormal electrocardiogram with signs of an old infero-lateral myocardial infarction scar. Hypertrophic cardiomyopathy has not one name]. AB - We described a case of a 59-year-old woman without clinical significance. Abnormal resting electrocardiogram (ECG) was the cause of the cardiology consultation. The patient complained of the poor exercise tolerance for a year. The resting ECG showed: sinus rhythm 58/min, left axis deviation (QRS axis: 79(o)), PQ interval: 108 ms, P wave axis: 77(o), QRS duration: 106 ms, QT/QTc interval: 452/450 ms. QS morphology in leads: II, III, aVF and V(5)-V(6) with QRS (QS) fragmentation. The Q wave in lead V(4) with its duration of 20 ms, and amplitude of 2 mm. The poor progression of R wave in leads V2 and V(3). Positive, symmetric T waves in leads: II, III, aVF and V(5)-V(5). Negative T wave in leads I and aVL. Increased S wave amplitude in leads: V(2) - 33 mm, V(3) - 29 mm. Positive QRS direction in lead aVR. What should be taken into consideration in differential diagnosis? 1) previous infero-lateral myocardial infarction; 2) myocardial hypertrophy; 3) possibility of preexcitation. Based on echocardiography hypertrophic cardiomyopathy was recognised with marked septum hypertrophy to 28 mm and with normal thickness of posterior wall (9 mm). The magnetic resonance of the heart confirmed the echocardiography findings. PMID- 23080103 TI - [ECG in hypertrophic cardiomyopathy--facts, opinions, hypotheses]. PMID- 23080104 TI - [Non-functional lead as a cause of detection disturbances in implantable cardioverter-defibrillator]. AB - The article presents the case of a patient treated with implantable cardioverter defibrillator, in whom an additional lead (integrated bipolar) was implanted because of the damage to the ventricular lead. Interactions between the electrodes led to detection disturbances. The patient required the removal of the non-functional lead. PMID- 23080105 TI - [Efficacy and safety of a new antiplatelet agent - vorapaxar: TRA2P-TIMI 50]. PMID- 23080107 TI - Acute coronary artery thrombosis during the postpartum period complicated by cardiogenic shock and AH1N1 infection. PMID- 23080108 TI - A pericardial cyst case evaluated with real time 3D transoesophageal echocardiography. PMID- 23080109 TI - [Optimum heart rate - the current goal of cardiovascular therapy. Position statement of the Polish Cardiac Society Working Group on Cardiovascular Drug Therapy]. PMID- 23080110 TI - [Standardised designation of commercial troponin immunoassays]. PMID- 23080111 TI - [Response]. PMID- 23080112 TI - C9ORF72 expansion is not a significant cause of sporadic spinocerebellar ataxia. PMID- 23080113 TI - Anti-erythropoietin receptor antibodies in systemic lupus erythematosus patients with anemia. AB - Anemia is a common hematologic abnormality in systemic lupus erythematosus (SLE). An inadequate erythropoietin (EPO) response in SLE patients with anemia has been described that may be due to the presence of antibodies to EPO in SLE patients. However, whether anemia in patients with SLE is related to antibodies to EPO receptor (EPOR) has not yet been investigated. We enlisted 169 consecutive patients with SLE and 45 normal individuals to investigate the existence and importance of circulating autoantibodies to EPOR in sera from patients with SLE. In all patients with SLE, the disease activity was evaluated by using the SLE disease activity index SLEDAI. Anti-EPOR antibodies were detected by using an enzyme-linked immunosorbent assay (ELISA). A higher frequency of anti-EPOR antibodies was observed in SLE patients than in healthy controls (18.3% vs 2.2%, p = 0.007). Moreover, anti-EPOR antibodies were detected in 22 of 69 (31.9%) SLE patients with anemia and in only nine of 100 (9.0%, p < 0.001) in those without. Furthermore, the patients with anti-EPOR antibodies exhibited more severe anemia and often presented as microcytic anemia (p = 0.001). Finally, anti-EPOR antibodies seemed more likely to occur in patients with rash (p = 0.008), lower levels of C(3) component (p = 0.01), higher titer of anti-dsDNA antibodies (p < 0.001) and higher disease activity scores (p = 0.024). The results of this study suggest that anti-EPOR antibodies might play a vital role in SLE patients developing anemia because of the higher incidence of antibodies to EPOR found in SLE patients with anemia. Thus, there might be clinical value in detecting anti EPOR antibodies in SLE patients with anemia. Therefore, the pathologic role of the antibodies in inducing anemia needs to be established in future studies. PMID- 23080114 TI - Discriminative modelling of context-specific amino acid substitution probabilities. AB - MOTIVATION: Protein sequence searching and alignment are fundamental tools of modern biology. Alignments are assessed using their similarity scores, essentially the sum of substitution matrix scores over all pairs of aligned amino acids. We previously proposed a generative probabilistic method that yields scores that take the sequence context around each aligned residue into account. This method showed drastically improved sensitivity and alignment quality compared with standard substitution matrix-based alignment. RESULTS: Here, we develop an alternative discriminative approach to predict sequence context specific substitution scores. We applied our approach to compute context-specific sequence profiles for Basic Local Alignment Search Tool (BLAST) and compared the new tool (CS-BLASTdis) to BLAST and the previous context-specific version (CS BLASTgen). On a dataset filtered to 20% maximum sequence identity, CS-BLASTdisis was 51% more sensitive than BLAST and 17% more sensitive than CS-BLASTgenin, detecting remote homologues at 10% false discovery rate. At 30% maximum sequence identity, its alignments contain 21 and 12% more correct residue pairs than those of BLAST and CS-BLASTgen, respectively. Clear improvements are also seen when the approach is combined with PSI-BLAST and HHblits. We believe the context-specific approach should replace substitution matrices wherever sensitivity and alignment quality are critical. PMID- 23080115 TI - Human protein-protein interaction prediction by a novel sequence-based co evolution method: co-evolutionary divergence. AB - MOTIVATION: Protein-protein interaction (PPI) plays an important role in understanding gene functions, and many computational PPI prediction methods have been proposed in recent years. Despite the extensive efforts, PPI prediction still has much room to improve. Sequence-based co-evolution methods include the substitution rate method and the mirror tree method, which compare sequence substitution rates and topological similarity of phylogenetic trees, respectively. Although they have been used to predict PPI in species with small genomes like Escherichia coli, such methods have not been tested in large scale proteome like Homo sapiens. RESULT: In this study, we propose a novel sequence based co-evolution method, co-evolutionary divergence (CD), for human PPI prediction. Built on the basic assumption that protein pairs with similar substitution rates are likely to interact with each other, the CD method converts the evolutionary information from 14 species of vertebrates into likelihood ratios and combined them together to infer PPI. We showed that the CD method outperformed the mirror tree method in three independent human PPI datasets by a large margin. With the arrival of more species genome information generated by next generation sequencing, the performance of the CD method can be further improved. AVAILABILITY: Source code and support are available at http://mib.stat.sinica.edu.tw/LAP/tmp/CD.rar. PMID- 23080116 TI - NARROMI: a noise and redundancy reduction technique improves accuracy of gene regulatory network inference. AB - MOTIVATION: Reconstruction of gene regulatory networks (GRNs) is of utmost interest to biologists and is vital for understanding the complex regulatory mechanisms within the cell. Despite various methods developed for reconstruction of GRNs from gene expression profiles, they are notorious for high false positive rate owing to the noise inherited in the data, especially for the dataset with a large number of genes but a small number of samples. RESULTS: In this work, we present a novel method, namely NARROMI, to improve the accuracy of GRN inference by combining ordinary differential equation-based recursive optimization (RO) and information theory-based mutual information (MI). In the proposed algorithm, the noisy regulations with low pairwise correlations are first removed by using MI, and the redundant regulations from indirect regulators are further excluded by RO to improve the accuracy of inferred GRNs. In particular, the RO step can help to determine regulatory directions without prior knowledge of regulators. The results on benchmark datasets from Dialogue for Reverse Engineering Assessments and Methods challenge and experimentally determined GRN of Escherichia coli show that NARROMI significantly outperforms other popular methods in terms of false positive rates and accuracy. AVAILABILITY: All the source data and code are available at: http://csb.shu.edu.cn/narromi.htm. PMID- 23080117 TI - Lengthening of 3'UTR increases with morphological complexity in animal evolution. AB - MOTIVATION: Evolutionary expansion of gene regulatory circuits seems to boost morphological complexity. However, the expansion patterns and the quantification relationships have not yet been identified. In this study, we focus on the regulatory circuits at the post-transcriptional level, investigating whether and how this principle may apply. RESULTS: By analysing the structure of mRNA transcripts in multiple metazoan species, we observed a striking exponential correlation between the length of 3' untranslated regions (3'UTR) and morphological complexity as measured by the number of cell types in each organism. Cellular diversity was similarly associated with the accumulation of microRNA genes and their putative targets. We propose that the lengthening of 3'UTRs together with a commensurate exponential expansion in post-transcriptional regulatory circuits can contribute to the emergence of new cell types during animal evolution. PMID- 23080118 TI - Assessing the relationship between conservation of function and conservation of sequence using photosynthetic proteins. AB - MOTIVATION: Assessing the false positive rate of function prediction methods is difficult, as it is hard to establish that a protein does not have a certain function. To determine to what extent proteins with similar sequences have a common function, we focused on photosynthesis-related proteins. A protein that comes from a non-photosynthetic organism is, undoubtedly, not involved in photosynthesis. RESULTS: We show that function diverges very rapidly: 70% of the close homologs of photosynthetic proteins come from non-photosynthetic organisms. Therefore, high sequence similarity, in most cases, is not tantamount to similar function. However, we found that many functionally similar proteins often share short sequence elements, which may correspond to a functional site and could reveal functional similarities more accurately than sequence similarity. CONCLUSIONS: These results shed light on the way biological function is conserved in evolution and may help improve large-scale analysis of protein function. PMID- 23080119 TI - CDRUG: a web server for predicting anticancer activity of chemical compounds. AB - Cancer is the leading cause of death worldwide. Screening anticancer candidates from tens of millions of chemical compounds is expensive and time-consuming. A rapid and user-friendly web server, known as CDRUG, is described here to predict the anticancer activity of chemical compounds. In CDRUG, a hybrid score was developed to measure the similarity of different compounds. The performance analysis shows that CDRUG has the area under curve of 0.878, indicating that CDRUG is effective to distinguish active and inactive compounds. PMID- 23080120 TI - Prenatal diagnosis of congenital heart disease: impact of mode of delivery on neonatal outcome. AB - OBJECTIVE: We sought to evaluate the impact of mode of delivery (MOD) on early outcome for neonates diagnosed prenatally with major forms of congenital heart disease (CHD). METHODS: We retrospectively studied infants admitted, over a 2 year period, to a single institution for cardiac intervention. Infants were grouped on the basis of timing of diagnosis (prenatal/postnatal) and MOD--planned (induced labor or planned cesarean delivery) versus spontaneous labor. Multivariate logistic regression was used to evaluate independent predictors for MOD and early outcomes. RESULTS: Of 329 patients, 45% received a prenatal diagnosis of CHD. A prenatal diagnosis of CHD increased the likelihood for planned delivery [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.6 to 4.5, p < 0.001]. Newborns prenatally diagnosed with CHD were more likely to have been delivered between 8 am and 6 pm, Monday through Friday (OR 2.3, 95% CI 1.1 to 4.8, p = 0.019). However, MOD had no statistical impact on Apgar score, duration of pre-operative intubation, and survival to surgery or to discharge. The Risk Adjustment for Congenital Heart Surgery 1 surgical mortality score was the only independent predictor of hospital mortality. CONCLUSIONS: In our experience, although a prenatal diagnosis of CHD decreased the likelihood of spontaneous labor, MOD had no demonstrable impact on neonatal outcome. PMID- 23080122 TI - The IMGT/HLA database. AB - It is 14 years since the IMGT/HLA database was first released, providing the HLA community with a searchable repository of highly curated HLA sequences. The HLA complex is located within the 6p21.3 region of human chromosome 6 and contains more than 220 genes of diverse function. Of these, 21 genes encode proteins of the immune system that are highly polymorphic. The naming of these HLA genes and alleles and their quality control is the responsibility of the World Health Organization Nomenclature Committee for Factors of the HLA System. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute, we are able to provide public access to these data through the website http://www.ebi.ac.uk/imgt/hla/. Regular updates to the website ensure that new and confirmatory sequences are dispersed to the HLA community and the wider research and clinical communities. This article describes the latest updates and additional tools added to the IMGT/HLA project. PMID- 23080123 TI - Acromegaly revealed by 18FDG-PET/CT in a plasmocytoma patient. PMID- 23080121 TI - Mre11 ATLD17/18 mutation retains Tel1/ATM activity but blocks DNA double-strand break repair. AB - The Mre11 complex (Mre11-Rad50-Nbs1 or MRN) binds double-strand breaks where it interacts with CtIP/Ctp1/Sae2 and ATM/Tel1 to preserve genome stability through its functions in homology-directed repair, checkpoint signaling and telomere maintenance. Here, we combine biochemical, structural and in vivo functional studies to uncover key properties of Mre11-W243R, a mutation identified in two pediatric cancer patients with enhanced ataxia telangiectasia-like disorder. Purified human Mre11-W243R retains nuclease and DNA binding activities in vitro. X-ray crystallography of Pyrococcus furiosus Mre11 indicates that an analogous mutation leaves the overall Mre11 three-dimensional structure and nuclease sites intact but disorders surface loops expected to regulate DNA and Rad50 interactions. The equivalent W248R allele in fission yeast allows Mre11 to form an MRN complex that efficiently binds double-strand breaks, activates Tel1/ATM and maintains telomeres; yet, it causes hypersensitivity to ionizing radiation and collapsed replication forks, increased Rad52 foci, defective Chk1 signaling and meiotic failure. W248R differs from other ataxia telangiectasia-like disorder analog alleles by the reduced stability of its interaction with Rad50 in cell lysates. Collective results suggest a separation-of-function mutation that disturbs interactions amongst the MRN subunits and Ctp1 required for DNA end processing in vivo but maintains interactions sufficient for Tel1/ATM checkpoint and telomere maintenance functions. PMID- 23080124 TI - A new three-dimensional metal-organic framework constructed from 9,10-anthracene dibenzoate and Cd(II) as a highly active heterogeneous catalyst for oxidation of alkylbenzenes. AB - A novel three-dimensional (3D) porous metal-organic framework, {[Cd(L)(H(2)O)].3H(2)O}(infinity) (1) (L-H(2) = 4,4'-(9,10 anthracenediyl)dibenzoic acid), was synthesized. 1 has a 3D framework formed by L connectors and the infinite {Cd(O(2)CR)(2)}(infinity) secondary building units (SBUs). Compound 1 was characterized by IR spectroscopy, thermogravimetry, single crystal, elemental analyses and powder X-ray diffraction methods. We then investigated its adsorption, catalysis and luminescent properties. Framework 1' exhibits permanent porosity (Langmuir surface area, 324 m(2) g(-1)), high thermal stability (up to 380 degrees C), and highly active properties for oxidation of alkylbenzenes. The catalytic results reveal that 1' is indeed an efficient heterogeneous catalyst with 100% selectivity. To the best of our knowledge, it is the first report that oxidation reactions of alkylbenzenes were performed using Cd(II) with unsaturated coordination spheres as active sites. PMID- 23080126 TI - Electroactive tetrathiafulvalenyl-1,2,3-triazoles by click chemistry: Cu- versus Ru-catalyzed azide-alkyne cycloaddition isomers. AB - Two series of 4- and 5-tetrathiafulvalenyl-1,2,3-triazoles, as multifunctional ligands and precursors for molecular materials, have been synthesized by copper- or ruthenium-based "click" chemistry. The solid-state structures of three ligands and two Cu(II) complexes were determined. Large differences in the electron donating properties between the 1,4- and 1,5-isomers were evidenced by cyclic voltammetry. Theoretical calculations support this observation and allow the assignment of the electronic transitions observed in UV/Vis spectra of the ligands. PMID- 23080125 TI - Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer. AB - PURPOSE: Prostate cells are dependent on androgens for growth and proliferation. Androgen deprivation therapy is the recommended treatment for advanced/metastatic prostate cancer. Under this therapy, prostate cancer will inevitably progress to castration resistant prostate cancer (CRPC). Despite putative castration resistance, testosterone might still play a crucial role in the progression of CRPC. The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings. METHODS: In vitro, the effect of testosterone and the non-aromatizable androgen methyltrienolone on migration, invasion and proliferation of a castration resistant prostate cancer rat cell line (Dunning R3327-MATLyLu) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67. Androgen receptor status was determined using Western blot. In vivo, Copenhagen rats were divided in four groups (males, females, castrated males and females with testosterone suppletion) and inoculated with MATLyLu cells. Tumor size was assessed daily. RESULTS: Testosterone increased cell migration and invasion in a concentration-dependent manner in vitro. Testosterone did not affect in vitro cell proliferation. No difference was shown between the effect of testosterone and methyltrienolone. In vivo, in groups with higher levels of circulating testosterone, more rats had (micro)metastases compared with groups with low levels of testosterone. No effect was observed on primary tumor size/growth. CONCLUSIONS: Despite assumed castration resistance, progression of prostate cancer is still influenced by androgens. Therefore, continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted. PMID- 23080127 TI - An architecture for diversity-aware search for medical web content. AB - OBJECTIVES: The Web provides a huge source of information, also on medical and health-related issues. In particular the content of medical social media data can be diverse due to the background of an author, the source or the topic. Diversity in this context means that a document covers different aspects of a topic or a topic is described in different ways. In this paper, we introduce an approach that allows to consider the diverse aspects of a search query when providing retrieval results to a user. METHODS: We introduce a system architecture for a diversity-aware search engine that allows retrieving medical information from the web. The diversity of retrieval results is assessed by calculating diversity measures that rely upon semantic information derived from a mapping to concepts of a medical terminology. Considering these measures, the result set is diversified by ranking more diverse texts higher. RESULTS: The methods and system architecture are implemented in a retrieval engine for medical web content. The diversity measures reflect the diversity of aspects considered in a text and its type of information content. They are used for result presentation, filtering and ranking. In a user evaluation we assess the user satisfaction with an ordering of retrieval results that considers the diversity measures. CONCLUSIONS: It is shown through the evaluation that diversity-aware retrieval considering diversity measures in ranking could increase the user satisfaction with retrieval results. PMID- 23080128 TI - Examining the neural impact of pediatric concussion: a scoping review of multimodal and integrative approaches using functional and structural MRI techniques. AB - PURPOSE OF REVIEW: This study presents the findings from a scoping review of recent, original research investigating changes in brain structure and/or function following pediatric concussion or mild traumatic brain injury (mTBI) using MRI and functional MRI techniques. RECENT FINDINGS: Our scoping review identified only five studies, two of which were focused specifically on sports related concussion. A common finding across studies was that traditional structural methods such as anatomical T1, T2, and even susceptibility-weighted MRI failed to reveal abnormalities in brain structure following pediatric concussion/mTBI. Although data suggest alterations in brain function associated with concussion, correlation with changes in performance is inconsistently found, possibly because of the use of compensatory cerebral mechanisms or alternate pathways while the brain is still dysfunctional. SUMMARY: In conclusion, the literature describing neuroimaging investigations of pediatric concussion is too scarce to allow the formulation of definitive conclusions regarding the impact of concussion on the developing brain. There is a dire need for longitudinal, multisite investigations focused on a wider age range and recovery period. PMID- 23080129 TI - Clinical application of whole exome sequencing: not (yet) ready for primetime. PMID- 23080130 TI - A pediatric perspective on concussion pathophysiology. AB - PURPOSE OF REVIEW: According to recent Centers for Disease Control (CDC) data, the annual incidence of traumatic brain injury (TBI) in the United States is 1.6 3.2 million, of which the majority is classified as mild. Over half of these injuries occur in the pediatric population, and can often be attributed to a sports-related mechanism. Although postconcussion symptoms are usually short lived, more lasting deficits can occur, which can be particularly disruptive to the developing brain. Recent literature detailing the pathophysiology of mild TBI (mTBI), with attention to pediatric studies, is presented. RECENT FINDINGS: Although concussion generally does not produce any structural damage on conventional computed tomography (CT) or MRI, advanced neuroimaging modalities reveal microstructural and functional neurobiological changes. Diffuse axonal injury, metabolic impairment, alterations in neural activation and cerebral blood flow perturbations can occur and may contribute to acute symptomatology. Although these physiological changes usually recover to baseline in 7-10 days, sustaining recurrent injury before full recovery may increase the potential for persistent deficits. SUMMARY: Understanding the pathophysiology of concussion in the pediatric population can potentially open therapeutic avenues to decrease symptom persistence and prevent further injury. Future studies in the pediatric population are necessary given the pathophysiologic differences between the developing and adult brains. PMID- 23080131 TI - Sun protection, probiotics and parental smoking cessation. AB - PURPOSE OF REVIEW: This article addresses three areas where new research demonstrates the potential to impact the health of children and adolescents: sun protection, probiotic use, and parental smoking cessation. RECENT FINDINGS: Skin cancer rates are rising, and sun exposure in childhood and exposure to tanning beds are important preventable risk factors. Research on the use of probiotics to treat a variety of intestinal and nonintestinal diseases is expanding. By counseling parents about smoking cessation, pediatricians can assist in decreasing childhood exposure to harmful second-hand and third-hand smoke. SUMMARY: New research on probiotic use in children shows its potential in prevention and treatment of common childhood illnesses. By finding ways to educate patients and parents on the dangers of ultraviolet radiation and smoke exposure, pediatricians can improve both short-term and long-term health of their patients. PMID- 23080132 TI - Neuropsychological evaluation and management of sport-related concussion. AB - PURPOSE OF REVIEW: Sport-related concussion (SRC) is common in children and adolescents. Although symptoms are typically self-limiting and short-lived, some individuals suffer persistent negative outcomes. The risk of repeat injury and prolonged recovery can be reduced by accurate diagnosis and management. In the absence of reported symptoms, neuropsychological assessment has been identified as objective means of determining dysfunction following concussion. Most research to date has focused on adult populations. This review summarizes the literature regarding neuropsychological evaluation of SRC in the pediatric athlete. RECENT FINDINGS: As with adult populations, neuropsychological evaluation of children and adolescents diagnosed with SRC has documented skills and abilities that are particularly sensitive to head injury. Difficulties with attention and concentration, speed of information processing, and memory are commonly reported in the literature. There is also some evidence to suggest that younger children are particularly vulnerable to neurologic insult and are at greater risk for secondary consequences. Although such findings argue for more conservative management, the availability of diagnostic tools, including computerized neurocognitive assessment batteries, is limited. SUMMARY: The neuropsychological impact of SRC on functioning is well established. Because documented deficits have the potential to interfere with critical aspects of normal development in children and adolescents, accurate diagnosis and management of SRC are especially important. Despite some limitations, there is good evidence to support the use of neuropsychological assessment to inform treatments and return-to-play decision making. PMID- 23080133 TI - New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma. AB - PURPOSE: Propranolol, a non-selective beta-adrenergic receptor blocker, has been used for the treatment of the patients with hypertension for more than 50 years. There are several in vitro and in vivo evidences that beta-adrenergic receptor antagonists inhibit proliferation and angiogenesis and also increase apoptosis in breast, skin, and colon cancers. The aim of this study was to investigate the cytotoxic and apoptotic effects of propranolol and the genes involved in propranolol-induced apoptosis in multiple myeloma cells. METHODS: Time-dependent antiproliferation and apoptotic effects of propranolol were subsequently determined by MTT cell proliferation assay, changes in caspase-3 activity, loss of mitochondrial membrane potential (MMP), and also the localization of phosphatidylserine in the plasma membrane. Changes in expression levels of NF KappaB pathway were examined by qRT-PCR array. RESULTS: IC50 values of propranolol on U266 cells were calculated as 141, 100, and 75 MUM after 24-, 48-, and 72-h propranolol exposure, respectively. There were significant increases in caspase-3 activity, loss of MMP, and increases in apoptotic cell population in response to propranolol in U266 cells in a time- and dose-dependent manner. There were increases in expression levels of BCL10, TRAF family members, interleukins, TLR1-4, TNFRSF10B, NF-kappaB, and the inhibitors of NF-kappaB genes, and significant decreases in expression levels of Bcl-2 in response to propranolol treatment were observed. CONCLUSION: These results revealed that propranolol has antiproliferative and apoptotic effects on multiple myeloma cells. Being supported with in vivo analyses, propranolol can be a good and economical way to treat multiple myeloma patients. PMID- 23080134 TI - Metastatic esophagogastric adenocarcinoma: trends in first-line treatment and predictive factors for the implementation of HER2 testing in clinical practice during the first year after trastuzumab market approval. AB - PURPOSE: Little is known about the use of first-line chemotherapy in clinical practice in patients with advanced esophagogastric adenocarcinoma, and no data have been published regarding potential obstacles for the implementation of molecular testing for targeted agents in this patient group. Here, we sought to evaluate factors influencing treatment decisions with special focus on the implementation of HER2 testing during the first year after trastuzumab market approval in Germany. METHODS: A total of 754 patients undergoing treatment decisions for palliative first-line therapy in 2010 were documented using Therapiemonitor((r)). Drug use and intensity of first-line treatment were analyzed. Data on HER2 testing and test algorithm are described, and variables influencing HER2 testing were selected using bivariate analysis. Significant factors were included in a multivariate logistic regression analysis. RESULTS: Compared with previous years, treatment intensity has further increased. The use of chemotherapy triplets rose from 10.1 % in 2006 to 60.3 % in 2010. In 2010, 49.1 % of patients were tested for HER2 and in 52.2 % of these patients the currently proposed test algorithm was used. Using multivariate logistic regression analysis age >=67 years and "initiating institution: practice" were found to negatively impact the likelihood of HER2 testing, while treatment goal "prevention of progression", multiple metastases and a Karnofsky status >80 % showed positive correlation with HER2 testing. CONCLUSION: The tendency to use more intensive first-line chemotherapy regimens in patients with advanced esophagogastric adenocarcinoma continued in 2010. Only a minority of patients had an access to the appropriate molecular diagnostics and therefore to treatment with trastuzumab. The access was limited due to the preselection following individual, clinical and institutional factors. PMID- 23080135 TI - Rare disease clinical research network's urea cycle consortium delivers a successful clinical trial to improve alternate pathway therapy. PMID- 23080137 TI - Neuronal mechanisms of oxygen chemoreception: an invertebrate perspective. AB - Since the evolution of aerobic metabolism, cellular requirements for molecular oxygen have been the major driver for the development of sophisticated mechanisms underlying both invertebrate and vertebrate respiratory behaviour. Among the most important characteristics of respiration is its adaptability, which allows animals to maintain oxygen homeostasis over a wide range of environmental and metabolic conditions. In all animals, the respiratory behaviour is controlled by neural networks often termed respiratory central pattern generators (rCPG). While rCPG neurons are intrinsically capable of generating rhythmical outputs, the respiratory needs are generally "sensed" by either central or peripheral chemoreceptive neurons. The mechanisms by which chemoreceptors respond to changes in oxygen and modulate central respiratory control centers have been the focus of decades of research. However, our understanding of these mechanisms has been limited due to an inability to precisely locate oxygen chemoreceptor populations, combined with the overwhelming complexity of vertebrate neural circuits. Although mammalian models remain the gold standard for research in general, invertebrates do nevertheless offer greatly simplified neural networks that share fundamental similarities with vertebrates. The following review will provide evidence for the existence of oxygen chemoreceptors in many invertebrate groups and reveal the mechanisms by which these neurons may "perceive" environmental oxygen and drive central rCPG activity. For this, we will specifically highlight an invertebrate model, the pond snail Lymnaea stagnalis whose episodic respiratory behaviour resembles that of diving mammals. The rCPG neurons have been identified and fully characterized in this model both in vivo and in vitro. The Lymnaea respiratory network has also been reconstructed in vitro and the contributions of individual rCPG neurons towards rhythm generation characterized through direct intracellular recordings. We now provide evidence for the presence of genuine peripheral oxygen chemoreceptors in Lymnaea, and demonstrate that these neurons respond to hypoxia in a manner analogous to that of mammalian carotid bodies. These chemoreceptor cells not only drive the activity of the rCPG neurons but their synaptic connections also exhibit hypoxia-induced plasticity. The lessons learned from this model will likely reveal fundamental principles underlying both peripheral and central respiratory control mechanisms, which may be conserved in both invertebrate and vertebrate species. PMID- 23080136 TI - The role of hypoxia-inducible factors in oxygen sensing by the carotid body. AB - Chronic intermittent hypoxia (IH) associated with sleep-disordered breathing is an important cause of hypertension, which results from carotid body-mediated activation of the sympathetic nervous system. IH triggers increased levels of reactive oxygen species (ROS) in the carotid body, which induce increased synthesis and stability of hypoxia-inducible factor 1alpha (HIF-1alpha) and calpain-dependent degradation of HIF-2alpha. HIF-1 activates transcription of the Nox2 gene, encoding NADPH oxidase 2, which generates superoxide. Loss of HIF-2 activity leads to decreased transcription of the Sod2 gene, encoding manganese superoxide dismutase, which converts superoxide to hydrogen peroxide. Thus, IH disrupts the balance between HIF-1-dependent pro-oxidant and HIF-2-dependent anti oxidant activities, and this loss of redox homeostasis underlies the pathogenesis of autonomic morbidities associated with IH. PMID- 23080138 TI - Peripheral chemoreceptors in air- versus water- breathers. AB - Among the vertebrates, peripheral chemoreceptors have evolved to play a key role in matching oxygen delivery to the metabolic needs of the body cells and tissues. Specialized neuroepithelial cells (NECs) distributed within the gill filaments and/or lamellae of water-breathers appear to subserve this function by initiating an increase in ventilation in response to lowering of blood or water PO(2) (hypoxia). It is only recently, however, that these cells have become amenable for detailed investigations using electrophysiological tools. By contrast, the well-studied specialized neuroendocrine cells (i.e. glomus or type I cells) located principally in the carotid body of air-breathers initiate a similar reflex ventilatory response to hypoxia so as to maintain blood PO(2) homeostasis. In some species, however, the carotid body is immature and relatively insensitive to hypoxia at birth; it is during this period that their sympathoadrenal counterparts in the adrenal medulla act as key PO(2) receptors, critical for the proper transition to air-breathing life. It is becoming increasingly clear that in general these chemoreceptors act as polymodal receptors, i.e. capable of detecting several sensory modalities including high CO(2)/H(+) or acid hypercapnia. Given the phylogenetic and ontogenetic evidence pointing to homology between the mammalian carotid artery and the first gill arch of teleosts, the question arises whether the mechanisms of chemosensing are conserved among these cell types. This review examines some of the anatomical and functional similarities among these peripheral chemoreceptors, while raising the possibility that the fundamental mechanisms of O(2) and CO(2)/H(+) sensing arose first in water-breathers and are conserved among the vertebrates. PMID- 23080139 TI - Sex-specific effects of daily gavage with a mixed progesterone and glucocorticoid receptor antagonist on hypoxic ventilatory response in newborn rats. AB - We tested the hypothesis that daily gavage with mifepristone, a mixed progesterone/glucocorticoid receptor antagonist would alter hypoxic ventilatory response (HVR) in newborn male and female rats. Rats were treated with mifepristone (40ug/g/day), or vehicle between postnatal days 3-12, and used at 10 12 days of age to record baseline ventilatory and metabolic values using whole body plethysmography. HVR was tested by exposing the animals to 14% and 12% O(2) for 20 minutes each. HVR was enhanced by mifepristone treatment, mainly due to an effect on tidal volume that remained higher in mifepristone treated rats during both levels of hypoxic exposure. This effect was sex-specific being apparent only in male rats. In Vehicle treated rats, HVR was higher in females than in males, which was also due to a higher tidal volume in hypoxia (at 14 and 12% O(2)). We conclude that the activity of the progesterone and/or glucocorticoid receptors modulates respiratory control in rat pups, and that these effects are different in males and females. PMID- 23080140 TI - Age-dependent changes in breathing stability in rats. PMID- 23080141 TI - Dose dependent effect of progesterone on hypoxic ventilatory response in newborn rats. AB - The effect of progesterone as a respiratory stimulant in newborn subjects is less known than that in adults. This study investigated the dose-response curve (0, 2, 4, and 8 mg/kg, ip) of progesterone on ventilation in non-anesthetized newborn rats at 4- and 12-days old using plethysmography. Progesterone had no effects in the regulation of normoxic ventilation. However, it enhanced the response to moderate hypoxia (FiO(2) 12%, 20 min) in 4- but not in 12-days old pups. This response was similar between the dose of 4 and 8 mg/kg. These observations suggested that progesterone enhances in age- and dose-dependent manner the hypoxic ventilatory response in newborn rats. PMID- 23080142 TI - Postnatal hyperoxia impairs acute oxygen sensing of rat glomus cells by reduced membrane depolarization. AB - Previous work demonstrated that hyperoxia (30-60% O(2)) exposure in the post natal period reduces the ventilatory response to acute hypoxia and this impairment may continue considerably beyond the period of hyperoxia exposure. Previous work from our laboratory demonstrated that 1-2 weeks of hyperoxia (60% O(2)) starting between P1 and P14: reduced the single chemoreceptor unit response to hypoxia, reduced the rise in glomus cell calcium caused by acute hypoxia and reduced hypoxia-induced catecholamine release (Donnelly 05, Donnelly 09). The present study asked whether the impairment extended to hypoxia-induced membrane depolarization, an earlier step in the transduction cascade. Perforated patch, whole-cell recordings were obtained from rat glomus cells exposed to hyperoxia from P0-P8 or P8-P15 and age-matched control groups. In both cases, hypoxia induced membrane depolarization was significantly less in the hyperoxia treated groups compared to controls, while depolarization to 20 mM K(+) was not significantly affected. Resting membrane potential and input resistance were also not different in the hyperoxia treated groups. Whole carotid body quantitative real time PCR showed that TASK-1, TASK-3 and L-type Ca(2+) channel expression was significantly down-regulated at Hyper 8-15 compared to controls. We conclude that 1 week of postnatal hyperoxia during the early and late stage of CB maturation impairs organ function by affecting the coupling between hypoxia and glomus cell depolarization. This may be caused by altered expression of TASK1, TASK3 or L type Ca(2+) channel gene expression. We speculate that an identification of cellular changes caused by hyperoxia may yield unique insights to the mechanism of oxygen sensing by the carotid bodies. PMID- 23080143 TI - Erythropoietin and the sex-dimorphic chemoreflex pathway. AB - During hypoxic or hypoxemic conditions, tissue oxygenation and arterial O(2) carrying capacity are upregulated by two complementary systems, namely the neural respiratory network (central and peripheral) that leads to increased minute ventilation thereby increasing tissue oxygenation, and erythropoietin (Epo) release by the kidney that activates erythropoiesis in bone marrow to augment arterial blood O(2) carrying capacity. Despite the fact that both neural respiratory control and Epo-mediated elevation of red blood cells are responsible for keeping arterial O(2) content optimal, no interaction between these systems has been described so far. Here we review data obtained in our laboratory demonstrating that ventilatory and erythropoietic systems are tightly connected. We found Epo is the key factor mediating this relationship through modulation of the chemoreflex pathway. Moreover, we showed that this interaction occurs in a sex-dependent manner. PMID- 23080144 TI - Time-course of ventilation, arterial and pulmonary CO(2) tension during CO (2) increase in humans. AB - A change of ventilation (VE), PaCO( 2 ) (arterial CO( 2 ) tension) and PvCO( 2 ) (pulmonary arterial CO( 2 ) tension) with time was not evaluated precisely during exercise or CO( 2 ) rebreathing in humans. In this study, changes of these variables with time were fitted to exponential curves {y = Exp ( x/ T + A ) + k} and compared. When exercise pulmonary hemodynamics was examined in 15 cardiac patients to decide therapies, we asked the patients to undergo CO( 2 ) rebreathing using air with supplementation of consumed O( 2 ). Arterial and pulmonary blood was drawn every minute. During exercise, T was 28.2 +/- 8.4 and 26.8 +/- 12.4, and A was 0.80 +/- 0.50 and 0.50 +/- 0.90 in VE and PvCO( 2 ), respectively, with no statistical differences. During CO( 2 ) rebreathing, T was 18.6 +/- 5.8, 41.8 +/- 38.0 and 21.6 +/- 9.7 and A was 0.39 +/- 0.67, 1.64 +/- 1.35 and 0.17 +/- 0.83 in VE, PaCO( 2 ) and PvCO( 2 ), respectively, with statistical difference of PaCO( 2 ) from other variables, suggesting that VE and PvCO( 2 ) showed same mode of change according to time but PaCO( 2 ) did not. PMID- 23080145 TI - Oxygen sensitive synaptic neurotransmission in anoxia-tolerant turtle cerebrocortex. AB - Anoxia rapidly elicits hyper-excitability and cell death in mammal brain but this is not so in anoxia-tolerant turtle brain where spontaneous electrical activity is suppressed by anoxia (i.e. spike arrest; SA). In anoxic turtle brain extracellular GABA concentrations increase dramatically and impact GABAergic synaptic transmission in a way that results in SA. Here we briefly review what is known about the regulation of glutamatergic signalling during anoxia and investigate the possibility that in anoxic turtle cortical neurons GABA(A/B) receptors play an important role in neuroprotection. Both AMPA and NMDA receptor currents decrease by about 50% in anoxic turtle cerebrocortex and therefore exhibit channel arrest, whereas GABA-A receptor currents increase twofold and increase whole-cell conductance. The increased post synaptic GABA-A receptor current is contrary to the channel arrest hypothesis but it does serve an important function. The reversal potential of the GABA-A receptor (E(GABA)) is only slightly depolarized relative to the resting membrane potential of the neuron and not sufficient to elicit an action potential. Therefore, when GABA-A receptors are activated, membrane potential moves to E(GABA) and prevents further depolarization by glutamatergic inputs during anoxia by a process termed shunting inhibition. Furthermore we discuss the presynaptic role of GABA-B receptors and show that increased endogenous GABA release during anoxia mediates SA by activating both GABA-A and B receptors and that this represents a natural oxygen sensitive adaptive mechanism to protect brain from anoxic injury. PMID- 23080146 TI - Ion channel regulation by the LKB1-AMPK signalling pathway: the key to carotid body activation by hypoxia and metabolic homeostasis at the whole body level. AB - Our recent investigations provide further support for the proposal that, consequent to inhibition of mitochondrial oxidative phosphorylation, activation of AMP-activated protein kinase (AMPK) mediates carotid body excitation by hypoxia. Consistent with the effects of hypoxia, intracellular dialysis from a patch pipette of an active (thiophosphorylated) recombinant AMPK heterotrimer (alpha2beta2gamma1) or application of the AMPK activators AICAR and A769662: (1) Inhibited BK(Ca) currents and TASK K(+) currents in rat carotid body type I cells; (2) Inhibited whole-cell currents carried by KCa1.1 and TASK3, but not TASK1 channels expressed in HEK293 cells; (3) Triggered carotid body activation. Furthermore, preliminary studies using mice with conditional knockout in type I cells of the primary upstream kinase that activates AMPK in response to metabolic stresses, LKB1, appear to confirm our working hypothesis. Studies on mice with knockout of the catalytic alpha1 subunit and alpha2 subunits of AMPK, respectively, have proved equally consistent. Accumulating evidence therefore suggests that the LKB1-AMPK signalling pathway is necessary for hypoxia-response coupling by the carotid body, and serves to regulate oxygen and therefore energy supply at the whole body level. PMID- 23080147 TI - Anoxia response in physiological potassium of the isolated inspiratory center in calibrated newborn rat brainstem slices. AB - Using newborn rat brainstem-spinal cords, we were the first to show that medullary inspiratory networks can generate the neonatal biphasic (initial acceleration-secondary slowing) respiratory response to severe hypoxia causing tissue anoxia. Our findings also indicated that medullary inspiratory interneurons remain functional during sustained anoxia due to effective utilization of anaerobic metabolism. In that previous work by us and related studies by others on respiratory anoxia responses in the above en bloc model or brainstem slices, presumptive recording sites within the pre-Botzinger complex (preBotC) inspiratory center were not histologically verified. Moreover, preBotC slices were studied in 7-9 mM K(+) to stabilize rhythm which can, however, affect respiratory neuromodulation. Here, we summarize our previous findings on respiratory anoxia responses in the en bloc model in physiological (3 mM) K(+). Using our recently developed 'calibrated' slices, we also exemplify anoxia effects in anatomically identified preBotC cells in physiological K(+) based on recording electrophysiological population activity in conjunction with either membrane potential or cytosolic Ca(2+). PMID- 23080148 TI - Hypoxic redistribution of iron and calcium in the cat glomus cells. AB - Both iron and calcium are essential for the hypoxia sensing mechanisms in the carotid body. However, trafficking of both ions in chemoreceptor cells in response to hypoxia is unclear. In the present study we seek to determine iron and calcium redistribution patterns in response to hypoxia in the cat chemoreceptor cells. Four cats were used: two each exposed to normoxia (PaO(2) = 90 mmHg) and hypoxia (PaO(2) = 20 mmHg) for 40 min. Carotid bodies were dissected, 150 nm sections made and processed for the measurements of iron and calcium content in the intracellular organelles of chemoreceptor cells with an energy dispersive X-ray spectroscopy. The results show that iron was distinctly lower in the hypoxic than normoxic chemoreceptor cells' cytoplasm. Conversely, calcium was increased in hypoxia, particularly in the nuclei and the dense-cored vesicles. These results highlight that regional distribution of iron does not coincide with calcium in glomus cells. Redistribution of both ions in response to hypoxia is congruous with their role in hypoxia-sensing. However, the exact determinants of iron/calcium redistribution patterns in glomus cells remain unsettled. PMID- 23080149 TI - Acute hypoxia does not influence intracellular pH in isolated rat carotid body Type I cells. PMID- 23080150 TI - Hydrogen sulfide (H(2)S): a physiologic mediator of carotid body response to hypoxia. AB - Carotid bodies are sensory organs for monitoring arterial blood O(2) levels. Nitric oxide and carbon monoxide function as inhibitory gasotransmitters in the carotid body. Hydrogen sulfide (H2S) is another emerging gasotransmitter. The purpose of this article is to review recent studies addressing the role of H2S in carotid body.Cystathionine gamma-lyase (CSE) and cystathionine beta synthase (CBS) are the two major enzymes that catalyze the formation of endogenous H2S. Both CSE and CBS are expressed in glomus cells, the putative site of sensorytransduction in the carotid body. Hypoxia increases H2S generation in the carotid body. CSE knockout mice displayed absence of hypoxia-evoked H2S generation and severely impaired sensory excitation by low O2. Pharmacological inhibitors of CSE as well as CBS showed a similar phenotype in mice and rats. Like hypoxia, H2S donors stimulated the carotid body sensory activity and this response required Ca(2+) influx via voltage-gated Ca2+ channels. Evidence is emerging implicating Ca2+ activated K+ channels in glomus cells as potential targets of H2S. PMID- 23080151 TI - The retrotrapezoid nucleus and breathing. AB - The retrotrapezoid nucleus (RTN) is located in the rostral medulla oblongata close to the ventral surface and consists of a bilateral cluster of glutamatergic neurons that are non-aminergic and express homeodomain transcription factor Phox2b throughout life. These neurons respond vigorously to increases in local pCO(2) via cell-autonomous and paracrine (glial) mechanisms and receive additional chemosensory information from the carotid bodies. RTN neurons exclusively innervate the regions of the brainstem that contain the respiratory pattern generator (RPG). Lesion or inhibition of RTN neurons largely attenuates the respiratory chemoreflex of adult rats whereas their activation increases respiratory rate, inspiratory amplitude and active expiration. Phox2b mutations that cause congenital central hypoventilation syndrome in humans prevent the development of RTN neurons in mice. Selective deletion of the RTN Phox2b-VGLUT2 neurons by genetic means in mice eliminates the respiratory chemoreflex in neonates.In short, RTN Phox2b-VGLUT2 neurons are a major nodal point of the CNS network that regulates pCO(2) via breathing and these cells are probable central chemoreceptors. PMID- 23080152 TI - The interaction between low glucose and hypoxia in the in vitro, rat carotid body. AB - A role for the carotid body (CB) in systemic glycaemic control is yet to be fully characterised. Observations made on fasted, anaesthetised cats, rats and dogs in vivo showed that intra-arterial injection of sodium cyanide into the carotid sinus region immediately increased carotid sinus nerve (CSN) discharge frequency and elicited a subsequent significant increase in the systemic arterial glucose concentration, within 2-8 min of drug administration (Alvarez-Buylla and Alvarez Buylla 1988). These responses were abolished in animals in which both CSNs had been surgically sectioned, demonstrating that the increased arterial glucose concentration detected following CB stimulation was dependent on CSN input into the NTS. Although not directly tested by these authors, it was proposed that low plasma glucose directly stimulated the CB, as the increase in CSN discharge frequency elicited with NaCN was attenuated by direct injection of a hyperglycaemic solution into the common carotid artery (Alvarez-Buylla and Alvarez-Buylla 1988; Alvarez-Buylla et al. 1997). Additionally, in dogs with bilateral CB resection (CBR), the rate of exogenous glucose infusion required to maintain a fixed hypoglycaemic level was significantly higher, whilst the endogenous hepatic glucose production was significantly lower, compared to control (CSN intact) animals (Koyama et al. 2000). These results further suggested a dependence on CB stimulation for the maintenance of a physiologically normal plasma glucose concentration, but again no direct measure of CB response to hypoglycaemia had been made. PMID- 23080153 TI - Do the carotid bodies modulate hypoglycemic counterregulation and baroreflex control of blood pressure in humans? AB - Peripheral chemoreceptors in the carotid body regulate respiration, sympathetic outflow, and blood pressure in response to hypoxia. The carotid bodies play a role in the counterregulatory response to hypoglycemia in animal models and may interact with the arterial baroreflex. We hypothesized that desensitization of the carotid bodies by hyperoxia in humans would blunt hypoglycemic counterregulation and baroreflex control of blood pressure during hypoglycemia. Seven healthy adults (age 26.7 +/- 0.39, BMI 25 +/- 0.32, M/4, F/3) each underwent two 180 min hyperinsulinemic (2 mU/kg FFM/min), hypoglycemic (3.33 mmol/L) clamps 1 week apart, randomized to either normoxia (arterial P(O2) (P(a)O(2)) 111 +/- 6.3 mmHg) or hyperoxia (P(a)O(2) 345 +/- 80.6 mmHg) (p < 0.05). Plasma glucose concentrations were similar during normoxia and hyperoxia at baseline and during the clamp. The glucose infusion rate was 44.2 +/- 3.5% higher (p < 0.01) during hyperoxia than normoxia during the clamp. Area under the curve values (expressed as % normoxia response) for counterregulatory hormones during hypoglycemia were significantly suppressed by hyperoxia. In addition, mean blood pressure during hypoglycemia was significantly lower with hyperoxia than with normoxia (delta reduction from baseline: -5.4 +/- 3.4 mmHg normoxia vs. 13.8 +/- 1.9 mmHg hyperoxia, p < 0.05). The typical baroreflex-mediated rise in heart rate and sympathetic activity with lower blood pressure did not occur when the CB were silenced. These data support the idea that the carotid bodies play a role in the counterregulatory response to hypoglycemia and in baroreflex control of blood pressure in humans. PMID- 23080154 TI - Shifting from hypoxia to hyperoxia to assess the peripheral chemosensory drive of ventilation. AB - The study of the initial effects of a sudden and brief replacement of air by pure oxygen has been proposed as a tool (Dejours' test) to determine the tonic influence that arterial (peripheral) chemoreceptors were exerting upon ventilation under previous normoxic conditions. Therefore, the acute ventilatory response to transient hyperoxia should be used to assess the level of hypoxic chemosensory drive. In spontaneously ventilated pentobarbitone-anesthetized cats, we observed that the degree of ventilatory depression provoked by hyperoxia was correlated to the degree of previous hypoxia. Minimal tidal volumes (V(T)) or transient apnea were reached between second to fourth cycles after switching from 5% to 100% O(2) breathing. Continuous recordings of chemosensory discharges from one carotid (sinus) nerve allowed correlation of the falls in frequency of chemosensory discharges to the degree of hyperoxia-induced ventilatory depression and provided an accurate measure of the prevailing chemosensory drive of ventilation exerted during hypoxic steady-state conditions. PMID- 23080155 TI - CO(2) signaling in chemosensory neuroepithelial cells of the zebrafish gill filaments: role of intracellular Ca(2+) and pH. AB - Adult zebrafish, Danio rerio, exhibit hyperventilatory responses to absolute environmental CO2 levels as low as 1.0 mmHg. The ability of zebrafish to detect and respond to low ambient CO2 appears to be mediated by chemosensory neuroepithelial cells (NECs) of the gill filaments. Recent electrophysiological characterization of this response revealed that the partial pressure-dependent depolarization of NECs in response to a hypercapnic stimulus is dependent on the rate of acidification associated with the hydration of CO2 and the inhibition of background K(+) channels. In order to further elucidate the signaling pathway underlying CO2 chemotransduction in NECs, we used microfluorimetric techniques to study intracellular changes in pH (pHi) and calcium ([Ca(2+)]i). Using the ratiometric indicators BCECF-AM and fura-2-AM, we found that a hypercapnic stimulus evoked a decrease in pHi and an increase in [Ca(2+)]i. PMID- 23080156 TI - Hyperplasia of pulmonary neuroepithelial bodies (NEB) in lungs of prolyl hydroxylase -1(PHD-1) deficient mice. AB - Pulmonary NEB, widely distributed within the airway mucosa of mammalian lungs, are presumed hypoxia sensitive airway O(2) sensors responding to changes in airway gas concentration. NEB cell hyperplasia has been reported after exposure to chronic hypoxia and in a variety of paediatric and adult lung disorders. Prolyl hydroxylases (PHD 1-3) regulate the stability of hypoxia-inducible factors (HIF's) in an O(2)-dependent manner and function as intrinsic oxygen sensors. To determine a possible role of PHD-1in NEB cells we have quantitated NEB's in lungs of neonatal (P2) and adult (2 months) PHD-1-deficient mice and compared them to wild type (WT) control mice. Lung tissues fixed in formalin and embedded in paraffin were processed for immunoperoxidase method and frozen sections for multilabel immunoflourescence using antibodies for NEB markers synaptophysin, synaptic vesicle protein 2 and the peptide CGRP. The frequency and size of NEB in lungs of PHD-1 deficient neonatal mice (P2) and at 2 months was increased significantly compared to WT controls (p < 0.01). The present data suggests an important role for PHD enzymes in NEB cell biology deserving further studies. Since the PHD-1 deficient mouse appears to be the first animal model showing NEB cell hyperplasia it may be useful for studies of NEB physiology and pathobiology. PMID- 23080157 TI - Precision-cut vibratome slices allow functional live cell imaging of the pulmonary neuroepithelial body microenvironment in fetal mice. AB - We recently developed an ex vivo lung slice model that allows for confocal live cell imaging (LCI) of neuroepithelial bodies (NEBs) in postnatal mouse lungs (postnatal days 1-21 and adult). NEBs are morphologically well-characterized, extensively innervated groups of neuroendocrine cells in the airway epithelium, which are shielded from the airway lumen by 'Clara-like' cells. The prominent presence of differentiated NEBs from early embryonic development onwards, strongly suggests that NEBs may exert important functions during late fetal and neonatal life. The main goal of the present study was to adapt the current postnatal LCI lung slice model to enable functional studies of fetal mouse lungs (gestational days 17-20).In vibratome lung slices of prenatal mice, NEBs could be unequivocally identified with the fluorescent stryryl pyridinium dye 4-Di-2-ASP. Changes in the intracellular free calcium concentration and in mitochondrial membrane potential could be monitored using appropriate functional fluorescent indicators (e.g. Fluo-4).It is clear that the described fetal mouse lung slice model is suited for LCI studies of Clara cells, ciliated cells, and the NEB microenvironment, and offers excellent possibilities to further unravel the significance of NEBs during the prenatal and perinatal period. PMID- 23080158 TI - Oxygen sensitivity of gill neuroepithelial cells in the anoxia-tolerant goldfish. AB - In the zebrafish, O(2)-chemoreceptive neuroepithelial cells (NECs) of the gill arches detect changes in PO(2) and are believed to initiate cardiorespiratory responses to hypoxia. Goldfish have gill NECs of similar morphology and innervation, yet these animals are naturally tolerant to prolonged periods of anoxia. Whole-cell, voltage-clamp experiments indicated that goldfish NECs express a variety of membrane ion channels, including background and Ca(2+) activated K(+) channels. Our initial studies suggest that goldfish NECs do not respond equally to hypoxia (N(2), 25 mmHg) as do those of zebrafish; however, current-clamp recordings indicated that anoxia produced membrane depolarization. In addition, we found that cyanide, which mimics hypoxia, depolarized NECs. Our goal is to further characterize these membrane conductances and determine their potential contribution to O(2) sensing in NECs of the anoxia-tolerant goldfish. PMID- 23080159 TI - Interaction of hypoxia and core temperature: potential role of TRPV1. AB - Hypoxia exposure in small mammals elicits an initial rise in ventilation followed by a reduction to levels that are often less than the normoxic value. The fall in ventilation is matched by a decrease in metabolism rate and a reduction in core body temperature (Tb). The transient receptor potential vanilloid 1 (TRPV1) ion channel has been implicated in thermoregulation (Caterina et al., Science 288:306 313, 2000) and recently shown to exert a tonic effect on Tb in human subjects (Gavva et al., Pain 136:202-210, 2008). We review herein the hypothesis that TRPV1 modulates the Tb response to hypoxia. We provide preliminary evidence that a 24 h hypoxia (FIO(2)=0.1) exposure caused an enhanced decrease in Tb in mutant TRPV1(-/-) mice compared to the TRPV1(+/+) genotype (Tb was " 1 degrees C lower than TRPV1(+/+)). Further investigation is warranted to determine the extent of TRPV1 ion channel involvement in acute and adaptive responses to hypoxia. PMID- 23080160 TI - Neonatal intermittent hypoxia induces persistent alteration of baroreflex in adult male rats. AB - Baroreflex is involved in the regulation of arterial blood pressure (BP). An increase in BP activates vagal inhibitory pathways to decrease heart rate; a concomitant decrease in sympathetic discharge reduces vascular resistance. Both responses reduce BP towards normal value. Conversely, a decrease in BP produces opposite effects to increase heart rate and vascular resistance. PMID- 23080161 TI - LPS-induced c-Fos activation in NTS neurons and plasmatic cortisol increases in septic rats are suppressed by bilateral carotid chemodenervation. AB - Lipopolysaccharide (LPS) administered I.P. increases significantly the activation of c-Fos in neurons of the nucleus of the solitary tract (NTS), which in turn activates hypothalamus-pituitary-adrenal axis. The vagus nerve appears to play a role in conveying cytokines signals to the central nervous system (CNS), since in rodent models of sepsis- bilateral vagotomy abolishes increases in plasmatic glucocorticoid levels, but does not suppress c-Fos NTS activation. Considering that NTS also receives sensory inputs from carotid body chemoreceptors, we evaluated c-Fos activation and plasmatic cortisol levels 90 min after I.P. administration of 15 mg/kg LPS. Experiments were performed in male Sprague-Dawley rats, in control conditions and after bilateral carotid neurotomy (BCN). LPS administration significantly increases the number of c-Fos positive NTS neurons and plasmatic cortisol levels in animals with intact carotid/sinus nerves. When LPS was injected after BCN, the number of c-Fos positive NTS neurons, and plasmatic cortisol levels were not significantly modified. Our data suggest that carotid body chemoreceptors might mediate CNS activation during sepsis. PMID- 23080162 TI - Developmental regulation of glucosensing in rat adrenomedullary chromaffin cells: potential role of the K(ATP) channel. AB - During birth, when the maternal supply of glucose is occluded, there is a drastic fall in blood glucose in the newborn. This stimulus triggers the non-neurogenic release of catecholamines from adrenomedullary chromaffin cells, which restores blood glucose homeostasis. In this report we present preliminary data showing that glucosensing is present in neonatal chromaffin cells from adrenal slices but absent in chromaffin cells from juvenile slices. Moreover, we show that the aglycemia-evoked rise in intracellular Ca2+ is robust in neonatal chromaffin cells but blunted in juvenile chromaffin cells. Lastly, we show that the Kir6.2 subunit of the KATP channel, is upregulated in the adrenal medulla in juvenile animals providing a potential mechanism for the developmental regulation of glucosensing. PMID- 23080163 TI - Contribution of inflammation on carotid body chemosensory potentiation induced by intermittent hypoxia. AB - Exposure to chronic intermittent hypoxia (CIH) produces hypertension. A critical process involved in the CIH-induced hypertension is the potentiation of the carotid body (CB) chemosensory responses to acute hypoxia. The CIH-induced changes in the CB chemosensory process have been related to an enhanced reactive oxygen species (ROS) production. However, it is still a matter of debate where ROS could directly modify the CB chemosensory discharge. Recently, we found that CIH-induced increase expression of TNF-a and IL-1b within the CB. Thus, we studied the contribution of these pro-inflammatory cytokines on the enhanced CB chemosensory response to acute hypoxia in rats exposed to CIH. To study the role of TNF-a and IL-1b, male Sprague-Dawley rats were submitted to CIH (5% O(2), 12 times/hr for 8 hr/day) and received chronic ibuprofen treatment (40 mg/kg). Following 21 days of CIH, rats were anaesthetized and the CB chemosensory discharge was recorded in response to several levels FiO2 (5-100%). Exposure to CIH significantly increases the immunorreactive levels of TNF-a and IL-1b in the CB, along with an increase accumulation of the p65 NF-kb subunit. Treating rats with ibuprofen significantly prevents the CIH-induced increases in TNF-a and IL 1b in the CB chemoreceptor cells but failed to decrease the enhanced CB chemosensory reactivity to hypoxia. Our results suggest that the mechanisms underlying the potentiation of the CB chemosensory response to acute hypoxia are not linked to the increased expression of TNF-a and IL-1b within the CBs of CIH exposed rats. PMID- 23080164 TI - Spexin is expressed in the carotid body and is upregulated by postnatal hyperoxia exposure. AB - Spexin is a recently identified peptide which is expressed in many different endocrine and nervous tissues. Due to the absence of data regarding spexin expression in the carotid body, the first aim of the present study was to investigate, through immunohistochemistry and Real-Time PCR, the expression and distribution of spexin in the rat and human carotid body. Moreover, the carotid body is known to undergo various structural and functional modifications in response to hyperoxic stimuli during the first postnatal period. Thus, we also evaluated if hyperoxia during the first postnatal weeks may produce changes in the spexin expression. Materials consisted of carotid bodies obtained at autopsy from five human adult subjects and sampled from 10 six-weeks old Sprague-Dawley rats. Five rats were maintained in normoxia for the first six postnatal weeks; five rats were exposed to 60% hyperoxia for 2 weeks and then maintained in normoxia for other 4 weeks. Diffuse anti-spexin immunoreactivity was found in type I cells of both humans and rats. No spexin immunoreactivity was visible in the type II cells. Hyperoxia exposure during the first 2 weeks of postnatal life caused a reduction of volume in the carotid body still apparent after 4 weeks of normoxia. Using real-time PCR, spexin expression was 6-7 times higher in hyperoxia-exposed rats than in normoxia-exposed ones. The expression of spexin in type I cells suggests a possible modulator role in peripheral chemoreception. Moreover, the ascertained role of spexin in the regulation of cell proliferation in other tissues (e.g., adrenal gland cortex) suggests a possible role of spexin also in the hyperoxia-induced plasticity of the carotid body. PMID- 23080165 TI - Cyclic AMP and Epac contribute to the genesis of the positive interaction between hypoxia and hypercapnia in the carotid body. AB - Carotid body chemoreceptor cells in response to hypoxic and hypercapnic stimulus increase their resting rate of release of neurotransmitters and their action potential frequency in the carotid sinus sensory nerve. When chemoreceptor activity is assessed at the level of the carotid sinus nerve and on ventilation, there exists an interaction between hypoxic and hypercapnic stimulus so that the response to both stimuli combined is additive or more than additive, over a wide range of stimulation. It is not clear if this interaction occurs at chemoreceptor cell or directly acting on the sensory nerve. In the present work we demonstrate for the first time the existence of a positive interaction between hypoxic and hypercapnic-acidotic stimuli at the level of both, membrane potential depolarization and neurotransmitter release in rat and rabbit carotid body. Inhibition of adenylate cyclase (SQ-22536) abolished the positive interaction between stimuli and the Epac (exchange proteins activated by cAMP) activator 8 pCPT-2'-O-Me-cAMP reversed the effect of adenylate cyclase inhibition. These results suggest that this interaction between the two natural stimuli is mediated by cAMP via an Epac-dependent pathway, at least at the level of neurotransmitter release. PMID- 23080166 TI - Interactions between postnatal sustained hypoxia and intermittent hypoxia in the adulthood to alter brainstem structures and respiratory function. AB - Neural plasticity is defined as a persistent change in the morphology and/or function based on prior experiences. Plasticity is well evident when the triggering experience occurs early in life, but in the case of respiratory control plasticity, it also can be triggered in adult life. We have combined a 10 days postnatal hypoxic (PH) (0-10 days of age;11% O(2)) and a 15 days intermittent hypoxia (IH) exposures in the adulthood (90-105 days of age; 5% O(2), 40 s/20% O(2), 80 s; 8 h/day) to test if early PH interacts with IH of the adulthood to generate detrimental plastic changes. After recording of ventilatory parameters, the brains were studied immunocytochemically for localization of the organization pattern of non-phosphorylated subunit of neurofilament H (NFH) and tyrosine hydroxylase (TH) expression in the nucleus tractus solitarius (Sol) and caudal (CVL) and rostral ventrolateral reticular (RVL) nuclei, areas related to central cardio-respiratory regulation. In comparison to control, PH male rats (but not females) at 1 month of age hyperventilated at rest, in response to moderate hypoxia (12% O(2)) and 5% CO(2), the effect being due to increased tidal volume. At 3.5 months sex differences in ventilation disappeared and it was indistinguishable between control and PH. IH tended to decrease ventilation in both control (C) and PH animals. PH augmented PENH values in air and in hypoxic conditions when compared with C group. IH in both groups, tended to decrease the PENH value, being statistically different in PH+IH. Results also show an increment of disorganization of NFH-positive labeled structures at the level of Sol and CVL/RVL nuclei in PH, IH and HP+HI groups. PH rats showed differences in the number of TH-positive neurons at the level of CVL/RVL nuclei, which was increased in the PH and PH+IH groups with respect to C one. In conclusion, PH alters the central morpho-physiological organization and the catecholaminergic components of cardio-respiratory nuclei, whose effects were enhanced after a period of IH in the adulthood. PMID- 23080167 TI - Brain-derived neurotrophic factor in the nucleus tractus solitarii modulates glucose homeostasis after carotid chemoreceptor stimulation in rats. AB - Neuronal systems, which regulate energy intake, energy expenditure and endogenous glucose production, sense and respond to input from hormonal related signals that convey information from body energy availability. Carotid chemoreceptors (CChr) function as sensors for circulating glucose levels and contribute to glycemic counterregulatory responses. Brain-derived neurotrophic factor (BDNF) that plays an important role in the endocrine system to regulate glucose metabolism could play a role in hyperglycemic glucose reflex with brain glucose retention (BGR) evoked by anoxic CChr stimulation. Infusing BDNF into the nucleus tractus solitarii (NTS) before CChr stimulation, showed that this neurotrophin increased arterial glucose and BGR. In contrast, BDNF receptor (TrkB) antagonist (K252a) infusions in NTS resulted in a decrease in both glucose variables. PMID- 23080168 TI - Hydrogen sulfide acting at the carotid body and elsewhere in the organism. PMID- 23080169 TI - Purinergic modulation of carotid body glomus cell hypoxia response during postnatal maturation in rats. AB - Carotid body (CB) glomus cells respond to hypoxia by releasing neurotransmitters, such as ATP, which are believed to stimulate excitatory receptors on apposed nerve endings of the carotid sinus nerves as well as bind to autoreceptors on the glomus cell membrane to modulate response magnitude. The CB response to hypoxia is small at birth and increases during postnatal maturation in mammals. As ATP has been shown to inhibit the glomus cell response to hypoxia via an autoreceptor mechanism, we hypothesized that ATP-mediated inhibition may vary with age and play a role in postnatal development of the hypoxia response magnitude. The effects of ATP on CB glomus cell intracellular calcium ([Ca(2+)](i)) responses to hypoxia were studied at two ages, P0-1 and P14-18. The inhibitory effect of ATP or a stable ATP analog on the glomus cell response to hypoxia was greater in newborn rats compared to the more mature age group. Use of selective P2Y receptor agonists and antagonists suggests that the inhibitory effect of ATP on the glomus cell [Ca(2+)](i) response to hypoxia may be mediated by a P2Y12 receptor. Thus, developmental changes in ATP-mediated glomus cell inhibition may play a role in carotid chemoreceptor postnatal maturation. PMID- 23080170 TI - Serotonin dynamics and actions in the rat carotid body: preliminary findings. AB - Serotonin or 5-HT is a biogenic amine present in the carotid body (CB) of several species as evidenced in many immunocytochemical studies and in a few biochemical measurements. Early literature on 5-HT actions in the CB in all studied species has lead to the conclusion that it does not participate in the setting of conducted action potentials in the sensory nerve of the CB. However, during the last 10 years very important roles in the cellular physiology of the CB have been proposed for this biogenic amine. These roles include a primary role in setting the excitability of chemoreceptor cells via an autocrine or paracrine action, and thereby, the conducted activity in the carotid sinus nerve, and a critical role in the genesis of long term sensory facilitation observed in CBs of animals exposed to intermittent hypoxia. These facts, along with important discrepancies in the endogenous levels of 5-HT in the CB prompted present study conducted in rat CBs. We measured CB endogenous 5-HT content by HPLC with electrochemical detection and found levels of 5-HT in the range of 15-22 pmole/mg tissue in control and chronically hypoxic animals either sustained or intermittent, with no significant differences among them. 5-HT and the 5-HT2A antagonist ketanserin dose-dependently activated chemoreceptor cells as assessed by their capacity to release catecholamines from freshly isolated CB. In preliminary experiments we have observed that intense hypoxia and high extracellular K(+) promote a small release of 5-HT from CB which is not dependent on the presence of extracellular Ca(2+). Further studies are needed to firmly establish the dynamics of 5-HT in the CB of the rat. PMID- 23080171 TI - Human carotid body HIF and NGB expression during human development and aging. AB - Hypoxia inducible factor 1(HIF-1alpha) is the regulator of oxygen homeostasis in tissue correlated with neuroglobin (NGB) a member of the family of globins in vertebrates. The present study investigates, the expression and the location of NGB, HIF-1alpha in human carotid bodies, sampled at autopsy from children (mean age: 2 year +/-), young (mean age: 27.5) and 4 old subjects (mean age: 73.5). The percentage of NGB positive area was higher in the old subjects (4.4 +/-2.8%), as compared with the young ones (2.4 +/-1.8%) and children (1.0 +/-1.8%). Positive HIF-1alpha nuclei were detected in young and old subjects (1.0 +/-0.14% vs 3.0 +/ 0.28%, respectively), whereas CB tissues from children did not show any HIF 1alpha reaction. The increase of NGB and HIF-1alpha expression suggests a possible role of the two oxygen sensors in the aging processes. Even though the physiological role of NGB is not well understood, it could be suggested that is act as a respiratory protein connected with HIF. PMID- 23080172 TI - Propranolol does not affect the hindlimb vasodilatation elicited by stimulation of superior laryngeal nerve paraganglia. PMID- 23080173 TI - ATP release from the carotid bodies of DBA/2J and A/J inbred mouse strains. AB - The purposes of this study were to: (1) establish an effective method to measure the release of ATP from the mouse carotid body (CB) and (2) determine the release of ATP from the CB of the DBA/2 J (high hypoxic responder) and A/J (low hypoxic responder) mouse in response to hypoxia and hypercapnia. An incubation chamber was constructed utilizing a Costar(r) Spin-X Centrifuge Tube Filter. The filter was coated with low melting point agarose to hold 4 CBs or 4 superior cervical ganglia (SCG). Hypoxia did not increase ATP release from the CB of either strain. ATP increased in response to a normoxic/hypercapnic challenge in the DBA/2 J's CB but not in the A/J's CB. ATP release from the SCG was affected by neither hypoxia nor hypercapnia in both strains. Thus, we have concluded: (1) we successfully established a chamber system to measure ATP released from the mouse CB; (2) ATP may not be an excitatory neurotransmitter in the CB of these mice under hypoxia; (3) ATP may be a neurotransmitter in the CB of the DBA/2 J mouse strain during hypercapnia. PMID- 23080174 TI - Effect of oxygen on phosphodiesterases (PDE) 3 and 4 isoforms and PKA activity in the superior cervical ganglia. AB - The cAMP-protein kinase A (PKA) signaling pathway is involved in regulating the release of transmitters from neurons and other cells. Multiple phosphodiesterase (PDE) isoforms regulate this pathway, however, the pattern of isoform expression and stimulus response across tissues has not been fully characterized.Using fluorescent resonance energy transfer (FRET)-based imaging in primary superior cervical ganglia (SCG) neurons and real-time qPCR, we explored the role of PDE3 and PDE4 isoforms and oxygen tension in the activation of PKA and changes in gene expression. These primary neurons were infected with an adenovirus containing A Kinase activity reporter (AKAR3) and assayed for responses to PDE inhibitors: rolipram (ROL, 1 MUM), milrinone (MIL, 10 MUM) and IBMX (100 MUM), and adenylyl cyclase activator forskolin (FSK, 50 MUM). Different PDE activity patterns were observed in different cells: high PDE4 activity (n = 3), high PDE3 activity (n = 3) and presence of activity of other PDEs (n = 3). Addition of PKA inhibitor H89 (10 MUM) completely reversed the response. We further studied the effect of oxygen in the PKA activity induced by PDE inhibition. Both normoxia (20%O(2)/5%CO(2)) and hypoxia (0%O(2)/5%CO(2)) induced a similar increase in the FRET emission ratio (14.5 +/- 0.8 and 14.7 +/- 0.8, respectively).PDE3a, PDE4b and PDE4d isoforms mRNAs were highly expressed in the whole SCG with no modulation by hypoxia. CONCLUSION: Using a FRET-based PKA activity sensor, we show that primary SCG neurons can be used as a model system to dissect the contribution of different PDE isoforms in regulating cAMP/PKA signaling. The differential patterns of PDE regulation potentially represent subpopulations of ganglion cells with different physiological functions. PMID- 23080175 TI - Chronic intermittent hypoxia alters genioglossus motor unit discharge patterns in the anaesthetized rat. AB - The respiratory control system is subject to diverse and considerable plasticity in health and disease. Intermittent hypoxia elicits expression of intrinsic plasticity within sensory and motor pathways involved in the control of breathing with potentially adaptive and maladaptive consequences for respiratory homeostasis. We and others have shown that chronic intermittent hypoxia (CIH) - a major feature of sleep-disordered breathing - has deleterious effects on rat upper airway dilator muscle contractile function and motor control. In the present study, we sought to test the hypothesis that CIH alters genioglossus (pharyngeal dilator) motor unit properties during basal breathing and obstructive airway events. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O(2) at nadir; SaO(2) ~ 80%) per hour, 8 h a day for 7 days (CIH, N = 5). The sham group (N = 5) were subject to alternating cycles of air under identical experimental conditions in parallel. Following gas treatments, rats were anaesthetized with an i.p injection of urethane (1.5 g/kg; 20% w/v). Fine concentric needle electrodes were inserted into the genioglossus and the costal diaphragm. Genioglossus motor unit potentials, together with arterial blood pressure, tracheal pressure and arterial O(2) saturation were recorded during quiet basal breathing and nasal airway occlusion. During basal breathing, the amplitude of genioglossus motor units was significantly different in sham vs. CIH treated rats (313 +/- 32 MUV vs. 430 +/- 46 MUV; mean +/- SEM, Student's t test, p = 0.0415). The most common instantaneous firing frequency of individual units determined from auto correlograms was also significantly different in the two groups (53 +/- 6 Hz vs. 37 +/- 3 Hz; sham vs. CIH p = 0.0318). In addition, the amplitude of motor units recruited during airway obstruction was significantly decreased in CIH-treated rats (939 +/- 102 MUV vs. 619 +/- 75 MUV; sham vs. CIH p = 0.0267). Our results indicate that CIH causes remodelling in the central respiratory motor network with potentially maladaptive consequences for the physiological control of upper airway patency. We conclude that CIH could serve to exacerbate and perpetuate obstructive events in patients with sleep-disordered breathing. PMID- 23080176 TI - Upregulation of pituitary adenylate cyclase activating polypeptide and its receptor expression in the rat carotid body in chronic and intermittent hypoxia. AB - The carotid body (CB) plays important roles in cardiorespiratory changes in chronic and intermittent hypoxia. Pituitary adenylate cyclase activating polypeptide (PACAP) is involved in the regulation of respiratory chemoresponse. We hypothesized an upregulation of the expressions of PACAP and its receptor (PAC1) in the rat CB in chronic and intermittent hypoxia. The CB expressions of PACAP and PAC1 were examined in rats breathing 10% O(2) (in isobaric chamber for chronic hypoxia, 24 h/day) or in intermittent hypoxia (cyclic between air and 5% O(2) per minute, 8 h/day) for 7 days. Immunohistochemical studies showed that the PACAP and PAC1 proteins were localized in CB glomic clusters containing tyrosine hydroxylase. The proportional amount of cells with positive staining of PACAP and PAC1 was significantly increased in both hypoxic groups when compared with the normoxic control. In addition, the mRNA level of PAC1 expression was markedly elevated in the hypoxic groups, despite no changes in the PACAP expression. These results suggest an upregulation of PACAP and its receptor expression in the rat CB under chronic and intermittent hypoxic conditions. The PACAP binding to its receptor could activate the PKA signaling pathway leading to an increased CB excitability under hypoxic conditions. PMID- 23080177 TI - Rabbit ventilatory responses to peripheral chemoexcitators: effects of chronic hypoxia. PMID- 23080178 TI - Effect of chronic caffeine intake on carotid body catecholamine dynamics in control and chronically hypoxic rats. AB - Caffeine is the most commonly psychoactive drug, an habitual drink in high altitude sporting, and when acutely taken, it causes profound alterations in carotid body (CB) function and ventilation via adenosine receptors antagonism. In the present work we have investigated the effects of chronic caffeine ingestion in catecholamine (CA) dynamics in the carotid body of control and chronic hypoxic rats. Four groups of animals were used: normoxic (N), caffeine-treated normoxic (1 mg/mL in drinking water 15 days; CafN), chronic hypoxic (CH, 12%O(2), 15 days) and chronically hypoxic-caffeine-treated (CafH).. Caffeine intake in controls rats did not modify CA content, synthesizing, and releasing responses, and the expression of tyrosine hydroxylase. CH increased dopamine content, synthesis, and basal and acute hypoxia-induced release; chronic caffeine ingestion augmented CH effects. Findings indicate that chronic caffeine ingestion in normoxic rats did not modify dopamine dynamics at the CB, but increases dopaminergic system during chronic hypoxia. PMID- 23080179 TI - Effects of cigarette smoke and chronic hypoxia on ventilation in guinea pigs. Clinical significance. AB - Ventilatory effects of chronic cigarette smoke (CS) alone or associated to chronic hypoxia (CH), as frequently occurs in chronic obstructive pulmonary disease (COPD), remain unknown. We have addressed this problem using whole-body plethysmography in guinea-pigs, common models to study harmful effects of CS on the respiratory system. Breathing frequencies (Bf) in control (2-5 months old) guinea pigs is 90-100 breaths/min, their tidal volume (TV) increased with age but lagged behind body weight gain and, as consequence, their minute volume (MV)/Kg decreased with age. MV did not change by acutely breathing 10% O(2) but doubled while breathing 5% CO(2) in air. Exposure to chronic sustained hypoxia (15 days, 12% O(2), CH) did not elicit ventilatory acclimatization nor adaptation. These findings confirm the unresponsiveness of the guinea pig CB to hypoxia. Exposure to CS (3 months) increased Bf and MV but association with CH blunted CS effects. We conclude that CS and CH association accelerates CS-induced respiratory system damage leading to a hypoventilation that can worsen the ongoing COPD process. PMID- 23080180 TI - Some reflections on intermittent hypoxia. Does it constitute the translational niche for carotid body chemoreceptor researchers? AB - The views presented in this article are the fruit of reflections and discussion with my colleagues at Valladolid and with the members of the Sleep Apnea Hypopnea Syndrome Group of the CIBERES (Spain). We have assembled the article in three sections. In the first one we provide a mechanistic description of obstructive sleep apnea (OSA) and all of its components, including the repetitive episodes of upper airways (UA) obstruction and accompanying hypoxic hypoxia, the respiratory efforts to fight and overcome the obstruction, and the sleep fragmentation due to the hypoxia-triggered arousal reactions, all events occurring during sleep hours with frequencies that might reach up >40-50 episodes/sleep hour. When OSA is accompanied by some of the elements of a big cohort of associated pathologies (vascular, metabolic, and neuropsychiatric) it conforms the obstructive sleep apnea syndrome (OSAS). The high frequency of OSAS in adults (>35 years old) and the costs in every regard of the treatment makes the syndrome a primary importance socio-sanitary problem. In the second section, we describe the experimental models of OSAS, basically the episodic repetitive hypoxic model described by Fletcher and coworkers in 1992, today named in short intermittent hypoxia (IH). From these lines, we want to call for some kind of consensus among researchers to lessen the dispersion of IH protocols. Finally, in the last section we intend to share our optimism with all ISAC members. The optimism is based on the recognition that carotid body (CB) chemoreceptors are critical elements of one of the main pathophysiologic loops in the genesis of OSAS. Therefore, we believe that all of us, as ISAC members, are well qualified to contribute in multidisciplinary research teams with well defined translational interests. PMID- 23080181 TI - Role of central/peripheral chemoreceptors and their interdependence in the pathophysiology of sleep apnea. AB - Unstable periodic breathing with intermittent ventilatory overshoots and undershoots commonly occurs in chronic heart failure, in hypoxia, with chronic opioid use and in certain types of obstructive sleep apnea. Sleep promotes breathing instability because it unmasks a highly sensitive dependence of the respiratory control system on chemoreceptor input, because transient cortical arousals promote ventilatory overshoots and also because upper airway dilator muscle tonicity is reduced and airway collapsibility enhanced. We will present data in support of the premise that carotid chemoreceptors are essential in the pathogenesis of apnea and periodicity; however it is the hyperadditive influence of peripheral chemoreceptor sensory input on central chemosensitivity that accounts for apnea and periodic breathing. This chemoreceptor interdependence also provides a significant portion of the normal drive to breathe in normoxia (i.e. eupnea) and in acute hypoxia. Finally, we discuss the effects of preventing transient hypocapnia (via selective increases in FICO(2)) on centrally mediated types of periodic breathing and even some varieties of cyclical obstructive sleep apnea. PMID- 23080182 TI - Physiologic basis for intermittent hypoxic episodes in preterm infants. AB - Intermittent hypoxic episodes are typically a consequence of immature respiratory control and remain a troublesome challenge for the neonatologist. Furthermore, their frequency and magnitude are commonly underestimated by clinically employed pulse oximeter settings. In extremely low birth weight infants the incidence of intermittent hypoxia [IH] progressively increases over the first 4 weeks of postnatal life, with a subsequent plateau followed by a slow decline beginning at weeks six to eight. Over this period of unstable respiratory control, increased oxygen-sensitive peripheral chemoreceptor activity has been associated with a higher incidence of apnea of prematurity. In contrast, infants with bronchopulmonary dysplasia [chronic neonatal lung disease] exhibit decreased peripheral chemosensitivity, although the effect on respiratory stability in this population is unclear. Such episodic hypoxia/reoxygenation in early life has the potential to sustain a proinflammatory cascade with resultant multisystem, including respiratory, morbidity. Therapeutic approaches for intermittent hypoxic episodes comprise careful titration of baseline or supplemental inspired oxygen as well as xanthine therapy to prevent apnea of prematurity. Characterization of the pathophysiologic basis for such intermittent hypoxic episodes and their consequences during early life is necessary to provide an evidence-based approach to their management. PMID- 23080183 TI - Chronic intermittent hypoxia increases apnoea index in sleeping rats. AB - Intermittent hypoxia (IH) is the dominant feature of sleep-disordered breathing which is very common. It is recognized that IH elicits plasticity in the respiratory control system. Recently it was reported in humans that IH destabilizes breathing during sleep increasing the susceptibility to apnoea. Many forms of respiratory plasticity are dependent upon reactive oxygen species (ROS), and NADPH oxidase has been identified as an important source of ROS necessary for IH-induced plasticity. In the present study, we sought to examine the effects of chronic IH (CIH) on the propensity for spontaneous apnoea during sleep. Adult male Wistar rats were exposed to 20 cycles of normoxia and hypoxia (5% O(2) at nadir; SaO(2) ~ 80%) per hour, 8 h a day for 7 consecutive days (CIH group, N = 6). The sham group (N = 6) were subject to alternating cycles of air under identical experimental conditions in parallel. Two additional groups of CIH treated rats were given either the superoxide dismutase mimetic - tempol (1 mM, N = 8), or the NAPDH oxidase inhibitor - apocynin (2 mM, N = 8) in their drinking water throughout the study. Following gas exposures, breathing during sleep was assessed in unrestrained animals using the technique of whole-body plethysmography. CIH significantly increased apnoea index during sleep (4.7 +/- 0.8 vs. 11.3 +/- 1.6 events/h; mean +/- SEM, sham vs. CIH, Student's t test, p = 0.0035). Apnoea duration was unaffected by CIH treatment. The CIH-induced increase in the occurrence of apnoea was completely reversed by antioxidant supplementation (4.9 +/- 0.9 events/h for CIH + tempol and 5.6 +/- 0.9 events/h for CIH + apocynin). CIH-induced increase in the propensity for apnoea may have clinical relevance and may explain the phenomenon of 'complex' apnoea in sleep apnoea patients. Our results suggest that oxidative stress is implicated in CIH induced respiratory disturbance during sleep. We conclude that antioxidants may be a realistic adjunct therapy in the treatment of sleep-disordered breathing. PMID- 23080184 TI - Contribution of TASK-like potassium channels to the enhanced rat carotid body responsiveness to hypoxia. AB - A major hallmark of obstructive sleep apnea is the potentiation of the carotid body (CB) chemosensory response to acute hypoxia, as result of the chronic intermittent hypoxia (CIH) exposition. Several mechanisms have been involved in this CB chemosensory potentiation, but the primary target of CIH remains elusive. In physiological conditions, hypoxia depolarized CB chemoreceptor cells, trigger an increase of intracellular Ca(2+), and the subsequent transmitter's release. Since the depolarization is initiated by the inhibition of a TASK-like K(+) channel, we studied if CIH may increase the amplitude of the hypoxic-induced depolarization in the chemoreceptor cells, due to an enhanced inhibition of the TASK-like current.CBs obtained from adult rats exposed to CIH (5% O2, 12 times/hr for 8 hr/day) for 7 days were acute dissociated, and the membrane potential and TASK-like current were recorded from isolated chemoreceptor cells. Resting membrane properties were not modified by CIH, but the amplitude of the hypoxic evoked depolarization increases ~2-fold. The same result was obtained when all the voltage-dependent K(+) currents were pharmacologically blocked. Accordingly, the inhibition of the TASK-like current induced by acute hypoxia (PO(2) ~5 torr) increased from ~62% in control cells to ~96% in the CIH cells.Present results show that acute hypoxic inhibition of TASK-like K(+) channel is potentiated by CIH exposure, suggesting that the enhancing effect of CIH on CB chemosensory responsiveness to hypoxia occurs at the initial step of the oxygen transduction in the CB chemoreceptor cells. PMID- 23080185 TI - Antioxidation and the hypoxic ventilatory response. AB - Reactive oxygen species favor the reductive state of iron. Antioxidation, by depleting biologically active ferrous iron, could then have a stabilizing effect, akin to hypoxia, on HIF-1alpha; the process which controls the genetic responses to hypoxia. However, the influence of antioxidation on the hypoxic ventilatory responses (HVR) is unclear. In this study we set out to determine the influence of mangiferin, a natural polyphenolic compound present in mango trees, with strong antioxidant and iron chelating properties, on the HVR. The study was performed in awake Wistar rats. Acute HVR to 12% and 8% FiO(2) before and 40 min after mangiferin (300 mg/kg, i.p.) pretreatment were recorded plethysmographically. We found that mangiferin significantly dampened the HVR over its course. To distinguish between the scavenging and chelating mechanisms of mangiferin we reinvestigated its effects on the HVR in a separate group of rats after chronic antecedent iron chelation with ciclopirox olamine (20 mg/kg daily for 1 week). The dampening effect on the HVR of mangiferin was preserved in the pre-chelated rats, which points to the preponderance of the antioxidant over chelating properties of mangiferin in its ventilatory effects. Although the exact determinants of mangiferin action remain unclear, the study suggests a role for oxidative signaling in the peripheral chemosensory processing of the HVR. The study also implies the possible clinical use of the antioxidant mangiferin in the regulation of lung ventilation. PMID- 23080186 TI - Differential regulation of tyrosine hydroxylase by continuous and intermittent hypoxia. AB - Although continuous hypoxia (CH) and intermittent hypoxia (IH) cause reduction in oxygen availability, organisms adapt to the effects of chronic CH whereas IH adversely impacts autonomic functions. Catecholamines are expressed both in the central and peripheral nervous systems and they play important roles in the regulation of cardio-respiratory functions during hypoxia. Tyrosine hydroxylase (TH) is the rate-limiting enzyme for catecholamine synthesis. Several studies have examined the effects of hypoxia on catecholamines by focusing on the regulation of TH. In this article, we present a brief overview of the impact of chronic CH and IH on TH expression, activity and the associated cellular mechanism(s). PMID- 23080187 TI - Heart failure and carotid body chemoreception. AB - There is substantial evidence to implicate a role of the carotid body (CB) chemoreflex in sympathetic and breathing dysregulation in several cardio respiratory diseases, drawing renewed interest in its potential implications for clinical treatment and management. Evidence from both chronic heat failure (CHF) patients and animal models indicates that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in sympathetic nerve activity (SNA) and periodic breathing associated with the disease. Although this maladaptive change likely derives from altered function at all levels of the reflex arc, a change in afferent function of the CB is likely to be a main driving force. This review will focus on recent advances in our understanding of the physiological mechanisms that alter CB function in CHF and their potential translational impact on treatment of CHF. PMID- 23080188 TI - Effects of strontium ranelate administration on calcium metabolism in female patients with postmenopausal osteoporosis and primary hyperparathyroidism. AB - We investigated possible changes of parameters of calcium metabolism induced by strontium ranelate (SR). Twenty-three patients with postmenopausal osteoporosis (PO) and 14 with primary hyperparathyroidism (PHPT) were studied while taking 2 g/day of SR. Women with PO and 10 healthy age-matched control women were also daily supplemented with 1,000 mg calcium and 800 IU vitamin D. All subjects were studied at baseline and after 7 and 30 days; PO women and controls were also investigated at 180 and 360 days of treatment. Serum ionized calcium (iCa), phosphate (sP), magnesium, creatinine, 25-hydroxycholecalciferol (25[OH]D), 1,25 dihydroxycholecalciferol (1,25[OH](2)D), serum parathyroid hormone (PTH) were measured. In spot urine, we assessed calcium and phosphate over creatinine ratios (uCa/Cr, uP/Cr), calcium excretion (Ca ex) and renal phosphate threshold (TmP/GFR); in 24-h urine, calcium and magnesium over creatinine clearance ratios (CaCl/CrCl and MgCl/CrCl). In PO, SR administration was associated with a significant decrease of PTH and 1,25(OH)(2)D levels but an increase of sP (p < 0.001). SR also significantly increased Ca/Cr, Ca ex, and TmP/GFR in spot urine and CaCl/CrCl in both spot and 24-h urine (p = 0.004 to <0.001). In PHPT, SR significantly decreased iCa and increased sP, slightly modifying PTH, 25(OH)D, and 1,25(OH)(2)D values. Also in PHPT, Ca ex and CaCl/CrCl of spot and 24-h urine, as TmP/GFR, significantly increased (all p < 0.02). SR influenced the main parameters of calcium homeostasis, probably through the calcium-sensing receptor. PMID- 23080189 TI - Cytofluorometric detection of wine lactic acid bacteria: application of malolactic fermentation to the monitoring. AB - In this study we report for the first time a rapid, efficient and cost-effective method for the enumeration of lactic acid bacteria (LAB) in wine. Indeed, up to now, detection of LAB in wine, especially red wine, was not possible. Wines contain debris that cannot be separated from bacteria using flow cytometry (FCM). Furthermore, the dyes tested in previous reports did not allow an efficient staining of bacteria. Using FCM and a combination of BOX/PI dyes, we were able to count bacteria in wines. The study was performed in wine inoculated with Oenococcus oeni (10(6) CFU ml(-1)) stained with either FDA or BOX/PI and analyzed by FCM during the malolactic fermentation (MLF). The analysis show a strong correlation between the numbers of BOX/PI-stained cells determined by FCM and the cell numbers determined by plate counts (red wine: R (2) >= 0.97, white wine R (2) >= 0.965). On the other hand, we found that the enumeration of O. oeni labeled with FDA was only possible in white wine (R (2) >= 0.97). Viable yeast and LAB populations can be rapidly discriminated and quantified in simultaneous malolactic-alcoholic wine fermentations using BOX/PI and scatter parameters in a one single measurement. This rapid procedure is therefore a suitable method for monitoring O. oeni populations during winemaking, offers a detection limit of <10(4) CFU ml(-1) and can be considered a useful method for investigating the dynamics of microbial growth in wine and applied for microbiological quality control in wineries. PMID- 23080190 TI - Assessment of quality-assured Tarocco orange fruit sorting rules by combined physicochemical and sensory testing. AB - BACKGROUND: The aim of this study was to extract a sorting rule for Tarocco orange fruit from several physicochemical and sensory tests performed on a marketable lot of 399 Tarocco orange fruits. RESULTS: The elastic tension at 5% strain (T5 ) was found to be linearly correlated (r = 0.65) with the Magness Taylor (MT) index. Thus T5 was regarded as a non-destructive parameter quantifying fruit firmness and used to categorise the aforementioned lot in three different firmness classes, high (HF), medium (MF) and low (LF). Only the MT index, fruit rind thickness near the fruit peduncle, lightness coefficient and yellow/blue hue component of the orange flesh, as well as total soluble solid content, confirmed the validity of this discrimination at the significance level of 5%. Sensory professionals recognised the greater compactness (7 +/- 2) but lower ease of peeling (4 +/- 2) and segment separation (4 +/- 2) of the HF oranges with respect to the corresponding sensory attributes of orange fruits grouped in the MF and LF classes. CONCLUSION: To limit the costly rejection of Tarocco orange fruit considered too soft, especially after long-term shipping, it would be reasonable to select only fruits characterised by a compressive force or tension at 5% strain in the range 23-41 N or 300-540 N m-1 respectively. PMID- 23080192 TI - Resources for life. AB - Understanding how gene expression is regulated requires much more than the identity of genomic sequences. PMID- 23080193 TI - Therapeutic potential of targeting IL-17. AB - A June 2012 meeting in Dublin, Ireland, showcased advances in the understanding of the role of IL-17 and related cytokines in host immunity and how these cytokines have been successfully targeted for the treatment of autoimmunity. PMID- 23080194 TI - TBK1 suppression of IgA in the NIK of time. PMID- 23080195 TI - The case of the missing c-Myc. PMID- 23080191 TI - Brain ischemia activates beta- and gamma-secretase cleavage of amyloid precursor protein: significance in sporadic Alzheimer's disease. AB - Amyloid precursor protein cleavage through beta- and gamma-secretases produces beta-amyloid peptide, which is believed to be responsible for death of neurons and dementia in Alzheimer's disease. Levels of beta- and gamma-secretase are increased in sensitive areas of the Alzheimer's disease brain, but the mechanism of this process is unknown. In this review, we prove that brain ischemia generates expression and activity of both beta- and gamma-secretases. These secretases are induced in association with oxidative stress following brain ischemia. Data suggest that ischemia promotes overproduction and aggregation of beta-amyloid peptide in brain, which is toxic for ischemic neuronal cells. In our review, we demonstrated the role of brain ischemia as a molecular link between the beta- and the gamma-secretase activities and provided a molecular explanation of the possible neuropathogenesis of sporadic Alzheimer's disease. PMID- 23080196 TI - Balancing pro- and anti-inflammatory TLR4 signaling. PMID- 23080197 TI - The ubiquitous nature of IL-17. PMID- 23080205 TI - Guided plasmonic modes of anisotropic slot waveguides. AB - We study guided optical modes of a planar plasmonic waveguide filled with a generic anisotropic medium. In particular, we show that both surface and oscillatory modes exist for such waveguides and find their numbers for two specific forms of the anisotropy tensor. We also show that lossless waveguides, characterized by a diagonal permittivity tensor, support simultaneously both the forward and backward propagating modes (surface or oscillatory type) with antisymmetric field patterns. Another family of guided oscillatory modes may be supported by the waveguide if its anisotropy is created by an external magnetic field. These new modes are asymmetric in nature, exhibit extremely low effective refractive indices and may propagate over macroscopic distances without significant attenuation, while remaining strongly confined to the waveguide. PMID- 23080206 TI - Fluorescence of colloidal PbSe/PbS QDs in NIR luminescent solar concentrators. AB - For applications in luminescent solar concentrators harvesting subgap photons, either via direct irradiation of solar cells with optimized band gap or via sensitization of an up-conversion process, exact knowledge and tunability of both the spectral shape and the intensity of the emission are of paramount importance. In this work, we investigate theoretically the photoluminescence spectra of colloidal core-shell PbSe/PbS QDs with type II alignments in the valence band. The method builds on a steady-state formulation of the non-equilibrium Greens function theory for a microscopic system of coupled electrons, photons and phonons interfaced with electronic structure calculations based on a k.p model for PbSe/PbS core-shell QDs. The resulting output spectral density of photons in a realistic QD ensemble is obtained via the renormalization of the incident spectrum according to the polarization of the system. PMID- 23080207 TI - What do repetitive and stereotyped movements mean for infant siblings of children with autism spectrum disorders? AB - Repetitive and stereotyped movements (RSMs) in infancy are associated with later diagnoses of autism spectrum disorder (ASD), yet this relationship has not been fully explored in high-risk populations. The current study investigated how RSMs involving object and body use are related to diagnostic outcomes in infant siblings of children with ASD (Sibs-ASD) and typically developing children (Sibs TD). The rate and number of different types of RSMs were measured at an average of 15 months with follow-up diagnostic evaluations approximately 18 months later. While Sibs-ASD displayed higher rates of RSMs relative to Sibs-TD, rates did not differ according to diagnostic outcome in Sibs-ASD. However preliminary evidence suggests that qualitative differences in RSM type warrant further investigation as early diagnostic markers. PMID- 23080204 TI - Cytokines of the gamma(c) family control CD4+ T cell differentiation and function. AB - Naive CD4(+) T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4(+) T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common gamma-chain (gamma(c)) family in the determination of the effector helper T cell phenotype that naive CD4(+) T cells adopt after being activated and in the function of these helper T cells. PMID- 23080208 TI - Brief report: learning via the electronic interactive whiteboard for two students with autism and a student with moderate intellectual disability. AB - The effects of a multicomponent intervention (a self-operated video modeling and self-monitoring delivered via an electronic interactive whiteboard (IWB) and a system of least prompts) on skill acquisition and interaction behavior of two students with autism and one student with moderate intellectual disability were examined using a multi-probe across students design. Students were taught to operate and view video modeling clips, perform a chain of novel tasks and self monitor task performance using a SMART Board IWB. Results support the effectiveness of a multicomponent intervention in improving students' skill acquisition. Results also highlight the use of this technology as a self-operated and interactive device rather than a traditional teacher-operated device to enhance students' active participation in learning. PMID- 23080210 TI - Clusters of personality disorder cognitions in the eating disorders. AB - This study examined whether comorbid personality disorder pathology in the eating disorders clusters into broader patterns, and whether those clusters have clinical validity in terms of levels of eating pathology and axis 1 comorbidity. The sample consisted of 214 eating-disordered women who completed measures of personality disorder cognitions, eating pathology and axis 1 pathology at assessment. Three clusters of eating disorder patients emerged-low levels of personality pathology overall, high levels of cognitions underpinning anxiety based personality pathology, and high levels of all of the dimensions of personality pathology. These groups were validated by differences in levels of eating cognitions and axis 1 pathology. Personality disorder cognitions are clinically relevant to the eating disorders, but they might best be understood as broader sets of cognitions ('anxiety-centred' and 'general'), rather than in terms of individual personality disorder comorbidity or existing DSM personality disorder clusters. PMID- 23080211 TI - Cortical maturation in fetuses referred for 'isolated' mild ventriculomegaly: a longitudinal ultrasound assessment. AB - OBJECTIVES: To compare cortical maturation between fetuses with isolated mild ventriculomegaly (IMV) and healthy fetuses, and to explore its potential prognostic value in IMV. METHODS: This prospective study quantified cortical maturation by ultrasound in 24 fetuses with IMV and 46 healthy fetuses. Depth and grading the developmental pattern of the parieto-occipital fissure (POF), calcarine fissure (CF) and sylvian fissure, and grading the Sylvian fissure operculization at 23-25, 27-28 and 31-32 weeks gestation were determined. RESULTS: At 23-25 and 27-28 gestational weeks, POF and CF mean depths were statistically lower in the IMV group. The POF and CF depth distribution had a normal distribution in the control group but displayed a bimodal distribution in the IMV group. IMV with progression of ventricular dilatation showed mean depth of CF lower than IMV in which ventriculomegaly regressed or remained stable. The sensitivity, specificity, positive predictive value and negative predictive value of a CF depth below the fifth percentile to predict progression of ventricular dilatation were, at 28 weeks, 100%, 88%, 67% and 100%, respectively. CONCLUSIONS: Cortical fissure assessment by ultrasound allowed the differentiation of a subgroup of IMV fetuses with a higher risk of progression of ventricular dilatation. PMID- 23080212 TI - Endovascular treatment of false-aneurysm ten years after dacron patch aortoplasty for coarctation of the aortic isthmus. Report of a case. AB - False aneurysm degeneration is a known complication of patch aortoplasty for coarctation of the aortic isthmus. Open surgical treatment consists of prosthetic graft repair of the involved aorta, often requires circulatory arrest to achieve a safe proximal aortic control and perform proximal anastomosis, and finally is associated with substantial perioperative morbidity. Endografting of the diseased aorta is a valuable alternative to open repair, when feasible, with good short and long term results. We now report one more case of false aneurysm ten years after Dacron patch aortoplasty for isthmic coarctation in a 26-year-old woman, successfully treated by endovascular repair via the left common iliac artery, and a complete exclusion of the aneurysm at two year follow-up. PMID- 23080209 TI - Pleiotropic function of SRY-related HMG box transcription factor 4 in regulation of tumorigenesis. AB - In addition to their critical roles in embryonic development, cell fate decision, and differentiation, members of Sox (Sry-related high-mobility group box) family of transcription factors including Sox4 have been implicated in various cancers. Multiple studies have revealed an increased expression along with specific oncogenic function of Sox4 in tumors, while others observed a reduced expression of Sox4 in different types of malignancies and suppression of tumor initiation or progression by this protein. More interestingly, the prognostic value of Sox4 is debated due to obvious differences between various reports as well as inconsistencies within specific studies. This review summarizes our current understanding of Sox4 expression pattern and its transcription-dependent, as well as transcription-independent, functions in tumor initiation or progression and its correlation with patient survival. We also discuss the existing discrepancies between different reports and their possible explanations. PMID- 23080213 TI - Architecture of fibrin network inside thrombotic material obtained from the right atrium and pulmonary arteries: flow and location matter. AB - Pulmonary embolectomy is a treatment option in selected patients with high-risk pulmonary embolism (PE). Efficiency of thrombus degradation in PE largely depends on the architecture of its fibrin network, however little is known about its determinants. We present the case of a 56-year-old woman with high-risk PE and proximal deep-vein thrombosis, whose thrombotic material removed during embolectomy from the right atrium and pulmonary (lobar and segmental) arteries has been studied using scanning electron microscopy (SEM). SEM images showed that distally located thrombi are richer in densely-packed fibrin fibers and contain more white cells and less erythrocytes than the proximal ones and the atrial thrombus. Fibrin fibers alignment along the flow vector was observed in the thrombi removed from high-velocity flow pulmonary arteries, and not in the atrial thrombus. The content of denser fibrin network and platelet aggregates was increased in segmental thromboemboli. Our findings describe the relation between thrombus architecture and location, and might help to elucidate thrombus resistance to anticoagulant therapy in some PE patients. PMID- 23080214 TI - Music therapy in dementia: a narrative synthesis systematic review. AB - OBJECTIVE: Recent reviews on music therapy for people with dementia have been limited to attempting to evaluate whether it is effective, but there is a need for a critical assessment of the literature to provide insight into the possible mechanisms of actions of music therapy. This systematic review uses a narrative synthesis format to determine evidence for effectiveness and provide insight into a model of action. METHOD: The narrative synthesis framework consists of four elements: (i) theory development; (ii) preliminary synthesis of findings; (iii) exploration of relationships between studies; and (iv) assessment of the robustness of the synthesis. RESULTS: Electronic and hand searches identified 263 potentially relevant studies. Eighteen studies met the full inclusion criteria. Three distinctive strands of investigations emerged: eight studies explored behavioural and psychological aspects, five studies investigated hormonal and physiological changes, and five studies focused on social and relational aspects of music therapy. The musical interventions in the studies were diverse, but singing featured as an important medium for change. CONCLUSIONS: Evidence for short-term improvement in mood and reduction in behavioural disturbance was consistent, but there were no high-quality longitudinal studies that demonstrated long-term benefits of music therapy. Future music therapy studies need to define a theoretical model, include better-focused outcome measures, and discuss how the findings may improve the well-being of people with dementia. PMID- 23080215 TI - Interactions of staphylococci with osteoblasts and phagocytes in the pathogenesis of implant-associated osteomyelitis. AB - In spite of great advancements in the field of biomaterials and in surgical techniques, the implant of medical devices is still associated with a high risk of bacterial infection. Implant-associated osteomyelitis is a deep infection of bone around the implant. The continuous inflammatory destruction of bone tissues characterizes this serious bone infectious disease. Staphylococcus aureus and Staphylococcus epidermidis are the most prevalent etiologic agents of implant associated infections, together with the emerging pathogen Staphylococcus lugdunensis. Various interactions between staphylococci, osteoblasts, and phagocytes occurring in the peri-prosthesis environment play a crucial role in the pathogenesis of implant-associated osteomyelitis. Here we focus on two main events: internalization of staphylococci into osteoblasts, and bacterial interactions with phagocytic cells. PMID- 23080216 TI - In vitro antibacterial activity of different self-etch adhesives. AB - PURPOSE: The aim of this study was to evaluate and compare the antimicrobial activity of different self-etch adhesives by means of the agar disc diffusion test. METHODS: Streptococcus salivarius, Streptococcus sanguis and Streptococcus mutans strains were selected to evaluate the antimicrobial activity of various self-etch adhesives (Futurabond NR, G-aenial Bond, AdperTM Easy Bond Self-Etch Adhesive, Clearfil Protect Bond, One Coat 7.0, Clearfil S3 Bond, Clearfil SE Bond) using the agar disc diffusion test; 0.2% Chlorexidine digluconate was used as control. Paper disks were saturated with 10 uL of each adhesive system and placed onto culture agar plates pre-adsorbed with bacterial cells and further incubated for 24 h at 37 degrees C. The growth inhibition zones around each adhesive were recorded and compared for each bacterial strain. RESULTS: The test results of the various self-etch adhesives were significantly different. CONCLUSIONS: The results of the present investigation showed that the addition of MDPB monomer to an adhesive system enhances its antibacterial effect against S. salivarius, S. sanguis and S. mutans. PMID- 23080217 TI - Antibacterial efficacy of conventional and single-use Ni-Ti endodontic instruments: an in vitro microbiological evaluation. AB - PURPOSE: The purpose of this in vitro study was to investigate the capability of different Ni-Ti instruments in disinfecting root canals previously infected with E. faecalis. METHODS: 60 single-rooted, freshly extracted teeth were selected, sterilized and inoculated with cells of E. faecalis strain. All root canals were shaped with different Ni-Ti instruments (MTwo, Revo-S, Reciproc, and OneShape) under irrigation with NaOCl and 17% EDTA solutions by the same trained operator. The number of Colony Forming Units (CFU)/ml of E. faecalis was evaluated for each group. Numeric data were submitted to statistical analysis. RESULTS: MTwo, REVO S, Reciproc and OneShape reported significantly lower CFU/ml values and showed no significant differences among them (p>0.05). All groups showed significantly higher CFU/ml values than not treated samples (negative control). CONCLUSIONS: All the Ni-Ti instrumentation efficiently reduced E. faecalis counts and no significant differences were found among them. Single-use files can offer antibacterial results comparable with traditional instruments. PMID- 23080218 TI - The kinetics of lanthanide complexation by EDTA and DTPA in lactate media. AB - The interaction of trivalent lanthanide and actinide cations with polyaminopolycarboxylic acid complexing agents in lactic acid buffer systems is an important feature of the chemistry of the TALSPEAK process for the separation of trivalent actinides from lanthanides. To improve understanding of metal ion coordination chemistry in this process, the results of an investigation of the kinetics of lanthanide complexation by ethylenediamine-N,N,N',N'-tetraacetic acid (EDTA) and diethylenetriamine-N,N,N',N'',N''-pentaacetic acid (DTPA) in 0.3 M lactic acid/0.3 M ionic strength solution are reported. Progress of the reaction was monitored using the distinctive visible spectral changes attendant to lanthanide complexation by the colorimetric indicator ligand Arsenazo III, which enables the experiment but plays no mechanistic role. Under the conditions of these experiments, the reactions occur in a time regime suitable for study by stopped-flow spectrophotometric techniques. Experiments have been conducted as a function of EDTA/DTPA ligand concentration, total lactic acid concentration, and pH. The equilibrium perturbation reaction proceeds as a first order approach to equilibrium over a wide range of conditions, allowing the simultaneous determination of complex formation and dissociation rate constants. The rate of the complexation reaction has been determined for the entire lanthanide series (except Pm(3+)). The predominant pathway for lanthanide-EDTA and lanthanide-DTPA dissociation is inversely dependent on the total lactate concentration; the complex formation reaction demonstrates a direct dependence on [H(+)]. Unexpectedly, the rate of the complex formation reaction is seen in both ligand systems to be fastest for Gd(3+). Correlation of these results indicates that in 0.3 M lactate solutions the exchange of lanthanide ions between lactate complexes and the polyaminopolycarboxylate govern the process. PMID- 23080219 TI - Divergence of water balance mechanisms in two sibling species (Drosophila simulans and D. melanogaster): effects of growth temperatures. AB - Drosophila simulans is more abundant under colder and drier montane habitats in the western Himalayas as compared to its sibling D. melanogaster but the mechanistic bases of such climatic adaptations are largely unknown. Previous studies have described D. simulans as a desiccation sensitive species which is inconsistent with its occurrence in temperate regions. We tested the hypothesis whether developmental plasticity of cuticular traits confers adaptive changes in water balance-related traits in the sibling species D. simulans and D. melanogaster. Our results are interesting in several respects. First, D. simulans grown at 15 degrees C possesses a high level of desiccation resistance in larvae (~39 h) and in adults (~86 h) whereas the corresponding values are quite low at 25 degrees C (larvae ~7 h; adults ~13 h). Interestingly, cuticular lipid mass was threefold higher in D. simulans grown at 15 degrees C as compared with 25 degrees C while there was no change in cuticular lipid mass in D. melanogaster. Second, developmental plasticity of body melanisation was evident in both species. Drosophila simulans showed higher melanisation at 15 degrees C as compared with D. melanogaster while the reverse trend was observed at 25 degrees C. Third, changes in water balance-related traits (bulk water, hemolymph and dehydration tolerance) showed superiority of D. simulans at 15 degrees C but of D. melanogaster at 25 degrees C growth temperature. Rate of carbohydrate utilization under desiccation stress did not differ at 15 degrees C in both the species. Fourth, effects of developmental plasticity on cuticular traits correspond with changes in the cuticular water loss i.e. water loss rates were higher at 25 degrees C as compared with 15 degrees C. Thus, D. simulans grown under cooler temperature was more desiccation tolerant than D. melanogaster. Finally, desiccation acclimation capacity of larvae and adults is higher for D. simulans reared at 15 degrees C but quite low at 25 degrees C. Thus, D. simulans and D. melanogaster have evolved different strategies of water conservation consistent with their adaptations to dry and wet habitats in the western Himalayas. Our results suggest that D. simulans from lowland localities seems vulnerable due to limited acclimation potential in the context of global climatic change in the western Himalayas. Finally, this is the first report on higher desiccation resistance of D. simulans due to developmental plasticity of both the cuticular traits (body melanisation and epicuticular lipid mass) when grown at 15 degrees C, which is consistent with its abundance in temperate regions. PMID- 23080220 TI - Metabolic and water loss rates of two cryptic species in the African velvet worm genus Opisthopatus (Onychophora). AB - Velvet worms (Onychophora) are characterised by a dearth of mechanisms to retain water, yet recently identified cryptic species are located in areas with seemingly different climates. Using flow-through respirometry, this study determined the metabolic, water loss and cuticular water loss rates of two cryptic species of Opisthopatus cinctipes s.l. from locations that differ in their current climate. When controlling for trial temperature and body mass, velvet worms from the drier and warmer site had significantly lower water loss rates than the wetter and cooler site. Mass-corrected metabolic rate and cuticular water loss did not differ significantly between the two sites. The scaling exponent for the relationship between log metabolic rate and log body mass for O. cinctipes s.l. declined with an increase in temperature from 5 to 15 degrees C. Females in the two cryptic Opisthopatus species had higher metabolic, water loss and cuticular water loss rates than males, which may represent the increased energetic demands of embryonic growth and development in these viviparous taxa. PMID- 23080221 TI - Aerobic training does not alter blood pressure in menopausal women with metabolic syndrome. AB - BACKGROUND: Arterial Hypertension (AH) is an aggravating condition for Metabolic Syndrome (MS), as well as being aggravated by it. Menopause can make hypertension treatment more difficult, as it favors the worsening of MS components. Although there is evidence that exercise training reduces blood pressure, whether menopause and SM affect the exercise-induced benefits is yet to be elucidated. OBJECTIVE: To compare the effects of aerobic training on blood pressure in non menopausal and menopausal women with MS METHODS: A total of 44 women were recruited and divided into four groups: non-menopausal control (NMC: 39.5 +/- 3.6 years, n = 11); menopausal control (MC: 54.9 +/- 5.9 years, n = 12), non menopausal aerobics (NMA: 43.1 +/- 6.8 years, n = 11) and menopausal aerobics (MA: 52.1 +/- 5 years, n = 10). The exercise groups performed aerobic training for three months, five times a week, at an intensity between 60% and 70% of heart rate reserve. The resting blood pressure and blood pressure response after 60 minutes of exercise were measured before and after the training period. The two way ANOVA test was used, considering a p value < 0.05. RESULTS: The training program resulted in a decrease in abdominal fat, blood glucose and improved VO2 max. Compared to pre-intervention values, Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) did not change after training in NMC, MC, MA and NMA groups (p > 0.05). CONCLUSION: Three months of aerobic training improved MS components, but did not alter resting blood pressure or the BP response after an acute exercise session in women with MS. PMID- 23080222 TI - Issuing electrocardiographic reports remotely: experience of the telemedicine network of Santa Catarina. AB - BACKGROUND: A growing use of telemedicine has been observed, especially as regards the sending and evaluation of electrocardiograms (ECG); this is a low cost procedure with a high potential to save lives. OBJECTIVES: To describe the form of systematic analysis and user profile of the Telemedicine Network of Santa Catarina during the time when the report was issued freely. METHODS: Observational cross-sectional study determining the associations between patient characteristics and electrocardiographic diagnoses issued among users of the Telemedicine Network of Santa Catarina during the time when the report was issued freely. This system was connected to 287 cities in Santa Catarina; the tests were done in the places of origin and the reports were issued in three tertiary-care hospitals. From 2005 to 2010 the reports were issued freely and a probabilistic method for data analysis was created. An experienced cardiologist evaluated all ECGs to assess the chances of abnormality. RESULTS: 243,363 ECGs were evaluated. The majority (58%) was performed on patients older than 50 years from primary care services (72%). There were differences in the frequency per region; this was partly related to the number of cardiologists/region (r = -0.551), to the distance from tertiary-care centers and potential differences of acceptance of the method. Approximately 53% of the ECGs were abnormal with greater frequency with increasing age (r(2) = 0.8166) and with significant regional differences (p < 0.0001). CONCLUSIONS: We built a data analysis system integrating prevalent terms, probabilistic analysis and specialized dictionaries. The system has covered a significant portion of the population of Santa Catarina, mainly elderly patients from the network of primary healthcare centers and remote regions of the State. PMID- 23080223 TI - Association of biomarkers with atherosclerosis and risk for coronary artery disease in patients with HIV. AB - BACKGROUND: The massive use of Highly-Active Antiretroviral Therapy (HAART) in individuals with human immunodeficiency virus (HIV) coincided with an increase in cardiovascular disease, a major cause of morbidity and mortality in this group. OBJECTIVE: To determine the frequency of carotid atherosclerosis and the association between biomarker levels and carotid intimal-medial thickening in HIV positive individuals treated for HIV at referral centers in Pernambuco. METHODS: This was a cross-sectional study of 122 HIV-positive patients. Subclinical carotid atherosclerosis was considered with the presence of increased intimal medial thickness of the common carotid artery > 0.8 mm or plaques in the carotid ultrasound. The following inflammatory biomarkers were analyzed: IL6, IL1-beta, TNF-alpha, high-sensitivity CRP, sVCAM-1 and sICAM-1. RESULTS: Of the 122 patients analyzed, most were men (60.7%) aged > 40 years (57.4%) receiving HAART (81.1%). The prevalence of atherosclerosis was 42.6% (52 cases). Patients older than 40 years and intermediate or high Framingham score were more likely to develop atherosclerosis at the univariate analysis. Age older than 40 years (OR = 6.57, 95%CI: 2.66 to 16.2, p = 0.000), male gender (OR = 2.76, 95%CI: 1.12 to 6.79, p = 0.027) and presence of syndrome metabolic (OR = 2.27, 95%CI: 0.94 to 5.50, p = 0.070) were associated with atherosclerosis at the multivariate analysis. Elevated levels of inflammatory cytokines and adhesion molecules were not associated with the presence of atherosclerosis. CONCLUSION: There was no association between inflammatory biomarkers, adhesion molecules and presence of carotid atherosclerosis. However, a higher chance of subclinical atherosclerosis was observed in men, those older than 40 years, with intermediate / high Framingham score or metabolic syndrome. PMID- 23080224 TI - Effectiveness and safety of antiplatelet therapy in stroke recurrence prevention in patients with liver cirrhosis: a 2-year follow-up study. AB - BACKGROUND: Data are limited on antiplatelet therapy for ischemic stroke prevention in liver cirrhosis patients. METHODS: This retrospective study identified cases of liver cirrhosis from the National Health Insurance Research Database. Antiplatelet therapy was administered for 2 years to patients who had experienced a first ischemic stroke between 1997 and 2006. Primary outcomes, including death and readmission to hospital for stroke, and secondary outcomes, including death, stroke, or gastrointestinal bleeding, were examined. RESULTS: One thousand one hundred eighty patients experienced a first stroke. According to time-dependent analysis, the hazard ratio for primary outcomes in patients treated with aspirin was 0.915 (95%CI: 0.872-0.960). In secondary outcomes, hazard ratio for readmission for stroke was 0.904 (95%CI: 0.836-0.978) and that for gastrointestinal bleeding was 0.998 (95%CI: 0.946-1.052) in patients treated with aspirin. Subgroup analysis showed that aspirin was more effective in patients with non-alcoholic cirrhosis than in those with other types of liver cirrhosis. Moreover, hyperlipidemia and statins may have decreased the efficacy of antiplatelet therapy in cirrhosis patients. CONCLUSIONS: This study includes the largest sample for evaluating outcomes of antiplatelet therapy in liver cirrhosis patients for preventing recurrent stroke. The study results show that antiplatelet therapy still offers safe and effective treatment for ischemic stroke prevention in patients with cirrhosis. PMID- 23080226 TI - Use of imaging techniques to predict progression in osteoarthritis. AB - PURPOSE OF REVIEW: Disease progression of osteoarthritis is usually assessed using radiographs. Utilizing sensitive measures such as magnetic resonance imaging (MRI) may allow us to understand the progressive trajectory of this disease from initial to joint failure stages. This review aims to describe the recent epidemiological and clinical evidence about osteoarthritis disease progression and the risk factors associated with disease progression. RECENT FINDINGS: Changes in MRI-detected structural abnormalities, including increases in cartilage defects and bone marrow lesions (BMLs), loss of cartilage volume and thickness, and alterations of compositional measures, have been utilized to assess osteoarthritis disease progression. Both clinical risk factors (such as obesity or body fat, muscle weakness, malalignment, metabolic disorders, inflammation, and joint pain) and joint structural factors (such as cartilage defects, BMLs, meniscal pathology, synovitis, and radiographic features) have been associated with osteoarthritis disease progression. With the modification of these factors through interventions such as weight loss, we may slow the progression. SUMMARY: MRI techniques allow us to measure osteoarthritis disease progression and to discover novel risk factors for prevention and innovative strategies for treatment. These also allow identifying persons at greatest risk of disease progression, which may enhance the efficiency of clinical trials through reducing sample size and shortening follow-up period. PMID- 23080227 TI - Aging processes and the development of osteoarthritis. AB - PURPOSE OF REVIEW: Aging is a primary risk factor for the development of osteoarthritis and the understanding of how aging processes contribute to the development of osteoarthritis is an important area of active research. The most recent literature in this area was reviewed in order to update investigators on the status of the field. RECENT FINDINGS: The field is beginning to move beyond a cartilage focus to include other joint tissues relevant to osteoarthritis such as ligaments, meniscus, and bone. Synovitis also appears to play a role in osteoarthritis but has not been a focus of aging studies. Studies in small animals, including mice and rats, demonstrate age-related changes that can contribute to osteoarthritis and show that animal age is a key factor to be considered in interpreting the results of studies using surgically induced models of osteoarthritis. There is accumulating evidence that cellular processes such as damage-induced cell senescence contribute to osteoarthritis and a growing body of literature on the role of epigenetic regulation of gene expression in aging and osteoarthritis. SUMMARY: Not all osteoarthritis is due to aging processes in joint tissues, but the age-related changes being discovered certainly could play a major contributing role. PMID- 23080228 TI - Cyclohexyne cycloinsertion in the divergent synthesis of guanacastepenes. AB - The guanacastepenes are a family of 15 diterpenes that share a common 5-6-7 tricyclic core, which is decorated with quaternary centers, unsaturation, hydroxyl and carbonyl groups. Some of these natural products show interesting antimicrobial potency. Their collective structural and biological features have stirred up vibrant activity among organic chemists. Herein, we disclose an account of our studies toward the synthesis of a number of guanacastepenes. The synthetic strategy relies on the use of cyclohexyne in a cycloinsertion reaction to rapidly construct the guanacastepene core. Isolation of a cyclobutenol as intermediate in the cyclohexyne cycloinsertion provided us with the possibility to study further the reactivity of this metastable compound, and we uncovered novel rearrangements and ring-opening reactions. Stereoselective, late-stage oxidative diversification of the carbon scaffold allowed the synthesis of guanacastepenes N and O and paved the way for the synthesis of guanacastepenes H and D. PMID- 23080225 TI - Genome-wide association study of plasma efavirenz pharmacokinetics in AIDS Clinical Trials Group protocols implicates several CYP2B6 variants. AB - OBJECTIVES: Prior candidate gene studies have associated CYP2B6 516G->T [rs3745274] and 983T->C [rs28399499] with increased plasma efavirenz exposure. We sought to identify novel variants associated with efavirenz pharmacokinetics. MATERIALS AND METHODS: Antiretroviral therapy-naive AIDS Clinical Trials Group studies A5202, A5095, and ACTG 384 included plasma sampling for efavirenz pharmacokinetics. Log-transformed trough efavirenz concentrations (Cmin) were previously estimated by population pharmacokinetic modeling. Stored DNA was genotyped with Illumina HumanHap 650Y or 1MDuo platforms, complemented by additional targeted genotyping of CYP2B6 and CYP2A6 with MassARRAY iPLEX Gold. Associations were identified by linear regression, which included principal component vectors to adjust for genetic ancestry. RESULTS: Among 856 individuals, CYP2B6 516G->T was associated with efavirenz estimated Cmin (P=8.5*10). After adjusting for CYP2B6 516G->T, CYP2B6 983T->C was associated (P=9.9*10). After adjusting for both CYP2B6 516G->T and 983T->C, a CYP2B6 variant (rs4803419) in intron 3 was associated (P=4.4*10). After adjusting for all the three variants, non-CYP2B6 polymorphisms were associated at P-value less than 5*10. In a separate cohort of 240 individuals, only the three CYP2B6 polymorphisms replicated. These three polymorphisms explained 34% of interindividual variability in efavirenz estimated Cmin. The extensive metabolizer phenotype was best defined by the absence of all three polymorphisms. CONCLUSION: Three CYP2B6 polymorphisms were independently associated with efavirenz estimated Cmin at genome-wide significance, and explained one-third of interindividual variability. These data will inform continued efforts to translate pharmacogenomic knowledge into optimal efavirenz utilization. PMID- 23080231 TI - Using statistical models in patient-oriented research. PMID- 23080229 TI - The role of CCAAT enhancer-binding protein homologous protein in human immunodeficiency virus protease-inhibitor-induced hepatic lipotoxicity in mice. AB - Human immunodeficiency virus (HIV) protease inhibitors (HIV PIs) are the core components of highly active antiretroviral therapy, which has been successfully used in the treatment of HIV-1 infection in the past two decades. However, benefits of HIV PIs are compromised by clinically important adverse effects, such as dyslipidemia, insulin resistance, and cardiovascular complications. We have previously shown that activation of endoplasmic reticulum (ER) stress plays a critical role in HIV PI-induced dys-regulation of hepatic lipid metabolism. HIV PI-induced hepatic lipotoxicity is closely linked to the up-regulation of CCAAT enhancer binding protein homologous protein (CHOP) in hepatocytes. To further investigate whether CHOP is responsible for HIV PI-induced hepatic lipotoxicity, C57BL/6J wild-type (WT) or CHOP knockout (CHOP(-/-) ) mice or the corresponding primary mouse hepatocytes were used in this study. Both in vitro and in vivo studies indicated that HIV PIs (ritonavir and lopinavir) significantly increased hepatic lipid accumulation in WT mice. In contrast, CHOP(-/-) mice showed a significant reduction in hepatic triglyceride accumulation and liver injury, as evidenced by hematoxylin and eosin and Oil Red O staining. Real-time reverse transcriptase polymerase chain reaction and immunoblotting data showed that in the absence of CHOP, HIV PI-induced expression of stress-related proteins and lipogenic genes were dramatically reduced. Furthermore, tumor necrosis factor alpha and interleukin-6 levels in serum and liver were significantly lower in HIV PI-treated CHOP(-/-) mice, compared to HIV PI-treated WT mice. CONCLUSION: Taken together, these data suggest that CHOP is an important molecular link of ER stress, inflammation, and hepatic lipotoxicity, and that increased expression of CHOP represents a critical factor underlying events leading to hepatic injury. (HEPATOLOGY 2013). PMID- 23080230 TI - Large mediastinal nodular ganglioneuroblastoma in a child from Africa. AB - Ganglioneuroblastoma, nodular (GNBn) is a subtype of neuroblastic tumors. This is a rare malignancy typically affecting young children. Few cases are reported in adolescents and adults. The prognosis is related to the surgical excision radicality. Hereby we present a case of a young male patient age 13 from the Horn of Africa presenting with vague symptoms of fatigue and weight loss. Chest X ray showed a large radiopaque mass occupying the right thorax. The chest Computed Tomograpy confirmed the presence of an 18-cm large mass originating from the posterior mediastinum and invading most of the right hemi-thorax. Surgical excision and histopathology study of the lesion clarified its rare nature: ganglioneuroblastoma nodular with a particular coexistence of a fibrous benign surface encapsulating a necrotic malignant core. In this case of large GNBn in a young adolescent, the surgical resection alone played a curative treatment role. PMID- 23080235 TI - 2012 outpatient therapy caps, prior authorization of threshold exceptions, and manual medical reviews. PMID- 23080236 TI - More frequent visits to wound care clinics result in faster times to close diabetic foot and venous leg ulcers. AB - OBJECTIVE: To determine whether patients with Wagner grades 1 and 2 diabetic foot ulcers (DFUs) or venous leg ulcers (VLUs) differed in terms of time to close depending on visit frequency to wound care centers. DESIGN: Retrospective cohort study. SETTING: Outpatients wound care centers. PATIENTS: Two hundred six patients with Wagner grade 1 or 2 DFUs and 215 patients with VLUs in the lower extremities collected from 9 wound care centers in 5 states (6 states for VLUs) during 2009/2010 and whose wounds had closed. INTERVENTIONS: For each type of DFU/VLU, 1 group had every-other-week visits, defined as more than 10 days between visits in the first 4 weeks, whereas the other group had weekly visits, defined as at least once a week. MAIN OUTCOMES MEASURES: Median time to close. MAIN RESULTS: For patients with DFUs, 63.8% of wounds had closed in the weekly visit group after 4 weeks compared with 2.0% in the every-other-week group (P = 2.3 * 10); for patients with VLUs, 78 of 105 wounds (52%) closed in the weekly visit group compared with 0% in the every-other-week group (P = 2.40 * 10). After controlling for all covariates in a Cox regression model, median time to close for weekly patients was 28 days versus 66 days for patients seen every other week. Adjusted median times to close VLUs in the same groups were 25 versus 55 days. CONCLUSIONS: More frequent visits can be extremely beneficial, with implications of lower costs and higher quality of life for patients. PMID- 23080237 TI - A randomized controlled trial to evaluate an antimicrobial dressing with silver alginate powder for the management of chronic wounds exhibiting signs of critical colonization. AB - OBJECTIVE: The primary objective of this study was to evaluate if a topical silver dressing that consists of silver alginate powder is effective in managing chronic wounds that exhibit signs of critical colonization and promoting wound healing. METHOD: This was a prospective, open-label, 4-week randomized controlled trial. The primary end points of the study were changes in signs associated with critical colonization and in wound surface areas. All subjects were evaluated at weeks 0, 2, and 4 at the end of the study. SUBJECT AND SETTINGS: Participants between 18 and 85 years of age were recruited from 2 wound care clinics in Canada. The study was reviewed and approved by research ethics boards. DATA ANALYSIS: Analyses of this study were carried out based on intent-to-treat principle; t tests were used to determine if the means were statistically different between treatment groups. RESULTS: Thirty-four subjects participated and completed in the study. In the control group, the mean infection checklist score was 2.2 at baseline and 2.3 at week 4 (t9 = -0.36, P = .73). In the silver alginate powder group, the infection score reduced from 3.3 at baseline to 1.3 at week 4; the result was significant (t23 = 7.62, P < .00). The difference in average surface reduction over time between the 2 groups was statistically significant (t32 = 3.56, P < .001). Subjects randomized to the silver group achieved a greater surface reduction than those who were randomized to the use of foam dressing as the control. CONCLUSION: Silver alginate powder is an effective treatment option for wounds with increased bacterial burden. PMID- 23080238 TI - The incidence of methicillin-resistant Staphylococcus aureus in pressure ulcers. AB - Colonization of chronic wounds with methicillin-resistant Staphylococcus aureus continues to be an important healthcare concern. Aside from the morbidity associated with infections, colonization alone can contribute to outbreaks at long-term-care facilities and within hospitals. Despite the prevalence of pressure ulcers, the incidence of S aureus in these chronic wounds is unknown. PMID- 23080239 TI - Interrater and intrarater reliability of silhouette wound imaging device. AB - OBJECTIVE: The objective of this study was to investigate the interrater and intrarater reliability of a wound imaging and measurement system called SilhouetteMobile. DESIGN: Interrater and intrarater reliability study. SETTING: Community nursing, Victoria, Australia. PARTICIPANTS: Seven community nurses including Wound Management Clinical Nurse Consultants and Wound Resource Nurses. MAIN OUTCOME MEASURE: Average wound surface area of 14 wound images as captured using a wound imaging and measurement system called SilhouetteMobile. MAIN RESULTS: High interrater and intrarater reliability were maintained across different users and different assessments by the same user and were also found to be unaffected by image quality. Reliability was poor when tracing small wounds. CONCLUSION: Silhouette is a highly reliable tool for wound imaging and measurement, although reliability is reduced when annotating small wound areas. PMID- 23080240 TI - Shear-reducing insoles to prevent foot ulceration in high-risk diabetic patients. AB - PURPOSE: To enhance the learner's competence with knowledge of the effectiveness of shear-reducing insoles for prevention of foot ulceration in patients with high risk diabetes. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to:1. Demonstrate knowledge of foot ulceration risk, risk factors, incidence, and prevention.2. Apply knowledge gained from reviewing this study and a literature review about the use of shear-reducing insoles to patient scenarios. OBJECTIVE: The objective of this study was to evaluate the effectiveness of a shear-reducing insole compared with a standard insole design to prevent foot ulceration in high-risk patients with diabetes. RESEARCH DESIGN AND METHODS: A total of 299 patients with diabetic neuropathy and loss of protective sensation, foot deformity, or history of foot ulceration were randomized into a standard therapy group (n = 150) or a shear-reducing insole group (n = 149). Patients were evaluated for 18 months. Standard therapy group consisted of therapeutic footwear, diabetic foot education, and regular foot evaluation by a podiatrist. The shear-reducing insole group included a novel insole designed to reduce both pressure and shear on the sole of the foot. Insoles were replaced every 4 months in both groups. The primary clinical outcome was foot ulceration. The authors used Cox proportional hazards regression to evaluate time to ulceration. RESULTS: There were 2 significant factors from the Cox regression model: insole treatment and history of a foot complication. The standard therapy group was about 3.5 times more likely to develop an ulcer compared with shear-reducing insole group (hazard ratio, 3.47; 95% confidence interval, 0.96-12.67). CONCLUSIONS: These results suggest that a shear-reducing insole is more effective than traditional insoles to prevent foot ulcers in high-risk persons with diabetes. PMID- 23080242 TI - The power of an electronic medical record: documentation drives data. PMID- 23080243 TI - Towards synthetic gene circuits with enhancers: biology's multi-input integrators. AB - One of the greatest challenges facing synthetic biology is to develop a technology that allows gene regulatory circuits in microbes to integrate multiple inputs or stimuli using a small DNA sequence "foot-print", and which will generate precise and reproducible outcomes. Achieving this goal is hindered by the routine utilization of the commonplace sigma(70) promoters in gene-regulatory circuits. These promoters typically are not capable of integrating binding of more than two or three transcription factors in natural examples, which has limited the field to developing integrated circuits made of two-input biological "logic" gates. In natural examples the regulatory elements, which integrate multiple inputs are called enhancers. These regulatory elements are ubiquitous in all organisms in the tree of life, and interestingly metazoan and bacterial enhancers are significantly more similar in terms of both Transcription Factor binding site arrangement and biological function than previously thought. These similarities imply that there may be underlying enhancer design principles or grammar rules by which one can engineer novel gene regulatory circuits. However, at present our current understanding of enhancer structure-function relationship in all organisms is limited, thus preventing us from using these objects routinely in synthetic biology application. In order to alleviate this problem, in this book chapter, I will review our current view of bacterial enhancers, allowing us to first highlight the potential of enhancers to be a game-changing tool in synthetic biology application, and subsequently to draw a road-map for developing the necessary quantitative understanding to reach this goal. PMID- 23080244 TI - Elementary mode analysis: a useful metabolic pathway analysis tool for reprograming microbial metabolic pathways. AB - Elementary mode analysis is a useful metabolic pathway analysis tool to characterize cellular metabolism. It can identify all feasible metabolic pathways known as elementary modes that are inherent to a metabolic network. Each elementary mode contains a minimal and unique set of enzymatic reactions that can support cellular functions at steady state. Knowledge of all these pathway options enables systematic characterization of cellular phenotypes, analysis of metabolic network properties (e.g. structure, regulation, robustness, and fragility), phenotypic behavior discovery, and rational strain design for metabolic engineering application. This chapter focuses on the application of elementary mode analysis to reprogram microbial metabolic pathways for rational strain design and the metabolic pathway evolution of designed strains. PMID- 23080245 TI - Evolutionary engineering for industrial microbiology. AB - Superficially, evolutionary engineering is a paradoxical field that balances competing interests. In natural settings, evolution iteratively selects and enriches subpopulations that are best adapted to a particular ecological niche using random processes such as genetic mutation. In engineering desired approaches utilize rational prospective design to address targeted problems. When considering details of evolutionary and engineering processes, more commonality can be found. Engineering relies on detailed knowledge of the problem parameters and design properties in order to predict design outcomes that would be an optimized solution. When detailed knowledge of a system is lacking, engineers often employ algorithmic search strategies to identify empirical solutions. Evolution epitomizes this iterative optimization by continuously diversifying design options from a parental design, and then selecting the progeny designs that represent satisfactory solutions. In this chapter, the technique of applying the natural principles of evolution to engineer microbes for industrial applications is discussed to highlight the challenges and principles of evolutionary engineering. PMID- 23080246 TI - Monitoring microbial diversity of bioreactors using metagenomic approaches. AB - With the rapid development of molecular techniques, particularly 'omics' technologies, the field of microbial ecology is growing rapidly. The applications of next generation sequencing have allowed researchers to produce massive amounts of genetic data on individual microbes, providing information about microbial communities and their interactions through in situ and in vitro measurements. The ability to identify novel microbes, functions, and enzymes, along with developing an understanding of microbial interactions and functions, is necessary for efficient production of useful and high value products in bioreactors. The ability to optimize bioreactors fully and understand microbial interactions and functions within these systems will establish highly efficient industrial processes for the production of bioproducts. This chapter will provide an overview of bioreactors and metagenomic technologies to help the reader understand microbial communities, interactions, and functions in bioreactors. PMID- 23080247 TI - Synthetic biology triggers new era of antibiotics development. AB - As a discipline to design and construct organisms with desired properties, synthetic biology has generated rapid progresses in the last decade. Combined synthetic biology with the traditional process, a new universal workflow for drug development has been becoming more and more attractive. The new methodology exhibits more efficient and inexpensive comparing to traditional methods in every aspect, such as new compounds discovery & screening, process design & drug manufacturing. This article reviews the application of synthetic biology in antibiotics development, including new drug discovery and screening, combinatorial biosynthesis to generate more analogues and heterologous expression of biosynthetic gene clusters with systematic engineering the recombinant microbial systems for large scale production. PMID- 23080248 TI - Cascades and networks of regulatory genes that control antibiotic biosynthesis. AB - Onset of the biosynthesis of bioactive secondary metabolites in batch cultures of actinomycetes occurs after the rapid growth phase, following a transition phase which involves complex metabolic changes. This transition is triggered by nutrient starvation or by other environmental stress signals. Expression of genes encoding bioactive secondary metabolites is governed by cascades of pathway specific regulators and networks of cross-talking global regulators. Pathway specific regulators such as Streptomyces antibiotic regulatory proteins, LAL-type and LysR-type regulators respond to autoregulatory proteins that act in concert with their cognate ligands (e.g. gamma-butyrolactone receptor proteins and their cognate gamma-butyrolactone ligands). Global regulators such as PhoR-PhoP and other two component systems and orphan response regulators, such as GlnR, control set of genes affecting primary and secondary metabolism. GlnR and, therefore, nitrogen metabolism genes are under phosphate control exerted by binding of PhoP to PHO boxes located in the promoter region of GlnR. A few pleiotropic regulatory genes, such as areB (ndgR), dmdR1 or dasR connect primary metabolism (amino acid biosynthesis, N-acetylglucosamine or iron levels) with antibiotic biosynthesis. Some atypical response regulators that require specific small ligands appear to be involved in feedback control of antibiotic production. All these mechanisms together modulate, in a coordinated manner, different aspects of Streptomyces metabolism as a real "protection net" that prevents drastic changes in metabolism that may be deleterious for cell survival. PMID- 23080249 TI - Systems analysis of microbial adaptations to simultaneous stresses. AB - Microbes live in multi-factorial environments and have evolved under a variety of concurrent stresses including resource scarcity. Their metabolic organization is a reflection of their evolutionary histories and, in spite of decades of research, there is still a need for improved theoretical tools to explain fundamental aspects of microbial physiology. Using ecological and economic concepts, this chapter explores a resource-ratio based theory to elucidate microbial strategies for extracting and channeling mass and energy. The theory assumes cellular fitness is maximized by allocating scarce resources in appropriate proportions to multiple stress responses. Presented case studies deconstruct metabolic networks into a complete set of minimal biochemical pathways known as elementary flux modes. An economic analysis of the elementary flux modes tabulates enzyme atomic synthesis requirements from amino acid sequences and pathway operating costs from catabolic efficiencies, permitting characterization of inherent tradeoffs between resource investment and phenotype. A set of elementary flux modes with competitive tradeoffs properties can be mathematically projected onto experimental fluxomics datasets to decompose measured phenotypes into metabolic adaptations, interpreted as cellular responses proportional to the experienced culturing stresses. The resource-ratio based method describes the experimental phenotypes with greater accuracy than other contemporary approaches and further analysis suggests the results are both statistically and biologically significant. The insight into metabolic network design principles including tradeoffs associated with concurrent stress adaptation provides a foundation for interpreting physiology as well as for rational control and engineering of medically, environmentally, and industrially relevant microbes. PMID- 23080250 TI - Metabolic reprogramming under microaerobic and anaerobic conditions in bacteria. AB - Oxygen has a great impact on the metabolism and physiology of microorganisms. It serves as the most efficient terminal electron acceptor to drive the energy conservation process of cellular respiration and is required in many biosynthetic reactions. Bacteria encounter oxygen fluctuation and limitation during their growth in both natural ecological niches and in laboratory vessels. In response to oxygen limitation, facultative bacteria undergo substantial metabolic reprogramming to switch from the aerobic respiration to either anaerobic respiration, fermentation, or photosynthesis. Two key factors determine the metabolic pathways bacteria adopt under oxygen deprived microaerobic and anaerobic conditions: maximal energy conservation and redox homeostasis. In this chapter, we first describe how the fulfillment of these two key factors governs the metabolic reprogramming of facultative bacteria and how the process is tightly controlled by several global regulatory factors: FNR, ArcBA, as well as NarL and NarP. We then utilizes fermentation of glycerol, a large surplus byproduct of biodiesel industry, as an example to illustrate how environment, process, and strain based approaches can be exploited to manipulate and engineer the anaerobic metabolic pathways so that desirable fermentation products can be achieved with optimal yield. PMID- 23080251 TI - Tunable promoters in synthetic and systems biology. AB - Synthetic and systems biologists need standardized, modular and orthogonal tools yielding predictable functions in vivo. In systems biology such tools are needed to quantitatively analyze the behavior of biological systems while the efficient engineering of artificial gene networks is central in synthetic biology. A number of tools exist to manipulate the steps in between gene sequence and functional protein in living cells, but out of these the most straight-forward approach is to alter the gene expression level by manipulating the promoter sequence. Some of the promoter tuning tools available for accomplishing such altered gene expression levels are discussed here along with examples of their use, and ideas for new tools are described. The road ahead looks very promising for synthetic and systems biologists as tools to achieve just about anything in terms of tuning and timing multiple gene expression levels using libraries of synthetic promoters now exist. PMID- 23080252 TI - Analysis of Corynebacterium glutamicum promoters and their applications. AB - Promoters are DNA sequences which function as regulatory signals of transcription initiation catalyzed by RNA polymerase. Since promoters substantially influence levels of gene expression, they have become powerful tools in metabolic engineering. Methods for their localization used in Corynebacterium glutamicum and techniques for the analysis of their function are described in this review. C. glutamicum promoters can be classified according to the respective sigma factors which direct RNA polymerase to these structures. C. glutamicum promoters are recognized by holo-RNA polymerase formed by subunits alpha(2)betabeta'omega + sigma. C. glutamicum codes for seven different sigma factors: the principal sigma factor sigma(A) and alternative sigma factors sigma(B), sigma(C), sigma(D), sigma(E), sigma(H) and sigma(M), which recognize various classes of promoters. The promoters of housekeeping genes recognized by sigma(A), which are active during the exponential growth, form the largest described group. These promoters and their mutant derivatives are the most frequently used elements in modulation of gene expression in C. glutamicum. Promoters recognized by alternative sigma factors and their consensus sequences are gradually emerging. PMID- 23080253 TI - Production of fumaric acid by fermentation. AB - Fermentative fumaric acid production from renewable resources may become competitive with petrochemical production. This will require very efficient processes. So far, using Rhizopus strains, the best fermentations reported have achieved a fumaric acid titer of 126 g/L with a productivity of 1.38 g L(-1) h( 1) and a yield on glucose of 0.97 g/g. This requires pH control, aeration, and carbonate/CO(2) supply. Limitations of the used strains are their pH tolerance, morphology, accessibility for genetic engineering, and partly, versatility to alternative carbon sources. Understanding of the mechanism and energetics of fumaric acid export by Rhizopus strains will be a success factor for metabolic engineering of other hosts for fumaric acid production. So far, metabolic engineering has been described for Escherichia coli and Saccharomyces cerevisiae. PMID- 23080254 TI - Metabolic engineering of microorganisms for vitamin C production. AB - Vitamin C, an important organic acid, is widely used in the industries of pharmaceuticals, cosmetics, food, beverage and feed additives. Compared with the Reichstein method, biotechnological production of vitamin C is an attractive approach due to the low cost and high product quality. In this chapter, biosynthesis of vitamin C, including one-step fermentation processes and two-step fermentation processes are discussed and compared. Furthermore, the prospects of the biotechnological production of vitamin C are also presented. PMID- 23080255 TI - Molecular mechanisms and metabolic engineering of glutamate overproduction in Corynebacterium glutamicum. AB - Glutamate is a commercially important chemical. It is used as a flavor enhancer and is a major raw material for producing industrially useful chemicals. A coryneform bacterium, Corynebacterium glutamicum, was isolated in 1956 by Japanese researchers as a glutamate-overproducing bacterium and since then, remarkable progress in glutamate production has been made using this microorganism. Currently, the global market for glutamate is over 2.5 million tons per year. Glutamate overproduction by C. glutamicum is induced by specific treatments-biotin limitation, addition of fatty acid ester surfactants such as Tween 40, and addition of beta-lactam antibiotics such as penicillin. Molecular biology and metabolic engineering studies on glutamate overproduction have revealed that metabolic flow is significantly altered by these treatments. These studies have also provided insight into the molecular mechanisms underlying these changes. In this chapter, we review our current understanding of the molecular mechanisms of glutamate overproduction in C. glutamicum, and we discuss the advances made by metabolic engineering of this microorganism. PMID- 23080256 TI - Microbial metabolic engineering for L-threonine production. AB - L-threonine, one of the three major amino acids produced throughout the world, has a wide application in industry, as an additive or as a precursor for the biosynthesis of other chemicals. It is predominantly produced through microbial fermentation the efficiency of which largely depends on the quality of strains. Metabolic engineering based on a cogent understanding of the metabolic pathways of L-threonine biosynthesis and regulation provides an effective alternative to the traditional breeding for strain development. Continuing efforts have been made in revealing the mechanisms and regulation of L-threonine producing strains, as well as in metabolic engineering of suitable organisms whereby genetically defined, industrially competitive L-threonine producing strains have been successfully constructed. This review focuses on the global metabolic and regulatory networks responsible for L-threonine biosynthesis, the molecular mechanisms of regulation, and the strategies employed in strain engineering. PMID- 23080257 TI - The production of coenzyme Q10 in microorganisms. AB - Coenzyme Q10 has emerged as a valuable molecule for pharmaceutical and cosmetic applications. Therefore, research into producing and optimizing coenzyme Q10 via microbial fermentation is ongoing. There are two major paths being explored for maximizing production of this molecule to commercially advantageous levels. The first entails using microbes that naturally produce coenzyme Q10 as fermentation biocatalysts and optimizing the fermentation parameters in order to reach industrial levels of production. However, the natural coenzyme Q10-producing microbes tend to be intractable for industrial fermentation settings. The second path to coenzyme Q10 production being explored is to engineer Escherichia coli with the ability to biosynthesize this molecule in order to take advantage of its more favourable fermentation characteristics and the well-understood array of genetic tools available for this bacteria. Although many studies have attempted to over-produce coenzyme Q10 in E. coli through genetic engineering, production titres still remain below those of the natural coenzyme Q10-producing microorganisms. Current research is providing the knowledge needed to alleviate the bottlenecks involved in producing coenzyme Q10 from an E. coli strain platform and the fermentation parameters that could dramatically increase production titres from natural microbial producers. Synthesizing the lessons learned from both approaches may be the key towards a more cost-effective coenzyme Q10 industry. PMID- 23080258 TI - Genetic modification and bioprocess optimization for S-Adenosyl-L-methionine biosynthesis. AB - S-Adenosyl-L-methionine is an important bioactive sulfur-containing amino acid. Large scale preparation of the amino acid is of great significance. S-Adenosyl-L methionine can be synthesized from L-methionine and adenosine triphosphate in a reaction catalyzed by methionine adenosyltransferase. In order to enhance S adenosyl-L-methionine biosynthesis by industrial microbial strains, various strategies have been employed to optimize the process. Genetic manipulation has largely focused on enhancement of expression and activity of methionine adenosyltransferase. This has included its overexpression in Pichia pastoris, Saccharomyces cerevisiae and Escherichia coli, molecular evolution, and fine tuning of expression by promoter engineering. Furthermore, knocking in of Vitreoscilla hemoglobin and knocking out of cystathionine-beta-synthase have also been effective strategies. Besides genetic modification, novel bioprocess strategies have also been conducted to improve S-adenosyl-L-methionine synthesis and inhibit its conversion. This has involved the optimization of feeding modes of methanol, glycerol and L-methionine substrates. Taken together considerable improvements have been achieved in S-adenosyl-L-methionine accumulation at both flask and fermenter scales. This review provides a contemporary account of these developments and identifies potential methods for further improvements in the efficiency of S-adenosyl-L-methionine biosynthesis. PMID- 23080259 TI - Manipulation of Ralstonia eutropha carbon storage pathways to produce useful bio based products. AB - Ralstonia eutrophais a Gram-negative betaproteobacterium found natively in soils that can utilize a wide array of carbon sources for growth, and can store carbon intracellularly in the form of polyhydroxyalkanoate. Many aspects of R. eutrophamake it a good candidate for use in biotechnological production of polyhydroxyalkanoate and other bio-based, value added compounds. Manipulation of the organism's carbon flux is a cornerstone to success in developing it as a biotechnologically relevant organism. Here, we examine the methods of controlling and adapting the flow of carbon in R. eutrophametabolism and the wide range of compounds that can be synthesized as a result. The presence of many different carbon utilization pathways and the custom genetic toolkit for manipulation of those pathways gives R. eutrophaa versatility that allows it to be a biotechnologically important organism. PMID- 23080260 TI - Metabolic engineering of inducer formation for cellulase and hemicellulase gene expression in Trichoderma reesei. AB - The filamentous fungus T. reeseiis today a paradigm for the commercial scale production of different plant cell wall degrading enzymes mainly cellulases and hemicellulases. Its enzymes have a long history of safe use in industry and well established applications are found within the pulp, paper, food, feed or textile processing industries. However, when these enzymes are to be used for the saccharification of cellulosic plant biomass to simple sugars which can be further converted to biofuels or other biorefinery products, and thus compete with chemicals produced from fossil sources, additional efforts are needed to reduce costs and maximize yield and efficiency of the produced enzyme mixtures. One approach to this end is the use of genetic engineering to manipulate the biochemical and regulatory pathways that operate during enzyme production and control enzyme yield. This review aims at a description of the state of art in this area. PMID- 23080261 TI - Microbiologically produced carboxylic acids used as building blocks in organic synthesis. AB - Oxo- and hydroxy-carboxylic acids are of special interest in organic synthesis. However, their introduction by chemical reactions tends to be troublesome especially with regard to stereoselectivity. We describe herein the biotechnological preparation of selected oxo- and hydroxycarboxylic acids under "green" conditions and their use as promising new building blocks. Thereby, our biotechnological goal was the development of process fundamentals regarding the variable use of renewable raw materials, the development of a multi purpose bioreactor and application of a pilot plant with standard equipment for organic acid production to minimize the technological effort. Furthermore the development of new product isolation procedures, with the aim of direct product recovery, capture of products or single step operation, was necessary. The application of robust and approved microorganisms, also genetically modified, capable of using a wide range of substrates as well as producing a large spectrum of products, was of special importance. Microbiologically produced acids, like 2-oxo-glutaric acid and 2-oxo-D-gluconic acid, are useful educts for the chemical synthesis of hydrophilic triazines, spiro-connected heterocycles, benzotriazines, and pyranoic amino acids. The chiral intermediate of the tricarboxylic acid cycle, (2R,3S) isocitric acid, is another promising compound. For the first time our process provides large quantities of enantiopure trimethyl (2R,3S)-isocitrate which was used in subsequent chemical transformations to provide new chiral entities for further usage in total synthesis and pharmaceutical research.Oxo- and hydroxy carboxylic acids are of special interest in organic synthesis. However, their introduction by chemical reactions tends to be troublesome especially with regard to stereoselectivity. We describe herein the biotechnological preparation of selected oxo- and hydroxycarboxylic acids under "green" conditions and their use as promising new building blocks. Thereby, our biotechnological goal was the development of process fundamentals regarding the variable use of renewable raw materials, the development of a multi purpose bioreactor and application of a pilot plant with standard equipment for organic acid production to minimize the technological effort. Furthermore the development of new product isolation procedures, with the aim of direct product recovery, capture of products or single step operation, was necessary. The application of robust and approved microorganisms, also genetically modified, capable of using a wide range of substrates as well as producing a large spectrum of products, was of special importance. Microbiologically produced acids, like 2-oxo-glutaric acid and 2-oxo D-gluconic acid, are useful educts for the chemical synthesis of hydrophilic triazines, spiro-connected heterocycles, benzotriazines, and pyranoic amino acids. The chiral intermediate of the tricarboxylic acid cycle, (2R,3S)-isocitric acid, is another promising compound. For the first time our process provides large quantities of enantiopure trimethyl (2R,3S)-isocitrate which was used in subsequent chemical transformations to provide new chiral entities for further usage in total synthesis and pharmaceutical research. PMID- 23080262 TI - Emotion in eating disorders. PMID- 23080263 TI - The 5' untranslated region of the soybean cytosolic glutamine synthetase beta(1) gene contains prokaryotic translation initiation signals and acts as a translational enhancer in plants. AB - Glutamine synthetase (GS) catalyzes the synthesis of glutamine from glutamate and ammonia. In plants, it occurs as two major isoforms, a cytosolic form (GS(1)) and a nuclear encoded chloroplastic form. The focus of this paper is to determine the role of the 5'UTR of a GS(1) gene. GS(1) gene constructs with and without its 5' and 3' UTRs, driven by a constitutive promoter, were agroinfiltrated into tobacco leaves and the tissues were analyzed for both transgene transcript and protein accumulation. The constructs were also tested in an in vitro transcription/translation system and in Escherichia coli. Our results showed that while the 3'UTR functioned in the destabilization of the transcript, the 5'UTR acted as a translation enhancer in plant cells but not in the in vitro translation system. The 5'UTR of the GS(1) gene when placed in front of a reporter gene (uidA), showed a 20-fold increase in the level of GUS expression in agroinfiltrated leaves when compared to the same gene construct without the 5'UTR. The 5'UTR-mediated translational enhancement is probably another step in the regulation of GS in plants. The presence of the GS(1) 5'UTR in front of the GS(1) coding region allowed for its translation in E. coli suggesting the commonality of the translation initiation mechanism for this gene between plants and bacteria. PMID- 23080265 TI - Screening of polyphenolic plant extracts for anti-obesity properties in Wistar rats. AB - BACKGROUND: Polyphenols have been reported to prevent chronic diseases such as cardiovascular diseases, cancers, diabetes and neurodegenerative diseases. The objective of the study was to conduct a screening for potential anti-obesity polyphenolic plant extracts using a diet-induced animal model. Rats were fed a high-fat-sucrose (HFS) diet with or without supplementation of different polyphenolic plant extracts (almond, apple, cinnamon, orange blossom, hamamelis, lime blossom, grape vine, and birch) for 56-64 days. RESULTS: Body weight gain was lower in rats supplemented with apple, cinnamon, hamamelis and birch extracts as compared to HFS non-supplemented group. Moreover, apple and cinnamon extracts prevented the increase in fat mass promoted by the HFS diet. Insulin resistance, estimated by the homostatic model assessment-insulin resistance (HOMA-IR) index, was reduced in rats fed apple, cinnamon, hamamelis and birch extracts. Apple extract also prevented the HFS-induced hyperglycaemia and hyperleptinaemia. CONCLUSION: Only apple and cinnamon extracts were finally considered as potentially important anti-obesogenic extracts, due to their body fat-lowering effects, while the improvement of obesity-related metabolic complications by apple polyphenols highlights this extract as a promising functional food ingredient for the management of obesity and its metabolic complications. PMID- 23080264 TI - Targeting presynaptic norepinephrine transporter in brown adipose tissue: a novel imaging approach and potential treatment for diabetes and obesity. AB - Brown adipose tissue (BAT) plays a significant role in metabolism. In this study, we report the use of atomoxetine (a clinically applicable norepinephrine reuptake inhibitor) for (18)F-FDG PET imaging of BAT and its effects on heat production and blood glucose concentration. Fasted-male Sprague-Dawley rats were administered with intravenous (18)F-FDG. The same rats were treated with atomoxetine (0.1 mg/kg, i.v.) 30 min before (18)F-FDG administration. To confirm the beta-adrenergic effects, propranolol (beta-adrenergic inhibitor) 5 mg/kg was given intraperitoneally 30 min prior to atomoxetine administration. The effect of atomoxetine on BAT metabolism was assessed in fasted and non-fasted rats and on BAT temperature and blood glucose in fasted rats. In (18)F-FDG PET/CT images, interscapular BAT (IBAT) and other areas of BAT were clearly visualized. When rats were fasted, atomoxetine (0.1 mg/kg) increased the (18)F-FDG uptake of IBAT by factor of 24 within 30 min. Propranolol reduced the average (18)F-FDG uptake of IBAT significantly. Autoradiography of IBAT and white adipose tissue confirmed the data obtained by PET. When rats were not fasted, atomoxetine-induced increase of (18)F-FDG uptake in IBAT was delayed and occurred in 120 min. For comparison, direct stimulation of beta(3)-adrenreceptors in non-fasted rats with CL-316, 243 occurred within 30 min. Atomoxetine-induced IBAT activation was associated with higher IBAT temperature and lower blood glucose. This was mediated by inhibition of norepinephrine reuptake transporters in IBAT leading to increased norepinephrine concentration in the synapse. Increased synaptic norepinephrine activates beta(3)-adrenreceptors resulting in BAT hypermetabolism that is visible and quantifiable by (18)F-FDG PET/CT. PMID- 23080266 TI - Prevention on parent to child transmission of HIV - what is new? AB - Prevention of Mother-To-Child Transmission (PMTCT) of HIV has been at the forefront of research in the field of HIV/AIDS since the PACTG 076 proved successful in 1994. This was followed by many trials with single, dual, or triple Anti Retroviral Therapy (ART), with or without breast-feeding, with different modes of delivery. These trials aimed and promised to find a relatively simple, low-cost intervention that could virtually eliminate the risk of HIV transmission from mother to child, cutting across all geographic boundaries. However, translation of the findings from most of these research studies into successful national PMTCT programs and health policies has not been optimal. In the west, parent to child transmission of HIV has been virtually eliminated due to universal coverage, screening, planned conception wherever possible, thorough evaluation and appropriate antenatal, intranatal and postnatal interventions. In contrast, in resource limited settings where the magnitude of the problem is the greatest accounting for more than 95 % of all vertical transmissions of HIV, there is a constant struggle dealing with the birth of an infected infant every minute. It is time to make optimal choices to prevent the transmission of HIV from an infected mother to her child and virtually eliminate this largely preventable scourge in children. PMID- 23080267 TI - Are Indian parents of children with Down syndrome engaged in the blame game? AB - OBJECTIVES: To study blame ascription among parents of children with Down syndrome and to study its correlation with sociodemographic factors, parental perception of dysmorphisms and parents' knowledge about Down syndrome. This is a prospective, observational, non-interventional case control study. METHODS: Interview of biological parents of children with Down syndrome less than 12 y of age was taken. Dysmorphism and parents' feeling of blame was assessed and graded by Likert's scale. Controls were parents of age and gender matched children with non-genetic chronic disorders. RESULTS: During the study period, 50 mothers and 46 fathers of cases and 50 control parents were interviewed. Parents in the study group were older; the mothers were better educated and had more frequent antenatal visits. There was no significant difference in the proportion of parents counseled but genetic counseling was associated with a significantly higher proportion of parents having knowledge about Down syndrome. A higher proportion of parents perceived their child with Down syndrome being dysmorphic. Blame ascription was not significantly different among the two groups and was seen only in a small proportion of parents of cases. When it did occur, it was directed at health professionals. CONCLUSIONS: Blame ascription is not frequent in a cohort of Indian parents of children with Down syndrome even when dysmorphism is perceived by parents. Genetic counseling was associated with better knowledge about Down syndrome in the parents. PMID- 23080268 TI - From tear to tears. PMID- 23080269 TI - Bacterial culture after three sterilization methods for cataract surgery. AB - PURPOSE: To compare bacterial cultures from three sterilization methods immediately before and after cataract surgery. DESIGN: A prospective randomized open-label group-comparison study. METHODS: We investigated 75 eyes in 73 consecutive patients undergoing cataract surgery. After swabbing the eyelid and surrounding area, patients were randomly assigned to one of 3 eye-washing methods: patients administered one drop of 5 % povidone-iodine (Group A); patients whose conjunctival sac was washed with 0.02 % chlorhexidine while everting the eyelid (Group B); or 0.02 % chlorhexidine as above but without eyelid eversion (Group C). In each group, specimens were collected from the conjunctival sac immediately before and after eye washing and again at completion of surgery, along with aqueous humor. The post-surgical condition of the corneal epithelium and the severity of anterior chamber inflammation were assessed by use of a slit-lamp microscope. RESULTS: In Groups A and C, the percentage of eyes with conjunctival bacteria decreased significantly from immediately before to immediately after washing (Group A, p = 0.008; Group C, p = 0.016), but there was no significant decrease in Group B (p = 0.125). Slit-lamp microscopy showed that inflammation of the anterior chamber 1 day after surgery was significantly milder in Group C than in Group B (p = 0.032). CONCLUSION: Eye-washing methods without eyelid eversion are more effective in reducing conjunctival bacteria before surgery and anterior chamber inflammation after surgery than those with eyelid eversion. PMID- 23080270 TI - Immunosuppressive therapy in virus-negative inflammatory cardiomyopathy. AB - While there is general agreement on the favorable impact of immunosuppression in eosinophilic, granulomatous, giant cell and lymphocytic myocarditis and with inflammatory myocardial disease associated with connective tissue disorders or with rejection of a transplanted heart, its therapeutic role in the treatment of lymphocytic inflammatory cardiomyopathy (ICM) is still debated. Previous retrospective studies reported a relevant (>= 10% left ventricular ejection fraction) clinical benefit in 90% of patients with virus-negative ICM and no cardiac impairment in 85% of patients with virus-positive ICM following immunosuppression. Some studies identified cardiomyocyte HLA up-regulation as an additional indicator of ICM susceptibility to immunosuppressive therapy. Recently in a single-center randomized prospective double-blind trial using a combination of prednisone (1 mg/kg per day for 4 weeks followed by 0.33 mg/kg per day for 5 months) and azathioprine (2 mg/kg per day for 6 months) in addition to supportive treatment in 85 virus-negative ICM patients, a significant improvement of left ventricular ejection fraction and a significant reduction of left ventricular dimensions in 88% of 43 treated patients was reported when compared to 42 patients receiving placebo who showed a cardiac impairment initially in 83% of cases (TIMIC study). These data confirm the efficacy of immunosuppression in virus-negative ICM. The lack of response in 12% of cases suggests that the missing response might be due to the presence of viruses which were not screened for or to mechanisms of damage and inflammation not susceptible to immunosuppression. The recovery of cardiac function in responders to immunosuppression was associated with the inhibition of cardiomyocyte death, an increase of cell proliferation and with newly synthesized contractile material. PMID- 23080271 TI - Gold oxidative dissolution by (thioamide)-I2 adducts. AB - Elemental gold powder is easily oxidised under mild reaction conditions with 1 : 1 I(2)-adducts of the thioamides 3-methyl-benzothiazole-2-thione (mbtt) and 1 methyl-1H-benzimidazole-2(3H)-thione (mbit) with separation of the ionic complexes [Au(I)(mbtt)(2)]I(3) (1) and [(mtbiH)(2)](AuI(4))I(3) (2) [mtbiH = the imido protonated form of 2-(methylthio)benzimidazole] (gold oxidation yield >78% and 45%, respectively). The X-ray crystal structure of 1 shows the Au(i) centre linearly bound by two neutral ligands via the sulphur atom, whereas the X-ray crystal structure of 2 shows the Au(III) centre surrounded by four iodides in a square-planar arrangement. The oxidising/complexing properties of the mbtt.I(2) and mbit.I(2) adducts were interpreted considering the S-donor to I(2) interaction that leads to a charge separation between the I(b) and I(t) iodine atoms in the fragment S-I(b)-I(t). The oxidation of gold in a non-aqueous solvent by thioamide-I(2) adducts could be a promising alternative process to the numerous hydrometallurgical ones for the recovery of gold from secondary sources. PMID- 23080272 TI - Isolation of multipotent neural stem or progenitor cells from both the dentate gyrus and subventricular zone of a single adult mouse. AB - In adult mammals, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone of the dentate gyrus (DG) show ongoing neurogenesis, and multipotent neural stem or progenitor cells (NSCs) in these two regions exhibit different intrinsic properties. However, investigation of the mechanisms underlying such differences has been limited by a lack of efficient methods for isolating NSCs, particularly from the adult DG. Here we describe a protocol that enables us to isolate self-renewing and multipotent NSCs from the SVZ and the DG of the same adult mouse. The protocol involves the microdissection of the SVZ and DG from one adult mouse brain, isolation of NSCs from specific regions and cultivation of NSCs in vitro. The entire procedure takes 2-3 h. As only one mouse is needed for each cell isolation procedure, this protocol will be particularly useful for studies with limited availability of mice, such as mice that contain multiple genetic modifications. PMID- 23080273 TI - Generation of integration-free human induced pluripotent stem cells from postnatal blood mononuclear cells by plasmid vector expression. AB - Several human postnatal somatic cell types have been successfully reprogrammed to induced pluripotent stem cells (iPSCs). Blood mononuclear cells (MNCs) offer several advantages compared with other cell types. They are easily isolated from umbilical cord blood (CB) or adult peripheral blood (PB), and can be used fresh or after freezing. A short culture allows for more efficient reprogramming, with iPSC colonies forming from blood MNCs in 14 d, compared with 28 d for age-matched fibroblastic cells. The advantages of briefly cultured blood MNCs may be due to favorable epigenetic profiles and gene expression patterns. Blood cells from adults, especially nonlymphoid cells that are replenished frequently from intermittently activated blood stem cells, are short-lived in vivo and may contain less somatic mutations than skin fibroblasts, which are more exposed to environmental mutagens over time. We describe here a detailed, validated protocol for effective generation of integration-free human iPSCs from blood MNCs by plasmid vectors. PMID- 23080274 TI - A scalable synthesis of 5,5'-dibromo-2,2'-bipyridine and its stepwise functionalization via Stille couplings. AB - The synthesis of 5,5'-dibromo-2,2'-bipyridine and 5-bromo-2,2'-bipyridine, useful intermediates for elaboration into more complex ligands through metal-catalyzed coupling reactions, can be efficiently conducted on a multigram scale from inexpensive starting materials. The described procedure is reliably scalable and suitable for the synthesis of tens of grams of 5,5'-dibromo-2,2'-bipyridine. 5 Bromo-2,2'-bipyridine is produced as a minor product. The 5,5'-disubstituted-2,2' bipyridine motif has excellent coordination properties and is a versatile building block for the synthesis of functional materials (including biodiagnostics, photovoltaics and organic light-emitting diodes) and complex molecular topologies (including catenanes and trefoil and pentafoil knots). The selective stepwise functionalization of 5,5'-dibromo-2,2'-bipyridine by consecutive Stille couplings is therefore illustrated and documented in detail. The synthesis of 5,5'-dibromo-2,2'-bipyridine takes 4-5 d: 1 d to prepare the key intermediate 2,2'-bipyridine dihydrobromide, 3 d for its reaction with bromine in a steel bomb reaction vessel and 8 h to isolate and purify the final product. PMID- 23080275 TI - Mitomania and Human ARTs: micromanaging the mitochondrial genome and metabolome. PMID- 23080276 TI - [Pregnancy in adolescence: current situation]. PMID- 23080277 TI - [External quality control for cervical cytology exams performed in the Brazilian Public Health System of Mato Grosso do Sul State]. AB - PURPOSE: To evaluate the diagnostic agreement between the cytopathology reports issued by accredited laboratories and those obtained by quality control. METHODS: We calculated the overall agreement and Cohen's kappa coefficients of a convenience sample of smears selected monthly by the Information System of Cervical Cancer (SISCOLO) for External Quality Control of the 15 laboratories that performed cytopathological PAP tests for the Brazilian Public Health System (SUS) between 2002 and 2011 in Mato Grosso do Sul, a State of the Midwest Region of the country. A comparison of the reliability values (coefficient of concordance and Kappa coefficient) between the initial and final years was computed by the absolute change (delta) and relative percent difference (RPD). RESULTS: There were 15.989 smears sent for rereading, 48.1% of which had a report of normal/benign changes, followed by atypical/low-grade squamous intraepithelial lesions (36.3%), high grade squamous intraepithelial lesion/carcinoma/adenocarcinoma (4.2%), and unsatisfactory (11.4%). The overall correlation coefficient ranged between 0.2 and 1.0, and the median value increased from 0.7 in 2002 to 1 in 2011 (RPD=+36.6%). During the same period, the median values of the Kappa coefficient increased from 0.5 to 0.9 (RPD=+80.8%). CONCLUSIONS: These results emphasize the feasibility of the External Quality Control of cytopathology at the state level and its implementation results in improvement in the diagnoses performed in the SUS network. PMID- 23080278 TI - [Frequency and risk factors for metabolic syndrome in adolescents and adults women with polycystic ovary syndrome]. AB - PURPOSE: To compare the frequency of metabolic syndrome (MetS) and the risk factors associated with this syndrome in women from the Brazilian Southeast with polycystic ovary syndrome (POS) evaluated during adolescence and adult age. METHODS: This was a cross-sectional study conducted on 147 patients with a diagnosis of POS who were divided into two groups: Adolescents, 42 adolescents aged 13 to 19 years, and Adults, 105 women aged 20 to 40 years. The following factors were evaluated: clinical characteristics (body mass index - BMI, Ferriman index, abdominal circumference - AC, and systemic arterial pressure), mean ovarian volume, laboratory variables (serum androgen profile, lipid profile, glycemia, and fasting insulin), and frequency of MetS. The results were expressed as mean+/-standard deviation. We used multiple logistic regression with the response variable being the presence of MetS and the predictor variables the levels of total testosterone, insulin and BMI. RESULTS: The frequency of MetS was approximately twice higher in the group of adult women compared to the adolescents with POS (Adolescents: 23.8 vs. Adults: 42.9%, p=0.04). Among the defining criteria of MetS, only the qualitative variable of systemic arterial pressure >=130/85 mmHg was more frequent among the adult women (p=0,01). The BMI was an independent predictor of MetS among the adolescent (p=0.03) and adult women (p<0.01) with POS. Serum insulin level was a predictor of MetS only among adult women with POS (p<0.01). AC was greater among adult women (p=0.04). CONCLUSION: Adult women with POS have a twice higher frequency of MetS than adolescents with POS from the Brazilian Southeast. Although the BMI is associated with the development of MetS in any phase of life in women with POS, serum insulin level was an independent predictor of MetS only among adult women with this disorder. PMID- 23080279 TI - [Alpha-tocopherol level in serum and colostrum of breastfeeding women and association with maternal variables]. AB - PURPOSE: To determine the nutritional status of vitamin E in breastfeeding women through the analysis of alpha-tocopherol concentration in serum and colostrum, to analyze its relation with maternal variables and to determine the prevalence of vitamin E deficiency in these women. METHODS: The study included 103 mothers who were classified according to maternal variables: age, nutritional status before pregnancy, gestational weight gain, parity and mode of delivery. Colostrum and serum samples were collected under fasting conditions in the immediate postpartum period. Alpha-tocopherol was analyzed by high performance liquid chromatography (HPLC). A serum cutoff of 697.7 MUg/dL was adopted to define the nutritional status of vitamin E. Statistical analysis was performed with the Student's t test for independent samples and Pearson's correlation. Differences were significant when p<0.05. RESULTS: The average concentration of alpha-tocopherol was 1.125+/ 551.0 MUg/dL in colostrum and 1,138.6+/-346.0 MUg/dL in serum, indicating adequate biochemical nutritional status. However, when analyzing the mothers individually, a 16% rate of subclinical vitamin E deficiency was detected. Women undergoing cesarean delivery had significantly higher alpha-tocopherol levels in colostrum (1.280+/-591 MUg/dL) compared with those undergoing normal delivery (961.7+/-370 MUg/dL) (p<0.05). It was found that mothers who were overweight before pregnancy had higher vitamin concentration in colostrum (1,331.5+/-548 MUg/dL) when compared to underweight women (982.1+/-374 MUg/dL) or women of normal weight (992.3+/-346 MUg/dL) (p<0.05). However, the other variables were not associated with alpha-tocopherol in colostrum. Moreover, no variable showed association with vitamin E levels in maternal serum and no correlation was demonstrated between the alpha-tocopherol levels in serum and in milk. CONCLUSIONS: Despite the diagnosis of satisfactory nutritional status, breastfeeding women showed significant risk of subclinical vitamin E deficiency. We suggest that the concentration of alpha-tocopherol in colostrum be associated with type of delivery and pre-gestational nutritional status of women. PMID- 23080280 TI - [Results of two treatment regimens for pyelonephritis during pregnancy and correlation with pregnancy outcome]. AB - PURPOSE: To determine the epidemiological profile of women admitted for urinary tract infection as well as to verify the most prevalent agents and response to antibiotic therapy. METHODS: A retrospective study of 106 pregnant women admitted to a university hospital for urinary tract infection treatment during the period between January 2007 to December 2010. The evaluation was based on analysis of the medical records of these pregnant women, with the observation of hospitalization and pregnancy data, as well as its outcome. Statistical analysis was performed using Statistical Package for the Social Science, version 15.0. The bilateral Fisher exact test and Student's t test were used for data analysis, as well as descriptive statistical methods. RESULTS: Positive urine cultures were observed in 60.5% of pregnant women admitted due to urinary tract infection. The most frequent infectious agent was Escherichia coli and no difference in resistance, recurrence or complications was observed between the most frequent etiologic agents. Pregnant women with previous UTI had a higher recurrence risk (OR=10.8; p<0.05). The antibiotics most commonly used during hospitalization were ampicillin and cefazolin. Change of therapeutic agent due to bacterial resistance occurred in 11.9% of patients who took cefazolin and in 20% of patients who took ampicillin (OR=5.5; p<0.05). The rate of gestational complications was the same for both treatments. There was no difference in mean number of days of hospitalization between the treatments. CONCLUSION: In the studied population ampicillin showed a higher rate of bacterial resistance than cefazolin, requiring a larger number of treatment regimen exchanges, without resulting in differences in clinical outcome or time of hospitalization. PMID- 23080281 TI - [Evaluation of gait initiation in low risk pregnant women in the three trimesters]. AB - PURPOSES: To describe the process of gait initiation of pregnant women and to compare the behavior of the pressure center in the three trimesters of pregnancy. METHODS: Fifty-seven low-risk pregnant women were evaluated, aged 18 to 35 years, selected for convenience location during the three trimesters of pregnancy. The women were divided into three groups of 19 subjects each, according to gestational age - 1st quarter (4-12 weeks), 2nd quarter (13-28 weeks), and 3rd quarter (29-42 weeks,). Each patient was positioned standing up with one foot on each AMTI force platform until she heard a beep indicating that she should start walking a distance of four meter. Data were analyzed using the SPSS software. The Kolmogorov Smirnov test, Tukey's test and Spearman correlation coefficient were used for group comparisons, with 5% significance level in all tests. RESULTS: Significant differences were found between the 1st quarter (GFT) and 3rd quarter (GTT) groups regarding mediolateral oscillation amplitude (GFT: 0.4 cm and GTT: 0.2 cm) and mediolateral displacement rate (GFT: 0.9 cm/s and GTT: 0.4 cm/s). There was a gradual decrease in anteroposterior and mediolateral oscillation rate, and in the speed of displacement from platform 1 to platform 2 in GFT. There was a significant difference in oscillation amplitude and mediolateral displacement speed between GFT and GTT. CONCLUSION: The variables analyzed showed minor differences and do not constitute an imminent risk for the stability dynamics of pregnant woman. PMID- 23080282 TI - [Perinatal factors associated with pH<7.1 in umbilical artery and Apgar 5 min <7.0 in term newborn]. AB - PURPOSE: To assess perinatal factors associated with term newborns with pH<7.1 in the umbilical artery and 5th min Apgar score<7.0. METHODS: Retrospective case control study carried out after reviewing the medical records of all births from September/1998 to March/2008, that occurred at the General Hospital of Caxias do Sul. The inclusion criterion was term newborns who presented a 5th min Apgar score <7.0 and umbilical artery pH<7.10. In the univariate analysis, we used the Student's t-test and the Mann-Whitney test for continuous variables, the c2 test for dichotomous variables and risk estimation by the odds ratio (OR). The level of significance was set at p<0.05. RESULTS: Of a total of 15,495 consecutive births, 25 term neonates (0.16%) had pH<7.1 in the umbilical artery and a 5th min Apgar score <7.0. Breech presentation (OR=12.9, p<0.005), cesarean section (OR=3.5, p<0.01) and modified intrapartum cardiotocography (OR=7.8, p<0.02) presented a significant association with the acidosis event. Among the fetal characteristics, need for hospitalization in the neonatal intensive care unit (OR=79.7, p <0.0001), need for resuscitation (OR=12.2, p <0.0001) and base deficit were associated with the event (15.0 versus -4.5, p<0.0001). CONCLUSION: Low Apgar score at the 5th min of life associated with pH<7.1 in the umbilical artery can predict adverse neonatal outcomes. PMID- 23080283 TI - [Adequacy of weight gain in pregnant women from two municipalities of Rio de Janeiro state (RJ), Brazil, 2008]. AB - PURPOSE: To evaluate sociodemographic, behavioral and reproductive factors and morbidities associated with inadequate weight gain during pregnancy. METHODS: Cohort study conducted from December 2007 to August 2008 with women in the first trimester of pregnancy looking for prenatal care in the Public Health System who lived in the cities of Petropolis or Queimados, Rio de Janeiro state (Brazil). Women with multiple pregnancy, who had a miscarriage in the index pregnancy or who lacked information for the assessment of pregravid nutritional status or weight gain were excluded. Pregravid nutritional status and weight gain during pregnancy were determined according to the criterion established by the Institute of Medicine (IOM). Statistical analysis was performed using a multinomial logistic regression model. RESULTS: A total of 1,287 women were included in the study; 26.6% of them were overweight or obese while 11% were underweight. Inadequate weight gain during pregnancy was observed in 71.4% of pregnant women; 35.6% of them did not gain enough weight while 35.8% gained more weight than recommended by the IOM. In the multivariate analysis, women with hypertension (OR=2.1; 95%CI 1.4-3.1), pregravid overweight (OR=2.5; 95%CI 1.4-4.5) or obesity (OR=2.7; 95%CI 1.8-3.9) and who had a higher educational level were more likely to gain more weight than recommended, while pregravid underweight (OR=0.6; 95%CI 0.4-0.9) represented a protection against excessive gain. CONCLUSION: Pregravid nutritional diagnosis and weight gain monitoring should be actions effectively instituted in the routine of health professionals. PMID- 23080284 TI - The effect of a 94 GHz electromagnetic field on neuronal microtubules. AB - Hardware that generates electromagnetic waves with wavelengths from 1 to 10 mm (millimeter waves, "MMW") is being used in a variety of applications, including high-speed data communication and medical devices. This raises both practical and fundamental issues concerning the interaction of MMW electromagnetic fields (EMF) with biological tissues. A 94 GHz EMF is of particular interest because a number of applications, such as active denial systems, rely on this specific frequency. Most of the energy associated with MMW radiation is absorbed in the skin and, for a 94 GHz field, the power penetration depth is shallow (~0.4 mm). At sufficiently high energies, skin heating is expected to activate thermal pain receptors, leading to the perception of pain. In addition to this "thermal" mechanism of action, a number of "non-thermal" effects of MMW fields have been previously reported. Here, we investigated the influence of a 94 GHz EMF on the assembly/disassembly of neuronal microtubules in Xenopus spinal cord neurons. We reasoned that since microtubule array is regulated by a large number of intracellular signaling cascades, it may serve as an exquisitely sensitive reporter for the biochemical status of neuronal cytoplasm. We found that exposure to 94 GHz radiation increases the rate of microtubule assembly and that this effect can be entirely accounted for by the rapid EMF-elicited temperature jump. Our data are consistent with the notion that the cellular effects of a 94 GHz EMF are mediated entirely by cell heating. PMID- 23080285 TI - Health insurance coverage, income distribution and healthcare quality in local healthcare markets. AB - We develop a theoretical model of a local healthcare system in which consumers, health insurance companies, and healthcare providers interact with each other in markets for health insurance and healthcare services. When income and health status are heterogeneous, and healthcare quality is associated with fixed costs, the market equilibrium level of healthcare quality will be underprovided. Thus, healthcare reform provisions and proposals to cover the uninsured can be interpreted as an attempt to correct this market failure. We illustrate with a numerical example that if consumers at the local level clearly understand the linkages between health insurance coverage and the quality of local healthcare services, health insurance coverage proposals are more likely to enjoy public support. PMID- 23080286 TI - Localized reentrant tachycardia in the aorta contiguity region mimicking perimitral atrial flutter in the context of atrial fibrillation ablation. AB - We describe a case with a focal atrial tachycardia (AT) masquerading as perimitral atrial flutter revealed after circumferential pulmonary vein antral isolation for atrial fibrillation. It was successfully terminated and became noninducible by a point ablation on the left atrial anterior wall (LAAW) near the mitral annulus in contact with the aortic root and on the left superior pulmonary vein-left atrial appendage ridge, without any linear ablation, using electroanatomical mapping and conventional precise mapping with a maximum amplified gain within the low-voltage area. The AT revealed in our case was an LAAW-aorta contiguity area-related AT. PMID- 23080287 TI - Blunted heart rate recovery is associated with exaggerated blood pressure response during exercise testing. AB - Increased sympathetic activity and endothelial dysfunction are the proposed mechanisms underlying exaggerated blood pressure response to exercise (EBPR). However, data regarding heart rate behavior in patients with EBPR are lacking. We hypothesized that heart rate recovery (HRR) could be impaired in patients with EBPR. A total of 75 normotensive subjects who were referred for exercise treadmill test examination and experienced EBPR were included to this cross sectional case-control study. The control group consisted of 75 age- and gender matched normotensive subjects without EBPR. EBPR was defined as a peak exercise systolic blood pressure (BP) >=210 mmHg in men and >=190 mmHg in women. HRR was defined as the difference in HR from peak exercise to 1 min in recovery; abnormal HRR was defined as <=12 beats/min. These parameters were compared with respect to occurrence of EBPR. Mean values of systolic and diastolic BP at baseline, peak exercise, and the first minute of the recovery were significantly higher in the subjects with EBPR. Mean HRR values were significantly lower (P < 0.001) in subjects with EBPR when compared with those without. Pearson's correlation analysis revealed a significant positive correlation between the decrease in systolic BP during the recovery and degree of HRR in individuals without EBPR (r = 0.42, P < 0.001). Such a correlation was not observed in subjects with EBPR (r = 0.11, P = 0.34). The percentage of abnormal HRR indicating impaired parasympathetic reactivation was higher in subjects with EBPR (29 % vs 13 %, P = 0.02). In logistic regression analyses, HRR and resting systolic BP were the only determinants associated with the occurrence of EBPR (P = 0.001 and P < 0.001, respectively). Decreased HRR was observed in normotensive individuals with EBPR. In subjects with normal BP response to exercise, a linear correlation existed between the degree of HRR and decrease in systolic BP during the recovery period. However, such a correlation was not found in subjects with EBPR. Our data suggest that mechanisms underlying the blunting of the HRR might be associated with the genesis of EBPR. The association between the extent of HRR and adverse cardiovascular outcomes in patients with EBPR needs to be investigated in detail in future research. PMID- 23080288 TI - Three-year antibody persistence and safety after a single dose of combined haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in Hib-primed toddlers. AB - BACKGROUND: Persistence of seroprotective bactericidal antibody titers is important for long-term protection against meningococcal serogroup C disease in young children. Antibody persistence values were determined in children up to 3 years after vaccination with a single dose of the combined Haemophilus influenzae type b (Hib)-Neisseria meningitidis serogroup C (MenC)-tetanus toxoid (TT) conjugate vaccine (Hib-MenC-TT; www.ClinicalTrials.gov: NCT00326118). METHODS: The children had been randomized at ages 12-18 months to receive either 1 dose of Hib-MenC-TT (Hib-MenC group) or separately administered Hib-TT conjugate vaccine and MenC-CRM197 (MCC) vaccine (Hib plus MCC group). All children had been primed in infancy with a Hib vaccine. Antibodies against MenC were measured by a serum bactericidal assay using rabbit complement (rSBA-MenC) and antibodies against Hib polyribosylribitol phosphate were assessed by enzyme-linked immunosorbent assay. RESULTS: The rSBA-MenC titers >=1:8 were demonstrated 3 years after vaccination in 64.2% and 53.2% of participants in the Hib-MenC group and in the Hib plus MCC group, respectively. Antipolyribosylribitol phosphate concentrations >=0.15 ug/mL persisted in >98% of participants in both groups. The rSBA-MenC geometric mean titers and antipolyribosylribitol phosphate geometric mean concentrations remained higher 3 years after vaccination than before vaccination. No serious adverse events assessed by the investigator as being related to vaccination were reported. CONCLUSION: In this antibody persistence study of Hib-primed but MenC naive toddlers who received a single dose of Hib-MenC-TT, protective antibody levels against Hib and MenC were maintained in the majority of children 3 years after vaccination. PMID- 23080289 TI - Comparison of moderate and severe hospitalized Pediatric 2009 H1N1 influenza cases. AB - Since its discovery in 2009, H1N1 influenza (H1N1) has spread globally. Predictive factors for severe disease in children are not well defined. Our retrospective data collection and logistic regression analysis on 137 patients hospitalized between April 2009 and February 2010 at Children's Hospital and Research Center Oakland describe clinical and epidemiologic features of H1N1 in children and determines predictors of severe disease. PMID- 23080290 TI - Pneumococcal carriage and invasive disease in children before introduction of the 13-valent conjugate vaccine: comparison with the era before 7-valent conjugate vaccine. AB - BACKGROUND: Nasopharyngeal (NP) carriage and invasive pneumococcal disease (IPD) attributable to serotypes in the 7-valent pneumococcal conjugate vaccine (PCV7) declined dramatically after vaccine introduction, whereas non-PCV7 serotypes increased modestly. Characteristics of pneumococcal carriage and IPD among children in Atlanta, GA, were compared during 2 time periods: before PCV7 introduction and before 13-valent PCV (PCV13) introduction. METHODS: NP swabs from 231 and 451 children 6-59 months old receiving outpatient medical care were obtained in 1995 and 2009, respectively. A total of 202 and 47 IPD cases were identified in children younger than 5 years of age in 1995 and in 2008 to 2009, respectively, through active, population-based surveillance in Atlanta. Isolates were serotyped, sequence-typed (ST) and tested for antimicrobial susceptibility. RESULTS: Forty percent (93/231) of children in 1995 and 31% (139/451) in 2009 were colonized with Streptococcus pneumoniae; 60% and 0.7% were PCV7 serotypes, respectively. In 1995, PCV7 serotypes accounted for 83% and 19A accounted for 5% of IPD compared with no PCV7 serotypes and 19A accounting for 49% of IPD in 2009 (P < 0.001). In 2009, PCV13 serotypes accounted for 22% of carriage (mostly 19A) and 60% of invasive isolates (P < 0.001). ST320 accounted for 66% and 52% of 19A carriage and IPD isolates in 2009, respectively; all ST320 isolates were multidrug-resistant. No ST320 NP or IPD isolates were identified before PCV7. CONCLUSIONS: Serotype distribution among NP and IPD isolates in Atlanta has shifted to non-PCV7 serotypes; 19A was the leading serotype for both. The multidrug-resistant ST320 strain was responsible for two-thirds of 19A carriage isolates and half of IPD isolates. The predominance of serotype 19A in carriage and IPD among children in Atlanta highlights the potential direct and indirect benefits anticipated by implementation of PCV13 in the community. PMID- 23080291 TI - Ciprofloxacin reduces occurrence of fever in children with acute leukemia who develop neutropenia during chemotherapy. AB - BACKGROUND: Fluoroquinolones reduce occurrence of fever in adult cancer patients who develop neutropenia, but there has been no randomized controlled trial in children, and there are only a few studies considering resistance in intestinal floral after ciprofloxacin has been used. METHODS: Children younger than 18 years with acute lymphoblastic leukemia or lymphoma scheduled to undergo chemotherapy were randomized to receive oral ciprofloxacin 20mg/kg/day or placebo from the beginning of their chemotherapy. Rectal swab cultures were taken before and at 1 and/or 2 weeks after the intervention. RESULTS: Of the total of 95 patients, 45 and 50 patients received ciprofloxacin and placebo, respectively. Of the 71 patients who developed neutropenia, the proportion of children who developed fever was significantly lower in the ciprofloxacin group than in the placebo group (17/34 [50.0%] versus 27/37 [73.0%]; absolute difference in risk, -23.0%; 95% confidence interval: -45.0% to -0.9%; P = 0.046). Ciprofloxacin significantly reduced the occurrence of febrile episodes in patients with acute lymphoblastic leukemia in the induction phase of chemotherapy, but not in patients with lymphoma or in the consolidation phase of chemotherapy. Adverse effects were not different between the groups. After intervention, the percentages of Escherichia coli and Klebsiella pneumoniae susceptible to ciprofloxacin were significantly lower in the ciprofloxacin group. CONCLUSION: Ciprofloxacin can prevent fever in neutropenic patients with acute lymphoblastic leukemia during the induction phase of chemotherapy with good tolerance and no serious side effects. Due to the selective pressure of intestinal flora resistance to ciprofloxacin, the long-term effectiveness needs further investigation. PMID- 23080292 TI - Genetic relatedness of coagulase-negative Staphylococci from gastrointestinal tract and blood of preterm neonates with late-onset sepsis. AB - BACKGROUND: Coagulase-negative staphylococci (CoNS) are the first colonizers of gastrointestinal tract (GIT) and the commonest cause of late-onset sepsis (LOS) in preterm neonates. Intravascular catheters are considered a major source of CoNS bacteremia. However, several cases of LOS remain without an identified source. To elucidate whether GIT could be a potential source of invasive strains, we aimed to assess the molecular similarity between CoNS from blood and GIT in preterm neonates with LOS. METHODS: Altogether 22 blood and 53 GIT isolates collected from 22 neonates with LOS caused by CoNS (Staphylococcus haemolyticus in 13, Staphylococcus epidermidis in 7 and Staphylococcus hominis in 2 patients) were included. Rectal swabs were collected twice weekly from birth, but only isolates obtained before LOS were analyzed. S. epidermidis isolates were typed by multilocus variable number of tandem repeats analysis and multilocus sequence typing, S. haemolyticus by pulsed-field gel electrophoresis. RESULTS: Eighteen of 22 neonates had the same CoNS species in GIT and bloodstream; all these isolates from them (altogether 18 blood and 28 GIT isolates) underwent typing. The genotypic similarity between bloodstream and >=1 antecedent GIT isolates was observed in 13 of 18 patients-3 of 7 with S. epidermidis and 10 of 11 with S. haemolyticus infection. The concordant GIT isolates were collected 0-7 days before the positive blood culture. CONCLUSIONS: The similarity between CoNS from GIT and bloodstream indicates that preterm neonates harbour invasive strains in GIT before LOS. Whether there is a causal relationship between GIT colonization and LOS remains to be elucidated in further studies. PMID- 23080293 TI - An omni-directional mid-infrared tunable plasmonic polarization filter. AB - In this paper, we show that a localized surface plasmon polariton in a plasmonic sandwich structure made of a (metal elliptical disc)/(dielectric spacer)/(metal film) can be used as an efficient angle-independent polarizer in the mid-infrared wavelength regime. The elliptical disc structure is characterized by using a Fourier transform infrared spectrometer and simulated via the rigorous coupled wave analysis (RCWA) method. For the optimum design, we can obtain a degree of polarization of 99% both experimentally and theoretically. A high extinction ratio between 20 and 40 dB can be obtained by changing the axis ratio of the elliptical disc between 0.65 and 0.85. The wavelength of polarized light can be tuned in a wide range by changing the structural parameters. The plasmon polariton band structures of the elliptical disc structure for both TM and TE polarizations are also studied theoretically via RCWA. PMID- 23080294 TI - Heterologous expression of cellobiohydrolase II (Cel6A) in maize endosperm. AB - The technology of converting lignocellulose to biofuels has advanced swiftly over the past few years, and enzymes are a significant constituent of this technology. In this regard, cost effective production of cellulases has been the focus of research for many years. One approach to reach cost targets of these enzymes involves the use of plants as bio-factories. The application of this technology to plant biomass conversion for biofuels and biobased products has the potential for significantly lowering the cost of these products due to lower enzyme production costs. Cel6A, one of the two cellobiohydrolases (CBH II) produced by Hypocrea jecorina, is an exoglucanase that cleaves primarily cellobiose units from the non-reducing end of cellulose microfibrils. In this work we describe the expression of Cel6A in maize endosperm as part of the process to lower the cost of this dominant enzyme for the bioconversion process. The enzyme is active on microcrystalline cellulose as exponential microbial growth was observed in the mixture of cellulose, cellulases, yeast and Cel6A, Cel7A (endoglucanase), and Cel5A (cellobiohydrolase I) expressed in maize seeds. We quantify the amount accumulated and the activity of the enzyme. Cel6A expressed in maize endosperm was purified to homogeneity and verified using peptide mass finger printing. PMID- 23080296 TI - Are consanguineous marriage and swaddling the risk factors of developmental dysplasia of the hip? AB - The purpose of this study was to investigate prospectively the effects of swaddling and consanguineous marriage on developmental dysplasia of the hip and associated risk factors. We screened by ultrasound 265 infants using the Graf method. The Pediatrics Department referred all newborn infants with suspected instability or a recognized risk factor to the orthopedic clinic. Risk factors of developmental dysplasia of the hip were searched and noted in these patients. Swaddling and consanguineous marriage were also determined and noted. We observed 164 of 265 infants (61.9 %) who had been swaddled and that 64 of 265 infants' parents were in a consanguineous marriage (24.2 %). In the statistical analysis that was conducted for swaddling and consanguineous marriage, highly significant differences were found. Our study showed that the rate of developmental dysplasia of the hip is very high, 11.7 %, in our region, eastern Turkey. Also, we commonly see improper swaddling and consanguineous marriage in our region, which affects many infants. PMID- 23080297 TI - Oxygen vacancy formation in CeO2 and Ce(1-x)Zr(x)O2 solid solutions: electron localization, electrostatic potential and structural relaxation. AB - Ceria (CeO(2)) and ceria-based composite materials, especially Ce(1-x)Zr(x)O(2) solid solutions, possess a wide range of applications in many important catalytic processes, such as three-way catalysts, owing to their excellent oxygen storage capacity (OSC) through the oxygen vacancy formation and refilling. Much of this activity has focused on the understanding of the electronic and structural properties of defective CeO(2) with and without doping, and comprehending the determining factor for oxygen vacancy formation and the rule to tune the formation energy by doping has constituted a central issue in material chemistry related to ceria. However, the calculation on electronic structures and the corresponding relaxation patterns in defective CeO(2-x) oxides remains at present a challenge in the DFT framework. A pragmatic approach based on density functional theory with the inclusion of on-site Coulomb correction, i.e. the so called DFT + U technique, has been extensively applied in the majority of recent theoretical investigations. Firstly, we review briefly the latest electronic structure calculations of defective CeO(2)(111), focusing on the phenomenon of multiple configurations of the localized 4f electrons, as well as the discussions of its formation mechanism and the catalytic role in activating the O(2) molecule. Secondly, aiming at shedding light on the doping effect on tuning the oxygen vacancy formation in ceria-based solid solutions, we summarize the recent theoretical results of Ce(1-x)Zr(x)O(2) solid solutions in terms of the effect of dopant concentrations and crystal phases. A general model on O vacancy formation is also discussed; it consists of electrostatic and structural relaxation terms, and the vital role of the later is emphasized. Particularly, we discuss the crucial role of the localized structural relaxation patterns in determining the superb oxygen storage capacity in kappa-phase Ce(1-x)Zr(1-x)O(2). Thirdly, we briefly discuss some interesting findings for the oxygen vacancy formation in pure ceria nanoparticles (NPs) uncovered by DFT calculations and compare those with the bulk or extended surfaces of ceria as well as different particle sizes, emphasizing the role of the electrostatic field in determining the O vacancy formation. PMID- 23080295 TI - The polyamine spermine protects Arabidopsis from heat stress-induced damage by increasing expression of heat shock-related genes. AB - It is known that the polyamine (PA) biosynthetic pathway is modulated at the transcriptional level during abiotic stresses. Here we studied the expression of PA biosynthetic pathway genes upon exposure to heat shock (HS) in Arabidopsis and showed that the spermine (Spm) synthase gene (SPMS) and S-adenosylmethionine decarboxylase 2 gene are induced at the earliest stage, followed by the induction of the arginine decarboxylase 2 gene. Correspondingly, Spm content increased linearly upon HS, and putrescine (Put) and spermidine (Spd) content also increased but not thermospermine (T-Spm) content. Exogenously applied Spm had a potential to protect Arabidopsis plants from HS-induced damage. Such protection was also observed to the same extent with T-Spm and by Spd to a lesser extent but not by Put. Then we tested whether altered endogenous Spm content affects sensitivity to HS using both transgenic plants overexpressing SPMS and a Spm deficient (spms) mutant plant. The result revealed that the higher the Spm content the higher the thermotolerance. Even in the spms plant, representative genes encoding heat shock proteins (HSPs) and heat shock transcription factors were upregulated upon HS, while the expression of such genes was increased in a positively correlated manner with Spm content. Furthermore four kinds of HSPs (HSP101, HSP90, HSP70 and HSP17.6) were detected proportionally with the levels of their respective transcripts upon HS. We propose that Spm increases the HS response at transcriptional and translational levels and protects host plants from HS-induced damage. PMID- 23080298 TI - Tumor progression locus 2/Cot is required for activation of extracellular regulated kinase in liver injury and toll-like receptor-induced TIMP-1 gene transcription in hepatic stellate cells in mice. AB - Toll-like receptors (TLRs) function as key regulators of liver fibrosis and are able to modulate the fibrogenic actions of nonparenchymal liver cells. The fibrogenic signaling events downstream of TLRs on Kupffer cells (KCs) and hepatic stellate cells (HSCs) are poorly defined. Here, we describe the MAP3K tumor progression locus 2 (Tpl2) as being important for the activation of extracellular regulated kinase (ERK) signaling in KCs and HSCs responding to stimulation of TLR4 and TLR9. KCs lacking Tpl2 display defects with TLR induction of cytokines interleukin (IL)-1beta, IL-10, and IL-23. tpl2(-/-) HSCs were unable to increase expression of fibrogenic genes IL-1beta and tissue inhibitor of metalloproteinase 1 (TIMP-1), with the latter being the result of defective stimulation of TIMP-1 promoter activity by TLRs. To determine the in vivo relevance of Tpl2 signaling in liver fibrosis, we compared the fibrogenic responses of wild-type (WT) and tpl2(-/-) mice in three distinct models of chronic liver injury. In the carbon tetrachloride and methionine-choline-deficient diet models, we observed a significant reduction in fibrosis in mice lacking Tpl2, compared to WT controls. However, in the bile duct ligation model, there was no effect of tpl2 deletion, which may reflect a lesser role for HSCs in wounding response to biliary injury. CONCLUSION: We conclude that Tpl2 is an important signal transducer for TLR activation of gene expression in KCs and HSCs by the ERK pathway and that suppression of its catalytic activity may be a route toward suppressing fibrosis caused by hepatocellular injuries. (HEPATOLOGY 2013). PMID- 23080299 TI - Improved preparation of methyl bis(2,2,2-trifluoroethoxy)-bromophosphonoacetate for the stereoselective synthesis of (E)-alpha-bromoacrylates. AB - We have established an efficient method for preparing methyl bis(2,2,2 trifluoroethoxy)bromophosphonoacetate, which we developed for the stereoselective synthesis of (E)-alpha-bromoacrylates. This improved method enables the reagent to be prepared reproducibly in one step from methyl bis(2,2,2 trifluoroethoxy)phosphonoacetate. PMID- 23080300 TI - Mixed-phenotype grouping: the interaction between oddity and crypsis. AB - Aggregations of different-looking animals are frequently seen in nature, despite well-documented selection pressures on individuals to maintain phenotypically homogenous groups. Two well-known theories, the 'confusion effect' (reduced ability of a predator to accurately target an individual in a group) and the 'oddity effect' (preferential targeting of phenotypically distinct, 'odd', individuals) act together to predict the evolution of behaviours in prey that lead to groups of animals that are homogeneous in appearance. In contrast, a recently proposed mechanism suggests that mixed groups could be maintained if one species in a mixed group is more conspicuous against the habitat than the other, as confusion effects generated by the conspicuous species impede predator targeting of the cryptic species; thus, cryptic species benefit from association with conspicuous ones. We test these contrasting predictions from the perspective of both predators and prey, and show that cryptic individual Daphnia are at reduced risk of predation from three-spine sticklebacks Gasterosteus aculeatus when in mixed-phenotype groups, a risk that is reduced further as the number of conspicuous individuals increases, supporting the hypothesis for the evolution of mixed groups. In contrast, while the preference for associating with colour matched conspecifics by mollies (Poecilia sphenops) was reduced when they were cryptic, we found no evidence for active association with conspicuous conspecifics. We conclude that prey animals must balance the relative risks of oddity and conspicuousness in their social decisions, and that this could potentially lead to the evolution of mixed-phenotype grouping as a response to predation risk alone. PMID- 23080301 TI - Florivores prefer white versus pink petal color morphs in wild radish, Raphanus sativus. AB - Many hypotheses suggest that pollinators act to maintain or change floral color morph frequencies in nature, although pollinator preferences do not always match color morph frequencies in the field. Therefore, non-pollinating agents may also be responsible for color morph frequencies. To test this hypothesis, we examined whether Raphanus sativus plants with white flowers received different amounts of florivory than plants with pink flowers, and whether florivores preferred one floral color over the other. We found that white-flowered plants received significantly more floral damage than pink-flowered plants in eight populations over 4 years in northern California. Both generalists and specialists on Brassicaceae preferred white petals in choice and short-term no choice tests. In performance tests, generalists gained more weight on white versus pink petals whereas specialists gained similar amounts of weight on pink and white morphs. Because our results suggest that florivores prefer and perform better on white versus pink flowers, these insects may have the opportunity to affect the frequency of color morphs in the field. PMID- 23080302 TI - Positive feedback favors invasion by a submersed freshwater plant. AB - The submersed macrophyte Utricularia inflata has invaded lakes in northern New York State, thereby threatening native isoetids such as Eriocaulon aquaticum. Isoetids often dominate and modify softwater lakes due to their capacity to oxidize sediment and thus influence solute mobilization. Greenhouse experiments tested the hypotheses that U. inflata invasion could result in higher porewater iron (Fe) concentrations and greater ammonium (NH4 (+)) and Fe release from the sediment into the water column, and that this mobilization would stimulate further U. inflata growth. In the first experiment, three levels of U. inflata impact on E. aquaticum were imposed using sediment cores overlain by lake water: E. aquaticum alone, E. aquaticum with a cover of U. inflata, and bare sediment- the latter to simulate local extirpation of the isoetid by the invasive. After 16 weeks, sediment porewater NH4 (+) and total dissolved Fe concentrations were significantly higher (P < 0.05) for the U. inflata and bare sediment treatments. Water column concentrations of these solutes were five-fold higher (P < 0.05) for the bare sediment treatment than E. aquaticum alone, indicating that isoetid extirpation by U. inflata can compromise water quality. A second experiment demonstrated that U. inflata grew faster over bare sediment than over sediment with E. aquaticum (P < 0.05), likely due to greater solute mobilization in the absence of E. aquaticum. Where U. inflata causes a decline of native isoetids in Adirondack Mountain lakes, changes to lake sediment and water chemistry can create a positive feedback loop further escalating the impact of this invasive species. PMID- 23080303 TI - Contrasting spatial and temporal responses of bird communities to landscape changes. AB - Quantifying the impact of land-use changes on biodiversity is a major challenge in conservation ecology. Static spatial relationships between bird communities and agricultural landscapes have been extensively studied. Yet, their ability to mirror the effects of temporal land-use dynamics remains to be demonstrated. Here, we test whether such space-for-time substitution approaches are relevant for explaining temporal variations in farmland bird communities. We surveyed 256 bird communities in an agricultural landscape in southwest France at the same locations in 1982 and 2007, and quantified the same seven landscape descriptors for each period. We compared the effects of spatial and temporal landscape changes over this 25-year period on bird species distributions and three community-level metrics: species richness and two community indices reflecting birds' specialisation regarding local vegetation structure (local CSI) and landscape composition (landscape CSI). Landscape heterogeneity decreased between 1982 and 2007 and crop area increased sharply at the expense of grassland as a result of agricultural intensification. We found that the correlations between temporal changes in bird distributions or community metrics and landscape components were less consistent than their spatial relationships in each year. This result advocates caution when using a space-for-time substitution approach to assess the effects of landscape changes on biodiversity. Additionally, community metrics showed contrasted responses to landscape changes. Species richness and local CSI for each period were negatively related to the area of crops and positively related to landscape heterogeneity. Conversely, the landscape CSI was positively related to the area of crop and negatively to landscape heterogeneity. To understand the ecological processes linked to changes in farm landscapes, our study underlines the need to develop long-term studies with bird and habitat data collected during several periods, and particularly to consider multiple community indices in monitoring change. PMID- 23080304 TI - Reproductive success of individuals with different fruit production patterns. What does it mean for the predator satiation hypothesis? AB - The predator satiation hypothesis states that synchronous periodic production of seeds is an adaptive strategy evolved to reduce the pressure of seed predators. The seed production pattern is crucial to the predator satiation hypothesis, but there are few studies documenting the success of individuals that are in synchrony and out of synchrony with the whole population. This study is based on long-term data on seed production of Sorbus aucuparia and specialised pre dispersal seed predation by Argyresthia conjugella, in a subalpine spruce forest in the Western Carpathians (Poland). At the population level, we tested whether functional and numerical responses of predators to the variation of fruit production operate. At the individual level, we tested whether individuals with higher interannual variability in their own seed crops and higher synchrony with the population have higher percentages of uninfested fruits. The intensity of pre dispersal seed predation was high (average 70 %; range 19-100 %). There were both functional and numerical responses of predators to the variation of fruit production at the population level. We found that individuals that were expected to be preferred under seed predator pressure had higher reproductive success. With increasing synchrony of fruit production between individual trees and the population, the percentage of infested fruits decreased. There was also a negative relationship between the interannual variation in individual fruit production and the percentage of infested fruits. These results confirm selection for individuals with a masting strategy. However, the population does not seem well adapted to strong seed predation pressure and we suggest that this may be a result of prolonged diapause of A. conjugella. PMID- 23080305 TI - Carbene-stabilized phosphenium oxides and sulfides. AB - Carbene->chalcogenophosphenium adducts, which correspond to an intermolecular stabilization mode of the so far elusive, free oxo- and thiooxophosphenium species [R(2)P(+) = X] (X = O, S) by imidazolylidene (NHC) and diaminocyclopropenylidene (BAC) donors, have been isolated and fully characterized. The dative character of the R(2)C:->P(+)(X)Ph(2) bond was confirmed experimentally by nucleophilic displacement of the carbene donor with a chloride ion and by an exchange reaction of the NHC ligand of the NHC: >P(+)(O)Ph(2) adduct with an independently prepared BAC ligand, thereby giving the BAC:->P(+)(O)Ph(2) adduct. This dative character was further characterized by the DFT-calculated preference of carbene->chalcogenophosphenium systems for a heterolytic dissociation mode over a homolytic one. PMID- 23080306 TI - Considerations in reporting palliative care clinical trials: standardizing information reported and authorship practices. AB - PURPOSE OF REVIEW: The nature of palliative care practice, especially the reliance on referrals and differing models of service delivery, poses unique challenges for the creation and interpretation of an evidence base, frequently limiting the applicability of data to patient care. Here we discuss two core aspects of clinical trials reporting in palliative medicine: proposed standards governing the collection and reporting of data, and rules governing authorship and publication. RECENT FINDINGS: Existing literature often inadequately describes the characteristics of patients, caregivers, clinicians, systems, and interventions included in studies, thereby limiting the utility of results. SUMMARY: A generalizability framework is needed to ensure a robust evidence base that advances practice. Lessons learned through the development of research cooperative groups in palliative care reinforce the importance of an authorship protocol for large trials and working groups. PMID- 23080307 TI - Integrating technology into palliative care research. AB - PURPOSE OF REVIEW: As palliative care research evolves and grows within resource strained environments, further integration of novel methods to assist in completing protocols is needed. Technology-assisted techniques, including the use of software and hardware, to aid in data collection, analysis and reporting are increasingly being incorporated into research investigations in palliative care. Reviewing reported successes of technology use in palliative care research is important to communicate lessons learned and principles to guide further implementation. RECENT FINDINGS: There is a growing body of evidence that technology can be effectively integrated into palliative care research. We review four diverse examples of the use of software and hardware technology for data collection from patients and other research participants. Early successes and challenges with technology are also discussed. In addition, seven guiding principles for technology design, implementation and upgrading are appraised to advise readers of the important pitfalls that can plague any well intentioned technology-based research programme. SUMMARY: Technology has been successfully integrated into some aspects of palliative care research. The growth of both palliative care research and use of electronic methods for data collection predict increased incorporation between the two fields. PMID- 23080308 TI - Outcome measures for palliative care research. AB - PURPOSE OF REVIEW: The aim of this review is to summarize the current state of the science in physical symptoms and other end-of-life care domains and/or illness-specific outcomes in palliative care. The review includes progress in outcome measure development and interpretation, with specific reference to the clinical trial context. RECENT FINDINGS: There are validated measures in a wide range of domains, which can measure outcomes specific to palliative care interventions; which are sufficiently validated to ensure the results of the trial are robust and measuring differences which are both clinically meaningful. In several areas, consensus is emerging which will allow consolidation of outcome measurement and the ability to extend measurement from the clinical trial setting into routine clinical practice. Potential exists for composite measures covering areas prioritized by patients to improve comparability and efficiency. Adverse events need to be measured with the same degree of rigor as efficacy outcomes. SUMMARY: Clinical trials of palliative care interventions need to consider a range of outcomes, however, the choice and timing of measurement of the primary outcome need to be guided by the domain most likely to be influenced by the intervention. PMID- 23080309 TI - Achieving palliative care research efficiency through defining and benchmarking performance metrics. AB - PURPOSE OF REVIEW: Research efficiency is gaining increasing attention in the research enterprise, including palliative care research. The importance of generating meaningful findings and translating these scientific advances to improved patient care creates urgency in the field to address well documented system inefficiencies. The Palliative Care Research Cooperative Group (PCRC) provides useful examples for ensuring research efficiency in palliative care. RECENT FINDINGS: Literature on maximizing research efficiency focuses on the importance of clearly delineated process maps, working instructions, and standard operating procedures in creating synchronicity in expectations across research sites. Examples from the PCRC support these objectives and suggest that early creation and employment of performance metrics aligned with these processes are essential to generate clear expectations and identify benchmarks. These benchmarks are critical in effective monitoring and ultimately the generation of high-quality findings that are translatable to clinical populations. Prioritization of measurable goals and tasks to ensure that activities align with programmatic aims is critical. SUMMARY: Examples from the PCRC affirm and expand the existing literature on research efficiency, providing a palliative care focus. Operating procedures, performance metrics, prioritization, and monitoring for success should all be informed by and inform the process map to achieve maximum research efficiency. PMID- 23080310 TI - Effects of chronic scopolamine administration on spatial working memory and hippocampal receptors related to learning. AB - Scopolamine has been used in neuropsychopharmacology as a standard drug that leads to symptoms mimicking cognitive deficits seen during the aging process in healthy humans and animals. Scopolamine is known to be a nonselective muscarinic receptor blocker, but its chronic effect on the expression of certain hippocampal receptors is not clear. The aim of the present study was to determine the effect of chronic scopolamine administration on hippocampal receptor expression and spatial working memory in two different learning tasks, the water maze and the eight-arm radial maze. Male rats (8-12 months) were trained in both tasks. Subsequently, different groups received physiological saline or 0.1, 0.8, or 2 mg/kg scopolamine hydrobromide, respectively, for 15 days. After drug administration, the rats were retested for both tasks, and hippocampal expressions of NR2A, NR2B, nAChRalpha7, and mAChRM1 receptors were assessed by western blotting analysis. In both tasks, the spatial working memory was decreased dose dependently in all groups compared with the control group. In terms of receptor expressions, 0.8 and 2 mg/kg scopolamine administration significantly decreased NR2A protein expression, which corroborates suggestions of an interaction between cholinergic and glutamatergic receptors in the hippocampus. PMID- 23080312 TI - Suppressive effect of triadimefon, a triazole fungicide, on spatial learning and reference memory in rats. AB - Although some central effects of triadimefon, a triazole fungicide, have been reported, its effects on spatial memory have not been examined. In this study, we used the Morris water maze to study the effect of triadimefon on spatial learning and memory in rats. To elucidate the mechanism of this effect, we also measured the retinoic acid concentration in the hippocampus by high-performance liquid chromatography. Our data showed that triadimefon inhibited spatial learning and impaired spatial reference memory, and decreased hippocampal retinoic acid concentration. There is evidence that triadimefon can regulate the metabolism of retinoic acid, which serves a critical function in the development and maintenance of spatial memory. Therefore, we speculate that the reduction in hippocampal retinoic acid concentration induced by triadimefon might be responsible for its suppressive effect on spatial learning and reference memory. PMID- 23080311 TI - A quantitative analysis of the reward-enhancing effects of nicotine using reinforcer demand. AB - Reward enhancement by nicotine has been suggested as an important phenomenon contributing toward tobacco abuse and dependence. Reinforcement value is a multifaceted construct not fully represented by any single measure of response strength. The present study evaluated the changes in the reinforcement value of a visual stimulus in 16 male Sprague-Dawley rats using the reinforcer demand technique proposed by Hursh and Silberberg. The different parameters of the model have been shown to represent differing facets of reinforcement value, including intensity, perseverance, and sensitivity to changes in response cost. Rats lever pressed for 1-min presentations of a compound visual stimulus over blocks of 10 sessions across a range of response requirements (fixed ratio 1, 2, 4, 8, 14, 22, 32). Nicotine (0.4 mg/kg, base) or saline was administered 5 min before each session. Estimates from the demand model were calculated between nicotine and saline administration conditions within subjects and changes in reinforcement value were assessed as differences in Q0, Pmax, Omax, and essential value. Nicotine administration increased operant responding across the entire range of reinforcement schedules tested, and uniformly affected model parameter estimates in a manner suggesting increased reinforcement value of the visual stimulus. PMID- 23080313 TI - Diagnostic accuracy of scapular physical examination tests for shoulder disorders: a systematic review. AB - OBJECTIVE: To systematically review and critique the evidence regarding the diagnostic accuracy of physical examination tests for the scapula in patients with shoulder disorders. METHODS: A systematic, computerised literature search of PubMED, EMBASE, CINAHL and the Cochrane Library databases (from database inception through January 2012) using keywords related to diagnostic accuracy of physical examination tests of the scapula. The Quality Assessment of Diagnostic Accuracy Studies tool was used to critique the quality of each paper. RESULTS: Eight articles met the inclusion criteria; three were considered to be of high quality. Of the three high-quality studies, two were in reference to a 'diagnosis' of shoulder pain. Only one high-quality article referenced specific shoulder pathology of acromioclavicular dislocation with reported sensitivity of 71% and 41% for the scapular dyskinesis and SICK scapula test, respectively. CONCLUSIONS: Overall, no physical examination test of the scapula was found to be useful in differentially diagnosing pathologies of the shoulder. PMID- 23080314 TI - Sports prehospital-immediate care and spinal injury: not a car crash in sight. AB - The prehospital management of serious injury is a key skill required of pitch side medical staff. Previously, specific training in sports prehospital-immediate care was lacking or not of a comparable standard to other aspects of emergency care. Many principles have been drawn from general prehospital care or in hospital training courses. This article discusses sports prehospital-immediate care as a niche of general prehospital care, using spinal injury management as an illustration of the major differences. It highlights the need to develop the sport-specific prehospital evidence base, rather than relying exclusively on considerations relevant to prolonged immobilisation of multiply injured casualties from motor vehicle accidents, falls from height or burns. PMID- 23080316 TI - Direct cell penetration of the antifungal peptide, MMGP1, in Candida albicans. AB - An antifungal peptide, MMGP1, was recently identified from marine metagenome. The mechanism of cellular internalization of this peptide in Candida albicans was studied using fluorescein 5-isothiocynate (Sigma, California, USA) labeling followed by fluorescence microscopy and flow cytometry analyses. The peptide could enter C. albicans cells even at 4 degrees C, where all energy-dependent transport mechanisms are blocked. In addition, the peptide internalization was not affected by the endocytic inhibitor, sodium azide. The kinetic study has shown that the peptide was initially localized on cell membrane and subsequently internalized into cytosol. The MMGP1 treatment exhibited time-dependent cytotoxicity in C. albicans as evidenced by SYTOX Green (Molecular Probes Inc., Eugene, Oreg) uptake. PMID- 23080315 TI - Terminology and classification of muscle injuries in sport: the Munich consensus statement. AB - OBJECTIVE: To provide a clear terminology and classification of muscle injuries in order to facilitate effective communication among medical practitioners and development of systematic treatment strategies. METHODS: Thirty native English speaking scientists and team doctors of national and first division professional sports teams were asked to complete a questionnaire on muscle injuries to evaluate the currently used terminology of athletic muscle injury. In addition, a consensus meeting of international sports medicine experts was established to develop practical and scientific definitions of muscle injuries as well as a new and comprehensive classification system. RESULTS: The response rate of the survey was 63%. The responses confirmed the marked variability in the use of the terminology relating to muscle injury, with the most obvious inconsistencies for the term strain. In the consensus meeting, practical and systematic terms were defined and established. In addition, a new comprehensive classification system was developed, which differentiates between four types: functional muscle disorders (type 1: overexertion-related and type 2: neuromuscular muscle disorders) describing disorders without macroscopic evidence of fibre tear and structural muscle injuries (type 3: partial tears and type 4: (sub)total tears/tendinous avulsions) with macroscopic evidence of fibre tear, that is, structural damage. Subclassifications are presented for each type. CONCLUSIONS: A consistent English terminology as well as a comprehensive classification system for athletic muscle injuries which is proven in the daily practice are presented. This will help to improve clarity of communication for diagnostic and therapeutic purposes and can serve as the basis for future comparative studies to address the continued lack of systematic information on muscle injuries in the literature. WHAT ARE THE NEW THINGS: Consensus definitions of the terminology which is used in the field of muscle injuries as well as a new comprehensive classification system which clearly defines types of athletic muscle injuries. LEVEL OF EVIDENCE: Expert opinion, Level V. PMID- 23080317 TI - Characterisation of commercial aromatised vinegars: phenolic compounds, volatile composition and antioxidant activity. AB - BACKGROUND: Nineteen commercially available aromatised vinegars, which were representative of this type of product, were tested to ascertain their phenolic and volatile composition and antioxidant activity. The aromatised vinegars came from different raw materials such as fruits, spices, herbs and vegetables. The antioxidant activity was determined by means of photochemiluminescence, phenolic profile by using ultra performance liquid chromatography with ultraviolet detection, and the volatile composition was determined by using stir bar sorptive extraction-gas chromatography-mass spectrometry. RESULTS: Nine polyphenolic compounds and 141 volatile compounds were identified. Vinegar aromatised with black truffle and rosemary obtained the highest values of antioxidant activity, followed by those aromatised with lemon, tarragon, aromatic herbs and vegetables. Antioxidant activity was highly correlated with the presence of trans-p-coutaric acid, trans-caftaric acid, 5-hydroxy-methylfurfural and furfural. Moreover, (Z)-3 hexen-1-ol was exclusive to the vinegar aromatised with tarragon, while p-menth 1,8-ol, dimethyl styrene, 4-methyl acetophenone and nootkatone were only found in vinegar aromatised with lemon. CONCLUSION: On the basis of the results from the cluster analysis of cases, it can be concluded that the grouping responds more to the trademark of each vinegar than to the raw material. PMID- 23080318 TI - Salivary mucoepidermoid carcinoma: a multi-institutional review of 76 patients. AB - Mucoepidermoid carcinoma (MEC) is a relatively common salivary tumor with varying potential for aggressive behavior. Mucoepidermoid carcinoma grading has evolved from descriptive two-tiered schemata to more objective three-tiered systems. In 2001, we published a grading system Brandwein et al. in Am J Surg Pathol 25:835 845, (2001) which modified the prevailing criteria of Auclair et al. in Cancer 69:2021-2030 (1992), and included additional features of aggressive MEC. Here we seek to validate our modified grading system in a new multicenter cohort. The retrospective cohort consisted of 76 patients with confirmed MEC and known outcome data. The resection specimens were reviewed and uniformly graded according to our modified criteria Brandwein et al. in Am J Surg Pathol 25:835 845 (2001), and the Auclair criteria Auclair et al. in Cancer 69:2021-2030, (1992), Goode et al. in Cancer 82:1217-1224, (1998). Case distribution was as follows: Montefiore Medical Center: 41 (1977-2009), University of Alabama at Birmingham: 21 (1999-2010), and Rhode Island Hospital: 14, (1995-2011). Patient age ranged from 7 to 81 years (mean 51 years). The female to male ratio was 3:1. The most commonly involved sites were: parotid: n = 39 (51%), palate: n = 10 (13%), retromolar trigone: n = 6 (8%), buccal: n = 5 (7%), and submandibular gland: n = 5 (7%). The modified criteria upgraded 41% MEC; 20/25 MEC from AFIP Grade 1 to Grade 2 and 5/25 from AFIP grade 1 to grade 3. Eleven patients had positive lymph nodes; the AFIP MEC grade for cases were: grade 1-3/11, Grade 2 1/11, and grade 3-7/11; the modified grading criteria distribution for these cases were Grade 1: 0/11, grade 2: 1/11, and grade 3: 10/11. Nine patients developed disease progression after definitive treatment. High-stage and positive lymph node status were significantly associated with disease progression (p = 0.0003 and p < 0.0001, respectively). For the nine patients with disease progression, the modified grading schema classified eight MEC as grade 3 and one as grade 2. By comparison, the AFIP grading schema classified three of these MEC as grade 1, and the remaining six as grade 3. Despite the fact that this multicenter retrospective study accrued 76 patients with outcome, the predictive performance of the two grading schema could not be compared due to the few patients who experienced disease progression and were also reclassified with respect to grade (n = 3). PMID- 23080319 TI - Repeated MRI of a patient with an intramedullary tumour and implanted cardiac resynchronization therapy defibrillator (CRT-D). PMID- 23080320 TI - Robot versus laparoscopic gastrectomy for cancer by an experienced surgeon: comparisons of surgery, complications, and surgical stress. AB - BACKGROUND: No previous robotic studies present an equivalent surgical quality comparison in an experienced setting for gastric cancer. In addition, a reliable postoperative complication assessment is needed to accurately evaluate surgical outcomes. METHODS: After 20 cases of robotic-assisted gastrectomy (RAG), a total of 121 consecutive gastric cancer patients underwent gastrectomy (38 RAG vs 83 laparoscopic-assisted gastrectomy [LAG]) from February 2009 to November 2010 at the Department of Surgery, Korea University Anam Hospital, Seoul, Korea. The Clavien-Dindo (C-D) classification was used to classify surgical complications. The granulocyte-to-lymphocyte (G:L) ratio was analyzed to evaluate surgical stress. RESULTS: The baseline characteristics, with the exception of age, were similar. The mean total operation time for RAG (234.4 +/- 48.0 min) was not significantly different than that for LAG (220.0 +/- 60.6 min; P = 0.198). However, in obese patients, fewer lymph nodes were harvested by RAG (23.4 +/- 7.0) than by LAG (32.2 +/- 12.5, P = 0.006). Overall C-D complications were more common for RAG (47.3 vs 38.5 %), but the difference was not significant (P = 0.361). The mean hospital stay was similar for the 2 groups. Surgical stress as estimated by the G:L ratio was comparable between the 2 groups. CONCLUSIONS: RAG performed by an experienced surgeon resulted in similar postoperative outcomes and complications to those of LAG. Assessment of operation time, C-D complication grade, and G:L ratio revealed that RAG is a practical and feasible alternative to LAG, with the possible exception of obese patients. PMID- 23080321 TI - Valuing QALY gains by applying a societal perspective. AB - Interpreting the outcomes of cost utility analyses requires an appropriately defined threshold for costs per quality-adjusted life year (QALY). A common view is that the threshold should represent the (consumption) value a society attaches to a QALY. So far, individual valuations of personal health gains have mainly been studied rather than potentially relevant social values. In this study, we present the first direct empirical estimates of the willingness to pay for a QALY from a societal perspective. We used the contingent valuation approach, valuing QALYs under uncertainty and correcting for probability weighting. The estimates obtained in a representative sample of the Dutch population (n = 1004) range from ?52,000 to ?83,000, depending on the specification of the societal perspective. The scale sensitivity was weak, however. PMID- 23080322 TI - Interplay of bite angle and cone angle effects. A comparison between o C6H4(CH2PR2)(PR'2) and o-C6H4(CH2PR2)(CH2PR'2) as ligands for Pd-catalysed ethene hydromethoxycarbonylation. AB - The following unsymmetrical diphosphines have been prepared: o C6H4(CH2PtBu2)(PR2) where R = PtBu2 (L3a); PCg (L3b); PPh2 (L3c); P(o-C6H4CH3)2 (L3d); P(o-C6H4OCH3)2 (L3e) and o-C6H4(CH2PCg)(PCg) (L3f) where PCg is 6-phospha 2,4,8-trioxa-1,3,5,7-tetramethyladamant-6-yl. Hydromethoxycarbonylation of ethene under commercially relevant conditions has been investigated in the presence of Pd complexes of each of the ligands L3a-f and the results compared with those obtained with the commercially used o-C6H4(CH2PtBu2)2 (L1a). The Pd complexes of the bulkiest ligands L3a, L3b and L3f are highly active catalysts but the Pd complexes of L3c, L3d and L3e are completely inactive. The crystal structures of the complexes [PtCl2(L1a)] (1a) and [PtCl2(L3a)] (2a) have been determined and show that the crystallographic bite angles and cone angles are greater for L1a than L3a. Solution NMR studies show that the seven-membered chelate in 1a is more rigid than the six-membered chelate in 2a. Treatment of [PtCl(CH3)(cod)] with L3a f gave [PtCl(CH3)(L3a-f)] as mixtures of 2 isomers 3a-f and 4a-f. The ratio of the products 4:3 ranges from 100:1 to 1:20, the precise proportion is apparently governed by a balance of two competing factors, steric bulk and the antisymbiotic effect. The palladium complexes [PdCl(CH3)(L3b)] (5b/6b) and [PdCl(CH3)(L3c)] (5c/6c) react with labelled 13CO to give the corresponding acyl species [PdCl(13COCH3)(L3b)] (7b/8b) and [PdCl(13COCH3)(L3c)] (7c/8c). Treatment of [PdCl(13COCH3)(L)] with MeOH gave CH3(13)COOMe rapidly when L = L3b but very slowly when L = L3c paralleling the contrasting catalytic activity of the Pd complexes of these two ligands. PMID- 23080323 TI - Cardiac resynchronization therapy for patients with congenital heart disease: technical challenges. AB - Cardiac resynchronization therapy (CRT) is a commonly used procedure to help patients with drug refractory heart failure (HF) symptoms. More patients with congenital heart disease (CHD) survive to adulthood with the improvements that have occurred as a result of surgical and medical care of these patients. However, patients with CHD may develop ventricular dysfunction and HF and thus be considered for CRT. In this review, we discuss the unique features of CRT in the adult CHD population. We examine the existing data on utilization of CRT in patients with HF and CHD and specifically discuss the limitations in terms of benefit as well as data availability. Finally, we review the specific coronary sinus anatomy and technical considerations for placing a left ventricular lead in patients with CHD. PMID- 23080324 TI - New insights into typical atrial flutter ablation: extra-isthmus activation time on the flutter wave is predictive of extra-isthmus conduction time after isthmus block. AB - PURPOSE: Catheter ablation of typical atrial flutter (AFl) is succesful if double electrograms on the ablation line are widely separated. Nevertheless, a small interval may also be compatible with complete isthmus block. Predicting such a situation may avoid useless additionnal radiofrequency (RF) applications. We postulated that measuring the extra-isthmus activation time (EIAT) on the counterclockwise (CCW) flutter wave is correlated with the extra-isthmus conduction time after a proven block. METHODS: Files of 76 patients (71 males, 71 +/- 12 years) ablated for typical CCW AFl were reviewed. Ten had 2/1 conduction prohibiting reliable measurement. Three patients with proven crista terminalis shunt were also excluded. In the remaining 63 patients, EIAT was measured on the surface ECG before the first RF pulse from the beginning of the negative deflection of the F wave in lead III to the end of the positive deflection (or beginning of the plateau). After successful ablation and completion of block, right atrial (RA) CCW (during low septal pacing), and clockwise (CW) (during low lateral pacing) activation times were measured. RESULTS: Flutter cycle length was 247 +/- 34 ms and EIAT was 142 +/- 25 ms. A bidirectionnal isthmus block was obtained in all patients after an RF delivery time of 623 +/- 546 s. At a pacing cycle length of 681 +/- 71 ms, RA CCW and CW activation times were 147 +/- 23 and 139 +/- 26 ms, respectively. There was a good correlation between EIA, RA CCW (r = 0.75, p < 0.0001), and CW (r = 0.69, p = 0.0002) activation times. CONCLUSION: EIAT on the flutter wave is an easy and feasible measure. It is correlated with extra-isthmus RA conduction time after block completion. EIAT can be used as a measure to predict the post cavo-tricuspid isthmus block RA activation time. PMID- 23080326 TI - Cryoablation versus radiofrequency ablation for the treatment of atrioventricular nodal reentrant tachycardia: results of a prospective randomized study. AB - PURPOSE: Radiofrequency ablation (RF) of atrioventricular reentrant tachycardia (AVNRT) is an effective method for treating this arrhythmia. However, inadverted AV block requiring implantation of permanent pacemaker is a worrisome side effect. Although permanent AV block seems to be rare nowadays, patients are by no means spared from this severe complication. Catheter cryoablation is emerging as an alternative technology with an excellent safety profile, but limited data exist regarding its efficacy. METHODS: We conducted a randomized study among patients with AVNRT remitted to our center for EP study and ablation between January 2008 and June 2010. After giving a written consent, patients were randomized to conventional RF or cryoablation, unless specific preference of patient was stated. Primary outcomes were acute success, SVT recurrence, and complications, including AV block. RESULTS: One hundred nineteen patients were included (60 cryoablation and 59 conventional RF). There were no differences in demographic and clinical baseline data between groups. Acute procedural success was achieved in 59 patients (98 %) in cryoablation group and 59 (100 %) in RF. One patient in RF group underwent complete AV block and pacemaker implantation. Over a mean follow-up period of 256.6 days, there was a significant difference in AVNRT recurrence between cryoablation and RF patients (15 versus 3.4 %, p = 0.03). CONCLUSION: Catheter cryoablation of AVNRT is a clinically effective alternative to RF ablation, with excellent acute success rate. Despite a slightly higher rate of recurrence during long-term follow-up, these results suggest that cryoablation may be considered as first-line approach, especially in younger people, where the risk of permanent pacing because of inadvertent AV block may be relevant. PMID- 23080328 TI - "Conventional" isthmus ablation without fluoroscopy. AB - Recently, a new technology for nonfluoroscopic 4-D catheter tracking has been introduced (MediGuide). This system allows precise catheter visualization on prerecorded conventional fluoroscopy loops. We report about the first experience in atrial flutter ablation using a MediGuide-supported ablation catheter. For successful ablation besides the 6 s for loop acquisition, no further fluoroscopy was used. PMID- 23080327 TI - Single-chamber ICD, single-zone therapy in primary and secondary prevention patients: the simpler the better? AB - BACKGROUND: It is now well established that implantable cardioverter defibrillator (ICD) implantation reduces mortality in patients at increased risk of sudden cardiac death. However, the best programming parameters remain controversial. Our traditional policy has followed a simple approach in the vast majority of patients. In accordance with ICD programming in the major randomized clinical trials, we programmed a single high-rate, shock-only therapy zone. We aimed to demonstrate in this observational study that simple programming is not associated with higher shock rates or mortality when compared to other published studies. METHODS: Consecutive patients who underwent single-chamber ICD implantation with single-zone, high-rate programming at our institution between 1993 and 2008 were retrospectively studied. Data were collected prospectively in a database regarding details of ICD implantation, demographic data, and indication. RESULTS: Three hundred thirty-two patients were included in our study, 31 % primary prevention and 68 % secondary prevention. Mean ejection fraction (EF) is 33.7 +/- 15.3. Over a mean follow-up period of 62.5 +/- 38.1 months, 135 patients experienced ICD shock (annualized event rate 7.7 %); 89 patients (26.8 %) appropriate shock in VT-ventricular fibrillation (VF), 68 patients (20.5 %) inappropriate shocks, and 22 patients (6.6 %) both. Twenty-nine patients (8.7 %) were reprogrammed to additional VT-ATP zones. Twenty-two (6.6 %) patients underwent heart transplantation. Sixty-two patients (18.6 %) died during follow-up, 43.6 % out of them due to cardiac cause, mainly progressive heart failure. CONCLUSION: Our results show that simpler settings with single-zone, high-rate programming is associated with ICD shock rates and long-term mortality that does not appear to be worse when compared with contemporary studies which include multizone ICD programming with antitachycardia pacing activated. PMID- 23080329 TI - An unusual case of vancomycin-related systemic reaction accompanied with severe thrombocytopenia mimicking pacemaker-related infective endocarditis: a case report and review of literature. AB - Vancomycin is a glycopeptide antibiotic used in the prophylaxis and treatment of infections caused by Gram-positive resistant bacteria. In recent years, several cases of vancomycin-associated immune thrombocytopenia have been presented as case reports, but the real incidence of this side effect is still unknown. In this report, we would like to present a case during which we confronted with a great dilemma: urgent removal of whole defibrillator system due to highly suspected infective endocarditis or leaving the defibrillator in place and simply switching vancomycin to another antibiotic agent and wait. PMID- 23080330 TI - Riata lead failure with normal electrical lead parameters and normal fluoroscopic appearance. AB - Recently, insulation breach of the Riata lead raised a big concern. Management of these externalized leads has been addressed by professional organizations. However, what to do in patients with Riata leads without manifested failure is an ongoing clinical dilemma. Here, we present two clinical scenarios where the implantable cardioverter defibrillator system failed to deliver shock therapy in spite of having a new ICD generator and "appropriately functioning leads" as revealed by lead interrogation. PMID- 23080332 TI - Thermotolerance does not reduce the size or remodeling of radiofrequency lesions in the rat myocardium. AB - PURPOSE: Late lesion extension may be involved in the genesis of delayed radiofrequency (RF) effects. Because RF lesion is thermally mediated, we hypothesized that induction of heat shock response (thermotolerance) would modulate lesion healing. We evaluated the effects of thermotolerance on the dimensions and remodeling of RF lesions in a rat model of heart failure. METHODS: Wistar rats (weight 300 g) subjected to heat stress (n = 22, internal temperature of 42 degrees C for 10 min) were compared to controls (n = 22, internal temperature of 37 degrees C for 10 min). After 48 h (peak of HSP70 myocardial concentration), a modified unipolar RF lesion (customized catheter, tip 4.5 mm in diameter; 12 W; 10 s) was created on the left ventricular free wall. Animals were sacrificed 2 h (n = 10 per group) and 4 weeks (n = 12 per group) after ablation for lesion analysis. An echocardiogram was obtained at 4 weeks. RESULTS: There was no difference between groups regarding the size of acute (controls 27 +/- 2 vs. treated 27 +/- 3 mm(2)) and chronic lesions (controls 17 +/- 1 vs. treated 19 +/- 1 mm(2)). Histology of lesions did not differ between groups. The echocardiogram revealed dilation of the cavities and moderate systolic dysfunction without difference between groups. Acute lesion dimensions were similar between control and treated animals over time (ablation undertaken 3, 12, 24, 48, and 72 h after hyperthermia) and also using a conventional ablation catheter (50 degrees C; 15 W; 10 s). CONCLUSION: Thermotolerance does not reduce the size or remodeling of RF lesions in the rat myocardium. PMID- 23080331 TI - Cardiac autonomic function in metabolic syndrome: a comparison of ethnic Turkish and Japanese patients. AB - BACKGROUND: Metabolic syndrome (MetS) prevalence shows some differences at various regions of the world in terms of race and ethnicity. The cardiac autonomic functions between Turkish and Japanese MetS patients with heart rate turbulence (HRT) and heart rate variability (HRV) were compared as the aim of this study. METHODS: This study consists of 149 nondiabetic subjects with MetS. All patients were further classified into subgroups based on ethnicity (76 from Turkey, 73 from Japan). Twenty-four-hour ambulatory Holter ECG recording was applied to all subjects whose HRV and HRT (total onset (TO), total slope (TS)) parameters were analyzed. RESULTS: The waist circumference was the only demographic parameter that was significantly different between the Turkish and Japanese patients with MetS (99.31 +/- 6.12 vs 91.12 +/- 6.89 for men and 91.48 +/- 7.45 vs 86.26 +/- 5.78 for woman; p < 0.001 and <0.001). There was a significant difference between Turkish and Japanese patients with MetS in terms of the HRT values. (TO Turkish, 0.77 +/- 0.19 %; TO Japanese, 0.49 +/- 1.03 %, p = 0.031; TS Turkish, 1.93 +/- 1.26; TS Japanese, 2.44 +/- 1.37, p = 0.041, respectively). As for HRV parameters, standard deviation of all NN intervals index was only different between Turkish and Japanese patients with MetS (90.79 +/- 58.94, 128.18 +/- 105.30; p = 0.034, respectively). CONCLUSION: HRT and some HRV scores of ethnic Turkish MetS patients are worse than the scores of ethnic Japan MetS patients. We think that these differences are related to the central obesity. PMID- 23080333 TI - Image-guided placement of port catheters: is there an increased risk of infection if the port is immediately accessed and used? AB - PURPOSE: To compare complication rates in patients who have port-a-catheters inserted and left accessed for immediate use and those who have ports inserted but not accessed. METHODS: In this retrospective, IRB-approved study, medical records of patients who received a port catheter between 9/2009 and 2/2010 were reviewed. The data collected included patient demographics, diagnosis, procedure and complications. The patients were categorized into two groups: accessed (patients in whom the port was accessed with a Huber needle for immediate intravenous use and the patient left the procedure area with needle indwelling) and control (patients in whom the ports were not accessed). Complications were classified according to Society of Interventional Radiology guidelines. Results are given as mean +/-SD. Statistical analysis was performed with student t test and statistical significance was considered at P<.05. RESULTS: A total of 467 ports were placed in 465 patients (Men: 206); 10.7% in the accessed group (n=50, age: 60+/-13.9) and 89.3% in the control group (n=417, age: 59+/-13.5). There were no statistically significant differences in patient demographics between the groups. The overall complication rate was 0.6% (n=3). Two complications (hematoma causing skin necrosis and thrombosis of the port) occurred in the control group and one (infection) in the accessed group. Infection rates after procedures were 2% (1/50) in the accessed group and 0% (0/417) in the control group. There was no statistically significant difference in overall complication (P=.1) and infection (P=.1) rates among the groups. CONCLUSIONS: Leaving the port accessed immediately after placement does not increase the risk of infection or other complications. PMID- 23080334 TI - Primary patency time of basilic vein transposition versus prosthetic brachioaxillary access grafts in hemodialysis patients. AB - PURPOSE: The aim of this study was to compare the primary patency time of basilic vein transposition and prosthetic brachioaxillary access grafts in hemodialysis patients. METHODS: In this randomized clinical trial, 60 hemodialysis patients who met the inclusion/exclusion criteria were recruited and randomly assigned to two intervention groups; Basilic vein transpositions (BVT) or Arteriovenous access grafts (AVG). Clinical follow-up for patency of the created accesses in at least one year, was performed at two weeks, one, two, three months and then every three months after surgery. Finally, patency rates and access-related complications were compared in the two groups studied. RESULTS: Thirty BVTs and thirty AVG were performed in each group studied. The groups were well matched for age, sex and comorbidity. After at least one year of follow-up, the access failure rate in the BVT and AVG groups was 23.3% and 30%, respectively. In addition, the mean primary patency time in the BVT and AVG groups was 244.13 +/- 103.65 and 264.97 +/- 149.28, respectively and there was no statistically significant difference between the two groups studied (P=.533). The common cause of access failure were thrombosis and infection but there were no statistically significant differences between the two groups (P>.05). CONCLUSION: Our results show that AVG offer similar patency and complication rates to BVT. Thus, authors consider them as the preferred hemodialysis access when there are no suitable forearm veins to create arteriovenous fistulas. PMID- 23080335 TI - A sterile elastic exsanguination tourniquet is effective in preventing blood loss during hemodialysis access surgery. AB - PURPOSE: We report the first use of a sterile elastic exsanguination tourniquet (SET) in performing hemodialysis vascular access procedures in 27 patients. The main advantages of this tourniquet are the reduction of blood loss and need for possible transfusions. Additional benefits are the near-perfect exsanguination and excellent exposure of the operative field. METHODS: This SET is a sterile elastic stockinet device that rolls up the arm starting from the hand by pulling on two handles. The elastic silicone ring provides sufficient pressure (220 +/- 30 mmHg) to block arterial flow into the limb. The stockinet can be cut to provide access to the incision area while providing an additional sterile cover over the rest of the limb. RESULTS: No transfusions were required in any patients. Minor adverse effects occurred in four patients, including a twisted vessel, a bleeding vascular branch, a tear in atrophic arm skin, and pain, all of which had resolved on subsequent follow-up. Operational recommendations to avoid these adverse effects are outlined. CONCLUSIONS: We conclude that this sterile elastic exsanguination tourniquet is effective and safe in preventing bleeding during upper extremity hemodialysis vascular access procedures. PMID- 23080336 TI - The management of malfunctioning prosthetic arteriovenous accesses by interventional nephrologists and surgeons: a retrospective comparison of long term outcomes. AB - PURPOSE: To compare the outcomes of arteriovenous grafts (AVG) managed by interventional nephrologists (IN) to those managed by vascular surgeons (VS). METHODS: Between January 2004 and February 2005, 106 forearm loop AVG were placed. Ten AVG did not meet inclusion criteria and thus were excluded from study. Forty-seven AVG were managed by IN using percutaneous interventional techniques. Vascular surgeons, using surgical techniques, cared for 49 AVG. High risk AVG in the IN group were surveyed with fistulagrams, whereas AVG in the VS group were not. Outcomes of the IN and VS groups were retrospectively compared. RESULTS: The secondary patency rates at 6 and 18 months were 84% and 69% in the IN group and 79% and 68% in the VS group, respectively (P=.38). Twenty-five (53%) AVG in the IN required at least one surgical procedure to achieve a patency equivalent to that of the VS group. The mean number of AVG interventions to final failure was 4.8 in the IN group and 3.0 in the VS group (P=.03). Infection requiring AVG removal occurred in six patients in the IN group and one patient in the VS group (P=.07). CONCLUSIONS: Surveillance fistulagrams and percutaneous intervention for malfunctioning AVG by IN do not provide superior patency and may require more interventions over the "life" of the graft when compared to no surveillance and surgical intervention by VS. In order to achieve optimal vascular access outcomes, a collaborative relationship between nephrologist and surgeon is essential so as to ensure that the most appropriate intervention is selected and futile interventions are avoided. PMID- 23080338 TI - Wet AMD market. PMID- 23080337 TI - MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. AB - In recent years, prominent roles for microRNAs (miRNAs) have been uncovered in several cardiovascular disorders. The ability to therapeutically manipulate miRNA expression and function through systemic or local delivery of miRNA inhibitors, referred to as antimiRs, has triggered enthusiasm for miRNAs as novel therapeutic targets. Here, we focus on the pharmacokinetic and pharmacodynamic properties of current antimiR designs and their relevance to cardiovascular indications, and evaluate the opportunities and obstacles associated with this new therapeutic modality. PMID- 23080339 TI - The nutritional value of peanut hay (Arachis hypogaea L.) as an alternate forage source for sheep. AB - The aim of this study was to evaluate the nutritional and feeding value of peanut hay (Arachis hypogaea L.) produced under tropical environment as an alternate forage resource for sheep. Peanut hay was appreciably high in crude protein [CP; 105 g/kg dry matter (DM)] and lower in neutral detergent fiber (NDF; 466 g/kg DM). Moreover, peanut hay was rich in Ca (12 g/kg DM) and P (1.7 g/kg DM). A feeding trial was conducted to investigate the effect of substituting wheat straw with peanut hay on nutrient intake, digestibility, and N utilization. Four adult Ramghani (Kaghani * Rambouillet) wethers (60 +/- 2.5 kg body weight) were randomly assigned to the four dietary treatments according to a 4 * 4 Latin square design. The four rations were formulated on isonitrogenous and isocaloric bases and differed in the proportion (in grams per kilogram DM) of wheat straw/peanut hay, i.e., 700:0, 460:240, 240:460, and 0:700. The replacement of wheat straw with peanut hay increased the intakes of DM (P < 0.001), NDF (P < 0.01), and N (P < 0.001). Moreover, apparent in vivo digestibility of DM, NDF, and CP increased (P < 0.001) with the increasing proportion of peanut hay in the ration. Nitrogen retention in the body increased (P < 0.01; 3.2 to 8.1 g/day) with the replacement of wheat straw with peanut hay. These findings showed that substitution of wheat straw with peanut hay can improve DM and nutrients intake, digestibility, and N retention in sheep. PMID- 23080340 TI - Bovine tuberculosis: prevalence and diagnostic efficacy of routine meat inspection procedure in Woldiya municipality abattoir north Wollo zone, Ethiopia. AB - Bovine tuberculosis (BTB) is a widespread and endemic disease of cattle in Ethiopia posing a significant threat to public health. Regular surveillance by skin test, bacteriology, and molecular methods is not feasible due to lack of resources. Thus, routine abattoir (RA) inspection will continue to play a key role for national surveillance. A cross-sectional study was conducted at Woldiya municipal abattoir from April 1, 2009 to April 5, 2010 to estimate the prevalence of BTB in slaughtered cattle on the basis of detailed abattoir inspection and to compare efficacy of RA inspection with respect to detailed abattoir inspection and isolation and identification of Mycobacterium. Diagnostic accuracies (with corresponding measures of statistical uncertainty) were determined by computing test property statistics (sensitivity and specificity). Agreement between RA and detailed abattoir inspections was measured using kappa statistics. Out of 1,029 slaughtered heads of cattle examined during the study period, 63 (6.12 %) and 15 (1.45 %) were diagnosed with gross tuberculous lesions by detailed abattoir meat inspections and RA meat inspections, respectively, making a prevalence of 6.12 % (95 % CI: 5.2-7.1) on the basis of detailed abattoir inspection. About 59.45 % of tuberculous lesions were observed in the lungs and associated lymph nodes, whereas 35.13 % lesions were from the lymph nodes of the head. From 63 cattle suspected with tuberculosis (TB) based on detailed abattoir meat inspection, nine (19.05 %) were identified as Mycobacterium bovis, while three (4.8 %) as Mycobacterium tuberculosis. The sensitivity of RA meat inspection was 23.8 % in comparison to the detailed abattoir meat inspection and 25 % in comparison to culture, respectively. Poor agreement (k = 0.37) was seen between RA meat examination and detailed abattoir meat examination methods. Similarly, poor agreement (k = 0.013) was seen between RA meat examination and culture results. In conclusion, relatively higher prevalence (6.12 %) was recorded in Woldiya municipal abattoir on the basis of detailed Abattoir inspection and RA meat inspection protocols currently utilized in Ethiopia which are insufficient to detect the majority (76.19 %) of TB lesions at the gross level, which indicates the magnitude of meat borne zoonotic TB as an ongoing risk to public health. Detailed abattoir inspection protocols were demonstrated to improve the detection level by approximately fourfold. In conclusion, routine meat inspections have limitations in detecting BTB-suggestive lesions which indicate the magnitude of meat-borne zoonotic TB as an ongoing risk to public health. PMID- 23080341 TI - Effect of replacing soybean protein with protein from ensiled stylo (Stylosanthes guianensis (Aubl.) Sw. var. guianensis) on growth performance, carcass traits and organ weights of exotic (Landrace * Yorkshire) and native (Moo Lath) Lao pigs. AB - The present study examined the impact of replacing crude protein (CP) from soybean with CP from ensiled stylo (ES) on growth performance, carcass traits and organ weights in Landrace * Yorkshire (LY) and Moo Lath (ML) native Lao pigs. Twenty-four castrated male pigs, 12 of each breed, were allocated to the diet treatments according to a completely randomised 3 * 2 factorial (three ES levels * two breeds) arrangement, with four pigs per diet treatment. Pigs were kept in individual pens and fed at 4 % dry matter of body weight for 98 days. The control diet was formulated with soybean meal as the main CP source, and in the other two experimental diets, CP from soybean was replaced at 25 % (ES25) and 50 % (ES50) by CP from ES. Calculated metabolisable energy intake decreased with ES50 diet, while dry matter intake (DMI) and CP intake (CPI) were the highest in ES25 diet (P < 0.001). Overall, average daily gain (ADG) and feed conversion ratio (FCR) were unaffected by diet treatments. Carcass weight, backfat thickness and dressing percentage were unaffected by soybean CP replacement, while the weights of lung, large intestine and stomach were higher (P < 0.001) when 25 % of soybean CP was replaced by CP from ES. LY pigs had higher (P < 0.001) DMI, CPI and ADG and poorer (P < 0.001) FCR than ML pigs. LY pigs had higher carcass weight (P < 0.001), lower backfat thickness (P < 0.001) and higher organ weight (P < 0.001) than ML pigs, except for small intestine weight, where there was no difference between the LY and ML pigs (P > 0.05). In conclusion, ES can replace up to 50 % of soybean CP in the diet of growing Lao LY and ML pigs without negative effects on performance and carcass traits. PMID- 23080342 TI - Control of late apoptotic events by the p38 stress kinase in L-glutamine-deprived mouse hybridoma cells. AB - L-Glutamine (Gln) starvation rapidly triggers apoptosis in Sp2/0-Ag14 (Sp2/0) murine hybridoma cells. Here, we report on the role played by the stress activated kinase p38 mitogen-activated protein kinase (MAPK) in this process. p38 activation was detected 2 h after Gln withdrawal and, although treatment with the p38 inhibitor SB203580 did not prevent caspase activation in Gln-starved cells, it reduced the occurrence of both nuclear condensation/fragmentation and apoptotic body formation. Similarly, transfection of Sp2/0 cells with a dominant negative p38 MAPK reduced the incidence of nuclear pyknosis and apoptotic body formation following 2 h of Gln starvation. Gln withdrawal-induced apoptosis was blocked by the overexpression of the anti-apoptotic protein Bcl-xL or by the caspase inhibitor Z-VAD-fmk. Interestingly, Bcl-xL expression inhibited p38 activation, but Z-VAD-fmk treatment did not, indicating that activation of this MAPK occurs downstream of mitochondrial dysfunction and is independent of caspases. Moreover, the anti-oxidant N-acetyl-l-cysteine prevented p38 phosphorylation, showing that p38 activation is triggered by an oxidative stress. Altogether, our findings indicate that p38 MAPK does not contribute to the induction of apoptosis in Gln-starved Sp2/0 cells. Rather, Gln withdrawal leads to mitochondrial dysfunction, causing an oxidative stress and p38 activation, the latter contributing to the formation of late morphological features of apoptotic Sp2/0 cells. PMID- 23080343 TI - Clinicopathological features of ulcerative colitis-associated colorectal cancer pointing to efficiency of surveillance colonoscopy in a large retrospective Japanese cohort. AB - PURPOSE: Cancer surveillance has been conducted in patients with ulcerative colitis (UC), and the number of operative cases of ulcerative colitis-associated colorectal cancer (UC-CRC) has been increasing. The aim of this study was to clarify the clinicopathological features and prognoses of UC-CRC patients and the relationship between surveillance colonoscopy and UC-CRC. METHODS: The clinical records of 1,274 UC patients who required surgery between 1984 and 2010 at a single institution were reviewed retrospectively. Of these, 83 patients had CRC (107 sections). All cases were extracted from the database, along with their clinicopathological data. RESULTS: The 5-year survival rate of the UC-CRC group was 89 %. The 5-year survival rate was 100 % in stages 0 and II, 96 % in stage I, 56 % in stage III, and 0 % in stage IV. Surveillance colonoscopy was performed for 40 of the 83 patients. Of 40 patients, 30 with UC who underwent surveillance colonoscopies and 22 of 43 patients without surveillance colonoscopies were in stages 0 to I (P = 0.04). CONCLUSION: The number of UC-CRC patients who are diagnosed by surveillance colonoscopy is increasing, and many of them are detected in the very early stages (stages 0 or I). Thus, the survival rate of UC CRC is better than before. Surveillance colonoscopy proofs efficient as CRC are detected in earlier stages. PMID- 23080344 TI - Impact of late anorectal dysfunction on quality of life after pelvic radiotherapy. AB - PURPOSE: Anorectal dysfunction is common after pelvic radiotherapy. This study aims to explore the relationship of subjective and objective anorectal function with quality of life (QoL) and their relative impact in patients irradiated for prostate cancer. METHODS: Patients underwent anal manometry, rectal barostat measurement, and completed validated questionnaires, at least 1 year after prostate radiotherapy (range 1-7 years). QoL was measured by the Fecal Incontinence Quality of Life scale (FIQL) and the Expanded Prostate Cancer Index Composite Bowel domain (EPICB)-bother subscale. Severity of symptoms was rated by the EPICB function subscale. RESULTS: Anorectal function was evaluated in 85 men. Sixty-three percent suffered from one or more anorectal symptoms. Correlations of individual symptoms ranged from r = 0.23 to r = 0.53 with FIQL domains and from r = 0.36 to r = 0.73 with EPICB bother scores. They were strongest for fecal incontinence and urgency. Correlations of anal sphincter pressures, rectal capacity, and sensory thresholds ranged from r = 0.00 to r = 0.42 with FIQL domains and from r = 0.15 to r = 0.31 with EPICB bother scores. Anal resting pressure correlated most strongly. Standardized regression coefficients for QoL outcomes were largest for incontinence, urgency, and anal resting pressure. Regression models with subjective parameters explained a larger amount (range 26 92 %) of variation in QoL outcome than objective parameters (range 10-22 %). CONCLUSIONS: Fecal incontinence and rectal urgency are the symptoms with the largest influence on QoL. Impaired anal resting pressure is the objective function parameter with the largest influence. Therefore, sparing the structures responsible for an adequate fecal continence is important in radiotherapy planning. PMID- 23080346 TI - Dipole field guided orientated attachment of nanocrystals to twin-brush ZnO mesocrystals. AB - Mesocrystals of ZnO were synthesized hydrothermally by using gum arabic as a structure-directing agent. Their hierarchical structure has a unique twin-brush form consisting of vertically aligned nanorods in a single-crystal-like porous form. The formation mechanism of the twin-brush ZnO was investigated by quenching a series of samples at different times and examining them by TEM, SEM, and XRD. The alignment of ZnO crystal units can be modulated by adding simple salts such as KCl to change the units from nanorods to nanoplates. This can be explained by screening the dipolar force of the polar crystal. Local cathodoluminescence of twin-brush ZnO was used to follow the local structure changes. PMID- 23080345 TI - Thrombocytosis before pre-operative chemoradiotherapy predicts poor response and shorter local recurrence-free survival in rectal cancer. AB - PURPOSE: Although thrombocytosis has been reported in patients with various cancers including the colorectal one, the impact of elevated platelet counts on the response to chemoradiotherapy (CRT) for rectal cancer has not been fully investigated. We investigated the clinical significance of pre- and post-CRT platelet counts in patients with rectal cancer. METHODS: The medical records of 101 patients with rectal cancer, who had received CRT followed by surgical resection, were retrospectively reviewed. The correlations between the clinicopathological variables and the pre- or post-CRT platelet counts were analyzed. The correlations between tumor regression rate induced by CRT, as evaluated by barium enema and pathological examination, and the pre- or post-CRT platelet counts were also evaluated. Finally, the impact of pre-CRT thrombocytosis on the prognosis of these patients was assessed. RESULTS: The pre CRT platelet count correlated with venous invasion and tumor size, and it strongly correlated with the response rate evaluated by barium enema and the grade of pathological tumor regression. Furthermore, patients with pre-CRT thrombocytosis had significantly shorter local recurrence-free survival. CONCLUSION: Platelet count before CRT should be a promising biomarker for predicting the efficacy of CRT and the risk of local recurrence in rectal cancer patients after CRT. PMID- 23080347 TI - The American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, and the Asian Australasian Federation of Pain Societies Joint Committee recommendations for education and training in ultrasound-guided interventional pain procedures. AB - The use of ultrasound in pain medicine for interventional axial, nonaxial, and musculoskeletal pain procedures is rapidly evolving and growing. Because of the lack of specialty-specific guidelines for ultrasonography in pain medicine, an international collaborative effort consisting of members of the Special Interest Group on Ultrasonography in Pain Medicine from the American Society of Regional Anesthesia and Pain Medicine, the European Society of Regional Anaesthesia and Pain Therapy, and the Asian Australasian Federation of Pain Societies developed the following recommendations for education and training in ultrasound-guided interventional pain procedures. The purpose of these recommendations is to define the required skills for performing ultrasound-guided pain procedures, the processes for appropriate education, and training and quality improvement. Training algorithms are outlined for practice- and fellowship-based pathways. The previously published American Society of Regional Anesthesia and Pain Medicine and European Society of Regional Anaesthesia and Pain Therapy education and teaching recommendations for ultrasound-guided regional anesthesia served as a foundation for the pain medicine recommendations. Although the decision to grant ultrasound privileges occurs at the institutional level, the committee recommends that the training guidelines outlined in this document serve as the foundation for educational training and the advancement of the practice of ultrasonography in pain medicine. PMID- 23080348 TI - Comparative perioperative outcomes associated with neuraxial versus general anesthesia for simultaneous bilateral total knee arthroplasty. AB - BACKGROUND AND OBJECTIVES: The influence of the type of anesthesia on perioperative outcomes after bilateral total knee arthroplasty (BTKA) remains unknown. Therefore, we examined a large sample of BTKA recipients, hypothesizing that neuraxial anesthesia would favorably impact on outcomes. METHODS: We identified patient entries indicating elective BTKA between 2006 and 2010 in a national database; subgrouped them by type of anesthesia: general (G), neuraxial (N), or combined neuraxial-general (NG); and analyzed differences in demographics and perioperative outcomes. RESULTS: Of 15,687 identified procedures, 6.8% (n = 1066) were performed under N, 80.1% (n = 12,567) under G, and 13.1% (n = 2054) under NG. Comparing N to G and NG, patients in group N were, on average, younger (63.9, 64.6, and 64.8 years; P = 0.030) but did not differ in overall comorbidity burden. Patients in group N required blood product transfusions significantly less frequently (28.5%, 44.7%, 38.0%; P < 0.0001). In-hospital mortality, 30-day mortality, and complication rates tended to be lower in group N, without reaching statistical significance. After adjusting for covariates, N and NG were associated with 16.0% and 6.0% reduction in major complications compared with G, but only the reduced odds for the requirement of blood transfusions associated with N reached statistical significance (N vs G: odds ratio, 0.52 [95% CI, 0.45 0.61], P < 0.0001; NG vs G: odds ratio, 0.77 [95% CI, 0.69-0.86], P < 0.0001). CONCLUSIONS: Neuraxial anesthesia for BTKA is associated with significantly lower rates of blood transfusions and, by trend, decreased morbidity. Although by itself the effect may be limited, N might be used within a multimodal approach to reduce complications after BTKA. PMID- 23080349 TI - Continuous peripheral nerve block compared with single-injection peripheral nerve block: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND OBJECTIVES: Many practitioners consider continuous peripheral nerve blocks (cPNBs) to be superior to single-injection peripheral nerve blocks (siPNBs). Several randomized controlled trials have demonstrated improved pain control, patient satisfaction, and other outcomes for patients with cPNBs compared with patients with siPNBs, whereas other trials have not shown significant differences. We sought to clarify any potential advantages of cPNBs over siPNBs. METHODS: We conducted a systematic review and meta-analysis of all prospective, randomized trials comparing cPNBs with siPNBs. We used a validated systematic search strategy to identify potentially eligible studies. For studies meeting inclusion criteria, methodologic quality was scored independently by 2 reviewers. Data from the studies were abstracted and pooled for meta-analysis. RESULTS: Compared with siPNBs, cPNBs were associated with a decreased rating of worst pain on postoperative day 0 (effect size [ES], -1.29; 95% confidence interval [CI], -2.19 to -0.40; P = 0.005), postoperative day 1 (ES, -1.87; 95% CI, -2.44 to -1.31; P < 0.001), and postoperative day 2 (ES, -2.03; 95% CI, -2.78 to -1.290; P < 0.001); decreased overall opioid use (ES, -15.70; 95% CI, -21.84 to -9.55; P < 0.001); less nausea (ES, 0.633; 95% CI, 0.407-0.983; P = 0.043); and higher patient satisfaction scores (weighted mean difference, -2.04; 95% CI, 1.24-2.85; P < 0.001). CONCLUSIONS: Compared with siPNBs, cPNBs were associated with improved pain control, decreased need for opioid analgesics, less nausea, and greater patient satisfaction. The effect of cPNBs on other clinically relevant outcomes, such as complications, long-term functional outcomes, or costs, remains unclear. PMID- 23080350 TI - A 3-dimensional ultrasound study of local anesthetic spread during lateral popliteal nerve block: what is the ideal end point for needle tip position? AB - BACKGROUND AND OBJECTIVES: Recent clinical trials suggest that subfascial (sometimes termed subepineural) injections result in faster block onset and success compared with conventional techniques. This prospective, randomized, observer-blinded study measured and compared the 3-dimensional spread pattern and volume of perineural local anesthetic (LA) in contact with the sciatic nerve after subfascial versus extrafascial lateral popliteal injections. METHODS: Sixty patients were randomly assigned to either the subfascial or the extrafascial injection group. All patients received a single-injection, US-guided lateral popliteal sciatic nerve block for postoperative pain. Depending on group assignment, the needle tip was placed outside or beneath the sciatic fascial sheath for a single injection of 30 mL of ropivacaine 0.5%. Using 3-dimensional ultrasound imaging, postblock scans were acquired to quantify the volume and spread pattern of perineural LA around the sciatic nerve in each group. RESULTS: The mean LA perineural volume for the extrafascial group was 1.48 (SD, 0.50) mL versus a mean of 5.57 (SD, 1.68) mL for the subfascial group, P < 0.05. The mean distance of longitudinal perineural LA spread (along the length of the nerve) for the subfascial group was 66% greater than that observed using the conventional technique (9.3 vs 5.6 cm, P < 0.01). Complete sensory block to pinprick for the extrafascial group was 63% versus 90% (P < 0.05) for the subfascial group. CONCLUSIONS: Placement of the needle tip beneath the complex fascial sheath of the sciatic nerve resulted in significantly greater perineural local anesthetic volume following a single-injection lateral popliteal approach at the nerve bifurcation and was associated with greater sensory blockade and a characteristic laminar LA spread pattern. PMID- 23080351 TI - The pharmacokinetics and pharmacodynamics of liposome bupivacaine administered via a single epidural injection to healthy volunteers. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to assess the pharmacokinetics, sensory/motor effects, and safety of epidurally administered liposome bupivacaine versus bupivacaine HCl in healthy volunteers. METHODS: Thirty subjects were randomized to receive liposome bupivacaine 89, 155, or 266 mg, or bupivacaine HCl 50 mg in a double-blind fashion. Occurrence/duration of motor blockade, pinprick/cold sensitivity, and plasma bupivacaine levels were assessed for 96 hours after study drug administration. Tolerability parameters were also assessed. RESULTS: All doses of liposome bupivacaine resulted in greater area under the curve and a longer time to observed maximum plasma concentration and terminal elimination half-life than bupivacaine HCl 50 mg. Mean maximum plasma concentration with liposome bupivacaine 89 and 155 mg (but not 266 mg) was statistically significantly lower than with bupivacaine HCl 50 mg (P < 0.001). Median duration of motor blockade with liposome bupivacaine 266 mg was 1 hour versus 2.8 hours for bupivacaine HCl. Of subjects who received liposome bupivacaine 266 mg, 29% (2/7) were unable to ambulate at 4 hours postdose versus 67% (4/6) of those receiving bupivacaine HCl. Median durations of pinprick/cold sensitivity loss were 36 and 69 hours, respectively, in the liposome bupivacaine 266-mg group versus 12 hours for both pinprick and cold in the bupivacaine HCl group. Liposome bupivacaine was well tolerated; the most common adverse event in all treatment groups was injection site pain, which resolved within 30 days for most subjects. CONCLUSIONS: Epidurally administered liposome bupivacaine 266 mg resulted in a longer duration of sensory blockade than liposome bupivacaine 89 or 155 mg or bupivacaine HCl 50 mg. Duration of motor blockade was shorter with liposome bupivacaine 266 mg versus bupivacaine HCl. PMID- 23080352 TI - Systematic ultrasound identification of the dorsal scapular and long thoracic nerves during interscalene block. AB - BACKGROUND AND OBJECTIVES: The use of ultrasound for in-plane interscalene block shifts needle insertion to a more posterior approach through the middle scalene muscle, when compared with classic nerve stimulator techniques. Branches from the brachial plexus, including the dorsal scapular and long thoracic nerves, are often anatomically located within the middle scalene muscle. The aim of this study was to use ultrasound to identify and characterize the frequency and position of the dorsal scapular and long thoracic nerves located in the middle scalene muscle. METHODS: We recruited 50 subjects who presented for shoulder surgery. Before block placement, ultrasound was used to evaluate the area posterior to the brachial plexus for visible segments of the long thoracic and dorsal scapular nerves. If nerves were identified, a stimulating Tuohy needle was advanced in close proximity. Current was then applied through the needle, and motor response confirmed the visualized nerve as being either the dorsal scapular nerve or long thoracic nerve. RESULTS: Ninety percent of the subjects had a nerve visible under ultrasound assessment within or superficial to the middle scalene muscle. The nerves were located at similar depth as the perceived C6 nerve root, at 1.1 +/- 0.4 cm from skin and 0.7 +/- 0.4 cm posterior from the brachial plexus. Stimulation revealed that the nerve identified on ultrasound was the dorsal scapular nerve (77%) or the long thoracic nerve (23%). CONCLUSIONS: This descriptive study revealed that the dorsal scapular and long thoracic nerves routinely could be identified with ultrasound. PMID- 23080353 TI - Opsin evolution in damselfish: convergence, reversal, and parallel evolution across tuning sites. AB - The visual system plays a role in nearly every aspect of an organism's life history, and there is a direct link between visual pigment phenotypes and opsin genotypes. In previous studies of African cichlid fishes, we found evidence for positive selection among some opsins, with sequence variation greatest for opsins producing the shortest and longest wavelength visual pigments. In this study, we examined opsin evolution in the closely related damselfish family (Pomacentridae), a group of reef fishes that are distributed widely and have a documented fossil record of at least 50 million years (MY). We found increased functional variation in the protein sequences of opsins at the short- and long wavelength ends of the visual spectrum, in agreement with the African cichlids, despite an order of magnitude difference in the ages of the two radiations. We also reconstructed amino acid substitutions across opsin tuning sites. These reconstructions indicated multiple instances of parallel evolution, at least one definitive case of convergent evolution, and one evolutionary reversal. Our findings show that the amino acids at spectral tuning sites are labile evolutionarily, and that the same codons evolve repeatedly. These findings emphasize that the aquatic light environment can shape opsin sequence evolution. They further show that phylogenetic approaches can provide important insights into the mechanisms by which natural selection "tinkers" with phenotypes. PMID- 23080354 TI - Thermo-optic control of dielectric-loaded plasmonic Mach-Zehnder interferometers and directional coupler switches. AB - We report detailed experimental studies of compact fiber-coupled dielectric loaded plasmonic waveguide components-Mach-Zehnder interferometers (MZIs) and directional couplers (DCs)-whose operation at telecom wavelengths is controlled via the thermo-optic effect by electrically heating the gold stripe of dielectric loaded plasmonic waveguides. The effect of the gaps isolating the heated part of the waveguide from the rest of the structure was examined showing the presence of a Fabry-Perot cavity in this MZI arm. Wavelength-dependent modulation is demonstrated with MZI-based components, and wavelength dependent low power (~0.92 mW) rerouting is achieved with DC switches. Furthermore, simulations were performed to confirm the switching characteristics of the components. PMID- 23080355 TI - [Real-time 3 dimensional full volume data set : benefits in problem focused intraoperative transesophageal echocardiography]. AB - BACKGROUND: Comprehensive intraoperative transesophageal echcardiography (TEE) includes various measurements for quantification of cardiac chambers and valves based on multiple two dimensional (2D) standard views. Due to shortness of time during cardiac surgery most centres in Germany only carry out problem focussed intraoperative examinations which does not allow the complete repertoire of measurements to be exhausted. The aim of this study was to investigate which measurements for cardiac chamber and valve quantification can be performed with the acquisition of a real-time 3D full volume (RT-3D-FV) data set and to compare these measurements with those based on standard 2D views. MATERIALS AND METHODS: In patients undergoing elective surgical mitral valve repair a comprehensive 2D TEE examination according to the guidelines of the American Society of Echocardiography (ASE) and the Society of Cardiovascular Anesthesiologists (SCA) was performed after induction of anesthesia. Additionally, a RT-3D-FV TEE data set based on the midesophageal four chamber view was recorded (iE 33, Philips, Netherlands). All measurements of the 2D TEE and the RT-3D-FV dataset (Qlab) were performed offline by two independent examiners. RESULTS: After approval by the local ethic committee and obtaining written informed consent 50 patients (31 male and 19 female) with a mean age of 59.4 +/- 11.5 years were enrolled in this study. All measurements recommended for chamber and valve quantification could be performed on the basis of the RT-3D-FV data set except for measurements of the sinus of Valsalva and the sinotubular junction. There was good correlation between the results of the two methods. CONCLUSIONS: For intraoperative problem focussed TEE examinations the acquisition of an additional RT-3D-FV TEE data set allows accurate measurement of most of the recommended chamber and valve quantification parameters. PMID- 23080356 TI - [Prevention of catheter-related infections]. AB - Bloodstream infections due to intravascular catheterization, peritoneal catheters for dialysis, suprapubic or transurethral catheters, are one of the major sources of nosocomial infections. Therefore, the prevention of catheter-associated infections is an important issue for physicians and nursing staff working in hospitals or in outpatient settings. The risk can be minimized by diligent checking of the indications, hygienic measures, using the right materials, thorough follow-up and education of the medical and nursing staff. Thus it is possible to avoid individual suffering of patients and to reduce costs in the healthcare system. PMID- 23080357 TI - Enhanced photocatalytic activity and structural stability by hybridizing Ag3PO4 nanospheres with graphene oxide sheets. AB - Graphene oxide (GO)-Ag(3)PO(4) nanocomposites synthesized through a facile solution approach via electrostatic interaction were investigated as excellent photocatalysts for the degradation of rhodamine B (RhB) under visible light irradiation. SEM and TEM observations indicate that Ag(3)PO(4) nanospheres of ~120 nm in diameter were well dispersed and anchored onto the exfoliated GO sheets. The characterizations of FTIR and Raman demonstrated the existence of strong charge interactions between GO sheets and Ag(3)PO(4) nanospheres. As compared to Ag(3)PO(4) nanospheres alone, the attachments of GO sheets led to a band gap narrowing (2.10 eV) and a strong absorbance in the near infrared region (NIR). The photoluminescence (PL) analysis indicates a more efficient separation of electron-hole pairs in the GO-Ag(3)PO(4) nanocomposites. Notably, the incorporation of GO sheets not only significantly enhances the photocatalytic activity but also improves the structural stability of Ag(3)PO(4). The positive synergistic effects between Ag(3)PO(4) nanospheres and GO sheets are proposed to contribute to the improved photocatalytic properties. A possible photocatalytic mechanism of the GO-Ag(3)PO(4) nanocomposites was assumed as well. The integration of these advantages enables such GO-Ag(3)PO(4) hybrid material to be a nice photocatalyst for broad applications in a sewage treatment system. PMID- 23080359 TI - Antiretroviral adherence among rural compared to urban veterans with HIV infection in the United States. AB - Rural-dwelling persons with HIV infection face barriers to maintaining high levels of antiretroviral adherence. We compared adherence among 1,782 rural and 18,519 urban veterans initiating antiretroviral therapy in the Veterans Affairs (VA) healthcare system in the United States between 1998 and 2007. Residence was determined using rural urban commuting area codes and adherence using pharmacy based refill measures. The median proportion of days covered (PDC) by combination antiretroviral therapy in the first year of treatment ranged from 0.72 among urban residents to 0.79 among rural-small town/remote residents (p < 0.0001). In multivariable logistic regression, predictors of high adherence (PDC greater than 0.90) were residence in a rural-small town/remote setting (odds ratio 1.24, 95 % CI 1.09-1.56, relative to urban), increasing age, white race, absence of an alcohol or substance use disorder, and absence of hepatitis C infection. Results may differ outside VA healthcare, where there may be fewer resources to support adherence among rural-dwelling persons with HIV. PMID- 23080358 TI - High acceptability of HIV pre-exposure prophylaxis but challenges in adherence and use: qualitative insights from a phase I trial of intermittent and daily PrEP in at-risk populations in Kenya. AB - This paper used qualitative methods to explore experiences of men who have sex with men and female sex workers in Nairobi and Mtwapa, Kenya, who used oral pre exposure prophylaxis (PrEP) for HIV prevention as part of a four-month trial of safety, acceptability and adherence. Fifty-one of 72 volunteers who took part in a randomized, placebo-controlled, blinded trial that compared daily and intermittent dosage of PrEP underwent qualitative assessments after completing the trial. Analyses identified three themes: (i) acceptability of PrEP was high, i.e. side effects were experienced early in the study but diminished over time, however characteristics of pills could improve comfort and use; (ii) social impacts such as stigma, rumors, and relationship difficulties due to being perceived as HIV positive were prevalent; (iii) adherence was challenged by complexities of daily life, in particular post-coital dosing adherence suffered from alcohol use around time of sex, mobile populations, and transactional sex work. These themes resonated across dosing regimens and gender, and while most participants favored the intermittent dosing schedule, those in the intermittent group noted particular challenges in adhering to the post-coital dose. Culturally appropriate and consistent counseling addressing these issues may be critical for PrEP effectiveness. PMID- 23080360 TI - HIV seroprevalence, associated risk behavior, and alcohol use among male Rwanda Defense Forces military personnel. AB - A cross-sectional study was conducted among active-duty male soldiers, aged >=21 years, in the Rwanda Defense Forces (RDF) and included an anonymous behavioral survey and HIV rapid testing to determine risk factors associated with HIV seroprevalence. Overall prevalence was 2.6 % (95 % CI: 1.84-3.66); personnel who were divorced, separated or widowed, served >=6 years, never deployed, uncircumcised, reported STI symptoms, had >=6 lifetime sex partners, or screened positive for harmful alcohol use (via Alcohol Use Disorders Identification Test) had higher HIV prevalence. Ever being divorced, separated or widowed (OR = 29.8; 95 % CI: 5.5-159.9), and STI symptoms (OR = 3.4; 95 % CI: 1.5-7.6) were significantly associated with infection, after multivariable adjustment, while circumcision was protective (OR = 0.4; 95 % CI: 0.2-0.9). Despite mobility and other factors that uniquely influence HIV transmission in militaries, RDF prevalence was similar to the general population. A reason for this finding may be conservative sexual behavior combined with effective leadership-supported prevention programs. Data suggest a concentrated rather than generalized epidemic, with targets identified for intervention. PMID- 23080361 TI - Attitudes toward sexual partner concurrency: development and evaluation of a brief, self-report measure for field research. AB - The purpose of this study was to develop a brief, reliable, and valid self-report measure of attitudes toward sexual partner concurrency. Focus groups, conducted with 59 participants, yielded 26 common attitudes. STD clinic patients (n = 370) reported their sexual risk history, and rated the 26 attitude statements. This sample was randomly divided into two subsamples, with some participants completing the items on two occasions (separated by 3 months) to evaluate test retest reliability. Both exploratory and confirmatory factor analyses confirmed a one-factor model. The final scale consisted of 10 items, with higher scores reflecting more positive attitudes toward sexual partner concurrency. This scale is internally consistent (alpha = 0.92) and stable over time (3-month retest ICC = 0.82), with a factor structure that is equivalent for men and women. Evidence of validity was also obtained by confirming hypothesized correlations with sexual risk history. Continued research is needed to confirm the usefulness of this measure as an antecedent of sexual risk behavior. PMID- 23080362 TI - Should vitamin K antagonist therapy be started simultaneously with parenteral anticoagulation: a meta-analysis? AB - For patients with an acute episode of venous thromboembolism (VTE), the optimal starting time of long-term therapy with vitamin K antagonists (VKA) and how much overlap should occur with heparin are unclear and the current guidelines and practice are not based on high-quality data. The objective of this study was to perform a meta-analysis on the evidence comparing early versus late initiation of VKA on the effectiveness and safety of anticoagulation. We searched for randomized controlled trials in Medline, EMBASE, Cochrane CENTRAL, IPA and ClinicalTrials.gov. Studies were included if they compared early initiation of VKA (within approximately 24 h) and late initiation (>4 days) of the onset of heparin therapy. Data were pooled using the Review Manager 5 software and the quality of evidence was appraised with Grading of Recommendations, Assessment, Development and Evaluation profiler. Five studies were included in the review, with a total of 840 patients. Meta-analysis of recurrence of VTE, death and major bleeding revealed no significant differences between the two treatment regimens. Minor bleeding [RR 0.65, 95% confidence interval (CI) 0.43-0.98] and hospital stay (mean difference 3.92 days, 95% CI -4.57 to -3.28) were reduced in the early VKA group (P < 0.05). The quality of evidence for each outcome except hospital stay was low. Results from this meta-analysis favour the early start of VKA (within 24 h of the initiation of heparin) based on minor bleeding and resource utilization. However, these results should be interpreted with caution, as the quality and quantity of evidence is limited. PMID- 23080363 TI - Comparative study of the reactivity of natural and mutated streptokinase with total antistreptokinase antibodies in human sera. AB - Streptokinase is widely used as an anticoagulant drug for the treatment of heart attacks. Because of antibody production against injected drug in individuals consuming streptokinase and causing allergic reactions, streptokinase treatment effects become neutral. Recombinant mutant type of streptokinase was prepared by removing of 42 amino acids from the C terminal region. ELISA plates were coated by natural and mutant streptokinase as antigen. Ninety-six normal serum samples as well as 27 streptokinase consumer serum samples (patients with acute myocardial infraction) were analyzed. The results showed that serum antibodies against natural streptokinase were three times more than those against the mutated streptokinase. In case of preserving thrombolytic activity, mutated streptokinase can be used as an alternative of the natural form. PMID- 23080364 TI - Diagnosis and treatment of intracranial hemorrhage in children with hemophilia. AB - Intracranial hemorrhage (ICH) is a significant complication for children with hemophilia. Identifying risk factors may allow us to establish clinically relevant guidelines for the diagnosis and management of ICH. The purpose of this review is to nucleate evidence from the available literature on the incidence, risk factors, presentation, treatment, and outcomes of ICH that can be utilized to develop a clinically useful framework for the diagnosis and management of hemophiliac patients with the condition. An electronic MEDLINE and EMBASE literature search was undertaken using the key words 'intracranial hemorrhage and hemophilia' and setting limits as: Last 10 years and Review or Randomized Controlled Trial (RCT) or Clinical Trial, or Practice Guidelines. Following review of all articles using predetermined search words and criteria, 31 were retrieved with sufficient data to address our objectives. An algorithm is presented for the management of children (>=3 years-18 years) with hemophilia and suspected ICH. A standardized approach to ICH may reduce unnecessary exposure to radiation via computed tomography scan in a select group of children. Currently there is limited scientific evidence to recommend a diagnostic and therapeutic algorithm for neonates with hemophilia. PMID- 23080365 TI - The coagulopathy of liver disease: does vitamin K help? AB - Vitamin K is frequently administered in cirrhotic patients to correct their coagulopathy, but evidence for such practice is lacking. We aimed to assess whether vitamin K administration increases the levels of the vitamin K-dependent factor VII (FVII), protein C, and protein S in patients with different stages of liver dysfunction. Eighty-nine patients were recruited into four groups: group 1 [hepatitis B virus (HBV) inactive carriers, n = 23]; group 2 [chronic HBV and hepatitis C virus (HCV) hepatitis, n = 21]; group 3 (cirrhosis, n = 24); group 4 (hepatocellular carcinoma, n = 21); and a healthy control group (n = 39). A single dose of 10 mg of vitamin K1 was administered subcutaneously to all patients. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, FVII, protein C, total and free protein S, and proteins induced by vitamin K absence (PIVKA)-II (des-gamma-carboxy prothrombin) were measured at baseline and 72 h after vitamin K administration. There was progressive increment in baseline PIVKA-II, and decrements in fibrinogen, FVII, protein C, and protein S across study groups (P < 0.0001). Compared to baseline, vitamin K administration did not affect the measured parameters, whereas TT showed no reduction in any of the groups. Protein C levels declined in group 2, whereas FVII, total and free protein S did not increase in any group, for all parameters. Vitamin K therapy does not cause significant improvements in the majority of coagulation parameters and hence does not seem to be routinely indicated in patients with liver disease. PMID- 23080366 TI - Acquired factor V inhibitor developing in a patient with esophageal squamous cell carcinoma. AB - An 82-year-old man referred to our medical ward because of epistaxis and melena was found to have 12 Bethesda units of factor V inhibitor. He was managed for bleeding with supportive care, followed by corticosteroid therapy. The bleeding completely stopped 1 week after corticosteroid therapy. Medical history revealed dysphagia during the past 6 months and further evaluation brought to light a squamous cell carcinoma (SCC) in the esophagus. This is the first case of an acquired factor V inhibitor developing in a patient with esophageal SCC without any other risk factors such as surgery. PMID- 23080367 TI - African-Caribbean ethnicity is associated with a hypercoagulable state as measured by thrombin generation. AB - African-Caribbean ethnicity is associated with an increased risk of both first and recurrent venous thromboembolism (VTE). The aim of this study was to evaluate thrombin generation in African-Caribbeans compared with whites in patients with deep vein thrombosis (DVT) and healthy volunteers. Thrombin generation was measured in a case-control study of 80 patients who had completed anticoagulation therapy for a first DVT (50 white and 30 African-Caribbean) and 66 controls. Peak thrombin with and without thrombomodulin was significantly higher in African Caribbeans with DVT compared with whites with DVT (P < 0.001 for both comparisons) and African-Caribbean controls (P < 0.001, 0.003, respectively). Endogenous thrombin potential (ETP) with and without thrombomodulin was significantly higher in African-Caribbeans with DVT than whites with DVT (P <= 0.001 for both comparisons). Maximum velocity and ETP ratio were increased in African-Caribbeans with DVT compared with whites with DVT (P < 0.001 and 0.030, respectively) and African-Caribbean controls (P < 0.001 and 0.019, respectively). Within the control group, peak thrombin was significantly increased in African Caribbeans compared with whites (P = 0.017). ETP, peak thrombin with thrombomodulin and maximum velocity were also increased in African-Caribbeans compared with white controls (P = 0.045 for all comparisons). African-Caribbeans with DVT had significantly higher factor VIII levels compared with whites with DVT and controls. African-Caribbean ethnicity confers a hypercoagulable state as measured by thrombin generation. This supports epidemiological findings of increased risk of first and recurrent VTE. Thrombin generation requires adjustment for ethnicity in studies undertaken in ethnically diverse populations. PMID- 23080368 TI - Usefulness of mean platelet volume for predicting stroke risk in atrial fibrillation patients. AB - Early detection of atrial fibrillation patients at high risk for stroke is important. There are some studies which indicate that mean platelet volume (MPV) determines the prognosis and risk in patients with a stroke. In this study, our aim was to investigate the association between the MPV measured in stroke patients with atrial fibrillation. Consecutive patients referred to our center between January 2010 and April 2012 were included in this study. The patients with atrial fibrillation were classified into two groups according to presence or absence of a history of stroke by combining data from the medical histories after a thorough review of the medical records. MPV determination was made within 24 h following the onset of stroke. We studied 63 consecutive stroke patients with atrial fibrillation and 77 atrial fibrillation patients without stroke history. In receiver-operating characteristic (ROC) curve analysis, the value for MPV levels to detect stroke with a sensitivity of 63.5% and specificity of 64.4% was 9.4 fl. High MPV (>9.4 fl) was significantly associated with the occurrence of stroke [odds ratio (OR) 4.021, 95% confidence interval (CI) 1709-9464, P < 0.001]. Our study supports the hypothesis that a high MPV is associated with an increased risk of stroke in atrial fibrillation patients. PMID- 23080369 TI - Inhibition of mammalian target of rapamycin aggravates the respiratory burst defect of neutrophils from decompensated patients with cirrhosis. AB - Cirrhosis is commonly accompanied by impaired defense functions of polymorphonuclear leucocytes (PMNs), increased patient susceptibility to infections, and hepatocellular carcinoma (HCC). PMN antimicrobial activity is dependent on a massive production of reactive oxygen species (ROS) by nicotinamide adenine dinucleotide phosphate (NADPH) 2 (NADPH oxidase 2; NOX2), termed respiratory burst (RB). Rapamycin, an antagonist of mammalian target of rapamycin (mTOR), may be used in the treatment of HCC and in transplanted patients. However, the effect of mTOR inhibition on the PMN RB of patients with cirrhosis remains unexplored and was studied here using the bacterial peptide, formyl-Met-Leu-Phe (fMLP), as an RB inducer. fMLP-induced RB of PMN from patients with decompensated alcoholic cirrhosis was strongly impaired (30%-35% of control) as a result of intracellular signaling alterations. Blocking mTOR activation (phospho-S2448-mTOR) with rapamycin further aggravated the RB defect. Rapamycin also inhibited the RB of healthy PMNs, which was associated with impaired phosphorylation of the NOX2 component, p47phox (phox: phagocyte oxidase), on its mitogen-activated protein kinase (MAPK) site (S345) as well as a preferential inhibition of p38-MAPK relative to p44/42-MAPK. However, rapamycin did not alter the fMLP-induced membrane association of p47phox and p38-MAPK in patients' PMNs, but did prevent their phosphorylation at the membranes. The mTOR contribution to fMLP-induced RB, phosphorylation of p47phox and p38-MAPK was further confirmed by mTOR knockdown in HL-60 cells. Finally, rapamycin impaired PMN bactericidal activity, but not bacterial uptake. CONCLUSION: mTOR significantly up-regulates the PMN RB of patients with cirrhosis by p38-MAPK activation. Consequently, mTOR inhibition by rapamycin dramatically aggravates their PMN RB defect, which may increase patients' susceptibility to infection. Thus, concerns should be raised about the use of rapamycin in immuno-depressed patients. PMID- 23080370 TI - Structural and reactivity comparison of analogous organometallic Pd(III) and Pd(IV) complexes. AB - The tetradentate ligands (R)N4 ((R)N4 = N,N'-di-alkyl-2,11 diaza[3,3](2,6)pyridinophane, R = Me or iPr) were found to stabilize cationic ((R)N4)PdMe(2) and ((R)N4)PdMeCl complexes in both Pd(III) and Pd(IV) oxidation states. This allows for the first time a direct structural and reactivity comparison of the two Pd oxidation states in an identical ligand environment. The Pd(III) complexes exhibit a distorted octahedral geometry, as expected for a d(7) metal center, and display unselective C-C and C-Cl bond formation reactivity. By contrast, the Pd(IV) complexes have a pseudo-octahedral geometry and undergo selective non-radical C-C or C-Cl bond formation that is controlled by the ability of the complex to access a five-coordinate intermediate. PMID- 23080371 TI - Electrophysiological and morphological evidence for synchronized GnRH pulse generator activity among Kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in goats. AB - Neurons in the arcuate nucleus (ARC) that concomitantly express kisspeptin, neurokinin B (NKB) and dynorphin A are termed KNDy neurons and are likely candidates for the intrinsic gonadotropin-releasing hormone (GnRH) pulse generator. Our hypothesis is that KNDy neurons are functionally and anatomically interconnected to generate discrete neural signals that govern pulsatile GnRH secretion. Our goal was to address this hypothesis using electrophysiological and anatomical experiments in goats. Bilateral electrodes targeting KNDy neurons were implanted into ovariectomized goats, and GnRH pulse generator activity, represented by characteristic increases in multiple-unit activity (MUA volleys), was measured. Spontaneous and pheromone- or senktide (an NKB receptor agonist) induced MUA volleys were simultaneously recorded from both sides of the ARC. An anterograde tracer, biotinylated dextran amine (BDA), was also injected unilaterally into the ARC of castrated male goats, and the distribution of fibers containing both BDA and NKB was examined using dual-labeling histochemistry. The results showed that MUA volleys, regardless of origin (spontaneous or experimentally induced), occur simultaneously between the right and left sides of the ARC. Tract tracing indicated that axons projecting from NKB neurons in the ARC were directly apposed to other NKB neuronal cells located bilaterally in the ARC. These results demonstrate that GnRH pulse generator activity occurs synchronously between both sides of the ARC in goats and that KNDy neurons are bilaterally interconnected in the ARC via NKB-containing fibers. Taken together, the results suggest that KNDy neurons form a neuronal circuit to synchronize burst activity among KNDy neurons and thereby generate discrete neural signals that govern pulsatile GnRH secretion. PMID- 23080372 TI - Functional analysis of lysosomes during mouse preimplantation embryo development. AB - Lysosomes are acidic and highly dynamic organelles that are essential for macromolecule degradation and many other cellular functions. However, little is known about lysosomal function during early embryogenesis. Here, we found that the number of lysosomes increased after fertilization. Lysosomes were abundant during mouse preimplantation development until the morula stage, but their numbers decreased slightly in blastocysts. Consistently, the protein expression level of mature cathepsins B and D was high from the one-cell to morula stages but low in the blastocyst stage. One-cell embryos injected with siRNAs targeted to both lysosome-associated membrane protein 1 and 2 (LAMP1 and LAMP2) were developmentally arrested at the two-cell stage. Pharmacological inhibition of lysosomes also caused developmental retardation, resulting in accumulation of lipofuscin. Our findings highlight the functional changes in lysosomes in mouse preimplantation embryos. PMID- 23080373 TI - Baseline depression levels do not affect efficacy of cognitive-behavioral self help treatment for insomnia. AB - BACKGROUND: Cognitive-behavioral therapy can effectively treat insomnia (CBT-I). Randomized controlled trials have shown efficacy of self-help CBT-I, but unclear is whether excluding depressive patients boosted treatment effects. METHOD: We administered unsupported self-help CBT-I to insomnia patients with low and high depression levels. Based on the validated Centre of Epidemiological Studies Depression (CES-D) scale, the internet-recruited sample (N = 479) was divided into three groups: low depression scores (n = 198), mild depression scores (n = 182), and high depression scores (n = 99). Follow-ups were 4 and 18 weeks after completion of the treatment. RESULTS: At 4-week follow-up, all groups had a similar amelioration on the primary sleep measures (d = 0.1-0.7; P < 0.05) and the secondary insomnia ratings (d = 1.2; P < 0.001). The only difference was that the high/mild depression groups had a steeper reduction in depression (d = 1.0 1.1; P < 0.001) and anxiety scores (d = 0.7-0.8; P < 0.001) than the low depression group (depression and anxiety: d = 0.3; P < 0.01), possibly due to floor effects in the latter group. The observed effects were sustained at the 18 week follow-up. CONCLUSIONS: This study showed that CBT-I is effective regardless of baseline depression levels. Treating the combination of insomnia and depression is an extra challenge since it is associated with increased sleep problems. These data may help us understand the relationship between insomnia and depression and indicate that self-help CBT-I may be a promising addition to regular depression treatment. PMID- 23080374 TI - Problem-focussed interactive telephone therapy for cancer patients: a phase II feasibility trial. AB - OBJECTIVE: The study aimed to evaluate Problem-Focussed Interactive Telephone Therapy, an individual psychological therapy based on cognitive-behavioural therapy adapted for telephone delivery to cancer patients with high psychological needs. METHODS: A non-randomised, within-group prospective design was used. Outcome measures pre-therapy and post-therapy included were as follows: Hospital Anxiety and Depression Scale, Mental Adjustment to Cancer Scale: helpless/hopeless sub-scale only, Checklist of Cancer Concerns, Cancer Coping Questionnaire and EQ-5D quality of life. A study-specific Service Evaluation Questionnaire was included. Eligible patients were either (i) offered out-patient screening for anxiety/depression/helplessness (n=649) or (ii) referred for psychological care by oncology clinicians (n=160). RESULTS: Thirty two percent (36/114) of screen-identified cases and 22% (35/160) of referred patients participated, and 42 were available for analysis. There were significant post therapy improvements in Hospital Anxiety and Depression Scale anxiety (p=0.002) and depression (p=0.003), Mental Adjustment to Cancer Scale helpless/hopeless (p=0.036), cancer concerns (p=0.005) and overall quality of life (p=0.048). Overall, 81% (34/42) of participants were defined as clinical cases at baseline and 32% were no longer cases post-therapy. There were significant improvements in coping consistent with the therapy method. CONCLUSIONS: A minority of symptomatic patients opt for telephone psychological therapy; however, where they do, there are significant improvements indicating that telephone-delivered therapy is feasible in patients with high needs. Findings are discussed in relation to current issues on the implementation of distress screening and psychological therapy provision within clinical settings. PMID- 23080376 TI - Reflections on 2011 from the obstetrical perspective. PMID- 23080375 TI - Simplified microenvironments and reduced cell culture size influence the cell differentiation outcome in cellular microarrays. AB - Cellular microarrays present a promising tool for multiplex evaluation of the signalling effect of substrate-immobilized factors on cellular differentiation. In this paper, we compare the early myoblast-to-osteoblast cell commitment steps in response to a growth factor stimulus using standard well plate differentiation assays or cellular microarrays. Our results show that restraints on the cell culture size, inherent to cellular microarrays, impair the differentiation outcome. Also, while cells growing on spots with immobilised BMP-2 are early biased towards the osteoblast fate, longer periods of cell culturing in the microarrays result in cell proliferation and blockage of osteoblast differentiation. The results presented here raise concerns about the efficiency of cell differentiation when the cell culture dimensions are reduced to a simplified microspot environment. Also, these results suggest that further efforts should be devoted to increasing the complexity of the microspots composition, aiming to replace signalling cues missing in this system. PMID- 23080378 TI - Quitline cessation counseling for young adult smokers: a randomized clinical trial. AB - INTRODUCTION: One in 5 young adults in the United States currently smoke, and young adults are less likely than other smokers to make aided quit attempts. Telephone quitlines may be a useful tool for treating this population. This study tested a quitline-based smoking cessation intervention versus mailed self-help materials in smokers 18-24 years old. METHODS: This was a 2-group randomized clinical trial. The quitline-based counseling intervention (CI) included up to 4 proactive telephone counseling sessions; participants in the self-help (SH) group received only mailed cessation materials. Participants included 410 young adults who had smoked at least 1 cigarette in the past 30 days and who called the Wisconsin Tobacco Quit Line (WTQL) for help with quitting. Primary study outcomes included whether or not a quit date was set, whether or not a serious quit attempt was undertaken, and self-reported 7-day point-prevalence abstinence at 1 , 3-, and 6-month postenrollment. RESULTS: The CI and SH groups did not differ in the intent-to-treat abstinence analyses at any of the follow-ups. However, the CI group was significantly more likely to set a quit date at 1-month postenrollment. Follow-up response rates were low (67.8% at 1 month; 53.4% at 3 months; and 48.3% at 6 months) reflecting lower motivation to participate in this kind of research. CONCLUSIONS: Relative to self-help, quitline counseling motivated young adults to set a quit date but abstinence rates were not improved. Research is needed on how to motivate young adult smokers to seek cessation treatment including quitline services. PMID- 23080380 TI - Iatrogenic fungal meningitis: tragedy repeated. PMID- 23080379 TI - Patterned assembly of quantum dots onto surfaces modified with click microcontact printing. AB - The self-assembly of CdSe quantum dots (QDs) onto a patterned silica surface generated from surface microcontact click printing is presented. The mechanically robust self-assembly process produces patterns of QDs which remain steadfast, even as subsequent reactions are performed on the substrate, demonstrating the utility and ease of this self-assembly process. PMID- 23080381 TI - Singlet oxygen photo-oxygenation in water/pluronic F-127 hydrogels: increased reaction efficiency coupled with a switch in regioselectivity. AB - Pluronic F-127 hydrogels are highly efficient microenvironments for photochemical reactions, as demonstrated for singlet oxygen reactions of monoalkenes. Nonpolar substrates are localized in the nanosized polymer compartment, which can be visualized by neutron scattering. The efficiency of (1)O(2) reactions is strongly increased for tiglate derivatives and the regioselectivity of the ene reaction of trisubstituted alkenes is completely switched in comparison with solution phase and inverted in comparison with intrazeolite photo-oxygenations. PMID- 23080382 TI - Phytochemical potential of Daphne gnidium in inhibiting growth of melanoma cells and enhancing melanogenesis of B16-F0 melanoma. AB - In this study, we have investigated inhibitory capacity of ethyl acetate, total oligomer flavonoid (TOF), aqueous extracts and beta amyrin acetate, a triterpene isolated from ethyl acetate extract obtained from leaves of Daphne gnidium, on mouse melanoma (B16-F0 and B16-F10 cells) proliferation. Influence of these products on percentage cell distribution in cycle phases and melanogenesis was also studied. Cell viability was determined using the 3-(4, 5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide assay, and flow cytometry was used to analyse effects of tested compounds on progression through the cell cycle. In addition, amounts of melanin and tyrosinase were measured spectrophotometrically at 475 nm. Ethyl acetate, TOF and aqueous extracts exhibited significant anti-proliferative activity after incubation with the two types of tumour skin cells B16-F0 and B16 F10. Furthermore, cell cycle analysis revealed that cells treated with ethyl acetate and TOF extracts were arrested predominantly in G2-M phase. Ethyl acetate extract has also the ability to enhance melanogenesis and tyrosinase activity of B16-F0 melanoma cells. PMID- 23080383 TI - Numerical investigation of an all-optical switch in a graded nonlinear plasmonic grating. AB - We have proposed and numerically investigated an all-optical switch based on a metal-insulator-metal waveguide with graded nonlinear plasmonic gratings. The influences of grating depth and refractive index of a Kerr nonlinear medium on the transmission of the switch are exactly analyzed by utilizing transmission line theory. The finite-difference time-domain simulation results show that the highly compact structure possesses excellent switch function by tuning the incident electric field intensity. In addition, the simulation results show that this all-optical switch has an ultrawide operating frequency regime and femtosecond-scale response time (~130 fs). Such a switch can find potential applications for all-optical signal processing and optical communication. PMID- 23080387 TI - T cells: when i get older, losing my miR.... PMID- 23080389 TI - Innate immunity: bitter enemies. PMID- 23080393 TI - Affective reactivity to daily stressors and long-term risk of reporting a chronic physical health condition. AB - BACKGROUND: Daily stressors, such as an argument with a spouse or an impending deadline, are associated with short-term changes in physical health symptoms. Whether these minor hassles have long-term physical health ramifications, however, is largely unknown. PURPOSE: The current study examined whether exposure and reactivity to daily stressors is associated with long-term risk of reporting a chronic physical health condition. METHODS: Participants (N = 435) from the National Study of Daily Experiences completed a series of daily diary interviews between 1995 and 1996 and again 10 years later. RESULTS: Greater affective (i.e., emotional) reactivity to daily stressors at time 1 was associated with an increased risk of reporting a chronic physical health condition at time 2. CONCLUSION: Results indicate that how people respond to the daily stressors in their lives is predictive of future chronic health conditions. PMID- 23080391 TI - Transcriptional control of effector and memory CD8+ T cell differentiation. AB - During an infection, T cells can differentiate into multiple types of effector and memory T cells, which help to mediate pathogen clearance and provide long term protective immunity. These cells can vary in their phenotype, function and location, and in their long-term fate in terms of their ability to populate the memory T cell pool. Over the past decade, the signalling pathways and transcriptional programmes that regulate the formation of heterogeneous populations of effector and memory CD8(+) T cells have started to be characterized, and this Review discusses the major advances in these areas. PMID- 23080394 TI - Cardiometabolic risk in adolescents: associations with physical activity, fitness, and sleep. AB - BACKGROUND: Physical activity and fitness are independently associated with cardiometabolic dysfunction, and short sleep duration is an emerging marker of obesity. Few have examined interrelations among these factors in a comprehensive risk model. PURPOSE: Investigate the influence of behavioral and lifestyle risk factors on the metabolic syndrome and inflammation. METHODS: A sample of 367 15 17-year-olds (73 % boys) from ethnic minority groups (45.8 % Hispanic, 30.8 % Black), most with elevated blood pressure (72 %), underwent aerobic fitness testing, blood sampling, and completed behavioral questionnaires. RESULTS: Structural model results are consistent with the notion that short sleep duration, poor sleep quality and fatigue, and decreased physical activity are associated with increased risk of metabolic syndrome and inflammation possibly via effects on reduced cardiorespiratory fitness. CONCLUSIONS: The combination of negative lifestyle and behavioral factors of physical inactivity, sleep loss, and poor fitness has serious implications for cardiovascular health complications in at-risk youth. PMID- 23080395 TI - In reply: advantage of Parker Flex-tip Tube((r)) in endotracheal intubation using AirwayScope((r)) videolaryngoscope. PMID- 23080396 TI - A response to Spitzer's (2012) reassessment of his 2003 study of reparative therapy of homosexuality. PMID- 23080397 TI - Sexting: research criteria of a globalized social phenomenon. PMID- 23080398 TI - A plea for consistent reliability in ambulatory blood pressure monitoring: an unusual case of software error in Spacelabs Report Management System 92506. AB - OBJECTIVE: Ambulatory blood pressure monitors are subject to extensive validation protocols, but no international guidelines on the software processing the collected raw data exist. Hence, there seems to be little or no control of ambulatory blood pressure monitoring (ABPM) software with respect to errors. In this paper, we wish to point out an important error in Spacelabs Report Management System 92506 software. METHODS: By chance, we noticed discrepancies in the Spacelabs Report Management System 92506 hourly average tabular as shown on screen and on printout. To exclude the possibility of a random error, 97 ABPM reports were evaluated. In a random patient, we calculated the hourly averages by the arithmetic mean from all measurements. Similarly, the summary average of 24 h, daytime and night-time blood pressure was calculated both by the arithmetic mean of all measurements and by the mean of hourly averages in the respective periods. RESULTS: Evaluation of ABPM reports showed errors in 89 out of 97 (92%). In a random patient, the numerical difference between printout and on-screen hourly averages was considerable, ranging from -37 to 18 mmHg systolic and from 16 to 10 mmHg diastolic. Calculation on the basis of raw data established that on screen hourly average tabular was correct, whereas printout values were erroneous. The erroneous values were also found in the exported hourly average tabular. CONCLUSION: If researchers base calculations on the use of erroneous data from printout or exported hourly average tabular, the results and hence the conclusions may be wrong. Focus on ABPM software is warranted. PMID- 23080399 TI - [Transfer included]. PMID- 23080400 TI - C2v symmetrical two-photon polymerization initiators with anthracene core: synthesis, optical and initiating properties. AB - A series of C(2v) symmetrical two-photon absorption compounds with anthracene core, 2,7-bis[2-(4-substituted phenyl)-vinyl]-9,10-dipentyloxyanthracenes designated as I, II and III (the substituted groups at the 4-position of phenyl of I, II and III were dimethylamino, methyl and cyano, respectively) were designed and synthesized as initiators in two-photon induced polymerization (TPIP). The anthracene ring was modified by linking vinylphenyl groups to the 2,7 position to extend conjugation system length and two pentyloxy groups to the 9,10 position to serve as electronic donors. Two-photon absorption cross section of I was around 300 GM, which was much larger than the 10 GM of II and 29 GM of III at 800 nm. I of 0.18% molar ratio in resin composed of methacrylic acid and dipentaerythritol hexaacrylate exhibited a dramatically low threshold of 0.64 mW compared with commercial photoinitiator benzil at a scanning speed 10 MUm s(-1). Moreover, the threshold of photoinitiator I was only increased to 2.53 mW at a scanning speed of 1000 MUm s(-1). The dependency of threshold on the concentration and exposure time was in accordance with theoretical calculation. Finally, a reasonable mechanism of the two-photon initiating process was proposed. This study provides good prospects for developing low threshold photoinitiator in TPIP. PMID- 23080401 TI - Designing psycho-oncology randomised trials and cluster randomised trials: variance components and intra-cluster correlation of commonly used psychosocial measures. AB - OBJECTIVE: The study aims to provide information about variance components of psychosocial outcomes: within and between-participant variance, within participant correlation and for cluster randomised trials, the intra-cluster correlation (ICC) and, also, to demonstrate how estimates of these variance components and ICCs can be used to design randomised trials and cluster randomised trials. METHOD: Data from 15 longitudinal multi-centre psycho-oncology studies were analysed, and variance components including ICCs were estimated. Studies with psychosocial outcomes that had at least one measurement post baseline including individual randomised controlled trials, cluster randomised trials and observational studies were included. RESULTS: Variance components and ICCs from 87 outcome measures were estimated. The unadjusted, single timepoint (first post-baseline) ICCs ranged from 0 to 0.16, with a median value of 0.022 and inter-quartile range 0 to 0.0605. The longitudinal ICCs ranged from 0 to 0.09 with a median value of 0.0007 and inter-quartile range 0 to 0.018. CONCLUSIONS: Although the magnitude of variance components and ICCs used for sample-size calculation cannot be known in advance of the study, published estimates can help reduce the uncertainty in sample-size calculations. Psycho-oncology researchers should be conservative in their sample-size calculations and use approaches that improve efficiency in their design and analysis. PMID- 23080402 TI - Detection of human enterovirus 71 and Coxsackievirus A16 in an outbreak of hand, foot, and mouth disease in Henan Province, China in 2009. AB - During 2009, an outbreak of hand, foot, and mouth disease (HFMD) enrolled 490 people in Henan Province, causing the death of two children. In order to investigate the pathogens responsible for this outbreak and characterize their genetic characteristics, a total of 508 clinical specimens (stool, throat swab, and vesicle fluid) were collected from the Center for Disease Control and Prevention of Henan Province. Virological investigations (virus isolation, conventional reverse transcription PCR, and real-time reverse transcription PCR) and phylogenetic analysis were performed. It was found that human enterovirus 71 (EV71) was the main pathogen causing this outbreak, while Coxsackievirus A16 (CoxA16) played only a subsidiary role. Phylogenetic analysis of 24 EV71 isolates collected during the period from March 11 to July 24, 2009 showed that they belonged to subgenotypes C4 and C5. Our study for the first time characterizes the epidemiology of HFMD and EV71 infection in Henan Province in 2009 and provides the first direct evidence of the genotype of EV71 circulating in Henan Province at that time. Our study should facilitate the development of public health measures for the control and prevention of HFMD and EV71 infection in at risk individuals in China. PMID- 23080403 TI - Causes of death in patients with hepatitis B: a natural history cohort study in the United States. AB - The natural history of hepatitis B virus (HBV) infection in a U.S. population has not been well described. We identified the causes of death in 6,689 health plan members infected with HBV who were followed between March 1, 1996 and December 31, 2005. Causes of death were grouped into HBV-related (subdivided into decompensated cirrhosis [DCC] and hepatocellular carcinoma [HCC]), cancer, cardiovascular, and other/unknown. The study cohort included 3,244 females and 3,445 males; 68.3% were of Asian-Pacific Islander (API) descent, 11.8% were white (non-Hispanic), and 19.9% were of other or unknown race. Exposure to HBV antivirals and preexisting comorbidities were uncommon. Males had higher overall 10-year death rates than females, both for total deaths (8.9% versus 4.1%) and for HBV-related deaths (4.8% versus 1.2%). The death rate rose markedly with increasing age, and approximately 40% of all deaths in subjects over the age of 40 were HBV related. The death rate from HCC was twice that of DCC. HCC deaths represented 70% of cancer deaths in males and 37% in females. On multivariable analysis, when subjects with antecedent HCC and DCC were excluded, the only significant predictor of HBV mortality in both sexes was age. CONCLUSION: HBV was the cause of death in over 40% of those who died during the study, and the mortality increased markedly with increasing age over 40 in males and over 50 in females. HBV-related mortality was four times more common in males than in females and was as common in non-Asians as in those of API origin. HBV-related deaths were twice as common from HCC as from DCC. PMID- 23080404 TI - Pilot study of the clinical and cognitive effects of high-frequency magnetic seizure therapy in major depressive disorder. AB - BACKGROUND: Electroconvulsive therapy (ECT) is a very commonly used treatment for patients with severe and treatment-resistant depression. Although effective, this treatment is complicated by a number of side effects including cognitive impairment motivating attempts to develop treatment alternatives. Magnetic seizure therapy (MST) is a brain stimulation technique using a high-powered transcranial magnetic stimulation device to produce therapeutic seizures. Preliminary research suggests that MST has antidepressant activity in the absence of cognitive side effects. The aim of this study was therefore to investigate the therapeutic efficacy and cognitive profile of MST provided at high frequency (100 Hz) and potentially longer stimulation trains and longer treatment courses than have been previously investigated. METHODS: Thirteen patients participated in an open-label clinical trial of up to 18 treatment sessions with 100-Hz MST. Assessments of depression severity and cognitive functioning were performed before and after treatment. RESULTS: Of the 13 patients who completed the study, five met clinical response criteria at study end. There was an overall group reduction in depression severity and no evidence of any impairment of orientation, memory, or other elements of cognition after MST treatment. The major limitation of the study was its lack of sham control. CONCLUSIONS: In conclusion, MST shows antidepressant efficacy without apparent cognitive side effects. However, substantial research is required to understand the optimal conditions for stimulation and to compare MST to established treatments including ECT. PMID- 23080405 TI - Characterization of functionally distinct mitochondrial subpopulations. AB - Mitochondrial stress results in changes in mitochondrial function, morphology and homeostasis (biogenesis, fission/fusion, mitophagy) and may lead to changes in mitochondrial subpopulations. While flow cytometric techniques have been developed to quantify features of individual mitochondria related to volume, Ca(2+) concentration, mtDNA content, respiratory capacity and oxidative damage, less information is available concerning the identification and characterization of mitochondrial subpopulations, particularly in epithelial cells. Mitochondria from rabbit kidneys were stained with molecular probes for cardiolipin content (nonyl acridine orange, NAO) and membrane potential (tetramethylrhodamine, TMRM) and analyzed using flow cytometry. We validated that side scatter was a better indicator of volume and that as side scatter (SSC) decreased mitochondrial volume increased. Furthermore, those mitochondria with the highest NAO content had greater side scattering and were most highly charged. Mitochondria with average NAO content were of average side scattering and maintained an intermediate charge. Those mitochondria with low NAO content had minimal side scattering and exhibited minimal charge. Upon titration with the uncoupler carbonylcyanide-4 (trifluoromethoxy)-phenylhydrazone (FCCP), it was found that the high NAO content subpopulations were more resistant to uncoupling than lower NAO content populations. Ca(2+)-induced swelling of mitochondria was evaluated using probability binning (PB) analyses of SSC. Interestingly, only 30% of the mitochondria showed changes in response to Ca(2+), which was blocked by cyclosporine A. In addition, the small, high NAO content mitochondria swelled differentially in response to Ca(2+) over time. Our results demonstrate that flow cytometry can be used to identify mitochondrial subpopulations based on high, mid and low NAO content and/or volume/complexity. These subpopulations showed differences in membrane potential, volume, and responses to uncoupling and Ca(2+) induced swelling. PMID- 23080406 TI - Effects of hydrogen sulfide on bacterial communities on the surface of galatheid crab, Shinkaia crosnieri, and in a bacterial mat cultured in rearing tanks. AB - To investigate the effects of H2S on the bacterial consortia on the galatheid crab, Shinkaia crosnieri, crabs of this species were cultivated in the laboratory under two different conditions, with and without hydrogen sulfide feeding. We developed a novel rearing tank system equipped with a feedback controller using a semiconductor sensor for hydrogen sulfide feeding. H2S aqueous concentration was successfully maintained between 5 to 40 uM for 80 d with the exception of brief periods of mechanical issues. According to real-time PCR analysis, the numbers of copies of partial 16S rRNA gene of an episymbiont of the crabs with H2S feeding was three orders of magnitude larger than that without feeding. By phylogenetic analysis of partial 16S rRNA gene, we detected several clones related to symbionts of deep sea organisms in Alphaproteobacteria, Gammaproteobacteria, Epsilonproteobacteria, and Flavobacteria, from a crab with H2S feeding. The symbiont-related clones were grouped into four different groups: Gammaproteobacteria in marine epibiont group I, Sulfurovum-affiliated Epsilonproteobacteria, Osedax mucofloris endosymbiont-affiliated Epsilonproteobacteria, and Flavobacteria closely related to CFB group bacterial epibiont of Rimicaris exoculata. The other phylotypes were related to Roseobacter, and some Flavobacteria, seemed to be free-living psychrophiles. Furthermore, white biofilm occurred on the surface of the rearing tank with H2S feeding. The biofilms contained various phylotypes of Gammaproteobacteria, Epsilonproteobacteria, and Flavobacteria, as determined by phylogenetic analysis. Interestingly, major clones were related to symbionts of Alviniconcha sp. type 2 and to endosymbionts of Osedax mucofloris, in Epsilonproteobacteria. PMID- 23080407 TI - Uranium (U)-tolerant bacterial diversity from U ore deposit of Domiasiat in North East India and its prospective utilisation in bioremediation. AB - Uranium (U)-tolerant aerobic chemo-heterotrophic bacteria were isolated from the sub-surface soils of U-rich deposits in Domiasiat, North East India. The bacterial community explored at molecular level by amplified ribosomal DNA restriction analysis (ARDRA) resulted in 51 distinct phylotypes. Bacterial community assemblages at the U mining site with the concentration of U ranging from 20 to 100 ppm, were found to be most diverse. Representative bacteria analysed by 16S rRNA gene sequencing were affiliated to Firmicutes (51%), Gammaproteobacteria (26%), Actinobacteria (11%), Bacteroidetes (10%) and Betaproteobacteria (2%). Representative strains removed more than 90% and 53% of U from 100 uM and 2 mM uranyl nitrate solutions, respectively, at pH 3.5 within 10 min of exposure and the activity was retained until 24 h. Overall, 76% of characterized isolates possessed phosphatase enzyme and 53% had PIB-type ATPase genes. This study generated baseline information on the diverse indigenous U tolerant bacteria which could serve as an indicator to estimate the environmental impact expected to be caused by mining in the future. Also, these natural isolates efficient in uranium binding and harbouring phosphatase enzyme and metal transporting genes could possibly play a vital role in the bioremediation of metal-/radionuclide-contaminated environments. PMID- 23080408 TI - Analysis of volatile organic compounds emitted by plant growth-promoting fungus Phoma sp. GS8-3 for growth promotion effects on tobacco. AB - We extracted volatile organic compounds (VOCs) emitted by a plant growth promoting fungus (PGPF) Phoma sp. GS8-3 by gas chromatography and identified them by mass spectrometry. All of the identified compounds belonged to C4-C8 hydrocarbons. Volatiles varied in number and quantity by the culture period of the fungus (in days). 2-Methyl-propanol and 3-methyl-butanol formed the main components of the volatile blends for all the culture periods of fungus. Growth promoting effects of the identified synthetic compounds were analyzed individually and in blends using tobacco plants. We found that the mixture of volatiles extracted from 3-day-old culture showed significant growth promotion in tobacco in vitro. The volatile blend showed better growth promotion at lower than higher concentrations. Our results confirm the potential role of volatile organic compounds in the mechanism of growth enhancement by GS8-3. PMID- 23080409 TI - Mercury and selenium concentrations in biofilm, macroinvertebrates, and fish collected in the Yankee Fork of the Salmon River, Idaho, USA, and their potential effects on fish health. AB - The Yankee Fork is a large tributary of the Salmon River located in central Idaho, USA, with an extensive history of placer and dredge-mining activities. Concentrations of selenium (Se) and mercury (Hg) in various aquatic trophic levels were measured in the Yankee Fork during 2001 and 2002. Various measurements of fish health were also performed. Sites included four on the mainstem of the Yankee Fork and two off-channel sites in partially reclaimed dredge pools used as rearing habitat for cultured salmonid eggs and fry. Hg concentrations in whole mountain whitefish and shorthead sculpin ranged from 0.28 to 0.56 MUg/g dry weight (dw), concentrations that are generally less than those reported to have significant impacts on fish. Biofilm and invertebrates ranged from 0.05 to 0.43 MUg Hg/g dw. Se concentrations measured in biota samples from the Yankee Fork were greater than many representative samples collected in the Snake and Columbia watersheds and often exceeded literature-based toxic thresholds. Biofilm and invertebrates ranged from 0.58 to 4.66 MUg Se/g dw. Whole fish ranged from 3.92 to 7.10 MUg Se/g dw, and gonads ranged from 6.91 to 31.84 MUg Se/g dw. Whole-body Se concentrations exceeded reported toxicological thresholds at three of four sites and concentrations in liver samples were mostly greater than concentrations shown to have negative impacts on fish health. Histological examinations performed during this study noted liver abnormalities, especially in shorthead sculpin, a bottom-dwelling species. PMID- 23080411 TI - Invisibility and cloaking based on scattering cancellation. AB - Advances in material synthesis and in metamaterial technology offer new venues to tailor the electromagnetic properties of devices, which may go beyond conventional limits in a variety of fields and applications. Invisibility and cloaking are perhaps one of the most thought-provoking possibilities offered by these new classes of advanced materials. Here, recently proposed solutions for invisibility and cloaking using metamaterials, metasurfaces, graphene and/or plasmonic materials in different spectral ranges are reviewed and highlighted. The focus is primarily on scattering-cancellation approaches, describing material challenges, venues and opportunities for the plasmonic and the mantle cloaking techniques, applied to various frequency windows and devices. Analogies, potentials and relevant opportunities of these concepts are discussed, their potential realization and the underlying technology required to verify these phenomena are reviewed with an emphasis on the material aspects involved. Finally, these solutions are compared with other popular cloaking techniques. PMID- 23080410 TI - Inter-cellular signaling network reveals a mechanistic transition in tumor microenvironment. AB - We conducted inter-cellular cytokine correlation and network analysis based upon a stochastic population dynamics model that comprises five cell types and fifteen signaling molecules inter-connected through a large number of cell-cell communication pathways. We observed that the signaling molecules are tightly correlated even at very early stages (e.g. the first month) of human glioma, but such correlation rapidly diminishes when tumor grows to a size that can be clinically detected. Further analysis suggests that paracrine is shown to be the dominant force during tumor initiation and priming, while autocrine supersedes it and supports a robust tumor expansion. In correspondence, the cytokine correlation network evolves through an increasing to decreasing complexity. This study indicates a possible mechanistic transition from the microenvironment controlled, paracrine-based regulatory mechanism to self-sustained rapid progression to fetal malignancy. It also reveals key nodes that are responsible for such transition and can be potentially harnessed for the design of new anti cancer therapies. PMID- 23080412 TI - Firearm-related injuries affecting the pediatric population. PMID- 23080413 TI - Total phenolics content, anthocyanins, and dietary fiber content of apple pomace powders produced by vacuum-belt drying. AB - BACKGROUND: Apple pomace is a waste material from apple juice processing, and contains significant amounts of dietary fiber and phytochemicals. Many of these compounds may be degraded post-pressing and during drying operations. Continuous vacuum-belt drying (VBD) was studied as a means of drying and maintaining quality of apple pomace. The color and chemical properties of samples dried by vacuum belt drying at different temperatures were evaluated including total phenolics content (TPC), monomeric anthocyanins (TMA) and dietary fiber content (TDF). RESULTS: VBD powders were pale golden yellow, and those dried at 80 degrees C did not differ in L*, a* and b* values from freeze-dried powders. VBD pomace had 44.9 to 51.9 g gallic acid equivalents kg(-1) TPC, with greatest retention for pomace dried at 80 and 95 degrees C. TPC for pomace dried at 80 or 95 degrees C was not significantly different from that for freeze-dried pomace. TMA levels (74.0 mg C3G kg(-1), where C3G is cyanidine 3-O-glucoside equivalents) were highest in pomace vacuum dried at 80 degrees C. TDF ranged from 442 to 495 g kg(-1) in vacuum-dried pomace and was not significantly different from TDF of freeze-dried poamce (480 g kg(-1)). CONCLUSION: In all cases, TPC, TMA and TDF were higher in VBD pomace than in freeze-dried whole apple, while VBD pomace prepared at 80 or 95 degrees C had fiber and phytochemical levels similar to freeze-dried powders. PMID- 23080414 TI - Hepatic endometrioma: a case report and review of the literature: report of a case. AB - Hepatic endometriosis has an extremely rare occurrence characterized by the presence of ectopic endometrium in the liver. A diagnosis of hepatic endometriosis is established after surgery. A 51-year-old multiparous female was referred to our unit for investigation of a liver tumor. The patient reported a 6 month history of epigastric pain and vomiting. She had undergone conservative hysterectomy for uterine leiomyomas several years earlier. The results of liver function tests and the levels of tumor markers (CA 19.9, CEA, CA125, alphaFP) were normal. Radiological imaging (USS, CT and MRI) suggested the presence of liver cystadenoma, liver cystadenocarcinoma or cystic metastasis of the liver in the left liver lobe extending to the diaphragm with left hepatic vein compression. Laparotomy was performed. The intraoperative frozen sections suggested a diagnosis of endometriosis. Anatomical resection was performed, including left lobectomy with diaphragm resection. The final histology confirmed the presence of hepatic endometrioma without malignant transformation. Fourteen cases of hepatic endometrioma have been described in the medical literature. We herein report the 15th case. Making a preoperative diagnosis of hepatic endometriosis is very difficult, despite conducting a complete investigation, in the absence of clinical and radiological characteristics. The diagnosis is made according to a histological examination of the whole surgical sample. PMID- 23080415 TI - The honeybee as a model for understanding the basis of cognition. AB - Honeybees contradict the notion that insect behaviour tends to be relatively inflexible and stereotypical. Indeed, they live in colonies and exhibit complex social, navigational and communication behaviours, as well as a relatively rich cognitive repertoire. Because these relatively complex behaviours are controlled by a brain consisting of only 1 million or so neurons, honeybees offer an opportunity to study the relationship between behaviour and cognition in neural networks that are limited in size and complexity. Most recently, the honeybee has been used to model learning and memory formation, highlighting its utility for neuroscience research, in particular for understanding the basis of cognition. PMID- 23080417 TI - Augmentation techniques for rotator cuff repair. AB - INTRODUCTION: There is a high rate of recurrence of tear and failed healing after rotator cuff repair. Several strategies have proposed to augment rotator cuff repairs to improve postoperative outcome and shoulder performance. We systematically review the literature on clinical outcome following rotator cuff augmentation. SOURCES OF DATA: We performed a comprehensive search of Medline, CINAHL, Embase and the Cochrane Central Registry of Controlled Trials, from inception of the database to 20 June 2012, using various combinations of keywords. The reference lists of the previously selected articles were then examined by hand. Only studies focusing on clinical outcomes of human patients who had undergone augmented rotator cuff repair were selected. We then evaluated the methodological quality of each article using the Coleman methodology score (CMS), a 10 criteria scoring list assessing the methodological quality of the selected studies (CMS). AREAS OF AGREEMENT: Thirty-two articles were included in the present review. Two were retrospective studies, and 30 were prospective. Biologic, synthetic and cellular devices were used in 24, 7 and 1 studies, respectively. The mean modified Coleman methodology score was 64.0. AREAS OF CONTROVERSY: Heterogeneity of the clinical outcome scores makes it difficult to compare different studies. GROWING POINTS: None of the augmentation devices available is without problems, and each one presents intrinsic weaknesses. There is no dramatic increase in clinical and functional assessment after augmented procedures, especially if compared with control groups. RESEARCH: More and better scientific evidence is necessary to use augmentation of rotator cuff repairs in routine clinical practice. PMID- 23080418 TI - Occupation and chronic obstructive pulmonary disease (COPD). AB - INTRODUCTION: There is growing interest in preventable, non-smoking causes of chronic obstructive pulmonary disease (COPD), among which are chronic exposures to respiratory irritants in the workplace. SOURCES OF DATA: Reviews of occupational COPD in specific occupations and industries and in general populations; supplemented with other or more recently published material. AREAS OF AGREEMENT: There is good evidence for an increased risk of COPD from certain specific exposures (coal mine dust, silica, welding fume, textile dust, agricultural dust, cadmium fume). AREAS OF CONTROVERSY: Less clear is the causal role of non-specific dusts or fumes/gases in general populations where the available literature is notably uncritical. GROWING POINTS: Other specific exposures, such as diesel fume; interactions between specific exposures and cigarette smoking; the development of safe working limits. AREAS TIMELY FOR DEVELOPING RESEARCH: Occupations with large numbers of exposed employees, particularly in low-income countries. PMID- 23080416 TI - The BCM theory of synapse modification at 30: interaction of theory with experiment. AB - Thirty years have passed since the publication of Elie Bienenstock, Leon Cooper and Paul Munro's 'Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex', known as the BCM theory of synaptic plasticity. This theory has guided experimentalists to discover some fundamental properties of synaptic plasticity and has provided a mathematical structure that bridges molecular mechanisms and systems-level consequences of learning and memory storage. PMID- 23080419 TI - Peripheral arterial disease: a literature review. AB - INTRODUCTION: Peripheral arterial disease (PAD) is a common vascular condition that affects both quality of life and life expectancy with an increased risk of cardiovascular events. SOURCES OF DATA: A literature search was carried out of Pub-Med, MEDLINE, the Cochrane Library and Google Scholar from the establishment of these databases up to February 2012. The search was performed by using the keywords 'peripheral arterial disease' and one of the following words: 'management', 'investigations', 'risk factors', 'epidemiology', 'revascularization', 'cryoplasty', 'atherectomy' and 'gene therapy'. Studies were limited to those published in English language. AREAS OF AGREEMENT: Aggressive risk factors modification is needed to reduce cardiovascular-related mortality in PAD patients. AREAS OF CONTROVERSY: Choice of endovascular or surgical intervention remains controversial in an ever-evolving field. GROWING POINTS: There is a rapid expansion of endovascular technologies aiming to improve the effectiveness of this modality. AREAS TIMELY FOR DEVELOPING RESEARCH: The advances in the fields of gene therapy and therapeutic angiogenesis mean these are potential future treatments. Tissue engineering is a developing area and aims to produce grafts with similar patency and infection profiles to those of autologous material. Further elucidation of the pathophysiology of atherosclerosis is required to provide new targets for pharmacotherapy. PMID- 23080420 TI - Treatment of aseptic loosened MTPI prosthesis by one-stage revision with ToeFit Plus prosthesis. AB - INTRODUCTION: Due to the missing bony integration of the ceramic Moje prosthesis for replacing the first metatarsophalangeal joint (MTPI) in hallux rigidus, the mid-term results were bad so far. In case of revision, the distraction arthrodesis with autologous bone taken from the iliac crest as a salvage procedure is the method of choice. METHOD: In our prospective case series, the short-term results after revision of the Moje prosthesis with the ToeFit Plus prosthesis were investigated. The clinical and radiological investigations were done in six MTPI over a 24-month period using AOFAS score and visual analogue scale. RESULTS: There were no radiological signs of loosening or implant migration of the ToeFit Plus 24 months, postoperatively. There was one fissure at the first proximal phalanx necessitating a wire stabilisation. No other complications could be observed. A significant improvement of the AOFAS score and the range of motion were observed 6 weeks postoperatively. CONCLUSION: We could show good and very good short-term results after the replacement of a loosened MTPI prosthesis with a ToeFit Plus. Due to the conic screw anchorage, ToeFit Plus is excellently suited for prosthesis replacement at the MTPI. With sufficient bony anchorage prerequisites, it is possible to preserve and improve the range of motion by changing the loosened MTPI prosthesis in the ToeFit Plus, thereby avoiding the morbidity of gaining autologous bone from the iliac crest. PMID- 23080421 TI - Risk factors for nonunion in 337 displaced midshaft clavicular fractures treated with Knowles pin fixation. AB - BACKGROUND: Clavicular fractures account for nearly 10 % of all fractures, and the majority of those fractures involve the midshaft. Historically, these fractures were treated nonoperatively; however, recent data suggest an increased risk of nonunion and symptomatic malunion for displaced, comminuted midshaft clavicular fractures treated conservatively. Surgical intervention via plate osteosynthesis or intramedullary fixation with pins, nails, or screws has been shown to reduce, but not eliminate, this risk. Identification of risk factors predictive of nonunion would improve the overall management of displaced, comminuted midshaft clavicular fractures. METHODS: The medical records of 337 consecutive patients who underwent Knowles pin fixation and supplemental cerclage for the treatment of displaced, comminuted midshaft clavicular fractures between April 2007 and March 2009 were retrospectively reviewed. The records of the mechanism of injury, side of injury, Robinson fracture classification, presence of associated injuries, cerclage material, and patient-related variables, including diabetes mellitus, hypertension and smoking, were analyzed. Variables were assessed by univariate and multivariate analysis to identify those factors significantly associated with the development of fracture nonunion. RESULTS: A total of 19 nonunions occurred. Increasing age and use of wire for supplemental cerclage fixation were significantly associated with an increased risk for fracture nonunion (p < 0.001). Although suggested as predictors of nonunion in other studies, female gender and fracture severity were not significantly associated with nonunion. CONCLUSIONS: Nonunion remains a significant complication in the treatment of displaced, comminuted midshaft clavicular fractures even with intramedullary fixation. Use of absorbable suture in place of wire for cerclage fixation and careful selection of treatment strategy in the elderly may reduce the risk for nonunion. PMID- 23080422 TI - A posterior inverted L-shaped approach for the treatment of posterior bicondylar tibial plateau fractures. AB - OBJECTIVES: To present a case series of patients with posterior bicondylar tibial plateau fractures treated by direct exposure and buttress plate fixation through posterior inverted L-shaped approach. METHODS: Between August 2007 and July 2010, eight middle aged patients were identified to have posterior bicondylar tibial plateau fractures. All the eight patients underwent direct fracture exposure, reduction under visualization, and buttress plate fixation through posterior inverted L-shaped approach. RESULTS: All the cases were followed for an average of 28.1 months (24-36 months). All the cases had satisfactory reduction except one case, which had a 3-mm stepoff postoperatively. None of the complications such as infection, necrosis of the skin incision or the loosening and breakage of the internal fixator occurred. The average radiographic bony union time and full weightbearing time were 11.5 weeks (10-14 weeks), and 13.8 weeks (11-17 weeks) respectively. The average range of motion of the affected knee was from 3.6 degrees to 127.8 degrees at 1 year after the operation. CONCLUSIONS: The posterior inverted L-shaped approach would not involve osteotomy, tendotomy or division of muscles, while allowing satisfied visualization of the entire posterior aspect of tibial plateau and appropriate placement of hardware. This approach is a safe and effective way for the treatment of posterior bicondylar tibial plateau fractures. PMID- 23080423 TI - 3 D MOFs containing trigonal bipyramidal Ln5 clusters as nodes: large magnetocaloric effect and slow magnetic relaxation behavior. AB - Two 3D heterometal-organic frameworks based on infrequent trigonal bipyramidal Ln(5) clusters as nodes were structurally and magnetically characterized (Ln=Gd (1), Dy (2)). The results indicate large MCE of up to 30.7 J kg(-1) K(-1) in 1 and slow magnetic relaxation behavior in 2. Expectedly, constructing 3D MOFs based on multinuclear clusters as nodes may will be a new strategy for achieving large -DeltaS(m). Additionally, compound 1 exhibits high thermal and solvent stabilities, providing a favorable foundation for realistic applications. PMID- 23080424 TI - Endogenous CSE/H2 S system mediates TNF-alpha-induced insulin resistance in 3T3 L1 adipocytes. AB - Tumour necrosis factor-alpha (TNF- alpha)is a major contributor to the pathogenesis of insulin resistance associated with obesity and type 2 diabetes. It has been found that endogenous hydrogen sulfide (H2 S) contributes to the pathogenesis of diabetes. We have hypothesized that TNF-alpha-induced insulin resistance is involved in endogenous H2 S generation. The aim of the present study is to investigate the role of endogenous H2 S in TNF-alpha-induced insulin resistance by studying 3T3-L1 adipocytes. We found that treatment of 3T3-L1 adipocytes with TNF-alpha leads to deficiency in insulin-stimulated glucose consumption and uptake and increase in endogenous H2 S generation. We show that cystathionine gamma-lyase (CSE) is catalysed in 3T3-L1 adipocytes to generate H2 S and that CSE expression and activity are upregulated by TNF-alpha treatment. Inhibited CSE by its potent inhibitors significantly attenuates TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes, whereas H2 S treatment of 3T3-L1 adipocytes impairs insulin-stimulated glucose consumption and uptake. These data indicate that endogenous CSE/H2 S system contributes to TNF-alpha-caused insulin resistance in 3T3-L1 adipocytes. Our findings suggest that modulation of CSE/H2 S system is a potential therapeutic avenue for insulin resistance. PMID- 23080425 TI - Variation in outcomes across centers after surgery for lumbar stenosis and degenerative spondylolisthesis in the spine patient outcomes research trial. AB - STUDY DESIGN: Retrospective review of a prospectively collected database. OBJECTIVE: To examine whether short- and long-term outcomes after surgery for lumbar stenosis (SPS) and degenerative spondylolisthesis (DS) vary across centers. SUMMARY OF BACKGROUND DATA: Surgery has been shown to be of benefit for both SPS and DS. For both conditions, surgery often consists of laminectomy with or without fusion. Potential differences in outcomes of these overlapping procedures across various surgical centers have not yet been investigated. METHODS: Spine Patient Outcomes Research Trial cohort participants with a confirmed diagnosis of SPS or DS undergoing surgery were followed from baseline at 6 weeks, 3, 6, and 12 months, and yearly thereafter, at 13 spine clinics in 11 US states. Baseline characteristics and short- and long-term outcomes were analyzed. RESULTS: A total of 793 patients underwent surgery. Significant differences were found between centers with regard to patient race, body mass index, treatment preference, neurological deficit, stenosis location, severity, and number of stenotic levels. Significant differences were also found in operative duration and blood loss, the incidence of durotomy, the length of hospital stay, and wound infection. When baseline differences were adjusted for, significant differences were still seen between centers in changes in patient functional outcome (Short Form-36 bodily pain and physical function, and Oswestry Disability Index) at 1 year after surgery. In addition, the cumulative adjusted change in the Oswestry Disability Index Score at 4 years significantly differed among centers, with Short Form-36 scores trending toward significance. CONCLUSION: There is a broad and statistically significant variation in short- and long-term outcomes after surgery for SPS and DS across various academic centers, when statistically significant baseline differences are adjusted for. The findings suggest that the choice of center affects outcome after these procedures, although further studies are required to investigate which center characteristics are most important. PMID- 23080426 TI - Larsen syndrome with C3-C4 spondyloptosis and atlantoaxial dislocation in an adult. AB - STUDY DESIGN: This is a clinical case report with a review of relevant literature. OBJECTIVE: To describe a case of Larsen syndrome with C3-C4 spondyloptosis and atlantoaxial dislocation in a middle-aged female patient and to discuss management strategies. SUMMARY OF BACKGROUND DATA: Spondyloptosis of the cervical spine is relatively rare and is caused by trauma, destruction of the vertebral bodies by tumors, or tuberculosis. Such gross vertebral displacement is usually associated with significant neurological deficits. Larsen syndrome is characterized by multiple joint displacements and can, very rarely, be associated with nontraumatic spondyloptosis of the cervical vertebra. A single case report of C1-C2 joint laxity causing atlantoaxial dislocation in a patient with Larsen syndrome is available in literature. No reports of any patient (with Larsen syndrome or nonsyndromic) who had both cervical spondyloptosis and atlantoaxial dislocation are available in literature. METHODS: A 36-year-old female presented with chronic neck pain, bilateral hand deformity, and mild spasticity involving all 4 limbs. Cervical radiograph, computed tomographic scan, and magnetic resonance image revealed C3-C4 spondyloptosis and atlantoaxial dislocation. RESULTS: A combined ventral decompression of subaxial spine and instrumentation from C2 to C5, followed by posterior C1-C2 distraction arthroplasty and lateral mass stabilization of the subaxial spine up to C6, was done. The cervical deformity was corrected, and the patient remains symptom free. CONCLUSION: Patients with spondyloptosis of the cervical spine can rarely present with chronic neck pain and minimal neurological deficits. An additional pathology, such as atlantoaxial dislocation, can add to the complexity. Circumferential stabilization and fusion would be required in such cases to achieve a good outcome. Larsen syndrome is a rare cause of nontraumatic cervical displacements. PMID- 23080427 TI - ProDisc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: Analyze the clinical outcomes at 5 years comparing cervical total disc replacement (TDR) with ProDisc C (Synthes Spine USA Products; LLC, West Chester, PA) with anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Previous reports of 2- and 4-year results have shown that ProDisc-C, a TDR for surgical treatment of patients experiencing single-level symptomatic cervical disc disease between C3 and C7, is safe and effective. METHODS: Two hundred nine patients (103 ProDisc-C and 106 ACDF) from 13 sites were randomized and treated. Results including neck disability index, visual analog scale (VAS) neck and arm pain, Short Form-36 (SF 36), neurological examination, device success, adverse event occurrence, and VAS patient satisfaction were analyzed. RESULTS: Demographics were similar between the 2 patient groups (ProDisc-C: 42.1 +/- 8.4 yr, 44.7% males; ACDF: 43.5 +/- 7.1 yr, 46.2% males). Rates of follow-up at 2 years were 98.1% ProDisc-C and 94.8% ACDF, and at 5 years 72.7% ProDisc-C and 63.5% ACDF. For all clinical outcomes for both groups, there was a statistically and clinically significant improvement at 2 and 5 years compared with baseline. At 5 years, ProDisc-C patients had statistically significantly less neck pain intensity and frequency. Both groups scored high VAS satisfaction scores at 5 years, with ProDisc-C 86.56 and ACDF 82.74. There were no reports of device failures or implant migration with ProDisc C. The ProDisc-C patients maintained motion at their index level. At 5 years, the ProDisc-C patients had a statistically significantly lower rate of reoperation compared with ACDF patients (2.9% vs. 11.3%). CONCLUSION: Five-year results show that TDR with ProDisc-C is a safe and effective treatment of single-level symptomatic cervical disc disease. Clinical outcomes were comparable with ACDF. ProDisc-C patients maintained motion at the index level and had significantly less neck pain intensity and frequency as well as a lower probability of secondary surgery. PMID- 23080428 TI - Is type of compensation a predictor of outcome after lumbar fusion? AB - STUDY DESIGN: Propensity-matched case-control study. OBJECTIVE: To examine the impact of compensation status on clinical outcomes after lumbar spine fusion. SUMMARY OF BACKGROUND DATA: Workers' compensation has been associated with inferior outcomes after treatment of low back pain. However, patients receiving other forms of compensation, such as long-term disability or government-supported insurance, have not been studied independently. METHODS: Patients with complete preoperative and 2-year postoperative data, including Oswestry disability index, 36-item short form health survey, and numeric rating scales for back and leg pain, after 1- or 2-level posterolateral lumbar fusion from a single spine surgery practice, were retrospectively identified. Fifty-nine patients 50 years or younger receiving disability compensation and 38 patients receiving workers' compensation were identified from 1144 patients with complete outcome measures. Propensity scoring was used to match cohorts not receiving compensation. Each group was matched for sex, age, smoking status, body mass index, surgical indication, number of levels fused, and baseline outcome measures. Fifty-one and 37 matched pairs were successfully identified for disability and workers' compensation cohorts, respectively. RESULTS: Consistent with propensity matching, no statistically significant difference between cohorts was observed for demographics and baseline outcome measures. At 2-year follow-up, the disability compensation group demonstrated similar degrees of improvement for all outcome measures compared with its matched nondisability cohort, whereas the workers' compensation group demonstrated less improvement than its matched cohort. CONCLUSION: This study demonstrates a difference in outcomes after lumbar spinal fusion between long-term disability and workers' compensation populations. Although, these populations achieve only marginal improvement, it seems that the type of compensation status influences outcome. Workers' compensation has a clear, negative influence on outcome when compared with controls, whereas well selected patients receiving disability compensation seem more likely to benefit from lumbar fusion. Therefore, surgeons and researchers alike should not include disability compensation patients in the same cohort as patients on workers' compensation. PMID- 23080429 TI - Does surgical technique affect the incidence of spondylodiscitis post-lumbar microdiscectomy? A retrospective analysis of 3063 patients. AB - STUDY DESIGN: Retrospective audit in a single center during a period of 7 years operated by 3 groups of surgeons after 3 different surgical techniques. OBJECTIVE: Our study aimed to determine whether surgical technique had any influence on the incidence of spondylodiscitis in patients undergoing lumbar microdiscectomy and to compare this with published rate of incidence of spondylodiscitis. SUMMARY OF BACKGROUND DATA: The incidence of spondylodiscitis post-lumbar microdiscectomy ranges from 0.2% to 15%. There is limited evidence to compare different techniques and the incidence of spondylodiscitis. METHODS: A total of 3063 patients were analyzed from 2005 to 2011 for discitis postoperatively. The first group followed a standard microdiscectomy technique, the second group used antiseptic (Savlon; Novartis Consumer Health UK Limited, Surrey, UK) irrigation at the end of the procedure to irrigate the disc space, and the third group followed standard microdiscectomy along with usage of a separate disc instruments when discectomy was performed. The number of patients operated in the individual groups was 559, 1122, and 1382. RESULTS: The total number of patients who had postoperative discitis was 3 (0.10%), with a range of 0.07% to 0.18%. There was 1 case of discitis in each group. The incidence of spondylodiscitis in groups A, B, and C were 0.18%, 0.09%, and 0.07%, respectively. CONCLUSION: This study concluded that different techniques used for lumbar microdiscectomy revealed that standard microsurgical technique with usage of antiseptic irrigation for the disc space and usage of separate disc instruments had lesser incidence of spondylodiscitis in comparison with standard microdiscectomy. The overall incidence of postoperative discitis remains less in our series. So far, to our knowledge, this report involves the largest number of patients studied to determine the incidence of discitis in patients undergoing lumbar microdiscectomy. LEVEL OF EVIDENCE: 3. PMID- 23080430 TI - BjHO-1 is involved in the detoxification of heavy metal in India mustard (Brassica juncea). AB - Heme oxygenase-1 (HO-1) is a stress-responsive gene coding for an enzyme catalyzing the catabolism of heme to yield biliverdin IXalpha, carbon monoxide (CO) and iron. However, its biological role in regulating metal homeostasis, particularly the tolerance to toxic heavy metals is poorly understood. In this study, a novel gene encoding a Brassica juncea heme oxygenase-1 (designated as BjHO-1) was cloned and functionally identified. Spatial expression of BjHO-1 showed that it was differentially expressed in cotyledon, hypocotyl, leaf and root. BjHO-1 was found to be induced significantly by heavy metal Hg. To understand whether BjHO-1 is able to regulate plant tolerance to Hg, we constructed transgenic B. juncea plants overexpressing HO-1, and showed that 35S::BjHO1 plants confer the plant resistance to Hg toxicity by improving plant dry mass, reducing Hg accumulation, and attenuating Hg-induced oxidative stress. We further cloned a 1,099 bp promoter sequence upstream of BjHO-1 using genome walking approach. Multiple stress-responsive elements were detected in the BjHO-1 promoter regions. The promoter can be activated by Zn, Cd, Hg and Pb exposure. Our results indicate that up-regulation of BjHO-1 is beneficial for limiting the uptake or accumulation of heavy metals into plants. This work also provides a new example for molecular breeding designed for plants that do not accumulate or minimizing accumulation of toxic trace metals growing on heavy metal-contaminated soils. PMID- 23080432 TI - LSPR enhanced MSM UV photodetectors. AB - We fabricated localized surface plasmon resonance enhanced UV photodetectors on MOCVD grown semi-insulating GaN. Plasmonic resonance in the UV region was attained using 36 nm diameter Al nanoparticles. Extinction spectra of the nanoparticles were measured through spectral transmission measurements. A resonant extinction peak around 300 nm was obtained with Al nanoparticles. These particles gave rise to enhanced absorption in GaN at 340 nm. Spectral responsivity measurements revealed an enhancement factor of 1.5. These results provided experimental verification for obtaining field enhancement by using Al nanoparticles on GaN. PMID- 23080431 TI - Effects of cadmium on the sub-cellular localization of beta-catenin and beta catenin-regulated gene expression in NRK-52E cells. AB - The E-cadherin/beta-catenin complex is a structural component of adherens-type junctions in epithelial cells. Moreover, beta-catenin acts as an intracellular signaling molecule that can influence the expression of a variety of genes that regulate apoptosis and cell cycle control. Cadmium (Cd) is an environmental toxicant that causes renal dysfunction and disrupts cadherin-dependent cell-cell adhesion in various types of epithelial cells. In this study, we examined the effects of Cd on the subcellular localization of beta-catenin, the cadherin/beta catenin complex and beta-catenin-mediated gene transcription in rat proximal tubule NRK-52E cells. Exposure to 5-10 MUM Cd for 4 h caused the NRK cells to separate from each other without killing the cells or causing them to detach from the growing surface. This effect was associated with the loss of beta-catenin and E-cadherin from the cell-cell contacts and apparent changes in the accumulation of beta-catenin in the nuclear cell subfraction. The expression of the beta catenin-sensitive gene, c-jun was significantly increased in cells exposed to 5 MUM Cd. However, there was no change in the expression of several other beta catenin-regulated genes including: c-myc, cyclin D1 and matrilysin. Additional studies utilizing the TOPFLASH beta-catenin reporter gene construct showed that Cd caused a 2-3 fold increase in the expression of the luciferase reporter gene. Overall, these results indicate that Cd disrupts the cadherin/beta-catenin complex in NRK-52E cells, but this effect leads to only partial activation of beta-catenin-mediated gene transcription. PMID- 23080433 TI - Differential promoter activities of functional haplotypes in the 5'-flanking region of human sulfotransferase 1A1. AB - Previously, we reported five common single nucleotide polymorphisms (SNPs), 624G>C, -396G>A, -358A>C, -341C>G, and -294T>C, and six common haplotypes (CGACT, GAACT, GGAGC, GGACC, CAACT, and GAACC) in the 5'-flanking region of the SULT1A1 gene that were associated with altered enzymatic activity. In the present study, we performed in vitro assays to determine the functional impact of these genetic variations on the promoter activity. Dual luciferase reporter assays revealed that these SNPs are located in a negative regulatory fragment of the SULT1A1 gene. Further experiments demonstrated that these SNPs and haplotypes affected promoter activities of SULT1A1. Electrophoretic mobility shift assays showed distinctive binding patterns for the SNPs -396G>A and -294T>C, due to differential binding affinities of the G/A alleles and the T/C alleles to nuclear proteins extracted from the liver carcinoma cell lines, HepG2 and Huh7. PMID- 23080434 TI - Anaesthesia and orphan disease: the child with 3M syndrome. PMID- 23080435 TI - Application of a contact mode AFM for spatially resolved electrochemical impedance spectroscopy measurements of a Nafion membrane electrode assembly. AB - A Nafion fuel cell membrane is investigated by means of electrochemical atomic force microscopy in different gas atmospheres. From chronoamperometric experiments with a point contact electrode spatially resolved electrochemical impedance spectra are obtained from which information about electrode processes and proton transport in the membrane is derived. In the first part the oxygen reduction reaction is investigated. Due to the absence of diffusion limitation, which is partly a result of the small electrode size, a low frequency inductive loop is observed, which is normally masked in macroscopic electrochemical impedance spectra. The influence of water formation from the oxygen reduction reaction at the cathode is discussed. The second part focuses on a hydrogen/oxygen fuel cell setup. A qualitative explanation is given for the necessity of an applied voltage in addition to the electrochemical potential. Electrochemical impedance spectra obtained at two different positions are compared and fitted based on a Randles-like equivalent circuit. A strongly inhomogeneous performance is observed which is attributed to the properties of the Nafion membrane. The electrolyte resistance and the Nernst impedance are restrictive parameters which describe the diffusion through the membrane. PMID- 23080436 TI - Synergy versus potency in the defensive secretions from nymphs of two pentatomomorphan families (Hemiptera: Coreidae and Pentatomidae). AB - One characteristic of true bugs (Heteroptera) is the presence of dorsal abdominal glands in the immature nymphal stages. These glands usually produce defensive chemicals (allomones) that vary among taxa but are still similar in closely related groups. Knowledge of the chemistry and prevalence of allomones in different taxa may clarify the evolution of these chemical defensive strategies. Within the infraorder Pentatomomorpha, the known secretions of nymphs of Pentatomidae tend to contain the hydrocarbon, n-tridecane, a keto-aldehyde, and an (E)-2-alkenal as the most abundant components. In the Coreidae, the dorsal abdominal gland secretions of nymphs often contain little or no hydrocarbon, and the most abundant keto-aldehyde and (E)-2-alkenal are often of shorter chain length than those of pentatomids. We hypothesized that the long chain compounds would be less potent than their shorter homologs, and that bugs that carry the former would benefit from a synergistic effect of n-tridecane. To test this hypothesis we used three different behavioral assays with ants. A predator-prey assay tested the deterrence of allomones toward predators; a vapor experiment tested the effectiveness of allomones in the gaseous phase toward predators; and application of allomones onto predators tested the effect of direct contact. The results substantiate the hypothesis of a synergistic effect between n-tridecane and longer chain keto-aldehyde and (E)-2-alkenal in deterring predators. The short chain keto-aldehyde 4-oxo-(E)-2-hexenal was highly effective on its own. Thus, it seems that different groups of the infraorder diverged in their strategies involving defensive chemicals. Implications of this divergence are discussed. PMID- 23080438 TI - "Near zero" catheter-related bloodstream infections: turning dreams into reality*. PMID- 23080437 TI - The effects of a newly developed miniaturized mechanical chest compressor on outcomes of cardiopulmonary resuscitation in a porcine model*. AB - OBJECTIVE: When the duration of cardiac arrest is prolonged, reperfusion of the vital organs by effective chest compression is the most important intervention for successful resuscitation. We investigated the effects of a newly developed miniaturized chest compressor on the outcomes of cardiopulmonary resuscitation. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University-affiliated animal research laboratory. SUBJECTS: Thirty male domestic pigs. INTERVENTIONS: Ventricular fibrillation was induced in 30 male domestic pigs weighing 35 +/- 2 kg. Cardiopulmonary resuscitation was initiated after 7 mins of untreated ventricular fibrillation. The animals were randomized to receive mechanical chest compression with a miniaturized chest compressor, a LUCAS device or a Thumper device. After 5 mins of cardiopulmonary resuscitation, a 150-J defibrillation was delivered. If resuscitation was not successful, cardiopulmonary resuscitation was continued for 2 mins before the next defibrillation. The protocol was continued until successful resuscitation or for a total of 15 mins of cardiopulmonary resuscitation. The animals were observed for 72 hrs after resuscitation. MEASUREMENTS AND MAIN RESULTS: The miniaturized chest compressor generated significantly greater coronary perfusion pressure, end tidal PCO2, carotid blood flow, and intrathoracic negative pressure, with significantly lower compression depth and fewer rib fractures when compared with both the LUCAS and Thumper devices. Both the miniaturized chest compressor and LUCAS devices required lower numbers of defibrillation for successful resuscitation when compared with the Thumper device. This was associated with lower prevalence of recurrent ventricular fibrillation and better postresuscitation myocardial and neurological function when compared with the Thumper device. CONCLUSIONS: The miniaturized chest compressor improves hemodynamic efficacy and the success of cardiopulmonary resuscitation with significantly less injury, which is as effective as the LUCAS device. It may provide a new option for cardiopulmonary resuscitation. PMID- 23080439 TI - Pediatric cardiopulmonary resuscitation outcomes: is bigger always better?*. PMID- 23080440 TI - Etomidate: buy now, pay later?*. PMID- 23080441 TI - The anti-arrhythmic potential of therapeutic hypothermia: another good reason for keeping your cool?*. PMID- 23080442 TI - To look or not to look: Is that the ultrasound question in venous thromboembolism after trauma?*. PMID- 23080443 TI - Resolving conflicting comparative effectiveness research in critical care*. PMID- 23080444 TI - Mirror mirror on the wall: physician and nurse perceptions of their quality of care for deteriorating patients*. PMID- 23080445 TI - Location, location, location--unraveling the nuances of innate immune regulation*. PMID- 23080446 TI - Mechanical devices for chest compression: an evolving process shedding light on mechanisms*. PMID- 23080447 TI - Clinically relevant animal models needed to advance state of the art fluid resuscitation*. PMID- 23080448 TI - A glass of wine: how good is good? The resveratrol lesson*. PMID- 23080449 TI - Is angiopoietin-2 the key piece in the sepsis puzzle?*. PMID- 23080450 TI - Cystic fibrosis transmembrane conductance regulator modulates acute lung injury: evidence from a genetic association study*. PMID- 23080451 TI - Introduction of a new tool to help assess parental needs surrounding the death of a child: will this help us do better?*. PMID- 23080452 TI - Changes in the inflammatory response following cardiac arrest: a matter of ischemia/reperfusion or induced hypothermia? PMID- 23080454 TI - High-frequency oscillatory ventilation and right ventricular function. PMID- 23080456 TI - The role of inflammatory mediators in the association of pulmonary edema with increased cardiac index and pulmonary vascular filling. PMID- 23080458 TI - Lumen nonpatency in the presence of competing risks. PMID- 23080460 TI - Transpulmonary thermodilution: the jury is out. PMID- 23080462 TI - Neuromuscular blocking agent for emergent tracheal intubation: more questions than answers. PMID- 23080464 TI - Not using neuromuscular blocking agents in emergent intubation should be a rarity. PMID- 23080466 TI - Polymerase chain reaction-based rapid screening method is the real tool to prevent methicillin-resistant Staphylococcus aureus infections in the intensive care unit. PMID- 23080468 TI - The association between intravascular fluid balance and patient outcomes in the intensive care unit. PMID- 23080469 TI - Intracranial monitoring and continuous data collection. PMID- 23080471 TI - Real availability of current devices in traumatic brain injury management. PMID- 23080473 TI - Defining the optimal target temperature following cardiac arrest. PMID- 23080475 TI - The use of customized TKA implants for increased efficiency in the OR. AB - Efficiency in surgical procedures saves time and money and can decrease medical complications. Several sources of inefficiency exist in the operating room, including preoperative and intraoperative. The instruments used during TKA are frequently redundant. Customized instruments and implants can improve efficiency by reducing steps. Additional benefits may include improved alignment and kinematics. This chapter addresses the various sources of inefficiency, provides suggestions to overcome them, and introduces the concept of customized guides and implants as a method to improve efficiency. PMID- 23080476 TI - Ventilators do not breathe. PMID- 23080478 TI - Unique eyelid manifestations in type 1 pseudohypoaldosteronism. PMID- 23080479 TI - Maternal use of SSRIs, SNRIs and NaSSAs: practical recommendations during pregnancy and lactation. AB - Selective serotonin reuptake inhibitors (SSRIs) are increasingly used during pregnancy and lactation, with 1.8-2.8% exposed pregnancies. Given the risks of untreated maternal depression for both mother and child, adequate treatment is essential. If pharmacological treatment with SSRIs is indicated, the fetal and neonatal effects of SSRIs have to be considered, as SSRIs cross the placenta and are excreted into breast milk. The overall risk of major congenital malformations during SSRI exposure in the first trimester does not appear to be greatly increased. Depending on the variability in pharmacokinetic properties between the different SSRIs and the individual drug metabolism of mother and child, SSRI exposure during late pregnancy can lead to serotonin reuptake inhibitor-related symptoms in up to 30% of exposed infants postnatally. Symptoms are generally mild and self-limited, but need observation during at least 48 h as some infants develop severe symptoms needing intervention. Limited data are available about the long-term neurodevelopmental outcomes after SSRI exposure during pregnancy and lactation, but currently, cognitive development seems normal, while behavioural abnormalities may be increased. In this article, the available clinical data are reviewed. Additionally, the authors provide a multidisciplinary guideline for the monitoring and management of neonates exposed to SSRIs during pregnancy and lactation. PMID- 23080480 TI - The impact of intrapersonal, interpersonal, and community factors on the identity formation of young adults with cancer: a qualitative study. AB - BACKGROUND: The purpose of this study was to examine how young adult cancer patients make sense of their experiences with cancer. METHODS: Semi-structured interviews were conducted with patients at an urban tertiary care center RESULTS: The sample for this study included 15 young adult cancer survivors. The ages of the participants ranged from 18 to 30 years. The sample was 67% female (n = 10) and 33% male (n = 5). The sample was 87% Caucasian (n = 13) and 13% Hispanic (n = 2). Fifty-three percent of the participants were between ages 18 and 23 years (n = 8), and 47% of the participants were between ages 24 and 30 years (n = 7). Three themes emerged from the data: intrapersonal change, interpersonal interactions, and role and identity in the hospital and the community. As they inevitably lose control in their lives, young adult patients seek to return to a familiar lifestyle that they consider as 'normal'. The formation of a revised identity and redefined set of norms allows the patients to regain control and express their individualism. CONCLUSIONS: This study contributes to our knowledge of the experiences of young adult cancer patients and survivors. The findings serve to inform young adults, caregivers, and health professionals on coping with illness and its aftermath. PMID- 23080477 TI - Brain injury following trial of hypothermia for neonatal hypoxic-ischaemic encephalopathy. AB - OBJECTIVE: The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic-ischaemic encephalopathy treated with hypothermia. DESIGN AND PATIENTS: Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18-22 months of age. RESULTS: Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. CONCLUSIONS: Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18-22 months following hypothermia for neonatal encephalopathy. PMID- 23080481 TI - Breathing irregularity during wakefulness associates with CPAP acceptance in sleep apnea. AB - PURPOSE: Individuals have different breathing patterns at rest, during wakefulness, and during sleep, and patients with sleep apnea are no different. The hypothesis for this study was that breathing irregularity during wakefulness associates with CPAP acceptance in obstructive sleep apnea (OSA). METHODS: From a 2007-2010-database of patients with a diagnostic polysomnography (PSG) and prescribed CPAP (n = 380), retrospectively, 66 patients who quit CPAP treatment at 6 months were identified. Among them, 27 OSA patients quit despite having no side effects for discontinuing CPAP (Group A) and were compared to a matched group (age, body mass index, and apnea-hypopnea index) with good 6-month CPAP adherence (Group B; n = 21). Five minutes of respiratory signal during wakefulness at the initial PSG were extracted from respiratory inductance plethysmography recordings, and measured in a blinded fashion. The coefficients of variation (CV) for the breath-to-breath inspiration time (T i), expiration time (T e), T i + T e (T tot), and relative tidal volume, as well as an independent information theory-based metric of signal pattern variability (mutual information) were compared between groups. RESULTS: The CV for tidal volume was significantly greater (p = 0.001), and mutual information was significantly lower (p = 0.041) in Group A as compared to Group B. CONCLUSIONS: Differences in two independent measures of breathing irregularity correlated with CPAP rejection in OSA patients without nasal symptoms or comorbidity. Prospective studies of adherence should examine traits of breathing stability. PMID- 23080482 TI - Ratiometric activatable cell-penetrating peptides provide rapid in vivo readout of thrombin activation. AB - In real time: thrombin activation in vivo can be imaged in real time with ratiometric activatable cell penetrating peptides (RACPPs). RACPPs are designed to combine 1) dual-emission ratioing, 2) far red to infrared wavelengths for in vivo mammalian imaging, and 3) cleavage-dependent spatial localization. The most advanced RACPP uses norleucine (Nle)-TPRSFL as a linker that increases sensitivity to thrombin by about 90-fold. PMID- 23080483 TI - The reliability, validity, and applicability of an English language version of the Mini-ICF-APP. AB - PURPOSE: This study aimed at establishing the validity and reliability of an English language version of the Mini-ICF-APP. METHODS: One hundred and five patients under the care of secondary mental health care services were assessed using the Mini-ICF-APP and several well-established measures of functioning and symptom severity. 47 (45 %) patients were interviewed on two occasions to ascertain test-retest reliability and 50 (48 %) were interviewed by two researchers simultaneously to determine the instrument's inter-rater reliability. Occupational and sick leave status were also recorded to assess construct validity. RESULTS: The Mini-ICF-APP was found to have substantial internal consistency (Chronbach's alpha 0.869-0.912) and all 13 items correlated highly with the total score. Analysis also showed that the Mini-ICF-APP had good test retest (ICC 0.832) and inter-rater (ICC 0.886) reliability. No statistically significant association with length of sick leave was found, but the unemployed scored higher on the Mini ICF-APP than those in employment (mean 18.4, SD 9.1 vs. 9.4, SD 6.4, p < 0.001). The Mini-ICF-APP correlated highly with the other measures of illness severity and functioning considered in the study. CONCLUSIONS: The English version of the Mini-ICF-APP is a reliable and valid measure of disorders of capacity as defined by the International Classification of Functioning. Further work is necessary to establish whether the scale could be divided into sub scales which would allow the instrument to more sensitively measure an individual's specific impairments. PMID- 23080484 TI - Sympathetic neurons modulate the beat rate of pluripotent cell-derived cardiomyocytes in vitro. AB - Although stem cell-derived cardiomyocytes have great potential for the therapy of heart failure, it is unclear whether their function after grafting can be controlled by the host sympathetic nervous system, a component of the autonomic nervous system (ANS). Here we demonstrate the formation of functional connections between rat sympathetic superior cervical ganglion (SCG) neurons and pluripotent (P19.CL6) cell-derived cardiomyocytes (P19CMs) in compartmentalized co-culture, achieved using photolithographic microfabrication techniques. Formation of synapses between sympathetic neurons and P19CMs was confirmed by immunostaining with antibodies against beta-3 tubulin, synapsin I and cardiac troponin-I. Changes in the beat rate of P19CMs were triggered after electrical stimulation of the co-cultured SCG neurons, and were affected by the pulse frequency of the electrical stimulation. Such changes in the beat rate were prevented when propranolol, a beta-adrenoreceptor antagonist, was added to the culture medium. These results suggest that the beat rate of differentiated cardiomyocytes can be modulated by electrical stimulation of connected sympathetic neurons. PMID- 23080485 TI - Low prevalence of transmitted genetic drug resistance in a cohort of HIV infected naive patients entering antiretroviral treatment programs at two sites in northern South Africa. AB - Infection with drug resistant viruses influences the outcome of antiretroviral therapy (ART). This study was carried out to determine the transmitted genetic drug resistance profile in a cohort of patients prior to initiation of treatment at two treatment sites in northern South Africa. These study sites were among the first to benefit from antiretroviral drugs in this region. Data on HIV drug resistance are also limited in northern South Africa; and resistance testing prior to initiation of treatment is not undertaken. In 2008, 80 protease and 80 reverse transcriptase nucleotide sequences obtained from 80 patients were analyzed for genetic drug resistance using the calibrated population resistance tool for transmitted drug resistance. Viral genetic subtypes were determined by phylogenetic analysis. Two drug resistance mutations (M41L and K103N) were detected in two different patients (2.5%; 95% CI: 0.0077-0.0863). Twenty-three sequences (29%) harbored at least one secondary mutation in the reverse transcriptase gene; while all sequences had at least one minor mutation in the protease gene. Phylogenetic analysis of the protease and reverse transcriptase genes showed that 79 out of 80 viruses were HIV-1 subtype C, and one was an A1/C recombinant. The observations suggest that after 4 and 8 years access to ART in Mankweng and the Bela Bela communities respectively, drug resistance mutations in the naive population was low. Regular studies are needed to update information on drug resistant viruses in treatment naive patients to inform better treatment policies. PMID- 23080486 TI - Unusual substitutions in HIV-1 vif from children infected perinatally without progression to AIDS for more than 8 years without therapy. AB - The HIV-1 vif gene encodes for an accessory protein that is central for virus replication due mainly to its capacity to counteract the antiviral action of host APOBEC3 restriction factors. In order to evaluate whether HIV-1 vif alterations account for a delayed progression to AIDS in children infected perinatally, the vif genes from a group of 11 patients who exhibited an extremely slow disease progression (slow progressors) were studied by direct sequencing. In addition, the vif genes from a group of 93 children with typical disease progression (typical progressors) were analyzed for comparison. Phylogenetic analysis indicated that sequences from slow progressors did not have a common origin, discarding a shared ancestor of reduced virulence. There were no differences in the diversity between the vif genes from slow and typical progressors. No gross defects showing a clear distinction among sequences from both groups of children were found. However, in the deduced Vif proteins, changes V13I, V55T, and L81M were observed only in sequences from slow progressors. By analyzing sequences stored in databases, these mutations were determined as unusual substitutions occurring at highly conserved Vif sites across different HIV-1 clades, but were observed with an increased frequency in sequences from elite controllers. These mutations were in the Vif regions reported as relevant for protein activity. These findings suggest that the Vif sequences from slow progressors carry unusual substitutions, which may alter the protein function and may contribute to viral attenuation. PMID- 23080487 TI - Natural evolution of CD4+ cell count in patients with CD4 >350 or >500 cells/mm3 at the time of diagnosis according to HIV-1 coreceptor tropism. AB - The HIV-1 coreceptor usage may play a critical role in AIDS pathogenesis and the X4-using viruses are considered to be more pathogenic than the R5-tropic viruses. These observations may influence the therapeutic decisions by asking for an earlier antiretroviral (ARV) treatment for the patients infected by the X4-tropic viruses compared with those infected by the R5-tropic viruses. The natural evolution of CD4+ cell count for 109 non-treated patients infected by the R5- or X4-tropic HIV-1 viruses with CD4+ >350 and >500 cells/mm(3) at time of diagnosis was compared until the initiation of an ARV regimen. The coreceptor usage was determined from the V3 env region sequence by Geno2Pheno (false positive rate 10%). A mixed linear regression model to analyse the CD4+ data with tropism as fixed effect in the model was used. Overall, 93 (85.3%) and 16 (14.7%) were infected by R5- and X4-tropic viruses, respectively. The median age, baseline CD4+ cell count, and viral load were 34 years (IQR: 30-42), 523 cells/mm(3) (IQR: 420-604), and 4.5 log(10) copies/ml (IQR: 3.9-5.0), respectively. There was no statistical difference in time to progression between the patients harboring R5- or X4-tropic viruses. The same results were observed for the sub-group of patients with CD4+ cell count >500 cells/mm(3). The virus tropism has no impact on the CD4+ cell count evolution in these HIV-1 patients diagnosed with CD4+ >350 or >500 cells/mm(3) suggesting that the tropism determination at time of diagnosis does not seem to be a useful tool to predict the clinical progression. PMID- 23080488 TI - Molecular epidemiology of recent HIV-1 infections in southern Poland. AB - The genetic diversity of human immunodeficiency virus type 1 (HIV-1) offers an opportunity to track the development of the epidemic across different populations. Viral pol gene fragments from 55 individuals of Polish origin with recent HIV-1 infection identified in 2008-2010 in four Polish cities were analyzed. Viral sequences were compared with sequences from 100 individuals (reference group) infected before 2004. Viral spread among groups with different HIV transmission categories was compared using a phylogenetic approach. The majority of sequences from individuals with recent infection were subtype B (93%) within which four transmission clusters (18% of samples) were detected. Samples from men infected through sex between men and from persons infected through injecting drugs were broadly separated (P < 0.0001), while samples from individuals infected by heterosexual contacts were dispersed uniformly within phylogenetic tree (P = 0.244) inferred from viral sequences derived from individuals infected recently and the reference group. The percentage of samples from persons infected by heterosexual contacts which clustered with samples from men infected through sex between men was not significantly higher for those with recent infection (47%), compared to the reference group (36%). In conclusion, men infected by sex between men and individuals infected through injecting drugs appear to form separate HIV transmission networks in Poland. The recent spread of HIV-1 among persons infected with subtype B by heterosexual contacts appears to be linked to both these groups. PMID- 23080489 TI - Monitoring the emergence of resistance mutations in patients infected with HIV-1 under salvage therapy with raltegravir in Rio de Janeiro, Brazil: a follow-up study. AB - The present study describes a follow-up of a prospective and observational cohort of patients infected with HIV-1 and treated with raltegravir for salvage therapy in Brazil. Two groups of patients were analyzed: switching from T20 to RAL (Group 1, n = 9) and salvage therapy containing RAL (Group 2, n = 10). Blood samples were drawn for CD4(+) T-cell counts and HIV-1 viral load determinations. Protease, reverse transcriptase, and integrase genotyping were performed at baseline and at the time of virologic failure. CD4(+) T-cells increased at 6 and 12 months in both groups; HIV-1 viral load was continuously suppressed for Group 1, and for Group 2 it significantly decreased after starting a RAL-containing regimen. Three out of 10 patients from Group 2 could not suppress HIV-1 viral load. The mutations Q148H + G140S were observed for two patients and for the third patient only mutations to PR/RT inhibitors were detected. The genotypic sensitivity score (GSS) was analyzed for all patients of Group 2 and both patients who developed resistance to raltegravir presented a GSS < 2.0 for the RAL-containing scheme, which could be associated to the lack of effectiveness of the proposed scheme. The present study describes, for the first time in Brazil, the close follow-up of a series of patients using a raltegravir-containing HAART, showing the safety of the enfuvirtide switch to RAL and the effectiveness of a therapeutic regimen with RAL in promoting immune reconstitution and suppressing HIV replication, as well as documenting the occurrence of resistance to integrase inhibitors in the country. PMID- 23080490 TI - Influence of age and CD4+ T cell counts on the prevalence of genital human papillomavirus infection among HIV-seropositive men who have sex with men in Taiwan. AB - This study aimed to examine the baseline prevalence of genital human papillomavirus (HPV) infection among human immunodeficiency virus (HIV) seropositive men who have sex with men in Taiwan and to determine the association of age and CD4+ T cell counts with HPV infection. In 2010, 305 men who have sex with men infected with HIV and 100 HIV-seronegative men who have sex with men were recruited. Genital swabs were collected and 37 HPV genotypes were detected using linear array HPV genotyping. HPV infection was present in 45.3% of the patients infected with HIV and in 18% of the HIV-negative subjects (P < 0.001). HPV types 52, 51, and 16 were the most commonly identified oncogenic types. Oncogenic HPV types were identified in 31.2% of the patients infected with HIV and in 13% of the seronegative subjects (P < 0.001). Adjusted odd ratios (ORs) for the detection of any HPV type were 2.9 (95% confidence interval [CI], 1.4 5.9) for men who have sex with men aged 30-34 and 2.1 (95% CI, 1.1-4.3) for those aged >35 compared with that for those aged <25. ORs were 2.8 (95% CI, 1.0-7.4) for a CD4+ T cell count of 200-350 cells/ul and 8.5 (95% CI, 2.9-24.5) for a CD4+ T cell count of <200 cells/ul compared with that for seronegative subjects. In conclusion, this novel HPV study, carried out in Northern Taiwan on men who have sex with men, revealed that age and immune state were associated significantly and independently with HPV infection. PMID- 23080491 TI - Performances of four fourth-generation human immunodeficiency virus-1 screening assays. AB - Fourth-generation human immunodeficiency virus-1 (HIV-1) screening assays have improved sensitivity, but vary in performance characteristics. The purpose of this study was to evaluate four different fourth-generation HIV-1 assays. These assays included the AxSYM HIV Ag/Ab Combo (Abbott diagnostics, Delkenheim, Germany), ARCHITECT HIV Ag/Ab Combo (Abbott), Elecsys 2010 HIV Combi (Roche Diagnostics GmbH, Mannheim, Germany), and Elecsys HIV Combi PT (Roche). A total of 1,306 samples that included 1,225 clinical samples and 81 samples consisting of seroconversion panels, an HIV-1 p24 antigen sensitivity panel, and dilution series of HIV-1 lysates and HIV-1 antibodies were tested. All of the assays had sensitivities of 100% on clinical samples. The specificities of the AxSYM, ARCHITECT, Elecsys 2010 HIV Combi, and Elecsys HIV Combi PT were 99.6, 99.6, 99.0, and 99.5%, respectively. Of the 81 samples with different levels of HIV antigen or antibody and/or subtypes, Elecsys HIV Combi PT and ARCHITECT HIV Ag/Ab Combo showed better analytical sensitivities than the other two assays. In summary, the performance characteristics of AxSYM, ARCHITECT, and Elecsys HIV Combi PT were comparable and satisfactory for clinical samples. ARCHITECT HIV Ag/Ab Combo and Elecsys HIV Combi PT have the higher analytical sensitivities, and would be preferable for reducing the window period. PMID- 23080492 TI - Influence of B cells in liver fibrosis associated with hepatitis B virus harboring basal core promoter mutations. AB - The development of the liver disease in chronic hepatitis B with common viral variants can be determined through the interaction between the virus and the host immune response. B cells constitute half of the intrahepatic lymphocyte population with an impact on fibrosis. A proliferation-inducing ligand (APRIL) has been shown to have a co-stimulatory activity on B cells. For this study HBV DNA was amplified and then sequenced to show the presence of the basal core promoter (BCP) mutations in the serum from 57 patients with chronic hepatitis B. The range of IgD-positive B cells was detected by immunohistochemistry in liver biopsies; and patients serum was assayed for APRIL levels by enzyme immunoassay. Twenty-seven patients (47.4%) harbored the A1762T-G1764A BCP mutations. Coefficients of logistic regression showed that the effect of increasing IgD positive B cells in rising odds of the liver disease is the same in the patients with BCP mutation A1762T-G1764A and in the patients without mutation, nevertheless the effect of APRIL is not similar in these two groups of patients. Logistic regression in patients with BCP A1762T-G1764A mutations demonstrated that increasing one score of APRIL decreased the odds of fibrosis stage about 8%. These results suggest that in infection with viral variants of hepatitis B virus, the population of IgD-positive B cells may play a decisive role in later stages of the liver disease which is reduced by APRIL in chronic hepatitis patients with BCP mutations. PMID- 23080493 TI - Case report: detection of a hepatitis B surface antigen variant emerging in an elderly patient after an ischemic cerebral vascular accident. AB - HBV reactivations are observed frequently in patients with past hepatitis B infection receiving cytotoxic and/or immunosuppressive chemotherapy for hemato oncological malignancies or autoimmune diseases. Recent ischemic stroke was shown to induce immunodepression by misunderstood mechanisms. To our knowledge, the association between HBV reactivation and ischemic stroke has not been reported before. This study reports the case of an anti-HBs- and anti-HBc-positive patient who presented HBV reactivation in a context of recent ischemic stroke, with no other intercurrent iatrogenic phenomenon or usual immunosuppressive pathology. PMID- 23080494 TI - Mutations in the major hydrophilic region (MHR) of hepatitis B virus genotype C in North China. AB - Hepatitis B virus (HBV) can evolve by mutations in the major hydrophilic region (MHR) of the HBV surface antigen (HBsAg) to permit its escape from neutralization by antibodies such as HBV surface antibody (anti-HBs) and from host immune responses. This study investigated the prevalence and pattern of MHR mutations in North China and the clinical correlations of these mutations. The MHRs of 161 HBsAg-positive patients were amplified using nested PCR, and directly sequenced to identify MHR mutations. It was showed that among the 161 patients infected with HBV genotype C in North China, the overall frequency of MHR mutation was 46.6%. Furthermore, MHR mutations were associated with high white blood cell counts (P = 0.025), high bilirubin levels (P = 0.048), and cirrhosis (P = 0.010). The most frequent mutations in patients with both HBsAg-positive and anti-HBs positive were located in subregion 1 and 3 of MHR, specifically, residue Q101 (29.9%) and I126 (70.6%), which was different from the mutation pattern found in Western Europe and the United States. Taken together, these data indicated important virological and clinical aspects of HBV evolution in terms of the surface gene of genotype C, which might be important for its response to the currently available HBV vaccine. PMID- 23080495 TI - Prevalence of viral hepatitis B and C in riverside communities of the Tucurui Dam, Para, Brazil. AB - Epidemiologically, the relevance of infection caused by hepatitis viruses is related mainly to their wide geographic distribution and the large number of infected individuals in all parts of the world. In this study, 668 residents from the islands around the Tucurui Dam were selected. Blood samples were collected for investigation of serological markers (HBsAg, total anti-HBc, anti-HBS, and anti-HCV) by enzyme immunoassays. HCV-positive subjects were tested using RT-PCR and RFLP for the identification of viral genotypes. Among the 668 subjects studied, 1.9% were HBsAg positive, 28% were total anti-HBc positive, and 41.9% were anti-HBs positive. The anti-HBs marker alone (vaccine response) was detected in 25.7% of the volunteers. Anti-HCV antibody was detected in 2.2% of the subjects and genotype 1 was the predominant genotype (70%). The results indicate an intermediate level of HBV and HCV endemicity in the region studied, as well as low HBV vaccination coverage. PMID- 23080496 TI - A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy. AB - Interleukin-28B (IL28B) polymorphisms are associated with viral response to peginterferon and ribavirin (RBV) in chronic hepatitis C (HCV). Their recognition represents a breakthrough in the understanding of the role of the host in viral eradication. How these polymorphisms determine viral eradication is unknown. The IL-28B variants are hypothesized to have a differential impact on HCV quasispecies evolution during treatment with pegylated interferon (PEG-IFN) and RBV. In this study, HCV RNA levels were measured at early time points in 33 naive genotype 1 hepatitis C patients and clonal analysis of the entire NS5A region was performed on sera from baseline and Day 7. Site rs12979860 polymorphisms were determined by direct sequencing of PCR products and classified into CC, CT, and TT and were identified in 13, 11, and 9 patients, respectively. The CC polymorphism more commonly was seen in Whites versus Blacks [12/21 (57%) vs. 1/12 (8%), P = 0.009] and HIV-infected versus mono-infected [13/25 (52%) vs. 0/8 (0%), P = 0.009]. Patients with CC and non-CC had similar baseline viral loads. More patients with the CC polymorphism had amino acid substitutions in NS5A compared to non-CC patients. Despite similar baseline viral diversity, by Day 7, significantly more patients with CC had higher non-synonymous substitution values compared to non-CC (P = 0.02). Chronic hepatitis C patients with the CC IL28B polymorphism have a higher number of amino acid substitutions in the NS5A region and early viral evolution due to greater interferon induced selective pressure during this critical period of treatment. PMID- 23080497 TI - Relationship between cervical disease and infection with human papillomavirus types 16 and 18, and herpes simplex virus 1 and 2. AB - Persistent infection with high-risk HPV, particularly Type HPV 16 and 18, is necessary in the development of cervical cancer, but apart from HPV infection, other causative factors of most cervical cancers remain unknown. The aim of this study was to determine the prevalence of HPV 16 and HPV 18 and HSV 1 and HSV 2 in cervical samples, and to assess the role of HSVs in cervical carcinogenesis. Two hundred thirty-three healthy controls and 567 cases (333 of cervicitis, 210 of cervical intraepithelial neoplasia, and 24 of squamous cell carcinoma) in cervical exfoliative cells were tested for HPV 16, HPV 18, HSV 1, and HSV 2 DNA using the triplex real-time polymerase chain reaction method. In contrast to healthy women, positive rate of HPV is related significantly to cervical lesions (odds ratios (ORs) = 4.1, P < 0.01 for cervical intraepithelial neoplasia; ORs = 24.9, P < 0.01 for squamous cell carcinoma), but not cervicitis (ORs = 2.3, P > 0.05). HSV 2 prevalence in cervical intraepithelial neoplasia and squamous cell carcinoma was higher than in healthy women (ORs = 4.9, P < 0.05 for cervical intraepithelial neoplasia; ORs = 4.7, P < 0.05 for squamous cell carcinoma). HSV 2 coinfection with HPV in cervical intraepithelial neoplasia and squamous cell carcinoma was strongly higher than in healthy women (ORs = 34.2, P < 0.01 for cervical intraepithelial neoplasia; ORs = 61.1, P < 0.01 for squamous cell carcinoma). The obtained results indicated that the presence of HPV is associated closely with cervical cancer, and that HSV 2 infection or co-infection with HPV might be involved in cervical cancer development, while HSV 1 might not be involved. PMID- 23080498 TI - Low IgG avidity and ultrasound fetal abnormality predict congenital cytomegalovirus infection. AB - Cytomegalovirus (CMV) causes congenital infection with high mortality and morbidity rates in affected neonates. The aim of this study was to assess whether prenatal clinical or laboratory findings in pregnant women who had high risks for primary CMV infection predicted the presence of congenital infection. Fifty pregnant women who had serum CMV IgG and positive or borderline tests for serum CMV IgM were included in this prospective study. Serum IgG avidity was measured, and PCR was conducted for CMV DNA in maternal serum, urine, and uterine cervical secretion. All neonates underwent PCR testing for CMV DNA in the urine for the presence of congenital infection. Risk factors were compared between congenital infection group and group without congenital infection. As a result, nine neonates (18%) were diagnosed as having congenital infection. The frequencies of ultrasound fetal abnormality and positive test for CMV DNA in cervical secretion, CMV IgM titer and IgM/IgG ratio in the congenital infection group were significantly higher than those in the group without congenital infection. Conversely, IgG avidity index in the congenital infection group was significantly lower than that in the group without congenital infection. By multivariate logistic regression analyses, IgG avidity index (Odds ratio 0.91, 95% CI: 0.83 0.99) and ultrasound fetal abnormality (291.22, 2.72-31125.05), were selected independently as significant signs predictive of congenital CMV infection. Among pregnant women with positive or borderline tests for CMV IgM, when they have findings of low serum CMV IgG avidity or ultrasound fetal abnormality, the probability of congenital CMV infection may increase. PMID- 23080499 TI - Cytomegalovirus-associated cerebral sinus vein thrombosis. AB - Cytomegalovirus (CMV)-associated thrombosis has been reported many times in the medical literature, and most patients had deep vein thrombosis and/or pulmonary embolism. CMV-associated cerebral sinus vein thrombosis has been reported only twice. We present an immunocompetent patient with CMV-associated cerebral sinus vein thrombosis and no other thrombosis risk factors. This is another example of the pro-thrombotic features of CMV. Physicians should be alert for symptoms and signs of acute CMV infection in patients with thrombosis. PMID- 23080500 TI - Incidence of Alpha-Herpes virus induced ocular disease in Suriname. AB - Herpes simplex virus (HSV) infection of the corneal stroma is the most prominent cause of scar formation impairing visual acuity and HSV keratitis is the leading cause of corneal opacity throughout the world. Suriname lacked test systems for microbial causes of ocular disease, therefore a polymerase chain reaction-based Herpes virus assay was introduced, enabling prompt recognition, and timely treatment, preventing progressive eye damage. The incidence and epidemiology of Herpes simplex virus type 1 (HSV-1), type 2 (HSV-2), and varicella zoster virus (VZV) in ocular disease in Suriname was assessed. In a cross-sectional prospective study, ocular swabs were collected from 91 patients with a presumptive alpha-Herpes virus ocular infection attending the Academic Hospital between November 2008 and August 2010 and were tested by a PCR-based alpha-Herpes virus assay. Alpha-Herpes virus ophthalmic infections were caused predominantly by HSV-1 with a prevalence of 31%. The prevalences of VZV, HSV-2, and a mixed HSV 1/HSV-2 infection were 4%, 3%, and 2%, respectively. The first reported annual incidence of herpetic induced ocular disease in Suriname was estimated at 11.4 per 100,000 person-years (95% CI, 4.8-18.1). No clear age, ethnic or gender dependent difference in incidence was observed. The information obtained on alpha Herpes virus positive ocular infections and the distribution of subtypes provided the first insight in the South American situation of alpha-Herpes virus induced ocular disease. PMID- 23080501 TI - Elevated post-transfusion serum transaminase values associated with a highly significant trend for increasing prevalence of anti-Vesivirus antibody in Korean patients. AB - A highly significant increase in anti-Vesivirus (family Caliciviridae) antibody prevalence, along the axis from healthy blood donors; donors with elevated transaminase; patients with clinical hepatitis; and patients with post transfusion/dialysis hepatitis, has been reported in human sera from the USA and Europe. Asian samples have now been tested retrospectively using serology and enzyme immunoassay (EIA) with a Vesivirus partial-capsid antigen expressed as a fusion protein. Anti-vesiviral antibodies were measured by optical densities (OD(650)) and compared in patients separated by age, gender and Groups A-F as follows: Control Group A, an Experimental Group B, which was divided further into Group C, patients with elevated enzymes (alanine transaminase (ALT), aspartate transaminase (AST), and gamma-glutamyl transpeptidase (gamma-GT); Group D, patients receiving transfused blood; Group E, patients with high enzyme levels after transfusion; and Group F, hepatitis B and C positive patients. Using multivariate logistic regression analyses, a significantly greater proportion of patients receiving transfusion(s), were positive for anti-Vesivirus antibody compared with non-transfused patients (P = 0.008; OR: 3.86, 95% CI: 1.43-10.43). Also, anti-Vesivirus antibody was significantly associated with elevated biochemical liver function tests: ALT >= 20 IU or AST >= 120 IU (P = 0.017; OR: 4.23, 95% CI: 1.30-13.80). In the blood transfusion group, anti-Vesivirus antibody was significantly correlated with high enzyme levels (ALT, P = 0.018; AST, P = 0.010; gamma-GT, P = 0.020). These data provide serologic evidence of vesiviral transfusion-transmission-associated disease, which could include infection of any organ system where cytopathology resulted in high levels of either ALT or AST. PMID- 23080502 TI - Relationship between beta-herpesviruses reactivation and development of complications after autologous peripheral blood stem cell transplantation. AB - The relationship between beta-herpesviruses reactivation and the development of complications after autologous peripheral blood stem cell transplantation was investigated. Viral genomic sequences were detected by the polymerase chain reaction, virus-specific antibodies by ELISA, and human herpesvirus (HHV)-6 variants by restriction endonuclease analysis. Virus reactivation, serum levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, soluble IL-2 receptor (sIL-2R), IL-2, and IL-4 were compared with clinical features in 44 patients before and after transplantation. Anti-CMV and anti-HHV-6 antibodies were found in 70.5% and 81.8% of patients, respectively. The frequency of plasma viremia was significantly higher in patients after transplantation (41% vs. 11.4%). Reactivation of more than one virus was identified in 55.6% of patients and reactivation of HHV-7 alone in 44.4%. In cases of concurrent infection, HHV-7 was reactivated before HHV-6, and both HHV-6 and HHV-7 were reactivated before CMV. There was a significant increase in HHV-6 load in peripheral blood leukocytes DNA during viremia. In all cases HHV-6B variant was detected. Complications after transplantation occurred in 27.3% of patients and virus reactivation was detected in all patients with complications. The significant increases in the rate of HHV-6 and HHV-7 reactivation and in serum levels of TNF alpha, IL-1beta, and sIL-2R, as well as aggravated immunosuppression, suggest that both viruses were involved in the complications after autologous peripheral blood stem cell transplantation, via their immunomodulatory activity. The kinetics of reactivation suggests a potential role of HHV-7 as a co-factor of HHV 6 reactivation, and of both HHV-6 and HHV-7 as co-factors of CMV reactivation. PMID- 23080503 TI - Molecular study of human herpesvirus 6 and 8 involvement in coronary atherosclerosis and coronary instability. AB - Several lines of evidence suggest the involvement of infectious agents in the pathogenesis of atherosclerosis. Furthermore, a correlation between infection driven inflammatory burden and acute manifestation of coronary artery disease has been hypothesized. The aim of this work was to assess whether human herpesvirus (HHV)-6 and HHV-8, two DNA viruses with a distinct tropism for endothelium and lymphocytes, may be associated with coronary instability. An age- and gender matched cross-sectional study was undertaken in 70 patients with testing of plasma HHV-6 and HHV-8 DNA load in different cardiovascular clinical settings: 29 patients with acute myocardial infarction, 21 patients with stable coronary artery disease, and 20 patients without coronary and carotid artery atherosclerosis subjected to cardiac valve replacement. In all patients, HHV-6 and HHV-8 plasma DNA was tested by using highly sensitive, calibrated quantitative real-time PCR assays which employ a synthetic DNA calibrator to adjust for DNA extraction and amplification efficiency. HHV-8 viremia was undetectable in all three groups. HHV-6 viremia was detected in a substantial fraction of the samples examined (18.6%) without significant differences among the three groups (ST segment elevation myocardial infarction: 17.2%; stable coronary artery disease: 14.3%; patients without coronary and carotid artery atherosclerosis: 25%). Furthermore, no significant differences in plasma HHV-6 load were observed amongst the three groups of patients. These findings indicate that coronary instability is not associated specifically with active HHV-6 or HHV 8 infection. However, an unusually high rate of active HHV-6 infection was documented among patients without atherosclerosis admitted to hospital with cardiac disease. PMID- 23080504 TI - Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. AB - Valganciclovir has been reported to improve physical and cognitive symptoms in patients with chronic fatigue syndrome (CFS) with elevated human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) IgG antibody titers. This study investigated whether antibody titers against HHV-6 and EBV were associated with clinical response to valganciclovir in a subset of CFS patients. An uncontrolled, unblinded retrospective chart review was performed on 61 CFS patients treated with 900 mg valganciclovir daily (55 of whom took an induction dose of 1,800 mg daily for the first 3 weeks). Antibody titers were considered high if HHV-6 IgG >= 1:320, EBV viral capsid antigen (VCA) IgG >= 1:640, and EBV early antigen (EA) IgG >= 1:160. Patients self-rated physical and cognitive functioning as a percentage of their functioning prior to illness. Patients were categorized as responders if they experienced at least 30% improvement in physical and/or cognitive functioning. Thirty-two patients (52%) were categorized as responders. Among these, 19 patients (59%) responded physically and 26 patients (81%) responded cognitively. Baseline antibody titers showed no significant association with response. After treatment, the average change in physical and cognitive functioning levels for all patients was +19% and +23%, respectively (P < 0.0001). Longer treatment was associated with improved response (P = 0.0002). No significant difference was found between responders and non-responders among other variables analyzed. Valganciclovir treatment, independent of the baseline antibody titers, was associated with self-rated improvement in physical and cognitive functioning for CFS patients who had positive HHV-6 and/or EBV serologies. Longer valganciclovir treatment correlated with an improved response. PMID- 23080505 TI - Comparative study of molecular and antigenic characterization for intratypic differentiation (ITD) of poliovirus strains. AB - This study was designed to compare the sensitivity of a Sabin vaccine strain specific PCR assay and an enzyme-linked immunosorbent assay with polyclonal cross absorbed antisera (PAb-E) for intratypic differentiation (ITD) of polioviruses (PVs). These were used for the definitive characterization of the strains. Poliovirus strains isolated in L20B and RD cell lines were subjected to both PCR and ELISA. Both PCR and ELISA identified 3 (13.6%) out of 22 isolates, respectively as poliovirus Sabin 1. PCR identified 4 (18.2%) out of 22 isolates as poliovirus Sabin 2 and ELISA identified 2 (9.1%) out of 22 isolates as poliovirus Sabin 2. None of the two assay identified poliovirus Sabin 3. Both PCR and ELISA identified 12 (54.5%) out of 22 isolates, respectively as wild poliovirus (WPV) 1. None of the assays identified any of the isolates as WPV 2 and 3. Only PCR assay was able to identify the mixture of two poliovirus Sabin serotypes (a mixture of Sabin 1 and 2) and two mixtures of poliovirus Sabin 2 and 3. In this study, only ELISA was able to identified two invalid results. Invalid results observed in this study are of important practical implication to the emergence of vaccine-derived poliovirus. This may have epidemic potential. Hence, the two ITD assays are of paramount importance for identification of PVs. It is therefore recommended in line with WHO guideline that at least two methods be used for the ITD of poliovirus isolates, and each method should be based on a different principle (i.e., antigenic and genetic properties). PMID- 23080506 TI - Surveillance of 16 respiratory viruses in patients with influenza-like illness in Nanjing, China. AB - Much less is known about the etiology of influenza-like illness in China. A continuous surveillance of 16 respiratory viruses was conducted from November 2010 to October 2011 of outpatients with influenza-like illness in Nanjing, China. The two largest general hospitals and a provincial virus laboratory in Nanjing participated in this study. Throat swabs were collected from outpatients during medical visits for influenza-like illness and were tested for 16 respiratory viruses using PCR. Three hundred seventeen viruses were detected in samples from 246 (50.6%) patients with influenza-like illness. The viruses found mostly commonly were influenza, rhinovirus, hCoV HKU1, and adenovirus. The identification rates of respiratory viruses differed significantly among different sampling seasons (P = 0.0002). The rates of influenza A and hCoV HKU1 were much higher during the influenza-like illness winter peak than during the influenza-like illness summer peak and other months. Co-infections were detected in 57 (11.7%) patients and were found most commonly in adults older than 60 years. RSV was detected in 5.9% and 2.6% of patients who were 0-5 and 6-15 years old, respectively, but was not detected in other age groups. This study confirmed that multiple respiratory viruses may circulate concurrently in the population and account for a large proportion of influenza-like illness. In addition to influenza virus, hCoV HKU1 may be associated with the influenza-like illness winter peak in Nanjing, China. PMID- 23080507 TI - A study of the genetic variability of human respiratory syncytial virus in Croatia, 2006-2008. AB - Human respiratory syncytial virus (HRSV) is a common etiological agent of acute lower respiratory tract disease in infants. The molecular epidemiology of HRSV in Croatia over four consecutive seasons (from 2006 to 2008) was investigated. A total of 72 HRSV samples were chosen from 696 screened cases in a pediatric clinic in Zagreb. Molecular characterization of HRSV revealed the predominance of HRSV group B viruses in the first two epidemic seasons and HRSV group A viruses in the next two seasons. According to the phylogenetic analysis, NA1 and BA9 were the predominant circulating HRSV genotypes detected during the study. Overall, 82.9% of all HRSV A strains belonged to the NA1 genotype. The HRSV B genotype BA9, detected in two consecutive seasons (2006 and 2007), was the predominant circulating HRSV B genotype, accounting for 80.6% of all HRSV B strains. This study provides data on the circulation pattern of HRSV genotypes in Croatia and their molecular characterization. PMID- 23080509 TI - Genotyping of rotaviruses detected in children admitted to hospital from Faisalabad Region, Pakistan. AB - Rotavirus infection is very common in developing countries and occurs at least once in children under the age of 5 years. The rate of detection of rotavirus infection in various age groups (0-5 years) in patients with gastroenteritis admitted to hospital from the Faisalabad region, Pakistan is reported. Out of 300 fecal samples, 189 (57.3%) were positive for rotavirus by immunoassay. Patients aged 7-12 months (35.4%) were infected most commonly followed by the age group 0 6 months (28%). Different genotypes of rotavirus were identified by hemi-nested RT-PCR. The most common genotype was G1P[8] (25.3%), followed by G1P[6] (21.1%). Other genotypes were G1P[9], G2P[6], G9P[10]), G3P[8] (1.5%), and G9P[11] (1%). There were two (1%) cases of mixed G genotype, one patient with two genotypes G1, G10 and another patient with 3 genotypes G1, G10, and G12. There were 6 (3.1%) cases of mixed P genotypes, 3 P[4], P[11] and 3 P[8], P[11]. These results provide an outline of rotavirus infection in this area for the first time. PMID- 23080508 TI - Phylogenetic analysis of probable non-human genes of group A rotaviruses isolated from children with acute gastroenteritis in Belem, Brazil. AB - Rotaviruses (RVs) are the main cause of acute viral gastroenteritis in both humans and young animals of various species such as calves, horses, pigs, dogs, cats, and birds. The genetic diversity of RVs is related to a variety of evolutionary mechanisms, including point mutation, and genome reassortment. The objective of this study was to characterize molecularly genes that encode structural and nonstructural proteins in unusual RV strains. The clinical specimens selected for this study were obtained from children and newborn with RV gastroenteritis, who participated in research projects on viral gastroenteritis conducted at the Evandro Chagas Institute. Structural (VP1-VP4, VP6, and VP7) and nonstructural (NSP1-NSP6) genes were amplified from stool samples by the polymerase chain reaction and subsequently sequenced. Eight unusual RV strains isolated from children and newborn with gastroenteritis were studied. Reassortment between genes of animal origin were observed in 5/8 (62.5%) strains analyzed. These results demonstrate that, although rare, interspecies (animal human) transmission of RVs occurs in nature, as observed in the present study in strains NB150, HSP034, HSP180, HST327, and RV10109. This study is the first to be conducted in the Amazon region and supports previous data showing a close relationship between genes of human and animal origin, representing a challenge to the large-scale introduction of RV vaccines in national immunization programs. PMID- 23080510 TI - Molecular characterization of group A rotavirus found in elderly patients in Ireland; predominance of G1P[8], continued presence of G9P[8], and emergence of G2P[4]. AB - Rotavirus is a major cause of gastroenteritis in young children worldwide. There have been several recent reports concerning rotavirus isolation from adults, particularly in the elderly, presenting with gastroenteritis. In this study, the authors report on rotavirus outbreaks in five separate elderly care facilities between April, and June 2011 in Ireland. The following genotypes were detected; G1P[8] (n = 5/11), G2P[4] (n = 2/11), and G9P[8] (n = 2/11). Thus, similarities to previous reports were found in that G1P[8] predominated, G9P[8] was still detected but G2P[4] was detected for the first time in a geriatric population in Ireland. Here also described is the detection of Group 2 lineage IIC rotavirus in Ireland for the first time. PMID- 23080511 TI - Systemic varicella zoster virus reactive effector memory T-cells impaired in the elderly and in kidney transplant recipients. AB - Varicella zoster virus (VZV) infections cause varicella and subsequently herpes zoster upon reactivation. Immune-compromised individuals and the elderly are at high risk of developing herpes zoster due to waning of VZV-specific T-cell immunity. In the present study, a novel functional T-cell assay was developed to test the correlation between age and VZV-specific T-cell responses in peripheral blood from healthy individuals. Secondly, VZV-specific T-cell responses from renal transplant recipients were compared with healthy individuals. Monocytes were differentiated into mature monocyte-derived dendritic cells (moDCs) and were infected with VZV. T-cells were co-cultured with autologous moDCs infected with VZV and subjected to flowcytometric analysis to identify the phenotype (i.e., naive [NA: CCR7(+) CD45RO(-) ], central [CM: CCR7(+) CD45RO(+) ] and effector memory [EM: CCR7(-) CD45RO(+) ] T-cells) and the frequency of VZV-reactive T-cell subsets by intra-cellular IFN-gamma flowcytometry. In contrast to NA and CM T cells, the frequency of VZV-reactive CD4 and CD8 EM T-cells was inversely correlated with age (P = 0.0007 and P = 0.01). No difference was found in the percentage of VZV-reactive CD4 NA, CM and EM T-cells between transplant recipients and controls. However, the percentage of VZV-reactive CD8 EM T-cells was significantly lower in transplant recipients compared to controls (P = 0.02). In conclusion, moDCs infected with VZV are efficient antigen presenting cells applicable to enumerate and characterize the phenotype and differentiation status of the systemic VZV-specific T-cell response ex-vivo. The data suggest that VZV reactive EM T-cells are impaired in the elderly and renal transplant recipients. PMID- 23080512 TI - Holographic molecularly imprinted polymers for label-free chemical sensing. AB - Holographic molecularly imprinted polymer films for the use in chemical sensors are obtained in one step through photopolymerization with interfering laser beams. This results in hierarchical structuring at four length scales: micrometer scale patterning of millimeter- to centimeter- size polymer objects with holographic optical properties, exhibiting nanometer-scale porosity and specific molecular recognition properties at the molecular scale through self-assembly. Specific binding of the target analyte testosterone is measured by diffraction analysis. PMID- 23080513 TI - Evidence for a cell cycle checkpoint that senses branched actin in the lamellipodium. AB - Recent evidence indicates that branched actin might control cell progression through G1 in addition to lamellipodium protrusion. PMID- 23080514 TI - Poly(acrylic acid)-modified Fe3O4 microspheres for magnetic-targeted and pH triggered anticancer drug delivery. AB - Monodisperse poly(acrylic acid)-modified Fe(3)O(4) (PAA@Fe(3)O(4)) hybrid microspheres with dual responses (magnetic field and pH) were successfully fabricated. The PAA polymer was encapsulated into the inner cavity of Fe(3)O(4) hollow spheres by a vacuum-casting route and photo-initiated polymerization. TEM images show that the samples consist of monodisperse porous spheres with a diameter around 200 nm. The Fe(3)O(4) spheres, after modification with the PAA polymer, still possess enough space to hold guest molecules. We selected doxorubicin (DOX) as a model drug to investigate the drug loading and release behavior of as-prepared composites. The release of DOX molecules was strongly dependent on the pH value due to the unique property of PAA. The HeLa cell-uptake process of DOX-loaded PAA@Fe(3)O(4) was observed by confocal laser scanning microscopy (CLSM). After being incubated with HeLa cells under magnet magnetically guided conditions, the cytotoxtic effects of DOX-loaded PAA@Fe(3)O(4) increased. These results indicate that pH-responsive magnetic PAA@Fe(3)O(4) spheres have the potential to be used as anticancer drug carriers. PMID- 23080516 TI - Inability of mutant transthyretin V30M to cross the blood-eye barrier. PMID- 23080515 TI - Role of translocator protein in melanoma growth and progression. AB - The 18 kDa translocator protein (TSPO) is a primarily mitochondrial protein that participates in steroid biosynthesis, cell proliferation, differentiation, apoptosis, and the regulation of mitochondrial function in general. TSPO has been implicated in carcinogenesis via its ability to transport cholesterol into mitochondria to meet the increased energy needs of tumor cells. The purpose of this study was to investigate TSPO involvement in melanoma pathogenesis. TSPO expression in melanoma and melanocytic nevi was analyzed by immunohistochemistry and real-time PCR, and TSPO levels were correlated to the invasiveness of the tumor. The number of TSPO-positive melanoma samples increased with tumor progression irrespective of age or gender of patients. Similar findings were obtained while examining TSPO expression levels in relation to the Clark invasion stage of the tumor. Indeed, the immunohistochemical index was elevated in invasive tumors characterized as Clark level V compared to those characterized as levels I and II. Besides, the elevation of immunohistochemical index was accompanied with a shift of homogeneous cytoplasmic subcellular expression pattern of the protein to nuclear and perinuclear. Taken together, these results suggest TSPO participation in melanoma growth and progression. PMID- 23080517 TI - New-onset Parkinson syndrome after liver transplantation. PMID- 23080519 TI - Antidotes for cyanide poisoning---author's reply. PMID- 23080520 TI - Transfection of nuclear factor-kappaB decoy oligodeoxynucleotide protects against ischemia/reperfusion injury in a rat epigastric flap model. AB - BACKGROUND: Nuclear factor-kappaB (NF-kappaB) is considered to play an important role in the response to ischemia/reperfusion (I/R) injury in flap surgery. To inhibit NF-kappaB, synthetic double-stranded oligodeoxynucleotide (ODN) was used as a decoy. The present study aimed to evaluate the suppressive effects of NF kappaB against I/R injury of experimental rat flap model. METHODS: An extended epigastric island flap was raised and ischemia was induced for 3 h. NF-kappaB decoy ODN (group D) or single-strand ODN (control; group S) was injected via the contralateral artery when the pedicle was clamped. Transfection efficiency was evaluated with fluorescein isothiocyanate (FITC)-labeled ODN. The effects of NF kappaB decoy ODN were analyzed in groups D and S, and an untreated group (group N). RESULTS: FITC-labeled ODN was distributed over the entire flap. Mean survival rate of the flap was significantly higher in group D than in the other groups (group D: 57.9%; group S: 31.1%; group N 31.7%; p < 0.005). Injured muscle fibers, neutrophils and the expression of inducible nitric oxide synthase were significantly lower in group D. A real-time polymerase chain reaction also demonstrated a tendency for suppression of tumor necrosis factor-alpha, interleukin (IL)-1beta and IL-6. CONCLUSIONS: We show that NF-kappaB decoy ODN protected against flap necrosis as a result of I/R injury in rats. We also indicate that intra-arterial injection of naked NF-kappaB decoy ODN is effective for transfection into target organs. Therefore, transfection of NF-kappaB decoy ODN represents a novel therapeutic strategy for the treatment of flap surgery in I/R injury. PMID- 23080521 TI - Enhancing the catalytic and electrocatalytic properties of Pt-based catalysts by forming bimetallic nanocrystals with Pd. AB - Bimetallic nanocrystals consisting of two distinct metals such as Pd and Pt are attractive for a wide variety of catalytic and electrocatalytic applications as they can exhibit not only a combination of the properties associated with both metals but also enhancement or synergy due to a strong coupling between the two metals. With Pd as the base metal, many methods have recently been demonstrated for the synthesis of Pd-Pt bimetallic nanocrystals having a wide variety of different structures in the form of alloys, dendrites, core-shells, multi-shells, and monolayers. In this tutorial review, we begin with a brief discussion on the possible structures of Pd-Pt bimetallic nanocrystals, followed by an account of recent progress on synthetic approaches to such nanocrystals with controlled structures, shapes and sizes. In addition to the experimental procedures and mechanistic studies, a number of examples are presented to highlight the use of such bimetallic nanocrystals as catalysts or electrocatalysts for various applications with enhanced performance relative to their monometallic counterparts. PMID- 23080522 TI - Sensitive, microliter PCR with consensus degenerate primers for Epstein Barr virus amplification. AB - Sensitive identification of the etiology of viral diseases is key to implementing appropriate prevention and treatment. The gold standard for virus identification is the polymerase chain reaction (PCR), a technique that allows for highly specific and sensitive detection of pathogens by exponentially amplifying a specific region of DNA from as little as a single copy through thermocycling a biochemical cocktail. Today, molecular biology laboratories use commercial instruments that operate in 0.5-2 h/analysis using reaction volumes of 5-50 MUL contained within polymer tubes or chambers. Towards reducing this volume and maintaining performance, we present a semi-quantitative, systematic experimental study of how PCR yield is affected by tube/chamber substrate, surface-area-to volume ratio (SA:V), and passivation methods. We perform PCR experiments using traditional PCR tubes as well as using disposable polymer microchips with 1 MUL reaction volumes thermocycled using water baths. We report the first oil encapsulation microfluidic PCR method without fluid flow and its application to the first microfluidic amplification of Epstein Barr virus using consensus degenerate primers, a powerful and broad PCR method to screen for both known and novel members of a viral family. The limit of detection is measured as 140 starting copies of DNA from a starting concentration of 3 * 10(5) copies/mL, regarded as an accepted sensitivity threshold for diagnostic purposes, and reaction specificity was improved as compared to conventional methods. Also notable, these experiments were conducted with conventional reagent concentrations, rather than commonly spiked enzyme and/or template mixtures. This experimental study of the effects of substrate, SA:V, and passivation, together with sensitive and specific microfluidic PCR with consensus degenerate primers represent advances towards lower cost and higher throughput pathogen screening. PMID- 23080524 TI - Heat shock protein 27 is increased in cyanotic tetralogy of Fallot myocardium and is associated with improved cardiac output and contraction. AB - Tetralogy of Fallot (TOF) is a congenital heart condition in which the right ventricle is exposed to cyanosis and pressure overload. Patients have an increased risk of right ventricle dysfunction following corrective surgery. Whether the cyanotic myocardium is less tolerant of injury compared to non cyanotic is unclear. Heat shock proteins (HSPs) protect against cellular stresses. The aim of this study was to examine HSP 27 expression in the right ventricle resected from TOF patients and determine its relationship with right ventricle function and clinical outcome. Ten cyanotic and ten non-cyanotic patients were studied. Western blotting was used to quantify HSP 27 in resected myocardium at (1) baseline (first 15 min of aortic cross clamp and closest representation of pre-operative status) and (2) after 15 min during ischemia until surgery was complete. The cyanotic group had significantly increased haematocrit, lower O2 saturation, thicker interventricular septal wall thickness and released more troponin-I on post-operative day 1 (p < 0.05). HSP 27 expression was significantly increased in the < 15 min cyanotic compared to the < 15 min non-cyanotic group (p = 0.03). In the cyanotic group, baseline HSP 27 expression also significantly correlated with oxygen extraction ratio (p = 0.028), post-operative basal septal velocity (p = 0.036) and mixed venous oxygen saturation (p = 0.02), markers of improved cardiac output/contraction. Increased HSP 27 expression and associated improved right ventricle function and systemic perfusion supports a cardio-protective effect of HSP 27 in cyanotic TOF. PMID- 23080525 TI - Analysis of simulated fluorescence intensities decays by a new maximum entropy method algorithm. AB - A new algorithm for the Maximum Entropy Method (MEM) is proposed for recovering the lifetime distribution in time-resolved fluorescence decays. The procedure is based on seeking the distribution that maximizes the Skilling entropy function subjected to the chi-squared constraint chi(2) ~ 1 through iterative linear approximations, LU decomposition of the Hessian matrix of the lagrangian problem and the Golden Section Search for backtracking. The accuracy of this algorithm has been investigated through comparisons with simulated fluorescence decays both of narrow and broad lifetime distributions. The proposed approach is capable to analyse datasets of up to 4,096 points with a discretization ranging from 100 to 1,000 lifetimes. A good agreement with non linear fitting estimates has been observed when the method has been applied to multi-exponential decays. Remarkable results have been also obtained for the broad lifetime distributions where the position is recovered with high accuracy and the distribution width is estimated within 3%. These results indicate that the procedure proposed generates MEM lifetime distributions that can be used to quantify the real heterogeneity of lifetimes in a sample. PMID- 23080527 TI - Anxious attachment may be a vulnerability factor for developing embitterment. AB - By predisposing to ego-defensive strategies in social situations, a negative attachment history may promote embitterment. The present study identified attachment anxiety - more than attachment avoidance - as a possible vulnerability factor for the development and maintenance of embitterment. This factor should be considered in theories and in interventions of embitterment. PMID- 23080526 TI - Validity and reliability assessment of health belief scales for mammography screening in Greek asymptomatic women. AB - OBJECTIVE: The purpose was to assess the validity and reliability of health belief model variables (perceived benefits, perceived barriers, and self-efficacy beliefs) that are often the target of mammography screening interventions. METHODS: Based on Champion's health belief model scales, questionnaire data were obtained from a nationally representative sample of 408 Greek women, 40 years of age or older and with no personal history of cancer. RESULTS: Using confirmatory factor analysis, we found all items to load significantly on their respective factors. Standardized factor loadings ranged from 0.55 to 0.88. An analysis of localized areas of respecification of a three-factor model revealed that measurement error correlations between a few items existed. Known-groups and criterion-related validity was supported for all scales, while internal consistency reliability of the scales was satisfactory, with Cronbach's alpha ranging from 0.71 to 0.88. CONCLUSIONS: The Greek version of the scales measuring perceived benefits, perceived barriers, and self-efficacy beliefs is a reliable and valid tool when used to assess health beliefs for mammography screening among women. Implications for intervention strategies aimed at increasing the likelihood of mammography utilization are considered. PMID- 23080528 TI - Incorporating spirituality in psychosocial group intervention for women undergoing in vitro fertilization: a prospective randomized controlled study. AB - OBJECTIVES: This study examined the efficacy of a group intervention, the Integrative Body-Mind-Spirit (I-BMS) intervention, which aims at improving the psychosocial and spiritual well-being of Chinese women undergoing their first IVF treatment cycle. DESIGN: The I-BMS intervention facilitates the search of meaning of life in the context of family and childbearing, as well as the letting go of high IVF expectations. A randomized controlled study of 339 women undergoing first IVF treatment cycle in a local Hong Kong hospital was conducted (intervention: n= 172; no-intervention control: n= 167). METHODS: Assessments of anxiety, perceived importance of childbearing, and spiritual well-being were made at randomization (T(0) ), on the day starting ovarian stimulations (T(1)), and on the day undertaking embryo transfer (T(2)). RESULTS: Comparing T(0) and T(2), interaction analyses showed women who had received the intervention reported lower levels of physical distress, anxiety, and disorientation. They reported being more tranquil and satisfied with their marriage, and saw childbearing as less important compared to women in the control group. CONCLUSIONS: These findings suggest that I-BMS intervention was successful at improving the psychosocial and spiritual well-being of women undergoing their first IVF treatment cycle. This study highlights the importance of providing integrative fertility treatment that incorporates psychosocial and spiritual dimensions. PMID- 23080529 TI - Fears of compassion and happiness in relation to alexithymia, mindfulness, and self-criticism. AB - BACKGROUND: There is increasing research to suggest that fears of, and resistances to, affiliative and positive emotions are linked to self-criticism and a range of psychopathologies. It is unclear how these fears and resistances are linked to each other and how these in turn are linked to psychological processes, such as abilities to be mindful and recognize and describe emotions. OBJECTIVES: This research explores the relationship between fears of compassion and happiness in general, with capacities for emotional processing (alexithymia), capacities for mindfulness, and empathic abilities. To advance this research, a new scale was developed to measure general fears of positive feelings - the Fear of Happiness Scale. RESULTS: The results showed that fears of compassion for self, from others and in particular fear of happiness, were highly linked to different aspects of alexithymia, mindfulness, empathy, self-criticism and depression, anxiety and stress. Especially noteworthy was the very high correlation between fear of happiness and depression (r= .70). CONCLUSION: While the development of positive emotions, especially those linked to affiliation and connectedness are increasingly seen as important therapeutic targets, little research has focused on the blocks and fears to positive emotions. This study used newly developed fears of positive affect scales (e.g., compassion and happiness) to explore these aspects and found they were significantly linked to psychopathology variables self-criticism and difficulties such as alexithymia. PMID- 23080530 TI - Dynamic mapping of the structures of content in clinical settings (DMSC). A new coding system for analysing the patient's narratives. AB - OBJECTIVES: The paper presents a method of content analysis framed within a semiotic and contextual model of the psychotherapy process as a situated dynamics of sensemaking: the Dynamic Mapping of the Structures of Content in Clinical Settings (DMSC). DESIGN: DMSC is a system of content analysis focused on a generalized level of meaning, concerning basic aspects of the patient's narrative (e.g., if the narrative concerns herself or other than herself). METHOD: The paper presents the result of the application of DMSC to an intensive single-case analysis (Katja). The method has been applied by judges to the transcripts of sessions and is aimed at identifying patterns of combinations (defined: Patterns of content) of the categories characterizing the patient's narratives (pattern analysis approach) as well as at mapping the transition among these patterns (sequential analysis approach). RESULTS: These results provide evidence of its construct validity. In accordance with the theoretical model grounding the method, we have found that: (a) DMSC provides a meaningful representation of the patient's narratives in terms of Patterns of content; (b) the probability of transition among the Patterns of content have proved to be significantly associated with the clinical quality of the sessions. CONCLUSION: The DMSC has to be considered an attempt paving the way for further investigations aimed at developing a deeper understanding of the role played by the dynamics of sensemaking in the psychotherapy process. PMID- 23080531 TI - 'Chipping in': clinical psychologists' descriptions of their use of formulation in multidisciplinary team working. AB - OBJECTIVES: To investigate clinical psychologists' accounts of their use of psychological case formulation in multidisciplinary teamwork. DESIGN: A qualitative study using inductive thematic analysis. METHODS: Ten clinical psychologists working in community and inpatient adult mental health services who identified themselves as using formulation in their multidisciplinary team work participated in semi-structured interviews. RESULTS: Psychological hypotheses were described as shared mostly through informal means such as chipping in ideas during a team discussion rather than through explicit means such as staff training or case presentations that usually only took place once participants had spent time developing their role within the team. Service context and staff's prior experience were also factors in how explicitly formulation was discussed. Participants reported that they believed that this way of working, although often not formally recognized, was valuable and improved the quality of clinical services provided. CONCLUSIONS: More investigation into this under-researched but important area of clinical practice is needed, in order to share ideas and support good practice. PMID- 23080532 TI - Traumatized refugees, their therapists, and their interpreters: three perspectives on psychological treatment. AB - OBJECTIVES: To study how traumatized refugees, their therapists, and their interpreters perceive both curative and hindering factors in psychological therapy, thereby highlighting the mediators of change in a transcultural clinical setting. DESIGN: Four experienced clinical psychologists affiliated to two centres for the rehabilitation of traumatized refugees, were asked to select their two 'most successful' and two 'least successful' cases by going back to all the cases that they had concluded within the last 2 years, a pool of approximately 200 patients. The selected 16 patients, their therapists, and their interpreters were invited to semi-structured, in-depth, individual interviews with the aim of acquiring more knowledge on what had been helpful and what not helpful in the psychological treatment. METHOD: The senior author who conducted the interviews was not aware of whether the patient belonged to the 'successful' or 'unsuccessful group' prior to the interview. All interviews were audio taped. A qualitative phenomenological approach was used in the analysis of the data. The data were analysed (1) triad by triad for the 16 triads consisting of a patient, his/her therapist, and his/her interpreter, and (2) separately for each of the three groups of respondents. The analysis involved going through each protocol sentence by sentence and developing key-concepts for the therapeutic interventions and for the interpersonal relations. When the generation of key concepts was finalized, the material was analysed for a second time, in order to place the relevant data under the key-concepts/categories. The categories and illustrative verbatim quotations from the interviews are presented in separate tables for the three groups. RESULTS: The relationship between the therapist, patient, and interpreter, and the development of trust and a good working alliance was seen by all as the most important curative factor. Psychoeducative methods, cognitive interventions, as well as the provision of practical help and advice were also regarded as curative and facilitating factors. Hindering factors fell into the following five categories: factors related to the patient, to the therapist, to the interpreter, to the therapeutic method itself, and to factors external to the therapy. Therapists and interpreters considered severe psychopathology and substance abuse in addition to PTSD; chronic pain and physical illness; lack of motivation for treatment; and overwhelming social and/or economic problems as obstructive factors for the establishment of a working alliance and more generally for a successful outcome. As to the patients who did not benefit from the treatment, the unsuitability of a psychological treatment for their symptoms, and social and economic problems were seen as the main hindering factors. CONCLUSION: The therapeutic or working alliance is a common element of all types of psychological treatments, and is generally considered as a 'non-specific' factor. There are grounds to modify this view in working with traumatized and tortured patients from different cultural backgrounds. In cases where patients have experienced humiliation and evil, and now live in exile, the establishment of a relation of trust in fellow human beings is the first aim of the treatment. The article argues that the professional's compassion constitutes a primary factor in the therapeutic process in such cases. The risks of overinvolvement in the treatment of heavily traumatized patients are well described in the literature, and have also appeared in this study. In psychotherapy research, strong personal commitment is seldom mentioned by therapists for fear of its being considered unprofessional or unethical. However, a strong commitment can be of value, not only for the patients, but also for the therapists and interpreters themselves. The results of this study suggest that deep compassion on the part of the professionals is widespread in the treatment of traumatized patients, and that it is considered as a healing factor by most patients, interpreters, and therapists. PMID- 23080533 TI - Service-users' experiences of an early intervention in psychosis service: an interpretative phenomenological analysis. AB - OBJECTIVES: Previous research regarding Early Intervention in Psychosis (EIP) services has mainly adopted quantitative methodologies, in order to study the effectiveness of EIP services. Research studies that have explored service-users' experiences of EIP services are small in number. This research aimed to explore service-users' experiences of being in contact with an EIP service, its impact of their experience of psychosis and current life situation. DESIGN: Interpretative Phenomenological Analysis (IPA) was used to conduct an in-depth qualitative study of a small sample of EIP service-users, in order to explore their experiences of being in contact with the service. METHOD: Flexibly guided interviews were conducted with eight service-users who had been receiving a service from an EIP team for more than 2 years and were recruited using a purposive sampling method. Verbatim interview transcripts were analysed using IPA. RESULTS: Five super ordinate themes, developed from the analysis, are discussed in sections: Stigma, Relationships, Understanding the experiences, Sense of agency, and Impact on sense of self. Sub-themes of these super-ordinate themes are also discussed. CONCLUSIONS: The themes developed from the analysis were envisioned as representing an overarching theme of 'A personal journey of recovery', which was influenced by participants' involvement with the EIP service. Clinical implications include the need for EIP services, as with other mental health services, to find ways to promote recovery and create opportunities for agency and control. Future research directions are also discussed. PMID- 23080534 TI - Measuring forces at the leading edge: a force assay for cell motility. AB - Cancer cells become mobile by remodelling their cytoskeleton to form migratory structures. This transformation is dominated by actin assembly and disassembly (polymerisation and depolymerisation) in the cytoplasm. Synthesis of filamentous actin produces a force at the leading edge that pushes the plasma membrane forward. We describe an assay to measure the restoring force of the membrane in response to forces generated within the cytoplasm adjacent to the membrane. A laser trap is used to form a long membrane nanotube from a living cell and to measure the axial membrane force at the end of the tube. When the tube, resembling a filopodium, is formed and in a relaxed state the axial membrane force exhibits a positive stationary value. This value reflects the influence of the cytoskeleton that acts to pull the tube back to the cell. A dynamic sawtooth force that rides upon the stationary value is also observed. This force is sensitive to a toxin that affects actin assembly and disassembly, but not affected by agents that influence microtubules and myosin light chain kinase. We deduce from the magnitude and characteristics of dynamic force measurements that it originates from depolymerisation and polymerisation of F-actin. The on- and off-rates, the number of working filaments, and the force per filament (2.5 pN) are determined. We suggest the force-dependent transitions are thermodynamically uncoupled as both the on- and off-rates decrease exponentially with a compressive load. We propose kinetic schemes that require attachment of actin filaments to the membrane during depolymerisation. This demonstrates that actin kinetics can be monitored in a living cell by measuring force at the membrane, and used to probe the mobility of cells including cancer cells. PMID- 23080535 TI - H-TiO(2) @MnO(2) //H-TiO(2) @C core-shell nanowires for high performance and flexible asymmetric supercapacitors. AB - A flexible solid-state asymmetric supercapacitor device with H-TiO(2) @MnO(2) core-shell NWs as the positive electrode and H-TiO(2) @C core-shell NWs as the negative electrode is developed. This device operates in a 1.8 V voltage window and is able to deliver a high specific capacitance of 139.6 F g(-1) and maximum volumetric energy density of 0.30 mWh cm(-3) with excellent cycling performance and good flexibility. PMID- 23080536 TI - Coping strategies of Spanish pregnant women and their impact on anxiety and depression. AB - The aims of this study were to analyze the coping strategies used by women in the first trimester of low-risk pregnancies, their relationships to sociodemographic and pregnancy variables, and their ability to predict anxiety and depression in the third trimester. Participants in the first trimester were 285 Spanish pregnant women, of whom 122 were followed into the third trimester. The use of problem-focused coping was stable, whereas variations occurred in emotion-focused coping. Age, educational level, employment, planned pregnancy, previous childbirth, and previous miscarriage were associated with adaptive coping. Coping strategies predicting anxiety and depressive symptoms were overt emotional expression and social support seeking. Coping through religion predicted anxiety. Coping is a complex process influenced by sociodemographic and obstetric factors that can contribute to the onset of psychological symptoms. PMID- 23080537 TI - Bioaccumulation of Zn, Cu and Mn in the caviar and muscle of Persian sturgeon (Acipenser persicus) from the Caspian Sea, Iran. AB - Concentrations of Zn, Cu and Mn were examined in caviar and muscle of the Persian sturgeon (Acipenser persicus) collected from coastal waters of south Caspian Sea during March and April, 2011. Mean Zn, Cu and Mn concentrations in caviar samples were 21.48, 2.05 and 1.66 MUg g(-1) wet weight basis, respectively. The mean Zn, Cu and Mn concentrations in muscle tissues were 7.49, 1.00 and 0.34 MUg g(-1) wet weight basis, respectively. The mean concentrations of Zn and Cu in caviar and muscle samples were under the permissible limits proposed by the United Kingdom's Ministry of Agriculture, Fisheries and Food (2000). PMID- 23080538 TI - Severity of bias of a simple estimator of the causal odds ratio in Mendelian randomization studies. AB - Mendelian randomization studies estimate causal effects using genetic variants as instruments. Instrumental variable methods are straightforward for linear models, but epidemiologists often use odds ratios to quantify effects. Also, odds ratios are often the quantities reported in meta-analyses. Many applications of Mendelian randomization dichotomize genotype and estimate the population causal log odds ratio for unit increase in exposure by dividing the genotype-disease log odds ratio by the difference in mean exposure between genotypes. This 'Wald-type' estimator is biased even in large samples, but whether the magnitude of bias is of practical importance is unclear. We study the large-sample bias of this estimator in a simple model with a continuous normally distributed exposure, a single unobserved confounder that is not an effect modifier, and interpretable parameters. We focus on parameter values that reflect scenarios in which we apply Mendelian randomization, including realistic values for the degree of confounding and strength of the causal effect. We evaluate this estimator and the causal odds ratio using numerical integration and obtain approximate analytic expressions to check results and gain insight. A small simulation study examines finite sample bias and mild violations of the normality assumption. For our simple data generating model, we find that the Wald estimator is asymptotically biased with a bias of around 10% in fairly typical Mendelian randomization scenarios but which can be larger in more extreme situations. Recently developed methods such as structural mean models require fewer untestable assumptions and we recommend their use when the individual-level data they require are available. The Wald type estimator may retain a role as an approximate method for meta-analysis based on summary data. PMID- 23080540 TI - Thin Au surface plasmon waveguide Schottky detectors on p-Si. AB - Surface plasmon sub-bandgap Schottky detectors based on an asymmetric Au stripe waveguide on p-Si are investigated theoretically and experimentally at free-space wavelengths of lambda(0) = 1310 and 1550 nm. Au on p-Si produces a low Schottky barrier (0.33 eV), which improves the internal quantum efficiency. Thick and thin Au stripes are compared, with the latter increasing the hot hole emission probability relative to the former, and thus also improving the internal quantum efficiency. Two excitation schemes are considered: end facet illumination which launches surface plasmons on the detector, and top illumination which does not. Both schemes are implemented using a piezoelectric positioner that is programmed to scan the detection area in steps of 100-200 nm, thus enabling the acquisition of high-resolution photocurrent maps. The surface plasmon detectors yield a responsivity of ~1 mA W(-1), ~2* larger than the same detectors under top illumination, due to the absorption of surface plasmons. We compare the measurements with theoretical results for both excitation schemes and estimate the hot hole attenuation length in our Au stripes to be ~23 nm. PMID- 23080539 TI - Pluripotent stem cells escape from senescence-associated DNA methylation changes. AB - Pluripotent stem cells evade replicative senescence, whereas other primary cells lose their proliferation and differentiation potential after a limited number of cell divisions, and this is accompanied by specific senescence-associated DNA methylation (SA-DNAm) changes. Here, we investigate SA-DNAm changes in mesenchymal stromal cells (MSC) upon long-term culture, irradiation-induced senescence, immortalization, and reprogramming into induced pluripotent stem cells (iPSC) using high-density HumanMethylation450 BeadChips. SA-DNAm changes are highly reproducible and they are enriched in intergenic and nonpromoter regions of developmental genes. Furthermore, SA-hypomethylation in particular appears to be associated with H3K9me3, H3K27me3, and Polycomb-group 2 target genes. We demonstrate that ionizing irradiation, although associated with a senescence phenotype, does not affect SA-DNAm. Furthermore, overexpression of the catalytic subunit of the human telomerase (TERT) or conditional immortalization with a doxycycline-inducible system (TERT and SV40-TAg) result in telomere extension, but do not prevent SA-DNAm. In contrast, we demonstrate that reprogramming into iPSC prevents almost the entire set of SA-DNAm changes. Our results indicate that long-term culture is associated with an epigenetically controlled process that stalls cells in a particular functional state, whereas irradiation-induced senescence and immortalization are not causally related to this process. Absence of SA-DNAm in pluripotent cells may play a central role for their escape from cellular senescence. PMID- 23080541 TI - Tetralogy of Fallot and aortic root dilation: a long-term outlook. AB - Dilation of the sinus of Valsalva (SoV) has been increasingly observed after repaired tetralogy of Fallot (TOF). We estimate the prevalence of SoV dilation in adults with repaired TOF and analyze possible factors related to aortic disease. Adults with TOF [n = 109, median age 33.2 years (range 18.1 to 69.5)] evaluated at Johns Hopkins Hospital from 2001 to 2009 were reviewed in an observational retrospective cohort study. Median follow-up was 27.3 (range 0.1-48.8) years. SoV dilation was defined as >95 % confidence interval adjusted for age and body surface area (z-score > 2). The prevalence of SoV dilation was 51 % compared with that of a normal population with a mean z-score of 2.03. Maximal aortic diameters were >= 4 cm in 39 % (42 of 109), >= 4.5 cm in 21 % (23 of 109), >= 5 cm in 8 % (9 of 109), and >= 5.5 cm in 2 % (2 of 109). There was no aortic dissection or death due contributable to aortic disease. Aortic valve replacement was performed in 1.8 % and aortic root or ascending aorta (AA) replacement surgery in 2.8 % of patients. By multivariate logistic regression analysis, aortic regurgitation (AR) [odds ratio (OR) = 3.09, p = 0.005], residual ventricular septal defect (VSD) (OR = 4.14, p < 0.02), and TOF with pulmonary atresia (TOF/PA) (OR = 6.75, p = 0.03) were associated with increased odds of dilated aortic root. SoV dilation after TOF repair is common and persists with aging. AR, residual VSD, and TOF/PA are associated with increased odds of dilation. AA evaluation beyond the SoV is important. Indexed values are imperative to avoid bias on the basis of age and body surface area. PMID- 23080544 TI - Increased calcium intake may reduce risk of primary hyperparathyroidism. PMID- 23080542 TI - Cranial irradiation as an additional risk factor for anthracycline cardiotoxicity in childhood cancer survivors: an analysis from the cardiac risk factors in childhood cancer survivors study. AB - Anthracycline-treated childhood cancer survivors experience cardiac damage that results in decreased left ventricular (LV) mass, leading to increased LV wall stress, which underlies their greater risk of cardiomyopathy. Many of these survivors also are at risk of growth hormone (GH) abnormalities from cranial irradiation exposure, although it is unknown whether such exposure is associated with cardiotoxicity. Echocardiograms and insulin-like growth factor-1 (IGF-1), a marker of GH, were measured in 130 anthracycline-treated childhood cancer survivors, 59 of whom had been exposed to cranial irradiation, a mean 10 years after their cancer diagnosis. Echocardiographic parameters and IGF-1 were standardized relative to age or body surface area using data from sibling control subjects and expressed as the percentage difference from normal values. The results showed that after adjustment for other risk factors, survivors exposed to cranial irradiation had an additional 12 % decrease in LV mass compared with unexposed survivors (P < 0.01) and an additional 3.6 % decrease in LV dimension (P = 0.03). Survivors exposed to cranial irradiation also had a 30.8 % decrease in IGF-1 relative to normal values, which was greater than the 10.5 % decrease in unexposed survivors (P < 0.01). The above findings led us to conclude that in anthracycline-treated childhood cancer survivors a mean 10 years after their diagnosis, those with cranial irradiation exposure had significantly greater decreases in LV mass and dimension. Because cranial irradiation also was associated with decreased IGF-1, it is possible that GH deficiencies mediated this effect, suggesting that GH replacement therapy may help to prevent the development of cardiotoxicity. PMID- 23080545 TI - Financing of certified centers: a willingness-to-pay analysis. AB - INTRODUCTION: Although care in certified breast centers is now established throughout Germany, numerous services are still not being reimbursed. This also affects other centers involved in the specialty of gynecology such as gynecological cancer centers, perinatal centers, and endometriosis centers. Although a certified center is entitled to charge additional fees, these are in most cases not reimbursed. Calculation of additional costs is limited by the fact that data from the Institute for the Hospital Reimbursement System (Institut fur das Entgeltsystem im Krankenhaus, InEK) do not reflect interdisciplinary services and procedures. For decision-makers, society's willingness to pay is an important factor in guiding decisions on the basis of social priorities. A hypothetical maximum willingness to pay can be calculated using a willingness-to-pay analysis, making it possible to identify deficiencies in the arbitrary setting of health budgets at the macro-level. MATERIALS AND METHODS: In a multicenter study conducted between November 2009 and December 2010, 2,469 patients at a university hospital and at a non-university hospital were asked about the extent of their awareness of certified centers, the influence of centers on hospital presentation, and about personal attitudes toward quality-oriented reimbursement. A subjective assessment of possible additional charges was calculated using a willingness-to-pay analysis. RESULTS: In the overall group, 53.4 % of the patients were aware of what a certified center is and 27.4 % had specific information (obstetrics 40.0/32.3 %; mastology 66.8/23.2 %; gynecological oncology 54.7/27.3 %; P < 0.001). For 43.8 %, a certified center was one reason or the major reason for presentation (obstetrics 26.2 %; mastology 66.8 %; gynecological oncology 46.6 %; P < 0.001). A total of 72.6 % were in favor of quality-oriented reimbursement and 69.7 % were in favor of an additional charge for a certified center amounting to ?538.56 (mastology ?643.65, obstetrics ?474.67, gynecological oncology ?532.47). In all, 33.9 % would accept an increase in health-insurance fees (averaging 0.3865 %), and 28.3 % were in favor of reduced remuneration for non-certified centers. CONCLUSIONS: The existence of certified centers is being increasingly recognized by patients. Additional charges for certified centers are generally supported. There is therefore a clear demand for them-from patients as well. This may be useful when negotiations are being conducted. PMID- 23080543 TI - Calcium intake and risk of primary hyperparathyroidism in women: prospective cohort study. AB - OBJECTIVE: To examine the association between calcium intake and risk of primary hyperparathyroidism in women. DESIGN: Prospective cohort study. SETTING: Nurses' Health Study I, which originally recruited participants from the 11 most populous states in the United States. PARTICIPANTS: 58,354 female registered nurses enrolled in the Nurses' Health Study I aged 39-66 years in 1986 and with no history of primary hyperparathyroidism. Calcium intake was assessed every four years using semiquantitative questionnaires on food frequency. MAIN OUTCOME MEASURE: Incident primary hyperparathyroidism, confirmed by medical record review. RESULTS: During 22 years of follow-up, we recorded 277 incident cases of primary hyperparathyroidism. Women were divided into five equal groups, according to intake of dietary calcium. After adjusting for age, body mass index, race, and other factors, the relative risk of primary hyperparathyroidism for women in the group with the highest intake of dietary calcium was 0.56 (95% confidence interval 0.37 to 0.86, P=0.009 for trend), compared with the group with the lowest intake. The multivariable relative risk of primary hyperparathyroidism for women taking more than 500 mg/day of calcium supplements compared with no calcium supplements was 0.41 (95% confidence interval 0.29 to 0.60, P<0.001 for trend). Analyses restricted to participants with regular physical exams did not significantly change the association between calcium intake and risk of primary hyperparathyroidism. CONCLUSION: Increased calcium intake is independently associated with a reduced risk of primary hyperparathyroidism in women. PMID- 23080546 TI - Analysis of the impact of PAPP-A, free beta-hCG and nuchal translucency thickness on the advanced first trimester screening. AB - OBJECTIVES: The intention of this study is to analyze the impact of the single parameters NT, PAPP-A and free beta-hCG used in combined first trimester screening and to determine their contribution in the risk assessment. METHODS: A retrospective risk assessment on the advanced first trimester screening (AFS) algorithm was made to determine the effect of a particular parameter while the remaining ones were fixed for calculation. Afterward data were recalculated by the AFS module. Test performance was measured by receiver operating characteristics (ROC) curves and their area under curve (AUC). RESULTS: Among the 14,862 cases are 14,748 healthy fetuses, 86 with trisomy 21, 22 with trisomy 18 and 6 with trisomy 13. Some settings obtain at default cut-off a very high sensitivity. However, a lack of specificity, as a high false-positive rate, too. The ROC analysis was best for NT, followed by PAPP-A. Free beta-hCG showed the lowest AUC. Combining PAPP-A and free beta-hCG offered a better AUC than each parameter alone. Best test performance was obtained by including all three parameters. DISCUSSION: A detection rate of 69 % for testing NT discretely is in order with present study data. PAPP-A is following and free beta-hCG is not useful with a test positive rate of about a third. The detection rate of the biochemical parameters combined is higher than for NT alone, but results in a five times higher punctuation rate. All parameters together in the AFS provide the best test performance. The impact of each parameter NT, PAPP-A and free-beta hCG in a combined test strategy is nearly a third. Thus, every single parameter is needed to provide a high detection rate for all of the trisomies and minimize the number of unnecessary invasive diagnostics. PMID- 23080547 TI - Aberrant histone acetylation and methylation levels in woman with endometriosis. AB - OBJECTIVE: To investigate the alterations in histone modifications in woman with endometriosis. METHODS: Global histone H3/H4 acetylation and H3K4/H3K9 methylation in eutopic and ectopic endometrium from 15 endometriosis patients were assayed using the EpiQuik global histone H3/H4 acetylation and H3K4/H3K9 methylation assay kits. Quantitative real-time reverse transcriptase-polymerase chain reaction was applied to measure mRNA levels of 12 members of histone related chromatin modifier genes. RESULTS: Histone H4 hypoacetylation was detected both in eutopic and ectopic endometrium. There were no difference between patients with endometriosis and controls on global levels of H3 acetylation. Furthermore, global histone H3K4 hypomethylation and H3K9 hypomethylation were detected both in ectopic and eutopic endometrium (p < 0.001), and in ectopic endometrium (p < 0.001), respectively. SIRT1 mRNA level was significantly decreased in eutopic endometrium, while mRNA levels of HDAC1, SUV39H1, SUV39H2 and G9a were significantly downregulated in ectopic endometrium. HDAC2 mRNA level was significantly increased in eutopic endometrium. PCAF mRNA level was significantly increased in ectopic endometrium. CONCLUSIONS: Aberrant histone modification may play an important role in the pathogenesis of endometriosis. PMID- 23080548 TI - Sequential clomiphene citrate/hMG versus hMG for ovulation induction in clomiphene citrate-resistant women. AB - OBJECTIVE: This study was designed to compare sequential clomiphene citrate/hMG regimen to hMG regimen for ovulation induction in clomiphene citrate-resistant women. STUDY DESIGN: A comparative prospective study. PATIENTS AND METHODS: Ninety infertile women were randomized to receive either sequential CC/hMG regimen (45 women) or low-dose step-up protocol of hMG (45 women). All participants had received at least six consecutive cycles of clomiphene citrate for ovulation induction within the last year before inclusion in this study, but they did not conceive. The CC/hMG regimen group received clomiphene citrate 100 mg/day for 5 days, followed by hMG 75 IU for 4 days. The hMG group received low dose step-up protocol for 10-14 days. To detect the number and size of the follicles, TVS was done on cycle day 8 and repeated daily or every other day according to follicular development. When one to three follicles reached a diameter >=18 mm, hCG injection was scheduled. Before hCG injection, the E2 level and endometrial thickness were evaluated. beta-hCG levels were measured on cycle day 22. RESULTS: There was no significant difference between the two studied groups regarding the demographic data, sperm parameters, and day 3 FSH, LH and estradiol. Also, there was no significant difference between the two studied groups regarding endometrial thickness, number of mature follicles, peak of E2 before hCG injection and number of cases that developed ovarian cyst or OHSS. The dose of gonadotropins used was significantly low in the CC/hMG group compared to the hMG group (295.2 +/- 75.5 vs. 625.3 +/- 65.0, respectively), and the pregnancy rate was significantly high in the CC/hMG group compared to the hMG group [12 (26.7 %) vs. 3 (6.7 %), respectively, p < 0.05]. CONCLUSION: The sequential CC/hMG regimen is as effective as hMG regimen for ovulation induction, produces satisfactory pregnancy results and reduces the treatment cost. PMID- 23080549 TI - Can leukocyte count during the first trimester of pregnancy predict later gestational complications? AB - PURPOSE: To examine whether an association exists between maternal leukocyte count in the first trimester of pregnancy and the risk for development of obstetric complications. METHODS: The study population included all the registered births (n = 33,866) with available white blood cell count (WBC) from the first trimester of pregnancy, during 2000-2010 in a tertiary medical center. The leukocyte count was sorted by the following groups: WBC < 3.5 10 * 9/l, WBC = 3.5 10 * 9/l-13.8 10 * 9/l, and WBC > 13.8 10 * 9/l. These groups were compared regarding obstetrical characteristics and perinatal outcomes. Multiple logistic regression models were used to control for confounders. RESULTS: The study population included 33,866 deliveries, of these 0.94 % had leukocytosis WBC > 13.8 10 * 9/l. Women with leukocytosis delivered significantly earlier, were more likely to be Jewish, and in their first pregnancy. There were significantly higher rates of preterm delivery before 37 weeks, fertility treatments, hypertensive disorders, gestational diabetes mellitus, and cesarean section among these patients. There was no significant difference between the groups regarding preterm premature rupture of membranes (PPROM) and chorioamnionitis. Women with leukocytosis during the first trimester had significantly higher rates of fetuses who were small for gestational age and with birth weight <2,500 g. Multivariable analysis showed a significant association between preterm delivery before 37 weeks and leukocytosis during the first trimester of pregnancy (p = 0.003). CONCLUSIONS: Leukocytosis during the first trimester is significantly associated with an increased risk for obstetrical complications, in particular preterm delivery. Nevertheless, further studies should focus on women with leukocytosis during the first trimester in order to verify our results. PMID- 23080550 TI - Optimizing alpha for better statistical decisions: a case study involving the pace-of-life syndrome hypothesis: optimal alpha levels set to minimize Type I and II errors frequently result in different conclusions from those using alpha = 0.05. AB - Setting optimal significance levels that minimize Type I and Type II errors allows for more transparent and well-considered statistical decision making compared to the traditional alpha = 0.05 significance level. We use the optimal alpha approach to re-assess conclusions reached by three recently published tests of the pace-of-life syndrome hypothesis, which attempts to unify occurrences of different physiological, behavioral, and life history characteristics under one theory, over different scales of biological organization. While some of the conclusions reached using optimal alpha were consistent to those previously reported using the traditional alpha = 0.05 threshold, opposing conclusions were also frequently reached. The optimal alpha approach reduced probabilities of Type I and Type II errors, and ensured statistical significance was associated with biological relevance. Biologists should seriously consider their choice of alpha when conducting null hypothesis significance tests, as there are serious disadvantages with consistent reliance on the traditional but arbitrary alpha = 0.05 significance level. PMID- 23080551 TI - A natural product inspired tetrahydropyran collection yields mitosis modulators that synergistically target CSE1L and tubulin. AB - A Prins cyclization between a polymer-bound aldehyde and a homoallylic alcohol served as the key step in the synthesis of tetrahydropyran derivatives. A phenotypic screen led to the identification of compounds that inhibit mitosis (as seen by the accumulation of round cells with condensed DNA and membrane blebs). These compounds were termed tubulexins as they target the CSE1L protein and the vinca alkaloid binding site of tubulin. PMID- 23080552 TI - Clinical features of patients bearing central nervous system hemangioblastoma in von Hippel-Lindau disease. AB - BACKGROUND: Central nervous system (CNS) hemangioblastoma (HB) is one of the most common manifestations in von Hippel-Lindau disease (VHL), but large-scale studies on clinical features of CNS HB in VHL are scarce. METHODS: On the basis of the results of a questionnaire, we collected data of VHL patients with CNS HB. RESULTS: The total number of CNS HBs in 111 VHL patients (male 59, female 52) was 264 with the following distributions: cerebellar, 65.4 %; brainstem, 9.9 %; spinal cord, 23.9 %; and pituitary, 1. 1 %. The follow-up period was 0.6 to 39.2 years, with the mean 12.5 years. Patients bearing brainstem or spinal cord HB also had another HB significantly more frequently than those bearing cerebellar HBs (P < 0.05). The mean onset age of CNS HB was 29.1 years, and that of patients bearing a single HB (mean 34.4 years) was significantly greater than that of multiple HBs (mean 25.7 years). Patients with multiple HBs under 40 years are more dominant than those with a single HB. The distribution rate of brainstem HB is significantly smaller in patients below 30 years than patients above 29 years. Although ECOG PS score increased along with number of operations, the onset age decreased with increasing number of operations. The mean ECOG PS score of patients below 20 years is significantly smaller than patients above 19 years. CONCLUSIONS: When the onset age of CNS HB is under 40 years, and CNS HB is located at the brainstem or spinal cord HB, the probability of multiple occurrence can be predicted. Since patients with an onset age under 20 years old preserve a high performance status, early detection of CNS HB would be important. In addition, since a multiple operations aggravate performance status, number of operations should be reduced. PMID- 23080553 TI - Reduction of choroidal neovascularization in mice by adeno-associated virus delivered anti-vascular endothelial growth factor short hairpin RNA. AB - BACKGROUND: Strategies leading to the long-term suppression of inappropriate ocular angiogenesis are required to avoid the need for repetitive monthly injections for treatment of diseases of the eye, such as age-related macular degeneration (AMD). The present study aimed to develop a strategy for the sustained repression of vascular endothelial growth factor (VEGF), which is identified as the key player in exudative AMD. METHODS: We have employed short hairpin (sh)RNAs combined with adeno-associated virus (AAV) delivery to obtain the targeted expression of potent gene-regulatory molecules. Anti-VEGF shRNAs were analyzed in human retinal pigment epithelial (RPE) cells using Renilla luciferase screening. For in vivo delivery of the most potent shRNA, self complementary AAV vectors were packaged in serotype 8 capsids (scAAV2/8-hU6-sh9). In vivo efficacy was evaluated either by injection of scAAV2/8-hU6-sh9 into murine hind limb muscles or in a laser-induced murine model of choroidal neovascularization (CNV) following scAAV2/8-hU6-sh9 subretinal delivery. RESULTS: Plasmids encoding anti-VEGF shRNAs showed efficient knockdown of human VEGF in RPEs. Intramuscular administration led to localized expression and 91% knockdown of endogenous murine (m)VEGF. Subsequently, the ability of AAV2/8-encoded shRNAs to impair vessel formation was evaluated in the murine model of CNV. In this model, the sizes of the CNV were significantly reduced (up to 48%) following scAAV2/8-hU6-sh9 subretinal delivery. CONCLUSIONS: Using anti-VEGF vectors, we have demonstrated efficient silencing of endogenous mVEGF and showed that subretinal administration of scAAV2/8-hU6-sh9 has the ability to impair vessel formation in an AMD animal model. Thus, AAV-encoded shRNA can be used for the inhibition of neovascularization, leading to the development of sustained anti VEGF therapy. PMID- 23080554 TI - A biomimetic pathway for vanadium-catalyzed aerobic oxidation of alcohols: evidence for a base-assisted dehydrogenation mechanism. AB - The first step in the catalytic oxidation of alcohols by molecular O(2), mediated by homogeneous vanadium(V) complexes [LV(V)(O)(OR)], is ligand exchange. The unusual mechanism of the subsequent intramolecular oxidation of benzyl alcoholate ligands in the 8-hydroxyquinolinato (HQ) complexes [(HQ)(2)V(V)(O)(OCH(2)C(6)H(4) p-X)] involves intermolecular deprotonation. In the presence of triethylamine, complex 3 (X = H) reacts within an hour at room temperature to generate, quantitatively, [(HQ)(2)V(IV)(O)], benzaldehyde (0.5 equivalents), and benzyl alcohol (0.5 equivalents). The base plays a key role in the reaction: in its absence, less than 12% conversion was observed after 72 hours. The reaction is first order in both 3 and NEt(3), with activation parameters DeltaH(?)=(28+/-4) kJ mol(-1) and DeltaS(?)=(-169+/-4) J K(-1) mol(-1). A large kinetic isotope effect, 10.2+/-0.6, was observed when the benzylic hydrogen atoms were replaced by deuterium atoms. The effect of the para substituent of the benzyl alcoholate ligand on the reaction rate was investigated using a Hammett plot, which was constructed using sigma(p). From the slope of the Hammett plot, rho=+(1.34+/ 0.18), a significant buildup of negative charge on the benzylic carbon atom in the transition state is inferred. These experimental findings, in combination with computational studies, support an unusual bimolecular pathway for the intramolecular redox reaction, in which the rate-limiting step is deprotonation at the benzylic position. This mechanism, that is, base-assisted dehydrogenation (BAD), represents a biomimetic pathway for transition-metal-mediated alcohol oxidations, differing from the previously identified hydride-transfer and radical pathways. It suggests a new way to enhance the activity and selectivity of vanadium catalysts in a wide range of redox reactions, through control of the outer coordination sphere. PMID- 23080555 TI - Shape control of bimetallic nanocatalysts through well-designed colloidal chemistry approaches. AB - Synthesis of bimetallic nanomaterials with well controlled shape is an important topic in heterogeneous catalysis, low-temperature fuel cell technology, and many other fields. Compared with monometallic counterparts, bimetallic nanocatalysts endow scientists with more opportunities to optimize the catalytic performance by modulating the charge transfer between different metals, local coordination environment, lattice strain and surface element distribution. Considering the current challenges in shape controlled synthesis of bimetallic nanocatalysts, this tutorial review highlights some significant achievements in preparing bimetallic alloy, core-shell and heterostructure nanocrystals with well-defined morphologies, summarizes four general routes and some key factors of the bimetallic shape control scenarios, and provides some general ideas on how to design synthetic strategies to control the shape and exposing facets of bimetallic nanocrystals. The composition and shape dependent catalytic behaviours of bimetallic nanocrystals are reviewed as well. PMID- 23080556 TI - Mitochondria organelle transplantation: introduction of normal epithelial mitochondria into human cancer cells inhibits proliferation and increases drug sensitivity. AB - Mitochondrial dysfunction of cancer cells includes increased aerobic glycolysis, elevated levels of ROS, decreased apoptosis, and resistance to chemotherapeutic agents. We hypothesized that the introduction of normal mitochondria into cancer cells might restore mitochondrial function and inhibit cancer cell growth, and reverse chemoresistance. First, in the present study, we tested if mitochondria of immortalized, untransformed mammary epithelial MCF-12A cells could enter into human cancer cell lines. Second, if introducing normal mitochondria into cancer cells would inhibit proliferation. And third, would the addition of normal mitochondria increase the sensitivity of human breast cancer MCF-7 cells to chemotherapy. We found that JC-1-stained mitochondria of immortalized, untransformed mammary epithelial MCF-12A cells can enter into the cancer cell lines MCF-7, MDA-MB-231, and NCI/ADR-Res, but cannot enter immortalized, untransformed MCF-12A cells. The normal mitochondria from immortalized, untransformed MCF-12A cells suppressed the proliferation of MCF-7 and NCI/ADR-Res cells in a dose-dependent pattern, but did not affect the proliferation of immortalized, untransformed MCF-12A cells. The normal mitochondria from immortalized, untransformed MCF-12A cells increased the sensitivity of human breast cancer MCF-7 cells to doxorubicin, Abraxane, and carboplatin. In conclusion, the introduction of normal mammary mitochondria into human breast cancer cells inhibits cancer cell proliferation and increases the sensitivity of the MCF-7 human breast cancer cell line to doxorubicin, Abraxane, and carboplatin. These results support the role of mitochondrial dysfunction in cancer and suggest the possible use of targeted mitochondria for cancer therapeutics. PMID- 23080557 TI - Linear measurement accuracy of dental CT images obtained by 64-slice multidetector row CT: the effects of mandibular positioning and pitch factor at CT scanning. AB - PURPOSE: To evaluate whether the measurement accuracy of dental CT images is affected by the mandibular positioning and the pitch factor at CT scanning. MATERIALS AND METHODS: Three dry mandibles were scanned by 64-slice multidetector row CT (MDCT) and micro-CT. For MDCT scanning, 7 different mandibular positioning and 3 different pitch factors were applied. After reformatting dental CT images, the bone height was measured on these images. It was also measured on the corresponding micro-CT image, which was defined as the actual value. The difference of the measurement values between these 2 was defined as the measurement error. RESULTS: There was no significant difference in the measurement errors due to either the mandibular positioning or the pitch factor. CONCLUSION: The measurement accuracy of dental CT images obtained was not affected by either mandibular positioning or pitch factor at CT scanning. PMID- 23081660 TI - Optoelectronic reconfigurable microchannels. AB - This paper reports a new optoelectronic reconfigurable microchannel (OERM) technology which uses low-power light to create and reconfigure microchannels within seconds. This technology thereby removes the need for complicated, on-chip fluidic interconnects and enables real-time modification of microchannel networks. In essence, OERM technology is based on the local thawing of a frozen solution using an optoelectronic heating effect powered by an external voltage supplier; a light pattern of microchannels is projected on an OERM chip containing a thin layer of frozen liquid, which produces microchannels corresponding to the light pattern via melting. When the pattern is modified, specific regions freeze and others melt according to the new light pattern, which causes the microchannel network to reconfigure. The versatility of this platform is illustrated by performing several experiments: single-phase flows are used to draw a smiley-face pattern, and multi-phase flow operations, such as generating and merging droplets and bubbles are demonstrated. Due to its low optical power requirement and its fast reconfiguration speed, OERM can dynamically alter microfluidic circuits while benefiting from the flexibility of light patterns and thereby offers a myriad of possible microfluidic applications. PMID- 23081659 TI - Exploring the role of neighborhood socio-demographic factors on HPV vaccine initiation among low-income, ethnic minority girls. AB - Little is known about whether neighborhood factors are associated with human papillomavirus (HPV) vaccine uptake, especially among disadvantaged groups that can benefit most from the vaccine. We used data collected from immigrant, low income mothers of adolescent girls and data from the 2005-2009 American Community Survey to investigate the relationship between HPV vaccine initiation and neighborhood characteristics. We compared initiation rates across levels of neighborhood disadvantage and employed multilevel logistic regression models to examine contextual effects on uptake. Overall, 27 % of girls (n = 479) initiated the vaccine. Initiation rates were highest among girls from the most disadvantaged neighborhoods (30 %), however, neighborhood factors were not independently associated with vaccine initiation after adjusting for individual factors. Mother's awareness of HPV, age, and insurance status were strong predictors for initiation. Future interventions should focus on improving awareness among low-income mothers as well as targeting vulnerable families outside the catchment area of public programs. PMID- 23081661 TI - Navigated treatment of metatarsal V fractures using a new image based guidance system. AB - BACKGROUND: Computer assisted imaging systems are rarely used for fracture treatment and foot surgery. We introduce a new system for image based guidance in traumatology. METHODS: We included 20 patients with a fracture of the fifth metatarsal. They were randomized on admission into two groups. Ten patients in the metatarsal group were operated conventionally and ten were operated with the assistance of a new image guidance system. This system is based on 2D-fluoro images which are acquired with a conventional c-arm and are transferred to the system workstation. After detecting marked tools, it can be used to display trajectories for K-wire guidance in the c-arm shot. RESULTS: The average duration of surgery in the image-guided group was 12.7 minutes. In the conventional treated group, it was 17 minutes. The average duration of radiation was 18 seconds in the image-guided group vs. 32.4 seconds in the conventional group. 1.6 trials were necessary to position the K-wire for image-guided procedures in comparison to 2.7 trials in the conventional group. CONCLUSION: Image-based guidance systems can be used for indications, were hitherto existing navigation systems are limited due to their dependence on fixed reference devices. Image guided systems can be integrated into existing workflows and can reduce the malpositioning of guidewires. PMID- 23081662 TI - Highly compression-tolerant supercapacitor based on polypyrrole-mediated graphene foam electrodes. AB - Deformation-tolerant devices are vital for the development of high-tech electronics of unconventional forms. In this study, a highly compressible supercapacitor has been fabricated by using newly developed polypyrrole-mediated graphene foam as electrode. The assembled supercapacitor performs based on the unique and robust foam electrodes achieves superb compression tolerance without significant variation of capacitances under long-term compressive loading and unloading processes. PMID- 23081663 TI - Measuring self-efficacy to deal with infertility: Psychometric properties and confirmatory factor analysis of the Portuguese version of the infertility self efficacy scale. AB - This study explores the psychometric properties and factor structure of the Portuguese version of the Infertility Self-Efficacy Scale (ISE-P), using translation and back-translation of the original version; principal component analysis; confirmatory factor analysis (CFA); and internal consistency, and test retest reliability analyses. A total of 287 participants (156 women and 131 men) seeking medical treatment were recruited from public and private fertility centers. CFA revealed that the single-component model fit the data well. The instrument showed excellent internal consistency, good test-retest reliability, and correlations with other mental health measures suggesting good convergent and discriminant validity. In conclusion, The ISE-P is a valid and reliable Portuguese-language measure of perceived self-efficacy to cope with infertility. PMID- 23081665 TI - Adaptive clinical trial designs with pre-specified rules for modifying the sample size: understanding efficient types of adaptation. AB - Adaptive clinical trial design has been proposed as a promising new approach that may improve the drug discovery process. Proponents of adaptive sample size re estimation promote its ability to avoid 'up-front' commitment of resources, better address the complicated decisions faced by data monitoring committees, and minimize accrual to studies having delayed ascertainment of outcomes. We investigate aspects of adaptation rules, such as timing of the adaptation analysis and magnitude of sample size adjustment, that lead to greater or lesser statistical efficiency. Owing in part to the recent Food and Drug Administration guidance that promotes the use of pre-specified sampling plans, we evaluate alternative approaches in the context of well-defined, pre-specified adaptation. We quantify the relative costs and benefits of fixed sample, group sequential, and pre-specified adaptive designs with respect to standard operating characteristics such as type I error, maximal sample size, power, and expected sample size under a range of alternatives. Our results build on others' prior research by demonstrating in realistic settings that simple and easily implemented pre-specified adaptive designs provide only very small efficiency gains over group sequential designs with the same number of analyses. In addition, we describe optimal rules for modifying the sample size, providing efficient adaptation boundaries on a variety of scales for the interim test statistic for adaptation analyses occurring at several different stages of the trial. We thus provide insight into what are good and bad choices of adaptive sampling plans when the added flexibility of adaptive designs is desired. PMID- 23081664 TI - TGF-beta-superfamily signaling regulates embryonic stem cell heterogeneity: self renewal as a dynamic and regulated equilibrium. AB - Embryonic stem cells dynamically fluctuate between phenotypic states, as defined by expression levels of genes such as Nanog, while remaining pluripotent. The dynamic phenotype of stem cells is in part determined by gene expression control and dictated by various signaling pathways and transcriptional regulators. We sought to define the activities of two TGF-beta-related signaling pathways, bone morphogenetic protein (BMP) and Nodal signaling, in modulating mouse embryonic stem (ES) cell heterogeneity in undifferentiated culture conditions. Both BMP and Nodal signaling pathways were seen to be active in distinct Nanog subpopulations, with subtle quantitative differences in activity. Pharmacological and genetic modulation of BMP or Nodal signaling strongly influenced the heterogeneous state of undifferentiated ES cells, as assessed by dynamic expression of Nanog reporters. Inhibition of Nodal signaling enhanced BMP activity, which through the downstream target Id factors, enhanced the capacity of ES cells to remain in the Nanog-high epigenetic state. The combined inhibition of Nodal and BMP signaling resulted in the accumulation of Nanog-negative cells, even in the presence of LIF, uncovering a shared role for BMP and Nodal signaling in maintaining Nanog expression and repression of differentiation. These results demonstrate a complex requirement for both arms of TGF-beta-related signaling to influence the dynamic cellular phenotype of undifferentiated ES cells in serum-based media, and that differing subpopulations of ES cells in heterogeneous culture have distinct responses to these signaling pathways. Several pathways, including BMP, Nodal, and FGF signaling, have important regulatory function in defining the steady state distribution of heterogeneity of stem cells. PMID- 23081666 TI - 64-MDCT showed the thrombus in the pulmonary vein of the patient with angina pectoris. AB - The vast majority of intracardiac thrombi of the patients with atrial fibrillation (AF) are reported to be in the left atrial appendage, which is thought to be an annual 6% to 10% risk. AF is responsible for 10% of ischaemic stroke. There have been few reports about the pulmonary vein thrombi. 64 Multidetector CT (64-MDCT) scan has recently become an optional diagnostic method for the assessment of coronary artery plaque. This study shows the pulmonary vein thrombus by 64-MDCT scan. The patient was a 79-year-old man and had hypertension, chest pain and no AF. 64-MDCT scan demonstrated 17.2*1.2*1.3 mm thrombus in the proximal side of the left upper pulmonary vein (LUPV). The distal portion of thrombus was seen to be attached to the wall of LUPV. This is the first report to show the pulmonary vein thrombus of the patient with hypertension, chest pain and no AF. PMID- 23081667 TI - Percutaneous minimally invasive necrosectomy following endoscopic transgastric drainage in acute necrotising pancreatitis. AB - A patient who had undergone failed transgastric placement of two cystgastrostomy stents referred to the regional pancreatic unit with ongoing sepsis for further management. Following stabilisation, percutaneous minimally invasive necrosectomy (MIN) was performed. MIN resulted in sustained clinical resolution of the sepsis and normalisation of serum C reactive protein levels. The transgastric drains were removed by MIN and, importantly, the patient did not develop a gastric fistula. To our knowledge, this is the first report of MIN following endoscopic cystgastrostomy stent placement. Pancreatic necrosis progresses from solid to semisolid to liquid states over a period of several months. Transgastric drainage should be reserved for subjects with either a pancreatic abscess or predominantly liquid necrosis reserving MIN for patients with systemic sepsis and those with semisolid necrosis. As increasing strategies to treat pancreatic necrosis become available clinicians must be alert to the development of new complications of these treatments. PMID- 23081668 TI - Low dose aspirin estimation: an application to a human pharmacokinetic study. AB - Low dose to very high dose aspirin is used to prevent heart attack. We have developed and validated a sensitive and robust method that could detect low levels of aspirin and salicylic acid in plasma and also a novel sample collection procedure to carry out sample preparation at room temperature. The total run time was 3.00 min; the developed method was validated in human plasma with a lower limit of quantitation of 0.99 ng/mL for aspirin and 2.01 ng/mL for salicylic acid. A linear response function was established for the range of concentrations 0.99-756.20 ng/mL (r > 0.998) for aspirin and 2.01-2486.86 ng/mL for salicylic acid. The intra- and inter-day precision values for aspirin and salicylic acid met the acceptance as per FDA guidelines. The developed assay method was applied to an oral pharmacokinetic study in humans. PMID- 23081669 TI - Flow cytometric determination of stem/progenitor content in epithelial tissues: an example from nonsmall lung cancer and normal lung. AB - Single cell analysis and cell sorting has enabled the study of development, growth, differentiation, repair and maintenance of "liquid" tissues and their cancers. The application of these methods to solid tissues is equally promising, but several unique technical challenges must be addressed. This report illustrates the application of multidimensional flow cytometry to the identification of candidate stem/progenitor populations in non-small cell lung cancer and paired normal lung tissue. Seventeen paired tumor/normal lung samples were collected at the time of surgical excision and processed immediately. Tissues were mechanically and enzymatically dissociated into single cell suspension and stained with a panel of antibodies used for negative gating (CD45, CD14, CD33, glycophorin A), identification of epithelial cells (intracellular cytokeratin), and detection of stem/progenitor markers (CD44, CD90, CD117, CD133). DAPI was added to measure DNA content. Formalin fixed paraffin embedded tissue samples were stained with key markers (cytokeratin, CD117, DAPI) for immunofluorescent tissue localization of populations detected by flow cytometry. Disaggregated tumor and lung preparations contained a high proportion of events that would interfere with analysis, were they not eliminated by logical gating. We demonstrate how inclusion of doublets, events with hypodiploid DNA, and cytokeratin+ events also staining for hematopoietic markers reduces the ability to quantify epithelial cells and their precursors. Using the lung cancer/normal lung data set, we present an approach to multidimensional data analysis that consists of artifact removal, identification of classes of cells to be studied further (classifiers) and the measurement of outcome variables on these cell classes. The results of bivariate analysis show a striking similarity between the expression of stem/progenitor markers on lung tumor and adjacent tumor-free lung. PMID- 23081670 TI - Long-term hearing result using Kurz titanium ossicular implants. AB - Titanium implants in middle ear surgery were introduced in the late 90s and are now frequently used in middle ear surgery. However, long-term studies of patient outcome are few and have only been published in subgroups of patients. We report the long-term effect of titanium middle ear implants for ossicular reconstruction in chronic ear disease investigated in a Norwegian tertiary otological referral centre. Retrospective chart reviews were performed for procedures involving 76 titanium implants between 2000 and 2007. All patients who underwent surgery using the Kurz Vario titanium implant were included in the study. Audiological parameters using four frequencies, 0.5, 1, 2, and 3 kHz, according to AAO-HNS guidelines, was assessed pre and postoperatively. Otosurgical procedures, complications, revisions, and extrusion rates were analyzed. The study had no dropouts. The partial ossicular replacement prosthesis (PORP) was used in 44 procedures and the total ossicular replacement prosthesis (TORP) in 32 procedures, respectively. Mean follow-up was 5.2 years (62 months). The ossiculoplasties were performed as staging procedures or in combination with other chronic ear surgery. The same surgeon performed all the procedures. A postoperative air-bone gap of <= 20 dB was obtained in 74 % of the patients, 82 % for the Bell (PORP) prosthesis, and 63 % for the Arial (TORP) prosthesis. The extrusion rate was 5 %. We conclude that titanium ossicular implants give stable and excellent long-term hearing results. PMID- 23081671 TI - Histone methylation and acetylation indicates epigenetic change in the aged cochlea of mice. AB - It is currently accepted that epigenetics plays an important role in normal genetics and differentiation, and its failure triggers various diseases such as cancer, aging, metabolic diseases, and abnormal differentiations. The typical mechanism involves the modification of histones and the methylation of DNA. In this study, we investigated the modification of histones in the aged cochlea of mice using immunohistochemistry. Eight mice [C57BL/6(B6)] at the age of 8 weeks (young group) and 132 weeks (aged group) were used. Cochleas were fixed with paraformaldehyde and then decalcified. Hematoxylin-eosin staining was performed for the morphological study using a light microscope. After removing paraffin, the sections were incubated with the primary antibody to acetyl-histone H3 Lys9 or dimethyl-histone H3 Lys9. Confocal scanning microscopy was performed for observation. The degeneration was severest in the spiral ganglion cells and the organ of Corti of the basal turn as determined by light microscopy. Acetylated histone H3 was detected in the spiral ganglion cells and the organ of Corti of the young group, but not in those of the aged group. Dimethylated histone H3 was detected in the spiral ganglion cells and the organ of Corti of the aged group, but not in those of the young group. Acetylation was switched to methylation during ageing. Histone modification is known to have a critical role in neuro degeneration. Our findings suggest that epigenetic change participates in the process of presbycusis. PMID- 23081672 TI - Are contrast swallows a relevant investigation for paediatric stridor? AB - The contrast swallow has traditionally been used in the investigation of paediatric stridor with the aim of identifying pathology such as vascular rings and confirming the presence of gastro-oesophageal reflux. Currently, a laryngotracheobronchoscopy (LTB) is the gold standard investigation for stridor and frequently, a child is commenced on antireflux medications based on clinical history. We seek to identify whether a contrast swallow has a valuable and cost effective role in the investigation of paediatric stridor. This was a retrospective audit study. All the children who underwent a contrast swallow as part of the investigation for stridor were identified from 2008 to 2011. All requests were made by clinicians from the ENT department at Birmingham Children's Hospital. All patient demographics and radiological reports were reviewed. The final patient list was cross referenced with theatre records to identify those that underwent a LTB The cost of the contrast swallow was identified by the contracting department at Birmingham Children's Hospital. A total of 117 contrast swallows were requested during the study period. The age range was 1 week to 50 months with an average patient age of 6 months. 45/117 (38 %) of contrast swallows identified pathology. 33/45 (73 %) demonstrated reflux. Only 12/117 (10 %) of all cases suggested pathology other than reflux. A total of 51 patients underwent LTB. 22/51 (43 %) had a subsequent contrast swallow. Since the average cost per contrast swallow in the outpatient setting was L 77, and only 9 cases demonstrated significant unexpected pathology, 108 children had a contrast swallow that did not significantly alter the management of their stridor. 9 cases were identified in which the contrast study results altered the management of the child. An estimated L 8,000 were spent on investigations that made no impact on the subsequent management of the child. Contrast swallows requested for the investigation of paediatric stridor identified 33 cases of gastro-oesophageal reflux and 12 cases of alternative pathology. Among those children with radiological evidence of reflux, 70 % (23/33) had already been commenced on antireflux medication based on their clinical symptoms. Only 8 % of findings from a contrast swallow investigation resulted in a change to the management of the stridulous child. The authors suggest that it is more cost effective to reserve requests for a contrast swallow until the diagnostic LTB is performed. This strategy will not only reduce exposure to ionising radiation in a significant number of children, but also identifies airway pathology more effectively and ensures that contrast swallows are used as an appropriate adjunctive diagnostic investigation. PMID- 23081673 TI - Impact of patient comorbidities on head and neck microvascular reconstruction. A report on 423 cases. AB - The aim of this study was to assess the impact of the different subtypes of patient comorbidities on the outcomes of head and neck microvascular reconstruction. A total of 423 patients who underwent head and neck free flap reconstruction in our institution between 2000 and 2010 were included in this retrospective study. The impact of the different subtypes of patient comorbidities (as defined by the Kaplan-Feinstein Index) and other global health status-related factors on free flap success, local and general complications, postoperative mortality and length of stay was assessed in univariate and multivariate analysis. We found no correlation between patient comorbidities and free flap failure. In multivariate analysis, we demonstrated a significant correlation between tobacco consumption (p = 0.04) and local complications. Gastro-intestinal comorbidity (p = 0.005) and malnutrition (p = 0.02) were associated with a higher risk of fistula formation. Diabetes mellitus (p = 0.003), gastro-intestinal (p = 0.02), systemic (p = 0.02) and cardiac comorbidities (p = 0.03) were significant predictors of medical complications. We concluded that the different subtypes of patient comorbidities were relevant predictors of complications in head and neck microvascular reconstruction. PMID- 23081674 TI - Postoperative nasal symptoms associated with an endoscopic endonasal transsphenoidal approach. AB - Recent studies have indicated the usefulness of endoscopic endonasal transsphenoidal approach (EETSA). A few studies have reported on the postoperative nasal symptoms of patients who have undergone EETSA. Therefore, we adopted a rhinologic perspective to compare preoperative and postoperative nasal symptoms after performing a binostril, four-hand EETSA. Patients who were scheduled to undergo binostril, four-hand EETSA underwent preoperative nasal evaluation using the Nasal Obstruction Symptom Evaluation (NOSE), Sino-Nasal Outcome Test-20 (SNOT-20), and a visual analogue scale (VAS) to assess several nasal symptoms. Repeat testing was performed 6 months postoperatively. Paired Student's t tests were used to compare preoperative and postoperative scores. A total of 142 patients who underwent a binostril, four-hand EETSA were included in this study. We found no statistically significant differences between preoperative and postoperative NOSE, total SNOT-20 scores, or scores on the VAS for nasal obstruction, sneezing, rhinorrhea, snoring, or facial pain. However, VAS of olfactory change increased significantly after EETSA (p < 0.05). The binostril, four-hand EETSA would be a useful method because it permits operative manipulability and a wide visual field for skull base lesions. However, rhinologists must consider postoperative nasal symptoms and perform a proper preoperative examination, especially with regard to the olfactory function, and inform patients scheduled for EETSA of potential postoperative changes. PMID- 23081675 TI - Umpolung by N-heterocyclic carbenes: generation and reactivity of the elusive 2,2 diamino enols (Breslow intermediates). PMID- 23081676 TI - Fulfilling Koch's postulates for beet curly top Iran virus and proposal for consideration of new genus in the family Geminiviridae. AB - Beet curly top Iran virus (BCTIV) is a divergent geminivirus with biological properties similar to those of curtoviruses; however, the virus is distinct from curtoviruses phylogenetically and in its genome organisation. The replication associated protein is phylogenetically more closely related to those of mastreviruses than to those of curtoviruses whereas the capsid protein shares high amino acid sequence identity (77-83 %) with those of curtoviruses. The 17 BCTIV genomes from Iran share ~77 % pairwise nucleotide sequence identity with spinach curly top Arizona virus (SCTAV) from Arizona, USA, which was characterised recently. To demonstrate the infectivity of the monopartite BCTIV genome and to fulfil Koch's postulates, an infectious clone was constructed using a dimer of the full-length genome of an isolate from this study - BCTIV [IR:Neg:B33P:Sug:08]. Agroinoculation with the cloned DNA resulted in the efficient infection of 74 % of sugar beet plants, which resulted in curly top symptoms. The curly top infection of agroinoculated plants was successfully transmitted to 80 % of healthy sugar beet plants by the natural BCTIV vector, Circulifer haematoceps. Since BCTIV and SCTAV share <62 % pairwise nucleotide sequence identity with all other geminiviruses and have unique genome architectures and properties, and since this is coupled with phylogenetic support at the full-genome level and that of it proteins, we propose that they should be re-classified as members of a new genus, "Becurtovirus", in the family Geminiviridae. PMID- 23081677 TI - Development of a full-length infectious clone of sunflower chlorotic mottle virus (SuCMoV). AB - A full-length cDNA clone (p35SuCMoV) of the sunflower chlorotic mottle virus common strain (SuCMoV-C) genomic RNA was constructed. Three cDNA fragments covering the whole genome of SuCMoV-C were cloned between a cauliflower mosaic virus 35S promoter and a nopaline synthase terminator. Mechanical inoculation of sunflower and Nicotiana occidentalis seedlings with p35SuCMoV DNA led to systemic infection. Symptoms induced by p35SuCMoV were similar to those caused by the wild type SuCMoV-C but appeared four days later. Infection was confirmed by a western blot test, electron microscopy, RT-PCR and inoculation of progeny virions to sunflower seedlings. This is the first report about the construction of a biologically active, full-length cDNA copy of the SuCMoV-C RNA genome. PMID- 23081678 TI - The complete genome sequence of a Brazilian isolate of yam mild mosaic virus. AB - In this study, the complete genome of an isolate of yam mild mosaic virus (YMMV) from Brazil was sequenced, and the predicted amino acid sequence was analyzed. The YMMV RNA genome consists of 9538 nt without the poly(A) tail, encoding a putative typical potyvirus polyprotein of 3084 amino acids. Furthermore, the small overlapping ORF (PIPO) in the P3 gene was also deduced, and the cleavage sites of the polyprotein were predicted. Multiple alignment with other potyviruses showed a maximum nucleotide sequence identity of 64 % to wild tomato mosaic virus. A phylogenetic tree showed that YMMV clustered with Asian potyviruses that mainly infect solanaceous plants. PMID- 23081679 TI - Isolation and genomic characterization of three enterovirus 90 strains in Shandong, China. AB - Enterovirus 90 (EV90) is a newly identified serotype of the species Human enterovirus A, and few nucleotide sequences of EV90 are available. In this study, three EV90 strains were isolated from acute flaccid paralysis (AFP) cases in Shandong Province, China, in 2001 and 2003. Sequence analysis revealed 96.7-98.0 % VP1 nucleotide identity among themselves and 77.7-92.3 % to other EV90 strains. Complete genome analysis provided evidence of recombination in the non-capsid coding region of strain 01421. This is the first report of EV90 in China, and the low isolation rate suggests that it has not been a prevalent serotype in China. PMID- 23081680 TI - Reproductive history and risk of small bowel cancer by histologic type: a population-based study. AB - PURPOSE: The male predominance of the two main histologic malignancies of the small bowel cancer may reflect a role of sex hormones which will be examined in this study. METHODS: This was a nationwide population-based nested case-control study, based on a cohort of subjects born between 1932 and 2008, as identified in the Swedish Multi-Generation Register. For each case of small bowel cancer, 10 age- and sex-matched controls were randomly selected. Number of children and age at having the first child were analyzed in relation to the risk of small bowel cancer using conditional logistic regression, providing odds ratios (ORs) and 95 % confidence intervals (CIs). RESULTS: A total of 632 female cases and 894 male cases of small bowel cancer were included. No overall increased risk of small bowel cancer was found in parous compared to non-parous women (OR = 1.02, 95 % CI 0.67-1.54). There was no association between age at first birth and small bowel cancer (>30 years of age vs <20 years; OR = 1.04, 95 % CI 0.72-1.50). No associations were detected in separate analyses of adenocarcinoma or carcinoid of the small bowel. No distinct risk patterns were discerned in men compared to women. CONCLUSIONS: Reproductive history does not seem to be associated with the risk of small bowel cancer, independent of histologic type. PMID- 23081682 TI - Application of quantitative 1H-NMR method to determination of paeoniflorin in Paeoniae radix. AB - A quantitative (1)H-NMR method (qHNMR) was used to measure paeoniflorin content in Paeoniae radix (dried root of Paeonia lactiflora), of which paeoniflorin is a major component. The purity of paeoniflorin was calculated from the ratio of the intensity of the H-9 signal at delta 5.78 ppm of paeoniflorin to that of a hexamethyldisilane (HMD) signal at 0 ppm. The concentration of HMD was corrected with SI traceability by using bisphenol A of certified reference material (CRM) grade. The paeoniflorin content in 2 separate samples of Paeoniae radix was determined by qHNMR and was found to be 2.15 and 2.45%. We demonstrated that this method is useful for quantitative analysis of crude drugs. PMID- 23081683 TI - [Symptom validation]. PMID- 23081681 TI - CYP2C9 variants increase risk of colorectal adenoma recurrence and modify associations with smoking but not aspirin treatment. AB - PURPOSE: The cytochrome P450 2C9 enzyme (CYP2C9) is involved in metabolism of endogenous compounds, drugs, and procarcinogens. Two common nonsynonymous polymorphisms in CYP2C9 are associated with reduced enzyme activity: CYP2C9*2 (rs1799853, R144C) and CYP2C9*3 (rs1057910, I359L). METHODS: We investigated whether CYP2C9 genotype was associated with risk of colorectal adenoma and/or modified associations with aspirin treatment or cigarette smoking in a cohort of 928 participants in a randomized trial of aspirin chemoprevention. Generalized linear regression was used to compute relative risks (RRs) and 95 % confidence intervals (95 % CIs). Multiplicative interactions terms were used to assess effect modification. RESULTS: CYP2C9 genotype was associated with increased risks for adenoma recurrence of 29 % (RR = 1.29, 95 % CI 1.09-1.51) for >=1 variant allele (CYP2C9*2 or *3) and 47 % (RR = 1.47, 95 % CI 1.19-1.83) for >=1 CYP2C9*3 allele. The risk for advanced lesions or multiple (>=3) adenomas was increased by 64 % (RR = 1.64, 95 % CI 1.18-2.28) for >=1 variant allele (CYP2C9*2 or *3) and 79 % (RR = 1.79, 95 % CI 1.16-2.75) for >=1 CYP2C9*3 allele. Genotype modified associations with smoking, but not aspirin treatment. The adenoma risk was increased by 26 % (RR = 1.26, 95 % CI 0.99-1.58) for former smokers and 60 % (RR = 1.60, 95 % CI 1.19-2.15) for current smokers among wild-type individuals, but there was no increased risk among individuals with >=1 variant allele (CYP2C9*2 or *3) (p (interaction) = 0.04). CONCLUSIONS: Carriers of CYP2C9 variants with lower enzyme activity have increased overall risk of colorectal adenoma but reduced adenoma risk associated with cigarette smoking. These results may be due to effects on the synthesis of endogenous eicosanoids and/or reduced activation of procarcinogens in smoke by CYP2C9 variants. PMID- 23081684 TI - Criterion validation of the rate of recovery, single alphanumeric measure, in patients with low back pain. AB - BACKGROUND AND PURPOSE: The aim of this study was to determine the criterion validity of patient rate of recovery with the Oswestry Disability Index (ODI) and the Numeric Pain Rating Scale (NPRS). METHODS: Associations between rate of recovery and ODI and pain were examined using a receiver operating characteristic (ROC) curve. Participants were dichotomized to ODI 50% change versus a <50% change. Pearson correlation coefficients were performed to determine the relationship between the continuous variables of rate of recovery and final ODI score at discharge. Spearman correlation coefficients were performed to determine the relationship between the continuous variable rate of recovery and ordinal variable final pain score at discharge. RESULTS: ROC curve statistics suggest that a cut-point of greater than 82.5% on the self-report rate of recovery (sensitivity = 0.72, specificity = 0.71 and positive likelihood ratio = 2.44) corresponded to a 50% change on the ODI. The correlation between ODI final score and self-report rate of recovery was a moderate, -0.45 (p < 0.01). Cut-points on the self-reported rate of recovery ranged from 72.5% to 82.5% depending upon the definition of change in pain (>=2, >=3 and >=4 points) score or final pain score (<5/10, <4/10 and <3/10). The correlation between NPRS final score and self report rate of recovery was -0.72 (p < 0.01). The correlation between NPRS change score and self-report rate of recovery was 0.42 (p < 0.01). DISCUSSION: Patients reporting greater than or equal to 82.5% on rate of recovery are likely to have met a 50% change on the ODI. The moderate correlation between rate of recovery and ODI suggests that rate of recovery may capture a dimension of recovery in addition to the self-reported function in patients with low back pain. Both outcomes measures can be used to capture a more comprehensive evaluation of recovery from low back pain. PMID- 23081685 TI - Evaluation of 36 formulas for calculating plasma osmolality. AB - PURPOSE: Measuring or calculating plasma osmolality is of interest in critical care medicine. Moreover, the osmolal gap (i.e. the difference between the measured and calculated osmolality) helps in the differentiation of metabolic acidosis. A variety of formulas for calculating osmolality have been published, most of them relying on sodium, urea and glucose. A novel formula developed by Zander has recently been published, which also takes into account the effects of potassium, chloride, lactate and bicarbonate on osmolality. We evaluate the previously published formulas including the novel formula by comparing calculated and measured osmolality. METHODS: Arterial or venous blood samples from 41 outpatients and 195 acutely ill inpatients (total 236 subjects) were used to compare measured osmolality with calculated osmolality as obtained from 36 published formulas including the new formula. The performance of the formulas was statistically evaluated using the method of Bland and Altman. RESULTS: Mean differences up to 35 mosmol/kg H(2)O were observed between measured and calculated osmolality using the previously published formulas. In contrast, the novel formula had a negligible mean difference of 0.5 mosmol/kg H(2)O. The novel formula also had the closest 95 % limits of agreement ranging from -6.5 to 7.5 mosmol/kg H(2)O. CONCLUSION: Only 4 out of the 36 evaluated formulas gave mean differences between measured and calculated osmolality of less than 1 mosmol/kg H(2)O. Zander's novel formula showed excellent concordance with measured osmolality and facilitates a more precise diagnosis based on blood gas analysers. The new equation has the potential to replace separate measurements of osmolality in many cases. PMID- 23081686 TI - A novel genetic marker of liver disease aetiology in hepatocellular carcinoma: culling the metabolic syndrome. PMID- 23081687 TI - Optical properties and photo-oxidation of tetraphenylethene-based fluorophores. AB - We report the optical properties of tetraphenylethene (TPE) and other TPE derivatives functionalised with an octyl group (TPE-OCT) and polyethyleneglycol group (TPE-PEG) in the side chain. We compared TPE-OCT and TPE-PEG with TPE in both organic solvents and under aqueous conditions. All materials exhibit aggregation-induced emission, however, uncommonly, TPE-PEG seems to aggregate in aqueous solution with enhanced photoluminescence quantum efficiency (PLQE) relative to that in organic solvents. All three materials can be photo-oxidised in solution to their diphenylphenanthrene derivative by irradiation with UV light (at both ~1 and ~5 mW cm(-2)), with a subsequent enhancement in PL efficiency. The electron-donating ether group increases the rate of oxidation relative to bare TPE and also photo-oxidation was shown to be solvent and concentration dependent. Finally, photo-oxidation was also demonstrated in the aggregate state. PMID- 23081688 TI - Periodic Mesoporous Organosilicas: from simple to complex bridges; a comprehensive overview of functions, morphologies and applications. AB - Periodic Mesoporous Organosilicas (PMOs) were developed in 1999 and are basically ordered templated mesoporous organosilicas, prepared by the combination of a surfactant as template and a silsesquioxane as the organosilica precursor. They were one of the first examples of the so-called "hybrid" organic/inorganic materials. In the years that followed, an amazing variety of functional groups, morphologies and applications has been developed. Some of these high-end applications, like low-k buffer layers in microelectronics, chiral catalysts, chromatographic supports, selective adsorbents and light-harvesting devices, have clearly shown their potential. In this review, we will give a comprehensive overview of all these different functionalities and applications that have been created for Periodic Mesoporous Organosilicas. PMID- 23081689 TI - Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. AB - OBJECTIVES: To assess the efficacy of three different daily doses of acetazolamide in the prevention of acute mountain sickness and to determine the lowest effective dose. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline and Embase along with a hand search of selected bibliographies. No language restrictions were applied. STUDY SELECTION: Randomised controlled trials assessing the use of acetazolamide at 250 mg, 500 mg, or 750 mg daily versus placebo in adults as a drug intervention for the prophylaxis of acute mountain sickness. Included studies were required to state the administered dose of acetazolamide and to randomise participants before ascent to either acetazolamide or placebo. Two reviewers independently carried out the selection process. DATA EXTRACTION: Two reviewers extracted data concerning study methods, pharmacological intervention with acetazolamide, method of assessment of acute mountain sickness, and event rates in both control and intervention groups, which were verified and analysed by the review team collaboratively. DATA SYNTHESIS: 11 studies (with 12 interventions arms) were included in the review. Acetazolamide at doses of 250 mg, 500 mg, and 750 mg were all effective in preventing acute mountain sickness above 3000 m, with a combined odds ratio of 0.36 (95% confidence interval 0.28 to 0.46). At a dose of 250 mg daily the number needed to treat for acetazolamide to prevent acute mountain sickness was 6 (95% confidence interval 5 to 11). Heterogeneity ranged from I(2)=0% (500 mg subgroup) to I(2)=44% (750 mg subgroup). CONCLUSIONS: Acetazolamide in doses of 250 mg, 500 mg, and 750 mg daily are all more effective than placebo for preventing acute mountain sickness. Acetazolamide 250 mg daily is the lowest effective dose to prevent acute mountain sickness for which evidence is available. PMID- 23081690 TI - Medical Council of India recommends removal of 25 doctors from medical register for falsely claiming to be faculty members. PMID- 23081691 TI - Association between sleep apnea, sleep duration, and serum lipid profile in an urban, male, working population in Japan. AB - BACKGROUND: Dyslipidemia is often comorbid with obstructive sleep apnea (OSA), but few population-based studies have investigated their relationship. Short sleep duration is associated with hypertension and diabetes; however, its association with dyslipidemia is not well known. We investigated relationships among OSA, sleep duration, and the lipid profile in a community-based study. METHODS: We measured the respiratory disturbance index (RDI) and sleep duration by a type 3 portable device and actigraph in 275 men in a Japanese company. Fasting blood parameters were obtained from periodic inspection data. RESULTS: According to Japanese criteria, 143 subjects had dyslipidemia. Percent sleep time of oxygen saturation as measured by pulse oximetry (SpO2) < 90% and prevalence of severe OSA were greater and sleep duration and mean SpO2 during sleep were lower in subjects with dyslipidemia than in those without. Univariate analysis showed that the RDI was positively correlated with serum triglyceride (TG) levels (rho = 0.20, P < .01), and sleep duration was negatively correlated with serum total cholesterol (TC) levels (gamma = -0.13, P = .03) and serum low-density lipoprotein cholesterol levels (gamma = -0.12, P = .04). Stepwise multiple regression analysis revealed that TG was correlated with RDI (beta = 0.14, P = .02), BMI (beta = 0.20, P < .01), and alcohol intake (beta = 0.20, P < .01), and that TC was correlated with sleep duration (beta = -0.13, P = .03), age (beta = 0.15, P = .02), and waist/hip ratio (beta = 0.15, P = .02). CONCLUSIONS: Short sleep duration was associated with TC levels and RDI was positively associated with TG levels among working-aged men in an urban Japanese company. Correcting the status of OSA and/or short sleep duration might improve the lipid profile and cardiovascular consequences. PMID- 23081692 TI - Robotic adrenalectomy: technical aspects, early results and learning curve. AB - BACKGROUND: Adrenal surgery is undergoing continuous evolution, and robotic technology may extend indications for a minimally invasive approach to adrenalectomy. METHODS: Thirty robot-assisted unilateral transperitoneal adrenalectomy procedures have been performed at our Department over the last 5 years. The presence of bilateral lesions and vascular involvement were the only contra-indications for a minimally invasive approach. Several patients presented with significant co-morbidities: BMI > 35 kg/m(2) (20%); ASA score III-IV (58.7%); and moderate to severe impaired respiratory function (36.6%). In addition, 40% of patients had undergone previous abdominal surgery. RESULTS: Two patients presented with intra-operative complications (6.6%) and only one patient required conversion to an open procedure (3.3%). None of the patients required intraoperative transfusions. Hospital morbidity was 10% but no mortality was recorded. The mean hospital stay was 5.2 +/- 2.2 days. The mean size of the resected adrenal mass was 5.1 +/- 2.4 cm. A significant reduction in operative times was found with gaining experience. CONCLUSIONS: Thanks to robotic technology, some subpopulations of patients with clinical or oncological contra indications to laparoscopic treatment may be addressed with minimally invasive treatment. PMID- 23081693 TI - Number of leads with fragmented QRS predicts response to cardiac resynchronization therapy. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an effective option in the treatment of patients with heart failure (HF) and wide QRS. Fragmented QRS (fQRS) on 12-lead electrocardiography has been shown to predict cardiac events in several patient populations. However, the relationship between the number of leads with fQRS and response to CRT has not been investigated. HYPOTHESIS: The number of leads with fQRS may predict response to CRT. METHODS: One hundred five patients with HF undergoing CRT were prospectively studied. The presence of fQRS was assessed using standardized criteria. Echocardiographic response to CRT was defined by a >=15% reduction in left ventricular end-systolic volume at 6 months follow-up. RESULTS: Seventy-four patients (71%) had CRT response after 6 months of follow-up. In multivariate analysis, significant associates of response to CRT were evaluated adjusting for gender, etiology of cardiomyopathy, QRS width, baseline left ventricular ejection fraction, and the number of leads with fQRS. The number of leads with fQRS was the only predictor of response to CRT (odds ratio: 0.61, 95% confidence interval: 0.48-0.77, P < 0.001). CONCLUSIONS: The more leads with fQRS predicts nonresponse to CRT and may help in the selection of CRT candidates. PMID- 23081694 TI - Nanostructured Si-nanowire microarrays for enhanced-performance bio-analytics. AB - We demonstrate the fabrication of a novel platform based on Si nanowire arrays integrated with a programmable DNA-directed homogeneous-phase analyte-capture strategy for robust detection of bio-analytes. The nanofabrication process used, based on a combination of glancing-angle-deposition and metal-assisted-catalytic etching, is capable of producing thousands of testing sites per chip, and the sites can be fabricated over entire wafers, with precise control of size and positioning, using conventional microelectronics technology. The analyte-capture strategy used eliminates the well-known interference of the heterogeneous-phase (substrate) with the capturing of analytes. We examine the effects of the nanoscale features of the substrates (nanowire porosity and clumping) on the coupling efficiency of analytes and show that the fabricated microarrays are robust, have high efficiency and capacity, and provide significantly enhanced signal-to-noise ratio detection. PMID- 23081696 TI - Photoalignment and surface-relief-grating formation are efficiently combined in low-molecular-weight halogen-bonded complexes. AB - It is demonstrated that halogen bonding can be used to construct low-molecular weight supramolecular complexes with unique light-responsive properties. In particular, halogen bonding drives the formation of a photoresponsive liquid crystalline complex between a non-mesogenic halogen bond-donor molecule incorporating an azo group, and a non-mesogenic alkoxystilbazole moiety, acting as a halogen bond-acceptor. Upon irradiation with polarized light, the complex exhibits a high degree of photoinduced anisotropy (order parameter of molecular alignment > 0.5). Moreover, efficient photoinduced surface-relief-grating (SRG) formation occurs upon irradiation with a light interference pattern, with a surface-modulation depth 2.4 times the initial film thickness. This is the first report on a halogen-bonded photoresponsive low-molecular-weight complex, which furthermore combines a high degree of photoalignment and extremely efficient SRG formation in a unique way. This study highlights the potential of halogen bonding as a new tool for the rational design of high-performance photoresponsive suprastructures. PMID- 23081695 TI - Disruption of mitochondrial homeostasis by phytanic acid in cerebellum of young rats. AB - Phytanic acid (Phyt) brain concentrations are highly increased in Refsum disease, a peroxisomal disorder clinically characterized by neurological features, cardiac abnormalities, and retinitis pigmentosa. Considering that the pathogenesis of cerebellar ataxia, a common finding in this disease, is still unknown, in the present work we investigated the in vitro effects of Phyt at concentrations similar to those found in affected patients on important parameters of mitochondrial homeostasis in cerebellum from young rats. The respiratory parameters states 3 and 4 and respiratory control ratio (RCR) determined by oxygen consumption, membrane potential (?Psim), NAD(P)H pool content, and swelling were evaluated in mitochondrial preparations from this cerebral structure. Phyt markedly increased state 4 respiration, whereas state 3 respiration, the RCR, the mitochondrial matrix NAD(P)H content, and ?Psim were decreased by this fatty acid, being the latter effect partially prevented by N acetylcysteine. These data indicate that Phyt behaves as an uncoupler of oxidative phosphorylation and as a metabolic inhibitor disrupting mitochondrial homeostasis in cerebellum. It is proposed that these pathomechanisms may contribute at least in part to the cerebellar alterations found in Refsum disease. PMID- 23081697 TI - Recruitment of a myeloid cell subset (CD11b/Gr1 mid) via CCL2/CCR2 promotes the development of colorectal cancer liver metastasis. AB - Liver metastasis from colorectal cancer is a leading cause of cancer mortality. Myeloid cells play pivotal roles in the metastatic process, but their prometastatic functions in liver metastasis remain incompletely understood. To investigate their role, we simulated liver metastasis in C57BL/6 mice through intrasplenic inoculation of MC38 colon carcinoma cells. Among the heterogeneous myeloid infiltrate, we identified a distinct population of CD11b/Gr1(mid) cells different from other myeloid populations previously associated with liver metastasis. These cells increased in number dramatically during establishment of liver metastases and were recruited from bone marrow by tumor-derived CCL2. Liver metastasis of Lewis lung carcinoma cells followed this pattern but this mechanism is not universal as liver colonization by B16F1 melanoma cells did not recruit similar subsets. Inhibition of CCL2 signaling and absence of its cognate receptor CCR2 reduced CD11b/Gr1(mid) recruitment and decreased tumor burden. Depletion of the CD11b/Gr1(mid) subset in a transgenic CD11b-diphtheria toxin receptor mouse model markedly reduced tumor cell proliferation. There was no evidence for involvement of an adaptive immune response in the prometastatic effects of CD11b/Gr1(mid) cells. Additionally, an analogous myeloid subset was found in liver metastases of some colorectal cancer patients. CONCLUSION: Collectively, our findings highlight the importance of myeloid cells--in this case a selective CD11b/Gr1(mid) subset--in sustaining development of colorectal cancer liver metastasis and identify a potential target for antimetastatic therapy. PMID- 23081698 TI - Seeing a difference in C. diff. PMID- 23081699 TI - The cancer stem cell: cell type or cell state? PMID- 23081700 TI - On the segregation of protein ionic residues by charge type. AB - Based on ubiquitous presence of large ionic motifs and clusters in proteins involved in gene transcription and protein synthesis, we analyzed the distribution of ionizable sidechains in a broad selection of proteins with regulatory, metabolic, structural and adhesive functions, in agonist, antagonist, toxin and antimicrobial peptides, and in self-excising inteins and intron-derived proteins and sequence constructs. All tested groups, regardless of taxa or sequence size, show considerable segregation of ionizable sidechains into same type charge (homoionic) tracts. These segments in most cases exceed half of the sequence length and comprise more than two-thirds of all ionizable sidechains. This distribution of ionic residues apparently reflects a fundamental advantage of sorted electrostatic contacts in association of sequence elements within and between polypeptides, as well as in interaction with polynucleotides. While large ionic densities are encountered in highly interactive proteins, the average ionic density in most sets does not change appreciably with size of the homoionic segments, which supports the segregation as a modular feature favoring association. PMID- 23081701 TI - Bone marrow microenvironment in cancer patients: immunological aspects and clinical implications. AB - The bone marrow (BM) of cancer patients is considered an essential secondary lymphoid organ with substantial impact on tumor cell dissemination and tumor immune responses. Recent advances in the understanding of BM/primary tumor crosstalk, homing processes, premetastatic niche formation, tumor cell dormancy, and ultimately, identification of the BM micromilieu cytokines, chemokines, and growth factors may provide the basis for the development of targeted therapeutic strategies potentially rendering primary cancers and cancer bone metastases more susceptible to chemotherapy. The present review aims to dissect the individual components of the BM microenvironment in cancer patients, compare it to the healthy BM, and discuss its impact on interactions between the tumor and the immune system. PMID- 23081703 TI - Comprehensive mapping of the bull sperm surface proteome. AB - While the mechanisms that underpin maturation, capacitation, and sperm-egg interactions remain elusive it is known that these essential fertilisation events are driven by the protein complement of the sperm surface. Understanding these processes is critical to the regulation of animal reproduction, but few studies have attempted to define the full repertoire of sperm surface proteins in animals of agricultural importance. Recent developments in proteomics technologies, subcellular fractionation, and optimised solubilisation strategies have enhanced the potential for the comprehensive characterisation of the sperm surface proteome. Here we report the identification of 419 proteins from a mature bull sperm plasma membrane fraction. Protein domain enrichment analyses indicate that 67% of all the proteins identified may be membrane associated. A large number of the proteins identified are conserved between mammalian species and are reported to play key roles in sperm-egg communication, capacitation and fertility. The major functional pathways identified were related to protein catabolism (26S proteasome complex), chaperonin-containing TCP-1 (CCT) complex and fundamental metabolic processes such as glycolysis and energy production. We have also identified 118 predicted transmembrane proteins, some of which are implicated in cell adhesion, acrosomal exocytosis, vesicle transport and immunity and fertilisation events, while others have not been reported in mammalian LC-MS derived sperm proteomes to date. Comparative proteomics and functional network analyses of these proteins expand our system's level of understanding of the bull sperm proteome and provide important clues toward finding the essential conserved function of these proteins. PMID- 23081702 TI - Animal models of leukemia: any closer to the real thing? AB - Animal models have been invaluable in the efforts to better understand and ultimately treat patients suffering from leukemia. While important insights have been gleaned from these models, limitations must be acknowledged. In this review, we will highlight the various animal models of leukemia and describe their contributions to the improved understanding and treatment of these cancers. PMID- 23081704 TI - The impact of Cytochrome P450 CYP1A2, CYP2C9, CYP2C19 and CYP2D6 genes on suicide attempt and suicide risk-a European multicentre study on treatment-resistant major depressive disorder. AB - Recently published data have reported associations between cytochrome P450 metabolizer status and suicidality. The aim of our study was to investigate the role of genetic polymorphisms of the cytochrome P450 genes on suicide risk and/or a personal history of suicide attempts. Two hundred forty-three major depressive disorder patients were collected in the context of a European multicentre resistant depression study and treated with antidepressants at adequate doses for at least 4 weeks. Suicidality was assessed using the Mini International Neuropsychiatric Interview and the Hamilton Rating Scale for Depression (HAM-D). Treatment response was defined as HAM-D <= 17 and remission as HAM-D <= 7 after 4 weeks of treatment with antidepressants at adequate dose. Genotyping was performed for all relevant variations of the CYP1A2 gene (*1A, *1F, *1C, *1 J, *1 K), the CYP2C9 gene (*2, *3), the CYP2C19 gene (*2, *17) and the CYP2D6 gene (*3, *4, *5, *6, *9, *19, *XN). No association between both suicide risk and personal history of suicide attempts, and the above mentioned metabolic profiles were found after multiple testing corrections. In conclusion, the investigated cytochrome gene polymorphisms do not seem to be associated with suicide risk and/or a personal history of suicide attempts, though methodological and sample size limitations do not allow definitive conclusions. PMID- 23081705 TI - Effects of nicotine on social cognition, social competence and self-reported stress in schizophrenia patients and healthy controls. AB - More than 80 % of patients diagnosed with schizophrenia are nicotine-dependent. Self-medication of cognitive deficits and an increased vulnerability to stress are discussed as promoting factors for the development of nicotine dependence. However, the effects of nicotine on social cognition and subjective stress responses in schizophrenia are largely unexplored. A 2 * 2-factorial design (drug * group) was used to investigate the effects of nicotine versus placebo in smoking schizophrenia patients and healthy controls after 24 h of abstinence from smoking. Participants performed a facial affect recognition task and a semi standardized role-play task, after which social competence and self-reported stress during social interaction were assessed. Data analysis revealed no significant group differences in the facial affect recognition task. During social interaction, healthy controls showed more non-verbal expressions and a lower subjective stress level than schizophrenia patients. There were no significant effects of nicotine in terms of an enhanced recognition of facial affect, more expressive behaviour or reduced subjective stress during social interaction. While schizophrenia patients unexpectedly recognized facial affect not significantly worse than healthy controls, the observed group differences in subjective stress and non-verbal expression during social interaction in the role play situation are in line with previous findings. Contrary to expectations derived from the self-medication hypothesis, nicotine showed no significant effects on the dependent variables, perhaps because of the dosage used and the delay between the administration of nicotine and the performance of the role play. PMID- 23081706 TI - Changing the enzyme reaction rate in magnetic nanosuspensions by a non-heating magnetic field. PMID- 23081707 TI - Cerebrovascular toxicity of PCB153 is enhanced by binding to silica nanoparticles. AB - Environmental polychlorinated biphenyls (PCBs) are frequently bound onto nanoparticles (NPs). However, the toxicity and health effects of PCBs assembled onto nanoparticles are unknown. The aim of this study was to study the hypothesis that binding PCBs to silica NPs potentiates PCB-induced cerebrovascular toxicity and brain damage in an experimental stroke model. Mice (C57BL/6, males, 12-week old) were exposed to PCB153 bound to NPs (PCB153-NPs), PCB153, or vehicle. PCB153 was administered in the amount of 5 ng/g body weight. A group of treated animals was subjected to a 40 min ischemia, followed by a 24 h reperfusion. The blood brain barrier (BBB) permeability, brain infarct volume, expression of tight junction (TJ) proteins, and inflammatory mediators were assessed. As compared to controls, a 24 h exposure to PCB153-NPs injected into cerebral vasculature resulted in significant elevation of the BBB permeability, disruption of TJ protein expression, increased proinflammatory responses, and enhanced monocyte transmigration in mouse brain capillaries. Importantly, exposure to PCB153-NPs increased stroke volume and potentiated brain damage in mice subjected to ischemia/reperfusion. A long-term (30 days) oral exposure to PCB153-NPs resulted in a higher PCB153 content in the abdominal adipose tissue and amplified adhesion of leukocytes to the brain endothelium as compared to treatment with PCB153 alone. This study provides the first evidence that binding to NPs increases cerebrovascular toxicity of environmental toxicants, such as PCB153. PMID- 23081708 TI - Photochemistry of fac-[Re(bpy)(CO)3Cl]. AB - The photochemistry of fac-[Re(bpy)(CO)(3)Cl] (1 a; bpy=2,2'-bipyridine) initiated by irradiation using <330 nm light has been investigated. Isomerization proceeded in THF to give the corresponding mer-isomer 1 b. However, in the presence of a small amount of MeCN, the main product was the CO-ligand-substituted complex (OC 6-24)-[Re(bpy)(CO)(2) Cl(MeCN)] (2 c; bpy=2,2'-bipyridine). In MeCN, two isomers, 2 c and its (OC-6-34) form (2 a), were produced. Only 2 c thermally isomerized to produce the (OC-6-44) form 2 b. A detailed investigation led to the conclusion that both 1 b and 2 c are produced by a dissociative mechanism, whereas 2 a forms by an associative mechanism. A comparison of the ultrafast transient UV-visible absorption, emission, and IR spectra of 1 a acquired by excitation using higher energy light (e.g., 270 nm) and lower-energy light (e.g., 400 nm) gave detailed information about the excited states, intermediates, and kinetics of the photochemical reactions and photophysical processes of 1 a. Irradiation of 1 a using the higher-energy light resulted in the generation of the higher singlet excited state with tau<=25 fs, from which intersystem crossing proceeded to give the higher triplet state ((3)HES(1)). In THF, (3)HES(1) was competitively converted to both the triplet ligand field ((3)LF) and metal-to-ligand charge transfer ((3)MLCT) with lifetimes of 200 fs, in which the former is a reactive state that converts to [Re(bpy)(CO)(2)Cl(thf)](+) (1 c) within 10 ps by means of a dissociative mechanism. Re-coordination of CO to 1 c gives both 1 a and 1 b. In MeCN, irradiation of 1 a by using high-energy light gives the coordinatively unsaturated complex, which rapidly converted to 2 c. A seven-coordinate complex is also produced within several hundred femtoseconds, which is converted to 2 a within several hundred picoseconds. PMID- 23081709 TI - Molluscan smooth catch muscle contains calponin but not caldesmon. AB - We isolated Ca(2+)-regulated thin filaments from the smooth muscle of the mussel Crenomytilus grayanus and studied the protein composition of different preparations from this muscle: whole muscle, heat-stable extract, fractions from heat-stable extract, thin filaments and intermediate stages of thin filaments purification. Among the protein components of the above-listed preparations, we did not find caldesmon (CaD), although two isoforms of a calponin-like (CaP-like) protein, which along with CaD is characteristic of vertebrate smooth muscle, were present in thin filaments. Thus, CaD is not Ca(2+)-regulator of thin filaments of this muscle. On the other hand, the mussel CaP-like protein is also not such Ca(2+)-regulator since we have shown that this protein can be selectively removed from isolated mussel thin filaments without loss of their Ca(2+)-sensitivity. We suggest that thin filaments in the smooth catch muscle possess other type of Ca(2+)-regulation, different from that in vertebrate smooth muscles. PMID- 23081710 TI - Anterior cruciate ligament reconstruction with 4-strand hamstring autograft and accelerated rehabilitation: a 10-year prospective study on clinical results, knee osteoarthritis and its predictors. AB - PURPOSE: Analysis of long-term clinical and radiological outcomes after anterior cruciate ligament (ACL) reconstruction with special attention to knee osteoarthritis and its predictors. METHODS: A prospective, consecutive case series of 100 patients. Arthroscopic transtibial ACL reconstruction was performed using 4-strand hamstring tendon autografts with a standardized accelerated rehabilitation protocol. Analysis was performed preoperatively and 10 years postoperatively. Clinical examination included Lysholm and Tegner scores, IKDC, KT-1000 testing (MEDmetric Co., San Diego, CA, USA) and leg circumference measurements. Radiological evaluation included AP weight bearing, lateral knee, Rosenberg and sky view X-rays. Radiological classifications were according to Ahlback and Kellgren & Lawrence. Statistical analysis included univariate and multivariate logistic regressions. RESULTS CLINICAL OUTCOME: A significant improvement (p < 0.001) between preoperative and postoperative measurements could be demonstrated for the Lysholm and Tegner scores, IKDC patient subjective assessment, KT-1000 measurements, pivot shift test, IKDC score and one-leg hop test. A pivot shift phenomenon (glide) was still present in 43 (50%) patients and correlated with lower levels of activity (p < 0.022). Radiological outcome: At follow-up, 46 (53.5%) patients had signs of osteoarthritis (OA). In this group, 33 patients (72%) had chondral lesions (>=grade 2) at the time of ACL reconstruction. A history of medial meniscectomy before or at the time of ACL reconstruction increased the risk of knee OA 4 times (95% CI 1.41-11.5). An ICRS grade 3 at the time of ACL reconstruction increased the risk of knee OA by 5.2 times (95% CI 1.09-24.8). There was no correlation between OA and activity level (Tegner score >=6) nor between OA and a positive pivot shift test. CONCLUSION: Transtibial ACL reconstruction with 4-strand hamstring autograft and accelerated rehabilitation restored anteroposterior knee stability. Clinical parameters and patient satisfaction improved significantly. At 10-year follow-up, radiological signs of OA were present in 53.5 % of the subjects. Risk factors for OA were meniscectomy prior to or at the time of ACL reconstruction and chondral lesions at the time of ACL reconstruction. LEVEL OF EVIDENCE: II. PMID- 23081711 TI - Influence of kinesiophobia and catastrophizing on pain and disability in anterior knee pain patients. AB - PURPOSE: To evaluate the prevalence and participation of catastrophizing and fear to movement beliefs on present pain and disability in anterior knee pain patients. METHODS: A cross-sectional study on 97 patients with chronic anterior knee pain was performed in a secondary healthcare setting. Pain was measured with Visual Analogue Scale and disability with Lysholm Scale. The psychological variables anxiety, depression, pain coping strategies, catastrophizing and fear to movement beliefs were studied by using auto-administered questionnaires. RESULTS: Patients showed a high incidence of psychological distress (anxiety and depression), kinesiophobia and catastrophizing. A moderate correlation between pain and disability was found. Among all the coping strategies, only catastrophizing correlated with pain and disability. Anxiety depression and kinesiophobia also correlated with present pain and disability. In the regression model, catastrophizing and depression explained 56 % of the variance of disability and catastrophizing alone explained 37 % of present pain. CONCLUSION: The moderate correlation between pain and disability suggests that pain per se is not able to explain all the variability of disability. Catastrophizing and kinesiophobia are shown to be predictors of present pain and disability in anterior knee pain patients. These findings support the fear avoidance model in the genesis and persistence of pain and disability in anterior knee pain patients and open the door to a biopsychosocial perspective in the management of these patients. LEVEL OF EVIDENCE: III. PMID- 23081712 TI - Patellar tilt and thickness do not influence postoperative flexion in a high-flex design total knee arthroplasty. AB - PURPOSE: The purpose of this short-term study was to determine whether patellar thickness and tilt influence the postoperative flexion in a high-flex design total knee arthroplasty (TKA). METHODS: Between 2007 and 2009, 106 patients underwent surgery for TKA using rotating platform flex prosthesis (DePuy, Warsaw, Ind). All of them were suffering from end-stage osteoarthritis. All patients were evaluated preoperatively and at 12 months of follow-up. Maximum active, non weight-bearing flexion was the primary outcome parameter. Standard standing antero-posterior and lateral weight-bearing radiographs were made. The patellofemoral joints were evaluated in skyline views taken with the knees at approximately 60 degrees of flexion. Patellar thickness, patellar tilt, Caton Deschamps indices and lower limb alignment were measured. RESULTS: The mean flexion observed before surgery was 125 degrees +/- 15 degrees and after 1 year was 128 degrees +/- 13 degrees . The mean patellar thickness preoperatively was 24.5 +/- 2.9 and 25.8 +/- 3.2 mm at 12 months after surgery. The mean patellar tilt before the procedure was 2.9 degrees +/- 4.1 degrees and after 12 months of follow-up was -0.8 degrees +/- 5.0 degrees . The mean preoperative hip-knee ankle was 2.6 degrees +/- 6.2 degrees . No significant correlation was found between postoperative patellar tilt and thickness and postoperative flexion (n.s.). CONCLUSIONS: Patellar tilt and thickness after TKA are factors that depend on the surgery. The resection of the patella can influence both patellar thickness and patellar tilt. By developing adequate surgical instruments, it would be possible to avoid the occurrence of an exaggerated patellar tilt or a major difference in patellar thickness. However, these two factors did not seem to influence the postoperative flexion in a high-flex design TKA, which can be seen as one of the most important outcome factors after TKA. PMID- 23081715 TI - Functional dissection of Pax3 in paraxial mesoderm development and myogenesis. AB - The paired box transcription factor Pax3 is well-known as a major regulator of embryonic myogenesis. Before Pax3 expression becomes restricted to the dermomyotome, this transcription factor is also expressed in the developing somites. The role of Pax3 at this early stage is unclear, in particular because of the scarce frequency of Pax3-positive cells in the early mouse embryo. Inducible gene expression in embryonic stem cells (ESCs) represents an excellent tool to overcome this limitation, since it can provide large quantities of otherwise rare embryonic populations expressing a factor of interest. Here we used engineered mouse ESCs to perform a functional analysis of Pax3 with the aim to identify the molecular determinants involved in the early functions of this transcription factor. We find that Pax3 induction during embryoid body differentiation results in the upregulation of genes expressed in the presomitic and somitic mesoderm. Moreover, we show that paraxial mesoderm induced by transient expression of Pax3 is not irreversibly committed to myogenesis rather requires sustained Pax3 expression. Using a series of deletion mutants of Pax3, which differentially affect its transcriptional activity, we map protein domains necessary for induction of paraxial mesoderm and induction of the myogenic program. The paired, homeo-, and transcriptional activation domains were each required for both processes, however, the paired-c-terminal RED domain showed a paraxial mesoderm-specific activity that was dispensable for myogenesis. These findings demonstrate and provide mechanistic insight into an early role for Pax3 in the generation of paraxial mesoderm. PMID- 23081716 TI - DNA self-assembly of targeted near-infrared-responsive gold nanoparticles for cancer thermo-chemotherapy. PMID- 23081717 TI - Design and evaluation of a slave manipulator with roll-pitch-roll wrist and automatic tool loading mechanism in telerobotic surgery. AB - BACKGROUND: As there is a shortage of scrub nurses in many hospitals, automatic surgical tool exchanging mechanism without human labour has been studied. Minimally invasive robotic surgeries (MIRS) also require scrub nurses. A surgical tool loading mechanism without a scrub nurse's assistance for MIRS is proposed. Many researchers have developed minimally invasive surgical instruments with a wrist joint that can be movable inside the abdomen. However, implementation of a distal rolling joint on a gripper is rare. METHODS: To implement surgical tool exchanging without a scrub nurse's assistance, a slave manipulator and a tool loader were developed to load and unload a surgical tool unit. A surgical tool unit with a roll-pitch-roll wrist was developed. Several experiments were performed to validate the effectiveness of the slave manipulator and the surgical tool unit. RESULTS: The slave manipulator and the tool loader were able to successfully unload and load the surgical tool unit without human assistance. The total duration of unloading and loading the surgical tool unit was 97 s. Motion tracking experiments of the distal rolling joint were performed. The maximum positioning error of the step input response was 2 degrees . CONCLUSIONS: The advantage of the proposed slave manipulator and tool loader is that other robotic systems or human labour are not needed for surgical tool loading. The feasibility of the distal rolling joint in MIS is verified. PMID- 23081718 TI - MicroRNAs: new tools for diagnosis, prognosis, and therapy in hepatocellular carcinoma? AB - MicroRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs involved in the regulation of gene expression and protein translation. Many studies have shown that they play a crucial role in driving organ and tissue differentiation during embryogenesis and in the fine-tuning of fundamental biological processes, such as proliferation and apoptosis. Growing evidence indicates that their deregulation plays an important role in cancer onset and progression as well, where they act as oncogenes or oncosuppressors. In this review, we highlight the most recent findings regarding the role of miRNAs in hepatocellular carcinoma (HCC) by analyzing the possible mechanisms by which they contribute to this neoplasm. Moreover, we discuss the possible role of circulating miRNAs as biomarkers, a field that needs urgent improvement in the clinical surveillance of HCC, and the fascinating possibility of using them as therapeutic targets or drugs themselves. PMID- 23081719 TI - Advances in metal-free heterocycle-based columnar liquid crystals. AB - Liquid crystals are ordered soft materials formed by self-organized molecules and can potentially be used as new functional materials for electron-, ion- or molecular-transport; optical; and bio-active materials. In particular, the columnar liquid crystals are promising candidates used in various optical and electronic devices. For this purpose, design and synthesis of unconventional materials are essential. In this review, we have summarized several approaches for the synthesis of columnar liquid crystals composed of various heterocyclic systems. We also outline their liquid crystalline and other relevant properties, and their suitability for applications in diverse fields. PMID- 23081720 TI - Quantitative assessment of cell viability based on flow cytometry and microscopy. AB - We compare flow cytometric and microscopic determination of cell viability by fluorescence labeling using calcein acetoxy-methyl-ester and ethidium homodimer-1 as live and dead stain, respectively. Peripheral blood monocytes served as model system and were accumulated applying density gradients. Subsequently, monocytes were further enriched by magnetic-activated or fluorescence-activated cell sorting (MACS, FACS) targeting the antigen CD14. Identical samples were used for flow cytometric and microscopic analysis to allow direct comparison of both analysis methods. More than 1,000 cells were measured for each sample to minimize the measurement uncertainty caused by counting statistics. We observed good agreement of flow cytometric and microscopic viability measurements. On average, the difference in viability measured by flow cytometry and microscopy amounted to (2.7 +/- 1.4)% for live staining and (1.7 +/- 1.2)% for dead staining. These deviations were similar to the uncertainty of measurement for cell viability, thus demonstrating that both methods delivered equal results. Besides monocytes, comparison of flow cytometric and microscopy viability for MACS enriched CD34 positive cells also showed consistent results. PMID- 23081721 TI - Design and development of photoanodes for water-splitting dye-sensitized photoelectrochemical cells. AB - Dye sensitized solar cells (DSSCs) use low-cost materials, feature tunable molecular sensitizers, and exhibit quantum efficiencies near unity. These advantageous features can be exploited in the context of solar water splitting by functionalizing DSSCs with catalysts for water oxidation and reduction. This article will cover the development of photoanodes for water splitting DSSCs from the perspective of water oxidation catalysts, sensitizers, electron transfer mediators, photoanode materials, and system level design. Within each section we will endeavor to highlight critical design elements and how they can affect the efficiency of the overall system. PMID- 23081722 TI - Podoplanin-positive cancer-associated fibroblasts could have prognostic value independent of cancer cell phenotype in stage I lung squamous cell carcinoma: usefulness of combining analysis of both cancer cell phenotype and cancer associated fibroblast phenotype. AB - BACKGROUND: The prognostic significance of the tumor microenvironment, which is created by both cancer cells and cancer-associated fibroblasts (CAFs), has been increasingly recognized. The purpose of this study was to analyze the prognostic markers of stage I squamous cell carcinoma (SqCC), with special reference to the immunophenotypes of both cancer cells and CAFs. METHODS: A total of 142 patients with stage I SqCC were included in this study. We examined the expressions of E cadherin, laminin-5, podoplanin, c-MET, carbonic anhydrase IX (CA-IX), CD10, and CD44 in the cancer cells and those of podoplanin, CA-IX, CD10, and CD44 in the CAFs to evaluate their prognostic value. RESULTS: Patients with low E-cadherin expression in the cancer cells showed a significantly poorer prognosis than those with high E-cadherin expression in the cancer cells ( P , .001). On the other hand, high podoplanin expression in the CAFs was also associated with a significantly poorer prognosis ( P , .001). A multivariate analysis identified low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs as significantly independent prognostic factors for overall survival ( P 5 .013 and P 5 .0011, respectively). According to subgroup analyses combining E cadherin expression in cancer cells and podoplanin expression in CAFs, 5-year overall survival of patients with low E-cadherin expression in the cancer cells and high podoplanin expression in the CAFs was 7.0% and showed a significantly poorer prognosis as compared with other groups ( P , .001). CONCLUSIONS: The current study indicates that immunophenotypes of CAFs could have a prognostic value independent of those of the cancer cells in SqCC. PMID- 23081723 TI - Cytotoxic and pro-apoptotic effects of Abrus precatorius L. on human metastatic breast cancer cell line, MDA-MB-231. AB - Abrus precatorius is highly regarded as a universal panacea in the herbal medicine with diverse pharmacological activity spectra. This experimental study on the mechanism of the anticancer activity of A. precatorius leaf extracts, may offer new evidence for A. precatorius in the treatment of breast cancer in clinical practice. Cell death was determined by using MTT assay. Further analyses were carried out by doing DNA laddering, PARP cleavage, FACS, semi-quantitative RT-PCR and detection of cellular reactive oxygen species (ROS) by DCFDA assay. A. precatorius showed very striking inhibition on MDA-MB-231 cells. MTT assay showed more than 75 % inhibition of the cells and treated cells indicated visible laddering pattern with thick compact band. PARP cleavage produced 89 kDa cleavage product which was associated with apoptosis. Flow cytometer exhibited a sub-G0/G1 peak as an indicative of apoptosis. mRNA expression level of apoptosis-related genes p21 and p53 was markedly increased in cells treated with the extract as compared to control. The up-regulation of p21 and p53 may be the molecular mechanisms by which A. precatorius extract which induces apoptosis. An increase in the concentration of A. precatorius extract does not generate ROS, instead it reduces ROS formation in MDA-MB-231 cells, as evident from the shift in fluorescence below untreated control. This is the first report showing that A. precatorius leaf extract exhibits a growth inhibitory effect by induction of apoptosis in MDA-MB-231 cells. Our results contribute towards validation of the A. precatorius extract as a potentially effective chemopreventive or therapeutic agent against breast cancer. PMID- 23081724 TI - Simultaneous detection of duplex DNA oligonucleotides using a SERS-based micro network gradient chip. AB - We report the development of a programmable surface-enhanced Raman scattering (SERS)-based micro-network gradient platform to simultaneously detect two different types of DNA oligomer mixtures. The utility of this platform was demonstrated by quantitative analysis of two breast cancer-related (BRCA1) DNA oligomer mixtures. To generate on-demand concentration gradients, the microfluidic circuit was designed using an electric-hydraulic analogy. Then a multi-gradient microfluidic channel was fabricated based on the theoretical design of the concentration control module. These micro-network structures automatically produce a series of different concentration gradients by continuously mixing Cy3-labeled DNA oligomers (BRAC1-Mutation) with TAMRA-labeled DNA oligomer (BRAC1-Wild). The SERS signals for different ratios of duplex DNA oligomer mixtures, adsorbed on the surface of silver nanoparticles, were measured under flowing conditions. Total analysis time from serial mixing to SERS detection takes less than 10 min because all experimental conditions are automatically controlled inside the exquisitely designed microfluidic channel. This novel SERS-based DNA sensing technology in a micro-network gradient channel is expected to be a powerful analytical tool to simultaneously detect multiple DNA oligomer mixtures. PMID- 23081725 TI - The time distribution of sulfadoxine-pyrimethamine protection from malaria. AB - Sulfadoxine-pyrimethamine (SP) has been one of the most widely used antimalarial treatments world-wide, and is also used prophylactically in vulnerable populations. In this paper, we develop a mathematical model which allows us to infer the time distribution of SP protection from drug-trial data. Fitting our model to data from a controlled field study in Mali, we find that SP provided protection from malaria for an average of 37.9 days in this pediatric population. We demonstrate that the duration of SP protection is not well described by an exponential distribution, and in fact has a much narrower dispersal about the mean; the best-fit standard deviation predicted by our model was only 17.0 days, as opposed to 41.8 days for the exponential model. We estimate the monthly entomological inoculation rate and the basic reproductive number for malaria in this population, and demonstrate that extremely high SP treatment rates would be necessary to maintain an effective reproductive number below one throughout a single rainy season. These results have implications for further efforts to model the impact of SP treatment, or for investigations of the optimal timing of prophylactic SP. PMID- 23081726 TI - Dynamics of influenza virus and human host interactions during infection and replication cycle. AB - The replication and life cycle of the influenza virus is governed by an intricate network of intracellular regulatory events during infection, including interactions with an even more complex system of biochemical interactions of the host cell. Computational modeling and systems biology have been successfully employed to further the understanding of various biological systems, however, computational studies of the complexity of intracellular interactions during influenza infection is lacking. In this work, we present the first large-scale dynamical model of the infection and replication cycle of influenza, as well as some of its interactions with the host's signaling machinery. Specifically, we focus on and visualize the dynamics of the internalization and endocytosis of the virus, replication and translation of its genomic components, as well as the assembly of progeny virions. Simulations and analyses of the models dynamics qualitatively reproduced numerous biological phenomena discovered in the laboratory. Finally, comparisons of the dynamics of existing and proposed drugs, our results suggest that a drug targeting PB1:PA would be more efficient than existing Amantadin/Rimantaine or Zanamivir/Oseltamivir. PMID- 23081727 TI - On the relationship of steady states of continuous and discrete models arising from biology. AB - For many biological systems that have been modeled using continuous and discrete models, it has been shown that such models have similar dynamical properties. In this paper, we prove that this happens in more general cases. We show that under some conditions there is a bijection between the steady states of continuous and discrete models arising from biological systems. Our results also provide a novel method to analyze certain classes of nonlinear models using discrete mathematics. PMID- 23081728 TI - Modelling cell migration and adhesion during development. AB - Cell-cell adhesion is essential for biological development: cells migrate to their target sites, where cell-cell adhesion enables them to aggregate and form tissues. Here, we extend analysis of the model of cell migration proposed by Anguige and Schmeiser (J. Math. Biol. 58(3):395-427, 2009) that incorporates both cell-cell adhesion and volume filling. The stochastic space-jump model is compared to two deterministic counterparts (a system of stochastic mean equations and a non-linear partial differential equation), and it is shown that the results of the deterministic systems are, in general, qualitatively similar to the mean behaviour of multiple stochastic simulations. However, individual stochastic simulations can give rise to behaviour that varies significantly from that of the mean. In particular, individual simulations might admit cell clustering when the mean behaviour does not. We also investigate the potential of this model to display behaviour predicted by the differential adhesion hypothesis by incorporating a second cell species, and present a novel approach for implementing models of cell migration on a growing domain. PMID- 23081729 TI - Dynamics of nephron-vascular network. AB - The paper presents a modeling study of the spatial dynamics of a nephro-vascular network consisting of individual nephrons connected via a tree-like vascular branching structure. We focus on the effects of nonlinear mechanisms that are responsible for the formation of synchronous patterns in order to learn about processes not directly amenable to experimentation. We demonstrate that: (i) the nearest nephrons are synchronized in-phase due to a vascular propagated electrical coupling, (ii) the next few branching levels display a formation of phase-shifted patterns due to hemodynamic coupling and mode elimination, and (iii) distantly located areas show asynchronous behavior or, if all nephrons and branches are perfectly identical, an infinitely long transient behavior. These results contribute to the understanding of mechanisms responsible for the highly dynamic and limited synchronization observed among groups of nephrons despite of the fairly strong interaction between the individual units. PMID- 23081730 TI - Analysis and characterization of asynchronous state transition graphs using extremal states. AB - Logical modeling of biological regulatory networks gives rise to a representation of the system's dynamics as a so-called state transition graph. Analysis of such a graph in its entirety allows for a comprehensive understanding of the functionalities and behavior of the modeled system. However, the size of the vertex set of the graph is exponential in the number of the network components making analysis costly, motivating development of reduction methods. In this paper, we present results allowing for a complete description of an asynchronous state transition graph of a Thomas network solely based on the analysis of the subgraph induced by certain extremal states. Utilizing this notion, we compare the behavior of a simple multivalued network and a corresponding Boolean network and analyze the conservation of dynamical properties between them. Understanding the relation between such coarser and finer models is a necessary step toward meaningful network reduction as well as model refinement methods. PMID- 23081731 TI - Temporal trend of overall survival in patients with advanced non-small cell lung cancer given first-line cytotoxic treatments. PMID- 23081732 TI - Vitamin D receptor gene polymorphisms and bone mass indices in post-menarchal Indian adolescent girls. AB - To study the association between vitamin D receptor (VDR) gene polymorphisms and bone mass indices in adolescent girls, a cross-sectional study was conducted in 120 post-menarchal girls aged 15-18 years in Pune city, India. Serum levels of ionised calcium, inorganic phosphorous, parathyroid hormone and 25-hydroxy vitamin-D were measured. Bone mineral content (BMC), bone area (BA) and bone mineral density (BMD) were measured at total body (TB), lumbar spine (LS) and left femoral neck (FN) using dual energy X-ray absorptiometry. Polymorphisms of the VDR gene at the Fok1 and Bsm1 loci were detected using SYBR Green quantitative polymerase chain reaction. The overall distribution of genotypes at the Bsm1 locus in this study was 33.3 % Bb, 29.2 % bb and 37.5 % BB while that for the Fok1 locus was 44.2 % Ff, 7.5 % ff and 48.3 % FF. There were no significant differences in the blood parameters when classified according to Bsm1 or Fok1 genotypes. Subjects with BB genotype have significantly higher mean TBBMC, TBBA, TBBMD and LSBMD than Bb and bb (p < 0.05) and showed a tendency for association with LSBMC and LSBA (p < 0.1). Subjects with Ff genotype showed a tendency for association with left FNBMC and FNBA (p < 0.1). Bsm1 genotype did not show an association with FN bone indices whereas Fok1 genotype did not show association with TB or LS bone indices. In conclusion, the present study demonstrates VDR gene polymorphism, defined by Bsm1 genotype, has an influence on total body and lumbar spine bone mass indices in post-menarchal Indian girls. PMID- 23081733 TI - Primary hyperparathyroidism in a patient with familial hypocalciuric hypercalcaemia due to a novel mutation in the calcium-sensing receptor gene. AB - We describe the clinical and genetic findings in pedigree with a novel mutation in the calcium sensing receptor (CaSR) gene and the unusual coexistence of primary hyperparathyroidism (HPT) and familial hypocalciuric hypercalcaemia (FHH) and its clinical management. The occurrence of both FHH and primary HPT in the same patient has been described rarely. Our pedigree has a novel mutation in the CaSR gene. Parathyroidectomy led to a reduction, but not normalization of the calcium levels in the patient identified as having HPT. The coexistence of HPT and FHH was considered in this patient as her calcium and PTH levels were rising with time. Surgical resection of her parathyroid adenoma resulted in reduction of her calcium levels to above normal and significant reduction in her symptoms of fatigue and low mood. PMID- 23081734 TI - LFQuant: a label-free fast quantitative analysis tool for high-resolution LC MS/MS proteomics data. AB - Database searching based methods for label-free quantification aim to reconstruct the peptide extracted ion chromatogram based on the identification information, which can limit the search space and thus make the data processing much faster. The random effect of the MS/MS sampling can be remedied by cross-assignment among different runs. Here, we present a new label-free fast quantitative analysis tool, LFQuant, for high-resolution LC-MS/MS proteomics data based on database searching. It is designed to accept raw data in two common formats (mzXML and Thermo RAW), and database search results from mainstream tools (MASCOT, SEQUEST, and X!Tandem), as input data. LFQuant can handle large-scale label-free data with fractionation such as SDS-PAGE and 2D LC. It is easy to use and provides handy user interfaces for data loading, parameter setting, quantitative analysis, and quantitative data visualization. LFQuant was compared with two common quantification software packages, MaxQuant and IDEAL-Q, on the replication data set and the UPS1 standard data set. The results show that LFQuant performs better than them in terms of both precision and accuracy, and consumes significantly less processing time. LFQuant is freely available under the GNU General Public License v3.0 at http://sourceforge.net/projects/lfquant/. PMID- 23081736 TI - [Comparison of quality on digital X-ray devices with 3D-capability for ENT clinical objectives in imaging of temporal bone and paranasal sinuses]. AB - PURPOSE: Comparison of dosage and spatial resolution of digital X-Ray devices with 3D-capability in head and neck imaging. MATERIALS AND METHODS: Three on-site X-Ray devices, a general purpose multi-slice CT (CT), a dedicated cone-beam CT (CBCT) and the CT-mode of a device for digital angiography (DSA) of the same generation were compared using paranasal sinus (PNS) and temporal bone imaging protocols. The radiation exposure was measured with a puncture measuring chamber on a CTDI head phantom as well as with chip-strate-dosimeters on an Alderson head phantom in the regions of the eyes and thyroid gland. By using the Alderson head phantom, the specific dosage of the X-Ray device with regard to different protocols was read out. For the assessment of the high-contrast resolution of the devices, images of a self-made phantom were qualitatively analysed by six observers. RESULTS: The three devices showed marked variations in the dosage and spatial resolution depending on the protocol and/or modus. In both parameters, CBCT was superior to CT and DSA using standard protocols, with the difference being less obvious for the investigation with PNS. CONCLUSION: For high-contrast investigations CBCT CT is a remarkable option in head and neck radiology. PMID- 23081735 TI - Bone marrow endothelial progenitors augment atherosclerotic plaque regression in a mouse model of plasma lipid lowering. AB - The major event initiating atherosclerosis is hypercholesterolemia-induced disruption of vascular endothelium integrity. In settings of endothelial damage, endothelial progenitor cells (EPCs) are mobilized from bone marrow into circulation and home to sites of vascular injury where they aid endothelial regeneration. Given the beneficial effects of EPCs in vascular repair, we hypothesized that these cells play a pivotal role in atherosclerosis regression. We tested our hypothesis in the atherosclerosis-prone mouse model in which hypercholesterolemia, one of the main factors affecting EPC homeostasis, is reversible (Reversa mice). In these mice, normalization of plasma lipids decreased atherosclerotic burden; however, plaque regression was incomplete. To explore whether endothelial progenitors contribute to atherosclerosis regression, bone marrow EPCs from a transgenic strain expressing green fluorescent protein (GFP) under the control of endothelial cell-specific Tie2 promoter (Tie2-GFP(+)) were isolated. These cells were then adoptively transferred into atheroregressing Reversa recipients where they augmented plaque regression induced by reversal of hypercholesterolemia. Advanced plaque regression correlated with engraftment of Tie2-GFP(+) EPCs into endothelium and resulted in an increase in atheroprotective nitric oxide and improved vascular relaxation. Similarly augmented plaque regression was also detected in regressing Reversa mice treated with the stem cell mobilizer AMD3100 which also mobilizes EPCs to peripheral blood. We conclude that correction of hypercholesterolemia in Reversa mice leads to partial plaque regression that can be augmented by AMD3100 treatment or by adoptive transfer of EPCs. This suggests that direct cell therapy or indirect progenitor cell mobilization therapy may be used in combination with statins to treat atherosclerosis. PMID- 23081737 TI - Intrinsic sphincter deficiency: what is it and does it matter anymore? PMID- 23081739 TI - Distribution and function of the endocannabinoid system in the rat and human bladder. AB - INTRODUCTION AND HYPOTHESIS: Our aim was to compare expression and distribution of cannabinoid receptors CB1 and CB2, transient receptor potential vanilloid receptor 1 (TRPV1), and modulating enzymes in human and rat bladder. We also evaluated effects of cannabinoid agonists (ACEA, agonist of CB1; GP1A, agonist of CB2) on contractile responses of rat bladder strips. METHODS: Distribution and expression of CB1, CB2 and TRPV1 receptors and enzymes fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) was studied using immunohistochemistry and immunoblotting on human and Wistar rat bladders. The effects of cannabinoid agonists on contractile responses of isolated rat bladder strips to electrical-field stimulation (EFS) or carbachol evoked responses were determined. RESULTS: Immunoreactivity for CB1 and TRPV1 receptors and FAAH and NAPE-PLD was present in the bladder of both species. CB1 proteins were of different sizes in rat (57 kDa) and human (40 kDa) bladder. CB2 (45 kDa in both species) immunolocalised to both urothelium and detrusor muscle in human bladder but only to detrusor muscle in rat. FAAH proteins were found at 55 kDa for both species. Rat NAPE-PLD protein (44 kDa) was similar in size to that in human bladder (45 kDa). TRPV1 proteins were found at 104 kDa in both species. ACEA (10(-4) M) attenuated bladder contractions by 35 +/- 5.4 % (p < 0.001); GP1a had no effect despite the EC50 values for the carbachol dose response curves for both agonists being significantly shifted to the right. CONCLUSIONS: The endocannabinoid system is functionally expressed in both species, with CB1 receptors showing both pre- and postsynaptic inhibitory effects on rat bladder contraction, whereas CB2 acts only postsynaptically. PMID- 23081740 TI - Work-related musculoskeletal disorders among vaginal surgeons. AB - INTRODUCTION AND HYPOTHESIS: Work-related musculoskeletal disorders (MSDs) reportedly affect a large proportion of providers in obstetrics and gynecology. We hypothesize a high MSD prevalence rate among vaginal surgeons associated with surgeon- and work-related characteristics. METHODS: Surveys were distributed to members of the International Urogynecological Association and American Urogynecological Society. Exclusion criteria included inability to read English, no computer access, invalid or unavailable e-mail address, and missing >50% of responses. RESULTS: Among respondents, 86.7% (436/503) reported ever having work related MSDs. On univariate analysis, surgeons involved in surgical teaching were significantly more likely to report work-related MSDs. Female surgeons had more frequent and more severe MSDs in the neck, dominant shoulder, and upper back. Older age and more years of work experience were associated with seeking medical attention. Right-hand dominance was associated with negative consequences on work behavior. CONCLUSIONS: A large proportion of vaginal surgeon respondents reported work-related MSDs. PMID- 23081741 TI - Reliability and validity of the Japanese version of the pelvic floor distress inventory-short form 20. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to translate the Pelvic Floor Distress Inventory-Short Form 20 (PFDI-20) into Japanese and test its reliability and validity among Japanese women. METHODS: Fifty-nine women with and without pelvic floor disorders (age 55.8 +/- 16.8 years, mean +/- SD) completed the Japanese PFDI-20 (J-PFDI-20) questionnaire at baseline and 2 weeks later. Intraclass correlation coefficients (ICC) and the Bland and Altman method for test-retest reliability and Cronbach's alpha for internal consistency of the J PFDI-20 were used. Scores of total and subscales were compared between women with and without pelvic floor disorders for known-groups validity. Spearman's correlation coefficients between the J-PFDI-20 and the severity of pelvic floor disorders and Urinary Incontinence Quality of Life Scale (I-QOL) were used for construct validity. RESULTS: The PFDI-20 was successfully translated from English into Japanese with face validity through rigorous cross-cultural validation. Test retest reliability of the J-PFDI-20 and three subscales was good to excellent (ICC=0.77-0.90). The Bland and Altman analysis showed that differences between the first and second scores of total J-PFDI-20 and its subscales were not significantly different from 0 and largely fell within the range of 0 +/- 1.96 SD. Cronbach's alpha values were 0.52-0.83. Analysis of known-groups validity showed differences in scores of the J-PFDI-20 between women with and without pelvic floor disorders. Acceptable construct validity was found in J-PFDI-20 total and subscale scores with positive correlations to severity of pelvic floor disorders (rho>0.35) and negative correlations to I-QOL (rho<-0.39). CONCLUSIONS: The results suggest that the J-PFDI-20 is a reliable and valid condition-specific quality of life instrument for women with pelvic floor disorders. PMID- 23081742 TI - Robustness analysis of a smart surgical drill for cochleostomy. AB - BACKGROUND: There is a need for sensor-guided robotic devices that discriminate working conditions and media, and control interaction of tool-points with respect to tissues. At the micro-surgical scale the need is to control exact penetration through flexible tissues and to control relative motion with respect to moving or deforming tissue targets and interfaces. METHODS: This paper describes a smart surgical drill that is able to control interaction with respect to the flexing tissue to avoid penetration or to control the extent of protrusion with respect to the position of the flexible tissue interface under drilling. The sensing scheme used is able to discriminate between the variations in types of conditions posed in the drilling environment. RESULTS: The fully autonomous system is able to respond to tissue type, behaviour and deflection in real time. The system is robust in terms of different drilling angle, thickness, stiffness, and disturbances encountered. Also it is intuitive to use, efficient to set up and uses standard drill bits. CONCLUSIONS: The smart drill has been used to prepare cochleostomies in theatre and was used to remove bone tissue leaving the endosteal membrane intact. This has enabled preservation of sterility and the drilling debris to be removed prior to insertion of the electrode. Results presented in this paper suggest that the robotic smart drill is tolerant and robust on various angled drilling trajectories with respect to tissues, tissue thickness, environmental disturbances, and has been used within the operating theatre. PMID- 23081743 TI - Detection of loci for allergic asthma using SMXA recombinant inbred strains of mice. AB - Asthma is regarded as a multifactorial inflammatory disorder arising as a result of inappropriate immune responses in genetically susceptible individuals to common environmental antigens. However, the precise molecular basis is unknown. To identify genes for susceptibility to three asthma-related traits, airway hyperresponsiveness (AHR), eosinophil infiltration, and allergen-specific serum IgE levels, we conducted a genetic analysis using SMXA recombinant inbred (RI) strains of mice. Quantitative trait locus analysis detected a significant locus for AHR on chromosome 17. For eosinophil infiltration, significant loci were detected on chromosomes 9 and 16. Although we could not detect any significant loci for allergen-specific serum IgE, analysis of consomic strains showed that chromosomes 17 and 19 carried genes that affected this trait. We detected genetic susceptibility loci that separately regulated the three asthma-related phenotypes. Our results suggested that different genetic mechanisms regulate these asthma-related phenotypes. Genetic analyses using murine RI and consomic strains enhance understanding of the molecular mechanisms of asthma in human. PMID- 23081745 TI - Onset of bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomized study. AB - INTRODUCTION: The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta(2)-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments. METHODS: Adults with mild-to-moderate-severe persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 MUg twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 MUg b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV(1)] was >=12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV(1) were assessed at days 0 (baseline) and 84. RESULTS: Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05-2.05]) and 84 (HR = 1.77 [95% CI 1.14 2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96-8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14-42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57-7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65-4.93]; P = 0.011). CONCLUSION: These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma. PMID- 23081744 TI - Influence of Tyrphostin AG490 on the expression of diabetes-associated markers in human adipocytes. AB - Tyrosine kinase inhibitors (TKi) hold promise as a treatment for a variety of disorders ranging from those in oncology to diseases thought as immune mediated. Tyrphostin AG490 is a potent Jak-Stat TKi shown effective in the prevention of allograft transplant rejection, experimental autoimmune disease, as well as the treatment of cancer. However, given its ability to modulate this important but pleiotropic intracellular pathway, we thought that it is important to examine its effects on glucose metabolism and expression of major transcription factors and adipokines associated with insulin insensitivity and diabetes. We investigated the metabolic effects of AG490 on glucose levels in vivo using an animal model of diabetes, nonobese diabetic (NOD) mice, and transcription factor expression through assessment of human adipocytes. AG490 treatment of young nondiabetic NOD mice significantly reduced blood glucose levels (p = 0.002). In vitro, treatment of adipocytes with rosiglitazone, an insulin sensitizer that binds to peroxisome proliferator-activated receptor (PPAR) receptors and increases the adipocyte response to insulin, significantly increased the expression of the antidiabetic adipokine adiponectin. Importantly, the combination of rosiglitazone plus Tyrphostin AG490 further increased this effect and was specifically associated with significant upregulation of C-enhanced binding protein (C/EBP) (p < 0.0001). In terms of the mechanism underlying this action, regulatory regions of the PPARgamma, ADIPOQ, and C/EBP contain the Stat5 DNA-binding sequences and were demonstrated, by gel shift experiments in vitro. These data suggest that blocking Jak-Stat signaling with AG490 reduces blood glucose levels and modulates the expression of transcription factors previously associated with diabetes, thereby supporting its potential as a therapy for this disease. PMID- 23081746 TI - Accurate dynamical structure factors from ab initio lattice dynamics: the case of crystalline silicon. AB - A fully ab initio technique is discussed for the determination of dynamical X-ray structure factors (XSFs) of crystalline materials, which is based on a standard Debye-Waller (DW) harmonic lattice dynamical approach with all-electron atom centered basis sets, periodic boundary conditions, and one-electron Hamiltonians. This technique requires an accurate description of the lattice dynamics and the electron charge distribution of the system. The main theoretical parameters involved and final accuracy of the technique are discussed with respect to the experimental determinations of the XSFs at 298 K of crystalline silicon. An overall agreement factor of 0.47% between the ab initio predicted values and the experimental determinations is found. The best theoretical determination of the anisotropic displacement parameter, of silicon is here 60.55 * 10(-4) A(2), corresponding to a DW factor B = 0.4781 A(2). PMID- 23081747 TI - Amidocuprates for directed ortho cupration: structural study, mechanistic investigation, and chemical requirements. PMID- 23081749 TI - Phospharadialenes--a new kid in town. PMID- 23081748 TI - ACACbeta gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes. AB - Patients with type 2 diabetes (T2DM) are usually obese and concurrent obesity results into activation of the renin-angiotensin-system (RAS) which is a risk factor for diabetic nephropathy (DN). Gene-gene interaction between acetyl coenzymeA carboxylase beta (ACACbeta) gene, which is involved in fatty acid metabolism and angiotensin II receptors (AGTR1) gene, which mediates RAS proteins actions on renal tissue, polymorphism with DN have not been studied earlier. The present study was designed with the aim to examine the association of an ACACbeta (rs2268388) and AGTR1 (rs5186) gene polymorphism with the risk of DN in Asian Indians. 1,158 patients with T2DM belonging to two independently ascertained North Indian and one South Indian cohorts were genotyped for ACACbeta (rs2268388) and AGTR1 (rs5186) polymorphism using real time PCR-based Taq-man assay and PCR RFLP assays. In all the three cohorts, a significantly higher frequency of T allele and TT genotypes of ACACbeta and C allele and CC genotypes of AGTR1 were found in patients with DN as compared to patients without nephropathy. Further, T allele of ACACbeta and C allele of AGTR1 were found to be significantly associated with proteinuria, a hallmark of DN. We also found significant epistatic interactions between these two genes. TT genotypes of ACACbeta gene and CC genotype of AGTR1 gene confers the risk of DN and both genes had significant epistatic interaction in Asian Indian patients with T2DM. PMID- 23081750 TI - Production of polyclonal antibody against madecassoside and development of immunoassay methods for analysis of triterpene glycosides in Centella asiatica. AB - INTRODUCTION: Centella asiatica (L.) Urban consists of two major triterpene glycosides, asiaticoside (AS) and madecassoside (MA), as active components used for wound healing and enhancing memory. OBJECTIVE: To produce a polyclonal antibody against madecassoside (MA-PAb) and develop enzyme-linked immunosorbent assay (ELISA) and Eastern blotting methods for quantitative analysis of triterpene glycosides in Centella asiatica. METHODS: An ELISA method was developed using polyclonal antibody against MA. An Eastern blotting method on the PES membrane was established for determination of MA and AS. The immunoassays were validated for sensitivity, precision, specificity and accuracy. RESULTS: The prepared MA-PAb shows specificity to MA and AS. The measuring range of triterpene glycosides was 0.39-50 ug/mL using the ELISA method. An Eastern blotting method was developed for determining individual MA and AS, which could be detected in the range of 62.5-500 ng. The limit of detection for MA and AS was 31.25 ng. The two methods developed showed good specificity, precision, and accuracy, and also correlated with high-performance liquid chromatography. CONCLUSION: These immunoassays have several advantages that include high sensitivity as well as being rapid and facile for determination of the triterpene glycosides in C. asiatica. PMID- 23081751 TI - Atrioventricular block as a presenting finding of silent right coronary artery disease: treatment by percutaneous coronary intervention. AB - Adult patients with clinically related symptoms and high degree atrioventricular block are routinely referred for permanent pacing. The incidence of coronary artery disease is higher in a middle-aged group of patients presenting with atrioventricular block. In patients with stable coronary artery disease, ischaemic episodes may result in intermittent atrioventricular block with clinical symptoms. Herein, we present the clinical course of four consecutive patients admitted to our hospital with the diagnosis of atrioventricular block. PMID- 23081752 TI - Translational research is a necessity for selecting the best components of the extracorporeal circuitry for neonatal and pediatric CPB patients. PMID- 23081754 TI - Repair bond strength of microhybrid, nanohybrid and nanofilled resin composites: effect of substrate resin type, surface conditioning and ageing. AB - OBJECTIVES: This study evaluated the microtensile bond strength (MTBS) of non aged and aged resin-based composites (RBC) (nanohybrid and nanofilled) after two surface conditioning methods, repaired using the composite of the same kind or a microhybrid composite. MATERIALS AND METHODS: Nanohybrid (Tetric EvoCeram--TE) and nanofilled (Filtek Supreme--FS) RBC blocks (5 * 5 * 6 mm) (N = 128) were fabricated and randomly divided into two groups: (a) no ageing (control group) and (b) ageing (5.000 thermocycling, 5-55 degrees C). RBC surfaces were polished by up to 1,200-grit silicone carbide papers and conditioned with either (a) air abrasion with 30-MUm SiO2 particles (CoJet Sand) for 4 s + silane coupling agent (ESPE-Sil) + adhesive resin (VisioBond) (n = 16) or (b) adhesive application only (Multilink A+B for TE; Adper ScotchBond 1XT for FS) (n = 16). In half of the groups, repair resin of the same kind with the RBC and, in the other half, a different kind of composite (microhybrid, Quadrant Anterior Shine--AS) with its corresponding adhesive (Quadrant UniBond) was used. The specimens were submitted to MTBS test (0.5 mm/min). Data were analysed using three-way ANOVA and Tukey's tests. Degree of conversion (DC) of non-aged and aged resin composites (TE, FS) (n = 3 per group) was measured by micro-Raman analyses. RESULTS: RBC type (p = 0.001) and ageing affected the MTBS results significantly (p = 0.001). Surface conditioning type did not show significant difference (p = 0.726), but less number of pre-test failures was experienced with the CoJet system compared to adhesive resin application only. Repair strength on aged TE showed significantly less (p < 0.05) MTBS than for FS. FS repaired with the same kind of RBC and adhesive resin presented the highest cohesive failures (43 %). DC was higher for TE (71 %) than for FS (58 %) before ageing. CONCLUSION: On the aged RBCs, less favourable repair strength could be expected especially for nanohybrid composite. For repair actions, RBC surface conditioning could be accomplished with either adhesive resin application only or with CoJet system, providing that the latter resulted in less pre-test failures. CLINICAL RELEVANCE: Clinicians could condition the resin surface prior to repair or relayering with either CoJet system or adhesive resin application only, depending on the availability of the system. PMID- 23081755 TI - Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study. AB - The association between cognitive impairment, health-related quality of life (HRQoL) and vocational status has been studied in recent years in cross-sectional studies in multiple sclerosis (MS), but longitudinal data are still lacking. This study assesses this association in a sample of 65 newly diagnosed MS patients followed longitudinally. Each patient underwent a standardised clinical assessment, cognitive tests and the HRQoL SEP-59 questionnaire six months after the MS diagnosis (baseline) and seven years later (y7).Vocational status was also established at baseline and at y7 in MS patients. The HRQoL at baseline was severely reduced in MS patients compared with healthy subjects. The independent predictors for HRQoL composite scores at y7 were the baseline depression score and the memory Z-score. Accordingly, 81.5 % of MS patients worked at baseline and only 54.4 % worked at y7. Among the MS patients who did not work at y7, 72.7 % of them were cognitively impaired, while 27.3 % were unimpaired at baseline. The vocational status at y7 was significantly associated with the baseline IPS Z score, EDSS and age. Vocational status at y7 and its change over 7 years was significantly associated with cognitive deterioration. IPS or memory dysfunction in the early stages of MS is correlated with a decreased level in health perception, independent of fatigue, depression and physical disability. Cognitive impairment at the diagnosis of MS increases the risk of changing vocational status in MS patients seven years later. PMID- 23081757 TI - Dye-sensitized solar cells based on a donor-acceptor system with a pyridine cation as an electron-withdrawing anchoring group. AB - New hemicyanine dyes (CM101, CM102, CM103, and CM104) in which tetrahydroquinoline derivatives are used as electron donors and N-(carboxymethyl) pyridinium is used as an electron acceptor and anchoring group were designed and synthesized for dye-sensitized solar cells (DSSCs). Compared with corresponding dyes that have cyanoacetic acid as the acceptor, N-(carboxymethyl)-pyridinium has a stronger electron-withdrawing ability, which causes the absorption maximum of dyes to be redshifted. The photovoltaic performance of the DSSCs based on dyes CM101-CM104 markedly depends on the molecular structures of the dyes in terms of the n-hexyl chains and methoxyl. The device sensitized by dye CM104 achieved the best conversion efficiency of 7.0% (J(sc) = 13.4 mA cm(-2), V(oc) = 704 mV, FF = 74.8%) under AM 1.5 irradiation (100 mW cm(-2)). In contrast, the device sensitized by reference dye CMR104 with the same donor but the cyanoacetic acid as the acceptor gave an efficiency of 3.4% (J(sc) =6.2 mA cm(-2), V(oc) = 730 mV, FF = 74.8%). Under the same conditions, the cell fabricated with N719 sensitized porous TiO(2) exhibited an efficiency of 7.9% (J(sc) = 15.4 mA cm(-2) , V(oc) = 723 mV, FF = 72.3%). The dyes CM101-CM104 show a broader spectral response compared with the reference dyes CMR101-CMR104 and have high IPCE exceeding 90% from 450 to 580 nm. Considering the reflection of sunlight, the photoelectric conversion efficiency could be almost 100% during this region. PMID- 23081756 TI - Disturbed vestibular-neck interaction in cerebellar disease. AB - Cerebellar dysfunction results in ataxia including postural deficits. Evidence from animal experiments suggests convergence of vestibular and neck-position related inputs in cerebellar midline structures. We investigated 20 ambulatory patients with cerebellar disease for disturbed postural control using posturography during static lateral head turns. Binaural bipolar sine-wave galvanic vestibular stimulation (GVS) was used to evoke specific body movements. The Klockgether clinical score was used to assess the severity of cerebellar dysfunction (4-17 of maximal 35 points). In 12 healthy controls and seven lightly affected patients (score <8), GVS elicited physiologic alternating body sway in the head-frontal plane in seven head-on-trunk positions (0 degrees ; 30 degrees , 45 degrees and 60 degrees left and right). Body sway turning with head excursion was progressively attenuated or abolished in more severely affected patients (scores 9-17; r = 0.57, p = 0.008). With most severe impairment, body sway was always in the body-frontal plane irrespective of head turn. A simple clinical test with walking under maximal head turn and closed eyes correlated with posturography data (r = 0.87, p < 0.001) and with Klockgether scores (r = 0.71, p < 0.001). Thus in cerebellar disease, head on trunk position can have a pronounced effect on postural control. PMID- 23081758 TI - Anionic surfactant templated mesoporous silicas (AMSs). AB - This tutorial review highlights the research on anionic surfactant templated mesoporous silica (AMS), which employs a co-structure directing agent (CSDA) to establish the critical interaction between the surfactant head group and silica species. As the geometry of anionic surfactants can be readily tuned via the ionisation of the surfactant head group, AMS materials possess a variety of mesostructures and morphologies. Chiral mesoporous silica (CMS) and helical ribbons can be formed via the chiral packing of the surfactant. Due to the pairing effect between the CSDA and the surfactant, a regular array of the organic groups is formed based on the stoichiometry and geometric arrangement of the surfactant, which produces functionalised materials with a uniform distribution of their organic groups. Furthermore, a brief introduction to the applications and future requirements of AMS is also included. This review is addressed to researchers and students interested in diverse areas of chemistry, particularly inorganic, physical, supramolecular and materials chemistry (63 references). PMID- 23081753 TI - Anemia during treatment with peginterferon Alfa-2b/ribavirin and boceprevir: Analysis from the serine protease inhibitor therapy 2 (SPRINT-2) trial. AB - Boceprevir (BOC) added to peginterferon alfa-2b (PegIFN) and ribavirin (RBV) significantly increases sustained virologic response (SVR) rates over PegIFN/RBV alone in previously untreated adults with chronic hepatitis C genotype 1. We evaluate the relationship of incident anemia with triple therapy. A total of 1,097 patients received a 4-week lead-in of PegIFN/RBV followed by: (1) placebo plus PegIFN/RBV for 44 weeks (PR48); (2) BOC plus PegIFN/RBV using response guided therapy (BOC/RGT); and (3) BOC plus PegIFN/RBV for 44 weeks (BOC/PR48). The management of anemia (hemoglobin [Hb]<10 g/dL) included RBV dose reduction and/or erythropoietin (EPO) use. A total of 1,080 patients had >=1 Hb measurement during treatment. The incidence of anemia was 50% in the BOC arms combined (363/726) and 31% in the PR48 arm (108/354, P<0.001). Among BOC recipients, lower baseline Hb and creatinine clearance were associated with incident anemia. In the BOC-containing arms, anemia was managed by the site investigators as follows: EPO without RBV dose reduction, 38%; RBV dose reduction without EPO, 8%; EPO with RBV dose reduction, 40%; and neither RBV dose reduction nor EPO, 14%. SVR rates were not significantly affected by management strategy (70%-74%), and overall patients with anemia had higher rates of SVR than those who did not develop anemia (58%). Serious and life-threatening adverse events (AEs) and discontinuations due to AEs among BOC-treated patients did not differ by EPO use. CONCLUSION: With BOC/PR therapy, SVR rates in patients with incident anemia were higher than nonanemic patients and did not vary significantly according to the investigator-selected approach for anemia management. Prospective studies are needed to confirm this observation. PMID- 23081759 TI - High temporal resolution in vivo blood oximetry via projection-based T2 measurement. AB - Measuring venous oxygen saturation (HbO2) in large blood vessels can provide important information about oxygen delivery and its consumption in vital organs. Quantification of blood's T2 value via MR can be utilized to determine HbO2 noninvasively. We propose a fast method for in vivo blood T2 quantification via computing the complex difference of velocity-encoded projections. As blood flows continuously, its signal can be robustly isolated from the surrounding tissue by computing the complex difference of two central k-space lines with different velocity encodings. This resultant signal can then be measured as a function of echo time for rapidly quantifying T2 of blood. We applied the method to quantify HbO2 in three cerebral veins at rest and in one of the veins in response to hypercapnia. Average HbO2 measurements in superior sagittal sinus (SSS), straight sinus and internal jugular vein in the group were 63 +/- 3%, 68 +/- 4% and 65 +/- 4%, respectively. Average HbO2 values in SSS during baseline, hypercapnia, and recovery were 63 +/- 2%, 79 +/- 5%, and 61 +/- 3%, respectively. When compared with standard T2 quantification techniques, the proposed method is fast, reliable, and robust against partial volume effects. PMID- 23081760 TI - Use of transgenic GFP reporter strains of the nematode Caenorhabditis elegans to investigate the patterns of stress responses induced by pesticides and by organic extracts from agricultural soils. AB - As a free-living nematode, C. elegans is exposed to various pesticides used in agriculture, as well as to persistent organic residues which may contaminate the soil for long periods. Following on from our previous study of metal effects on 24 GFP-reporter strains representing four different stress-response pathways in C. elegans (Anbalagan et al. Ecotoxicology 21:439-455, 2012), we now present parallel data on the responses of these same strains to several commonly used pesticides. Some of these, like dichlorvos, induced multiple stress genes in a concentration-dependent manner. Unusually, endosulfan induced only one gene (cyp 34A9) to very high levels (8-10-fold) even at the lowest test concentration, with a clear plateau at higher doses. Other pesticides, like diuron, did not alter reporter gene expression detectably even at the highest test concentration attainable, while others (such as glyphosate) did so only at very high concentrations. We have also used five responsive GFP reporters to investigate the toxicity of soil pore water from two agricultural sites in south-east Spain, designated P74 (used for cauliflower production, but significantly metal contaminated) and P73 (used for growing lettuce, but with only background levels of metals). Both soil pore water samples induced all five test genes to varying extents, yet artificial mixtures containing all major metals present had essentially no effect on these same transgenes. Soluble organic contaminants present in the pore water were extracted with acetone and dichloromethane, then after evaporation of the solvents, the organic residues were redissolved in ultrapure water to reconstitute the soluble organic components of the original soil pore water. These organic extracts induced transgene expression at similar or higher levels than the original pore water. Addition of the corresponding metal mixtures had either no effect, or reduced transgene expression towards the levels seen with soil pore water only. We conclude that the main toxicants present in these soil pore water samples are organic rather than metallic in nature. Organic extracts from a control standard soil (Lufa 2.2) had negligible effects on expression of these genes, and similarly several pesticides had little effect on the expression of a constitutive myo-3::GFP transgene. Both the P73 and P74 sites have been treated regularly with (undisclosed) pesticides, as permitted under EU regulations, though other (e.g. industrial) organic residues may also be present. PMID- 23081761 TI - Dual-energy perfusion CT of non-diseased lung segments using dual-source CT: correlation with perfusion SPECT. AB - PURPOSE: To determine the utility of dual-energy perfusion CT (DEpCT) of non diseased lung segments, using dual-source CT, in comparison with perfusion single photon emission computed tomography (SPECT). MATERIALS AND METHODS: 28 patients (18 male and 10 female; mean age 63 years; age range 18-86 years) underwent DEpCT and SPECT within a 3-day interval. The presence and location of perfusion defects in each segment of the lungs were evaluated. RESULTS: Perfusion defects were noted in 7 of 361 segments (1.9%) by DEpCT and in 19 of 361 segments (5.3%) by perfusion SPECT. DEpCT was in good agreement with perfusion SPECT for 338 of 361 segments (93.6%). Intraobserver agreement was also good, ranging from 93.4 to 93.6% (kappa = 0.64-0.75, p < 0.01). CONCLUSION: For non-diseased lung segments, DEpCT correlated well with SPECT. PMID- 23081762 TI - Validation of an axially distributed model for quantification of myocardial blood flow using 13N-ammonia PET. AB - BACKGROUND: Estimation of myocardial blood flow (MBF) with cardiac PET is often performed with conventional compartmental models. In this study, we developed and evaluated a physiologically and anatomically realistic axially distributed model. Unlike compartmental models, this axially distributed approach models both the temporal and the spatial gradients in uptake and retention along the capillary. METHODS: We validated PET-derived flow estimates with microsphere studies in 19 (9 rest, 10 stress) studies in five dogs. The radiotracer, (13)N-ammonia, was injected intravenously while microspheres were administered into the left atrium. A regional reduction in hyperemic flow was forced by an external occluder in five of the stress studies. The flow estimates from the axially distributed model were compared with estimates from conventional compartmental models. RESULTS: The mean difference between microspheres and the axially distributed blood flow estimates in each of the 17 segments was 0.03 mL/g/minute (95% CI [-0.05, 0.11]). The blood flow estimates were highly correlated with each regional microsphere value for the axially distributed model (y = 0.98x + 0.06 mL/g/minute; r = 0.74; P < .001), for the two-compartment (y = 0.64x + 0.34; r = 0.74; P < .001), and for three compartment model (y = 0.69x + 0.54; r = 0.74; P < .001). The variance of the error of the estimates is higher with the axially distributed model than the compartmental models (1.7 [1.3, 2.1] times higher). CONCLUSION: The proposed axially distributed model provided accurate regional estimates of MBF. The axially distributed model estimated blood flow with more accuracy, but less precision, than the evaluated compartmental models. PMID- 23081763 TI - Correlates of life satisfaction among aging veterans. AB - BACKGROUND: The purpose of this study was to document the associations of stressors (combat exposure, retirement concerns, and late-life stressful events), personal resources (social support, sense of mastery, and positive appraisal of military experiences), and functional health (both physical and mental) with life satisfaction in older veterans. METHODS: Participants were 562 male combat veterans (mean age = 70). Self-report questionnaires were administered via mail survey. A hierarchical multiple regression analysis was performed. RESULTS: Each step of the regression analysis demonstrated a significant contribution to variance in life satisfaction (48% in total). Although stressors were significant when entered as a set, their influence dissipated in the presence of personal resources and functional health. For the full model, seven of 11 independent variables were unique and significant predictors, including all personal resource factors and both functional health indices. Sense of mastery was most potent. CONCLUSIONS: Even in the presence of stressors, personal resources and functional health appear to serve protective roles in explaining levels of life satisfaction among aging veterans. PMID- 23081764 TI - The relationship of the job demands-control-support model with vigor across time: testing for reciprocality. AB - We used a longitudinal design to investigate the hypotheses that the components of the Job Demands-Control-Support model and changes in their levels over time predict subsequent changes in levels of positive affect of vigor over time, and vice versa. Our study was conducted on a sample of adults working in a variety of occupations (N = 909, 68% men) at three points in time (T1, T2, and T3), over a period of about four years, controlling for neuroticism and other potential confounding variables. Job control at T1 and increase in its levels from T1 to T2 predicted an increase from T2 to T3 in the levels of vigor, whereas for social support, only its level at T1 predicted an increase from T2 to T3 in levels of vigor. An increase from T1 to T2 in levels of job demands predicted an increase from T2 to T3 in levels of vigor only for those rated low on neuroticism. Vigor at T1 predicted an increase from T2 to T3 in levels of job control and social support, but not changes from T2 to T3 in levels of job demands. The reciprocal causal relationship between job resources and vigor exists regardless of the demands of the work environment. PMID- 23081765 TI - Effects of on-call work on well-being: results of a daily survey. AB - BACKGROUND: Flexible work schedules and on-call work are becoming more and more common in working life. However, little is known about the effects of on-call work on health. METHODS: Using a daily survey method, 31 employees from an Information Technology Service Organisation filled out a questionnaire four times a week while they were on call and another four times a week while they were not on call. An evaluation of cortisol levels was included. Multilevel analyses were used to evaluate the data. RESULTS: Results showed increases in irritation and negative mood and decreases in social activities, household activities, and low effort activities. No effects were found concerning the secretion of cortisol. There were no significant differences between those employees who were actually called in to work during the on-call period and those who were not. CONCLUSIONS: Flexible work schedules like on-call work have effects on well-being. The mere possibility of being disturbed by calls shows negative consequences, regardless of whether the employees are actually called in or not. PMID- 23081766 TI - Perception makes the difference: the association of actual and perceived weight status with self-reported and parent-reported personal resources and well-being in adolescents. AB - The study analyzed associations between actual weight status and weight perceptions with personal resources, physical and psychological health, as well as physical performance among adolescents (N = 5,518; age: 11-17 years). Analyses are based on data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). Self-report measures, parental reports, as well as objective test data were considered. Results indicate that weight perceptions, rather than actual weight status, were associated with personal resources, health, and perceived physical performance. Comparing groups, we found that adolescents who felt they had "just the right weight" achieved more favourable results than those who perceived themselves as "too fat", regardless of their actual weight status. However, actual physical performance was predicted better by actual weight status. Furthermore, weight perceptions were found to mediate the link between actual weight status and all the assessed outcomes (personal resources, health, and physical performance). With respect to self-reports, the mediational effect was consistently stronger for girls, whereas the reverse was true regarding physical performance. Parental reports were not moderated by sex. Findings provide further evidence that among overweight adolescents there are subgroups that differ significantly with regard to risks and resources. Implications for practice are discussed. PMID- 23081767 TI - Passion for work and emotional exhaustion: the mediating role of rumination and recovery. AB - The purpose of the present research is to present a model pertaining to the mediating roles of rumination and recovery experiences in the relationship between a harmonious and an obsessive passion (Vallerand et al., 2003) for work and workers' emotional exhaustion. Two populations were measured in the present research: namely elite coaches and nurses. Study 1's model posits that obsessive passion positively predicts rumination about one's work when being physically away from work, while harmonious passion negatively predicts ruminative thoughts. In turn, rumination is expected to positively contribute to emotional exhaustion. The results of Study 1 were replicated in Study 2. In addition, in the model of Study 2, obsessive passion was expected to undermine recovery experiences, while harmonious passion was expected to predict recovery experiences. In turn, recovery experiences were expected to protect workers from emotional exhaustion. Results of both studies provided support for the proposed model. The present findings demonstrate that passion for work may lead to some adaptive and maladaptive psychological processes depending on the type of passion that is prevalent. PMID- 23081768 TI - The CHANGE program: comparing an interactive versus prescriptive obesity intervention on university students' self-esteem and quality of life. AB - BACKGROUND: Previous studies incorporating Motivational Interviewing administered via Co-Active Life Coaching tools (MI-via-CALC) have elicited positive results among adults with obesity. However, there is a paucity of this research that includes sufficient power and a comparison group. This study's purpose was to compare MI-via-CALC with a validated obesity intervention among university students. METHODS: Participants (n = 45) were randomised to either a telephone based 12-week: (a) MI-via-CALC program whereby a certified coach worked with subjects to achieve goals through dialogue; or (b) lifestyle modification treatment following the LEARN Program for Weight Management. Participants completed the Rosenberg Self-Esteem Scale and Short Form Functional Health Status Scale (SF-36) at baseline, mid-, and post-treatment, and 3 and 6 months following the program. RESULTS: Analyses revealed that both conditions elicited significant time effects between baseline and 6 months for self-esteem and all dimensions of the SF-36 (e.g. overall health). CONCLUSIONS: MI-via-CALC compares favorably with LEARN as an obesity treatment. Given that self-esteem and quality of life are essential for promoting behavior change among individuals with obesity, this study offers unique insights into their change processes. Future research should provide both treatments and allow participants to choose based on their personal preferences, learning styles, and needs. PMID- 23081769 TI - Molecular rectification in triangularly shaped graphene nanoribbons. AB - We present a theoretical study of electron transport in tailored zigzag graphene nanoribbons (ZGNRs) with triangular structure using density functional theory together with the nonequilibrium Green's function formalism. We find significant rectification with a favorite electron transfer direction from the vertex to the right edge. The triangular ZGNR connecting to the electrode with one thiol group at each terminal shows an average rectification ratio of 8.4 over the bias range from -1.0 to 1.0 V. This asymmetric electron transport property originates from nearly zero band gap of triangular ZGNR under negative bias, whereas a band gap opens under positive bias. When the molecule is connected to the electrode by multithiol groups, the current is enhanced due to strong interfacial coupling; however, the rectification ratio decreases. The simulation results indicate that the unique electronic states of triangular ZGNR are responsible for rectification, rather than the asymmetric anchoring groups. PMID- 23081770 TI - Impact of air pollution on cystic fibrosis pulmonary exacerbations: a case crossover analysis. AB - BACKGROUND: Pulmonary exacerbations in cystic fibrosis (CF) contribute to the burden of disease, with a negative impact on quality of life, costs, and lung function. Our aim was to evaluate whether exacerbations, defi ned by antibiotic use, were triggered by daily fl uctuations in air pollution. METHODS: In a case crossover analysis, we evaluated 215 patients with CF and pollution data from January 1, 1998, to December 31, 2010. Exacerbation was defi ned as the start of IV or oral antibiotic use in a home or hospital setting. We calculated regional background levels of particulate matter with a diameter , 10 m m (PM 10 ), ozone, and nitrogen dioxide (NO 2 ) on the day of the event and on the 2 days prior to the event at each patient's home address. We matched for day of the week and controlled for temperature on the day of the event and the 2 preceding days. In the month where antibiotic treatment was started, all days with the same temperature ( 2 degrees C) as the event day served as control days, excluding 3 days before and after the start of treatment. RESULTS: A total of 215 patients (male sex, 49%, mean age, 21 13 years) had 2,204 antibiotic treatments (1,107 IV and 1,097 oral). Over a period of 12 years, an increase in risk of antibiotic use was associated with increasing concentrations of PM 10 , NO 2 , and ozone on the event day and for NO 2 on the day before. A tendency toward signifi cance was seen the day before antibiotic use for PM 10 and ozone. Overall, a rise in OR was seen from 2 days before until the day of the start of antibiotics. CONCLUSIONS: In patients with CF and exacerbations, ambient concentrations of ozone, PM 10 , and NO 2 play a role in triggering an exacerbation. PMID- 23081771 TI - Bioconversion of p-coumaric acid to p-hydroxystyrene using phenolic acid decarboxylase from B. amyloliquefaciens in biphasic reaction system. AB - Phenolic acid decarboxylase (PAD) catalyzes the non-oxidative decarboxylation of p-coumaric acid (pCA) to p-hydroxystyrene (pHS). PAD from Bacillus amyloliquefaciens (BAPAD), which showed k (cat)/K (m) value for pCA (9.3 * 103 mM 1 s-1), was found as the most active one using the "Subgrouping Automata" program and by comparing enzyme activity. However, the production of pHS of recombinant Escherichia coli harboring BAPAD showed only a 22.7 % conversion yield due to product inhibition. Based on the partition coefficient of pHS and biocompatibility of the cell, 1-octanol was selected for the biphasic reaction. The conversion yield increased up to 98.0 % and 0.83 g/h/g DCW productivity was achieved at 100 mM pCA using equal volume of 1-octanol as an organic solvent. In the optimized biphasic reactor, using a three volume ratio of 1-octanol to phosphate buffer phase (50 mM, pH 7.0), the recombinant E. coli produced pHS with a 88.7 % conversion yield and 1.34 g/h/g DCW productivity at 300 mM pCA. PMID- 23081772 TI - Identification of B cell epitopes of dengue virus 2 NS3 protein by monoclonal antibody. AB - Dengue virus is a major international public health concern, and there is a lack of available effective vaccines. Virus-specific epitopes could help in developing epitope peptide vaccine. Previously, a neutralizing monoclonal antibody (mAb) 4F5 against nonstructural protein 3 (NS3) of dengue virus 2 (DV2) was developed in our lab. In this work, the B cell epitope recognized by mAb 4F5 was identified using the phage-displayed peptide library. The results of the binding assay and competitive inhibition assay indicated that the peptides, residues 460-469 (U460 469 RVGRNPKNEN) of DV2 NS3 protein, were the B cell epitopes recognized by mAb 4F5. Furthermore, the epitope peptides and a control peptide were synthesized and then immunized female BALB/c mice. ELISA analysis showed that immunization with synthesized epitope peptide elicited a high level of antibody in mice, and immunofluorescent staining showed that the antisera from fusion epitope-immunized mice also responded to DV2 NS3 protein, which further characterized the specific response of the present epitope peptide. Therefore, the present work revealed the specificity of the newly identified epitope (U460-469) of DV2 NS3 protein, which may shed light on dengue virus (DV) vaccine design, DV pathogenesis study, and even DV diagnostic reagent development. PMID- 23081773 TI - Antifungal effects of citronella oil against Aspergillus niger ATCC 16404. AB - Essential oils are aromatic oily liquids obtained from some aromatic plant materials. Certain essential oils such as citronella oil contain antifungal activity, but the antifungal effect is still unknown. In this study, we explored the antifungal effect of citronella oil with Aspergillus niger ATCC 16404. The antifungal activity of citronella oil on conidia of A. niger was determined by poisoned food technique, broth dilution method, and disc volatility method. Experimental results indicated that the citronella oil has strong antifungal activity: 0.125 (v/v) and 0.25 % (v/v) citronella oil inhibited the growth of 5 * 105 spore/ml conidia separately for 7 and 28 days while 0.5 % (v/v) citronella oil could completely kill the conidia of 5 * 105 spore/ml. Moreover, the fungicidal kinetic curves revealed that more than 90 % conidia (initial concentration is 5 * 105 spore/ml) were killed in all the treatments with 0.125 to 2 % citronella oil after 24 h. Furthermore, with increase of citronella oil concentration and treatment time, the antifungal activity was increased correspondingly. The 0.5 % (v/v) concentration of citronella oil was a threshold to kill the conidia thoroughly. The surviving conidia treated with 0.5 to 2 % citronella oil decreased by an order of magnitude every day, and no fungus survived after 10 days. With light microscope, scanning electron microscope, and transmission electron microscope, we found that citronella oil could lead to irreversible alteration of the hyphae and conidia. Based on our observation, we hypothesized that the citronella oil destroyed the cell wall of the A. niger hyphae, passed through the cell membrane, penetrated into the cytoplasm, and acted on the main organelles. Subsequently, the hyphae was collapsed and squashed due to large cytoplasm loss, and the organelles were severely destroyed. Similarly, citronella oil could lead to the rupture of hard cell wall and then act on the sporoplasm to kill the conidia. Nevertheless, the citronella oil provides a potential of being a safe and environmentally friendly fungicide in the future. PMID- 23081774 TI - Developmental cycle and pharmaceutically relevant compounds of Salinispora actinobacteria isolated from Great Barrier Reef marine sponges. AB - The developmental cycle of the obligate marine antibiotic producer actinobacterium Salinispora arenicola isolated from a Great Barrier Reef marine sponge was investigated in relation to mycelium and spore ultrastructure, synthesis of rifamycin antibiotic compounds, and expression of genes correlated with spore formation and with rifamycin precursor synthesis. The developmental cycle of S. arenicola M413 on solid agar medium was characterized by substrate mycelium growth, change of colony color, and spore formation; spore formation occurred quite early in colony growth but development of black colonies occurred only at late stages, correlated with a change in spore maturity in relation to cell wall layers. Rifamycins were detected throughout the growth cycle, but changed in relative quantity at particular phases in the cycle, with a marked increase after 32 days. Expression of the spore division gene ssgA and the rifK gene for 3-amino-5-hydroxybenzoate synthase responsible for rifamycin precursor synthesis was seen even at early stages of the growth cycle. ssgA expression significantly increased between days 26 and 31, but rifK expression effectively remained constant throughout the growth cycle, consistent with the early synthesis of rifamycin. Factors other than precursor synthesis may be responsible for an observed late increase in rifamycin production. A useful approach for measuring and exploring the regulation of antibiotic synthesis and gene expression in the marine natural product producer S. arenicola has been established. PMID- 23081775 TI - Sugar transport systems in Corynebacterium glutamicum: features and applications to strain development. AB - Corynebacterium glutamicum uses the phosphoenolpyruvate-dependent sugar phosphotransferase system (PTS) to take up and phosphorylate glucose, fructose, and sucrose, the major sugars from agricultural crops that are used as the primary feedstocks for industrial amino acid fermentation. This means that worldwide amino acid production using this organism has depended exclusively on the PTS. Recently, a better understanding not only of PTS-mediated sugar uptake but also of global regulation associated with the PTS has permitted the correction of certain negative aspects of this sugar transport system for amino acid production. In addition, the recent identification of different glucose uptake systems in this organism has led to a strategy for the generation of C. glutamicum strains that express non-PTS routes instead of the original PTS. The potential practical advantages of the development of such strains are discussed. PMID- 23081776 TI - In vitro propagation and production of cardiotonic glycosides in shoot cultures of Digitalis purpurea L. by elicitation and precursor feeding. AB - Digitalis purpurea L. (Scrophulariaceae; Foxglove) is a source of cardiotonic glycosides such as digitoxin and digoxin which are commercially applied in the treatment to strengthen cardiac diffusion and to regulate heart rhythm. This investigation deals with in vitro propagation and elicited production of cardiotonic glycosides digitoxin and digoxin in shoot cultures of D. purpurea L. In vitro germinated seedlings were used as a primary source of explants. Multiple shoot formation was achieved for three explant types (nodal, internodal, and leaf) cultured on Murashige and Skoog (MS) medium with several treatments of cytokinins (6-benzyladenine-BA; kinetin-Kin; and thidiazuron-TDZ) and auxins (indole-3-acetic acid-IAA; alpha-naphthaleneacetic acid-NAA; and 2,4 dichlorophenoxy acetic acid-2,4-D). Maximum multiple shoots (12.7 +/- 0.6) were produced from nodal explants on MS + 7.5 MUM BA. Shoots were rooted in vitro on MS containing 15 MUM IAA. Rooted plantlets were successfully acclimatized. To further maintain the multiple shoot induction, mother tissue was cut into four equal parts and repeatedly sub-cultured on fresh shoot induction liquid medium after each harvest. On adaptation of this strategy, an average of 18 shoots per explant could be produced. This strategy was applied for the production of biomass and glycosides digitoxin and digoxin in shoot cultures on MS medium supplemented with 7.5 MUM BA and several treatments with plant growth regulators, incubation period, abiotic (salicylic acid, mannitol, sorbitol, PEG-6000, NaCl, and KCl), biotic (Aspergillus niger, Helminthosporium sp., Alternaria sp., chitin, and yeast extract) elicitors, and precursors (progesterone, cholesterol, and squalene). The treatment of KCl, mycelial mass of Helminthosporium sp., and progesterone were highly effective for the production of cardenolides. In the presence of progesterone (200 to 300 mg/l), digitoxin and digoxin accumulation was enhanced by 9.1- and 11.9-folds respectively. PMID- 23081777 TI - Exploration of BAC versus plasmid expression vectors in recombinant CHO cells. AB - Vector engineering approaches are commonly used to increase recombinant protein production in mammalian cells, and among various concepts, bacterial artificial chromosomes (BAC) have been proposed to serve as open chromatin regions to omit chromosome positional effects. For proof of concept, we developed stable recombinant Chinese hamster ovary (CHO) cell lines using different expression vector systems: the plasmid vectors contained the identical expression cassette as the BAC constructs. Two anti-HIV1 antibody derivates served as model proteins (3D6scFc and 2F5scFc) for generation of four stable recombinant CHO cell lines. The BAC-derived clones showed three to four times higher specific productivity, and therefore, gene copy numbers and transcript level were quantified. The active chromatin region provided with the BAC environment significantly improved transcription evidenced with both model proteins. Specific transcription was approximately six times higher from BAC-based vectors compared to the corresponding plasmid vectors for both single-chain fragment crystallizable (scFc) proteins. Our accurate investigations elucidated also differences between translational activities related to the protein of choice. 3D6scFc expressed specifically three to four times more product than 2F5scFc indicating that the product by itself also contributes to enhanced productivity. This study indicated comparable increase of transcription level for both scFc proteins when using the BAC system, but translation, maturation, and secretion of individual proteins seem to be protein specific. PMID- 23081778 TI - Strict control of auricin production in Streptomyces aureofaciens CCM 3239 involves a feedback mechanism. AB - The polyketide gene cluster aur1 is responsible for the production of the angucycline antibiotic auricin in Streptomyces aureofaciens CCM 3239. Auricin production is regulated in a complex manner involving several regulators, including a key pathway-specific positive regulator Aur1P that belongs to the family of 'atypical' response regulators. Production of auricin is induced after entry into stationary phase. However, auricin was produced in only a short time interval of several hours. We found that the decrease of auricin production was due to a strict regulation of auricin biosynthetic genes at the transcriptional level by a feedback mechanism; auricin and/or its intermediate(s) inhibited binding of Aur1P to its cognate biosynthetic promoter aur1Ap and consequently stopped its activation. In addition, we also determined that synthesised auricin is unstable during growth of S. aureofaciens CCM3239 in the production medium even though purified auricin is stable for days in various organic solvents. The critical parameter affecting its stability was pH. Auricin is stable at acid pH and unstable at neutral and alkaline pH. The drop in auricin concentration was due to an increase of pH shortly after induction of auricin production during cultivation of S. aureofaciens CCM3239. PMID- 23081780 TI - Robot-assisted hysterectomy vs total laparoscopic hysterectomy: a comparison of short-term surgical outcomes. AB - BACKGROUND: The objective of the study was to compare the short-term outcomes of robot-assisted hysterectomy with laparoscopic hysterectomy. METHODS: This study compared 60 patients who underwent robot-assisted hysterectomy (RAH) with 60 patients who underwent laparoscopic hysterectomy (LH). RESULTS: The mean ages of the patients in the RAH and LH groups were 51.52 +/- 6.97 and 50.68 +/- 8.92 years, respectively. The mean operative times for the RAH and LH groups were 108.12 +/- 34.65 and 90.67 +/- 25.20 min, respectively (p = 0.002). None of the cases in the RAH group required conversion to laparotomy; the rate of conversion to open laparotomy in the LH group was 1.6%. The complication rate among patients who underwent RAH was 8.3% compared with 6.6% in the laparoscopic cohort. CONCLUSIONS: Robot-assisted hysterectomy is feasible and safe, resulting in similar surgical results when compared with traditional laparoscopic hysterectomy. It appears that, in the hands of a skilled laparoscopic surgeon, robot-assisted hysterectomy is not superior to the laparoscopic approach. PMID- 23081779 TI - LGR5-positive colon cancer stem cells interconvert with drug-resistant LGR5 negative cells and are capable of tumor reconstitution. AB - The cancer stem cell (CSC) concept has been proposed as an attractive theory to explain cancer development, and CSCs themselves have been considered as targets for the development of diagnostics and therapeutics. However, many unanswered questions concerning the existence of slow cycling/quiescent, drug-resistant CSCs remain. Here we report the establishment of colon cancer CSC lines, interconversion of the CSCs between a proliferating and a drug-resistant state, and reconstitution of tumor hierarchy from the CSCs. Stable cell lines having CSC properties were established from human colon cancer after serial passages in NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice and subsequent adherent cell culture of these tumors. By generating specific antibodies against LGR5, we demonstrated that these cells expressed LGR5 and underwent self-renewal using symmetrical divisions. Upon exposure to irinotecan, the LGR5(+) cells transitioned into an LGR5(-) drug-resistant state. The LGR5(-) cells converted to an LGR5(+) state in the absence of the drug. DNA microarray analysis and immunohistochemistry demonstrated that HLA-DMA was specifically expressed in drug-resistant LGR5(-) cells, and epiregulin was expressed in both LGR5(+) and drug-resistant LGR5(-) cells. Both cells sustained tumor initiating activity in NOG mice, giving rise to a tumor tissue hierarchy. In addition, anti-epiregulin antibody was found to be efficacious in a metastatic model. Both LGR5(+) and LGR5(-) cells were detected in the tumor tissues of colon cancer patients. The results provide new biological insights into drug resistance of CSCs and new therapeutic options for cancer treatment. PMID- 23081781 TI - Label-free somatic cell cytometry in raw milk using acoustophoresis. AB - A microfluidic system for cell enumeration in raw milk was developed. The new method, preconditions the milk sample using acoustophoresis that removes lipid particles which are larger than a few micrometers. The acoustophoretic preprocessing eliminates the need for conventional sample preparation techniques, which include chemical solvents, cell labeling and centrifugation, and facilitates rapid cell enumeration using microscopy or coulter counter measurements. By introducing an acoustic standing wave with three pressure nodes in a microchannel at the same time as the milk sample is laminated to the channel center, lipids are acoustically driven to the closest pressure antinode at each side of the channel center and the cells in the milk sample are focused in the central pressure node. The extracted center fraction with cells becomes sufficiently clean from lipid vesicles to enable enumeration of somatic cells without any labeling step either by direct light microscopy or by coulter counting. Obtained lipid free milk fractions clearly revealed the cell fraction when analyzed by Coulter Counting. Cell counting as measured by a Coulter Counter after acoustophoretic lipid depletion aligned with the corresponding data obtained by reference measurements based on fluorescence staining and subsequent flow cytometer analysis. PMID- 23081782 TI - The experience of addiction as told by the addicted: incorporating biological understandings into self-story. AB - How do the addicted view addiction against the framework of formal theories that attempt to explain the condition? In this empirical paper, we report on the lived experience of addiction based on 63 semi-structured, open-ended interviews with individuals in treatment for alcohol and nicotine abuse at five sites in Minnesota. Using qualitative analysis, we identified four themes that provide insights into understanding how people who are addicted view their addiction, with particular emphasis on the biological model. More than half of our sample articulated a biological understanding of addiction as a disease. Themes did not cluster by addictive substance used; however, biological understandings of addiction did cluster by treatment center. Biological understandings have the potential to become dominant narratives of addiction in the current era. Though the desire for a "unified theory" of addiction seems curiously seductive to scholars, it lacks utility. Conceptual "disarray" may actually reflect a more accurate representation of the illness as told by those who live with it. For practitioners in the field of addiction, we suggest the practice of narrative medicine with its ethic of negative capability as a useful approach for interpreting and relating to diverse experiences of disease and illness. PMID- 23081783 TI - Template assembly of spin crossover one-dimensional nanowires. PMID- 23081784 TI - Rapid natural-abundance 2D 13C-13C correlation spectroscopy using dynamic nuclear polarization enhanced solid-state NMR and matrix-free sample preparation. PMID- 23081785 TI - Partnering with parents to enhance habilitation: a parent's perspective. AB - Parents play a very important role in language habilitation for their children who are deaf or hard of hearing. However, many times parents are not aware of the difference they can make in their child's language development. It is important that professionals working with children support parents in understanding their role and identifying language learning strategies that parents can incorporate into their daily routines to increase language development opportunities. Parents also have a key role in monitoring their child's progress to assist the professionals in assessing how well the habilitation strategies they are using are working. Family support and coaching strategies that professionals can use to encourage and support the parent's role in habilitation are discussed. PMID- 23081786 TI - Child-centered collaborative conversations that maximize listening and spoken language development for children with hearing loss. AB - In the period that begins with early intervention enrollment and ends with the termination of formal education, speech-language pathologists (SLPs) will have numerous opportunities to form professional relationships that can enhance any child's listening and spoken language accomplishments. SLPs who initiate and/or nurture these relationships are urged to place the needs of the child as the core value that drives decision making. Addressing this priority will allow for the collaborative conversations necessary to develop an effective intervention plan at any level. For the SLP, the purpose of these collaborative conversations will be twofold: identifying the functional communication needs of the child with hearing loss across settings and sharing practical strategies to encourage listening and spoken language skill development. Auditory first, wait time, sabotage, and thinking turns are offered as four techniques easily implemented by all service providers to support the child with hearing loss in all educational settings. PMID- 23081787 TI - Supporting communicative development of infants and toddlers with hearing loss. AB - Newborn hearing screening has increased the number of families enrolled in early intervention during a sensitive period of communication development. The primary role of the speech-language pathologist in early intervention is to facilitate natural parent-infant interactions and support parents' feelings of confidence in communicating with their child. Feelings of self-efficacy can be increased when parents understand how hearing loss impacts their child's communication development, understand how to monitor hearing technology and hearing status, and receive consistent feedback related to their child's progress. This article reviews the evidence behind benefits of early parent-child interactions and outlines strategies and resources for speech-language pathologists to use in supporting communication development with infants and toddlers with hearing loss. PMID- 23081788 TI - Literacy strategies for young children: considerations for auditory and visual environments. AB - Literacy can be a challenging skill for children who are deaf or hard of hearing. However, there are a variety of strategies we can use with young children to develop literacy skills based on the type of communication chosen by their families. Specific auditory and visual considerations for applying the literacy strategies to maximize the child's learning are recommended according to the communication decision of the family. By analyzing these strategies from both an auditory and visual perspective, the service provider can easily model and support the families as they incorporate literacy activities into their daily routines. This article focuses on a few of the strategies that are important for helping children develop literacy skills, and highlights how these strategies could be incorporated in both auditory and visual environments. PMID- 23081789 TI - The school to home link: summer preschool and parents. AB - This study investigates the amount of language available to children in the home environment and a summer preschool program. The purpose of this study was twofold. First, the study sought to gain information about patterns of language use among families of preschoolers with hearing loss. Additionally, the project was designed to provide an initial investigation into the impact of reduced educational programming over summer months for children with hearing loss. Children with varying degrees of hearing loss were enrolled in an auditory-oral 6 week part-time program. The language environment during preschool and at home was analyzed through use of Language ENvironment Analysis (LENA). LENA is a digital language processor that can record and analyze through specific measurements the natural language environment of a child. Overall, the children studied received significantly more complex language in preschool than in the home environment. The data suggest that children with hearing loss benefit from the opportunity to attend summer preschool programming. Additionally, it is critical that parents of preschoolers continue to receive parental education surrounding use of language strategies in the home environment. Implications for practice are discussed. PMID- 23081791 TI - Students who are deaf and hard of hearing and use sign language: considerations and strategies for developing spoken language and literacy skills. AB - There is a core body of knowledge, experience, and skills integral to facilitating auditory, speech, and spoken language development when working with the general population of students who are deaf and hard of hearing. There are additional issues, strategies, and challenges inherent in speech habilitation/rehabilitation practices essential to the population of deaf and hard of hearing students who also use sign language. This article will highlight philosophical and practical considerations related to practices used to facilitate spoken language development and associated literacy skills for children and adolescents who sign. It will discuss considerations for planning and implementing practices that acknowledge and utilize a student's abilities in sign language, and address how to link these skills to developing and using spoken language. Included will be considerations for children from early childhood through high school with a broad range of auditory access, language, and communication characteristics. PMID- 23081790 TI - The missing link in language development of deaf and hard of hearing children: pragmatic language development. AB - This article will provide information about the Pragmatics Checklist, which consists of 45 items and is scored as: (1) not present, (2) present but preverbal, (3) present with one to three words, and (4) present with complex language. Information for both children who are deaf or hard of hearing and those with normal hearing are presented. Children who are deaf or hard of hearing are significantly older when demonstrating skill with complex language than their normal hearing peers. In general, even at the age of 7 years, there are several items that are not mastered by 75% of the deaf or hard of hearing children. Additionally, the article will provide some suggestions of strategies that can be considered as a means to facilitate the development of these pragmatic language skills for children who are deaf or hard of hearing. PMID- 23081792 TI - Classroom listening assessment: strategies for speech-language pathologists. AB - Emphasis on classroom listening has gained importance for all children and especially for those with hearing loss and special listening needs. The rationale can be supported from trends in educational placements, the Response to Intervention initiative, student performance and accountability, the role of audition in reading, and improvement in hearing technologies. Speech-language pathologists have an instrumental role advocating for the accommodations that are necessary for effective listening for these children in school. To identify individual listening needs and make relevant recommendations for accommodations, a classroom listening assessment is suggested. Components of the classroom listening assessment include observation, behavioral assessment, self-assessment, and classroom acoustics measurements. Together, with a strong rationale, the results can be used to implement a plan that results in effective classroom listening for these children. PMID- 23081793 TI - Using Language ENvironment Analysis to improve outcomes for children who are deaf or hard of hearing. AB - Very little is known about the language environments of children in the United States in non-English-speaking homes. There is currently no published research that analyzes deaf or hard of hearing children in Spanish-speaking households, although the Colorado Home Intervention Program demographics indicate that these households account for 10 to 15% of the population of children who are deaf or hard of hearing. In other geographic regions in the United States, it is likely that the population of deaf and hard of hearing children from Spanish-speaking homes is considerably larger. The Spanish-speaking population in the United States has grown considerably within the last 5 to 10 years and will continue to expand. For these children to receive adequate treatment, research must be conducted to understand their language environment. The Language ENvironment Analysis (LENA) System uses a small recording device to collect, analyze, and sort a child's language environment into multiple categories and analyzes variables such as child vocalizations, adult words, and conversational turn taking. The normative data for the LENA System are from families who are English speaking. The article demonstrates the feasibility of using the LENA System to gain understanding of the language environment of a child who is deaf or hard of hearing in a Spanish-speaking household. PMID- 23081794 TI - A tutorial on auditory neuropathy/dyssynchrony for the speech-language pathologist and audiologist. AB - This article presents information about developmental outcomes of children with auditory neuropathy/auditory dyssynchrony (AN). Colorado data on the number of children screened and the number of children identified with unilateral and bilateral AN will be described. Descriptive information about the percent of children with AN with cognitive disability and disabilities other than hearing loss will be presented. Language outcomes of children with normal cognitive development will be presented. This article will also provide information about etiologies and audiological information of children with AN. It includes assessment tools that have been useful in decision making for children with AN. PMID- 23081796 TI - The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination. AB - Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. CONCLUSION: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI. PMID- 23081797 TI - CT assessment of the prevalence of retinacular injuries associated with hindfoot fractures. AB - OBJECTIVE: To determine the incidence of injuries to the flexor and peroneal retinacula in hindfoot fractures as demonstrated on ankle computed tomography (CT). MATERIALS AND METHODS: Study patients were identified via review of CT records at a single institution. CT scans were retrospectively reviewed and compared with surgical reports. RESULTS: Hindfoot fractures undergoing CT showed flexor retinacular injuries in 23.7% of cases and peroneal retinacular injuries in 10.2%. The posterior tibial tendon was partly torn in 4.2% of cases, and entrapped between fracture fragments in 16.1%. The peroneal tendon was rarely injured, being entrapped in 1.7% of cases. Pilon, distal tibial shaft, malleolar, talar, and calcaneal fractures were all associated with retinacular injuries. CT findings correlated well with surgical findings; there were no false-positive CT findings, and only 1 false-negative finding, a posterior tibial tendon that was entrapped at surgery, but in a normal position on the CT. CONCLUSIONS: Retinacular injuries are commonly demonstrated on CT in patients with ankle fractures. The contribution of these injuries to fracture outcomes is unknown. PMID- 23081798 TI - Geodermatophilus arenarius sp. nov., a xerophilic actinomycete isolated from Saharan desert sand in Chad. AB - A novel Gram-positive, aerobic, actinobacterial strain, CF5/4(T), was isolated in 2007 during an environmental screening of arid desert soil in Oure Cassoni, Chad. The isolate grew best in a temperature range of 28-40 degrees C and at pH 6.0 8.5, with 0-1 % (w/v) NaCl, forming brown-coloured and nearly circular colonies on GYM agar. Chemotaxonomic and molecular characteristics of the isolate matched those described for members of the genus Geodermatophilus. The DNA G + C content of the novel strain was 75.9 mol %. The peptidoglycan contained meso diaminopimelic acid as diagnostic diaminoacid. The main phospholipids were phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol, diphosphatidylglycerol and a small amount of phosphatidylglycerol; MK-9(H(4)) was identified as the dominant menaquinone and galactose as diagnostic sugar. The major cellular fatty acids were branched-chain saturated acids: iso-C(15:0) and iso-C(16:0). The 16S rRNA gene showed 96.2-98.3 % sequence identity with the three members of the genus Geodermatophilus: G. obscurus (96.2 %), G. ruber (96.5 %), and G. nigrescens (98.3 %). Based on the chemotaxonomic results, 16S rRNA gene sequence analysis and DNA-DNA hybridization with the type strain of G. nigrescens, the isolate is proposed to represent a novel species, Geodermatophilus arenarius (type strain CF5/4(T) = DSM 45418(T) = MTCC 11413(T) = CCUG 62763(T)). PMID- 23081799 TI - Two-dimensional radial sodium heart MRI using variable-rate selective excitation and retrospective electrocardiogram gating with golden angle increments. AB - PURPOSE: Two-dimensional projection reconstruction methods provide advantages over three-dimensional techniques because of higher flexibility regarding the resolution and shorter scan time needed. To optimize a two-dimensional radial sequence with respect to signal-to-noise ratio, variable-rate selective excitation and retrospective electrocardiogram gating is investigated. METHODS: The minimal radiofrequency pulse duration is simulated in dependence of the flip angle and coil parameters using sinc waveforms with two different variable-rate selective excitation approaches and a Fermi pulse. Retrospectively electrocardiogram-gated imaging with Golden Angle incremented projections was implemented to allow for continuous data acquisition enabling the possibility of dynamic electrocardiogram-gated heart imaging. RESULTS: Especially for abdominal coils with high transmitter voltages required, variable-rate selective excitation strongly reduces the radiofrequency pulse duration and echo time resulting in a signal-to-noise ratio gain up to 15.5% (if the fast relaxation component of sodium is in the order of the radiofrequency pulse duration) compared with standard sinc-shaped radiofrequency pulses. Retrospective electrocardiogram gating shows higher flexibility with regard to the trigger delay enabling the trade-off between heart motion artifacts and signal-to-noise ratio. CONCLUSION: A two-dimensional radial sequence is optimized for sodium heart imaging regarding signal-to-noise ratio. Different sodium contrasts of the human heart are shown, which can give additional information on heart diseases. PMID- 23081800 TI - TNF-alpha has tropic rather than apoptotic activity in human hematopoietic progenitors: involvement of TNF receptor-1 and caspase-8. AB - Tumor necrosis factor-alpha (TNF-alpha) has been suggested to exert detrimental effects on hematopoietic progenitor function that might limit the success of transplants. In this study, we assessed the influences of TNF-alpha and its two cognate receptors on the function of fresh umbilical cord blood (UCB) and cryopreserved mobilized peripheral blood (mPB). CD34(+) progenitors from both sources are less susceptible to spontaneous apoptosis than lineage-committed cells and are not induced into apoptosis by TNF-alpha. Consequently, the activity of UCB-derived severe combined immune deficiency (SCID) reconstituting cells and long-term culture-initiating cells is unaffected by this cytokine. On the contrary, transient exposure of cells from both sources to TNF-alpha stimulates the activity of myeloid progenitors, which persists in vivo in UCB cell transplants. Progenitor stimulation is selectively mediated by TNF-R1 and involves activation of caspase-8, without redundant activity of TNF-R2. Despite significant differences between fresh UCB cells and cryopreserved mPB cells in susceptibility to apoptosis and time to activation, TNF-alpha is primarily involved in tropic signaling in hematopoietic progenitors from both sources. Cytokine-mediated tropism cautions against TNF-alpha neutralization under conditions of stress hematopoiesis and may be particularly beneficial in overcoming the limitations of UCB cell transplants. PMID- 23081801 TI - RNA isolation from fetal and adult human tissues for transcriptional profiling. AB - Investigations involving rare human tissues that are difficult to acquire due to their scarcity are highly challenging. The need to verify microarray analysis data by additional methods such as immunohistochemical staining and quantitative PCR creates an even greater demand for these valuable tissues. Furthermore, since rare human tissues may come from different sources and may have been processed by variable methods, the comparability of these samples must be verified. The aim of this study was to determine and validate a processing method that allows the analysis of human fetal and adult cardiovascular tissues from different sources that were preserved using varying methods. Due to restricted access to fresh human tissues and the need to accumulate these samples over an extended period of time, we used formalin-fixed paraffin-embedded tissues for gene expression analyses. We analyzed RNA levels from four different age groups: fetal first and second trimester, adolescents, and adults. In this study, we present an improved standard processing procedure for tissue sample processing and analysis of rare human cardiovascular tissues. PMID- 23081802 TI - Silica monoliths with hierarchical porosity obtained from porous glasses. AB - This review deals with "classical" porous glasses which are prepared by physical phase separation of alkali borosilicate glasses of suitable composition in combination with selective leaching. The resulting materials are characterized by a controllable pore size in the nanometer range, high mechanical, thermal and chemical stability and an adjustable macroscopic shape, which enables manufacturing of glass monoliths with various geometries. As a result of their formation, porous glasses obtained from physical phase separation exhibit a monomodal pore structure. There are only a few examples in the literature for the synthesis of hierarchically porous glasses. This review covers several synthesis strategies for the introduction of hierarchy into "classical" porous glass monoliths, including sintering and fusion of alkali borosilicate initial glasses as well as partial or complete pseudomorphic transformation of porous glasses into zeolites or ordered mesoporous materials. PMID- 23081803 TI - Encapsulation of luminescent homoleptic [Ru(dpp)3](2+)-type chromophores within an amphiphilic dendritic environment. AB - A new series of homoleptic metallodendrimers has been synthesized through ruthenium-metal complexation by dendritically modified bathophenanthroline ligands. The presence of hydrophilic oligo(ethylene glycol) groups on the surface of the monodisperse metal complexes enabled the solubilization of all of the fractal species in a wide range of solvents, including water. The specific properties of all of these compounds have been systematically investigated by using photophysical techniques as a function of the generation number. Accordingly, the encapsulation of the highly luminescent [Ru(dpp)(3)](2+)-type (dpp=4,7-diphenyl-1,10-phenanthroline) core unit within a dendritic microenvironment creates a powerful means to shield the center from dioxygen quenching. This shielding effect, as exerted on the phosphorescent ruthenium derived center, is reflected by enhanced emission intensities and extended excited-state lifetimes that are close to the highest values reported so far, even in an air-equilibrated aqueous medium. Interestingly, when inspecting the largest dendritic assembly, that is, the third-generation assembly, significant drops in emission quantum yields and lifetimes are observed. This anomalous behavior has been attributed to the folding of the branches towards the luminescent core. PMID- 23081804 TI - Intraoperative measurement of femoral antetorsion using the anterior cortical angle method: a novel use for smartphones. AB - BACKGROUND: Malrotation after femoral nailing is a common problem, yet estimation of the correct rotation during nailing remains a technical challenge. In the current study, a novel technique was developed for determining femoral antetorsion, the anterior cortical angle (ACA) method. The ACA is the angle between a line along the anterior aspect of the femoral neck and the posterior condylar line of the distal femur. The principal advantage of this method is that it facilitates intra-operative assessment of femoral antetorsion by utilizing the positional technology integrated in smartphones. This measurement is directly comparable to measurements made using computed tomography (CT) scans. The objective of the current study was to investigate the possibility and to validate the feasibility and accuracy of the new method and compare the results obtained with the traditional methods of antetorsion estimation via CT and surgical navigation technology. METHODS: Twelve cadaveric femora were used. Femoral antetorsion was measured with the ACA method, using a smartphone with integrated gyroscope (Apple IPhone, Cupertino, CA, USA) and by a conventional navigated technique (Brainlab, Feldkirchen, Germany). Subsequently, all femora underwent CT scanning to measure their respective antetorsion via the ACA and the method of Jend (1986). Next, a mid-diaphyseal osteotomy was performed and the distal fragment was rotated and were adjusted to 10-15 degrees using ACA by smartphone. All measurements were repeated with this new position of the femoral fragments. RESULTS: Both radiological measurements according ACA and Jend (1986) demonstrated a statistically significant correlation (intact femur, r = 0.773, p = 0.003; after fixation, r = 0.898, p < 0.001). Comparing the measurements derived from the ACA, as analysed on CT images, and that gleaned from the experimental use of the same method with the smartphone, a statistically significant correlation was also demonstrated (intact femur, r = 0.826, p = 0.001; after fixation, r = 0.932, p < 0.001). Comparing the navigation system and the ACA measured by smartphone there was, on intact femora, a fair correlation without statistical significance and after fixation a good correlation with statistical significance (intact femur, r = 0.467, p = 0.126; after fixation, r = 0.869, p = 0.001). CONCLUSIONS: The ACA method generated acceptable results and could contribute to improving the results of femoral nailing. The use of this device in a real clinical setting is necessary to truly elucidate its utility. PMID- 23081805 TI - Iron-catalyzed polymerization of isoprene and other 1,3-dienes. PMID- 23081806 TI - Temperature-switched binding of a RuII (dppz)/DNA light-switch complex. PMID- 23081808 TI - Erratum to: Ruptured sinus of Valsalva aneurysm association with bicuspid aortic valve. PMID- 23081807 TI - Comparison of two flow-based imaging methods to measure individual red blood cell area and volume. AB - The red blood cells (RBCs) population is characterized by a high heterogeneity in membrane area, cellular volume, and mechanical properties, mainly due to the variety of mechanical and chemical stresses that a red cell undergoes in its entire life span. Here, we provide the first simultaneous area and volume measurements of RBCs flowing in microcapillaries, by using high-speed video microscopy imaging and quantitative data processing based on image analysis techniques. Both confined and unbounded flow conditions (depending on the relative size of RBCs and microcapillary diameter) are investigated. The results are compared with micropipette experiments from the literature and data from Coulter counter routine clinical blood tests. Good agreement is found for RBC volume, especially in the case of confined flow conditions. Surface area measurements, which are lacking in the routine clinical test, are of special interest being a potential diagnostic parameter of altered cell deformability and aggregability. Overall, our results provide a novel flow methodology suitable for high-throughput measurements of RBC geometrical parameters, allowing one to overcome the limits of classical static methods, such as micropipette aspiration, which are not suitable for handling a large number of cells. PMID- 23081809 TI - Sinus rhythm with an isolated ST-segment elevation in V2. PMID- 23081810 TI - A cataclasm due to spasm. AB - We describe a 59-year-old patient presenting with ST-elevation acute coronary syndrome. Coronary angiography with intravascular ultrasound (IVUS) showed an important nonsignificant atherosclerotic lesion in the proximal left anterior descending artery (LAD) and presence of bridging in the mid-LAD. Our hypothesis was that focal spasm at this site was the cause of transmural ischaemia; therefore, treatment was given by performing a percutaneous coronary intervention (PCI) of the lesion. The patient remained symptom-free which confirmed our conclusion. The myocardial bridging had no clinical implications at this moment. PMID- 23081811 TI - On the choice of a reference state for one-step perturbation calculations between polar and nonpolar molecules in a polar environment. AB - One-step perturbation is an efficient method to estimate free energy differences in molecular dynamics (MD) simulations, but its accuracy depends critically on the choice of an appropriate, possibly unphysical, reference state that optimizes the sampling of the physical end states. In particular, the perturbation from a polar moiety to a nonpolar one and vice versa in a polar environment such as water poses a challenge which is of importance when estimating free energy differences that involve entropy changes and the hydrophobic effect. In this work, we systematically study the performance of the one-step perturbation method in the calculation of the free enthalpy difference between a polar water solute and a nonpolar "water" solute molecule solvated in a box of 999 polar water molecules. Both these polar and nonpolar physical reference states fail to predict the free enthalpy difference as obtained by thermodynamic integration, but the result is worse using the nonpolar physical reference state, because both a properly sized cavity and a favorable orientation of the polar solute in a polar environment are rarely, if ever, sampled in a simulation of the nonpolar solute in such an environment. Use of nonphysical soft-core reference states helps to sample properly sized cavities, and post-MD simulation rotational and translational sampling of the solute to be perturbed leads to much improved free enthalpy estimates from one-step perturbation. PMID- 23081812 TI - GSA: a GPU-accelerated structure similarity algorithm and its application in progressive virtual screening. AB - A new algorithm is proposed for accelerating chemical structure similarity search by means of graphic processing unit technology. Experiments demonstrate that the new algorithm is on average more than 120-times faster than the one implemented in conventional central processing unit technology. In order to test the generality of the new algorithm, it has been applied in seven progressive virtual screening experiments on NCI/DTP 60 human cancer cell lines data. The progressive virtual screening results show that the technology can select 10-20% compounds for screening to get 70-80% intrinsic hits for a given chemical library and target. PMID- 23081813 TI - In vivo efficacy of a chimeric peptide derived from the conserved region of the M protein against group C and G streptococci. AB - The J8 peptide from the conserved region of the M protein protects against group A streptococcus infections. In this study, we demonstrate that vaccination with a J8-containing formulation induces IgG that recognizes and binds group C and G streptococci. Moreover, this formulation has the potential to provide protection against infections caused by these organisms. PMID- 23081814 TI - Comparison of four assays for the detection of cryptococcal antigen. AB - We compared the performance of four assays for the detection of cryptococcal antigen in serum samples (n = 634) and cerebrospinal fluid (CSF) samples (n = 51). Compared to latex agglutination, the sensitivity and specificity of the Premier enzyme immunoassay (EIA), Alpha CrAg EIA, and CrAg lateral flow assay (LFA) were 55.6 and 100%, 100 and 99.7%, and 100 and 99.8%, respectively, from serum samples. There was 100% agreement among the four tests for CSF samples, with 18 samples testing positive by each of the assays. PMID- 23081815 TI - Assessment of antigen-specific and cross-reactive antibody responses to an MF59 adjuvanted A/H5N1 prepandemic influenza vaccine in adult and elderly subjects. AB - Preparedness against an A/H5N1 influenza pandemic requires well-tolerated, effective vaccines which provide both vaccine strain-specific and heterologous, cross-clade protection. This study was conducted to assess the immunogenicity and safety profile of an MF59-adjuvanted, prepandemic influenza vaccine containing A/turkey/Turkey/01/2005 (H5N1) strain viral antigen. A total of 343 participants, 194 adults (18 to 60 years) and 149 elderly individuals (>=61 years), received two doses of the investigational vaccine given 3 weeks apart. Homologous and heterologous antibody responses were analyzed by hemagglutination inhibition (HI), single radial hemolysis (SRH), and microneutralization (MN) assays 3 weeks after administration of the first vaccine dose and 3 weeks and 6 months after the second dose. Immunogenicity was assessed according to European licensure criteria for pandemic influenza vaccines. After two vaccine doses, all three European licensure criteria were met for adult and elderly subjects against the homologous vaccine strain, A/turkey/Turkey/1/2005, when analyzed by HI and SRH assays. Cross reactive antibody responses were observed by HI and SRH analyses against the heterologous H5N1 strains, A/Indonesia/5/2005 and A/Vietnam/1194/2004, in adult and elderly subjects. Solicited local and systemic reactions were mostly mild to moderate in severity and occurred less frequently in the elderly than in adult vaccinees. In both adult and elderly subjects, MF59-adjuvanted vaccine containing 7.5 MUg of A/Turkey strain influenza virus antigen was highly immunogenic, well tolerated, and able to elicit cross-clade, heterologous antibody responses against A/Indonesia and A/Vietnam strains 6 weeks after the first vaccination. PMID- 23081816 TI - Bioluminescent enzyme immunoassay for the detection of norovirus capsid antigen. AB - An ultrasensitive and fully automated bioluminescent enzyme immunoassay (BLEIA) was developed for the detection of norovirus (NV) capsid antigen. In the evaluation tests with recombinant virus-like particles, the BLEIA demonstrated broad reactivity against several NV genotypes (genotypes 1, 3, 4, 7, 8, and 12 in genogroup I [GI] and genotypes 1, 2, 3, 4, 5, 6, 12, and 13 in GII), a wide dose response range from 0.25 pg/ml to 10,000 pg/ml, and good reproducibility with low coefficients of variation (CVs) (within-run CVs of <2.8%, between-day CVs of <3.7%). In the evaluation tests with NV-positive fecal samples, a good correlation (y = 0.66x - 3.21, r = 0.84) between the BLEIA and real-time quantitative reverse transcription-PCR was obtained. Furthermore, in the dilution test with NV specimens, the analytical sensitivity of NV was estimated to be 10(5) to 10(6) copies/g of fecal sample, indicating that the analytical sensitivity of the BLEIA is comparable to that of commercially available molecular methods. All assay steps are fully automated, the turnaround time is 46 min, and the throughput of the assay is 120 tests/h. These results indicate that the BLEIA is potentially useful for the rapid diagnosis of NV in epidemic and sporadic gastroenteritis. PMID- 23081817 TI - Clade A HIV-1 Gag-specific T cell responses are frequent but do not correlate with viral loads in a cohort of treatment-naive HIV-infected individuals living in Guinea-Bissau. PMID- 23081818 TI - Effect of heat-killed Escherichia coli, lipopolysaccharide, and muramyl dipeptide treatments on the immune response phenotype and allergy in neonatal pigs sensitized to the egg white protein ovomucoid. AB - Predisposition to food allergies may reflect a type 2 immune response (IR) bias in neonates due to the intrauterine environment required to maintain pregnancy. The hygiene hypothesis states that lack of early environmental stimulus leading to inappropriate development and bias in IR may also contribute. Here, the ability of heat-killed Escherichia coli, lipopolysaccharide (LPS), or muramyl dipeptide (MDP) to alter IR bias and subsequent allergic response in neonatal pigs was investigated. Three groups of three litters of pigs (12 pigs/litter) were given intramuscular injections of E. coli, LPS, MDP, or phosphate-buffered saline (PBS) (control) and subsequently sensitized to the egg white allergen ovomucoid using an established protocol. To evaluate change in IR bias, immunoglobulin isotype-associated antibody activity (AbA), concentrations of type 1 and 2 and proinflammatory cytokines released from mitogen-stimulated blood mononuclear cells, and the percentage of T-regulatory cells (T-regs) in blood were measured. Clinical signs of allergy were assessed after oral challenge with egg white. The greatest effect on IR bias was observed in MDP-treated pigs, which had a type 2-biased phenotype by isotype-specific AbA, cytokine production, and a low proportion of T-regs. LPS-treated pigs had decreased type 1- and type 2 associated AbA. E. coli-treated pigs displayed increased response to Ovm as AbA and had more balanced cytokine profiles, as well as the highest proportion of T regs. Accordingly, pigs treated with MDP were more susceptible to allergy than PBS controls, while pigs treated with LPS were less susceptible. Treatment with E. coli did not significantly alter the frequency of clinical signs. PMID- 23081819 TI - Antimicrobial drug-induced thrombocytopenia: a review of the literature. AB - The incidence of drug-induced thrombocytopenia (DIT) is not well-defined, but is estimated to occur at a minimum of 10 cases per million per year. This review will focus on the potential DIT associated with specific antibacterial, antifungal, antiviral, and antiparasitic agents. Case reports, cohort studies, and clinical trials were identified using PubMed search terms for each antimicrobial along with the Boolean combiner AND to match with the following outcomes: thrombocytopenia and bleed. Thrombocytopenia was defined as a platelet count of < 100 * 10(9)/L or a decrease in platelet count of at least 50% from baseline. A majority of the data supporting antimicrobial-induced thrombocytopenia consist of case reports and small studies. However, clinicians should be vigilant in monitoring patient platelet counts, as an immune-mediated mechanism is frequently responsible for this hematologic adverse effect and is therefore unpredictable. PMID- 23081820 TI - A novel mechanism of ligand binding and release in the odorant binding protein 20 from the malaria mosquito Anopheles gambiae. AB - Anopheles gambiae mosquitoes that transmit malaria are attracted to humans by the odor molecules that emanate from skin and sweat. Odorant binding proteins (OBPs) are the first component of the olfactory apparatus to interact with odorant molecules, and so present potential targets for preventing transmission of malaria by disrupting the normal olfactory responses of the insect. AgamOBP20 is one of a limited subset of OBPs that it is preferentially expressed in female mosquitoes and its expression is regulated by blood feeding and by the day/night light cycles that correlate with blood-feeding behavior. Analysis of AgamOBP20 in solution reveals that the apo-protein exhibits significant conformational heterogeneity but the binding of odorant molecules results in a significant conformational change, which is accompanied by a reduction in the conformational flexibility present in the protein. Crystal structures of the free and bound states reveal a novel pathway for entrance and exit of odorant molecules into the central-binding pocket, and that the conformational changes associated with ligand binding are a result of rigid body domain motions in alpha-helices 1, 4, and 5, which act as lids to the binding pocket. These structures provide new insights into the specific residues involved in the conformational adaptation to different odorants and have important implications in the selection and development of reagents targeted at disrupting normal OBP function. PMID- 23081821 TI - CD133-expressing thyroid cancer cells are undifferentiated, radioresistant and survive radioiodide therapy. AB - PURPOSE: (131)I therapy is regularly used following surgery as a part of thyroid cancer management. Despite an overall relatively good prognosis, recurrent or metastatic thyroid cancer is not rare. CD133-expressing cells have been shown to mark thyroid cancer stem cells that possess the characteristics of stem cells and have the ability to initiate tumours. However, no studies have addressed the influence of CD133-expressing cells on radioiodide therapy of the thyroid cancer. The aim of this study was to investigate whether CD133(+) cells contribute to the radioresistance of thyroid cancer and thus potentiate future recurrence and metastasis. METHODS: Thyroid cancer cell lines were analysed for CD133 expression, radiosensitivity and gene expression. RESULTS: The anaplastic thyroid cancer cell line ARO showed a higher percentage of CD133(+) cells and higher radioresistance. After gamma-irradiation of the cells, the CD133(+) population was enriched due to the higher apoptotic rate of CD133(-) cells. In vivo (131)I treatment of ARO tumour resulted in an elevated expression of CD133, Oct4, Nanog, Lin28 and Glut1 genes. After isolation, CD133(+) cells exhibited higher radioresistance and higher expression of Oct4, Nanog, Sox2, Lin28 and Glut1 in the cell line or primarily cultured papillary thyroid cancer cells, and lower expression of various thyroid-specific genes, namely NIS, Tg, TPO, TSHR, TTF1 and Pax8. CONCLUSION: This study demonstrates the existence of CD133-expressing thyroid cancer cells which show a higher radioresistance and are in an undifferentiated status. These cells possess a greater potential to survive radiotherapy and may contribute to the recurrence of thyroid cancer. A future therapeutic approach for radioresistant thyroid cancer may focus on the selective eradication of CD133(+) cells. PMID- 23081822 TI - The value of 18F-FDG PET/CT for assessing the response to neoadjuvant therapy in locally advanced rectal cancer. AB - PURPOSE: Neoadjuvant radiochemotherapy (RCT) is an accepted treatment for locally advanced rectal cancer (LARC) that improves surgical outcomes. If a pathological complete response is achieved, conservative surgery can be considered. The objective of our study was to assess the reliability of (18)F-FDG PET/CT for evaluating the response to neoadjuvant RCT in LARC. METHODS: We prospectively studied 41 patients diagnosed with LARC and candidates for neoadjuvant RCT. PET/CT was performed before RCT and again 7 weeks later. A visual and semiquantitative analysis was carried out. The pathological response was classified according to the Mandard tumour regression grade (TRG). We analysed: (a) the relationship between TRG and the result of the posttreatment PET/CT scan, and (b) the correlation between the percentage of pathological response and the percentage decrease in SUVmax according to the response index (RI). RESULTS: The mean SUVmax of the rectal lesions at diagnosis was 13.6 and after RCT 3.96. The mean RI was 65.32 %. Sensitivity was 88.88 %, specificity 92.86 %, positive predictive value 96 %, negative predictive value 81 %. Of the 41 patients, 8 had TRG I (all negative PET/CT); 6 had TRG II (5 negative, 1 positive PET/CT); 16 had TRG III (13 positive, 3 negative PET/CT); 9 had TRG IV (all positive PET/CT); 2 had TRG V (all positive PET/CT). Of the 14 patients classified as responders (TRG I, II), 13 (92.86 %) had negative PET/CT. Of the 27 patients classified as nonresponders (TRG III-V), 24 (88.88 %) had positive PET/CT. Differences were statistically significant (p < 0.0001). The RI in responders was 79.9 % and in nonresponders was 60.3 %. Differences were statistically significant (p < 0.037). CONCLUSION: PET/CT is a reliable technique for assessing response to neoadjuvant RCT in LARC, with a view to considering more conservative surgical treatment. The combination of the visual and semiquantitative analysis increases the diagnostic validity of PET/CT. PMID- 23081823 TI - Assessing the activity of cardiac sympathetic innervation with a novel PET tracer. PMID- 23081824 TI - Endotoxin removal and prevention for pre-clinical biologics production. AB - The removal of endotoxin from protein solutions and its prevention are key to the success of recombinant protein production due to the possible pyogenic response in mammals caused by contaminated samples. In the pre-clinical situation, protein production is often carried out in a non-good manufacturing practice (GMP) setting, utilizing bacterial DNA for transient transfection and non-validated cleaning techniques. Here, we present our findings evaluating various options for endotoxin removal, and propose strategies for endotoxin prevention with emphasis on chromatographic separations, endotoxin-removing membranes and on-column wash strategies. PMID- 23081826 TI - A highly stereoselective synthesis of glycidic amides based on a new class of chiral sulfonium salts: applications in asymmetric synthesis. AB - A new type of chiral sulfonium salts that are characterized by a bicyclic system has been designed and synthesized from alpha-amino acids. Their corresponding ylides, which were prepared by basic treatment of the sulfonium salts, reacted smoothly with a broad array of simple and chiral aldehydes to provide trans-epoxy amides in reasonable to very good yields and excellent stereoselectivities (>98%). The obtained epoxy amides were found to be useful as synthetic building blocks. Thus, they were reduced into their corresponding epoxy alcohols and subjected to oxirane-ring-opening reactions with different types of nucleophiles. PMID- 23081825 TI - Aging promotes the development of diet-induced murine steatohepatitis but not steatosis. AB - The prevalence of the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD) in humans increases with age. It is unknown whether this association is secondary to the increased incidence of risk factors for NAFLD that occurs with aging, reflects the culmination of years of exposure to lifestyle factors such as a high-fat diet (HFD), or results from physiological changes that characterize aging. To examine this question, the development of NAFLD in response to a fixed period of HFD feeding was examined in mice of different ages. Mice aged 2, 8, and 18 months were fed 16 weeks of a low-fat diet or HFD. Increased body mass and insulin insensitivity occurred in response to HFD feeding irrespective of the age of the mice. The amount of HFD-induced hepatic steatosis as determined biochemically and histologically was also equivalent among the three ages. Liver injury occurred exclusively in the two older ages as reflected by increased serum alanine aminotransferase levels, positive terminal deoxynucleotide transferase mediated deoxyuridine triphosphate nick end-labeling, and caspase activation. Older mice also had an elevated innate immune response with a more pronounced polarization of liver and adipose tissue macrophages into an M1 phenotype. Studies of cultured hepatocytes from young and old mice revealed that aged cells were selectively sensitized to the Fas death pathway. CONCLUSION: Aging does not promote the development of hepatic steatosis but leads to increased hepatocellular injury and inflammation that may be due in part to sensitization to the Fas death pathway and increased M1 macrophage polarization. PMID- 23081827 TI - Characterizing antiprion compounds based on their binding properties to prion proteins: implications as medical chaperones. AB - A variety of antiprion compounds have been reported that are effective in ex vivo and in vivo treatment experiments. However, the molecular mechanisms for most of these compounds remain unknown. Here we classified antiprion mechanisms into four categories: I, specific conformational stabilization; II, nonspecific stabilization; III, aggregation; and IV, interaction with molecules other than PrP(C). To characterize antiprion compounds based on this classification, we determined their binding affinities to PrP(C) using surface plasmon resonance and their binding sites on PrP(C) using NMR spectroscopy. GN8 and GJP49 bound specifically to the hot spot in PrP(C), and acted as "medical chaperones" to stabilize the native conformation. Thus, mechanisms I was predominant. In contrast, quinacrine and epigallocathechin bound to PrP(C) rather nonspecifically; these may stabilize the PrP(C) conformation nonspecifically including the interference with the intermolecular interaction following mechanism II. Congo red and pentosan polysulfate bound to PrP(C) and caused aggregation and precipitation of PrP(C), thus reducing the effective concentration of prion protein. Thus, mechanism III was appropriate. Finally, CP 60, an edarabone derivative, did not bind to PrP(C). Thus these were classified into mechanism IV. However, their antiprion activities were not confirmed in the GT + FK system, whose details remain to be elucidated. This proposed antiprion mechanisms of diverse antiprion compounds could help to elucidate their antiprion activities and facilitate effective antiprion drug discovery. PMID- 23081829 TI - Stereostructure of mycoheptin A(2). AB - The absolute configurations of all the stereogenic centers of the antibiotic mycoheptin A(2) were established upon previously elaborated general procedure, consisting of DQF-COSY, NOESY, ROESY, HSQC and HMBC experiments as major tools. The structure of mycoheptin A(2) without stereochemistry of its aglycone has been reported before. PMID- 23081828 TI - Concise review: The evolution of human pluripotent stem cell culture: from feeder cells to synthetic coatings. AB - Current practices to maintain human pluripotent stem cells (hPSCs), which include induced pluripotent stem cells and embryonic stem cells, in an undifferentiated state typically depend on the support of feeder cells such as mouse embryonic fibroblasts (MEFs) or an extracellular matrix such as Matrigel. Culture conditions that depend on these undefined support systems limit our ability to interpret mechanistic studies aimed at resolving how hPSCs interact with their extracellular environment to remain in a unique undifferentiated state and to make fate-changing lineage decisions. Likewise, the xenogeneic components of MEFs and Matrigel ultimately hinder our ability to use pluripotent stem cells to treat debilitating human diseases. Many of these obstacles have been overcome by the development of synthetic coatings and bioreactors that support hPSC expansion and self-renewal within defined culture conditions that are free from xenogeneic contamination. The establishment of defined culture conditions and synthetic matrices will facilitate studies to more precisely probe the molecular basis of pluripotent stem cell self-renewal and differentiation. When combined with three dimensional cultures in bioreactors, these systems will also enable large-scale expansion for future clinical applications. PMID- 23081830 TI - Does the use of an intramedullary nail alter the duration of external fixation and rate of consolidation in tibial lengthening procedures? A systematic review. AB - We performed this systematic review to evaluate tibial lengthening procedures with the use of an intramedullary nail. We investigated the hypothesis that lengthening over a nail can reduce the time spent in an external fixator and increase the rate of consolidation thereby reducing the risk of complications and improving patient satisfaction. We conducted a comprehensive literature search using the MEDLINE, EMBASE and PubMed databases using the key words 'tibia' or 'tibial lengthening' and 'nail'. This search was performed in December 2011 and repeated by both authors. Specific outcome measures were the duration of external fixation, rate of consolidation and complication rates. A total of 6 comparative studies published between 2005 and 2011 consisting of 494 procedures met our inclusion and exclusion criteria and were eligible for critical appraisal. The methodological quality of the studies was variable, and they were not homogenous enough for meta-analysis. Patients who have tibial lengthening over an intramedullary nail spend significantly less time in an external fixator. However, there is no reliable evidence to suggest that the rates of consolidation or complication are any different to those lengthened without an intramedullary nail. PMID- 23081831 TI - A remarkable organometallic transformation on a cage-incarcerated dinuclear ruthenium complex. PMID- 23081832 TI - Hard autonomous self-healing supramolecular materials--a contradiction in terms? PMID- 23081833 TI - Equine cellular therapy--from stall to bench to bedside? AB - Pioneering clinical stem cell research is being performed in the horse, a recipient of cutting edge veterinary medicine as well as a unique animal model, paving the way for human medical applications. Although demonstrable progress has been made on the clinical front, in vitro characterization of equine stem cells is still in comparatively early stages. To translate the promising results of clinical stem cell therapy in the horse, advances must be made in the characterization of equine stem cells. Aiming to improve communication between veterinarians and other natural scientists, this review gives an overview of veterinary "bedside" achievements, focusing on stem cell therapies in equine orthopedics as well as the current state of in vitro characterization of equine multipotent mesenchymal stromal cells (MSCs) and equine embryonic stem cells (ESCs). PMID- 23081834 TI - Collagen gentamicin for prevention of sternal wound infection: effective or not? AB - BACKGROUND: Prophylactic local application of collagen-gentamicin sponges for prevention of sternal wound infections (SWI) after cardiac surgery has been used routinely in risk patients for several years at our center. However, a recent US study failed to show a significant reduction in SWI with the prophylaxis. Therefore, a systematic reevaluation of the effect of local collagen gentamicin was conducted. METHODS: A complete follow-up of all cardiac surgery patients 2 months postoperatively was achieved. All SWIs were recorded. The effect of the prophylaxis was analyzed, and differences in risk factors were compensated for using multiple logistic regression analyses and Coarsened Exact Matching (CEM). RESULTS: A total of 950 patients were included. Established risk factors for SWI were confirmed. The use of collagen-gentamicin prophylaxis was independently associated with a highly significant reduction in SWI (odds ratio [OR] = 0.30, 95% confidence interval = 0.16 to 0.57; p < 0.001). Applying the more advanced statistical method, CEM indicated that the effect of the prophylaxis may be even greater. CONCLUSIONS: The use of local collagen-gentamicin prophylaxis was associated with an approximately 70% reduction in the rate of SWI compared with standard intravenous antibiotic prophylaxis alone. PMID- 23081835 TI - Enhanced performance of quasi-solid-state dye-sensitized solar cells by branching the linear substituent in sensitizers based on thieno[3,4-c]pyrrole-4,6-dione. AB - Thieno[3,4-c]pyrrole-4,6-dione-based organic sensitizers with triphenylamine (FNE38 and FNE40) or julolidine (FNE39 and FNE41) as electron-donating unit have been designed and synthesized. A linear hexyl group or a branched alkyl chain, the 2-ethylhexyl group, is incorporated into molecular skeleton of the dyes to minimize intermolecular interactions. The absorption, electrochemical, and photovoltaic properties for these sensitizers were then systematically investigated. It is found that the sensitizers have similar photophysical and electrochemical properties, such as absorption spectra and energy levels, owing to their close chemical structures. However, the quasi-solid-state dye-sensitized solar cells (DSSCs) based on the two types of sensitizers exhibit very different performance parameters. Upon the incorporation of the short ethyl group on the hexyl moiety, enhancements in both open-circuit voltage (V(oc)) and short-circuit current (J(sc)) are achieved for the quasi-solid-state DSSCs. The V(oc) gains originating from the suppression of charge recombination were quantitatively investigated and are in good agreement with the experimentally observed V(oc) enhancements. Therefore, an enhanced solar energy conversion efficiency (eta) of 6.16%, constituting an increase by 23%, is achieved under standard AM 1.5 sunlight without the use of coadsorbant agents for the quasi-solid-state DSSC based on sensitizer FNE40, which bears the branched alkyl group, in comparison with that based on FNE38 carrying the linear alkyl group. This work presents a design concept for considering the crucial importance of the branched alkyl substituent in novel metal-free organic sensitizers. PMID- 23081836 TI - Biochemical characterization of a novel laccase from the basidiomycete fungus Cerrena sp. WR1. AB - This study reports a new white-rot fungus Cerrena sp. WR1, identified based on an 18S rDNA sequence, which can secrete extracellular forms of laccase with a maximal activity reaching 202 000 U l-1 in a 5-l fermenter. A laccase protein, designated Lcc3, was purified and shown to be N-linked glycosylated by PNGase F and liquid chromatography tandem mass spectrometry analyses. The respective full length cDNA gene (lcc3) of the Lcc3 protein was obtained using polymerase chain reaction-based methods. Kinetic studies showed that the K(m) and k(cat) of the native Lcc3 were 3.27 MUM and 934.6 s-1 for 2,2'-Azino-bis-(3-ethylbenzthiazoline 6-sulfonic acid), 849.1 MUM and 147.9 s-1 for guaiacol, 392.7 MUM and 109.2 s-1 for 2,6-dimethoxyphenol, and 881 MUM and 115.5 s-1 for catechol, respectively. The T(m) of Lcc3 was determined at 73.9 degrees C and it showed a long t(1/2) (120 min) at 50 degrees C. The laccase was highly ethanol resistant, with 80% of its original activity was detected when incubated in 25% ethanol for 14 days. Furthermore, crude enzyme broth or Lcc3 could degrade lignin in kraft paper (26.5%), and showed high decoloration efficiency (90%) on synthetic dye Remazol Brilliant Blue R. Together, these data demonstrate that Cerrena sp. WR1 Lcc3 possesses novel biochemical and kinetic properties that may aid its application in industry. PMID- 23081837 TI - An efficient method for enzyme immobilization evidenced by atomic force microscopy. AB - Immobilization of proteins in a functionally active form and proper orientation is fundamental for effective surface-based protein analysis. A new method is presented for the controlled and oriented immobilization of ordered monolayers of enzymes whose interaction site had been protected using the protein ligand. The utility of this method was demonstrated by analyzing the interactions between the enzyme ferredoxin-NADP+ reductase (FNR) and its redox partner ferredoxin (Fd). The quality of the procedure was deeply evaluated through enzymatic assays and atomic force microscopy. Single-molecule force spectroscopy revealed that site specifically targeted FNR samples increased the ratio of recognition events 4 fold with regard to the standard randomly modified FNR samples. The results were corroborated using the cytochrome c reductase activity that gave an increase on surface between 6 and 12 times for the site-specifically targeted FNR samples. The activity in solution for the enzyme labeled from the complex was similar to that exhibited by wild-type FNR while FNR randomly tagged showed a 3-fold decrease. This indicates that random targeting protocols affect not only the efficiency of immobilized proteins to recognize their ligands but also their general functionality. The present methodology is expected to find wide applications in surface-based protein-protein interactions biosensors, single molecule analysis, bioelectronics or drug screening. PMID- 23081838 TI - Engineering of dual-functional hybrid glucanases. AB - 1,3-1,4-beta-D-Glucanase (lichenase) and 1,3-beta-D-glucanase (laminarinase) are fibrolytic enzymes which play an important role in the hydrolysis of polysaccharide components. Both of these glucanases have been employed in a number of industrial applications. This study aims to improve or combine the novel properties of both glucanases in an attempt to create desirable hybrid enzymes with economic benefits for industrial applications. A truncated and mutated 1,3-1,4-beta-D-glucanase gene (TFs(W203F)) from Fibrobacter succinogenes, and a 1,3-beta-D-glucanase gene (TmLam) from hyperthermophilic Thermotoga maritima were used as target enzymes. The substrate-binding domains (TmB1 and TmB2) and the catalytic domain (TmLam(CD)) of TmLam were ligated to the N- or C terminus of TFsW203F to create four hybrid enzymes, TmB1-TFs(W203F), TFs(W203F) TmB2, TmB1-TFs(W203F)-TmB2 and TFs(W203F)-TmLam(CD). The results obtained from kinetic studies show that increased specific activities and turnover rate for lichenan and laminarin were observed in TmB1-TFs(W203F)-TmB2 and TFs(W203F) TmLam(CD), respectively. Furthermore, fluorescence and circular dichroism spectrometric analyses indicated that the hybrid TFs(W203F)-TmLam(CD) was structurally more stable than the parental TFs(W203F), which was attributed to an improved thermal tolerance of the hybrid enzyme. This study has been successful in creating bifunctional hybrid glucanases with dual substrate catalytic functions which warrant further evaluation of their possible use in industrial applications. PMID- 23081839 TI - Endopeptidase activity characterization of E. coli-derived infectious bursal disease virus protein 4 tubules. AB - Viral protein 4 (VP4) is a serine protease that catalyzes the hydrolysis of polyprotein pVP2-VP4-VP3 of infectious bursal disease virus. In this report, the recombinant VP4 with a His-tag and three mutants (VP4-S652A, VP4-K692A and VP4 S652A.K692A) were expressed in Escherichia coli. Soluble VP4 was purified using immobilized metal-ion affinity chromatography or sucrose density gradient following with gel-filtration chromatography. The purified VP4 has a tubular structure with 25-30 nm in width and ~300 nm in length, as observed by transmission electron microscope. A similar tubular structure was also found for these three mutants. The endopeptidase activity of these VP4 tubules was characterized by fluorescence resonance energy transfer using a synthetic fluorogenic oligopeptide as a substrate. The results show that the tubule-like VP4 is a functional enzyme with K(m) of 43 +/- 2 MUM and k(cat) of 0.04 +/- 0.01 min-1; however, k(cat) of three mutants were significantly reduced. This is the first report to demonstrate that VP4 protein expressed in E. coli can self assemble into functional tubule-like particles and its activity can be completely inhibited by 1 mM of Ni+2 ions. PMID- 23081840 TI - A highly stable protein chimera built from fragments of different folds. AB - Proteins increased in complexity during the course of evolution. Domains as well as subdomain-sized fragments were recruited and adapted to form new proteins and novel folds. This concept can be used in engineering to construct new proteins. We previously reported the combination of fragments from two ancient protein folds, a flavodoxin-like and a (betaalpha)8-barrel protein. Here we report two further attempts at engineering a chimeric protein from fragments of these folds. While one of the constructs showed a high tendency to aggregate, the other turned out to be a highly stable, well-structured protein. In terms of stability against heat and chemical denaturation this chimera, named NarLHisF, is superior to the earlier presented CheYHisF. This is the second instance of a chimera build from two different protein folds, which demonstrates how easily recombination can lead to the development and diversification of new proteins--a mechanism that most likely occurred frequently in the course of evolution. Based on the results of the failed and the successful chimera, we discuss important considerations for a general design strategy for fold chimeras. PMID- 23081841 TI - beta-catenin regulates innate and adaptive immunity in mouse liver ischemia reperfusion injury. AB - Dendritic cells (DCs) are critical mediators of immune responses that integrate signals from the innate immune system to orchestrate adaptive host immunity. This study was designed to investigate the role and molecular mechanisms of STAT3 induced beta-catenin in the regulation of DC function and inflammatory responses in vitro and in vivo. STAT3 induction in lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived DCs (BMDCs) triggered beta-catenin activation by way of GSK-3beta phosphorylation. The activation of beta-catenin inhibited phosphatase and tensin homolog delete on chromosome 10 (PTEN) and promoted the phosphoinositide 3-kinase (PI3K)/Akt pathway, which in turn down-regulated DC maturation and function. In contrast, knockdown of beta-catenin increased PTEN/TLR4 (Toll-like receptor 4), interferon regulatory factor-3 (IRF3), nuclear factor kappa B (NF-kappaB) activity, and proinflammatory cytokine programs in response to LPS stimulation. In a mouse model of warm liver ischemia and reperfusion injury (IRI), disruption of beta-catenin signaling increased the hepatocellular damage, enhanced hepatic DC maturation/function, and PTEN/TLR4 local inflammation in vivo. CONCLUSION: These findings underscore the role of beta-catenin to modulate DC maturation and function at the innate-adaptive interface. Activation of beta-catenin triggered PI3K/Akt, which in turn inhibited TLR4-driven inflammatory response in a negative feedback regulatory mechanism. By identifying the molecular pathways by which beta-catenin regulates DC function, our findings provide the rationale for novel therapeutic approaches to manage local inflammation and injury in IR-stressed liver. PMID- 23081842 TI - Residual beta cell function at diagnosis of type 1 diabetes in children and adolescents varies with gender and season. AB - BACKGROUND: There are seasonal variations and gender differences in incidence of type 1 diabetes (T1D), metabolic control and responses to immune interventions at onset of the disease. We hypothesized that there are seasonal and gender differences in residual insulin secretion already at diagnosis of T1D. METHODS: In 2005, a national study, the Better Diabetes Diagnosis, was started to classify all newly diagnosed children and adolescents with diabetes. About 95% (3824/4017) of the patients were classified as T1D, and our analyses are based on the patients with T1D. RESULTS: C-peptide was lower in younger children, 0-10 years of age (0.23 +/- 0.20 nmol/L) than in older children, 11-18 years of age (0.34 +/ 0.28 nmol/L) (p < 0.000 ). There was a seasonal variation in non-fasting serum C peptide, significantly correlated to the seasonal variation of diagnosis (p < 0.01). Most children were diagnosed in January, February and March as well as in October when C-peptide was highest, whereas fewer patients were diagnosed in April and May when serum C-peptide was significantly lower (p < 0.01). The seasonal variation of C-peptide was more pronounced in boys than in girls (p < 0.000 and p < 0.01, respectively). Girls had higher C-peptide than boys (p < 0.05), especially in early puberty. CONCLUSIONS: Both seasonal and gender differences in residual beta cell function exist already at diagnosis of T1D. These observations have consequences for treatment and for randomizing patients in immune intervention clinical trials. PMID- 23081843 TI - The effect of adding gentamicin to contrast media for prevention of cholangitis after biliary stenting for non-calculous biliary obstruction, a randomized controlled trial. AB - AIM: Cholangitis is the most common infectious complication of ERCP. In vitro studies showed that addition of aminoglycosides to contrast medium was effective in reducing cholangitis but the results of clinical trials are conflicting. We studied the effect of adding gentamicin to contrast medium in reducing the rate of post-ERCP cholangitis in patients with non-calculous obstructive jaundice. METHODS: All patients with non-calculous obstructive jaundice who underwent endoscopic biliary stenting at the Shariati Hospital, Tehran, between December 2009 and October 2010 were enrolled in the study. Gentamicin (10 mg) or distilled water was added to each 10 cc contrast medium during ERCP. Intravenous antibiotics were administered before and after the procedure in all patients. After ERCP and stent deployment, patients were followed for 72 h for symptoms and signs of cholangitis. RESULTS: A total of 114 patients were eligible for the study. Of these, 57 patients were included in each group. Cholangiocarcinoma was the most prevalent diagnosis. The obstruction was relieved in all patients by stenting. Five patients in each group (8.8 %) developed cholangitis. There was no significant difference in the incidence of cholangitis between the two groups (p = 1.000). CONCLUSIONS: With adequate drainage of the obstructed biliary tract by proper stenting, adding gentamicin to contrast media had no significant effect on incidence of post-ERCP cholangitis. PMID- 23081844 TI - Familial chylomicronemia syndrome- an uncommon cause of acute pancreatitis with encephalopathy. PMID- 23081845 TI - National consensus on inflammatory bowel disease in India-an initiator's perspective. PMID- 23081846 TI - Hepatitis B and C co-infection in HIV patients. PMID- 23081847 TI - Eco-friendly combination of the immobilized PGA enzyme and the S-Phacm protecting group for the synthesis of Cys-containing peptides. AB - Enzyme-labile protecting groups have emerged as a green alternative to conventional protecting groups. These groups introduce a further orthogonal dimension and eco-friendliness into protection schemes for the synthesis of complex polyfunctional organic molecules. S-Phacm, a Cys-protecting group, can be easily removed by the action of a covalently immobilized PGA enzyme under very mild conditions. Herein, the versatility and reliability of an eco-friendly combination of the immobilized PGA enzyme and the S-Phacm protecting group has been evaluated for the synthesis of diverse Cys-containing peptides. PMID- 23081849 TI - Applying the Balanced Scorecard approach in teaching hospitals: a literature review and conceptual framework. AB - Teaching hospitals (THs) simultaneously serve three different roles: offering medical treatment, teaching future doctors and promoting research. The international literature recognises such organisations as 'peaks of excellence' and highlights their economic function in the health system. In addition, the literature describes the urgent need to manage the complex dynamics and inefficiency issues that threaten the survival of teaching hospitals worldwide. In this context, traditional performance measurement systems that focus only on accounting and financial measures appear to be inadequate. Given that THs are highly specific and complex, a multidimensional system of performance measurement, such as the Balanced Scorecard (BSC), may be more appropriate because of the multitude of stakeholders, each of whom seek a specific type of accountability. The aim of the paper was twofold: (i) to review the literature on the BSC and its applications in teaching hospitals and (ii) to propose a scorecard framework that is suitable for assessing the performance of THs and serving as a guide for scholars and practitioners. In addition, this research will contribute to the ongoing debate on performance evaluation systems by suggesting a revised BSC framework and proposing specific performance indicators for THs. PMID- 23081850 TI - Construction of conjugated carbon nitride nanoarchitectures in solution at low temperatures for photoredox catalysis. PMID- 23081848 TI - Transient receptor potential melastatin 4 channel controls calcium signals and dental follicle stem cell differentiation. AB - Elevations in the intracellular Ca(2+) concentration are a phenomena commonly observed during stem cell differentiation but cease after the process is complete. The transient receptor potential melastatin 4 (TRPM4) is an ion channel that controls Ca(2+) signals in excitable and nonexcitable cells. However, its role in stem cells remains unknown. The aim of this study was to characterize TRPM4 in rat dental follicle stem cells (DFSCs) and to determine its impact on Ca(2+) signaling and the differentiation process. We identified TRPM4 gene expression in DFSCs, but not TRPM5, a closely related channel with similar function. Perfusion of cells with increasing buffered Ca(2+) resulted in a concentration-dependent activation of currents typical for TRPM4, which were also voltage-dependent and had Na(+) conductivity. Molecular suppression with shRNA decreased channel activity and cell proliferation during osteogenesis but not adipogenesis. As a result, enhanced mineralization and phosphatase enzyme activity were observed during osteoblast formation, although DFSCs failed to differentiate into adipocytes. Furthermore, the normal agonist-induced first and secondary phases of Ca(2+) signals were transformed into a gradual and sustained increase which confirmed the channels' ability to control Ca(2+) signaling. Using whole genome microarray analysis, we identified several genes impacted by TRPM4 during DFSC differentiation. These findings suggest an inhibitory role for TRPM4 on osteogenesis while it appears to be required for adipogenesis. The data also provide a potential link between the Ca(2+) signaling pattern and gene expression during stem cell differentiation. PMID- 23081851 TI - Role of continuous glucose monitoring in the management of diabetic pregnancy. AB - Self-monitoring of blood glucose (SMBG) with intermittent capillary glucose fingerstick tests is currently the universally accepted method of glucose monitoring in pregnancy. During pregnancy SMBG tests are recommended before and after meals and before bed (typically 7 values/d). Continuous glucose monitoring systems consist of a disposable subcutaneous glucose-sensing device, electrochemically measuring glucose levels in subcutaneous tissues every 10 seconds, providing an average interstitial glucose value every 5 minutes (typically 288 values/d). From a research perspective this provides unprecedented insights into the pathophysiology of glucose metabolism, while from a clinical perspective it can facilitate enhanced patient-professional decision making, patient motivation, and improved glycaemic control. CGM has thus been described as a "roadmap for effective self-management" and as a "stepping stone in the journey towards a cure." This review will consider the lessons learned and evidence supporting current and potential future use of CGM in the management of diabetes in pregnancy. PMID- 23081852 TI - OMIP-014: validated multifunctional characterization of antigen-specific human T cells by intracellular cytokine staining. PMID- 23081853 TI - Synthesis, characterization, and structures of a persistent aniline radical cation. PMID- 23081854 TI - Luminescence tuning and white-light emission of co-doped Ln-Cd-organic frameworks. AB - Four new three-dimensional isostructural lanthanide-cadmium metal-organic frameworks (Ln-Cd MOFs), [LnCd(2)(imdc)(2)(Ac)(H(2)O)(2) ].H(2)O (Ln=Pr (1), Eu (2), Gd (3), and Tb (4); H(3)imdc=4,5-imidazoledicarboxylic acid; Ac=acetate), have been synthesized under hydrothermal conditions and characterized by IR, elemental analyses, inductively coupled plasma (ICP) analysis, and X-ray diffraction. Single-crystal X-ray diffraction shows that two Ln(III) ions are surrounded by four Cd(II) ions to form a heteronuclear building block. The blocks are further linked to form 3D Ln-Cd MOFs by the bridging imdc(3-) ligand. Furthermore, the left- and right-handed helices array alternatively in the lattice. Eu-Cd and Tb-Cd MOFs can emit characteristic red light with the Eu(III) ion and green light with the Tb(III) ion, respectively, while both Gd-Cd and Pr Cd MOFs generate blue emission when they are excited. Different concentrations of Eu(3+) and Tb(3+) ions were co-doped into Gd-Cd/Pr-Cd MOFs, and tunable luminescence from yellow to white was achieved. White-light emission was obtained successfully by adjusting the excitation wavelength or the co-doping ratio of the co-doped Gd-Cd and Pr-Cd MOFs. These results show that the relative emission intensity of white light for Gd-Cd:Eu(3+),Tb(3+) MOFs is stronger than that of Pr Cd:Eu(3+),Tb(3+) MOFs, which implies that the Gd complex is a better matrix than the Pr complex to obtain white-light emission materials. PMID- 23081855 TI - Double hydrogen-bonding pH-sensitive hydrogels retaining high-strengths over a wide pH range. AB - Traditional pH-sensitive hydrogels inevitably suffer strength deterioration while the responsive weak acid or base groups are in the ionized state. In this study, we report on a facile approach to fabricate a novel pH-sensitive high-strength hydrogel from copolymerization of two hydrogen-bonding motif-containing monomers, 3-acrylamidophenylboronic acid and 2-vinyl-4,6-diamino-1,3,5-triazine with a crosslinker N,N-methylenebisacrylamide through hydrophilic optimization of the comonomer oligo(ethylene glycol) methacrylate. The double hydrogen bonding hydrogel exhibits both high tensile and compressive strengths over a broad pH range due to the unique ability to maintain at least one type of hydrogen-bonding crosslink over the whole course of pH change. PMID- 23081856 TI - Detection of metal ions (Cu2+, Hg2+) and cocaine by using ligation DNAzyme machinery. AB - The Cu(2+)-dependent ligation DNAzyme is implemented as a biocatalyst for the colorimetric or chemiluminescence detection of Cu(2+) ions, Hg(2+) ions, or cocaine. These sensing platforms are based on the structural tailoring of the sequence of the Cu(2+)-dependent ligation DNAzyme for specific analytes. The tethering of a subunit of the hemin/G-quadruplex DNAzyme to the ligation DNAzyme sequence, and the incorporation of an imidazole-functionalized nucleic-acid sequence, which acts as a co-substrate for the ligation DNAzyme that is tethered to the complementary hemin/G-quadruplex subunit. In the presence of different analytes, Cu(2+) ions, Hg(2+) ions, or cocaine, the pretailored Cu(2+)-dependent ligation DNAzyme sequence stimulates the respective ligation process by combining the imidazole-functionalized co-substrate with the ligation DNAzyme sequence. These reactions lead to the self-assembly of stable hemin/G-quadruplex DNAzyme nanostructures that enable the colorimetric analysis of the substrate through the DNAzyme-catalyzed oxidation of 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), ABTS(2-), by H(2)O(2) into the colored product ABTS(.-), or the chemiluminescence detection of the substrate through the DNAzyme-catalyzed oxidation of luminol by H(2)O(2). The detection limits for the sensing of Cu(2+) ions, Hg(2+) ions, and cocaine correspond to 1 nM, 10 nM and 2.5 MUM, respectively. These different sensing platforms also reveal impressive selectivities. PMID- 23081857 TI - Biofeedback can reduce foot pressure to a safe level and without causing new at risk zones in patients with diabetes and peripheral neuropathy. AB - BACKGROUND: Plantar pressure reduction is mandatory for diabetic foot ulcer healing. Our aim was to evaluate the impact of a new walking strategy learned by biofeedback on plantar pressure distribution under both feet in patients with diabetic peripheral neuropathy. METHODS: Terminally augmented biofeedback has been used for foot off-loading training in 21 patients with diabetic peripheral sensory neuropathy. The biofeedback technique was based on a subjective estimation of performance and objective visual feedback following walking sequences. The patient was considered to have learned a new walking strategy as soon as the peak plantar pressure (PPP) under the previously defined at-risk zone was within a range of 40-80% of baseline PPP in 70% of the totality of steps and during three consecutive walking sequences. The PPP was measured by a portable in shoe foot pressure measurement system (PEDAR((r))) at baseline (T0), directly after learning (T1) and at 10-day retention test (T2). RESULTS: The PPP under at risk zones decreased significantly at T1 (165 +/- 9 kPa, p < 0.0001) and T2 (167 +/- 11, p = 0.001), as compared with T0 (242 +/- 12 kPa) without any increase of the PPP elsewhere. At the contralateral foot (not concerned by off-loading), the PPP was slightly higher under the lateral midfoot at T1 (68 +/- 8 kPa, p = 0.01) and T2 (65 +/- 8 kPa, p = 0.01), as compared with T0 (58 +/- 6 kPa). CONCLUSIONS: The foot off-loading by biofeedback leads to a safe and regular plantar pressure distribution without inducing any new 'at-risk' area under both feet. PMID- 23081858 TI - mTORC1 and mTORC2 play different roles in the functional survival of transplanted adipose-derived stromal cells in hind limb ischemic mice via regulating inflammation in vivo. AB - Poor cell survival severely limits the beneficial effects of stem cell therapy for peripheral arterial disease (PAD). This study was designed to investigate the role of mammalian target of rapamycin (mTOR) in the survival and therapeutic function of transplanted murine adipose-derived stromal cells (mADSCs) in a murine PAD model. mADSCs (1.0 * 10(7)) were isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein-positive transgenic mice, intramuscularly implanted into the hind limb of C57BL/6 mice after femoral artery ligation/excision, and monitored using noninvasive bioluminescence imaging (BLI). Although engrafted mADSCs produced antiapoptotic/proangiogenic effects in vivo by modulating the inflammatory and angiogenic cytokine response involving the mTOR pathway, longitudinal BLI revealed progressive death of post-transplant mADSCs within ~4 weeks in the ischemic hind limb. Selectively targeting mTOR complex-1 (mTORC1) using low-dose rapamycin treatment with mADSCs attenuated proinflammatory cytokines (interleukin [IL]-1beta and tumor necrosis factor-alpha [TNF-alpha]) expression and neutrophil/macrophage infiltration, which overtly promoted mADSCs viability and antiapoptotic/proangiogenic efficacy in vivo. However, targeting dual mTORC1/mTORC2 using PP242 or high-dose rapamycin caused IL-1beta/TNF-alpha upregulation and anti-inflammatory IL-10, IL-6, and vascular endothelial growth factor/vascular endothelial growth factor receptor 2 downregulation, undermining the survival and antiapoptotic/proangiogenic action of mADSCs in vivo. Furthermore, low-dose rapamycin abrogated TNF-alpha secretion by mADSCs and rescued the cells from hypoxia/reoxygenation-induced death in vitro, while PP242 or high-dose rapamycin exerted proinflammatory effects and promoted cell death. In conclusion, mTORC1 and mTORC2 may differentially regulate inflammation and affect transplanted mADSCs' functional survival in ischemic hind limb. These findings uncover that mTOR may evolve into a promising candidate for mechanism-driven approaches to facilitate the translation of cell-based PAD therapy. PMID- 23081859 TI - Ameliorative effect of Vernonia cinerea in vincristine-induced painful neuropathy in rats. AB - The present study was designed to investigate the antinociceptive potential of Vernonia cinerea (VC) on vincristine-induced painful neuropathy in rats. A chemotherapeutic agent, vincristine (50 MUg/kg intraperitoneally for 10 consecutive days), was administered for the induction of neuropathic pain in rats. The painful behavioral changes were assessed using hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests to assess the degree of hyperalgesic and allodynic pain sensation in paw and tail. Tissue biomarker changes including thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH) and total calcium levels were estimated in sciatic nerve tissue samples to assess the degree of oxidative stress. Histopathological changes were also observed in transverse sections of rat sciatic nerve tissue. Ethanolic extract of VC leaves and pregabalin were administered for 14 consecutive days from day 0 (day of surgery). Pregabalin served as a positive control in the present study. Vincristine administration resulted in a significant reduction in painful behavioral changes along with a rise in the levels of TBARS, total calcium and decrease in GSH levels when compared with the normal control group. Furthermore, significant histopathological changes were also observed. Pretreatment with VC significantly attenuated vincristine-induced development of painful behavioral, biochemical and histological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. The attenuating effect of VC in vincristine-induced nociceptive painful sensation may be due to its potential of antioxidative, neuroprotective and calcium channel inhibitory action. PMID- 23081860 TI - In silico predictive studies of mAHR congener binding using homology modelling and molecular docking. AB - The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic, nuclear receptor that is responsible for the early events involved in the transcription of a complex set of genes comprising the CYP450 gene family. In the present computational study, homology modelling and molecular docking were carried out with the objective of predicting the relationship between the binding efficiency and the lipophilicity of different polychlorinated biphenyl (PCB) congeners and the AHR in silico. Homology model of the murine AHR was constructed by several automated servers and assessed by PROCHECK, ERRAT, VERIFY3D and WHAT IF. The resulting model of the AHR by MODWEB was used to carry out molecular docking of 36 PCB congeners using PatchDock server. The lipophilicity of the congeners was predicted using the XLOGP3 tool. The results suggest that the lipophilicity influences binding energy scores and is positively correlated with the same. Score and Log P were correlated with r = +0.506 at p = 0.01 level. In addition, the number of chlorine (Cl) atoms and Log P were highly correlated with r = +0.900 at p = 0.01 level. The number of Cl atoms and scores also showed a moderate positive correlation of r = +0.481 at p = 0.01 level. To the best of our knowledge, this is the first study employing PatchDock in the docking of AHR to the environmentally deleterious congeners and attempting to correlate structural features of the AHR with its biochemical properties with regards to PCBs. The result of this study are consistent with those of other computational studies reported in the previous literature that suggests that a combination of docking, scoring and ranking organic pollutants could be a possible predictive tool for investigating ligand-mediated toxicity, for their subsequent validation using wet lab-based studies. PMID- 23081861 TI - Mitigation of hepatotoxic effects of arsenic trioxide through omega-3 fatty acid in rats. AB - Arsenic trioxide (As(2)O(3)) is an effective drug in the treatment of leukaemia and many solid tumours. In clinical trials, arsenic therapy is closely associated with hepatic toxicity. The present study was designed to investigate the efficacy of omega-3 fatty acid against As(2)O(3)-induced hepatotoxicity. A 4 mg/kg body weight (bw) of As(2)O(3) was orally administered to Wistar male rats for 45 days. Hepatotoxicity was evaluated by biochemical tests, antioxidant assays and histopathological examinations. Arsenic accumulation was found in the liver tissue of rats treated with As(2)O(3). Hepatoprotective efficacy of omega-3 fatty acid was analysed by the combination therapy with As(2)O(3). In vivo studies revealed a significant rise in lipid peroxidation with concomitant decline in reduced glutathione, glutathione-dependant antioxidant enzymes and antiperoxidative enzymes in the liver tissue of rats treated with arsenic. The supplementation of omega-3 fatty acid at a dose of 50 mg/kg bw with As(2)O(3) offers ameliorative effect against hepatocellular toxicity. Omega-3 fatty acid maintained hepatic marker enzymes, antioxidant enzymes and decreased lipid peroxidation. The combination treatment clearly reduced the hepatic structural abnormalities such as haemorrhage, necrosis and cholangiofibrosis in the rats treated with arsenic. This study concludes that the omega-3 fatty acid might be useful for the protection against As(2)O(3)-induced hepatotoxicity. PMID- 23081862 TI - Could 8-oxoguanine DNA glycosylase 1 Ser326Cys polymorphism be a biomarker of susceptibility in cancer? AB - Biomarkers are key molecular or cellular events that give an indication whether there is a threat for disease, whether a disease already exists, or how such disease may develop in an individual case. The discovery of polymorphisms in genes that function in the metabolism of chemicals and in DNA repair has demonstrated the importance of understanding the phenomenon of genetic susceptibility in a population. Polymorphisms in DNA repair genes as an important component of the individual susceptibility to the development of cancer and various hereditary diseases have been commonly studied, since these genes have critical roles in maintaining genome integrity. Furthermore, the evaluation of cancer risk depends on the level of exposure to carcinogenic factors as well as on the genetic codes of the individual. This approach is supported by studies that present positive association between these polymorphic genes and cancers. Although 8-oxoguanine DNA glycosylase 1 (OGG1) is one of the promising biomarker candidates of cancer susceptibility, there are also some controversial results. Epidemiological studies show that the OGG1 might be a biomarker of susceptibility for various cancers; however, the small sample size and difference in the eligibility criteria for inclusion of subjects and sources might limit the studies to demonstrate the association between the OGG1 Ser326Cys polymorphism and the risk of cancer. Thus, meta-analyses may provide more valuable and reliable data to demonstrate the potential of OGG1 Ser326Cys DNA repair enzyme polymorphisms that could be the biomarkers of susceptibility of cancer. Our aim in this review is to compile published studies, including some controversial results on the association between the OGG1 Ser326Cys polymorphism and the risk of cancer. PMID- 23081863 TI - Intramolecular 1,3-dipolar cycloaddition-mediated stereoselective synthesis of disubstituted cyclopentane: a simple model for the cyclopentane ring system of polycyclic oroidine alkaloids. AB - We present a diastereoselective synthesis of disubstituted cyclopentane 8 having a nitrogen-containing quaternary carbon center, which is found in axinellamine A (5) and related compounds. During this work, we found that the 1,3-dipolar cycloaddition product 24 immediately underwent intramolecular redox reaction at the newly formed morpholin-2-one moiety, thus affording disubstituted cyclopentane containing a tertiary amine (9) stereoselectively in good yield. The amine 9 was successfully converted into guanidine 31, which corresponds to 8, through iminium cation-enamine isomerization. PMID- 23081864 TI - Development of a Povarov reaction/carbene generation sequence for alkenyldiazocarbonyl compounds. PMID- 23081865 TI - A flow cytometric method for viability assessment of Staphylococcus aureus and Burkholderia cepacia in mixed culture. AB - Mixed bacterial communities are commonly encountered in microbial infections of humans. Knowledge on the composition of species and viability of each species in these communities allows for a detailed description of the complexity of interspecies dynamics and contributes to the assessment of the severity of infections. Several assays exist for quantification of specific species in mixed communities, including analysis of quantitative terminal restriction fragment length polymorphisms. While this method allows for species-specific cell enumeration, it cannot provide viability data. In this study, flow cytometry was applied to assess the viability of Staphylococcus aureus and Burkholderia cepacia in mixed culture by membrane integrity analysis using SYBR(r) Green I and propidium iodide staining. Both bacteria are relevant to pulmonary infections of cystic fibrosis patients. Fluorescence staining was optimized separately for each species in pure culture due to differences between species in cell wall structure and metabolic capabilities. To determine viability of species in mixed culture, a protocol was established as a compromise between optimum conditions determined before for pure cultures. This protocol allowed the detection of viable and dead cells of both species, exhibiting an intact and a permeabilized membrane, respectively. To discriminate between S. aureus and B. cepacia, the protocol was combined with Gram-specific fluorescent staining using wheat germ agglutinin. The established three-color staining method was successfully tested for viability determination of S. aureus and B. cepacia in mixed culture cultivations. In addition, growth of both species was monitored by quantitative terminal restriction fragment length polymorphisms. The obtained data revealed alterations in viability during cultivations for different growth phases and suggest interspecies effects in mixed culture. Overall, this method allows for rapid simultaneous Gram-differentiation and viability assessment of bacterial mixed cultures and is therefore suitable for the analysis of dynamics of mixed communities of medical, environmental, and biotechnological relevance. PMID- 23081866 TI - Muscle-like supramolecular polymers: integrated motion from thousands of molecular machines. AB - Pumping iron: Double-threaded rotaxanes can be linked to coordination units and polymerized in the presence of iron or zinc ions. pH modulation triggers cooperative contractions (or extensions) of the individual rotaxanes, thus resulting in an amplified motion of the muscle-like supramolecular chains with changes of their contour lengths of several micrometers (see picture). PMID- 23081867 TI - Essential oils and their compositions as spatial repellents for pestiferous social wasps. AB - BACKGROUND: The study objectives were: (1) to field test potential repellency of common essential oils against several pestiferous social wasps (Hymenoptera: Vespidae), using attractant-baited traps; (2) to identify vespid antennally active compounds from the repellent essential oils; (3) to determine potential repellency of these electroantennographic detection (EAD) active compounds in the field. RESULTS: Of the 21 essential oils tested, 17 showed significant repellency on yellowjackets [mainly Vespula pensylvanica (Saussure)] and paper wasps [mainly Polistes dominulus (Christ)]: clove, pennyroyal, lemongrass, ylang ylang, spearmint, wintergreen, sage, rosemary, lavender, geranium, patchouli, citronella, Roman chamomile, thyme, fennel seed, anise and peppermint. Two essential oil mixtures - 3EO-mix (clove, geranium and lemongrass) and 4EO-mix (clove, geranium, lemongrass and rosemary) - totally blocked the attraction of vespid workers. Twenty-nine vespid antennally active compounds were identified from solid-phase microextraction (SPME) samples of 11 strongly repellent essential oils by GC-EAD/MS techniques. Among the synthetic EAD-active compounds field tested, eugenol, P/I-menthone, pulegone, alpha/beta-thujone, l-carvone, E/Z citral, citronellal, methyl benzoate, benzyl acetate, methyl salicylate and 3 octanol showed a significant repellency on vespid workers. These compounds are likely responsible for the repellency of their corresponding essential oils. CONCLUSION: These repellent essential oils and their active compositions have great potential for efficient, environmentally sound semiochemical-based IPM of pestiferous vespid wasps. PMID- 23081868 TI - Long-term reproductive outcomes in women whose first pregnancy is ectopic: a national controlled follow-up study. AB - STUDY QUESTION: How does long-term reproductive prognosis among women whose first pregnancy is ectopic differ from prognosis in women with other initial pregnancy outcomes? SUMMARY ANSWER: Women with a first recorded ectopic pregnancy (EP) have a significantly lower long-term delivery rate and a manifold increased risk of further EPs. WHAT IS KNOWN ALREADY: Women with a first EP have an increased risk of further EPs. Few studies have assessed long-term reproductive outcomes after an EP, and none was controlled. STUDY DESIGN: The study was designed as a historical controlled cohort study. MATERIALS AND METHODS: Data were collected from four Danish registries covering the period 1977-2009. Women with an EP as their first recorded pregnancy during the period 1977-1982 were age matched with women whose first recorded pregnancy was a miscarriage, an induced abortion, a delivery, or women with no recorded pregnancies, respectively. The cohorts were followed until the end of 2009 or on average through 30 years. MAIN RESULTS: When compared with women with a first miscarriage, women with a first EP had a relative risk of deliveries of 0.55 [95% confidence interval (CI) 0.52-0.58], miscarriages of 0.46 (0.41-0.52) and induced abortions of 0.72 (0.65-0.80) and a 4.7 (3.8-5.8)-fold increased risk of further EPs. The relative delivery rate when compared with women with a first induced abortion was 0.89 (0.84-0.95) and with women with no pregnancy 0.69 (0.65-0.72). LIMITATIONS: We had no information about the attempts to become pregnant in the different cohorts. New fertility techniques may have improved the prognosis among women with a first EP. WIDER IMPLICATIONS OF THE FINDINGS: These results indicate that fertility is compromised in women whose first pregnancy is ectopic. It is possible that better assisted reproductive techniques that have been developed in recent years could improve the long-term delivery rates for women with EP. STUDY FUNDING: All the expenses were covered by Gynaecological Clinic, Rigshospitalet. O.L. has within the last 3 years received honoraria for speeches in pharmacoepidemiological issues. L.L.K., P.E. and C.W.S. had no conflict of interest to declare. PMID- 23081869 TI - A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies. AB - STUDY QUESTION: Is thin endometrium unresponsive to standard treatments expandable by intrauterine perfusion with granulocyte colony-stimulating factor (G-CSF)? SUMMARY ANSWER: This cohort study is supportive of the effectiveness of G-CSF in expanding chronically unresponsive endometria. WHAT IS KNOWN ALREADY: In a previous small case series, we reported the successful off-label use of G-CSF in four consecutive patients, who had previously failed to expand their endometria beyond 6.9 mm with the use of standard treatments. STUDY DESIGN, SIZE AND DURATION: In a prospective observational cohort pilot study over 18 months, we described 21 consecutive infertile women with endometria <7 mm on the day of hCG administration in their first IVF cycles at our center. All previous cycles using traditional treatments with estradiol, sildenafil citrate (ViagraTM) and/or beta-blockers had been unsuccessful. G-CSF (NupogenTM) was administered per intrauterine catheter by slow infusion before noon on the day of hCG administration. If the endometrium had not reached at least a 7-mm within 48h, a second infusion was given following oocyte retrieval. Primary and secondary main outcomes were an increase in endometrial thickness and clinical pregnancy, respectively. Endometrial thickness was assessed by vaginal ultrasound at the most expanded area of the endometrial stripe. PARTICIPANTS/MATERIALS, SETTINGS AND METHOD: This study was uncontrolled, each patient serving as her own control in a prospective evaluation of endometrial thickness. The mean +/- SD age of the cohort was 40.5 +/- 6.6 years, gravidity was 1.8 +/- 2.1 (range 0-7) and parity was 0.4 +/- 1.1 (range 0-4); 76.2% of women had, based on age-specific FSH and anti-Mullerian hormone, an objective diagnosis of diminished ovarian reserve and had failed 2.0 +/- 2.1 prior IVF cycles elsewhere. MAIN RESULTS AND THE ROLE OF CHANCE: With 5.2 +/- 1.9 days between G-CSF perfusions and embryo transfers, endometrial thickness increased from 6.4 +/- 1.4 to 9.3 +/- 2.1 mm (P < 0.001). The Delta in change was 2.9 +/- 2.0 mm, and did not vary between conception and non-conception cycles. A 19.1% ongoing clinical pregnancy rate was observed, excluding one ectopic pregnancy. LIMITATIONS AND REASONS FOR CAUTION: Small sample size (but a highly selected patient population) in an uncontrolled cohort study and in unselected first IVF cycles at our center. WIDER IMPLICATIONS OF THE FINDINGS: This pilot study supports the utility of G-CSF in the treatment of chronically thin endometrium and suggests that such treatment will, in very adversely affected patients, result in low but very reasonable clinical pregnancy rates. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Foundation for Reproductive Medicine, New York, New York, USA, a not-for-profit research foundation and intramural grants from the Center for Human Reproduction (CHR)-New York. N.G. and D.H.B. are members of the board of the Foundation for Reproductive Medicine. N.G. is owner of CHR-New York, where the study was conducted. N.G. and D.H.B. have been recipients of research awards, travel grants and speaker honoraria from various pharmaceutical and medical device companies. None of these companies was, however, in any way associated with the materials and the manuscript presented here. N.G. and D.H.B. are listed as co-inventors on a number of awarded and still pending U.S. patents, none related to the materials presented here. N.G. is on the board of a medically related company, not in any way associated with the data presented here. PMID- 23081870 TI - Natural therapies assessment for the treatment of endometriosis. AB - STUDY QUESTION: Can resveratrol and epigallocatechin-3-gallate (EGCG) inhibit the growth and survival of endometriotic-like lesions in vivo in a BALB/c model of endometriosis, and in vitro in primary cultures of human endometrial epithelial cells (EECs)? SUMMARY ANSWER: Resveratrol and EGCG exerted a potent inhibitory effect on the development of endometriosis in a BALB/c murine model and on the survival of EECs. WHAT IS KNOWN ALREADY: Endometriosis is a common condition associated with infertility and pelvic pain in women of reproductive age. Resveratrol and EGCG are two polyphenols with anticarcinogenic and antioxidant properties that have been proposed as natural therapies to treat endometriosis. STUDY DESIGN, SIZE, DURATION: Fifty-six 2-month-old female BALB/c mice underwent surgical induction of endometriosis. Treatments with resveratrol or EGCG started 15 days post-surgery and continued for 4 weeks. Human biopsies were taken with a metal Novak curette from the posterior uterine wall from 16 patients with untreated endometriosis and 15 controls who underwent diagnostic laparoscopy for infertility. MATERIALS, SETTING, METHODS: After the treatments, animals were sacrificed and lesions were counted, measured, excised and fixed. Immunohistochemistry for proliferating cell nuclear antigen and CD34 was performed for cell proliferation and vascularization assessment in the lesions. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) technique was performed for apoptosis evaluation. Peritoneal fluid was collected to analyze vascular endothelial growth factor levels. Human EECs were purified from proliferative-phase endometrial biopsies and cultured. The effect of both polyphenols on cell proliferation was determined by a colorimetric assay using the CellTiter 96(r)AQueous One Solution Cell Proliferation Assay kit and on apoptosis by the TUNEL technique, using an In Situ Cell Death Detection Kit with Fluorescein. MAIN RESULTS: In the mouse model, both treatments significantly reduced the mean number (P < 0.05 versus control) and the volume of established lesions (P < 0.05 versus control). Treatments consistently statistically significantly diminished cell proliferation (resveratrol P < 0.01 and EGCG P < 0.05, versus control), reduced vascular density (resveratrol P < 0.01 and EGCG P < 0.001, versus control) and increased apoptosis within the lesions (resveratrol P < 0.01 and EGCG P < 0.05, versus control). Both compounds induced reduction in human EEC proliferation (P < 0.05 versus basal) and increased apoptosis (P < 0.05 versus basal) in primary cultures. LIMITATIONS: In vitro studies were only carried out in epithelial cells from human eutopic endometrium. WIDER IMPLICATIONS OF THE FINDINGS: The present findings are promising and will assist the development of novel natural treatments for endometriosis. STUDY FUNDING: This study was supported by ANPCYT (PICT 6384 BID 1201 OC-AR) and CONICET (PIP 5471), Argentina. None of the authors has any conflict of interest to declare. PMID- 23081871 TI - Pregnancy outcomes following robot-assisted myomectomy. AB - STUDY QUESTION: What are the characteristics of the pregnancy outcomes in women undergoing robot-assisted laparoscopic myomectomy (RALM) for symptomatic leiomyomata uteri? SUMMARY ANSWER: Despite a high prevalence of women with advanced maternal age, obesity and multiple pregnancy in our cohort, the outcomes are comparable with those reported in the literature for laparoscopic myomectomy. WHAT IS KNOWN ALREADY: Reproductive outcomes after traditional laparoscopic myomectomy are well documented. However, reproductive outcomes following robotic myomectomy are not well studied. This paper describes the pregnancy outcomes for a large cohort of women after robotic myomectomy. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort of women who became pregnant after robot-assisted myomectomy at three centers. Of the 872 women who underwent robotic myomectomy during the period October 2005-November 2010, 107 subsequently conceived resulting in 127 pregnancies and 92 deliveries through 2011. PARTICIPANTS/MATERIAL, SETTING, METHODS: Women of reproductive age with fibroids who wanted a minimally invasive treatment option and desired uterine preservation were recruited. We conducted a multicentre study with three centers, two in a private practice and one in an academic setting. Pregnancy outcomes and their relationship to myoma characteristics were analyzed. MAIN RESULTS AND ROLE OF CHANCE: Mean +/- SD age at myomectomy was 34.8 +/- 4.5 years and 57.4% [95% confidence interval (CI) 48.0, 66.3] of women were overweight or obese. The mean number of myomas removed was 3.9 +/- 3.2 with a mean size of 7.5 +/- 3.0 cm and mean weight of 191.7 +/- 144.8 g. Entry of the myoma into the endometrial cavity occurred in 20.6% (95% CI 15.0, 27.7) of patients. The mean time to conception was 12.9 +/- 11.5 months. Assisted reproduction techniques were employed in 39.4% (95% CI 32.6, 46.7) of these women. Seven twin pregnancies and two triplet pregnancies occurred, for a multiple pregnancy birth rate of 9.8% (95% CI 5.0, 17.8). Spontaneous abortions occurred in 18.9% (95% CI 13.0, 26.6). Preterm delivery prior to 35 weeks of gestational age occurred in 17.4% (95% CI 10.9, 26.5). One uterine rupture (1.1%; 95% CI 0.3, 4.7) was documented. Pelvic adhesions were discovered in 11.4% (95% CI 7.0, 18.0) of patients delivered by Cesarean section. Higher preterm delivery rates were significantly associated with a greater number of myomas removed and anterior location of the largest incision (compared with all other sites) in logistic regression analyses (P = 0.01). None of the myoma characteristics were related to spontaneous abortion. BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION: Given the retrospective nature of the data collection, some pregnancies may not have been captured. In addition, owing to the high prevalence of infertility patients in this cohort, the data cannot be used to counsel women who are undergoing RALM about fertility rates after surgery. GENERALIZABILITY TO OTHER POPULATIONS: Prospective studies are needed to determine if the results shown in our cohort are generalizable to all women seeking a minimally invasive option for the conservative treatment of symptomatic fibroids with pregnancy as a desired outcome. STUDY FUNDING/COMPETING INTEREST(S): There was no funding source for this study. PMID- 23081872 TI - Home ovulation tests and stress in women trying to conceive: a randomized controlled trial. AB - STUDY QUESTION: Does the use of a digital home ovulation test have any effect on the level of stress in women seeking to conceive? SUMMARY ANSWER: No difference was found in levels of stress between women using digital ovulation tests to time intercourse compared with women who were trying to conceive without any additional aids: in addition, their use did not negatively impact time to conception in users but may provide additional benefits, including an increased understanding of the menstrual cycle, reassurance and confidence in focusing conception attempts to the correct time in the cycle. WHAT IS KNOWN ALREADY: It has been suggested that timing of intercourse in such a way that it coincides with ovulation by using ovulation tests can lead to emotional distress; however, no study has been conducted to investigate this hypothesis specifically, until now. STUDY DESIGN, SIZE AND DURATION: The study was performed over two complete menstrual cycles as a prospective, randomized, controlled trial including quantitative and qualitative methods. The intervention (test) group were given digital ovulation tests to time intercourse to the most fertile time of the cycle and the control group were provided with the current National Institute for Health and Clinical Excellence guidelines for increasing the chances of conception (intercourse every 2-3 days) and asked not to use any additional methods to time when ovulation occurs. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A total of 210 women who were seeking to conceive were recruited from the general UK population. A total of 115 women were randomized to the test group and 95 to the control group through block randomization. The positive and negative affect schedule (PANAS) and the Perceived Stress Scale (PSS) were used to measure subjective stress levels, the Short-Form 12 health survey was used as a measure of general health and well-being and urine samples were measured for biochemical markers of stress including urinary cortisol. Qualitative data were collected in the form of a telephone interview upon study completion. MAIN RESULTS AND THE ROLE OF CHANCE: There was no evidence for a difference either in total stress as measured using the PSS or in total positive or negative affect using the PANAS questionnaire between the test and control groups at any time point for the duration of the study. During cycle 1, for example, on Day 6, the difference in total stress score (test-control) was -0.62 [95% confidence interval (CI) -2.47 to 1.24] and on the day of the LH surge, it was 0.53 (95% CI 1.38 to 2.44). In addition, no correlation was observed between time trying to conceive and levels of stress, or between age and levels of stress, and no evidence was found to show that stress affected whether or not a pregnancy was achieved. There is also no evidence that the biochemistry measurements are related to whether a pregnancy was achieved or of a difference in biochemistry between the treatment groups. The use of digital ovulation tests did not negatively affect time to conception and with an adequately sized study, could potentially show improvement. To ensure that the results of this study were not affected by chance, we used a number of different methods for measuring stress, each of which had been independently validated. LIMITATIONS AND REASONS FOR CAUTION: Randomization occurred before the start of the study because of the need to provide the ovulation tests in readiness for Day 6 of the first cycle. As a consequence, a number of women fell pregnant during this period (22 and 13 in the test and control groups, respectively). A further 15 women were either lost to follow-up or withdrew consent prior to study start. Pregnancy rate was higher overall in the test group, so to ensure that there were sufficient data from women who failed to become pregnant in the test group, we implemented an additional biased recruitment. This second cohort may have been different from the first, although no significant differences were observed between the two phases of recruitment for any of the information collected upon admission to the study. WIDER IMPLICATIONS OF THE FINDINGS: Women who seek medical advice while trying to conceive should not be discouraged by health care professionals from using digital ovulation tests in order to time intercourse. The cohort of women recruited to this study initially had no evidence of infertility and were looking to conceive in a non-medical setting. A separate study to assess the impact of home ovulation tests in a subfertile population would be of interest and complementary to the present study. STUDY FUNDING/COMPETING INTERESTS: This study was funded by SPD Swiss Precision Diagnostics, GmbH, manufacturer of Clearblue((r)) pregnancy and ovulation tests. SPD Development Company Ltd is a wholly owned subsidiary of SPD Swiss Precision Diagnostics GmbH; together referred to as SPD. TRIAL REGISTRATION NUMBER: NCT01084304 (www.clinicaltrials.gov). PMID- 23081873 TI - Methotrexate or expectant management in women with an ectopic pregnancy or pregnancy of unknown location and low serum hCG concentrations? A randomized comparison. AB - STUDY QUESTION: What is the treatment success rate of systemic methotrexate (MTX) compared with expectant management in women with an ectopic pregnancy or a pregnancy of unknown location (PUL) with low and plateauing serum hCG concentrations? SUMMARY ANSWER: In women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations, expectant management is an alternative to medical treatment with single-dose systemic MTX. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: MTX is often used in asymptomatic women with an ectopic pregnancy or a PUL with low and plateauing serum hCG concentrations. These pregnancies may be self-limiting and watchful waiting is suggested as an alternative, but evidence from RCTs is lacking. The results of this RCT show that expectant management is an alternative to treatment with systemic MTX in a single dose regimen in these women. STUDY DESIGN, SIZE, DURATION: A multicentre RCT women were assigned to systemic MTX (single dose) treatment or expectant management, using a web-based randomization program, block randomization with stratification for hospital and serum hCG concentration (<1000 versus 1000-2000 IU/l). The primary outcome measure was an uneventful decline of serum hCG to an undetectable level (<2 IU/l) by the initial intervention strategy. Secondary outcome measures included additional treatment, side effects and serum hCG clearance time. PARTICIPANTS, SETTING, METHODS: From April 2007 to January 2012, we performed a multicentre study in The Netherlands. All haemodynamically stable women >18 years old with both an ectopic pregnancy visible on transvaginal sonography and a plateauing serum hCG concentration <1500 IU/l or with a PUL and a plateauing serum hCG concentration <2000 IU/l were eligible for the trial. MAIN RESULTS: We included 73 women of whom 41 were allocated to single-dose MTX and 32 to expectant management. There was no difference in primary treatment success rate of single-dose MTX versus expectant management, 31/41 (76%) and 19/32 (59%), respectively [relative risk (RR) 1.3 95% confidence interval (CI) 0.9-1.8]. In nine women (22%), additional MTX injections were needed, compared with nine women (28%) in whom systemic MTX was administered after initial expectant management (RR 0.8; 95% CI 0.4-1.7). One woman (2%) from the MTX group underwent surgery compared with four women (13%) in the expectant management group (RR 0.2; 95% CI 0.02-1.7), all after experiencing abdominal pain within the first week of follow up. In the MTX group, nine women reported side effects versus none in the expectant management group. No serious adverse events were reported. Single-dose systemic MTX does not have a larger treatment effect compared with expectant management in women with an ectopic pregnancy or a PUL and low and plateauing serum hCG concentrations. WIDER IMPLICATIONS OF THE FINDINGS: Sixty percent of women after expectant management had an uneventful clinical course with steadily declining serum hCG levels without any intervention, which means that MTX, a potentially harmful drug, can be withheld in these women. BIAS, LIMITATION AND GENERALISABILITY: A limitation of this RCT is that it was an open (not placebo controlled) trial. Nevertheless, introduction of bias was probably limited by the strict criteria to be fulfilled for treatment with MTX. STUDY FUNDING: This trial is supported by a grant of the Netherlands Organization for Health Research and Development (ZonMw Clinical fellow grant 90700154). TRIAL REGISTRATION: ISRCTN 48210491. PMID- 23081874 TI - DNMT3B promoter polymorphisms and maternal risk of birth of a child with Down syndrome. AB - STUDY QUESTION: Are DNMT3B promoter polymorphisms among maternal risk factors for the birth of a child with Down syndrome (DS)? SUMMARY ANSWER: Present results suggest that combinations of functional DNMT3B promoter polymorphisms might modulate maternal risk of birth of a child with DS. WHAT IS KNOWN ALREADY: The DNMT3B gene codes for DNA methyltransferase 3b (DNMT3b), a protein required for genome-wide de novo methylation, for the establishment of DNA methylation patterns during development and for regulating the histone code and DNA methylation at centromeric regions. Two common functional DNMT3B promoter polymorphisms, namely -149 C > T (rs2424913) and -579 G > T (rs1569686), have been extensively investigated in cancer genetic association studies but less is known about their role in non-cancer diseases. Early in 1999, it was supposed that impaired DNA methylation of pericentromeric regions might represent a maternal risk factor for having a baby with DS. STUDY DESIGN, SIZE AND DURATION: We aimed to investigate DNMT3B -149 C > T and -579 G > T polymorphisms as maternal risk factors for the birth of a child with DS. The study was performed on DNA samples from 172 mothers of DS individuals (135 aged <35 years when they conceived) and 157 age-matched mothers of unaffected individuals. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Genotyping was performed by means of the PCR-RFLP technique. MAIN RESULTS AND THE ROLE OF CHANCE: The DNMT3B -579T allele [odds ratio (OR) = 0.68; 95% confidence interval (CI) = 0.48-0.94, P = 0.02], the DNMT3B -579 GT genotype (OR = 0.55; 95% CI = 0.35-0.87 , P = 0.01) and the combined DNMT3B -579 GT + TT genotype (OR = 0.55; 95% CI = 0.36-0.86 , P = 0.008) were associated with reduced risk of birth of a child with DS. A joint effect of the two polymorphisms was observed and the combined -579 GT/-149 CC genotype resulted in decreased DS risk (OR = 0.22; 95% CI = 0.08-0.64, P = 0.003). The effect remained statistically significant after Bonferroni's correction for multiple comparisons. Similar results were obtained when the analysis was restricted to women who conceived a DS child before 35 years of age. LIMITATIONS AND REASONS FOR CAUTION: To the best of our knowledge, this is the first genetic association study aimed at evaluating DNMT3B polymorphisms as maternal risk factors for DS. Replication of the findings in other populations is required. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed in subsequent studies, DNMT3B promoter polymorphisms might be additional markers to be taken into account when evaluating the contribution of one-carbon (folate) metabolism to the maternal risk of birth of a child with DS. PMID- 23081875 TI - Diagnostic and prognostic value of calcium oscillatory pattern analysis for patients with ICSI fertilization failure. AB - STUDY QUESTION: Does calcium oscillatory pattern analysis following heterologous intra-cytoplasmic sperm injection (ICSI) of human sperm into mouse oocytes lead to diagnostic and prognostic information for patients suffering from ICSI fertilization failure? SUMMARY ANSWER: We found that calcium oscillatory pattern analysis following heterologous ICSI has the strength to reveal, for the individual patient, the most probable underlying reason for low or failed fertilization after conventional ICSI. WHAT IS KNOWN ALREADY: Fertilization failure occurs in 1-3% of the couples undergoing conventional ICSI, for whom the mouse oocyte activation test (MOAT) or a similar heterologous ICSI model is the only diagnostic test available to evaluate the oocyte-activating capacity of human sperm cells. The MOAT classifies the patients into three groups: a low (group 1), an intermediate (group 2) and a high (group 3) activating group. In MOAT group 1 patients, a sperm-related deficiency is likely to be the cause of previous fertilization failures, while in MOAT group 3 patients a sperm-related deficiency can most probably be refuted. For MOAT group 2 patients, the result is called inconclusive; hence, both sperm and oocyte deficiencies may still contribute to the previous ICSI fertilization failure. STUDY DESIGN, SIZE, DURATION: The calcium-releasing ability of sperm from 26 MOAT patients with a history of zero or low fertilization following conventional ICSI was compared with the calcium-releasing ability of sperm from 4 control patients, with proven oocyte activation potential. Per case an average of 19 mouse oocytes were injected. Calcium imaging started within 5-10 min after ICSI and continued for 2 h. PARTICIPANTS/MATERIALS, SETTING, METHODS: Human sperm were demembranated with 0.02% lysolecithin for 1 min immediately before heterologous piezo-driven ICSI. For calcium imaging, metaphase II oocytes from B6D2/F1 mice were loaded with fura 2 acetoxymethyl ester. The calcium oscillatory patterns following heterologous ICSI were scored per oocyte and per patient individually based on the presence of calcium spikes and their frequency and amplitude. MAIN RESULTS AND THE ROLE OF CHANCE: For patients with low or high MOAT activating capacity (MOAT group 1 or 3, respectively), calcium analysis confirmed the MOAT result. For patients with a former inconclusive intermediate MOAT activating capacity result (MOAT group 2), no or strongly dissimilar calcium oscillatory patterns were seen, with significantly lower amplitude and frequency compared with control sperm. When the product of the amplitude and the frequency of the calcium traces was compared between the groups, MOAT group 1 and 2 cases differed significantly from MOAT group 3 cases and the control sperm (P < 0.01). LIMITATIONS, REASONS FOR CAUTION: The results of the calcium analysis in mouse oocytes should not be directly extrapolated to human oocytes, since it is well known that human spermatozoa exhibit a greater activating potency in mouse oocytes compared with mouse spermatozoa. Furthermore, not much is known yet about the influence of aberrant calcium oscillatory patterns, such as found in MOAT group 2 patients, on pre- and post-implantation embryo development in the human. WIDER IMPLICATIONS OF THE FINDINGS: Based on the current calcium oscillatory pattern analysis, we found that the product of calcium spike amplitude with its frequency allowed us to create a new threshold value, which can assist in confirming or refuting, on a single patient base, a sperm-borne activation deficiency. The latter is especially interesting for patients with a former intermediate inconclusive MOAT result (MOAT group 2 patients), for whom calcium oscillatory pattern analysis should be considered. STUDY FUNDING/COMPETING INTEREST(S): F.V.M. is holder of an aspirant clinical research mandate by the Flemish foundation of Scientific Research (FWO-Vlaanderen). B.H. is supported by a Ghent University grant (KAN-BOF E/01321/01). P.D.S. is holder of a fundamental clinical research mandate by the same Flemish foundation of Scientific Research (FWO-Vlaanderen). PMID- 23081876 TI - Factors affecting prevalence and extent of intimate partner violence in Ukraine: evidence from a nationally representative survey. AB - This study examined the prevalence and ecological correlates of intimate partner violence against women in Ukraine. A nationally representative sample of ever married female respondents of the 2007 Ukraine Demographic Health Survey was used for this analysis. Findings suggest that although numerous ecological factors predict women's experiences of emotional, physical, and sexual intimate partner violence, two factors were common correlates of all three forms of violence: the frequent intoxication of women's partners and the exhibition of marital controlling behaviors by male perpetrators. Implications for the development of effective programming to prevent violence against Ukrainian women are provided. PMID- 23081877 TI - In Situ intercalating expandable graphite for mesoporous carbon/graphite nanosheet composites as high-performance supercapacitor electrodes. AB - Mesoporous-carbon-coated graphite nanosheet (GNS@MC) composites have been synthesized by the intercalation of resol prepolymer into the interlayers of expandable graphite (EG) under vacuum-assisted conditions, followed by the exfoliation of EG through in situ polymerization, the growth of resol under hydrothermal conditions, and carbonization under Ar. The GNS@MC composites exhibit enhanced capacitive performance compared to mesoporous carbon (MC), microwaved EG after thermal treatment (T-EG), and the physical mixture of MC and T-EG (MC+T-EG). In particular, the GNS@MC-35-800 composite carbonized at 800 degrees C, which has a graphite-nanosheet content of 35 % and a Brunauer-Emmett Teller surface area (S(BET) ) of 432.3 m(2) g(-1) , exhibits the highest capacitance of 203 F g(-1) at 1 A g(-1) in 6 M KOH electrolyte. Furthermore, the GNS@MC-35-800 composite exhibits a good cyclic stability with 95 % capacitance retention and a high columbic efficiency of 99 % after 5000 cycles. The energy density of the symmetric supercapacitor GNS@MC-35-800/GNS@MC-35-800 achieved was as high as 11.5 Wh kg(-1) at a high power density of 10 kW kg(-1) . This good performance is attributable to the GNSs in the GNS@MC composite facilitating electron transport owing to its excellent conductivity; moreover, the MC in GNS@MC favors the rapid diffusion of ions by providing low-resistance pathways. The GNS@MC composite may find application in high-performance energy storage and conversion devices. PMID- 23081878 TI - Histone H5-chromatin interactions in situ are strongly modulated by H5 C-terminal phosphorylation. AB - We used linker histone-depleted normal human fibroblast nuclei as templates to study how phosphorylation affects histone H5 binding to chromatin in situ. Permeabilized cells were treated with 0.7 M NaCl to extract the native linker histones. Histone H5 was purified from chicken erythrocytes and phosphorylated in vitro by recombinant cdk5/p35 kinase. High performance capillary electrophoresis (HPCE) showed that the phosphorylated protein contained a mixture of multiply phosphorylated forms. Control experiments, using mass spectrometry, revealed that up to five SPXK motifs in the C terminus were phosphorylated, but also that about 10% of the protein contained one phosphoserine in the N-terminus. Reconstitution of H1-depleted fibroblast nuclei with nonphosphorylated or phosphorylated H5 was performed at physiological ionic strength. The bound H5 was then extracted using NaCl concentrations in the range of 0.15 to 0.7 M. The release of the H5 molecules was monitored by DAPI staining and image cytofluorometry. Our results show that H5 phosphorylation substantially reduced its affinity for chromatin in situ, which support previous observations indicating that C-terminal phosphorylation may be essential for the biological functions of linker histones. PMID- 23081879 TI - Divergent total synthesis of the antimitotic agent leiodermatolide. PMID- 23081880 TI - Cohort profile: Shahroud Eye Cohort Study. AB - The Shahroud Eye Cohort Study was set up to determine the prevalence and incidence of visual impairment and major eye conditions in the 40-64-year-old population of Shahroud as a Middle Eastern population. The first phase of the study was conducted in 2009-10. Using random cluster sampling, 6311 Shahroud inhabitants were invited for ophthalmologic examinations; of these, 5190 participants completed phase 1 (participation rate of 82.2%). All participants were interviewed to collect data on participants' demographics, occupation status, socioeconomic status, history of smoking, and medical and ophthalmic history, as well as history of medication, and the quality and duration of their insurance. DNA and plasma samples, as well as four dots of whole blood were collected from participants. Extensive optometric and ophthalmologic examinations were performed for each participant, including lensometry of current glasses, testing near and far visual acuity; determining objective and subjective refraction; eye motility; cycloplegic refraction; colour vision test; slit-lamp biomicroscopy and intraocular pressure measurement; direct and indirect fundoscopy; perimetry test; ocular biometry; corneal topography; lens and fundus photography; and the Schirmer's (1008 participants) and tear breakup time tests (1013 participants). The study data are available for collaborative research at Noor Ophthalmology Research Center, Tehran, Iran. PMID- 23081881 TI - Power shifts track serial position and modulate encoding in human episodic memory. AB - The first events in a series exert a powerful influence on cognition and behavior in both humans and animals. This is known as the law of primacy. Here, we analyze the neural correlates of primacy in humans by analyzing electrocorticographic recordings in 84 neurosurgical patients as they studied and subsequently recalled lists of common words. We found that spectral power in the gamma frequency band (28-100 Hz) was elevated at the start of the list and gradually subsided, whereas lower frequency (2-8 Hz) delta and theta band power exhibited the opposite trend. This gradual shift in the power spectrum was found across a widespread network of brain regions. The degree to which the subsequent memory effect was modulated by list (serial) position was most pronounced in medial temporal lobe structures. These results suggest that globally increased gamma and decreased delta-theta spectral powers reflect a brain state that predisposes medial temporal lobe structures to enhance the encoding and maintenance of early list items. PMID- 23081882 TI - Structural dynamics of dendritic spines are influenced by an environmental enrichment: an in vivo imaging study. AB - Sensory experience alters neuronal circuits, which is believed to form the basis for learning and memory. On a microscopic level, structural changes of the neuronal network are prominently observable as experience-dependent addition and removal of cortical dendritic spines. By environmental enrichment, we here applied broad sensory stimulation to mice and followed the consequences to dendritic spines in the somatosensory cortex utilizing in vivo microscopy. Additionally to apical dendrites of layer V neurons, which are typically analyzed in in vivo imaging experiments, we investigated basal dendrites of layer II/III neurons and describe for the first time experience-dependent alterations on this population of dendrites. On both classes of cortical dendrites, enriched environment-induced substantial changes determined by increases in density and turnover of dendritic spines. Previously established spines were lost after enriched stimulation. A fraction of experience-induced gained spines survived for weeks, which might therefore be functionally integrated into the neuronal network. Furthermore, we observed an increased density of spines that appeared only transiently. Together, we speculate that the cognitive benefits seen in environmental-enriched animals might be a consequence of both, a higher connectivity of the neuronal network due to more established synapses and an enhanced flexibility due to more transient spines. PMID- 23081883 TI - Number-space interactions in the human parietal cortex: Enlightening the SNARC effect with functional near-infrared spectroscopy. AB - Interactions between numbers and space have become a major issue in cognitive neuroscience, because they suggest that numerical representations might be deeply rooted in cortical networks that also subserve spatial cognition. The spatial numerical association of response codes (SNARC) is the most robust and widely replicated demonstration of the link between numbers and space: in magnitude comparison or parity judgments, participants' reaction times to small numbers are faster with left than right effectors, whereas the converse is found for large numbers. However, despite the massive body of research on number-space interactions, the nature of the SNARC effect remains controversial and no study to date has identified its hemodynamic correlates. Using functional near-infrared spectroscopy, we found a hemodynamic signature of the SNARC effect in the bilateral intraparietal sulcus, a core region for numerical magnitude representation, and left angular gyrus (ANG), a region implicated in verbal number processing. Activation of intraparietal sulcus was also modulated by numerical distance. Our findings point to number semantics as cognitive locus of number-space interactions, thereby revealing the intrinsic spatial nature of numerical magnitude representation. Moreover, the involvement of left ANG is consistent with the mediating role of verbal/cultural factors in shaping interactions between numbers and space. PMID- 23081884 TI - Sustained NMDA receptor hypofunction induces compromised neural systems integration and schizophrenia-like alterations in functional brain networks. AB - Compromised functional integration between cerebral subsystems and dysfunctional brain network organization may underlie the neurocognitive deficits seen in psychiatric disorders. Applying topological measures from network science to brain imaging data allows the quantification of complex brain network connectivity. While this approach has recently been used to further elucidate the nature of brain dysfunction in schizophrenia, the value of applying this approach in preclinical models of psychiatric disease has not been recognized. For the first time, we apply both established and recently derived algorithms from network science (graph theory) to functional brain imaging data from rats treated subchronically with the N-methyl-D-aspartic acid (NMDA) receptor antagonist phencyclidine (PCP). We show that subchronic PCP treatment induces alterations in the global properties of functional brain networks akin to those reported in schizophrenia. Furthermore, we show that subchronic PCP treatment induces compromised functional integration between distributed neural systems, including between the prefrontal cortex and hippocampus, that have established roles in cognition through, in part, the promotion of thalamic dysconnectivity. We also show that subchronic PCP treatment promotes the functional disintegration of discrete cerebral subsystems and also alters the connectivity of neurotransmitter systems strongly implicated in schizophrenia. Therefore, we propose that sustained NMDA receptor hypofunction contributes to the pathophysiology of dysfunctional brain network organization in schizophrenia. PMID- 23081886 TI - Design for learning: adapting the microscopic anatomy laboratory to adult learners. AB - Medical school curricula are undergoing transformational change in response to calls for integrating content across courses and years to enable better retention and application and for individualizing learning to meet the diverse backgrounds and thus differing needs of students. To address the related teaching challenges, faculty can employ solid principles of adult learning and instructional design and use teaching strategies that stimulate different learning styles. We developed laboratory sessions that follow a learner-centered instructional design model we refer to as "PLHET," reflecting the steps of preparing, linking, hooking, engaging, and transferring learning, and also applied teaching strategies that reflect Kolb's four styles of learning (accommodative, divergent, assimilative, and convergent). We utilized a group learning format to promote active learning, teamwork, and self-direction. Preliminary data based on student surveys of laboratory activity show positive responses. In the future, we will test the hypothesis that this design will improve medical students' performance. PMID- 23081885 TI - Fetal brain mTOR signaling activation in tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is characterized by developmental malformations of the cerebral cortex known as tubers, comprised of cells that exhibit enhanced mammalian target of rapamycin (mTOR) signaling. To date, there are no reports of mTORC1 and mTORC2 activation in fetal tubers or in neural progenitor cells lacking Tsc2. We demonstrate mTORC1 activation by immunohistochemical detection of substrates phospho-p70S6K1 (T389) and phospho-S6 (S235/236), and mTORC2 activation by substrates phospho-PKCalpha (S657), phospho-Akt (Ser473), and phospho-SGK1 (S422) in fetal tubers. Then, we show that Tsc2 shRNA knockdown (KD) in mouse neural progenitor cells (mNPCs) in vitro results in enhanced mTORC1 (phospho-S6, phospho-4E-BP1) and mTORC2 (phospho-Akt and phospho-NDRG1) signaling, as well as a doubling of cell size that is rescued by rapamycin, an mTORC1 inhibitor. Tsc2 KD in vivo in the fetal mouse brain by in utero electroporation causes disorganized cortical lamination and increased cell volume that is prevented with rapamycin. We demonstrate for the first time that mTORC1 and mTORC2 signaling is activated in fetal tubers and in mNPCs following Tsc2 KD. These results suggest that inhibition of mTOR pathway signaling during embryogenesis could prevent abnormal brain development in TSC. PMID- 23081887 TI - Giardia diagnostic methods in human fecal samples: a comparative study. AB - Several methods were tried for Giardia detection in stool. This study aimed to compare between the results of ordinary microscopy, direct immunofluorescence assay (DIF), and flow cytometry (FC) for the detection of Giardia cyst in human stool samples. The study included 84 children recruited from outpatient clinics of Mansoura University Children Hospital. Fecal samples were processed and examined for Giardia cysts using conventional microscopy, DIF, and FC. Among 84 fecal samples, 40 (47.6%) were diagnosed as Giardia-positive by saline wet mount, while DIF and FC detected 52 (61.9%), and 38 (45%) Giardia-positive cases, respectively. When compared with DIF as a gold standard method, ordinary microscopy had 76.9% sensitivity and 100% specificity while the FC had a sensitivity of 73.1% and 100% specificity, with statistically significant differences between DIF and the other two methods (P < 0.05). DIF was able to detect as few as 500 cysts/g of concentrated stool, yielding a threshold higher than ordinary microscopy (1,800 cyst/g) even after concentration. It is concluded that direct microscopic examination is reliable in Giardia diagnosis as a first choice test. DIF is an excellent technique in clinically suspected cases after negative microscopy. FC was found to be less sensitive to obtain accurate organisms' count but it could be an effective alternative method for the detection of Giardia cysts, especially for large-scale epidemiological studies or extensive surveillance programs as it has the beneficial attribute of speed and do not depend on an experienced microscope viewer. However, DIF remains the gold standard while FC still requires significant technical improvements before it can compete with DIF for Giardia diagnosis. PMID- 23081888 TI - Cholestatic hepatitis C following liver transplantation: an outcome-based histological definition, clinical predictors, and prognosis. AB - Cholestatic hepatitis C virus (HCV) is a rare form of recurrent HCV following liver transplantation (LT) without specific diagnostic criteria. An outcome-based method to improve its diagnosis and a description of its prognosis are needed. All 1-year post-LT protocol liver biopsy samples and biopsy samples initially reported to show cholestatic HCV from patients transplanted with HCV between February 2002 and December 2009 were reviewed for the inflammation grade, the fibrosis stage, and 4 cholestatic HCV features: ductular proliferation, canalicular cholestasis with or without intracellular cholestasis, hepatocyte swelling with or without lobular disarray, and sinusoidal/pericellular fibrosis. We used patient and graft survival to define histological criteria for cholestatic HCV, and compared the clinical features of these patients to those of patients with minimal or significant post-LT fibrosis. One hundred seventy-nine patients were analyzed, the median age was 56 years, and 73% were male. Patients with 3 or more of the 4 cholestatic HCV criteria had significantly worse survival (log-rank P < 0.001) regardless of the fibrosis stage, and this was used as our novel definition of cholestatic HCV. Using this definition, we found that 27 patients (15%) had cholestatic HCV, 53 (30%) had significant fibrosis (stage >= 2/4), and 99 (55%) had minimal fibrosis (stage < 2/4). The final model for clinical predictors of cholestatic HCV included donor age [odds ratio (OR) = 1.37 per decade, P = 0.04] and previous rejection (Banff grade >= 5; OR = 4.19, P = 0.002). Total bilirubin was the strongest laboratory predictor of cholestatic HCV (area under the curve = 0.93), whereas the HCV viral load was not a significant predictor. The final model of post-LT survival included the pathology group {cholestatic HCV [hazard ratio (HR) = 6.07, P < 0.001] and significant fibrosis (HR = 2.53, P = 0.02)}, donor age (HR = 1.49 per decade, P < 0.001), and cold ischemia time (HR = 1.11 per hour, P = 0.02). In conclusion, we propose diagnostic criteria for cholestatic HCV that include specific criteria (the presence of at least 3 of the 4 histopathological features on biopsy) and other supportive and exclusionary criteria. Older donor age and rejection increase the risk of cholestatic HCV, and an elevation in the total bilirubin level may help to identify these patients. These criteria must be validated prospectively. PMID- 23081889 TI - A boron-containing PAH as a substructure of boron-doped graphene. PMID- 23081890 TI - Traumatic nonanastomotic pseudoaneurysm of axillofemoral bypass graft: a case report and review of the literature. AB - Traumatic nonanastomtic disruption of an axillofemoral bypass graft (AFBG) is a relatively rare entity. However, we are reporting on an 82-year-old female who presented with a pulsating mass on her left side, which was noticed about 2 weeks after she fell on her side. The patient had undergone an ABFG about 15 years earlier for limb revascularization, and she had an occluded aortobifemoral bypass graft. A diagnosis of localized rupture with pseudoaneurysm (PSA) was confirmed with arterial duplex ultrasound and computed tomograph (CT) angiogram scans. A 7 cm PSA with partial disruption of the polytetrafluoroethylene (PTFE) graft at the level of the fifth thoracic vertebrae was noted. An initial work-up to eliminate the possibility of sepsis and localized mycotic seeding was negative. The patient was taken to the hybrid angiogram room, and a percutaneous cut down of the AFBG was performed with local dissection below the site of rupture. A limited angiogram showed a focal PSA of the AFBG. An intravascular ultrasound (IVUS) was performed to calibrate the diameter of the AFBG, and a covered stent was deployed across the area of the disrupted graft. A completion angiogram showed complete exclusion of the PSA with good runoff throughout the graft. The authors will review the management of the traumatic PSA with an endovascular approach. PMID- 23081891 TI - A Mycobacterium bovis mycotic abdominal aortic aneurysm resulting from bladder cancer treatment, resection, and reconstruction with a cryopreserved aortic graft. AB - Mycotic abdominal aortic aneurysms (AAAs) are a clinical challenge for vascular surgeons due to their critical location, surrounding inflammation, risk of rupture, and danger of reinfection following treatment. We present a case of Mycobacterium bovis AAA in a 69-year-old male after treatment with intravesicular bacillus Calmette-Guerin (BCG) therapy for bladder carcinoma. The classical approach for mycotic AAA entails extra-anatomic reconstruction followed by resection with oversewing of the proximal and distal aortic stumps. Alternative in-line reconstruction options have also been advocated. This case illustrates a technically straightforward, durable, in-line repair within an infected field utilizing cryopreserved aortic allograft. PMID- 23081892 TI - Sex differences in developmental programming models. AB - The theory of developmental programming suggests that diseases such as the metabolic syndrome may be 'programmed' by exposure to adverse stimuli during early development. The developmental programming literature encompasses the study of a wide range of suboptimal intrauterine environments in a variety of species and correlates these with diverse phenotypic outcomes in the offspring. At a molecular level, a large number of variables have been measured and suggested as the basis of the programmed phenotype. The range of both dependent and independent variables studied often makes the developmental programming literature complex to interpret and the drawing of definitive conclusions difficult. A common, though under-explored, theme of many developmental programming models is a sex difference in offspring outcomes. This holds true across a range of interventions, including dietary, hypoxic, and surgical models. The molecular and phenotypic outcomes of adverse in utero conditions are often more prominent in male than female offspring, although there is little consideration given to the basis for this observation in most studies. We review the evidence that maternal energy investment in male and female conceptuses may not be equal and may be environment dependent. It is suggested that male and female development could be viewed as separate processes from the time of conception, with differences in both timing and outcomes. PMID- 23081893 TI - Arginine enhances embryo implantation in rats through PI3K/PKB/mTOR/NO signaling pathway during early pregnancy. AB - Our previous study has demonstrated that dietary arginine supplementation during early pregnancy enhanced embryo implantation in rats. However, the mechanism was not clear. The objective of this study was to determine the mechanism that arginine enhanced embryo implantation during early pregnancy. Rats were fed the basal diets supplemented with 1.3% (wt:wt) L-arginine-HCl or 2.2% (wt:wt) L alanine (isonitrogenous control) once pregnancy. On d4 of pregnancy, rats were given intrauterine injection of L-NG-nitro arginine methyl ester (L-NAME, nitric oxide synthase inhibitor), alpha-difluoromethylornithine (DFMO, polyamine synthesis inhibitor), wortmannin (PI3K inhibitor), or rapamycin (mTOR inhibitor). On d7 of pregnancy, rats were killed. Intrauterine injection of L-NAME decreased the implantation sites, while dietary arginine supplementation increased the implantation sites. Intrauterine injection of DFMO decreased the pregnancy rate, which was reversed by dietary arginine supplementation. Intrauterine injection of rapamycin or wortmannin inhibited embryo implantation. However, dietary arginine supplementation did not reverse this inhibition. Western blot analysis revealed that the expression of uterine p-PKB and p-S6K1 was greater in rats fed the arginine-supplemented diet in the presence of L-NAME treatment compared with rats fed the control diet. In the presence of DFMO treatment, the expression of uterine iNOS and eNOS was significantly enhanced in the arginine group compared with the control group. Similarly, intrauterine injection of wortmannin or rapamycin decreased the expression of uterine iNOS and eNOS, which was enhanced by dietary arginine supplementation. These data indicated that dietary arginine supplementation during early pregnancy could enhance embryo implantation through stimulation of PI3K/PKB/mTOR/NO signaling pathway. PMID- 23081894 TI - The in vitro metabolism of cortisol by ovarian follicles of rainbow trout (Oncorhynchus mykiss): comparison with ovulated oocytes and pre-hatch embryos. AB - Mid-vitellogenic stage rainbow trout (Oncorhynchus mykiss) ovarian follicles (both intact and yolk free (YF)), ovulated oocytes and embryos were co-incubated with [2,4,6,7-(3)H]cortisol for 18 h to determine the degree and nature of the metabolism and biotransformation of the glucocorticoid. There was evidence of the conversion of cortisol to the less biologically potent glucocorticoid, cortisone, and the formation of glucocorticoid sulphates (both cortisol and cortisone) for all cell and tissue samples, suggesting the presence of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) and glucocorticoid sulphotransferase (GST) activity at all stages; however, GST activity was particularly marked in both intact and YF ovarian follicles, suggesting an important role of follicles in limiting the exposure of oocyte to maternal cortisol. As there was no evidence of 11beta-HSD or GST activity in ovarian fluid, the findings affirm that ovarian follicles (probably the thecal and granulosa cells) provide a barrier against the transfer of cortisol to the oocytes by forming sulphated steroids, whereas ovulated oocytes and early embryos have a more limited capacity to either metabolize or conjugate cortisol and are therefore more vulnerable at the post-ovulatory and early embryonic stages to increases in exposure to the glucocorticoid. PMID- 23081895 TI - Alteration in localization of steroid hormone receptors and coregulatory proteins in follicles from cows with induced ovarian follicular cysts. AB - Cystic ovarian disease (COD) is an important cause of infertility in cattle. The altered follicular dynamics and cellular differentiation observed in COD may be mediated through a disruption of the expression of steroid receptors and their associated transcriptional cofactors. The aim of this study was to determine the protein expression profiles of ESR1, ESR2, PGR, AR, NCOA3, NCOR2, and PHB2 (REA) in ovarian follicles in an experimental model of COD induced by the administration of ACTH. Ovaries were collected and follicles were dissected from heifers during the follicular phase (control) or from heifers treated with ACTH to induce the formation of ovarian follicular cysts. Ovaries were fixed, sectioned, and stained immunohistochemically for steroid receptors and the associated transcription factors. The relative expression of ESR1 was similar in follicular cysts and in tertiary follicles from both control and cystic cows and was significantly higher than in secondary follicles. The expression of ESR2 in the granulosa was higher in cystic follicles. No differences were seen for PGR. The expression of androgen receptor was significantly increased in tertiary follicles with lower immunostaining in cysts. The expression of NCOA3 was observed in the granulosa and theca with a significantly increased expression in the theca interna of cystic follicles. The highest levels of NCOR2 expression in granulosa, theca interna, and theca externa were observed in cysts. In granulosa cells, NCOR2 levels increase progressively as follicles mature and the treatment had no effect. In summary, ovaries from animals with induced COD exhibited altered steroid receptor expression compared with normal animals, as well as changes in the expression of their regulators. It is reasonable to suggest that in conditions characterized by altered ovulation and follicular persistence, such as COD, changes in the intra-ovarian expression of these proteins could play a role in their pathogenesis. PMID- 23081896 TI - Inhibitors of zinc-dependent metalloproteases hinder sperm passage through the cumulus oophorus during porcine fertilization in vitro. AB - In this study, we report for the first time on a possible contribution of metalloproteases in sperm passage through the cumulus matrix in pigs. The presence of 20 MUM 1,10-phenanthroline (1,10-PHEN), inhibitor of zinc-dependent metalloproteases, strongly inhibited the degree of sperm penetration in cumulus intact (CI), but not in cumulus-free (CF), porcine oocytes during IVF. The inhibitory effect of 1,10-PHEN was due to the chelation of metal ions as a non chelating analog (1,7-PHEN) did not affect IVF rates. Furthermore, incubation with 1,10-PHEN did not affect sperm binding to the zona pellucida nor sperm motility, membrane integrity, or acrosomal status. These findings led to the assumption that 1,10-PHEN interacts with a sperm- or cumulus-derived metalloprotease. Metalloproteases are key players in physiological processes involving degradation or remodeling of extracellular matrix. In vivo, their proteolytic activity is regulated by tissue inhibitors of metalloproteases (TIMP1 TIMP4). We tested the effect of TIMP3 on fertilization parameters after porcine IVF. Similar to 1,10-PHEN, TIMP3 inhibited total fertilization rate of CI but not CF oocytes and did not influence sperm quality parameters. Although the inhibitory effect was stronger in CI oocytes, TIMP3 also reduced the degree of sperm penetration in CF oocytes, suggesting the involvement of a metalloprotease in a subsequent step during fertilization. In conclusion, our results indicate the involvement of TIMP3-sensitive, zinc-dependent metalloprotease activity in sperm passage through the cumulus oophorus in pigs. The results should provide the basis for further biochemical research toward the localization and identification of the metalloprotease involved. PMID- 23081901 TI - Bonding beyond borders: the Nozoe Autograph Books and other collections. PMID- 23081897 TI - GC-MS and GC-IRD studies on the six-ring regioisomeric dimethoxybenzylpiperazines (DMBPs). AB - Gas chromatography with infrared detection (GC-IRD) provides direct confirmatory data for the differentiation between the six regioisomeric aromatic ring substituted dimethoxybenzylpiperazines (DMBPs). These regioisomeric substances are resolved by GC and the vapour-phase infrared spectra clearly differentiate among the six dimethoxybenzyl substitution patterns. The mass spectra for these regioisomeric substances are almost identical. With only the 2,3-dimethoxy isomer showing one unique major fragment ion at m/z 136. Thus mass spectrometry does not provide for the confirmation of identity of any one of these compounds to the exclusion of the other isomers. Perfluoroacylation of the secondary amine nitrogen for each of the six regioisomers gave mass spectra showing some differences in the relative abundance of fragment ions without the appearance of any unique fragments for specific confirmation of structure. Gas chromatography coupled with time-of-flight mass spectrometric detection (GC-TOF) provided an additional means of confirmation of the elemental composition of the major fragment ions in the mass spectra of these compounds. PMID- 23081904 TI - The Nozoe Autograph Books: segment 1. PMID- 23081902 TI - The Nozoe Autograph Books: instructions for data entry website. PMID- 23081905 TI - Bioorthogonal copper-free click chemistry in vivo for tumor-targeted delivery of nanoparticles. PMID- 23081906 TI - Mass spectrometric analysis of EPO IEF-PAGE interfering substances in nitrile examination gloves. AB - Direct detection of doping with recombinant erythropoietins (rhEPO) is accomplished by isoelectric focusing (IEF) or sodium dodecylsulfate (SDS) polyacrylamide gel electrophoresis (PAGE). In a recent publication, Lasne et al. (Electrophoresis 2011, 32, 1444) showed that improper use of nitrile examination gloves during sample collection, sample preparation, and IEF-PAGE may lead to distorted or absent EPO IEF-profiles. In order to clarify which substances are responsible for this observation, a mass spectrometric study on water extractable compounds found in nitrile gloves was performed. Several substance classes were shown to be present, among them polyethylene glycols (PEG), anionic and nonionic surfactants, as well as alcohol ethoxylates and plasticizers. It could be demonstrated that alkylbenzenesulfonates, the main category of detectable anionic detergents, and among them sodium dodecylbenzenesulfonate (SDBS) and its homologs, are the prime reason for the interference of nitrile gloves with EPO IEF-PAGE. PMID- 23081907 TI - The association of health workforce capacity and quality of pediatric care in Afghanistan. AB - OBJECTIVE: To examine the relationship between workforce capacity and quality of pediatric care in outpatient clinics in Afghanistan. DESIGN: Annual national performance assessments were conducted between 2005 and 2008 to determine quality of care through patient observations in >600 health facilities, selected by stratified random sampling each year. Other variables measured were health provider capacity, competency and adequacy of support systems. SETTING: Primary care facilities in 29 provinces in Afghanistan. PARTICIPANTS: Pediatric patients and their caretakers greater than 2400 were selected at random each year. MAIN OUTCOME MEASURES: Index of observed quality of care for patient assessment and counseling based on WHO's Integrated Management of Childhood Illness (IMCI) clinical guidelines. RESULTS: Quality of care improved for all IMCI indices between 2005 and 2008 (IMCI index increased from 43.1 to 56.1; P < 0.001) and was significantly associated with the availability of doctors, IMCI training and knowledge and factors such as provider job satisfaction, availability of clinical guidelines, frequency of supervision and the presence of community councils. There was also a progressive increase in the index summarizing staffing capacity during the study period. Basic health centers increased from 75.6 to 85.5% (P < 0.001), comprehensive health centers increased from 27.9 to 37.9% (P < 0.03) and district hospitals increased from 34.1 to 37.2% (P > 0.05). CONCLUSIONS: Enhancing workforce capacity and competency and ensuring appropriate supervision and systems support mechanisms can contribute to improved quality of care. Although the results indicate sustained improvements over the study period, further research on the mixture of provider skills, competency and factors influencing provider motivation are essential to determine the optimal workforce capacity in Afghanistan. PMID- 23081908 TI - Assessment of infection control practices in maternity units in Southern Nigeria. AB - OBJECTIVE: Puerperal sepsis accounts for 12% of maternal deaths in Nigeria. To date, little is known about the background hospital factors that predispose pregnant women to puerperal infection that leads to mortality. The objective of this study was to investigate the nature and pattern of existing policies and practices relating to infection control in maternity care centres in Edo state, South-South Nigeria. DESIGN: Cross-sectional study consisting of in-depth interviews with service providers, observation of clinical practices and examination of medical records. SETTING: Public and private health-care facilities in eight local government areas (LGAs) selected from the three senatorial districts of Edo State, Nigeria. PARTICIPANTS: Health providers from 63 primary, secondary and tertiary maternity care centres. METHODS: Sixty-three health-care facilities were sampled from eight LGAs from the three senatorial districts in Edo State. Three pre-tested tools were adapted to the local setting and used to interview key informants in the health facilities and to observe for practices and records relating to infection control. RESULTS: Of the 63 health facilities, 68% (43) reported that they had infection control procedures in place, while only 25% (16) reported that they documented these as manuals or charts. Only 13% (8) of facilities had infection control committees; 11% (7) routinely carried out audits of maternal deaths, while 33% (21) reported that they had an ongoing programme for staff training on infection control. A high proportion of the health facilities reported that staff routinely wash their hands before and after sterile procedures, but only half of the facilities were observed to have 24-h running water and only two-thirds had soap and antiseptic solutions in delivery and operating theatre areas. Although more than 90% (57) of the health facilities reported that they use sterile gloves routinely, unused sterile gloves were found in only 60% (38) of these facilities, and recycled gloves in 11.1% (7). CONCLUSION: The results of this study suggest the need for improved record-keeping procedures, the development of appropriate policies and protocols for infection control and staff training on infection control in maternity care facilities in Edo State. A public health education and advocacy programme to create awareness on clean delivery places as an approach for reducing maternal morbidity and mortality and to build political will for implementing related activities is also urgently needed. PMID- 23081909 TI - A phylogenetic approach to ontogeny and heterochrony in the fossil record: cranial evolution and development in anguimorphan lizards (Reptilia: Squamata). AB - The incorporation of ontogeny into the interpretation of the vertebrate fossil record promises major advances in palaeontology, systematics, and macroevolution. Here, a key additional component, the incorporation of phylogenetic bracketing into ontogenetic considerations, is demonstrated using cranial anatomy in anguimorphan lizards, a diverse modern clade with an extensive fossil record. The obstacles of fragmentary disarticulated fossil material and low representation in museum collections are overcome by using detailed analysis of individual elements and binning into broad ontogenetic stages, respectively. Results indicate the prevalence of classical macroevolutionary phenomena, notably heterochrony and homoplasy (convergence), throughout anguimorphan evolution. Furthermore, two problematic fossil anguimorph taxa are examined, both of which are unusually small for their clades, suggesting either immaturity or dwarfism. Using extant phylogenetic brackets of ontogenetic trajectories to distinguish between these hypotheses, it is shown that the holotype of one of these taxa is indeed a juvenile (also calling into question its taxonomy) and that the other is a dwarf. It is expected that a phylogenetic approach to ontogeny will yield similar insights across a broad range of fossil and extant organisms. PMID- 23081911 TI - Frustrated Lewis pair induced boroauration of terminal alkynes. PMID- 23081912 TI - Fungicide prochloraz and environmental pollutant dioxin induce the ABCG2 transporter in bovine mammary epithelial cells by the arylhydrocarbon receptor signaling pathway. AB - The molecular mechanisms by which environmental pollutants including 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) or widely used imidazole fungicide prochloraz display their toxic effects in vertebrates are still not well understood. Using computer analysis, we recently identified nuclear aryl hydrocarbon receptor (AhR) binding sites termed "dioxin response elements" (DREs) in the 5'-untranslated region (5'-UTR) of efflux transporter ABCG2 (Accession No. EU570105) from the bovine mammary gland. As these regulatory motifs mediate regulation of target genes by AhR agonists including TCDD and prochloraz, we have systematically investigated the effect of both contaminants on functional ABCG2 transport activity in primary bovine mammary epithelial cells. TCDD or prochloraz doubled ABCG2-mediated Hoechst H33342 secretion. This effect was almost completely reversed by specific ABCG2 inhibitor Ko143. In further mechanistic studies, we showed that this induction was due to binding of activated AhR to DRE sequences in the ABCG2 5'-UTR. Receptor binding was significantly reduced by specific AhR antagonist salicyl amide. Induction of AhR by TCDD and prochloraz resulted in a time- and dose-dependent increase of ABCG2 gene expression and transporter protein levels. As ABCG2 represents the main mammary transporter for xenobiotics including drugs and toxins, exposure to prevalent AhR agonists may enhance transporter-mediated secretion of potential harmful compounds into milk. Through identification of mammary ABCG2 as a novel target gene of pesticide prochloraz and dioxin, our results may therefore help to improve the protection of breast feeding infants and the consumer of dairy products. PMID- 23081913 TI - Identification of recombinant human relaxin-2 in equine plasma by liquid chromatography-high resolution mass spectrometry. AB - Relaxin (RLX) is a peptide hormone belonging to the relaxin-like peptide family. Relaxin-2 (RLX-2), a heteromeric polypeptide consisting of an A-chain (24 amino acids) and a B-chain (29 amino acids) linked together by two inter-chain disulfide bonds, is the main circulating RLX hormone in human. Due to its ability to dilate blood vessels surrounding the smooth muscles via induction of nitric oxide resulting in the increase of blood and oxygen supplies to the muscles, it may enhance athletic performance and is therefore banned in horseracing, equestrian competitions, and human sports. In order to control the abuse of rhRLX 2, a definitive method is required to detect and confirm the presence of rhRLX-2 in biological samples. This paper describes, for the first time, the detection and confirmation of rhRLX-2 in equine plasma by liquid chromatography-high resolution mass spectrometry (LC-HRMS) after immunoaffinity extraction. rhRLX-2 could be detected at less than 0.1 ng/ml, and confirmed at less than 0.2 ng/ml in plasma samples. PMID- 23081914 TI - Bioactive natural products from Papua New Guinea marine sponges. AB - The discovery of novel natural products for drug development relies heavily upon a rich biodiversity, of which the marine environment is an obvious example. Marine natural product research has spawned several drugs and many other candidates, some of which are the focus of current clinical trials. The sponge megadiversity of Papua New Guinea is a rich but underexplored source of bioactive natural products. Here, we review some of the many natural products derived from PNG sponges with an emphasis on those with interesting biological activity and, therefore, drug potential. Many bioactive natural products discussed here appear to be derived from non-ribosomal peptide and polyketide biosynthesis pathways, strongly suggesting a microbial origin of these compounds. With this in mind, we also explore the notion of sponge-symbiont biosynthesis of these bioactive compounds and present examples to support the working hypothesis. PMID- 23081915 TI - Flavonoids in subtribe Centaureinae (Cass.) Dumort. (tribe Cardueae, Asteraceae): distribution and (13)C-NMR spectral data. AB - This review reports the occurrence of flavonoids in subtribe Centaureinae of Asteraceae family. It extensively covers the literature up to 2010 and collects all available (13)C-NMR data. PMID- 23081916 TI - Small organic solutes in sticky droplets from orb webs of the spider Zygiella atrica (Araneae; Araneidae): beta-alaninamide is a novel and abundant component. AB - In northeastern North America, Zygiella atrica often build their orb webs near the ocean. We analyzed individual field-built Z. atrica webs to determine if organic low-molecular-mass solutes (LMM) in their sticky droplets showed any unusual features not previously seen in orb webs of other species living in less salty environments. While two of the three most abundant organic LMM (putrescine (butane-1,4-diamine) and GABamide (4-aminobutanamide)) are already well-known from webs of inland spiders, the third major LMM, beta-alaninamide (3 aminopropanamide), a homolog of GABamide, has not been detected in sticky droplets from any other araneoid spiders (27 species). It remains to be established, however, whether or not use of beta-alaninamide is related to proximity to saltwater. We observed variability in organic LMM composition in Z. atrica webs that appeared to be influenced more by an undetermined factor associated with different collecting locations and/or collection dates than by different genders or instars. Shifts in composition when adult females were transferred from the field to the laboratory were also observed. Structural similarities and inverse correlations among beta-alaninamide, GABamide, and N acetylputrescine suggest that they may form a series of LMM fulfilling essentially the same, as yet unknown, role in the webs of those species in which they occur. PMID- 23081917 TI - Water-soluble cationic derivatives of indirubin, the active anticancer component from Indigo naturalis. AB - To overcome the problem of poor aqueous solubility and bioavailability of indirubin-3-oximes, the compounds were modified by attaching a quaternary ammonium group at the oxime moiety. Exploring the prodrug concept, an oxime ester with acetyl-l-carnitine was prepared, and the rate of its hydrolysis was investigated to assess its suitability for clinical administration. In addition, the cytotoxic potency of new stable oxime ethers with a choline moiety and their influence on the cell cycle were tested in human cancer cell lines. PMID- 23081918 TI - Synthesis, and in vitro enzymatic and antiviral evaluation of d4T polyphosphate derivatives as chain terminators. AB - A series of d4T di- or triphosphate derivatives have been synthesized and evaluated as effective substrates for HIV-1 RT, and also tested for their in vitro anti-HIV activity. The steady-state kinetic study of compounds 1-4 in an enzymatic incorporation assay by HIV-1 RT follows Michaelis-Menten profile. In addition, compounds 2-4 are able to inhibit HIV-1 replication to the same extent as d4T and d4TMP in MT-4 cells, as well as in CEM/0 cells and CEM/TK(-) cells. The data suggests that these d4T polyphosphate derivatives are hydrolyzed to d4T and rephosphorylated to d4TTP before exerting their antiviral activity. PMID- 23081919 TI - Novel zierane- and guaiane-type sesquiterpenes from the root of Melicope denhamii. AB - Two novel zierane-type sesquiterpenes, named melicodenones A and B (1 and 2, resp.), and three new guaiane-type sesquiterpenes, named melicodenones C-E (3-5), were isolated from the root of Melicope denhamii (Seem.) T. G. Hartley together with zierone (6). Their structures were established by extensive NMR spectroscopic analyses. Compounds 1-6 were tested for cytotoxicity using human colon cancer DLD-1 cells, and melicodenone A (1) was found to exhibit moderate activity. PMID- 23081920 TI - Cytotoxic activity of fungal strains isolated from the ascidian Eudistoma vannamei. AB - The cytotoxic activity at 50 MUg/ml of extracts obtained from eleven fungal strains associated to Eudistoma vannamei, an endemic ascidian from Northeast Brazil, against two cell lines, i.e., the HCT-8 (colon cancer) and the MDA-MB-435 (melanoma) cell lines, was investigated. The most promising extract (EV10) was obtained from a fungus identified as Aspergillus sp. by molecular analysis and was selected for bioassay-guided isolation of its active principals. Large-scale fermentation of EV10 in potato-dextrose broth followed by chromatographic purification of the active extract from the liquid medium allowed the isolation of the isocoumarins mellein, cis-4-hydroxymellein, and trans-4-hydroxymellein, besides penicillic acid. All isolated compounds were tested for their cytotoxicity against the tumor cell lines MDA-MB-435 and HCT-8 and revealed penicillic acid as the only cytotoxic compound (cell growth inhibitions >95%). PMID- 23081921 TI - Chemical diversity of wild growing Origanum majorana in Cyprus. AB - The present work aims at tracing the essential-oil diversity of wild growing Origanum majorana plants in Cyprus. The study of six populations scattered over the western part of the island has shown that the essential oils were rich either in trans-sabinene hydrate/terpinen-4-ol or in alpha-terpineol/trans-sabinene hydrate. The former oil type is more common and responsible for the typical marjoram odor of the plants. The comparison of our results with published data concerning wild and cultivated O. majorana showed that the oil composition of the Cypriot populations had not been reported from wild plants from other parts of the Mediterranean region, while it is very common among the cultivated plants. Thus, it seems probable that the nowadays cultivated marjoram may originate from Cypriot wild populations. PMID- 23081922 TI - Cytotoxic tetraprenylated alkaloids from the South China Sea gorgonian Euplexaura robusta. AB - Nine achiral tetraprenylated alkaloids, including three new compounds, named malonganenones I-K (1-3, resp.), together with six known analogs, 4-9, were isolated from the gorgonian Euplexaura robusta collected from Weizhou Island of Guangxi Province, China. The structures of compounds 1-3 were elucidated by extensive spectral analyses, especially of their 1D- and 2D-NMR data. Compounds 1, 4, 6, and 7 showed moderate cytotoxicities against K562 and HeLa tumor cell lines with IC(50) values ranging from 0.35 to 10.82 MUM. Compound 6 also showed moderate inhibitory activity against c-Met kinase at a concentration of 10 MUM. PMID- 23081923 TI - Increased humoral immune responses of pigs to foot-and-mouth disease vaccine supplemented with ginseng stem and leaf saponins. AB - Vaccination is a conventional approach against foot-and-mouth disease (FMD) in pigs. However, failure to elicit an immune response to vaccine has been reported. Our previous investigation showed that ginseng stem and leaf saponins (GSLS) and mineral oil acted synergistically to promote Th1/Th2 immune responses to FMD vaccine in mice. This study was designed to i) find the optimal doses of GSLS in oil-emulsified FMD vaccines to induce immune responses in mice and pigs and ii) to evaluate the effect of oil-emulsified FMD vaccine supplemented with GSLS on the immune responses in pigs, by measuring the serum indirect hemagglutination (IHA) titer and IgG and IgG subclass levels. The GSLS-enhanced immune response to FMD oil-emulsion vaccine depended on the dose of GSLS added to the vaccine. Addition of GSLS at a dose of 40 MUg to 2 ml of FMD oil-emulsified vaccine significantly enhanced the humoral immune responses in pigs, when compared to the vaccine without GSLS (P<0.05). The increased antibodies included IgG1 and IgG2. Hence, GSLS and oil adjuvant synergistically promoted the immune responses to vaccination against FMD in pigs, and GSLS could be a promising vaccine additive to improve oil-emulsified veterinary vaccines. PMID- 23081924 TI - Sulfur-containing ferrocenyl alcohols and oximes: new promising antistaphylococcal agents. AB - A small library containing four different series of new ferrocene derivatives, 2 (alkylsulfanyl)-1-ferrocenylethan-1-ols, 3-(alkylsulfanyl)-1-ferrocenylpropan-1 ols, (E)- and (Z)-2-(alkylsulfanyl)-1-ferrocenylethan-1-one oximes, and (E)- and (Z)-3-(alkylsulfanyl)-1-ferrocenylpropan-1-one oximes (36 different compounds in total) was synthesized starting from ferrocene and the corresponding sulfanyl acids. All compounds were spectrally (IR and NMR) and electrochemically characterized. In general, the obtained compounds were found to exhibit very strong antimicrobial activities (broth microdilution assay) against the tested microorganisms (six common human pathogens). For the majority of the tested compounds, the determined MIC values were either under the 10 MUg/ml MIC limit recognized to delimit efficient antimicrobials or were comparable to/lower than those of the used positive controls (tetracycline/nystatin). The most susceptible organism was found to be Staphylococcus aureus with MIC values even reaching 0.001 MUg/ml. The presence of -CH(OH)(CH(2))(n)S- and -CH(=NOH)(CH(2))(n)S- (n=1 or 2) structural fragments seems to be essential for the observed strong activity (introduction of hydroxyimino and alcohol functionalities, instead of the keto function, resulted in a more than 10(5)-fold increase in antistaphylococcal activity in some instances). Nevertheless, a possible influence of the ferrocenyl core redox chemistry (Fe(2+)/Fe(3+)) should not be disregarded. The studied alcohols exhibited a reversible one-electron redox couple at almost the same position as ferrocene, while the hydroxyimino group conjugated with cyclopentadienyl ring considerably shifted the redox potential of the ferrocene unit in oximes. PMID- 23081925 TI - Bioactive sesquiterpenoids and diterpenoids from the liverwort Bazzania albifolia. AB - One undescribed 6,7-secofusicoccane-type diterpene, albifolione (1), and one new aromadendrane-type sesquiterpenoid ketone, methyl 2-oxoaromadendra-1(10),3-dien 12-oate (2), along with four known compounds, delta-cuparenol (3), fusicoauritone (4), chiloscyphenols A and B (5 and 6, resp.), were isolated from the liverwort Bazzania albifolia Horik. The structures and relative configurations of 1 and 2 were established unequivocally on the basis of spectroscopic data analysis. Preliminary bioassay revealed that compound 5 showed quite strong cytotoxicity against the human tumor cell line MCF-7, with an IC(50) value of 5.6 MUM. PMID- 23081926 TI - 2-Hydroxynaphthalene-1-carbaldehyde- and 2-(aminomethyl)pyridine-based Schiff base Cu(II) complexes for DNA binding and cleavage. AB - Three mononuclear Cu(II) complexes, [CuCl(naph-pa)] (1), [Cu(bipy)(naph-pa)]Cl (2), and [Cu(naph-pa)(phen)]Cl (3) ((naph-pa)=Schiff base derived from the condensation of 2-hydroxynaphthalene-1-carbaldehyde and 2-picolylamine (=2 (aminomethyl)pyridine), bipy=2,2'-bypiridine, and phen=1,10-phenanthroline) were synthesized and characterized. Complex 1 exhibits square-planar geometry, and 2 and 3 exhibit square pyramidal geometry, where Schiff base and bipy/phen act as NNO and as NN donor ligands, respectively. CT (Calf thymus)-DNA-binding studies revealed that the complexes bind through intercalative mode and show good binding propensity (intrinsic binding constant K(b): 0.98*10(5), 2.22*10(5), and 2.67*10(5) M(-1) for 1-3, resp.). The oxidative and hydrolytic DNA-cleavage activity of these complexes has been studied by gel electrophoresis: all the complexes displayed chemical nuclease activity in the presence and absence of H(2)O(2). From the kinetic experiments, hydrolytic DNA cleavage rate constants were determined as 2.48, 3.32, and 4.10 h(-1) for 1-3, respectively. It amounts to (0.68-1.14)*10(8)-fold rate enhancement compared to non-catalyzed DNA cleavage, which is impressive. The complexes display binding and cleavage propensity to DNA in the order of 3>2>1. PMID- 23081927 TI - Variation in terpene and linear-chain hydrocarbon content in yarrow (Achillea millefolium L.) germplasm from the Rhaetian Alps, Italy. AB - Yarrow (Achillea millefolium L.) is a herbaceous species common in the Alpine region of Europe and used in folk medicine since antiquity. Its organs are rich in monoterpenes and sesquiterpenes, two subclasses of plant terpenoids with relevant ecological significance, which were reported as valuable markers for the traceability of mountain dairy products. The variability in chemical composition of yarrow germplasm may be related with its genetic diversity, accounting for possible differences in medical properties, and supporting its use as a specific territorial marker. Aim of this work was to assess the leaf chemical composition of 16 yarrow populations collected at altitudes exceeding 1600 m in three valleys of the Rhaetian Alps, Italy, and jointly evaluated in a lowland site. The most abundant compounds detected generally differed from those of the germplasm from other countries. A trend of valley-specific pattern of composition was evident. However, the variability among individual populations was even more remarkable, regardless of their valley of origin. The concentrations of sesquiterpene hydrocarbons, oxygenated monoterpenes, and oxygenated sesquiterpenes discriminated the populations in multivariate analysis. A few prevailing chemotypes were characterized, which differed from those previously reported in the literature. The geographic isolation from other germplasms, and the local ecotypization, likely originated a chemically distinct gene pool. PMID- 23081928 TI - Studies on chemical-structure modification and structure-activity relationship of gambogic acid derivatives at carbon(34). AB - Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structure-activity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB 231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC(50) values ranging between 0.24 and 1.09 MUM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents. PMID- 23081929 TI - High diversity of indigenous populations of dalmatian sage (Salvia officinalis L.) in essential-oil composition. AB - Essential oils of 25 indigenous populations of Dalmatian sage (Salvia officinalis L.) that represent nearly half of native distribution area of the species were analyzed. Plantlets collected from wild populations were grown in the same field under the same environmental conditions and then sampled for essential-oil analysis. The yield of essential oil ranged from 1.93 to 3.70% with average of 2.83%. Among the 62 compounds detected, eight (cis-thujone, camphor, trans thujone, 1,8-cineole, beta-pinene, camphene, borneol, and bornyl acetate) formed 78.13-87.33% of essential oils of individual populations. Strong positive correlations were observed between camphor and beta-pinene, beta-pinene and borneol, as well as between borneol and bornyl acetate. The strongest negative correlation was detected between camphor and trans-thujone. Principal component analysis (PCA) on the basis of eight main compounds showed that first main component separated populations with high thujone content, from those rich in camphor, while the second component separated populations rich in cis-thujone from those rich in trans-thujone. Cluster analysis (CA) led to the identification of three chemotypes of S. officinalis populations: cis-thujone; trans-tujone, and camphor/beta-pinene/borneol/bornyl acetate. We propose that differences in essential oils of 25 populations are mostly genetically controlled, since potential environmental factors were controlled in this study. PMID- 23081930 TI - Chemical composition of Hypericum rumeliacum Boiss. essential oil. A new chemotype of this pharmacologically valuable species? AB - Analysis by GC and GC/MS of the essential-oil samples obtained from dry above ground parts of Hypericum rumeliacum Boiss. (collected in the flowering and fruit forming vegetative stages) allowed the identification of 212 components in total, comprising >=97.8% of the total oil composition. In the flowering phase, the major identified volatile compounds were undecane (6.6%), dodecanal (10.8%), and germacrene D (14.1%), whereas alpha-pinene (7.3%), beta-pinene (26.1%), (Z)-beta ocimene (8.5%), (E)-beta-ocimene (10.2%), bicyclogermacrene (7.7%), and germacrene D (15.1%) were dominant in the fruit-forming phase. Some of the minor constituents found in the studied oil samples (e.g., a homologous series of four 6-alkyl-5,6-dihydro-2H-pyran-2-ones, i.e., massoia dodeca-, trideca-, tetradeca-, and hexadecalactones) have a restricted occurrence in the Plant Kingdom, and their presence in Hypericum L. spp. has not been previously reported. The chemical compositions of the herein studied additional 34 oils obtained from selected Hypericum taxa were compared using multivariate statistical analysis (agglomerative hierarchical cluster analysis and principal component analysis). The results of these statistical analyses could not be used to either confirm or discard the existence of different H. rumeliacum chemotypes. However, they have implied that the volatile profile of this plant species is determined by the stage of its phenological development. PMID- 23081931 TI - Amido-bridged nucleic acids (AmNAs): synthesis, duplex stability, nuclease resistance, and in vitro antisense potency. PMID- 23081932 TI - Sample size determination for clinical trials with co-primary outcomes: exponential event times. AB - Clinical trials with event-time outcomes as co-primary contrasts are common in many areas such as infectious disease, oncology, and cardiovascular disease. We discuss methods for calculating the sample size for randomized superiority clinical trials with two correlated time-to-event outcomes as co-primary contrasts when the time-to-event outcomes are exponentially distributed. The approach is simple and easily applied in practice. PMID- 23081933 TI - Analysis of 30 synthetic cannabinoids in oral fluid using liquid chromatography electrospray ionization tandem mass spectrometry. AB - In recent years, the analysis of synthetic cannabinoids in human specimens has gained enormous importance in the broad field of drug testing. Nevertheless, the considerable structural diversity among synthetic cannabinoids already identified in 'herbal mixtures' hampers the development of comprehensive analytical methods. As the identification of the main metabolites of newly appearing substances is very laborious and time-consuming, the detection of the parent compounds in blood samples is the current approach of choice for drug abstinence testing. Whenever blood sampling is not possible however, the need for alternative matrices arises. In this article, we present a fully validated liquid chromatography-electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for the analysis of 30 synthetic cannabinoids in oral fluid samples collected with the Drager DCD 5000 collection device. The method proved to be suitable for the quantification of 28 substances. The limits of detection were in the range from 0.015 to 0.9 ng/ml, while the lower limits of quantification ranged from 0.15 to 3.0 ng/ml. The method was successfully applied to 264 authentic samples during routine analysis. A total of 31 samples (12%) was tested positive for at least one of the following synthetic cannabinoids: AM-694, AM-2201, JWH-018, JWH-019, JWH-081, JWH-122, JWH 203, JWH-210, JWH-250, JWH-307, MAM-2201, and RCS-4. Given that stabilization of the collection pads after sampling is warranted, the collection device provides satisfactory sensitivity. Hence, whenever blood sampling is not possible, the Drager DCD 5000 collection device offers a good tool for the analysis of synthetic cannabinoids in oral fluid in the broad field of drug testing. PMID- 23081934 TI - Pine nut allergy: clinical features and major allergens characterization. AB - SCOPE: The aims of this study were to evaluate IgE-mediated hypersensitivity to pine nut with details of clinical reactions and to characterize major pine nut allergens. METHODS AND RESULTS: The study included ten consecutive teenagers and adults diagnosed with IgE-mediated clinical allergy to pine nut. Two major pine nut allergens were purified and identified and the secondary structures and susceptibility to digestion were characterized. Severe reactions represent 80% of allergic reactions to pine nut in this study. Moreover, 70% of the patients were monosensitized to this nut. Two major allergens with molecular weights of 6 and 50 kDa were purified and identified as albumin and vicilin, respectively. The 6 kDa protein (albumin), rich in alpha-helix content, was far more stable to peptic and tryptic digestion as compared with 50 kDa protein (vicilin), which was quickly broken down. The secondary structure of the purified 50 kDa protein showed 41% beta-sheet, 5% alpha-helix, and 54% random coil and/or loops. CONCLUSION: Eighty percent of allergic reactions to pine nut in the ten patients included in this study were severe. Most patients (70%) were monosensitized to this nut. Two major allergens with molecular weights of 6 and 50 kDa were purified and identified as albumin and vicilin, respectively. PMID- 23081936 TI - Impact of quantitative feedback and benchmark selection on radiation use by cardiologists performing cardiac angiography. AB - Audit of and feedback on both group and individual data provided immediately after the point of care and compared with realistic benchmarks of excellence have been demonstrated to drive change. This study sought to evaluate the impact of immediate benchmarked quantitative case-based performance feedback on the clinical practice of cardiologists practicing at a private hospital in Brisbane, Australia. The participating cardiologists were assigned to one of two groups: Group 1 received patient and procedural details for review and Group 2 received Group 1 data plus detailed radiation data relating to the procedures and comparative benchmarks. In Group 2, Linear-by-Linear Association analysis suggests a link between change in radiation use and initial radiation dose category (p=0.014) with only those initially 'challenged' by the benchmarks showing improvement. Those not 'challenged' by the benchmarks deteriorated in performance compared with those starting well below the benchmarks showing greatest increase in radiation use. Conversely, those blinded to their radiation use (Group 1) showed general improvement in radiation use throughout the study compared with those performing initially close to the benchmarks showing greatest improvement. This study shows that use of non-challenging benchmarks in case based radiation risk feedback does not promote a reduction in radiation use; indeed, it may contribute to increased doses. Paradoxically, cardiologists who are aware of performance monitoring but blinded to individual case data appear to maintain, if not reduce, their radiation use. PMID- 23081935 TI - Altered infant feeding patterns in boys with acquired nonsyndromic cryptorchidism. AB - BACKGROUND: Genetic and environmental factors likely influence susceptibility to nonsyndromic cryptorchidism, a common disease presenting at birth or in later childhood. We compared cases and controls to define differential risk factors for congenital versus acquired cryptorchidism. METHODS: We compared questionnaire and clinical data from cases of congenital cryptorchidism (n = 230), acquired cryptorchidism (n = 182) and hernia/hydrocele (n = 104) with a group of healthy male controls (n = 358). Potential predictor variables (p < 0.2 in univariable analysis) were included in stepwise multivariable logistic regression models. RESULTS: Temporary (odds ratio [OR], 0.5; 95% confidence interval [CI], 0.4-0.8) or exclusive (OR, 0.6; 95% CI, 0.4-0.9) breastfeeding was reduced and soy formula feeding increased (OR, 1.8; 95% CI, 1.2-2.9) in acquired but not congenital or hernia/hydrocele groups. The highest risk estimates were observed for primary soy formula feeding with limited or no breastfeeding (OR 2.5; 95% CI, 1.4-4.3; adjusted OR, 2.7; 95% CI, 1.4-5.4) in the acquired group. Primary feeding risk estimates were equivalent or strengthened when multivariable models were limited to age greater than 2 years, full-term or not small for gestational age, or Caucasian subjects. Pregnancy complications and increased maternal exposure to cosmetic or household chemicals were not consistently associated with either form of cryptorchidism in these models. CONCLUSIONS: Our data support reduced breastfeeding and soy formula feeding as potential risk factors for acquired cryptorchidism. Although additional studies are needed, hormonally active components of breast milk and soy formula could influence the establishment of normal testis position in the first months of life, leading to apparent ascent of testes in childhood. Birth Defects Research (Part A), 2012. PMID- 23081937 TI - Coupling reaction of indolepyruvic acid by StaD and its product: implications for biosynthesis of indolocarbazole and violacein. PMID- 23081939 TI - Improved and emerging gel-free separation and detection methods for proteomics. PMID- 23081944 TI - Resequencing of VAX1 in patients with nonsyndromic cleft lip with or without cleft palate. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common of all congenital anomalies, and has a multifactorial etiology involving both environmental and genetic factors. Recent genome-wide association studies (GWAS) identified strong association between a locus on chromosome 10q25.3 and NSCL/P in European samples. One gene at 10q25.3, the ventral anterior homeobox 1 (VAX1) gene, is considered a strong candidate gene for craniofacial malformations. The purpose of the present study was to provide further evidence that VAX1 is the causal gene at the 10q25.3 locus through identification of an excess of rare mutations in patients with NSCL/P. METHODS: The 5'UTR, complete coding regions, and adjacent splice sites of the two known VAX1 isoforms were sequenced in 384 patients with NSCL/P and 384 controls of Central European descent. Observed variants were investigated with respect to familial cosegregation or de novo occurrence, and in silico analyses were performed to identify putative effects on the transcript or protein level. RESULTS: Eighteen single-base variants were found, 15 of them rare and previously unreported. In the long VAX1 isoform, predicted functionally relevant variants were observed more often in NSCL/P cases, although this difference was not significant (p = 0.17). Analysis of family members demonstrated incomplete cosegregation in most pedigrees. CONCLUSION: Our data do not support the hypothesis that highly penetrant rare variants in VAX1 are a cause of NSCL/P. To determine whether VAX1 is the causative gene at 10q25.3 further research, in particular into the biologic function of its long isoform, is warranted. Birth Defects Research (Part A), 2012. PMID- 23081945 TI - A peptide photoaffinity probe specific for the active conformation of the Abl tyrosine kinase. PMID- 23081946 TI - In vivo kinematics of high-flex mobile-bearing total knee arthroplasty, with a new post-cam design, in deep knee bending motion. AB - PURPOSE: The objective of this study was to evaluate the in vivo knee kinematics to assess the available functional motion of the characteristic mobile-bearing prosthesis design and to examine whether the artificial joint would work in vivo according to its design concept. METHODS: We studied 14 knees (11 patients) implanted with the Vanguard RP Hi-Flex prosthesis. This prosthesis has a highly original form of post-cam called a PS saddle design with high compatibility, and with a rotating plate mobile-bearing mechanism. The cylinder-type post-cam is designed to enable contact in early flexion ranges, and to prevent paradoxical anterior femoral component movement. Each patient performed weight-bearing deep knee bending under fluoroscopic surveillance. Motion between each component including the polyethylene insert was analyzed using the 2D/3D registration technique. RESULTS: The mean range of motion was 122.0 degrees . The mean femoral component rotation for the tibial tray was 5.0 degrees . No paradoxical anterior movement of the nearest point was confirmed between the femoral component and the tibial tray in the early flexion ranges. Initial contact of the post-cam was confirmed at a knee flexion angle of 33.8 degrees . Subsequently, the wide contact of the post-cam was maintained until flexion reached 120 degrees in all knees, but disengagement of the post-cam was observed in two knees when flexion was >=130 degrees . CONCLUSIONS: The results of this study demonstrated that the prosthesis design generally works in vivo as intended by its design concept. The present kinematic data may provide useful information for improvement of high flex type prostheses. PMID- 23081947 TI - Chlorine-enhanced surface mobility of Au(100). AB - Motivated by experimental studies of two-dimensional Ostwald ripening on Au(100) electrodes in chlorine-containing electrolytes, we have studied diffusion processes using density functional theory. We find that chlorine has a propensity to temporary form AuCl complexes, which diffuse significantly faster than gold adatoms. With and without chlorine, the lowest activation energy is found for the exchange mechanism. Chlorine furthermore reduces the activation energy for the detachment from kink sites. Kinetic Monte Carlo simulations were performed on the basis of extensive density functional theory calculations. The island-decay rate obtained from these Monte Carlo simulations, as well as the decay rate obtained from the theoretical activation energies and frequency factors when inserted into analytical solutions for Ostwald ripening, are in agreement with experimental island-decay rates in chlorine-containing electrolytes. PMID- 23081950 TI - Gene therapy awaits approval in Europe: gene transfer offers both promise and peril for children with some genetic diseases. PMID- 23081951 TI - RASopathy diagnosis advances: quick, accurate diagnoses are now commonplace. PMID- 23081953 TI - Limitation of diffusion effects in ultrafast 2D nuclear magnetic resonance by encapsulation of analytes in phospholipidic vesicles. AB - Increased sensitivity: A new sample-preparation procedure is described to limit molecular diffusion effects in NMR experiments. It is based on analyte encapsulation in liposomes and is particularly useful for ultrafast multidimensional NMR experiments. PMID- 23081954 TI - Impact of contrast-enhanced intraoperative ultrasound on operation strategy in case of colorectal liver metastasis. AB - BACKGROUND: Surgical treatment is the only option for long-term survival in patients with colorectal liver metastasis (CRLM). Contrast-enhanced CT and MRI are usually used for preoperative liver imaging. The initial surgical strategy for liver resection is based upon these findings. Further optimization of the surgical strategy by contrast-enhanced intraoperative ultrasound (CE-IOUS) might further improve the surgical outcome. PURPOSE: To evaluate the current impact of CE-IOUS with SonoVue((r)) on the initial surgical strategy for CRLM. MATERIAL AND METHODS: Eighty-six consecutive patients undergoing open liver resection for CRLM were evaluated retrospectively over a 2.5-year period. The patients underwent 97 operations. Preoperative staging was performed with contrast-enhanced CT in all patients and MRI was available in 66 of 86 patients. CE-IOUS was performed in all patients according to a standardized examination technique. Curved array and linear transducers were used. CRLM were identified in venous phase as hypovascular lesions. CE-IOUS findings were compared with preoperative staging. RESULTS: Combined CT/MRI identified preoperatively 328 CRLM (mean 3.4, range 0 14). Seventy-two additional lesions (18%) were identified in 38 patients during the operation. Intraoperatively 41 additional CRLM in 20 patients were identified by inspection, palpation, and CE-IOUS (10%), and another 31 CRLM in 17 patients were identified by CE-IOUS alone (8%). All additional CRLM detected by CE-IOUS were confirmed by histology if resection was performed. CE-IOUS changed planned operation strategy in 29.9% of operations. A larger resection was necessary in 13.4% of the cases, reduced liver resection was found sufficient in 11.3%, and 5.2% were found inoperable. For patients diagnosed preoperatively with solitary lesions CE-IOUS changed operation strategy in 19% and radical tumor resection would have failed in 4.8% without CE-IOUS. CONCLUSION: CE-IOUS is essential to ensure optimal and complete tumor resection both in patient with solitary CRLM and multiple metastases. PMID- 23081955 TI - Clinical and CT manifestation of pleural schwannoma. AB - BACKGROUND: A schwannoma arising from the pleura is rare. The computer tomography (CT) features, however, have seldom been disclosed in the English literature. PURPOSE: To retrospectively assess the role of CT in the diagnosis of pleural schwannomas. MATERIAL AND METHODS: Eleven patients with pathologically confirmed pleural schwannomas were included in the study. CT images and clinical data were analyzed. The CT features emphasized included the location of the neoplasm, as well as its diameter, origin, margin, shape, attenuation, enhancement pattern, and extent and invasion into adjacent structures, all of which were observed and recorded. RESULTS: Seven patients were men, while four were women; patients were aged 21-60 years, with a mean age of 45 years. Most cases were incidentally detected. Seven cases involved neoplasms located in the right hemithorax whereas four cases involved neoplasms in the left hemithorax. The mean tumor diameter was 4.4 cm (range, 2.3-6.4 cm). All of the tumors were solitary and well-defined ovoid (n = 7) or round (n = 4) in shape. The schwannomas showed isoattenuation (four cases) or mild hypoattenuation (seven cases) to the chest wall muscle on unenhanced CT. All cases showed minimal enhancement on contrast-medium-enhanced CT. Two bony erosions of the rib were also observed. CONCLUSION: CT findings may suggest the diagnosis of pleural schwannoma preoperatively. Pleural schwannoma should be included in the differential diagnosis of solid, solitary, and well defined pleural tumors. PMID- 23081956 TI - In-vivo metabolic characterization of healthy prostate and orthotopic prostate cancer in rats using proton magnetic resonance spectroscopy at 4.7 T. AB - BACKGROUND: To assist the development of new anti-cancer drugs, it is important to identify biomarkers of treatment efficacy in the preclinical phases of drug development. In order to improve the predictivity of preclinical experiments, more realistic animal models are needed, for example, tumors xenografted directly on the prostate gland of rodents. PURPOSE: To characterize the in-vivo metabolism of healthy rat prostate and of an orthotopic human prostate cancer model using proton magnetic resonance spectroscopy (MRS). MATERIAL AND METHODS: The highly metastatic and hormone-independent PC3-MM2 human prostate cancer model was implanted into the ventral prostate lobe of three Nude rats. Healthy Nude (n = 6) and Sprague-Dawley (n = 6) rats were also studied for interspecies comparison of normal prostate metabolism. Magnetic resonance imaging and short echo-time (TE 11.2 ms) single voxel PRESS spectroscopy were performed on dorsal (DP) and ventral (VP) prostate as well as tumor at 4.7 T. The metabolic content and volume of dorsal and ventral lobes were characterized as a function of species and age. RESULTS: Slightly lower total creatine (tCr)/water (11.3 +/- 2.6 vs. 15.3 +/- 3.0, NS), but significantly higher Inositol (Ins)/water (18.9 +/- 1.9 vs. 6.6 +/- 3.3, P < 0.003) and total choline (tCho)/water (15.0 +/- 2.1 vs. 5.6 +/- 1.1, P < 0.00007) were observed within healthy DP lobes with respect to VP lobes. No significant variation in metabolic content was seen in healthy DP and VP lobes of Nude rats as a function of age, and no species dependence was observed in their metabolic content. For the orthotopic PC3-MM2 tumor, implanted in VP, the tCr/water ratio was significantly lower (3.1 +/- 0.9) than neighboring DP (12.8 +/- 1.8, P < 0.00003) and healthy VP (15.3 +/- 3.0, P < 0.00006). For Ins, the metabolite ratio in PC3-MM2 was close to that of healthy VP (4.3 +/- 2.8 vs. 6.6 +/- 3.3, p = NS), but much lower than in neighboring DP (19.1 +/- 1.3, P < 0.00005). A similar trend was also observed for tCho, where metabolite ratios in PC3-MM2, healthy VP and neighboring DP were 3.5 +/- 0.9, 5.6 +/- 1.1, and 15.9 +/ 0.8, respectively. CONCLUSION: The in-vivo MRS study of healthy prostate and orthotopic prostate cancer is feasible in rats. Such baseline data could be important when following the modifications in metabolism, including during anti cancer drug development protocols or following radiotherapy. PMID- 23081957 TI - Thromboembolic complications in nephrotic syndrome: imaging spectrum. AB - Thromboembolism is a well-known complication of nephrotic syndrome. Pulmonary embolism, renal vein thrombosis, and deep vein thrombosis are the most common venous thromboembolic diseases in patients with nephrotic syndrome, while arterial thromboembolic complications are observed less frequently. Imaging plays an important role in the detection and follow-up of thromboembolism in these patients. The purpose of this essay is to describe the epidemiology, pathophysiological mechanisms, the imaging diagnosis, and treatment of thromboembolism in patients with nephrotic syndrome. PMID- 23081958 TI - Intracranial metastases: spectrum of MR imaging findings. AB - Intracranial metastatic lesions arise through a number of routes. Therefore, they can involve any part of the central nervous system and their imaging appearances vary. Magnetic resonance imaging (MRI) plays a key role in lesion detection, lesion delineation, and differentiation of metastases from other intracranial disease processes. This article is a reasoned pictorial review illustrating the many faces of intracranial metastatic lesions based on the location - intra-axial metastases, calvarial metastases, dural metastases, leptomeningeal metastases, secondary invasion of the meninges by metastatic disease involving the calvarium and skull base, direct or perineural intracranial extension of head and neck neoplasm, and other unusual manifestations of intracranial metastases. We also review the role of advanced MRI to distinguish metastases from high-grade gliomas, tumor-mimicking lesions such as brain abscesses, and delayed post radiation changes in radiosurgically treated patients. PMID- 23081959 TI - Uterine morphology and peristalsis in women with polycystic ovary syndrome. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is associated with chronic oligo anovulation and high circulating sex hormone levels. Women with PCOS have an increased risk of developing endometrial cancer. In anovulatory women with PCOS a positive relationship between endometrial thickness and endometrial hyperplasia has been observed. Uterine peristalsis, which has been suggested to be of importance for female fertility, has not previously been studied in PCOS. PURPOSE: To assess whether women with PCOS have altered endometrial thickness, uterine wall morphology, and peristalsis. MATERIAL AND METHODS: In this prospective case-control study 55 women with PCOS (mean age, 29.5 years +/- 4.5 SD) and 28 controls (27.6 +/- 3.2) were examined using magnetic resonance imaging (MRI), assessing thickness of endometrium, junctional zone (JZ), and myometrium, and evaluating the occurrence, frequency (waves/min), strength (amplitude), pattern, and direction of peristalsis. Uterine morphology was also assessed by transvaginal ultrasonography (TVUS). RESULTS: The endometrium was thinner in PCOS with oligo-amenorrhea compared to controls, also after adjustments for age and BMI (adjusted P = 0.043). There was no difference in thickness of the JZ or the myometrium in cases versus controls. Uterine peristalsis was less commonly observed in women with PCOS than in controls (adjusted P = 0.014). CONCLUSION: There were no differences in myometrial morphology between PCOS and controls, but the endometrium was thinner in PCOS with oligo-amenorrhea. Based on cine MRI, uterine peristalsis was less common in PCOS than in controls. PMID- 23081960 TI - Adenoma malignum of the uterine cervix: imaging features with clinicopathologic correlation. AB - BACKGROUND: Adenoma malignum, also known as minimal deviation adenocarcinoma, is a subtype of mucinous adenocarcinoma of the cervix. PURPOSE: To evaluate the clinical, pathologic, and imaging features of the adenoma malignum of the uterine cervix. MATERIAL AND METHODS: We retrospectively analyzed the CT and MRI findings in 13 patients: size, endoluminal fluid, appearance of the solid and cystic component, margin, enhancement, characteristics of locules of the cystic lesion, tumor spread, and associated ovarian lesion. Clinical and pathologic features were determined in 24 patients. RESULTS: The mean of the major tumor diameter was 4.1 cm (range, 2.2-6.5 cm). In the imaging features, 77% of 13 tumors demonstrated endoluminal fluid. All tumors showed enhancing solid components; 62% were multicystic and 38% had solid lesions. Most solid lesions exhibited an irregular margin (80%). The locules of the multicystic lesions tended to have smooth margins (75%), to have an average major diameter of <=1 cm (88%), and to be 11-20 in number (75%). The solid lesions were associated with invasion and metastases (60%). Clinically, 38% of 24 patients had watery discharge and 13% had Peutz-Jeghers syndrome, while pathologically, most patients were low stage (I or II) (83%). Over the 2-year follow-up of 17 patients, 82% was free from disease. The patients with more aggressive tumors or an unfavorable prognosis that manifested as tumor recurrence or metastasis tended to have invasion, watery discharges, high stages (III or IV) (100%) and solid lesions, metastases, and associated ovarian lesions (67%). CONCLUSION: Awareness of imaging features as well as clinicopathologic manifestations of adenoma malignum can aid in accurate diagnosis, treatment, and prediction of prognosis. PMID- 23081961 TI - Gadobenate dimeglumine (MultiHance) in MR angiography: an in-vitro phantom comparison with gadopentetate dimeglumine (Magnevist) at different concentrations. AB - BACKGROUND: Numerous clinical studies suggest that gadobenate dimeglumine is diagnostically superior to other gadolinium chelates for MR imaging applications, including contrast-enhanced MR angiography (CE-MRA). However, confirmatory in vitro phantom studies have thus far been lacking. PURPOSE: To evaluate the difference in signal intensity achieved with the high-relaxivity MR contrast agent gadobenate dimeglumine (MultiHance) relative to that achieved with the standard-relaxivity non-specific agent gadopentetate dimeglumine (Magnevist) at different concentrations using an in-vitro phantom study design. MATERIAL AND METHODS: Test tubes with whole human blood were prepared with concentrations of gadobenate dimeglumine or gadopentetate dimeglumine ranging from 0 to 12 mM. A three-dimensional (3D) T1-weighted gradient echo sequence normally used for CE MRA of the renal arteries was performed at flip angles of 25 degrees and 35 degrees . The signal-to-noise ratio (SNR) was calculated for all concentrations of both contrast agents. Furthermore a Look-Locker sequence was used and quantitative T1 mapping was performed for all the test tubes. The contrast agent concentration in the aorta was simulated using previously published data on T1 in the aorta during the first pass of a contrast agent. The differences between gadobenate dimeglumine and gadopentetate dimeglumine were compared at the simulated concentrations. RESULTS: The SNR achieved with gadobenate dimeglumine was consistently greater than that achieved with gadopentetate dimeglumine at all concentrations. An improvement of 15-25% in SNR was obtained when increasing the flip angle from 25 degrees to 35 degrees . The relative improvement in SNR with gadobenate dimeglumine relative to gadopentetate dimeglumine ranged from 25-72% and was markedly greater at lower concentrations with a flip angle of 35 degrees . CONCLUSION: Our findings suggest that the relative benefit of gadobenate dimeglumine over gadopentetate dimeglumine for CE-MRA applications is greater at lower concentrations. PMID- 23081966 TI - Selectivity tuning in pressurized capillary electrochromatography with a zwitterionic monolithic column. AB - A polymethacrylate-based capillary monolithic column with zwitterionic functional groups was prepared by an in situ copolymerization method. The column was used in pressurized capillary electrochromatography (pCEC) for the separation of a test mixture of basic, neutral and acidic analytes. Unique manipulation of selectivity in pCEC was demonstrated by fine-tuning the applied voltage. The separation mechanism for neutral compounds was primarily attributed to hydrophilic interaction, whereas the separation mechanism for charged compounds was attributed to electrophoresis. Due to the multiple retention mechanisms, the pCEC system using a zwitterionic monolithic column showed better separation of the mixture consisting of neutral and charged molecules than capillary liquid chromatography with an identical column. PMID- 23081967 TI - Simultaneous quantification of capsaicinoids and ascorbic acid from pungent peppers. AB - The development of simultaneous extraction and determination of bioactive molecules from natural products is becoming more popular. The present study reports the development of a method for the simultaneous extraction and determination of both capsaicinoids and ascorbic acid in peppers. Capsaicin (341.61 ug/g), dihydrocapsaicin (119.91 ug/g) and ascorbic acid (2,109.60 ug/g) were extracted with 3% metaphosphoric acid-ethanol (2:8) as a solvent. The efficient extraction of capsaicinoids (412.61 ug/g) and ascorbic acid (2,785.93 ug/g) was achieved at a sample-to-solvent ratio of 1:8 after 30 minutes of sonication. Simultaneous separation of capsaicinoids and ascorbic acid was achieved using a Gemini C18 column with a gradient elution of 0.03M phosphoric acid and methanol. Capsaicinoids and ascorbic acid were simultaneously detected at 282 and 254 nm, respectively. The recovery of capsaicinoids ranged from 96.21 to 108.71%, and the recovery of ascorbic acid ranged from 97.01 to 98.83%. The limits of detection for capsaicin, dihydrocapsaicin and ascorbic acid were 0.24, 0.21 and 0.26 ug, respectively. Relative standard deviation for the intra-day and inter-day variability in the results was less than 3%, indicating that the method produced highly reproducible results. Therefore, this method enables the reproducible, simultaneous separation and quantification of capsaicinoids and ascorbic acid from peppers. PMID- 23081968 TI - RP-HPLC/pre-column derivatization for analysis of omeprazole, tinidazole, doxycycline and clarithromycin. AB - A validated, reliable and accurate reversed-phase high performance liquid chromatographic method using pre-column derivatization was adopted for the simultaneous determination of two ternary mixtures containing omeprazole, tinidazole and doxycycline hyclate or clarithromycin. Separation was achieved on a C18 column, through a gradient elution system using acetonitrile-methanol-water adjusted to pH = 6.60. Drugs were detected at 277 nm over concentration ranges of 1-112, 5-125, 2.5-550 and 2.5-100 ug/mL for omeprazole, tinidazole, doxycycline hyclate and clarithromycin, respectively. This is the first method that has isolated and identified clarithromycin derivative by infrared and mass spectroscopy. This method is the first study for the simultaneous determination of omeprazole, tinidazole, doxycycline hyclate and clarithromycin in combined mixtures and pharmaceutical formulations. PMID- 23081972 TI - Unpacking the evidence on competition and outcomes in the NHS in England. PMID- 23081973 TI - Understanding patterns of complex care: putting the pieces together. PMID- 23081975 TI - Effects of diet on total calcium, vitamin D and parathyroid hormone in falcons. PMID- 23081974 TI - Breast cancer patient stories project. AB - OBJECTIVE: It is estimated that there are almost half a million women living with or beyond a breast cancer diagnosis in the UK, often referred to as the breast cancer survivor population. We report on the setting up of a dedicated breast cancer and menopause symptoms service (BCMS), and present results from research undertaken with breast cancer survivors with the aim of obtaining their perspectives on the BCMS service. METHOD: An action-oriented approach incorporating improvement science methodology has been used to help develop and drive changes to support a high standard of NHS patient care delivery for women with breast cancer within the BCMS setting. Evaluation was undertaken of this innovative service using qualitative methodology, and included discussion within a focus group setting, patient consent to record discussion, followed by thematic analysis of transcription. RESULTS: Women who have survived breast cancer identified a need for specialist support to help improve their quality of life, which is also affected by menopause type symptomology. This support can be provided within the BCMS service setting. Our recommendations are that the BCMS service model is incorporated into any regional or national breast cancer patient pathway and service redesign work in place. CONCLUSIONS: Breast cancer survivors would support the setting up of a BCMS service, and would actively help raise awareness and market this service. PMID- 23081976 TI - An investigation into the epidemiology of feline obesity in Great Britain: results of a cross-sectional study of 47 companion animal practises. AB - Previous epidemiological studies of feline obesity have been restricted to small geographical areas of Great Britain. This study represents the first published description of the prevalence and risk factors for obesity from a nationally distributed population of cats. Data were gathered from 3227 cats through 47 primary companion animal veterinary practises. The overall prevalence of overweight/obesity was 11.5 per cent (95% confidence interval 10.4 per cent to 12.6 per cent) in cats attending the charity's clinics. Cats in Scotland appeared to have a greater age and neutered-adjusted prevalence compared with cats in England. Neutered status, being male and middle age (around 7 years), were all significant risk factors for feline overweight/obesity, although they did not fully explain an individual cat's risk of overweight/obesity. Breed was not found to be a statistically significant risk factor. Partial attributable fractions were calculated from each of the significant risk factors. Neutered status appeared to contribute the most to the prevalence of obesity, followed by prime/mature lifestage (3-10 years of age). Any interpretations of these findings should take into account the multitude of biases inherent in this study. Nevertheless, weight management following neutering appears to be very important to reduce the overall prevalence of overweight/obesity in this population of cats. PMID- 23081977 TI - Tools of the trade: theory and method in mindfulness neuroscience. AB - Mindfulness neuroscience is an emerging research field that investigates the underlying mechanisms of different mindfulness practices, different stages and different states of practice as well as different effects of practice over the lifespan. Mindfulness neuroscience research integrates theory and methods from eastern contemplative traditions, western psychology and neuroscience, and from neuroimaging techniques, physiological measures and behavioral tests. We here review several key theoretical and methodological challenges in the empirical study of mindfulness neuroscience and provide suggestions for overcoming these challenges. PMID- 23081979 TI - Profile of local interleukin expression in a cohort of ocular cicatricial pemphigoid patients. AB - PURPOSE: We investigated the expression of IL-1, IL-6, IL-12, IL-13, and IL-17 in the conjunctiva of patients with ocular cicatricial pemphigoid (OCP), also labeled as ocular mucous membrane pemphigoid (MMP). METHODS: A retrospective case control study was done on 5 biopsy-proven OCP subjects and 6 healthy volunteers. Conjunctival specimens were obtained, and the local expression of IL-1, IL-6, IL 12, IL-13, and IL-17 was studied by immunohistochemistry. Clinical and therapeutic features were collected during follow-up. RESULTS: No remarkable IL 1, IL-6, IL-12, IL-13, or IL-17 expression was observed in normal conjunctival specimens. All OCP samples had remarkable amounts of IL-12 and IL-17 expression especially in the epithelium and stroma; there also was stromal overexpression of IL-6. The mean follow-up after the biopsy was 13 months (range 9-15 months). CONCLUSIONS: Our results demonstrated, for the first time to our knowledge, a local overexpression of IL-6, IL-12, and IL-17 in conjunctiva of OCP compared to controls. PMID- 23081978 TI - Protective effect of carnosic acid, a pro-electrophilic compound, in models of oxidative stress and light-induced retinal degeneration. AB - PURPOSE: The herb rosemary has been reported to have antioxidant and anti inflammatory activity. We have previously shown that carnosic acid (CA), present in rosemary extract, crosses the blood-brain barrier to exert neuroprotective effects by upregulating endogenous antioxidant enzymes via the Nrf2 transcriptional pathway. Here we investigated the antioxidant and neuroprotective activity of CA in retinal cell lines exposed to oxidative stress and in a rat model of light-induced retinal degeneration (LIRD). METHODS: Retina-derived cell lines ARPE-19 and 661W treated with hydrogen peroxide were used as in vitro models for testing the protective activity of CA. For in vivo testing, dark adapted rats were given intraperitoneal injections of CA prior to exposure to white light to assess protection of the photoreceptor cells. Retinal damage was assessed by measuring outer nuclear layer thickness and by electroretinogram (ERG). RESULTS: In vitro, CA significantly protected retina-derived cell lines (ARPE-19 and 661W) against H(2)O(2)-induced toxicity. CA induced antioxidant phase 2 enzymes and reduced formation of hyperoxidized peroxiredoxin (Prx)2. Similarly, we found that CA protected retinas in vivo from LIRD, producing significant improvement in outer nuclear layer thickness and ERG activity. CONCLUSIONS: These findings suggest that CA may potentially have clinical application to diseases affecting the outer retina, including age-related macular degeneration and retinitis pigmentosa, in which oxidative stress is thought to contribute to disease progression. PMID- 23081980 TI - Expression and role of VEGF--a in the ciliary body. AB - PURPOSE: The role of VEGF-A in the normal ciliary body is largely unexplored. The ciliary body is similar in many respects to the choroid plexus of the brain, and we demonstrated previously the importance of VEGF-A in maintenance of choroid plexus vasculature and ependymal cells. Therefore, the role of VEGF-A in ciliary body homeostasis was explored. METHODS: Swiss-Webster mice (VEGF-LacZ) were used to determine VEGF-A expression during ciliary body development and in the adult. VEGFR2 expression was determined in adult wild type C56BL/6J mice. Systemic VEGF A neutralization in vivo was achieved with adenovirus-mediated overexpression of soluble VEGFR1 (sFlt1). Following VEGF-A neutralization, the ciliary epithelium was analyzed by light microscopy and transmission electron microscopy (TEM). The effect of VEGF-A blockade on ciliary body function also was assessed by measuring intraocular pressure. RESULTS: VEGF-A expression was detected at embryonic day 18.5 (E18.5), the onset of ciliary process formation. In the adult ciliary body, VEGF-A was expressed by the pigmented epithelium, whereas VEGFR2 was localized primarily to the capillary endothelium and nonpigmented epithelium. Systemic VEGF A neutralization led to a thinning of the nonpigmented epithelium, vacuolization of the pigmented epithelium, loss of capillary fenestrations, and thrombosis. These changes were associated with impaired ciliary body function, as evidenced by decreased intraocular pressure in sFlt1-overexpressing animals (15.31 +/- 2.06 mm Hg) relative to controls (18.69 +/- 1.49 mm Hg). CONCLUSIONS: VEGF-A has an important role in ciliary body homeostasis. Potential for undesired off-target effects should be considered with the chronic use of anti-VEGF-A therapies. PMID- 23081981 TI - Role of hepatocyte growth factor in promoting the growth of human corneal endothelial cells stimulated by L-ascorbic acid 2-phosphate. AB - PURPOSE: To investigate the mechanisms by which L-ascorbic acid 2-phosphate (Asc 2P) increases the proliferation of human corneal endothelial cells (HCECs). METHODS: Growth of cultured HCECs was examined in the presence of various antioxidants, including Asc-2P, retinyl acetate (vitamin A), reduced glutathione, oxidized glutathione, carnosine, and sodium alpha-tocopherol phosphate (a water soluble vitamin E derivative). Synthesis of type I, III, and IV collagen by HCECs cultured with or without Asc-2P was evaluated by measuring cell lysates and conditioned medium with Western blotting, immunocytochemistry, or enzyme-linked immunosorbent assay (ELISA). The gene expression profiles of HCECs cultured with or without Asc-2P were compared by microarray analysis to determine critical proliferative factors, and the proliferative response of these cells to selected factors was tested. RESULTS: Among the antioxidants tested, only Asc-2P promoted the growth of HCECs. Asc-2P did not promote deposition of type I, III, or IV collagen. Microarray analysis revealed that several cytokines were potently upregulated by Asc-2P, but among them, only hepatocyte growth factor (HGF) stimulated HCEC growth. ELISA revealed the upregulation of HGF protein production by Asc-2P, while the stimulatory effect of Asc-2P was abolished by an anti-HGF neutralizing antibody or PHA-665752 (a specific inhibitor of the HGF receptor, c Met). CONCLUSIONS: Asc-2P increases the proliferation of cultured HCECs through upregulation of HGF production via an HGF/c-Met autocrine loop. PMID- 23081982 TI - Analysis of grain characters in temperate grasses reveals distinctive patterns of endosperm organization associated with grain shape. AB - Members of the core pooids represent the most important crops in temperate zones including wheat, barley, and oats. Their importance as crops is largely due to the grain, particularly the storage capabilities of the endosperm. In this study, a comprehensive survey of grain morphology and endosperm organization in representatives of wild and cultivated species throughout the core pooids was performed. As sister to the core pooid tribes Poeae, Aveneae, Triticeae, and Bromeae within the Pooideae subfamily, Brachypodium provides a taxonomically relevant reference point. Using macroscopic, histological, and molecular analyses distinct patterns of grain tissue organization in these species, focusing on the peripheral and modified aleurone, are described. The results indicate that aleurone organization is correlated with conventional grain quality characters such as grain shape and starch content. In addition to morphological and organizational variation, expression patterns of candidate gene markers underpinning this variation were examined. Features commonly associated with grains are largely defined by analyses on lineages within the Triticeae and knowledge of grain structure may be skewed as a result of the focus on wheat and barley. Specifically, the data suggest that the modified aleurone is largely restricted to species in the Triticeae tribe. PMID- 23081984 TI - Problem-solving therapy for psychological distress in Japanese early-stage breast cancer patients. AB - OBJECTIVE: The current report provides the result of a Phase II clinical trial regarding the effectiveness and feasibility of problem-solving therapy for psychological distress experienced by Japanese early-stage breast cancer patients. METHODS: Participants were 36 post-surgery Japanese breast cancer patients in a university hospital located in Osaka Prefecture, Japan. After screening for psychological distress using the Distress and Impact Thermometer and the Hospital Anxiety and Depression Scale, highly distressed patients were exposed to 5 weekly sessions of the problem-solving therapy program. RESULTS: Nineteen patients completed the intervention and follow-up. There was a significant difference between the pre-intervention and the 3-month follow-up in the total Hospital Anxiety and Depression Scale score (P = 0.02), and the mean change score from the pre-intervention to the follow-up was 6.05 (SD = 1.94). The intervention had a large effect size (d = 0.82). There were also significant changes in worry, self-efficacy and quality of life measures. CONCLUSIONS: The findings of our study suggest that the problem-solving therapy program has potential to be effective for alleviating psychological distress experienced by Japanese early-stage breast cancer patients. The true effectiveness of the program should be confirmed by a future randomized control trial. PMID- 23081983 TI - Transcriptome-wide mining of the differentially expressed transcripts for natural variation of floral organ size in Physalis philadelphica. AB - Natural phenotypic variation, a result of genetic variation, developed during evolution in response to environmental selections. Physalis philadelphica, known as tomatillo in the Solanaceae, is rich in floral and post-floral organ size diversity. However, its genetic variation is unknown. Here P. philadelphica was classified into three groups with large, intermediate, and small reproductive organ size, and a positive correlation was observed between floral organ and berry sizes. Through cDNA-amplified fragment length polymorphism (AFLP) analyses, 263 differentially expressed transcript-derived fragments (TDFs) were isolated from two accessions with different floral organ sizes. The genes encode various transcription factors, protein kinases, and enzymes, and they displayed multiple expression patterns during floral development, indicating a complexity in the genetic basis of phenotypic variation. Detailed expression analyses revealed that they were differentially expressed during floral and post-floral development, implying that they have roles in the development of flowers and fruits. Expression of three genes was further monitored in 26 accessions, and in particular the expression variation of Pp30, encoding an AP2-like transcription factor, correlates well with the observed phenotypic variations, which strongly supports an essential role for the gene in the natural variation of floral and post-floral organ size in Physalis. The results suggest that alteration in the expression pattern of a few key regulatory genes in the developmental process may be an important source of genetic variations that lead to natural variation in morphological traits. PMID- 23081985 TI - Gender difference in hematological toxicity among lung cancer patients receiving amrubicin monotherapy. AB - BACKGROUND: Severe hematological toxicity has been frequently observed during amrubicin monotherapy for patients with lung cancer despite the favorable anti tumor response. The purpose of this retrospective study was to identify pretreatment factors associated with severe hematological toxicity. METHODS: The medical records of lung cancer patients treated with amrubicin monotherapy were reviewed, and univariate and multivariate analyses were conducted. RESULTS: From January 2003 to December 2006, the medical records of 103 patients were extracted. Grade 4 neutropenia was frequently observed in females (male, 66% and female, 90%, P = 0.036 in a univariate analysis). In a multivariate analysis, female gender (P = 0.019), body weight loss (P = 0.021) and amrubicin dose (P = 0.028) were significantly correlated with Grade 4 neutropenia. CONCLUSION: Gender could be considered as one of the important predictive factors associated with Grade 4 neutropenia in patients receiving amrubicin monotherapy. PMID- 23081986 TI - Influence of rotational setup error on tumor shift in bony anatomy matching measured with pulmonary point registration in stereotactic body radiotherapy for early lung cancer. AB - OBJECTIVE: To examine the correlation between the patient rotational error measured with pulmonary point registration and tumor shift after bony anatomy matching in stereotactic body radiotherapy for lung cancer. METHODS: Twenty-six patients with lung cancer who underwent stereotactic body radiotherapy were the subjects. On 104 cone-beam computed tomography measurements performed prior to radiation delivery, rotational setup errors were measured with point registration using pulmonary structures. Translational registration using bony anatomy matching was done and the three-dimensional vector of tumor displacement was measured retrospectively. Correlation among the three-dimensional vector and rotational error and vertebra-tumor distance was investigated quantitatively. RESULTS: The median and maximum rotational errors of the roll, pitch and yaw were 0.8, 0.9 and 0.5, and 6.0, 4.5 and 2.5, respectively. Bony anatomy matching resulted in a 0.2-1.6 cm three-dimensional vector of tumor shift. The shift became larger as the vertebra-tumor distance increased. Multiple regression analysis for the three-dimensional vector indicated that in the case of bony anatomy matching, tumor shifts of 5 and 10 mm were expected for vertebra-tumor distances of 4.46 and 14.1 cm, respectively. CONCLUSIONS: Using pulmonary point registration, it was found that the rotational setup error influences the tumor shift. Bony anatomy matching is not appropriate for hypofractionated stereotactic body radiotherapy with a tight margin. PMID- 23081988 TI - Increased circulating levels of 3-nitrotyrosine autoantibodies: marker for or maker of cardiovascular disease? PMID- 23081987 TI - Involvement of guanylin and GC-C in rat mesenteric macrophages in resistance to a high-fat diet. AB - A high-fat diet (HFD) is a well-known contributing factor in the development of obesity. Most rats fed HFDs become obese. Those that avoid obesity when fed HFDs are considered diet resistant (DR). We performed a microarray screen to identify genes specific to the mesenteric fat of DR rats and revealed high expression of guanylin and guanylyl cyclase C (GC-C) in some subjects. Our histologic studies revealed that the cellular source of guanylin and GC-C is macrophages. Therefore, we developed double-transgenic (Tg) rats overexpressing guanylin and GC-C in macrophages and found that they were resistant to the effects of HFDs. In the mesenteric fat of HFD-fed Tg rats, Fas and perilipin mRNAs were downregulated, and those of genes involved in fatty acid oxidation were upregulated, compared with the levels in HFD-fed wild-type rats. In vitro studies demonstrated that lipid accumulation was markedly inhibited in adipocytes cocultured with macrophages expressing guanylin and GC-C and that this inhibition was reduced after treatment with guanylin- and GC-C-specific siRNAs. Our results suggest that the macrophagic guanylin-GC-C system contributes to the altered expression of genes involved in lipid metabolism, leading to resistance to obesity. PMID- 23081989 TI - Immunoglobulins against tyrosine-nitrated epitopes in coronary artery disease. AB - BACKGROUND: Several lines of evidence support a pathophysiological role of immunity in atherosclerosis. Tyrosine-nitrated proteins, a footprint of oxygen- and nitrogen-derived oxidants generated by cells of the immune system, are enriched in atheromatous lesions and in circulation of patients with coronary artery disease (CAD). However, the consequences of possible immune reactions triggered by the presence of nitrated proteins in subjects with clinically documented atherosclerosis have not been explored. METHODS AND RESULTS: Specific immunoglobulins that recognize 3-nitrotyrosine epitopes were identified in human lesions, as well as in circulation of patients with CAD. The levels of circulating immunoglobulins against 3-nitrotyrosine epitopes were quantified in patients with CAD (n=374) and subjects without CAD (non-CAD controls, n=313). A 10-fold increase in the mean level of circulating immunoglobulins against protein bound 3-nitrotyrosine was documented in patients with CAD (3.75+/-1.8 MUg antibody Eq/mL plasma versus 0.36+/-0.8 MUg antibody Eq/mL plasma), and was strongly associated with angiographic evidence of significant CAD. CONCLUSIONS: The results of this cross-sectional study suggest that posttranslational modification of proteins via nitration within atherosclerotic plaque-laden arteries and in circulation serve as neo-epitopes for the elaboration of immunoglobulins, thereby providing an association between oxidant production and the activation of the immune system in CAD. PMID- 23081991 TI - Serial block-face scanning electron microscopy combined with double-axis electron beam tomography provides new insight into cellular relationships. AB - To evaluate the advantages of combination of two advanced electron microscopic technologies such as serial block-face scanning electron microscopy and double axis electron beam tomography, we analyzed the three-dimensional morphology of cellular relationships between dendritic and plasma cells in the synovial membrane from patients with rheumatoid arthritis, using the combined approach. PMID- 23081990 TI - The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells. AB - BACKGROUND: Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. METHODS AND RESULTS: In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein. CONCLUSIONS: Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease. PMID- 23081993 TI - Comparison of segmentation-based attenuation correction methods for PET/MRI: evaluation of bone and liver standardized uptake value with oncologic PET/CT data. AB - For attenuation correction (AC) in PET/MRI systems, segmentation-based methods are most often used. However, the standardized uptake value (SUV) of lesions in the bone and liver, which have higher attenuation coefficients than other organs, can be underestimated, potentially leading to misinterpretation of clinical cases. Errors in SUV estimation are also dependent on the segmentation schemes used in the segmentation-based AC. In this study, this potential bias in SUV estimation using 4 different segmentation-based AC methods was evaluated for the PET/CT data of cancer patients with bone and liver lesions. METHODS: Forty patients who had spine or liver lesions and underwent (18)F-FDG PET/CT participated (18 women and 22 men; 20 spine lesions and 20 liver lesions; mean age (+/- SD), 60.5 +/- 11.4 y; mean body weight, 57.7 +/- 10.4 kg). The patient body region was extracted from the CT image and categorized into 5 tissue groups (air, lungs, fat, water, and bone) using Hounsfield unit thresholds, which were determined from the CT histogram. Four segmentation-based AC methods (SLA [soft tissue/lung/air], WFLA [water/fat/lung/air], SLAB [soft-tissue/lung/air/bone], and WFLAB [water/fat/lung/air/bone]) were compared with CT-based AC. The mean attenuation coefficient for each group was calculated from 40 CT images and assigned to the attenuation maps. PET sinograms were reconstructed using segmentation- and CT-based AC maps, and mean SUV in the lesions was compared. RESULTS: Mean attenuation coefficients for air, lungs, fat, water, and bone were 0.0058, 0.0349, 0.0895, 0.0987, and 0.1178 cm(-1), respectively. In the spine lesions, the SUVs were underestimated by 16.4% +/- 8.5% (SLA AC) and 14.7% +/- 7.5% (WFLA AC) but not to a statistically significant extent for SLAB and WFLAB AC relative to CT AC. In the liver lesions, the SUVs were underestimated by 11.1% +/- 2.6%, 8.1% +/- 3.0%, 6.8% +/- 3.8%, and 4.1% +/- 3.8% with SLA, SLAB, WFLA, and WFLAB AC, respectively. CONCLUSION: Without bone segmentation, the SUVs of spine lesions were considerably underestimated; however, the bias was acceptable with bone segmentation. In liver lesions, the segmentation-based AC methods yielded a negative bias in SUV; however, inclusion of the bone and fat segments reduced the SUV bias. The results of this study will be useful for understanding organ-dependent bias in SUV between PET/CT and PET/MRI. PMID- 23081994 TI - Correlation of 18F-FLT uptake with tumor grade and Ki-67 immunohistochemistry in patients with newly diagnosed and recurrent gliomas. AB - We evaluated 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) uptake in patients with newly diagnosed and recurrent gliomas and correlated the results with tumor grade and proliferative activity. METHODS: (18)F-FLT PET was investigated retrospectively in 56 patients, including 36 with newly diagnosed gliomas and 20 with recurrent gliomas. The standardized uptake values for tumor and normal contralateral hemisphere were calculated, and the tumor-to-normal (T/N) ratio was determined. Tumor grading and proliferative activity were estimated in tissue specimens. RESULTS: There was a significant difference in T/N ratio among different grades of newly diagnosed gliomas and between low- and high-grade newly diagnosed and recurrent gliomas. (18)F-FLT uptake correlated more strongly with the proliferative activity in newly diagnosed gliomas than in recurrent gliomas. CONCLUSION: (18)F-FLT PET seems to be useful in the noninvasive assessment of grade and proliferation in gliomas, especially newly diagnosed gliomas. PMID- 23081992 TI - In vivo measurements of glutamate, GABA, and NAAG in schizophrenia. AB - The major excitatory and inhibitory neurotransmitters, glutamate (Glu) and gamma aminobutyric acid (GABA), respectively, are implicated in the pathophysiology of schizophrenia. N-acetyl-aspartyl-glutamate (NAAG), a neuropeptide that modulates the Glu system, may also be altered in schizophrenia. This study investigated GABA, Glu + glutamine (Glx), and NAAG levels in younger and older subjects with schizophrenia. Forty-one subjects, 21 with chronic schizophrenia and 20 healthy controls, participated in this study. Proton magnetic resonance spectroscopy ((1)H-MRS) was used to measure GABA, Glx, and NAAG levels in the anterior cingulate (AC) and centrum semiovale (CSO) regions. NAAG in the CSO was higher in younger schizophrenia subjects compared with younger control subjects. The opposite pattern was observed in the older groups. Glx was reduced in the schizophrenia group irrespective of age group and brain region. There was a trend for reduced AC GABA in older schizophrenia subjects compared with older control subjects. Poor attention performance was correlated to lower AC GABA levels in both groups. Higher levels of CSO NAAG were associated with greater negative symptom severity in schizophrenia. These results provide support for altered glutamatergic and GABAergic function associated with illness course and cognitive and negative symptoms in schizophrenia. The study also highlights the importance of studies that combine MRS measurements of NAAG, GABA, and Glu for a more comprehensive neurochemical characterization of schizophrenia. PMID- 23081995 TI - Quantitative immuno-SPECT monitoring of pretargeted radioimmunotherapy with a bispecific antibody in an intraperitoneal nude mouse model of human colon cancer. AB - The prospects for using pretargeted immuno-SPECT to monitor the response to pretargeted radioimmunotherapy were examined. In this study, a bispecific anticarcinoembryonic antigen (CEACAM5; CD66e) * antihapten monoclonal antibody, TF2, was used in combination with a small (1.5 kD) peptide, IMP288, labeled with (111)In and (177)Lu. METHODS: First, tumor uptake of (111)In-IMP288 and (177)Lu IMP288, as determined by immuno-SPECT, was validated by ex vivo counting. Two groups of female BALB/c nude mice had LS174T tumors implanted in the peritoneal cavity. They received intravenous injections of TF2, followed by 10 MBq of (111)In-IMP288 or 90 MBq of (177)Lu-IMP288. A control group of non-tumor-bearing mice received TF2 and (111)In-IMP288. One hour after the radiolabeled IMP288 was given, small-animal SPECT/CT images were acquired, and subsequently animals were dissected. Furthermore, a survival study was performed in 3 groups of 10 mice with intraperitoneal tumors: mice received TF2 and (177)Lu-IMP288 (60 MBq), nonpretargeted (177)Lu-IMP288 (60 MBq), or phosphate-buffered saline. Immuno SPECT scans were acquired directly after therapy and at 14 and 45 d after therapy. Tumor growth was analyzed in the successive scans in each animal. RESULTS: (111)In- and (177)Lu-labeled IMP288 had similar in vivo distribution. The activity measured in the pretargeted immuno-SPECT images correlated well with the uptake measured in the dissected tumors (Pearson r = 0.99, P < 0.05). In the therapy study, the SPECT images showed rapid and selective tumor targeting with high tumor-to-background contrast (30 +/- 12) as early as 1 h after injection. The successive images of the treated mice showed delayed tumor growth in the pretargeted radioimmunotherapy group, corresponding with their prolonged survival. CONCLUSION: Pretargeted immuno-SPECT with TF2 and (111)In- or (177)Lu IMP288 can be used to predict and confirm tumor targeting and monitor the therapeutic effect of pretargeted radioimmunotherapy. PMID- 23081996 TI - Clinical relevance of 18F-FDG PET and 18F-DOPA PET in recurrent medullary thyroid carcinoma. AB - The transition from stable to progressive disease is unpredictable in patients with biochemical evidence of medullary thyroid carcinoma (MTC). Calcitonin and carcinoembryonic antigen (CEA) doubling times are currently the most reliable markers for progression, but for accurate determination, serial measurements, which need time, are required. We compared (18)F-FDG PET and (18)F dihydroxyphenylanaline ((18)F-DOPA) PET with biochemical parameters and survival to assess whether these imaging modalities could be of value in detecting progressive disease. METHODS: We evaluated the outcome of (18)F-FDG PET or (18)F DOPA PET with calcitonin and CEA doubling times in 47 MTC patients. A subgroup of patients was included in the whole metabolic burden (WBMTB) analysis, with determination of standardized uptake values and number of lesions. WBMTB of (18)F DOPA PET and (18)F-FDG PET was compared with biochemical parameters. Furthermore, survival was compared with (18)F-DOPA PET or (18)F-FDG PET positivity. RESULTS: Doubling times were available for 38 of 40 patients undergoing (18)F-FDG PET. There was a significant correlation with (18)F-FDG PET positivity. Doubling times were less than 24 mo in 77% (n = 10/13) of (18)F-FDG PET-positive patients, whereas 88% (n = 22/25) of (18)F-FDG PET-negative patients had doubling times greater than 24 mo (P < 0.001). Between doubling times and (18)F-DOPA PET positivity, no significant correlation existed. (18)F-DOPA PET detected significantly more lesions (75%, 56/75) than did (18)F-FDG PET (47%, 35/75) in the 21 patients included in WBMTB analysis (P = 0.009). Calcitonin and CEA levels correlated significantly with WBMTB on (18)F-DOPA PET, but doubling times did not. (18)F-FDG PET positivity was a more important indicator for poor survival in patients for whom both scans were obtained. CONCLUSION: (18)F-FDG PET is superior in detecting patients with biochemical progressive disease and identifying patients with poor survival. Although (18)F-DOPA PET has less prognostic value, it can more accurately assess the extent of the disease in patients with residual MTC. Hence, both scans are informative about tumor localization and behavior. On the basis of these results, we designed a clinical flow diagram for general practice in detecting recurrent MTC. PMID- 23081997 TI - Personality traits of British hospice volunteers. AB - In total, 120 British female hospice volunteers completed the NEO five-factor inventory (NEO-FFI) of Costa Jr and McCrae. The NEO-FFI measures the so-called big 5 personality traits of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Compared to both American NEO-FFI norms for adult females and emerging British NEO-FFI norms for adult females, the hospice volunteers scored significantly lower, on average, in neuroticism and significantly higher, on average, in agreeableness and conscientiousness. No significant differences were found on any of the 5 traits between the British female hospice volunteers' scores and the NEO-FFI scores previously collected from a sample of Canadian female hospice palliative care volunteers. Implications for the recruitment of British hospice volunteers are discussed. PMID- 23081998 TI - Does art imitate death? Depictions of suicide in fiction. AB - OBJECTIVE: To determine whether fiction (narrative products) deals with the issue of suicide and, if so, what it tells us about suicide "drivers". METHOD: Accounts of suicide in narrative products were sought through web-based lists, book club members, other active readers and a prize-winning film writer and producer. RESULTS: Seventy-one depictions of fictional suicidal events were identified. In 12 suicides, the author appeared to indicate that the death was directly or indirectly due to mental disorder. In 15 suicides, the motivation could not be determined by the reader, and in 44 cases the motivation was social/situational factors. CONCLUSIONS: Suicidal events are depicted in fiction, and the features are broadly similar to the features of suicide in the real world. Should it be determined that cultural influences, including fiction, are important in suicide, any preventive activities aimed at modifying cultural influences will need to consider all forms of narrative product. PMID- 23081999 TI - Behavioural treatment of severe chronic self-loathing in people with borderline personality disorder. Part 2: Self-compassion and other interventions. AB - OBJECTIVE: This article is the second in a series of two on the topic. The purpose of the article is to discuss the intervention of self-compassion (and briefly other behavioural interventions) in treating severe chronic self-loathing in people with borderline personality disorder (BPD). The first article focuses on interrupting the self-loathing cycle. CONCLUSIONS: Self-compassion has promise as an intervention in the behavioural treatment of severe chronic self-loathing in people with BPD. Due to the challenges faced, it is useful for behavioural clinicians to have a range of flexible treatment approaches embedded into a coherent principled treatment in treating severe chronic self-loathing in people with BPD. PMID- 23082000 TI - Translating the therapeutic potential of AZD4547 in FGFR1-amplified non-small cell lung cancer through the use of patient-derived tumor xenograft models. AB - PURPOSE: To investigate the incidence of FGFR1 amplification in Chinese non-small cell lung cancer (NSCLC) and to preclinically test the hypothesis that the novel, potent, and selective fibroblast growth factor receptor (FGFR) small-molecule inhibitor AZD4547 will deliver potent antitumor activity in NSCLC FGFR1-amplified patient-derived tumor xenograft (PDTX) models. EXPERIMENTAL DESIGN: A range of assays was used to assess the translational relevance of FGFR1 amplification and AZD4547 treatment including in vitro lung cell line panel screening and pharmacodynamic (PD) analysis, FGFR1 FISH tissue microarray (TMA) analysis of Chinese NSCLC (n = 127), and, importantly, antitumor efficacy testing and PD analysis of lung PDTX models using AZD4547. RESULTS: The incidence of FGFR1 amplification within Chinese patient NSCLC tumors was 12.5% of squamous origin (6 of 48) and 7% of adenocarcinoma (5 of 76). AZD4547 displayed a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified FGFR1 (GI(50) = 0.003-0.111 MUmol/L). AZD4547 induced potent tumor stasis or regressive effects in four of five FGFR1-amplified squamous NSCLC PDTX models. Pharmacodynamic modulation was observed in vivo, and antitumor efficacy correlated well with FGFR1 FISH score and protein expression level. CONCLUSIONS: This study provides novel epidemiologic data through identification of FGFR1 gene amplification in Chinese NSCLC specimens (particularly squamous) and, importantly, extends the clinical significance of this finding by using multiple FGFR1-amplified squamous lung cancer PDTX models to show tumor stasis or regression effects using a specific FGFR inhibitor (AZD4547). Thus, the translational science presented here provides a strong rationale for investigation of AZD4547 as a therapeutic option for patients with squamous NSCLC tumors harboring amplification of FGFR1. PMID- 23082001 TI - Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1. AB - PURPOSE: Arsenic trioxide (ATO) as a single agent is used for treatment of acute promyelocytic leukemia (APL) with minimal toxicity, but therapeutic effect of ATO in other types of malignancies has not been achieved. We tested whether a combination with ethacrynic acid (EA), a glutathione S-transferase P1-1 (GSTP1-1) inhibitor, and a reactive oxygen species (ROS) inducer will extend the therapeutic effect of ATO beyond APL. EXPERIMENTAL DESIGN: The combined apoptotic effects of ATO plus ethacrynic acid were tested in non-APL leukemia and lymphoma cell lines. The role of ROS, GSTP1-1, glutathione (GSH), and Mcl-1 in apoptosis was determined. The selective response to this combination of cells with and without GSTP1-1 expression was compared. RESULTS: ATO/EA combination synergistically induced apoptosis in myeloid leukemia and lymphoma cells. This treatment produced high ROS levels, activated c-jun-NH(2)-kinase (JNK), and reduced Mcl-1 protein. This led to the decrease of mitochondrial transmembrane potential, release of cytochrome c, and subsequently, to activation of caspase-3 and -9. Induction of apoptosis in leukemia and lymphoma cells expressing GSTP1-1 required high ethacrynic acid concentrations to be combined with ATO. Silencing of GSTP1 in leukemia cells sensitized them to ATO/EA-induced apoptosis. In a subgroup of B-cell lymphoma, which does not express GSTP1-1, lower concentrations of ethacrynic acid and its more potent derivative, ethacrynic acid butyl-ester (EABE), decreased intracellular GSH levels and synergistically induced apoptosis when combined with ATO. CONCLUSION: B-cell lymphoma cells lacking GSTP1-1 are more sensitive than myeloid leukemia cells to ATO/EA-induced apoptosis. PMID- 23082002 TI - A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer. AB - PURPOSE: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC). EXPERIMENTAL DESIGN: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions. RESULTS: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab. CONCLUSIONS: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy. PMID- 23082003 TI - The PI3K/AKT/mTOR pathway as a therapeutic target in endometrial cancer. AB - Endometrial cancer is the most common gynecologic malignancy in the United States. Overactivation of the PI3K/AKT/mTOR pathway, a signaling pathway that plays an important role in cellular growth and survival, has recently been implicated in endometrial cancer pathogenesis, and as such, inhibition of the PI3K/AKT/mTOR pathway is of therapeutic interest. Preclinical and clinical studies are proving useful in elucidating the antitumor effects of different PI3K/AKT/mTOR pathway inhibitors, and in defining which patient populations these inhibitors might be most effective in. For example, an increasing amount of preclinical data suggest that loss of PTEN or genetic alteration of PIK3CA may be indicators of sensitivity to PI3K/AKT/mTOR pathway inhibition, while activating KRAS mutations may predict resistance. In the latter case, combined inhibition of the RAS/RAF/MEK and PI3K/AKT/mTOR pathways has been suggested as a therapeutic strategy. In addition, the PI3K/AKT/mTOR pathway has been implicated in conferring resistance to conventional therapies, and so PI3K/AKT/mTOR pathway inhibitors in combination with hormonal and/or cytotoxic agents are being evaluated. In conclusion, preclinical models are providing insights into the antitumor activity of PI3K/AKT/mTOR pathway inhibition, and are helping define patient populations most likely to benefit from these therapies. Clinical validation of these findings is ongoing. PMID- 23082004 TI - Understanding the role of immunoaffinity-based mass spectrometry methods for clinical applications. PMID- 23082005 TI - Mineralocorticoid receptor antagonists and renal involvement in primary aldosteronism: opening of a new era. AB - Primary aldosteronism (PA) is one of the commonest forms of curable hypertension, and use of the plasma aldosterone-to-renin ratio as a screening test has led to a more efficient identification of this condition. Both animal and human studies have indicated that PA is associated with a variety of cardiovascular and renal complications that reflect the capability of elevated aldosterone to induce tissue damage exceeding that induced by hypertension itself. Involvement of the kidney in PA is highly relevant because structural renal damage is associated with less favorable outcome, both in terms of blood pressure response to treatment and possibility to develop progressive renal failure. However, early involvement of the kidney in PA is characterized by functional changes that are largely reversible with treatment. Unilateral adrenalectomy or administration of mineralocorticoid receptor antagonists are the current options for treating an aldosterone-producing adenoma or idiopathic adrenal hyperplasia. Both treatments are effective in correcting hypertension and hypokalemia, and currently available information on their capability to prevent deterioration of renal function indicates that both surgery and medical treatment are of considerable value. PMID- 23082006 TI - Acylated ghrelin as a provocative test for the diagnosis of GH deficiency in adults. AB - OBJECTIVE: Insulin tolerance test (ITT) is the test of reference for the diagnosis of adult GH deficiency (GHD), although GHRH in combination with arginine (ARG) or GH secretagogues are considered equally reliable tests. Testing with GH secretagogue alone is, anyway, a potent stimulus exploring the integrity of hypothalamic pathways controlling somatotropic function. We therefore aimed to determine the diagnostic reliability of testing with ghrelin, the natural GH secretagogue. METHODS: We studied the GH response (every 15 MIN from 15 TO +120 MIN) to acylated ghrelin (1G/KG I.V. AT 0MIN) IN 78 patients with a history of pituitary disease (49 male, 29 female; age (MEANS.D.): 52.1+/-18.7 years; BMI: 26.7+/-5.3 kg/m(2)). The lack of GH response to GHRH+ARG and/or ITT was considered the gold standard for the diagnosis of GHD. The best GH cut-off to ghrelin test, defined as the one with the best sensitivity (SE) and specificity (SP), was identified using the receiver-operating characteristic curve analysis. RESULTS: The best GH cut-off to ghrelin test was 7.3 MUg/l in lean subjects (SE 88.2%, SP 90.9%), 2.9 MUg/l in overweight subjects (SE 92.6%, SP 100%) and 0.6 MUg/l in obese subjects (SE 50%, SP 100%). The diagnostic accuracy was 89.3, 94.1 and 62.5% respectively. CONCLUSIONS: Our data show that testing with acylated ghrelin represents a reliable diagnostic tool for the diagnosis of adult GHD, in lean and overweight subjects, if appropriate cut-off limits are assumed. Obesity strongly reduces GH response to ghrelin, GH weight-related cut-off limit and diagnostic reliability of the test. PMID- 23082007 TI - PROKR2 and PROK2 mutations cause isolated congenital anosmia without gonadotropic deficiency. AB - OBJECTIVE: Isolated congenital anosmia (ICA) is a rare phenotype defined as absent recall of any olfactory sensations since birth and the absence of any disease known to cause anosmia. Although most cases of ICA are sporadic, reports of familial cases suggest a genetic cause. ICA due to olfactory bulb agenesis and associated to hypogonadotropic hypogonadism defines Kallmann syndrome (KS), in which several gene defects have been described. In KS families, the phenotype may be restricted to ICA. We therefore hypothesized that mutations in KS genes cause ICA in patients, even in the absence of family history of reproduction disorders. DESIGN AND METHODS: In 25 patients with ICA and olfactory bulb agenesis, a detailed phenotype analysis was conducted and the coding sequences of KAL1, FGFR1, FGF8, PROKR2, and PROK2 were sequenced. RESULTS: Three PROKR2 mutations previously described in KS and one new PROK2 mutation were found. Investigation of the families showed incomplete penetrance of these mutations. CONCLUSIONS: This study is the first to report genetic causes of ICA and indicates that KS genes must be screened in patients with ICA. It also confirms the considerable complexity of GNRH neuron development in humans. PMID- 23082008 TI - Detection of papillary muscle infarction by late gadolinium enhancement: incremental value of short-inversion time vs. standard imaging. AB - AIMS: Late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging can detect myocardial scar in patients with myocardial infarction. The detection of papillary muscle infarction (PMI) may be difficult due to the bright blood signal. The aim of our study was to evaluate the incremental value of LGE CMR imaging using an inversion recovery (IR)-GRE with a short-inversion time (TI) over standard LGE imaging in identifying PMI. METHODS AND RESULTS: Fifty-six patients with myocardial infarction were studied using a standard IR-GRE LGE sequence with an adjusted TI to null the signal intensity of normal myocardium and with a 3D IR-GRE with a short TI (<180 ms). Signal-to-noise and contrast-to noise ratios (CNR) and the frequency of PMI were determined. Image quality and infarction sharpness were evaluated. The short-TI LGE sequence detected a higher number of PMI compared with standard LGE sequence (19/54 vs. 15/54) with an increased sharpness of PMI (84.2 vs. 53.3%). The CNR was higher between infarcted myocardium and blood (77.9 +/- 60 vs. 19.3 +/- 16, P < 0.001) and between PMI and blood (69.4 +/- 51 vs. 39.4 +/- 26, respectively, P = 0.0157). CONCLUSIONS: Our data indicate that in patients with myocardial infarction, LGE CMR imaging using a short TI may be more sensitive than standard LGE imaging for the detection of PMI. PMID- 23082009 TI - Oncophagy: harnessing regulation of autophagy in cancer therapy. AB - Autophagy is an increasingly well-characterised process of cell component auto digestion and recycling thought necessary for cellular subsistence. As we gain a more thorough understanding of the mechanisms underlying autophagy, its relevance to human disease and therapeutic potential are being clarified. This review summarises the evidence implicating autophagy in the pathogenesis and potential treatment of malignant disease. In addition, we explore the molecular role of microRNAs as key regulators in what we propose should now become known as 'oncophagy'. PMID- 23082010 TI - Left ventricular pacing rate lower than expected during manual pacing threshold test in a biventricular defibrillator. PMID- 23082022 TI - Type I: families, planning and errors. PMID- 23082023 TI - Voltage-gated Na+ channels: novel players in fibroblast-to-myofibroblast transition with a potential role in atrial arrhythmogenesis? PMID- 23082024 TI - Central versus peripheral control of cardiac output in humans: insight from atrial pacing. PMID- 23082025 TI - Hard-wired for hypertension? The sympathetic nervous system causing havoc to non responders' blood pressure. PMID- 23082026 TI - Regional disparity of cerebral vessel reactivity. PMID- 23082027 TI - A novel role for the red blood cell in the regulation of tissue O2 supply. PMID- 23082028 TI - A bioinformatics approach for integrated transcriptomic and proteomic comparative analyses of model and non-sequenced anopheline vectors of human malaria parasites. AB - Malaria morbidity and mortality caused by both Plasmodium falciparum and Plasmodium vivax extend well beyond the African continent, and although P. vivax causes between 80 and 300 million severe cases each year, vivax transmission remains poorly understood. Plasmodium parasites are transmitted by Anopheles mosquitoes, and the critical site of interaction between parasite and host is at the mosquito's luminal midgut brush border. Although the genome of the "model" African P. falciparum vector, Anopheles gambiae, has been sequenced, evolutionary divergence limits its utility as a reference across anophelines, especially non sequenced P. vivax vectors such as Anopheles albimanus. Clearly, technologies and platforms that bridge this substantial scientific gap are required in order to provide public health scientists with key transcriptomic and proteomic information that could spur the development of novel interventions to combat this disease. To our knowledge, no approaches have been published that address this issue. To bolster our understanding of P. vivax-An. albimanus midgut interactions, we developed an integrated bioinformatic-hybrid RNA-Seq-LC-MS/MS approach involving An. albimanus transcriptome (15,764 contigs) and luminal midgut subproteome (9,445 proteins) assembly, which, when used with our custom Diptera protein database (685,078 sequences), facilitated a comparative proteomic analysis of the midgut brush borders of two important malaria vectors, An. gambiae and An. albimanus. PMID- 23082030 TI - Is the HFEA's policy on compensating egg donors and egg sharers defensible? AB - This paper asks whether the Human Fertilisation and Embryology Authority's (HFEA's) recently revised policies on compensating egg donors and egg sharers are defensible, paying particular heed to the ethical arguments, concepts, and principles deployed in support of them. The paper proceeds by briefly outlining both the 'old' and 'new' HFEA policies before describing and explaining the main arguments that are supposed to underpin these. The arguments are then subjected to scrutiny and generally found wanting. The paper's primary conclusion is that treating egg sharers more generously than egg donors (which is what both the 'old' and 'new' policies do) is inconsistent and unjustified. In order to render the HFEA's policies consistent, it would need either to limit more strictly the benefits-in-kind available to egg sharers or to take a more permissive approach to monetary compensation for egg donors. The paper's secondary conclusion is that the latter is preferable. Egg donors could, provided that suitable regulatory controls were in place, be compensated more generously without this being ethically problematic. Furthermore, since egg sharing is in some respects more problematic than other forms of egg donation, there is something to be said for encouraging a move away from sharing to donation. PMID- 23082031 TI - Structure of rrn operons in pathogenic non-cultivable treponemes: sequence but not genomic position of intergenic spacers correlates with classification of Treponema pallidum and Treponema paraluiscuniculi strains. AB - This study examined the sequences of the two rRNA (rrn) operons of pathogenic non cultivable treponemes, comprising 11 strains of T. pallidum ssp. pallidum (TPA), five strains of T. pallidum ssp. pertenue (TPE), two strains of T. pallidum ssp. endemicum (TEN), a simian Fribourg-Blanc strain and a rabbit T. paraluiscuniculi (TPc) strain. PCR was used to determine the type of 16S-23S ribosomal intergenic spacers in the rrn operons from 30 clinical samples belonging to five different genotypes. When compared with the TPA strains, TPc Cuniculi A strain had a 17 bp deletion, and the TPE, TEN and Fribourg-Blanc isolates had a deletion of 33 bp. Other than these deletions, only 17 heterogeneous sites were found within the entire region (excluding the 16S-23S intergenic spacer region encoding tRNA-Ile or tRNA-Ala). The pattern of nucleotide changes in the rrn operons corresponded to the classification of treponemal strains, whilst two different rrn spacer patterns (Ile/Ala and Ala/Ile) appeared to be distributed randomly across species/subspecies classification, time and geographical source of the treponemal strains. It is suggested that the random distribution of tRNA genes is caused by reciprocal translocation between repetitive sequences mediated by a recBCD-like system. PMID- 23082032 TI - Diagnosis of Tritrichomonas foetus-infected bulls, an ultimate approach to eradicate bovine trichomoniasis in US cattle? AB - Bovine trichomoniasis is a sexually transmitted protozoan disease with a worldwide distribution. It has been endemic in the USA for more than 80 years. Mississippi and all the states west of the Mississippi River, except Iowa and Minnesota, have rules/regulations to reduce the spread of the disease. The core of these regulations consists of testing bulls and prohibiting importation of non Tritrichomonas foetus-free bulls. Factors such as sampling methods and intervals, shipping medium and temperature, and testing techniques are reviewed for their effect on diagnostic accuracy. Finally, a comprehensive approach for controlling and eventually eradicating the disease is presented. PMID- 23082029 TI - Quantitative proteomic analysis in metastatic renal cell carcinoma reveals a unique set of proteins with potential prognostic significance. AB - Metastatic renal cell carcinoma (RCC) is one of the most treatment-resistant malignancies, and patients have a dismal prognosis, with a <10% five-year survival rate. The identification of markers that can predict the potential for metastases will have a great effect in improving patient outcomes. In this study, we used differential proteomics with isobaric tags for relative and absolute quantitation (iTRAQ) labeling and LC-MS/MS analysis to identify proteins that are differentially expressed in metastatic and primary RCC. We identified 1256 non redundant proteins, and 456 of these were quantified. Further analysis identified 29 proteins that were differentially expressed (12 overexpressed and 17 underexpressed) in metastatic and primary RCC. Dysregulated protein expressions of profilin-1 (Pfn1), 14-3-3 zeta/delta (14-3-3zeta), and galectin-1 (Gal-1) were verified on two independent sets of tissues by means of Western blot and immunohistochemical analysis. Hierarchical clustering analysis showed that the protein expression profile specific for metastatic RCC can distinguish between aggressive and non-aggressive RCC. Pathway analysis showed that dysregulated proteins are involved in cellular processes related to tumor progression and metastasis. Furthermore, preliminary analysis using a small set of tumors showed that increased expression of Pfn1 is associated with poor outcome and is a potential prognostic marker in RCC. In addition, 14-3-3zeta and Gal-1 also showed higher expression in tumors with poor prognosis than in those with good prognosis. Dysregulated proteins in metastatic RCC represent potential prognostic markers for kidney cancer patients, and a greater understanding of their involved biological pathways can serve as the foundation of the development of novel targeted therapies for metastatic RCC. PMID- 23082033 TI - Characterization of the ROK-family transcriptional regulator RokA of Streptococcus pneumoniae D39. AB - The Gram-positive human pathogen Streptococcus pneumoniae possesses an unusually high number of gene clusters specific for carbohydrate utilization. This provides it with the ability to use a wide array of sugars, which may aid during infection and survival in different environmental conditions present in the host. In this study, the regulatory mechanism of transcription of a gene cluster, SPD0424-8, putatively encoding a cellobiose/lactose-specific phosphotransferase system is investigated. We demonstrate that this gene cluster is transcribed as one transcriptional unit directed by the promoter of the SPD0424 gene. Upstream of SPD0424, a gene was identified encoding a ROK-family transcriptional regulator (RokA: SPD0423). DNA microarray and transcriptional reporter analyses with a rokA mutant revealed that RokA acts as a transcriptional repressor of the SPD0424-8 operon. Furthermore, we identified a 25 bp AT-rich DNA operator site (5' TATATTTAATTTATAAAAAATAAAA-3') in the promoter region of SPD0424, which was validated by promoter truncation studies, DNase I footprinting and electrophoretic mobility-shift assays. We tested a large range of different sugars for their effect on the expression of the SPD0424-8 operon, but only moderate variation in expression was observed in the conditions applied. Therefore, a co-factor for RokA-mediated transcriptional control could not be identified. PMID- 23082035 TI - Manuka honey is bactericidal against Pseudomonas aeruginosa and results in differential expression of oprF and algD. AB - The presence of Pseudomonas aeruginosa in cutaneous wounds is of clinical significance and can lead to persistent infections. Manuka honey has gained ground in clinical settings due to its effective therapeutic action and broad spectrum of antibacterial activity. In this study, the effect of manuka honey on P. aeruginosa was investigated using MIC, MBC, growth kinetics, confocal microscopy, atomic force microscopy and real-time PCR. A bactericidal mode of action for manuka honey against P. aeruginosa was deduced (12 %, w/v, MIC; 16 %, w/v, MBC) and confirmed by confocal and atomic force microscopy, which showed extensive cell lysis after 60 min exposure to inhibitory concentrations of manuka honey. The inability of honey-treated cells to form microcolonies was demonstrated and investigated using Q-PCR for three key microcolony-forming genes: algD, lasR and oprF. The expression of algD increased 16-fold whereas oprF expression decreased 10-fold following honey treatment; lasR expression remained unaltered. These findings confirm that manuka honey is effective at inducing cell lysis and identify two targets, at the genetic level, that might be involved in this process. PMID- 23082036 TI - Quantile Regression for Analyzing Heterogeneity in Ultra-high Dimension. AB - Ultra-high dimensional data often display heterogeneity due to either heteroscedastic variance or other forms of non-location-scale covariate effects. To accommodate heterogeneity, we advocate a more general interpretation of sparsity which assumes that only a small number of covariates influence the conditional distribution of the response variable given all candidate covariates; however, the sets of relevant covariates may differ when we consider different segments of the conditional distribution. In this framework, we investigate the methodology and theory of nonconvex penalized quantile regression in ultra-high dimension. The proposed approach has two distinctive features: (1) it enables us to explore the entire conditional distribution of the response variable given the ultra-high dimensional covariates and provides a more realistic picture of the sparsity pattern; (2) it requires substantially weaker conditions compared with alternative methods in the literature; thus, it greatly alleviates the difficulty of model checking in the ultra-high dimension. In theoretic development, it is challenging to deal with both the nonsmooth loss function and the nonconvex penalty function in ultra-high dimensional parameter space. We introduce a novel sufficient optimality condition which relies on a convex differencing representation of the penalized loss function and the subdifferential calculus. Exploring this optimality condition enables us to establish the oracle property for sparse quantile regression in the ultra-high dimension under relaxed conditions. The proposed method greatly enhances existing tools for ultra-high dimensional data analysis. Monte Carlo simulations demonstrate the usefulness of the proposed procedure. The real data example we analyzed demonstrates that the new approach reveals substantially more information compared with alternative methods. PMID- 23082037 TI - Work, Health, and Family at Older Ages in Japan. AB - In this paper, we investigate ways in which the relationship between health and labor force exit at older ages is moderated by family characteristics. Using two waves of data from a national sample of older Japanese men collected 1999 and 2002, we estimate logistic regression models for labor force exit beyond age 63 as a function of health change, family characteristics, and their interactions. We confirm that poor health is strongly associated with labor force exit and find evidence that moderating influences of family context depend upon the level of health. However, results are only partially consistent with hypotheses that the relationship between health and the likelihood of labor force exit should be stronger for (a) those with good health and family incentives to exit the labor force and (b) those with poor health and family incentives to remain in the labor force. PMID- 23082034 TI - Functional amyloid formation by Streptococcus mutans. AB - Dental caries is a common infectious disease associated with acidogenic and aciduric bacteria, including Streptococcus mutans. Organisms that cause cavities form recalcitrant biofilms, generate acids from dietary sugars and tolerate acid end products. It has recently been recognized that micro-organisms can produce functional amyloids that are integral to biofilm development. We now show that the S. mutans cell-surface-localized adhesin P1 (antigen I/II, PAc) is an amyloid forming protein. This conclusion is based on the defining properties of amyloids, including binding by the amyloidophilic dyes Congo red (CR) and Thioflavin T (ThT), visualization of amyloid fibres by transmission electron microscopy and the green birefringent properties of CR-stained protein aggregates when viewed under cross-polarized light. We provide evidence that amyloid is present in human dental plaque and is produced by both laboratory strains and clinical isolates of S. mutans. We provide further evidence that amyloid formation is not limited to P1, since bacterial colonies without this adhesin demonstrate residual green birefringence. However, S. mutans lacking sortase, the transpeptidase enzyme that mediates the covalent linkage of its substrates to the cell-wall peptidoglycan, including P1 and five other proteins, is not birefringent when stained with CR and does not form biofilms. Biofilm formation is inhibited when S. mutans is cultured in the presence of known inhibitors of amyloid fibrillization, including CR, Thioflavin S and epigallocatechin-3-gallate, which also inhibited ThT uptake by S. mutans extracellular proteins. Taken together, these results indicate that S. mutans is an amyloid-forming organism and suggest that amyloidogenesis contributes to biofilm formation by this oral microbe. PMID- 23082038 TI - The Mediated and Moderated Effects of Family Support on Child Maltreatment. AB - Previous research has linked parents' social support to decreased child maltreatment but questions remain surrounding the mechanisms explaining this association. Further, it is unclear whether this association applies to support provided by family alone (and not friends), and whether it is moderated by the presence of neighborhood violence. Based on a sample of parents of children aged 3-15 in Chicago, we find that parents' family support is associated with a lower risk of child maltreatment. This association is partly mediated by reduced parental depression, but only in neighborhoods with average or high levels of violence. In neighborhoods with low levels of violence, the inverse association between family support and maltreatment is equally strong, but it is not mediated by reduced depression. PMID- 23082039 TI - On existence of reporter strands in DNA-based graph structures. AB - Through self-assembly of branched junction molecules many different DNA structures (graphs) can be assembled. We show that every multigraph can be assembled by DNA such that there is a single strand that traces each edge in the graph at least once. This strand corresponds to a boundary component of a two dimensional orientable surface that has the given graph as a deformation retract. This boundary component traverses every edge at least once, and it defines a circular path in the graph that "preserves the graph structure" and traverses each edge. PMID- 23082040 TI - Do Advance Yield Markings Increase Safe Driver Behaviors at Unsignalized, Marked Midblock Crosswalks? Driving Simulator Study. AB - In the United States, 78% of pedestrian crashes occur at noninter-section crossings. As a result, unsignalized, marked midblock crosswalks are prime targets for remediation. Many of these crashes occur under sight-limited conditions in which the view of critical information by the driver or pedestrian is obstructed by a vehicle stopped in an adjacent travel or parking lane on the near side of the crosswalk. Study of such a situation on the open road is much too risky, but study of the situation in a driving simulator is not. This paper describes the development of scenarios with sight limitations to compare potential vehicle-pedestrian conflicts on a driving simulator under conditions with two different types of pavement markings. Under the first condition, advance yield markings and symbol signs (prompts) that indicated "yield here to pedestrians" were used to warn drivers of pedestrians at marked, midblock crosswalks. Under the second condition, standard crosswalk treatments and prompts were used to warn drivers of these hazards. Actual crashes as well as the drivers' point of gaze were measured to determine if the drivers approaching a marked midblock crosswalk looked for pedestrians in the crosswalk more frequently and sooner in high-risk scenarios when advance yield markings and prompts were present than when standard markings and prompts were used. Fewer crashes were found to occur with advance yield markings. Drivers were also found to look for pedestrians much more frequently and much sooner with advance yield markings. The advantages and limitations of the use of driving simulation to study problems such as these are discussed. PMID- 23082041 TI - Do Crashes and Near Crashes in Simulator-Based Training Enhance Novice Drivers' Visual Search for Latent Hazards? AB - Young drivers (younger than 25 years of age) are overrepresented in crashes. Research suggests that a relevant cause is inadequate visual search for possible hazards that are hidden from view. The objective of this study was to develop and evaluate a low-cost, fixed-base simulator training program that would address this failure. It was hypothesized that elicited crashes in the simulator training would result in better scanning for latent hazards in scenarios that were similar to the training scenarios but situated in a different environment (near transfer), and, to a lesser degree, would result in better scanning in scenarios that had altogether different latent hazards than those contained in the training scenarios (far transfer). To test the hypotheses, 18 trained and 18 untrained young novice drivers were evaluated on an advanced driving simulator (different from the training simulator). The eye movements of both groups were measured. In near transfer scenarios, trained drivers fixated the hazardous region 84% of the time, compared with only 57% of untrained drivers. In far transfer scenarios, trained drivers fixated the hazardous region 71 % of the time, compared with only 53% of untrained drivers. The differences between trained and untrained drivers in both the near transfer scenarios and the far transfer scenarios were significant, with a large effect size in the near transfer scenarios and a medium effect size in the far transfer scenarios [respectively: U = 63.00, p(2-tailed) < .01, r = -.53, and U = 88.00, p(2-tailed)<.05,r = -.39]. PMID- 23082043 TI - Initial experiences of simultaneous laparoscopic resection of colorectal cancer and liver metastases. AB - Introduction. Simultaneous resection of primary colorectal carcinoma (CRC) and synchronous liver metastases (SLMs) is subject of debate with respect to morbidity in comparison to staged resection. The aim of this study was to evaluate our initial experience with this approach. Methods. Five patients with primary CRC and a clinical diagnosis of SLM underwent combined laparoscopic colorectal and liver surgery. Patient and tumor characteristics, operative variables, and postoperative outcomes were evaluated retrospectively. Results. The primary tumor was located in the colon in two patients and in the rectum in three patients. The SLM was solitary in four patients and multiple in the remaining patient. Surgical approach was total laparoscopic (2 patients) or hand assisted laparoscopic (3 patients). The midline umbilical or transverse suprapubic incision created for the hand port and/or extraction of the specimen varied between 5 and 10 cm. Median operation time was 303 (range 151-384) minutes with a total blood loss of 700 (range 200-850) mL. Postoperative hospital stay was 5, 5, 9, 14, and 30 days. An R0 resection was achieved in all patients. Conclusions. From this initial single-center experience, simultaneous laparoscopic colorectal and liver resection appears to be feasible in selected patients with CRC and SLM, with satisfying short-term results. PMID- 23082042 TI - Surgical options for initially unresectable colorectal liver metastases. AB - Although the frontiers of liver resection for colorectal liver metastases have broadened in recent decades, approximately 75% of these patients present with unresectable metastases at the time of their diagnosis. In the past, these patients underwent only palliative treatment, without the chance of a cure. In the previous two decades, several therapeutic strategies have been developed that render resectable those metastases that were initially unresectable, thus offering the chance of long-term survival and even a cure to these patients. The oncosurgical modalities that are available include liver resection following portal vein ligation/embolization, "two-stage" liver resection, one-stage ultrasonically guided liver resection, hepatectomy following conversion chemotherapy, and liver resection combined with thermal ablation. Moreover, in recent years, certain authors have recommended the revisiting of the concept of liver transplantation in highly selected patients with unresectable colorectal liver metastases and favorable prognostic factors. By employing such therapies, the number of patients with colorectal liver metastases who undergo a potentially curative treatment could increase to 40%. The safety profile of these approaches is acceptable (morbidity rates as high as 45%, mortality rates of less than 5%). Furthermore, the 5-year survival rates (approximately 30%) are significantly increased over those that were achieved with palliative treatment. PMID- 23082044 TI - Initial experience in single-incision transumbilical laparoscopic liver resection: indications, potential benefits, and limitations. AB - Background. Single-incision transumbilical laparoscopic liver resection (SITLLR) has been recently described in limited series. We report our experience in SITLLR and discuss the future of this approach in terms of indications, potential benefits, and limitations, with a special reference to laparoscopic liver resection (LLR). Patients and Methods. Six patients underwent SITLLR. Indications were biliary cysts (3 cases), hydatid cysts (2), and colorectal liver metastasis (1). Procedures consisted in cysts unroofing, left lateral lobectomy, pericystectomy, and wedge resection. SITLLR was performed with 11 mm reusable trocar, 10 or 5 mm 30 degrees scopes, 10 mm ultrasound probe, curved reusable instruments, and straight disposable bipolar shears. Results. Neither conversion to open surgery nor insertion of supplementary trocars was necessary. Median laparoscopic time was 105.5 minutes and median blood loss 275 mL. Median final umbilical scar length was 1.5 cm, and median length of stay was 4 days. No early or late complications occurred. Conclusion. SITLLR remains a challenging procedure. It is feasible in highly selected patients, requiring experience in hepatobiliary and laparoscopic surgery and skills in single-incision laparoscopy. Apart from cosmetic benefit, our experience and literature review did not show significant advantages if compared with multiport LLR, underlying that specific indications remain to be established. PMID- 23082045 TI - Identifying and Remediating Failures of Selective Attention in Older Drivers. AB - Older drivers are primarily overinvolved in crashes at intersections, and failure to attend to regions that contain relevant information about potential hazards is a major contributor to this problem. Corroborating this, we have found that older drivers in both controlled scenarios on a driving simulator and somewhat less controlled situations on the road attend to (i.e., fixate) target regions in intersections significantly less frequently than do younger experienced drivers. Moreover, we have developed a training program that substantially improves older drivers' attention to these regions. Together, these findings indicate that older drivers' less frequent scanning of regions at intersections from which hazards may emerge may be due to their developing something like an unsafe habit rather than to deteriorating physical or mental capabilities and thus that training may be effective in reducing crashes. PMID- 23082046 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: where are we? AB - Peritoneal surface malignancies are generally associated with poor prognosis. In daily clinical routine, systemic chemotherapy is still considered the only reasonable therapy despite of encouraging results of cytoreductive surgery (CRS) along with intraperitoneal hyperthermic chemotherapy (HIPEC). The Achilles heel of CRS and HIPEC is appropriate patient selection and precise surgical technique preventing patients from excessive morbidity and mortality. Given these findings, new concepts of second look surgery for high risk patients allow detection of peritoneal spread ahead of clinical symptoms or presence of peritoneal masses reducing perioperative morbidity. In addition, personalized intraperitoneal chemotherapy might further improve outcome by appreciating individual tumor biology. These days, every physician should be aware of CRS and HIPEC for treatment of peritoneal surface malignancies. Since there is now sufficient data for the superiority of CRS and HIPEC to systemic chemotherapy in selected patients, our next goal should be providing this strategy with minimal morbidity and mortality even in the presence of higher tumor load. PMID- 23082047 TI - c-Met in pancreatic cancer stem cells: therapeutic implications. AB - Pancreatic cancer is the deadliest solid cancer and currently the fourth most frequent cause of cancer-related deaths. Emerging evidence suggests that cancer stem cells (CSCs) play a crucial role in the development and progression of this disease. The identification of CSC markers could lead to the development of new therapeutic targets. In this study, the authors explore the functional role of c Met in pancreatic CSCs, by analyzing self-renewal with sphere assays and tumorigenicity capacity in NOD SCID mice. They concluded that c-Met is a novel marker for identifying pancreatic CSCs and c-Met(high) in a higher tumorigenic cancer cell population. Inhibition of c-Met with XL184 blocks self-renewal capacity in pancreatic CSCs. In pancreatic tumors established in NOD SCID mice, c Met inhibition slowed tumor growth and reduced the population of CSCs, along with preventing the development of metastases. PMID- 23082048 TI - Magnets, children and the bowel: a dangerous attraction? AB - Reports of magnet ingestion are increasing rapidly globally. However, multiple magnet ingestion, the subsequent potential complications and the importance of the early identification and proper management remain both under-recognized and underestimated. Published literature on such cases could possibly represent only the tip of an iceberg with press reports, web blogs and government documents highlighting further occurrence of many more such incidents. The increasing number of complications worldwide being reported secondary to magnet ingestion point not only to an acute lack of awareness about this condition among the medical profession but also among parents and carers who will be in most cases the first to pick up on magnet ingestion. There still seems to be no consensus on the management of magnet ingestion with several algorithms being proposed for management. Prevention of this condition remains a much better option than cure. Proper education and improved awareness among parents and carers and frontline medical staff is key in addressing this rapidly emerging problem. The goal of managing such cases of suspected magnet ingestion should be aimed at reducing delays between ingestion time, diagnosis time and intervention time. PMID- 23082049 TI - Laparoscopic distal pancreatectomy: up-to-date and literature review. AB - Pancreatic surgery represents one of the most challenging areas in digestive surgery. In recent years, an increasing number of laparoscopic pancreatic procedures have been performed and laparoscopic distal pancreatectomy (LDP) has gained world-wide acceptance because it does not require anastomosis or other reconstruction. To date, English literature reports more than 300 papers focusing on LDP, but only 6% included more than 30 patients. Literature review confirms that LDP is a feasible and safe procedure in patients with benign or low grade malignancies. Decreased blood loss and morbidity, early recovery and shorter hospital stay may be the main advantages. Several concerns still exist for laparoscopic pancreatic adenocarcinoma excision. The individual surgeon determines the technical conduction of LDP, with or without spleen preservation; currently robotic pancreatic surgery has gained diffusion. Additional researches are necessary to determine the best technique to improve the procedure results. PMID- 23082051 TI - Anti-inflammatory effects of Lacto-Wolfberry in a mouse model of experimental colitis. AB - AIM: To investigate the anti-inflammatory properties of Lacto-Wolfberry (LWB), both in vitro and using a mouse model of experimental colitis. METHODS: The effects of LWB on lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) and interleukin (IL)-6 secretion were assessed in a murine macrophage cell line. in vitro assessment also included characterizing the effects of LWB on the activation of NF-E2 related 2 pathway and inhibition of tumor necrosis factor alpha (TNF-alpha)-induced nuclear factor-kappaB (NF-kappaB) activation, utilizing reporter cell lines. Following the in vitro assessment, the anti-inflammatory efficacy of an oral intervention with LWB was tested in vivo using a preclinical model of intestinal inflammation. Multiple outcomes including body weight, intestinal histology, colonic cytokine levels and anti-oxidative measures were investigated. RESULTS: LWB reduced the LPS-mediated induction of ROS production [+LPS vs 1% LWB + LPS, 1590 +/- 188.5 relative luminescence units (RLU) vs 389 +/ 5.9 RLU, P < 0.001]. LWB was more effective than wolfberry alone in reducing LPS induced IL-6 secretion in vitro (wolfberry vs 0.5% LWB, 15% +/- 7.8% vs 64% +/- 5%, P < 0.001). In addition, LWB increased reporter gene expression via the anti oxidant response element activation (wolfberry vs LWB, 73% +/- 6.9% vs 148% +/- 28.3%, P < 0.001) and inhibited the TNF-alpha-induced activation of the NF-kappaB pathway (milk vs LWB, 10% +/- 6.7% vs 35% +/- 3.3%, P < 0.05). Furthermore, oral supplementation with LWB resulted in a reduction of macroscopic (-LWB vs +LWB, 5.39 +/- 0.61 vs 3.66 +/- 0.59, P = 0.0445) and histological scores (-LWB vs +LWB, 5.44 +/- 0.32 vs 3.66 +/- 0.59, P = 0.0087) in colitic mice. These effects were associated with a significant decrease in levels of inflammatory cytokines such as IL-1beta (-LWB vs +LWB, 570 +/- 245 MUg/L vs 89 +/- 38 MUg/L, P = 0.0106), keratinocyte-derived chemokine/growth regulated protein-alpha (-LWB vs +LWB, 184 +/- 49 MUg/L vs 75 +/- 20 MUg/L, P = 0.0244), IL-6 (-LWB vs +LWB, 318 +/- 99 MUg/L vs 117 +/- 18 MUg/L, P = 0.0315) and other pro-inflammatory proteins such as cyclooxygenase-2 (-LWB vs +LWB, 0.95 +/- 0.12 AU vs 0.36 +/- 0.11 AU, P = 0.0036) and phosphorylated signal transducer and activator of transcription-3 ( LWB vs +LWB, 0.51 +/- 0.15 AU vs 0.1 +/- 0.04 AU, P = 0.057). Moreover, antioxidant biomarkers, including expression of gene encoding for the glutathione peroxidase, in the colon and the plasma anti-oxidant capacity were significantly increased by supplementation with LWB (-LWB vs +LWB, 1.2 +/- 0.21 mmol/L vs 2.1 +/- 0.19 mmol/L, P = 0.0095). CONCLUSION: These results demonstrate the anti inflammatory properties of LWB and suggest that the underlying mechanism is at least in part due to NF-kappaB inhibition and improved anti-oxidative capacity. PMID- 23082050 TI - Theoretical basis of a beneficial role for vitamin D in viral hepatitis. AB - Abnormal bone metabolism and dysfunction of the calcium-parathyroid hormone vitamin D axis have been reported in patients with viral hepatitis. Some studies suggested a relationship between vitamin D and viral hepatitis. Genetic studies have provided an opportunity to identify the proteins that link vitamin D to the pathology of viral hepatitis (i.e., the major histocompatibility complex class II molecules, the vitamin D receptor, cytochrome P450, the renin-angiotensin system, apolipoprotein E, liver X receptor, toll-like receptor, and the proteins regulated by the Sp1 promoter gene). Vitamin D also exerts its effects on viral hepatitis via non-genomic factors, i.e., matrix metalloproteinase, endothelial vascular growth factor, prostaglandins, cyclooxygenase-2, and oxidative stress. In conclusion, vitamin D could have a beneficial role in viral hepatitis. Calcitriol is best used for viral hepatitis because it is the active form of the vitamin D3 metabolite. PMID- 23082053 TI - Axl glycosylation mediates tumor cell proliferation, invasion and lymphatic metastasis in murine hepatocellular carcinoma. AB - AIM: To investigate the effects of Axl deglycosylation on tumor lymphatic metastases in mouse hepatocellular carcinoma cell lines. METHODS: Western blotting was used to analyze the expression profile of Axl glycoprotein in mouse hepatocellular carcinoma cell line Hca-F treated with tunicamycin and PNGase F 3 (4,5)-dimethylthiazol(-zyl)-3,5-diphenyltetrazolium bromide (MTT) assay, extracellular matrix (ECM) invasion assay (in vitro) and tumor metastasis assay (in vivo) were utilized to evaluate the effect of Axl deglycosylation on the Hca F cell proliferation, invasion and lymphatic metastasis. RESULTS: Tunicamycin and PNGase F treatment markedly inhibited Axl glycoprotein synthesis and expression, proliferation, invasion, and lymphatic metastasis both in vitro and in vivo. In the MTT assay, proliferation was apparent in untreated Hca-F cells compared with treated Hca-F cells. In the ECM invasion assay (in vitro), treated cells passed through the ECMatrix gel in significantly smaller numbers than untreated cells (tunicamycin 5 MUg/mL: 68 +/- 8 vs 80 +/- 9, P = 0.0222; 10 MUg/mL: 50 +/- 6 vs 80 +/- 9, P = 0.0003; 20 MUg/mL: 41 +/- 4 vs 80 +/- 9, P = 0.0001); (PNGase F 8 h: 66 +/- 7 vs 82 +/- 8, P = 0.0098; 16 h: 49 +/- 4 vs 82 +/- 8, P = 0.0001; 24 h: 34 +/- 3 vs 82 +/- 8, P = 0.0001). In the tumor metastasis assay (in vivo), average lymph node weights of the untreated Hca-F group compared with treated Hca F groups (tunicamycin 5 MUg/mL: 0.84 +/- 0.21 g vs 0.72 +/- 0.19 g, P = 0.3237; 10 MUg/mL: 0.84 +/- 0.21 g vs 0.54 +/- 0.11 g, P = 0.0113; 20 MUg/mL: 0.84 +/- 0.21 g vs 0.42 +/- 0.06 g, P = 0.0008); (PNGase F 8 h: 0.79 +/- 0.15 g vs 0.63 +/ 0.13 g, P = 0.0766; 16 h: 0.79 +/- 0.15 g vs 0.49 +/- 0.10 g, P = 0.0022; 24 h: 0.79 +/- 0.15 g vs 0.39 +/- 0.05 g, P = 0.0001). Also, average lymph node volumes of the untreated Hca-F group compared with treated Hca-F groups (tunicamycin 5 MUg/mL: 815 +/- 61 mm3 vs 680 +/- 59 mm3, P = 0.0613; 10 MUg/mL: 815 +/- 61 mm3 vs 580 +/- 29 mm3, P = 0.0001; 20 MUg/mL: 815 +/- 61 mm3 vs 395 +/- 12 mm3, P = 0.0001); (PNGase F 8 h: 670 +/- 56 mm3 vs 581 +/- 48 mm3, P = 0.0532; 16 h: 670 +/- 56 mm3 vs 412 +/- 22 mm3, P = 0.0001; 24 h: 670 +/- 56 mm3 vs 323 +/- 11 mm3, P = 0.0001). CONCLUSION: Alteration of Axl glycosylation can attenuate neoplastic lymphatic metastasis. Axl N-glycans may be a universal target for chemotherapy. PMID- 23082052 TI - Increased tumor necrosis factor receptor 1 expression in human colorectal adenomas. AB - AIM: To determine the expression statuses of tumor necrosis factor (TNF)-alpha, its receptors (TNF-R) and downstream effector molecules in human colorectal adenomas. METHODS: We measured the serum concentrations of TNF-alpha and its receptors in 62 colorectal adenoma patients and 34 healthy controls. The protein expression of TNF-alpha, TNF-R1, TNF-R2 and downstream signals of the TNF receptors, such as c-Jun N-terminal kinase (JNK), nuclear factor-kappa B and caspase-3, were also investigated in human colorectal adenomas and in normal colorectal mucosal tissues by immunohistochemistry. Immunofluorescence confocal microscopy was used to investigate the consistency of expression of TNF-R1 and phospho-JNK (p-JNK). RESULTS: The serum levels of soluble TNF-R1 (sTNF-R1) in adenoma patients were significantly higher than in the control group (3.67 +/- 0.86 ng/mL vs 1.57 +/- 0.72 ng/mL, P < 0.001). Receiver operating characteristic analysis revealed the high diagnostic sensitivity of TNF-R1 measurements (AUC was 0.928) for the diagnosis of adenoma, and the best cut-off level of TNF-R1 was 2.08 ng/mL, with a sensitivity of 93.4% and a specificity of 82.4%. There were no significant differences in the serum levels of TNF-alpha or sTNF-R2 between the two groups. Immunohistochemistry showed high levels of TNF-R1 and p-JNK expression in the epithelial cells of adenomas. Furthermore, a high incidence of co-localization of TNF-R1 and p-JNK was identified in adenoma tissue. CONCLUSION: TNF-R1 may be a promising biomarker of colorectal adenoma, and it may also play an important role in the very early stages of colorectal carcinogenesis. PMID- 23082054 TI - Protection of ghrelin postconditioning on hypoxia/reoxygenation in gastric epithelial cells. AB - AIM: To investigate the protective effect and mechanisms of ghrelin postconditioning against hypoxia/reoxygenation (H/R)-induced injury in human gastric epithelial cells. METHODS: The model of H/R injury was established in gastric epithelial cell line (GES-1) human gastric epithelial cells. Cells were divided into seven groups: normal control group (N); H/R postconditioning group; DMSO postconditioning group (DM); ghrelin postconditioning group (GH); D-Lys3 GHRP-6 + ghrelin postconditioning group (D + GH); capsazepine + ghrelin postconditioning group (C + GH); and LY294002 + ghrelin postconditioning group (L + GH). 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to detect GES-1 cell viability. Hoechst 33258 fluorochrome staining and flow cytometry were conducted to determine apoptosis of GES-1 cells. Spectrophotometry was performed to determine release of lactate dehydrogenate (LDH). Protein expression of Bcl-2, Bax, Akt, and glycogen synthase kinase (GSK) 3beta was determined by western blotting. Expression of vanilloid receptor subtype 1 (VR1), Akt and GSK-3beta was observed by immunocytochemistry. RESULTS: Compared with the H/R group, cell viability of the GH group was significantly increased in a dose-dependent manner (55.9% +/- 10.0% vs 69.6% +/- 9.6%, 71.9% +/ 17.4%, and 76.3% +/- 13.3%). Compared with the H/R group, the percentage of apoptotic cells in the GH group significantly decreased (12.38% +/- 1.51% vs 6.88% +/- 0.87%). Compared with the GH group, the percentage of apoptotic cells in the D + GH group, C + GH group and L + GH groups significantly increased (11.70% +/- 0.88%, 11.93% +/- 0.96%, 10.20% +/- 1.05% vs 6.88% +/- 0.87%). There were no significant differences in the percentage of apoptotic cells between the H/R and DM groups (12.38% +/- 1.51% vs13.00% +/- 1.13%). There was a significant decrease in LDH release following ghrelin postconditioning compared with the H/R group (561.58 +/- 64.01 U/L vs 1062.45 +/- 105.29 U/L). There was a significant increase in LDH release in the D + GH, C + GH and L + GH groups compared with the GH group (816.89 +/- 94.87 U/L, 870.95 +/- 64.06 U/L, 838.62 +/- 118.45 U/L vs 561.58 +/- 64.01 U/L). There were no significant differences in LDH release between the H/R and DM groups (1062.45 +/- 105.29 U/L vs 1017.65 +/- 68.90 U/L). Compared with the H/R group, expression of Bcl-2 and Akt increased in the GH group, whereas expression of Bax and GSK-3beta decreased. Compared with the GH group, expression of Bcl-2 decreased and Bax increased in the D + GH, C + GH and L + GH groups, and Akt decreased and GSK-3beta increased in the L + GH group. The H/R group also upregulated expression of VR1 and GSK-3beta and downregulated Akt. The number of VR1-positive and Akt-positive cells in the GH group significantly increased, whereas the number of GSK-3beta-positive cells significantly decreased. These effects of ghrelin were reversed by capsazepine and LY294002. CONCLUSION: Ghrelin postconditioning protected against H/R-induced injury in human gastric epithelial cells, which indicated that this protection might be associated with GHS-R, VR1 and the PI3K/Akt signaling pathway. PMID- 23082055 TI - Carbon dioxide accumulation during analgosedated colonoscopy: comparison of propofol and midazolam. AB - AIM: To characterize the profiles of alveolar hypoventilation during colonoscopies performed under sedoanalgesia with a combination of alfentanil and either midazolam or propofol. METHODS: Consecutive patients undergoing routine colonoscopy were randomly assigned to sedation with either propofol or midazolam in an open-labeled design using a titration scheme. All patients received 4 MUg/kg per body weight alfentanil for analgesia and 3 L of supplemental oxygen. Oxygen saturation (SpO2) was measured by pulse oximetry (POX), and capnography (PcCO2) was continuously measured using a combined dedicated sensor at the ear lobe. Instances of apnea resulting in measures such as stimulation of the patient, a chin lift, a mask maneuver, or withholding of sedation were recorded. PcCO2 values (as a parameter of sedation-induced hypoventilation) were compared between groups at the following distinct time points: baseline, maximal rise, termination of the procedure and 5 min after termination of the procedure. The number of patients in both study groups who regained baseline PcCO2 values (+/- 1.5 mmHg) five minutes after the procedure was determined. RESULTS: A total of 97 patients entered this study. The data from 14 patients were subsequently excluded for clinical procedure-related reasons or for technical problems. Therefore, 83 patients (mean age 62 +/- 13 years) were successfully randomized to receive propofol (n = 42) or midazolam (n = 41) for sedation. Most of the patients were classified as American Society of Anesthesiologists (ASA) II [16 (38%) in the midazolam group and 15 (32%) in the propofol group] and ASA III [14 (33%) and 13 (32%) in the midazolam and propofol groups, respectively]. A mean dose of 5 (4-7) mg of IV midazolam and 131 (70-260) mg of IV propofol was used during the procedure in the corresponding study arms. The mean SpO2 at baseline (%) was 99 +/- 1 for the midazolam group and 99 +/- 1 for the propofol group. No cases of hypoxemia (SpO2 < 85%) or apnea were recorded. However, an increase in PcCO2 that indicated alveolar hypoventilation occurred in both groups after administration of the first drug and was not detected with pulse oximetry alone. The mean interval between the initiation of sedation and the time when the PcCO2 value increased to more than 2 mmHg was 2.8 +/- 1.3 min for midazolam and 2.8 +/- 1.1 min for propofol. The mean maximal rise was similar for both drugs: 8.6 +/- 3.7 mmHg for midazolam and 7.4 +/- 3.2 mmHg for propofol. Five minutes after the end of the procedure, the mean difference from the baseline values was significantly lower for the propofol treatment compared with midazolam (0.9 +/- 3.0 mmHg vs 4.3 +/- 3.7 mmHg, P = 0.0000169), and significantly more patients in the propofol group had regained their baseline value +/- 1.5 mmHg (32 of 41 vs 12 of 42, P = 0.0004). CONCLUSION: A significantly higher number of patients sedated with propofol had normalized PcCO2 values five minutes after sedation when compared with patients sedated with midazolam. PMID- 23082056 TI - Similar fecal immunochemical test results in screening and referral colorectal cancer. AB - AIM: To improve the interpretation of fecal immunochemical test (FIT) results in colorectal cancer (CRC) cases from screening and referral cohorts. METHODS: In this comparative observational study, two prospective cohorts of CRC cases were compared. The first cohort was obtained from 10 322 average risk subjects invited for CRC screening with FIT, of which, only subjects with a positive FIT were referred for colonoscopy. The second cohort was obtained from 3637 subjects scheduled for elective colonoscopy with a positive FIT result. The same FIT and positivity threshold (OC sensor; >= 50 ng/mL) was used in both cohorts. Colonoscopy was performed in all referral subjects and in FIT positive screening subjects. All CRC cases were selected from both cohorts. Outcome measurements were mean FIT results and FIT scores per tissue tumor stage (T stage). RESULTS: One hundred and eighteen patients with CRC were included in the present study: 28 cases obtained from the screening cohort (64% male; mean age 65 years, SD 6.5) and 90 cases obtained from the referral cohort (58% male; mean age 69 years, SD 9.8). The mean FIT results found were higher in the referral cohort (829 +/- 302 ng/mL vs 613 +/- 368 ng/mL, P = 0.02). Tissue tumor stage (T stage) distribution was different between both populations [screening population: 13 (46%) T1, eight (29%) T2, six (21%) T3, one (4%) T4 carcinoma; referral population: 12 (13%) T1, 22 (24%) T2, 52 (58%) T3, four (4%) T4 carcinoma], and higher T stage was significantly associated with higher FIT results (P < 0.001). Per tumor stage, no significant difference in mean FIT results was observed (screening vs referral: T1 498 +/- 382 ng/mL vs 725 +/- 374 ng/mL, P = 0.22; T2 787 +/- 303 ng/mL vs 794 +/- 341 ng/mL, P = 0.79; T3 563 +/- 368 ng/mL vs 870 +/- 258 ng/mL, P = 0.13; T4 not available). After correction for T stage in logistic regression analysis, no significant differences in mean FIT results were observed between both types of cohorts (P = 0.10). CONCLUSION: Differences in T stage distribution largely explain differences in FIT results between screening and referral cohorts. Therefore, FIT results should be reported according to T stage. PMID- 23082057 TI - Different risk factors influence peptic ulcer disease development in a Brazilian population. AB - AIM: To investigate age, sex, histopathology and Helicobacter pylori (H. pylori) status, as risk factors for gastroduodenal disease outcome in Brazilian dyspeptic patients. METHODS: From all 1466 consecutive dyspeptic patients submitted to upper gastroscopy at Hospital das Clinicas of Marilia, antral biopsy specimens were obtained and subjected to histopathology and H. pylori diagnosis. All patients presenting chronic gastritis (CG) and peptic ulcer (PU) disease localized in the stomach, gastric ulcer (GU) and/or duodenal ulcer (DU) were included in the study. Gastric biopsies (n = 668) positive for H. pylori by rapid urease test were investigated for vacuolating cytotoxin A (vacA) medium (m) region mosaicism by polymerase chain reaction. Logistic regression analysis was performed to verify the association of age, sex, histopathologic alterations, H. pylori diagnosis and vacA m region mosaicism with the incidence of DU, GU and CG in patients. RESULTS: Of 1466 patients submitted to endoscopy, 1060 (72.3%) presented CG [male/female = 506/554; mean age (year) +/- SD = 51.2 +/- 17.81], 88 (6.0%) presented DU [male/female = 54/34; mean age (year) +/- SD = 51.4 +/- 17.14], and 75 (5.1%) presented GU [male/female = 54/21; mean age (year) +/- SD = 51.3 +/- 17.12] and were included in the comparative analysis. Sex and age showed no detectable effect on CG incidence (overall chi2 = 2.1, P = 0.3423). Sex [Odds ratios (OR) = 1.8631, P = 0.0058] but not age (OR = 0.9929, P = 0.2699) was associated with DU and both parameters had a highly significant effect on GU (overall chi2 = 30.5, P < 0.0001). The histopathological results showed a significant contribution of ageing for both atrophy (OR = 1.0297, P < 0.0001) and intestinal metaplasia (OR = 1.0520, P < 0.0001). Presence of H. pylori was significantly associated with decreasing age (OR = 0.9827, P < 0.0001) and with the incidence of DU (OR = 3.6077, P < 0.0001). The prevalence of m1 in DU was statistically significant (OR = 2.3563, P = 0.0018) but not in CG (OR = 2.678, P = 0.0863) and GU (OR = 1.520, P= 0.2863). CONCLUSION: In our population, male gender was a risk factor for PU; ageing for GU, atrophy and metaplasia; and H. pylori of vacA m1 genotype for DU. PMID- 23082058 TI - Argon plasma coagulation for superficial esophageal squamous-cell carcinoma in high-risk patients. AB - AIM: To evaluate the usefulness and safety of argon plasma coagulation (APC) for superficial esophageal squamous-cell carcinoma (SESC) in high-risk patients. METHODS: We studied 17 patients (15 men and 2 women, 21 lesions) with SESC in whom endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), and open surgery were contraindicated from March 1999 through February 2009. None of the patients could tolerate prolonged EMR/ESD or open surgery because of severe concomitant disease (e.g., liver cirrhosis, cerebral infarction, or ischemic heart disease) or scar formation after EMR/ESD and chemoradiotherapy. After conventional endoscopy, an iodine stain was sprayed on the esophageal mucosa to determine the lesion margins. The lesion was then ablated by APC. We retrospectively studied the treatment time, number of APC sessions per site, complications, presence or absence of recurrence, and time to recurrence. RESULTS: The median duration of follow-up was 36 mo (range: 6-120 mo). All of the tumors were macroscopically classified as superficial and slightly depressed type (0-IIc). The preoperative depth of invasion was clinical T1a (mucosal cancer) for 19 lesions and clinical T1b (submucosal cancer) for 2. The median treatment time was 15 min (range: 10-36 min). The median number of treatment sessions per site was 2 (range: 1-4). The median hospital stay was 14 d (range: 5-68 d). Among the 17 patients (21 lesions), 2 (9.5%) had recurrence and underwent additional APC with no subsequent evidence of recurrence. There were no treatment-related complications, such as bleeding or perforation. CONCLUSION: APC is considered to be safe and effective for the management of SESC that cannot be resected endoscopically because of underlying disease, as well as for the control of recurrence after EMR and local recurrence after chemoradiotherapy. PMID- 23082059 TI - Hepatitis B virus pre-S2 start codon mutations in Indonesian liver disease patients. AB - AIM: To identify the prevalence of pre-S2 start codon mutations and to assess their association with liver disease progression. METHODS: The mutations were identified by direct sequencing from 73 asymptomatic carriers, 66 chronic hepatitis (CH), 66 liver cirrhosis (LC) and 63 hepatocellular carcinoma (HCC) patients. Statistical significances were determined using Fisher's exact test, chi2 test, and t-test analyses whenever appropriate. Pre-S mutation as a risk factor for advanced liver disease was estimated by unconditional logistic regression model adjusted with age, sex, and hepatitis B e antigen (HBeAg). P < 0.05 was considered significant. RESULTS: Mutation of the hepatitis B virus (HBV) pre-S2 start codon was found in 59 samples from 268 subjects (22.0%), with higher prevalence in patients with cirrhosis 27/66 (40.9%) followed by HCC 18/63 (28.6%), chronic hepatitis 12/66 (18.2%) and asymptomatic carriers 2/73 (2.7%) (P < 0.001). Logistic regression analysis showed that pre-S2 start codon mutation was an independent factor for progressive liver disease. Other mutations, at T130, Q132, and A138, were also associated with LC and HCC, although this was not statistically significant when adjusted for age, sex, and HBeAg. The prevalence of pre-S2 start codon mutation was higher in HBV/B than in HBV/C (23.0% vs 19.1%), whilst the prevalence of T130, Q132, and A138 mutation was higher in HBV/C than in HBV/B. The prevalence of pre-S2 start codon mutation was higher in LC (38.9%) and HCC (40.0%) than CH (5.6%) in HBeAg+ group, but it was similar between CH, LC and HCC in HBeAg- group. CONCLUSION: Pre-S2 start codon mutation was higher in Indonesian patients compared to other Asian countries, and its prevalence was associated with advanced liver disease, particularly in HBeAg+ patients. PMID- 23082060 TI - Oxaliplatin-induced severe anaphylactic reactions in metastatic colorectal cancer: case series analysis. AB - AIM: To investigate oxaliplatin-induced severe anaphylactic reactions (SAR) in metastatic colorectal cancer in a retrospective case series analysis and to conduct a systemic literature review. METHODS: During a 6-year period from 2006 to 2011 at Kaohsiung Veterans General Hospital, a total of 412 patients exposed to oxaliplatin-related chemotherapy were retrospectively reviewed. Relevant English-language studies regarding life-threatening SAR following oxaliplatin were also reviewed in MEDLINE(r) and PubMed(r) search. RESULTS: Eight patients (1.9%, 8 of 412 cases) were identified. Seven patients were successful resuscitated without any sequelae and one patient expired. We changed the chemotherapy regimen in five patients and rechallenged oxaliplatin use in patient 3. Twenty-three relevant English-language studies with 66 patients were reported. Patients received a median of 10 cycles of oxaliplatin (range, 2 to 29). Most common symptoms were respiratory distress (60%), fever (55%), and hypotension (54%). Three fatal events were reported (4.5%). Eleven patients (16%) of the 66 cases were rechallenged by oxaliplatin. CONCLUSION: SAR must be considered in patients receiving oxaliplatin-related chemotherapy, especially in heavily pretreated patients. Further studies on the mechanism, predictors, preventive methods and management of oxaliplatin-related SAR are recommended. PMID- 23082061 TI - Myofibrillogenesis regulator-1 overexpression is associated with poor prognosis of gastric cancer patients. AB - AIM: To investigate the expression of myofibrillogenesis regulator-1 (MR-1) in relation to clinicopathological parameters and postoperative survival in a group of Chinese patients with gastric cancer. METHODS: In our previous study of human whole-genome gene expression profiling, the differentially expressed genes were detected in the gastric cancer and its adjacent noncancerous mucosa. We found that MR-1 was associated with the location and differentiation of tumors. In this study, MR-1 protein expression was determined by immunohistochemistry in specimens of primary cancer and the adjacent noncancerous tissues from gastric cancer patients. A set of real-time quantitative polymerase chain reaction assays based on the Universal ProbeLibrary-a collection of 165 presynthesized, fluorescence-labeled locked nucleic acid hydrolysis probes-was designed specifically to detect the expression of MR-1 mRNA. The correlation was analyzed between the expression of MR-1 and other tumor characteristics which may influence the prognosis of gastric cancer patients. A retrospective cohort study on the prognosis was carried out and clinical data were collected from medical records. RESULTS: MR-1 mRNA and protein could be detected in gastric cancer tissues as well as in matched noncancerous tissues. MR-1 was up-regulated at both mRNA (5.459 +/- 0.639 vs 1.233 +/- 0.238, P < 0.001) and protein levels (34.2% vs 13.2%, P = 0.003) in gastric cancer tissues. Correlation analysis demonstrated that high expression of MR-1 in gastric cancer was significantly correlated with clinical stage (P = 0.034). Kaplan-Meier analysis showed that the postoperative survival of the MR-1 positive group tended to be poorer than that of the MR-1 negative group, and the difference was statistically significant (P = 0.002). Among all the patients with stage I-IV carcinoma, the 5-year survival rates of MR 1 positive and negative groups were 50.40% and 12.70%, respectively, with respective median survival times of 64.27 mo (95%CI: 13.41-115.13) and 16.77 mo (95%CI: 8.80-24.74). Univariate and multivariate analyses were performed to compare the impact of MR-1 expression and other clinicopathological parameters on prognosis. In a univariate analysis on all 70 specimens, 6 factors were found to be significantly associated with the overall survival statistically: including MR 1 expression, depth of invasion, distant metastasis, lymph node metastasis, vascular invasion and the tumor node metastasis (TNM) stage based on the 7th edition of the International Union against Cancer TNM classification. To avoid the influence caused by univariate analysis, the expressions of MR-1 as well as other parameters were examined in multivariate Cox analysis. Clinicopathological variables that might affect the prognosis of gastric cancer patients were analyzed by Cox regression analysis, which showed that MR-1 expression and TNM stage were independent predictors of postoperative survival. The best mathematical multivariate Cox regression model consisted of two factors: MR-1 expression and TNM stage. Our results indicated that MR-1 protein could act as an independent marker for patient overall survival [Hazard ratio (HR): 2.215, P = 0.043]. CONCLUSION: MR-1 is an important variable that can be used to evaluate the outcome, prognosis and targeted therapy of gastric cancer patients. PMID- 23082062 TI - Identification of deregulated miRNAs and their targets in hepatitis B virus associated hepatocellular carcinoma. AB - AIM: To identify the differentially expressed miRNAs and their targets in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). METHODS: Six hundred and sixty seven human miRNAs were quantitatively analyzed by Taqman low density miRNA array (TLDA) in HBV-HCC tissues. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyze the significant function and pathway of the differentially expressed miRNAs in HBV-HCC. TargetScan software was used to predict the targets of deregulated miRNAs. Western blotting and luciferase assay were performed to verify the targets of these miRNAs. RESULTS: Ten up-regulated miRNAs (miR-217, miR-518b, miR 517c, miR-520g, miR-519a, miR-522, miR-518e, miR-525-3p, miR-512-3p, and miR-518a 3p) and 11 down-regulated miRNAs (miR-138, miR-214, miR-214#, miR-199a-5p, miR 433, miR-511, miR-592, miR-483-3p, miR-483-5p, miR-708 and miR-1275) were identified by Taqman miRNAs array and confirmed quantitatively by reverse transcription polymerase chain reaction in HCC and adjacent non-tumor tissues. GO and KEGG pathway analysis revealed that "regulation of actin cytoskeleton" and "pathway in cancer" are most likely to play critical roles in HCC tumorigenesis. MiR-519a and ribosomal protein S6 kinase polypeptide 3 (RPS6KA3) were predicted as the most significant candidates by miRNA-mRNA network. In addition, cyclin D3 (CCND3) and clathrin heavy chain (CHC), usually up-regulated in HCC tissues, were validated as the direct target of miR-138 and miR-199a-5p, respectively. CONCLUSION: Our data suggest an importance of miR-138 and miR-199a-5p as well as their targets CCND3 and CHC in HCC tumorigenesis, and may provide more evidence for reliability of integrative bioinformatics analysis. PMID- 23082063 TI - Correlation between circulating myeloid-derived suppressor cells and Th17 cells in esophageal cancer. AB - AIM: To perform a comprehensive investigation into the potential correlation between circulating myeloid-derived suppressor cells (MDSCs) and Th17 cells in esophageal cancer (ECA). METHODS: A total of 31 patients newly diagnosed with ECA and 26 healthy subjects were included in the current study. The frequencies of MDSCs and Th17 cells in peripheral blood were determined by flow cytometry. The mRNA expression of cytokines, arginase 1 (Arg1) and inducible NO synthase (iNOS) in peripheral blood mononuclear cells (PBMCs) and plasma Arg1 were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: There was an increased prevalence of MDSCs in the peripheral blood from ECA patients (15.21% +/- 2.25%) when compared with healthy control (HC) (1.10% +/- 0.12%, P < 0.0001). The plasma levels of Arg1 in ECA patients were significantly higher than those in HC (28.28 +/- 4.10 ng/mL vs 9.57 +/- 1.51 ng/mL, P = 0.0003). iNOS mRNA levels in the peripheral blood of ECA patients also showed a threefold increase compared with HC (P = 0.0162). The frequencies of Th17 cells (CD4+IL-17A+) were significantly elevated in ECA patients versus HC (3.50% +/- 0.33% vs 1.82% +/- 0.19%, P = 0.0001). Increased mRNA expression of IL-17 and ROR-gammat was also observed in ECA patients compared with HC (P = 0.0041 and P = 0.0004, respectively), while the mRNA expression of IL-6 and tumor necrosis factor-alpha (TNF-alpha) showed significant decreases (P = 0.0049 and P < 0.0001, respectively). No obvious correlations were found between the frequencies of MDSCs and Th17 cells in the peripheral blood from ECA patients(r = -0.1725, P = 0.3534). Arg1 mRNA levels were positively correlated with levels of IL-6 (r = 0.6404, P = 0.0031) and TNF-alpha (r = 0.7646, P = 0.0001). Similarly, iNOS mRNA levels were also positively correlated with levels of IL-6 (r = 0.6782, P = 0.0007) and TNF-alpha (r = 0.7633, P < 0.0001). CONCLUSION: This study reveals the relationship between circulating MDSCs and Th17 cells, which may lead to new immunotherapy approaches for ECA based on the associated metabolites and cytokines. PMID- 23082064 TI - Effect of the ginsenoside Rb1 on the spontaneous contraction of intestinal smooth muscle in mice. AB - AIM: To investigate the effect and the possible mechanism of ginsenoside Rb1 on small intestinal smooth muscle motility in mice. METHODS: Intestinal smooth muscle strips were isolated from male ICR mice (5 wk old), and the effect of ginsenoside Rb1 on spontaneous contraction was recorded with an electrophysiolograph. The effect of ginsenoside Rb1 on ion channel currents, including the voltage-gated K+ channel current (IK(V)), calcium-activated potassium channel currents (IK(Ca)), spontaneous transient outward currents and ATP-sensitive potassium channel current (IK(ATP)), was recorded on freshly isolated single cells using the whole-cell patch clamp technique. RESULTS: Ginsenoside Rb1 dose-dependently inhibited the spontaneous contraction of intestinal smooth muscle by 21.15% +/- 3.31%, 42.03% +/- 8.23% and 67.23% +/- 5.63% at concentrations of 25 MUmol/L, 50 MUmol/L and 100 MUmol/L, respectively (n = 5, P < 0.05). The inhibitory effect of ginsenoside Rb1 on spontaneous contraction was significantly but incompletely blocked by 10 mmol/L tetraethylammonium or 0.5 mmol/L 4-aminopyridine, respectively (n = 5, P < 0.05). However, the inhibitory effect of ginsenoside Rb1 on spontaneous contraction was not affected by 10 MUmol/L glibenclamide or 0.4 MUmol/L tetrodotoxin. At the cell level, ginsenoside Rb1 increased outward potassium currents, and IK(V) was enhanced from 1137.71 +/- 171.62 pA to 1449.73 +/- 162.39 pA by 50 MUmol/L Rb1 at +60 mV (n = 6, P < 0.05). Ginsenoside Rb1 increased IK(Ca) and enhanced the amplitudes of spontaneous transient outward currents from 582.77 +/- 179.09 mV to 788.12 +/- 278.34 mV (n = 5, P < 0.05). However, ginsenoside Rb1 (50 MUmol/L) had no significant effect on IK(ATP) (n = 3, P < 0.05). CONCLUSION: These results suggest that ginsenoside Rb1 has an inhibitory effect on the spontaneous contraction of mouse intestinal smooth muscle mediated by the activation of IK(V) and IK(Ca), but the K(ATP) channel was not involved in this effect. PMID- 23082065 TI - Tumor size as a prognostic factor in patients with advanced gastric cancer in the lower third of the stomach. AB - AIM: To explore the impact of tumor size on outcomes in patients with advanced gastric cancer in the lower third of the stomach. METHODS: We retrospectively analyzed the clinical records of 430 patients with advanced gastric cancer in the lower third of the stomach who underwent distal subtotal gastrectomy and D2 lymphadenectomy in our hospital from January 1998 to June 2004. Receiver operating characteristic (ROC) curve analysis was used to determine the appropriate cutoff value for tumor size, which was measured as maximum tumor diameter. Based on this cutoff value, patients were divided into two groups: those with large-sized tumors (LSTs) and those with small-sized tumors (SSTs). The correlations between other clinicopathologic factors and tumor size were investigated, and the 5-year overall survival (OS) rate was compared between the two groups. Potential prognostic factors were evaluated by univariate Kaplan Meier survival analysis and multivariate Cox's proportional hazard model analysis. The 5-year OS rates in the two groups were compared according to pT stage and pN stage. RESULTS: The 5-year OS rate in the 430 patients with advanced gastric cancer in the lower third of the stomach was 53.7%. The mean +/- SD tumor size was 4.9 +/- 1.9 cm, and the median tumor size was 5.0 cm. ROC analysis indicated that the sensitivity and specificity results for the appropriate tumor size cutoff value of 4.8 cm were 80.0% and 68.2%, respectively (AUC = 0.795, 95%CI: 0.751-0.839, P = 0.000). Using this cutoff value, 222 patients (51.6%) had LSTs (tumor size >= 4.8 cm) and 208 (48.4%) had SSTs (tumor size < 4.8 cm). Tumor size was significantly correlated with histological type (P = 0.039), Borrmann type (P = 0.000), depth of tumor invasion (P = 0.000), lymph node metastasis (P = 0.000), tumor-nodes metastasis stage (P = 0.000), mean number of metastatic lymph nodes (P = 0.000) and metastatic lymph node ratio (P = 0.000). Patients with LSTs had a significantly lower 5-year OS rate than those with SSTs (37.1% vs 63.3%, P = 0.000). Univariate analysis showed that depth of tumor invasion (chi2 = 69.581, P = 0.000), lymph node metastasis (chi2 = 138.815, P = 0.000), tumor size (chi2 = 78.184, P = 0.000) and metastatic lymph node ratio (chi2 = 139.034, P = 0.000) were significantly associated with 5-year OS rate. Multivariate analysis revealed that depth of tumor invasion (P = 0.000), lymph node metastasis (P = 0.019) and tumor size (P = 0.000) were independent prognostic factors. Gastric cancers were divided into 12 subgroups: pT2N0; pT2N1; pT2N2; pT2N3; pT3N0; pT3N1; pT3N2; pT3N3; pT4aN0; pT4aN1; pT4aN2; and pT4aN3. In patients with pT2-3N3 stage tumors and patients with pT4a stage tumors, 5-year OS rates were significantly lower for LSTs than for SSTs (P < 0.05 each), but there were no significant differences in the 5-year OS rates in LST and SST patients with pT2-3N0-2 stage tumors (P > 0.05). CONCLUSION: Using a tumor size cutoff value of 4.8 cm, tumor size is a prognostic factor in patients with pN3 stage or pT4a stage advanced gastric cancer located in the lower third of the stomach. PMID- 23082066 TI - Metachronous penile metastasis from rectal cancer after total pelvic exenteration. AB - Despite its abundant vascularization and extensive circulatory communication with neighboring organs, metastases to the penis are a rare event. A 57-year-old male, who had undergone total pelvic exenteration for rectal cancer sixteen months earlier, demonstrated an abnormal uptake within his penis by positron emission tomography/computed tomography. A single elastic nodule of the middle penis shaft was noted deep within Bucks fascia. No other obvious recurrent site was noted except the penile lesion. Total penectomy was performed as a curative resection based on a diagnosis of isolated penile metastasis from rectal cancer. A histopathological examination revealed an increase of well differentiated adenocarcinoma in the corpus spongiosum consistent with his primary rectal tumor. The immunohistochemistry of the tumor cells demonstrated positive staining for cytokeratin 20 and negative staining for cytokeratin 7, which strongly supported a diagnosis of penile metastasis from the rectum. The patient is alive more than two years without any recurrence. PMID- 23082067 TI - Primary hepatic leiomyosarcoma with liver metastasis of rectal cancer. AB - Primary hepatic leiomyosarcoma is a particularly rare tumor with a poor prognosis. Curative resection is currently the only effective treatment, and the efficacy of chemotherapy is unclear. This represents the first case report of a patient with primary hepatic leiomyosarcoma co-existing with metastatic liver carcinoma. We present a 59-year-old man who was diagnosed preoperatively with rectal cancer with multiple liver metastases. He underwent a curative hepatectomy after a series of chemotherapy regimens with modified FOLFOX6 consisting of 5 fluorouracil, leucovorin and oxaliplatin plus bevacizumab, FOLFIRI consisting of 5-fluorouracil, leucovorin and irinotecan plus bevacizumab, and irinotecan plus cetuximab. One of the liver tumors showed a different response to chemotherapy and was diagnosed as a leiomyosarcoma following histopathological examination. This case suggests that irinotecan has the potential to inhibit the growth of hepatic leiomyosarcomas. The possibility of comorbid different histological types of tumors should be suspected when considering the treatment of multiple liver tumors. PMID- 23082068 TI - Duodenal obstruction following acute pancreatitis caused by a large duodenal diverticular bezoar. AB - Bezoars are concretions of indigestible materials in the gastrointestinal tract. It generally develops in patients with previous gastric surgery or patients with delayed gastric emptying. Cases of periampullary duodenal divericular bezoar are rare. Clinical manifestations by a bezoar vary from no symptom to acute abdominal syndrome depending on the location of the bezoar. Biliary obstruction or acute pancreatitis caused by a bezoar has been rarely reported. Small bowel obstruction by a bezoar is also rare, but it is a complication that requires surgery. This is a case of acute pancreatitis and subsequent duodenal obstruction caused by a large duodenal bezoar migrating from a periampullary diverticulum to the duodenal lumen, which mimicked pancreatic abscess or microperforation on abdominal computerized tomography. The patient underwent surgical removal of the bezoar and recovered completely. PMID- 23082069 TI - Contraceptive use and associated factors among women enrolling into HIV care in southwestern Uganda. AB - BACKGROUND: Preventing unintended pregnancies among women living with HIV is an important component of prevention of mother-to-child HIV transmission (PMTCT), yet few data exist on contraceptive use among women entering HIV care. METHODS: This was a retrospective study of electronic medical records from the initial HIV clinic visits of 826 sexually active, nonpregnant, 18-49-year old women in southwestern Uganda in 2009. We examined whether contraceptive use was associated with HIV status disclosure to one's spouse. RESULTS: The proportion reporting use of contraception was 27.8%. The most common method used was injectable hormones (51.7%), followed by condoms (29.6%), and oral contraceptives (8.7%). In multivariable analysis, the odds of contraceptive use were significantly higher among women reporting secondary education, higher income, three or more children, and younger age. There were no significant independent associations between contraceptive use and HIV status disclosure to spouse. DISCUSSION: Contraceptive use among HIV-positive females enrolling into HIV care in southwestern Uganda was low. Our results suggest that increased emphasis should be given to increase the contraception uptake for all women especially those with lower education and income. HIV clinics may be prime sites for contraception education and service delivery integration. PMID- 23082070 TI - Digital chromoendoscopy for diagnosis of diminutive colorectal lesions. AB - Introduction. To compare the accuracy of digital and real-time chromoendoscopy for the differential diagnosis of diminutive (<5 mm) neoplastic and nonneoplastic colorectal lesions. Materials and Methods. This is a prospective randomized study comparing the Fujinon intelligent color enhancement (FICE) system (65 patients/95 lesions) and indigo carmine (69 patients/120 lesions) in the analysis of capillary meshwork and pit pattern, respectively. All lesions were less than 5 mm in diameter, and magnification was used in both groups. Histopathology was the gold standard examination. Results. Of 215 colorectal lesions, 153 (71.2%) were adenomas, and 62 were hyperplastic polyps (28.8%). Morphological analysis revealed 132 (61.4%) superficial lesions, with 7 (3.3%) depressed lesions, and 83 (38.6%) protruding lesions. Vascular meshwork analysis using FICE and magnification resulted in 91.7% sensitivity, 95.7% specificity, and 92.6% accuracy in differentiating neoplastic from nonneoplastic lesions. Pit pattern analysis with indigo carmine and magnification showed 96.5% sensitivity, 88.2% specificity, and 94.2% accuracy for the same purpose. Conclusion. Both magnifying virtual chromoendoscopy and indigo carmine chromoendoscopy showed high accuracy in the histopathological diagnosis of colorectal lesions less than 5 mm in diameter. PMID- 23082071 TI - Measuring central-spin interaction with a spin-bath by pulsed ENDOR: Towards suppression of spin diffusion decoherence. AB - We present pulsed electron-nuclear double resonance (ENDOR) experiments which enable us to characterize the coupling between bismuth donor spin-qubits in Si and the surrounding spin-bath of (29)Si impurities which provides the dominant decoherence mechanism (nuclear spin diffusion) at low temperatures (< 16 K). Decoupling from the spin-bath is predicted and cluster correlation expansion simulations show near-complete suppression of spin diffusion, at optimal working points. The suppression takes the form of sharply peaked divergences of the spin diffusion coherence time, in contrast with previously identified broader regions of insensitivity to classical fluctuations. ENDOR data shows anisotropic contributions are comparatively weak, so the form of the divergences is independent of crystal orientation. PMID- 23082074 TI - Spectroscopic Characterization and Biological Activity of Mixed Ligand Complexes of Ni(II) with 1,10-Phenanthroline and Heterocyclic Schiff Bases. AB - Mixed ligand complexes of Ni(II) with 1,10-phenanthroline (1,10-Phen) and Schiff bases L(1)(MIIMP); L(2)(CMIIMP); L(3)(EMIIMP); L(4)(MIIMNP); L(5)(MEMIIMP); L(6)(BMIIMP); L(7)(MMIIMP); L(8)(MIIBD) have been synthesized. These metal chelates have been characterized by elemental analysis, IR, (1)H-NMR, (13)C-NMR, Mass, UV-Vis, magnetic moments, and thermogravimetric (TG&DTA) analysis. Spectral data showed that the 1,10-phenanthroline act as neutral bidentate ligand coordinating to the metal ion through two nitrogen donor atoms and Schiff bases acts as monobasic bidentate coordinating through NO donor atoms. All Ni(II) complexes appear to have an octahedral geometry. The antimicrobial activity of mixed ligand complexes has been studied by screening against various microorganisms, it is observed that the activity enhances upon coordination. The DNA binding studies have been investigated by UV-Vis spectroscopy, and the experimental results indicate that these complexes bind to CT DNA with the intrinsic binding constant K(b) = 2.5 +/- 0.2 * 10(5) M(-1). MTT is used to test the anticancer effect of the complexes with HL60 tumor cell. The inhibition ratio was accelerated by increasing the dosage, and it had significant positive correlation with the medication dosage. PMID- 23082073 TI - The Role of Surface Feature Continuity in Object-based Inhibition of Return. AB - The contribution of surface feature continuity to object-based inhibition of return (IOR) was tested in three experiments. Participants executed a saccade to a previously fixated or unfixated colored disk after the object had moved to a new location. Object-based IOR was observed as lengthened saccade latency to a previously fixated object. The consistency of surface feature (color) and spatiotemporal information was manipulated to examine the feature used to define the persisting objects to which inhibition is assigned. If the two objects traded colors during motion, object-based IOR was reliably reduced (Experiment 2), suggesting a role for surface feature properties in defining the objects of object-based IOR. However, if the two objects changed to new colors during motion, object-based IOR was preserved (Experiment 1), and color consistency was not sufficient to support object continuity across a salient spatiotemporal discontinuity (Experiment 3). These results suggest that surface feature consistency plays a significant role in defining object persistence for the purpose of IOR, although surface features may be weighted less strongly than spatiotemporal features in this domain. PMID- 23082072 TI - Research progress on criteria for discontinuation of EGFR inhibitor therapy. AB - The clinical success of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) as therapeutic agents has prompted great interest in their further development and clinical testing for a wide variety of malignancies. However, most studies have focused on the efficacy of TKI, and few studies have been done on the criteria for their discontinuation. The current standard for drug discontinuation is "until progression", based on change in tumor size. However, tumor size is not related to the gene expression which determines the efficacy of TKI in the final analysis, and it is also difficult to make a thorough and correct prediction based on tumor size when the TKI is discontinued. Nevertheless, clinical evaluation of the criteria for TKI discontinuation is still in its early days. Some promising findings have started to emerge. With the improving knowledge of EGFR and its inhibitors, it is expected that the criteria for discontinuation of EGFR inhibitor therapy will become clearer. PMID- 23082075 TI - Diabetes and cancer: epidemiological, clinical, and experimental perspectives. PMID- 23082076 TI - The effects of local administration of aminophylline on transureteral lithotripsy. AB - Introduction. Urinary stone is a common cause of urinary tract disease. Stone excretion using ureteroscope is effective in inferior ureter. The aim of this study was to investigate the effects of aminophylline on ureteral spasm during ureteroscopy in acute phase of renal colic. Methods. In this double-blind randomized clinical trial, 120 patients with ureteral stones were enrolled and randomized into two groups. The bladder was drained and then received a 150 mL irrigation solution. Irrigation solution was saline and saline plus 10 mL aminophylline at 250 mg dose for control and case groups, respectively. Ureteroscopy and transureteral lithotripsy (TUL) were performed five minutes after irrigation. Results. The mean duration of TUL was 4.2 +/- 2.61 min and 8.4 +/- 2.9 min for control and case groups, respectively. The successful rate was 95% and 76.1% in case and control groups, respectively. Further extracorporeal shock wave lithotripsy (SWL) was performed in 5% and 30% for patients in case and control groups, respectively. Conclusion. Aminophylline facilitated ureteroscopy and increased the success rate in the treatment of renal colic using TUL. No significant complications from post-TUL were observed. Using aminophylline carries several advantages such as reducing procedure duration, decreasing the need for ureteral and double-J catheter, and reducing stone migration to the kidney and use of SWL. PMID- 23082077 TI - The zebrafish as a tool to study hematopoiesis, human blood diseases, and immune function. PMID- 23082078 TI - Marked Regression of Left Ventricular Hypertrophy after Outflow Desobliteration in HOCM. AB - We present an HOCM patient in whom marked regression of left ventricular hypertrophy occurred within two years following outflow desobliteration by percutaneous septal ablation. Maximum wall thickness (initially documented by both echo and MRI) decreased from 34 mm to 22 mm (followup by echo only due to presence of the ICD), crossing the threshold value of 30 mm which was one of the risk markers that had triggered the primary prophylactic ICD implantation in this case prior to septal ablation. PMID- 23082079 TI - Guidelines for developing yoga interventions for randomized trials. AB - Little guidance is available to assist researchers in developing treatment protocols for research on yoga for health concerns. Because yoga is a complex multifactorial mind-body discipline historically developed for nonmedical purposes, numerous decisions must be made in order to thoughtfully develop such protocols. In this paper, a systematic approach is proposed to assist researchers in selecting an intervention that is appropriate for the condition under consideration and explicitly developed. Researchers need to consider the type or "style" of yoga, the components to include (e.g., breathing exercises, postures) as well as the specific protocol for each component, the dose to be delivered (frequency, duration of practice, and the total duration of practice), and issues related to selection of instructors and monitoring the fidelity to the intervention. Each of these domains and the key issues for the development of protocols is discussed. Finally, some areas for further research related to protocol development are recommended. PMID- 23082080 TI - Hwangryun-Haedok-Tang Fermented with Lactobacillus casei Suppresses Ovariectomy Induced Bone Loss. AB - Hwangryun-haedok-tang (HRT) is the common recipe in traditional Asian medicine, and microbial fermentation is used for the conventional methods for processing traditional medicine. We investigated the inhibitory effect of the n-butanol fraction of HRT (HRT-BU) and fHRT (fHRT-BU) on the RANKL-induced osteoclastogenesis in bone-marrow-derived macrophages. mRNA expression of osteoclastogenesis-related genes were evaluated by real-time QPCR. The activation of signaling pathways was determined by western blot analysis. The marker compounds of HRT-BU and fHRT-BU were analyzed by HPLC. The inhibitory effect of HRT or fHRT on ovariectomy-induced bone loss were evaluated using OVX rats with orally administered HRT, fHRT (300, 1000 mg/kg), or its vehicle for 12 weeks. fHRT-BU significantly inhibited RANKL-induced osteoclastogenesis, and phosphorylation of p38, IKKalpha/beta, and NF-kappaBp65 compared to HRT-BU. In addition, fHRT-BU also significantly inhibited the mRNA expression of Nfkappab2, TNF-alpha, NFATc1, TRAP, ATPv0d2, and cathepsin K. Furthermore, administration of fHRT had a greater effect on the increase of BMD, and greater improved bone microstructure of the femora than that of HRT in ovariectomy rats. This study demonstrated that bacterial fermentation enhances the inhibitory effect of HRT on osteoclastogenesis and bone loss. These results suggest that fermented HRT might have the beneficial effects on bone disease by inhibiting osteoclastogenesis. PMID- 23082081 TI - Phytochemical Analysis and Antimicrobial, Antinociceptive, and Anti-Inflammatory Activities of Two Chemotypes of Pimenta pseudocaryophyllus (Myrtaceae). AB - Preparations from Pimenta pseudocaryophyllus (Gomes) L.R. Landrum (Myrtaceae) have been widely used in Brazilian folk medicine. This study aims to evaluate the antimicrobial activity of the crude ethanol extracts, fractions, semipurified substances, and essential oils obtained from leaves of two chemotypes of P. pseudocaryophyllus and to perform the antinociceptive and anti-inflammatory screening. The ethanol extracts were purified by column chromatography and main compounds were spectrally characterised (1D and 2D (1)H and (13)C NMR). The essential oils constituents were identified by GC/MS. The broth microdilution method was used for testing the antimicrobial activity. The abdominal contortions induced by acetic acid and the ear oedema induced by croton oil were used for screening of antinociceptive and anti-inflammatory activities, respectively. The phytochemical analysis resulted in the isolation of pentacyclic triterpenes, flavonoids, and phenol acids. The oleanolic acid showed the best profile of antibacterial activity for Gram-positive bacteria (31.2-125 MUg mL(-1)), followed by the essential oil of the citral chemotype (62.5-250 MUg mL(-1)). Among the semipurified substances, Ppm5, which contained gallic acid, was the most active for Candida spp. (31.2 MUg mL(-1)) and Cryptococcus spp. (3.9-15.6 MUg mL(-1)). The crude ethanol extract and fractions from citral chemotype showed antinociceptive and anti-inflammatory effects. PMID- 23082083 TI - Morphostructural Damage in Food-Spoiling Bacteria due to the Lemon Grass Oil and Its Vapour: SEM, TEM, and AFM Investigations. AB - In this study, antimicrobial activity and morphostructural damages due to lemon grass oil (LGO) and its vapour (LGOV) against Escherichia coli strains were investigated. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of LGO were determined by broth-dilution method to be 0.288 mg/mL and 0.567 mg/mL, respectively. Furthermore, the zone of inhibition (45 mm) due to the vapour phase antimicrobial efficacy evaluated using disc volatilization assay was compared with that using disc diffusion assay (i.e., 13.5 mm for the same dose of oil). The morphological and ultrastructural alterations in LGO- and LGOV-treated E. coli cells were studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM). In SEM observation, LGO-treated cells appeared to be aggregated and partially deformed, while LGOV-treated cells lost their turgidity, and the cytoplasmic material completely leaked from the cells. In TEM observation, extensive intracytoplasmic changes and various abnormalities were observed in LGOV-treated cells more than LGO-treated cells. Significant variations in the height and root mean square values of untreated, LGO-, and LGOV treated E. coli cells were noticed by AFM. Present results indicate that LGO is highly effective against E. coli in vapour phase. PMID- 23082084 TI - In vitro screening of medicinal plants used in Mexico as antidiabetics with glucosidase and lipase inhibitory activities. AB - This work shows the inhibitory effect on glucosidase and lipase enzymes of 23 medicinal plants described as traditional treatments for diabetes in several Mexican sources. Hydroalcoholic extracts of selected plants were evaluated at 1 mg/mL for glucosidase and 0.25 mg/mL for lipase inhibitory activities, respectively. Camellia sinensis, acarbose, and orlistat were used as positive controls. Dose-response curves were done with the most active species. Sixty percent of all tested extracts inhibited more than 25% of alpha-glucosidase activity. C. sinensis displayed an inhibition of 85% (IC(50) = 299 MUg/mL), while Ludwigia octovalvis and Iostephane heterophylla showed the highest inhibition (82.7 %, IC(50) = 202 MUg/mL and 60.6%, CI(50) = 509 MUg/mL, resp.). With respect to lipase activity, L. octovalvis and Tecoma stans were the most inhibiting treatments (31.4%, IC(50) = 288 MUg/mL; 27.2%, IC(50) = 320 MUg/mL), while C. sinensis displayed 45% inhibition (IC(50) = 310 MUg/mL). These results indicate that a high proportion of plants used in Mexico as treatment for diabetes displays significant inhibition of these digestive enzymes. PMID- 23082082 TI - LC-MS/MS Identification of a Bromelain Peptide Biomarker from Ananas comosus Merr. AB - Bromelain (Br) is a cysteine peptidase (GenBank AEH26024.1) from pineapple, with over 40 years of clinical use. The constituents mediating its anti-inflammatory activity are not thoroughly characterized and no peptide biomarker exists. Our objective is to characterize Br raw material and identify peptides in the plasma of Br treated mice. After SDS-PAGE in-gel digestion, Br (VN#3507; Middletown, CT, USA) peptides were analyzed via LC/MS/MS using 95% protein probability, 95% peptide probability, and a minimum peptide number = 5. Br spiked mouse plasma (1 ug/ul) and plasma from i.p. treated mice (12 mg/kg) were assessed using SRM. In Br raw material, we identified seven proteins: four proteases, one jacalin-like lectin, and two protease inhibitors. In Br spiked mouse plasma, six proteins (ananain, bromelain inhibitor, cysteine proteinase AN11, FB1035 precursor, FBSB precursor, and jacalin-like lectin) were identified. Using LC/MS/MS, we identified the unique peptide, DYGAVNEVK, derived from FB1035, in the plasma of i.p. Br treated mice. The spectral count of this peptide peaked at 6 hrs and was undetectable by 24 hrs. In this study, a novel Br peptide was identified in the plasma of treated mice for the first time. This Br peptide could serve as a biomarker to standardize the therapeutic dose and maximize clinical utility. PMID- 23082085 TI - Effect of Alpinia katsumadai Hayata on House Dust Mite-Induced Atopic Dermatitis in NC/Nga Mice. AB - We evaluated the effects of Alpinia katsumadai Hayata (AKH, Zingiberaceae) extract on the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in RAW 264.7 cells, thymus- and-activation-regulated chemokine (TARC/CCL17) in HaCaT cells, and histamine level in HMC-1 cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for 4 weeks, and the protective effects of AKH was investigated by measuring the severity of the skin reaction on the back and ears, and plasma levels of immunoglobulin E (IgE) and histamine. AKH extract suppressed the production of NO and PGE(2) in RAW 264.7 cells, TARC in HaCaT cells, and histamine in HMC-1 cells in a dose dependent manner. In in vivo experiments, the severity of dermatitis, including erythema/hemorrhage, edema, erosion and scaling, and plasma levels of IgE, and histamine were lower in NC/Nga mice with atopic dermatitis, treated with AKH extract than in untreated mice. AKH extract reduced the histological manifestations of atopic dermatitis-like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration on the skin of the back and ear. These results suggest that AKH inhibits the development of house dust mite-induced atopic dermatitis in NC/Nga mice. PMID- 23082086 TI - Management of Diabetes and Its Complications with Banaba (Lagerstroemia speciosa L.) and Corosolic Acid. AB - Banaba (Lagerstroemia speciosa L.) extracts have been used for many years in folk medicine to treat diabetes, with the first published research study being reported in 1940. This paper summarizes the current literature regarding Banaba and its constituents. The hypoglycemic effects of Banaba have been attributed to both corosolic acid as well as ellagitannins. Studies have been conducted in various animal models, human subjects, and in vitro systems using water soluble Banaba leaf extracts, corosolic acid, and ellagitannins. Corosolic acid has been reported to decrease blood sugar levels within 60 min in human subjects. Corosolic acid also exhibits antihyperlipidemic and antioxidant activities. The beneficial effects of Banaba and corosolic acid with respect to various aspects of glucose and lipid metabolism appear to involve multiple mechanisms, including enhanced cellular uptake of glucose, impaired hydrolysis of sucrose and starches, decreased gluconeogenesis, and the regulation of lipid metabolism. These effects may be mediated by PPAR and other signal transduction factors. Banaba extract, corosolic acid, and other constituents may be beneficial in addressing the symptoms associated with metabolic syndrome, as well as offering other health benefits. PMID- 23082087 TI - Hesperidin-3'-o-methylether is more potent than hesperidin in phosphodiesterase inhibition and suppression of ovalbumin-induced airway hyperresponsiveness. AB - Hesperidin is present in the traditional Chinese medicine, "Chen Pi," and recently was reported to have anti-inflammatory effects. Therefore, we were interested in comparing the effects of hesperidin and hesperidin-3'-O-methylether on phosphodiesterase inhibition and airway hyperresponsiveness (AHR) in a murine model of asthma. In the present results, hesperidin-3'-O-methylether, but not hesperidin, at 30 MUmol/kg (p.o.) significantly attenuated the enhanced pause (P(enh)) value, suppressed the increases in numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, suppressed total and OVA specific immunoglobulin (Ig)E levels in the serum and BALF, and enhanced the level of total IgG(2a) in the serum of sensitized and challenged mice, suggesting that hesperidin-3'-O-methylether is more potent than hesperidin in suppression of AHR and immunoregulation. The different potency between them may be due to their aglycons, because these two flavanone glycosides should be hydrolyzed by beta glucosidase after oral administration. Neither influenced xylazine/ketamine induced anesthesia, suggesting that they may have few or no adverse effects, such as nausea, vomiting, and gastric hypersecretion. In conclusion, hesperidin-3'-O methylether is more potent in phosphodiesterase inhibition and suppression of AHR and has higher therapeutic (PDE4(H)/PDE4(L)) ratio than hesperidin. Thus, hesperidin-3'-O-methylether may have more potential for use in treating allergic asthma and chronic obstructive pulmonary disease. PMID- 23082088 TI - A new particle swarm optimization-based method for phase unwrapping of MRI data. AB - A new method based on discrete particle swarm optimization (dPSO) algorithm is proposed to solve the branch-cut phase unwrapping problem of MRI data. In this method, the optimal order of matching the positive residues with the negative residues is first identified by the dPSO algorithm, then the branch cuts are placed to join each pair of the opposite polarity residues, and in the last step phases are unwrapped by flood-fill algorithm. The performance of the proposed algorithm was tested on both simulated phase image and MRI wrapped phase data sets. The results demonstrated that, compared with conventionally used branch-cut phase unwrapping algorithms, the dPSO algorithm is rather robust and effective. PMID- 23082089 TI - Modified global and modified linear contrast stretching algorithms: new colour contrast enhancement techniques for microscopic analysis of malaria slide images. AB - Malaria is one of the serious global health problem, causing widespread sufferings and deaths in various parts of the world. With the large number of cases diagnosed over the year, early detection and accurate diagnosis which facilitates prompt treatment is an essential requirement to control malaria. For centuries now, manual microscopic examination of blood slide remains the gold standard for malaria diagnosis. However, low contrast of the malaria and variable smears quality are some factors that may influence the accuracy of interpretation by microbiologists. In order to reduce this problem, this paper aims to investigate the performance of the proposed contrast enhancement techniques namely, modified global and modified linear contrast stretching as well as the conventional global and linear contrast stretching that have been applied on malaria images of P. vivax species. The results show that the proposed modified global and modified linear contrast stretching techniques have successfully increased the contrast of the parasites and the infected red blood cells compared to the conventional global and linear contrast stretching. Hence, the resultant images would become useful to microbiologists for identification of various stages and species of malaria. PMID- 23082090 TI - A computational modeling approach for investigating soft tissue balancing in bicruciate retaining knee arthroplasty. AB - Bicruciate retaining knee arthroplasty, although has shown improved functions and patient satisfaction compared to other designs of total knee replacement, remains a technically demanding option for treating severe cases of arthritic knees. One of the main challenges in bicruciate retaining arthroplasty is proper balancing of the soft tissue during the surgery. In this study biomechanics of soft tissue balancing was investigated using a validated computational model of the knee joint with high fidelity definitions of the soft tissue structures along with a Taguchi method for design of experiments. The model was used to simulate intraoperative balancing of soft tissue structures following the combinations suggested by an orthogonal array design. The results were used to quantify the corresponding effects on the laxity of the joint under anterior-posterior, internal-external, and varus-valgus loads. These effects were ranked for each ligament bundle to identify the components of laxity which were most sensitive to the corresponding surgical modifications. The resulting map of sensitivity for all the ligament bundles determined the components of laxity most suitable for examination during intraoperative balancing of the soft tissue. Ultimately, a sequence for intraoperative soft tissue balancing was suggested for a bicruciate retaining knee arthroplasty. PMID- 23082091 TI - Automated quantification of pneumothorax in CT. AB - An automated, computer-aided diagnosis (CAD) algorithm for the quantification of pneumothoraces from Multidetector Computed Tomography (MDCT) images has been developed. Algorithm performance was evaluated through comparison to manual segmentation by expert radiologists. A combination of two-dimensional and three dimensional processing techniques was incorporated to reduce required processing time by two-thirds (as compared to similar techniques). Volumetric measurements on relative pneumothorax size were obtained and the overall performance of the automated method shows an average error of just below 1%. PMID- 23082092 TI - Dynamic variability of isometric action tremor in precision pinching. AB - Evolutionary development of isometric force impulse frequencies, power, and the directional concordance of changes in oscillatory tremor during performance of a two-digit force regulation task was examined. Analyses compared a patient group having tremor confounding volitional force regulation with a control group having no neuropathological diagnosis. Dependent variables for tremor varied temporally and spatially, both within individual trials and across trials, across individuals, across groups, and between digits. Particularly striking findings were magnitude increases during approaches to cue markers and shifts in the concordance phase from pinching toward rigid sway patterns as the magnitude increased. Magnitudes were significantly different among trace line segments of the task and were characterized by differences in relative force required and by the task progress with respect to cue markers for beginning, reversing force change direction, or task termination. The main systematic differences occurred during cue marker approach and were independent of trial sequence order. PMID- 23082093 TI - Explaining Society: An Expanded Toolbox for Social Scientists. AB - We propose for social scientists a theoretical toolbox containing a set of motivations that neurobiologists have recently validated. We show how these motivations can be used to create a theory of society recognizably similar to existing stable societies (sustainable, self-reproducing, and largely peaceful). Using this toolbox, we describe society in terms of three institutions: economy (a source of sustainability), government (peace), and the family (reproducibility). Conducting a thought experiment in three parts, we begin with a simple theory with only two motivations. We then create successive theories that systematically add motivations, showing that each element in the toolbox makes its own contribution to explain the workings of a stable society and that the family has a critical role in this process. PMID- 23082094 TI - Porphyrins and phthalocyanines for theranostics. PMID- 23082095 TI - Monitoring photosensitizer uptake using two photon fluorescence lifetime imaging microscopy. AB - Photodynamic Therapy (PDT) provides an opportunity for treatment of various invasive tumors by the use of a cancer targeting photosensitizing agent and light of specific wavelengths. However, real-time monitoring of drug localization is desirable because the induction of the phototoxic effect relies on interplay between the dosage of localized drug and light. Fluorescence emission in PDT may be used to monitor the uptake process but fluorescence intensity is subject to variability due to scattering and absorption; the addition of fluorescence lifetime may be beneficial to probe site-specific drug-molecular interactions and cell damage. We investigated the fluorescence lifetime changes of Photofrin((r)) at various intracellular components in the Mat-LyLu (MLL) cell line. The fluorescence decays were analyzed using a bi-exponential model, followed by segmentation analysis of lifetime parameters. When Photofrin((r)) was localized at the cell membrane, the slow lifetime component was found to be significantly shorter (4.3 +/- 0.5 ns) compared to those at other locations (cytoplasm: 7.3 +/- 0.3 ns; mitochondria: 7.0 +/- 0.2 ns, p < 0.05). PMID- 23082096 TI - Image-Based Quantification of Benzoporphyrin Derivative Uptake, Localization, and Photobleaching in 3D Tumor Models, for Optimization of PDT Parameters. AB - Photodynamic therapy (PDT) is a light-based treatment modality in which wavelength specific activation of a photosensitizer (PS) generates cytotoxic response in the irradiated region. PDT response is critically dependent on several parameters including light dose, PS dose, uptake time, fluence rate, and the mode of light delivery. While the systematic optimization of these treatment parameters can be complex, it also provides multiple avenues for enhancement of PDT efficacy under diverse treatment conditions, provided that a rational framework is established to quantify the impact of parameter selection upon treatment response. Here we present a theranostic technique, combining the inherent ability of the PS to serve simultaneously as a therapeutic and imaging agent, with the use of image-based treatment assessment in three dimensional (3D) in vitro tumor models, to comprise a platform to evaluate the impact of PDT parameters on treatment outcomes. We use this approach to visualize and quantify the uptake, localization, and photobleaching of the PS benzoporphyrin derivative monoacid ring-A (BPD) in a range of treatment conditions with varying uptake times as well as continuous and fractionated light delivery regimens in 3D cultures of AsPC-1 and PANC-1 cells. Informed by photobleaching patterns and correlation with cytotoxic response, asymmetric fractionated light delivery at 4 hours BPD uptake was found to be the most effective regimen assessed. Quantification of the spatial profile of cell killing within multicellular nodules revealed that these conditions also achieve the highest depth of cytotoxicity along the radial axis of 3D nodules. The framework introduced here provides a means for systematic assessment of PDT treatment parameters in biologically relevant 3D tumor models with potential for broader application to other systems. PMID- 23082097 TI - Confocal fluorescence imaging enables noninvasive quantitative assessment of host cell populations in vivo following photodynamic therapy. AB - We report the use of optical imaging strategies to noninvasively examine photosensitizer distribution and physiological and host responses to 2-[1 hexyloxyethyl]-2 devinyl pyropheophorbide-a (HPPH)-mediated photodynamic therapy (PDT) of EMT6 tumors established in the ears of BALB/c mice. 24 h following intravenous (IV) administration of 1 MUmol kg(-1) HPPH, wide-field fluorescence imaging reveals tumor selectivity with an approximately 2-3-fold differential between tumor and adjacent normal tissue. Confocal microscopy demonstrates a relatively homogeneous intratumor HPPH distribution. Labeling of host cells using fluorophore-conjugated antibodies allowed the visualization of Gr1(+)/CD11b(+) leukocytes and major histocompatibility complex class II (MHC-II)(+) cells in vivo. Imaging of the treated site at different time-points following irradiation shows significant and rapid increases in Gr1(+) cells in response to therapy. The maximum accumulation of Gr1(+) cells is found at 24 h post-irradiation, followed by a decrease at the 48 h time-point. Using IV-injected FITC-conjugated dextran as a fluorescent perfusion marker, we imaged tissue perfusion at different times post-irradiation and found that the reduced Gr1(+ )cell density at 48 h correlated strongly with functional damage to the vasculature as reported via decreased perfusion status. Dual color confocal imaging experiments demonstrates that about 90% of the anti-Gr1 cell population co-localized with anti-CD11b labeling, thus indicating that majority of the Gr1-labeled cells were neutrophils. At 24 h post-PDT, an approximately 2-fold increase in MHC-II+ cells relative to untreated control is also observed. Co-localization analysis reveals an increase in the fraction of Gr1(+) cells expressing MHC-II, suggesting that HPPH-PDT is stimulating neutrophils to express an antigen-presenting phenotype. PMID- 23082098 TI - Syntheses and Photodynamic Activity of Pegylated Cationic Zn(II)-Phthalocyanines in HEp2 Cells. AB - Di-cationic Zn(II)-phthalocyanines (ZnPcs) are promising photosensitizers for the photodynamic therapy (PDT) of cancers and for photoinactivation of viruses and bacteria. Pegylation of photosensitizers in general enhances their water solubility and tumor cell accumulation. A series of pegylated di-cationic ZnPcs were synthesized from conjugation of a low molecular weight PEG group to a pre formed Pc macrocycle, or by mixed condensation involving a pegylated phthalonitrile. All pegylated ZnPcs were highly soluble in polar organic solvents but were insoluble in water; they have intense Q absorptions centered at 680 nm and fluorescence quantum yields of ca. 0.2 in DMF. The non-pegylated di-cationic ZnPc 6a formed large aggregates, which were visualized by atomic force microscopy. The cytotoxicity, cellular uptake and subcellular distribution of all cationic ZnPcs were investigated in human carcinoma HEp2 cells. The most phototoxic compounds were found to be the alpha-substituted Pcs. Among these, Pcs 4a and 16a were the most effective (IC(50) ca. 10 MUM at 1.5 J/cm(2)), in part due to the presence of a PEG group and the two positive charges in close proximity (separated by an ethylene group) in these macrocycles. The beta substituted ZcPcs 6b and 4b accumulated the most within HEp2 cells but had low photocytoxicity (IC(50) > 100 MUM at 1.5 J/cm(2)), possibly as a result of their lower electron density of the ring and more extended conformations compared with the alpha-substituted Pcs. The results show that the charge distribution about the Pc macrocycle and the intracellular localization of the cationic ZnPcs mainly determine their photodynamic activity. PMID- 23082099 TI - Phthalocyanine-aggregated polymeric nanoparticles as tumor-homing near-infrared absorbers for photothermal therapy of cancer. AB - Phthalocyanine-aggregated Pluronic nanoparticles were constructed as a novel type of near-infrared (NIR) absorber for photothermal therapy. Tiny nanoparticles (~ 60 nm, FPc NPs) were prepared by aqueous dispersion of phthalocyanine-aggregated self-assembled nanodomains that were phase-separated from the melt mixture with Pluronic. Under NIR laser irradiation, FPc NPs manifested robust heat generation capability, superior to an individual cyanine dye and cyanine-aggregated nanoparticles. Micro- and macroscopic imaging experiments showed that FPc NPs are capable of internalization into live cancer cells as well as tumor accumulation when intravenously administered into living mice. It is shown here that continuous NIR irradiation of the tumor-targeted FPc NPs can cause phototherapeutic effects in vitro and in vivo through excessive local heating, demonstrating potential of phthalocyanine-aggregated nanoparticles as an all organic NIR nanoabsorber for hyperthermia. PMID- 23082100 TI - Involvement of reactive oxygen species in sonodynamically induced apoptosis using a novel porphyrin derivative. AB - In this study, we investigated the induction of apoptosis by ultrasound in the presence of the novel porphyrin derivative DCPH-P-Na(I). HL-60 cells were exposed to ultrasound for up to 3 min in the presence and absence of DCPH-P-Na(I), and the induction of apoptosis was examined by analyzing cell morphology, DNA fragmentation, and caspase-3 activity. Reactive oxygen species were measured by means of ESR and spin trapping technique. Cells treated with 8 MUM DCPH-P-Na(I) and ultrasound clearly showed membrane blebbing and cell shrinkage, whereas significant morphologic changes were not observed in cells exposed to either ultrasound or DCPH-P-Na(I) alone. Also, DNA ladder formation and caspase-3 activation were observed in cells treated with both ultrasound and DCPH-P-Na(I) but not in cells treated with ultrasound or DCPH-P-Na(I) alone. In addition, the combination of DCPH-P-Na(I) and the same acoustical arrangement of ultrasound substantially enhanced nitroxide generation by the cells. Sonodynamically induced apoptosis, caspase-3 activation, and nitroxide generation were significantly suppressed by histidine. These results indicate that the combination of ultrasound and DCPH-P-Na(I) induced apoptosis in HL-60 cells. The significant reduction in sonodynamically induced apoptosis, nitroxide generation, and caspase 3 activation by histidine suggests active species such as singlet oxygen are important in the sonodynamic induction of apoptosis. These experimental results support the possibility of sonodynamic treatment for cancer using the induction of apoptosis. PMID- 23082101 TI - Multifunctional Peptide-conjugated hybrid silica nanoparticles for photodynamic therapy and MRI. AB - Photodynamic therapy (PDT) is an emerging theranostic modality for various cancer as well as non-cancer diseases. Its efficiency is mainly based on a selective accumulation of PDT and imaging agents in tumor tissue. The vascular effect is widely accepted to play a major role in tumor eradication by PDT. To promote this vascular effect, we previously demonstrated the interest of using an active- targeting strategy targeting neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels. For an integrated vascular-targeted PDT with magnetic resonance imaging (MRI) of cancer, we developed multifunctional gadolinium-based nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 peptide and polysiloxane nanoparticles with gadolinium chelated by DOTA derivatives on the surface and a chlorin as photosensitizer. The nanoparticles were surface-functionalized with hydrophilic DOTA chelates and also used as a scaffold for the targeting peptide grafting. In vitro investigations demonstrated the ability of multifunctional nanoparticles to preserve the photophysical properties of the encapsulated photosensitizer and to confer photosensitivity to MDA-MB-231 cancer cells related to photosensitizer concentration and light dose. Using binding test, we revealed the ability of peptide-functionalized nanoparticles to target NRP-1 recombinant protein. Importantly, after intravenous injection of the multifunctional nanoparticles in rats bearing intracranial U87 glioblastoma, a positive MRI contrast enhancement was specifically observed in tumor tissue. Real-time MRI analysis revealed the ability of the targeting peptide to confer specific intratumoral retention of the multifunctional nanoparticles. PMID- 23082102 TI - Porphyrins as theranostic agents from prehistoric to modern times. AB - Long before humans roamed the planet, porphyrins in blood were serving not only as indispensable oxygen carriers, but also as the bright red contrast agent that unmistakably indicates injury sites. They have proven valuable as whole body imaging modalities have emerged, with endogenous hemoglobin porphyrins being used for new approaches such as functional magnetic resonance imaging and photoacoustic imaging. With the capability for both near infrared fluorescence imaging and phototherapy, porphyrins were the first exogenous agents that were employed with intrinsic multimodal theranostic character. Porphyrins have been used as tumor-specific diagnostic fluorescence imaging agents since 1924, as positron emission agents since 1951, and as magnetic resonance (MR) contrast agents since 1987. Exogenous porphyrins remain in clinical use for photodynamic therapy. Because they can chelate a wide range of metals, exogenous porphyrins have demonstrated potential for use in radiotherapy and multimodal imaging modalities. Going forward, intrinsic porphyrin biocompatibility and multimodality will keep new applications of this class of molecules at the forefront of theranostic research. PMID- 23082104 TI - Perceptions of heatwave risks to health: results of an qualitative interview study with older people and their carers in Freiburg, Germany. AB - AIMS AND OBJECTIVES: Heatwaves can pose a severe threat to health, especially to older people. However, warnings do not necessarily lead to preventive action. This study aims at exploring individual risk perception and adaptive measures of older people and their carers. Their views are explored, taking into account personal backgrounds. METHODS: Questionnaire-based interviews were administered to 20 men and women (64-94 years, living in their own homes or nursing homes) and 13 carers. A qualitative analysis following a framework approach was performed. RESULTS: The majority of respondents stated that older people might be compromised by heatwaves; however, a large proportion of respondents saw themselves as less affected than the average population. Most respondents adopted preventive measures during heatwaves and a majority received warnings or pieces of information. The role of general practitioners in direct warning situations was judged controversial. Survey respondents displayed resistance to the use of technical devices to monitor potentially dangerous situations. In addition, the results support many previous findings. In particular, the relative concepts of ageing, variety of information channels used, and control orientations could be confirmed. CONCLUSIONS: General practitioners hold a position of trust and play a central role in the promotion of preventive action, but there are also limitations to their outreach. Many respondents could be classified as socially active, which has implications for preventive information campaigns. Information campaigns using different channels and targeting a larger audience should be considered. The degree of information of carers can partly be improved. PMID- 23082105 TI - Neural stimulation with optical radiation. AB - This paper reviews the existing research on infrared neural stimulation, a means of artificially stimulating neurons that has been proposed as an alternative to electrical stimulation. Infrared neural stimulation (INS) is defined as the direct induction of an evoked potential in response to a transient targeted deposition of optical energy. The foremost advantage of using optical radiation for neural stimulation is its spatial resolution. Exogenously applied or trans genetically synthesized fluorophores are not used to achieve stimulation. Here, current work on INS is presented for motor nerves, sensory nerves, central nervous system, and in vitro preparations. A discussion follows addressing the mechanism of INS and its potential use in neuroprostheses. A brief review of neural depolarization involving other optical methods is also presented. Topics covered include optical stimulation concurrent with electrical stimulation, optical stimulation using exogenous fluorophores, and optical stimulation by transgenic induction of light-gated ion channels. PMID- 23082107 TI - Metagenomic exploration of viruses throughout the Indian Ocean. AB - The characterization of global marine microbial taxonomic and functional diversity is a primary goal of the Global Ocean Sampling Expedition. As part of this study, 19 water samples were collected aboard the Sorcerer II sailing vessel from the southern Indian Ocean in an effort to more thoroughly understand the lifestyle strategies of the microbial inhabitants of this ultra-oligotrophic region. No investigations of whole virioplankton assemblages have been conducted on waters collected from the Indian Ocean or across multiple size fractions thus far. Therefore, the goals of this study were to examine the effect of size fractionation on viral consortia structure and function and understand the diversity and functional potential of the Indian Ocean virome. Five samples were selected for comprehensive metagenomic exploration; and sequencing was performed on the microbes captured on 3.0-, 0.8- and 0.1 um membrane filters as well as the viral fraction (<0.1 um). Phylogenetic approaches were also used to identify predicted proteins of viral origin in the larger fractions of data from all Indian Ocean samples, which were included in subsequent metagenomic analyses. Taxonomic profiling of viral sequences suggested that size fractionation of marine microbial communities enriches for specific groups of viruses within the different size classes and functional characterization further substantiated this observation. Functional analyses also revealed a relative enrichment for metabolic proteins of viral origin that potentially reflect the physiological condition of host cells in the Indian Ocean including those involved in nitrogen metabolism and oxidative phosphorylation. A novel classification method, MGTAXA, was used to assess virus-host relationships in the Indian Ocean by predicting the taxonomy of putative host genera, with Prochlorococcus, Acanthochlois and members of the SAR86 cluster comprising the most abundant predictions. This is the first study to holistically explore virioplankton dynamics across multiple size classes and provides unprecedented insight into virus diversity, metabolic potential and virus-host interactions. PMID- 23082108 TI - Image and diagnosis quality of X-ray image transmission via cell phone camera: a project study evaluating quality and reliability. AB - INTRODUCTION: Developments in telemedicine have not produced any relevant benefits for orthopedics and trauma surgery to date. For the present project study, several parameters were examined during assessment of x-ray images, which had been photographed and transmitted via cell phone. MATERIALS AND METHODS: A total of 100 x-ray images of various body regions were photographed with a Nokia cell phone and transmitted via email or MMS. Next, the transmitted photographs were reviewed on a laptop computer by five medical specialists and assessed regarding quality and diagnosis. RESULTS: Due to their poor quality, the transmitted MMS images could not be evaluated and this path of transmission was therefore excluded. Mean size of transmitted x-ray email images was 394 kB (range: 265-590 kB, SD +/- 59), average transmission time was 3.29 min +/- 8 (CI 95%: 1.7-4.9). Applying a score from 1-10 (very poor - excellent), mean image quality was 5.8. In 83.2 +/- 4% (mean value +/- SD) of cases (median 82; 80-89%), there was agreement between final diagnosis and assessment by the five medical experts who had received the images. However, there was a markedly low concurrence ratio in the thoracic area and in pediatric injuries. DISCUSSION: While the rate of accurate diagnosis and indication for surgery was high with a concurrence ratio of 83%, considerable differences existed between the assessed regions, with lowest values for thoracic images. Teleradiology is a cost effective, rapid method which can be applied wherever wireless cell phone reception is available. In our opinion, this method is in principle suitable for clinical use, enabling the physician on duty to agree on appropriate measures with colleagues located elsewhere via x-ray image transmission on a cell phone. PMID- 23082106 TI - Genome analysis of a highly virulent serotype 1 strain of Streptococcus pneumoniae from West Africa. AB - Streptococcus pneumoniae is a leading cause of pneumonia, meningitis, and bacteremia, estimated to cause 2 million deaths annually. The majority of pneumococcal mortality occurs in developing countries, with serotype 1 a leading cause in these areas. To begin to better understand the larger impact that serotype 1 strains have in developing countries, we characterized virulence and genetic content of PNI0373, a serotype 1 strain from a diseased patient in The Gambia. PNI0373 and another African serotype 1 strain showed high virulence in a mouse intraperitoneal challenge model, with 20% survival at a dose of 1 cfu. The PNI0373 genome sequence was similar in structure to other pneumococci, with the exception of a 100 kb inversion. PNI0373 showed only 15 lineage specific CDS when compared to the pan-genome of pneumococcus. However analysis of non-core orthologs of pneumococcal genomes, showed serotype 1 strains to be closely related. Three regions were found to be serotype 1 associated and likely products of horizontal gene transfer. A detailed inventory of known virulence factors showed that some functions associated with colonization were absent, consistent with the observation that carriage of this highly virulent serotype is unusual. The African serotype 1 strains thus appear to be closely related to each other and different from other pneumococci despite similar genetic content. PMID- 23082103 TI - Unique diagnostic and therapeutic roles of porphyrins and phthalocyanines in photodynamic therapy, imaging and theranostics. AB - Porphyrinic molecules have a unique theranostic role in disease therapy; they have been used to image, detect and treat different forms of diseased tissue including age-related macular degeneration and a number of different cancer types. Current focus is on the clinical imaging of tumour tissue; targeted delivery of photosensitisers and the potential of photosensitisers in multimodal biomedical theranostic nanoplatforms. The roles of porphyrinic molecules in imaging and pdt, along with research into improving their selective uptake in diseased tissue and their utility in theranostic applications are highlighted in this Review. PMID- 23082109 TI - Evaluation of 14 organic solvents and carriers for screening applications in zebrafish embryos and larvae. AB - Zebrafish are rapidly growing in popularity as an in vivo model system for chemical genetics, drug discovery, and toxicology, and more recently also for natural product discovery. Experiments involving the pharmacological evaluation of small molecules or natural product extracts in zebrafish bioassays require the effective delivery of these compounds to embryos and larvae. While most samples to be screened are first solubilized in dimethyl sulfoxide (DMSO), which is then diluted in the embryo medium, often this method is not sufficient to prevent the immediate or eventual precipitation of the sample. Certain compounds and extracts are also not highly soluble in DMSO. In such instances the use of carriers and/or other solvents might offer an alternative means to achieve the required sample concentration. Towards this end, we determined the maximum tolerated concentration (MTC) of several commonly used solvents and carriers in zebrafish embryos and larvae at various developmental stages. Solvents evaluated for this study included acetone, acetonitrile, butanone, dimethyl formamide, DMSO, ethanol, glycerol, isopropanol, methanol, polyethylene glycol (PEG-400), propylene glycol, and solketal, and carriers included albumin (BSA) and cyclodextrin (2-hydroxypropyl-beta-cyclodextrin, or HPBCD). This study resulted in the identification of polyethylene glycol (PEG400), propylene glycol, and methanol as solvents that were relatively well-tolerated over a range of developmental stages. In addition, our results showed that acetone was well tolerated by embryos but not by larvae, and 1% cyclodextrin (HPBCD) was well tolerated by both embryos and larvae, indicating the utility of this carrier for compound screening in zebrafish. However, given the relatively small differences (2-3 fold) between concentrations that are apparently safe and those that are clearly toxic, further studies - e.g. omics analyses -should be carried out to determine which cellular processes and signalling pathways are affected by any solvents and carriers that are used for small-molecule screens in zebrafish. PMID- 23082111 TI - Total sleep time severely drops during adolescence. AB - Restricted sleep duration among young adults and adolescents has been shown to increase the risk of morbidities such as obesity, diabetes or accidents. However there are few epidemiological studies on normal total sleep time (TST) in representative groups of teen-agers which allow to get normative data. PURPOSE: To explore perceived total sleep time on schooldays (TSTS) and non schooldays (TSTN) and the prevalence of sleep initiating insomnia among a nationally representative sample of teenagers. METHODS: Data from 9,251 children aged 11 to 15 years-old, 50.7% of which were boys, as part of the cross-national study 2011 HBSC were analyzed. Self-completion questionnaires were administered in classrooms. An estimate of TSTS and TSTN (week-ends and vacations) was calculated based on specifically designed sleep habits report. Sleep deprivation was estimated by a TSTN - TSTS difference >2 hours. Sleep initiating nsomnia was assessed according to International classification of sleep disorders (ICSD 2). Children who reported sleeping 7 hours or less per night were considered as short sleepers. RESULTS: A serious drop of TST was observed between 11 yo and 15 yo, both during the schooldays (9 hours 26 minutes vs. 7 h 55 min.; p<0.001) and at a lesser extent during week-ends (10 h 17 min. vs. 9 h 44 min.; p<0.001). Sleep deprivation concerned 16.0% of chidren aged of 11 yo vs. 40.5% of those of 15 yo (p<0.001). Too short sleep was reported by 2.6% of the 11 yo vs. 24.6% of the 15 yo (p<0.001). CONCLUSION: Despite the obvious need for sleep in adolescence, TST drastically decreases with age among children from 11 to 15 yo which creates significant sleep debt increasing with age. PMID- 23082110 TI - Altered regulation of Akt signaling with murine cerebral malaria, effects on long term neuro-cognitive function, restoration with lithium treatment. AB - Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3beta) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3beta activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3beta inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3beta with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3beta signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM. PMID- 23082112 TI - Traditional male circumcision in Uganda: a qualitative focus group discussion analysis. AB - BACKGROUND: The growing body of evidence attesting to the effectiveness of clinical male circumcision in the prevention of HIV/AIDS transmission is prompting the majority of sub-Saharan African governments to move towards the adoption of voluntary medical male circumcision (VMMC). Even though it is recommended to consider collaboration with traditional male circumcision (TMC) providers when planning for VMMC, there is limited knowledge available about the TMC landscape and traditional beliefs. METHODOLOGY AND MAIN FINDINGS: During 2010 11 over 25 focus group discussions (FGDs) were held with clan leaders, traditional cutters, and their assistants to understand the practice of TMC in four ethnic groups in Uganda. Cultural significance and cost were among the primary reasons cited for preferring TMC over VMMC. Ethnic groups in western Uganda circumcised boys at younger ages and encountered lower rates of TMC related adverse events compared to ethnic groups in eastern Uganda. Cutting styles and post-cut care also differed among the four groups. The use of a single razor blade per candidate instead of the traditional knife was identified as an important and recent change. Participants in the focus groups expressed interest in learning about methods to reduce adverse events. CONCLUSION: This work reaffirmed the strong cultural significance of TMC within Ugandan ethnic groups. Outcomes suggest that there is an opportunity to evaluate the involvement of local communities that still perform TMC in the national VMMC roll-out plan by devising safer, more effective procedures through innovative approaches. PMID- 23082113 TI - Profound olfactory dysfunction in myasthenia gravis. AB - In this study we demonstrate that myasthenia gravis, an autoimmune disease strongly identified with deficient acetylcholine receptor transmission at the post-synaptic neuromuscular junction, is accompanied by a profound loss of olfactory function. Twenty-seven MG patients, 27 matched healthy controls, and 11 patients with polymiositis, a disease with peripheral neuromuscular symptoms analogous to myasthenia gravis with no known central nervous system involvement, were tested. All were administered the University of Pennsylvania Smell Identification Test (UPSIT) and the Picture Identification Test (PIT), a test analogous in content and form to the UPSIT designed to control for non-olfactory cognitive confounds. The UPSIT scores of the myasthenia gravis patients were markedly lower than those of the age- and sex-matched normal controls [respective means (SDs) =20.15 (6.40) & 35.67 (4.95); p<0.0001], as well as those of the polymiositis patients who scored slightly below the normal range [33.30 (1.42); p<0.0001]. The latter finding, along with direct monitoring of the inhalation of the patients during testing, implies that the MG-related olfactory deficit is unlikely due to difficulties sniffing, per se. All PIT scores were within or near the normal range, although subtle deficits were apparent in both the MG and PM patients, conceivably reflecting influences of mild cognitive impairment. No relationships between performance on the UPSIT and thymectomy, time since diagnosis, type of treatment regimen, or the presence or absence of serum anti nicotinic or muscarinic antibodies were apparent. Our findings suggest that MG influences olfactory function to the same degree as observed in a number of neurodegenerative diseases in which central nervous system cholinergic dysfunction has been documented. PMID- 23082114 TI - Degree-strength correlation reveals anomalous trading behavior. AB - Manipulation is an important issue for both developed and emerging stock markets. Many efforts have been made to detect manipulation in stock markets. However, it is still an open problem to identify the fraudulent traders, especially when they collude with each other. In this paper, we focus on the problem of identifying the anomalous traders using the transaction data of eight manipulated stocks and forty-four non-manipulated stocks during a one-year period. By analyzing the trading networks of stocks, we find that the trading networks of manipulated stocks exhibit significantly higher degree-strength correlation than the trading networks of non-manipulated stocks and the randomized trading networks. We further propose a method to detect anomalous traders of manipulated stocks based on statistical significance analysis of degree-strength correlation. Experimental results demonstrate that our method is effective at distinguishing the manipulated stocks from non-manipulated ones. Our method outperforms the traditional weight-threshold method at identifying the anomalous traders in manipulated stocks. More importantly, our method is difficult to be fooled by colluded traders. PMID- 23082115 TI - Prion remains infectious after passage through digestive system of American crows (Corvus brachyrhynchos). AB - Avian scavengers, such as American crows (Corvus brachyrhynchos), have potential to translocate infectious agents (prions) of transmissible spongiform encephalopathy (TSE) diseases including chronic wasting disease, scrapie, and bovine spongiform encephalopathy. We inoculated mice with fecal extracts obtained from 20 American crows that were force-fed material infected with RML-strain scrapie prions. These mice all evinced severe neurological dysfunction 196-231 d postinoculation (x =198; 95% CI: 210-216) and tested positive for prion disease. Our results suggest a large proportion of crows that consume prion-positive tissue are capable of passing infectious prions in their feces (^p=1.0; 95% CI: 0.8-1.0). Therefore, this common, migratory North American scavenger could play a role in the geographic spread of TSE diseases. PMID- 23082116 TI - Similarities in the neural control of the shoulder and elbow joints belie their structural differences. AB - Movement of the hand in three dimensional space is primarily controlled by the orientation of the shoulder and elbow complexes. Due to discrepancies in proprioceptive acuity, overlap in motor cortex representation and grossly different anatomies between these joints, we hypothesized that there would be differences in the accuracy of aimed movements between the two joints. Fifteen healthy young adults were tested under four conditions - shoulder motion with the elbow constrained and unconstrained, and elbow motion with the shoulder constrained and unconstrained. End point target locations for each joint were set to coincide with joint excursions of 10, 20 or 30 degrees of either the shoulder or elbow joint. Targets were presented in a virtual reality environment. For the constrained condition, there were no significant differences in angular errors between the two joints, suggesting that the central nervous system represents linked segment models of the limb in planning and controlling movements. For the unconstrained condition, although angle errors were higher, hand position errors remained the same as those of the constrained trials. These results support the idea that the CNS utilizes abundant degrees of freedom to compensate for the potentially different contributions to end-point errors introduced by each joint. PMID- 23082117 TI - Generation of lung adenocarcinoma DNA aptamers for cancer studies. AB - Lung cancer is the most lethal malignancy in the world, and each year thousands of people die from this disease. Early detection has proven to increase the 5 year survival for this cancer in general, independent of the origination site in the lung. To address this challenge, we have used cell-based SELEX (Systematic Evolution of Ligands by Exponential Enrichment) to select a panel of aptamers capable of distinguishing lung adenocarcinoma cells from normal lung epithelial cells. These aptamers bind at physiological and formalin-fixed conditions and display affinity for their targets with apparent K(d')s in the nanomolar range. Our findings suggest that the selected aptamers have the potential to be used in clinical settings, as well as to improve classification of nonsurgical specimens, another current challenge in lung cancer. PMID- 23082118 TI - Functional significance of SRJ domain mutations in CITED2. AB - CITED2 is a transcriptional co-activator with 3 conserved domains shared with other CITED family members and a unique Serine-Glycine Rich Junction (SRJ) that is highly conserved in placental mammals. Loss of Cited2 in mice results in cardiac and aortic arch malformations, adrenal agenesis, neural tube and placental defects, and partially penetrant defects in left-right patterning. By screening 1126 sporadic congenital heart disease (CHD) cases and 1227 controls, we identified 19 variants, including 5 unique non-synonymous sequence variations (N62S, R92G, T166N, G180-A187del and A187T) in patients. Many of the CHD-specific variants identified in this and previous studies cluster in the SRJ domain. Transient transfection experiments show that T166N mutation impairs TFAP2 co activation function and ES cell proliferation. We find that CITED2 is phosphorylated by MAPK1 in vitro at T166, and that MAPK1 activation enhances the coactivation function of CITED2 but not of CITED2-T166N. In order to investigate the functional significance in vivo, we generated a T166N mutation of mouse Cited2. We also used PhiC31 integrase-mediated cassette exchange to generate a Cited2 knock-in allele replacing the mouse Cited2 coding sequence with human CITED2 and with a mutant form deleting the entire SRJ domain. Mouse embryos expressing only CITED2-T166N or CITED2-SRJ-deleted alleles surprisingly show no morphological abnormalities, and mice are viable and fertile. These results indicate that the SRJ domain is dispensable for these functions of CITED2 in mice and that mutations clustering in the SRJ region are unlikely to be the sole cause of the malformations observed in patients with sporadic CHD. Our results also suggest that coding sequence mutations observed in case-control studies need validation using in vivo models and that predictions based on structural conservation and in vitro functional assays, or even in vivo global loss of function models, may be insufficient. PMID- 23082119 TI - Role of TLR4/NF-kappaB in damage to intestinal mucosa barrier function and bacterial translocation in rats exposed to hypoxia. AB - The role of Toll-like receptor 4 (TLR4)/nuclear factor-kappa-B (NF-kappaB) in intestinal mucosal barrier damage and bacterial translocation under hypoxic exposure is unclear. Here, we investigated their role using an acute hypobaric hypoxia model. Adult Sprague-Dawley rats were divided into control (C), hypoxia (H), hypoxia+NF-kappaB inhibitor pyrrolidinedithiocarbamic acid (PDTC) (100 mg. kg) (HP), hypoxia+0.5 mg/kg lipopolysaccharide (HPL), and hypoxia+PDTC+LPS (HPL) group. Except control group, other four groups were placed in a hypobaric chamber set at 7000 m. Samples were collected at 72 h after pressure reduction. Damage in ultrastructure of the intestinal tract was examined by transmission electron microscopy and bacterial translocation was detected by cultivation. Kinetic turbidimetric assay was used to measure the serum LPS.ELISA was performed to detect TNF-alpha and IL-6 serum concentrations. Fluorescent quantitative RT-PCR was used to measure TLR4 mRNA levels was measured using quantitative RT-PCR and protein of NF-kappaB p65 was measured by western blotting. Different degrees of intestinal mucosa damage were observed in groups H and HL. The damage was significantly alleviated after blockage of the TLR4/NF-kappaB signaling pathway. PDTC- treatment also reversed hyoxia- and LPS-induced bacterial translocation rate and increased serum levels of LPS, TNF-alpha, and IL-6. TLR4 mRNA levels and NF-kappaB p65 expression were consistent with the serum factor results. This study suggested that TLR4 and NF-kappaB expression increased in rat intestinal tissues after acute hypoxia exposure. PDTC-treatment reversed TLR4 and NF-kappaB upregulation and alleviated damage to the intestinal tract and bacterial translocation. Thus, the TLR4/NF-kappaB signaling pathway may be critical to the mechanism underlying hypoxia-induced damage to intestinal barrier function and bacterial translocation. PMID- 23082120 TI - N-3 long-chain polyunsaturated fatty acid supplementation significantly reduces liver oxidative stress in high fat induced steatosis. AB - Omega-3 (n-3) long-chain polyunsaturated fatty acids (n-3 LCPUFA) are associated with several physiological functions, suggesting that their administration may prevent non transmissible chronic diseases. Therefore, we investigate whether dietary n-3 LCPUFA supplementation triggers an antioxidant response preventing liver steatosis in mice fed a high fat diet (HFD) in relation to n-3 LCPUFA levels. Male C57BL/6J mice received (a) control diet (10% fat, 20% protein, 70% carbohydrate), (b) control diet plus n-3 LCPUFA (108 mg/kg/day eicosapentaenoic acid plus 92 mg/kg/day docosahexaenoic acid), (c) HFD (60% fat, 20% protein, 20% carbohydrate), or (d) HFD plus n-3 LCPUFA for 12 weeks. Parameters of liver steatosis, glutathione status, protein carbonylation, and fatty acid analysis were determined, concomitantly with insulin resistance and serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 levels. HFD significantly increased total fat and triacylglyceride contents with macrovesicular steatosis, concomitantly with higher fasting serum glucose and insulin levels, HOMA, and serum TNF-alpha, IL-1beta, and IL-6. Reduced and total liver glutathione contents were diminished by HFD, with higher GSSG/GSH ratio and protein carbonylation, n-3 LCPUFA depletion and elevated n-6/n-3 ratio over control values. These changes were either reduced or normalized to control values in animals subjected to HFD and n-3 LCPUFA, with significant increased hepatic total n-3 LCPUFA content and reduced n-6/n-3 ratio being observed after n-3 LCPUFA supplementation alone. So, repletion of liver n-3 LCPUFA levels by n-3 LCPUFA dietary supplementation in HFD obese mice reduces hepatic lipid content, with concomitant antioxidant and anti-inflammatory responses favouring insulin sensitivity. PMID- 23082121 TI - Bio-logic builder: a non-technical tool for building dynamical, qualitative models. AB - Computational modeling of biological processes is a promising tool in biomedical research. While a large part of its potential lies in the ability to integrate it with laboratory research, modeling currently generally requires a high degree of training in mathematics and/or computer science. To help address this issue, we have developed a web-based tool, Bio-Logic Builder, that enables laboratory scientists to define mathematical representations (based on a discrete formalism) of biological regulatory mechanisms in a modular and non-technical fashion. As part of the user interface, generalized "bio-logic" modules have been defined to provide users with the building blocks for many biological processes. To build/modify computational models, experimentalists provide purely qualitative information about a particular regulatory mechanisms as is generally found in the laboratory. The Bio-Logic Builder subsequently converts the provided information into a mathematical representation described with Boolean expressions/rules. We used this tool to build a number of dynamical models, including a 130-protein large-scale model of signal transduction with over 800 interactions, influenza A replication cycle with 127 species and 200+ interactions, and mammalian and budding yeast cell cycles. We also show that any and all qualitative regulatory mechanisms can be built using this tool. PMID- 23082122 TI - The lipid phenotype of breast cancer cells characterized by Raman microspectroscopy: towards a stratification of malignancy. AB - Although molecular classification brings interesting insights into breast cancer taxonomy, its implementation in daily clinical care is questionable because of its expense and the information supplied in a single sample allocation is not sufficiently reliable. New approaches, based on a panel of small molecules derived from the global or targeted analysis of metabolic profiles of cells, have found a correlation between activation of de novo lipogenesis and poorer prognosis and shorter disease-free survival for many tumors. We hypothesized that the lipid content of breast cancer cells might be a useful indirect measure of a variety of functions coupled to breast cancer progression. Raman microspectroscopy was used to characterize metabolism of breast cancer cells with different degrees of malignancy. Raman spectra from MDA-MB-435, MDA-MB-468, MDA MB-231, SKBR3, MCF7 and MCF10A cells were acquired with an InVia Raman microscope (Renishaw) with a backscattered configuration. We used Principal Component Analysis and Partial Least Squares Discriminant Analyses to assess the different profiling of the lipid composition of breast cancer cells. Characteristic bands related to lipid content were found at 3014, 2935, 2890 and 2845 cm(-1), and related to lipid and protein content at 2940 cm(-1). A classificatory model was generated which segregated metastatic cells and non-metastatic cells without basal-like phenotype with a sensitivity of 90% and a specificity of 82.1%. Moreover, expression of SREBP-1c and ABCA1 genes validated the assignation of the lipid phenotype of breast cancer cells. Indeed, changes in fatty acid unsaturation were related with the epithelial-to-mesenchymal transition phenotype. Raman microspectroscopy is a promising technique for characterizing and classifying the malignant phenotype of breast cancer cells on the basis of their lipid profiling. The algorithm for the discrimination of metastatic ability is a first step towards stratifying breast cancer cells using this rapid and reagent-free tool. PMID- 23082123 TI - Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial. AB - BACKGROUND: Influenza is an important cause of morbidity and mortality for frail older people. Whilst the antiviral drug oseltamivir (a neuraminidase inhibitor) is approved for treatment and prophylaxis of influenza during outbreaks, there have been no trials comparing treatment only (T) versus treatment and prophylaxis (T&P) in Aged Care Facilities (ACFs). Our objective was to compare a policy of T versus T&P for influenza outbreaks in ACFs. METHODS AND FINDINGS: We performed a cluster randomised controlled trial in 16 ACFs, that followed a policy of either "T"-oseltamivir treatment (75 mg twice a day for 5 days)-or "T&P"-treatment and prophylaxis (75 mg once a day for 10 days) for influenza outbreaks over three years, in addition to enhanced surveillance. The primary outcome measure was the attack rate of influenza. Secondary outcomes measures were deaths, hospitalisation, pneumonia and adverse events. Laboratory testing was performed to identify the viral cause of influenza-like illness (ILI) outbreaks. The study period 30 June 2006 to 23 December 2008 included three southern hemisphere winters. During that time, influenza was confirmed as the cause of nine of the 23 ILI outbreaks that occurred amongst the 16 ACFs. The policy of T&P resulted in a significant reduction in the influenza attack rate amongst residents: 93/255 (36%) in residents in T facilities versus 91/397 (23%) in T&P facilities (p=0.002). We observed a non-significant reduction in staff: 46/216 (21%) in T facilities versus 47/350 (13%) in T&P facilities (p=0.5). There was a significant reduction in mean duration of outbreaks (T=24 days, T&P=11 days, p=0.04). Deaths, hospitalisations and pneumonia were non-significantly reduced in the T&P allocated facilities. Drug adverse events were common but tolerated. CONCLUSION: Our trial lacked power but these results provide some support for a policy of "treatment and prophylaxis" with oseltamivir in controlling influenza outbreaks in ACFs. TRIAL REGISTRATION: [corrected] Australian Clinical Trials Registry ACTRN12606000278538. PMID- 23082124 TI - Assessing water filtration and safe storage in households with young children of HIV-positive mothers: a randomized, controlled trial in Zambia. AB - BACKGROUND: Unsafe drinking water presents a particular threat to people living with HIV/AIDS (PLHIV) due to the increased risk of opportunistic infections, diarrhea-associated malabsorption of essential nutrients, and increased exposure to untreated water for children of HIV-positive mothers who use replacement feeding to reduce the risk of HIV transmission. This population may particularly benefit from an intervention to improve water quality in the home. METHODS AND FINDINGS: We conducted a 12-month randomized, controlled field trial in Zambia among 120 households with children <2 years (100 with HIV-positive mothers and 20 with HIV-negative mothers to reduce stigma of participation) to assess a high performance water filter and jerry cans for safe storage. Households were followed up monthly to assess use, drinking water quality (thermotolerant coliforms (TTC), an indicator of fecal contamination) and reported diarrhea (7 day recall) among children <2 years and all members of the household. Because previous attempts to blind the filter have been unsuccessful, we also assessed weight-for-age Z-scores (WAZ) as an objective measure of diarrhea impact. Filter use was high, with 96% (596/620) of household visits meeting the criteria for users. The quality of water stored in intervention households was significantly better than in control households (3 vs. 181 TTC/100 mL, respectively, p<0.001). The intervention was associated with reductions in the longitudinal prevalence of reported diarrhea of 53% among children <2 years (LPR=0.47, 95% CI: 0.30-0.73, p=0.001) and 54% among all household members (LPR=0.46, 95% CI: 0.30-0.70, p<0.001). While reduced WAZ was associated with reported diarrhea (-0.26; 95% CI: -0.37 to -0.14, p<0.001), there was no difference in WAZ between intervention and control groups. CONCLUSION: In this population living with HIV/AIDS, a water filter combined with safe storage was used correctly and consistently, was highly effective in improving drinking water quality, and was protective against diarrhea. TRIAL REGISTRATION: Clinicaltrials.gov NCT01116908. PMID- 23082125 TI - Transition pattern and mechanism of B-lymphocyte precursors in regenerated mouse bone marrow after subtotal body irradiation. AB - Little is known about the effects of ionizing radiation on the transition and the related signal transduction of progenitor B cells in the bone marrow. Thus, using an NIH Swiss mouse model, we explored the impact of ionizing radiation on the early stage of B-cell development via an examination of the transition of CLP to pro-B to pre-B cells within bone marrow as a function of radiation doses and times. Our results showed that while the total number of bone marrow lymphoid cells at different stages were greatly reduced by subtotal body irradiation (sub TBI), the surviving cells continued to transition from common lymphoid progenitors to pro-B and then to pre-B in a reproducible temporal pattern. The rearrangement of the immunoglobulin heavy chain increased significantly 1-2 weeks after irradiation, but no change occurred after 3-4 weeks. The rearrangement of the immunoglobulin light chain decreased significantly 1-2 weeks after sub-TBI but increased dramatically after 3-4 weeks. In addition, several key transcription factors and signaling pathways were involved in B-precursor transitions after sub-TBI. The data indicate that week 2 after irradiation is a critical time for the transition from pro-B cells to pre-B cells, reflecting that the functional processes for different B-cell stages are well preserved even after high-dose irradiation. PMID- 23082126 TI - Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. AB - Cancer can be envisioned as a metabolic disease driven by pressure selection and intercellular cooperativeness. Together with anaerobic glycolysis, the Warburg effect, formally corresponding to uncoupling glycolysis from oxidative phosphorylation, directly participates in cancer aggressiveness, supporting both tumor progression and dissemination. The transcription factor hypoxia-inducible factor-1 (HIF-1) is a key contributor to glycolysis. It stimulates the expression of glycolytic transporters and enzymes supporting high rate of glycolysis. In this study, we addressed the reverse possibility of a metabolic control of HIF-1 in tumor cells. We report that lactate, the end-product of glycolysis, inhibits prolylhydroxylase 2 activity and activates HIF-1 in normoxic oxidative tumor cells but not in Warburg-phenotype tumor cells which also expressed lower basal levels of HIF-1alpha. These data were confirmed using genotypically matched oxidative and mitochondria-depleted glycolytic tumor cells as well as several different wild-type human tumor cell lines of either metabolic phenotype. Lactate activates HIF-1 and triggers tumor angiogenesis and tumor growth in vivo, an activity that we found to be under the specific upstream control of the lactate transporter monocarboxylate transporter 1 (MCT1) expressed in tumor cells. Because MCT1 also gates lactate-fueled tumor cell respiration and mediates pro angiogenic lactate signaling in endothelial cells, MCT1 inhibition is confirmed as an attractive anticancer strategy in which a single drug may target multiple tumor-promoting pathways. PMID- 23082127 TI - An integrated approach for identifying wrongly labelled samples when performing classification in microarray data. AB - BACKGROUND: Using hybrid approach for gene selection and classification is common as results obtained are generally better than performing the two tasks independently. Yet, for some microarray datasets, both classification accuracy and stability of gene sets obtained still have rooms for improvement. This may be due to the presence of samples with wrong class labels (i.e. outliers). Outlier detection algorithms proposed so far are either not suitable for microarray data, or only solve the outlier detection problem on their own. RESULTS: We tackle the outlier detection problem based on a previously proposed Multiple-Filter-Multiple Wrapper (MFMW) model, which was demonstrated to yield promising results when compared to other hybrid approaches (Leung and Hung, 2010). To incorporate outlier detection and overcome limitations of the existing MFMW model, three new features are introduced in our proposed MFMW-outlier approach: 1) an unbiased external Leave-One-Out Cross-Validation framework is developed to replace internal cross-validation in the previous MFMW model; 2) wrongly labeled samples are identified within the MFMW-outlier model; and 3) a stable set of genes is selected using an L1-norm SVM that removes any redundant genes present. Six binary-class microarray datasets were tested. Comparing with outlier detection studies on the same datasets, MFMW-outlier could detect all the outliers found in the original paper (for which the data was provided for analysis), and the genes selected after outlier removal were proven to have biological relevance. We also compared MFMW-outlier with PRAPIV (Zhang et al., 2006) based on same synthetic datasets. MFMW-outlier gave better average precision and recall values on three different settings. Lastly, artificially flipped microarray datasets were created by removing our detected outliers and flipping some of the remaining samples' labels. Almost all the 'wrong' (artificially flipped) samples were detected, suggesting that MFMW-outlier was sufficiently powerful to detect outliers in high dimensional microarray datasets. PMID- 23082128 TI - National approaches to monitoring population salt intake: a trade-off between accuracy and practicality? AB - AIMS: There is strong evidence that diets high in salt are bad for health and that salt reduction strategies are cost effective. However, whilst it is clear that most people are eating too much salt, obtaining an accurate assessment of population salt intake is not straightforward, particularly in resource poor settings. The objective of this study is to identify what approaches governments are taking to monitoring salt intake, with the ultimate goal of identifying what actions are needed to address challenges to monitoring salt intake, especially in low and middle-income countries. METHODS AND RESULTS: A written survey was issued to governments to establish the details of their monitoring methods. Of the 30 countries that reported conducting formal government salt monitoring activities, 73% were high income countries. Less than half of the 30 countries, used the most accurate assessment of salt through 24 hour urine, and only two of these were developing countries. The remainder mainly relied on estimates through dietary surveys. CONCLUSIONS: The study identified a strong need to establish more practical ways of assessing salt intake as well as technical support and advice to ensure that low and middle income countries can implement salt monitoring activities effectively. PMID- 23082130 TI - Analysis of intron sequence features associated with transcriptional regulation in human genes. AB - Although some preliminary work has revealed the potential transcriptional regulatory function of the introns in eukaryotes, additional evidences are needed to support this conjecture. In this study, we perform systemic analyses of the sequence characteristics of human introns. The results show that the first introns are generally longer and C, G and their dinucleotide compositions are over-represented relative to other introns, which are consistent with the previous findings. In addition, some new phenomena concerned with transcriptional regulation are found: i) the first introns are enriched in CpG islands; and ii) the percentages of the first introns containing TATA, CAAT and GC boxes are relatively higher than other position introns. The similar features of introns are observed in tissue-specific genes. The results further support that the first introns of human genes are likely to be involved in transcriptional regulation, and give an insight into the transcriptional regulatory regions of genes. PMID- 23082129 TI - Genome-wide identification and analysis of MAPK and MAPKK gene families in Brachypodium distachyon. AB - MAPK cascades are universal signal transduction modules and play important roles in plant growth, development and in response to a variety of biotic and abiotic stresses. Although MAPKs and MAPKKs have been systematically investigated in several plant species including Arabidopsis, rice and poplar, no systematic analysis has been conducted in the emerging monocot model plant Brachypodium distachyon. In the present study, a total of 16 MAPK genes and 12 MAPKK genes were identified from B. distachyon. An analysis of the genomic evolution showed that both tandem and segment duplications contributed significantly to the expansion of MAPK and MAPKK families. Evolutionary relationships within subfamilies were supported by exon-intron organizations and the architectures of conserved protein motifs. Synteny analysis between B. distachyon and the other two plant species of rice and Arabidopsis showed that only one homolog of B. distachyon MAPKs was found in the corresponding syntenic blocks of Arabidopsis, while 13 homologs of B. distachyon MAPKs and MAPKKs were found in that of rice, which was consistent with the speciation process of the three species. In addition, several interactive protein pairs between the two families in B. distachyon were found through yeast two hybrid assay, whereas their orthologs of a pair in Arabidopsis and other plant species were not found to interact with each other. Finally, expression studies of closely related family members among B. distachyon, Arabidopsis and rice showed that even recently duplicated representatives may fulfill different functions and be involved in different signal pathways. Taken together, our data would provide a foundation for evolutionary and functional characterization of MAPK and MAPKK gene families in B. distachyon and other plant species to unravel their biological roles. PMID- 23082131 TI - Shark predation on migrating adult American eels (Anguilla rostrata) in the Gulf of St. Lawrence. AB - In an attempt to document the migratory pathways and the environmental conditions encountered by American eels during their oceanic migration to the Sargasso Sea, we tagged eight silver eels with miniature satellite pop-up tags during their migration from the St. Lawrence River in Quebec, Canada. Surprisingly, of the seven tags that successfully transmitted archived data, six were ingested by warm gutted predators, as observed by a sudden increase in water temperature. Gut temperatures were in the range of 20 to 25 degrees C-too cold for marine mammals but within the range of endothermic fish. In order to identify the eel predators, we compared their vertical migratory behavior with those of satellite-tagged porbeagle shark and bluefin tuna, the only endothermic fishes occurring non marginally in the Gulf of St. Lawrence. We accurately distinguished between tuna and shark by using the behavioral criteria generated by comparing the diving behavior of these two species with those of our unknown predators. Depth profile characteristics of most eel predators more closely resembled those of sharks than those of tuna. During the first days following tagging, all eels remained in surface waters and did not exhibit diel vertical migrations. Three eels were eaten at this time. Two eels exhibited inverse diel vertical migrations (at surface during the day) during several days prior to predation. Four eels were eaten during daytime, whereas the two night-predation events occurred at full moon. Although tagging itself may contribute to increasing the eel's susceptibility to predation, we discuss evidence suggesting that predation of silver-stage American eels by porbeagle sharks may represent a significant source of mortality inside the Gulf of St. Lawrence and raises the possibility that eels may represent a reliable, predictable food resource for porbeagle sharks. PMID- 23082132 TI - Measurement of phospholipids may improve diagnostic accuracy in ovarian cancer. AB - BACKGROUND: More than two-thirds of women who undergo surgery for suspected ovarian neoplasm do not have cancer. Our previous results suggest phospholipids as potential biomarkers of ovarian cancer. In this study, we measured the serum levels of multiple phospholipids among women undergoing surgery for suspected ovarian cancer to identify biomarkers that better predict whether an ovarian mass is malignant. METHODOLOGY/PRINCIPAL FINDINGS: We obtained serum samples preoperatively from women with suspected ovarian cancer enrolled through a prospective, population-based rapid ascertainment system. Samples were analyzed from all women in whom a diagnosis of epithelial ovarian cancer (EOC) was confirmed and from benign disease cases randomly selected from the remaining (non EOC) samples. We measured biologically relevant phospholipids using liquid chromatography/electrospray ionization mass spectrometry. We applied a powerful statistical and machine learning approach, Hybrid huberized support vector machine (HH-SVM) to prioritize phospholipids to enter the biomarker models, and used cross-validation to obtain conservative estimates of classification error rates. RESULTS: The HH-SVM model using the measurements of specific combinations of phospholipids supplements clinical CA125 measurement and improves diagnostic accuracy. Specifically, the measurement of phospholipids improved sensitivity (identification of cases with preoperative CA125 levels below 35) among two types of cases in which CA125 performance is historically poor - early stage cases and those of mucinous histology. Measurement of phospholipids improved the identification of early stage cases from 65% (based on CA125) to 82%, and mucinous cases from 44% to 88%. CONCLUSIONS/SIGNIFICANCE: Levels of specific serum phospholipids differ between women with ovarian cancer and those with benign conditions. If validated by independent studies in the future, these biomarkers may serve as an adjunct at the time of clinical presentation, to distinguish between women with ovarian cancer and those with benign conditions with shared symptoms and features. PMID- 23082134 TI - Poststroke depression and risk of recurrent stroke at 1 year in a Chinese cohort study. AB - BACKGROUND: Studies show that poststroke depression (PSD) increases mortality risk at 1 year. However, whether PSD increases the risk of recurrent stroke at 1 year remains unclear. This study was to investigate whether PSD at 2 weeks following a stroke could increase risk of recurrent stroke at 1 year. METHODS AND RESULTS: This was a multi-centered prospective cohort study. A total of 2306 patients with acute stroke were enrolled in our study. PSD was diagnosed according to the criteria set by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). The outcomes of recurrent stroke were followed up via face-to-face or phone interview. A total of 1713 patients had complete follow-up data, with 481 (28.1%) cases of PSD and 158 (9.2%) cases of cumulative recurrent stroke at 1 year. Multivariate logistic regression analysis showed a 49% increase of OR of recurrent stroke at 1 year in patients with PSD, compared to patients without PSD following a stroke (OR=1.49, 95%CI: 1.03-2.15). There was no significant correlation between anti-depressant drugs and the risk of recurrent stroke at 1 year following a stroke (OR=1.96, 95%: CI 0.95-4.04). CONCLUSIONS: Based on the DSM-IV diagnostic criteria, nearly 3 out of 10 hospitalized stroke patients in China were diagnosed with PSD at 2 weeks following a stroke. PSD is associated with a higher risk of recurrent stroke at 1 year. Our study did not find benefit of anti-depressant drugs in reducing such risk. PMID- 23082133 TI - Angiotensin converting enzyme inhibitor and HMG-CoA reductase inhibitor as adjunct treatment for persons with HIV infection: a feasibility randomized trial. AB - BACKGROUND: Treatments that reduce inflammation and cardiovascular disease (CVD) risk among individuals with HIV infection receiving effective antiretroviral therapy (ART) are needed. DESIGN AND METHODS: We conducted a 2 * 2 factorial feasibility study of lisinopril (L) (10 mg daily) vs L-placebo in combination with pravastatin (P) (20 mg daily) vs P-placebo among participants receiving ART with undetectable HIV RNA levels, a Framingham 10 year risk score (FRS) >= 3%, and no indication for ACE-I or statin therapy. Tolerability and adherence were evaluated. Longitudinal mixed models assessed changes in blood pressure (BP), blood lipids, and inflammatory biomarkers from baseline through months 1 and 4. RESULTS: Thirty-seven participants were randomized and 34 [lisinopril/pravastatin (n=9), lisinopril/P-placebo (n=8), L-placebo/pravastatin (n=9), L-placebo/P placebo (n=8)] attended at least one follow-up visit. Participants were 97% male, 41% white, 67% were current smokers, and 65% were taking a protease inhibitor. Median age was 48 years, CD4 count 483 cells/mm(3), FRS 7.79%, total cholesterol 184 mg/dL, and LDL-C 95 mg/dL. There was no treatment difference for pravastatin vs P-placebo in total cholesterol, LDL-C, or any of the inflammatory biomarkers. Participants randomized to lisinopril vs. L-placebo had significant declines in diastolic BP (-3.3 mmHg, p=0.05), hsCRP (-0.61 ug/mL, p=0.02) and TNF-alpha ( 0.17 pg/mL, p=0.04). Participants taking lisinopril vs L-placebo were more likely to report missed doses (88 vs 35%; p=0.001) and have adherence <90% by pill count (42 vs. 0%; p=0.02). Few participants from either group reported side effects (n=3 vs. n=1). CONCLUSIONS: The modest BP changes and decreased adherence with lisinopril and absence of lipid differences with pravastatin suggest future studies of these drug classes should consider a run-in period to assess adherence and use a different statin. Our results also indicate that ACE-I therapy may have anti-inflammatory benefits for ART-treated persons with HIV infection and this should be further evaluated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00982189. PMID- 23082135 TI - Formation of phosphoglycosides in Caenorhabditis elegans: a novel biotransformation pathway. AB - BACKGROUND: Caenorhabditis elegans (C. elegans) has become a widely used model to explore the effect of food constituents on health as well as on life-span extension. The results imply that besides essential nutrients several flavonoids are able to impact the aging process. What is less investigated is the bioavailability and biotransformation of these compounds in C. elegans. In the present study, we focused on the soy isoflavone genistein and its metabolism in the nematode as a basis for assessing whether this model system mimics the mammalian condition. PRINCIPAL FINDINGS: C. elegans was exposed to 100 uM genistein for 48 hours. The worm homogenate was extracted and analyzed by liquid chromatography (LC). 11 metabolites of genistein were detected and characterized using LC electrospray ionization mass spectrometry. All genistein metabolites formed by C. elegans were found to be sugar conjugates, primarily genistein-O glucosides. The dominant metabolite was identified as genistein-7-O phosphoglucoside. Further interesting metabolites include two genistein-di-O glycosides, a genistein-O-disaccharide as well as a genistein-O phosphodisaccharide. CONCLUSIONS/SIGNIFICANCE: Our study provides evidence for a novel biotransformation pathway in C. elegans leading to conjugative metabolites which are not known for mammals. The metabolism of genistein in mammals and in C. elegans differs widely which may greatly impact the bioactivity. These differences need to be appropriately taken into consideration when C. elegans is used as a model to assess possible health or aging effects. PMID- 23082136 TI - The first occurrence in the fossil record of an aquatic avian twig-nest with Phoenicopteriformes eggs: evolutionary implications. AB - BACKGROUND: We describe the first occurrence in the fossil record of an aquatic avian twig-nest with five eggs in situ (Early Miocene Tudela Formation, Ebro Basin, Spain). Extensive outcrops of this formation reveal autochthonous avian osteological and oological fossils that represent a single taxon identified as a basal phoenicopterid. Although the eggshell structure is definitively phoenicopterid, the characteristics of both the nest and the eggs are similar to those of modern grebes. These observations allow us to address the origin of the disparities between the sister taxa Podicipedidae and Phoenicopteridae crown clades, and traces the evolution of the nesting and reproductive environments for phoenicopteriforms. METHODOLOGY/PRINCIPAL FINDINGS: Multi-disciplinary analyses performed on fossilized vegetation and eggshells from the eggs in the nest and its embedding sediments indicate that this new phoenicopterid thrived under a semi-arid climate in an oligohaline (seasonally mesohaline) shallow endorheic lacustine environment. High-end microcharacterizations including SEM, TEM, and EBSD techniques were pivotal to identifying these phoenicopterid eggshells. Anatomical comparisons of the fossil bones with those of Phoenicopteriformes and Podicipediformes crown clades and extinct palaelodids confirm that this avian fossil assemblage belongs to a new and basal phoenicopterid. CONCLUSIONS/SIGNIFICANCE: Although the Podicipediformes-Phoenicopteriformes sister group relationship is now well supported, flamingos and grebes exhibit feeding, reproductive, and nesting strategies that diverge significantly. Our multi-disciplinary study is the first to reveal that the phoenicopteriform reproductive behaviour, nesting ecology and nest characteristics derived from grebe-like type strategies to reach the extremely specialized conditions observed in modern flamingo crown groups. Furthermore, our study enables us to map ecological and reproductive characters on the Phoenicopteriformes evolutionary lineage. Our results demonstrate that the nesting paleoenvironments of flamingos were closely linked to the unique ecology of this locality, which is a direct result of special climatic (high evaporitic regime) and geological (fault system) conditions. PMID- 23082137 TI - Food marketing towards children: brand logo recognition, food-related behavior and BMI among 3-13-year-olds in a south Indian town. AB - OBJECTIVES: To assess exposure to marketing of unhealthy food products and its relation to food related behavior and BMI in children aged 3-13, from different socioeconomic backgrounds in a south Indian town. METHODS: Child-parent pairs (n=306) were recruited at pediatric clinics. Exposure to food marketing was assessed by a digital logo recognition test. Children matched 18 logos of unhealthy food (high in fat/sugar/salt) featured in promotion material from the food industry to pictures of corresponding products. Children's nutritional knowledge, food preferences, purchase requests, eating behavior and socioeconomic characteristics were assessed by a digital game and parental questionnaires. Anthropometric measurements were recorded. RESULTS: Recognition rates for the brand logos ranged from 30% to 80%. Logo recognition ability increased with age (p<0.001) and socioeconomic level (p<0.001 comparing children in the highest and lowest of three socioeconomic groups). Adjusted for gender, age and socioeconomic group, logo recognition was associated with higher BMI (p=0.022) and nutritional knowledge (p<0.001) but not to unhealthy food preferences or purchase requests. CONCLUSIONS: Children from higher socioeconomic groups in the region had higher brand logo recognition ability and are possibly exposed to more food marketing. The study did not lend support to a link between exposure to marketing and poor eating behavior, distorted nutritional knowledge or increased purchase requests. The correlation between logo recognition and BMI warrants further investigation on food marketing towards children and its potential role in the increasing burden of non-communicable diseases in this part of India. PMID- 23082138 TI - Functional haplotypes of the hTERT gene, leukocyte telomere length shortening, and the risk of peripheral arterial disease. AB - BACKGROUND: The development of peripheral arterial disease (PAD) is heterogeneous even in the presence of similar risk factors. Our aim was to determine whether inter-individual differences in leukocyte telomere length contribute to the susceptibility of PAD. METHODS: A total of 485 patients with PAD (defined by the ankle-brachial index) and 970 age- and gender-matched controls were recruited from seven rural communities in Henan Province in China. The relative leukocyte telomere length was determined by a quantitative PCR-based method. Two common promoter variants of the hTERT gene were genotyped to assess their effects on telomere length and the risk of PAD. In vivo luciferase assay was performed to study the transcriptional activity. RESULTS: After adjustment for vascular risk factors and genetic variants in the hTERT gene, individuals in the lowest and middle tertiles of telomere length had a significantly higher risk of PAD than did those in the highest tertile (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.29-2.49 in the middle tertile; 3.15, 95%CI 2.31-4.29 in the lowest tertile). Haplotype analysis using the 2 variants (rs2735940 and rs2853669) showed that subjects with the at-risk C-C haplotype had shorter telomere length than those individuals with the T-T haplotype and consistently had 1.30-fold (OR 1.30, 95%CI 1.06-1.58; P=0.005) increased risk for PAD. The C-C haplotype had 43% lowered transcription activity of hTERT promoter (P<0.001). CONCLUSION: The associations between the functional haplotype of hTERT gene and telomere length and the risk of atherosclerotic PAD suggested that mean leukocyte telomere length may independently serve as a potential predictor of PAD. PMID- 23082139 TI - Sleep deprivation impairs consolidation of cued fear memory in rats. AB - Post-learning sleep facilitates negative memory consolidation and also helps preserve it over several years. It is believed, therefore, that sleep deprivation may help prevent consolidation of fearful memory. Its effect, however, on consolidation of negative/frightening memories is not known. Cued fear conditioning (CuFC) is a widely used model to understand the neural basis of negative memory associated with anxiety disorders. In this study, we first determined the suitable circadian timing for consolidation of CuFC memory and changes in sleep architecture after CuFC. Thereafter, we studied the effect of sleep deprivation on CuFC memory consolidation. Three sets of experiments were performed in male Wistar rat (n=51). In experiment-I, animals were conditioned to cued-fear by presenting ten tone-shock paired stimuli during lights-on (7 AM) (n=9) and lights-off (7 PM) (n=9) periods. In experiment-II, animals were prepared for polysomnographic recording (n=8) and changes in sleep architecture after CuFC was determined. Further in experiment-III, animals were cued fear conditioned during the lights-off period and were randomly divided into four groups: Sleep-Deprived (SD) (n=9), Non-Sleep Deprived (NSD) (n=9), Stress Control (SC) (n=9) and Tone Control (n=7). Percent freezing amount, a hallmark of fear, was compared statistically in these groups. Rats trained during the lights-off period exhibited significantly more freezing compared to lights-on period. In CuFC trained animals, total sleep amount did not change, however, REM sleep decreased significantly. Further, out of total sleep time, animals spent proportionately more time in NREM sleep. Nevertheless, SD animals exhibited significantly less freezing compared to NSD and SC groups. These data suggest that sleep plays an important role in the consolidation of cued fear-conditioned memory. PMID- 23082140 TI - Pyruvate kinase deficiency in sub-Saharan Africa: identification of a highly frequent missense mutation (G829A;Glu277Lys) and association with malaria. AB - BACKGROUND: Pyruvate kinase (PK) deficiency, causing hemolytic anemia, has been associated to malaria protection and its prevalence in sub-Saharan Africa is not known so far. This work shows the results of a study undertaken to determine PK deficiency occurrence in some sub-Saharan African countries, as well as finding a prevalent PK variant underlying this deficiency. MATERIALS AND METHODS: Blood samples of individuals from four malaria endemic countries (Mozambique, Angola, Equatorial Guinea and Sao Tome and Principe) were analyzed in order to determine PK deficiency occurrence and detect any possible high frequent PK variant mutation. The association between this mutation and malaria was ascertained through association studies involving sample groups from individuals showing different malaria infection and outcome status. RESULTS: The percentage of individuals showing a reduced PK activity in Maputo was 4.1% and the missense mutation G829A (Glu277Lys) in the PKLR gene (only identified in three individuals worldwide to date) was identified in a high frequency. Heterozygous carrier frequency was between 6.7% and 2.6%. A significant association was not detected between either PK reduced activity or allele 829A frequency and malaria infection and outcome, although the variant was more frequent among individuals with uncomplicated malaria. CONCLUSIONS: This was the first study on the occurrence of PK deficiency in several areas of Africa. A common PKLR mutation G829A (Glu277Lys) was identified. A global geographical co-distribution between malaria and high frequency of PK deficiency seems to occur suggesting that malaria may be a selective force raising the frequency of this 277Lys variant. PMID- 23082141 TI - Genome-wide DNA methylation and gene expression analyses of monozygotic twins discordant for intelligence levels. AB - Human intelligence, as measured by intelligence quotient (IQ) tests, demonstrates one of the highest heritabilities among human quantitative traits. Nevertheless, studies to identify quantitative trait loci responsible for intelligence face challenges because of the small effect sizes of individual genes. Phenotypically discordant monozygotic (MZ) twins provide a feasible way to minimize the effects of irrelevant genetic and environmental factors, and should yield more interpretable results by finding epigenetic or gene expression differences between twins. Here we conducted array-based genome-wide DNA methylation and gene expression analyses using 17 pairs of healthy MZ twins discordant intelligently. ARHGAP18, related to Rho GTPase, was identified in pair-wise methylation status analysis and validated via direct bisulfite sequencing and quantitative RT-PCR. To perform expression profile analysis, gene set enrichment analysis (GSEA) between the groups of twins with higher IQ and their co-twins revealed up regulated expression of several ribosome-related genes and DNA replication related genes in the group with higher IQ. To focus more on individual pairs, we conducted pair-wise GSEA and leading edge analysis, which indicated up-regulated expression of several ion channel-related genes in twins with lower IQ. Our findings implied that these groups of genes may be related to IQ and should shed light on the mechanism underlying human intelligence. PMID- 23082142 TI - Cumulus cells gene expression profiling in terms of oocyte maturity in controlled ovarian hyperstimulation using GnRH agonist or GnRH antagonist. AB - In in vitro fertilization (IVF) cycles controlled ovarian hyperstimulation (COH) is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists, to prevent premature luteinizing hormone (LH) surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC) in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI) and mature metaphase II (MII) oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti Mullerian hormone receptor 2 (AMHR2), follicle stimulating hormone receptor (FSHR), vascular endothelial growth factor C (VEGFC) and serine protease inhibitor E2 (SERPINE2). Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and gamma-Aminobutyric acid (GABA). No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven. PMID- 23082143 TI - Pica and amylophagy are common among Malagasy men, women and children. AB - Pica, the craving and purposive consumption of non-food substances, is of public health concern for its potential deleterious and salubrious health consequences. However, neither its prevalence nor demographic correlates have been well characterized. Therefore, we conducted the first population-based study of pica and amylophagy in Madagascar. From February to December 2009, we surveyed pica and amylophagy behaviors in a random sample of 760 individuals >5 years in 167 households among two ethnic groups in 16 villages in the Makira Protected Area of Madagascar. Of the 760 individuals interviewed, 62.5% were children (5-11 years), 5.4% were adolescents (12-16 years), and 35.1% were adults (>= 17 years). Thirteen non-food items were reported being consumed. Across the entire population in the prior year, the prevalence of geophagy was 53.4%, of amylophagy, 85.2%, and of other pica substances (e.g. charcoal, chalk) was 19.0%. The prevalence of these behaviors was not higher during pregnancy. These findings differ from previous studies in terms of the higher overall prevalence of these behaviors, the high prevalence among men, and the absence of any peak in behaviors during pregnancy. However, there are two categories of substances that elevate our estimates but fall outside the strict definition of pica as a craving: 1) substances consumed for self-medication and 2) substances viewed as food, such as all amylophagic substances in this case. Our results suggest that population-based studies of pica should include males of all ages. Further, the prevalence of the behavior underscores the importance of understanding the etiology and health consequences of these ingestive behaviors (Abstract S1). PMID- 23082144 TI - Second-to-fourth digit ratio and impulsivity: a comparison between offenders and nonoffenders. AB - Personality characteristics, particularly impulsive tendencies, have long been conceived as the primary culprit in delinquent behavior. One crucial question to emerge from this line of work is whether impulsivity has a biological basis. To test this possibility, 44 male offenders and 46 nonoffenders completed the Eysenck Impulsivity Questionnaire, and had their 2D?4D ratio measured. Offenders exhibited smaller right hand digit ratio measurements compared to non-offenders, but higher impulsivity scores. Both impulsivity and 2D?4D ratio measurements significantly predicted criminality (offenders vs. nonoffenders). Controlling for education level, the 2D?4D ratio measurements had remained a significant predictor of criminality, while impulsivity scores no longer predicted criminality significantly. Our data, thus, indicates that impulsivity but not 2D?4D ratio measurements relate to educational attainment. As offenders varied in their number of previous convictions and the nature of their individual crimes, we also tested for differences in 2D?4D ratio and impulsivity among offenders. Number of previous convictions did not correlate significantly with the 2D?4D ratio measurements or impulsivity scores. Our study established a link between a biological marker and impulsivity among offenders (and lack thereof among non offenders), which emphasise the importance of studying the relationship between biological markers, impulsivity and criminal behavior. PMID- 23082145 TI - The speed of range shifts in fragmented landscapes. AB - Species may be driven extinct by climate change, unless their populations are able to shift fast enough to track regions of suitable climate. Shifting will be faster as the proportion of suitable habitat in the landscape increases. However, it is not known how the spatial arrangement of habitat will affect the speed of range advance, especially when habitat is scarce, as is the case for many specialist species. We develop methods for calculating the speed of advance that are appropriate for highly fragmented, stochastic systems. We reveal that spatial aggregation of habitat tends to reduce the speed of advance throughout a wide range of species parameters: different dispersal distances and dispersal kernel shapes, and high and low extinction probabilities. In contrast, aggregation increases the steady-state proportion of habitat that is occupied (without climate change). Nonetheless, we find that it is possible to achieve both rapid advance and relatively high patch occupancy when the habitat has a "channeled" pattern, resembling corridors or chains of stepping stones. We adapt techniques from electrical circuit theory to predict the rate of advance efficiently for complex, realistic landscape patterns, whereas the rate cannot be predicted by any simple statistic of aggregation or fragmentation. Conservationists are already advocating corridors and stepping stones as important conservation tools under climate change, but they are vaguely defined and have so far lacked a convincing basis in fundamental population biology. Our work shows how to discriminate properties of a landscape's spatial pattern that affect the speed of colonization (including, but not limited to, patterns like corridors and chains of stepping stones), and properties that affect a species' probability of persistence once established. We can therefore point the way to better land use planning approaches, which will provide functional habitat linkages and also maintain local population viability. PMID- 23082146 TI - Depletion of regulatory T lymphocytes reverses the imbalance between pro- and anti-tumor immunities via enhancing antigen-specific T cell immune responses. AB - BACKGROUND: The regulatory T cells (Tregs) can actively suppress the immune responses. However, literature about detailed changes of host effective and suppressive immunities before and after depletion of Tregs in ovarian carcinomas, is rare. MATERIALS AND METHODS: Ovarian cancer patients and the ascitogenic animal model were employed. Immunologic profiles with flow cytometric analyses, immunohistochemistric staining, RT-PCR, ELISA, and ELISPOT assays were performed. In vivo depletion of Treg cells with the mAb PC61was also performed in the animal model. RESULTS: The cytokines, including IL-4 (p=0.017) and TNF-alpha (p=0.046), significantly decreased while others such as TGF-beta (p=0.013), IL-6 (p=0.016), and IL-10 (p=0.018) were elevated in ascites of ovarian cancer patients, when the disease progressed to advanced stages. The ratio of CD8(+) T cell/Treg cell in ascites was also lower in advanced diseases than in early diseases (advanced 7.37 +/- 0.64 vs. early 14.25 +/- 3.11, p=0.037). The kinetic low-dose CD25 Ab depletion group had significantly lower intra-peritoneal tumor weight (0.20 +/- 0.03 g) than the sequential high-dose (0.69 +/- 0.06 g) and sequential low-dose (0.67 +/- 0.07 g) CD25 Ab deletion groups (p=0.001) after 49 days of tumor challenge in the animal. The kinetic low-dose CD25 Ab depletion group generated the highest number of IFN-gamma-secreting, mesothelin-specific T lymphocytes compared to the other groups (p<0.001). CONCLUSIONS: The imbalance between effective and suppressive immunities becomes more severe as a tumor progresses. The depletion of Treg cells can correct the imbalance of immunologic profiles and generate potent anti-tumor effects. Targeting Treg cells can be a new strategy for the immunotherapy of ovarian carcinoma. PMID- 23082147 TI - The 1973 WHO Classification is more suitable than the 2004 WHO Classification for predicting prognosis in non-muscle-invasive bladder cancer. AB - BACKGROUND: Predicting the recurrence and progression of Non-muscle-invasive bladder cancer(NMIBC) is critical for urologist. Histological grade provides significant prognostic information, especially for prediction of progression. Currently, the 1973 and the 2004 WHO classification co-exist. Which system is better for predicting rumor recurrence and progression still a matter for debate. METHODOLOGY/PRINCIPAL FINDINGS: 348 patients diagnosed with Non-muscle invasive bladder cancer were enrolled in our retrospective study. Paraffin sections were assessed by an experienced urological pathologist according to both the 1973 and 2004 WHO classifications. Tumor recurrence and progression was followed-up in all patients. During follow-up, corresponding 5-year recurrence-free survival rates of G1, G2 and G3 were 82.1%, 55.9%, 32.1% and the 5-year progression-free survival rates were 95.9%, 84.4% and 43.3%, respectively. The 5-year recurrence free survival rates of papillary urothelial neoplasm of low malignant potential (PUNLMP), low-grade papillary urothelial carcinoma(LGPUC) and high-grade papillary urothelial carcinoma (HGPUC) were 69.8%, 67.1% and 42.0% respectively and the 5-year progression-free survival rates were 100%, 90.9% and 54.8% respectively. In multivariate analysis, the 1973 WHO classification significantly associated with both tumor recurrence and progression(p=0.010 and p=0.022, respectively); the 2004 WHO classification correlated with tumor progression(p=0.019), while was not proved to be a variable that can predict the risk of recurrence(p=0.547). Kaplan-Meier plots showed that both the 1973 WHO and the 2004 WHO classifications were significantly associated with progression-free survival (p<0.0001, log-rank test). For prediction of recurrence, significant differences were observed between the tumor grades classified using the 1973 WHO grading system (p<0.0001, log-rank test), while a significant overlap was observed between PUNLMP and LG plots using the 2004 WHO grading system(p=0.616, log-rank test). CONCLUSION/SIGNIFICANCE: Both the 1973 WHO and the 2004 WHO Classifications are effective in predicting tumor progression in Non-muscle invasive bladder cancer, while the 1973 WHO Classification is more suitable for predicting tumor recurrence. PMID- 23082148 TI - Selective effect of physical fatigue on motor imagery accuracy. AB - While the use of motor imagery (the mental representation of an action without overt execution) during actual training sessions is usually recommended, experimental studies examining the effect of physical fatigue on subsequent motor imagery performance are sparse and yielded divergent findings. Here, we investigated whether physical fatigue occurring during an intense sport training session affected motor imagery ability. Twelve swimmers (nine males, mean age 15.5 years) conducted a 45 min physically-fatiguing protocol where they swam from 70% to 100% of their maximal aerobic speed. We tested motor imagery ability immediately before and after fatigue state. Participants randomly imagined performing a swim turn using internal and external visual imagery. Self-reports ratings, imagery times and electrodermal responses, an index of alertness from the autonomic nervous system, were the dependent variables. Self-reports ratings indicated that participants did not encounter difficulty when performing motor imagery after fatigue. However, motor imagery times were significantly shortened during posttest compared to both pretest and actual turn times, thus indicating reduced timing accuracy. Looking at the selective effect of physical fatigue on external visual imagery did not reveal any difference before and after fatigue, whereas significantly shorter imagined times and electrodermal responses (respectively 15% and 48% decrease, p<0.001) were observed during the posttest for internal visual imagery. A significant correlation (r=0.64; p<0.05) was observed between motor imagery vividness (estimated through imagery questionnaire) and autonomic responses during motor imagery after fatigue. These data support that unlike local muscle fatigue, physical fatigue occurring during intense sport training sessions is likely to affect motor imagery accuracy. These results might be explained by the updating of the internal representation of the motor sequence, due to temporary feedback originating from actual motor practice under fatigue. These findings provide insights to the co-dependent relationship between mental and motor processes. PMID- 23082149 TI - The effect of selected synbiotics on microbial composition and short-chain fatty acid production in a model system of the human colon. AB - BACKGROUND: Prebiotics, probiotics and synbiotics can be used to modulate both the composition and activity of the gut microbiota and thereby potentially affecting host health beneficially. The aim of this study was to investigate the effects of eight synbiotic combinations on the composition and activity of human fecal microbiota using a four-stage semicontinuous model system of the human colon. METHODS AND FINDINGS: Carbohydrates were selected by their ability to enhance growth of the probiotic bacteria Lactobacillus acidophilus NCFM (NCFM) and Bifidobacterium animalis subsp. lactis Bl-04 (Bl-04) under laboratory conditions. The most effective carbohydrates for each probiotic were further investigated, using the colonic model, for the ability to support growth of the probiotic bacteria, influence the composition of the microbiota and stimulate formation of short-chain fatty acids (SCFA).The following combinations were studied: NCFM with isomaltulose, cellobiose, raffinose and an oat beta-glucan hydrolysate (OBGH) and Bl-04 with melibiose, xylobiose, raffinose and maltotriose. All carbohydrates showed capable of increasing levels of NCFM and Bl 04 during fermentations in the colonic model by 10(3)-10(4) fold and 10-10(2) fold, respectively. Also the synbiotic combinations decreased the modified ratio of Bacteroidetes/Firmicutes (calculated using qPCR results for Bacteroides Prevotella-Porphyromonas group, Clostridium perfringens cluster I, Clostridium coccoides - Eubacterium rectale group and Clostridial cluster XIV) as well as significantly increasing SCFA levels, especially acetic and butyric acid, by three to eight fold, as compared to the controls. The decreases in the modified ratio of Bacteroidetes/Firmicutes were found to be correlated to increases in acetic and butyric acid (p=0.04 and p=0.03, respectively). CONCLUSIONS: The results of this study show that all synbiotic combinations investigated are able to shift the predominant bacteria and the production of SCFA of fecal microbiota in a model system of the human colon, thereby potentially being able to manipulate the microbiota in a way connected to human health. PMID- 23082150 TI - The effect of social stress on chronic pain perception in female and male mice. AB - The current investigations on social stress primarily point to the negative health consequences of being in a stressful social hierarchy. The repetitive nature of such stressors seems to affect behavioral response to pain both in rodents and humans. Moreover, a large discrepancy in the possibility of social stresses affecting pain perception in the two genders exists. The present study examined the effect of chronic social stress on nociceptive responses of both sexes by implementing of food deprivation, food intake inequality and unstable social status (cage-mate change every 3 days) for a period of 14 days in 96 Balb/c mice. In this regard we injected 20 ul formalin 2% into the plantar surface of hind paw at the end of stress period and scored pain behaviors of all subjects, then serum concentrations of proinflammatory cytokines were measured. Our results showed that there was significant difference in chronic phase of formalin test following implementation of food deprivation and inequality (P<0.05) as compared to control group, so that pain perception was decreased considerably and this decline in inequality exposed subjects was well above isolated ones (P<0.05); whereas unstable social situation did not affect pain perception. Moreover, IL-1 and IL-6 concentrations in serum of stressed mice of both genders were well above control group (p<0.05). Finally, despite chronic pain perception in control and unstable male subjects was larger than females; the decrease of chronic pain perception in male stressed animals (poverty and inequality experienced subjects) was much more than stressed females. These results revealed that although food deprivation and social inequality can induce hypoalgesia, some socioeconomic situations like social instability don't affect pain sensation, whereas there were similar increases of proinflammatory cytokines level in all socially stressed subjects. In addition, males display larger hypoalgesic responses to inequality as compared with females. PMID- 23082151 TI - Is he being bad? Social and language brain networks during social judgment in children with autism. AB - Individuals with autism often violate social rules and have lower accuracy in identifying and explaining inappropriate social behavior. Twelve children with autism (AD) and thirteen children with typical development (TD) participated in this fMRI study of the neurofunctional basis of social judgment. Participants indicated in which of two pictures a boy was being bad (Social condition) or which of two pictures was outdoors (Physical condition). In the within-group Social-Physical comparison, TD children used components of mentalizing and language networks [bilateral inferior frontal gyrus (IFG), bilateral medial prefrontal cortex (mPFC), and bilateral posterior superior temporal sulcus (pSTS)], whereas AD children used a network that was primarily right IFG and bilateral pSTS, suggesting reduced use of social and language networks during this social judgment task. A direct group comparison on the Social-Physical contrast showed that the TD group had greater mPFC, bilateral IFG, and left superior temporal pole activity than the AD group. No regions were more active in the AD group than in the group with TD in this comparison. Both groups successfully performed the task, which required minimal language. The groups also performed similarly on eyetracking measures, indicating that the activation results probably reflect the use of a more basic strategy by the autism group rather than performance disparities. Even though language was unnecessary, the children with TD recruited language areas during the social task, suggesting automatic encoding of their knowledge into language; however, this was not the case for the children with autism. These findings support behavioral research indicating that, whereas children with autism may recognize socially inappropriate behavior, they have difficulty using spoken language to explain why it is inappropriate. The fMRI results indicate that AD children may not automatically use language to encode their social understanding, making expression and generalization of this knowledge more difficult. PMID- 23082152 TI - An MRI study of symptomatic adhesive capsulitis. AB - BACKGROUND: Appilication of MR imaging to diagnose Adhesive Capsulitis (AC) has previously been described. However, there is insufficient information available for the MRI analysis of AC. This study is to describe and evaluate the pathomorphology of the shoulder in Asian patients with AC compared to healthy volunteers. METHODOLOGY/PRINCIPAL FINDINGS: 60 Asian patients with clinically diagnosed AC and 60 healthy volunteers without frozen shoulder underwent MRI of the shoulder joint. All subjects who were age- and sex-matched control ones underwent routine MRI scans of the affected shoulder, including axial, oblique coronal, oblique sagittal T1WI SE and coronal oblique T2WI FSE sequences. Significant abnormal findings were observed on MRI, especially at the rotator cuff interval. The coracohumeral ligament (CHL), articular capsule thickness in the rotator cuff interval as well as the fat space under coracoid process were evaluated. MRI showed that patients with adhesive capsulitis had a significantly thickened coracohumeral ligament and articular capsule in the rotator cuff interval compared to the control subjects (4.2 vs. 2.4 mm, 7.2 vs. 4.4 mm; p<0.05). Partial or complete obliteration of the subcoracoid fat triangle was significantly more frequent in patients with adhesive capsulitis compared with control subjects (73% vs. 13%, 26% vs. 1.6%; p<0.001). Synovitis-like abnormality around the long biceps tendon was significantly more common in patients with adhesive capsulitis than in control subjects. With regards to the inter-observer variability, two MR radiologists had an excellent kappa value of 0.86. CONCLUSIONS/SIGNIFICANCE: MRI can be used to show characteristic findings in diagnosing AC. Thickening of the CHL and the capsule at the rotator cuff interval and complete obliteration of the fat triangle under the coracoid process have been shown to be the most characteristic MR findings seen with AC. PMID- 23082153 TI - Nf1 RasGAP inhibition of LIMK2 mediates a new cross-talk between Ras and Rho pathways. AB - BACKGROUND: Ras GTPases mediate numerous biological processes through their ability to cycle between an inactive GDP-bound form and an active GTP-bound form. Guanine nucleotide exchange factors (GEFs) favor the formation of the active Ras GTP, whereas GTPase activating proteins (GAPs) promote the formation of inactive Ras-GDP. Numerous studies have established complex signaling cross-talks between Ras GTPases and other members of the superfamily of small GTPases. GEFs were thought to play a major role in these cross-talks. However, recently GAPs were also shown to play crucial roles in these processes. Among RasGAPs, Nf1 is of special interest. Nf1 is responsible for the genetic disease Neurofibromatosis type I, and recent data strongly suggest that this RasGAP connects different signaling pathways. METHODOLOGY/PRINCIPAL FINDINGS: In order to know if the RasGAP Nf1 might play a role in connecting Ras GTPases to other small GTPase pathways, we systematically looked for new partners of Nf1, by performing a yeast two-hybrid screening on its SecPH domain. LIMK2, a major kinase of the Rho/ROCK/LIMK2/cofilin pathway, was identified in this screening. We confirmed this interaction by co-immunoprecipitation experiments, and further characterized it. We also demonstrated its specificity: the close related homolog of LIMK2, LIMK1, does not interact with the SecPH domain of Nf1. We then showed that SecPH partially inhibits the kinase activity of LIMK2 on cofilin. Our results furthermore suggest a precise mechanism for this inhibition: in fact, SecPH would specifically prevent LIMK2 activation by ROCK, its upstream regulator. CONCLUSIONS/SIGNIFICANCE: Although previous data had already connected Nf1 to actin cytoskeleton dynamics, our study provides for the first time possible detailed molecular requirements of this involvement. Nf1/LIMK2 interaction and inhibition allows to directly connect neurofibromatosis type I to actin cytoskeleton remodeling, and provides evidence that the RasGAP Nf1 mediates a new cross-talk between Ras and Rho signaling pathways within the superfamily of small GTPases. PMID- 23082154 TI - Involvement of CXCR4 chemokine receptor in metastastic HER2-positive esophageal cancer. AB - A functional linkage of the structurally unrelated receptors HER2 and CXCR4 has been suggested for breast cancer but has not been evaluated for esophageal carcinoma. The inhibition of HER2 leads to a reduction of primary tumor growth and metastases in an orthotopic model of esophageal carcinoma. The chemokine receptor CXCR4 has been implicated in metastatic dissemination of various tumors and correlates with poor survival in esophageal carcinoma. The aim of this study was to investigate a correlation between the expression levels of HER2 and CXCR4 and to evaluate the involvement of CXCR4-expression in HER2-positive esophageal carcinoma. The effects of HER2-inhibition with trastuzumab and of CXCR4 inhibition with AMD3100 on primary tumor growth, metastatic homing, and receptor expression were evaluated in vitro and in an orthotopic model of metastatic esophageal carcinoma using MRI for imaging. The clinical relevance of HER2- and CXCR4-expression was examined in esophageal carcinoma patients. A significant correlation of HER2- and CXCR4-expression in primary tumor and metastases exists in the orthotopic model. Trastuzumab and AMD3100 treatment led to a significant reduction of primary tumor growth, metastases and micrometastases. HER2 expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases. The positive correlation between HER2- and CXCR4-expression was validated in esophageal cancer patients. The correlation of CXCR4- and HER2-expression and the elevation of HER2-expression and reduction of metastases through CXCR4-inhibition suggest a possible functional linkage and a role in tumor dissemination in HER2-positive esophageal carcinoma. PMID- 23082155 TI - Participation in mass gatherings can benefit well-being: longitudinal and control data from a North Indian Hindu pilgrimage event. AB - How does participation in a long-duration mass gathering (such as a pilgrimage event) impact well-being? There are good reasons to believe such collective events pose risks to health. There are risks associated with communicable diseases. Moreover, the physical conditions at such events (noise, crowding, harsh conditions) are often detrimental to well-being. Yet, at the same time, social psychological research suggests participation in group-related activities can impact well-being positively, and we therefore investigated if participating in a long-duration mass gathering can actually bring such benefits. In our research we studied one of the world's largest collective events - a demanding month-long Hindu religious festival in North India. Participants (comprising 416 pilgrims who attended the gathering for the whole month of its duration, and 127 controls who did not) completed measures of self-assessed well-being and symptoms of ill-health at two time points. The first was a month before the gathering commenced, the second was a month after it finished. We found that those participating in this collective event reported a longitudinal increase in well being relative to those who did not participate. Our data therefore imply we should reconceptualise how mass gatherings impact individuals. Although such gatherings can entail significant health risks, the benefits for well-being also need recognition. Indeed, an exclusive focus on risk is misleading and limits our understanding of why such events may be so attractive. More importantly, as our research is longitudinal and includes a control group, our work adds robust evidence to the social psychological literature concerning the relationship between participation in social group activities and well-being. PMID- 23082156 TI - Establishment of inducible wild type and mutant myocilin-GFP-expressing RGC5 cell lines. AB - BACKGROUND: Myocilin is a gene linked directly to juvenile- and adult-onset open angle glaucoma. Mutations including Gln368stop (Q368X) and Pro370Leu (P370L) have been identified in patients. The exact role of myocilin and its functional association with glaucoma are still unclear. In the present study, we established tetracycline-inducible (Tet-on) wild type and mutant myocilin-green fluorescence protein (GFP) expressing RGC5 stable cell lines and studied the changes in cell migration and barrier function upon induction. METHODOLOGY/PRINCIPAL FINDINGS: After several rounds of selection, clones that displayed low, moderate, or high expression of wild type, Q368X or P370L myocilin-GFP upon doxycycline (Dox) induction were obtained. The levels of wild type and mutant myocilin-GFP in various clones were confirmed by Western blotting. Compared to non-induced controls, the cell migration was retarded, the actin stress fibers were fewer and shorter, and the trypsinization time needed for cells to round up was reduced when wild type or mutant myocilin was expressed. The barrier function was in addition aberrant following induced expression of wild type, Q368X or P370L myocilin. Immunoblotting further showed that tight junction protein occludin was downregulated in induced cells. CONCLUSIONS/SIGNIFICANCE: Tet-on inducible, stable RGC5 cell lines were established. These cell lines, expressing wild type or mutant (Q368X or P370L) myocilin-GFP upon Dox induction, are valuable in facilitating studies such as proteomics, as well as functional and pathogenesis investigations of disease-associated myocilin mutants. The barrier function was found impaired and the migration of cells was hindered with induced expression of wild type and mutant myocilin in RGC5 cell lines. The reduction in barrier function might be related to the declined level of occludin. The retarded cell migration was consistent with demonstrated myocilin phenotypes including the loss of actin stress fibers, lowered RhoA activities and compromised cell-matrix adhesiveness. PMID- 23082157 TI - Mortality and health outcomes of HIV-exposed and unexposed children in a PMTCT cohort in Malawi. AB - BACKGROUND: Mortality and morbidity among HIV-exposed children are thought to be high in Malawi. We sought to determine mortality and health outcomes of HIV exposed and unexposed infants within a PMTCT program. METHOD: Data were collected as part of a retrospective cohort study in Zomba District, Malawi. HIV-infected mothers were identified via antenatal, delivery and postpartum records with a delivery date 18-20 months prior; the next registered HIV-uninfected mother was identified as a control. By interview and health record review, data on socio demographic characteristics, service uptake, and health outcomes were collected. HIV-testing was offered to all exposed children. RESULTS: 173 HIV-infected and 214 uninfected mothers were included. 4 stillbirths (1.0%) occurred; among the 383 livebirths, 41 (10.7%) children died by 20 months (32 (18.7%) HIV-exposed and 9 unexposed children (4.3%; p<0.0001)). Risk factors for child death included: HIV-exposure [adjOR2.9(95%CI 1.1-7.2)], low birthweight [adjOR2.5(1.0-6.3)], previous child death (adjOR25.1(6.5-97.5)] and maternal death [adjOR5.3(11.4 20.5)]. At 20 months, HIV-infected children had significantly poorer health outcomes than HIV-unexposed children and HIV-exposed but uninfected children (HIV EU), including: hospital admissions, delayed development, undernutrition and restrictions in function (Lansky scale); no significant differences were seen between HIV-EU and HIV-unexposed children. Overall, no difference was seen at 20 months among HIV-infected, HIV-EU and HIV-unexposed groups in Z-scores (%<-2.0) for weight, height and BMI. Risk factors for poor functional health status at 20 months included: HIV-infection [adjOR8.9(2.4-32.6)], maternal illness [adjOR2.8(1.5-5.0)] and low birthweight [adjOR2.0(1.0-4.1)]. CONCLUSION: Child mortality remains high within this context and could be reduced through more effective PMTCT including prioritizing the treatment of maternal HIV infection to address the effect of maternal health and survival on infant health and survival. HIV-infected children demonstrated developmental delays, functional health and nutritional deficits that underscore the need for increased uptake of early infant diagnosis and institution of ART for all infected infants. PMID- 23082158 TI - Integrin alphaIIb-mediated PI3K/Akt activation in platelets. AB - Integrin alphaIIbbeta3 mediated bidirectional signaling plays a critical role in thrombosis and haemostasis. Signaling mediated by the beta3 subunit has been extensively studied, but alphaIIb mediated signaling has not been characterized. Previously, we reported that platelet granule secretion and TxA2 production induced by alphaIIb mediated outside-in signaling is negatively regulated by the beta3 cytoplasmic domain residues R(724)KEFAKFEEER(734). In this study, we identified part of the signaling pathway utilized by alphaIIb mediated outside-in signaling. Platelets from humans and gene deficient mice, and genetically modified CHO cells as well as a variety of kinase inhibitors were used for this work. We found that aggregation of TxA2 production and granule secretion by beta3Delta724 human platelets initiated by alphaIIb mediated outside-in signaling was inhibited by the Src family kinase inhibitor PP2 and the PI3K inhibitor wortmannin, respectively, but not by the MAPK inhibitor U0126. Also, PP2 and wortmannin, and the palmitoylated beta3 peptide R(724)KEFAKFEEER(734), each inhibited the phosphorylation of Akt residue Ser473 and prevented TxA2 production and storage granule secretion. Similarly, Akt phosphorylation in mouse platelets stimulated by the PAR4 agonist peptide AYPGKF was alphaIIbbeta3-dependent, and blocked by PP2, wortmannin and the palmitoylated peptide p-RKEFAKFEEER. Akt was also phosphorylated in response to mAb D3 plus Fg treatment of CHO cells in suspension expressing alphaIIbbeta3-Delta724 or alphaIIbbeta3E(724)AERKFERKFE(734), but not in cells expressing wild type alphaIIbbeta3. In summary, SFK(s) and PI3K/Akt signaling is utilized by alphaIIb mediated outside-in signaling to activate platelets even in the absence of all but 8 membrane proximal residues of the beta3 cytoplasmic domain. Our results provide new insight into the signaling pathway used by alphaIIb-mediated outside in signaling in platelets. PMID- 23082160 TI - Shrimp alpha-2-macroglobulin prevents the bacterial escape by inhibiting fibrinolysis of blood clots. AB - Proteomic analysis of the hemocytic proteins of Penaeus monodon (Pm) has previously shown that alpha-2-macroglobulin (A2M) was among the proteins that showed substantially altered expression levels upon Vibrio harveyi infection. Therefore, in this study its potentially important role in the response of shrimp to bacterial infection was further characterized. The yeast two-hybrid system revealed that the receptor binding domain of PmA2M interacted with the carboxyl terminus of one or both of the transglutaminase type II isoforms, which are key enzymes involved in the shrimp clotting system. In accord with this, PmA2M was found to be localized on the extracellular blood clots and to colocalize with clottable proteins. RNA interference (RNAi)-mediated knockdown of A2M transcript levels reduced the PmA2M transcript levels (~94%) and significantly reduced the bacterial seizing ability of the clotting system, resulting in an up to 3.3-fold higher number of V. harveyi that systemically disseminated into the circulatory system at 5 min post-infection before subsequent clearance by the immune system. Furthermore, an appearance of PmA2M depleted clots in the presence of V. harveyi strikingly demonstrated fibrinolysis zones surrounding the bacteria. This study provides the first evidence of the vital role of PmA2M in enhancing bacterial sequestration by protecting blood clots against fibrinolysis. PMID- 23082159 TI - Association between childhood obesity and metabolic syndrome: evidence from a large sample of Chinese children and adolescents. AB - Data about metabolic syndrome (MetS) in children is limited in China. We aimed to assess the prevalence of MetS related components, and their association with obesity. Data were collected as part of a representative study on MetS among 19593 children, aged 6-18 years old in Beijing. General obesity was assessed by body mass index (BMI) and central obesity by waist circumference. Finger capillary blood tests were used to assess triglyceride (TG), total cholesterol (TC) and impaired fasting glucose (IFG). Vein blood samples were collected from a subsample of 3814 children aged 10-18 years to classify MetS. MetS was defined according to the International Diabetes Federation 2007 definition. The associations between MetS related components and the degree and type of obesity were tested using logistic regression models. The prevalence of overweight, obesity, high blood pressure, elevated TG, TC and IFG were 13.6%, 5.8%, 8.5%, 8.8%, 1.2% and 2.5%, respectively. Compared with normal weight children, overweight and obese children were more likely to have other MetS related components. In the subsample of 3814 children aged 10-18 years, the prevalence of MetS was much higher in obese subjects than in their normal weight counterparts (27.6% vs. 0.2%). Children with both general and central obesity had the highest prevalence of MetS. Compared with normal weight children, overweight and obese children were more likely to have MetS (overweight: OR=67.33, 95%CI=21.32-212.61; obesity: OR=249.99, 95% CI=79.51-785.98). Prevalence of MetS related components has reached high level among Beijing children who were overweight or obese. The association between metabolic disorders and obesity was strong. PMID- 23082161 TI - Non-motor symptoms in patients with Parkinson's disease - correlations with inflammatory cytokines in serum. AB - BACKGROUND: Parkinson's Disease (PD) is the second most common neurodegenerative disorder of the central nervous system. Motor symptoms are the focus of pharmacotherapy, yet non-motor features of the disease (e.g. fatigue, mood disturbances, sleep disturbances and symptoms of anxiety) are both common and disabling for the patient. The pathophysiological mechanisms behind the non-motor symptoms in PD are yet to be untangled. The main objective of this study was to investigate associations between pro-inflammatory substances and non-motor symptoms in patients with PD. METHODS AND MATERIALS: We measured C-reactive protein, interleukin (IL)-6, soluble IL-2 receptor (sIL-2R) and tumor necrosis factor-alpha (TNF-alpha) in blood samples from PD patients (n=86) and healthy controls (n=40). Symptoms of fatigue, depression, anxiety and sleeping difficulties were assessed using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT), the Hospital Anxiety and Depression Scale (HAD), and the Scales for Outcome in PD-Sleep Scale respectively. RESULTS: IL-6 was significantly higher in PD patients than in healthy controls. Compared to healthy controls, PD patients displayed significantly higher mean scores on HAD and lower scores on FACIT, thus indicating more severe symptoms as measured with these scales. Within the PD sample, high levels of both sIL-2R and TNF-alpha were significantly associated with more severe symptoms assessed by means of FACIT and HAD (depression and anxiety subscales). SIL-2-R levels were able to significantly predict FACIT and HAD scores after the effects of age, gender, anti-parkinsonian medications, and severity of motor symptoms were controlled for. DISCUSSION: We suggest that non-motor symptoms in PD patients, such as fatigue and depressive symptoms, might be generated via inflammatory mechanisms. This knowledge might contribute to the development of novel treatment options in PD, specifically targeting non-motor symptoms. PMID- 23082162 TI - Safety of over twelve hundred infant male circumcisions using the Mogen clamp in Kenya. AB - BACKGROUND: Several sub-Saharan African countries plan to scale-up infant male circumcision (IMC) for cost-efficient HIV prevention. Little data exist about the safety of IMC in East and southern Africa. We calculated adverse event (AE) rate and risks for AEs associated with introduction of IMC services at five government health facilities in western Kenya. METHODS: AE data were analyzed for IMC procedures performed between September, 2009 and November, 2011. Healthy infants aged <= 2 months and weighing >= 2.5 kg were eligible for IMC. Following parental consent, trained clinicians provided IMC services free of charge under local anesthesia using the Mogen clamp. Odds ratios and 95% confidence intervals were used to explore AE risk factors. FINDINGS: A total of 1,239 IMC procedures were performed. Median age of infants was 4 days (IQR=1, 16). The overall AE rate among infants reviewed post-operatively was 2.7% (18/678; 95%CI: 1.4, 3.9). There was one severe AE involving excision of a small piece of the lateral aspect of the glans penis. Other AEs were mild or moderate and were treated conservatively. Babies one month of age or older were more likely to have an AE (OR 3.20; 95%CI: 1.23, 8.36). AE rate did not differ by nurse versus clinical officer or number of previous procedures performed. CONCLUSION: IMC services provided in Kenyan Government hospitals in the context of routine IMC programming have AE rates comparable to those in developed countries. The optimal time for IMC is within the first month of life. PMID- 23082163 TI - Monitoring bacterial burden, inflammation and bone damage longitudinally using optical and MUCT imaging in an orthopaedic implant infection in mice. AB - BACKGROUND: Recent advances in non-invasive optical, radiographic and MUCT imaging provide an opportunity to monitor biological processes longitudinally in an anatomical context. One particularly relevant application for combining these modalities is to study orthopaedic implant infections. These infections are characterized by the formation of persistent bacterial biofilms on the implanted materials, causing inflammation, periprosthetic osteolysis, osteomyelitis, and bone damage, resulting in implant loosening and failure. METHODOLOGY/PRINCIPAL FINDINGS: An orthopaedic implant infection model was used in which a titanium Kirshner-wire was surgically placed in femurs of LysEGFP mice, which possess EGFP fluorescent neutrophils, and a bioluminescent S. aureus strain (Xen29; 1*10(3) CFUs) was inoculated in the knee joint before closure. In vivo bioluminescent, fluorescent, X-ray and MUCT imaging were performed on various postoperative days. The bacterial bioluminescent signals of the S. aureus-infected mice peaked on day 19, before decreasing to a basal level of light, which remained measurable for the entire 48 day experiment. Neutrophil EGFP-fluorescent signals of the S. aureus-infected mice were statistically greater than uninfected mice on days 2 and 5, but afterwards the signals for both groups approached background levels of detection. To visualize the three-dimensional location of the bacterial infection and neutrophil infiltration, a diffuse optical tomography reconstruction algorithm was used to co-register the bioluminescent and fluorescent signals with MUCT images. To quantify the anatomical bone changes on the MUCT images, the outer bone volume of the distal femurs were measured using a semi-automated contour based segmentation process. The outer bone volume increased through day 48, indicating that bone damage continued during the implant infection. CONCLUSIONS/SIGNIFICANCE: Bioluminescent and fluorescent optical imaging was combined with X-ray and MUCT imaging to provide noninvasive and longitudinal measurements of the dynamic changes in bacterial burden, neutrophil recruitment and bone damage in a mouse orthopaedic implant infection model. PMID- 23082165 TI - A dark incubation period is important for Agrobacterium-mediated transformation of mature internode explants of sweet orange, grapefruit, citron, and a citrange rootstock. AB - BACKGROUND: Citrus has an extended juvenile phase and trees can take 2-20 years to transition to the adult reproductive phase and produce fruit. For citrus variety development this substantially prolongs the time before adult traits, such as fruit yield and quality, can be evaluated. Methods to transform tissue from mature citrus trees would shorten the evaluation period via the direct production of adult phase transgenic citrus trees. METHODOLOGY/PRINCIPAL FINDINGS: Factors important for promoting shoot regeneration from internode explants from adult phase citrus trees were identified and included a dark incubation period and the use of the cytokinin zeatin riboside. Transgenic trees were produced from four citrus types including sweet orange, citron, grapefruit, and a trifoliate hybrid using the identified factors and factor settings. SIGNIFICANCE: The critical importance of a dark incubation period for shoot regeneration was established. These results confirm previous reports on the feasibility of transforming mature tissue from sweet orange and are the first to document the transformation of mature tissue from grapefruit, citron, and a trifoliate hybrid. PMID- 23082164 TI - Routine habitat change: a source of unrecognized transient alteration of intestinal microbiota in laboratory mice. AB - The mammalian intestine harbors a vast, complex and dynamic microbial population, which has profound effects on host nutrition, intestinal function and immune response, as well as influence on physiology outside of the alimentary tract. Imbalance in the composition of the dense colonizing bacterial population can increase susceptibility to various acute and chronic diseases. Valuable insights on the association of the microbiota with disease critically depend on investigation of mouse models. Like in humans, the microbial community in the mouse intestine is relatively stable and resilient, yet can be influenced by environmental factors. An often-overlooked variable in research is basic animal husbandry, which can potentially alter mouse physiology and experimental outcomes. This study examined the effects of common husbandry practices, including food and bedding alterations, as well as facility and cage changes, on the gut microbiota over a short time course of five days using three culture independent techniques, quantitative PCR, terminal restriction fragment length polymorphism (TRFLP) and next generation sequencing (NGS). This study detected a substantial transient alteration in microbiota after the common practice of a short cross-campus facility transfer, but found no comparable alterations in microbiota within 5 days of switches in common laboratory food or bedding, or following an isolated cage change in mice acclimated to their housing facility. Our results highlight the importance of an acclimation period following even simple transfer of mice between campus facilities, and highlights that occult changes in microbiota should be considered when imposing husbandry variables on laboratory animals. PMID- 23082166 TI - Relationship between chlorophyll a concentration, light attenuation and diving depth of the Southern elephant seal Mirounga leonina. AB - Recently, a number of Antarctic marine environmental studies have used oceanographic parameters collected from instrumented top predators for ecological and physical information. Phytoplankton concentration is generally quantified through active measurement of chlorophyll fluorescence. In this study, light absorption coefficient (K(0.75)) was used as an indicator of phytoplankton concentration. This measurement, easy to obtain and requiring low electric power, allows for assessing of the fine scale horizontal structuring of phytoplankton. As part of this study, Southern elephant seals (SES) were simultaneously equipped with a fluorometer and a light logger. Along the SES tracks, variations in K(0.75) were strongly correlated with chlorophyll, a concentration measured by the fluorometer within the euphotic layer. With regards to SES foraging behaviour, bottom depth of the seal's dive was highly dependent on light intensity at 150 m, indicating that the vertical distribution of SES's prey such as myctophids is tightly related to light level. Therefore, change in phytoplankton concentration may not only have a direct effect on SES's prey abundance but may also determine their vertical accessibility with likely consequences on SES foraging efficiency. PMID- 23082167 TI - Prosody discrimination by songbirds (Padda oryzivora). AB - In human verbal communication, not only lexical information, but also paralinguistic information plays an important role in transmitting the speakers' mental state. Paralinguistic information is conveyed mainly through acoustic features like pitch, rhythm, tempo and so on. These acoustic features are generally known as prosody. It is known that some species of birds can discriminate certain aspects of human speech. However, there have not been any studies on the discrimination of prosody in human language which convey different paralinguistic meanings by birds. In the present study, we have shown that the Java sparrow (Padda oryzivora) can discriminate different prosodic patterns of Japanese sentences. These birds could generalize prosodic discrimination to novel sentences, but could not generalize sentence discrimination to those with novel prosody. Moreover, unlike Japanese speakers, Java sparrows used the first part of the utterance as the discrimination cue. PMID- 23082168 TI - Comparison of conventional chemotherapy, stealth liposomes and temperature sensitive liposomes in a mathematical model. AB - Various liposomal drug carriers have been developed to overcome short plasma half life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 ug/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with ~4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index. PMID- 23082169 TI - Discrete choice experiment to evaluate factors that influence preferences for antibiotic prophylaxis in pediatric oncology. AB - BACKGROUND: Bacterial and fungal infections in pediatric oncology patients cause morbidity and mortality. The clinical utility of antimicrobial prophylaxis in children is uncertain and the personal utility of these agents is disputed. Objectives were to use a discrete choice experiment to: (1) describe the importance of attributes to parents and healthcare providers when deciding between use and non-use of antibacterial and antifungal prophylaxis; and (2) estimate willingness-to-pay for prophylactic strategies. METHODS: Attributes were chances of infection, death and side effects, route of administration and cost of pharmacotherapy. Respondents were randomized to a discrete choice experiment outlining hypothetical treatment options to prevent antibacterial or antifungal infections. Each respondent was presented 16 choice tasks and was asked to choose between two unlabeled treatment options and an opt-out alternative (no prophylaxis). RESULTS: 102 parents and 60 healthcare providers participated. For the antibacterial discrete choice experiment, frequency of administration was significantly associated with utility for parents but not for healthcare providers. Increasing chances of infection, death, side effects and cost were all significantly associated with decreased utility for parents and healthcare providers in both the antibacterial and antifungal discrete choice experiment. Parental willingness-to-pay was higher than healthcare providers for both strategies. CONCLUSION: Chances of infection, death, side effects and costs were all significantly associated with utility. Parents have higher willingness-to-pay for these strategies compared with healthcare providers. This knowledge can help to develop prophylaxis programs. PMID- 23082170 TI - Dolphins can maintain vigilant behavior through echolocation for 15 days without interruption or cognitive impairment. AB - In dolphins, natural selection has developed unihemispheric sleep where alternating hemispheres of their brain stay awake. This allows dolphins to maintain consciousness in response to respiratory demands of the ocean. Unihemispheric sleep may also allow dolphins to maintain vigilant states over long periods of time. Because of the relatively poor visibility in the ocean, dolphins use echolocation to interrogate their environment. During echolocation, dolphin produce clicks and listen to returning echoes to determine the location and identity of objects. The extent to which individual dolphins are able to maintain continuous vigilance through this active sense is unknown. Here we show that dolphins may continuously echolocate and accurately report the presence of targets for at least 15 days without interruption. During a total of three sessions, each lasting five days, two dolphins maintained echolocation behaviors while successfully detecting and reporting targets. Overall performance was between 75 to 86% correct for one dolphin and 97 to 99% correct for a second dolphin. Both animals demonstrated diel patterns in echolocation behavior. A 15 day testing session with one dolphin resulted in near perfect performance with no significant decrement over time. Our results demonstrate that dolphins can continuously monitor their environment and maintain long-term vigilant behavior through echolocation. PMID- 23082171 TI - Prey responses to predator chemical cues: disentangling the importance of the number and biomass of prey consumed. AB - To effectively balance investment in predator defenses versus other traits, organisms must accurately assess predation risk. Chemical cues caused by predation events are indicators of risk for prey in a wide variety of systems, but the relationship between how prey perceive risk in relation to the amount of prey consumed by predators is poorly understood. While per capita predation rate is often used as the metric of relative risk, studies aimed at quantifying predator-induced defenses commonly control biomass of prey consumed as the metric of risk. However, biomass consumed can change by altering either the number or size of prey consumed. In this study we determine whether phenotypic plasticity to predator chemical cues depends upon prey biomass consumed, prey number consumed, or both. We examine the growth response of red-eyed treefrog tadpoles (Agalychnis callidryas) to cues from a larval dragonfly (Anax amazili). Biomass consumed was manipulated by either increasing the number of prey while holding individual prey size constant, or by holding the number of prey constant and varying individual prey size. We address two questions. (i) Do prey reduce growth rate in response to chemical cues in a dose dependent manner? (ii) Does the magnitude of the response depend on whether prey consumption increases via number or size of prey? We find that the phenotypic response of prey is an asymptotic function of prey biomass consumed. However, the asymptotic response is higher when more prey are consumed. Our findings have important implications for evaluating past studies and how future experiments should be designed. A stronger response to predation cues generated by more individual prey deaths is consistent with models that predict prey sensitivity to per capita risk, providing a more direct link between empirical and theoretical studies which are often focused on changes in population sizes not individual biomass. PMID- 23082172 TI - Social environment affects acquisition and color of structural nuptial plumage in a sexually dimorphic tropical passerine. AB - Structural colors result from the physical interaction of light with organic materials of differing refractive indexes organized at nanoscale dimensions to produce significant interference effects. Because color properties emerge from these finely organized nanostructures, the production of structural coloration could respond to environmental factors and be developmentally more plastic than expected, functioning as an indicator of individual quality. However, there are many unknown factors concerning the function and mechanisms regulating structural coloration, especially relative to social environment. We hypothesized that social environment, in the form of competitive settings, can influence the developmental pathways involving production of feather structural coloration. We experimentally assessed the impact of social environment upon body condition, molt and spectral properties of two types of structural color that compose the nuptial plumage in blue-black grassquits: black iridescent plumage and white underwing patches. We manipulated male social environment during nine months by keeping individuals in three treatments: (1) pairs; (2) all-male groups; and (3) male-female mixed groups. All morphological characters and spectral plumage measures varied significantly through time, but only acquisition of nuptial plumage coverage and nuptial plumage color were influenced by social environment. Compared with males in the paired treatment, those in treatments with multiple males molted into nuptial plumage faster and earlier, and their plumage was more UV-purple-shifted. Our results provide experimental evidence that social context strongly influences development and expression of structural plumage. These results emphasize the importance of long-term experimental studies to identify the phenotypic consequences of social dynamics relative to ornament expression. PMID- 23082174 TI - Rethinking clinical trials of transcranial direct current stimulation: participant and assessor blinding is inadequate at intensities of 2mA. AB - BACKGROUND: Many double-blind clinical trials of transcranial direct current stimulation (tDCS) use stimulus intensities of 2 mA despite the fact that blinding has not been formally validated under these conditions. The aim of this study was to test the assumption that sham 2 mA tDCS achieves effective blinding. METHODS: A randomised double blind crossover trial. 100 tDCS-naive healthy volunteers were incorrectly advised that they there were taking part in a trial of tDCS on word memory. Participants attended for two separate sessions. In each session, they completed a word memory task, then received active or sham tDCS (order randomised) at 2 mA stimulation intensity for 20 minutes and then repeated the word memory task. They then judged whether they believed they had received active stimulation and rated their confidence in that judgement. The blinded assessor noted when red marks were observed at the electrode sites post stimulation. RESULTS: tDCS at 2 mA was not effectively blinded. That is, participants correctly judged the stimulation condition greater than would be expected to by chance at both the first session (kappa level of agreement (kappa) 0.28, 95% confidence interval (CI) 0.09 to 0.47 p=0.005) and the second session (kappa=0.77, 95%CI 0.64 to 0.90), p=<0.001) indicating inadequate participant blinding. Redness at the reference electrode site was noticeable following active stimulation more than sham stimulation (session one, kappa=0.512, 95%CI 0.363 to 0.66, p<0.001; session two, kappa=0.677, 95%CI 0.534 to 0.82) indicating inadequate assessor blinding. CONCLUSIONS: Our results suggest that blinding in studies using tDCS at intensities of 2 mA is inadequate. Positive results from such studies should be interpreted with caution. PMID- 23082173 TI - Long-term effects of intermittent IL-2 in HIV infection: extended follow-up of the INSIGHT STALWART Study. AB - BACKGROUND: The Study of Aldesleukin with and without Antiretroviral Therapy (STALWART) was designed to evaluate whether intermittent IL-2 alone or with peri cycle ART increased CD4+ cell counts (and so delayed initiation of ART) in HIV infected individuals having >= 300 CD4+ cells/mm(3) compared to untreated controls. When the results of two large clinical trials, ESPRIT and SILCAAT, showed no clinical benefit from IL-2 therapy, IL-2 administration was halted in STALWART. Because IL-2 recipients in STALWART experienced a greater number of opportunistic disease (OD) or death and adverse events (AEs), participants were asked to consent to an extended follow-up phase in order to assess persistence of IL-2 effects. METHODOLOGY: Participants in this study were followed for clinical events and AEs every 4 months for 24 months. Unadjusted Cox proportional hazards models were used to summarize death, death or first OD event, and first grade 3 or 4 AE. PRINCIPAL FINDINGS: A total of 267 persons were enrolled in STALWART (176 randomized to the IL-2 arms and 91 to the no therapy arm); 142 individuals in the IL-2 group and 80 controls agreed to enter the extended follow-up study. Initiation of continuous ART was delayed in the IL-2 groups, but once started, resulted in similar CD4+ cell and viral load responses compared to controls. The hazard ratios (95% CI) for IL-2 versus control during the extension phase for death or OD, grade 3 or 4 AE, and grade 4 AE were 1.45 (0.38, 5.45), 0.43 (0.24, 1.63) and 0.20 (0.04, 1.03), respectively. The hazard ratios for the AE outcomes were significantly lower during the extension than during the main study. CONCLUSIONS: Adverse events associated with IL-2 cycling did not persist upon discontinuation of IL-2. The use of IL-2 did not impact the subsequent response to initiation of cART. PMID- 23082176 TI - A culture-independent approach to unravel uncultured bacteria and functional genes in a complex microbial community. AB - Most microorganisms in nature are uncultured with unknown functionality. Sequence based metagenomics alone answers 'who/what are there?' but not 'what are they doing and who is doing it and how?'. Function-based metagenomics reveals gene function but is usually limited by the specificity and sensitivity of screening strategies, especially the identification of clones whose functional gene expression has no distinguishable activity or phenotypes. A 'biosensor-based genetic transducer' (BGT) technique, which employs a whole-cell biosensor to quantitatively detect expression of inserted genes encoding designated functions, is able to screen for functionality of unknown genes from uncultured microorganisms. In this study, BGT was integrated with Stable isotope probing (SIP)-enabled Metagenomics to form a culture-independent SMB toolbox. The utility of this approach was demonstrated in the discovery of a novel functional gene cluster in naphthalene contaminated groundwater. Specifically, metagenomic sequencing of the (13)C-DNA fraction obtained by SIP indicated that an uncultured Acidovorax sp. was the dominant key naphthalene degrader in-situ, although three culturable Pseudomonas sp. degraders were also present in the same groundwater. BGT verified the functionality of a new nag2 operon which co-existed with two other nag and two nah operons for naphthalene biodegradation in the same microbial community. Pyrosequencing analysis showed that the nag2 operon was the key functional operon in naphthalene degradation in-situ, and shared homology with both nag operons in Ralstonia sp. U2 and Polaromonas naphthalenivorans CJ2. The SMB toolbox will be useful in providing deep insights into uncultured microorganisms and unravelling their ecological roles in natural environments. PMID- 23082178 TI - Subtle increases in interletter spacing facilitate the encoding of words during normal reading. AB - BACKGROUND: Several recent studies have revealed that words presented with a small increase in interletter spacing are identified faster than words presented with the default interletter spacing (i.e., w a t e r faster than water). Modeling work has shown that this advantage occurs at an early encoding level. Given the implications of this finding for the ease of reading in the new digital era, here we examined whether the beneficial effect of small increases in interletter spacing can be generalized to a normal reading situation. METHODOLOGY: We conducted an experiment in which the participant's eyes were monitored when reading sentences varying in interletter spacing: i) sentences were presented with the default (0.0) interletter spacing; ii) sentences presented with a +1.0 interletter spacing; and iii) sentences presented with a +1.5 interletter spacing. PRINCIPAL FINDINGS: Results showed shorter fixation duration times as an inverse function of interletter spacing (i.e., fixation durations were briefest with +1.5 spacing and slowest with the default spacing). CONCLUSIONS: Subtle increases in interletter spacing facilitate the encoding of the fixated word during normal reading. Thus, interletter spacing is a parameter that may affect the ease of reading, and it could be adjustable in future implementations of e-book readers. PMID- 23082175 TI - The serotonergic central nervous system of the Drosophila larva: anatomy and behavioral function. AB - The Drosophila larva has turned into a particularly simple model system for studying the neuronal basis of innate behaviors and higher brain functions. Neuronal networks involved in olfaction, gustation, vision and learning and memory have been described during the last decade, often up to the single-cell level. Thus, most of these sensory networks are substantially defined, from the sensory level up to third-order neurons. This is especially true for the olfactory system of the larva. Given the wealth of genetic tools in Drosophila it is now possible to address the question how modulatory systems interfere with sensory systems and affect learning and memory. Here we focus on the serotonergic system that was shown to be involved in mammalian and insect sensory perception as well as learning and memory. Larval studies suggested that the serotonergic system is involved in the modulation of olfaction, feeding, vision and heart rate regulation. In a dual anatomical and behavioral approach we describe the basic anatomy of the larval serotonergic system, down to the single-cell level. In parallel, by expressing apoptosis-inducing genes during embryonic and larval development, we ablate most of the serotonergic neurons within the larval central nervous system. When testing these animals for naive odor, sugar, salt and light perception, no profound phenotype was detectable; even appetitive and aversive learning was normal. Our results provide the first comprehensive description of the neuronal network of the larval serotonergic system. Moreover, they suggest that serotonin per se is not necessary for any of the behaviors tested. However, our data do not exclude that this system may modulate or fine-tune a wide set of behaviors, similar to its reported function in other insect species or in mammals. Based on our observations and the availability of a wide variety of genetic tools, this issue can now be addressed. PMID- 23082177 TI - Detoxifying antitumoral drugs via nanoconjugation: the case of gold nanoparticles and cisplatin. AB - Nanoparticles (NPs) have emerged as a potential tool to improve cancer treatment. Among the proposed uses in imaging and therapy, their use as a drug delivery scaffold has been extensively highlighted. However, there are still some controversial points which need a deeper understanding before clinical application can occur. Here the use of gold nanoparticles (AuNPs) to detoxify the antitumoral agent cisplatin, linked to a nanoparticle via a pH-sensitive coordination bond for endosomal release, is presented. The NP conjugate design has important effects on pharmacokinetics, conjugate evolution and biodistribution and results in an absence of observed toxicity. Besides, AuNPs present unique opportunities as drug delivery scaffolds due to their size and surface tunability. Here we show that cisplatin-induced toxicity is clearly reduced without affecting the therapeutic benefits in mice models. The NPs not only act as carriers, but also protect the drug from deactivation by plasma proteins until conjugates are internalized in cells and cisplatin is released. Additionally, the possibility to track the drug (Pt) and vehicle (Au) separately as a function of organ and time enables a better understanding of how nanocarriers are processed by the organism. PMID- 23082179 TI - A hydrazine coupled cycling assay validates the decrease in redox ratio under starvation in Drosophila. AB - A commonly used enzymatic recycling assay for pyridine nucleotides has been adapted to directly measure the NAD(+)/NADH redox ratio in Drosophila melanogaster. This method is also suitable for quantification of NADP(+) and NADPH. The addition of a coupling reaction removing acetaldehyde produced from the alcohol dehydrogenase (ADH) reaction was shown to improve the linearity of NAD(H) assay. The advantages of this assay method are that it allows the determination of both NAD(+) and NADH simultaneously while keeping enzymatic degradation of pyridine nucleotides minimal and also achieving better sensitivity. This method was used to determine the redox ratio of D. melanogaster and validated substantial decrease of redox ratio during starvation. PMID- 23082180 TI - Genetic structure of the French red squirrel populations: implication for conservation. AB - The decline of the red squirrel (Sciurus vulgaris) in several European countries due to the introduction of the American grey squirrel (S. carolinensis) and the predicted arrival of the grey squirrel in France in the near future has lead to the development of a preventative conservation project in this country. In this study, we conducted an extensive survey of mitochondrial DNA variation in French red squirrels using a fragment of the mitochondrial D-loop and we compared the results with previously published data from other European populations. Our main aims were: (1) to determine whether genetically differentiated populations, which could represent prioritized units for conservation purposes, were present in France and (2) to determine whether the French population, which is currently largely undisturbed, could provide information on the postglacial recolonization history of the species. We found that French D-loop haplotypes show almost no tendency to cluster by geographic origin, be it region or country, suggesting that French red squirrels have not been isolated from other populations during an evolutionarily significant period and that they do not constitute an Evolutionary Significant Unit. The French red squirrels showed strong signals of population expansion, the opposite to what is observed in most other European populations, making them of particular interest to study the postglacial expansion history of the species. PMID- 23082181 TI - Evolutionary adaptation of the amino acid and codon usage of the mosquito sodium channel following insecticide selection in the field mosquitoes. AB - Target site insensitivity resulting from point mutations within the voltage-gated sodium channel of the insect nervous system is known to be of primary importance in the development of resistance to pyrethroid insecticides. This study shifts current research paradigms by conducting, for the first time, a global analysis of all the naturally occurring mutations, both nonsynonymous and synonymous mutations, as well as mutation combinations in the entire mosquito sodium channel of Culex quinquefasciatus and analyzing their evolutionary and heritable feature and roles in insecticide resistance. Through a systematic analysis of comparing nucleotide polymorphisms in the entire sodium channel cDNAs of individuals between susceptible and resistant mosquito strains, between field parental mosquitoes and their permethrin selected offspring, and among different mosquito groups categorized by their levels of tolerance to specific permethrin concentrations within and among the mosquito strains of the field parental strains and their permethrin selected offspring, 3 nonsynonymous (A(109)S, L(982)F, and W(1573)R) and 6 synonymous (L(852), G(891), A(1241), D(1245), P(1249), and G(1733)) mutations were identified. The co-existence of all 9 mutations, both nonsynonymous and synonymous, and their homozygousity were found to be important factors for high levels of resistance. Our study, for the first time, provide a strong case demonstrating the co-existence of both nonsynonymous and synonymous mutations in the sodium channel of resistant mosquitoes in response to insecticide resistance and the inheritance of these mutations in the offspring of field mosquito strains following insecticide selection. PMID- 23082182 TI - Rotavirus infection of cells in culture induces activation of RhoA and changes in the actin and tubulin cytoskeleton. AB - Rotavirus infection induces an increase in [Ca(2+)](cyto), which in turn may affect the distribution of the cytoskeleton proteins in the infected cell. Changes in microfilaments, including the formation of stress fibers, were observed starting at 0.5 h.p.i. using fluorescent phalloidin. Western blot analysis indicated that RhoA is activated between 0.5 and 1 h.p.i. Neither the phosphorylation of RhoA nor the formation of stress fibers were observed in cells infected with virions pre-treated with an anti-VP5* non-neutralizing mAb, suggesting that RhoA activation is stimulated by the interaction of the virus with integrins forming the cell receptor complex. In addition, the structure of the tubulin cytoskeleton was also studied. Alterations of the microtubules were evident starting at 3 h.p.i. and by 7 h.p.i. when microtubules were markedly displaced toward the periphery of the cell cytoplasm. Loading of rotavirus infected cells with either a Ca(2+) chelator (BAPTA) or transfection with siRNAs to silence NSP4, reversed the changes observed in both the microfilaments and microtubules distribution, but not the appearance of stress fibers. These results indicate that alterations in the distribution of actin microfilaments are initiated early during infection by the activation of RhoA, and that latter changes in the Ca(2+) homeostasis promoted by NSP4 during infection may be responsible for other alterations in the actin and tubulin cytoskeleton. PMID- 23082183 TI - Significant expression levels of transgenic PPP1CC2 in testis and sperm are required to overcome the male infertility phenotype of Ppp1cc null mice. AB - PPP1CC2, one of four isoforms of the ser/thr protein phosphatase PP1, is a mammalian-specific splice variant of the Ppp1cc gene, and the only isoform whose expression is confined almost completely to spermatogenic cells. Additionally, PPP1CC2 is the sole isoform found in mammalian spermatozoa. Although PPP1CC1, the other Ppp1cc product, is expressed in many tissues including testis, the only phenotype resulting from deletion of Ppp1cc gene is male infertility. To determine which of the products of Ppp1cc is essential for male fertility, we created two PPP1CC2 transgenes, eTg-G2 and pTg-G2, where Ppp1cc2 expression was driven by the putative endogenous promoter of Ppp1cc or by the testis specific human Pgk2 promoter, respectively. Our results demonstrate that the 2.6-kb genomic region directly upstream of the Ppp1cc structural gene can drive expression of Ppp1cc2, and recapitulate the wild-type tissue specificity of PPP1CC2 in transgenic mice. More importantly, we show that expression of PPP1CC2 alone, via either promoter, is able not only to restore normal spermatogenesis, but the fertility of Ppp1cc null mice as well, provided that transgenic PPP1CC2 expression in testis reaches at least a lower threshold level equivalent to approximately 50% of its expression by a Ppp1cc +/- male. We conclude that the endogenous Ppp1cc promoter normally functions in the testis to maintain a sufficient level of PPP1CC2 expression for normal spermatogenesis to occur, and that production of spermatozoa capable of fertilization in vivo can take place in the complete absence of PPP1CC1 expression. PMID- 23082184 TI - Epidemiological characteristics of novel influenza A (H1N1) in antiviral drug users in Korea. AB - Soon after the first novel influenza A (H1N1) death was documented in Korea on August 15, 2009, prompt treatment with antiviral drugs was recommended when an infection was suspected. Free antiviral drugs were distributed to patients who met the case definition in the treatment guidelines, and patients prescribed the antiviral drugs were included in the Antiviral Drug Surveillance System (ADSS). A total of 2,825,821 patients were reported to the ADSS from September 1 to December 31, 2009. Odds ratios were calculated to compare the risks of severe diseases, as indicated by general hospital admissions or intensive care unit (ICU) admissions according to demographic characteristics, underlying medical conditions, and behavioral factors. Approximately 6% of the total population received antiviral drugs during the study period. Of these, 2,709,611 (95.9%) were outpatients, 114,840 (4.06%) were hospitalized, and 1,370 (0.05%) were admitted to the ICU. Children aged 0-9 yr accounted for 33.94% of all reported cases, whereas only 3.89% of the patients were >= 60 yr. The estimated incidence of novel influenza A (H1N1) during the pandemic was 5.68/100 of all reported cases. Mortality due to influenza A (H1N1) during the pandemic was 0.33/100,000, with the highest mortality of 1.31/100,000 for patients aged >= 60 years. Severe pandemic H1N1 influenza was associated with the presence of one or more underlying medical conditions in elderly aged >= 60 years and with lower economic status. Moreover, influenza A (H1N1) appeared to be age-specific in terms of mortality. Although the incidence and admission rates of influenza A (H1N1) were higher in younger age groups, fatal cases were much more likely to occur in the elderly (>= 60 years). In contrast to earlier influenza A (H1N1) reports, the risks of a severe outcome were elevated among those who were underweight (body mass index < 18.5 kg/m(2)). PMID- 23082185 TI - Enzymatic relay mechanism stimulates cyclic GMP synthesis in rod photoresponse: biochemical and physiological study in guanylyl cyclase activating protein 1 knockout mice. AB - Regulation of cGMP synthesis by retinal membrane guanylyl cyclase isozymes (RetGC1 and RetGC2) in rod and cone photoreceptors by calcium-sensitive guanylyl cyclase activating proteins (GCAP1 and GCAP2) is one of the key molecular mechanisms affecting the response to light and is involved in congenital retinal diseases. The objective of this study was to identify the physiological sequence of events underlying RetGC activation in vivo, by studying the electrophysiological and biochemical properties of mouse rods in a new genetic model lacking GCAP1. The GCAP1(-/-) retinas expressed normal levels of RetGC isozymes and other phototransduction proteins, with the exception of GCAP2, whose expression was elevated in a compensatory fashion. RetGC activity in GCAP1(-/-) retinas became more sensitive to Ca(2+) and slightly increased. The bright flash response in electroretinogram (ERG) recordings recovered quickly in GCAP1(-/-), as well as in RetGC1(-/-)GCAP1(-/-), and RetGC2(-/-)GCAP1(-/-) hybrid rods, indicating that GCAP2 activates both RetGC isozymes in vivo. Individual GCAP1(-/ ) rod responses varied in size and shape, likely reflecting variable endogenous GCAP2 levels between different cells, but single-photon response (SPR) amplitude and time-to-peak were typically increased, while recovery kinetics remained faster than in wild type. Recovery from bright flashes in GCAP1(-/-) was prominently biphasic, because rare, aberrant SPRs producing the slower tail component were magnified. These data provide strong physiological evidence that rod photoresponse recovery is shaped by the sequential recruitment of RetGC isozyme activation by GCAPs according to the different GCAP sensitivities for Ca(2+) and specificities toward RetGC isozymes. GCAP1 is the 'first-response' sensor protein that stimulates RetGC1 early in the response and thus limits the SPR amplitude, followed by activation of GCAP2 that adds stimulation of both RetGC1 and RetGC2 to speed-up photoreceptor recovery. PMID- 23082186 TI - Ancient Ephemeroptera-Collembola symbiosis fossilized in amber predicts contemporary phoretic associations. AB - X-ray computed tomography is used to identify a unique example of fossilized phoresy in 16 million-year-old Miocene Dominican amber involving a springtail being transported by a mayfly. It represents the first evidence (fossil or extant) of phoresy in adult Ephemeroptera and only the second record in Collembola (the first is also preserved in amber). This is the first record of Collembola using winged insects for dispersal. This fossil predicts the occurrence of similar behaviour in living springtails and helps explain the global distribution of Collembola today. PMID- 23082188 TI - MOCAT: a metagenomics assembly and gene prediction toolkit. AB - MOCAT is a highly configurable, modular pipeline for fast, standardized processing of single or paired-end sequencing data generated by the Illumina platform. The pipeline uses state-of-the-art programs to quality control, map, and assemble reads from metagenomic samples sequenced at a depth of several billion base pairs, and predict protein-coding genes on assembled metagenomes. Mapping against reference databases allows for read extraction or removal, as well as abundance calculations. Relevant statistics for each processing step can be summarized into multi-sheet Excel documents and queryable SQL databases. MOCAT runs on UNIX machines and integrates seamlessly with the SGE and PBS queuing systems, commonly used to process large datasets. The open source code and modular architecture allow users to modify or exchange the programs that are utilized in the various processing steps. Individual processing steps and parameters were benchmarked and tested on artificial, real, and simulated metagenomes resulting in an improvement of selected quality metrics. MOCAT can be freely downloaded at http://www.bork.embl.de/mocat/. PMID- 23082187 TI - Hybrid sequencing approach applied to human fecal metagenomic clone libraries revealed clones with potential biotechnological applications. AB - Natural environments represent an incredible source of microbial genetic diversity. Discovery of novel biomolecules involves biotechnological methods that often require the design and implementation of biochemical assays to screen clone libraries. However, when an assay is applied to thousands of clones, one may eventually end up with very few positive clones which, in most of the cases, have to be "domesticated" for downstream characterization and application, and this makes screening both laborious and expensive. The negative clones, which are not considered by the selected assay, may also have biotechnological potential; however, unfortunately they would remain unexplored. Knowledge of the clone sequences provides important clues about potential biotechnological application of the clones in the library; however, the sequencing of clones one-by-one would be very time-consuming and expensive. In this study, we characterized the first metagenomic clone library from the feces of a healthy human volunteer, using a method based on 454 pyrosequencing coupled with a clone-by-clone Sanger end sequencing. Instead of whole individual clone sequencing, we sequenced 358 clones in a pool. The medium-large insert (7-15 kb) cloning strategy allowed us to assemble these clones correctly, and to assign the clone ends to maintain the link between the position of a living clone in the library and the annotated contig from the 454 assembly. Finally, we found several open reading frames (ORFs) with previously described potential medical application. The proposed approach allows planning ad-hoc biochemical assays for the clones of interest, and the appropriate sub-cloning strategy for gene expression in suitable vectors/hosts. PMID- 23082189 TI - Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells. AB - OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-kappaB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression. PMID- 23082190 TI - Rereplication in emi1-deficient zebrafish embryos occurs through a Cdh1-mediated pathway. AB - Disruption of early mitotic inhibitor 1 (Emi1) interferes with normal cell cycle progression and results in early embryonic lethality in vertebrates. During S and G2 phases the ubiquitin ligase complex APC/C is inhibited by Emi1 protein, thereby enabling the accumulation of Cyclins A and B so they can regulate replication and promote the transition from G2 phase to mitosis, respectively. Depletion of Emi1 prevents mitotic entry and causes rereplication and an increase in cell size. In this study, we show that the developmental and cell cycle defects caused by inactivation of zebrafish emi1 are due to inappropriate activation of APC/C through its cofactor Cdh1. Inhibiting/slowing progression into S-phase by depleting Cdt1, an essential replication licensing factor, partially rescued emi1 deficiency-induced rereplication and the increased cell size. The cell size effect was enhanced by co-depletion of cell survival regulator p53. These data suggest that the increased size of emi1-deficient cells is either directly or indirectly caused by the rereplication defects. Moreover, enforced expression of Cyclin A partially ablated the rereplicating population in emi1-deficient zebrafish embryos, consistent with the role of Cyclin A in origin licensing. Forced expression of Cyclin B partially restored the G1 population, in agreement with the established role of Cyclin B in mitotic progression and exit. However, expression of Cyclin B also partially inhibited rereplication in emi1 deficient embryos, suggesting a role for Cyclin B in regulating replication in this cellular context. As Cyclin A and B are substrates for APC/C-Cdh1 - mediated degradation, and Cdt1 is under control of Cyclin A, these data indicate that emi1 deficiency-induced defects in vivo are due to the dysregulation of an APC/C-Cdh1 molecular axis. PMID- 23082191 TI - Activation of Fms-like tyrosine kinase 3 signaling enhances survivin expression in a mouse model of rheumatoid arthritis. AB - Survivin is known as an inhibitor of apoptosis and a positive regulator of cell division. We have recently identified survivin as a predictor of joint destruction in patients with rheumatoid arthritis (RA). Flt3 ligand (Flt3L) is expressed in the inflamed joints and has adjuvant properties in arthritis. Studies on 90 RA patients (median age 60.5 years [range, 24-87], disease duration 10.5 years [range, 0-35]) show a strong positive association between the levels of survivin and Flt3L in blood. Here, we present experimental evidence connecting survivin and Flt3L signaling. Treatment of BALB/c mice with Flt3L led to an increase of survivin in the bone marrow and in splenic dendritic cells. Flt3L changed the profile of survivin splice variants, increasing transcription of the short survivin40 in the bone marrow. Treatment with an Flt3 inhibitor reduced total survivin expression in bone marrow and in the dendritic cell population in spleen. Inhibition of survivin transcription in mice, by shRNA lentiviral constructs, reduced the gene expression of Flt3L. We conclude that expression of survivin is a downstream event of Flt3 signaling, which serves as an essential mechanism supporting survival of leukocytes during their differentiation, and maturation of dendritic cells, in RA. PMID- 23082192 TI - Microbial diversity of bovine mastitic milk as described by pyrosequencing of metagenomic 16s rDNA. AB - Dairy cow mastitis is an important disease in the dairy industry. Different microbial species have been identified as causative agents in mastitis, and are traditionally diagnosed by bacterial culture. The objective of this study was to use metagenomic pyrosequencing of bacterial 16S rRNA genes to investigate bacterial DNA diversity in milk samples of mastitic and healthy dairy cows and compare the results with those obtained by classical bacterial culture. One hundred and thirty-six milk samples were collected from cows showing signs of mastitis and used for microbiological culture. Additionally, 20 milk samples were collected from healthy quarters. Bacterial DNA was isolated from the same milk samples and the 16S rRNA genes were individually amplified and pyrosequenced. Discriminant analysis showed that the groups of samples that were most clearly different from the rest and thus easily discriminated were the normal milk samples from healthy cows and those characterised by culture as Trueperella pyogenes and Streptococcus spp. The mastitis pathogens identified by culture were generally among the most frequent organisms detected by pyrosequencing, and in some cases (Escherichia coli, Klebsiella spp. and Streptococcus uberis mastitis) the single most prevalent microorganism. Trueperella pyogenes sequences were the second most prevalent sequences in mastitis cases diagnosed as Trueperella pyogenes by culture, Streptococcus dysgalactiae sequences were the second most prevalent sequences in mastitis cases diagnosed as Streptococcus dysgalactiae by culture, and Staphyloccocus aureus sequences were the third most prevalent in mastitis cases diagnosed as Staphylococcus aureus by culture. In samples that were aerobic culture negative, pyrosequencing identified DNA of bacteria that are known to cause mastitis, DNA of bacteria that are known pathogens but have so far not been associated with mastitis, and DNA of bacteria that are currently not known to be pathogens. A possible role of anaerobic pathogens in bovine mastitis is also suggested. PMID- 23082193 TI - Restoration of proper trafficking to the cell surface for membrane proteins harboring cysteine mutations. AB - A common phenotype for many genetic diseases is that the cell is unable to deliver full-length membrane proteins to the cell surface. For some forms of autism, hereditary spherocytosis and color blindness, the culprits are single point mutations to cysteine. We have studied two inheritable cysteine mutants of cyclic nucleotide-gated channels that produce achromatopsia, a common form of severe color blindness. By taking advantage of the reactivity of cysteine's sulfhydryl group, we modified these mutants with chemical reagents that attach moieties with similar chemistries to the wild-type amino acids' side chains. We show that these modifications restored proper delivery to the cell membrane. Once there, the channels exhibited normal functional properties. This strategy might provide a unique opportunity to assess the chemical nature of membrane protein traffic problems. PMID- 23082194 TI - The human factor: behavioral and neural correlates of humanized perception in moral decision making. AB - The extent to which people regard others as full-blown individuals with mental states ("humanization") seems crucial for their prosocial motivation towards them. Previous research has shown that decisions about moral dilemmas in which one person can be sacrificed to save multiple others do not consistently follow utilitarian principles. We hypothesized that this behavior can be explained by the potential victim's perceived humanness and an ensuing increase in vicarious emotions and emotional conflict during decision making. Using fMRI, we assessed neural activity underlying moral decisions that affected fictitious persons that had or had not been experimentally humanized. In implicit priming trials, participants either engaged in mentalizing about these persons (Humanized condition) or not (Neutral condition). In subsequent moral dilemmas, participants had to decide about sacrificing these persons' lives in order to save the lives of numerous others. Humanized persons were sacrificed less often, and the activation pattern during decisions about them indicated increased negative affect, emotional conflict, vicarious emotions, and behavioral control (pgACC/mOFC, anterior insula/IFG, aMCC and precuneus/PCC). Besides, we found enhanced effective connectivity between aMCC and anterior insula, which suggests increased emotion regulation during decisions affecting humanized victims. These findings highlight the importance of others' perceived humanness for prosocial behavior - with aversive affect and other-related concern when imagining harming more "human-like" persons acting against purely utilitarian decisions. PMID- 23082195 TI - Persistent histamine excitation of glutamatergic preoptic neurons. AB - Thermoregulatory neurons of the median preoptic nucleus (MnPO) represent a target at which histamine modulates body temperature. The mechanism by which histamine excites a population of MnPO neurons is not known. In this study it was found that histamine activated a cationic inward current and increased the intracellular Ca(2+) concentration, actions that had a transient component as well as a sustained one that lasted for tens of minutes after removal of the agonist. The sustained component was blocked by TRPC channel blockers. Single cell reverse transcription-PCR analysis revealed expression of TRPC1, TRPC5 and TRPC7 subunits in neurons excited by histamine. These studies also established the presence of transcripts for the glutamatergic marker Vglut2 and for the H1 histamine receptor in neurons excited by histamine. Intracellular application of antibodies directed against cytoplasmic sites of the TRPC1 or TRPC5 channel subunits decreased the histamine-induced inward current. The persistent inward current and elevation in intracellular Ca(2+) concentration could be reversed by activating the PKA pathway. This data reveal a novel mechanism by which histamine induces persistent excitation and sustained intracellular Ca(2+) elevation in glutamatergic MnPO neurons. PMID- 23082196 TI - Differences in the endocannabinoid system of sperm from fertile and infertile men. AB - Male infertility is a major cause of problems for many couples in conceiving a child. Recently, lifestyle pastimes such as alcohol, tobacco and marijuana have been shown to have further negative effects on male reproduction. The endocannabinoid system (ECS), mainly through the action of anandamide (AEA) and 2 arachidonoylglycerol (2-AG) at cannabinoid (CB(1), CB(2)) and vanilloid (TRPV1) receptors, plays a crucial role in controlling functionality of sperm, with a clear impact on male reproductive potential. Here, sperm from fertile and infertile men were used to investigate content (through LC-ESI-MS), mRNA (through quantitative RT-PCR), protein (through Western Blotting and ELISA) expression, and functionality (through activity and binding assays) of the main metabolic enzymes of AEA and 2-AG (NAPE-PLD and FAAH, for AEA; DAGL and MAGL for 2-AG), as well as of their binding receptors CB(1), CB(2) and TRPV1. Our findings show a marked reduction of AEA and 2-AG content in infertile seminal plasma, paralleled by increased degradation: biosynthesis ratios of both substances in sperm from infertile versus fertile men. In addition, TRPV1 binding was detected in fertile sperm but was undetectable in infertile sperm, whereas that of CB(1) and CB(2) receptors was not statistically different in the two groups. In conclusion, this study identified unprecedented alterations of the ECS in infertile sperm, that might impact on capacitation and acrosome reaction, and hence fertilization outcomes. These alterations might also point to new biomarkers to determine male reproductive defects, and identify distinct ECS elements as novel targets for therapeutic exploitation of ECS-oriented drugs to treat male fertility problems. PMID- 23082197 TI - Antimicrobial resistance and spread of multi drug resistant Escherichia coli isolates collected from nine urology services in the Euregion Meuse-Rhine. AB - We determined the prevalence and spread of antibiotic resistance and the characteristics of ESBL producing and/or multi drug resistant (MDR) Escherichia coli isolates collected from urine samples from urology services in the Euregio Meuse-Rhine, the border region of the Netherlands (n=176), Belgium (n=126) and Germany (n=119). Significant differences in resistance between the three regions were observed. Amoxicillin-clavulanic acid resistance ranged from 24% in the Netherlands to 39% in Belgium (p=0.018), from 20% to 40% (p<0.004) for the fluoroquinolones and from 20% to 40% (p=0.018) for the folate antagonists. Resistance to nitrofurantoin was less than 5%. The prevalence of ESBL producing isolates varied from 2% among the Dutch isolates to 8% among the German ones (p=0.012) and were mainly CTX-M 15. The prevalence of MDR isolates among the Dutch, German and Belgian isolates was 11%, 17% and 27%, respectively (p< =0.001 for the Belgian compared with the Dutch isolates). The majority of the MDR and ESBL producing isolates belonged to ST131. This study indicates that most antibiotics used as first choice oral empiric treatment for UTIs (amoxicillin clavulanic acid, fluoroquinolones and folate antagonists) are not appropriate for this purpose and that MDR strains such as CTX-M producing ST131 have spread in the entire Euregion. Our data stress the importance of ward specific surveillance to optimize empiric treatment. Also, prudent use of antibiotics and further research to alternative agents are warranted. PMID- 23082198 TI - Measurements of CFTR-mediated Cl- secretion in human rectal biopsies constitute a robust biomarker for Cystic Fibrosis diagnosis and prognosis. AB - BACKGROUND: Cystic Fibrosis (CF) is caused by ~1,900 mutations in the CF transmembrane conductance regulator (CFTR) gene encoding for a cAMP-regulated chloride (Cl(-)) channel expressed in several epithelia. Clinical features are dominated by respiratory symptoms, but there is variable organ involvement thus causing diagnostic dilemmas, especially for non-classic cases. METHODOLOGY/PRINCIPAL FINDINGS: To further establish measurement of CFTR function as a sensitive and robust biomarker for diagnosis and prognosis of CF, we herein assessed cholinergic and cAMP-CFTR-mediated Cl(-) secretion in 524 freshly excised rectal biopsies from 118 individuals, including patients with confirmed CF clinical diagnosis (n=51), individuals with clinical CF suspicion (n=49) and age-matched non-CF controls (n=18). Conclusive measurements were obtained for 96% of cases. Patients with "Classic CF", presenting earlier onset of symptoms, pancreatic insufficiency, severe lung disease and low Shwachman-Kulczycki scores were found to lack CFTR-mediated Cl(-) secretion (<5%). Individuals with milder CF disease presented residual CFTR-mediated Cl(-) secretion (10-57%) and non-CF controls show CFTR-mediated Cl(-) secretion >= 30-35% and data evidenced good correlations with various clinical parameters. Finally, comparison of these values with those in "CF suspicion" individuals allowed to confirm CF in 16/49 individuals (33%) and exclude it in 28/49 (57%). Statistical discriminant analyses showed that colonic measurements of CFTR-mediated Cl(-) secretion are the best discriminator among Classic/Non-Classic CF and non-CF groups. CONCLUSIONS/SIGNIFICANCE: Determination of CFTR-mediated Cl(-) secretion in rectal biopsies is demonstrated here to be a sensitive, reproducible and robust predictive biomarker for the diagnosis and prognosis of CF. The method also has very high potential for (pre-)clinical trials of CFTR-modulator therapies. PMID- 23082199 TI - Associations between pathogens in the upper respiratory tract of young children: interplay between viruses and bacteria. AB - BACKGROUND: High rates of potentially pathogenic bacteria and respiratory viruses can be detected in the upper respiratory tract of healthy children. Investigating presence of and associations between these pathogens in healthy individuals is still a rather unexplored field of research, but may have implications for interpreting findings during disease. METHODOLOGY/PRINCIPAL FINDINGS: We selected 986 nasopharyngeal samples from 433 6- to 24-month-old healthy children that had participated in a randomized controlled trial. We determined the presence of 20 common respiratory viruses using real-time PCR. Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus were identified by conventional culture methods. Information on risk factors was obtained by questionnaires. We performed multivariate logistic regression analyses followed by partial correlation analysis to identify the overall pattern of associations. S. pneumoniae colonization was positively associated with the presence of H. influenzae (adjusted odds ratio 1.60, 95% confidence interval 1.18 2.16), M. catarrhalis (1.78, 1.29-2.47), human rhinoviruses (1.63, 1.19-2.22) and enteroviruses (1.97, 1.26-3.10), and negatively associated with S. aureus presence (0.59, 0.35-0.98). H. influenzae was positively associated with human rhinoviruses (1.63, 1.22-2.18) and respiratory syncytial viruses (2.78, 1.06 7.28). M. catarrhalis colonization was positively associated with coronaviruses (1.99, 1.01-3.93) and adenoviruses (3.69, 1.29-10.56), and negatively with S. aureus carriage (0.42, 0.25-0.69). We observed a strong positive association between S. aureus and influenza viruses (4.87, 1.59-14.89). In addition, human rhinoviruses and enteroviruses were positively correlated (2.40, 1.66-3.47), as were enteroviruses and human bocavirus, WU polyomavirus, parainfluenza viruses, and human parechovirus. A negative association was observed between human rhinoviruses and coronaviruses. CONCLUSIONS/SIGNIFICANCE: Our data revealed high viral and bacterial prevalence rates and distinct bacterial-bacterial, viral bacterial and viral-viral associations in healthy children, hinting towards the complexity and potential dynamics of microbial communities in the upper respiratory tract. This warrants careful consideration when associating microbial presence with specific respiratory diseases. PMID- 23082200 TI - Longitudinal liver stiffness assessment in patients with chronic hepatitis C undergoing antiviral therapy. AB - BACKGROUND/AIMS: Liver stiffness (LS) measurement by means of transient elastography (TE) is accurate to predict fibrosis stage. The effect of antiviral treatment and virologic response on LS was assessed and compared with untreated patients with chronic hepatitis C (CHC). METHODS: TE was performed at baseline, and at weeks 24, 48, and 72 in 515 patients with CHC. RESULTS: 323 treated (62.7%) and 192 untreated patients (37.3%) were assessed. LS experienced a significant decline in treated patients and remained stable in untreated patients at the end of study (P<0.0001). The decline was significant for patients with baseline LS >= 7.1 kPa (P<0.0001 and P 0.03, for LS >= 9.5 and >= 7.1 kPa vs lower values, respectively). Sustained virological responders and relapsers had a significant LS improvement whereas a trend was observed in nonresponders (mean percent change -16%, -10% and -2%, for SVR, RR and NR, respectively, P 0.03 for SVR vs NR). In multivariate analysis, high baseline LS (P<0.0001) and ALT levels, antiviral therapy and non-1 genotype were independent predictors of LS improvement. CONCLUSIONS: LS decreases during and after antiviral treatment in patients with CHC. The decrease is significant in sustained responders and relapsers (particularly in those with high baseline LS) and suggests an improvement in liver damage. PMID- 23082201 TI - ExpI and PhzI are descendants of the long lost cognate signal synthase for SdiA. AB - SdiA of E. coli and Salmonella is a LuxR homolog that detects N-acyl homoserine lactones (AHLs). Most LuxR homologs function together with a cognate AHL synthase (a LuxI homolog), but SdiA does not. Instead, SdiA detects AHLs produced by other bacterial species. In this report, we performed a phylogenetic analysis of SdiA. The results suggest that one branch of the Enterobacteriaceae obtained a rhlR/rhlI pair by horizontal transfer. The Erwinia and Pantoea branches still contain the complete pair where it is known as expR/expI and phzR/phzI, respectively. A deletion event removed the luxI homolog from the remainder of the group, leaving just the luxR homolog known as sdiA. Thus ExpR and PhzR are SdiA orthologs and ExpI and PhzI are descendants of the long lost cognate signal synthase of SdiA. PMID- 23082202 TI - The stomatin-like protein SLP-1 and Cdk2 interact with the F-Box protein Fbw7 gamma. AB - Control of cellular proliferation is critical to cell viability. The F-box protein Fbw7 (hAgo/hCdc4/FBXW7) functions as a specificity factor for the Skp1 Cul1-F-box protein (SCF) ubiquitin ligase complex and targets several proteins required for cellular proliferation for ubiquitin-mediated destruction. Fbw7 exists as three splice variants but the mechanistic role of each is not entirely clear. We examined the regulation of the Fbw7-gamma isoform, which has been implicated in the degradation of c-Myc. We show here that Fbw7-gamma is an unstable protein and that its turnover is proteasome-dependent in transformed cells. Using a two-hybrid screen, we identified a novel interaction partner, SLP 1, which binds the N-terminal domain of Fbw7-gamma. Overexpression of SLP-1 inhibits the degradation of Fbw7-gamma, suggesting that this interaction can happen in vivo. When Fbw7-gamma is stabilized by overexpression of SLP-1, c-Myc protein abundance decreases, suggesting that the SCF(Fbw7-gamma) complex maintains activity. We demonstrate that Cdk2 also binds the N-terminal domain of Fbw7-gamma as well as SLP-1. Interestingly, co-expression of Cdk2 and SLP-1 does not inhibit Fbw7-gamma degradation, suggesting that Cdk2 and SLP-1 may have opposing functions. PMID- 23082203 TI - Enrichment and stratification for predementia Alzheimer disease clinical trials. AB - The tau and amyloid pathobiological processes underlying Alzheimer disease (AD) progresses slowly over periods of decades before clinical manifestation as mild cognitive impairment (MCI), then more rapidly to dementia, and eventually to end stage organ failure. The failure of clinical trials of candidate disease modifying therapies to slow disease progression in patients already diagnosed with early AD has led to increased interest in exploring the possibility of early intervention and prevention trials, targeting MCI and cognitively healthy (HC) populations. Here, we stratify MCI individuals based on cerebrospinal fluid (CSF) biomarkers and structural atrophy risk factors for the disease. We also stratify HC individuals into risk groups on the basis of CSF biomarkers for the two hallmark AD pathologies. Results show that the broad category of MCI can be decomposed into subsets of individuals with significantly different average regional atrophy rates. By thus selectively identifying individuals, combinations of these biomarkers and risk factors could enable significant reductions in sample size requirements for clinical trials of investigational AD-modifying therapies, and provide stratification mechanisms to more finely assess response to therapy. Power is sufficiently high that detecting efficacy in MCI cohorts should not be a limiting factor in AD therapeutics research. In contrast, we show that sample size estimates for clinical trials aimed at the preclinical stage of the disorder (HCs with evidence of AD pathology) are prohibitively large. Longer natural history studies are needed to inform design of trials aimed at the presymptomatic stage. PMID- 23082204 TI - CD200R1 supports HSV-1 viral replication and licenses pro-inflammatory signaling functions of TLR2. AB - The CD200R1:CD200 axis is traditionally considered to limit tissue inflammation by down-regulating pro-inflammatory signaling in myeloid cells bearing the receptor. We generated CD200R1(-/-) mice and employed them to explore both the role of CD200R1 in regulating macrophage signaling via TLR2 as well as the host response to an in vivo, TLR2-dependent model, herpes simplex virus 1 (HSV-1) infection. CD200R1(-/-) peritoneal macrophages demonstrated a 70-75% decrease in the generation of IL-6 and CCL5 (Rantes) in response to the TLR2 agonist Pam(2)CSK(4) and to HSV-1. CD200R1(-/-) macrophages could neither up-regulate the expression of TLR2, nor assemble a functional inflammasome in response to HSV-1. CD200R1(-/-) mice were protected from HSV-1 infection and exhibited dysfunctional TLR2 signaling. Finally, both CD200R1(-/-) mice and CD200R1(-/-) fibroblasts and macrophages showed a markedly reduced ability to support HSV-1 replication. In summary, our data demonstrate an unanticipated and novel requirement for CD200R1 in "licensing" pro-inflammatory functions of TLR2 and in limiting viral replication that are supported by ex vivo and in vivo evidence. PMID- 23082205 TI - Pseudomonas aeruginosa keratitis in mice: effects of topical bacteriophage KPP12 administration. AB - The therapeutic effects of bacteriophage (phage) KPP12 in Pseudomonas aeruginosa keratitis were investigated in mice. Morphological analysis showed that phage KPP12 is a member of the family Myoviridae, morphotype A1, and DNA sequence analysis revealed that phage KPP12 is similar to PB1-like viruses. Analysis of the phage KPP12 genome did not identify any genes related to drug resistance, pathogenicity or lysogenicity, and so phage KPP12 may be a good candidate for therapeutic. KPP12 showed a broad host range for P. aeruginosa strains isolated from clinical ophthalmic infections. Inoculation of the scarified cornea with P. aeruginosa caused severe keratitis and eventual corneal perforation. Subsequent single-dose administration of KPP12 eye-drops significantly improved disease outcome, and preserved the structural integrity and transparency of the infected cornea. KPP12 treatment resulted in the suppression of neutrophil infiltration and greatly enhanced bacterial clearance in the infected cornea. These results indicate that bacteriophage eye-drops may be a novel adjunctive or alternative therapeutic agent for the treatment of infectious keratitis secondary to antibiotic-resistant bacteria. PMID- 23082206 TI - The real importance of pre-existing comorbidities on long-term mortality after acute kidney injury. AB - BACKGROUND: The causes of death on long-term mortality after acute kidney injury (AKI) have not been well studied. The purpose of the study was to evaluate the role of comorbidities and the causes of death on the long-term mortality after AKI. METHODOLOGY/PRINCIPAL FINDINGS: We retrospectively studied 507 patients who experienced AKI in 2005-2006 and were discharged free from dialysis. In June 2008 (median: 21 months after AKI), we found that 193 (38%) patients had died. This mortality is much higher than the mortality of the population of Sao Paulo City, even after adjustment for age. A multiple survival analysis was performed using Cox proportional hazards regression model and showed that death was associated with Khan's index indicating high risk [adjusted hazard ratio 2.54 (1.38-4.66)], chronic liver disease [1.93 (1.15-3.22)], admission to non-surgical ward [1.85 (1.30-2.61)] and a second AKI episode during the same hospitalization [1.74 (1.12 2.71)]. The AKI severity evaluated either by the worst stage reached during AKI (P=0.20) or by the need for dialysis (P=0.12) was not associated with death. The causes of death were identified by a death certificate in 85% of the non survivors. Among those who died from circulatory system diseases (the main cause of death), 59% had already suffered from hypertension, 34% from diabetes, 47% from heart failure, 38% from coronary disease, and 66% had a glomerular filtration rate <60 previous to the AKI episode. Among those who died from neoplasms, 79% already had the disease previously. CONCLUSIONS: Among AKI survivors who were discharged free from dialysis the increased long-term mortality was associated with their pre-existing chronic conditions and not with the severity of the AKI episode. These findings suggest that these survivors should have a medical follow-up after hospital discharge and that all efforts should be made to control their comorbidities. PMID- 23082207 TI - Concordance of two diabetes diagnostic criteria using fasting plasma glucose and hemoglobin A1c: the Yuport Medical Checkup Centre study. AB - BACKGROUND: We tested the concordance of the two diagnostic criteria for diabetes using fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) by the Japan Diabetes Society (JDS) and American Diabetes Association (ADA). METHODS: We used data from 7,328 subjects without known diabetes who participated in a voluntary health checkup program at least twice between 1998 and 2006, at intervals <= 2 years. For repeat participants who attended the screening over two times, data from the first and second checkups were used for this study. At the first visit, diabetes was diagnosed both at FPG >= 7.0 mmol/L and HbA1c >= 6.5% using the JDS criteria. In addition, diabetes was diagnosed using two ADA criteria; ADA-FPG diabetes for persistent fasting hyperglycemia (FPG >= 7.0 mmol/L) or ADA-HbA1c diabetes for hyper-glycated hemoglominemia (HbA1c >= 6.5%), both at the first and second checkups. Subsequently, the concordance of diagnosis between the JDS and the ADA criteria was evaluated. RESULTS: At the first checkup, 153 (2.1%) persons were diagnosed with diabetes by the JDS criteria. They had higher levels of risk factors for diabetes than non-diabetic subjects. Using the first and second checkups, 174 (2.4%) and 175 (2.4%) were diagnosed with diabetes by the ADA-FPG criteria, respectively. Among 153 subjects diagnosed with diabetes by the JDS criteria, 125 (81.7%) and 129 (84.3%) had ADA-FPG and ADA-HbA1c diabetes, respectively. The kappa coefficients of the JDS criteria with ADA-FPG and ADA HbA1c criteria were 0.759 and 0.782 (P<0.001), respectively. In the subgroup analysis stratified by sex, the concordance was well preserved at the kappa coefficients around 0.8 (between 0.725 and 0.836). CONCLUSION: The JDS diagnostic criteria for diabetes have a substantial and acceptable concordance with the ADA criteria. The JDS criteria may be a practical method for diagnosing diabetes that maintains compatibility with the ADA criteria. PMID- 23082208 TI - Improved STD syndrome management by a network of clinicians and pharmacy workers in Peru: The PREVEN Network. AB - BACKGROUND: Sexually Transmitted diseases (STD) syndrome management has been one cornerstone of STD treatment. Persons with STD symptoms in many countries, especially those with limited resources, often initially seek care in pharmacies. The objective of the study was to develop and evaluate an integrated network of physicians, midwives and pharmacy workers trained in STD syndromic management (The PREVEN Network) as part of a national urban community-randomized trial of sexually transmitted infection prevention in Peru. METHODS AND FINDINGS: After a comprehensive census of physicians, midwives, and pharmacies in ten intervention and ten control cities, we introduced seminars and workshops for pharmacy workers, and continuing education for physicians and midwives in intervention cities and invited graduates to join the PREVEN Network. "Prevention Salespersons" visited pharmacies, boticas and clinicians regularly for educational support and collection of information on numbers of cases of STD syndromes seen at pharmacies and by clinicians in intervention cities. Simulated patients evaluated outcomes of training of pharmacy workers with respect to adequate STD syndrome management, recommendations for condom use and for treatment of partners. In intervention cities we trained, certified, and incorporated into the PREVEN Network the workers at 623 (80.6%) of 773 pharmacies and 701 (69.6%) of 1007 physicians and midwives in private practice. Extremely high clinician and pharmacy worker turnover, 13.4% and 44% respectively in the first year, dictated continued training of new pharmacy workers and clinicians. By the end of the intervention the Network included 792 pharmacies and 597 clinicians. Pharmacies reported more cases of STDs than did clinicians. Evaluations by simulated patients showed significant and substantial improvements in the management of STD syndromes at pharmacies in intervention cities but not in control cities. CONCLUSIONS: Training pharmacy workers linked to a referral network of clinicians proved feasible and acceptable. High turn-over was challenging but over come. PMID- 23082209 TI - The impact of travel time on geographic distribution of dialysis patients. AB - BACKGROUNDS: The geographic disparity of prevalence rates among dialysis patients is unclear. We evaluate the association between travel time to dialysis facilities and prevalence rates of dialysis patients living in 1,867 census areas of Hiroshima, Japan. Furthermore, we study the effects of geographic features (mainland or island) on the prevalence rates and assess if these effects modify the association between travel time and prevalence. METHODS: The study subjects were all 7,374 people that were certified as the "renal disabled" by local governments in 2011. The travel time from each patient to the nearest available dialysis facility was calculated by incorporating both travel time and the capacity of all 98 facilities. The effect of travel time on the age- and sex adjusted standard prevalence rate (SPR) and 95% confidence intervals (CIs) at each census area was evaluated in two-level Poisson regression models with 1,867 census areas (level 1) nested within 35 towns or cities (level 2). The results were adjusted for area-based parameters of socioeconomic status, urbanity, and land type. Furthermore, the SPR of dialysis patients was calculated in each specific subgroup of population for travel time, land type, and combination of land type and travel time. RESULTS: In the regression analysis, SPR decreased by 5.2% (95% CI: -7.9--2.3) per 10-min increase in travel time even after adjusting for potential confounders. The effect of travel time on prevalence was different in the mainland and island groups. There was no travel time-dependent SPR disparity on the islands. The SPR among remote residents (>30 min from facilities) in the mainland was lower (0.77, 95% CI: 0.71-0.85) than that of closer residents (<= 30 min; 0.95, 95% CI: 0.92-0.97). CONCLUSIONS: The prevalence of dialysis patients was lower among remote residents. Geographic difficulties for commuting seem to decrease the prevalence rate. PMID- 23082210 TI - Better than I thought: positive evaluation bias in hypomania. AB - BACKGROUND: Mania is characterised by increased impulsivity and risk-taking, and psychological accounts argue that these features may be due to hypersensitivity to reward. The neurobiological mechanisms remain poorly understood. Here we examine reinforcement learning and sensitivity to both reward and punishment outcomes in hypomania-prone individuals not receiving pharmacotherapy. METHOD: We recorded EEG from 45 healthy individuals split into three groups by low, intermediate and high self-reported hypomanic traits. Participants played a computerised card game in which they learned the reward contingencies of three cues. Neural responses to monetary gain and loss were measured using the feedback related negativity (FRN), a component implicated in motivational outcome evaluation and reinforcement learning. RESULTS: As predicted, rewards elicited a smaller FRN in the hypomania-prone group relative to the low hypomania group, indicative of greater reward responsiveness. The hypomania-prone group also showed smaller FRN to losses, indicating diminished response to negative feedback. CONCLUSION: Our findings indicate that proneness to hypomania is associated with both reward hypersensitivity and discounting of punishment. This positive evaluation bias may be driven by aberrant reinforcement learning signals, which fail to update future expectations. This provides a possible neural mechanism explaining risk-taking and impaired reinforcement learning in BD. Further research will be needed to explore the potential value of the FRN as a biological vulnerability marker for mania and pathological risk-taking. PMID- 23082211 TI - Hypertension and obesity in adults living in a high HIV prevalence rural area in South Africa. AB - Hypertension and excess body weight are major risk factors of cardiovascular morbidity and mortality in developing countries. In countries with a high HIV prevalence, it is unknown how increased antiretroviral treatment and care (ART) coverage has affected the prevalence of overweight, obesity, and hypertension. We conducted a health survey in 2010 based on the WHO STEPwise approach in 14,198 adult resident participants of a demographic surveillance area in rural South Africa to investigate factors associated with hypertension and excess weight including HIV infection and ART status. Women had a significantly higher median body mass index (BMI) than men (26.4 vs. 21.2 kg/m(2), p<0.001). The prevalence of obesity (BMI >= 30 kg/m(2)) in women (31.3%, 95% confidence interval (CI) 30.2 32.4) was 6.5 times higher than in men (4.9%, 95% CI 4.1-5.7), whereas prevalence of hypertension (systolic or diastolic blood pressure >= 140 or 90 mm Hg, respectively) was 1.4 times higher in women than in men (28.5% vs 20.8%, p<0.001). In multivariable regression analysis, both hypertension and obesity were significantly associated with sex, age, HIV and ART status. The BMI of women and men on ART was on average 3.8 (95% CI 3.2-3.8) and 1.7 (95% CI 0.9-2.5) kg/m(2) lower than of HIV-negative women and men, respectively. The BMI of HIV infected women and men not on ART was on average 1.2 (95% CI 0.8-1.6) and 0.4 (95% CI -0.1-0.9) kg/m(2) lower than of HIV-negative women and men, respectively. Obesity was a bigger risk factor for hypertension in men (adjusted odds ratio (aOR) 2.99, 95% CI 2.00-4.48) than in women (aOR 1.64, 95% CI 1.39-1.92) and overweight (25 <= BMI<30) was a significant risk factor for men only (aOR 1.53 95% CI 1.14-2.06). Our study suggests that, cardiovascular risk factors of hypertension and obesity differ substantially between women and men in rural South Africa. PMID- 23082212 TI - North African populations carry the signature of admixture with Neandertals. AB - One of the main findings derived from the analysis of the Neandertal genome was the evidence for admixture between Neandertals and non-African modern humans. An alternative scenario is that the ancestral population of non-Africans was closer to Neandertals than to Africans because of ancient population substructure. Thus, the study of North African populations is crucial for testing both hypotheses. We analyzed a total of 780,000 SNPs in 125 individuals representing seven different North African locations and searched for their ancestral/derived state in comparison to different human populations and Neandertals. We found that North African populations have a significant excess of derived alleles shared with Neandertals, when compared to sub-Saharan Africans. This excess is similar to that found in non-African humans, a fact that can be interpreted as a sign of Neandertal admixture. Furthermore, the Neandertal's genetic signal is higher in populations with a local, pre-Neolithic North African ancestry. Therefore, the detected ancient admixture is not due to recent Near Eastern or European migrations. Sub-Saharan populations are the only ones not affected by the admixture event with Neandertals. PMID- 23082213 TI - Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a meta-analysis. AB - BACKGROUND: Three first-line antituberculosis drugs, isoniazid, rifampicin and pyrazinamide, may induce liver injury, especially isoniazid. This antituberculosis drug-induced liver injury (ATLI) ranges from a mild to severe form, and the associated mortality cases are not rare. In the past decade, many investigations have focused the association between drug-metabolising enzyme (DME) gene polymorphisms and risk for ATLI; however, these studies have yielded contradictory results. METHODS: PubMed, EMBASE, ISI web of science and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. A meta-analysis was performed to examine the association between polymorphisms from 4 DME genes (NAT2, CYP2E1, GSTM1 and GSTT1) and susceptibility to ATLI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Heterogeneity among articles and their publication bias were also tested. RESULTS: 38 studies involving 2,225 patients and 4,906 controls were included. Overall, significantly increased ATLI risk was associated with slow NAT2 genotype and GSTM1 null genotype when all studies were pooled into the meta-analysis. Significantly increased risk was also found for CYP2E1*1A in East Asians when stratified by ethnicity. However, no significant results were observed for GSTT1. CONCLUSIONS: Our results demonstrated that slow NAT2 genotype, CYP2E1*1A and GSTM1 null have a modest effect on genetic susceptibility to ATLI. PMID- 23082215 TI - Effect of clazosentan in patients with aneurysmal subarachnoid hemorrhage: a meta analysis of randomized controlled trials. AB - BACKGROUND: Cerebral vasospasm is the most important potentially treatable cause of mortality and morbidity following aneurysmal subarachnoid hemorrhage (aSAH). Clazosentan, a selective endothelinreceptor antagonist, has been suggested to help reduce the incidence of vasospasm in patients with aSAH. However, the results were controversial in previous trials. This meta-analysis attempts to assess the effect of clazosentan in patients with aSAH. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Pubmed, Embase, and the Cochrane Library from their inception until June, 2012. All randomized controlled trials (RCTs) related to the effect of clazosentan in aSAH were included. The primary outcomes included the incidence of angiographic vasospasm, new cerebral infarction (NCI), delayed ischemic neurological deficits (DIND), and vasospasm-related morbidity/mortality (M/M); the second outcomes included the occurrence of rescue therapy, all-cause-mortality, and poor outcome. 4 RCTs were included with a total of 2156 patients. The risk of angiographic vasospasm (relative risk [RR] =0.58; 95% CI, 0.48 to 0.71), DIND (RR=0.76; 95% CI, 0.62 to 0.92), and vasospasm related M/M (RR=0.80; 95% CI, 0.67 to 0.96) were statistically significantly reduced in the clazosentan group. Patients treated with clazosentan had a reduced occurrence of rescue therapy (RR=0.62; 95% CI, 0.49 to 0.79). However, no statistically significant effects were observed in NCI (RR=0.74; 95% CI, 0.52 to 1.04), mortality (RR=1.03; 95% CI, 0.71 to 1.49), and poor outcome (RR=1.12; 95% CI, 0.96 to 1.30). CONCLUSIONS/SIGNIFICANCE: Our pooling data supports that clazosentan is probably effective in preventing the occurrence of angiographic vasospasm, vasospasm-related DIND, vasospasm related M/M, and rescue therapy. However, no evidence lends significant supports to the benefits of clazosentan in decreasing the occurrence of NCI, mortality or improving the functional outcome. PMID- 23082214 TI - Birth weight and long-term overweight risk: systematic review and a meta-analysis including 643,902 persons from 66 studies and 26 countries globally. AB - BACKGROUND: Overweight is among the major challenging health risk factors. It has been claimed that birth weight, being a critical indicator of prenatal developmental conditions, is related to long-term overweight risk. In order to check this important assumption of developmental and preventive medicine, we performed a systematic review and comprehensive meta-analysis. METHODS AND FINDINGS: Relevant studies published up to January 2011 that investigated the relation between birth weight and later risk of overweight were identified through literature searches using MEDLINE and EMBASE. For meta-analysis, 66 studies from 26 countries and five continents were identified to be eligible, including 643,902 persons aged 1 to 75 years. We constructed random-effects and fixed-effects models, performed subgroup-analyses, influence-analyses, assessed heterogeneity and publication bias, performed meta-regression analysis as well as analysis of confounder adjusted data. Meta-regression revealed a linear positive relationship between birth weight and later overweight risk (p<0.001). Low birth weight (<2,500 g) was found to be followed by a decreased risk of overweight (odds ratio (OR) =0.67; 95% confidence interval (CI) 0.59-0.76). High birth weight (>4,000 g) was associated with increased risk of overweight (OR=1.66; 95% CI 1.55-1.77). Results did not change significantly by using normal birth weight (2,500-4,000 g) as reference category (OR=0.73, 95% CI 0.63-0.84, and OR=1.60, 95% CI 1.45-1.77, respectively). Subgroup- and influence-analyses revealed no indication for bias/confounding. Adjusted estimates indicate a doubling of long term overweight risk in high as compared to normal birth weight subjects (OR=1.96, 95% CI 1.43-2.67). CONCLUSIONS: Findings demonstrate that low birth weight is followed by a decreased long-term risk of overweight, while high birth weight predisposes for later overweight. Preventing in-utero overnutrition, e.g., by avoiding maternal overnutrition, overweight and/or diabetes during pregnancy, might therefore be a promising strategy of genuine overweight prevention, globally. PMID- 23082216 TI - Phosphorylation of 4E-BP1 in the mammalian brain is not altered by LRRK2 expression or pathogenic mutations. AB - Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of autosomal dominant familial Parkinson's disease (PD). LRRK2 encodes a multi domain protein containing GTPase and kinase enzymatic domains. Disease-associated mutations in LRRK2 variably influence enzymatic activity with the common G2019S variant leading to enhanced kinase activity. Mutant LRRK2 induces neuronal toxicity through a kinase-dependent mechanism suggesting that kinase activity is important for mediating the pathogenic effects of LRRK2 mutations. A number of LRRK2 kinase substrates have been identified in vitro but whether they represent authentic physiological substrates in mammalian cells or tissues is not yet clear. The eukaryotic initiation factor 4E (eIF4E)-binding protein, 4E-BP1, was recently identified as a potential substrate of LRRK2 kinase activity in vitro and in Drosophila with phosphorylation occurring at Thr37 and Thr46. Here, we explore a potential interaction of LRRK2 and 4E-BP1 in mammalian cells and brain. We find that LRRK2 can weakly phosphorylate 4E-BP1 in vitro but LRRK2 overexpression is not able to alter endogenous 4E-BP1 phosphorylation in mammalian cells. In mammalian neurons LRRK2 and 4E-BP1 display minimal co localization, whereas the subcellular distribution, protein complex formation and covalent post-translational modification of endogenous 4E-BP1 are not altered in the brains of LRRK2 knockout or mutant LRRK2 transgenic mice. In the brain, the phosphorylation of 4E-BP1 at Thr37 and Thr46 does not change in LRRK2 knockout or mutant LRRK2 transgenic mice, nor is 4E-BP1 phosphorylation altered in idiopathic or G2019S mutant PD brains. Collectively, our results suggest that 4E-BP1 is neither a major nor robust physiological substrate of LRRK2 in mammalian cells or brain. PMID- 23082217 TI - Active smoking and risk of metabolic syndrome: a meta-analysis of prospective studies. AB - BACKGROUND: Epidemiological evidence suggests that smoking has been associated with emergence of metabolic syndrome. However, data on this issue are inconsistent and controversial. We therefore conducted a meta-analysis to examine the association between smoking and metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS: We searched the Medline, Embase and the Cochrane Library database up to March 2012 to identify prospective cohort studies related to smoking and metabolic syndrome. Reference lists of retrieved articles were also reviewed. Summary effect estimates were derived using a random-effects model and stratified by gender, smoking dose, follow-up duration and geographical area. Primary analysis of 13 studies involving 56,691 participants and 8,688 cases detected a significant positive association between active smoking and risk of metabolic syndrome (pooled relative risk [RR] 1.26, 95% CI: 1.10-1.44). Estimates of effects were substantially consistent in the stratified analyses. In the dose response analysis, risk of metabolic syndrome was stronger for active male smokers (pooled RR 1.34, 95% CI: 1.20-1.50) than it was for former male smokers (pooled RR 1.19, 95% CI: 1.00-1.42), and greater for heavy smokers (pooled RR 1.42, 95% CI: 1.27-1.59) compared with light smokers (pooled RR 1.10, 95% CI: 0.90-1.35). No evidence of statistical publication bias was found (Egger' s test P=0.227, Begg' s test P=0.113). CONCLUSIONS: Active smoking is associated with development of metabolic syndrome. Smoking cessation appears to reduce the risk of metabolic syndrome. PMID- 23082218 TI - Protection against recurrent stroke with resveratrol: endothelial protection. AB - Despite increased risk of a recurrent stroke following a minor stroke, information is minimal regarding the interaction between injurious mild cerebral ischemic episodes and the possible treatments which might be effective. The aim of the current study was to investigate recurrent ischemic stroke and whether resveratrol, a nutritive polyphenol with promising cardio- and neuro- protective properties, could ameliorate the associated brain damage. Experiments in adult rats demonstrated that a mild ischemic stroke followed by a second mild cerebral ischemia exacerbated brain damage, and, daily oral resveratrol treatment after the first ischemic insult reduced ischemic cell death with the recurrent insult (P<0.002). Further investigation demonstrated reduction of both inflammatory changes and markers of oxidative stress in resveratrol treated animals. The protection observed with resveratrol treatment could not be explained by systemic effects of resveratrol treatment including effects either on blood pressure or body temperature measured telemetrically. Investigation of resveratrol effects on the blood-brain barrier in vivo demonstrated that resveratrol treatment reduced blood-brain barrier disruption and edema following recurrent stroke without affecting regional cerebral blood flow. Investigation of the mechanism in primary cell culture studies demonstrated that resveratrol treatment significantly protected endothelial cells against an in vitro 'ischemia' resulting in improved viability against oxygen and glucose deprivation (39.6 +/- 6.6% and 81.3 +/- 9.5% in vehicle and resveratrol treated cells, respectively). An inhibition of nitric oxide synthesis did not prevent the improved cell viability following oxygen glucose deprivation but SIRT-1 inhibition with sirtinol partially blocked the protection (P<0.001) suggesting endothelial protection is to some extent SIRT-1 dependent. Collectively, the results support that oral resveratrol treatment provides a low risk strategy to protect the brain from enhanced damage produced by recurrent stroke which is mediated in part by a protective effect of resveratrol on the endothelium of the cerebrovasculature. PMID- 23082219 TI - Regulated proteolytic processing of Reelin through interplay of tissue plasminogen activator (tPA), ADAMTS-4, ADAMTS-5, and their modulators. AB - The extracellular signaling protein Reelin, indispensable for proper neuronal migration and cortical layering during development, is also expressed in the adult brain where it modulates synaptic functions. It has been shown that proteolytic processing of Reelin decreases its signaling activity and promotes Reelin aggregation in vitro, and that proteolytic processing is affected in various neurological disorders, including Alzheimer's disease (AD). However, neither the pathophysiological significance of dysregulated Reelin cleavage, nor the involved proteases and their modulators are known. Here we identified the serine protease tissue plasminogen activator (tPA) and two matrix metalloproteinases, ADAMTS-4 and ADAMTS-5, as Reelin cleaving enzymes. Moreover, we assessed the influence of several endogenous protease inhibitors, including tissue inhibitors of metalloproteinases (TIMPs), alpha-2-Macroglobulin, and multiple serpins, as well as matrix metalloproteinase 9 (MMP-9) on Reelin cleavage, and described their complex interplay in the regulation of this process. Finally, we could demonstrate that in the murine hippocampus, the expression levels and localization of Reelin proteases largely overlap with that of Reelin. While this pattern remained stable during normal aging, changes in their protein levels coincided with accelerated Reelin aggregation in a mouse model of AD. PMID- 23082220 TI - A flexible alternative to the Cox proportional hazards model for assessing the prognostic accuracy of hospice patient survival. AB - Prognostic models are often used to estimate the length of patient survival. The Cox proportional hazards model has traditionally been applied to assess the accuracy of prognostic models. However, it may be suboptimal due to the inflexibility to model the baseline survival function and when the proportional hazards assumption is violated. The aim of this study was to use internal validation to compare the predictive power of a flexible Royston-Parmar family of survival functions with the Cox proportional hazards model. We applied the Palliative Performance Scale on a dataset of 590 hospice patients at the time of hospice admission. The retrospective data were obtained from the Lifepath Hospice and Palliative Care center in Hillsborough County, Florida, USA. The criteria used to evaluate and compare the models' predictive performance were the explained variation statistic R(2), scaled Brier score, and the discrimination slope. The explained variation statistic demonstrated that overall the Royston Parmar family of survival functions provided a better fit (R(2) =0.298; 95% CI: 0.236-0.358) than the Cox model (R(2) =0.156; 95% CI: 0.111-0.203). The scaled Brier scores and discrimination slopes were consistently higher under the Royston Parmar model. Researchers involved in prognosticating patient survival are encouraged to consider the Royston-Parmar model as an alternative to Cox. PMID- 23082221 TI - Genome-wide association identifies multiple genomic regions associated with susceptibility to and control of ovine lentivirus. AB - BACKGROUND: Like human immunodeficiency virus (HIV), ovine lentivirus (OvLV) is macrophage-tropic and causes lifelong infection. OvLV infects one quarter of U.S. sheep and induces pneumonia and body condition wasting. There is no vaccine to prevent OvLV infection and no cost-effective treatment for infected animals. However, breed differences in prevalence and proviral concentration have indicated a genetic basis for susceptibility to OvLV. A recent study identified TMEM154 variants in OvLV susceptibility. The objective here was to identify additional loci associated with odds and/or control of OvLV infection. METHODOLOGY/PRINCIPAL FINDINGS: This genome-wide association study (GWAS) included 964 sheep from Rambouillet, Polypay, and Columbia breeds with serological status and proviral concentration phenotypes. Analytic models accounted for breed and age, as well as genotype. This approach identified TMEM154 (nominal P=9.2*10(-7); empirical P=0.13), provided 12 additional genomic regions associated with odds of infection, and provided 13 regions associated with control of infection (all nominal P<1 * 10(-5)). Rapid decline of linkage disequilibrium with distance suggested many regions included few genes each. Genes in regions associated with odds of infection included DPPA2/DPPA4 (empirical P=0.006), and SYTL3 (P=0.051). Genes in regions associated with control of infection included a zinc finger cluster (ZNF192, ZSCAN16, ZNF389, and ZNF165; P=0.001), C19orf42/TMEM38A (P=0.047), and DLGAP1 (P=0.092). CONCLUSIONS/SIGNIFICANCE: These associations provide targets for mutation discovery in sheep susceptibility to OvLV. Aside from TMEM154, these genes have not been associated previously with lentiviral infection in any species, to our knowledge. Further, data from other species suggest functional hypotheses for future testing of these genes in OvLV and other lentiviral infections. Specifically, SYTL3 binds and may regulate RAB27A, which is required for enveloped virus assembly of human cytomegalovirus. Zinc finger transcription factors have been associated with positive selection for repression of retroviral replication. DLGAP1 binds and may regulate DLG1, a known regulator of HIV infectivity. PMID- 23082222 TI - Cross-sectional and longitudinal associations of different sedentary behaviors with cognitive performance in older adults. AB - BACKGROUND: The deleterious health effects of sedentary behaviors, independent of physical activity, are increasingly being recognized. However, associations with cognitive performance are not known. PURPOSE: To estimate the associations between different sedentary behaviors and cognitive performance in healthy older adults. METHODS: Computer use, time spent watching television (TV), time spent reading and habitual physical activity levels were self-reported twice (in 2001 and 2007) by participants in the SUpplementation en Vitamines et MinerauX (SU.VI.MAX and SU.VI.MAX2) study. Cognitive performance was assessed at follow-up (in 2007-2009) via a battery of 6 neuropsychological tests used to derive verbal memory and executive functioning scores. Analyses (ANCOVA) were performed among 1425 men and 1154 women aged 65.6 +/- 4.5 at the time of the neuropsychological evaluation. We estimated mean differences with 95% confidence intervals (95%CI) in cognitive performance across categories of each type of sedentary behavior. RESULTS: In multivariable cross-sectional models, compared to non-users, participants using the computer for >1 h/day displayed better verbal memory (mean difference=1.86; 95%CI: 0.95, 2.77) and executive functioning (mean difference=2.15; 95%CI: 1.22, 3.08). A negative association was also observed between TV viewing and executive functioning. Additionally, participants who increased their computer use by more than 30 min between 2001 and 2007 showed better performance on both verbal memory (mean difference=1.41; 95%CI: 0.55, 2.27) and executive functioning (mean difference=1.41; 95%CI: 0.53, 2.28) compared to those who decreased their computer use during that period. CONCLUSION: Specific sedentary behaviors are differentially associated with cognitive performance. In contrast to TV viewing, regular computer use may help maintain cognitive function during the aging process. CLINICAL TRIAL REGISTRATION: clinicaltrial.gov (number NCT00272428). PMID- 23082223 TI - Applicability of hydrogen peroxide in brown tide control - culture and microcosm studies. AB - Brown tide algal blooms, caused by the excessive growth of Aureococcus anophagefferens, recur in several northeastern US coastal bays. Direct bloom control could alleviate the ecological and economic damage associated with bloom outbreak. This paper explored the effectiveness and safety of natural chemical biocide hydrogen peroxide (H(2)O(2)) for brown tide bloom control. Culture studies showed that H(2)O(2) at 1.6 mg L(-1) effectively eradicated high density A. anophagefferens within 24-hr, but caused no significant growth inhibition in the diatoms, prymnesiophytes, green algae and dinoflagellates of >2-3 MUm cell sizes among 12 phytoplankton species tested over 1-week observation. When applied to brown tide bloom prone natural seawater in a microcosm study, this treatment effectively removed the developing brown tide bloom, while the rest of phytoplankton assemblage (quantified via HPLC based marker pigment analyses), particularly the diatoms and green algae, experienced only transient suppression then recovered with total chlorophyll a exceeding that in the controls within 72 hr; cyanobacteria was not eradicated but was still reduced about 50% at 72-hr, as compared to the controls. The action of H(2)O(2) against phytoplankton as a function of cell size and cell wall structure, and a realistic scenario of H(2)O(2) application were discussed. PMID- 23082225 TI - Age and growth of endangered smalltooth sawfish (Pristis pectinata) verified with LA-ICP-MS analysis of vertebrae. AB - Endangered smalltooth sawfish (Pristis pectinata) were opportunistically sampled in south Florida and aged by counting opaque bands in sectioned vertebrae (n=15). Small sample size precluded traditional age verification, but fish collected in spring and summer had translucent vertebrae margins, while fish collected in winter had opaque margins. Trends in Sr:Ca measured across vertebrae with laser ablation-inductively coupled plasma-mass spectrometry corresponded well to annual salinity trends observed in sawfish estuarine nursery habitats in south Florida, thus serve as a chemical marker verifying annual formation of opaque bands. Based on that finding and assumptions about mean birth date and timing of opaque band formation, estimated age ranged from 0.4 y for a 0.60 m total length (TL) male to 14.0 y for a 4.35 m TL female. Von Bertalanffy growth parameters computed from size at age data were 4.48 m for L(infinity), 0.219 y(-1)for k, and -0.81 y for t(0). Results of this study have important implications for sawfish conservation as well as for inferring habitat residency of euryhaline elasmobranchs via chemical analysis of vertebrae. PMID- 23082224 TI - Novel frataxin isoforms may contribute to the pathological mechanism of Friedreich ataxia. AB - Friedreich ataxia (FRDA) is an inherited neurodegenerative disease caused by frataxin (FXN) deficiency. The nervous system and heart are the most severely affected tissues. However, highly mitochondria-dependent tissues, such as kidney and liver, are not obviously affected, although the abundance of FXN is normally high in these tissues. In this study we have revealed two novel FXN isoforms (II and III), which are specifically expressed in affected cerebellum and heart tissues, respectively, and are functional in vitro and in vivo. Increasing the abundance of the heart-specific isoform III significantly increased the mitochondrial aconitase activity, while over-expression of the cerebellum specific isoform II protected against oxidative damage of Fe-S cluster-containing aconitase. Further, we observed that the protein level of isoform III decreased in FRDA patient heart, while the mRNA level of isoform II decreased more in FRDA patient cerebellum compared to total FXN mRNA. Our novel findings are highly relevant to understanding the mechanism of tissue-specific pathology in FRDA. PMID- 23082226 TI - Nicotinamide mononucleotide adenylyltransferase 2 (Nmnat2) regulates axon integrity in the mouse embryo. AB - Using transposon-mediated gene-trap mutagenesis, we have generated a novel mouse mutant termed Blad (Bloated Bladder). Homozygous mutant mice die perinatally showing a greatly distended bladder, underdeveloped diaphragm and a reduction in total skeletal muscle mass. Wild type and heterozygote mice appear normal. Using PCR, we identified a transposon insertion site in the first intron of Nmnat2 (Nicotinamide mononucleotide adenyltransferase 2). Nmnat2 is expressed predominantly in the brain and nervous system and has been linked to the survival of axons. Expression of this gene is undetectable in Nmnat2(blad/blad) mutants. Examination of the brains of E18.5 Nmnat2(blad/blad) mutant embryos did not reveal any obvious morphological changes. In contrast, E18.5 Nmnat2(blad/blad) homozygotes showed an approximate 60% reduction of spinal motoneurons in the lumbar region and a more than 80% reduction in the sensory neurons of the dorsal root ganglion (DRG). In addition, facial motoneuron numbers were severely reduced, and there was virtually a complete absence of axons in the hind limb. Our observations suggest that during embryogenesis, Nmnat2 plays an important role in axonal growth or maintenance. It appears that in the absence of Nmnat2, major target organs and tissues (e.g., muscle) are not functionally innervated resulting in perinatal lethality. In addition, neither Nmnat1 nor 3 can compensate for the loss of Nmnat2. Whilst there have been recent suggestions that Nmnat2 may be an endogenous modulator of axon integrity, this work represents the first in vivo study demonstrating that Nmnat2 is involved in axon development or survival in a mammal. PMID- 23082228 TI - The novel cis-encoded small RNA h2cR is a negative regulator of hfq2 in Burkholderia cenocepacia. AB - Small non-coding regulatory RNAs (sRNAs) post-transcriptionally affect multiple phenotypes in prokaryotes and eukaryotes, yet most of the underlying regulatory mechanisms and the nature of the target mRNAs remain unclear. Here we report the identification and functional analysis of the novel cis-encoded sRNA h2cR, from the human opportunistic pathogen Burkholderia cenocepacia J2315. The sRNA was found to negatively regulate the hfq2 mRNA, through binding to part of the 5'-UTR region of the hfq2 mRNA, resulting in accelerated hfq2 mRNA decay and reduced protein levels in exponentially growing cells. Both the h2cR transcript and the hfq2 mRNA are stabilized by the other B. cenocepacia RNA chaperone, Hfq. Infection experiments using the nematode Caenorhabditis elegans revealed that down-regulation of Hfq2 by h2cR decreases the B. cenocepacia ability to colonize and persist within the nematode, suggesting a role for h2cR on bacterial persistence in the host. PMID- 23082227 TI - Structural characterization of the enzymes composing the arginine deiminase pathway in Mycoplasma penetrans. AB - The metabolism of arginine towards ATP synthesis has been considered a major source of energy for microorganisms such as Mycoplasma penetrans in anaerobic conditions. Additionally, this pathway has also been implicated in pathogenic and virulence mechanism of certain microorganisms, i.e. protection from acidic stress during infection. In this work we present the crystal structures of the three enzymes composing the gene cluster of the arginine deiminase pathway from M. penetrans: arginine deiminase (ADI), ornithine carbamoyltransferase (OTC) and carbamate kinase (CK). The arginine deiminase (ADI) structure has been refined to 2.3 A resolution in its apo-form, displaying an "open" conformation of the active site of the enzyme in comparison to previous complex structures with substrate intermediates. The active site pocket of ADI is empty, with some of the catalytic and binding residues far from their active positions, suggesting major conformational changes upon substrate binding. Ornithine carbamoyltransferase (OTC) has been refined in two crystal forms at 2.5 A and 2.6 A resolution, respectively, both displaying an identical dodecameric structure with a 23-point symmetry. The dodecameric structure of OTC represents the highest level of organization in this protein family and in M.penetrans it is constituted by a novel interface between the four catalytic homotrimers. Carbamate kinase (CK) has been refined to 2.5 A resolution and its structure is characterized by the presence of two ion sulfates in the active site, one in the carbamoyl phosphate binding site and the other in the beta-phosphate ADP binding pocket of the enzyme. The CK structure also shows variations in some of the elements that regulate the catalytic activity of the enzyme. The relatively low number of metabolic pathways and the relevance in human pathogenesis of Mycoplasma penetrans places the arginine deiminase pathway enzymes as potential targets to design specific inhibitors against this human parasite. PMID- 23082229 TI - Persurf, a new method to improve surfactant delivery: a study in surfactant depleted rats. AB - PURPOSE: Exogenous surfactant is not very effective in adults with ARDS, since surfactant does not reach atelectatic alveoli. Perfluorocarbons (PFC) can recruit atelectatic areas but do not replace impaired endogenous surfactant. A surfactant PFC-mixture could combine benefits of both therapies. The aim of the proof-of principal-study was to produce a PFC-in-surfactant emulsion (Persurf) and to test in surfactant depleted Wistar rats whether Persurf achieves I.) a more homogenous pulmonary distribution and II.) a more homogenous recruitment of alveoli when compared with surfactant or PFC alone. METHODS: Three different PFC were mixed with surfactant and phospholipid concentration in the emulsion was measured. After surfactant depletion, animals either received 30 ml/kg of PF5080, 100 mg/kg of stained (green dye) CurosurfTM or 30 ml/kg of Persurf. Lungs were fixated after 1 hour of ventilation and alveolar aeration and surfactant distribution was estimated by a stereological approach. RESULTS: Persurf contained 3 mg/ml phospholipids and was stable for more than 48 hours. Persurf-administration improved oxygenation. Histological evaluation revealed a more homogenous surfactant distribution and alveolar inflation when compared with surfactant treated animals. CONCLUSIONS: In surfactant depleted rats administration of PFC in-surfactant emulsion leads to a more homogenous distribution and aeration of the lung than surfactant alone. PMID- 23082230 TI - Outcome following nerve repair of high isolated clean sharp injuries of the ulnar nerve. AB - OBJECTIVE: The detailed outcome of surgical repair of high isolated clean sharp (HICS) ulnar nerve lesions has become relevant in view of the recent development of distal nerve transfer. Our goal was to determine the outcome of HICS ulnar nerve repair in order to create a basis for the optimal management of these lesions. METHODS: High ulnar nerve lesions are defined as localized in the area ranging from the proximal forearm to the axilla just distal to the branching of the medial cord of the brachial plexus. A meta-analysis of the literature concerning high ulnar nerve injuries was performed. Additionally, a retrospective study of the outcome of nerve repair of HICS ulnar nerve injuries at our institution was performed. The Rotterdam Intrinsic Hand Myometer and the Rosen Lundborg protocol were used. RESULTS: The literature review identified 46 papers. Many articles presented outcomes of mixed lesion groups consisting of combined ulnar and median nerves, or the outcome of high and low level injuries was pooled. In addition, outcome was expressed using different scoring systems. 40 patients with HICS ulnar nerve lesions were found with sufficient data for further analysis. In our institution, 15 patients had nerve repair with a median interval between trauma and reconstruction of 17 days (range 0-516). The mean score of the motor and sensory domain of the Rosen's Scale instrument was 58% and 38% of the unaffected arm, respectively. Two-point discrimination never reached less then 12 mm. CONCLUSION: From the literature, it was not possible to draw a definitive conclusion on outcome of surgical repair of HICS ulnar nerve lesions. Detailed neurological function assessment of our own patients showed that some ulnar nerve function returned. Intrinsic muscle strength recovery was generally poor. Based on this study, one might cautiously argue that repair strategies of HICS ulnar nerve lesions need to be improved. PMID- 23082231 TI - "Do octopuses have a brain?" Knowledge, perceptions and attitudes towards neuroscience at school. AB - The present study contributes to the question of school literacy about the brain, with an original survey conducted on Italian students from the 3(rd) to 10(th) grades (n=508). The main goal was to test student's knowledge, attitudes, and interests about neuroscience, to assess needs, prospects, and difficulties in teaching about the brain from elementary to high school. A written questionnaire, maintaining anonymity, asked 12 close-ended multiple choice questions on topics related to human and animal brains, plus one facultative open-ended question about interests and curiosities on brain topics. The results show that respondents have a fragmentary level of basic knowledge about the brain, with aspects related to brain functions and consciousness the most challenging. As expected, degrees of performance improve with school level; elementary school students answered correctly an average number of 5.3 questions, middle school 6.5, and high school 7.4. Overall, students show great interest in the brain, as shown by the large number of questions gathered through the open-ended question (n=384). Other topics are addressed, mostly related to brain structure/functions and the role of the brain in the everyday life. The survey indicates the need of more thorough school programs on this subject, reinforced by interdisciplinary teaching where comparative anatomy and evolutionary aspects of brain development are covered. PMID- 23082232 TI - Physical performance limitations in adolescent and adult survivors of childhood cancer and their siblings. AB - PURPOSE: This study investigates physical performance limitations for sports and daily activities in recently diagnosed childhood cancer survivors and siblings. METHODS: The Swiss Childhood Cancer Survivor Study sent a questionnaire to all survivors (>= 16 years) registered in the Swiss Childhood Cancer Registry, who survived >5 years and were diagnosed 1976-2003 aged <16 years. Siblings received similar questionnaires. We assessed two types of physical performance limitations: 1) limitations in sports; 2) limitations in daily activities (using SF-36 physical function score). We compared results between survivors diagnosed before and after 1990 and determined predictors for both types of limitations by multivariable logistic regression. RESULTS: The sample included 1038 survivors and 534 siblings. Overall, 96 survivors (9.5%) and 7 siblings (1.1%) reported a limitation in sports (Odds ratio 5.5, 95%CI 2.9-10.4, p<0.001), mainly caused by musculoskeletal and neurological problems. Findings were even more pronounced for children diagnosed more recently (OR 4.8, CI 2.4-9.6 and 8.3, CI 3.7-18.8 for those diagnosed <1990 and >= 1990, respectively; p=0.025). Mean physical function score for limitations in daily activities was 49.6 (CI 48.9-50.4) in survivors and 53.1 (CI 52.5-53.7) in siblings (p<0.001). Again, differences tended to be larger in children diagnosed more recently. Survivors of bone tumors, CNS tumors and retinoblastoma and children treated with radiotherapy were most strongly affected. CONCLUSION: Survivors of childhood cancer, even those diagnosed recently and treated with modern protocols, remain at high risk for physical performance limitations. Treatment and follow-up care should include tailored interventions to mitigate these late effects in high-risk patients. PMID- 23082233 TI - E2F6 associates with BRG1 in transcriptional regulation. AB - The E2F6 protein functions as an Rb-independent repressor of gene transcription. We have previously provided evidence suggesting a role for E2F6 in repression of E2F-responsive genes at S phase. Here, we have identified BRG1, the ATPase subunit of the SWI/SNF chromatin-remodeling complex, as an E2F6 interacting protein. Immunoprecipitation experiments demonstrate that BRG1 binds specifically to E2F6 and E2F4 but not the activator E2Fs. E2F6 was also able to interact with BAF155, a BRG1-associated factor, in the SWI/SNF complex. Chromatin immunoprecipitation assays demonstrate the binding of BRG1 coincident with E2F6 on G1/S gene promoters during S phase. Collectively, our studies suggest that E2F6 may recruit BRG1 in transcriptional regulation of genes important for G1/S phase transition of the cell cycle. PMID- 23082234 TI - Soil respiration in different agricultural and natural ecosystems in an arid region. AB - The variation of different ecosystems on the terrestrial carbon balance is predicted to be large. We investigated a typical arid region with widespread saline/alkaline soils, and evaluated soil respiration of different agricultural and natural ecosystems. Soil respiration for five ecosystems together with soil temperature, soil moisture, soil pH, soil electric conductivity and soil organic carbon content were investigated in the field. Comparing with the natural ecosystems, the mean seasonal soil respiration rates of the agricultural ecosystems were 96%-386% higher and agricultural ecosystems exhibited lower CO(2) absorption by the saline/alkaline soil. Soil temperature and moisture together explained 48%, 86%, 84%, 54% and 54% of the seasonal variations of soil respiration in the five ecosystems, respectively. There was a significant negative relationship between soil respiration and soil electrical conductivity, but a weak correlation between soil respiration and soil pH or soil organic carbon content. Our results showed that soil CO(2) emissions were significantly different among different agricultural and natural ecosystems, although we caution that this was an observational, not manipulative, study. Temperature at the soil surface and electric conductivity were the main driving factors of soil respiration across the five ecosystems. Care should be taken when converting native vegetation into cropland from the point of view of greenhouse gas emissions. PMID- 23082235 TI - Technology Interventions to Curb Obesity: A Systematic Review of the Current Literature. AB - Obesity is a public health crisis that has reached epidemic proportions. Although intensive behavioral interventions can produce clinically significant weight loss, their cost to implement, coupled with resource limitations, pose significant barriers to scalability. To overcome these challenges, researchers have made attempts to shift intervention content to the Internet and other mobile devices. This article systematically reviews the recent literature examining technology-supported interventions for weight loss and maintenance among overweight and obese adults. Thirteen studies were identified that satisfied our inclusion criteria (12 weight loss trials, 1 weight maintenance trial). Our findings suggest that technology interventions may be efficacious at producing weight loss. However, several studies are limited by methodologic shortcomings. There are insufficient data to evaluate their efficacy for weight maintenance. Further research is needed that employs state-of-the-art methodology, with careful attention being paid to adherence and fidelity to intervention protocols. PMID- 23082236 TI - Event perception. AB - Events are central elements of human experience. Formally, they can be individuated in terms of the entities that compose them, the features of those entities, and the relations amongst entities. Psychologically, representations of events capture their spatiotemporal location, the people and objects involved, and the relations between these elements. Here, we present an account of the nature of psychological representations of events and how they are constructed and updated. Event representations are like images in that they are isomorphic to the situations they represent. However, they are like models or language in that they are constructed of components rather than being holistic. Also, they are partial representations that leave out some elements and abstract others. Representations of individual events are informed by schematic knowledge about general classes of events. Event representations are constructed in a process that segments continuous activity into discrete events. The construction of a series of event representations forms a basis for predicting the future, planning for that future, and imagining alternatives. WIREs Cogni Sci 2011 2 608-620 DOI: 10.1002/wcs.133 This article is categorized under: Psychology > Memory. PMID- 23082237 TI - A comparison of diabetic smokers and non-smokers who undergo lower extremity amputation: a retrospective review of 112 patients. AB - BACKGROUND: A diabetic foot or lower extremity amputation may be exacerbated by or related to the smoking habits and history of the patient. PATIENTS AND METHODS: Of the 112 diabetic patients in this retrospective study, 46 were non smokers and 66 were smokers. The smokers were further categorized into patients who: 1) did not cease smoking; 2) ceased in the immediate post-operative period but resumed within 3 months; and 3) ceased up to and at the 3-month post operative period. The patients were also divided by their amputation level of forefoot, midfoot/rearfoot, and proximal leg. RESULTS: Smoking diabetic patients underwent more amputations, as well as more proximal amputations than those who did not smoke. The higher amount of smoking in pack years followed an increasing trend of more proximal amputations as well. CONCLUSION: Neither the amputation level nor the amputation itself was enough motivation for the patients to participate in smoking cessation. PMID- 23082238 TI - Non-clinicians' judgments about asylum seekers' mental health: how do legal representatives of asylum seekers decide when to request medico-legal reports? AB - BACKGROUND: Procedures for determining refugee status across Europe are being speeded up, despite the high prevalence of mental health difficulties among asylum seekers. An assurance given is that ''vulnerable applicants'' will be identified and excluded from accelerated procedures. Although experts have recommended assessments to be undertaken by experienced clinicians, this is unlikely to happen for political and financial reasons. Understanding how non clinically qualified personnel perform assessments of mental health issues is timely and crucial. Misrecognition of refugees due to the inappropriate use of accelerated procedures involves the risk of returning the very people who have the right to protection from further persecution. OBJECTIVE: To examine the decision making of immigration lawyers, who are an example of a group of nonclinicians who decide when and whether to refer asylum-seekers for psychiatric assessment. METHOD: Semi-structured interviews were conducted with 12 legal representatives working with people seeking refugee or human rights protection in the United Kingdom. The resultant material was analysed using Framework Analysis. RESULTS: Themes clustered around the legal case, the client, the representative and the systems, all with sub-themes. A mapping exercise integrated these themes to show how representatives brought together questions of (1) evidential reasons for a report, influenced by their legal, psychological and case law knowledge, and (2) perceived evidence of mental distress, influenced by professional and personal experiences and expectations. CONCLUSIONS: The legal representatives interviewed were well-informed and trained in psychological issues as well as clearly dedicated to their clients. This helped them to attempt quasi-diagnoses of common mental health problems. They nonetheless demonstrated stereotypical understanding of post-traumatic stress disorder and other possible diagnoses and the role of subjectivity. The study has implications for other groups - particularly those less trained and compassionate - who are required to make clinical judgments without the necessary expertise. PMID- 23082239 TI - TRANSPOSED LETTER EFFECTS IN PREFIXED WORDS: IMPLICATIONS FOR MORPHOLOGICAL DECOMPOSITION. AB - A crucial issue in word encoding is whether morphemes are involved in early stages. One paradigm that tests for this employs the transposed letter (TL) effect - the difference in the times to process a word (misfile) when it is preceded by a TL prime (mifsile) and when it is preceded by a substitute letter (SL) prime (mintile) - and examines whether the TL effect is smaller when the two adjacent letters cross a morpheme boundary. The evidence from prior studies is not consistent. Experiments 1 and 2 employed a parafoveal preview paradigm in which the transposed letters either crossed the prefix-stem boundary or did not, and found a clear TL effect regardless of whether the two letters crossed the morpheme boundary. Experiment 3 replicated this finding employing a masked priming lexical-decision paradigm. It thus appears that morphemes are not involved in early processes in English that are sensitive to letter order. There is some evidence for morphemic modulation of the TL effect in other languages; thus, the properties of the language may modulate when morphemes influence early letter position encoding. PMID- 23082240 TI - MtDNA analysis of global populations support that major population expansions began before Neolithic Time. AB - Agriculture resulted in extensive population growths and human activities. However, whether major human expansions started after Neolithic Time still remained controversial. With the benefit of 1000 Genome Project, we were able to analyze a total of 910 samples from 11 populations in Africa, Europe and Americas. From these random samples, we identified the expansion lineages and reconstructed the historical demographic variations. In all the three continents, we found that most major lineage expansions (11 out of 15 star lineages in Africa, all autochthonous lineages in Europe and America) coalesced before the first appearance of agriculture. Furthermore, major population expansions were estimated after Last Glacial Maximum but before Neolithic Time, also corresponding to the result of major lineage expansions. Considering results in current and previous study, global mtDNA evidence showed that rising temperature after Last Glacial Maximum offered amiable environments and might be the most important factor for prehistorical human expansions. PMID- 23082241 TI - Field electron emission based on resonant tunneling in diamond/CoSi2/Si quantum well nanostructures. AB - Excellent field electron emission properties of a diamond/CoSi(2)/Si quantum well nanostructure are observed. The novel quantum well structure consists of high quality diamond emitters grown on bulk Si substrate with a nanosized epitaxial CoSi(2) conducting interlayer. The results show that the main emission properties were modified by varying the CoSi(2) thickness and that stable, low-field, high emission current and controlled electron emission can be obtained by using a high quality diamond film and a thicker CoSi(2) interlayer. An electron resonant tunneling mechanism in this quantum well structure is suggested, and the tunneling is due to the long electron mean free path in the nanosized CoSi(2) layer. This structure meets most of the requirements for development of vacuum micro/nanoelectronic devices and large-area cold cathodes for flat-panel displays. PMID- 23082242 TI - Quantifying the behavior of stock correlations under market stress. AB - Understanding correlations in complex systems is crucial in the face of turbulence, such as the ongoing financial crisis. However, in complex systems, such as financial systems, correlations are not constant but instead vary in time. Here we address the question of quantifying state-dependent correlations in stock markets. Reliable estimates of correlations are absolutely necessary to protect a portfolio. We analyze 72 years of daily closing prices of the 30 stocks forming the Dow Jones Industrial Average (DJIA). We find the striking result that the average correlation among these stocks scales linearly with market stress reflected by normalized DJIA index returns on various time scales. Consequently, the diversification effect which should protect a portfolio melts away in times of market losses, just when it would most urgently be needed. Our empirical analysis is consistent with the interesting possibility that one could anticipate diversification breakdowns, guiding the design of protected portfolios. PMID- 23082243 TI - Modelling the effects of sanitary policies on European vulture conservation. AB - Biodiversity losses are increasing as a consequence of negative anthropogenic effects on ecosystem dynamics. However, the magnitude and complexity of these effects may still be greatly underestimated. Most Old World vultures have experienced rapid population declines in recent years. In Europe, their immediate conservation depends on changes in health regulations affecting the availability of food provided by domestic carcasses. Information is lacking on the effects of a hypothetical food shortage on the population dynamics of vultures, and is necessary to assess the potential impacts of policy decisions on future changes in biodiversity and ecosystem services. A novel computational model (P-systems) was used to model these effects, forecasting a rapid decline in the Eurasian griffon vulture (Gyps fulvus). By contrast, vulture species with greater plasticity in their dietary range appeared less sensitive to declining food availability. This study extends our understanding of vulture ecosystem services, which have social and economic implications. PMID- 23082244 TI - A stable solution-processed polymer semiconductor with record high-mobility for printed transistors. AB - Microelectronic circuits/arrays produced via high-speed printing instead of traditional photolithographic processes offer an appealing approach to creating the long-sought after, low-cost, large-area flexible electronics. Foremost among critical enablers to propel this paradigm shift in manufacturing is a stable, solution-processable, high-performance semiconductor for printing functionally capable thin-film transistors - fundamental building blocks of microelectronics. We report herein the processing and optimisation of solution-processable polymer semiconductors for thin-film transistors, demonstrating very high field-effect mobility, high on/off ratio, and excellent shelf-life and operating stabilities under ambient conditions. Exceptionally high-gain inverters and functional ring oscillator devices on flexible substrates have been demonstrated. This optimised polymer semiconductor represents a significant progress in semiconductor development, dispelling prevalent skepticism surrounding practical usability of organic semiconductors for high-performance microelectronic devices, opening up application opportunities hitherto functionally or economically inaccessible with silicon technologies, and providing an excellent structural framework for fundamental studies of charge transport in organic systems. PMID- 23082245 TI - Aberrant Activation of Heat Shock Protein 60/65 Reactive T Cells in Patients with Behcet's Disease. AB - Behcet's disease (BD) is a multisystemic inflammatory disease and is characterized by recurrent attacks on eyes, brain, skin, and gut. There is evidence that skewed T-cell responses contributed to its pathophysiology in patients with BD. We found that heat shock proteins (HSPs) reactive T cells were prevalent in patients with BD. Here, we summarize current findings on HSP reactive T cells and their contribution to the pathogenesis in patients with BD. PMID- 23082246 TI - Voice-related quality of life in patients with multiple sclerosis. AB - Objective. To investigate the voice-related quality of life in a group of patients with multiple sclerosis. Participants. A total of 87 subjects (59 MS subjects and 28 controls) participated in this study. Main Outcome Measures. Variables included presence or absence of phonatory symptoms, duration of the disease, the expanded disability status scale (EDSS), the severity of fatigue, and depression. All patients were asked to fill the Voice Handicap Index. Results. The average age was 35.47 years + 10.92 with 39% being males. The average duration of the disease was 77.93 months. The EDSS score was 1.94 + 1.84, the FSS score was 4.07 + 2.09, and the HRSD was 7.28 + 7.70. Only 7 subjects out of the 59 had vocal symptoms compared to 3 in the control group. There was no significant difference in the VHI total score between cases (5.9 + 15.5) and controls (5.4 + 8.2). There was a positive correlation between VHI total score, FSS score, and HRSD (P values of 0.011 and <0.01. Conclusion. The voice-related quality of life in MS is within normal with no disability. PMID- 23082247 TI - A molecular, genetic, and diagnostic spotlight on fanconi anemia. PMID- 23082248 TI - Impact of 6-hour sepsis resuscitation bundle compliance on hospital mortality in a saudi hospital. AB - Purpose. To assess the effect of improved compliance with 6-hour sepsis resuscitation bundle on mortality in patients with severe sepsis and septic shock. Materials and Methods. A quasi-experimental prospective study was conducted at a 10-bedded combined medical and surgical intensive care unit. The historical group included all consecutive patients with severe sepsis and septic shock admitted from January 2008 to March 2009. Intervention included evidence based written sepsis pathway, antibiotic recommendations, and an educational program.The post-intervention group included all consecutive patients admitted from July 2009 to June 2011. The primary outcome measures were the overall compliance to seven 6-hour sepsis resuscitation bundle elements and 30-day hospital mortality. There were 99 patients in the historical group and 199 in the post-intervention group. Results. The baseline patients' characteristics were similar. Overall compliance to all seven sepsis resuscitation bundle elements in historical group was 5.1% [95% confidence interval (CI), 2.1-11.3] which improved after intervention to 23.6% (95% CI, 17.9-30.1); P < 0.001. The overall compliance to 6-hour sepsis resuscitation bundle elements was associated with improved survival [odds ratio (OR), 5.8 (95% CI, 2.2-15.1; P < 0.001)]. 30-day hospital mortality reduced from 31.3% in the historical group to 21.1% in the intervention group; P = 0.05. Conclusion. Improvement in compliance to 6-hour sepsis resuscitation bundle was associated with a reduction in 30-day hospital mortality. PMID- 23082249 TI - The Global Economic Cost of Osteoarthritis: How the UK Compares. AB - Aims. To examine all relevant literature on the economic costs of osteoarthritis in the UK, and to compare such costs globally. Methods. A search of MEDLINE was performed. The search was expanded beyond peer-reviewed journals into publications by the department of health, national orthopaedic associations, national authorities and registries, and arthritis charities. Results. No UK studies were identified in the literature search. 3 European, 6 North American, and 2 Asian studies were reviewed. Significant variation in direct and indirect costs were seen in these studies. Costs for topical and oral NSAIDs were estimated to be L19.2 million and L25.65 million, respectively. Cost of hip and knee replacements was estimated to exceed L850 million, arthroscopic surgery for osteoarthritis was estimated to be L1.34 million. Indirect costs from OA caused a loss of economic production over L3.2 billion, L43 million was spent on community services and L215 million on social services for osteoarthritis. Conclusions. While estimates of economic costs can be made using information from non published data, there remains a lack of original research looking at the direct or indirect costs of osteoarthritis in the UK. Differing methodology in calculating costs from overseas studies makes direct comparison with the UK difficult. PMID- 23082250 TI - Origin and regenerative potential of vertebrate mechanoreceptor-associated stem cells. AB - Meissner corpuscles and Merkel cell neurite complexes are highly specialized mechanoreceptors present in the hairy and glabrous skin, as well as in different types of mucosa. Several reports suggest that after injury, such as after nerve crush, freeze injury, or dissection of the nerve, they are able to regenerate, particularly including reinnervation and repopulation of the mechanoreceptors by Schwann cells. However, little is known about mammalian cells responsible for these regenerative processes. Here we review cellular origin of this plasticity in the light of newly described adult neural crest-derived stem cell populations. We also discuss further potential multipotent stem cell populations with the ability to regenerate disrupted innervation and to functionally recover the mechanoreceptors. These capabilities are discussed as in context to cellularly reprogrammed Schwann cells and tissue resident adult mesenchymal stem cells. PMID- 23082251 TI - Inhibition of Mammalian target of rapamycin in human acute myeloid leukemia cells has diverse effects that depend on the environmental in vitro stress. AB - Effects of the mTOR inhibitor rapamycin were characterized on in vitro cultured primary human acute myeloid leukemia (AML) cells and five AML cell lines. Constitutive mTOR activation seemed to be a general characteristic of primary AML cells. Increased cellular stress induced by serum deprivation increased both mTOR signaling, lysosomal acidity, and in vitro apoptosis, where lysosomal acidity/apoptosis were independent of increased mTOR signaling. Rapamycin had antiproliferative and proapoptotic effects only for a subset of patients. Proapoptotic effect was detected for AML cell lines only in the presence of serum. Combination of rapamycin with valproic acid, all-trans retinoic acid (ATRA), and NF-kappaB inhibitors showed no interference with constitutive mTOR activation and mTOR inhibitory effect of rapamycin and no additional proapoptotic effect compared to rapamycin alone. In contrast, dual inhibition of the PI3K-Akt mTOR pathway by rapamycin plus a PI3K inhibitor induced new functional effects that did not simply reflect a summary of single drug effects. To conclude, (i) pharmacological characterization of PI3K-Akt-mTOR inhibitors requires carefully standardized experimental models, (ii) rapamycin effects differ between patients, and (iii) combined targeting of different steps in this pathway should be further investigated whereas combination of rapamycin with valproic acid, ATRA, or NF kappaB inhibitors seems less promising. PMID- 23082252 TI - Role of HLA in Hematopoietic Stem Cell Transplantation. AB - The selection of hematopoietic stem cell transplantation (HSCT) donors includes a rigorous assessment of the availability and human leukocyte antigen (HLA) match status of donors. HLA plays a critical role in HSCT, but its involvement in HSCT is constantly in flux because of changing technologies and variations in clinical transplantation results. The increased availability of HSCT through the use of HLA-mismatched related and unrelated donors is feasible with a more complete understanding of permissible HLA mismatches and the role of killer-cell immunoglobulin-like receptor (KIR) genes in HSCT. The influence of nongenetic factors on the tolerability of HLA mismatching has recently become evident, demonstrating a need for the integration of both genetic and nongenetic variables in donor selection. PMID- 23082253 TI - Parents' source of vaccine information and impact on vaccine attitudes, beliefs, and nonmedical exemptions. AB - In recent years, use of the Internet to obtain vaccine information has increased. Historical data are necessary to evaluate current vaccine information seeking trends in context. Between 2002 and 2003, surveys were mailed to 1,630 parents of fully vaccinated children and 815 parents of children with at least one vaccine exemption; 56.1% responded. Respondents were asked about their vaccine information sources, perceptions of these sources accuracy, and their beliefs about vaccination. Parents who did not view their child's healthcare provider as a reliable vaccine information source were more likely to obtain vaccine information using the Internet. Parents who were younger, more highly educated, and opposed to school immunization requirements were more likely than their counterparts to use the Internet for vaccine information. Compared to parents who did not use the Internet for vaccine information, those who sought vaccine information on the Internet were more likely to have lower perceptions of vaccine safety (adjusted odds ratio (aOR), 1.66; 95% CI, 1.18-2.35), vaccine effectiveness (aOR, 1.83; 95% CI, 1.32-2.53), and disease susceptibility (aOR, 2.08; 95% CI, 1.49-2.90) and were more likely to have a child with a nonmedical exemption (aOR 3.53, 95% CI, 2.61-4.76). These findings provide context to interpret recent vaccine information seeking research. PMID- 23082254 TI - Fetal hydantoin syndrome and its anaesthetic implications: a case report. AB - Fetal hydantoin syndrome is a rare disorder that is believed to be caused by exposure of a fetus to the anticonvulsant drug phenytoin. The classic features of fetal hydantoin syndrome include craniofacial anomalies, prenatal and postnatal growth deficiencies, underdeveloped nails of the fingers and toes, and mental retardation. Less frequently observed anomalies include cleft lip and palate, microcephaly, ocular defects, cardiovascular anomalies, hypospadias, umbilical and inguinal hernias, and significant developmental delays. Anaesthesia for incidental surgery in such a patient poses unique challenges for the anesthesiologist. We report the successful management of a 4-year-old male child with fetal hydantoin syndrome, cleft palate, spina bifida, atrial septal defect, and dextrocardia for tibialis anterior lengthening under subarachnoid block. PMID- 23082255 TI - Gorlin-goltz syndrome. AB - The Gorlin-Goltz syndrome (GGS) (the nevoid basal cell carcinoma syndrome-NBCCS) is a rare autosomal dominant syndrome caused due to mutations in the PTCH (patched) gene found on chromosome arm 9q. The syndrome, characterized by increased predisposition to develop basal cell carcinoma and associated multiorgan anomalies, has a high level of penetrance and variable expressiveness. GGS is a multidisciplinary problem, early diagnosis of which allows introduction of secondary prophylaxis and following an appropriate treatment to delay the progress of the syndrome. The following report emphasizes the need for awareness of the diagnostic criteria of this syndrome in cases with no typical skin lesions. PMID- 23082256 TI - Gingival recession: review and strategies in treatment of recession. AB - One of the most common esthetic concerns associated with the periodontal tissues is gingival recession. Gingival recession is the exposure of root surfaces due to apical migration of the gingival tissue margins; gingival margin migrates apical to the cementoenamel junction. Although it rarely results in tooth loss, marginal tissue recession is associated with thermal and tactile sensitivity, esthetic complaints, and a tendency toward root caries. This paper reviews etiology, consequences, and the available surgical procedures for the coverage of exposed root surfaces, including three case reports. PMID- 23082257 TI - An Unusual Mishap during Root Canal Access in Retreatment Case. AB - Varieties of objects have been introduced into the root canal system accidentally or intentionally; removal of these objects necessitates the success of the treatment. This paper explains an unusual bur fracture during nonsurgical endodontic treatment and its removal by ultrasonic energy with ease and without the removal of extra large amount of root dentin. PMID- 23082258 TI - Allogeneic Hematopoietic Stem Cell Transplantation for a BCR-FGFR1 Myeloproliferative Neoplasm Presenting as Acute Lymphoblastic Leukemia. AB - Hematopoietic myeloproliferative neoplasms (MPNS) with rearrangements of the receptor tyrosine kinase FGFR1 gene, located on chromosome 8p11, are uncommon and associated with diverse presentations such as atypical chronic myeloid leukemia, acute myeloid leukemia, or an acute T- or B-lymphoblastic leukemia, reflecting the hematopoietic stem cell origin of the disease. A review of MPN patients with the t(8;22) translocation that results in a chimeric BCR-FGFR1 fusion gene reveals that this disease either presents or rapidly transforms into an acute leukemia that is generally unresponsive to currently available chemotherapeutic regimens including tyrosine kinase inhibitors (TKIS). The first case of a rare BCR-FGFR1 MPN presenting in a B-acute lymphoblastic phase who underwent allogeneic hematopoietic stem cell transplantation (HSCT) with a subsequent sustained complete molecular remission is described. Allogeneic HSCT is currently the only available therapy capable of achieving long-term remission in BCR-FGFR1 MPN patients. PMID- 23082259 TI - Placenta percreta at 17 weeks with consecutive hysterectomy: a case report and review of the literature. AB - Placenta percreta in early pregnancy is an extremely rare but life-threatening complication, for which very few cases have been reported in the literature worldwide, none from the United States. We report a patient with two previous cesarean deliveries, who presented with incomplete abortion at 17 weeks and underwent dilatation and curettage. She was found to have retained, adherent placenta that led to extensive hemorrhage, requiring emergency supracervical hysterectomy. Postoperative course was also complicated by severe consumption coagulopathy, necessitating reexploration after hysterectomy. Pathology revealed a placenta percreta. Patient lost more than 8000 cc blood through the 2 surgeries, received massive transfusions due to severe disseminated intravascular coagulopathy (DIC), and underwent a complicated surgery because of great difficulty in separating lower uterine segment and cervix from the bladder. Abnormal placentation in early pregnancy has increased in prevalence due to marked rise in cesarean deliveries and curettages in recent decades. We reviewed all reported cases of first and second trimester placenta percreta in the literature, to emphasize the early recognition of abnormal placentations in patients with risk factors, consider prenatal evaluation in such patients, anticipate complicated placental implantations during termination procedures, and prevent associated maternal morbidity and mortality. PMID- 23082260 TI - Benign mucinous tumor of ovary with a sarcoma-like mural nodule: a case report. AB - Sarcoma-like mural nodules occur predominantly in middle-aged women. Distinction of these lesions from true sarcomatous nodules and foci of anaplastic carcinoma is important because of the worse prognosis of these tumors in comparison with the favorable behavior of sarcoma-like mural nodules. In this report we describe the case of a 35-year-old woman with a mucinous ovarian tumor having a mural nodule in the wall. PMID- 23082262 TI - A patient with corneal epithelial disorder that developed after administration of a latanoprost generic, but not a brand-name drug, eye drop. AB - Background. We report a patient who developed corneal epithelial disorder repeatedly after changing the prescription from Xalatan eye drops (Pfizer Inc.) to Latanoprost eye drops (Kaken Pharmaceutical Co., Ltd.), both containing 0.005% latanoprost. Case Report. An 88-year-old male with glaucoma had been treated with Timoptol eye drops and Xalatan eye drops for a few years. While he stayed in a health care facility for the elderly, Xalatan eye drops was changed to Latanoprost eye drops usage, and eye pain developed on the day of this change. On the next day, he visited our department, and corneal epithelial disorder was observed. The drops were discontinued, and the corneal epithelial disorder healed after 2 days. Twenty days after the first consultation, Xalatan eye drops and Latanoprost eye drops were resumed by a physician of internal medicine in the health care facility, but eye pain developed again. After discontinuation of the two drugs, Xalatan eye drops usage was resumed the next day, but no corneal epithelial disorder was observed thereafter. Conclusions. This clinical history strongly suggested the association between a generic drug, Latanoprost eye drops, and the development of corneal epithelial disorder. PMID- 23082261 TI - Recurrent thrombotic thrombocytopenic purpura-like syndrome as a paraneoplastic phenomenon in malignant peritoneal mesothelioma: a case report and review of the literature. AB - We report the case of an African American male with no significant past medical history presenting with recurrent, rapidly relapsing episodes of thrombotic thrombocytopenic purpura (TTP) despite aggressive treatment with several lines of treatment. Incidentally, these episodes were associated with severe abdominal pain which eventually developed into acute abdomen and prompted exploratory laparotomy, revealing diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology made a final diagnosis of peritoneal mesothelioma. TTP-like syndrome (TTP-LS) has been described as a paraneoplastic phenomenon in several malignancies but never before in the setting of malignant mesothelioma. Paraneoplastic TTP-like syndrome has historically been associated with a dismal prognosis and particular clinical and laboratory abnormalities described in this paper. It is of utmost importance to make a prompt determination whether TTP is idiopathic or secondary to an underlying condition because of significant differences in their prognosis, treatment, and response. This paper also reviews the current literature regarding this challenging condition. PMID- 23082263 TI - Extramedullary plasmacytoma of the larynx: a case report of subglottic localization. AB - Extramedullary plasmacytoma (EMP) is a rare neoplasm of plasma cells, described in soft tissue outside the bone marrow. EMP of the larynx represents 0.04 to 0.45% of malignant tumors of the larynx. A male of 57 years old presented with hoarseness, dyspnea, and biphasic stridor of 2 months. The indirect laryngoscopy (IL) revealed severe edema of the posterior commissure and a polypoid mass in the right posterior lateral subglottic wall. A biopsy of the subglottic mass was performed by a direct laryngoscopy (DL). The histopathologic diagnosis was EMP CD138+, therefore radiotherapy was given at 54 Gy in 30 sessions. The patient had an adequate postoperative clinical course and a new biopsy was performed having tumor-free margins. All laryngeal lesions should be biopsied prior to treatment to determine an accurate diagnosis to guide a proper management of the condition. Radiation therapy to the EMP is considered the treatment of choice, having local control rates of 80% to 100%. The subglottis is the least accessible area of view and the least frequent location of a laryngeal mass, nevertheless the otolaryngologist should always do a complete and systematic exam of the larynx when a tumor is suspected, to detect diagnoses such as a subglottic plasmacytoma. PMID- 23082264 TI - Malignant transformation in a mature teratoma with metastatic deposits in the omentum: a case report. AB - Malignant transformation of a mature cystic teratoma (MCT) is a very rare complication with an incidence of 0.17-2%;. The most common form of malignant transformation of the MCT is squamous cell carcinoma. Other tumors arising in MCT include basal cell carcinoma, sebaceous tumor, malignant melanoma, adenocarcinoma, sarcoma, and neuroectodermal tumor. However malignant transformation with metastatic deposits in the omentum is extremely rare. The present case highlights the rarity of the occurrence of an omental deposits in a case of mature cystic teratoma with malignant transformation. PMID- 23082265 TI - Combined cutaneous sarcoma: pleomorphic liposarcoma and conventional osteosarcoma the so-called malignant mesenchymoma. AB - Malignant mesenchymoma is combined soft tissue tumors of mesenchymal origin. Cutaneous combined sarcomas are exceedingly rare. We report the case of an 81 year-old woman who presented a left cutaneous mass. She underwent a wide local excision. Histopathological and immunohistochemical studies were consistent with the diagnosis of combined pleomorphic liposarcoma and conventional osteosarcoma (malignant mesenchymoma). Although it is extremely rare, this case suggests that combined sarcoma should be considered in the differential diagnosis of undifferentiated pleomorphic neoplasms. PMID- 23082266 TI - Successful treatment of acute lymphoblastic leukemia in a child with trisomy 21 and complex congenital heart disease with mechanical prosthetic valve. AB - A 10-year-old girl with trisomy 21 and complex congenital heart disease presented with acute lymphoblastic leukemia. Her chemotherapy required modifications due to poor baseline cardiac status and a mechanical prosthetic heart valve that was dependent on anticoagulation. We describe our management including the use of low molecular-weight heparin as anticoagulation for a mechanical heart valve, the safe delivery of intrathecal chemotherapy included bridging with unfractionated heparin, and the use of fluoroscopic guidance to minimize the risk of bleeding. Adjustments were made to avoid anthracyclines. The child tolerated therapy well without complications and remains relapse free five years after diagnosis. PMID- 23082267 TI - Anaplastic large-cell lymphoma in a child with type I diabetes and unrecognised coeliac disease. AB - Screening for coeliac disease is recommended for children from certain risk groups, with implications for diagnostic procedures and dietetic management. The risk of a malignant complication in untreated coeliac disease is not considered high in children. We present the case of a girl with type I diabetes who developed weight loss, fatigue, and inguinal lymphadenopathy. Four years before, when she was asymptomatic, a screening coeliac tTG test was positive, but gluten was not eliminated from her diet. Based on clinical examination, a duodenal biopsy, and an inguinal lymph node biopsy were performed, which confirmed both coeliac disease and an anaplastic large-cell lymphoma. HLA-typing demonstrated that she was homozygous for HLA-DQ8, which is associated with higher risk for celiac disease, more severe gluten sensitivity, and diabetes susceptibility. She responded well to chemotherapy and has been in remission for over 4 years. She remains on a gluten-free diet. This is the first case reporting the association of coeliac disease, type I diabetes, and anaplastic large-cell lymphoma in childhood. The case highlights the malignancy risk in a genetically predisposed individual, and the possible role of a perpetuated immunologic response by prolonged gluten exposure. PMID- 23082268 TI - Multimodal imaging in the prenatal diagnosis of tuberous sclerosis complex. AB - Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in which benign hamartomas develop in multiple organ systems. Increasingly, stigmata of the disease, such as cardiac rhabdomyomas, are detected on routine prenatal ultrasound. Such a finding should prompt additional imaging studies in order to confirm diagnosis and to identify potential complications, which vary greatly from patient to patient. Early diagnosis allows for accurate parental counseling, coordination of high-level perinatal care, and subspecialty followup. We present a case of TSC in utero wherein access to and use of multiple imaging modalities confirmed diagnosis and allowed the patient to receive optimal care prior to birth. PMID- 23082269 TI - Cognitive adaptation training provided to chronically hospitalized patients with schizophrenia in the Netherlands: two case reports. AB - Cognitive adaptation training (CAT) improves functional outcome in outpatients with schizophrenia living in the United States of America. The efficacy of CAT has never been demonstrated for patients living in a residential facility. We describe how CAT was delivered to two chronically hospitalized patients with schizophrenia living in The Netherlands. CAT was delivered for 8 months, and consisted of weekly home visits by a psychiatric nurse. Both patients improved on measures of functional outcome used in the US studies. These results indicate that CAT may improve outcomes, even in patients that have been hospitalized for several years. PMID- 23082270 TI - Frontotemporal dementia, manifested as schizophrenia, with decreased heterochromatin on chromosome 1. AB - Introduction. Frontotemporal dementia is a disorder of complex etiology, with genetic components contributing to the disease. The aim of this report is to describe a young patient suffering from frontotemporal dementia, misdiagnosed as schizophrenia, related to a genetic defect on chromosome 1. Case Presentation. A 29-year-old female patient, previously diagnosed as having schizophrenia, was hospitalized with severe behavioural disturbances. She demonstrated severe sexual disinhibition, hyperphagia, lack of motivation, apathy, psychotic symptoms, suicidal thoughts, and cognitive deterioration. Focal atrophy of frontal and anterior temporal structures bilaterally was found on brain MRI, as well as bifrontal hypo perfusion of the brain on SPECT scan. The diagnosis of frontotemporal dementia was made clinically, according to Lund and Manchester groups and Neary diagnostic criteria. Chromosomal analysis was conducted and revealed decrease in length of heterochromatin on the long arm of chromosome 1 (46, XX, 1qh-). Parental karyotypes were normal. Discussion. Frontotemporal dementia, and particularly early-onset cases, can be often misdiagnosed as schizophrenia, with negative impact on case management. Genetic testing could be an aid to the correct diagnosis, which is crucial for optimal patient care. PMID- 23082271 TI - Reversible Pulmonary Hypertension Associated with Whipple's Disease. AB - We describe a case of Whipple's disease with pulmonary hypertension in a 72-year old woman in whom the pulmonary hypertension resolved completely after antibiotic therapy. She was admitted to study with a 2-months history of weight loss, diarrhoea, abdominal pain, asthenia, inappetence, and fever. She did not have dyspnoea or respiratory symptoms. A casual echocardiogram showed a pulmonary artery systolic pressure of 95 mmHg. Forty days after starting antibiotic therapy, an echocardiogram showed a complete normalisation of right ventricular involvement. Whipple's disease is a rare and multisystemic disorder in which pulmonary involvement is not a well-known finding. Although Whipple's disease is not generally considered as a possible cause of pulmonary hypertension, such awareness is important because it may be potentially resolved with antibiotic therapy. PMID- 23082272 TI - Successful treatment of long-term severe progressive interstitial pneumonia with low-dose corticosteroid and azathioprine in a patient with diffuse systemic sclerosis. AB - For progressive interstitial pneumonia (progressive IP) that accompanies diffuse systemic sclerosis (diffuse SSc), no treatment guidelines have yet been established, and it is a complication with a poor prognosis. We herein report a case in which combination therapy of a low-dose corticosteroid and low-dose azathioprine was performed for progressive SSc-IP in a 64-year-old female whose respiratory function was severely damaged for a long period of time and for whom improvement was achieved. The beneficial effect has continued for 3 years with no side effects being observed during the course. PMID- 23082273 TI - The "reverse" latissimus dorsi flap for large lower lumbar defect. AB - The latissimus dorsi (LD) flap is one of the most common flaps used in plastic surgery based on its dominant thoracodorsal pedicle as well as free tissue transfer. The "distally based" or "reverse" fashion design has been used to repair myelomeningoceles, congenital diaphragmatic agenesis, or thoracolumbar defects. We present a case of a large lumbar defect after cancer resection covered by a combined tegument solution starring the "reverse" LD flap in its muscular version with a cutaneous gluteal flap. This flap is a safe and reliable way to cover large distal lumbar defect. PMID- 23082274 TI - Renal Parenchyma Perforation and Hematoma Formation following Double-J Stent Insertion in a Solitary Functioning Kidney: An Unusual Complication. AB - Double-J ureteral stent insertion is a common urological procedure performed for the relief of ureteral obstruction or as a part of other endourological procedures. Several complications have been reported in the past. A case of a 62 year-old woman who was stented due to hydronephrosis of her solitary functioning left kidney and had renal perforation and retroperitoneal hematoma formation is presented. She was managed conservatively with blood transfusion and double-J stent repositioning in the collecting system the fifth postoperative day. Follow up noncontrast computed tomography (CT) of the abdomen was performed the first and third months after stent placement which showed stabilization of the hematoma. PMID- 23082275 TI - Inhibition of Akt Attenuates RPO-Induced Cardioprotection. AB - Previous studies have shown that red palm oil (RPO) supplementation protected rat hearts against ischaemia-reperfusion injury. Evidence from these studies suggested that Akt may be partly responsible for the observed protection. The aim of the current study was therefore to prove or refute the involvement of Akt in the RPO-induced cardioprotection by administration of a specific Akt inhibitor (A6730). Male Wistar rats were randomly divided into 2 groups: a control group receiving standard rat chow and an experimental group receiving standard rat chow plus 2 mL RPO for six weeks. Hearts were excised and mounted on the Langendorff perfusion system. Functional recovery was documented. A different set of hearts were freeze-clamped to assess total and phosphorylation status of Akt. Another set of hearts were subjected to the same perfusion conditions with addition of A6730. Hearts from this protocol were freeze-clamped and assessed for total and phospho-Akt. RPO improved functional recovery which was associated with increased phosphorylation of Akt on Ser473 and Thr308 residues. Blockade of Akt phosphorylation caused poor functional recovery. For the first time, these results prove that Akt plays an important role in the RPO-induced cardioprotection. PMID- 23082276 TI - Long-Term Costs of Ischemic Stroke and Major Bleeding Events among Medicare Patients with Nonvalvular Atrial Fibrillation. AB - Purpose. Acute healthcare utilization of stroke and bleeding has been previously examined among patients with nonvalvular atrial fibrillation (NVAF). The long term cost of such outcomes over several years is not well understood. Methods. Using 1999-2009 Medicare medical and enrollment data, we identified incident NVAF patients without history of stroke or bleeding. Patients were followed from the first occurrence of ischemic stroke, major bleeding, or intracranial hemorrhage (ICH) resulting in hospitalization. Those with events were matched with 1-5 NVAF patients without events. Total incremental costs of events were calculated as the difference between costs for patients with events and matched controls for up to 3 years. Results. Among the 25,465 patients who experienced events, 94.5% were successfully matched. In the first year after event, average incremental costs were $32,900 for ischemic stroke, $23,414 for major bleeding, and $47,640 for ICH. At 3 years after these events, costs remained elevated by $3,156-$5,400 per annum. Conclusion. While the costs of stroke and bleeding among patients with NVAF are most dramatic in the first year, utilization remained elevated at 3 years. Cost consequences extend beyond the initial year after these events and should be accounted for when assessing the cost-effectiveness of treatment regimens for stroke prevention. PMID- 23082277 TI - Automatic and robust calibration of optical detector arrays for biomedical diffuse optical spectroscopy. AB - The design and testing of a new, fully automated, calibration approach is described. The process was used to calibrate an image-guided diffuse optical spectroscopy system with 16 photomultiplier tubes (PMTs), but can be extended to any large array of optical detectors and associated imaging geometry. The design goals were accomplished by developing a routine for robust automated calibration of the multi-detector array within 45 minutes. Our process was able to characterize individual detectors to a median norm of the residuals of 0.03 V for amplitude and 4.4 degrees in phase and achieved less than 5% variation between all the detectors at the 95% confidence interval for equivalent measurements. Repeatability of the calibrated data from the imaging system was found to be within 0.05 V for amplitude and 0.2 degrees for phase, and was used to evaluate tissue-simulating phantoms in two separate imaging geometries. Spectroscopic imaging of total hemoglobin concentration was recovered to within 5% of the true value in both cases. Future work will focus on streamlining the technology for use in a clinical setting with expectations of achieving accurate quantification of suspicious lesions in the breast. PMID- 23082278 TI - Extended depth of focus adaptive optics spectral domain optical coherence tomography. AB - We present an adaptive optics spectral domain optical coherence tomography (AO SDOCT) with a long focal range by active phase modulation of the pupil. A long focal range is achieved by introducing AO-controlled third-order spherical aberration (SA). The property of SA and its effects on focal range are investigated in detail using the Huygens-Fresnel principle, beam profile measurement and OCT imaging of a phantom. The results indicate that the focal range is extended by applying SA, and the direction of extension can be controlled by the sign of applied SA. Finally, we demonstrated in vivo human retinal imaging by altering the applied SA. PMID- 23082279 TI - Separation of absorption and scattering properties of turbid media using relative spectrally resolved cw radiance measurements. AB - We present a new method for extracting the effective attenuation coefficient and the diffusion coefficient from relative spectrally resolved cw radiance measurements using the diffusion approximation. The method is validated on both simulated and experimental radiance data sets using Intralipid-1% as a test platform. The effective attenuation coefficient is determined from a simple algebraic expression constructed from a ratio of two radiance measurements at two different source-detector separations and the same 90 degrees angle. The diffusion coefficient is determined from another ratio constructed from two radiance measurements at two angles (0 degrees and 180 degrees ) and the same source-detector separation. The conditions of the validity of the method as well as possible practical applications are discussed. PMID- 23082280 TI - Cerenkov radiation emission and excited luminescence (CREL) sensitivity during external beam radiation therapy: Monte Carlo and tissue oxygenation phantom studies. AB - Radiotherapy generates Cerenkov radiation emission in tissue, and spectral absorption features appearing in the emission spectrum can be used to quantify blood oxygen saturation (S(t)O(2)) from the known absorptions of hemoglobin. Additionally, the Cerenkov light can be used to excite oxygen-sensitive phosphorescence of probe PtG4, whose emission lifetime directly reports on tissue oxygen partial pressure (pO(2)). Thus, it is feasible to probe both hemoglobin S(t)O(2) and pO(2) using external radiation therapy beam to create as an internal light source in tumor tissue. In this study, the sensitivity and spatial origins of these two signals were examined. Emission was detected using a fiber-optic coupled intensifier-gated CCD camera interfaced to a spectrometer. The phosphorescence lifetimes were quantified and compared with S(t)O(2) changes previously measured. Monte Carlo simulations of the linear accelerator beam were used together with tracking of the optical signals, to predict the spatial distribution and zone sensitivity within the phantom. As the fiber-to-beam distance (FBD) varied from 0 to 30 mm, i.e. the distance from the fiber tip to the nearest side of the radiotherapy beam, the effective sampling depth for CR emission changed from 4 to 29 mm for the wavelengths in the range of 600-1000 nm. For the secondary emission (phosphorescence) the effective sampling depth was determined to be in the range of 9 to 19 mm. These results indicate that sampling of S(t)O(2) and pO(2) in tissue should be feasible during radiation therapy, and that the radiation beam and fiber sampling geometry can be set up to acquire signals that originate as deep as a few centimeters in the tissue. PMID- 23082281 TI - Retrieving the optical parameters of biological tissues using diffuse reflectance spectroscopy and Fourier series expansions. I. theory and application. AB - The determination of optical parameters of biological tissues is essential for the application of optical techniques in the diagnosis and treatment of diseases. Diffuse Reflection Spectroscopy is a widely used technique to analyze the optical characteristics of biological tissues. In this paper we show that by using diffuse reflectance spectra and a new mathematical model we can retrieve the optical parameters by applying an adjustment of the data with nonlinear least squares. In our model we represent the spectra using a Fourier series expansion finding mathematical relations between the polynomial coefficients and the optical parameters. In this first paper we use spectra generated by the Monte Carlo Multilayered Technique to simulate the propagation of photons in turbid media. Using these spectra we determine the behavior of Fourier series coefficients when varying the optical parameters of the medium under study. With this procedure we find mathematical relations between Fourier series coefficients and optical parameters. Finally, the results show that our method can retrieve the optical parameters of biological tissues with accuracy that is adequate for medical applications. PMID- 23082282 TI - Hydrogenated amorphous silicon nitride photonic crystals for improved-performance surface electromagnetic wave biosensors. AB - We exploit the properties of surface electromagnetic waves propagating at the surface of finite one dimensional photonic crystals to improve the performance of optical biosensors with respect to the standard surface plasmon resonance approach. We demonstrate that the hydrogenated amorphous silicon nitride technology is a versatile platform for fabricating one dimensional photonic crystals with any desirable design and operating in a wide wavelength range, from the visible to the near infrared. We prepared sensors based on photonic crystals sustaining either guided modes or surface electromagnetic waves, also known as Bloch surface waves. We carried out for the first time a direct experimental comparison of their sensitivity and figure of merit with surface plasmon polaritons on metal layers, by making use of a commercial surface plasmon resonance instrument that was slightly adapted for the experiments. Our measurements demonstrate that the Bloch surface waves on silicon nitride photonic crystals outperform surface plasmon polaritons by a factor 1.3 in terms of figure of merit. PMID- 23082283 TI - Effects of tissue heterogeneity on the optical estimate of breast density. AB - Breast density is a recognized strong and independent risk factor for developing breast cancer. At present, breast density is assessed based on the radiological appearance of breast tissue, thus relying on the use of ionizing radiation. We have previously obtained encouraging preliminary results with our portable instrument for time domain optical mammography performed at 7 wavelengths (635 1060 nm). In that case, information was averaged over four images (cranio-caudal and oblique views of both breasts) available for each subject. In the present work, we tested the effectiveness of just one or few point measurements, to investigate if tissue heterogeneity significantly affects the correlation between optically derived parameters and mammographic density. Data show that parameters estimated through a single optical measurement correlate strongly with mammographic density estimated by using BIRADS categories. A central position is optimal for the measurement, but its exact location is not critical. PMID- 23082284 TI - Optical stretching of giant unilamellar vesicles with an integrated dual-beam optical trap. AB - We have integrated a dual-beam optical trap into a microfluidic platform and used it to study membrane mechanics in giant unilamellar vesicles (GUVs). We demonstrate the trapping and stretching of GUVs and characterize the membrane response to a step stress. We then measure area strain as a function of applied stress to extract the bending modulus of the lipid bilayer in the low-tension regime. PMID- 23082285 TI - Real-time video mosaicing with a high-resolution microendoscope. AB - Microendoscopes allow clinicians to view subcellular features in vivo and in real time, but their field-of-view is inherently limited by the small size of the probe's distal end. Video mosaicing has emerged as an effective technique to increase the acquired image size. Current implementations are performed post procedure, which removes the benefits of live imaging. In this manuscript we present an algorithm for real-time video mosaicing using a low-cost high resolution microendoscope. We present algorithm execution times and show image results obtained from in vivo tissue. PMID- 23082286 TI - Resonant waveguide sensing made robust by on-chip peak tracking through image correlation. AB - We demonstrate a solution to make resonant-waveguide-grating sensing both robust and simpler to optically assess, in the spirit of biochips. Instead of varying wavelength or angle to track the resonant condition, the grating itself has a step-wise variation with typically few tens of neighboring "micropads." An image capture with incoherent monochromatic light delivers spatial intensity sequences from these micropads. Sensitivity and robustness are discussed using correlation techniques on a realistic model (Fano shapes with noise and local distortion contributions). We confirm through fluid refractive index sensing experiments an improvement over the step-wise maximum position tracking by more than 2 orders of magnitude, demonstrating sensitivity down to 2 * 10(-5) RIU, giving high potential development for bioarray imaging. PMID- 23082287 TI - Use of a coherent fiber bundle for multi-diameter single fiber reflectance spectroscopy. AB - Multi-diameter single fiber reflectance (MDSFR) spectroscopy enables quantitative measurement of tissue optical properties, including the reduced scattering coefficient and the phase function parameter gamma. However, the accuracy and speed of the procedure are currently limited by the need for co-localized measurements using multiple fiber optic probes with different fiber diameters. This study demonstrates the use of a coherent fiber bundle acting as a single fiber with a variable diameter for the purposes of MDSFR spectroscopy. Using Intralipid optical phantoms with reduced scattering coefficients between 0.24 and 3 mm(-1), we find that the spectral reflectance and effective path lengths measured by the fiber bundle (NA = 0.40) are equivalent to those measured by single solid-core fibers (NA = 0.22) for fiber diameters between 0.4 and 1.0 mm (r >= 0.997). This one-to-one correlation may hold for a 0.2 mm fiber diameter as well (r = 0.816); however, the experimental system used in this study suffers from a low signal-to-noise for small dimensionless reduced scattering coefficients due to spurious back reflections within the experimental system. Based on these results, the coherent fiber bundle is suitable for use as a variable-diameter fiber in clinical MDSFR quantification of tissue optical properties. PMID- 23082288 TI - Optical stirring in a droplet cell bioreactor. AB - In the context of a bioreactor, cells are sensitive to cues from other cells and mechanical stimuli from movement. The ability to provide the latter in a discrete fluidic system presents a significant challenge. From a prior finding that the location of the focus of a laser below particles relative to the beam axis producing a pushing effect in a predominant lateral sense, we advance an approach here that generates a gentle and tunable stirring effect. Computer simulation studies show that we are able to characterize this effect from the parameters that govern the optical forces and the movement of the particles. Experimental results with polystyrene microbeads and red blood cells confirm the notions from the simulations. PMID- 23082289 TI - In vivo human crystalline lens topography. AB - Custom high-resolution high-speed anterior segment spectral domain optical coherence tomography (OCT) was used to characterize three-dimensionally (3-D) the human crystalline lens in vivo. The system was provided with custom algorithms for denoising and segmentation of the images, as well as for fan (scanning) and optical (refraction) distortion correction, to provide fully quantitative images of the anterior and posterior crystalline lens surfaces. The method was tested on an artificial eye with known surfaces geometry and on a human lens in vitro, and demonstrated on three human lenses in vivo. Not correcting for distortion overestimated the anterior lens radius by 25% and the posterior lens radius by more than 65%. In vivo lens surfaces were fitted by biconicoids and Zernike polynomials after distortion correction. The anterior lens radii of curvature ranged from 10.27 to 14.14 mm, and the posterior lens radii of curvature ranged from 6.12 to 7.54 mm. Surface asphericities ranged from -0.04 to -1.96. The lens surfaces were well fitted by quadrics (with variation smaller than 2%, for 5-mm pupils), with low amounts of high order terms. Surface lens astigmatism was significant, with the anterior lens typically showing horizontal astigmatism ([Formula: see text] ranging from -11 to -1 um) and the posterior lens showing vertical astigmatism ([Formula: see text] ranging from 6 to 10 um). PMID- 23082290 TI - Fluorescent labeling of Acanthamoeba assessed in situ from corneal sectioned microscopy. AB - Acanthamoeba keratitis is a serious pathogenic corneal disease, with challenging diagnosis. Standard diagnostic methods include corneal biopsy (involving cell culture) and in vivo reflection corneal microscopy (in which the visualization of the pathogen is challenged by the presence of multiple reflectance corneal structures). We present a new imaging method based on fluorescence sectioned microscopy for visualization of Acanthamoeba. A fluorescent marker (MT-11-BDP), composed by a fluorescent group (BODIPY) inserted in miltefosine (a therapeutic agent against Acanthamoeba), was developed. A custom-developed fluorescent structured illumination sectioned corneal microscope (excitation wavelength: 488 nm; axial/lateral resolution: 2.6 MUm/0.4-0.6 MUm) was used to image intact enucleated rabbit eyes, injected with a solution of stained Acanthamoeba in the stroma. Fluorescent sectioned microscopic images of intact enucleated rabbit eyes revealed stained Acanthamoeba trophozoites within the stroma, easily identified by the contrasted fluorescent emission, size and shape. Control experiments show that the fluorescent maker is not internalized by corneal cells, making the developed marker specific to the pathogen. Fluorescent sectioned microscopy shows potential for specific diagnosis of Acanthamoeba keratitis. Corneal confocal microscopy, provided with a fluorescent channel, could be largely improved in specificity and sensitivity in combination with specific fluorescent marking. PMID- 23082291 TI - Silica-coated super paramagnetic iron oxide nanoparticles (SPION) as biocompatible contrast agent in biomedical photoacoustics. AB - In this study, we report for the first time the use of silica-coated superparamagnetic iron oxide nanoparticles (SPION) as contrast agents in biomedical photoacoustic imaging. Using frequency-domain photoacoustic correlation (the photoacoustic radar), we investigated the effects of nanoparticle size, concentration and biological media (e.g. serum, sheep blood) on the photoacoustic response in turbid media. Maximum detection depth and the minimum measurable SPION concentration were determined experimentally. The nanoparticle-induced optical contrast ex vivo in dense muscular tissues (avian pectus and murine quadricept) was evaluated and the strong potential of silica coated SPION as a possible photoacoustic contrast agents was demonstrated. PMID- 23082292 TI - Measuring aberrations in the rat brain by coherence-gated wavefront sensing using a Linnik interferometer. AB - Aberrations limit the resolution, signal intensity and achievable imaging depth in microscopy. Coherence-gated wavefront sensing (CGWS) allows the fast measurement of aberrations in scattering samples and therefore the implementation of adaptive corrections. However, CGWS has been demonstrated so far only in weakly scattering samples. We designed a new CGWS scheme based on a Linnik interferometer and a SLED light source, which is able to compensate dispersion automatically and can be implemented on any microscope. In the highly scattering rat brain tissue, where multiply scattered photons falling within the temporal gate of the CGWS can no longer be neglected, we have measured known defocus and spherical aberrations up to a depth of 400 um. PMID- 23082293 TI - Assessment of transferrin recycling by Triplet Lifetime Imaging in living cells. AB - An optical method is presented that allows the measurement of the triplet lifetime of a fluorescent molecule. This is a characteristic specific to each fluorophore. Based on differences in triplet lifetimes of two fluorescent species (autofluorescence versus label), this novel approach measures relative quantities of a transmembrane receptor and associated fluorescently labeled ligand during its recycling in living cells. Similarly to fluorescence-lifetime based methods, our approach is almost insensitive to photobleaching. A simple theory for unmixing two known triplet lifetimes is presented along with validation of the method by measurements of transferrin recycling in a model system based on chinese hamster ovarian cells (CHO). Transferrin is the delivery carrier for Fe(3+) to the cell. PMID- 23082294 TI - The use of forward scatter to improve retinal vascular imaging with an adaptive optics scanning laser ophthalmoscope. AB - Retinal vascular diseases are a leading cause of blindness and visual disability. The advent of adaptive optics retinal imaging has enabled us to image the retinal vascular at cellular resolutions, but imaging of the vasculature can be difficult due to the complex nature of the images, including features of many other retinal structures, such as the nerve fiber layer, glial and other cells. In this paper we show that varying the size and centration of the confocal aperture of an adaptive optics scanning laser ophthalmoscope (AOSLO) can increase sensitivity to multiply scattered light, especially light forward scattered from the vasculature and erythrocytes. The resulting technique was tested by imaging regions with different retinal tissue reflectivities as well as within the optic nerve head. PMID- 23082295 TI - Systematic investigation of changes in oxidized cerebral cytochrome c oxidase concentration during frontal lobe activation in healthy adults. AB - Using transcranial near-infrared spectroscopy (NIRS) to measure changes in the redox state of cerebral cytochrome c oxidase (Delta[oxCCO]) during functional activation in healthy adults is hampered by instrumentation and algorithm issues. This study reports the Delta[oxCCO] response measured in such a setting and investigates possible confounders of this measurement. Continuous frontal lobe NIRS measurements were collected from 11 healthy volunteers during a 6-minute anagram-solving task, using a hybrid optical spectrometer (pHOS) that combines multi-distance frequency and broadband components. Only data sets showing a hemodynamic response consistent with functional activation were interrogated for a Delta[oxCCO] response. Simultaneous systemic monitoring data were also available. Possible influences on the Delta[oxCCO] response were systematically investigated and there was no effect of: 1) wavelength range chosen for fitting the measured attenuation spectra; 2) constant or measured, with the pHOS in real time, differential pathlength factor; 3) systemic hemodynamic changes during functional activation; 4) changes in optical scattering during functional activation. The Delta[oxCCO] response measured in the presence of functional activation was heterogeneous, with the majority of subjects showing significant increase in oxidation, but others having a decrease. We conclude that the heterogeneity in the Delta[oxCCO] response is physiological and not induced by confounding factors in the measurements. PMID- 23082296 TI - Multispectral image alignment using a three channel endoscope in vivo during minimally invasive surgery. AB - Sequential multispectral imaging is an acquisition technique that involves collecting images of a target at different wavelengths, to compile a spectrum for each pixel. In surgical applications it suffers from low illumination levels and motion artefacts. A three-channel rigid endoscope system has been developed that allows simultaneous recording of stereoscopic and multispectral images. Salient features on the tissue surface may be tracked during the acquisition in the stereo cameras and, using multiple camera triangulation techniques, this information used to align the multispectral images automatically even though the tissue or camera is moving. This paper describes a detailed validation of the set up in a controlled experiment before presenting the first in vivo use of the device in a porcine minimally invasive surgical procedure. Multispectral images of the large bowel were acquired and used to extract the relative concentration of haemoglobin in the tissue despite motion due to breathing during the acquisition. Using the stereoscopic information it was also possible to overlay the multispectral information on the reconstructed 3D surface. This experiment demonstrates the ability of this system for measuring blood perfusion changes in the tissue during surgery and its potential use as a platform for other sequential imaging modalities. PMID- 23082297 TI - Phase-sensitive OCT imaging of multiple nanoparticle species using spectrally multiplexed single pulse photothermal excitation. AB - We apply phase-sensitive optical coherence tomography to image multiple nanoparticle species with two excitation wavelengths matched to their distinct absorption peaks. Using different modulation frequencies, multiple species collocated within the sample can be distinguished. In addition, we characterize single-pulse excitation schemes as a method to minimize bulk heating of the sample. We demonstrate this new scheme with B-mode photothermal measurements of tissue phantoms. PMID- 23082298 TI - In vivo absorption spectroscopy for absolute measurement. AB - In in vivo spectroscopy, there are differences between individual subjects in parameters such as tissue scattering and sample concentration. We propose a method that can provide the absolute value of a particular substance concentration, independent of these individual differences. Thus, it is not necessary to use the typical statistical calibration curve, which assumes an average level of scattering and an averaged concentration over individual subjects. This method is expected to greatly reduce the difficulties encountered during in vivo measurements. As an example, for in vivo absorption spectroscopy, the method was applied to the reflectance measurement in retinal vessels to monitor their oxygen saturation levels. This method was then validated by applying it to the tissue phantom under a variety of absorbance values and scattering efficiencies. PMID- 23082299 TI - In vivo feasibility of endovascular Doppler optical coherence tomography. AB - Feasibility of detecting intravascular flow using a catheter based endovascular optical coherence tomography (OCT) system is demonstrated in a porcine carotid model in vivo. The effects of A-line density, radial distance, signal-to-noise ratio, non-uniform rotational distortion (NURD), phase stability of the swept wavelength laser and interferometer system on Doppler shift detection limit were investigated in stationary and flow phantoms. Techniques for NURD induced phase shift artifact removal were developed by tracking the catheter sheath. Detection of high flow velocity (~51 cm/s) present in the porcine carotid artery was obtained by phase unwrapping techniques and compared to numerical simulation, taking into consideration flow profile distortion by the eccentrically positioned imaging catheter. Using diluted blood in saline mixture as clearing agent, simultaneous Doppler OCT imaging of intravascular flow and structural OCT imaging of the carotid artery wall was feasible. To our knowledge, this is the first in vivo demonstration of Doppler imaging and absolute measurement of intravascular flow using a rotating fiber catheter in carotid artery. PMID- 23082300 TI - High-speed, image-based eye tracking with a scanning laser ophthalmoscope. AB - We demonstrate a high-speed, image-based tracking scanning laser ophthalmoscope (TSLO) that can provide high fidelity structural images, real-time eye tracking and targeted stimulus delivery. The system was designed for diffraction-limited performance over an 8 degrees field of view (FOV) and operates with a flexible field of view of 1 degrees -5.5 degrees . Stabilized videos of the retina were generated showing an amplitude of motion after stabilization of 0.2 arcmin or less across all frequencies. In addition, the imaging laser can be modulated to place a stimulus on a targeted retinal location. We show a stimulus placement accuracy with a standard deviation less than 1 arcmin. With a smaller field size of 2 degrees , individual cone photoreceptors were clearly visible at eccentricities outside of the fovea. PMID- 23082301 TI - In vivo imaging and quantitative analysis of zebrafish embryos by digital holographic microscopy. AB - Digital holographic microscopy (DHM) has been applied extensively to in vitro studies of different living cells. In this paper, we present a novel application of an off-axis DHM system to in vivo study of the development of zebrafish embryos. Even with low magnification microscope objectives, the morphological structures and individual cell types inside developing zebrafish embryos can be clearly observed from reconstructed amplitude images. We further study the dynamic process of blood flow in zebrafish embryos. A calibration routine and post-processing procedures are developed to quantify physiological parameters at different developmental stages. We measure quantitatively the blood flow as well as the heart rate to study the effects of elevated D-glucose (abnormal condition) on circulatory and cardiovascular systems of zebrafish embryos. To enhance our ability to use DHM as a quantitative tool for potential high throughput screening application, the calibration and post-processing algorithms are incorporated into an automated processing software. Our results show that DHM is an excellent non invasive imaging technique for visualizing the cellular dynamics of organogenesis of zebrafish embryos in vivo. PMID- 23082302 TI - In situ structural and microangiographic assessment of human skin lesions with high-speed OCT. AB - We demonstrate noninvasive structural and microvascular contrast imaging of different human skin diseases in vivo using an intensity difference analysis of OCT tomograms. The high-speed swept source OCT system operates at 1310 nm with 220 kHz A-scan rate. It provides an extended focus by employing a Bessel beam. The studied lesions were two cases of dermatitis and two cases of basal cell carcinoma. The lesions show characteristic vascular patterns that are significantly different from healthy skin. In case of inflammation, vessels are dilated and perfusion is increased. In case of basal cell carcinoma, the angiogram shows a denser network of unorganized vessels with large vessels close to the skin surface. Those results indicate that assessing vascular changes yields complementary information with important insight into the metabolic demand. PMID- 23082303 TI - Extended coherence length megahertz FDML and its application for anterior segment imaging. AB - We present a 1300 nm Fourier domain mode locked (FDML) laser for optical coherence tomography (OCT) that combines both, a high 1.6 MHz wavelength sweep rate and an ultra-long instantaneous coherence length for rapid volumetric deep field imaging. By reducing the dispersion in the fiber delay line of the FDML laser, the instantaneous coherence length and hence the available imaging range is approximately quadrupled compared to previously published MHz-FDML setups, the imaging speed is increased by a factor of 16 compared to previous extended coherence length results. We present a detailed characterization of the FDML laser performance. We demonstrate for the first time MHz-OCT imaging of the anterior segment of the human eye. The OCT system provides enough imaging depth to cover the whole range from the top surface of the cornea down to the crystalline lens. PMID- 23082304 TI - Validation and perspectives of a femtosecond laser fabricated monolithic optical stretcher. AB - The combination of high power laser beams with microfluidic delivery of cells is at the heart of high-throughput, single-cell analysis and disease diagnosis with an optical stretcher. So far, the challenges arising from this combination have been addressed by externally aligning optical fibres with microfluidic glass capillaries, which has a limited potential for integration into lab-on-a-chip environments. Here we demonstrate the successful production and use of a monolithic glass chip for optical stretching of white blood cells, featuring microfluidic channels and optical waveguides directly written into bulk glass by femtosecond laser pulses. The performance of this novel chip is compared to the standard capillary configuration. The robustness, durability and potential for intricate flow patterns provided by this monolithic optical stretcher chip suggest its use for future diagnostic and biotechnological applications. PMID- 23082305 TI - A comparison of Doppler optical coherence tomography methods. AB - We compare, in detail, the phase-resolved color Doppler (PRCD), phase-resolved Doppler variance (PRDV) and intensity-based Doppler variance (IBDV) methods. All the methods are able to quantify flow speed when the flow rate is within a certain range, which is dependent on the adjacent A-line time interval. While PRCD is most sensitive when the flow direction is along the probing beam, PRDV and IBDV can be used to measure the flow when the flow direction is near perpendicular to the probing beam. However, the values of PRDV and IBDV are Doppler angle-dependent when the Doppler angle is above a certain threshold. The sensitivity of all the methods can be improved by increasing the adjacent A-line time interval while still maintaining a high sampling density level. We also demonstrate for the first time, to the best of our knowledge, high resolution inter-frame PRDV method. In applications where mapping vascular network such as angiogram is more important than flow velocity quantification, IBDV and PRDV images show better contrast than PRCD images. The IBDV and PRDV show very similar characteristics and demonstrate comparable results for vasculature mapping. However, the IBDV is less sensitive to bulk motion and with less post-processing steps, which is preferred for fast data processing situations. In vivo imaging of mouse brain with intact skull and human skin with the three methods were demonstrated and the results were compared. The IBDV method was found to be able to obtain high resolution image with a relative simple processing procedure. PMID- 23082306 TI - Effect of molecular organization on the image histograms of polarization SHG microscopy. AB - Based on its polarization dependency, second harmonic generation (PSHG) microscopy has been proven capable to structurally characterize molecular architectures in different biological samples. By exploiting this polarization dependency of the SHG signal in every pixel of the image, average quantitative structural information can be retrieved in the form of PSHG image histograms. In the present study we experimentally show how the PSHG image histograms can be affected by the organization of the SHG active molecules. Our experimental scenario grounds on two inherent properties of starch granules. Firstly, we take advantage of the radial organization of amylopectin molecules (the SHG source in starch) to attribute shifts of the image histograms to the existence of tilted off the plane molecules. Secondly, we use the property of starch to organize upon hydration to demonstrate that the degree of structural order at the molecular level affects the width of the PSHG image histograms. The shorter the width is the more organized the molecules in the sample are, resulting in a reliable method to measure order. The implication of this finding is crucial to the interpretation of PSHG images used for example in tissue diagnostics. PMID- 23082308 TI - [Liraglutide: new results in the treatment of type 2 diabetes mellitus]. AB - New drugs for type 2 diabetes that act on incretin metabolism have been shown to improve glycemic control, reduce body weight and have a low risk for hypoglycemia. Among these, liraglutide is the first glucagon-like peptide 1 (GLP 1) analogue approved for subcutaneous, once-daily administration. According to results from clinical trials, liraglutide is an attractive alternative for the early treatment of type 2 diabetes. The results of the LEAD (Liraglutide Effect and Action in Diabetes) study program demonstrated the efficacy and safety of liraglutide in terms of reduction of glycated hemoglobin (HbA1c) levels, significant loss of body weight that was maintained over the long term, better control of the lipid profile and systolic arterial pressure, reduction of the risk for hypoglycemia and reduction of cardiovascular risk. Moreover, the drug was demonstrated to be safe and can be co-administered with oral antidiabetic agents. The product's tolerability has been demonstrated, with nausea as the most common adverse event, which waned from the fourth week of treatment. PMID- 23082310 TI - Clinical effectiveness of direct class II restorations - a meta-analysis. AB - PURPOSE: More than five hundred million direct dental restorations are placed each year worldwide. In about 55% of the cases, resin composites or compomers are used, and in 45% amalgam. The longevity of posterior resin restorations is well documented. However, data on resin composites that are placed without enamel/dentin conditioning and resin composites placed with self-etching adhesive systems are missing. MATERIAL AND METHODS: The database SCOPUS was searched for clinical trials on posterior resin composites without restricting the search to the year of publication. The inclusion criteria were: (1) prospective clinical trial with at least 2 years of observation; (2) minimum number of restorations at last recall = 20; (3) report on dropout rate; (4) report of operative technique and materials used; (5) utilization of Ryge or modified Ryge evaluation criteria. For amalgam, only those studies were included that directly compared composite resin restorations with amalgam. For the statistical analysis, a linear mixed model was used with random effects to account for the heterogeneity between the studies. P-values under 0.05 were considered significant. RESULTS: Of the 373 clinical trials, 59 studies met the inclusion criteria. In 70% of the studies, Class II and Class I restorations had been placed. The overall success rate of composite resin restorations was about 90% after 10 years, which was not different from that of amalgam. Restorations with compomers had a significantly lower longevity. The main reason for replacement were bulk fractures and caries adjacent to restorations. Both of these incidents were infrequent in most studies and accounted only for about 6% of all replaced restorations after 10 years. Restorations with macrofilled composites and compomer suffered significantly more loss of anatomical form than restorations with other types of material. Restorations that were placed without enamel acid etching and a dentin bonding agent showed significantly more marginal staining and detectable margins compared to those restorations placed using the enamel-etch or etch-and-rinse technique; restorations with self-etching systems were between the other groups. Restorations with compomer suffered significantly more chippings (repairable fracture) than restorations with other materials, which did not statistically differ among each other. Restorations that were placed with a rubber-dam showed significantly fewer material fractures that needed replacement, and this also had a significant effect on the overall longevity. CONCLUSION: Restorations with hybrid and microfilled composites that were placed with the enamel-etching technique and rubber-dam showed the best overall performance; the longevity of these restorations was similar to amalgam restorations. Compomer restorations, restorations placed with macrofilled composites, and resin restorations with no etching or self-etching adhesives demonstrated significant shortcomings and shorter longevity. PMID- 23082311 TI - Influence of temperature and relative humidity on dentin and enamel bonding: a critical review of the literature. Part 1. Laboratory studies. AB - PURPOSE: The aim of this literature review was to investigate the results from in vitro laboratory studies on the influence of temperature and relative humidity present before polymerization on enamel and dentin bonding systems. MATERIALS AND METHODS: A systematic search was carried out including articles published in English, in peer reviewed journals, and indexed in MEDLINE/PubMed database. The search was carried out using the terms: relative AND humidity AND dental. In vitro studies were retrieved and divided into laboratory simulation studies and studies on physical properties. Laboratory simulation studies were addressed by subtopic: resin-enamel bond strength, resin-dentin bond strength, and dentin enamel microleakage. Studies on physical properties tested the influence of humidity and temperature through polymerization contraction, flexural strength, and dentin wettability. RESULTS: Laboratory simulation studies demonstrated a strong influence of humidity and temperature on dentin and enamel bond strength and microleakage with dental adhesives systems. The studies on physical properties failed to demonstrate any influence of humidity on the adhesion performance, except for wettability measurement. CONCLUSION: The clinical relevance of these in vitro results remains to be demonstrated. A review of in vivo clinical studies will complete the literature data presented here. PMID- 23082312 TI - Fiber post cementation strategies: effect of mechanical cycling on push-out bond strength and cement polymerization stress. AB - PURPOSE: To evaluate the effect of mechanical cycling and cementation strategies on the push-out bond strength between fiber posts and root dentin and the polymerization stresses produced using three resin cements. MATERIALS AND METHODS: Eighty bovine mandibular teeth were sectioned to a length of 16 mm, prepared to 12 mm, and embedded in self-curing acrylic resin. The specimens were then distributed into 8 groups (n = 10): Gr1 - Scotchbond Multi Purpose + RelyX ARC; Gr2 - Scotchbond Multi Purpose + RelyX ARC + mechanical cycling; Gr3 - AdheSE + Multilink Automix; Gr4 - AdheSE + Multilink Automix + mechanical cycling; Gr5 - phosphoric acid + RelyX U100 (self-adhesive cement); Gr6 - phosphoric acid+ RelyX U100 + mechanical cycling; Gr7 - RelyX U100; Gr8 - RelyX U100 + mechanical cycling. The values obtained from the push-out bond strength test were submitted to two-way ANOVA and Tukey's test (p = 0.05), while the values obtained from the polymerization stress test were subjected to one-way ANOVA and Tukey's test (alpha = 0.05). RESULTS: Mechanical cycling did not affect the bond strength values (p = 0.236), while cementation strategies affected the push-out bond strength (p < 0.001). Luting with RelyX U100 and Scotch Bond Multi Purpose + RelyX ARC yielded higher push-out bond strength values. The polymerization stress results were affected by the factor "cement" (p = 0.0104): the self-adhesive cement RelyX U100 exhibited the lowest values, RelyX ARC resulted in the highest values, while Multilink Automix presented values statistically similar to the other two cements. CONCLUSION: The self-adhesive cement appears to be a good alternative for luting fiber posts due to the high push-out bond strengths and lower polymerization stress values. PMID- 23082313 TI - Glucose sensor based on an electrochemical reduced graphene oxide-poly(L-lysine) composite film modified GC electrode. AB - A convenient and environmentally friendly method of fabricating glucose biosensors is proposed. Glucose oxidase (GOD) was immobilized on electrochemically reduced graphene oxide (ERGO) which was adsorbed on the poly-L lysine (PLL) modified glassy carbon electrode after being immersed in GO solution for 4 h. The electrochemical behaviors of GOD/ERGO/PLL/GC electrode have been investigated by cyclic voltammetry. Direct electron transfer between GOD immobilized with ERGO/PLL and GC electrode was observed. Moreover, the GOD/ERGO/PLL/GC electrode exhibited excellent electrocatalytic activity for the detection of glucose with a linear range from 0.25 to 5 mmol L(-1). PMID- 23082307 TI - Kaposi Sarcoma Pathogenesis: A Triad of Viral Infection, Oncogenesis and Chronic Inflammation. AB - Kaposi sarcoma (KS) is a complex cancer that arises from the initial infection of an appropriate endothelial or progenitor cell by Kaposi Sarcoma Herpesvirus/Human Herpesvirus-8 (KSHV/HHV8). However, the majority of KS cases occur when infected patients also suffer from some coincident form of immune deregulation, providing a favorable microenvironment for tumor development. Cellular hallmarks of KS progression include both the hyper-proliferation of KSHV-infected cells and the infiltration of immune modulatory cells into KS lesions, which together result in chronic inflammation, the induction of angiogenesis and tumor growth. This review describes the current understanding of the interactions between KSHV and host responses that result in this unusual cancer, along with existing treatments and prospects for future therapeutic approaches. PMID- 23082314 TI - A simple and sensitive sensor for rapid detection of sulfide anions using DNA templated copper nanoparticles as fluorescent probes. AB - A simple and rapid method for the detection of S(2-) anions with high selectivity and sensitivity has been developed by using random double-strand DNA-templated formation of copper nanoparticles as novel fluorescence probes in aqueous solution. PMID- 23082315 TI - A ligation-triggered highly sensitive fluorescent assay of adenosine triphosphate based on graphene oxide. AB - A simple, amplification-free and sensitive fluorescent biosensor for ATP detection was developed based on the ATP-dependent enzymatic reaction (ATP-DER) and the different adsorption affinity between graphene oxide (GO) and DNA structures. The proposed method was simple and convenient and also showed high sensitivity and selectivity to ATP. PMID- 23082316 TI - A novel supramolecular ternary polymer with two orthogonal host-guest interactions. AB - A linear supramolecular ternary polymer based on two host-guest interactions in an orthogonal way was constructed, by taking advantage of the distinguishable binding properties between cyclodextrin and calixarene. PMID- 23082317 TI - Gate adsorption of CO2 on a flexible one-dimensional copper-based coordination polymer crystal. AB - A flexible one-dimensional copper-based coordination polymer (CP) crystal was synthesized and the crystal structure was solved. This CP crystal shows a single step gate adsorption uptake of CO(2) under moderate conditions (268 K <= T <= 303 K, P < 1 atm) irrespective of no N(2) uptake at 77 K. PMID- 23082318 TI - Stabilizing gold clusters by heterostructured transition-metal oxide-mesoporous silica supports for enhanced catalytic activities for CO oxidation. AB - A strategy for stabilizing ultrasmall gold clusters under thermal treatment has been developed. The essence of this methodology lies in construction of heterostructured transition-metal oxide-mesoporous silica supports. The supported clusters have been demonstrated to be sintering resistant and highly active for catalytic CO oxidation. PMID- 23082319 TI - Imbalanced tunneling ready states in alcohol dehydrogenase model reactions: rehybridization lags behind H-tunneling. AB - The secondary kinetic isotope effects for the hydride transfer reactions from aliphatic alcohols to two carbocations (NAD(+) models) in acetonitrile were determined. The results suggest that the hydride transfer takes place by tunneling and that the rehybridizations of both donor and acceptor carbons lag behind the H-tunneling. This is quite contrary to the observations in alcohol dehydrogenases where the importance of enzyme motions in catalysis is manifested. PMID- 23082320 TI - Lamotrigine and aseptic meningitis. PMID- 23082322 TI - In sickness and in health. PMID- 23082323 TI - Innovation: Brushing up on business. PMID- 23082324 TI - How ants find their way. PMID- 23082321 TI - A calorie-restricted diet decreases brain iron accumulation and preserves motor performance in old rhesus monkeys. AB - Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using magnetic resonance imaging, to determine the potential effect of CR on elderly rhesus macaques eating restricted (n=24, 13 males, 11 females) and standard (n=17, 8 males, 9 females) diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A Diet X Age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species. PMID- 23082325 TI - Tomoko Ohta. PMID- 23082326 TI - Diagnosis, evaluation and monitoring of asthma. PMID- 23082327 TI - Treatment of HIV infection: are we failing children? PMID- 23082328 TI - Highlights from the 19th International AIDS Conference. PMID- 23082329 TI - Lymphocytosis: T-cell large granular lymphocyte leukemia. PMID- 23082330 TI - Life after death. PMID- 23082331 TI - Global reach. PMID- 23082332 TI - Badger away. PMID- 23082333 TI - I check my blood pressure regularly with a home monitor, and it varies a lot. When my doctor takes it, it's different, too. How do I know what my blood pressure really is? PMID- 23082334 TI - Foods high in B vitamins may lower cardiovascular risks. Folate and vitamins B6 and B12 appear to be beneficial, but supplements should be taken only when recommended by a doctor. PMID- 23082335 TI - [Ankle osteoarthritis - distraction is good, additional exercise is better]. PMID- 23082336 TI - [Regeneration of hyaline cartilage - how to treat cartilage damage?]. PMID- 23082337 TI - [Endoprosthesis - weighing the costs]. PMID- 23082338 TI - Gastrointestinal endoscopy. PMID- 23082339 TI - [Knee replacement - better results with navigation?]. PMID- 23082340 TI - Uterine artery embolization. PMID- 23082341 TI - Laparoscopic Nissen fundoplication. PMID- 23082342 TI - Pediatric emergency medicine. PMID- 23082343 TI - Virtual colonoscopy. PMID- 23082344 TI - Sengstaken-Blakemore tube insertion. PMID- 23082345 TI - Plastic surgery. PMID- 23082346 TI - MERCI Retriever. PMID- 23082347 TI - Flexible fiberoptic bronchoscopy. PMID- 23082348 TI - Physical medicine and rehabilitation. PMID- 23082349 TI - In health care spending, Americans who make the least contribute the greatest share of income. AB - Key findings. (1) Health care spending, both public and private, accounted for more than 20 percent of family income for families in the lowest-income quintile, but no more than 16 percent for families in any other income quintile. (2) The Affordable Care Act should reduce, but is unlikely to completely eliminate, some of this inequity through its heavy reliance on federal funding for the Medicaid expansion and income-related subsidies for private insurance. PMID- 23082350 TI - Child-only coverage and the Affordable Care Act: lessons for policymakers. AB - The Affordable Care Act prohibited insurers from denying or limiting cover-age for children under the age of 19 in 2010. In response, some insurers ceased to offer coverage to children in need of individual health insurance, known as a "child-only" pol-icy. This issue brief examines new state legislative and regulatory action to promote the availability of child-only policies in response to this market disruption. The analysis finds that 22 states and the District of Columbia passed new legislation or issued a new regula-tion or subregulatory guidance. As a result, child-only coverage is available in nearly all of these states. These findings suggest that states have flexibility to take innovative actions to maintain or improve their markets and insurers are highly sensitive to the risk of adverse selection. The findings also suggest the need for meaningful regulatory incentives to avoid market disruption in successfully implementing broader reforms in 2014. PMID- 23082351 TI - Epigenetics and the prognosis of hepatocellular carcinoma. PMID- 23082352 TI - Behind the worthy words lies a financial black hole. PMID- 23082353 TI - NHS Commissioning Board begins 3m pounds sterling senior level recruitment drive. PMID- 23082354 TI - Pressure builds on the regulator to justify proposed fee increase. PMID- 23082355 TI - Wage bill is obvious starting point for cutting costs, says pay 'cartel'. PMID- 23082356 TI - Lack of funding could scupper DH bid to raise school nursing profile. PMID- 23082357 TI - Staff hampered by red tape when caring for people in disaster zones. PMID- 23082358 TI - Running down prejudice. AB - Nurses hope the Paralympic Games in London are helping to challenge patronising ideas about disability. An event which began as an archery competition for war veterans at Stoke Mandeville Hospital in 1948 has grown into a huge showcase for sport at the highest level, focusing on athletes, not their disabilities. PMID- 23082359 TI - Campaign for our future. AB - This is Nursing is an RCN initiative that will challenge negative assumptions about the profession, and showcase the skills and diversity to be found in nursing. Anyone in health care can get involved in the initiative, which will focus on the important issues facing the profession. PMID- 23082360 TI - Time to be a united force. AB - The RCN is not affiliated to the Trades Union Congress, but the case for joining has been debated since the 1970s. Supporters argue that the current turbulence in the NHS strengthens the need for unity with other unions, but opponents claim affiliation would be expensive and undermine the college's professional role. PMID- 23082361 TI - A change in attitudes. AB - The British Thoracic Society has issued national quality standards for the diagnosis, treatment and management of the chronic lung disease bronchiectasis. Despite being the third most common lung disease in the UK, the condition is often overlooked by clinicians. The new standards should help more patients manage the condition at home. PMID- 23082362 TI - Stroke rehabilitation and discharge planning. AB - Nurses play a pivotal role in the rehabilitation and discharge planning process of patients who have had a stroke. The nurse's role in the wider stroke multidisciplinary team is complex and diverse and, as such, stroke nurses may find it hard to describe their role and how it fits into the rehabilitation and discharge planning process. A definition of the stroke nurse role in prominent publications such as those of the Scottish Intercollegiate Guidelines Network and the Royal College of Physicians is lacking. This article emphasises the role of the stroke nurse in the rehabilitation and discharge planning process in the stroke unit, while highlighting the complexity, diversity and importance of this role in providing holistic care and support for patients who have survived a stroke. The author draws on his clinical experience of stroke nursing practice in primary, secondary and tertiary care in west central Scotland. PMID- 23082363 TI - End of life care for people with a learning disability. AB - AIM: To explore the experiences of learning disability and district nurses caring for people with a learning disability at the end of their lives. METHOD: A small scale semi-structured qualitative study involving interviews was carried out to explore the experiences of healthcare professionals from two specialist healthcare settings. FINDINGS: Healthcare professionals felt that formal guidelines and support were needed in this complex area. The study also revealed that successful provision of palliative care for people with a learning disability requires a person-centred approach. CONCLUSION: Modifications to existing palliative care services, involving joint working, improved co ordination and reasonable adjustments, is recommended. This aims to address any inequalities in care provision for people with a learning disability who are at the end of their lives. PMID- 23082364 TI - Pin site care: guidance and key recommendations. AB - Pin site infection is the most common complication of external fixation, a complex orthopaedic procedure used to stabilise fractures and correct limb deformity. The care of pin sites has long been debated among healthcare professionals. It is widely acknowledged that there is a lack of high quality research in this area. In 2010 a meeting with the aim of achieving consensus about pin site care took place, funded by the Royal College of Nursing Society of Orthopaedic and Trauma Nursing. The aim was for practitioners who care for pin sites on a regular basis in adult, paediatric, hospital and community environments around the UK to explore and debate current practice. This article reports the findings of this meeting and discusses the difficulties in creating guidance on this area of practice. PMID- 23082365 TI - Atrial fibrillation. PMID- 23082366 TI - Lessons on the street. PMID- 23082367 TI - A fair way to plan your career. PMID- 23082368 TI - Get on course for nutrition. PMID- 23082369 TI - From your president. PMID- 23082370 TI - Be it ever so humble... PMID- 23082371 TI - Dismissing a patient from a dental practice. PMID- 23082372 TI - Assessing progressive anterior open bites. PMID- 23082373 TI - Oral Pathology Quiz #76. Case number 1. Hemangioma. PMID- 23082374 TI - Oral Pathology Quiz #76. Case number 2. Ameloblastoma. PMID- 23082375 TI - Oral Pathology Quiz #76. Case number 3. Radicular cyst. PMID- 23082376 TI - Oral Pathology Quiz #76. Case number 4. Oral focal mucinosis. PMID- 23082378 TI - Why we love dentistry. PMID- 23082377 TI - Cast gold restorations--still the best? Or an aging dinosaur? PMID- 23082379 TI - Stress management in the dental chair. PMID- 23082380 TI - Spectrophotometric evaluation of color match of three different porcelain systems for all-ceramic zirconia-based restorations. AB - PURPOSE: To determine by a spectrophotometric analysis the variations in color between the intended and the fabricated shades of three different porcelain systems when applied in a standardized thickness on a zirconia core. METHODS: Three porcelain systems for zirconia based restorations, Ivoclar IPS e.max Ceram, VITA VM9, and Creation Zi-F were tested. Nine disc-shaped (15 mm diameter, 0.5 mm thickness) specimens of VITA YZ zirconia core per group were made comprising a total of 27 discs. Three different shades (A2, A3, A4) of the Vitapan Classical shade guide were investigated. The porcelain veneer total thickness was set at 1.0 mm in all groups. The porcelain stratification was made by applying calibrated layers of porcelain. Thicknesses of single porcelain layers were calculated from drawings retrieved from the manufacturers' instructions. Color parameters (L*, a*, b*) of veneered specimens were measured by a clinical spectrophotometer. Color differences (deltaE) were calculated using a color difference formula. Two-way ANOVA and Tukey's test were used to analyze the data. RESULTS: The mean color differences for the three ceramic systems, Ivoclar IPS e.max Ceram, VITA VM9 and Creation Zi-F were respectively 4.1, 2.7 and 3.2, regardless of the shades. VITA VM9 resulted in the best average shade matching among the porcelain systems, even if results with shade A3 were considerably worse than shades with A2 and A4 (P<0.05). Color matching appeared not to be shade dependent (P>0.05) among the tested shades. PMID- 23082381 TI - Antiplaque and antigingivitis efficacy of an alcohol-free essential-oil containing mouthrinse: a 2-week clinical trial. AB - PURPOSE: This randomized, examiner blind, parallel group, controlled clinical study evaluated the antiplaque and antigingivitis potential of an alcohol-free essential oils containing mouthrinse (Listerine Zero) compared to a 5% hydroalcohol mouthrinse (negative control), using a 2-week experimental gingivitis model. METHODS: 92 subjects, male and female, ranging in age from 18 68 years, in good general health, were assigned to one of the two treatment groups: Alcohol-free essential oils containing mouthrinse (LZ) or 5% hydroalcohol negative control (C) rinse. The mean Turesky Modification of the Quigley-Hein Plaque Index (PI) and the mean Modified Gingival Index (MGI) at 2 weeks were the primary efficacy endpoints. Following baseline examinations, subjects received a complete dental prophylaxis and began supervised rinsing with their assigned mouthrinse twice daily for 2 weeks, as their sole oral hygiene measure. RESULTS: 90 subjects completed the trial. At 2 weeks, LZ was more effective (P<0.001) than C in reducing plaque (23.9%) and gingivitis (10.4%). PMID- 23082382 TI - Long-term efficacy of in-office and at-home bleaching: a 2-year double-blind randomized clinical trial. AB - PURPOSE: This parallel, double-blind randomized clinical trial evaluated the 2 year bleaching efficacy and sensitivity produced by at-home (AH) and in-office (IO) bleaching therapies. METHODS: 60 participants with tooth color darker than C2, without restorations in the anterior dentition and older than 18 years old, were randomly allocated into two groups to receive either IO with 35% hydrogen peroxide or AH with 16% carbamide peroxide. Color was recorded at baseline (BA); 1-week (1W); end of the treatment (ET); and 2 years (2Y) after bleaching, using the Vita Classical shade guide. The perception of TS was recorded on a 0-4 scale during and 2Y after bleaching. The variation in shade guide units (deltaSGU) from BA vs. 1W was compared to deltaSGU from BA vs. 2Y using paired t-test. The percentage of subjects who reported TS was evaluated by Fisher's exact test. The intensity of TS was evaluated by a Mann-Whitney test (alpha=0.05). RESULTS: Both bleaching techniques demonstrated equivalent and significant tooth color shade lightening. No significant color rebound occurred after 2Y for both techniques (P= 0.77 and 0.87, for AH and IO respectively). The absolute risk of TS was similar for IO and AH (P= 0.12), however the intensity of TS was significantly higher for IO (P= 0.001). No subjects reported sensitivity after 2Y. PMID- 23082383 TI - Fluoride dose-response of human and bovine enamel caries lesions under remineralizing conditions. AB - PURPOSE: To investigate the relative fluoride dose-response of human and bovine enamel caries lesions under remineralizing conditions and utilizing an established pH cycling model. METHODS: Early caries-like lesions were formed in human and bovine enamel, characterized using Vickers surface microhardness (VHN) and assigned to five dentifrice treatment groups: 0/250/1100 ppm fluoride as sodium fluoride (F as NaF) formulation 1; 1100 ppm F as NaF formulation 2; 1000 ppm F as monofluorophosphate (MFP) formulation 3. The daily pH cycling regimen comprised: 4x1-minute dentifrice slurry treatments; 1 x 4-hour acid challenge and intermittent remineralization in a 1:1-mixture of pooled human/artificial saliva. After 20 days, VHN of specimens were measured again and changes from lesion baseline calculated (REM). Subsequently, enamel fluoride uptake (EFU) was determined using the microdrill technique and specimens were demineralized again to determine their acid resistance (DEM). Data were analyzed using two-way ANOVA (factors: enamel, dentifrice). RESULTS: Both enamel type and dentifrice as well as their interaction affected REM and DEM. EFU was only affected by dentifrice. Human and bovine enamel showed a good fluoride dose-response for REM and correlated well. However, bovine enamel showed more remineralization than human enamel. There were good correlations between dentifrice-F concentration vs. REM and EFU, and between REM vs. EFU, regardless of enamel type. PMID- 23082384 TI - Efficacy of a desensitizing toothpaste containing arginine and calcium carbonate on dentin surface pore structure and dentin morphology. AB - PURPOSE: To investigate the laboratory changes in dentin tubule occlusion morphology during short term use of desensitizing products as evaluated by electron microscopy and an image analysis. METHODS: Freshly extracted human third molar teeth were collected at random and 40 dentin discs were prepared. These dentin samples were then divided in to four groups (n=10). The test treatment consisted of undiluted Colgate Sensitive Pro-Relief Toothpaste containing 8.0% arginine and calcium carbonate that was applied on the dentin surface under a brushing cycle of 200 strokes, 2 times/day, for 10 days and then soaked in the filtrated human saliva. The two other test products were a commercial toothpaste, Sensodyne Original, containing 10% strontium chloride and a professional re mineralizing treatment paste (GC Tooth Mousse). The negative control group was soaked in human saliva that had been sterilized by filtration. The occluding ability of the dentin tubules, using the dentin disc model, was evaluated using scanning electron microscopy (SEM). The degree of occlusion of the dentin tubules was quantified using an image analyzer and the results were analyzed by ANOVA and a Tukey's test. RESULTS: All test products created a smear layer on the dentin surface that significantly reduced the diameter of dentin tubules after treatment. Compared to the dentin tubule area on disks treated with the negative control (72.02 +/- 7.23 microm2), disks treated with Colgate Sensitive Pro Relief, Sensodyne Original, and GC Mousse had dentin tubule areas of 2.10 +/- 0.42 microm2, 10.11 +/- 2.83 microm2, and 30.40 +/- 4.04 microm2 respectively. These differences were statistically significant. PMID- 23082385 TI - Azithromycin as an adjunctive treatment of aggressive periodontitis: radiographic findings of a 12-month randomized clinical trial. AB - PURPOSE: To compare the 12-month radiographic outcomes following the use of azithromycin or placebo as adjuncts to non-surgical periodontal treatment of AgP. METHODS: 17 aggressive periodontitis (AgP) subjects 13-26 years old were randomly assigned to receive scaling and root planing (SRP) with systemic azithromycin or placebo. Standardized radiographs were taken at baseline and 12 months postoperatively. Recall visits consisting of oral prophylaxis and oral hygiene instructions were performed during the 12 months. Digital image subtraction analysis and linear bone measurements were conducted by a blinded and calibrated examiner. Student t-tests were used for within and between-groups comparisons. ANCOVA was applied for between-group comparisons of changes in linear bone level adjusting for baseline values. RESULTS: There were significant gains in linear bone levels in the azithromycin (0.55 +/- 0.10 mm) and placebo (0.42 +/- 0.07 mm) groups between the baseline and 12-month postoperative visits. There were also significant gains in bone density in the two treatment groups. No significant differences were observed between the two treatments in the amount of linear bone gain or bone density during the follow-up period. The use of azithromycin as an adjunct to SRP in the treatment of AgP did not result in significant radiographic bone level changes compared to placebo. PMID- 23082386 TI - Estimation of the surface gloss of dental nano composites as a function of color measuring geometry. AB - PURPOSE: To estimate the surface gloss of various dental nano composites by using the correlation between deltaE* specular component excluded (SCE) - specular component included (SCI) and surface roughness (Ra). METHODS: Two brands of commercial and two experimental light-cured resin composites were used. Resin composite discs were prepared 10 mm in diameter and 3 mm in thickness. 56 subgroups (n=5) were designed according to two different curing conditions (hand light curing and additional post-heat curing) and seven different polishing methods (Mylar, 4000-, 2400-, 1200- and 320- SiC paper, rubber-based silicone, three-step polishing kit). deltaE*SCE-SCI and Ra measurements were done. Two specimens in each subgroup were analyzed by SEM. Multifactorial ANOVA and post hoc Tukey test were applied for the evaluation of the deltaE*SCE-SCI and Ra data (P<0.05). Moreover, Spearman's rank correlation test was used to determine the correlation between deltaE*SCE-SCI and Ra results (P<0.01). RESULTS: A strong correlation was found between deltaE*(SCE-SCI) and Ra results indicating the surface gloss of the tested composite resin materials after different curing and surface polishing methods. A three-factor interaction was found between curing conditions, surface polishing methods and resin composites (P<0.05) in deltaE*SCE SCI and Ra results. Additionally, significant differences were found between composites and between polishing methods (P<0.05). Furthermore, there were significant differences between curing conditions in Ra results (P<0.05). PMID- 23082387 TI - Effects of polishing on surface roughness and gloss of S-PRG filled flowable resin composite. AB - PURPOSE: To evaluate the effects of polishing on surface roughness (Ra, microm) and gloss of different shades of a surface pre-reacted glass-ionomer (S-PRG) filled flowable resin composite. METHODS: Resin disks of 15 mm diameter and 2 mm thickness and final polish with 3000-grit SiC paper (#3000), super fine cut diamond point (FG) and Super-Snap mini-disk red (SNAP) were made with Beautifil Flow Plus (shades: A2, A20, Inc). The surface roughness and gloss were measured 1 week after curing. Data was analyzed with ANOVA and Fisher's PLSD with alpha=0.05. RESULTS: The order of Ra differed among the composite shades. For all shades in all polishing groups, the Ra was over 0.5 microm. For all shades, the gloss of the #3000 group was significantly higher than that of the FG and SNAP groups with no significant difference between the FG and SNAP groups except for the A20 shade. For A20 shade, the gloss of the SNAP group was significantly higher than that of the FG group. PMID- 23082388 TI - Ceramic bond durability and degradation mechanism of commercial gamma methacryloxypropyl trimethoxysilane-based ceramic primers. AB - PURPOSE: To investigate the bond durability and degradation mechanism of various commercial ceramic primers that are based on gamma-methacryloxypropyl trimethoxysilane (gamma-MPTS) and contain various organic additives. The null hypotheses tested were that (1) the type of ceramic primer had no effect on the bond strength after thermocycling and (2) the type of ceramic primer had no effect on the water contact angle after rinsing with THF. METHODS: The adherent was a silica-based ceramic block used for computer-aided design/computer-aided manufacturing (CAD-CAM). Four commercial ceramic primers, Clearfil Mega Bond Porcelain Bonding kit (CM), Tokuso ceramic primer (TC), GC ceramic primer (CP), and Porcelain Liner M (PL), were compared with a simplified experimental ceramic primer (EP) that comprised gamma-MPTS and an inorganic acid (hydrochloric acid) but no other organic additives. The specimens for the adhesion test were prepared after a dual-curing type resin cement (Link Max) had adhered to the ceramic surfaces treated with each ceramic primer. The bonded specimens were then stored in water at 37 degrees C for 1 day. Then, the bonded specimens were thermocycled between 5 degrees C and 55 degrees C in water baths for 5000 or 10,000 cycles. The dwell time in each water bath and the transfer time were 60 and 7 seconds, respectively. The shear bond strength of resin to the ceramic surface was measured under a crosshead speed of 1.0 mm/minute by a conventional testing machine. Thereafter, the fracture mode for each specimen was determined. In addition, the water contact angle on the treated ceramic surfaces was measured before and after THF using a cotton pellet. As a control, the contact angle on the ground ceramic surface was measured without any ceramic primer. RESULTS: For all samples, thermocycling led to an increase in the frequency of interfacial failure, reflecting reduced mean bond strength of the resin to the treated ceramic surfaces. However, the bond degradation behavior differed among commercial ceramic primers; in particular, PL exhibited different ceramic bond durability from the others. However, the mean bond strength of PL was only 11.8 MPa and over half the specimens exhibited interfacial failure. In contrast, EP provided significantly higher mean bond strength of 17.2 MPa and most specimens exhibited cohesive failure of the ceramic. Furthermore, the contact angle measurements clearly demonstrated that the commercial ceramic primers created a multilayer consisting of gamma-MPTS species and the organic additives on the ceramic surface. PMID- 23082389 TI - Effect of acid etching time on demineralization of primary and permanent coronal dentin. AB - PURPOSE: To determine the effect of acid etching time on dentin calcium solubilization and to compare the solubilization rate of primary and permanent dentin when etched for the same period of time. METHODS: Flat coronal dentin surfaces were produced on primary (n=8) and permanent (n=8) sound teeth. Three 2 mm-diameter areas were delimited on each surface and assigned to 5, 10 or 15 seconds of acid etching. Five microliters of 35% H3PO4 were applied on each area during the preset times, and 4 microL were retrieved for analysis. The amount of calcium was determined colorimetrically using Arsenazo III reagent and expressed as microg Ca/mm2 of dentin. Data were subjected to two-way ANOVA, Tukey's test and linear regression (alpha=5%). RESULTS: For both primary and permanent dentin, a statistically significant correlation was observed between acid etching time and calcium concentration (primary dentin R2 = 0.79; permanent dentin R2 = 0.73). Mean (sd) values of dissolved primary dentin after 5, 10 and 15 seconds were 1.00 (0.25), 1.74 (0.11) and 2.30 (0.42), whereas for permanent dentin the values were 0.47 (0.13), 0.89 (0.36) and 1.38 (0.20) microg Ca/mm2, respectively. Greater calcium solubilization (P<0.05) was detected for primary dentin than for permanent dentin after all acid etching times. PMID- 23082390 TI - Enamel and dentin bond strength of new simplified adhesive materials with and without preliminary phosphoric acid-etching. AB - PURPOSE: To assess the influence of preliminary phosphoric acid-etching on shear bond strength (SBS) to enamel and dentin of a self-adhering restorative composite and of a new self-etch adhesive used in combination with the proprietary flowable composite. METHODS: 100 human molars were selected. SBS was assessed on flat buccal enamel surfaces and mid-coronal dentin. Teeth from each group were divided into five subgroups (n=10): (1) FL: etch-and-rinse adhesive OptiBond FL/Premise flowable; (2) XTR: 2-step self-etch adhesive OptiBond XTR/Premise flowable; (3) eXTR: OptiBond XTR on etched substrates/Premise flowable; (4) VF: self-adhering flowable composite Vertise Flow; (5) eVF: Vertise Flow on etched substrates. Specimens were stressed in shear until failure. Failure modes were evaluated under a stereomicroscope. Data were analyzed by two-way ANOVA and Fisher's exact test (P< 0.05). RESULTS: Dental substrate, material and between-factor interaction significantly influenced SBS (MPa). In FL group (16.83 +/- 2.93) significantly higher SBS to enamel than in the other groups (XTR 8.59 +/- 4.39; eXTR 7.04 +/- 3.63; VF 6.61 +/- 2,41; eVF 9.87 +/- 4.24) was measured. On dentin FL (8.15 +/- 3.88) performed similarly to XTR (10.60 +/- 5.0), eXTR (9.60 +/- 4.91) and eVF (5.48 +/- 4.94); VF recorded significantly lower SBS (2.94 +/- 2.79 MPa). Failure modes differed significantly among groups. PMID- 23082391 TI - Influence of gaps in adhesive restorations in the development of secondary caries lesions: an in situ evaluation. AB - PURPOSE: To investigate in situ the influence of gaps in the development of secondary caries lesion in adhesive restorations. METHODS: 10 volunteers utilized intra-oral appliances, containing three human dental blocks (enamel and dentin), representing the three different groups (two restored, one sound): (1) restored with resin composite using the total acid etch adhesive technique (37% H3PO4 + Single Bond + Z250); (2) restored with resin composite but without acid etching (Single Bond + Z250); (3) and sound blocks (control group). The dental blocks (n=30) were randomly positioned inside the intra-oral appliances, and covered by a porous tissue (gabardine base) to induce a cariogenic biofilm. The volunteers used the appliances 24 hours daily for a 28-day period, removing just during meals and oral hygiene. Eight times a day, a 20% sucrose solution was dripped onto the blocks. Five minutes later, the appliance was washed with distilled water and replaced in the oral environment. After the experimental period, the dental blocks were removed from the appliance and examined by visual examination to detect the presence or the absence of an active carious lesion (kappa= 0.89). Posteriorly, they were prepared for the polarized light microscopy examination, which was performed to describe enamel surface characteristics on the restored and unrestored blocks with active caries lesion (kappa= 1). RESULTS: The visual examination demonstrated that almost all (29/30) of the blocks showed non cavitated active caries lesion on the enamel surface. The microscopic evaluation showed non-cavitated caries lesions on enamel surfaces for all groups. In the restored blocks (with and without the total etch technique), the demineralization was first identified as an outer lesion that follows the enamel prism directions, and in some cases, reached the cavity walls. The results showed that caries lesion development adjacent to the restoration was determined by the cariogenic challenge of the oral environment, instead of the restoration adhesive quality, and the wall lesion was determined by the prism orientation, regardless of the presence of gaps. PMID- 23082392 TI - Two-week extrinsic stain removal efficacy of a sodium fluoride dentifrice with high cleaning silica: results from two randomized, controlled clinical trials. AB - PURPOSE: To evaluate a stannous-containing sodium fluoride dentifrice with high cleaning silica and polychelation technology (test dentifrice) compared to a currently marketed whitening dentifrice, which carries the ADA Seal of Acceptance for whitening, for its efficacy in removing existing natural stain over a 2-week period. METHODS: Two independent, randomized, positive-controlled, 2-treatment, parallel group, double-blind, 2-week studies with identical protocols were conducted in China. At baseline, subjects received an oral soft tissue (OST) examination followed by a Lobene stain examination. In each study, approximately 60 subjects having a Lobene stain composite score above 1 were randomized to one of two dentifrice products: the test dentifrice or the positive control. Subjects were instructed to brush twice daily for at least 1 minute with their assigned product. Lobene stain and OST examinations were conducted again after 2 weeks of use. RESULTS: In both studies, the test dentifrice and the positive control dentifrice demonstrated statistically significant reductions in Lobene composite (P<0.0001), area (P<0.0001) and intensity (P<0.0001) stain scores after 2 weeks of use versus baseline. At Week 2, there were no statistically significant differences in stain scores between treatment groups in either study (P>0.12). PMID- 23082393 TI - Connection as part of soulful midwifery. PMID- 23082394 TI - Cleft lip and palate in Scotland: a survey. AB - The aim of the survey was to assess midwives' experiences and knowledge of cleft lip and/or palate (CL+/-P), confidence in supporting the families and giving feeding advice, and to identify areas for input from the cleft team. In order to do so, questionnaires were sent to maternity units across Scotland. The results were as follows: 206 questionnaires were returned (42 per cent response rate). Forty one per cent of the midwives had helped a baby with CL+/-P to be born; 23 per cent knew the incidence of CL+/-P; 33 per cent were aware of the stages in treating CL+/- P; 99 per cent were aware that feeding difficulties are a potential complication. When asked about offering support to the families, 70 per cent were not confident and 60 per cent were not confident at giving feeding advice. Regarding cleft team input, 65 per cent would like a training day, 45 per cent requested small group teaching, 50 per cent would like a website and 57 per cent would like printed literature. Our recommendations are to implement training, for midwives, along with supporting websites and literature. PMID- 23082395 TI - Pre registration midwifery education in Scotland. AB - Pre registration midwifery education in Scotland is facing an exciting future. Although there has been a reduction in student numbers and a subsequent 50 per cent reduction in HEIs commissioned by Scottish Government to provide pre registration midwifery courses, there has been a sustained effort to increase collaborative working between HEIs and explore innovative ways to maintain sign of mentors and support students in practice. Scotland offers midwifery students a wealth of opportunities through a wide range of practice placements form urban to remote and rural enabling them to gain the knowledge skills and experience required to enter the midwifery profession on a sound footing. PMID- 23082396 TI - Ringing in my ears: tinnitus in pregnancy. AB - A number of ear, nose and throat symptoms are often associated with pregnancy, which although transient (most will disappear after birth), can have a significant impact on the woman's quality of life. It is essential therefore that midwives are aware of how such symptoms might present during pregnancy, in order to appropriately inform women and safely manage those symptoms. Tinnitus, the most common ear symptom experienced by women during pregnancy, for some will be a distressing experience and for others may indicate more serious conditions such as pre eclampsia, requiring careful monitoring and confident management. PMID- 23082397 TI - Moxibustion to turn the breech. AB - Midwives at West Middlesex NHS Trust (WMUH) have been trained in the use of moxibustion to turn a breech presentation. This paper informs the reader of this service, how it was implemented, the audit and importance of maintaining accurate data as well as the resulting changes to the service. Moxibustion appears to be a safe, easy and cost effective way to promote cephalic presentation and is offered prior to external cephalic version (ECV). PMID- 23082398 TI - What midwives need to know about baby massage. AB - Baby massage has become increasingly popular in the West among parents and healthcare practitioners alike, with numerous studies continuing to hail the benefits of taking time to massage and bond with your baby. Newborn and infant massage is of particular interest to midwives in their primary role, helping families to bond and heal the pain of traumatic births, but now many midwives are offering baby massage sessions privately in their spare time also. Here's the low down. PMID- 23082399 TI - How complimentary can midwives be about acupuncture? AB - As midwives we strive to provide woman centred holist care and acupuncture fits this paradigm well. It creates an opportunity for a woman to gain control, an alternative to the medical solutions. Studies on neurophysiology may explain why acupuncture has a calming effect. Midwives and obstetricians are well placed to offer pregnant women acupuncture and although more research is needed, there is enough evidence to consider its development within maternity services as an option. This article provides evidence that acupuncture can be an effective treatment and should be a part of informed choice discussions for conditions related to pregnancy. PMID- 23082400 TI - Hypnotherapy for childbirth. AB - The birthing process, although often a joyful and proud moment, can also create an overwhelming sense of anxiety. As a result some women are now turning to hypnobirthing to help them to cope. This practice is used to relax women before and during their labour. It also helps encourage a stress free birth and reduce the need for drugs and interventions, such as caesarean section. In this article, Sheila Granger helps to dispel some of the myths surrounding the use of hypnotherapy and looks specifically at its application to childbirth. The role of midwives and the benefits to them are also discussed. PMID- 23082401 TI - Homeopathy for common complaints during pregnancy and childbirth. AB - Many expectant mothers do not want to use conventional medicine during pregnancy. As homeopathic remedies contain minute doses of specially prepared substances, unwanted side effects are avoided, making such remedies useful alternatives to use during pregnancy or when treating infants. This article describes various conditions of pregnancy and the homeopathic remedies which can help to alleviate unpleasant or harmful symptoms. PMID- 23082402 TI - Preparation for birth and beyond: caring for our baby. AB - A baby's earliest relationships with the mother and father are critical in terms of the way in which their highly plastic brain develops. It is through 'mutual gaze'-that is looking at the parents'faces - that s/he learns about the range of emotions which humans experience. As a result of being talked to, touched and responded to when distressed, s/he develops social skills and emotional intelligence. Preparation for birth and beyond looks at how parents can interact with their babies both through physical care and through talking and playing. PMID- 23082403 TI - This is how we do it. AB - The purpose of this article is to explore students' experiences of variations in practice and how this impacts on their learning. This is particularly pertinent in terms of reconfiguration of services instigated by the Department of Health's (DH) Making it better agenda (DH 2007), meaning that many qualified staff are moving hospitals and also experiencing changes in practice. Students are thus being mentored by a range of mentors in a variety of settings, which can often mean that practice can be perceived as inconsistent and even idiosyncratic (Jones et al 2005). This writing is unique in that the midwifery lecturer facilitated the students' development of the work in a truly collaborative piece, developed through a writing and journal club. All details of the practice placements and the student comments have been anonymised. PMID- 23082404 TI - Breastfeeding: looking beyond the debate. AB - A Patchwork text is typically a series of short pieces of writing relating to one topic from different perspectives (Winter 2003). For example: critique of an article; detailed analytical accounts of personal experience; appraisal of culture and society within practice. The pieces are written over a period of time and discussed with peers for review to encourage reflection in an attempt to move away from surface learning. This particular patchwork offers a critical appraisal of support offered to a breastfeeding woman, from a student midwife perspective. Through the medium of a patchwork text, Amy Morton was able to critically reflect on her practice, appreciate the cultural issues regarding the woman's experience and explore the relationship between key ideas to engage in a deeper level of learning and formulate an action plan for her future practice. PMID- 23082405 TI - Supervised practice: a midwife's reflective journey. AB - The Nursing and Midwifery Council (NMC) (2007) defines supervised practice as a structured and formal programme, devised to provide a midwife whose practice falls short of the required professional standards, with learning opportunities to enrich his/her clinical experience and improve practice. The primary aim is to ensure that the period of development agreed by the Local Supervising Authority Midwifery Officer (LSAMO) in supporting the midwife to improve their knowledge and skills, is subject to scrutiny through assessment, evaluation and reflection. The importance of reflective learning in midwifery practice is well recognised. This article provides the reflective account of a midwife's personal experience of supervised practice. PMID- 23082406 TI - Parents, we need your views. AB - In order to meet NMC requirements, the University of Hertfordshire (UH) has recently begun inviting service users to participate in the interviewing of candidates for the pre registration midwifery programmes. Inclusion and exclusion criteria for the definition of'service user' were agreed. Service users were sourced initially from UH staff, then from a wider pool including members of relevant local organisations. Recruitment is an ongoing process and now that payment has been agreed, it is hoped to attract service users from wider social backgrounds. Service users interview alongside lecturers or clinicians and verbal feedback has been very positive. Unexpected issues have nevertheless arisen and a working party has been set up to discuss these. Formal evaluation of service user involvement is expected before 2013. PMID- 23082407 TI - A multi disciplinary obstetric emergency training programme. AB - The Rotunda Hospital (Dublin) obstetric emergency training programme (RHOET) was designed, in 2008, to meet the ongoing education and training needs of the local multidisciplinary team. Prior to its implementation, senior midwives attended the advanced life support in obstetrics (ALSO) course, and many of the obstetricians attended the Management of obstetric emergencies and trauma (MOET) and/or ALSO courses. Attendance at these off site courses meant that the only opportunity for team training was the informal and ad hoc 'drills and skills' that took place in the birthing suite. This paper documents our journey since RHOET was implemented. PMID- 23082408 TI - Best practice into common practice. PMID- 23082409 TI - ["A matter of balance--Netherlands": an effective intervention to reduce concerns about falls and related avoidance of activity in older people]. AB - Concerns about falls and related avoidance behavior are common among older people and may lead to decreased quality of life, decreased physical and psychosocial functioning, and premature admission to a nursing home. In a randomized controlled trial among 540 community-dwelling older people we studied the feasibility and effects of a cognitive behavioral program on concerns about falls, related avoidance of activity, and falls. Data of the process evaluation obtained from participants in the intervention group (n = 280) and the trainers (n = 6) showed that the program was considered as feasible by the trainers, and positively judged by participants and trainers. Furthermore, participants experienced benefits from attending the program (61% still reported benefits one year after the program). Prior to the start of the program 26% of the participants of the intervention dropped out, yet, among the participants who started the program completion was high (84%). The effect evaluation showed positive outcomes for concerns about falls, related avoidance of activity, and daily activity at 2 months (after the program) when comparing the intervention group with the control group (n = 260). Long-term effects were also shown for, amongst others, concerns about falls and recurrent falls. Following these positive results the cognitive behavioral group program is currently made available to geriatric care settings nationwide in the Netherlands. PMID- 23082410 TI - [Routinization in old age]. AB - Although it is generally known, and even quoted as a quite ordinary failing of old age, routinization has been rarely the subject of scientific investigation. Is this behaviour so "ordinary" as seem to affirm the usual prejudices? In the present article, the authors present an overview of their work on this question. They developed a 10-item 5-point Likert Scale of Preference in Routine. The scale has been validated and related to age, anxiety and depression as well as cognitive deterioration. The results confirm that the routinization can be an interesting indication of vulnerability that must be taken in consideration especially in dealing with institutionalized elderly. PMID- 23082411 TI - Stroke registry--relevance and contributions. PMID- 23082412 TI - Contemporary surgical management of advanced end stage emphysema: an evidence based review. AB - Emphysema is a progressive unrelenting component of chronic obstructive pulmonary disease and a major source of mortality and morbidity globally. The prevalence of moderate to severe emphysema is approximately 5% in Malaysia and likely to increase in the future. Hence advanced emphysema will emerge as a leading cause of hospital admission and a major consumer of healthcare resources in this country in the future. Patients with advanced disease have a poor quality of life and reduced survival. Medical therapy has been largely ineffective for many patients however certain subgroups have disease amenable to surgical palliation. Effective surgical therapies include lung volume reduction surgery, lung transplantation and bullectomy. This article is a comprehensive evidence based review of the literature evaluating the rationale, efficacy, safety and limitations of surgery for advanced emphysema highlighting the importance of meticulous patient selection and local factors relevant to Malaysia. PMID- 23082413 TI - The use of laboratory and physiological parameters in predicting mortality in sepsis induced hypotension and septic shock patients attending the emergency department. AB - INTRODUCTION: In this study, we sought to determine whether laboratory and physiological parameters can be useful in predicting mortality in patients with sepsis-induced hypotension and septic shock. METHODOLOGY: This prospective cohort study was carried out in the emergency department at an academic medical center. A total of 51 patients met enrollment criteria during the study period and 41 of them were included in the study. Inclusion criteria were patients 18 years old or older, diagnosed to have either sepsis-induced hypotension or septic shock and investigated sepsis marker (blood lactate and leukocytes) measured. Other physiological variables were also measured in this study. The main outcome measure was 30-day mortality. Kaplan-Meier, Log-rank and Cox's methods were used for statistical analysis using SPSS version 12.0.1. RESULTS: 61% were diagnosed to have sepsis-induced hypotension and 39% were diagnosed with septic shock. Twenty two (54%) deaths occurred within the 30 day follow up. The overall mean blood lactate level and leukocyte counts were 3.52 mmol/L (5D = 2.29) and 11.37 x 109 (SD = 6.38) respectively. A Cox Proportional Hazard Analysis revealed an increase in blood lactate levels in the ED was associated with an increased risk of death (B = 0.35, HR = 1.45, 95% CI 1.22, 1.73, p < 0.001). However no significant correlation between the physiological parameters and the 30-day mortality. Patients with septic shock state prior to initial presentation has a lower 30 day survival compared to any other septic conditions. CONCLUSION: Our results support blood lactate level as a promising risk stratification tool when compared with leukocytes counts and other physiological parameters. The multivariate analysis showed that for every increment of lactate value of 1 mmol/L, the hazards of dying are expected to increase by 1.5 times (p < 0.001). PMID- 23082414 TI - Short term outcome of therapeutic hypothermia in term infants with moderate to severe hypoxic ischaemic encephalopathy; the Sungai Buloh experience. AB - This analysis is a case-series to document the outcome of term newborns with hypoxic ischaemic encephalopathy (HIE), enrolled into total body hypothermia therapy, in a tertiary neonatal unit in Malaysia. The method used to achieve total body hypothermia is a novel method using just environmental temperature, without the need of expensive equipment. A total of 17 babies were eligible to be included in this study, from the 1st of January 2010 to the 31st of December 2010. 14 out of 15 babies who had Stage 2 HIE had no neurological deficit at follow-up. All Stage 3 HIE babies passed away. Allowing for the small sample size, we can conclude that total body hypothermia therapy is feasible and is a safe treatment modality for HIE Stage 2 babies in a Malaysian setting, by manipulating environmental temperature to achieve therapeutic hypothermia. Further work is needed to determine the long-term outcome of passive cooling total body hypothermia in Stage 2 HIE babies in Malaysia. PMID- 23082415 TI - The presence of heterogeneous vancomycin-lntermediate Staphylococcus aureus (heteroVISA) in a major Malaysian hospital. AB - This study was conducted to detect the presence of heterogenous vancomycin intermediate Staphylococcus aureus (heteroVISA) among MRSA isolates in a major hospital. Forty-three MRSA isolates with vancomycin MIC 2 microg/ml collected in 2009 was screened for heteroVISA using Etest Glycopeptide Resistance Detection (GRD) and confirmed by population analysis profile-area under curve method. The genetic relatedness of heteroVISA strains with other MRSA was examined by pulsed field gel electrophoresis (PFGE) method. Two isolates were shown to be heteroVISA and derived from the same clone. This showed that heteroVISA strains were already present among our local strains since 2009 and were genetically related to other susceptible strains. PMID- 23082416 TI - Habits of contact lens wearers toward lens care in Malaysia. AB - The purpose to do this research was to find out the habits of contact lens wearers towards lens care in this country, and to evaluate the compliance of contact lens wearers. METHODS: All respondents underwent an interview regarding questionnaire which was carried out at the Klang Valley and Sabah, Malaysia by trained bilingual optometrists. The questionnaire was obtained from a study by Yvonne Wu et al., 2010. The questionnaire included information about respondents' demographics, contact lens hygiene behaviors and attitudes toward lens care. Comparison between groups and certain factors of lens care were analyzed. RESULTS: Within the 100 respondents, 74% were female. The majority used monthly disposable lens (53%, 53/100), 35% (35/100) wore daily lens, 3% (3/100) wore biweekly disposable lens, 8% (8/100) wore quarter-yearly (3 months) lens, and only a participant (1%) used conventional lenses. The major non-compliance aspect that found out from this research were poor lens case (46%), inadequate cleaning of lens before storing (38%) and wearers not remembering how often they were advised to return for an aftercare (24%). CONCLUSION: The poor lens care hygiene, inadequate cleaning of lens before storing may due to lack of proper advice to the contact lens wearers during examination or lack of awareness of aftercare visit. PMID- 23082417 TI - Factors predicting outcome of cardiopulmonary resuscitation among elderly Malaysians: a retrospective study. AB - Cardiopulmonary resuscitation (CPR) has been standard treatment for all cardiac arrest patients that arrive at the Emergency Department. However it is unclear whether prolonging resuscitation among the elderly victims will provide any benefit or improve outcome. This study is to evaluate factors that can influence outcome of CPR among the elderly, such as time of arrest, duration of CPR, lactate levels and age (among elderly age groups). 89 patients fit the inclusion criteria from January 2007 to January 2009, and all underwent CPR. Lactate levels (p=0.047) and duration of CPR performed (p=0.019) had significant relation to outcome. Time of arrest to CPR and age had no significance. Of 89 patients studied, 4 (4.5%) survived to hospital discharge. The remaining 85 (95.5%) died either in the emergency department, the wards or the Intensive Care Unit. Among the survivors, only 2 (2.3%) functional (independent on activities of daily life) patients were identified. Among the survivors, the mean lactate level was 4.0 mmol/L. The mean lactate levels among the dead were 9.84 mmol/L. The mean length of CPR among the survivors was 5.42 minutes and for the non-survivors, 19.28 minutes. This study reports certain factors such as duration of resuscitation and initial lactate levels that can be valuable tools in decision making when resuscitating an elderly. PMID- 23082418 TI - Does oral lansoprazole really reduce gastric acidity in VLBW premature neonates? AB - Premature neonates of very low birth weight (VLBW) whose treatment required the use of naso-gastric tube feeding were investigated. 10 infants suspected of having GERD (gastroesophageal reflux) received oral lansoprazole therapy by tube administration. 9 other infants formed a control group. In the treated group a fasting pH was determined before treatment and again after 7 days treatment. The control group was similarly assessed at an interval of 7 days. Despite acid reduction, the post-treatment pH mean of 1.31 would continue to pose a threat to the esophageal mucosa. The physiology of neonatal acid secretion is discussed to explain these findings. PMID- 23082419 TI - Comparing the morbidity of external laryngeal nerve injury in thyroid surgery with and without identifying the nerve using intraoperative neuromonitoring. AB - OBJECTIVE: To describe and determine the possibility of surgical trauma to the external branch of the superior laryngeal nerve and to assess the role of intraoperative neuromonitoring in thyroid surgery. DESIGN AND SETTING: Prospective, randomized, controlled study in a teaching Hospital Universiti Sains Malaysia (HUSM), Kota Bharu, Kelantan, Malaysia. SUBJECTS: Forty two patients of both genders, whom underwent thyroid surgery divided into two groups (21 patients control group and 21 patients study group) in HUSM and were randomly selected for our study. METHODS: The use of nerve monitoring and proper surgical technique of upper thyroid pole dissection followed by its lateralization and exposure of cricothyroid space were performed in each subject in study group in order to preserve EBSLN after its identification. In control group upper thyroid vessels were ligated close to the upper thyroid pole without any effort of EBSLN identification. RESULTS: Total of 42 (35 females and 7 males) patients who underwent thyroid surgery in a period of 2 years. Evaluation of all subjects 1 case in control group presented with symptoms of EBSLN injury. CONCLUSION: Intraoperative identification and neuromonitoring can avoid injury to the EBSLN and prevent its sequential changes in voice especially for those who professionally depend to their voice. PMID- 23082420 TI - Outbreak of melioidosis and leptospirosis co-infection following a rescue operation. AB - We analyzed the epidemiological data of all people who were involved in the search and rescue operation in Lubuk Yu, a natural recreational forest with waterfall and stream. The hospital admission records of the cases who fulfilled the case definition and the environmental samples result taken at Lubuk Yu recreational area were studied. 153 people were exposed to this outbreak, 85 (55.5%) were professional rescuers from various government agencies and 68 (44.5%) were villagers. 21 fulfilled the case definition. Ten cases were confirmed melioidosis, six melioidosis alone and four coinfected with leptospirosis. There were eight deaths in this outbreak, seven were villagers and one professional rescuer. Overall case fatality was 70%. All confirmed melioidosis cases and seven who died had diabetes mellitus. The morbidity rate were higher among the villagers, 23.5% compared to professional rescuers, 5.9%. The case fatality rate were also higher in this group which was 100% compared to 33.3% in professional rescuers. The soil and water samples in Lubuk Yu recreational area were positive for leptospira and Burkholderia pseudomallei. The presence of co-infection and co-morbidities especially diabetes mellitus among the exposed led to the high mortality in this outbreak hence a high index of suspicion is important among the healthcare professionals in the management of melioidosis cases. To avoid similar incident in future, search and rescue operation should be only conducted by professional rescuers with appropriate personal protective equipment. A register of rescuers should be maintained for surveillance and follow up if necessary. PMID- 23082421 TI - Oral health quality-of-life among undergraduate Malaysian dental students. AB - AIM: To assess the oral health quality of life among Malaysian dental students using the Oral Impacts on Daily Performance (OIDP) scale. MATERIAL AND METHOD: Malaysian dental students of Melaka Manipal Medical College, Manipal campus, Manipal University, Manipal answered a structured questionnaire recording the demographic characteristics, behavioral characteristics and eight items of OIDP. RESULTS: The mean OIDP ADD and OIDP SC scores were respectively, 4.10 (sd = 5.16, range 8 - 40) and 2. 3 (sd = 2.3, range 0-8). A total of 50%, 32.9% and 28.6% of the dental students confirmed difficulties with eating, cleaning teeth and sleeping and relaxing, respectively. Statistically significant relationships were observed between OIDP (ultimate oral impact) and a count of non-clinical oral health indicators representing the second (intermediate) levels of oral impact. Logistic regression analysis revealed that dental students who were dissatisfied with their oral health had greater oral impact than their counterparts. The odds ratios for satisfaction with oral health, dental visits and frequency of brushing teeth were respectively 1.74 (0.58-5.32), 0.59 (0.11-3.24) and 1.33 (0.41-4.30). CONCLUSION: The study reports the Oral Impact on Daily Performance among Malaysian dental students and provides evidence of importance of social and behavioral characteristics in shaping dental students response. PMID- 23082422 TI - National Stroke Registry (NSR): Terengganu and Seberang Jaya experience. AB - The National Stroke Registry (NSR) was established in 2009 under National Neurology Registry (NNeuR) . The main objectives of NSR were to describe the demographic and disease pattern of stroke patients in Malaysia, to examine the risk factors and evaluate the specified treatment and outcomes. This prospective observational study was carried out from August 2009 until December 2010 using a standardized case report form which involved two participating hospital, namely Hospital Sultanah Nur Zahirah, Kuala Terengganu and Hospital Seberang Jaya, Pulau Pinang. There were 1018 patients registered. Ischemic stroke accounted for the majority of cases (73.3%). The most common risk factor was hypertension (75.5 %), followed by diabetes mellitus, previous stroke or Transient Ischemic Attack (TIA), hyperlipidemia and active smoker: 45.6%, 25.1%, 22.4%, and 19.4%, respectively. Overall, our stroke management, based on nine stroke key performance indicators (KPI) still needs to be improved. There was a total of 121 mortality cases with the main contributing factor was massive cerebral bleed (21.6%). In conclusion, the findings highlight the important of primary and secondary stroke management. Further and continuous observation with more site date provider (SDP) involvement is needed to get a more comprehensive data on stroke in Malaysia. PMID- 23082423 TI - The role of repeat head computed tomography in the management of mild traumatic brain injury patients with a positive initial head CT. AB - This was a prospective observational study done to evaluate the role of a repeat head CT in patients with mild traumatic brain injury. The aim was to evaluate wether the repeat head CT were useful in providing information that leads to any neurosurgical intervention. 279 adult patients with a mild head injury (GCS 13 15) were enrolled, and these comprised of patients with an initial traumatic intracranial haemorrhage not warranting any surgical intervention. All patients were subjected to a repeat head CT within 48 hours of admission and these showed no change or improvements of the brain lesion in 217 patients (79.2%) and worsening in 62 patients (20.8%). In thirty-one patients, surgical intervention was done following the repeat head CT. All of these patients had a clinical deterioration prior to the repeat head CT. Even if a repeat head CT had not been ordered on these patients, they would have had a repeat head CT due to deteriorating neurological status. When the 62 patients with a worsening repeat head CT were compared with the 217 patients with an improved or unchanged repeat head CT, they were found to have older age, lower GCS on admission, presenting symptoms of headache, higher incidence of multiple traumatic intracranial pathology and lower haemoglobin level on admission. On stepwise multiple logistic regression analysis, three factors were found to independently predict a worse repeat head CT (Table IV). This includes age of 65 years or older, GCS score of less than 15 and multiple traumatic intracranial lesion on initial head CT. As a conclusion, we recommend that, in patients with a MTBI and a normal neurological examination, a repeat cranial CT is not indicated, as it resulted in no change in management or neurosurgical intervention. Close monitoring is warranted in a subset of patients with risk factors for a worsening repeat head CT. PMID- 23082424 TI - Criterion validity of the PHQ-9 (Malay version) in a primary care clinic in Malaysia. AB - OBJECTIVE: This study was conducted to determine the validity of the 9-item Patient Health Questionnaire (PHQ-9) (Malay version) as a case-finding instrument for depression among women in a primary care clinic. METHODS: A cross sectional study was conducted in a primary care clinic in Malaysia. Consecutive adult women patients who attended the clinic during data collection were given self administered questionnaires, which included the PHQ-9 (Malay version). Systematic weighted random sampling was used to select participants for Composite International Diagnostic Interviews (CIDI). The PHQ-9 was validated against the CIDI reference standard. RESULTS: The response rate was 87.5% for the questionnaire completion (895/1023), and 96.8% for the CIDI interviews (151/156). The prevalence of depression was 12.1% (based on PHQ-9 scores of 10 and above). The PHQ-9 had a sensitivity of 87% (95% confidence interval 71% to 95%), a specificity of 82% (74% to 88%), positive LR 4.8 (3.2 to 7.2) and negative LR 0.16 (0.06 to 0.40). CONCLUSIONS: The Malay version of the PHQ-9 was found to be a valid and reliable case-finding instrument for depression in this study. Together with its brevity, it is a suitable case-finding instrument to be used in Malaysian primary care clinics. PMID- 23082425 TI - The role of multislice computed tomography (MSCT) in the detection of blunt traumatic intra abdominal injury: our experience in Hospital Tengku Ampuan Afzan (HTAA), Kuantan, Pahang. AB - Multislice computed tomography (MSCT) is the imaging modality of choice in assessing clinically stable patients with blunt abdominal trauma. This study assessed the role of MSCT in the detection of intra abdominal injury caused by blunt trauma in our centre within a two-year-period (2008-2009). A total of 151 patients had MSCT abdomen for blunt abdominal trauma within this study period. Positive scan were seen in 126 patients (83.4%). Out of these positive scans, liver, spleen and renal injuries were seen in 42.1% (n = 53), 34.9% (n = 44) and 30.0% (n = 34) of cases respectively. Laparotomies were performed in 45 patients. Out of these 45 laparotomies, 10 patients had surgically significant injuries that were missed on CT scan findings. The injuries were bowel perforation (n = 4), serosal tear of bowel (n = 1), mesenteric injuries with active haemorrhage (n=3), spleen injury (n = 1) and liver injury (n = 1). PMID- 23082426 TI - Concurrent massive breast enlargement, myasthenia gravis and dermopathy as manifestations of penicillamine toxicity in a Wilson's disease patient. AB - Penicillamine toxicity in Wilson's disease has been well reported but rarely seen now as newer agents are being used. We present a case who developed multiple rare complications of Penicillamine concurrently. Our patient is one of three siblings on Penicillamine, she was the only one who developed massive breast enlargement four months after commencing Penicillamine therapy, as well as dermatological adverse reactions and myasthenia gravis three more months later. All the adverse effects improved soon after substitution of the offending agent with Trientine. PMID- 23082427 TI - A rare case of autoimmune hepatitis overlapping with autoimmune haemolytic anaemia and immune thrombocytopenic purpura in a male patient. PMID- 23082428 TI - Recurrent glossal leiomyoma. AB - Oral leiomyomas are rare benign tumour of smooth muscle. The first case of oral leiomyoma was reported by Blanc in 1884 and since then more cases has been published following advancement in immunohistochemical study. This tumour has an excellent prognosis and recurrences are extremely rare. We report a case of a recurrent glossal leiomyoma in a patient with HIV infection and the lesion recurred one year after the first excision. PMID- 23082429 TI - Mason on a surgical mission. PMID- 23082430 TI - Gouty wrist arthritis causing carpal tunnel syndrome--a case report. AB - A 63 year old male with a history of gout and hypertension presented with carpal tunnel syndrome. He gave history of bilateral wrist pain associated with numbness over the median nerve distribution of the hand. Tinels sign and Phalens test were positive with no obvious thenar muscle wasting on examination. Tophaceous deposits in the flexor tendons and within the synovium of the wrist joint was seen during surgery and this established gout as the cause of median nerve entrapment in this patient. PMID- 23082431 TI - Primary clear cell carcinoma of minor salivary gland of the soft palate: a case report. AB - Clear cells can be found in numerous salivary and non-salivary tumors in the head and neck region, including metastatic lesions. They are rare low-grade tumors accounting for less than 1% of all salivary gland tumors and occur almost exclusively in the intra-oral minor salivary glands. Hyalinizing clear cell carcinoma (HCCC) is an extremely rare and recently described neoplasm predominantly affecting the oral cavity. Histologically, it is characterized by nests of glycogen-rich monomorphic clear cells within a hyaline stroma. HCCC often follows an indolent course with a limited metastatic potential. It is therefore important to differentiate this entity from other more aggressive clear cell tumors including metastatic tumors such as renal cell carcinoma. We hereby report a case of HCCC localized in minor salivary glands specifically in soft palate for its rarity, as well as to discuss the role of immunohistochemical stains, essential for its definitive diagnosis. PMID- 23082432 TI - Citrobacter koseri bacteraemia complicated by paraspinal abscess and spondylodiscitis--a case report. AB - Paraspinal abscess and spondylodiscitis due to Citrobacter koseri is a very rare condition. We report a remarkable case of Citrobacter koseri bacteraemia complicated by paraspinal abscess and spondylodiscitis in a patient who has successfully been treated in our hospital. Our patient demonstrates one of the common challenges in the practice of infectious disease medicine, wherein an innocuous presentation may and often underlie a serious infection. This case report elucidates to us that the diagnosis of a paraspinal abscess and spondylodiscitis requires a high index of suspicion in at risk patient presenting with compatible signs and symptoms. PMID- 23082433 TI - Lemierre syndrome. AB - Lemierre syndrome is an uncommon disease which commonly arise from acute bacterial oropharyngeal infection. This disease was first described in 1900 by Courmont and Cade Lemierre. It is commonly caused by Fusobacterium necrophorum. Lemierre syndrome has been reported to be serious and potentially fatal in the preantibiotic era. It is characterized by an oropharyngeal infection leading to secondary septic thrombophlebitis of the internal jugular vein with embolization to the lungs and other organs. The incidence has become relatively rare at present and is usually only diagnosed when unsuspected culture results are available. We report a case of Lemierre syndrome which was recently diagnosed in our centre. PMID- 23082434 TI - An extensive cervical vagal nerve schwannoma: a case report. AB - Vagal nerve schwannoma is extremely rare. The majority of cases present with a slow growing neck swelling without neurological deficit. Magnetic resonance imaging is the gold standard investigation to establish a pre-operative diagnosis. We report a case of a 32-year-old man with an extensive right vagal nerve schwannoma involving the right jugular foramen and parapharyngeal space. The tumour was resected via a transcervical approach. Complete excision of the tumour is the key to prevent recurrence. PMID- 23082435 TI - Cervical schwannoma: report of four cases. AB - Extracranial schwannomas in the head and neck region are rare neoplasms. The tumours often present as asymptomatic, slowly enlarging lateral neck masses and determination of the nerve origin is not often made until the time of surgery. Preoperative diagnosis maybe aided by imaging studies such as magnetic resonance imaging or computed tomography, while open biopsy is no longer recommended. The accepted treatment for these tumors is surgical resection with preservation of the neural pathway. We report four cases of cervical schwannomas that we encountered at our center during four years of period. The clinical features, diagnosis and origin, management and pathological findings of these benign tumors are discussed. PMID- 23082436 TI - The use of dental drill in removing entrapped finger by metal ring in emergency department. AB - Ring removal is indicated in a number of clinical circumstances to manage or prevent tourniquet effect of the digit. A ring made from hardened metal may defy commonly known methods of removal. We reported a case of unusual difficulty in removing a ring of hardened metal composition using a dental drill. We believed the unusual circumstances of this case is likely to be repeated in some other clinical practice and this instrument is an appropriate option to consider in such cases. PMID- 23082437 TI - Successful treatment of perioperative very late stent thrombosis with thromboaspiration device. PMID- 23082438 TI - Ear foreign body: tackling the uncommons. PMID- 23082439 TI - Managing diabetes during the Muslim fasting month of Ramadan. AB - Target blood sugar levels in diabetes are achieved through manipulation of diet, exercise and medication. A change in any one of these three things can skew blood sugar levels and create complications associated with hyperglycemia or hypoglycemia. Fasting during the month of Ramadan is a religious activity that devout Muslims practice whether they are diabetic or not. Since such fasting involves abstinence from food and water for twelve hours or more during the day from dawn to dusk, it is evident that advice regarding exercise and medication will have to be modified during this period. PMID- 23082440 TI - The Kuala Lumpur Declaration on Promotion of Scholarly Writing Skills and Standards in the Asia Pacific Region. PMID- 23082441 TI - Hypertension control in chronic kidney disease: don't miss the forest for the trees. PMID- 23082442 TI - Morbidity profiles at three primary care clinics in Perlis, Malaysia. PMID- 23082443 TI - Diabetic retinopathy in native and non-native Sarawakians--findings from the Diabetic Eye Registry. AB - This study aims to determine the risk factors associated with diabetic retinopathy (DR) among natives and non-natives Sarawakians who were seen at 3 public hospitals and one health clinic in Sarawak. It is a cross sectional study where data on patients with DM were collected by staff at these healthcare facilities and entered into the web-based Diabetic Eye Registry. Univariate and multivariate analysis was used to determine the association factors for DR. DR was significantly less associated with natives (24.4%) compared to non-native Sarawakians (34.1%) (p < 0.001). The odds of getting DR was higher in patients whose duration of DM was more than 20 years (OR = 2.6), who have renal impairment (OR = 1.7) and non-natives (OR = 1.4). PMID- 23082444 TI - Respiratory symptoms and pulmonary function of workers employed in textile dyeing factory in Turkey. AB - Dyes are known to be a causative agent of occupational asthma exposed to them. We evaluate respiratory symptoms among textile. The study population comprised 106 exposed workers and control (unexposed) group. Data were collected by a questionnaire. Pulmonary Function Tests (PFTs) were performed. Among the exposed workers 36.8% defined phlegm. Respiratory symptoms were not significantly different between two groups. The employment duration of the exposed workers with phlegm was longer than those without phlegm (p = 0.027). The mean % predicted of forced expiratory flow (FEF) 25-75 of the exposed workers was found to be significantly lower than the control (unexposed) group (p = 0.01). Our study suggests that textile dyeing might cause respiratory symptoms at workers. PMID- 23082445 TI - Effectiveness of antihypertensive drugs in hypertensive patients with end stage renal failure. AB - Hypertension has been identified as one of the causes for end stage renal failure (ESRF) and is likely to worsen kidney function. This retrospective study was carried out at a tertiary hospital in Malaysia with the objective of determining the effectiveness of combination antihypertensive drugs in hypertensive patients with ESRF admitted between 2006 and 2008. Patients with incomplete data and who were on monotherapy were excluded from this study. Although six different combinations gave significant reductions in systolic blood pressure (SBP) (13.38 +/- 9.11 mmHg, p < 0.05) and diastolic blood pressure (DBP) (6.03 +/- 11.39 mmHg, p < 0.05), 69.16% patients did not achieve target blood pressure (BP) (< or = 130/80 mmHg). Combination of beta blocker (BB) with calcium channel blocker (CCB) was the most commonly used. The CCB-diuretic regimen achieved highest percentage of BP control compared to others (40%). Comparison of blood pressure reduction between different combinations of antihypertensive drugs were not significant (p > 0.05) except for CCB-diuretics and BB-CCB-alpha blocker. The findings suggested better BP control with CCB-diuretic relative to other combinations used. PMID- 23082446 TI - Clinical use of Malay Version of Vertigo Symptom Scale (MWSS) in patients with peripheral vestibular disorder (PVD). AB - INTRODUCTION: The Vertigo symptom scale (VSS) is a well established tool for the evaluation of vestibular disorders and the associated symptoms of autonomic arousal and somatosensation. By using a validated Malay version of vertigo symptom scale (MVVSS) questionnaire, the severity of the vertigo from patients' perspective can be determined and rated. Before MVVSS can be applied clinically among Malaysians, it was of interest to determine its clinical value in identifying vestibular disorders. METHOD: Forty normal and 65 PVD subjects participated in this cross-sectional study. Normal subjects were recruited amongst Universiti Sains Malaysia (USM) staff and students who had no history of ear and vestibular disorders. RESULTS: Mean total score of MVVSS in normal and PVD subjects were 13.9 +/- 11.1 and 30.1 +/- 20.9, respectively. When the total scores of normal and PVD group were compared, the Mann-Whitney U test showed that there was a significant difference between the two groups (p < 0.05). This is consistent with previous studies. It was also of interest to see if subtypes of PVD [benign paroxymal positional vertigo (BPPV), Meniere's disease, labyrinthitis and unknown] have different MVVSS results. However, analysis of variance (ANOVA) found no significant difference in term of outcomes of MVVSS among the different PVD pathologies. Using receiver operating characteristic curve (ROC) method, the sensitivity and specificity of MVVSS were 71% and 60%, respectively. CONCLUSION: MVVSS is able to discriminate clinically among the normal and PVD subjects. However, it is not a good indicator for differential diagnosis of PVD subtypes, at least in this study. Its sensitivity and specificity in clinical diagnosis are reasonably high. Perhaps a bigger sample size would be useful to further study the clinical usefulness of MVVSS. PMID- 23082447 TI - Cabergoline effect on blood sugar in type 2 diabetic patients with oral agent failure. AB - Ergot-derived dopamine D2 receptor agonists are the usual treatment of hyperprolactinemia and Parkinson's disease and recently bromocriptine has been approved for the treatment of type 2 diabetes. The aim of this study was the evaluation of short-term effect of cabergoline in poorly controlled diabetic patients with oral agent failure who refused insulin therapy. METHODS: This study was performed in 17 overweight women and men with type 2 diabetes with persistent hyperglycemia in spite of treatment with maximum dose of sulfonylurea, metformin and pioglitazone. 10 patients (group I) randomized to be treated with cabergoline 0.5 mg weekly for 3 months and 7 patients (group II) with placebo. Fasting and postprandial plasma glucose concentration and HbAlc measured in beginning and end of the study. RESULTS: FBS decreased from 210.70 +/- 21.29 to 144.90 +/- 26.56 mg/dl in cabergoline group whereas it decreased in placebo group insignificantly. Postprandial blood glucose decreased from 264.2 +/- 28 mg/dl to 203.6 +/- 34.34 mg/dl in cabergoline group whereas it increased in placebo group insignificantly. HbA1c decreased in cabergoline group from 8.48 +/- 0.44 to 7.7 +/- 0.11 whereas in control group it increased insignificantly from 8.7 +/- 0.33 to 8.8 +/- 0.16. CONCLUSION: Cabergoline improves glycemic control in type 2 diabetic patients with oral agent failure. It reduces both fasting and postprandial plasma glucose levels and causes 0.45-1.11 reduction in HbA1c. PMID- 23082448 TI - Risk factors for neurosurgical site infections after a neurosurgical procedure: a prospective observational study at Hospital Kuala Lumpur. AB - INTRODUCTION: Surgical site infection (SSI) after craniotomy even though rare, poses a real risk of surgery and represents a substantial burden of disease for both patients and healthcare services in terms of morbidity, mortality and economic cost. The knowledge of risk factor for surgical site infection after craniotomy will allow the authority to implement specific preventive measures to reduce the infection rate. Therefore, the objectives of this study are to determine the incidence and the risk factors of surgical site infection after craniotomy. MATERIAL AND METHODS: This study highlights an observational prospective study on adult patients who has undergone neurosurgical procedures in Hospital Kuala Lumpur (HKL) over a period of 2 years (June 2007 to June 2009). The neurosurgical procedures are craniectomy, craniotomy, cranioplasty and burrhole. A total of 390 cases fulfilled the requirements of inclusion and exclusion criteria were included in the study. Every patient in the study population was prospectively evaluated for development and risk factors for SSI. The follow-up cases were done by direct observation of the wound during their post-operative stay and ideally up to and including day 30 post-operatively, either as in-patients or through post discharge surveillance i.e. follow-up in the clinic 30 days post-operatively. SSIs were defined according to the Center for Disease Control definitions. Incidence was calculated per patient. Univariate Simple Logistic Regression analysis was used to analyse the association of the risk factors and SSI. RESULTS: A total of 30 post craniotomy surgical site infections (SSI) has been identified among 390 cases included in the study, resulting in an overall infection rate of 7.7%. This included 19 with superficial wound infection (63.3%), 9 with bone flap osteitis (30%) and 2 with organ/space infection (6.7%). Most of SSIs were detected during in patient cases accounting for 20 cases. The mean time between surgery and the onset of infection was 11.8 +/- 21.8 days (median 10 days). The predominantly isolated organism in patients with SSIs were Staphylococcus aureus (11 or 36%) followed by MRSA (4 or 13%), and Acinetobacter spp (3 or 10%). Independent risk factors for SSI were surgeries that were performed by specialist (OR, 76.90 CI, 1.22-39.04.9; P 0.029) and senior medical officer (OR, 8.69 CI, 1.39-54.29.04.9; P 0.021) and surgery that was done for infective causes (OR, 4.44 CI, 1.33-14.81; P 0.015). ASA 2 and clean contaminated wound were independent predictive risk factors for SSI. CONCLUSIONS: Post craniotomy surgical site infection remains an important problem in neurosurgery. Identification of risk factors for SSI should help us to improve patient care, reduce mortality, morbidity and economic burden of health care cost. Post surgical surveillance is important as well to identify the reliable risk factors for SSI. PMID- 23082449 TI - Indications and outcome of anti-phospholipid syndrome testing in an obstetric population at Sabah Women & Children Hospital, Kota Kinabalu, Sabah, Borneo Malaysia. AB - AIM: We audited indications and outcomes of antiphospholipid syndrome (APS) screening in the pregnant population at our centre. METHOD: Prospective and observational. All APS test results returned were audited for validity of indication and subsequent outcome. RESULT: 24 of a total of 146 (16%) of requests for the antiphospholipid antibodies and lupus anticoagulant were not indicated. Two positive results returned for a total of 116 "indicated" requests (1.7%). CONCLUSION: There needs to be increased awareness among obstetricians on the indications for screening for antiphospholipid syndrome (APS). The prevalence of antiphospholipid syndrome with obstetric manefestations in the study population is lower than rates published in the literature. PMID- 23082450 TI - Prevalence of Clostridium difficile toxin in diarhoeal stool samples of patients from a tertiary hospital in North Eastern Penisular Malaysia. AB - This study describes the prevalence of Clostridium difficile toxin (CDT) in loose stool samples from inpatients aged more than two years of a tertiary hospital. A total of 175 samples that had been examined were from stool samples that were sent to the Medical Microbiology & Parasitology Laboratory for various clinical indications. The toxin was detected by a commercial immunochromatograhic test, and the patients' demography, clinical features, treatment and outcomes were analyzed from their medical records. Clostridium difficile toxin was positive in 24 (13.7%) of the stool samples. Male and female were 11 (45.8%) and 13 (54.2%) respectively, with the majority of them aged more than 50 years. Most were from medical wards (n = 21, 87.5%), with the rest from surgical wards (n = 2, 8.3%) and intensive care units (n = 1, 3.4%). All the CDT positive patients had history of prior antibiotic usage within 6 weeks before the detection of the toxin. The mean duration of antibiotics usage was 17.75 (+/- 13.75) days, while the mean duration of diarrhea was 5.21((+/- 5.85) days. Eighteen patients had underlying medical illnesses that were diabetes mellitus, chronic renal disease, hypertension, ischaemic heart disease, cerebrovascular disease and malignancy; with seven of them being CDT positive while on chemotherapy. Stool occult blood test was positive in 15 patients whereas presence of pus cells in the CD positive stool samples were detected in 21 patients. The duration of hospitalization among the patients was 27.96 (+/- 23.22) days. PMID- 23082451 TI - Value of Shock Index in prognosticating the short-term outcome of death for patients presenting with severe sepsis and septic shock in the emergency department. AB - INTRODUCTION: The importance of early recognition and treatment of sepsis and its effects on short-term survival outcome have long been recognized. Having reliable indicators and markers that would help prognosticate the survival of these patients is invaluable and would subsequently assist in the course of effective dynamic triaging and goal directed management. STUDY OBJECTIVES: To determine the prognosticative value of Shock Index (SI), taken upon arrival to the emergency department and after 2 hours of resuscitation on the shortterm outcome of severe sepsis and septic shock patients. METHODOLOGY: This is a retrospective observational study involving 50 patients admitted to the University of Malaya Medical Centre between June 2009 and June 2010 who have been diagnosed with either severe sepsis or septic shock. Patients were identified retrospectively from the details recorded in the registration book of the resuscitation room. 50 patients were selected for this pilot study. The population comprised 19 males (38%) and 31 females (62%). The median (min, max) age was 54.5 (17.0, 84.0) years. The number of severe sepsis and septic shock cases were 31 (62%), and 19 (38%) respectively. There were 17 (34%) cases of pneumonias, 13 (26%) cases of urological sepsis, 8 (16%) cases of gastro intestinal tract related infections and 12 (24%) cases of other infections. There were a total of 23 (46%) survivors and 27 (54%) deaths. The value of the shock index is defined as systolic blood pressure divided by heart rate was calculated. Shock Index on presentation to ED (SI 1) and after 2 hours of resuscitation in the ED (SI 2). The median, minimum and maximum variables were tested using Mann-Whitney U and Chi square analysis. The significant parameters were re-evaluated for sensitivity, specificity and cut off points. ROC curves and AUC values were generated among these variables to assess prognostic utility for outcome. RESULTS: Amongst all 7 variables tested, 2 were tested to be significant (p: < 0.05). From the sensitivity, specificity and ROC analysis, the best predictor for death was (SI 2) with a sensitivity of 80.8%, specificity of 79.2%, AUC value of 0.8894 [CI 95 0.8052, 0.9736] at a cut off point of > or = 1.0. CONCLUSION: (SI 2) may potentially be utilized as a reliable predictor for death in patients presenting with septic shock and severe sepsis in an emergency department. This parameters should be further analyzed in a larger scale prospective study to determine its validity. PMID- 23082452 TI - Co-morbid medical conditions and medical complications of prostate cancer in Southern Nigeria. AB - BACKGROUND: Prostate cancer often co-exists with other diseases. It accounts for 11% of all cancers in Nigerian men, and it is the commonest cause of mortality due to cancer in elderly males in Nigeria. OBJECTIVE: To present co-morbid medical conditions and medical complications of prostate cancer in patients with the disease in Southern Nigeria. PATIENTS AND METHODS: The study was carried out prospectively (2002 to 2003) at University of Port Harcourt Teaching Hospital (UPTH), and Nnamdi Azikiwe University Teaching Hospital (NAUTH) Nnewi- both in Southern Nigeria. Using common proforma, patients who presented to the urology units of the two teaching hospitals were evaluated clinically and with relevant investigations for prostate cancer and other diseases. Those with histologically confirmed prostate cancer were included in this study. Data was also collected retrospectively by using the same proforma to obtain information from case files of 37 patients diagnosed with prostate cancer at UPTH. Data from the two institutions were collated and analysed. RESULTS: Of 189 cases analysed, 73.4% had significant medical co-morbid diseases/complications. These included anaemia (69.8%), urinary tract infection (56.1%), chronic renal failure (33.9%), hypertension (41.8%), diabetes mellitus (9.5%), paraplegia (9.5%), congestive cardiac failure (9.0%) and cerebrovascular disease (5.3%). CONCLUSION/RECOMMENDATIONS: These patients had high disease burden. Improved health education and well coordinated interdisciplinary team work are suggested in managing this malignancy. PMID- 23082453 TI - Age and pathology of prostate cancer in South-Southern Nigeria; is there a pattern? AB - BACKGROUND: Prostate cancer is a common health problem world wide. Age is its strong risk factor. OBJECTIVE: To study the relationship between age at presentation and pathological features of prostate cancer in patients with the disease in South-Southern Nigeria. MATERIALS AND METHODS: Pathology slides of prostate specimens and clinical data were studied. Those with histological diagnosis of prostate cancer had these features analysed statistically. RESULTS: Three hundred and eighty three cases of adenocarcinoma of the prostate were studied. A falling mean age at presentation was observed. Observed pathological features had no statististically significant variation with ages. Poorly differentiated adenocarcinoma was the most common variant. CONCLUSION: The mean age at presentation of prostate cancer patients in Port Harcourt is decreasing. Gleason's score and level of cellular differentiation of the tumours have no statistically significant relationship with ages of the patients. These observations and the preponderance of poorly differentiated variant of the disease in Nigerian patients merit further studies. PMID- 23082454 TI - Moxifloxacin-warfarin interaction. PMID- 23082455 TI - Malignant melanoma of the foot in patients with diabetes mellitus--a trap for the unwary. AB - Melanomas on the foot are difficult to differentiate from diabetic foot ulcers (DFU). In particular, acral lentiginous and amelanotic melanomas have a high chance of being misdiagnosed. We present two patients with diabetes mellitus and malignant melanomas of the foot initially diagnosed as DFU. Both cases were treated with wide excision amputation and local dissection, without adjuvant chemotherapy or radiotherapy. Both patients remain disease-free up to the last follow-up visit. It is important to maintain a high index of suspicion and a skin biopsy should be done in any DFU with atypical features. PMID- 23082456 TI - Imaging findings of extensive splenic infarction after cyanoacrylate injection for gastric varices--a case report. AB - Endoscopic injection of N-Butyl-2-cyanoacrylate is a widely accepted treatment for esophagogastric varices. This procedure is commonly associated with minor complications which include transient pyrexia and abdominal discomfort. Serious vascular complications secondary to systemic embolization of cyanoacrylate have rarely been reported. We describe the CT findings of extensive splenic infarction in a patient following cyanoacrylate injection for gastric varices. PMID- 23082457 TI - Transcatheter closure of ventricular septal rupture with Swan Ganz balloon. PMID- 23082458 TI - A rare case of nasopharyngeal carcinosarcoma. AB - Nasopharnygeal carcinoma is known to be the commonest tumour of the nasopharynx. However, the incidence of nasopharngeal carcinosarcoma is extremely rare. Carcinosarcoma has been reported to be aggressive in nature and therefore early diagnosis and prompt treatment is important. We report a young lady who was diagnosed with nasopharyngeal carcinosarcoma in our centre. She presented with only 2 weeks history of nose block and was noted to have a mass occupying the nasopharynx with neck metastasis. She underwent panendoscope and biopsy with radical radiotherapy. PMID- 23082459 TI - Cutaneous metastases from head and neck squamous cell carcinoma. AB - The presence of cutaneous metastases in squamous cell carcinomas of the head and neck (SCCHN) is rare and associated with a dismal prognosis. It is vital to distinguish these lesions from direct invasion of the skin by SCCHN or primary cutaneous malignancies as the prognosis is vastly different and so is the management. In this case report, we present four cases of cutaneous metastases and also briefly review the literature pertaining to this phenomenon. PMID- 23082460 TI - First detected human bocavirus in a Malaysian child with pneumonia and pre existing asthma: a case report. AB - Human bocavirus (HBoV) is a newly discovered parvovirus associated with respiratory disease in children. There are many reports worldwide on the endemicity of this virus. Since it is relatively new, detection in clinical laboratories is not routinely performed. We describe the first detection of HBoV in Malaysia in a 13-month-old boy with pneumonia and underlying asthma. The infective agent was confirmed by molecular methods. PMID- 23082461 TI - Sturge-Weber-Syndrome with extreme ocular manifestation and rare association of upper airway angioma with anticipated difficult airway. AB - We report a rare case of an 18 year old girl with Sturge-Weber syndrome, she had extensive facial port wine stains, right bupthalmos and advanced glaucoma involving both eyes. She underwent right eye glaucoma drainage device surgery under general anaesthesia, and had a difficult intubation due to extensive angiomatous like soft tissue swelling at her upper airway. This report highlights the importance of being aware of the need for continuous follow-up in Sturge Weber syndrome patients as this syndrome can lead to blindness due to advance glaucoma and the awareness of possible difficult intubation for this group of patients. PMID- 23082462 TI - Case report: a rare case of pediatric conus medularis glioblastoma multiforme. PMID- 23082463 TI - Prevalence of overweight/obesity among the medical students, Malaysia. AB - BACKGROUND: Overweight and obesity are defined as abnormal or excessive fat accumulation that may impair health. Body mass index is a simple index of weight for-height that is commonly used in classifying overweight and obesity in adult populations and individuals. OBJECTIVES: A study was conducted to screen the medical students of AIMST University for overweight/obesity using Body Mass Index(BMI) and to determine the prevalence among them. MATERIALS AND METHODS: This is an institution based cross sectional study was conducted among 290 medical students using a pre-tested questionnaire and measured their Body Mass Index (BMI). Data obtained was analyzed statistically by calculating proportions. RESULTS: Out of 290 students who participated in the study, 45.2% were males. In the study, 14.8% were found to be overweight (BMI 23-24.9 kg/m2); 13.7% of males and 15.7% of females. Pre-obese students (BMI 25-29kg/m2) accounted for 15.9% of the total (males 18.3% and females 13.8%). 5.2% were found to be obese (BMI > 30 kg/m2): males 9.2% and females 1.9%. Also 14.8% were found to be underweight (males 12.2% and females 17.0%). The study group consisted of 63.8% Indian, 32.4% Chinese and 3.8% Malay students. CONCLUSIONS: The study reveals that the prevalence of overweight and obesity among the medical students of AIMST University is on the high, which is comparable to the findings of earlier studies conducted in Malaysia, reinforcing the need to encourage healthy lifestyle, healthy food habits and a physically active daily routine, among the adolescents and youth of this country. PMID- 23082464 TI - Computed tomography (CT) of bowel and mesenteric injury in blunt abdominal trauma: a pictorial essay. AB - Computed tomography (CT) is currently the diagnostic modality of choice in the evaluation of clinically stable patients with blunt abdominal trauma, including the assessment of blunt bowel and mesenteric injuries. CT signs of bowel and/or mesenteric injuries are bowel wall defect, free air, oral contrast material extravasation, extravasation of contrast material from mesenteric vessels, mesenteric vascular beading, abrupt termination of mesenteric vessels, focal bowel wall thickening, mesenteric fat stranding, mesenteric haematoma and intraperitoneal or retroperitoneal fluid. This pictorial essay illustrates CT features of bowel and/or mesenteric injuries in patients with blunt abdominal trauma. Pitfalls in interpretation of images are emphasized in proven cases. PMID- 23082465 TI - Usefulness of non-invasive serum markers for predicting liver fibrosis in Egyptian patients with chronic HCV infection. AB - Accurate monitoring of liver fibrosis changes in patients with hepatitis C virus (HCV) infection would be helpful in defining the need to intervene, implement the appropriate response in treatment and to minimize the use of liver biopsy. We aimed to evaluate the diagnostic utility of the different serum markers and indices in detecting liver fibrosis in study patients. Initial liver biopsy, routine liver function tests, estimation of hyaluronic acid, MMP-1, and PIIINP levels was performed for 30 Egyptian patients with HCV and 15 controls. Marker algorithms based on common laboratory such APRI score, Fibrotest and Actitest. PIIINP and MMP-1 serum markers were combined and entered into a stepwise logistic regression analysis with formulation of a score equation for fibrosis staging. Combined PIIINP and MMP-1 yielded different cut off scores to estimate two clinically relevant fibrosis stages: "significant fibrosis" versus "extensive fibrosis. Apri score also showed AUC of 1.0 with 100 % sensitivity and specificity to exclude the presence of cirrhosis and was significantly correlated to Metavair fibrosis stage in early fibrosis. On the other hand, PIIINP, Fibrotest and acti test were significantly correlated to Metavair fibrosis stage in both early and late fibrosis. In conclusion, integrating PIIINP/MMP-1 score was able to provide reliable information about the degree of liver fibrosis in chronic hepatitis C patients using different cut-offs values. A combination of liver markers as well as its related indices is an emerging tool to differentiate early from advanced liver fibrosis in HCV patients. PMID- 23082466 TI - Human leukocyte antigens as a risk factor for the primary diseases leading to end stage renal disease in Egyptian patients. AB - The number of patients with end stage renal disease (ESRD) is increasing considerably worldwide. The incidence of ESRD is likely to be higher than that reported from the developed world, with diabetic nephropathy, hypertension and chronic glomerulonephritis being the most common causes in Egypt. The aim of the present study is to investigate the Human leukocyte antigens [HLA-A,-B and -DRB1 antigens] as a risk factor for the primary diseases leading to ESRD in Egyptian patients. Our study included a total of 457 individuals comprising 207 ESRD patients and 250 healthy controls were enrolled into the study. Class I [HLA-A and-B] typing was performed by complement-dependent cytotoxicity (CDC) method, while class II HLA-DRB1 typing was performed by low resolution polymerase chain reaction (PCR)-sequence-specific oligonucleotide probe [PCR-SSOP]. We found that the most common primary disease groups leading to ESRD classified as Diabetic nephropathy, hypertensive nephrosclerosis and chronic glomerulonephritis. HLA-A2, -B8 and DRB1*3 and HLA-DRB1*11 significantly correlated with diabetic nephropathy, respectively. B8-DR3 haplotype is susceptible to DM. In, conclusion, determination of HLA-A,-B and -DRB1 as a risk factor for primary diseases leading to ESRD might be beneficial in preventing progression to ESRD and recurrence of the primary disease post-transplantation. PMID- 23082467 TI - Clinical significance of T-regulatory cells in B-cell non-Hodgkin's lymphoma. AB - Regulatory T cells (Tregs) play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. The expansion and accumulation of these immunosuppressive cells correlate with advanced tumor growth and predict poor disease prognosis. The study aims at evaluation of the clinical role of regulatory T cells in B-cell Non Hodgkin's lymphoma. The study was carried out on 45 de novo patients with B- NHL, they included 26 males and 19 females and 20 apparently healthy age-matched as control. Diagnosis of lymphoma was done by lymph node biopsy, 15 patients had diffuse large B cell lymphoma (DLBCL), 9 follicular lymphoma (FL), 8 small cell lymphocytic lymphoma (SCLL), 7 marginal zone lymphoma (MZL) and 6 had mantle cell lymphoma (MCL). Tregs (CD4+CD25+ FoxP+3) were analyzed by Flowcytometry. The mean percent was 10.9 +/- 1.6% in diffuse large B cell lymphoma, 12.4 +/- 1.4% in follicular lymphoma, 13.7 +/- 2.4% in small cell lymphocytic lymphoma, 11.9 +/- 1.9% in marginal zone lymphoma and 13.5 +/- 1.35% in mantle cell lymphoma as compared to 5.9 +/- 0.96% in controls with a significant increase in the patients in relation to control group. Tregs was significantly increased in advanced stages of the disease, in bone marrow infiltration and in patients with increased LDH level. In conclusion, Tregs may play a role in modifying immune responses in patients with lymphomas and may be useful in immunotherapy and new anti-lymphoma strategies involving depletion of Tregs. PMID- 23082468 TI - Lipocalin-2 as a marker of bacterial infections in chronic liver disease: a study in Egyptian children. AB - Bacterial infections are common in chronic liver disease, and may precipitate other complications, such as encephalopathy and hepatorenal syndrome. The physiologic functions of lipocalin-2 remain poorly understood. Our aim was to elucidate lipocalin-2 as a useful marker of bacterial infections in children with CLD. A total of 79 children were enrolled in the study; 29 CLD with bacterial infection (infected group); 25 with CLD without bacterial infection (uninfected group); and 25 as controls. Serum lipocalin-2 level was measured in all children. A battery of laboratory investigations was also performed on all study children. Lipocalin-2 was higher in the infected than uninfected group (P<0.05). Lipocalin 2 level was not different between uninfected and control groups (P>0.05). Lipocalin-2 at cutoff value of 48.1 ng/ml could predict bacterial infection in the subclinical subgroup, versus uninfected groups with sensitivity 100% and NPV 100%. Lipocalin-2 is a promising marker, particularly for, early detection of bacterial infection. PMID- 23082469 TI - Cytokine profiling as a prognostic markers in chronic myeloid leukemia patients. AB - Chronic myeloid leukemia (CML) accounts for 20% of all adult leukemias worldwide. Most Egyptian patients are diagnosed in the chronic phase and progress to the accelerated or blastic phase, which is related with decreased survival. Various pro-inflammatory cytokines are involved in the pathogenesis of chronic leukemia but their prognostic significance is unknown. The aim of the current study is to determine the validity of TNF-alpha, IL-6, IL-18 and CRP levels as prognostic markers in CML patients. These parameters were monitored with clinical routine tests in 25 CML patients besides ten healthy control subjects at National Cancer Institute, Cairo, Egypt. IL-6 and IL-18 levels before hydroxyurea treatment were significantly higher in all patients compared to controls (P<0.001 for both levels). At hematological remission, significant reductions were observed for IL 6 (P<0.001), IL-18 (P<0.001) and CRP (P<0.001) whereas reduction in the levels of TNF were non-significant. Moreover, an inverse correlation was observed between both of TNF (P<0.05) and CRP (p<0.01) on one side and megakaryocytic dysplasia on the other side. These findings offer evidence that TNF may have potential prognostic role in megakaryocytic dysplasia detection. PMID- 23082470 TI - Prevalence of anti-HEV IgM among blood donors in Egypt. AB - Hepatitis E virus (HEV) is a common cause of acute viral hepatitis (AVH) in developing countries. In Egypt; where up to 80% of the inhabitants of rural villages have anti-HEV antibodies denoting past infection, most of these infections are asymptomatic with little evidence that the infection causes AVH. There are accumulating reports which suggest potential risk of HEV transmission by blood transfusion. However, detection of serological markers for HEV infection or HEV RNA in Egyptian blood banks is not routinely performed. 760 blood samples from apparently healthy donors at the National blood bank were tested for markers of acute HEV infection to estimate the seroprevalence of acute HEV infection, and potential risk of infection by blood transfusion. They included 124 females (16.82%) and 636 males (83.68%), with a mean age of 23.8 +/- 5.3 years and mean ALT value of 23.3 +/- 13.2 IU/ml. Samples were tested as pools of 10 subjects. Pools with highest reactivity were retested individually to determine the frequency of positive subjects. Out of the 760 samples, three (0.45%) samples were positive for anti-HEV IgM and two of them had HEV RNA as determined by RT PCR. In conclusion, this study suggests that the tested blood donors have low prevalence of ongoing subclinical infection with HEV and that the potential risk of transfusion may be low. PMID- 23082471 TI - Diagnostic and prognostic values of adhesion molecules VCAM-1, ICAM-1 and C reactive protein in Egyptian patients with chronic kidney disease. AB - Soluble intracellular adhesion molecule-1 (ICAM-1) and soluble vascular adhesion molecule-1 (VCAM-1) are markers of endothelial dysfunction which is linked to the atherosclerotic process causing a series of complications in patients with chronic kidney disease. The aim of this study was to evaluate C-reactive protein and adhesion molecules VCAM-1, ICAM-1 in patients with predialysis, chronic renal failure (CRF), on maintenance hemodialysis (HD) and after kidney transplantation (KT). Ten patients with predialysis CRF, 20 on maintenance HD, 5 after KT and 10 subjects as a control group were included in this study. We evaluated serum levels of ICAM-1, VCAM-1 as acute phase proteins, C-reactive protein (CRP) as an inflammatory marker and body mass indices (BMI), serum albumin, cholesterol, triglyceride as nutritional indices. The mean values of serum levels of VCAM-1 and ICAM-1 were significantly higher in the three groups of patients than those of the controls (P < or = 0.05). There was statistically significant difference between the serum levels of VCAM-1 in the HD patients versus all other groups with the highest level in the HD patients. The circulating level of CRP, there was a progressive increase from controls to KT, CRF and to HD with the highest level in HD patients. There was a statistically significant difference between CRP serum levels in the HD patients versus all other groups with the highest level in the HD patients. Regression analysis showed significant positive correlation between CRP and ICAM-1 in KT patients (r = 0.9051; P = 0.0346), in CRF patients (r = 0.7621; P = 0.0170) and in HD patients (r = 0.4449, P = 0.0493). As regards the correlation between CRP and VCAM-1, there was positive correlation in KT patients (r = 0.9006; P = 0.0370), in CRF patients (r = 0.7088; p = 0.0326) and in HD patients (r = 0.4498; P = 0.0466). Age and BMI did not statistically differ in the study groups. In conclusion, serum levels of soluble adhesion molecules sVCAM-1, sICAM-1 correlate positively with the stage of renal disease. Also their serum levels were correlated positively with CRP as an inflammatory index in renal diseases. Further studies are needed to assess use of monoclonal antibodies against adhesion molecules and CRP as targets for therapeutic intervention in chronic kidney diseases. PMID- 23082472 TI - Detection of bacterial DNA in peripheral blood mononuclear cells of patients with reactive arthritis. AB - Reactive arthritis (ReA) is an infection-induced systemic illness characterized by an aseptic inflammatory joint involvement and occurring in genetically predisposed patients with a bacterial infection localized in a distant organ or system. We evaluated the possible role of bacterial infection in the etiology of reactive arthritis by testing peripheral blood monocytes (PBMCs) for the presence of prokaryotic 16S ribosomal RNA genes which are known as 16S rDNA. PBMCs were isolated from 40 patients with ReA and 10 healthy controls. Clinical, laboratory and radiological evaluations were carried out for all patients and controls. Bacterial DNA was extracted from the PBMCs and subjected to PCR amplification of the 16S rDNA gene followed by DNA sequencing and database comparative analysis. Bacterial DNA was detected in 16/40 (40%) patients and 3/10 (30%) healthy controls. No significant difference was detected between the PCR +ve and -ve groups of patients as regards arthritis, arthralgia, sacroiliitis, low back pain and enthesopathies (P>0.05), while a significant difference was detected in the PCR +ve females with gynaecological infection (P<0.05). A significant difference of the pattern of arthritis was also observed between the two groups of patients. Comparative analysis of 7 16S rDNA sequences from patients and controls using Basic Local Alignment Search Tool (BLAST) and the National Center for Biotechnology Information (NCB1) database revealed high % similarity with potential pathogens and nonpathogenic bacteria. Further studies are needed to establish the exact role of these organisms in the pathogenesis of ReA. PMID- 23082473 TI - The study of different chromosomal aberrations, CD38 and ZAP-70 in chronic lymphocytic leukemia patients. AB - Chronic lymphocytic leukemia (CLL) follows an extremely variable clinical course with overall survival times ranging from months to decades. The clinical staging systems do not allow one to predict if and at what rate there will be disease progression in an individual patient diagnosed with early stage disease. There has been intensive work on clinical and biological factors of potential prognostic relevance that may add to the classic assessment provided by the staging systems. Among these are: Laboratory parameters reflecting the tumor burden or disease activity such as lymphocyte count, lactate dehydrogenase (LDH) elevation, bone marrow infiltration pattern or lymphocyte doubling time (LDT), serum markers such as soluble CD23, beta2-microglobulin (beta2-MG) or thymidine kinase (TK), and genetic markers of tumor cells such as genomic aberrations, the mutation status of the variable segments of immunoglobulin heavy chain genes (VH), or surrogate markers for these factors (CD38, ZAP-70, LPL). Thirty patients were included in our study, the investigation included CD38 expression, ZAP-70 expression, and interphase Fluorescence In Situ Hybridization (FISH) for the detection of trisomy 12, del 13q14.3, del 17p13, and del 11q22.3. Our results showed positive statistical significant correlation between ZAP-70 expression and CD38 expression with some of the chromosomal aberrations encompassing bad prognosis as ATM and p53. Also CD38 expression was positively correlated with trisomy 12 and p53 deletions. Chromosomal aberrations were found to be present in 76.6% of our patients with 13q deletion as the most frequent abnormality in our patients (46.7%), followed by trisomy 12 (36.7%), then ATM and p53 deletion (26.7%) each. Another interesting finding in our study is the fact that 100% of the ZAP-70 positive patients were of bad prognosis, 58.3% of the CD38 positive cases, 81.8% of the positive trisomy 12 cases, 100% of the ATM deletion, 62.5% of the p53 deletion, and 64.3% of the 13q- cases were also of bad prognosis, which indicates that ZAP-70, trisomy 12, and ATM deletion are powerful indicators of prognosis. We conclude that FISH for the detection of the most important chromosomal aberrations in CLL is an important laboratory parameter that is recommended for assessment and correlation with simultaneous evaluation of ZAP-70 and CD38 expression which could help in the prediction of outcome of CLL patients. PMID- 23082474 TI - Serum levels of IL-18, IL-12 and TH-1/TH-2 ratio in patients with pre-eclampsia. AB - The syndrome of pre-eclampsia has been ascribed to generalized maternal endothelial dysfunction, poor placentation and excessive maternal inflammatory response. It has been suggested that T-helper (Th)2 dominance in normal pregnancy shifts to Th1 dominance in pre-eclampsia and that IL-18 acts in synergy with IL 12 to promote development of T-helper (Th)1 responses. In the present study, serum IL-18 and IL-12 levels and Th1:Th2 ratio were assessed in 120 pregnant women with PE, as well as 60 normotensive pregnant women in their third trimester demographically matched to the diseased women. The results obtained showed that IL-18 was significantly higher in women with PE (whether mild or severe) than in normal pregnancy. The IL-12 was not significantly increased in mild PE but significantly increased in severe cases. The Th1: Th2 ratio was significantly higher in women with PE when compared to normal pregnant women. Such data may suggest that PE is a Th1-type immunity disorders. PMID- 23082475 TI - Detection of BRCA1 and BRCA2 gene mutation in Egyptian females with breast cancer and their relatives by PCR-SSCP method. AB - Germline mutations in the BRCA1 or BRCA2 genes predispose their carriers to breast or/and ovarian cancers during their lifetime. This study was performed to identify germline mutations in BRCA1 and BRCA2 genes for the early detection of pre-symptomatic mutation carriers in Egyptian healthy females who were first degree relatives of affected women from families with and without family history of breast cancer. Sixty-two patients (index cases) with invasive breast cancer belonging to sixty families and their asymptomatic female first-degree relatives (300 cases) were studied for germline mutations of BRCA1 and BRCA2 genes. Five mutations were detected in 52 families (86.7%) with inherited mutations in either BRCA1 or BRCA2. Sixty percent of these families had BRCA1 mutation and 26.7% had BRCA2 mutations. They were identified by using the combination of SSCP and heteroduplex analysis. All but one of the mutations were detected within the BRCA1 gene in addition to one mutation in the BRCA2 gene. PMID- 23082476 TI - Serum adiponectin and fetuin-A levels in children with nephrotic syndrome. AB - Nephrotic syndrome is associated with an increased risk of atherosclerosis and endothelial dysfunction. The aim of this work was to evaluate serum adiponectin and fetuin-A levels in children with idiopathic nephrotic syndrome. The study was carried out on 70 children, divided into 2 groups. Group I included 35 children with steroid responsive idiopathic nephrotic syndrome (15 in relapse and 20 in remission) and group II included 35 apparently healthy children served as control with matched age and sex. The results showed significantly higher adiponectin with significantly lower fetuin-A in patients than controls and in relapse group as compared to both remission and control groups. There was a significant negative correlation between adiponectin and fetuin-A. IN CONCLUSION: Both adiponectin and fetuin-A may be useful markers of activity of nephrotic syndrome. Increased serum adiponectin levels in relapse compared to remission might be the reflection of a compensatory response to nephrotic state characterized by massive proteinuria, hypoalbuminemia and hyperlipidemia. Low concentration of fetuin-A in relapsed children of NS may depend on proteinuria. PMID- 23082477 TI - Serum visfatin levels in a group of Egyptian obese individuals. AB - Adipose tissue is an endocrine organ that secretes many adipokines. Visfatin is a relatively novel adipocytokine predominantly secreted from adipocytes and shows insulin mimetic properties. The aim of the study was to assess visfatin levels as well as its relation to selected anthropometric and biochemical parameters in adult obesity. The study included 46 adult obese subjects with body mass index of 52.9 +/- 9 kg/m2. In addition, the control group included 44 healthy individuals with matched age and sex and with BMI values of 23.1 +/- 1 kg/m2. Anthropometric measures included also the height, weight, waist and hip circumferences. Serum visfatin and fasting insulin were assessed using commercially available enzyme immunoassay kits. The insulin resistance index was estimated using the Homeostasis Model Assessment (HOMA). Other biochemical parameters assessed included fasting blood sugar, total serum cholesterol and triglycerides. Significant higher serum visfatin levels were found in obese subjects compared to controls (P<0.05). In addition, a statistically significant positive correlation was obtained between serum visfatin and each of BMI (P<0.05), waist circumference (P<0.001), hip circumference (P<0.001), as well as HOMA (P<0.05) in obese subjects unlike in control group. In conclusion, the observed visfatin increase in obesity together with its positive correlation to HOMA might be suggestive of a role in glucose homeostasis. PMID- 23082478 TI - Assessment of matrix metalloproteinase-1 for marking liver cirrhosis in chronic hepatitis C patients. AB - Our objective in the present study was to observe the change in the serum MMP-1 concentration using ELISA in 129 chronic hepatitis C (CHC) (78 non-cirrhotic and 51 with cirrhotic liver) and 50 healthy controls. The values of MMP-1 concentration increased in patients with CHC according to the stage of liver fibrosis. An area under the ROC curves (AUC) of the MMP-1 was 0.98 for discriminating patients with cirrhotic liver from healthy individuals and was 0.78 for discriminating patients with cirrhotic liver from non cirrhotic patients. The diagnostic potential of MMP-1 for discriminating cirrhosis from healthy individuals was very high with 98% sensitivity and 97% efficiency. MMP-1 detected cirrhosis in CHC with 71% sensitivity and 73% efficiency. In Conclusion, measurement of serum MMP-1 is useful for diagnosing liver cirrhosis in CHC patients. PMID- 23082479 TI - Exploring disease activity and cardiovascular events by raised serum asymmetric dimethyl arginine among systemic lupus erythematosus patients. AB - Asymmetric Dimethyl Arginine (ADMA) is an endogenous nitric oxide inhibitor and a potential independent risk factor for endothelial dysfunction and cardiovascular disease. The current study attempted to investigate the association of serum ADMA levels to serological markers and cardiovascular events among Systemic Lupus Erythematosus (SLE) patients. The study included 45 subjects (91.1% female), divided equally into 3 groups: patients with lupus flare, patients without flare according to SLE Disease Activity Index (SLEDAI), and apparently healthy individuals. Serum ADMA, ANA, Anti-ds DNA, C3, ESR, and lipid profile were measured. There was a significantly higher ADMA level among active patients, with history of cardiovascular events, compared to inactive and control subjects. There were positive correlations between ADMA levels and anti-ds DNA, ESR, SLEDAI, and cardiovascular events, but negative correlation with C3, LDL, HDL and total cholesterol. In conclusion, high serum ADMA level may represents an independent risk factor for disease activity and poor prognosis among lupus patients. PMID- 23082480 TI - Role of TNF-alpha as a survival prognostic marker in chronic lymphocytic leukemia patients. AB - Pro-inflammatory cytokines play a central role in the pathogenesis of chronic leukemia. This pilot study assesses the potential value of measuring TNF-alpha, IL-6, IL-18 and CRP levels as prognostic markers for disease monitoring in CLL patient. These parameters were evaluated in 45 CLL patients and 25 healthy control subjects IL-6 on contraire to the other cytokines, was significantly higher (P<0.05) in patients compared to controls. At hematological remission, only CRP was significantly reduced (P<0.005). IL-6 is inversely correlated with Hb (P<0.05). In the meantime, IL-18 is correlated to splenomegaly, and CRP (P<0.05; for both). TNF-alpha level in non-survived patients was significantly higher than both survived patients (P<0.05), and controls (P<0.01). In conclusion, TNF-alpha can be potentially used as a survival prognostic factor in CLL. PMID- 23082481 TI - A study of innate and adaptive immune responses in beta-thalassemic patients with chronic hepatitis C virus infection. AB - Thalassemia major is an inherited disorder particularly common in people of Mediterranean, African, and Southeast Asian ancestry. Hepatitis C virus (HCV) is responsible for 80 - 90% of post transfusion hepatitis in beta-Thalassemic patients. Marked liver iron overload, which is often inevitable in patients on regular blood transfusion, and HCV infection have been shown to have a potentiating effect on hepatic fibrogenesis in thalassemic patients. This study aimed at investigating the impact of combined chronic hepatitis C and beta Thalassemia on innate and adaptive immune responses. The study was conducted on 60 patients and 15 apparently healthy controls. Patients were dived into three groups: group 1: 35 patients with combined beta-thalassemia and chronic hepatitis C (CHC) (betaTH/CHC), group II: 15 beta-thalassemia patients without HCV infection (betaTH), group III: 10 patients with chronic hepatitis C infection (CHC). Assessment of the number of CD3+, CD4+, CD8+ T cells, NK cells, and NKT cells was done by flowcytometry. Human IFN-delta and IL-15 levels were estimated by Enzyme -Linked Immunosorbent Assay (ELISA). betaTH/CHC patients had significantly reduced numbers of conventional T lymphocytes, NK, NKT, CD4+, and CD8+ T cells when compared to betaTH patients. Serum IFN-gamma levels were significantly reduced in betaTH/CHC patients (2.57 pg/ml) in comparison to CHC patients (6.89pg/ml) and normal controls (4.73 pg/ml). A significant elevation of serum IL-15 levels in betaTH/CHC patients (38.04pg/ml) was found when compared to betaTH patients (16.22 pg/ml). Splenectomized patients showed reduced numbers of NK cells, NK T cells and lower CD4:CD8 ratio in comparison to non-splenectomized ones among betaTH/CHC patients. In conclusion our data show an obvious defective cellular innate immunity (NK & NKT cells) and cellular adaptive immunity (CD4+ T cells, CD8+ T cells, & INF-gamma) in (betaTH/CHC) patients, in comparison to (betaTH) patients. This observation suggests a potentiating effect of both CHC and beta-thalassemia on depression of innate and adaptive immune status in these patients PMID- 23082482 TI - Serological markers as indicators for congenital cytomegalovirus infection. AB - To assess the problem of CMV infection in pregnant women in Sohag community and to determine the risk of congenital CMV infection. The study was performed on 900 pregnant women residing in Sohag, during the period from June, 2006 till January 2010. Detection of CMV antibodies (IgM and IgG) was carried out using microparticle enzyme immunoassay. Women proved positive (+ve) for CMV IgM or IgG antibodies were considered the seropositive group (group 1), while women proved negative (-ve) for both antibodies were the seronegative group (group II). Serum samples of IgM +ve females and with rising IgG titers were further subjected to PCR to detect CMV DNA. Of the 900 pregnant women, 850 (94.4%) were seropositive for CMV antibodies. Of these, 828 females (97.4%) had +ve IgG and -ve IgM antibodies, and 22 (2.6%) women had positive IgM. Viral DNA was detected in 12 of the 22 IgM +ve and 8 out of 10 women with rising IgG titer. CMV antibodies and serum PCR were done for 15 live births whose mothers had positive CMV PCR. Of 7 infants whose mothers had CMV IgM and CMV PCR positive, 4 infants had positive PCR results. Eight live births, whose mothers had rising IgG titer and positive PCR test, were negative for viral DNA. In conclusions, CMV specific IgM or rising IgG antibodies in maternal serum could predict congenital CMV infection. PMID- 23082483 TI - Assessment of the role of interleukin-6 in diagnosis of hepatocellular carcinoma. AB - Interleukin-6 (IL-6) is a promising tumor marker for hepatocellular carcinoma; HCC. IL-6 may help to identify a subset of HCC patients with low alpha fetoprotein (AFP) level, and may serve as complementary tumor marker, however, this has to be clarified. This study assesses the value of measuring serum level of interleukin-6 in patients with chronic liver disease and HCC, and evaluates its sensitivity and specificity in comparison to AFP in early diagnosis of HCC. Seventy five patients with chronic liver disease (CLD) with or without HCC and 25 healthy controls were included. Patients were divided into Group I: 25 patients with CLD but no evidence of HCC. Group II: 25 patients with HCC on top of post viral hepatitic with elevation in AFP (> 200 ng); and Group III: 25 patients with HCC on top of post-viral hepatitic but without elevation in AFP (< 200 ng). Analysis of the mean serum IL-6 levels revealed a statistically significant difference between all groups (P < 0.01). A significant positive correlation was found between mean levels of IL- 6 & AFP in HCC (P < 0.05), the mean IL-6 levels in patients with Child classification C was higher than in those with Child A and B.After adjustment using multiple logistic regressions, only loss of weight and AFP were found to be significantly associated with HCC (P < 0.05). It is concluded that the diagnostic value of IL-6 increased when it is associated with AFP measurement. Combining the two markers can provide a new perspective in the diagnosis of HCC. PMID- 23082484 TI - Prognostic significance of FLT3 internal tandem duplication in egyptian patients with acute myeloid leukemia with normal or favorable risk cytogenetics. AB - Internal tandem duplication (ITD) of the FLT3 gene (FLT3/ITD) has been linked to poor outcome in acute myeloid leukemia (AML). However, the prognostic value of FLT3/ITD in various cytogenetic risk groups is still a matter of debate. The aim of this study was to evaluate the prognostic significance of FLT3/ITD in patients with de novo AML and normal or favorable risk cytogenetics (NFC-AML). Blood samples from 39 patients with AML were subjected to PCR of exons 14 and 15 of the FLT3 gene. Patients included 25 with normal cytogenetics, 8 with t(15;17), 4 with t(8;21) and 2 with inv(16). FLT3/1ITD was found in 6/39 (15.4%) patients, 4 of them showed normal cytogenetic, 1 positive for t(15;17) and 1 positive for t(8;21). Patients were M1 3/13, M2 2/12, M3 1/9, M4 0/4 and M5 0/1. The patients were followed up for a mean of 34.5 +/- 2.3 months. The complete remission (CR) rates for the FLT3/ITD+ and FLTITD- groups were 50% vs 63.6%, while the relapse rates were 50% vs 28.6% respectively. Interestingly, disease free survival (DFS) at 3 years was significantly different in studied patients: DFS was 5% in patients with FLT3/ITD+ vs 30% of patients with FLT3/ITD- (P = 0.001). Our data suggest a possible high prognostic value of FLT3/ITD in patients with normal/favorable cytogenetics. PMID- 23082486 TI - Comparison of different phenotypic and molecular methods for detection of methicillin-resistant Staphylococcus aureus in intensive care patients. AB - Detection of methicillin-resistant Staphylococcus aureus (MRSA) has been problematic ever since its discovery. This work was performed to evaluate the effectiveness of different phenotypic methods for MRSA detection in intensive care patients. Three hundred and eighty-nine specimens from 100 patients were inoculated onto mannitol salt agar. All S. aureus isolates were examined by four selective culture media [ORSAB, MSO, MSA-Cefox, OAS], two disc diffusion methods [CDD and ODD], and MicroScan panel for MRSA. Polymerase chain reaction (PCR) for mecA gene was performed as the gold standard. S. aureus isolates were revealed from 56 patients, 41 of them were found to be MRSA by PCR. CDD yielded the best sensitivity (97.6%), followed by ODD and MSA-Cefox (92.7%). CDD, MSA-Cefox and OAS showed the best specificity (100%). In conclusion, MSA-Cefox and CDD showed improved sensitivity and excellent specificity compared to other methods. It is advisable to use the two methods for MRSA detection if PCR is not available. PMID- 23082485 TI - Hepcidin levels and iron status in beta-thalassemia major patients with hepatitis C virus infection. AB - Beta-thalassemia is an inherited anemia in which synthesis of the hemoglobin beta chain is decreased. Clinical features of beta-thalassemia include variably severe anemia and iron overload due to increased intestinal iron absorption, which may result in damage to vital organs. The hepatic peptide; hepcidin is a key regulator of iron metabolism in mammals. The present study aimed to determine the relationship between hepcidin expression and iron status in beta-thalassemia patients with hepatitis C virus infection. The study included 50 patients diagnosed as beta-thalassemia major (21 of them were HCV infected and 29 were HCV negative), in addition, 20 healthy subjects were enrolled in the study. The hepatic iron and hepcidin mRNA concentration in liver biopsy samples were measured, as well as serum ferritin, serum iron, hemoglobin and levels and serum hepcidin. Result showed remarkable decrease of serum and liver hepcidin mRNA expression in thalassemic patients as compared to controls, and showed a positive correlation with hemoglobin concentration, but negatively correlated with serum ferritin level and hepatic iron index (HII). In HCV infected patients, serum and liver hepcidin mRNA were markedly depressed in HCV positive beta-thalassemia cases, and positively correlated serum albumin and prothrombin concentrations, but inversely correlated with HII and fibrosis score. In HCV positive beta thalassemia major patients, the hepcidin mRNA level was positively correlated with the synthetic function of the liver (namely serum albumin and prothrombin concentration) and with serum hepcidin level. While, both serum and hepcidin mRNA level was inversely correlated with HII and fibrosis score in these patients. These results suggest a possible role of hepcidin expression in iron overload in beta-thalassemia major, consequent disease progression and development of liver fibrosis. PMID- 23082487 TI - Effect of controlling blood glucose level on apoptosis in type II diabetes mellitus. AB - Diabetes mellitus (DM) and its complications are complex syndromes representing universal health problems. Egypt ranks ninth among countries with diabetes where the problem is magnified. Researchers have discussed the effect of hyper glycaemia on apoptosis. However, the aims of this study were to assess CD95 positive cells in controlled and uncontrolled type II diabetic patients and to elucidate the effect of controlling blood glucose level on apoptosis. The study was a case control, included controlled type II diabetics and uncontrolled with or without complications) and healthy control groups. Apoptosis was detected by serum DNA fragmentation using ELISA and CD95 positive cells by flow cytometry. There was highly significant increased serum DNA fragmentation and CD95-positive cells in uncontrolled TII DM (complicated and non-complicated) than controlled DM and healthy control groups. In conclusions, poor glycemic control was associated with increased apoptosis. PMID- 23082488 TI - T-cell function, T-cell phenotype and its role in responsiveness to recombinant human erythropoietin in hemodialysis patients. AB - Resistance to recombinant human erythropoietin (Epo) occurs in a small proportion of hemodialysis (HD) patients. In this study we investigated the relationship between T-cell phenotype (using flow cytometry), T-cell function (by measuring in vitro cytokine production) and responsiveness to Epo in HD patients and to compare the results with those from healthy controls. T-cell phenotypes were assessed and T-cell function was studied. The study included 24 chronic renal failure (CRF) patients on HD treated with rHuEPO as well as 14 normal control subjects. Dual-colour immunofluorescence and flow cytometry were used to compare the surface antigen expression on freshly isolated CD4+ and CD8+ T-cells from PBMC of the studied groups. Levels of a panel of selected cytokines (IL-4, IFN gamma, slL-2R and IL-10) were determined in PBMC culture supernatants and in plasma samples (TNF-alpha, IFN-gamma, IL-6, slL-2R) using (ELISA) kits. Patients were followed-up for 24 months and a survival study was carried out. T-cells from poor responders showed increased proportions of CD4+/CD28- cells and CD8+/CD28- cells compared with both good responders and controls. Compared with their CD28+ counterparts, CD4+/CD28- T-cells produced significantly more IFN-gamma, enabling them to function as pro-inflammatory cells. There was no difference in secretion of IFN-gamma, slL-2R or IL-4 in PBMC cultures obtained from HD patients and controls. However, Unstimulated PBMC from poor responders generated increased levels of IL-10 poor compared with both good responders and controls. Plasma slL 2R and IL-6 were significantly elevated in both good and poor responders compared with controls. Plasma levels of IFN-gamma and TNF-alpha were undetectable in both HD patients and controls. In the follow up period, more deaths were occurring among the poor responders than the good responders. Based on the finding of the this study we may suggest that, in the absence of any obvious cause, poor response to Epo may be mediated by generation of cytokines from a subpopulation of activated T-cells, which might promote apoptosis in erythroid progenitor cells in the bone marrow. PMID- 23082489 TI - Genetic profiling of non-Hodgkin's lymphoma with or without hepatitis C virus infection. AB - Hepatitis C virus (HCV) which is one of the endemic viral infections in Egypt is not only hepatotropic, but also a lymphotropic virus and has many extrahepatic manifestations as mixed cryoglobulinemia and non-Hodgkin's lymphoma. We studied gene expression profile of 20 B-cell non-Hodgkin's lymphoma with HCV infection and 20 B-cell non-Hodgkin's lymphoma without HCV infection as a control group by c-DNA microarray. Out of the 15,500 studied genes, more than 1000 genes were differentially expressed; either upregulated or downregulated. We found that HCV may rescue B lymphocytes from apoptosis possibly through causing suppression of CASP1 and CASP4 and causing overexpression of the anti-apoptotic BCL2 gene. Also, HCV was associated with overexpression of the genes related to myeloid/lymphoid leukemia and B lymphoma as MLLT3, BAL, influences the overexpression of transcription regulator genes as TATA box binding protein (TBP) and may influence the overexpression of some immunoglobulin genes as immunoglobulin superfamily containing leucine gene in B cells resulting in overproduction of immunoglobulins in B-lymphocyte disorders. Moreover HCV was associated with reduced expression of MHC class II molecules in B lymphocytes, and therefore inhibition of antigen processing and presentation through downregulation of different MHC class II molecules genes. We conclude that the upregulated and the downregulated genes identified through the studied expression profiles of NHL with HCV infection may shed light on the mechanisms of HCV lymphomagenesis. PMID- 23082490 TI - Manipulation of the immune evasive properties of circulating cathodic antigen induces protective immunity against Schistosomiasis mansoni in C57BL/6 mice. AB - Schistosome circulating cathodic antigen (CCA) has been hypothesized to take part in immune evasion mechanisms that protect against host's immunity. To dissect its immunogenicity, lymphoproliferative responses of splenocytes were assessed in C57BL/6 mice immunized with recombinant plasmid constructs expressing full-length and truncated fragments of CCA cDNA, before and after challenge infection with S. mansoni cercariae. Prior to challenge, splenocytes of immunized mice showed low responses to phytohaemagglutinin (PHA) and high responses to native CCA, compared to controls. After challenge, PHA-responses increased on day 3 through day 7 and subsequently declined. On the other hand, CCA-induced responses increased on day 3 post-challenge then declined in mice immunized with CCA fragments lacking the N terminus (-N CCA). Whereas, mice immunized with full-length or CCA fragment lacking the C-terminus (-C CCA) showed a delayed increase of CCA-induced responses that maximize on day 25. Interestingly, animals immunized with -N CCA showed a significant reduction in worm burden between 42-51%, while, mice immunized with full-length or -C CCA showed lower protection levels of about 15 and 37%, respectively. These findings suggest that CCA may contain immunosuppressive epitopes on the N-terminus. Abrogation of these epitopes could disrupt the immune evasion mechanism orchestrated by CCA, which could aid the development of an alternative vaccination approach. PMID- 23082491 TI - Immune events associated with protection in C57BL/6 mice immunized with anti idiotypic antibodies mimicking protective antigens shared between gamma irradiated cercariae vaccine and human resistance model of Schistosoma haematobium. AB - Immunoregulation is central for successful manipulation of schistosomiasis. Unlike schistosome vaccine development strategies that relied on direct selection of antigens from crude responses leading to selection of mildly protective antigens, the present study tested the utility of selection of potentially protective antigens encompassed rounds of immunoregulation via idiotypic network. Anti-idiotypic antibodies (Ab2) were purified from sera of New Zealand white rabbits multiply immunized with gamma-irradiated cercariae of S. haematobium, using adult worm specific idiotypes (Ab1) purified from sera of subjects resistant to reinfection. Ab2 was used for immunization of C57BL/6 mice and consequences of immunization were monitored before and after challenge infection with S. haematobium. Results showed an increase of splenic T cell expression of intercellular adhesion molecule-1 (ICAM-1) and very late antigen-4 (VLA-4) upon immunization (average % stimulated cells 54.9 vs. 20.4, P < 0.05 for ICAM-1 and 31.1 vs. 6.6, P < 0.01 for VLA-4) and challenge, especially at day 6 (83.5 vs. 45.6, P < 0.01) for ICAM-1 and day 10 (50.4 vs. 20.8, P < 0.05) for VLA-4. Thereafter, both adhesion molecules declined at day 28 through 90. Similarly, lymphoproliferation was manifested upon immunization (OD570-630 0.27 vs. 0.09, P < 0.01) and challenge at day 6 (0.5 vs. 0.17, P < 0.01) through day 10 (0.49 vs.0.18, P < 0.05), then declined at day 28 through 90. Moreover, sera of Ab2 immunized mice exhibited an anti-anti-ids (Ab3) reactivity against antigens of approximate molecular weight 40, 80 and 160 kDa of adult worms, which were also recognized by Ab1. However, in contrast to Ab1, Ab3 showed no surface binding to 3 hr schistosomula. Strikingly, mice immunized with Ab2 showed strong resistance to challenge infection (approximately 82% reduction in worm burden, P < 0.001). Taking all, this alternative vaccine development strategy appears to filter out non-protective antigens. Indeed Ab3 recognizes much fewer numbers of antigens, which passed through two rounds of immune regulation. These antigens appear to represent a significant proportion of the protective response in the gamma irradiated cercariae vaccine and human resistance model as well, providing the basis for an alternative vaccine for schistosomiasis. PMID- 23082492 TI - Hypoxia-induced EMAP-II transcription in colorectal cancer. AB - Endothelial monocyte-activating polypeptide-II (p431EMAP-II) is a proinflammatory cytokine and a chemoattractant for mononuclear phagocytes and polymorphonuclear leucocytes, found in culture supernatants of many tumour cell lines. It was demonstrated that p43/EMAP-II induces apoptosis in mitogen-stimulated lymphocytes, and suggested that it may be a constituent of a novel immune evasion mechanism employed by tumour cells. Quantitative real-time reverse transcription- polymerase chain reaction (qRT-PCR) analysis for EMAP-II mRNA was performed for colorectal adenocarcinoma cell lines, DLD-1, HT 29; human umbilical vein endothelial cells (HUVEC); and normal colon under normal and hypoxic conditions. Under hypoxic conditions, EMAP-II transcript expression increased up to 22-fold over normoxia in tumour cells, while there was 1-fold increase due to hypoxia in HUVEC and no increase in normal colon. These results demonstrate that EMAP-II transcripts are upregulated in tumour cells in hypoxic conditions and support the notion that EMAP-II plays a complex and important role in human cancer. PMID- 23082493 TI - Mannose binding lectin gene polymorphism and preclinical carotid atherosclerosis in patients with systemic lupus erythematosus. AB - Patients with systemic lupus erythematosus (SLE) have increased risk of atherosclerosis and CVD that cannot be explained by traditional risk factors. Previous studies indicated that mannose binding lectin (MBL) may modify the development of atherosclerosis. This study was designed to investigate association of MBL gene polymorphism with occurrence of preclinical atherosclerosis in SLE. The study included 46 patients with SLE and 17 age and sex matched controls. MBL2 genotypes were assessed in patients and controls by the PCR-RFLP method and intima-media thickness of the common carotid artery (cclMT) was determined by means of ultrasonography. Also, serological markers were measured and the disease activity index (SLEDAI) was estimated. SLE patients had higher frequency of MBL A/B + B/B genotypes (47.8%) than controls (29.4%). ccIMT was higher in patients having A/B, B/B, A/B+B/B genotypes when compared with wild genotype (A/A). Patients with A/B+B/B genotypes showed high serum level of LDL, TG, ESRI, CRP and SLEDAI score, but low level of HDL, C3, and C4 compared to wild genotype. ccIMT of mutant SLE subgroup correlated well with SLE risk factors for atherosclerosis. In conclusion, mutant genotypes of MBL may be atherogenic as SLE patients had a higher IMT, which correlated significantly with SLE risk factors for atherosclerosis. PMID- 23082494 TI - [Seasonal dynamics of the fauna and of the component community structure of parasites of the minnow Phoxinus phoxinus (L.) from the Pechora River. 2]. AB - It is demonstrated that the component community of parasites of the minnow in the midle Pechora River in September-Decemner corresponds in its characteristics to the forming community, when relations between species in the community are formed again, but the rate of these transformation is significantly lower than in spring summer. PMID- 23082495 TI - [Trematodes (trematoda) of amphibia from the Middle Volga region. 1. Orders Fasciolida, Hemiurida, Paramphistomida and Strigeida]. AB - Data on trematodes of the orders Fasciolida, Hemiurida, Paramphistomida and Strigeida from 11 amphibian species of the Middle Volga region are given. Literature data for the last 30 years are reviewed for the first time; these data are supplemented by our own material. Reliable recordings are confirmed for 23 trematode species. Two of these species are new for amphibian trematode fauna of Russia. New hosts were revealed for 12 trematode species. Trematodes of the new for the region amphibian species, the edible frog Rana esculenta Linnaeus, 1758, are recorded for the first time. Two trematodes from freshwater fishes are shown to be temporary or occasional parasites of amphibians. The following characteristics are given for each parasite: it's systematic position, the spectrum of hosts, localization, collecting site, biology, geographical range, and the degree of host specificity. The morphological description and original figures are given for 9 species of parasites. PMID- 23082496 TI - [Ecological analysis of the fauna of infusoria of the family Trichodinidae Claus, 1874 (Ciliophora Dofflein, 1901, Peritrichida F. Stein, 1859) in pond fishes of Kaliningrad province]. AB - A total of 21 Infusoria species of the family Trichodinidae parasitize in pond fishes of Kaliningrad Province. Species of the genus Trichodina dominate, being represented by 15 species. The majority of revealed Infusoria are characterized by wide specificity. Narrow specificity is characteristic of Trichodina urinaria (the bass) and Trichodinella lotae (the burbot). Extensiveness and intensity of the invasion depends on host species, its biology, and the character of the reservoir. PMID- 23082497 TI - [Symbionts of Mytilus edulis in the littoral and sublittoral zones of the Kandalaksha and Onega Gulfs of the White Sea]. AB - Composition of the fauna of organisms associated with Mytilus edulis in the Kandalaksha and Onega Gulfs of the White Sea has been examined. The following 8 symbiotic species were revealed: Choricystis sp. (Chloro[hyceae), Peniculistoma mytili, Ancistrum mytili (Ciliata, Oligohymenophorea), Urastoma cyprinae, Paravortex sp. (Platyhelminthes, Rhabditophora), and metacercaria of Cercaria parvicaudata, Himasthla sp., and Gymnophallus sp. (Platyhelminthes, Trematoda). Besides, different free-living organisms were found in the mantle cavity; 6 species of nematodes, the planktonic copepod Microsetella norvegica, undetermined copepods, isopod Jaera sp., sea mites of the family Halacaridae, and chironomid larvae. Parameters of infestation and places of localization in the host are given for each group of organisms. Some regularities in the horizontal and vertical distribution of organisms associated with M. edulis are noted. PMID- 23082498 TI - [Estimation of the biological age in males of the taiga tick (Ixodes persulcatus: Ixodinae) by fat reserves in the midgut]. AB - Some criteria for the estimation of the biological and calendar age by the fat storage in midgut cells of Ixodes persulcatus males were established on the basis of examination of ticks from the laboratory culture. PMID- 23082499 TI - [Feather mite fauna (Astigmata) of birds of some passerine families (Passeriformes) in the south of Western Siberia]. AB - Feather mites (Astigmata) are specialized parasites living on the plumage and skin of birds. The paper presents the data on the infestation of some passerines (Passeriformes) by feather mites in the south of the Western Siberia (Omsk and Tyumen Provinces). On 16 bird species, we found 24 species of feather mites, belonging to the families Analgidae, Dermoglyphidae, Pteronyssidae, Trouessartiidae and Proctophyllodidae. Among them, 19 species are common parasites of passerine birds examined; five species were detected on atypical hosts. Ten mite species were recorded for the first time on examined passerine species. The analysis of the distribution of abundant and ordinary mite species on their hosts demonstrated that the majority of bird species possesses specific distribution pattern on host plumage with the preference of certain feather types. We also obtained new data on host associations of several mite species. PMID- 23082500 TI - Globalization of Chagas disease (American trypanosomiasis): the situation in Europe and Belgium. AB - Trypanosoma cruzi, the protozoan agent of Chagas disease infects ten million people in Latin America where it is the main cause of cardiac failure. It is transmitted by insect vectors in endemic areas, and also congenitally, by transfusion of infected blood, transplantation of infected organs and oral route in both endemic and non-endemic areas. Since the 1990s, a constant decrease of incidence of infection is observed in Latin America, where vector control programmes and improvement of blood banks have been implemented. However, the important migration flows in the last decades for economic reasons have brought considerable numbers of Latin American subjects infected with T. cruzi, in US, Europe, Japan and Australia. Such globalization of T. cruzi infection/Chagas disease has been confirmed in an WHO historical meeting in 2007, emphasizing the importance of a wise management of such patients and the need of implementing control measures in blood banks, transplantation centres and maternities of involved countries in non-endemic areas. This paper considers these elements and the present situation of Chagas disease in Europe and Belgium. PMID- 23082501 TI - [Molecular dialogue between African trypanosomes and humans]. AB - The evolutionary origin of Man in the African continent has imposed the requirement to resist endemic parasites, in particular African trypanosomes (prototype: Trypanosoma brucei). Therefore, human serum is provided with an efficient system of innate immunity against these parasites, as discovered by A. Laveran in 1902. However, two T. brucei clones, termed T. b. rhodesiense and T. b. gambiense, managed to escape this immunity system, enabling them to grow in humans where they cause sleeping sickness. We have identified the gene allowing T. b. rhodesiense to resist trypanolysis by human serum, which led us to discover that the trypanolytic factor is apolipoprotein L1 (apoL1). ApoL1 is a human specific serum protein bound to HDL particles that also contain another human specific protein termed "haptoglobin-related protein " (Hpr). Following the binding of hemoglobin (Hb) to Hpr, the apoL1-bearing HDL particles are avidly taken up by the trypanosome through their binding to a parasite surface receptor for the Hp-Hb complex. After endocytosis apoL1 kills the parasite by generating anionic pores in the lysosomal membrane. In our laboratory, mutant versions of apoL1 have been constructed, which are no longer neutralized by the resistance protein of T. b. rhodesiense and are therefore able to kill this human pathogen. Unexpectedly, we have recently discovered that similar mutants do actually exist in nature : in Africans and Americans of recent African origin, even a single allele of these mutants allows protection against infection by T. b. rhodesiense, but the price to pay is a high frequency of end-stage renal disease when doubly allelic. The evidence of natural selection of these apoL1 mutations despite their deleterious potential for kidneys highlights the importance of the resistance to trypanosomes in the evolution of Man. The mechanism by which mutant apoL1 triggers end-stage renal disease is currently studied. PMID- 23082502 TI - [The creation of a vascularized tracheal transplantation]. AB - Reconstruction of long-segment tracheal defects requires a vascularized allograft. We report successful tracheal allotransplantation after indirect revascularization of the graft in a heterotopic position. Immunosuppressive therapy was administered before the operation, and the allograft was wrapped in the recipient's forearm fascia. Once revascularization was achieved, the mucosal lining was replaced progressively with buccal mucosa from the recipient. At four months, the tracheal chimera was fully lined with mucosa, which consisted of respiratory epithelium from the donor and buccal mucosa from the recipient. After withdrawal of immunosuppressive therapy, the tracheal allograft was moved to its correct anatomical position with an intact blood supply. No treatment-limiting adverse effects occurred. PMID- 23082503 TI - Liver transplantation or Starzl's legacy. A look backward, a look forward. AB - Since the first successful liver transplantation (LT) in 1963 by Starzl, enormous progresses have been made in this field of medicine. The author looks back at the recommendations put forward at the 1983 NIH Consensus conference on liver transplantation in order to show the enormous progresses that have been made in his field during the last four decades. Today almost none of the original indications and contraindications remain in place. Despite the extension of indications, results of LT continuously improved. The attention of the transplant physicians should from now onwards be focused on the achievement of an immunosuppressive free (or tolerant) status in order to further consolidate the excellent obtained long-term results. PMID- 23082504 TI - New viral pathogens from wildlife. PMID- 23082505 TI - Massively parallel sequencing: a new tool in virus discovery and vaccine safety. AB - The introduction of new sequencing technologies is revolutionizing virus discovery and providing a new means to demonstrate the safety of vaccines. Since these methods do not depend on prior assumptions of the types of viruses that may be present, they have detected viruses missed by other methods like degenerate or, family specific, PCRs. We have used massively parallel sequencing (MP-Seq) to detect new viruses in bovine serum and in the faeces of animals. When applied to sequencing the transcriptome, MP-Seq can reveal latent or silent infections. While the sequencing technology is impressive, it is bioinformatics that is the key to its successful application. PMID- 23082506 TI - Motor nerve conduction and repetitive nerve stimulation in captive ring-tailed coati (Nasua nasua). AB - There are few electrophysiologic studies in wild animals. The aim of this study was to determine normal data for motor nerve conduction studies and repetitive stimulation in sciatic-tibial and ulnar nerves in clinically normal captive coati. Eight adult ring-tailed coatis (Nasua nasua), two females and six males weighing 6-8 kg, were used. Average nerve conduction velocity was 70.81 m/sec (standard deviation [SD] = 3.98) and 56.93 m/ sec (SD = 4.31) for the sciatic tibial and ulnar nerves, respectively. Repetitive stimulation responses demonstrated minimal variations of the area of the compound muscle action potentials at low (3 Hz) and high (20 Hz) frequencies. The maximal obtained decremental area response was 8%. These normal data of conduction studies may be used in assessing abnormalities for clinical diagnosis. In addition, the obtained normal repetitive stimulation data were similar to dogs and humans and may be used for post- and presynaptic disturbances of the neuromuscular transmission in coatis. PMID- 23082507 TI - Validation of lactate measurement in American flamingo (Phoenicopterus ruber) plasma and correlation with duration and difficulty of capture. AB - Capture myopathy and associated death have been reported with capture and restraint of greater flamingos (Phoenicopterus ruber roseus) and lesser flamingos (Phoeniconaias minor). In chickens (Gallus gallus), blood lactate concentration levels have been used as indicators of muscle damage. Lactate has also been used to predict survival in humans and dogs. The goals of this study were to validate two common methods for measuring lactate (i-STAT and VetTest analyzers) in flamingo plasma by comparing measurements to a reference analyzer; and to correlate blood lactate concentration levels in captured flamingos with the duration and difficulty of capture as a possible indicator of capture myopathy. Twenty-seven banked flamingo plasma samples were run in triplicate on each of the three blood analyzers. Values from the i-STAT analyzer were consistently lower than those from the ABL analyzer, while values from the VetTest were consistently higher than those from the ABL analyzer. However, there was a good level of correlation between all three analyzers. Two of the three analyzers were determined to have acceptable total allowable error levels, calculated at 3.6% for the ABL and 10.7% for the VetTest. For clinical purposes, both the i-STAT and the VetTest analyzers provide adequate evaluation of lactate levels when serial samples are measured on the same analyzer. After validating the assay, 34 captive flamingos were captured for routine examinations. Blood lactate concentration levels were positively correlated with the length of time of the individual capture, but lactate did not increase significantly as capture difficulty increased. Only one animal was considered to have a difficult capture. No flamingos demonstrated clinical signs of capture myopathy during this study. Further research is required to determine if blood lactate concentration is a useful indicator of capture myopathy. PMID- 23082508 TI - Hematologic and biochemical reference intervals for wild osprey nestlings (Pandion haliaetus). AB - A retrospective study of blood samples from 95 osprey (Pandion haliaetus) nestlings from Scotland and England, collected opportunistically over a 10-yr period, was performed to determine hematologic and plasma biochemistry reference intervals. The age of the sampled nestlings was estimated to be between 4 and 8 wk. Ninety-five percent reference intervals were determined for all hematologic and biochemical variables using parametric and nonparametric methods as appropriate. No blood parasites were detected. This is the first published study providing baseline reference data for osprey nestlings, and it is hoped the data will be of use to wildlife veterinarians and biologists in assessing the health of this species. PMID- 23082509 TI - Prevalence and spatial distribution of antibodies to bovine viral diarrhea virus and Coxiella burnetii in white-tailed deer (Odocoileus virginianus) in New York and Pennsylvania. AB - Significant pathogens of domestic livestock and public-health related pathogens, such as bovine viral diarrhea virus (BVDV) and Coxiella burnetii, are commonly diagnosed in some wildlife species. BVDV is an economically important pathogen of domestic bovids and Coxiella burnetii is a highly infectious zoonotic bacterium. As a result of recent shifting patterns of disease, it is critical that baseline information regarding the status of both significant pathogens of domestic livestock and public-health related pathogens are established for commonly encountered wildlife such as white-tailed deer (Odocoileus virginianus). White tailed deer are susceptible to both BVDV and C. burnetii infection, and the purpose of this study was to investigate for the presence of antibodies to these two pathogens in New York and Pennsylvania white-tailed deer. Exposure to BVDV and C. burnetii was determined using sera collected from 333 (219 males and 114 females) wild white-tailed deer in New York and 291 (130 males and 161 females) wild white-tailed deer from Pennsylvania. Samples were collected from hunter harvested deer in central New York State in 2009 and live-captured deer in Pennsylvania in 2010. Sera were screened for anti-BVDV antibodies via a commercial blocking BVDV enzyme-linked immunosorbent assay. Coxiella burnetii phase II whole-cell antigen-coated slides were used to screen sera via an indirect microimmunofluorescence assay. Antibody prevalence was compared by sex class and location of collection. Deer in New York had higher antibody prevalence to BVDV (6.01%) than did deer in Pennsylvania (0.34%). Conversely, C. burnetii phase II antibodies were more common in Pennsylvania (20.96%) than in New York (14.41%). No statistically significant difference between locations was observed in either BVDV or C. burnetii antibody prevalence when data were analyzed by sex class. Overall, C. burnetii seroprevalence was not significantly higher in Pennsylvania than in New York. PMID- 23082510 TI - Gallstones in slender lorises (Loris tardigradus). AB - A total of 32 slender lorises (Loris tardigradus) kept in captivity were investigated postmortem. In five adult lorises (4 females, 1 male), the gallbladder contained either one gallstone or multiple gallstones. Except for one 5-yr-old female, the affected individuals were between 11 and 13 yr of age. All of the gallstones consisted of 100% cholesterol. Besides other predisposing factors such as species, sex, increasing age, and diabetes mellitus, nutrition may play a major role in the occurrence of these gallstones. PMID- 23082511 TI - Corticosterone and thyroxine in cold-stunned Kemp's ridley sea turtles (Lepidochelys kempii). AB - Kemp's ridley sea turtles (Lepidochelys kempii), a critically endangered species, frequently strand on the shores of Cape Cod (Massachusetts, USA) in late autumn in a state of "cold-stunning" exhibiting low body temperature and related clinical issues. Stranded turtles are transported to the New England Aquarium (Boston, Massachusetts, USA) for treatment and rehabilitation. This study tested the hypothesis that cold-stunned sea turtles might exhibit high corticosterone ("stress hormone") or low thyroxine (which is often affected by temperature), or both, and that monitoring of both hormones may be useful for assessing recovery. In a retrospective analysis, 87 archived plasma samples were assayed from 56 cold stunned juvenile Kemp's ridley sea turtles for corticosterone and free thyroxine (fT4). Upon admission, mean corticosterone was the highest yet reported for a population of sea turtles (39.3 +/- 2.5 ng/ml; mean +/- standard error of the mean [SEM]) and fT4 was usually undetectable. On admission, corticosterone was negatively correlated with white blood cell count but was not correlated with blood glucose. There were no differences in either hormone between survivors and nonsurvivors on admission. After 18+ days in recovery, surviving turtles' corticosterone dropped significantly to levels typical of baseline in other species (0.9 +/- 1.0 ng/ml) while fT4 increased significantly (1.3 +/- 1.5 pg/ml). During recovery, corticosterone was positively correlated with blood glucose and was not correlated with white blood cell count. Turtles that showed persistent deficits in feeding, activity, or both during recovery had significantly lower fT4 than did turtles with no such deficits. The "high corticosterone, low fT4" endocrine profile seen on admission may be a useful marker of cold-stunning in this and other species. Further studies are necessary to determine whether low thyroid hormones play a causal role in deficits in feeding and activity during recovery. Monitoring of both hormones may be useful for triage, monitoring of recovery, and assessing readiness for release. PMID- 23082512 TI - Growth pattern differences of captive born Antillean manatee (Trichechus manatus) calves and those rescued in the Brazilian northeastern coast. AB - The aim of this work was to analyze whether there are differences between the development pattern of Antillean manatee (Trichechus manatus) calves born in captivity and those rescued and kept under rehabilitation. Biometrics data were collected from 1990 to 2010 from 38 calves, 29 of which still had the remnants of the umbilical cord and had been rescued from the Brazilian northeastern coastline (Group I), and nine individuals that were born in captivity and remained with their mothers (Group II). Among the measures obtained through biometry, the total length and weight of the animal were recorded. Given that the breastfeeding of calves occurs approximately until the age of 2 yr, data obtained until the 24th month of life of each individual were evaluated. An average increase in weight of 53.50 +/- 38.54 kg (mean +/- standard deviation [SD]) was detected in Group I and a gain of 106.87 +/- 47.21 kg (mean +/- SD) in Group II. From months 13 to 24, no significant difference in the weight increment was observed. A similar pattern occurred with regard to the increase in the overall length during the first year, where animals from Group I grew 34.81 +/- 17.94 cm (mean +/- SD) and from Group II grew 83.83 +/- 28.21 cm, a statistically significant difference. The growth was not significantly different from 13 to 24 mo. The results found in this study identified the need for a review of the nutritional diet offered to orphaned calves rescued and kept in captivity. The results also support the need for a better adequacy of facilities for these animals as a way to encourage the management strategies adopted for manatee calves maintained in captivity. PMID- 23082513 TI - Sulawesi tortoise adenovirus-1 in two impressed tortoises (Manouria impressa) and a Burmese star tortoise (Geochelone platynota). AB - Sulawesi tortoise adenovirus-1 (STAdV-1) is a newly discovered virus infecting endangered and threatened tortoises. It was initially described from a confiscated group of 105 Sulawesi tortoises (Indotestudo forsteni) obtained by the Turtle Survival Alliance and distributed to five sites with available veterinary care across the United States. In a 3-yr period from the initial outbreak, one multi-species collection that rehabilitated and housed adenovirus infected Sulawesi tortoises experienced deaths in impressed tortoises (Manouria impressa) and a Burmese star tortoise (Geochelone platynota). Impressed tortoises that died had evidence of systemic viral infection with histopathologic features of adenovirus. Adenovirus was identified by consensus nested polymerase chain reaction (PCR) testing and subsequent sequencing of PCR products. Sequencing indicated that the adenovirus infecting these impressed tortoises and Burmese star tortoise was STAdV-1. In one impressed tortoise, viral infection was confirmed using transmission electron microscopy. In situ hybridization using a semiautomated protocol and fluorescein-labeled riboprobe identified STAdV-1 inclusions in spleen, liver, kidney, and testis of one impressed tortoise. The impact of this virus on captive and wild populations of tortoises is unknown; however, these findings indicate that STAdV-1 can be transmitted to and can infect other tortoise species, the impressed tortoise and Burmese star tortoise, when cohabitated with infected Sulawesi tortoises. PMID- 23082514 TI - Quill mites in Brazilian psittacine birds (Aves: Psittaciformes). AB - The primary and secondary feathers of 170 Brazilian psittacine birds (Aves: Psittaciformes) were examined in order to identify feather quill mite fauna. Birds were held captive in two locations in the state of Minas Gerais (MG), and two in the state of Espirito Santo (ES). The quills were cut longitudinally and were examined under optical microscopy. The genus of quill mites most frequently found was Paralgopsis (Astigmata: Pyrogliphidae), followed by Cystoidosoma (Astigmata: Syringobiidae). Astigmata: Syringophilidae mites were sporadically observed. After analyzing the data using logistic regression models, it was determined that there was higher infestation risk for psittacines in ES state, as compared with those in MG, and a significant increase in risk depending on the psittacine host species. However, the location of captivity did not have a significant effect. Lesions were observed in infested feathers. Cystoidosoma sp. and Paralgopsis sp. were always observed together, with parts of Paralgopsis found inside Cystoidosoma sp., suggesting thanatochresis or predation. PMID- 23082515 TI - Body temperatures of selected amphibian and reptile species. AB - Ectothermic vertebrates are a diverse group of animals that rely on external sources to maintain a preferred body temperature. Amphibians and reptiles have a preferred optimal temperature zone that allows for optimal biological function. Physiologic processes in ectotherms are influenced by temperature; these animals have capabilities in which they make use of behavioral and physiologic mechanisms to thermoregulate. Core body, ambient air, body surface, and surface/water temperatures were obtained from six ectothermic species including one anuran, two snakes, two turtles, and one alligator. Clinically significant differences between core body temperature and ambient temperature were noted in the black rat snake, corn snake, and eastern box turtle. No significant differences were found between core body and ambient temperature for the American alligator, bullfrog, mata mata turtle, dead spotted turtle, or dead mole king snake. This study indicates some ectotherms are able to regulate their body temperatures independent of their environment. Body temperature of ectotherms is an important component that clinicians should consider when selecting and providing therapeutic care. Investigation of basic physiologic parameters (heart rate, respiratory rate, and body temperature) from a diverse population of healthy ectothermic vertebrates may provide baseline data for a systematic health care approach. PMID- 23082516 TI - Ultrasonographic abdominal anatomy of healthy captive caracals (Caracal caracal). AB - Abdominal ultrasonography was performed in six adult captive caracals (Caracal caracal) to describe the normal abdominal ultrasonographic anatomy. Consistently, the splenic parenchyma was hyperechoic to the liver and kidneys. The relative echogenicity of the right kidney's cortex was inconsistent to the liver. The gall bladder was prominent in five animals and surrounded by a clearly visualized thin, smooth, regular echogenic wall. The wall thickness of the duodenum measured significantly greater compared with that of the jejunum and colon. The duodenum had a significantly thicker mucosal layer compared with that of the stomach. Such knowledge of the normal abdominal ultrasonographic anatomy of individual species is important for accurate diagnosis and interpretation of routine health examinations. PMID- 23082517 TI - Biochemical values in free-ranging white rhinoceros (Ceratotherium simum) in Kruger National Park, South Africa. AB - Biochemical panels were analyzed on 181 individual free-ranging white rhinoceros (Ceratotherium simum) from Kruger National Park, South Africa. These animals were immobilized between July 2006 and May 2010 for management purposes. Serum and heparinized plasma samples were analyzed using an in-house chemistry analyser (ABAXIS VetScan2). The objectives of this study were to establish biochemical references ranges for Kruger National Park's population of white rhinoceros; to assess differences in values obtained using sera or plasma; and to assess differences in values between gender and different age categories. Significant differences between plasma and serum values were found in most measured parameters except minerals (calcium and magnesium). Because all animals appeared clinically healthy at the time of blood collection, it is hypothesized that choice of anticoagulant may affect certain parameters. Comparison between age categories and gender also resulted in significant differences in a few measured parameters. Identifying differences are important when establishing baseline reference ranges for wildlife populations to allow accurate monitoring of trends that may change over time. The paucity of data on normal biochemical ranges for free-ranging white rhinoceros demonstrates the value of this study and importance of evaluating potential confounding variables. PMID- 23082518 TI - Health assessment of captive tinamids (Aves, Tinamiformes) in Brazil. AB - Ninety-five (95) captive tinamids (Aves, Tinamiformes) of species Crypturellus obsoletus (brown tinamou), Crypturellus parvirostris (small-billed tinamou), Crypturellus tataupa (Tataupa tinamou), Crypturellus undulatus (undulated tinamou), Rhynchotus rufescens (red-winged tinamou), and Tinamus solitarius (solitary tinamou) were evaluated for diseases of mandatory control in the Brazilian Poultry Health Program (PNSA). Antibodies were detected by serum agglutination test (SAT) in 4 birds for Mycoplasma gallisepticum (MG) and in 27 birds for Salmonella Pullorum (SP) and Salmonella Gallinarum (SG). However, by hemagglutination inhibition (HI), sera were negative to MG and Mycoplasma synoviae (MS). Bacteriology was negative for SP and SG. No antibody was detected by HI to avian paramyxovirus type 1. However, antibodies to infectious bursal disease virus were detected in 9.4% (9/95) by ELISA. Fecal parasitology and necropsy revealed Capillaria spp. in 44.2% (42/95), Eimeria rhynchoti in 42.1% (40/95), Strongyloides spp. in 100% (20/20), Ascaridia spp., and unknown sporozoa in small-billed tinamou. Ectoparasites were detected in 42.1% (40/95) by inspection, and collected for identification. The louse Strongylocotes lipogonus (Insecta: Phthiraptera) was found on all Rhynchotus rufescens. An additional four lice species were found on 14 individuals. Traumatic lesions included four individual R. rufescens (4/40, 10%) with rhinotheca fracture, one with mandible fracture and three with posttraumatic ocular lesions (3/40, 7.5%). One C. parvirostris had phalangeal loss, another had tibiotarsal joint ankylosis and another had an open wound on the foot. Results suggest that major poultry infections/ diseases may not be relevant in tinamids, and that this group of birds, as maintained within distances for biosecurity purposes, may not represent a risk to commercial poultry. Ecto- and endoparasites were common, disseminated, and varied; regular monitoring of flocks is recommended for best performance. PMID- 23082519 TI - Fluorosis as a probable factor in metabolic bone disease in captive New Zealand native frogs (Leiopelma species). AB - This report describes the investigations into the cause and treatment of metabolic bone disease (MBD) in captive native New Zealand frogs (Leiopelma spp.) and the role of fluoride in the disease. MBD was diagnosed in Leiopelma archeyi and Leiopelma hochstetteri in 2008 at three institutions: Auckland Zoo, Hamilton Zoo, and the University of Otago. Most of these frogs had originally been held at the University of Canterbury for several years (2000-2004) but some were collected directly from the wild. Radiographs on archived and live frogs showed that MBD had been present at Canterbury, but at a lower rate (3%) than in the current institutions (38-67%). Microcomputed tomography showed that the femoral diaphyses of the captive frogs at Auckland Zoo had greater bone volume, bone surface, cross-sectional thickness, and mean total cross-sectional bone perimeter, which is consistent with osteofluorosis. On histology of the same femurs, there was hyperplasia, periosteal growth, and thickening of trabeculae, which are also consistent with skeletal fluorosis. An increase in fluoride levels in the water supply preceded the rise in the incidence of the above pathology, further supporting the diagnosis of osteofluorosis. Analysis of long-standing husbandry practices showed that ultraviolet B (UVB) exposure and the dietary calcium:phosphorus ratio were deficient when compared with wild conditions-likely causing chronic underlying MBD. To prevent multifactorial MBD in captive Leiopelma, the authors recommend increasing dietary calcium by incorporating into the captive diet inherently calcium-rich invertebrates; increasing exposure to natural or artificial (UVB) light; and using defluoridated water. Addressing these three factors at Auckland Zoo reduced morbidity, bone fractures, and mortality rates. PMID- 23082520 TI - Laparoscopic-assisted ovariectomy of tigers (Panthera tigris) with the use of the LigaSure device. AB - Laparoscopic ovariectomy was performed in seven tigers with the use of a vessel sealing device and a three-port technique. A comparison group of seven tigers that underwent traditional ovariohysterectomy was assembled with the use of a medical records search. Mean operative times for laparoscopic ovariectomy were compared to standard ovariohysterectomy, and mean combined laparoscopic incision length compared to standard ovariohysterectomy incision lengths. Significance was set at P < or = 0.05. Mean surgical time for laparoscopic ovariectomy (82 min, range 71-126 min) was significantly shorter than standard ovariohysterectomy surgical time (129 min, range 80-165 min, P = 0.007). Mean combined laparoscopic incision length (8.07 cm, range 3.80-9.50 cm) was significantly shorter than the mean incision length for standard ovariohysterectomy (13.57 cm, range 12.00-20.00 cm, P = 0.009). There were no clinically important complications observed in either group. Laparoscopic ovariectomy has a significantly shorter surgical time and combined incision length compared to standard ovariohysterectomy in tigers, and appears to be a safe and rapid sterilization method for tigers. Equipment cost and the necessity for advanced training may limit its use in some institutions. Further prospective evaluation is warranted to determine whether it is associated with decreased morbidity, mortality, or cost. PMID- 23082521 TI - Lead toxicity: consequences and interventions in an intensively managed (Gyps coprotheres) vulture colony. AB - The National Zoological Gardens of South Africa (NZG) is involved in the ex situ conservation of Gyps coprotheres, the Cape Griffon vulture (CGV) and houses 24 birds in a 100-yr-old aviary. Following the death of one vulture with high liver lead concentrations, an investigation was launched to ascertain the source(s) and consequences of lead toxicity in this breeding colony. Whole blood from 24 CGV, paint from the enclosure, water, and soil sampled at various locations within the enclosure were evaluated for their lead concentration, and data were gathered from NZG's medical records. The lead concentration in the paint, water, and enclosure soil was 5,100 microg/g, 0.5 microg/dl, and 72.48 +/- 21.83 microg/g, respectively. The whole-blood lead concentrations were 56.58 +/- 11 microg/dl. The breeding history of six pairs within the contaminated enclosure since 2002 showed 45 eggs laid, of which 44% were infertile and 24% successfully reared. The medical records revealed evidence of osteodystrophy despite adequate nutrition. As intervention measures, six birds were treated with Ca2+EDTA and the topsoil inside the enclosure was replaced. As a result, the lead concentration in the enclosure soil dropped to 14.74 +/- 14.39 microg/g, and the whole-blood lead concentrations declined to 42.75 +/- 11.64 microg/dl. It was concluded that lead concentrations in whole blood in excess of 100 microg/dl leads to clinical signs of lead toxicity in the CGV. Lower levels appear to interfere mainly with reproductive potential. PMID- 23082522 TI - Trombiculid mites (Hannemania sp.) in Leptodactylus chaquensis (Amphibia: Anura) inhabiting selected soybean and rice agroecosystems of Argentina. AB - Trombiculid mites are known to parasitize a variety of amphibian species; however, few comparisons of mite parasitism among sites have been made. Here, Hannemania sp. parasitism in frogs (Leptodactylus chaquensis) inhabiting agroecosystems from mideastern Argentina was described. A total of 40 adult frogs (22 females and 18 males) were analyzed to detect ectoparasite Hannemania spp. larvae. Prevalence and mean abundance of Hannemania sp. were consistently higher in frogs from the agroecosystems (rice and soybean fields) than from two reference sites. Leptodactylus chaquensis might be considered an important host species of Hannemania sp., particularly in agricultural areas. PMID- 23082523 TI - Ascaridiasis in peafowl Pavo cristatus (Phasianidae) due to Ascaridia galli Schrank, 1788. AB - Twelve white peafowl (Pavo cristatus) affected by an outbreak of an intestinal disease were referred for more detailed examination at the Universidade Estadual de Santa Cruz-BA, Brazil. During the course of the disease, peachicks were severely affected, with enteric signs such as diarrhea plus dehydration, decreased feed intake and progressive weight loss. After examination, 8 of 12 samples (66.6%) presented single or mixed nematode infection and Ascarid eggs were the most frequent finding on fecal examination. Adult peafowl did not present clinical signs even when positive after fecal exam. Morphological analysis, clinical signs, fecal and gross examinations resulted in a diagnosis of ascaridiasis caused by Ascaridia galli Schrank (1788). PMID- 23082524 TI - Spinal cord compression in two related Ursus arctos horribilis. AB - Two 15-yr-old grizzly bear littermates were evaluated within 9 mo of each other with the symptom of acute onset of progressive paraparesis and proprioceptive ataxia. The most significant clinical examination finding was pelvic limb paresis in both bears. Magnetic resonance examinations of both bears showed cranial thoracic spinal cord compression. The first bear had left-sided extradural, dorsolateral spinal cord compression at T3-T4. Vertebral canal stenosis was also observed at T2-T3. Images of the second bear showed lateral spinal cord compression from T2-T3 to T4-T5. Intervertebral disk disease and associated spinal cord compression was also observed at T2-T3 and T3-T4. One grizzly bear continued to deteriorate despite reduced exercise, steroid, and antibiotic therapy. The bear was euthanized, and a necropsy was performed. The postmortem showed a spinal ganglion cyst that caused spinal cord compression at the level of T3-T4. Wallerian-like degeneration was observed from C3-T6. The second bear was prescribed treatment that consisted of a combination of reduced exercise and steroid therapy. He continued to deteriorate with these medical therapies and was euthanized 4 mo after diagnosis. A necropsy showed hypertrophy and protrusion of the dorsal longitudinal ligament at T2-T3 and T3-T4, with resulting spinal cord compression in this region. Wallerian-like degeneration was observed from C2-L1. This is one of few case reports that describes paresis in bears. It is the only case report, to the authors' knowledge, that describes spinal magnetic resonance imaging findings in a grizzly bear and also the only report that describes a cranial thoracic myelopathy in two related grizzly bears with neurologic signs. PMID- 23082525 TI - Successful treatment of a severe case of fusariomycosis in a beluga whale (Delphinapterus leucas leucas). AB - An adult male beluga whale (Delphinapterus leucas leucas) was presented with a 4 cm-diameter, raised, firm nodule on the medial aspect of the left pectoral fin. A fissure developed within the center of the nodule, which formed an ulcerated cyst like lesion. The lesion rapidly progressed in size, and, with peeling of material present within the cyst, the lesion flattened to a 36 x 25-cm cutaneous ulcer that extended into the axilla. Histopathologic features were consistent with lymphocytic and suppurative dermatitis with intralesional fungi. Fusarium solani was diagnosed by polymerase chain reaction (PCR). Fungal susceptibility testing was performed and revealed drug resistance to multiple antifungal medications tested individually and in combination therapies. Treatments used included serial surgical debridement of affected and surrounding tissue, topical application and regional infusion of various azole, and allylamine antifungals combined with either dimethyl sulfoxide or Tricide for absorption potentiation, and oral voriconazole administration. Although susceptibility testing revealed resistance to voriconazole, visible improvement of the lesion was noted after 6 weeks of oral voriconazole therapy. The voriconazole dosage was tapered based on serum levels and was administered over a 12-mo period. No local recurrence or new lesions were visible by 14 mo from first presentation. PMID- 23082526 TI - Effects of a gonadotropin-releasing hormone vaccine on ovarian cyclicity and uterine morphology of an Asian elephant (Elephas maximus). AB - This report describes the successful use of a gonadotropin-releasing hormone (GnRH) vaccine to suppress ovarian steroidogenic activity and to treat hemorrhage and anemia associated with reproductive tract pathology in a 59-year-old Asian elephant (Elephas maximus). The Repro-BLOC GnRH vaccine was administered subcutaneously as a series of 4 boosters of increasing dose from 3 to 30 mg of recombinant ovalbumin-GnRH fusion protein given at variable intervals after initial vaccination with 3 mg protein. Efficacy was confirmed over a year after initial vaccination based on complete ovarian cycle suppression determined by serum progestagen analyses. Estrous cycle suppression was associated with a significant increase in GnRH antibody binding and subsequent decrease in serum luteinizing hormone and follicle-stimulating hormone concentrations. Ultrasonographic examinations of the reproductive tract documented a reduction in uterine size and vascularity after immunization. The hematocrit level normalized soon after the initial intrauterine hemorrhage, and no recurrence of anemia has been detected. No substantive adverse effects were associated with GnRH vaccination. The results indicate that GnRH vaccination in elephants shows potential for contraception and management of uterine pathology in older elephants. PMID- 23082527 TI - Endoscopic evaluation and biopsy collection of the gastrointestinal tract in the green moray eel (Gymnothorax funebris): application in a case of chronic regurgitation with gastric mucus gland hyperplasia. AB - A green moray eel (Gymnothorax funebris) was evaluated for chronic regurgitation. By using flexible endoscopy, the gastrointestinal tract was evaluated and revealed multifocal proliferative gastric masses and an intestinal ulcer. Biopsy specimens revealed gastric mucus gland hyperplasia, intestinal nematodiasis, and mild enteritis. Esophagoscopy and gastroscopy were performed by using a larger endoscope (length, 200 cm). A smaller endoscope (length, 100 cm) facilitated entering the intestinal tract in normograde or retrograde directions. A control eel was also evaluated, and no gross or histologic abnormalities were detected. The case eel was treated with metoclopramide and fenbendazole, responded well to therapy, and regurgitation decreased. A year later, the animal died of unrelated causes. Necropsy revealed coelomic gastric adhesions. The gastric proliferative lesions were associated with degeneration and necrosis of gastric pit mucosa without significant inflammation; etiology was unknown. Gastrointestinal endoscopy proved a useful diagnostic tool for evaluation and biopsy collection in this eel species. PMID- 23082528 TI - The onset of goiter in several species of sharks following the addition of ozone to a touch pool. AB - This report describes the onset of goiter in several species of shark following the addition of ozone to a touch pool. A detailed description of a female brown banded bamboo shark (Chiloscyllium punctatum) that was presented with multinodular goiter is provided. Four other brown-banded bamboo sharks and 11 white-spotted bamboo sharks (Chiloscyllium plagiosum) housed in the same system developed clinical disease consistent with goiter, but two zebra bullhead sharks (Heterodontus zebra) did not. Plasma thyroxine (T4) concentration was 4.64 ng/ml before euthanasia, consistent with a diagnosis of hypothyroidism. The sharks had been chronically exposed to mean (+/- standard error) NO3-N concentrations of 35 +/- 5.12 mg/L before ozonation of the system. Ozonation of aquarium water causes a reduction in environmental iodide, which is required for thyroid hormone synthesis. Nitrate is goitrogenic and would further decrease I- absorption by competitive inhibition. Multinodular goiter is consistent with goiter caused by chronic iodide deficiency. Understanding the interaction between water chemistry and goiter development is critical to development of elasmobranch health management systems. PMID- 23082529 TI - Abscesses associated with a Brucella inopinata-like bacterium in a big-eyed tree frog (Leptopelis vermiculatus). AB - A 4-yr-old big-eyed tree frog (Leptopelis vermiculatus) was submitted with two pea-sized (4-mm diameter), firm, and painful masses on the right side of its back. The two abscess-like masses were surgically opened, and a whitish-yellow pasty content was removed. A Brucella inopinata-like bacterium was obtained in pure culture and was resistant against ampicillin and tylosin but sensitive to the 8 other antibiotics tested. The organism was identified by polymerase chain reaction and sequencing of the 16S ribosomal ribonucleic acid (acc. no. HE608873) and recA (acc. no. HE608874) genes after preliminary misidentification as Ochrobactrum anthropi when using a commercial identification system. To the authors' knowledge, a B. inopinata-like bacterium has not been reported previously in amphibians. The organism is a potential human pathogen and may present a risk for people handling amphibians. PMID- 23082530 TI - Subependymal glioneuronal hamartoma in the mesencephalic aqueduct of a giraffe. AB - A 1-day-old male giraffe calf (Giraffa camelopardalis) was submitted for necropsy examination after sustaining postnatal head trauma from the cow. In addition to the expected findings of severe cerebral edema and epidural and subarachnoid hemorrhage, there also was present an incidental finding of a subependymal glioneuronal aqueductal hamartoma. Reports of this type of congenital lesion are rare in the human literature, and the lesion has not, to the authors' knowledge, previously been reported in this or any other veterinary species. PMID- 23082531 TI - Occurrence of Thelazia callipaeda and Toxocara cati in an imported European lynx (Lynx lynx) in Japan. AB - A necropsy was performed on an adult European lynx, Lynx lynx (Linnaeus, 1758), held in captivity until its death, to determine level of parasitism. Examination of the eyes revealed the oriental eyeworm, Thelazia callipaeda, in the conjunctival sac and the third eyelid of both eyes. The species was confirmed by location and morphology. Intact worms were fixed, mounted, and identified. Examination of the alimentary tract revealed the common ascaroid nematode, Toxocara cati. Species was confirmed by the arrow-like anterior end. One hundred and forty-one adult worms were collected. The presence of these nematodes indicated the importance of eliminating the contact of zoo animals with Amiota spp. vectors and to prevent contamination with the infective T. cati eggs. PMID- 23082532 TI - First report of a successful treatment of a mucodegenerative disease in the chambered nautilus (Nautilus pompilius). AB - A single Nautilus pompilius manifested a bacterial infection and nematode infestation soon after it was received from the wild, resulting in a significant buildup of mucus above the left eye and tentacles. This condition is known to lead to rapid mucodegeneration of the tentacles and epithelium, resulting in death. The specimen was quarantined 24 days after arrival. Initial topical treatments of 10% povidone solution were effective at slowing the progression of the mucus but did not eliminate it. After 26 days in quarantine, a new treatment regimen was developed that coupled a whole-animal dip in 25 mg/L oxytetracycline solution with the 10% povidone treatment on alternate days, for 5 days. After this treatment, mucus production ceased and nematodes were not present in tissue samples. The specimen was moved back to the original holding system after a quarantine period of 53 days. PMID- 23082533 TI - Detection and phylogenetic characterization of hepatitis E virus genotype 3 in a captive wild boar in Thailand. AB - Hepatitis E virus (HEV) was studied in different types of wild boar captive settings in Thailand, including a wildlife breeding research station, zoo, and commercial wild boar farm, which were located in different locations of Thailand. Fifty-one fecal samples were collected and screened for HEV RNA and then analyzed. One sample obtained from a wildlife breeding research station in Ratchaburi province was HEV positive. Phylogenetic characterization revealed that the virus was HEV genotype 3 and belongs to subgroup 3e, which is closely related to HEV recently isolated from domestic pigs and humans in the country. It was hypothesized that HEV is shared among wild boars, domestic pigs, and humans in Thailand. PMID- 23082534 TI - Acute granulocytic anaplasmosis in a captive timber wolf (Canis lupus occidentalis). AB - A 2-yr-old male captive timber wolf, kept in an outdoor enclosure in Austria, presented with anorexia, depression, and fever in June. Tick infestation was reported despite monthly acaricidal treatment. The microscopic examination of a blood smear revealed elementary bodies and morulae suspicious for Anaplasma phagocytophilum. Polymerase chain reaction confirmed the infection by the G variant of the pathogen, also found in horses and humans but not in wild ruminants. The wolf seroconverted within 2 wk, and antibodies persisted thereafter. Therapy was started with doxycycline for 10 days, and the wolf recovered within 24 hr. Clinical symptoms and temporary changes in blood parameters (thrombocytopenia, lymphopenia, mild anemia) in this wolf show high similarity to granulocytic anaplasmosis seen in dogs. This is the first report on granulocytic anaplasmosis in a wolf, indicating that A. phagocytophilum might cause clinical disease in the wolf. PMID- 23082535 TI - Cystine urolithiasis in a caracal (Caracal caracal). AB - In July 2009, a 14-yr-old male caracal (Caracal caracal) at the National Zoological Gardens of South Africa was found, on abdominal ultrasound, to have a single large cystolith. The cystolith was removed, and the composition was determined to be 100% cystine. Blood and urine samples were also collected from three other apparently healthy caracals at the zoo and were submitted, together with the samples from the affected animal, for analysis using gas chromatograph mass spectrometry for cystine, lysine, alanine, and ornithine levels. The cystine levels in the urine, the fractional excretion of cystine, and the normalized excretion of cystine (micromol/g of creatinine) were all higher in the affected caracal than in the healthy animals. Only a single other case of cystine urolithiasis has been previously reported in any wild felid in the literature. PMID- 23082536 TI - Treatment of vasculitis and dermatitis in a 59-yr-old Nile hippopotamus (Hippopotamus amphibius). AB - A 59-yr-old female Nile hippopotamus (Hippopotamus amphibius) was diagnosed and treated for severe dermatitis. Lesions included large areas of depigmentation, erosions, and ulcerations on glabrous skin areas, limbs, and perineal region. Histopathologic lesions included a markedly edematous, focally eroded, ulcerative to necrotic epidermis; foci of keratinocyte apoptosis; and a mixed suppurative dermatitis. Most of the dermal vessels had variable hyalinized walls with plump endothelial cells and frequent intramural neutrophils, and some vessels had vascular thrombi consistent with vasculitis. Culture of the lesions yielded beta hemolytic Streptococcus, Morganella morgannii, and Enterococcus sp. The hippopotamus was successfully treated with sulfamethoxazole and trimethoprim, amoxicillin, and pentoxifylline for more than 2 mo, and the condition did not recur over the subsequent 16 mo. PMID- 23082537 TI - Accessory carpal bone luxation in two gray wolves (Canis lupus). AB - Two sibling male castrated gray wolves (Canis lupus) developed acute onset right forelimb lameness, one at 8 and the other at 11 yr of age. In both cases, the right carpus was swollen, carpal hyperextension was notable, and the wolves exhibited significant intermittent lameness of the affected limb. Radiographs revealed right accessory carpal bone luxation in both cases, with type III fracture of the accessory carpal bone in one wolf. Although carpal bone luxation in domestic dogs is frequently treated surgically, conservative medical management resolved the lameness in both wolves with no further complications. PMID- 23082538 TI - Antinociceptive efficacy of buprenorphine and hydromorphone in red-eared slider turtles (Trachemys scripta elegans). AB - Despite the frequent clinical use of buprenorphine in reptiles, its antinociceptive efficacy is not known. In a randomized, complete cross-over study, the antinociceptive efficacy of buprenorphine (0.2 mg/kg s.c.) was compared with hydromorphone (0.5 mg/kg s.c.), and saline (0.9% s.c. equivalent volume) in 11 healthy red-eared slider turtles (Trachemys scripta elegans). Additionally, buprenorphine at 0.1 and 1 mg/kg was compared with saline in six turtles. Hindlimb withdrawal latencies were measured after exposure to a focal, thermal noxious stimulus before and between 3 hr and up to 96 hr after drug administration. Buprenorphine did not significantly increase hindlimb withdrawal latencies at any time point compared with saline. In contrast, hydromorphone administration at 0.5 mg/kg significantly increased hindlimb withdrawal latencies for up to 24 hr. These results show that hydromorphone, but not buprenorphine, provides thermal antinociception in red-eared slider turtles. PMID- 23082539 TI - Suspected neurotoxicity due to Clostridium perfringens type B in a tiger (Panthera tigris). AB - A 4-yr-old tiger (Panthera tigris) was referred with acute onset of severe abnormal consciousness. Neurological evaluation showed normal palpebral and corneal reflexes, normal pupil diameter with normal direct and consensual papillary light reflex, and absent menace response bilaterally. Diffuse forebrain lesion or focal lesion affecting the ascending reticular activating system was suspected. Complete blood examination and cerebrospinal fluid analysis were normal. Magnetic resonance imaging of the brain showed an empty sella as the only result. Clostridium perfringens 10(4) to 10(7) colony-forming units/g were detected in fecal flora samples. Multiplex polymerase chain reaction assay identified serotype B counts with production of epsilon toxin. This toxin specifically accumulates in the central nervous system, where it causes acute neurological signs in humans, domestic animals, and wildlife. In this communication, the acute onset of neurological signs without evidence of trauma, vascular, metabolic, or inflammatory diseases may be caused by neurotoxicity due to C. perfringens. PMID- 23082540 TI - Hysteroscopy and episiotomy in a rescued, cold-stressed Florida manatee (Trichechus manatus latirostris) for diagnosis and treatment of a retained fetal skeleton. AB - A rescued female manatee was observed expelling a fetal bone from the vulva. The manatee was anesthetized and diagnosed with uterine retention of a fetal skeleton by ultrasound and hysteroscopy. Episiotomy was performed to gain manual access to the vagina and uterus for removal of the skeleton. Second intention healing of the episiotomy site produced excellent results. Rescued female manatees should receive a thorough reproductive tract evaluation since presence of retained fetal tissues might not be evident in blood or hormone analyses. Retention of a whole or partial dead fetus can be life-threatening to manatees, and retained tissues should be removed as early as possible. PMID- 23082541 TI - Oslerus osleri (Cobbold, 1876) infection in maned wolf (Chrysocyon brachyurus, illiger, 1815). AB - Oslerus osleri is a small nematode that infects the respiratory tract of domestic and wild canids and is responsible for causing chronic nodular tracheobronchitis. This paper aims to report a case of parasitism by O. osleri in a free-living maned wolf (Chrysocyon brachyurus) that was struck by a motor vehicle. Fecal samples were collected, and the presence of spiral larvae, with "S"-shaped tails, was observed on flotation. This characteristic was compatible with the Filaroididae Family larvae of O. osleri. Although the animal did not show clinical signs of respiratory system impairment, a tracheobronchoscopy was performed. Semitransparent nodules, 5 mm in diameter, containing adult parasites were observed in the third distal portion of the trachea, cranial to the carina. Larval morphological characteristics and the nodular locations were compatible with an O. osleri respiratory tract infection. PMID- 23082543 TI - Detection of gastrointestinal parasites in raccoon dogs (Nyctereutes procyonoides) in the Seosan reclaimed lands, Korea. AB - This study examined gastrointestinal parasites of raccoon dogs in the Seosan reclaimed lands, Korea. We collected 882 raccoon dog fecal samples and examined them using a fecal flotation technique following standard procedures. Identification was based on the morphology and size of the parasite eggs and oocysts. Nine different helminth eggs and oocysts of Isospora spp. were identified. In total, 314 (35.5%) fecal samples were positive for gastrointestinal helminths or Isospora spp. Double (6%), triple (1%), and quadruple (0.3%) infections were observed. The rates of parasite infection in spring, summer, fall, and winter were 29.8, 20.7, 39.0, and 42.9%, respectively. These results indicate that raccoon dogs host diverse helminths and Isospora spp., posing a potential risk of transmitting parasites to domestic pets and residents in the area. Active epidemiological surveillance with modern molecular techniques and ancillary epidemiological tools is recommended. PMID- 23082542 TI - Cefovecin (Convenia) for the treatment of septic peritonitis in a female lion (Panthera leo). AB - An 8-yr-old intact female African lion (Panthera leo) presented with a 3-day history of lethargy, anorexia, and vomiting. Hematologic and biochemical abnormalities included a leukocytosis, 41,700/microl (4,700-15,300) with a neutrophilia (37,530/microl; 2,000-9,200) and a left shift (1,250/microl bands; 0 300), and mild hypokalemia of 2.1 mEq/L (2.8-4.8). Abdominal radiographs revealed evidence of intestinal ileus, peritonitis, and the presence of effusion. An exploratory laparotomy was performed, and septic peritonitis due to a pyometra was diagnosed. The lion was treated with an ovariohysterectomy, abdominal lavage, fluid therapy, and a subcutaneous injection of cefovecin. The lion recovered, and clinical signs associated with septic peritonitis resolved within 36 hr. It was returned to conspecifics 3 wk later. Three months postoperatively, the lion showed no residual signs of septic peritonitis. PMID- 23082544 TI - Leishmania infantum infection in two captive barbary lions (Panthera leo leo). AB - A female barbary lion (Panthera leo leo) from the Montpellier Zoological Park (France) showing colitis, epistaxis, and lameness with pad ulcers was positive by polymerase chain reaction (PCR) for Leishmania infantum. Further indirect immunofluorescence (IFAT) tests on the banked sera from all lions of the park detected another infected but asymptomatic female, which was confirmed by PCR on ethylenediaminetetraacetic acid (EDTA) blood sample. Leishmania infantum zymodeme MON-1 was cultured from EDTA bone marrow samples sampled from this second animal. The first female was successfully treated with marbofloxacine at 2 mg/kg s.i.d. for 28 days (Marbocyl, Vetoquinol 70204 Lure, France) and allopurinol at 30 mg/kg s.i.d. for 3 mo (Allopurinol Mylan, Mylan SAS, 69800 Saint-Priest, France) and then 1 wk/mo. Both positive animals were born at the Rabat Zoological Park, Morocco, and arrived together at Montpellier in 2003. The chronicity and source of this current infection are unknown since Morocco and southern France are well known to be enzootic for leishmaniasis. PMID- 23082545 TI - Air sac fluke Circumvitellatrema momota in a captive blue-crowned motmot (Momotus momota) in France. AB - Postmortem examination of a 4-mo-old captive-born blue-crowned motmot (Momotus momota) at the Montpellier Zoo in France revealed the presence of air sac flukes. Circumvitellatrema momota (Digenea: Cyclocoelidae) was suspected and confirmed by molecular genetic analysis. Digenean metacercariae were extracted from an invasive species of terrestrial snail, the conical periwinkle, Subulina striatella. Molecular genetic analysis determined that these metacercariae were also C. momota, confirming that all the stages of this parasite's life cycle were present and that birds were likely becoming infected by eating these infected snails. It is likely that this trematode was imported into the greenhouse with a wild-caught motmot. The conical periwinkle snail appears to have been imported into the zoo with the plants in 2007 when the greenhouse was built. Treatments, which have been disappointing, are discussed, as well as preventive measures to avoid dissemination of the parasite into other bird collections in Europe. PMID- 23082546 TI - Clinical challenge. Avulsion fracture of the caudal cruciate ligament. PMID- 23082547 TI - Effects of antimalarial drugs on movement of Plasmodium falciparum. AB - In vitro antimalarial drug susceptibility is conventionally assessed by the concentration dependent growth inhibition of Plasmodium in an in vitro culture system. Inhibition of the kinetic properties of the parasites could provide an alternative method to assess in vitro antimalarial drugs sensitivity. In this study we used a novel real time microscopic technique, which does not require fixation and staining of the parasite, to study the effects of antimalarial drugs on the intracellular movement of Plasmodium (P.) falciparum trophozoites. Using real time microscopy movement of P. falciparum pigment within erythrocytes was investigated before and after antimalarial drugs exposure (artesunate, quinine, and piperaquine). For artesunate, the 50% inhibition concentration (IC50) at which movement in half of the trophozoites was abolished was estimated by sigmoid curve fitting. Intra- and inter-observer agreements were also assessed. Healthy unexposed P. falciparum trophozoites in culture showed very active movement of malaria pigment. Quinine and piperaquine had no effect but artesunate did reduce pigment movement which started after 2.5 hours exposure to the drug. The mean (SD) IC50 for artesunate regarding abolishment of pigment movement was 54 (14) ng/ml. Assessments of intra- and inter-rater agreement showed good reproducibility of the technique (Kappa value 0.82 to 0.91). Abolishment of active movement of malaria pigment is an alternative approach to assess drug sensitivity for artesunate. Malaria pigment movement is abolished by artesunate early after exposure, but at concentrations higher than those inhibiting growth. PMID- 23082548 TI - Cloning and expression of Toxoplasma gondii dense granule antigen 2 (GRA2) gene by Pichia pastoris. AB - Detection of Toxoplasma gondii infection is essential in pregnant women and immunosuppressed patients. Numerous studies have shown that the recombinant production of several Toxoplasma antigens, including dense granule antigens (GRAs) has high potential as diagnostic reagents. In the present study, we produced GRA2 using Pichia pastoris system. RNA of T. gondii RH strain tachyzoite was used as a template to produce cDNA clones of full-length GRA2 via reverse transcriptase PCR. Amplicons were inserted into pPICZalpha A and the recombinant plasmid transformed into P. pastoris, X-33 strain. The expressed recombinant protein was identified by SDS-PAGE and Western blotting. A recombinant protein of -28 kDa was produced, which could be detected by toxoplasmosis positive human sera indicating that the recombinant protein retained its antigenicity. The present study indicates that P. pastoris-expressed GRA2 should be useful for detection of Toxoplasma infection. PMID- 23082549 TI - The first reported case of autochthonous cutaneous leishmaniasis in Thailand. AB - Thailand is not an endemic area for leishmaniasis. Several cases of autochthonous visceral leishmaniasis have been reported from Thailand but cutaneous leishmaniasis has never been reported. We reported a three-year-old girl who presented with a chronic ulcer on her cheek which proved to be cutaneous leishmaniasis. The diagnosis was made by finding amastigotes on skin biopsy; the patient had a therapeutic response to itraconazole. PMID- 23082550 TI - Diversity of gastrointestinal helminths among murid rodents from northern and northeastern Thailand. AB - The presence of gastrointestinal helminths (GI helminths) was investigated among 725 murid rodents, trapped in various habitats of Nan, Loei and Buri Ram Provinces, Thailand. The study revealed 17 species of rodents infected with 21 species or taxonomic groups of parasites (3 trematodes, 3 cestodes, 14 nematodes and 1 acanthocephalan). The overall prevalence of infection was 57.7% (418/725). Of the gastrointestinal (GI) helminths, the dominant parasitic group was members of the family Trichostrongylidae (24.3%), followed by the cestodes Raillietina sp (17.1%) and Hymenolepis diminuta (8.6%) and the nematode Syphacia muris (8.6%). The GI helminthic infection rates were highest in Mus caroli (81.8%), Mus cervicolor (76.5%), Leopoldamys edwardsi (75.0%), Bandicota indica (71.5%) and Bandicota savilei (71.4%). Highest rodent species richness (RSR) and helminth species richness (HSR) rates were found in Loei, followed by Nan and Buri Ram. The helminth prevalence rate was higher in rodents from Nan, followed by rodents from Loei and Buri Ram. Rodents from irrigated fields had the highest infection rates followed by rodents from upland or dry agricultural areas, forests and domestic habitats. Raillietina sp, Rodentolepis nana (syn. Hymenolepis nana), Hymenolepis diminuta, Moniliformis moniliformis and Cyclodontostomum purvisi, considered zoonotic parasites, were mainly found in rodents from domestic habitats and lowland irrigated fields. PMID- 23082551 TI - Resistance of Aedes aegypti (L.) larvae to temephos in Surabaya, Indonesia. AB - The resistance of Aedes aegypti mosquitoes to insecticides threatens dengue virus control efforts. In this study, Ae. aegypti larvae collected from 12 subdistricts in Surabaya, Indonesia, where dengue is endemic, were tested for resistance to the organophosphate, temephos. Susceptibility testing, performed according to World Health Organization (WHO) methods, showed all field strains were resistant to temephos at a dose of 0.012 mg/l, with mortality rates at 24 hours of 22% to 60%. Another susceptibility test to determine median lethal time (LT50) indicates resistance ratios ranging from 2.2 to 8.5. Although incipient resistance was detected at a dosage of 1 mg/l, as determined by the LT50, mortalities higher than 80% within 24 hours were detected using the WHO method in nine subdistricts of Surabaya, indicating temephos at 1 mg/l is still effective in field conditions in these areas. In three subdistricts (Tambaksari, Gubeng and Sawahan), the mortality rates were under 80%, indicating possible resistance to temephos. PMID- 23082552 TI - Insecticide susceptibility status of field-collected Aedes (Stegomyia) aegypti (L.) at a dengue endemic site in Shah Alam, Selangor, Malaysia. AB - Biweekly ovitrap surveillance (OS) was conducted for a year (August 2007 - September 2008) at two different dengue endemic sites in Shah Alam, Selangor, Malaysia, 50 km from Kuala Lumpur. Aedes aegypti collected from these 2 locations were raised to the F3 stage and subjected to a WHO standard bioassay method to determine lethal time (LT) against pyrethroids (permethrin 0.75%, cyfluthrin 0.15%), organophosphates (malathion 5.0%, fenitrothion 1.0%), carbamates (propoxur 0.1%, bendiocarb 0.1%) and organochlorine (DDT 4.0%). Insecticide susceptibilities were analyzed for one year. Aedes aegypti were resistant to DDT with a mortality range of 0 - 13.3% throughout the year at both sites. Susceptibilities to pyrethroids and carbamates varied throughout the year. In contrast, susceptibilities to pyrethroids and carbamates varied throughout the year: resistant to propoxur, bendiocarb and permethrin with mortality of < 80% in most months; but, showed incipient resistant to cyfluthrin in most months. Mosquitoes were consistently susceptible to malathion and fenitrothion, with complete mortality during most months. They were especially susceptible to malathion with LT50 values of 21.32 - 36.37 minutes, suggesting effectiveness of malathion for control of dengue. PMID- 23082553 TI - Literature review of parasitoids of filth flies in Thailand: a list of species with brief notes on bionomics of common species. AB - We reviewed the literature for surveys of parasitoid of filth flies in Thailand. We found 5 families, with 9 genera and 14 species identified in Thailand. We describe the ecological niches and biology of common species, including Spalangia cameroni, S. endius, S. nigroaenea and Pachycrepoideus vindemmiae. PMID- 23082554 TI - Evaluation of two IgM rapid immunochromatographic tests during circulation of Asian lineage Chikungunya virus. AB - Chikungunya is an emerging viral disease, which is clinically difficult to distinguish from dengue. Current laboratory methods to diagnose chikungunya infection, such as virus isolation, RT-PCR and ELISA, are not readily available in many clinical settings. In order to provide a rapid and easy method for the diagnosis of chikungunya infection, rapid immunochromatographic tests to detect chikungunya IgM have recently become commercially available. The sensitivity and specificity of the OnSite Chikungunya IgM Rapid Test-Cassette and the SD Bioline CHIK IgM rapid test were evaluated in comparison to a capture ELISA. The sensitivity of the OnSite test was 20.5% while its specificity was 100%. The sensitivity of the SD Bioline test was 50.8% while its specificity was 89.2%. The sensitivity of the SD Bioline test increased with increasing CHIK IgM titers and with days of onset in samples collected before day 21 of illness. Increasing the reading time from the manufacturer's suggested time of 10 to 20 minutes significantly increased the sensitivity of the SD Bioline test to 68.2%, but did not significantly change its specificity. PMID- 23082555 TI - Severe perinatal dengue hemorrhagic fever in a low birth weight infant. AB - A 31-year-old Hmong (Thai hilltribe) multiparous (G5P2) female with dengue hemorrhagic fever delivered a low birth weight male infant at 34 weeks estimated gestational age. The mother had fever for a total of 6 days, along with hepatomegaly, hepatic dysfunction and thrombocytopenia. Serology showed acute secondary dengue infection. She had no serious complications. The infant (birth weight 1,850 grams) developed a fever 140 hours postpartum of 37.8 degrees C for one day, then developed drowsiness, poor feeding and apnea. Hepatomegaly, thrombocytopenia, hepatic dysfunction and moderate coagulopathy were detected, with consequential shock and anemia due to gastrointestinal and pulmonary hemorrhage. Vigorous treatment with mechanical ventilation, packed red cells (PRC), fresh frozen plasma (FFP) and platelet concentrate transfusions were given and the child recovered successfully and commenced breast-feeding. At six months of age the child's growth and development were normal except for an impaired hearing screening test. PMID- 23082556 TI - Epidemiological characteristics, clinical presentation and diagnosis at point-of care during the first wave of the H1N1 influenza pandemic in Cambodia. AB - We conducted clinic-based surveillance for influenza virus among cases with acute febrile illness at 9 medical clinics in south-central Cambodia during 2006-2009. Patients greater than or equal to 24 months old presenting with acute fever (> 38 degrees C) were enrolled. In late July 2009, the study identified its first case of pandemic H1N1 (pH1N1) influenza virus infection. The prevalence of pH1N1 infections increased rapidly during August and September and by October, pH1N1 infections had peaked replacing H3N2 as the dominant subtype. The incidence of pH1N1 subsequently decreased, with only one case identified in late December. From late July through December 2009, 42.4% of all influenza cases were caused by pH1N1. Except for headache, less frequently reported among pH1N1-infected patients, patients infected with the pH1N1 reported symptoms (eg, cough, diarrhea, vomiting and nausea) similar to seasonal H3N2 and B virus infections. Among children 6 to 12 years old, there was a higher number of hospitalizations campared to other age groups. Identification of influenza virus types A and B using the QuickVue rapid diagnostic test was found to be equally sensitive for pH1N1 (50.4%), H3N2 (51.7%) and influenza B (53.9%) viruses, although the sensitivity was low among all subtypes. The pH1N1 virus rapidly became the dominant virus subtype in 2009 in Cambodia, but no symptoms consistently distinguished the pandemic strain from other influenza virus subtypes. The QuickVue test was as sensitive for detecting pH1N1 viral as well as other circulating seasonal influenza viruses. PMID- 23082558 TI - Detection of multidrug-resistant Mycobacterium tuberculosis directly from sputum samples of patients from Jakarta, Indonesia by radioisotope-based PCR-dot blot hybridization. AB - The problem of eradicating tuberculosis (TB) has become more complicated by the emergence of multidrug resistant TB (MDR-TB). Any rapid laboratory method that can be used to detect drug susceptibility of Mycobacterium tuberculosis (MTB) is urgently needed. In this study, we employed the radioisotope (32P)-based PCR-dot blot hybridization method on sputum samples from patients in Jakarta, Indonesia. Bacterial DNA was extracted using BOOM method. KatG and rpobeta were amplified by PCR and katG315 or rpobeta531 mutations were identified by dot blot hybridization. Of 100 samples, 11% and 22% showed presence of mutation at codons 315 (AGC --> ACC) of katG and 531 (TCG --> TTG) of rpobeta, respectively. Five percent of the samples showed both mutations. This method is rapid, sensitive, and reliable and can be used to screen large numbers of samples in epidemiological studies. PMID- 23082557 TI - Influence of ABCB-1 C3435T polymorphisms on plasma nevirapine and efavirenz levels and their effects on virologic and immunological outcomes in HIV/TB co infected Thai adults under anti-retroviral therapy. AB - ATP-binding cassette, sub-family B (encoded by ABCB-1 or MDR-1) has an important role in cellular export of antiretroviral agents. A previous study showed that ABCB-1 C3435T polymorphism affects plasma efavirenz and nelfinavir concentrations and rate of CD4+ T cell recovery after starting antiretroviral treatment (ART). The present study examined the influence of ABCB-1 polymorphisms on plasma nevirapine and efavirenz levels when co-administered with rifampicin in 124 HIV/TB patients who received nevirapine- (400 mg/day) (n = 59) and efavirenz- (600 mg/day) (n = 65) based ART. ABCB-1 C3435T polymorphisms were genotyped using real-time PCR. CD4 T cell counts and HIV-1 viral RNA were evaluated in response to ART. The frequencies of CC, CT and TT genotypes of ABCB-1 C3435T polymorphism were 34% (n = 42), 55% (n = 68) and 12% (n = 14), respectively. Contrary to the previous report, no association was found among these genotypes and plasma drug concentrations at weeks 6 and 12 of ART and after rifampicin discontinuation. We also observed no differences in CD4+ T cell recovery rate among different ABCB-1 C3435T genotypes. In nevirapine group, however, all the patients with CT genotype achieved HIV-1 RNA levels of < 50 copies/ml, while 67% of those with TT and 95% with CC genotypes achieved < 50 copies/ml (p = 0.040). These data suggested that ABCB-1 C3435T polymorphisms do not affect plasma nevirapine and efavirenz concentrations in HIV/TB co-infected Thai patients or their immunological outcome, but had an effect on virologic outcome in the nevirapine-treated group. PMID- 23082559 TI - Campylobacter in chicken carcasses and slaughterhouses in Malaysia. AB - This study was conducted to determine the Campylobacter contamination rate of chicken carcasses and the processing lines of modern processing plants in Malaysia. Three hundred sixty samples were collected from 24 flocks of broiler chickens at 12 modern poultry processing plants in 6 states of Malaysia. Fresh fecal droppings were collected from crates in the arrival area. Neck skin samples were taken from processed chicken carcasses at 3 different processing stages: before inside-outside washing, after inside-outside washing and post chilling. Swab samples from the scalding tank, chilling tank and conveyer belt before chilling were also collected to determine contamination with Campylobacter in the slaughter house environment prior to slaughter. Isolation for Campylobacter was performed following ISO 10272-1:2006(E). The overall of contamination rate with Campylobacter at the 12 plants was 61.0% (220/360). Eighty point six percent of the samples from before the inside-outside wishing step were contaminated with Campylobacter, as were 62.5% of the samples after the inside washing and 38.9% after the post-chilling step. This study shows extensive contamination of chicken carcasses and slaughtering houses in Malaysia with Campylobacter. PMID- 23082561 TI - Antimicrobial susceptibility pattern and distribution of exoU and exoS in clinical isolates of Pseudomonas aeruginosa at a Malaysian hospital. AB - This study was conducted to determine the antibiotic susceptibility pattern and distribution of exoU and exoS among 44 clinical isolates of P. aeruginosa collected from different patients over a 3-month period in 2010 at a major Malaysian hospital. Susceptibility data by disk diffusion method for cefepime (30 microg), ceftazidime (30 microg), gentamicin (10 microg), piperacillin-tazobactam (100/10 microg) and ciprofloxacin (5 microg) were available for 38 isolates. Resistance to ceftazidime and piperacillin-tazobactam was the most common (74%) with five isolates not susceptible to three or more different antibiotics. PCR detection of exoU and exoS of all 44 isolates showed the former gene to be present in 18 and exoS in 41. In analyzing the two genes together, 17 isolates were detected for exoU and exoS with only two being negative for both genes. Only one isolate was detected for exoU alone whereas 24 for exoS alone. Distribution of the genes in relation to antibiotic susceptibility was inapplicable due to the majority of the isolates having similar susceptibility patterns, but the tendency of exoU-carrying isolates to be present in male patients (83%) and respiratory sites (61%) was observed (p < 0.050). The finding warrants further investigation in a larger sample of isolates. PMID- 23082560 TI - Prevalence of cagA EPIYA motifs in Helicobacter pylori among dyspeptic patients in northeast Thailand. AB - The aims of this study were to determine the prevalence of cagA type in Helicobacter pylori isolated from dyspeptic patients in northeastern Thailand and to determine whether the pattern of cagA EPIYA motifs were associated with clinical outcomes. One hundred and forty-seven H. pylori-infected dyspeptic patients were enrolled, of whom 68 had non-ulcer dyspepsia (NUD), 57 peptic ulcer disease (PUD), 18 gastric cancer (GCA), and 4 other gastroduodenal diseases. PCR and DNA sequence analysis were used to determine the cagA genotype and the pattern of EPIYA motifs. cagA-positive H. pylori were identified in 138 (94%) of H. pylori-infected dyspeptic patients of whom 75 (54%) were of the Western-type, 44 (32%) the East Asian type and 19 (14%) of the other types. The Western type is significantly found in PUD patients (p = 0.0175). The majority of cagA EPIYA was EPIYA-ABC (43%) and EPIYA-ABD (28%). There is no significant correlation between the increase in number of EPIYA-C motifs and clinical outcomes. Thus, the most frequent cagA type found among northeastern Thai dyspeptic patients was the Western cagA type, which is significantly associated with PUD indicating a possible predictive parameter for clinical outcome. PMID- 23082562 TI - Tn5-OT182 should not be used to identify genes involved in biofilm formation in Burkholderia pseudomallei. AB - Burkholderia pseudomallei, a gram-negative bacterium, is the causative agent of melioidosis. One of the important virulence properties of this bacteria is its ability to form a biofilm. Genes involved in biofilm formation in B. pseudomallei have not been thoroughly studied. In this study, Tn5-OT182 mutagenesis was used to isolate of B. pseudomallei strain A2 mutants unable to produce biofilm. Ten biofilm-defective transposon mutants were isolated and analyzed. Flanking DNA from each transposon mutant were self-cloned and sequenced, then the sequences were analyzed with the BLAST program. To confirm these genes are involved in biofilm formation, we constructed three gene deletion mutants marked with a tetracycline resistance gene. The constructed tet(r)-marked deletion mutants were checked for correct structure and size by polymerase chain reaction. When subjected to biofilm assay, all tested tet(r)-marked deletion mutants were still able to produce biofilm, indicating the three genes are not involved in biofilm formation. These results suggest integration of Tn5-OT182 in genes not involved in biofilm production can render B. pseudomallei unable to produce biofilm by an unknown mechanism. This information demonstrates Tn5-OT182 is not a reliable tool for identifying genes involved in biofilm formation unless a confirmatory experiment is carried out in parallel. PMID- 23082563 TI - Clostridium perfringens and sulphite reducing clostridia densities in selected tropical Malaysian rivers. AB - Clostridium perfringens (CP) and sulphite reducing clostridia (SRC) densities in the Selangor River, Bernam River and Tengi River Canal were examined between April 2007 and January 2008. Water samples were taken from two or three locations along each river, using either depth-integration or grab sampling methods. The downstream sampling site of the Selangor River, Rantau Panjang, reported the highest arithmetic mean of CP and SRC densities (583.45 and 8,120.08 cfu/100 ml, respectively). Both CP and SRC densities in the Selangor River increased further downstream, but the reverse was true in the Bernam River. The SRC densities in these rivers were significantly different from each other (p < 0.05) when comparing upstream and downstream results, but CP densities were not significantly different (p > 0.05). SRC densities were significantly correlated (p < 0.05) in different locations along the Selangor River and the Bernam River. The CP densities did not show such pattern (p > 0.05). River discharge had no significant correlation with SRC or CP densities by study site (p > 0.05). Since the Selangor River has a denser human population along its banks, this study confirms CP as a suitable indicator of human fecal contamination. However, tracing CP distribution along the river is more difficult than SRC. To our knowledge, this is the first study of CP and SRC densities from Malaysian rivers. CP densities found in this study were within the range of general water bodies reported from other countries. PMID- 23082564 TI - Invasive pneumococcal disease among hospitalized children aged 28 days to 60 months in Jarkarta. AB - Streptococcus pneumoniae is a leading cause of morbidity and mortality among children worldwide. Prevention of invasive pneumococcal disease (IPD) with a pneumococcal conjugate vaccine (PCV) is an effective approach to reduce the burden of pneumococcal disease. Nationwide epidemiological data is required prior to considering universal pneumococcal immunization for Indonesia. This preliminary study aimed to quantify the burden of IPD among hospitalized children at Cipto Mangunkusumo Hospital and Fatmawati Hospital, Jakarta. We studied 205 subjects aged 28 days to 60 months who were admitted with the diagnosis of pneumonia, meningitis, sepsis, and suspected occult bacteremia. Streptococcus pneumoniae was isolated from 1 of 205 blood specimens, giving an IPD proportion of 0.5%. The IPD case in this study was a 3-month-old baby with meningitis and bilateral lobar pneumonia. The Quellung test demonstrated serotype 7F. The isolate was susceptible to amoxicillin and Cotrimoxazole. Incidence of IPD could not be calculated due to low number of cases; this underscores the importance of surveillance of pneumococcal disease in Indonesia. PMID- 23082565 TI - Early onset neonatal bacterial meningitis caused by Streptococcus gallolyticus subsp. paste urianus. AB - We report a case of neonatal meningitis due to Streptococcus gallolyticus subsp. pasteurianus born to a mother with an asymptomatic urinary tract infection due to Streptococcus group D and Escherichia coli. In the past, this organism may have been reported as Streptococcus bovis or S. bovis biotype II/2. Accurate identification of this organism is necessary to determine the etiology of infection and give correct treatment of neonatal meningitis, caused by this organism. PMID- 23082566 TI - Obstructive sleep apnea among children with severe beta-thalassemia. AB - The aim of this study was to determine the prevalence and associated factors for obstructive sleep apnea (OSA) among children with severe beta-thalassemia. Children with severe beta-thalassemia without a history of bone marrow transplantation were studied. Polysomnography (PSG) was performed in those who habitually snored to identify OSA. One hundred twenty children (aged 9.3 +/- 3.7 years; 42% male) were studied. Nineteen patients (15.8%) habitually snored. Sixteen had PSG performed. OSA was demonstrated in 10 patients. Six had moderate to-severe OSA. The estimated prevalence of OSA was 8.3%. All OSA patients had adenoid hypertrophy and 80% had associated tonsil enlargement. The OSA group had a higher serum ferritin level compared to the non-OSA group (3,785 +/- 1,780 vs 1,885 +/- 677 ng/ml; p = 0.03). Six of 10 patients who had OSA underwent adenotonsillectomy. Reactive lymphoid hyperplasia was demonstrated in all cases. The estimated prevalence of OSA in children with severe beta-thalassemia was high (8.3%) and some had severe OSA. Adenotonsillar lymphoid hyperplasia was common among those who had OSA. A high serum ferritin level was associated with the occurrence of OSA. A history of snoring and OSA symptoms should be periodically assessed in children with severe beta-thalassemia. PMID- 23082567 TI - Predictors of family management behavior for children with thalassemia. AB - Children with thalassemia can thrive with quality care by their families. The purpose of this study was to examine predictors of family care behavior by family caregivers of children with thalassemia. Eighty-eight family caregivers for children with thalassemia aged 1-16 years were recruited by purposive sampling from in-patient and out-patient clinics in an eastern regional hospital in Thailand. Research instruments were 5 self-administered questionnaires: 1) demographics of family caregivers, 2) perceived family management, 3) medical adherence, 4) health literacy, and 5) family management behavior. Data were analyzed by percentages, means, standard deviations, Pearson's product moment correlation and multiple regression. The strongest predictor for family management behavior was perceived family management (B = 0.550, p < 0.001), it accounted for 26.3% of the variance. Health literacy (B = 0.337, p = 0.024) accounted for 4.5% of the variance. When these two dependent measures were combined, they accounted for 30.8% of the variance (R2 = 0.308, F = 18.933, p < 0.001). Within the three subscales of family management behavior (medical, role, and psychosocial management), medical adherence, health literacy and perceived family management, together accounted for 22.6% of the variance for medical management. Perceived family management and health literacy together accounted for 30.3% of the variance in role management. Perceived family management accounted for 20.9% of the variance in psychosocial management. These findings suggest a tailored intervention program should emphasize promoting family management and increasing health literacy to improve the quality of family management behavior for children with thalassemia. PMID- 23082568 TI - Glycemic control, quality of life and self-care behavior among adolescents with type 1 diabetes who attended a diabetes camp. AB - A prospective study was conducted at the tenth Siriraj diabetes camp with the objectives of evaluating the effectiveness of diabetes camp on 1) glycemic control, 2) knowledge, 3) quality of life, and 4) self-care behavior of adolescents with type 1 diabetes (T1D) who participated in the diabetes camp. During the 5-day camp, twenty-seven participants (mean age 15.6 +/- 2.1 years, mean duration 6.3 +/- 3.0 years) were taught diabetes self-management education (DSME) and engaged in psychosocial support sessions. Post-camp activities were held every 3 months and participants were followed for 12 months post-camp. Glycemic control was assessed prior to the camp, then every 3 months. Knowledge level was assessed prior to the camp, at the end of the camp, and every 3 months. Diabetes self-care behavior and quality of life were evaluated prior to the camp, at 3 months and 12 months after the camp. After attending the camp, participants had improvement in knowledge but there were no changes in HbA1c levels or quality of life scores. Quality of life was not consistently associated with HbA1c. In general, participants did not perceive their quality of life was poor or feel having diabetes affected their social life. The issue participants worried about most was whether they would develop complications from diabetes. There were several weak points found among participant self-care behavior, particularly in diet-related matters. Despite no improvement in glycemic control, participants gained knowledge from attending the camp. Diet related self-care behavior is difficult for teenagers with T1D to be compliant. PMID- 23082569 TI - Identification of tropomyosin as major allergen of white squid (Loligo edulis) by two-dimensional immunoblotting and mass spectrometry. AB - IgE-mediated allergic reaction to squid is one of the most frequent molluscan shellfish allergies. Previously, we have detected a 36 kDa protein as the major allergen of Loligo edulis (white squid) by immunoblotting using sera from patients with squid allergy. The aim of this present study was to further identify this major allergen using a proteomics approach. The major allergen was identified by a combination of two-dimensional electrophoresis (2-DE), immunoblotting, mass spectrometry and bioinformatics tools. The 2-DE gel fractionated the cooked white squid proteins to more than 50 different protein spots between 10 to 38 kDa and isoelectric point (pI) from 3.0 to 10.0. A highly reactive protein spot of a molecular mass of 36 kDa and pI of 4.55 was observed in all of the patients' serum samples tested. Mass spectrometry analysis led to identification of this allergen as tropomyosin. This finding can contribute to advancement in component-based diagnosis, management of squid allergic patients, to the development of immunotherapy and to the standardization of allergenic test products as tools in molecular allergology. PMID- 23082570 TI - Nutrition education and knowledge, attitude and hemoglobin status of Malaysian adolescents. AB - A higher occurrence of iron deficiency anemia is present in rural Malaysia than urban Malaysia due to a lower socio-economic status of rural residents. This study was conducted in Tanah Merah, a rural district of Kelantan, Malaysia. Our objective was to investigate the impact of nutrition education alone, daily iron, folate and vitamin C supplementation or both on knowledge, attitudes and hemoglobin status of adolescent students. Two hundred eighty fourth year secondary students were each assigned by school to 1 of 4 different treatment groups. Each intervention was carried out for 3 months followed by 3 months without treatment. A validated self-reported knowledge and attitude questionnaire was administered; hemoglobin levels were measured before and after intervention. At baseline, no significant difference in hemoglobin was noted among the 4 groups (p = 0.06). The changes in hemoglobin levels at 3 months were 11, 4.6, 3.9 and 3.7% for the supplementation, nutrition education, combination and control groups, respectively. The changes at 6 months were 1.0, 6.8, 3.7 and -14.8%, respectively. Significant improvements in knowledge and attitude were evidenced in both the nutritional education and combination groups. The supplementation and control groups had no improvement in knowledge or attitudes. This study suggests nutritional education increases knowledge, attitudes and hemoglobin levels among Malaysian secondary school adolescents. PMID- 23082571 TI - Exposure to volatile organic compounds and health risks among residents in an area affected by a petrochemical complex in Rayong, Thailand. AB - In Thailand, there is a growing concern regarding the possible effects of air pollution on the health of residents living near a petrochemical complex in Map Ta Phut Industrial Estate (MTPIE), Rayong Province, Thailand. We studied exposure to selected volatile organic compounds (VOCs) in Map Ta Phut and the association between residing near the petrochemical complex and respiratory ailments. We carried out a population-based cross-sectional study, utilizing health data regarding respiratory problems among adults collected as part of a Health Effects of Air Pollution study of residents living in Map Ta Phut Municipality, Thailand, using a standardized questionnaire. The distance from the subject's residence to the center of the MTPIE was mapped using a geographical information system (GIS). A total of 15,441 adults aged > or = 13 years who lived in Map Ta Phut Municipality for at least 1 year were included in the study. Multiple logistic regression models were used to examine the relationship between the distance between the subject's residence and the MTPIE and the presence of the respiratory problems during the previous 12 months. A 5 km distance was chosen as the maximum study radius. Volatile organic compounds were observed higher concentrations at sites downwind from the MTPIE, and closer to the MTPIE. Study subjects who lived closer to the MTPIE reported an odor more frequently than subjects who lived farther from the MTPIE. Living closer to the MTPIE was associated with more acute respiratory problems, but not more chronic respiratory problems than living farther from the MTPIE. Adults aged > or = 40 years were more likely to have respiratory symptoms and eye irritation than those aged < 40 years. Females were more likely to have dyspnea, wheezing and upper respiratory symptoms than males. Living near the MTPIE for more than 5 years was associated with an increased risk of wheezing and upper respiratory symptoms. PMID- 23082572 TI - Exhaled carbon monoxide levels among Malaysian male smokers with nicotine dependence. AB - We studied the use of exhaled carbon monoxide (CO) to identify nicotine dependence among adult Malaysian male smokers. We conducted a cross-sectional study among 107 male smoking staff at a university hospital. We measured their exhaled CO using a piCO+ Smokerlyzer and diagnosed nicotine dependence using a Mini-International Neuropsychiatric Interview (MINI). The optimal cut-off value for exhaled CO was determined. The correlation between exhaled CO level and the Fagerstrom Test for Nicotine Dependence (FTND) was also assessed. The mean exhaled CO level among subjects with nicotine dependence (15.78 ppm) was significantly higher than subjects without nicotine dependence (9.62 ppm). The cut-off value used to identify smokers with nicotine dependence was set at 10 ppm (specificity = 0.721, sensitivity = 0.731, positive predictive value = 0.817 and negative predictive value = 0.617). Psychometric properties were stable with various durations of smoking. Exhaled CO correlated positively with FTND scores (Pearson's rho = 0.398, p = 0.01). Our findings show exhaled CO can be used to identify nicotine dependence among adult Malaysian male smokers. PMID- 23082573 TI - Smoking behavior among 14-17 year old students: a comparison between Pakistan and the UK. AB - Smoking is a major public problem concern the world over. It is one of the major preventable causes of premature death and disease in the world. Fourteen to seventeen year olds are among a vulnerable group of individuals in society and susceptible to cigarette smoking. Older students act as role models to younger pupils and could influence smoking behavior. In a cross-sectional study we compared the differences in smoking between high school students in Pakistan and the United Kingdom. A self-administered anonymous questionnaire, adapted from a WHO questionnaire about tobacco smoking, was distributed to the students. In the UK, 235 participants were recruited; 16% (n = 38) were regular smokers. In Pakistan, 350 participants were recruited; 17% (n = 58) were regular smokers. In both countries males were significantly more likely to smoke. Reasons for smoking varied between the UK and Pakistan. In the UK, the majority smoked for recreational or social purposes and in Pakistan peer pressure played the major role. Beliefs regarding smoking were similar between the two countries. The lifetime prevalence of smoking was higher in the UK, but more students in Pakistan smoked daily. There were important differences in the smoking patterns between the two countries, which have potential public health implications. PMID- 23082574 TI - Health impact assessment: a case study on renovation of a slaughterhouse. AB - The purpose of this study was to conduct a health impact assessment (HIA) in a community where an old slaughterhouse was to be renovated. The authors conducted a cross-sectional study in March, 2011. Questionnaires were used to collect data and focus group discussions were conducted to solicit the community concerns and recommendations regarding the project. The results reveal positive impacts in 4 aspects of health: physical, mental, social, and spiritual. The current substandard slaughterhouse was perceived negatively by the surrounding community. They were happy the slaughterhouse would be renovated, and some preferred it moved elsewhere. This HIA had 2 positive results: first, we tested our HIA tool in a real situation and found it practical on a small scale; second, the municipality obtained the community's opinions and concerns and the community knew their opinions reached the municipality, so they were more positive about the municipality. PMID- 23082575 TI - Testing a health impact assessment tool by assessing community opinion about a public park. AB - The purpose of this study was to assess a health impact assessment (HIA) tool to determine the perceived health impact by the public of a public park. The authors conducted a cross-sectional study from March to April, 2011, using this HIA questionnaire to collect data and through focus group discussions. We also assessed community concerns about the park and obtained recommendations of how to mitigate possible negative aspects of the parks. Four aspects were listed as possible benefits of the park: physical, mental, social, and spiritual health. The negative aspects mentioned by participants were that a park could be a potential place of assembly for teenagers, a place for theft and crime and accidents among children. The HIA tool used for this research seemed appropriate. The next challenge is to use this tool to assess a more controversial project. PMID- 23082576 TI - Effect of an essential oil-containing dentifrice on established plaque and gingivitis. AB - A six-months, double-blind, parallel, clinical study was conducted to evaluate the efficacy of an essential oil containing dentifrice on established plaque and gingivitis compared with a placebo dentifrice. A total of 104 subjects were stratified into two groups according to baseline Quigley-Hein Plaque Index scores and Loe-Silness Gingival Index scores. Each group was randomly assigned to use either an essential oil dentifrice or placebo dentifrice. The subjects were instructed to brush their teeth in the customary manner for 1 minute, twice daily, with the provided dentifrice using a soft-bristle toothbrush. After six months, the essential oil containing dentifrice gave a 25.4% reduction (p < 0.001) in supragingival plaque accumulation and a 19.5% reduction (p < 0.001) in gingivitis compared to the placebo dentifrice. PMID- 23082577 TI - Factors associated with parent capability on child's oral health care. AB - We investigated parental attitudes and behavior affecting their ability to care for their children's oral health among Thais who reside in or near Bangkok and to develop a Thai version of a factor analysis questionnaire in order to assess the risk of developing early childhood caries. There were 241 participants, 48.1% were aged 20-to-30 years, 86.3% were married and 48% had two children. Thirty seven percent of subjects had a monthly income between 10,001 and 30,000 Baht. There were significant associations (p < 0.05) between parental education levels, monthly incomes and attitudes and behaviors. There were significant associations (p < 0.05) between parental education levels, careers and causes of stress that affected care of their child's oral health. Factors that affected their ability to care for their child's oral health were from most to least was lack of time, lack of knowledge about brushing, stress from work, not raising their child by themselves, economics problems and being a single parent. Parental attitudes and behavior in regard to their child's oral health were associated with their education levels and monthly income. Factors that affected their ability to care for their child's oral health were their education levels and their careers. These factors should be considered when giving oral hygiene education to improve their parenting capabilities. PMID- 23082578 TI - Characteristics and malaria prevalence of migrant populations in malaria-endemic areas along the Thai-Cambodian border. AB - The rise of artemisinin resistant Plasmodium falciparum along the Thai-Cambodian border is an urgent public health threat. We conducted an employer-based survey of migrant workers in two provinces in Thailand along the Thai-Cambodian border to explore socio-economic conditions, bednet ownership, and parasite prevalence among migrant workers. Five thousand three hundred seventy-one migrant workers were enrolled in this study; 56.9% were male. Cambodians comprised 69.0%, migrants from Myanmar comprised 20.7% and Mon and Laotian comprised 10.3%. Short term (< 6 months) Cambodian migrants, primarily located in Chanthaburi Province, typically work in orchards or on cassava farms. The majority did not speak Thai and bednet ownership was low. The only cases of malaria, all P. vivax, were found in Chanthaburi. Migrants in Trat Province were primarily long-term residents (> 6 months) from Cambodia and Myanmar and were engaged in rubber tapping, fisheries and domestic work. Bednet ownership and oral Thai fluency were higher, though Thai literacy remained low. Migrants from Myanmar had higher mother tongue literacy than migrants from Cambodia. The low oral Thai fluency and literacy rates suggest a Behavior Change Communication (BCC) package for Cambodian migrants should be developed in the Cambodian language. The low parasite prevalence and absence of P. falciparum in this study are encouraging signs in the fight against artemisinin resistance in eastern Thailand. PMID- 23082579 TI - In vitro and in vivo anti-plasmodial activity of essential oils, including hinokitiol. AB - Abstract. The anti-plasmodial activity of 47 essential oils and 10 of their constituents were screened for in vitro activity against Plasmodium falciparum. Five of these essential oils (sandalwood, caraway, monarda, nutmeg, and Thujopsis dolabrata var. hondai) and 2 constituents (thymoquinone and hinokitiol) were found to be active against P. falciparum in vitro, with 50% inhibitory concentration (IC50) values equal to or less than 1.0 microg/ml. Furthermore, in vivo analysis using a rodent model confirmed the anti-plasmodial potential of subcutaneously administered sandalwood oil, and percutaneously administered hinokitiol and caraway oil against rodent P. berghei. Notably, these oils showed no efficacy when administered orally, intraperitoneally or intravenously. Caraway oil and hinokitiol dissolved in carrier oil, applied to the skin of hairless mice caused high levels in the blood, with concentrations exceeding their IC50 values. PMID- 23082580 TI - Genetic diversity of plasmodium vivax merozoite surface protein-3alpha (Pvmsp 3alpha) gene in Jhapa District of Nepal. AB - In Nepal, Plasmodium vivax accounts for approximately 80-90% of the malaria cases, but limited studies have been conducted on the genetic diversity of this parasite population. This study was carried out to determine the genetic diversity of P. vivax population sampled from subjects living in an endemic area of Jhapa District by analyzing the polymorphic merozoite surface protein-3alpha (Pvmsp-3alpha) gene by using PCR-restriction fragment length polymorphism. Three distinct genotypes were obtained from 96 samples; type A: 40 (71%), type B: 7 (13%), and type C: 9 (16%) which could be categorized into 13 allelic patterns: A1-A9, B1, B2, C1 and C2. These results indicated a high genetic diversity within the studied P. vivax population. As the transmission rate of malaria is low in Nepal, the diversity is most likely due to migration of people between the malaria endemic regions, either within the country or between Nepal and India. Similar prevalence of the three genotypes of Pvmsp-3alpha between the two countries likely supports the latter explanation. PMID- 23082581 TI - Stereo and scanning electron microscopic studies of the third stage larvae of Anisakis simplex. AB - This study was to demonstrate the surface anatomy of the third stage larvae of Anisakis simplex in marine fish using stereo and scanning electron microscopes (SEM). The round worm is slender, elongated and of cylindrically shaped. The head of this worm is a globular structure. The mouth is triangularly shaped and surrounded by three lips. A boring tooth projects dorsally at the anterior end. There are four pairs of tactoreceptors, the labial papillae, enclosing the lips. The tail end is blunt and acquires a distinct slender process, the mucron. Stereomicroscopy revealed the esophagus is elongated, bulbous and club shaped, subdivided into an anterior muscular part and a posterior glandular part or ventriculus. The intestine is a long straight tube where the digestion and absorption occur. Waste pass through the intestine and is stored in the rectum until excreted via the anus. A SEM is a powerful tool in distinguishing worm species, as was seen when examining that the mouth of Anisakis simplex, which is triangular shaped and enclosed by three lips with one boring tooth; other species are different. The mucron projection at the distal end is another distinctive structure revealed by SEM. PMID- 23082582 TI - Spray application of Bacillus thuringiensis israelensis (Bti strain AM65-52) against Aedes aegypti (L.) and Ae. albopictus Skuse populations and impact on dengue transmission in a dengue endemic residential site in Malaysia. AB - A one year study was conducted to evaluate the impact of spray application of Bacillus thuringiensis israelensis (Bti), strain AM65-52 on vector populations and dengue transmission in a dengue endemic state in Malaysia. Residential sites with similar populations of Aedes aegypti (L.) and Aedes albopictus Skuse were studied. One site was treated with spray application of Bti into all outdoor target vector habitats, which consisted of natural and artificial containers. The other site was not treated. The impact of spray application was measured with an indoor and outdoor ovitrap index (OI) and epidemiologic data. Significant reductions in both Ae. aegypti and Ae. albopictus, OI were observed both indoors and outdoors, in treated sites compared to untreated sites (p < 0.05). OI reduction was achieved over time in the treated area. The OI was suppressed to below 10%. This was maintained for 4 weeks into the post-treatment phase. The outdoor OI at the untreated site remained at more than 40% for 38 weeks during the evaluation period. One dengue case occurred at the Bti treatment site at the beginning of the treatment phase, but no further cases were detected during the remainder of the treatment phase. However, there was an ongoing dengue outbreak in the untreated area with 15 serologically confirmed cases during weeks 37-54. Intensive fogging operations with pyrethroids at the untreated (Bti) site had a positive impact on Ae. albopictus, but not on Ae. aegypti. PMID- 23082584 TI - Detection and genetic characterization of norovirus in environmental water samples in Thailand. AB - The aim of this study was to detect and characterize noroviruses (NoVs) in environmental water samples. One hundred and fourteen water samples were collected from a river and irrigation canals in central Thailand during 2006 2007. NoVs were detected by RT-nested PCR in 13% of the samples. The river samples (22%) contained NoVs at a higher frequency than the irrigation canal samples (4%). Among the 15 NoV-positive samples, 9 harbored genogroup (G) I, 2 samples with GII, and 4 samples with mixed GI and GII. DNA sequencing of PCR amplicons and phylogenetic analysis of partial capsid gene revealed that 5 samples were of genotype GI-2, 1 sample was GI-6, and 1 sample was a mix of GI-2 and GII-unclassified genotypes. NoVs in water samples quantified using quantitative RT-PCR were in the range of 4.91 x 10(2) -1.26 x 10(3) copies/ml for NoV GI and 3.51 x 10(3) copies/ml for NoV GII. This is the first study demonstrating the presence of NoV variants in water samples collected from a river and the adjacent canals of Thailand. PMID- 23082583 TI - Dengue infection in hematologic-oncologic pediatric patients: aggravation of anemia and bleeding risk. AB - We studied anemia and bleeding risk among hematologic-oncologic pediatric patients with dengue infection. A total of 907 patients suspected of having dengue infection were included in the study. They were categorized into 2 groups: 1) patients with confirmed dengue infection (n=843) and 2) patients with other febrile illnesses (n = 64). Both groups included patients with underlying hematologic-oncologic diseases (55 vs 14) and without underlying disease (788 vs 50). Patients with underlying diseases were divided into 3 subgroups by risk: Subgroup A, anemia risk, including patients with thalassemia and hemoglobinopathies (n = 39) and G6PD deficiency (n=6); Subgroup B, patients with bleeding risk, including hemophilia (n = 7), von Willebrand disease (n = 1) and thrombocytopenia (n = 4); and Subgroup C, patients with anemia and bleeding risk, including oncologic diseases (n =12). Acute hemolysis in Subgroup A started during the febrile stage and required packed red cell transfusions. Bleeding risk in Subgroup B started during the early febrile stage with vasculopathy and continued to the late febrile stage with thrombocytopenia. These patients required factor concentrate and platelet concentrate transfusions. Anemia and bleeding risk in Subgroup C was greater among patients undergoing chemotherapy than those who had discontinued treatment. The greater the length of time since discontinuation of treatment, the lower risk. The case-fatality rate among dengue infected patients with underlying disease (2/55 = 3.64%) was significantly higher than those without underlying disease 0.63% (5/788). PMID- 23082585 TI - Use of dried blood spots for HIV-1 genotyping in Southeast Asia: Thailand experience. AB - The multi-region hybridization assay (MHAbce) for genotyping HIV-1 subtypes B, C and circulating recombinant form (CRF01_AE) was evaluated on paired plasma and dried blood spots (DBS) collected from 68 HIV-1 infected individuals in Thailand. CRF01_AE was the predominant subtype identified using plasma samples (51/62) and DBS (24/27). There was no discordance in subtype designations between plasma and DBS. PMID- 23082586 TI - Knowledge, attitudes, and acceptability of a human papilloma virus vaccine among students, parents and teachers in Thailand. AB - The purpose of this study was to assess the knowledge and attitudes about human papilloma virus (HPV) and cervical cancer, and the acceptability of HPV vaccine among students, parents and teachers in secondary schools in Bangkok, Thailand. We conducted a school-based cross-sectional study at four public secondary schools in Bangkok. A total of 644 students aged 12-15 years, 664 parents and 304 teachers were recruited into the study. Data were collected by self-administered questionnaires. The percentages of students, parents and teachers who were willing to be vaccinated were 26, 49 and 43%, respectively. Forty-one percent of parents wanted their children to be vaccinated. Students, parents and teachers had a moderate knowledge of HPV, cervical cancer and the HPV vaccine with mean scores of 6.91 (SD = 1.75), 6.82 (SD = 1.88), and 6.70 (SD = 1.89), respectively. The attitudes of students, parents, and teachers were fair with scores of 3.46 (SD = 0.41), 3.52 (SD = 0.43), and 3.46 (SD = 0.47) out of 5, respectively. Twenty-nine percent of students and 36% of parents were willing to pay USD 14.3 28.5 per dose for the quadrivalent vaccine; 33% of teachers were willing to pay < USD 14.3 per dose for the quadrivalent vaccine. This study is the first study to report the knowledge, and attitudes and acceptability of HPV vaccination in Thailand. The findings suggest the willingness to pay was relatively low and related to the price, while knowledge and attitudes regarding the importance of the HPV vaccine were fair particularly among parents and teachers. Greater effort may be needed to educate people regarding the cost and benefits of HPV vaccination before it would be more acceptable to parents, teachers and students in Thailand. PMID- 23082587 TI - Prevalence of drug resistant tuberculosis among patients at high-risk for Hiv attending outpatient clinics in Delhi, India. AB - We sought to determine tuberculosis (TB) prevalence including multidrug resistant (MDR)-TB among a cohort of high risk patients at two directly observed treatment short course (DOTS) clinics in Delhi, India. We also aimed to compare the sensitivity of acid-fast bacilli (AFB) smear tests for patients with HIV using sputum cultures as the gold standard. A cross-section study was conducted among adult patients (> or = 18 years old) with prolonged cough (greater than two weeks), night sweats, fever, and/or weight loss suspected of pulmonary TB between February and March 2006. Sputum samples were obtained and processed for 165 patients; 53 (32.1%) were culture positive for TB. Patients with TB were predominantly male (92.1%), young (median age of 32 years), and the HIV seroprevalence was high (41.5%). In the multivariable analysis adjusted for age, HIV infection was significantly associated (POR = 2.0, p < 0.05) with the presence of TB disease. Among Mycobacterium tuberculosis isolates recovered from 53 cases, 25 (47.2%) were resistant to > or = 1 first line anti-TB drugs and 7 (13.2%) were MDR-TB. The sensitivity of AFB smears among HIV negative and positive participants was 35.5% and 18.0%, respectively. Our findings demonstrated that the sensitivity of AFB smears to detect TB among HIV positive patients was low. Additionally, we found that even in regions where population drug resistance estimates are low, sentinel surveillance of MDR-TB in high-risk populations is useful to prioritize target groups in need of additional prevention, monitoring and health outreach. PMID- 23082588 TI - Male genitourinary tuberculosis--13 years experience at a tertiary care center in India. AB - We conducted a retrospective study of genitourinary tuberculosis (TB) among males attending a hospital in the northern Himalayan region of India. Records from 1 January 1997 to 31 December 2009 were reviewed for clinical history, relevant radiological findings laboratory data, histopathology and treatment. Of the 1,113 male urogenital non-neoplastic specimens received at the histopathology laboratory of the hospital, tuberculosis was diagnosed in 25 cases (2.2%). Urinary bladder and prostate were the most common organs involved. Thirty-six percent of cases had a previous history of TB; 12% of cases presented with no symptoms. Ziehl-Neelsen staining was positive in 72% of cases. Cultures were positive for TB in 42.8% of cases and polymerase chain reaction was positive in two cases in which it was performed. Antituberculosis treatment was required for up to 12 months in some cases and surgery was required in 32% of cases. Genitourinary TB in this study had varying presentations. Cases having strong clinical and radiological findings and suggestive histopathology for tuberculosis, even without demonstration of mycobacteria may be considered for TB treatment, particularly in endemic areas. Patients living in more remote areas may have more specific and severe symptoms due to late presentation. Histopathology plays a crucial role in diagnosis due to lack of sophisticated techniques. The emphasis should be on early detection followed by prompt treatment to avoid further complications. PMID- 23082589 TI - Mycobacterium tuberculosis uvrC essentiality in response to UV-induced cell damage. AB - Control of tuberculosis depends both on an effective, accurate, and rapid diagnosis and an effective treatment and management. Antituberculous drugs have been used for more than 50 years and are likely ineffective against multidrug resistant strains, leading to an urgent need for new drugs. Comparative genome analysis has indicated that Mycobacterium tuberculosis uvrC, a component of nucleotide excision repair (NER) system, is an essential gene without any human homolog. This raises the possibility to use this gene as a new drug target. This study investigated the essential role of uvrC on growth of M. tuberculosis in the presence of DNA damaging agents, UV light and hydrogen peroxide (generator of reactive oxygen species). Results revealed that the M. tuberculosis uvrC mutant was more sensitive to UV than the control strain (p < 0.01), but was not more sensitive to hydrogen peroxide. These results showed that uvrC is essential for M. tuberculosis DNA repair system, particularly in response to DNA damage caused by UV irradiation. PMID- 23082590 TI - Class 1 integrons in Pseudomonas aeruginosa and Acinetobacter baumannii isolated from clinical isolates. AB - Resistance to various antimicrobial agents is an increasing problem in Pseudomonas aeruginosa and Acinetobacter baumannii infections. In this study, the roles of integrons were examined in 101 P. aeruginosa isolates and 176 A. baumannii isolates from patients. The frequencies and characteristics of class 1, 2 and 3 integrons were investigated and the horizontal transfer of integrons was assessed. Among these isolates, class 1 integrons with a resistance gene cassette were detected in 69.3% of P. aeruginosa and 31.8% of A. baumannii isolates, but class 2 and 3 integrons were not found. Five novel gene cassette arrays were identified in P. aeruginosa: aacA7-cmlA, aadB-blaOXA,-o-aadA1, aadB-arr-2-cmlA blaOXA,-o-aadA1, aadB-cmlA-aadA1 and aadB-cmlA-blaOXA-10-aadA15. The integrons found in A. baumannii isolates in this study were previously reported. Horizontal transfer of some class 1 integrons was detected in both P. aeruginosa (2/70) and A. baumannii (5/57). These data confirm the high prevalence of class 1 integrons with a variety of gene cassette combinations among multidrug-resistant P. aeruginosa and A. baumannii clinical isolates. PMID- 23082591 TI - Antimicrobial resistance among pathogenic bacteria in Southeast Asia. AB - Antimicrobial drug resistance is a problem in both developing and developed countries, in hospitals as well as in the community. Much data exists about antimicrobial resistance in Southeast Asia, but this information is fragmented, being published in different papers from different countries over several decades. We reviewed all available information about antimicrobial resistance in Southeast Asia using the PubMed database, concentrating on bacteria that commonly cause infection. From January 1, 1995 to January 1, 2007, 97 reports were published with accurate data regarding resistance patterns among the major pathogens. Thailand was the country where most of the published data were found. No reports were published for East Timor. From the available data, the following trends were observed: 1) there was a high prevalence of resistance to penicillin among Streptococcus pneumoniae and Neisseria gonorrhoeae; 2) pathogens causing diarrheal diseases are now often resistant to inexpensive, older antibiotics; 3) among Enterobacteriaceae and nonfermenting gram-negative bacteria, resistance to virtually all antibiotic classes has been reported, but it is unclear whether multidrug resistant gram-negative bacteria have emerged as a major problem; 4) the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) is not clear; in some countries, such as Singapore, MRSA is endemic in the health care system. This review shows that antimicrobial resistance to pathogenic bacteria has been and still is on the rise in Southeast Asia. However, there is great variation in resistance by hospital, patient type and country. PMID- 23082592 TI - Abdominal ultrasonographic findings in typhoid fever: a comparison between typhoid patients and those with non-typhoidal Salmonella and Campylobacter jejuni enterocolitis. AB - Typhoid fever is a major health problem in many developing countries and its clinical features are similar to other types of bacterial enterocolitis. Definitive diagnosis by blood culture requires several days and is often unfeasible to perform in developing countries. More efficient and rapid diagnostic methods for typhoid are needed. We compared the pathological changes in the bowel and adjacent tissues of patients having typhoid fever with those having bacterial enterocolitis using ultrasonography. A characteristic of patients with non-typhoidal Salmonella and Campylobacter jejuni enterocolitis was mural thickening of the terminal ileum; only mild mural swelling or no swelling was observed in patients with typhoid fever. Mesenteric lymph nodes in patients with typhoid fever were significantly more enlarged compared to patients with other types of bacterial enterocolitis. Our findings suggest typhoid fever is not fundamentally an enteric disease but rather resembles mesenteric lymphadenopathy and ultrasound is a promising modality for diagnosing typhoid fever in developing countries. PMID- 23082593 TI - Prevalence of genomic island PAPI-1 in clinical isolates of Pseudomonas aeruginosa in Iran. AB - Pseudomonas aeruginosa, a gram-negative rod-shaped bacterium, is an opportunistic pathogen, which causes various serious diseases in humans and animals. The aims of this study were to evaluate of the presence of genomic island PAPI-1 in Pseudomonas aeruginosa isolated from Reference Laboratory of Ilam, Milad Hospital and Emam Khomeini Hospital, Iran and to study the frequency of extended spectrum beta-lactamases (ESBLs) among isolates. Forty-eight clinical isolates of P. aeruginosa were obtained during April to September 2010, and were evaluated for ESBLs by screening and confirmatory disk diffusion methods and PAPI-1 by PCR. Fifteen of 48 P. aeruginosa isolates were positive for ESBLs and 17 isolates positive for PAPI-1. This was first study of the prevalence of PAPI-1 in clinical isolates of P. aeruginosa in Iran, showing that most of PAPI-1 positive strains had high levels of antibiotic resistance and produced ESBLs. PMID- 23082594 TI - Histoplasmosis and penicilliosis among HIV-infected Thai patients: a retrospective review. AB - Histoplasmosis and penicilliosis are fungal infections with similar clinical presentation and laboratory findings that were reported mainly in the era prior to highly active antiretroviral therapy. We conducted a retrospective review at two hospitals in Central Thailand of the medical records of HIV-positive patients with microbiologic evidence of histoplasmosis or penicilliosis between January 2003 to September 2007 when antiretrovirals became widely available in Thailand. Fifty patients met inclusion criteria; 36 had histoplasmosis, and 14 had penicilliosis. Symptoms and laboratory findings on presentation were similar between the two infections except for a greater incidence of tachypnea and neutropenia among patients with histoplasmosis (both p < 0.05). For histoplasmosis, blood culture had a significantly lower yield for detecting infection compared to tissue microscopic examination highlighting the importance of obtaining tissue for diagnosis (p < 0.05). PMID- 23082595 TI - Antibody persistence after primary and booster doses of a pentavalent vaccine against diphtheria, tetanus, acellular pertussis, inactivated poliovirus, haemophilus influenzae type B vaccine among Thai children at 18-19 months of age. AB - The World Health Organization recommends a booster dose of a pertussis-containing vaccine for children aged 1-6 years, preferably during the second year of life. This study assessed the immunogenicity and safety of a pentavalent combination vaccine containing diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and conjugated-Hib polysaccharide antigens, [(DTaP-IPV//PRP-T (Pentaxim)], as a booster at 18-19 months of age. Participants had received primary doses of the same vaccine at 2, 4 and 6 months of age. Antibody concentrations were measured immediately before and one month after the booster dose. Adverse events were evaluated from parental reports. Geometric mean concentrations (GMCs) or titers (GMTs) decreased from post-primary to pre-booster vaccination; however, at least 94.4% of children had protective levels of anti tetanus (> or = 0.01 IU/ml), antipoliovirus (> or = 81/dil) and anti-PRP (Hib, > or = 0.15 microg/ml) antibodies prior to the booster. Anti-diphtheria antibody titers > or = 0.01 IU/ml were also observed in the majority of children pre booster. One month after the booster, seroprotection rates were 99.4% for PRP (> or = 1.0 microg/ml), 95.0% for diphtheria (> or = 0.10 IU/ml) and 100% for tetanus (> or = 0.1 IU/ml) and poliovirus types 1, 2, 3 (> or = 81/dil). At least 93.1% of subjects had 4 fold post-booster increases in anti-pertussis antibody titers. GMCs increased from 14.0 to 307.3 EU/ml and from 13.9 to 271.9 EU/ml for anti-PT and anti-FHA, respectively. Anti-PRP GMC increased from 1.2 to 62.2 microg/ml. The booster was well tolerated. A booster dose during the second year of life was safe and induced a strong immune response, indicative of long-term protection. PMID- 23082596 TI - Meta-regression of risk factors for microalbuminuria in type 2 diabetes. AB - We aimed to determine the risk factors associated with microalbuminuria in type 2 diabetes patients through a systematic review and meta-regression analysis. The analyzed studies were obtained from PubMed, Scopus, British Medical Journal and ProQuest databases. All studies published from 2000 to 2009 were included. The search yielded 1,243 citations, of which 22 studies were analyzed. Pooled odds ratio estimates were obtained using a random effect model. The association of each risk factor with microalbuminuria was examined after adjusting for age and sex using meta-regression analysis. The adjusted odds ratio was 1.26 (95% CI 1.08 1.46) for systolic blood pressure; 1.16 (95% CI 1.03-1.31) for diastolic blood pressure; 1.43 (95% CI 1.14-1.80) for fasting plasma glucose level; 1.37 (95% CI 0.95-1.98) for smoking and 1.49 (95% CI 0.91-2.46) for waist circumference. The risk factors associated with microalbuminuria were found to be poor glycemic control, uncontrolled hypertension, smoking and central obesity. There is an urgent need to launch a health promotion program for changes in individual health behaviors to mitigate these risk factors for microalbuminuria in patients with type 2 diabetes. PMID- 23082597 TI - Frequency of ABO and rhesus blood groups among neonates born at a private hospital in Istanbul. AB - In this study we used gel centrifugation to determine the frequency and sex distribution of ABO and Rh blood group antigens among 4,656 neonates (2,317 males, 2,339 females) born at a private hospital in Istanbul. Group A Rh+ was the most frequent blood type and AB Rh- was the least frequent. Female neonates had a higher frequency of Rh+ blood than male neonates. Group A blood was detected most frequently followed by group O, group B, and group AB. Sex was not significantly associated with blood type. These results fall within the range of previously reported blood type frequencies for Turkey. Our data allow the creation of a blood bank database for the hospital. PMID- 23082598 TI - Knowledge and practices among medical abortion seekers in southeastern Nigeria. AB - Nigeria has restrictive abortion laws; unsafe abortion and its complications are major public health challenges. Access to reproductive health services in Nigeria, including medical abortion, is poor. We determined the socio-demographic characteristics, patterns of abortion practices, and experiences of medical abortions among abortion seekers in southeastern Nigeria. We carried out a descriptive, cross sectional survey of 100 consecutive medical abortion seekers in southeastern Nigeria. Subjects had a mean age of 23.5 + 4.4 years. Fifty-five percent of respondents were students. Sixty-four percent had a secondary educational level, 33% had a tertiary education level and 3% had a primary educational level. Fifty-eight percent of subjects were ages 18-20 years at coitarche; 25% had one or more previous deliveries and 49% had a previous termination of pregnancy. Forty-eight percent had used drugs for pregnancy terminations. Drugs used for termination included quinine combined with other drugs in 8%; gynaecosid alone in 6%, gynaecosid combined with other drugs in 6% menstrogen combined with other drugs in 6% and an unclassified drug in 14%. Thirty-three percent of subjects purchased their abortion drugs in a pharmacy. Three percent, 2%, and 0% of subjects had a knowledge of misoprostol, mifepristone and methotrexate, respectively. One percent of respondents had used misoprostol. We detected serious information gaps regarding abortion and poor access to reproductive health services. There is a need for policies and program to bridge this gap, and a need for revision of the present Nigerian abortion law. PMID- 23082599 TI - Use and perceptions of sexual and reproductive health services among northern Thai adolescents. AB - This study sheds light on obstacles to safe sexual health for young Thais and their need for appropriate sexual and reproductive health services. The study population was 1,745 unmarried adolescents aged 17-20 who resided or worked in Chiang Mai, the major city in northern Thailand. The study used quantitative and qualitative methods to explore the vulnerability of sexually active adolescents as well as the lack of support and care for them from parents and health providers. We found that young Thais still prefer pharmacies for self-medication and use government health care facilities as a last resort. Current health services are not suitable for adolescents in northern Thailand because they lack privacy and impose judgemental attitudes, especially towards sexually active adolescent females. Current programs for adolescent sexual and reproductive health focus on education and counselling and do not provide appropriate privacy or clinical care. There is a pressing need for advocacy, and policy support for the development of youth-friendly sexual and reproductive health services in Thailand. PMID- 23082600 TI - Can initial perceptions about quitting predict smoking cessation among Malaysian smokers? AB - Perceived risks and benefits of quitting smoking may be important factors in successful treatment. This study examined the association between initial perceived risks and benefits of quitting smoking and outcomes during a two month smoking cessation attempt. Participants (n = 185) were treatment-seeking smokers attending two smoking cessation clinics in Klang Valley, Malaysia. They received structured behavioral therapy and free Nicotine Replacement Therapy (NRT). Prior to treatment, a 12 item Perceived Risks and Benefits Questionnaire (PRBQ) was administered. This was used to assess the smoker's initial perceptions during their quit attempt. Participants were re-contacted at the end of two months to determine their smoking status. The results show participants intending to quit demonstrated a greater understanding of the benefits of quitting smoking than the risks of quitting. Those with a higher education level had a greater understanding of the benefits of quitting (p = 0.02). PRBQ items, such as perceived risks of quitting (ie weight gain, negative affect, social ostracism, loss of enjoyment and craving) were not associated with abstinence at two months. However, those who perceived a benefit of higher physical attraction post cessation were less likely to have stopped smoking at two months (OR 0.18; 95% CI 0.08-0.45). Other perceived benefits at baseline, such as health, general well being, self-esteem, finances and social approval, were not associated with smoking cessation at two months. The results suggest that in our study population, smokers' baseline perceptions of the benefits of cessation of smoking prior to therapy are not associated with quit results at two months. Counseling patients regarding the advantages and disadvantages of quitting may have changed their perceptions during quitting process and should be further explored in future studies. PMID- 23082601 TI - Interventions to prevent musculoskeletal disorders among informal sector workers: a literature review. AB - Despite the increasing incidence of musculoskeletal injuries among informal sector workers due to exposure to workplace risk factors, there is a dearth of literature examining the effectiveness of interventions to prevent musculoskeletal disorders. The aim of this study was to investigate the effectiveness of interventions to prevent musculoskeletal health problems and/or reduce risk factors among informal sector workers. A systematic review of the literature was conducted using an appraisal checklist developed by the Joanna Briggs Institute. The heterogeneity of the studies precluded a meta-analysis, so a narrative synthesis method was used. Eight intervention studies met the inclusion criteria. This review identified three types of interventions: 1) mechanical exposure interventions, 2) production systems/organizational culture interventions and 3) modifier intervention. These interventions provided high and moderate evidence to support the use of these strategies for prevention of musculoskeletal injuries or workplace risk. The effects, whether positive, negative or none, was influenced by sample size, sampling technique, comparison group and time examined. PMID- 23082602 TI - The evaluation of a multi-level oral health intervention to improve oral health practices among caregivers of preschool children. AB - Abstract. This study reports the effects of a pilot multi-level oral health intervention on caregivers' oral health practices and their determinants. Quasi experimental, pretest-posttest evaluations using a comparison group design were employed to evaluate the effectiveness of a proposed intervention for promoting caregiver oral health behavior. The intervention consisted of three components: home visits by lay health workers (LHWs), enhancing oral health education and services at health centers, and community mobilization. These components were designed to target factors at intrapersonal, interpersonal, organizational and community levels based on a Social Ecological Model (SEM). Four oral health behaviors associated with early childhood caries (infant bottle feeding, tooth brushing, snack consumption and fluoride use), and multi-level determinants were assessed during pre- and post-tests. The one-year intervention demonstrated a positive effect on tooth brushing, using toothpaste, and fluoride supplements, but did not have a significant effect on bottle feeding and snack consumption among children. The intervention also had no effect on dental caries; in fact caries increased in both control and experimental groups. The caregiver knowledge, attitudes, outcome expectations, and self-efficacy towards these behaviors were significantly increased in the experimental group after intervention. Caregivers in the experimental group received greater social support by LHWs and health center staff than those in the control group (p < 0.001). The program had an impact on integrating oral health services at health centers and community participation in children's oral health. These findings confirm multi-level factors influence reported oral health behavior, but not outcomes in terms of caries. Process evaluation is needed to determine actual implementation levels, barriers and suggests for modification of the program in the future to improve outcomes in terms of caries. PMID- 23082603 TI - Convenient care for baby boomers. PMID- 23082604 TI - How can you improve health literacy? PMID- 23082605 TI - Righting the circadian rhythm: diagnosing and treating shift work disorder. PMID- 23082606 TI - Breast cancer and menopause: art, science and quality of life. PMID- 23082607 TI - Generation gap? In the workplace, the divide is smaller than you might think. PMID- 23082608 TI - Labor limits: does restricting movement result in higher cesarean section rates? PMID- 23082609 TI - Caring for gay persons: stop the hurt. PMID- 23082610 TI - JCN appeals to heart and practice. PMID- 23082611 TI - Presence. PMID- 23082612 TI - Understanding the DNP. PMID- 23082613 TI - Courage, conscience, cost. PMID- 23082614 TI - Compassionately caring for LGBT persons in your faith community. AB - Nurses have a professional duty to provide care for all patients regardless of race, ethnicity, religion, gender, disability, sexual orientation, or gender identity. As Christian nurses, we are called by our profession and faith to welcome and care for those who are stigmatized by others. This article defines LGBT (Lesbian, Gay, Bisexual, Transgender), offers reasons why LGBT persons are at risk for healthcare disparities, discusses referral of LGBT persons to healthcare resources, and states ways to be more welcoming for LGBT persons in a faith setting. PMID- 23082615 TI - Pet therapy: dogs de-stress students. AB - Research supports the efficacy of the human-animal bond and pet therapy in a variety of settings. At nursing students' request at one school, the author began offering pet therapy prior to examinations. Anecdotal evidence of a study with the author's Golden Retriever, Goldilocks, demonstrates that pet therapy can reduce test anxiety and improve nursing student performance. PMID- 23082616 TI - Using community-based participatory research in parish nursing: a win-win situation! AB - Parish nurses contribute to community health through the expertise and programming they provide to and through faith communities. Application of community-based participatory research (CBPR) principles helps develop, implement, and evaluate effective community interventions. University graduate students partnered with a Hospital Parish Nurse Program (HPNP) in an urban community to provide assessment data in a CBPR project that led the HPNP to focus resources and interventions on high obesity rates. The HPNP utilized data to write grant proposals to expand community services to impact obesity. PMID- 23082617 TI - Creating a culture of kindness. AB - Although known for being kind, nurses understand that the culture of nursing and the nature of our fast-paced stressful work make kindness difficult. Where does kindness come from? How does being a Christian make a difference in bringing kindness to nursing culture? PMID- 23082618 TI - Faith community nurses: protecting our elders through immunizations. AB - An estimated 226,000 hospitalizations and 36,000 deaths from influenza-related causes occur in the United States annually; adults ages 65 and older comprise 90% of flu deaths and 65% of hospitalizations. Older adult immunization rates are far from the Healthy People 2020 goal of 90% coverage. This article explores immunization in the elderly and how faith community/parish nurses can improve immunization rates. PMID- 23082619 TI - The passion journey: bringing meaning to suffering, spiritual crisis, and recovery in cancer. AB - Experiencing cancer is a terrifying, life-changing experience. Faced with locally advanced breast cancer, this author discovered the passion journey, walking and journaling with Jesus through the Wilderness and Gethsemane, Good Friday, Easter Saturday, and Easter Sunday. PMID- 23082620 TI - Teleclasses: improve belonging, vitality, and health in church homebound. AB - Telemedicine or telehealth is a growing area of healthcare, using modern technology and communication resources. This nurse started a teleclass in her church to reach out to and connect homebound members using the telephone and conference calling. The results and health outcomes are astonishing. PMID- 23082621 TI - How can we put care back into spiritual care? PMID- 23082622 TI - Caring for strangers. PMID- 23082623 TI - Dare to discipline. PMID- 23082624 TI - Pull up a chair. PMID- 23082625 TI - Diversity and antibiograms of bacterial organisms isolated from samples of household drinking-water consumed by HIV-positive individuals in rural settings, South Africa. AB - Diarrhoea is a hallmark of HIV infections in developing countries, and many diarrhoea-causing agents are often transmitted through water. The objective of the study was to determine the diversity and antibiotic susceptibility profiles of bacterial organisms isolated from samples of household drinking-water consumed by HIV-infected and AIDS patients. In the present study, household water stored for use by HIV-positive patients was tested for microbial quality, and isolated bacterial organisms were analyzed for their susceptibility profiles against 25 different antibiotics. The microbial quality of water was generally poor, and about 58% of water samples (n=270) were contaminated with faecal coliforms, with counts varying from 2 colony-forming unit (CFU)/100 mL to 2.4x104 CFU/100 mL. Values of total coliform counts ranged from 17 CFU/100 mL to 7.9x105/100 mL. In total, 37 different bacterial species were isolated, and the major isolates included Acinetobacter lwoffii (7.5%), Enterobacter cloacae (7.5%), Shigella spp. (14.2%), Yersinia enterocolitica (6.7%), and Pseudomonas spp. (16.3%). No Vibrio cholerae could be isolated; however, V. fluvialis was isolated from three water samples. The isolated organisms were highly resistant to cefazolin (83.5%), cefoxitin (69.2%), ampicillin (66.4%), and cefuroxime (66.2%). Intermediate resistance was observed against gentamicin (10.6%), cefepime (13.4%), ceftriaxone (27.6%), and cefotaxime (29.9%). Levofloxacin (0.7%), ceftazidime (2.2%), meropenem (3%), and ciprofloxacin (3.7%) were the most active antibiotics against all the microorganisms, with all recording less than 5% resistance. Multiple drug resistance was very common, and 78% of the organisms were resistant to three or more antibiotics. Education on treatment of household water is advised for HIV positive patients, and measures should be taken to improve point-of-use water treatment as immunosuppressed individuals would be more susceptible to opportunistic infections. PMID- 23082626 TI - 16S rRNA gene-targeted TTGE in determining diversity of gut microbiota during acute diarrhoea and convalescence. AB - The human gut microbiota play a vital role in health and nutrition but are greatly modified during severe diarrhoea due to purging and pathogenic colonization. To understand the extent of loss during and after diarrhoea, faecal samples collected from children (n=21) suffering from acute diarrhoea and from their healthy siblings (n=9) were analyzed by 16S rRNA gene-targeted universal primer polymerase chain reaction (PCR), followed by temporal temperature gradient gel electrophoresis (TTGE). The gut microbiota decreased significantly as indicated by the number of TTGE bands at day 0 of acute diarrhoea [patients vs healthy siblings: 11+/-0.9 vs 21.8+/-1.1 (mean +/- standard error), p<0.01]. The number of bands showed a steady increase from day 1 to day 7; however, it remained significantly less than that in healthy siblings (15+/-0.9, p<0.01). These results suggest that appropriate therapeutic and post-diarrhoeal nutritional intervention might be beneficial for the early microbial restoration and recovery. PMID- 23082627 TI - Haemolytic-uraemic syndrome as a sequela of diarrhoeal disease. AB - Haemolytic-uraemic syndrome (HUS) is a serious sequela of diarrhoea and results in a high mortality rate. This systematic review aimed at estimating the proportion of HUS cases that are linked to prior infection due to Shiga toxin producing Escherichia coli (STEC) or Shigella dysenteriae type 1. A systematic review of the existing literature was done to identify cohort and case-control studies that examined the relationship between STEC and S. dysenteriae type 1 and HUS. After screening 2,516 articles, 11 studies were found that met the inclusion/exclusion criteria. Findings of case-control studies suggest that 60.8% of the HUS cases may be attributable to a previous infection with STEC. In cohort studies, 7.8% of participants with STEC and 8% of participants with S. dysenteriae type 1 developed HUS during follow-up. HUS is linked to diarrhoea due to both STEC and S. dysenteriae type 1. Thus, preventing infections caused by both pathogens is critical for the prevention and control of HUS, especially in areas where timely and effective treatment is not available. PMID- 23082628 TI - Quality of life and mental health status of arsenic-affected patients in a Bangladeshi population. AB - Contamination of groundwater by inorganic arsenic is one of the major public health problems in Bangladesh. This cross-sectional study was conducted (a) to evaluate the quality of life (QOL) and mental health status of arsenic-affected patients and (b) to identify the factors associated with the QOL. Of 1,456 individuals, 521 (35.78%) were selected as case and control participants, using a systematic random-sampling method. The selection criteria for cases (n=259) included presence of at least one of the following: melanosis, leucomelanosis on at least 10% of the body, or keratosis on the hands or feet. Control (nonpatient) participants (n=262) were selected from the same villages by matching age (+/-5 years) and gender. The Bangladeshi version of the WHOQOL-BREF was used for assessing the QOL, and the self-reporting questionnaire (SRQ) was used for assessing the general mental health status. Data were analyzed using Student's t test and analysis of covariance (ANCOVA), and the WHOQOL-BREF and SRQ scores between the patients and the non-patients were compared. The mean scores of QOL were significantly lower in the patients than those in the non-patients of both the sexes. Moreover, the mental health status of the arsenic-affected patients (mean score for males=8.4 and females=10.3) showed greater disturbances than those of the non-patients (mean score for males=5.2 and females=6.1) of both the sexes. The results of multiple regression analysis revealed that the factors potentially contributing to the lower QOL scores included: being an arsenic affected patient, having lower age, and having lower annual income. Based on the findings, it is concluded that the QOL and mental health status of the arsenic affected patients were significantly lower than those of the non-patients in Bangladesh. Appropriate interventions are necessary to improve the well-being of the patients. PMID- 23082629 TI - Rates and predictors of consistent condom-use by people living with HIV/AIDS on antiretroviral treatment in Uganda. AB - Antiretroviral treatment (ART) has been recognized as one of the methods for reducing the risk of HIV transmission, and access to this is being rapidly expanded. However, in a generalized HIV epidemic, ART could increase unprotected sex by people living with HIV/AIDS (PHAs). This paper assessed the rates and predictors of consistent condom-use by sexually-active PHAs after initiating ART. The study used cross-sectional data on sexual behaviour of 269 sexually-active ART-experienced individuals (95 males and 174 females) aged 18 years and above. The results revealed that 65% (70% of men and 61% of women) used condom consistently after initiating ART. Consistent use of condom was more likely if PHAs had secondary- or tertiary-level education and had more than one sex partner in the 12 months preceding the study. However, PHAs were less likely to have used condom consistently if they worked in the informal and formal sectors, belonged to the medium- and high-income groups, and were married. PHAs, who were on ART for less than 1 year and 1-2 year(s), had a good self-perception of health, had a sexual partner who was HIV-negative or a partner with unknown HIV status, and desired to bear children, were also less likely to have used condom consistently. The paper concluded that, although the majority of PHAs consistently used condom, there was potential for unprotected sex by PHAs on ART. PMID- 23082630 TI - Body composition of Bangladeshi children: comparison and development of leg-to leg bioelectrical impedance equation. AB - The aim of this study was to investigate the validity of the Tanita TBF 300A leg to-leg bioimpedance analyzer for estimating fat-free mass (FFM) in Bangladeshi children aged 4-10 years and to develop novel prediction equations for use in this population, using deuterium dilution as the reference method. Two hundred Bangladeshi children were enrolled. The isotope dilution technique with deuterium oxide was used for estimation of total body water (TBW). FFM estimated by Tanita was compared with results of deuterium oxide dilution technique. Novel prediction equations were created for estimating FFM, using linear regression models, fitting child's height and impedance as predictors. There was a significant difference in FFM and percentage of body fat (BF%) between methods (p<0.01), Tanita underestimating TBW in boys (p=0.001) and underestimating BF% in girls (p<0.001). A basic linear regression model with height and impedance explained 83% of the variance in FFM estimated by deuterium oxide dilution technique. The best-fit equation to predict FFM from linear regression modelling was achieved by adding weight, sex, and age to the basic model, bringing the adjusted R2 to 89% (standard error=0.90, p<0.001). These data suggest Tanita analyzer may be a valid field-assessment technique in Bangladeshi children when using population-specific prediction equations, such as the ones developed here. PMID- 23082631 TI - Food insecurity, health and nutritional status among sample of palm-plantation households in Malaysia. AB - Food insecurity is a worldwide problem and has been shown to contribute to poor health and nutritional outcomes. In Malaysia, poor dietary intake, overweight and obesity, diabetes mellitus, and hypercholesterolaemia have been reported to be more prevalent in females compared to males and in Indians compared to other ethnic groups. A cross-sectional study was designed to investigate the relationship between food insecurity and health and nutritional status among 169 Indian women (19-49 years old, non-pregnant, and non-lactating) from randomly selected palm-plantation households in Negeri Sembilan, Malaysia. Subjects were interviewed for socioeconomic and demographic data, and information on household food security and dietary intake. They were examined for weight, height, waist circumference, blood pressure and lipids, and plasma glucose levels. For analysis of data, descriptive statistics, ANOVA, and logistic regression were used. Majority (85.2%) of the households showed food insecurity as assessed using the Radimer/Cornell Hunger and Food Insecurity Instrument. The food-secure women had significantly higher mean years of education and lower mean number of children than food-insecure groups (p<0.05). There was a significant decrease in the mean household income and income per capita as food insecurity worsened (p<0.05). Women who reported food security had significantly higher mean diet diversity score (11.60+/-4.13) than child hunger (9.23+/-3.36). The group of subjects with higher intake of meat/fish/poultry/legumes (crude odds ratio [OR]=0.53, confidence interval [CI]=0.29-0.95) and higher diet diversity score (crude OR=0.87, CI=0.78-0.97) was more likely to have < 3 health risks. Diet diversity score remained a significant protective factor against heath risks even after adjusting for other variables. The present study showed that food insecurity is indirectly associated with poor health and nutritional status. Therefore, appropriate community-based interventions should be designed and implemented to address the problems of food insecurity and possible health and nutritional outcomes. PMID- 23082632 TI - Relationship between breastfeeding and obesity in childhood. AB - A cross-sectional study was conducted to investigate the weight status and the relationship of infant-feeding variables, birthweight and birth order with BMI in a group of Iranian children. Five hundred and eleven students of both sexes at the first grade in elementary schools (aged 7 years) were recruited randomly from all 19 educational districts of Tehran. Weights and heights of children and their mothers were measured. Data on breastfeeding (BF), formula-feeding, the timing of introduction of complementary foods (CF), birthweight, and birth order were collected from the mothers. The 2007 WHO reference value was used for determining child's weight status. Regression analysis in single and a 2-level linear regression models was used for examining the independent relationships of infant feeding variables, birthweight and birth order with childhood BMI. The prevalence of underweight and overweight in this group of children was 7.6% and 19.7%, respectively. Total time of BF and duration of exclusive BF were not associated with childhood BMI. The timing of introduction of CF was inversely related to childhood BMI after controlling for other variables (beta:-0.34; 95% CI:-0.58, 0.10). Children with an early introduction of CF had significantly higher mean BMI (p for linear trend=0.012). Birth order and birthweight were related to childhood BMI significantly. These data suggest that overweight and obesity are nutritional problems among 7 years old Teharani children. The timing of introduction of CF, birth order, and birthweight were independent predictors of childhood BMI. Neither total time of BF nor duration of exclusive breastfeeding was associated with adiposity in children. PMID- 23082633 TI - Beliefs about causes and consequences of obesity among women in two Mexican cities. AB - Personal beliefs might be barriers to the prevention and treatment of obesity. To assess the beliefs about causes and consequences of and possible solutions to obesity among 18-40 years old women in two Mexican cities and to analyze the association with demographic variables, we developed a questionnaire and assessed the women's weight status. The questionnaire was applied at two outpatient healthcare centres and assessed the responses by the Likert scale. Results were analyzed by demographics, using the chi-square and Spearman correlations. One thousand one hundred adult women participated in the study. Mean age was 27.8 years, and mean BMI (kg/m2) was 27.05. The prevalence of overweight and obesity was 35% and 24% respectively. The most mentioned causes of obesity were eating oil and fat (4.1), fried foods (4.1), and eating too much (4.00). The most reported consequences were diseases (4.1), discrimination (3.9), and early death (3.7). The main solutions were physical activity (4.2), healthful eating (4.2), and personal motivation (4.1). Age of participants higher than 30 years, living with a partner, having more than 6 years of education, and having overweight and obesity were predictors of more knowledge about the causes, consequences, and solutions. These Mexican women from low SES had reasonably good knowledge about the causes and consequences of obesity. Although improving education might be beneficial to prevent obesity, changes in environmental contingencies are also necessary to prevent this epidemic. PMID- 23082634 TI - Decline in child marriage and changes in its effect on reproductive outcomes in Bangladesh. AB - This paper explores the decline in child marriage and changes in its effect on reproductive outcomes of Bangladeshi women, using the 2007 Bangladesh Demographic and Health Survey data. Chi-square tests, negative binomial Poisson regression and binary logistic regression were performed in analyzing the data. Overall, 82% of women aged 20-49 years were married-off before 18 years of age, and 63% of the marriages took place before 16 years of age. The incidence of child marriage was significantly less among the young women aged 20-24 years compared to their older counterparts. Among others, women's education appeared as the most significant single determinant of child marriage as well as decline in child marriage. Findings revealed that, after being adjusted for sociodemographic factors, child marriage compared to adult marriage appeared to be significantly associated with lower age at first birth (OR=0.81, 95% CI=76-0.86), higher fertility (IRR=1.45, 95% WCI=1.35-1.55), increased risk of child mortality (IRR=1.64, 95% WCI=1.44 1.87), decreased risk of contraceptive-use before any childbirths (OR=0.56, 95% CI=0.50-0.63), higher risk of giving three or more childbirth (OR=3.94, 95% CI=3.38-4.58), elevated risk of unplanned pregnancies (OR=1.21, 95% CI=1.02 1.45), increased risk of pregnancy termination (OR=1.16, 95% CI=1.00-1.34), and higher risk of the use of any current contraceptive method (OR=1.20, 95% CI=1.06 1.35). Increased enforcement of existing policies is crucial for the prevention of child marriage. Special programmes should be undertaken to keep girls in school for longer period to raise the age of females at first marriage in Bangladesh and thereby reduce the adverse reproductive outcomes. PMID- 23082635 TI - Geographic differentials in mortality of children in Mozambique: their implications for achievement of Millennium Development Goal 4. AB - In the light of Mozambique's progress towards the achievement of Millennium Development Goal 4 of reducing mortality of children aged less than five years (under-five mortality) by two-thirds within 2015, this study investigated the relationship between the province of mother's residence and under-five mortality in Mozambique, using data from the 2003 Mozambican Demographic and Health Survey. The analyses included 10,326 children born within 10 years before the survey. Results of univariate and multivariate analyses showed a significant association between under-five mortality and province (region) of mother's residence. Children of mothers living in the North provinces (Niassa, Cabo Delgado, and Nampula) and the Central provinces (Zambezia, Sofala, Manica, and Tete) had higher risks of mortality than children whose mothers lived in the South provinces, especially Maputo province and Maputo city. However, controlling for the demographic, socioeconomic and environmental variables, the significance found between the place of mother's residence and under-five mortality reduced slightly. This suggests that other variables (income distribution and trade, density of population, distribution of the basic infrastructure, including healthcare services, climatic and ecologic factors), which were not included in the study, may have confounding effects. This study supports the thought that interventions aimed at reducing under-five mortality should be tailored to take into account the subnational/regional variation in economic development. However, research is warranted to further investigate the potential determinants behind the observed differences in under-five mortality. PMID- 23082636 TI - Attitudes of healthcare providers towards non-initiation and withdrawal of neonatal resuscitation for preterm infants in Mongolia. AB - Antenatal parental counselling by healthcare providers is recommended to inform parents and assist with decision-making before the birth of a child with anticipated poor prognosis. In the setting of a low-income country, like Mongolia, attitudes of healthcare providers towards resuscitation of high-risk newborns are unknown. The purpose of this study was to examine the attitudes of healthcare providers regarding ethical decisions pertaining to non-initiation and withdrawal of neonatal resuscitation in Mongolia. A questionnaire on attitudes towards decision-making for non-initiation and withdrawal of neonatal resuscitation was administered to 113 healthcare providers attending neonatal resuscitation training courses in 2009 in Ulaanbaatar, the capital and the largest city of Mongolia where -40% of deliveries in the country occur. The questionnaire was developed in English and translated into Mongolian and included multiple choices and free-text responses. Participation was voluntary, and anonymity of the participants was strictly maintained. In total, 113 sets of questionnaire were completed by Mongolian healthcare providers, including neonatologists, paediatricians, neonatal and obstetrical nurses, and midwives, with 100% response rate. Ninety-six percent of respondents were women, with 73% of participants from Ulaanbaatar and 27% (all midwives) from the countryside. The majority (96%) of healthcare providers stated they attempt pre-delivery counselling to discuss potential poor outcomes when mothers present with preterm labour. However, most (90%) healthcare providers stated they feel uncomfortable discussing not initiating or withdrawing neonatal resuscitation for a baby born alive with little chance of survival. Religious beliefs and concerns about long term pain for the baby were the most common reasons for not initiating neonatal resuscitation or withdrawing care for a baby born too premature or with congenital birth-defects. Most Mongolian healthcare providers provide antenatal counselling to parents regarding neonatal resuscitation. Additional research is needed to determine if the above-said difficulty with counselling stems from deficiencies in communication training and whether these same counselling-related issues exist in other countries. Future educational efforts in teaching neonatal resuscitation in Mongolia should incorporate culturally-sensitive training on antenatal counselling. PMID- 23082637 TI - Healthcare-seeking behaviour among the tribal people of Bangladesh: Can the current health system really meet their needs? AB - Despite the wealth of studies on health and healthcare-seeking behaviour among the Bengali population in Bangladesh, relatively few studies have focused specifically on the tribal groups in the country. This study aimed at exploring the context, reasons, and choices in patterns of healthcare-seeking behaviour of the hill tribal population of Bangladesh to present the obstacles and challenges faced in accessing healthcare provision in the tribal areas. Participatory tools and techniques, including focus-group discussions, in-depth interviews, and participant-observations, were used involving 218 men, women, adolescent boys, and girls belonging to nine different tribal communities in six districts. Data were transcribed and analyzed using the narrative analysis approach. The following four main findings emerged from the study, suggesting that the tribal communities may differ from the predominant Bengali population in their health needs and priorities: (a) Traditional healers are still very popular among the tribal population in Bangladesh; (b) Perceptions of the quality and manner of treatment and communication can override costs when it comes to provider preference; (c) Gender and age play a role in making decisions in households in relation to health matters and treatment-seeking; and (d) Distinct differences exist among the tribal people concerning their knowledge on health, awareness, and treatment-seeking behaviour. The findings challenge the present service delivery system that has largely been based on the needs and priorities of the plainland population. The present system needs to be reviewed carefully to include a broader approach that takes the sociocultural factors into account, if meaningful improvements are to be made in the health of the tribal people of Bangladesh. PMID- 23082638 TI - Changing pattern of dengue virus serotypes in Thailand between 2004 and 2010. AB - Dengue virus infection is a major concern in several countries, and more than 50 million people are infected worldwide each year. Thailand is one of the countries where people are susceptible to infection due to favourable geographical and environmental conditions. In this retrospective study, we reported the changing pattern of dengue virus serotypes during the period between 2004 and 2010. The following percentage prevalence showed different serotypes of dengue virus (DENV) predominant in respective years: DENV1 in 2004 (56.41%), DENV4 in 2007 (50%), DENV1 in 2008 (57.41%), and DENV3 in 2010 (38.7%). Moreover, the major serotypes were not stable as they showed a shift from one serotype to another. We also found co-infection with two different serotypes and reported the clinical manifestations, which were not different from infection with a single serotype. Co-infection with various serotypes may not necessarily cause more severe disease. PMID- 23082639 TI - Use of only oral rehydration salt solution for successful management of a young infant with serum sodium of 201 mmol/L in an urban diarrhoeal diseases hospital, Bangladesh. AB - A boy aged 4 months 7 days was admitted to the Intensive Care Unit (ICU) of the Dhaka Hospital of icddr,b, Dhaka, Bangladesh, with the problems of acute watery diarrhoea with some dehydration, pneumonia, lethargy, and hypernatraemia (serum sodium of 201 mmol/L). Correction for hypernatraemia was tried by using only oral rehydration salt (ORS) solution. Seizures occurred during correction of the hypernatraemia. These were difficult to control and required three doses of injection lorazepam, a loading dose of injection phenobarbitone, followed by injection phenytoin and finally two doses of injection mannitol (even though there was no clinical or imaging evidence by ultrasonography or computed tomography of cerebral oedema). The correction was continued with ORS, and all the anticonvulsants were successfully weaned without any further seizures, and the patient recovered without any overt neurological sequelae. We present a case report of extreme hypernatraemia, which was successfully managed using only ORS. PMID- 23082640 TI - [Fragile brain--the very young and the old]. PMID- 23082641 TI - [Postoperative cognitive dysfunction in elderly patients]. AB - The review describes postoperative disorders of the cognitive functions' (memory attention, speech, abstract thinking etc.) which is known as POCD. Frequency of POCD depending on pathology and age of patients, type of surgery and anesthesia is considered. Risk factors of POCD, especially advanced age and initial cognitive disorders are also noted. Modern diagnostic, treatment and prophylaxis facilities are discussed. PMID- 23082642 TI - [Delirium in neurointensive care unit. Literature review]. AB - The review describes modern diagnostic criteria for delirium in patients in ICU. Classification and prognostic significance of delirium are discussed. Prophylaxis and treatment of delirium in patients in ICU are considered in the review in details. PMID- 23082643 TI - [Awake craniotomy]. AB - The article is a literature review on awake craniotomy. History of method, indications and contraindications, necessary conditions for successful application as well as complications and their prevention and correction are considered Outcomes in patients with neuro-oncological pathology and in patients with intractable epilepsy after awake craniotomy are also analyzed. It's also shown that awake craniotomy can make removal of tumors near eloquent cortex more radical and improve neurological outcome in such patients. PMID- 23082644 TI - [Cognitive status assessment after spinal surgery]. AB - 38 patients after spinal surgery were involved in the study. Patients were divided into two groups similar by anthropometric factors, pathology and preoperative pain syndrome. The first group included 15 patients older than 60 years (mean age 66 +/- 5.77 years), second group--23 patients younger than 60 years (mean age 43 +/- 10.7 years). The authors analyzed influence of anesthetic method, duration of anesthesia, hemodynamic parameters, BIS values on POCD syndrome. Duration and depth of anesthesia, episodes of hypotension are main predictors of POCD. Maintenance of optimal depth of anesthesia defined by BIS monitoring decreases the frequency of POCD. Patients of all ages with chronic pain syndrome usually have memory and attention disturbances. PMID- 23082645 TI - [Diencephalic syndrome]. AB - Diencephalic structures are thalamus, hypothalamus, epithalamus, subthalamus and hypophysis. Diencephalic structures injury lead to several syndromes: diencephalic dysthermia, hypothalamic obesity, pediatric diencephalic syndrome, Cushing's disease, etc. Diencephalic syndrome manifests in 15-33% of patients with TBI. The goal of our study was to describe diencepalic syndrome in patients in neurointensive care unit. 76 patients took part in the study, 43 women and 33 men among them. The age of patients ranged from 19 to 77 years. All patients had consciousness disorders (CD) and dysnatremia. The patients were divided into 6 groups according to the number of somatic organ dysfunctions (SOD). 12 patients had only dysnatremia and CD without SOD (91.7% of them with benign outcome; 7.3% of them with poor outcome (GOS-3)). 11 patients in the second group had CD, dysnatremia and 1 SOD (45.5% of them had benign outcome; 54.5%--poor outcome). In the third group patients had 2 SOD (42% of them had poor outcome (GOS-3) and 33%- lethal outcome (GOS-1)). The worst outcome was in the 6th group, where patients had 5 SOD. All the patients in that group died. So, in patients with neurosurgical pathology in chiasmal area dienchephalic syndrome manifests by combination of CD, dysnatremia and at least 1 SOD. The number of SOD determines the outcome and severity of diencephalic syndrome. PMID- 23082646 TI - [Intensive therapy in patients with severe traumatic brain injury complicated by delirium]. AB - Delirium can greatly complicate progressing of TBI. Early diagnosis and intensive therapy optimization can improve the outcome. Retrospective-prospective study was performed in patients with severe TBI and delirium. 27 patients (mean age--40.8 +/- 3.3 years) were involved in experimental group and 25 patients (mean age 49.0 +/- 4.5 years)--in control group. The ISS and the APA CHE II scores were similar in both groups. Reamberin ("Polisan", Russia) infusion (800 ml/day for 7 days after injury) was included in the therapy plan for the experimental group. Modified RASS score was equal in both groups on the first day (1.67 +/- 0.37 in experimental and 1.88 +/- 0.28 in control group), but later RASS score was lower in experimental group (0.7 +/- 0.30 and 1.41 +/- 0.26 (p = 0.042) on the third day; 0.45 +/- 0.20 and 1.09 +/- 0.36 (p = 0.012) on the 5th day; 0.2. +/- 0.14 and 1.00 +/- 0.39 (p = 0.008) on the 7th day). The correlation of the modified Richmond Agitation Sedation Scale (RASS) score with the ISS score and with the length of stay in ICU was noted Reamberin improves mental status in patients with severe TBI complicated by delirium, especially, with alcohol intoxication. PMID- 23082647 TI - [Intracranial, cerebral perfusion pressure and systemic hemodynamic parameters during anesthesia induction in patients with traumatic brain compression]. AB - The study reports the dynamic of ICP, CPP and systemic hemodynamic rates during midazolam induction of anesthesia in patients with traumatic brain compression. Patients who need urgent surgery to eliminate brain compression of various degrees generally have intracranial hypertension. Midazolam administration decreases ICP by 22% from baseline under condition of stable hemodynamic and CPP. Depolarizing neuromuscular blocking agents' administration, mechanical ventilation and tracheal intubation lead to ICP elevation and CPP decreasing. The combination of midazolam and fentanil provides more reliable protection from hypertensive reactions. PMID- 23082648 TI - [PO.1 index as a predictor of successful extubation in patients after posterior fossa tumors removal]. AB - The goal of the study was to assess the clinical value of PO. 1 index for prognosis of successful weaning from mechanical ventilation in patients after posterior fossa tumors removal. 25 patients were involved in the study. 15 patients were successfully extubated in 24 hours time after surgery and 10 patients had prolonged mechanical ventilation. PO. 1 indexes in both groups were assessed and compared. Successfully extubated patients had higher PO. 1 index. PO. 1 index > 2 indicated that extubation would be successful with 93.3% sensitivity and 87.5% specificity. In successfully extubated patients the elevation of PO. 1 index during spontaneous breathing test was noted In the second group there was no such an effect. Elevation of PO. 1 index during spontaneous breathing test predicted successful extubation with 100% sensitivity and 80% specificity. PMID- 23082649 TI - [Cerebral hemodynamic in acute phase of traumatic brain injury]. AB - The study was aimed at investigating cerebral hemodynamic during acute phase of TBI in connection to ICP and initial S(Vj)O2. 80 patients with severe TBI were divided into 2 groups (with ICP > 20 mm Hg and ICP < 20 mm Hg) and 3 subgroups (with S(Vj)O2 < 55%, 55% < S(Vj)O2 < 75% and S(Vj)O2 > 75%). Minimal disturbances of cerebral hemodynamic were observed in patients with S(Vj)O2 from 55% to 75%. Autoregulation of cerebral blood flow in this group recovered on the 6th - 7th day after an injury. Low S(Vj)O2 corresponded to severe systemic and cerebral hemodynamic disturbances and often lethal outcome. In patients with high S(Vj)O2 disturbances of cerebral hemodynamic were insignificant and pattern of impeded perfusion was observed. PMID- 23082650 TI - [HES 130/0,4/9:1 effect on intracranial pressure, cerebral blood flow, oxygenation and cerebral vasospasm]. AB - The paper contains results of clinical investigation of influence of intravenous infusion of 6% Hydroxyethyl starch 130/0.4/9:1 (Voluven, Fresenius Kabi) on cerebral blood flow, cerebral metabolism and ICP in 7 patients with cerebral angiospasm after subarachnoid hemorrhage. It's shown that such infusion in patients with cerebral vasospasm doesn't lead to ICP elevation but can cause regional volumetric blood flow rising and improving of cerebral metabolism. PMID- 23082651 TI - [Mean ICP, ICP amplitude, mean AP and mean CPP dynamic in changing the position of the head of the bed in patients with severe TBI]. AB - The study included 34 patient with severe TBI (GCS--5.6 +/- 1.2, age--35 +/- 8.2 years). ICP, AP and CPP monitored by Philips MP 4060 with ICM Plus software (UK). Autoregulation of blood flow was evaluated with Prx index. The backrest position was moving in the range 0-30-60-30-0 degrees. Minimal mean ICP was noted in 300 position. ICP in positions 0 degrees and 60 degrees did'nt differ significantly ICP in position 60 degrees was higher then ICP in position 30 degrees. ICP amplitude was raising during changing the position from 0 degrees to 60 degrees and was decreasing during reversing changing. Arterial pressure (AP) was decreasing during movement the head of the bed from 0 degrees to 60 degrees, the maximum of AP was noted in flat position. CPP was increasing during lowering the head of the bed. ICP amplitude and CPP had inverse correlation. ICP amplitude is a simple method of assessment of CPP adequacy during changing the position of the head of the bed in patients with intact autoregulation of cerebral blood flow. PMID- 23082652 TI - [Residual neuromuscular blockade after muscle relaxants administration in neurosurgical patients]. AB - The paper analyzes the incidence of residual neuromuscular blockade (NMB) after pipecuronium and rocuronium administration in 124 neurosurgical patients. We analyzed neuromuscular conductance with TOF-Watch SX Residual NMB incidence after neuromuscular blocking agents administration in neurosurgical patients is 87.7%. Use of pipecuronium accompanied by a greater incidence and duration of residual NMB in comparison with rocuronium. Sugammadex administration is effective method of residual NMB reversal and can restore NMC in 3-5 minutes. PMID- 23082653 TI - [Diagnostic value of blood myoglobin level elevation in patient in intensive care unit]. AB - The goal of the study was assessment of clinical value of myoglobin level elevation in patients in neurointensive care unit. 15 healthy volunteers and 60 patients of neuroICU (40 postoperative patients and 20 patients with prolonged consciousness disorders of different states) were involved in the study. Myoglobin level was assessed immunologically. Episodes of arterial hypotension (< or = 50% from baseline) for 10-15 minutes were the cause of myoglobin level elevation in 11 from 40 postoperative patients. Association of myoglobin level elevation with type of pathology (tumor or aneurism), localization and surgery duration wasn't found. Severe hemodynamic disturbances with hypotension in 3-4 days before measurement were noted also in patients with hypermyoglobinemia in the group with prolonged consciousness disorders. Correlation of myoglobin level and duration of polyneuromyopathy, sepsis, MODS wasn't noted. Authors conclude that myoglobin level elevation is associate with hemodynamic instability and isn't specific marker of polyneuromyopathy or its duration. PMID- 23082654 TI - [Myorelaxation tactic with sugammadex in surgery with neurophysiological monitoring]. AB - The case contains description of spinal intramedullary tumor removal with neurophysiologic monitoring. It required well controlled neuromuscular blockade. For this purpose anesthesiologist used sugammadex, specific antagonist of steroid neuromuscular blocking agents. PMID- 23082655 TI - [Cerebrocardial syndrome. Differential diagnosis and treatment]. AB - The paper contains two cases of cordial complications of acute cerebral injury (TBI with hematoma and stroke). Diagnosis of coronary and cerebrocardial syndromes is discussed. PMID- 23082656 TI - [Centrogenic reactions monitoring with PICCOplus during large and giant posterior fossa tumors removal]. AB - The article contains two observations of centrogenic reactions (systemic hemodynamic responces) during posterior fossa tumors removal. PICCOplus was used as additional monitoring modality. In the second case, where authors observed second type of centrogenic reactions by their classification, significant increasing of extravascular lung water was noted. Causes of this effect are disscussed. PMID- 23082657 TI - [A case of early detection of a giant postoperative posterior fossa hematoma after tumor excision under xenon anaesthesia]. AB - We report a case of a life-threatening postoperative posterior fossa hematoma whose early detection and successful removal become possible owing to rapid awakening after xenon anesthesia and thorough postoperative follow-up in the recovery room. Postoperative management of neurosurgical patients and perspectives of xenon anesthesia in neurosurgery are discussed. PMID- 23082659 TI - [Results and prospects of the guarantee of sanitary-epidemiological welfare of population of the Russian Federation]. AB - The issues of further development of scientific and methodological basis of the guarantee of sanitary-epidemiological welfare of population of the Russian Federation are highlighted in accordance with the implementation of the Concept of the activity of the Federal Service for the Oversight of Consumer Protection and Welfare until 2015. Features of this work over the past 5 years have been characterized, they include: changes in the structure of the objects under surveillance; integration processes in the economy of the country rise of attention to social problems of society strengthening the influence of epidemiological and natural man-made disasters in the world and the country, improvement of the supervisory authorities of the Service, the formation of its new structure and development of legislative assembly, including sanitary legislation. PMID- 23082658 TI - [A case of acute motor acsonal neuropathy in patient after removal of giant adenoma of hypophysis]. AB - Authors described a case of development of Acute Motor Acsonal Neuropathy (AMAN)- the one of variations of Guillian-Barre syndrome. They discuss clinical and diagnostic peculiarities of AMAN. Treatment by specific immunoglobulins is a method of choice for patients with this pathology. PMID- 23082660 TI - [Problem questions of hygiene of residential and public buildings and concept of development of studies for the future]. AB - The article presents the main areas of cooperating activity of hygienists and architects on creating an environmentally safe and comfortable human habitat at the current stage of housing construction. This creative cooperation has been summed and the prospects for further development of research on the hygiene of residential and public buildings have been indicated. PMID- 23082661 TI - [Features of prevalence of sarcoidosis among the inhabitants of Moscow]. AB - The present study was designed to investigate the prevalence of sarcoidosis in Moscow under the impact of various social-hygienic factors. 302 residents in Moscow with a confirmed diagnosis of "sarcoidosis" were examined. Relationships between exposure to social-hygienic factors and epidemiological characteristics of the patients' population have been analyzed The requirement of separate analysis of male and female populations of patients with sarcoidosis has been established in connection with independent formation of these samples, as well as differences in their response to the social and hygienic factors. The results indicate that male and female populations of patients with sarcoidosis are formed independently, express different reaction to social-hygienic factors and should be analyzed separately. PMID- 23082662 TI - [Visit a swimming pool in Moscow as a risk of skin diseases of fungal etiology]. AB - 450 persons visited swimming pools in Moscow out of 900 patients seen by a dermatologist, have been questioned. Skin and toenail mycoses plates (18.7% and 21.8% respectively) were shown to prevail in the overall structure of the skin disease in persons who regularly visited swimming pool for a long time. In the structure of the species composition of fungal pathogens of diseases in such persons Trichophyton rubrum (51%) takes the first place, Candida albcans (25.5%) takes the second place. PMID- 23082663 TI - [Peculiarities of exposure to polychlorinated biphenyls (PCBS) in the indigenous population of the coastal and mainland Chukotka]. AB - The indigenous people of coastal areas show a low percentage of low chlorinated and dioxin-like PCB congeners (as opposed to mainland aborigines) with a significant proportion of the "triad" in the amount of PCBs. 5 years after the first survey the ratio of the analyzed groups of PCB congeners in the blood of parturients - mothers, as well as in the fetus - child in the coastal Chukotka remained unchanged, indicating that the equal share rate of clearance accumulation of congeners and is almost equal share content of PCB congeners in the mother and child. The average duration of half-lives of PCB congeners (#105 187) from the mother's body was 4-6 years (for the sum of PCBs - 5.7 years), which is broadly consistent with the results of foreign studies. The composition of PCB congeners in the blood of the continental population significantly differs from those in the food, while coastal residents--similar to the composition of PCBs in marine mammals. The content of PCB congeners in the domestic sources of pollution has no resemblance to the composition of PCBs in the blood of the natives. PMID- 23082664 TI - [Sanitary and bacteriological characteristics of water of the lower Don]. AB - The long-term data on the monitoring of bacterial quality of water in the Don River are reported in the article. The evaluation of the epidemiological significance of indicators of microbial pollution of surface water body has been performed Group of Enteric Bacteria and Klebsiella reflect the degree of potential risk of epidemic reservoir most adequately, and a presence of Salmonella and Shigella indicates a direct epidemic danger. PMID- 23082665 TI - [Studies of cellular immunity in medical workers with occupational asthma and obstructive bronchitis in health care institutions of Primorsky Krai]. AB - Research was carried out on the basis of voluntary consent to the study of the characteristics of cellular immunity from the blood samples of the medical staff of health institutions of Primorsky Krai suffered from occupational bronchial asthma and obstructive bronchitis. For this purpose, 23 female patients with a diagnosis of occupational asthma, 100 female cases with obstructive bronchitis were examined. Mean age was 47.9 +/- 3.5 years. The control group was consisted of 30 healthy women, average age of 46.7 +/- 3.7 years. The aim of our study was to investigate the changes of cellular immunity in health care workers with occupational asthma and obstructive bronchitis. There is an urgent need to study the dynamics of immunogram for proper interpretation and to take measures to prevent complications timely. PMID- 23082666 TI - [Night shift and the risk of hormone-dependent diseases in women]. AB - From cards of follow-up of industrial contingent passing preventive medical examinations, the frequency of disorders of the reproductive sphere and the endocrine system in 208 women employed in shift work including the night shift was investigated in comparison with 102 female members of administrative and managerial staff The relative risk (RR) of all investigated pathologies associated with employment in night shifts, was 1.52 (95% confidence interval (CI): 1.06-2.18). The increased risk of mastitis (OR = 1.13, 95% CI 0.95-1.35), and a uterine myoma (RR = 1.16, 95% CI: 1.00-1.36) was on the border of statistical significance. Endometriosis was significantly more frequent in the study group: RR = 1.23 (1.04-1.45). The risk of developing ovarian cysts was not significantly lower: RR = 0.94 (95% CI: 0.72-1.24). In connection with the employment in night shifts increased risk of all endocrine diseases was observed on the border of statistical significance: RR = 1.18 (95% CI: 0.99-1.40), including the development of obesity: RR = 1.22 (95% CI 1.05-1.43). The frequency of diabetes in the group of workers with night shifts was statistically significantly higher (OR = 1.13, 95% CI: 0.84-1.51). The pathology of the thyroid gland in the study group occurred less frequently than in the control one: RR = 0.88 (95% CI: 0.73-1.07). These data are preliminary, but they are consistent with the available experimental and epidemiological data. PMID- 23082667 TI - [Improvement of sanitary and epidemiological safety of rail transport--a requirement of the new legislation of the Russian Federation]. AB - Brief analysis of the legal framework in recent years, both in the sphere of technical regulation, and in the field of sanitary and epidemiological welfare of the population is presented in this article. The necessity of inclusion in the technical regulations for the safety of railway rolling stock and elements of railway infrastructure the requirements for sanitary-epidemiological safety and hygiene regulations has been proved. Fragments of technical regulations for railway equipment and infrastructure elements, including the basic requirements for the sanitary-epidemiological security are presented. The position of authors in the processing of the regulatory framework in the field of sanitary epidemiological welfare of population in standardization documents in accordance with the requirements of federal law "On technical regulation" has been reflected. PMID- 23082668 TI - [Alterations of immunoreactivity in cnemical production workers in dependence on dose exposure to toxicants]. AB - The immunological examination of employees working in the production of caustic soda, vinyl chloride, polyvinyl chloride and epichlorohydrin has been performed. The features of the relationship between alterations in indices of immunoreactivity and dose exposure for total years of employment in persons exposed to various chemical substances have been established. PMID- 23082669 TI - [Protective properties of respirators in working conditions]. AB - A review of the results of measurements of protective properties of respirators (Respiratory protective equipment (RPE)), conducted in recent decades in industrialized countries is presented. These studies formed the basis for the development of regulations governing the selection, delivery and use of RPE. Information on modes applied for the prevention of occupational diseases with the use of respirators has been provided. The measures to preserve the health of workers, based on the common practice of using RPE, including: development and application of regulations governing the selection and use of respirators, employee training, use of more effective respirators, the protection factor are suggested. PMID- 23082670 TI - [Comparative analysis of physical and biological development of schoolchildren in Moscow]. AB - The study of physical development in lateral (longitudinal) studies is carried out with the aim to determine the dynamics of alterations of anthropometric indices, the level of biological maturation and functional indices of children and adolescents in different time intervals. The longitudinal study (2003-2010) allowed to discover that modern schoolchildren exceed their peers of 60th and 80th in main anthropologic indices and the level of biological development but they seriously get behind on functional indices. The findings show the necessity of the working out of modern normatives for the assessment of physical development, rescheduling of normatives of biological development of schoolchildren and search of mechanisms for decrease of functional indices. PMID- 23082671 TI - [Experience of application of social hygienic monitoring in hygiene of children and adolescents and the lessons resulting from it]. AB - The adoption of the law of the Russian Federation "On the sanitary epidemiological welfare of population" called for the creation of a tool "measurement" of the specified condition. This tool was the socio-hygienic monitoring (SHM)--a complex system of long-term monitoring changes in the state of health of the population and the surrounding environment. Goal, objectives and the technology of SHM have been formulated in the decisions of the Government of the Russian Federation No426 of 1 June 2000 and 3385 from 26.04.2005. Methodology of SHM provides for the forecasting and management of health of the population on the basis of the establishment of cause-and-effect relations in the system of "environment-health" and making managerial decisions, proceeding from the priority of primary prevention and the establishment of priority in the conduct of recreational activities at designated areas. Currently, the country has established a system of SHM designed to operate at the federal (Russian Federation), regional (republic, kray, oblast, okrug, the mega-cities), local (city, region) level with a vertical management structure. Some experience of SHM was gained and in the hygiene of children and adolescents. On the basis of this experience purpose is to identify opportunities of SHM to solve the priority (as required by the methodology) and other own problems of hygiene of children and adolescents, to give the characteristic used in SHM criteria for the evaluation of the health of students and the status of the school environment and offer a more informative, in our opinion, the criteria. PMID- 23082672 TI - [Comparative characteristics of physical development in rural and urban schoolchildren in the Krasnoyarsk region]. AB - We examined schoolchildren aged from 7 to 17 years: 2683 in Krasnoyarsk and 1552 in districts of Krasnoyarsk territory in order to study the level of their physical development. We performed somatometry (body mass and length measurements) and worked out comparative evaluation of harmony in physical development upon Ketle2 index (BM1 kg/m2). We found out that the majority of the tested schoolchildren show disharmony variants in physical development. Body mass deficit was registered more often in rural (26.8%), than in urban schoolchildren (15.4%; p < 0.001). Overweight was marked more often in urban (38.2%) than in rural schoolchildren (26.4%; p < 0.001). In 6.9% of urban and in 6.8% of rural schoolchildren the overweight approached the level, which is diagnosed as obesity. PMID- 23082673 TI - [Dynamics of functional status and adaptation processes in students during period of studies in a higher education institution]. AB - The dynamics of the functional status and adaptation processes in students during the period of study in a higher education institution was investigated. Adaptation processes in students during period of studies in a higher education institution, assessed in terms of the nature of the shift in cardiac rhythm variability indices and characterized by having a positive trend in junior courses were shown to change an intensification of mechanisms of cardiac rhythm control in senior courses. PMID- 23082674 TI - [Description of anthropometric indices and nutritional status in students in Ufa city]. AB - The evaluation of the anthropometric measures and body mass index describing the nutritional status of students in Ufa has been performed. Anthropometric measures of students in Ufa were established to be significantly lower in comparison with anthropometric measures of their peers from other regions. It was noted that the deficit in body weight in girls occurs 2.6 times more often, and obesity is 4.2 times less than in boys at approximately equal high percentage of individuals with normal body weight. PMID- 23082675 TI - [Effect of chromium on the trace element homeostasis of biosubstrates in laboratory animals]. AB - The authors studied the levels of chromium in potable water, snow, soil, and the hair of inhabitants in 3 territorial economic zones of the Orenburg region, water and snow prooxidant loads, and the impact of excessive potassium bichromate intake on the imbalance of some elements in the blood and spleen of laboratory animals. There was dissimilar distribution between the media in relation to the area, as well as a pronounced imbalance of trace elements in the biosubstrates of experimental animals. PMID- 23082676 TI - [Study of the mutagenic activity of petroleum upon chronic exposure in laboratory animals]. AB - A metaphase chromosome analysis method was used to evaluate the mutagenic activity of volatile petroleum fractions in chronically intoxicated rats. The findings indicate that chronic inhalation exposure of the rats to volatile petroleum fractions at different concentrations results in a significant (2.5 fold) increase, compared to the spontaneous level, in the occurrence of chromosomal aberrations in the bone marrow cells in a number of generations. In addition to chromosomal structural abnormalities, there are genomic changes (aneuploidy, polyploidy). There is a tendency towards an increased rate of petroleum-induced chromosomal aberrations in a number of generations (P, F1, and F2) in the rat bone marrow cells. The maximum mutagenic effect of volatile petroleum fractions was found when used at concentrations of 10 and 100 mg/l upon long-term chronic exposure during three generations (P1, F1, and F2). The findings are indicative of the mutagenic activity of volatile petroleum fractions, which is likely to pose a potential risk from environmental pollution to biota and population health in the area of intensive oil extraction and refining. PMID- 23082677 TI - [Toxicological-hygienic substantiation of maximum allowable concentration of Dalinka insecticides in the atmospheric air]. AB - The results of experimental studies on the reflex and resorptive action of different concentrations of insecticide Dalinka in the atmospheric air are presented in this paper. As a result of experimental studies hygienic rules and defined the hazard class of insecticide Dalinka were developed for the first time to assess the level of air pollution during the period of production, storage, transportation, and its application in agriculture. PMID- 23082678 TI - [Development of the method for determining substances--markers of the hazardous production of advanced oil processing (ethylene oxide, 1,3-butadiene) in the air at the level of reference concentrations]. AB - The results of experimental studies on the development of gas chromatographic method for the determination of 1,3-butadiene and ethylene oxide in ambient air at the level of reference concentration with the use of sorption of the compounds studied from ambient air on the adsorbent TenaxTA in conjunction with optimum conditions of thermal desorption and the use of capillary gas chromatography are presented. The parameters of adsorption, thermal desorption and gas chromatographic determination of 1,3-butadiene and ethylene oxide in ambient air have been justified. A high sensitivity of gas chromatographic determination in the range of concentrations (in mg/m3) of 1,3-butadiene, 0,002 - 5, 0, ethylene oxide 0.005 - 1, 0 with 25% uncertainty in the determination has been reached . PMID- 23082679 TI - [The improved probit-method of sanitary-and-hygienic expert examination of substances]. AB - In this paper the method for calculating the parameters of the characteristic curve has been reported. As an example, the results of calculations of parameters of the curve on the basis of experimental data describing the possible effects of the substance are presented. The advantages of the proposed method in comparison with those adopted in the present are pointed. PMID- 23082680 TI - [Ecological and hygienic evaluation of production waste of diagnostic preparations]. AB - For the first time eco-hygienic evaluation of waste materials of production of diagnostic products has been performed. The methodology of risk assessment included consideration of the technology for their delivery, assessment of potential hazards (biological, chemical, and toxicological) based on the study of physico-chemical properties and performance of toxicological, hygienic and ecological research. PMID- 23082681 TI - [Structure-energy indices assessment of the quality of drinking water]. AB - The conceptual statements for bioenergetic activity of drinking water, relied upon the basis of the dependence of homeostasis of organisms on the electronic state of the environment are reported. Indices for assessment of the bioenergetic status of drinking water and a system of their categorization on the levels of bio-energetic activity have been proposed. PMID- 23082682 TI - [New conceptual approach to the assessment of the physical health of adult population]. AB - The new concept of assessing the physical health of the adult population, based on the score estimation of the functional parameters of human adaptive capacities, as the leading criterion for his health has been suggested. The proposed methodological approaches were successfully tested during the comprehensive study of health of adult population of the Novgorod region, based on the total sample (approx. 5000 inhabitants), adjusted for its regional and age gender structure. The study showed that nearly 80% of the adult population of the Novgorod region have normal health, characterized by relatively high adaptive capacity that enables them to lead a full-scale life style and to participate actively in life of the society. PMID- 23082683 TI - [Academician G. N. Serdyukovskaya in hygiene of children and adolescents (on her 90th birthday)]. PMID- 23082684 TI - Counteracting an unflattering portrayal of dentistry. PMID- 23082685 TI - Capitol roundup. PMID- 23082686 TI - Heed the warning. PMID- 23082687 TI - Unwelcome change. PMID- 23082688 TI - Mystery solved. PMID- 23082689 TI - Negotiating a managed care contract. PMID- 23082690 TI - Membership matters. PMID- 23082691 TI - Treating the patient with oral motor dysfunction using intraoral prosthetic therapy. AB - Included in this article are discussions of normal growth and development of the oral cavity and new treatment available for grossly damaged oral structures, along with a case study demonstrating successful treatment. This treatment approach can be a useful addition to dental office practice. PMID- 23082692 TI - BMP-2: biological challenges to its clinical use. AB - Protein therapy using osteogenic factors is an exciting technique for bone regeneration and implant placement. BMPs are known to stimulate bone formation in ectopic sites; BMP-2 is the most commonly used. In 2007, the FDA approved BMP-2 delivered with an absorbable collagen sponge (ACS) carrier for clinical use in craniofacial deformities. Almost all the publications on BMP-2 showed relatively significant results in augmenting bone at the site of implantation for a period of up to 16 weeks; however, the long-term clinical outcome of BMP-2 application is lacking and yet to be proven reproducible. Many biological obstacles prevent the maintenance and prolonged existence of high bone volume initially formed, thus compromising the long-term implant survival. In this paper, we review these obstacles and highlight their importance in the oral environment. We underscore the ambiguity that has emerged about the safety of BMP-2 in clinical application. Since biology dictates success, we believe at present that any protein therapy for bone regeneration is likely to be ineffective over a long period of time. PMID- 23082693 TI - Rational endodontics must pass the commonsense test. AB - By applying the principles of common sense, we can arrive at a rational approach to endodontics that eliminates concerns we have in using the rotary NiTi. We can use this same approach to improve our choices of what to use to create the original glide path. By switching from the poorly designed K-file to the more rationally designed and utilized relieved reamers, we not only create a more usable glide path, we quickly learn that an extension of this approach can eliminate the use of rotary NiTi and the various compromises it makes us incorporate in an attempt to use it safely. PMID- 23082694 TI - Risperidone-induced rabbit syndrome: an unusual movement disorder. AB - Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth and lips, resembling the chewing motion of a rabbit. The motion consists of vertical movement; the tongue is not involved. The reported prevalence of rabbit syndrome ranges from 2.3% to 4.4% of patients treated with typical antipsychotic drugs. There have been isolated reports of rabbit syndrome in patients treated with atypical antipsychotics. Rabbit syndrome needs to be closely differentiated from tardive dyskinesia, the tongue-involving movement disorder. Treatment of rabbit syndrome is empirical, reflecting poor understanding of this syndrome. The striking aspect of this syndrome is its specificity. The etiology of rabbit syndrome focuses attention on the basal ganglia, which is also implicated in oral dyskinesia. Continuing neuro-physiological research of the basal ganglia probably holds the key to better understanding of this syndrome. The aim of this article is to create awareness of rabbit syndrome and its implications in clinical dentistry. PMID- 23082695 TI - MTAD: a review of a promising endodontic irrigant. AB - The essential role of microorganisms in the initiation and perpetuation of pulp and periapical pathosis has been well documented. The major objective in endodontic therapy is to disinfect the entire root canal system. Considering the complex anatomy of the root canal system, complete elimination of bacteria by cleaning the root canal with instrumentation alone is unlikely. Therefore, an appropriate antimicrobial irrigant is needed to decrease the microbial load, especially in necrotic and retreatment cases. Another important issue in endodontics is the smear layer. Although there is no general consensus on removal of the smear layer, it seems that removing it enhances the sealing ability of the root canal filling. MTAD is an endodontic irrigant with both antibacterial and smear layer removal abilities. The aim of this paper is to review these different aspects of MTAD. PMID- 23082696 TI - Efficacy of F file compared to ultrasonic techniques using scanning electron microscopy. AB - A study was undertaken to compare the debridement efficacy of the F file with ultrasonics. Thirty mandibular premolars were instrumented with the Protaper file series using a crown-down technique. All the canals were irrigated using 2 ml of 5.25% sodium hypochlorite and 2 ml of 17% EDTA for one minute, alternating each instrument. The teeth were then divided into three groups of 10 each. In Group I, a final flush with only 5.25% NaOCl concluded the preparation (control group). Group II underwent 5.25% NaOCl and ultrasonic irrigation for one minute. Group III, 5.25% NaOCl and F-file for 30 seconds. Smear layer and debris scores were examined under a scanning electron microscope. In a blind manner, two investigators scored the presence or absence of smear layer and debris. Significantly higher smear layer and debris scores were found at the apical level compared to the middle and coronal levels in all the three groups. In the end, the F file proved more beneficial in removing smear layer and debris than ultrasonics. PMID- 23082697 TI - New York State ranked favorably for adults and reasonably well for children in terms of oral health standards. AB - Results from the National Health Interview Survey place New York State at or near the top among states for the oral health standards of its residents. Nevertheless, continued unmet service needs exist, particularly for minority populations, individuals in lower income families and residents with disabilities. PMID- 23082698 TI - Genomic instability in ulcerative colitis: a prerequisite for cancer in the inflammatory colon? AB - Ulcerative colitis (UC), a chronic and relapsing idiopathic inflammatory disease of the colon, although not associated with an increased mortality compared to the general population, has a substantial morbidity leading to sizable health care costs, as it carries an increased risk for development of colorectal cancer (CRC). The pathophysiology behind this carcinogenic pathway is multifactorial. This review summarizes the major pathogenetic steps from which the inflamed colonic epithelium is transformed to a dysplastic and/or cancerous one. The role of the inflammatory and immune system, the oxidative stress generated as well as the genomic stability observed in UC-associated CRC is presented so as to provide a more spherical view of the tumorigenic process and, if possible, offer new diagnostic approaches for the early detection of CRC. PMID- 23082699 TI - Halitosis--a common medical and social problem. A review on pathology, diagnosis and treatment. AB - Bad breath is a condition that has health and social implications. This paper provides a comprehensive review of the classification of halitosis, it's etiology, it's prevalence, diagnosis and treatment strategies for the condition. Halitosis is affecting about 25-30% of world's population. It includes categories of genuine halitosis, pseudo-halitosis and halitophobia. It is believed that in 80-90% of cases halitosis origins in the oral cavity and the most common causes are: gingival pathologies, caries and poor oral hygiene. Extraoral sources of halitosis are responsible for 10-20% of all cases and are caused by poor diet, alcohol abuse, tobacco smoking, certain drugs and diseases of other parts of digestive tract as well as some systemic conditions. Diagnostics of halitosis includes subjective methods (examiner's sense of smell) and objective methods (instrumental analysis). Simple, subjective examination is considered a "golden standard" in clinical practice. In case of pathological halitosis identifying the direct cause of halitosis is essential. After excluding, or after successful treatment, of all oral pathologies, in case of remaining fetor ex ore identification and treatment of halitosis often requires multidisciplinary approach. Many unknowns remain in causes and mechanisms of halitosis. It can significantly impair quality of life, social interactions, lead directly to depression,low self-esteem or other mood disorders, therefore it is important to properly identify, treat and continue research on halitosis. PMID- 23082700 TI - Eosinophils in the gastrointestinal tract: friends or foes? AB - Eosinophils play an important role in the mucosal immune system of the gastrointestinal tract under resting and under inflammatory conditions. Under steady-state conditions, the mucosa of the digestive tract is the only organ harboring a substantial number of eosinophils, which, if need be, get activated and exert several effector and immunoregulatory functions. The precise function of these late-phase inflammatory cells is not yet completely understood. Nevertheless, it has recently been demonstrated that lipopolysaccharides from gram-negative bacteria activate eosinophils to rapidly release mitochondrial DNA in the extracellular space. Released mitochondrial DNA and eosinophil granule proteins form extracellular structures able to bind and inactivate bacteria. These findings suggest a novel mechanism of eosinophil-mediated innate immune responses that might be important in maintaining the intestinal barrier function. Moreover, eosinophils also play a crucial role in several inflammatory conditions, such as intestinal infections, immune-mediated inflammations and hypersensitivity reactions. Under chronic inflammatory conditions, the ability of the eosinophils to induce repair can lead to pathological sequelae in the tissue, such as esophageal remodeling in eosinophilic esophagitis. It is established that the uncontrolled eosinophilic inflammation induces fibrosis, esophageal wall thickening and strictures leading to damage that results in a loss of esophageal function. One potential mechanism of this remodeling is so-called 'epithelial mesenchymal transition', which is triggered by eosinophils and is potentially reversible under successful anti-eosinophil treatment. Therefore, eosinophils may act either as friends or as foes, depending on the microenvironment. PMID- 23082701 TI - Comparison of the antiviral effects of entecavir and adefovir dipivoxil in chronic HBV infection: a randomized control trial. AB - AIMS: The purpose of this study is to compare the antiviral efficacy of entecavir (ETV) and adefovir dipivoxil (ADV) at various time points during the treatment. METHODS: A randomized, controlled, open-label study was designed to analyze the kinetics of HBeAg seroconversion, HBV DNA level, and liver and renal functions in 72 ETV-treated chronic hepatitis B (CHB) patients and 66 ADV-treated CHB patients. The data was collected every 12 weeks up to 96 weeks after drug administration. RESULTS: The negative rate of HBeAg seroconversion was significantly increased at 24 weeks in ETV-treated patients, whereas in ADV treated patients, these changes were not significant. The serum HBV DNA levels were significantly decreased from 24 weeks in both ETV- and ADV-treated patients. Other than ETV showing significantly decreased levels of HBV DNA at 24 weeks when compared with ADV, there was no difference in virological response between two treatments at any other time points. The serum alanine aminotransferase (ALT) and total bilirubin (TBIL) levels were significantly decreased 12 weeks after either ETV- or ADV-treated patients without differences between two treatments. The urea nitrogen levels were in normal range and there was no difference between two groups. CONCLUSIONS: Our study suggested that both ETV and ADV could be used as monotherapy for nucleotide-naive patients, but ETV has displayed potential efficacy in HBeAg seroconversion. PMID- 23082702 TI - Hepatitis E seroprevalence in east and west Flanders, Belgium. AB - BACKGROUND AND STUDY AIM: Hepatitis E virus (HEV) infection is increasingly recognized as a cause of hepatitis in developed countries. The goal of this study is to provide an estimate of the seroprevalence of HEV in Belgium, more precisely in East and West Flanders, since data for this country are currently lacking. PATIENTS AND METHODS: One hundred patients presenting at the gynecological (mainly fertility center) or orthopedic clinics of our hospital were randomly selected to be tested for anti-HEV IgG antibodies using a sensitive indirect ELISA and, in the case of a borderline result, a strip immunoassay. RESULTS: The anti-HEV IgG seroprevalence was found to be 14%. CONCLUSIONS: The observed seroprevalence rate suggests that HEV infection is not an uncommon occurrence in Belgium. Comparisons with published seroprevalence data of other Western European countries should be made with caution due to differences in the analytical performance of anti-HEV IgG assays. PMID- 23082703 TI - Seroprevalence of celiac disease in Belgian children and adolescents. AB - BACKGROUND: Celiac Disease (CD) has a high prevalence worldwide. Because the disease may be underdiagnosed in Belgium, we wanted to evaluate the seroprevalence of CD in children and adolescents. PATIENTS AND METHODS: Serum samples from 1159 apparently healthy children and adolescents aged between 1-19 years, were prospectively collected in 2006 by 15 Belgian diagnostic laboratories. In September 2009, all samples were analyzed for human tissue transglutaminase IgA antibodies (IgA tTG) and total IgA levels by, respectively a commercial ELISA and immunonephelometry. Sera, found positive, were assessed by immunofluorescence for the presence of IgA and IgG antiendomysium antibodies (IgA/IgG EMA). In patients with IgA deficiency IgG antibodies against deamidated gliadin peptides (IgG DGP) and IgG antiendomysium antibodies (IgG EMA) were determined. RESULTS: Ten of the 1159 individuals (0.86%) tested positive for IgA tTG. A further 0.86% showed borderline IgA tTG results. In almost two percent (198%) of the analyzed samples total IgA levels below the lower limit of normal were observed. Four out of eight positive IgA tTG samples tested positive for IgA EMA. All samples with borderline IgA tTG results were negative for IgA EMA. Twenty-six percent (6/23) of the IgA deficient samples showed positive IgG DGP antibodies, but none of those tested positive for IgG EMA. CONCLUSION: The seroprevalence of IgA tTG in this non-IgA deficient population (n = 1136) in Belgium is 1:114. The combined seroprevalence of IgA tTG and IgA EMA in that same population is 1:284. The seroprevalence based on positive IgA tTG or DPG IgG in, respectively, non-IgA deficient and IgA deficient subjects is 1:72 (n = 1159). These seroprevalences are similar to those found in neighbouring countries. PMID- 23082704 TI - Effect of Linum usitatissimum (linseed/flaxseed) fixed oil on experimental esophagitis in albino rats. AB - INTRODUCTION: The present study was undertaken to elucidate the effect of Linum usitatissimum fixed oil on experimental esophagitis in albino rats. METHODS: Group of rats (n = 6), treated with vehicle control (0.9% NaCl, 3 mL/kg, i.p.) or L. usitatissimum fixed oil (1, 2, 3 mL/kg, i.p.) or omeprazole (30 mg/kg, i.p.). Rats were subjected to pylorus and forestomach ligation to induce esophagitis and were compared to a control sham group. Animals were sacrificed after 6 h and evaluated for the gastric pH, gastric volume, total acidity and esophagitis index. Esophageal tissues were further subjected to estimations of sialic acid, collagen, thiobarbituric acid reactive substances, tissue glutathione, catalase and superoxide dismutase. RESULTS: Treatment with fixed oil significantly inhibited the gastric secretion, total acidity and esophagitis index. The oil also altered the levels of sialic acid and collagen towards normal with significant antioxidant activity in esophageal tissues. CONCLUSION: The lipoxygenase inhibitory, histamine antagonistic, antisecretory (anticholinergic) and antioxidant activity of the oil was attributed for its effect in reflux esophagitis. PMID- 23082705 TI - Protective effect of ethyl pyruvate on liver injury in streptozotocin-induced diabetic rats. AB - BACKGROUND AND AIMS: Diabetes Mellitus, leading to an increase in oxidative stress, can cause liver damage. Our aim was to investigate the antioxidant effects of Ethyl Pyruvate (EP) on the liver tissue in diabetic rats. MATERIALS AND METHODS: Thirty-two Wistar albino rats were separated into four equal groups. Groups were assigned as follows: (1) Non-diabetic group; (2) EP-treated non diabetic group; (3) diabetic group; and (4) EP-treated diabetic group. In order to induce diabetes mellitus, 45 mg/kg b.w. streptozotocin was administered intraperitoneally to the rats in groups 3 and 4. On the 3rd day, blood glucose was assessed. Rats with blood glucose levels higher than 300 mg/dl were considered to be diabetic. The EP solution was administered intraperitoneally at a dose of 50 mg/kg b.w. twice daily for 14 days to the rats in groups 2 and 4. The other rats were simultaneously given the same amount of Ringer's lactate solution intraperitoneally. Liver tissue was obtained for malondialdehyde (MDA) analyses and histopathological examination. RESULTS: In group 4, Total Antioxidant Status (TOS) and MDA levels were significantly lower as compared to group 3. Also, morphological abnormalities occurred in group 3 when compared with non-diabetic groups (groups 1 and 2), whereas the disorders resulting from diabetes improved significantly in group 4. CONCLUSIONS: These findings show that EP has protective effects against diabetes-induced liver injury. PMID- 23082706 TI - A comparative study of two kinds of small bowel cleaning score system for capsule endoscopy. AB - AIM: The study is aim to compare two kinds of cleaning score system for capsule endoscopy, with a view of these two cleaning score system can help to evaluate small bowel cleanliness. METHODS: Three readers evaluated these two cleaning score system by assessing the inter-observer, intra-patient, and intraobserver agreement. RESULTS: The assessment of the reliability and concordance, inter observer agreement and intra-patient agreement of System1 and System2 was excellent with the intraclass correlation coefficient (ICC) values of 0.873, 0.821, 0.863 and 0.772. The data regarding the assessment on intra-observer agreement and intrapatient agreement of System1 and System2 were available and the results were also excellent with ICC values of 0.887, 0.846, 0.870 and 0.809. The overall adequacy assessment of System1 and System2, there was no significant difference among the three readers of inter-observer agreement (X2 = 0.051, P = 0.822, X2 = 0.085, P = 0.081, X2 = 0.048, P = 0.827) and intra- patient agreement (X2 = 0.196, P = 0.658, X2 = 0.208, P = 0.648, X2 = 0.054, P = 0.817), neither was intra-observer agreement (X2 = 0.208, P = 0.648, X2 = 0.223, P = 0.637, X2 = 0.484, P = 0.487) and intrapatient agreement (X2 = 0.054, P = 0.817, X2 = 0.054, P = 0.817, X2 = 0519, P = 0.471). CONCLUSION: The two system both are simple, operable, and can be used in clinical practice. PMID- 23082707 TI - Premedication with peppermint oil capsules in colonoscopy: a double blind placebo controlled randomized trial study. AB - BACKGROUND: Colonic spasm is an important problem in colonoscopy for endoscopists to advance the colonoscope and visualize the mucosa. STUDY AIMS: In the present study, we evaluated the efficacy of enteric-coated peppermint oil capsules (Colpermin) as an orally administered antispasmodic premedication in colonoscopy. PATIENTS AND METHODS: Sixty-five adult patients undergoing colonoscopy were randomized to receive either Colpermin (n = 33) or placebo capsules (n = 32) as premedication, 4 hours before the procedure. An experienced endoscopist performed colonoscopy. Outcome measures included cecal intubation and total procedure time, spasm score, pain score, endoscopist satisfaction and patients' willingness to repeat colonoscopy. RESULTS: Duration of both total procedure time and cecal intubation time in patients in the Colpermin group were shorter than that in ones in the placebo group. Scores for colonic spasm and pain were significantly lower in the Colpermin group. The endoscopist satisfaction score was higher in the Colpermin group and patients in the Colpermin group were more willing to repeat colonoscopy in the future. CONCLUSIONS: Premedication with Colpermin was beneficial in terms of the time required for cecal intubation and total procedure time, reducing colonic spasm, increasing endoscopist satisfaction and decreasing pain in patients during colonoscopy. PMID- 23082708 TI - Pericarditis with massive pericardial effusion: an unusual complication of primary biliary cirrhosis. AB - Primary Biliary Cirrhosis (PBC) is a debilitating autoimmune condition associated with a constellation of extrahepatic inflammatory manifestations accentuating its morbidity and mortality. Pericarditis and pericardial effusion had been rarely associated with and inadequately characterized in PBC. We present a challenging case of inflammatory pericarditis and life-threatening massive pericardial effusion in a 49 year old patient with PBC. This complication should be more recognized and appropriately treated to avoid progression to cardiac tamponade. PMID- 23082709 TI - Neuroendocrine tumor of the cystic duct. AB - Neuroendocrine tumours of the extrahepatic bile ducts are extremely rare with less than 70 cases having been reported in the literature. Neuroendocrine tumours are neoplasms of variable malignant potential that arise from the embryonic neural crest cells. They most commonly occur in young females and usually present with painless jaundice. Preoperative diagnosis is seldom made and neuroendocrine tumours are usually incidentally found during abdominal surgical intervention for other indication. Due to their indolent biological behaviour aggressive surgical treatment is recommended. We present a case of an incidentally discovered neuroendocrine tumour of the cystic duct in a 41 year old woman following laparoscopic cholecystectomy for symptomatic gallbladder microlithiasis. The present case is the 8th case of cystic duct NET and the 63rd of extrahepatic bile duct NET. While a rare location for a NET, it is important to report cases of biliary tract neuroendocrine tumours in order for their pathogenesis and physical history to be clarified. PMID- 23082711 TI - Acute intestinal anisakiasis: CT findings. AB - Small bowel anisakiasis is a relatively uncommon disease that results from consumption of raw or insufficiently pickled, salted, smoked, or cooked wild marine fish infected with Anisakis larvae. We report a case of intestinal anisakiasis in a 63-year-old woman presenting with acute onset of abdominal complaints one day after ingestion of raw wild-caught herring from the Northsea. Computed tomography (CT) scanning demonstrated thickening of the distal small bowel wall, mucosa with hyperenhancement, mural stratification, fluid accumulation within dilated small-bowel loops and hyperemia of mesenteric vessels. In patients with a recent history of eating raw marine fish presenting with acute onset of abdominal complaints and CT features of acute small bowel inflammation the possibility of anisakiasis should be considered in the differential diagnosis of acute abdominal syndromes. PMID- 23082710 TI - Concomitant herpetic and eosinophilic esophagitis--a causality dilemma. AB - Eosinophilic and herpetic esophagitis are listed as independent causes of dysphagia, especially in young adult males. However, herpetic esophagitis rarely affects immunocompetent individuals. We report the case of a young, not immunocompromised patient, admitted because of severe dysphagia secondary to herpes simplex virus esophagitis. After complete resolution, an endoscopic and histologic reevaluation established the diagnosis of eosinophilic esophagitis. The potential association between the two conditions is discussed. PMID- 23082712 TI - A catastrophic event caused by Pasteurella multocida in an alcoholic cirrhotic patient. PMID- 23082713 TI - Both biliopleural fistula and portal hypertension with giant hydatid cyst of the liver. PMID- 23082714 TI - Fatal fulminant hepatitis B after withdrawal of entecavir treatment in a patient with HBeAg seroconversion. PMID- 23082715 TI - Pancreatitis associated panniculitis. PMID- 23082716 TI - ERCP in patients with Jaboulay pyloroplasty. PMID- 23082717 TI - Freehand endoscopic lithotripsy for Bouveret's syndrome. PMID- 23082718 TI - Gastrointestinal stromal tumor in the duodenal blind spot: role of pediatric colonoscope and endoscopic ultrasound. PMID- 23082719 TI - An infrequent variant of Stauffer's syndrome. PMID- 23082720 TI - Laparoscopic lymph node biopsy in the diagnosis of lymphoma. Indications and results. AB - BACKGROUND: Exclusive abdominal nodal involvement due to Hodgkin or non Hodgkin lymphoma (HL,NHL) is a rare condition, but its occurrence requires a good enough specimen for diagnosis and therapy. Aim of this work is to evaluate the results of laparoscopic lymph node biopsy (LLNB) in a series of patients where a primitive or relapsing lymphoma was suspected. METHODS: This study has been carried on the patients submitted to LLNB from 2007 to 2011. Cases records were retrospectively reviewed for age, sex, diagnostic work up, previous biopsy, conversion to laparotomy, pathologic diagnosis and perioperative complications. RESULTS: Eleven cases were evaluated including 4 males and 7 females; mean age was 56.5 years. All patients underwent Ultrasound (US) and CT scan. A previous US or CT guided biopsy was performed in 5 cases, but in all of them failed to obtain a diagnosis. LLNB was successfully performed in 8 cases and required a conversion in three. Causes of conversion were obesity in one case and previous surgery in two. Results of pathology were NHL 5 cases, HL 2, follicular hyperplasia 2, sarcoidosis and tuberculosis 1 case respectively. No mortality nor morbidity occurred. Mean hospital stay was of 2.7 days. CONCLUSION: LLNB proved to be a safe procedure with no perioperative complications. Laparoscopy however should not be undertaken if superficial lymphadenopathy is present. A thorough CT evaluation of abdominal nodal involvement by the surgical team is mandatory prior to laparoscopy in order to plan the surgical approach and the route to reach the node. PMID- 23082722 TI - Ketone body utilization drives tumor growth and metastasis. AB - We have previously proposed that catabolic fibroblasts generate mitochondrial fuels (such as ketone bodies) to promote the anabolic growth of human cancer cells and their metastasic dissemination. We have termed this new paradigm "two compartment tumor metabolism." Here, we further tested this hypothesis by using a genetic approach. For this purpose, we generated hTERT-immortalized fibroblasts overexpressing the rate-limiting enzymes that promote ketone body production, namely BDH1 and HMGCS2. Similarly, we generated MDA-MB-231 human breast cancer cells overexpressing the key enzyme(s) that allow ketone body re-utilization, OXCT1/2 and ACAT1/2. Interestingly, our results directly show that ketogenic fibroblasts are catabolic and undergo autophagy, with a loss of caveolin-1 (Cav 1) protein expression. Moreover, ketogenic fibroblasts increase the mitochondrial mass and growth of adjacent breast cancer cells. However, most importantly, ketogenic fibroblasts also effectively promote tumor growth, without a significant increase in tumor angiogenesis. Finally, MDA-MB-231 cells overexpressing the enzyme(s) required for ketone re-utilization show dramatic increases in tumor growth and metastatic capacity. Our data provide the necessary genetic evidence that ketone body production and re-utilization drive tumor progression and metastasis. As such, ketone inhibitors should be designed as novel therapeutics to effectively treat advanced cancer patients, with tumor recurrence and metastatic disease. In summary, ketone bodies behave as onco metabolites, and we directly show that the enzymes HMGCS2, ACAT1/2 and OXCT1/2 are bona fide metabolic oncogenes. PMID- 23082721 TI - Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells. AB - We have previously suggested that ketone body metabolism is critical for tumor progression and metastasis. Here, using a co-culture system employing human breast cancer cells (MCF7) and hTERT-immortalized fibroblasts, we provide new evidence to directly support this hypothesis. More specifically, we show that the enzymes required for ketone body production are highly upregulated within cancer associated fibroblasts. This appears to be mechanistically controlled by the stromal expression of caveolin-1 (Cav-1) and/or serum starvation. In addition, treatment with ketone bodies (such as 3-hydroxy-butyrate, and/or butanediol) is sufficient to drive mitochondrial biogenesis in human breast cancer cells. This observation was also validated by unbiased proteomic analysis. Interestingly, an MCT1 inhibitor was sufficient to block the onset of mitochondrial biogenesis in human breast cancer cells, suggesting a possible avenue for anticancer therapy. Finally, using human breast cancer tumor samples, we directly confirmed that the enzymes associated with ketone body production (HMGCS2, HMGCL and BDH1) were preferentially expressed in the tumor stroma. Conversely, enzymes associated with ketone re-utilization (ACAT1) and mitochondrial biogenesis (HSP60) were selectively associated with the epithelial tumor cell compartment. Our current findings are consistent with the "two-compartment tumor metabolism" model. Furthermore, they suggest that we should target ketone body metabolism as a new area for drug discovery, for the prevention and treatment of human cancers. PMID- 23082724 TI - Two-step binding of O2 to a vanadium(III) trisanilide complex to form a non vanadyl vanadium(V) peroxo complex. AB - Treatment of V(N[(t)Bu]Ar)(3) (1) (Ar = 3,5-Me(2)C(6)H(3)) with O(2) was shown by stopped-flow kinetic studies to result in the rapid formation of (eta(1) O(2))V(N[(t)Bu]Ar)(3) (2) (DeltaH(?) = 3.3 +/- 0.2 kcal/mol and DeltaS(?) = -22 +/- 1 cal mol(-1) K(-1)), which subsequently isomerizes to (eta(2) O(2))V(N[(t)Bu]Ar)(3) (3) (DeltaH(?) = 10.3 +/- 0.9 kcal/mol and DeltaS(?) = -6 +/- 4 cal mol(-1) K(-1)). The enthalpy of binding of O(2) to form 3 is -75.0 +/- 2.0 kcal/mol, as measured by solution calorimetry. The reaction of 3 and 1 to form 2 equiv of O=V(N[(t)Bu]Ar)(3) (4) occurs by initial isomerization of 3 to 2. The results of computational studies of this rearrangement (DeltaH = 4.2 kcal/mol; DeltaH(?) = 16 kcal/mol) are in accord with experimental data (DeltaH = 4 +/- 3 kcal/mol; DeltaH(?) = 14 +/- 3 kcal/mol). With the aim of suppressing the formation of 4, the reaction of O(2) with 1 in the presence of (t)BuCN was studied. At -45 degrees C, the principal products of this reaction are 3 and (t)BuC(?O)N=V(N[(t)Bu]Ar)(3) (5), in which the bound nitrile has been oxidized. Crystal structures of 3 and 5 are reported. PMID- 23082723 TI - Identificaton of 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one isolated from Lactobacillus pentosus strain S-PT84 culture supernatants as a compound that stimulates autonomic nerve activities in rats. AB - Intestinal administration of various lactobacilli has been reported to affect autonomic neurotransmission, blood pressure, and body weight in rats. In this study, three molecules (peaks A, B, and C) were isolated from Lactobacillus pentosus strain S-PT84 (S-PT 84) culture supernatants. Intraduodenal (ID) injection of these molecules increased or inhibited renal sympathetic nerve activity (RSNA) in rats as follows: peak A, 134%; peak B, 40.1%; peak C, 408%. Furthermore, we identified peak C as 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran 4-one (DDMP). ID injection of DDMP increased brown adipose tissue sympathetic nerve activity (BAT-SNA; 118 +/- 15.3%), whereas intraoral injection of DDMP increased the body temperature above the interscapular brown adipose tissue (BAT T; 0.72 +/- 0.13 degrees C) in rats. These data suggest that S-PT84 produces molecules that modulate autonomic nerve activity. In addition, DDMP increased BAT SNA and BAT-T, and these changes in BAT-T may be caused by changes in BAT-SNA. PMID- 23082725 TI - Venous malformations: Clinical course and management of vascular birthmark clinic cases. AB - BACKGROUND/OBJECTIVES: Venous malformations (VM) are an uncommon vascular malformation with an estimated incidence of 1-2 per 10 000 births. The aim was to define the clinical characteristics and management of children with VM and develop a database for future research. METHODS: A retrospective chart review of all children presenting to the Vascular Birth Mark clinic with VM from 2000 to 2011. RESULTS: In total 128 patients were included, of whom 59.4% were female, 78.1% were Caucasian and 56.3% resided in a metropolitan area. Most lesions were noted at birth (64.1%) with an average age when VM was first noticed of 17.1 months. The average age of definitive diagnosis was 65.9 months. Locations most frequently involved were the lower limb (41.4%), face (21.1%), trunk (17.2%) and upper limb (15.6%). The most commonly associated conditions were capillary malformation (28.9%) and lymphatic malformation (28.1%). Magnetic resonance imaging was used in the majority of patients (86.7%) to assess tissue distribution of the lesions. Skin and subcutaneous tissue (61.3%), muscle (49.5%) and joints (11.7%) were most commonly involved. Complications of VM resulted in morbidity in 68.8% of cases, most commonly pain (52.3%), thrombophlebitis (17.2%), bleeding (13.3%) and limb length discrepancy (13.3%). Intervention was employed in 68.0%, most often with sclerotherapy (61.8%), compression garments (43.0%), and endovascular laser (17.2%) and surgical management (13.3%). CONCLUSIONS: Given the frequent association of VM with other vascular lesions, considerable morbidity, and specialised treatment, a multidisciplinary approach to their management in childhood is important and should include dermatology, diagnostic and interventional radiology, haematology, paediatric surgery, physiotherapy and social services. PMID- 23082726 TI - Synthesis, photophysical and electrochemistry of near-IR absorbing bacteriochlorins related to bacteriochlorophyll a. AB - A series of new bacteriochlorins was synthesized using 13(2)-oxo bacteriopyropheophorbide a (derived from bacteriochlorophyll a) as a starting material, which on reacting with o-phenylenediamine and 1,10-diaminonaphthalene afforded highly conjugated annulated bacteriochlorins with fused quinoxaline, benzimidazole, and perimidine rings, respectively. The absorption spectra of these novel bacteriochlorins demonstrated remarkably red-shifted intense Q(y) absorption bands observed in the range of 816-850 nm with high molar extinction coefficients (89,900-136,800). Treatment of 13(2)-oxo-bacteriopyropheophorbide a methyl ester with diazomethane resulted in the formation of bacterioverdins containing a fused six-membered methoxy-substituted cyclohexenone (verdin) as an isomeric mixture. The pure isomers which exhibit long-wavelength absorptions in the near-IR region (865-890 nm) are highly stable at room temperature with high reactivity with O(2) at the triplet photoexcited state and favorable redox potential and could be potential candidates for use as photosensitizers in photodynamic therapy (PDT). PMID- 23082727 TI - Dextran vesicular carriers for dual encapsulation of hydrophilic and hydrophobic molecules and delivery into cells. AB - Dextran vesicular nanoscaffolds were developed based on polysaccharide and renewable resource alkyl tail for dual encapsulation of hydrophilic and hydrophobic molecules (or drugs) and delivery into cells. The roles of the hydrophobic segments on the molecular self-organization of dextran backbone into vesicles or nanoparticles were investigated in detail. Dextran vesicles were found to be a unique dual carrier in which water-soluble molecules (like Rhodamine-B, Rh-B) and polyaromatic anticancer drug (camptothecin, CPT) were selectively encapsulated in the hydrophilic core and hydrophobic layer, respectively. The dextran vesicles were capable of protecting the plasma sensitive CPT lactone pharmacophore against the hydrolysis by 10* better than the CPT alone in PBS. The aliphatic ester linkage connecting the hydrophobic tail with dextran was found to be cleaved by esterase under physiological conditions for fast releasing of CPT or Rh-B. Cytotoxicity of the dextran vesicle and its drug conjugate were tested on mouse embryonic fibroblast cells (MEFs) using MTT assay. The dextran vesicular scaffold was found to be nontoxic to living cells. CPT loaded vesicles were found to be 2.5-fold more effective in killing fibroblasts compared to that of CPT alone in PBS. Confocal microscopic images confirmed that both Rh-B and CPT loaded vesicles to be taken up by fibroblasts compared to CPT alone, showing a distinctly perinuclear localization in cells. The custom designed dextran vesicular provides new research opportunities for dual loading and delivering of hydrophilic and hydrophobic drug molecules. PMID- 23082728 TI - Temporal changes in geographical disparities in alcohol-attributed disease mortality before and after implementation of the alcohol tax policy in Taiwan. AB - BACKGROUND: Taxation of alcohol-containing products may effectively reduce alcohol consumption. However, whether alcohol taxation may lead to a decrease in alcohol-attributed disease mortality (ADM) remains unclear. The objective of this study was to assess the effect of alcohol tax policy in 2002 in Taiwan on temporal changes in geographical disparities in ADM before and after implementation of the policy. METHODS: Local spatial statistical methods were used to explore the geographic variations in ADM rates and identify statistically significant clusters among townships. RESULTS: Our results indicate that the areas with the highest rates of ADM (127-235 deaths per 100,000 people) were located in mountainous regions, and the areas with the lowest rates of ADM (less than 26 deaths per 100,000 people) were clustered in the most populated areas. The areas where the rates of ADM significantly declined after alcohol taxation was initiated were clustered in the central, southwest and northeast parts of the country. CONCLUSIONS: This study provides evidence of a township-level relationship between the reduction of ADM and alcohol taxation in Taiwan. PMID- 23082729 TI - More than child's play: the potential benefits of play-based interventions for young children with ADHD. PMID- 23082730 TI - Glutamate hypothesis of depression and its consequences for antidepressant treatments. PMID- 23082731 TI - Should dendritic cell-based tumor vaccination be incorporated into standard therapy for newly diagnosed glioblastoma patients? PMID- 23082733 TI - Electric fields for the treatment of glioblastoma. AB - Glioblastoma (GBM) is the most common primary malignant cerebral tumor in adults, with a poor prognosis despite several therapeutic efforts. Electric fields (EFs) have shown promising results as a new anticancer treatment. Stupp et al. report on the first Phase III trial comparing EF versus chemotherapy in patients with recurrent GBM. The study was designed for superiority; although well conducted, it might not have shown it for a limited compliance in the EF group. Even with this limitation, the trial has shown at least equivalence of EF to chemotherapy, with a decreased toxicity and increased quality of life favoring EF. Further basic and clinical studies are warranted to increase knowledge, efficacy, compliance and cost-effectiveness. This trial has opened a new promising field in GBM treatment. PMID- 23082734 TI - Early switch strategy in patients with major depressive disorder. AB - Major depressive disorder is a highly prevalent and chronic mental disorder. There have been a number of antidepressants with different class employing different pharmacological profiles for treatment of major depressive disorder; however, currently available placebo-controlled or large practical clinical trials demonstrated that the efficacy of antidepressants is quite limited to yield full recovery for such patients. Approximately 30% of major depressive disorder patients remit with initial antidepressant treatment, whereas a chance of recurrence significantly increases with subsequent treatment failures. Hence, most treatment guidelines propose various treatment approaches such as augmentation, combination and switching strategies for such patients with initial treatment failure. Among these treatment approaches, switching strategies are widely used in clinical practice. However, controlled clinical trials of the proper timing of antidepressant switch have not been adequately evaluated yet. The authors of the article under evaluation have investigated whether an early switch strategy should result in shorter times to response and remission in patients with initial treatment failure. They found that a higher remission rate was seen with the early switch strategy than conventional switch strategies. This article will discuss the clinical significance, related practical issues, potential limitations and future research implications based on findings from the original study. PMID- 23082735 TI - Chemotherapy: What is its role in meningioma? AB - While strong evidence exists for the standard therapy for meningiomas, inclusive of surgery and/or radiation therapy, for those tumors which recur, progress or are inoperable, the optimal medical therapies are yet to be elucidated. This article reviews the current literature for chemotherapeutic options for this subset of tumors, including cytotoxic agents, biologic agents, targeted molecular agents and hormonal agents. At this point in time, the most data is with hydroxyurea and somatostatin, although further trials with combination and targeted molecular therapies are still underway. PMID- 23082736 TI - Primary CNS lymphoma: a clinician's guide. AB - Primary CNS lymphoma is a high malignant disease of the brain which can lead rapidly to death if diagnosis and/or the start of treatment is delayed. The age at time of diagnosis is a strong factor influencing prognosis so that in younger patients <65 years of age long-term survival may be achieved in a substantial percentage of patients, while in elderly patients long-term survival is seen much more rarely. First-line therapy consists of high-dose methotrexate-based (poly)chemotherapy. This review provides an overview of clinical presentation, steps to diagnosis, detailed information about current treatment concepts and specific information for particular clinical situations. PMID- 23082738 TI - Psychotherapy in adult attention deficit hyperactivity disorder: implications for treatment and research. AB - Attention deficit hyperactivity disorder (ADHD) is a risk factor for co-occurring psychiatric disorders and negative psychosocial consequences in adulthood. Previous trials of psychotherapeutic programs for adult ADHD were based on cognitive behavioral psychotherapeutic approaches and showed significant effects. Targets of psychotherapeutic interventions include not only coping with the core symptoms and associated problems such as depression and anxiety, but also probable consequences such as low self-esteem. Improvements in ADHD symptomatology and associated symptoms have been reported after psychotherapeutic treatment. The support of other participants is strongly regarded as helpful by patients in group therapy. This manuscript provides an overview of psychotherapy approaches and results of studies evaluating programs developed to treat adults with ADHD. Finally, the specific requirements of psychotherapy for adult ADHD as well as further research questions will be discussed. PMID- 23082737 TI - Melanoma brain metastasis: overview of current management and emerging targeted therapies. AB - The high rate of brain metastasis in patients with advanced melanoma has been a clinical challenge for oncologists. Despite considerable progress made in the management of advanced melanoma over the past two decades, improvement in overall survival has been elusive. This is due to the high incidence of CNS metastases, which progress relentlessly and which are only anecdotally responsive to systemic therapies. Surgery, stereotactic radiosurgery and whole-brain radiotherapy with or without cytotoxic chemotherapy remain the mainstay of treatment. However, new drugs have been developed based on our improved understanding of the molecular signaling mechanisms responsible for host immune tolerance and for melanoma growth. In 2011, the US FDA approved two agents, one antagonizing each of these processes, for the treatment of advanced melanoma. The first is ipilimumab, an anti-CTLA-4 monoclonal antibody that enhances cellular immunity and reduces tolerance to tumor-associated antigens. The second is vemurafenib, an inhibitor that blocks the abnormal signaling for melanoma cellular growth in tumors that carry the BRAF(V600E) mutation. Both drugs have anecdotal clinical activity for brain metastasis and are being evaluated in clinical trial settings. Additional clinical trials of newer agents involving these pathways are also showing promise. Therefore, targeted therapies must be incorporated into the multimodality management of melanoma brain metastasis. PMID- 23082739 TI - Iron and attention deficit/hyperactivity disorder: What is the empirical evidence so far? A systematic review of the literature. AB - The authors systematically reviewed evidence on iron status, as well as studies of iron supplementation, in individuals with attention deficit/hyperactivity disorder (ADHD). PubMed, Ovid, EMBASE and Web of Knowledge were searched on 4 July 2012. Quantitative appraisal of trials was performed using Jadad's score. Most (n = 20) of the retrieved studies assessed an index of peripheral iron status (i.e., serum ferritin), with overall mixed results - that is, both significant and nonsignificant association between ADHD symptoms and serum ferritin levels. One MRI study reported significantly lower indices of thalamic iron in ADHD versus comparison subjects. Two trials, an open-label and a pilot randomized placebo-controlled study with high Jaded score (4), showed improvement in some but not all measures of ADHD symptoms. Three studies showed that children with ADHD plus sleep disorders, in particular restless legs syndrome, are at risk of iron deficiency. Finally, two studies suggested that iron deficiency might decrease the effectiveness of psychostimulant treatment. The authors discussed how the field could move from initial research mainly focused on serum ferritin towards a more comprehensive and translational investigation of iron in ADHD, with the potential to inform clinical practice in terms of screening and treating iron deficiency in individuals with ADHD. PMID- 23082740 TI - Emotional dysregulation in adult ADHD: What is the empirical evidence? AB - Attention deficit/hyperactivity disorder (ADHD) is a common psychiatric disorder characterized by symptoms of inattention, hyperactivity and impulsivity. There is an ongoing discussion whether symptoms of emotional dysregulation should be added to the conceptualization of ADHD in order to describe the psychopathology of ADHD more precisely, at least in adult patients. Symptoms of emotional dysregulation are well defined and seem to be distinct factors of the psychopathology of adult ADHD. Assessment of this psychopathological dimension has shown sufficient reliability and validity. Empirical studies have confirmed a high prevalence of this psychopathological feature in adults with ADHD that compares to the frequency of the ADHD core symptoms, inattention, hyperactivity and impulsivity. Evidence is given that emotional dysregulation has an independent effect on social problems associated with ADHD in adult life. Moreover, pharmacological and psychotherapeutic interventions help to ameliorate emotional dysregulation together with symptoms of inattention and hyperactivity/impulsivity. Thus, there is growing evidence that emotional dysregulation might be recognized as a core feature of ADHD. PMID- 23082743 TI - Short DNA sequences and bacterial DNA induce esophageal, gastric, and colorectal cancer cell invasion. AB - Toll-like receptor 9 (TLR9) recognizes both bacterial and self-DNA and it is abundantly expressed in the gastrointestinal tract. In this study, we investigated the influences of both bacterial DNA and specific short DNA sequences on TLR9-mediated gastrointestinal cancer cell invasion. We assessed the effect of various DNA ligands on cellular invasion and on TLR9 and matrix metalloproteinase expression of three gastrointestinal cancer cell lines. DNA ligands described in this study include CpG-ODN M362, 9-mer (hairpin), human telomeric sequence h-Tel22 G-quadruplex, and bacterial DNAs from Escherichia coli and Helicobacter pylori. All of the DNAs studied were demonstrated to induce invasion in the studied cells. The DNA-induced invasion was inhibited with a broad-spectrum MMP inhibitor and partly also with chloroquine suggesting that it could be mediated via MMP activation, endosomal signaling, and TLR9. Interestingly, H. pylori DNA was shown to induce a more pronounced invasion in a gastric cancer cell line than in the other cell lines. Our results suggest that bacterial DNA as well as deoxynucleotides having stable secondary structures (i.e. hairpins or G-quadruplex structures) may serve as endogenous, invasion inducing TLR9-ligands and promote local progression and metastasis of cancers in the alimentary tract. PMID- 23082741 TI - Prevention of serious conduct problems in youth with attention deficit/hyperactivity disorder. AB - The purpose of this review is to discuss issues in the prevention of serious conduct problems among children and adolescents with attention deficit/hyperactivity disorder (ADHD). The authors began by reviewing research on the common genetic and environmental etiological factors, developmental trajectories, characteristics and impairments associated with ADHD and comorbid oppositional defiant and conduct disorders. Next, the authors presented empirically based models for intervention with children and adolescents with ADHD that are at risk of developing serious conduct problems and detailed the evidence supporting these models. Researchers have demonstrated the utility of medication and psychosocial intervention approaches to treat youth with these problems, but current evidence appears to support the superiority of multimodal treatments that include both approaches. Future directions for researchers are discussed. PMID- 23082744 TI - Method for estimating the tip geometry of scanning ion conductance microscope pipets. AB - Scanning ion conductance microscopy (SICM) offers the ability to perform contact free, high-resolution imaging of biological cells and tissues at physiological conditions. However, imaging resolution is highly dependent on the geometry of the SICM probe, which is generally not known. Small, high-resolution probes are too fine to image optically and, to date, geometry estimation has usually required electron microscopy (EM). This is time-consuming and prone to failure and cannot provide information about the crucial internal geometry of the probe. Here we demonstrate a new method for determining SICM tip geometry that overcomes the limitations of EM imaging. The method involves fitting an analytical model to current changes during quasi-controlled breakage of the pipet tip. The data can be routinely obtained using the SICM apparatus itself and our method thus opens the way for substantially better quantification in SICM imaging and measurement. PMID- 23082745 TI - Toward understanding life under subzero conditions: the significance of exploring psychrophilic "cold-shock" proteins. AB - Understanding the behavior of proteins under freezing conditions is vital for detecting and locating extraterrestrial life in cold environments, such as those found on Mars and the icy moons of Jupiter and Saturn. This review highlights the importance of studying psychrophilic "cold-shock" proteins, a topic that has yet to be explored. A strategy for analyzing the psychrophilic RNA helicase protein CsdA (Psyc_1082) from Psychrobacter arcticus 273-4 as a key protein for life under freezing temperatures is proposed. The experimental model presented here was developed based on previous data from investigations of Escherichia coli, P. arcticus 273-4, and RNA helicases. P. arcticus 273-4 is considered a model for life in freezing environments. It is capable of growing in temperatures as cold as -10 degrees C by using physiological strategies to survive not only in freezing temperatures but also under low-water-activity and limited-nutrient availability conditions. The analyses of its genome, transcriptome, and proteome revealed specific adaptations that allow it to inhabit freezing environments by adopting a slow metabolic strategy rather than a cellular dormancy state. During growth at subzero temperatures, P. arcticus 273-4 genes related to energy metabolism and carbon substrate incorporation are downregulated, and genes for maintenance of membranes, cell walls, and nucleic acid motion are upregulated. At -6 degrees C, P. arcticus 273-4 does not upregulate the expression of either RNA or protein chaperones; however, it upregulates the expression of its cold-shock induced DEAD-box RNA helicase protein A (CsdA - Psyc_1082). CsdA - Psyc_1082 was investigated as a key helper protein for sustaining life in subzero conditions. Proving CsdA - Psyc_1082 to be functional as a key protein for life under freezing temperatures may extend the known minimum growth temperature of a mesophilic cell and provide key information about the mechanisms that underlie cold-induced biological systems in icy worlds. PMID- 23082746 TI - Observing the mouse thyroid sphingomyelin under space conditions: a case study from the MDS mission in comparison with hypergravity conditions. AB - This is a case report of apparent thyroid structural and functional alteration in a single mouse subjected to low Earth orbit spaceflight for 91 days. Histological examination of the thyroid gland revealed an increase in the average follicle size compared to that of three control animals and three animals exposed to hypergravity (2g) conditions. Immunoblotting analysis detected an increase in two thyroid gland enzymes, sphingomyelinase and sphingomyelin-synthase1. In addition, sphingomyelinase, an enzyme confined to the cell nucleus in the control animals, was found in the mouse exposed to hypogravity to be homogeneously distributed throughout the cell bodies. It represents the first animal observation of the influence of weightlessness on sphingomyelin metabolism. PMID- 23082747 TI - Hydroxyl radical oxidation of cylindrospermopsin (cyanobacterial toxin) and its role in the photochemical transformation. AB - Cylindrospermopsin (CYN), an alkaloid guanidinium sulfated toxin, is produced by a number of cyanobacteria regularly found in lakes, rivers, and reservoirs. Steady-state and time-resolved radiolysis methods were used to determine reaction pathways and kinetic parameters for the reactions of hydroxyl radical with CYN. The absolute bimolecular reaction rate constant for the reaction of hydroxyl radical with CYN is (5.08 +/- 0.16) * 10(9) M(-1) s(-1). Comparison of the overall reaction rate of CYN with hydroxyl radical with the individual reaction rate for addition to the uracil ring in CYN indicate the majority of the hydroxyl radicals (84%) react at the uracil functionality of CYN. Product analyses using liquid chromatography-mass spectrometry indicate the major products from the reaction of hydroxyl radical with CYN involve attack of hydroxyl radical at the uracil ring and hydrogen abstraction from the hydroxy-methine bridge linking the uracil ring to the tricyclic guanidine functionality. The role of hydroxyl radical initiated pathways in the natural organic matter (NOM) photosensitized transformation of CYN were evaluated. Scavenger and trapping experiments indicate that hydroxyl radical mediated transformations account for approximately ~70% of CYN destruction in surface waters under solar irradiation in the presence of NOM. The absence of solvent isotope effect indicates singlet oxygen does not play a significant role in the NOM sensitized transformation of CYN. The primary degradation pathways for HO* mediated and NOM photosensitized destruction of CYN involve destruction of the uracil ring. The fundamental kinetic parameters determined from these studies are critical for the accurate evaluation of hydroxyl-radical based technologies for the remediation of this problematic cyanotoxin in drinking water and important in the assessment of the environmental oxidative transformation of uracil based compounds. PMID- 23082749 TI - Understanding processing speed--its subcomponents and their relationship to characteristics of people with schizophrenia. AB - INTRODUCTION: Processing speed has been advanced as one of the core cognitive deficits of schizophrenia. Several methods were developed to assess this domain; however, most tasks, despite indexing several cognitive and motor components, tend to characterise processing speed as a unitary construct. This study explores potential subcomponents of processing speed in schizophrenia and their relationship with demographic, clinical, and neuropsychological characteristics. METHODS: One hundred and sixty participants with a diagnosis of schizophrenia were assessed on neuropsychological tasks measuring processing speed, executive function, and memory. Demographics and clinical characteristics were also recorded. Three independent measures were extracted to account for subcomponents of processing speed: behavioural execution, response processing, and accuracy. RESULTS: The identified components of processing speed were differently predicted by demographic characteristics, clinical characteristics, and overall intelligence estimates. Age and symptom severity were important predictors for behavioural execution; intelligence and social withdrawal predicted response processing; and accuracy was predicted by illness duration. Correlations showed executive function and memory to be associated with response processing and accuracy but not with behavioural execution. CONCLUSIONS: Distinct characteristics of schizophrenia seem to predict processing speed subcomponents. Distinguishing between behavioural, processing, and accuracy may be a useful way forward to refine our understanding of processing speed impairment in schizophrenia. PMID- 23082748 TI - Molecular detection of a novel paramyxovirus in fruit bats from Indonesia. AB - BACKGROUND: Fruit bats are known to harbor zoonotic paramyxoviruses including Nipah, Hendra, and Menangle viruses. The aim of this study was to detect the presence of paramyxovirus RNA in fruit bats from Indonesia. METHODS: RNA samples were obtained from the spleens of 110 fruit bats collected from four locations in Indonesia. All samples were screened by semi-nested broad spectrum reverse transcription PCR targeting the paramyxovirus polymerase (L) genes. RESULTS: Semi nested reverse transcription PCR detected five previously unidentified paramyxoviruses from six fruit bats. Phylogenetic analysis showed that these virus sequences were related to henipavirus or rubulavirus. CONCLUSIONS: This study indicates the presence of novel paramyxoviruses among fruit bat populations in Indonesia. PMID- 23082750 TI - Potential sources of interference on Abeta immunoassays in biological samples. AB - Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers is particularly meaningful in the context of selecting the patient population where the therapeutic treatment is believed to be efficacious (patient enrichment). Currently available 'research-use-only' assays for Alzheimer's disease diagnosis all suffer from non-analyte and analyte-specific interferences. The impact of these interferences on the outcome of the assays is not well understood. The confounding factors are hampering correct value determination in biological samples and are intrinsic to the assay concept, the assay design, the presence in the sample of heterophilic antibodies and auto-antibodies, or might be the result of the therapeutic approach. This review focuses on the importance of assay interferences and considers how these might be minimized with the final aim of making the assays more acceptable as in vitro diagnostic biomarker tests for theranostic use. PMID- 23082752 TI - Investigation into immunological responses against a native recombinant CTB whole cell Vibrio cholerae vaccine in a rabbit model. AB - AIM: The aim of this study was to express and purify the recombinant CTB (rCTB) protein from Vibrio cholerae and investigate the biological and immunological characteristics of purified protein in rabbit animal model and in combination with Iranian inactivated V. cholerae whole cells as a domestic recombinant WC-CTB vaccine. METHODS AND RESULTS: Expressed 6XHis-tagged rCTB was properly purified, and its identity was confirmed by Western blotting using cholera toxin-specific antibody. Concentration of purified protein was assessed to be 700 mg l(-1) . GM(1) -ELISA assay showed that purified rCTB pentamer was functionally active and able to bind GM(1) in a dose-dependent manner. Recombinant CTB was inoculated into rabbits through intestinal rout alone and in combination with inactivated whole-cell V. cholerae strains (WC). The anti-CTB IgG titre showed that serum IgG responses were significantly increased in groups immunized with rCTB mixed with inactivated WC in comparison with control group. Furthermore, rCTB without V. cholerae WC also stimulated the IgG responses when inoculated into rabbit intestine. Challenge experiments of immunized rabbits showed an adequate protection against V. cholerae strains. CONCLUSIONS: Recombinant CTB alone and in combination with inactivated Iranian strains was protective against live toxigenic V. cholerae strains, made it a potential candidate for an indigenous vaccine. SIGNIFICANCE AND IMPACT OF THE STUDY: It was proved that rCTB produced in this system can be used as a potent immunogenic protein to stimulate the immunity against V. cholerae strains and can be used for developing a native vaccine composed of our local strains with their own surface structures and antigenic determinants against cholera. PMID- 23082753 TI - Suicide attempts and suicide among Marines: a decade of follow-up. AB - Suicidal behavior among military personnel is of paramount public health importance because of the increased risk of death from suicide in this population. Pre- and post-Marine recruit training risk factors for suicide attempts among current and former Marines were examined in 10 years following recruit training. The characteristics of the subsample of current and former Marines who died by suicide during this time are also described. Stressful and traumatic life events (e.g., childhood physical, sexual, and emotional abuse, sexual harassment during recruit training) and pre-recruit training suicide attempts emerged as having strong associations with post-recruit training attempts. Half of those who died by suicide in the 10 years following recruit training endorsed at least one significant life stressor prior to joining the Marines. This study highlights the importance of screening for stressful and potentially traumatic experiences occurring both before and during military service as part of a comprehensive suicide risk assessment in military samples. PMID- 23082751 TI - Involvement of bacterial TonB-dependent signaling in the generation of an oligogalacturonide damage-associated molecular pattern from plant cell walls exposed to Xanthomonas campestris pv. campestris pectate lyases. AB - BACKGROUND: Efficient perception of attacking pathogens is essential for plants. Plant defense is evoked by molecules termed elicitors. Endogenous elicitors or damage-associated molecular patterns (DAMPs) originate from plant materials upon injury or pathogen activity. While there are comparably well-characterized examples for DAMPs, often oligogalacturonides (OGAs), generated by the activity of fungal pathogens, endogenous elicitors evoked by bacterial pathogens have been rarely described. In particular, the signal perception and transduction processes involved in DAMP generation are poorly characterized. RESULTS: A mutant strain of the phytopathogenic bacterium Xanthomonas campestris pv. campestris deficient in exbD2, which encodes a component of its unusual elaborate TonB system, had impaired pectate lyase activity and caused no visible symptoms for defense on the non-host plant pepper (Capsicum annuum). A co-incubation of X. campestris pv. campestris with isolated cell wall material from C. annuum led to the release of compounds which induced an oxidative burst in cell suspension cultures of the non host plant. Lipopolysaccharides and proteins were ruled out as elicitors by polymyxin B and heat treatment, respectively. After hydrolysis with trifluoroacetic acid and subsequent HPAE chromatography, the elicitor preparation contained galacturonic acid, the monosaccharide constituent of pectate. OGAs were isolated from this crude elicitor preparation by HPAEC and tested for their biological activity. While small OGAs were unable to induce an oxidative burst, the elicitor activity in cell suspension cultures of the non-host plants tobacco and pepper increased with the degree of polymerization (DP). Maximal elicitor activity was observed for DPs exceeding 8. In contrast to the X. campestris pv. campestris wild type B100, the exbD2 mutant was unable to generate elicitor activity from plant cell wall material or from pectin. CONCLUSIONS: To our knowledge, this is the second report on a DAMP generated by bacterial features. The generation of the OGA elicitor is embedded in a complex exchange of signals within the framework of the plant-microbe interaction of C. annuum and X. campestris pv. campestris. The bacterial TonB-system is essential for the substrate-induced generation of extracellular pectate lyase activity. This is the first demonstration that a TonB-system is involved in bacterial trans-envelope signaling in the context of a pathogenic interaction with a plant. PMID- 23082754 TI - Inhibitory control and adaptive behaviour in children with mild intellectual disability. AB - BACKGROUND: Inhibitory control, as one of the basic mechanisms of executive functions, is extremely important for adaptive behaviour. The relation between inhibitory control and adaptive behaviour is the most obvious in cases of behavioural disorders and psychopathology. Considering the lack of studies on this relation in children with disabilities, the aim of our research is to determine the relation between inhibitory control and adaptive behaviour in children with mild intellectual disability. METHOD: The sample consists of 53 children with mild intellectual disability. Selection criteria were: IQ between 50 and 70, age between 10 and 14, absence of bilingualism, and with no medical history of neurological impairment, genetic and/or emotional problems. Modified Day-Night version of the Stroop task, and Go-no-Go Tapping task were used for the assessment of inhibitory control. Data on adaptive behaviour were obtained by applying the first part of AAMR (American Association on Mental Retardation) Adaptive Behaviour Scale-School, Second Edition (ABS-S:2). RESULTS: Significant relationships were determined between some aspects of inhibitory control and the most of assessed domains of adaptive behaviour. Inhibitory control measures, as a unitary inhibition model, significantly predict results on Independent Functioning, Economic Activity, Speech and Language Development, and Number and Times domains of the ABS-S:2. Inhibitory control, assessed by second part of the Stroop task, proved to be a significant factor in practical (Independent Functioning) and conceptual (Economic Activity, Speech and Language Development, and Numbers and Time) adaptive skills. The first part of the Stroop task, as a measure of selective attention, proved to be a significant factor in language and numerical demands, along with second one. Inhibitory control through motor responses proved to be a significant factor in independent functioning, economic activities, language and self-direction skills. CONCLUSION: We can conclude that inhibitory control represents a significant developmental factor of different adaptive behaviour domains in children with mild intellectual disability. PMID- 23082755 TI - What is your diagnosis? Fecal smear from a Mallard duck (Anas platyrhynchos). PMID- 23082756 TI - The cast imaging of the osteon lacunar-canalicular system and the implications with functional models of intracanalicular flow. AB - A casting technique with methyl-methacrylate (MMA) was applied to the study of the osteon lacunar-canalicular network of human and rabbit cortical bone. The MMA monomer infiltration inside the vascular canals and from these into the lacunar canalicular system was driven by capillarity, helped by evaporation and the resulting negative pressure in a system of small pipes. There was uniform, centrifugal penetration of the resin inside some osteons, but this was limited to a depth of four to five layers of lacunae. Moreover, not all of the osteon population was infiltrated. This failure can be the result of one of two factors: the incomplete removal of organic debris from the canal and canalicular systems, and lack of drainage at the osteon external border. These data suggest that each secondary osteon is a closed system with a peripheral barrier (represented by the reversal line). As the resin advances into the osteon, the air contained inside the canalicula is compressed and its pressure increases until infiltration is stopped. The casts gave a reliable visualization of the lacunar shape, position and connections between the lacunae without the need for manipulations such as cutting or sawing. Two systems of canalicula could be distinguished, the equatorial, which connected the lacunae (therefore the osteocytes) lying on the same concentric level, and the radial, which established connections between different levels. The equatorial canalicula radiated from the lacunar border forming ramifications on a planar surface around the lacuna, whereas the radial canalicula had a predominantly straight direction perpendicular to the equatorial plane. The mean length of the radial canalicula was 40.12 +/- 10.26 MUm in rabbits and 38.4 +/- 7.35 MUm in human osteons; their mean diameter was 174.4 +/- 71.12 nm and 195.7 +/- 79.58 nm, respectively. The mean equatorial canalicula diameter was 237 +/- 66.04 nm in rabbit and 249.7 +/- 73.78 nm in human bones, both significantly larger (P < 0.001) than the radial. There were no significant differences between the two species. The lacunar surface measured on the equatorial plane was higher in rabbit than in man, but the difference was not statistically significant. The cast of the lacunar-canalicular network obtained with the reported technique allows a direct, 3-D representation of the system architecture and illustrates how the connections between osteocytes are organized. The comparison with models derived by the assumption of the role of hydraulic conductance and other mechanistic functions provides descriptive, morphological data to the ongoing discussion on the Haversian system biology. PMID- 23082757 TI - Medial canthal area reconstruction with horizontal advancement flap. AB - The medial canthal area is a common site for the development of skin cancer, the reconstruction of this area can be challenging for the dermatologic surgeon. The author describes the reconstruction of a defect measured about 1.5 * 1.5 cm, localized on the inner canthal area of the left eye with a horizontal advancement flap. PMID- 23082758 TI - Structural basis of peptide recognition by the angiotensin-1 converting enzyme homologue AnCE from Drosophila melanogaster. AB - Human somatic angiotensin-1 converting enzyme (ACE) is a zinc-dependent exopeptidase, that catalyses the conversion of the decapeptide angiotensin I to the octapeptide angiotensin II, by removing a C-terminal dipeptide. It is the principal component of the renin-angiotensin-aldosterone system that regulates blood pressure. Hence it is an important therapeutic target for the treatment of hypertension and cardiovascular disorders. Here, we report the structures of an ACE homologue from Drosophila melanogaster (AnCE; a proven structural model for the more complex human ACE) co-crystallized with mammalian peptide substrates (bradykinin, Thr(6) -bradykinin, angiotensin I and a snake venom peptide inhibitor, bradykinin-potentiating peptide-b). The structures determined at 2-A resolution illustrate that both angiotensin II (the cleaved product of angiotensin I by AnCE) and bradykinin-potentiating peptide-b bind in an analogous fashion at the active site of AnCE, but also exhibit significant differences. In addition, the binding of Arg-Pro-Pro, the cleavage product of bradykinin and Thr(6) - bradykinin, provides additional detail of the general peptide binding in AnCE. Thus the new structures of AnCE complexes presented here improves our understanding of the binding of peptides and the mechanism by which peptides inhibit this family of enzymes. DATABASE: The atomic coordinates and structure factors for AnCE-Ang II (code 4AA1), AnCE-BPPb (code 4AA2), AnCE-BK (code 4ASQ) and AnCE-Thr6-BK (code 4ASR) complexes have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/) STRUCTURED DIGITAL ABSTRACT: * AnCE cleaves Ang I by enzymatic study (View interaction) * Bradykinin and AnCE bind by x-ray crystallography (View interaction) * BPP and AnCE bind by x-ray crystallography (View interaction) * AnCE cleaves Bradykinin by enzymatic study (View interaction) * Ang II and AnCE bind by x-ray crystallography (View interaction). PMID- 23082759 TI - A retrospective study of efficacy and side effects of intrathecal administration of hyperbaric bupivacaine and morphine solution in 39 dogs undergoing hind limb orthopaedic surgery. AB - OBJECTIVE: To evaluate the intraoperative efficacy of intrathecal anaesthesia with hyperbaric bupivacaine 0.5% and morphine 1% solution (HIA) in dogs undergoing hind limb orthopaedic surgery, using the cardiovascular response to surgical stimulation and to report the perioperative side effects. STUDY DESIGN: Retrospective clinical study. ANIMALS: Forty-three dogs that underwent general anaesthesia for hind limb orthopaedic surgery between 2010 and 2011. METHODS: The anaesthesia records of dogs that received HIA were reviewed. The bupivacaine and morphine doses were calculated based on body mass (BM) and spinal cord length (SCL). Cardiovascular response (CR) to surgical stimulation, the incidence of hypotension, bradycardia, urinary retention, pruritus and offset of motor block were all reported. The intraoperative time-to-event probability of CR was analyzed using Kaplan-Meier survival analysis. RESULTS: The median (range) bupivacaine dose related to BM was 0.57 (0.40-0.78) mg kg(-1) , while that related to SCL was 0.13 (0.08-0.19) mg cm(-1) . A CR was observed in 3/39 (8%) dogs within the first hour after intrathecal injection (Ii) and in 9/39 (23%) dogs over the entire duration of surgery. At 70 minutes from Ii the event-free probability of CR fell below 80%. Hypotension was observed in 12/39 (31%), bradycardia in 6/39 (15%), pruritus in 3/39 (8%), and urinary retention in 3/39 (8%) dogs respectively. Five hours after Ii, 35/39 (89%) dogs were able to walk with only residual ataxia. CONCLUSIONS AND CLINICAL RELEVANCE: Intrathecal anaesthesia with hyperbaric bupivacaine 0.5% and morphine 1% solution provided effective intraoperative antinociception up to 70 minutes in dogs undergoing hind limb surgery. The technique of HIA can provide effective analgesia during short hind limb surgeries in dogs. PMID- 23082762 TI - Continuous health monitoring: integrating biomarkers for the management of chronic diseases. AB - With the recent progresses of the information and communication technologies, biosensors and nanotechnologies, the access to continuing health monitoring is becoming real. The development of efficient, accurate and interactive solutions integrating biomarkers for continuing health monitoring might contribute to an improved care of some chronic diseases like hypertension, diabetes or heart failure. Continuing health monitoring might also enhance the efficiency and safety of patient's treatments. PMID- 23082760 TI - Transfer of growth factor receptor mRNA via exosomes unravels the regenerative effect of mesenchymal stem cells. AB - Bone marrow-mesenchymal stem cells (BM-MSC) ameliorate renal dysfunction and repair tubular damage of acute kidney injury by locally releasing growth factors, including the insulin-like growth factor-1 (IGF-1). The restricted homing of BM MSC at the site of injury led us to investigate a possible gene-based communication mechanism between BM-MSC and tubular cells. Human BM-MSC (hBM-MSC) released microparticles and exosomes (Exo) enriched in mRNAs. A selected pattern of transcripts was detected in Exo versus parental cells. Exo expressed the IGF-1 receptor (IGF-1R), but not IGF-1 mRNA, while hBM-MSC contained both mRNAs. R- cells lacking IGF-1R exposed to hBM-MSC-derived Exo acquired the human IGF-1R transcript that was translated in the corresponding protein. Transfer of IGF-1R mRNA from Exo to cisplatin-damaged proximal tubular cells (proximal tubular epithelial cell [PTEC]) increased PTEC proliferation. Coincubation of damaged PTEC with Exo and soluble IGF-1 further enhanced cell proliferation. These findings suggest that horizontal transfer of the mRNA for IGF-1R to tubular cells through Exo potentiates tubular cell sensitivity to locally produced IGF-1 providing a new mechanism underlying the powerful renoprotection of few BM-MSC observed in vivo. PMID- 23082763 TI - Completely miscible polyethylene nanocomposites. AB - A route to fully miscible polyethylene (PE) nanocomposites has been established based on polymer-brush-coated nanoparticles. These nanoparticles can be mixed with PE at any ratio, with homogeneous dispersion, and without aggregation. This allowed a first systematic study of the thermomechanical properties of PE nanocomposites without interference from aggregation effects. We observe that the storage modulus in the semicrystalline state and the softening temperature increase significantly with increasing nanoparticle content, whereas the melt viscosity is unaltered by the presence of nanoparticles. We show that the complete miscibility with the semicrystalline polymer matrix and the improvement of thermomechanical properties in the solid state is caused by the PE-coated nanoparticles being nucleating agents for the crystallization of PE. This provides a general route to fully miscibility nanocomposites with semicrystalline polymers. PMID- 23082764 TI - Single leg mini squat: an inter-tester reproducibility study of children in the age of 9-10 and 12-14 years presented by various methods of kappa calculation. AB - BACKGROUND: Multiple studies suggest that reduced postural orientation is a possible risk factor for both patello-femoral joint pain (PFP) and rupture of the anterior cruciate ligament (ACL). In order to prevent PFP and ACL injuries in adolescent athletes, it is necessary to develop simple and predictive screening tests to identify those at high risk. Single Leg Mini Squat (SLMS) is a functional and dynamic real-time screening test, which has shown good validity and reproducibility in evaluation of postural orientation of the knee in an adult population. The aim of this study was to determine the inter-tester reproducibility of SLMS in the age group of 9-10 and 12-14 years by evaluating postural orientation of the ankle, knee, hip and trunk. Further on, this study exemplify the divergence of kappa values when using different methods of calculating kappa for the same dataset. METHODS: A total of 72 non-injured children were included in the study. Postural orientation of the ankle, knee, hip and trunk for both legs was determined by two testers using a four-point scale (ordinal, 0-3). Prevalence, overall agreement as well as four different methods for calculating kappa were evaluated: linear weighted kappa in comparison with un weighted kappa, prevalence-adjusted bias-adjusted kappa (PABAK) and quadratic weighted kappa. RESULTS: The linear weighted kappa values ranged between 0.54 0.86 (overall agreement 0.86-0.97), reflecting a moderate to almost perfect agreement. When calculating un-weighted kappa (with and without PABAK) and quadratic weighted kappa, the results spread between 0.46-0.88, 0.50-0.94, and 0.76-0.95, reflecting the various results when using different methods of kappa calculation. CONCLUSIONS: The Single Leg Mini Squat test has moderate to almost perfect reproducibility in children aged 9-10 and 12-14 years when evaluating postural orientation of the ankles, knees, hips and trunk, based on the excellent strength of agreement as presented by linear weighted kappa. The inconsistency in results when using different methods of kappa calculation demonstrated the linear weighted kappa being generally 15% lower than the quadratic weighted values. On average, prevalence-adjusted bias-adjusted kappa increased the un-weighted kappa values by 7% and 12% by children aged 9-10 and 12-14, respectively. PMID- 23082765 TI - Theory of mind performance using a story comprehension task in bipolar mania compared to schizophrenia and healthy controls. AB - INTRODUCTION: Theory of mind (ToM) refers to the ability to understand the mental state of self and others. There is limited research into this topic in bipolar disorder (BD), with no previous study examining ToM in a BD group within a psychotic manic phase. METHODS: Twenty-eight psychotic manic BD patients were compared with 30 schizophrenia (SCZ) patients and 29 healthy controls (HC). Participants performed a ToM story comprehension task that compared ToM stories and non-ToM stories (which we relabelled non-ToM "semantic" stories). Performance was examined by answering comprehension questions. RESULTS: Both patient groups were equally impaired on their scores for ToM stories (scores BD = 10/24, SCZ = 9/24, HC = 14/24, p < .001). Interestingly, both patient groups showed reduced performance on non-ToM semantic stories (scores BD = 12/24, SCZ = 9/24, HC = 15/24, p < .001); SCZ showed a larger deficit. Reduced ToM performance was correlated with delusion severity in the BD group only. CONCLUSIONS: ToM performance was impaired in BD patients experiencing psychotic symptoms. Patient performance was also impaired on the control condition (i.e., non-ToM semantic stories) supporting an additional deficit in semantic processing. PMID- 23082766 TI - Molecular characterization of rifampicin-resistant Staphylococcus aureus isolates in a Chinese teaching hospital from Anhui, China. AB - BACKGROUND: Staphylococcus aureus (S. aureus) is a major nosocomial pathogen that causes a variety of infections and toxicoses. In recent years, the percentage of rifampicin-resistant S. aureus has increased rapidly in China. The aims of this study were to analyze 1) the level of rifampicin resistance in S. aureus and its correlation with mutations in the rpoB gene, and 2) the molecular characterization of rifampicin-resistant S. aureus isolates. RESULTS: 88 rifampicin-resistant S. aureus isolates were collected for this study. Of the 88 isolates, 83 (94.3%) were high-level rifampicin resistant (MIC>=8 mg/L) while the remaining 5 isolates (5.7%) had a low-level resistance to rifampicin (MIC, 2 to 4 mg/L). Four amino acid substitutions were found in the 88 isolates, which were 481His/Asn (95.5%), 466Leu/Ser (87.5%), 477Ala/Asp (6.8%) and 486Ser/Leu (4.5%) respectively. All mutations were found to be present in cluster I of the rpoB gene. The low-level resistant isolates were found to have only one mutation, while the high-level resistant isolates had at least two or more mutations. The most common multiple mutations were 481His/Asn+466Leu/Ser(92.8%,77/83). The other multiple mutations found were 481His/Asn+477Ala/Asp (6.0%,5/83), and 481His/Asn+466Leu/Ser+477Ala/Asp (1.2%,1/83). Out of 28 high-level rifampicin resistant S. aureus isolates, three molecular types were found, namely, ST239 MRSA-III-spa t030 (25/28, 89.3%), ST239-MRSA-III-spa t021 (2/28, 7.1%), and ST239 MRSA-III-spa t045 (1/28, 3.6%). CONCLUSIONS: Rifampicin resistance in S. aureus was closely associated with mutations in the rpoB gene. High-level rifampicin resistant S. aureus is one of the most important features in Anhui Provincial Hospital, and high-level rifampicin resistance in S. aureus is associated with multiple mutations of rpoB gene. The prevalence of high-level rifampicin resistant S. aureus in Anhui may be associated with the spread of the ST239-MRSA III-spa t030 clone. PMID- 23082767 TI - Genetic diversity and recombination analysis of sweepoviruses from Brazil. AB - BACKGROUND: Monopartite begomoviruses (genus Begomovirus, family Geminiviridae) that infect sweet potato (Ipomoea batatas) around the world are known as sweepoviruses. Because sweet potato plants are vegetatively propagated, the accumulation of viruses can become a major constraint for root production. Mixed infections of sweepovirus species and strains can lead to recombination, which may contribute to the generation of new recombinant sweepoviruses. RESULTS: This study reports the full genome sequence of 34 sweepoviruses sampled from a sweet potato germplasm bank and commercial fields in Brazil. These sequences were compared with others from public nucleotide sequence databases to provide a comprehensive overview of the genetic diversity and patterns of genetic exchange in sweepoviruses isolated from Brazil, as well as to review the classification and nomenclature of sweepoviruses in accordance with the current guidelines proposed by the Geminiviridae Study Group of the International Committee on Taxonomy of Viruses (ICTV). Co-infections and extensive recombination events were identified in Brazilian sweepoviruses. Analysis of the recombination breakpoints detected within the sweepovirus dataset revealed that most recombination events occurred in the intergenic region (IR) and in the middle of the C1 open reading frame (ORF). CONCLUSIONS: The genetic diversity of sweepoviruses was considerably greater than previously described in Brazil. Moreover, recombination analysis revealed that a genomic exchange is responsible for the emergence of sweepovirus species and strains and provided valuable new information for understanding the diversity and evolution of sweepoviruses. PMID- 23082768 TI - Choroidal and orbital metastases from thyroid cancer. AB - BACKGROUND: Metastases of thyroid carcinomas to the choroid and/or orbit are infrequent. PubMed was searched for English-language articles and case reports published from 1977 to 2012. In our survey, we looked for reports of orbital and/or ocular metastases from the thyroid and found 31 reported cases from 1979 to 2012. SUMMARY: At the time of onset of ocular symptoms, the vast majority of patients had a long history of thyroid malignancy and evidence of widely disseminated metastatic disease. The age of the reported patients ranged from 29 to 83 years. Among the 22 reported cases of thyroid carcinomas with metastases to the choroid from 1979 to 2012, the most common primary tumor was papillary thyroid carcinoma (PTC); this occurred in seven patients. This was followed by medullary thyroid carcinoma in six cases and follicular thyroid carcinoma (FTC) in five cases. Orbital metastases were reported in nine patients with thyroid carcinomas (PTC=4, FTC=3, Hurthle cell=1, not specified=1). Patients with choroidal metastases presented with decreased or blurred vision, eye pain, and flashes in 81%, 5%, and 5% of cases, respectively. The diagnosis of a choroidal tumor was usually based on noninvasive diagnostic techniques such as ultrasonography, transillumination, computer tomography (CT), and/or magnetic resonance imaging (MRI) scanning. 131I scanning revealed uptake in the orbit in 26% of cases with choroidal and/or orbital PTC or FTC. For a metastasis that causes a definitive loss of vision and/or persistent pain, the treatment of choice was enucleation. The other treatment options were brachyradiotherapy using 125I episcleral radioactive plaque insertion, external beam radiation, 131I therapy, chemotherapy, and/or targeted therapy with small molecules. CONCLUSIONS: The orbit and globe are not common sites for metastatic thyroid carcinomas. Diagnosis of a choroidal tumor is usually based on clinical judgment and results of noninvasive diagnostic techniques such as ultrasonography, transillumination, CT, and/or MRI scanning. Fundoscopic examination and ocular ultrasonography by an ophthalmologist are recommended for identification and monitoring of choroidal metastatic deposits. PMID- 23082769 TI - Interprofessional collaborative practice and relational coordination: improving healthcare through relationships. PMID- 23082770 TI - Temperature-induced ultradense PEG polyelectrolyte surface grafting provides effective long-term bioresistance against mammalian cells, serum, and whole blood. AB - We report a facile method of generating ultradense poly(l-lysine)-graft poly(ethylene glycol) (PLL-g-PEG) surface by using high temperature alone, which in turn provides dramatic improvement in resisting nonspecific bioadsorption. X ray photoelectron spectroscopy (XPS) revealed that the surface graft density increased ~4 times higher on the surface prepared at 80 degrees C compared to 20 degrees C. The studies from small-angle X-ray scattering (SAXS) and the effect of varying ionic strength during/post assemblies at 20 and 80 degrees C indicated that the "cloud point grafting effect" is not the cause for obtaining high density grafting. Stringent long-term bioresistance tests have been conducted and the temperature-induced PLL-g-PEG surfaces have achieved (1) zero mammalian cell adsorption/migration for up to 36 days and (2) extremely close-to zero protein adsorptions have been observed even after 36 days in 10% serum media and 24 h in whole blood within the ultrasensitive detection limit of time-of flight secondary ion mass spectrometry (ToF-SIMS). PMID- 23082771 TI - ALK-positive anaplastic large cell lymphoma presenting as intradural spinal mass: first reported case and review of literature. AB - Anaplastic large cell lymphoma (ALCL) is characterized by large anaplastic cells of T-cell or null-cell phenotype expressing CD30 (Ki-1 antigen). In most cases this neoplasm expresses the anaplastic lymphoma kinase (ALK), a chimeric protein resulting from the t(2;5)(p23;q35) translocation. ALK-positive anaplastic large cell lymphoma is most frequent in the first three decades of life and shows a male predominance, involving both nodal and extranodal sites, but rarely the CNS. We report a 21-year-old patient with a previous history of nodal ALK-positive ALCL, lymphohistiocytic subtype, who was admitted for recent occurrence of left sided anesthesia with pain and progressive motor weakness of both legs. An MRI of the spine documented an intradural extramedullary mass dislocating the thoracic cord, suggesting a meningioma and the patient underwent surgical decompression. Histological examination revealed a lymphoproliferative neoplasm with morphology and immunophenotype of ALK-positive anaplastic large cell lymphoma. After surgery, all preoperative symptoms disappeared. To our knowledge, no cases of ALCL presenting as secondary localization with an intradural extramedullary spinal mass have been reported in the literature. PMID- 23082772 TI - Long-term quality of life in patients with acute respiratory distress syndrome requiring extracorporeal membrane oxygenation for refractory hypoxaemia. AB - INTRODUCTION: The purpose of the study was to assess the long term outcome and quality of life of patients with acute respiratory distress syndrome (ARDS) receiving extracorporeal membrane oxygenation (ECMO) for refractory hypoxemia. METHODS: A retrospective observational study with prospective health related quality of life (HRQoL) assessment was conducted in ARDS patients who had ECMO as a rescue therapy for reversible refractory hypoxemia from January 2009 until April 2011 in a tertiary Australian centre. Survival and long-term quality of life assessment, using the Short-Form 36 (SF-36) and the EuroQol health related quality of life questionnaire (EQ5D) were assessed and compared to international data from other research groups. RESULTS: Twenty-one patients (mean age 36.3 years) with ARDS receiving ECMO for refractory hypoxemia were studied. Eighteen (86%) patients were retrieved from external intensive care units (ICUs) by a dedicated ECMO retrieval team. Eleven (55%) had H1N1 influenza A-associated pneumonitis. Eighteen (86%) patients survived to hospital discharge. Of the 18 survivors, ten (56%) were discharged to other hospitals and 8 (44%) were discharged directly home. Sequelae and health related quality of life were evaluated for 15 of the 18 (71%) long-term survivors (assessment at median 8 months). Mean SF-36 scores were significantly lower across all domains compared to age and sex matched Australian norms. Mean SF-36 scores were lower (minimum important difference at least 5 points) than previously described ARDS survivors in the domains of general health, mental health, vitality and social function. One patient had long-term disability as a result of ICU acquired weakness. Only 26% of survivors had returned to previous work levels at the time of follow-up. CONCLUSIONS: This ARDS cohort had a high survival rate (86%) after use of ECMO support for reversible refractory hypoxemia. Long term survivors had similar physical health but decreased mental health, general health, vitality and social function compared to other ARDS survivors and an unexpectedly poor return to work. PMID- 23082773 TI - Emotional and behavioural outcomes later in childhood and adolescence for children with specific language impairments: meta-analyses of controlled prospective studies. AB - BACKGROUND: Prospective evidence on psychological outcomes for children with specific language impairments (SLI) is accumulating. To date, there has been no attempt to summarise what this evidence says about the strength of link between SLI and later child and adolescent emotional and behavioural (EB) outcomes. METHODS: We undertook a systematic review and meta-analysis (following PRISMA guidelines and involving a literature search to June 2012 of seven databases, including MEDLINE and PsychAPA) of prospective, cohort studies of children with SLI and typical language development (TLD) reporting on the incidence and severity of EB problems later in childhood or adolescence. RESULTS: Nineteen follow-up reports of eight cohorts with 553 SLI children and 1533 TLD controls were identified. Initial assessment was at 3-8.8 years of age and follow-up duration from 2 to 12 years. Pooled across comparable studies, SLI children were about two times more likely to show disorder levels of overall internalising problems, overall externalising and ADHD problems than TLD children. Compared with the average TLD child (50 percentile), at follow-up, the symptom severity of the average SLI child was at the 72 percentile (95% CI 65-79 percentile) on internalising symptoms, the 69 percentile (95% CI 63-74 percentile) on externalising symptoms and the 60 percentile (95% CI 52-68 percentile) on AHDH severity. The findings about risk to specific mental disorders and the severity of specific problems were inconclusive. CONCLUSIONS: Relative to typical children, SLI children experience clinically important increases in the severity of diverse emotional, behavioural and ADHD symptoms and more frequently show a clinical level of these problems. The small number of studies included in pooled analysis and methodological heterogeneity reduce the precision and generalisability of the findings. Most studies do not account for initial levels of EB problems. PMID- 23082774 TI - Sex offenders with intellectual disabilities and their academic observers: popular methodologies and research interests. AB - BACKGROUND: Over the past two decades, disability activists and scholars have developed research paradigms that aim to place (some of the) control over the research process in the hands of disabled people. This paper discusses the appropriateness of applying such paradigms to sex offenders with intellectual disabilities (ID). It exposes to what extent current research about this population is affected by these developments. METHODS: A content analysis of a sample of 80 articles across 20 academic journals was carried out. This recorded the data collection methods used, to what extent the views of people with ID were represented, subject affiliations of the authors and the subject matter discussed. RESULTS: Few studies make sense of the personal accounts of this population. Social scientists have mostly not engaged in this area of research, which results in significant gaps in knowledge. CONCLUSIONS: We currently know little about the subjectivity of sex offenders with ID. Research that seeks to explore this may enhance our understanding of this population and thus contribute towards the effectiveness of preventative work and risk management. PMID- 23082775 TI - Growth optimization of Lactobacillus rhamnosus FTDC 8313 and the production of putative dermal bioactives in the presence of manganese and magnesium ions. AB - AIMS: The study aimed to optimize the growth and evaluate the production of putative dermal bioactives from Lactobacillus rhamnosus FTDC 8313 using response surface methodology, in the presence of divalent metal ions, namely manganese and magnesium. METHODS AND RESULTS: A central composite design matrix (alpha value of +/- 1.414) was generated with two independent factors, namely manganese sulphate (MnSO(4) ) and magnesium sulphate (MgSO(4) ). The second-order regression model indicated that the quadratic model was significant (P < 0.01), suggesting that the model accurately represented the data in the experimental region. Three dimensional response surfaces predicted an optimum point with maximum growth of 10.59 log(10) CFU ml(-1) . The combination that produced the optimum point was 0.80 mg ml(-1) MnSO(4) and 1.09 mg ml(-1) MgSO(4) . A validation experiment was performed, and data obtained showed a deviation of 0.30% from the predicted value, ascertaining the predictions and the reliability of the regression model used. Effects of divalent metal ions on the production of putative dermal bioactives, namely hyaluronic acid, diacetyl, peptidoglycan, lipoteichoic acid and organic acids in the region of optimized growth, were evaluated using 3D response surfaces generated. Evaluation based on the individual and interaction effects showed that both manganese and magnesium played an important role in the production of these putative bioactives. CONCLUSIONS: Optimum growth of Lact. rhamnosus FTDC 8313 in reconstituted skimmed milk was achieved at 10.59 log(10) CFU ml(-1) in the presence of MnSO(4) (0.80 mg ml(-1) ) and MgSO(4) (1.09 mg ml( 1) ). Production of putative dermal bioactive and inhibitory compounds including hyaluronic acid, diacetyl, peptidoglycan, lipoteichoic acid and organic acids at the regions of optimized growth showed potential dermal applications. SIGNIFICANT AND IMPACT OF THE STUDY: This research can serve as a fundamental study to further evaluate the potential of Lactobacillus strains in non-gut-related roles such as dermal applications. PMID- 23082776 TI - Structurally defined graphene nanoribbons with high lateral extension. AB - Oxidative cyclodehydrogenation of laterally extended polyphenylene precursor allowed bottom-up synthesis of structurally defined graphene nanoribbons (GNRs) with unprecedented width. The efficiency of the cyclodehydrogenation was validated by means of MALDI-TOF MS, FT-IR, Raman, and UV-vis absorption spectroscopies as well as investigation of a representative model system. The produced GNRs demonstrated broad absorption extended to near-infrared region with the optical band gap of as low as 1.12 eV. PMID- 23082777 TI - Long-term maintenance of normoglycaemia using everolimus in a patient with disseminated insulinoma and severe hypoglycaemia. PMID- 23082778 TI - Comparative and targeted proteomic analyses of urinary microparticles from bladder cancer and hernia patients. AB - Bladder cancer is a common urologic cancer whose incidence continues to rise annually. Urinary microparticles are an attractive material for noninvasive bladder cancer biomarker discovery. In this study, we applied isotopic dimethylation labeling coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to discover bladder cancer biomarkers in urinary microparticles isolated from hernia (control) and bladder cancer patients. This approach identified 2964 proteins based on more than two distinct peptides, of which 2058 had not previously been reported as constituents of human urine exosomes/microparticles. A total of 107 differentially expressed proteins were identified as candidate biomarkers. Differences in the concentrations of 29 proteins (41 signature peptides) were precisely quantified by LC-MRM/MS in 48 urine samples of bladder cancer, hernia, and urinary tract infection/hematuria. Concentrations of 24 proteins changed significantly (p<0.05) between bladder cancer (n=28) and hernia (n=12), with area-under-the-curve values ranging from 0.702 to 0.896. Finally, we quantified tumor-associated calcium-signal transducer 2 (TACSTD2) in raw urine specimens (n=221) using a commercial ELISA and confirmed its potential value for diagnosis of bladder cancer. Our study reveals a strong association of TACSTD2 with bladder cancer and highlights the potential of human urinary microparticles in the noninvasive diagnosis of bladder cancer. PMID- 23082779 TI - A case of pemphigoid gestationis with concurrent IgG antibodies to BP180, BP230 and type VII collagen. AB - A 22-year-old primigravida had a pruritic, erythematous, bullous eruption on the skin during the 26th week of gestation. After delivery the eruption flared up. The diagnosis of pemphigoid gestationis was confirmed based on histopathological and immunofluorescence findings. The result of immunoblotting showed IgG autoantibodies which reacted against BP230 in epidermal extracts and 290 kDa type VII collagen in dermal extracts. The BP180 antibodies were also detected by an enzyme-linked immunosorbent assay BP180NC16a diagnosis kit. Pulsed corticosteroid and cyclophosphamide resulted in a favourable response at the acute stage. The patient was cured in 2 years. The analysis of the patient's autoantibodies provides strong evidence for the involvement of epitope spreading in her autoimmune disease. PMID- 23082780 TI - Intestinal microbial profiles in extremely preterm infants with and without necrotizing enterocolitis. AB - AIM: Necrotizing enterocolitis (NEC) represents one of the gravest complications in premature infants. The suggested role of intestinal microbiota in the development of NEC needs to be elucidated. METHODS: This prospective single centre case-control study applied barcoded pyrosequencing to map the bacterial composition of faecal samples from extremely preterm infants. Ten patients were diagnosed with NEC and matched to healthy controls with regard to sex, gestational age and mode of delivery prior to analysis of the samples. RESULTS: Enterococcus, Bacillales and Enterobacteriaceae dominated the flora. Although not statistically significant, a high relative abundance of Bacillales and Enterobacteriaceae was detected at early time points in patients developing NEC, while healthy controls had a microbiota more dominated by Enterococcus. A low diversity of intestinal microbial flora was found without any differences between NEC patients and controls. In 16 healthy controls, Firmicutes (Enterococcus and Bacillales) dominated the faecal flora during the first weeks after birth and were then succeeded by Enterobacteriaceae. CONCLUSION: No significant differences in the composition of intestinal microbiota of patients developing NEC were detected; however, some findings need to be scrutinized in subsequent studies. PMID- 23082781 TI - Relationship of absorption, depersonalisation, and self-focused attention in subjects with and without hallucination proneness. AB - INTRODUCTION: The purpose of this work was to study the relationship of absorption, depersonalisation, and self-focused attention in subjects prone to hallucination. METHODS: A sample of 218 healthy subjects was given the LSHS-R Hallucination Scale (Bentall & Slade, 1985). Three groups, subjects with high, medium, and low hallucination proneness, were formed from this sample. The Tellegen Absorption Scale (TAS; Tellegen & Atkinson, 1974), Cambridge Depersonalisation Scale (CDS; Sierra & Berrios, 2000), and Self-Absorption Scale (SAS; McKenzie & Hoyle, 2008) were also given to all the participants. The Metacognitions Questionnaire (MCQ-30; Wells & Cartwright-Hatton, 2004) was used as a covariant to control for the effects of emotional vulnerability on the dependent variables studied. RESULTS: The results showed that subjects highly prone to hallucinations had significantly higher absorption, depersonalisation, and self-focused attention than the subjects in the other two groups. A hierarchical regression analysis showed that absorption and depersonalisation predict hallucination proneness. CONCLUSIONS: The importance of the absorption, depersonalisation, and self-focused attention variables for understanding the aetiology of hallucinations is discussed in the Conclusions, where some approaches to its treatment are also suggested. PMID- 23082782 TI - Muscle-derived stem cells promote angiogenesis and attenuate intimal hyperplasia in different murine vascular disease models. AB - Muscle-derived stem cells (MDSCs) are known to promote angiogenesis, but have never been studied in vascular diseases. We differentiated MDSCs into endothelial lineage cells in vitro by stimulation with shear stress and vascular endothelial growth factor. Such differentiated MDSCs (diff-MDSC) showed strong angiogenic potential in vitro. When tested in ischemic hindlimbs of mice, diff-MDSCs increased perfusion and decreased necrosis of the ischemic limbs, by promoting new vessel formation and by upregulating genes involved in endothelial expression. Such effects were not observed with native MDSCs (without endothelial stimulation in vitro). Diff-MDSCs were also injected into carotid arteries of rats after balloon denudation of the intima layer to induce intimal hyperplasia. The cell-treated group had significantly reduced intima-to-media thickness ratio compared to control, thus attenuating intimal hyperplasia by early re endothelialization of the intima layer. Our findings suggest that MDSCs are a potential source of stem cell therapy for treatment of various vascular diseases, by inducing angiogenesis to improve perfusion in sites of ischemia, and by preventing intimal hyperplasia in sites of vessel injury. PMID- 23082783 TI - Interpersonal features and functions of nonsuicidal self-injury. AB - Etiological models of nonsuicidal self-injury (NSSI) suggest interpersonal features may be important to understand this behavior, but social functions and correlates have not been extensively studied. This study addresses existing limitations by examining interpersonal correlates and functions of NSSI within a stratified random sample of 1,243 predominantly Caucasian college students (mean age = 21.52, SD = 4.15 years). Participants completed an anonymous online survey assessing NSSI features, perceived social support, and disclosure experiences. Approximately 15% of the students endorsed NSSI. Interpersonal reasons were endorsed proportionally more often for initiating rather than repeating the behavior. Individuals with repetitive NSSI reported significantly lower perceived social support from family members and fewer individuals to seek advice from than single-act and control participants. Fifty-nine percent had disclosed their NSSI, but rarely to mental health professionals. Conversations with others about NSSI were rated as being mostly unhelpful. These results emphasize the importance of interpersonal features and functions of NSSI, suggesting treatments should focus on strengthening interpersonal bonds alongside emotion regulation. Improving responses to disclosures of NSSI is needed to promote communication about this behavior and perceived helpfulness of such conversations. PMID- 23082784 TI - Efficacy of maropitant in preventing vomiting in dogs premedicated with hydromorphone. AB - OBJECTIVE: The goal of this study was to evaluate the effectiveness of maropitant (Cerenia((r))) in preventing vomiting after premedication with hydromorphone. STUDY DESIGN: Randomized, blinded, prospective clinical study. ANIMALS: Eighteen dogs ASA I/II admitted for elective orthopedic surgical procedures. The dogs were a mixed population of males and females, purebreds and mixed breeds, 1.0-10.2 years of age, weighing 3-49.5 kg. METHODS: Dogs were admitted to the study if they were greater than 1 year of age, healthy and scheduled to undergo elective orthopedic surgery. Dogs were randomly selected to receive one of two treatments administered by subcutaneous injection. Group M received 1.0 mg kg(-1) of maropitant, Group S received 0.1 mL kg(-1) of saline 1 hour prior to anesthesia premedication. Dogs were premedicated with 0.1 mg kg(-1) of hydromorphone intramuscularly. A blinded observer documented the presence of vomiting, retching and/or signs of nausea for 30 minutes after premedication. RESULTS: All dogs in S vomited (6/9), retched (1/9) or displayed signs of nausea (2/9). None (0/9) of the dogs in M vomited, retched or displayed signs of nausea. Dogs in M had significantly fewer incidences of vomiting (p=0.0090), vomiting and retching (p=0.0023) and vomiting, retching and nausea (p<0.0001) when compared to S. CONCLUSION AND CLINICAL RELEVANCE: Maropitant prevents vomiting, retching and nausea associated with intramuscular hydromorphone administration in dogs. PMID- 23082785 TI - Investigation of ejaculatory disorder by silodosin in the treatment of prostatic hyperplasia. AB - BACKGROUND: To assess the ejaculatory disorder caused by silodosin in the prostatic hyperplasia patients who carry out sexual actions (sexual intercourse, masturbation). METHOD: The subjects of this study were 91 patients who had been clinically diagnosed to have LUTS/BPH at this hospital, who were administered silodosin at 4 mg twice a day, and who gave response to a questionnaire survey related to ejaculatory disorder. Sexual intercourse and masturbation were regarded as sexual actions in this study. RESULTS: Ejaculatory disorder occurred in 38 (42%) of the 91 silodosin administration cases. Forty (44%) of the 91 patients answered that they carried out sexual actions after oral intake of silodosin. When the investigation was conducted only in those who exercised sexual actions, ejaculatory disorder was observed in 38 (95%) of these 40 patients, indicating a high incidence. When asked if disturbed by the ejaculatory disorder, 29 (76%) of the 38 patients who had ejaculatory disorder answered yes. Oral silodosin was discontinued due to the ejaculatory disorder in 2 (5%) of these patients. On the whole, the discontinuation rate of oral silodosin was 2% (2/91 patients). CONCLUSION: It was demonstrated that the administration of silodosin induced ejaculatory disorder at a high incidence. Since it is possible that the high frequency of ejaculatory disorder by silodosin may reduce QOL, it is considered necessary to provide sufficient information related to ejaculatory disorder at the time of treatment with silodosin. PMID- 23082786 TI - Conformer generation with OMEGA: learning from the data set and the analysis of failures. AB - We recently published a high quality validation set for testing conformer generators, consisting of structures from both the PDB and the CSD (Hawkins, P. C. D. et al. J. Chem. Inf. Model. 2010, 50, 572.), and tested the performance of our conformer generator, OMEGA, on these sets. In the present publication, we focus on understanding the suitability of those data sets for validation and identifying and learning from OMEGA's failures. We compare, for the first time we are aware of, the coverage of the applicable property spaces between the validation data sets we used and the parent compound sets to determine if our data sets adequately sample these property spaces. We also introduce the concept of torsion fingerprinting and compare this method of dissimilation to the more traditional graph-centric diversification methods we used in our previous publication. To improve our ability to programmatically identify cases where the crystallographic conformation is not well reproduced computationally, we introduce a new metric to compare conformations, RMSTanimoto. This new metric is used alongside those from our previous publication to efficiently identify reproduction failures. We find RMSTanimoto to be particularly effective in identifying failures for the smallest molecules in our data sets. Analysis of the nature of these failures, particularly those for the CSD, sheds further light on the issue of strain in crystallographic structures. Some of the residual failure cases not resolved by simple changes in OMEGA's defaults present significant challenges to conformer generation engines like OMEGA and are a source of new avenues to further improve their performance, while others illustrate the pitfalls of validating against crystallographic ligand conformations, particularly those from the PDB. PMID- 23082787 TI - Synthesis and reversible transformation of Cu(n)-bridged (n = 1, 2, or 4) silicodecatungstate dimers. AB - Three copper-bridged sandwich-type silicodecatungstate dimers, TBA(8)[Cu(gamma SiW(10)O(34))(2)(CH(3)CONH)(2)].4H(2)O (Cu-1, TBA = tetra-n-butylammonium), TBA(8)H(4)[Cu(2)(gamma-SiW(10)O(36))(2)H(2)O].11H(2)O.CH(3)COCH(3) (Cu-2), and TBA(8)H(2)[Cu(4)(gamma-SiW(10)O(36))(2)(CH(3)COO)(2)].5H(2)O (Cu-4) have been selectively synthesized by reactions of divacant lacunary TBA(4)[H(4)(gamma SiW(10)O(36))] (SiW10) with copper acetate in organic media. The copper cation(s) in Cu-1, Cu-2, and Cu-4 possess square-planar four-coordinate (Cu-1), square pyramidal five-coordinate (Cu-2), and octahedral six-coordinate (Cu-4) geometries, respectively. These compounds can reversibly be transformed simply by controlling the copper/SiW10 molar ratios in solutions. PMID- 23082789 TI - Characterization of organic anion transporting polypeptide (OATP) expression and its functional contribution to the uptake of substrates in human hepatocytes. AB - Since the substrate specificities of OATP1B1, 1B3, and 2B1 are broad and overlapping, the contribution of each isoform to the overall hepatic uptake is of concern when assessing transporter-mediated drug-drug interactions (DDIs) or genetic polymorphism impact in the clinic. Herein, we quantitatively measured OATP proteins in cryopreserved hepatocytes, sandwich-cultured human hepatocytes (SCHH), and the liver, and examined the relationship with functional uptake of OATP substrates in an effort to identify the OATP isoform(s) contributing to the hepatic uptake of pitavastatin. The modulation of OATP expression in SCHH was found to be lot-dependent. However, OATP protein measurements averaged from 5 lots of SCHH were comparable to that of suspended hepatocytes. All three OATP transporters in suspended hepatocytes and SCHH were significantly lower than those in the liver. In SCHH, the uptake of CCK-8 and pravastatin was found to be associated with the expression of OATP1B3 and OATP1B1, respectively. In suspended hepatocytes, OATP1B1 appeared to show a positive trend with respect to the uptake of pitavastatin, which suggests a selective contribution of OATP1B1 to pitavastatin transport and thus an OATP quantitative protein expression-activity relationship. While the passive diffusion of rosuvastatin in SCHH was consistent across hepatocyte lots, the passive diffusion of pitavastatin varied over a broad range (>4-fold) in suspended hepatocytes and was inversely correlated with transporter-mediated uptake, presumably due to cell membrane alterations imparted by cryopreservation. Collectively, SCHH maintains OATP protein expression and membrane integrity and, if feasible when considering research goals, would be considered a superior tool for the characterization of in vitro transport parameters without the complication of membrane leakage. PMID- 23082791 TI - Biointerface properties of core-shell poly(vinyl alcohol)-hyaluronic acid microgels based on chemoselective chemistry. AB - Chemoselective chemistry is one of the main synthetic strategies for the design of bioactive constructs. In this contribution we report on the fabrication of core-shell microgel particles, obtained by "click chemistry" and "inverse emulsion droplets" techniques. Azido and alkyne derivatives of poly(vinyl alcohol) (PVA) in a 1:2 mol ratio of functional groups, respectively, were crosslinked by click chemistry method. The microgel particles were spherical in shape with an average diameter of about 2 MUm and with a narrow size distribution. Residual unreacted alkyne groups present on the particle surface were "clicked" with an azido-grafted hyaluronic acid. These microgel particles with a PVA core and a hyaluronic acid shell were tested for bioorthogonality, that is, for the absence of cytotoxicity in the presence of unreacted clickable functionalities and demonstrated a remarkable ability to target adenocarcinoma colon cells (HT- 29) as well as to release locally the antitumor drug, doxorubicin. Internalization process was studied in connection with the presence of hyaluronic acid on the microgel particles surface. In this paper we introduce a concept device based on chemoselective chemistry, which may contribute to the design of micro- and nanoplatforms having controlled and multifunctional structures. PMID- 23082792 TI - A home telemonitoring program reduced exacerbation and healthcare utilization rates in COPD patients with frequent exacerbations. AB - RATIONALE: As the impact of home telemonitoring on patients with chronic obstructive pulmonary disease (COPD) is not fully understood and reduction in healthcare utilization is not proven, we attempt to evaluate the effects of home telemonitoring on healthcare utilization in patients with COPD. SUBJECTS AND METHODS: We conducted a retrospective cohort study using the Veterans Health Administration database of COPD patients enrolled in the Care Coordination Home Telehealth (CCHT) program. We evaluated the effects of monitoring through this program in patients with moderate to severe COPD and frequent exacerbations. Numbers of emergency department (ED) visits, urgent care (UC) visits, and hospitalizations were all evaluated before and after enrollment. The differences in average pre-enrollment and during-enrollment numbers of hospital admissions, ED/UC visits, and exacerbations were tested for significance among all patients enrolled in the program who had one or more exacerbations at pre-enrollment; results were expressed on a per-year basis. RESULTS: Data were available on a total of 1,133 patients with COPD enrolled in the CCHT program between 2005 and 2009. Given the objectives of our study, we only included 369 patients who had at least one exacerbation per year in the year prior to enrollment. Of these, 71.5% had a reduction in numbers of ED visits and exacerbations requiring hospitalizations after enrollment in the program. The average number of hospital admissions, ED visits, and total exacerbations were all reduced (0.41 +/- 1.68, 0.15 +/- 1.65, and 0.56 +/- 2.3, respectively; all with p<0.01). The pre enrollment number of exacerbations was the only factor observed to be significantly associated with the reduction in number of exacerbations. CONCLUSIONS: In patients with COPD and frequent exacerbations, enrollment in a home telemonitoring program may decrease healthcare utilization. PMID- 23082790 TI - A hypomethylated population of Brassica rapa for forward and reverse epi genetics. AB - BACKGROUND: Epigenetic marks superimposed on the DNA sequence of eukaryote chromosomes provide agility and plasticity in terms of modulating gene expression, ontology, and response to the environment. Modulating the methylation status of cytosine can generate epialleles, which have been detected and characterised at specific loci in several plant systems, and have the potential to generate novel and relatively stable phenotypes. There have been no systematic attempts to explore and utilise epiallelic variation, and so extend the range of phenotypes available for selection in crop improvement. We developed an approach for generating novel epialleles by perturbation of the DNA methylation status. 5- Azacytidine (5-AzaC) provides selective targeting of 5 mCG, which in plants is associated with exonic DNA. Targeted chemical intervention using 5-AzaC has advantages over transgenic or mutant modulation of methyltransferases, allowing stochastic generation of epialleles across the genome. RESULTS: We demonstrate the potential of stochastic chemically-induced hypomethylation to generate novel and valuable variation for crop improvement. Systematic analysis of dose-response to 5-AzaC in B. rapa guided generation of a selfed stochastically hypomethylated population, used for forward screening of several agronomic traits. Dose-response was sigmoidal for several traits, similar to that observed for chemical mutagens such as EMS. We demonstrated transgenerational inheritance of some phenotypes. BraRoAZ is a unique hypomethylated population of 1000 E2 sib lines. When compared to untreated controls, 5-Aza C-treated lines exhibited reduced immuno-staining of 5mC on pachytene chromosomes, and Methylation Sensitive Amplified Polymorphism (MSAP) profiles that were both divergent and more variable. There was coincident phenotypic variation among these lines for a range of seed yield and composition traits, including increased seed protein content and decreased oil content, as well as decreased erucic acid and corresponding increases in linoleic and/or palmitic acid. Each 5-AzaC-treated line represents a unique combination of hypomethylated epialleles. CONCLUSIONS: The approach and populations developed are available for forward and reverse screening of epiallelic variation and subsequent functional and inheritance studies. The generation of stochastically hypomethylated populations has utility in epiallele discovery for a wide range of crop plants, and has considerable potential as an intervention strategy for crop improvement. PMID- 23082793 TI - Patient-centeredness and e-health among Italian hospitals: results of a cross sectional web-based survey. AB - OBJECTIVES: Given the growing recognition of patient-centeredness as a healthcare quality indicator and its limited implementation in practice, our study evaluated how the Italian hospitals (ItHs), including research hospitals (IRCCSs), research teaching hospitals (THs), and independent public hospital trusts (AOs), address the dimension of online data access through their institutional Web sites to promote a patient-centered care. MATERIALS AND METHODS: To address patient centeredness and e-health, eight specific indicators adapted from the Euro Health Consumer Index were evaluated from 169 ItHs: online booking of healthcare services; access to medical records; register of legitimate doctors; waiting times for most commonly delivered healthcare services; transport information; centralized booking; public relations office; and pain management hospital committee. Univariate and bivariate statistics and a logistic regression analysis have been performed. RESULTS: The majority of the ItHs were under public ownership, and half of them are located in Northern Italy. From the logistic regression analysis, AOs appeared to be more likely to develop a patient-centered healthcare approach (odds ratio [OR]=3.69; 95% confidence interval [CI] 1.14 11.89) compared with IRCCSs or THs. In addition, when grouped together, all public hospitals show more than threefold higher implementation of patient centeredness strategies (OR=3.60; 95% CI 1.49-8.72) with respect to private ones. Northern hospitals are more likely to ensure wider implementation of a patient centered approach to healthcare (OR=3.37; 95% CI 1.49-7.62). CONCLUSIONS: According to our results, most of the ItHs are under public ownership, and half of them are located in the northern regions of Italy. The higher implementation of patient-centeredness strategies observed for Northern hospitals highlights interregional disparity in healthcare that needs a coordinated effort at both the hospital and policymaker levels to ensure a widespread implementation of patient centered care among all Italian regions. PMID- 23082794 TI - Reactions to a remote-controlled video-communication robot in seniors' homes: a pilot study of feasibility and acceptance. AB - OBJECTIVE: Remote telepresence provided by tele-operated robotics represents a new means for obtaining important health information, improving older adults' social and daily functioning and providing peace of mind to family members and caregivers who live remotely. In this study we tested the feasibility of use and acceptance of a remotely controlled robot with video-communication capability in independently living, cognitively intact older adults. MATERIALS AND METHODS: A mobile remotely controlled robot with video-communication ability was placed in the homes of eight seniors. The attitudes and preferences of these volunteers and those of family or friends who communicated with them remotely via the device were assessed through survey instruments. RESULTS: Overall experiences were consistently positive, with the exception of one user who subsequently progressed to a diagnosis of mild cognitive impairment. Responses from our participants indicated that in general they appreciated the potential of this technology to enhance their physical health and well-being, social connectedness, and ability to live independently at home. Remote users, who were friends or adult children of the participants, were more likely to test the mobility features and had several suggestions for additional useful applications. CONCLUSIONS: Results from the present study showed that a small sample of independently living, cognitively intact older adults and their remote collaterals responded positively to a remote controlled robot with video-communication capabilities. Research is needed to further explore the feasibility and acceptance of this type of technology with a variety of patients and their care contacts. PMID- 23082795 TI - Increased nociceptive sensitivity and nociceptin/orphanin FQ levels in a rat model of PTSD. AB - BACKGROUND: Clinical studies indicate that post-traumatic stress disorder (PTSD) frequently shares co-morbidity with chronic pain. Although in animals acute stress-induced antinociception is well documented, the effect of PTSD-like stress on nociceptive sensitivity is unclear. Though a few studies measured nociceptive responses at a single time point, no studies have examined changes in nociceptive sensitivity over time following exposure to PTSD-like stress. Nociceptin/orphanin FQ (N/OFQ), an endogenous ligand for the N/OFQ peptide (NOP) receptor, modulates various biological functions in the central nervous system that are affected by PTSD, including nociceptive sensitivity, stress and anxiety, learning and memory. RESULTS: The present study examined thermal and mechanical nociceptive sensitivity in male Sprague Dawley rats between 7 and 28 days after single prolonged stress (SPS), an established animal model for PTSD. Rat paw withdrawal thresholds (PWT) to von Frey and paw withdrawal latencies (PWL) to radiant heat stimuli, respectively, dramatically decreased as early as 7 days after initiation of SPS and lasted the length of the study, 28 days. In addition, N/OFQ levels increased in cerebrospinal fluid (CSF; on days 9, 14 and 28) and serum (day 28), while levels of circulating corticosterone (CORT) decreased 28 days after initiation of SPS. SPS exposure induced anxiety-like behavior and enhanced inhibition of the hypothalamo-pituitary-adrenal (HPA) axis, as previously reported for this model. CONCLUSIONS: Our results demonstrate that SPS induces the development of persistent mechanical allodynia and thermal hyperalgesia that is accompanied by increased N/OFQ content in the CSF, and eventually, in serum. These findings suggest a link between N/OFQ and the development of hyperalgesia and allodynia in a rat model of PTSD. PMID- 23082796 TI - Frequency, patterns, and preferences of lubricant use during anal intercourse within male sexual partnerships in Lima, Peru: implications for a rectal microbicide HIV prevention intervention. AB - Understanding current practices of lubricant use during anal intercourse can help to assess the contexts for the introduction of topical rectal microbicides as an HIV prevention tool for men who have sex with men (MSM). We used quantitative and qualitative methods to assess: current patterns of lubricant use; preferred characteristics of commercial lubricant formulations; and social and behavioral contexts of lubricant use within male sexual partnerships in Lima, Peru. Between 2007 and 2008, we conducted a quantitative behavioral survey with 547 MSM followed by qualitative individual and group interviews with 36 MSM from Lima, Peru. Approximately half of all participants in the quantitative survey (50.3%) reported using commercial lubricant during intercourse occasionally or consistently during the preceding two months, with lack of availability at the time of intercourse the most commonly reported reason for non-use. No clear preferences regarding the color, smell, taste, or viscosity of commercial lubricants were identified, and all participants who reported using a commercial lubricant used the same product ("Love-Lub"). In the qualitative analysis, participants characterized lubricant use as a sexual practice consistently controlled by the receptive partner, who typically obtained and applied lubricant independently, with or without the consent of the insertive partner. Quantitative findings supported this differential pattern of lubricant use, with men who reported sexual identities or roles consistent with receptive anal intercourse, including unprotected receptive intercourse, more likely to report lubricant use than MSM who claimed an exclusively insertive sexual role. Given the social, behavioral, and biological factors contributing to increased vulnerability for HIV and STI acquisition by the receptive partner in anal intercourse, delivery of a topical rectal microbicide as a lubricant formulation could provide an important HIV prevention resource for at-risk MSM in Lima, Peru. PMID- 23082797 TI - Brain structure abnormalities in adolescent girls with conduct disorder. AB - BACKGROUND: Conduct disorder (CD) in female adolescents is associated with a range of negative outcomes, including teenage pregnancy and antisocial personality disorder. Although recent studies have documented changes in brain structure and function in male adolescents with CD, there have been no neuroimaging studies of female adolescents with CD. Our primary objective was to investigate whether female adolescents with CD show changes in grey matter volume. Our secondary aim was to assess for sex differences in the relationship between CD and brain structure. METHODS: Female adolescents with CD (n = 22) and healthy control participants matched in age, performance IQ and handedness (n = 20) underwent structural magnetic resonance imaging. Group comparisons of grey matter volume were performed using voxel-based morphometry. We also tested for sex differences using archive data obtained from male CD and control participants. RESULTS: Female adolescents with CD showed reduced bilateral anterior insula and right striatal grey matter volumes compared with healthy controls. Aggressive CD symptoms were negatively correlated with right dorsolateral prefrontal cortex volume, whereas callous-unemotional traits were positively correlated with bilateral orbitofrontal cortex volume. The sex differences analyses revealed a main effect of diagnosis on right amygdala volume (reflecting reduced amygdala volume in the combined CD group relative to controls) and sex-by-diagnosis interactions in bilateral anterior insula. CONCLUSIONS: We observed structural abnormalities in brain regions involved in emotion processing, reward and empathy in female adolescents with CD, which broadly overlap with those reported in previous studies of CD in male adolescents. PMID- 23082799 TI - Highly proliferative sellar chordoma with unusually rapid recurrence. AB - Chordomas are tumors of notochordal differentiation of low to intermediate grade malignancy. These tumors are typically slow growing, with an indolent but progressive clinical course. We present a case of a highly proliferative chordoma arising in a 73-year-old woman with unusually rapid clinical growth and aggressive histologic and immunohistochemical features. This patient had an unusually brief preclinical course and within 1 month of developing headaches presented to medical attention with diplopia. The resected chordoma showed uncommonly elevated mitotic activity, without the histologic hallmarks of de differentiation. This proliferative activity correlated with elevated Ki67 staining (60%), B-cell leukemia/lymphoma1 (BCL1) expression (100%), and topoisomerase IIalpha staining (>95%). E-cadherin expression was also lost throughout the majority of the tumor. Other markers of epithelial mesenchymal transition (EMT) including vimentin, N-cadherin, Slug and Twist, were also strongly expressed in this aggressive tumor. The sellar component of the tumor recurred within a 2-month interval. The evaluation of the additional biomarkers, including makers of EMT studied in this, case may allow for identification of aggressive chordomas in which the tempo of disease is significantly more rapid than in typical cases of chordoma. PMID- 23082798 TI - Optimal glycemic control in neurocritical care patients: a systematic review and meta-analysis. AB - INTRODUCTION: Hyper- and hypoglycemia are strongly associated with adverse outcomes in critical care. Neurologically injured patients are a unique subgroup, where optimal glycemic targets may differ, such that the findings of clinical trials involving heterogeneous critically ill patients may not apply. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing intensive insulin therapy with conventional glycemic control among patients with traumatic brain injury, ischemic or hemorrhagic stroke, anoxic encephalopathy, central nervous system infections or spinal cord injury. RESULTS: Sixteen RCTs, involving 1248 neurocritical care patients, were included. Glycemic targets with intensive insulin ranged from 70-140 mg/dl (3.9-7.8 mmol/L), while conventional protocols aimed to keep glucose levels below 144-300 mg/dl (8.0-16.7 mmol/L). Tight glycemic control had no impact on mortality (RR 0.99; 95% CI 0.83-1.17; p = 0.88), but did result in fewer unfavorable neurological outcomes (RR 0.91; 95% CI 0.84-1.00; p = 0.04). However, improved outcomes were only observed when glucose levels in the conventional glycemic control group were permitted to be relatively high [threshold for insulin administration > 200 mg/dl (> 11.1 mmol/L)], but not with more intermediate glycemic targets [threshold for insulin administration 140-180 mg/dl (7.8-10.0 mmol/L)]. Hypoglycemia was far more common with intensive therapy (RR 3.10; 95% CI 1.54-6.23; p = 0.002), but there was a large degree of heterogeneity in the results of individual trials (Q = 47.9; p<0.0001; I2 = 75%). Mortality was non significantly higher with intensive insulin in studies where the proportion of patients developing hypoglycemia was large (> 33%) (RR 1.17; 95% CI 0.79-1.75; p = 0.44). CONCLUSIONS: Intensive insulin therapy significantly increases the risk of hypoglycemia and does not influence mortality among neurocritical care patients. Very loose glucose control is associated with worse neurological recovery and should be avoided. These results suggest that intermediate glycemic goals may be most appropriate. PMID- 23082800 TI - Evaluation of the microbial community in industrial rye sourdough upon continuous back-slopping propagation revealed Lactobacillus helveticus as the dominant species. AB - AIMS: To assess the structure and stability of a dominant lactic acid bacteria (LAB) population during the propagation of rye sourdough in an industrial semi fluid production over a period of 7 months. METHODS AND RESULTS: The sourdough was started from a 6-year-old freeze-dried sourdough originating from the same bakery. A unique microbial consortium consisting mainly of bacteria belonging to species Lactobacillus helveticus, Lactobacillus panis and Lactobacillus pontis was identified based on culture-dependent (Rep-PCR) and culture-independent [denaturing gradient gel electrophoresis (DGGE)] methods. Three of the isolated Lact. helveticus strains showed remarkable adaptation to the sourdough conditions. They differed from the type strain by the ability to ferment compounds specific to plant material, like salicin, cellobiose and sucrose, but did not ferment lactose. CONCLUSION: We showed remarkable stability of a LAB consortium in rye sourdough started from lyophilized sourdough and propagated in a large bakery for 7 months. Lactobacillus helveticus was detected as the dominant species in the consortium and was shown to be metabolically adapted to the sourdough environment. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of an established and adapted microbial consortium as a starter is a good alternative to commercial starter strains. PMID- 23082801 TI - Adjunctive clinical effect of a water-cooled Nd:YAG laser in a periodontal maintenance care programme: a randomized controlled trial. AB - BACKGROUND: Various laser systems are currently available for intra-oral use. Neodymium:Yttrium-Aluminium Garnet lasers(Nd:YAG) have been approved by the US Food and Drug Administration for soft tissue treatment in the oral cavity. OBJECTIVES: The aim of this study was to test whether the use of a water-cooled Nd:YAG laser during a maintenance care programme as an adjunct to supragingival and subgingival debridement (scaling and root planing, SRP) with hand and ultrasonic instruments results in clinical improvement compared with SRP alone. MATERIAL AND METHODS: This study was an examiner-blind, randomized and controlled clinical trial using a split-mouth design. Thirty subjects were selected, originally diagnosed with moderate to severe generalized periodontitis, following a periodontal maintenance care programme (PMC). Immediately after SRP in two randomly assigned contra-lateral quadrants, all pockets >=5 mm were additionally treated with a Nd:YAG laser (1064 nm, 4W, 250-MUsec pulse). Clinical assessments [probing pocket depth PPD, bleeding on pocket probing (BOPP)] were performed pre treatment and at 6 months. Based on these assessments, the periodontal inflamed surface area (PISA) was calculated. RESULTS: At 6 months, the clinical parameters had significantly improved for both regimens. No statistically significant differences between treatment modalities were observed for PPD and BOPP scores at any time. PISA scores supported these findings. CONCLUSIONS: In residual pockets >=5 mm, treated in a PMC, the adjunctive use of an Nd:YAG laser does not provide a clinically significant additional advantage. PMID- 23082802 TI - TAC7, an essential component of the plastid transcriptionally active chromosome complex, interacts with FLN1, TAC10, TAC12 and TAC14 to regulate chloroplast gene expression in Arabidopsis thaliana. AB - Transcriptionally active chromosome (TAC) is a fraction of protein/DNA complexes with RNA polymerase activity in the plastid. However, the function of most TAC proteins remains unknown. Here, we isolated two allelic mutants of the gene for a TAC component, TAC7, and performed functional analysis in plastid gene expression and chloroplast development in Arabidopsis. tac7-1 is a mutant with a premature translation termination isolated from a population treated with ethyl methane sulfonate, and tac7-2 is a transfer-DNA tagging mutant. Both of them showed an albino phenotype when grown under normal light conditions, and a few appressed membranes were observed inside the defective chloroplasts. These data indicate that TAC7 is important for thylakoid biogenesis. The TAC7 gene encodes an uncharacterized 161 amino acids polypeptide localized in chloroplast. The transcriptional levels of plastid-encoded polymerase (PEP)-dependent genes were downregulated in tac7-2, suggesting that PEP activity was decreased in the mutant. Yeast two-hybrid assay shows that TAC7 can interact with the four TAC components including FLN1, TAC10, TAC12 and TAC14 which are involved in redox state changes, phosphorylation processes and phytochrome-dependent light signaling, respectively, These data indicate that TAC7 plays an important role for TAC to regulate PEP-dependent chloroplast gene expression and chloroplast development. PMID- 23082803 TI - Occurrence of metachronous pure germinomas long after treatment of a mixed germ cell tumor containing yolk sac tumor and germinoma. AB - The authors report a rare case involving the occurrence of metachronous pure germinomas long after treatment of a mixed germ cell tumor (GCT) categorized as having a poor prognosis. A neurohypophysial germinoma occurred 4 years and 6 months after the initial treatment of a mixed pineal GCT containing a yolk sac tumor and a germinoma. Furthermore, intramedullary germinomas occurred 21 years after the initial treatment of the mixed GCT and 15 years after the second treatment of the neurohypophysial germinoma. The neurohypophysial germinoma was not confirmed histopathologically, but the intramedullary germinoma was histopathologically diagnosed as a pure germinoma. Serum alpha-fetoprotein levels at the second neurohypophysial and third intramedullary occurrences of the germinomas were less than 10 ng/ml. Therefore, no yolk sac components seemed to be contained in the tumors. The second neurohypophysial and third intramedullary germinomas might be recurrences of the germinoma component of the pineal mixed GCT, which consisted of a yolk sac tumor and a germinoma. However, it seems very unlikely that only the germinoma, categorized in the good prognosis group, would be the only one to recur. Hence, it seems plausible that both the second and the third occurrences of pure germinoma were de novo metachronous GCTs arising after the pineal mixed GCT was cured. The authors' case indicates the possibility of multicentric GCTs in the CNS. PMID- 23082804 TI - Growth of extremely preterm infants born in 2001-2010. PMID- 23082805 TI - Hematopoietic colony formation from human growth factor-dependent TF1 cells and human cord blood myeloid progenitor cells depends on SHP2 phosphatase function. AB - The protein tyrosine phosphatase, SHP2, is widely expressed; however, previous studies demonstrated that hematopoietic cell development more stringently requires Shp2 expression compared to other tissues. Furthermore, somatic gain-of function SHP2 mutants are commonly found in human myeloid leukemias. Given that pharmacologic inhibitors to SHP2 phosphatase activity are currently in development as putative antileukemic agents, we conducted a series of experiments examining the necessity of SHP2 phosphatase activity for human hematopoiesis. Anti-sense oligonucleotides to human SHP2 coding sequences reduced human cord blood- and human cell line, TF1-derived colony formation. Expression of truncated SHP2 bearing its Src homology 2 (SH2) domains, but lacking the phosphatase domain similarly reduced human cord blood- and TF1-derived colony formation. Mechanistically, expression of truncated SHP2 reduced the interaction between endogenous, full-length SHP2 with the adapter protein, Grb2. To verify the role of SHP2 phosphatase function in human hematopoietic cell development, human cord blood CD34+ cells were transduced with a leukemia-associated phosphatase gain-of function SHP2 mutant or with a phosphatase dead SHP2 mutant, which indicated that increased phosphatase function enhanced, while decreased SHP2 phosphatase function reduced, human cord blood-derived colonies. Collectively, these findings indicate that SHP2 phosphatase function regulates human hematopoietic cell development and imply that the phosphatase component of SHP2 may serve as a pharmacologic target in human leukemias bearing increased SHP2 phosphatase activity. PMID- 23082807 TI - Protein profiling of active cysteine cathepsins in living cells using an activity based probe containing a cell-penetrating peptide. AB - Cell-permeable activity-based probes (ABPs) are capable of labeling target proteins in living cells, thereby providing a powerful tool for profiling active enzymes in their native environment. In this study, we describe the synthesis and use of a novel trifunctional cell-permeable activity-based probe (TCpABP) for proteomic profiling of active cysteine cathepsins in living cells. We demonstrate that although TCpABP contains cell-impermeable tags, it was able to enter living cells efficiently via the delivery of a cell-penetrating peptide. TCpABP also allowed simultaneous detection and affinity isolation of labeled proteins with a fluorophore and a biotin motif, respectively. We optimized the enrichment protocol to minimize contaminants and identified 7 cathepsins, 2 of which have never been identified using existing ABPs. We also used a label-free quantification approach to quantify the relative abundances of active cathepsins and compared them with their previously published mRNA expression levels. A high degree of correlation between the mRNA expression levels and protein relative activities was observed for most of the identified cathepsins except cathepsin H. The results herein indicate that TCpABP is valuable for the detection of active cathepsins in living cells and provides useful guidelines for designing novel cell-permeable ABPs for in vivo labeling and their applications in in vivo proteomics studies. PMID- 23082808 TI - Antipsychotic-like activity of noni (Morinda citrifolia Linn.) in mice. AB - BACKGROUND: Noni fruit is widely consumed in tropical regions of Indonesia to the Hawaiian Islands. The noni plant has a long history of use as a medicinal plant to treat a wide variety of ailments including CNS disorders. The present investigation was designed to evaluate the antipsychotic effect of noni fruits (Morinda citrifolia Linn.) using mouse models of apomorphine-induced climbing behaviour and methamphetamine-induced stereotypy (licking, biting, gnawing and sniffing). METHODS: In acute study, the methanolic extract of Morinda citrifolia (MMC) at different doses 1, 3, 5, 10 g/kg was administered orally one hour prior to apomorphine (5 mg/kg, i.p) and methamphetamine (5 mg/kg, i.p) injection respectively in Swiss albino mice. In chronic studies, (TAHITIAN NONI(r) Juice, TNJ) was made available freely in daily drinking water at 30, 50 and 100% v/v for 7 days; 30 and 50% v/v for 21 days respectively. On the test day, an equivalent average daily divided dose of TNJ was administered by oral gavage one hour prior to apomorphine treatment. Immediately after apomorphine/ methamphetamine administration, the animals were placed in the cylindrical metal cages and observed for climbing behaviour/ stereotypy and climbing time. RESULTS: The acute treatment of MMC (1, 3, 5, 10 g/kg, p.o) significantly decreased the apomorphine induced cage climbing behaviour and climbing time in mice in a dose dependent manner. The MMC also significantly inhibited methamphetamine-induced stereotypy behaviour and climbing time in mice dose-dependently. The 7 and 21 days treatment of TNJ in drinking water at 50 and 100%v/v significantly alleviated the apomorphine-induced climbing behaviour and climbing time in mice. CONCLUSIONS: The present study results demonstrated the antidopaminergic effect of Morinda citrifolia Linn. in mice, suggesting that noni has antipsychotic-like activity which can be utilized in the treatment of psychiatric disorders. However further studies are warranted to identify the active principles responsible for the antipsychotic activity of noni. PMID- 23082809 TI - Biologics for psoriasis: current evidence and future use. PMID- 23082810 TI - Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. AB - Conventional non-biologic systemic agents are regarded as second-line therapy for the treatment of moderate-to-severe plaque psoriasis after topical treatments. However, long-term data have highlighted a number of safety concerns associated with their prolonged use. Biologic agents targeting specific immune mediators have emerged as an alternative treatment option for patients with moderate-to severe plaque psoriasis who are unresponsive to, or intolerant of, non-biologic systemic agents. Although several biologics have demonstrated good efficacy and tolerability in short-term trials, treatment guidelines recommend them as third line therapies due to a relative lack of long-term safety data. Here, we have reviewed the long-term (>= 1 year) safety data from randomized controlled trials, open-label extension studies and meta-analyses of etanercept, infliximab, efalizumab, adalimumab, alefacept and ustekinumab in the treatment of adults with moderate-to-severe plaque psoriasis. With the exception of efalizumab, which has been withdrawn from both the European and U.S. markets due to long-term safety concerns, these biologics are generally well tolerated in long-term studies, and offer a viable alternative to conventional non-biologic agents in patients with moderate-to-severe plaque psoriasis. PMID- 23082811 TI - Sequential use of biologics in the treatment of moderate-to-severe plaque psoriasis. AB - A number of biologic agents, including the tumour necrosis factor (TNF) antagonists etanercept, adalimumab and infliximab, and the interleukin (IL)-12/IL 23 antagonist ustekinumab, are available for the treatment of moderate-to-severe plaque psoriasis in the U.K. Currently, the selection of the first biologic, and the choice of sequential biologics in the event of efficacy/tolerability concerns, is made using a limited evidence base. The efficacy of biologics, the potential mechanisms of primary and secondary failure and the evidence for sequencing therapy among TNF antagonists and between TNF antagonists and IL-12/IL 23 blockade are reviewed. As psoriasis biologics registers begin to produce long term safety and efficacy data, therapy decisions in plaque psoriasis may become more objective, and it may be possible to individualize treatment based on clinical or pharmacogenetic information. PMID- 23082812 TI - Sequential use of biologics in moderate-to-severe plaque psoriasis: case studies illustrating an individualized approach. AB - Biologics have added great value to the treatment of psoriasis; however, there is currently little guidance on which biologic to use and at what stage of disease, and even less guidance on how to switch therapy in the event of treatment failure or the occurrence of side-effects. Furthermore, drug switching may not always be essential in cases of biologic failure, and adding conventional systemics has a role in some patients. It is clear that we have limited data to support any particular policy in initiating and switching biologics in psoriasis, but a pragmatic approach to therapy is supported by the case reports described within this article. Specifically, the case studies include patients who were initiated on different biologics and subsequently switched to alternatives for a variety of reasons, such as unresponsiveness or a concomitant disease. As more evidence emerges from long-term studies and registry data, a clearer picture should emerge on how best to use biologics in different situations to aid successful treatment outcomes. Comparative studies are necessary before firm recommendations about sequential use can be made. PMID- 23082813 TI - Structural and sequence analysis of the human gammaD-crystallin amyloid fibril core using 2D IR spectroscopy, segmental 13C labeling, and mass spectrometry. AB - Identifying the sequence and structural content of residues that compose the core of amyloid fibrils is important because core regions likely control the process of fibril extension and provide potential drug targets. Human gammaD-crystallin is an eye lens protein that aggregates into amyloid fibrils under acidic conditions. In this manuscript, we use a pepsin enzymatic digest to isolate the core of the amyloid fibrils. The sequence of the core is identified with MALDI MS/MS and its structure is probed with 2D IR spectroscopy and (13)C isotope labeling. Mass spectrometry of the digest identifies residues 80-163 as the amyloid core, which spans most of the C-terminal domain, the linker, and a small portion of the N-terminal domain. From 2D IR spectroscopy of the digested fibrils, we learn that only the C-terminal domain contributes to the amyloid beta sheets while the N-terminal and linker residues are disordered. A comparison to the native crystal structure reveals that loops and alpha-helices in the native state must undergo conformational transitions to beta-strands upon aggregation. These locations may be good drug binding targets. Besides providing new information about gammaD-crystallin, this study demonstrates the complementarity of mass spectrometry and 2D IR spectroscopy to obtain both sequence and structure information that neither technique provides individually, which will be especially useful for samples only available in microgram quantities. PMID- 23082814 TI - Vibrational probes and determinants of the S = 0 ? S = 2 spin crossover in five coordinate [Fe(TPP)(CN)]-. AB - The low-frequency vibrational characterization of the spin-crossover complex, five-coordinate cyano(tetraphenylporphyrinato)iron(II), [Fe(TPP)(CN)](-), is reported. Nuclear resonance vibrational spectroscopy has been used to measure all low-frequency vibrations involving iron at several temperatures; this yields vibrational spectra of both the low- (S = 0) and high-spin (S = 2) states. Multitemperature oriented single-crystal measurements facilitate assignments of the vibrational character of all modes and are consistent with the DFT-predicted spectra. The availability of the entire iron vibrational spectrum allows for the complete correlation of the modes between the two spin states. These data demonstrate that not only do the frequencies of the vibrations shift to lower values for the high-spin species as would be expected owing to the weaker bonds in the high-spin state, but also the mixing of iron modes with ligand modes changes substantially. Diagrams illustrating the changing character of the modes and their correlation are given. The reduced iron-ligand frequencies are the primary factor in the entropic stabilization of the high-spin state responsible for the spin crossover. PMID- 23082815 TI - Competitive ligand exchange between Cu-humic acid complexes and methanobactin. AB - Copper has been found to play a key role in the physiology of methanotrophic micro-organisms, and methane oxidation may critically depend on the availability of Cu. In natural environments, such as soils, sediments, peat bogs, and surface waters, the presence of natural organic matter (NOM) can control the bioavailability of Cu by forming strong metal complexes. To promote Cu acquisition, methanotrophs exude methanobactin, a ligand known to have a high affinity for Cu. In this study, the capability of methanobactin for Cu acquisition from NOM was investigated using humic acid (HA) as a model substance. The kinetics of ligand exchange between Cu-HA and methanobactin was observed by UV-vis spectroscopy, and the speciation of Cu bound to methanobactin was determined by size-exclusion chromatography coupled to an ICP-MS. The results showed that Cu was mobilized from HA by a fast ligand exchange reaction following a second-order rate law with first-order kinetics for both methanobactin and Cu HA complexes. The reaction rates decreased with decreasing temperature. Equilibrium experiments indicated that methanobactin was not sorbed to HA and proved that methanobactin is competitive with HA for Cu binding by forming strong 1:1 Cu-methanobactin complexes. Consequently, our results demonstrate that methanobactin can efficiently acquire Cu in organic-rich environments. PMID- 23082816 TI - Robust algorithm for aligning two-dimensional chromatograms. AB - Comprehensive two-dimensional gas chromatography (GC * GC) chromatograms typically exhibit run-to-run retention time variability. Chromatogram alignment is often a desirable step prior to further analysis of the data, for example, in studies of environmental forensics or weathering of complex mixtures. We present a new algorithm for aligning whole GC * GC chromatograms. This technique is based on alignment points that have locations indicated by the user both in a target chromatogram and in a reference chromatogram. We applied the algorithm to two sets of samples. First, we aligned the chromatograms of twelve compositionally distinct oil spill samples, all analyzed using the same instrument parameters. Second, we applied the algorithm to two compositionally distinct wastewater extracts analyzed using two different instrument temperature programs, thus involving larger retention time shifts than the first sample set. For both sample sets, the new algorithm performed favorably compared to two other available alignment algorithms: that of Pierce, K. M.; Wood, Lianna F.; Wright, B. W.; Synovec, R. E. Anal. Chem.2005, 77, 7735-7743 and 2-D COW from Zhang, D.; Huang, X.; Regnier, F. E.; Zhang, M. Anal. Chem.2008, 80, 2664-2671. The new algorithm achieves the best matches of retention times for test analytes, avoids some artifacts which result from the other alignment algorithms, and incurs the least modification of quantitative signal information. PMID- 23082817 TI - Chronic asymptomatic inflammation of the prostate type IV and carcinoma of the prostate: is there a correlation? AB - OBJECTIVE: The aim of this study was to detect possible correlations between chronic asymptomatic inflammation of the prostate type IV and prostate cancer in patients undergoing radical prostatectomy (RPE). MATERIAL AND METHODS: Between January and December 2010, 57 RPE specimens were prospectively evaluated with regard to histological signs of chronic inflammation. This RPE group was compared to specimens of 82 men undergoing transurethral resection of the prostate (TURP) or transvesical enucleation (TVE) of a benign prostate (BPH group). To characterize inflammatory changes, inflammatory "hot spots" were defined according to the histological criteria of Irani et al. (J Urol 1997;157:1301-3). Total prostate-specific antigen (PSA), cholesterol, triglycerides, uric acid, International Prostate Symptom Score and body mass index (BMI) were evaluated preoperatively and were correlated to the histological findings. RESULTS: Chronic inflammation was verified in 43.86% of the RPE group, compared to 70.74% of the BPH group (p < 0.001). Multivariate analysis found a significant correlation between older patients and the inflammation score (p < 0.03) and prostate volume (p < 0.03). There was no difference in the PSA values between the inflammation and non-inflammation groups: mean PSA was 5.7 vs 6.1 ng/ml in the RPE group (p < 0.89), and 2.8 vs 2.9 ng/ml in the BPH group (p < 0.94). Gleason score distribution (5-9) and tumour stage (TNM) were similar in the inflammation and non-inflammation groups (p < 0.99, p < 0.21). CONCLUSIONS: No significant correlation between chronic prostatic inflammation and carcinoma of the prostate was detected. Contrary to expectations, a significantly higher score of inflammatory changes was found in BPH patients; also, total PSA levels were lower in the inflammation group. PMID- 23082818 TI - Travestis, an unexplored population at risk of HIV in a large metropolis of northeast Brazil: a respondent-driven sampling survey. AB - Travestis are highly vulnerable to HIV infection in Brazil. We conducted a survey among 304 travestis using Respondent-Driven Sampling from August to December 2008. Travestis are young (49% <24 years), poorly educated (55% just elementary school), low social class (62% Class C-E), reside with families (49%) or friends/madam (22%), are victims of homophobia (91%) and violence (61%). They report early sexual debut (75% <14), many sexual partners, drug use during sex (43%), and unprotected sex (male partner, 47%, both male and female partners, 50%). Sex work is common (82%, 59% >10 partners last six months) and relatively low cost (median=US$24). A majority report testing for HIV (69%), and report high prevalence (12% disclosed a positive result). Almost all the respondents refused to test in the study. Interventions, targeted to both travestis and to the general community about sexual discrimination, are necessary. PMID- 23082820 TI - Syntheses and applications of functionalized bicyclo[3.2.1]octanes: thirteen years of progress. PMID- 23082819 TI - A comprehensive morphological study for basal-like breast carcinomas with comparison to nonbasal-like carcinomas. AB - BACKGROUND: Breast carcinomas can be classified into five subtypes based on gene expression profiling or immunohistochemical characteristics. Among these subtypes, basal-like breast carcinomas (BLBCs) are one of the most studied group, due to their poor prognosis. The aim of this study was to investigate the prevalance, morphological and immunohistochemical features of BLBCs, in Turkish population. METHODS: Five hundred invasive breast carcinomas were reviewed for several morphological features and immunostained for oestrogen and progesterone receptors, c-ERB-B2, cytokeratin5/6, cytokeratin14, vimentin and epidermal growth factor receptor (EGFR). Basal-like breast carcinoma was defined as a triple negative tumor with cytokeratin5/6 and/or EGFR positive. RESULTS: The prevalance of BLBC was 9.6%. All medullary carcinomas and 55.6% of metaplastic carcinomas showed basal-like immunophenotype. Patients with BLBC were younger (p=0.04) and had higher-grade tumors (p<0.0001). Morphologic features associated with BLBC included increased mitosis, nuclear pleomorphism, presence of geographic and/or central necrosis, pushing margin of invasion and stromal lymphocytic response (p<0.0001). Presence of prominent nucleoli and vesicular nuclear chromatin were the cytological features correlated with basal-like phenotype (p<0.0001). On multivariate analyses, BLBCs were associated with high mitotic number (p<0.0001), the presence of vesicular chromatin (p=0.004), high tubular grade (p=0.011), lymphocytic response (p=0.031) and the absence of carcinoma insitu (p=0.039). Vimentin was positive in 53.2% of BLBCs, while cytokeratin14 was less frequently expressed (27.7%). CONCLUSIONS: BLBCs have some distinctive, but not pathognomonical, morphological features. Paying attention to these features and adding cytokeratin14 and vimentin to the immunohistochemical panel can help the definitive diagnosis of BLBCs. VIRTUAL SLIDE: Http://www.diagnosticpathology.diagnomx.eu/vs/5962175467857400. PMID- 23082821 TI - Purifying and concentrating genomic DNA from mock forensic samples using Millipore Amicon filters. AB - Regenerated cellulose filters are used for concentrating and purifying genomic DNA from casework samples, due to the high yields and low retentate volumes that these filters provide. The Millipore Ultracel YM-100 is an example of this filter type and has been available to the forensics community for this application since 1990. In 2002, Millipore introduced the Amicon line of vertical filters that provide a larger area for filtration and have a dead space to prevent spinning to dryness. In the present study, Amicon filters were optimized in terms of g force and spin times for their ability to concentrate and purify genomic DNA. The Amicon Ultra 0.5 mL 30 K was used with mock forensic samples containing as little as 160 buccal cells, 20 nL of blood, or 8 nL of semen. In conclusion, the Amicon line of filters can be used to purify genomic DNA from small numbers of cells. PMID- 23082822 TI - Elevated CO(2) and drought stress effects on the chemical composition of maize plants, their ruminal fermentation and microbial diversity in vitro. AB - Climate changes are supposed to influence productivity and chemical composition of plants. In the present experiments, it was hypothesised that the incubation of plants exposed to elevated atmospheric carbon dioxide concentrations ([CO2]) and drought stress will result in different ruminal fermentation pattern and microbial diversity compared to unaffected plants. Maize plants were grown, well watered under ambient (380 ppm CO2, Variant A) and elevated [CO2] (550 ppm CO2, Variant B). Furthermore, each CO2 treatment was also exposed to drought stress (380 ppm and 550 ppm CO2,Variants C and D, respectively), which received only half as much water as the well-watered plants. Plant material from these treatments was incubated in a semi-continuous in vitro fermentation experiment using the rumen simulation technique. Single strand conformation polymorphism (SSCP) analysis was conducted for Bacteria and Archaea specific profiles. The analysis of crude nutrients showed higher contents of fibre fraction in drought stress Variants C and D. Crude protein content was increased by drought stress under ambient but not under elevated [CO2]. Fermentation of drought stress variants resulted in significantly increased pH values, decreased digestibilities of organic matter and increased ammonia-N (NH3-N) concentrations compared with well-watered variants. Additionally, the 550 ppm CO2 Variants B and D showed significantly lower NH3-N concentrations than Variants A and C. The Bacteria- and Archaea-specific SSCP profiles as well as the production rates of short-chain fatty acids and their molar percentages were not affected by treatments. During the first four days of equilibration period, a decrease of molar percentage of acetate and increased molar percentages of propionate were observed for all treatments. These alterations might have been induced by adaptation of the in vitro system to the new substrate. The rumen microflora appeared to be highly adaptive and could cope with altered contents of crude nutrients in plants as induced by elevated [CO2] and drought stress. PMID- 23082823 TI - Exogenous ergosterol protects Saccharomyces cerevisiae from D-limonene stress. AB - AIMS: Enhancement of the tolerance of Saccharomyces cerevisiae to monoterpenes has the potential to improve the de novo biosynthesis of these chemicals as well as the efficient utilization of monoterpene-containing citrus waste. The aims of the current work are to demonstrate the mechanisms by which ergosterol, an important component of cell membranes, protects S. cerevisiae from D-limonene stress and to provide some useful information for further metabolic engineering of the yeast. METHODS AND RESULTS: Saccharomyces cerevisiae cells were treated with a sublethal dose of D-limonene for 2 h, and then ergosterol was added to investigate the physiological responses of S. cerevisiae. In D-limonene-treated cells, the membrane fluidity, permeability and saturated fatty acid ratio increased, whereas the intracellular ergosterol concentration decreased sharply. Addition of ergosterol restored membrane and intracellular ergosterol to normal levels. Exogenous ergosterol triggered nearly all of the genes that encode the biosynthesis of ergosterol. CONCLUSIONS: In S. cerevisiae, the cell membrane is the target of D-limonene. Intracellular ergosterol availability is correlated with the D-limonene tolerance of the cells. SIGNIFICANCE AND IMPACT OF THE STUDY: The results indicate that modification of the ergosterol biosynthesis pathway could be a promising strategy for constructing a robust yeast strain with enhanced tolerance. PMID- 23082824 TI - Effects of salt stress on ion balance and nitrogen metabolism of old and young leaves in rice (Oryza sativa L.). AB - BACKGROUND: It is well known that salt stress has different effects on old and young tissues. However, it remains largely unexplored whether old and young tissues have different regulatory mechanism during adaptation of plants to salt stress. The aim of this study was to investigate whether salt stress has different effects on the ion balance and nitrogen metabolism in the old and young leaves of rice, and to compare functions of both organs in rice salt tolerance. RESULTS: Rice protected young leaves from ion harm via the large accumulation of Na+ and Cl- in old leaves. The up-regulation of OsHKT1;1, OsHAK10 and OsHAK16 might contribute to accumulation of Na+ in old leaves under salt stress. In addition, lower expression of OsHKT1;5 and OsSOS1 in old leaves may decrease frequency of retrieving Na+ from old leaf cells. Under salt stress, old leaves showed higher concentration of NO3- content than young leaves. Up-regulation of OsNRT1;2, a gene coding nitrate transporter, might contribute to the accumulation of NO3- in the old leaves of salt stressed-rice. Salt stress clearly up-regulated the expression of OsGDH2 and OsGDH3 in old leaves, while strongly down-regulated expression of OsGS2 and OsFd-GOGAT in old leaves. CONCLUSIONS: The down regulation of OsGS2 and OsFd-GOGAT in old leaves might be a harmful response to excesses of Na+ and Cl-. Under salt stress, rice might accumulate Na+ and Cl- to toxic levels in old leaves. This might influence photorespiration process, reduce NH4+ production from photorespiration, and immediately down-regulate the expression of OsGS2 and OsFd-GOGAT in old leaves of salt stressed rice. Excesses of Na+ and Cl- also might change the pathway of NH4+ assimilation in old leaves of salt stressed rice plants, weaken GOGAT/GS pathway and elevate GDH pathway. PMID- 23082825 TI - CdS-decorated ZnO nanorod heterostructures for improved hybrid photovoltaic devices. AB - Cadmium sulfide (CdS)-decorated zinc oxide (ZnO) nanorod heterostructures have been grown by a combination of hydrothermal and pulsed laser deposition techniques. Hybrid photovoltaic devices have been fabricated with CdS modified and unmodified ZnO nanorods blended separately with regioregular poly(3 hexylthiophene) (P3HT) polymer as the active layer. The solar cell performance has been studied as a function of ZnO concentration and the casting solvent (chlorobenzene, chloroform, and toluene) in the unmodified ZnO:P3HT devices. The power conversion efficiency is found to be enhanced with the increase of ZnO concentration up to a certain limit, and decreases at a very high concentration. The surface modification of ZnO nanorods with CdS leads to an increase in the open circuit voltage and short-circuit current, with enhanced efficiency by 300% over the unmodified ZnO:P3HT device, because of the cascaded band structure favoring charge transfer to the external circuit. PMID- 23082826 TI - Presence of anti-mullerian hormone in the squirrel monkey (Saimiri boliviensis): gender and seasonal differences. AB - BACKGROUND: Anti-mullerian hormone (AMH) is a glycoprotein of the transforming growth factor-beta superfamily secreted by male Sertoli cells and female ovarian granulosa cells. This study determined squirrel monkey AMH levels as influenced by gender and seasonality. METHODS: Squirrel monkey sera AMH were measured by an enzymatically amplified two-site immunoassay. RESULTS: A significant difference (P<0.001) was found in AMH levels between male (mean=3.46 ng/ml) and female squirrel monkeys (mean=22.12 ng/ml). A significant difference (P<0.05) was found in male AMH levels between breeding (mean=4.21 ng/ml) and non-breeding seasons (mean=2.78 ng/ml). No significant differences were found between female groups. CONCLUSIONS: Anti-mullerian hormone levels in female squirrel monkeys are the highest in any primate species reported, whereas in the male, levels are within reported ranges. The AMH assay may allow us soon to assess the squirrel monkey fertility potential as a function of various factors. PMID- 23082827 TI - Do manualized psychosocial interventions help reduce relapse among alcohol dependent adults treated with naltrexone or placebo? A meta-analysis. AB - BACKGROUND: During the past decade, several novel medication treatments and psychosocial interventions have been tested. Overall, their impact on reducing alcohol use and preventing relapse has been modest. These outcomes have spurred researchers to investigate whether the addition of manualized psychosocial therapies with demonstrated efficacy to pharmacotherpy would have a synergistic effect. OBJECTIVES: We conducted a meta-analysis to test the hypothesis that the addition of manualized psychosocial therapies would reduce the frequency of relapse. RESULTS: This review analyzed data from six studies. Among studies that used random assignment to manually guided psychosocial interventions, the rates of relapse between the naltrexone plus a psychosocial intervention and naltrexone without a psychosocial intervention were very similar. Among patients allocated to placebo, similar rates of relapse were also found between Cognitive Behavioral Therapy (CBT) and non-CBT. In studies which used manualized psychotherapies as a platform, relapse rates were similar between naltrexone and placebo. In contrast, studies using Treatment As Usual psychotherapy as a platform demonstrated lower rates of relapse in the naltrexone group, compared to placebo group. CONCLUSIONS: We conclude that CBT does not appear to offer benefits beyond those derived from study medications. SCIENTIFIC SIGNIFICANCE: The benefit of the addition of CBT to medication in preventing relapse may be limited. PMID- 23082828 TI - Gambling severity, impulsivity, and psychopathology: comparison of treatment- and community-recruited pathological gamblers. AB - BACKGROUND AND OBJECTIVES: Because most studies of pathological gambling gather data from participants recruited from treatment, this study compared community and treatment-enrolled pathological gamblers (PGs) with respect to demographics, gambling severity, impulsivity, and psychopathology. METHODS: One hundred six PGs were recruited as part of two larger studies in Farmington, Connecticut (n= 61) and Windsor, Ontario (n= 45) using radio advertising, word of mouth, and/or newspaper ads, as well as a gambling treatment program at each location. RESULTS: Community (n= 49) and treatment-enrolled (n= 57) PGs did not differ on age, education, gender, race, employment, or marital status. Treatment-enrolled PGs were more likely to report past year illegal behaviors, preoccupation with gambling, and higher scores on the Barratt Impulsiveness Scale (BIS) Attention Impulsivity subscale. Assessment of psychopathology in the Ontario study indicated that treatment-enrolled PGs were more likely to present with Major Depressive and Dysthymic Disorders. Community-recruited PGs in the Connecticut study were overall more likely to present with any substance use disorder relative to their treatment-enrolled counterparts. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our findings inform intervention and research within the field of pathological gambling. Specifically, the distressing aspects of pathological gambling, such as legal issues, preoccupation with gambling, and depression, may be present more in treatment-enrolled PGs than in those recruited from the community. Such emotional disturbances should be further explored to increase motivation and treatment adherence in PGs. In addition, due to relative absence of overall differences between the groups, research findings utilizing treatment enrolled PGs may be a good representation of both groups. PMID- 23082829 TI - Association between adverse life events and addictive behaviors among male and female adolescents. AB - BACKGROUND: Adverse life events have been associated with gambling and substance use as they can serve as forms of escapism. Involvement in gambling and substance use can also place individuals in adversely stressful situations. OBJECTIVES: To explore potential male-female differences in the association between addictive behavior and adverse life events among an urban cohort of adolescents. METHOD: The study sample comprised of 515 adolescent participants in a randomized prevention trial. With self-reported data, four addictive behavior groups were created: nonsubstance users and nongamblers, substance users only, gamblers only, and substance users and gamblers. Multinomial logistic regression analyses with interaction terms of sex and adverse life events were conducted. RESULTS: Adverse life events and engaging in at least one addictive behavior were common for both sexes. Substance users and gamblers had more than twice the likelihood of nonsubstance users and nongamblers to experience any event as well as events of various domains (ie, relationship, violence, and instability). Neither relationship nor instability events' associations with the co-occurrence of substance use and gambling significantly differed between sexes. Conversely, females exposed to violence events were significantly more likely than similarly exposed males to report the co-occurrence of substance use and gambling. CONCLUSION: Findings from the current study prompt future studies to devote more attention to the development of effective programs that teach adaptive coping strategies to adolescents, particularly to females upon exposure to violence. PMID- 23082830 TI - Posttraumatic stress disorder and one-year outcome in methadone maintenance treatment. AB - BACKGROUND: Although opiate use may be associated with posttraumatic stress disorder (PTSD), it is not clear whether PTSD is associated with retention in methadone maintenance. OBJECTIVES: To evaluate among those receiving methadone maintenance at an urban methadone maintenance clinic the frequency of life-time traumatic experiences, the predictors and prevalence of current PTSD, and whether PTSD affects retention at 1 year. METHODS: Eighty-nine people participated in the study. The Post Traumatic Diagnostic Scale was used to determine the prevalence of PTSD. The Life Stressor Checklist Revised was used to evaluate trauma history. Logistic regression analyses examined associations between demographic characteristics, substance use, trauma-related variables, and PTSD. Similar logistic regression analyses were used to examine retention in methadone maintenance at 1 year. RESULTS: The mean number of reported lifetime stressful events was 8.0 (SD = 3.7). Twenty-seven percent were diagnosed with PTSD. Nearly 92% of those with PTSD had co-occurring depressive symptoms. Female gender (adjusted odds ratio [AOR][95% CI]; 3.89 [1.07-14.01]), number of traumatic events (AOR [95% CI]; 1.34 [1.13-1.61]), and less education (AOR [95% CI]; 4.13 [1.14-14.98]) were significantly associated with PTSD. Those with a toxicology positive screen were 80% less likely to remaine in methadone maintenance at 1 year (OR [95% CI]; 0.20 [0.07-0.52]). PTSD diagnosis was not significantly associated with treatment retention at 1 year (OR [95% CI]; 0.61 [0.23-1.64]). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Future studies are needed to determine if treatment of PTSD that is integrated into methadone maintenance programs may impact continued substance abuse use and thereby improve retention in care. PMID- 23082831 TI - Self-reported psychotic disorders among Individuals with substance use disorders: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - BACKGROUND AND OBJECTIVES: Comorbidity of substance use disorders (SUDs) and psychotic disorders (PDs) presents many challenges in diagnosis and treatment. Most reports to-date focus on the prevalence of SUDs among clinical populations of patients with PDs, and there is a lack of data pertaining to rates of PDs among individuals with substance use and SUDs. METHODS: We analyzed data on 43,093 respondents age 18 and above from the National Epidemiologic Survey on Alcohol and Related Conditions, a nationally representative US survey (Wave 1, 2001-2002). Cross-tabulations were used to derive prevalence estimates of PDs among individuals with 12-month substance use or SUDs across 10 categories of substances. Odds ratios (ORs) were derived from bivariate logistic regression analyses to examine the relationships between lifetime PDs and 12-month substance use or SUDs for the specific categories of substances. RESULTS: Among individuals with 12-month substance use, prevalence of PDs was found to be elevated in 8 of 10 categories of substances, particularly among amphetamine (OR = 8.8) and cocaine (OR = 10.3) users compared to nonusers. Among individuals with SUDs, prevalence of PDs was elevated in 9 of 10 categories of substances compared to individuals without SUDs. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our findings on the increased rates of PDs among substance users and individuals with SUDs across a wide range of substances emphasize the importance of screening for PDs while treating patients with substance use and SUDs. This may allow for early intervention and adequate referral to appropriate settings. PMID- 23082832 TI - Depression symptoms associated with cannabis dependence in an adolescent American Indian community sample. AB - BACKGROUND: Depression and substance use disorders, including cannabis dependence, arise during adolescence, are frequently comorbid, and represent major health burdens in the general US population. Yet little is known about the association of depression symptoms with cannabis and other substance use and use disorders in Native American adolescents. OBJECTIVE: To investigate the comorbidity of cannabis use and depression symptoms in Native American adolescents. METHODS: This study used the Children's Semi-Structured Assessment for the Genetics of Alcoholism (Adolescent Version) to obtain lifetime DSM-III-R diagnoses from a community sample of 202 (98 boys, 104 girls) American Indian adolescents living on contiguous reservations. RESULTS: Thirteen percent of boys and 38% of girls had a lifetime DSM-III-R major depression disorder (MDD) independent of substance use. Fifteen percent of boys and 41% of girls had a major depression episode (MDE) either coincident with or independent of cannabis use. MDE and several individual depression symptoms were significantly associated with cannabis dependence in boys but not in girls. The median ages of onset of MDE were the same in the boys and girls who had experienced both depression and cannabis use. CONCLUSIONS: These findings suggest that the association of depression with cannabis dependence is more significant in boys than girls in this population of adolescents. SCIENTIFIC SIGNIFICANCE: Understanding comorbidity between depression and cannabis use is important in order to disentangle the etiological relationship between the two and also for designing more effective treatment and prevention strategies, particularly in Native Americans who are at high risk for both disorders. PMID- 23082833 TI - College drinking among Latinos(as) in the United States and Mexico. AB - BACKGROUND AND OBJECTIVES: Existing studies of Latino(a) college students in the United States suggest that self-reported alcohol consumption tends to be higher among males, and that drinking among Latinas is often influenced by social and contextual factors. The current study extended this work by examining both self reported drinking levels and predictors of drinking among Latino(a) college students in the United States and Mexico (MX). METHODS: Latino(a) college students (N = 376) from three universities in the South Central United States and Northern Mexico completed pencil-and-paper surveys about alcohol. RESULTS: US Latino students (vs. MX males), reported drinking more frequently and had more positive expectancies about alcohol. Latinas in the United States (vs. MX females) were more likely to report regular drinking. Across countries, both female gender and the Mexican orientation component of acculturation predicted lower reported alcohol consumption. Positive expectancies about drinking predicted increased drinking. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Self reported college drinking and expectancies about alcohol may differ subtly among individuals in the United States and Mexico based on gender and endorsement of traditional Mexican values. These findings could ultimately be applied to the development of more tailored programs for the treatment and prevention of alcohol abuse on college campuses. PMID- 23082834 TI - Differences in drinking patterns, occupational stress, and exposure to potentially traumatic events among firefighters: predictors of smoking relapse. AB - BACKGROUND AND OBJECTIVES: Despite the increased awareness regarding the risks of cigarette smoking, this behavior continues to be a serious public health concern. As such, the goal of the current study was to examine risk factors for smoking relapse among individuals employed through fire service. METHODS: In this report, drinking changes, trauma exposure, and occupational stress were compared among firefighters (N = 81) who reported a relapse to cigarette smoking (n = 27), a lifetime former history of smoking (n = 27), or no history of smoking (n = 27). Mechanisms behind tobacco relapse occurring after employment in fire service were explored. RESULTS: Firefighters who relapsed to smoking, when compared to their nonsmoking peers, had higher rates of weekly alcohol consumption throughout their first year of fire service and had greater increases in drinking from preacademy to postacademy. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Gaining a better understanding of these behaviors within this understudied and high-risk population may provide valuable information that can be used in designing future relapse prevention strategies as well as smoking cessation interventions. PMID- 23082835 TI - Effects on smokers of exposure to graphic warning images. AB - BACKGROUND AND OBJECTIVES: Several countries have introduced graphic warning images aimed at discouraging smoking. The objective of this study was to evaluate the impact on smokers of graphic warnings showing cosmetically important harm caused by smoking. METHODS: Fifty-six adult smokers were randomly assigned to view either written smoking warnings or the same written warnings with related graphic images. The smokers viewed the warnings at a rate of one per week for 4 weeks. The smokers were assessed before and after the warnings with regard to stage of change toward smoking cessation and level of smoking. RESULTS: The randomized control trial showed that the warnings with graphic images led to significantly more progress in stage of change toward smoking cessation than written warnings alone. However, the images did not lead to decreases in smoking rates. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The results indicate that written smoking warnings accompanied by images of cosmetically important harm caused by smoking have more potential than warnings alone in prompting changes in the direction of quitting. PMID- 23082838 TI - Adverse effects and detection of synthetic cannabinoids. PMID- 23082836 TI - Impact of nursing intervention on decreasing substances among homeless youth. AB - BACKGROUND: Alcohol use, and in particular, binge drinking, and methamphetamine use is pervasive among homeless youth and remains a social pressure among this vulnerable population. However, there is no compelling evidence that specific interventions for reducing drug and alcohol use are effective for homeless youth. OBJECTIVES: This community-based participatory action pilot study assessed the impact of an intervention study focused on decreasing use of drugs and alcohol among a sample of homeless young adults (N= 154) visiting a drop-in site in Santa Monica, California. The two programs consisted of an HIV/AIDS and Hepatitis Health Promotion (HHP) program led by nurses and an Art Messaging (AM) program led by artists. Six-month follow-up data were obtained from 100 of these individuals. RESULTS: Findings revealed significant reductions in alcohol and marijuana use and binge drinking in both the HHP and AM programs. However, homeless youth in the HHP program reported additional reductions in methamphetamine, cocaine, and hallucinogen use at 6-month follow-up. CONCLUSIONS: Reductions in drugs and alcohol are important as these substances are linked to HIV/AIDS, hepatitis, and other health risks in homeless youth. SCIENTIFIC SIGNIFICANCE: The successful outcomes of the study intervention validate the utility of nurse-led and artistic health promotion strategies to decrease drug and alcohol use and other risky behaviors in homeless youth populations. PMID- 23082839 TI - Mania, cocaine, and rhabdomyolysis: a case report. PMID- 23082840 TI - "Bath salts": a new drug epidemic-a case report. PMID- 23082841 TI - Virado: a new method of crack consumption in Brazil. PMID- 23082842 TI - Circadian dysregulation, zolpidem dependence, and withdrawal seizure in a resident physician performing shift work. PMID- 23082843 TI - Ulnar nerve tuberculoma. AB - The authors report a very rare case of tuberculoma involving the ulnar nerve. The patient, a 7-year-old girl, presented with swelling over the medial aspect of her right forearm just below the elbow joint, with features of ulnar nerve palsy, including paresthesias along the little and ring fingers and claw hand deformity. There was a history of trauma and contact with a contagious case of tuberculosis. There were no other signs of tuberculosis. At surgical exploration the ulnar nerve was found to be thickened, and on opening the sheath there was evidence of caseous material enclosed in a fibrous capsule compressing and displacing the nerve fibers. The lesion, along with the capsule, was subtotally removed using curettage, and a part of the capsule that was densely adherent to the nerve fibers was left in the patient. Histopathological examination of the specimen was consistent with tuberculoma. The patient received adequate antitubercular treatment and showed significant improvement. PMID- 23082844 TI - Obstructive sleep apnoea and cardiovascular complications: perception versus knowledge. AB - Epidemiological evidence has confirmed that obstructive sleep apnoea (OSA) significantly promotes cardiovascular risk, independent of age, sex, race and other common risk factors for cardiovascular diseases, such as smoking, drinking, obesity, diabetes mellitus, dyslipidaemia and hypertension. Patients with severe OSA exhibit a higher prevalence of coronary artery disease, heart failure and stroke. Despite the tight correlation between sleep apnoea and these comorbidities, the mechanisms behind increased cardiovascular risk in OSA remain elusive. Several theories have been postulated, including sympathetic activation, endothelial dysfunction, oxidative stress and inflammation. The association between OSA and cardiovascular diseases may be rather complicated and compounded by the presence of components of metabolic syndrome, such as obesity, hypertension, diabetes mellitus and dyslipidaemia. The present minireview updates current knowledge with regard to the cardiovascular sequelae of OSA and the mechanisms involved. PMID- 23082845 TI - Ipsilateral corticospinal responses to ballistic training are similar for various intensities and timings of TMS. AB - AIM: In previous studies, unilateral ballistic training either increased or decreased corticospinal excitability for the untrained opposite limb. The objective here was to investigate whether these discrepancies can be explained by methodological differences such as the intensity of stimulation assessing excitability or the timing of excitability testing after training. METHODS: Motor evoked potentials (MEP) were elicited by stimulating the ipsilateral cortex at high intensity (70% MEPmax) and low intensity (20% MEPmax) at specific time points after performance of 300 ballistic movements of the index finger. RESULTS: Ballistic practice significantly facilitated MEP size for high-intensity stimuli, whereas responses to low-intensity stimulation were variable. MEP sizes at individual time-points were not significantly facilitated until 4 min after training, although there was no difference between early and late responses when grouped over multiple time-points. CONCLUSIONS: The data indicate that previous discrepancies in ipsilateral responses to ballistic training cannot be attributed to specific procedures used to assess corticospinal excitability as there was no tendency towards depression of MEP amplitude at any point post-exercise for both testing intensities. This suggests that other experimental factors such as locus of attention or availability of visual feedback are more likely to account for the discrepancies. PMID- 23082846 TI - Five-year results of the prospective, randomized, multicenter, Food and Drug Administration investigational device exemption study of the ProDisc-L total disc replacement versus circumferential arthrodesis for the treatment of single-level degenerative disc disease. AB - OBJECT: The purpose of this study was to evaluate the long-term safety and effectiveness of the ProDisc-L total disc replacement (TDR) as part of an FDA mandated postmarket approval study. This report summarizes the clinical findings after 5 years of follow-up. METHODS: Two hundred thirty-six patients were treated and followed up for 5 years; 161 TDRs and 75 fusions had been performed in these patients. The primary outcome was a 10-component success end point. Secondary outcome measures included neurological status, secondary surgery, Oswestry Disability Index (ODI), 36-Item Short Form Health Survey (SF-36), visual analog scale (VAS) assessing pain and satisfaction, radiographic data, narcotic use, activity, and recreation status. Patients were monitored through their 5-year postoperative visits under the FDA postmarket surveillance provisions in the original investigational device exemption approval. RESULTS: The overall follow up rate at 5 years was 81.8%. Study success demonstrated that TDR was noninferior to fusion with a 12.5% margin (p = 0.0099). Both TDR and fusion treatment groups maintained significant improvement on the ODI at 5 years compared with baseline (p < 0.0001). Secondary surgeries at the index level were performed in 12% of fusion patients and 8% of TDR patients. Radiographically, none of the TDRs developed spontaneous fusion. The segmental range of motion following TDR remained within normal range, although it decreased by approximately 0.5 degrees in years 3 to 5. The VAS pain scores decreased from preoperative values by 48% in both treatment groups at 5 years. Patient satisfaction remained high in both groups (77%), while the percentage of patients indicating that they would have the surgery again was higher in TDR patients (82.5%) than in fusion patients (68.0%). CONCLUSIONS: Patients in both groups maintained significant improvement during the 5-year follow-up. The TDR group had significantly better improvement on some scales. Although TDR patients avoid the stiffness of fusion and are more satisfied than fusion patients, both fusion and TDR are reasonable surgical options in this specific patient population. PMID- 23082847 TI - Editorial: Disc replacement versus fusion. PMID- 23082848 TI - Editorial: disc replacement or arthrodesis. PMID- 23082849 TI - Five-year adjacent-level degenerative changes in patients with single-level disease treated using lumbar total disc replacement with ProDisc-L versus circumferential fusion. AB - OBJECT: The authors report the 5-year results for radiographically demonstrated adjacent-level degenerative changes from a prospective multicenter study in which patients were randomized to either total disc replacement (TDR) or circumferential fusion for single-level lumbar degenerative disc disease (DDD). METHODS: Two hundred thirty-six patients with single-level lumbar DDD were enrolled and randomly assigned to 2 treatment groups: 161 patients in the TDR group were treated using the ProDisc-L (Synthes Spine, Inc.), and 75 patients were treated with circumferential fusion. Radiographic follow-up data 5 years after treatment were available for 123 TDR patients and 43 fusion patients. To characterize adjacent-level degeneration (ALD), radiologists at an independent facility read the radiographic films. Adjacent-level degeneration was characterized by a composite score including disc height loss, endplate sclerosis, osteophytes, and spondylolisthesis. At 5 years, changes in ALD (DeltaALDs) compared with the preoperative assessment were reported. RESULTS: Changes in ALD at 5 years were observed in 9.2% of TDR patients and 28.6% of fusion patients (p = 0.004). Among the patients without adjacent-level disease preoperatively, new findings of ALD at 5 years posttreatment were apparent in only 6.7% of TDR patients and 23.8% of fusion patients (p = 0.008). Adjacent level surgery leading to secondary surgery was reported for 1.9% of TDR patients and 4.0% of fusion patients (p = 0.6819). The TDR patients had a mean preoperative index-level range of motion ([ROM] of 7.3 degrees ) that decreased slightly (to 6.0 degrees ) at 5 years after treatment (p = 0.0198). Neither treatment group had significant changes in either ROM or translation at the superior adjacent level at 5 years posttreatment compared with baseline. CONCLUSIONS: At 5 years after the index surgery, ProDisc-L maintained ROM and was associated with a significantly lower rate of DeltaALDs than in the patients treated with circumferential fusion. In fact, the fusion patients were greater than 3 times more likely to experience DeltaALDs than were the TDR patients. Clinical trial registration no.: NCT00295009. PMID- 23082850 TI - Aquaporin-4 expression and blood-spinal cord barrier permeability in canalicular syringomyelia. AB - OBJECT: Noncommunicating canalicular syringomyelia occurs in up to 65% of patients with Chiari malformation Type I. The pathogenesis of this type of syringomyelia is poorly understood and treatment is not always effective. Although it is generally thought that syringomyelia is simply an accumulation of CSF from the subarachnoid space, the pathogenesis is likely to be more complex and may involve cellular and molecular processes. Aquaporin-4 (AQP4) has been implicated in numerous CNS pathological conditions involving fluid accumulation, including spinal cord edema. There is evidence that AQP4 facilitates the removal of extracellular water following vasogenic edema. The aim of this study was to investigate AQP4 expression and the structural and functional integrity of the blood-spinal cord barrier (BSCB) in a model of noncommunicating canalicular syringomyelia. METHODS: A kaolin-induced model of canalicular syringomyelia was used to investigate BSCB permeability and AQP4 expression in 27 adult male Sprague-Dawley rats. Control groups consisted of nonoperated, laminectomy-only, and saline-injected animals. The structural integrity of the BSCB was assessed using immunoreactivity to endothelial barrier antigen. Functional integrity of the BSCB was assessed by extravasation of systemically injected horseradish peroxidase (HRP) at 1, 3, 6, or 12 weeks after surgery. Immunofluorescence was used to assess AQP4 and glial fibrillary acidic protein (GFAP) expression at 12 weeks following syrinx induction. RESULTS: Extravasation of HRP was evident surrounding the central canal in 11 of 15 animals injected with kaolin, and in 2 of the 5 sham-injected animals. No disruption of the BSCB was observed in laminectomy-only controls. At 12 weeks the tracer leakage was widespread, occurring at every level rostral to the kaolin injection. At this time point there was a decrease in EBA expression in the gray matter surrounding the central canal from C-5 to C-7. Aquaporin-4 was expressed in gray- and white-matter astrocytes, predominantly at the glia limitans interna and externa, and to a lesser extent around neurons and blood vessels, in both control and syrinx animals. Expression of GFAP and APQ4 directly surrounding the central canal in kaolin-injected animals was variable and not significantly different from expression in controls. CONCLUSIONS: This study demonstrated a prolonged disruption of the BSCB directly surrounding the central canal in the experimental model of noncommunicating canalicular syringomyelia. The disruption was widespread at 12 weeks, when central canal dilation was most marked. Loss of integrity of the barrier with fluid entering the interstitial space of the spinal parenchyma may contribute to enlargement of the canal and progression of syringomyelia. Significant changes in AQP4 expression were not observed in this model of canalicular syringomyelia. Further investigation is needed to elucidate whether subtle changes in AQP4 expression occur in canalicular syringomyelia. PMID- 23082851 TI - Skills of primary healthcare physicians in paediatric cardiac auscultation. AB - AIM: To evaluate the performance of primary healthcare physicians in paediatric cardiac auscultation and the impact of a multimedia-based teaching intervention. METHODS: A total of 106 primary healthcare physicians (77 paediatricians, 14 general practitioners and 15 medical graduates) attended four paediatric cardiac auscultation teaching courses based on virtual patients' presentation (digital phonocardiography). Their auscultatory performance was documented at the beginning of each course and at the end of two of the courses. RESULTS: Participants initially detected 73% of abnormal murmurs and 17% of additional sounds, while 22% of innocent murmurs were interpreted as abnormal. Overall cardiac auscultation performance, assessed by a combined auscultation score, was low and independent of training level (graduates: 39.5/trainees: 42.8/board certified: 42.6, p = 0.89) or specialty (paediatricians: 42.7/general practitioners: 43.1, p = 0.89). Multimedia-based teaching was associated with a significant improvement in abnormal murmur (92.5%) and additional sound (40%) detection (p < 0.001), while 25% of innocent murmurs were still interpreted as abnormal (p = 0.127). CONCLUSION: Clinical skills of primary healthcare physicians in paediatric cardiac auscultation, independent of training level or specialty, still leave potential for improvement. Multimedia-based teaching interventions represent an effective means of improving paediatric cardiac auscultatory skills. PMID- 23082852 TI - NMDA receptor dysfunction contributes to impaired brain-derived neurotrophic factor-induced facilitation of hippocampal synaptic transmission in a Tau transgenic model. AB - While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and N-methyl-d-Aspartate receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory postsynaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of the NR2B main kinases, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies. PMID- 23082853 TI - Elusive metal-free primary amination of arylboronic acids: synthetic studies and mechanism by density functional theory. AB - Herein, we disclose the first metal-free synthesis of primary aromatic amines from arylboronic acids, a reaction that has eluded synthetic chemists for decades. This remarkable transformation affords structurally diverse primary arylamines in good chemical yields, including a variety of halogenated primary anilines that often cannot be prepared via transition-metal-catalyzed amination. The reaction is operationally simple, requires only a slight excess of aminating agent, proceeds under neutral or basic conditions, and, importantly, can be scaled up to provide multigram quantities of primary anilines. Density functional calculations reveal that the most likely mechanism involves a facile 1,2-aryl migration and that the presence of an ortho nitro group in the aminating agent plays a critical role in lowering the free energy barrier of the 1,2-aryl migration step. PMID- 23082854 TI - Analysis of multivariate mixed longitudinal data: a flexible latent process approach. AB - Multivariate ordinal and quantitative longitudinal data measuring the same latent construct are frequently collected in psychology. We propose an approach to describe change over time of the latent process underlying multiple longitudinal outcomes of different types (binary, ordinal, quantitative). By relying on random effect models, this approach handles individually varying and outcome-specific measurement times. A linear mixed model describes the latent process trajectory while equations of observation combine outcome-specific threshold models for binary or ordinal outcomes and models based on flexible parameterized non-linear families of transformations for Gaussian and non-Gaussian quantitative outcomes. As models assuming continuous distributions may be also used with discrete outcomes, we propose likelihood and information criteria for discrete data to compare the goodness of fit of models assuming either a continuous or a discrete distribution for discrete data. Two analyses of the repeated measures of the Mini Mental State Examination, a 20-item psychometric test, illustrate the method. First, we highlight the usefulness of parameterized non-linear transformations by comparing different flexible families of transformation for modelling the test as a sum score. Then, change over time of the latent construct underlying directly the 20 items is described using two-parameter longitudinal item response models that are specific cases of the approach. PMID- 23082855 TI - Assessment of two immunodepletion methods: off-target effects and variations in immunodepletion efficiency may confound plasma proteomics. AB - Immunodepletion of abundant plasma proteins increases the depth of proteome penetration by mass spectrometry. However, the nature and extent of immunodepletion and the effect of off-target depletion on the quantitative comparison of the residual proteins have not been critically addressed. We performed mass spectrometry label-free quantitation to determine which proteins were immunodepleted and by how much. Two immunodepletion resins were compared: Qproteome (Qiagen) which removes albumin+immunoglobulins and Seppro IgY14+SuperMix (Sigma-Aldrich) which removes 14 target proteins plus a number of unidentified proteins. Plasma collected by P100 proteomic plasma collection tubes (BD) from 20 human subjects was individually immunodepleted to minimize potential variability, prior to pooling. The abundant proteins were quantified better when using only albumin+immunoglobulins removal (Qproteome), while lower abundance proteins were evaluated better using exhaustive immunodepletion (Seppro IgY14+SuperMix). The latter resin removed at least 155 proteins, 38% of the plasma proteome in protein number and 94% of plasma protein in mass. The depth of immunodepletion likely accounts for the effectiveness of this resin in revealing low abundance proteins. However, the more profound immunodepletion achieved with the IgY14+SuperMix may lead to false-positive fold-changes between comparison groups if the reproducibility and efficiency of the depletion of a given protein are not considered. PMID- 23082856 TI - Antinociceptive effect of ethanolic extract of Selaginella convoluta in mice. AB - BACKGROUND: Selaginella convoluta (Arn.) Spring (Selaginellaceae), commonly known as "jerico", is a medicinal plant found in northeastern Brazil. S. convoluta is used in folk medicine as an antidepressant, aphrodisiac, diuretic, analgesic, anti-inflammatory and it is used to combat amenorrhea, coughing and bleeding. This study was performed to evaluate the antinociceptive effects of ethanolic extract from S. convoluta in mice exposed to chemical and thermal models of nociception. METHODS: Preliminary phytochemical analysis of the ethanolic extract was performed. The ethanolic extract from Selaginella convoluta (Sc-EtOH) was examined for its intraperitoneal (i.p.) antinociceptive activity at the doses of 100, 200 and 400 mg/kg body weight. Acetic acid-induced writhing, formalin injection and hot plate tests were used to evaluate the antinociceptive activity of Sc-EtOH extract. The rota-rod test was used to evaluate motor coordination. RESULTS: A preliminary analysis of Sc-EtOH revealed that it contained phenols, steroids, terpenoids and flavonoids. In the acetic acid-induced writhing test, mice treated with Sc-EtOH (100, 200 and 400 mg/kg, i.p.) exhibited reduced writhing (58.46, 75.63 and 82.23%, respectively). Secondly, Sc-EtOH treatment (100, 200 and 400 mg/kg, i.p.) decreased the paw licking time in mice during the first phase of the formalin test (by 44.90, 33.33 and 34.16%, respectively), as well as during the second phase of the test (by 86.44, 56.20 and 94.95%, respectively). Additionally, Sc-EtOH treatment at doses of 200 and 400 mg/kg increased the latency time in the hot plate test after 60 and 90 minutes, respectively. In addition, Sc-EtOH did not impair motor coordination. CONCLUSION: Overall, these results indicate that Sc-EtOH is effective as an analgesic agent in various pain models. The activity of Sc-EtOH is most likely mediated via the inhibition of peripheral mediators and central inhibitory mechanisms. This study supports previous claims of traditional uses for S. convoluta. PMID- 23082857 TI - Oxyhydrides of (Ca,Sr,Ba)TiO3 perovskite solid solutions. AB - The oxyhydride solid solutions (Ca,Sr)TiO(3-x)H(x) and (Sr,Ba)TiO(3-x)H(x) have been prepared by reducing the corresponding ATiO(3) oxides with calcium hydride. Under the reaction conditions examined, a hydride content of x = 0.1-0.3 was obtained for all compositions. Compared to our previous result with BaTiO(3 x)H(x), the larger particle size in this study (20-30 MUm vs 170 nm) resulted in a somewhat lower hydride amount despite prolonged reaction times. We examined changes in cell volume, octahedral tilt angle, and site occupancy of different anion sites after conversion to oxyhydrides; it appears that these oxyhydrides fit the geometrical descriptions typical for regular ABO(3) perovskites quite well. The hydrogen release temperature, previously shown to be indicative of the hydride exchange temperature, however, does not scale linearly with the A-site composition, indicating a potential effect of chemical randomness. PMID- 23082858 TI - Medicinal plants potential and use by pastoral and agro-pastoral communities in Erer Valley of Babile Wereda, Eastern Ethiopia. AB - BACKGROUND: Ethiopian plants have shown remarkably effective medicinal values for many human and livestock ailments. Some research results are found on medicinal plants of the south, south west, central, north and north western parts of Ethiopia. However, there is lack of data that quantitatively assesses the resource potential and the indigenous knowledge on use and management of medicinal plants in eastern Ethiopia. The main thrust of the present ethnobotanical study centres around the potential and use of traditional medicinal plants by pastoral and agro-pastoral communities in Babile Wereda (district) of eastern Ethiopia. The results can be used for setting up of conservation priorities, preservation of local biocultural knowledge with sustainable use and development of the resource. MATERIALS AND METHODS: Fifty systematically selected informants including fifteen traditional herbalists (as key informants) participated in the study. Semi-structured interviews, discussions and guided field walk constituted the main data collection methods. Techniques of preference ranking, factor of informant consensus and Spearman rank correlation test were employed in data analysis. Medicinal plant specimens were collected, identified and kept at the National Herbarium (ETH) of Addis Ababa University and Haramaya University Herbarium. RESULTS: Fifty-one traditional medicinal plant species in 39 genera and 28 families were recorded, constituting 37% shrubs, 29% trees, 26% herbs, 6% climbers and 2% root parasites. Leaves contributed to 35.3% of the preparations, roots (18.8%) and lower proportions for other parts. Formulations recorded added to 133 remedies for 54 human ailments, in addition to some used in vector control. The majority of remedies were the juice of single species, mixtures being generally infrequent. Aloe pirottae, Azadirachta indica and Hydnora johannis were the most cited and preferred species. Aloe pirottae, a species endemic to Ethiopia, is valued as a remedy for malaria, tropical ulcer, gastro-intestinal parasites, gallstone, eye diseases and snake bite. The jel extracted from dried and ground plant material, called SIBRI (Oromo language), was acclaimed as a cleaner of the human colon. Concoction made from leaf, seed and flower of Azadirachta indica was given for treatment of malaria, fungal infections and intestinal worms. Root preparations from Hydnora johannis were prescribed as remedy for diarrhoea, haemorrhage, wound and painful body swelling, locally called GOFLA (Oromo language). CONCLUSIONS: The study documented many well known and effective medicinal species of relevance for human healthcare, including for the treatment of malaria which is rampant in the area as it is in many parts of Ethiopia. This underscores the importance of the traditional medicinal plants for the people living in the area and the potential of the resource for development. Consequently, the study area deserves urgent conservation priority coupled with mechanisms for the protection of the associated indigenous medical lore as well as development and effective use of the medicinal plant resource. PMID- 23082859 TI - The Yersinia pseudotuberculosis degradosome is required for oxidative stress, while its PNPase subunit plays a degradosome-independent role in cold growth. AB - Yersinia polynucleotide phosphorylase (PNPase), a 3'-5' exoribonuclease, has been shown to affect growth during several stress responses. In Escherichia coli, PNPase is one of the subunits of a multiprotein complex known as the degradosome, but also has degradosome-independent functions. The carboxy-terminus of E. coli ribonuclease E (RNase E) serves as the scaffold upon which PNPase, enolase (a glycolytic enzyme), and RhlB helicase all have been shown to bind. In the yersiniae, only PNPase has thus far been shown to physically interact with RNase E. We show by bacterial two-hybrid and co-immunoprecipitation assays that RhlB and enolase also interact with RNase E. Interestingly, although PNPase is required for normal growth at cold temperatures, assembly of the yersiniae degradosome was not required. However, degradosome assembly was required for growth in the presence of reactive oxygen species. These data suggest that while the Yersinia pseudotuberculosis PNPase plays a role in the oxidative stress response through a degradosome-dependent mechanism, PNPase's role during cold stress is degradosome-independent. PMID- 23082861 TI - Self reported risk reduction behavior associated with HIV counseling and testing: a comparative analysis of facility- and home-based models in rural Uganda. AB - Home-based human immunodeficiency virus (HIV) voluntary counseling and testing (VCT) in Uganda is being promoted to increase coverage, in addition to main stay approach of service provision through health facilities. The aim of this study was to compare self reported risk reduction behavior among clients receiving facility and home-based HIV VCT within a rural context. Pre-post intervention client surveys were conducted in November 2007 (baseline) and March 2008 (follow up) in southwestern Uganda. The facility-based VCT intervention was provided to 500 clients and home-based VCT to 494 clients at baseline, in 2 different sub counties. A total of 76% (759/994) of these clients were interviewed at the follow up visit. The respondents who received facility-based VCT were more likely to report abstinence (adjusted Odds Ratio [aOR]=1.47, 95% CI 1.074, 2.02), reducing multi sexual relationships (aOR=3.23, 95% CI 2.02, 5.16) and more frequent use of condoms (aOR=3.14, 95% CI 1.60, 6.18). However, they were less likely to report, discussing HIV (aOR=0.63, 95% CI 0.46, 0.85) with their sexual partner/s and having sex with only one partner (aOR=0.72, 95% CI 0.519-0.99). While facility-based VCT appears to promote abstinence and condom use home-based VCT on the other hand promotes faithfulness and disclosure. VCT services should, therefore, be provided through both models in a complementary relationship and not as surrogates within given settings. PMID- 23082860 TI - Discovery of 3-alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitriles as selective, orally bioavailable CHK1 inhibitors. AB - Inhibitors of checkpoint kinase 1 (CHK1) are of current interest as potential antitumor agents, but the most advanced inhibitor series reported to date are not orally bioavailable. A novel series of potent and orally bioavailable 3 alkoxyamino-5-(pyridin-2-ylamino)pyrazine-2-carbonitrile CHK1 inhibitors was generated by hybridization of two lead scaffolds derived from fragment-based drug design and optimized for CHK1 potency and high selectivity using a cell-based assay cascade. Efficient in vivo pharmacokinetic assessment was used to identify compounds with prolonged exposure following oral dosing. The optimized compound (CCT244747) was a potent and highly selective CHK1 inhibitor, which modulated the DNA damage response pathway in human tumor xenografts and showed antitumor activity in combination with genotoxic chemotherapies and as a single agent. PMID- 23082862 TI - Age estimation using foot radiographs from a modern Scottish population. AB - The Hoerr et al. atlas was published in 1962 and provides a standard for the age estimation of juveniles through radiographs of the feet. This study examines the accuracy of this atlas when used as an age estimation method on a modern Scottish population. A total of 403 left foot/ankle radiographs (175 female, 228 male) were age assessed using the Hoerr et al. atlas method. Analysis showed that there was a strong correlation between chronological age and estimated age (female R2 = 0.952, male R2 = 0.962). The atlas had a tendency to underage all ages of females and to underage males up to the age of 10 years after which point the pattern is one of both over and underaging. This study showed that the Hoerr et al. atlas method can be applied to a modern population. PMID- 23082863 TI - A biofilm model developed to investigate survival and disinfection of Mycobacterium mucogenicum in potable water. AB - Water in healthcare environments can be a source for healthcare-associated infections (HAI). However, information on the exposure risk to opportunistic pathogens in potable water distribution systems (PWDS) is lacking. Laboratory studies characterizing the interaction of opportunistic pathogens with biofilms are needed to understand their role in water systems within healthcare facilities. A stable, repeatable, PWDS multi-species biofilm model comprising Sphingomonas paucimobilis, Methylobacterium sp., Delftia acidovorans, and Mycobacterium mucogenicum was developed in the CDC Biofilm Reactor (CBR), reaching 6 log(10) CFU cm(-2) within 6 days. The model was used to investigate the interaction of the opportunistic pathogen M. mucogenicum with the other species, and to determine the efficacy of monochloramine (NH(2)Cl) as a disinfectant against 2-week-old biofilms. Addition of 1 or 2 mg l(-1) NH(2)Cl resulted in the same or an increased log density of viable M. mucogenicum in the biofilm while inactivating some of the Proteobacteria. Although M. mucogenicum preferentially resided in the biofilm, NH(2)Cl exposure caused release of viable M. mucogenicum from the biofilm into the water. Additional studies with this model should determine if sodium hypochlorite has a comparative effect and if other nontuberculous mycobacteria (NTM) respond to NH(2)Cl similarly. PMID- 23082864 TI - A nitric oxide-releasing solution as a potential treatment for fungi associated with tinea pedis. AB - AIMS: To test a nitric oxide-releasing solution (NORS) as a potential antifungal footbath therapy against Trichophyton mentagrophytes and Trichophyton rubrum during the mycelial and conidial phases. METHODS AND RESULTS: NORS (sodium nitrite citric acid) produces nitric oxide verified by gas chromatography and mass spectrometry (GC-MS). Antifungal activity of this solution was tested against mycelia and conidia of T. mentagrophytes and T. rubrum, using 1-20 mmol l(-1) nitrites and 10-30 min exposure times. The direct effect of the gas released from the solution on the viability of those fungi was tested. NORS demonstrated strong antifungal activity and was found to be dose and time dependent. NO and nitrogen dioxide (NO(2) ) were the only gases detected from this reaction and are likely responsible for the antifungal effect. CONCLUSIONS: This in vitro research suggests that a single 20-min exposure to NORS could potentially be used as an effective single-dose treatment against fungi that are associated with tinea pedis in both mycelia and spore phase. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides the background for developing a user friendly footbath treatment for Athlete's Foot that will kill both vegetative fungi and its spores. PMID- 23082865 TI - Electric fields guide migration of epidermal stem cells and promote skin wound healing. AB - Migration of epidermal stem cells (EpSCs) into wounds may play an important role in wound healing. Endogenous electric fields (EFs) arise naturally at wounds. Consistent with previous reports, we measured outward electric currents at rat skin wounds using vibrating probes. Topical use of prostaglandin E2 significantly promoted wound healing. However, it is not known whether EpSCs respond to EFs. We first isolated and characterized EpSCs from rat skin. We then demonstrated that EpSCs isolated from the epidermis migrated directionally toward the cathode in EFs of 50-400 mV/mm. The directedness values increased in a dose- and time dependent fashion. The migration speed of EpSCs was significantly increased in EFs. EFs induced asymmetric polymerization of intracellular F-actin and activation of the extracellular signal-regulated kinase 1/2 and phosphatidylinositol-3-kinase (PI3K)/protein kinase B pathways. Inhibition of epidermal growth factor receptor, extracellular signal-regulated kinase 1/2, or PI3K significantly inhibited the cathodal distribution of F-actin and the electrotactic response of EpSCs. These data for the first time show that EpSCs possess obvious electrotaxis, in which the epidermal growth factor receptor mitogen activated protein kinase-PI3K pathways are involved. These data thus suggest a novel aspect of electric signaling in wound healing-to stimulate and guide migration of EpSCs and to regulate wound healing. PMID- 23082868 TI - Abstracts of the 12th International Congress of the European Association for Veterinary Pharmacology and Toxicology (EAVPT 2012). July 8-12, 2012. Noordwijkerhout, The Netherlands. PMID- 23082866 TI - Gene doping: gene delivery for olympic victory. AB - With one recently recommended gene therapy in Europe and a number of other gene therapy treatments now proving effective in clinical trials it is feasible that the same technologies will soon be adopted in the world of sport by unscrupulous athletes and their trainers in so called 'gene doping'. In this article an overview of the successful gene therapy clinical trials is provided and the potential targets for gene doping are highlighted. Depending on whether a doping gene product is secreted from the engineered cells or is retained locally to, or inside engineered cells will, to some extent, determine the likelihood of detection. It is clear that effective gene delivery technologies now exist and it is important that detection and prevention plans are in place. PMID- 23082869 TI - Influence of cross-linkers on the cohesive and adhesive self-healing ability of polysulfide-based thermosets. AB - Synthetic systems with intrinsic self-repairing or self-healing abilities have emerged during the past decade. In this work, the influence of the cross-linker and chain rigidity on the healing ability of thermoset rubbers containing disulfide bonds have been investigated. The produced materials exhibit adhesive and cohesive self-healing properties. The recovery of these two functionalities upon the thermally triggered healing events has shown to be highly dependent on the network cross-link density and chain rigidity. As a result, depending on the rubber thermoset intrinsic physical properties, the thermal mending leading to full cohesive recovery can be achieved in 20-300 min at a modest healing temperature of 65 degrees C. The adhesive strength ranges from 0.2 to 0.5 MPa and is fully recovered even after multiple failure events. PMID- 23082870 TI - Evaluation of incidental neutropenia in a multi-ethnic setting. PMID- 23082871 TI - Assessment of sperm function parameters and DNA fragmentation in ejaculated alpaca sperm (Lama pacos) by flow cytometry. AB - Flow cytometry has been shown to be an accurate and highly reproducible tool for the analysis of sperm function. The main objective of this study was to assess sperm function parameters in ejaculated alpaca sperm by flow cytometry. Semen samples were collected from six alpaca males and processed for flow cytometric analysis of sperm viability and plasma membrane integrity using SYBR-14/PI staining; acrosomal membrane integrity using FITC-conjugated Pisum Sativum Agglutinin/PI labelling; mitochondrial membrane potential (Deltapsim) by staining with JC-1 and DNA Fragmentation Index (DFI) by TUNEL. The results indicate that the mean value for sperm viability was 57 +/- 8 %. Spermatozoa with intact acrosome membrane was 87.9 +/- 5%, and viable sperm with intact acrosomal membrane was 46.8 +/- 9%, high mitochondrial membrane potential (Deltapsim) was detected in 66.32 +/- 9.51% of spermatozoa and mean DFI value was 0.91 +/- 0.9%. The DFI was inversely correlated with high Deltapsim (p = 0.04; r = -0.41) and with plasma membrane integrity (p = 0.01; r = -0.47). To our knowledge, this is the first report of the assessment on the same sample of several parameters of sperm function in ejaculated alpaca sperm by flow cytometry. PMID- 23082873 TI - Titanocene-catalyzed multicomponent coupling approach to diarylethynyl methanes. AB - A titanocene-catalyzed multicomponent coupling to provide diarylethynyl methanes is described. By combining the multifunctionality of Cp(2)TiCl(2) with the traceless dielectrophilicity of aryl aldehydes, all-carbon tertiary centers are obtained in 55-99% yield. PMID- 23082872 TI - The effect of alpha-v integrin inhibition on the malignant characteristics of medulloblastoma. AB - OBJECT: Hypoxia induces an aggressive phenotype in some brain tumors in part due to hypoxia-inducible factor-1alpha (HIF-1alpha) and integrin expression. The importance of hypoxia in medulloblastoma is unclear and the interaction of HIF 1alpha and c-Myc in medulloblastoma has not been explored. The objective of this study was to determine if hypoxia induces an aggressive phenotype in human medulloblastoma cells that constitutively express high (D283 Med) or low (DAOY) levels of c-Myc and to determine if blocking alpha(v) integrins with the monoclonal antibody intetumumab inhibits hypoxia-induced cellular stress responses. METHODS: Cells were grown at 21% and 1% O(2) and in the presence or absence of intetumumab. Measures of malignancy evaluated included cell proliferation, cell migration, and expression of vascular endothelial growth factor (VEGF), alpha(v) integrins, HIF-1alpha, and c-Myc. RESULTS: Both cell lines robustly expressed alpha(v) integrins. Hypoxic DAOY cells showed significantly increased proliferation compared with normoxic controls (p < 0.05), whereas D283 Med cells did not. Both cell lines exhibited a dose-dependent decrease in proliferation when treated with intetumumab (p < 0.05). Hypoxia did not increase DAOY migration, but intetumumab significantly inhibited migration at both oxygen conditions (p < 0.05). Intetumumab significantly decreased VEGF levels in DAOY cells at both oxygen conditions (p < 0.05) and in normoxic D283 cells (p < 0.01). Neither cell line demonstrated increased HIF-1alpha expression in response to hypoxia. However, hypoxic D283 Med cells grown in the presence of intetumumab demonstrated significantly decreased c-Myc expression (p < 0.05). CONCLUSIONS: Hypoxia did not clearly induce a more aggressive phenotype in medulloblastoma cells. Despite this result, intetumumab decreased medulloblastoma cell proliferation and migration and variably decreased VEGF and c-Myc expression in hypoxic conditions. Targeting alpha(v) integrins represents a promising potential adjuvant modality in the treatment of medulloblastoma, particularly subtypes that metastasize and overexpress VEGF and c-Myc. PMID- 23082874 TI - Enforcement of a lifespan-sustaining distribution of Sir2 between telomeres, mating-type loci, and rDNA repeats by Rif1. AB - Telomere dysfunction is linked with genome instability and premature aging. Roles for sirtuin proteins at telomeres are thought to promote lifespan in yeast and mammals. However, replicative lifespan of the budding yeast Saccharomyces cerevisiae shortens upon deletion of Rif1, a protein that limits the recruitment of the sirtuin histone deacetylase Sir2 to telomeres. Here we show that Rif1 maintains replicative lifespan by ultimately stabilizing another age-related chromosomal domain harboring the ribosomal DNA (rDNA) repeats. Deletion of Rif1 increases Sir2 localization to telomeres and the silent mating-type loci, while releasing a pool of the histone deacetylase from the intergenic spacer 1 (IGS1) of rDNA. This is accompanied by a disruption of IGS1 silent chromatin assembly and increases in aberrant recombination within rDNA repeats. Lifespan defects linked with Rif1 deletion are abolished if rDNA repeats are forcibly stabilized via deletion of the replication fork-blocking protein Fob1. In addition, Sir2 overexpression prevents Rif1 deletion from disrupting Sir2 at IGS1 and shortening lifespan. Moreover, subjecting cells lacking Rif1 to caloric restriction increases IGS1 histone deacetylation and lifespan, while uncovering novel genetic interactions between RIF1 and SIR2. Our data indicate that Rif1 maintains lifespan-sustaining levels of Sir2 at rDNA by preventing excessive recruitment of the histone deacetylase to telomeric and silent mating-type loci. As sirtuin histone deacetylases, such as Sir2 or mammalian SIRT6, each operate at multiple age-related loci, we propose that factors limiting the localization of sirtuins to certain age-related loci can promote lifespan-sustaining roles of these sirtuins elsewhere in the genome. PMID- 23082875 TI - Relationship between oxygen affinity and autoxidation of myoglobin. AB - Studies using myoglobins reconstituted with a variety of chemically modified heme cofactors revealed that the oxygen affinity and autoxidation reaction rate of the proteins are highly correlated to each other, both decreasing with decreasing the electron density of the heme iron atom. An Fe(3+)-O(2)(-)-like species has been expected for the Fe(2+)-O(2) bond in the protein, and the electron density of the heme iron atom influences the resonance process between the two forms. A shift of the resonance toward the Fe(2+)-O(2) form results in lowering of the O(2) affinity due to an increase in the O(2) dissociation rate. On the other hand, a shift of the resonance toward the Fe(3+)-O(2)(-)-like species results in acceleration of the autoxidation through increasing H(+) affinity of the bound ligand. PMID- 23082877 TI - Impact of infectious complications after elective surgery on hospital readmission and late deaths in the U.S. Medicare population. AB - BACKGROUND AND PURPOSE: Whereas the negative impact of infectious complications (IC) during the index hospitalization after elective surgery is well established, the long-term ramifications of hospital-acquired post-operative infections are not well studied. This analysis evaluated the impact of a hospital-acquired IC after open abdominal vascular surgery on the readmission rate and the mortality rates 30 and 90 days after initial discharge. METHODS: Data from all hospitals in the United States that performed elective open abdominal vascular operations in the Medicare population from 2005 to 2007 were extracted from the national Medicare Provider Analysis and Review database. The cohort consisted of all patients undergoing open abdominal vascular operations, including aortic, iliac, and visceral procedures. The ICs evaluated were pneumonia, urinary tract infection (UTI), postoperative sepsis (sepsis), surgical site infection (SSI), and Clostridium difficile infection (CDI). Patients were categorized as either developing an IC during their initial hospitalization (Index+INF) or not developing an IC (No INF). The rates of 30-day readmission, 30-day IC, and 30- and 90-day mortality after the initial discharge were evaluated longitudinally and compared in patients with and without an IC. RESULTS: A total of 29,549 open abdominal vascular procedures were identified, and 4,016 patients (13.6%) developed an IC during their index hospitalization: Pneumonia (5.1% of the total), UTI (2.7%), sepsis (1.6%), SSI (1.4%), and CDI (0.6%). Additionally, 1.13% of patients developed pneumonia, UTI, SSI, or CDI complicated by sepsis. The hospital mortality rate during the initial hospitalization was 13.7% (Index+INF) versus 4.0% (No INF) (p<0.0002). Infectious processes (pneumonia, UTI, SSI, and CDI) complicated by sepsis had an in-hospital mortality rate significantly higher than patients having an IC alone (50.9% vs. 13.7%; p<0.002). The mortality rate 30 and 90 days after the initial discharge was significantly higher for Index+INF than for No INF (4.4% vs. 1.2% and 8.6% vs. 2.6%, respectively; p<0.0002). The highest 30-day mortality rates after discharge were found after CDI+sepsis (30%), pneumonia+sepsis (12.6%), and postoperative sepsis alone (8.6%). The same rank was found for the 90-day mortality rate: 30%, 22.5%, and 13.8%. Overall, readmission was more likely for Index+INF than for No INF (33.7% vs. 21.5%; p<0.0002). Rates of 30-day readmission after an index IC ranged from 32% to 50%. CONCLUSION: For Medicare beneficiaries undergoing elective open abdominal vascular procedures, the development of any IC significantly increased not only the in-hospital mortality rate but also the mortality rates 30 and 90 days after discharge from the hospital. Index ICs also were associated with a higher 30-day readmission rate. Hospital-acquired infections have a profound late effect on outcomes after discharge. Future programs targeting high-risk patients may improve long-term survival and minimize readmissions. PMID- 23082876 TI - Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation. AB - BACKGROUND: Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children. METHODS: 60 consecutive pediatric patients with a median age of 6.0 years who underwent allogeneic HSCT between August 2007 and July 2010 received antifungal prophylaxis with posaconazole in the outpatient setting. 28 pediatric patients received an oral suspension at 5 mg/kg body weight b.i.d., and 32 pediatric patients received the suspension at 4 mg/kg body weight t.i.d. The observation period lasted from start of treatment with posaconazole until its termination (maximum of 200 days post-transplant). RESULTS: Pediatric patients who received posaconazole at 4 mg/kg body weight t.i.d. had a median trough level of 383 MUg/L. Patients who received posaconazole at 5 mg/kg body weight b.i.d. had a median trough level of 134 MUg/L. Both regimens were well tolerated without severe side effects. In addition, no proven or probable invasive mycosis was observed. CONCLUSION: Posaconazole was a well-tolerated, safe, and effective oral antifungal prophylaxis in pediatric patients who underwent high-dose chemotherapy and HSCT. Posaconazole at a dosage of 12 mg/kg body weight divided in three doses produced consistently higher morning trough levels than in patients who received posaconazole 5 mg/kg body weight b.i.d. Larger prospective trials are needed to obtain reliable guidelines for antifungal prophylaxis in children after HSCT. PMID- 23082878 TI - Correlation of expression levels of ANXA2, PGAM1, and CALR with glioma grade and prognosis. AB - OBJECT: Biomarkers for the diagnosis and prognosis of gliomas are lacking. To elucidate new diagnostic and prognostic targets, a routine method is used to evaluate differences between the protein profile of normal and tumor cells. The object of the current study was to investigate novel differentially expressed proteins and their roles in gliomas. METHODS: Differences in the protein profile were compared using 2D polyacrylamide gel electrophoresis using C6 glioma cells and rat astrocytes. The mRNA and protein expression of ANXA2, PGAM1, and CALR were analyzed in glioma tissues and normal brain tissues. The expression of ANXA2 in the U87 glioma cell line was interrupted using short interfering RNA duplexes, and the role of ANXA2 in the migration and invasiveness of glioma cells was assessed. The expression of ANXA2, PGAM1, and CALR was examined further by immunohistochemical analysis using 130 glioma samples obtained in patients, and their prognostic roles in gliomas were evaluated using Kaplan-Meier and Cox regression analyses. RESULTS: Significantly higher expression levels of ANXA2 and PGAM1 and a lower level of CALR were found in glioma samples than in the normal brain samples. ANXA2, PGAM1, and CALR expression correlated with the grade and survival of patients with gliomas. Multivariate analysis further revealed that ANXA2 was an independent prognostic marker for glioma. After ANXA2 expression was suppressed using short interfering RNA, U87 cells had decreased migratory and invasive capabilities in vitro. CONCLUSIONS: Protein expression alterations in ANXA2, PGAM1, and CALR were found in gliomas, and ANXA2 provided a novel prognostic value. PMID- 23082879 TI - Occipitotemporal hippocampal depth electrodes in intracranial epilepsy monitoring: safety and utility. AB - OBJECT: Intracranial monitoring for epilepsy has been proven to enhance diagnostic accuracy and provide localizing information for surgical treatment of intractable seizures. The authors investigated the usefulness of hippocampal depth electrodes in the era of more advanced imaging techniques. METHODS: Between 1988 and 2010, 100 patients underwent occipitotemporal hippocampal depth electrode (OHDE) implantation as part of invasive seizure monitoring, and their charts were retrospectively reviewed. The authors' technique involved the stereotactically guided (using the Leksell model G frame) implantation of a 12 contact depth electrode directed along the long axis of the hippocampus, through an occipital twist drill hole. RESULTS: Of the 100 patients (mean age 35.0 years [range 13-58 years], 51% male) who underwent intracranial investigation, 84 underwent resection of the seizure focus. Magnetic resonance imaging revealed mesial temporal sclerosis (MTS) in 27% of patients, showed abnormal findings without MTS in 55% of patients, and showed normal findings in 18% of patients. One patient developed a small asymptomatic occipital hemorrhage around the electrode tract. The use of OHDEs enabled epilepsy resection in 45.7% of patients who eventually underwent standard or selective temporal lobe resection. The hippocampal formation was spared during surgery because data obtained from the depth electrodes showed no or only secondary involvement in 14% of patients with preoperative temporal localization. The use of OHDEs prevented resections in 12% of patients with radiographic evidence of MTS. Eighty-three percent of patients who underwent resection had Engel Class I (68%) or II (15%) outcome at 2 years of follow-up. CONCLUSIONS: The use of OHDEs for intracranial epilepsy monitoring has a favorable risk profile, and in the authors' experience it proved to be a valuable component of intracranial investigation. The use of OHDEs can provide the sole evidence for resection of some epileptogenic foci and can also result in hippocampal sparing or prevent likely unsuccessful resection in other patients. PMID- 23082880 TI - Cerebral revascularization and carotid artery resection at the skull base for treatment of advanced head and neck malignancies. AB - OBJECT: Resection of cancer and the involved artery in the neck has been applied with some success, but the indications for such an aggressive approach at the skull base are less well defined. The authors therefore evaluated the outcomes of advanced skull base malignancies in patients who were treated with bypass and resection of the internal carotid artery (ICA). METHODS: The authors retrospectively reviewed the charts of all patients with advanced head and neck cancers who underwent ICA sacrifice with revascularization in which an extracranial-intracranial bypass was used between 1995 and 2010 at the Barrow Neurological Institute. RESULTS: Eighteen patients (11 male and 7 female patients; mean age 46 years, range 7-69 years) were identified. There were 4 sarcomas and 14 carcinomas that involved the ICA at the skull base. All patients underwent ICA sacrifice with revascularization. One patient died of a stroke after revascularization. A second patient died of the effects of a fistula between the oral and cranial cavities (surgery-related mortality rate 11.1%). Eight months after the operation, 1 patient developed occlusion of the bypass and died. Complications associated with the bypass surgery included 1 case of subdural hematoma (SDH) with blindness, 1 case of status epilepticus, and 1 case of asymptomatic bypass occlusion (bypass-related morbidity 16.7%). Complications associated with tumor resection included 3 cases of CSF leakage requiring repair and shunting, 1 case of hydrocephalus requiring shunting, 1 case of SDH, and 1 case of contralateral ICA injury requiring a bypass (tumor resection morbidity rate 33.3%). In 1 patient treated with adjuvant therapy before surgery, the authors identified only a radiation effect and no tumor on resection. In a second patient the bypass was occluded, and her tumor was not resected. The other 16 patients underwent gross-total resection of their tumor. Excluding the surgery related deaths, the mean and median lengths of survival in this series were 13.2 and 8.3 months, respectively (range 1.5-48 months). Including the surgery-related deaths, the mean and median lengths of survival were 11.8 and 8 months, respectively (range 17 days-48 months). At last follow-up all patients had died of cancer or cancer-related causes. CONCLUSIONS: Despite maximal surgical intervention, including ICA sacrifice at the skull base with revascularization, patient survival was dismal, and the complication rate was significant. The authors no longer advocate such an aggressive approach in this patient population. On rare occasions, however, such an approach may be considered for low-grade malignancies. PMID- 23082881 TI - Using a modified far-lateral approach to remove hypoglossal neurilemmomas: notes on technique. AB - OBJECT: In this paper the authors describe a modified far-lateral transcondylar approach to remove hypoglossal neurilemmomas (HGNs). METHODS: Between September 2008 and June 2011, 11 consecutive patients with HGNs underwent tumor removal via a modified far-lateral transcondylar approach. The average age at presentation, tumor characteristics, cranial nerve (CN) deficits, and outcomes were assessed. The modified far-lateral transcondylar approach comprises several important steps. The first step is to remove the limited posterior aspect of the condylar facet to open the hypoglossal canal. The second step is to expose the posterior arch and the transverse process of C-1. A fat layer covers the venous plexus of the vertebral artery, and careful dissection along this surface of the fat layer is important to protect the vertebral artery from damage. The neck muscles are dissected caudally to expose the extracranial component of the tumor, which is located in front of the transverse process of C-1. RESULTS: Eleven cases of HGNs were treated during the study period. The mean patient age was 47.4 +/- 8.9 years (range 31-59 years); there were 3 men and 8 women. The mean follow-up period was 14.1 +/- 9 months. All patients presented with hypoglossal nerve deficits; other commonly observed deficits included glossopharyngeal and vestibular/cochlear nerve deficits. Gross-total resection of the tumor was achieved in 10 patients. A subtotal resection of the tumor was achieved in the remaining patient. Two patients had transient postoperative facial nerve palsies, 1 patient developed a new CN XI palsy postoperatively, and 5 patients experienced transient hoarseness and difficulty swallowing. Two patients required a tracheotomy because they demonstrated dysfunction of the caudal CNs and subsequently developed postoperative pneumonia. Postoperatively, 5 patients required the temporary placement of a nasogastric feeding tube. There were no surgery-related deaths in this series. CONCLUSIONS: The modified far-lateral transcondylar approach is an effective treatment for HGNs, yielding a high total tumor removal rate with an acceptable rate of morbidity. PMID- 23082882 TI - Long-term outcome of Gamma Knife stereotactic radiosurgery for arteriovenous malformations graded by the Spetzler-Martin classification. AB - OBJECT: The object of this study was to assess outcomes in patients with arteriovenous malformations (AVMs) treated by Gamma Knife stereotactic radiosurgery (SRS); lesions were stratified by size, symptomatology, and Spetzler Martin (S-M) grade. METHODS: The authors performed a retrospective analysis of 102 patients treated for an AVM with single-dose or staged-dose SRS between 1993 and 2004. Lesions were grouped by S-M grade, as hemorrhagic or nonhemorrhagic, and as small (< 3 cm) or large (>= 3 cm). Outcomes included death, morbidity (new neurological deficit, new-onset seizure, or hemorrhage/rehemorrhage), nidus obliteration, and Karnofsky Performance Scale score. RESULTS: The mean follow-up was 8.5 years (range 5-16 years). Overall nidus obliteration (achieved in 75% of patients) and morbidity (19%) correlated with lesion size and S-M grade. For S-M Grade I-III AVMs, nonhemorrhagic and hemorrhagic combined, treatment yielded obliteration rates of 100%, 89%, and 86%, respectively; high functional status (Karnofsky Performance Scale Score >= 80); and 1% mortality. For S-M Grade IV and V AVMs, outcomes were less favorable, with obliteration rates of 54% and 0%, respectively. The AVMs that were not obliterated had a mean reduction in nidus volume of 69% (range 35%-96%). On long-term follow-up, 10% of patients experienced hemorrhage/rehemorrhage (6% mortality rate), which correlated with lesion size and S-M grade; the mean interval to hemorrhage was 81 months. CONCLUSIONS: For patients with S-M Grade I-III AVMs, SRS offers outcomes that are favorable and that, except for the timing of obliteration, appear to be comparable to surgical outcomes reported for the same S-M grades. Staged-dose SRS results in lesion obliteration in half of patients with S-M Grade IV lesions. PMID- 23082883 TI - Metachronous, multicentric glioma of pilocytic astrocytoma with oligodendroglioma like component and oligodendroglioma through distinct genetic aberrations. AB - This patient presented with a rare case of metachronous, multicentric gliomas first manifesting as headache and nausea in 1983 when he was an 8-year-old boy. Computed tomography revealed a cerebellar tumor and the tumor was subtotally resected. The histological diagnosis was pilocytic astrocytoma, and radiation therapy to the posterior fossa and chemotherapy consisting of nimustine hydrochloride and fluorouracil were performed. In 1989, at age 14 years, the patient presented with local recurrence. He underwent gross-total resection of the tumor, and histological examination revealed that the tumor consisted of classic pilocytic astrocytoma with a biphasic pattern and a small oligodendroglioma-like component. In 2011, at age 36 years, he presented with seizure. Magnetic resonance imaging revealed a mass lesion in the right middle frontal gyrus. Gross-total resection of the tumor was performed, and the histological diagnosis was oligodendroglioma. Genetic analyses revealed amplification of the BRAF gene in both the primary cerebellar pilocytic astrocytoma and the recurrent tumor with biphasic features, as well as a BRAF V600E missense mutation in the oligodendroglioma-like component. On the other hand, the IDH1 R132H mutation, instead of aberrations of the BRAF gene, was identified in the oligodendroglioma arising in the right frontal lobe. Different types of aberrations of the BRAF gene in the classic and oligodendroglioma-like component in the recurrent pilocytic astrocytoma suggest that they had different cell origins or that amplification of BRAF was negatively selected under the de novo BRAF V600E mutation. In addition, the aberration profiles of IDH1 and BRAF suggest that the oligodendroglioma arose independent of cerebellar pilocytic astrocytoma. PMID- 23082884 TI - Multiple resections for patients with glioblastoma: prolonging survival. AB - OBJECT: Glioblastoma is the most common and aggressive type of primary brain tumor in adults. These tumors recur regardless of intervention. This propensity to recur despite aggressive therapies has made many perceive that repeated resections have little utility. The goal of this study was to evaluate if patients who underwent repeat resections experienced improved survival as compared with patients with fewer numbers of resections, and whether the number of resections was an independent predictor of prolonged survival. METHODS: The records of adult patients who underwent surgery for an intracranial primary glioblastoma at an academic tertiary-care institution between 1997 and 2007 were retrospectively reviewed. Multivariate proportionalhazards regression analysis was used to identify an association between glioblastoma resection number and survival after controlling for factors known to be associated with survival, such as age, functional status, periventricular location, extent of resection, and adjuvant therapy. Survival as a function of time was plotted using the Kaplan Meier method, and survival rates were compared using log-rank analysis. RESULTS: Five hundred seventy-eight patients with primary glioblastoma met the inclusion/exclusion criteria. At last follow-up, 354, 168, 41, and 15 patients underwent 1, 2, 3, or 4 resections, respectively. The median survival for patients who underwent 1, 2, 3, and 4 resections was 6.8, 15.5, 22.4, and 26.6 months (p < 0.05), respectively. In multivariate analysis, patients who underwent only 1 resection experienced shortened survival (relative risk [RR] 3.400, 95% CI 2.423-4.774; p < 0.0001) as compared with patients who underwent 2 (RR 0.688, 95% CI 0.525-0.898; p = 0.0006), 3 (RR 0.614, 95% CI 0.388-0.929; p = 0.02), or 4 (RR 0.600, 95% CI 0.238-0.853; p = 0.01) resections. These results were verified in a case-control evaluation, controlling for age, neurological function, periventricular tumor location, extent of resection, and adjuvant therapy. Patients who underwent 1, 2, or 3 resections had a median survival of 4.5, 16.2, and 24.4 months, respectively (p < 0.05). Additionally, the risk of infections or iatrogenic deficits did not increase with repeated resections in this patient population (p > 0.05). CONCLUSIONS: Patients with glioblastoma will inevitably experience tumor recurrence. The present study shows that patients with recurrent glioblastoma can have improved survival with repeated resections. The findings of this study, however, may be limited by an intrinsic bias associated with patient selection. The authors attempted to minimize these biases by using strict inclusion criteria, multivariate analyses, and case-control evaluation. PMID- 23082885 TI - Effect of acetylsalicylic acid usage and platelet transfusion on postoperative hemorrhage and activities of daily living in patients with acute intracerebral hemorrhage. AB - OBJECT: The authors evaluated the effects of acetylsalicylic acid (ASA) usage and transfusion of previously frozen apheresis platelets on postoperative hemorrhage, activities of daily living (ADL) score, and mortality rate in patients with acute hypertensive basal ganglia hemorrhage undergoing craniotomy. METHODS: This was a prospective, double-blind, parallel, randomized controlled trial in patients with acute hypertensive basal ganglia hemorrhage, who had either not received ASA therapy (control) or received ASA therapy. The patients who received ASA therapy were divided according to the results of a platelet aggregation test into ASA resistant, ASA-semiresponsive, and ASA-sensitive groups. All patients required an emergency craniotomy for hematoma removal after hospitalization. The patients who were sensitive to ASA were randomized to receive one of the following transfusion regimens of previously frozen apheresis platelets: no transfusion, 1 therapeutic dose before surgery, or 2 therapeutic doses (1 before surgery and 1 after 24 hours of hospitalization). The postoperative hemorrhage rate and the average postoperative hemorrhage volume were recorded and the ADL scores and mortality rate were measured during a 6-month follow-up period. RESULTS: The rate of postoperative hemorrhage, average postoperative hemorrhage volume, and mortality rate were significantly higher in the ASA-sensitive patients who received ASA therapy compared with patients who did not receive ASA therapy (all p < 0.005). The ADL scores were grouped into different grades and the number of cases in the lower grades was higher and the overall scores were poorer in patients who received ASA therapy compared with those who did not (all p < 0.005). After transfusion of previously frozen apheresis platelets, the postoperative hemorrhage rate, average postoperative hemorrhage volume, and mortality rate of the ASA-sensitive patients were significantly lowered (all p < 0.005), and the ADL scores and their classification level were better than those of patients who did not undergo transfusion (all p < 0.005). CONCLUSIONS: Transfusion of previously frozen apheresis platelets reduces the rate of postoperative hemorrhage, average postoperative hemorrhage volume, disability rate, and mortality rate in ASA-sensitive patients with acute hypertensive basal ganglia hemorrhage undergoing craniotomy. PMID- 23082886 TI - Cerebrospinal fluid volume-depletion headaches in patients with traumatic brachial plexus injury. AB - OBJECT: Patients with brachial plexus injury (BPI) present with a combination of motor weakness/paralysis, sensory deficits, and pain. Brachial plexus injury is generally not believed to be associated with headaches. However, CSF leaks may be associated with CSF volume-depletion (low-pressure) headaches and can occur in BPI secondary to nerve root avulsion. Only a few cases of headaches associated with BPI have been reported. It is unknown if headaches in patients with BPI occur so rarely, or if they are just unrecognized by physicians and/or patients in which the focus of attention is the affected limb. The aim of this study was to determine the prevalence of CSF volume-depletion headaches in patients with BPI. METHODS: All adult patients presenting at the Mayo brachial plexus clinic with traumatic BPI were asked to complete a questionnaire addressing the presence and quality of headaches following their injury. The patients' clinical, injury, and imaging characteristics were subsequently reviewed. RESULTS: Between December 2008 and July 2010, 145 patients completed the questionnaire. Twenty-two patients reported new onset headaches occurring after their BPI. Eight of these patients experienced positional headaches, suggestive of CSF volume depletion. One of the patients with orthostatic headaches was excluded because the headaches immediately followed a lumbar puncture for a myelogram. Six of the other 7 patients with positional headaches had a clear preganglionic BPI. The available imaging studies in these 6 patients revealed evidence of CSF leaks: pseudomeningoceles (n = 5), CSF tracking into soft tissues (n = 3), CSF tracking into the intraspinal compartment (n = 3), CSF tracking into the pleural space (n = 2), and low-positioned cerebellar tonsils (n = 2). CONCLUSIONS: In this retrospective study, 15.2% of patients (22 of 145 patients) with traumatic BPI suffered from a new-onset headache. Seven of these patients (4.8%) experienced postural headaches clearly suggestive of CSF volume depletion likely secondary to a CSF leak associated with the BPI, whereas the other 15 patients (10.3%) suffered headaches that may have represented a variant of CSF depletion headaches without a postural characteristic or a headache from another cause. These data suggest that CSF volume-depletion headaches occur in a significant proportion of patients with BPI and have been underrecognized and underreported. PMID- 23082887 TI - Editorial: glioblastoma and surgery. PMID- 23082888 TI - Preoperative assessment of meningioma stiffness using magnetic resonance elastography. AB - OBJECT: The object of this study was to determine the potential of magnetic resonance elastography (MRE) to preoperatively assess the stiffness of meningiomas. METHODS: Thirteen patients with meningiomas underwent 3D brain MRE examination to measure stiffness in the tumor as well as in surrounding brain tissue. Blinded to the MRE results, neurosurgeons made a qualitative assessment of tumor stiffness at the time of resection. The ability of MRE to predict the surgical assessment of stiffness was tested using a Spearman rank correlation. RESULTS: One case was excluded due to a small tumor size. In the remaining 12 cases, both tumor stiffness alone (p = 0.023) and the ratio of tumor stiffness to surrounding brain tissue stiffness (p = 0.0032) significantly correlated with the surgeons' qualitative assessment of tumor stiffness. Results of the MRE examination provided a stronger correlation with the surgical assessment of stiffness compared with traditional T1- and T2-weighted imaging (p = 0.089), particularly when considering meningiomas of intermediate stiffness. CONCLUSIONS: In this cohort, preoperative MRE predicted tumor consistency at the time of surgery. Tumor stiffness as measured using MRE outperformed conventional MRI because tumor appearance on T1- and T2-weighted images could only accurately predict the softest and hardest meningiomas. PMID- 23082889 TI - A stroke of silence: tinnitus suppression following placement of a deep brain stimulation electrode with infarction in area LC. AB - The authors report on a case of tinnitus suppression following deep brain stimulation (DBS) for Parkinson disease. A perioperative focal vascular injury to area LC, a locus of the caudate at the junction of the head and body of the caudate nucleus, is believed to be the neuroanatomical correlate. A 56-year-old woman underwent surgery for implantation of a DBS lead in the subthalamic nucleus to treat medically refractory motor symptoms. She had comorbid tinnitus localized to both ears. The lead trajectory was adjacent to area LC. Shortly after surgery, she reported tinnitus suppression in both ears. Postoperative MRI showed focal hyperintensity of area LC on T2-weighted images. At 18 months, tinnitus localized to the ipsilateral ear remained completely silenced, and tinnitus localized to the contralateral ear was substantially suppressed due to left area LC injury. To the authors' knowledge, this is the first report of a discrete injury to area LC that resulted in bilateral tinnitus suppression. Clinicians treating patients with DBS may wish to include auditory phantom assessment as part of the neurological evaluation. PMID- 23082890 TI - Potentiation of response to low doses of levodopa in MPTP-injected monkeys by chemical unilateral subthalamotomy. AB - OBJECT: Subthalamotomy is a stereotactic surgery performed in patients with disabling dyskinesias due to Parkinson disease. The authors set out to model this human condition in MPTP monkeys and determine if subthalamotomy allowed a reduction of levodopa for similar benefit. METHODS: The authors performed unilateral subthalamotomy in 4 parkinsonian dyskinetic monkeys by stereotactic injection of ibotenic acid. An optimal dose, defined as the highest dose of levodopa improving parkinsonian motor symptoms while inducing low or no dyskinesias, was established in these animals. Each monkey was scored for the antiparkinsonian and dyskinetic effects of the optimal dose of levodopa, as well as suboptimal and dyskinesia-inducing doses (60% and 140% of the optimal dose, respectively), and these scores were compared with those obtained at baseline before and after subthalamotomy. Bradykinesia was assessed by a prehension task. RESULTS: Unilateral subthalamotomy had a positive effect on the antiparkinsonian response for all doses of levodopa as well as the baseline. There were no differences in the antiparkinsonian response between the suboptimal dose postsurgery and the optimal dose presurgery. Dyskinesias were increased at the suboptimal and the optimal doses. After surgery, the duration of response to levodopa increased between 20% and 25% in the suboptimal dose, whereas it remained unchanged with higher doses. Bradykinesia was significantly reduced after surgery only at the suboptimal dose. CONCLUSIONS: Subthalamotomy potentiated the response to suboptimal doses of levodopa. Thus, levodopa can be reduced by 40% after surgery for similar beneficial antiparkinsonian response and less dyskinesia than with an optimal dose before surgery. PMID- 23082891 TI - Effects of private-land use, livestock management, and human tolerance on diversity, distribution, and abundance of large african mammals. AB - Successful conservation of large terrestrial mammals (wildlife) on private lands requires that landowners be empowered to manage wildlife so that benefits outweigh the costs. Laikipia County, Kenya, is predominantly unfenced, and the land uses in the area allow wide-ranging wildlife to move freely between different management systems on private land. We used camera traps to sample large mammals associated with 4 different management systems (rhinoceros sanctuaries, no livestock; conservancies, intermediate stocking level; fenced ranches, high stocking level; and group ranches, high stocking level, no fencing, pastoralist clan ownership) to examine whether management and stocking levels affect wildlife. We deployed cameras at 522 locations across 8 properties from January 2008 through October 2010 and used the photographs taken during this period to estimate richness, occupancy, and relative abundance of species. Species richness was highest in conservancies and sanctuaries and lowest on fenced and group ranches. Occupancy estimates were, on average, 2 and 5 times higher in sanctuaries and conservancies as on fenced and group ranches, respectively. Nineteen species on fenced ranches and 25 species on group ranches were considered uncommon (occupancy < 0.1). The relative abundance of most species was highest or second highest in sanctuaries and conservancies. Lack of rights to manage and utilize wildlife and uncertain land tenure dampen many owners' incentives to tolerate wildlife. We suggest national conservation strategies consider landscape-level approaches to land-use planning that aim to increase conserved areas by providing landowners with incentives to tolerate wildlife. Possible incentives include improving access to ecotourism benefits, forging agreements to maintain wildlife habitat and corridors, resolving land ownership conflicts, restoring degraded rangelands, expanding opportunities for grazing leases, and allowing direct benefits to landowners through wildlife harvesting. . PMID- 23082892 TI - Versican expression in canine carcinomas in benign mixed tumours: is there an association with clinical pathological factors, invasion and overall survival? AB - BACKGROUND: Components of the extracellular matrix have been studied in an attempt to elucidate the mechanisms involved in the biological behaviour of tumours. The presence of the proteoglycan versican has been strongly associated with cancer development and progression. However, relationship between versican expression and clinical pathological factors and overall survival has not been previously studied in veterinary medicine. Carcinomas in benign mixed tumours (CBMTs) are one of the most common malignant tumours in female canines and can serve as models for studies of tumour progression. The aim of this study was to evaluate the expression of versican in in situ and invasive carcinomatous areas of canine CBMTs and to evaluate possible associations of versican expression with other classic prognostic factors and overall survival. RESULTS: Clinical staging; histological grade determination; immunohistochemical staining for versican, E cadherin and Ki-67; and confirmation of invasion areas by staining for p63 and smooth muscle alpha-actin (alpha-SMA) were performed on 49 canine cases of CBMT. Tumour invasion was considered when suspicious Haematoxylin-Eosin (HE)-stained areas showed a total loss of alpha-SMA and p63 immunoreactivity. Versican immunoreactivity was less intense in the areas adjacent to the in situ carcinomatous regions, compared to invasive regions, which showed extensive and strong staining. CONCLUSIONS: Our data reveal that in canine CBMTs, versican expression differs significantly between invasive and in situ areas, suggesting a role for this molecule in tumour progression. Although a direct relationship exists between versican and invasiveness, our results indicate that the isolated evaluation of this proteoglycan does not represent an independent prognostic factor in canine CBMTs. PMID- 23082893 TI - Measuring change for a multidimensional test using a generalized explanatory longitudinal item response model. AB - Even though many educational and psychological tests are known to be multidimensional, little research has been done to address how to measure individual differences in change within an item response theory framework. In this paper, we suggest a generalized explanatory longitudinal item response model to measure individual differences in change. New longitudinal models for multidimensional tests and existing models for unidimensional tests are presented within this framework and implemented with software developed for generalized linear models. In addition to the measurement of change, the longitudinal models we present can also be used to explain individual differences in change scores for person groups (e.g., learning disabled students versus non-learning disabled students) and to model differences in item difficulties across item groups (e.g., number operation, measurement, and representation item groups in a mathematics test). An empirical example illustrates the use of the various models for measuring individual differences in change when there are person groups and multiple skill domains which lead to multidimensionality at a time point. PMID- 23082894 TI - On the versatility of urethane/urea bonds: reversibility, blocked isocyanate, and non-isocyanate polyurethane. PMID- 23082895 TI - A drug fatality involving Kratom. AB - A 17-year-old white man who showed no obvious signs of trauma was found unresponsive in bed and was pronounced dead at the scene. The decedent had a documented history of heroin abuse and chronic back pain and reportedly self medicated with Kratom (mitragynine). The autopsy was remarkable only for pulmonary congestion and edema and a distended bladder, both of which are consistent with, though not diagnostic of, opiate use. A laboratory work-up revealed therapeutic levels of over-the-counter cold medications and benzodiazepines. However, of interest was a level of mitragynine at 0.60 mg/L. Given the facts of the case, the Medical Examiner certified the cause of death as "possible Kratom toxicity" and the manner of death was classified as "accident." PMID- 23082897 TI - Detection and identification of heme c-modified peptides by histidine affinity chromatography, high-performance liquid chromatography-mass spectrometry, and database searching. AB - Multiheme c-type cytochromes (proteins with covalently attached heme c moieties) play important roles in extracellular metal respiration in dissimilatory metal reducing bacteria. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) characterization of c-type cytochromes is hindered by the presence of multiple heme groups, since the heme c modified peptides are typically not observed or, if observed, not identified. Using a recently reported histidine affinity chromatography (HAC) procedure, we enriched heme c tryptic peptides from purified bovine heart cytochrome c, two bacterial decaheme cytochromes, and subjected these samples to LC-MS/MS analysis. Enriched bovine cytochrome c samples yielded 3- to 6-fold more confident peptide-spectrum matches to heme c containing peptides than unenriched digests. In unenriched digests of the decaheme cytochrome MtoA from Sideroxydans lithotrophicus ES-1, heme c peptides for 4 of the 10 expected sites were observed by LC-MS/MS; following HAC fractionation, peptides covering 9 out of 10 sites were obtained. Heme c peptide spiked into E. coli lysates at mass ratios as low as 1*10(-4) was detected with good signal-to noise after HAC and LC-MS/MS analysis. In addition to HAC, we have developed a proteomics database search strategy that takes into account the unique physicochemical properties of heme c peptides. The results suggest that accounting for the double thioether link between heme c and peptide, and the use of the labile heme fragment as a reporter ion, can improve database searching results. The combination of affinity chromatography and heme-specific informatics yielded increases in the number of peptide-spectrum matches of 20-100-fold for bovine cytochrome c. PMID- 23082896 TI - Chotosan ameliorates cognitive and emotional deficits in an animal model of type 2 diabetes: possible involvement of cholinergic and VEGF/PDGF mechanisms in the brain. AB - BACKGROUND: Diabetes is one of the risk factors for cognitive deficits such as Alzheimer's disease. To obtain a better understanding of the anti-dementia effect of chotosan (CTS), a Kampo formula, we investigated its effects on cognitive and emotional deficits of type 2 diabetic db/db mice and putative mechanism(s) underlying the effects. METHODS: Seven-week-old db/db mice received daily administration of CTS (375 - 750 mg/kg, p.o.) and the reference drug tacrine (THA: 2.5 mg/kg, i.p.) during an experimental period of 7 weeks. From the age of 9-week-old, the animals underwent the novel object recognition test, the modified Y-maze test, and the water maze test to elucidate cognitive performance and the elevated plus maze test to elucidate anxiety-related behavior. After completing behavioral studies, Western blotting and immunohistochemical studies were conducted. RESULTS: Compared with age-matched non-diabetic control strain (m/m) mice, db/db mice exhibited impaired cognitive performance and an increased level of anxiety. CTS ameliorated cognitive and emotional deficits of db/db mice, whereas THA improved only cognitive performance. The phosphorylated levels of Akt and PKCalpha in the hippocampus were significantly lower and higher, respectively, in db/db mice than in m/m mice. Expression levels of the hippocampal cholinergic marker proteins and the number of the septal cholinergic neurons were also reduced in db/db mice compared with those in m/m mice. Moreover, the db/db mice had significantly reduced levels of vasculogenesis/angiogenesis factors, vascular endothelial growth factor (VEGF), VEGF receptor type 2, platelet-derived growth factor-B, and PDGF receptor beta, in the hippocampus. CTS and THA treatment reversed these neurochemical and histological alterations caused by diabetes. CONCLUSION: These results suggest that CTS ameliorates diabetes-induced cognitive deficits by protecting central cholinergic and VEGF/PDGF systems via Akt signaling pathway and that CTS exhibits the anxiolytic effect via neuronal mechanism(s) independent of cholinergic or VEGF/PDGF systems in db/db mice. PMID- 23082898 TI - One-year follow-up of treatment with once-daily tacrolimus in de novo renal transplant. AB - OBJECTIVES: The once-daily prolonged-release formulation of tacrolimus (tacrolimus QD) is expected to demonstrate equivalent efficacy and safety to the twice-daily formulation (tacrolimus BID). We reviewed the 1-year outcomes of tacrolimus QD in de novo renal transplant. MATERIALS AND METHODS: We reviewed 50 de novo renal transplant patients assigned in a nonrandomized fashion to either tacrolimus QD (n=23, historic control group) or tacrolimus BID (n=27). Other immunosuppressive drugs used in both groups included mycophenolate mofetil, basiliximab, and steroids. We evaluated trough levels, required dosages, renal function, rejection rates, and episodes of infection within 1 year after transplant. RESULTS: Trough levels of both drugs varied during the perioperative periods, but subsequently stabilized in both groups. There was a tendency toward a slow elevation and a higher dosage requirement in the tacrolimus QD group, compared with the tacrolimus BID group in the early stages, though the required dosages decreased steadily. The rejection rate in the tacrolimus QD group was low, and only 1 patient experienced subclinical rejection. No severe infectious adverse events were observed. CONCLUSIONS: Patients taking tacrolimus QD tended to have lower trough levels and require higher dosages than those taking tacrolimus BID during the early posttransplant period, though the differences decreased with increasing time after transplant. Tacrolimus QD can be administered with excellent efficacy and safety in de novo renal transplant recipients. PMID- 23082899 TI - The provider perception inventory: psychometrics of a scale designed to measure provider stigma about HIV, substance abuse, and MSM behavior. AB - Nongay identified men who have sex with men and women (NGI MSMW) and who use alcohol and other drugs are a vulnerable, understudied, and undertreated population. Little is known about the stigma faced by this population or about the way that health service providers view and serve these stigmatized clients. The provider perception inventory (PPI) is a 39-item scale that measures health services providers' stigma about HIV/AIDS, substance use, and MSM behavior. The PPI is unique in that it was developed to include service provider stigma targeted at NGI MSMW individuals. PPI was developed through a mixed methods approach. Items were developed based on existing measures and findings from focus groups with 18 HIV and substance abuse treatment providers. Exploratory factor analysis using data from 212 health service providers yielded a two dimensional scale: (1) individual attitudes (19 items) and (2) agency environment (11 items). Structural equation modeling analysis supported the scale's predictive validity (N=190 sufficiently complete cases). Overall findings indicate initial support for the psychometrics of the PPI as a measure of service provider stigma pertaining to the intersection of HIV/AIDS, substance use, and MSM behavior. Limitations and implications to future research are discussed. PMID- 23082900 TI - Pharmacokinetics of macrolides in foals. AB - Macrolides are used for treatment of pneumonia and extrapulmonary conditions caused by Rhodococcus equi. In foals, macrolides have an extraordinary capacity to accumulate in different lung tissue compartments. These drugs show unique pharmacokinetic features such as rapid and extensive distribution and long persistence in pulmonary epithelial lining fluid (PELF) and bronchoalveolar lavage (BAL) cells from foals. This article reviews the pharmacokinetic characteristics of erythromycin, azithromycin, clarithromycin, tulathromycin, telithromycin, gamithromycin, and tilmicosin in foals, with emphasis on PELF and BAL cell concentrations. PMID- 23082901 TI - Ultraviolet A1 phototherapy for mycosis fungoides. AB - BACKGROUND: Mycosis fungoides (MF) is the most common form of primary cutaneous lymphoma, and is characterized by a malignant proliferation of CD4+ cells. Psoralen ultraviolet A (PUVA) irradiation is the most common treatment for cutaneous lesions. However, PUVA carries the risk of adverse reactions to psoralens and long-term risk of skin cancer. UVA1 may be a safer alternative. AIM: To assess the efficacy of UVA1 phototherapy in patients with early-stage MF (T1-T2). METHODS: Four patients with early-stage MF were treated with 1630-2710 J/cm(2) UVA1 given in 29-40 fractions, and the effect was assessed by clinical examination and by high-resolution ultrasonography. RESULTS: Complete clinical remission of MF was achieved in all cases. CONCLUSIONS: This preliminary report indicates that UVA1 phototherapy might be an efficient treatment for early-stage MF. PMID- 23082903 TI - Cylindrospermopsin: occurrence, methods of detection and toxicology. AB - Cyanobacteria are aquatic micro-organisms that pose a great threat to aquatic ecosystems by the production of dense blooms, but most importantly by the production of secondary metabolites, namely the cyanotoxins. One of these is cylindrospermopsin (CYN), a hepatotoxic polyketide-derived alkaloid with well known associated cases of animal mortalities and human morbidity. First described as being associated with liver damage, this toxin is now considered a cytotoxic and a genotoxic toxin, due to its effects in other organs and in DNA. Its occurrence has been reported so far in eight different cyanobacteria species and in several water samples from four of the five continents. With a guideline value of 1 MUg l(-1), CYN is now considered the second most studied cyanotoxin worldwide. It is important to review the information regarding the findings made until now about this cyanotoxin 30 years since its first report. PMID- 23082902 TI - Characterization of acute and long-term pathologies of superficial and deep dermal sulfur mustard skin lesions in the hairless guinea pig model. AB - Sulfur mustard induces severe acute and prolonged damage to the skin and only partially effective treatments are available. We have previously validated the use of hairless guinea pigs as an experimental model for skin lesions. The present study aimed to characterize a model of a deep dermal lesion and to compare it with the previously described superficial lesion. Clinical evaluation of the lesions was conducted using reflectance colorimetry, trans-epidermal water loss and wound area measurements. Prostaglandin E(2) content, matrix metalloproteinase-2 and 9 activity, and histopathology were conducted up to 4 weeks post-exposure. Sulfur mustard skin injury, including erythema and edema, impairment of skin barrier and wounds developed in a dose-dependent manner. Prostaglandin E(2) content and matrix metalloproteinase-2 and 9 activities were elevated during the wound development and the healing process. Histological evaluation revealed severe damage to the epidermis and deep dermis and vesications. At 4 weeks postexposure, healing was not completed: significantly impaired stratum corneum, absence of hair follicles, and epidermal hyperplasia were observed. These results confirm the use of the superficial and deep dermal skin injuries in the hairless guinea pigs as suitable models that can be utilized for the investigation of the pathological processes of acute as well as long-term injuries. These models will be further used to develop treatments to improve the healing process and prevent skin damage and long-term effects. PMID- 23082908 TI - Single-crystal X-ray diffraction study of three Yb@C82 isomers cocrystallized with Ni(II)(octaethylporphyrin). AB - Single crystals of three soluble Yb@C(82) isomers, namely, Yb@C(2)(5)-C(82), Yb@C(s)(6)-C(82), and Yb@C(2v)(9)-C(82), cocrystallized with Ni(II)(octaethylporphyrin), allowed accurate crystallographic elucidation of their molecular structures in terms of both cage symmetry and metal location. Multiple metal positions were found in all these isomers, but the major metal sites were found in some specific regions within these cages. Specifically, the Yb(2+) ion prefers to reside close to a hexagonal ring in Yb@C(2)(5)-C(82) and Yb@C(2v)(9)-C(82) but a [5,6,6]-junction carbon atom in Yb@C(s)(6)-C(82). Theoretical calculations at the B3LYP level revealed that these metal positions all correspond to energy minima from the electrostatic potential maps and give rise to the most stable configurations of these Yb@C(82) isomers. Furthermore, it is noteworthy that this is the first report on X-ray crystallographic studies of such metallofullerenes with the popular C(2v)(9)-C(82) encapsulating a divalent metal ion, described as M(2+)@[C(2v)(9)-C(82)](2-). PMID- 23082909 TI - Home screening for bacteriuria in children with spina bifida and clean intermittent catheterization. AB - BACKGROUND: Significant bacteriuria (SBU) and urinary tract infections (UTIs) are common in patients with spina bifida and neuropathic detrusor sphincter dysfunction. Laboratory agar plated culture is the gold standard to establish SBU. It has the disadvantage of diagnostic and subsequent therapeutic delay. Leukocyte esterase tests (LETs) and dip slides proved to be useful in the general populations to exclude SBU and UTI. The aim of this study was to evaluate the reliability of LET and dip slide in children with spina bifida without symptoms of UTI. The reliability in children with asymptomatic SBU was not studied before. METHODS: In one hundred and twelve children with spina bifida on clean intermittent catheterization LETs and dip slides were compared with laboratory cultures. Both tests and agar plated cultures were performed on catheterized urine samples. The hypothesis was that the home tests are as accurate as laboratory cultures. RESULTS: A SBU was found in 45 (40%) of the 112 laboratory cultures. A negative LET excluded SBU (negative predictive value 96%), while a positive LET had a positive predictive value of 72%. The false positive rate was 28%. Dip slide determination of bacterial growth had no added value, other than serving as transport medium. CONCLUSIONS: In spina bifida children, leukocyte esterase testing can be used to exclude significant bacteriuria at home, while dip slide tests have no added value to diagnose or exclude significant bacteriuria. PMID- 23082910 TI - Effects of over-expression of TLR2 in transgenic goats on pathogen clearance and role of up-regulation of lysozyme secretion and infiltration of inflammatory cells. AB - BACKGROUND: Toll-like receptor 2 (TLR2) is important to host recognition of invading gram-positive microbes. In goats, these microbes can cause serious mastitis, anthrax, tetanus, and other problems. Transgenic goats constitutively over-expressing TLR2 in many tissues serve as a suitable model for the study of the role of TLR2 over-expression in bacterial clearance. RESULTS: Capra hircus TLR2 over-expression vector (p3S-LoxP-TLR2) was used to generate transgenic goats by egg microinjection. The integration efficiency was 8.57%. Real-time PCR and immunohistochemical results confirmed that the goats over-expressing the TLR2 gene (Tg) expressed more TLR2 than wild-type goats (WT). Monocyte-macrophages from the bloodstreams of transgenic goats were stimulated with synthetic bacterial lipoprotein (Pam3CSK4) and by the promotion of interleukin-6 (IL-6) and IL-10 expression in vitro. The oxidative damage was significantly reduced, and lysozyme (LZM) secretion was found to be up-regulated. Ear tissue samples from transgenic goats that had been stimulated with Pam3CSK4 via hypodermic injection showed that transgenic individuals can undergo the inflammation response very quickly. CONCLUSIONS: Over-expression of TLR2 was found to decrease radical damage to host cells through low-level production of NO and MDA and to promote the clearance of invasive bacteria by up-regulating lysozyme secretion and filtration of inflammatory cells to the infected site. PMID- 23082912 TI - PfRIO-2 kinase is a potential therapeutic target of antimalarial protein kinase inhibitors. AB - Protein kinases (PKs) present in Plasmodium falciparum catalyze phosphorylation reaction to control growth and differentiation of the parasite throughout the life cycle. Protein kinase inhibitors are found to kill the parasite but their cellular target enzymes are not known. Protein kinase inhibitors are evaluated in an in sillico docking studies using plasmodium falciparum RIO-2 kinase (right open reading frame-2 protein kinase) as target enzyme. Most of the protein kinase inhibitors showed appropriate docking within the ATP binding domain of the PfRIO 2 kinase. The initial docking experiments were further validated by a substrate competition experiment to validate the preliminary screening results and test the potentials of these inhibitors under in vivo conditions. Docking and substrate competition study identifies wortmannin, enzastaurin, indirubin-3'-monoxime, apigenin, kaempferol and 8-hydroxy-4-methyl-9-nitro-2H-benzo[g]chromen-2-one as lead inhibitors against native/active form of the PfRIO-2 kinase. The top protein kinase inhibitors bind into the ATP binding site with a similar conformation as ATP. The docking result is in good agreement with the antimalarial schizonticidal IC50 (MUg/ml) of an inhibitor and gives a correlation factor (R2) of 0.82 whereas top hit antimalarial inhibitors gives a correlation factor (R2) of 0.99. In summary, our work highlights the importance of PfRIO-2 kinase as a target behind the antimalarial action of protein kinase inhibitors and might help to design a new set of antimalarial remedies. PMID- 23082913 TI - Congenital solitary infantile myofibromatosis involving the spinal cord. AB - Infantile myofibromatosis, a rare mesenchymal disorder that develops in early childhood, is classified by the number of lesions that occur: solitary or multicentric. Involvement of the CNS is unusual in either type. Infantile myofibromatosis in the spine is exceptional, and most published cases represent a secondary invasion. Here, the authors report on an 8-month-old girl presenting with weakness below the ankle and an intraspinal mass extending from T-6 to the conus. The patient underwent only partial surgical removal of the lesion, and the pathology was confirmed as infantile myofibromatosis. After the operation, weakness in the lower extremities gradually improved; however, she could not walk at the time of the final follow-up. On follow-up MRI performed 19 months after the operation, the residual lesion remained unchanged with decreased enhancement. PMID- 23082914 TI - Exchange of type II dockerin-containing subunits of the Clostridium thermocellum cellulosome as revealed by SNAP-tags. AB - Clostridium thermocellum is a thermophilic anaerobic bacterium which efficiently hydrolyzes and metabolizes cellulose to ethanol through the action of its cellulosome, a multiprotein enzymatic complex. A fluorescent protein probe, consisting of a type II dockerin module fused to a SNAP-tag, was developed in order to gain insight into the quaternary configuration of the cellulosome and to investigate the effect of deleting cipA, the protein scaffold on which the cellulosome is built. Fluorescence microscopy suggested that the probe had localized to polycellulosomal protuberances on the cell surface. Surprisingly, fluorescence intensity did not substantially change in the cipA deletion mutants. Sequential labeling experiments suggested that this was a result of bound type II dockerins from CipA being replaced by unbound type II dockerins from the fluorophore-SNAP-XDocII probe. This mechanism of dockerin exchange could represent an efficient means for modifying cellulosome composition. PMID- 23082915 TI - An incidental scalp finding. PMID- 23082916 TI - The incidence of diabetes mellitus following pulmonary embolism: a retrospective cohort study. PMID- 23082917 TI - The evaluation of fatty acid ratios in latent fingermarks by gas chromatography/mass spectrometry (GC/MS) analysis. AB - Despite advances in DNA, fingermarks remain one the best forms of evidence available. While fingermarks are routinely analyzed in terms of their patterns, it may be possible to obtain additional information in terms of their chemical composition. If successful, a chemical analysis of the constituents of a fingermark may give scientists additional information that may help in the identification of a person. The results presented herein describe the initial investigation into the analytical determination of some of these compounds, specifically the fatty acids. This study was specifically aimed at identifying possible fatty acids, which could aid in profiling or perhaps uniquely identifying an individual. Preliminary data obtained in this study suggests that this may in fact be possible, though additional research is certainly necessary. Utilizing gas chromatography-mass spectrometry, significant differences in the ratios of several fatty acid methyl esters were found when comparing individuals of varying race and gender. In addition, large intervariability and intravariability was discovered for some compounds, suggesting the possibility of being able to individualize based on chemical profile. Follow-up investigations will continue to determine whether this continues to be the case as greater numbers of individuals are sampled and more extensive control and information on the subjects is obtained. PMID- 23082918 TI - Nutritional status and the impact of socioeconomic factors on pregnant women in Kamrup district of Assam. AB - Pregnancy is a critical time in the course of life, having both health and social impacts for individuals, family, and society. The prevalence of undernutrition among pregnant women in a rural area of Assam, India, was examined using anthropometric and biochemical assessments. Key socioeconomic factors that affect nutritional status were examined. A cross-sectional study with a sample of 285 women from all three trimesters was done. The results found that 48% of the women were below normal for Body Mass Index (BMI), indicating a high level of undernutrition. The age of the mother and husband's occupation showed a strong positive correlation with BMI, while family size and income level showed a negative correlation. The results of the biochemical analysis showed that 62% of the women were anemic, and copper and zinc levels were 29% and 12% below normal levels, respectively. The study findings indicate that undernutrition is far higher than national and global standards. PMID- 23082919 TI - Factors influencing ordering practices at Baltimore City carryouts: qualitative research to inform an obesity prevention intervention. AB - Low-income African Americans bear a disproportionately high burden of chronic diseases associated with intakes of prepared foods, including those commonly found in carryout restaurants. This study collected formative data to investigate the main factors that influence ordering practices in carryout restaurants and to identify possible intervention strategies. Twenty in-depth interviews and two focus groups were conducted. From the perspectives of carryout customers and owners, the most salient factors affecting ordering practices were habit, price, taste, and food appearance. Study recommendations include manipulating prices and adding photographs of healthy items to carryout menus to encourage healthier ordering practices in carryout restaurants. PMID- 23082920 TI - Consumer attitudes toward food consumption and purchase in Turkey. AB - This study was conducted in the Ankara Province of Turkey to determine the attitudes of adult consumers toward food consumption and purchasing activities. The data were collected by conducting face-to-face interviews with 700 adults working in ministries (government office) to fill in a questionnaire prepared especially for this purpose. The responses to the questionnaire were evaluated by assigning points for the "food-consumption-and-purchasing attitudes" of each respondent based on their replies. These food-consumption-and-purchasing attitude points have been then analyzed in terms of the gender, age, and educational level of the adults involved. The results showed that women, the 30-39 age group, and university graduates have a higher score of food-consumption-and-purchasing attitude points than do men, the age group comprising respondents < 30 and >= 40 years of age, and those with lower education levels, respectively. A statistically significantly relation was observed between food-consumption-and purchasing attitude points and age. PMID- 23082921 TI - Indigenous knowledge of shea processing and quality perception of shea products in Benin. AB - A survey among 246 people belonging to 14 ethnic groups and living in 5 different parklands in Benin revealed different practices to process shea kernels (namely boiling followed sun drying and smoking) and extract shea butter. A relation between parklands, gathering period, and sun-drying conditions was established. Moisture content and appearance of kernels were the selection criteria for users of shea kernels; color was the main characteristic to buy butter. Constraints to be solved are long processing times, lack of milling equipment and high water requirements. Best practices for smoking, sun drying, and roasting operations need to be established for further improvement. PMID- 23082922 TI - Associations between body mass index, shopping behaviors, amenity density, and characteristics of the neighborhood food environment among female adult Supplemental Nutrition Assistance Program (SNAP) participants in eastern North Carolina. AB - We examined associations between body mass index (BMI) and the food environment among adult female Supplemental Nutrition Assistance Program (SNAP) participants (N = 197) in eastern North Carolina. Food venue proximity to residential addresses was calculated using a geographic information system. Walk Score was used as a measure of amenity density. Correlation and linear regression analyses were used to examine associations between BMI and distance to and use of food venues, and residential amenity density. Frequency of supercenter use was significantly inversely associated with distance to supercenters. Walk Score was significantly inversely associated with BMI. BMI was not associated with distance to or use of any particular food venue. Future studies should examine specific health-promoting elements of amenity-dense neighborhoods accessible to limited income populations. PMID- 23082925 TI - Concerted reactions and mechanism of glucose pyrolysis and implications for cellulose kinetics. AB - Concerted reactions are proposed to be keys to understanding thermal decomposition of glucose in the absence of ionic chemistry, including molecular catalysis by ROH molecules such as H(2)O, other glucose molecules, and most of the intermediates and products. Concerted transition states, elementary-reaction pathways, and rate coefficients are computed for pyrolysis of beta-D-glucose (beta-D-glucopyranose), the monomer of cellulose, and for related molecules, giving an improved and elementary-reaction interpretation of the reaction network proposed by Sanders et al. (J. Anal. Appl. Pyrolysis, 2003, 66, 29-50). Reactions for ring-opening and formation, ring contraction, retro-aldol condensation, keto enol tautomerization, and dehydration are included. The dehydration reactions are focused on bicyclic ring formations that lead to levoglucosan and 1,6-beta-D anhydrousglucofuranose. The bimolecular ROH-assisted reactions are found to have lower activation energy compared to the unimolecular reactions. The same dehydration reaction to levoglucosan should occur for cellulose going to cellosan (e.g., cellotriosan) plus a shortened cellulose chain, a hypothesis supported by the very similar activation energies computed when alternate groups were substituted at the C1 glycosidic oxygen. The principles of Sanders et al. that distinguish D-glucose, D-fructose, sucrose, and cellulose pyrolysis prove useful in providing qualitative insights into cellulose pyrolysis. PMID- 23082924 TI - Timosaponin-BII inhibits the up-regulation of BACE1 induced by ferric chloride in rat retina. AB - BACKGROUND: Our previous studies indicated that oxidative stress up-regulated the expression of beta-amyloid precursor protein cleavage enzyme-1 (BACE1) in rat retina. Pharmacological reports have shown Timosaponin-BII, a purified extract originating from Chinese medical herb Rhizoma Anemarrhenae, is characterized as an antioxidant. Our present study aimed to determine whether Timosaponin-BII affected the expression of BACE1, beta-amyloid precursor protein cleavage production of Abeta1-40 and beta-C-terminal fragment (beta-CTF) in rat retina, which were pre-treated with the oxidizing agent (solution of FeCl3). RESULTS: Few distinctions of BACE1 distribution were observed among all groups (normal control group, model group, Timosaponin-BII treated and vehicle control groups). Rat retinas in model group and vehicle control group manifested an apparent up regulation of BACE1 expression. Meanwhile, the level of malonaldehyde (MDA), Abeta1-40 and beta-CTF were increased. However, when comparing with the vehicle control group, the retinas in Timosaponin-BII treated group showed significantly less BACE1 (p<0.05) and accumulated less Abeta1-40 or beta-CTF (p<0.05). It also showed significantly decreased level of MDA (p<0.05) and prolonged partial thromboplastin time (p<0.05). CONCLUSION: Our data suggested that Timosaponin-BII remarkably inhibited the up-regulation of BACE1 and reduced the over-production of beta-CTF and Abeta in rat retina, which was induced by FeCl3. The mechanism of Timosaponin-BII on BACE1 expression may be related to its antioxidant property. PMID- 23082926 TI - Variation with land use of immune function and prevalence of avian pox in Galapagos finches. AB - Introduced disease has been implicated in recent wildlife extinctions and population declines worldwide. Both anthropogenic-induced change and natural environmental features can affect pathogen spread. Furthermore, environmental disturbance can result in changes in stress physiology, nutrition, and social structure, which in turn can suppress immune system function. However, it remains unknown whether landscape variation results in heterogeneity in host resistance to pathogens. Avian pox virus, a pathogen implicated in avian declines and extinctions in Hawaii, was introduced to the Galapagos in the 1890 s, and prevalence (total number of current infections) has increased recently in finches. We tested whether prevalence and recovery trends in 7 species of Galapagos finches varied by elevation or human land use. To do so, we used infection data obtained from 545 wild-caught birds. In addition, we determined whether annual changes in 4 aspects of innate immune function (complement protein activity, natural antibody activity, concentration of PIT54 protein, and heterophil:lymphocyte ratio) varied by elevation or land use. Prevalence and recovery rates did not vary by elevation from 2008 to 2009. Avian pox prevalence and proportion of recovered individuals in undeveloped and urban areas did not change from 2008 to 2009. In agricultural areas, avian pox prevalence increased 8 fold (from 2% to 17% of 234 individuals sampled) and proportion of recovered individuals increased (11% to 19%) from 2008 to 2009. These results suggest high disease-related mortality. Variation in immune function across human land-use types correlated with variation in both increased prevalence and susceptibility, which indicates changes in innate immune function may underlie changes in disease susceptibility. Our results suggest anthropogenic disturbance, in particular agricultural practices, may underlie immunological changes in host species that themselves contribute to pathogen emergence. PMID- 23082927 TI - What's in a name? Our false uniqueness! AB - The current study investigated our perception of first names. In Study 1, participants estimated their own first name to be less frequent compared with estimates from yoked controls. The first name uniqueness effect was seen for both rare and common names, and male and female names. The uniqueness bias was not due to differential encoding of variegated and shortened names, such as different versions of the name Caitlyn. Study 2 established that rarer names are preferred, and, that when we contemplate a name change, we often consider rare names. Several theoretical explanations for a general name uniqueness effect are proposed. PMID- 23082928 TI - Social and cultural contexts of HIV risk behaviors among Thai female sex workers in Bangkok, Thailand. AB - Recently, the number of indirect female sex workers (FSWs) who work at bars/clubs and massage parlors is substantially increasing in Thailand; however, there are huge gaps in knowledge about HIV risk behaviors among indirect FSWs. This study aimed to describe and understand HIV risk behaviors among Thai FSWs in Bangkok in relation to sociocultural factors and work environment (e.g., bars/clubs, massage parlors, brothels, and street). Based on venue-based purposive sampling methods, Thai FSWs were recruited for qualitative interviews (n=50) and survey interviews (n=205). Based on mixed methods, the study revealed that HIV risk and substance use behaviors among FSWs significantly differed depending on work venues, although there were no significant differences between work venues on some key risk behaviors (e.g., inconsistent condom use with primary partners and customers; willingness to engage in unsafe sex with customers). A multiple linear regression analysis revealed that FSWs who had used illicit drugs, were young, had low levels of self-esteem, or reported STIs had frequently engaged in unprotected vaginal sex with customers. Also, FSWs who worked at bars/clubs, were young, had higher income, or reported STIs had frequently engaged in sex with customers under the influence of alcohol. Qualitative interviews illustrated FSWs' alcohol and drug use due to their stressful life (e.g., long working hours and a large number of customers) and easy access to alcohol and drugs. FSWs had shown inaccurate knowledge about HIV prevention methods and engaged in risky behaviors, such as washing vagina with water or toothpaste after having had sex with customers. The HIV prevention strategies in Thailand need to be re structured through implementing evidence-based HIV prevention intervention programs for FSWs, which must address sociocultural factors (e.g., self-esteem) and alcohol and drug use specific to work venues. PMID- 23082929 TI - Human skin transcriptome during superficial cutaneous wound healing. AB - Healing of the epidermis is a crucial process for maintaining the skin's defense integrity and its resistance to environmental threats. Compromised wound healing renders the individual readily vulnerable to infections and loss of body homeostasis. To clarify the human response of reepithelialization, we biopsied split-thickness skin graft donor site wounds immediately before and after harvesting, as well as during the healing process 3 and 7 days thereafter. In all, 25 biopsies from eight patients qualified for the study. All samples were analyzed by genome-wide microarrays. Here, we identified the genes associated with normal skin reepithelialization over time and organized them by similarities according to their induction or suppression patterns during wound healing. Our results provide the first elaborate insight into the transcriptome during normal human epidermal wound healing. The data not only reveal novel genes associated with epidermal wound healing but also provide a fundamental basis for the translational interpretation of data acquired from experimental models. PMID- 23082930 TI - Coexisting lower urinary tract symptoms and erectile dysfunction: a systematic review of epidemiological data. AB - OBJECTIVE: Assess and categorise the available prevalence data on coexistent LUTS and ED in the general population and among individuals consulting a healthcare provider for any reason or when seeking treatment for LUTS and/or ED. METHODS: Literature search of English-language articles published during the last 15 years. RESULTS: Of 23 relevant studies identified, 12 used both the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF) as assessment tools and 11 used alternative approaches. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS/ED of any severity was not assessable for men in the general population, but rates ranged from 14-37% based on alternative assessments. In the general male population, 13-29% had moderate to severe LUTS and 8-35% had moderate to severe ED. In studies using both IPSS and IIEF, overall prevalence of coexistent LUTS and ED of any severity was 71-80% among men seeking treatment for LUTS, and 74% based on alternative assessments. Among men who sought treatment for either condition, 67-100% had moderate to severe LUTS and 43-59% had moderate to severe ED. Coexistence of LUTS and ED increased with age, ranging from 59-86% among men aged 40s to 60s in primary care to 79-100% in treatment-seeking men with LUTS aged 50s to 70s. Impact on QoL varied, but health-related QoL was generally worse in treatment-seeking men compared with men in the general population. CONCLUSIONS: Although less than one third of middle-aged and older men in the general population have coexisting LUTS and ED, most men seeking treatment for either LUTS or ED have both conditions. Symptom severity and impact on QoL in each condition increase when LUTS and ED coexist. PMID- 23082931 TI - Multinational study of oestrogen and progesterone receptor immunocytochemistry on breast carcinoma fine needle aspirates. AB - OBJECTIVES: To collect data on the variability of immunocytochemical (ICC) procedures used to detect oestrogen/progesterone receptors (ER/PR) on cytological material; to test the reproducibility of results; and to identify the crucial points in the ICC procedures that affect the result. METHODS: Ten laboratories from eight countries participated in a two-part study. In the first part, one of the participants (the coordinator) prepared and distributed cytospins from a fine needle aspirate of a primary breast carcinoma. Laboratories performed ICC staining for ER/PR according to their own methods on the test slides and in-house positive controls. Slides were returned to the coordinator together with information on the preparation of positive control slides and the ICC methodology used. In the second part, obligatory methods of fixation and antigen retrieval were specified. Evaluation of results included grading the number of positive cells, staining intensity, background staining, cytoplasmic staining, sample condition and cellularity. Participants evaluated their own results, which were subsequently evaluated by the coordinator. RESULTS: There was great variability in the preparation of slides for in-house controls and ICC methodology. The outcome of ICC staining of in-house control slides was excellent in two laboratories, adequate in three, sub-optimal in four and inadequate in one. Only six obtained a positive reaction on the test slides and not all were of a high quality. Results of the second run were greatly improved in terms of cellularity of in-house positive control slides, and scores for the percentage of stained cells and staining intensity of control and test slides. Cytospins and monolayer (ThinPrep((r))) preparations were superior to direct smears; methods of fixation and antigen retrieval were the key points in the staining process. CONCLUSIONS: Our experience points to the need for guidelines for hormonal receptor determination and external quality control on cytological material, in order for cytological methods to be used in routine clinical practice with a suitable degree of confidence. PMID- 23082932 TI - Rapid color change in fish and amphibians - function, regulation, and emerging applications. AB - Physiological color change is important for background matching, thermoregulation as well as signaling and is in vertebrates mediated by synchronous intracellular transport of pigmented organelles in chromatophores. We describe functions of and animal situations where color change occurs. A summary of endogenous and external factors that regulate this color change in fish and amphibians is provided, with special emphasis on extracellular stimuli. We describe not only color change in skin, but also highlight studies on color change that occurs using chromatophores in other areas such as iris and on the inside of the body. In addition, we discuss the growing field that applies melanophores and skin color in toxicology and as biosensors, and point out research areas with future potential. PMID- 23082933 TI - High-density reconstitution of functional water channels into vesicular and planar block copolymer membranes. AB - The exquisite selectivity and unique transport properties of membrane proteins can be harnessed for a variety of engineering and biomedical applications if suitable membranes can be produced. Amphiphilic block copolymers (BCPs), developed as stable lipid analogs, form membranes that functionally incorporate membrane proteins and are ideal for such applications. While high protein density and planar membrane morphology are most desirable, BCP-membrane protein aggregates have so far been limited to low protein densities in either vesicular or bilayer morphologies. Here, we used dialysis to reproducibly form planar and vesicular BCP membranes with a high density of reconstituted aquaporin-0 (AQP0) water channels. We show that AQP0 retains its biological activity when incorporated at high density in BCP membranes, and that the morphology of the BCP protein aggregates can be controlled by adjusting the amount of incorporated AQP0. We also show that BCPs can be used to form two-dimensional crystals of AQP0. PMID- 23082934 TI - Evaluation of database search programs for accurate detection of neuropeptides in tandem mass spectrometry experiments. AB - Neuropeptide identification in mass spectrometry experiments using database search programs developed for proteins is challenging. Unlike proteins, the detection of the complete sequence using a single spectrum is required to identify neuropeptides or prohormone peptides. This study compared the performance of three open-source programs used to identify proteins, OMSSA, X!Tandem and Crux, to identify prohormone peptides. From a target database of 7850 prohormone peptides, 23550 query spectra were simulated across different scenarios. Crux was the only program that correctly matched all peptides regardless of p-value and at p-value<1*10(-2), 33%, 64%, and >75%, of the 5, 6, and >=7 amino acid-peptides were detected. Crux also had the best performance in the identification of peptides from chimera spectra and in a variety of missing ion scenarios. OMSSA, X!Tandem and Crux correctly detected 98.9% (99.9%), 93.9% (97.4%) and 88.7% (98.3%) of the peptides at E- or p-value<1*10(-6) (<1*10(-2)), respectively. OMSSA and X!Tandem outperformed the other programs in significance level and computational speed, respectively. A consensus approach is not recommended because some prohormone peptides were only identified by one program. PMID- 23082935 TI - Hepatitis B and C infection in haemodialysis patients in Libya: prevalence, incidence and risk factors. AB - BACKGROUND: Patients receiving maintenance haemodialysis (HD) are at higher risk for acquiring Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections than the general population. Strict infection control measures are essential to prevent nosocomial transmission. We aimed to investigate the incidence and prevalence of HBV and HCV infection in the HD population of Libya as well as risk factors for infection. METHODS: All adult patients receiving maintenance HD (n=2382) in Libyan dialysis centres (n=39) were studied between May 2009 and October 2010. Testing for Hepatitis B surface antigen (HBsAg) and anti-HCV antibodies was performed at initiation of dialysis and every 3-6 months thereafter. Patients who were sero-negative for HBV and HCV (n=1160) were followed up for 1 year to detect sero-conversions. RESULTS: Participant median age was 49 years and 58% were male. 831 patients (34.9%) were sero-positive for HBV and/or HCV (anti-HCV positive 31.1%; HBsAg positive 2.6%; both positive 1.2%). Of the sero-positive patients 4.7% were known to be infected before the initiation of HD. The prevalence of HBV+/-HCV infection varied widely between HD centres from 0% to 75.9%. Sero-positive patients were younger, had longer time on dialysis and more previous blood transfusions. Prospective follow-up revealed an incidence of sero-conversion of 7.7% during 1 year (7.1% HCV; 0.6% HBV). Wide variation in rates of newly acquired infections was observed between dialysis centres. All new HBV cases were referred from centres already treating HBV infected patients. New HCV infections were reported in most centres but the rate of HCV sero-conversion varied widely from 1.5% to 31%. Duration of dialysis, history of previous renal transplant and history of receiving HD in another centre in Libya were significantly associated with sero-conversion. CONCLUSION: Patients on maintenance HD in Libya have a high incidence and prevalence of HCV infection and lower rates of HBV infection. The factors associated with HBV and HCV infection are highly suggestive of nosocomial transmission within HD units. Urgent action is required to improve infection control measures in HD centres and to reduce dependence on blood transfusions for the treatment of anaemia. PMID- 23082936 TI - Transcriptional silencing by single-stranded RNAs targeting a noncoding RNA that overlaps a gene promoter. AB - RNAi using single-strand RNA would provide new options for therapeutic development and for investigating critical questions of mechanism. Using chemically modified single-strands, we test the hypothesis that single-stranded RNAs can engage the RNAi pathway and silence gene transcription. We find that a chemically modified single-stranded silencing RNA (ss-siRNA) designed to be complementary to a long noncoding RNA (lncRNA) requires argonaute protein, functions through the RNAi pathway, and inhibits gene transcription. These data expand the use of single-stranded RNA to cell nuclei. PMID- 23082939 TI - A collation of recently published Western European formulae for age estimation of subadult skeletal remains: recommendations for forensic anthropology and osteoarchaeology. AB - The aim of this study is to provide an effective and quick reference guide based on the most useful European formulae recently published for subadult age estimation. All of these formulae derive from studies on postnatal growth of the scapula, innominate, femur, and tibia, based on modern skeletal data (173 ?, 173 ?) from five documented collections from Spain, Portugal, and Britain. The formulae were calculated from Inverse Regression. For this reason, these formulae are especially useful for modern samples from Western Europe and in particular on 20th century human remains from the Iberian Peninsula. Eleven formulae were selected as the most useful because they can be applied to individuals from within a wide age range and in individuals of unknown sex. Due to their high reliability and because they derive from documented European skeletal samples, we recommend these formulae be used on individuals of Caucasoid ancestry from Western Europe. PMID- 23082937 TI - In vivo transplantation of autogenous marrow-derived cells following rapid intraoperative magnetic separation based on hyaluronan to augment bone regeneration. AB - INTRODUCTION: This project was designed to test the hypothesis that rapid intraoperative processing of bone marrow based on hyaluronan (HA) could be used to improve the outcome of local bone regeneration if the concentration and prevalence of marrow-derived connective tissue progenitors (CTPs) could be increased and nonprogenitors depleted before implantation. METHODS: HA was used as a marker for positive selection of marrow-derived CTPs using magnetic separation (MS) to obtain a population of HA-positive cells with an increased CTP prevalence. Mineralized cancellous allograft (MCA) was used as an osteoconductive carrier scaffold for loading of HA-positive cells. The canine femoral multidefect model was used and four cylindrical defects measuring 10 mm in diameter and 15 mm in length were grafted with MCA combined with unprocessed marrow or with MS processed marrow that was enriched in HA(+) CTPs and depleted in red blood cells and nonprogenitors. Outcome was assessed at 4 weeks using quantitative 3D microcomputed tomography (micro-CT) analysis of bone formation and histomorphological assessment. RESULTS: Histomorphological assessment showed a significant increase in new bone formation and in the vascular sinus area in the MS-processed defects. Robust bone formation was found throughout the defect area in both groups (defects grafted with unprocessed marrow or with MS processed marrow.) Percent bone volume in the defects, as assessed by micro-CT, was greater in defects engrafted with MS processed cells, but the difference was not statistically significant. CONCLUSION: Rapid intraoperative MS processing to enrich CTPs based on HA as a surface marker can be used to increase the concentration and prevalence of CTPs. MCA grafts supplemented with heparinized bone marrow or MS processed cells resulted in a robust and advanced stage of bone regeneration at 4 weeks. A greater new bone formation and vascular sinus area was found in defects grafted with MS processed cells. These data suggest that MS processing may be used to enhance the performance of marrow-derived CTPs in clinical bone regeneration procedures. Further assessment in a more stringent bone defect model is proposed. PMID- 23082940 TI - Fc-independent phagocytosis: implications for IVIG and other therapies in immune mediated thrombocytopenia. AB - Phagocytes were first described by Dr. Metchnikoff in 1873. The roles of phagocytes in innate and adaptive immunity have been well established to date, although the molecular mechanisms involved in initiating phagocytosis (through Fc or other receptors) remain to be further explored. Phagocytes in the reticuloendothelial system, particularly macrophages, have been implicated in the clearance of senescent blood cells. The destruction of these cells may be primarily mediated via an Fc-independent pathway. Fc-independent phagocytosis may also play an important role in platelet clearance, including in autoimmune thrombocytopenia (ITP), and in clearance of platelet-rich emboli detached from sites of vascular injury. In ITP, the two major platelet auto-antigens have been located on glycoprotein (GP)IIbIIIa and the GPIb complex. It has been demonstrated that anti-GPIb antibodies, in contrast to anti-GPIIbIIIa, can induce thrombocytopenia in an Fc-independent manner. We further demonstrated in an animal model that intravenous IgG (IVIG) is unable to ameliorate thrombocytopenia caused by most anti-GPIb antibodies, despite its efficacy in anti- GPIIbIIIa mediated thrombocytopenia. Our data was supported by subsequent retrospective studies with ITP patients by several independent groups. Most recently, we found that anti-GPIb-mediated ITP was also resistant to steroid therapy and that platelet activation and apoptosis induced by anti-GPIb antibodies may be involved in the Fc-independent platelet clearance. Therefore, identification of antibody specificity in patients, e.g. anti-GPIIbIIIa (Fc-dependent) versus anti-GPIb (Fc independent), may be important for therapies against ITP, as well as other immune mediated thrombocytopenias. PMID- 23082941 TI - Teacher-made models: the answer for medical skills training in developing countries? AB - BACKGROUND: The advantages of using simulators in skills training are generally recognized, but simulators are often too expensive for medical schools in developing countries. Cheaper locally-made models (or part-task trainers) could be the answer, especially when teachers are involved in design and production (teacher-made models, TM). METHODS: We evaluated the effectiveness of a TM in training and assessing intravenous injection skills in comparison to an available commercial model (CM) in a randomized, blind, pretest-posttest study with 144 undergraduate nursing students. All students were assessed on both the TM and the CM in the pre-test and post-test. After the post-test the students were also assessed while performing the skill on real patients. RESULTS: Differences in the mean scores pre- and post-test were marked in all groups. Training with TM or CM improved student scores substantially but there was no significant difference in mean scores whether students had practiced on TM or CM. Students who practiced on TM performed better on communication with the patient than did students who practiced on CM. Decreasing the ratio of students per TM model helped to increase practice opportunities but did not improve student's mean scores. The result of the assessment on both the TM and the CM had a low correlation with the results of the assessment on real persons. CONCLUSIONS: The TM appears to be an effective alternative to CM for training students on basic IV skills, as students showed similar increases in performance scores after training on models that cost considerably less than commercially available models. These models could be produced using locally available materials in most countries, including those with limited resources to invest in medical education and skills laboratories. PMID- 23082942 TI - Studies on the antioxidant activity of the essential oil and extract of Tunisian Tetraclinis articulata (Vahl) Mast. (Cupressaceae). AB - This study analyses the chemical composition and in vitro antioxidant activity of both the essential oil and the 80% aqueous acetone extract of Tetraclinis articulata leaves. The GC-MS analysis of the essential oil identified 66 components that comprise 93.5% of the oil. The major constituents of the oil are: bornyl acetate (31.4%), alpha-pinene (24.5%) and camphor (20.3%). Antioxidant activities of the samples were determined using four different test systems, namely DPPH, beta-carotene/linoleic acid, reducing power and metal chelating activity assay. Test results from the DPPH system showed the strongest radical scavenging activity was exhibited by the 80% aqueous acetone extract (IC50 = 5.5 ug mL-1), which was two times higher than the positive control (BHT). The amount of the total phenolics, flavonoids and condensed tannins was very high in the 80% aqueous acetone extracts. The correlation between the antioxidant activity potential and total phenolic level of the extract was noted. PMID- 23082944 TI - Lipopolysaccharide-binding protein is increased in patients with psoriasis with metabolic syndrome, and correlates with C-reactive protein. AB - Lipopolysaccharide-binding protein (LBP) is a reliable indicator of serum lipopolysaccharide (LPS) concentration. Raised levels of circulating LPS can trigger an increase in chronic pro-inflammatory cytokines, which may mediate the development of insulin resistance and obesity. Psoriasis is a chronic inflammatory skin disease that has been associated with metabolic syndrome. We aimed to study the expression of LBP in patients with psoriasis treated with narrowband ultraviolet B phototherapy, and controls matched by age, gender and body mass index (BMI). We did not find any differences in serum LBP concentration between patients and controls, and serum LBP did not correlate with the Psoriasis Area and Severity Index. However, patients with psoriasis and metabolic syndrome had higher serum concentration of LBP than controls. Furthermore, correlation with BMI and apolipoprotein B was present in controls, but not in patients with psoriasis. Serum LBP level did not change significantly after treatment with phototherapy. PMID- 23082945 TI - Photochromism of 1,2-bis(2-thienyl)perfluorocyclopentene derivatives: substituent effect on the reactive carbon atoms. AB - In this work, we prepared a new 1,2-bis(3-cyanothiophen-2 yl)perfluorocyclopentene with electro-withdrawing cyano groups at both reactive carbon atoms. Furthermore, we studied the substituent effects of the reactive carbon atoms on the photochromic properties of 1,2-bis(3-R-substituted thiophen-2 yl)perfluorocyclopentene derivatives by comparing the absorption wavelengths and quantum yields of the derivatives having R = cyano, methyl, and methoxy groups. The absorption bands of the closed-ring isomers generated by UV irradiation shifted to longer wavelengths with an increase in the electron-donating characteristic of the substituents. The closed-ring isomer having cyano groups at both reactive carbon atoms has an absorption band at 427 nm (lambda(max)), whereas those of methyl and methoxy derivatives have bands at 432 and 481 nm, respectively. The derivative with cyano groups shows the largest cycloreversion quantum yield (0.45), and this yield decreased with an increase in the substituents' donating characteristic. Theoretical calculation explains that the excited state of the closed-ring isomer with cyano groups has the highest energy, because there is no barrier to ring-opening on the excited potential surface. PMID- 23082946 TI - Denitrification-derived nitric oxide modulates biofilm formation in Azospirillum brasilense. AB - Azospirillum brasilense is a rhizobacterium that provides beneficial effects on plants when they colonize roots. The formation of complex bacterial communities known as biofilms begins with the interaction of planktonic cells with surfaces in response to appropriate signals. Nitric oxide (NO) is a signaling molecule implicated in numerous processes in bacteria, including biofilm formation or dispersion, depending on genera and lifestyle. Azospirillum brasilense Sp245 produces NO by denitrification having a role in root growth promotion. We analyzed the role of endogenously produced NO on biofilm formation in A. brasilense Sp245 and in a periplasmic nitrate reductase mutant (napA::Tn5; Faj164) affected in NO production. Cells were statically grown in media with nitrate or ammonium as nitrogen sources and examined for biofilm formation using crystal violet and by confocal laser microscopy. Both strains formed biofilms, but the mutant produced less than half compared with the wild type in nitrate medium showing impaired nitrite production in this condition. NO measurements in biofilm confirmed lower values in the mutant strain. The addition of a NO donor showed that NO influences biofilm formation in a dose-dependent manner and reverses the mutant phenotype, indicating that Nap positively regulates the formation of biofilm in A. brasilense Sp245. PMID- 23082947 TI - Investigation of the epithelial to mesenchymal transition markers S100A4, vimentin and Snail1 in gastroesophageal junction tumors. AB - Epithelial to mesenchymal transition (EMT) promotes tumor progression and invasion. As no study has focused on gastroesophageal junction (GEJ) tumors, the expression of three EMT-related proteins (S100A4, vimentin, and Snail1) was investigated with the aim of assessing their pathologic and prognostic significance. Resection specimens were obtained from 104 patients who underwent surgery for GEJ adenocarcinoma, without preoperative chemotherapy. Three tissue cores were obtained from each of the tumor body (TB), luminal surface (LS), and invasive edge (IE) to produce tissue microarrays, and immunohistochemical staining was performed. The microarrays were scored independently by two observers. The demographic and histopathologic details of the patients were collected. Overall positive expression was observed in 88 (S100A4, 85%), 16 (vimentin, 14%), and 92 (Snail1, 89%) tumors. Staining for S100 A4 was positive in 79 (76%) of TB, 69 (66%) of IE, and 69 (66%) of LS specimens. Staining for vimentin was positive in 7 (6%) of TB, 11 (11%) of IE, and 5 (5%) of LS specimens. Staining for Snail1 was positive in 83 (80%) of TB, 51 (49%) of IE, and 78 (75%) of LS specimens. Positive staining of TB for S100A4 (P = 0.04) and Snail1 at IE (P = 0.01) was associated with involvement of circumferential resection margins. Positive staining for S100A4 in the TB (P = 0.02) and LS (P = 0.01) was associated with poor 5-year overall survival. Vimentin had no statistically significant relationships with pathologic factors or outcome. The acquisition of mesenchymal protein S100A4 is associated with a poor prognosis in patients with GEJ tumors who undergo potentially curative surgery, and LS samples can be used to obtain prognostic information. Increased EMT-related protein expression (S100A4, Snail1) is associated with the involvement of circumferential resection margin. PMID- 23082948 TI - Congenital disorder of glycosylation (PMM2-CDG) in a patient with antithrombin deficiency and severe thrombophilia. PMID- 23082950 TI - Essentialism, historical construction, and social influence: representations of Pomakness in majority talk in Western Thrace (Greece). AB - Social psychological research has been particularly interested to study essentialism in the construction of social categories and to manifest its potential consequences in intergroup attitudes. Drawing upon this literature, the present study focuses on the argumentative resources employed to construct ethnic categories in a specific rhetorical context: focus group discussions between majority Greek educators about the minority group of Pomaks, historically residing in Western Thrace (Greece). Discussions were framed as an attempt to capture the particularities of minority education and data were analysed by the use of tools and concepts of discursive and rhetorical psychology. Analysis indicates that participants have multiple and complex recourses available to construct Pomakness. Representations of Pomakness as an essential a-historical entity coexist with conceptions of category membership and identification as a result of certain historical conditions and processes of social influence. Essential and de-essential category constructions are approached as rhetorically situated, oriented towards specific rhetorical ends in specific argumentative contexts. They are also considered, however, to be nested within a complex and dynamic intergroup context which reflects the ideological contradictions of the Greek policy towards the minority and which constitutes (but it is also reconstituted by) shifting group definitions and boundaries. PMID- 23082951 TI - Validation of the Greek version of the Health of the Nation Outcome Scales for Elderly People (HoNOS65+, version 3). AB - OBJECTIVES: There is a growing need for evaluation of the results of mental health services and clinical treatment in older people, but evidence for effectiveness is limited in Greece. The Health of the Nations Outcome Scales for Elderly People (HoNOS65+) are promising instruments for the assessment of mental, physical and social health in older persons. They have been translated into the Greek language but have not been validated. The aim was to assess the inter-rater reliability, intraclass correlation, concurrent validity, internal consistency and sensitivity to change of HoNOS65+ in a Greek sample of older people with mental health problems. METHOD: Two samples, one of inpatients in a psychiatric hospital and the other of older people living in the community were used. In order to test the extent to which the HoNOS65+ were sensitive to change the first sample was reassessed after two months and the second after three months. For each participant HoNOS65+ were completed by two independent raters, and the clinician rated blindly each participant on the Stockton Geriatric Rating Scale and a scale which measured behavioural, physical, cognitive and emotional status. RESULTS: In both groups (inpatients n = 50, community n = 65), the inter-rater reliability, intraclass correlation and concurrent validity were high while internal consistency of the scales taken together was low. At reassessment in 98 participants, HoNOS65+ showed changes comparable to clinician ratings. CONCLUSION: The Greek version of HoNOS65+ can achieve high levels of reliability, validity and sensitivity to change for measuring outcomes in older people with mental health problems. PMID- 23082952 TI - Outcome of relapse after allogeneic stem cell transplant in patients with acute myeloid leukemia. AB - Although allogeneic stem cell transplant (Allo-SCT) is an effective treatment for high-risk acute myeloid leukemia (AML), relapses remain a major cause of treatment failure. There is currently no standard of care for post-transplant relapse of AML, but the increasing numbers of investigational agents in this setting require a better knowledge of their outcome. We retrospectively evaluated the efficacy of salvage therapies in 54 patients with AML relapsing after Allo SCT. Twenty-four patients received intensive salvage treatment (17 non-intensive chemotherapy, 13 supportive care). Complete remissions (CRs) were seen only in the group who received intensive salvage (CR rate: 17/24 [71%]). One-year overall survival was 19% (median: 3.4 months) in the whole study group and 33% in the intensive savage group (vs. 7% for patients without intensive salvage, p = 0.004). Factors influencing overall survival (OS) were: time to relapse after Allo-SCT (hazard ratio [HR]: 3.7 [1.6-8.8]) and performance status (PS) at relapse (HR: 2.2 [1.1-4.4]) by multivariate analysis. Our results confirm the poor prognosis of AML relapse after Allo-SCT. In selected patients salvage chemotherapy produces CRs, but these are short lived. Other strategies aiming at modulating immune antileukemic activity have to be developed. PMID- 23082949 TI - Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research. AB - The medical impact of pain is such that much effort is being applied to develop novel analgesic drugs directed towards new targets and to investigate the analgesic efficacy of known drugs. Ongoing research requires cost-saving tools to translate basic science knowledge into clinically effective analgesic compounds. In this review we have re-examined the prediction of clinical analgesia by human experimental pain models as a basis for model selection in phase I studies. The overall prediction of analgesic efficacy or failure of a drug correlated well between experimental and clinical settings. However, correct model selection requires more detailed information about which model predicts a particular clinical pain condition. We hypothesized that if an analgesic drug was effective in an experimental pain model and also a specific clinical pain condition, then that model might be predictive for that particular condition and should be selected for development as an analgesic for that condition. The validity of the prediction increases with an increase in the numbers of analgesic drug classes for which this agreement was shown. From available evidence, only five clinical pain conditions were correctly predicted by seven different pain models for at least three different drugs. Most of these models combine a sensitization method. The analysis also identified several models with low impact with respect to their clinical translation. Thus, the presently identified agreements and non agreements between analgesic effects on experimental and on clinical pain may serve as a solid basis to identify complex sets of human pain models that bridge basic science with clinical pain research. PMID- 23082953 TI - Detection of engineered silver nanoparticle contamination in pears. AB - Engineered nanomaterials such as silver nanoparticles (Ag NPs) have been increasingly used in agriculture owning to their antimicrobial and insecticidal properties. However, the contamination of Ag NPs in foods and water may pose a great risk to public health and the environment. In this study, the contamination of Ag NPs in pears was detected, characterized, and quantified by a combination of techniques, including transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), and inductively coupled plasma optical emission spectrometry (ICP-OES). Pear samples were treated with two different sizes (20 and 70 nm in diameter) of Ag NPs and stored for different times. Quantification results of Ag NPs in pear samples by ICP-OES demonstrate that there is a good linear relationship (R(2) = 0.983) between the spiked values and recovered values. Residual Ag NPs of both 20 and 70 nm were still detected in samples after 4-day treatment followed by rinsing with water. The penetration study reveals that 20 nm Ag NPs might penetrate the pear skin and pulp after 4-day treatment, while this phenomenon was not observed for 70 nm Ag NPs. These results demonstrate that a combination of techniques could provide accurate results for detection, characterization, and quantification of engineered nanoparticles in agricultural products. PMID- 23082954 TI - Toward a more balanced view of non-native species. PMID- 23082955 TI - Metabolic footprinting of mutant libraries to map metabolite utilization to genotype. AB - The discrepancy between the pace of sequencing and functional characterization of genomes is a major challenge in understanding complex microbial metabolic processes and metabolic interactions in the environment. Here, we identified and validated genes related to the utilization of specific metabolites in bacteria by profiling metabolite utilization in libraries of mutant strains. Untargeted mass spectrometry based metabolomics was used to identify metabolites utilized by Escherichia coli and Shewanella oneidensis MR-1. Targeted high-throughput metabolite profiling of spent media of 8042 individual mutant strains was performed to link utilization to specific genes. Using this approach we identified genes of known function as well as novel transport proteins and enzymes required for the utilization of tested metabolites. Specific examples include two subunits of a predicted ABC transporter encoded by the genes SO1043 and SO1044 required for the utilization of citrulline and a predicted histidase encoded by the gene SO3057 required for the utilization of ergothioneine by S. oneidensis. In vitro assays with purified proteins showed substrate specificity of SO3057 toward ergothioneine and histidine betaine in contrast to substrate specificity of a paralogous histidase SO0098 toward histidine. This generally applicable, high-throughput workflow has the potential both to discover novel metabolic capabilities of microorganisms and to identify the corresponding genes. PMID- 23082956 TI - The effect of lowering salt intake on ambulatory blood pressure to reduce cardiovascular risk in chronic kidney disease (LowSALT CKD study): protocol of a randomized trial. AB - BACKGROUND: Despite evidence implicating dietary sodium in the pathogenesis of cardiovascular disease (CVD) in chronic kidney disease (CKD), quality intervention trials in CKD patients are lacking. This study aims to investigate the effect of reducing sodium intake on blood pressure, risk factors for progression of CKD and other cardiovascular risk factors in CKD. METHODS/DESIGN: The LowSALT CKD study is a six week randomized-crossover trial assessing the effect of a moderate (180 mmol/day) compared with a low (60 mmol/day) sodium intake on cardiovascular risk factors and risk factors for kidney function decline in mild-moderate CKD (stage III-IV). The primary outcome of interest is 24-hour ambulatory blood pressure, with secondary outcomes including arterial stiffness (pulse wave velocity), proteinuria and fluid status. The randomized crossover trial (Phase 1) is supported by an ancillary trial (Phase 2) of longitudinal-observational design to assess the longer term effectiveness of sodium restriction. Phase 2 will continue measurement of outcomes as per Phase 1, with the addition of patient-centered outcomes, such as dietary adherence to sodium restriction (degree of adherence and barriers/enablers), quality of life and taste assessment. DISCUSSION: The LowSALT CKD study is an investigator initiated study specifically designed to assess the proof-of-concept and efficacy of sodium restriction in patients with established CKD. Phase 2 will assess the longer term effectiveness of sodium restriction in the same participants, enhancing the translation of Phase 1 results into practice. This trial will provide much-needed insight into sodium restriction as a treatment option to reduce risk of CVD and CKD progression in CKD patients. TRIAL REGISTRATION: Universal Trial Number: U1111-1125-2149. Australian New Zealand Clinical Trials Registry Number: ACTRN12611001097932. PMID- 23082957 TI - Discrimination of differentially inhibited cysteine proteases by activity-based profiling using cystatin variants with tailored specificities. AB - Recent research has shown the possibility of tailoring the inhibitory specificity of plant cystatins toward cysteine (Cys) proteases by single mutations at positively selected amino acid sites. Here we devised a cystatin activity-based profiling approach to assess the impact of such mutations at the proteome scale using single variants of tomato cystatin SlCYS8 and digestive Cys proteases of the herbivorous insect, Colorado potato beetle, as a model. Biotinylated forms of SlCYS8 and SlCYS8 variants were used to capture susceptible Cys proteases in insect midgut protein extracts by biotin immobilization on avidin-embedded beads. A quantitative LC-MS/MS analysis of the captured proteins was performed to compare the inhibitory profile of different SlCYS8 variants. The approach confirmed the relevance of phylogenetic inferences categorizing the insect digestive Cys proteases into six functionally distinct families. It also revealed significant variation in protease family profiles captured with N-terminal variants of SlCYS8, in line with in silico structural models for Cys protease SlCYS8 interactions suggesting a functional role for the N-terminal region. Our data confirm overall the usefulness of cystatin activity-based protease profiling for the monitoring of Cys protease-inhibitor interactions in complex biological systems. They also illustrate the potential of biotinylated cystatins to identify recombinant cystatin candidates for the inactivation of specific Cys protease targets. PMID- 23082958 TI - Monoamine oxidase enzymes and oxidative stress in the rat optic nerve: age related changes. AB - In this study, age-related changes in the monoamine oxidases (MAO) were studied in the optic nerve (ON) of both young and aged male rats. The aim of the study was to assess the role of MAO in age-related changes in the rat ON and explain the mechanisms of neuroprotection mediated by MAO-B-specific inhibitors. Fifteen three month old and fifteen 26 month old Sprague-Dawley rats were used. The animals were killed by terminal anaesthesia. Staining of MAO, quantitative analysis of images, biochemical assays and statistical analysis of data were carried out. Samples of the ON were washed in water, fixed in Bowen fluid, dehydrated and embedded in Entellan. Histological sections were stained for MAO enzymatic activities. The specificity of the reaction was evaluated by incubating control sections in a medium either without substrate or without dye. The quantitative analysis of images was carried out at the same magnification and the same lighting using a Zeiss photomicroscope. The histochemical findings were compared with the biochemical results. After enzymatic staining, MAO could be demonstrated in the ON fibres of both young and aged animals; however, MAO were increased in the nerve fibres of the elderly rats. These morphological findings were confirmed biochemically. The possibility that age-related changes in MAO levels may be attributed to impaired energy production mechanisms and/or represent the consequence of reduced energy needs is discussed. PMID- 23082959 TI - Biology of circulating nucleic acids and possible roles in diagnosis and treatment in diabetes and cancer. AB - The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology. PMID- 23082960 TI - Malaria, anti malarial drugs and the role of melatonin. AB - Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections successfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent advances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man. PMID- 23082962 TI - Updating the relationship between hyperhomocysteinemia lowering therapy and cardiovascular events. AB - Hyperhomocysteinemia (Hhcy) was defined as an independent risk factor for cardiovascular events. A number of clinical trials had investigated the relationship between Hhcy lowering treatment and cardiovascular diseases, however, the results of these studies remain controversial. This review article gave an over view of the homocysteine metabolisms and updated the recently published results in the role of Hhcy lowering therapy on cardiovascular events. PMID- 23082961 TI - Lessons from Anaplasma phagocytophilum: chromatin remodeling by bacterial effectors. AB - Bacterial pathogens can alter global host gene expression via histone modifications and chromatin remodeling in order to subvert host responses, including those involved with innate immunity, allowing for bacterial survival. Shigella flexneri, Listeria monocytogenes, Chlamydia trachomatis, and Anaplasma phagocytophilum express effector proteins that modify host histones and chromatin structure. A. phagocytophilum modulates granulocyte respiratory burst in part by dampening transcription of several key phagocyte oxidase genes. The A. phagocytophilum protein AnkA localizes to the myeloid cell nucleus where it binds AT-rich regions in the CYBB promoter and decreases its transcription. AT-rich regions of DNA are characteristic of matrix attachment regions (MARs) which are critical for chromatin structure and transcription. MAR-binding proteins, such as SATB1, interact with histone modifying enzymes resulting in altered gene expression. With A. phagocytophilum infection, histone deacetylase 1 (HDAC1) expression is increased and histone H3 acetylation is decreased at the CYBB promoter, suggesting a role for AnkA in altering host epigenetics and modulating gene transcription, at this, and perhaps other loci. This review will focus on how bacterial pathogens alter host epigenetics, by specifically examining A. phagocytophilum AnkA cis-regulation of CYBB transcription and epigenetic changes associated with infection. PMID- 23082963 TI - Calculating the weight of evidence in low-template forensic DNA casework. AB - Interpreting and assessing the weight of low-template DNA evidence presents a formidable challenge in forensic casework. This report describes a case in which a similar mixed DNA profile was obtained from four different bloodstains. The defense proposed that the low-level minor profile came from an alternate suspect, the defendant's mistress. The strength of the evidence was assessed using a probabilistic approach that employed likelihood ratios incorporating the probability of allelic drop-out. Logistic regression was used to model the probability of drop-out using empirical validation data from the government laboratory. The DNA profile obtained from the bloodstain described in this report is at least 47 billion times more likely if, in addition to the victim, the alternate suspect was the minor contributor, than if another unrelated individual was the minor contributor. This case illustrates the utility of the probabilistic approach for interpreting complex low-template DNA profiles. PMID- 23082965 TI - 'Congenital follicular melanocytic naevi': a more appropriate term for spotted grouped pigmented naevi. AB - We report two patients with an uncommon form of pigmented naevus consisting of grouped follicular papules. A biopsy taken from the lesions showed multiple naevus cells, predominantly around the hair follicles, with sparing of the eccrine glands. The clinicohistopathological term given for this condition is 'spotted grouped pigmented naevi type I', and has rarely been reported. We discuss the unusual morphology and differential diagnosis of this condition, and suggest that the term 'congenital follicular melanocytic naevi' is more appropriate for this presentation. PMID- 23082964 TI - Calcium-alginate hydrogel-encapsulated fibroblasts provide sustained release of vascular endothelial growth factor. AB - Vascularization of engineered or damaged tissues is essential to maintain cell viability and proper tissue function. Revascularization of the left ventricle (LV) of the heart after myocardial infarction is particularly important, since hypoxia can give rise to chronic heart failure due to inappropriate remodeling of the LV after death of cardiomyocytes (CMs). Fibroblasts can express vascular endothelial growth factor (VEGF), which plays a major role in angiogenesis and also acts as a chemoattractant and survival factor for CMs and cardiac progenitors. In this in vitro model study, mouse NIH 3T3 fibroblasts encapsulated in 2% w/v Ca-alginate were shown to remain viable for 150 days. Semiquantitative reverse transcription-polymerase chain reaction and immunohistochemistry demonstrated that over 21 days of encapsulation, fibroblasts continued to express VEGF, while enzyme-linked immunosorbent assay showed that there was sustained release of VEGF from the Ca-alginate during this period. The scaffold degraded gradually over the 21 days, without reduction in volume. Cells released from the Ca-alginate at 7 and 21 days as a result of scaffold degradation were shown to retain viability, to adhere to fibronectin in a normal manner, and continue to express VEGF, demonstrating their potential to further contribute to maintenance of cardiac function after scaffold degradation. This model in vitro study therefore demonstrates that fibroblasts encapsulated in Ca-alginate provide sustained release of VEGF. PMID- 23082966 TI - Gamma knife surgery for a hemangioma of the cavernous sinus in a child. AB - Cavernous sinus (CS) hemangiomas are rare vascular abnormalities that constitute 0.4%-2% of all lesions within the CS. Cavernous sinus hemangiomas are high-flow vascular tumors that tend to hemorrhage profusely during resection, leading to incomplete resection and high morbidity and mortality. While Gamma Knife surgery (GKS) has proven to be an effective treatment of CS hemangiomas in the adult population, few reports of GKS for treatment of CS hemangiomas exist in the pediatric literature. Here, the authors present the first case of a 15-year-old girl with a biopsy-proven CS hemangioma who achieved complete resolution of her symptoms and a complete imaging-defined response following GKS. If suspicion for a CS hemangioma is high in a pediatric patient, GKS may be considered as an effective treatment modality, thus avoiding the morbidities of open resection. PMID- 23082967 TI - Assessing effectiveness of a community based health insurance in rural Burkina Faso. AB - BACKGROUND: Financial barriers are a recognized major bottleneck of access and use of health services. The aim of this study was to assess effectiveness of a community based health insurance (CBHI) scheme on utilization of health services as well as on mortality and morbidity. METHODS: Data were collected from April to December 2007 from the Nouna's Demographic Surveillance System on overall mortality, utilization of health services, household characteristics, distance to health facilities, membership in the Nouna CBHI. We analyzed differentials in overall mortality and selected maternal health process measures between members and non-members of the insurance scheme. RESULTS: After adjusting for covariates there was no significant difference in overall mortality between households who could not have been members (because their area was yet to be covered by the stepped-wedged scheme), non-members but whose households could have been members (areas covered but not enrolled), and members of the insurance scheme. The risk of overall mortality increased significantly with distance to health facility (35% more outside Nouna town) and with education level (37% lower when at least primary school education achieved in households). CONCLUSION: There was no statistically significant difference in overall mortality between members and non members. The enrolment rates remain low, with selection bias. It is important that community based health insurances, exemptions fees policy and national health insurances be evaluated on prevention of deaths and severe morbidities instead of on drop-out rates, selection bias, adverse selection and catastrophic payments for health care only. Effective social protection will require national health insurance. PMID- 23082968 TI - Machilusmarin, a new neuroprotective isocoumarin dimer from the stems of Machilus ichangensis Rehd. et Wils. AB - A new isocoumarin dimer, Machilusmarin (1), was isolated from the stem of Machilus ichangensis Rehd. et Wils., together with two known coumarins, scopoletin (2) and isoscopoletin (3). The structure of Machilusmarin (1) was elucidated by HRMS and NMR spectrums. Machilusmarin (1) showed significant neuroprotective activity against SH-SY5Y human neuroblastoma cells apoptosis induced by hydrogen peroxide at concentrations ranging from 0.625 to 10.0 ug mL( 1). PMID- 23082969 TI - (E)-2,4-bis(p-hydroxyphenyl)-2-butenal has an antiproliferative effect on NSCLC cells induced by p38 MAPK-mediated suppression of NF-kappaB and up-regulation of TNFRSF10B (DR5). AB - BACKGROUND AND PURPOSE: The Maillard Reaction Products (MRPs) are known to be effective in chemoprevention. Here we focused on the anticancer effects of (E) 2,4-bis(p-hydroxyphenyl)-2-butenal (a MRP) on human non-small-cell lung cancer (NSCLC) cells and its mechanism of action. EXPERIMENTAL APPROACH: We analysed the activity of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal on NSCLC cells (NCI-H460 and A549) by use of Western blot analysis for major apoptotic proteins, MAPK, NF kappaB and death receptor expression. We also used RT-PCR to determine its effects on death receptor mRNA expression, EMSA for effects on NF-kappaB DNA binding activity and colony formation assay for effects of inhibitors on (E)-2,4 bis(p-hydroxyphenyl)-2-butenal's actions. KEY RESULTS: (E)-2,4-bis(p hydroxyphenyl)-2-butenal induced a concentration (10-40 MUg.mL-1)- and time (30 min-72 h)-dependent inhibitory effect on the growth of NSCLC cells due to induction of apoptosis. Concomitantly, it significantly increased the expression of apoptotic proteins such as cleaved caspase-3, cleaved caspase-9, Bax and p53, but down-regulated the expression of anti-apoptotic proteins Bcl-2, cIAP1 and cIAP2. This effect was induced by up-regulation of MAPK and death receptor proteins TNFRSF12, TNFRSF10B and TNFRSF21, but suppression of NF-kappaB. Of the death receptors activated, only TNFRSF10B knock down with siRNA reversed the effect of (E)-2,4-bis(p-hydroxyphenyl)-2-butenal. Even though all the MAPKs were activated, only pretreatment with a p38 MAPK inhibitor reversed (E)-2,4-bis(p hydroxyphenyl)-2-butenal-induced cell growth inhibition, increase in cleaved caspase-3, -9 and TNFRSF10B expression, and NF-kappaB inactivation. CONCLUSIONS AND IMPLICATIONS: (E)-2,4-bis(p-hydroxyphenyl)-2-butenal induces apoptosis in NSCLC cells by p38 MAPK-mediated suppression of NF-kappaB and activation of TNFRSF10B, which then activates the caspase-3 and caspase-9 pathways. PMID- 23082971 TI - Conjugative DNA transfer in Streptomyces by TraB: is one protein enough? AB - Antibiotic-producing soil bacteria of the genus Streptomyces form a huge natural reservoir of antibiotic resistance genes for the dissemination within the soil community. Streptomyces plasmids encode a unique conjugative DNA transfer system clearly distinguished from classical conjugation involving a single-stranded DNA molecule and a type IV protein secretion system. Only a single plasmid-encoded protein, TraB, is sufficient to translocate a double-stranded DNA molecule into the recipient in Streptomyces matings. TraB is a hexameric pore-forming ATPase that resembles the chromosome segregator protein FtsK and translocates DNA by recognizing specific 8-bp repeats present in the plasmid clt locus. Mobilization of chromosomal genes does not require integration of the plasmid, because TraB also recognizes clt-like sequences distributed all over the chromosome. PMID- 23082970 TI - Calcium ion gradients modulate the zinc affinity and antibacterial activity of human calprotectin. AB - Calprotectin (CP) is an antimicrobial protein produced and released by neutrophils that inhibits the growth of pathogenic microorganisms by sequestering essential metal nutrients in the extracellular space. In this work, spectroscopic and thermodynamic metal-binding studies are presented to delineate the zinc binding properties of CP. Unique optical absorption and EPR spectroscopic signatures for the interfacial His(3)Asp and His(4) sites of human calprotectin are identified by using Co(II) as a spectroscopic probe. Zinc competition titrations employing chromophoric Zn(II) indicators provide a 2:1 Zn(II):CP stoichiometry, confirm that the His(3)Asp and His(4) sites of CP coordinate Zn(II), and reveal that the Zn(II) affinity of both sites is calcium-dependent. The calcium-insensitive Zn(II) competitor ZP4 affords dissociation constants of K(d1) = 133 +/- 58 pM and K(d2) = 185 +/- 219 nM for CP in the absence of Ca(II). These values decrease to K(d1) <= 10 pM and K(d2) <= 240 pM in the presence of excess Ca(II). The K(d1) and K(d2) values are assigned to the His(3)Asp and His(4) sites, respectively. In vitro antibacterial activity assays indicate that the metal-binding sites and Ca(II)-replete conditions are required for CP to inhibit the growth of both Gram-negative and -positive bacteria. Taken together, these data provide a working model whereby calprotectin responds to physiological Ca(II) gradients to become a potent Zn(II) chelator in the extracellular space. PMID- 23082972 TI - The association between labour force participation and being in income poverty amongst those with mental health problems. AB - OBJECTIVES: Mental health conditions are associated with lower standards of living. This study quantifies the relationship between employment, depression and other mental health conditions and being in income poverty. METHODS: Cross sectional analysis was undertaken using the 2003 Survey of Disability, Ageing and Carers data for Australians aged 45-64 years. RESULTS: Those not in the labour force due to depression and other mental health conditions are significantly more likely (odds ratio (OR) 12.53, 95% CI: 12.20-12.86, p < 0.0001; OR 20.10, 95% CI: 19.67-20.54, p < 0.0001) to be in income poverty than those not in the labour force with no chronic health condition. Amongst those with depression and other mental health conditions, those who were in employment were significantly less likely to be in income poverty than those who have had to retire because of the condition. CONCLUSION: Due to the association between leaving the workforce due to mental health problems and poverty status, efforts to increase the employment of individuals with mental health conditions, or prevent the onset of the conditions, will likely improve living standards. PMID- 23082973 TI - Monte Carlo method for the evaluation of symptom association. AB - Gastroesophageal monitoring is limited to 96 hours by the current technology. This work presents a computational model to investigate symptom association in gastroesophageal reflux disease with larger data samples proving important deficiencies of the current methodology that must be taking into account in clinical evaluation. A computational model based on Monte Carlo analysis was implemented to simulate patients with known statistical characteristics Thus, sets of 2000 10-day-long recordings were simulated and analyzed using the symptom index (SI), the symptom sensitivity index (SSI), and the symptom association probability (SAP). Afterwards, linear regression was applied to define the dependency of these indexes with the number of reflux, the number of symptoms, the duration of the monitoring, and the probability of association. All the indexes were biased estimators of symptom association and therefore they do not consider the effect of chance: when symptom and reflux were completely uncorrelated, the values of the indexes under study were greater than zero. On the other hand, longer recording reduced variability in the estimation of the SI and the SSI while increasing the value of the SAP. Furthermore, if the number of symptoms remains below one-tenth of the number of reflux episodes, it is not possible to achieve a positive value of the SSI. A limitation of this computational model is that it does not consider feeding and sleeping periods, differences between reflux episodes or causation. However, the conclusions are not affected by these limitations. These facts represent important limitations in symptom association analysis, and therefore, invasive treatments must not be considered based on the value of these indexes only until a new methodology provides a more reliable assessment. PMID- 23082974 TI - Binding site detection and druggability prediction of protein targets for structure-based drug design. AB - Assessing whether a protein structure is a good target or not before actually doing structure-based drug design on it is an important step to speed up the ligand discovery process. This is known as the "druggability" or "ligandability" assessment problem that has attracted increasing interest in recent years. The assessment typically includes the detection of ligand-binding sites on the protein surface and the prediction of their abilities to bind drug-like small molecules. A brief summary of the established methods of binding sites detection and druggability(ligandability) prediction, as well as a detailed description of the CAVITY approach developed in the authors' group was given. CAVITY showed good performance on ligand-binding site detection, and was successfully used to predict both the ligandabilities and druggabilities of the detected binding sites. PMID- 23082975 TI - Rational drug design: the search for Ras protein hydrolysis intermediate conformation inhibitors with both affinity and specificity. AB - Computer-aided drug design (CADD) plays significant roles in all stages of today's drug discovery. Many CADD technologies and methods were employed in finding promising hits against different targets during the past several decades. In this review, the most common molecular modeling methods applied to computer aided drug design are discussed. However, how to effectively integrate these computational methods and then combine them with experiments to improve the hit rate is still a challenge. In addition, the present study reviews the ISR (intrinsic specificity ratio) as a novel concept and quantitative criterion for binding specificity to be applied as a complement in addition to binding affinity for finding new leads. Using Ras protein as a case study, Molecular modeling calculations and the subsequent biological testings for the hits are performed, the specificity of these hits is also studies against the normal and cancer cells aiming at discovering the novel chemical compounds with minimal side effects. Herein, the case study also includes the evaluations for tumor-specific cytotoxicity on different cell lines. The current results suggest that ISR is useful for quantitative assessment of specificity of small molecules. PMID- 23082976 TI - Selective induction of apoptosis: promising therapy in pancreatic cancer. AB - Pancreatic cancer is one of lethal and poor prognostic malignancies. Due to the absence of effective detecting methods, quite a number of efforts have been made to improve a survival advantage for treatment in patients with pancreatic cancer. Over the past decade, single-agent gemcitabine and gemcitabine-containing combinations were considered standard first-line therapies for advanced pancreatic cancer. Although these routine uses of chemotherapy failed to significantly improve survival benefit for most therapies, these trials provided insights into the molecular mechanisms involved in the development of pancreatic cancer and therefore opened up new therapeutic avenues. Apoptotic inducer as a therapeutic concept has been widely proposed and experimentally identified in some works. Some reviews have revealed that apoptosis-inducing was a promising therapy in cancers with the least side effects and more effectiveness. Apoptosis is a highly controlled physiological mechanism and proceeds through two major pathways for apoptosis-inducing. Some anticancer drugs kill cancer cells by inducing apoptosis via death receptor pathway; however, other chemotherapeutic drugs trigger apoptosis via mitochondrial pathway. In this review, we summarize briefly current chemotherapy in pancreatic cancer, describe the apoptotic mechanisms, and provide a novel therapeutic strategy by targeting Ras intermediate. PMID- 23082977 TI - Role of bivalent cations in structural stabilities of new drug targets--vaccinia related kinases (VRK) from molecular dynamics simulations. AB - Protein kinases, which play an important role in the regulation of the majority of cellular processes, especially those involved in cellular signal transduction, by catalyzing the phosphorylation of specific proteins, are the attractive targets of drug design in pharmaceuticals industry. Interestingly, up to 10% of proteins in the human kinome termed pseudokinases are predicted to be enzymatically inactive, but are still pivotal in regulating diverse cellular processes and thus may be a potential therapeutic target to a certain extent. To study the underlying molecular mechanisms, molecular dynamics simulations were performed to investigate the role of bivalent cations Mg2+ and Mn2+ in the structural stabilities and dynamical behaviors of vaccinia related kinase 3 (VRK3), which was the first solved crystal structure of the pseudokinase, and that of its closest active relatives VRK1 and VRK2. Toward this end, a series of molecular dynamics simulations have been performed with different divalent cations binding modes in the active site. The simulations suggested that the binding of Mg2+ in the active site played a key structural role in the stabilization of VRK1 and VRK2, and Mn2+ was slightly required for VRK2. By contrast, the pseudokinase VRK3 was well ordered with lower RMSD values indicating it was rigid and very stable regardless of whether the bivalent cations were bound or not during the simulations. The present study provided evidence for the role of bivalent cations in structural stabilities of VRKs and the proposed simulation model reconciled the interpretation of available experimental structural and thermal denaturation assay data. These results gave us further information on the dynamical behaviors of the active site of VRKs and suggested a mechanism of regulation of their structural stabilities, and might provide a starting point for the more detailed follow- up investigation of drug design. PMID- 23082978 TI - The challenge to the rule of homology modeling: folding mechanism study of protein G(A) and G(B) with high sequence identity but different native structures. AB - As one of the most valuable methods for drug design, homology modeling shows that protein structures are more conserved than protein sequences, that is, the proteins with high sequence identity have high structural similarity, but protein pairs G(A)88/G(B)88 and G(A)95/G(B)95 prove the opposite. The pairs G(A)88 and G(B)88 shares the 88% sequence identity, but display different structures, and the pair G(A)95 and G(B)95 with 95% sequence identity yet presents different structures. The research on these proteins provides an opportunity of complementary study. In the process of protein folding, at which stage the protein final structure was determined and which residues were important for folding to a given structure were still unknown. Here we used OPLS all-atom force field for molecular dynamics simulations to study the unfolding of G(A)88, G(B)88, G(A)95 and G(B)95 at high temperatures, and used the process of protein unfolding to reverse the process of protein folding. G(B)88 and G(B)95 folded to the alpha+beta structure, but G(A)88 and G(A)95 folded to the all-alpha-helix structure. In the process of G(A)88 and G(A)95 folding, the helices folded earlier than the formation of tertiary interactions. In the process of folding to G(B)88 and G(B)95, the alpha-helix formed earlier. We showed that early along the folding pathway, the final protein structure was confirmed, and very small differences between protein sequences determined the protein structure. PMID- 23082979 TI - Binding free energy estimation for protein-ligand complex based on MM-PBSA with various partial charge models. AB - An accurate estimation of binding free energy between protein and ligand, is one of the most important issues in the drug discovery process. However, it is an arduous and hard process to obtain accurate energy, especially the experimentally relevant free energies for protein-ligand in solution, including a proper treatment of the long-range electrostatics and solvation effects that are involved in optimization of atomic net charges and so on. In this study, the impacts of the various atomic net charge models were considered, and their effects on binding free energy profiles also were investigated. The methods were tested on: the 30 structurally diverse ligands of diverse protein complexes, the 14 structurally diverse ligands of the protein kinase B (PKB) and the 10 structurally diverse ligands of the cyclin-dependent kinases 2 (CDK2) with measured affinities. The tested charges were calculated based on AM1 (Austin Method, version 1) - BCC (bond charge correction), MNDO (modified neglect of diatomic differential overlay), PM5 (Parameterisation Model, version 5), MUL (Mulliken), CM2 (Charge Model 2), CM3 (Charge Model 3), RESP (restrained electrostatic potential) and QM/MM (quantum mechanics/molecular mechanics) models. Our findings showed that the MNDO charge model was best propitious for PKB system and QM/MM for CDK2, whereas none of any given models was suited for the diverse ligands of diverse protein complexes. The trends of MM-PBSA binding free energies using all charge models were in good accord with experimental results for CDK2 but not for PKB in most cases. Considering the above results, particular attention should be paid to the ligand-charge and maybe protein-charge during the estimation of accurate binding free energies in drug design. PMID- 23082980 TI - Exploring the relationship between sequences, structures, dynamical behaviors and functions of new type protein drugs: DARPins. AB - DARPins (designed ankyrin repeat proteins), new kinds of binding proteins, have the potential to overcome the defects of monoclonal antibodies, and hence may become the alternatives to antibodies and generate a novel therapeutic approach. DARPins can be selected to bind any given target proteins with high affinity and specificity. In the process of binding to target proteins, the reason why DARPins have high affinity to target proteins as well as the correlation among sequences, structures, dynamical behaviors and binding to target proteins are still unknown. This paper studied DARPins using the AMBER package with ff03 force field for molecular dynamics simulations, providing a theoretical basis for the research on a new type of protein drug. This shows that the DARPins have more dynamical behaviors regularity after binding to target proteins compared with non-binding DARPins, but the binding to target proteins does not always stabilize the structures of DARPins, and the changes in the regions of beta-turn and loop are the most obvious. The changes in hydrogen bonds and hydrophobic interactions have close relationship with the changes in the stability and cross correlation of DARPins. PMID- 23082981 TI - Targeting the nuclear transport machinery by rational drug design. AB - CRM1 (also referred as exportin1 or Xpo1) is a key member of the importin beta superfamily of nuclear transport receptors. Its potential as therapeutic target has attracted significant attention in recent years. CRM1 controls the transport of a number of growth regulatory proteins and tumor suppressor proteins including p53, p21, FOXO, PI3K/AKT, Wnt/beta-catenin, AP-1 and NF-kB etc. The overexpression of CRM1 has been found to correlate with a variety of neoplastic conditions such as pancreatic and liver cancer. In addition, CRM1 could mediate the transport of viral proteins such as Rev, an essential factor protein for HIV replication. Moreover, CRM1 has been implicated in key steps of mitosis during cell cycles. Over the past years, the in-depth biological studies have rendered CRM1 as a promising clinical target. The interference of CRM1-mediated transport machinery could lead to the effective treatment of a variety of human disease related to cell proliferation. The aim of this paper is to summarize the research progress of CRM1 inhibitors in the late 30 years. More importantly, we want to provide new insights for the CRM1 drug design from the perspective of molecular simulation. PMID- 23082982 TI - Rational drug design with the aid of molecular modeling and bioinformatics. PMID- 23082983 TI - The vitronectin-binding domain of plasminogen activator inhibitor-1 plays an important functional role in lipopolysaccharide-induced lethality in mice. PMID- 23082984 TI - Evaluating alternative strategies for minimizing unintended fitness consequences of cultured individuals on wild populations. AB - Artificial propagation strategies often incur selection in captivity that leads to traits that are maladaptive in the wild. For propagation programs focused on production rather than demographic contribution to wild populations, effects on wild populations can occur through unintentional escapement or the need to release individuals into natural environments for part of their life cycle. In this case, 2 alternative management strategies might reduce unintended fitness consequences on natural populations: (1) reduce selection in captivity as much as possible to reduce fitness load (keep them similar), or (2) breed a separate population to reduce captive-wild interactions as much as possible (make them different). We quantitatively evaluate these 2 strategies with a coupled demographic-genetic model based on Pacific salmon hatcheries that incorporates a variety of relevant processes and dynamics: selection in the hatchery relative to the wild, assortative mating based on the trait under selection, and different life cycle arrangements in terms of hatchery release, density dependence, natural selection, and reproduction. Model results indicate that, if natural selection only occurs between reproduction and captive release, the similar strategy performs better. However, if natural selection occurs between captive release and reproduction, the different and similar strategies present viable alternatives to reducing unintended fitness consequences because of the greater opportunity to purge maladaptive individuals. In this case, the appropriate approach depends on the feasibility of each strategy and the demographic goal (e.g., increasing natural abundance, or ensuring that a high proportion of natural spawners are naturally produced). In addition, the fitness effects of hatchery release are much greater if hatchery release occurs before (vs. after) density-dependent interactions. Given the logistical challenges to achieving both the similar and different strategies, evaluation of not just the preferred strategy but also the consequences of failing to achieve the desired target is critical. PMID- 23082985 TI - Why and how are you attached to your social group? Investigating different forms of social identification. AB - Social identity is a key social psychological variable to understand intergroup behaviours. Over and above the different dimensions of social identity (e.g., quality or degree of identification), recent research has looked at different forms of social identity, such as the clarity of one's collective identity, the self-determined motivations underlying one's identification, and the contingencies attached to social identification. These forms of social identification reveal how and why group members are attached to their social group. The current research aims to directly test how these three forms of social identification regroup together and predict different individual and intergroup outcomes. Findings from three studies conducted in Quebec (Ns = 119, 91) and Australia (N = 136) confirmed that the more comparative and competitive forms of social identification (i.e., non-self-determination to identify, collective self esteem contingency) tend to predict nationalism and ingroup bias. In contrast, the forms of social identity that capture the inherent satisfaction of being part of the group and the cognitive clarity of this group membership (i.e., self determined motivation to identity, clarity of collective identity) predict outcomes pertaining to patriotism, personal self-esteem, and positive emotions. Results are interpreted in light of social identity theory and social psychological models of the self. PMID- 23082986 TI - Ultradepletion of human plasma using chicken antibodies: a proof of concept study. AB - Human plasma arguably represents the most comprehensive version of the human proteome. Despite its immense theoretical discovery potential, plasma has many high and medium abundance proteins that mask low abundance protein disease biomarkers of relevance, making the discovery of novel diagnostic markers particularly difficult. Some form of protein depletion and/or fractionation is essential in order to detect markers of low abundance. Here, we describe a "proof of concept" two-pronged approach to immunodeplete abundant proteins from human plasma. The method, called API (Abundant Protein Immunodepletion), involves the fractionation of plasma using dual ion exchange columns (protein repetitive orthogonal offline fractionation (PROOF)) to simplify the proteome, the production of polyclonal IgY against each fraction and finally using the purified antibodies in a immunodepletion column. We explored the use of this product for immunodepletion of human plasma and identified a total of 165 nonredundant proteins after depletion. Of these, 38 proteins that were not previously identified in nondepleted plasma were now detected. It is envisaged that further optimization of the method as well as its cyclic implementation (by reinjecting depleted plasma into chickens for second round of antibody production) can make this technology highly robust, extremely cost-effective, and ideal for high throughput biomarker discovery. PMID- 23082987 TI - Commotio cordis--a report of two similar cases. AB - Commotio cordis is a rare and fatal mechano-electric arrhythmogenic syndrome, occurring mainly during sports activities. The present study describes two similar cases of sudden death caused by commotio cordis associated with homicide. The two decedents were both 15-year-old male teenagers. Both collapsed within several minutes after being punched in the precordial region, as observed by witnesses at the scenes. Although electrocardiograms were not recorded at the scenes or the hospitals, the sudden onset of cardiovascular, respiratory, and neural symptoms were consistent with sudden cardiac death caused by commotio cordis. Autopsy and forensic morphology both revealed no cardiac or pericardiac structural damage, evident lesions of other internal organs, or underlying diseases, along with negative toxicological analysis, conforming to criteria for diagnosis of commotio cordis. The diagnosis of commotio cordis by forensic pathologists is important in deliberating a verdict of homicide, especially involuntary homicide. In rare instances, a death caused by commotio cordis may have a homicide manner of death. PMID- 23082989 TI - Role of altered expression of Nedd4L in the pathogenesis of systemic malignancies. PMID- 23082988 TI - Tbx3 represses PTEN and is over-expressed in head and neck squamous cell carcinoma. AB - BACKGROUND: Despite advances in diagnostic and treatment strategies, head and neck squamous cell cancer (HNSCC) constitutes one of the worst cancer types in terms of prognosis. PTEN is one of the tumour suppressors whose expression and/or activity have been found to be reduced in HNSCC, with rather low rates of mutations within the PTEN gene (6-8%). We reasoned that low expression levels of PTEN might be due to a transcriptional repression governed by an oncogene. Tbx2 and Tbx3, both of which are transcriptional repressors, have been found to be amplified or over-expressed in various cancer types. Thus, we hypothesize that Tbx3 may be over expressed in HNSCC and may repress PTEN, thus leading to cancer formation and/or progression. METHODS: Using immunohistochemistry and quantitative PCR (qPCR), protein and mRNA levels of PTEN and Tbx3 were identified in samples excised from cancerous and adjacent normal tissues from 33 patients who were diagnosed with HNSCC. In addition, HeLa and HEK cell lines were transfected with a Tbx3 expressing plasmid and endogenous PTEN mRNA and protein levels were determined via qPCR and flow cytometry. Transcription assays were performed to demonstrate effects of Tbx3 on PTEN promoter activity. Mann-Whitney, Spearman's Correlation and Wilcoxon signed-rank tests were used to analyze the data. RESULTS: We demonstrate that in HNSCC samples, Tbx3 mRNA levels are increased with respect to their normal tissue counterparts (p<0.001), whereas PTEN mRNA levels are significantly reduced in cancer tissues. Moreover, Tbx3 protein is also increased in HNSCC tissue sections. Over-expression of Tbx3 in HeLa and HEK cell lines causes reduction in endogenous PTEN mRNA and protein levels. In addition, transcription activity assays reveal that Tbx3 is capable of repressing both the basal and induced promoter activity of PTEN. CONCLUSIONS: We show that Tbx3 is up-regulated in tissue samples of HNSCC patients and that Tbx3 represses PTEN transcription. Thus, our data not only reveals a new mechanism that may be important in cancer formation, but also suggests that Tbx3 can be used as a potential biomarker in cancer. PMID- 23082990 TI - Rituximab administration in a community hospital environment. PMID- 23082991 TI - Excitation spectra of the jet-cooled 4-phenylbenzyl and 4-(4'-methylphenyl)benzyl radicals. AB - The excitation spectra of jet-cooled 4-phenylbenzyl and 4-(4'-methylphenyl)benzyl radicals have been identified by a combination of resonant two-color two-photon ionization mass spectrometry and quantum chemical methods. Both radicals exhibit progressions in the biphenyl torsional mode, peaking near nu = 17. The lowest observed peak for 4-phenylbenzyl was observed at 18598 cm(-1) and is estimated to be the nu = 3 of the progression, while the lowest observed peak for the 4-(4' methylphenyl)benzyl radical was observed at 18183 cm(-1) and is possibly the origin. The spectra are discussed and compared to other biphenyl and benzyl chromophores. PMID- 23082992 TI - Epidemiological patterns of perniosis, and its association with systemic disorder. AB - BACKGROUND: There are few studies exploring the epidemiological properties of perniosis (chilblains) and its association with systemic disorders. AIM: To collect epidemiological data for perniosis, to investigate any association with systemic disorders, and to identify markers for the differential diagnosis of idiopathic and secondary perniosis. METHODS: This was a prospective study of 51 patients with perniosis [female : male ratio 2.64 : 1, mean +/- SD age 24.6 +/- 14.7 years, with 25 patients (49%) aged 0-18 years]. Each patient was interviewed, and signs suggestive of connective-tissue disorders were recorded. Detailed laboratory investigations including autoimmune parameters were performed. RESULTS: Significant proportions of the patients had both chronic and idiopathic perniosis (P < 0.001 for both). The mean age of the group with secondary perniosis was significantly higher than that of the idiopathic group (P < 0.01). There was no significant gender difference in the secondary perniosis group (P = 0.71). Clerking work was the most common occupation (37%, P = 0.01). Persistence beyond the cold seasons, and presence of photosensitivity, hypergammaglobulinaemia and rheumatoid factor were significant findings in the secondary group (P = 0.02, P = 0.02, P < 0.01, P < 0.05, respectively). CONCLUSIONS: Perniosis is not rare in children, but patients with secondary perniosis are more likely to be older. In terms of underlying systemic disorder, advanced age and male gender may be important demographic features. Measurement of cryoglobulin levels in the initial laboratory investigations of patients with perniosis is not necessary. Persistence beyond the cold seasons, and presence of photosensitivity, hypergammaglobulinaemia and rheumatoid factor may be useful in differentiating between idiopathic and secondary perniosis. PMID- 23082993 TI - Carbon in intimate contact with quartz reduces the biological activity of crystalline silica dusts. AB - To evaluate the effect of carbonaceous materials on the pathogenic activity of quartz dusts, mixtures of carbon soot (1 and 10%) and quartz (Min-U-Sil) were prepared and then milled so to attain an intimate association of carbon and the quartz surface. Both cellular and cell-free tests show that carbon associated to quartz completely inhibits the typical free radical generation of quartz dusts (through Fenton activity and homolytic cleavage of a C-H bond) and suppresses the oxidative stress and inflammation induced by quartz alone on MH-S murine macrophage cells (lipid peroxidation, nitric oxide release, and tumor necrosis factor-alpha synthesis). The cytotoxic response to quartz is also largely reduced. An extremely pure quartz milled with 10% of soot showed inactivating effects on the adverse reactions to quartz similar to Min-U-Sil quartz. None of these effects takes place when the same experiments are carried out with mechanically mixed samples, which suggests that carbon acts not just as a radical quencher but because of its association to the quartz surface. PMID- 23082994 TI - Site-specific noncovalent interaction of the biopolymer poly(ADP-ribose) with the Werner syndrome protein regulates protein functions. AB - Werner syndrome is a premature aging disorder that is caused by defects in the Werner protein (WRN). WRN is a member of the RecQ helicase family and possesses helicase and exonuclease activities. It is involved in various aspects of DNA metabolism such as DNA repair, telomere maintenance, and replication. Poly(ADP ribose) polymerase 1 (PARP1) is also involved in these processes by catalyzing the formation of the nucleic-acid-like biopolymer poly(ADP-ribose) (PAR). It was previously shown that WRN interacts with PARP1 and that WRN activity is inhibited by PARP1. Using several bioanalytical approaches, here we demonstrate that the enzymatic product of PARP1, i.e., PAR, directly interacts with WRN physically and functionally. First, WRN binds HPLC-size-fractionated short and long PAR in a noncovalent manner. Second, we identified and characterized a PAR-binding motif (PBM) within the WRN sequence and showed that several basic and hydrophobic amino acids are of critical importance for mediating the PAR binding. Third, PAR binding inhibits the DNA-binding, the helicase and the exonuclease activities of WRN in a concentration-dependent manner. On the basis of our results we propose that the transient nature of PAR produced by living cells would provide a versatile and swiftly reacting control system for WRN's function. More generally, our work underscores the important role of noncovalent PAR-protein interactions as a regulatory mechanism of protein function. PMID- 23082995 TI - Risk factors for nonsuicidal self-injury in Japanese college students: the moderating role of mood regulation expectancies. AB - Self-injurious behavior is increasing among college students, and is common in both psychiatric and nonclinical populations. People's engaging in self-injury is associated with childhood maltreatment, poor negative mood regulation expectancies, and depression. During times of distress, maltreated children without healthy coping strategies tend to have impairment in mood regulation, which contributes to engaging in self-injury. This study investigated differences between nonsuicidal self-injury (NSSI) and non-self-injury groups in history of childhood maltreatment, negative mood regulation expectancies, and depression in a sample of Japanese college students. We also assessed risk factors for self injurious behavior, including mood regulation expectancies as a moderator of the relationship between childhood maltreatment and NSSI. Participants were 313 undergraduate students, who completed anonymous self-report questionnaires Deliberate Self-Harm Inventory, Child Abuse and Trauma Scale, Negative Mood Regulation Scale, and short version of the Center for Epidemiological Studies Depression Scale. Ten percent (n = 31) of all participants had injured themselves. Consistent with past literature, participants with self-injury history reported more severe childhood maltreatment, poorer mood regulation expectancies, and more depression, compared to non-self-injurers. Frequency of NSSI positively correlated with childhood maltreatment and depression, and negatively correlated with negative mood regulation expectancies. Regression analysis revealed that stronger expectancies for negative mood regulation interacted with maltreatment to predict self-injury: More maltreatment was associated with more self-injury, particularly among those with weaker expectancies. Results suggested childhood maltreatment, low expectancies for negative mood regulation, and depression predicted self-injury. Consistent with our moderation hypothesis, strong expectancies for negative mood regulation buffered the effects of childhood maltreatment, reducing the risk for self injury. PMID- 23082996 TI - ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells. AB - BACKGROUND AND PURPOSE: GPCRs undergo both homologous and heterologous regulatory processes in which receptor phosphorylation plays a critical role. The protein kinases responsible for each pathway are well established; however, other molecular details that characterize each pathway remain unclear. In this study, the molecular mechanisms that determine the differences in the functional roles and intracellular trafficking between homologous and PKC-mediated heterologous internalization pathways for the dopamine D2 receptor were investigated. EXPERIMENTAL APPROACH: All of the S/T residues located within the intracellular loops of D2 receptor were mutated, and the residues responsible for GRK- and PKC mediated internalization were determined in HEK-293 cells and SH-SY5Y cells. The functional role of receptor internalization and the cellular components that determine the post-endocytic fate of internalized D2 receptors were investigated in the transfected cells. KEY RESULTS: T134, T225/S228/S229 and S325 were involved in PKC-mediated D2 receptor desensitization. S229 and adjacent S/T residues mediated the PKC-dependent internalization of D2 receptors, which induced down-regulation and desensitization. S/T residues within the second intracellular loop and T225 were the major residues involved in GRK-mediated internalization of D2 receptors, which induced receptor resensitization. ARF6 mediated the recycling of D2 receptors internalized in response to agonist stimulation. In contrast, GASP-1 mediated the down-regulation of D2 receptors internalized in a PKC-dependent manner. CONCLUSIONS AND IMPLICATIONS: GRK- and PKC-mediated internalizations of D2 receptors occur through different intracellular trafficking pathways and mediate distinct functional roles. Distinct S/T residues within D2 receptors and different sorting proteins are involved in the dissimilar regulation of D2 receptors by GRK2 and PKC. PMID- 23082997 TI - Exogenous basic fibroblast growth factor inhibits ER stress-induced apoptosis and improves recovery from spinal cord injury. AB - AIM: To investigate the mechanism of endoplasmic reticulum (ER) stress-induced apoptosis as well as the protective action of basic fibroblast growth factor (bFGF) both in vivo and in vitro. METHODS AND RESULTS: ER stress-induced apoptosis was involved in the injuries of spinal cord injury (SCI) model rat. bFGF administration improved the recovery and increased the survival of neurons in spinal cord lesions in model rat. The protective effect of bFGF is related to the inhibition of CHOP, GRP78 and caspase-12, which are ER stress-induced apoptosis response proteins. bFGF administration also increased the survival of neurons and the expression of growth-associated protein 43 (GAP43), which is related to neural regeneration. The protective effect of bFGF is related to the activation of downstream signals, PI3K/Akt/GSK-3beta and ERK1/2, especially in the ER stress cell model. CONCLUSIONS: This is the first study to illustrate that the role of bFGF in SCI recovery is related to the inhibition of ER stress induced cell death via the activation of downstream signals. Our work also suggested a new trend for bFGF drug development in central neural system injuries, which are involved in chronic ER stress-induced apoptosis. PMID- 23082998 TI - The composition of engineered cartilage at the time of implantation determines the likelihood of regenerating tissue with a normal collagen architecture. AB - The biomechanical functionality of articular cartilage is derived from both its biochemical composition and the architecture of the collagen network. Failure to replicate this normal Benninghoff architecture in regenerating articular cartilage may in turn predispose the tissue to failure. In this article, the influence of the maturity (or functionality) of a tissue-engineered construct at the time of implantation into a tibial chondral defect on the likelihood of recapitulating a normal Benninghoff architecture was investigated using a computational model featuring a collagen remodeling algorithm. Such a normal tissue architecture was predicted to form in the intact tibial plateau due to the interplay between the depth-dependent extracellular matrix properties, foremost swelling pressures, and external mechanical loading. In the presence of even small empty defects in the articular surface, the collagen architecture in the surrounding cartilage was predicted to deviate significantly from the native state, indicating a possible predisposition for osteoarthritic changes. These negative alterations were alleviated by the implantation of tissue-engineered cartilage, where a mature implant was predicted to result in the formation of a more native-like collagen architecture than immature implants. The results of this study highlight the importance of cartilage graft functionality to maintain and/or re-establish joint function and suggest that engineering a tissue with a native depth-dependent composition may facilitate the establishment of a normal Benninghoff collagen architecture after implantation into load-bearing defects. PMID- 23082999 TI - Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. AB - Type II toxin-antitoxin (TA) systems are believed to be widely distributed amongst bacteria although their biological functions are not clear. We have identified eight candidate TA systems in the genome of the human pathogen Burkholderia pseudomallei. Five of these were located in genome islands. Of the candidate toxins, BPSL0175 (RelE1) or BPSS1060 (RelE2) caused growth to cease when expressed in Escherichia coli, whereas expression of BPSS0390 (HicA) or BPSS1584 (HipA) (in an E. coli DeltahipBA background) caused a reduction in the number of culturable bacteria. The cognate antitoxins could restore growth and culturability of cells. PMID- 23083000 TI - Does an anti-oxidant ascorbic acid improve the condition of hippocampal formation slice preparations? A micro-EEG approach. AB - The objective of this study was to assess whether ascorbic acid (AA), an intracellular anti-oxidant critical for neuronal protection, when added to artificial cerebrospinal fluid (ACSF), is able to protect hippocampal (HPC) formation slice preparations from ageing. In this research, the micro electroencephalographic (EEG) technique was applied. Experiments were performed on 72 HPC formation slices obtained from 12 male Wistar rats. Two series of experiments were conducted: the control experiment, in which ACSF was used as an incubation medium, and the research one, in which ACSF was supplemented with 200 MUM AA. The experimental model of carbachol-induced EEG theta rhythm was applied. The following parameters of theta rhythm after 15, 30 and 45 min of recording were analysed: frequency, power, time duration of theta epochs and time duration of intervals between theta epochs. The results show that AA causes a statistically significant decrease in the power of theta rhythm after 15, 30 and 45 min of recording. The time duration of intervals between theta epochs was almost twice as long in slices incubated in ACSF + AA than in ACSF after 45 min of recording. The data obtained indicate that AA does not improve the condition of HPC slices. On the contrary, it worsens the ability of slice preparations to generate theta oscillations. We hypothesize that our data may result from the Fenton reaction or changes in the conformation of connexins. PMID- 23083001 TI - Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: the Taichung Diabetes Study. AB - BACKGROUND: Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes. METHODS: Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick. RESULTS: A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0-5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1-3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2. CONCLUSION: The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality. PMID- 23083003 TI - Boron nitride on Cu(111): an electronically corrugated monolayer. AB - Ultrathin films of boron nitride (BN) have recently attracted considerable interest given their successful incorporation in graphene nanodevices and their use as spacer layers to electronically decouple and order functional adsorbates. Here, we introduce a BN monolayer grown by chemical vapor deposition of borazine on a single crystal Cu support, representing a model system for an electronically patterned but topographically smooth substrate. Scanning tunneling microscopy and spectroscopy experiments evidence a weak bonding of the single BN sheet to Cu, preserving the insulating character of bulk hexagonal boron nitride, combined with a periodic lateral variation of the local work function and the surface potential. Complementary density functional theory calculations reveal a varying registry of the BN relative to the Cu lattice as origin of this electronic Moire like superstructure. PMID- 23083002 TI - Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. AB - BACKGROUND: Despite standard dual antiplatelet therapy (DAT) (acetylsalicylic acid [ASA] and clopidogrel), there is a >= 1.4% incidence of in-stent thrombosis in patients with acute coronary syndrome. Factor Xa inhibitors are being investigated for secondary prevention after acute coronary syndrome. OBJECTIVE: To study the antithrombotic effects of the FXa inhibitor rivaroxaban alone or in combination with DAT. METHODS: Bare metal stents (12 per animal, three per intervention period) were deployed in a porcine ex vivo arteriovenous shunt and exposed to flowing arterial blood (shear rate: 1500 s(-1)). In-stent thrombus formation was analyzed under different treatments: vehicle (n = 7 animals); intravenous (i.v.) rivaroxaban (0.11, 0.33, and 1.0 MUg kg(-1) min(-1)) (n = 8); rivaroxaban + ASA (1.0 mg kg(-1) i.v.) (n = 6); rivaroxaban + ASA (1.0 mg kg(-1) i.v.) + clopidogrel (0.5 mg kg(-1) i.v.) (n = 7); and ASA (1.0 mg kg(-1) i.v.) + clopidogrel (0.5 mg kg(-1) i.v.) (n = 6). RESULTS: Rivaroxaban dose-dependently reduced stent thrombus weight by <= 66% vs. vehicle (P < 0.05, all doses). Rivaroxaban + ASA further reduced thrombus weight vs. vehicle (86% at the highest rivaroxaban dose; P < 0.001). DAT reduced thrombus weight by <= 79%. However, rivaroxaban + ASA + clopidogrel almost completely abolished in-stent thrombus formation (98% reduction vs. vehicle at the highest rivaroxaban dose; P < 0.001). CONCLUSIONS: Our data on the inhibitory effect of rivaroxaban alone or with DAT are consistent with the ATLAS 2 trial findings, and support its potential use for preventing stent thrombosis after stent deployment. PMID- 23083004 TI - Photodynamic and photothermal effects of semiconducting and metallic-enriched single-walled carbon nanotubes. AB - Semiconducting and metallic single-walled carbon nanotubes (s-SWNTs and m-SWNTs) were enriched by agarose gel chromatography and their photothermal and photodynamic effects were compared in H(2)O. Under near-infrared laser irradiation, s-SWNTs generated reactive oxygen species (ROS) more than m-SWNTs, whereas m-SWNTs produced heat more efficiently than s-SWNTs. More importantly, cancer cell killing by PDE of s-SWNTs has been disclosed for the first time. PMID- 23083005 TI - Revisiting the potential conservation value of non-native species. PMID- 23083006 TI - Heterogeneous reactions of pirimiphos-methyl and pirimicarb with NO3 radicals. AB - Pirimiphos-methyl (PMM) and pirimicarb (PM) are two typical N,N-dialkyl substituted pyrimidine pesticides. The heterogeneous reactions of suspended PMM and PM particles with NO(3) radicals are investigated using an online aerosol time-of-flight mass spectrometer and a real-time atmospheric gas analysis mass spectrometer. Three products for PMM and five products for PM are observed and assigned with the aid of GC/MS. Phosphoric acid 2-diethylamino-6-methyl-4 pyrimidinyl dimethyl ester and 2-(dimethylamino)-5,6-dimethyl-4-hydroxy pyrimidine are the main reaction products observed for PMM and PM, respectively. The effective rate constants for the reactions of PMM and PM particles with NO(3) radicals are (9.9 +/- 0.3) * 10(-12) and (7.5 +/- 0.3) * 10(-13) cm(3) molecule( 1) s(-1), respectively, obtained using a mixed-phase relative rate method. Geometries and energies of transition states (TS) and intermediates (IM) are obtained by DFT calculation to elucidate the detailed mechanism of the P?S group oxidation into the P?O group for PMM. The theoretical studies present the reasonable intermediates including the S-oxide and the diradical (IM1(a) and IM2(a)). The mechanism explanation may provide useful information for understanding the degradation mechanism of organothionophosphorus compounds in the environment. PMID- 23083007 TI - 'They're more than animals': refugees' accounts of racially motivated violence. AB - Previous discursive research has found that minority group members may deny or downplay the existence of discrimination. However, to date, little research has addressed the issue of violence against minority group members. This study therefore draws on interviews with asylum seekers and refugees in a Scottish city to analyse their reports of violence committed against them. One form of reporting violence was by way of a complaint available to any speaker, in making no reference to attributes of attackers or victim. When racism was alleged, it was presented as a tentative, reluctant or 'last resort' explanation. The descriptions offered by interviewees reflected the contributions made by the interviewer, highlighting the ways in which these reports are interactional co productions. The results suggest that accounts from victims of seemingly racially motivated violence may function in similar ways to 'new racism' in making racism seem to 'disappear'. These findings point to the potential difficulties that arise in identifying and looking to challenge instances of 'new racism'. PMID- 23083008 TI - Comparison of sample preparation methods and evaluation of intra- and intersample reproducibility in bacteria MALDI-MS profiling. AB - A study is presented on the reproducibility of mass spectral profiles of the whole bacterium E. coli resulting from laser sampling at different regions within and between matrix-assisted laser desorption ionization (MALDI) samples deposited onto the plate. Samples were prepared with different deposition methods and using different MALDI matrices. The three most common matrices used in MALDI-mass spectrometry (MS) bacteria profiling, alpha-cyano-4-hydroxycinnamic acid (CHCA), sinapinic acid (SA), and ferulic acid (FA), were compared in this study along with two pipet-based sample deposition methods, dried-droplet and premix. Sample variability was determined by analysis of variances (ANOVA), principal component analysis (PCA), and multivariate ANOVA (MANOVA). For the two pipet-based sample deposition methods tested in this study, the intrasample variability (most commonly referred to as "spot-to-spot" reproducibility) was of the same magnitude as the intersample variability for all MALDI matrices tested. By incorporating a spray nebulizer sample deposition method to produce uniform sample/matrix mixtures onto the MALDI plate, we demonstrate that the crystalline morphology of the MALDI sample greatly influences the intrasample reproducibility (i.e., spot to-spot) of the resulting whole cell MALDI-MS profiles. Overall, for the pipet based deposition methods, results showed that the smallest variability in bacteria MALDI mass spectral profiles was obtained from samples deposited using the premix method, regardless of the MALDI matrix used, with the best reproducibility obtained with the CHCA matrix. It is concluded that a sample preparation strategy that reduces or eliminates the MALDI matrix morphology heterogeneity can reduce variability (i.e., spot-to-spot) of the bacteria mass spectral profiles by up to 90%. PMID- 23083009 TI - Death due to apparent intravenous injection of tapentadol. AB - This case report describes a 34-year-old male who died as the result of tapentadol toxicity. This case apparently represents the first reported description of a death because of this drug. The toxicologic features of this case, namely concentrations of tapentadol in the femoral blood and heart blood, 1.05 and 3.20 mg/L, respectively, may assist other individuals in evaluating deaths where tapentadol concentration is a factor. Analysis of the blood based upon enzyme-linked immunosorbent assays, liquid chromatography-mass spectrometry, and gas chromatography-mass spectrometry revealed no other substance of significance, only nicotine and cotinine, and the autopsy findings were consistent with an opiate-type drug overdose, and indicated no competing cause of death. PMID- 23083010 TI - The clinical case for proton beam therapy. AB - Over the past 20 years, several proton beam treatment programs have been implemented throughout the United States. Increasingly, the number of new programs under development is growing. Proton beam therapy has the potential for improving tumor control and survival through dose escalation. It also has potential for reducing harm to normal organs through dose reduction. However, proton beam therapy is more costly than conventional x-ray therapy. This increased cost may be offset by improved function, improved quality of life, and reduced costs related to treating the late effects of therapy. Clinical research opportunities are abundant to determine which patients will gain the most benefit from proton beam therapy. We review the clinical case for proton beam therapy. SUMMARY SENTENCE: Proton beam therapy is a technically advanced and promising form of radiation therapy. PMID- 23083011 TI - Maintenance bevacizumab beyond first-line paclitaxel plus bevacizumab in patients with Her2-negative hormone receptor-positive metastatic breast cancer: efficacy in combination with hormonal therapy. AB - BACKGROUND: Data on efficacy of bevacizumab (B) beyond first-line taxane including regimen (BT) as first-line treatment are lacking. Although preclinical results that anti-angiogenic agents combined with hormonal therapy (HT) could be active, no clinical data exist about combination of maintenance Bevacizumab (mBev) with HT. METHODS: Thirty-five patients who experienced a response after first-line BT, were given mBev at the dose of 15 mg/kg every 3 weeks. Among 30 pts with hormonal receptor-positive metastatic breast cancer (MBC), 20 (66.6%) received HT with mBev (mHTBev). Objective of the study was the outcome and safety of mBev and in two groups of patients receiving HT or not. RESULTS: Complete response and partial response was achieved/maintained in 4 (11.4%) and 13 (37.1%) patients, respectively (overall response rate: 48.5%). Clinical benefit was obtained on 23 patients (65.7%). Median of mBev PFS and clinical benefit were 6.8 months (95% CI: 0.8-12.7) and 17.1 months (95% CI :12.2-21.9), respectively. Median PFS of patients who received mHTBev was longer than mBev without HT (13 months and 4.1 months, respectively, p = 0.05). The most common severe toxicities were proteinuria (11.4%) and hypertension (8.5%). No additional toxicity was observed with HTBev. CONCLUSION: Maintenance bevacizumab with or without anti hormonal therapy in patients with hormone receptor positive breast cancer is tolerable and associated with long-term clinical outcome; these results encourage the strategy of prolonging bevacizumab until progression in combination with anti hormonal agents. PMID- 23083012 TI - Hepatosplenic alphabeta T-cell lymphoma arising after long-term azathioprine therapy successfully treated with allogeneic bone marrow transplant. PMID- 23083013 TI - Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease affecting > 10% of children and 1-3% of adults, and can cause significant morbidity. The incidence of AD seems to be increasing. Omalizumab, a monoclonal antibody, has recently been suggested as a potential new systemic treatment for patients with recalcitrant AD with elevated IgE levels, based on its efficacy in treating asthma and allergic rhinitis. We report a study of 10 patients with AD (aged 19-35 years) who received anti-IgE treatment for persistent asthma. All patients, regardless of IgE value, were treated with a fixed schedule of eight cycles of omalizumab 300 mg administered subcutaneously at intervals of 2 weeks. Eczema symptoms were scored at baseline and after 2, 4 and 6 months of treatment. There was a steady improvement in the objective SCORAD (SCORing Atopic Dermatitis), with significantly lower scores observed at the 6-month evaluation. At 2 months after the end of treatment, two patients had a very good result (SCORAD reduction of > 50%), five patients had a satisfactory result (reduction of 25-50%), and three patients had no clinically relevant result (reduction of 25 50%). No patient had worsening of the AD (increase of > 25% in SCORAD), and once a clinical improvement occurred, none of the patients experienced worsening of their eczema symptoms while on omalizumab. With the caveats of the financial expense and unknown long-term risks of malignancy associated with omalizumab, this drug should be considered for treatment-resistant patients with AD, particularly patients with high IgE level whose symptoms are not controlled by routine therapies. Omalizumab has proven useful in treating asthma, but it may also prove valuable for other conditions, such as allergic rhinitis, food allergies, chronic urticaria, and AD, as shown by the present study. PMID- 23083014 TI - Poly specific trans-acyltransferase machinery revealed via engineered acyl-CoA synthetases. AB - Polyketide synthases construct polyketides with diverse structures and biological activities via the condensation of extender units and acyl thioesters. Although a growing body of evidence suggests that polyketide synthases might be tolerant to non-natural extender units, in vitro and in vivo studies aimed at probing and utilizing polyketide synthase specificity are severely limited to only a small number of extender units, owing to the lack of synthetic routes to a broad variety of acyl-CoA extender units. Here, we report the construction of promiscuous malonyl-CoA synthetase variants that can be used to synthesize a broad range of malonyl-CoA extender units substituted at the C2-position, several of which contain handles for chemoselective ligation and are not found in natural biosynthetic systems. We highlighted utility of these enzymes by probing the acyl CoA specificity of several trans-acyltransferases, leading to the unprecedented discovery of poly specificity toward non-natural extender units, several of which are not found in naturally occurring biosynthetic pathways. These results reveal that polyketide biosynthetic machinery might be more tolerant to non-natural substrates than previously established, and that mutant synthetases are valuable tools for probing the specificity of biosynthetic machinery. Our data suggest new synthetic biology strategies for harnessing this promiscuity and enabling the regioselective modification of polyketides. PMID- 23083015 TI - Dysphoric students show higher use of the observer perspective in their retrieval of positive versus negative autobiographical memories. AB - Autobiographical memories are retrieved as images from either a field perspective or an observer perspective. The observer perspective is thought to dull emotion. Positive affect is blunted in depressed mood. Consequently, are positive events recalled from an observer perspective in depressed mood? We investigated the relationship between memory vantage perspective and depressive symptoms in a student sample. Participants completed the Autobiographical Memory Test (AMT; Williams & Broadbent, 1986) and assessed the perspective accompanying each memory. The Beck Depression Inventory-II (BDI-II; Beck, Steer, & Brown, 1996) and the Responses to Positive Affect questionnaire (RPA; Feldman, Joormann, & Johnson, 2008) were administered. The results showed a small positive association between depressive symptoms and the use of an observer perspective for positive autobiographical memories, but not for negative memories. Furthermore, comparing a subgroup with clinically significant symptom levels (dysphoric students) with non-dysphoric individuals revealed that dysphoric students used an observer perspective more for positive memories compared with negative memories. This was not the case for non-dysphoric students. The observer perspective in dysphorics was associated with a dampening cognitive style in response to positive experiences. PMID- 23083016 TI - Sulfonyl fluoride inhibitors of fatty acid amide hydrolase. AB - Sulfonyl fluorides are known to inhibit esterases. Early work from our laboratory has identified hexadecyl sulfonylfluoride (AM374) as a potent in vitro and in vivo inhibitor of fatty acid amide hydrolase (FAAH). We now report on later generation sulfonyl fluoride analogs that exhibit potent and selective inhibition of FAAH. Using recombinant rat and human FAAH, we show that 5-(4 hydroxyphenyl)pentanesulfonyl fluoride (AM3506) has similar inhibitory activity for both the rat and the human enzyme, while rapid dilution assays and mass spectrometry analysis suggest that the compound is a covalent modifier for FAAH and inhibits its action in an irreversible manner. Our SAR results are highlighted by molecular docking of key analogs. PMID- 23083018 TI - From the Editor-in-Chief's Desk. PMID- 23083017 TI - Therapeutic efficacy of artemether-lumefantrine for Plasmodium vivax infections in a prospective study in Guyana. AB - BACKGROUND: In Guyana, chloroquine + primaquine is used for the treatment of vivax malaria. A worldwide increase of chloroquine resistance in Plasmodium vivax led to questioning of the current malaria treatment guidelines. A therapeutic efficacy study was conducted using artemether-lumefantrine + primaquine against P. vivax to evaluate a treatment alternative for chloroquine. METHODS: From 2009 to 2010, a non-controlled study in two hospitals in Guyana was conducted. A total 61 patients with P. vivax infection were treated with artemether-lumefantrine as a six-dose regimen twice a day for three days with additional 0.25 mg/kg/d primaquine at day 0 for 14 days. Clinical and parasitological parameters were followed on days 0,1,2,3,7,14 and 28 in agreement with WHO guidelines. Plasmodium vivax DNA from eight patients was analysed for pvmdr1, molecular marker of resistance. RESULTS: Artemether-lumefantrine cleared 100% of parasites on day 1, but two patients (3%) had recurrence of parasites on day 28, suggesting relapse. No pvmdr1 Y976F polymorphism was detected. The treatment regimen was well tolerated. CONCLUSIONS: In Guyana, artemether-lumefantrine represents an adequate treatment option against P. vivax when combined with primaquine. Availability of this alternative will be of great importance in case of emerging chloroquine resistance against P. vivax. PMID- 23083019 TI - Attention-deficit/hyperactivity disorder: diagnosis before treatment. PMID- 23083020 TI - Efficacy and safety of quetiapine in adolescents with schizophrenia investigated in a 6-week, double-blind, placebo-controlled trial. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of acute quetiapine monotherapy in adolescents with schizophrenia. METHODS: Patients ages 13-17 years with an American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed., Text Revision (DSM-IV-TR) diagnosis of schizophrenia and a Positive and Negative Syndrome Scale (PANSS) total score >=60 were randomized to 6 weeks of quetiapine (400 or 800 mg/day) or placebo treatment. The primary efficacy measure was change in PANSS total score from baseline to day 42. Safety endpoints included adverse events and assessments of clinical chemistry values, suicidality, and extrapyramidal symptoms. RESULTS: The intent-to-treat population included 220 patients. Least-squares mean change in PANSS total score from baseline to endpoint was -27.31 with quetiapine 400 mg/day, -28.44 with quetiapine 800 mg/day, and -19.15 with placebo (p=0.043 and 0.009 for quetiapine 400 and 800 mg/day, respectively, vs. placebo; mixed-model, repeated-measures analysis). Several secondary efficacy outcomes, including Clinical Global Impressions-Improvement score, supported the primary outcome measure in demonstrating significantly greater improvement in quetiapine groups than in the placebo group. Mean changes in body weight at day 42 were 2.2 kg and 1.8 kg for quetiapine 400 and 800 mg/day, respectively, and -0.4 kg for placebo. Mean changes in certain clinical chemistry parameters, including total cholesterol and triglycerides, were numerically greater in the quetiapine groups than in the placebo group. Adverse events associated with quetiapine were mostly mild to moderate in intensity and were consistent with its known profile in adults with schizophrenia. CONCLUSIONS: In this 6-week study of adolescent patients, quetiapine at doses of 400 and 800 mg/day provided significant improvements in symptoms associated with schizophrenia in adolescent patients, including the primary efficacy measure of PANSS total score change. Quetiapine was generally well tolerated with a profile broadly similar to that reported in adult and adolescent populations. CLINICAL TRIAL REGISTRATION INFORMATION: Quetiapine Fumarate (SEROQUEL(TM)) Compared to Placebo in the Treatment of Adolescent Patients With Schizophrenia (ANCHOR 112). Available at: http://www.clinicaltrials.gov/ct2/show/NCT00090324?term=quetiapine+112&rank=1. PMID- 23083021 TI - Dopaminergic and noradrenergic gene polymorphisms and response to methylphenidate in korean children with attention-deficit/hyperactivity disorder: is there an interaction? AB - OBJECTIVE: We aimed to investigate the independent and interaction effects of dopamine transporter gene (DAT1), dopamine D4 receptor gene (DRD4), alpha-2A adrenergic receptor gene (ADRA2A), and norepinephrine transporter gene (NET1), with regard to treatment response to methylphenidate (MPH) in attention deficit/hyperactivity disorder (ADHD). METHODS: The participants of the study were 103 children and adolescents (ages 9.1+/-2.1 years) diagnosed as having ADHD according to American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria. They were enrolled in an 8-week, open-label trial of MPH. The good responder group was defined as subjects having an >=50% decrease in the ADHD Rating Scale-IV (ADHD-RS) total score from the baseline, and at the same time a Clinical Global Impressions-Improvement Scale (CGI-I) score of 1 or 2, both at the 8th week of MPH treatment. Multivariate stepwise logistic regression was performed to examine the independent and interaction effects of genotypes on the dichotomized MPH treatment response. RESULTS: Significant interaction effects on MPH response were detected between the genotypes of the DRD4 variable number of tandem repeat (VNTR) polymorphisms and those of either the ADRA2A DraI or the NET1 -3081(A/T) polymorphisms; significant interaction effects were also detected between the genotypes of the ADRA2A DraI polymorphisms and those of either the NET1 G1287A or the NET1 3081(A/T) polymorphisms (Nagelkerke R(2)=0.40). No significant independent effect of a genotype was detected according to the stepwise logistic regression results. CONCLUSION: The results suggest that genes involved in the dopaminergic and noradrenergic systems might interact to form important predictors of short-term response to MPH. PMID- 23083022 TI - Improving visual memory, attention, and school function with atomoxetine in boys with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Atomoxetine is efficacious in reducing symptoms of attention- deficit/hyperactivity disorder (ADHD), but its effect on visual memory and attention needs more investigation. This study aimed to assess the effect of atomoxetine on visual memory, attention, and school function in boys with ADHD in Taiwan. METHOD: This was an open-label 12 week atomoxetine treatment trial among 30 drug-naive boys with ADHD, aged 8-16 years. Before administration of atomoxetine, the participants were assessed using psychiatric interviews, the Wechsler Intelligence Scale for Children, 3rd edition (WISC-III), the school function of the Chinese version of the Social Adjustment Inventory for Children and Adolescents (SAICA), the Conners' Continuous Performance Test (CPT), and the tasks of the Cambridge Neuropsychological Test Automated Battery (CANTAB) involving visual memory and attention: Pattern Recognition Memory, Spatial Recognition Memory, and Reaction Time, which were reassessed at weeks 4 and 12. RESULTS: Our results showed there was significant improvement in pattern recognition memory and spatial recognition memory as measured by the CANTAB tasks, sustained attention and response inhibition as measured by the CPT, and reaction time as measured by the CANTAB after treatment with atomoxetine for 4 weeks or 12 weeks. In addition, atomoxetine significantly enhanced school functioning in children with ADHD. CONCLUSION: Our findings suggested that atomoxetine was associated with significant improvement in visual memory, attention, and school functioning in boys with ADHD. PMID- 23083023 TI - SMARTer discontinuation trial designs for developing an adaptive treatment strategy. AB - OBJECTIVE: Developing evidenced-based practices for the management of childhood psychiatric disorders requires research studies that address how to treat children during both the acute phase of the disorder and beyond. Given the selection of a medication for acute treatment, discontinuation trials are used to evaluate the effects of treatment duration (e.g., time on medication) and/or maintenance strategies following successful acute-phase treatment. Recently, sequential multiple assignment randomized trials (SMART) have been proposed for use in informing sequences of critical clinical decisions such as those mentioned. The objective of this article is to illustrate how a SMART study is related to the standard discontinuation trial design, while addressing additional clinically important questions with similar trial resources. METHOD: The recently completed Child/Adolescent Anxiety Multimodal Study (CAMS), a randomized trial that examined the relative efficacy of three acute-phase treatments for pediatric anxiety disorders, along with a next logical step, a standard discontinuation trial design, is used to clarify the ideas. This example is used to compare the discontinuation trial design relative to the SMART design. RESULTS: We find that the standard discontinuation trial can be modified slightly using a SMART design to yield high-quality data that can be used to address a wider variety of questions in addition to the impact of treatment duration. We discuss how this innovative trial design is ultimately more efficient and less costly than the standard discontinuation trial, and may result in more representative comparisons between treatments. CONCLUSIONS: Mental health researchers who are interested in addressing questions concerning the effects of continued treatment (for different durations) following successful acute-phase treatment should consider SMART designs in place of discontinuation trial designs in their research. SMART designs can be used to address these and other questions concerning individualized sequences of treatment, such as the choice of a rescue treatment in case of postacute phase relapse. PMID- 23083024 TI - Survey of United States child and adolescent psychiatrists' cardiac screening practices prior to starting patients on stimulants. AB - OBJECTIVE: The purpose of this study was to determine psychiatrists' barriers, attitudes, and practices regarding cardiac screening prior to initiating stimulants in children with attention-deficit/hyperactivity disorder. BACKGROUND: Professional and federal oversight organizations recently have debated the evidence regarding sudden cardiac death (SCD) risk with stimulants, and have published guidelines recommending cardiac screening. It is not known how psychiatrists have responded. METHODS: This study was a cross-sectional survey of 1,600 randomly-selected U.S. members of the American Academy of Child and Adolescent Psychiatry. Analyses included descriptive statistics and logistic regression. RESULTS: Response rate was 40%; 96% met eligibility criteria. Barriers to identifying cardiac disorders in general included ability to perform a routine physical examination (74%) and care coordination with primary care providers (35%). Only 27% agreed that SCD risk warranted cardiac assessment. Prior to starting a patient on stimulants, 95% of psychiatrists obtained a routine history. The majority either conducted (9%), or relied on primary care providers to conduct (67%) a physical examination; 26% did not obtain a physical examination. Nineteen percent of psychiatrists ordered an electrocardiogram (ECG), of those, non-mutually exclusive reasons for ordering an ECG included standard practice procedure (62%), clinical findings (27%), medicolegal considerations (25%), and guideline adherence (24%). On multivariate modeling, psychiatrists were less likely to conduct cardiac screening themselves if in private practice (referent: academic medical center), if >50% of their patients had private insurance, or if they believed their ability to perform a physical examination to be a barrier. When modeling cardiac screening performed by any healthcare professional (e.g., psychiatrist, primary care practitioner), screening was less likely if the psychiatrist was practicing in a community mental health center (referent: academic medical center), was male, or if >50% of that psychiatrist's patients had private insurance. CONCLUSION: Findings suggest the tacit interplay between primary care and psychiatry for the assessment and management of medical risks associated with psychotropic medications should be improved, and solutions prioritized. PMID- 23083026 TI - Onset of abnormal movements and cardiovascular symptoms after acute change in complex polypharmacy in a child with attention-deficit/hyperactivity disorder and mood symptoms. PMID- 23083027 TI - Synthetic cannabinoid-induced psychosis: two adolescent cases. PMID- 23083028 TI - Effectiveness of naltrexone for treating pathologic skin picking behavior in an adolescent with Prader-Willi syndrome. PMID- 23083029 TI - Prazosin treatment of nightmares and sleep disturbances associated with posttraumatic stress disorder: two adolescent cases. PMID- 23083030 TI - A case of antipsychotic-induced hyperglycemia in a child with insulin dependent diabetes mellitus. PMID- 23083031 TI - Potential serious adverse interactions between linezolid and atomoxetine. PMID- 23083033 TI - Biomarkers for systemic lupus erythematosus. AB - In recent years, biomarkers have shown significant promise in helping decision making in drug development. Systemic lupus erythematosus (SLE) is a complicated and highly heterogeneous disease that involves all organs. Only one drug, belimumab, has been approved by the US Food and Drug Administration to treat SLE during the last 50 years and there remains a high unmet medical need to develop new and effective therapies to benefit different patient populations in SLE. Due to the extreme heterogeneity of the disease and the complex and rigorous process to validate individual biomarkers, there is currently a very limited number of consensus biomarkers to aid the treatment decision-making in SLE. This review provides a snapshot of some biomarkers in the field that have the potential to make a big impact on drug development and/or treatment decisions by physicians. These include: type I interferon (IFN) gene signature as a pharmacodynamic marker and potential predictive marker for anti-type I IFN therapy; anti-double stranded DNA as a disease marker and potential predictive marker for flares; the complements and neutrophil signatures as disease marker of SLE; and TWEAK (a tumor necrosis factor family member produced by macrophages) and MCP-1 as potential markers to predict renal flares. Most of these markers need carefully planned and prospective studies with high statistical power to confirm their respective utilities. With the development and application of powerful new technologies, more successful biomarkers will emerge in SLE. This could improve the management of patients in the clinic and facilitate the development of novel and more effective therapeutics for this difficult-to-treat disease. PMID- 23083032 TI - Antithrombotic effect of Z4A5 on coronary thrombosis in a canine model of acute unstable angina. AB - BACKGROUND AND PURPOSE: The glycoprotein IIb/IIIa receptor is the final common pathway of platelet aggregation, regardless of the agonist, and thus represents an ideal therapeutic target for blocking coronary thrombosis. In this study, the anti-platelet and antithrombotic actions of Z4A5, a new glycoprotein IIb/IIIa receptor inhibitor, were evaluated in a canine model of acute unstable angina. EXPERIMENTAL APPROACH: Z4A5 was given i.v. as a bolus followed by 60 min of continuous infusion at doses of 30 MUg.kg-1 + 1 MUg.kg-1.min-1, 30 MUg.kg-1 + 5 MUg.kg-1.min-1 or 300 MUg.kg-1 + 5 MUg.kg-1.min-1. Its antithrombotic effect was evaluated in a model of coronary thrombosis, the injured, stenosed left circumflex coronary artery, in which platelet-dependent cyclic flow reductions (CFRs) were induced by vascular compression and constriction to simulate clinical acute unstable angina. Platelet aggregation and coagulation parameters were determined in platelet-rich plasma and platelet poor plasma respectively. KEY RESULTS: The Z4A5 infusion induced a dose-dependent reduction in CFR frequency, which returned to baseline levels after the termination of the infusion at low doses. At medium dose that inhibited most part of platelet aggregation, it increased tongue bleeding time marginally with no dramatic changes in haemodynamic and coagulation parameters. Furthermore, the inhibition of ADP induced platelet aggregation and prolonged bleeding time observed during Z4A5 infusion reverted to baseline levels after the termination of the infusion. CONCLUSIONS AND IMPLICATIONS: Z4A5 is an effective antithrombotic agent for coronary artery thrombosis with a rapid-on and rapid-off pharmacological profile, and could be used as an alternative treatment of coronary artery ischaemic syndromes. PMID- 23083034 TI - Update on biologic therapies in ankylosing spondylitis: a literature review. AB - AIM: The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis (AS). METHOD: Medline and abstracts submitted to the recent European League Against Rheumatism (EULAR) congress were searched to obtain quality-controlled information on the management of AS. RESULTS: The use of magnetic resonance imaging (MRI) allows the diagnosis of AS to be made in the pre-radiographic stage. The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non-radiographic spondyloarthritis (SpA) can now be considered for biological therapy. The 'older' anti-tumour necrosis factor (TNF) continued to be effective in longer-term studies. Studies with longer duration of follow-up have shown that some patients with pre-radiographic SpA entered into prolonged drug-free remission. It is likely that in the foreseeable future, more AS patients will be treated with biological therapies at an earlier stage of the disease. New biologic therapies, golimumab and secukinumab, are looking promising in improving the signs and symptoms of AS, at least in the short-term. CONCLUSION: Longer-term studies of AS patients treated with infliximab, etanercept and adalimumab continued to show a good clinical response. There is a need for more long-term studies to examine the longitudinal efficacy of golimumab and secukinumab in AS. PMID- 23083035 TI - Performance of the 2010 Rheumatoid Arthritis Classification Criteria. AB - OBJECTIVES: Rheumatoid arthritis (RA) needs early treatment to improve clinical outcome by reducing joint damage, radiographic progression and disability. The aim of this study was to evaluate the 2010 Rheumatoid Arthritis Classification Criteria for its ability to classify RA patients, in their early stages, not exceeding 12 months of disease progression. METHODS: Rheumatoid arthritis (RA) patients were selected from August to December 2010, among those coming for their follow-up. The inclusion criteria were patients with not more than 12 months of disease progression at their first evaluation. Patients were selected from four rheumatology subspecialty clinics. RESULTS: Nine hundred and ninety-seven patients with a confirmed diagnosis of RA entered the study. The female-to-male ratio was 4.3/1.0. Mean age was 46.4 years. Mean disease progression at first visit was 6.3 months. The mean follow-up of their disease was 5.9 years. The 1987 American College of Rheumatology (ACR) criteria were fulfilled for 74% of patients. The ACR/EULAR (European League Against Rheumatism) criteria were fulfilled for 69% of patients. Ten percent had involvement of 2-10 large joints, 29% 1-3 small joints, 25% 4-10 small joints and 32% more than 10 joints. Low rheumatoid factor (RF)/anticytoplasmic antibodies (ACPA) were discovered in 30%, high RF/ACPA in 37%; high erythrocyte sedimentation rate/C-reactive protein in 77%, and duration of 6 weeks or more in 92% of patients. There was no significant difference between men and women. CONCLUSIONS: The 2010 ACR/EULAR criteria have good performance: sensitivity of 69% in early disease (first year), with the same sensitivity in both genders. PMID- 23083036 TI - Performance of hands and feet radiographs in differentiation of psoriatic arthritis from rheumatoid arthritis. AB - AIM: The purpose of this study was to determine useful radiographic findings for differentiating psoriatic arthritis (PsA) from rheumatoid factor (RF)-positive or -negative rheumatoid arthritis (RA) in Japanese patients. METHODS: We accrued 85 patients with PsA. Controls included 135 patients with RA (85 RF-positive, 50 RF negative) matched for gender and disease duration with PsA patients. Radiographs of hands and feet were obtained, and distal interphalangeal (DIP) erosive disease, joint osteolysis, tuft osteolysis, juxta-articular bony proliferation (JBP), periosteal new bone formation and bony ankylosis, which were identified using the definitions developed by an earlier study, were compared between the PsA and RA groups. RESULTS: For radiographic features of hands, the frequencies of JBP, periosteal new bone, and diffuse soft tissue swelling of the fingers were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. In feet, the frequencies of DIP erosive disease, tuft osteolysis, JBP, and diffuse soft tissue swelling of the toes were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. CONCLUSION: JBP was the most important radiographic feature for discriminating PsA from both RF positive and -negative RA, confirming the study by the CASPAR group that showed that JBP is the only radiologic feature that can discriminate PsA from other inflammatory arthritides. This study showed the utility of plain radiographs for diagnosis of PsA. PMID- 23083037 TI - Sexual dysfunction and its determinants in Malaysian women with rheumatoid arthritis. AB - AIM: To determine the prevalence of sexual dysfunction (FSD) among women with rheumatoid arthritis attending the Rheumatology Clinic in Universiti Kebangsaan Malaysia Medical Centre (UKMMC) and Hospital Putrajaya, Malaysia, and to determine its associations with potential clinical and disease activity factors. METHOD: This was a cross-sectional study involving women with rheumatoid arthritis between the ages of 20 and 60 years. A validated Malay Version Female Sexual Function Index (MVFSFI) was administered to diagnose FSD. Sociodemographic and disease activity profiles were obtained and those who had and did not have FSD were compared. RESULTS: Among 63 respondents, 51 patients were included in the analysis for FSD. The prevalence of FSD in women with rheumatoid arthritis attending UKMMC and Hospital Putrajaya Rheumatology Clinic was 29.4%. Erythrocyte sedimentation rate (ESR) and Disease Activity Score in 28 joints (DAS28-ESR) correlates with MVFSFI score with r=-0.364 (P=0.009) and r=-0.268 (P=0.057), respectively. Sociodemographic factors that correlate with MVFSFI score were: patient's age (r=0.520, P<0.001); duration of marriage (r=-0.355, P=0.001); husband's age (r=-0.460, P=0.001); age of oldest child (r=-0.449, P=0.001); and age of youngest child (r=-0.627, P<0.001). CONCLUSION: We found in this study that the prevalence of FSD in rheumatoid arthritis in our centers was 29.4%. Age and family dynamics appear to be more important predictors compared to disease activity. PMID- 23083038 TI - Comparative study on the level of B lymphocyte stimulator (BlyS) and frequency of lymphocytes between sero-negative and sero-positive rheumatoid arthritis patients. AB - AIM: To investigate the differences of B lymphocyte stimulator (BlyS) level and frequency of lymphocytes between sero-negative and sero-positive rheumatoid arthritis (RA) patients. METHODS: Sixty-nine RA patients were enrolled into this study and their clinical data were recorded. The BlyS levels in plasma, frequency of T and B lymphocytes, as well as T-helper (Th) subgroups were compared between sero-negative and sero-positive RA patients. Furthermore, the correlations between clinical features and immunological features were analyzed. RESULTS: The plasma BlyS level in sero-negative RA was higher compared to the sero-positive RA patients (1.73+/-1.71 vs. 0.99+/-0.59 ng/mL, P<0.05) and osteoarthritis (OA) patients (1.73+/-1.71 vs. 0.59+/-0.12 ng/mL, P<0.05). Plasma BlyS level was correlated with disease activity score (DAS-28, erythrocyte sedimentation rate and C-reactive protein), but had no correlation with the titers of rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies. The patients with more advanced changes in X-rays had high plasma BlyS levels. No significant differences in the frequency of T lymphocytes, Th subpopulations and B lymphocytes in peripheral blood were observed between sero-negative and sero positive RA patients. CONCLUSIONS: Plasma BlyS level was correlated with disease activity and radiological progress, which indicates that plasma BlyS level may become a useful biological marker to reflect DAS and to predict RA prognosis. PMID- 23083039 TI - Serum proteome analysis in patients with rheumatoid arthritis receiving therapy with etanercept, a chimeric tumor necrosis factor-alpha receptor. AB - AIM: Rheumatoid arthritis (RA) is a chronic inflammatory disorder of the synovium resulting in the destruction of affected joint cartilage and bone structures. Etanercept is a biological agent that blocks the tumor necrosis factor-alpha (TNF alpha)-mediated inflammatory processes in RA patients, and has a regenerative effect on cartilage. In order to identify novel disease-related proteins and candidate biomarkers, we performed proteomic profiling of the serum in patients with RA who were treated with etanercept. METHOD: Serum samples were obtained from eight RA patients before and after etanercept treatment. The low molecular weight proteins in the serum were concentrated and analyzed by liquid chromatography-tandem mass spectrometry. The results before and after etanercept treatment were compared by the spectrum count method. RESULTS: Among a total of 477 proteins identified, 12 were found to be decreased and five were increased by etanercept treatment. Some of the changed proteins were known to be related to RA, and most of the other changed proteins may play possible roles in the TNF alpha signaling pathway or the state of cartilage and extracellular matrix. CONCLUSION: The present proteomic study identified several proteins that could be involved in the pathogenesis of RA. These findings could thus lead to the identification of novel candidate disease-related protein biomarkers for RA, or indicate new targets for therapy. PMID- 23083041 TI - Evaluation of pulsed electromagnetic field therapy in the management of patients with discogenic lumbar radiculopathy. AB - AIM: This randomized clinical trial was designed to evaluate the effect of pulsed electromagnetic field therapy (PEMF) in the management of patients with discogenic lumbar radiculopathy. METHODS: Forty patients suffering from lumbar radiculopathy due to lumbar disc prolapse were randomly assigned to one of two groups: a study group that included 20 patients who received PEMF therapy and a control group that included 20 patients who received placebo treatment. Both groups were evaluated at bases line and after 3 weeks by using a visual analogue scale (VAS) (0-10), somatosensory evoked potentials (SSEPs) for selected dermatomes and Modified Oswestry Low Back Pain Disability Questionnaire (OSW), and findings were compared before and after treatment. RESULTS: Significant differences were observed between both groups before and after application of PEMF therapy relative to VAS (P=0.024), total OSW (P<0.001), and other domains of OSW score (pain intensity [P=0.009], personal care [P=0.01], lifting [P<0.001], walking [P<0.001], sitting [P<0.001], standing [P<0.001], sleeping [P<0.001], social life [P<0.001] and employment [P=0.003]). Other significant differences were observed between both groups relative to SSEP latency and amplitude of the evaluated dermatomes on the right side (P=0.022 and P=0.001, respectively), and left side latency and amplitude (P=0.016 and P=0.002, respectively). CONCLUSION: PEMF therapy is an effective method for the conservative treatment of lumbar radiculopathy caused by lumbar disc prolapse. In addition to improvement of clinically observed radicular symptoms, PEMF also seems effective in reducing nerve root compression as evidenced by improvement of SSEP parameters after treatment. PMID- 23083042 TI - Recurrent polymyositis triggered by bronchiectasis-associated infections. AB - Polymyositis is a cell-mediated autoimmune disease and various systemic infections can trigger it. However, there have been only rare reports of recurrent polymyositis triggered by systemic infections. We report the case of a 69-year-old woman with recurrent polymyositis triggered by bronchiectasis associated infections. This case indicates that recurrent polymyositis triggered by systemic infections suggests a non-specific autoimmune antigenic response of polymyositis. PMID- 23083043 TI - Acute exacerbation of ankylosing spondylitis after chlamydial infection in a patient well-controlled with etanercept. PMID- 23083044 TI - IgA myeloma in a patient with ankylosing spondylitis. PMID- 23083045 TI - Etanercept-associated right abducens nerve palsy in rheumatoid arthritis. PMID- 23083046 TI - Hypertrophic pachymeningitis in systemic sclerosis sine scleroderma. PMID- 23083047 TI - Anti-annexin V antibodies in neuro-Behcet patients: clinical significance and relation to disease activity. PMID- 23083048 TI - Rituximab in refractory cutaneous polyarteritis. PMID- 23083049 TI - Comparing the usefulness of four imaging techniques in the same gouty arthritis patient. PMID- 23083050 TI - Spontaneous pneumomediastinum: a rare complication of juvenile dermatomyositis. PMID- 23083051 TI - A case of primary systemic amyloidosis. PMID- 23083053 TI - Pattern of skin thickness progression and clinical correlation in Thai scleroderma patients. AB - BACKGROUND: Skin thickness progression in scleroderma (SSc) varies in daily clinical practice observation. OBJECTIVES: To define the pattern of skin thickness among Thai sufferers of SSc and to ascertain the clinical correlation with each skin pattern. METHODS: A 3-year follow-up cohort was performed on patients over 15 years of age in Khon Kaen, Thailand, between January 1, 2005 and December 31, 2006. The progression of skin thickness equals the modified Rodnan skin score at the end minus the score at onset divided by the duration of the disease. RESULTS: SSc cases (117) were included and the female-to-male ratio was 70:47. The mean age at onset was 49.8 years (range 24.4-75.5). The most common skin patterns were: (i) 'slow progression to peak then slow regression' (77 cases; 65.8%); followed by (ii) 'continuous slow progression' (37; 31.6%); (iii) 'continuous intermediate progression' (2; 1.7%); and (iv) 'slow progression to peak then intermediate regression' (1; 0.9%). The respective mean peak skin score and duration of disease at peak skin score was 19.8 points (range 4-45) and 20.3 months (range 1.0-42.2). Only telangiectasia at onset and contracture of joint(s) were related to 'continuous slow progression' of skin thickness with P=0.001 and P=0.042, respectively. Neither SSc subsets nor internal organ involvement were correlated with skin thickness pattern. CONCLUSION: The most common skin pattern in Thai SSc was 'slow progression to peak then slow regression'. Telangiectasia at onset and contracture of joint(s) were predictive of continuous progressive skin thickness in the first 3 years. PMID- 23083052 TI - Pulmonary hypertension associated with rheumatic diseases: baseline characteristics from the Korean registry. AB - OBJECTIVES: The REgistry of Pulmonary Hypertension Associated with Rheumatic Disease (REOPARD) was established in Korea. The baseline data are described from the second year of the registry's operation. METHODS: Patients with a connective tissue disease (CTD) who met the modified definition of the WHO group I pulmonary arterial hypertension (PAH) were enrolled. PAH was defined as a systolic pulmonary arterial pressure> 40 mmHg by echocardiography or mean pulmonary arterial pressure> 25 mmHg by right heart catheterization. Hemodynamic parameters and clinical data such as demographics, functional class, underlying disease, organ involvement, laboratory tests and current treatment were recorded. RESULTS: A total of 321 patients were enrolled during the 2-year study period from 2008 to 2010. The mean age of the patients at registration was 51.9 years and 87.5% were female. Most patients were diagnosed by echocardiography and only 24 patients (7.5%) underwent cardiac catheterization. Exertional dyspnea was present in 63.6% of patients and 31.8% were New York Heart Association class III or IV. Among the patients, systemic lupus erythematosus accounted for 35.3%, systemic sclerosis 28.3%, rheumatoid arthritis 7.8%, overlap syndrome 9.0%, and mixed connective tissue disease 5.9%. There were no significant differences in hemodynamics, functional class, diffusing capacity and N-terminal pro-brain natriuretic peptide levels between the disease subgroups. Treatments consisted of calcium antagonists (57.0%), endothelin antagonists (32.7%), prostanoids (27.1%), phosphodiesterase-5 inhibitors (14.3%) and combinations (37.4%). CONCLUSION: Compared with previous studies, the results showed some differences: underlying diseases, functional status and treatments. This may be due to differences in ethnic background and diagnostic methods of our study. PMID- 23083054 TI - 'The eyes see what the mind knows.' Adult-onset Still's disease, a case series and review in a south Asian population. AB - AIM: Adult-onset Still's disease (AOSD) is a rare disease. Very few cases have been reported from the South-Asian region so the aim of this study is to assess the clinical and laboratory aspects of 15 patients with AOSD in a tertiary referral hospital in Karachi. METHODS: Retrospective data was collected from all patients diagnosed using Yamaguchi criteria for AOSD between January 2004 and December 2010 at Jinnah Medical College Hospital, Karachi. RESULTS: Data of 15 patients with AOSD were analyzed. Their ages ranged from 17 to 55 years, the male to-female ratio being 6:1. The most common clinical features were fever and articular symptoms (100%), sore throat (60%), rash (53.3%), weight loss (93.3%), lymphadenopathy (40%) and elevated erythrocyte sedimentation rate (86.7%). All patients had leukocytosis with counts>20,000/mm 3 were seen in 40%. Elevated liver enzymes were present in 80% of the case series and hyperferritinemia in 100% with a mean of 3,962 ng/mL (range 555-13,865). Ambiguity in presentation and lack of serologic markers make diagnosis of AOSD difficult as 40% of patients were receiving empirical anti-tuberculous therapy prior to final diagnosis. CONCLUSION: It is necessary for physicians to have a high index of suspicion for AOSD in patients with high-grade fever, arthralgia and leukocytosis. PMID- 23083055 TI - Improved electrical conductivity of graphene films integrated with metal nanowires. AB - Polycrystalline graphene grown by chemical vapor deposition (CVD) on metals and transferred onto arbitrary substrates has line defects and disruptions such as wrinkles, ripples, and folding that adversely affect graphene transport properties through the scattering of the charge carriers. It is found that graphene assembled with metal nanowires (NWs) dramatically decreases the resistance of graphene films. Graphene/NW films with a sheet resistance comparable to that of the intrinsic resistance of graphene have been obtained and tested as a transparent electrode replacing indium tin oxide films in electrochromic (EC) devices. The successful integration of such graphene/NW films into EC devices demonstrates their potential for a wide range of optoelectronic device applications. PMID- 23083056 TI - Coffee consumption is associated with a reduced risk of venous thrombosis that is mediated through hemostatic factor levels. AB - BACKGROUND: Coffee consumption is associated with a lower risk of venous thrombosis, but the role of confounding and the pathophysiology behind these findings are unclear. OBJECTIVE: To assess the role of hemostatic factors in the relationship between coffee consumption and venous thrombosis. METHODS: From a large case-control study, 1803 patients with a first venous thrombosis and 1803 partner controls were included. With conditional logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for venous thrombosis were calculated for coffee consumption vs. no coffee consumption. In addition, mean differences in hemostatic factor levels between these groups were calculated in the controls. RESULTS: Coffee consumption yielded a 30% lower risk of venous thrombosis than no coffee consumption (OR 0.7, 95% CI 0.5-0.9). Adjustment for several putative confounders (age, sex, body mass index, smoking, hormonal factors, statin, aspirin, alcohol, malignancy, and chronic disease) yielded an OR of 0.8 (95% CI 0.6-1.1). Results were similar for provoked and unprovoked events, and for deep vein thrombosis and pulmonary embolism. In controls, von Willebrand factor levels were 11 (3-19) IU dL(-1) lower and factor (F) VIII levels were 11 (1-21) IU dL( 1) lower in coffee consumers than in non-consumers. After adjustment of the risk estimates for these hemostatic factors, the inverse association between coffee consumption and venous thrombosis diminished (OR 1.0, 95% CI 0.7-1.4). There was no association between coffee consumption and anticoagulant proteins, fibrinogen levels, or fibrinolytic markers. CONCLUSIONS: Coffee consumption is associated with a lower risk of venous thrombosis, which seems to be mediated through von Willebrand factor and FVIII. PMID- 23083057 TI - Presence of SXT integrating conjugative element in marine bacteria isolated from the mucus of the coral Fungia echinata from Andaman Sea. AB - In this study, we characterize 18 cultivable bacteria associated within the mucus of the coral Fungia echinata from Andaman Sea, India. 16S rRNA gene sequence analysis showed that all the 18 strains isolated in this study from the coral mucus belong to the group Gammaproteobacteria and majority of them were identified as Vibrio core group. Our objective was to investigate the presence of the SXT/R391 integrating conjugative elements (ICEs) targeting integrase int(SXT) and SXT Hotspot IV genetic elements in these isolates. SXT/ICE initially reported in Vibrio cholerae contains many antibiotic and heavy metal resistance genes and acts as an effective tool for the horizontal transfer of resistance genes in other bacterial populations. Two of our strains, AN44 and AN60, were resistant to sulfamethoxazole, trimethoprim, chloramphenicol, and streptomycin, in addition to other antibiotics such as neomycin, ampicillin, rifampicin, and tetracycline. Using PCR followed by sequencing, we detected the SXT/ICE in these strains. The SXT integrase genes of AN44 and AN60 had a 99% and 100% identity with V. cholerae serogroup O139 strain SG24. This study provides the first evidence of the presence of SXT/R391 ICEs in Marinomonas sp. strain AN44 (JCM 18476(T) ) and Vibrio fortis strain AN60 (DSM 26067(T) ) isolated from the mucus of the coral F. echinata. PMID- 23083058 TI - In vivo performance of chitosan/soy-based membranes as wound-dressing devices for acute skin wounds. AB - Wound management represents a major clinical challenge on what concerns healing enhancement and pain control. The selection of an appropriate dressing plays an important role in both recovery and esthetic appearance of the regenerated tissue. Despite the wide range of available dressings, the progress in the wound care market relies on the increasing interest in using natural-based biomedical products. Herein, a rat wound-dressing model of partial-thickness skin wounds was used to study newly developed chitosan/soy (cht/soy)-based membranes as wound dressing materials. Healing and repair of nondressed, cht/soy membrane-dressed, and Epigard((r))-dressed wounds were followed macroscopically and histologically for 1 and 2 weeks. cht/soy membranes performed better than the controls, promoting a faster wound repair. Re-epithelialization, observed 1 week after wounding, was followed by cornification of the outermost epidermal layer at the second week of dressing, indicating repair of the wounded tissue. The use of this rodent model, although in impaired healing conditions, may enclose some drawbacks regarding the inevitable wound contraction. Moreover, being the main purpose the evaluation of cht/soy-based membranes' performance in the absence of growth factors, the choice of a clinically relevant positive control was limited to a polymeric mesh, without any growth factor influencing skin healing/repair, Epigard. These new cht/soy membranes possess the desired features regarding healing/repair stimulation, ease of handling, and final esthetic appearance-thus, valuable properties for wound dressings. PMID- 23083059 TI - Setting realistic recovery targets for two interacting endangered species, sea otter and northern abalone. AB - Failure to account for interactions between endangered species may lead to unexpected population dynamics, inefficient management strategies, waste of scarce resources, and, at worst, increased extinction risk. The importance of species interactions is undisputed, yet recovery targets generally do not account for such interactions. This shortcoming is a consequence of species-centered legislation, but also of uncertainty surrounding the dynamics of species interactions and the complexity of modeling such interactions. The northern sea otter (Enhydra lutris kenyoni) and one of its preferred prey, northern abalone (Haliotis kamtschatkana), are endangered species for which recovery strategies have been developed without consideration of their strong predator-prey interactions. Using simulation-based optimization procedures from artificial intelligence, namely reinforcement learning and stochastic dynamic programming, we combined sea otter and northern abalone population models with functional response models and examined how different management actions affect population dynamics and the likelihood of achieving recovery targets for each species through time. Recovery targets for these interacting species were difficult to achieve simultaneously in the absence of management. Although sea otters were predicted to recover, achieving abalone recovery targets failed even when threats to abalone such as predation and poaching were reduced. A management strategy entailing a 50% reduction in the poaching of northern abalone was a minimum requirement to reach short-term recovery goals for northern abalone when sea otters were present. Removing sea otters had a marginally positive effect on the abalone population but only when we assumed a functional response with strong predation pressure. Our optimization method could be applied more generally to any interacting threatened or invasive species for which there are multiple conservation objectives. PMID- 23083060 TI - Myosin-X facilitates Shigella-induced membrane protrusions and cell-to-cell spread. AB - The intracellular pathogen Shigella flexneri forms membrane protrusions to spread from cell to cell. As protrusions form, myosin-X (Myo10) localizes to Shigella. Electron micrographs of immunogold-labelled Shigella-infected HeLa cells reveal that Myo10 concentrates at the bases and along the sides of bacteria within membrane protrusions. Time-lapse video microscopy shows that a full-length Myo10 GFP-construct cycles along the sides of Shigella within the membrane protrusions as these structures progressively lengthen. RNAi knock-down of Myo10 is associated with shorter protrusions with thicker stalks, and causes a >80% decrease in confluent cell plaque formation. Myo10 also concentrates in membrane protrusions formed by another intracellular bacteria, Listeria, and knock-down of Myo10 also impairs Listeria plaque formation. In Cos7 cells (contain low concentrations of Myo10), the expression of full-length Myo10 nearly doubles Shigella-induced protrusion length, and lengthening requires the head domain, as well as the tail-PH domain, but not the FERM domain. The GFP-Myo10-HMM domain localizes to the sides of Shigella within membrane protrusions and the GFP-Myo10 PH domain localizes to host cell membranes. We conclude thatMyo10 generates the force to enhance bacterial-induced protrusions by binding its head region to actin filaments and its PH tail domain to the peripheral membrane. PMID- 23083061 TI - Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1). AB - BACKGROUND: Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. METHODS: Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL -1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. RESULTS: Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. CONCLUSIONS: A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. TRIAL REGISTRATION NUMBER: NCT01108042 (ClinicalTrials.gov Identifier). PMID- 23083062 TI - Histological findings of the atrioventricular conductive system in street heroin addicts, victims of sudden unexpected death. AB - A study of the atrioventricular (AV) conducting tissue was considered necessary for the examination of probable histologic changes that could justify the arrhythmias observed in street-heroin addicts. Postmortem coronary angiography and microscopic examination were performed in 50 heroin addicts (group A) and in 50 nonaddicts (group B), all male 16-40 years old. In group A, fatty and/or fibrous tissue replaced the AV node in 50% of cases while in group B in 14%. The main bundle was replaced by fatty and/or fibrous tissue in 44% in group A cases and 10% in group B. Intimal proliferation and fibromuscular dysplasia of the AV arteries in group A were correspondingly 26% and 14% and in group B 6% and 2%. Inflammation with focal and/or diffuse concentration of round cells of the AV node was detected in 54% in group A. These findings could explain a possible arrhythmia mechanism in this population. PMID- 23083063 TI - Indolent non-Hodgkin lymphoma primarily involving the hard palate: outcome following radiotherapy. AB - The aim of this study was to report the clinical and pathological characteristics, treatment strategies and outcome in patients with indolent non Hodgkin lymphoma (NHL) primarily involving the hard palate. Nine consecutive patients with indolent NHL of the hard palate were identified. The palate was a site of initial disease for six patients (four stage IAE and two stage IIIAE) and of relapse for three. There were four cases of grade 1-2 follicular lymphoma (FL), two of mantle cell lymphoma (MCL) and three of marginal zone lymphoma (MZL). All nine patients received involved site radiation therapy (RT) alone. There was no grade >= 3 toxicity. At a median follow-up of 55 months, 5-year freedom from local progression was 100%, disease-free survival was 38% and overall survival was 80%. In conclusion, involved site RT is well tolerated and provides excellent local control in the management of indolent lymphoma of the hard palate. PMID- 23083064 TI - Design for gas chromatography-corona discharge-ion mobility spectrometry. AB - A corona discharge ionization-ion mobility spectrometry (CD-IMS) with a novel sample inlet system was designed and constructed as a detector for capillary gas chromatography. In this design, a hollow needle was used instead of a solid needle which is commonly used for corona discharge creation, helping us to have direct axial interfacing for GC-IMS. The capillary column was passed through the needle, resulting in a reaction of effluents with reactant ions on the upstream side of the corona discharge ionization source. Using this sample introduction design, higher ionization efficiency was achieved relative to the entrance direction through the side of the drift tube. In addition, the volume of the ionization region was reduced to minimize the resistance time of compounds in the ionization source, increasing chromatographic resolution of the instrument. The effects of various parameters such as drift gas flow, makeup gas flow, and column tip position inside the needle were investigated. The designed instrument was exhaustively validated in terms of sensitivity, resolution, and reproducibility by analyzing the standard solutions of methyl isobutyl ketone, heptanone, nonanone, and acetophenone as the test compounds. The results obtained by CD-IMS detector were compared with those of the flame ionization detector, which revealed the capability of the proposed GC-IMS for two-dimensional separation (based on the retention time and drift time information) and identification of an analyte in complex matrixes. PMID- 23083065 TI - A CellML simulation compiler and code generator using ODE solving schemes. AB - : Models written in description languages such as CellML are becoming a popular solution to the handling of complex cellular physiological models in biological function simulations. However, in order to fully simulate a model, boundary conditions and ordinary differential equation (ODE) solving schemes have to be combined with it. Though boundary conditions can be described in CellML, it is difficult to explicitly specify ODE solving schemes using existing tools. In this study, we define an ODE solving scheme description language-based on XML and propose a code generation system for biological function simulations. In the proposed system, biological simulation programs using various ODE solving schemes can be easily generated. We designed a two-stage approach where the system generates the equation set associating the physiological model variable values at a certain time t with values at t + Deltat in the first stage. The second stage generates the simulation code for the model. This approach enables the flexible construction of code generation modules that can support complex sets of formulas. We evaluate the relationship between models and their calculation accuracies by simulating complex biological models using various ODE solving schemes. Using the FHN model simulation, results showed good qualitative and quantitative correspondence with the theoretical predictions. Results for the Luo Rudy 1991 model showed that only first order precision was achieved. In addition, running the generated code in parallel on a GPU made it possible to speed up the calculation time by a factor of 50. The CellML Compiler source code is available for download at http://sourceforge.net/projects/cellmlcompiler. PMID- 23083066 TI - Efficacy and safety of a combination herbal medicinal product containing Tropaeoli majoris herba and Armoraciae rusticanae radix for the prophylactic treatment of patients with respiratory tract diseases: a randomised, prospective, double-blind, placebo-controlled phase III trial. AB - OBJECTIVE: The aim of this ICH-GCP study was to investigate the efficacy and safety of a prophylactic administration of a combination herbal medicinal product (CHMP) in two dosages compared to placebo with respect to the incidence of new occurring infections of the respiratory tract (RTI). Clinical experience of prophylactic treatment of respiratory tract infections with the marketed CHMP containing horseradish root (Armoraciae rusticanae radix) and nasturtium (Tropaeoli majoris herba) has existed for decades. METHODS: The study was performed as a phase III, multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group trial. All groups received two film coated tablets three times a day. Group 1 received the CHMP tablets 3 * 2 per day, group 2 the CHMP tablets 2 * 2 and placebo tablets 2 * 1 per day and group 3 received placebo tablets 3 * 2 per day. Maximum duration of treatment was 84 days. The primary efficacy criterion was the comparison of the incidences of new occurring RTIs between the treatment groups during the prophylactic treatment. In addition the character of occurring infections, number of sick days and severity of infections were compared. Further criteria were subjects' well being, the satisfaction of subjects with the respective treatments and severity and incidence of the observed adverse events (AE) and serious adverse events (SAE) during the study period. TRIAL REGISTRATION: EudraCT No. 2010-023227-26. RESULTS: From 371 subjects screened, a total of 351 subjects of both sexes from 18 to 75 years were randomly allocated to one of the three groups. In order to achieve scientifically and medically impeccable results it was necessary to address acute infections of the respiratory tract occurring during the normal incubation period. Early infections (<=day 7) were excluded from the data set in a sensitivity analysis. In the intention to treat (ITT) population excluding early infections <=day 7 (n = 344) the infection rates were 13.3% for CHMP 3 * 2 (n = 113), 18.4% for CHMP 2 * 2 (n = 114) and 25.6% for placebo (n = 117). The statistical trend test showed significant results (p = 0.0171). For the per protocol (PP) population - also excluding infections <=day 7 (n = 334) - infection rates were: CHMP 3 * 2 (n = 110) 12.7%, CHMP 2 * 2 (n = 113) 18.6% and placebo (n = 111) 24.3% (p = 0.0266). Secondary parameters of infections (infection diagnosis, intensity, duration) showed no relevant differences between the treatment groups. The study medication was well tolerated. LIMITATIONS: This was the first clinical ICH-GCP study with the CHMP conducted in this indication and with a sufficient number of subjects. The study population comprised subjects from 18 to 75 years and covered different diagnoses of RTIs. The results show a benefit when using 3 * 2 film tablets of CHMP for prophylaxis of RTIs. However, no data are available on use of the CHMP in this indication in children, adolescents and the elderly (over 75 years). CONCLUSION: This trial demonstrates the efficacy and safety of the combination herbal medicinal product as the treatment of first choice in the prophylactic treatment of episodes of respiratory tract infections. Clinical experience was confirmed in an ICH-GCP study. PMID- 23083068 TI - Social psychology cares about causal conscious thought, not free will per se. AB - The target article is a response to internet blog posts and not to the published record. This distinction matters because while the blog posts debated free will, within the peer-reviewed, scientific psychological literature the debate has always been over a somewhat different issue: the causal nature of conscious as opposed to automatic cognitive processes on higher mental processes such as judgment, behaviour, and motivation. These are distinct issues because conscious processes can be part of the causal chain even though they themselves are caused; thus, logically, conscious processes can be causal even though free will (the 'uncaused causer') does not exist. This debate within psychology over the causal efficacy of conscious processes is now 100 years old (Watson, 1912) and the recent blog exchanges that prompted the target article are better understood within that historical context instead of within the definitional debates within philosophy about the concept of free will. PMID- 23083067 TI - Benzimidazolones enhance the function of epithelial Na+ transport. AB - BACKGROUND AND PURPOSE: Pharmacological enhancement of vectorial Na+ transport may be useful to increase alveolar fluid clearance. Herein, we investigated the influence of the benzimidazolones 1-ethyl-1,3-dihydro-2-benzimidazolone (1-EBIO), 5,6-dichloro-1-EBIO (DC-EBIO) and chlorzoxazone on vectorial epithelial Na+ transport. EXPERIMENTAL APPROACH: Effects on vectorial Na+ transport and amiloride-sensitive apical membrane Na+ permeability were determined by measuring short-circuit currents (I(SC)) in rat fetal distal lung epithelial (FDLE) monolayers. Furthermore, amiloride-sensitive membrane conductance and the open probability of epithelial Na+ channels (ENaC) were determined by patch clamp experiments using A549 cells. KEY RESULTS: I(SC) was increased by approximately 50% after addition of 1-EBIO, DC-EBIO and chlorzoxazone. With permeabilized basolateral membranes in the presence of a 145:5 apical to basolateral Na+ gradient, the benzimidazolones markedly increased amiloride-sensitive I(SC). 5-(N Ethyl-N-isopropyl)amiloride-induced inhibition of I(SC) was not affected. The benzamil-sensitive I(SC) was increased in benzimidazolone-stimulated monolayers. Pretreating the apical membrane with amiloride, which inhibits ENaC, completely prevented the stimulating effects of benzimidazolones on I(SC). Furthermore, 1 EBIO (1 mM) and DC-EBIO (0.1 mM) significantly increased (threefold) the open probability of ENaC without influencing current amplitude. Whole cell measurements showed that DC-EBIO (0.1 mM) induced an amiloride-sensitive increase in membrane conductance. CONCLUSION AND IMPLICATIONS: Benzimidazolones have a stimulating effect on vectorial Na+ transport. The antagonist sensitivity of this effect suggests the benzimidazolones elicit this action by activating the highly selective ENaC currents. Thus, the results demonstrate a possible new strategy for directly enhancing epithelial Na+ transport. PMID- 23083069 TI - Harnessing the skin-thyroid connection for wound healing: a prospective controlled trial in guinea pigs. AB - BACKGROUND: Different elements of the hypothalamic-pituitary-thyroid axis have been found to be implicated in the normal physiology of the human skin. Their effects on wound healing and hair growth in rats have been described previously. There is close homology between the thyroid hormone receptors in humans and guinea pigs. AIM: To assess the effect of different doses of topical 3,3',5 triiodo-L-thyronine (T3) and recombinant human thyroid-stimulating hormone (TSH) on wound healing in guinea pigs. METHODS: Wounds were dressed every other day for 7 days, during which clinical measurements of the wounded areas were performed. Histological examination was performed at the end of the study. RESULTS: Application of high and low concentrations of topical T3 but not TSH demonstrated a significant dose-dependent reduction in the wound surface area through a process of contraction. The main significant histological result was an increase in the hair-follicle count. CONCLUSION: Topical T3 enhances wound healing in guinea pigs, primarily by wound contraction. As this is a critical stage in healing of chronic ulcers, topical T3 could be a useful treatment for wounds. PMID- 23083070 TI - Association between bisphenol A exposure and body mass index in Chinese school children: a cross-sectional study. AB - BACKGROUND: There is increasing evidence suggesting that Bisphenol A (BPA), one of the highest volume chemicals produced worldwide, can interfere with the body's natural weight control mechanisms to promote obesity. However, epidemiological studies for this are limited, especially for children. METHODS: A cross-sectional study was conducted to investigate the association between BPA exposure and body mass index (BMI) in school children. Three primary and three middle schools were randomly selected from 26 primary and 30 middle candidate schools in Changning District of Shanghai City in China. According to the BMI-based criteria by age and sex for screening of overweight or obese children, we randomly chose 20 obese, 10 overweight, and 30 normal weight children aged 8-15 years of age from each selected school. First morning urine was collected and total urine BPA concentrations were determined by ultra-performance liquid chromatography tandem mass spectrometry. Multiple linear regression analysis was conducted to examine the association of urine BPA concentrations and daily intake estimates with BMI. RESULTS: BPA was detected in 84.9% of urine samples with a geometric mean of 0.45 ng/mL. The daily intake estimates ranged from 0.03 MUg/day to 1.96 MUg/day with a geometric mean of 0.37 MUg/day. The average urine BPA concentrations and daily intake estimates were similar for boys and girls, but significantly higher in older children than younger ones, and showed an increasing trend with BMI. Multiple linear regression analyses showed that urine BPA concentrations were significantly associated with increasing BMI values in all subjects after adjustment for age and sex and the results were similar before and after corrected by urine specific gravity. When stratified by age or sex, the associations remained significant in females and in those 8-11 years of age before corrected by specific gravity. Similar results were shown for the association between BMI and daily intake estimates. CONCLUSIONS: There is a possibility that BPA exposure increases BMI in school children. Given the cross sectional nature of this study, longitudinal studies are warranted to confirm BPA exposure as a contributor to increased BMI in children. PMID- 23083071 TI - Mesenchymal stem cell osteodifferentiation in response to alternating electric current. AB - The present study addressed adult human mesenchymal stem cell (MSC) differentiation toward the osteoblastic lineage in response to alternating electric current, a biophysical stimulus. For this purpose, MSCs (chosen because of their proven capability for osteodifferentiation in the presence of select bone morphogenetic proteins) were dispersed and cultured within electric conducting type I collagen hydrogels, in the absence of supplemented exogenous dexamethasone and/or growth factors, and were exposed to either 10 or 40 MUA alternating electric current for 6 h per day. Under these conditions, MSCs expressed both early- (such as Runx-2 and osterix) and late- (specifically, osteopontin and osteocalcin) osteogenic genes as a function of level, and duration of exposure to alternating electric current. Compared to results obtained after 7 days, gene expression of osteopontin and osteocalcin (late osteogenic genes) increased at day 14. In contrast, expression of these osteogenic markers from MSCs cultured under similar conditions and time periods, but not exposed to alternating electric current, did not increase as a function of time. Most importantly, expression of genes pertinent to the either adipogenic (specifically, Fatty Acid Binding Protein-4) or chondrogenic (specifically, type II collagen) pathways was not detected when MSCs were exposed to the aforementioned alternating electric-current conditions tested in the present study. The present research study was the first to provide evidence that alternating electric current promoted the differentiation of adult human MSCs toward the osteogenic pathway. Such an approach has the yet untapped potential to provide critically needed differentiated cell supplies for cell-based assays and/or therapies for various biomedical applications. PMID- 23083072 TI - Use of ceramides and related products for childhood-onset eczema. AB - Atopic eczema or dermatitis (AD) is a chronically relapsing dermatosis associated with pruritus, sleep disturbance and impaired quality of life. AD affects 10 to 20% of school-aged children. The prevalence has increased two to three folds over the past three decades in industrialized countries and there is evidence to suggest that this prevalence is increasing. AD is frustrating to both patients and caregivers and can impose considerable financial impact on the families. The pruritus and sleep disturbance can be intractable and the disease has important physical and psychological implications. Filaggrin (filament-aggregating protein) has an important function in epidermal differentiation and barrier function. Null mutations within the filaggrin gene cause ichthyosis vulgaris and are major risk factors for developing AD. The affected skin of atopic individuals is deficient in natural moisturizing factors (derived from deiminated filaggrin peptides filaggrin) or ceramides (a family of lipid molecules, composed of sphingosine and a fatty acid, found in high concentrations within the cell membrane of cells in the stratum corneum). Avoidance of triggering factors, optimal skin care and topical corticosteroids are the mainstay of therapy for AD. There are two important dermatologic facets to its management, namely, preventive and therapeutic measures. Preventive measures refer to the frequent and proper application of skin moisturizers. When these preventive measures fail to control the disease exacerbation, therapeutic measures such as topical/systemic corticosteroids, antibiotics and immunomodulating agents may be required to control the skin inflammation. Proper moisturizer therapy can reduce the frequency of flares and the demand of topical corticosteroids or topical calcineurin inhibitors. Regular topical application of a moisturizer is the key in the management of patients with AD. Moisturizer therapy of childhood-onset AD is significantly complicated by the diversity of disease manifestations and by a variety of complex immune abnormalities. Recent advances in the understanding of the pathophysiological process of AD leads to the production of new moisturizers and topical skin products targeted to correct reduced amount of ceramides in the skin with ceramide and pseudoceramide products. However, many cosmetic products claimed to have these ingredients have no or limited studies to document their clinical efficacy. Recent studies have shown the therapeutic efficacy of several new compounds. This review provides an update on recent patents that could develop into novel therapeutics available to the clinical armamentarium for the management of the disease. PMID- 23083073 TI - Evolution of cutaneous tuberculosis over the past 30 years in a tertiary hospital on the European Mediterranean coast. AB - BACKGROUND: There have been few studies on cutaneous tuberculosis (TB) in Europe in recent years. Objective. To retrospectively analyse the evolution of the various types of cutaneous TB over the past 30 years in an adult population in Spain. METHODS: Patients with cutaneous TB diagnosed between 1981 and 2011 at Bellvitge Hospital, Barcelona, Spain, were included in the study. Chest radiography was performed for all patients, and the presence of TB elsewhere in the body was excluded when clinically suspected. RESULTS: In total, 36 patients (15 male, 21 female, mean age 53.72 years) were diagnosed with cutaneous TB. There were 22 patients with lupus vulgaris (LV), 4 with scrofuloderma, 4 with miliary TB, 3 with tuberculous abscess/ulcer, and 1 each with orificial TB, warty TB, and an iatrogenic inoculation from underlying visceral focus. Of the 36 patients, 16 (38.88%) had TB presenting simultaneously in other organs. Mycobacterial culture from skin biopsies was positive for Mycobacterium tuberculosis complex in 17 of the 32 cases tested (53.12%), whereas stains for acid-fast bacilli in skin samples were positive in only 3 of 36 patients (8.33%). CONCLUSIONS: Although the number of cases of cutaneous TB diagnosed yearly in our population has declined over the past 30 years, cutaneous TB still exists in Europe, and its incidence is expected to increase, owing to the increased immigration into the continent in recent years. The most common type of cutaneous TB in our adult population was LV. It should be noted that despite being considered a benign form of TB, cutaneous TB can be accompanied by TB in internal organs, and severe complications can occur, such as the development of squamous cell carcinoma in long-lasting lesions. PMID- 23083074 TI - Multiplex detection of protein toxins using MALDI-TOF-TOF tandem mass spectrometry: application in unambiguous toxin detection from bioaerosol. AB - Protein toxins, such as botulinum neurotoxins (BoNTs), Clostridium perfringens epsilon toxin (ETX), staphylococcal enterotoxin B (SEB), shiga toxin (STX), and plant toxin ricin, are involved in a number of diseases and are considered as potential agents for bioterrorism and warfare. From a bioterrorism and warfare perspective, these agents are likely to cause maximum damage to a civilian or military population through an inhalational route of exposure and aerosol is considered the envisaged mode of delivery. Unambiguous detection of toxin from aerosol is of paramount importance, both for bringing mitigation protocols into operation and for implementation of effective medical countermeasures, in case a "biological cloud" is seen over a population. A multiplex, unambiguous, and qualitative detection of protein toxins is reported here using tandem mass spectrometry with MALDI-TOF-TOF. The methodology involving simple sample processing steps was demonstrated to identify toxins (ETX, Clostridium perfringes phospholipase C, and SEB) from blind spiked samples. The novel directed search approach using a list of unique peptides was used to identify toxins from a complex protein mixture. The bioinformatic analysis of seven protein toxins for elucidation of unique peptides with conservation status across all known sequences provides a high confidence for detecting toxins originating from any geographical location and source organism. Use of tandem MS data with peptide sequence information increases the specificity of the method. A prototype for generation of aerosol using a nebulizer and collection using a cyclone collector was used to provide a proof of concept for unambiguous detection of toxin from aerosol using precursor directed tandem mass spectrometry combined with protein database searching. ETX prototoxin could be detected from aerosol at 0.2 ppb concentration in aerosol. PMID- 23083075 TI - Polymer nanoreactors with dual functionality: simultaneous detoxification of peroxynitrite and oxygen transport. AB - The design of multifunctional systems is in focus today as a key strategy for coping with complex challenges in various domains that include chemistry, medicine, environmental sciences, and technology. Herein, we introduce protein containing polymer nanoreactors with dual functionality: peroxynitrite degradation and oxygen transport. Vesicles made of poly-(2-methyloxazoline) poly(dimethylsiloxane)-poly(2-methyloxazoline) successfully encapsulated hemoglobin (Hb), which serves as a model protein because of its dual function in oxygen transport and peroxynitrite degradation. By inserting channel proteins, the polymer membranes of vesicles permitted passage of various compounds that served for the assessment of in situ Hb activity. The requisite conformational changes in the protein structure and the change in oxidation states that took place within the confined space of the vesicle cavity demonstrated that Hb preserved its dual functionality: peroxynitrite degradation and oxygen transport. The functionality of our nanoreactor, combined with its simple procedure of production and extensive stability over several months, supports it as a promising system for further medical applications. PMID- 23083076 TI - Structural diversity of new C13-polyketides produced by Chaetomium mollipilium cultivated in the presence of a NAD(+)-dependent histone deacetylase inhibitor. AB - Cultivation of Chaetomium mollipilium with nicotinamide, a NAD(+)-dependent HDAC inhibitor, stimulated its secondary metabolism, leading to the isolation of structurally diverse new C(13)-polyketides, mollipilin A-E (1-5) as well as two known compounds (6 and 7). Spectroscopic methods, X-ray single crystal diffraction analysis, and VCD elucidated the absolute configurations of structures 1-6, and plausible biosynthetic pathways for 1-7 were proposed based on structural relationships. Mollipilins A (1) and B (2) exhibited moderate growth inhibitory effects on HCT-116 cells. PMID- 23083077 TI - Inhibition of radiation-induced skin fibrosis with imatinib. AB - PURPOSE: Dermal fibrosis is a disabling late toxicity of radiotherapy. Several lines of evidence suggest that overactive signaling via the Platelet-derived growth factor receptor-beta (PDGFR-beta) and V-abl Abelson murine leukemia viral oncogene homolog 1 (cAbl) may be etiologic factors in the development of radiation-induced fibrosis. We tested the hypothesis that imatinib, a clinically available inhibitor of PDGFR-beta, Mast/stem cell growth factor receptor (c-kit) and cAbl, would reduce the severity of dermal fibrosis in a murine model. MATERIALS AND METHODS: The right hind legs of female C3H/HeN mice were exposed to 35 Gy of X-rays. Cohorts of mice were maintained on chow formulated with imatinib 0.5 mg/g or control chow for the duration of the experiment. Bilateral hind limb extension was measured serially to assess fibrotic contracture. Immunohistochemistry and biochemical assays were used to evaluate the levels of collagen and cytokines implicated in radiation-induced fibrosis. RESULTS: Imatinib treatment significantly reduced hind limb contracture and dermal thickness after irradiation. Immunohistochemical studies demonstrated a substantial reduction in PDGFR-beta phosphorylation. We also observed reduced Transforming Growth factor-beta (TGF-beta) and collagen expression in irradiated skin of imatinib-treated mice, suggesting that imatinib may suppress the fibrotic process by interrupting cross-talk between these pathways. CONCLUSIONS: Taken together, these results support that imatinib may be a useful agent in the prevention and treatment of radiation-induced dermal fibrosis. PMID- 23083078 TI - African horse sickness outbreaks caused by multiple virus types in Ethiopia. AB - African horse sickness (AHS) is associated with high morbidity and mortality in equids, especially horses. A retrospective analysis was carried out concerning 737 AHS outbreaks that occurred during 2007-2010 in Ethiopia. A total of ten outbreaks were investigated in the study period. All four forms of the disease (pulmonary, cardiac, horse sickness fever and the combined form) were observed, with the cardiac form being the most prevalent. Multiple African horse sickness virus serotypes (AHSV-2, AHSV-4, AHSV-6, AHSV-8 and AHSV-9) were detected by molecular methods (type-specific real-time RT-PCR assays), and fourteen isolates were derived from blood and tissue samples collected during 2009-2010. This is the first report of AHSV-4, AHSV-6 or AHSV-8 in Ethiopia. PMID- 23083079 TI - The relationship between rural status, individual characteristics, and self-rated health in the Behavioral Risk Factor Surveillance System. AB - PURPOSE: To examine rural status and social factors as predictors of self-rated health in community-dwelling adults in the United States. METHODS: This study uses multinomial logistic and cumulative logistic models to evaluate the associations of interest in the 2006 U.S. Behavioral Risk Factor Surveillance System, a cross-sectional survey of 347,709 noninstitutionalized adults. FINDINGS: Self-rated health was poorer among rural residents, compared to urban residents (OR = 1.77, 95% CI: 1.54, 1.90). However, underlying risk factors such as obesity, low income, and low educational attainment were found to vary by rural status and account for the observed increased risk (OR = 1.03, 95% CI: 0.94, 1.12). There was little evidence of effect modification by rural status, though the association between obesity and self-rated health was stronger among urban residents (OR = 2.50, 95% CI: 2.38, 2.64) than among rural residents (OR = 2.18, 95% CI: 2.03, 2.34). CONCLUSIONS: Our findings suggest that differences in self-rated health by rural status were attributable to differential distributions of participant characteristics and not due to differential effects of those characteristics. PMID- 23083080 TI - Quality of life in rural and urban adults 65 years and older: findings from the National Health and Nutrition Examination survey. AB - PURPOSE: The proportion of people over 65 years of age is higher in rural areas than in urban areas, and their numbers are expected to increase in the next decade. This study used Andersen's behavioral model to examine quality of life (QOL) in a nationally representative sample of community-dwelling adults 65 years and older according to geographic location. Specifically, associations between 3 dimensions of QOL (health-related QOL [HQOL], social functioning, and emotional well-being) and needs and health behaviors were examined. METHODS: The 2005-2006 National Health and Nutrition Examination survey was linked with the 2007 Area Resources File via the National Center for Health Statistics' remote access system. Frequencies and distribution patterns were assessed according to rural, adjacent, and urban locations. FINDINGS: Older adults reported high levels of QOL; however, rural older adults had lower social functioning than their urban counterparts. Older blacks and Hispanics had lower scores than whites on 2 dimensions of QOL. Associations between QOL and needs and health behaviors varied. Although activities of daily living were associated with all 3 dimensions, others were associated with 1 or 2 dimensions. CONCLUSIONS: The lower scores on social functioning in rural areas suggest that rural older adults may be socially isolated. Older rural adults may need interventions to maintain physical and mental health, strengthen social relationships and support, and increase their participation in the community to promote QOL. In addition, older blacks and Hispanics seem more vulnerable than whites and may need more assistance. PMID- 23083081 TI - Psychological traumas of war: training school counselors as home-front responders. AB - PURPOSE: With nearly 3 million U.S. troops having deployed for Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND) since the conflicts began, an estimated 2 million children have been separated from a parent. This manuscript describes a collaborative project between a state's Veterans Healthcare System, a branch of the American Counseling Association, and a medical university on the OEF/OIF/OND deployment experience. METHODS: The project sought to educate school counselors about experiences of OEF/OIF/OND families and learn from their observations as home-front responders in public schools during a 2-day summer workshop. This manuscript describes the framework of the workshop, pre/post evaluation results, and implications for counselors, educators, and supervisors. FINDINGS: School counselors identified childcare and parenting, emotions and behaviors, finances, and barriers to counseling services as challenges for military children and families. Following the workshop, school counselors reported a greater knowledge concerning understanding aspects of outreach for schools and communities in working with veterans and their families. They also reported a better understanding of the impact of war on military families and knowledge of local and state resources for this population. Specifically, attendees felt they could better identify issues and needs of OEF/OIF/OND families with young children, recommend parenting skills to assist these families, and recognize their psychiatric or medical issues. CONCLUSION: In addressing the mental health disparities of military children experiencing combat related parental separation, it is important to identify protective environments that could provide prevention interventions for this population. Collaboration between the Department of Defense, Department of Veterans Affairs (VA), and Department of Education could help support military families and a society facing continued conflicts abroad. PMID- 23083083 TI - At what age should children engage in agricultural tasks? AB - PURPOSE: We compared parents' perceived-as-appropriate ages with actual performance ages for their children engaging in selected agricultural tasks or practices, and we examined the factors associated with age discrepancy. METHODS: We analyzed data from the Keokuk County Rural Health Study collected among parents of children age 17 or younger. Parents were interviewed separately regarding the age of their children's involvement in 14 selected agricultural tasks and their opinions about appropriate age of involvement. FINDINGS: Of the 264 families included, 86.5% with a son and 69.8% with a daughter reported having children involved in at least 1 of 14 selected agricultural tasks. The average actual-performance ages for children to be involved in any of the tasks were younger than those that parents perceived appropriate. Furthermore, in 6 of the 9 North American Guidelines for Children's Agricultural Tasks (NAGCAT) that we assessed, parents' perceived-as-appropriate ages were younger than minimum ages recommended by the NAGCAT. Driving an all-terrain vehicle (ATV) was the most common task with actual-performance age younger than the NAGCAT-recommended age; 53.0% of boys (n = 106) and 36.1% of girls (n = 61) did so under the recommended age. Boys and children who live on a farm, or whose parents have been or are farmers, were significantly more likely to perform agricultural tasks at earlier ages. CONCLUSIONS: Our results suggest farm parents and other rural stakeholders need to be better educated and encouraged to follow the NAGCAT guidelines, and that multilevel interventions need to be developed to ensure protection of children from agricultural injury and death. PMID- 23083082 TI - Quality of diabetes mellitus care by rural primary care physicians. AB - PURPOSE: To explore the relationship between degree of rurality and glucose (hemoglobin A1c), blood pressure (BP), and lipid (LDL) control among patients with diabetes. METHODS: Descriptive study; 1,649 patients in 205 rural practices in the United States. Patients' residence ZIP codes defined degree of rurality (Rural-Urban Commuting Areas codes). Outcomes were measures of acceptable control (A1c < = 9%, BP < 140/90 mmHg, LDL < 130 mg/dL) and optimal control (A1c < 7%, BP < 130/80 mmHg, LDL < 100 mg/dL). Statistical significance was set at P < .008 (Bonferroni's correction). FINDINGS: Although the proportion of patients with reasonable A1c control worsened by increasing degree of rurality, the differences were not statistically significant (urban 90%, large rural 88%, small rural 85%, isolated rural 83%; P = .10); mean A1c values also increased by degree of rurality, although not statistically significant (urban 7.2 [SD 1.6], large rural 7.3 [SD 1.7], small rural 7.5 [SD 1.8], isolated rural 7.5 [SD 1.9]; P = .16). We observed no differences between degree of rural and reasonable BP or LDL control (P = .42, P = .23, respectively) or optimal A1c or BP control (P = .52, P = .65, respectively). Optimal and mean LDL values worsened as rurality increased (P = .08, P = .029, respectively). CONCLUSIONS: In patients with diabetes who seek care in the rural Southern United States, we observed no relationship between degree of rurality of patients' residence and traditional measures of quality of care. Further examination of the trends and explanatory factors for relative worsening of metabolic control by increasing degree of rurality is warranted. PMID- 23083084 TI - Child nutritional status by rural/urban residence: a cross-national analysis. AB - PURPOSE: Rural children in developing countries have poor health outcomes in comparison with urban children. This paper considers 4 questions regarding the rural/urban difference, namely: (1) do individual-level characteristics account for rural/urban differences in child nutritional status; (2) do community-level characteristics account for rural/urban differences net of individual-level characteristics; (3) does type of residence alter the influence of individual characteristics; and (4) does the rural/urban difference vary across national contexts? METHOD: Analysis is based on demographic and health survey data from 35 developing countries. Multilevel regression is used to examine rural/urban differences in nutritional status net of individual, community and national determinants of health status. FINDINGS: Rural children have a substantially higher risk of poor nutrition. Much of this disadvantage is because of socioeconomic disadvantage, reproductive norms favoring early and more rapid childbearing, and lack of access to modern medicine. Rural residence also structures the nature of the relationships between socioeconomic status, access to medical care, and nutrition. Finally, the rural/urban gap declines as countries develop. CONCLUSION: Rural/urban differences in child nutritional status are substantial, and some-but not all-of the differences are attributable to socioeconomic status, access to medical care, and reproductive norms. PMID- 23083085 TI - Prevalence of obesity among adults from rural and urban areas of the United States: findings from NHANES (2005-2008). AB - PURPOSE: Rural residents have higher rates of chronic diseases compared to their urban counterparts, and obesity may be a major contributor to this disparity. This study is the first analysis of obesity prevalence in rural and urban adults using body mass index classification with measured height and weight. In addition, demographic, diet, and physical activity correlates of obesity across rural and urban residence are examined. METHODS: Analysis of body mass index (BMI), diet, and physical activity from 7,325 urban and 1,490 rural adults in the 2005-2008 National Health and Nutrition Examination Survey (NHANES). FINDINGS: The obesity prevalence was 39.6% (SE = 1.5) among rural adults compared to 33.4% (SE = 1.1) among urban adults (P = .006). Prevalence of obesity remained significantly higher among rural compared to urban adults controlling for demographic, diet, and physical activity variables (odds ratio = 1.18, P = .03). Race/ethnicity and percent kcal from fat were significant correlates of obesity among both rural and urban adults. Being married was associated with obesity only among rural residents, whereas older age, less education, and being inactive was associated with obesity only among urban residents. CONCLUSIONS: Obesity is markedly higher among adults from rural versus urban areas of the United States, with estimates that are much higher than the rates suggested by studies with self reported data. Obesity deserves greater attention in rural America. PMID- 23083086 TI - Natural environments, obesity, and physical activity in nonmetropolitan areas of the United States. AB - PURPOSE: To assess the associations of the natural environment with obesity and physical activity in nonmetropolitan areas of the United States among representative samples by using 2 indices of outdoor activity potential (OAP) at the county level. METHODS: We used the data from 457,820 and 473,296 noninstitutionalized adults aged over 18 years for obesity and physical activity, respectively, from the 2000-2006 Behavioral Risk Factor Surveillance System. The OAP indices were (1) a recreational opportunity index based on 24 variables related to outdoor physical activity, such as the number of facilities available for walking, biking, hiking, and swimming derived from the 1997 National Outdoor Recreation Supply Information System; and (2) a natural amenities index which was based on physical and social environmental characteristics, such as climate, topographic relief, land cover, and tourism. We fitted logistic regression models using generalized estimating equations to control for county level intracorrelation and tested each index separately to assess its relationship with obesity and physical activity. FINDINGS: Recreational opportunities were higher in areas with greater natural amenities. After controlling for individual-level socioeconomic and demographic characteristics, the prevalence of obesity decreased and propensity for physical activity increased with increasing levels of both recreational opportunities and natural amenities. CONCLUSIONS: Multiple indices of OAP based on characteristics of the built, natural and social environments were associated with decreased obesity and increased physical activity in nonmetropolitan areas. Public health interventions should consider the opportunities and limitations offered by the natural environment for promoting physical activity and reducing obesity in rural areas. PMID- 23083087 TI - States' experiences with loan repayment programs for health care professionals in a time of state budget cuts and NHSC expansion. AB - PURPOSE: The landscape of education loan repayment programs for health care professionals has been turbulent in recent years, with doubling of the funding for the National Health Service Corps (NHSC) and cuts in funding for some states' programs. We sought to understand how this turbulence is being felt within the state offices involved in recruiting clinicians to rural and urban underserved communities. METHODS: We conducted key informant telephone interviews with staff of state offices of rural health, primary care organizations, and/or related organizations within 28 diverse states to answer questions about perceived changes and interplay among solely state-funded loan repayment programs, joint state-federal programs, and the NHSC federal program. Interviews were transcribed, formally analyzed, and key issues summarized. FINDINGS: Informants reported that solely state-funded and joint state-federal loan repayment programs are greatly valued for their ability to target a state's particular needs and to complement the NHSC federal program. However, budgets for state programs have been threatened, reduced, or eliminated entirely in many cases. All informants positively perceived the NHSC's recent growth and changes, which they feel are helping fill important workforce needs for their states. Nevertheless, the much larger NHSC federal program now competes with some states' programs for clinicians and service sites; states' programs are pushed to adjust their operations to maintain a unique "niche". CONCLUSIONS: States' key recruiters lament reductions in funding for states' loan repayment programs, and welcome the NHSC's recent growth and changes. Better coordination is needed to minimize competition and maximize complementarity between state and federal programs. PMID- 23083088 TI - A comparative study of financial data sources for critical access hospitals: audited financial statements, the Medicare cost report, and the Internal Revenue Service form 990. AB - PURPOSE: Medicare cost reports (MCR), Internal Revenue Service form 990s (IRS 990), and audited financial statements (AFS) vary in their content, detail, purpose, timeliness, and certification. The purpose of this study was to compare selected financial data elements and characterize the extent of differences in financial data and ratios across the MCR, IRS 990, and AFS for a sample of nonprofit critical access hospitals (CAHs). METHODS: Line items from AFS of 47 CAHs were compared to data reported in the hospitals' MCR and IRS 990s. Line items were based on 9 financial indicators commonly used to assess hospital financial performance. FINDINGS: Of the indicators examined, the equity financing ratio most frequently matched between the 3 reports, while salaries and benefits to total expenses and debt service coverage were often different. Variances were driven by differences in individual account balances used to construct the ratios. Relative to AFS, cash was frequently lower on the IRS 990 while marketable securities and unrestricted investments were often higher. Other revenue and net income were consistently lower on the MCR and IRS 990, and depreciation was often higher on the MCR. The majority of total assets and fund balance (equity) values matched across the 3 reports, suggesting differences in classification among detailed accounts were more common than variances between the component totals (total assets, total liabilities, and fund balance). CONCLUSIONS: Health policy researchers should consider the impact of these variances on study results and consider ways to improve the availability and quality of financial accounting information. PMID- 23083089 TI - Redefining the role of the pharmacist: medication therapy management. AB - PURPOSE: The purpose of this paper is to explore better use of pharmacists in rural communities as a partial solution to scarcity of physicians and other health care providers. It discusses expected reduction in public subsidies for rural health care and the changing market for pharmacists. The paper emphasizes the use of pharmacists as a backdrop for description of medication therapy management (MTM). A pilot study of MTM is also reported. METHODS: This article explores rural health access, the market for pharmacists and MTM using the literature, and economic concepts to provide historical context for this new form of health care delivery. A small case study from a university-based clinic provided primary data to demonstrate viability. FINDINGS: MTM can augment rural health by providing care for patients who receive increasing numbers of complex medications. It helps better integrate pharmacists into primary care and holds promise as a cost-effective, if not cost-saving alternative. CONCLUSION: More constrained fiscal conditions are a virtual certainty going forward. The rural health community needs cost-effective health care alternatives that can prosper with lower levels of public financial support. MTM is one such option. PMID- 23083093 TI - N-[5-(5-fluoropyridin-3-yl)-1H-pyrazol-3-yl]-4-piperidin-1-ylbutyramide (SEN78702, WYE-308775): a medicinal chemistry effort toward an alpha7 nicotinic acetylcholine receptor agonist preclinical candidate. AB - alpha7 Nicotinic acetylcholine receptors (alpha7 nAChR) represent promising therapeutic candidates for the treatment of cognitive impairment associated with Alzheimer's disease (AD) and schizophrenia. A medicinal chemistry effort around previously reported compound 1 (SEN15924, WAY-361789) led to the identification of 12 (SEN78702, WYE-308775) a potent and selective full agonist of the alpha7 nAChR that demonstrated improved plasma stability, brain levels, and efficacy in behavioral cognition models. PMID- 23083094 TI - Practice and prospects of microbial preservation. AB - A growing interest in culturable diversity has required microbiologists to think seriously about microbial preservation. In addition to the isolation and cultivation of pure strains, adequate preservation without changes in morphological, physiological and genetic traits is necessary. This review consolidates different methods used for preservation of microorganisms with an emphasis on cryopreservation and lyophilization. The critical points of cryopreservation and lyophilization are highlighted to explain how several extrinsic and intrinsic factors affect the cell survival and recovery during the process of long-term preservation. Factors responsible for alteration in genotypic and phenotypic integrity of cultures during preservation and methods used for their evaluation have been incorporated. We emphasize the importance of depositories and highlight their current funding status. Future areas for preservation research, including cell dormancy, ecosystem and community level preservation and the effects of the viable but non-culturable state on post preservation recovery of the cells are also discussed. PMID- 23083095 TI - Pharmacological characterization of LPS and opioid interactions at the toll-like receptor 4. AB - BACKGROUND AND PURPOSE: Previous work in our laboratory showed opioid agents inhibit cytokine expression in astrocytes. Recently, Watkins and colleagues hypothesized that opioid agonists activate toll-like receptor 4 (TLR4) signalling, which leads to neuroinflammation. To test this hypothesis, we characterized LPS and opioid effects on TLR4 signalling in reporter cells. EXPERIMENTAL APPROACH: NF-kappaB reporter cells expressing high levels of TLR4 were used to compare LPS and opioid effects on NF-kappaB activation, a pathway activated by TLR4 stimulation. KEY RESULTS: LPS increased TLR4 signalling in a concentration-dependent manner and was antagonized by LPS antagonist (LPS-RS, from Rhodobacter sphaeroides). A concentration ratio analysis showed that LPS-RS was a competitive antagonist. The opioid agonists, morphine and fentanyl, produced minor activation of TLR4 signalling when given alone. When tested following LPS stimulation, opioid agonists inhibited NF-kappaB activation but this inhibition was not blocked by the general opioid antagonist, naloxone, nor by the selective MU opioid receptor antagonist, beta-FNA. Indeed, both naloxone and beta-FNA also inhibited NF-kappaB activation in reporter cells. Further examination of fentanyl and beta-FNA effects revealed that both opioid agents inhibited LPS signalling in a non-competitive fashion. CONCLUSIONS AND IMPLICATIONS: These results show that LPS-RS is a competitive antagonist at the TLR4 complex, and that both opioid agonists and antagonists inhibit LPS signalling in a non-competitive fashion through a non-GPCR, opioid site(s) in the TLR4 signalling pathway. If confirmed, existing opioid agents or other drug molecules more selective at this novel site may provide a new therapeutic approach to the treatment of neuroinflammation. PMID- 23083096 TI - Synaptosomes secrete and uptake functionally active microRNAs via exocytosis and endocytosis pathways. AB - In this study, we first characterized synaptosome microRNA (miRNA) profiles using microarray and qRT-PCR. MicroRNAs were detected in isolated synaptic vesicles, and Ago2 immunoprecipitation studies revealed an association between miRNAs and Ago2. Second, we found that miR-29a, miR-99a, and miR-125a were significantly elevated in synaptosome supernatants after depolarization. MiRNA secretion by the synaptosome was Ca(2+)-dependent and was inhibited by the exocytosis inhibitor, okadaic acid. Furthermore, application of nerve growth factor increased miRNA secretion without altering the spontaneous release of miRNAs. Conversely, kainic acid decreased miRNA secretion and enhanced the spontaneous release of miRNAs. These results indicate that synaptosomes could secrete miRNAs. Finally, synthesized miRNAs were taken up by synaptosomes, and the endocytosis inhibitor Dynasore blocked this process. After incubation with miR-125a, additional miR 125a was bound to Ago2 in the synaptosome, and expression of the miR-125a target gene (PSD95 mRNA) was decreased; these findings suggest that the ingested miRNAs were assembled in the RNA-induced silencing complex, resulting in the degradation of target mRNAs. To our knowledge, this is the first study that demonstrates the secretion of miRNAs by synaptosomes under physiological stimulation and demonstrates that secreted miRNAs might be functionally active after being taken up by the synaptic fraction via the endocytic pathway. PMID- 23083097 TI - Attentional breadth and proximity seeking in romantic attachment relationships. AB - The present study provides first evidence that attentional breadth responses can be influenced by proximity-distance goals in adult attachment relationships. In a sample of young couples, we measured attachment differences in the breadth of attentional focus in response to attachment-related cues. Results showed that priming with a negative attachment scenario broadens attention when confronted with pictures of the attachment figure in highly avoidant men. In women, we found that attachment anxiety was associated with a more narrow attentional focus on the attachment figure, yet only at an early stage of information processing. We also found that women showed a broader attentional focus around the attachment figure when their partner was more avoidantly attached. This pattern of results reflects the underlying action of attachment strategies and provides insight into the complex and dynamic influence of attachment on attentional processing in a dyadic context. PMID- 23083098 TI - Development of a novel vesicular system using a binary mixture of sorbitan monostearate and polyethylene glycol fatty acid esters for rectal delivery of rutin. AB - Anorectal diseases, such as hemorrhoids, are bothersome benign conditions that warrant special attention. The design of an optimized vesicular system for localized rectal delivery can be a suitable conservative treatment. The feasibility of preparing proniosomes using different types of Gelucires(r), in combination with Span((r)) 60 as binary mixtures of nonionic surfactants, was checked, then the prepared proniosomes using Span 60 or Span 60/Gelucire were compared to conventional niosomes through investigations comprising the following: encapsulation efficiency (EE%); particle-size analysis; transmission electron microscopy; zeta potential (Z), and in vitro release study and ex vivo permeation study using excised rat rectum. All preparations showed satisfactory stability (Z >30 mV), particle size <300 nm with niosomes showing the lowest EE%, and the largest particle size, together with the least amount of drug released or accumulated in the rectal walls. Span 60/Gelucire proniosomes exhibited lower particle size as well as better release and permeation results, compared to Span 60 proniosomes. Span 60/Gelucire 44/14 (2:1) proniosomes attained the highest percentage of drug released (98.39%) and drug deposition in the rectal walls (86.26%) after 8 hours, which therefore seems to be the most suitable formula able to achieve targeted therapeutic efficacy, aiming to improve the patient's quality of life. PMID- 23083099 TI - L-DOPA decarboxylase mRNA expression is associated with tumor stage and size in head and neck squamous cell carcinoma: a retrospective cohort study. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) represents one of the most commonly diagnosed malignancies worldwide. The DDC gene encodes L-DOPA decarboxylase, an enzyme catalyzing the decarboxylation of L-DOPA to dopamine. We have recently shown that DDC mRNA is a significant predictor of patients' prognosis in colorectal adenocarcinoma and prostate cancer. The aim of the current study was to analyze the DDC mRNA expression in HNSCC patients. METHODS: 53 malignant tumors were resected from the larynx, pharynx, tongue, buccal mucosa, parotid glands, and nasal cavity, as well as from 34 adjacent non cancerous tissues of HNSCC patients, and were homogenized. Total RNA was isolated and converted into first-strand cDNA. An ultrasensitive real-time PCR method based on the SYBR Green chemistry was used for DDC mRNA quantification in head and neck tissue specimens. Relative quantification was performed using the comparative Ct (2-ddCt) method. RESULTS: DDC mRNA levels were lower in squamous cell carcinomas (SCCs) of the larynx and tongue than in adjacent non-cancerous tissue specimens. Furthermore, low DDC mRNA expression was noticed in laryngeal and tongue tumors of advanced TNM stage or bigger size, compared to early-stage or smaller tumors, respectively. No statistically significant differences were observed between SCCs resected from pharynx, buccal mucosa, or nasal cavity, and their normal counterparts. CONCLUSION: This is the first study examining the DDC mRNA expression in HNSCC. According to our results, DDC mRNA expression may constitute a potential prognostic biomarker in tongue and/or larynx SCCs, which principally represent the overwhelming majority of HNSCC cases. PMID- 23083100 TI - Computational codon optimization of synthetic gene for protein expression. AB - BACKGROUND: The construction of customized nucleic acid sequences allows us to have greater flexibility in gene design for recombinant protein expression. Among the various parameters considered for such DNA sequence design, individual codon usage (ICU) has been implicated as one of the most crucial factors affecting mRNA translational efficiency. However, previous works have also reported the significant influence of codon pair usage, also known as codon context (CC), on the level of protein expression. RESULTS: In this study, we have developed novel computational procedures for evaluating the relative importance of optimizing ICU and CC for enhancing protein expression. By formulating appropriate mathematical expressions to quantify the ICU and CC fitness of a coding sequence, optimization procedures based on genetic algorithm were employed to maximize its ICU and/or CC fitness. Surprisingly, the in silico validation of the resultant optimized DNA sequences for Escherichia coli, Lactococcus lactis, Pichia pastoris and Saccharomyces cerevisiae suggests that CC is a more relevant design criterion than the commonly considered ICU. CONCLUSIONS: The proposed CC optimization framework can complement and enhance the capabilities of current gene design tools, with potential applications to heterologous protein production and even vaccine development in synthetic biotechnology. PMID- 23083101 TI - In non-transplant patients with multiple myeloma, the pre-treatment level of clonotypic cells predicts event-free survival. AB - BACKGROUND: In multiple myeloma (MM), the immunoglobulin heavy chain VDJ gene rearrangement is a unique clonotypic signature that identifies all members of the myeloma clone independent of morphology or phenotype. Each clonotypic MM cell has only one genomic copy of the rearranged IgH VDJ. METHODS: Pre-treatment bone marrow aspirates from myeloma patients at diagnosis or in relapse were evaluated for the number of clonotypic cells using real time quantitative PCR (RPCR). RPCR measured the level of clonal cells, termed VDJ%, in 139 diagnosis and relapse BM aspirates from MM patients. RESULTS: Patients with a VDJ% below the median had a significantly longer event free survival (EFS) then those with a VDJ% higher than the median (p=0.0077, HR=0.57). Further, although the VDJ% from non-transplant patients predicted EFS (p=0.0093), VDJ% failed to predict outcome after autologous stem cell transplant (p=0.53). CONCLUSIONS: Our results suggest that for non-transplant patients, the tumor burden before treatment, perhaps reflecting cancer stem cell progeny/output, is an indirect measure that may indicate the number of MM cancer stem cells and hence event free survival. PMID- 23083102 TI - Shigella flexneri T3SS effector IpaH4.5 modulates the host inflammatory response via interaction with NF-kappaB p65 protein. AB - Shigella species possess a type III secretion system (T3SS), which is required for human infection and that delivers effector proteins into target host cells. Here, we show that the effector, IpaH4.5 dampens the pro-inflammatory cytokine response. In both the Sereny test and a murine lung infection model, the Shigella DeltaipaH4.5 mutant strain caused more severe inflammatory responses and significantly induced higher pro-inflammatory cytokine levels (MIP-2 and TNF alpha) in the lung homogenates of wild type-infected mice. Moreover, there was a threefold decrease in bacterial colonization of the mutant compared with the WT and DeltaipaH4.5/ipaH4.5-rescued strains. Yeast two-hybrid screening showed that IpaH4.5 specifically interacts with the p65 subunit of NF-kappaB. Ten truncated versions of IpaH4.5 and p65 spanning different regions were constructed and expressed to further map the IpaH binding sites with p65. The results revealed thatthe p65 region spanning amino acids 1-190 of p65 interacted with the IpaH4.5/1-293 N-terminal region. In vitro, IpaH4.5 displayed ubiquitin ligase activity towards ubiquitin and p65. Furthermore, the transcriptional activity of NF-kappaB was shown to be inhibited by IpaH4.5 utilizing a dual-luciferase reporter gene detection system containing NF-kappaB promoter response elements. Thus, we conclude that the IpaH4.5 protein is an E3 ubiquitin ligase capable of directly regulating the host inflammatory response by inhibiting the NF-kappaB signalling pathway. PMID- 23083103 TI - Modified diadenosine tetraphosphates with dual specificity for P2Y1 and P2Y12 are potent antagonists of ADP-induced platelet activation. AB - BACKGROUND: Diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap(4)A), a natural compound stored in platelet dense granules, inhibits ADP-induced platelet aggregation. Ap(4)A inhibits the platelet ADP receptors P2Y(1) and P2Y(12), is a partial agonist of P2Y(12), and is a full agonist of the platelet ATP-gated ion channel P2X1. Modification of the Ap(4)A tetraphosphate backbone enhances inhibition of ADP-induced platelet aggregation. However, the effects of these Ap(4)A analogs on human platelet P2Y(1), P2Y(12) and P2X1 are unclear. OBJECTIVE: To determine the agonist and antagonist activities of diadenosine tetraphosphate analogs towards P2Y(1), P2Y(12), and P2X1. METHODS: We synthesized the following Ap(4)A analogs: P(1),P(4)-dithiotetraphosphate; P(2),P(3) chloromethylenetetraphosphate; P(1)-thio-P(2),P(3)-chloromethylenetetraphosphate; and P(1),P(4)-dithio-P(2),P(3)-chloromethylenetetraphosphate. We then measured the effects of these analogs on: (i) ADP-induced platelet aggregation; (ii) P2Y(1)-mediated changes in cytosolic Ca(2+); (iii) P2Y(12)-mediated changes in vasodilator-stimulated phosphoprotein phosphorylation; and (iv) P2X1-mediated entry of extracellular Ca(2+). RESULTS: Ap(4)A analogs with modifications in the phosphate backbone inhibited both P2Y(1) and P2Y(12), and showed no agonist activity towards these receptors. The dithio modification increased inhibition of P2Y(1), P2Y(12), and platelet aggregation, whereas the chloromethylene modification increased inhibition of P2Y(12) and platelet aggregation, but decreased P2Y(1) inhibition. Combining the dithio and chloromethylene modifications increased P2Y(1) and P2Y(12) inhibition. As compared with Ap(4)A, each modification decreased agonist activity towards P2X1, and the dual modification completely eliminated P2X1 agonist activity. CONCLUSIONS: As compared with Ap(4)A, tetraphosphate backbone analogs of Ap(4)A have diminished activity towards P2X1 but inhibit both P2Y(1) and P2Y(12) and, with greater potency, inhibit ADP-induced platelet aggregation. Thus, diadenosine tetraphosphate analogs with dual receptor selectivity may have potential as antiplatelet drugs. PMID- 23083104 TI - Fabrication of electrospun poly (lactide-co-glycolide)-fibrin multiscale scaffold for myocardial regeneration in vitro. AB - Myocardial tissue engineering is one of the most promising treatment strategies to restore heart function after a massive heart attack. The biomaterials, cells, and scaffold design play important roles in engineering of heart tissue. In this study, we have developed a fibrin-based multiscale electrospun composite scaffold for myocardial regeneration. Fibrin is the natural wound-healing matrix having angiogenic potential and comprehensively used for tissue engineering applications. It provides a natural environment for cell attachment, migration, and proliferation. Morphological, chemical, and mechanical characterization of the scaffolds was done by scanning electron microscopy, fibrin-specific phosphotungstic acid hematoxylin staining, and mechanical testing. The fiber diameters of fibrin nanofibers range from 50 to 300 nm and that of poly (lactide co-glycolide) microfibers range from 2 to 4 MUm, which mimics the structural hierarchy of native myocardial tissue. Our results indicate that this scaffold enhances the differentiation of mesenchymal stem cells into cardiomyocytes. The cardiac phenotype of the cells was confirmed by the presence of cardiac-specific proteins like alpha-sarcomeric actinin, troponin, tropomyosin, desmin, and atrial natriuretic peptide Estimation of D-Dimer in the culture supernatant for 2 weeks and analysis of scaffold for 3 weeks of in vitro culture of cardiomyocytes indicated the degradation of fibrin and presence of newly synthesized collagen respectively. Our results demonstrate the promising potential of this scaffold for myocardial tissue engineering applications. PMID- 23083105 TI - Clear association between serum levels of adipokines and T-helper 17-related cytokines in patients with psoriasis. AB - BACKGROUND: Psoriasis represents one of the T-helper (Th)17-mediated autoimmune diseases, and has been shown to be associated with metabolic syndrome (MetS). It has been reported that some adipokines and Th17-related cytokines are altered in patients with psoriasis. AIM: To examine the relationship between levels of adipokines and Th17-related cytokines in the serum of patients with psoriasis compared with healthy controls. METHODS: We enrolled 30 patients with psoriasis and 30 normal controls in the study, and used ELISA to measure serum adipokines and Th17-related cytokines. The association between each adipokine and each cytokine was determined using Pearson correlation analysis. Multiple regression analysis using all adipokines and Th17-related cytokines as covariates was also performed. RESULTS: Pearson correlation analysis showed a strong positive association between chemerin and resistin levels and between adiponectin and high molecular weight adiponectin in normal controls. By contrast, in patients with psoriasis, resistin levels were significantly positively associated with tumour necrosis factor-alpha, while there was a strong negative association between retinol binding protein-4 and interleukin (IL)-6 levels. Interestingly, a marked positive correlation between IL-22 and adiponectin was also found in patients with psoriasis. Leptin levels correlated positively with IL-6 in patients with psoriasis, but this did not reach significance. The correlations identified by the multiple regression analyses were almost identical to those from the Pearson analyses. CONCLUSIONS: These data suggest that distinct interaction between adipokines and Th17 cytokines is involved in the pathogenesis of psoriasis. PMID- 23083106 TI - On the hybrid glassy carbon electrode/OligoThiophene/Ag(NP) interface. AB - GC/OligoThiophene/Ag(NP) hybrid interfaces are synthesized and characterized: GC is the glassy carbon surface; OligoThiophene stands for both an ultrathin bithiophene grafted film and a 4-Br-Bithiophene grafted polymer; Ag(NP) stands for silver nanoparticles. The hybrid interface preparation involves different steps: first, the electrode surface is functionalized through a combination of electrochemically assisted grafting (under reduction regime) and polymerization (under oxidation regime); then, silver nanoparticles are chemisorbed by dipping. In particular, an ultrathin film of grafted bithiophene can be obtained by applying one cyclic voltammetry reduction cycle (GC/BT surface), while subsequent cyclic voltammetry cycling under oxidation regime yields an immobilized 4Br Bithiophene polymer (GC/4BrBT surface). AFM and TEM images were recorded to investigate the morphology and chemical composition of the Ag(NP). Fe(II)/Fe(III) cyclic voltammetry, Zn underpotential deposition (UPD), XPS, LA-ICP-MS, and Raman techniques were exploited to characterize both the GC/OligoThiophene and GC/OligoThiophene/Ag(NP) interfaces. Theoretical calculation, at the B3LYP/6 311G** level of the theory, enabled rationalization of the electroreduction mechanism and the Raman results. PMID- 23083107 TI - mFISH analysis of chromosome aberrations induced in vitro by alpha-particle radiation: examination of dose-response relationships. AB - A multicolored FISH (mFISH) technique was used to characterize the cytogenetic damage associated with exposure to alpha-particle radiation with particular emphasis on the quality and quantity that is likely to be transmitted through cell division to descendant cells. Peripheral blood lymphocytes were irradiated in vitro with (238)Pu alpha particles with a range of mean doses up to 936 mGy and were cultured for 47 h. The dose responses for total aberrant cells, stable and unstable cells, and cells with one simple chromosome aberration and multiple chromosome aberrations were predominantly linear for doses that resulted in cell nuclei receiving a single alpha-particle traversal. However, there was a decrease per unit dose in aberrant cells of all types at higher doses because of cells increasingly receiving multiple traversals. The proportion of radiation-induced aberrant cells containing multiple aberrations ranged from 48 to 74% with little evidence of dose dependency. Ninety-one percent of all cells with multiple aberrations were classified as unstable. Resolving the chromosome rearrangements into simple categories resulted in a linear dose response for dicentrics of 24.9 +/- 3.3 * 10(-2) per Gy. The predominant aberration in stable transmissible cells was a single translocation with a dose response for predominantly single hit cell nuclei of 4.1 +/- 1.3 * 10(-2) per Gy. Thus, translocations are the most likely aberration to be observed in peripheral blood lymphocytes from individuals with incorporated alpha-emitting radionuclides resulting in long-term chronic exposure. PMID- 23083108 TI - Determination of pore sizes and relative porosity in porous nanoshell architectures using dextran retention with single monomer resolution and proton permeation. AB - Unilamellar phospholipid vesicles prepared using the polymerizable lipid bis sorbylphosphatidylcholine (bis-SorbPC) yield three-dimensional nanoarchitectures that are highly permeable to small molecules. The resulting porous phospholipid nanoshells (PPNs) are potentially useful for a range of biomedical applications including nanosensors and nanodelivery vehicles for cellular assays and manipulations. The uniformity and size distribution of the pores, key properties for sensor design and utilization, have not previously been reported. Fluorophore assisted carbohydrate electrophoresis (FACE) was utilized to assess the nominal molecular weight cutoff limit (NMCL) of the PPN via analysis of retained dextran with single monomer resolution. The NMCL of PPNs prepared from pure bis-SorbPC was equivalent to a 1800 Da linear dextran, corresponding to a maximum pore diameter of 2.6 nm. Further investigation of PPNs prepared using binary mixtures of bis-SorbPC and dioleoylphosphatidylcholine (DOPC) revealed a similar NMCL when the bis-SorbPC content exceeded 30 mol %, whereas different size-dependent permeation was observed below this composition. Below 30 mol % bis-SorbPC, dextran retention provided insufficient mass resolution (162 Da) to observe porosity on the experimental time scale; however, proton permeability showed a marked enhancement for bis-SorbPC >= 10 mol %. Combined, these data suggest that the NMCL for native pores in bis-SorbPC PPNs results from an inherent property within the lipid assembly that can be partially disrupted by dilution of bis SorbPC below a critical value for domain formation. Additionally, the analytical method described herein should prove useful for the challenging task of elucidating porosity in a range of three-dimensional nanomaterials. PMID- 23083109 TI - NRTI backbone in HIV treatment: will it remain relevant? AB - Nucleoside reverse transcriptase inhibitors (NRTIs) remain a critical component of therapy for HIV-infected patients. The drugs are effective, relatively inexpensive and an important component of antiretroviral therapy (ART), particularly in areas where the introduction of effective therapy has been delayed. They are an essential part of initial therapy for HIV and for prevention of mother-to-child transmission; however, toxicities and resistance may limit their use. The role for pre-exposure prophylaxis (PrEP) to reduce sexual transmission of HIV is still undefined, but this use may have a significant impact on NRTI resistance worldwide, most particularly in areas where subtype C predominates. With increasing prevalence of resistant HIV, the approval of new agents that are effective against resistant virus, and those that use novel cellular targets, are essential. Large studies are now in progress examining the safety and efficacy of NRTI-sparing regimens, but results are not currently available. NRTIs may lose relevance in the not distant future unless steps are put in place to reduce the development and spread of NRTI-resistant viruses, and new NRTIs with minimal toxicity are developed that have a novel resistance profile. This article describes the principal NRTIs, their mechanism of action, and resistance and selected toxicities of the class and of the individual drugs. PMID- 23083112 TI - Linaclotide: first global approval. AB - Linaclotide is a once-daily, orally administered, first-in-class agonist of guanylate cyclase-C that is minimally absorbed. It is being developed to treat gastrointestinal disorders by Ironwood Pharmaceuticals and its partners, Forest Laboratories (North America), Almirall (Europe) and Astellas Pharma (Asia Pacific). Linaclotide has received its first global approval in the US for the treatment of constipation-predominant irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC), and a marketing submission has been filed in the EU for IBS-C. This article summarizes the milestones in the development of linaclotide leading to this first approval for IBS-C and CIC. This profile has been extracted and modified from the Adis R&D Insight drug pipeline database. Adis R&D Insight tracks drug development worldwide through the entire development process, from discovery, through pre-clinical and clinical studies to market launch. PMID- 23083111 TI - Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections. AB - Intravenous micafungin (Mycamine(r); Fungard(r)), an echinocandin, is approved in the EU for the treatment of adult (aged >= 16 years) and paediatric patients with invasive candidiasis and for the treatment of adult patients with oesophageal candidiasis. It is also approved in the EU as prophylactic treatment to prevent Candida infections in adult and paediatric patients undergoing haematopoietic stem cell transplant (HSCT) or patients who are expected to have neutropenia for >= 10 days. This article reviews the therapeutic use of micafungin for the treatment and prophylaxis of Candida infections in adult and paediatric patients, focusing on approved indications in Europe, and briefly discusses the pharmacology of the drug. Micafungin shows very good in vitro activity against clinically relevant isolates of Candida spp., with a low propensity to be associated with the emergence of resistant isolates. The drug has a convenient once-daily dosage regimen and is associated with relatively few drug-drug interactions. In large, multinational trials in adult and/or paediatric patients with invasive candidiasis, micafungin was noninferior to intravenous caspofungin or liposomal amphotericin B. In similarly designed trials in adult patients with oesophageal candidiasis, treatment with micafungin was noninferior to that with intravenous fluconazole or caspofungin. As prophylactic treatment in adult and paediatric patients who had undergone HSCT, micafungin was superior to fluconazole therapy and noninferior to oral itraconazole in large, multicentre trials. Micafungin was generally well tolerated by participants in these clinical trials, given the severe morbidity of the underlying conditions of patients, with a similar tolerability profile to caspofungin and, in general, to fluconazole. It was better tolerated than liposomal amphotericin B or oral itraconazole. Thus, micafungin is a valuable first-line or alternative option to other antifungal agents for the management of candidaemia and invasive candidiasis in adult and paediatric patients, including neonates, and as prophylaxis against fungal infections in patients undergoing HSCT. PMID- 23083114 TI - Effects of meloxicam and phenylbutazone on equine gastric mucosal permeability. AB - BACKGROUND: Newer NSAIDs that more selectively target the induced isoform of the cyclooxygenase enzyme (COX2) activity might reduce adverse effects while preserving therapeutic benefits of these drugs. OBJECTIVES: To compare the effect of oral administration of multiple dose rates of meloxicam and phenylbutazone (PBZ) on gastric mucosal integrity in horses. ANIMALS: Twenty-five light breed horses. METHODS: In vivo toxicity study. Horses were randomly assigned to 5 treatment groups, receiving placebo, PBZ (4.4 mg/kg PO q12h day 1, 2.2 mg/kg PO q12h for 4 days, 2.2 mg/kg PO q24h for 9 days), or 3 dose rates of meloxicam (0.6 mg/kg q24h, 1.8 mg/kg q24h, 3.0 mg/kg q24h) for 14 days. Sucrose permeability testing was performed on Day 0 (before treatment) and on Day 13. All personnel involved with data collection or analysis were blinded to treatment. RESULTS: Administration of PBZ at the above dose rate significantly increased gastric permeability to sucrose, evidenced by increased peak serum sucrose concentrations (280-1,580 pg/MUL, P = .001) after treatment. Similar changes were not evident after administration of meloxicam at any dose rate tested, or in control horses (P > .05). Treatment was not associated with significant differences in ulceration of the squamous or glandular mucosa. Peak sucrose concentrations were not correlated with serum total protein or albumin concentrations (R(2) = -0.07, P = .61, R(2) = -0.08, P = .58, respectively). CONCLUSION AND CLINICAL IMPORTANCE: These results suggest that PBZ was associated with greater compromise to gastric mucosal integrity than meloxicam. PMID- 23083110 TI - The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. AB - Our knowledge of the mechanisms of platelet-mediated thrombosis has increased dramatically over the last 40 years. This increased understanding has identified treatment strategies for acute coronary syndromes (ACS) by targeting key mediators of platelet activation and aggregation processes. Aspirin (acetylsalicylic acid) monotherapy improves patient outcomes by irreversibly inhibiting the cyclooxygenase (COX)-1 enzyme in the arachidonic acid pathway. The later-developed thienopyridines, prodrugs that irreversibly inhibit the P2Y(12) receptor, and therefore adenosine diphosphate (ADP) binding, further enhance platelet inhibition and patient outcomes. The thienopyridine clopidogrel has been the standard of care, but it is limited by variable response and treatment failure. A more potent thienopyridine, prasugrel, requires fewer hepatic metabolic steps for activation, and elicits significantly improved outcomes for patients with ACS. The increased potency of prasugrel is associated with an increase in Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding compared with clopidogrel. Ticagrelor represents a new chemical class of agents called the cyclopentyltriazolopyrimidines. It interacts reversibly with the platelet P2Y(12) receptor, and does not require metabolic bioactivation for activity. Data show a significant improvement in ischaemic outcomes, including mortality, for ticagrelor compared with clopidogrel, without an increase in overall major bleeding, although non-coronary artery bypass graft bleeding is increased. Glycoprotein IIb/IIIa targeted agents (abciximab, tirofiban and eptifibatide) are also used in ACS patients undergoing percutaneous coronary interventions. These inhibitors utilize a different mechanism of action by preventing fibrinogen-mediated platelet aggregation. Other therapeutic strategies for platelet inhibition are being evaluated, including the investigative protease activated receptor (PAR)-1 and thromboxane A(2) antagonists. This review highlights the mechanisms of action of these agents, and the continuing evolution of ACS therapy. PMID- 23083116 TI - 6-chloro-7-methyl-3', 4'-dimethoxyflavone - a potent selective COX-2 inhibitor. AB - Some unnatural chalcones (1a-q) and flavones (2a-d) have been synthesized and evaluated for their antiinflammatory activity using carrageenan-induced rat paw edema assay. The flavone 2c (6-Chloro-7-methyl-3', 4'- dimethoxyflavone) had higher anti-inflammatory activity and superior gastrointestinal safety profiles than the reference drug celecoxib. Compound 2c showed almost two times better selective inhibitory activity towards COX-2 enzyme than celecoxib. 2' Hydroxychalcones (1a-h) showed moderate to strong anti-inflammatory activity (38.6-82.4 % at 3h and 52.4-80.2 % at 5h). Among 2'-methoxychalcones (1i-q) 1k and 1q exhibited maximum activity 82.6% (at 3h) and 84.3% (at 5h) respectively. PMID- 23083115 TI - Type I collagen D-spacing in fibril bundles of dermis, tendon, and bone: bridging between nano- and micro-level tissue hierarchy. AB - Fibrillar collagens in connective tissues are organized into complex and diverse hierarchical networks. In dermis, bone, and tendon, one common phenomenon at the micrometer scale is the organization of fibrils into bundles. Previously, we have reported that collagen fibrils in these tissues exhibit a 10 nm width distribution of D-spacing values. This study expands the observation to a higher hierarchical level by examining fibril D-spacing distribution in relation to the bundle organization. We used atomic force microscopy imaging and two-dimensional fast Fourier transform analysis to investigate dermis, tendon, and bone tissues. We found that, in each tissue type, collagen fibril D-spacings within a single bundle were nearly identical and frequently differ by less than 1 nm. The full 10 nm range in D-spacing values arises from different values found in different bundles. The similarity in D-spacing was observed to persist for up to 40 MUm in bundle length and width. A nested mixed model analysis of variance examining 107 bundles and 1710 fibrils from dermis, tendon, and bone indicated that fibril D spacing differences arise primarily at the bundle level (~76%), independent of species or tissue types. PMID- 23083117 TI - Synthesis and biological activity of 28-amide derivatives of 23-hydroxy betulinic Acid as antitumor agent candidates. AB - Based on the structure of 23-hydroxybetulinic acid (1), a series of 28-amide derivatives were synthesized. Biological evaluation in vitro for their antitumor activities against five cell lines (A549, BEL-7402, SF-763, B16 and HL-60) has indicated that compound 6g possesses the most effective antitumor activity with an IC50 value of 10.47 MUM when treated with HL-60 cells. In vivo testing has also shown a comparable activity of 6g to cyclophosphamide against H22 liver tumor in mice and 5-fluorouracil against B16 melanoma, respectively. PMID- 23083118 TI - Design, synthesis and biological evaluation of novel imidazolone derivatives as dipeptidyl peptidase 4 inhibitors. AB - A series of novel imidazolone derivatives were designed and synthesized via a rational drug design strategy. These compounds were obtained from 3-substituted imidazolidine-2,4-dione through alkylation, formylation, dehydration, and amination. The structures were characterized by (1)H NMR, (13)C NMR, and MS. All target compounds were screened for their DPP-4 inhibitory activity in vitro. The results revealed that some imidazolone derivatives showed potent DPP-4 inhibition. Compound 5b had an IC50 value of 2.21 uM inhibitory activity against DPP-4. As a promising lead compound, compound 5b with DPP-4 binding mode was further studied by docking analysis. The expected interaction mode was obtained. PMID- 23083119 TI - Novel tetrahydropyrido[1,2-a]isoindolone derivatives (valmerins): potent cyclin dependent kinase/glycogen synthase kinase 3 inhibitors with antiproliferative activities and antitumor effects in human tumor xenografts. AB - The development of CDK and GSK3 inhibitors has been regarded as a potential therapeutic approach, and a substantial number of diverse structures have been reported to inhibit CDKs and GSK-3beta in recent years. Only a few molecules have gone through or are currently undergoing clinical trials as CDK and GSK inhibitors. In this paper, we prepared valmerins, a new family containing the tetrahydropyrido[1,2-a]isoindone core. The fused heterocycle was prepared with a straightforward synthesis that was functionalized by a (het)arylurea. Twelve valmerins inhibited the CDK5 and GSK3 with an IC(50) < 100 nM. A semiquantitative kinase scoring was realized, and a cellular screening was done. At the end of our study, we investigated the in vivo potency of one valmerin. Mice exhibited good tolerance to our lead, which proved its efficacy and clearly blocked tumor growth. Valmerins appear also as good candidates for further development as anticancer agents. PMID- 23083120 TI - The impact of congenital cardiovascular malformations on the assessment and surgical management of infants with cleft lip and/or palate. AB - OBJECTIVE: The purpose of this study was to assess the cardiac evaluation of cleft lip and/or palate patients, characterize their cardiovascular malformations, and determine the impact of cardiovascular malformations on surgical management. DESIGN: A single-institution retrospective study of 329 consecutive cleft patients was performed. Cardiovascular malformations were categorized according to involvement of cardiac septa, vasculature, and valves. Their impact on the need for cardiac surgery, timing of cleft repair, need for subacute bacterial endocarditis (SBE) prophylaxis, and the perioperative experience was evaluated. RESULTS: Ten percent (33/329) of cleft patients had a cardiovascular malformation, and 3% underwent cardiac surgery prior to cleft repair. Malformations of the septa, vasculature, and valves were present in 9%, 6%, and 2% of cleft infants, respectively. Murmur as a sign of structural cardiovascular disease was 79% sensitive and 97% specific. Cleft palate repair was delayed by 2 months in patients with a cardiovascular malformation (P = .001). Subacute bacterial endocarditis prophylaxis was recommended, not recommended, or not specified by cardiology in 18%, 33%, and 48% of cleft patients with a cardiovascular malformation, respectively. Postoperative stay and surgical complications were not associated with cardiovascular malformation. CONCLUSIONS: Even in the absence of a murmur, echocardiographic screening should be considered in infants with nonspecific signs of cardiovascular disease. Greater awareness of the guidelines for SBE prophylaxis is needed. Most cleft patients with a cardiovascular malformation do not require cardiac surgery and do not experience an increased rate of complications associated with cleft surgery. PMID- 23083121 TI - Perioperative risk factors for adverse airway events in patients undergoing cleft palate repair. AB - Objective : To establish the incidence of perioperative airway complications in a large series of pediatric patients undergoing palatoplasty and to identify which specific patient, procedural, and provider factors are associated with increased risk for perioperative adverse airway events (AAEs). Design : Retrospective chart review. Setting : Tertiary pediatric hospital. Patients : Included were 300 patients who underwent primary cleft palate repair using the modified Furlow technique between 2008 and 2011. Patients were 2 years or younger at the time of the operation. Main Outcome Measure(s) : Charts were reviewed for perioperative AAEs, which were defined as postoperative airway obstruction, oxyhemoglobin saturation <=85% for >=45 seconds, bronchospasm, laryngospasm, reintubation, and unplanned admission to the intensive care unit. Patient specific factors (diagnosis of a craniofacial syndrome, Veau cleft type, preoperative pulmonary and airway history), procedural factors (operative time, anesthesia time, opioid dose, administration and reversal of neuromuscular blockers), and provider factors (experience, number of providers), were documented, and associations with AAEs were investigated. Results : AAEs occurred in 23% of patients overall and were significantly more common in syndromic patients (P = .003), patients with jaw or tracheal anomalies (P = .001), and patients with a history of difficult airway (P = .001). Other significant factors included prior history of difficult intubation (P = .05), surgeon (P = .02) and anesthesiologist experience (P = .05), and operative time (P = .02). Conclusions : Diagnosis of a craniofacial syndrome, a history of preoperative airway problems, and provider inexperience correlated with increased risk for airway complications after palatoplasty. Recognizing patients at risk for AAEs may permit improved preoperative planning to optimize surgical outcomes and minimize complications. PMID- 23083122 TI - Adenovirus signalling in entry. AB - Viruses carry nucleic acids between and within host cells. Invariably, virus attachment to host cells leads to activation of cell signalling. These so-called forward signals emerge from interactions with cell surface receptors or cytosolic proteins and elicit profound responses in the cells, for example induction of growth or innate immunity responses. They can enhance or suppress infection. In addition, viruses receive signals from the cell. These reverse signals can impact on the structure of the virus leading to genome uncoating. They can enhance infection or inactivate virus, for example by facilitating degradation. Here we discuss the nature and mechanisms by which forward and reverse signals emerge and affect the outcome of human adenovirus infections. We describe how human adenoviruses use cell surface receptors for forward signalling to activate cell growth, intracellular transport or innate immune response. We also discuss how adenoviruses use acto-myosin, integrins or microtubule-based kinesin motors for reverse signalling to facilitate their stepwise uncoating programme. PMID- 23083123 TI - The hyperfibrinolytic state of mice with combined thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 gene deficiency is critically dependent on TAFI deficiency. AB - BACKGROUND: Mice with single gene deficiency of thrombin-activatable fibrinolysis inhibitor (TAFI) or plasminogen activator inhibitor-1 (PAI-1) have an enhanced fibrinolytic capacity. OBJECTIVES: To unravel the function and relevance of both antifibrinolytic proteins through the generation and characterization of mice with combined TAFI and PAI-1 gene deficiency. RESULTS: Mating of TAFI knockout (KO) mice with PAI-1 KO mice resulted in the production of TAFI/PAI-1 double-KO mice that were viable, were fertile, and developed normally. In a tail vein bleeding model, the bleeding time and hemoglobin content of the TAFI/PAI-1 double KO mice did not deviate significantly from those of the single-KO mice or of the wild-type (WT) counterparts. Interestingly, in ex vivo rotational thromboelastometry measurements with whole blood samples, TAFI KO mice and TAFI/PAI-1 double-KO mice were more sensitive to fibrinolytic activation with tissue-type plasminogen activator than WT or PAI-1 KO mice. This enhanced fibrinolytic capacity was confirmed in vivo in a mouse thromboembolism model, as shown by decreased fibrin deposition in the lungs of TAFI KO mice and TAFI/PAI-1 double-KO mice as compared with WT or PAI-1 KO mice. CONCLUSIONS: TAFI gene inactivation predominantly contributes to the increased fibrinolytic capacity of TAFI and PAI-1 double-gene-deficient mice, as observed in some basic thrombosis models. PMID- 23083125 TI - "The logic of care" - parents' perceptions of the educational process when a child is newly diagnosed with type 1 diabetes. AB - BACKGROUND: The number of new cases of type 1 diabetes mellitus (T1DM) has increased substantially in recent years and it is now one of the most common long term endocrine disorders in childhood. In Sweden the child and family are hospitalised in accordance with the national guidelines for one to two weeks at diagnosis. The purpose of this study was to describe parents' perceptions of the educational process when their child is newly diagnosed with T1DM. METHODS: Qualitative interviews were performed in the south western part of Sweden with ten mothers and eight fathers of children, diagnosed with T1DM, at three to six months after they had received the diagnosis. The interviews were analysed using deductive content analysis and Mol's philosophical theory. RESULTS: The results show that almost all parents had experienced the educational process as being satisfactory. However, most parents felt that the teaching needed to be adapted to the individual families and to help them to learn to live with diabetes in their everyday lives. Rather than merely teaching according to a fixed schedule and cramming knowledge, the education should be parent-centered and provide time for grief and shock. There should also be a greater emphasis on why certain things should be done rather than on what should be done. The routines learned at the hospital made the efforts to be good parents managing the child's disease, and continuing to lead a normal family life, a difficult task. CONCLUSIONS: In order to optimize the educational process for families with children newly diagnosed with T1DM an increased focus on the families' perceptions might be helpful in that this could lead to further revelations of the educational process thus making it more understandable for the family members involved. PMID- 23083126 TI - A novel KIT frame-shift mutation in a large Chinese family with variably severe phenotypes of piebaldism. PMID- 23083124 TI - Activation and desensitization of TRPV1 channels in sensory neurons by the PPARalpha agonist palmitoylethanolamide. AB - BACKGROUND AND PURPOSE: Palmitoylethanolamide (PEA) is an endogenous fatty acid amide displaying anti-inflammatory and analgesic actions. To investigate the molecular mechanism responsible for these effects, the ability of PEA and of pain inducing stimuli such as capsaicin (CAP) or bradykinin (BK) to influence intracellular calcium concentrations ([Ca2+](i)) in peripheral sensory neurons, has been assessed in the present study. The potential involvement of the transcription factor PPARalpha and of TRPV1 channels in PEA-induced effects was also studied. EXPERIMENTAL APPROACH: [Ca2+](i) was evaluated by single-cell microfluorimetry in differentiated F11 cells. Activation of TRPV1 channels was assessed by imaging and patch-clamp techniques in CHO cells transiently transfected with rat TRPV1 cDNA. KEY RESULTS: In F11 cells, PEA (1-30 MUM) dose dependently increased [Ca2+](i). The TRPV1 antagonists capsazepine (1 MUM) and SB 366791 (1 MUM), as well as the PPARalpha antagonist GW-6471 (10 MUM), inhibited PEA-induced [Ca2+](i) increase; blockers of cannabinoid receptors were ineffective. PEA activated TRPV1 channels heterologously expressed in CHO cells; this effect appeared to be mediated at least in part by PPARalpha. When compared with CAP, PEA showed similar potency and lower efficacy, and caused stronger TRPV1 currents desensitization. Sub-effective PEA concentrations, closer to those found in vivo, counteracted CAP- and BK-induced [Ca2+](i) transients, as well as CAP-induced TRPV1 activation. CONCLUSIONS AND IMPLICATIONS: Activation of PPARalpha and TRPV1 channels, rather than of cannabinoid receptors, largely mediate PEA-induced [Ca2+](i) transients in sensory neurons. Differential TRPV1 activation and desensitization by CAP and PEA might contribute to their distinct pharmacological profile, possibly translating into potentially relevant clinical differences. PMID- 23083127 TI - Characterization of PVL/ACME-positive methicillin-resistant Staphylococcus aureus (genotypes ST8-MRSA-IV and ST5-MRSA-II) isolated from a university hospital in Japan. AB - The ST8 methicillin-resistant Staphylococcus aureus (MRSA) with Staphylococcal cassette chromosome mec (SCCmec) type IVa, known as USA300, is a prevalent community-acquired MRSA (CA-MRSA) clone in the United States and has been spreading worldwide. The USA300 characteristically harbors Panton-Valentine Leukocidin (PVL) genes and the arginine catabolic mobile element (ACME, type I). Prevalence and molecular characteristics of PVL(+) and/or ACME(+) S. aureus were investigated in a university hospital located in northern Japan, for 1,366 S. aureus isolates, including 601 MRSA strains derived from clinical specimens collected from 2008 to 2010. The PVL gene was identified in three MRSA strains with SCCmec IV, which belonged to ST8, spa type t008, coagulase type III, and agr type I. Two PVL-positive MRSA strains had also type I ACME, and were isolated from skin abscess of outpatients who have not travelled abroad recently. One of these PVL(+)/ACME(+) strains carried tet(K), msrA, and aph(3')-IIIa, showing resistance to kanamycin, tetracycline, erythromycin, and ciprofloxacin, suggesting acquisition of more resistance than ST8 CA-MRSA reported in Japan previously. In contrast, another PVL(+)/ACME(+) strain and a PVL(+)/ACME(-) strain were susceptible to more antimicrobials and had less virulence factors than PVL(-)/ACME(+) MRSA strains. Besides the two PVL(+) MRSA strains, ACME (type DeltaII) was identified into seven MRSA strains with SCCmec II belonging to ST5, one of the three spa types (t002, t067, and t071), coagulase type II, and agr type II. These PVL(-)/ACME(+) MRSA strains showed multiple drug resistance and harbored various toxin genes as observed for ST5 PVL(-)/ACME(-) MRSA-II. The present study suggested the spread of ST8-MRSA-IV in northern Japan, and a potential significance of ACME-positive ST5-MRSA-II as an emerging MRSA clone in a hospital. PMID- 23083128 TI - SMRT-mediated co-shuttling enables export of class IIa HDACs independent of their CaM kinase phosphorylation sites. AB - The Class IIa histone deacetylases (HDAC)4 and HDAC5 play a role in neuronal survival and behavioral adaptation in the CNS. Phosphorylation at 2/3 N-terminal sites promote their nuclear export. We investigated whether non-canonical signaling routes to Class IIa HDAC export exist because of their association with the co-repressor Silencing Mediator Of Retinoic And Thyroid Hormone Receptors (SMRT). We found that, while HDAC5 and HDAC4 mutants lacking their N-terminal phosphorylation sites (HDAC4(MUT), HDAC5(MUT)) are constitutively nuclear, co expression with SMRT renders them exportable by signals that trigger SMRT export, such as synaptic activity, HDAC inhibition, and Brain Derived Neurotrophic Factor (BDNF) signaling. We found that SMRT's repression domain 3 (RD3) is critical for co-shuttling of HDAC5(MUT), consistent with the role for this domain in Class IIa HDAC association. In the context of BDNF signaling, we found that HDAC5(WT), which was more cytoplasmic than HDAC5(MUT), accumulated in the nucleus after BDNF treatment. However, co-expression of SMRT blocked BDNF-induced HDAC5(WT) import in a RD3-dependent manner. In effect, SMRT-mediated HDAC5(WT) export was opposing the BDNF-induced HDAC5 nuclear accumulation observed in SMRT's absence. Thus, SMRT's presence may render Class IIa HDACs exportable by a wider range of signals than those which simply promote direct phosphorylation. PMID- 23083129 TI - Reconstitution and phenotype of Tregs in CMV reactivating patients following allogeneic hematopoietic stem cell transplantation. AB - In experimental and clinical settings Tregs prevent graft-versus-host disease (GvHD) by inhibiting the proliferation and function of conventional T cells (Tconv). The suppressive potency of Tregs might also lead to the inhibition of protective antiviral T cell responses. As the control of CMV reactivation is important to improve the clinical outcome in allogeneic HSCT, we analyzed the Treg reconstitution in CMV reactivating patients with and without GvHD (n=47) in the first 6 months following transplantation. Most importantly, CMV reactivation does not correlate with the numerical reconstitution of CD4(+)CD25(high)CD127(-) Tregs. During CMV reactivation the proportion of Tregs within the CD4(+) T cell population decreased significantly independent of GvHD manifestation. A comprehensive FACS analysis was performed in order to characterize the phenotype of Tregs and Tconv cells in greater detail for activation, co-stimulation, proliferation, suppressive function and migratory capability. Interestingly, Tregs of patients with CMV reactivation showed a significantly higher CXCR3 expression. CD4(+) Tconv cells expressed significantly higher protein levels of the proliferation marker Ki67 correlating with a numerical increase of CD4(+) T cells. Our results indicate that Tregs are not inhibiting pathogen clearance by Tconv following HSCT, which is of high relevance for future Treg cell-based clinical trials in allogeneic HSCT. PMID- 23083130 TI - Post-traumatic pulmonary pseudocyst with hemopneumothorax following blunt chest trauma: a case report. AB - INTRODUCTION: Post-traumatic pulmonary pseudocyst is an uncommon cavitary lesion of the lung and develops after blunt chest trauma and even more rarely following penetrating injuries. It is generally seen in young adults presenting with cough, chest pain, hemoptysis, and dyspnea. Post-traumatic pulmonary pseudocyst should be included in the differential diagnosis of cavitary pulmonary lesions. We describe the case of a 60-year-old Caucasian Greek woman who sustained traumatic pulmonary pseudocyst with hemopneumothorax due to a blunt chest trauma after a traffic accident. CASE PRESENTATION: After a traffic accident, a 60-year-old Caucasian Greek woman sustained a hemopneumothorax due to a blunt chest trauma. There was evidence of an extensive contusion in the posterior and lateral segments of the right lower lobe, a finding that was attributed to an early sign of a cavitation, and the presence of a thin-walled air cavity was detected on the anterior segment of the right lower lobe in the control computed tomography taken 24 hours after admission. Our patient was treated by catheter aspiration, and the findings of computed tomography evaluation about one month later showed complete resolution of one of the two air-filled cavitary lesions. The second pseudocyst also disappeared completely, as shown by the control computed tomography scan performed six months later. CONCLUSIONS: Traumatic pulmonary pseudocyst is a rare complication of blunt chest trauma, and computed tomography is a more valuable imaging technique than chest radiograph for early diagnosis. PMID- 23083131 TI - When are support and opposition not opposites? Depth of processing as a moderator of the valence-framing effect. AB - Prior research has demonstrated the valence-framing effect, in which leading people to frame a preference negatively (e.g., 'I oppose Romney') yields stronger attitudes than does leading people to frame that same preference positively (e.g., 'I support Obama'). Three studies tested whether or not depth of processing (as operationalized by manipulations of motivation and ability to cognitively process) moderate the effect. The valence-framing effect was replicated, such that opposers manifested stronger attitudes than did supporters, but only when attitudes were relevant to the participants (Experiments 1 and 3), and when participants were not under cognitive load (Experiment 2). Our results thus identify depth of processing as an important moderator of the valence framing effect and provide potential insight into the effect's mechanism. PMID- 23083132 TI - The combined use of photoaffinity labeling and surface plasmon resonance-based technology identifies multiple salicylic acid-binding proteins. AB - Salicylic acid (SA) is a small phenolic molecule that not only is the active ingredient in the multi-functional drug aspirin, but also serves as a plant hormone that affects diverse processes during growth, development, responses to abiotic stresses and disease resistance. Although a number of SA-binding proteins (SABPs) have been identified, the underlying mechanisms of action of SA remain largely unknown. Efforts to identify additional SA targets, and thereby elucidate the complex SA signaling network in plants, have been hindered by the lack of effective approaches. Here, we report two sensitive approaches that utilize SA analogs in conjunction with either a photoaffinity labeling technique or surface plasmon resonance-based technology to identify and evaluate candidate SABPs from Arabidopsis. Using these approaches, multiple proteins, including the E2 subunit of alpha-ketoglutarate dehydrogenase and the glutathione S-transferases GSTF2, GSTF8, GSTF10 and GSTF11, were identified as SABPs. Their association with SA was further substantiated by the ability of SA to inhibit their enzymatic activity. The photoaffinity labeling and surface plasmon resonance-based approaches appear to be more sensitive than the traditional approach for identifying plant SABPs using size-exclusion chromatography with radiolabeled SA, as these proteins exhibited little to no SA-binding activity in such an assay. The development of these approaches therefore complements conventional techniques and helps dissect the SA signaling network in plants, and may also help elucidate the mechanisms through which SA acts as a multi-functional drug in mammalian systems. PMID- 23083133 TI - Bone regeneration by transplantation of human mesenchymal stromal cells in a rabbit mandibular distraction osteogenesis model. AB - Ex vivo expanded mesenchymal stromal cells (MSCs) represent a potential cell population for tissue regeneration strategy. Xenogeneic transplantation using human MSCs (hMSCs) can be an approach to reveal what hMSCs guide in bone regeneration with distinguishable gene expression from a host animal. In this study, we investigated the regenerating effect of hMSCs varying injection time point in a rabbit distraction osteogenesis model. Undifferentiated hMSCs (2*10(6) cells) were injected transcutaneously into the osteotomy site of one side of the mandible 1 day before the onset of distraction (Group 1) or after distraction (Group 2). The contralateral side of the mandible, which was subjected to distraction, but no hMSC injection, was used as the control in each group. hMSCs showed lack of major histocompatibility complex class II expression and suppression of xenogeneic lymphocyte proliferation stimulated by a proinflammatory cytokine. A microcomputed tomography-based evaluation showed a significant increase in new bone volume in the distracted callus in Group 1 compared to the contralateral side. Injection of hMSCs increased the bone mineral density (BMD) of the regenerated bone in both Group 1 and 2, although the former had a higher BMD than the latter. hMSCs of Group 1 subjected to distraction after injection expressed insulin-like growth factor-1 (IGF-1) and fibronectin (FN), while the expression of most osteoblast differentiation-related markers and growth factors was negligible. These results demonstrated that hMSCs exerted immune suppressive behavior in rabbit T cells in vitro, and hMSC transplantation into the distracted callus of a rabbit model provided osteogenic benefits that were more pronounced when the hMSCs were injected just before distraction than at the end of distraction. The beneficial effect of hMSCs might be mediated, partly by the expression of matrix proteins or IGF-1, which are known to favor bone formation. PMID- 23083135 TI - A scaly plaque on the left buttock. PMID- 23083134 TI - Epidermal growth factor (EGF) and interleukin (IL)-1beta synergistically promote ERK1/2-mediated invasive breast ductal cancer cell migration and invasion. AB - BACKGROUND: Patients with invasive breast ductal carcinoma (IBDC) with metastasis have a very poor prognosis. Little is known about the synergistic action of growth and inflammatory factors in IBDC metastases. METHODS: The expression of activated extracellular signal-regulated kinase1/2 (phosphorylated or p-ERK1/2) was analyzed by immunohistochemistry in IBDC tissue samples from 80 cases. BT474 IBDC cell migration and invasion were quantified using the Transwell assay. Matrix metalloproteinase (MMP)-9 expression and activity were analyzed by RT-PCR, Western blotting and zymography. Activator protein (AP)-1 activity was measured with a luciferase reporter gene assay. The Wilcoxon signed-rank test, Chi-square test, the partition of Chi-square test, independent t-test, and Spearman's method were used for the statistical analysis. RESULTS: Phosphorylated ERK1/2 was detected in 58/80 (72.5%) IBDC tissues, and was associated with higher TNM stage and lymph node metastasis, but not patient age or tumor size. Individually, epidermal growth factor (EGF), and interleukin (IL)-1beta activated ERK1/2, increased cell migration and invasion, MMP-9 expression and activity, AP-1 activation in vitro and the expression of p-ERK1/2 was positively correlated with EGF expression levels, as well as IL-1beta, MMP-9 and c-fos in IBDC tissue samples. Co-stimulation with EGF and IL-1beta synergistically increased ERK1/2 and AP-1 activation, cell migration and invasion, and MMP-9 expression and activity. Inhibition of ERK1/2 using U0126 or siRNA abolished EGF and/or IL-1beta induced cell migration and invasion in a dose-dependent manner. CONCLUSION: Activated ERK1/2 was associated with higher TNM stage and lymph node metastasis in IBDC. Both in vitro and in vivo studies indicated that ERK-1/2 activation may increase the metastatic ability of IBDC cells. Growth and inflammatory factors synergistically induced IBDC cell migration and invasion via ERK1/2 signaling, AP 1 activation and MMP-9 upregulation. PMID- 23083136 TI - Ganjam virus/Nairobi sheep disease virus induces a pro-inflammatory response in infected sheep. AB - Partly due to climate change, and partly due to changes of human habitat occupation, the impact of tick-borne viruses is increasing. Nairobi sheep disease virus (NSDV) and Ganjam virus (GV) are two names for the same virus, which causes disease in sheep and goats and is currently known to be circulating in India and East Africa. The virus is transmitted by ixodid ticks and causes a severe hemorrhagic disease. We have developed a real-time PCR assay for the virus genome and validated it in a pilot study of the pathogenicity induced by two different isolates of NSDV/GV. One isolate was highly adapted to tissue culture, grew in most cell lines tested, and was essentially apathogenic in sheep. The second isolate appeared to be poorly adapted to cell culture and retained pathogenicity in sheep. The real-time PCR assay for virus easily detected 4 copies or less of the viral genome, and allowed a quantitative measure of the virus in whole blood. Measurement of the changes in cytokine mRNAs showed similar changes to those observed in humans infected by the closely related virus Crimean Congo hemorrhagic fever virus. PMID- 23083137 TI - Thermodynamic characterization of polypeptide complex coacervation. AB - The interactions between a series of oppositely charged polypeptide pairs are probed using isothermal titration calorimetry (ITC) in combination with turbidity measurements and optical microscopy. Polypeptide complex coacervation is described as a sequence of two distinct binding steps using an empirical extension of a simple ITC binding model. The first step consists of the formation of soluble complexes from oppositely charged polypeptides (ion pairing), which in turn aggregate into insoluble interpolymer complexes in the second step (complex coacervation). Polypeptides have identical backbones and differ only in their charged side groups, making them attractive model systems for this work. The poly(l-ornithine hydrobromide) (PO)/poly(l-glutamic acid sodium salt) (PGlu) system is used to examine the effects of parameters such as the salt concentration, pH, temperature, degree of polymerization, and total polymer concentration on the thermodynamic characteristics of complexation. Complex coacervation in all probed systems is found to be endothermic, essentially an entropy-driven processes. Increasing the screening effect of the salt on the polyelectrolyte charges diminishes their propensity to interact, leading to a decrease in the observed energy change and coacervate quantity. The pH plays an important role in complex formation through its effect on the degree of ionization of the functional groups. Plotting the change in enthalpy with temperature allows the calculation of the heat capacity change (DeltaC(p)) for the PO/PGlu interactions. Finally, ITC revealed that complex coacervation is promoted when higher total polymer concentrations or polypeptide chain lengths are used. PMID- 23083138 TI - Ability to pay and impoverishment among women who give birth at a University Hospital in Kathmandu, Nepal. AB - Pregnant women giving birth in Nepal need to use out-of-pocket payment for delivery care services due to a lack of insurance policies. The objective of this study was to examine the ability of pregnant Nepalese women to pay for delivery care services and the effects of the current household health expenditure on impoverishment due to hospital-based delivery services, especially normal delivery (ND) and caesarean section (CS). A cross-sectional study was conducted from May to August 2009 at Tribhuvan University Teaching Hospital. Ability to pay was defined as the current health spending being less than 5% of annual household income. Poverty occurred when a household's per capita income fell to less than US$1 per day. Impoverishment was considered as poverty headcount and normalised poverty gap. On average, the percentage of annual household income spent on current delivery care was 5.9% in the ND group and 9.7% in the CS group. The CS group had a stronger impoverishment effect resulting in a high per cent change of payment-induced poverty headcount by 78.1% and poverty gap by 97.3% compared to 7.7 and 24.1% in the ND group, respectively. There is a strong need to develop a well-prepared financial system to prevent the issue of poverty and impoverishment. PMID- 23083139 TI - Moderate acne as a potential barrier to social relationships: myth or reality? AB - Acne vulgaris is a skin disease affecting many young people and, if it continues into their twenties, can be a substantial barrier to social relationships. Although there is evidence that sufferers are adversely psychologically affected, what is less apparent from research to date is whether this is because of negative self-beliefs or the discriminatory attitudes of others. This study set out to explore how far young people with moderate acne are viewed less favourably compared to their clear-skinned peers. The design was quasi-experimental. The faces of two male and two female 21-year-old volunteers with clear skin were photographed and then photographed again after having had facial signs of moderate acne simulated by a professional make-up artist. Photographs of a male and female face were given to 143 participants who were divided randomly into two conditions: "Clear" and "acne". The former were shown the unblemished faces and the latter were given the faces with acne. The participants were asked to estimate the age of the person in the photograph and then rate the volunteer on a scale of 16 personality items. It was found that the participants in the "clear" condition estimated the volunteers as two years older and more mature than in the "acne" condition. In terms of personality, the photographs in the "clear" condition were given higher scores for potential friendship, attractiveness and overall positive personality features than the photographs in the "acne" condition. The conclusion is that moderate acne vulgaris could be a potential barrier to social relationships for young people not simply because of their social anxiety but because they may well be meeting with prejudice. It is suggested that attitudes might be changed by more accurate information about the condition. PMID- 23083140 TI - Communication: Quantitative estimate of the water surface pH using heterodyne detected electronic sum frequency generation. AB - Most chemical reactions in water are very sensitive to pH. Many environmentally important chemical reactions are known to take place at the water surface (i.e., air/water interface). However, the pH of the water surface is still controversial. Spectroscopic experiments and theoretical calculations indicate that the water surface is more acidic than the bulk, whereas electrophoretic experiments provide a contrary view. Here, we report that a novel nonlinear optical experiment with a surface-active pH indicator can quantitatively evaluate the pH of the water surface. The result clearly shows that the pH of the water surface is lower than that of the bulk by 1.7. This is the first study to apply a principle of bulk pH measurements to the water surface, and therefore provides a reliable experimental estimate for the pH difference between the water surface and bulk. It is considered that the higher acidity of the water surface plays a key role in marine and atmospheric chemical reactions. PMID- 23083141 TI - Communication: Imaging the indirect dissociation dynamics of temporary negative ion: N2O- -> N2 + O-. AB - We reported an imaging study of the dissociation dynamics of temporary negative ion N(2)O(-) formed in the low-energy electron attachment, e(-) + N(2)O -> N(2)O( ) -> N(2) + O(-). With the help of ab initio molecular dynamics calculations, the evolution of momentum distributions of the O(-) fragment in terms of the electron attachment energy is identified as the result of a competition between two distinctly different indirect pathways, namely, climbing over and bypassing the energy ridge after the molecular structure bending. These two pathways prefer leaving the N(2) fragment at the high vibrational and rotational states, respectively. PMID- 23083142 TI - Aqueous interaction site integral-equation theory that exactly takes into account intramolecular correlations. AB - We report the development of a formally exact integral equation for the three dimensional hydration structure around molecular solutes of arbitrary complexity. A distinctive feature of our theory--termed aqueous interaction site (AXIS) integral-equation theory--is that it fully takes into account the intramolecular structural correlations of solvent water, which has been missing in the previous integral-equation theories such as the three-dimensional reference interaction site model (3D-RISM) theory. With a simplifying approximation in which the intermolecular bridge function is neglected, an illustrative application of the AXIS theory is made on the equilibrium oxygen and hydrogen distributions of solvent water surrounding a solute water molecule at ambient and supercritical conditions. We demonstrate through a comparison with molecular dynamics simulation results that the inclusion of the exact intramolecular correlations improves upon the 3D-RISM theory in describing the water distribution around molecular solute, in particular near the surface region of the solute molecule, though there still remain quantitative differences from the simulation results. To further improve the quantitative accuracy of the theory, one needs to incorporate the intermolecular bridge function, and a possible formulation for the approximate bridge function is suggested based on the angular decomposition. PMID- 23083143 TI - Time-averaging approximation in the interaction picture: anisotropy of vibrational pump-probe experiments for coupled chromophores with application to liquid water. AB - A time-averaging approximation method developed to efficiently calculate the short-time dynamics of coupled vibrational chromophores using mixed quantum/classical theories is extended in order to be applicable to the study of vibrational dynamics at longer time scales. A quantum mechanical time propagator for long times is decomposed into the product of short-time propagators, and a time-averaging approximation is then applied to each of the latter. Using the extended time-averaging approximation, we calculate the anisotropy decay of the data obtained from impulsive vibrational pump-probe experiments on the OH stretching modes of water, which is in excellent agreement with numerically exact results. PMID- 23083144 TI - Relativistic diffusion Monte Carlo method: zeroth-order regular approximation diffusion Monte Carlo method in a spin-free formalism. AB - A diffusion Monte Carlo (DMC) method for the relativistic zeroth-order regular approximation (ZORA) is proposed. In this scheme, a novel approximate Green's function is derived for the spin-free ZORA Hamiltonian. Several numerical tests on atoms and small molecules showed that by combining with the relativistic cusp correction scheme, the present approach can include both relativistic and electron-correlation effects simultaneously. The correlation energies recovered by the ZORA-DMC method are comparable with the nonrelativistic DMC results and superior to the coupled cluster singles and doubles with perturbative triples correction results when the correlation-consistent polarized valence triple-zeta Douglas-Kroll basis set is used. For the heavier CuH molecule, the ZORA-DMC estimation of its dissociation energy agrees with the experimental value within the error bar. PMID- 23083145 TI - Comparison of two generation-recombination terms in the Poisson-Nernst-Planck model. AB - Two phenomenological forms proposed to take into account the generation recombination phenomenon of ions are investigated. The first form models the phenomenon as a chemical reaction, containing two coefficients describing the dissociation of neutral particles in ions, and the recombination of ions to give neutral particles. The second form is based on the assumption that in thermodynamical equilibrium, a well-defined density of ions is stable. Any deviation from the equilibrium density gives rise to a source term proportional to the deviation, whose phenomenological coefficient plays the role of a life time. The analysis is performed by evaluating the electrical response of an electrolytic cell to an external stimulus for both forms. For simplicity we assume that the electrodes are blocking, that there is only a group of negative and positive ions, and that the negative ions are immobile. For the second form, two cases are considered: (i) the generation-recombination phenomenon is due to an intrinsic mechanism, and (ii) the production of ions is triggered by an external source of energy, as in a solar cell. We show that the predictions of the two models are different at the impedance as well as at the admittance level. In particular, the first model predicts the existence of two plateaux for the real part of the impedance, whereas the second one predicts just one. It follows that impedance spectroscopy measurements could give information on the model valid for the generation-recombination of ions. PMID- 23083146 TI - On the Chan-Das gauge for the calculation of molecular magnetizabilities. AB - It is proven that the common origin gauge proposed by Chan and Das for the calculation of molecular magnetizabilities within the conventional approach using gaugeless basis sets, i.e., the center of electronic charge, does not minimize the van Vleck paramagnetic contribution to the diagonal tensor components, unless the Arrighini-Maestro-Moccia sum rules for gauge invariance, and charge conservation are satisfied. Additional quantum mechanical constraints for extremum values of formally diamagnetic and paramagnetic contributions have also been obtained for magnetizabilities calculated via procedures allowing for a continuous translation of the origin of the current density. PMID- 23083147 TI - Chemical potential evaluation in NVT lattice-gas simulations. AB - The discrete nature of the partition function of a lattice-gas system can be exploited to build an efficient strategy for the evaluation of the chemical potential of a periodic lattice-gas with arbitrarily ranged interactions during a simulation in the canonical ensemble, with the need of no additional sampling as it were required instead by the Widom insertion/deletion approach. The present method is based on the main concepts of the small system grand ensemble [for details, see G. Soto-Campos, D. S. Corti, and H. Reiss, J. Chem. Phys. 108, 2563 (1998)], whose key idea is to study the properties of a sublattice (called small system) and of its complementary (the reservoir sublattice) as they were two separated subsystems. The accuracy of the measured chemical potential can be further improved by artificially "restoring" the missing connections among the reservoir sublattice sites located at the boundaries with the small system. We first illustrate the theory and then we compare MUVT with NVT simulation results on several test systems. PMID- 23083148 TI - A Cartesian classical second-quantized many-electron Hamiltonian, for use with the semiclassical initial value representation. AB - A new classical model for the general second-quantized many-electron Hamiltonian in Cartesian coordinates and momenta is presented; this makes semiclassical (SC) calculations using an initial value representation (IVR) more useful than the classical Hamiltonian in action-angle variables given earlier by Miller and White [J. Chem. Phys. 84, 5059-5066 (1986)]. If only 1-electron terms are included in this Hamiltonian, the classical equations of motion for the Cartesian variables are linear, and the SC-IVR gives exact results for the propagator (and thus for transition probabilities, the energy spectrum, etc.), as confirmed by analytic proof and numerical calculations. Though this new Hamiltonian is not exact when 2 electron interactions are included, we observe good results for the SC-IVR transition probabilities for times that are not too long. Test calculations, for example, show that the SC-IVR is accurate for times long enough to obtain good result for the eigenvalue spectrum (i.e., the energy levels of the electronic system). PMID- 23083149 TI - Specification, construction, and exact reduction of state transition system models of biochemical processes. AB - Biochemical reaction systems may be viewed as discrete event processes characterized by a number of states and state transitions. These systems may be modeled as state transition systems with transitions representing individual reaction events. Since they often involve a large number of interactions, it can be difficult to construct such a model for a system, and since the resulting state-level model can involve a huge number of states, model analysis can be difficult or impossible. Here, we describe methods for the high-level specification of a system using hypergraphs, for the automated generation of a state-level model from a high-level model, and for the exact reduction of a state level model using information from the high-level model. Exact reduction is achieved through the automated application to the high-level model of the symmetry reduction technique and reduction by decomposition by independent subsystems, allowing potentially significant reductions without the need to generate a full model. The application of the method to biochemical reaction systems is illustrated by models describing a hypothetical ion-channel at several levels of complexity. The method allows for the reduction of the otherwise intractable example models to a manageable size. PMID- 23083150 TI - Effective diffusivity through arrays of obstacles under zero-mean periodic driving forces. AB - We perform a numerical investigation of the transport of Brownian particles driven by a zero-mean periodic force across two-dimensional arrays of obstacles with finite length. By applying axial and transversal driving forces relative to the diffusion transport direction, the effective diffusivity is determined as function of the array geometry and the driving frequency, finding excess diffusion peaks at certain frequency ranges. The results indicate that a suitable selection of the axial and transversal frequencies yields enhanced diffusion transport along the axial direction. Symmetric and asymmetric arrays are considered, showing that the asymmetry has a detrimental effect in the magnitude of the excess diffusion peaks. This suggests that enhanced diffusion is obtained because the oscillatory driving force exploits preferential transport channels, whose effective obstacle spacing is maximized under symmetric configurations. PMID- 23083151 TI - Model GW study of the late transition metal monoxides. AB - The model GW method [F. Gygi and A. Baldereschi, Phys. Rev. Lett. 62, 2160 (1989)] is an efficient simplification to the standard GW approximation which uses model dielectric function to describe the long range Coulomb interactions in semiconductors. In this work, the model GW method is used to calculate the quasiparticle band structures of MnO, FeO, CoO, and NiO. All four late transition metal monoxides are predicted to be insulators. The band gaps, magnetic moments, and quasiparticle spectra are in good agreement with the experiments, except for the satellite structures which are missing in the density of states because the model GW self-energy is static. The high accuracy of model GW is due to the usage of the accurate dielectric constants in the construction of the model dielectric functions which ensures the correct asymptotic behavior of the long range Coulomb interactions. Besides, we find that the transition metal 4s states are irrelevant to the formation of the band gaps, which supports the local approaches and the experimental interpretations of the band gaps by photoemission and electron energy loss spectroscopy, while contradicts the recent calculations by hybrid functionals, exact exchange, and one shot GW approximations. PMID- 23083153 TI - Calculation and analysis of the harmonic vibrational frequencies in molecules at extreme pressure: methodology and diborane as a test case. AB - We present a new quantum chemical method for the calculation of the equilibrium geometry and the harmonic vibrational frequencies of molecular systems in dense medium at high pressures (of the order of GPa). The new computational method, named PCM-XP, is based on the polarizable continuum model (PCM), amply used for the study of the solvent effects at standard condition of pressure, and it is accompanied by a new method of analysis for the interpretation of the mechanisms underpinning the effects of pressure on the molecular geometries and the harmonic vibrational frequencies. The PCM-XP has been applied at the density functional theory level to diborane as a molecular system under high pressure. The computed harmonic vibrational frequencies as a function of the pressure have shown a satisfactory agreement with the corresponding experimental results, and the parallel application of the method of analysis has reveled that the effects of the pressure on the equilibrium geometry can be interpreted in terms of direct effects on the electronic charge distribution of the molecular solutes, and that the effects on the harmonic vibrational frequencies can be described in terms of two physically distinct effects of the pressure (curvature and relaxation) on the potential energy for the motion of the nuclei. PMID- 23083152 TI - Improved spatial direct method with gradient-based diffusion to retain full diffusive fluctuations. AB - The spatial direct method with gradient-based diffusion is an accelerated stochastic reaction-diffusion simulation algorithm that treats diffusive transfers between neighboring subvolumes based on concentration gradients. This recent method achieved a marked improvement in simulation speed and reduction in the number of time-steps required to complete a simulation run, compared with the exact algorithm, by sampling only the net diffusion events, instead of sampling all diffusion events. Although the spatial direct method with gradient-based diffusion gives accurate means of simulation ensembles, its gradient-based diffusion strategy results in reduced fluctuations in populations of diffusive species. In this paper, we present a new improved algorithm that is able to anticipate all possible microscopic fluctuations due to diffusive transfers in the system and incorporate this information to retain the same degree of fluctuations in populations of diffusing species as the exact algorithm. The new algorithm also provides a capability to set the desired level of fluctuation per diffusing species, which facilitates adjusting the balance between the degree of exactness in simulation results and the simulation speed. We present numerical results that illustrate the recovery of fluctuations together with the accuracy and efficiency of the new algorithm. PMID- 23083154 TI - Chemically transferable coarse-grained potentials from conditional reversible work calculations. AB - The representability and transferability of effective pair potentials used in multiscale simulations of soft matter systems is ill understood. In this paper, we study liquid state systems composed of n-alkanes, the coarse-grained (CG) potential of which may be assumed pairwise additive and has been obtained using the conditional reversible work (CRW) method. The CRW method is a free-energy based coarse-graining procedure, which, by means of performing the coarse graining at pair level, rigorously provides a pair potential that describes the interaction free energy between two mapped atom groups (beads) embedded in their respective chemical environments. The pairwise nature of the interactions combined with their dependence on the chemically bonded environment makes CRW potentials ideally suited in studies of chemical transferability. We report CRW potentials for hexane using a mapping scheme that merges two heavy atoms in one CG bead. It is shown that the model is chemically and thermodynamically transferable to alkanes of different chain lengths in the liquid phase at temperatures between the melting and the boiling point under atmospheric (1 atm) pressure conditions. It is further shown that CRW-CG potentials may be readily obtained from a single simulation of the liquid state using the free energy perturbation method, thereby providing a fast and versatile molecular coarse graining method for aliphatic molecules. PMID- 23083155 TI - On the spin separation of algebraic two-component relativistic Hamiltonians. AB - The separation of the spin-free and spin-dependent terms of a given relativistic Hamiltonian is usually facilitated by the Dirac identity. However, this is no longer possible for the recently developed exact two-component relativistic Hamiltonians derived from the matrix representation of the Dirac equation in a kinetically balanced basis. This stems from the fact that the decoupling matrix does not have an explicit form. To resolve this formal difficulty, we first define the spin-dependent term as the difference between a two-component Hamiltonian corresponding to the full Dirac equation and its one-component counterpart corresponding to the spin-free Dirac equation. The series expansion of the spin-dependent term is then developed in two different ways. One is in the spirit of the Douglas-Kroll-Hess (DKH) transformation and the other is based on the perturbative expansion of a two-component Hamiltonian of fixed structure, either the two-step Barysz-Sadlej-Snijders (BSS) or the one-step exact two component (X2C) form. The algorithms for constructing arbitrary order terms are proposed for both schemes and their convergence patterns are assessed numerically. Truncating the expansions to finite orders leads naturally to a sequence of novel spin-dependent Hamiltonians. In particular, the order-by-order distinctions among the DKH, BSS, and X2C approaches can nicely be revealed. The well-known Pauli, zeroth-order regular approximation, and DKH1 spin-dependent Hamiltonians can also be recovered naturally by appropriately approximating the decoupling and renormalization matrices. On the practical side, the sf-X2C+so DKH3 Hamiltonian, together with appropriately constructed generally contracted basis sets, is most promising for accounting for relativistic effects in two steps, first spin-free and then spin-dependent, with the latter applied either perturbatively or variationally. PMID- 23083156 TI - Fast convergence to equilibrium for long-chain polymer melts using a MD/continuum hybrid method. AB - Effective and fast convergence toward an equilibrium state for long-chain polymer melts is realized by a hybrid method coupling molecular dynamics and the elastic continuum. The required simulation time to achieve the equilibrium state is reduced compared with conventional equilibration methods. The polymers move on a wide range phase space due to large-scale fluctuation generated by the elastic continuum. A variety of chain structures is generated in the polymer melt which results in the fast convergence to the equilibrium state. PMID- 23083157 TI - Eddy current effects in plain and hollow cylinders spinning inside homogeneous magnetic fields: application to magnetic resonance. AB - We present a thorough analysis of eddy currents that develop in a rectangular cross section toroid rotating in a uniform magnetic field. The slow rotation regime is assumed. Compact expressions for the current density, the total dissipated power, and the braking torque are given. Examination of the topology of current lines reveals that depending upon the relative dimensions of the side and length of the toroid two different regimes exist. The conditions of existence of the two regimes are analytically established. In view of nuclear magnetic resonance (NMR) applications, we derive the angular variation of the magnetic field created by eddy currents and lay down the formalism necessary for calculating the effect of this field on the NMR spectra of the conductor itself or of a sample co-rotating with the conductor, a situation encountered when dealing with rotating detectors. Examples of calculations for cases of practical interest are presented. The theory is confronted with available data, and we give guidelines for the design of optimized rotating micro-coils. PMID- 23083158 TI - Crossed molecular beams study of inelastic non-adiabatic processes in gas phase collisions between sodium ions and ZnBr2 molecules in the 0.10-3.50 keV energy range. AB - Inelastic electronically non-adiabatic reactions between Na(+) ions and neutral ZnBr(2) molecules, both in their electronic ground state, have been studied using crossed beams techniques and measuring the decaying emission radiation of the excited species produced. The fluorescent emission corresponding to Na(3 (2)P) produced by a charge transfer reaction was observed, as well as that corresponding to the decay of Zn(4s 5s (3)S), generated by dissociation of the neutral target molecule, to Zn(4s 4p (3)P). The phosphorescent decaying emission of Zn*(4s 4p (3)P) to the zinc ground state was also observed. For each emission process, the cross section energy dependences have been measured in the 0.10-3.50 keV energy range in the laboratory system. The ground electronic state of the (NaZnBr(2))(+) collision system has been characterized by ab initio chemical structure calculations at the second order Moller-Plesset perturbation level of theory using pseudo-potentials. By performing restricted open shell Hartree-Fock calculations for C(2v) geometries, four singlet and four triplet potential energy surfaces of the system have been calculated and used to interpret qualitatively the observed reactions. A simple two-state dynamical model is presented that allows an estimation of the maximum values for measured cross sections at high collision energies to be made. PMID- 23083159 TI - First-principles calculations of rovibrational energies, dipole transition intensities and partition function for ethylene using MULTIMODE. AB - Large-scale, rovibrational variational calculations are performed for ethylene, using the potential energy surface published by Avila and Carrington [J. Chem. Phys. 135, 064101 (2011)]. Energies for J = 0 are in very good agreement with their benchmark results. Corresponding energies for J = 1 and J = 2 are also given. Calculations with a slightly reduced basis permit energies to J = 40, allowing a reliable determination of the partition function at 296 K. Using a new ab initio dipole moment surface, reported here, the infrared spectra of five dipole-allowed fundamentals are calculated. Both the partition function and infrared spectra are shown to be in excellent agreement with those in the experimental HITRAN database, with the exception of one band, which we believe is partially mis-assigned in HITRAN. PMID- 23083160 TI - A theoretical study of SnF2+, SnCl2+, and SnO2+ and their experimental search. AB - We present a detailed theoretical study of the stability of the gas-phase diatomic dications SnF(2+), SnCl(2+), and SnO(2+) using ab initio computer calculations. The ground states of SnF(2+), SnCl(2+), and SnO(2+) are thermodynamically stable, respectively, with dissociation energies of 0.45, 0.30, and 0.42 eV. Whereas SnF(2+) dissociates into Sn(2+) + F, the long range behaviour of the potential energy curves of SnCl(2+) and SnO(2+) is repulsive and wide barrier heights due to avoided crossing act as a kind of effective dissociation energy. Their equilibrium internuclear distances are 4.855, 5.201, and 4.852 a(0), respectively. The double ionisation energies (T(e)) to form SnF(2+), SnCl(2+), and SnO(2+) from their respective neutral parents are 25.87, 23.71, and 25.97 eV. We combine our theoretical work with the experimental results of a search for these doubly positively charged diatomic molecules in the gas phase. SnO(2+) and SnF(2+) have been observed for prolonged oxygen ((16)O(-)) ion beam sputtering of a tin metal foil and of tin (II) fluoride (SnF(2)) powder, respectively, for ion flight times of about 10(-5) s through a magnetic-sector mass spectrometer. In addition, SnCl(2+) has been detected for (16)O(-) ion surface bombardment of stannous (tin (II)) chloride (SnCl(2)) powder. To our knowledge, SnF(2+) is a novel gas-phase molecule, whereas SnCl(2+) had been detected previously by electron-impact ionization mass spectrometry, and SnO(2+) had been observed before by spark source mass spectrometry as well as by atom probe mass spectrometry. We are not aware of any previous theoretical studies of these molecular systems. PMID- 23083161 TI - Ortho-para-H2 conversion by hydrogen exchange: comparison of theory and experiment. AB - We report fully-quantum time-independent calculations of cross sections and rate coefficients for the collisional (de)excitation of H(2) by H. Our calculations are based on the H(3) global potential energy surface of Mielke et al. [J. Chem. Phys. 116, 4142 (2002)]. The reactive hydrogen exchange channels are taken into account. We show that the ortho-para and para-ortho conversion of H(2) are significant processes at temperatures above ~300 K and for the last process we provide the first comparison with available experimental rate coefficients between 300 and 444 K. The good agreement between theory and experiment is a new illustration of our detailed understanding of the simplest chemical reaction. The importance of the ortho-para-H(2) conversion by hydrogen exchange in astrophysics is discussed. PMID- 23083162 TI - Ab initio study of low-lying excited states of HCl: accurate calculations of optical valence-shell excitations. AB - We present accurate ab initio potential energy surfaces and dipole transition moments of numerous low-lying states of HCl in a large range of internuclear distances. Using these results, we computed the visible/ultra-violet absorption spectrum of HCl covering the energy range up to the first ionization potential and the absolute optical oscillator strengths for the first discrete electronic transitions. Comparison of these theoretical results is done with the available experimental and theoretical data. Finally, we present a complete peaks attribution of the HCl electronic absorption spectrum. Our results are in good agreement with the available experimental results. PMID- 23083163 TI - A new potential energy surface for OH(A 2Sigma+)-Kr: the van der Waals complex and inelastic scattering. AB - New ab initio studies of the OH(A(2)Sigma(+))-Kr system reveal significantly deeper potential energy wells than previously believed, particularly for the linear configuration in which Kr is bound to the oxygen atom side of OH(A(2)Sigma(+)). In spite of this difference with previous work, bound state calculations based on a new RCCSD(T) potential energy surface yield an energy level structure in reasonable accord with previous studies. However, the new calculations suggest the need for a reassignment of the vibrational levels of the electronically excited complex. Quantum mechanical and quasi-classical trajectory scattering calculations are also performed on the new potential energy surface. New experimental measurements of rotational inelastic scattering cross sections are reported, obtained using Zeeman quantum beat spectroscopy. The values of the rotational energy transfer cross sections measured experimentally are in good agreement with those derived from the dynamical calculations on the new adiabatic potential energy surface. PMID- 23083164 TI - Driving photochemistry by clustering: the ICl-Xe case. AB - We present slice imaging data demonstrating the influence of clustering on the photodissociation dynamics of a diatomic molecule: iodine monochloride (ICl) was dissociated at 235 nm in He and Xe seed gasses, probing both Cl and I photofragment energy and angular distributions. We observe that the kinetic energy releases of both Cl and I fragments change from He to Xe seeding. For Cl fragments, the seeding in Xe increases the kinetic energy release of some Cl fragments with a narrow kinetic energy distribution, and leads to some fragments with rather broad statistical distribution falling off exponentially from near zero energies up to about 2.5 eV. Iodine fragment distribution changes even more dramatically from He to Xe seeding: sharp features essentially disappear and a broad distribution arises reaching to about 2.5 eV. Both these observations are rationalized by a simple qualitative cluster model assuming ICl dissociation inside larger xenon clusters and "on surface" of smaller Xe species. PMID- 23083165 TI - Pure rotational spectra of the CO-trans-HOCO complex. AB - Pure rotational spectra of the CO-trans-HOCO complex have been observed by Fourier transform microwave (FTMW) and millimeter-wave FTMW double resonance spectroscopy. The complex was produced in a supersonic jet by discharging a mixture gas of CO and H(2)O diluted in Ar. The molecular constants including the fine and hyperfine coupling constants have been precisely determined. The inter molecular distance between the CO and trans-HOCO monomers has been determined by fixing the structures of the trans-HOCO and CO monomers, where this complex has the OC...HO configuration with the C...HO angle almost linear. The C...H distance, 2.166 A, is much shorter than those of the closed shell complexes, CO CH(3)OH and CO-H(2)O. The Fermi contact constant of the proton for the complex was compared with that of the trans-HOCO monomer, leading to a conclusion that there is almost no induced effect for the spin density on the proton of HOCO by the complex formation. PMID- 23083166 TI - Second virial coefficients of H2 and its isotopologues from a six-dimensional potential. AB - We employ path-integral Monte Carlo techniques to compute the second virial coefficient as a function of temperature for molecular hydrogen (H(2)), deuterium (D(2)), and tritium (T(2)), along with the mixed isotopologues HD, HT, and DT. The calculations utilize a new six-dimensional (6D) potential, which is derived by combining our previous high-quality ground-state 4D potential for the H(2) dimer with the 6D potential of Hinde. This new 6D potential is reduced to a set of 4D potentials by fixing the intramolecular coordinates at their expectation values for each temperature and isotopic combination. The results for H(2) are in good agreement with experimental data; the effect of the temperature dependence of the average bond length is only significant above approximately 1000 K. For D(2) and HD, the available experimental data are much more limited; our results agree with the data and provide reliable values at temperatures where no experimental data exist. For the species containing tritium, our results provide the only data available. PMID- 23083167 TI - Role of electronic localization in the phosphorescence of iridium sensitizing dyes. AB - In this work we present a systematic study of three representative iridium dyes, namely, Ir(ppy)(3), FIrpic, and PQIr, which are commonly used as sensitizers in organic optoelectronic devices. We show that electronic correlations play a crucial role in determining the excited-state energies in these systems, due to localization of electrons on Ir d orbitals. Electronic localization is captured by employing hybrid functionals within time-dependent density-functional theory and with Hubbard-model corrections within the Delta-SCF approach. The performance of both methods are studied comparatively and shown to be in good agreement with experiment. The Hubbard-corrected functionals provide further insight into the localization of electrons and on the charge-transfer character of excited-states. The gained insight allows us to comment on envisioned functionalization strategies to improve the performance of these systems. Complementary discussions on the Delta-SCF method are also presented in order to fill some of the gaps in the literature. PMID- 23083168 TI - X-ray diffraction assisted spectroscopy of Rydberg states. AB - X-ray diffraction combined with conventional spectroscopy could provide a powerful means to characterize electronically excited atoms and molecules. We demonstrate theoretically how x-ray diffraction from laser excited atoms can be used to determine electronic structure, including angular momentum composition, principal quantum numbers, and channel populations. A theoretical formalism appropriate for highly excited atoms, and easily extended to molecules, is presented together with numerical results for Xe and H atoms. PMID- 23083169 TI - The rotational spectra of HD17O and D2(17)O: experiment and quantum-chemical calculations. AB - Guided by theoretical predictions, the rotational spectrum of HD(17)O was recorded and assigned for the first time, while the measurements for D(2)(17)O were extended up to the THz region. For both isotopic species, a large portion of the rotational spectrum, from 65 GHz (from 200 GHz for the bideuterated isotopologue) up to 1.6 THz, was investigated, thus allowing the accurate determination of the ground-state rotational and centrifugal-distortion constants. Considering that the rotational spectra of water isotopologues are characterized by a very low density of lines and strong centrifugal-distortion effects, the accurate quantum-chemical prediction of the relevant spectroscopic parameters played a crucial role in the line search and assignment as well as in supporting the fitting procedure. In addition to rotational and centrifugal distortion constants, the knowledge of the oxygen quadrupole-coupling constants was essential, as the corresponding interaction leads to characteristic features (hyperfine structure) that enabled proper line assignments. PMID- 23083170 TI - Ion imaging study of reaction dynamics in the N+ + CH4 system. AB - The velocity map ion imaging method is applied to the ion-molecule reactions of N(+) with CH(4). The velocity space images are collected at collision energies of 0.5 and 1.8 eV, providing both product kinetic energy and angular distributions for the reaction products CH(4)(+), CH(3)(+), and HCNH(+). The charge transfer process is energy resonant and occurs by long-range electron transfer that results in minimal deflection of the products. The formation of the most abundant product, CH(3)(+), proceeds by dissociative charge transfer rather than hydride transfer, as reported in earlier publications. The formation of HCNH(+) by C-N bond formation appears to proceed by two different routes. The triplet state intermediates CH(3)NH(+) and CH(2)NH(2)(+) that are formed as N(+)((3)P) approaches CH(4) may undergo sequential loss of two hydrogen atoms to form ground state HCNH(+) products on a spin-allowed pathway. However, the kinetic energy distributions for formation of HCNH(+) extend past the thermochemical limit to form HCNH(+) + 2H, implying that HCNH(+) may also be formed in concert with molecular hydrogen, and requiring that intersystem crossing to the singlet manifold must occur in a significant (~25%) fraction of reactive collisions. We also report GAUSSIAN G2 calculations of the energies and structures of important singlet and triplet [CNH(4)(+)] complexes that serve as precursors to product formation. PMID- 23083171 TI - Long range coupling between defect centres in inorganic nanostructures: valence alternation pairs in nanoscale silica. AB - Valence alternation pair (VAP) states are formed by a closed-shell combination of two space- and charge-separated topological defect centres. These pairs of defects, although historically invoked to explain the electronic properties of bulk inorganic glassy materials (e.g., amorphous silicon dioxide) via the concept of negative-U defects, have more recently been found in a number of theoretical studies of silica surfaces and nanoscale silica clusters. Using density functional theory we systematically probe the structure and internal stability of VAPs in a number of silica nanoclusters with respect to the separation of the two constituent defect centres. We find that VAP states in nanosilica are strongly stabilised by the attractive electrostatic interaction between their separated oppositely charged component defects such that VAPs can persist up to an internal separation of a least 1.5 nanometres. Beyond this distance VAPs become unstable with respect to an open-shell combination of topological defects, virtually indistinguishable from two isolated open-shell defect centres. Finally, we theoretically analyse the possibility of experimental observation of VAP states through their infra-red vibrational spectra. PMID- 23083172 TI - Optical properties of an organic dye from time-dependent density functional theory with explicit solvent: the case of alizarin. AB - The influence of a water solvent on the optical absorption properties of alizarin is investigated using time-dependent density functional theory (TDDFT). The solvent is modeled at two different levels of theory: a structureless dielectric medium, using a polarizable continuum model, and the explicit inclusion of water molecules which are treated at the same level of theory as the solute. Thermal effects on the photoabsorption spectra are included by combining TDDFT with first principle molecular dynamics. The effect of molecular distortions on the excitation energies and oscillator strengths is analyzed, and a strong correlation between particular structural and optical properties is found. PMID- 23083173 TI - Nonadiabatic effects in substitutional isomers of Jahn-Teller molecules: the strange case of hydroxymethoxy. AB - The effects of nonadiabatic interactions attributable to a seam of conical intersections on the electronic structure of the 1,2(2)A states of hydroxymethoxy (HO)CH(2)O is explored. Illuminating comparisons are made between hydroxymethoxy and ethoxy and isopropoxy, all of which can be thought of as substitutional isomers of the methoxy radical. Surprisingly, the potential energy surfaces and conical topographies for hydroxymethoxy are shown to be dramatically different from those evidenced in ethoxy or isopropoxy radicals, dissimilarities traced to the hydroxyl group. Also considered in this study was the feasibility of representing the coupled 1,2(2)A adiabatic electronic states of hydroxymethoxy within the vibronic coupling approximation using a quasi-diabatic Hamiltonian and subsequently using that representation to simulate the photoelectron spectrum of the hydroxymethoxide anion. Complications attributable to the torsional motion of the hydroxyl hydrogen are analyzed. PMID- 23083174 TI - Interatomic relaxation effects in double core ionization of chain molecules. AB - Core vacancies created on opposite sides of a molecule operate against each other in polarizing the environment between them. Consequently, the relaxation energy associated with the simultaneous creation of these two core holes turns out to be smaller than the sum of the relaxation energies associated with each individual single core vacancy created independently. The corresponding residual, termed interatomic relaxation energy, is sensitive to the environment. In the present paper we explore how the interatomic relaxation energy depends on the length and type of carbon chains bridging two core ionized nitrile groups (-C=N). We have uncovered several trends and discuss them with the help of simple electrostatic and quantum mechanical models. Namely, the absolute value of the interatomic relaxation energy depends strongly on the orbital hybridization in carbons being noticeably larger in conjugated chains (sp and sp(2) hybridizations) possessing highly mobile electrons in delocalized pi-type orbitals than in saturated chains (sp(3) hybridization) where only sigma bonds are available. The interatomic relaxation energy decreases monotonically with increasing chain length. The corresponding descent is determined by the energetics of the molecular bridge, in particular, by the HOMO-LUMO gap. The smallest HOMO-LUMO gap is found in molecules with the sp(2)-hybridized backbone. Here, the interatomic relaxation energy decreases slowest with the chain length. PMID- 23083175 TI - Volumes of aqueous hydrogen and hydroxide ions at 0 to 200 degrees C. AB - The electrostriction of aqueous hydrogen and hydroxide ions at infinite dilution was calculated by the shell-by-shell method over the temperature range 0 to 200 degrees C. The calculation required an estimate of the ionic radius of these ions, and comparison with data for aqueous lithium, sodium, and fluoride ions provided values for the nominal sizes of the hydrogen and hydroxide ions in solution. From the volumetric standpoint, these sizes are surprisingly smaller than the size of a water molecule. PMID- 23083176 TI - Vapor-deposited alpha,alpha,beta-tris-naphthylbenzene glasses with low heat capacity and high kinetic stability. AB - The reversing heat capacity of vapor-deposited glasses of alpha,alpha,beta-tris naphthylbenzene (alphaalphabeta-TNB) was measured using alternating current (AC) nanocalorimetry. Glasses deposited at 0.85 T(g), where T(g) is the glass transition temperature, have a 4 +/- 1% lower heat capacity than the ordinary glass prepared by cooling from the liquid. This is a result of efficient packing and is consistent with the higher density of the vapor-deposited glass. Isothermal experiments show that vapor-deposited alphaalphabeta-TNB glasses also have enhanced kinetic stability with respect to transformation into the supercooled liquid, as expected from previous work, with transformation times approaching 10(5) times the structural relaxation time of the liquid. Films thinner than 1 MUm exhibit a thickness dependence to their transformation times that is consistent with transformation to the supercooled liquid via a surface initiated growth front. PMID- 23083177 TI - Understanding anisotropic growth behavior of hexagonal ice on a molecular scale: a molecular dynamics simulation study. AB - Although distinct growth behaviors on different faces of hexagonal ice have long been suggested, their understanding on a molecular scale has been hampered due to experimental difficulties near interfaces. We present a molecular dynamics simulation study to unravel the molecular origin of anisotropy in the growth kinetics of hexagonal ice by visualizing the formation of transient water structures in the growing ice interface. During ice growth, the formation of transient structures and their rearrangement to the final ice configuration are observed irrespective of growth direction. However, we find that their structure and duration differ significantly depending on growth direction. In the direction perpendicular to the basal face of hexagonal ice along which growth occurs most slowly, a two-dimensional transient structure, which is formed by competing hexagonal and cubic arrangements within the same layer, persists for a significant period of time, contrasted with short-lived transient structures in other directions. This observation of such transient water structures and their rearrangement during ice growth provides a clear explanation of different growth rates on each face of hexagonal ice on a molecular scale. PMID- 23083178 TI - How intermolecular charge transfer influences the air-water interface. AB - The interfacial properties of three water models that allow for intermolecular charge rearrangement were examined with molecular dynamics simulations. They included the TIP4P water model, the TIP4P-FQ water model, which recently were modified to include intermolecular charge transfer [A. J. Lee and S. W. Rick, J. Chem. Phys. 134, 184507 (2011)]. Furthermore, another model with intermolecular charge transfer was developed for this work that was both flexible and polarizable. The effect of including intermolecular charge transfer is modest on most interfacial properties, including surface tension, electrostatic potential, interfacial dipole, and structure. However, a negative charge was found to build up at the air-water interface, but much smaller than has been measured experimentally. PMID- 23083179 TI - Surface electrostatic potential transformation of nanodiamond induced by graphitization. AB - The surface electrostatic potential of raw nanodiamonds is implied to be altered permanently during in the spontaneously occurred graphitization process by recent reports. With all-electron ab initio density functional theory methods, the intrinsic effect of graphitization on the electrostatic potential of nanodiamonds is investigated. It is exposed that while the graphitization process goes on, the dangling bonds on the (111) surface transfer into the inner side and subsequently the surface potential changes from negative to positive. Our results may be of great help in understanding the various electrostatic properties of nanodiamonds. PMID- 23083180 TI - Thin film growth by deposition of randomly shaped clusters. AB - We have investigated the growth of a porous thin surface film by deposition of randomly shaped clusters with different sizes over an initially flat linear substrate in (1 + 1) dimensions. In analogy with the ballistic deposition process, our approach results in aggregation of clusters with a porous bulk and a rough surface that obeys the Family-Vicsek dynamic scaling. The scaling exponents are calculated and found to agree with the ballistic deposition model. Moreover, the bulk porosity and its dependence on time and cluster size are also investigated. We have also studied the influence of the cluster size on the scaling exponents and the stationary porosity. PMID- 23083181 TI - A mirage study of CdSe colloidal quantum dot films, Urbach tail, and surface states. AB - Thermal deflection spectroscopy allows to measure very small absorption and uncovers absorption tails extending well below the bulk bandgap energy for CdSe quantum dots films after ligand exchange by sulfide. In this monodispersed system, the redshift, the broadening, and the absorption tails cannot be solely attributed to electronic coupling between the dots. Instead, mixing of hole states from the quantum dot and surface is proposed to dominate the changes of the interband spectra at the absorption edge. PMID- 23083182 TI - Car-Parrinello molecular dynamics study of the uranyl behaviour at the gibbsite/water interface. AB - The uranyl cation UO(2)(2+) adsorption on the basal face of gibbsite is studied via Car-Parrinello molecular dynamics. In a first step, we study the water sorption on a gibbsite surface. Three different sorption modes are observed and their hydrogen bond patterns are, respectively, characterized. Then we investigate the sorption properties of an uranyl cation, in the presence of water. In order to take into account the protonation state of the (001) gibbsite face, both a neutral (001) face and a locally deprotonated (001) face are modeled. In the first case, three adsorbed uranyl complexes (1 outer sphere and 2 inner spheres) with similar stabilities are identified. In the second case, when the gibbsite face is locally deprotonated, two adsorbed complexes (1 inner sphere and 1 outer one) are characterized. The inner sphere complex appears to be the most strongly linked to the gibbsite face. PMID- 23083183 TI - Density functional theory study of rutile VO2 surfaces. AB - We present the results of a density functional theory investigation of the surfaces of rutile-like vanadium dioxide, VO(2)(R). We calculate the surface energies of low Miller index planes and find that the most stable surface orientation is the (110). The equilibrium morphology of a VO(2)(R) particle has an acicular shape, laterally confined by (110) planes and topped by (011) planes. The redox properties of the (110) surface are investigated by calculating the relative surface free energies of the non-stoichiometric compositions as a function of oxygen chemical potential. It is found that the VO(2)(110) surface is oxidized with respect to the stoichiometric composition, not only at ambient conditions but also at the more reducing conditions under which bulk VO(2) is stable in comparison with bulk V(2)O(5). The adsorbed oxygen forms surface vanadyl species much more favorably than surface peroxo species. PMID- 23083184 TI - Effect of spin-orbit coupling on the actinide dioxides AnO2 (An=Th, Pa, U, Np, Pu, and Am): a screened hybrid density functional study. AB - We present a systematic comparison of the lattice structures, electronic density of states, and band gaps of actinide dioxides, AnO(2) (An=Th, Pa, U, Np, Pu, and Am) predicted by the Heyd-Scuseria-Ernzerhof screened hybrid density functional (HSE) with the self-consistent inclusion of spin-orbit coupling (SOC). The computed HSE lattice constants and band gaps of AnO(2) are in consistently good agreement with the available experimental data across the series, and differ little from earlier HSE results without SOC. ThO(2) is a simple band insulator (f(0)), while PaO(2), UO(2), and NpO(2) are predicted to be Mott insulators. The remainders (PuO(2) and AmO(2)) show considerable O2p/An5f mixing and are classified as charge-transfer insulators. We also compare our results for UO(2), NpO(2), and PuO(2) with the PBE+U, self interaction correction (SIC), and dynamic mean-field theory (DMFT) many-body approximations. PMID- 23083185 TI - Deformable homeotropic nematic droplets in a magnetic field. AB - We present a Frank-Oseen elasticity theory for the shape and structure of deformable nematic droplets with homeotropic surface anchoring in the presence of a magnetic field. Inspired by recent experimental observations, we focus on the case where the magnetic susceptibility is negative, and find that small drops have a lens shape with a homogeneous director field for any magnetic-field strength, whereas larger drops are spherical and have a radial director field, at least if the magnetic field is weak. For strong magnetic fields the hedgehog configuration transforms into a split-core line defect that, depending on the anchoring strength, can be accompanied by an elongation of the tactoid itself. We present a three-dimensional phase diagram that shows the tactoid shape and director field for a given anchoring strength, tactoid size, and magnetic-field strength. Our findings rationalize the different shapes and structures that recently have been observed experimentally for nematic droplets found in dispersions of gibbsite platelets in two types of solvent. PMID- 23083186 TI - Multi-chain slip-spring model for entangled polymer dynamics. AB - It has been established that entangled polymer dynamics can be reasonably described by single chain models such as tube and slip-link models. Although the entanglement effect is a result of hard-core interaction between chains, linkage between the single chain models and the real multi-chain system has not been established yet. In this study, we propose a multi-chain slip-spring model where bead-spring chains are dispersed in space and connected by slip-springs inspired by the single chain slip-spring model [A. E. Likhtman, Macromolecules 38, 6128 (2005)]. In this model the entanglement effect is replaced by the slip-springs, not by the hard-core interaction between beads so that this model is located in the niche between conventional multi-chain simulations and single chain models. The set of state variables are the position of beads and the connectivity (indices) of the slip-springs between beads. The dynamics of the system is described by the time evolution equation and stochastic transition dynamics for these variables. We propose a simple model which is based on the well-defined total free-energy and detailed balance condition. The free energy in our model contains a repulsive interaction between beads, which compensate the attractive interaction artificially generated by the slip-springs. The explicit expression of linear relaxation modulus is also derived by the linear response theory. We also propose a possible numerical scheme to perform simulations. Simulations reproduced expected bead number dependence in transitional regime between Rouse and entangled dynamics for the chain structure, the central bead diffusion, and the linear relaxation modulus. PMID- 23083187 TI - Nucleation of colloids and macromolecules in a finite volume. AB - A recently formulated description of homogeneous nucleation for Brownian particles in the over-damped limit based on fluctuating hydrodynamics is used to determine the nucleation pathway, characterized as the most likely path (MLP), for the nucleation of a dense-concentration droplet of globular protein from a dilute solution in a small, finite container. The calculations are performed by directly discretizing the equations for the MLP and it is found that they confirm previous results obtained for infinite systems: the process of homogeneous nucleation begins with a long-wavelength, spatially-extended concentration fluctuation that condenses to form the pre-critical cluster. This is followed by a classical growth processes. The calculations show that the post-critical growth involves the formation of a depletion zone around the cluster whereas no such depletion is observed in the pre-critical cluster. The approach therefore captures dynamical effects not found in classical density functional theory studies while consistently describing the formation of the pre-critical cluster. PMID- 23083188 TI - Response behavior of diblock copolymer brushes in explicit solvent. AB - The understanding of phase behavior of copolymer brushes is of fundamental importance for the design of smart materials. In this paper, we have performed classical density functional theory calculations to study diblock copolymer brushes (A-B) in an explicit solvent which prefers the A block to B block. With increasing B-block length (N(B)), we find a structural transition of the copolymer brush from mixed to collapsed, partial-exposed, and exposed structure, which is qualitatively consistent with experiments. The phase transitions are attributed to the interplay between entropic cost of folding copolymer brushes and enthalpic effect of contact between unlike components. In addition, we examine the effect of different parameters, such as grafting density (rho(g)), the bottom block length (N(A)), and the chain length of solvent (N(S)) on the solvent response of copolymer brushes. The transition chain length (N(B)) increases with decreasing rho(g) and N(A), and a smaller solvent molecule makes the collapsed structure less stable due to its lower penetration cost. Our results provide the insight to phase behavior of copolymer brushes in selective solvents from a molecular view. PMID- 23083192 TI - Site-specific quantification of bone quality using highly nonlinear solitary waves. AB - Osteoporosis is a well recognized problem affecting millions of individuals worldwide. The ability to diagnose problems in an effective, efficient, and affordable manner and identify individuals at risk is essential. Site-specific assessment of bone mechanical properties is necessary, not only in the process of fracture risk assessment, but may also be desirable for other applications, such as making intraoperative decisions during spine and joint replacement surgeries. The present study evaluates the use of a one-dimensional granular crystal sensor to measure the elastic properties of bone at selected locations via direct mechanical contact. The granular crystal is composed of a tightly packed chain of particles that interact according to the Hertzian contact law. Such chains represent one of the simplest systems to generate and propagate highly nonlinear acoustic signals in the form of compact solitary waves. First, we investigated the sensitivity of the sensor to known variations in bone density using a synthetic cancellous bone substitute, representing clinical bone quality ranging from healthy to osteoporotic. Once the relationship between the signal response and known bone properties was established, the sensor was used to assess the bone quality of ten human cadaveric specimens. The efficacy and accuracy of the sensor was then investigated by comparing the sensor measurements with the bone mineral density (BMD) obtained using dual-energy x-ray absorptiometry (DEXA). The results indicate that the proposed technique is capable of detecting differences in bone quality. The ability to measure site-specific properties without exposure to radiation has the potential to be further developed for clinical applications. PMID- 23083193 TI - Potassium titanyl phosphate laser tissue ablation: development and experimental validation of a new numerical model. AB - The photoselective vaporization of prostate (PVP) green light (532 nm) laser is increasingly being used as an alternative to the transurethral resection of prostate (TURP) for treatment of benign prostatic hyperplasia (BPH) in older patients and those who are poor surgical candidates. In order to achieve the goals of increased tissue removal volume (i.e., "ablation" in the engineering sense) and reduced collateral thermal damage during the PVP green light treatment, a two dimensional computational model for laser tissue ablation based on available parameters in the literature has been developed and compared to experiments. The model is based on the control volume finite difference and the enthalpy method with a mechanistically defined energy necessary to ablate (i.e., physically remove) a volume of tissue (i.e., energy of ablation E(ab)). The model was able to capture the general trends experimentally observed in terms of ablation and coagulation areas, their ratio (therapeutic index (TI)), and the ablation rate (AR) (mm(3)/s). The model and experiment were in good agreement at a smaller working distance (WD) (distance from the tissue in mm) and a larger scanning speed (SS) (laser scan speed in mm/s). However, the model and experiment deviated somewhat with a larger WD and a smaller SS; this is most likely due to optical shielding and heat diffusion in the laser scanning direction, which are neglected in the model. This model is a useful first step in the mechanistic prediction of PVP based BPH laser tissue ablation. Future modeling efforts should focus on optical shielding, heat diffusion in the laser scanning direction (i.e., including 3D effects), convective heat losses at the tissue boundary, and the dynamic optical, thermal, and coagulation properties of BPH tissue. PMID- 23083194 TI - Modeling degenerative disk disease in the lumbar spine: a combined experimental, constitutive, and computational approach. AB - Using a continuum approach for modeling the constitutive mechanical behavior of the intervertebral disk's annulus fibrosus holds the potential for facilitating the correlation of morphology and biomechanics of this clinically important tissue. Implementation of a continuum representation of the disk's tissues into computational models would yield a particularly valuable tool for investigating the effects of degenerative disease. However, to date, relevant efforts in the literature towards this goal have been limited due to the lack of a computationally tractable and implementable constitutive function. In order to address this, annular specimens harvested from a total of 15 healthy and degenerated intervertebral disks were tested under planar biaxial tension. Predictions of a strain energy function, which was previously shown to be unconditionally convex, were fit to the experimental data, and the optimized coefficients were used to modify a previously validated finite element model of the L4/L5 functional spinal unit. Optimization of material coefficients based on experimental results indicated increases in the micro-level orientation dispersion of the collagen fibers and the mechanical nonlinearity of these fibers due to degeneration. On the other hand, the finite element model predicted a progressive increase in the stress generation in annulus fibrosus due to stepwise degeneration of initially the nucleus and then the entire disk. Range of motion was predicted to initially increase with the degeneration of the nucleus and then decrease with the degeneration of the annulus in all rotational loading directions, except for axial rotation. Overall, degeneration was observed to specifically impact the functional effectiveness of the collagen fiber network of the annulus, leading to changes in the biomechanical behavior at both the tissue level and the motion-segment level. PMID- 23083195 TI - Movement of the distal carpal row during narrowing and widening of the carpal arch width. AB - Change in carpal arch width (CAW) is associated with wrist movement, carpal tunnel release, or therapeutic tunnel manipulation. This study investigated the angular rotations of the distal carpal joints as the CAW was adjusted. The CAW was narrowed and widened by 2 and 4 mm in seven cadaveric specimens while the bone positions were tracked by a marker-based motion capture system. The joints mainly pronated during CAW narrowing and supinated during widening. Ranges of motion about the pronation axis for the hamate-capitate (H-C), capitate-trapezoid (C-Td), and trapezoid-trapezium (Td-Tm) joints were 8.1 +/- 2.3 deg, 5.3 +/- 1.3 deg, and 5.5 +/- 3.5 deg, respectively. Differences between the angular rotations of the joints were found at DeltaCAW = -4 mm about the pronation and ulnar deviation axes. For the pronation axis, angular rotations of the H-C joint were larger than that of the C-Td and Td-Tm joints. Statistical interactions among the factors of joint, rotation axis, and DeltaCAW indicated complex joint motion patterns. The complex three-dimensional motion of the bones can be attributed to several anatomical constraints such as bone arrangement, ligament attachments, and articular congruence. The results of this study provide insight into the mechanisms of carpal tunnel adaptations in response to biomechanical alterations of the structural components. PMID- 23083197 TI - Identification of human inertia properties using a momentum-based approach. AB - This paper presents a momentum-based approach for identifying the barycentric parameters of a human body. The human body is modeled as a multiple rigid-body dynamical system with a tree-type topology using the principle of impulse and momentum. Since the resulting impulse-momentum equations are linear in terms of the unknown barycentric parameters, these parameters can be easily solved using the least-square method or other well-understood solution techniques. The approach does not require measuring or estimating accelerations and internal forces because they do not appear in the impulse-momentum equations and, thus, the resulting identification procedure is less demanding on the measurement and also less sensitive to measurement errors in comparison with other existing methods derived based on Newton-Euler or Lagrangian equations. The momentum-based approach has been studied by dynamics simulations with the consideration of possible measurement errors. The study showed good results. PMID- 23083196 TI - Effects of myocardial infarction on the distribution and transport of nutrients and oxygen in porcine myocardium. AB - One of the primary limitations of cell therapy for myocardial infarction is the low survival of transplanted cells, with a loss of up to 80% of cells within 3 days of delivery. The aims of this study were to investigate the distribution of nutrients and oxygen in infarcted myocardium and to quantify how macromolecular transport properties might affect cell survival. Transmural myocardial infarction was created by controlled cryoablation in pigs. At 30 days post-infarction, oxygen and metabolite levels were measured in the peripheral skeletal muscle, normal myocardium, the infarct border zone, and the infarct interior. The diffusion coefficients of fluorescein or FITC-labeled dextran (0.3-70 kD) were measured in these tissues using fluorescence recovery after photobleaching. The vascular density was measured via endogenous alkaline phosphatase staining. To examine the influence of these infarct conditions on cells therapeutically used in vivo, skeletal myoblast survival and differentiation were studied in vitro under the oxygen and glucose concentrations measured in the infarct tissue. Glucose and oxygen concentrations, along with vascular density were significantly reduced in infarct when compared to the uninjured myocardium and infarct border zone, although the degree of decrease differed. The diffusivity of molecules smaller than 40 kD was significantly higher in infarct center and border zone as compared to uninjured heart. Skeletal myoblast differentiation and survival were decreased stepwise from control to hypoxia, starvation, and ischemia conditions. Although oxygen, glucose, and vascular density were significantly reduced in infarcted myocardium, the rate of macromolecular diffusion was significantly increased, suggesting that diffusive transport may not be inhibited in infarct tissue, and thus the supply of nutrients to transplanted cells may be possible. in vitro studies mimicking infarct conditions suggest that increasing nutrients available to transplanted cells may significantly increase their ability to survive in infarct. PMID- 23083198 TI - Predicting distal radius bone strains and injury in response to impacts using multi-axial accelerometers. AB - Measuring a bone's response to impact has traditionally been done using strain gauges that are attached directly to the bone. Accelerometers have also been used for this purpose because they are reusable, inexpensive and can be attached easily. However, little data are available relating measured accelerations to bone injury, or to judge if accelerometers are reasonable surrogates for strain gauges in terms of their capacity to predict bone injuries. Impacts were applied with a custom designed pneumatic impact system to eight fresh-frozen human cadaveric radius specimens. Impacts were repeatedly applied with increasing energy until ultimate failure occurred. Three multiaxial strain gauge rosettes were glued to the bone (two distally and one proximally). Two multiaxial accelerometers were attached to the distal dorsal and proximal volar aspects of the radius. Overall, peak minimum and maximum principal strains were calculated from the strain-time curves from each gauge. Peak accelerations and acceleration rates were measured parallel (axial) and perpendicular (off-axis) to the long axis of the radius. Logistic generalized estimating equations were used to create strain and acceleration-based injury prediction models. To develop strain prediction models based on the acceleration variables, Linear generalized estimating equations were employed. The logistic models were assessed according to the quasi-likelihood under independence model criterion (QIC), while the linear models were assessed by the QIC and the marginal R(2). Peak axial and off axis accelerations increased significantly (with increasing impact energy) across all impact trials. The best injury prediction model (QIC = 9.42) included distal resultant acceleration (p < 0.001) and donor body mass index (BMI) (p < 0.001). Compressive and tensile strains were best predicted by separate uni-variate models, including peak distal axial acceleration (R(2 )= 0.79) and peak off-axis acceleration (R(2 )= 0.79), respectively. Accelerometers appear to be a valid surrogate to strain gauges for measuring the general response of the bone to impact and predicting the probability of bone injury. PMID- 23083199 TI - A multiplanar radiography method for assessing cup orientation in total hip arthroplasty. AB - Correct orientation of the acetabular cup considering patient-specific functional pelvic angles is an important factor for improving outcomes and avoiding complications after total hip arthroplasty. This study introduces a new, noninvasive radiographic tool for accurately determining a patient's specific pelvic tilt angle preoperatively, as well as accurately assessing acetabular cup orientation with respect to bony landmarks intraoperatively and postoperatively. The method was validated by imaging a bone replica model of the pelvis with implanted hip components, in comparison to digitized references, and verified with a cadaveric specimen. Pelvic tilt was measured with an accuracy of 0.1 deg and SD of 0.4 deg. Operative cup inclination and anteversion showed accuracies of 0.6 deg and 2.5 deg, with SD of 0.4 deg and 0.6 deg, respectively; these could be improved further by subtracting systematic bias. The method shows accuracy advantages over existing radiographic and fluoroscopic methods and exposes the subjects to a lower radiation dose compared to the similar computed tomography methods. These results suggest that the proposed method is feasible for assessing cup placement with reference to the functional and anatomical references. Furthermore, the ability to reference the same bony landmarks preoperatively, intraoperatively, and postoperatively has important research and clinical advantages. PMID- 23083200 TI - A quasi-nonlinear analysis of the anisotropic behaviour of human gallbladder wall. AB - Estimation of biomechanical parameters of soft tissues from noninvasive measurements has clinical significance in patient-specific modeling and disease diagnosis. In this work, we present a quasi-nonlinear method that is used to estimate the elastic moduli of the human gallbladder wall. A forward approach based on a transversely isotropic membrane material model is used, and an inverse iteration is carried out to determine the elastic moduli in the circumferential and longitudinal directions between two successive ultrasound images of gallbladder. The results demonstrate that the human gallbladder behaves in an anisotropic manner, and constitutive models need to incorporate this. The estimated moduli are also nonlinear and patient dependent. Importantly, the peak stress predicted here differs from the earlier estimate from linear membrane theory. As the peak stress inside the gallbladder wall has been found to strongly correlate with acalculous gallbladder pain, reliable mechanical modeling for gallbladder tissue is crucial if this information is to be used in clinical diagnosis. PMID- 23083201 TI - Tissue modification of the lateral compartment of the tibio-femoral joint following in vivo varus loading in the rat. AB - This study describes the first application of a varus loading device (VLD) to the rat hind limb to study the role of sustained altered compressive loading and its relationship to the initiation of degenerative changes to the tibio-femoral joint. The VLD applies decreased compressive load to the lateral compartment and increased compressive load to the medial compartment of the tibio-femoral joint in a controlled manner. Mature rats were randomized into one of three groups: unoperated control, 0% (sham), or 80% body weight (BW). Devices were attached to an animal's leg to deliver altered loads of 0% and 80% BW to the experimental knee for 12 weeks. Compartment-specific material properties of the tibial cartilage and subchondral bone were determined using indentation tests. Articular cartilage, calcified cartilage, and subchondral bone thicknesses, articular cartilage cellularity, and degeneration score were determined histologically. Joint tissues were sensitive to 12 weeks of decreased compressive loading in the lateral compartment with articular cartilage thickness decreased in the peripheral region, subchondral bone thickness increased, and cellularity of the midline region decreased in the 80% BW group as compared to the 0% BW group. The medial compartment revealed trends for diminished cellularity and aggregate modulus with increased loading. The rat-VLD model provides a new system to evaluate altered quantified levels of chronic in vivo loading without disruption of the joint capsule while maintaining full use of the knee. These results reveal a greater sensitivity of tissue parameters to decreased loading versus increased loading of 80% BW for 12 weeks in the rat. This model will allow future mechanistic studies that focus on the initiation and progression of degenerative changes with increased exposure in both magnitude and time to altered compressive loads. PMID- 23083202 TI - Validation of an improved method to calculate the orientation and magnitude of pedicle screw bending moments. AB - Previous methods of pedicle screw strain measurement have utilized complex, time consuming methods of strain gauge application, experience high failure rates, do not effectively measure resultant bending moments, and cannot predict moment orientation. The purpose of this biomechanical study was to validate an improved method of quantifying pedicle screw bending moment orientation and magnitude. Pedicle screws were instrumented to measure biplanar screw bending moments by positioning four strain gauges on flat, machined surfaces below the screw head. Screws were calibrated to measure bending moments by hanging certified weights a known distance from the strain gauges. Loads were applied in 30 deg increments at 12 different angles while recording data from two independent strain channels. The data were then analyzed to calculate the predicted orientation and magnitude of the resultant bending moment. Finally, flexibility tests were performed on a cadaveric motion segment implanted with the instrumented screws to demonstrate the implementation of this technique. The difference between the applied and calculated orientation of the bending moments averaged (+/-standard error of the mean (SEM)) 0.3 +/- 0.1 deg across the four screws for all rotations and loading conditions. The calculated resultant bending moments deviated from the actual magnitudes by an average of 0.00 +/- 0.00 Nm for all loading conditions. During cadaveric testing, the bending moment orientations were medial/lateral in flexion extension, variable in lateral bending, and diagonal in axial torsion. The technique developed in this study provides an accurate method of calculating the orientation and magnitude of screw bending moments and can be utilized with any pedicle screw fixation system. PMID- 23083203 TI - A novel device to quantify the mechanical properties of electrospun nanofibers. AB - Mechanical deformation of cell-seeded electrospun matrices plays an important role in cell signaling. However, electrospun biomaterials have inherently complex geometries due to the random deposition of fibers during the electrospinning process. This confounds attempts at quantifying strains exerted on adherent cells during electrospun matrix deformation. We have developed a novel mechanical test platform that allows deposition and tensile testing of electrospun fibers in a highly parallel arrangement to simplify mechanical analysis of the fibers alone and with adherent cells. The device is capable of optically recording fiber strain in a cell culture environment. Here we report on the mechanical and viscoelastic properties of highly parallel electrospun poly(epsilon-caprolactone) fibers. Force-strain data derived from this device will drive the development of cellular mechanotransduction studies as well as the customization of electrospun matrices for specific engineered tissue applications. PMID- 23083204 TI - Effect of perturbing a simulated motion on knee and anterior cruciate ligament kinetics. AB - Current surgical treatments for common knee injuries do not restore the normal biomechanics. Among other factors, the abnormal biomechanics increases the susceptibility to the early onset of osteoarthritis. In pursuit of improving long term outcome, investigators must understand normal knee kinematics and corresponding joint and anterior cruciate ligament (ACL) kinetics during the activities of daily living. Our long term research goal is to measure in vivo joint motions for the ovine stifle model and later simulate these motions with a 6 degree of freedom (DOF) robot to measure the corresponding 3D kinetics of the knee and ACL-only joint. Unfortunately, the motion measurement and motion simulation technologies used for our project have associated errors. The objective of this study was to determine how motion measurement and motion recreation error affect knee and ACL-only joint kinetics by perturbing a simulated in vivo motion in each DOF and measuring the corresponding intact knee and ACL-only joint forces and moments. The normal starting position for the motion was perturbed in each degree of freedom by four levels (-0.50, -0.25, 0.25, and 0.50 mm or degrees). Only translational perturbations significantly affected the intact knee and ACL-only joint kinetics. The compression-distraction perturbation had the largest effect on intact knee forces and the anterior posterior perturbation had the largest effect on the ACL forces. Small translational perturbations can significantly alter intact knee and ACL-only joint forces. Thus, translational motion measurement errors must be reduced to provide a more accurate representation of the intact knee and ACL kinetics. To account for the remaining motion measurement and recreation errors, an envelope of forces and moments should be reported. These force and moment ranges will provide valuable functional tissue engineering parameters (FTEPs) that can be used to design more effective ACL treatments. PMID- 23083205 TI - Child care quality and cognitive development: trajectories leading to better preacademic skills. AB - The associations between trajectories of child care quality from ages 2 to 4 years and children's cognitive performance at 4 years (n = 250) were tested. Distinct quality trajectories were identified: low and high ascending Teaching and Interactions trajectory; low and high Provision for Learning trajectory. Membership in the high ascending Teaching and Interactions trajectory was associated with better numeracy (effect size [ES] = .39, confidence interval [CI] = .21-.66), receptive vocabulary (ES = .41, CI = .14-.68), and school readiness (ES = .32, CI = .06-.58). The results suggest that a pattern of increasing quality of teacher-child interactions during the preschool years, particularly with regard to supporting the development of language, has a moderate impact on children's cognitive development. PMID- 23083206 TI - Genetic interactions between protein phosphatases CaPtc2p and CaPph3p in response to genotoxins and rapamycin in Candida albicans. AB - In Saccharomyces cerevisiae cells, both of the two PP2C protein phosphatases ScPtc2p and ScPtc3p and the PP4 protein phosphatase ScPph3 are responsible for ScRad53p dephosphorylation after the DNA methylation agent methylmethane sulfonate (MMS)-induced DNA damage. In this study, we show that CaPtc2p is not required for the CaRad53p dephosphorylation during the recovery from DNA damage, as is CaPph3p in Candida albicans. However, deletion of CaPPH3 has an additive effect on the sensitivity of C. albicans cells lacking CaPTC2 to MMS and the DNA synthesis inhibitor hydroxyurea (HU). In addition, deletion of CaPPH3 promotes in vitro filamentation of C. albicans cells. Furthermore, mutation of CaPTC2 is epistatic to that of CaPPH3 in the sensitivity of C. albicans cells to rapamycin. Therefore, CaPtc2p and CaPph3p might play a role in the target of rapamycin (TOR) signaling in C. albicans cells. PMID- 23083207 TI - Total synthesis of pactamycin and pactamycate: a detailed account. AB - This article describes synthetic studies that culminated in the first total synthesis of pactamycin and pactamycate and, in parallel, the two known congeners, de-6-MSA-pactamycin and de-6-MSA-pactamycate, lacking the 6 methylsalicylyl moiety. Starting with L-threonine as a chiron, a series of stereocontrolled condensations led to a key cyclopentenone harboring a spirocyclic oxazoline. A series of systematic functionalizations led initially to the incorrect cyclopentanone epoxide, which was "inverted" under solvolytic conditions. Installation of the remaining groups and manipulation of the oxazoline eventually led to pactamycin, pactamycate, and their desalicylyl analogues. PMID- 23083208 TI - An unusual antithrombin-binding heparin octasaccharide with an additional 3-O sulfated glucosamine in the active pentasaccharide sequence. AB - The 3-O-sulfation of N-sulfated glucosamine is the last event in the biosynthesis of heparin/heparan sulfate, giving rise to the antithrombin-binding pentasaccharide sequence AGA*IA, which is largely associated with the antithrombotic activity of these molecules. The aim of the present study was the structural and biochemical characterization of a previously unreported AGA*IA* containing octasaccharide isolated from the very-low-molecular-mass heparin semuloparin, in which both glucosamine residues of the pentasaccharide moiety located at the non-reducing end bear 3-O-sulfate groups. Two-dimensional and STD (saturation transfer difference) NMR experiments clearly confirmed its structure and identified its ligand epitope binding to antithrombin. The molecular conformation of the octasaccharide-antithrombin complex has been determined by NMR experiments and docking/energy minimization. The presence of the second 3-O sulfated glucosamine in the octasaccharide induced more than one order of magnitude increase in affinity to antithrombin compared to the pentasaccharide AGA*IA. PMID- 23083209 TI - The impact of ADHD symptoms and global impairment in childhood on working disability in mid-adulthood: a 28-year follow-up study using official disability pension records in a high-risk in-patient population. AB - BACKGROUND: Individuals with ADHD have been associated with more employment difficulties in early adulthood than healthy community controls. To examine whether this association is attributable specifically to disturbance of activity and attention (ADHD) or to psychopathology in general, we wanted to extend existing research by comparing the rate of mid-adulthood working disabilities for individuals diagnosed with ADHD as children with the rate for clinical controls diagnosed with either conduct disorder, emotional disorder or mixed disorder of conduct and emotions. METHODS: Former Norwegian child-psychiatric in-patients (n = 257) were followed up 17-39 years after hospitalization by record linkage to the Norwegian national registry of disability pension (DP) awards. Based on the hospital records, the patients were re-diagnosed according to ICD-10. Associations between the diagnoses, other baseline factors and subsequent DP were investigated using Kaplan-Meier survival analyses and logrank testing. RESULTS: At follow-up, 19% of the participants had received a DP award. In the logrank testing, ADHD was the only disorder associated with a subsequent DP, with 30% being disabled at follow-up (p = 0.01). Low psychosocial functioning (assessed by the Children's Global Assessment Scale) at admission uniquely predicted future DP (p = 0.04). CONCLUSIONS: ADHD in childhood was highly associated with later receiving a DP. Our finding of worse prognosis in ADHD compared with other internalizing and externalizing disorders in mid-adulthood supports the assumption of ADHD being specifically linked to working disability. Assessment of psychosocial functioning in addition to diagnostic features could enhance prediction of children who are most at risk of future disability. PMID- 23083210 TI - Cyclooxygenase-1 inhibition reduces amyloid pathology and improves memory deficits in a mouse model of Alzheimer's disease. AB - Several epidemiological and preclinical studies suggest that non-steroidal anti inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), reduce the risk of Alzheimer's disease (AD) and can lower beta-amyloid (Abeta) production and inhibit neuroinflammation. However, follow-up clinical trials, mostly using selective cyclooxygenase (COX)-2 inhibitors, failed to show any beneficial effect in AD patients with mild to severe cognitive deficits. Recent data indicated that COX-1, classically viewed as the homeostatic isoform, is localized in microglia and is actively involved in brain injury induced by pro-inflammatory stimuli including Abeta, lipopolysaccharide, and interleukins. We hypothesized that neuroinflammation is critical for disease progression and selective COX-1 inhibition, rather than COX-2 inhibition, can reduce neuroinflammation and AD pathology. Here, we show that treatment of 20-month-old triple transgenic AD (3 * Tg-AD) mice with the COX-1 selective inhibitor SC-560 improved spatial learning and memory, and reduced amyloid deposits and tau hyperphosphorylation. SC-560 also reduced glial activation and brain expression of inflammatory markers in 3 * Tg-AD mice, and switched the activated microglia phenotype promoting their phagocytic ability. The present findings are the first to demonstrate that selective COX-1 inhibition reduces neuroinflammation, neuropathology, and improves cognitive function in 3 * Tg-AD mice. Thus, selective COX-1 inhibition should be further investigated as a potential therapeutic approach for AD. PMID- 23083211 TI - Low prevalence of autoantibodies to CENP-H, -I, -K, -L, -M, -N, -T and -U in a Japanese cohort of anti-centromere positive samples. AB - OBJECTIVE: The constituents of the centromere region, centromere protein (CENP) A, -B, and -C, are mainly targeted by anticentromere antibodies (ACA). Many other proteins also assemble around CENP-A nucleosomes in interphase nuclei to form the interphase centromere complex (ICEN). CENP-H, -I, -K, -L, -M, -N, -T, and -U have been reported as the constitutive components of ICEN. In this study, we examined the reactivities of ACA to the 8 CENPs for the purpose of investigating their autoantigenicity. METHODS: Sera from 95 patients with ACA were tested by western blotting (WB) and enzyme-linked immunosorbent assay (ELISA) with the recombinant C-terminal of CENP-B (Ct-CENP-B). Next, the sera were examined for autoantibodies against the 8 CENPs by WB with each recombinant protein. Furthermore, the coiled coil motifs and granzyme B (GB) cleavage for various CENPs were analyzed with computer tools. RESULTS: Out of 95 ACA-positive sera, 85 and 93 sera were positive for anti-Ct-CENP-B antibodies in WB and in ELISA, respectively. In WB using the 8 CENPs, no sera reacted to any other 7 CENPs, except 1 serum, which reacted weakly to CENP-T. We were unable to find any obvious relationships between the autoantigenicity of CENPs and coiled-coil-forming probabilities or potential substrates for GB. CONCLUSION: This study demonstrates that ACA rarely target the 8 CENPs, in contrast to CENP-B. Protein structures might not contribute in a major way to the autoantigenicity of CENPs. PMID- 23083212 TI - Eosinophilic pustular folliculitis: a review of the Japanese published works. AB - Eosinophilic pustular folliculitis (EPF), also known as Ofuji's disease, is an inflammatory dermatosis that was first described in Japan in 1970. More than 300 cases have been reported so far, and 113 Japanese cases have been reported in Japan since 1980. To comprehend the characteristics of Japanese EPF cases, we classified these cases into three types: classic, immunosuppression-associated (IS-EPF), and infancy-associated (I-EPF). Trends in age of onset and in distribution and characterization of eruptions differed between the types. We found 91 cases of classic EPF (mean age, 39.7 years), consisting of 66 males (73%) and 25 females (27%), in most of which eruptions primarily affected the face; 18 cases of IS-EPF (44.2 years), consisting of 15 males (83%) and three females (17%), in which eruptions affected the face less predominantly; and four cases of I-EPF (7.0 years), consisting of two males (50%) and two females (50%), primarily affecting the scalp. The number of IS-EPF cases has increased since the late 1990s, reflecting the increasing number of HIV-positive patients in Japan. Systemic non-steroidal anti-inflammatory drugs were effective in more than 70% of cases. Dimethyl diphenyl sulfone, antibiotics including minocycline, psoralen plus ultraviolet A therapy and ultraviolet B treatments worked in some cases. Topical steroids and tacrolimus were also effective in some cases of EPF, while topical indomethacin was less effective. PMID- 23083213 TI - A structure-activity relationship study for 2'-deoxyadenosine analogs at A9 position in the catalytic core of 10-23 DNAzyme for rate enhancement. AB - Modification on the catalytic core of 10-23 DNAzyme with protein-like functional groups is a potential approach to obtain its more efficient analogs. In our efforts for this purpose, a lead structure (DZ-2-9) with 8-aza-7-deaza-2' deoxyadenosine at the A9 position in its catalytic core was obtained. Here we report our structure-activity relationship studies on this lead structure. Various functional groups of different chemical properties were introduced through the 7-substituents of 8-aza-7-deaza-2'-deoxyadenosine to DZ-2-9. The functional groups capable of forming hydrogen bonds, like amino and hydroxyl groups, are more favorable for catalytic rate enhancement than the large groups with spacial occupation, like phenyl and tert-butylphenyl groups, and the flexible alkyl linkage was the more preferred choice for optimizing their positive effect. Furthermore, they exerted positive effect cooperatively with the N8 atom. These results give us a clear hint in the design of compounds for A9 substitution of 10-23 DNAzyme for more efficient DNAzymes. PMID- 23083214 TI - Assays for methionine gamma-lyase and S-adenosyl-L-homocysteine hydrolase based on enzymatic formation of CdS quantum dots in situ. AB - S-Adenosyl-L-homocysteine hydrolase (AHCY) hydrolyzes its substrate S-adenosyl-L homocysteine (AdoHcy) to L-homocysteine (Hcy). Methionine gamma-lyase (MGL) catalyzes the decomposition of Hcy to hydrogen sulfide which forms fluorescent CdS nanoparticles in the presence of Cd(NO(3))(2). On the basis of these enzymatic reactions, two new simple and robust fluorogenic enzymatic assays for MGL and AHCY were developed and applied to detection of AHCY inhibitors. PMID- 23083215 TI - Pseudoaneurysm of the mitral-aortic intervalvular fibrosa presenting after chest trauma and diagnosed by cardiac magnetic resonance: a case report. AB - INTRODUCTION: Annular subvalvular pseudoaneurysm is a rare example of left ventricle aneurysm described predominantly in young African people. These aneurysms are divided into two different types, namely, submitral or subaortic, with subaortic being the less frequent kind. The subaortic type is most often localized in the mitral-aortic intervalvular fibrosa. To the best of our knowledge, this is the first report of a mitral-aortic intervalvular fibrosa pseudoaneurysm associated with coarctation of the aorta, anomalous pulmonary venous return, bicuspid aortic valve and patent ductus arteriosus diagnosed by cardiovascular magnetic resonance. CASE PRESENTATION: We report the case of a 15 year-old African-American boy with a history of mild chest trauma who underwent echocardiographic evaluation as part of an out-patient work up. The echocardiogram was suspicious for the presence of mitral-aortic intervalvular fibrosa pseudoaneurysm and cardiovascular magnetic resonance was then performed to better characterize this finding. In addition to confirming the presence of the aneurysm, cardiovascular magnetic resonance also revealed coarctation of the aorta, a bicuspid aortic valve, and anomalous pulmonary venous return. CONCLUSION: In our case, cardiovascular magnetic resonance was helpful in: (a) making a definite diagnosis of mitral-aortic intervalvular fibrosa pseudoaneurysm and its borders, which was not clear with an echocardiogram examination; and (b) illustrating additional associated congenital anomalies including the anomalous pulmonary venous return. PMID- 23083216 TI - Pregnancy outcome following use of levodopa, pramipexole, ropinirole, and rotigotine for restless legs syndrome during pregnancy: a case series. AB - BACKGROUND: Restless legs syndrome (RLS) is related to parity, and its symptoms may worsen during pregnancy. Treatment with levodopa or dopamine agonists is the first-line therapy for RLS; however, there are limited data on treatment in pregnancy. We therefore assessed the safety of levodopa, pramipexole, rotigotine, and ropinirole in pregnancy. METHODS: Prospective documentation of pregnancies exposed to levodopa, pramipexole, rotigotine, and ropinirole between 1998 and 2011 was evaluated as to their outcome (teratogenicity or fetotoxicity) by the Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy. RESULTS: We were able to complete 59 pregnancy outcomes exposed to RLS pharmacotherapy. For specific treatments, the numbers of exposed pregnancies/live born children/spontaneous abortions/induced abortions/malformations were as follows: levodopa only: 38/29 (one pair of twins)/3/7/3; pramipexole only: 12/9/3/0/0; rotigotine only: 2/2/0/0/0; ropinirole only: 3/2/0/1/0; levodopa combined with pramipexole: 3/3/0/0/0; levodopa combined with ropinirole: 1/1/0/0/0. No major birth defects were found with any RLS treatment, and three infants exposed to levodopa had minor anomalies. CONCLUSIONS: In our small prospective case series, there was no increased risk above baseline for major malformations or other adverse outcomes for levodopa and pramipexole. If necessary, levodopa treatment may be considered as an alternative to cabergoline, for which safety has been well documented in pregnancy. PMID- 23083217 TI - Arterial blood pressure, proteinuria, and renal histopathology in clinically healthy retired racing greyhounds. AB - BACKGROUND: Physiologic peculiarities of Greyhounds as compared to other dogs make interpretation of laboratory results in this breed challenging for veterinarians. Hypertension in retired racing Greyhounds (RRG) can contribute to microalbuminuria (MA), overt proteinuria, and renal histologic lesions. OBJECTIVES: To evaluate clinicopathologic findings, hemodynamic status, and renal histology in a population of healthy RRG. ANIMALS: RRG presented to Ohio State University College of Veterinary Medicine for inclusion in a spay and neuter program. METHODS: Cross-sectional study. RRG were classified as normotensive (<160 mmHg) or hypertensive (>160 mmHg) based on blood pressure (BP) determinations using Doppler and oscillometric methods. Of the dogs evaluated, 62% (n = 29) were hypertensive and 38% (n = 18) were normotensive. Health status was evaluated using routine clinicopathologic tests (CBC, serum biochemistry, urinalysis) as well as evaluation of fractional excretion of electrolytes and MA determinations. Adequate renal biopsy specimens (n = 15) were evaluated using light, immunofluoresence, and electron microscopy. RESULTS: All serum biochemistry results were normal in 45/49 dogs, but MA was more common in hypertensive (84% positive for MA) as compared with normotensive (18% positive for MA) RRG. Observed renal lesions were mild and renal biopsy scores were low in this sample of RRG. CONCLUSIONS: Hypertension is common in RRG and might be breed related. It is associated with MA, but observed renal lesions are mild. Whether or not hypertension and MA in RRG leads to progressive renal damage requires longitudinal study. PMID- 23083218 TI - Aluminum conducts better than copper at the atomic scale: a first-principles study of metallic atomic wires. AB - Using a first-principles density functional method, we have studied the electronic structure, electron-phonon coupling, and quantum transport properties of atomic wires of Ag, Al, Au, and Cu. Non-equilibrium Green's function-based transport studies of finite atomic wires suggest that the conductivity of Al atomic wires is higher than that of Ag, Au, and Cu in contrast to the bulk where Al has the lowest conductivity among these systems. This is attributed to the higher number of eigenchannels in Al wires, which becomes the determining factor in the ballistic limit. On the basis of density functional perturbation theory, we find that the electron-phonon coupling constant of the Al atomic wire is lowest among the four metals studied, and more importantly, that the value is reduced by a factor of 50 compared to the bulk. PMID- 23083220 TI - Explaining dehumanization among children: the interspecies model of prejudice. AB - Although many theoretical approaches have emerged to explain prejudices expressed by children, none incorporate outgroup dehumanization, a key predictor of prejudice among adults. According to the Interspecies Model of Prejudice, beliefs in the human-animal divide facilitate outgroup prejudice through fostering animalistic dehumanization (Costello & Hodson, 2010). In the present investigation, White children attributed Black children fewer 'uniquely human' characteristics, representing the first systematic evidence of racial dehumanization among children (Studies 1 and 2). In Study 2, path analyses supported the Interspecies Model of Prejudice: children's human-animal divide beliefs predicted greater racial prejudice, an effect explained by heightened racial dehumanization. Similar patterns emerged among parents. Furthermore, parent Social Dominance Orientation predicted child prejudice indirectly through children's endorsement of a hierarchical human-animal divide and subsequent dehumanizing tendencies. Encouragingly, children's human-animal divide perceptions were malleable to an experimental prime highlighting animal-human similarity. Implications for prejudice interventions are considered. PMID- 23083219 TI - dsPIG: a tool to predict imprinted genes from the deep sequencing of whole transcriptomes. AB - BACKGROUND: Dysregulation of imprinted genes, which are expressed in a parent-of origin-specific manner, plays an important role in various human diseases, such as cancer and behavioral disorder. To date, however, fewer than 100 imprinted genes have been identified in the human genome. The recent availability of high throughput technology makes it possible to have large-scale prediction of imprinted genes. Here we propose a Bayesian model (dsPIG) to predict imprinted genes on the basis of allelic expression observed in mRNA-Seq data of independent human tissues. RESULTS: Our model (dsPIG) was capable of identifying imprinted genes with high sensitivity and specificity and a low false discovery rate when the number of sequenced tissue samples was fairly large, according to simulations. By applying dsPIG to the mRNA-Seq data, we predicted 94 imprinted genes in 20 cerebellum samples and 57 imprinted genes in 9 diverse tissue samples with expected low false discovery rates. We also assessed dsPIG using previously validated imprinted and non-imprinted genes. With simulations, we further analyzed how imbalanced allelic expression of non-imprinted genes or different minor allele frequencies affected the predictions of dsPIG. Interestingly, we found that, among biallelically expressed genes, at least 18 genes expressed significantly more transcripts from one allele than the other among different individuals and tissues. CONCLUSION: With the prevalence of the mRNA-Seq technology, dsPIG has become a useful tool for analysis of allelic expression and large-scale prediction of imprinted genes. For ease of use, we have set up a web service and also provided an R package for dsPIG at http://www.shoudanliang.com/dsPIG/. PMID- 23083221 TI - Possible benefit from treatment of Helicobacter pylori in antihistamine-resistant chronic urticaria. AB - BACKGROUND: Some patients with chronic spontaneous urticaria (CU) are resistant to conventional doses of antihistamine (AH) medications. Some research groups have reported an association between CU and Helicobacter pylori infection. AIM: To determine whether H. pylori eradication can reverse AH resistance in CU. METHODS: We retrospectively reviewed cases of patients with CU, and recorded their Urticaria Activity Score (UAS) and results of a (13)C-urea breath test ((13)C-UBT) for H. pylori infection. Patients without improvement in CU despite a full 8 weeks of AH treatment at four times the initial dose comprised the resistant CU group, while the patients who did respond comprised the responsive CU group. Patients with resistant CU and a positive (13)C-UBT (n = 46) were offered a 14-day treatment with amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily and omeprazole 20 mg twice daily. The effect of H. pylori eradication on CU was evaluated by the UAS, measured at baseline and at 8, 16, and 28 weeks after triple therapy. RESULTS: Of the 46 patients with resistant CU, 29 (63%) had a positive (13)C-UBT result. Treatment eradicated H. pylori in 18 of the 29 patients (subgroup A), and 11 patients refused the triple therapy (subgroup B). The remaining 17 patients had a negative (13)C-UBT result, (subgroup C). In subgroup A, baseline UAS reduced from 5.29 +/- 0.94 to 3.62 +/- 0.96 (P = 0.03) at week 8; to 1.43 +/- 0.41 (P < 0.001) at week 16, and to 1.17 +/- 0.32 (P = 0.04) at week 28. Five of the patients (27.8%) in this group were completely free of symptoms at week 28, whereas none of the untreated patients achieved complete remission. CONCLUSION: Some patients with resistant CU might benefit from H. pylori eradication. PMID- 23083222 TI - NELL-1 injection maintains long-bone quantity and quality in an ovariectomy induced osteoporotic senile rat model. AB - Over 10 million Americans have osteoporosis, and is the predominant cause of fractures in the elderly. Treatment of fractures in the setting of osteoporosis is complicated by a suboptimal bone regenerative response due to a decline in the number of osteoblasts, their function, and survival. Consequently, an osteogenic therapeutic to prevent and treat fractures in patients with osteoporosis is needed. Nel-like molecule-1 (NELL-1), a novel osteoinductive growth factor, has been shown to promote bone regeneration. In this study, we aim to demonstrate the capacity of recombinant NELL-1 to prevent ovariectomy (OVX)-induced osteoporosis in a senile rat model. Ten-month-old female Sprague-Dawley rats underwent either sham surgery or OVX. Subsequently, 50 MUL of 600 MUg/mL NELL-1 lyophilized onto a 0-50-MUm tricalcium phosphate (TCP) carrier was injected into the femoral bone marrow cavity while phosphate-buffered saline (PBS) control was injected into the contralateral femur. Our microcomputed tomography results showed that OVX+PBS/TCP control femurs showed a continuous decrease in the bone volume (BV) and bone mineral density (BMD) from 2 to 8 weeks post-OVX. In contrast, OVX+NELL-1/TCP femurs showed resistance to OVX-induced bone resorption showing BV and BMD levels similar to that of SHAM femurs at 8 weeks post-OVX. Histology showed increased endosteal-woven bone, as well as decreased adipocytes in the bone marrow of NELL 1-treated femurs compared to control. NELL-1-treated femurs also showed increased immunostaining for bone differentiation markers osteopontin and osteocalcin. These findings were validated in vitro, in which addition of NELL-1 in OVX bone marrow stem cells resulted in increased osteogenic differentiation. Thus, NELL-1 effectively enhances in situ osteogenesis in the bone marrow, making it potentially useful in the prevention and treatment of osteoporotic fractures. PMID- 23083223 TI - Effects of cationic hydroxyethyl cellulose on dyslipidemia in hamsters. AB - Cationic hydroxyethyl cellulose (cHEC) was supplemented in a high-fat diet to determine if this new soluble fiber had an effect on hypercholesterolemia and dyslipidemia associated with cardiovascular disease using Golden Syrian hamster as an animal model. Supplementation of 3-5% cHEC in a high-fat diet for 4 weeks led to significant weight gain reduction in hamsters. In addition, significant decreases in adipose and liver weights, concentrations of plasma total, VLDL, and LDL cholesterol, and hepatic lipids were shown. No significant improvements in glucose and insulin levels were observed with cHEC; however, a significant increase in plasma adiponectin and a decrease in leptin were observed. As compared with controls, 8% cHEC-fed hamsters had greater levels of mRNA for CYP7A1 (cytochrome P450 7A1; 2-fold of control; P < 0.05), CYP51 (lanosterol 14alpha-demethylase; 6-fold of control; P < 0.05), and LDLR (LDL receptor; 1.5 fold of control) in the liver. These findings suggest the possibility of the use of cHEC for cholesterol reduction and beneficial effects on the cardiovascular risk factors. PMID- 23083224 TI - Could titanium oxide coating from a sol-gel process make stone baskets more resistant to laser radiation at 2.1 MUm? AB - BACKGROUND: Stone baskets could be easily destroyed by Holmium:YAG-laser at an endourologic treatment, with respect to this, we try to improve the resistance by coating them with a titanium oxide layer. The layer was established by a sol-gel process. MATERIALS AND METHODS: Six new baskets (Equadus, Opi Med, Ettlingen, Germany) were used: 1.8 Ch. with 4 wires (diameter 0.127 mm). Three baskets were coated with a layer of titanium oxide established by a sol-gel process at the BioCerEntwicklungs GmbH in Bayreuth (~100 nanometres thickness). The lithotripter was a Holmium:YAG laser (Auriga XL, Starmedtec, Starnberg, Germany). 10 uncoated and 10 coated wires were tested with 610 mJ (the minimal clinical setting) and 2 uncoated and 2 coated wires were tested with 110 mJ. The wires were locked in a special holding instrument under water and the laser incident angle was 90 degrees . The endpoint was gross visible damage to the wire and loss of electric conduction. RESULTS: Only two coated wires resisted two pulses (one in the 610 mJ and one in the 110 mJ setting). All other wires were destroyed after one pulse. CONCLUSION: This was the first attempt at making stone baskets more resistant to a Holmium:YAG laser beam. Titanium oxide deposited by a sol-gel-process on a titanium-nickel alloy did not result in better resistance to laser injuries. PMID- 23083225 TI - Evaluation of a Short Message Service diary methodology in a nonclinical, naturalistic setting. AB - Particularly suited to repeated measures in naturalistic settings, Short Message Service (SMS) is garnering increasing attention as a viable method of data collection. The current study explored issues of practical importance for the development of this methodology, including factors impacting on attrition and compliance, and participant perception of SMS. Using a business-card-sized questionnaire key, 98 university students were sent prompt SMS messages nightly for a week. Completion and compliance were very high in all participants who responded to at least one prompt SMS; those who responded at least once (n=63) responded to 83 percent of all seven prompts, with 95 percent of responses containing appropriate alphanumeric answers to all questions. However, a time lag between recruitment and participation was associated with a failure to commence the diary study. Participants reported positive perceptions of SMS privacy and convenience. PMID- 23083226 TI - Why extreme dilutions reach non-zero asymptotes: a nanoparticulate hypothesis based on froth flotation. AB - Extreme dilutions, especially homeopathic remedies of 30c, 200c, and higher potencies, are prepared by a process of serial dilution of 1:100 per step. As a result, dilution factors of 10(60), 10(400), or even greater are achieved. Therefore, both the presence of any active ingredient and the therapeutic efficacy of these medicines have been contentious because the existence of even traces of the starting raw materials in them is inconceivable. However, physicochemical studies of these solutions have unequivocally established the presence of the starting raw materials in nanoparticulate form even in these extreme (super-Avogadro, >10(23)) dilutions. In this article, we propose and validate a hypothesis to explain how nanoparticles are retained even at such enormous dilution levels. We show that once the bulk concentration is below a threshold level of a few nanograms/milliliter (ng/mL), at the end of each dilution step, all of the nanoparticles levitate to the surface and are accommodated as a monolayer at the top. This dominant population at the air liquid interface is preserved and carried to the subsequent step, thereby forming an asymptotic concentration. Thus, all dilutions are only apparent and not real in terms of the concentrations of the starting raw materials. PMID- 23083227 TI - Endoscopic mucosal resection vs endoscopic submucosal dissection for rectal carcinoid tumours: a systematic review and meta-analysis. AB - AIM: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are used for the removal of rectal carcinoid tumours. There are no current guidelines or consensus on the optimal treatment strategy for these lesions. A systematic review was conducted to compare the efficacy and safety of ESD and EMR. METHOD: The generation of inclusion criteria and analysis of data were based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. A systematic literature review was conducted using the following databases: Medline, Embase, SpringerLink, Elsevier ScienceDirect, Science Citation Index and the Cochrane Library. Only papers comparing treatment of rectal carcinoid tumours by EMR and by ESD were selected. The data collected included the patients' demographic information, interventions made, observed outcome and sources of bias. RESULTS: Four papers were included in this systematic review and meta-analysis. ESD was more effective than EMR in complete resection (OR 0.29; 95% CI 0.14-0.58; P = 0.000). ESD was as safe as EMR [rate difference (RD) -0.01; 95% CI -0.07 to 0.05; P = 0.675]. Recurrence rates did not differ significantly between the EMR and ESD groups (RD 0.04; 95% CI -0.01 to 0.09; P = 0.150). The duration of ESD was longer than EMR (standardized mean difference -1.73; 95% CI -2.73 to -0.74; P = 0.001). CONCLUSION: The study indicates that ESD is the better treatment for rectal carcinoid tumours. PMID- 23083228 TI - Effects of topical application of Astragalus membranaceus on allergic dermatitis. AB - Astragalus membranaceus (AM) is one of the most popular health-promoting herbs in East Asia, and has been used in traditional medicine for more than 2000 years. This study was performed to examine whether AM suppresses atopic dermatitis (AD) like skin lesions in BALB/c mice. Seven-week-old female BALB/c mice were sensitized with 1-chloro-2,4-dinitrobenzene (DNCB) to induce allergic dermatitis. Skin sections were stained with hematoxylin and eosin (H&E) to assess epidermal and dermal hyperplasia, which were determined by measuring the thicknesses of the epidermis and dermis, respectively. The serum immunoglobulin G (IgE) concentration was quantified by enzyme-linked immunosorbent assay (ELISA). In addition, the levels of interleukins (IL)-4, -5, -6, and -13 and tissue necrosis factor (TNF)-alpha were measured in mouse serum. Significance was determined by one-way analysis of variance (ANOVA). Topical AM markedly improved the AD skin lesions in DNCB-induced mice. The AD skin lesions were significantly thinner in the AM treatment group compared with untreated controls, and the hyperkeratosis disappeared. Topical treatment of AM also restored nuclear factor-kappaB (NF kappaB) expression. In addition, the serum IgE level was reduced. AM suppressed the expression of Th2 cytokines (IL-4, -5, -6, and -13) and significantly decreased the TNF-alpha level. AM is effective for treating AD by regulating cytokines. AM may be an alternative or complementary therapeutic option for treating patients with AD. More in-depth studies are necessary to clarify the mechanisms of AM. PMID- 23083229 TI - Lower bound on the entropy of boundaries and junctions in (1+1)-dimensional quantum critical systems. AB - A lower bound is derived for the boundary entropy s=lng of a (1+1)-dimensional quantum critical system with boundary under the conditions c>=1 on the bulk conformal central charge and Delta1>(c-1)/12 on the most relevant bulk scaling dimension. This is the first general restriction on the possible values of g for bulk critical systems with c>=1. PMID- 23083230 TI - Molecule and polaron in a highly polarized two-dimensional fermi gas with spin orbit coupling. AB - We show that spin-orbit coupling (SOC) gives rise to pairing instability in a highly polarized two-dimensional Fermi gas for an arbitrary interaction strength. The pairing instability can lead to a Fulde-Ferrell-Larkin-Ovchinnikov-like molecular state, which undergoes a first-order transition into a pairing state with zero center-of-mass momentum as the parameters are tuned. These pairing states are metastable against a polaron state dressed by particle-hole fluctuations for small SOC. At large SOC, a polaron-molecule transition exists, which suggests a phase transition between the topological superfluid state and the normal state for a highly polarized Fermi gas in the thermodynamic limit. As polarization in a Fermi gas with SOC is induced by the effective Zeeman field, we also discuss the influences of the effective Zeeman field on the ground state of the system. Our findings may be tested directly in future experiments. PMID- 23083231 TI - Nonperturbative master equation solution of central spin dephasing dynamics. AB - We solve the long-standing central spin problem for a general set of inhomogeneous bath couplings and a large class of initial bath states. We compute the time evolution of the coherence of a central spin coupled to a spin bath by resumming all orders of the time-convolutionless master equation, thus avoiding the need to assume weak coupling to the bath. The fully quantum, non-markovian solution is obtained in the large-bath limit and is valid up to a time scale set by the largest coupling constant. Our result captures the full decoherence of an electron spin qubit coupled to a nuclear spin bath in a GaAs quantum dot for experimentally relevant parameters. In addition, our solution is quite compact and can readily be used to make quantitative predictions for the decoherence process and to guide the design of nuclear state preparation protocols. PMID- 23083232 TI - Low-temperature triple-alpha rate in a full three-body nuclear model. AB - A new three-body method is used to compute the rate of the triple-alpha capture reaction, which is the primary source of 12C in stars. In this Letter, we combine the Faddeev hyperspherical harmonics and the R-matrix method to obtain a full solution to the three-body alpha+alpha+alpha continuum. Particular attention is paid to the long-range effects caused by the pairwise Coulomb interactions. The new rate agrees with the Nuclear Astrophysics Compilation of Reaction rates for temperatures greater than 0.07 GK, but a large enhancement at lower temperature is found (~10(12) at 0.02 GK). Our results are compared to previous calculations where additional approximations were made. We show that the new rate does not significantly change the evolution of stars around one solar mass. In particular, such stars still undergo a red-giant phase consistent with observations, and no significant differences are found in the final white dwarfs. PMID- 23083233 TI - Is black-hole ringdown a memory of its progenitor? AB - We perform an extensive numerical study of coalescing black-hole binaries to understand the gravitational-wave spectrum of quasinormal modes excited in the merged black hole. Remarkably, we find that the masses and spins of the progenitor are clearly encoded in the mode spectrum of the ringdown signal. Some of the mode amplitudes carry the signature of the binary's mass ratio, while others depend critically on the spins. Simulations of precessing binaries suggest that our results carry over to generic systems. Using Bayesian inference, we demonstrate that it is possible to accurately measure the mass ratio and a proper combination of spins even when the binary is itself invisible to a detector. Using a mapping of the binary masses and spins to the final black-hole spin allows us to further extract the spin components of the progenitor. Our results could have tremendous implications for gravitational astronomy by facilitating novel tests of general relativity using merging black holes. PMID- 23083234 TI - Testing Planck-scale gravity with accelerators. AB - Quantum or torsion gravity models predict unusual properties of space-time at very short distances. In particular, near the Planck length, around 10(-35) m, empty space may behave as a crystal, singly or doubly refractive. However, this hypothesis remains uncheckable for any direct measurement, since the smallest distance accessible in experiment is about 10(-19) m at the LHC. Here I propose a laboratory test to measure the space refractivity and birefringence induced by gravity. A sensitivity from 10(-31) m down to the Planck length could be reached at existent GeV and future TeV energy lepton accelerators using laser Compton scattering. There are already experimental hints for gravity signature at distances approaching the Planck length by 5-7 orders of magnitude, derived from SLC and HERA data. PMID- 23083235 TI - Astrophysics-independent bounds on the annual modulation of dark matter signals. AB - We show how constraints on the time integrated event rate from a given dark matter (DM) direct detection experiment can be used to bound the amplitude of the annual modulation signal in another experiment. The method requires only mild assumptions about the properties of the local DM distribution: that it is temporally stable on the scale of months and spatially homogeneous on the ecliptic. We apply the method to the annual modulation signal in DAMA/LIBRA, which we compare to the bounds derived from XENON10, XENON100, cryogenic DM search, and SIMPLE data. Assuming a DM mass of 10 GeV, we show that under the above assumptions about the DM halo, a DM interpretation of the DAMA/LIBRA signal is excluded for several classes of models: at 6.3sigma (4.6sigma) for elastic isospin conserving (violating) spin-independent interactions, and at 4.9sigma for elastic spin-dependent interactions on protons. PMID- 23083237 TI - Proposal for an electron antineutrino disappearance search using high-rate 8Li production and decay. AB - This paper introduces an experimental probe of the sterile neutrino with a novel, high-intensity source of electron antineutrinos from the production and subsequent decay of 8Li. When paired with an existing ~1 kton scintillator-based detector, this = 6.4 MeV source opens a wide range of possible searches for beyond standard model physics via studies of the inverse beta decay interaction nu(e) + p -> e+ + n. In particular, the experimental design described here has unprecedented sensitivity to nu(e) disappearance at Deltam2 ~ 1 eV2 and features the ability to distinguish between the existence of zero, one, and two sterile neutrinos. PMID- 23083238 TI - E2 interference effects in the 12C(alpha,gamma0)16O reaction. AB - The E1-E2 interference sign between the E(c.m.)=2.68-MeV E2 resonance and an underlying E1 strength has been measured for the first time. An E1-E2 asymmetry parameter of a=0.07+/-0.05 was extracted from the thick-target gamma-ray yields of the narrow resonance at angles of 45 degrees and 135 degrees . The positive sign of a corresponded to constructive interference at forward angles and, further, allowed the interference between the resonance and an E2 background to be identified as constructive below the resonance energy. The E2-E2 interference was then used to evaluate the global S(E2) data within the vicinity of the resonance 2.5<=E(c.m.)<=3.0 MeV. An analysis of the global S(E2) data that agreed with the interference scenario has determined the E2-E2 interference scheme of the 4.34-MeV resonance and background, resulting in a value of S(E2)(300)=62(-6)(+9) keV b. PMID- 23083239 TI - Revealing the Cooper minimum of N2 by molecular frame high-harmonic spectroscopy. AB - Molecular frame high-harmonic spectra of aligned N2 molecules reveal a Cooper like minimum. By deconvolving the laboratory frame alignment distribution, what was previously thought to be a maximum of emission along the molecular axis is found to be maxima at 35 degrees off axis, with a spectral minimum on axis. Both of these features are supported by photoionization calculations that underline the relationship between high-harmonic spectroscopy and photoionization measurements. The calculations reveal that the on axis spectral minimum is a Cooper-like minimum that arises from the destructive interference of the p and f partial wave contributions to high-harmonic photorecombination. Features such as Cooper minima and shape resonances are ubiquitous in molecular photoionization or recombination. PMID- 23083240 TI - Entanglement swapping with local certification: application to remote micromechanical resonators. AB - We propose a protocol for entanglement swapping which involves tripartite systems. The generation of remote entanglement induced by the Bell measurement can be easily certified by additional local measurements. We illustrate the protocol in the case of continuous variable systems where the certification is effective for an appropriate class of three-mode gaussian states. We then apply the protocol to optomechanical systems, showing how mechanical entanglement between two remote micromechanical resonators can be generated and certified via local optical measurements. PMID- 23083241 TI - Vortex induction via anisotropy stabilized light-matter interaction. AB - By sending circularly polarized light beams onto a homeotropic nematic liquid crystal cell with a photosensitive wall, we are able to locally induce spontaneous matter vortices that remain, each, stable and trapped at the chosen location. We discuss the dual light-matter nature of the created vortices and demonstrate the ability of the system to create optical vortices with opposite topological charges that, consistent with angular momentum conservation, both derive from the same defect created in the liquid crystal texture. Theoretically, we identify a self-stabilizing mechanism for the matter vortex, which is provided by the concurrency of light-induced gradients and anisotropy of the elastic constants that characterize the deformation of the liquid crystal medium. PMID- 23083242 TI - Frequency conversion in a high Q-factor sapphire whispering gallery mode resonator due to paramagnetic nonlinearity. AB - Nonlinear frequency conversion is a well known and widely exploited family of effects in optics, often arising from a Kerr nonlinearity in a crystal medium. Here, we report high stability frequency conversion in the microwave regime due to a chi(3) nonlinearity in sapphire introduced by a dilute concentration of paramagnetic spins. First, we produce a high stability comb from two microwave fields at 12.029 and 12.037 GHz corresponding to two high Q-factor whispering gallery (WG) modes within the electron spin resonance bandwidth of the Fe3+ ion. The resulting comb is generated by a cascaded four-wave mixing effect with a 7.7 MHz repetition rate. Then, by suppressing four-wave mixing by increasing the threshold power, third harmonic generation is achieved in a variety of WG modes coupled to various species of paramagnetic ion within the sapphire. PMID- 23083243 TI - Optical extinction in a single layer of nanorods. AB - We demonstrate that almost 100% of incident photons can interact with a monolayer of scatterers in a symmetrical environment. Nearly perfect optical extinction through free-standing transparent nanorod arrays has been measured. The sharp spectral opacity window, in the form of a characteristic Fano resonance, arises from the coherent multiple scattering in the array. In addition, we show that nanorods made of absorbing material exhibit a 25-fold absorption enhancement per unit volume compared to unstructured thin film. These results open new perspectives for light management in high-Q, low volume dielectric nanostructures, with potential applications in optical systems, spectroscopy, and optomechanics. PMID- 23083244 TI - Revisiting algorithms for generating surrogate time series. AB - The method of surrogates is one of the key concepts of nonlinear data analysis. Here, we demonstrate that commonly used algorithms for generating surrogates often fail to generate truly linear time series. Rather, they create surrogate realizations with Fourier phase correlations leading to nondetections of nonlinearities. We argue that reliable surrogates can only be generated, if one tests separately for static and dynamic nonlinearities. PMID- 23083245 TI - Geometry-induced rigidity in nonspherical pressurized elastic shells. AB - We present results from an experimental investigation of the indentation of nonspherical pressurized elastic shells with a positive Gauss curvature. A predictive framework is proposed that rationalizes the dependence of the local rigidity of an indented shell on the curvature in the neighborhood of the locus of indentation, the in-out pressure differential, and the material properties. In our approach, we combine classic theory for spherical shells with recent analytical developments for the pressurized case, and proceed, for the most part, by analogy, guided by our own experiments. By way of example, our results elucidate why an eggshell is significantly stiffer when compressed along its major axis, as compared to doing so along its minor axis. The prominence of geometry in this class of problems points to the relevance and applicability of our findings over a wide range of length scales. PMID- 23083246 TI - Indentation of ellipsoidal and cylindrical elastic shells. AB - Thin shells are found in nature at scales ranging from viruses to hens' eggs; the stiffness of such shells is essential for their function. We present the results of numerical simulations and theoretical analyses for the indentation of ellipsoidal and cylindrical elastic shells, considering both pressurized and unpressurized shells. We provide a theoretical foundation for the experimental findings of Lazarus et al. [following paper, Phys. Rev. Lett. 109, 144301 (2012)] and for previous work inferring the turgor pressure of bacteria from measurements of their indentation stiffness; we also identify a new regime at large indentation. We show that the indentation stiffness of convex shells is dominated by either the mean or Gaussian curvature of the shell depending on the pressurization and indentation depth. Our results reveal how geometry rules the rigidity of shells. PMID- 23083247 TI - Extreme events in the dispersions of two neighboring particles under the influence of fluid turbulence. AB - We present a numerical study of two-particle dispersion from point sources in three-dimensional incompressible homogeneous and isotropic turbulence at Reynolds number Re?300. Tracer particles are emitted in bunches from localized sources smaller than the Kolmogorov scale. We report the first quantitative evidence, supported by an unprecedented statistics, of the deviations of relative dispersion from Richardson's picture. Deviations are due to extreme events of pairs separating much faster than average, and of pairs remaining close for long time. The two classes of events are the fingerprints of complete different physics, the former dominated by inertial subrange and large-scale fluctuations, and the latter by dissipation subrange. A comparison of the relative separation in surrogate white-in-time velocity field, with correct viscous-, inertial-, and integral-scale properties, allows us to assess the importance of temporal correlations along tracer trajectories. PMID- 23083248 TI - Minimization of viscous fluid fingering: a variational scheme for optimal flow rates. AB - Conventional viscous fingering flow in radial Hele-Shaw cells employs a constant injection rate, resulting in the emergence of branched interfacial shapes. The search for mechanisms to prevent the development of these bifurcated morphologies is relevant to a number of areas in science and technology. A challenging problem is how best to choose the pumping rate in order to restrain the growth of interfacial amplitudes. We use an analytical variational scheme to look for the precise functional form of such an optimal flow rate. We find it increases linearly with time in a specific manner so that interface disturbances are minimized. Experiments and nonlinear numerical simulations support the effectiveness of this particularly simple, but nontrivial, pattern controlling process. PMID- 23083249 TI - Determination of the pulse duration of an x-ray free electron laser using highly resolved single-shot spectra. AB - We determined the pulse duration of x-ray free electron laser light at 10 keV using highly resolved single-shot spectra, combined with an x-ray free electron laser simulation. Spectral profiles, which were measured with a spectrometer composed of an ultraprecisely figured elliptical mirror and an analyzer flat crystal of silicon (555), changed markedly when we varied the compression strength of the electron bunch. The analysis showed that the pulse durations were reduced from 31 to 4.5 fs for the strongest compression condition. The method, which is readily applicable to evaluate shorter pulse durations, provides a firm basis for the development of femtosecond to attosecond sciences in the x-ray region. PMID- 23083250 TI - Evolution of an electron current layer prior to reconnection onset. AB - Electron current layers (ECLs) are the sites where magnetic reconnection initiates in a current sheet. Using three-dimensional particle-in-cell simulations, we study the plasma processes that occur in an ECL as it evolves rapidly over a short time scale much shorter than the ion cyclotron period. The processes include its thinning, generation of electrostatic instabilities, trapping and heating of electrons in growing waves, its rebroadening, generation of anomalous resistivity, and eventually the generation of large-amplitude magnetic fluctuations. These fluctuations could be interpreted in terms of electron tearing and/or Weibel instabilities, which are commonly invoked as mechanisms for the magnetic reconnection onset. The widths of the broadened ECL are compared with those measured in the magnetic reconnection experiment, showing excellent agreement. PMID- 23083251 TI - Nonlinear excitations of zonal structures by toroidal Alfven eigenmodes. AB - Zonal flows and, more generally, zonal structures are known to play important self-regulatory roles in the dynamics of microscopic drift-wave-type turbulences. Since toroidal Alfven eigenmode (TAE) plays crucial roles in the Alfven wave instabilities in burning fusion plasmas, it is, thus, important to understand and assess the possible roles of zonal flow and structures on the nonlinear dynamics of TAE. It is shown that zonal flow or structure spontaneous excitation is more easily induced by finite amplitude TAEs including the proper trapped-ion responses, causing the zonal structure to be dominated by the zonal current instead of the usual zonal flow. This work shows that proper accounting for plasma equilibrium geometry as well as including kinetic thermal ion treatment in the nonlinear simulations of Alfvenic modes are important ingredients for realistic comparisons with experimental measurements, where the existence of zonal fields has been clearly observed. PMID- 23083252 TI - Appearance and dynamics of helical flux tubes under electron cyclotron resonance heating in the core of KSTAR plasmas. AB - Dual (or sometimes multiple) flux tubes (DFTs) have been observed in the core of sawtoothing KSTAR tokamak plasmas with electron cyclotron resonance heating. The time evolution of the flux tubes visualized by a 2D electron cyclotron emission imaging diagnostic typically consists of four distinctive phases: (1) growth of one flux tube out of multiple small flux tubes during the initial buildup period following a sawtooth crash, resulting in a single dominant flux tube along the m/n=1/1 helical magnetic field lines, (2) sudden rapid growth of another flux tube via a fast heat transfer from the first one, resulting in approximately identical DFTs, (3) coalescence of the two flux tubes into a single m/n=1/1 flux tube resembling the internal kink mode in the normal sawteeth, which is explained by a model of two current-carrying wires confined on a flux surface, and (4) fast localized crash of the merged flux tube similar to the standard sawtooth crash. The dynamics of the DFTs implies that the internal kink mode is not a unique prerequisite to the sawtooth crash, providing a new insight on the control of the sawtooth. PMID- 23083253 TI - Determination of the hohlraum M-band fraction by a shock-wave technique on the SGIII-prototype laser facility. AB - The proposal of simultaneously determining the hohlraum peak radiation temperature T(R) and M-band fraction f(M) by shock velocity measurement technique [Y. S. Li et al. Phys. Plasmas 18, 022701 (2011)] is demonstrated for the first time in recent experiments conducted on SGIII-prototype laser facility. In the experiments, T(R) and f(M) are determined by using the observed shock velocities in Al and Ti. For the Au hohlraum used in the experiments, T(R) is about 160 eV and f(M) is around 4.3% under a 1 ns laser pulse of 2 kJ. The results from this method are complementary to those from the broadband x-ray spectrometer, and the technique can be further used to determine T(R) and f(M) inside an ignition hohlraum. PMID- 23083254 TI - Ion motion in self-modulated plasma wakefield accelerators. AB - The effects of plasma ion motion in self-modulated plasma-based accelerators are examined. An analytical model describing ion motion in the narrow beam limit is developed and confirmed through multidimensional particle-in-cell simulations. It is shown that the ion motion can lead to the early saturation of the self modulation instability and to the suppression of the accelerating gradients. This can reduce the total energy that can be transformed into kinetic energy of accelerated particles. For the parameters of future proton-driven plasma accelerator experiments, the ion dynamics can have a strong impact. Possible methods to mitigate the effects of the ion motion in future experiments are demonstrated. PMID- 23083255 TI - Dynamics of relativistic laser-plasma interaction on solid targets. AB - A novel time-resolved diagnostic is used to record the critical surface motion during picosecond-scale relativistic laser interaction with a solid target. Single-shot measurements of the specular light show a redshift decreasing with time during the interaction, corresponding to a slowing-down of the hole boring process into overdense plasma. On-shot full characterization of the laser pulse enables simulations of the experiment without any free parameters. Two dimensional particle-in-cell simulations yield redshifts that agree with the data, and support a simple explanation of the slowing-down of the critical surface based on momentum conservation between ions and reflected laser light. PMID- 23083256 TI - Non-abelian gauge fields and topological insulators in shaken optical lattices. AB - Time-periodic driving like lattice shaking offers a low-demanding method to generate artificial gauge fields in optical lattices. We identify the relevant symmetries that have to be broken by the driving function for that purpose and demonstrate the power of this method by making concrete proposals for its application to two-dimensional lattice systems: We show how to tune frustration and how to create and control band touching points like Dirac cones in the shaken kagome lattice. We propose the realization of a topological and a quantum spin Hall insulator in a shaken spin-dependent hexagonal lattice. We describe how strong artificial magnetic fields can be achieved for example in a square lattice by employing superlattice modulation. Finally, exemplified on a shaken spin dependent square lattice, we develop a method to create strong non-abelian gauge fields. PMID- 23083257 TI - Fracture strength of AlLiB14. AB - The orthorhombic boride crystal family XYB14, where X and Y are metal atoms, plays a critical role in a unique class of superhard compounds, yet there have been no studies aimed at understanding the origin of the mechanical strength of this compound. We present here the results from a comprehensive investigation into the fracture strength of the archetypal AlLiB14 crystal. First principles, ab initio, methods are used to determine the ideal brittle cleavage strength for several high-symmetry orientations. The elastic tensor and the orientation dependent Young's modulus are calculated. From these results the lower bound fracture strength of AlLiB14 is predicted to be between 29 and 31 GPa, which is near the measured hardness reported in the literature. These results indicate that the intrinsic strength of AlLiB14 is limited by the interatomic B-B bonds that span between the B layers. PMID- 23083258 TI - Measuring electric field induced subpicometer displacement of step edge ions. AB - We provide unambiguous evidence that the applied electrostatic field displaces step atoms of ionic crystal surfaces by subpicometers in different directions via the measurement of the lateral force interactions by bimodal dynamic force microscopy combined with multiscale theoretical simulations. Such a small imbalance in the electrostatic interaction of the shifted anion-cation ions leads to an extraordinary long-range feature potential variation and is now detectable with the extreme sensitivity of the bimodal detection. PMID- 23083259 TI - Atomic structure of Mn wires on Si(001) resolved by scanning tunneling microscopy. AB - At submonolayer coverage, Mn forms atomic wires on the Si(001) surface oriented perpendicular to the underlying Si dimer rows. While many other elements form symmetric dimer wires at room temperature, we show that Mn wires have an asymmetric appearance and pin the Si dimers nearby. We find that an atomic configuration with a Mn trimer unit cell can explain these observations as due to the interplay between the Si dimer buckling phase near the wire and the orientation of the Mn trimer. We study the resulting four wire configurations in detail using high-resolution scanning tunneling microscopy (STM) imaging and compare our findings with the STM images simulated by density functional theory. PMID- 23083260 TI - Role of activated chemisorption in gas-mediated electron beam induced deposition. AB - Models of adsorbate dissociation by energetic electrons are generalized to account for activated sticking and chemisorption, and used to simulate the rate kinetics of electron beam induced chemical vapor deposition (EBID). The model predicts a novel temperature dependence caused by thermal transitions from physisorbed to chemisorbed states that govern adsorbate coverage and EBID rates at elevated temperatures. We verify these results by experiments that also show how EBID can be used to deposit high purity materials and characterize the rates and energy barriers that govern adsorption. PMID- 23083261 TI - Strength of the effective Coulomb interaction at metal and insulator surfaces. AB - The effective on-site Coulomb interaction (Hubbard U) between localized electrons at crystal surfaces is expected to be enhanced due to the reduced coordination number and reduced subsequent screening. By means of first principles calculations employing the constrained random-phase approximation we show that this is indeed the case for simple metals and insulators but not necessarily for transition metals and insulators that exhibit pronounced surface states. In the latter case, the screening contribution from surface states as well as the influence of the band narrowing increases the electron polarization to such an extent as to overcompensate the decrease resulting from the reduced effective screening volume. The Hubbard U parameter is thus substantially reduced in some cases, e.g., by around 30% for the (100) surface of bcc Cr. PMID- 23083262 TI - Density-functional theory for f-electron systems: the alpha-gamma phase transition in cerium. AB - The isostructural alpha-gamma phase transition in cerium is analyzed using density-functional theory with different exchange-correlation functionals, in particular the PBE0 hybrid functional and the exact-exchange plus correlation in the random-phase approximation [(EX+cRPA)@PBE0] approach. We show that the Hartree-Fock exchange part of the hybrid functional gives rise to two distinct solutions at zero temperature that can be associated with the alpha and gamma phases of cerium. However, despite the relatively good structural and magnetic properties, PBE0 predicts the gamma phase to be the stable phase at ambient pressure and zero temperature, in contradiction with low temperature experiments. EX+cRPA reverses the energetic ordering, which emphasizes the importance of correlation for rare-earth systems. PMID- 23083263 TI - Interplay of disorder and interaction in Majorana quantum wires. AB - We study the interplay between disorder and interaction in one-dimensional topological superconductors which carry localized Majorana zero-energy states. Using Abelian bosonization and the perturbative renormalization group approach, we obtain the renormalization group flow and the associated scaling dimensions of the parameters and identify the critical points of the low-energy theory. We predict a quantum phase transition from a topological superconducting phase to a nontopological localized phase, and obtain the phase boundary between these two phases as a function of the electron-electron interaction and the disorder strength in the nanowire. Based on an instanton analysis which incorporates the effect of disorder, we also identify a large regime of stability of the Majorana carrying topological phase in the parameter space of the model. PMID- 23083264 TI - Topological phase transition in the interaction of surface Dirac fermions in heterostructures. AB - Material with a nontrivial topology in its electronic structure enforces the existence of helical Dirac fermionic surface states. We discover emergent topological phases in the stacked structures of topological insulator and band insulator layers where the surface Dirac fermions interact with each other with a particular helicity ordering. Using first-principles calculations and a model Lagrangian, we explicitly demonstrate that such helicity ordering occurs in real materials of ternary chalcogen compounds and determines their topological insulating phase. Our results reveal the rich collective nature of interacting surface Dirac fermions and pave the way for utilizing topological phases for technological devices such as nonvolatile memories. PMID- 23083265 TI - Unified formalism of Andreev reflection at a ferromagnet/superconductor interface. AB - We present a unified formalism of Andreev reflection of a partial polarized current at a ferromagnet/superconductor interface instead of assuming a linear combination of unpolarized and polarized currents. The Andreev reflection is limited by the states of minority spins and the extra majority spins become evanescent wave. We further study the effects of spin polarization, inelastic scattering, and interfacial scattering on the Andreev reflection, normal reflection, and transmitted probabilities in equilibrium as well as under a bias. Our model, which reduces to those of Blonder, Tinkham, and Klapwijk, Mazin, and Dynes in three limiting cases, provides a significantly better description of the experimental results. PMID- 23083266 TI - Electric field-driven coherent spin reorientation of optically generated electron spin packets in InGaAs. AB - Full electric-field control of spin orientations is one of the key tasks in semiconductor spintronics. We demonstrate that electric-field pulses can be utilized for phase-coherent +/-pi spin rotation of optically generated electron spin packets in InGaAs epilayers detected by time-resolved Faraday rotation. Through spin-orbit interaction, the electric-field pulses act as local magnetic field pulses. By the temporal control of the local magnetic field pulses, we can turn on and off electron spin precession and thereby rotate the spin direction into arbitrary orientations in a two-dimensional plane. Furthermore, we demonstrate a spin-echo-type spin drift experiment and find an unexpected partial spin rephasing, which is evident by a doubling of the spin dephasing time. PMID- 23083267 TI - Thermoelectric probe for neutral edge modes in the fractional quantum Hall regime. AB - The nu=5/2 anti-Pfaffian state and the nu=2/3 state are believed to have an edge composed of counterpropagating charge and neutral modes. This situation allows the generation of a pure thermal bias between two composite edge states across a quantum point contact as was experimentally established by Bid et al. [Nature 466, 585 (2010)]. We show that replacing the quantum point contact by a quantum dot provides a natural way for detecting the neutral modes via the dc current generated by the thermoelectric response of the dot. We also show that the degeneracies of the dot spectrum, dictated by the conformal field theories describing these states, induce asymmetries in the thermoelectric current peaks. This in turn provides a direct fingerprint of the corresponding conformal field theory. PMID- 23083268 TI - Magneto-optical measurements of a cascade of transitions in superconducting La1.875Ba0.125CuO4 single crystals. AB - Recent experiments on the original cuprate high-temperature superconductor, La(2 x)Ba(x)CuO4, revealed a remarkable sequence of phase transitions. Here we investigate such crystals with the polar Kerr effect, which is sensitive to time reversal-symmetry breaking. Concurrent birefringence measurements accurately locate the structural phase transitions from high-temperature tetragonal to low temperature orthorhombic, and then to lower-temperature tetragonal, at which temperature strong Kerr signal onsets. Hysteretic behavior of the Kerr signal suggests that time-reversal symmetry is already broken well above room temperature, an effect that was previously observed in high quality YBa2Cu3O(6+x) crystals. PMID- 23083269 TI - Universal broadening of the Bardeen-Cooper-Schrieffer coherence peak of disordered superconducting films. AB - In disordered superconductors, the local pairing field fluctuates in space, leading to the smearing of the BCS peak in the density of states and the appearance of the subgap tail states. We analyze the universal mesoscopic contributions to these effects and show that they are enhanced by the Coulomb repulsion. In the vicinity of the quantum critical point, where superconductivity is suppressed by the "fermionic mechanism," strong smearing of the peak due to mesoscopic fluctuations is predicted. PMID- 23083270 TI - Effective doping and suppression of Fermi surface reconstruction via Fe vacancy disorder in K(x)Fe(2-y)Se2. AB - We investigate the effect of disordered vacancies on the normal-state electronic structure of the newly discovered alkali-intercalated iron selenide superconductors. To this end, we use a recently developed Wannier function based method to calculate from first principles the configuration-averaged spectral function of K0.8Fe1.6Se2 with disordered Fe and K vacancies. We find that the disorder can suppress the expected Fermi surface reconstruction without completely destroying the Fermi surface. More interestingly, the disorder effect raises the chemical potential significantly, giving enlarged electron pockets similar to highly doped KFe2Se2, without adding carriers to the system. PMID- 23083271 TI - Theory of a large thermoelectric effect in superconductors doped with magnetic impurities. AB - We argue that parametrically strong enhancement of a thermoelectric current can be observed in conventional superconductors doped by magnetic impurities. This effect is caused by the violation of the symmetry between electronlike and holelike excitations due to formation of subgap bound Andreev states in the vicinity of magnetic impurities. We develop a quantitative theory of this effect and demonstrate that it can be detected in modern experiments. PMID- 23083272 TI - Interlayer charge disproportionation in the layered organic superconductor kappa(H)-(DMEDO-TSeF)2[Au(CN)4](THF) with polar dielectric insulating layers. AB - We report the molecular dipole effect on conduction electrons in the title superconductor. The angular-dependent magnetoresistance has a peak for fields nearly parallel to the conducting layer, and the peak width scales as the field component perpendicular to the layer, indicating incoherent interlayer transport. However, two closed Fermi surfaces are observed in quantum oscillation. Accordingly, crystallographically independent layers have different charge densities in a bulk single crystal. The electric dipole of tetrahydrofuran gives rise to interlayer charge disproportionation. PMID- 23083273 TI - Disorder, cluster spin glass, and hourglass spectra in striped magnetic insulators. AB - Hourglass-shaped magnetic excitation spectra have been detected in a variety of doped transition-metal oxides with stripelike charge order. Compared to the predictions of spin-wave theory for perfect stripes, these spectra display a different intensity distribution and anomalous broadening. Here we show, based on a comprehensive modeling for La5/3Sr1/3CoO4, how quenched disorder in the charge sector causes frustration, and consequently cluster-glass behavior at low temperatures, in the spin sector. This spin-glass physics, which is insensitive to the detailed nature of the charge disorder, but sensitive to the relative strength of the magnetic interstripe coupling, ultimately determines the distribution of magnetic spectral weight: The excitation spectrum, calculated using spin waves in finite disordered systems, is found to match in detail the observed hour-glass spectrum. PMID- 23083274 TI - Reversible change of the spin state in a manganese phthalocyanine by coordination of CO molecule. AB - We show that the magnetic state of individual manganese phthalocyanine (MnPc) molecules on a Bi(110) surface is modified when the Mn2+ center coordinates to CO molecules adsorbed on top. Using scanning tunneling spectroscopy we identified this change in magnetic properties from the broadening of a Kondo-related zero bias anomaly when the CO-MnPc complex is formed. The original magnetic state can be recovered by selective desorption of individual CO molecules. First principles calculations show that the CO molecule reduces the spin of the adsorbed MnPc from S=1 to S=1/2 and strongly modifies the respective screening channels, driving a transition from an underscreened Kondo state to a state of mixed valence. PMID- 23083275 TI - Direct observation of magnetic anisotropy in an individual Fe4 single-molecule magnet. AB - We study three-terminal charge transport through individual Fe4 single-molecule magnets. Magnetic anisotropy of the single molecule is directly observed by introducing a spectroscopic technique based on measuring the position of the degeneracy point as a function of gate voltage and applied magnetic field. A nonlinear field-dependence is observed which changes by rotating the sample and is, thus, a direct proof of magnetic anisotropy. The sensitivity of this method allows us to observe small changes in the orientation and magnitude of the anisotropy in different charge states. We find that the easy axes in adjacent states are (almost) collinear. PMID- 23083276 TI - Coexistence of long-range and algebraic correlations for short-range valence-bond wave functions in three dimensions. AB - We investigate nearest-neighbor valence-bond wave functions on bipartite three dimensional lattices. By performing large-scale Monte Carlo simulations, we find that long-range magnetic order coexists with dipolar four-spin correlations on the cubic lattice, this latter feature being reminiscent of the Coulomb phase for classical dimers on the same geometry. Similar properties are found for the lower coordination diamond lattice. While this suggests that the coexistence of magnetic order and dipolar four-spin correlations is generic for such states on bipartite three-dimensional lattices, we show that simple generalizations of these wave functions can encode different ordering behaviors. PMID- 23083277 TI - Quantum magnetomechanics with levitating superconducting microspheres. AB - We show that by magnetically trapping a superconducting microsphere close to a quantum circuit, it is possible to perform ground-state cooling and prepare quantum superpositions of the center-of-mass motion of the microsphere. Due to the absence of clamping losses and time-dependent electromagnetic fields, the mechanical motion of micrometer-sized metallic spheres in the Meissner state is predicted to be very well isolated from the environment. Hence, we propose to combine the technology of magnetic microtraps and superconducting qubits to bring relatively large objects to the quantum regime. PMID- 23083278 TI - Quantum magnetomechanics: ultrahigh-Q-levitated mechanical oscillators. AB - Engineering nanomechanical quantum systems possessing ultralong motional coherence times allows for applications in precision quantum sensing and quantum interfaces, but to achieve ultrahigh motional Q one must work hard to remove all forms of motional noise and heating. We examine a magneto-meso-mechanical quantum system that consists of a 3D arrangement of miniature superconducting loops which is stably levitated in a static inhomogeneous magnetic field. The motional decoherence is predominantly due to loss from induced eddy currents in the magnetized sphere which provides the trapping field ultimately yielding Q~10(9) with motional oscillation frequencies of several hundreds of kilohertz. By inductively coupling this levitating object to a nearby driven flux qubit one can cool its motion very close to the ground state and this may permit the generation of macroscopic entangled motional states of multiple clusters. PMID- 23083280 TI - Correlation functions in SU(2)-invariant resonating-valence-bond spin liquids on nonbipartite lattices. AB - We introduce a Monte Carlo scheme based on sampling of Pfaffians to investigate Anderson's resonating-valence-bond (RVB) spin liquid wave function on the kagome and the triangular lattice. This eliminates a sign problem that prevents utilization of the valence bond basis in Monte Carlo studies for nonbipartite lattices. Studying lattice sizes of up to 600 sites, we calculate singlet-singlet and spin-spin correlations and demonstrate how the lattice symmetry is restored within each topological sector as the system size is increased. Our findings are consistent with the expectation that the nearest-neighbor RVB states describe a topological spin liquid on these nonbipartite lattices. PMID- 23083279 TI - Exchange field-mediated magnetoresistance in the correlated insulator phase of Be films. AB - We present a study of the proximity effect between a ferromagnet and a paramagnetic metal of varying disorder. Thin beryllium films are deposited onto a 5 nm thick layer of the ferromagnetic insulator EuS. This bilayer arrangement induces an exchange field, H(ex), of a few tesla in low-resistance Be films with sheet resistance R?R(Q), where R(Q)=h/e2 is the quantum resistance. We show that H(ex) survives in very high-resistance films and, in fact, appears to be relatively insensitive to the Be disorder. We exploit this fact to produce a giant low-field magnetoresistance in the correlated-insulator phase of Be films with R?R(Q). PMID- 23083281 TI - Frustrated resonating valence bond states in two dimensions: classification and short-range correlations. AB - Resonating valence bond (RVB) states are of crucial importance in our intuitive understanding of quantum spin liquids in 2D. We systematically classify short range bosonic RVB states into symmetric or nematic spin liquids by examining their flux patterns. We further map short-range bosonic RVB states into projected BCS wave functions, on which we perform large-scale Monte Carlo simulations without the minus sign problem. Our results clearly show that both spin and dimer correlations decay exponentially in all the short-range frustrated (nonbipartite or Z2) bosonic RVB states we studied, indicating that they are gapped Z2 quantum spin liquids. Generically, we conjecture that all short-range frustrated bosonic RVB states in 2D have only short-range correlations. PMID- 23083282 TI - Universal recovery of the energy-level degeneracy of bright excitons in InGaAs quantum dots without a structure symmetry. AB - The lack of structural symmetry which usually characterizes semiconductor quantum dots lifts the energetic degeneracy of the bright excitonic states and hampers severely their use as high-fidelity sources of entangled photons. We demonstrate experimentally and theoretically that it is always possible to restore the excitonic degeneracy by the simultaneous application of large strain and electric fields. This is achieved by using one external perturbation to align the polarization of the exciton emission along the axis of the second perturbation, which then erases completely the energy splitting of the states. This result, which holds for any quantum dot structure, highlights the potential of combining complementary external fields to create artificial atoms meeting the stringent requirements posed by scalable semiconductor-based quantum technology. PMID- 23083283 TI - Electron transfer in a virtual quantum state of LiBH4 induced by strong optical fields and mapped by femtosecond x-ray diffraction. AB - Transient polarizations connected with a spatial redistribution of electronic charge in a mixed quantum state are induced by optical fields of high amplitude. We determine for the first time the related transient electron density maps, applying femtosecond x-ray powder diffraction as a structure probe. The prototype ionic material LiBH4 driven nonresonantly by an intense sub-40 fs optical pulse displays a large-amplitude fully reversible electron transfer from the BH4(-) anion to the Li+ cation during excitation. Our results establish this mechanism as the source of the strong optical polarization which agrees quantitatively with theoretical estimates. PMID- 23083284 TI - Nonperturbative interband response of a bulk InSb semiconductor driven off resonantly by terahertz electromagnetic few-cycle pulses. AB - Intense multiterahertz pulses are used to study the coherent nonlinear response of bulk InSb by means of field-resolved four-wave mixing spectroscopy. At amplitudes above 5 MV/cm the signals show a clear temporal substructure which is unexpected in perturbative nonlinear optics. Simulations based on a model of a two-level quantum system demonstrate that in spite of the strongly off-resonant character of the excitation the high-field few-cycle pulses drive the interband resonances into a nonperturbative regime of Rabi flopping. The rotating wave approximation breaks down in this case and the system reaches a complete population inversion. PMID- 23083285 TI - Visible-to-telecom quantum frequency conversion of light from a single quantum emitter. AB - We demonstrate efficient (>30%) quantum frequency conversion of visible single photons (711 nm) emitted by a quantum dot to a telecom wavelength (1313 nm). Analysis of the first- and second-order coherence before and after wavelength conversion clearly proves that pivotal properties, such as the coherence time and photon antibunching, are fully conserved during the frequency translation process. Our findings underline the great potential of single photon sources on demand in combination with quantum frequency conversion as a promising technique that may pave the way for a number of new applications in quantum technology. PMID- 23083286 TI - Two-photon interference using background-free quantum frequency conversion of single photons emitted by an InAs quantum dot. AB - We show that quantum frequency conversion (QFC) can overcome the spectral distinguishability common to inhomogeneously broadened solid-state quantum emitters. QFC is implemented by combining single photons from an InAs/GaAs quantum dot (QD) at 980 nm with a 1550 nm pump laser in a periodically poled lithium niobate (PPLN) waveguide to generate photons at 600 nm with a signal-to background ratio exceeding 100:1. Photon correlation and two-photon interference measurements confirm that both the single photon character and wave packet interference of individual QD states are preserved during frequency conversion. Finally, we convert two spectrally separate QD transitions to the same wavelength in a single PPLN waveguide and show that the resulting field exhibits nonclassical two-photon interference. PMID- 23083287 TI - Multiscaling analysis of ferroelectric domain wall roughness. AB - Using multiscaling analysis, we compare the characteristic roughening of ferroelectric domain walls in Pb(Zr0.2Ti0.8)O3 thin films with numerical simulations of weakly pinned one-dimensional interfaces. Although at length scales up to L(MA)>=5 MUm the ferroelectric domain walls behave similarly to the numerical interfaces, showing a simple monoaffine scaling (with a well-defined roughness exponent zeta), we demonstrate more complex scaling at higher length scales, making the walls globally multiaffine (varying zeta at different observation length scales). The dominant contributions to this multiaffine scaling appear to be very localized variations in the disorder potential, possibly related to dislocation defects present in the substrate. PMID- 23083288 TI - Optical control of surface anchoring and reorientation of liquid crystals via a plasmon-enhanced local field. AB - Gold nanoparticles deposited on the windows of a liquid crystal (LC) cell were found to be able to reduce the surface anchoring energy of the LC, and hence the threshold for its reorientation phase transition, by 1 to 2 orders of magnitude when a cw pump light was used to excite the local plasmon resonance of the nanoparticles. The effect was due to the disorientation of LC molecules between nanoparticles by the plasmon-enhanced local field that softens the effective surface anchoring. A light-controlled variation of surface anchoring energy could provide new opportunities for optoelectronic applications of a LC. PMID- 23083289 TI - Branching with local probability as a paradigm of self-organized criticality. AB - A self-organized critical branching process based on a local interaction rule is presented. In accordance with the self-organized branching process model introduced by Zapperi, Lauritsen, and Stanley, its event-size distribution follows a power law with scaling exponent tau=3/2, but the new model does not require a global variable to self-organize to a critical point. The self organized critical behavior of the model seems to be extremely robust. The model may be seen as a new paradigm for progressive mechanical failure (e.g., earthquakes or landslides) or other avalanching phenomena, and perhaps even for self-organized criticality in general. PMID- 23083290 TI - Signaling noise enhances chemotactic drift of E. coli. AB - Noise in the transduction of chemotactic stimuli to the flagellar motor of E. coli will affect the random run-and-tumble motion of the cell and the ability to perform chemotaxis. Here we use numerical simulations to show that an intermediate level of noise in the slow methylation dynamics enhances drift while not compromising localization near concentration peaks. A minimal model shows how such an optimal noise level arises from the interplay of noise and the dependence of the motor response on the network output. Our results suggest that cells can exploit noise to improve chemotactic performance. PMID- 23083291 TI - Elasticity theory of macromolecular aggregates. AB - We present a version of continuum elasticity theory applicable to aggregates of functional biomolecules at length scales comparable to that of the component molecules. Unlike classical elasticity theory, the stress and strain fields have mathematical discontinuities along the interfaces of the macromolecules, due to conformational incompatibility and large scale conformational transitions. The method is applied to the P-II to EI shape transition of the protein shell of the virus HK97. We show that protein residual stresses generated by incompatibility drive a "reverse buckling" transition from an icosahedral to a dodecahedral shape via a "critical" spherical shape, which can be identified as the P-II state. PMID- 23083292 TI - Manifestations of charge induced instability in droplets effected by charged macromolecules. AB - Ion-release processes from droplets that contain excess charge are of central importance in determining the charge-state distributions of macromolecules in electrospray ionization methods. We develop an analytical theory to describe the mechanism of contiguous extrusion of a charged macromolecule from a droplet. We find that the universal parameter determining the system behavior is the ratio of solvation energy per unit length to the square of the ion charge density per unit length. Systems with the same value of the ratio will follow the same path in the course of droplet evaporation. The analytical model is compared with molecular simulations of charged polyethylene glycol macroion in aqueous droplets, and the results are in excellent agreement. PMID- 23083293 TI - Translationally invariant slip-spring model for entangled polymer dynamics. AB - The topological effect of noncrossability of long flexible macromolecules is effectively described by a slip-spring model, which represents entanglements by local, pairwise, translationally invariant interactions that do not alter any equilibrium properties. We demonstrate that the model correctly describes many aspects of the dynamical and rheological behavior of entangled polymer liquids, such as segmental mean-square displacements and shear thinning, in a computationally efficient manner. Furthermore, the model can account for the reduction of entanglements under shear. PMID- 23083294 TI - Association of HLA locus variant in Parkinson's disease. AB - A variant (rs3129882) in the genome-wide association study (GWAS)-linked variant [in the human leukocyte antigen (HLA) gene region] has been reported to associate with an increased risk of Parkinson's disease (PD) in Caucasian population. Studies among Chinese are limited. To address this, we analysed rs3129882 in a total of 1312 subjects of Chinese ethnicity from independent Asian centers comprising of 675 controls and 637 PD cases. The rs3129882 variant was associated with a decreased risk in our ethnic Chinese PD patients. Logistic regression analysis taking into consideration variables of age, gender and race showed that allele A reduced the risk of PD via a dominant model [odds ratio (OR) = 0.77, 95% confidence interval (CI) = 0.62, 0.96, p = 0.018]. As HLA is a highly polymorphic region, it is possible that ethnic-specific effect or environmental agents may modulate the effect of this GWAS-linked locus in influencing the risk of PD. PMID- 23083295 TI - Microglial and astroglial activation by 3,4-methylenedioxymethamphetamine (MDMA) in mice depends on S(+) enantiomer and is associated with an increase in body temperature and motility. AB - Evidence is accumulating to suggest that 3,4-methylenedioxymethamphetamine (MDMA) has neurotoxic and neuroinflammatory properties. MDMA is composed of two enantiomers with different biological activities. In this study, we evaluated the in vivo effects of S(+)-MDMA, R(-)-MDMA, and S(+)-MDMA in combination with R(-) MDMA on microglial and astroglial activation compared with racemic MDMA, by assessment of complement type 3 receptor (CD11b) and glial fibrillary acidic protein (GFAP) immunoreactivity in the mouse striatum, nucleus accumbens, motor cortex, and substantia nigra. Motor activity and body temperature were also measured, to elucidate the physiological modifications paired with the observed glial changes. Similar to racemic MDMA (4 * 20 mg/kg), S(+)-MDMA (4 * 10 mg/kg) increased both CD11b and GFAP in the striatum, although to a lower degree, whereas R(-)-MDMA (4 * 10 mg/kg) did not induce any significant glial activation. Combined administration of S(+) plus R(-)-MDMA did not induce any further activation compared with S(+)-MDMA. In all other areas, only racemic MDMA was able to slightly activate the microglia, but not the astroglia, whereas enantiomers had no effect, either alone or in combination. Racemic MDMA and S(+) MDMA similarly increased motor activity and raised body temperature, whereas R(-) MDMA affected neither body temperature nor motor activity. Interestingly, the increase in body temperature was correlated with glial activation. The results show that no synergism, but only additivity of effects, is caused by the combined administration of S(+)- and R(-)-MDMA, and underline the importance of investigating the biochemical and behavioral properties of the two MDMA enantiomers to understand their relative contribution to the neuroinflammatory and neurotoxic effects of MDMA. PMID- 23083296 TI - First case of mycetoma associated with Nocardia takedensis. PMID- 23083297 TI - Grip strength in CIDP: does one function fit all? PMID- 23083298 TI - Thickness and fit of mouthguards according to a vacuum-forming process. AB - The purpose of this study was to examine the difference in the thickness and the fit of mouthguards fabricated with a vacuum-forming method of the mouthguard sheet material. The material used in this study was Sports Mouthguard (3.8 mm thickness). Two forming conditions were performed. In the first condition, the sheet was lowered over the working model after the vacuum was applied, and in the other trial, the sheet was lowered over the working model before the vacuum was applied. The sheets were formed using a vacuum former when the heated sheets hung 1.5 cm from the baseline. We measured the thickness and the fit of the mouthguard at the areas of the central incisor and first molar in both conditions. The difference of the thickness at the areas of the central incisor and first molar and the forming condition was analyzed by Two-way anova. The difference of the fit according to the forming conditions was analyzed by the Mann-Whitney U test. The results showed that the thickness of the mouthguard differed at the areas of the central incisor and first molar, but the thickness of the mouthguard did not differ according to the forming conditions. The fit of the mouthguard at the central incisor and first molar was significantly different between the forming conditions (P < 0.01 and P < 0.05). These results suggested that the fit of the mouthguard was the best without any deficiency of thickness when the vacuum was applied first and then the sheet was pressed onto the working model. These results may be useful in fabricating proper mouthguards. PMID- 23083299 TI - Electrical hypothesis of toxicity of the Cry toxins for mosquito larvae. AB - Many electrical properties of insect larval guts have been studied, but their importance for toxicity of the Cry-type toxins has never been reported in the literature. In the present work, we observed potential-dependent permeabilization of plasma membrane by several polycationic peptides derived from the Cry11Bb protoxin. The peptide BTM-P1d, all D-type amino acid analogue of the earlier reported peptide BTM-P1, demonstrated high membrane-permeabilizing activity in experiments with isolated rat liver mitochondria, RBC (red blood cells) and mitochondria in homogenates of Aedes aegypti larval guts. Two larger peptides, BTM-P2 and BTM-P3, as well as the Cry11Bb protoxin treated with the protease extract of mosquito larval guts showed similar effects. Only protease-resistant BTM-P1d, in comparison with other peptides, displayed A. aegypti larval toxicity. Taking into account the potential-dependent mechanism of membrane permeabilization by studied fragments of the Cry11Bb protoxin and the literature data related to the distribution of membrane and transepithelial potentials in the A. aegypti larval midgut, we suggest an electrical hypothesis of toxicity of the Cry toxins for mosquito larvae. According to this hypothesis, the electrical field distribution is one of the factors determining the midgut region most susceptible for insertion of activated toxins into the plasma membrane to form pores. In addition, potential-dependent penetration of short active toxin fragments into the epithelial cells could induce permeabilization of mitochondria and subsequent apoptosis or necrosis. PMID- 23083300 TI - Synthesis of bridged polycyclic ring systems via carbene cascades terminating in C-H bond insertion. AB - A carbene cascade reaction that constructs functionalized bridged bicyclic systems from alkynyl diazoesters is presented. The cascade proceeds through diazo decomposition, carbene/alkyne metathesis, and C-H bond insertion. The diazoesters are easily synthesized from cyclic ketones. Substrate ring size and substitution patterns control the connectivity and diastereomeric preference found in the products. PMID- 23083303 TI - Kinetics of low-pressure, low-temperature graphene growth: toward single-layer, single-crystalline structure. AB - Graphene grown on metal catalysts with low carbon solubility is a highly competitive alternative to exfoliated and other forms of graphene, yet a single layer, single-crystal structure remains a challenge because of the large number of randomly oriented nuclei that form grain boundaries when stitched together. A kinetic model of graphene nucleation and growth is developed to elucidate the effective controls of the graphene island density and surface coverage from the onset of nucleation to the full monolayer formation in low-pressure, low temperature CVD. The model unprecedentedly involves the complete cycle of the elementary gas-phase and surface processes and shows a precise quantitative agreement with the recent low-energy electron diffraction measurements and also explains numerous parameter trends from a host of experimental reports. These agreements are demonstrated for a broad pressure range as well as different combinations of precursor gases and supporting catalysts. The critical role of hydrogen in controlling the graphene nucleation and monolayer formation is revealed and quantified. The model is generic and can be extended to even broader ranges of catalysts and precursor gases/pressures to enable the as yet elusive effective control of the crystalline structure and number of layers of graphene using the minimum amounts of matter and energy. PMID- 23083301 TI - What are the risk factors for the comorbidity of posttraumatic stress disorder and depression in a war-affected population? A cross-sectional community study in South Sudan. AB - BACKGROUND: Limited data exists on the association of war trauma with comorbid posttraumatic stress disorder (PTSD)-depression in the general population of low income countries. The present study aimed to evaluate socioeconomic and trauma related risk factors associated with PTSD, depression, and PTSD-depression comorbidity in the population of Greater Bahr el Ghazal States, South Sudan. METHODS: In this cross-sectional community study (n=1200) we applied the Harvard Trauma Questionnaire (HTQ) and MINI International Neuropsychiatric Interview (MINI) to investigate the prevalence of PTSD, depression, and PTSD-depression comorbidity. Multinomial logistic regression analyses were conducted to examine the association between these disorders, previous trauma exposure, sociodemographic, and socioeconomic factors. RESULTS: PTSD only was found in 331 (28%) and depression only in 75 (6.4%) of the study population. One hundred and twelve (9.5%) of the participants had PTSD-depression comorbid diagnosis. Exposure to traumatic events and socioeconomic disadvantage were significantly associated with having PTSD or PTSD-depression comorbidity but not with depression. Participants with a comorbid condition were more likely to be socioeconomic disadvantaged, have experienced more traumatic events, and showed higher level of psychological distress than participants with PTSD or depression alone. CONCLUSIONS: In individuals exposed to war trauma, attention should be given to those who may fulfill criteria for a diagnosis of both PTSD and depression. PMID- 23083304 TI - Investigation of acetic acid hydration shell formation through Raman spectra line shape analysis. AB - Raman spectra of acetic acid aqueous solutions in the 500-4000 cm(-1) range have been measured as a function of water concentration to investigate the hydration shell formation mechanism around the acetic acid molecules. A fitting procedure based on the Kubo-Anderson model has been applied to the spectra. This has allowed us to determine the average lifetime of the hydrogen bonds involving a given functional group, as well as their geometrical distribution as a function of water concentration. The comparison of our results with literature data has demonstrated that the fitting model is adequate to describe organic water mixtures. Finally, the role of water in the formation of the hydrophobic shell around the methyl group in diluted acetic acid water solutions has been discussed, evidencing how the methyl group hydrophobicity strongly influences the acetic acid behavior in aqueous solutions. PMID- 23083306 TI - Clinical and immunological profile of umbilical involvement in pemphigus vulgaris and pemphigus foliaceus. AB - BACKGROUND: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune vesicobullous disorders with IgG autoantibodies directed against desmoglein (Dsg)1 and 3, which lead to intraepidermal acantholysis. AIM: To characterize the clinical and immunological profile of patients with PF or PV with umbilical involvement. METHODS: In total, 10 patients (7 women, 3 men; age range 24-70 years, disease duration 3-16 years) diagnosed with either PV (n = 5) or mucocutaneous PF (n = 5) were assessed according to their clinical features, histopathology and immunological findings [direct and indirect immunofluorescence (DIF and IIF) and ELISA with recombinant Dsg1 and Dsg3]. RESULTS: Erythema, erosions, crusts and vegetating skin lesions were the main clinical features of the umbilical region. DIF of the umbilical region gave positive results for intercellular epidermal IgG and C3 deposits in eight patients and for IgG alone in the other two. Indirect immunofluorescence with IgG conjugate showing the typical pemphigus pattern was positive in all 10 patients, with titres varying from 1 : 160 to 1 : 2560. ELISA with recombinant Dsg1 gave scores of 24-266 in PF and 0-270 in PV. Reactivity to recombinant Dsg3 was positive in all five patients with PV (ELISA 22-98) and was negative in all PF sera. CONCLUSIONS: All 10 patients with pemphigus with umbilical presentation had the clinical and immunopathological features of either PF or PV. This peculiar presentation, not yet completely elucidated, has rarely been reported in the literature. A possible explanation for this unique presentation may be the presence of either novel epitopes or an association with embryonic or scar tissue located in the umbilical cord region. PMID- 23083305 TI - Comparison of methods for whole-organ decellularization in tissue engineering of bioartificial organs. AB - Organ transplantation is now a well-established procedure for the treatment of end-stage organ failure due to various causes, but is a victim of its own success in that there is a growing disparity in numbers between the donor organ pool available for transplantation and the patients eligible for such a procedure; hence, an alternative solution to the limited donor organ pool is both desirable and necessary. Tissue engineering is an interdisciplinary field that applies the principles of engineering and life sciences toward the development of functional replacement tissues for clinical use. A recent innovation in tissue and organ engineering is the technique of whole-organ decellularization, which allows the production of complex three-dimensional extracellular matrix (ECM) bioscaffolds of the entire organ with preservation of the intrinsic vascular network. These bioscaffolds can then be recellularized to create potentially functional organ constructs as a regenerative medicine strategy for organ replacement. We review the current applications and methods in using xenogeneic whole-organ ECM scaffolds to create potentially functional bioartificial organ constructs for surgical implantation, and present a comparison of specific trends within this new and developing technique. PMID- 23083307 TI - Computed tomography (CT) colonography with CT arteriography and venography for the workup of intestinal transplant candidates. AB - Prior to intestinal transplantation, prospective candidates must undergo a series of radiologic examinations to address a variety of clinical issues. To date, little literature exists to guide physicians in this preoperative assessment. Multiple imaging studies can provide overlapping information. We have developed a simple two- or three-test protocol to streamline the workup. Sixteen adult patients presented as potential intestinal transplant candidates to Georgetown University Hospital. All but two patients underwent the full protocol of a biphasic IV contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis with rectal carbon dioxide, an upper gastrointestinal study with small bowel follow through, and fistulogram when appropriate. Three dimensional (3-D) reconstructions of the vascular anatomy as well as the colon were also generated. A telephone survey to other transplant centers was additionally conducted to compare radiographic evaluations. Overall, 15 of the 16 scans were diagnostic. One patient required a barium enema. Mean examinations per patient was 2.4. Only one of seven other centers was performing CT colonography in prospective intestinal transplant candidates. Our protocol provided all the necessary anatomic information needed to evaluate prospective transplant candidates. CT colonography with angiography is a suitable alternative to more time-consuming radiological studies. PMID- 23083236 TI - Search for a W' or techni-rho decaying into WZ in pp Collisions at sqrt[s] = 7 TeV. AB - A search is performed in pp collisions at sqrt[s]=7 TeV for exotic particles decaying via WZ to final states with electrons and muons. The data sample corresponds to an integrated luminosity of approximately 5 fb(-1). No significant excess is observed in the data above the expected standard model background. Upper bounds at 95% confidence level are set on the production cross section of the W' boson described by the sequential standard model and on the W' WZ coupling. W' bosons with masses below 1143 GeV are excluded. Limits are also set in the context of low-scale technicolor models, under a range of assumptions concerning the model parameters. PMID- 23083309 TI - Combined proteomic analysis of liver tissue and serum in chronically alcohol-fed rats. AB - BACKGROUND: Proteomic approaches may provide new insights into pathological conditions associated with alcoholism. The aim of this study was to conduct a proteomic analysis of liver tissue and serum in chronically alcohol-fed rats using agarose 2-dimensional gel electrophoresis (2-DE) and 3-step serum proteome analysis. METHODS: A total of 12 rats were pair-fed nutritionally adequate liquid diet containing ethanol as 36% of the total energy or an isocaloric control diet for 2 months. Rat liver homogenates and cytosol fractions were subjected to agarose 2-DE. Serum samples were subjected to 3-step serum proteome analysis involving immunodepletion of abundant proteins followed by fractionation using reverse-phase high-performance liquid chromatography and 1-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Candidate proteins were digested with trypsin and identified using mass spectrometry. Observed differences in protein expression levels were confirmed using Western blotting. RESULTS: A total of 46 protein spots were found to be differentially expressed in the liver homogenates and cytosol fractions of alcohol-fed rats relative to pair fed controls. The most notable change was down-regulation of a 29-kDa protein, which was subsequently identified as carbonic anhydrase III (CA III). Down regulation of this protein in alcohol-fed rats was confirmed by Western blotting. The messenger RNA level of CA III was decreased as well. In rat serum, a total of 41 proteins were differentially expressed. Of these proteins, only betaine homocysteine methyltransferase (BHMT) was also found to be differentially expressed in the liver. CONCLUSIONS: A combined proteomic analysis of liver tissue and serum in chronically alcohol-fed rats revealed that the expression of CA III is significantly down-regulated in the liver of alcohol-fed rats. Our results also showed that BHMT expression is up-regulated in both the liver and serum of alcohol-fed rats. PMID- 23083308 TI - Balancing selection and genetic drift at major histocompatibility complex class II genes in isolated populations of golden snub-nosed monkey (Rhinopithecus roxellana). AB - BACKGROUND: Small, isolated populations often experience loss of genetic variation due to random genetic drift. Unlike neutral or nearly neutral markers (such as mitochondrial genes or microsatellites), major histocompatibility complex (MHC) genes in these populations may retain high levels of polymorphism due to balancing selection. The relative roles of balancing selection and genetic drift in either small isolated or bottlenecked populations remain controversial. In this study, we examined the mechanisms maintaining polymorphisms of MHC genes in small isolated populations of the endangered golden snub-nosed monkey (Rhinopithecus roxellana) by comparing genetic variation found in MHC and microsatellite loci. There are few studies of this kind conducted on highly endangered primate species. RESULTS: Two MHC genes were sequenced and sixteen microsatellite loci were genotyped from samples representing three isolated populations. We isolated nine DQA1 alleles and sixteen DQB1 alleles and validated expression of the alleles. Lowest genetic variation for both MHC and microsatellites was found in the Shennongjia (SNJ) population. Historical balancing selection was revealed at both the DQA1 and DQB1 loci, as revealed by excess non-synonymous substitutions at antigen binding sites (ABS) and maximum likelihood-based random-site models. Patterns of microsatellite variation revealed population structure. FST outlier analysis showed that population differentiation at the two MHC loci was similar to the microsatellite loci. CONCLUSIONS: MHC genes and microsatellite loci showed the same allelic richness pattern with the lowest genetic variation occurring in SNJ, suggesting that genetic drift played a prominent role in these isolated populations. As MHC genes are subject to selective pressures, the maintenance of genetic variation is of particular interest in small, long-isolated populations. The results of this study may contribute to captive breeding and translocation programs for endangered species. PMID- 23083310 TI - Metabolic profiling and outer pericarp water state in Zespri, CI.GI, and Hayward kiwifruits. AB - The metabolic profiling of aqueous extracts of Zespri Gold ( Actinidia chinensis ) and CI.GI (a controlled crossbreed from different species of Actinidia deliciosa ) kiwifruits and the water state of the outer pericarp of entire fruits were monitored over the season by means of high-field NMR spectroscopy and T(2) relaxation time measurements, respectively, and compared with the corresponding ones of Hayward kiwifruits previously investigated. A more complete assignment of the (1)H spectrum with respect to that obtained previously was reported: histidine, phenylalanine, quercetin 3-rhamnoside, and epicatechin were identified. Metabolic profiling confirmed Zespri's earlier maturation compared with the two other varieties. The water state of entire kiwifruits was measured nondestructively on fruits attached to the plants or detached from the plants. T(2) relaxation times were found to be sensitive to the kiwifruit developmental stage. PMID- 23083312 TI - Fungal infections associated with contaminated methylprednisolone injections. PMID- 23083311 TI - The index case for the fungal meningitis outbreak in the United States. AB - Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department. PMID- 23083313 TI - The use of incentives in vulnerable populations for a telephone survey: a randomized controlled trial. AB - BACKGROUND: Poor response rates in prevalence surveys can lead to nonresponse bias thereby compromising the validity of prevalence estimates. We conducted a telephone survey of randomly selected households to estimate the prevalence of food allergy in the 10 Canadian provinces between May 2008 and March 2009 (the SCAAALAR study: Surveying Canadians to Assess the Prevalence of Common Food Allergies and Attitudes towards Food LAbeling and Risk). A household response rate of only 34.6% was attained, and those of lower socioeconomic status, lower education and new Canadians were underrepresented. We are now attempting to target these vulnerable populations in the SPAACE study (Surveying the Prevalence of Food Allergy in All Canadian Environments) and are evaluating strategies to increase the response rate. Although the success of incentives to increase response rates has been demonstrated previously, no studies have specifically examined the use of unconditional incentives in these vulnerable populations in a telephone survey. The pilot study will compare response rates between vulnerable Canadian populations receiving and not receiving an incentive. FINDINGS: Randomly selected households were randomly assigned to receive either a $5 incentive or no incentive. The between group differences in response rates and 95% confidence intervals (CIs) were calculated. The response rates for the incentive and non incentive groups were 36.1% and 28.7% respectively, yielding a between group difference of 7.4% (-0.7%, 15.6%). CONCLUSION: Although the wide CI precludes definitive conclusions, our results suggest that unconditional incentives are effective in vulnerable populations for telephone surveys. PMID- 23083314 TI - Association of anemia with worsened activities of daily living and health-related quality of life scores derived from the Minimum Data Set in long-term care residents. AB - BACKGROUND: Among long-term care (LTC) residents, we explored the association between anemia status and hemoglobin (Hb) level with Activities of Daily Living (ADL) functioning and health-related quality of life (HRQOL). METHODS: Data were derived from the AnalytiCare database, containing laboratory and Minimum Data Set (MDS) reports for 27 LTC facilities in Colorado. Study timeframe was 1/1/07 9/15/08. Patients were selected based on: residence in LTC >90 days, Hb and serum creatinine value within 90 days of the earliest non-admission (index) MDS. From the index MDS, the method of 1) Carpenter et al. [BMC Geriatrics 6:7(2006)] was used to derive a summary measure of ADL performance (the MDS-ADL score) and 2) Wodchis et al. [IJTAHC 19:3(2003)] was used to assign HRQOL scores (MDS items were mapped to the Health Utilities Index Mark 2 (HUI2) scoring function to create the MDS-HSI score). Anemia was defined as Hb <12 g/dL females and <13 g/dL males. Adjusted linear regression was used to evaluate the independent association of anemia and hemoglobin level on MDS-ADL and MDS-HSI scores. RESULTS: 838 residents met all inclusion criteria; 46% of residents were anemic. Mean (SD) MDS-ADL score was 14.9 (7.5) [0-28 scale, where higher score indicates worse functioning]. In the adjusted model, anemia was associated with a significantly worse MDS-ADL score (+1.62 points, P=.001). Residents with Hb levels 10 to <11 g/dL had significantly worse ADL score (+2.06 points, P=.005) than the >13 g/dL reference. The mean MDS-HSI score was 0.431 (0.169) [range, where 0=dead to 1=perfect health]. Compared with non-anemic residents, in this adjusted model, residents with anemia had significantly worse MDS-HSI scores ( 0.034 points, P=.005). Residents with hemoglobin levels <10 g/dL had significantly worse MDS-HSI scores (-0.058 points, P=.016) than the >13 g/dL reference. CONCLUSIONS: After adjusting for several covariates, LTC residents with anemia, and many of those with moderate to severe declines in Hb level, had significantly poorer outcomes in both ADL functioning and HRQOL. The association between Hb level and the HRQOL measure of MDS-HSI appears to be largely explained by the mobility domain of the HRQOL measure. PMID- 23083315 TI - Phytosulfokine control of growth occurs in the epidermis, is likely to be non cell autonomous and is dependent on brassinosteroids. AB - Phytosulfokine (PSK) is a secreted disulfated pentapeptide that controls root and shoot growth. The ubiquitous expression of PSK precursor and of the LRR receptor kinase genes in Arabidopsis raised the question of whether PSK acts as an autocrine growth factor in planta. Expression of PSKR1 under the control of tissue- and cell type-specific promoters in a receptor null background strongly suggests that PSK is a non-cell autonomous signal that controls growth through localized activity in the epidermis. pskr1-3 pskr2-1 seedlings had shorter roots and hypocotyls than the wild type, whereas 35S: PSKR1 or 35S: PSKR2 seedlings were larger, indicating that receptor abundance limits growth in planta. The preferential expression of PSKR1 in the epidermis of CER6: PSKR1 pskr1-3 pskr2-1 seedlings was sufficient to promote wild-type growth. Moreover, in GL2:PSKR1 pskr1-3 pskr2-1 seedlings that express PSKR1 in atrichoblasts of the root epidermis, root growth was restored to wild-type levels. In pskr1-3 pskr2-1 seedlings, trichoblasts and atrichoblasts were shorter than in the wild type. Trichoblasts of GL2:PSKR1 pskr1-3 pskr2-1 seedlings, which are unable to sense PSK, nonetheless had acquired wild-type length, suggesting that PSK acts as a non cell autonomous signal. Inhibition of brassinosteroid (BR) biosynthesis with brassinazole (BZ) caused a loss of responsiveness to PSK in wild-type, tpst-1 (tyrosylprotein sulfotransferase-1), PSKR1ox12 and CER6:PSKR1-3-1 seedlings, as did the genetic knock-out of BR synthesis in det2-1 and of BR perception in bri1 9, suggesting that BR mediates PSK-dependent growth. Quantitative PCR analysis of BR-related genes in wild-type, pskr1-3 pskr2-1, PSKR1ox and tpst-1 seedlings showed largely unchanged transcript levels of BR biosynthesis genes. PMID- 23083317 TI - Polyelectrolyte complexes of DNA and linear PEI: formation, composition and properties. AB - In the present study, the complexation between linear 13.4 kDa poly(ethylene imine) (LPEI) and plasmid DNA was investigated. Analytical ultracentrifugation (AUC) was used for size and molar mass determination. Additionally, the morphology was studied by scanning force microscopy. The polyplex formation was investigated in a wide range of PEI nitrogen to DNA phosphate ratios (N/P). At N/P ratios below 1, the PEI/DNA complex formation is characterized by an incomplete DNA condensation and the formation of the primary DNA/PEI complexes. The merging of the initially formed polyplexes occurs at N/P ~2, resulting in the formation of polyplexes with much larger size and high aggregation rate. Stable and uniform polyplexes were formed at N/P > 10, with average sizes of the polyplexes of about 170 +/- 65 nm. The content of uncomplexed PEI chains in the polyplex dispersion was estimated at four different N/P ratios, 6.2, 11.6, 28.6, and 57.8, by combining preparative centrifugation with a copper complex assay and by sedimentation velocity analysis as an alternative method. It is demonstrated that virtually all added PEI binds to the DNA at N/P < 2.5; further addition of PEI results in the appearance of a large amount of free PEI in solution. Nevertheless, PEI is able to bind in the whole range of N/P ratios tested. According to the data collected by sedimentation velocity analysis and scanning force microscopy, the single PEI/DNA complexes are composed on average of 8 to 32 single condensed DNA plasmids and 70 +/- 25 PEI molecules. PMID- 23083316 TI - Polar auxin transport is essential for gall formation by Pantoea agglomerans on Gypsophila. AB - The virulence of the bacterium Pantoea agglomerans pv. gypsophilae (Pag) on Gypsophila paniculata depends on a type III secretion system (T3SS) and its effectors. The hypothesis that plant-derived indole-3-acetic acid (IAA) plays a major role in gall formation was examined by disrupting basipetal polar auxin transport with the specific inhibitors 2,3,5-triiodobenzoic acid (TIBA) and N-1 naphthylphthalamic acid (NPA). On inoculation with Pag, galls developed in gypsophila stems above but not below lanolin rings containing TIBA or NPA, whereas, in controls, galls developed above and below the rings. In contrast, TIBA and NPA could not inhibit tumour formation in tomato caused by Agrobacterium tumefaciens. The colonization of gypsophila stems by Pag was reduced below, but not above, the lanolin-TIBA ring. Following Pag inoculation and TIBA treatment, the expression of hrpL (a T3SS regulator) and pagR (a quorum-sensing transcriptional regulator) decreased four-fold and that of pthG (a T3SS effector) two-fold after 24 h. Expression of PIN2 (a putative auxin efflux carrier) increased 35-fold, 24 h after Pag inoculation. However, inoculation with a mutant in the T3SS effector pthG reduced the expression of PIN2 by two-fold compared with wild-type infection. The results suggest that pthG might govern the elevation of PIN2 expression during infection, and that polar auxin transport derived IAA is essential for gall initiation. PMID- 23083318 TI - Case of drug-induced hypersensitivity syndrome with multiple skin ulcers caused by herpes simplex virus reactivation. PMID- 23083319 TI - Boar seminal plasma components and their relation with semen quality. AB - Select boar seminal plasma (SP) components and their relation to semen quality were investigated. Thirty nine boars from three artificial insemination (AI) centers were divided into group A (GA: > 80% normal sperm and >70% motility) and group B (GB: < 80% normal sperm and < 70% motility). Each ejaculate was collected and semen volume, concentration, sperm motility (computer aided semen analysis; CASA), morphology, and vitality (both eosin nigrosin staining) were investigated. The SP was separated and analyzed for aspartate-amino-transferase (AST), gamma glutamyl-transferase (GGT), alkaline phosphatase (ALP) activity, and the concentrations of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), phosphate (PO(4)(3-)), magnesium (Mg), selenium (Se) and zinc (Zn) were assessed. Repeated measures (2 months interval) were conducted in eight boars of GA from one AI center. The activity of GGT (r = -0.482) and ALP (r = -0.459) was moderately associated (p < 0.05) with ejaculate volume and strongly associated with concentration (r = 0.580 and r = 0.618, respectively; p = 0.000). Moderate associations (p < 0.05) were found between ALP (r = 0.439), GGT (r = 0.387), Na (r = -0.428), K (r = 0.354), and Se (r = 0.354) with progressive motility. The SP concentration of Na (r = -0.401), Cl (r = -0.521), and K (r = 0.350) was associated (p < 0.05) with normal morphology. Only Mg was associated (p < 0.05) with membrane damage (r = -0.335). The concentration of Na, Cl, and Zn (1681.0 vs. 1701.0 ug/dL) was different between groups (p < 0.05). Repeated measures showed significant differences in time but only for Na, Mg, and Zn (p < 0.05). In conclusion, several biochemical components of SP were related to semen quality. The analysis of biochemical parameters could provide extra information about reproductive health of AI boars. PMID- 23083321 TI - The promise and challenge of systems biology in translational medicine. AB - Abnormalities in clinical parameters and routine laboratory tests are frequently detected at late stages of many diseases (too late to cure or to prevent life threatening complications). Hence earlier diagnostic and prognostic markers are needed for decision making and improving therapeutic outcome. In the present issue of Clinical Science, Rudiger and co-workers report findings from a transcriptomic study, which revealed that changes in transcripts involved in amino-sugar metabolism, p53-dependent cell-cycle arrest, beta-adrenergic signalling and intracellular calcium cycling in cardiac tissue of rats with early sepsis could discriminate survivors from non-survivors. These findings underscore the great potential of systems biology in translational medicine. However, further investigations should be done to make the benchside results more feasible for routine clinical practice. PMID- 23083320 TI - PRBC-derived plasma induces non-muscle myosin type IIA-mediated neutrophil migration and morphologic change. AB - CONTEXT: Neutrophils are the primary effector cells in the pathogenesis of transfusion-related acute lung injury or multiple organ failure after blood transfusion. OBJECTIVE: We aimed to investigate the effect of fresh (1 day preparation) and aged (42 day preparation) PRBC-derived plasma on neutrophil morphology, migration and phagocytosis. MATERIALS AND METHODS: We evaluated the production of reactive oxygen species (ROS) and the expression of non-muscle myosin heavy chain IIA (MYH9) in neutrophils treated with PRBC-derived plasma. We used western blots and antibody arrays to evaluate changes in signal transduction pathways in plasma-treated neutrophils. RESULTS: Aged PRBC-derived plasma elicited a stronger oxidative burst in neutrophils when compared with fresh PRBC derived plasma (p < 0.05). Antibody arrays showed increased phosphorylation of NF KB proteins (p105, p50 and Ikk) in aged PRBC-derived plasma-treated neutrophils. The expression of non-muscle myosin IIA (MYH9), a cytoskeleton protein involved in immune cell migration and morphological change, was also significantly upregulated in neutrophils treated with aged PRBC-derived plasma compared to fresh plasma (p < 0.05). Pretreatment of neutrophils with blebbistatin (a specific type II myosin inhibitor), ascorbic acid (an antioxidant), or staurosporine (a protein tyrosine kinase inhibitor), effectively abrogated the morphological changes, neutrophil migration, and phagocytosis induced by aged PRBC-derived plasma. CONCLUSION: Upregulation of MYH9 in neutrophils treated with aged PRBC-derived plasma and abrogation of neutrophil migration in blebbistatin treated neutrophils suggested a functional role of MYH9 in the directional migration of immune cells. Our data help elucidate the cellular and molecular mechanisms of transfusion-related injury. PMID- 23083322 TI - Relationships between online gambling, mental health, and substance use: a review. AB - This review deals with the published literature to date while examining the relationship between online gambling, mental health problems, and substance use. Online gambling, particularly problematic gambling online, was found to be associated with poor mental health and use of various substances. Recent preliminary evidence also suggests that online gamblers may be at a greater risk of some substance use and mental health problems, relative to nononline gamblers. However, many of the reviewed studies were limited by investigation of online gambling behaviors only; these samples may have inadvertently comprised individuals who engage in both online and nononline gambling. Future research is required to address these limitations. PMID- 23083323 TI - Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats. AB - Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations. PMID- 23083324 TI - Local unfolding is required for the site-specific protein modification by transglutaminase. AB - The transglutaminase (TGase) from Streptomyces mobaraensis catalyzes transamidation reactions in a protein substrate leading to the modification of the side chains of Gln and Lys residues according to the A-CONH(2) + H(2)N-B -> A CONH-B + NH(3) reaction, where both A and B can be a protein or a ligand. A noteworthy property of TGase is its susbstrate specificity, so that often only a few specific Gln or Lys residues can be modified in a globular protein. The molecular features of a globular protein dictating the site-specific reactions mediated by TGase are yet poorly understood. Here, we have analyzed the reactivity toward TGase of apomyoglobin (apoMb), alpha-lactalbumin (alpha-LA), and fragment 205-316 of thermolysin. These proteins are models of protein structure and folding that have been studied previously using the limited proteolysis technique to unravel regions of local unfolding in their amino acid sequences. The three proteins were modified by TGase at the level of Gln or Lys residues with dansylcadaverine or carbobenzoxy-l-glutaminylglycine, respectively. Despite these model proteins containing several Gln and Lys residues, the sites of TGase derivatization occur over restricted chain regions of the protein substrates. In particular, the TGase-mediated modifications occur in the "helix F" region in apoMb, in the beta-domain in apo-alpha-LA in its molten globule state, and in the N-terminal region in fragment 205-316 of thermolysin. Interestingly, the sites of limited proteolysis are located in the same chain regions of these proteins, thus providing a clear-cut demonstration that chain flexibility or local unfolding overwhelmingly dictates the site-specific modification by both TGase and a protease. PMID- 23083325 TI - Rhythmic neuronal activity in S2 somatosensory and insular cortices contribute to the initiation of absence-related spike-and-wave discharges. AB - PURPOSE: The origin of bilateral synchronous spike-and-wave discharges (SWDs) that underlie absence seizures has been widely debated. Studies in genetic rodent models suggest that SWDs originate from a restricted region in the somatosensory cortex. The properties of this initiation site remain unknown. Our goal was to characterize the interictal, preictal and ictal neuronal activity in the primary and secondary cortical regions (S1, S2) and in the adjacent insular cortex (IC) in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). METHODS: We performed electroencephalography (EEG) recordings in combination with multisite local field potential (LFP) and single cell juxtacellular recordings, and cortical electrical stimulations, in freely moving rats and those under neurolept-anesthesia. KEY FINDINGS: The onset of the SWDs was preceded by 5-9 Hz field potential oscillations, which were detected earlier in S2 and IC than in S1. Sustained SWDs could be triggered by a 2-s train of 7-Hz electrical stimuli at a lower current intensity in S2 than in S1. In S2 and IC, subsets of neurons displayed rhythmic firing (5-9 Hz) in between seizures. S2 and IC layers V and VI neurons fired during the same time window, whereas in S1 layer VI, neurons fired before layer V neurons. Just before the spike component of each SW complex, short-lasting high frequency oscillations consistently occurred in IC ~20 msec before S1. SIGNIFICANCE: Our findings demonstrate that the S2/IC cortical areas are a critical component of the macro-network that is responsible for the generation of absence-related SWDs. PMID- 23083326 TI - Cocaine produces conditioned place aversion in mice with a cocaine-insensitive dopamine transporter. AB - Cocaine is an inhibitor of the dopamine, norepinephrine and serotonin reuptake transporters. Because its administration would elevate signaling of all these three neurotransmitters, many studies have been aimed at attributing individual effects of cocaine to specific transmitter systems. Using mice with a cocaine insensitive dopamine transporter (DAT-CI mice), we previously showed that cocaine induced dopamine elevations were necessary for its rewarding and stimulating effects. In this study, we observe that DAT-CI mice exhibit cocaine-conditioned place aversion (CPA), and that its expression depends on their genetic background. Specifically, DAT-CI mice backcrossed to the C57Bl/6J strain background did not display a preference or an aversion to cocaine, whereas DAT-CI mice that were on a mixed 129S1/SvImJ * C57Bl/6J (129B6) background had a robust CPA to cocaine. These results indicate that while inhibition of the DAT is necessary for cocaine reward, other cocaine targets and neurotransmitter systems may mediate the aversive properties of cocaine. Furthermore, the aversive effect of cocaine can be observed in the absence of a DAT-mediated rewarding effect, and it is affected by genomic differences between these two mouse strains. PMID- 23083327 TI - Ideal discrete energy levels in synthesized Au nanoparticles for chemically assembled single-electron transistors. AB - Ideal discrete energy levels in synthesized Au nanoparticles (6.2 +/- 0.8 nm) for a chemically assembled single-electron transistor (SET) are demonstrated at 300 mK. The spatial structure of the double-gate SET is determined by two gate and drain voltages dependence of the stability diagram, and electron transport to the Coulomb box of a single, nearby Coulomb island of Au nanoparticles is detected by the SET. The SET exhibits discrete energy levels, and the excited energy level spacing of the Coulomb island is evaluated as 0.73 meV, which well corresponds to the expected theoretical value. The discrete energy levels show magnetic field evolution with the Zeeman effect and dependence on the odd-even electron number of a single Au nanoparticle. PMID- 23083328 TI - Pain-autonomic interaction after work-induced sleep restriction. AB - BACKGROUND AND PURPOSE: Poor sleep is commonly associated with alterations in pain perception. However, there is a lack of studies that address work-associated sleep restriction (SR) and changes in non-nociceptive perception and autonomic responses after work-induced SR. METHODS: This study was performed with 19 medical students after a normal-sleep night (NS phase) and after a night shift at the local emergency room (SR phase). We performed clinical assessment, quantitative sensory testing for electrical and temperature sensation, RR interval analysis, and recorded sudomotor skin responses (SSRs). RESULTS: The total mean duration of sleep was 436 +/- 18 min in the NS group and 120 +/- 28 min in the SR group (P<0.001). The anxiety scores were higher following the SR phase compared with those after the NS phase (P<0.01). After SR, there was a decrease in heat-pain threshold, but neither warm nor electrical thresholds were affected. Following SR, subjects showed higher SSR amplitudes and an increased number of double responses at an interstimulus interval of 2 s. We also observed a moderate inverse correlation between heat-pain thresholds and SSR amplitude (r= -0.46; P<0.01). However, there was no correlation between anxiety scores and SSR parameters. CONCLUSIONS: The effects of SR in the context of work stress on pain are specific and appear unrelated to general changes in sensory perception. Hyperalgesia was associated with abnormal autonomic responses, but not with increased anxiety, which suggests an association between the nociceptive and autonomic nervous systems that is independent of the emotional state. PMID- 23083329 TI - Slow single-molecule diffusion in liquid crystals. AB - We report on measurements of single-molecule Brownian motion in liquid crystals, unravelling the anisotropic mobility of individual dye molecules. This anisotropic Brownian motion is directly correlated with the structural properties in a smectic A (8CB) and a nematic (5CB) liquid crystal sample cell on the micrometer scale using polarization contrast microscopy. A considerably slower mobility of dye molecules is found as compared to self-diffusion measurements by NMR, while anisotropy values compare well to recent literature data. This is suggested to be related to local distortions of the director structure around the dye molecules. PMID- 23083330 TI - Acute interstitial nephritis secondary to long-term use of cetirizine for the treatment of urticaria pigmentosa. PMID- 23083331 TI - Muscle performance following an acute bout of plyometric training combined with low or high intensity weight exercise. AB - To determine the time course of performance responses after an acute bout of plyometric exercise combined with high and low intensity weight training, a 3 group (including a control group), repeated-measures design was employed. Changes in performance were monitored through jumping ability by measuring countermovement and squat jumping, and strength performance assessment through isometric and isokinetic testing of knee extensors (at two different velocities). Participants in both experimental groups performed a plyometric protocol consisting of 50 jumps over 50 cm hurdles and 50 drop jumps from a 50 cm plyometric box. Additionally, each group performed two basic weight exercises consisting of leg presses and leg extensions at 90-95% of maximum muscle strength for the high intensity group and 60% of maximum muscle strength for the low intensity group. The results of the study suggest that an acute bout of intense plyometric exercise combined with weight exercise induces time-dependent changes in performance, which are also dependent on the nature of exercise protocol and testing procedures. In conclusion, acute plyometric exercise with weight exercise may induce a substantial decline in jumping performance for as long as 72 hours but not in other forms of muscle strength. PMID- 23083332 TI - Emergency management in health: key issues and challenges in the UK. AB - BACKGROUND: Emergency planning in the UK has grown considerably in recent years, galvanised by the threat of terrorism. However, deficiencies in NHS emergency planning were identified and the evidence-base that underpins it is questionable. Inconsistencies in terminologies and concepts also exist. Different models of emergency management exist internationally but the optimal system is unknown. This study examines the evidence-base and evidence requirements for emergency planning in the UK health context. METHODS: The study involved semi-structured interviews with key stakeholders and opinion leaders. Purposive sampling was used to obtain a breadth of views from various agencies involved in emergency planning and response. Interviews were then analysed using a grounded approach using standard framework analysis techniques. RESULTS: We conducted 17 key informant interviews. Interviewees identified greater gaps in operational than technical aspects of emergency planning. Social and behavioural knowledge gaps were highlighted with regards to how individuals and organisations deal with risk and behave in emergencies. Evidence-based approaches to public engagement and for developing community resilience to disasters are lacking. Other gaps included how knowledge was developed and used. Conflicting views with regards to the optimal configuration and operation of the emergency management system were voiced. CONCLUSIONS: Four thematic categories for future research emerged:(i) Knowledge base for emergency management: Further exploration is needed of how knowledge is acquired, valued, disseminated, adopted and retained.(ii) Social and behavioural issues: Greater understanding of how individuals approach risk and behave in emergencies is required.(iii) Organisational issues in emergencies: Several conflicting organisational issues were identified; value of planning versus plans, flexible versus standardized procedures, top-down versus bottom-up engagement, generic versus specific planning, and reactive versus proactive approaches to emergencies.(iv) Emergency management system: More study is required of system-wide issues relating to system configuration and operation, public engagement, and how emergency planning is assessed. PMID- 23083333 TI - OsVIL2 functions with PRC2 to induce flowering by repressing OsLFL1 in rice. AB - Flowering is exquisitely regulated by both promotive and inhibitory factors. Molecular genetic studies with Arabidopsis have verified several epigenetic repressors that regulate flowering time. However, the roles of chromatin remodeling factors in developmental processes have not been well explored in Oryza sativa (rice). We identified a chromatin remodeling factor OsVIL2 (O. sativa VIN3-LIKE 2) that promotes flowering. OsVIL2 contains a plant homeodomain (PHD) finger, which is a conserved motif of histone binding proteins. Insertion mutations in OsVIL2 caused late flowering under both long and short days. In osvil2 mutants OsLFL1 expression was increased, but that of Ehd1, Hd3a and RFT1 was reduced. We demonstrated that OsVIL2 is bound to native histone H3 in vitro. Chromatin immunoprecipitation analyses showed that OsVIL2 was directly associated with OsLFL1 chromatin. We also observed that H3K27me3 was significantly enriched by OsLFL1 chromatin in the wild type, but that this enrichment was diminished in the osvil2 mutants. These results indicated that OsVIL2 epigenetically represses OsLFL1 expression. We showed that OsVIL2 physically interacts with OsEMF2b, a component of polycomb repression complex 2. As observed from osvil2, a null mutation of OsEMF2b caused late flowering by increasing OsLFL1 expression and decreasing Ehd1 expression. Thus, we conclude that OsVIL2 functions together with PRC2 to induce flowering by repressing OsLFL1. PMID- 23083335 TI - Role of the P-F bond in fluoride-promoted aqueous VX hydrolysis: an experimental and theoretical study. AB - Following our ongoing studies on the reactivity of the fluoride ion toward organophosphorus compounds, we established that the extremely toxic and environmentally persistent chemical warfare agent VX (O-ethyl S-2 (diisopropylamino)ethyl methylphosphonothioate) is exclusively and rapidly degraded to the nontoxic product EMPA (ethyl methylphosphonic acid) even in dilute aqueous solutions of fluoride. The unique role of the P-F bond formation in the reaction mechanism was explored using both experimental and computational mechanistic studies. In most cases, the "G-analogue" (O-ethyl methylphosphonofluoridate, Et-G) was observed as an intermediate. Noteworthy and of practical importance is the fact that the toxic side product desethyl-VX, which is formed in substantial quantities during the slow degradation of VX in unbuffered water, is completely avoided in the presence of fluoride. A computational study on a VX-model, O,S-diethyl methylphosphonothioate (1), clarifies the distinctive tendency of aqueous fluoride ions to react with such organophosphorus compounds. The facility of the degradation process even in dilute fluoride solutions is due to the increased reactivity of fluoride, which is caused by the significant low activation barrier for the P-F bond formation. In addition, the unique nucleophilicity of fluoride versus hydroxide toward VX, in contrast to their relative basicity, is discussed. Although the reaction outcomes were similar, much slower reaction rates were observed experimentally for the VX-model (1) in comparison to VX. PMID- 23083334 TI - The independent prokaryotic origins of eukaryotic fructose-1, 6-bisphosphatase and sedoheptulose-1, 7-bisphosphatase and the implications of their origins for the evolution of eukaryotic Calvin cycle. AB - BACKGROUND: In the Calvin cycle of eubacteria, the dephosphorylations of both fructose-1, 6-bisphosphate (FBP) and sedoheptulose-1, 7-bisphosphate (SBP) are catalyzed by the same bifunctional enzyme: fructose-1, 6 bisphosphatase/sedoheptulose-1, 7-bisphosphatase (F/SBPase), while in that of eukaryotic chloroplasts by two distinct enzymes: chloroplastic fructose-1, 6 bisphosphatase (FBPase) and sedoheptulose-1, 7-bisphosphatase (SBPase), respectively. It was proposed that these two eukaryotic enzymes arose from the divergence of a common ancestral eubacterial bifunctional F/SBPase of mitochondrial origin. However, no specific affinity between SBPase and eubacterial FBPase or F/SBPase can be observed in the previous phylogenetic analyses, and it is hard to explain why SBPase and/or F/SBPase are/is absent from most extant nonphotosynthetic eukaryotes according to this scenario. RESULTS: Domain analysis indicated that eubacterial F/SBPase of two different resources contain distinct domains: proteobacterial F/SBPases contain typical FBPase domain, while cyanobacterial F/SBPases possess FBPase_glpX domain. Therefore, like prokaryotic FBPase, eubacterial F/SBPase can also be divided into two evolutionarily distant classes (Class I and II). Phylogenetic analysis based on a much larger taxonomic sampling than previous work revealed that all eukaryotic SBPase cluster together and form a close sister group to the clade of epsilon proteobacterial Class I FBPase which are gluconeogenesis-specific enzymes, while all eukaryotic chloroplast FBPase group together with eukaryotic cytosolic FBPase and form another distinct clade which then groups with the Class I FBPase of diverse eubacteria. Motif analysis of these enzymes also supports these phylogenetic correlations. CONCLUSIONS: There are two evolutionarily distant classes of eubacterial bifunctional F/SBPase. Eukaryotic FBPase and SBPase do not diverge from either of them but have two independent origins: SBPase share a common ancestor with the gluconeogenesis-specific Class I FBPase of epsilon proteobacteria (or probably originated from that of the ancestor of epsilon proteobacteria), while FBPase arise from Class I FBPase of an unknown kind of eubacteria. During the evolution of SBPase from eubacterial Class I FBPase, the SBP-dephosphorylation activity was acquired through the transition "from specialist to generalist". The evolutionary substitution of the endosymbiotic origin cyanobacterial bifunctional F/SBPase by the two light-regulated substrate specific enzymes made the regulation of the Calvin cycle more delicate, which contributed to the evolution of eukaryotic photosynthesis and even the entire photosynthetic eukaryotes. PMID- 23083336 TI - High-throughput real-time PCR-based genotyping without DNA purification. AB - BACKGROUND: While improvements in genotyping technology have allowed for increased throughput and reduced time and expense, protocols remain hindered by the slow upstream steps of isolating, purifying, and normalizing DNA. Various methods exist for genotyping samples directly through blood, without having to purify the DNA first. These procedures were designed to be used on smaller throughput systems, however, and have not yet been tested for use on current high throughput real-time (q)PCR based genotyping platforms. In this paper, a method of quantitative qPCR-based genotyping on blood without DNA purification was developed using a high-throughput qPCR platform. FINDINGS: The performances of either DNA purified from blood or the same blood samples without DNA purification were evaluated through qPCR-based genotyping. First, 60 different mutations prevalent in the Ashkenazi Jewish population were genotyped in 12 Ashkenazi Jewish individuals using the QuantStudioTM12K Flex Real-Time PCR System. Genotyping directly from blood gave a call rate of 99.21%, and an accuracy of 100%, while the purified DNA gave a call rate of 92.49%, and an accuracy of 99.74%. Although no statistical difference was found for these parameters, an F test comparing the standard deviations of the wild type clusters for the two different methods indicated significantly less variation when genotyping directly from blood instead of after DNA purification. To further establish the ability to perform high-throughput qPCR based genotyping directly from blood, 96 individuals of Ashkenazi Jewish decent were genotyped for the same 60 mutations (5,760 genotypes in 5 hours) and resulted in a call rate of 98.38% and a diagnostic accuracy of 99.77%. CONCLUSION: This study shows that accurate qPCR-based high throughput genotyping can be performed without DNA purification. The direct use of blood may further expedite the entire genotyping process, reduce costs, and avoid tracking errors which can occur during sample DNA purification. PMID- 23083337 TI - Does anti-hepatitis B virus vaccine make any difference in long-term number of liver transplantation? AB - BACKGROUND: Hepatitis B virus (HBV) infection is a major cause of morbidity and mortality worldwide. Chronic hepatitis B infection is associated with an increased risk of cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Our aim is to analyze, through a mathematical model, the potential impact of anti-HBV vaccine in the long-term (that is, decades after vaccination) number of LT. METHODS: The model simulated that the prevalence of HBV infection was 0.5% and that approximately 20% of all the liver transplantation carried out in the state of Sao Paulo are due to HBV infection. RESULTS: The theoretical model suggests that a vaccination program that would cover 80% of the target population would reach a maximum of about 14% reduction in the LT program. CONCLUSION: Increasing the vaccination coverage against HBV in the state of Sao Paulo would have a relatively low impact on the number of liver transplantation. In addition, this impact would take several decades to materialize due to the long incubation period of liver failure due to HBV. PMID- 23083338 TI - Case of spontaneous regression of carotid body tumor in a SDHD mutant: a discussion on potential mechanisms based on a review of the literature. AB - BACKGROUND: Head and neck paragangliomas are tumors associated with the parasympathetic nerve system and typically show an indolent growth pattern. Therefore a conservative management strategy is considered in selected cases. METHODS AND RESULTS: We present a case of a female patient who presented in 2003 with bilateral carotid body tumors and a tympanic tumor, associated with a mutation in the succinate dehydrogenase -sub-unit-D (SDHD). She was operated on the right carotid body tumor and the tympanic tumor. Thereafter the follow-up was performed with MR examinations at 2-year intervals. After an initial stable phase, over the last 3 years a spontaneous near-total regression of the contralateral carotid body tumor was observed, with only subtle rest abnormalities visible in 2011. CONCLUSIONS: The present case underlines the indolent growth pattern of head and neck paragangliomas and for the first time describes a rare manifestation of spontaneous regression of a carotid body tumor. The literature was reviewed to discuss this phenomenon. PMID- 23083339 TI - Solid-state phosphorescence-to-fluorescence switching in a cyclometalated Ir(III) complex containing an acid-labile chromophoric ancillary ligand: implication for multimodal security printing. AB - In this study, we have demonstrated the reconstruction of encrypted information by employing photoluminescence spectra and lifetimes of a phosphorescent Ir(III) complex (IrHBT). IrHBT was constructed on the basis of a heteroleptic structure comprising a fluorescent N^O ancillary ligand. From the viewpoint of information security, the transformation of the Ir(III) complex between phosphorescent and fluorescent states can be encoded with chemical/photoirradiation methods. Thin polymer films (poly(methylmethacrylate), PMMA) doped with IrHBT display long lived emission typical of phosphorescence (lambda(max) = 586 nm, tau(obs) = 2.90 MUs). Meanwhile, exposure to HCl vapor switches the emission to fluorescence (lambda(max) = 514 nm, tau(obs) = 1.53 ns) with drastic changes in both the photoluminescence color and lifetime. Security printing on paper impregnated with IrHBT or on a PMMA film containing IrHBT and photoacid generator (triphenylsulfonium triflate) enables the bimodal readout of photoluminescence color and lifetime. PMID- 23083340 TI - A further tool to monitor the coffee roasting process: aroma composition and chemical indices. AB - Coffee quality is strictly related to its flavor and aroma developed during the roasting process, that, in their turn, depend on variety and origin, harvest and postharvest practices, and the time, temperature, and degree of roasting. This study investigates the possibility of combining chemical (aroma components) and physical (color) parameters through chemometric approaches to monitor the roasting process, degree of roasting, and aroma formation by analyzing a suitable number of coffee samples from different varieties and blends. In particular, a correlation between the aroma composition of roasted coffee obtained by HS-SPME GC-MS and degree of roasting, defined by the color, has been researched. The results showed that aroma components are linearly correlated to coffee color with a correlation factor of 0.9387. The study continued looking for chemical indices: 11 indices were found to be linearly correlated to the color resulting from the roasting process, the most effective of them being the 5-methylfurfural/2 acetylfuran ratio (index). PMID- 23083341 TI - Intervention to increase condom use and HIV testing among men who have sex with men in China: a meta-analysis. AB - Behavioral interventions have been shown to both promote and change many health related behaviors and issues. This meta-analysis was performed to assess whether behavioral interventions have the potential to increase condom use and HIV testing uptake among men who have sex with men (MSM) in China. PubMed, Elsevier Science Direct, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), and Wanfang (Chinese) were searched to June 2011 to identify relevant articles. Data of eligible citations were extracted by two reviewers. Sixteen studies were identified. Aggregated findings indicated that interventions were associated with a significant increase in condom use between MSM and male sex partners in the last anal sex act (RR=1.17, 95% CI=1.05-1.29) and consistent condom use between MSM and male sex partners in the past 6 months (RR=1.36, 95% CI=1.15-1.60) and HIV testing (RR=2.22, 95% CI=1.72-2.88). However, no significant increase was detected in condom use over the course of the intervention among MSM engaging in sex with women. In the subgroup analyses, the positive effects were not detected in some subgroups such as anal sex with casual partners and intervention interval less than or equal to 6 months. The sensitivity analysis showed that these estimates were unchanged after removal of the study that had the biggest sample or the studies that had the most rigorous study design. This meta-analysis can inform future intervention design and implementation in terms of sample size, target populations, settings, goals for process measures, and intervention interval. PMID- 23083342 TI - Topics in this issue: cancer testes antigens, immune checkpoints, inflammation associated with ischemia-reperfusion and integrin targeting. AB - This issue of the International Reviews of Immunology is dedicated to several topics: cancer immunotherapy, and basic and translational aspects of immunity. Two reviews, one focused on breast and the other on lung cancer, highlight the need to redefine the cancer testes antigens (CTAs) as novel information regarding their expression profile and biological role emerges. Two other reviews showcase pivotal molecules that keep in check immunity at two different levels: the transcription factor autoimmune regulator (AIRE) important to negative selection of the T-cell repertoire, and CD22 that limits the antigen-initiated B-cell response. Two other articles focus on the debated role of Toll-like receptors (TLRs) and inflammation in general, in ischemia-reperfusion lesions that follow cardiovascular disorders and stroke. Last but not the least, this issue hosts a review that discusses the role and translational potential of the alpha4 integrin for the treatment of inflammatory bowel disease (IBD). PMID- 23083343 TI - Cancer testes antigens in breast cancer: biological role, regulation, and therapeutic applicability. AB - Breast cancer remains one of the leading causes of death among women across the world. The last few decades have seen significant reduction in mortality owing to earlier detection and better adjuvant treatments that were developed based on clinical staging and morphological features. As these treatments have evolved, the heterogeneity of breast cancer poses a new challenge, since there is no standard gold-therapy suitable for all tumors of the mammary gland. Therefore, contemporary management and research efforts are directed toward specific prognostic and predictive molecular signatures that can guide targeted individualized therapy. The goal of ongoing research in this field is to identify specific molecular targets for developing novel therapeutic approaches. These targets can also serve to improve screening of breast cancer. This review focuses on the role of cancer testis antigens (CTAs) in breast carcinogenesis and explores the potential for development of targeted screening and therapeutic approaches. Normally found in the testes, these antigens are highly correlative with cancers of the breast, skin, and ovaries. These implications have been further corroborated through uncovering the interaction of CTAs with genes and proteins involved in tumor suppression and homeostasis like p53. There is some evidence that these genes can be targeted for early detection in addition to being candidates for cancer immunotherapy. PMID- 23083344 TI - Cancer testis antigens: a novel target in lung cancer. AB - Lung cancer is the main cause of cancer mortality worldwide. This is mainly due to the fact that it is diagnosed in advanced stage patients, which are no more surgically curable. Consequently, searching for novel treatments and new modalities for early diagnosis offers great promise to improve the clinical outcome. Recently, a new group of antigens, the cancer testis antigens, have been described as possible early diagnostic tools and therapeutic targets in cancer therapy.This review will report emerging evidences of cancer testis antigens deregulation in lung cancer and explore the state of the art of their currently known role and potential as markers for early diagnosis and disease progression and targets of an immunotherapeutic approach aiming to improve the cure rate of this tumor. PMID- 23083345 TI - Genetic basis of altered central tolerance and autoimmune diseases: a lesson from AIRE mutations. AB - The thymus is a specialized organ that provides an inductive environment for the development of T cells from multipotent hematopoietic progenitors. Self-nonself discrimination plays a key role in inducing a productive immunity and in preventing autoimmune reactions. Tolerance represents a state of immunologic nonresponsiveness in the presence of a particular antigen. The immune system becomes tolerant to self-antigens through the two main processes, central and peripheral tolerance. Central tolerance takes place within the thymus and represents the mechanism by which T cells binding with high avidity self antigens, which are potentially autoreactive, are eliminated through so-called negative selection. This process is mostly mediated by medullary thymic epithelia cells (mTECs) and medullary dendritic cells (DCs). A remarkable event in the process is the expression of tissue-specific antigens (TSA) by mTECs driven by the transcription factor autoimmune regulator (AIRE). Mutations in this gene result in autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a rare autosomal recessive disease (OMIM 240300). Thus far, this syndrome is the paradigm of a genetically determined failure of central tolerance and autoimmunty. Patients with APECED have a variable pattern of autoimmune reactions, involving different endocrine and nonendocrine organs. However, although APECED is a monogenic disorder, it is characterized by a wide variability of the clinical expression, thus implying a further role for disease modifying genes and environmental factors in the pathogenesis. Studies on this polyreactive autoimmune syndrome contributed enormously to unraveling several issues of the molecular basis of autoimmunity. This review focuses on the developmental, functional, and molecular events governing central tolerance and on the clinical implication of its failure. PMID- 23083346 TI - CD22 and autoimmune disease. AB - CD22 is a 140-kDa member of the Siglec family of cell surface proteins that is expressed by most mature B-cell lineages. As a co-receptor of the B-cell receptor (BCR), it is known to contribute to the sensitive control of the B-cell response to antigen. Cross-linking of CD22 and the BCR by antigen triggers the phosphorylation of CD22, which leads to activation of signaling molecules such as phosphatases. Signal transduction pathways involving CD22 have been explored in a number of mouse models, some of which have provided evidence that in the absence of functional CD22, B cells have a "hyperactivated" phenotype, and suggest that loss of CD22 function could contribute to the pathogenesis of autoimmune diseases. Modulating CD22 activity has therefore been suggested as a possible therapeutic approach to such diseases. For example, the novel CD22-targeting monoclonal antibody epratuzumab is currently under investigation as a treatment for the connective tissue disorder systemic lupus erythematosus (SLE). PMID- 23083347 TI - Toll-like receptor signaling pathways in cardiovascular diseases: challenges and opportunities. AB - Toll-like receptors (TLRs), a family of surface molecules, are involved in innate immune responses. Recent studies indicated that TLRs play a critical role in inflammatory responses to exogenous and endogenous triggers. This article focuses on probable effects of TLRs in the morbidity of cardiovascular events, e.g., ischemic reperfusion (I/R) injury and atherosclerosis. TLR2 and TLR4 have been shown to have the most fundamental role in promoting cytokine production and subsequent inflammatory damages in these states. Blockade of these receptors may be beneficial in both preventing the occurrence and decreasing the complications in cardiovascular events. However, controversies exist on the certainty of this beneficial effect; therefore, additional studies are needed. PMID- 23083348 TI - Post-stroke immunodeficiency: effects of sensitization and tolerization to brain antigens. AB - Acute onset of cerebrovascular diseases seems to be related to a number of immunological alternations. After the initial pro-inflammatory response to brain ischemia accompanied by systemic inflammatory response syndrome, stroke interferes with function of the innate and the adaptive immune cells, resulting in systemic immunosuppression. Although post-stroke immunodeficiency could predispose patients to life-threatening infections, it could potentially protect brain via reducing autoimmune reaction to the brain antigens. In this paper, we review current knowledge on the immunological alterations after brain ischemia, particularly effects of infection for stimulation of autoimmune response against brain antigens. PMID- 23083351 TI - The diverse identity of angiogenic monocytes. AB - BACKGROUND: The role of bone marrow-derived cells in stimulating angiogenesis, vascular repair or remodelling has been well established, but the nature of the circulating angiogenic cells is still controversial. DESIGN: The existing literature on different cell types that contribute to angiogenesis in multiple pathologies, most notably ischaemic and tumour angiogenesis, is reviewed, with a focus on subtypes of angiogenic mononuclear cells and their local recruitment and activation. RESULTS: A large number of different cells of myeloid origin support angiogenesis without incorporating permanently into the newly formed vessel, which distinguishes these circulating angiogenic cells (CAC) from endothelial progenitor cells (EPC). Although CAC frequently express individual endothelial markers, they all share multiple characteristics of monocytes and only express a limited set of discriminative surface markers in the circulation. When cultured ex vivo, or surrounding the angiogenic vessel in vivo, however, many of them acquire similar additional markers, making their discrimination in situ difficult. CONCLUSION: Different subsets of monocytes show angiogenic properties, but the distinct microenvironment, in vitro or in vivo, is needed for the development of their pro-angiogenic function. PMID- 23083349 TI - Inhibition of selective adhesion molecules in treatment of inflammatory bowel disease. AB - Lymphocyte infiltration into the intestinal tract in inflammatory bowel disease (IBD) is mediated by interaction between alpha4 integrin and its specific ligands. Development of monoclonal antibodies against alpha4 integrin allowed targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention. Natalizumab, vedolizumab, alicaforsen AJM300, rhuMAb beta7, CCX282 B, and PF-00547,659 are few of monoclonal antibodies that have shown high promise in trials with the potential for more attractive benefit:risk ratio than currently available therapies. In this review, an attempt is made to underline the therapeutic potential and the safety of anti-adhesion molecule treatment in IBD. PMID- 23083352 TI - The spatial epidemiology of tuberculosis in Linyi City, China, 2005-2010. AB - BACKGROUND: Tuberculosis (TB) remains a major public health burden in many developing countries. China alone accounted for an estimated 12% of all incident TB cases worldwide in 2010. Several studies showed that the spatial distribution of TB was nonrandom and clustered. Thus, a spatial analysis was conducted with the aim to explore the spatial epidemiology of TB in Linyi City, which can provide guidance for formulating regional prevention and control strategies. METHODS: The study was based on the reported cases of TB, between 2005 and 2010. 35,308 TB cases were geo-coded at the town level (n = 180). The spatial empirical Bayes smoothing, spatial autocorrelation and space-time scan statistic were used in this analysis. RESULTS: Spatial distribution of TB in Linyi City from 2005 to 2010 was mapped at town level in the aspects of crude incidence, excess hazard and spatial smoothed incidence. The spatial distribution of TB was nonrandom and clustered with the significant Moran's I for each year. Local G(i)* detected five significant spatial clusters for high incidence of TB. The space-time analysis identified one most likely cluster and nine secondary clusters for high incidence of TB. CONCLUSIONS: There is evidence for the existence of statistically significant TB clusters in Linyi City, China. The result of this study may assist health departments to develop a better preventive strategy and increase the public health intervention's effectiveness. PMID- 23083368 TI - Improving the limit of detection for Sanger sequencing: A comparison of methodologies for KRAS variant detection. AB - Fluorescent dye terminator Sanger sequencing (FTSS), with detection by automated capillary electrophoresis (CE), has long been regarded as the gold standard for variant detection. However, software analysis and base-calling algorithms used to detect mutations were largely optimized for resequencing applications in which different alleles were expected as heterozygous mixtures of 50%. Increasingly, the requirements for variant detection are an analytic sensitivity for minor alleles of <20%, in particular, when assessing the mutational status of heterogeneous tumor samples. Here, we describe a simple modification to the FTSS workflow that improves the limit of detection of cell-line gDNA mixtures from 50% 20% to 5% for G>A transitions and from 50%-5% to 5% for G>C and G>T transversions. In addition, we use two different sample types to compare the limit of detection of sequence variants in codons 12 and 13 of the KRAS gene between Sanger sequencing and other methodologies including shifted termination assay (STA) detection, single-base extension (SBE), pyrosequencing (PS), high- resolution melt (HRM), and real-time PCR (qPCR). PMID- 23083372 TI - Observation and quantification of chondrocyte aggregation behavior on fibroin surfaces using Voronoi partition. AB - Cell migration is one of the fundamental processes in histogenesis, and it is necessary to investigate such multicellular behavior quantitatively in cell regeneration studies. In this study, Voronoi diagram analysis was first confirmed in simulation testing, and then used to evaluate the multicellular behavior of chondrocytes on three different substrates: (1) wild-type fibroin (FIB); (2) L RGDSx2 transgenic fibroin; (3) and collagen. The indices for the round factor average, round factor homogeneity, and area disorder (AD), calculated from Voronoi diagram analysis, were used to characterize the difference in spatiotemporal changes for the different chondrocyte populations, and a regression analysis of the AD index was used to measure the speed of cell aggregation. The results suggested that the arginine-glycine-aspartic acid-serine sequence affects aggregate formation of chondrocytes cultured on FIB. The Voronoi diagram analysis represents one of the promising quantitative analyses for cell regeneration studies. PMID- 23083373 TI - Posttraumatic lipogranuloma on the lower leg. PMID- 23083374 TI - Navigating airport security with an insulin pump and/or sensor. PMID- 23083375 TI - Temporal expression of metalloproteinase-8 and -13 and their relationships with extracellular matrix metalloproteinase inducer in the development of ligature induced periodontitis in rats. AB - BACKGROUND AND OBJECTIVE: Matrix metalloproteinases (MMPs) play important roles in extracellular matrix degradation and may be regulated by extracellular matrix metalloproteinase inducer (EMMPRIN). The aim of this study was to investigate the temporal expression and localization of MMP-8 and MMP-13 during the development of ligature-induced periodontitis in rats, and to analyze the correlations of EMMPRIN with MMP-8 and MMP-13 in periodontitis. MATERIAL AND METHODS: Periodontitis was simulated in rats by ligaturing the cervix of the lower first molars, as described in our previous method. The rats were killed 0, 3, 5, 7, 11, 15 and 21 d after ligation. Micro-computed tomography examinations were performed to detect alveolar bone loss. Semiquantitative western blotting was used to assess the temporal changes in the levels of MMP-8, MMP-13 and EMMPRIN proteins in gingival tissue. Immunohistochemistry was applied to detect the expression and locations of MMP-8 and MMP-13 in gingival tissue and alveolar bone. RESULTS: Alveolar bone loss showed an exponential increase from days 3 to 11, followed by a slower rate of loss at subsequent study time points. MMP-8 showed a rapid increase of expression from baseline to a peak on day 3, a gradual decrease from days 5 to 7 and then stabilized thereafter. MMP-8 was predominantly located in neutrophil-like cells. Statistically, the expression of MMP-8 was not correlated with the expression of EMMPRIN. The expression of MMP-13 and of EMMRPIN increased from days 3 to 7, and showed a moderate decrease thereafter. The immunoreactivity of MMP-13 was mainly detected in monocytes/macrophages, on the alveolar bone surface, in osteoclasts and in gingival epithelial cells. Statistically, MMP-13 had a strong, positive correlation with EMMPRIN (r = 0.855, p < 0.01). CONCLUSION: The levels of expression of MMP-8 and MMP-13 are temporally varied at different periods during the development of experimental periodontitis. The level of expression of EMMPRIN is closely associated with the expression of MMP-13, but not with the expression of MMP-8. In addition, MMP-13 might be involved in alveolar bone destruction, as well as in physiological bone remodeling. PMID- 23083376 TI - Contact doping of silicon wafers and nanostructures with phosphine oxide monolayers. AB - Contact doping method for the controlled surface doping of silicon wafers and nanometer scale structures is presented. The method, monolayer contact doping (MLCD), utilizes the formation of a dopant-containing monolayer on a donor substrate that is brought to contact and annealed with the interface or structure intended for doping. A unique feature of the MLCD method is that the monolayer used for doping is formed on a separate substrate (termed donor substrate), which is distinct from the interface intended for doping (termed acceptor substrate). The doping process is controlled by anneal conditions, details of the interface, and molecular precursor used for the formation of the dopant-containing monolayer. The MLCD process does not involve formation and removal of SiO(2) capping layer, allowing utilization of surface chemistry details for tuning and simplifying the doping process. Surface contact doping of intrinsic Si wafers (i Si) and intrinsic silicon nanowires (i-SiNWs) is demonstrated and characterized. Nanowire devices were formed using the i-SiNW channel and contact doped using the MLCD process, yielding highly doped SiNWs. Kelvin probe force microscopy (KPFM) was used to measure the longitudinal dopant distribution of the SiNWs and demonstrated highly uniform distribution in comparison with in situ doped wires. The MLCD process was studied for i-Si substrates with native oxide and H terminated surface for three types of phosphorus-containing molecules. Sheet resistance measurements reveal the dependency of the doping process on the details of the surface chemistry used and relation to the different chemical environments of the P?O group. Characterization of the thermal decomposition of several monolayer types formed on SiO(2) nanoparticles (NPs) using TGA and XPS provides insight regarding the role of phosphorus surface chemistry at the SiO(2) interface in the overall MLCD process. The new MLCD process presented here for controlled surface doping provides a simple yet highly versatile means for achieving postgrowth doping of nanometer scale structures and interfaces. PMID- 23083377 TI - Nitrosative stress: a hallmark of the junctional inflammation in cutaneous lupus erythematosus. PMID- 23083378 TI - Detection of nitrogen deficiency QTL in juvenile wild barley introgression lines growing in a hydroponic system. AB - BACKGROUND: In this report we studied the genetic regulation of juvenile development of wild barley introgression lines (S42ILs) under two contrasting hydroponic nitrogen (N) supplies. Ten shoot and root related traits were examined among 42 S42ILs and the recurrent parent 'Scarlett'. The traits included tiller number, leaf number, plant height, leaf and root length, leaf to root length ratio, shoots and root dry weight, shoot to root weight ratio, and chlorophyll content. Our aims were (1) to test the suitability of a hydroponic system for early detection of favourable S42ILs, (2) to locate quantitative trait loci (QTL) that control the examined traits, (3) to identify favourable wild barley alleles that improve trait performances in regard to N treatment and, finally, (4) to validate the identified QTL through comparison with previously reported QTL originating from the same parental cross. RESULTS: The phenotypic data were analysed in a mixed model association study to detect QTL. The post-hoc Dunnett test identified 28 S42ILs that revealed significant (P < 0.01) effects for at least one trait. Forty-three, 41 and 42 S42ILs revealed effects across both N treatments, under low N and under high N treatment, respectively. Due to overlapping or flanking wild barley introgressions of the S42ILs, these associations were summarised to 58 QTL. In total, 12 QTL of the hydroponic N study corresponded to QTL that were also detected in field trials with adult plants of a similar S42IL set or of the original S42 population. For instance, S42IL-135, -136 and -137, revealed increasing Hsp effects for tiller number, leaf number, leaf length, plant height and leaf to root ratio on the long arm of chromosome 7H. These QTL correspond to QTL for ears per plant and plant height that were previously detected in field trials conducted with the same S42ILs or with the S42 population. CONCLUSION: Our results suggest that the QTL we identified under hydroponic N cultivation partly correspond to QTL detected in field experiments. Due to this finding, screening of plants in early developmental stages grown in a hydroponic system may be a fast and cost effective method for early QTL detection and marker-assisted allelic selection, potentially speeding up elite barley breeding programs. PMID- 23083380 TI - Editorial: Societal impact - an important performance indicator of nursing research. PMID- 23083381 TI - Keynote summary and overview Rotterdam Congress. PMID- 23083379 TI - Assessment of vitamin D concentration in non-supplemented professional athletes and healthy adults during the winter months in the UK: implications for skeletal muscle function. AB - The current study implemented a two-part design to (1) assess the vitamin D concentration of a large cohort of non-vitamin D supplemented UK-based athletes and 30 age-matched healthy non-athletes and (2) to examine the effects of 5000 IU . day(-1) vitamin D(3) supplementation for 8-weeks on musculoskeletal performance in a placebo controlled trial. Vitamin D concentration was determined as severely deficient if serum 25(OH)D < 12.5 nmol . l(-1), deficient 12.5-30 nmol . l(-1) and inadequate 30-50 nmol . l(-1). We demonstrate that 62% of the athletes (38/61) and 73% of the controls (22/30) exhibited serum total 25(OH)D < 50 nmol . l(-1). Additionally, vitamin D supplementation increased serum total 25(OH)D from baseline (mean +/- SD = 29 +/- 25 to 103 +/- 25 nmol . l(-1), P = 0.0028), whereas the placebo showed no significant change (53 +/- 29 to 74 +/- 24 nmol . l(-1), P = 0.12). There was a significant increase in 10 m sprint times (P = 0.008) and vertical-jump (P = 0.008) in the vitamin D group whereas the placebo showed no change (P = 0.587 and P = 0.204 respectively). The current data supports previous findings that athletes living at Northerly latitudes (UK = 53 degrees N) exhibit inadequate vitamin D concentrations (<50 nmol . l(-1)). Additionally the data suggests that inadequate vitamin D concentration is detrimental to musculoskeletal performance in athletes. Future studies using larger athletic groups are now warranted. PMID- 23083382 TI - Systematic pain assessment using an observational scale in nursing home residents with dementia: exploring feasibility and applied interventions. AB - AIMS AND OBJECTIVES: To investigate the feasibility of regular pain assessment using an observational scale in nursing home residents with dementia and; determine interventions applied after diagnosing possible pain. BACKGROUND: Pain occurs regularly among nursing home residents with dementia and is frequently undertreated. Over the last decade a variety of observational scales have been developed to assess pain in elderly people with dementia. One of these observational scales is pain assessment using an observational scale. There are indications that the regular use of pain assessments scales can contribute to an adequate diagnosis of pain and therefore would improve pain treatment. DESIGN: In this exploratory descriptive observational study regular pain assessment using an observational scale as an intervention was evaluated. METHODS: Data were collected during a 6-week period (August-September 2009) where pain was measured twice a week among 22 residents of a psychogeriatric nursing home ward, using the pain assessment using an observational scale scale. Interventions undertaken as a result of the pain score were recorded on a datasheet. After the third and sixth week the implementation of pain assessment was evaluated with staff members using interviews. RESULTS: In total, 264 pain assessments were conducted using the pain assessment using an observational scale. Of all scheduled standardized assessments, 90% were completed. Sixty out of 264 assessment resulted in a pain score. The completed datasheets (n = 39), including information on the selected intervention and the reason for selecting a specific intervention, showed that a pain score (n = 17) did not often result in any intervention. The majority of interventions undertaken consisted of a non-pharmacological approach (n = 19). CONCLUSION: This study demonstrates that although there was a high compliance rate, pain relieving interventions were not frequently applied. Interventions undertaken after pain assessment were mainly non-pharmacological. RELEVANCE TO CLINICAL PRACTICE: Providing nursing staff with adequate pain assessment tools alone is not sufficient to change the pain management practices. PMID- 23083383 TI - The diagnostic value of the numeric pain rating scale in older postoperative patients. AB - AIMS AND OBJECTIVES: To measure the diagnostic value of the Numeric Rating Scale by comparing it to a Verbal Rating Scale in older patients. BACKGROUND: Pain management in older patients is an important challenge because of their greater susceptibility to adverse effects of analgesics. Nurses play an important role in applying guidelines for postoperative pain treatment. However, effective pain management is dependent upon valid and reliable pain assessment. DESIGN: Cross sectional study. METHODS: In total, 2674 older patients scored their postoperative pain on an 11-point numeric rating scale (NRS) and an adjective scale (VRS) including no pain, little pain, painful but bearable, considerable pain and terrible pain. The diagnostic value of different NRS cut-off values for administering analgesics is determined by an ROC curve. RESULTS: Sensitivity of NRS > 3 for 'unbearable' pain in older patients was 72% with a specificity of 97.2%. With a cut-off point NRS > 4, sensitivity increased to 83%, while specificity was 96.7%. With a cut-off point NRS > 5, sensitivity was 94%, while specificity was 85%. A high proportion (75%) of older old patients (>= 75 years) with 'painful but bearable' considers NRS 4, 5 and 6 to this VRS category. CONCLUSION: Using an NRS cut-off point > 3 or > 4, a large group of older patients with 'bearable' pain would incorrectly classified as 'unbearable'. When we make the assumption that bearable pain means no wish for additional analgesics, this misclassification might result in overtreatment with analgesics, while 3% would be undertreated. With NRS cut-off point > 5, 6% have a risk of overtreatment and 15% of undertreatment. RELEVANCE TO CLINICAL PRACTICE: Nurses should not rely solely on the NRS score in determining pain treatment; they need to communicate with older patients about their pain, the need for analgesics and eventual misconceptions about analgesics. PMID- 23083384 TI - Validation of the NOSCA - nurses' observation scale of cognitive abilities. AB - AIMS AND OBJECTIVES: To examine the psychometric properties of the Nurses' Observation Scale for Cognitive Abilities. BACKGROUND: Nurses' Observation Scale for Cognitive Abilities is a behavioural rating scale comprising eight subscales that represent different cognitive domains. It is based on observations during contact between nurse and patient. DESIGN: Observational study. METHODS: A total of 50 patients from two geriatric wards in acute care hospitals participated in this study. Reliability was examined via internal consistency and inter-rater reliability. Construct validity of the Nurses' Observation Scale for Cognitive Abilities and its subscales were explored by means of convergent and divergent validity and post hoc analyses for group differences. RESULTS: Cronbach's alphas of the total Nurses' Observation Scale for Cognitive Abilities and its subscales were 0.98 and 0.66-0.93, respectively. The item-total correlations were satisfactory (overall > 0.4). The intra-class coefficients were good (37 of 39 items > 0.4). The convergent validity of the Nurses' Observation Scale for Cognitive Abilities against cognitive ratings (MMSE, NOSGER) and severity of dementia (Clinical Dementia Rating) demonstrated satisfactory correlations (0.59 0.70, p < 0.01), except for IQCODE (0.30, p > 0.05). The divergent validity of the Nurses' Observation Scale for Cognitive Abilities against depressive symptoms was low (0.12, p > 0.05). The construct validity of the Nurses' Observation Scale for Cognitive Abilities subscales against 13 specific neuropsychological tests showed correlations varying from poor to fair (0.18-0.74; 10 of 13 correlations p < 0.05). CONCLUSIONS: Validity and reliability of the total Nurses' Observation Scale for Cognitive Abilities are excellent. The correlations between the Nurses' Observation Scale for Cognitive Abilities subscales and standard neuropsychological tests were moderate. More conclusive results may be found if the Nurses' Observation Scale for Cognitive Abilities subscales were to be validated using more ecologically valid tests and in a patient population with less cognitive impairment. RELEVANCE TO CLINICAL PRACTICE: Use of the Nurses' Observation Scale for Cognitive Abilities yields standardised, reliable and valid information about patient's cognitive behaviour in daily practice. The Nurses' Observation Scale for Cognitive Abilities aids in tailoring nursing interventions to patients' specific cognitive needs. We advocate the implementation of the Nurses' Observation Scale for Cognitive Abilities both in research and at geriatric units in acute care hospitals. PMID- 23083385 TI - Determination of older people's level of loneliness. AB - AIMS AND OBJECTIVES: To determine levels of loneliness of individuals aged 60 and above. BACKGROUND: Loneliness stands out as a social problem observed amongst old individuals living in both urban and rural areas. DESIGN: Descriptive study. METHODS: A total of 330 individuals aged 60 and above who visited a local health care centre at Sinop, Turkey, because of various health problems are included in the research. Data were collected using a questionnaire that determines the patients' socio-demographics and clinic specifications and uses the UCLA Loneliness Scale, Satisfaction with Life Scale and the instrumental activities of daily living list. For data analysis, percentage calculation, one-way anova, the student t-test and regression analysis were used. RESULTS: It has been determined that older people's UCLA Loneliness Scale point average is 47.3 +/- 8.6; most of them (49.1%) were seen to have a middle-level loneliness point. Older people's Satisfaction with Life Scale point average has been determined as 12.7 +/- 6.8. There is no statistically meaningful relationship between older people's life satisfaction score average and socio-demographic and clinical specifications (p > 0.05). Older people's points in IADL are 18.8 +/- 7.6. Most of them are independent in terms of fulfilment of the instrumental activities. Conclusions. In the study, when compared with the other groups, loneliness point averages were found significantly higher for men, those who had never married, primary school graduates, the childless, those who lived alone, those had a chronic disease or those who used continual medication. RELEVANCE TO CLINICAL PRACTICE: The social and health care systems need to recognise and address loneliness problems amongst older people. It is important to develop and test new interventions aimed at alleviating loneliness. PMID- 23083386 TI - Health outcomes and quality of life of residents of shared-housing arrangements compared to residents of special care units - results of the Berlin DeWeGE-study. AB - AIMS AND OBJECTIVES: To compare different health outcomes as well as quality of life (QoL) between people with dementia living in shared-housing arrangements (SHA) and special care units (SCU) in nursing homes. BACKGROUND: Often situated in large apartments in mostly urban settings, SHA are a specific German kind of small-scale living facilities for older care-dependent persons, predominantly suffering from dementia. SHA are completely disconnected from traditional nursing homes. DESIGN: In a longitudinal design, all new residents of SHA and SCU suffering with dementia in Berlin were surveyed for one year. They were assessed when they moved into the SHA or SCU and again 6 and 12 months later. METHODS: We surveyed physical and psychological health outcomes including ADL-functioning (Barthel), neuropsychiatric symptoms of dementia (NPI) and challenging behaviour (Cohen-Mansfield agitation inventory) as well as QoL (Qualidem). RESULTS: Fifty six persons (43 women, 13 men) were recruited into the longitudinal study. The average age was 82.5 years at admission, participants mostly had a moderate level of cognitive impairment (mean Mini Mental State Examination = 13.3), prevalence of neuropsychiatric symptoms was high. During the one-year follow-up, analyses show a significant decrease in cognitive abilities but also of neuropsychiatric symptoms in both groups. In SHA, QoL increases on average during the one-year study period. CONCLUSIONS: Both types of facilities attract slightly different populations according to our data. Comparison of SHA residents to SCU residents documented no significant beneficial effects of settings in terms of health outcomes. RELEVANCE TO CLINICAL PRACTICE: As no clear advantage of either SHA or SCU in nursing homes can be demonstrated for residents with dementia who move in newly, it is impossible to give a clear evidence-based recommendation and the decision for one setting or the other can be made according solely to personal preference of the resident. PMID- 23083388 TI - Distress experienced by nurses in response to the challenging behaviour of residents - evidence from German nursing homes. AB - AIMS AND OBJECTIVES: The aim of this research is to investigate the degree of distress experienced by nurses in response to the challenging behaviour of nursing home residents (residents' challenging behaviour) and their impact on nurses individual resources (general health, burnout and work ability). BACKGROUND: Because of the increasing and ageing population of nursing home residents, professional nursing care faces several challenges. One highly prevalent issue among nursing home residents is the so-called 'challenging behaviour'. However, to date, 'challenging behaviour' has not yet been recognised as an occupational stressor, and the extent of the impact of 'challenging behaviour' on nurses' well-being and functioning is not well understood. DESIGN: Cross-sectional study. METHOD: Self-report questionnaire data collected from 731 registered nurses and nursing aides in 56 German nursing homes were used in a secondary data analysis. The level of residents' challenging behaviour-related distress that nurses experienced was assessed using a scale consisting of nine questions. Validated instruments were used for the assessment of individual resources. RESULTS: The mean score for residents' challenging behaviour-related distress was 41.3 (SD 21.2). Twenty-seven per cent of all nurses reported over 50 residents' challenging behaviour. Residents' challenging behaviour had a significant impact on all three measures of individual resources. Specifically, nurses exposed to frequent residents' challenging behaviour reported a significantly lower quality of general health, reduced workability and high burnout levels. CONCLUSION: Our findings indicate that residents' challenging behaviour-related distress is a significant work place stressor for nurses in nursing homes with a clear impact on general health, the risk of burnout and work ability. RELEVANCE TO CLINICAL PRACTICE: Our findings suggest that residents' challenging behaviour is a stressor for nurses in nursing homes. Further scientific and practical attention is necessary from the point of view of working conditions for nurses. The development of preventive concepts for nursing staff and residents is recommended. PMID- 23083389 TI - Talking in triads: communication with Turkish and Moroccan immigrants in the palliative phase of cancer. AB - AIMS AND OBJECTIVES: To gain insight into the factors that influence communication between health professionals and Turkish and Moroccan immigrants in the palliative phase of cancer. BACKGROUND: In palliative care, communication is crucial. The question, however, is whether Dutch healthcare providers, on the one hand, and Turkish and Moroccan patients and their family members, on the other, agree on what is constituted by good communication. DESIGN: A descriptive qualitative method is used. METHODS: Data of semi-structured interviews with 83 persons (six patients, 30 relatives and 47 professional care providers) were analysed to determine perceptual communication differences about care and treatment during the palliative phase of 33 cases. RESULTS: As many patients with a Turkish or Moroccan background speak little Dutch, conversations often take place in triads, which makes it difficult for the actors to understand and resolve communication problems arising from diverging perceptions of 'good communication'. CONCLUSION: Miscommunication around palliative care cannot solely be explained by the different cultural backgrounds of patients and their care providers. The multilingual communication triangle of patient - family - care provider often also complicates the bridging of differences in care perceptions. RELEVANCE TO CLINICAL PRACTICE: Professional care providers should develop adequate strategies to handle triads, explore their own conventions and those of patients and relatives. PMID- 23083387 TI - Nurses Improving Care for Healthsystem Elders - a model for optimising the geriatric nursing practice environment. AB - AIMS AND OBJECTIVES: To explain the relationship between a positive nurse practice environment (NPE) and implementation of evidence-based practices. To describe the components of NICHE (Nurses Improving Care for Healthsystem Elders) programmes that contribute to a positive geriatric nursing practice environment. BACKGROUND: The NPE is a system-level intervention for promoting quality and patient safety; however, there are population-specific factors that influence the nurses' perception of their practice and its' relationship with patient outcomes. Favourable perceptions of the geriatric-specific NPE are associated with better perceptions of geriatric care quality. DESIGNS: Discursive paper. METHOD: In this selective critical analysis of the descriptive and empirical literature, we present the implementation of geriatric models in relation to the NPE and components of the NICHE programme that support hospitals' systemic capacity to effectively integrate and sustain evidence-based geriatric knowledge into practice. RESULTS: Although there are several geriatric models and chronic care models available, NICHE has been the most successful in recruiting hospital membership as well as contributing to the depth of geriatric hospital programming. CONCLUSIONS: Although all geriatric care models require significant nursing input, only NICHE focuses on the nursing staff's perception of the care environment for geriatric practice. Studies in NICHE hospitals demonstrate that quality geriatric care requires a NPE in which the structure and processes of hospital services focus on specific patient care needs. RELEVANCE TO CLINICAL PRACTICE: The implementation of evidence-based models addressing the unique needs of hospitalised older adults requires programmes such as NICHE that serve as technical resources centre and a catalyst for networking among facilities committed to quality geriatric care. Unprecedented international growth in the ageing population compels us to examine how to adapt the successful components of NICHE to the distinctive needs of health systems throughout the world that serve older adults. PMID- 23083390 TI - Caring to achieve the maximum independence possible: a synthesis of qualitative evidence on older adults' adaptation to dependency. AB - AIMS AND OBJECTIVES: To understand the process of adaptation to dependency in older adults and their families. BACKGROUND: Dependency and family care giving are attracting the attention of policymakers, service providers and researchers. DESIGN: An interpretative synthesis of qualitative studies has been conducted. METHODS: An extensive search without time and idiom limitations was conducted using the main databases (MEDLINE, CINAHL, EMBASE, PsycINFO, SSCI, LILACS, CUIDEN, Cochrane Library and JBI): personal communication from expert panel was used to detect filters strategies to find qualitative studies; these strategies were combined with search terms for dependence in older adults. The studies (2164 potentially relevant papers) were judged by two reviewers based on reading title, abstract, keywords and/or full text (English, Spanish, French and Portuguese) to determine their inclusion. After, 203 papers were critically appraised by two reviewers (disagreements were resolved by discussions). Finally, the synthesis of the 20 studies with best interpretative character was carried out based on the principles and procedures of Grounded Theory. RESULTS: The findings were related to the process of adaptation to dependency, the factors and the strategies used, the emotions, perceptions and feelings of care givers and older adults. The central category that emerged was 'Caring to achieve the maximum independence possible', and this could be seen as a transition period in which older adults and their families progressed in a mutually determined adaptation process. This category is made up of several redefinitions of concepts, phases, adaptation strategies and final responses to the process. CONCLUSIONS: The findings show the interconnected nature of physical, material, social and emotional aspects of care; and the profound social impact of providing and receiving care. Relevance to clinical practice. The nurses can assist families and older adults to enhance adaptation to dependency, anticipating and helping to redefine the concepts of care. PMID- 23083391 TI - The 75-year-old persons' self-reported health conditions: a knowledge base in the field of preventive home visits. AB - AIMS AND OBJECTIVES: To describe and analyse 75-year-old persons' health conditions and how they were associated with socio-demographic status and sense of coherence to produce a knowledge base for district nurse's preventive home visits. BACKGROUND: Action plans are needed to promote health and to prevent diseases amongst older people. One action plan is preventive home visits to 75 year-old persons by the district nurse. Though the district nurse has a broad knowledge in the field of preventive health work, preventive home visits to 75 year-old persons was a new responsibility. Although aging and older persons health have been investigated in many varied studies, it was difficult to find a comprehensive view, in general and from a district nursing perspective, of 75 year olds' health conditions. DESIGN: Cross-sectional. METHODS: In total 583, 75 year-olds (74%) answered a questionnaire regarding health and well-being, health problems, health behaviour and sense of coherence. RESULTS: Most 75-year-old persons reported their health as good or very good, but they also reported health problems such as: pain, sleeping problems, memory failure, fatigue, poor understanding of their own health and illnesses, problems with elimination patterns and underweight and overweight. 75-year-old persons living alone, those with elementary school education and women reported worse health and well-being than other groups. CONCLUSION: This study contributes to the knowledge about health issues that concern persons of 75 years of age. It gives a suggestion as to what the district nurses should be aware of when performing preventive home visits. RELEVANCE TO CLINICAL PRACTICE: This study raises the importance of preventive health work regarding 75-year-old persons. It suggests how to educate district nurses in how to perform preventive home visits to older persons. PMID- 23083392 TI - Editorial: Keeping it simple: the power of three clinical protocols. PMID- 23083393 TI - Decision-making related to complementary and alternative medicine use by people with Type 2 diabetes: a qualitative study. AB - AIMS AND OBJECTIVES: To explore how complementary and alternative medicine (CAM) users make decisions about CAM use. Specifically, an exploration of the processes used by people with Type 2 diabetes, related to the assessment of information sources, factors influencing decision-making and the role of other key individuals, was undertaken. BACKGROUND: Patients with chronic illnesses increasingly seek to use CAM to improve their well-being. Currently, however, the decision-making processes related to CAM use among people with Type 2 diabetes are poorly understood. METHODS: An exploratory study using a naturalistic design, with in-depth semi-structured interviews, was undertaken. Purposive sampling was used to recruit participants with Type 2 diabetes who used CAM alongside conventional medicine. The data were analysed in a three-step coding process. Ethical approval was gained from a human research ethics committee. RESULTS: Evidence about CAM use from interview data was consistent with a multi dimensional decision-making processes used by participants. Four major categories emerged: recognising the need for using CAM; assessing the potential CAM before use; matching CAM use to personal philosophy; and ongoing evaluation of CAM. CONCLUSION: As diabetes affects the entirety of a person's being self-management, incorporating CAMs has become a way of controlling the condition and improving well-being. It is important for health professionals to consider clients' CAM use and to incorporate this information, where appropriate, into management plans. RELEVANCE TO CLINICAL PRACTICE: Health care professionals should be aware of patients who use CAM while under conventional medical care and should discuss CAM use at various points in the client journey to facilitate better communication. PMID- 23083394 TI - Gestational diabetes: prospective interview-study of the developing beliefs about health, illness and health care in migrant women. AB - AIMS AND OBJECTIVES: To explore the development over time of beliefs about health, illness and health care in migrant women with gestational diabetes mellitus born in the Middle East and living in Sweden and to study the influence on self-care and care seeking. BACKGROUND: With today's extensive global migration, contact with the new society/health care confronts the migrant's culture of origin with the culture of the host country. The question is whether immigrants' patterns of beliefs about health, illness and health-related behaviour change over time, as no previous studies have been found on this topic. DESIGN: A qualitative prospective exploratory study. METHODS: Semi-structured interviews, with 14 women (28-44 years), on three occasions: during pregnancy in gestational weeks 34-38 and three and 14 months after delivery. RESULTS: There was a U-shaped development of beliefs, from focusing on worries about the baby's health during pregnancy and trying to comply with advice from health professionals, particularly a healthy diet, through regression to dietary habits (more sugar, less fibre) and lifestyle held before being diagnosed with gestational diabetes mellitus three months after delivery, back to a healthy diet/lifestyle and worries 14 months after delivery but then focusing on their own risk, as mothers, of developing type 2 diabetes and being unable to care for the child. Over time, the number of persons perceiving gestational diabetes mellitus as a transient condition decreased. Respondents lacked information about gestational diabetes mellitus, diet and follow-ups. CONCLUSION: Beliefs changed over time and influenced health-related behaviour. Beliefs about the seriousness of gestational diabetes mellitus among healthcare staff/care organisation influence the development of patients' beliefs and need to be considered in planning care. RELEVANCE TO CLINICAL PRACTICE: Pregnancy should be used as an opportunity to provide complete information about gestational diabetes mellitus and future health risks. This should continue after delivery and wishes for regular follow-ups should be met. PMID- 23083395 TI - A survey of parental self-efficacy experiences: maximising potential through health visiting and universal parenting support. AB - AIMS AND OBJECTIVES: To examine parental self-efficacy experiences for users of a parenting support programme and consider the pertinence of self-efficacy theory to health visiting (public health nursing) practice. BACKGROUND: Commonly, successful parenting training programmes are underpinned by social learning principles and aim to strengthen parental self-efficacy. However, research examining programme effectiveness rarely discusses how self-efficacy outcomes are achieved. DESIGN: A descriptive survey was completed as the first part of a realistic evaluation study examining how a UK parenting support programme worked. METHODS: The first part of the realistic evaluation involved validating outcome measures (the Parenting Self-Agency Measure and Self-Efficacy for Parenting Tasks Index subscales) and administering a questionnaire survey. The questionnaire was completed by adults accessing a parenting support programme during a 10-month period (n = 168). Data were analysed using descriptive and inferential statistics. RESULTS: Women were the main users of the programme, which included informal drop-in groups as well as more formalised health visiting services and parenting training courses. The Parenting Self-Agency Measure results indicated good general parental self-efficacy; however, the task-specific Self-Efficacy for Parenting Tasks Indexes scales suggested that parents were less self-efficacious in disciplining children. Lower self-efficacy scores correlated with high ratings for 'feeling tired', 'receiving negative comments' and 'giving-in to a child's demands'. CONCLUSIONS: Study results indicate that the domain general and task specific measures provide different, but helpful, insights into parental self efficacy experiences. By identifying factors associated with the levels of general and task-specific parental self-efficacy, health visitors can gain a fuller appreciation of support needs. RELEVANCE TO PRACTICE: To maximise potential through parenting support, attention should be given to addressing factors associated with poorer self-efficacy experiences, including parental tiredness. Equally, practice should be directed at developing community environments that offer exposure to positive praise and the opportunity to practice new skills without facing criticism. PMID- 23083396 TI - Hybrid and electric low-noise cars cause an increase in traffic accidents involving vulnerable road users in urban areas. AB - Due to resource scarcity, the number of low-noise and electric cars is expected to increase rapidly. The frequent use of these cars will lead to a significant reduction of traffic related noise and pollution. On the other hand, due to the adaption and conditioning of vulnerable road users the number of traffic accidents involving pedestrians and bicyclists is postulated to increase as well. Children, older people with reduced eyesight and the blind are especially reliant on a combination of acoustic and visual warning signals with approaching or accelerating vehicles. This is even more evident in urban areas where the engine sound is the dominating sound up to 30 kph (kilometres per hour). Above this, tyre-road interaction is the main cause of traffic noise. With the missing typical engine sound a new sound design is necessary to prevent traffic accidents in urban areas. Drivers should not be able to switch the sound generator off. PMID- 23083397 TI - A multi-center inter-manufacturer study of the temporal stability of phase contrast velocity mapping background offset errors. AB - BACKGROUND: Phase-contrast velocity images often contain a background or baseline offset error, which adds an unknown offset to the measured velocities. For accurate flow measurements, this offset must be shown negligible or corrected. Some correction techniques depend on replicating the clinical flow acquisition using a uniform stationary phantom, in order to measure the baseline offset at the region of interest and subtract it from the clinical study. Such techniques assume that the background offset is stable over the time of a patient scan, or even longer if the phantom scans are acquired later, or derived from pre-stored background correction images. There is no published evidence regarding temporal stability of the background offset. METHODS: This study assessed the temporal stability of the background offset on 3 different manufacturers' scanners over 8 weeks, using a retrospectively-gated phase-contrast cine acquisition with fixed parameters and at a fixed location, repeated 5 times in rapid succession each week. A significant offset was defined as 0.6 cm/s within 50 mm of isocenter, based upon an accuracy of 10% in a typical cardiac shunt measurement. RESULTS: Over the 5 repeated cine acquisitions, temporal drift in the baseline offset was insignificant on two machines (0.3 cm/s, 0.2 cm/s), and marginally insignificant on the third machine (0.5 cm/s) due to an apparent heating effect. Over a longer timescale of 8 weeks, insignificant drift (0.4 cm/s) occurred on one, with larger drifts (0.9 cm/s, 0.6 cm/s) on the other machines. CONCLUSIONS: During a typical patient study, background drift was insignificant. Extended high gradient power scanning with work requires care to avoid drift on some machines. Over the longer term of 8 weeks, significant drift is likely, preventing accurate correction by delayed phantom corrections or derivation from pre-stored background offset data. PMID- 23083398 TI - Fluorescence response of coumarin-153 in N-alkyl-N-methylmorpholinium ionic liquids: are these media more structured than the imidazolium ionic liquids? AB - The fluorescence behavior of coumarin-153 (C153) has been studied in four N-alkyl N-methylmorpholinium ionic liquids differing in the alkyl chain length attached to the N-methylmorpholinium cation as a function of the excitation wavelength and temperature to understand some of the physicochemical characteristics of these largely unexplored ionic liquids. While the polarity of the ionic liquid with the smallest alkyl chain length is found comparable to that of the commonly used imidazolium ionic liquids, the probe molecule experiences a less polar environment with increasing chain length of the alkyl group attached to the morpholinium cation. The room temperature steady-state fluorescence spectrum of C153 in these solvents is found to be dependent on the excitation wavelength, and this effect is most pronounced in long chain containing ionic liquids. A bathochromic shift of the fluorescence maximum is observed at higher temperature. The excitation wavelength and temperature dependence of the fluorescence of C153 is explained considering a domain structure of these ionic liquids. The time resolved fluorescence anisotropy measurements indicate the microviscosity around the probe molecule to be significantly different from the bulk viscosity of the long-chain ionic liquids. The solvent reorganization dynamics, as studied by monitoring the time-dependent fluorescence Stokes shift of C153 in these ionic liquids, is found to be slow and similar to that in imidazolium ionic liquids. The time-resolved measurements under isoviscous conditions seem to provide additional support to the organized domain structure of these ionic liquids. PMID- 23083399 TI - Determinants of vitamin D status in long-term renal transplant patients. AB - In this study, we explored the determinants of vitamin D status in a large cohort of stable, Long-term renal transplant (RTx) patients. Serum 25(OH)D concentrations, and bone biochemistry parameters, were retrospectively analyzed from 266 RTx patients (>10 yr post-engraftment) presenting to clinic over the course of a year. Forty-five percent of the cohort were vitamin D deficient (<37.5 nM), 38% insufficient (37.5 75-nM), and 17% sufficient (>75 nM). Serum 25(OH)D concentrations were higher in patients presenting in summer (p<0.001) and in more active patients (p<0.05). RTx patients with non-melanoma skin cancer (NMSC) (n=45) had higher 25(OH)D concentrations than patients without NMSC (n=221; p<0.05) despite these patients being older, having worse eGFR, transplanted for longer, and less active physically (p<0.05). Lower 25(OH)D concentrations were associated with higher PTH concentrations (p<0.05) which, in the setting of widespread hypovitaminosis, suggests that secondary hyperparathyroidism was common in this cohort. In conclusion, season and activity status are important determinants of vitamin D status. We report, for the first time, that NMSC is associated with higher 25(OH)D, probably through increased UV radiation exposure. Long-term RTx patients may benefit from oral vitamin D supplementation, but this requires a randomized controlled trial to confirm. PMID- 23083400 TI - Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study. AB - BACKGROUND: Following Helicobacter pylori eradication in idiopathic parkinsonism (IP), hypokinesia improved but flexor-rigidity increased. Small intestinal bacterial-overgrowth (SIBO) is a candidate driver of the rigidity: hydrogen breath-test-positivity is common in IP and case histories suggest that Helicobacter keeps SIBO at bay. METHODS: In a surveillance study, we explore relationships of IP-facets to peripheral immune/inflammatory-activation, in light of presence/absence of Helicobacter infection (urea-breath- and/or stool-antigen test: positivity confirmed by gastric-biopsy) and hydrogen-breath-test status for SIBO (positivity: >20 ppm increment, 2 consecutive 15-min readings, within 2h of 25G lactulose). We question whether any relationships found between facets and blood leukocyte subset counts stand in patients free from anti-parkinsonian drugs, and are robust enough to defy fluctuations in performance consequent on short t1/2 therapy. RESULTS: Of 51 IP-probands, 36 had current or past Helicobacter infection on entry, 25 having undergone successful eradication (median 3.4 years before). Thirty-four were hydrogen-breath-test-positive initially, 42 at sometime (343 tests) during surveillance (2.8 years). Hydrogen breath-test-positivity was associated inversely with Helicobacter-positivity (OR 0.20 (95% CI 0.04, 0.99), p<0.05).In 38 patients (untreated (17) or on stable long-t1/2 IP-medication), the higher the natural-killer count, the shorter stride, slower gait and greater flexor-rigidity (by mean 49 (14, 85) mm, 54 (3, 104) mm.s-1, 89 (2, 177) Nm.10-3, per 100 cells.MUl-1 increment, p=0.007, 0.04 & 0.04 respectively, adjusted for patient characteristics). T-helper count was inversely associated with flexor-rigidity before (p=0.01) and after adjustment for natural-killer count (-36(-63, -10) Nm.10-3 per 100 cells.MUl-1, p=0.007). Neutrophil count was inversely associated with tremor (visual analogue scale, p=0.01). Effect-sizes were independent of IP-medication, and not masked by including 13 patients receiving levodopa (except natural-killer count on flexor rigidity). Cellular associations held after allowing for potentially confounding effect of hydrogen-breath-test or Helicobacter status. Moreover, additional reduction in stride and speed (68 (24, 112) mm & 103 (38, 168) mm.s-1, each p=0.002) was seen with Helicobacter-positivity. Hydrogen-breath-test-positivity, itself, was associated with higher natural-killer and T-helper counts, lower neutrophils (p=0.005, 0.02 & 0.008). CONCLUSION: We propose a rigidity-associated subordinate pathway, flagged by a higher natural-killer count, tempered by a higher T-helper, against which Helicobacter protects by keeping SIBO at bay. PMID- 23083401 TI - A viral RNA silencing suppressor interferes with abscisic acid-mediated signalling and induces drought tolerance in Arabidopsis thaliana. AB - Cucumber mosaic virus (CMV) encodes the 2b protein, which plays a role in local and systemic virus movement, symptom induction and suppression of RNA silencing. It also disrupts signalling regulated by salicylic acid and jasmonic acid. CMV induced an increase in tolerance to drought in Arabidopsis thaliana. This was caused by the 2b protein, as transgenic plants expressing this viral factor showed increased drought tolerance, but plants infected with CMVDelta2b, a viral mutant lacking the 2b gene, did not. The silencing effector ARGONAUTE1 (AGO1) controls a microRNA-mediated drought tolerance mechanism and, in this study, we noted that plants (dcl2/3/4 triple mutants) lacking functional short-interfering RNA-mediated silencing were also drought tolerant. However, drought tolerance engendered by CMV may be independent of the silencing suppressor activity of the 2b protein. Although CMV infection did not alter the accumulation of the drought response hormone abscisic acid (ABA), 2b-transgenic and ago1-mutant seeds were hypersensitive to ABA-mediated inhibition of germination. However, the induction of ABA-regulated genes in 2b-transgenic and CMV-infected plants was inhibited more strongly than in ago1-mutant plants. The virus engenders drought tolerance by altering the characteristics of the roots and not of the aerial tissues as, compared with the leaves of silencing mutants, leaves excised from CMV-infected or 2b-transgenic plants showed greater stomatal permeability and lost water more rapidly. This further indicates that CMV-induced drought tolerance is not mediated via a change in the silencing-regulated drought response mechanism. Under natural conditions, virus-induced drought tolerance may serve viruses by aiding susceptible hosts to survive periods of environmental stress. PMID- 23083402 TI - Porphyromonas gingivalis and Escherichia coli lipopolysaccharide causes resistin release from neutrophils. AB - OBJECTIVES: It was reported that periodontitis is associated with increased serum resistin levels. We examined whether there was a difference between the release of resistin from neutrophils incubated lipopolysaccharide (LPS) from Porphyromonas gingivalis and with LPS from Escherichia coli, and which cell surface receptors and intracellular kinases were involved in this process. METHODS: Several concentrations of P. gingivalis-LPS and E. coli-LPS were added to neutrophils, supernatant from cultured neutrophils was collected, and resistin levels were measured by ELISA. To examine signaling pathways, neutrophils were pretreated with monoclonal antibodies against CD14, CD18, TLR2, and TLR4, and specific inhibitors of PI3K and MAPKs. RESULTS: Resistin release from neutrophils was induced both by P. gingivalis-LPS and E. coli-LPS, but resistin release by P. gingivalis-LPS was weaker than E. coli-LPS in low concentrations. Resistin release was decreased by pretreatment with monoclonal antibodies against CD14, CD18, and TLR4, but not by TLR2. Moreover, it was decreased by inhibitors of PI3K, JNK, and p38 MAPK, but not by ERK1/2. CONCLUSIONS: Resistin release from neutrophils was induced by both P. gingivalis-LPS and E. coli-LPS. This was decreased by CD14, CD18, and TLR4 and was dependent on PI3K, JNK, and p38 MAPK, but not on ERK1/2 in intracellular pathways of neutrophils. PMID- 23083403 TI - Evolution of Pb(1-x)Sn(x)Te thin films from dendrites to nanoparticles on gold substrates by electrodeposition. AB - Dendritic and nanostructured Pb(1-x)Sn(x)Te thin films were synthesized on gold substrates from acidic solutions through a simple electrodeposition route. The deposition potential of thin films was determined using cyclic voltammetry. All of the thin films were deposited in both the absence and presence of cetyltrimethylammonium bromide (CTAB) as a cationic surfactant. X-ray diffraction (XRD), scanning electron microscopy (SEM), atomic force microscopy (AFM), and Fourier transform infrared (FT-IR) spectroscopy were employed to characterize the deposits. XRD results showed that the diffraction peaks shift to larger angles as mole fraction x increases, indicating the formation of Pb(1-x)Sn(x)Te alloy. Morphological analysis revealed that the obtained thin films in the absence of CTAB were composed of dendrites, while the obtained thin films in the presence of CTAB were made of nanoparticles. Growth mechanisms for the dendritic and nanostructured thin films were discussed. The optical absorption studies show that the band gap of Pb(1-x)Sn(x)Te thin films grown with short deposition times could be tuned from 0.21 to 0.35 eV by adding only the surfactant to the deposition solution. PMID- 23083404 TI - Palladium-catalyzed Sonogashira-coupling conjoined C-H activation: a regioselective tandem strategy to access indolo- and pyrrolo[1,2-a]quinolines. AB - An operationally simple approach for the regioselective tandem synthesis of indolo[1,2-a]quinolines 4a-v and pyrrolo[1,2-a]quinolines 5a-k from 1-(2 bromophenyl)-1H-indole/pyrrole/imidazole 1a-c, 2a,b by the palladium-catalyzed sequential C-C bond formation is described. The developed approach involves the palladium-catalyzed Sonogashira coupling followed by the intramolecular C-C bond formation via C-H activation, which leads to the formation of 6-endo-dig cyclized product. This synthetic methodology accommodates wide functional group variation on alkyne, which proves to be advantageous for the structural and biological activity assessments. PMID- 23083405 TI - The parent-child relationship and adolescent alcohol use: a systematic review of longitudinal studies. AB - BACKGROUND: Alcohol use among adolescents has become a major public health problem in the past decade and has large short- and long-term consequences on their health. The aim of this systematic review was to provide an overview of longitudinal cohort studies that have analyzed the association between the parent child relationship (PCR) and change in alcohol use during adolescence. METHODS: A search of the literature from 1985 to July 2011 was conducted in Medline, PsycINFO, and EMBASE in order to identify longitudinal, general population studies regarding the influence of the PCR on alcohol use during adolescence. The studies were screened, and the quality of the relevant studies was assessed. A best-evidence synthesis was used to summarize the results. RESULTS: Twenty-eight relevant studies were identified. Five studies found that a negative PCR was associated with higher levels of alcohol use. Another seven papers only found this association for certain subgroups such as boys or girls, or a specific age group. The remaining sixteen studies did not find any association. CONCLUSIONS: We found weak evidence for a prospective association between the PCR and adolescent alcohol use. Further research to the association of the PCR with several types of alcohol use (e.g., initiation or abuse) and to the potential reversed causality of the PCR and alcohol use is required. PMID- 23083406 TI - Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition. AB - BACKGROUND: In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this study was to compare cognitive functioning of patients who are treated for acromegaly with patients with non-functioning pituitary adenomas (NFA). In addition, we assessed the influence of prolonged medical treatment after initial transsphenoidal surgery on cognition. DESIGN: In this cross-sectional study, 74 patients participated, who were treated for acromegaly (n = 50; median [interquartile range] age: 53 [45-65] years) or NFA (n = 24; age: 63 [59-70] years). The NFA patients were selected for a high likelihood of normal GH secretion based on an IGF-1 z-score within the normal range (> -2) and zero or one axis substituted. Of the acromegaly patients, 28 had achieved remission, while 22 were biochemically controlled with long-acting somatostatin analogues and/or pegvisomant. Memory and executive functioning were assessed by the 15 Words Test and the Ruff Figural Fluency Test, and reported as z-scores. RESULTS: The total patient group scored significantly poorer than the reference population on memory and executive functioning (P < 0.001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients. CONCLUSION: The total patient group scored worse compared with reference populations. We found no association between previous GH excess and cognition. In addition, current medical treatment for GH excess in acromegaly was not related to memory and executive functioning. PMID- 23083407 TI - Interaction of different extracts of Primula heterochroma Stapf. with red blood cell membrane lipids and proteins: antioxidant and antihemolytic effects. AB - In recent years, considerable attention has been paid to plants as potent natural drugs for their ameliorative roles against free-radical-mediated oxidative stress. Therefore, their interactions with cell membrane lipids and proteins, which generally serve as primary targets of lipid peroxidation, are of much interest. In the current investigation, in vitro and ex vivo studies are performed in order to estimate possible effects of different extracts of Primula heterochroma Stapf. on red blood cell membranes of rat erythrocytes using colorimetric methods. The results indicate that binding of the extracts to lipids and proteins of red blood cell membranes both significantly inhibits lipid peroxidation, and also increases red blood cell integrity against hemolysis. Moreover, a polyphenol extract, in particular, demonstrates notable antihemolytic activity in hydrogen peroxide-induced hemolysis model (IC(50) = 199.49 +/- 9.1 MUg ml(-1)). PMID- 23083408 TI - Erythema dyschronicum perstans with both a macular lesion and a linear lesion following the lines of Blaschko. PMID- 23083409 TI - Leg ulcers associated with nicorandil are possibly underdiagnosed. PMID- 23083411 TI - Integration of the ferromagnetic insulator EuO onto graphene. AB - We have demonstrated the deposition of EuO films on graphene by reactive molecular beam epitaxy in a special adsorption-controlled and oxygen-limited regime, which is a critical advance toward the realization of the exchange proximity interaction (EPI). It has been predicted that when the ferromagnetic insulator (FMI) EuO is brought into contact with graphene, an overlap of electronic wave functions at the FMI/graphene interface can induce a large spin splitting inside the graphene. Experimental realization of this effect could lead to new routes for spin manipulation, which is a necessary requirement for a functional spin transistor. Furthermore, EPI could lead to novel spintronic behavior such as controllable magnetoresistance, gate tunable exchange bias, and quantized anomalous Hall effect. However, experimentally, EuO has not yet been integrated onto graphene. Here we report the successful growth of high-quality crystalline EuO on highly oriented pyrolytic graphite and single-layer graphene. The epitaxial EuO layers have (001) orientation and do not induce an observable D peak (defect) in the Raman spectra. Magneto-optic measurements indicate ferromagnetism with a Curie temperature of 69 K, which is the value for bulk EuO. Transport measurements on exfoliated graphene before and after EuO deposition indicate only a slight decrease in mobility. PMID- 23083410 TI - Oocyte-somatic cells interactions, lessons from evolution. AB - BACKGROUND: Despite the known importance of somatic cells for oocyte developmental competence acquisition, the overall mechanisms underlying the acquisition of full developmental competence are far from being understood, especially in non-mammalian species. The present work aimed at identifying key molecular signals from somatic origin that would be shared by vertebrates. RESULTS: Using a parallel transcriptomic analysis in 4 vertebrate species - a teleost fish, an amphibian, and two mammals - at similar key steps of developmental competence acquisition, we identified a large number of species specific differentially expressed genes and a surprisingly high number of orthologous genes exhibiting similar expression profiles in the 3 tetrapods and in the 4 vertebrates. Among the evolutionary conserved players participating in developmental competence acquisition are genes involved in key processes such as cellular energy metabolism, cell-to-cell communications, and meiosis control. In addition, we report many novel molecular actors from somatic origin that have never been studied in the vertebrate ovary. Interestingly, a significant number of these new players actively participate in Drosophila oogenesis. CONCLUSIONS: Our study provides a comprehensive overview of evolutionary-conserved mechanisms from somatic origin participating in oocyte developmental competence acquisition in 4 vertebrates. Together our results indicate that despite major differences in ovarian follicular structure, some of the key players from somatic origin involved in oocyte developmental competence acquisition would be shared, not only by vertebrates, but also by metazoans. The conservation of these mechanisms during vertebrate evolution further emphasizes the important contribution of the somatic compartment to oocyte quality and paves the way for future investigations aiming at better understanding what makes a good egg. PMID- 23083412 TI - Effects of foliar iron application on iron concentration in polished rice grain and its bioavailability. AB - Iron (Fe) deficiency in humans caused by inadequate dietary intake is a global nutritional problem. A glass house pot experiment was conducted to evaluate the effect of foliar FeSO4 containing applications on concentrations of Fe, Zn, and Fe bioavailability in polished rice among five rice cultivars. The results showed that foliar application of FeSO4, FeSO4, plus nicotianamine (NA), and FeSO4 plus NA with ZnSO4 increased the grain Fe concentration by 16.97%, 29.9%, and 27.08%, respectively. The grain Fe bioavailability also increased by foliar application of FeSO4, FeSO4 plus NA, and FeSO4 plus NA with ZnSO4; these represent increases of 12.63%, 20.86%, and 18.75%, respectively. Foliar FeSO4 containing applications improved the Fe bioavailability and might be attributed to the reduction of phytic acid and the increase of Fe concentration in polished rice. Addition of ZnSO4 to foliar Fe application increased both Fe and Zn content without altering Fe content and bioavailability. In addition, the cultivar difference in Fe and Zn concentration was observed and may be due to the genetic control of leaf absorption and seed deposition of foliar application. Furthermore, the cultivar difference in Fe bioavailability observed might be attributed to the variation of grain Fe, phytic acid, and total phenolics contents among the five rice cultivars. The results suggested that foliar FeSO4 containing applications represent a promising agricultural approach to reduce Fe deficiency in countries where polished rice is extensively consumed. PMID- 23083413 TI - Continuous use of oral contraceptives: an overview of effects and side-effects. AB - OBJECTIVE: To describe the effects and side-effects of the continuous use of oral contraceptives. DESIGN: A review of articles concerning oral contraceptives taken continuously or in cycles with hormones taken for more than 21 days per cycle. METHODS: We searched publications in PubMed and Embase. Randomized controlled trials were selected if possible, otherwise case-control studies or cohort studies with controls were chosen. A level of evidence as described by the Centre for Evidence Based Medicine (Oxford University, Oxford, UK) was assigned to all selected studies. MAIN OUTCOME MEASURES: Clinical and paraclinical effects and side-effects of oral contraceptives administered continuously. RESULTS: The studies suggest that the endometrium is inactive during continuous use of oral contraceptives and the risk of endometrial hyperplasia is not increased. Numbers of bleeding days are halved with continuous use; however, spotting and irregular bleeding are more often seen in the beginning of use, decreasing with time. Hemostatic parameters and serum lipid and carbohydrate profiles in continuous and conventional users do not differ. Menstrual cycle-related symptoms are relieved better by continuous treatment. After surgery for endometriosis, the effect of continuously used oral contraceptives on the risk of recurrence of pain has been found to be less than that of gonadotropin-releasing hormone (GnRH) analogues, but better than the rate seen during conventional cyclic use. CONCLUSION: Oral contraceptives taken continuously or in long cycles seem to offer benefits with regard to menstrual symptoms and the recurrence of symptoms related to endometriosis. Long-term studies, comprising large groups of women, are lacking. PMID- 23083414 TI - Application of gastrointestinal modelling to the study of the digestion and transformation of dietary glycidyl esters. AB - Glycidyl esters (GEs) are known to be formed during vegetable oil processing. Because of their structure, it has been hypothesised that GEs, like fatty acid esters of chloropropanols (MCPD esters), may be accepted as substrates by gut lipases to release the epoxide glycidol. If confirmed such a hypothesis would be important for risk assessment since glycidol is considered as a genotoxic carcinogen. In the present study, biotransformation was investigated using static and dynamic gastrointestinal models. During the experiments, aliquots were analysed for non-digested GEs using liquid chromatography-time-of-flight-mass spectrometry (LC-ToF-MS). In the static model, a fast hydrolysis of GEs was observed as a result of lipase action. Lipase was very efficient at pH 4.8, and totally inhibited at very low pH (1.7). In the absence of lipase, GEs were found to be relatively stable. The potential impact of food matrix was studied using milk in a dynamic model simulating human physiological conditions. The fast, pH dependent hydrolysis of GEs was further confirmed. The possible transformation of the digestion products was then investigated using gas chromatography coupled to mass spectrometry (GC-MS), mainly the epoxide ring-opening to glycerol followed by additional reactions. In any conditions applied, neither 2- nor 3-mono chloropropanediol (2- nor 3-MCPD) were formed, indicating that a ring-opening of the epoxide group of GEs or glycidol followed by a reaction with chloride was unlikely. A small transformation of glycidol into glycerol was observed after longer incubation time correlated with a low pH. This suggested that ring-opening and reaction with water is possible in strongly acidic conditions. Overall, it is concluded that GEs are rapidly digested by gut lipases to form glycidol. Consequently, GEs should be considered as sources of glycidol exposure. In addition, risk assessment of GEs can likely rely on hazard identification and characterisation data specific for glycidol. PMID- 23083415 TI - Serum uric acid: marker for atherosclerosis as it is positively associated with "atherogenic index of plasma". AB - CONTEXT: Serum uric acid (SUA) has been known to be associated with cardiovascular diseases. "Atherogenic index of plasma" (AIP) is considered a very sensitive predictor of future cardiovascular events. OBJECTIVES: This study was conducted to analyse the association of AIP with SUA and various other lipid parameters. METHODS: Parameters were measured on a fully automated analyser using standard reagent kits in a retrospective study involving 248 male Indian subjects between 40 to 59 years of age. RESULTS: AIP correlates: moderately with TC/HDL-C (r = 0.47, p < 0.0001); to a lesser extent but comparably (r = 0.2, p < 0.01) with SUA, LDL-C/HDL-C and TC; negligibly with LDL-C and age. DISCUSSION AND CONCLUSION: As SUA is positively associated with AIP it can be used as a supplementary marker for atherosclerosis/CVD in upper-middle-aged men. PMID- 23083416 TI - A pilot randomized controlled trial of an early multidisciplinary model to prevent disability following traumatic injury. AB - PURPOSE: Chronic pain, posttraumatic stress disorder (PTSD), and depression are common outcomes following traumatic injury. Yet, screening and early intervention to prevent the onset of these disorders do not occur routinely in acute trauma settings. This pilot study examined the clinical utility of screening and early multidisciplinary intervention for reducing disability following traumatic injury. METHOD: 142 non-severe head injured trauma inpatients (26% female, Injury Severity Score M = 9.65, M age = 36 years) were assessed for injury-related factors, pain, and psychological function within 4 weeks post injury. Patients were randomly allocated to a Multidisciplinary Intervention (MI) or Usual Care (UC) group. MI patients received assessment and treatment at one and 3 months post injury from pain and rehabilitation medicine doctors, physiotherapists, occupational therapists, and clinical psychologists. Outcomes at 6 months were then compared. RESULTS: Acute pain intensity, posttraumatic adjustment, depression and acute trauma symptoms, and alcohol use predicted a significant 26%, 49%, 56%, and 30% of the variance in pain, depressive, and PTSD severity, and physical mobility respectively at 6 months. Despite MI group patients reporting no improvement in the severity of pain and psychological symptoms, these patients reported significantly improved relief from pain symptoms as a result of treatment at 6 months. Twenty four per cent of the UC group initially below the cut-off for being at risk of developing PTSD/Depression received new clinical diagnoses at 6 months compared with none of the 'not at risk' MI group attendees who remained asymptomatic. CONCLUSIONS: Early findings point to the value of early screening to identify patients at risk of treatable pain, physical, and psychological impairments. Moreover, early multidisciplinary intervention models following traumatic injury show promise for protecting against the onset of posttraumatic psychological disorders. PMID- 23083417 TI - Sequential interactions of silver-silica nanocomposite (Ag-SiO2 NC) with cell wall, metabolism and genetic stability of Pseudomonas aeruginosa, a multiple antibiotic-resistant bacterium. AB - The study was carried out to understand the effect of silver-silica nanocomposite (Ag-SiO(2) NC) on the cell wall integrity, metabolism and genetic stability of Pseudomonas aeruginosa, a multiple drug-resistant bacterium. Bacterial sensitivity towards antibiotics and Ag-SiO(2) NC was studied using standard disc diffusion and death rate assay, respectively. The effect of Ag-SiO(2) NC on cell wall integrity was monitored using SDS assay and fatty acid profile analysis, while the effect on metabolism and genetic stability was assayed microscopically, using CTC viability staining and comet assay, respectively. Pseudomonas aeruginosa was found to be resistant to beta-lactamase, glycopeptidase, sulfonamide, quinolones, nitrofurantoin and macrolides classes of antibiotics. Complete mortality of the bacterium was achieved with 80 MUg ml(-1) concentration of Ag-SiO(2) NC. The cell wall integrity reduced with increasing time and reached a plateau of 70% in 110 min. Changes were also noticed in the proportion of fatty acids after the treatment. Inside the cytoplasm, a complete inhibition of electron transport system was achieved with 100 MUg ml(-1) Ag-SiO(2) NC, followed by DNA breakage. The study thus demonstrates that Ag-SiO(2) NC invades the cytoplasm of the multiple drug-resistant P. aeruginosa by impinging upon the cell wall integrity and kills the cells by interfering with electron transport chain and the genetic stability. SIGNIFICANCE AND IMPACT OF STUDY: Although the synthesis, structural characteristics and biofunction of silver nanoparticles are well understood, their application in antimicrobial therapy is still at its infancy as only a small number of microorganisms are tested to be sensitive to nanoparticles. A thorough knowledge of the mode of interaction of nanoparticles with bacteria at subcellular level is mandatory for any clinical application. The present study deals with the interactions of Ag-SiO2NC with the cell wall integrity, metabolism and genetic stability of Pseudomonas aeruginosa, which would contribute substantially in strengthening the therapeutic applications of silver nanoparticles. PMID- 23083419 TI - The interaction between tobacco use and oral health among tribes in central India. AB - BACKGROUND: A study was undertaken to evaluate the effect of tobacco related practices on oral health of tribes in Central India. The use of smokeless tobacco, gutkha & associated products is on the rise amongst the younger generation making oral precancer & cancer a public health concern. METHODOLOGY: A pioneering study was conducted to evaluate the tobacco related practices amongst tribes and its impact on oral health. The study included 411 tribals of the Baiga group. Guided dialogue techniques and proforma based evaluation formed a part of the study. RESULT: 53.04% of individuals between 21 to 40yrs are addicted to deleterious habits. There is a marked consumption (72%) of tobacco & associated products among the geriatric population (60 yrs & above).Insecure livelihoods, malnutrition & increased stress levels contribute to the stark increase of addiction of tobacco related practices. CONCLUSION: The healthcare infrastructure needs to be upgraded to meet the demands of changing disease profile amongst the vulnerable population. Assessment of impact of disease on existing public health would enable formulation of adaptive measures and suggestions for amelioration. PMID- 23083418 TI - BK virus viremia in a well-HLA-matched kidney transplant population mainly on low dose cyclosporine-based immunosuppression. AB - The incidence and clinical course of polyomavirus-associated nephropathy (PyVAN) in our well-HLA-matched kidney transplant population mainly on low-dose cyclosporine-based triple-drug immunosuppression has not been described in detail. We aimed to characterize our patients with PyVAN and BK virus (BKV) viremia. Among 166 kidney transplantations between January 2007 and February 2011 followed up at Helsinki University Hospital nephrology clinic, 136 were screened for BKV viremia by quantitative analysis of BKV DNA in plasma. PyVAN was diagnosed by biopsy histopathology and SV40 T-antigen detection. BKV viremia or PyVAN were treated by reducing immunosuppression. BKV viremia was detected in 12 (9%) patients. PyVAN was diagnosed in six patients (4%). In the six patients with no PyVAN, four had low-level viremia (<10,000 copies/mL) of short duration (<2 months), one had high-level viremia, and one had sustained low-level viremia. After reduction of immunosuppression, all except one patient were able to clear viremia. No grafts were lost due to PyVAN. Even in a low-risk population, BKV viremia and PyVAN occur, highlighting the importance of monitoring viral loads. Reduction of immunosuppression was successful, and no grafts were lost due to PyVAN. PMID- 23083420 TI - Demonstration of the usefulness of a theoretical framework for humanising care with reference to a residential aged care service in Australia. AB - AIMS AND OBJECTIVES: To demonstrate the usefulness of a theoretical framework for humanising care of dementia patients. BACKGROUND: The term humanisation of care has been increasingly used to describe an approach to health care that is informed by core dimensions of what it means to be human. Recent developments in dementia care highlight the importance of maintaining personhood in people with dementia. DESIGN: A conceptual framework is proposed by which the humanisation of care can be understood and applied. Eight dimensions that articulate core features of what needs to be attended to in order for a person to feel more deeply 'met' as a human being are discussed. Evidence from an evaluative study of a dementia outreach service is used to illustrate the usefulness of the humanising framework. METHODS: Case study examples demonstrate the value of this framework by describing how a dementia outreach service enables care staff in residential aged care facilities to change their focus in the provision of care to residents with dementia. Each of the eight dimensions of humanisation/dehumanisation is used to illustrate how the dementia outreach service team have led to the improvements in resident care. RESULTS: Positive outcomes can be achieved by providing humanised care to residents with dementia. CONCLUSION: The paper highlights the potential for the humanising framework to be used in dementia care and shows how the framework can be helpfully translated into practice so that carers are supported to adopt an inclusive view of care delivery. RELEVANCE TO CLINICAL PRACTICE: A comprehensive framework, grounded in a strong philosophical foundation, can name a breadth of criteria for humanly sensitive care and can be translated into practice in such a way as to potentially transform the provision of care to residents in residential aged care facilities. PMID- 23083421 TI - An evaluation of personalised insoles developed using additive manufacturing. AB - The aim of the study was to evaluate the short and medium term use of personalised insoles, produced by combining additive manufacturing (AM) with three-dimensional (3-D) foot scanning and computer aided design (CAD) systems. For that, 38 runners (19 pairings) were recruited. The experimental conditions were: personalised and control. The personalised condition consisted of trainers fitted with personalised glove fit insoles manufactured using AM and using foot scans to match the plantar geometry of the feet. The control condition consisted of the same trainers fitted with insoles also manufactured using AM but using scans of the original insole shape. Participants were allocated to one of the experimental conditions and wore the trainers for 3 months. Over this period they attended three laboratory sessions (at months 0, 1.5 and 3) and completed an Activity Diary after each training session. The footwear was evaluated in terms of discomfort and biomechanics. Lower discomfort ratings were found in the heel area (P <= 0.05) and for overall fit (P <= 0.05), with the personalised insole. However, discomfort was reported under the arch region for both conditions. With regard to the biomechanical data, differences between conditions were detected for ankle dorsiflexion at footstrike (P <= 0.05), maximum ankle eversion (P <= 0.05) and peak mean pressure under the heel (P <= 0.01): the personalised condition had lower values which may reduce injury risk. The personalisation of the geometry of insoles through advances in AM together with 3-D scanning and CAD technologies can provide benefits and has potential. PMID- 23083422 TI - Bioaccumulation of gold nanomaterials by Manduca sexta through dietary uptake of surface contaminated plant tissue. AB - We investigated the potential for bioaccumulation of engineered nanomaterials (ENMs) by tobacco hornworm (Manduca sexta) caterpillars resulting from the ingestion of plant tissue surface contaminated with ENMs. Caterpillars were fed tomato leaf tissue that had been surface contaminated with 12 nm tannate coated Au ENMs. After dosing was complete, bulk Au concentrations in individual caterpillars were measured after 0, 1, 4, and 7 days of elimination. Growth, mortality, and ingestion rate were monitored. This experiment revealed (1) no evidence that caterpillars were affected by ingestion of ENM contaminated plant tissue; (2) low bioaccumulation factors (BAF = 0.16) compared to a previous study where hornworm caterpillars were fed plants that had previously bioaccumulated Au ENMs (BAF = 6.2-11.6); (3) inefficient elimination of accumulated Au ENMs not associated with hornworm gut contents; and (4) regional differences in translocation of Au ENMs into tissues surrounding the hornworm gut, possibly the result of the interaction between ENM surface chemistry and regional differences in hornworm gut chemistry. These data, along with previous findings, indicate that although ENMs resuspended from soil onto plant surfaces by wind, water, biota, and/or mechanical disturbances are bioavailable to terrestrial consumers, bioaccumulation efficiency may be much lower via this pathway than through direct trophic exposure. PMID- 23083423 TI - Breast cancer in women 80 years of age and older: a comprehensive analysis of an underreported entity. AB - BACKGROUND: Approximately 10% of breast cancer (BC) patients are over the age of 80. We present the first comprehensive review on this particular group of patients. PATIENTS AND METHODS: The treatments and disease courses of an unselected cohort of patients, whose age at first diagnosis was >= 80 years (n = 151), were compared to those of a group of women, who were aged 56-66 years (n = 372). RESULTS: The group of elderly patients had larger tumors at first diagnosis (25 mm vs. 18 mm, p < 0.001) and higher disease stages (I: 31.1% vs. 44.1%, IV: 11.9% vs. 5.4%; each p < 0.001). There were no significant differences between both groups in terms of histologic subtype, grading, hormonal receptor status and HER2 status. The tumors of older patients were more often detected by clinical examination (38.9% vs. 17.0%, p < 0.001) and less often by mammography/sonography (10.4% vs. 29.9%, p < 0.001). The rate of patients who died of BC were similar in both groups (21.2% vs. 21.5%, p = 1.00). In the patients who had no evidence of metastases and who opted for primary non-surgical management (n = 21), the tumor could be stabilized without considerable morbidity in only 42.9%. Persistence to adjuvant endocrine therapy was comparable (83.0% vs. 88.3%, p = 0.357). In the adjuvant as well as in the palliative settings, elderly patients received less chemotherapy than younger ones (adjuvant: 1.6% vs. 23.3%; palliative: 32.3% vs. 68.4%; each p < 0.001). For palliative treatments only, elderly patients received fewer treatment regimens (>= 3 therapy lines: 16.0% vs. 54.9%, p < 0.001). In those patients who died of BC, elderly women had inferior overall (25 vs. 54.5 months, p < 0.001) as well as metastatic-disease survival (11.5 vs. 19 months, p = 0.062). CONCLUSION: It must be ensured that appropriate standard therapies should not be routinely withheld in older patients based on erroneous perceptions regarding the biological nature of BC in the elderly and lack of knowledge about available therapy regimens. Physicians should consider that preservation of current life circumstances and maintenance of quality of life are frequently more important than "classical" hard medical facts such as survival times. PMID- 23083424 TI - The hydrogen-bonding ability of the amino acid glutamine revealed by neutron diffraction experiments. AB - Hydrogen bonding between glutamine residues has been identified as playing an important role in the intermolecular association and aggregation of proteins. To establish the molecular mechanisms of glutamine interactions, neutron diffraction coupled with hydrogen/deuterium isotopic substitution in combination with computational modeling has been used to investigate the structure and hydration of glutamine in aqueous solution. The final structures obtained are consistent with the experimental data and provide insight into the hydrogen-bonding ability of glutamine. We find that the backbone of glutamine is able to coordinate more water molecules than the side chain, suggesting that charged groups on the glutamine molecule are more successful in attracting water than the dipole in the side chain. In both the backbone and the side chain, we find that the carbonyl groups interact more readily with water molecules than the amine groups. We find that glutamine-glutamine interactions are present, despite their low concentration in this dilute solution. This is evidenced through the occurrence of dimers of glutamine molecules in the solution, demonstrating the effective propensity of this molecule to associate through backbone-backbone, backbone-side chain, and side chain-side chain hydrogen bond interactions. The formation of dimers of glutamine molecules in such a dilute solution (30 mg/mL glutamine) may have implications in the aggregation of glutamine-rich proteins in neurological diseases where aggregation is prevalent. PMID- 23083425 TI - Neuroendocrine cells are present in the domestic fowl ovary. AB - Neuroendocrine cells are present in virtually all organs of the vertebrate body; however, it is yet uncertain whether they exist in the ovaries. Previous reports of ovarian neurons and neuron-like cells in mammals and birds might have resulted from misidentification. The aim of the present work was to determine the identity of neuron-like cells in immature ovaries of the domestic fowl. Cells immunoreactive to neurofilaments, synaptophysin, and chromogranin-A, with small, dense-core secretory granules, were consistently observed throughout the sub cortical ovarian medulla and cortical interfollicular stroma. These cells also displayed immunoreactivity for tyrosine, tryptophan and dopamine beta hydroxylases, as well as to aromatic L-DOPA decarboxylase, implying their ability to synthesize both catecholamines and indolamines. Our results support the argument that the ovarian cells previously reported as neuron-like in birds, are neuroendocrine cells. PMID- 23083426 TI - Synthesis and reactivity of N-alkyl carbamoylimidazoles: development of N-methyl carbamoylimidazole as a methyl isocyanate equivalent. AB - A high-yielding synthesis of N-methyl carbamoylimidazole from 1,1 carbonyldiimidazole (CDI) and MeNH(3)Cl is described. The product is a crystalline, readily storable, water-stable compound that reacts as a methyl isocyanate (MIC) substitute. Reaction of N-methyl carbamoylimidazole in the presence of a base such as triethylamine occurs with nucleophiles such as amines, protected and unprotected amino acids, thiols and alcohols. The product N methylureas, carbamates and thiocarbamates are obtained in good to excellent yields, with reactions occurring in either organic solvents or water. The protocol for the synthesis of N-methyl carbamoylimidazole is both scalable and general, occurring in quantitative yield at scales ranging from 300 mg to 20 g. The success of this method relies upon the reaction of CDI with the ammonium salt rather than the free amine, resulting in a significant improvement in the yield of N-methyl carbamoylimidazole. The reaction presumably involves a proton transfer from MeNH(3)Cl to the CDI, which results in the release of MeNH(2) with simultaneous activation of the CDI as its protonated form. Other primary ammonium hydrochloride salts, including protected alpha-amino acid salts, give excellent yields of the corresponding N-alkyl carbamoylimidazoles and serve as alkyl isocyanate surrogates. The resultant N-alkyl carbamoylimidazoles can be converted to ureas in high yields without the formation of intermediary isocyanates. PMID- 23083427 TI - Association between periodontal status and pre-term and/or low-birth weight in Spain: clinical and microbiological parameters. AB - BACKGROUND AND OBJECTIVE: Studies performed over the last 15 years have suggested that periodontal diseases may be associated with adverse pregnancy outcomes. However, this association has not been found in all populations. The aim of this study was to evaluate whether periodontal status and the presence of specific periodontal pathogens may influence the incidence of adverse pregnancy outcomes. MATERIAL AND METHODS: Pregnant women were clinically examined before 26th week of gestation, and divided in two groups: non-periodontitis and periodontitis. Microbial samples were obtained in the periodontitis group and processed by anaerobic culturing. After delivery, data on the pregnancy outcome were taken; mother's socio-demographic and risk factors were obtained at inclusion. Simple and multiple regression analysis were performed. RESULTS: One hundred and seventy women were included in the study (116 non-periodontitis and 54 with periodontitis). The incidence of preterm (PTB) and low-birth weight (LBW) was 2.94% and 3.53%, respectively. Periodontal status did not show any association with adverse pregnancy outcomes. The presence of Eikenella corrodens was significantly related to PTB (p = 0.022) and the presence Capnocytophaga spp. was related to LBW (p = 0.008). The multivariate analyses showed a significant association between PTB and newborn weight and counts of E. corrodens. Maternal health and counts of E. corrodens were significantly associated with PTB or LBW. CONCLUSION: The clinical periodontal condition was not associated with adverse pregnancy outcomes in a Spanish Caucasian population with medium-high educational level. The presence and counts of E. corrodens and the presence of Capnocytophaga spp. showed a significant association with PTB and LBW, respectively, in the bivariate and/or multivariate model. PMID- 23083428 TI - Supporting bereaved parents: a phenomenological study of a telephone intervention programme in a paediatric oncology unit. AB - AIMS AND OBJECTIVES: This study sought to discover bereaved parents' perspectives and experiences of a nurse-led, ward-based, telephone support programme in a children's oncology unit. BACKGROUND: Parental grief is especially intense and long-lasting, and many parents can experience serious psychological problems. The oncology team learned that some parents felt 'forgotten' or 'abandoned' following their child's death and addressed this concern by initiating and subsequently evaluating a telephone bereavement support programme. DESIGN: An interpretive phenomenological investigation of the experiences of six parents who participated in the programme. METHODS: Parents shared their experiences and perceptions of the programme in individual interviews. Interpretive phenomenology and thematic analysis guided the interviews' interpretation to ascertain both the parents' experiences of the programme and their understandings of everyday clinical terms such as 'support' or 'reassurance'. RESULTS: Parents found the programme supportive, especially valuing ongoing contact with a nurse who 'knew them'. Telephone contact was preferred to visiting the hospital, which brought back painful memories. Calls were important elements in helping parents create meaning and memory around their deceased child. CONCLUSIONS: Regular telephone contact over an agreed period from a familiar member of the child's treating team can create a more positive and supportive bereavement experience for parents in the year following their child's death. The specific findings are discussed in the context of the death of a child as a crisis of meaning. RELEVANCE TO CLINICAL PRACTICE: Clinical nurses are ideally placed to use existing close relationships to extend care and support to bereaved parents. This study shows how nurses can identify service gaps, work with interdisciplinary team colleagues to initiate appropriate actions and participate in the essential evaluation subsequently required. PMID- 23083429 TI - Comparing the impact of socio-demographic factors associated with traffic injury among older road users and the general population in Japan. AB - BACKGROUND: The increasing number of older road users represents a public health issue because older individuals are more susceptible to traffic injury and mortality than the general population. This study investigated the association between socio-demographic factors and traffic injury and traffic mortality for the general population and among older road users in Japan. METHODS: An ecological study was conducted using national data in Japan. Multivariate regression methods were applied to investigate the association of traffic injury and traffic mortality for the general population and among older road users with significant demographic, economic, road traffic, and medical/cultural factors. RESULTS: Income per capita, total road length, and alcohol consumption per person were significantly associated with traffic injury and traffic mortality both for the general population and among older road users in Japan. Income per capita and alcohol consumption per person were negatively associated with traffic mortality for both groups. Meanwhile, for both groups, income per capita was positively associated with traffic injury, while total road length and alcohol consumption per person were negatively associated with traffic injury. CONCLUSIONS: The effects of socio-demographic factors on traffic injury and traffic mortality in Japan were similar for both the general population and older road users. The study results suggest that injury preventive measures designed for the general population will be beneficial also for older road users in Japan. PMID- 23083430 TI - Predictive and preventive strategies to advance the treatments of cardiovascular and cerebrovascular diseases: the Ukrainian context. AB - Despite great efforts in treatments of cardiovascular diseases, the field requires innovative strategies because of high rates of morbidity, mortality and disability, indicating evident deficits in predictive vascular diagnosis and individualized treatment approaches. Talking about the vascular system, currently, physicians are not provided with integrated medical approaches to diagnose and treat vascular diseases. Only an individual global approach to the analysis of all segments in the vascular system of a patient allows finding the optimal way for vascular disease treatment. As for the existing methodology, there is a dominance of static methods such as X-ray contrast angiography and magnetic resonance imaging in angiomode. Taking into account the world experience, this article deals with innovative strategies, aiming at predictive diagnosis in vascular system, personalization of the biomedical treatment approaches, and targeted prevention of individual patient cohorts. Clinical examples illustrate the advances in corresponding healthcare sectors. Recommendations are provided to promote the field. PMID- 23083431 TI - The inter-kingdom solo OryR regulator of Xanthomonas oryzae is important for motility. AB - The LuxR-type transcriptional regulator OryR of the rice pathogen Xanthomonas oryzae pv. oryzae (Xoo) is a member of a subgroup of regulators found in plant associated bacteria that are known to respond to plant signals. OryR has been shown previously to positively regulate the neighbouring pip gene and to be important for rice virulence. The role of this inter-kingdom signalling regulator was investigated through a genome-wide transcriptome analysis. OryR was found to positively regulate 220 genes, whereas 110 were down-regulated. A significant over-representation of movement-related genes among the positively regulated ones was found, including 30 flagellar genes, accounting for 14% of the up-regulated genes above the two-fold cut-off value. In Xoo, both swimming and swarming respond to rice macerate and OryR plays a role in the induction of both of these types of motility under these conditions. In this study, we have also shown that the flagellar regulator flhF contains a lux box-like element in its promoter region, similar to the oryR-regulated neighbouring pip gene; via the use of a transcriptional fusion reporter, it was shown that flhF is regulated by OryR. Finally, the role of OryR in motility was also demonstrated by the significant reduction in flagellin content in the oryR Xoo mutant with respect to the wild type, as observed by in planta proteomics studies. PMID- 23083432 TI - Cutaneous epitheliotropic lymphoma with dual CD3 and c-kit expression in a dog. AB - An 11-year-old 8.9-kg spayed female Boston Terrier was presented for evaluation of a mucocutaneous tumor on the right side of the upper lip that had been biopsied (punch biopsy) by the referring veterinarian. The histologic diagnosis was poorly differentiated round cell tumor involving the submucosa with patchy involvement of the mucosa. On presentation of the dog to Louisiana State University, the tumor was found to involve the mucosa and haired skin surface of the right upper lip. A fine-needle aspirate of the right mandibular lymph node contained atypical poorly differentiated round cells similar to those in the histologic sections. To further characterize the tumor, immunohistochemical analysis of the tumor on the lip was performed; tumor cells were strongly immunoreactive for both CD3 and c-kit in a cytoplasmic to membranous pattern, with CD3 expression having a more intense membranous component. The diagnosis was cutaneous epitheliotropic T-cell lymphoma with co-expression of CD3 and c-kit by neoplastic lymphocytes, an unusual finding. As receptor tyrosine kinases can be attractive targets for cancer treatment, expression of these molecular targets in tumors is a promising subject of future research. PMID- 23083434 TI - A cementless, elastic press-fit socket with and without screws. AB - BACKGROUND: The acetabular component has remained the weakest link in hip arthroplasty regarding achievement of long-term survival. Primary fixation is a prerequisite for long-term performance. For this reason, we investigated the stability of a unique cementless titanium-coated elastic monoblock socket and the influence of supplementary screw fixation. PATIENT AND METHODS: During 2006-2008, we performed a randomized controlled trial on 37 patients (mean age 63 years (SD 7), 22 females) in whom we implanted a cementless press-fit socket. The socket was implanted with additional screw fixation (group A, n = 19) and without additional screw fixation (group B, n = 18). Using radiostereometric analysis with a 2-year follow-up, we determined the stability of the socket. Clinically relevant migration was defined as > 1 mm translation and > 2o rotation. Clinical scores were determined. RESULTS: The sockets without screw fixation showed a statistically significantly higher proximal translation compared to the socket with additional screw fixation. However, this higher migration was below the clinically relevant threshold. The numbers of migratory sockets were not significantly different between groups. After the 2-year follow-up, there were no clinically relevant differences between groups A and B regarding the clinical scores. 1 patient dropped out of the study. In the others, no sockets were revised. INTERPRETATION: We found that additional screw fixation is not necessary to achieve stability of the cementless press-fit elastic RM socket. We saw no postoperative benefit or clinical effect of additional screw fixation. PMID- 23083433 TI - Increasing risk of prosthetic joint infection after total hip arthroplasty. AB - BACKGROUND AND PURPOSE: The risk of revision due to infection after primary total hip arthroplasty (THA) has been reported to be increasing in Norway. We investigated whether this increase is a common feature in the Nordic countries (Denmark, Finland, Norway, and Sweden). MATERIALS AND METHODS: The study was based on the Nordic Arthroplasty Register Association (NARA) dataset. 432,168 primary THAs from 1995 to 2009 were included (Denmark: 83,853, Finland 78,106, Norway 88,455, and Sweden 181,754). Adjusted survival analyses were performed using Cox regression models with revision due to infection as the endpoint. The effect of risk factors such as the year of surgery, age, sex, diagnosis, type of prosthesis, and fixation were assessed. RESULTS: 2,778 (0.6%) of the primary THAs were revised due to infection. Compared to the period 1995-1999, the relative risk (with 95% CI) of revision due to infection was 1.1 (1.0-1.2) in 2000-2004 and 1.6 (1.4-1.7) in 2005-2009. Adjusted cumulative 5-year revision rates due to infection were 0.46% (0.42-0.50) in 1995-1999, 0.54% (0.50-0.58) in 2000-2004, and 0.71% (0.66-0.76) in 2005-2009. The entire increase in risk of revision due to infection was within 1 year of primary surgery, and most notably in the first 3 months. The risk of revision due to infection increased in all 4 countries. Risk factors for revision due to infection were male sex, hybrid fixation, cement without antibiotics, and THA performed due to inflammatory disease, hip fracture, or femoral head necrosis. None of these risk factors increased in incidence during the study period. INTERPRETATION: We found increased relative risk of revision and increased cumulative 5-year revision rates due to infection after primary THA during the period 1995-2009. No change in risk factors in the NARA dataset could explain this increase. We believe that there has been an actual increase in the incidence of prosthetic joint infections after THA. PMID- 23083435 TI - Salvage of failed trochanteric and subtrochanteric fractures using a distally fixed, modular, uncemented hip revision stem. AB - BACKGROUND AND PURPOSE: Treatment options for failed internal fixation of hip fractures include prosthetic replacement. We evaluated survival, complications, and radiographic outcome in 30 patients who were operated with a specific modular, uncemented hip reconstruction prosthesis as a salvage procedure after failed treatment of trochanteric and subtrochanteric fractures. PATIENTS AND METHODS: We used data from the Swedish Hip Arthroplasty Register and journal files to analyze complications and survival. Initially, a high proportion of trochanteric fractures (7/10) were classified as unstable and 12 of 20 subtrochanteric fractures had an extension through the greater trochanter. Modes of failure after primary internal fixation were cutout (n = 12), migration of the femoral neck screw (n = 9), and other (n = 9). RESULTS: Mean age at the index operation with the modular prosthesis was 77 (52-93) years and the mean follow-up was 4 (1-9) years. Union of the remaining fracture fragments was observed in 26 hips, restoration of proximal bone defects in 16 hips, and bone ingrowth of the stem in 25 hips. Subsidence was evident in 4 cases. 1 patient was revised by component exchange because of recurrent dislocation, and another 6 patients were reoperated: 5 because of deep infections and 1 because of periprosthetic fracture. The cumulative 3-year survival for revision was 96% (95% CI: 89-100) and for any reoperation it was 83% (68-93). INTERPRETATION: The modular stem allowed fixation distal to the fracture system. Radiographic outcome was good. The rate of complications, however-especially infections-was high. We believe that preoperative laboratory screening for low-grade infection and synovial cultures could contribute to better treatment in some of these patients. PMID- 23083436 TI - Total shoulder arthroplasty does not correct the orientation of the eroded glenoid. AB - BACKGROUND AND PURPOSE: Alignment of the glenoid component with the scapula during total shoulder arthroplasty (TSA) is challenging due to glenoid erosion and lack of both bone stock and guiding landmarks. We determined the extent to which the implant position is governed by the preoperative erosion of the glenoid. Also, we investigated whether excessive erosion of the glenoid is associated with perforation of the glenoid vault. METHODS: We used preoperative and postoperative CT scans of 29 TSAs to assess version, inclination, rotation, and offset of the glenoid relative to the scapula plane. The position of the implant keel within the glenoid vault was classified into three types: centrally positioned, component touching vault cortex, and perforation of the cortex. RESULTS: Preoperative glenoid erosion was statistically significantly linked to the postoperative placement of the implant regarding all position parameters. Retroversion of the eroded glenoid was on average 10 degrees (SD10) and retroversion of the implant after surgery was 7 degrees (SD11). The implant keel was centered within the vault in 7 of 29 patients and the glenoid vault was perforated in 5 patients. Anterior cortex perforation was most frequent and was associated with severe preoperative posterior erosion, causing implant retroversion. INTERPRETATION: The position of the glenoid component reflected the preoperative erosion and "correction" was not a characteristic of the reconstructive surgery. Severe erosion appears to be linked to vault perforation. If malalignment and perforation are associated with loosening, our results suggest reorientation of the implant relative to the eroded surface. PMID- 23083437 TI - Prognostic factors in lumbar spinal stenosis surgery. AB - BACKGROUND AND PURPOSE: A considerable number of patients who undergo surgery for spinal stenosis have residual symptoms and inferior function and health-related quality of life after surgery. There have been few studies on factors that may predict outcome. We tried to find predictors of outcome in surgery for spinal stenosis using patient- and imaging-related factors. PATIENTS AND METHODS: 109 patients in the Swedish Spine Register with central spinal stenosis that were operated on by decompression without fusion were prospectively followed up 1 year after surgery. Clinical outcome scores included the EQ-5D, the Oswestry disability index, self-estimated walking distance, and leg and back pain levels (VAS). Central dural sac area, number of levels with stenosis, and spondylolisthesis were included in the MRI analysis. Multivariable analyses were performed to search for correlation between patient-related and imaging factors and clinical outcome at 1-year follow-up. RESULTS: Several factors predicted outcome statistically significantly. Duration of leg pain exceeding 2 years predicted inferior outcome in terms of leg and back pain, function, and HRLQoL. Regular and intermittent preoperative users of analgesics had higher levels of back pain at follow-up than those not using analgesics. Low preoperative function predicted low function and dissatisfaction at follow-up. Low preoperative EQ-5D scores predicted a high degree of leg and back pain. Narrow dural sac area predicted more gains in terms of back pain at follow-up and lower absolute leg pain. INTERPRETATION: Multiple factors predict outcome in spinal stenosis surgery, most importantly duration of symptoms and preoperative function. Some of these are modifiable and can be targeted. Our findings can be used in the preoperative patient information and aid the surgeon and the patient in a shared decision making process. PMID- 23083439 TI - Recommendations for a patient-centered approach to the assessment and treatment of scalp psoriasis: a consensus statement from the Asia Scalp Psoriasis Study Group. AB - BACKGROUND: International consensus statements on the management of scalp psoriasis are available, but no such recommendations exist for Asia. METHODS: The Asia Scalp Psoriasis Study Group (ASPSG) met in May 2011 to review the epidemiologic pattern of scalp psoriasis in Southeast Asia and to develop Asia specific recommendations for its management. RESULTS: The overall prevalence of psoriasis in Asia is <0.3%, but 75-90% have scalp involvement, whether isolated or with lesions elsewhere, which can negatively impact quality of life (QoL). Treatment decisions should be based primarily on objective disease severity, but should also take account of patient QoL. Psychosocial support and more aggressive treatment should be offered to all patients with moderate to severe QoL impairment. Topical therapy is indicated first-line in all patients, with combination therapy (corticosteroid + calcipotriol), more occlusive formulations, keratolytics, and very potent corticosteroids for patients needing greater or faster efficacy. Systemic therapies, light or laser treatments should be reserved for patients with severe and recalcitrant disease. CONCLUSIONS: The ASPSG recommends a patient-centered approach to scalp psoriasis management, consistent with the international consensus statements. Asian physicians should also consider patient QoL, prior treatment response, formulation preferences, likely adherence, cost, time available for self-management, and potential adverse events. PMID- 23083440 TI - Magnetic field alignment of randomly oriented, high aspect ratio silicon microwires into vertically oriented arrays. AB - External magnetic fields have been used to vertically align ensembles of silicon microwires coated with ferromagnetic nickel films. X-ray diffraction and image analysis techniques were used to quantify the degree of vertical orientation of the microwires. The degree of vertical alignment and the minimum field strength required for alignment were evaluated as a function of the wire length, coating thickness, magnetic history, and substrate surface properties. Nearly 100% of 100 MUm long, 2 MUm diameter, Si microwires that had been coated with 300 nm of Ni could be vertically aligned by a 300 G magnetic field. For wires ranging from 40 to 60 MUm in length, as the length of the wire increased, a higher degree of alignment was observed at lower field strengths, consistent with an increase in the available magnetic torque. Microwires that had been exposed to a magnetic sweep up to 300 G remained magnetized and, therefore, aligned more readily during subsequent magnetic field alignment sweeps. Alignment of the Ni-coated Si microwires occurred at lower field strengths on hydrophilic Si substrates than on hydrophobic Si substrates. The magnetic field alignment approach provides a pathway for the directed assembly of solution-grown semiconductor wires into vertical arrays, with potential applications in solar cells as well as in other electronic devices that utilize nano- and microscale components as active elements. PMID- 23083438 TI - Pharmacological treatments for neuropsychiatric symptoms of dementia in long-term care: a systematic review. AB - BACKGROUND: Medications are frequently prescribed for neuropsychiatric symptoms (NPS) associated with dementia, although information on the efficacy and safety of medications for NPS specifically in long-term care (LTC) settings is limited. The objective of this study was to provide a current review of the efficacy and safety of pharmacological treatments for NPS in LTC. METHODS: We searched MEDLINE, EMBASE, PsychINFO, and the Cochrane Library for randomized controlled trials comparing medications with either placebo or other interventions in LTC. Study quality was described using the Cochrane collaboration risk of bias tool. The efficacy of medications was evaluated using NPS symptom rating scales. Safety was evaluated through rates of trial withdrawals, trial withdrawals due to adverse events, and mortality. RESULTS: A total of 29 studies met inclusion criteria. The most common medications evaluated in studies were atypical antipsychotics (N = 15), typical antipsychotics (N = 7), anticonvulsants (N = 4), and cholinesterase inhibitors (N = 3). Statistically significant improvements in NPS were noted in some studies evaluating risperidone, olanzapine, and single studies of aripiprazole, carbamazepine, estrogen, cyproterone, propranolol, and prazosin. Study quality was difficult to rate in many cases due to incomplete reporting of details. Some studies reported higher rates of trial withdrawals, adverse events, and mortality associated with medications. CONCLUSIONS: We conclude that there is limited evidence to support the use of some atypical antipsychotics and other medications for NPS in LTC populations. However, the generally modest efficacy and risks of adverse events highlight the need for the development of safe and effective pharmacological and non-pharmacological interventions for this population. PMID- 23083441 TI - The thyroid hormone receptor alpha locus and white matter lesions: a role for the clock gene REV-ERBalpha. AB - BACKGROUND: Thyroid disorders are associated with an increased risk of cognitive impairment and Alzheimer's disease. Both small vessel disease and neurodegeneration have a role in the pathogenesis of cognitive impairment and Alzheimer's disease. Thyroid hormone receptor alpha (TRalpha) is the predominant TR in brain. The circadian clock gene REV-ERBalpha overlaps with the TRalpha gene and interferes with TRalpha expression. Limited data are available on the role of the TRalpha/REV-ERBalpha locus in small vessel disease and neurodegeneration. We therefore studied genetic variation in the TRalpha/REV-ERBalpha locus in relation to brain imaging data, as early markers for small vessel disease and neurodegeneration. METHODS: Fifteen polymorphisms, covering the TRalpha/REV ERBalpha locus, were studied in relation to white matter lesion (WML), total brain, and hippocampal volumes in the Rotterdam Study I (RS-I, n=454). Associations that remained significant after multiple testing correction were subsequently studied in an independent population for replication (RS-II, n=607). RESULTS: No associations with total brain or hippocampal volumes were detected. A haplotype block in REV-ERBalpha was associated with WML volumes in RS-I. Absence of this haplotype was associated with larger WML volumes in women (0.38%+/-0.18% [beta+/-SE], p=0.007), but not in men (0.04%+/-0.11%, p=0.24), which was replicated in RS-II (women: 0.15%+/-0.05%, p=0.04; men: 0.05%+/-0.07%, p=0.80). Meta-analysis of the two populations showed that women lacking this haplotype have a 1.9 times larger WML volume (p=0.001). CONCLUSION: Our results suggest a role for REV-ERBalpha in the pathogenesis of WMLs. PMID- 23083442 TI - The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. AB - BACKGROUND: Ultrasound and prophylactic dissections have facilitated identification of small-volume cervical lymph node (LN) metastases in patients with papillary thyroid carcinoma (PTC). Since most staging systems do not stratify risk based on size or number of LN metastases, even a single-microscopic LN metastasis can upstage a patient with low-risk papillary thyroid microcarcinoma (PMC) to an intermediate risk of recurrence in the American Thyroid Association (ATA) system and to an increased risk of death in the American Joint Committee on Cancer (AJCC) staging system (stage III if the metastatic node is in the central neck or stage IVA if the microscopic LN metastasis is identified in the lateral neck). Such microscopic upstaging may lead to potentially unnecessary or additional treatments and follow-up studies. The goal of this review is to determine if the literature supports the concept that specific characteristics (clinically apparent size, number, and extranodal extension) of LN metastases can be used to stratify the risk of recurrence in PTC. SUMMARY: In patients with pathological proven cervical LN metastases (pathological N1 disease; pN1), the median risk of loco-regional LN recurrence varies markedly by clinical staging, with recurrence rates for patients who are initially clinically N0 (clinical N0 disease; cN0) of 2% (range 0%-9%) versus rates of recurrence for patients who are initially clinically N-positive (clinical N1 disease; cN1) of 22% (range 10%-42%). Furthermore, the median risk of recurrence in pN1 patients varies markedly by the number of positive nodes, <5 nodes (4%, range 3%-8%) vs. >5 nodes (19%, range 7%-21%). Additionally, the presence of extranodal extension was associated with a median risk of recurrence of 24% (range 15%-32%) and possibly a worse disease-specific survival. CONCLUSION: Our previous paradigm assigned the same magnitude of risk for all patients with N1 disease. However, small-volume subclinical microscopic N1 disease clearly conveys a much smaller risk of recurrence than large-volume, macroscopic clinically apparent loco-regional metastases. Armed with this information, clinicians will be better able to tailor initial treatment and follow-up recommendations. Implications of N1 stratification for PTC into small volume microscopic disease versus clinically apparent macroscopic disease importantly relate to issues of prophylactic neck dissection utility, need for pathologic nodal size description, and suggest potential modifications to the AJCC TNM (tumor, nodal disease, and distant metastasis) and ATA risk recurrence staging systems. PMID- 23083443 TI - Elevation of thyrotropin upon accidental hypothermia in an elderly man. AB - BACKGROUND: Although "polar triiodothyronine (T(3)) syndrome" in chronic dwellers/workers in Antarctica has been established, alteration of the pituitary thyroid-axis upon accidental hypothermia is not well recognized. We report here a rare case of elevation of thyrotropin (TSH) upon accidental hypothermia. PATIENT FINDINGS: A 75-year-old man was admitted because of consciousness disturbance.The mean outside temperature was approximately -2.0 degrees C (28.4 degrees F) but his house was inadequately heated. His rectal temperature was 29.5 degrees C (85.1 degrees F). Goiter was not palpable and pitting edema, not myxedema, was present. Serum TSH was elevated (28.3 mU/L, reference range 0.27-4.2), and free T(3) (FT(3)) and free thyroxine (FT(4)) lowered (FT(3), 3.25 pmol/L with a reference range of 4.00-7.85, and FT(4), 9.18 pmol/L with a reference range of 12.87-23.179), but thyroid-related autoantibodies were all negative. By the next morning, body temperature had risen to >36 degrees C (>96.8 degrees F) and there was no further recurrence of hypothermia. Serum TSH decreased exponentially and the patient's condition had become normal by day 22. FT(3) and FT(4) were found to be slightly lowered and elevated, respectively, during the same period, in the subnormal range. At the end of the observation period, the patient settled into the state known as "nonthyroidal illness syndrome." SUMMARY: Elevation of TSH in an elderly patient with accidental hypothermia was normalized after restoration of normal body temperature. Elevation of TSH upon accidental hypothermia was probably an adaptive response. CONCLUSIONS: In patients with accidental hypothermia, the possibility of an adaptive elevation of TSH should be borne in mind. This clearly warrants further studies of the adaptation of the pituitary thyroid axis in patients with accidental hypothermia. PMID- 23083444 TI - Under the shadow of vesuvius: a risk for thyroid cancer? PMID- 23083445 TI - Disseminated epidermolytic acanthoma with partial response to calcipotriol ointment. PMID- 23083447 TI - Multifunctional branched gold-carbon nanotube hybrid for cell imaging and drug delivery. AB - Branched gold nanoparticles were grown on oxidized multiwalled carbon nanotubes by one-step reduction of gold chloride in water. The carbon nanotube/gold hybrids were used for the delivery of the anticancer drug doxorubicin hydrochloride into A549 lung cancer cell line. Doxorubicin (Dox) can be adsorbed in high quantity on both inner and outer surfaces of oxidized carbon nanotubes by pi-pi stacking interactions between doxorubicin aromatic groups and carbon nanotube (CNT) backbone. Carbon nanotube/gold hybrids display a broad absorption band in the red and near-infrared regions allowing their use for imaging applications. In vitro cellular tests showed that the nanostructures can efficiently transport and deliver doxorubicin inside the cells. PMID- 23083446 TI - Alternative mRNA fates identified in microRNA-associated transcriptome analysis. AB - BACKGROUND: MicroRNA (miRNA) are small non-coding RNA molecules which function as nucleic acid-based specificity factors in the universal RNA binding complex known as the RNA induced silencing complex (RISC). In the canonical gene-silencing pathway, these activated RISC particles are associated with RNA decay and gene suppression, however, there is evidence to suggest that in some circumstances they may also stabilise their target RNA and even enhance translation. To further explore the role of miRNA in this context, we performed a genome-wide expression analysis to investigate the molecular consequences of bidirectional modulation of the disease-associated miRNAs miR-181b and miR-107 in multiple human cell lines. RESULTS: This data was subjected to pathways analysis and correlated against miRNA targets predicted through seed region homology. This revealed a large number of both conserved and non-conserved miRNA target genes, a selection of which were functionally validated through reporter gene assays. Contrary to expectation we also identified a significant proportion of predicted target genes with both conserved and non-conserved recognition elements that were positively correlated with the modulated miRNA. Finally, a large proportion of miR-181b associated genes devoid of the corresponding miRNA recognition element, were enriched with binding motifs for the E2F1 transcription factor, which is encoded by a miR-181b target gene. CONCLUSIONS: These findings suggest that miRNA regulate target genes directly through interactions with both conserved and non conserved target recognition elements, and can lead to both a decrease and increase in transcript abundance. They also multiply their influence through interaction with transcription factor genes exemplified by the observed miR 181b/E2F1 relationship. PMID- 23083448 TI - Control over hierarchy levels in the self-assembly of stackable nanotoroids. AB - We report a precise control over the hierarchy levels in the outstanding self organization process shown by chiral azobenzene dimer 1. This compound forms uniform toroidal nanostructures that can hierarchically organize into chiral nanotubes under the control by temperature, concentration, or light. The nanotubes further organized into supercoiled fibrils, which finally intertwined to form double helices with one-handed helical sense. PMID- 23083449 TI - Growth-related structural, biochemical, and mechanical properties of the functional bone-cartilage unit. AB - Articular cartilage and subchondral bone act together, forming a unit as a weight bearing loading-transmitting surface. A close interaction between both structures has been implicated during joint cartilage degeneration, but their coupling during normal growth and development is insufficiently understood. The purpose of the present study was to examine growth-related changes of cartilage mechanical properties and to relate these changes to alterations in cartilage biochemical composition and subchondral bone structure. Tibiae and femora of both hindlimbs from 7- and 13-week-old (each n = 12) female Sprague-Dawley rats were harvested. Samples were processed for structural, biochemical and mechanical analyses. Immunohistochemical staining and protein expression analyses of collagen II, collagen IX, COMP and matrilin-3, histomorphometry of cartilage thickness and COMP staining height were performed. Furthermore, mechanical testing of articular cartilage and micro-CT analysis of subchondral bone was conducted. Growth decreased cartilage thickness, paralleled by a functional condensation of the underlying subchondral bone due to enchondral ossification. Cartilage mechanical properties seem to be rather influenced by growth-related changes in the assembly of major ECM proteins such as collagen II, collagen IX and matrilin-3 than by growth-related alterations in its underlying subchondral bone structure. Importantly, the present study provides a first insight into the growth-related structural, biochemical and mechanical interaction of articular cartilage and subchondral bone. Finally, these data contribute to the general knowledge about the cooperation between the articular cartilage and subchondral bone. PMID- 23083450 TI - Quantitative evaluation of auraptene and umbelliferone, chemopreventive coumarins in citrus fruits, by HPLC-UV-FL-MS. AB - An analytical strategy, based on the development of two HPLC methods with spectrophotometric (UV), spectrofluorometric (FL), and mass spectrometric (MS) detection, has been developed to investigate the presence of and to quantitate two important chemopreventive coumarins, auraptene and umbelliferone, in foodstuffs. The analytes were determined in fruits, and fruit parts, of plants belonging to the Citrus , Poncirus , and Fortunella genera, to test their nutraceutical potential. The method validation has been carried out according to international guidelines, with good results in terms of precision (RSD < 6.9%) and extraction yields (>91%). Application to the quantitative analysis of auraptene and umbelliferone in several kinds of citrus fruits was successful, providing reliable and consistent data. Exploiting three different kinds of detection, the analytical methodology proposed herein has been demonstrated to be sound but versatile, as well as reliable. Performances and results were compared and always found in good agreement among themselves. Thus, this approach is suitable for the identification and simultaneous quantitation of auraptene and umbelliferone in citrus fruits, with the aim of evaluating their nutraceutical potential. PMID- 23083453 TI - Chemical and technological delivery systems for idebenone: a review of literature production. AB - INTRODUCTION: Idebenone (IDE) is an antioxidant compound, structurally related to coenzyme Q10. Its therapeutic potential is growing in different application areas, as demonstrated by the number of experimental works and patents produced in very recent years. AREAS COVERED: Cyclodextrin inclusion complexes, liposomes, microemulsions, prodrugs, polymeric and lipid nanoparticles have been explored to achieve different goals, such as topical administration, brain targeting or increasing the bioavailability of this highly lipophilic drug. This review summarizes the results of works published in the last 20 years for the delivery and targeting of this drug. EXPERT OPINION: A direct comparison of the different carrier systems is not easy and could not even be significant, due to the large variables existing among them. However, the different forms of delivery can help increase idebenone solubility, stability and biochemical activity. Further studies will be developed in order to improve the controlled release and targeting of idebenone. PMID- 23083455 TI - Resistance rates of metronidazole and other antibacterials in Helicobacter pylori from previously untreated patients in Norway. AB - The aim of the study was to describe the antimicrobial resistance rate of Helicobacter pylori isolated from previously untreated patients in Norway, including the application of two different methods for the determination of metronidazole susceptibility. Altogether 102 isolates obtained in 2008 and 2009 from previously untreated patients suspected of H. pylori related disease, were examined applying a standardized European study protocol. The activity of amoxicillin, tetracycline, clarithromycin, metronidazole, rifabutin and levofloxacin was recorded after an incubation period of 72-96 h in a microaerobic atmosphere. Strains resistant to metronidazole were re-examined for metronidazole resistance applying anaerobic conditions for the first 24 h. None of the isolates were resistant to amoxicillin or tetracycline, whereas 5, 9% were resistant to clarithromycin and 22, 5% resistant to metronidazole tested conventionally. Applying local standards the metronidazole resistance rate fell to 7, 8%, highlighting the importance of the methodology applied for metronidazole susceptibility testing. PMID- 23083451 TI - Cigarette smoking, nicotine dependence and anxiety disorders: a systematic review of population-based, epidemiological studies. AB - BACKGROUND: Multiple studies have demonstrated that rates of smoking and nicotine dependence are increased in individuals with anxiety disorders. However, significant variability exists in the epidemiological literature exploring this relationship, including study design (cross-sectional versus prospective), the population assessed (random sample versus clinical population) and diagnostic instrument utilized. METHODS: We undertook a systematic review of population based observational studies that utilized recognized structured clinical diagnostic criteria (Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD)) for anxiety disorder diagnosis to investigate the relationship between cigarette smoking, nicotine dependence and anxiety disorders. RESULTS: In total, 47 studies met the predefined inclusion criteria, with 12 studies providing prospective information and 5 studies providing quasiprospective information. The available evidence suggests that some baseline anxiety disorders are a risk factor for initiation of smoking and nicotine dependence, although the evidence is heterogeneous and many studies did not control for the effect of comorbid substance use disorders. The identified evidence however appeared to more consistently support cigarette smoking and nicotine dependence as being a risk factor for development of some anxiety disorders (for example, panic disorder, generalized anxiety disorder), although these findings were not replicated in all studies. A number of inconsistencies in the literature were identified. CONCLUSIONS: Although many studies have demonstrated increased rates of smoking and nicotine dependence in individuals with anxiety disorders, there is a limited and heterogeneous literature that has prospectively examined this relationship in population studies using validated diagnostic criteria. The most consistent evidence supports smoking and nicotine dependence as increasing the risk of panic disorder and generalized anxiety disorder. The literature assessing anxiety disorders increasing smoking and nicotine dependence is inconsistent. Potential issues with the current literature are discussed and directions for future research are suggested. PMID- 23083456 TI - Macrocyclic molecular rotors with bridged steroidal frameworks. AB - In this work, we describe the synthesis and solid-state dynamics of isomeric molecular rotors 7E and 7Z, consisting of two androstane steroidal frameworks linked by the D rings by triple bonds at their C17 positions to a 1,4-phenylene rotator. They are also linked by the A rings by an alkenyl diester bridge to restrict the conformational flexibility of the molecules and reduce the number of potential crystalline arrays. The analysis of the resulting molecular structures and packing motifs offered insights of the internal dynamics that were later elucidated by means of line shape analyses of the spectral features obtained through variable-temperature solid-state (13)C NMR; such analysis revealed rotations in the solid state occurring at kilohertz frequency at room temperature. PMID- 23083457 TI - Infant feeding and the development of food allergies and atopic eczema: An update. AB - There is an increasing awareness of food allergies in the community. Dermatologists frequently see patients with atopic eczema, where parents are extremely concerned about the role of food allergy. Advice given to parents regarding the timing of introduction of solid foods has changed markedly over the past decade. Whereas previous advice advocated delaying the introduction of solid foods until the infant's gastrointestinal system had matured, recent studies suggest that the introduction of solids from around 4 to 6 months may actually prevent the development of allergies. Studies on maternal dietary restrictions during pregnancy and lactation have led researchers to believe that antigen avoidance does not play a significant role in the prevention of atopic disease. Breastfeeding exclusively for 4 to 6 months has multiple benefits for mother and child, however, it does not convincingly prevent food allergies or decrease atopic eczema. New evidence suggests that the use of hydrolysed formulas does not delay or prevent atopic eczema or food allergy. This article aims to highlight current evidence and provide an update for dermatologists on the role of food exposure in the development of atopic disease, namely atopic eczema. PMID- 23083458 TI - Simultaneous interfacial and precipitated supracrystals of Au nanocrystals: experiments and simulations. AB - Under solvent saturation, a precipitation of full-grown supracrystals on the one hand and the formation of well-defined supracrystalline films at the air-liquid interface on the other hand were previously observed for the first time (J. Am. Chem. Soc.2012, 134, 3714-3719). Here, these two simultaneous growth processes are studied by additional experiments and by Brownian dynamics simulations. The thickness of the supracrystalline films and the concentration of free nanocrystals within the solution are measured as a function of the nanocrystal size. The simulations show that the first process of supracrystal growth is due to a homogeneous nucleation favored by solvent-mediated ligand interactions, while the second one is explained in terms of a diffusion process caused by a decrease in the surface energy when the particles penetrate the air-liquid interface. It is also verified that the presence of thiol molecules at the air solution interface does not hinder the formation of supracrystalline films. PMID- 23083460 TI - Clinical neuropathology practice guide 06-2012: MGMT testing in elderly glioblastoma patients--yes, but how? AB - In 2005, a seminal paper showed that glioblastoma patients aged 18 to 70, whose tumors have a methylated MGMT promoter have a better prognosis than patients with tumors carrying an unmethylated MGMT promoter. As a consequence of this and several confirmatory studies, routine MGMT testing in the clinical setting was promoted. However, only few centers have indeed implemented routine clinical MGMT testing, mostly due the lack of clear clinical consequence and because of considerable technical issues with the testing itself. Recently published results of trials on elderly patients with malignant gliomas have revived the call for routine MGMT testing for clinical decision making. These studies strongly support that MGMT status is a predictive factor for response to temozolomide treatment in elderly patients with malignant astrocytic gliomas and its use for therapy decisions could improve patient management, avoid treatment toxicities and save costs. However, although a number of different protocols for MGMT testing from routinely collected and formalin-fixed and paraffin-embedded tissue have been suggested, there is still no commonly accepted test method with sufficient analytical performance. Protocols established in high-throughput specialized academic or commercial laboratories may not be easily transferable to less specialized laboratories. Thus, before MGMT testing can be used and recommended for clinical decision making, an adequate test method with confirmed high repeatability and reproducibility needs to be identified. To this end, specifically designed investigations including stringently controlled interlaboratory ring trials are needed. Such studies need to take into account the considerable variation in pre-analytical tissue handling (e.g., tissue fixation conditions) between laboratories. PMID- 23083461 TI - Prominent oligodendroglial response in surgical specimens of patients with temporal lobe epilepsy. AB - Temporal lobe epilepsy (TLE) is characterized by distinct neuropathological findings, such as hippocampal sclerosis and reactive astrogliosis. Recently, MRI studies have revealed the presence of white matter pathology in brains of epilepsy patients. The purpose of this study is to evaluate the involvement of oligodendroglia in the epileptogenic process. Using TPPP/p25 as a marker for mature oligodendroglia, we evaluated the hippocampus in 26 surgical specimens from patients with TLE and 9 autopsy controls without neuropathological alterations for changes in oligodendroglial cell densities (mm2) in hippocampal, entorhinal, and temporal white matter, and the amount of perineuronal oligodendrocytes in CA1 subregion. Oligodendrocyte cell densities were significantly elevated in epilepsy patients compared to controls in all four examined white matter subregions. In addition, in the CA1 sector, the percentage of neurons showing more than one perineuronal oligodendrocyte was significantly higher in epilepsy patients. In conclusion, our study expands the glial reactions beyond astrogliosis and shows that prominent oligodendroglial response is a consistent pathological feature characteristic for TLE. PMID- 23083462 TI - The discovery of oligodendroglia cells by Rio-Hortega: his original articles. 1921. AB - Comment on: del Rio-Hortega P. Glia with very few processes (oligodendroglia). Clin Neuropathol. 2012; 31: 440-459, originally published in Archivos de Neurobiologia. 1921; 2: 16-43 and del Rio-Hortega P. Are the glia with very few processes homologous with Schwann cells? Clin Neuropathol. 2012; 31: 460-462, originally published in Bol de la Soc Esp de Biol. 1922; X: 25-28. PMID- 23083463 TI - Studies on neuroglia: Glia with very few processes (oligodendroglia) by PA-o del RA-o-Hortega. 1921. PMID- 23083464 TI - Are the glia with very few processes homologous with Schwann cells? by Pio del Rio-Hortega. 1922. PMID- 23083466 TI - Children with paralytic poliomyelitis: a cross-sectional study of knowledge, attitudes and beliefs of parents in Zamfara state, Nigeria. AB - BACKGROUND: Nigeria is one of the major African countries in which incidences of polio infection persist in spite of several eradication efforts. The preponderance of paralytic poliomyelitis particularly in the northern part of Nigeria raises the question as to whether parents of children affected with polio know how polio is contracted and spread, whether having a disabled child affects the parents' attitude towards these children, and what they believe about poliomyelitis in view of their socio-cultural and belief system in the sub region. Zamfara State, in the north-west of Nigeria is one of the endemic areas where resistance to the global campaign on polio eradication was very high. Therefore this study was conducted to investigate the knowledge, attitudes and beliefs of parents/primary caregivers of children affected with paralytic poliomyelitis in Zamfara State. METHODS: This study is a cross-sectional survey in which the multistage probability sampling technique was used to randomly select two local government areas in Zamfara State where consenting parents/primary caregivers of children with paralytic poliomyelitis were purposively selected. The knowledge, attitudes and beliefs of parents were assessed with the aid of a 4-part 52-item structured researcher administered questionnaire and the data obtained were analyzed. RESULTS: Two hundred and seventeen parents/primary caregivers participated in the study. One hundred and forty-two, (65.4%) reported good, 51 (23.8%) reported fair, while 24 (11%) of participants reported poor knowledge of paralytic poliomyelitis. More respondents 120 (55.3%) showed a positive attitude towards children with paralytic poliomyelitis. Younger age (P=0.016) and paid employment (P=0.020) were positively associated with good knowledge of paralytic poliomyelitis. Female gender (P=0.020), higher educational level (P=0.015), being employed (P=0.010) and having from middle to high household income (P=0.016) were positively associated with a positive attitude toward children with paralytic poliomyelitis. Most respondents showed a reasonable belief over the cause of their children's condition rather than the erroneous traditional belief that paralytic poliomyelitis is caused by spirit forces. CONCLUSIONS: It is of great concern that the good knowledge, positive attitude and reasonable belief by parents/primary caregivers about paralytic poliomyelitis observed in this study did not play a prominent role in preventing susceptibility of children in north west Nigeria to paralytic poliomyelitis. It is imperative that Nigerian policy makers should device more strategic measures toward the prevention of paralytic poliomyelitis in this sub region. PMID- 23083467 TI - Molecular cloning of the apoptosis-related calcium-binding protein AsALG-2 in Avena sativa. AB - Victorin, the host-selective toxin produced by the fungus Cochliobolus victoriae, induces programmed cell death (PCD) in victorin-sensitive oat lines with characteristic features of animal apoptosis, such as mitochondrial permeability transition, chromatin condensation, nuclear DNA laddering and rRNA/mRNA degradation. In this study, we characterized a calcium-binding protein, namely AsALG-2, which might have a role in the victorin-induced PCD. AsALG-2 is homologous to the Apoptosis-Linked Gene ALG-2 identified in mammalian cells. Northern blot analysis revealed that the accumulation of AsALG-2 transcripts increased during victorin-induced PCD, but not during necrotic cell death. Salicylic acid, chitosan and chitin strongly activated the expression of general defence response genes, such as PR-10; however, neither induced cell death nor the accumulation of AsALG-2 mRNA. Pharmacological studies indicated that victorin induced DNA laddering and AsALG-2 expression were regulated through similar pathways. The calcium channel blocker, nifedipine, moderately inhibited the accumulation of AsALG-2 mRNA during cell death. Trifluoperazine (calmodulin antagonist) and K252a (serine-threonine kinase inhibitor) reduced the victorin induced phytoalexin accumulation, but did not prevent the victorin-induced DNA laddering or accumulation of AsALG-2 mRNA. Taken together, our investigations suggest that there is a calcium-mediated signalling pathway in animal and plant PCD in common. PMID- 23083465 TI - A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. AB - Microdeletion and microduplication copy number variations are found in patients with autism spectrum disorder and in a number of cases they include genes that are involved in the canonical Wnt signaling pathway (for example, FZD9, BCL9 or CDH8). Association studies investigating WNT2, DISC1, MET, DOCK4 or AHI1 also provide evidence that the canonical Wnt pathway might be affected in autism. Prenatal medication with sodium-valproate or antidepressant drugs increases autism risk. In animal studies, it has been found that these medications promote Wnt signaling, including among others an increase in Wnt2 gene expression. Notably, the available genetic information indicates that not only canonical Wnt pathway activation, but also inhibition seems to increase autism risk. The canonical Wnt pathway plays a role in dendrite growth and suboptimal activity negatively affects the dendritic arbor. In principle, this provides a logical explanation as to why both hypo- and hyperactivity may generate a similar set of behavioral and cognitive symptoms. However, without a validated biomarker to stratify for deviant canonical Wnt pathway activity, it is probably too dangerous to treat patients with compounds that modify pathway activity. PMID- 23083468 TI - A systematic insight into a single-stage deammonification process operated in granular sludge reactor with high-loaded reject-water: characterization and quantification of microbiological community. AB - AIMS: Reject-water from sludge dewatering was treated in a single-stage deammonification reactor. The aims were to characterize the microbiological community within deammonification granules. METHODS AND RESULTS: In situ mapping of the intact granular sludge were made with fluorescent in situ hybridization (FISH). The Planctomycetes community in the destroyed granular sludge was characterized by FISH, polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE), cloning and sequence analysis. CONCLUSIONS: AOB within Betaproteobacteria were concentrated within the first 50-100 MUm of the granule, and Planctomycetes in the first 100-200 MUm were responsible for nitrogen elimination. PCR-DGGE verified the higher diversity of Planctomycetes in the deammonification reactor than the anaerobic cultivation. The sequence analysis after PCR-DGGE and cloning identified the dominant Planctomycetes species for anammox reaction as Ca. Brocadia fulgida (accession no. EU478693). FISH detection using the universal probe AMX368 specific for all anammox bacteria including Ca. Brocadia fulgida failed; however, the probe BFU613 specific for Ca. Brocadia fulgida gave clear positive FISH signals. The three-dimensional structure of the ribosome may hinder binding of the universal probe to the corresponding 16S rRNA region. SIGNIFICANCE AND IMPACT OF THE STUDY: A combination of multiple methods for the analysis of the microbiological community was necessary. Oligonucleotide probes should be carefully selected, and a negative FISH analysis has to be verified by other molecular biological techniques. PMID- 23083470 TI - Infection of neonatal Biomphalaria glabrata with the miracidia of Echinostoma caproni. AB - We used a Biomphalaria glabrata snail model for our studies and investigated the suitability of B. glabrata neonates, reared on a Nostoc sp. diet, for infection with Echinostoma caproni miracidia. We found that neonatal snails could become infected with E. caproni miracidia with 31 +/- 11% standard error (SE) of our exposed snails containing rediae infections at 4 wk post-exposure (PE). However, the survival of exposed neonates was significantly (P < 0.05, Student's t-test) less than that of the unexposed controls at 1, 2, 3, and 4 wk PE. PMID- 23083469 TI - What is your diagnosis? Abdominal fluid from a dog. PMID- 23083471 TI - Urease gene of Trichophyton rubrum var. raubitschekii. AB - The recent description (in GenBank) of a urease-encoding gene from Trichophyton rubrum provides an opportunity to compare this species to the highly similar T. rubrum var. raubitschekii. Therefore, the corresponding genomic DNA was recovered from T. rubrum var. raubitschekii, and the sequence and expression were compared for this urease gene in urease-positive and -negative isolates of T. rubrum and T. rubrum var. raubitschekii. The sequence (2371 bp) of the T. rubrum var. raubitschekii urease gene revealed the presence of three exons. Except for a three-amino acid insertion, the predicted proteins were identical, but demonstrated protein identity of approximately 70% compared to an Arthroderma gypseum homolog. Reverse transcription polymerase chain reaction analysis revealed the presence of a corresponding transcript in both urease-positive T. rubrum var. raubitschekii isolates examined; the same analysis did not detect this transcript in urease-negative isolates of T. rubrum. PMID- 23083472 TI - A high-throughput diagnostic method for measuring human exposure to organophosphorus nerve agents. AB - An automated high-throughput immunomagnetic separation (IMS) method for diagnosing exposure to the organophosphorus nerve agents (OPNAs) sarin (GB), cyclohexylsarin (GF), VX, and Russian VX (RVX) was developed to increase sample processing capacity for emergency response applications. Diagnosis of exposure to OPNAs was based on the formation of OPNA adducts to butyrylcholinesterase (BuChE). Data reported with this method represent a ratio of the agent-specific BuChE adduct concentration, relative to the total BuChE peptide concentration that provides a nonactivity measurement expressed as percent adducted. All magnetic bead transfer steps and washes were performed using instrumentation in a 96-well format allowing for simultaneous extraction of 86 clinical samples plus reference materials. Automating extractions increased sample throughput 50-fold, as compared to a previously reported manual method. The limits of detection, determined using synthetic peptides, were 1 ng/mL for unadducted BuChE and GB-, GF-, VX-, and RVX-adducted BuChE. The automated method was characterized using unexposed serum and serum pools exposed to GB, GF, VX, or RVX. Variation for the measurement of percent adducted was <12% for all characterized quality control serum pools. Twenty-six (26) serum samples from individuals asymptomatic for cholinesterase inhibitor exposure were analyzed using this method, and no background levels of OPNA exposure were observed. Unexposed BuChE serum concentrations measured using this method ranged from 2.8 MUg/mL to 10.6 MUg/mL, with an average concentration of 6.4 MUg/mL. PMID- 23083473 TI - How is the distal pocket of a heme protein optimized for binding of tryptophan? AB - Indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase catalyze the O(2) dependent oxidation of l-tryptophan to N-formylkynurenine. Both are heme containing enzymes, with a proximal histidine ligand, as found in the globins and peroxidases. From the structural information available so far, the distal heme pockets of these enzymes can contain a histidine residue (in tryptophan 2,3 dioxygenases), an arginine residue and numerous hydrophobic residues that line the pocket. We have examined the functional role of each of these residues in both human indoleamine 2,3-dioxygenase and human tryptophan 2,3-dioxygenase. We found that the distal histidine does not play an essential catalytic role, although substrate binding can be affected by removing the distal arginine and reducing the hydrophobic nature of the binding pocket. We collate the information obtained in the present study with that reported in the available literature to draw comparisons across the family and to provide a more coherent picture of how the heme pocket is optimized for tryptophan binding. PMID- 23083474 TI - Microfluidic fabrication of self-assembled peptide-polysaccharide microcapsules as 3D environments for cell culture. AB - We report a mild cell encapsulation method based on self-assembly and microfluidics technology. Xanthan gum, an anionic polysaccharide, was used to trigger the self-assembly of a positively charged multidomain peptide. The self assembly resulted in the formation of a nanofibrous matrix and using a microfluidic device, microcapsules with homogeneous size were fabricated. The properties and performance of xanthan-peptide microcapsules were optimized by changing peptide/polysaccharide ratio and their effects on the microcapsule permeability and mechanical stability were analyzed. The effect of microcapsule formulation on viability and proliferation of encapsulated chondrocytic (ATDC5) cells was also investigated. The encapsulated cells were metabolically active, showing an increased viability and proliferation over 21 days of in vitro culture, demonstrating the long-term stability of the self-assembled microcapsules and their ability to support and enhance the survival of encapsulated cells over a prolonged time. Self-assembling materials combined with microfluidics demonstrated to be an innovative approach in the fabrication of cytocompatible matrix for cell microencapsulation and delivery. PMID- 23083475 TI - Toward predictive oral and maxillofacial medicine: perspective on Zavras et al. PMID- 23083476 TI - Widespread purple bulla-like masses of the oral mucosa. PMID- 23083477 TI - The role of direct visual fluorescent examination (VELscope) in routine screening for potentially malignant oral mucosal lesions. AB - OBJECTIVE: Direct visual fluorescent examination (DVFE) is a proposed adjunct to conventional oral examination (COE). We evaluate the benefit of DVFE in screening for potentially malignant mucosal lesions in a general population of patients presenting for dental care. STUDY DESIGN: A total of 130 patients were evaluated by COE followed by DVFE. Areas clinically suspicious by COE or with positive DVFE (visual fluorescence loss [VFL]) underwent surgical biopsy. Association between COE and DVFE was assessed and compared with histopathology. RESULTS: A total of 42 subjects had one or more areas of VFL, yet histologic evidence of premalignancy/malignancy was only identified in a single individual. Further, one lesion negative by DVFE exhibited epithelial dysplasia. DVFE was statistically different from scalpel biopsy (P = .0001). No difference was found between COE and scalpel biopsy (P = 1.0). CONCLUSIONS: Results suggest that COE is more valid than DVFE at discriminating benign mucosal alterations from premalignancy and do not support use of DVFE as an oral cancer screening adjunct. PMID- 23083478 TI - Application of magnetic resonance T2 mapping in the temporomandibular joints. AB - OBJECTIVES: The objective of this study was to apply magnetic resonance (MR) T2 mapping to the normal temporomandibular joint (TMJ) disk and to determine its T2 character. STUDY DESIGN: Fourteen volunteers with 28 healthy TMJs were selected for this study. MR T2 maps of all of the disks were acquired. The global disk area and 6 zonal regions of interest (ROIs) of superior, inner, and inferior layers and anterior, middle, and posterior bands were defined for each disk. T2 values of the global disk and each zonal ROI were calculated. Comparisons of the T2 values among the 3 layers and among the 3 bands were performed using the general linear model. RESULTS: The T2 value for the whole disk was 40.21 +/- 2.95. The T2 values of the superior (39.42 +/- 3.73) and inferior layers (40.11 +/- 3.29) were significantly higher than the inner layer (37.28 +/- 3.54) (P < .05). The T2 values of the anterior (36.96 +/- 3.43) and posterior bands (36.01 +/- 3.72) were significantly lower than the middle band (41.04 +/- 5.51) (P < .05). CONCLUSIONS: Preliminary determinations of T2 values for the bands and layers of normal TMJ disks were calculated. PMID- 23083479 TI - Contrast-to-noise ratio with different large volumes in a cone-beam computerized tomography machine: an in vitro study. AB - OBJECTIVES: The objectives were to determine whether the images obtained from different cone-beam computerized tomography (CBCT) field of view (FOV) sizes with varying scan time and kilovolt peak using the Picasso Master 3D machine (Vatech, Hwasung, South Korea) differ in contrast-to-noise ratio (CNR). STUDY DESIGN: A phantom was used. Scans were acquired using the same voxel size, 2 scan times (15 and 24 seconds) for 3 different FOV sizes and 5 different kilovolt peaks. The contrast and CNR were calculated for each FOV. RESULTS: The CNRs were similar for the 2 scan times for all 3 FOV sizes. The CNR was lower in the 20 * 19 cm FOV compared with the other 2 FOVs for both scan times. CONCLUSIONS: The CNR does not vary significantly with increasing scan times for all FOV sizes. Smaller FOVs result in enhanced CNR and contrast. PMID- 23083481 TI - Transoral anterior approach using median mandibular splitting in upper spinal tumor extirpation. AB - OBJECTIVE: Transoral approach from the anterior direction is necessary if an upper spinal tumor is too big to extirpate via the posterior approach alone. To obtain a good anterior view of the surgical field, the mandible, tongue, and soft palate have to be split, and we developed a criterion to select the surgical strategy. STUDY DESIGN: We indicated a decision-making process of splitting techniques and indications with actual cases and review of literatures. RESULT: Tumors were located from the level of C1 to the lower part of C3. Computerized tomography and magnetic resonance imaging were important to decide approaches. The orthopedic surgical team invited oral and maxillofacial surgeons team to assist in all transoral anterior approach cases. CONCLUSIONS: Vertical splitting of the mandible, incising the skin of the mental region, and splitting the middle of the tongue were combined according to the position of the spinal tumor. PMID- 23083482 TI - Sialoendoscopic management of submandibular gland obstruction caused by intraglandular foreign body. AB - OBJECTIVE: Submandibular gland obstruction caused by foreign body is relatively uncommon. We discuss the diagnosis and management of foreign body-induced submandibular sialadenitis by an illustrative case report and review of the literature. STUDY DESIGN: We report a case of a patient who suffered from obstructive submandibular sialadenitis caused by an intraglandular fish bone, indicating the benefits of sialoendoscopy in diagnosis and treatment of such diseases. A search of the Medline database (from 1967 to February 2011) for foreign body-caused submandibular sialadenitis was performed. RESULTS: The clinical outcome was satisfactory during a 14 months' follow-up, with no evidence of recurrence. Literature review showed that obstructive submandibular sialadenitis originating from a foreign body is relatively rare, and successful removal of an intraglandular foreign body with gland preservation had never been reported before. CONCLUSIONS: Sialoendoscopy can be served as an organ-preserving approach for diagnosis and treatment of foreign body-induced obstructive salivary diseases. PMID- 23083483 TI - Multidisciplinary approach for the aesthetic treatment of maxillary lateral incisors agenesis: thinking about implants? AB - Missing maxillary lateral incisors create an esthetic problem with specific orthodontic and prosthetic considerations. Implants are commonly used to replace congenitally missing lateral incisors in adolescent orthodontic patients. However, an interdisciplinary approach should be observed during the diagnosis, prognosis, and treatment plan to provide a result with good predictability and meet the esthetic and functional expectations of the patient. The present study describes a case of a young patient with tooth agenesis of maxillary lateral incisors, which was conducted with an integrated planning. After 5-year follow-up of 2 fixed implant-supported prostheses, clinical and radiographic examination showed the treatment to be successful. PMID- 23083484 TI - A novel c.1255G>T (p.D419Y) mutation in SH3BP2 gene causes cherubism in a Turkish family. AB - Cherubism (MIM no. 118400) is a rare autosomal dominant disorder characterized by bilateral multilocular lesions of the upper and lower jaws. The lesions usually manifest clinically during early childhood, progress until puberty, and regress in adulthood. SH3BP2 is the only gene currently known to be associated with cherubism. This study began with an 8-year-old boy who was referred owing to overgrowth of mandible. A panoramic radiograph revealed multilocular radiolucent lesions of the upper/lower jaws, suggestive of cherubism. Sequence analysis of SH3BP2 revealed a novel c.G1255T change in exon 9 of the gene where 80% of the disease-causing mutations were observed. We report here the clinical and molecular findings of a family with 3 affected members in two generations showing variable clinical expressivity with the regression of symptoms with advancing age and the lack of penetrance. PMID- 23083485 TI - Primary glycogen-rich clear cell squamous cell carcinoma of the mandibular gingiva. AB - Clear cell squamous cell carcinoma (CCSCC) is a rare variant of squamous cell carcinoma, first reported by Kuo, who described 6 cases of squamous cell carcinoma of the skin of the head and neck. CCSCC is composed of cells with clear cytoplasm, which Kuo attributed to the accumulation of intracellular fluid and not the presence of glycogen, lipid, or mucin. This case describes a 59-year-old woman who presented with an exophytic, hemorrhagic lesion on the posterior mandibular gingiva of 2 months' duration. Histologic examination revealed dysplastic stratified squamous epithelium showing transition to an infiltrating tumor composed of islands of epithelial cells with clear cytoplasm. The cytoplasm stained positive with periodic acid Schiff but was diastase labile. Mucicarmine stains were negative for intracytoplasmic mucin. This is the first reported case describing primary glycogen-rich CCSCC of the mandibular gingiva. PMID- 23083486 TI - Dental treatment of a patient with central sleep apnea and phobic anxiety under sedation: report of a case and clinical considerations. AB - Central sleep apnea (CSA) results from a reduction in lack of output from the central respiratory generator in the brainstem, manifesting as apneas and hypopneas without discernible efforts. CSA can lead to hypercarbia, arrhythmias, pulmonary hypertension, and heart failure. Indeed, the patient may develop a disturbed breathing during sedation procedures. We report a patient who was diagnosed with CSA and had been on continuous positive airway pressure (CPAP) therapy for 5 years. He was referred for multiple tooth extractions under sedation owing to severe gag reflex and phobic anxiety disorder. The treatment was completed uneventfully under N(2)O and sevoflurane inhalation accompanied by midazolam and ketamine induction. The role of sedative, analgesic, and anesthetic agents as a precipitating factor for CSA is of particular concern. The combined administration of midazolam, ketamine, sevoflurane, and N(2)O/O(2) is a useful and safe option for patients requiring sedation. PMID- 23083488 TI - Synthesis, computed stability, and crystal structure of a new family of inorganic compounds: carbonophosphates. AB - Ab initio-based high-throughput computing and screening are now being used to search and predict new functional materials and novel compounds. However, systematic experimental validation on the predictions remains highly challenging, yet desired. Careful comparison between computational predictions and experimental results is sparse in the literature. Here we report on a systematic experimental validation on previously presented computational predictions of a novel alkali carbonophosphate family of compounds. We report the successful hydrothermal synthesis and structural characterization of multiple sodium carbonophosphates. The experimental conditions for formation of the carbonophosphates and the computational results are compared and discussed. We also demonstrate topotactic chemical de-sodiation of one of the compounds, indicating the potential use of this novel class of compounds as Li(+) or Na(+) insertion electrodes. PMID- 23083487 TI - The genome sequence of Propionibacterium acidipropionici provides insights into its biotechnological and industrial potential. AB - BACKGROUND: Synthetic biology allows the development of new biochemical pathways for the production of chemicals from renewable sources. One major challenge is the identification of suitable microorganisms to hold these pathways with sufficient robustness and high yield. In this work we analyzed the genome of the propionic acid producer Actinobacteria Propionibacterium acidipropionici (ATCC 4875). RESULTS: The assembled P. acidipropionici genome has 3,656,170 base pairs (bp) with 68.8% G + C content and a low-copy plasmid of 6,868 bp. We identified 3,336 protein coding genes, approximately 1000 more than P. freudenreichii and P. acnes, with an increase in the number of genes putatively involved in maintenance of genome integrity, as well as the presence of an invertase and genes putatively involved in carbon catabolite repression. In addition, we made an experimental confirmation of the ability of P. acidipropionici to fix CO2, but no phosphoenolpyruvate carboxylase coding gene was found in the genome. Instead, we identified the pyruvate carboxylase gene and confirmed the presence of the corresponding enzyme in proteome analysis as a potential candidate for this activity. Similarly, the phosphate acetyltransferase and acetate kinase genes, which are considered responsible for acetate formation, were not present in the genome. In P. acidipropionici, a similar function seems to be performed by an ADP forming acetate-CoA ligase gene and its corresponding enzyme was confirmed in the proteome analysis. CONCLUSIONS: Our data shows that P. acidipropionici has several of the desired features that are required to become a platform for the production of chemical commodities: multiple pathways for efficient feedstock utilization, ability to fix CO2, robustness, and efficient production of propionic acid, a potential precursor for valuable 3-carbon compounds. PMID- 23083489 TI - Protein disulfide isomerase modification and inhibition contribute to ER stress and apoptosis induced by oxidized low density lipoproteins. AB - AIMS: Protein disulfide isomerase (PDI) is an abundant endoplasmic reticulum (ER) resident chaperone and oxidoreductase that catalyzes formation and rearrangement (isomerization) of disulfide bonds, thereby participating in protein folding. PDI modification by nitrosative stress is known to increase protein misfolding, ER stress, and neuronal apoptosis. As LDL oxidation and ER stress may play a role in atherogenesis, this work was designed to investigate whether PDI was inactivated by oxLDLs, thereby participating in oxLDL-induced ER stress and apoptosis. RESULTS: Preincubation of human endothelial HMEC-1 and of macrophagic U937 cells with toxic concentration of oxLDLs induced PDI inhibition and modification, as assessed by 4-HNE-PDI adducts formation. PDI inhibition by bacitracin potentiated ER stress (increased mRNA expression of CHOP and sXBP1) and apoptosis induced by oxLDLs. In contrast, increased PDI activity by overexpression of an active wild type PDI was associated with reduced oxLDL-induced ER stress and toxicity, whereas the overexpression of a mutant inactive form was not protective. These effects on PDI were mimicked by exogenous 4-HNE and prevented by the carbonyl scavengers N-acetylcysteine and pyridoxamine, which reduced CHOP expression and toxicity by oxLDLs. Interestingly, 4-HNE-modified PDI was detected in the lipid rich areas of human advanced atherosclerotic lesions. Innovation and CONCLUSIONS: PDI modification by oxLDLs or by reactive carbonyls inhibits its enzymatic activity and potentiates both ER stress and apoptosis by oxLDLs. PDI modification by lipid peroxidation products in atherosclerotic lesions suggests that a loss of function of PDI may occur in vivo, and may contribute to local ER stress, apoptosis, and plaque progression. PMID- 23083490 TI - Self-reported depressive syndromes in mild cognitive impairment and mild Alzheimer's disease. AB - BACKGROUND: There is suggestion that self-reported depressive syndromes can independently manifest in the general population as cognitive/affective or somatic/vegetative. The Beck Depression Inventory, 2nd edition (BDI-II), a self report measure of depressive symptoms, has been shown to support this two-factor structure. However, this finding has not been examined in an older adult sample with cognitive impairment. In order to determine whether older adults with cognitive impairments exhibit similarly independent cognitive/affective and somatic/vegetative depressive syndromes, we explored the factor structure of the BDI-II in this population. METHODS: Participants were 228 older adults (mean age = 74, SD = 7.9) diagnosed with mild cognitive impairment (MCI; n = 137) or early Alzheimer's disease (n = 85), who completed the BDI-II as part of an outpatient neuropsychological evaluation. Exploratory principal component factor analysis with direct Oblimin rotation was conducted, and a two-factor solution was specified based on our theoretical conceptualization of the cognitive/affective and somatic/vegetative items from the scale. RESULTS: The first factor represented cognitive/affective symptoms of depression (e.g. self-dislike, pessimism, worthlessness), and accounted for 36% of the variance. Adding the second factor, reflecting somatic/vegetative items (e.g. sleep and appetite changes, loss of energy), accounted for an additional 6.8% of the variance. CONCLUSION: Results supported the presence of two distinct depressive syndromes, cognitive/affective and somatic/vegetative symptoms. Thus, cognitively impaired older adults report mood symptoms relatively similarly to younger and midlife adults. This supports the validity of self-reported mood in this group, and the results may have implications for psychiatric treatment in this population. PMID- 23083493 TI - Self-assembled block copolymer-nanoparticle hybrids: interplay between enthalpy and entropy. AB - The dispersion of nanoparticles in ordered block copolymer nanostructures can provide control over particle location and orientation, and pave the way for engineered nanomaterials that have enhanced mechanical, electrical, or optical properties. Fundamental questions pertaining to the role of enthalpic and entropic particle-polymer interactions remain open and motivate the present work. We consider here a system of 10.6 nm silica nanoparticles (NPs) dispersed in ordered cylinders formed by hydrated poly(ethylene oxide)-poly(propylene oxide) block copolymers (Pluronic P105: EO(37)PO(56)EO(37)). Protonation of silica was used to vary the NP-polymer enthalpic interactions, while polar organic solvents (glycerol, DMSO, ethanol, and DMF) were used to modulate the NP-polymer entropic interactions. The introduction of deprotonated NPs in the place of an equal mass of water did not affect the lattice parameter of the PEO-PPO-PEO block copolymer hexagonal lyotropic liquid crystalline structures. However, the dispersion of protonated NPs led to an increase in the lattice parameter, which was attributed to stronger NP-polymer hydrogen bonding (enthalpic) interactions. Dispersion of protonated NPs into cylindrical structures formed by Pluronic P105 in 80/20 water/organic solvents does not influence the lattice parameter, different from the case of protonated NP in plain water. Organic solvents appear to screen the NP-polymer hydrogen bonding interactions. PMID- 23083492 TI - Interventions to maintain mobility: What works? AB - Mobility, in broad terms, includes everything from the ability to move within your immediate environment (e.g., get out of bed) to the ability to drive across the country. Mobility is essential to maintaining independence and wellbeing, particularly for older adults. This is highlighted by the large number of interventions developed for older adults with the goal of maintaining such mobility. The current paper reviews the state of the science with respect to mobility interventions. Inclusion criteria for the review were: (1) articles must have been peer-reviewed; (2) interventions were evaluated in a randomized controlled trial (RCT); (3) studies included a mobility outcome such as lifespace, driving, or walking ability; (4) studies included a sample of healthy community-dwelling older adults (e.g., not investigations of disease conditions); and (5) studies must have reported enough empirical data and detail such that results could potentially be replicated. Three main types of interventions were identified: cognitive training, educational interventions, and exercise interventions. A detailed summary and evaluation of each type of intervention, and the current evidence regarding its effectiveness in maintaining mobility, are discussed. Several interventions show clear evidence of effectiveness, and thus are prime areas for translation of results to the older population. Needs and issues for future intervention research are also detailed. PMID- 23083494 TI - An inflatable ergonomic 3-chamber fundal pressure belt to assist vaginal delivery. AB - OBJECTIVE: To evaluate whether Baby-guard-a new medical device with an ergonomic 3-chamber inflatable abdominal belt-can reduce complications associated with vaginal delivery. METHODS: A randomized controlled single-blind prospective study of 80 pregnant women delivering at term was conducted at San Giuseppe Hospital, Empoli, Italy. In the study group (n=40), the abdominal belt was inflated to optimal therapeutic pressures. In the control group (n=40), the abdominal belt was inflated to minimal, non-therapeutic pressures. Factors relating to maternal, fetal, and labor complications during vaginal delivery were evaluated. RESULTS: Compared with the control group, women in the study group experienced a lower incidence of perineal and cervical lacerations (P<0.001); reduced use of the Kristeller maneuver (P<0.001); shorter duration of the second stage of labor (P<0.001); less psychologic and physical fatigue (P<0.001); fewer maternal requests for cesarean delivery during labor (P<0.001); fewer vacuum extractions (P<0.01); and fewer cesarean deliveries (P<0.02). No neonatal intensive care unit admissions were recorded in the study group versus 7 in the control group (P<0.012). CONCLUSION: Use of the ergonomic 3-chamber inflatable abdominal belt system reduced the incidence of risks associated with vaginal labor. Clinical trials.gov identifier: NCT01566331. PMID- 23083495 TI - Induced abortion, contraceptive use, and dual protection among female sex workers in Moscow, Russia. AB - OBJECTIVE: To describe abortion history and current contraceptive use among female sex workers (FSWs) in Moscow, Russia. METHODS: A clinic-based survey was conducted among 147 FSWs in Moscow during an 8-month period in 2005. RESULTS: In total, 83 of 143 (58.0%) FSWs reported a history of abortion, with 45 of 143 (31.5%) indicating multiple abortions. Condoms were the primary form of contraception (145/146 [99.3%]); just 17 of 142 (12.0%) FSWs reported using non barrier modern contraception. All women who reported using a non-barrier modern method also indicated condom use (i.e. dual protection). Non-barrier contraceptive use was associated with inconsistent condom use (odds ratio [OR] 3.10; 95% confidence interval [CI], 1.07-9.02) and multiple abortions (OR 4.71; 95% CI, 1.19-18.62). CONCLUSION: The results illustrate substantial risk for unintended pregnancy among FSWs. Further research is needed regarding the dynamics of non-barrier contraception and condom use. Efforts to improve the health and wellbeing of FSWs should include access to safe and effective contraception, in addition to HIV prevention. PMID- 23083496 TI - IL-8 and mortality prediction in post-surgical septic shock. PMID- 23083497 TI - FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. AB - PURPOSE: Hypoxia is a cause of resistance to radiotherapy, especially in patients with head and neck squamous cell carcinoma (HNSCC). The purpose of this study was to evaluate (18)F-fluoroazomycin arabinoside (FAZA) positron emission tomography (PET)/computed tomography (CT) hypoxia imaging as a prognostic factor in HNSCC patients receiving radiotherapy. MATERIAL AND METHODS: Forty patients with HNSCC treated with radiotherapy (66-76 Gy) were included. Static FAZA PET/CT imaging 2h post injection was conducted prior to irradiation. The hypoxic volume (HV) was delineated using a tumor-to-muscle value >= 1.4. In 13 patients, a repetitive FAZA PET/CT scan was conducted during the radiotherapy treatment. RESULTS: A hypoxic volume could be identified in 25 (63%) of the 40 tumors. FAZA PET HV varied considerably with a range from 0.0 to 30.9 (median: 0.3) cm(3). The T(max)/M(med) ranged from 1.1 to 2.9 (median: 1.5). The distribution of hypoxia among the Human Papillomavirus (HPV) positive (12/16) and negative (13/24) tumors was not significant different. In the FAZA PET/CT scans performed during radiotherapy, hypoxia could be detected in six of the 13 patients. For these six patients the location of HV remained stable in location during radiotherapy treatment, though the size of the HV decreased. In 30 patients a positive correlation was detected between maximum FAZA uptake in the primary tumor and the lymph node. During a median follow up of 19 months a significant difference in disease free survival rate with 93% for patients with non hypoxic tumors and 60% for patients with hypoxic tumors could be detected. CONCLUSION: This study emphasizes the role of FAZA PET/CT imaging as a suitable assay with prognostic potential for detection of hypoxia in HNSCC. PMID- 23083500 TI - Effects of DNA ploidy and S-phase fraction on fluorine-18 FDG uptake of primary breast cancer lesions. AB - BACKGROUND: Flow cytometry (FCM) evaluating DNA content is emerging as the tool to monitor cell proliferation and malignant potential in several cancers such as stomach, lung, and salivary gland tumor. The purpose of this study was to correlate (18)F-FDG uptake of dual-time-point (DTP) positron emission tomography (PET) imaging with DNA ploidy and S-phase fraction (SPF) in primary breast cancer lesions. PATIENTS AND METHODS: Seventy-two consecutive female patients (mean age +/- SD, 52.7 +/- 11.1 years; range, 28-81 years) had undergone (18)F-FDG DTP PET/computed tomography (CT) imaging for staging of breast malignancy in our institution during a 5-month period. FCM was performed on fresh-frozen samples of specimens obtained from surgery. (18)F-FDG uptake was then compared with DNA content. RESULTS: Forty-four malignant lesions were included in this study. On FCM, DNA aneuploidy was detected in 14 lesions (31.8%). The maximum standardized uptake values (SUV(max1) and SUV(max2)) (SUV(max1), 6.8 +/- 4.6 vs. 3.4 +/- 2.4; P = .017), (SUV(max2), 7.9 +/- 5.7 vs. 3.6 +/- 2.7; P = .015) and retention index (RI) (12.8 +/- 11.6 vs. 2.4 +/- 10.8; P = .010) were significantly higher in DNA aneuploidy cancer than in DNA diploidy cancer. The value of RI (11.3 +/- 11.5 vs. 2.6 +/- 11.2; P = .022) was significantly higher in high SPF (> 15%) breast cancer than in low SPF (<= 15%) breast cancer. CONCLUSIONS: High (18)F-FDG uptake in breast cancer might be an indicator of DNA aneuploidy and high SPF. We propose that (18)F-FDG PET/CT imaging may be a noninvasive and useful tool for predicting the DNA content in breast cancer. PMID- 23083501 TI - North central cancer treatment group (NCCTG) N0537: phase II trial of VEGF-trap in patients with metastatic breast cancer previously treated with an anthracycline and/or a taxane. AB - INTRODUCTION: Angiogenesis is an established target for the treatment of MBC. Aflibercept (VEGF-Trap) is a humanized fusion protein, which binds VEGF-A, VEGF B, and PIGF-1 and -2. PATIENTS AND METHODS: A 2-stage phase II study with primary end points of confirmed tumor response and 6-month progression-free survival (PFS). If either end point was promising after the initial 21 patients, an additional 20 patients would be enrolled. Measurable disease, <2 previous chemotherapy treatments, previous anthracycline or taxane therapy, and Eastern Cooperative Oncology Group performance status of 0 or 1 were required. Aflibercept was given at a dose of 4 mg/kg intravenous every 14 days. RESULTS: Twenty-one patients were enrolled; 71% had visceral disease, 57% were estrogen receptor negative, 19% had HER2(+) disease with previous trastuzumab treatment, and 33% had 2 previous chemotherapy regimens. Partial response rate was 4.8% (95% confidence interval [CI], 0.1%-23.8%) and 6-month PFS was 9.5% (95% CI, 1.2% 30.4%). Neither primary end point met efficacy goals and the study was terminated. A median of 3 cycles was given. Median PFS was 2.4 months. Common grade 3 or 4 adverse events were hypertension (33%), fatigue (19%), dyspnea (14%), and headache (14%). Two cases of severe left ventricular dysfunction were noted. CONCLUSIONS: Aflibercept did not meet efficacy goals in patients previously treated with MBC. Toxicity was as expected for anti-VEGF therapy. PMID- 23083502 TI - Ductal carcinoma in situ that involves sclerosing adenosis: high frequency of bilateral breast cancer occurrence. AB - BACKGROUND: The radiologic and pathologic characteristics of ductal carcinoma in situ (DCIS) that involves sclerosing adenosis (SA) (SA DCIS) resemble those of invasive carcinoma. However, differences in the clinical features of these conditions remain unclear. This study was designed to clarify the clinicopathologic characteristics of SA DCIS compared with those of DCIS not involving SA (non,-SA DCIS). METHODS: We retrospectively studied 1309 patients who underwent breast surgery at our hospital between January 2007 and December 2008. A total of 205 cases of DCIS were diagnosed in 198 patients, and 28 (13.7%) cases of breast SA DCIS were diagnosed in 24 patients. We compared clinical characteristics as well as radiologic and pathologic findings between SA DCIS and non-SA DCIS. RESULTS: Synchronous and metachronous bilateral breast cancer was detected at a significantly higher rate in SA DCIS (9 [38%] of 24 patients) than in non-SA DCIS (22 [13%] of 174 patients; P < .01). As for radiologic findings, architectural distortion was more frequent in patients with SA DCIS than in those with non-SA DCIS (15 [54%] of 28 cases vs. 5 [2%] of 177 cases on mammography; P < .01; and 14 [50%] of 28 cases vs. 4 [2%] of 177 cases on ultrasound; P < .01). The rate of negativity for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 was significantly higher in SA DCIS than in non-SA DCIS (5 [18%] of 28 cases vs. 5 [3%] of 177 cases, P = .005) with immunohistochemical studies. CONCLUSIONS: The rate of bilateral breast cancer and of architectural distortion on radiologic studies was higher in patients with SA DCIS than in those with non-SA DCIS. Our findings suggest that patients with SA DCIS should be closely monitored by radiologic and pathologic examinations to detect the presence of contralateral lesions. PMID- 23083503 TI - Frequency of positive patch test reactions to preservatives: The Australian experience. AB - BACKGROUND/OBJECTIVES: Preservatives are important causes of allergic contact dermatitis. The frequency of allergy to preservatives in Australia has been unknown to date. Our objectives are to report the frequency of positive preservative patch test reactions in Australia, comparing them to the published international data, as well as exploring the current regulations in place for preservative use in Australia. METHODS: This was the first retrospective study of patch testing results, aggregated from four patch test clinics in three centres in Melbourne and Sydney. RESULTS: In all, 6845 patients were patch-tested during 1993-2006 and in this period the five most frequent preservative allergens were formaldehyde (4.6%), Euxyl K400 (containing methyldibromo glutaronitrile and phenoxyethanol) (3.3%), quaternium-15 (2.9%), diazolidinyl urea (2.4%), and methylchloroisothiazolinone/methylisothiazolinone (2.3%). These were followed by dimethylol dimethyl DMDM hydantoin (2.1%), chloroacetamide (2.1%) and imidazolidinyl urea (1.9%). The least frequent sensitisers were parabens (1.1%), 2-bromo-2-nitropropane-1, 3-diol (0.9%) and benzyl alcohol (0.4%). CONCLUSIONS: Formaldehyde was the most prevalent preservative allergen. Chloroacetamide allergy was more commonly seen in Australia. Parabens, 2-bromo-2-nitropropane-1,3 diol and benzyl alcohol were the least frequent sensitisers. Household products in Australia are not required to list all ingredients preventing sensitised individuals from properly assessing their exposure. PMID- 23083504 TI - Alginate hydrogel has a negative impact on in vitro collagen 1 deposition by fibroblasts. AB - Hydrogels have been widely investigated as 3D culture substrates because of their reported structural similarity to the extracellular matrix (ECM). Limited ECM deposition, however, occurs within these materials, so the resulting "tissues" bear little resemblance to those found in the body. Here matrix deposition by fibroblasts encapsulated within a calcium alginate (Ca-alg) hydrogel was investigated. Although the cells transcribed mRNA for coll Ialpha over a period of 3 weeks, very little collagen protein deposition was observed within the gel by histology or immunohistochemistry (IHC). Although molecular diffusion demonstrated charge dependency, this did not prevent the flux of both positively and negative charged amino acids through the gel, suggesting that the absence of ECM could not be attributed to substrate limitation. The flux of protein, however, was charge-dependent as proteins with a net negative charge passed quickly through the Ca-alg into the medium. The minimal collagen deposition within the Ca-alg was attributed to a combination of rapid movement of negatively charged procollagen through the gel and steric hindrance of fibril formation. PMID- 23083505 TI - Direct costs associated with depressive symptoms in late life: a 4.5-year prospective study. AB - BACKGROUND: Depression in old age is common. Only few studies examined the association of depressive symptoms and direct costs in the elderly in a cross sectional way. This study aims to investigate prospectively health service use and direct costs over a course of 4.5 years considering also different courses of depressive symptomatology. METHODS: 305 primary care patients aged 75+ were assessed face-to-face regarding depressive symptoms (Geriatric Depression Scale), and service use and costs at baseline and 4.5 years later. Resource utilization was monetarily valued using 2004/2005 prices. The association of baseline factors and direct costs after 4.5 years was analyzed by multivariate linear regression. RESULTS: Mean annual direct costs of depressed individuals at baseline and follow up were almost one-third higher than of non-depressed, and highest for individuals with chronic depressive symptoms. Most relevant cost drivers were costs for inpatient care, pharmaceuticals, and home care. Costs for home care increased at most in individuals with chronic depressive symptoms. Baseline variables that were associated with direct costs after 4.5 years were number of medications as a measure of comorbidity, age, gender, and depressive symptoms. CONCLUSIONS: Presence and persistence of depressive symptoms in old age seems to be associated with future direct costs even after adjustment for comorbidity. The findings deign a look to the potential economic consequences of depressive symptoms in the elderly for the healthcare system in the future. PMID- 23083506 TI - Caudal epidural anti-nociception using lidocaine, bupivacaine or their combination in cows undergoing reproductive procedures. AB - OBJECTIVE: To evaluate the anti-nociceptive effects of lidocaine, lidocaine bupivacaine combination or bupivacaine following caudal epidural administration in cows undergoing reproductive procedures. STUDY DESIGN: Blinded, randomized experimental study. ANIMALS: Thirty seven healthy Holstein cows (mean weight +/- SD, 633 +/- 41 kg). METHODS: Animals were allocated randomly to receive one of four treatments: group LID, 0.2 mg kg(-1) lidocaine 2%; group LID-BUP, lidocaine bupivacaine mixture in a 1:1 volume ratio (0.1 mg kg(-1) and 0.025 mg kg(-1), respectively); group BUP-LD, 0.05 mg kg(-1) bupivacaine 0.5%; and group BUP-HD, 0.06 mg kg(-1) bupivacaine 0.5%. The onset and duration of perineal anti nociception were determined using superficial and deep pin pricks and the number of cows with complete perineal anti-nociception was recorded. Parameters were compared using anova followed by Duncan's test where relevant. RESULTS: Mean +/- SD time to onset of anti-nociception following epidural administration of BUP-LD was significantly longer than for LID-BUP (p < 0.05). The duration (in minutes) of perineal anti-nociception was significantly longer following epidural administration of BUP-HD (247 +/- 31) versus LID-BUP (181 +/- 33) and LID (127 +/ 25) minutes respectively. The % of cows with complete anti-nociception was increased in the group treated with BUP-HD compared to BUP-LD. Severe ataxia or recumbency did not occur in any groups. CONCLUSIONS AND CLINICAL RELEVANCE: Epidurally administered bupivacaine, at a dose of 0.06 mg kg(-1), may provide satisfactory caudal epidural anti-nociception for longer-duration obstetric and surgical procedures. PMID- 23083507 TI - Postoperative stability after setback of sagittal split ramus osteotomy: a comparison of three techniques. AB - PURPOSE: The aim of the present study was to evaluate the postoperative stability after bilateral sagittal split ramus osteotomy (BSSRO) for the treatment of mandibular prognathism, in addition to a posterior ostectomy of the distal segment and mandibular angle resection. PATIENTS AND METHODS: The present retrospective study included patients with mandibular prognathism who were treated with BSSRO at Kangdong Sacred Heart Hospital from July 2007 to July 2011. We assessed the linear changes in the chin position in 17 patients with BSSRO only (control group), 10 with BSSRO and posterior ostectomy of the distal segment (experimental group 1), and 13 with BSSRO and mandibular angle resection (experimental group 2). A cephalogram was taken 2 weeks before surgery and 1 day and 2 months postoperatively. Differences among the groups were determined using 1-way analysis of variance. RESULTS: The demographic and surgical variables were similar among the groups. With regard to the changes observed 1 day to 2 months postoperatively, no statistically significant differences were found; however, the proportion of patients who had highly significant changes (>4 mm) was different. Point B moved forward and upward more than 4 mm in approximately 18% and 12% of patients, respectively, in the control group. However, such movement was not observed in any patient in the experimental group. CONCLUSIONS: Less postoperative instability was present in the experimental groups than in the control group. This might have resulted from the reduced tension in the pterygomasseteric sling and the minimized interference between the bony segments. Therefore, improved stability can be obtained regardless of the type of additional procedures. PMID- 23083508 TI - Implementing health promotion in schools: protocol for a realist systematic review of research and experience in the United Kingdom (UK). AB - BACKGROUND: School-based interventions and campaigns are used to promote health and address a wide variety of public health problems. Schools are considered to be key sites for the implementation of health promotion programmes for their potential to reach the whole population in particular age-groups and instil healthy patterns of behavior early in life. However, evidence for the effectiveness of school-based health promotion interventions is highly variable. Systematic reviews of the evidence of school-based interventions tend to be highly problem- or intervention- specific, thereby missing potential generic insights into implementation and effectiveness of such programmes across problems. METHODS/DESIGN: A realist systematic review will be undertaken to explain how, why and in what circumstances schools can provide feasible settings for effective health promotion programmes in the United Kingdom (UK). The review will be conducted in two phases. Phase 1 will identify programme theories about implementation (ideas about what enables or inhibits effective health promotion to be delivered in a school setting). Phase 2 will test the programme theories so that they can be challenged, endorsed and/or refined. A Review Advisory Group of education and health professionals will be convened to help identify and choose potential programme theories, provide a 'reality check' on the clarity and explanatory strength of the mechanisms to be tested, and help shape the presentation of findings to be usable by practitioners and decision-makers. Review findings will be disseminated through liaison with decision-makers, and voluntary and professional groups in the fields of education and health. PMID- 23083509 TI - Traumatic panniculitis with localized hypertrichosis: two new cases and considerations. PMID- 23083510 TI - miR-16 inhibits the proliferation and angiogenesis-regulating potential of mesenchymal stem cells in severe pre-eclampsia. AB - Pre-eclampsia is thought to be a systemic disease of maternal endothelial cell dysfunctions. miRNAs regulate various basic biological functions in cells, including stem cells. Mesenchymal stem cells exist in almost all tissues and are the key cellular source for tissue repair and regeneration. Our aims are to investigate whether miRNAs regulate MSCs in fetal-maternal interfaces to influence the pathogenesis of pre-eclampsia. The differential expression of miRNAs in decidua-derived mesenchymal stem cells of all patients with severe pre eclampsia (n = 20) and normal groups (n = 20) was first screened by microarray analysis and validated by quantitative real-time PCR analysis. The integrated bioinformatics analysis showed that miR-16 showed the highest number of connections in the miRNA GO network and the miRNA gene network. Moreover, over expressed miR-16 inhibited the proliferation and migration of decidua-derived mesenchymal stem cells and induced cell-cycle arrest by targeting cyclin E1. Interestingly, over-expression of miR-16 by decidua-derived mesenchymal stem cells reduced the ability of human umbilical vein endothelial cells to form blood vessels and reduced the migration of trophoblast cells. Furthermore, decidua derived mesenchymal stem cell-expressed endothelial growth factor VEGF-A was involved in migration of trophoblast cells and human umbilical vein endothelial cells as well as tube and network formation. Importantly, the levels of cyclin E1 and VEGF-A were negatively correlated with the level of miR-16 expression in decidua-derived mesenchymal stem cells from the patients with severe pre eclampsia. Together, these data suggest that the alteration of miR-16 expression in decidua-derived mesenchymal stem cells may be involved in the development of pre-eclampsia. PMID- 23083511 TI - FK506 biosynthesis is regulated by two positive regulatory elements in Streptomyces tsukubaensis. AB - BACKGROUND: FK506 (Tacrolimus) is an important immunosuppressant, produced by industrial biosynthetic processes using various Streptomyces species. Considering the complex structure of FK506, it is reasonable to expect complex regulatory networks controlling its biosynthesis. Regulatory elements, present in gene clusters can have a profound influence on the final yield of target product and can play an important role in development of industrial bioprocesses. RESULTS: Three putative regulatory elements, namely fkbR, belonging to the LysR-type family, fkbN, a large ATP-binding regulator of the LuxR family (LAL-type) and allN, a homologue of AsnC family regulatory proteins, were identified in the FK506 gene cluster from Streptomyces tsukubaensis NRRL 18488, a progenitor of industrial strains used for production of FK506. Inactivation of fkbN caused a complete disruption of FK506 biosynthesis, while inactivation of fkbR resulted in about 80% reduction of FK506 yield. No functional role in the regulation of the FK506 gene cluster has been observed for the allN gene. Using RT-PCR and a reporter system based on a chalcone synthase rppA, we demonstrated, that in the wild type as well as in fkbN- and fkbR-inactivated strains, fkbR is transcribed in all stages of cultivation, even before the onset of FK506 production, whereas fkbN expression is initiated approximately with the initiation of FK506 production. Surprisingly, inactivation of fkbN (or fkbR) does not abolish the transcription of the genes in the FK506 gene cluster in general, but may reduce expression of some of the tested biosynthetic genes. Finally, introduction of a second copy of the fkbR or fkbN genes under the control of the strong ermE* promoter into the wild type strain resulted in 30% and 55% of yield improvement, respectively. CONCLUSIONS: Our results clearly demonstrate the positive regulatory role of fkbR and fkbN genes in FK506 biosynthesis in S. tsukubaensis NRRL 18488. We have shown that regulatory mechanisms can differ substantially from other, even apparently closely similar FK506-producing strains, reported in literature. Finally, we have demonstrated the potential of these genetically modified strains of S. tsukubaensis for improving the yield of fermentative processes for production of FK506. PMID- 23083513 TI - Dynamics of turning sharpness influences freezing of gait in Parkinson's disease. AB - BACKGROUND: Despite the strong association between turning and Freezing of gait (FOG) in Parkinson's disease (PD), there has been little research to evaluate the specific turn characteristics (i.e. turn angles) that might contribute to freezing. Therefore, the purpose of the present study has three aims: examine the turning gait kinematics in freezers, evaluate the prevalence of FOG at different turn angles, and characterize whether the specific turning strategies employed by PD patients might be associated with turning deficits. METHODS: 20 PD participants (10 freezers, 10 non-freezers) and 10 healthy controls walked down a 6-m pathway and completed randomized trials of 0 degrees , 90 degrees , 120 degrees , and 180 degrees turns. Spatiotemporal gait kinematics were analysed using motion capture, while presence of FOG and classification of turn types (step out, crossover, or mixed strategy) were identified by two independent raters using video analysis. RESULTS: Freezers significantly increased step time variability and elicited more freezing episodes at sharper turns. Healthy controls consistently implemented a crossover turning strategy for all turning angles, while freezers tended to use a step out and mixed strategy especially during 180 degrees turns. This strategy in freezers was associated with a failure to increase step width (as healthy controls do). Additionally, in contrast to healthy controls and non-freezers, a dramatic decrease in velocity was identified in freezers for all turning angles. CONCLUSIONS: Freezing episodes are associated with a deficit in controlling gait timing. Additionally, freezers fail to increase step width despite employing a safer turn strategy. PMID- 23083512 TI - Epidemiology and neuropsychiatric manifestations of Young Onset Parkinson's Disease in the United States. AB - BACKGROUND: To determine the demographic distribution of Young Onset Parkinson's Disease (YOPD) in the United States and to quantify the burden of neuropsychiatric disease manifestations. METHODS: Cross sectional study of 3,459,986 disabled Americans, aged 30-54, who were receiving Medicare benefits in the year 2005. We calculated race and sex distributions of YOPD and used logistic regression to compare the likelihood of common and uncommon psychiatric disorders between beneficiaries with YOPD and the general disability beneficiary population, adjusting for race, age, and sex. RESULTS: We identified 14,354 Medicare beneficiaries with YOPD (prevalence = 414.9 per 100,000 disabled Americans). White men comprised the majority of cases (48.9%), followed by White women (34.7%), Black men (6.8%), Black women (5.0%), Hispanic men (2.4%), and Hispanic women (1.2%). Asian men (0.6%) and Asian women (0.4%) were the least common race-sex pairs with a YOPD diagnosis in this population (chi square, p < 0.001). Compared to the general population of medically disabled Americans, those with YOPD were more likely to receive medical care for depression (OR: 1.89, 1.83 1.95), dementia (OR: 7.73, 7.38-8.09), substance abuse/dependence (OR: 3.00, 2.99 3.01), and were more likely to be hospitalized for psychosis (OR: 3.36, 3.19 3.53), personality/impulse control disorders (OR: 4.56, 3.28-6.34), and psychosocial dysfunction (OR: 3.85, 2.89-5.14). CONCLUSIONS: Young Onset Parkinson's Disease is most common among white males in our study population. Psychiatric illness, addiction, and cognitive impairment are more common in YOPD than in the general population of disabled Medicare beneficiaries. These may be key disabling factors in YOPD. PMID- 23083514 TI - Polymerization kinetics and reactivity of alternative initiators systems for use in light-activated dental resins. AB - OBJECTIVES: The purpose of this study was to evaluate the reactivity and polymerization kinetics behavior of a model dental adhesive resin with water soluble initiator systems. METHODS: A monomer blend based on Bis-GMA, TEGDMA and HEMA was used as a model dental adhesive resin, which was polymerized using a thioxanthone type (QTX) as a photoinitiator. Binary and ternary photoinitiator systems were formulated using 1mol% of each initiator. The co-initiators used in this study were ethyl 4-dimethylaminobenzoate (EDAB), diphenyliodonium hexafluorophosphate (DPIHFP), 1,3-diethyl-2-thiobarbituric acid (BARB), p toluenesulfinic acid and sodium salt hydrate (SULF). Absorption spectra of the initiators were measured using a UV-Vis spectrophotometer, and the photon absorption energy (PAE) was calculated. The binary system camphorquinone (CQ)/amine was used as a reference group (control). Twelve groups were tested in triplicate. Fourier-transform infrared spectroscopy (FTIR) was used to investigate the polymerization reaction during the photoactivation period to obtain the degree of conversion (DC) and maximum polymerization rate (R(p)(max)) profile of the model resin. RESULTS: In the analyzed absorption profiles, the absorption spectrum of QTX is almost entirely localized in the UV region, whereas that of CQ is in the visible range. With respect to binary systems, CQ+EDAB exhibited higher DC and R(p)(max) values. In formulations that contained ternary initiator systems, the group CQ+QTX+EDAB was the only one of the investigated experimental groups that exhibited an R(p)(max) value greater than that of CQ+EDAB. The groups QTX+EDAB+DPIHFP and QTX+DPIHFP+SULF exhibited values similar to those of CQ+EDAB with respect to the final DC; however, they also exhibited lower reactivity. SIGNIFICANCE: Water-soluble initiator systems should be considered as alternatives to the widely used CQ/amine system in dentin adhesive formulations. PMID- 23083515 TI - Vitamin D inhibits the expression of interleukin-8 in human periodontal ligament cells stimulated with Porphyromonas gingivalis. AB - OBJECTIVE: Vitamin D has been known to be closely associated with periodontitis while the exact mechanisms remain unclear. The present study aimed to discover the effects of 1a,25-dihydroxyvitamin D3 (1,25D) on the expressions of interleukin (IL)-6 and IL-8 in human periodontal ligament cells (hPDLCs) stimulated with Porphyromonas gingivalis (P. gingivalis) W83. DESIGN: Primary cultures of hPDLCs from ten donors were established and the cells of passage four were treated with 1,25D or P. gingivalis individually or 1,25D combined with P. gingivalis. The levels of IL-6 and IL-8 protein in hPDLCs were detected with enzyme-linked immunosorbent assay (ELISA) and the mRNA levels were detected with real-time RT-PCR. RESULTS: P. gingivalis significantly promoted the protein expressions of IL-6 and IL-8. P. gingivalis at the multiplicity of infection (MOI) 100 exerted the strongest promotion effect on the IL-6 protein expression by 5.83-fold compared with the controls (2482.88+/-26.53pg/ml versus 425.80+/ 77.25pg/ml, P<0.0005) and the IL-8 protein expression by 12.39-fold (4965.81+/ 1072.55pg/ml versus 400.75+/-2.27pg/ml, P=0.005) in hPDLCs at 24h. At 48h, 10( 8)mol/L 1,25D had the best inhibition on the IL-8 protein expression in hPDLCs by 2.00-fold compared with the controls (100.76+/-21.11pg/ml versus 201.75+/ 18.15pg/ml, P<0.0005) and the IL-8 mRNA expression by 2.13-fold (P<0.0005). 10( 8)mol/L 1,25D combined with P. gingivalis (MOI 100) exerted the strongest inhibition effect on the IL-8 protein expression by 1.54-fold compared with P. gingivalis treatment alone (3077.33+/-210.04pg/ml versus 4738.24+/-1386.17pg/ml, P=0.018) and the IL-8 mRNA expression by 1.78-fold (P=0.012) in hPDLCs at 12h. 1,25D did not influence the expression of IL-6 in hPDLCs with or without P. gingivalis treatment. CONCLUSION: Vitamin D may potentially inhibit the periodontal inflammation induced by P. gingivalis partly by decreasing the IL-8 expression in hPDLCs. PMID- 23083516 TI - Clinical factors predictive of long-term survival in advanced non-small cell lung cancer. AB - PURPOSE: While the overall prognosis of non-molecularly selected advanced non small cell lung cancer (NSCLC) patients is poor, a subset of these patients has durable survival. We examined which clinical factors might be predictive for this favourable outcome. PATIENTS AND METHODS: Long-term NSCLC survivors (LTS, i.e. >2 years) were retrieved from all our out- and in-patient contacts in a 6 month period (March-August 2009). LTS records were compared with a group of short-term survivors (STS). Both baseline clinical factors (sex, age, smoking status, weight loss, performance status, co-morbidity, histological subtype, place and number of metastasis) and treatment-related features (number and type of therapeutic lines, response, duration of treatment-free interval) were compared. RESULTS: 31 LTS were retrieved (stage IV patients with potentially radical treatment options, e.g. solitary brain or adrenal metastasis, were excluded), and compared with 34 STS. In the LTS group, median survival was 53 months, with 47% of patients alive at 5 years, in the STS patients this was 9.7 months, with 24% alive at 1-year. Baseline factors had little predictive value, but response to 1st line therapy (P = 0.0001), response duration (P = 0.009), and the number of systemic lines (P = 0.0023) were of importance. CONCLUSION: These data confirm the existence of LTS in patients with advanced NSCLC. There are very little clinical factors at the time of diagnosis that help to distinguish future LTS from STS patients. Factors related to the effect of 1st line treatment are important, and further prospects of patients achieving a 2-year survival are in general quite good. PMID- 23083517 TI - Can we eliminate squamous cell carcinoma of the lung from testing of EML4-ALK fusion gene? PMID- 23083518 TI - Dysregulation of toll-like receptor (TLR) 2 expression on monocytes and upregulation of the frequency of T cells expressing TLR2 in patients with chronic hepatitis C virus infection. AB - Toll-like receptors (TLRs) initiate inflammatory responses that may play a role in disease progression in patients infected with hepatitis C virus (HCV). TLR2 and TLR4 surface expression were assessed on CD14(+) monocytes, CD4(+) and CD8(+) T cells in treatment naive patients with chronic HCV infection with fibrosis, without fibrosis, co-infected with human immunodeficiency virus (HIV), and in healthy controls. Increased expression of TLR2 was found on monocytes in HCV infected patients with fibrosis (p < 0.01), co-infected with HIV (p = 0.03), and possibly in patients without fibrosis (p = 0.07) when compared to controls. TLR2 positive CD4(+) and CD8(+) T cells were upregulated in patients with fibrosis only (p < 0.01). However, expression of TLR2 was not associated with T cell activation. TLR4 expression was similar in patients and healthy controls. In conclusion, TLR2 expression on monocytes and the frequency of T cells expressing TLR2 may contribute to disease progression in chronic HCV infection. PMID- 23083519 TI - Activation of the cholinergic anti-inflammatory system in peripheral blood mononuclear cells from patients with borderline personality disorder. AB - A case-control study including patients (n = 20) with Borderline Personality Disorder (BPD) and healthy controls (n = 33) was carried out. To avoid interferences of other clinical conditions on biological findings, patients were free of current major depressive episodes or substance dependence disorders, and had no life history of schizophrenia, bipolar or neuropsychiatric disorders. Patients were free of medication for at least two weeks at the time of the study. Studies carried out in peripheral mononuclear blood cells and plasma evidence a systemic inflammatory condition in unstable-impulsive BPD patients. Specifically, a significant increase in some intracellular components of two main pro inflammatory pathways such as iNOS and COX-2, as well as an increase in the plasma levels of the inflammatory cytokine IL1beta. Interestingly, patients have an increase in the protein expression of the anti-inflammatory subtype of nicotinic receptor alpha7nAChR. This finding may reflect a possible mechanism trying to maintain intracellular inflammation pathways under control. All together, these results describe an imbalanced, pro-inflammatory and oxidant phenotype in BPD patients independent of plasma cotinine levels. Although more scientific evidence is needed, the determination of multiple components of pro- and anti-inflammatory cellular pathways have interesting potential as biological markers for BPD and other generalized impulsive syndromes, specially data obtained with alpha7nAChR and its lack of correlation with plasma levels of nicotine metabolites. Their pharmacological modulation with receptor modulators can be a promising therapeutic target to take into account in mental health conditions associated with inflammatory or oxido/nitrosative consequences. Also, identifying at-risk individuals would be of importance for early detection and intervention in adolescent subjects before they present severe behavioural problems. PMID- 23083520 TI - Synthesis and micropatterning of photocatalytically reactive self-assembled monolayers covalently linked to Si(100) surfaces via a Si-C bond. AB - Selective generation of an amine-terminated self-assembled monolayer bound to silicon wafers via a silicon-carbon linkage was realized by photocatalytically reducing the corresponding azide-terminated, self-assembled monolayers (Az-SAMs). The Az-SAM was obtained by thermal deposition of 11-chloroundecene onto a hydrogen-terminated silicon wafer followed by nucleophilic substitution of the chloride with the azide ion in warm N,N'-dimethylformamide (DMF). The presence of the terminal azide group on the SAM was confirmed by reflection absorption infrared spectroscopy (RAIRS), by X-ray photoelectron spectroscopy (XPS), and by detecting the formation of a triazole upon reaction of the azide with an activated alkyne. The desired terminal amine groups were generated by photocatalytic reduction of the Az-SAM with cadmium selenide quantum dots (CdSe Qdots) using lambda > 400 nm. Analysis of the reduced SAM by XPS gave results that were consistent with those obtained with an amine-terminated surface obtained by reducing the Az-SAM with triphenylphosphine. To demonstrate the feasibility of using the Az-SAM for surface patterning, a sample was coated with adsorbed CdSe Qdots and exposed to the output of a diode laser at lambda = 407 nm through a micropatterned mask. Using a SEM, the pattern formed in this manner was revealed after removing the CdSe Qdots and subsequently adsorbing 10 nm gold nanoparticles (AuNPs) to the positively charged terminal-amine groups. The formation of the pattern by CdSe-photocatalyzed reduction of the azide demonstrates a novel route to create features by selective modification of organic monolayers on silicon wafers. PMID- 23083521 TI - Microcoils and microsamples in solid-state NMR. AB - Recent reports on microcoils are reviewed. The first part of the review includes a discussion of how the geometries of the sample and coil affect the NMR signal intensity. In addition to derivation of the well-known result that the signal intensity increases as the coil size decreases, the prediction that dilution of a small sample with magnetically inert matter leads to better sensitivity if a tiny coil is not available is given. The second part of the review focuses on the issues specific to solid-state NMR. They include realization of magic-angle spinning (MAS) using a microcoil and harnessing of such strong pulses that are feasible only with a microcoil. Two strategies for microcoil MAS, the piggyback method and magic-angle coil spinning (MACS), are reviewed. In addition, MAS of flat, disk-shaped samples is discussed in the context of solid-state NMR of small volume samples. Strong RF irradiation, which has been exploited in wide-line spectral excitation, multiple-quantum MAS (MQMAS), and dipolar decoupling experiments, has been accompanied by new challenges regarding the Bloch-Siegert effect, the minimum time resolution of the spectrometer, and the time scale of pulse transient effects. For a possible solution to the latter problem, recent reports on active compensation of pulse transients are described. PMID- 23083522 TI - Accuracy of whole-body FDG-PET and FDG-PET/CT in M staging of nasopharyngeal carcinoma: a systematic review and meta-analysis. AB - BACKGROUND: A meta-analysis was conducted to evaluate the accuracy of whole-body positron emission tomography (PET) or PET/CT in M staging of nasopharyngeal carcinoma (NPC). METHODS: Through a search of relevant English language studies from October 1996 to September 2011, pooled estimated sensitivity, specificity, positive likelihood ratios, negative likelihood ratios, and summary receiver operating characteristic (SROC) curves of whole-body PET or PET/CT in M staging of NPC were calculated. RESULTS: Three PET and 5 PET/CT studies were identified. The pooled sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of FDG-PET or PET/CT were 0.83 (95% confidence interval [CI], 0.77-0.88), 0.97 (95% CI, 0.95-0.98), 23.38 (95% CI, 16.22-33.69), and 0.19 (95% CI, 0.13-0.25), respectively. The area under curve was 0.9764 and Q* index estimate was 0.9307 for FDG-PET or PET/CT. CONCLUSION: Current evidence confirms the good diagnostic performance of the whole-body FDG-PET or PET/CT in M staging of NPC. PMID- 23083523 TI - Quantitative hepatic CT perfusion measurement: comparison of Couinaud's hepatic segments with dual-source 128-slice CT. AB - PURPOSE: To compare the quantitative liver computed tomography perfusion (CTP) differences among eight hepatic segments. MATERIALS AND METHODS: This retrospective study was based on 72 acquired upper abdomen CTP scans for detecting suspected pancreas tumor. Patients with primary or metastatic liver tumor, any focal liver lesions except simple cyst (<3 cm in diameter), history of liver operation or splenectomy, evidence of liver cirrhosis or invasion of portal vein were excluded. The final analysis included 50 patients (M:F=21:29, mean age=43.2 years, 15-76 years). Arterial liver perfusion (ALP), portal-venous perfusion (PVP), total hepatic perfusion (THP=ALP+PVP), and hepatic perfusion index (HPI) of each hepatic segment were calculated and compared by means of one way analysis of variance (ANOVA) and the Bonferonni correction method. RESULTS: Compared to hepatic segments 5, 6, 7 and 8, segments 2 and 3 showed a tendency of higher ALPs, lower PVPs, and higher HPIs, most of which were statistically significant (p<0.05). Hepatic segments 1 and 4 had higher mean values of ALP and HPI and lower mean values of PVP than segments 5, 6, 7 and 8 as well, although no significant differences were detected except for ALP and HPI for liver segments 1 and 7 (p=0.001 and 0.035 respectively), and ALP for liver segments 1 and 5 (p=0.039). Higher ALP and HPI were showed in hepatic segment 3 compared to segment 4 (p=0.000 and 0.000 respectively). No significant differences were found for THP among eight segments. CONCLUSIONS: Intra-hepatic perfusion differences exist in normal hepatic parenchyma especially between lateral sector (segments 2 and 3) and right lobe (segments 5, 6, 7 and 8). This might have potential clinical significance in liver-perfusion-related protocol design and result analysis. PMID- 23083524 TI - Brain stem and cerebellar atrophy in chronic progressive neuro-Behcet's disease. AB - PURPOSE: Chronic progressive neuro-Behcet's disease (CPNBD) resembles multiple sclerosis (MS) on patient background and image findings, and therefore is difficult to diagnose. The purpose is to identify the characteristic magnetic resonance imaging (MRI) findings of CPNBD and to clarify the differences between the MRI findings of CPNBD and those of MS. MATERIALS AND METHODS: The subjects consist of a CPNBD group (n=4; 1 male and 3 females; mean age, 51 y.o.), a MS group (n=19; 3 males and 16 females; mean age, 45 y.o.) and a normal control group (n=23; 10 males and 13 females; mean age, 45 y.o.). Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were retrospectively evaluated in each subjects. In middle sagittal brain MR images, the prepontine distance was measured as an indirect index of brain stem and cerebellar atrophy and the pontine and mesencephalic distance was measured as a direct index of brain stem atrophy. These indexes were statistically analyzed. RESULTS: Brain stem atrophy, cerebellar atrophy, and leukoencephalopathy were seen in all CPNBD cases. Prepontine distance was significantly different between the CPNBD group and the MS group (p<0.05), and between the CPNBD group and the normal control group (p<0.001). Pontine and mesencephalic distance were significantly different between the CPNBD group and the MS group (p<0.001, p<0.01 respectively), and between the CPNBD group and the normal control group (p<0.001). CONCLUSIONS: Chronic progressive neuro-Behcet's disease should be considered in patients with brain stem and cerebellar atrophy in addition to leukoencephalopathy similar to that seen in multiple sclerosis. PMID- 23083525 TI - Recent combined hormonal contraceptives (CHCs) and the risk of thromboembolism and other cardiovascular events in new users. AB - BACKGROUND: Combined hormonal contraceptives (CHCs) place women at increased risk of venous thromboembolic events (VTEs) and arterial thrombotic events (ATEs), including acute myocardial infarction and ischemic stroke. There is concern that three recent CHC preparations [drospirenone-containing pills (DRSPs), the norelgestromin-containing transdermal patch (NGMN) and the etonogestrel vaginal ring (ETON)] may place women at even higher risk of thrombosis than other older low-dose CHCs with a known safety profile. STUDY DESIGN: All VTEs and all hospitalized ATEs were identified in women, ages 10-55 years, from two integrated health care programs and two state Medicaid programs during the time period covering their new use of DRSP, NGMN, ETON or one of four low-dose estrogen comparator CHCs. The relative risk of thrombotic and thromboembolic outcomes associated with the newer CHCs in relation to the comparators was assessed with Cox proportional hazards regression models adjusting for age, site and year of entry into the study. RESULTS: The hazards ratio for DRSP in relation to low-dose estrogen comparators among new users was 1.77 (95% confidence interval 1.33-2.35) for VTE and 2.01 (1.06-3.81) for ATE. The increased risk of DRSP was limited to the 10-34-year age group for VTE and the 35-55-year group for ATE. Use of the NGMN patch and ETON vaginal ring was not associated with increased risk of either thromboembolic or thrombotic outcomes. CONCLUSIONS: In new users, DRSP was associated with higher risk of thrombotic events (VTE and ATE) relative to low dose estrogen comparator CHCs, while the use of the NGMN patch and ETON vaginal ring was not. PMID- 23083526 TI - Evidence-based guidance on Selected Practice Recommendations for Contraceptive Use: identification of research gaps. PMID- 23083527 TI - Effect of missed combined hormonal contraceptives on contraceptive effectiveness: a systematic review. AB - BACKGROUND: Combined hormonal contraceptives (CHCs) are popular methods of reversible contraception in the United States, but adherence remains an issue as reflected in their lower rates of typical use effectiveness. The objective of this systematic review was to evaluate evidence on the effect of missed CHCs on pregnancy rates as well as surrogate measures of contraceptive effectiveness (e.g., ovulation, follicular development, changes in hormone levels, cervical mucus quality). STUDY DESIGN: We searched the PubMed database for peer-reviewed articles published in any language from database inception through April 2012. We included studies that examined measures of contraceptive effectiveness during cycles with extended hormone-free intervals or nonadherence (e.g., omission of pills, delayed patch replacement) on days not adjacent to the hormone-free interval. We used standard abstract forms and grading systems to summarize and assess the quality of the evidence. RESULTS: The search strategy identified 1387 articles, of which 26 met our study selection criteria. There is wide variability in the amount of follicular development and risk of ovulation among women who extended the pill-free interval to 8-14 days; in general, the risk of ovulation was low, and among women who did ovulate, cycles were usually abnormal (i.e., low progesterone levels, small follicles and/or poor cervical mucus) (Level I, good, indirect to Level II-3, fair, indirect). Studies of women who missed one to four consecutive pills or 1-3 consecutive days of delay before patch replacement at times other than adjacent to the hormone-free interval reported little follicular activity and low risk of ovulation (Level I, fair, indirect to Level II-3, poor, indirect). Studies comparing 30 mcg versus 20 mcg mc ethinyl estradiol pills showed more follicular activity when 20 mcg ethinyl estradiol pills were missed (Level I, good, indirect). CONCLUSION: Most of the studies in this evidence base relied on surrogate measures of pregnancy risk and ranged in quality. For studies providing indirect evidence on the effects of missed CHCs, it is unclear how differences in surrogate measures correspond to pregnancy risk. Fewer studies examined the transdermal patch and vaginal ring than combined oral contraceptives. PMID- 23083528 TI - Perceived susceptibility to pregnancy and its association with safer sex, contraceptive adherence and subsequent pregnancy among adolescent and young adult women. AB - BACKGROUND: The study was conducted to examine the hypotheses that adolescent and young adult women who perceived they are susceptible to pregnancy when birth control is not used are less likely to practice unsafe sex, discontinue oral contraception (OC) and become pregnant during a 12-month follow-up period. STUDY DESIGN: We conducted secondary analyses using data collected for a randomized controlled trial on OC adherence among 1155 low-income women 16-24 years of age. Demographics, lifestyle variables, perceived susceptibility to pregnancy assessed at baseline, and data on OC and condom use and pregnancy status collected during 12 months of follow-up were used for the analyses. RESULTS: Overall, 62.3% of women accurately understood the risks of pregnancy without using any birth control method. However, perceived susceptibility was not associated with OC continuation [odds ratio (OR) 0.94, 95% confidence interval (CI) 0.79-1.11], condom use at last sexual intercourse (OR 1.02, 95% CI 0.84-1.24), dual method use (OR 1.17, 95% CI 0.92-1.48) and subsequent pregnancy (hazards ratio 1.08, 95% CI 0.77-1.49) during the 12-month follow-up period. CONCLUSIONS: Perceived susceptibility to pregnancy, an important component of the health belief model, does not seem to have any impact on use of birth control methods, safer sex or rate of subsequent pregnancy among low-income adolescent and young adult women. PMID- 23083529 TI - Cilostazol blocks pregnancy in naturally cycling mice. AB - BACKGROUND: Administration of a phosphodiesterase three enzyme inhibitor (PDE3-I) in rodents and primates results in ovulation of immature oocytes. Concerns regarding inhibition of PDE3 enzymes that are expressed in heart and blood vessels discouraged further development of PDE3-Is as nonsteroidal contraceptives. Cilostazol (CLZ) is a PDE3A-I that is approved for medical indications in humans and has an additional effect of adenosine uptake inhibition that is believed to counterbalance the undesirable outcomes resulting from PDE inhibition. STUDY DESIGN: Cycling mature female mice were treated with 7.5 or 15 mg CLZ, dimethyl sulfoxide or water beginning on the day of proestrus. Animals were placed with fertility-proven males after 3 days of treatment. Treatments were continued until 1 day after detection of a vaginal plug, and then females were monitored up to 30 days postbreeding to assess the effects of the compounds on pregnancy. Each of the treated female with CLZ was then remated with the same male and again monitored up to 30 days. RESULTS: None of the CLZ-treated mice produced offspring, whereas all of the control animals maintained pregnancy and delivered normal pups (p<.0001). Remating of the previously CLZ-treated females exhibited normal pregnancies and gave birth to live offspring that were not different from the controls. CONCLUSION: CLZ is a potential nonsteroidal contraceptive agent that merits further evaluation in other mammals. PMID- 23083530 TI - Continuation of copper-containing intrauterine devices at 6 months. AB - BACKGROUND: Intrauterine devices (IUDs) are highly effective at preventing pregnancy and cost-effective. Suboptimal continuation of IUDs places women at risk of unintended pregnancy. Little is known about prevalence or predictors of discontinuation of IUDs within the first 6 months. STUDY DESIGN: A retrospective cohort analysis was conducted among 306 family planning patients who had a CuT380A IUD inserted from November 2008-August 2011. Rates of continuation among 283 users were calculated using survival analyses, and predictors of removal within 6 months of insertion were assessed using logistic regression. RESULTS: Among 306 IUD insertions, 13 (4.2%) full or partial expulsions occurred within the first 6 months: 9 (10.7%) among nulliparous and 4 (2.0%) among parous women (chi-square, p<.001). In the first 6 months, four (1.3%) pregnancies occurred among women without prior removal or expulsion of the device (unadjusted Pearl Index: 2.61 per 100 woman-years at 6 months), all among parous women. Of 283 women in continuation analyses, 26% were under 20 years old and 29% nulliparous. Most (84%) received health education specific to IUDs before insertion. Overall, 11% had their IUD removed within 6 months of insertion. In an adjusted logistic regression model, women who did not receive health education were significantly more likely (Adjusted Odds Ratio=3.37, 95% confidence interval: 1.35-8.39) to have a removal within 6 months, but no significant association was found for age, race/ethnicity or parity. CONCLUSION: Early discontinuation of IUDs was prevalent but lower among women who received method-specific health education. PMID- 23083531 TI - Physicochemical and biological factors controlling water column metabolism in Sundarbans estuary, India. AB - BACKGROUND: Sundarbans is the single largest deltaic mangrove forest in the world, formed at estuarine phase of the Ganges - Brahmaputra river system. Primary productivity of marine and coastal phytoplankton contributes to 15% of global oceanic production. But unfortunately estuarine dynamics of tropical and subtropical estuaries have not yet received proper attention in spite of the fact that they experience considerable anthropogenic interventions and a baseline data is required for any future comparison. This study is an endeavor to this end to estimate the primary productivity (gross and net), community respiration and nitrification rates in different rivers and tidal creeks around Jharkhali island, a part of Sundarbans estuary surrounded by the mangrove forest during a period of three years starting from November'08 to October'11. RESULTS: Various physical and chemical parameters of water column like pH, temperature, conductivity, dissolved oxygen, turbidity, suspended particulate matter, secchi disc index, tidal fluctuation and tidal current velocity, standing crop and nutrients were measured along with water column productivity. Relationship of net water column productivity with algal biomass (standing crop), nutrient loading and turbidity were determined experimentally. Correlations of bacterial abundance with community respiration and nitrification rates were also explored. Annual integrated phytoplankton production rate of this tidal estuary was estimated to be 151.07 gC m-2 y-1. Gross primary productivity showed marked inter annual variation being lowest in monsoon and highest in postmonsoon period. CONCLUSION: Average primary production was a function of nutrient loading and light penetration in the water column. High aquatic turbidity, conductivity and suspended particulate matter were the limiting factors to attenuate light penetration with negative influence on primary production. Community respiration and nitrification rates of the estuary were influenced by the bacterial abundance. The estuary was phosphorus limited in postmonsoon whereas nitrogen limited in premonsoon and monsoon period. High algal biomass and primary productivity indicated the estuary to be in eutrophic state in most of the time throughout the year. Our study also indicated a seasonal shifting between autotrophic and heterotrophic conditions in Sundarban estuarine ecosystem and it is a tropical, well mixed (high tidal influx) and marine dominated (no fresh water connection) system. PMID- 23083532 TI - The role of major vault protein (MVP) in drug resistance. PMID- 23083533 TI - Longitudinal relationships between subjective fatigue, cognitive function, and everyday functioning in old age. AB - BACKGROUND: The present study examined the prospective relationships between subjective fatigue, cognitive function, and everyday functioning. METHODS: A cohort study with secondary data analysis was conducted using data from 2,781 community-dwelling older adults without dementia who were enrolled to participate in the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) randomized intervention trial. Measures included demographic and health information at baseline, and annual assessments of subjective fatigue, cognitive function (i.e. speed of processing, memory, and reasoning), and everyday functioning (i.e. everyday speed and everyday problem-solving) over five years. RESULTS: Four distinct classes of subjective fatigue were identified using growth mixture modeling: one group complaining fatigue "some of the time" at baseline but "most of the time" at five-year follow-up (increased fatigue), one complaining fatigue "a good bit of the time" constantly over time (persistent fatigue), one complaining fatigue "most of the time" at baseline but "some of the time" at five-year follow-up (decreased fatigue), and the fourth complaining fatigue "some of the time" constantly over time (persistent energy). All domains of cognitive function and everyday functioning declined significantly over five years; and the decline rates, but not the baseline levels, differed by the latent class of subjective fatigue. Except for the decreased fatigue class, there were different degrees of significant associations between the decline rates of subjective fatigue and all domains of cognitive function and everyday functioning in other classes of subjective fatigue. CONCLUSION: Future interventions should address subjective fatigue when managing cognitive and functional abilities in community-dwelling older adults. PMID- 23083535 TI - [A new column on calcium metabolism and its disorders]. PMID- 23083534 TI - Molecular phylogeny of unikonts: new insights into the position of apusomonads and ancyromonads and the internal relationships of opisthokonts. AB - The eukaryotic supergroup Opisthokonta includes animals (Metazoa), fungi, and choanoflagellates, as well as the lesser known unicellular lineages Nucleariidae, Fonticula alba, Ichthyosporea, Filasterea and Corallochytrium limacisporum. Whereas the evolutionary positions of the well-known opisthokonts are mostly resolved, the phylogenetic relationships among the more obscure lineages are not. Within the Unikonta (Opisthokonta and Amoebozoa), it has not been determined whether the Apusozoa (apusomonads and ancyromonads) or the Amoebozoa form the sister group to opisthokonts, nor to which side of the hypothesized unikont/bikont divide the Apusozoa belong. Aiming at elucidating the evolutionary tree of the unikonts, we have assembled a dataset with a large sampling of both organisms and genes, including representatives from all known opisthokont lineages. In addition, we include new molecular data from an additional ichthyosporean (Creolimax fragrantissima) and choanoflagellate (Codosiga botrytis). Our analyses show the Apusozoa as a paraphyletic assemblage within the unikonts, with the Apusomonadida forming a sister group to the opisthokonts. Within the Holozoa, the Ichthyosporea diverge first, followed by C. limacisporum, the Filasterea, the Choanoflagellata, and the Metazoa. With our data-enriched tree, it is possible to pinpoint the origin and evolution of morphological characters. As an example, we discuss the evolution of the unikont kinetid. PMID- 23083536 TI - Chronobiological variation in the occurrence of Tako-tsubo cardiomyopathy: experiences of two tertiary cardiovascular centers. AB - BACKGROUND: There have been few data to review and analyze the temporal preference of the onset of Tako-tsubo cardiomyopathy (TTC). Aim of this study was to investigate chronobiological variations in the occurrence of TTC and changes of these variations according to age and gender. METHODS: One hundred and thirty seven patients were enrolled from our TTC registry database from January 2004 to December 2010 in Korea. RESULTS: The median age of the entire study population was 59 years (inter-quartile range 53-72 years). The majority of patients were women (n = 101, 74%). The onset of TTC differed as a function of season (P = .001), with the peak in July and the nadir in March. Events were most frequent in summer (n = 53%, 38.7%) and least so in winter (n = 26, 19%, chi-square = 13.92, P = .003). TTC was most frequent in the morning (n = 56, 40.9%) and least so at night (n = 22, 16.1%, chi-square = 21.98, P = .001). Also, TTC was most frequent on Monday (n = 34, 24.8%) and least so on Saturday (n = 7, 5.1%, chi-square = 30.44, P = .001). Stressor pattern, age and gender do not influence these increases of occurrence in summer, on Monday, and in the morning of TTC. CONCLUSIONS: TTC seems to exhibit a temporal variation of occurrence with preferred peaks during morning, Monday, and summer. Stressor pattern, age and gender do not influence these temporal patterns of the occurrence of TTC. Further studies are needed to investigate the potential link between chronobiological variations of TTC onset and underlying pathophysiologic mechanisms. PMID- 23083537 TI - Caring for heart transplant recipients: The lived experience of primary caregivers. AB - OBJECTIVE: To understand the experience of primary caregivers of heart transplant recipients. METHODS: A phenomenological approach was used to understand the caregivers' experience of caring for a heart transplant patient. In-depth interviews were conducted with 11 caregivers, in a Brazilian hospital, from December 2008 to March 2009. RESULTS: Following the transplant, caregivers' lives change drastically; their priority becomes providing care for their relative. Despite successful transplant results, the uncertainty about future remains, generating permanent distress. Anxiety is exacerbated by familial or economic problems and, consequently, many participants turn to their local communities for support. Some caregivers learn from the experience and plan return to regular activities. Others feel helpless, unable to overcome personal losses and difficulties. CONCLUSIONS: Nurses are ideally placed to lead the way by providing family-centered support and education for caregivers of heart recipients. Listening to the concerns of family caregivers seems to be an essential aspect of effective interventions. PMID- 23083538 TI - Phrenic nerve injury and diaphragmatic paralysis following pacemaker pulse generator replacement. AB - Diaphragmatic paralysis (DP) is a common condition. It can be unilateral or bilateral and the diagnosis is usually based on a clinical and radiological findings. Bilateral diaphragmatic paralysis is usually symptomatic with dyspnea and acute respiratory failure while unilateral diaphragmatic paralysis is typically asymptomatic and when present, symptoms usually depend on the presence of underlying pulmonary or neurologic disease. DP can be the result of various chest conditions that affect the phrenic nerve such as tumors, vascular abnormalities or traumatic incidents during surgery as well as blunt or penetrating chest or neck injuries. We report a unique case of phrenic nerve injury and unilateral diaphragmatic paralysis secondary to pacemaker pulse generator replacement that was successfully treated with diaphragmatic plication. PMID- 23083541 TI - Estimating the burden of healthcare-associated infections caused by selected multidrug-resistant bacteria Finland, 2010. AB - BACKGROUND: Knowledge of the burden of healthcare-associated infections (HAI) and antibiotic resistance is important for resource allocation in infection control. Although national surveillance networks do not routinely cover all HAIs due to multidrug-resistant bacteria, estimates are nevertheless possible: in the EU, 25,000 patients die from such infections annually. We assessed the burden of HAIs due to multidrug-resistant bacteria in Finland in 2010. METHODS: By combining data from the National Infectious Disease Registry on the numbers of bacteremias caused by Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Pseudomonas aeruginosa and Acinetobacter spp., and susceptibility data from the National Antimicrobial Resistance Network and the Finnish Hospital Infection Program, we assessed the numbers of healthcare-associated bacteremias due to selected multidrug-resistant bacteria. We estimated the number of pneumonias, surgical site and urinary tract infections by applying the ratio of these infections in the first national prevalence survey for HAI in 2005. Attributable HAI mortality (3.2%) was also derived from the prevalence survey. RESULTS: The estimated annual number of the most common HAIs due to the selected multidrug-resistant bacteria was 2804 (530 HAIs per million), 6% of all HAIs in Finnish acute care hospitals. The number of attributable deaths was 89 (18 per million). CONCLUSIONS: Resources for infection control should be allocated not only in screening and isolation of carriers of multidrug-resistant bacteria, even when they are causing a small proportion of all HAIs, but also in preventing all clinical infections. PMID- 23083542 TI - A systematic review of the pharmacological management of aortic root dilation in Marfan syndrome. AB - BACKGROUND: Marfan syndrome causes aortic dilation leading to dissection and death. This systematic review examined the use of beta-blockers, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers in the management of aortic dilation in this disease. METHODS: We searched four databases--Medline, EMBASE, Web of Science, and The Cochrane Central Register of Controlled Trials--two conference proceedings, references of retrieved articles, and a web-based trial registry. The primary outcome was mortality. The secondary outcomes were aortic dissection, need for elective surgical repair, change in aortic dilation, and adverse events. Two reviewers selected studies, abstracted data, and assessed study quality. Meta-analyses were not performed because of study heterogeneity. RESULTS: A total of 18 studies were included--12 completed and six in progress. Of the completed studies, three before-and-after treatment, one prospective cohort, three retrospective cohorts, and two randomised control trials examined beta-blockers; one randomised and one non-randomised trial examined angiotensin-converting enzyme inhibitors; and one retrospective cohort study examined angiotensin II receptor blockers. Studies in progress are all randomised trials. Mortality was not impacted by drug therapy, although studies were underpowered with respect to this outcome. All drug classes were associated with a decrease in the rate of aortic dilation (angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers >beta-blockers); none had an impact on other secondary outcomes. CONCLUSIONS: On the basis of existing evidence, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers slow the progression of aortic dilation in Marfan syndrome. Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may have more effect than beta-blockers; however, more methodologically rigorous studies currently in progress are needed to evaluate the impact of drug therapy on clinical outcomes. PMID- 23083540 TI - Metformin alters the insulin signaling pathway in ischemic cardiac tissue in a swine model of metabolic syndrome. AB - OBJECTIVE: The purpose of this study is to evaluate the effect of metformin on insulin signaling in ischemic cardiac tissue in a swine model of metabolic syndrome. METHODS: Ossabaw miniswine were fed either a regular diet (Ossabaw control [OC]) or a hypercaloric diet (Ossabaw high cholesterol [OHC], Ossabaw high cholesterol with metformin [OHCM]). After 9 weeks, all animals underwent placement of an ameroid constrictor to the left circumflex artery to induce chronic ischemia. OHC animals were continued on a hypercaloric diet alone; the OHCM group was supplemented with metformin in addition to the hypercaloric diet. Seven weeks after ameroid placement, myocardial perfusion was measured and ischemic cardiac tissue was harvested for protein expression and histologic analysis. RESULTS: The OHC and OHCM groups had significantly higher body mass indices and serum insulin levels compared with the OC group. There were no differences in myocardial perfusion in the chronically ischemic territories. In the OHC group, there was upregulation of both an activator of insulin signaling insulin receptor substrate 1, and an inhibitor of insulin signaling phosphorylated insulin receptor substrate 2. In the OHCM group, there was upregulation of activators of insulin signaling including phosphorylated adenosine monophosphate-activated protein kinase alpha, protein kinase B, phosphorylated protein kinase B, mammalian target of rapamycin, phosphorylated mammalian target of rapamycin, and phosphoinostitide 3-kinase, and upregulation of inhibitors including phosphorylated insulin receptor substrate 1, phosphorylated insulin receptor substrate 2, and retinol binding protein 4. Histologic analysis demonstrated increased expression of glucose transporter 1 at the plasma membrane in the OHCM group, but there was no difference in cardiomyocyte glycogen stores among groups. CONCLUSIONS: Metformin treatment in the context of metabolic syndrome and myocardial ischemia dramatically upregulates the insulin signaling pathway in chronically ischemic myocardium, which is at the crossroads of known metabolic and survival benefits of metformin. PMID- 23083543 TI - A sibling-controlled, prospective study of outcomes at home and school in children with severe congenital heart disease. AB - OBJECTIVES: The objectives of this study were to compare behaviour problems and competencies, at home and school, in 7-year-old children with congenital heart disease with a sibling control group, to examine the prospective determinants of outcome from infancy, and to explore whether any gains were maintained in our sub group of children who had participated in a previous trial of psychological interventions in infancy. METHODS: A total of 40 children who had undergone surgery to correct or palliate a significant congenital heart defect in infancy were compared (Child Behavior Checklist) with a nearest-age sibling control group (18 participants). Comparisons were made between sub-groups of children and families who had and had not participated in an early intervention trial. RESULTS: Problems with attention, thought and social problems, and limitations in activity and school competencies, were found in comparison with siblings. Teacher reports were consistent with parents, although problems were of a lower magnitude. Disease, surgical, and neurodevelopmental functioning in infancy were related to competence outcomes but not behaviour problems. The latter were mediated by family and maternal mental health profiles from infancy. Limited, but encouraging, gains were maintained in the sub-group that had participated in the early intervention programme. CONCLUSIONS: The present study is strengthened by its longitudinal design, use of teacher informants, and sibling control group. The patterns of problems and limitations discerned, and differential determinants thereof, have clear implications for interventions. We consider these in the light of our previously reported intervention trial with this sample and current outcomes at the 7-year follow-up. PMID- 23083544 TI - Assessment of the apparent diffusion coefficient (ADC) of normal breast tissue during the menstrual cycle at 3T using image segmentation. PMID- 23083545 TI - Lessons learned from MR-guided breast-biopsy. PMID- 23083546 TI - High resolution images of the breast. PMID- 23083547 TI - MR spectroscopy in the breast clinic is improving. PMID- 23083548 TI - What is new in breast MRI spectroscopy. PMID- 23083549 TI - Breast MRI using SWeep Imaging with Fourier Transform (SWIFT). PMID- 23083550 TI - Molecular and functional ultrasound imaging of breast tumors. PMID- 23083551 TI - MRI for treatment planning: a necessity. PMID- 23083552 TI - Can breast MRI facilitate decision-making in equivocal mammography and ultrasonography findings? PMID- 23083553 TI - Disseminated tumor cells: a clinical help or over-information? PMID- 23083554 TI - Screening women at intermediate risk: harm or charm? PMID- 23083555 TI - MRgFUS: from diagnosis to therapy. PMID- 23083556 TI - Unenhanced MRI at 3T in neo-adjuvant chemotherapy. PMID- 23083557 TI - Theranostic imaging of cancer. PMID- 23083558 TI - Do we really need new contrast agents for MR-mammography? PMID- 23083559 TI - L-COSY of breast cancer at 3T. PMID- 23083560 TI - Post surgery: blood, scar, clips etc. How to get out of it? PMID- 23083561 TI - Clinical role of detecting circulating tumor cells. PMID- 23083562 TI - 3D ultrasound computer tomography of the breast: a new era? AB - A promising candidate for imaging of breast cancer is ultrasound computer tomography (USCT). The main advantages of a USCT system are simultaneous recording of reproducible reflection, attenuation and speed of sound volumes, high image quality, and fast data acquisition. The here presented 3D USCT prototype realizes for the first time the full potential of such a device. It is ready for a clinical study. Full volumes of a breast can be acquired in four minutes. In this paper images acquired with a clinical breast phantom are presented. The resolution and imaged details of the reflectivity reconstruction are comparable to a 3 tesla MRI volume of the phantom. Image quality and resolution is isotropic in all three dimensions, confirming the successful implementation experimentally. PMID- 23083564 TI - Screening high risk women with MRI alone? PMID- 23083563 TI - Preoperative MRI: did randomized trials conclude the debate? PMID- 23083565 TI - Positron emission mammography: better than magnetic resonance mammography? PMID- 23083566 TI - Whole-body MR or PET-CT? PMID- 23083567 TI - CEST-imaging: A new contrast in MR-mammography by means of chemical exchange saturation transfer. PMID- 23083568 TI - Neoadjuvant chemotherapy--monitoring: clinical examination, ultrasound, mammography, MRI, elastography: only one, only few or all? PMID- 23083569 TI - Dedicated PET device for breast PET and MRI/PET correlations. PMID- 23083570 TI - Clinical results of DTI. PMID- 23083571 TI - Supine breast MRI and assessment of future clinical applications. PMID- 23083572 TI - Tomosynthesis in X-ray: proven additional value? PMID- 23083573 TI - Symmetry-based detection of ductal carcinoma in situ in breast MRI. PMID- 23083574 TI - Molecular imaging of breast cancer lymph node metastasis. PMID- 23083575 TI - Contrast enhanced spectral mammography: better than MRI? PMID- 23083576 TI - What is specific in hereditary breast cancer? High T2 signal intensity as a new semeiotic pattern? PMID- 23083577 TI - Can we use MR-mammography to predict nodal status? PMID- 23083578 TI - Exploiting sparsity in x-f space for higher spatiotemporal resolution in breast dynamic contrast-enhanced (DCE)-MRI. PMID- 23083579 TI - Stem cells of the mammary epithelium and their role in breast cancer. PMID- 23083580 TI - Kinetic characterization of non-mass lesions on breast MRI using manual and computer assisted methods. PMID- 23083581 TI - The fibrotic focus in MR-mammography. PMID- 23083582 TI - Extramammary findings in T2-weighted MR breast images. PMID- 23083583 TI - MALDI-imaging: what can be expected? PMID- 23083584 TI - Diffusion weighted imaging: a long way to clinical routine. PMID- 23083585 TI - MR galactography: is it necessary? PMID- 23083586 TI - MRI in B3 lesions, low grade DCIS, high DCIS: is MR selecting the dangerous cases? PMID- 23083587 TI - MRI in high risk women: benefits and problems. PMID- 23083589 TI - MRI before initial surgery outside of clinical trials: the real world! PMID- 23083590 TI - Breast MRI without gadolinium: utility of 3D DESS, a new 3D diffusion weighted gradient-echo sequence. PMID- 23083591 TI - Co-registration of MR-mammography and X-ray mammography. PMID- 23083592 TI - MR-mammography: high sensitivity but low specificity? New thoughts and fresh data on an old mantra. PMID- 23083593 TI - Potential of MR-mammography for identification of intraductual papillomas. PMID- 23083594 TI - MRI guidelines: what a surgeon needs to know. PMID- 23083595 TI - Clinical value of second-look ultrasound: is there a way to make it objective? PMID- 23083596 TI - A simple and robust classification tree for differentiation between benign and malignant lesions in MR-mammography. PMID- 23083597 TI - The role of sonography in staging invasive breast cancer. PMID- 23083598 TI - Advantages and drawbacks of breast DTI. PMID- 23083599 TI - A unifying theory of carcinogenesis, and why targeted therapy doesn't work. PMID- 23083600 TI - Minimally invasive cancer therapy using polyhydroxy fullerenes. PMID- 23083601 TI - Accelerated breast MRI with compressed sensing. PMID- 23083602 TI - Metals in MR-mammography: how to deal with it? PMID- 23083603 TI - Breast MR for intraductal masses. PMID- 23083604 TI - MR-spectroscopy at 1.5 tesla and 3 tesla. Useful? A systematic review and meta analysis. PMID- 23083605 TI - Potential of near infrared fluorescence optical imaging in diagnostic radiology. PMID- 23083606 TI - Updated breast MRI Lexicon. PMID- 23083607 TI - Integrated quantitative DCE-MRI and DW-MRI to characterize breast lesions. PMID- 23083608 TI - Malignant transformation: the role of MRS. PMID- 23083609 TI - Economic aspects of MR-mammography in dense breasts. PMID- 23083610 TI - Focal transitional mastitis in MR-mammography: preliminary findings. PMID- 23083611 TI - The "perirenal edema sign" as a hint towards hypertension--preliminary observations on cofindings in MRI breast cancer staging. PMID- 23083612 TI - It is not all in the CAD or BI-RADS. PMID- 23083613 TI - Wish list for future features of breast MRI computer aided evaluation. PMID- 23083614 TI - Diffusion weighted imaging (DWI) of the breast: ready for clinical practice? PMID- 23083615 TI - Clinical indications: what is the evidence? PMID- 23083616 TI - Hyperpolarized C-13 studies of cancer metabolism in animal models. Hype or real? PMID- 23083617 TI - Second-look ultrasound: only for biopsy or more? PMID- 23083618 TI - What to do with B3 lesions at needle biopsy. PMID- 23083619 TI - New insights from breast pathology: should we consider low grade DCIS NOT a cancer? PMID- 23083620 TI - Reproducibility of breast biopsy. PMID- 23083621 TI - Fat necrosis in the breast after reconstruction with transverse rectus abdominis myocutaneous flap: MRI features. PMID- 23083622 TI - Do we really need contrast agents? PMID- 23083623 TI - Stroke survivors' experiences of the fundamentals of care: a qualitative analysis. AB - BACKGROUND: Managing the fundamentals of care (e.g. elimination, personal hygiene, eating,) needs to be more explicitly addressed within the patient centred care discourse. It is not possible to investigate issues of patient dignity and respect without acknowledging these basic physical needs. While the literature on caring for people with a stroke is extensive, no studies to date have described stroke survivors' experiences of all of these fundamentals during the in-hospital phase of their care. DESIGN: Secondary analysis of qualitative data grounded in interpretative phenomenology Participants and settings: Fifteen stroke survivors with in-hospital experiences from multiple healthcare settings and healthcare professionals across the United Kingdom were included. METHOD: A secondary thematic analysis of primary narrative interview data from stroke survivors. RESULTS: Survivors of strokes have vivid and often distressing recollections of their experiences of the fundamentals of care. For every description of a physical need (elimination, eating and drinking, personal hygiene) there where lucid accounts of the psychosocial and emotional impact (humiliation, distress, lack of dignity, recovery, confidence). Linked to the somatic and emotional dimensions were narratives around the relationship between the patient and the carer (nurse, doctor, allied health professional). Positive recollections of the fundamentals of care were less evident than more distressing experiences. Consistent features of positive experiences included: stroke survivors describing how the physical, psychosocial and relational dimensions of care were integrated and coordinated around their particular need. They reported feeling involved in setting achievable targets to regain control of their bodily functions and regain a sense of personal integrity and sense of self. Sociological constructs such as biographical disruption and loss of self were found to be relevant to stroke survivors' experiences. Indeed, such constructs may be more linked to the disruption of such fundamental activities rather than the experience of the illness itself. CONCLUSIONS: We recommend more practical and integrated approaches be taken around understanding and meeting the physical, psychosocial and relational needs of patients in hospital which could lead to more patient-centred care experiences. These three dimensions need to co-exist in every care episode. More exploration is required to identify the common fundamentals of care needs of patients regardless of illness experience. PMID- 23083624 TI - The relationship between posterior septum deviation and depth of maxillopalatal arch. AB - OBJECTIVE: To investigate the relationship between depth of maxillopalatal arch and deviation of posterior septum. METHODS: This study is based on paranasal sinus CT (PNSCT) scan in the coronal plane evaluation, and sinus paranasal scans were obtained from the database. One-hundred and fifty PNSCT scans were randomly chosen among the PNSCT scans which belong to adult (18 and older) patients. All scans were divided to three different groups. The first group constituted by those patients who had more convex deviation. The second group had those patients with either crest or spur deviations. The last group (control group) had no septum deviation. The data collected from each group were statistically compared. EXCLUSION CRITERIA: CT imaging which has a chronic sinusitis, nasal cavity mass, and nasal polyps. MAIN OUTCOME MEASURES: angle and distance measures were taken on maxillopalatal arch and posterior nasal septum. RESULTS: Strongly positive correlation between posterior septum deviation and depth of maxillopalatal arch was determined (r=0.479, p=0.001). CONCLUSION: These findings suggest that posterior septum deviations are considered as a result of increase in maxillopalatal depth. PMID- 23083625 TI - How to optimize laryngeal and hypopharyngeal exposure in transoral robotic surgery. AB - OBJECTIVE: The aim of this study was to present the various strategies adopted in our center to improve and overcome problems with exposure of the operative field in 48 patients who underwent TORS for the treatment of laryngeal and hypopharyngeal cancer. METHODS: We present our operative and preoperative treatment protocols for patients undergoing TORS for laryngeal and hypopharyngeal cancer. In particular, we emphasize the role of preoperative exposure assessment and the usefulness of simple measures to overcome problems with exposure of the operative field. RESULTS: In 12 patients (25%), we experienced difficult laryngeal-hypopharyngeal exposure. However the correct positioning of the robotic arms, the proper use of the laryngeal and tongue blade and some simple maneuvers, such as the anterior traction of the tongue and the partial epiglottectomy, ensured the feasibility of TORS with negative margins in all patients. CONCLUSION: In TORS, the exposure of larynx and hypopharynx can be difficult, but the adoption of certain methods may make it possible in most patients. An accurate preoperative evaluation under general anesthesia is the primary strategy for reducing the number of cases terminated intraoperatively. Currently, TORS is not feasible in all patients, but in our opinion, reductions in the size of robotic equipment and development of new devices will extend the application of TORS to a larger number of patients. PMID- 23083626 TI - Tuberculosis--from ancient plague to modern-day nemesis. PMID- 23083628 TI - Depression and stigma: from attitudes to discrimination. PMID- 23083629 TI - Toxicity of MPTP on neurotransmission in three mouse models of Parkinson's disease. AB - Parkinson's disease (PD) is recognized as the second most common neurodegenerative disorder after Alzheimer's disease. PD is mainly characterized by a selective degeneration of the dopaminergic neurons in the substantia nigra. Also, it is observed imbalances in some nondopaminergic systems, including the serotonergic system. Serotonergic dysfunction appears to play a role in some parkinsonian symptoms, including motor function, L-dopa-induced dyskinesia, mood, psychosis, and constipation. The fact that 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) causes a parkinsonian syndrome was discovered in 1982 and has been used extensively and successfully in various mammalian species, including monkeys and mice, to produce an experimental model of PD. Three common dosing regimens of the MPTP-induced mice model of PD were compared on dopaminergic neurotransmission and serotonin levels in various brain regions. Results showed that tyrosine hydroxylase activity and dopaminergic transporter density were reduced in striatum and substantia nigra of mice and that this reduction was dependent on the cumulative dose of MPTP injected. Furthermore, for the three protocols, a decrease of dopamine (DA) level was observed in striatum, associated with a significant diminution of DA concentration in frontal cortex only for the chronic treatment. Moreover, a decrease of serotonin level was observed in midbrain and hippocampus of acute and sub-acute intoxicated-mice. In all, the results suggested that dosing regimen should be carefully pre considered. Furthermore, the acute and sub-acute MPTP protocols represent good models of early, subclinical stages of PD, ideal in the development of neuroprotective strategies. PMID- 23083627 TI - Global pattern of experienced and anticipated discrimination reported by people with major depressive disorder: a cross-sectional survey. AB - BACKGROUND: Depression is the third leading contributor to the worldwide burden of disease. We assessed the nature and severity of experienced and anticipated discrimination reported by adults with major depressive disorder worldwide. Moreover, we investigated whether experienced discrimination is related to clinical history, provision of health care, and disclosure of diagnosis and whether anticipated discrimination is associated with disclosure and previous experiences of discrimination. METHODS: In a cross-sectional survey, people with a diagnosis of major depressive disorder were interviewed in 39 sites (35 countries) worldwide with the discrimination and stigma scale (version 12; DISC 12). Other inclusion criteria were ability to understand and speak the main local language and age 18 years or older. The DISC-12 subscores assessed were reported discrimination and anticipated discrimination. Multivariable regression was used to analyse the data. FINDINGS: 1082 people with depression completed the DISC-12. Of these, 855 (79%) reported experiencing discrimination in at least one life domain. 405 (37%) participants had stopped themselves from initiating a close personal relationship, 271 (25%) from applying for work, and 218 (20%) from applying for education or training. We noted that higher levels of experienced discrimination were associated with several lifetime depressive episodes (negative binomial regression coefficient 0.20 [95% CI 0.09-0.32], p=0.001); at least one lifetime psychiatric hospital admission (0.29 [0.15-0.42], p=0.001); poorer levels of social functioning (widowed, separated, or divorced 0.10 [0.01 0.19], p=0.032; unpaid employed 0.34 [0.09-0.60], p=0.007; looking for a job 0.26 [0.09-0.43], p=0.002; and unemployed 0.22 [0.03-0.41], p=0.022). Experienced discrimination was also associated with lower willingness to disclose a diagnosis of depression (mean discrimination score 4.18 [SD 3.68] for concealing depression vs 2.25 [2.65] for disclosing depression; p<0.0001). Anticipated discrimination is not necessarily associated with experienced discrimination because 147 (47%) of 316 participants who anticipated discrimination in finding or keeping a job and 160 (45%) of 353 in their intimate relationships had not experienced discrimination. INTERPRETATION: Discrimination related to depression acts as a barrier to social participation and successful vocational integration. Non disclosure of depression is itself a further barrier to seeking help and to receiving effective treatment. This finding suggests that new and sustained approaches are needed to prevent stigmatisation of people with depression and reduce the effects of stigma when it is already established. FUNDING: European Commission, Directorate General for Health and Consumers, Public Health Executive Agency. PMID- 23083630 TI - Patients with inhibitory and neutralizing auto-antibodies to interferon-gamma resemble the sporadic adult-onset phenotype of Mendelian Susceptibility to Mycobacterial Disease (MSMD) lacking Bacille Calmette-Guerin (BCG)-induced diseases. AB - To recognize patients with inhibitory and neutralizing auto-antibodies to interferon-gamma (AutoAbs-IFN-gamma) presenting with the sporadic phenotype of Mendelian Susceptibility to Mycobacterial Disease (MSMD) mainly characterized by recurrent intracellular mycobacterium or/and salmonella infections, we comprehensively investigated IL12/23-IFN-gamma signaling, candidate genetic sequencings or/and protein expressions of IL12RB1, IFNRG1, IL12p40, IFNRG2, STAT1, IKKA, NEMO, CYBB and IRF8 in four patients. Their serum was further titrated to detect AutoAbs-IFN-gamma, for which the biological activity was assessed in Jurkat T cells. The patients mainly presented with recurrent non tuberculous mycobacterium osteomyelitis and lymphadenopathy (Mycobacterium abscessus, chelonae and avium intracellular complex), and salmonella sepsis (S. enterica serogroup B, C2 and D). Additionally, Penicillium marneffei, varicella zoster virus, and herpes simplex virus infections occurred. Inhibitory and neutralizing IFN-gamma downstream signaling was elucidated in Jurkat cell lines as decreased MHC class I and phosphorylated STAT1 expression. Together with 24 patients from the PubMed search, the majority of the AutoAbs-IFN-gamma patients were Asian (25/28). The most common involvement was lymph nodes (in 22/28), lungs (19/28) and bones (12/28). Mycobacterium avium complex (in 14) and chelonae (7) were the most common pathogens from 40 isolations. In contrast to those with the mild form of MSMD phenotype, AutoAbs-IFN-gamma patients, in the absence of BCG induced diseases, had a more persistent course and poor response to IFN-gamma treatment. In conclusion, AutoAbs-IFN-gamma patients may have a sporadic adult onset MSMD phenotype in Asian regions endemic for mycobacterial infections. PMID- 23083631 TI - A negative role for MyD88 in the resistance to starvation as revealed in an intestinal infection of Drosophila melanogaster with the Gram-positive bacterium Staphylococcus xylosus. AB - Drosophila melanogaster is a useful model to investigate mucosal immunity. The immune response to intestinal infections is mediated partly by the Immune deficiency (IMD) pathway, which only gets activated by a type of peptidoglycan lacking in several medically important Gram-positive bacterial species such as Staphylococcus. Thus, the intestinal host defense against such bacterial strains remains poorly known. Here, we have used Staphylococcus xylosus to develop a model of intestinal infections by Gram-positive bacteria. S. xylosus behaves as an opportunistic pathogen in a septic injury model, being able to kill only flies immunodeficient either for the Toll pathway or the cellular response. When ingested, it is controlled by IMD-independent host intestinal defenses, yet flies eventually die. Having excluded an overreaction of the immune response and the action of toxins, we find that flies actually succumb to starvation, likely as a result of a competition for sucrose between the bacteria and the flies. Fat stores of wild-type flies are severely reduced within a day, a period when sucrose is not yet exhausted in the feeding solution. Interestingly, the Toll pathway mutant MyD88 is more resistant to the ingestion of S. xylosus and to starvation than wild-type flies. MyD88 flies do not rapidly deplete their fat stores when starved, in contrast to wild-type flies. Thus, we have uncovered a novel function of MyD88 in the regulation of metabolism that appears to be independent of its known roles in immunity and development. PMID- 23083632 TI - Paradoxical downregulation of HLA-A expression by IFNgamma associated with schizophrenia and noncoding genes. AB - Neuronal MHC/HLA regulates the synapses of the central nervous system (CNS). The expression of MHC/HLA is, in turn, regulated by immune cytokines. We were therefore interested in the regulation of schizophrenia-associated HLA antigens, specifically their regulation of expression by interferons. We had previously observed a moderately increased frequency of HLA-A10 expression in schizophrenic patients. While searching for the "true" disease gene near the HLA-A gene, we discovered that homozygosity of the HLA-J M80469 pseudogene allele, in combination with HLA-A10 or HLA-A9, was associated with a high risk of schizophrenia (HLA-A10 relative risk = 29.33, p = 0.00019, patients N = 77, controls N = 214). The allele HLA-J M80468, which codes for interferon-inducible mRNA, conferred protection on carriers of HLA-A9 and HLA-A10 (HLA-A10 relative risk = 0.022, p = 0.00017). Functional analysis revealed that interferon gamma (IFNgamma) downregulated the expression of HLA-A9 and HLA-A10 in monocytes from HLA-J M80469 homozygous patients but not from carriers of the HLA-J M80468 allele. This is the first demonstration of an inverse effect of IFNgamma on HLA expression that is associated with non-coding gene variants and schizophrenia. Our findings suggest that the interferons secreted during acute and chronic infections may interfere in synaptic regulation via neuronal HLA and that this disturbance in synaptic regulation may induce the symptoms of mental illness. PMID- 23083633 TI - Looks like lung cancer acts like colon cancer. PMID- 23083634 TI - Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR-based therapy in patients with metastatic colorectal cancer. AB - Half of patients with KRAS wild-type colorectal cancer do not benefit from adding anti-epithelial growth factor receptor (EGFR) to standard chemotherapy regimens. This retrospective study was performed in 94 patients with metastatic colorectal cancer (mCRC) treated in the second line with cetuximab and chemotherapy. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in tumor cells was correlated with decreased median progression-free survival and overall survival (OS). These results highlight the potential role of STAT3 as a molecular target to optimize anti-EGFR therapies. BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in epithelial growth factor receptor (EGFR) signaling in a KRAS-independent manner. Phosphorylated STAT3 (pSTAT3) expression in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR-containing salvage chemotherapy has never been investigated. PATIENTS AND METHODS: : The first endpoint of this retrospective study was to evaluate the impact of pSTAT3 on the time to progression (TTP) in 94 patients with mCRC treated with anti-EGFR-based therapies in the second- or third-line setting between July 2004 and November 2009. The influence of pSTAT3 on objective response rate and overall survival (OS) was also reported. Nuclear expression of pSTAT3 status was evaluated by immunohistochemical tests on formalin-fixed and paraffin-embedded tumor samples obtained before therapy. RESULTS: Positive expression of pSTAT3 was observed in 24.5% of the tumor samples. The probability of achieving an objective response was 13% among patients with positive nuclear expression of pSTAT3 compared with 41% for patients displaying pSTAT3-negative tumors (P = .02). In a multivariate logistic regression model, high-grade skin rash, wild-type KRAS status, and negative pSTAT3 status significantly improved TTP and OS. CONCLUSION: These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker. PMID- 23083636 TI - Effectiveness of GnRH antagonist in intrauterine insemination cycles. AB - OBJECTIVE: To evaluate the effectiveness of GnRH antagonists in women undergoing controlled ovarian stimulation and intrauterine insemination cycles (COS/IUI). STUDY DESIGN: Randomized controlled trial. Recruited women were randomized into two groups: GnRH antagonist and control group. The primary outcomes were incidence of premature LH surge and clinical pregnancy rates. RESULTS: One hundred and forty-one consecutive women were included in the study, with 70 in the antagonist group and 71 in the control arm. The baseline clinical characteristics were similar in both groups. The incidence of premature LH surge and premature luteinization was lower in the antagonist group as compared to the control group (5% vs. 10.3%, P=0.45 and 5% vs. 13.8, P=0.31) but not statistically significant. The clinical pregnancy rates were lower in the antagonist group (2.8% vs. 10%, P=0.12), which was also not statistically significant. CONCLUSION: The addition of GnRH antagonist during controlled ovarian stimulation and intrauterine insemination cycles does not lead to improvement in clinical pregnancy rates. PMID- 23083635 TI - Clinical utility and economic impact of conventional transbronchial needle aspiration of mediastinal lymphadenopathies in bronchogenic carcinoma. AB - OBJECTIVES: To analyze the clinical utility and economic impact of conventional transbronchial needle aspiration (TBNA) in patients with diagnosis of bronchogenic carcinoma (BC) and mediastinal lymphadenopathies in thoracic computed tomography (CT). To assess the predictive factors of valid aspirations. PATIENTS AND METHODS: Retrospective observational study between 2006 and 2011 of all TBNA performed in patients with final diagnosis of BC and accessible hilar or mediastinal lymphadenopathies on thoracic CT. RESULTS: We performed TBNA on 267 lymphadenopathies of 192 patients. In 34.9% of patients, two or more lymph nodes were biopsied. Valid aspirations were obtained in 153 patients (79.7%) that were diagnostic in 124 (64.6%). Multivariate analysis showed that factors associated with valid or diagnostic results are the diameter of the lymph node and the number of lymph nodes explored. TBNA was the only endoscopic technique that provided the diagnosis of BC in 54 patients (28.1%). Staging mediastinoscopy was avoided in 67.6% of patients. The prevalence of mediastinal lymph node involvement was 74.4%, sensitivity of TBNA was 86.2% and negative predictive value was 63.6%. Including mediastinoscopy and other avoided diagnostic techniques, TBNA saved 451.57 ? per patient. CONCLUSIONS: TBNA is a clinically useful, cost-effective technique in patients with BC and mediastinal or hilar lymphadenopathies. It should therefore be performed on a regular basis during diagnostic bronchoscopy of these patients. PMID- 23083637 TI - Antibiotic susceptibility of Moraxella catarrhalis biofilms in a continuous flow model. AB - Antibiotic susceptibility of Moraxella catarrhalis biofilms was assessed using a Sorbarod filter continuous flow model. Ceftriaxone, erythromycin, amoxicillin, and Augmentin produced significant decreases in both biofilm and planktonic viable cell populations collected from the effluent. Augmentin produced the greatest reduction in biofilm (2.5 orders of magnitude) and planktonic populations (4 orders of magnitude). However, the minimum biofilm eradication concentration was not reached within the concentration range tested (4-64 mg/L), despite demonstrable susceptibility in standard microdilution tests (minimum bactericidal concentrations [MBC] <=0.06 mg/L). Antibiotic tolerance of M. catarrhalis biofilm populations was partly due to an inoculum effect and partly inherent. Amoxicillin had no effect against a beta-lactamase-producing M. catarrhalis. Compared to batch-grown cells, planktonic cells recovered from the Sorbarod filter effluent were more resistant to the antibiotics tested (MBC <=0.06 and >64 mg/L, respectively). Overall, the findings may explain the lack of response of some M. catarrhalis infections to antimicrobial therapy. PMID- 23083638 TI - Evaluation of the specificity and sensitivity of a potential rapid influenza screening system. AB - Influenza remains a serious worldwide health threat with numerous deaths attributed to influenza-related complications. It is likely that transmission of influenza and both the morbidity and mortality of influenza could be reduced if inexpensive but reliable influenza screening assays were more available to the general public or local medical treatment facilities. This report provides the initial evaluation of a pilot system designed by Lucigen Corp. (Middleton, WI, USA) as a potential rapid near point-of-care screening system for influenza A and influenza B. The evaluation of specificity and sensitivity was conducted on stored nasal swab samples collected from emergency department patients presenting with influenza-like symptoms at a large military academic hospital and on de identified nasal swabs and isolated RNA from a local epidemiology laboratory. The gold standard for assessment of specificity and sensitivity was the Luminex(r) Respiratory Viral Panel. PMID- 23083639 TI - The holy grail: a biomarker for acute rejection in liver transplantation. PMID- 23083640 TI - TLR3 agonist improves survival to secondary pneumonia in a double injury model. AB - BACKGROUND: Toll-like receptors (TLR) can initiate various immune responses and are therefore activated under diverse infectious states. Previous studies have focused on TLR3 primarily as an antiviral pathway. However, recent research has demonstrated its efficacy in bacterial infection. Having developed a murine double injury model of cecal ligation and puncture (CLP) followed by Pseudomonas aeruginosa (Pa), we hypothesized that targeted administration of Poly I:C, a TLR3 agonist, would protect mice against secondary pneumonia. MATERIAL AND METHODS: B6 mice underwent CLP followed 4 d afterward by an intranasal dose of Pa. Animals were given Poly I:C or vehicle (phosphate-buffered saline) intranasally 24 h post CLP and every day thereafter for a total of 6 d. For acute studies, mice were sacrificed at two time points, 4 d post CLP and 1 d post pneumonia (Pa). RESULTS: Poly I:C treatment led to a significant improvement in survival (69% versus 33%). Cytokine analysis from bronchioalveolar lavage displayed significant differences both immediately before and after pneumonia. Bronchioalveolar lavage cultures taken at 24 h post double injury showed significantly higher colony counts in the lungs of control animals compared with those of Poly I:C animals. Measurements of TLR3 expression showed significant increases within both the immune and lung epithelial cells of Poly I:C-treated mice. Finally, the lungs of treated animals had significant increases in lymphocytes and innate cells. CONCLUSIONS: The prophylactic treatment applied in this clinically relevant model further illustrates the overarching hypothesis of immune dysfunction and the possibility of corrective immune modulation within the setting of sepsis. PMID- 23083641 TI - Aspects of body image after mastectomy due to breast cancer - a two-year follow up study. AB - PURPOSE: This 2-year follow-up study explores aspects of body image after mastectomy due to breast cancer. MATERIALS AND METHODS: This population-based study included 76 women living in northern Sweden who, during November 2006 to October 2007, underwent mastectomy due to breast cancer. The women completed a questionnaire entitled "Life After Mastectomy (LAM)" 10 months after the mastectomy and again 2 years later. We used SPSS version 18.0 for data processing and analysis. RESULTS: The findings indicate that few significant changes in body image had taken place during the 2-year interval between the first and second completion of the questionnaire. An exception was a significant decrease in feelings of sexual attractiveness and comfort during sexual intimacy. At follow up, 21% of the women had undergone breast reconstruction (BR). They were significantly younger than the women who had not had BR (53 vs. 63 years). Besides being younger, no other significant differences could be found between those women who had undergone BR and those who had not. The fact that the decrease in sexual attractiveness and feelings of comfort during sexual intimacy also applied to the subgroup of women who had had BR may therefore be surprising. A better understanding of issues related to breast cancer treatment and sexual function is vital. CONCLUSION: It is important for health care professionals to be aware of problems related to sexual intimacy and to be prepared not just to provide information about these, but also to reflect on expectations vs. reality together with the women. PMID- 23083642 TI - Iranian obstetricians' views about the factors that influence pregnant women's choice of delivery method: a qualitative study. AB - BACKGROUND: Caesarean section is a commonly performed childbirth procedure. While caesarean section is undeniably a lifesaving procedure for some mothers and babies, it can also be an unnecessary procedure for others. Different factors may be involved in the rate of birth by caesarean section. QUESTION: This qualitative study was conducted in Kashan city, Iran, to explore obstetrician's views of what might influence pregnant women's choice of delivery method. METHODS: Obstetricians' views and experiences were collected using semi-structured interviews. Interviews were conducted in a clinic or hospital, based on the preference of the 18 physicians who agreed to participate in the study. All interviews were recorded and transcribed. Participants were asked key questions, including: "Why do some women prefer caesarean section?"; "What kind of delivery did you have and why?"; "What kind of delivery would you recommend to pregnant women and why?" Inductive qualitative content analysis was undertaken using the method described by Morreti with 120 initial codes categorized into six categories. FINDINGS: The six categories developed from the initial codes were: factors relating to women, obstetricians, delivery conditions, complications, society's beliefs and the health system. CONCLUSION: A qualitative study conducted in Iran showed that most of the factors identified by participants facilitated the choice of caesarean section. Vaginal birth was anticipated as a painful and lengthy process, with low cultural acceptance and resulting in less income for obstetricians. PMID- 23083643 TI - Transurethral prostate resection in patients with hypocontractile detrusor--what is the predictive value of ultrastructural detrusor changes? AB - PURPOSE: Men with detrusor failure and chronic urinary retention have a lower voiding success rate and higher postoperative morbidity following transurethral prostatectomy than those with bladder outlet obstruction. Current investigations, including urodynamics, may be unable to predict the response to surgical treatment. We identified ultrastructural features on detrusor biopsy that correlated with the postoperative voiding outcome in patients with a hypocontractile detrusor undergoing transurethral prostatectomy. MATERIALS AND METHODS: Detrusor biopsies were obtained from 17 patients with urodynamic evidence of bladder outlet obstruction or a hypocontractile detrusor undergoing transurethral prostatectomy and from 5 controls. Specimens were examined by transmission electron microscopy. Ten individual detrusor ultrastructural features were analyzed. Findings were compared with preoperative and postoperative clinical parameters. RESULTS: Failure to void after transurethral prostatectomy was significantly associated with the ultrastructural features of variation in muscle cell size, muscle cell shape, collagenosis and abnormal fascicles. These 4 features were significantly associated with each other, defining a distinctive pattern of detrusor failure. For transurethral prostatectomy failure the sensitivity, specificity, and positive and negative predictive values of all 4 features together were 60%, 91%, 75% and 84%, respectively. Three or 4 features on detrusor biopsy predicted voiding failure. CONCLUSIONS: Detrusor ultrastructural analysis is highly predictive of voiding outcome following transurethral prostatectomy in patients with detrusor failure. Patients with ultrastructural features previously described as part of the myohypertrophy pattern do not have a primary diagnosis of bladder outlet obstruction but rather detrusor failure secondary to bladder outlet obstruction. PMID- 23083644 TI - Editorial comment. PMID- 23083645 TI - Editorial comment. PMID- 23083647 TI - Baseline functional status may predict decisional regret following robotic prostatectomy. AB - PURPOSE: Physician knowledge of factors related to patient decisional regret following definitive management for localized prostate cancer is an important but under evaluated element in comprehensive patient counseling. Using validated instruments, we analyzed the relationships of pathological, perioperative and functional health related quality of life variables to treatment related regret following robot-assisted laparoscopic prostatectomy. MATERIALS AND METHODS: Of 953 consecutive patients presenting for followup after robot-assisted laparoscopic prostatectomy 703 (74%) completed validated measures of health related quality of life and treatment decisional regret. Baseline functional measures were assessed with the Sexual Health Inventory for Men and International Prostate Symptom Score. Questionnaires were administered a median of 11.1 months (IQR 4.6-26.1) after surgery. Clinicopathological, perioperative and functional outcomes were analyzed with univariable and multivariable models to examine associations with patient decisional regret. RESULTS: Of the patients 88% did not regret the decision to undergo robot-assisted laparoscopic prostatectomy. Baseline health related quality of life, specifically baseline incontinence and superior erectile function, independently predicted increased postoperative decisional regret. In addition, older age, postoperative incontinence measured by pad use, postoperative erectile dysfunction and longer time from surgery were independent predictors of increased decisional regret. Preoperative cancer risk, and histopathological and short-term biochemical outcomes were unrelated to decisional regret. CONCLUSIONS: Decisional regret following robot-assisted laparoscopic prostatectomy is independently predicted by age, baseline urinary and erectile function, perioperative outcomes, and postoperative urinary and erectile function. These results may be useful to urologists during preoperative patient counseling to set realistic expectations for the postoperative course, potentially improving the surgical experience. PMID- 23083648 TI - Treatment of neurogenic stress urinary incontinence using an adjustable continence device: 4-year followup. AB - PURPOSE: We evaluated the long-term safety and efficacy of an adjustable continence device (ACT(r) or ProACTTM) in male and female patients with neurogenic stress urinary incontinence. MATERIALS AND METHODS: Data on patients consecutively treated with implantation of an adjustable continence device due to neurogenic stress urinary incontinence were reviewed from the start of our experience to the current 4-year followup. RESULTS: We reviewed data on 13 male and 24 female patients with neurogenic stress urinary incontinence due to different forms of pelvic nerve or spinal cord lesions. Mean +/- SD age at implantation was 46.2 +/- 17.4 years. Of the patients 92% performed clean intermittent self-catheterization. The device was implanted bilaterally using general and local anesthesia in 16.2% and 83.8% of cases, respectively. From before implantation to 48-month followup the mean number of urinary incontinence episodes decreased from 6.1 +/- 2.4 to 2.8 +/- 3.1 and the mean number of pads used per 24 hours decreased from 4.2 +/- 2.7 to 2.2 +/- 2.2. Of the patients 54.5% indicated more than 50% improvement of stress urinary incontinence symptoms after 48 months, of whom 38.9% indicated complete continence. Adverse events included erosion/migration, device infection or failure, implantation site pain, bladder stone formation and difficult clean intermittent self-catheterization. CONCLUSIONS: Implantation of the ProACT/ACT device in patients with neurogenic stress urinary incontinence is minimally invasive and safe. It can significantly improve neurogenic stress urinary incontinence in the long term. Thus, it might be a reasonable option for patients who are not willing, not suitable or not yet ready for more invasive surgery, such as artificial urinary sphincter or fascial suspension sling placement. PMID- 23083649 TI - Risks of nocturia in patients with chronic kidney disease--do the metabolic syndrome and its components matter? AB - PURPOSE: We evaluate the risk factors for nocturia in patients with chronic kidney disease, and determine whether the metabolic syndrome and its components aggravate nocturia in these patients. MATERIALS AND METHODS: We enrolled patients with chronic kidney disease who had regular followup at nephrology clinics, and excluded from study those patients undergoing dialysis, and those with neurogenic bladder or active urinary tract infection. Patients were asked to complete a questionnaire including medical history, clinical parameters and times of nocturnal voids in the last month. Laboratory parameters were checked when the questionnaire was completed. Clinically significant nocturia was defined as voiding 2 or more times per night. The metabolic syndrome was defined according to the ATP III (National Cholesterol Education Program Adult Treatment Panel III) guidelines. Chronic kidney disease was divided into 5 stages (based on National Kidney Foundation guidelines). Multivariate logistic regression was used to evaluate the risk factors for clinically significant nocturia. RESULTS: A total of 202 men and 234 women were eligible for analysis (mean age 68.4 years). The prevalence rate of clinically significant nocturia in patients with chronic kidney disease was 64.0%. Statistically significant risk factors for clinically significant nocturia were patient age (OR 1.02, 95% CI 1.003-1.04) and chronic kidney disease stage (OR 1.47, 95% CI 1.19-1.81) but not gender. Although 53.9% of our patients with chronic kidney disease had the metabolic syndrome, the metabolic syndrome (adjusted OR 0.96, 95% CI 0.64-1.44) and its components had no significant correlations with clinically significant nocturia. CONCLUSIONS: Clinically significant nocturia is prevalent in patients with chronic kidney disease, and the severity increased with chronic kidney disease stage and patient age. Contrary to previous reports, the metabolic syndrome did not increase the risk of clinically significant nocturia in patients with chronic kidney disease. PMID- 23083650 TI - Residual fragments following ureteroscopic lithotripsy: incidence and predictors on postoperative computerized tomography. AB - PURPOSE: Residual fragments following ureteroscopy for calculi may contribute to stone growth, symptoms or additional interventions. We reviewed our experience with ureteroscopy for calculus disease to define the incidence and establish factors predictive of residual fragments. MATERIALS AND METHODS: Records associated with 667 consecutive ureteroscopic lithotripsy procedures for upper urinary calculi were reviewed. In 265 procedures (40%) computerized tomography was done between 30 and 90 days postoperatively. They comprised the study group. Residual fragments were defined as any residual ipsilateral stone greater than 2 mm. RESULTS: Included in the study were 121 men and 127 women with a mean age of 47 years. Mean target stone diameter was 7.6 mm. The stone location was the kidney in 30% of cases, ureter in 50%, and kidney and ureter in 20%. Residual fragments were detected on computerized tomography after 101 of 265 procedures (38%). Pretreatment stone size was associated with residual fragments at a rate of 24%, 40% and 58% for stones 5 or less, 6 to 10 and greater than 10 mm, respectively (p <0.001). Additionally, stone location in the kidney (p <0.001) or the kidney and ureter (p = 0.044), multiple calculi (p = 0.003), longer operative time (p = 0.008) and exclusive use of flexible ureteroscopy (p = 0.029) were associated with residual fragments. In a multivariate model only pretreatment stone diameter greater than 5 mm was independently associated with residual fragments after ureteroscopy (diameter 6 to 10 and greater than 10 mm OR 2.03, p = 0.03 and OR 3.74, p = 0.003, respectively). CONCLUSIONS: Of patients who underwent ureteroscopic lithotripsy for calculi 38% had residual fragments by computerized tomography criteria, including more than 50% with stones 1 cm or greater. Such data may guide expectations regarding the success of ureteroscopy in attaining stone-free status. PMID- 23083651 TI - Fulguration for Hunner ulcers: long-term clinical outcomes. AB - PURPOSE: Cystoscopic fulguration of Hunner ulcers in patients with interstitial cystitis/bladder pain syndrome is a recommended therapy because it has the potential to rapidly ameliorate symptoms. We reviewed our experience with Hunner ulcer fulguration. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with interstitial cystitis/bladder pain syndrome treated with Hunner ulcer fulguration who were seen at our pelvic pain referral center between 1993 and 2011. Patient demographics, clinical characteristics, intraoperative findings and long-term clinical outcomes were assessed. The Kaplan-Meier product limit method was used to evaluate time to the first repeat procedure. Potential risk factors associated with repeat procedures were examined using the log rank test. RESULTS: A total of 106 procedures were performed in 59 patients. The mean history of illness before first fulguration was 5 years and overall median followup was 44.8 months (IQR 52.2), as calculated from the time of the first fulguration. There were no significant associations between time to the first repeat procedure and any demographic criteria analyzed, patient reported interstitial cystitis/bladder pain syndrome associated conditions or the number of Hunner ulcers fulgurated at the initial session. A total of 27 patients (45.8%) required repeat fulguration. Time to event analysis demonstrated that 12 months after the initial fulguration 13.1% of patients required repeat treatment. This rate increased to 57.2% at 48 months, when it plateaued. CONCLUSIONS: Fulguration of Hunner ulcers can be an effective treatment for patients with interstitial cystitis/bladder pain syndrome and focal Hunner ulcers involving less than 25% of the bladder who have symptoms refractory to other therapies. However, a significant subset requires repeat treatment and some patients may even go on to require cystectomy. PMID- 23083652 TI - Chronic pelvic pain syndrome in men is associated with reduction of relative gray matter volume in the anterior cingulate cortex compared to healthy controls. AB - PURPOSE: Although chronic pelvic pain syndrome impairs the life of millions of people worldwide, the exact pathomechanisms involved remain to be elucidated. As with other chronic pain syndromes, the central nervous system may have an important role in chronic pelvic pain syndrome. Thus, we assessed brain alterations associated with abnormal pain processing in patients with chronic pelvic pain syndrome. MATERIALS AND METHODS: Using brain morphology assessment applying structural magnetic resonance imaging, we prospectively investigated a consecutive series of 20 men with refractory chronic pelvic pain syndrome, and compared these patients to 20 gender and age matched healthy controls. Between group differences in relative gray matter volume and the association with bother of chronic pelvic pain syndrome were assessed using whole brain covariate analysis. RESULTS: Patients with chronic pelvic pain syndrome had a mean (+/- SD) age of 40 (+/- 14) years, a mean NIH-CPSI (National Institutes of Health Chronic Prostatitis Symptom Index) total score of 28 (+/- 6) and a mean pain subscale of 14 (+/- 3). In patients with chronic pelvic pain syndrome compared to healthy controls there was a significant reduction in relative gray matter volume in the anterior cingulate cortex of the dominant hemisphere. This finding correlated with the NIH-CPSI total score (r = 0.57) and pain subscale (r = 0.51). CONCLUSIONS: Reduction in relative gray matter volume in the anterior cingulate cortex and correlation with bother of chronic pelvic pain syndrome suggest an essential role for the anterior cingulate cortex in chronic pelvic pain syndrome. Since this area is a core structure of emotional pain processing, central pathomechanisms of chronic pelvic pain syndrome may be considered a promising therapeutic target and may explain the often unsatisfactory results of treatments focusing on peripheral dysfunction. PMID- 23083653 TI - Treatment success of retropubic and transobturator mid urethral slings at 24 months. AB - PURPOSE: Longer term comparative efficacy information regarding transobturator and retropubic mid urethral slings is needed. We report 24-month continence rates, complications and symptom outcomes from a randomized equivalence trial. MATERIALS AND METHODS: Primary outcomes were objective (negative stress test, negative pad test and no re-treatment for stress urinary incontinence) and subjective (no self-report of stress urinary incontinence symptoms, no leakage episodes on 3-day bladder diary and no re-treatment for stress urinary incontinence) success at 24 months. The predetermined equivalence margin was +/- 12%. RESULTS: Of 597 randomized participants 516 (86.4%) were assessed. Objective success rates for retropubic and transobturator mid urethral slings were 77.3% and 72.3%, respectively (95% CI for difference of 5.1% was -2.0, 12.1), and subjective success rates were 55.7% and 48.3%, respectively (CI for difference of 7.4% was -0.7, 15.5). Neither objective nor subjective success rates met the prespecified criteria for equivalence. Patient satisfaction (retropubic 86.3% vs transobturator 88.1%, p = 0.58), frequency of de novo urgency incontinence (retropubic 0% vs transobturator 0.3%, p = 0.99) and occurrence of mesh exposure (retropubic 4.4% vs transobturator 2.7%, p = 0.26) were not significantly different. The retropubic mid urethral sling group had higher rates of voiding dysfunction requiring surgery (3.0% vs 0%, p = 0.002) and urinary tract infections (17.1% vs 10.7%, p = 0.025), whereas the transobturator group had more neurological symptoms (9.7% vs 5.4%, p = 0.045). CONCLUSIONS: Objective success rates met the criteria for equivalence at 12 months but no longer met these criteria at 24 months. Subjective success rates remained inconclusive for equivalence. Patient satisfaction remained high and symptom severity remained markedly improved. Continued surveillance is important in women undergoing mid urethral sling surgery. PMID- 23083654 TI - Repeat urethroplasty after failed urethral reconstruction: outcome analysis of 130 patients. AB - PURPOSE: Male urethral stricture disease accounts for a significant number of hospital admissions and health care expenditures. Although much research has been completed on treatment for urethral strictures, fewer studies have addressed the treatment of strictures in men with recurrent stricture disease after failed prior urethroplasty. We examined outcome results for repeat urethroplasty. MATERIALS AND METHODS: A prospectively collected, single surgeon urethroplasty database was queried from 1977 to 2011 for patients treated with repeat urethroplasty after failed prior urethral reconstruction. Stricture length and location, and repeat urethroplasty intervention and failure were evaluated with descriptive statistics, and univariate and multivariate logistic regression. RESULTS: Of 1,156 cases 168 patients underwent repeat urethroplasty after at least 1 failed prior urethroplasty. Of these patients 130 had a followup of 6 months or more and were included in analysis. Median patient age was 44 years (range 11 to 75). Median followup was 55 months (range 6 months to 20.75 years). Overall, 102 of 130 patients (78%) were successfully treated. For patients with failure median time to failure was 17 months (range 7 months to 16.8 years). Two or more failed prior urethroplasties and comorbidities associated with urethral stricture disease were associated with an increased risk of repeat urethroplasty failure. CONCLUSIONS: Repeat urethroplasty is a successful treatment option. Patients in whom treatment failed had longer strictures and more complex repairs. PMID- 23083655 TI - The impact of anatomical radical retropubic prostatectomy on cancer control: the 30-year anniversary. AB - PURPOSE: Radical prostatectomy has decreased prostate cancer specific mortality in men with clinically localized prostate cancer. We report oncological outcomes of the longest running series of nerve sparing radical retropubic prostatectomy on the 30th anniversary of the inaugural operation. MATERIALS AND METHODS: A total of 4,478 men underwent anatomical radical retropubic prostatectomy, as performed by a single surgeon (PCW), at the Johns Hopkins Medical Institutions from 1982 to 2011, without neoadjuvant or adjuvant therapy. During a median followup of 10 years (range 1 to 29), we examined progression-free, metastasis free and cancer specific survival. RESULTS: The overall 25-year progression-free, metastasis-free and cancer specific survival rates were 68%, 84% and 86%, respectively, although there were significant differences in treatment outcomes between men treated in the pre-PSA and PSA eras. In each era, there were significant differences in progression-free, metastasis-free and cancer specific survival by D'Amico risk groups. In multivariable models considering prostatectomy features, pathological stage and grade were significantly associated with the risk of metastatic progression and disease specific mortality. CONCLUSIONS: Excellent prostate cancer specific survival was demonstrated up to 30 years after surgery. Clinical risk categories and pathological tumor features were significant predictors of long-term disease specific outcomes, supporting their ongoing use in risk stratification and management decisions. Anatomical radical retropubic prostatectomy continues to represent the gold standard in the surgical management of clinically localized prostate cancer to which alternate treatment options should be compared. PMID- 23083657 TI - Robot-assisted radical prostatectomy: 5-year oncological and biochemical outcomes. AB - PURPOSE: We investigated oncological outcomes in patients who underwent robot assisted radical prostatectomy more than 5 years previously. MATERIALS AND METHODS: Between June 2002 and August 2006 we prospectively followed 435 consecutive patients who underwent robot-assisted radical prostatectomy. Five patients were excluded from analysis, including 4 lost to followup and 1 with prior therapy. Biochemical recurrence was denoted as 1) adjuvant therapy or 2) 2 prostate specific antigen values above 0.2 ng/ml. Biochemical recurrence-free survival, and patient and tumor characteristics were investigated. RESULTS: Mean +/- SD patient age was 61.4 +/- 7.1 years. A total of 289 patients (63%) had 5 or more years of followup and 4 (1%) were lost to followup. Median time to biochemical recurrence was 18 months (range 1 month to 9.1 years). Four patients (0.93%) died of prostate cancer. The 5-year biochemical recurrence-free survival rate was 84.9% (95% CI 81.4-88.4). Five-year biochemical recurrence-free survival was 94.4% (95% CI 91.7-97.1) for pT2 disease compared to 63.8% (95% CI 53.4-74.1) and 47.1% (95% CI 27.3-67.0) for pT3a and pT3b, respectively (p <0.001). Patients with a Gleason score of 3 or less + 3, 3 + 4, 4 + 3 and 4 or greater + 4 experienced a 5-year biochemical recurrence-free survival of 97%, 86%, 62% and 43%, respectively (p <0.001). Patients with positive margins had a 5-year biochemical recurrence-free survival of 60.7% (95% CI 48.7-72.7) compared to 89.6% (95% CI 86.3-92.9) in those with negative margins (p <0.001). CONCLUSIONS: This represents the third report of the oncological outcomes of robot-assisted radical prostatectomy, demonstrating a 5-year biochemical recurrence rate of approximately 14% and just below 1% prostate cancer specific mortality. PMID- 23083658 TI - Editorial comment. PMID- 23083656 TI - Associations between improvements in lower urinary tract symptoms and sleep disturbance over time in the CAMUS trial. AB - PURPOSE: We recently reported an association between the bother and severity of lower urinary tract symptoms secondary to benign prostatic hyperplasia and the severity of sleep disturbance. However, few studies have examined whether alterations in the severity of urinary symptoms influence the degree of sleep problems over time. MATERIALS AND METHODS: The severity of lower urinary tract symptoms in men enrolled in CAMUS (Complementary and Alternative Medicine for Urological Symptoms), a clinical trial of saw palmetto (Serenoa repens), was evaluated using AUASI (American Urological Association symptom index) and quality of life scores. Sleep disturbance was evaluated by the Jenkins sleep scale at 0, 24, 48 and 72 weeks. Statistical analyses were used to assess the relationship(s) between changes in lower urinary tract symptoms and sleep disturbance. RESULTS: The baseline characteristics of the 339 men (172 placebo arm and 167 saw palmetto arm) enrolled in the CAMUS trial with assessment of sleep disturbance and urinary symptoms were similar. There were no differences between improvements in the severity of sleep disturbance or urinary symptoms between the 2 experimental arms. Combined analyses of the entire cohort revealed significant associations (p <0.001) between the AUASI score and sleep disturbance severity with time. Multivariate analyses demonstrated that improvements in lower urinary tract symptoms other than nocturia were the most significant predictors of improvements in sleep disturbance. Specific analyses adjusting for other baseline characteristics demonstrated that a 3-point improvement in AUASI score was associated with a 0.73-point improvement in the Jenkins sleep scale with time. CONCLUSIONS: Improvements in lower urinary tract symptoms correlate with changes in sleeping abilities with time in men with benign prostatic hyperplasia. While nocturia is significantly associated with sleep disturbance, other changes in overall lower urinary tract symptoms are better predictors of changes in sleep dysfunction. PMID- 23083659 TI - Editorial comment. PMID- 23083660 TI - Influence of surgeon and hospital volume on radical prostatectomy costs. AB - PURPOSE: While higher radical prostatectomy hospital and surgeon volume are associated with better outcomes, the effect of provider volume on health care costs remains unclear. We performed a population based study to characterize the effect of surgeon and hospital volume on radical prostatectomy costs. MATERIALS AND METHODS: We used SEER (Surveillance, Epidemiology and End Results)-Medicare linked data to identify 11,048 men who underwent radical prostatectomy from 2003 to 2009. We categorized hospital and surgeon radical prostatectomy volume into tertiles (low, intermediate, high) and assessed costs from radical prostatectomy until 90 days postoperatively using propensity adjusted analyses. RESULTS: Higher surgeon volume at intermediate volume hospitals (surgeon volume low $9,915; intermediate $10,068; high $9,451; p = 0.021) and high volume hospitals (surgeon volume low $11,271; intermediate $10,638; high $9,529; p = 0.002) was associated with lower radical prostatectomy costs. Extrapolating nationally, selective referral to high volume radical prostatectomy surgeons at high and intermediate volume hospitals netted more than $28.7 million in cost savings. Conversely, higher hospital volume was associated with greater radical prostatectomy costs for low volume surgeons (hospital volume low $9,685; intermediate $9,915; high $11,271; p = 0.010) and intermediate volume surgeons (hospital volume low $9,605; intermediate $10,068; high $10,638; p = 0.029). High volume radical prostatectomy surgeon costs were not affected by varying hospital volume, and among low volume hospitals radical prostatectomy costs did not differ by surgeon volume. CONCLUSIONS: Selective referral to high volume radical prostatectomy surgeons operating at intermediate and high volume hospitals nets significant cost savings. However, higher radical prostatectomy hospital volume was associated with greater costs for low and intermediate volume radical prostatectomy surgeons. PMID- 23083661 TI - Editorial comment. PMID- 23083662 TI - Invited commentary. PMID- 23083663 TI - Invited commentary. PMID- 23083664 TI - Early duplex predicts restenosis after renal artery angioplasty and stenting. AB - OBJECTIVE: To examine the relationship between early renal duplex sonography (RDS) and restenosis after primary renal artery percutaneous angioplasty and stenting (RA-PTAS). METHODS: Consecutive patients undergoing RA-PTAS for hemodynamically significant atherosclerotic renal artery stenosis with hypertension and/or ischemic nephropathy between September 2003 and July 2010 were identified from a prospective registry. Patients had renal RDS pre-RA-PTAS, within 1 week of RA-PTAS and follow-up RDS examinations after the first postoperative week for surveillance of restenosis. Restenosis was defined as a renal artery peak systolic velocity (PSV) >= 180 cm/s on follow-up RDS. Associations between RDS and restenosis were examined using proportional hazards regression. RESULTS: Eighty-three patients (59% female; 12% nonwhite; mean age, 70 +/- 10 years; mean pre-RA-PTAS PSV, 276 +/- 107 cm/s) undergoing 91 RA-PTAS procedures comprised the sample for this study. All procedures included a completion arteriogram demonstrating no significant residual stenosis. Mean follow-up time was 14.9 +/- 10.8 months. Thirty-four renal arteries (RAs) demonstrated restenosis on follow-up with a median time to restenosis of 8.7 months. There was no significant difference in the mean PSV pre-RA-PTAS in those with and without restenosis (287 +/- 96 cm/s vs 269 +/- 113 cm/s; P = .455), and PSV pre-RA-PTAS was not predictive of restenosis. Within 1 week of RA-PTAS, mean renal artery PSV differed significantly for renal arteries with and without restenosis (112 +/- 27 cm/s vs 91 +/- 34 cm/s; P = .003). Proportional hazards regression analysis demonstrated increased PSV on first post-RA-PTAS RDS was significantly and independently associated with subsequent restenosis during follow-up (hazard ratio for 30 cm/s increase, 1.81; 95% confidence interval, 1.32 2.49; P = .0003). There was no difference in pre- minus postprocedural PSV in those with and without restenosis on follow-up (175 +/- 104 cm/s vs 179 +/- 124 cm/s; P = .88), nor was this associated with time to restenosis. Best subsets model selection identified first postprocedural RDS as the only factor predictive of follow-up restenosis. A receiver-operating characteristic curve was examined to assess the first week PSV post-RA-PTAS most predictive of restenosis during follow-up. The ideal cut point for RA-PSV was 87 cm/s or greater. This value was associated with a sensitivity of 82.4%, specificity of 52.6%, and area under the receiver-operating characteristic curve of 69.3%. Increased first postprocedural RA-PSV was predictive of lower estimated glomerular filtration rate in the first 2 years after the procedure (-1.6 +/- 0.7 mL/min/1.73 m(2) lower estimated glomerular filtration rate per 10 cm/s increase in RA-PSV; P = .010). CONCLUSIONS: Early renal artery PSV within 1 week after RA-PTAS predicted renal artery restenosis and lower postprocedure renal function. Recurrent stenosis demonstrated no association with absolute elevation in PSV prior to RA-PTAS nor with the change in PSV after RA-PTAS. These data suggest that detectable differences exist in renal artery flow parameters following RA-PTAS that are predictive of restenosis during follow-up but are not apparent on completion arteriography or detectable by intra-arterial pressure measurements. Further study is warranted. PMID- 23083666 TI - Idiopathic true brachial artery aneurysm in an 18-month-old girl. PMID- 23083667 TI - Mycotic abdominal aortic and iliac aneurysms in a 4-month-old treated with a cryopreserved homograft. PMID- 23083668 TI - Comparison of vein valve function following pharmacomechanical thrombolysis versus simple catheter-directed thrombolysis for iliofemoral deep vein thrombosis. PMID- 23083669 TI - Regarding "Blunt abdominal aortic injury: initial experience with endovascular repair". PMID- 23083671 TI - A plea for reporting the major and minor axes of the aortic bifurcation. PMID- 23083672 TI - Possible role of TH17 cells in the pathogenesis of Stevens-Johnson syndrome and toxic epidermal necrolysis. PMID- 23083673 TI - Maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of eczema in the infant. AB - BACKGROUND: Probiotics have shown promising potential in reducing the risk of eczema in infants. Optimal probiotic intervention regimen remains to be determined. OBJECTIVE: We investigated whether maternal probiotic supplementation during pregnancy and breast-feeding reduces the risk of developing eczema in high risk infants. METHODS: This was a parallel, double-blind placebo-controlled trial of 241 mother-infant pairs. Mothers with allergic disease and atopic sensitization were randomly assigned to receive (1) Lactobacillus rhamnosus LPR and Bifidobacterium longum BL999 (LPR+BL999), (2) L paracasei ST11 and B longum BL999 (ST11+BL999), or (3) placebo, beginning 2 months before delivery and during the first 2 months of breast-feeding. The infants were followed until the age of 24 months. Skin prick tests were performed at the ages of 6, 12, and 24 months. RESULTS: Altogether 205 infants completed the follow-up and were included in the analyses. The risk of developing eczema during the first 24 months of life was significantly reduced in infants of mothers receiving LPR+BL999 (odds ratio [OR], 0.17; 95% CI, 0.08-0.35; P < .001) and ST11+BL999 (OR, 0.16; 95% CI, 0.08-0.35; P < .001). The respective ORs for chronically persistent eczema were 0.30 (95% CI, 0.12-0.80; P = .016) and 0.17 (95% CI, 0.05-0.56; P = .003). Probiotics had no effect on the risk of atopic sensitization in the infants. No adverse effects were related to the use of probiotics. CONCLUSION: Prevention regimen with specific probiotics administered to the pregnant and breast-feeding mother, that is, prenatally and postnatally, is safe and effective in reducing the risk of eczema in infants with allergic mothers positive for skin prick test. PMID- 23083674 TI - Antigen-specific T-cell responses in patients with non-IgE-mediated gastrointestinal food allergy are predominantly skewed to T(H)2. PMID- 23083675 TI - Absence of the coronary sinus with coronary venous drainage into the main pulmonary artery. AB - We describe the case of a 9-year-old girl demonstrating isolated absence of the coronary sinus with abnormal coronary venous drainage into the main pulmonary artery. Coronary angiography showed normal coronary arterial trees and contrast medium from both coronary arteries drained into the main pulmonary artery via an abnormal cardiac vein on the anterior wall of the right ventricle. PMID- 23083676 TI - The evidence base of taming continuously proliferating evidence. PMID- 23083677 TI - Acute injury affects lubricin expression in knee menisci: an immunohistochemical study. AB - The aim of this study was to investigate for the first time lubricin expression in intact menisci and in menisci from patients with recent knee joint injury using histology, immunohistochemistry, Western blotting and gene expression analysis, to provide insights into pathological processes affecting meniscal tissue. Lubricin expression was studied in vivo in 20 patients (14 males and 6 females) with recent joint injury subjected to arthroscopic partial meniscectomy and in vitro in fibroblast-like cells from meniscus tissue to establish whether it is down-regulated following acute traumatic knee injury. The control group consisted of cadaver donors with normal menisci. Histology demonstrated a normal tissue without structural changes in control samples and structural alterations and clefts in injured menisci. Very strong lubricin immunohistochemical staining was observed in intact menisci; in contrast weak staining was seen in injured menisci. Western blot and mRNA expression analysis also demonstrated strong lubricin expression in control cells and a negligible amount of lubricin in injured fibroblast-like cells. Our data provide information concerning the immediate in vivo response to injury of human knee menisci by documenting early changes in the boundary-lubricating ability of synovial fluid and articular cartilage integrity. These findings may provide the biological basis for developing novel medical therapies to be applied before surgical treatment to preserve tissue function and prevent cartilage damage. PMID- 23083678 TI - Progress and prospective of plant sterol and plant stanol research: report of the Maastricht meeting. AB - Abundant evidence over past decades shows that foods with added plant sterols and plant stanols lower serum LDL cholesterol concentrations. However, despite the overwhelming data, numerous scientific questions still remain. The objective of this paper is to summarize the considerations of 60 academic and industrial experts who participated in the scientific meeting in Maastricht, the Netherlands, on issues related to the health effects of plant sterols and plant stanols. The meeting participants discussed issues including efficacy profiling, heterogeneity in responsiveness, effects beyond LDL-C lowering, and food formulation aspects of plant sterol and stanol consumption. Furthermore, aspects related to the potential atherogenicity of elevated circulatory plant sterol concentrations were discussed. Until the potential atherogenicity of plant sterols is resolved, based on the results >200 clinical trials, the risk to benefit of plant sterol use is favorable. Evidence on these topics in plant sterol and plant stanol research was presented and used to reach consensus where possible. It was concluded that endpoint studies looking at plant sterol and plant stanol efficacy are needed, however, there was no clear opinion on the best marker and best design for such a study. Based on the current scientific evidence, plant sterols and plant stanols are recommended for use as dietary options to lower serum cholesterol. PMID- 23083679 TI - Does 17beta-estradiol play a role in SLE-associated atherosclerosis? PMID- 23083680 TI - Pulse wave velocity is associated with early clinical outcome after ischemic stroke. AB - BACKGROUND AND PURPOSES: Pulse wave analysis (PWV), a marker of aortic stiffness, has independent predictive value for cardiovascular morbidity and mortality in both healthy and high-risk populations, especially fatal stroke, and for long term functional stroke prognosis. Whether arterial stiffness and wave reflection are related to stroke in-hospital short-term outcome has never been demonstrated. METHODS: In a prospective study, we enrolled 134 patients with acute ischemic stroke, aged 63.4 +/- 12.5 years, mean +/- SD, National Institutes of Health stroke scale (NIHSS) scored 7.1 +/- 6.5 at admission. Carotid-femoral (CF) PWV and central augmentation index (cAIx) were measured (SphygmoCor) one week after stroke onset. At hospital discharge, favorable outcome was defined as a 4 or more point improvement from baseline NIHSS or NIHSS of 0-1. Data were analyzed with logistic regression. RESULTS: In univariate analysis, low CF-PWV (P = 0.000,001), but not cAIx, was significantly associated with early favorable outcome. In multivariate analysis, CF-PWV > 9.0 m/s remained significantly associated with favorable early outcome after adjustment for age, NIHSS and blood glucose level on admission, as well as heart rate, systolic and mean blood pressure, measured at day 7 (OR = 0.17 [95% CI, 0.05-0.60];P = 0.006). CONCLUSIONS: In ischemic stroke, low aortic stiffness (CF-PWV) is associated with early favorable outcome, independently of other known prognostic factors. PMID- 23083681 TI - An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: potential implications in cardiovascular disease. AB - The introduction of dipeptidyl peptidase 4 (DPP4) inhibitors for the treatment of Type 2 diabetes acknowledges the fundamental importance of incretin hormones in the regulation of glycemia. Small molecule inhibitors of DPP4 exert their effects via inhibition of enzymatic degradation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). The widespread expression of DPP4 in tissues such as the vasculature and immune cells suggests that this protein may play a role in cardiovascular function. DPP4 is known to exert its effects via both enzymatic and non-enzymatic mechanisms. A soluble form of DPP4 lacking the cytoplasmic and transmembrane domain has also been recently recognized. Besides enzymatic inactivation of incretins, DPP4 also mediates degradation of many chemokines and neuropeptides. The non-enzymatic function of DPP4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase (ADA). DPP4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. The multiplicity of functions and targets suggests that DPP4 may play a distinct role aside from its effects on the incretin axis. Indeed recent studies in experimental models of atherosclerosis provide evidence for a robust effect for these drugs in attenuating inflammation and plaque development. Several prospective randomized controlled clinical trials in humans with established atherosclerosis are testing the effects of DPP4 inhibition on hard cardiovascular events. PMID- 23083682 TI - Commentary on "Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease" by Zimran et al. PMID- 23083683 TI - Fragmental or massive embolization in cardiogenic stroke caused by nonvalvular atrial fibrillation. AB - BACKGROUND: After cardioembolic stroke (CES), left atrial thrombus (LAT) is detected by transesophageal echocardiography (TEE) in some cases but not in others. We propose that there are 2 types of embolization in CES: fragmental and massive embolization. METHODS: Consecutive patients with nonvalvular atrial fibrillation (AF) of acute CES or transient ischemic attack (TIA) were prospectively enrolled in the study between May 2009 and July 2011. TEE was performed within 7 days of admission. The patients were classified into 2 groups: those with occlusion of the main trunk (internal carotid artery, M1, and basilar artery; group M) and those with occlusion of other distal arteries (group D). Clinical features were compared between patients who did and did not have a thrombus on TEE. RESULTS: Of the 41 patients in the study, 21 were in group M and 20 were in group D. Age, sex, and treatment with tissue plasminogen activator did not differ significantly between the 2 groups. The rate of detection of LAT was significantly higher in group D (14% v 65%; P < .001). CONCLUSIONS: Patients with distal artery occlusion had a significantly higher rate of LAT compared to those with main trunk occlusion. Distal artery occlusion in CES therefore tends to result from fragmental embolization and is associated with a remnant LAT, with which there may be a concern of a risk of early recurrence. PMID- 23083684 TI - Overexpression of OrbHLH001, a putative helix-loop-helix transcription factor, causes increased expression of AKT1 and maintains ionic balance under salt stress in rice. AB - The basic helix-loop-helix family of proteins, which function as transcription factors, have been intensively studied in plants and animals. However, the molecular mechanism of these factors contributing to stress tolerance is unknown. Here, we report on the overexpression of OrbHLH001 from Dongxiang wild rice (Oryza rufipogon) conferring salt tolerance in transgenic rice plants. The expression of OrbHLH001 was tissue specific, mainly in phloem tissues throughout the plant. Ion assay with the scanning ion-selective electrode technique showed that NaCl stress has a greater influence on Na(+) efflux and K(+) influx in OrbHLH001-overexpressed plants than the wild type. OrbHLH001 protein can induce the expression of OsAKT1 to regulate the Na(+)/K(+) ratio in OrbHLH001 overexpressed plants by specifically binding to an E-box motif in the promoter region of OsAKT1. The mechanism may have potential use in rice molecular breeding. PMID- 23083685 TI - [Children and air travel: national survey results]. AB - Airplanes are widely used by families and their children and pediatricians are increasingly asked to answer questions on this subject. The main purpose of this study was to evaluate the knowledge of pediatricians in this field except for medical transportation. Pediatricians belonging to the AFPA, the SFP, the SNPEH, or the SP2A were emailed a questionnaire on the physiological particularities of airborne transportation, contraindications to flight related to diseases (infections, diabetes, sickle-cell anemia, respiratory diseases, etc.) and the possible medication intake on board. Among the 232 responders, 82.3% had an exclusive hospital practice and 65% were specialized in more than one area of medicine. Regarding contraindications to flying, the rate of correct answers varied from 14 to 84% with divided opinions regarding respiratory and hematological pathologies. However, contraindications related to infections were well known. Items related to oxygen therapy raised questions as 35-68% of pediatricians stated that they could not answer. On the whole, this work demonstrated very fragmented knowledge on this topic. PMID- 23083686 TI - [Hepatic alveolar echinococcosis: a rare cause of recurrent, surgically curable abdominal pain in children]. AB - Hepatic alveolar echinococcosis is a rare parasitic zoonosis, potentially lethal in childhood. It is due to Echinococcosis multilocularis whose larva insidiously develops in the liver. We report the case of a 13-year-old girl, living in the Vosges Mountains, followed for recurrent abdominal pain, with recent worsening. Diagnosis of alveolar echinococcosis was immediately suspected based on the liver ultrasound scan and then confirmed by imaging (CT scan, NMR) and serology. A curative surgical treatment (segmentectomy) was performed 3 months after diagnosis, under oral albendazole treatment, maintained for at least 2 years. Hepatic alveolar echinococcosis usually has a negative prognosis, except if diagnosed early, which allows rapid surgical treatment, as in our patient. PMID- 23083687 TI - Epigenetics and imprinting. PMID- 23083688 TI - Effect of combination fluticasone propionate and salmeterol or inhaled corticosteroids on asthma-related outcomes in a Medicare-eligible population. AB - BACKGROUND: National asthma treatment guidelines recommend either the use of inhaled corticosteroids (ICS) or ICS in combination with a long-acting bronchodilator for the treatment of moderate to severe asthma. Even though asthma is common among older adults, few studies have assessed the differences in effectiveness between these two recommended therapies in patients over 65 years of age. OBJECTIVE: The aim of this study was to assess the association of the fluticasone-salmeterol combination (FSC) or ICS initiation on asthma-related events in Medicare-eligible asthma patients. METHODS: This was a retrospective observational study using a large health claims database (July 1, 2001 to June 30, 2008). Subjects 65 to 79 years of age with 12-month preindex and 3- to 12 month postindex eligibility, an asthma diagnosis (ICD-493.xx), and with 1 or more FSC or ICS claims at index were included. Subjects with an FSC or ICS claim in the preindex and any claim for chronic obstructive pulmonary disease were excluded. Subjects were observed until they had an event (emergency department [ED] inpatient hospitalization [IP], combined IP/ED or oral corticosteroid [OCS] use) or were no longer eligible in the database, whichever came first. Cox proportional hazards regression was used to assess risk of an asthma-related event (IP, ED, or IP/ED). Baseline characteristics (age, sex, region, index season, comorbidities, preindex use of short-acting beta-agonists, OCS, other asthma controllers, and asthma-related ED/IP visits) were independent covariates in the model. RESULTS: A total of 10,837 met the criteria (4843 ICS and 5994 FSC). Age (70.4 and 70.5 years, respectively) and the percentage of female subjects (65.5% and 64.8%, respectively) were similar. Asthma-related events were also similar at baseline. Postindex unadjusted rates occurring after >30 days were ED (1.8% vs 1.5%, P = 0.18), IP (2.7% vs 1.7%, P < 0.001), and ED/IP (4.1% vs 2.8%, P < 0.001) for ICS and FSC, respectively. Subjects who received FSC were associated with a 32% (adjusted HR = 0.68; 95% CI, 0.51-0.91) lower risk of experiencing an IP visit and a 22% (HR = 0.78; 95% CI, 0.62-0.98) lower risk of experiencing an ED/IP visit. No differences were observed for ED visits (HR = 0.94; 95% CI, 0.68-1.29). CONCLUSIONS: In Medicare-eligible asthma patients, FSC use was associated with lower rates of asthma-related serious exacerbations compared with ICS. PMID- 23083689 TI - The unique co-occurrence of spinocerebellar ataxia type 10 (SCA10) and Huntington disease. AB - We present a unique thirty-nine year old woman with both Huntington's disease (HD) and spinocerebellar ataxia type 10 (SCA10). She has 48 CAG repeats in the HD gene and 2511 ATTCT repeats in the ATX10 gene. Although both conditions are repeat expansion diseases they are thought to have quite different pathogenic mechanisms. The symptomatic age of onset in this patient (mid30s) is within the expected range for her repeat expansion sizes for each condition, but we discuss the evidence that the two conditions may interact to produce a more severe cognitive phenotype than would be expected for either of the conditions independently. The subject has Amerindian background on the maternal side from Colombia, South America, thus adding a 5th country expressing SCA10, all with Amerindian ancestry. PMID- 23083690 TI - Lamellar ichthyosis due to ALOX12B mutation. PMID- 23083691 TI - Animal-type melanoma: clinical and dermoscopic features of 3 cases. AB - Animal-type melanoma is a rare variant of malignant melanoma in humans. Although many patients develop locoregional and distant metastases, mortality is lower than in other types of melanoma. We present 3 cases of animal-type melanoma in elderly men and include a description of common clinical and dermoscopic features (homogeneous blue pattern, irregular whitish structures, and irregular large vessels). PMID- 23083692 TI - Spatial analysis of CO2 concentration in an unpolluted environment in northern Spain. AB - CO(2) transport in the low atmosphere near the surface at night was analysed using spatial procedures applied to back trajectories. Concentration and meteorological data were obtained at a rural site during a seven and a half month campaign. Daily evolution of CO(2) skewness showed positive values during the night and negative values during the day. One concentration and one recirculation factor, an indicator of local recirculation, were associated with each back trajectory calculated during the night to study source and meteorological influences on concentrations recorded. Moreover, four procedures were used to analyse the trajectories, and their strengths and weaknesses were also investigated. (1) The nonparametric trajectory analysis applied with two weight functions successfully marked the most contributing region. (2) Hexagonal cells were used to account for radial distribution of trajectories. The potential source contribution function calculated in these cells highlighted the influence of the source against meteorology, this procedure therefore proving the best to mark the source direction. (3) Trajectory sector analysis revealed the most contributing wind sector and emphasised the role of recirculation in the E-S sectors. (4) Cluster analysis grouped neighbouring trajectories and was the most flexible procedure to classify them, providing a contrast of around 12 ppm between medians obtained in the SE cluster and the least contributing group. PMID- 23083693 TI - Shared cultural norms for justice in water institutions: results from Fiji, Ecuador, Paraguay, New Zealand, and the U.S. AB - It is widely agreed that current institutions are insufficient to meet global water challenges, and extensive institutional reforms are needed. To achieve effective local water management, institutional rules should be congruent with local cultural norms. Conversely, a major potential challenge is posed by tensions between institutional rules and local cultural norms for justice. We propose and demonstrate a new approach to cross-cultural analysis designed to investigate this tension, which can assess when local cultural norms are likely to facilitate or impede the acceptance of specific institutional rules. Using data from 238 respondents in five global sites (in Fiji, Ecuador, Paraguay, New Zealand, and the U.S.) analyzed using cultural consensus analysis, we find evidence of culturally-shared norms of justice in water institutions in at least six domains: a human right to water, water governance, water access, environmental stewardship, aspects of water markets, and aspects of water quality and health. Additionally, local cultural models across sites differed on only two topics: (1) ownership and allocation and (2) restrictions and enforcement. Indigenous heritage is the best single predictor of views on controversial institutional rules dealing with water restrictions/enforcement and ownership/allocation. This approach can help build effective water management solutions by identifying cases in which specific institutional reforms are congruent with local cultural norms (or not), and when those will matter most. PMID- 23083694 TI - [Inadequate antidiuretic hormone secretion secondary to microcytic carcinoma of the urinary bladder: an undescribed association]. PMID- 23083695 TI - [Oral florid papillomatosis]. PMID- 23083696 TI - [Pseudopheochromocytoma (or when we do not find pheocromocytoma)]. PMID- 23083697 TI - Orbital and optic nerve complications of inflammatory bowel disease. AB - BACKGROUND AND AIMS: Extraintestinal manifestations of inflammatory bowel disease (IBD) can involve the orbit and the optic nerve. Although these manifestations are rare, they can be particularly serious as they can lead to permanent loss of vision. The aim of the review is to present the existing literature on IBD related optic nerve and orbital complications. METHODS: A literature search identified the publications reporting on incidence, clinical features and management of IBD patients with optic nerve and orbital manifestations. RESULTS: Posterior scleritis and orbital inflammatory disease (orbital pseudotumor) are the most commonly encountered entities affecting the structures of the orbit. On the other hand, the optic nerve of IBD patients can be affected by conditions such as optic (demyelinating) neuritis ("retrobulbar" neuritis), or ischaemic optic neuropathy. Other neuro-ophthalmic manifestations that can be encountered in patients with IBD are related to increased intracranial pressure or toxicity secondary to anti tumour necrosis factor (anti-TNF) agents. CONCLUSIONS: IBD related optic nerve and orbital complications are rare but potentially vision threatening. Heightened awareness and close cooperation between gastroenterologists and ophthalmologists are warranted. PMID- 23083698 TI - Hand-held fractional exhaled nitric oxide measurements as a non-invasive indicator of systemic inflammation in Crohn's disease. AB - BACKGROUND AND AIMS: Active inflammatory bowel disease (IBD) is associated with increased activity of inducible nitric oxide synthase (iNOS), which increases both mucosal and plasma nitric oxide (NO) levels. Increased fractional exhaled nitric oxide (FeNO) levels have been described in patients with IBD. Currently, hand-held FeNO measurement devices are available, enabling a fast in-office analysis of this non-invasive disease activity marker. In this pilot study, we investigated the utility of in-office FENO measurements in patients with Crohn's disease (CD). METHODS: Fifty CD patients and 25 healthy controls (HC) were included, all of whom were free of atopic or pulmonary disorders and respiratory symptoms at the time of inclusion. The Crohn's disease activity index (CDAI) was calculated, and the inflammatory parameters and fecal calprotectin levels were assessed. FeNO was measured with a hand-held device. RESULTS: A significant increase in FeNO (median, [interquartile range]) was observed in steroid-free CD patients with clinically active disease (CDAI>150; 22 [8] ppb) compared with CD patients in clinical remission (CDAI<150; 11 [6] ppb; P<0.001) and HC's (17 [9] ppb; P<0.05). Active CD patients treated with corticosteroids had significantly lower FeNO compared with active CD patients without steroids (12 [10] ppb vs 25 [19] ppb; P<0.05). FeNO displayed a strong correlation with the CDAI (R=0.68; P<0.001). Fair correlations were found between FeNO and several systemic inflammatory markers, but no significant correlation was found with fecal calprotectin. CONCLUSION: This pilot study suggests that hand-held FeNO measurements could be an attractive non-invasive indicator of systemic inflammation in Crohn's disease. PMID- 23083699 TI - How do psychological variables influence coping strategies in inflammatory bowel disease? AB - BACKGROUND: Adjusting to chronic disease is a complex process and one that, in the case of inflammatory bowel disease (IBD), has received very little attention. The objectives of this study were to identify coping strategies used by patients with IBD and to explore how these strategies are related to psychological characteristics. METHODS: A transversal study was designed in which 875 patients with IBD were prospectively enrolled. Independent variables were evaluated using a sociodemographic questionnaire and a clinical questionnaire-the Hospital Anxiety and Depression Scale (HADS) and the Perceived Stress Scale (PSS); dependent variables were evaluated using the COPE Inventory (Coping Orientation to Problems Experienced), a multidimensional scale for evaluating general coping styles. Multiple linear regression was used to identify the variables associated with the type of coping used. RESULTS: The participation rate was 91.3%. The most common coping strategy was emotion-focused coping (X=2.64; 95% CI=2.61-2.69), with no differences in relation to type of disease. The highest scores for anxiety were associated with emotion-focused coping (beta=0.164, p=0.001) whereas, for depression, the highest scores were associated with escape-avoidance (beta=0.108, p=0.044). No correlation was found between stress levels and type of coping. CONCLUSIONS: Patients with IBD have a tendency to focus on emotions in their coping process, and this process appears to be related not only to sociodemographic characteristics or features of the disease itself but also to psychological factors-anxiety and depression, primarily. PMID- 23083700 TI - Water soluble acyloxy nitroso compounds: HNO release and reactions with heme and thiol containing proteins. AB - Nitroxyl (HNO) has gained interest as a potential treatment of congestive heart failure through the ability of the HNO donor, Angeli's salt (AS), to evoke positive inotropic effects in canine cardiac muscle. The release of nitrite during decomposition limits the use of AS requiring other HNO sources. Acyloxy nitroso compounds liberate HNO and small amounts of nitrite upon hydrolysis and the synthesis of the water-soluble 4-nitrosotetrahydro-2H-pyran-4-yl acetate and pivalate allows for pig liver esterase (PLE)-catalysis increasing the rate of decomposition and HNO release. The pivalate derivative does not release HNO, but the addition of PLE catalyzes hydrolysis (t(1/2)=39 min) and HNO formation (65% after 30 min). In the presence of PLE, this compound converts metmyoglobin (MetMb) to iron nitrosyl Mb and oxyMb to metMb indicating that these compounds only react with heme proteins as HNO donors. The pivalate in the presence and the absence of PLE inhibits aldehyde dehydrogenase (ALDH) with IC(50) values of 3.5 and 3.3 MUM, respectively, in a time-dependent manner. Reversibility assays reveal reversible inhibition of ALDH in the absence of PLE and partially irreversible inhibition with PLE. Liquid chromatography-mass spectrometry (LC-MS) reveals formation of a disulfide upon incubation of an ALDH peptide without PLE and a mixture of disulfide and sulfinamide in the presence of PLE. A dehydroalanine residue forms upon incubation of this peptide with excess AS. These results identify acyloxy nitroso compounds as unique HNO donors capable of thiol modification through direct electrophilic reaction or HNO release. PMID- 23083701 TI - Water soluble fluorescent-magnetic perylenediimide-containing maghemite nanoparticles for bimodal MRI/OI imaging. AB - The protein shell of apoferritin-encapsulated maghemite nanoparticles was functionalized with two different red-emitting perylenediimide fluorophores (PDI). One glycosacharide-PDI complex has been synthesized for the first time to be labeled to apoferritin-encapsulated maghemite nanoparticles. Bifunctionality of maghemite@perylenediimide was demonstrated by both magnetic-core and fluorescent-labeled shell properties. SQUID measurements confirmed superparamagnetic behavior above 35K. Fluorescence of perylenediimides is retained once attached to the magnetic nanoparticle. Moreover, fluorescence microscopy showed that one of these fluorescent-magnetic nanoparticles was specifically internalized in bifidobacteria without affecting cell viability. These results revealed that the dual-modal imaging probes of maghemite@perylenediimide nanoparticles have the potential to be used as optical/MR dual imaging agents. PMID- 23083703 TI - Multidetector computed tomography imaging of coronary artery anomalies. AB - PURPOSE: The purpose of the study was to determine the prevalence of coronary artery anomalies and to demonstrate in which cases multidetector computed tomography has an additional clinical value compared with the conventional angiography. MATERIAL AND METHODS: A total of 2375 multidetector computed tomography studies were retrospectively reviewed to determine the dominance of the coronary artery anomalies. The classification of coronary artery anomalies was made according to anatomical criteria--origin, course, intrinsic anatomy, and termination--and clinical relevance--benign versus malignant. RESULTS: The coronary artery system was right dominant in 83.99%, left dominant in 8.0%, and co-dominant in 9.01% of the cases. The incidence of the origin and/or course anomalies was 1.76%, that of fistulas was 0.42%, and that of myocardial bridges was 10.82%. Multidetector computed tomography was performed after conventional angiography in 23 cases and it provided additional information regarding its origin and proximal course, as well as its relationship with the aortic root and main pulmonary trunk in 100% of the cases; eight malignant cases were found. In addition, in all of (100%) the six cases with coronary artery fistulas, conventional angiography failed to detect their terminations, which were clearly depicted by multidetector computed tomography. CONCLUSION: Multidetector computed tomographic angiography is superior to conventional angiography in delineating the ostial origin and proximal course of anomalous coronary arteries. Furthermore, it reveals the exact relationship of anomalous coronary arteries with the aorta and the pulmonary artery. Anomalies of the intrinsic anatomy and the termination of coronary arteries are also better visualised with multidetector computed tomography. PMID- 23083702 TI - Programmed cell death in plants: lessons from bacteria? AB - Programmed cell death (PCD) has well-established roles in the development and physiology of animals, plants, and fungi. Although aspects of PCD control appear evolutionarily conserved between these organisms, the extent of conservation remains controversial. Recently, a putative bacterial PCD protein homolog in plants was found to play a significant role in cell death control, indicating a conservation of function between these highly divergent organisms. Interestingly, these bacterial proteins are thought to be evolutionarily linked to the Bcl-2 family of proteins. In this opinion article, we propose a new unifying model to describe the relationship between bacterial and plant PCD systems and propose that the underlying control of PCD is conserved across at least three Kingdoms of life. PMID- 23083704 TI - The effect of electromagnetic navigation in total knee arthroplasty on knee kinematics during functional activities using flexible electrogoniometry. AB - BACKGROUND: Navigated total knee arthroplasty has been shown to increase accuracy in post operative implant alignment. By contrast navigated total knee arthroplasty has not shown significant functional improvements to date, when compared with conventional surgery using subjective clinical questionnaire scores. The aim of this study was to compare the knee joint kinematics measured during functional activities using electrogoniometry 12 months after total knee arthroplasty in randomised navigated and conventional total knee arthroplasty groups. METHODS: The study design was a double blinded, randomised, prospective, controlled trial. The patients were randomised into 2 surgical groups (n=102 navigated group, n=98 conventional group; mean age navigated=67, conventional=67). Flexible electrogoniometry was used to measure patient's knee kinematics with respect to time during 12 functional activities. FINDINGS: No significant difference was found in terms of the maximum, minimum and excursion knee joint angle during any of the functional activities. However there was a statistically significant improvement in the level and slope gait cycle at the pre swing phase in the navigated group. INTERPRETATION: There were minimal functional improvements in the navigated total knee arthroplasty group 12 months after surgery. However, these are unlikely to have a significant effect on daily activity for the navigated group. PMID- 23083705 TI - Membrane cholesterol strongly influences confined diffusion of prestin. AB - Prestin is the membrane motor protein that drives outer hair cell (OHC) electromotility, a process that is essential for mammalian hearing. Prestin function is sensitive to membrane cholesterol levels, and numerous studies have suggested that prestin localizes in cholesterol-rich membrane microdomains. Previously, fluorescence recovery after photobleaching experiments were performed in HEK cells expressing prestin-GFP after cholesterol manipulations, and revealed evidence of transient confinement. To further characterize this apparent confined diffusion of prestin, we conjugated prestin to a photostable fluorophore (tetramethylrhodamine) and performed single-molecule fluorescence microscopy. Using single-particle tracking, we determined the microscopic diffusion coefficient from the full time course of the mean-squared deviation. Our results indicate that prestin undergoes diffusion in confinement regions, and that depletion of membrane cholesterol increases confinement size and decreases confinement strength. By interpreting the data in terms of a mathematical model of hop-diffusion, we quantified these cholesterol-induced changes in membrane organization. A complementary analysis of the distribution of squared displacements confirmed that cholesterol depletion reduces prestin confinement. These findings support the hypothesis that prestin function is intimately linked to membrane organization, and further promote a regulatory role for cholesterol in OHC and auditory function. PMID- 23083706 TI - Differential dynamic microscopy: a high-throughput method for characterizing the motility of microorganisms. AB - We present a fast, high-throughput method for characterizing the motility of microorganisms in three dimensions based on standard imaging microscopy. Instead of tracking individual cells, we analyze the spatiotemporal fluctuations of the intensity in the sample from time-lapse images and obtain the intermediate scattering function of the system. We demonstrate our method on two different types of microorganisms: the bacterium Escherichia coli (both smooth swimming and wild type) and the biflagellate alga Chlamydomonas reinhardtii. We validate the methodology using computer simulations and particle tracking. From the intermediate scattering function, we are able to extract the swimming speed distribution, fraction of motile cells, and diffusivity for E. coli, and the swimming speed distribution, and amplitude and frequency of the oscillatory dynamics for C. reinhardtii. In both cases, the motility parameters were averaged over ~10(4) cells and obtained in a few minutes. PMID- 23083707 TI - Amplification and temporal filtering during gradient sensing by nerve growth cones probed with a microfluidic assay. AB - Nerve growth cones (GCs) are chemical sensors that convert graded extracellular cues into oriented axonal motion. To ensure a sensitive and robust response to directional signals in complex and dynamic chemical landscapes, GCs are presumably able to amplify and filter external information. How these processing tasks are performed remains however poorly known. Here, we probe the signal processing capabilities of single GCs during gamma-Aminobutyric acid (GABA) directional sensing with a shear-free microfluidic assay that enables systematic measurements of the GC output response to variable input gradients. By measuring at the single molecule level the polarization of GABA(A) chemoreceptors at the GC membrane, as a function of the external GABA gradient, we find that GCs act as i), signal amplifiers over a narrow range of concentrations, and ii), low-pass temporal filters with a cutoff frequency independent of stimuli conditions. With computational modeling, we determine that these systems-level properties arise at a molecular level from the saturable occupancy response and the lateral dynamics of GABA(A) receptors. PMID- 23083708 TI - Molecular brightness analysis reveals phosphatidylinositol 4-Kinase IIbeta association with clathrin-coated vesicles in living cells. AB - Mammalian cells express two classes of phosphatidylinositol 4-kinase (PI4K), designated as Types II and III, that phosphorylate phosphatidylinositol to generate PI4P. A number of studies have indicated that these enzymes are important for Golgi trafficking and both early and late stages of endocytosis. In this study, we focus on PI4KIIbeta, a protein that is evenly distributed between membrane and soluble fractions, and is believed to participate in stimulus dependent phosphoinositide signaling. Using molecular brightness analysis, we found that EGFP-tagged PI4KIIbeta exists as two distinct species in the cytoplasm: a soluble monomer and a high-order complex enriched with multiple copies of PI4KIIbeta. This observation was confirmed by an autocorrelation analysis that identified two species with distinct mobilities. We further demonstrate that the high-order complex enriched with PI4KIIbeta is sensitive to inhibition of palmitoylation, indicating that it is associated with membranes, very likely vesicles. Indeed, we show that the high-order PI4KIIbeta complex is sensitive to expression of dynamin 2 (K44A), a dominant-negative inhibitor of endocytosis. Using dual-color heterospecies partition analysis, we directly detected that PI4KIIbeta comoves with clathrin light chain on vesicles. This analysis allows us to isolate the comobile species in the presence of strong background contribution from the monomeric pool of PI4KIIbeta. Our results strongly suggest that PI4KIIbeta is involved in an early stage of endocytosis and is associated with clathrin-coated vesicles. Moreover, we establish molecular brightness as a powerful tool for characterizing cellular cytosolic vesicles that are otherwise difficult to characterize by other techniques. PMID- 23083709 TI - Characterization of curli A production on living bacterial surfaces by scanning probe microscopy. AB - Curli are adhesive surface fibers produced by many Enterobacteriaceae, such as Escherichia coli and Salmonella enterica. They are implicated in bacterial attachment and invasion to epithelial cells. In this study, atomic force microscopy was used to determine the effects of curli on topology and mechanical properties of live E. coli cells. Young's moduli of both curli-deficient and curli-overproducing mutants were significantly lower than that of their wild-type (WT) strain, while decay lengths of the former strains were higher than that of the latter strain. Surprisingly, topological images showed that, unlike the WT and curli-overproducing mutant, the curli-deficient mutant produced a large number of flagella-like fibers, which may explain why the strain had a lower Young's modulus than the WT. These results suggest that the mechanical properties of bacterial surfaces are greatly affected by the presence of filamentous structures such as curli and flagella. PMID- 23083710 TI - STICCS reveals matrix-dependent adhesion slipping and gripping in migrating cells. AB - Two-color spatio-temporal image cross-correlation spectroscopy (STICCS) is a new, to our knowledge, image analysis method that calculates space-time autocorrelation and cross-correlation functions from fluorescence intensity fluctuations. STICCS generates cellular flow and diffusion maps that reveal interactions and cotransport of two distinct molecular species labeled with different fluorophores. Here we use computer simulations to map the capabilities and limitations of STICCS for measurements in complex heterogeneous environments containing micro- and macrostructures. We then use STICCS to analyze the co-flux of adhesion components in migrating cells imaged using total internal reflection fluorescence microscopy. The data reveal a robust, time-dependent co-fluxing of certain integrins and paxillin in adhesions in protrusions when they pause, and in adhesions that are sliding and disassembling, demonstrating that the molecules in these adhesions move as a complex. In these regions, both alpha6beta1- or alphaLbeta2-integrins, expressed in CHO.B2 cells, co-flux with paxillin; an analogous cotransport was seen for alpha6beta1-integrin and alpha-actinin in U2OS. This contrasts with the behavior of the alpha5beta1-integrin and paxillin, which do not co-flux. Our results clearly show that integrins can move in complexes with adhesion proteins in protrusions that are retracting. PMID- 23083711 TI - Bacterial thermotaxis by speed modulation. AB - Naturally occurring gradients often extend over relatively long distances such that their steepness is too small for bacteria to detect. We studied the bacterial behavior in such thermal gradients. We find that bacteria migrate along shallow thermal gradients due to a change in their swimming speed resulting from the effect of temperature on the intracellular pH, which also depends on the chemical environment. When nutrients are scarce in the environment the bacteria's intracellular pH decreases with temperature. As a result, the swimming speed of the bacteria decreases with temperature, which causes them to slowly drift toward the warm end of the thermal gradient. However, when serine is added to the medium at concentrations >300 MUM, the intracellular pH increases causing the swimming speed to increase continuously with temperature, and the bacteria to drift toward the cold end of the temperature gradient. This directional migration is not a result of bacterial thermotaxis in the classical sense, because the steepness of the gradients applied is below the sensing threshold of bacteria. Nevertheless, our results show that the directional switch requires the presence of the bacterial sensing receptors. This seems to be due to the involvement of the receptors in regulating the intracellular pH. PMID- 23083712 TI - Video-rate confocal microscopy for single-molecule imaging in live cells and superresolution fluorescence imaging. AB - There is no confocal microscope optimized for single-molecule imaging in live cells and superresolution fluorescence imaging. By combining the swiftness of the line-scanning method and the high sensitivity of wide-field detection, we have developed a, to our knowledge, novel confocal fluorescence microscope with a good optical-sectioning capability (1.0 MUm), fast frame rates (<33 fps), and superior fluorescence detection efficiency. Full compatibility of the microscope with conventional cell-imaging techniques allowed us to do single-molecule imaging with a great ease at arbitrary depths of live cells. With the new microscope, we monitored diffusion motion of fluorescently labeled cAMP receptors of Dictyostelium discoideum at both the basal and apical surfaces and obtained superresolution fluorescence images of microtubules of COS-7 cells at depths in the range 0-85 MUm from the surface of a coverglass. PMID- 23083713 TI - Design of peptide-membrane interactions to modulate single-file water transport through modified gramicidin channels. AB - Water permeability through single-file channels is affected by intrinsic factors such as their size and polarity and by external determinants like their lipid environment in the membrane. Previous computational studies revealed that the obstruction of the channel by lipid headgroups can be long-lived, in the range of nanoseconds, and that pore-length-matching membrane mimetics could speed up water permeability. To test the hypothesis of lipid-channel interactions modulating channel permeability, we designed different gramicidin A derivatives with attached acyl chains. By combining extensive molecular-dynamics simulations and single-channel water permeation measurements, we show that by tuning lipid channel interactions, these modifications reduce the presence of lipid headgroups in the pore, which leads to a clear and selective increase in their water permeability. PMID- 23083715 TI - Tuning of CFTR chloride channel function by location of positive charges within the pore. AB - High unitary Cl(-) conductance in the cystic fibrosis transmembrane conductance regulator Cl(-) channel requires a functionally unique, positively charged lysine residue (K95) in the inner vestibule of the channel pore. Here we used a mutagenic approach to investigate the ability of other sites in the pore to host this important positive charge. The loss of conductance observed in the K95Q mutation was >50% rescued by substituting a lysine for each of five different pore-lining amino acids, suggesting that the exact location of the fixed positive charge is not crucial to support high conductance. Moving the positive charge also restored open-channel blocker interactions that are lost in K95Q. Introducing a second positive charge in addition to that at K95 did not increase conductance at any site, but did result in a striking increase in the strength of block by divalent Pt(NO(2))(4)(2-) ions. Based on the site dependence of these effects, we propose that although the exact location of the positive charge is not crucial for normal pore properties, transplanting this charge to other sites results in a diminution of its effectiveness that appears to depend on its location along the axis of the pore. PMID- 23083714 TI - CLC anion channel regulatory phosphorylation and conserved signal transduction domains. AB - The signaling mechanisms that regulate CLC anion channels are poorly understood. Caenorhabditis elegans CLH-3b is a member of the CLC-1/2/Ka/Kb channel subfamily. CLH-3b is activated by meiotic cell-cycle progression and cell swelling. Inhibition is brought about by GCK-3 kinase-mediated phosphorylation of S742 and S747 located on a ~176 amino acid disordered domain linking CBS1 and CBS2. Much of the inter-CBS linker is dispensable for channel regulation. However, deletion of a 14 amino acid activation domain encompassing S742 and S747 inhibits channel activity to the same extent as GCK-3. The crystal structure of CmCLC demonstrated that CBS2 interfaces extensively with an intracellular loop connecting membrane helices H and I, the C-terminus of helix D, and a short linker connecting helix R to CBS1. Point mutagenesis of this interface identified two highly conserved aromatic amino acid residues located in the H-I loop and the first alpha-helix (alpha1) of CBS2. Mutation of either residue to alanine rendered CLH-3b insensitive to GCK-3 inhibition. We suggest that the dephosphorylated activation domain normally interacts with CBS1 and/or CBS2, and that conformational information associated with this interaction is transduced through a conserved signal transduction module comprising the H-I loop and CBS2 alpha1. PMID- 23083716 TI - Size of cell-surface Kv2.1 domains is governed by growth fluctuations. AB - The Kv2.1 voltage-gated potassium channel forms stable clusters on the surface of different mammalian cells. Even though these cell-surface structures have been observed for almost a decade, little is known about the mechanism by which cells maintain them. We measure the distribution of domain sizes to study the kinetics of their growth. Using a Fokker-Planck formalism, we find no evidence for a feedback mechanism present to maintain specific domain radii. Instead, the size of Kv2.1 clusters is consistent with a model where domain size is established by fluctuations in the trafficking machinery. These results are further validated using likelihood and Akaike weights to select the best model for the kinetics of domain growth consistent with our experimental data. PMID- 23083717 TI - Structure and orientation of bovine lactoferrampin in the mimetic bacterial membrane as revealed by solid-state NMR and molecular dynamics simulation. AB - Bovine lactoferrampin (LFampinB) is a newly discovered antimicrobial peptide found in the N1-domain of bovine lactoferrin (268-284), and consists of 17 amino acid residues. It is important to determine the orientation and structure of LFampinB in bacterial membranes to reveal the antimicrobial mechanism. We therefore performed (13)C and (31)P NMR, (13)C-(31)P rotational echo double resonance (REDOR), potassium ion-selective electrode, and quartz-crystal microbalance measurements for LFampinB with mimetic bacterial membrane and molecular-dynamics simulation in acidic membrane. (31)P NMR results indicated that LFampinB caused a defect in mimetic bacterial membranes. Ion-selective electrode measurements showed that ion leakage occurred for the mimetic bacterial membrane containing cardiolipin. Quartz-crystal microbalance measurements revealed that LFampinB had greater affinity to acidic phospholipids than that to neutral phospholipids. (13)C DD-MAS and static NMR spectra showed that LFampinB formed an alpha-helix in the N-terminus region and tilted 45 degrees to the bilayer normal. REDOR dephasing patterns between carbonyl carbon nucleus in LFampinB and phosphorus nuclei in lipid phosphate groups were measured by (13)C (31)P REDOR and the results revealed that LFampinB is located in the interfacial region of the membrane. Molecular-dynamics simulation showed the tilt angle to be 42 degrees and the rotation angle to be 92.5 degrees for Leu(3), which are in excellent agreement with the experimental values. PMID- 23083718 TI - Mechanical properties of beta-catenin revealed by single-molecule experiments. AB - beta-catenin is a central component of the adaptor complex that links cadherins to the actin cytoskeleton in adherens junctions and thus, it is a good candidate to sense and transmit mechanical forces to trigger specific changes inside the cell. To fully understand its molecular physiology, we must first investigate its mechanical role in mechanotransduction within the cadherin system. We have studied the mechanical response of beta-catenin to stretching using single molecule force spectroscopy and molecular dynamics. Unlike most proteins analyzed to date, which have a fixed mechanical unfolding pathway, the beta-catenin armadillo repeat region (ARM) displays low mechanostability and multiple alternative unfolding pathways that seem to be modulated by its unstructured termini. These results are supported by steered molecular dynamics simulations, which also predict its mechanical stabilization and unfolding pathway restrictions when the contiguous alpha-helix of the C-terminal unstructured region is included. Furthermore, simulations of the ARM/E-cadherin cytosolic tail complex emulating the most probable stress geometry occurring in vivo show a mechanical stabilization of the interaction whose magnitude correlates with the length of the stretch of the cadherin cytosolic tail that is in contact with the ARM region. PMID- 23083719 TI - The effect of nonspecific binding of lambda repressor on DNA looping dynamics. AB - The lambda repressor (CI) protein-induced DNA loop maintains stable lysogeny, yet allows efficient switching to lysis. Herein, the kinetics of loop formation and breakdown has been characterized at various concentrations of protein using tethered particle microscopy and a novel, to our knowledge, method of analysis. Our results show that a broad distribution of rate constants and complex kinetics underlie loop formation and breakdown. In addition, comparison of the kinetics of looping in wild-type DNA and DNA with mutated o3 operators showed that these sites may trigger nucleation of nonspecific binding at the closure of the loop. The average activation energy calculated from the rate constant distribution is consistent with a model in which nonspecific binding of CI between the operators shortens their effective separation, thereby lowering the energy barrier for loop formation and broadening the rate constant distribution for looping. Similarly, nonspecific binding affects the kinetics of loop breakdown by increasing the number of loop-securing protein interactions, and broadens the rate constant distribution for this reaction. Therefore, simultaneous increase of the rate constant for loop formation and reduction of that for loop breakdown stabilizes lysogeny. Given these simultaneous changes, the frequency of transitions between the looped and the unlooped state remains nearly constant. Although the loop becomes more stable thermodynamically with increasing CI concentration, it still opens periodically, conferring sensitivity to environmental changes, which may require switching to lytic conditions. PMID- 23083720 TI - Prediction of protein relative enthalpic stability from molecular dynamics simulations of the folded and unfolded states. AB - For proteins of known structure, the relative enthalpic stability with respect to wild-type, DeltaDeltaH(U), can be estimated by direct computation of the folded and unfolded state energies. We propose a model by which the change in stability upon mutation can be predicted from all-atom molecular dynamics simulations for the folded state and a peptide-based model for the unfolded state. The unfolding enthalpies are expressed in terms of environmental and hydration-solvent reorganization contributions that readily allow a residue-specific analysis of DeltaDeltaH(U). The method is applied to estimate the relative enthalpic stability of variants with buried charged groups in T4 lysozyme. The predicted relative stabilities are in good agreement with experimental data. Environmental factors are observed to contribute more than hydration to the overall DeltaDeltaH(U). The residue-specific analysis finds that the effects of burying charge are both localized and long-range. The enthalpy for hydration-solvent reorganization varies considerably among different amino-acid types, but because the variant folded state structures are similar to those of the wild-type, the hydration-solvent reorganization contribution to DeltaDeltaH(U) is localized at the mutation site, in contrast to environmental contributions. Overall, mutation of apolar and polar amino acids to charged amino acids are destabilizing, but the reasons are complex and differ from site to site. PMID- 23083721 TI - Early stages of the HIV-1 capsid protein lattice formation. AB - The early stages in the formation of the HIV-1 capsid (CA) protein lattice are investigated. The underlying coarse-grained (CG) model is parameterized directly from experimental data and examined under various native contact interaction strengths, CA dimer interfacial configurations, and local surface curvatures. The mechanism of early contiguous mature-style CA p6 lattice formation is explored, and a trimer-of-dimers structure is found to be crucial for CA lattice production. Quasi-equivalent generation of both the pentamer and hexamer components of the HIV-1 viral CA is also demonstrated, and the formation of pentamers is shown to be highly sensitive to local curvature, supporting the view that such inclusions in high-curvature regions allow closure of the viral CA surface. The complicated behavior of CA lattice self-assembly is shown to be reducible to a relatively simple function of the trimer-of-dimers behavior. PMID- 23083722 TI - Long-timescale molecular dynamics simulations elucidate the dynamics and kinetics of exposure of the hydrophobic patch in troponin C. AB - Troponin (Tn) is an important regulatory protein in the thin-filament complex of cardiomyocytes. Calcium binding to the troponin C (TnC) subunit causes a change in its dynamics that leads to the transient opening of a hydrophobic patch on TnC's surface, to which a helix of another subunit, troponin I (TnI), binds. This process initiates contraction, making it an important target for studies investigating the detailed molecular processes that underlie contraction. Here we use microsecond-timescale Anton molecular dynamics simulations to investigate the dynamics and kinetics of the opening transition of the TnC hydrophobic patch. Free-energy differences for opening are calculated for wild-type Ca(2+)-bound TnC (~8 kcal/mol), V44Q Ca(2+)-bound TnC (3.2 kcal/mol), E40A Ca(2+)-bound TnC (~12 kcal/mol), and wild-type apo TnC (~20 kcal/mol). These results suggest that the mutations have a profound impact on the frequency with which the hydrophobic patch presents to TnI. In addition, these simulations corroborate that cardiac wild-type TnC does not open on timescales relevant to contraction without calcium being bound. PMID- 23083723 TI - Molecular dynamics of class A beta-lactamases-effects of substrate binding. AB - The effects of substrate binding on class A beta-lactamase dynamics were studied using molecular dynamics simulations of two model enzymes; 40 100-ns trajectories of the free and substrate-bound forms of TEM-1 (with benzylpenicillin) and PSE-4 (with carbenicillin) were recorded (totaling 4.0 MUs). Substrates were parameterized with the CHARMM General Force Field. In both enzymes, the Omega loop exhibits a marked flexibility increase upon substrate binding, supporting the hypothesis of substrate gating. However, specific interactions that are formed or broken in the Omega loop upon binding differ between the two enzymes: dynamics are conserved, but not specific interactions. Substrate binding also has a global structuring effect on TEM-1, but not on PSE-4. Changes in TEM-1's normal modes show long-range effects of substrate binding on enzyme dynamics. Hydrogen bonds observed in the active site are mostly preserved upon substrate binding, and new, transient interactions are also formed. Agreement between NMR relaxation parameters and our theoretical results highlights the dynamic duality of class A beta-lactamases: enzymes that are highly structured on the ps-ns timescale, with important flexibility on the MUs-ms timescale in regions such as the Omega loop. PMID- 23083724 TI - On the role of CD8 T cells in the control of persistent infections. AB - The control of pathogen density during infections is typically assumed to be the result of a combination of resource limitation (loss of target cells that the pathogen can infect), innate immunity, and specific immunity. The contributions of these factors have been considered in acute infections, which are characterized by having a short duration. What controls the pathogen during persistent infections is less clear, and is complicated by two factors. First, specific immune responses become exhausted if they are subject to chronic stimulation. Exhaustion has been best characterized for CD8 T cell responses, and occurs through a combination of cell death and loss of functionality of surviving cells. Second, new nonexhausted T cells can immigrate from the thymus during the infection, and may play a role in the control of the infection. In this article, we formulate a partial-differential-equation model to describe the interaction between these processes, and use this model to explore how thymic influx and exhaustion might affect the ability of CD8 T cell responses to control persistent infections. We find that although thymic influx can play a critical role in the maintenance of a limited CD8 T cell response during persistent infections, this response is not sufficiently large to play a significant role in controlling the infection. In doing so, our results highlight the importance of resource limitation and innate immunity in the control of persistent infections. PMID- 23083725 TI - Increasing membrane tension decreases miscibility temperatures; an experimental demonstration via micropipette aspiration. AB - It has been hypothesized that cytoskeletal tension prevents large-scale phase separation within cell plasma membranes. Here, we microaspirate giant unilamellar vesicles to determine the effect of mechanical stress on the liquid/liquid miscibility temperature of a membrane composed of a ternary lipid mixture. An increase in tension of 0.1 mN/m induces a decrease in miscibility temperature on the order of a few tenths of a degree K, which validates recent theoretical predictions. PMID- 23083726 TI - The physical foundation of vasoocclusion in sickle cell disease. AB - The pathology of sickle cell disease arises from the occlusion of small blood vessels because of polymerization of the sickle hemoglobin within the red cells. We present measurements using a microfluidic method we have developed to determine the pressure required to eject individual red cells from a capillary sized channel after the cell has sickled. We find that the maximum pressure is only ~100 Pa, much smaller than typically found in the microcirculation. This explains why experiments using animal models have not observed occlusion beginning in capillaries. The magnitude of the pressure and its dependence on intracellular concentration are both well described as consequences of sickle hemoglobin polymerization acting as a Brownian ratchet. Given the recently determined stiffness of sickle hemoglobin gels, the observed obstruction seen in sickle cell disease as mediated by adherent cells can now be rationalized, and surprisingly suggests a window of maximum vulnerability during circulation of sickle cells. PMID- 23083727 TI - Antigen sampling in the small intestine. AB - Active sampling of intestinal antigen initiates regulated immune responses that ensure intestinal homeostasis. Several specialized mechanisms transport luminal antigen across the gut epithelium. Epithelium overlying lymphoid compartments is equipped with transcytotic microfold (M) cells that transport particulate material either directly or with the help of dendritic cells (DCs). By contrast, normal villous epithelium transports antigen by means of antigen-shuttling receptors together with phagocytes that scan the gut epithelium and potentially the gut lumen. Here, we examine recent insights into the nature of the epithelial and immune cell types involved in antigen uptake and describe how the process of antigen transport has been visualized by intravital microscopy. These new findings might help optimize antigen delivery systems for mucosal vaccination. PMID- 23083728 TI - What the fish's eye tells the fish's brain. AB - In this issue of Neuron, Nikolaou et al. (2012) place the first pins in the functional map of the optic tectum. They show that retinal ganglion cells coding for the trajectory of motion target the most superficial layer in the tectum, whereas ganglion cells carrying information on the orientation of stimuli target deeper layers. PMID- 23083729 TI - A prion-mediated mechanism for memory proposed in Drosophila. AB - Memories are remarkably persistent, but rely on transient signaling. The prion like properties of CPEB suggested a solution to this problem. The paper by Kruttner et al. (2012) in this issue of Neuron demonstrates that the prion-like domain of Drosophila CPEB functions independently of its RNA-binding domain for memory. PMID- 23083730 TI - Cell assemblies of the superficial cortex. AB - The auditory cortex encodes information about sounds through the combined activity of large numbers of neurons, but the way this population activity is organized has not been clear. In this issue of Neuron, Bathellier et al. (2012) show that firing in the superficial layers of auditory cortex is organized into a small number of attractor-like neuronal assemblies, whose responses can predict an animal's sound discrimination performance. PMID- 23083731 TI - The neuronal organization of the retina. AB - The mammalian retina consists of neurons of >60 distinct types, each playing a specific role in processing visual images. They are arranged in three main stages. The first decomposes the outputs of the rod and cone photoreceptors into ~12 parallel information streams. The second connects these streams to specific types of retinal ganglion cells. The third combines bipolar and amacrine cell activity to create the diverse encodings of the visual world--roughly 20 of them- that the retina transmits to the brain. New transformations of the visual input continue to be found: at least half of the encodings sent to the brain (ganglion cell response selectivities) remain to be discovered. This diversity of the retina's outputs has yet to be incorporated into our understanding of higher visual function. PMID- 23083732 TI - Attention, learning, and the value of information. AB - Despite many studies on selective attention, fundamental questions remain about its nature and neural mechanisms. Here I draw from the animal and machine learning fields that describe attention as a mechanism for active learning and uncertainty reduction and explore the implications of this view for understanding visual attention and eye movement control. I propose that a closer integration of these different views has the potential greatly to expand our understanding of oculomotor control and our ability to use this system as a window into high level but poorly understood cognitive functions, including the capacity for curiosity and exploration and for inferring internal models of the external world. PMID- 23083733 TI - Imaging neural activity using Thy1-GCaMP transgenic mice. AB - The ability to chronically monitor neuronal activity in the living brain is essential for understanding the organization and function of the nervous system. The genetically encoded green fluorescent protein-based calcium sensor GCaMP provides a powerful tool for detecting calcium transients in neuronal somata, processes, and synapses that are triggered by neuronal activities. Here we report the generation and characterization of transgenic mice that express improved GCaMPs in various neuronal subpopulations under the control of the Thy1 promoter. In vitro and in vivo studies show that calcium transients induced by spontaneous and stimulus-evoked neuronal activities can be readily detected at the level of individual cells and synapses in acute brain slices, as well as chronically in awake, behaving animals. These GCaMP transgenic mice allow investigation of activity patterns in defined neuronal populations in the living brain and will greatly facilitate dissecting complex structural and functional relationships of neural networks. PMID- 23083734 TI - A subtype-specific function for the extracellular domain of neuroligin 1 in hippocampal LTP. AB - At neuronal excitatory synapses, two major subtypes of the synaptic adhesion molecule neuroligin are present. These subtypes, neuroligin 1 and neuroligin 3, have roles in synaptogenesis and synaptic maintenance that appear largely overlapping. In this study, we combine electrophysiology with molecular deletion and replacement of these proteins to identify similarities and differences between these subtypes. In doing so, we identify a subtype-specific role in LTP for neuroligin 1 in young CA1, which persists into adulthood in the dentate gyrus. As neuroligin 3 showed no requirement for LTP, we constructed chimeric proteins of the two excitatory neuroligin subtypes to identify the molecular determinants particular to the unique function of neuroligin 1. Using in vivo molecular replacement experiments, we find that these unique functions depend on a region in its extracellular domain containing the B site splice insertion previously shown to determine specificity of neurexin binding. PMID- 23083735 TI - Parametric functional maps of visual inputs to the tectum. AB - How features of the visual scene are encoded in the population activity of retinal ganglion cells (RGCs) targeting specific regions of the brain is not well understood. To address this, we have used a genetically encoded reporter of presynaptic function (SyGCaMP3) to record visually evoked activity in the population of RGC axons innervating the zebrafish tectum. Using unbiased voxel wise analysis of SyGCaMP3 signals, we identify three subtypes of direction selective and two subtypes of orientation-selective retinal input. Composite parametric functional maps generated across many larvae show laminar segregation of direction- and orientation-selective responses and unexpected retinotopic biases in the distribution of functional subtypes. These findings provide a systematic description of the form, organization, and dimensionality of visual inputs to the brain and will serve as a platform for understanding emergent properties in tectal circuits associated with visually driven behavior. PMID- 23083736 TI - Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. AB - Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS. PMID- 23083737 TI - Slit/Robo signaling modulates the proliferation of central nervous system progenitors. AB - Neurogenesis relies on a delicate balance between progenitor maintenance and neuronal production. Progenitors divide symmetrically to increase the pool of dividing cells. Subsequently, they divide asymmetrically to self-renew and produce new neurons or, in some brain regions, intermediate progenitor cells (IPCs). Here we report that central nervous system progenitors express Robo1 and Robo2, receptors for Slit proteins that regulate axon guidance, and that absence of these receptors or their ligands leads to loss of ventricular mitoses. Conversely, production of IPCs is enhanced in Robo1/2 and Slit1/2 mutants, suggesting that Slit/Robo signaling modulates the transition between primary and intermediate progenitors. Unexpectedly, these defects do not lead to transient overproduction of neurons, probably because supernumerary IPCs fail to detach from the ventricular lining and cycle very slowly. At the molecular level, the role of Slit/Robo in progenitor cells involves transcriptional activation of the Notch effector Hes1. These findings demonstrate that Robo signaling modulates progenitor cell dynamics in the developing brain. PMID- 23083738 TI - Reelin controls neuronal positioning by promoting cell-matrix adhesion via inside out activation of integrin alpha5beta1. AB - Birthdate-dependent neuronal layering is fundamental to neocortical functions. The extracellular protein Reelin is essential for the establishment of the eventual neuronal alignments. Although this Reelin-dependent neuronal layering is mainly established by the final neuronal migration step called "terminal translocation" beneath the marginal zone (MZ), the molecular mechanism underlying the control by Reelin of terminal translocation and layer formation is largely unknown. Here, we show that after Reelin binds to its receptors, it activates integrin alpha5beta1 through the intracellular Dab1-Crk/CrkL-C3G-Rap1 pathway. This intracellular pathway is required for terminal translocation and the activation of Reelin signaling promotes neuronal adhesion to fibronectin through integrin alpha5beta1. Since fibronectin is localized in the MZ, the activated integrin alpha5beta1 then controls terminal translocation, which mediates proper neuronal alignments in the mature cortex. These data indicate that Reelin dependent activation of neuronal adhesion to the extracellular matrix is crucial for the eventual birth-date-dependent layering of the neocortex. PMID- 23083739 TI - Calcium feedback to cGMP synthesis strongly attenuates single-photon responses driven by long rhodopsin lifetimes. AB - Rod photoreceptors generate amplified, reproducible responses to single photons via a G protein signaling cascade. Surprisingly, genetic perturbations that dramatically alter the deactivation of the principal signal amplifier, the GPCR rhodopsin (R*), do not much alter the amplitude of single-photon responses (SPRs). These same perturbations, when crossed into a line lacking calcium feedback regulation of cGMP synthesis, produced much larger alterations in SPR amplitudes. Analysis of SPRs from rods with and without feedback reveal that the consequences of trial-to-trial fluctuations in R* lifetime in normal rods are also dampened by feedback regulation of cGMP synthesis. Thus, calcium feedback trumps the mechanisms of R* deactivation in determining the SPR amplitude, attenuating responses arising from longer R* lifetimes to a greater extent than those arising from shorter ones. As a result, rod SPRs achieve a more stereotyped amplitude, a characteristic considered important for reliable transmission through the visual system. PMID- 23083740 TI - Drosophila CPEB Orb2A mediates memory independent of Its RNA-binding domain. AB - Long-term memory and synaptic plasticity are thought to require the synthesis of new proteins at activated synapses. The CPEB family of RNA binding proteins, including Drosophila Orb2, has been implicated in this process. The precise mechanism by which these molecules regulate memory formation is however poorly understood. We used gene targeting and site-specific transgenesis to specifically modify the endogenous orb2 gene in order to investigate its role in long-term memory formation. We show that the Orb2A and Orb2B isoforms, while both essential, have distinct functions in memory formation. These two isoforms have common glutamine-rich and RNA-binding domains, yet Orb2A uniquely requires the former and Orb2B the latter. We further show that Orb2A induces Orb2 complexes in a manner dependent upon both its glutamine-rich region and neuronal activity. We propose that Orb2B acts as a conventional CPEB to regulate transport and/or translation of specific mRNAs, whereas Orb2A acts in an unconventional manner to form stable Orb2 complexes that are essential for memory to persist. PMID- 23083742 TI - Activity-dependent proteolytic cleavage of neuroligin-1. AB - Neuroligin (NLG), a postsynaptic adhesion molecule, is involved in the formation of synapses by binding to a cognate presynaptic ligand, neurexin. Here we report that neuroligin-1 (NLG1) undergoes ectodomain shedding at the juxtamembrane stalk region to generate a secreted form of NLG1 and a membrane-tethered C-terminal fragment (CTF) in adult rat brains in vivo as well as in neuronal cultures. Pharmacological and genetic studies identified ADAM10 as the major protease responsible for NLG1 shedding, the latter being augmented by synaptic NMDA receptor activation or interaction with soluble neurexin ligands. NLG1-CTF was subsequently cleaved by presenilin/gamma-secretase. Secretion of soluble NLG1 was significantly upregulated under a prolonged epileptic seizure condition, and inhibition of NLG1 shedding led to an increase in numbers of dendritic spines in neuronal cultures. Collectively, neuronal activity-dependent proteolytic processing of NLG1 may negatively regulate the remodeling of spines at excitatory synapses. PMID- 23083741 TI - Transsynaptic signaling by activity-dependent cleavage of neuroligin-1. AB - Adhesive contact between pre- and postsynaptic neurons initiates synapse formation during brain development and provides a natural means of transsynaptic signaling. Numerous adhesion molecules and their role during synapse development have been described in detail. However, once established, the mechanisms of adhesive disassembly and its function in regulating synaptic transmission have been unclear. Here, we report that synaptic activity induces acute proteolytic cleavage of neuroligin-1 (NLG1), a postsynaptic adhesion molecule at glutamatergic synapses. NLG1 cleavage is triggered by NMDA receptor activation, requires Ca2+ /calmodulin-dependent protein kinase, and is mediated by proteolytic activity of matrix metalloprotease 9 (MMP9). Cleavage of NLG1 occurs at single activated spines, is regulated by neural activity in vivo, and causes rapid destabilization of its presynaptic partner neurexin-1beta (NRX1beta). In turn, NLG1 cleavage depresses synaptic transmission by abruptly reducing presynaptic release probability. Thus, local proteolytic control of synaptic adhesion tunes synaptic transmission during brain development and plasticity. PMID- 23083743 TI - Slow cortical dynamics and the accumulation of information over long timescales. AB - Making sense of the world requires us to process information over multiple timescales. We sought to identify brain regions that accumulate information over short and long timescales and to characterize the distinguishing features of their dynamics. We recorded electrocorticographic (ECoG) signals from individuals watching intact and scrambled movies. Within sensory regions, fluctuations of high-frequency (64-200 Hz) power reliably tracked instantaneous low-level properties of the intact and scrambled movies. Within higher order regions, the power fluctuations were more reliable for the intact movie than the scrambled movie, indicating that these regions accumulate information over relatively long time periods (several seconds or longer). Slow (<0.1 Hz) fluctuations of high frequency power with time courses locked to the movies were observed throughout the cortex. Slow fluctuations were relatively larger in regions that accumulated information over longer time periods, suggesting a connection between slow neuronal population dynamics and temporally extended information processing. PMID- 23083744 TI - Discrete neocortical dynamics predict behavioral categorization of sounds. AB - The ability to group stimuli into perceptual categories is essential for efficient interaction with the environment. Discrete dynamics that emerge in brain networks are believed to be the neuronal correlate of category formation. Observations of such dynamics have recently been made; however, it is still unresolved if they actually match perceptual categories. Using in vivo two-photon calcium imaging in the auditory cortex of mice, we show that local network activity evoked by sounds is constrained to few response modes. Transitions between response modes are characterized by an abrupt switch, indicating attractor-like, discrete dynamics. Moreover, we show that local cortical responses quantitatively predict discrimination performance and spontaneous categorization of sounds in behaving mice. Our results therefore demonstrate that local nonlinear dynamics in the auditory cortex generate spontaneous sound categories which can be selected for behavioral or perceptual decisions. PMID- 23083745 TI - Opposing mechanisms support the voluntary forgetting of unwanted memories. AB - Reminders of the past can trigger the recollection of events that one would rather forget. Here, using fMRI, we demonstrate two distinct neural mechanisms that foster the intentional forgetting of such unwanted memories. Both mechanisms impair long-term retention by limiting momentary awareness of the memories, yet they operate in opposite ways. One mechanism, direct suppression, disengages episodic retrieval through the systemic inhibition of hippocampal processing that originates from right dorsolateral prefrontal cortex (PFC). The opposite mechanism, thought substitution, instead engages retrieval processes to occupy the limited focus of awareness with a substitute memory. It is mediated by interactions between left caudal and midventrolateral PFC that support the selective retrieval of substitutes in the context of prepotent, unwanted memories. These findings suggest that we are not at the mercy of passive forgetting; rather, our memories can be shaped by two opposite mechanisms of mnemonic control. PMID- 23083747 TI - Does doping with aluminum alter the effects of ZnO nanoparticles on the metabolism of soil pseudomonads? AB - Doping of ZnO nanoparticles (NPs) is being used to increase their commercialization in the optical and semiconductor fields. This paper addresses whether doping with Al alters how ZnO NPs at nonlethal levels modifies the metabolism of soil-borne pseudomonads which are beneficial in performing bioremediation or promoting plant growth. The differences in X-ray diffraction (XRD) patterns, observed between commercial ZnO and Al-doped ZnO NPs indicated the aluminum was present as Al NPs. Both particles aggregated in the bacterial growth medium and formed colloids of different surface charges. They had similar effects on bacterial metabolism: rapid, dose-dependent loss in light output indicative of temporary toxicity in a biosensor constructed in Pseudomonas putida KT2440; increased production of a fluorescent pyoverdine-type siderophore, and decreased levels of indole acetic acid and phenazines in Pseudomonas chlororaphis O6. Solubilization of Zn and Al from the NPs contributed to these responses to different extents. These findings indicate that Al-doping of the ZnO NPs did not reduce the ability of the NPs to alter bacterial metabolism in ways that could influence performance of the pseudomonads in their soil environment. PMID- 23083746 TI - Microbial population index and community structure in saline-alkaline soil using gene targeted metagenomics. AB - Population indices of bacteria and archaea were investigated from saline-alkaline soil and a possible microbe-environment pattern was established using gene targeted metagenomics. Clone libraries were constructed using 16S rRNA and functional gene(s) involved in carbon fixation (cbbL), nitrogen fixation (nifH), ammonia oxidation (amoA) and sulfur metabolism (apsA). Molecular phylogeny revealed the dominance of Actinobacteria, Firmicutes and Proteobacteria along with archaeal members of Halobacteraceae. The library consisted of novel bacterial (20%) and archaeal (38%) genera showing <=95% similarity to previously retrieved sequences. Phylogenetic analysis indicated ability of inhabitant to survive in stress condition. The 16S rRNA gene libraries contained novel gene sequences and were distantly homologous with cultured bacteria. Functional gene libraries were found unique and most of the clones were distantly related to Proteobacteria, while clones of nifH gene library also showed homology with Cyanobacteria and Firmicutes. Quantitative real-time PCR exhibited that bacterial abundance was two orders of magnitude higher than archaeal. The gene(s) quantification indicated the size of the functional guilds harboring relevant key genes. The study provides insights on microbial ecology and different metabolic interactions occurring in saline-alkaline soil, possessing phylogenetically diverse groups of bacteria and archaea, which may be explored further for gene cataloging and metabolic profiling. PMID- 23083749 TI - Classification, diagnosis, and referral of patients with axial spondyloarthritis. AB - The concepts for classification, diagnosis and referral of patients with axial spondyloarthitis differ, although they of course basically relate to the same disease. While classification criteria and referral strategies concentrate largely on patients with chronic back pain with an age at onset before 45 years, the rheumatologist can make a diagnosis of axial SpA in patients with late onset or in patients with back pain for only some weeks if other items are fulfilled. Early recognition of patients with axial SpA is important to establish the diagnosis, potentially start therapeutic interventions and avoid unnecessary health care procedures. PMID- 23083750 TI - Inflammatory back pain. AB - Inflammatory back pain (IBP) is a concept, which elements characterize the spinal involvement of patients with ankylosing spondylitis (AS) and axial spondyloarthritis (axSpA). The identification of patients with IBP depends on the clinical setting and the diagnostic value of several IBP criteria. IBP differentiation from non-inflammatory, mechanical chronic back might be sometimes difficult, but the role of IBP diagnosis in the early stage of axSpA and AS leads to a better treatment. PMID- 23083748 TI - Epidemiology of spondyloarthritis. AB - Spondyloarthritis (SpA) represents a group of interrelated diseases with common clinical features and a close association with HLA-B27. Reports of incidence and prevalence of diseases vary depending on methodological differences between studies, the case definition used to classify disease, and the prevalence of HLA B27 in the population studied. Newly proposed criteria for axial SpA and peripheral SpA present a new approach to facilitate classification of the SpA into 2 main subtypes and the criteria allow earlier detection of patents with inflammatory back pain. These criteria were developed for use in a (specialized) clinical setting and not for large epidemiologic studies. PMID- 23083751 TI - Inflammatory back pain: the United States perspective. AB - Inflammatory back pain (IBP) is a relatively recent and well-accepted concept whose precise definition remains elusive. The definition of IBP varies by criteria set, as does its sensitivity and specificity regarding screening and case ascertainment in various clinical or epidemiologic settings. This article reviews the history of efforts to define IBP, particularly the criteria sets that have been built around its measurement, describes assessment of IBP in the clinical setting, and illustrates how IBP has been used in epidemiologic and clinical research. PMID- 23083752 TI - Imaging in axial spondyloarthritis: diagnostic problems and pitfalls. AB - Magnetic Structural changes in axial Spondyloarthritis (axSpA) are best identified by conventional radiographs, while magnetic resonance imaging (MRI) is considered the gold standard for assessment of inflammatory changes. Imaging of the axial skeleton is crucial for the diagnosis but also for classification to non-radiographic axSpA according to the 2009 ASAS classification criteria. Despite the existing definitions for a positive MRI for the sacroiliac joints and the spine, these predefined lesions can also be seen in other conditions, representing pitfalls and false-positive conclusions in patients with similar clinical symptoms who do not have SpA. Diagnosis of SpA should result from the combination of clinical, laboratory and imaging findings. PMID- 23083753 TI - Comorbidities in patients with spondyloarthritis. AB - Chronic inflammatory spondyloarthritis involves axial symptoms of the spine and sacroiliac joints, or peripheral arthritis. Many patients suffer from extra articular manifestations. With acute anterior uveitis, rapid treatment prevents synechiae. Other organs can be involved. Treatment includes exercise, nonsteroidal antiinflammatory drugs (if insufficient response, tumor necrosis factor blockers), and (with peripheral arthritis) sulfasalazine. Patients with ankylosing spondylitis have comorbidities and increased cardiovascular risk. For uveitis or inflammatory bowel disease, patients should be referred to an ophthalmologist or gastroenterologist. Cardiovascular risk may originate from atherosclerotic disease and cardiac manifestations. Epidemiological studies should be conducted before echocardiogram screening and cardiovascular risk management. PMID- 23083754 TI - The genetics of ankylosing spondylitis and axial spondyloarthritis. AB - Ankylosing spondylitis (AS) and spondyloarthritis are strongly genetically determined. The long-standing association with HLA-B27 is well described, although the mechanism by which that association induces AS remains uncertain. Recent developments include the description of HLA-B27 tag single nucleotide polymorphisms in European and Asian populations. An increasing number of non-MHC genetic associations have been reported, which provided amongst other things the first evidence of the involvement of the IL-23 pathway in AS. The association with ERAP1 is now known to be restricted to HLA-B27 positive disease. Preliminary studies on the genetics of axial spondyloarthritis demonstrate a lower HLA-B27 carriage rate compared with AS. Studies with larger samples and including non European ethnic groups are likely to further advance the understanding of the genetics of AS and spondyloarthritis. PMID- 23083755 TI - Pathophysiology of new bone formation and ankylosis in spondyloarthritis. AB - The outcome of patients suffering from spondyloarthritis is determined by chronic inflammation and new bone formation leading to ankylosis. The latter process manifests by new cartilage and bone formation leading to joint or spine fusion. This article discusses the main mechanisms of new bone formation in spondyloarthritis. It reviews the key molecules and concepts of new bone formation and ankylosis in animal models of disease and translates these findings to human disease. In addition, proposed biomarkers of new bone formation are evaluated and the translational current and future challenges are discussed with regards to new bone formation in spondyloarthritis. PMID- 23083756 TI - Pathophysiology and role of the gastrointestinal system in spondyloarthritides. AB - Inflammatory bowel disease (IBD) is a well-known extra-articular manifestation in spondyloarthritis (SpA); about 6.5% of patients with ankylosing spondylitis develop IBD during the course of the disease. The pathogenesis of both SpA and IBD is considered to be the result of a complex interplay between the host (genetic predisposition), the immune system and environmental factors, notably microorganisms, leading to a disturbed immune system and chronic inflammation. Over the past decade, the role of tumor necrosis factor inhibition (infliximab, etanercept, adalimumab, golimumab) in improving signs and symptoms and overall quality of life has been well documented in various forms of SpA. Future research will clarify the role of other potential targets. PMID- 23083757 TI - Therapy for spondyloarthritis: the role of extra-articular manifestations (eye, skin). AB - Spondyloarthritis can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. Extra-articular manifestations are all the medical conditions and symptoms that are not directly related to the locomotor system. Besides inflammatory bowel diseases, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations regarding the treatment of spondyloarthritis. PMID- 23083758 TI - Therapeutic controversies in spondyloarthritis: nonsteroidal anti-inflammatory drugs. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered a first-line therapy in patients with axial spondyloarthritis (axSpA), including ankylosing spondylitis. NSAIDs reduce pain and stiffness effectively in most patients, are able to reduce systemic and local inflammation, and can inhibit progression of structural damage in the spine. However, effective control of symptoms and retardation of radiographic progression often require continuous and long-term treatment, which raises safety concerns. This article discusses controversies related to the current role of NSAIDs in axSpA treatment, risks and benefits of this treatment, and current trends for individualized treatment. PMID- 23083759 TI - Therapeutic controversies: tumor necrosis factor alpha inhibitors in ankylosing spondylitis. AB - Tumor necrosis factor alpha inhibitors (TNF blockers) have revolutionized the treatment of patients with anklyosing spondylitis. Despite clinical efficacy, there are questions and controversies treating rheumatologists face, which this review discusses: whether there are specific indications for specific TNF blockers; whether the dose of TNF blockers can be decreased; whether immunogenicity plays a role; what the role of residual active inflammation MRI might be; and whether there is a window of opportunity to treat patients with anklyosing spondylitis and prevent radiographic progression. This article summarizes evidence for switching between TNF blockers and addresses the question of malignancies. PMID- 23083760 TI - How important is early therapy in axial spondyloarthritis? AB - There are 2 groups of drugs that have been shown effective in the treatment of patients with axial spondyloarthritis: nonsteroidal anti-inflammatory drugs and tumor necrosis factor alpha blockers. Conventional disease-modifying drugs and some other biologics have not been shown clinically efficacious in this disease. This overview discusses the available data on whether early treatment strategies in patients with axial spondyloarthritis have an effect on (1) the percentage of patients reaching clinical remission, (2) achieving drug-free remission, and (3) the progress of radiographic progression in the spine as a parameter for structural damage. PMID- 23083761 TI - Rheumatic Disease Clinics of North America. Spondyloarthritis. Foreword. PMID- 23083762 TI - Rheumatic Disease Clinics of North America. Spondyloarthritis. Preface. PMID- 23083764 TI - [Osteolytic lesions on SPECT-CT]. PMID- 23083763 TI - Dorsomedial hypothalamic NPY and energy balance control. AB - Neuropeptide Y (NPY) is a potent hypothalamic orexigenic peptide. Within the hypothalamus, Npy is primarily expressed in the arcuate nucleus (ARC) and the dorsomedial hypothalamus (DMH). While the actions of ARC NPY in energy balance control have been well studied, a role for DMH NPY is still being unraveled. In contrast to ARC NPY that serves as one of downstream mediators of actions of leptin in maintaining energy homeostasis, DMH NPY is not under the control of leptin. Npy gene expression in the DMH is regulated by brain cholecystokinin (CCK) and other yet to be identified molecules. The findings of DMH NPY overexpression or induction in animals with increased energy demands and in certain rodent models of obesity implicate a role for DMH NPY in maintaining energy homeostasis. In support of this view, adeno-associated virus (AAV) mediated overexpression of NPY in the DMH causes increases in food intake and body weight and exacerbates high-fat diet-induced hyperphagia and obesity. Knockdown of NPY in the DMH via AAV-mediated RNAi ameliorates hyperphagia, obesity and glucose intolerance of Otsuka Long-Evans Tokushima Fatty rats in which DMH NPY overexpression has been proposed to play a causal role. NPY knockdown in the DMH also prevents high-fat diet-induced hyperphagia, obesity and impaired glucose homeostasis. A detailed examination of actions of DMH NPY reveals that DMH NPY specifically affects nocturnal meal size and produces an inhibitory action on within meal satiety signals. In addition, DMH NPY modulates energy expenditure likely through affecting brown adipocyte formation and thermogenic activity. Overall, the recent findings provide clear evidence demonstrating critical roles for DMH NPY in energy balance control, and also imply a potential role for DMH NPY in maintaining glucose homeostasis. PMID- 23083765 TI - Urgent surgery in a Kasabach-Merrit syndrome associated with a giant hepatic angiosarcoma. PMID- 23083766 TI - [Multiple liver and spleen haemangiomas]. PMID- 23083767 TI - Electrophoresis of a single charged porous sphere in an infinite medium of electrolyte solution. AB - Electrophoresis of a single charged porous sphere in an infinite medium of electrolyte solution is investigated theoretically. The porous sphere is treated as a Brinkman medium with uniformly distributed electric charges. General electrokinetic equations including the full nonlinear Poisson equation are employed as the governing equations, which are then solved with a pseudo-spectral method based on Chebyshev polynomials. Key parameters of electrokinetic interest are examined for their effects on particle motion. Motion-deterring nonlinear effects, the condensation effect and the double layer polarization effect, are separated from each other and examined in detail for their respective impact on the particle motion. The Debye-Huckel approximation is found to overestimate the particle mobility severely: Up to ten times for a porous sphere both highly charged and highly permeable in some situations, which is attributed to the polarization effect. Convenient charts of correction factors for this overestimation are provided to facilitate the usage by interested experimental researchers in the field of the study of polyelectrolytes, such as DNA and proteins, which are well modeled as charged porous spheres. PMID- 23083768 TI - Voltage dependent closure of PorB class II porin from Neisseria meningitidis investigated using impedance spectroscopy in a tethered bilayer lipid membrane interface. AB - Electrochemical impedance spectroscopy (EIS) was used to characterize voltage dependent closure of PorB class II (PorBII) porin from Neisseria meningitidis incorporated in a tethered bilayer lipid membrane (tBLM). The tBLM's lower leaflet was fabricated by depositing a self assembled monolayer (SAM) of 1,2 dipalmitoyl-sn-glycero-3-phosphothioethanol (DPPTE) on a gold electrode, and the upper leaflet was formed by depositing1,2-dioleoyl-sn-glycero-3-phoshocholine (DOPC) liposomes. At 0mV bias DC potential, incorporation of PorBII decreased the membrane resistance (R(m)) from 2.5 MOmegac m(2) to 0.6 MOmega cm(2), giving a DeltaR(m) of 1.9 MOmega cm(2) and a normalized DeltaR(m) (DeltaR(m) divided by the R(m) of the tBLM without PorBII) of 76%. When the bias DC potential was increased to 200 mV, the normalized DeltaR(m) value decreased to 20%. The effect of applied voltage on DeltaR(m) was completely reversible, suggesting voltage dependent closure of PorBII. The voltage dependence of PorBII was further studied in a planar bilayer lipid membrane made from 1,2-diphytanoyl-sn-glycero-3 phosphocholine (DPhytPC). Following a single insertion event, PorBII exhibited multiple conductance states, with reversible, voltage-dependent closure of PorBII porin occurring at high transmembrane potentials. The trimetric porin closed in three discrete steps, each step corresponding to closure of one conducting monomer unit. The most probable single channel conductance was 4.2 nS. The agreement between results obtained with the tBLM and pBLM platforms demonstrates the utility of EIS to screen channel proteins immobilized in tBLM for voltage gated behavior. PMID- 23083769 TI - Phosphotungstic acid anchored to amino-functionalized core-shell magnetic mesoporous silica microspheres: a magnetically recoverable nanocomposite with enhanced photocatalytic activity. AB - H(3)PW(12)O(40) was successfully anchored to the surface of amino-functionalized Fe(3)O(4)@SiO(2)@meso-SiO(2) microspheres by means of chemical bonding to aminosilane groups, aiming to remove unwanted organic compounds from aqueous media. The resultant multifunctional microspheres were thoroughly characterized by transmission electron microscopy, scanning electron microscopy, X-ray diffraction, infrared spectroscopy, inductively coupled plasma, and N(2) adsorption-desorption. The as-prepared microspheres possess unique properties including high magnetization (46.8 emu g(-1)), large BET surface area (135 m(2) g(-1)), and highly open mesopores (~5.0 nm), and H(3)PW(12)O(40) loading is calculated to be ~16.8%; and as a result, the as-prepared microspheres exhibit enhanced performance in degrading dyes under UV irradiation compared with pure H(3)PW(12)O(40). Additionally, the photocatalyst can be easily recycled using an external magnetic field without losing the photocatalytic activity. PMID- 23083770 TI - [The eye and Behcet's disease]. AB - Behcet's disease (BD) is a systemic inflammatory disorder for which the underlying histopathology is an occlusive vasculitis. This disease is more common in the Mediterranean region, the middle east and the far east. It is characterized by oral and genital ulcerations, ocular inflammatory involvement, skin lesions, vascular involvement and numerous systemic manifestations that may affect mortality. The pathogenesis of the disease still remains poorly characterized, although infectious, genetic (HLA-B51 antigen polymorphism), and environmental factors have been implicated. Uveitis is by far the most common ocular manifestation of BD. It is an important diagnostic criterion and may be associated with severe visual loss. Management of both the patient's ocular and extra-ocular involvement requires close collaboration between the ophthalmologist and internist. Treatment of Behcet's uveitis has been better defined by the EULAR recommendations. It relies on azathioprine and systemic corticosteroids, the timely and more controlled institution of which has largely contributed to the improved visual prognosis. If the patient has severe eye disease, it is recommended that either cyclosporine A or infliximab be used in combination with azathioprine and corticosteroids; alternatively IFNalpha with or without corticosteroids may be used instead. The introduction of biological agents into the therapeutic armamentarium represents a significant advance in the treatment of severe refractory forms of the disease, compared to conventional treatment. A better understanding of the process of auto-immunity and the role of cytokines responsible for tissue damage in Behcet's disease and uveitides in general will allow new, more specific and effective therapeutic approaches to emerge in the near future. PMID- 23083771 TI - [Atypical metastatic sites for adenocarcinoma of the lung]. AB - Lung carcinomas have a high propensity to metastasize to the liver, adrenal, bone or brain. However, certain atypical intracranial sites may occur. We report two cases of adenocarcinoma of the lung discovered by peculiar brain metastases. The first patient presented with an orbital apex syndrome due to a metastasis to the cavernous sinus with intraorbital extension. The second patient presented with headache and visual loss due to metastasis to the pituitary. Intrasellar and parasellar metastases are rare sequelae of pulmonary neoplasms. Etiological diagnosis is based on imaging and sampling or biopsy. They are often associated with a poor prognosis. The differential diagnosis of an intracranial process in the area of the sella should include metastasis even in the absence of a known primary cancer. PMID- 23083772 TI - Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins. AB - OBJECTIVES: The aim of this study was to evaluate the safety, tolerability, and effects of AMG 145 on low-density lipoprotein cholesterol (LDL-C) in healthy and hypercholesterolemic subjects on statin therapy. BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) down-regulates surface expression of the low-density lipoprotein receptor (LDL-R), increasing serum LDL-C. AMG 145, a fully human monoclonal antibody to PCSK9, prevents PCSK9/LDL-R interaction, restoring LDL-R recycling. METHODS: Healthy adults (phase 1a) were randomized to 1 dose of AMG 145: 7, 21, 70, 210, or 420 mg SC; 21 or 420 mg IV; or matching placebo. Hypercholesterolemic adults (phase 1b) receiving low- to moderate-dose statins were randomized to multiple SC doses of AMG 145: 14 or 35 mg once weekly (QW) *6, 140 or 280 mg every 2 weeks (Q2W) *3, 420 mg every 4 weeks *2, or matching placebo. Eleven subjects receiving high-dose statins and 6 subjects with heterozygous familial hypercholesterolemia were randomized to SC AMG 145 140 mg or placebo Q2W *3. RESULTS: In the trials (AMG 145 n = 85, placebo n = 28), AMG 145 reduced LDL-C up to 64% (p < 0.0001) versus placebo after 1 dose >=21 mg and up to 81% (p < 0.001) with repeated doses >=35 mg QW. No serious adverse events (AEs) occurred. Overall incidence of treatment-emergent AEs was similar in AMG 145 versus placebo groups: 69% versus 71% (phase 1a); 65% versus 64% (phase 1b). CONCLUSIONS: In phase 1 studies, AMG 145 significantly reduced serum LDL-C in healthy and hypercholesterolemic statin-treated subjects, including those with heterozygous familial hypercholesterolemia or taking the highest doses of atorvastatin or rosuvastatin, with an overall AE profile similar to placebo. PMID- 23083773 TI - Nonsustained ventricular tachycardia. AB - Nonsustained ventricular tachycardia (NSVT) has been recorded in a wide range of conditions, from apparently healthy individuals to patients with significant heart disease. In the absence of heart disease, the prognostic significance of NSVT is debatable. When detected during exercise, and especially at recovery, NSVT indicates increased cardiovascular mortality within the next decades. In trained athletes, NSVT is considered benign when suppressed by exercise. In patients with non-ST-segment elevation acute coronary syndrome, NSVT occurring beyond 48 h after admission indicates an increased risk of cardiac and sudden death, especially when associated with myocardial ischemia. In acute myocardial infarction, in-hospital NSVT has an adverse prognostic significance when detected beyond the first 13 to 24 h. In patients with prior myocardial infarction treated with reperfusion and beta-blockers, NSVT is not an independent predictor of long term mortality when other covariates such as left ventricular ejection fraction are taken into account. In patients with hypertrophic cardiomyopathy, and most probably genetic channelopathies, NSVT carries prognostic significance, whereas its independent prognostic ability in ischemic heart failure and dilated cardiomyopathy has not been established. The management of patients with NSVT is aimed at treating the underlying heart disease. PMID- 23083774 TI - Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial. AB - OBJECTIVES: The aim of this study was to confirm prior modeling data suggesting that prasugrel 5 mg in low-body-weight (LBW) patients would be noninferior to prasugrel 10 mg in higher-body-weight (HBW) patients as assessed by maximal platelet aggregation (MPA). BACKGROUND: Prasugrel 10 mg reduced ischemic events compared with clopidogrel 75 mg but increased bleeding, particularly in LBW patients. METHODS: In this blinded, 3-period, crossover study in stable patients with coronary artery disease (CAD) taking aspirin, prasugrel 5 and 10 mg and clopidogrel 75 mg were administered to LBW (56.4 +/- 3.7 kg; n = 34) and HBW patients (84.7 +/- 14.9 kg; n = 38). Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN), and vasodilator-associated stimulated phosphoprotein (VASP) level measured predose and after each 12-day treatment. RESULTS: Median MPA by LTA for prasugrel 5 mg in LBW patients was noninferior to the 75th percentile for prasugrel 10 mg in HBW patients (primary endpoint) and mean MPA was similar, but active metabolite exposure was lowered by 38%. Within LBW patients, prasugrel 5 mg lowered MPA more than clopidogrel (least squares mean difference [95% confidence interval]: -3.7% [-6.72%, -0.69%]) and resulted in lower rates of high on-treatment platelet reactivity (HPR). Within HBW patients, prasugrel 10 mg lowered MPA more than clopidogrel (-16.9% [-22.3%, 11.5%]). Similar results were observed by VN and VASP. Prasugrel 10 mg in LBW patients was associated with more mild to moderate bleeding (mainly bruising) compared with prasugrel 5 mg and clopidogrel. CONCLUSIONS: In aspirin-treated patients with CAD, prasugrel 5 mg in LBW patients reduced platelet reactivity to a similar extent as prasugrel 10 mg in HBW patients and resulted in greater platelet inhibition, lower HPR, and similar bleeding rates compared with clopidogrel. (Comparison of Prasugrel and Clopidogrel in Low Body Weight Versus Higher Body Weight With Coronary Artery Disease [FEATHER]; NCT01107925). PMID- 23083775 TI - Will cholesteryl ester transfer protein inhibition succeed primarily by lowering low-density lipoprotein cholesterol? Insights from human genetics and clinical trials. PMID- 23083776 TI - Moderate renal insufficiency does not attenuate the clinical benefit of aldosterone antagonists in heart failure. PMID- 23083777 TI - Novel insights into beta-blocker therapy for long QT syndromes. PMID- 23083778 TI - Fibrates and cardiorenal outcomes. PMID- 23083779 TI - Incremental prognostic value of assessing left ventricular myocardial mechanics in patients with chronic systolic heart failure. AB - OBJECTIVES: This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF). BACKGROUND: Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. METHODS: In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. RESULTS: In our study cohort (age 57 +/- 14 years, left ventricular ejection fraction [LVEF] 26 +/- 6%, median N-terminal pro-B-type natriuretic peptide [NT-proBNP] 1,158 pg/ml), the mean GLS was -7.1 +/- 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = -0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s': r = -0.30, p < 0.0001), and RV diastolic function (RV e'/a': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS >=-6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011). CONCLUSIONS: In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF. PMID- 23083780 TI - Coronary computed tomographic angiography as a gatekeeper to invasive diagnostic and surgical procedures: results from the multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: an International Multicenter) registry. AB - OBJECTIVES: This study sought to examine patterns of follow-up invasive coronary angiography (ICA) and revascularization (REV) after coronary computed tomography angiography (CCTA). BACKGROUND: CCTA is a noninvasive test that permits direct visualization of the extent and severity of coronary artery disease (CAD). Post CCTA patterns of follow-up ICA and REV are incompletely defined. METHODS: We examined 15,207 intermediate likelihood patients from 8 sites in 6 countries; these patients were without known CAD, underwent CCTA, and were followed up for 2.3 +/- 1.2 years for all-cause mortality. Coronary artery stenosis was judged as obstructive when >=50% stenosis was present. A multivariable logistic regression was used to estimate ICA use. A Cox proportional hazards model was used to estimate all-cause mortality. RESULTS: During follow-up, ICA rates for patients with no CAD to mild CAD according to CCTA were low (2.5% and 8.3%), with similarly low rates of REV (0.3% and 2.5%). Most ICA procedures (79%) occurred <=3 months of CCTA. Obstructive CAD was associated with higher rates of ICA and REV for 1-vessel (44.3% and 28.0%), 2-vessel (53.3% and 43.6%), and 3-vessel (69.4% and 66.8%) CAD, respectively. For patients with <50% stenosis, early ICA rates were elevated; over the entirety of follow-up, predictors of ICA were mild left main, mild proximal CAD, respectively, or higher coronary calcium scores. In patients with <50% stenosis, the relative hazard for death was 2.2 (p = 0.011) for ICA versus no ICA. Conversely, for patients with CAD, the relative hazard for death was 0.61 for ICA versus no ICA (p = 0.047). CONCLUSIONS: These findings support the concept that CCTA may be used effectively as a gatekeeper to ICA. PMID- 23083781 TI - The risk of adverse cardiac and bleeding events following noncardiac surgery relative to antiplatelet therapy in patients with prior percutaneous coronary intervention. AB - Noncardiac surgery (NCS) may be required within the first year after percutaneous coronary intervention (PCI) in approximately 4% of patients and is the second most common reason for premature discontinuation of antiplatelet therapy (APT),which may, in turn, increase the risk of perioperative ischemic events, particularly stent thrombosis. Its continuation may increase the risk of perioperative bleeding. We review current information on the incidence of these events, particularly related to APT, describe potentially useful strategies to minimize the risks of adverse outcomes, and provide recommendations on APT use. PMID- 23083782 TI - Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. AB - OBJECTIVES: The purpose of this study was to compare the efficacy of beta blockers in congenital long QT syndrome (LQTS). BACKGROUND: Beta-blockers are the mainstay in managing LQTS. Studies comparing the efficacy of commonly used beta blockers are lacking, and clinicians generally assume they are equally effective. METHODS: Electrocardiographic and clinical parameters of 382 LQT1/LQT2 patients initiated on propranolol (n = 134), metoprolol (n = 147), and nadolol (n = 101) were analyzed, excluding patients <1 year of age at beta-blocker initiation. Symptoms before therapy and the first breakthrough cardiac events (BCEs) were documented. RESULTS: Patients (56% female, 27% symptomatic, heart rate 76 +/- 16 beats/min, QTc 472 +/- 46 ms) were started on beta-blocker therapy at a median age of 14 years (interquartile range: 8 to 32 years). The QTc shortening with propranolol was significantly greater than with other beta-blockers in the total cohort and in the subset with QTc >480 ms. None of the asymptomatic patients had BCEs. Among symptomatic patients (n = 101), 15 had BCEs (all syncopes). The QTc shortening was significantly less pronounced among patients with BCEs. There was a greater risk of BCEs for symptomatic patients initiated on metoprolol compared to users of the other 2 beta-blockers combined, after adjustment for genotype (odds ratio: 3.95, 95% confidence interval: 1.2 to 13.1, p = 0.025). Kaplan-Meier analysis showed a significantly lower event-free survival for symptomatic patients receiving metoprolol compared to propranolol/nadolol. CONCLUSIONS: Propranolol has a significantly better QTc shortening effect compared to metoprolol and nadolol, especially in patients with prolonged QTc. Propranolol and nadolol are equally effective, whereas symptomatic patients started on metoprolol are at a significantly higher risk for BCEs. Metoprolol should not be used for symptomatic LQT1 and LQT2 patients. PMID- 23083783 TI - Lipoprotein-associated phospholipase A(2) bound on high-density lipoprotein is associated with lower risk for cardiac death in stable coronary artery disease patients: a 3-year follow-up. AB - OBJECTIVES: The aim of this study was to examine the prognostic value of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) associated with high density lipoprotein (HDL) (HDL-Lp-PLA(2)) in patients with stable coronary artery disease (CAD). BACKGROUND: Lp-PLA(2) is a novel risk factor for cardiovascular disease. It has been postulated that the role of Lp-PLA(2) in atherosclerosis may depend on the type of lipoprotein with which it is associated. METHODS: Total plasma Lp-PLA(2) and HDL-Lp-PLA(2) mass and activity, lipids, and C-reactive protein were measured in 524 consecutive patients with stable CAD who were followed for a median of 34 months. The primary endpoint was cardiac death, and the secondary endpoint was hospitalization for acute coronary syndromes, myocardial revascularization, arrhythmic event, or stroke. RESULTS: Follow-up data were obtained from 477 patients. One hundred twenty-three patients (25.8%) presented with cardiovascular events (24 cardiac deaths, 47 acute coronary syndromes, 28 revascularizations, 22 arrhythmic events, and 2 strokes). Total plasma Lp-PLA(2) mass and activity were predictors of cardiac death (hazard ratio [HR]: 1.013; 95% confidence interval [CI]: 1.005 to 1.021; p = 0.002; and HR: 1.040; 95% CI: 1.005 to 1.076; p = 0.025, respectively) after adjustment for traditional risk factors for CAD. In contrast, HDL-Lp-PLA(2) mass and activity were associated with lower risk for cardiac death (HR: 0.972; 95% CI: 0.952 to 0.993; p = 0.010; and HR: 0.689; 95% CI: 0.496 to 0.957; p = 0.026, respectively) after adjustment for traditional risk factors for CAD. CONCLUSIONS: Total plasma Lp-PLA(2) is a predictor of cardiac death, while HDL-Lp-PLA(2) is associated with lower risk for cardiac death in patients with stable CAD, independently of other traditional cardiovascular risk factors. PMID- 23083784 TI - A contemporary view of diagnostic cardiac catheterization and percutaneous coronary intervention in the United States: a report from the CathPCI Registry of the National Cardiovascular Data Registry, 2010 through June 2011. AB - OBJECTIVES: This study sought to provide a report to the public of data from the CathPCI Registry of the National Cardiovascular Data Registry. BACKGROUND: The CathPCI Registry collects data from approximately 85% of the cardiac catheterization laboratories in the United States. METHODS: Data were summarized for 6 consecutive calendar quarters beginning January 1, 2010, and ending June 30, 2011. This report includes 1,110,150 patients undergoing only diagnostic cardiac catheterization and 941,248 undergoing percutaneous coronary intervention (PCI). RESULTS: Some notable findings include, for example, that on-site cardiac surgery was not available in 83% of facilities performing fewer than 200 PCIs annually, with these facilities representing 32.6% of the facilities reporting, but performing only 12.4% of the PCIs in this data sample. Patients 65 years of age or older represented 38.7% of those undergoing PCI, with 12.3% being 80 years of age or older. Almost 80% of PCI patients were overweight (body mass index >=25 kg/m(2)), 80% had dyslipidemia, and 27.6% were current or recent smokers. Among patients undergoing elective PCI, 52% underwent a stress study before the procedure, with stress myocardial perfusion being used most frequently. Calcium scores and coronary computed tomography angiography were used very infrequently (<3%) before diagnostic or PCI procedures. Radial artery access was used in 8.3% of diagnostic and 6.9% of PCI procedures. Primary PCI was performed with a median door-to-balloon time of 64.5 min for nontransfer patients and 121 min for transfer patients. In-hospital risk-adjusted mortality in ST-segment elevation myocardial infarction patients was 5.2% in this sample. CONCLUSIONS: Data from the CathPCI Registry provide a contemporary view of the current practice of invasive cardiology in the United States. PMID- 23083785 TI - The importance of the muscle and ventilatory blood pumps during exercise in patients without a subpulmonary ventricle (Fontan operation). AB - OBJECTIVES: The aim of this study was to determine the relative contribution of the muscle and ventilatory pumps to stroke volume in patients without a subpulmonic ventricle. BACKGROUND: In patients with Fontan circulation, it is unclear how venous return is augmented to increase stroke volume and cardiac output during exercise. METHODS: Cardiac output (acetylene rebreathing), heart rate (electrocardiography), oxygen uptake (Douglas bag technique), and ventilation were measured in 9 patients age 15.8 +/- 6 years at 6.1 +/- 1.8 years after Fontan operation and 8 matched controls. Data were obtained at rest, after 3 min of steady-state exercise (Ex) on a cycle ergometer at 50% of individual working capacity, during unloaded cycling at 0 W (muscle pump alone), during unloaded cycling with isocapnic hyperpnea (muscle and ventilatory pump), during Ex plus an inspiratory load of 12.8 +/- 1.5 cm water, and during Ex plus an expiratory load of 12.8 +/- 1.6 cm water. RESULTS: In Fontan patients, the largest increases in stroke volume and stroke volume index were during zero resistance cycling. An additional increase with submaximal exercise occurred in controls only. During Ex plus expiratory load, stroke volume indexes were reduced to baseline, non-exercise levels in Fontan patients, without significant changes in controls. CONCLUSIONS: With Fontan circulation increases in cardiac output and stroke volume during Ex were due to the muscle pump, with a small additional contribution by the ventilatory pump. An increase in intrathoracic pressure played a deleterious role in Fontan circulation by decreasing systemic venous return and stroke volume. PMID- 23083786 TI - Effects of fibrates in kidney disease: a systematic review and meta-analysis. AB - OBJECTIVES: The purpose of this systematic review and meta-analysis was to determine the efficacy and safety of fibrate therapy in the chronic kidney disease (CKD) population. BACKGROUND: Fibrate therapy produces modest cardiovascular benefits in people at elevated cardiovascular risk. There is limited evidence about the clinical benefits and safety of fibrate therapy in the CKD population. METHODS: MEDLINE, EMBASE, and the Cochrane Library were systematically searched (1950 to January 2012) for prospective randomized controlled trials assessing the effects of fibrate therapy compared with placebo in people with CKD or on kidney-related outcomes were included. RESULTS: Ten studies including 16,869 participants were identified. In patients with mild-to moderate CKD (estimated glomerular filtration rate [eGFR] <=60 ml/min/1.73 m(2)), fibrates improved lipid profiles (lowered total cholesterol [-0.32 mmol/l, p = 0.05] and triglyceride levels [-0.56 mmol/l, p = 0.03] but not low-density lipoprotein cholesterol [-0.01 mmol/l, p = 0.83]; increased high-density lipoprotein cholesterol [0.06 mmol/l, p = 0.001]). In people with diabetes, fibrates reduced the risk of albuminuria progression (relative risk [RR]: 0.86; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.02). Serum creatinine was elevated by fibrate therapy (33 MUmol/l, p < 0.001), calculated GFR was reduced ( 2.67 ml/min/1.73 m(2), p = 0.01) but there was no detectable effect on the risk of end-stage kidney disease (RR: 0.85; 95% CI: 0.49 to 1.49; p = 0.575). In patients with eGFR of 30 to 59.9 ml/min/1.73 m(2), fibrates reduced the risk of major cardiovascular events (RR: 0.70; 95% CI: 0.54 to 0.89; p = 0.004) and cardiovascular death (RR: 0.60; 95% CI: 0.38 to 0.96; p = 0.03) but not all-cause mortality. There were no clear safety concerns specific to people with CKD but available data were limited. CONCLUSIONS: Fibrates improve lipid profiles and prevent cardiovascular events in people with CKD. They reduce albuminuria and reversibly increase serum creatinine but the effects on major kidney outcomes remain unknown. These results suggest that fibrates have a place in reducing cardiovascular risk in people with mild-to-moderate CKD. PMID- 23083787 TI - Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: insights from RALES (Randomized Aldactone Evaluation Study). AB - OBJECTIVES: This study investigated the influence of baseline and worsening renal function (WRF) on the efficacy of spironolactone in patients with severe heart failure (HF). BACKGROUND: Renal dysfunction or decline in renal function is a known predictor of adverse outcome in patients with HF, and treatment decisions are often on the basis of measures of renal function. METHODS: We used data from the RALES (Randomized Aldactone Evaluation Study) in 1,658 patients with New York Heart Association functional class III or IV HF and an ejection fraction <35%. Participants were randomized to spironolactone 25 mg, which could be titrated to 50 mg, or placebo daily. Renal function (estimated glomerular filtration rate [eGFR]) was estimated by the Modification of Diet in Renal Disease equation. Worsening renal function was defined as a 30% reduction in eGFR from baseline to 12 weeks post-randomization. RESULTS: Individuals with reduced baseline eGFR exhibited similar relative risk reductions in all-cause death and the combined endpoint of death or hospital stays for HF as those with a baseline eGFR >60 ml/min/1.73 m(2) and greater absolute risk reduction compared with those with a higher baseline eGFR (10.3% vs. 6.4%). Moreover, WRF (17% vs. 7% for spironolactone and placebo groups, p < 0.001) was associated with an increased adjusted risk of death in the placebo group (hazard ratio: 1.9, 95% confidence interval: 1.3 to 2.6) but not in those randomized to spironolactone (hazard ratio: 1.1, 95% confidence interval: 0.79 to 1.5, p interaction = 0.009). The risk of hyperkalemia and renal failure was higher in those with worse baseline renal function and those with WRF, particularly in the spironolactone arm, but the substantial net benefit of spironolactone therapy remained. CONCLUSIONS: The absolute benefit of spironolactone was greatest in patients with reduced eGFR. Worsening renal function was associated with a negative prognosis, yet the mortality benefit of spironolactone was maintained. PMID- 23083788 TI - The case for treating hypercholesterolemia at an earlier age: moving toward consensus. PMID- 23083789 TI - Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. AB - OBJECTIVES: The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). BACKGROUND: LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. METHODS: We conducted a series of meta-analyses to estimate the effect of long term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. RESULTS: All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3 fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 * 10(-19)). CONCLUSIONS: Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life. PMID- 23083790 TI - Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. AB - OBJECTIVES: This study tested whether genetic variation in the CETP gene is consistent with a protective effect of cholesteryl ester transfer protein (CETP) inhibition on risk of ischemic events and on total mortality, without the adverse effects reported for torcetrapib. BACKGROUND: Torcetrapib, an inhibitor of CETP, increased risk of death and ischemic cardiovascular disease of those randomized to the drug, despite improving the lipid profile. METHODS: The Copenhagen City Heart Study is a prospective cohort study of 10,261 individuals, aged 20 to 93 years, who were followed for up to 34 years (1976 to 2010). Of these, 2,087 developed ischemic heart disease, 1,064 developed ischemic cerebrovascular disease, and 3,807 died during follow-up. We selected 2 common genetic variants in CETP previously associated with reductions in CETP activity, thus mimicking the effect of pharmacological CETP inhibition. RESULTS: In individuals carrying 4 versus 0 high-density lipoprotein cholesterol-increasing alleles, there was an increase in levels of high-density lipoprotein cholesterol of up to 14% (0.2 mmol/l), and concomitant decreases in triglycerides, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol of, respectively, 6% (0.1 mmol/l), 3% (0.1 mmol/l), and 4% (0.2 mmol/l) (p for trend 0.004 to <0.001). Corresponding hazard ratios were 0.76 (95% confidence interval [CI]: 0.68 to 0.85) for any ischemic vascular event, 0.74 (95% CI: 0.65 to 0.85) for ischemic heart disease, 0.65 (95% CI: 0.54 to 0.79) for myocardial infarction, 0.77 (95% CI: 0.65 to 0.93) for ischemic cerebrovascular disease, 0.71 (95% CI: 0.58 to 0.88) for ischemic stroke, and 0.88 (95% CI: 0.80 to 0.97) for total mortality. CETP genotypes did not associate with variation in markers of possible side effects previously reported for torcetrapib. CONCLUSIONS: Genetic CETP inhibition associates with reductions in risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects. PMID- 23083792 TI - David valve-sparing aortic root replacement: equivalent mid-term outcome for different valve types with or without connective tissue disorder. AB - OBJECTIVE: Although implicitly accepted by many that the durability of valve sparing aortic root replacement in patients with bicuspid aortic valve disease and connective tissue disorders will be inferior, this hypothesis has not been rigorously investigated. METHODS: From 1993 to 2009, 233 patients (27% bicuspid aortic valve, 40% Marfan syndrome) underwent Tirone David valve-sparing aortic root replacement. Follow-up averaged 4.7 +/- 3.3 years (1102 patient-years). Freedom from adverse outcomes was determined using log-rank calculations. RESULTS: Survival at 5 and 10 years was 98.7% +/- 0.7% and 93.5% +/- 5.1%, respectively. Freedom from reoperation (all causes) on the aortic root was 92.2% +/- 3.6% at 10 years; 3 reoperations were aortic valve replacement owing to structural valve deterioration. Freedom from structural valve deterioration at 10 years was 96.1% +/- 2.1%. No significant differences were found in survival (P = .805, P = .793, respectively), reoperation (P = .179, P = .973, respectively), structural valve deterioration (P = .639, P = .982, respectively), or any other functional or clinical endpoints when patients were stratified by valve type (tricuspid aortic valve vs bicuspid aortic valve) or associated connective tissue disorder. At the latest echocardiographic follow-up (95% complete), 202 patients (94.8%) had none or trace aortic regurgitation, 10 (4.7%) mild, 0 had moderate to severe, and 1 (0.5%) had severe aortic regurgitation. Freedom from greater than 2+ aortic regurgitation at 10 years was 95.3% +/- 2.5%. Six patients sustained acute type B aortic dissection (freedom at 10 years, 90.4% +/- 5.0%). CONCLUSIONS: Tirone David reimplantation valve-sparing aortic root replacement in carefully selected young patients was associated with excellent clinical and echocardiographic outcome in patients with either a tricuspid aortic valve or bicuspid aortic valve. No demonstrable adverse influence was found for Marfan syndrome or connective tissue disorder on durability, clinical outcome, or echocardiographic results. PMID- 23083793 TI - Primary graft dysfunction does not lead to increased cardiac allograft vasculopathy in surviving patients. AB - OBJECTIVE: Early injury is associated with the development of cardiac allograft vasculopathy in heart transplantation. We examined whether adult heart transplant recipients surviving primary graft dysfunction were more susceptible to the development of cardiac allograft vasculopathy than their nonprimary graft dysfunction counterparts. METHODS: A total of 857 patients who underwent heart transplantation between January 1994 and December 2008 at our institution were reviewed. Primary graft dysfunction was defined as the need for extracorporeal membrane oxygenation, open chest, or intra-aortic balloon pump placement within 72 hours of transplantation. Cardiac allograft vasculopathy was defined as >=50% coronary artery stenosis in any vessel. Allograft survival was defined by patient death or need for retransplantation. RESULTS: Completed follow-up was available for 32 patients in the primary graft dysfunction group and 701 patients in the nonprimary graft dysfunction group. Mean recipient ages (56 years vs 55 years, respectively; P = .50) and ischemic times (220 minutes vs 208 minutes, respectively; P = .35) were similar. Donor age was significantly higher in the primary graft dysfunction group (38 years vs 32 years, P = .02). Five-year survivals for the primary graft dysfunction and nonprimary graft dysfunction groups were 46.9% versus 78.9% (P < .001). Conditional 5-year survivals in patients surviving the first year were 78.9% and 88.3% for the primary graft dysfunction and nonprimary graft dysfunction groups, respectively (P = .18). Within a 30-day postoperative period, there were more deaths in the primary graft dysfunction group (28.1% vs 2.3%, P < .0001) and more retransplants (6.25% vs 0%, P = .002). Of the patients surviving past 30 days, only 2 (8.7%) of the primary graft dysfunction patients developed cardiac allograft vasculopathy versus 144 (21.0%) in the nonprimary graft dysfunction group (P < .001). CONCLUSIONS: Primary graft dysfunction was associated with lower 30-day, 1-year, and 5-year allograft survival rates. Surviving patients, however, did not show increased tendency toward cardiac allograft vasculopathy development. PMID- 23083794 TI - Cumulative team experience matters more than individual surgeon experience in cardiac surgery. AB - OBJECTIVES: Individual surgeon experience and the cumulative experience of the surgical team have both been implicated as factors that influence surgical efficiency. We sought to quantitatively evaluate the effects of both individual surgeon experience and the cumulative experience of attending surgeon cardiothoracic fellow collaborations in isolated coronary artery bypass graft (CABG) procedures. METHODS: Using a prospectively collected retrospective database, we analyzed all medical records of patients undergoing isolated CABG procedure at our institution. We used multivariate generalized estimating equation regression models to adjust for patient mix and subsequently evaluated the effect of both attending cardiac surgeon experience (since fellowship graduation) and the number of previous collaborations between attending cardiac surgeons and cardiothoracic fellow pairs on cardiopulmonary bypass and crossclamp times. RESULTS: From 2001 to 2010, 4068 consecutive patients underwent isolated CABG procedure at our institution performed by 11 attending cardiac surgeons and 73 cardiothoracic fellows. Mean attending experience after fellowship graduation was 10.9 +/- 8.0 years and mean number of cases between unique pairs of attending cardiac surgeons and cardiothoracic fellows was 10.0 +/- 10.0 cases. After patient risk adjustment, both attending surgical experience since fellowship graduation and the number of previous collaborations between attending surgeons and cardiothoracic fellows were significantly associated with a reduction in cardiopulmonary bypass and crossclamp times (P < .001). The influence of attending-fellow pair experience far exceeded the influence of surgical experience with beta estimates for attending-fellow pair experience nearly three times that of attending surgeon experience. CONCLUSIONS: Cumulative experience of attending cardiac surgeons and cardiothoracic fellows has a dramatic effect on both cardiopulmonary bypass and crossclamp times, whereas attending cardiac surgeon learning curves following fellowship graduation are clinically insignificant. Taken together, these findings suggest that the primary driver of operative efficiency in CABG procedure is the collaborative experience of the attending surgeon-cardiothoracic fellow operative team, rather than the individual experience of the attending surgeon. PMID- 23083795 TI - Incidence and predictors of poor laryngoscopic view in children undergoing pediatric cardiac surgery. AB - OBJECTIVE: Previous investigations reported a higher incidence of poor laryngoscopic views in pediatric patients undergoing cardiac surgery. The objective of this study was to analyze why children undergoing cardiac surgery have such an increased incidence of poor laryngoscopic views during anesthesia induction. DESIGN: This study was designed as a retrospective analysis. SETTING: This analysis was based on a single-center cohort of a university hospital. PARTICIPANTS: One thousand one hundred seventy-seven general anesthesia procedures, including a direct laryngoscopic view over a period of 6 consecutive years, in pediatric patients undergoing cardiac surgery. INTERVENTIONS: Because of the retrospective character of this study, there were no study-related interventions. MEASUREMENTS AND MAIN RESULTS: Poor laryngoscopic views were defined as Cormack and Lehane (CML) grade III and IV. The overall incidence of poor laryngoscopic views was 3.5%. In patients younger than 1 year of age, the incidence of CML III or IV was significantly higher than in the older patients (5.6% v 1.7%). None of the patients with CML III/IV findings had Down syndrome; whereas in 9 of 41 patients with CML grade III/IV, a concomitant congenital syndrome like DiGeorge syndrome or CHARGE syndrome was found. CONCLUSIONS: The general incidence of CML III/IV findings during the induction of anesthesia for pediatric cardiac surgery is more than twice as high as reported in unselected pediatric cohorts. In patients below 1 year of age and in male patients, difficult laryngoscopy is more frequent. Concomitant Down syndrome was not associated with difficult laryngoscopy. PMID- 23083796 TI - Recurrent polymorphic ventricular tachycardia: the real thing or a soapy explanation? PMID- 23083797 TI - Is the pretreatment neutrophil to lymphocyte ratio an important prognostic parameter in patients with metastatic renal cell carcinoma? AB - BACKGROUND: Tyrosine kinase inhibitor is a standard treatment for mRCC. The NLR, an index of systemic inflammation, is associated with outcome in several cancer types. To study the association of pretreatment NLR with PFS and overall survival (OS) of patients treated with VEGF-targeted therapy. PATIENTS AND METHODS: We retrospectively studied an unselected cohort of patients with mRCC, who were treated with TKIs. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analyzed clinical parameters for their prognostic relevance. RESULTS: A total of 100 patients with mRCC who had early progressed after first-line therapy with interferon-alpha were included in this retrospective multicenter study conducted at 4 centers between February 2008 and December 2011. The median of the NLR was 3.04 and patients were divided into 2 higher and lower NLR groups according to median of NLR. Median PFS was 9 versus 11 months in patients with baseline NLR > 3.04 versus <= 3.04 (P = .009). The median OS was 16 months versus 29 months, in patients with NLR > 3.04 versus <= 3.04, respectively (P = .004). In the whole group OS was independently associated with higher NLR (hazard ratio [HR], 2.406; P = .004), PFS more than 6 months (HR, 4.081; P = .0001), and sex (HR, 2.342; P = .040). On the other hand in the higher NLR group (HR, 1.107; P = .009) Memorial Sloan-Kettering Cancer Center score (HR, 3.398; P = .0001) was associated with PFS. CONCLUSION: In patients with mRCC treated with VEGF-targeted therapy, pretreatment NLR, the duration of PFS might be associated with OS. This should be investigated prospectively. PMID- 23083798 TI - Bcl-2 family of proteins as therapeutic targets in genitourinary neoplasms. AB - INTRODUCTION: Overexpression of antiapoptotic B-cell lymphoma (Bcl-2) proteins confers the dysregulation of apoptosis and results in drug resistance in a variety of cancers, including those of the genitourinary tract. Inhibitors that target prosurvival Bcl-2 proteins are in preclinical and clinical development. The objective of this review is to assess the involvement of Bcl-2 proteins as well as the preclinical and clinical activity of Bcl-2 inhibitors under evaluation for genitourinary neoplasms. MATERIALS AND METHODS: PubMed was used with both medical subject heading terms and free search to identify the relevant literature. Information on clinical trials was obtained using http://Clincaltrials.gov, EU Clinical Trials Register, and meeting abstracts of the American Society of Clinical Oncology. RESULTS: To date, 2 Bcl-2 inhibitors have been evaluated in clinical trials for genitourinary tumors (oblimersen and AT-101 (R-(-)-gossypol)). Both agents demonstrated some success in early stages of development, but their clinical activity did not meet expectations. Preclinical studies are under way for other Bcl-2 inhibitors including ABT-737, HA14-1, and Bcl-2 homology 3 inhibitors. CONCLUSION: Antiapoptotic Bcl-2 proteins are potential molecular targets in genitourinary cancers. Bcl-2 inhibitors might be effective as single agents or in combination with conventional therapies. However, the biology of the Bcl-2 family in genitourinary cancers remains poorly understood and robust preclinical studies are needed to inform clinical development. Such studies should aim to identify: (1) pharmacodynamic markers that could help guide patient selection for treatment with Bcl-2 inhibitors, and (2) optimal combinations of Bcl-2 inhibitors with other anticancer agents for future clinical investigation. PMID- 23083799 TI - Cixutumumab-associated pancolitis in a patient with prostate cancer. PMID- 23083800 TI - Positive surgical margins after nephron-sparing surgery for renal cell carcinoma: incidence, clinical impact, and management. AB - Nephron-sparing surgery (NSS) for renal cell carcinoma (RCC) offers comparable oncologic results but a lower risk of chronic kidney disease when compared with radical nephrectomy; however it can result in positive surgical margins (PSMs) and consequently to a possible risk of oncologic failure. The aim of this review is to evaluate the incidence of PSMs after nephron-sparing surgery, to assess their clinical and oncologic impact, and to provide an overview of the possible therapeutic management. We performed a nonsystematic review of the literature in the MEDLINE database using the following keywords: partial nephrectomy, nephron sparing surgery, and positive margin. We reviewed articles published only in English from January 2002 to May 2012. The overall incidence of PSMs after NSS ranges from 0% to 7%, with no significant differences in open, laparoscopic, and robot-assisted techniques. Smaller tumor size could result in a higher risk of PSMs. Even if there is not a clear agreement in the clinical evidence, local recurrence seems to be more likely in patients with PSMs, especially in those with high-grade tumors. Development of metastases and cancer-specific survival, as seen in midterm follow-up studies, seems to be comparable to those in patients with negative surgical margins. Considering the globally low risk of local recurrence, development of metastasis, or cancer-specific mortality, careful surveillance could be the best management option for most patients with PSMs after NSS. PMID- 23083801 TI - [Ischaemic cardiogenic shock. Where do we stand in 2012?]. AB - With a stable frequency (about 5% of acute coronary syndromes) and a mortality of nearly 45%, cardiogenic shock (CS), especially when it occurs in the immediate waning of myocardial infarction, still represents a therapeutic challenge. In this review, will be detailed the actual epidemiologic data of CS, its physiopathology and the different modalities of treatments available to the interventional cardiologist, especially the coronary revascularisation and the percutaneous left ventricular assistance, whether by intra-aortic balloon counterpulsation or by more complex systems. PMID- 23083802 TI - Prevalence of elevated mean arterial pressure and how fitness moderates its association with BMI in youth. AB - OBJECTIVE: Cardiorespiratory fitness is known to be cardioprotective and its association with the components of the metabolic syndrome in children is becoming clearer. The aim of the present study was to examine the extent to which cardiorespiratory fitness may offset the weight-related association with mean arterial pressure (MAP) in schoolchildren. DESIGN: Cross-sectional study. SETTINGS: Schoolchildren from the East of England, U.K. SUBJECTS: A total of 5983 (48% females) schoolchildren, 10 to 16 years of age, had height, weight and blood pressure measured by standard procedures and cardiorespiratory fitness assessed by the 20 m shuttle-run test. Participants were classified as fit or unfit using internationally accepted fitness cut-off points; and as normal weight, overweight or obese based on BMI, again using international cut-off points. Age-adjusted ANCOVA was used to determine the main effects and interaction of fitness and BMI on MAP Z-score. Logistic regression models were used to estimate odds ratios of elevated MAP. RESULTS: Prevalence of elevated MAP in schoolchildren was 14.8% overall and 35.7% in those who were obese-unfit. Approximately 21% of participants were overweight and 5% obese, while 23% were classified as unfit. MAP generally increased across BMI categories and was higher in the aerobically unfit participants. Obese-fit males had lower MAP compared with obese-unfit males (P < 0.001); this trend was similar in females (P = 0.05). CONCLUSIONS: Increasing fitness level may have a positive impact on the weight-related elevations of MAP seen in obese and overweight schoolchildren. PMID- 23083803 TI - Prostate-specific antigen (PSA) testing is prevalent and increasing in Stockholm County, Sweden, Despite no recommendations for PSA screening: results from a population-based study, 2003-2011. AB - BACKGROUND: Prostate-specific antigen (PSA) testing has increased in several countries. There is incomplete knowledge of PSA testing patterns. OBJECTIVE: Determine the prevalence of PSA testing and explore patterns of PSA retesting in Stockholm County, Sweden. DESIGN, SETTING, AND PARTICIPANTS: A population-based study was performed. Through registry linkages, we collected population information, data on PSA tests, pathology reports, and clinical information. The study population comprised males living in Stockholm County in 2011 (n=1034129), of which 229 872 had a PSA test during the period 2003-2011. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We determined limited-duration-point prevalence of PSA testing and performed survival analysis on PSA retesting for men aged 40-89 yr. RESULTS AND LIMITATIONS: The number of PSA tests increased from 54239 in 2003 to 124613 in 2011. During the 9-yr study period, 46%, 68%, and 77% of men without a prior prostate cancer (PCa) diagnosis and aged 50-59 yr, 60-69 yr, and 70-79 yr, respectively, had a PSA test. During 2010 and 2011, 25%, 40%, and 46% of men aged 50-59 yr, 60-69 yr, and 70-79 yr, respectively, had a PSA test. The prevalence of PSA testing increased from 2003 to 2011. The probability of retesting was PSA and age dependent, with a 26-mo cumulative incidence of 0.337 (95% confidence interval, 0.333-0.341) if the first PSA value was <1 ng/ml. The main limitations were (1) that PSA data prior to 2003 were not available and (2) that the study cohort was restricted to men who were alive in 2011. CONCLUSIONS: Although screening for PCa is not recommended in Sweden, PSA testing in Stockholm County was high across ages ranging from 40 to 89 yr and increased during the period 2003-2011. The probability of PSA retesting was high, regardless of the original PSA level. These results contrast with current clinical recommendations and raise calls for a change, either through structured PCa testing or more detailed guidelines on PSA testing. PMID- 23083804 TI - ICUD-EAU International Consultation on Bladder Cancer 2012: Pathology. AB - CONTEXT: To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the pathology of bladder cancer using an evidence-based strategy. OBJECTIVE: To standardize descriptions of the diagnosis and reporting of urothelial carcinoma of the bladder and help optimize uniformity between individual pathology practices and institutions. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to pathology. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. CONCLUSIONS: Providing the best management for patients with bladder neoplasia relies on close cooperation and teamwork among urologists, oncologists, radiologists, and pathologists. PMID- 23083805 TI - Comments on: "aseptic arthritis after ACL reconstruction by Tape Locking Screw (TLS): report of two cases" by F. Colin, F. Lintz, K. Bargoin, C. Guillard, G. Venet, A. Tesson, F. Gouin published in Orthop Traumatol Surg Res 2012;98(3):363 5. PMID- 23083806 TI - Two- and three-body wear of composite resins. AB - OBJECTIVE: The aim of the present study was to investigate two- and three-body wear of microfilled, micro-hybrid and nano-hybrid composite resins using a ball on-disc sliding device. METHODS: One microfilled (Durafill VS), one micro-hybrid (Filtek Z250), one hybrid (Clearfil AP-X), one nanofilled (Filtek Supreme XT), and two nano-hybrid (MI Flow, Venus Diamond) composite resins were examined. The composites were filled in a cylindrical cavity, and light polymerized. After storage in 37 degrees C distilled water for 7days, all specimens were tested with a custom-made ball-on-disc sliding device with a zirconia ball as antagonist (50N loads, 1.2Hz, 10,000 cycles) immersed in water, poppy seed slurry and polymethyl methacrylate slurry, respectively. Maximum wear depth and volume loss of worn surfaces were quantified by a digital CCD microscope and analyzed with two-way analysis of variance. RESULTS: The interactions between composite resin and condition of their maximum wear depth and volume loss were significant (p<0.01). The abrasive wear produced at three-body loading with poppy seed slurry was very large for the microfilled composite, and small for all other composites tested. In contrast, two-body wear of the microfilled composite, and one nano-hybrid composite was very low. SIGNIFICANCE: The ball-on-disc sliding device used is considered suitable to simulate sliding of an antagonist cusp on an opposing occlusal composite restoration, either in the two- or the three-body wear mode. All tested materials except for the microfilled composite showed low surface wear when exposed to poppy seed as the third-body medium. PMID- 23083808 TI - Programmed cell death in the cellular differentiation of microbial eukaryotes. AB - Programmed cell death (PCD) is a ubiquitous feature of multicellular and unicellular organisms. Eukaryotic microbes use PCD to regulate the development of specialized cells and structures. Many different types of PCD occur, ranging from apoptosis-like cell death, programmed necrosis and autophagic death. An overview of cell death pathways is undertaken, highlighting new elements in the PCD molecular machinery. Examples of PCD in cellular differentiation are explored alongside evolutionary scenarios that could initiate and maintain PCD in microbes, including the evolution of multicellularity. The finding that defects in PCD can lead to antimicrobial drug resistance is also considered. Greater understanding of PCD and its role in differentiation offers new hope for discovery of therapeutic agents that manipulate endogenous cell suicide pathways. PMID- 23083807 TI - Initial attachment, subsequent cell proliferation/viability and gene expression of epithelial cells related to attachment and wound healing in response to different titanium surfaces. AB - OBJECTIVES: A tight seal between the epithelium and the dental implant surface is required to prevent bacterial inflammation and soft tissue recession and therefore to demonstrate a long-term success. Surface hydrophilicity was recently shown to promote osseointegration. The aim of this study was to investigate the influence of surface hydrophilicity in combination with surface topography of Ti implant surfaces on the behavior and activation/differentiation of epithelial cells using a set of in vitro experiments mimicking the implant-soft tissue contact. METHODS: Hydrophobic acid-etched (A) and coarse-grit-blasted, acid etched (SLA) surfaces and hydrophilic acid-etched (modA) and modSLA surfaces were produced. The behavior of an oral squamous cell carcinoma cell line (HSC-2) grown on all surfaces was compared through determination of cell attachment and proliferation/viability (CCK-8 and MTT assay), time-lapse microscopy of fluorescence labeled cells and determination of gene expression by real time polymerase chain reaction. RESULTS: Within the surfaces with similar wettability cell spreading and cell movements observed by time-lapse microscopy after one day of incubation were most pronounced on smoother (A and modA) surfaces compared to rougher (SLA and modSLA) surfaces. Within the surfaces with similar roughness the hydrophilic surfaces (modA and modSLA) showed more cell spreading and cell activity compared to the hydrophobic surfaces (A and SLA). The relative gene expressions of cytokeratin14, integrin alpha6, integrin beta4, vinculin, transforming growth factor (TGF)-beta, TGF-beta1, and TGF-beta3 were decreased in HSC-2 on all four types of Ti surfaces compared to control surfaces (tissue culture polystyrene; p<0.01) and there was no significant difference of gene expression on the four different implant-surfaces. SIGNIFICANCE: We have demonstrated that for proliferation and spreading of HSC-2 cells the smoother and hydrophilic surface is optimal (modA). These results suggest that surface hydrophilicity might positively influence the epithelial seal around dental implants. All tested titanium surfaces downregulate cell attachment, cell proliferation, expression of adhesion promoters, and cytokines involved in wound healing in HSC-2 cells compared to control surfaces. PMID- 23083809 TI - Controversies on the role of Th17 in cancer: a TGF-beta-dependent immunosuppressive activity? AB - The immune system has important roles in limiting the spread of cancer and shaping the tumor microenvironment. Although the contributions of T helper 17 (Th17) cells (a subtype of CD4(+) T lymphocytes) to autoimmunity and allergy response are well known, their roles in cancer remain ambiguous. Despite adoptive transfer studies indicating that mouse Th17 cells support anticancer immunity, the Th17 cells that naturally infiltrate experimental tumors appear to have a tumor-promoting effect. These contradictory properties can be related to the high degree of plasticity inherent in Th17 cells and their capacity to differentiate into tumoricidal Th1-like cells. Mouse Th17 cells induced by transforming growth factor-beta (TGF-beta) express CD39 and CD73 ectonucleotidases on their surfaces, which leads to adenosine release and suppression of T cell immunity. Here, we discuss how TGF-beta acts as a molecular switch controlling the immunoregulatory properties of Th17 cells. PMID- 23083810 TI - Sense from nonsense: therapies for premature stop codon diseases. AB - Ten percent of inherited diseases are caused by premature termination codon (PTC) mutations that lead to degradation of the mRNA template and to the production of a non-functional, truncated polypeptide. In addition, many acquired mutations in cancer introduce similar PTCs. In 1999, proof-of-concept for treating these disorders was obtained in a mouse model of muscular dystrophy, when administration of aminoglycosides restored protein translation by inducing the ribosome to bypass a PTC. Since, many studies have validated this approach, but despite the promise of PTC readthrough therapies, the mechanisms of translation termination remain to be precisely elucidated before even more progress can be made. Here, we review the molecular basis for PTC readthrough in eukaryotes and describe currently available compounds with significant therapeutic potential for treating genetic disorders and cancer. PMID- 23083811 TI - Thrombocytopenia associated with one type of polysulfone hemodialysis membrane: a report of 5 cases. AB - Much progress has been made in the biocompatibility of hemodialysis membranes with the development of synthetic membranes. However, despite better biocompatibility, thrombocytopenia has been observed in patients who are dialyzed with various polysulfone membranes. Recent publications have attributed this phenomenon to the electron-beam sterilization of dialyzers. We report 5 cases of thrombocytopenia in patients treated by hemodialysis with an electron-beam sterilized polysulfone membrane. The thrombocytopenia resolved after switching to either of 2 polysulfone membranes, one of which also was electron-beam sterilized. Although we were unable to elucidate the exact biochemical mechanism, the cause of the thrombocytopenia in this series appears to be related to the type of polysulfone and not due to the sterilization technique. PMID- 23083812 TI - In vitro activity of telavancin and occurrence of vancomycin heteroresistance in isolates from patients enrolled in phase 3 clinical trials of hospital-acquired pneumonia. AB - In phase 3 studies of the efficacy of telavancin for the treatment of hospital acquired pneumonia, 704 Gram-positive and 627 Gram-negative aerobic bacterial pathogens were obtained at baseline from 1503 patients. The majority of Gram positive isolates (n = 650 [92%]) were Staphylococcus aureus, of which 410 (63%) were methicillin-resistant (MRSA). Of the MRSA isolates, 9.5% were identified as heterogeneous vancomycin-intermediate S. aureus. All Gram-positive isolates were inhibited by <=1 MUg/mL of telavancin. PMID- 23083813 TI - Acute assessment of an aspalathin-enriched green rooibos (Aspalathus linearis) extract with hypoglycemic potential. AB - Rooibos, an endemic South African plant, known for its use as herbal tea, has potential as an antidiabetic herbal product, following recent demonstration of the glucose lowering effect of its major flavonoid, the dihydrochalcone C glucoside aspalathin. The purpose of this study was to confirm antidiabetic activity for rooibos extract high in aspalathin content. An extract (SB1) was selected after screening for high aspalathin content and alpha-glucosidase inhibition activity. On-line HPLC-biochemical detection confirmed alpha glucosidase inhibitory activity for aspalathin. In vitro the extract induced a dose response increase in glucose uptake (5 * 10-5 to 5 MUg/ml) on C2C12 myotubules. Aspalathin was effective at 1, 10 and 100 MUM, while rutin was effective at 100 MUM. In the Chang cells only the extract was effective. In vivo the extract sustained a glucose lowering effect comparable to metformin over a 6h period after administration (25mg/kg body weight (BW)) to STZ-induced diabetic rats. In an oral glucose tolerance test the extract (30 mg/kg BW) was more effective than vildagliptin (10mg/kg BW), a dipeptidyl peptidase-4 inhibitor. An aspalathin-rutin mixture (1:1; m/m) dosed at 1.4 mg/kg BW, but not the single compounds separately, reduced blood glucose concentrations of STZ-induced diabetic rats over a 6h monitoring period. The improved hypoglycemic activity of the aspalathin-rutin mixture and the extract illustrated synergistic interactions of polyphenols in complex mixtures. PMID- 23083814 TI - Herbal formula Astragali Radix and Rehmanniae Radix exerted wound healing effect on human skin fibroblast cell line Hs27 via the activation of transformation growth factor (TGF-beta) pathway and promoting extracellular matrix (ECM) deposition. AB - Astragali Radix (AR) and Rehmanniae Radix (RR) have long been used in traditional Chinese Medicine and as the principal herbs in treating diabetic foot ulcer. In this study, we investigated the effect of NF3, which comprises of AR and RR in the ratio of 2:1(w/w), on skin fibroblast cell migration and the activation of selected genes and proteins related to wound healing. Human skin fibroblast cell line Hs27 was treated with NF3 at 4 mg/ml for 24h, and in vitro scratch wound healing and quantitative cell migration assays were performed, respectively. The expression of transformation growth factor (TGF-beta1) and bone morphogenetic protein 6 (BMP6) in Hs27 cells with or without NF3 treatment was analyzed by western blot analysis. In addition, the expression of a panel of genes involved in human TGF-beta signaling pathway was analyzed in Hs27 cells upon NF3 treatment (4 mg/ml, 24 h) by quantitative real-time PCR (qRT-PCR). Furthermore, the expression of several genes and proteins associated with ECM synthesis was investigated by qRT-PCR analysis or/and ELISA techniques. The results suggested that NF3 promoted the migration of human skin fibroblast cells. Western blot analysis demonstrated that NF3 up-regulated TGF-beta1 and BMP-6 synthesis. qRT PCR analysis revealed that the expression of 26 genes in Hs27 cells was changed upon NF3 induction, including TGF-beta superfamily ligands and down stream effectors genes, and genes involved in TGF/Smad pathway, and Ras/MAPK (non-Smad) pathway. Among the extracellular matrix (ECM)-related molecules, it was found that NF3 up-regulated the expression of type I and III collagens, fibronectin as well as TIMP-1, and down-regulated the MMP-9 expression in skin fibroblast cells. This study demonstrated that herb formula NF3 could enhance skin fibroblast cell migration and activated genes involved in TGF-beta1 pathway. NF3 could regulate gene transcription for extracellular matrix synthesis via the Smad pathway, and gene transcription for cell motility via the Ras/MAPK (non-Smad) pathway. PMID- 23083815 TI - Curcumin attenuates lipolysis stimulated by tumor necrosis factor-alpha or isoproterenol in 3T3-L1 adipocytes. AB - BACKGROUND AND AIM: Curcumin, an active component derived from dietary spice turmeric (Curcuma longa), has been demonstrated antihyperglycemic, antiinflammatory and hypocholesterolemic activities in obesity and diabetes. These effects are associated with decreased level of circulating free fatty acids (FFA), however the mechanism has not yet been elucidated. The flux of FFA and glycerol from adipose tissue to the blood stream primarily depends on the lipolysis of triacylglycerols in the adipocytes. Adipocyte lipolysis is physiologically stimulated by catecholamine hormones. Tumor necrosis factor-alpha (TNFalpha) stimulates chronic lipolysis in obesity and type 2 diabetes. In this study, we examined the role of curcumin in inhibiting lipolytic action upon various stimulations in 3T3-L1 adipocytes. METHODS: Glycerol release from TNFalpha or isoproterenol-stimulated 3T3-L1 adipocytes in the absence or presence of curcumin was determined using a colorimetric assay (GPO-Trinder). Western blotting was used to investigate the TNFalpha-induced phosphorylation of MAPK and perilipin expression. Fatcake and cytosolic fractions were prepared to examine the isoproterenol-stimulated hormone-sensitive lipase translocation. RESULTS: Treatment with curcumin attenuated TNFalpha-mediated lipolysis by suppressing phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and reversing the downregulation of perilipin protein in TNFalpha-stimulated adipocytes (p<0.05). The acute lipolytic response to adrenergic stimulation of isoproterenol was also restricted by curcumin (10-20 MUM, p<0.05), which was compatible with reduced perilipin phosphorylation(29%, p<0.05) and hormone-sensitive lipase translocation(20%, p<0.05). CONCLUSIONS: This study provides evidence that curcumin acts on adipocytes to suppress the lipolysis response to TNFalpha and catecholamines. The antilipolytic effect could be a cellular basis for curcumin decreasing plasma FFA levels and improving insulin sensitivity. PMID- 23083816 TI - Effects of bilobalide on anxiety, spatial learning, memory and levels of hippocampal glucocorticoid receptors in male Kunming mice. AB - With various constituents in ginkgo biloba extract, the detailed internal mechanism underlying a reduction in anxiety and improvements to learning and memory from GBE is not well understood. The present study investigated whether bilobalide, an important constituent in GBE, could affect anxiety, spatial learning and memory in male mice and whether hippocampal glucocorticoid receptor expression is associated with alteration in these behaviors. Mice were treated orally either with sesame seed oil or one of three dosages of bilobalide (2.5, 5.0 and 10.0 mg/kg) daily until testing. A series of behavioral tests showed that repeated bilobalide treatment decreased levels of anxiety-like behavior and increased locomotor activity in open field and elevated plus maze tests. Treatment with bilobalide also shortened the time taken to find the platform in a Morris water-maze test. Mice exposed to bilobalide showed higher and dose dependent levels of glucocorticoid receptor expression in the hippocampus. These results suggest that bilobalide reduces anxiety levels and enhances spatial learning and memory, possibly through an increase in hippocampal glucocorticoid receptor expression. This finding sheds light on the mechanisms underlying the effect of ginkgo biloba extract on behavior and also provides an important candidate drug in treatment of anxiety, depression, hypomnesia and amnesia. PMID- 23083817 TI - Antidyslipidemic and antioxidant activity of the constituents isolated from the leaves of Calophyllum inophyllum. AB - In continuation of our drug discovery program on Indian medicinal plants, we isolated bioactive compounds (1-5) from the leaves of Calophyllum inophyllum and evaluated their antidyslipidemic activity in triton induced hyperlipidemia model. The calophyllic acid (1A) and isocalophyllic acid (1B) mixture, canophyllic acid (4) and amentoflavone (5) showed dose dependent lipid lowering activity in in vivo experiments. The compounds 1A+1B mixture and 3 also showed good in vitro antioxidant activity. PMID- 23083818 TI - Why should infectious disease physicians care for the hepatitis C-infected patient? AB - Hepatitis C virus (HCV) has evolved into a true infectious disease that needs the increased involvement of infectious disease (ID) physicians. HCV is a serious public health concern requiring screening, education, reduction of disease transmission, and access to care. Patients coinfected with HCV/human immunodeficiency virus need their ID physicians to be more involved in HCV care and the unique challenges that exist in this patient population. HCV patients overall need more provider resources with expertise. The era of direct-acting antivirals for HCV is creating the need and opportunity for ID physicians to assume an active role in this disease. PMID- 23083819 TI - Staging of liver disease: which option is right for my patient? AB - It is important to assess the stage of liver fibrosis in chronic hepatitis C to guide treatment decisions. Liver biopsy has limitations in staging fibrosis. Several blood tests, algorithms, and imaging tests have been studied as noninvasive markers to stage fibrosis in hepatitis C. In patients without suspicion for cirrhosis, 2 noninvasive methods can be used to predict presence of absence of significant liver fibrosis; however, liver biopsy remains the gold standard. It is imperative not to miss the diagnosis of cirrhosis, because this has further implications for screening of hepatocellular carcinoma and varices. PMID- 23083821 TI - The importance of rapid viral suppression in the era of directly acting antiviral therapy for hepatitis C virus. AB - An increased understanding of viral kinetics has allowed clinicians to tailor therapy for hepatitis C virus through identifying patients who have the best chance of viral eradication and those for whom therapy will likely fail. Nonetheless, sustained viral response rates with pegylated interferon (PegIFN) and ribavirin remain disappointingly low. However, exciting advancements in the field of hepatitis C therapy include the development of new direct-acting antiviral agents, which offer much higher rates of sustained viral eradication when used in combination with PegIFN and ribavirin. PMID- 23083820 TI - IL28B polymorphisms as a pretreatment predictor of response to HCV treatment. AB - Genome-wide association studies have identified polymorphisms located near the gene encoding IL28B, which turned out to be the best predictor of response to pegylated interferon plus ribavirin for chronic hepatitis C virus (HCV) genotype 1 infection. This association was extended to spontaneous clearance of HCV, suggesting shared mechanisms of treatment and natural control of this virus. In addition to the biologic implications for innate immunity and HCV, a variety of clinical studies have suggested possible translation to a useful genetic test for practitioners. This article reviews the discovery, biology, and potential clinical applications that have stemmed from the seminal observation that IL28B polymorphisms are a main predictor of HCV clearance. PMID- 23083822 TI - Approach to the treatment-naive patient with HCV genotype 1 infection. AB - In May 2011, the protease inhibitors boceprevir and telaprevir were approved in combination with peginterferon-alpha and ribavirin for the treatment of genotype 1 chronic hepatitis C virus infection in the United States. These regimens brought substantial improvements in sustained virologic response rates, especially for treatment-naive patients. This article reviews the approach to therapy with these genotype 1 treatment-naive patients. PMID- 23083823 TI - Approach to the treatment-experienced patient with hepatitis C virus genotype 1 infection. AB - A significant proportion of treatment-experienced hepatitis C virus genotype 1 (GT1) patients will not achieve sustained virologic response [corrected] with protease inhibitor-triple therapy, and so the need for alternative therapies for these patients remains high. The aim of this article is to provide a critical evaluation of the available data, highlighting the knowledge gaps and providing a practical framework for making treatment decisions in treatment-experienced GT1 patients with currently approved drugs. PMID- 23083824 TI - Managing adverse effects of interferon-alfa and ribavirin in combination therapy for HCV. AB - This article focuses on the adverse effects of hepatitis C therapy, which includes pegylated interferon alfa-2a or -2b with ribavirin. The hepatitis C virus provider should remain cognizant of the various organ systems that can be affected, which adverse effects should be addressed with the help of an expert, and the presentation of symptoms as they occur throughout the course of therapy. A systems-based approach should help to characterize the nature of the adverse effects that patients experience, and also to determine when patients should be further investigated by a consultant. PMID- 23083825 TI - Treatment of hepatitis C in patients infected with human immunodeficiency virus in the direct-acting antiviral era. AB - Chronic hepatitis C is a leading cause of clinical complications and mortality in individuals infected with human immunodeficiency virus (HIV). Approval for the first direct-acting antiviral (DAA) against the hepatitis C virus (HCV) has been eagerly awaited for treating patients coinfected with HIV/HCV. The use of first generation HCV protease inhibitors is challenged by complicated dosing schedules, frequent serious toxicities, unwanted drug interactions, drug resistance, and high cost. First-generation DAAs will eventually be replaced by more potent, well tolerated, and convenient agents. HIV/HCV co-infection will become restricted to individuals without proper access to health care. PMID- 23083827 TI - Hepatitis C virus drug resistance: implications for clinical management. AB - The addition of hepatitis C virus NS3 protease inhibitors to interferon-based regimens has dramatically improved response rates. Despite these improvements treatment is now more complex, associated with increased side effects, and has the potential to select resistant variants in those who are not cured. This article discusses the virologic underpinnings for the development of hepatitis C virus-resistant variants (with a focus on telaprevir and boceprevir) and their impact on therapeutic success. Interim guidance on the use of resistance testing and management is provided based on the limited data. Finally, resistance considerations for other classes of inhibitors and the rapidly approaching interferon-free therapeutics regimens are offered. PMID- 23083826 TI - Future classes of hepatitis C virus therapeutic agents. AB - Recent advances in understanding of the molecular characteristics of the hepatitis C virus have led to the development of novel antiviral therapeutics. Direct-acting antivirals are designed to inhibit viral targets, whereas host targeted antivirals block host factors that are used by the virus for its own life cycle. The rapid development of agents in multiple classes has led to the promise of shorter therapy duration, an improved side effect profile, and eventually interferon-sparing regimens. This article reviews novel hepatitis C virus therapeutics in development, including mechanism of action, efficacy, and adverse effects. PMID- 23083828 TI - Care of the cirrhotic patient. AB - The clinical manifestations of cirrhotic liver disease encompass a broad spectrum of conditions that reflect the consequence of high portal pressures that result from fibrosis and diminished hepatic synthetic reserve. Patients with cirrhosis are at heightened risk for the development of infection, and although the use of prophylactic antimicrobial therapy may be considered lifesaving in the setting of gastrointestinal hemorrhage, there remains controversy regarding such therapy in the management of cirrhotic ascites. The infectious disease specialist is now becoming familiarized with the management of viral hepatitis, which includes screening for hepatocellular carcinoma and vigilance for infectious complications of antiviral therapy. PMID- 23083829 TI - Diagnosis and treatment of acute hepatitis C virus infection. AB - The first 6 months after exposure to hepatitis C virus (HCV) are regarded as acute hepatitis C (AHC). Two patient populations worldwide share the highest prevalence of AHC virus infection: injection drug users and HIV-positive men who have sex with men. Diagnosis of AHC is often difficult in both patient populations as the acute inflammatory phase can be clinically asymptomatic and patients at highest risk for acquiring AHC (injection drug users) tend to evade regular medical care. This article addresses similarities and differences in the epidemiology, diagnosis, and management of AHC monoinfection and coinfection. PMID- 23083830 TI - Care of the patient with hepatitis C virus infection. Preface. PMID- 23083831 TI - Reducing blood loss at abdominal myomectomy with preoperative use of dinoprostone intravaginal suppository: a randomized placebo-controlled pilot study. AB - OBJECTIVE: To determine the effect of a single preoperative intravaginal prostaglandin E(2) (PGE(2); dinoprostone) suppository on reducing intraoperative blood loss and the need for subsequent blood transfusion at abdominal myomectomy for symptomatic leiomyomas. STUDY DESIGN: In a prospective randomized double blind placebo-controlled pilot study, 108 women who had abdominal myomectomy for symptomatic leiomyomas were enrolled. Patients were randomly assigned to receive a single dose of intravaginal 20mg dinoprostone (n=54) or placebo (n=54) 60 min before the operation. The primary outcome was the operative blood loss. The secondary outcomes were the need for blood transfusion, change in hemoglobin (Hb) level 24h after operation, and the prevalence of side effects. RESULTS: Blood loss and transfusion rate were significantly greater in the group without PGE(2) suppository (group B) than in the group with PGE(2) (group A): they were respectively 485.7 +/- 361.3 mL vs 364.1 +/- 279.4 mL (P=.02; relative risk [RR] 0.95; 95% confidence interval [CI], 0.63-1.45) and 18.5% vs 3.7% (P=.04; RR 1.32; 95% CI, 3.7-18.5). Group B had a significant decrease in Hb level 24h after operation compared with group A (P<.05). There was no difference in the patient demographics, intraoperative characteristics, postoperative stay, complications, and the side effects between the two groups. CONCLUSION: A single pre-operative dose of dinoprostone administered intravaginally could be a safe and reliable method to help decrease blood loss during abdominal myomectomy. Further larger prospective studies are required to support this conclusion. PMID- 23083832 TI - A 12-gene expression signature is associated with aggressive histological in prostate cancer: SEC14L1 and TCEB1 genes are potential markers of progression. AB - The main challenge for clinical management of prostate cancer is to distinguish tumors that will progress faster and will show a higher tendency to recur from the more indolent ones. We have compared expression profiles of 18 prostate cancer samples (seven with a Gleason score of 6, eight with a Gleason score of 7, and three with a Gleason score of >=8) and five nonneoplastic prostate samples, using the Affymetrix Human Array GeneChip Exon 1.0 ST. Microarray analysis revealed 99 genes showing statistically significant differences among tumors with Gleason scores of 6, 7, and >=8. In addition, mRNA expression of 29 selected genes was analyzed by real-time quantitative RT-PCR with microfluidic cards in an extended series of 30 prostate tumors. Of the 29 genes, 18 (62%) were independently confirmed in the extended series by quantitative RT-PCR: 14 were up regulated and 4 were down-regulated in tumors with a higher Gleason score. Twelve of these genes were differentially expressed in tumors with a Gleason score of 6 to 7 versus >=8. Finally, IHC validation of the protein levels of two genes from the 12-gene signature (SEC14L1 and TCEB1) showed strong protein expression levels of both genes, which were statistically associated with a high combined Gleason score, advanced stage, and prostate-specific antigen progression. This set of genes may contribute to a better understanding of the molecular basis of prostate cancer. TCEB1 and SELC14L1 are good candidate markers for predicting prognosis and progression of prostate cancer. PMID- 23083833 TI - Network analysis of transcriptional responses induced by mesenchymal stem cell treatment of experimental sepsis. AB - Although bone marrow-derived mesenchymal stem cell (MSC) systemic administration reduces sepsis-associated inflammation, organ injury, and mortality in clinically relevant models of polymicrobial sepsis, the cellular and molecular mechanisms mediating beneficial effects are controversial. This study identifies the molecular mechanisms of MSC-conferred protection in sepsis by interrogating transcriptional responses of target organs to MSC therapy. Sepsis was induced in C57Bl/6J mice by cecal ligation and puncture, followed 6 hours later by an i.v. injection of either MSCs or saline. Total RNA from lungs, hearts, kidneys, livers, and spleens harvested 28 hours after cecal ligation and puncture was hybridized to mouse expression bead arrays. Common transcriptional responses were analyzed using a network knowledge-based approach. A total of 4751 genes were significantly changed between placebo- and MSC-treated mice (adjusted P <= 0.05). Transcriptional responses identified three common effects of MSC administration in all five organs examined: i) attenuation of sepsis-induced mitochondrial related functional derangement, ii down-regulation of endotoxin/Toll-like receptor innate immune proinflammatory transcriptional responses, and iii) coordinated expression of transcriptional programs implicated in the preservation of endothelial/vascular integrity. Transcriptomic analysis indicates that the protective effect of MSC therapy in sepsis is not limited to a single mediator or pathway but involves a range of complementary activities affecting biological networks playing critical roles in the control of host cell metabolism and inflammatory response. PMID- 23083834 TI - Erysipelothrix rhusiopathiae isolates recovered from fish, a harbour seal (Phoca vitulina) and the marine environment are capable of inducing characteristic cutaneous lesions in pigs. AB - In order to determine the diversity and pathogenicity of Erysipelothrix spp. isolates recovered from marine fish, a harbour seal (Phoca vitulina) and the marine environment, 14 isolates were characterized by genotyping, serotyping, determination of the surface protective antigen (spa) gene type and assessment of virulence in a pig bioassay. All 14 isolates were Erysipelothrix rhusiopathiae. Isolates were determined to be of serotypes 2 (n = 3), 3 (n = 1), 4 (n = 1), 12 (n = 1), 15 (n = 1) or 21 (n = 6), and one isolate cross-reacted with serotypes 5 and 21. The spa gene analysis determined that 64.3% (n = 9) were spaA and 35.7% (n = 5) were spaB1. In pigs, 10/14 isolates induced small plaques to diamond shaped cutaneous lesions consistent with Erysipelothrix spp. infection. The results of this study indicate that the marine E. rhusiopathiae isolates have greater genetic and antigenic diversity than pig isolates and are capable of inducing classical skin lesions in pigs. PMID- 23083835 TI - Early and late peritoneal and hepatic changes in goats immunized with recombinant cathepsin L1 and infected with Fasciola hepatica. AB - The aim of the present study was to study peritoneal and hepatic changes during early [7-9 days postinfection (dpi)] and late [15 weeks postinfection (wpi)] infection of goats immunized with recombinant F. hepatica pro cathepsin L1 (rCL1) in Quil A and challenged with Fasciola hepatica. Despite finding no significant reduction in fluke burdens between the control and immunized group, at 15 dpi the rCL1-vaccinated group showed significantly higher weight gain and reduced severity of hepatic lesions compared with the control group that received only Quil A. In the rCL1-vaccinated group, two of three goats sacrificed at 7-9 dpi had little hepatic damage and had a higher percentage of peritoneal eosinophils and elevated induced nitric oxide synthase (iNOS) expression in peritoneal cells than the goats from the control group. Moreover, while these two goats showed a heavy infiltration of eosinophils surrounding migrating flukes, the remaining animals examined at 7-9 dpi had no inflammatory infiltration surrounding migrating flukes. Two out of seven goats in the rCL1-vaccinated group had low fluke burdens and little hepatic damage at 15 wpi, suggesting an effective protective response in some of the vaccinated goats. This protective response did not correlate with peripheral eosinophilia or with serum titres of anti-rCL1 immunoglobulin (Ig) G. The results of the present work suggest that an eosinophil mediated immune response plays a crucial role in the early effective host response against F. hepatica in goats. Adjuvants designed to increase cell mediated immunity should be tested in future vaccine trials against F. hepatica. PMID- 23083836 TI - What's for dinner? Types of food served at family dinner differ across parent and family characteristics. AB - OBJECTIVE: To examine the types of food served at family dinner in the homes of adolescents and correlations with parent and family sociodemographic characteristics, psychosocial factors and meal-specific variables. DESIGN: A cross-sectional population-based survey completed by mail or telephone by parents participating in Project F-EAT (Families and Eating and Activity in Teens) in 2009-2010. SETTING: Homes of families with adolescents in Minneapolis/St. Paul urban area, MN, USA. SUBJECTS: Participants included 1923 parents/guardians (90.8% female; 68.5% from ethnic/racial minorities) of adolescents who participated in EAT 2010. RESULTS: Less than a third (28%) of parents reported serving a green salad at family dinner on a regular basis, but 70% reported regularly serving vegetables (other than potatoes). About one-fifth (21%) of families had fast food at family dinners two or more times per week. Variables from within the sociodemographic domain (low educational attainment) psychosocial domain (high work-life stress, depressive symptoms, low family functioning) and meal-specific domain (low value of family meals, low enjoyment of cooking, low meal planning, high food purchasing barriers and fewer hours in food preparation) were associated with lower healthfulness of foods served at family dinners, in analyses adjusted for sociodemographic characteristics. CONCLUSIONS: There is a need for interventions to improve the healthfulness of food served at family meals. Interventions need to be suitable for parents with low levels of education; take parent and family psychosocial factors into account; promote more positive attitudes toward family meals; and provide skills to make it easier to plan and prepare healthful family meals. PMID- 23083838 TI - Inhibition of ABCG2/BCRP transporter by soy isoflavones genistein and daidzein: effect on plasma and milk levels of danofloxacin in sheep. AB - Danofloxacin is a synthetic fluoroquinolone antibacterial agent and a substrate for ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). This protein actively extrudes drugs from cells in the intestine, liver, kidney, and other organs, such as the mammary gland. The purpose of this study was to determine whether genistein and daidzein, isoflavones present in soy and known inhibitors of ABCG2, could diminish danofloxacin secretion into milk. The results obtained from BCRP-transduced MDCK-II cells (Mardin-Darby canine kidney) showed that both isoflavones efficiently inhibited the in vitro transport of the drug. In addition, danofloxacin transport into milk was studied in Assaf sheep. The experimental design with ewes (n = 18) included ewes fed with standard forage, soy-enriched forage for 15 days prior to the experiment or standard forage paired with orally administered exogenous genistein and daidzein. The danofloxacin levels in the milk of ewes in the soy-enriched diet group were decreased. The area under concentration-time curve AUC (0-24 h) was 9.3 +/- 4.6 vs. 16.58 +/- 4.44 MUgh/mL in the standard forage or control group. The plasma levels of danofloxacin were unmodified. The AUC (0-24 h) milk/plasma ratio decreased by over 50% in the soy-enriched diet group, compared to the control group (4.90 +/- 2.65 vs. 9.58 +/- 2.17). Exogenous administration of isoflavones did not modify danofloxacin secretion into milk. This study showed that milk excretion of a specific substrate of BCRP, such as danofloxacin, can be diminished by the presence of isoflavones in the diet. PMID- 23083837 TI - Missing the target: characterization of bullous pemphigoid patients who are negative using the BP180 enzyme-linked immunosorbant assay. AB - BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies specific for the 180-kd BP antigen-2 (BP180) (also termed "type XVII collagen") protein. The BP180 enzyme-linked immunosorbent assay (ELISA) is specific for the immunodominant NC16A domain of the protein. However, we and others have observed patients whose reactivity to BP180 is exclusive of the NC16A domain (referred to henceforth as non-NC16A BP). OBJECTIVE: We sought to determine the incidence of non-NC16A BP and identify regions of reactivity within the BP180 protein. METHODS: Sera from 51 patients who met the clinical and histologic criteria for BP were screened for NC16A reactivity by ELISA. Sera that were negative by ELISA were screened for IgG reactivity to an epidermal extract, recombinant BP180 protein, and subregions of BP180, by immunoblot. Demographic and clinical data were also collected on all patients. RESULTS: Four sera (7.8%) were negative using the BP180 ELISA but positive for IgG reactivity to the extracellular domain of BP180. Further mapping identified 4 regions outside of NC16A recognized by these sera: amino acid (AA) 1280 to 1315, AA 1080 to 1107, AA 1331 to 1404, and AA 1365 to 1413. One of these sera also had IgE specific for NC16A. One patient had an atypical presentation with lesions limited to the lower aspect of the legs and scarring of the nail beds. LIMITATIONS: The small total number of patients with non-NC16A BP limits the identification of demographic or clinical correlates. CONCLUSION: It is significant that 7.8% of sera from patients with new BP react to regions of BP180 exclusively outside of NC16A and, thus, would not be identified using the currently available BP180 ELISA. PMID- 23083839 TI - Effect of an additional dose of indacaterol in COPD patients under regular treatment with indacaterol. AB - AIM: In this randomized, double-blind, crossover study, we explored the acute effects on respiratory function and safety of an additional dose of indacaterol 150 MUg in stable COPD patients regularly treated with a conventional dose of indacaterol 150 MUg. METHODS: On two non-consecutive days, patients inhaled indacaterol 150 MUg. After 180 min, they inhaled an additional dose of indacaterol 150 MUg or placebo. Lung function, oxygen saturation by pulse oximetry (SpO(2)) and heart rate were measured before the first drug administration and up to 360 min thereafter. RESULTS: In both treatment groups, indacaterol induced a significant (P < 0.05) bronchodilation during all the study time. The difference between the FEV(1) AUCs(0-180 min) was not statistically significant (P = 0.971). On the contrary, the difference between the FEV(1) AUCs(180-360 min) was significant (P < 0.0001). However, only 8 out of 20 patients showed a further increase of at least 100 ml from the peak obtained after the first administration of indacaterol 150 MUg with the second dose of 150 MUg. Indacaterol 150 MUg induced a modest but significant decrease in SpO(2) up to 60 min and a second dose of indacaterol 150 MUg significantly decreased the SpO(2) mean value up to 360 min. CONCLUSION: This study suggests that it is reasonable and safe to increase the dose of indacaterol in those stable COPD patients who are under regular therapy with indacaterol 150 MUg from which they do not draw the maximum benefit because they are unable to perceive bronchodilation. However, only a minority of patients seem to benefit from this dose escalation, at least in terms of spirometric improvement. PMID- 23083840 TI - Concomitant asthma medications in moderate-to-severe allergic asthma treated with omalizumab. AB - BACKGROUND: Omalizumab is a recombinant humanized monoclonal anti-IgE antibody approved in adults and adolescents with moderate-to-severe persistent allergic asthma inadequately controlled with inhaled corticosteroids (ICS). EXCELS is an ongoing prospective observational cohort study of approximately 5000 omalizumab treated and >2800 non-omalizumab-treated patients aged >=12 years. OBJECTIVE: We evaluated concomitant medication use changes (total ICS dose [including monotherapy and combination therapy, fluticasone equivalent], short-acting beta agonists [SABA], and leukotriene modifier [LTM]) over 2 years among subsets of patients enrolled in EXCELS. METHODS: Patient subsets included "new starts" (omalizumab initiated at baseline [n = 549], "established users" (omalizumab initiated >7 days before baseline [n = 4421]), and "non-omalizumab" patients (not treated with omalizumab [n = 2867]). RESULTS: At baseline, mean +/- SD total daily ICS doses were 680 +/- 414 MUg/d in new starts, 642 +/- 431 MUg/d in established users, and 548 +/- 382 MUg/d in non-omalizumab patients. From baseline through year 2, total ICS dose decreased in 65% of new starts (mean +/- SD change, -393 +/- 504 MUg/d), 57% of established users (-287 +/- 492 MUg/d), and 54% of non-omalizumab patients (-232 +/- 431 MUg/d). At baseline, SABA use for new starts, established users, and non-omalizumab patients was 1.9, 1.3, and 1.4 puffs/d, respectively. At year 2, SABA use decreased in 65% of new starts, 55% of established users, and 54% of non-omalizumab patients. At year 2, LTM dose decreased in 52% of new starts, 44% of established users, and 40% of non omalizumab patients. CONCLUSION: Omalizumab therapy initiation was associated with decreased doses of ICS, SABA, and LTM over 2 years of follow-up for the majority of patients in a "real-world" cohort study of moderate-to-severe allergic asthma patients. PMID- 23083841 TI - CRP is associated with lung function decline in men but not women: a prospective study. AB - Systemic inflammation is associated with impaired lung function. Studies, most cross-sectional, report a stronger association between systemic inflammation and lung function impairment in men than women. The aim was to evaluate gender differences in the longitudinal association between systemic inflammation and lung function. We used data from randomly chosen residents of Reykjavik, born 1940-54, who were investigated in three stages: Baseline (1973-75; 1983-85) and follow-up (2001-03). The participants (n = 1049, 574 women) had a mean age of 28 +/- 6 years at baseline and mean follow-up time of 27 +/- 4 years. At each stage lung function (FEV(1) and FVC) and C-reactive protein (CRP) were evaluated. Change in FEV(1) (p = 0.04) and FVC (p = 0.01) was associated with baseline CRP in men but not in women. In the multiple variable analysis, CRP at baseline was associated with a decline in FEV(1) (-3.1 mL/year, 95% CI: -5.1, -0.99) and FVC ( 2.5 mL/year, 95% CI: -4.4, -0.65) in men but not in women. Similarly during follow-up, change in CRP, standardised to 1SD, was associated with a decline in FEV(1) (-0.19 mL/year, 95% CI: -0.30, -0.07) and FVC (-0.11 mL/year, 95% CI: 0.22, -0.01)) in men but not in women. This prospective study confirms a stronger association between systemic inflammation and lung function decline in men than in women. This may indicate a gender difference in the mechanisms of lung function decline. PMID- 23083842 TI - Influenza control can be achieved in a custodial setting: pandemic (H1N1) 2009 and 2011 in an Australian prison. AB - OBJECTIVES: Information on the effectiveness of interventions regarding control in closed institutional settings, including prisons, is limited. This study gathered evidence relating to influenza control in an Australian prison. STUDY DESIGN: This study built on a 2009 H1N1 outbreak investigation at the Alexander Maconochie Centre (AMC) in the Australian Capital Territory (ACT). METHODS: Influenza surveillance data, ACT 2010 Inmate Health Survey data, New South Wales 2001 and 2009 Inmate Health Survey data, ACT Department of Corrective Services administrative data, and ACT Health clinical data were analysed. RESULTS: In 2011, the AMC was exposed to influenza virus, resulting in a single case. Public health activities included exclusion of symptomatic cases from the health facility, isolation of cases, and quarantine of contacts. Contact between prisoners and the ACT community was maintained; the AMC detainee visitor rate was one visitor per prisoner every 10 days. CONCLUSIONS: The rehabilitative benefits of human contact for AMC detainees were not compromised during the surveillance period, despite the potential that a higher visitor rate may suggest. This highlights some features of the AMC which make its operational context different from many other correctional settings, but gives some indication of how good public health practice supports human rights. PMID- 23083843 TI - Tourism engaging with the public health agenda: can we promote 'wellville' as a destination of choice? PMID- 23083844 TI - Neighborhood socioeconomic status and coronary heart disease risk prediction in a nationally representative sample. AB - OBJECTIVES: Test the association between coronary heart disease (CHD) risk scores and neighborhood socioeconomic status (NSES) in a US nationally-representative sample and describe whether the association varies by gender and race/ethnicity. STUDY DESIGN: Cross-sectional study. METHODS: We use Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004 linked with Census tract data. Multivariable regression models and propensity score adjusted models are employed to test the association between NSES and 10-year risk of CHD based on the Framingham Risk Score (FRS), adjusting for individual-level characteristics. RESULTS: An individual living in a neighborhood at the 75th percentile of NSES (high NSES) has, on average, a 10-year CHD risk that is 0.16 percentage points lower (95% Confidence Interval 0.16, 0.17) than a similar person residing in a neighborhood at the 25th percentile of NSES (low NSES). Race/ethnicity and gender were found to significantly modify the association between NSES and CHD risk: the association is larger in men than women and in whites than minorities. Propensity score models showed that findings on the main effects of NSES were robust to self selection into neighborhoods. Similar results were observed between NSES and risk of cardiovascular disease events. CONCLUSIONS: NSES is significantly associated with CHD risk, and the relationship varies by gender and race/ethnicity. PMID- 23083845 TI - Changes in the social gradients for Pap smears and mammograms in Argentina: evidence from the 2005 and 2009 National Risk Factor Surveys. AB - OBJECTIVES: To identify changes in the social gradients for Pap smears and mammograms in Argentina. STUDY DESIGN: Secondary analysis of the 2005 and 2009 Argentine National Risk Factor Surveys. METHODS: Logistic regression analysis was used to examine social gradients by income and education, adjusting for age and health insurance. RESULTS: The proportion of women who received a Pap smear in the previous 2 years increased from 51.6% in 2005 to 60.5% in 2009 (chi(2) = 344.8, P < 0.001). A significant increase was also seen in the receipt of a mammogram in the previous 2 years by women aged >=50 years, with an increase from 39.6% in 2005 to 52.6% in 2009 (chi(2) = 279.6, P < 0.001). In 2005, low-income women were most likely not to have received a Pap test [odds ratio (OR) = 3.27, 95% confidence interval (CI) = 2.70-3.98], followed by medium-income women (OR = 1.73, 95% CI = 1.41-2.12), compared with high-income women. The gradient by education was of a similar magnitude, and both income and education gradients remained stable from 2005 to 2009. Restricting the analysis to eight provinces that have been deemed to be high priority due to their high levels of mortality from cervical cancer reveals an increasing income-based gradient in Pap smears. In contrast, inequalities in mammography diminished across the country, with a significant reduction in the social gradient measured either by income or education. In contrast to high-income women, low-income women experienced higher odds of not having a mammogram, but the gap diminished over time [OR = 4.14 (95% CI = 2.96-5.78) in 2005 vs OR = 2.37 (95% CI = 1.81-3.11) in 2009]. CONCLUSION: Social gradients in cancer screening are changing in Argentina. There are signs of a reduction in inequalities in mammograms, although this is attenuated by indications that inequalities in Pap smear utilization in priority provinces are growing. Surveillance of population indicators is needed to verify whether these short-term changes persist over time. PMID- 23083847 TI - Editorial comment. PMID- 23083848 TI - Editorial comment. PMID- 23083849 TI - Improvement in overall survival of patients with advanced renal cell carcinoma: prognostic factor trend analysis from an international data set of clinical trials. AB - PURPOSE: We assessed temporal shifts in the frequency of risk factors for patients with metastatic renal cell carcinoma in a multicenter, international data set. MATERIALS AND METHODS: An international database of 3,748 patients treated with systemic therapy for metastatic renal cell carcinoma from 1975 to 2002 was constructed by pooling clinical trial data. Proportions of previously identified risk factors were examined during 6 specified time cohorts. Overall survival for each cohort was examined using the Kaplan-Meier method. Trends in overall survival from 1973 to 2008 were also examined in 25,271 patients from the SEER (Surveillance, Epidemiology and End Results) database. RESULTS: Median overall survival from start of treatment increased with each consecutive time cohort group. In the earliest cohort median overall survival was 0.5 years (95% CI 0.43-0.57), which increased to 1.63 years (95% CI 1.28-1.79) in 2001 to 2002. More patients had a history of nephrectomy in the most recent cohort (p = 0.001). The proportion of patients with low performance status, high lactate dehydrogenase and high adjusted calcium decreased by study entry year (each p <0.01). Analysis of overall survival from the SEER database showed similar improvement in the more contemporary diagnosis cohorts (p <0.001). Two-year overall survival in the earliest and latest diagnosis cohort was 14% (95% CI 13 14) and 22% (95% CI 21-24), respectively. CONCLUSIONS: Higher representation of favorable risk factors in recent years may have partly contributed to the improvement in overall survival observed in more recent metastatic renal cell carcinoma clinical trials. These shifts could affect the outcome interpretation. PMID- 23083850 TI - Competing risks of death in patients with localized renal cell carcinoma: a comorbidity based model. AB - PURPOSE: Multiple risks compete with cancer as the primary cause of death. These factors must be considered against the benefits of treatment. We constructed a model of competing causes of death to help contextualize treatment trade-off analyses in patients with localized renal cell carcinoma. MATERIALS AND METHODS: We identified 6,655 individuals 66 years old or older with localized renal cell carcinoma in the linked SEER (Surveillance, Epidemiology and End Results) Medicare data set for 1995 to 2005. We used Fine and Gray competing risks proportional hazards regression to predict probabilities of competing mortality outcomes. Prognostic markers included race, gender, tumor size, age and the Charlson comorbidity index score. RESULTS: At a median followup of 43 months, age and comorbidity score strongly correlated with patient mortality and were most predictive of nonkidney cancer death, as measured by concordance statistics. Patients with localized, node negative kidney cancer had a low 3 (4.7%), 5 (7.5%) and 10-year (11.9%) probability of cancer specific death but a significantly higher overall risk of death from competing causes within 3 (10.9%), 5 (20.1%) and 10 years (44.4%) of renal cell carcinoma diagnosis, depending on comorbidity score. CONCLUSIONS: Informed treatment decisions regarding patients with solid tumors must integrate not only cancer related variables but also factors that predict noncancer death. We established a comorbidity based predictive model that may assist in patient counseling by allowing quantification and comparison of competing risks of death in patients 66 years old or older with localized renal cell carcinoma who elect to proceed with surgery. PMID- 23083851 TI - Editorial comment. PMID- 23083852 TI - Readability of websites containing information about prostate cancer treatment options. AB - PURPOSE: Approximately 90 million American adults have literacy skills that test below a high school reading level. Websites written above this level can pose a challenge for those seeking online information about prostate cancer treatment options. In this study we determine the readability of selected websites using a systematic search process and validated readability formulas. MATERIALS AND METHODS: We identified the 3 most popular keywords from 513 terms related to prostate cancer treatment options. We then systematically collected 270 websites from the top 3 search engines, and excluded from study those that were nonEnglish, not primarily text, irrelevant and/or duplicated. We used the Flesch Kincaid grade level and Flesch Reading Ease to determine scores for each site. RESULTS: A total of 62 unique websites were analyzed. Median Flesch-Kincaid grade level was 12.0 (range 8.0 to 12.0) and median Flesch Reading Ease score was 38.1 (range 0.0 to 65.5). Only 3 sites (4.8%) were written below a high school reading level (less than 9.0). CONCLUSIONS: Few websites with discussions on prostate cancer treatment options are written below a high school reading level. This is problematic for a third of Americans who seek to further educate themselves using online resources. Clinicians can use this information to guide their patients to appropriate websites. PMID- 23083854 TI - Detecting DNA methylation of the BCL2, CDKN2A and NID2 genes in urine using a nested methylation specific polymerase chain reaction assay to predict bladder cancer. AB - PURPOSE: Detection of methylated DNA has been shown to be a good biomarker for bladder cancer. Bladder cancer has the highest recurrence rate of any cancer and, as such, patients are regularly monitored using invasive diagnostic techniques. As urine is easily attainable, bladder cancer is an optimal cancer to detect using DNA methylation. DNA methylation is highly specific in cancer detection. However, it is difficult to detect because of the limited amount of DNA present in the urine of patients with bladder cancer. Therefore, an improved, sensitive and noninvasive diagnostic test is needed. MATERIALS AND METHODS: We developed a highly specific and sensitive nested methylation specific polymerase chain reaction assay to detect the presence of bladder cancer in small volumes of patient urine. The genes assayed for DNA methylation are BCL2, CDKN2A and NID2. The regions surrounding the DNA methylation sites were amplified in a methylation independent first round polymerase chain reaction and the amplification product from the first polymerase chain reaction was used in a real-time methylation specific polymerase chain reaction. Urine samples were collected from patients receiving treatment at Wolfson Medical Center in Holon, Israel. RESULTS: In a pilot clinical study using patient urine samples we were able to differentiate bladder cancer from other urogenital malignancies and nonmalignant conditions with a sensitivity of 80.9% and a specificity of 86.4%. CONCLUSIONS: We developed a novel methylation specific polymerase chain reaction assay for the detection and monitoring of bladder cancer using DNA extracted from patient urine. The assay may also be combined with other diagnostic tests to improve accuracy. PMID- 23083855 TI - Editorial comment. PMID- 23083856 TI - Editorial comment. PMID- 23083857 TI - Economic and humanistic consequences of preventable bladder tumor recurrences in nonmuscle invasive bladder cancer cases. AB - PURPOSE: Perioperative intravesical chemotherapy following transurethral resection of bladder tumor has been underused despite level 1 evidence supporting its performance. The primary objective of this study was to estimate the economic and humanistic consequences associated with preventable recurrences in patients initially diagnosed with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Using population based estimates of nonmuscle invasive bladder cancer incidence, a 2-year model was developed to estimate the number of preventable recurrences in eligible patients untreated with perioperative intravesical chemotherapy. Therapy utilization rates were obtained from a retrospective database analysis and a chart review study of 1,010 patients with nonmuscle invasive bladder cancer. Recurrence rates of nonmuscle invasive bladder cancer were obtained from a randomized clinical trial comparing transurethral resection of bladder tumor with or without perioperative mitomycin C. Costs were estimated using prevailing Medicare reimbursement rates. Quality adjusted life-year estimates and disutilities for complications were obtained from the literature. RESULTS: The model estimated that 7,827 bladder recurrences could be avoided if all patients received immediate intravesical chemotherapy. It estimated an economic savings of $3,847 per avoidable recurrence, resulting in an aggregate savings of $30.1 million. The model also estimated that 1,025 quality adjusted life-years are lost every 2 years due to preventable recurrences, resulting in 0.13 quality adjusted life-years (48 quality adjusted days) lost per avoidable recurrence. This translates into 0.02 quality adjusted life-years (8.1 quality adjusted days) lost per patient not receiving immediate intravesical chemotherapy. CONCLUSIONS: Greater use of immediate intravesical chemotherapy in the United States has the potential to substantially decrease the economic and humanistic burdens of nonmuscle invasive bladder cancer. PMID- 23083859 TI - Impact of androgen deprivation therapy on weight gain differs by age in men with nonmetastatic prostate cancer. AB - PURPOSE: Although androgen deprivation therapy leads to weight gain within the first year in men with prostate cancer, longer term changes and the relationship to patient age are not well characterized. We examined long-term weight gain by age group in men on androgen deprivation therapy for up to 36 months. MATERIALS AND METHODS: Three cohorts matched by age and education were recruited in this prospective study, including men in whom continuous androgen deprivation therapy was initiated, controls with prostate cancer and healthy controls. All patients with prostate cancer had nonmetastatic disease. We performed age stratified (less than 65 vs 65 years or greater) comparisons. Univariate and multivariable associations with weight change with time were evaluated using linear regression. RESULTS: We included 257 men with a mean age of 69.1 years. At baseline the cohorts were similar in age, education, body mass index, weight and comorbidity. Androgen deprivation therapy was associated with weight gain from baseline at 6, 12, 18, 24, 30 and 36 months compared to controls with prostate cancer and healthy controls (p = 0.006, 0.015, 0.028, 0.003, 0.014 and 0.0004, respectively). The proportion of men who gained weight was higher among androgen deprivation therapy users than controls with prostate cancer and healthy controls at most time points. Age stratified analyses showed that younger patients (age less than 65 years) on androgen deprivation therapy had significantly greater weight gain with time than older patients (4.7 vs 1.4 kg, p = 0.005). However, age did not appear to affect weight change with time in men not on androgen deprivation therapy (p = 0.37). CONCLUSIONS: Androgen deprivation therapy was associated with an increase in weight during 36 months and weight gain was significantly higher in patients younger than 65 years. PMID- 23083860 TI - Editorial comment. PMID- 23083858 TI - Outcomes of patients with surgically treated bilateral renal masses and a minimum of 10 years of followup. AB - PURPOSE: Nephron sparing surgery has been advocated for patients with bilateral renal masses but long-term functional and oncological outcomes are lacking. We report the outcomes of patients with bilateral renal masses and a minimum 10-year followup. MATERIALS AND METHODS: Patients with bilateral renal masses evaluated at our institution who were treated with initial surgery at least 10 years ago and underwent interventions on each renal unit were included in the analysis. Collected data included demographics, hereditary diagnosis, number of renal interventions, renal function and mortality status. Overall and renal cell carcinoma specific survival was assessed. Comparisons were made of renal function and overall survival between groups with 2 renal units and a surgically solitary kidney. RESULTS: A total of 128 patients met study inclusion criteria. Median followup in our cohort was 16 years (mean 17, range 10 to 49). The median number of surgical interventions was 3 (range 2 to 10). Of the patients 87 (68%) required repeat interventions on the ipsilateral renal unit at last followup with a median of 6.2 years (range 0.7 to 21) between interventions. Overall and renal cell cancer specific survival was 88% and 97%, respectively. Six patients (4.7%) ultimately underwent bilateral nephrectomy. Although renal function was better preserved in patients with 2 kidneys (70 vs 53 ml/minute/1.73 m(2), p = 0.0002), there was no difference in overall survival between those with bilateral kidneys or a surgically solitary kidney. CONCLUSIONS: At a minimum 10-year followup after initial surgery, nephron sparing surgery allowed for excellent oncological and functional outcomes. Despite the need for repeat surgical interventions, nephron sparing surgery enabled dialysis to be avoided in more than 95% of patients. PMID- 23083861 TI - Value of prostate specific antigen density and percent free prostate specific antigen for prostate cancer prognosis. AB - PURPOSE: Limited data exist on the relationship of percent free prostate specific antigen and prostate specific antigen density with prostate cancer prognosis. Therefore, we compared percent free prostate specific antigen and prostate specific antigen density with prostate specific antigen, Gleason sum and stage to predict prostate cancer prognosis in a large cohort using a single prostate specific antigen and free prostate specific antigen assay. MATERIALS AND METHODS: Between 1999 and 2007 a total of 1,656 patients with prostate cancer underwent laparoscopic radical prostatectomy at the Charite Berlin. There were 322 patients excluded from analysis for a variety of reasons. The final 1,334 patients had prostate specific antigen, free prostate specific antigen, prostate volume and complete pathological analysis available. RESULTS: Median followup was 60.3 months (range 0.2 to 135). Median age (63 years, range 43 to 75) did not differ between the 1,092 patients without and the 242 with biochemical recurrence (p = 0.956), but prostate volume, prostate specific antigen and percent free prostate specific antigen differed significantly (p <0.0001). While prostate specific antigen and prostate specific antigen density increased significantly in patients with Gleason less than 7, 7 and greater than 7 tumors, percent free prostate specific antigen decreased significantly (p <0.0001). Prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density differed significantly between pT2 and pT3 tumors, and between patients with vs without positive surgical margins. On univariate analysis Gleason sum, pathological stage, positive surgical margin, total prostate specific antigen, percent free prostate specific antigen and prostate specific antigen density were predictors of biochemical recurrence-free survival. Multivariate Cox regression analysis identified Gleason sum, pathological stage, positive surgical margin and prostate specific antigen density as independent predictors of biochemical recurrence-free survival, while percent free prostate specific antigen and total prostate specific antigen failed to be significant. CONCLUSIONS: Few models for prostate cancer prognosis include prostate specific antigen density. There is substantial value in prostate specific antigen density but not in percent free prostate specific antigen for improving prostate cancer prognosis and biochemical recurrence prediction. PMID- 23083862 TI - Salvage lymph node dissection with adjuvant radiotherapy for nodal recurrence of prostate cancer. AB - PURPOSE: We evaluated the impact of salvage lymph node dissection with adjuvant radiotherapy in patients with nodal recurrence of prostate cancer. By default, nodal recurrence of prostate cancer is treated with palliative antihormonal therapy, which causes serious side effects and invariably leads to the development of hormone refractory disease. MATERIALS AND METHODS: A total of 47 patients with nodal recurrence of prostate cancer based on evidence of (11)C choline/(18)F-choline ((18)F-fluorethylcholine) positron emission tomography computerized tomography underwent primary (2 of 52), secondary (45 of 52), tertiary (4 of 52) and quaternary (1 of 52) salvage lymph node dissection with histological confirmation. Of 52 salvage lymph node dissections 27 were followed by radiotherapy. Biochemical response was defined as a prostate specific antigen less than 0.2 ng/ml after salvage therapy. The Kaplan-Meier method, binary logistic regression and Cox regression were used to analyze survival as well as predictors of biochemical response and clinical progression. RESULTS: Mean prostate specific antigen at salvage lymph node dissection was 11.1 ng/ml. A mean of 23.3 lymph nodes were removed per salvage lymph node dissection. Median followup was 35.5 months. Of 52 salvage lymph node dissections 24 resulted in complete biochemical response followed by 1-year biochemical recurrence-free survival of 71.8%. Gleason 6 or less (OR 7.58, p = 0.026), Gleason 7a/b (OR 5.91, p = 0.042) and N0 status at primary therapy (OR 8.01, p = 0.011) were identified as independent predictors of biochemical response. Gleason 8-10 (HR 3.5, p = 0.039) as a preoperative variable, retroperitoneal positive lymph nodes (HR 3.76, p = 0.021) and incomplete biochemical response (HR 4.0, p = 0.031) were identified as postoperative predictors of clinical progression. Clinical progression-free survival was 25.6% and cancer specific survival was 77.7% at 5 years. CONCLUSIONS: Based on (11)C/(18)F-choline positron emission tomography computerized tomography as a diagnostic tool, salvage lymph node dissection is feasible for the treatment of nodal recurrence of prostate cancer. Most patients experience biochemical recurrence after salvage lymph node dissection. However, a specific population has a lasting complete prostate specific antigen response. PMID- 23083863 TI - Tumor complexity predicts malignant disease for small renal masses. AB - PURPOSE: Approximately 20% to 30% of suspicious small renal tumors are benign. A significant proportion of malignant tumors are low grade and potentially indolent. We evaluated whether preoperative patient and tumor characteristics are associated with adverse pathological features. MATERIALS AND METHODS: A total of 886 patients underwent robot-assisted partial nephrectomy, as done by 1 of 5 high volume surgeons. Demographic and clinical data were compared between patients with benign/malignant disease, clear cell/nonclear cell renal cell carcinoma and high/low grade tumors. Tumor complexity was quantified by R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system or sinus, anterior/posterior, hilar and location relative to polar lines) nephrometry score and described as low--4 to 6, intermediate--7 to 9 or high--10 or greater. Logistic regression analyses were performed to test the association between tumor and patient characteristics, and high grade renal cell carcinoma. Subanalyses were done for patients with renal tumors 4 cm or less. RESULTS: High grade renal cell carcinoma was larger and more likely to develop in men. Patients with malignant tumors and with clear cell histology were more likely to have intermediate or high complexity tumors. Increasing tumor complexity independently predicted malignancy, high grade malignancy and clear cell histology on multivariate regression analysis (each p <0.05). Male gender was independently associated with malignancy and high grade renal cell carcinoma. When considering tumors 4 cm or less, tumor complexity predicted malignancy but not tumor grade. CONCLUSIONS: High R.E.N.A.L nephrometry score and male gender are associated with an increased risk of malignancy and high grade malignancy in tumors treated with partial nephrectomy. PMID- 23083864 TI - Volume outcomes of cystectomy--is it the surgeon or the setting? AB - PURPOSE: Hospital volume and surgeon volume are each associated with outcomes after complex oncological surgery. However, the interplay between hospital and surgeon volume, and their impact on these outcomes has not been well characterized. We studied the relationship between surgeon and hospital volume, and overall mortality after radical cystectomy. MATERIALS AND METHODS: The SEER (Surveillance, Epidemiology and End Results)-Medicare linked database was used to identify 7,127 patients with urothelial carcinoma of the bladder who underwent radical cystectomy from 1992 to 2006. Hospital volume and surgeon volume were expressed by tertile. The primary outcome measure was overall survival. Covariates included age, Charlson comorbidity index, stage, grade, node count, node density, number of positive nodes, urinary diversion and year of surgery. Multivariate analyses using generalized linear multilevel models were used to determine the independent association between hospital and surgeon volume and survival. RESULTS: When hospital volume or surgeon volume was included in the multivariate model, a significant volume-survival relationship was observed for each. However, when both were in the model, hospital volume attenuated the impact of surgeon volume on mortality while the significant hospital volume-mortality relationship persisted (HR 1.18, 95% CI 1.08-1.30, p <0.01). In addition, the adjusted 3-year probability of survival was significantly correlated with hospital volume in each distinct surgeon volume stratum while survival was not correlated with surgeon volume in each hospital volume stratum. CONCLUSIONS: After adjustment for patient and disease characteristics, the relationship between surgeon volume and survival after radical cystectomy is accounted for by hospital volume. In contrast, hospital volume remained an independent predictor of survival, suggesting that structure and process characteristics of high volume hospitals drive long-term outcomes after radical cystectomy. PMID- 23083865 TI - Understanding the use of immediate intravesical chemotherapy for patients with bladder cancer. AB - PURPOSE: Despite its established efficacy in reducing recurrence rates for patients with urothelial carcinoma, immediate intravesical chemotherapy is reportedly used infrequently. Accordingly, the Urological Surgery Quality Collaborative implemented a project aimed at understanding and improving the use of immediate intravesical chemotherapy. MATERIALS AND METHODS: Surgeons in 5 Urological Surgery Quality Collaborative practices prospectively collected clinical and baseline intravesical chemotherapy use data for patients undergoing bladder biopsy or transurethral bladder tumor resection from September 2010 through January 2012. In the second phase of data collection (June 2011 through January 2012) treating surgeons also documented reasons for not administering intravesical chemotherapy. We defined patients with 1 to 2 clinical stage Ta/T1, completely resected, papillary tumor(s) as ideal candidates for treatment with immediate intravesical chemotherapy. For ideal and nonideal patients we examined baseline use of intravesical chemotherapy across Urological Surgery Quality Collaborative practices as well as reasons for not administering therapy among ideal patients. RESULTS: Among 1,931 patients 37.2% met criteria as ideal cases for intravesical chemotherapy administration. We observed significant variation in the use of intravesical chemotherapy across Urological Surgery Quality Collaborative practices for ideal (range 27% to 50%) and nonideal cases (9% to 24%) (p <0.001). Reasons for not treating ideal candidates included lack of confirmation of malignancy (4, 2.8%), uncertainty regarding the benefits of intravesical chemotherapy (28, 19.6%) and logistic factors such as the unavailability of medication (34, 23.8%). CONCLUSIONS: Use of immediate intravesical chemotherapy by Urological Surgery Quality Collaborative practices is higher than reported elsewhere but still varies widely, even among ideal candidates. Efforts to optimize use will be aided by disseminating evidence supporting indications and benefits of intravesical chemotherapy, and by addressing local logistic factors that limit access to this evidence-based therapy. PMID- 23083866 TI - Resection of ureteral orifice during transurethral resection of bladder tumor: functional and oncologic implications. AB - PURPOSE: We assessed the risk of upper urinary tract obstruction and tumor recurrence following ureteral orifice resection during transurethral resection of bladder tumor. MATERIALS AND METHODS: We reviewed the medical records of patients treated with transurethral resection of bladder tumors involving the ureteral orifice from 2008 to 2011. Patients with preoperative hydronephrosis or prior ipsilateral nephrectomy and those in whom a ureteral stent was placed during the procedure were excluded from analysis. Study end points were clinical or radiographic evidence of upper urinary tract obstruction and disease recurrence. RESULTS: The study group included 65 men (82%) and 14 women (18%) in whom a total of 84 orifice resections were performed. Hydronephrosis was observed in 11 patients (13%) during a median followup of 15 months (IQR 7-26). Hydronephrosis was secondary to muscle invasive disease in 5 patients (6%) and it resolved spontaneously in 3 (4%). In the remaining 3 patients (4%) overt stricture was detected at the ureterovesical junction, requiring endoscopic intervention. One patient was diagnosed with recurrent tumor in the upper urinary tract. The estimated bladder disease recurrence rate was 28% at 1 year and 54% at 2 years. Corresponding disease progression rates were 4% and 12%, respectively. CONCLUSIONS: Ureteral orifice resection during transurethral resection of bladder tumor is rarely associated with detrimental renal obstruction or an increased risk of tumor recurrence in the upper urinary tract. New onset hydronephrosis is mostly attributable to muscle invasive disease or temporary obstruction. However, the few cases of overt stricture underscore the importance of meticulous followup with imaging. PMID- 23083867 TI - Upper urinary tract recurrence following radical cystectomy for bladder cancer: a meta-analysis on 13,185 patients. AB - PURPOSE: Patients who undergo radical cystectomy for urothelial cancer are at risk for upper urinary tract disease in the remnant transitional tissue. Previous studies have identified several risk factors for upper urinary tract recurrence but the predictive value of each factor remains controversial. Furthermore, the schedule for surveillance of the upper urinary tract with imaging techniques and cytology has not been established. International guidelines do not address these topics and refer only to isolated works with a large case based analysis. We performed this meta-analysis to evaluate the effective incidence of upper urinary tract recurrence after cystectomy for bladder cancer, to analyze the risk factors so we can create subgroups of patients at high risk for recurrence and to investigate the real role of screening in the detection of upper tract lesions at an early stage. MATERIALS AND METHODS: A bibliographic search covering the period from January 1970 to July 2010 was conducted using PubMed(r), MEDLINE and EMBASE(r). This analysis is based on the 27 studies that fulfilled the predefined inclusion criteria. Data were analyzed using a fixed effect logistic regression approach and classic meta-analysis. RESULTS: A total of 13,185 participants were included in the analysis. Followup was described in 22 studies and ranged from 0.36 to 349.2 months. The overall prevalence of upper tract transitional cell cancer after cystectomy ranged from 0.75% to 6.4%. Recurrence appeared at a range of 2.4 to 164 months, and in an advanced (64.6%) or metastatic state (35.6%) as reflected in poor survival rates. Patients with low grade vs high grade lesions at cystectomy showed as strong a significant difference in incidence as those with carcinoma in situ and superficial cancer vs invasive cancers and as strong as in those without lymph node involvement, with multifocal disease, with a history of multiple urothelial recurrences, with positive ureteral margins, with positive urethral margins, with urethral involvement and a history of upper urinary tract urothelial cancer. Data do not support a statistically significant difference in recurrence among patients with a history of carcinoma in situ, solitary lesion and among various types of urinary diversion adopted. In 24 studies the followup schedule included periodic radiological assessment of the upper urinary tract and in 20 it included urinary cytology. In 14 studies in 63 of 166 patients (38%) upper urinary tract recurrence was diagnosed by followup investigation whereas in the remaining 62% diagnosis was based on symptoms. When urine cytology was used in surveillance the rate of primary detection was 7% and with upper urinary tract imaging it was 29.6%. Of 5,537 patients who underwent routine cytological examination, recurrence was diagnosed in 1.8/1,000 and of those who underwent upper urinary tract imaging recurrence was diagnosed in 7.6/1,000. CONCLUSIONS: The recurrence values could appear low when considering the pan-urothelial field defect theory, but these values reflect, in part, the mortality associated with the initial bladder cancer. Based on anamnesis and pathological examination of cystectomy specimens, a group of patients is at high risk. Extensive regular followup with cytology, urography and loopgraphy yields insufficient benefits. Periodic computerized tomography with urography combines the ability to study the upper urinary tract oncologically and functionally, and the identification of any parenchymal, osseous or lymph node secondary lesion. PMID- 23083868 TI - Impact of smoking on outcomes of patients with a history of recurrent nonmuscle invasive bladder cancer. AB - PURPOSE: We investigated the effects of cigarette smoking status, cumulative exposure and time from cessation on disease recurrence and progression in patients with a history of recurrent nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 390 patients with recurrent nonmuscle invasive bladder cancer were treated with transurethral resection of the bladder, of whom 159 (41%) received instillation therapy immediately postoperatively and 73 (19%) received adjuvant intravesical immunotherapy or chemotherapy. Smoking history included smoking status, number of cigarettes per day, smoking duration in years and years since smoking cessation. Cumulative smoking exposure was categorized as light short-term--19 or fewer cigarettes per day and 19.9 years or less, moderate -all combinations except light short-term and heavy long-term, and heavy long term--20 or greater cigarettes per day and 20 years or greater. RESULTS: A total of 91 (23%), 192 (49%) and 107 patients (28%) were never, former and current smokers, respectively. Of ever smokers 56 (19%), 156 (52%) and 87 (29%) were light short-term, moderate and heavy long-term smokers, respectively. There was no difference in the risk of disease recurrence and progression among current, former and never smokers. On univariable analyses in ever smokers the risk of disease recurrence and progression increased with augmented smoking intensity (p <= 0.015), duration (p <0.001) and cumulative exposure (p <0.001). On multivariable analyses cumulative smoking exposure was an independent risk factor for disease recurrence and progression (p <= 0.003). Smoking cessation greater than 10 years before treatment was independently associated with decreased disease recurrence compared to current smoking (HR 0.4, p <0.001). In addition, current smokers had worse survival than former smokers, who in turn had worse survival than never smokers (p >0.05). CONCLUSIONS: There is a dose-response relationship of smoking exposure and smoking cessation with disease recurrence and progression in ever smokers with a history of recurrent nonmuscle invasive bladder cancer. These findings support counseling on smoking cessation benefits. PMID- 23083870 TI - Editorial comment. PMID- 23083871 TI - Editorial comment. PMID- 23083872 TI - Routine transition zone biopsy during active surveillance for prostate cancer rarely provides unique evidence of disease progression. AB - PURPOSE: Routine sampling of the transition zone during prostate biopsy has become increasingly common. Although approximately 10% of prostate cancers originate in the transition zone, the benefit of transition zone biopsies may be limited. We evaluated the usefulness of transition zone biopsy in patients with prostate cancer enrolled in active surveillance. MATERIALS AND METHODS: Patients on active surveillance followed at our institution between 1993 and 2011 were identified in the urological oncology database. All surveillance biopsies were stratified by transition and peripheral zone pathology results. The usefulness of transition zone biopsy was assessed by whether transition zone specific cancer characteristics, eg volume and grade, changed disease management recommendations. RESULTS: A single surgeon performed a total of 244 prostate biopsies in 92 men. Each patient underwent initial positive prostate biopsy and at least 1 active surveillance prostate biopsy. Mean age was 69 years. A mean of 2.7 biopsies were done per patient. Nine patients (10%) had positive transition zone cores on initial positive prostate biopsy, of whom 3 had transition zone unique cancers. One of these patients showed transition zone disease progression on active surveillance prostate biopsy, which led to up staging and exclusion from active surveillance. A total of 16 patients (17%) had positive transition zone cores on active surveillance prostate biopsy, of whom 13 had a negative transition zone on initial positive prostate biopsy. Transition and peripheral zone Gleason scores were identical in 9 of these patients and the transition zone score was lower in 4. Thus, transition zone pathology did not result in up staging or disease management alterations in any patient with new transition zone pathology. CONCLUSIONS: Up staging due to transition zone specific pathology is exceedingly rare. Transition zone biopsy in patients on active surveillance should be limited to those with transition zone involvement on initial positive prostate biopsy only. PMID- 23083873 TI - Intravesical oncoviral therapy for bladder cancer. PMID- 23083874 TI - Reproductive organ involvement in female patients undergoing radical cystectomy for urothelial bladder cancer. AB - PURPOSE: We evaluated pathological involvement of the reproductive organs in a cohort of female patients treated with anterior pelvic exenteration for invasive urothelial carcinoma of the bladder. MATERIALS AND METHODS: A total of 2,098 patients with bladder cancer underwent cystectomy at our institution between 1971 and 2008, including 458 females, of whom 411 had urothelial carcinoma of the bladder. Median followup was 12.2 years (range 0.1 to 35.5). We reviewed the clinicopathological features of female patients treated with cystectomy who had pathological reproductive organ involvement. Recurrence-free and overall survival is reported using Kaplan-Meier survival curves. RESULTS: Of 411 patients with urothelial carcinoma of the bladder 267 underwent reproductive organ removal with cystectomy. A total of 20 patients (7.5%) had reproductive organ involvement, including 10 (3.8%) with vaginal, 2 (0.7%) with cervical and 1 (0.3%) with uterine involvement only, while the remaining 7 (2.6%) had multiple reproductive organs involved. Median age was 71 years. Clinical stage T4a was diagnosed in 25% of cases. A palpable mass, hydronephrosis (each p <0.001) and positive lymph nodes at anterior pelvic exenteration (p = 0.001) were associated with reproductive organ involvement. Recurrence developed in 14 patients (70%) at a median of 7 months (range 1 to 22). Five-year recurrence-free and overall survival rates were 14.9% and 8.8%, respectively. CONCLUSIONS: The risk of reproductive organ involvement in female patients who undergo anterior pelvic exenteration for urothelial carcinoma of the bladder was about 7.5% with the vagina the most commonly involved organ. A palpable mass and hydronephrosis were among the preoperative clinical factors associated with reproductive organ involvement. The prognosis is poor in patients with reproductive organ involvement. PMID- 23083875 TI - Multiparametric magnetic resonance imaging and ultrasound fusion biopsy detect prostate cancer in patients with prior negative transrectal ultrasound biopsies. AB - PURPOSE: Patients with negative transrectal ultrasound biopsies and a persistent clinical suspicion are at risk for occult but significant prostate cancer. The ability of multiparametric magnetic resonance imaging/ultrasound fusion biopsy to detect these occult prostate lesions may make it an effective tool in this challenging scenario. MATERIALS AND METHODS: Between March 2007 and November 2011 all men underwent prostate 3 T endorectal coil magnetic resonance imaging. All concerning lesions were targeted with magnetic resonance imaging/ultrasound fusion biopsy. In addition, all patients underwent standard 12-core transrectal ultrasound biopsy. Men with 1 or more negative systematic prostate biopsies were included in our cohort. RESULTS: Of the 195 men with previous negative biopsies, 73 (37%) were found to have cancer using the magnetic resonance imaging/ultrasound fusion biopsy combined with 12-core transrectal ultrasound biopsy. High grade cancer (Gleason score 8+) was discovered in 21 men (11%), all of whom had disease detected with magnetic resonance imaging/ultrasound fusion biopsy. However, standard transrectal ultrasound biopsy missed 12 of these high grade cancers (55%). Pathological upgrading occurred in 28 men (38.9%) as a result of magnetic resonance imaging/ultrasound fusion targeting vs standard transrectal ultrasound biopsy. The diagnostic yield of combined magnetic resonance imaging/ultrasound fusion platform was unrelated to the number of previous negative biopsies and persisted despite increasing the number of previous biopsy sessions. On multivariate analysis only prostate specific antigen density and magnetic resonance imaging suspicion level remained significant predictors of cancer. CONCLUSIONS: Multiparametric magnetic resonance imaging with a magnetic resonance imaging/ultrasound fusion biopsy platform is a novel diagnostic tool for detecting prostate cancer and may be ideally suited for patients with negative transrectal ultrasound biopsies in the face of a persistent clinical suspicion for cancer. PMID- 23083876 TI - Succinate dehydrogenase kidney cancer: an aggressive example of the Warburg effect in cancer. AB - PURPOSE: Recently, a new renal cell cancer syndrome has been linked to germline mutation of multiple subunits (SDHB/C/D) of the Krebs cycle enzyme, succinate dehydrogenase. We report our experience with the diagnosis, evaluation and treatment of this novel form of hereditary kidney cancer. MATERIALS AND METHODS: Patients with suspected hereditary kidney cancer were enrolled on a National Cancer Institute institutional review board approved protocol to study inherited forms of kidney cancer. Individuals from families with germline SDHB, SDHC and SDHD mutations, and kidney cancer underwent comprehensive clinical and genetic evaluation. RESULTS: A total of 14 patients from 12 SDHB mutation families were evaluated. Patients presented with renal cell cancer at an early age (33 years, range 15 to 62), metastatic kidney cancer developed in 4 and some families had no manifestation other than kidney tumors. An additional family with 6 individuals found to have clear cell renal cell cancer that presented at a young average age (47 years, range 40 to 53) was identified with a germline SDHC mutation (R133X) Metastatic disease developed in 2 of these family members. A patient with a history of carotid body paragangliomas and an aggressive form of kidney cancer was evaluated from a family with a germline SDHD mutation. CONCLUSIONS: SDH mutation associated renal cell carcinoma can be an aggressive type of kidney cancer, especially in younger individuals. Although detection and management of early tumors is most often associated with a good outcome, based on our initial experience with these patients and our long-term experience with hereditary leiomyomatosis and renal cell carcinoma, we recommend careful surveillance of patients at risk for SDH mutation associated renal cell carcinoma and wide surgical excision of renal tumors. PMID- 23083877 TI - Does partial nephrectomy result in a durable overall survival benefit in the Medicare population? AB - PURPOSE: We assessed whether the impact of partial nephrectomy and radical nephrectomy on overall mortality differed by patient age in a Medicare population undergoing surgery for T1a renal cell carcinoma. MATERIALS AND METHODS: Using linked SEER (Surveillance, Epidemiology and End Results)-Medicare data, we identified patients older than 66 years who underwent partial nephrectomy or radical nephrectomy for T1a (4 cm or smaller) renal cell carcinoma from 1995 to 2007. The effects of procedure type on overall mortality by age were assessed using time dependent Cox proportional hazards models adjusted by propensity score based weighting. RESULTS: A total of 5,496 patients (mean age 74.2 +/- 5.6 years, 55.9% male) who underwent partial nephrectomy (1,665; 30.3%) or radical nephrectomy (3,831; 69.7%) for 4 cm or smaller renal cell carcinoma (mean tumor size 2.8 +/- 0.9 cm) were identified. After adjustment, a statistically significant survival benefit for partial nephrectomy compared to radical nephrectomy was observed at 1 year (age 68, HR 1.6, CI 1.2-2.3; age 75, HR 1.5, CI 1.1-1.9; age 85, HR 1.7, CI 1.1-2.5) and 3 years (age 68, HR 1.4, CI 1.03-2.0; age 75, HR 1.3, CI 1.1-1.6; age 85, HR 1.5, CI 1.02-2.3), while these trends became insignificant in patients younger than 68 and older than 85 years. However, the survival benefit decreased with time, and little significant benefit with partial nephrectomy was observed at 5 and 10 years after surgery regardless of age (66 years or older). CONCLUSIONS: Lacking strong evidence regarding a long term survival benefit, the decision to perform partial nephrectomy in elderly patients should be individualized, and placed in the context of baseline renal function, expected surgical morbidity and competing risks to survival. PMID- 23083878 TI - Acute porphyric attack with cold sweating and low blood pressure. PMID- 23083879 TI - Can cardiopulmonary resuscitation using only abdominal compressions provide greater oxygenation and perfusion of vital organs than only chest compressions? PMID- 23083880 TI - Propafenone-induced cardiac arrest: full recovery with insulin, is it possible? PMID- 23083881 TI - A case of childhood vasculitis presenting in adulthood. PMID- 23083882 TI - The impact of a mass gathering events with an on-site medical management team on municipal 911 emergency medical services. PMID- 23083883 TI - Emergency airway management in geriatric and younger patients: analysis of a multicenter prospective observational study. AB - OBJECTIVES: There is little information on geriatric emergency airway management. We sought to describe intubation practices and outcomes for emergency department (ED) geriatric and younger patients in Japan. METHOD: We formed the Japanese Emergency Airway Network, a consortium of 11 medical centers, and prospectively collected data on ED intubations between 2010 and 2011. All patients 18 years or older who underwent emergent airway management were included in our study. Patients were divided to into 2 groups: 18 to 64-year olds and 65 years or older. We present descriptive data as proportions with 95% confidence intervals (CI). RESULTS: The database recorded 3277 patients (capture rate 96%), and 3178 met the inclusion criteria. Of 3178 patients, 1844 (58%) were 65 years or older, 1334 (42%) were 18 to 64 years old, 809 (25%) were 80 years or older, and 407 (50%) of them were in the state of cardiac arrest. The geriatric group, compared to the younger group, had a higher success rate on the initial attempt (71% vs 64%; difference 7%; 95% CI 4%-10%;) and in 2 attempts (90% vs 88%; difference 3%; 95% CI 1%-5%) or less. There was no significant difference in the adverse event rates by age group (difference 0%; 95% CI -2% to 3%). CONCLUSION: In our multicenter study involving a large geriatric population, we found that geriatric patients were intubated with a higher success rate, compared to younger patients. These data provide implications for the geriatric ED airway practice that may lead to better patient-centered emergency care. PMID- 23083884 TI - Proper performance of chest compressions in cardiopulmonary resuscitation. PMID- 23083885 TI - High discordance of chest x-ray and computed tomography for detection of pulmonary opacities in ED patients: implications for diagnosing pneumonia. AB - OBJECTIVE: To evaluate the diagnostic performance of chest x-ray (CXR) compared to computed tomography (CT) for detection of pulmonary opacities in adult emergency department (ED) patients. METHODS: We conducted an observational cross sectional study of adult patients presenting to 12 EDs in the United States from July 1, 2003, through November 30, 2006, who underwent both CXR and chest CT for routine clinical care. CXRs and CT scans performed on the same patient were matched. CXRs and CT scans were interpreted by attending radiologists and classified as containing pulmonary opacities if the final radiologist report noted opacity, infiltrate, consolidation, pneumonia, or bronchopneumonia. Using CT as a criterion standard, the diagnostic test characteristics of CXR to detect pulmonary opacities were calculated. RESULTS: The study cohort included 3423 patients. Shortness of breath, chest pain and cough were the most common complaints, with 96.1% of subjects reporting at least one of these symptoms. Pulmonary opacities were visualized on 309 (9.0%) CXRs and 191 (5.6 %) CT scans. CXR test characteristics for detection of pulmonary opacities included: sensitivity 43.5% (95% CI, 36.4%-50.8%); specificity 93.0% (95% CI, 92.1%-93.9%); positive predictive value 26.9% (95% CI, 22.1%-32.2%); and negative predictive value 96.5% (95% CI, 95.8%-97.1%). CONCLUSION: In this multicenter cohort of adult ED patients with acute cardiopulmonary symptoms, CXR demonstrated poor sensitivity and positive predictive value for detecting pulmonary opacities. Reliance on CXR to identify pneumonia may lead to significant rates of misdiagnosis. PMID- 23083886 TI - Utility of point-of-care testing in ED triage. AB - BACKGROUND: Triage systems are commonly used in emergency departments (ED) to prioritize patients. Laboratory testing is not typically used to help risk stratify patients at triage. OBJECTIVES: We studied the utility of point-of-care (POC) testing at triage in ED patients with high-risk complaints. METHODS: We conducted a prospective observational study on a convenience sample of ED patients at an urban academic hospital with 60,000 annual visits. Patients who were triaged to the waiting area with any of the following criteria were approached for enrollment: (1) chest pain or shortness of breath in patients older than 40 years, (2) possible infection in the presence of two or more systemic inflammatory response system criteria in patients older than 18 years, and (3) patients >65 years with non-traumatic complaints. A total of 300 subjects were enrolled. All enrolled patients received POC testing that included a combination of Chem8+, hemoglobin, troponin, B-type natriuretic peptide, and lactate. The triage nurse completed a survey after receiving the results. RESULTS: POC results was reported to be helpful in 56% of patients, changed the triage level in 15% of patients and led to 6% of patients being brought back for rapid physician evaluation. Overall, 50% of patients had one or more abnormal POC laboratory tests. There was no relationship between ED census and the likelihood of being helpful, changing the triage level, changing management, or bringing patients back any faster. CONCLUSION: POC testing at triage is a helpful adjunct in triage of patients with high-risk ED complaints. PMID- 23083887 TI - One-and-a-half syndrome: a less appreciated emergency in native valve infective endocarditis. PMID- 23083888 TI - What videos can tell us about falling. PMID- 23083889 TI - Video capture of the circumstances of falls in elderly people residing in long term care: an observational study. AB - BACKGROUND: Falls in elderly people are a major health burden, especially in the long-term care environment. Yet little objective evidence is available for how and why falls occur in this population. We aimed to provide such evidence by analysing real-life falls in long-term care captured on video. METHODS: We did this observational study between April 20, 2007, and June 23, 2010, in two long term care facilities in British Columbia, Canada. Digital video cameras were installed in common areas (dining rooms, lounges, hallways). When a fall occurred, facility staff completed an incident report and contacted our teams so that we could collect video footage. A team reviewed each fall video with a validated questionnaire that probed the cause of imbalance and activity at the time of falling. We then tested whether differences existed in the proportion of participants falling due to the various causes, and while engaging in various activities, with generalised linear models, repeated measures logistic regression, and log-linear Poisson regression. FINDINGS: We captured 227 falls from 130 individuals (mean age 78 years, SD 10). The most frequent cause of falling was incorrect weight shifting, which accounted for 41% (93 of 227) of falls, followed by trip or stumble (48, 21%), hit or bump (25, 11%), loss of support (25, 11%), and collapse (24, 11%). Slipping accounted for only 3% (six) of falls. The three activities associated with the highest proportion of falls were forward walking (54 of 227 falls, 24%), standing quietly (29 falls, 13%), and sitting down (28 falls, 12%). Compared with previous reports from the long term care setting, we identified a higher occurrence of falls during standing and transferring, a lower occurrence during walking, and a larger proportion due to centre-of-mass perturbations than base-of-support perturbations. INTERPRETATION: By providing insight into the sequences of events that most commonly lead to falls, our results should lead to more valid and effective approaches for balance assessment and fall prevention in long-term care. FUNDING: Canadian Institutes for Health Research. PMID- 23083891 TI - Composition of plant virus RNA replicase complexes. AB - The replication of the genome of positive-strand RNA viruses depends on their own RNA replicase complexes. Substantial advances in the experimental approaches used to determine the composition of the viral replicase complexes revealed that the replicase complexes of eukaryotic positive-strand RNA viruses are assembled in a host-membrane-derived microenvironment and that this process is regulated by orchestrated interactions between viral proteins, viral genomic RNAs, and co opted host factors, including molecular chaperones, RNA-binding proteins, and proteins associated with membrane remodeling and lipid synthesis. This review focuses on recent progress in our understanding of how plant RNA viruses organize viral and host factors to form their replicase complexes. PMID- 23083890 TI - Lack of CAK complex accumulation at DNA damage sites in XP-B and XP-B/CS fibroblasts reveals differential regulation of CAK anchoring to core TFIIH by XPB and XPD helicases during nucleotide excision repair. AB - Transcription factor II H (TFIIH) is composed of core TFIIH and Cdk-activating kinase (CAK) complexes. Besides transcription, TFIIH also participates in nucleotide excision repair (NER), verifying DNA lesions through its helicase components XPB and XPD. The assembly state of TFIIH is known to be affected by truncation mutations in xeroderma pigmentosum group G/Cockayne syndrome (XP G/CS). Here, we showed that CAK component MAT1 was rapidly recruited to UV induced DNA damage sites, co-localizing with core TFIIH component p62, and dispersed from the damage sites upon completion of DNA repair. While the core TFIIH-CAK association remained intact, MAT1 failed to accumulate at DNA damage sites in fibroblasts harboring XP-B or XP-B/CS mutations. Nevertheless, MAT1, XPD and XPC as well as XPG were able to accumulate at damage sites in XP-D fibroblasts, in which the core TFIIH-CAK association also remained intact. Interestingly, XPG recruitment was impaired in XP-B/CS fibroblasts derived from patients with mild phenotype, but persisted in XP-B/CS fibroblasts from severely affected patients resulting in a nonfunctional preincision complex. An examination of steady-state levels of RNA polymerase II (RNAPII) indicated that UV-induced RNAPII phosphorylation was dramatically reduced in XP-B/CS fibroblasts. These results demonstrated that the CAK rapidly disassociates from the core TFIIH upon assembly of nonfunctional preincision complex in XP-B and XP B/CS cells. The persistency of nonfunctional preincision complex correlates with the severity exhibited by XP-B patients. The results suggest that XPB and XPD helicases differentially regulate the anchoring of CAK to core TFIIH during damage verification step of NER. PMID- 23083893 TI - Birth weight, infant mortality, and race: twin comparisons and genetic/environmental inputs. AB - Genetic and environmental inputs may shape population health disparities in varying ways. In this article, we use unique variation involved in twin births to attempt to untangle how genetic and prenatal environmental variation may make different contributions to infant health among white and black populations in the United States. Using twin fixed effects models and data from the 1995-1997 Matched Multiple Birth Dataset we compare birth weight-mortality associations across twin sex composition, zygosity, and race. Findings reveal suggestive differences between fraternal and imputed identical twin estimates for white and black twin pairs. PMID- 23083892 TI - Hepatitis C virus-host interactions, replication, and viral assembly. AB - As a relatively simple virus, hepatitis C virus (HCV) depends extensively on its host to infect, replicate and disseminate. HCV has evolved host interactions that result in a restricted tropism, both in terms of cell type and species. Efforts into identifying and validating HCV-host interactions have been hampered by a limited number of infectious virus clones and cell lines that support HCV infection. Despite these limitations, consensus HCV-host interactions have emerged that help define the entry, replication, assembly, and tropism of HCV. This has had important implications in expanding our in vitro and in vivo systems to study HCV replication and pathogenesis. Additionally, a number of these host factors are being targeted for therapeutic development. In this review, we focus on medically relevant pro-viral host factors, their role in HCV biology, and their importance in expanding our model systems. PMID- 23083894 TI - Priority-setting and rationing in healthcare: evidence from the English experience. AB - In a context of ever increasing demand, the recent economic downturn has placed further pressure on decision-makers to effectively target healthcare resources. Over recent years there has been a push to develop more explicit evidence-based priority-setting processes, which aim to be transparent and inclusive in their approach and a number of analytical tools and sources of evidence have been developed and utilised at national and local levels. This paper reports findings from a qualitative research study which investigated local priority-setting activity across five English Primary Care Trusts, between March and November 2012. Findings demonstrate the dual aims of local decision-making processes: to improve the overall effectiveness of priority-setting (i.e. reaching 'correct' resource allocation decisions); and to increase the acceptability of priority setting processes for those involved in both decision-making and implementation. Respondents considered priority-setting processes to be compartmentalised and peripheral to resource planning and allocation. Further progress was required with regard to disinvestment and service redesign with respondents noting difficulty in implementing decisions. While local priority-setters had begun to develop more explicit processes, public awareness and input remained limited. The leadership behaviours required to navigate the political complexities of working within and across organisations with differing incentives systems and cultures remained similarly underdeveloped. PMID- 23083895 TI - Nutritional knowledge levels of nursing students in a tertiary institution: lessons for curriculum planning. AB - This article presents findings of a study which assessed the nutritional knowledge levels of nursing students as nurses are in a better position to serve as nutrition educators and counselors by engaging their clients in discussions that would increase their knowledge about disease prevention and management through nutrition. This was a descriptive cross-sectional study, where a selfadministered questionnaire was completed by 166 undergraduate consenting third (3rd) and final (4th) year nursing students in a public university in Ghana who answered 20 multiple choice general nutrition questions. An average score of 8.95 +/- 2.01 corresponding to 44.8%, below average, was obtained by the respondents. It was determined that the nutrition knowledge of 3.6%, 62.7% and 33.7% of the study participants was good, adequate and inadequate respectively. It was found that the differences with respect to the nutrition knowledge levels between the age groups, gender, work experience and educational background of respondents were not statistically significant at p < 0.05. The findings of this study support other reports that nurses need more training in nutrition and therefore have important implications for professionals planning curricula for nursing education at the undergraduate level in the university. PMID- 23083896 TI - The strategies used to deal with emotion work in student paramedic practice. AB - Preregistration paramedic science students are quickly introduced to the reality of emergency paramedic practice (British Paramedic Association (BPA) 2008) and are expected to manage both their own emotions and those of potentially distressed patients and relatives. Despite the evident importance of emotion work, there is a lack of research evidence on this phenomenon and none at all from the student perspective. A qualitative study, using semi-structured interviews was undertaken with 8 s year paramedic science students to explore their perceptions and experiences of emotion work and the strategies used to deal with it. Thematic content analysis produced four themes, 'getting on with the job', 'struggling with emotion', 'talking it through' and humour. This paper focuses on the strategies used to help deal with the emotional demands of practice. Participants emphasised the importance of talking it through and 'off loading' with friends, colleagues, partners and their clinical mentor. Going through the job with their mentor centred on the technical aspects of care and helped to reassure students that they had done their best. Humour was another useful strategy which also helped students to 'off load' and move on after difficult experiences. These findings highlight the importance of talking about experiences within available support systems and the role of the clinical mentor in facilitating debriefing and reflection. It is crucial that paramedic students are also made aware of the support services available to them to ensure their emotional needs are met. PMID- 23083897 TI - Complementary and alternative medicine use among undergraduate nursing & midwifery students in Turkey. AB - The aim of this study was to determine the use of complementary and alternative medicine (CAM) by nursing and midwifery students. A cross-sectional survey was performed among nursing and midwifery students. Second, third and fourth year students were taken in the sample group. The mean age of the students was 21.37 +/- 2.23. 72.4% of the participants had knowledge about CAM. The sources of information were firstly books/magazines (65.5%) and school (60.3%). 93.5% of the students preferred to use both CAM and medical treatments at their illnesses. The rate of the students, who use CAM in patient care, was 72.7%. Hot and cold application (51.6%), massage (50.9%) and exercise (48.7%) were the most chosen methods by students, to use in patient care and to recommend them to the patients. They also pointed that, CAM affects the psychology of patients positively (65.5%), accelerates the healing process (59.6%). 86.5% of the participants pointed that; they want the integration of CAM, especially massage (74.2%) and meditation (46.9%) into the curriculum. The majority of the students reported that using and recommending CAM to their patients is beneficial. These methods should be integrated into the curriculum. PMID- 23083898 TI - Systems and strategies for identifying and enumerating children outside of family care. AB - Methodologies to identify and enumerate children outside of family care vary as do the vulnerability categories of the children themselves. Children outside of family care is a broad term encompassing children absent of permanent family care, e.g., institutionalized children, children on/of the street, child-headed households, separated or unaccompanied children, trafficked children, children working in exploitive labor situations, etc. This paper reviews the various methodologies applied to identify and enumerate these often hidden and/or mobile populations. Methodologies that identify and enumerate children outside of family strive to meet two objectives: (1) to estimate the number and characteristics of a specific vulnerability category and (2) to determine eligibility to receive services. The paper reviews eight methodologies; six are categorized as survey sample methods (time-location sampling, capture recapture sampling, respondent driven sampling, the neighborhood method, household surveys, and establishment surveys) while two were labeled as data management systems (child labor management system, and databases of institutions). Each review includes a concise description of the methodology, its strengths and limitations, the most appropriate population it is suited to identify and/or enumerate, and any necessary conditions. Conclusions from these reviews advocate for tailoring a methodology (or a combination of methodologies) to the specific circumstances under which it is meant to identify or enumerate children outside of family care. In addition, further research and validation studies are needed to identify the conditions under which the strategies described here can be used and to develop appropriate protocols for utilization. PMID- 23083899 TI - Evidence acquisition and evaluation for a U.S. Government Evidence Summit on Protecting Children Outside Family Care. AB - Recognizing the need for evidence to inform policies, strategies, and programs to care for vulnerable children, the U.S. Government convened an Evidence Summit on Protecting Children Outside of Family Care on December 12-13, 2011, in Washington, DC, USA. This paper summarizes the background and methods for the acquisition and evaluation of the evidence used to achieve the goals of the Summit. A multistep process was undertaken to identify the appropriate evidence for review. It began by identifying crucial focal questions intended to inform low and middle income governments and the U.S. Government about effective systems for protecting children outside family care. This was followed by a systematic attempt to gather relevant peer reviewed and gray literature that would inform these focal questions. The search processes, methods used for screening and quality reviews are described. In addition, members of the Evidence Review Teams were invited to add relevant papers not identified in the initial literature review to complete the bibliographies. These teams were asked to comply with a specific evaluation framework for recommendations on practice and policy based on both expert opinion and the quality of the data. This was the first U.S. Government Evidence Summit originating in the U.S. Agency for International Development Global Health Bureau and valuable lessons were learned on the identification and assessment of evidence informing complex development challenges. PMID- 23083900 TI - What strategies are appropriate for monitoring children outside of family care and evaluating the impact of the programs intended to serve them? AB - OBJECTIVES: To strengthen the evidence-base for policy and practice for support of children outside of family care requires effective, efficient and sustainable mechanisms for monitoring and evaluation. Toward that end, two core questions guided a systematic review of evidence: What strategies are appropriate for monitoring the needs and circumstances of children outside of family care? What strategies are suitable for evaluating the impact of the programs intended to serve such children? METHODS: A structured document search and review process was implemented within the context of the U.S. Government Evidence Summit on Protecting Children Outside of Family Care of December 2011. Through successive review phases, initially using structured screening criteria, followed by thematic review by an expert panel, 73 documents were identified for analysis. RESULTS: Analysis of models and strategies indicates that: (1) tools are available for assessment of children's needs, but require refining to accommodate contextual demands; (2) well-designed evaluations are able to identify the influence of assistance; (3) long-term follow-up is crucial to developing a strong evidence-base on effective strategies; and (4) insights into systems-wide monitoring mechanisms are emerging. In addition to describing key components of monitoring and evaluation strategies, findings draw attention to the evaluation of children's resiliency and protective factors, community based monitoring and the role of caregivers, as well as concerns over the stigmatization of children (through data collection methodologies encouraging the 'labeling' of children) and the importance of children's participation. CONCLUSIONS: Fostering a stronger evidence-base to improve protection for vulnerable children requires evaluations that are integrated into program development, use context-appropriate methodologies able to assess intervention scalability and employ more longitudinal designs to explore children's trajectories. Further, future programming will benefit from systems-wide data coordination and international comparisons, research that emphasizes coping and resilience mechanisms, and children's participation in monitoring and evaluation. PMID- 23083901 TI - Prevalence, incidence, and resolution of nocturnal polyuria in a longitudinal community-based study in older men: the Krimpen study. AB - BACKGROUND: Nocturnal polyuria (NP) is common in older men and can lead to nocturia. However, no longitudinal data are available on the natural history of NP. OBJECTIVE: To determine prevalence, incidence, and resolution rates of NP. DESIGN, SETTING, AND PARTICIPANTS: A longitudinal, community-based study was conducted among 1688 men aged 50-78 yr in Krimpen aan den IJssel, The Netherlands (reference date: 1995), with planned follow-up rounds at 2, 4, and 6 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: NP was determined with frequency-volume charts. Two definitions of NP were used: (1) a nocturnal urine production (NUP) of >90 ml/h (NUP90) and (2) the nocturnal voided volume plus first morning void being >33% of the 24-h voided volume (NUV33). Nocturia was defined as two or more voids per night. We determined the prevalence of NP at each study round. At first follow-up, we determined the incidence in men without baseline NP and the resolution in men with baseline NP. Prevalence of NP in men with or without nocturia was also determined. RESULTS AND LIMITATIONS: At baseline, the prevalence of NUP90 was 15.0% and increased to 21.7% after 6.5 yr, whereas the prevalence of NUV33 was 77.8% at baseline and 80.5% after 6.5 yr. At 2.1 yr of follow-up, the incidences of NUP90 and NUV33 were 13.6% and 60.3%, respectively, and the resolution rates were 57.0% and 17.8%, respectively. Because of this fluctuation in NP, no reliable long-term incidences could be calculated. At baseline, NUP90 was prevalent in 27.7% of men with nocturia and in 8.0% of those without nocturia. At baseline, NUV33 was prevalent in 91.9% of men with nocturia and in 70.1% of men without nocturia. CONCLUSIONS: Due to the fluctuation of NP, it is advisable to first determine its chronicity and cause before starting treatment. Because of the high prevalence of NP in men without nocturia, NUV33 should be reconsidered as a discriminative definition of NP. PMID- 23083902 TI - ICUD-EAU International Consultation on Bladder Cancer 2012: Screening, diagnosis, and molecular markers. AB - CONTEXT AND OBJECTIVE: To present a summary of the 2nd International Consultation on Bladder Cancer recommendations on the screening, diagnosis, and markers of bladder cancer using an evidence-based strategy. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing bladder cancer with regard to screening, diagnosis, markers, and pathology. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. Large retrospective and prospective data were analyzed. CONCLUSIONS: Cystoscopy alone is the most cost effective method to detect recurrence of bladder cancer. White-light cystoscopy is the gold standard for evaluation of the lower urinary tract; however, technology like fluorescence-aided cystoscopy and narrow-band imaging can aid in improving evaluations. Urine cytology is useful for the diagnosis of high-grade tumor recurrence. Molecular medicine holds the promise that clinical outcomes will be improved by directing therapy toward the mechanisms and targets associated with the growth of an individual patient's tumor. The challenge remains to optimize measurement of these targets, evaluate the impact of such targets for therapeutic drug development, and translate molecular markers into the improved clinical management of bladder cancer patients. Physicians and researchers eventually will have a robust set of molecular markers to guide prevention, diagnosis, and treatment decisions for bladder cancer. PMID- 23083903 TI - Informing patients about medicines--a hospital in-patient survey in England. AB - OBJECTIVE: To determine the frequency with which hospital in-patients receive information about medicines and whether this varies dependent on patient characteristics or hospitals. METHODS: Cross-sectional survey of medical in patients in six hospitals in North West England. RESULTS: 1218 questionnaires were completed sufficiently for analysis by medical in-patients. 534 (43.9%) respondents were informed fully about their medicines by a hospital doctor, nurse or pharmacist and 411 (33.9%) partly informed, but 272 (22.49%) had received no information or could not recall any. Fewer than 20% had received written medicines information. The majority of respondents (763; 62.6%) were not asked if they had any concerns or could not recall this. Patient factors including age, educational level and number of medicines taken did not influence whether or not medicines information was provided, but there were differences between hospitals. CONCLUSION: There is considerable variation between hospitals in the frequency with which patients are given verbal and written information about medicines and are asked about any medicine-related concerns. PRACTICE IMPLICATIONS: Informing patients about medicines while in hospital needs to be improved. Doctors, nurses and pharmacists all need to accept and co-ordinate responsibility for informing patients about medicines and asking if they have any concerns or questions. PMID- 23083904 TI - Multifunctional microelectrode array (mMEA) chip for neural-electrical and neural chemical interfaces: characterization of comb interdigitated electrode towards dopamine detection. AB - Microelectrode array platforms have attracted considerable interest owing to their ability to facilitate interactive communications between investigators and neuronal network. We herein present an integrated multifunctional microelectrode array (mMEA) chip harnessed with multiple measurement modalities of both neural electrical and neural-chemical recordings to enable simultaneous monitoring of action potential and the level of the specific neurotransmitter. A dopamine sensor modality fabricated in interdigitated electrodes (IDE) fashion was realized and characterized, subsequently applied to trace dopamine exocytosis in PC12 cells cultured on such mMEA chip. Facile fabrication process leveraging electroplating technique to implement the regulation of gap width was investigated and resulted in preferred IDE configuration. Collection efficiency and amplification effect were systematically evaluated. The as-fabricated sensing device exhibited a favorable diffusion-determining behavior reflected by the steady state current output, and in virtue of this feature, to detect dopamine in connection with limit of detection at 0.62 MUM. The current signal was observed linear against the level of dopamine over the investigated concentration range with a resulting sensitivity of 0.096 nA MUM(-1). PMID- 23083905 TI - Advantages of substituting bioluminescence for fluorescence in a resonance energy transfer-based periplasmic binding protein biosensor. AB - A genetically encoded maltose biosensor was constructed, comprising maltose binding protein (MBP) flanked by a green fluorescent protein (GFP(2)) at the N terminus and a Renilla luciferase variant (RLuc2) at the C-terminus. This Bioluminescence resonance energy transfer(2) (BRET(2)) system showed a 30% increase in the BRET ratio upon maltose binding, compared with a 10% increase with an equivalent fluorescence resonance energy transfer (FRET) biosensor. BRET(2) provides a better matched Forster distance to the known separation of the N and C termini of MBP than FRET. The sensor responded to maltose and maltotriose and the response was completely abolished by introduction of a single point mutation in the BRET(2) tagged MBP protein. The half maximal effective concentration (EC(50)) was 0.37 MUM for maltose and the response was linear over almost three log units ranging from 10nM to 3.16 MUM maltose for the BRET(2) system compared to an EC(50) of 2.3 MUM and a linear response ranging from 0.3 MUM to 21.1 MUM for the equivalent FRET-based biosensor. The biosensor's estimate of maltose in beer matched that of a commercial enzyme-linked assay but was quicker and more precise, demonstrating its applicability to real-world samples. A similar BRET(2)-based transduction scheme approach would likely be applicable to other binding proteins that have a "venus-fly-trap" mechanism. PMID- 23083906 TI - An integrated chip capable of performing sample pretreatment and nucleic acid amplification for HIV-1 detection. AB - This study reports on a microfluidic system equipped with a sample pretreatment device and a nucleic acid amplification device for the rapid diagnosis of the human immunodeficiency virus-1 (HIV-1). The system analyzed proviral deoxyribonucleic acid (DNA) from an HIV-infected Jurkat T cell line. In order to ensure accurate diagnosis among other prevalent B-type strains, simultaneous detections of four conserved HIV-1 B-type DNA fragments were performed in this integrated microfluidic system. The entire protocol including cell lysis, extraction of DNA, polymerase chain reaction (PCR), and optical detection were successfully integrated in order to perform a rapid, automated diagnosis. Experimental results showed that four primer sets with conserved HIV-1 B-type sequences specific for the 167-bp RU5 promoter region, the 424-bp int, the 117-bp tat, and the 162-bp vpr coding regions were successfully amplified from the respective regions of the proviral DNA, even from a single infected cell. This accurate real-time detection was achieved within 95 min using the integrated optical system. PMID- 23083907 TI - A simple one-step assay platform based on fluorescence quenching of macroporous silicon. AB - We synthesized 3D macroporous silicon through a simple electrochemical dissolution process and systematically estimated its protein adsorption and effect on fluorescence emission. Compared with conventional 2D polystyrene plate, the macroporous silicon showed a superior protein adsorption capacity and significant fluorescence quenching effect. We developed a 3D macroporous silicon based adenosine assay system through the following fabrication process: streptavidin molecules that have been immobilized on the surface of macroporous silicon are attached with biotin-linked and adenosine-specific DNA aptamer, followed by hybridization between the attached aptamer and fluorescent chemical (carboxytetramethylrhodamine/CTMR) that is conjugated with a short complementary DNA sequence. In the absence of adenosine, the aptamer-CTMR complexes remain closely attached to the surface of porous silicon, hence fluorescence being significantly quenched. Upon binding to adenosine, the DNA aptamer is subject to structure switching that leads to dissociation of CTMR from DNA aptamer, and consequently the CTMR fluorescence is restored, indicating a simple one-step assay of adenosine. Compared to the conventional 2D PS and ZnO nanorods-based assays, adenosine at much lower (sub-micromolar) concentration was successfully detected through the 3D macroporous silicon-based assay. The three-dimensionally and densely immobilized aptamer probes and effective fluorescence quenching on the surface of macroporous silicon enables adenosine to be detected at lower levels. Although the adenosine detection is reported here as a proof-of-concept, the developed macroporous silicon-based simple one-step assay platform can be applied in general to fluorescence quenching -based detection of many other biomolecules. PMID- 23083908 TI - Carbon nanotubes-nanoflake-like SnS2 nanocomposite for direct electrochemistry of glucose oxidase and glucose sensing. AB - Multi-walled carbon nanotubes (MWCNTs)-nanoflake-like SnS(2) nanocomposite were designed for immobilization of glucose oxidase (GOx). The direct electrochemistry of GOx and glucose sensing at MWCNTs-SnS(2) modified glassy carbon electrode were studied. Compared with single MWCNTs or SnS(2), the MWCNTs-SnS(2) film has larger surface area and provides a more favorable microenvironment for facilitating the electron transfer between enzyme and electrode surface. The properties of GOx/MWCNTs-SnS(2) were examined by scanning electron microscopy, UV-vis spectroscopy, Fourier transform infrared spectroscopy and cyclic voltammetry. The immobilized enzyme on MWCNTs-SnS(2) composite film retained its native structure and bioactivity and showed a surface controlled, reversible two-proton and two electron transfer reaction with a apparent electron transfer rate constant of 3.96 s(-1). The constructed glucose biosensor exhibits wider linear range from 2.0*10(-5) M to 1.95*10(-3) M, much lower detection limit of 4.0*10(-6) M at signal-to-noise of 3 and higher sensitivity of 21.65 mA M(-1) cm(-2) than our previous nanoflake-like SnS(2)-based glucose sensor. The proposed biosensor has excellent selectivity, good reproducibility, and acceptable operational stability and can be successfully applied in the reagentless glucose sensing at -0.43 V. This MWCNTs-SnS(2) composite provides a new avenue for immobilizing proteins and fabricating excellent biosensors. PMID- 23083909 TI - Amplified electrochemiluminescence detection of DNA-binding protein based on the synergy effect of electron and energy transfer between CdS nanocrystals and gold nanoparticles. AB - In this work, we firstly enunciated the presence of synergy effect between the electron and energy transfer in an electrochemiluminescence (ECL) system involving the CdS NCs and Au NPs, based on which an amplified ECL biosensor was constructed for sensitive detection of DNA-protein interactions. Specifically, Au NPs modified on electrode, following by assembled probe DNA. Then the modified GCE was hybridized with SiO(2)@CdS/DNA conjugates. With DNA duplex as a rigid spacer, Au NPs could not only accelerate the electron transfer but also produce the surface plasma resonance upon excited ECL of CdS NCs. However, the enhanced ECL could be greatly suppressed by the binding of target protein. The prepared biosensor possesses excellent analytical performance with the linear range of target protein from 0.015 to 150 nM. PMID- 23083910 TI - Polymer thin films embedded with metal nanoparticles for electrochemical biosensors applications. AB - Currently, polymer thin films embedded with metal nanoparticles provided the suitable microenvironment for biomolecules immobilization retaining their biological activity with desired orientation, to facilitate electron transfer between the immobilized enzymes and electrode surfaces, better conformation and high biological activity, resultant in enhanced sensing performance. This article reviews focus on various methods for brief discussion of fabrication of metal nanoparticles-polymer hybrid materials and their applications in different electrochemical biosensors. The performance of hybrid materials based electrochemical biosensor can be improved by synergic properties of the metal nanoparticles and polymer network with biomolecules interface via engineering of morphology, particle size, effective surface area, functionality, adsorption capability and electron-transfer properties. These attractive features to hybrid materials are expected to find applications in a new generation of miniaturized, smart biochip devices. PMID- 23083911 TI - Flexible direct-growth CNT biosensors. AB - A biosensor was fabricated by growing carbon nanotubes (CNTs) directly on a polyimide flexible substrate at low temperatures (<=400 degrees C). A biocompatible polymer (poly(para-xylylene), parylene) was subsequently coated on the surface without CNTs as an insulator for future applications of flexible biosensors in in vivo sensing. The feasibility of the CNT flexible biosensor was demonstrated by quantitatively detecting human serum albumin (HSA). The CNT surface was modified with functional groups using UV-ozone, 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC), and treated with N-hydroxysuccinimide (NHS) to improve the biocompatibility for the conjugation of protein. In addition, anti-HSA (AHSA) was used to capture HSA specifically, and bovine serum albumin (BSA) was applied to block the non-specific sites. The electrical properties of the biosensors applied with various HSA concentrations were measured and quantified using an electrochemical impedance spectroscopy system under AC conditions. The detection limit of the biosensor for HSA detection was approximately 3*10(-11) mg/ml. The proposed sensor has considerable potential for future application in wearable biosensors and implant detection. PMID- 23083912 TI - Top ten clinical research downloads of 2011. PMID- 23083914 TI - Understanding hypnosis metacognitively: rTMS applied to left DLPFC increases hypnotic suggestibility. AB - INTRODUCTION: According to the cold control theory of hypnosis (Dienes and Perner, 2007), hypnotic response occurs because of inaccurate higher order thoughts of intending. The dorsolateral prefrontal cortex (DLPFC) is a region likely involved in constructing accurate higher order thoughts. Thus, disrupting DLPFC with low frequency repetitive transcranial magnetic stimulation (rTMS) should make it harder to be aware of intending to perform an action. That is, it should be easier to respond to a hypnotic suggestion. METHOD: Twenty-four medium hypnotisable subjects received low frequency rTMS to the left DLPFC and to a control site, the vertex, in counterbalanced order. The hypnotist was blind to which site had been stimulated. Subjects rated how strongly they expected to respond to each suggestion, and gave ratings on a 0-5 scale of the extent to which they experienced the response, for four suggestions (magnetic hands, arm levitation, rigid arm and taste hallucination). The experimenter also rated behavioural response. RESULTS: Low frequency rTMS to the DLPFC rather than vertex increased the degree of combined behavioural and subjective response. Further, subjects did not differ in their expectancy that they would respond in the two conditions, so the rTMS had an effect on hypnotic response above and beyond expectancies. CONCLUSIONS: The results support theories, including cold control theory, postulating a component of hypofrontality in hypnotic response. PMID- 23083915 TI - Heterogeneity of compulsive buyers based on impulsivity and compulsivity dimensions: a latent profile analytic approach. AB - Despite the recognition that compulsive buyers are not one homogenous group, there is a dearth of theory-guided empirical investigation. Furthermore, although compulsivity and impulsivity are used as major psychiatric criteria for diagnosing compulsive buyers, these dimensions have rarely been considered in assessing the heterogeneity issue. We fill this gap by applying the motivation shift model of addiction to compulsive buying and empirically assessing the heterogeneity issue in the bi-dimensional space represented by the buying impulsivity and compulsivity dimensions. These hypotheses were tested with latent profile analysis based on survey data (N=445). Consistent with the hypothesis, we identified the cluster of buyers with high buying compulsivity and impulsivity ("compulsive-impulsive buyers"), the cluster of buyers with low buying compulsivity and high impulsivity ("impulsive excessive buyers"), and the cluster of ordinary buyers. Furthermore, it was found that disparate clusters of buyers exhibit unique dispositional tendencies. Theoretical contributions and policy implications of the findings are discussed as well. PMID- 23083916 TI - Does originating from a genetic isolate affect the level of cognitive impairments in schizophrenia families? AB - Earlier studies have detected differences in the prevalence, symptomatology and genetic risk variants of schizophrenia between a north-eastern Finnish genetic isolate and the rest of Finland. This study compared a population-based isolate sample (145 persons with schizophrenia, 304 first-degree relatives and 32 controls) with a rest of Finland sample (73 persons with schizophrenia, 100 first degree relatives and 80 controls) in cognitive functioning. Persons from the isolate outperformed persons in the rest of Finland sample in verbal learning, verbal ability and cognitive flexibility in the schizophrenia groups and in verbal learning, speeded processing and attentional control in the relatives groups. The differences between the subsamples remained significant after taking into account an intragenic Reelin STR allele, previously associated with cognitive impairments and almost absent from the isolate, in addition to disorder characteristics and familial loading. In control groups, we observed no differences between the isolate and the rest of Finland. In conclusion, cognitive impairments were milder in schizophrenia patients and their first-degree relatives within than outside the isolate. An absence of differences between the control samples suggests that the differences in schizophrenia families may relate to genetic background, possibly to partly distinct variants affecting the liability inside and outside the isolate. PMID- 23083917 TI - Cortisol response and desire to binge following psychological stress: comparison between obese subjects with and without binge eating disorder. AB - While stress and negative affect are known to precede "emotional eating", this relationship is not fully understood. The objective of this study was to explore the relationship between induced psychological stress, hypothalamic-pituitary adrenal (HPA) axis activity, and eating behavior in binge eating disorder (BED). The Trier Social Stress Test (TSST) was applied in obese participants with (n=8) and without BED (n=8), and normal weight controls (n=8). Psychological characteristics, eating-related symptoms, and cortisol secretion were assessed. Baseline stress, anxiety and cortisol measures were similar in all groups. At baseline desire to binge was significantly higher among the BED group. While the TSST induced an increase in cortisol levels, a blunted cortisol response was observed in the BED group. In the BED group, a positive correlation was found between cortisol (area under the curve) levels during the TSST and the change in VAS scores for desire to binge. Post-TSST desire to binge and sweet craving were significantly higher in the BED group and correlated positively with stress, anxiety, and cortisol response in the BED group only. These results suggest chronic down-regulation of the HPA axis in participants with BED, and a relationship between psychological stress, the acute activation of the HPA axis, and food craving. PMID- 23083919 TI - Reply to: Kampf G, Ostermeyer C. World Health Organization-recommended hand-rub formulations do not meet European efficacy requirements for surgical hand disinfection in five minutes (J Hosp Infect 2011;78:123-127). PMID- 23083918 TI - Assessment of self-reported negative affect in the NIH Toolbox. AB - We report on the selection of self-report measures for inclusion in the NIH Toolbox that are suitable for assessing the full range of negative affect including sadness, fear, and anger. The Toolbox is intended to serve as a "core battery" of assessment tools for cognition, sensation, motor function, and emotional health that will help to overcome the lack of consistency in measures used across epidemiological, observational, and intervention studies. A secondary goal of the NIH Toolbox is the identification of measures that are flexible, efficient, and precise, an agenda best fulfilled by the use of item banks calibrated with models from item response theory (IRT) and suitable for adaptive testing. Results from a sample of 1763 respondents supported use of the adult and pediatric item banks for emotional distress from the Patient-Reported Outcomes Measurement Information System (PROMIS((r))) as a starting point for capturing the full range of negative affect in healthy individuals. Content coverage for the adult Toolbox was also enhanced by the development of a scale for somatic arousal using items from the Mood and Anxiety Symptom Questionnaire (MASQ) and scales for hostility and physical aggression using items from the Buss-Perry Aggression Questionnaire (BPAQ). PMID- 23083920 TI - Atomic resolution phase contrast imaging and in-line holography using variable voltage and dose rate. AB - The TEAM 0.5 electron microscope is employed to demonstrate atomic resolution phase contrast imaging and focal series reconstruction with acceleration voltages between 20 and 300 kV and a variable dose rate. A monochromator with an energy spread of <=0.1 eV is used for dose variation by a factor of 1,000 and to provide a beam-limiting aperture. The sub-Angstrom performance of the instrument remains uncompromised. Using samples obtained from silicon wafers by chemical etching, the [200] atom dumbbell distance of 1.36 A can be resolved in single images and reconstructed exit wave functions at 300, 80, and 50 kV. At 20 kV, atomic resolution <2 A is readily available but limited by residual lens aberrations at large scattering angles. Exit wave functions reconstructed from images recorded under low dose rate conditions show sharper atom peaks as compared to high dose rate. The observed dose rate dependence of the signal is explained by a reduction of beam-induced atom displacements. If a combined sample and instrument instability is considered, the experimental image contrast can be matched quantitatively to simulations. The described development allows for atomic resolution transmission electron microscopy of interfaces between soft and hard materials over a wide range of voltages and electron doses. PMID- 23083921 TI - Glycans: pervasive regulators of protein and cellular function. PMID- 23083922 TI - Pattern and consequences of krathom (Mitragyna speciosa Korth.) use among male villagers in southern Thailand: a qualitative study. AB - BACKGROUND: Krathom is currently the most popular illicit substance in use in southern Thailand. Research regarding its effects and health impacts is scarce. This study explored the pattern of krathom use and users' perceptions of the consequences of its use. METHODS: An in-depth qualitative interview. A group of 34 self-identified regular users, occasional users, non-users and ex-users of krathom was used in this study. Health volunteer as a key-contact person helped the researcher to invite villagers to participate in the study using snowballing technique. The process of data analysis was guided by Strauss and Corbin's grounded theory. RESULTS: The core category, 'Understanding krathom use', was generated from three inter-related categories: (i) reasons for continuing krathom use, (ii) the way of applying krathom, and (iii) perceiving positive and realizing the negative effects of krathom use and their 18 subcategories. CONCLUSIONS: The study findings reveal the importance of considering krathom use from the perspective and belief of the villagers. Krathom is addictive with its own characteristic symptoms and signs. The results provide support for policy interventions to control the availability of krathom according to the community context. In addition, krathom misuse by adolescents must be considered. PMID- 23083923 TI - Serological survey of Encephalitozoon cuniculi infection in commercially reared rabbit does in Northern Italy. AB - The aim of the study was to carry out a serological survey of Encephalitozoon cuniculi in commercially reared rabbit does (Oryctolagus cuniculi) in Veneto region (Northern Italy). Two hundred and sixty blood samples from 13 farms were examined by a carbon immunoassay (CIA test) to detect the presence of antibodies anti-E. cuniculi. All sampled rabbit does were clinically healthy. Seropositivity against E. cuniculi was found in 196/260 (75.4%) sera and in all the sampled farms (100%). Logistic regression analysis showed that the size of the farm had no statistically significant effect on E. cuniculi positivity; whereas rabbits of the hybrid X showed a higher seropositivity (p<0.01) than rabbits belonging to other commercial breeds. Moreover, the age seemed to influence the seropositivity (p<0.05). This serological survey showed a high prevalence of E. cuniculi infection suggesting that this parasite may be endemic in industrial rabbitries in Northern Italy. PMID- 23083924 TI - Mature oocyte cryopreservation: a guideline. AB - There is good evidence that fertilization and pregnancy rates are similar to IVF/ICSI with fresh oocytes when vitrified/warmed oocytes are used as part of IVF/ICSI for young women. Although data are limited, no increase in chromosomal abnormalities, birth defects, and developmental deficits has been reported in the offspring born from cryopreserved oocytes when compared to pregnancies from conventional IVF/ICSI and the general population. Evidence indicates that oocyte vitrification and warming should no longer be considered experimental. This document replaces the document last published in 2008 titled, "Ovarian Tissue and Oocyte Cryopreservation," Fertil Steril 2008;90:S241-6. PMID- 23083926 TI - Increase of litter at the Arctic deep-sea observatory HAUSGARTEN. AB - Although recent research has shown that marine litter has made it even to the remotest parts of our planet, little information is available about temporal trends on the deep ocean floor. To quantify litter on the deep seafloor over time, we analysed images from the HAUSGARTEN observatory (79 degrees N) taken in 2002, 2004, 2007, 2008 and 2011 (2500 m depth). Our results indicate that litter increased from 3635 to 7710 items km-2 between 2002 and 2011 and reached densities similar to those reported from a canyon near the Portuguese capital Lisboa. Plastic constituted the majority of litter (59%) followed by a black fabric (11%) and cardboard/paper (7%). Sixty-seven percent of the litter was entangled or colonised by invertebrates such as sponges (41%) or sea anemones (15%). The changes in litter could be an indirect consequence of the receding sea ice, which opens the Arctic Ocean to the impacts of man's activities. PMID- 23083925 TI - Detection of cardiovascular autonomic neuropathy using exercise testing in patients with type 2 diabetes mellitus. AB - AIMS: This study investigated autonomic nervous system function in subjects with diabetes during exercise and recovery. METHODS: Eighteen type 2 diabetics (age 55+/-2 years) and twenty healthy controls (age 51+/-1 years) underwent two 16-min bicycle submaximal ECG stress tests followed by 45 min of recovery. During session #2, atropine (0.04 mg/kg) was administered at peak exercise, and the final two minutes of exercise and entire recovery occurred under parasympathetic blockade. Plasma catecholamines were measured throughout. Parasympathetic effect was defined as the difference between a measured parameter at baseline and after parasympathetic blockade. RESULTS: The parasympathetic effect on the RR interval was blunted (P=.004) in diabetic subjects during recovery. Parasympathetic effect on QT-RR slope during early recovery was diminished in the diabetes group (diabetes 0.13+/-0.02, control 0.21+/-0.02, P=.03). Subjects with diabetes had a lower heart rate recovery at 1 min (diabetes 18.5+/-1.9 bpm, control 27.6+/-1.5 bpm, P<.001). CONCLUSIONS: In subjects with well-controlled type 2 diabetes, even with minimal evidence of CAN using current methodology, altered cardiac autonomic balance is present and can be detected through an exercise-based assessment for CAN. The early post-exercise recovery period in diabetes was characterized by enhanced sympathoexcitation, diminished parasympathetic reactivation and delay in heart rate recovery. PMID- 23083927 TI - Seasonal variation of polycyclic aromatic hydrocarbons concentrations in urban streams at Niteroi City, RJ, Brazil. AB - Polycyclic aromatic hydrocarbons (PAHs) were determined in water samples collected in two streams and a lake located at Niteroi City, Rio de Janeiro State, Brazil between October 2008 and September 2009. Samples were extracted using liquid-liquid extraction and analyzed using high performance liquid chromatography with fluorescence detection. The limits of quantification were sufficiently low to accomplish PAH determination below the maximum concentration levels established by the Brazilian (50 ng/L) and USEPA legislations, with recoveries larger than 81.6%. Phenanthrene, fluoranthene, pyrene and benz[a]anthracene predominated among PAHs. Total concentrations of PAHs were well correlated with rainfall indicating a possible role of runoff to local pollution of water by PAHs and showed a seasonal variation in wet and dry seasons. Our results highlight the contribution of the widespread streams located around Guanabara Bay to the PAH burden found in its waters. PMID- 23083928 TI - Integration as interdependent workaround. AB - PURPOSE: The paper focuses on how new, poorly charted complexities emerge when disparate systems in healthcare are integrated across organizational, geographical or professional boundaries. METHOD: Interpretive and longitudinal. RESULTS: The paper illustrates empirically how the interdependencies of integrated systems result in escalation of the type, extent and degree of complexities that cuts across previously "local" systems and practices. This implies that a local workaround also becomes interdependent across practices. CONCLUSION: The analytical concept of information infrastructure proves useful in dismantling a local/global separation, as it supports an empirical strategy of tracing out the concrete manifestations of how, where and when the "local" and the "global" are interdependent. PMID- 23083929 TI - Copper-containing mesoporous bioactive glass scaffolds with multifunctional properties of angiogenesis capacity, osteostimulation and antibacterial activity. AB - It is of great importance to develop multifunctional bioactive scaffolds, which combine angiogenesis capacity, osteostimulation, and antibacterial properties for regenerating lost bone tissues. In order to achieve this aim, we prepared copper (Cu)-containing mesoporous bioactive glass (Cu-MBG) scaffolds with interconnective large pores (several hundred micrometer) and well-ordered mesopore channels (around 5 nm). Both Cu-MBG scaffolds and their ionic extracts could stimulate hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF) expression in human bone marrow stromal cells (hBMSCs). In addition, both Cu-MBG scaffolds and their ionic extracts significantly promoted the osteogenic differentiation of hBMSCs by improving their bone-related gene expression (alkaline phosphatase (ALP), osteopontin (OPN) and osteocalcin (OCN)). Furthermore, Cu-MBG scaffolds could maintain a sustained release of ibuprofen and significantly inhibited the viability of bacteria. This study indicates that the incorporation of Cu(2+) ions into MBG scaffolds significantly enhances hypoxia like tissue reaction leading to the coupling of angiogenesis and osteogenesis. Cu(2+) ions play an important role to offer the multifunctional properties of MBG scaffold system. This study has demonstrated that it is possible to develop multifunctional scaffolds by combining enhanced angiogenesis potential, osteostimulation, and antibacterial properties for the treatment of large bone defects. PMID- 23083930 TI - Iodinated alpha-tocopherol nano-emulsions as non-toxic contrast agents for preclinical X-ray imaging. AB - Micro-computed tomography (micro-CT) is an emerging imaging modality, due to the low cost of the imagers as well as their efficiency in establishing high resolution (1-100 MUm) three-dimensional images of small laboratory animals and facilitating rapid, structural and functional in vivo visualization. However use of a contrast agent is absolutely necessary when imaging soft tissues. The main limitation of micro-CT is the low efficiency and toxicity of the commercially available blood pool contrast agents. This study proposes new, efficient and non toxic contrast agents for micro-CT imaging. This formulation consists of iodinated vitamin E (alpha-tocopheryl 2,3,5-triiodobenzoate) as an oily phase, formulated as liquid nano-emulsion droplets (by low-energy nano-emulsification), surrounded by a hairy PEG layer to confer stealth properties. The originality and strength of these new contrast agents lie not only in their outstanding contrasting properties, biocompatibility and low toxicity, but also in the simplicity of their fabrication: one-step synthesis of highly iodinated oil (iodine constitutes 41.7% of the oil molecule weight) and its spontaneous emulsification. After i.v. administration in mice (8.5% of blood volume), the product shows stealth properties towards the immune system and thus acts as an efficient blood pool contrast agent (t(1/2) = 9.0 h), exhibiting blood clearance following mono-exponential decay. A gradual accumulation predominantly due to hepatocyte uptake is observed and measured in the liver, establishing a strong hepatic contrast, persistent for more than four months. To summarize, in the current range of available or developed contrast agents for preclinical X-ray imaging, this agent appears to be one of the most efficient. PMID- 23083932 TI - Temporal application of topography to increase the rate of neural differentiation from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) are a promising cell source for tissue engineering and regenerative medicine, especially in the field of neurobiology. Neural differentiation protocols have been developed to differentiate hPSCs into specific neural cells, but these predominantly rely on biochemical cues. Recently, differentiation protocols have incorporated topographical cues to increase the total neuronal yield. However, the means by which these topographical cues improve neuronal yield remains unknown. In this study, we explored the effect of topography on the neural differentiation of hPSC by quantitatively studying the changes in marker expression at a transcript and protein level. We found that 2 MUm gratings increase the rate of neural differentiation, and that an additional culture period of 2 MUm gratings in the absence of neurotrophic signals can improve the neural differentiation of hPSCs. We envisage that this work can be incorporated into future differentiation protocols to decrease the differentiation period as well as the biochemical signals added, thus generating hPSC-derived neural cells in a more cost effective and efficient manner. PMID- 23083931 TI - The effect of controlled expression of VEGF by transduced myoblasts in a cardiac patch on vascularization in a mouse model of myocardial infarction. AB - Key requirements for cardiac tissue engineering include the maintenance of cell viability and function and the establishment of a perfusable vascular network in millimeters thick and compact cardiac constructs upon implantation. We investigated if these requirements can be met by providing an intrinsic vascularization stimulus (via sustained action of VEGF secreted at a controlled rate by transduced myoblasts) to a cardiac patch engineered under conditions of effective oxygen supply (via medium flow through channeled elastomeric scaffolds seeded with neonatal cardiomyocytes). We demonstrate that this combined approach resulted in increased viability, vascularization and functionality of the cardiac patch. After implantation in a mouse model of myocardial infarction, VEGF expressing patches displayed significantly improved engraftment, survival and differentiation of cardiomyocytes, leading to greatly enhanced contractility as compared to controls not expressing VEGF. Controlled VEGF expression also mediated the formation of mature vascular networks, both within the engineered patches and in the underlying ischemic myocardium. We propose that this combined cell-biomaterial approach can be a promising strategy to engineer cardiac patches with intrinsic and extrinsic vascularization potential. PMID- 23083933 TI - Endonuclease-responsive aptamer-functionalized hydrogel coating for sequential catch and release of cancer cells. AB - Rare circulating tumor cells are a promising biomarker for the detection, diagnosis, and monitoring of cancer. However, it remains a challenge to develop biomedical devices for specific catch and nondestructive release of circulating tumor cells. The purpose of this study was to explore a unique system for cell catch and release by using aptamer-functionalized hydrogels and restriction endonucleases. The results show that the hydrogel coating was highly resistant to nonspecific cell binding with ~5-15 cells/mm(2) on the hydrogel surface. In contrast, under the same condition, the aptamer-functionalized hydrogel coating could catch target cancer cells with a density over 1000 cells/mm(2). When the hydrogel coating was further treated with the restriction endonucleases, the bound cells were released from the hydrogel coating because of the endonuclease mediated sequence-specific hydrolysis of the aptamer sequences. The release efficiency reached ~99%. Importantly, ~98% of the released cells maintained viability. Taken together, this study demonstrates that it is promising to apply endonuclease-responsive aptamer-functionalized hydrogels as a coating material to develop medical devices for specific catch and nondestructive release of rare circulating tumor cells. PMID- 23083934 TI - Silica nanogelling of environment-responsive PEGylated polyplexes for enhanced stability and intracellular delivery of siRNA. AB - In this study, poly(ethylene glycol) (PEG)-block-polycation/siRNA complexes (PEGylated polyplexes) were wrapped with a hydrated silica, termed "silica nanogelling", in order to enhance their stability and functionality. Silica nanogelling was achieved by polycondensation of soluble silicates onto the surface of PEGylated polyplexes comprising a disulfide cross-linked core. Formation of silica nanogel layer on the PEGylated cross-linked polyplexes was confirmed by particle size increase, surface charge reduction, and elemental analysis of transmission electron micrographs. Silica nanogelling substantially improved polyplex stability against counter polyanion-induced dissociation under non-reductive condition, without compromising the reductive environment responsive siRNA release triggered by disulfide cleavage. Silica nanogelling significantly enhanced the sequence-specific gene silencing activity of the polyplexes in HeLa cells without associated cytotoxicity, probably due lower endosomal entrapment (or lysosomal degradation) of delivered siRNA. The lower endosomal entrapment of the silica nanogel system could be explained by an accelerated endosomal escape triggered by deprotonated silanol groups in the silica (the proton sponge hypothesis) and/or a modulated intracellular trafficking, possibly via macropinocytosis, as evidenced by the cellular uptake inhibition assay. Henceforth, silica nanogelling of PEGylated siRNA polyplexes is a promising strategy for preparation of stable and functional siRNA delivery vehicles. PMID- 23083935 TI - Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. Response to Dr Schwartz. PMID- 23083936 TI - Pathophysiology and pharmacologic control of osseous mandibular condylar resorption. PMID- 23083937 TI - Attenuated Salmonella Gallinarum secreting an Escherichia coli heat-labile enterotoxin B subunit protein as an adjuvant for oral vaccination against fowl typhoid. AB - In our previous study, we constructed a vaccine candidate (JOL916) for fowl typhoid (FT). A live adjuvant Salmonella Gallinarum (SG) strain was generated in the present study to facilitate efficacious oral vaccination with this vaccine. The Escherichia coli eltB gene secreting heat-labile enterotoxin B subunit (LTB) was cloned into an Asd(+) plasmid pJHL65. This was transformed into a Deltalon DeltacpxR Deltaasd SG strain and the resulting strain was designated JOL1229. Secretion of LTB from JOL1229 was confirmed with an immunoblot assay. To determine the optimal dose of the strain, 50 six-week-old female chickens were divided into five groups (Groups A-E, n=10 per group) and orally inoculated with various doses of JOL1229 and JOL916. In Group B (consisting of four parts JOL916 and one part JOL1229), significant cell-mediated immune responses, plasma IgG levels and intestinal secretary IgA levels were induced after inoculation with both strains. On challenge with the wild-type strain, significant reductions in mortality were observed in the group. In addition, after inoculation the LTB strain was not recovered in feces samples, and resulted in no, or very mild, gross lesions in the liver and spleen. Both CD4(+) and CD8(+) T-cells were significantly increased in peripheral blood samples from the chickens immunized with the LTB strain. Expression of the interleukin-6 (IL-6) gene in splenocytes was induced in the chickens immunized with the LTB strain. These results suggest that oral immunization with the LTB-adjuvant strain, in particular with the four parts JOL916 and one part JOL1229 mixture, increased the immune response and provided efficient protection against FT in chickens. PMID- 23083938 TI - Escherichia coli virulence factors. AB - Escherichia coli was described in 1885 by a German pediatrician, Theodor Escherich, in the faeces of a child suffering diarrhoea. In 1893, a Danish veterinarian postulated that the E. coli species comprises different strains, some being pathogens, others not. Today the E. coli species is subdivided into several pathogenic strains causing different intestinal, urinary tract or internal infections and pathologies, in animal species and in humans. Since this congress topic is the interaction between E. coli and the mucosal immune system, the purpose of this manuscript is to present different classes of adhesins (fimbrial adhesins, afimbrial adhesins and outer membrane proteins), the type 3 secretion system, and some toxins (oligopeptide, AB, and RTX pore-forming toxins) produced by E. coli, that can directly interact with the epithelial cells of the intestinal, respiratory and urinary tracts. PMID- 23083939 TI - Comparative toxicity assessment of CeO2 and ZnO nanoparticles towards Sinorhizobium meliloti, a symbiotic alfalfa associated bacterium: use of advanced microscopic and spectroscopic techniques. AB - Cerium oxide (CeO(2)) and zinc oxide (ZnO) nanoparticles (NPs) are extensively used in a variety of instruments and consumer goods. These NPs are of great concern because of potential toxicity towards human health and the environment. The present work aimed to assess the toxic effects of 10nm CeO(2) and ZnO NPs towards the nitrogen fixing bacterium Sinorhizobium meliloti. Toxicological parameters evaluated included UV/Vis measurement of minimum inhibitory concentration, disk diffusion tests, and dynamic growth. Ultra high-resolution scanning transmission electron microscopy (STEM) and infrared spectroscopy (FTIR) were utilized to determine the spatial distribution of NPs and macromolecule changes in bacterial cells, respectively. Results indicate that ZnO NPs were more toxic than CeO(2) NPs in terms of inhibition of dynamic growth and viable cells counts. STEM images revealed that CeO(2) and ZnO NPs were found on bacterial cell surfaces and ZnO NPs were internalized into the periplasmic space of the cells. FTIR spectra showed changes in protein and polysaccharide structures of extra cellular polymeric substances present in bacterial cell walls treated with both NPs. The growth data showed that CeO(2) NPs have a bacteriostatic effect, whereas ZnO NPs is bactericidal to S. meliloti. Overall, ZnO NPs were found to be more toxic than CeO(2) NPs. PMID- 23083940 TI - Risk assessment of sedimentary metals in the Yangtze Estuary: new evidence of the relationships between two typical index methods. AB - The contamination and ecological risks of six metals (i.e., As, Cu, Mn, Pb, Sb and Zn) in sediments of the Yangtze Estuary were assessed using two typical index approaches, (i.e., total content and speciation indices). Special attention was paid to the relationships between the two index methods. The ecological risk of each sampling site was uniformly low to moderate in degree. The contamination levels of these sites were low to moderate according to the speciation index used, while the total content indices indicated a moderate to considerate contamination. A significant positive relationship existed between the two index methods when assessing the risks of Cu, Pb and Zn, while negative correlations and inconsistencies existed for As, Mn and Sb. The correlation behaviors were mainly dependent to three metal factors: the fractional distribution, the enrichment degree and the toxic response factors. Significant correspondences were observed between the total content and the speciation indices when assessing the ecological risks of each sampling site and each metal (Cu, Pb or Zn), while discrepancies were found between the two approaches when assessing the contamination of specific sites in the estuary area. PMID- 23083941 TI - Catalytic removal of carbon monoxide over carbon supported palladium catalyst. AB - Carbon supported palladium (Pd/C) catalyst was prepared by impregnation of palladium chloride using incipient wetness technique, which was followed by liquid phase reduction with formaldehyde. Thereafter, Pd/C catalyst was characterized using X-ray diffractometery, scanning electron microscopy, atomic absorption spectroscopy, thermo gravimetry, differential scanning calorimetry and surface characterization techniques. Catalytic removal of carbon monoxide (CO) over Pd/C catalyst was studied under dynamic conditions. Pd/C catalyst was found to be continuously converting CO to CO(2) through the catalyzed reaction, i.e., CO+1/2O(2)->CO(2). Pd/C catalyst provided excellent protection against CO. Effects of palladium wt%, CO concentration, humidity, space velocity and reaction environment were also studied on the breakthrough behavior of CO. PMID- 23083942 TI - [Guillain-Barre syndrome and anti-ganglioside antibodies]. PMID- 23083943 TI - Effectiveness and tolerability of rufinamide in children and young adults with Lennox-Gastaut syndrome: a single center study in Korea. AB - PURPOSE: Rufinamide is a novel antiepileptic drug (AED), which is known to be effective in the treatment of partial seizures and drop attacks in patients with Lennox-Gastaut syndrome (LGS). The aim of this study is to evaluate the efficacy and tolerability of rufinamide in those with LGS. METHODS: Patients with LGS who had received rufinamide adjunctive therapy were enrolled in this study. We retrospectively reviewed these patient's baseline clinical characteristics, and the reduction of seizure frequency and adverse events after the use of rufinamide. RESULTS: Twenty-three patients (15 males and 8 females, ages 4-22 years) were enrolled in the study. All the patients suffered from daily head drops and tonic seizures despite multiple antiepileptic drugs. After one month of rufinamide, one patient (4.3%) achieved freedom from seizures, ten (43.5%) achieved a >=50% decrease in seizure frequency. After six months of rufinamide, eight patients (34.8%) maintained a satisfactory response (seizure free in one, and greater than 50% seizure reduction in seven). Adverse events were reported in six (26.0%) patients, which were somnolence in three, aggressive behavior in two, and aggravation of seizure in one patient. CONCLUSIONS: Our results suggest that rufinamide is effective and safe in children and young adults with LGS. PMID- 23083944 TI - Quality of life of community-based palliative care clients and their caregivers. AB - OBJECTIVE: This study aimed to investigate health-related quality of life of palliative care (PC) clients and their caregivers, at baseline and follow-up, following a referral to a community PC service. METHOD: Quality of life of clients and their caregivers was respectively measured using the McGill Quality of Life instrument (MQoL) and the Caregiver Quality of Life Cancer Index (CQoLC) instruments. Participants were recruited from June 8 to October 27, 2006. This study was undertaken in one zone of an Area Health Service in New South Wales, which has a diverse socioeconomic population. The zone covers an area of 6237 km2 and is divided into five sectors, each with a PC service, all of which participated in this study. RESULTS: Data were obtained from 49 clients and 43 caregivers at baseline, and 22 clients and 12 caregivers at 8 week follow-up. Twenty-one participants died and six moved out of the area during the study. At baseline, clients reported a low mean score for physical symptoms (3.3 +/- 1.9) and a high score for support (8.7 +/- 1.0). Caregivers scored a total CQoLC of 63.9 +/- 21.4 and clients had a total QOL of 6.1 +/- 1.3. At follow up, matched data for 22 clients and 13 caregivers demonstrated no statistical differences in quality of life. SIGNIFICANCE OF RESULTS: This study has provided evidence that health-related quality of life questionnaires show lower scores for physical health and higher scores for support, which can directly inform specific interventions targeted at the physical and support domains. PMID- 23083945 TI - Psychotomimetic effects of kappa opioid receptor agonists. PMID- 23083946 TI - Progress in gene environment studies. PMID- 23083947 TI - Cognitive consequences of alterations in functional circuitry induced by chronic cocaine use and the potential impact for treatment. PMID- 23083948 TI - A descriptive epidemiologic study of cleft lip and palate in Spain. AB - OBJECTIVE: The purpose of this study was to investigate the distribution of different cleft patterns by sex, side of the cleft, and family history of clefts in a referral hospital in the south of Spain. STUDY DESIGN: One hundred twenty three consecutive cleft lip subjects, with or without palates, attending the Stomatology Unit in the Virgen del Rocio University Hospital and in the Virgen Macarena University Hospital from October 2009 to May 2010 were studied. RESULTS: The unilateral complete cleft lip and palate (54.4%) was most frequently found, followed by the bilateral complete cleft lip and palate (16.3%). Male patients (60.97%) and the left side (41.46%) were the most affected. A positive family history was observed in 21.94% of subjects. CONCLUSIONS: The most frequent profile in the affected population was male with left unilateral complete cleft lip and palate. The high incidence of family history of cleft on the father's side prompts us to recommend further genetic research in this area. PMID- 23083949 TI - Symmetry in nasolabial area of UCCL patients one year after primary lip repair with modified Millard technique. AB - OBJECTIVE: The aim of this study was to assess the nasolabial symmetry of unilateral complete cleft lip patients repaired by West China modified Millard technique. STUDY DESIGN: Photographs of 31 unilateral complete cleft lip patients were taken before, immediately after, and 1 year after the surgery. Photogrammetric measurements were taken to evaluate nasolabial symmetry. RESULTS: Symmetry for the christa philtri point was attained immediately after the surgery and maintained in the 1-year follow-up. The cheilion point and the sub alare point, however, did not achieve symmetry until 1 year after surgery. The alar point, unfortunately, never achieved satisfactory symmetry in this study. The ratio of symmetry for none of the above-mentioned facial landmarks had linear correlations with the width of the fissure or other facial anthropometric measurements. CONCLUSIONS: Symmetry could be achieved in most of the nasolabial anthropometric landmarks after our modified Millard procedure. PMID- 23083950 TI - Pain related to mandibular block injections and its relationship with anxiety and previous experiences with dental anesthetics. AB - OBJECTIVE: Anesthetic injections should reassure patients with the prospect of painless treatment, but for some patients it is the main source of their fear. We investigated pain resulting from mandibular block injections in relation to anxiety and previous experience with receiving injections. STUDY DESIGN: Patients (n = 230) filled out questionnaires before oral surgery. They were then asked to raise their hand when they felt pain as a result of the injection. The injection was administered, and pain intensity (11-point numeric rating scale) and pain duration (in seconds) was measured. RESULTS: In general, patients expected (mean 4.2, SD 2.7) significantly more pain than they experienced (2.4 +/- 2.2). About 8.3% of patients reported a score in the range of 7 to 10. On average, pain lasted for 6.2 seconds (range 1-24.5 s), ~ 36% of patients raised their hand for <= 2 seconds, and 14.6% raised their hand for >= 10 seconds. Pain was significantly positively associated with anxiety and the way previous injections were experienced. CONCLUSIONS: Mandibular block injections can be considered to be mildly painful, with pain lasting only a few seconds. The pain experience of a mandibular block seems only partly dependent on experienced anxiety and previous experiences with receiving injections. PMID- 23083951 TI - Radiographic evaluation of maxillofacial region in oncology patients treated with bisphosphonates. AB - OBJECTIVE: This study aimed to identify radiographic alterations in patients administered bisphosphonate treatment that would permit early diagnosis of osteonecrosis of the jaw. STUDY DESIGN: A prospective study was conducted with clinical and radiographic analysis of 60 patients divided into 2 groups. Thirty patients treated with zoledronate were included in group 1, and 30 patients that had never been treated with bisphosphonate were included in group 2. Digital panoramic radiographs were performed on all patients and subsequently evaluated by 2 radiologists. RESULTS: Data analysis revealed that patients treated with zoledronate presented a statistically significant increase in the number of radiographic abnormalities compared with the control group. Female patients presented significantly more alterations than male patients, and the posterior region of the mandible was the most affected region. CONCLUSIONS: Analysis of the data obtained revealed that the use of panoramic radiographs facilitates early identification of bone alterations, which can improve early diagnosis of bisphosphonate-associated osteonecrosis of the jaw. PMID- 23083952 TI - Clinical and surgical evaluation of the indication of postoperative antibiotic prescription in third molar surgery. AB - OBJECTIVE: The aim of this study was to evaluate the need for antibiotic prescription in third molar surgery. STUDY DESIGN: A double-blind randomized study was carried out with 71 patients from CODONT (Dentistry Center of the Police of Sao Paulo). Amoxicillin, clindamycin, or no medication was administered for 7 days immediately after surgery. The participants evaluated the presence of pain, edema, interincisal distance (ID), presence of infection, Pell and Gregory classification, rescue analgesia, osteotomy, and odontosection. RESULTS: There was no difference (P < .05) between antibiotics and control over the surgery duration, dose, visual analog scale (VAS), ID, and edema, yet significant differences were seen over time for VAS, edema, and ID. CONCLUSIONS: Antibiotic prescription should not be indicated in all clinical conditions, yet it is necessary to correctly evaluate factors such as systemic condition of the patient, skill of the operator, and contamination of the surgical environment. PMID- 23083953 TI - Osteogenic differentiation of muscle satellite cells induced by platelet-rich plasma encapsulated in three-dimensional alginate scaffold. AB - OBJECTIVE: Osteogenic potential of muscle satellite cells (MSCs) makes them a possible source of seeding cells for bone tissue engineering. The objective of the present study was to determine the effects of platelet-rich plasma (PRP) on proliferation and osteogenic differentiation of MSCs by encapsulation of PRP into 3-dimensional alginate hydrogel in vitro and in vivo. STUDY DESIGN: PRP was obtained from Sprague-Dawley rats using 2 centrifugation techniques. MSCs were expanded and differentiated in the presence or absence of PRP in monolayer and 3 dimensional cultures. Cell viability was evaluated with the use of an MTT proliferation assay after 1, 7, 14, and 21 days of stimulation. Alkaline phosphatase (ALP) activity, calcium deposition, and real-time reverse transcription polymerase chain reaction (RT-PCR) of osteogenic-related genes were performed to study the effects of PRP on osteogenic differentiation of cultured MSCs by encapsulation of PRP in alginate gel. For in vivo study, the PRP-MSCs alginate gel mixture was implanted in subcutaneous pockets of nude mice to examine the ectopic bone formation at 2 weeks. RESULTS: After 1, 7, 14, and 21 days of stimulation, PRP significantly promoted MSC proliferation in PRP-alginate gel mixture cultures. ALP activity, calcium deposition, and real-time RT-PCR showed enhanced cell osteogenic differentiation in the PRP-alginate group. Histologic examination demonstrated that large amount of fibrous tissue capsule, collagen, and new vascular growth were detected in the PRP-MSCs-alginate group compared with the alginate and MSCs-alginate groups. CONCLUSIONS: The results of this study suggest that MSCs induced by PRP encapsulated in an alginate gel mixture can undergo induction into osteoblastic phenotype both in vitro and in vivo, which makes the production of PRP-enhanced tissue-engineered bone using MSCs possible. PMID- 23083954 TI - A laboratory study comparing the effect of ridge exposure using tissue punch versus mucoperiosteal flap on the formation of the implant-epithelial junction. AB - OBJECTIVE: The objective of the present study was to clarify the influence of the incision design at the time of implant placement on the consolidation of the implanto-epithelial junction. STUDY DESIGN: Twelve minipigs were chosen for the study. Four weeks after premolar extraction in the maxilla, 4 BEGO Semados RI implants were inserted in each quadrant. Using a split-mouth design, the alveolar crest was exposed by a punch ("flapless surgery") on one side and by a crestal incision ("flap surgery") on the other side. Biopsies were obtained from the peri implant soft tissue at weeks 1, 2, 4, and 12 postinsertion, respectively, and analyzed for the expression of integrin alpha(6)beta(4) chain beta(4) (ITGB4) and laminin 5 gamma(2) chain (lamc2), 2 important marker molecules for the formation of the implanto-epithelial junction. RESULTS: Following exposure of the alveolar crest by the punch technique, a significantly higher expression of ITGB4 was found at the 2- (P = .009), 4- (P = .001), and 12-week (P = .005) follow-up. Furthermore, the expression of lamc2 was significantly higher following punch exposure after 1 (P = .033), 2 (P = .041), 3 (P = .004), and 12 weeks (P = .002) of transmucosal implant healing. CONCLUSIONS: The data of the present study indicate that flapless placement improved the formation of a sufficient implanto epithelial junction. PMID- 23083955 TI - Cementum status in natural teeth opposing implant-borne bridgework in Macaca fascicularis. AB - OBJECTIVE: The objective of this study was to investigate the cementum status in natural teeth opposing implant-supported bridgework. METHODS: Maxillary premolars and molars opposing immediate-loading (IL) and delayed-loading (DL) mandibular implant-supported bridgework in 4 Macaca fascicularis were harvested after 3 months of functional loading. Another 2 monkeys without mandibular fixed prostheses served as control. The cervical (CCW) and apical cementum width (ACW), and resorption craters (RCs) were measured. RESULTS: No significant differences were observed between test and control groups for mean CCW (control = 26.79 +/- 3.28, IL = 21.29 +/- 9.12, and DL = 20.32 +/- 5.65 MUm) and for ACW (control = 937.97 +/- 353.74, IL = 955.26 +/- 720.05, and DL = 750.56 +/- 517.26 MUm) (P > .05). In test and control monkeys, RCs were uncommon and showed no significant differences in width (control = 0.71 +/- 0.38, IL = 1.02 +/- 0.49, DL = 0.85 +/- 1.02 mm) and depth (control = 0.15 +/- 0.07, IL = 0.25 +/- 0.40, DL = 0.22 +/- 0.15 mm) (P > .05). CONCLUSIONS: Present findings suggest that implant-supported bridgework does not produce any adverse effects on the cementum of opposing natural teeth after 3 months of functional loading. PMID- 23083956 TI - The comparison of psychological adjustment of patients with cleft lip and palate after maxillary distraction osteogenesis and conventional orthognathic surgery. AB - OBJECTIVE: The objective of this study was to compare the psychological changes of patients with cleft lip and palate (CLP) undergoing maxillary Le Fort I advancement by distraction osteogenesis (DO) and conventional orthognathic surgery (CO). STUDY DESIGN: Prospective randomized controlled study. Participants completed a set of questionnaires to measure their psychological states preoperatively and postoperatively. RESULT: When compared with CO, CLP patients treated with DO had lower social self-esteem and higher social avoidance and distress levels during the first 3 postoperative months. Their self-esteem, social avoidance, and distress levels improved after the distractors were removed. Both CO and DO patients had similar levels of self-esteem, social avoidance, and distress levels 2 years postoperatively. The CLP patients treated with DO were more satisfied with their lives after 2 years. CONCLUSIONS: DO may induce short-term distress to patients up to 3 months but CLP patients who received DO were more satisfied with their lives in the long term. PMID- 23083957 TI - Measurement of somatosensory-evoked potential to evaluate function of the trigeminal nerve after rapid palatal expansion treatment in a rabbit model. AB - OBJECTIVE: The aim of this study was to evaluate whether high force or stress response occurs in rapid palatal expansion (RPE) on the skull base would affect the function of trigeminal nerve and its branches by measuring trigeminal somatosensory-evoked potential (TSEP). STUDY DESIGN: Twenty-four male New Zealand white rabbits were selected when they were 12-13 weeks old with mean weight around 3.05 +/- 0.33 kg. A modified acrylic-bonded RPE appliance was used as an expansion tool. Through a series of TSEP measurements performed before the expansion treatment (T0), on the third day of the expansion (T1), at the end of the expansion process (T2), and after 10 days of retention (T3), function of the trigeminal nerve was analyzed with statistical models, including the Kruskal Wallis test and paired t tests. RESULTS: A stable short-latency response represented by a "W" waveform was consistently identified on the TSEP spectram analysis. Within-subject comparisons between the experimental group and control group did not show significant differences on TSEP of maxillary nerve and of mandibular nerve. CONCLUSIONS: TSEP is a valuable technique for a comprehensive evaluation of the trigeminal system. Our study demonstrates that rapid palatal expansion is a safe orthopedic method regarding function of the trigeminal nerve during expansion and short-term retention period in young rabbits. PMID- 23083959 TI - An epidemiologic analysis of 1,142 maxillofacial fractures and concomitant injuries. AB - OBJECTIVE: The aim of this study was to evaluate the incidence and etiology of maxillofacial fractures in the Greek population over the past 5 years. A comparison of findings with 2 earlier studies from the same department was also performed. STUDY DESIGN: Seven hundred twenty-seven patients treated for a total of 1,142 facial fractures in the period from 2005 to 2009 were included in a retrospective, clinical, and epidemiologic study. Cause, type, site of injury, gender, age, and nationality of the patient were the parameters evaluated. RESULTS: Road traffic accidents remained the most common cause of injury (50.8%) followed by assaults (26.3%), falls (13.8%), work-related injuries (3.2%), and sport injuries (3%). CONCLUSIONS: Road traffic accidents remain the most frequent etiology of maxillofacial fractures. Fractures of the facial skeleton caused by assault increased significantly in the period assessed. Concomitant injuries were most frequently associated with motorcycle accidents. PMID- 23083958 TI - A comparative evaluation of the hybrid technique for fixation of the sagittal split ramus osteotomy in mandibular advancement by mechanical, photoelastic, and finite element analysis. AB - OBJECTIVE: This study evaluated the mechanical characteristics and stress distribution of the hybrid technique fixation of the sagittal split ramus osteotomy. STUDY DESIGN: In the mechanical test, 10 polyurethane replicas of human hemimandibles of each group were submitted to linear loading test. For the photoelastic evaluation, 3 hemimandible replicas of photoelastic resin were subjected to photoelastic analysis. In the finite element analysis, 3 computer models simulated the displacement and the results of maximum principal stress were analyzed. RESULTS: The results of this study demonstrated that the fixation technique with 3 bicortical screws presented better mechanical resistance and stress distribution pattern when compared with the hybrid technique that, on the other hand, presents better results in comparison with a miniplate and monocortical screws. CONCLUSIONS: The results suggest that the hybrid technique increased the resistance and improved stress distribution of miniplate/monocortical screw fixation, maintaining most of the advantages of this technique. PMID- 23083960 TI - Correction of maxillary deformity in infants with bilateral cleft lip and palate using computer-assisted design. AB - OBJECTIVE: The aim of this study was to introduce a method of presurgical maxillary molding using computer-aided design and rapid prototyping in infants with bilateral cleft lip and palate. STUDY DESIGN: Seven infants (4 male and 3 female with overall mean age of 7 days) with bilateral cleft lip and palate were subjected to nasoalveolar molding (NAM) technique before the cleft lip repair. The upper denture casts were scanned by a 3-dimensional laser scanner. The digital geometric data were exported to print the solid model with rapid prototyping system. The NAM appliances were fabricated based on these solid models. RESULTS: The computer-aided design could simplify the NAM procedure and estimate the treatment objective. The appliances could be fabricated based on the rapid prototyping system. CONCLUSIONS: In infants with bilateral cleft lip and palate, the presurgical orthopedic treatment design and the appliance fabrication could be simplified with computer-aided reverse engineering and rapid prototyping technique. PMID- 23083961 TI - Hypernociception and wound healing after application of cyanoacrylate ester as a tissue adhesive in rats. AB - OBJECTIVE: The present study assessed and compared postoperative hypernociception and skin healing after cyanoacrylate and classic suture as well as analyzed morphologic features of the tissue repair. STUDY DESIGN: The intensity of hypernociception was measured with an electronic pressure-meter test. Rats were given an incised wound in the middle of the palms of the right and left paws. The left side was treated with a silk suture, and the right with cyanoacrylate. Control groups were treated locally with dipyrone or received a systemic pretreatment with valdecoxib. RESULTS: Cyanoacrylate was associated with less inflammation (first week), and the healing wound site was rich in collagenous extracellular matrix and neovascularization. Dipyrone in combination with cyanoacrylate greatly increased the antinociceptive effect. These results were not repeated after systemic treatment with valdecoxib, suggesting that the antinociceptive effect seen in the tissue adhesive was due to formation of a physical barrier. PMID- 23083962 TI - Real-time ultrasound-guided central venous catheterization reduces the need for prophylactic platelet transfusion in thrombocytopenic patients with hematological malignancy. PMID- 23083963 TI - Matrix metalloproteinase-8 is the major potential collagenase in active peri implantitis. AB - PURPOSE: Current clinical procedures to control or regenerate bone loss due to peri-implantitis are not predictable neither accomplish complete resolution. Therefore, early detection of the onset and the active periods of bone loss are crucial for prevention of extensive peri-implant bone resorption. This study aimed to determine a possible association between the presence of collagenases (MMP-1, MMP-8 and MMP-13) in peri-implant sulcular fluid (PISF) and active periods of bone loss by annually adjusted vertical bone loss (AVBL) measurements. METHODS: Intended sample consisted of 76 consecutive patients who received oral implant treatment at the Fixed Prosthodontic Clinic of Okayama University Hospital from 1990 to 2000. Twelve subjects were lost to follow-up or refused to participate. Consequently, the actual sample consisted of 64 patients who were followed-up for at least one year. Those patients with AVBL>0.6mm were included in the severe peri-implantitis group, and randomly selected, age-, gender- and implantation site-matched healthy patients (AVBL<0.3mm) comprised the control group. PISF samples were collected from both groups and further analyzed by western blot for detection of collagenases. RESULTS: Four patients presented severe peri-implantitis. MMP-8 was the only collagenase detected in peri-implant sites with ongoing bone loss. PISF samples from control group showed no positive reactions to any collagenase. CONCLUSION: This study showed MMP-8 as a possible marker for progressive bone loss in peri-implantitis. PMID- 23083964 TI - Perceptions of the effect of information and communication technology on the quality of care delivered in emergency departments: a cross-site qualitative study. AB - STUDY OBJECTIVE: We identify and describe emergency physicians' and nurses' perceptions of the effect of an integrated emergency department (ED) information system on the quality of care delivered in the ED. METHODS: A qualitative study was conducted in 4 urban EDs, with each site using the same ED information system. Participants (n=97) were physicians and nurses with data collected by 69 detailed interviews, 5 focus groups (28 participants), and 26 hours of structured observations. RESULTS: Results revealed new perspectives on how an integrated ED information system was perceived to affect incentives for use, awareness of colleagues' activities, and workflow. A key incentive was related to the positive effect of the ED information system on clinical decisionmaking because of improved and quicker access to patient-specific and knowledge-base information compared with the previous stand-alone ED information system. Synchronous access to patient data was perceived to lead to enhanced awareness by individual physicians and nurses of what others were doing within and outside the ED, which participants claimed contributed to improved care coordination, communication, clinical documentation, and the consultation process. There was difficulty incorporating the use of the ED information system with clinicians' work, particularly in relation to increased task complexity; duplicate documentation, and computer issues related to system usability, hardware, and individuals' computer skills and knowledge. CONCLUSION: Physicians and nurses perceived that the integrated ED information system contributed to improvements in the delivery of patient care, enabling faster and better-informed decisionmaking and specialty consultations. The challenge of electronic clinical documentation and balancing data entry demands with system benefits necessitates that new methods of data capture, suited to busy clinical environments, be developed. PMID- 23083965 TI - In infants younger than 24 months old and with bronchiolitis, does nebulized epinephrine improve clinical status? PMID- 23083966 TI - Measuring the value of the emergency department from the patient's perspective. PMID- 23083967 TI - Emergency medicine rural rotations: a program director's guide. AB - The Institute of Medicine's 2006 report titled "Hospital-Based Emergency Care: At the Breaking Point" called national attention to the lack of specialty-trained emergency care practitioners, particularly in rural America. One suggested strategy for narrowing the gap between the prevalence of residency-trained, board certified emergency physicians practicing in rural and urban emergency departments is the development of rural clinical experiences for emergency medicine residents during the course of their training. This article addresses promotion of a rural emergency medicine rotation to hospital leadership and resident recruits, examines funding sources, discusses medical liability and disability insurance options, provides suggestions for meeting faculty and planned educational activity residency review committee requirements, and offers guidance about site selection to direct emergency medicine academic leaders considering or planning a new rural emergency medicine rotation. PMID- 23083968 TI - Understanding and interpreting the National Hospital Ambulatory Medical Care Survey: key questions and answers. PMID- 23083970 TI - Phosphorus biotechnology. PMID- 23083969 TI - Videolaryngoscopy versus direct laryngoscopy in simulated pediatric intubation. AB - STUDY OBJECTIVE: We determine whether videolaryngoscopy results in a higher prevalence of first-attempt intubation success and improved glottic visualization than direct laryngoscopy when performed by pediatric emergency medicine providers in simulated patients. METHODS: This was a cross-sectional study at a single institution. Fellows and faculty in pediatric emergency medicine were invited to participate. Each subject performed intubations on 3 simulators (newborn, infant, adult), using a videolaryngoscope; each simulator was intubated by each subject with and without use of video. Primary outcome was first-attempt intubation success; secondary outcome was percentage of glottic opening score (POGO). RESULTS: Twenty-six participants performed 156 intubations; complete data were available for 148 intubations. First-attempt success in the neonate was 88%; in the infant, 79%; and in the adult, 60%. In the adult simulator, videolaryngoscopy use showed a first-attempt success in 81% of subjects compared with 39% with direct laryngoscopy (difference 43%; 95% confidence interval [CI] 18% to 67%). There was no difference in first-attempt success rates between videolaryngoscopy and direct laryngoscopy in the newborn or infant simulators. Videolaryngoscopy use led to increased POGO scores in all 3 simulators, with a difference of 25% (95% CI 2% to 48%) in newborn simulators, 23% (95% CI 2% to 48%) in infant simulators, and 42% (95% CI 18% to 66%) in adult simulators. CONCLUSION: Videolaryngoscopy was associated with greater first-attempt success during intubation by pediatric emergency physicians on an adult simulator. POGO score was significantly improved in all 3 simulators with videolaryngoscopy. PMID- 23083971 TI - Impact of catabolic plasmids on host cell physiology. AB - It is difficult to know the exact extent to which catabolic plasmids influence the metabolism of different hosts, but this information is crucial for improving the use of xenobiotic degraders possessing conjugative catabolic plasmids. To determine the molecular mechanisms by which catabolic plasmids affect host-cell physiology and host responses, comprehensive molecular surveys have examined host responses to plasmid carriage. These studies have clarified the various interactions between catabolic plasmids and host cells and the importance of the effects on host-cell physiology and metabolic pathways. It has been suggested that catabolic plasmid-borne nucleoid-associated proteins play key roles in the adaptation of catabolic plasmids to the host-cell regulatory network. PMID- 23083972 TI - Substance abuse treatment implementation research. PMID- 23083974 TI - The variability in nutrient composition of Anaerobic Digestate granules produced from high shear granulation. AB - This study investigates the production of organic fertilizer using Anaerobic Digestate (as a nutrient source) and limestone powder as the raw materials. A two level factorial experimental design was used to determine the influence of process variables on the nutrient homogeneity within the granules. Increasing the liquid-to-solid ratio during granulation resulted in increased granule nutrient homogeneity. Increasing the processing time and the impeller speed were also found to increase the nutrient homogeneity. In terms of nutrients release into deionized water, the granules effectively released both potassium and phosphate into solution. PMID- 23083976 TI - [Complicated hepatic hydatid cyst with a ruptured diaphragm and spillage of its contents into the pleural cavity]. PMID- 23083975 TI - Characterization of bone marrow derived mesenchymal stem cells in suspension. AB - INTRODUCTION: Bone marrow mesenchymal stem cells (BMMSCs) are a heterogeneous population of postnatal precursor cells with the capacity of adhering to culture dishes generating colony-forming unit-fibroblasts (CFU-F). Here we identify a new subset of BMMSCs that fail to adhere to plastic culture dishes and remain in culture suspension (S-BMMSCs). METHODS: To catch S-BMMSCs, we used BMMSCs produced extracellular cell matrix (ECM)-coated dishes. Isolated S-BMMSCs were analyzed by in vitro stem cell analysis approaches, including flow cytometry, inductive multiple differentiation, western blot and in vivo implantation to assess the bone regeneration ability of S-BMMSCs. Furthermore, we performed systemic S-BMMSCs transplantation to treat systemic lupus erythematosus (SLE) like MRL/lpr mice. RESULTS: S-BMMSCs are capable of adhering to ECM-coated dishes and showing mesenchymal stem cell characteristics with distinction from hematopoietic cells as evidenced by co-expression of CD73 or Oct-4 with CD34, forming a single colony cluster on ECM, and failure to differentiate into hematopoietic cell lineage. Moreover, we found that culture-expanded S-BMMSCs exhibited significantly increased immunomodulatory capacities in vitro and an efficacious treatment for SLE-like MRL/lpr mice by rebalancing regulatory T cells (Tregs) and T helper 17 cells (Th17) through high NO production. CONCLUSIONS: These data suggest that it is feasible to improve immunotherapy by identifying a new subset BMMSCs. PMID- 23083977 TI - [Can sugammadex save the situation of a "no intubation, no ventilation" patient?]. PMID- 23083978 TI - [Comment on the article "reconstructive breast surgery: effect of paravertebral block with and without pectoral nerve block"]. PMID- 23083979 TI - [Trichobezoar and anaesthesia]. PMID- 23083981 TI - Reprint of BMCL_19101. AB - The pathogenesis of rheumatoid arthritis is mainly driven by NF-kappaB-mediated production of cytokines, such as TNF-alpha. We report herein that the orally available imidazoline-based NF-kappaB inhibitor, TCH-013, was found to significantly reduce TNF-alpha signaling and attenuate collagen antibody induced arthritis in BALB/c mice. PMID- 23083982 TI - Presentation of celiac disease. AB - The mode of presentation of patients with celiac disease has changed dramatically over the recent decades, with diarrheal or classic presentations becoming less common. This trend is most markedly seen in children, whose main presentations include recurrent abdominal pain, growth issues, and screening groups at risk. Among adults, presentations include diarrhea, anemia, osteoporosis, and recognition at endoscopy performed for gastroesophageal reflux disease, as well as screening. The groups most commonly screened include family members of patients with celiac disease, Down syndrome, and autoimmune diseases. PMID- 23083980 TI - The relationship between clinician turnover and adolescent treatment outcomes: an examination from the client perspective. AB - The turnover of substance use disorder (SUD) treatment staff has been assumed to adversely impact treatment effectiveness, yet only limited research has empirically examined this assumption. Representing an extension of prior organizational-level analyses of the impact of staff turnover on client outcomes, this study examined the impact of SUD clinician turnover on adolescent treatment outcomes using a client perspective. Multilevel regression analysis did reveal that relative to those adolescents who did not experience clinician turnover, adolescents who experienced both direct and indirect clinician turnover reported a significantly higher percentage of days using alcohol or drugs at 6-month follow-up. However, clinician turnover was not found to have significant associations (negative or positive) with the other five treatment outcomes examined (e.g., substance-related problems, involvement in illegal activity). Thus, consistent with our prior findings, the current study provides additional evidence that turnover of SUD clinicians is not necessarily associated with adverse treatment outcomes. PMID- 23083983 TI - The irritable bowel syndrome-celiac disease connection. AB - Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder that has a significant impact on quality of life and health care resources. Celiac disease (CD), a gluten-sensitive enteropathy, can be mistaken for IBS. This article discusses the connection between IBS and CD and the new concept of nonceliac gluten sensitivity (NCGS). NCGS may occur in the presence of a normal or near-normal small bowel biopsy. Some patients with IBS without CD may derive symptomatic benefit from a gluten-free diet. Future research could facilitate a significant impact on the quality of life in this potential subgroup of patients. PMID- 23083986 TI - Histopathology of celiac disease. AB - Small bowel biopsy remains the gold standard for diagnosing celiac disease (CD). Intraepithelial lymphocytosis in the context of villous atrophy is considered a characteristic histologic finding of CD. However, studies have also indicated that the detection of intraepithelial lymphocytosis in the absence of villous atrophy is not specific for CD, having been documented in other small intestinal disorders. This review summarizes key aspects regarding the histopathologic assessment, impact of the site and number of small bowel biopsy samples on diagnosis, old and emerging classifications, and benefit of standardized pathology report in the diagnostic workup of CD. PMID- 23083984 TI - Pathophysiology of celiac disease. AB - Celiac disease results from the interplay of genetic, environmental, and immunologic factors. An understanding of the pathophysiology of celiac disease, in which the trigger (wheat, rye, and barley) is known, will undoubtedly reveal basic mechanisms that underlie other autoimmune diseases (eg, type 1 diabetes) that share many common pathogenic perturbations. This review describes seminal findings in each of the 3 domains of the pathogenesis of celiac disease, namely genetics, environmental triggers, and immune dysregulation, with a focus on newer areas of investigation such as non-HLA genetic variants, the intestinal microbiome, and the role of the innate immune system. PMID- 23083985 TI - Diagnosis of celiac disease. AB - This article reviews issues related to identifying the appropriate patient to test for celiac disease, the performance characteristics of serologic testing, the role of gene testing for human leukocyte antigen DQ2 and DQ8 haplotypes, and issues related to the performance of small intestinal biopsy. The article concludes with a review of special diagnostic considerations in pediatric patients. PMID- 23083987 TI - Management of celiac disease. AB - Celiac disease (CD) is an enteropathy-induced immune response that occurs on exposure to toxic gluten in the diet and is reversible once gluten is withdrawn. A gluten-free diet is the preferred treatment for CD and leads to reversal of villous atrophy. Counseling, nutritional support, and follow-up are vital aspects in CD management. The pickup rate of CD has improved with the availability of serologic tests, and this has led to a reduction in morbidity in treated CD cases. Managing CD can potentially prevent or cure some of the associated conditions, such as neurologic complications, nutritional deficiencies, and osteoporosis. PMID- 23083988 TI - Mortality and malignancy in celiac disease. AB - This article reviews the risk of mortality and malignancy in celiac disease (CD) and examines the evidence of the protective effect of a gluten-free diet (GFD) on mortality and malignancy. Population-based studies have confirmed that patients with diagnosed CD are at increased risk of mortality. However, patients with CD do not seem to be at an increased risk of malignancy, except for an increased risk of lymphoproliferative malignancy and gastrointestinal cancer. The evidence that a GFD reduces the risk of mortality is weak, but there is some evidence suggesting that a GFD may reduce the risk of lymphoproliferative malignancy. PMID- 23083989 TI - Non-celiac gluten sensitivity. AB - Gluten sensitivity has been best recognized and understood in the context of two conditions, celiac disease and wheat allergy. However, some individuals complain of symptoms in response to ingestion of "gluten," without histologic or serologic evidence of celiac disease or wheat allergy. The term non-celiac gluten sensitivity (NCGS) has been suggested for this condition, although a role for gluten proteins as the sole trigger of the associated symptoms remains to be established. This article reviews the available information regarding symptomatology, epidemiology and genetics, serology and histology, and in vitro and in vivo experimental data on the pathophysiology of NCGS. PMID- 23083990 TI - Small bowel imaging in celiac disease. AB - Celiac disease is a common inflammatory disease of the small intestine triggered by gluten in genetically susceptible individuals. Diagnosis is made by serologic testing and upper endoscopy with small bowel biopsy in most individuals. Celiac patients may present with abdominal pain or nonspecific gastrointestinal complaints that result in radiologic imaging before diagnosis of celiac disease. Wireless video capsule endoscopy, device-assisted enteroscopy, and enterography allow careful examination of the entire small bowel and targeted sampling of suspicious lesions. This review focuses on the role of device-assisted enteroscopy and radiologic imaging, in particular enterography, in celiac disease. PMID- 23083991 TI - Video capsule endoscopy in celiac disease. AB - Video capsule endoscopy (VCE) provides a safe, non-invasive way to visualize the small intestine and is helpful in celiac disease patients in select situations. VCE can be performed in patients who are unable or unwilling to undergo conventional endoscopy, those with positive celiac serology with normal duodenal biopsies, and also in those who develop alarm symptoms. VCE has limitations including subjective interpretation. Techniques are being developed to standardize assessment of VCE images in patients with known or suspected celiac disease. Pilot studies using computer-based quantification methods have shown promise in examining the 3-dimensional mucosal structure and motility. PMID- 23083992 TI - Refractory celiac disease. AB - A small subset of patients with celiac disease become refractory to a gluten-free diet, with persistent or recurrent symptoms of malabsorption and intestinal villous atrophy. This condition, defined as refractory celiac disease (RCD), is diagnosed after other small bowel diseases with villous atrophy are excluded. RCD is subdivided into 2 subgroups: type I RCD and type II RCD (RCDII). This latter condition is considered a low-grade intraepithelial lymphoma and has a poor prognosis. This article reviews the clinical and pathologic features of RCD and recent pathogenic findings in RCDII, offering a model to study how inflammation can drive T-cell lymphomagenesis. PMID- 23083993 TI - Celiac disease in the developing world. AB - The prevalence of celiac disease (CD) in many developing countries is similar to that of developed areas, in both low- and high-risk groups. The disorder is underestimated because of lack of disease awareness. CD is strongly associated with HLA-DQ2 in developing countries. Clinical presentation may be characterized by chronic diarrhea, anemia, stunting and increased mortality. Few studies have addressed atypical or silent CD. Diagnosis is initially made by serologic tests and is confirmed by small intestinal biopsies. In developing countries the adherence to the treatment is still difficult because of poor availability of dedicated gluten-free food. PMID- 23083994 TI - Nutrition assessment in celiac disease. AB - The gluten-free diet is currently the only treatment for celiac disease, and patients should be monitored closely by a dietitian who is knowledgeable regarding this diet. Evaluation by a dietitian includes a comprehensive assessment of dietary history, with an emphasis on caloric and micronutrient intake. Patient knowledge of the gluten-free diet is assessed and interpretation of food labels is taught. Identification of micronutrient deficiencies or comorbid gastrointestinal conditions may occur during a comprehensive dietary assessment. In patients with evidence of gluten exposure, a thorough evaluation for cross-contamination is performed. PMID- 23083995 TI - Nondietary therapies for celiac disease. AB - Currently, the only available therapy for celiac disease is strict lifelong adherence to a gluten-free diet (GFD). Although safe and effective, the GFD is not ideal. It is frequently expensive, of limited nutritional value, and not readily available in many countries. Consequently, a need exists for novel, nondietary therapies for celiac disease. Based on the current understanding of celiac disease pathogenesis, several potential targets of therapeutic intervention exist. These novel strategies provide promise of alternative, adjunctive treatment options but also raise important questions regarding safety, efficacy, and monitoring of long-term treatment effect. PMID- 23083996 TI - Celiac Disease. Foreword. PMID- 23083997 TI - Celiac disease. Preface. PMID- 23083998 TI - Hypersensitivity pneumonitis due to isocyanates: lung function, clinical and radiological characteristics. AB - The objective of this present study was to describe the clinical-radiological and lung function characteristics of hypersensitivity pneumonitis due to exposure to isocyanates (HPI). Included for study were all those patients diagnosed with HPI (n = 5) from 1995-2010. In all cases, chest CT and complete lung function studies were done. The diagnosis was made with positive specific bronchial provocation tests (BPT). A predominance of males and pattern variability in the radiological alterations were observed. The BPT was positive due to a decline in FVC or DL(CO) in all cases except in one patient in whom the diagnosis was established with clinical criteria. Positive IgG to isocyanates was confirmed in only one patient. The radiological presentation of HPI may be different from the more common HP in our setting and run their course with less clinical affectation on the BPT. PMID- 23083999 TI - Alterations of maternal plasma HTRA1 level in preeclampsia complicated by IUGR. AB - We evaluated the presence of HtrA1 in maternal plasma of normal pregnancies and of pregnancies complicated by preeclampsia (PE) without and with Intrauterine Growth Restriction (IUGR). We demonstrate that HtrA1 maternal plasma levels show significant different concentrations in first, second and third trimester of gestation and that HtrA1 concentration increases in maternal plasma of gestations complicated by PE with IUGR compared with control maternal plasma matched for gestational age. Based on these data high maternal plasma levels of HtrA1 could be considered as a possible marker of an occurring IUGR in preeclamptic women. PMID- 23084000 TI - Anionic salts and dietary 25-hydroxyvitamin D stimulate calcium availability in steers. AB - The influence of feeds containing varying dietary cation-anion differences (DCADs) with and without supplements of 25-hydroxyvitamin D (25(OH)D) on urine pH and excretion of macro minerals was determined in fistulated crossbred steers (mean live weight 315 +/- 45 kg). A basal forage diet comprising lucerne hay and wheat chaff was used, to which varying quantities of MgCl(2) or K(2)CO(3) were added to achieve four levels of DCAD: -300, 50, 150 or 250 mEq/kg dry matter (DM). Steers were allocated to one of six treatments, one treatment for each diet and a further treatment for both the 50 and 150 mEq/kg DCAD diets, which were supplemented with 25(OH)D at a rate of 3 mg/steer per day. Urine pH from steers offered the diets comprising DCADs of 50, 150 and 250 mEq/kg ranging from 8.3 to 8.8. In treatments not containing 25(OH)D with DCADs of 50 to 250 mEq/kg, there were no significant differences in urine pH or Ca excretion. However, steers offered the diet with a DCAD of -300 mEq/kg DM produced urine with a significantly lower pH (6.5 to 7.5). Daily output of Ca in urine was also significantly higher from steers given this diet. Supplementation with 25(OH)D significantly increased urinary Ca excretion from steers offered diets of DCADs 50 and 150 mEq/kg DM. Estimates of daily urinary Ca excretion, calculated using the ratio of creatinine to Ca in 'spot' urine samples, were less variable than those based on total collection (residual mean square of 0.54 and 0.63, respectively). PMID- 23084001 TI - Rotation advancement flap for isolated congenital alar rim defect: an effortless paradigm? AB - Congenital isolated alar defects are exceptionally rare with 6 cases reported out of all cranio-facial clefts. This entity provokes the ingenuity of the surgeon to manifest a symmetry in form, shape and contour with aesthetically acceptable scarring of the most dominant structure defining the mid face. We present a rotation advancement flap, from the armamentarium of the surgeon, proficient in addressing all the concerns of the patient and treating surgeon for congenital alar cleft. PMID- 23084002 TI - Optimism lowers pain: evidence of the causal status and underlying mechanisms. AB - Previous studies have demonstrated a relation between dispositional optimism and lower pain sensitivity, but the causal status of this link remains unclear. This study sought to test the causal status by experimentally inducing a temporary optimistic state by means of writing about and visualizing a future best possible self. In addition, we explored pain expectations and (situational) pain catastrophizing as possible underlying mechanisms of the link between optimism and pain. Seventy-nine university students participated in a cold pressor task (CPT). Before the CPT, half of them received the optimism manipulation and the other half a control manipulation. Induced optimism was related to lower pain intensity ratings during the CPT compared to the control group, thereby experimentally confirming causality. This effect was not explained by pain related expectations about the task. Situational pain catastrophizing, however, did seem to mediate the relation between optimism and pain. This study is novel in that it confirms the causal status of optimism towards pain. Additionally, the results reveal that positive interventions might provide a useful alternative in reducing pain catastrophizing as an extremely relevant target in pain treatment. PMID- 23084003 TI - Widespread pain in older Germans is associated with posttraumatic stress disorder and lifetime employment status--results of a cross-sectional survey with a representative population sample. AB - Whether self-reported lifetime civilian and war-related potential traumatic events are associated with widespread pain (WP) and if so, whether the association is attributable to posttraumatic stress disorder (PTSD) and depression has not been studied in a representative sample of the general population. In a randomly selected sample of the German general population, persons aged 60-85 years answered validated self-rating instruments: Regional Pain Scale, trauma list of the Composite International Diagnostic Interview, Posttraumatic Diagnostic Scale, and Patient Health Questionnaire 2. Participants with WP were compared with participants with no or local or regional pain (controls). Stepwise hierarchical logistic regression analyses were performed with WP as the dependent variable and demographic data, potential traumatic events, PTSD, and depressive disorder as independent variables. Of 773 respondents, 147 (19.0%) reported WP. Participants with WP reported rape (4.1% vs 1.0%, P=0.01), life-threatening illness (11.6% vs 6.1%, P=0.02), witnessing trauma (19.2% vs 8.4%, P=0.001), and cumulative potential traumatic events (24.5% vs. 16.5%, P=0.004) more frequently than the 626 controls. The prevalence of full PTSD (10.9% vs 2.2%; P<0.0001) and of potential depressive disorder (13.7% vs 6.6%, P=0.02) was higher in participants with WP than in controls. The significant association between some potential traumatic events and WP was completely abrogated after adjusting for demographic variables and PTSD. In the final model, PTSD (odds ratio 3.43, 95% confidence interval 1.88-6.26) and lifetime employment status as a worker (odds ratio 1.55, 95% confidence interval 1.04-2.31) predicted WP. Prospective studies are necessary to understand the temporal association of PTSD and WP. PMID- 23084004 TI - Infrared camera assessment of skin surface temperature--effect of emissivity. AB - Infrared thermoimaging is one of the options for object temperature analysis. Infrared thermoimaging is unique due to the non-contact principle of measurement. So it is often used in medicine and for scientific experimental measurements. The presented work aims to determine whether the measurement results could be influenced by topical treatment of the hand surface by various substances. The authors attempted to determine whether the emissivity can be neglected or not in situations of topical application of substances such as ultrasound gel, ointment, disinfection, etc. The results of experiments showed that the value of surface temperature is more or less distorted by the topically applied substance. Our findings demonstrate the effect of emissivity of applied substances on resulting temperature and showed the necessity to integrate the emissivity into calculation of the final surface temperature. Infrared thermoimaging can be an appropriate method for determining the temperature of organisms, if this is understood as the surface temperature, and the surrounding environment and its temperature is taken into account. PMID- 23084005 TI - Expeditious neutralization assay for human metapneumovirus based on a recombinant virus expressing Renilla luciferase. AB - BACKGROUND: Human metapneumovirus (HMPV) is a common cause of respiratory diseases in persons of all ages. Because of its slow replication and weak cytopathic effect in cultured cells, conventional neutralization assays for HMPV require around one week for completion. OBJECTIVES: The purpose of this study is to establish a rapid neutralization assay based on a recombinant virus expressing Renilla luciferase (Rluc). STUDY DESIGN: A recombinant HMPV expressing both Rluc and green fluorescent protein (GFP) was created by reverse genetics method. Two fold serial dilutions of human 23 sera were made in a 96-well plate and incubated with 50 pfu/well of the recombinant virus at 4 degrees C for 1 h. The mixtures were then transferred to LLC-MK2 cells in a 96-well plate, incubated for 2 h, and replaced with trypsin-free fresh media. After incubation at 32 degrees C for 24 h, the cells were lysed and measured for Rluc activity. The neutralization titer was defined as the reciprocal of the highest serum dilution that resulted in 50% reduction of Rluc activity. RESULTS: The novel assay could be completed within 24 h and eliminated the requirement of trypsin supporting multistep replication in cultured cells, as well as laborious processes including the plaque assay with immunostaining. Neutralization titers correlated well with those determined by a GFP-based assay previously developed. CONCLUSIONS: The neutralization assay based on Rluc activity is the fastest and the most straightforward of all previous assays, and may be available for high throughput screening of neutralizing antibodies. PMID- 23084006 TI - Virtual quantification of influenza A virus load by real-time RT-PCR. AB - BACKGROUND: The pan-influenza A real-time RT-PCR detection assay developed by the Centers for Disease Control and Prevention (CDC) during the 2009 pandemic is widely utilized. A quantitative version of the assay may be useful to monitor influenza A infection and response to treatment. OBJECTIVES: To prove in principle the possibility that a virtual quantification tool (VQT) would allow conversion of CDC real-time RT-PCR cycle threshold (Ct) values in virus RNA copy number. STUDY DESIGN: A plasmid carrying the CDC real-time RT-PCR target region of the influenza A Matrix (M) gene was generated. In a multicenter study, a set of 5 ten-fold dilutions (equivalent to 1*10(2) to 1*10(6)copies/reaction) were prepared and distributed to the 4 participating virology laboratories and then amplified to generate a virtual quantification standard curve. Clinical samples (n=120) were quantified in parallel by interpolation with locally generated standard curves and using the VQT. RESULTS: A total of 40 standard curves were obtained by the participating centers (ten from each center). The intra- and inter-laboratory variability showed a coefficient of variation (CV) <=5%. Influenza A virus quantification in 120 respiratory samples showed a significant correlation between interpolation with locally generated standard curves and the VQT (R(2)=0.9655). Bland Altman analysis showed that the majority (no. 111, 92.5%) of clinical samples had <0.5 log(10) variation. CONCLUSIONS: VQT proofs the concept that qualitative results from real-time RT-PCR assays can be converted into quantitative determination of virus load in clinical samples without running standard curves in parallel. PMID- 23084007 TI - Early pregnancy failure: beware of the pitfalls of modern management. AB - The evolution of the diagnosis and management of women with an early pregnancy loss has been a success story. The mortality from ectopic pregnancy has objectively been decreased in the past few decades. However, modern management has resulted in a new set of issues. Over-interpretation of a single ultrasound, misunderstanding of the utility of serial hCG values, and inappropriate use of methotrexate can result in iatrogenic complications. Modern management has successfully improved the diagnosis of ectopic pregnancy before rupture; it should now also focus on ensuring that an intrauterine pregnancy is not interrupted as a result of diagnosis and treatment. This article reviews some of the pitfalls of the modern management of early pregnancy failure and introduces a series of articles on the subject. PMID- 23084008 TI - Ectopic pregnancy: how the diagnostic and therapeutic management has changed. AB - Nowadays ectopic pregnancy often can be diagnosed before the woman's condition has deteriorated, which has altered the former clinical picture of a life threatening disease into a more benign condition. This review describes the historical developments in the diagnostic and therapeutic management of ectopic pregnancy leading up to current clinical practice. The first attempts to diagnose ectopic pregnancy originate from the beginning of the 20th century. PMID- 23084009 TI - Do you need to definitively diagnose the location of a pregnancy of unknown location? The case for "yes". AB - Pregnancy of unknown location (PUL) is a common diagnostic challenge. The primary diagnostic goal is to ensure that the PUL is nonviable prior to proceeding with any invasive procedures. In nonviable PUL, there are several diagnostic and treatment strategies, which are generally quite safe. However, the management option that provides the most definite diagnosis is uterine curettage. We advocate use of uterine curettage in all cases of nonviable PUL because it limits exposure to a chemotherapeutic agent to only those who need it and it allows for the most accurate information for counseling the patient on prognosis of future pregnancies. PMID- 23084010 TI - Is there a need to definitively diagnose the location of a pregnancy of unknown location? The case for "no". AB - The ability to predict the outcome of a pregnancy of unknown location (PUL) has been extensively studied over the past decade. Between 8%-14% of PULs will develop into ectopic pregnancies (EP), and therefore the need to confirm pregnancy location is not without good reason. Strategies to predict EP in the PUL population have included the use of various maternal serum biomarkers and repeat transvaginal ultrasound (TVS) examinations in order to avoid delaying this diagnosis. These follow-up tests are associated with substantial financial cost to the healthcare system, as well as impacting on maternal anxiety. However, the majority of women with a PUL at follow-up will either have an intra-uterine pregnancy or a spontaneously resolving PUL, and therefore represent low-risk PULs. Most of these low-risk PULs do not need intervention and expectant management has been shown to be safe and not associated with adverse outcomes. Therefore we need consider whether the current strategies to determine pregnancy location are indeed essential for women with a PUL, especially when balancing the additional health care burden with the potential increase in maternal morbidity/mortality associated with delay in diagnosis. This beckons the question, "Do we really need to definitively diagnose pregnancy location in women with a PUL? PMID- 23084011 TI - When is a pregnancy nonviable and what criteria should be used to define miscarriage? AB - In 2011, the first systematic review of the evidence behind the diagnostic criteria for miscarriage was published. It states, "findings were limited by the small number and poor quality of the studies," and concluded that further studies were, "urgently required before setting future standards for the accurate diagnosis of early embryonic demise." This implies that data used to define criteria to diagnose miscarriage are unreliable. The 2011 Irish Health Service executive review into miscarriage misdiagnosis highlighted this issue. In parallel to these publications a multicenter prospective study was published examining cut-off values for mean sac diameter (MSD) and embryo size to define miscarriage. The authors also published evidence on expected findings when ultrasonography is repeated at an interval. This led to guidance on diagnostic criteria for miscarriage in the UK changing. These new criteria state miscarriage be considered only when: an empty gestation sac has an MSD of >= 25 mm (with no obvious yolk sac), or embryonic crown rump length >= 7 mm (the latter without evidence of fetal heart activity). If in doubt, repeating scans at an interval is emphasized. It is axiomatic that decisions about embryonic viability must not be open to doubt. So it is surprising how little evidence exists to support previous guidance. Any clinician working in this area knows of women being wrongly informed that their pregnancy has failed. This cannot be acceptable and guidance in this area must be "failsafe." PMID- 23084012 TI - Diagnostic yield of baseline and follow-up PET/CT studies in ablative therapy for non-small cell lung cancer. AB - Although they have proven effectiveness, radiofrequency and microwave ablation techniques have a high rate of partial responses. Diagnostic studies that anticipate the changes in morphology are essential for earlier detection of residual viable tumor tissue or local recurrences to identify patients who will benefit from a new treatment. Our study has determined the diagnostic yield of PET/CT studies at baseline and follow-up and adequate time between them and the ablation intervention. Seven patients with single tumor lesion with a total of 8 ablations were included. CT and PET/CT studies were performed at baseline and follow-up after ablation. Average times between PET studies at baseline and follow-up and the ablative therapy were 1.8 and 3.4 months, respectively. Mean scores in metabolic activities of the PET at baseline and follow-up were 7.6 and 4.3g/ml of SUVmax, respectively. The Dual Time Point technique helped to identify viable tissue after ablation in 3 cases. Follow-up PET/CT studies have conditioned the various treatment strategies adopted by clinical oncologists. The high yield of the PET/CT study including the Dual Time Point technique may be considered as a study replacement of initial and follow-up Contrast-Enhanced CT before and after treatment with RFA and AMO, this achieving considerable reduction in the exposure to high radiation levels. We propose conducting the first PET/CT follow-up study at 3 months of the RFA and AMO. PMID- 23084013 TI - 18F-FDG semi-quantitative parameters and biological prognostic factors in locally advanced breast cancer. AB - AIM: To analyse the correlation between (18)F-FDG uptake assessed by PET/CT in locally advanced breast tumours and histopathological and immunohistochemical prognostic factors. MATERIAL AND METHODS: Thirty-six women with breast cancer were prospectively evaluated. PET/CT was requested in the initial staging previous to adjuvant chemotherapy (multicentric study). All the patients underwent an (18)F-FDG PET/CT with a dual-time-point acquisition. Both examinations were evaluated qualitatively and semiquantitatively with calculation of SUVmax values in PET-1 (SUV-1) and in PET-2 (SUV-2) and the percentage variation of the standard uptake values (retention index) between PET-1 and PET 2. Clinical and metabolic stages were assessed according to TNM classification. The biological prognostic parameters, such as the steroid receptor status, p53 and c-erbB-2 expression, proliferation rate (Ki-67), and grading were determined from tissue of the primary tumour. Metabolic and biological parameters were correlated. RESULTS: A positive relationship was found between semiquantitative metabolic parameters and biological parameters. SUV-1 and SUV-2 values did not show significant statistical correlation (p<.05) except for the clinical tumour size. About the biological parameters, retention index showed the best results with positive and significant relation (p<.05) with estrogen and progesterone receptor status and Ki-67. Isolated SUV values did not show significant relation to these parameters. CONCLUSION: Retention index showed the best relation with biological parameters compared to isolated SUVmax values. These data suggest that SUV change over time is a prognostic marker. PMID- 23084014 TI - Value of the negative PET-FDG in the middle term follow-up of differentiated thyroid cancer in patients with negative 131 I-Na scan and elevated thyroglobulin serum levels. AB - OBJECTIVE: This study has aimed to analyze the evolution of patients diagnosed with differentiated thyroid carcinoma (DTC) with a negative (131)I-Na whole body scan (WBS), high levels of serum thyroglobulin (Tg) and negative (18F)fluorodeoxyglucose positron emission tomography (PET-FDG) study. MATERIAL AND METHODS: Twenty-three patients diagnosed and treated for DTC were studied retrospectively. Patients were aged between 23 and 83 and had shown, between January 2001 and December 2002, negative WBS, Tg values in a range of suspected recurrence or metastasis (Tg>2 ng / mL with thyroid hormone withdrawal) and a negative PET-FDG study. The patients were monitored clinically, radiologically and analytically for a minimum period of 4 years. After this, a new evaluation was made of their state of disease with a control WBS, also observing the evolution of Tg. All WBS were performed with a 185 MBq diagnostic dose of (131)I Na. RESULTS: In 18/23 patients, Tg decreased and in 5 it increased. Four patients (17%) were free of active disease (negative WBS Tg<2 ng / mL). A total of 16 patients (70%) were free of disease according to the WBS but had elevated Tg. Three patients (13%) had disease and high levels of Tg, two of them with positive WBS and the third with (99m)Tc-MIBI scan and CT positive. CONCLUSIONS: Most patients with a negative WBS, high Tg serum levels and negative FDG PET had good evolution, with descending Tg levels, normal levels even being reached in a significant percentage of them. PMID- 23084015 TI - Monitoring of renal function using 99mTc-DMSA and 99mTc-DTPA scintigraphy in patients with spinal cord injury. AB - AIM: The aim of this study was to assess the degree of alterations of renal function by using 99m-technetium dimercaptosuccinic acid ((99m)Tc-DMSA) and 99m technetium diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) scintigraphy in spinal cord injury (SCI) patients. MATERIAL AND METHODS: Twenty-two consecutive SCI (15 paraplegic and 7 tetraplegic) patients (mean age: 49.1+/-13.4 years) who had no urinary symptoms participated in this prospective study. The mean duration of injury was 45.6+/-48.8 months before. Sixteen patients had at least one urinary tract infection history. Renal cortical scintigraphy with (99m)Tc-DMSA, radionuclide renography with (99m)Tc-DTPA and renal ultrasound were performed within 2-week period. RESULTS: Four (18%) patients had serious pathology on their kidneys such as unilateral or bilateral parenchymal scarring and increased background uptake in their renal cortical scintigraphy with (99m)Tc-DMSA. Two of them had grade 3-4 pelvicaliceal ectasia on ultrasound. Additionally, 2 of 18 remaining patients had grade 2 pelvicaliceal ectasia on ultrasound. Sixteen (73%) patients had markedly delayed or delayed and decreased functions of one or both of kidneys on radionuclide renography. However, only four patients had grade 2-4 pelvicaliceal ectasia and none of them had a finding of loosening of renal parenchyma. CONCLUSION: Combined use of renal cortical scintigraphy and radionuclide renography appears to be contributive to renal ultrasound in the long-term follow-up of patients with SCI. Patients with abnormal findings should be closely followed, and early therapeutic interventions may enable lower morbidity and mortality rates in these patients. PMID- 23084016 TI - Lung metastases in patients with differentiated thyroid carcinoma and evaluation of response to radioiodine therapy. AB - INTRODUCTION: The most common site of metastases in differentiated thyroid carcinomas is the lungs. In our study, we aimed to determine the ratios of lung metastases in patients with differentiated thyroid carcinoma and response to radioiodine therapy. MATERIAL AND METHODS: A total of 542 patients with differentiated thyroid carcinoma who were admitted to our clinic were included in the study. High doses of (131)I were administered to the patients with lung metastases. Response to therapy were evaluated with (131)I scans and stimulated serum Tg levels were examined at least 6 months after therapy. RESULTS: Lung metastases were detected in 17 (3.1%) of 542 patients with differentiated thyroid carcinoma. Of these patients to whom high doses of (131)I therapy were administered, complete response to therapy was obtained in 5 (29.4%), partial response was obtained in 3 (17.6%) and no response could be obtained in 9 (53%) patients. CONCLUSION: Although lung metastases from differentiated thyroid carcinomas are rare, those are more common in advanced ages and in males. High doses of (131)I therapy may be partially beneficial in these patients. Thus repetition of therapy is frequently required. PMID- 23084017 TI - FDG PET/CT in monitoring treatment of retroperitoneal fibrosis. AB - Retroperitoneal fibrosis is an uncommon disease characterized by inflammatory fibrosis typically surrounding abdominal aorta and iliac arteries. The glucose analogue F18-fluorodeoxyglucose can be used to image inflammatory cell activity non-invasively by PET. In this report we investigated the usefulness of the FDG PET/CT in the disease activity and therapy response evaluation of retroperitoneal fibrosis. PMID- 23084018 TI - Findings in the Gerstmann-Straussler-Scheinker syndrome in an 18F-FDG PET-CT study. PMID- 23084019 TI - Simultaneous visualization of FDG avid and non-avid metastases in renal cell cancer. PMID- 23084020 TI - FDG-PET/MRI fusion demonstrating cricoarytenoid muscle hypermetabolism due to contralateral true vocal cord paralysis. PMID- 23084021 TI - Effects of chronic exposure to the aqueous fraction of produced water on growth, detoxification and immune factors of Atlantic cod. AB - The biggest discharge from the offshore oil industry is produced water (PW). As new technologies emerge to remove oil from such discharges, the question remains as to the effect that the water soluble fraction of contaminants present in PW may have on the biota surrounding the areas of discharge. We investigated the effects of 8 weeks of intermittent exposure to environmentally relevant concentrations (100 or 1000mg/L) of the aqueous fraction of PW (AFPW) on growth parameters, food consumption, respiratory burst activity of head kidney leukocytes (RB), activity of antioxidant enzymes and mRNA expression of immune- and detoxification-related genes of Atlantic cod. No significant effects of AFPW were seen on growth parameters, food consumption and/or RB. Furthermore, the activity of antioxidant enzymes and the expression of CYP1A, GST and UGT were not impacted by AFPW treatment. The mRNA expression of some immune related genes was affected in a similar manner as what has been described in Atlantic cod exposed to full PW suggesting that short chain soluble compounds present in PW might be responsible for its immunomodulatory effect. Traditionally used biomarkers of toxicant exposure such as phase I (CYP1A) and phase II (GST, UGT) genes do not seem to be reliable indicators of exposure to AFPW. This study confirms the fact that some immune related genes are affected by soluble components of PW and that further investigation on potential increased disease susceptibility is warranted. PMID- 23084022 TI - Typhoid fever vs. malaria in a febrile returning traveler: typhomalaria revisited -an Oslerian perspective. AB - Diagnostic efforts are usually centered on malaria in febrile travelers returning from the tropics. However, by focusing on malaria other important diagnostic considerations are easily overlooked. Patients returning from malarial areas are also exposed to other tropical diseases which have features in common with malaria, e.g., typhoid fever, dengue fever, chikungunya fever. However, there are a few key findings that clinically differentiate these infections from malaria. We present a case of a traveler with fever returning from India without localizing signs with persistent monocytosis initially thought to have malaria. PMID- 23084023 TI - Trisomy correction in Down syndrome induced pluripotent stem cells. AB - Human trisomies can alter cellular phenotypes and produce congenital abnormalities such as Down syndrome (DS). Here we have generated induced pluripotent stem cells (iPSCs) from DS fibroblasts and introduced a TKNEO transgene into one copy of chromosome 21 by gene targeting. When selecting against TKNEO, spontaneous chromosome loss was the most common cause for survival, with a frequency of ~10(-4), while point mutations, epigenetic silencing, and TKNEO deletions occurred at lower frequencies in this unbiased comparison of inactivating mutations. Mitotic recombination events resulting in extended loss of heterozygosity were not observed in DS iPSCs. The derived, disomic cells proliferated faster and produced more endothelia in vivo than their otherwise isogenic trisomic counterparts, but in vitro hematopoietic differentiation was not consistently altered. Our study describes a targeted removal of a human trisomy, which could prove useful in both clinical and research applications. PMID- 23084024 TI - Continuous passive disinfection of catheter hubs prevents contamination and bloodstream infection. AB - BACKGROUND: Catheter hub decontamination requires a thorough scrub and compliance varies. This study evaluates the effectiveness of a disinfection cap with 70% alcohol in preventing contamination/infection. METHODS: A 3-phased, multifacility, quasi-experimental study of adult patients with central lines divided into P1 (baseline), when the standard scrub was used; P2, when the cap was used on all central lines; and P3, when standard disinfection was reinstituted. House-wide central-line associated bloodstream infection (CLABSI) rates are reported with catheter-associated urinary tract infections (CAUTI) as a control measure. Adults with peripherally inserted central catheters inserted during hospitalization having 5+ consecutive line-days gave consent and were enrolled, and 1.5 mL of blood was withdrawn from each lumen not in use and quantitatively cultured. RESULTS: Contamination was 12.7% (32/252) during P1; 5.5% (20/364) in P2 (P = .002), and 12.0% (22/183; P = 0.88 vs P1 and P = .01 vs P2) in P3 (P = .001 vs P2). The median colony-forming units per milliliter was 4 for P1, 1 for P2 (P = .009), and 2 for P3 (P = .05 vs P2). CLABSI rates declined from 1.43 per 1,000 line-days (16/11,154) to 0.69 (13/18,972) in P2 (P = .04) and increased to 1.31 (7/5,354) in P3. CAUTI rates remained stable between P1 and P2 (1.42 and 1.41, respectively, P = .90) but declined in P3 (1.04, P = .03 vs P1 and P2). CONCLUSION: Disinfecting caps reduce line contamination, organism density, and CLABSIs. PMID- 23084025 TI - The mesenchymal-to-epithelial transition in somatic cell reprogramming. AB - The epithelial-to-mesenchymal transition (EMT) is a process that confers migratory characteristics to epithelial cells. It is a major force driving embryonic development, tissue fibrosis and malignant progression, and can also create cells with properties of stem cells. The mesenchymal-to-epithelial transition (MET) has the opposite course and frequently coexists with the EMT, but the underlying mechanisms are less well studied. The recent discovery that the MET is required for transforming somatic cells into pluripotent stem cells suggests that the intersection between EMT and MET is a fundamental crossroad for cell fate decisions. Further understanding of the molecular events controlling both situations has relevant implications for regenerative medicine and disease. PMID- 23084026 TI - Vitamin B12 status, cognitive decline and dementia: a systematic review of prospective cohort studies. AB - Poor vitamin B12 status may lead to the development of cognitive decline and dementia but there is a large variation in the quality, design of and results reported from these investigations. We have undertaken a systematic review of the evidence for the association between vitamin B12 status and cognitive decline in older adults. A database search of the literature to 2011 was undertaken, using keywords related to vitamin B12 and cognition. All prospective cohort studies assessing the association of serum vitamin B12 or biomarkers were included. Quality assessment and extraction of the data were undertaken by two researchers. The quality assessment tool assigns a positive, neutral or negative rating. Of 3772 published articles, thirty-five cohort studies (n 14 325 subjects) were identified and evaluated. No association between serum vitamin B12 concentrations and cognitive decline or dementia was found. However, four studies that used newer biomarkers of vitamin B12 status (methylmalonic acid and holotranscobalamin (holoTC)) showed associations between poor vitamin B12 status and the increased risk of cognitive decline or dementia diagnosis. In general, the studies were of reasonable quality (twenty-one positive, ten neutral and four negative quality) but of short duration and inadequate subject numbers to determine whether an effect exists. Future studies should be of adequate duration (at least 6 years), recruit subjects from the seventh decade, choose markers of vitamin B12 status with adequate specificity such as holoTC and/or methylmalonic acid and employ standardised neurocognitive assessment tools and not screening tests in order to ascertain any relationship between vitamin B12 status and cognitive decline. PMID- 23084027 TI - A multiplex and straightforward aqueous phase immunoassay protocol through the combination of SERS-fluorescence dual mode nanoprobes and magnetic nanobeads. AB - A novel aqueous phase immunoassay protocol was demonstrated, using surface enhanced Raman scattering (SERS)-fluorescence dual mode nanoprobes combined with magnetic nanobeads (MBs). Here, the dual mode nanoprobes provide an excellent multiplexing ability while the MBs greatly simplify the immunoassay process. Basically, the nanoprobes were acquired by assembling the Raman reporter tagged Au@Ag core-shell nanorods and quantum dots onto the silica nanospheres. When the specific antigens are presented in the immunoassay system containing antibody modified nanoprobes and MBs, the nanoprobes are captured by the MBs and further precipitated by a magnet. Consequently, both SERS and fluorescence signals are detected in the precipitates. Sandwich type immunoassay was conducted to examine the practicability of this protocol. Experimental results confirmed that the presented immunoassay protocol can accomplish highly specific and sensitive recognition of the target antigens. The detection limit was found out to be 0.1 pg/mL. We anticipate that high throughput bioanalysis can be fulfilled using the proposed immunoassay protocol, as the dual mode nanoprobes provide a great multiplexing capability while the MBs facilitate the convenient aqueous phase detection of the analytes. PMID- 23084028 TI - Ethanol consumption impairs the hemodynamic response to hemorrhagic shock in rats. AB - Alcohol intoxication can exacerbate hemodynamic instability following hemorrhagic shock. Impairment of hormonal, neurohumoral, and immune responses can contribute to such instability; however, the relationship between blood alcohol levels and the progression of hemorrhagic shock accompanied with these responses has not been clearly demonstrated. Herein, we examined this relationship in rats treated with various dose of alcohol. After oral administration of alcohol and then hemorrhage, the recovery of mean blood pressure (MBP); increase in plasma level of norepinephrine, epinephrine, and vasopressin; and survival interval decreased in a dose-dependent manner as the blood alcohol level increased. There were no significant differences in the production of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta among the groups. The present results demonstrated alcohol aggravates hemorrhagic shock in a dose dependent manner not by alerting the immune response, but by suppressing hormonal and neurohumoral responses, thereby inhibiting hemodynamic autoregulation and shortening the survival interval. PMID- 23084029 TI - Effect of dissolved oxygen in alcoholic beverages and drinking water on alcohol elimination in humans. AB - Oxygen plays an important role in the metabolism of alcohol. An increased dissolved oxygen level in alcoholic beverages reportedly accelerates the elimination of alcohol. Therefore, we evaluated the effect of dissolved oxygen in alcohol and the supportive effect of oxygenated water on alcohol pharmacokinetics after the excessive consumption of alcohol, i.e., 540 ml of 19.5% alcohol (v/v). Fifteen healthy males were included in this randomized, 3 * 3 crossover study. Three combinations were tested: X, normal alcoholic beverage and normal water; Y, oxygenated alcoholic beverage and normal water; Z, oxygenated alcoholic beverage and oxygenated water. Blood alcohol concentrations (BACs) were determined by conversion of breath alcohol concentrations. Four pharmacokinetic parameters (C(max), T(max), K(el), and AUCall) were obtained using non-compartmental analysis and the times to reach 0.05% and 0.03% BAC (T(0.05%) and T(0.03%)) were compared using one-way analysis of variance (ANOVA) and Duncan's post hoc test. With combination Z, the BAC decreased to 0.05% significantly faster (p < 0.05) than with combination X. Analyzing the pharmacokinetic parameters, the mean K(el) was significantly higher for combination Z than for combinations X and Y (p < 0.05), whereas the mean values of C(max), T(max) and AUCall did not differ significantly among the combinations. Dissolved oxygen in drinks accelerates the decrease in BAC after consuming a large amount of alcohol. However, the oxygen dissolved in the alcoholic beverage alone did not have a sufficient effect in this case. We postulate that highly oxygenated water augments the effect of oxygen in the alcoholic beverage in alcohol elimination. Therefore, it is necessary to investigate the supportive effect of ingesting additional oxygenated water after heavy drinking of normal alcoholic beverages. PMID- 23084030 TI - Strongyloidiasis in a high risk community of Dhaka, Bangladesh. AB - Residents of a slum community of Dhaka city, Bangladesh were tested by serological and faecal examination for evidence of Strongyloides stercoralis infection. In stool specimens from a total of 147 participants Strongyloides larvae were found in 34 (23.1%) by Harada-Mori culture, 15 (10.2%) by agar plate culture (APC) and one (0.7%) by microscopy. Strongyloides IgG, IgG1 and IgG4 antibodies were found in 90 (61.2%), 46 (31.3%) and 53 (36.1%) of participants, respectively. A positive correlation was observed between total IgG levels and the presence of isotypes IgG1 and IgG4 (p<0.001). Six sera (4.0%) reacted to the recombinant filaria antigen Bm 14, three of which were Strongyloides IgG positive. This indicates either there is cross reactivity or some participants are co-infected with lymphatic filariasis. No correlations were found between positive serology and Strongyloides infection in stool, socio- demographic factors or domestic hygienic practices. However, positive stool cultures showed significant associations with irregular nail trimming, walking bare-foot and irregular hand washing after defecation (p<0.05). Other enteric parasites were detected in stools of some participants but their presence showed no correlation with S. stercoralis infection or socio demographic factors. This study confirms that squatters in this slum community in Dhaka have a high prevalence of S. stercoralis infection identified both by serological and coprological methods. PMID- 23084031 TI - The sorting receptor Sortilin exhibits a dual function in exocytic trafficking of interferon-gamma and granzyme A in T cells. AB - Immunological control of infections or tumors depends on the release of effector cytokines and polarized secretion of cytotoxic granules from T cells and natural killer cells. Here we show that the sorting receptor Sortilin controlled both processes. In murine Sortilin-deficient cytotoxic T lymphocytes, regulated secretion of granzyme A and cytotoxic killing was enhanced and correlated with increased vesicle-associated membrane protein 7 availability. In contrast, loss of Sortilin reduced the release of interferon-gamma upon infections and in autoimmune colitis. Exit of interferon-gamma from the Golgi apparatus required the presence of Sortilin. Furthermore, we tracked the transport route of interferon-gamma beyond this Sortilin-dependent Golgi to early endosome step. In wild-type T cells, trafficking of interferon-gamma from the endosomal sorting platform to the plasma membrane proceeded independently of recycling endosomes, and interferon-gamma remained excluded from late endosomes. Our results suggest that Sortilin modulates systemic immune responses through exocytic sorting of immunological effector molecules. PMID- 23084032 TI - Severity of alcohol dependence in the Swedish adult population: association with consumption and social factors. AB - The severity of alcohol dependence can be estimated by the number of DSM-IV criteria that are fulfilled for this disorder. This paper describes the proportions in a general population sample that meet different numbers of diagnostic criteria for alcohol dependence and their association with drinking and social background factors. Data came from a random, cross-sectional, self report survey of adults from 12 Swedish communities. 28,800 persons, age 19-70, were surveyed through postal questionnaires. 14,706 questionnaires (51%) could be used for analysis. Alcohol dependence was assessed by questions relating to the seven DSM-IV criteria for alcohol dependence. Alcohol consumption and social background factors were examined in relation to alcohol dependence. A total of 73.8% of the general population fulfilled no criteria for alcohol dependence; 4.0% reported 3 or more criteria and qualified for the diagnosis of alcohol dependence. There were trends toward an increasing number of dependence criteria with increasing consumption levels and negative social background factors. The majority of people with alcohol dependence however did not drink at the highest consumption levels, did not live alone, and were not unemployed. Given the current definition of alcohol dependence the majority of people have few criteria fulfilled (3 or 4) and few social problems. This has important implications for treatment as dependence with low severity may require less treatment and less specialist involvement. PMID- 23084033 TI - The Hungarian Twin Registry. AB - The first Hungarian Twin Registry was established in Budapest in 1970 through the mandatory reporting of multiple-births. In the 1980s a second, volunteer adult registry was also founded. Unfortunately, both registries ceased to exist in the 1990s. Efforts started in 2006 to revive a Hungarian twin registry. The team spearheading this effort reports here on this progress. Currently, the voluntary Hungarian Twin Registry consists of 310 adult twin pairs and multiplets. Current research focuses on cardiovascular and respiratory health and yielded multiple awards and publications. Efforts are on the way to expand into social, psychological, and obesity studies. PMID- 23084034 TI - Exercise improves cardiac autonomic function in obesity and diabetes. AB - Physical activity is a key element in the prevention and management of obesity and diabetes. Regular physical activity efficiently supports diet-induced weight loss, improves glycemic control, and can prevent or delay type 2 diabetes diagnosis. Furthermore, physical activity positively affects lipid profile, blood pressure, reduces the rate of cardiovascular events and associated mortality, and restores the quality of life in type 2 diabetes. However, recent studies have documented that a high percentage of the cardiovascular benefits of exercise cannot be attributed solely to enhanced cardiovascular risk factor modulation. Obesity in concert with diabetes is characterized by sympathetic overactivity and the progressive loss of cardiac parasympathetic influx. These are manifested via different pathogenetic mechanisms, including hyperinsulinemia, visceral obesity, subclinical inflammation and increased thrombosis. Cardiac autonomic neuropathy is an underestimated risk factor for the increased cardiovascular morbidity and mortality associated with obesity and diabetes. The same is true for the role of physical exercise in the restoration of the heart cardioprotective autonomic modulation in these individuals. This review addresses the interplay of cardiac autonomic function in obesity and diabetes, and focuses on the importance of exercise in improving cardiac autonomic dysfunction. PMID- 23084035 TI - Reconstruction of the posterior bundle of the medial collateral ligament: a solution for posteromedial olecranon deficiency--a case report. PMID- 23084036 TI - Diagnostic accuracy of tests and measures for shoulder labral dysfunction. PMID- 23084037 TI - Aberrant origin of the long head of the biceps. PMID- 23084038 TI - Acaricidal properties of Ricinus communis leaf extracts against organophosphate and pyrethroids resistant Rhipicephalus (Boophilus) microplus. AB - Indian cattle ticks have developed resistance to commonly used acaricides and an attempt has been made to formulate an ecofriendly herbal preparation for the control of acaricide resistant ticks. A 95% ethanolic extract of Ricinus communis was used to test the efficacy against reference acaricide resistant lines by in vitro assay. In in vitro assay, the extract significantly affects the mortality rate of ticks in dose-dependent manner ranging from 35.0 +/- 5.0 to 95.0 +/- 5.0% with an additional effect on reproductive physiology of ticks by inhibiting 36.4 63.1% of oviposition. The leaf extract was found effective in killing 48.0, 56.7 and 60.0% diazinon, deltamethrin and multi-acaricide resistant ticks, respectively. However, the cidal and oviposition limiting properties of the extract were separated when the extract was fractionated with hexane, chloroform, n-butanol and water. The HPTLC finger printing profile of R. communis leaf extract under lambda(max.) - 254 showed presence of quercetin, gallic acid, flavone and kaempferol which seemed to have synergistic acaricidal action. In vivo experiment resulted in 59.9% efficacy on Ist challenge, however, following 2nd challenge the efficacy was reduced to 48.5%. The results indicated that the 95% ethanolic leaf extract of R. communis can be used effectively in integrated format for the control of acaricide resistant ticks. PMID- 23084039 TI - Screening acute cytotoxicity biomarkers using a microalga as test organism. AB - The present study checked the suitability of the integration of flow cytometry (FCM) as technique and a freshwater microalga (Chlamydomonas moewusii) as cell system model for ecotoxicological studies, looking for sensitive biomarkers of acute cytotoxicity of potential contaminants in aquatic systems. The detection of the potential acute toxicity of a pollutant is of interest because pulse discharges of contaminants to natural waters could lead to high concentrations of these substances that are only present for short periods of time but can affect aquatic organisms such as microalgae. Physiological alterations in C. moewusii cells were analysed after 1h of exposure to different concentrations of the herbicide paraquat. Cell viability was not affected, but the acute toxicity of paraquat was evident at other levels of cell physiology. Herbicide-treated cells showed lower autofluorescence and higher size and internal complexity, lower esterase activity and lower mitochondrial membrane potential. Paraquat induced the depolarisation of the plasma membrane and the increase of intracellular free calcium level and cytosolic pH in a concentration-dependent percentage of cells. All these effects can be related to the oxidative stress induced by the herbicide, as revealed the significantly increased intracellular levels of reactive oxygen species in cultures exposed to paraquat concentrations which induced the physiological alterations mentioned above. Excluding cell viability and mitochondrial membrane potential, these cytotoxicity endpoints could be considered sensitive biomarkers for the short-term exposure to pollutants such as herbicides. PMID- 23084040 TI - Influence of nine antibiotics on key secondary metabolites and physiological characteristics in Triticum aestivum: leaf volatiles as a promising new tool to assess toxicity. AB - Extensive worldwide use of antibiotics has resulted in significant diffuse pollution of antibiotics in environment, but understanding the effects of many important antibiotics on plant physiological activity is still limited, especially at realistic environmental concentrations of antibiotics. To gain insight into influences of different antibiotics on plant performance and identify the most promising traits for fast assessment of toxicity, we studied impacts of nine antibiotics (amoxicillin, ampicillin, penicillin G, ceftazidime, ceftriaxone, tetracycline, doxycycline, ciprofloxacin and erythromycin) on foliage photosynthesis, photosynthetic pigment content and emissions of secondary volatile metabolites in wheat (Triticum aestivum L. cv. "Lovrin"). The antibiotics were applied at concentrations of 0.5 mg L-1 or 1.5 mg L-1 either by watering for one week (0.5 L solution) or for two weeks (1 L solution) with given solution. Net assimilation rate was inhibited most strongly by ciprofloxacin and cephalosporins, but the inhibition was mainly due to reductions in stomatal conductance. Photosynthetic electron transport rate was affected by penicillins, cephalosporins and tetracyclines. Contents of photosynthetic pigments, chlorophylls and carotenoids, were most strongly reduced in treatments with tetracyclines, ciprofloxacin and erythromycin. The magnitude of plant photosynthetic and pigment responses generally increased with increasing the antibiotics' dose, but the overall effects were moderate, 10-20 percent in most cases. Emissions of the lipoxygenase pathway products (LOX, green leaf volatiles) were most sensitive indicators of antibiotic treatments. LOX emissions were increased by five to six fold in response to antibiotic treatments and the emissions were quantitatively associated with the treatment dose. Monoterpene emissions were also strongly enhanced by antibiotic treatments, but the dose dependence was weaker. These data collectively suggest that analysis of leaf volatiles can provide a novel sensitive assay to gauge the toxicity of different antibiotics. PMID- 23084041 TI - Asymptomatic insulinoma: a case report and autopsy series. AB - AIMS: We investigated the prevalence and characterization of asymptomatic pancreatic tumors in response to our experience of asymptomatic insulinoma. METHODS: A patient with a moderately low glucose level and pancreatic incidentaloma detected by CT was examined. Pancreas specimens from 423 autopsy cases were also pathologically examined systematically by hematoxylin-eosin staining. RESULTS: The examined patient showed no profile characteristic of insulinoma by fasting or loading tests, however, ASVS led to diagnosis of insulin producing tumor. The tumor was resected with the pancreatic body and tail and revealed to be 10 mm in diameter, with 98.5% of the cells positive for insulin. Pathological evaluation confirmed a well-differentiated endocrine pancreatic tumor, which was suggestive of an incidentally detected asymptomatic insulinoma. Microscopic evaluations of pancreatic specimens from 423 autopsy cases revealed pancreatic monotonous lesions in 6 cases (1.42%). In 4 autopsy specimens large enough for immuno-histochemical evaluation, the lesions were positive for glucagon but negative for insulin. CONCLUSIONS: As concerns the present study, retrospective immunohistochemical investigation in autopsy cases revealed the presence of asymptomatic glucagonoma but no asymptomatic insulinoma. Advances in diagnostic imaging, however, might raise the probability of detecting early asymptomatic stages of insulinoma incidentally. ASVS appears to be sensitive even for asymptomatic incidental insulinomas. PMID- 23084042 TI - Acute blood glucose fluctuations can decrease blood glutathione and adiponectin levels in patients with type 2 diabetes. AB - INTRODUCTION: Glutathione appears to have apparent antioxidant activity to counter regulate hyperglycemia induced oxidative stress. Adiponectin also plays a role in the suppression of the metabolic derangements in type 2 diabetes mellitus (DM). The aim of this study was to determine whether blood glucose fluctuations can alter blood levels of glutathione and adiponectin. METHODS: We enrolled 34 patients with type 2 DM. As a measure of short-term glycemic variability, the mean amplitude of glycemic excursions (MAGE) was computed from a continuous glucose monitor system (CGMS), and data were recorded over 72 h. For long-term glycemic variability, we calculated the standard deviation (SD) of HbA1c over a 2 year period. Glutathione and adiponectin levels were measured after completing the 72-h CGMS data collection. RESULTS: The blood levels of glutathione were significantly and negatively correlated with MAGE (r = -0.543; P < 0.001), but not with HbA1c and SD of HbA1c. Adiponectin levels were also significantly and negatively correlated with MAGE and SD of HbA1c (r = -0.64 and r = -0.55, respectively; P < 0.001). Using generalized estimating equations, multivariate regression analysis revealed that MAGE is an independent predictor of serum levels of adiponectin (P = 0.002) and glutathione (P = 0.004). CONCLUSIONS: We found strong associations between acute blood glucose variability, glutathione, and adiponectin in type 2 diabetic patients treated with oral hypoglycemic agent therapy. PMID- 23084043 TI - In vivo evaluation of [123I]mZIENT as a SPECT radioligand for the serotonin transporter. AB - INTRODUCTION: In vivo imaging of the serotonin transporter continues to be a valuable tool in drug development and in monitoring diseases that alter serotonergic function. The purposes of this study were to: 1) evaluate the test/retest reproducibility of [123I] 2beta-Carbomethoxy-3beta-(3'-((Z)-2 iodoethenyl)phenyl)nortropane ([123I]mZIENT); and 2) to assess displacement of [123I]mZIENT following administration of SERT specific drugs. METHODS: Six female baboons (Papio anubis) were scanned following i.v. administration of [123I]mZIENT. The regional binding potential (BP(nd)) was determined using a simplified reference tissue model, with the cerebellum used as a reference region. The test/retest reproducibility of BP(nd) was determined following repeated injection of [123I]mZIENT on a different day. To assess the displacement of [123I]mZIENT from SERT, citalopram (0.01-5mg/kg) or sertraline (0.01-0.5mg/kg) was given as iv bolus at ~4h following administration of [123I]mZIENT. RESULTS: The test/retest variability of BP(nd) was less than 10% for all SERT-rich brain regions. Estimates of ED50 for displacement of [123I]mZIENT in SERT-rich regions were consistent with previous reports for the [11C] analog of [123I]mZIENT. Both citalopram and sertraline displaced [123I]mZIENT from SERT in a dose-dependent manner, with maximal observed displacements of greater than 80% in the diencephalon and greater than 75% in brainstem for both citalopram and sertraline. CONCLUSIONS: [123I] mZIENT demonstrates good test-retest reproducibility; and initial displacement studies suggest that this compound is highly selective for SERT. Overall, this radioligand has favorable characteristics for use in drug development studies and/or longitudinal studies interrogating SERT. PMID- 23084044 TI - Is [(99m)Tc]glucarate uptake mediated by fructose transporter GLUT-5? AB - PURPOSE: There is growing interest in the ability of [(99m)Tc]Glucarate ([(99m)Tc]GLA) to accumulate in viable tumor cells. Recent vivo studies suggest that [(99m)Tc]Glucarate could be helpful for tumor detection. Fructose transport is thought to be implicated. It is clearly established that facilitated fructose transport in tumor cells is related to the GLUT-5 transporter. This study therefore investigated whether [(99m)Tc]GLA uptake is mediated by GLUT-5 transporter. METHODS: Different tumor cell lines were used. Modulation of GLUT-5 expression was assessed with and without antisense oligonucleotides directed against GLUT-5. GLUT-5 expression was assessed by indirect cell ELISA. To correlate GLUT-5 expression with tracer accumulation, [(99m)Tc]GLA uptake was determined after antisense treatment. A competition with fructose was also monitored. RESULTS: Inhibition of GLUT-5 expression by antisense oligonucleotides directed against GLUT-5 was effective after 24 h. An optimal of 10MUM antisense oligonucleotides directed against GLUT-5 produced a 30%-40% decrease in protein expression. Modulation of [(99m)Tc]GLA uptake was monitored either by use of specific antisense oligonucleotides or by competition with fructose. Both of them produced a significant decrease of [(99m)Tc]GLA accumulation in all tested cell lines. CONCLUSION: Our results clearly demonstrate that [(99m)Tc]GLA uptake is related to GLUT-5 transporter expression and transport. In tumor imaging, [(99m)Tc]GLA may be a useful tool for non-invasive detection of malignant tumors expressing high levels of GLUT-5 transporter as, for example, breast cancers. PMID- 23084045 TI - The weak interfaces within tough natural composites: experiments on three types of nacre. AB - Mineralization is a typical strategy used in natural materials to achieve high stiffness and hardness for structural functions such as skeletal support, protection or predation. High mineral content generally leads to brittleness, yet natural materials such as bone, mollusk shells or glass sponge achieve relatively high toughness considering the weakness of their constituents through intricate microstructures. In particular, nanometers thick organic interfaces organized in micro-architectures play a key role in providing toughness by various processes including crack deflection, crack bridging or energy dissipation. While these interfaces are critical in these materials, their composition, structure and mechanics is often poorly understood. In this work we focus on nacre, one of the most impressive hard biological materials in terms of toughness. We performed interfacial fracture tests on chevron notched nacre samples from three different species: red abalone, top shell and pearl oyster. We found that the intrinsic toughness of the interfaces is indeed found to be extremely low, in the order of the toughness of the mineral inclusions themselves. Such low toughness is required for the cracks to follow the interfaces, and to deflect and circumvent the mineral tablets. This result highlights the efficacy of toughening mechanisms in natural materials, turning low-toughness inclusions and interfaces into high performance composites. We found that top shell nacre displayed the highest interfacial toughness, because of higher surface roughness and a more resilient organic material, and also through extrinsic toughening mechanisms including crack deflection, crack bridging and process zone. In the context of biomimetics, the main implication of this finding is that the interface in nacre-like composite does not need to be tough; the extensibility or ductility of the interfaces may be more important than their strength and toughness to produce toughness at the macroscale. PMID- 23084046 TI - Sub-lethal effects of titanium dioxide nanoparticles on the physiology and reproduction of zebrafish. AB - There are limited data on the sub-lethal physiological effects of titanium dioxide nanoparticles (TiO(2) NPs) in adult fishes, and the consequences of TiO(2) NP exposure on reproductive success are also unclear. This study aimed to examine the sub-lethal effects of a 14-d aqueous TiO(2) (TiO(2) NP, 0.1 or 1.0 mg l(-1); TiO(2) bulk, 1.0 mg l(-1)) exposure on the physiology and reproductive health of zebrafish. After the 14-d exposure, fish were examined for haematology, whole body electrolyte and trace metal profiles, biochemistry, and histopathology. Then, during a 21-d post exposure recovery period, effects of the TiO(2) exposure on reproductive success were evaluated. Whole body Ti concentrations increased significantly in fish exposed to both the 1.0 mg l(-1) TiO(2) NP and bulk TiO(2) compared to controls, but concentrations returned to control levels by the end of the recovery period. No change in erythrocyte counts were observed, but there was a two-fold decline in leukocyte counts in all TiO(2) treatment groups relative to time-matched controls. Whole body electrolyte and trace metal profiles were not affected by exposure to TiO(2), and there were no changes in Na(+)K(+)-ATPase activity in brain, gill or liver tissues. Total glutathione (GSH) levels in brain, gill and liver tissues were higher in fish exposed to TiO(2) NP (both 0.1 and 1.0 mg l(-1)) compared to bulk TiO(2) and control fish. Histological examination of gill, liver, brain and gonad tissues showed little evidence of treatment-related morphological change. At the end of the 14-d exposure adult zebrafish were able to reproduce; however, the cumulative number of viable embryos produced was lower in fish exposed to 1.0 mg l(-1) TiO(2) (both NP and bulk) by the end of the 21-d recovery period. Overall, this study showed limited toxicity of bulk or nano scale TiO(2) during the exposure; however reproduction was affected in both bulk and NP 1.0 mg l(-1) groups. PMID- 23084047 TI - Toxic effects of microcystin-LR on the reproductive system of male Rana nigromaculata in vitro. AB - This study aims to demonstrate that microcystin-LR (MC-LR) has toxic effects on the reproductive system of male Rana nigromaculata in vitro. R. nigromaculata were treated with 0, 0.1, 1, 10, and 100 nmol/L of MC-LR for 6 h. Results show that exposure to 1 nmol/L to 100 nmol/L of MC-LR decreased sperm motility and number of sperm cells and increased the sperm abnormality rate, whose values were significantly different from those of the control (P<0.01). Moreover, the same dosage of MC-LR increased reactive oxygen species production and malondialdehyde content. At the same time, antioxidant enzyme (catalase and glutathione S transferase) activity and glutathione reduced content rapidly increased, whereas antioxidant enzyme superoxide dismutase activity significantly decreased. These results imply that the defense system of the testes quickly responds to oxidative stress. Ultrastructural observation shows distention of the mitochondria, endoplasmic reticulum, and Golgi apparatus and changes in the mitochondrial matrix color, cristae number, and morphology. Moreover, using real-time PCR, increased relative expressions of P450 aromatase and SF-1 genes were observed. The results demonstrate for the first time that MC-LR could induce toxicity in the male reproductive system of R. nigromaculata. The findings in this research will provide more insights into the relationships between aquatic microcystins and amphibians. PMID- 23084048 TI - Fluorescent nanoparticles for intracellular sensing: a review. AB - Fluorescent nanoparticles (NPs), including semiconductor NPs (Quantum Dots), metal NPs, silica NPs, polymer NPs, etc., have been a major focus of research and development during the past decade. The fluorescent nanoparticles show unique chemical and optical properties, such as brighter fluorescence, higher photostability and higher biocompatibility, compared to classical fluorescent organic dyes. Moreover, the nanoparticles can also act as multivalent scaffolds for the realization of supramolecular assemblies, since their high surface to volume ratio allow distinct spatial domains to be functionalized, which can provide a versatile synthetic platform for the implementation of different sensing schemes. Their excellent properties make them one of the most useful tools that chemistry has supplied to biomedical research, enabling the intracellular monitoring of many different species for medical and biological purposes. In this review, we focus on the developments and analytical applications of fluorescent nanoparticles in chemical and biological sensing within the intracellular environment. The review also points out the great potential of fluorescent NPs for fluorescence lifetime imaging microscopy (FLIM). Finally, we also give an overview of the current methods for delivering of fluorescent NPs into cells, where critically examine the benefits and liabilities of each strategy. PMID- 23084049 TI - Sensing colorimetric approaches based on gold and silver nanoparticles aggregation: chemical creativity behind the assay. A review. AB - Localized surface plasmon resonance (LSPR) is one of the most remarkable features of gold nanoparticles (Au NPs) and silver nanoparticles (Ag NPs). Due to these inherent optical properties, colloidal solutions of Au and Ag NPs have high extinction coefficients and different colour in the visible region of the spectrum when they are well-spaced in comparison with when they are aggregated. Therefore, a well-designed chemical interaction between the analyte and NPs surroundings leads to a change of colour (red to blue for Au NPs and yellow to brown for Ag NPs from well-spaced to aggregated ones, respectively) allowing the visual detection of the target analyte. These approaches have exhibited an excellent analytical performance with high sensitivities due to the strong LSPR and excellent selectivity strategically driven by the interaction analyte-NPs surroundings involving mainly electrostatic and hydrogen bond interactions as well as donor-acceptor chemical reactions, among others. In addition, this kind of colorimetric assays has received considerable attention in the analytical field because of their simplicity and low cost since they do not require any expensive or complex instrumentation. As a consequence of this, detection of molecules with a high significance in the bio-medical, clinical, food safety and environmental fields including DNA, proteins and a wide spectrum of organic molecules as well as inorganic ions have been impressively reported in the most relevant literature using these assays. This timely review offers a rational vision of the main achievements yielded in the relevant literature according to this exciting and creative analytical field. PMID- 23084050 TI - Validation of analytical methods involved in dissolution assays: acceptance limits and decision methodologies. AB - Dissolution tests are key elements to ensure continuing product quality and performance. The ultimate goal of these tests is to assure consistent product quality within a defined set of specification criteria. Validation of an analytical method aimed at assessing the dissolution profile of products or at verifying pharmacopoeias compliance should demonstrate that this analytical method is able to correctly declare two dissolution profiles as similar or drug products as compliant with respect to their specifications. It is essential to ensure that these analytical methods are fit for their purpose. Method validation is aimed at providing this guarantee. However, even in the ICHQ2 guideline there is no information explaining how to decide whether the method under validation is valid for its final purpose or not. Are the entire validation criterion needed to ensure that a Quality Control (QC) analytical method for dissolution test is valid? What acceptance limits should be set on these criteria? How to decide about method's validity? These are the questions that this work aims at answering. Focus is made to comply with the current implementation of the Quality by Design (QbD) principles in the pharmaceutical industry in order to allow to correctly defining the Analytical Target Profile (ATP) of analytical methods involved in dissolution tests. Analytical method validation is then the natural demonstration that the developed methods are fit for their intended purpose and is not any more the inconsiderate checklist validation approach still generally performed to complete the filing required to obtain product marketing authorization. PMID- 23084051 TI - Nanoplatinum-enclosed gold nanocores as catalytically promoted nanolabels for sensitive electrochemical immunoassay. AB - Here we designed a new electrochemical immunoassay protocol for determination of carcinoembryonic antigen (CEA) using nanoplatinum-enclosed gold nanocores (Pt@Au) as catalytically promoted nanolabels on the carbon nanospheres and graphene modified immunosensor. The Pt@Au nanolabels were synthesized and functionalized with monoclonal anti-CEA antibodies and glucose oxidase (GOx). Using the functional Pt@Au nanolabels as molecular tags, the assay was implemented relative to glucose-hydroquinone system with a sandwich-type immunoassay. Initially, the added glucose was oxidized to gluconolactone and H(2)O(2) by the labeled GOx, and then the generated H(2)O(2) was reduced with the help of platinum nanoparticles, leading to the production of oxygen. The self-produced oxygen could promote the re-oxidation of the glucose, thus resulting in the dual amplification of the electrochemical signal. Several nanolabels, such as multiarmed star-like platinum nanowires, hollow platinum nanospheres and Pt@Au nanostructures, were investigated for CEA detection and improved analytical features were obtained with the Pt@Au nanostructures. Under optimal conditions, the Pt@Au-based immunoassay displayed a wide working range from 0.001 to 120 ng mL(-1) with a low detection limit of 0.5 pg mL(-1) CEA at 3s(B). Intra- and inter-assay coefficients of variation were <10.9%. The system was evaluated with 10 clinical serum samples, receiving good accordance with results from enzyme-linked immunosorbent assay method. PMID- 23084052 TI - Poly(methylene blue) functionalized graphene modified carbon ionic liquid electrode for the electrochemical detection of dopamine. AB - An ionic liquid 1-butylpyridinium hexafluorophosphate based carbon ionic liquid electrode (CILE) was used as the substrate electrode and a poly(methylene blue) (PMB) functionalized graphene (GR) composite film was co-electrodeposited on CILE surface by cyclic voltammetry. The PMB-GR/CILE exhibited better electrochemical performances with higher conductivity and lower electron transfer resistance. Electrochemical behavior of dopamine (DA) was further investigated by cyclic voltammetry and a pair of well-defined redox peaks appeared with the peak-to-peak separation (DeltaE(p)) as 0.058V in 0.1 mol L(-1) pH 6.0 phosphate buffer solution, which proved a fast quasi-reversible electron transfer process on the modified electrode. Electrochemical parameters of DA on PMB-GR/CILE were calculated with the electron transfer number as 1.83, the charge transfer coefficients as 0.70, the apparent heterogeneous electron transfer rate constant as 1.72 s(-1) and the diffusional coefficient (D) as 3.45*10(-4) cm(2) s(-1), respectively. Under the optimal conditions with differential pulse voltammetric measurement, the linear relationship between the oxidation peak current of DA and its concentration was obtained in the range from 0.02 to 800.0 MUmol L(-1) with the detection limit as 5.6 nmol L(-1) (3sigma). The coexisting substances exhibited no interference and PMB-GR/CILE was applied to the detection of DA injection samples and human urine samples with satisfactory results. PMID- 23084053 TI - Voltammetric detection of the alpha-dicarbonyl compound: methylglyoxal as a flavoring agent in wine and beer. AB - A simple, rapid and highly selective method for the determination of the most abundant alpha-dicarbonyl compound in wine and beer has been developed for the first time by employing square wave voltammetry. A novel electrochemical sensor, based on the electrodeposition of platinum nanoparticles onto single wall carbon nanotubes that were cast on a glassy carbon electrode (GCE) substrate, is presented in this paper. This modified electrode exhibited excellent catalytic activity in the electroreduction of methylglyoxal, showing much higher peak currents than those measured on an unmodified GCE. The effects of different experimental and instrumental parameters, such as solution pH and square wave frequency, were examined. The reduction peak current showed a linear range of from 0.1*10(-6) to 100*10(-6)M with a 0.9979 correlation coefficient; and a low detection limit of 2.8*10(-9)M was also obtained. The proposed methodology was successfully applied to the quantitative analysis of methylglyoxal in wine and beer samples. The developed sensor possesses advantageous properties such as a high active surface area, stability, and rapid electron transfer rate, which cumulatively demonstrate high performance toward the electrocatalytic reduction and detection of methylglyoxal. PMID- 23084054 TI - Liquid-liquid-solid microextraction and detection of nerve agent simulants by on membrane Fourier transform infrared spectroscopy. AB - A coupling of novel liquid-liquid-solid microextraction (LLSME) technique based on porous hydrophobic membrane and Fourier-transform infrared spectroscopy has been presented for the detection, identification and quantification of markers and simulants of nerve agents. Two isomers O,O'-dihexyl methylphosphonate (DHMP) and O,O'-dipentyl isopropylphosphonate (DPIPP) were chosen as model analytes for the study. In the present technique, organic phase was immobilised within the pores of membrane after fixing it in an assembly, which was then immersed into aqueous sample of target analytes for extraction. The analytes were directly determined on the surface of membrane by FTIR spectroscopy without elution. On comparison with solid phase microextraction (SPME), LLSME was found to be much more efficient. The method was optimised and quantitative analyses were performed using calibration curves obtained via Beer's law and employing processing of spectra obtained, via a multivariate calibration technique partial least square (PLS). Relative standard deviations (RSDs) for intraday repeatability and interday reproducibility were found to be in the range of 0.20-0.50% and 0.20 0.60%, respectively. Limit of detection (LOD) was achieved up to 15 ng mL(-1). Applicability of the method was tested with an unknown real sample obtained in an international official proficiency test (OPT). PMID- 23084055 TI - Emulsification liquid phase microextraction followed by on-line phase separation coupled to high performance liquid chromatography. AB - An emulsification liquid phase microextraction followed by on-line phase separation coupled to high performance liquid chromatography (HPLC) is introduced based on a novel idea for the separation of dispersed organic phase from aqueous phase. In this method, the dispersed organic extraction phase was filtered using an in-line filter and it was separated from the water sample. The new approach is simple and, in addition to improving some limitations of the conventional emulsification liquid phase microextraction, eliminates the need for centrifugation in the phase separation step. To demonstrate the applicability of the method, it was applied for the extraction and determination of trace amounts of selected parabens as model analytes. In this procedure, 30 MUL of 1-octanol was injected slowly into 10 mL of the aqueous sample inside the ultrasonic water bath. Then, the emulsion formed was passed through the in-line filter located in the loop of the HPLC valve and the organic extraction phase was separated and it was retained in the filter. By changing the position of the valve, the filter was located in the mobile phase pass and the retained organic phase was eluted and transferred to the separation column. The effects of some important parameters such as types of extraction solvent and its volume, ionic strength, and ultrasonication time on extraction efficiency were investigated and optimized. Under optimal conditions, preconcentration factors and limits of detection for the compounds studied were obtained in the ranges of 289-595 and 0.05-0.2 MUg L( 1), respectively. Finally, the method was successfully applied to determine selected parabens in some water and cosmetic samples. PMID- 23084056 TI - New needle packed with polydimethylsiloxane having a micro-bore tunnel for headspace in-needle microextraction of aroma components of citrus oils. AB - A novel in-needle microextraction (INME) for headspace sampling evaluated in this study has significantly higher extraction speed and the practical merits of a durable stainless steel needle to overcome some exposed fiber related drawbacks. A prototype stainless steel needle (Hamilton 90022, 22 gauge bevel tip, 51 mm length) packed with polydimethylsiloxane (PDMS, 0.413 mm O.D., 10mm length) having a micro-bore (200 MUm I.D.) tunnel was prepared as a new INME device. This needle with a barrel and a plunger is then inserted and exposed into the headspace over the sample. Headspace sampling can be speeded up by an automatic reciprocating pump. The extraction parameters have been optimized along with the validation of method performance. The methodology has been applied for the analysis of volatile aroma active components emitted from eight kinds of citrus essential oils by GC-FID or GC/MS. The proposed method showed excellent linearity, reproducibility, and low detection limit. This solventless technique is simple to operate, inexpensive to fabricate, and provides a facile means for collecting and introducing volatile aroma active components of essential oils. PMID- 23084057 TI - A method to detect metal-drug complexes and their interactions with pathogenic bacteria via graphene nanosheet assist laser desorption/ionization mass spectrometry and biosensors. AB - A new method was proposed to probe the interactions between transition metals of Fe(II), Fe(III), Cu(II) with a non steroidal anti-inflammatory drug (NSAID), flufenamic acid (FF) using graphene as a matrix for Graphene assisted laser desorption ionization mass spectrometry (GALDI-MS). Metal-drug complexation was confirmed via UV absorption spectroscopy, fluorescence spectroscopy, pH meter, and change in solution conductivity. The optimal molar ratios for these complexation interactions are stoichiometry 1:2 in both Cu(II) and Fe(II) complexes, and 1:3 in Fe(III) complexes at physiological pH (7.4). Metal complexation of the drug could enhance fluorescence for 20 fold which is due to the charge transfer reaction or increase rigidity of the drug. The main interaction between graphene and flufenamic acid is the P-P interaction which allows us to probe the metal-drug complexation. The GALDI-MS could sensitively detect the drug at m/z 281.0 Da (protonated molecule) with detection limit 2.5 pmol (1.0 MUM) and complexation at m/z 661.0, 654.0 and 933.0 Da corresponding to [Cu(II)(FF)(2)(H(2)O)(2)+H](+), [Fe(II)(FF)(2)(H(2)O)(2)+H](+) and [Fe(III) (FF)(3)(H(2)O)(2)+H](+), respectively (with limit of detection (LOD) 2.0 pmol (10.0 MUM). Matrix assisted laser desorption ionization mass spectrometry (MALDI MS) spectra show change in the protein profile of intact pathogenic bacteria (Pseudomonas aeroginosa, Staphylococcus aureus). The change in the ionization ability (mainly proton affinity) of pathogenic bacteria may be due to the interactions between the bacteria with the drug (or its complexes). Shielding carboxylic group by metals and increase the hydrophilicity could enhance the biocompatibility of complexes toward the pathogenic bacteria which can be used as biosensors with high sensitivity and lowest detectable concentrations are in the range of 3.3*10(3)-3.9*10(4) cfu mL(-1) with large linear dynamic range. PMID- 23084058 TI - A set of triple-resonance nuclear magnetic resonance experiments for structural characterization of organophosphorus compounds in mixture samples. AB - The (1)H, (13)C correlation NMR spectroscopy utilizes J(CH) couplings in molecules, and provides important structural information from small organic molecules in the form of carbon chemical shifts and carbon-proton connectivities. The full potential of the (1)H, (13)C correlation NMR spectroscopy has not been realized in the Chemical Weapons Convention (CWC) related verification analyses due to the sample matrix, which usually contains a high amount of non-related compounds obscuring the correlations of the relevant compounds. Here, the results of the application of (1)H, (13)C, (31)P triple-resonance NMR spectroscopy in characterization of OP compounds related to the CWC are presented. With a set of two-dimensional triple-resonance experiments the J(HP), J(CH) and J(PC) couplings are utilized to map the connectivities of the atoms in OP compounds and to extract the carbon chemical shift information. With the use of the proposed pulse sequences the correlations from the OP compounds can be recorded without significant artifacts from the non-OP compound impurities in the sample. Further selectivity of the observed correlations is achieved with the application of phosphorus band-selective pulse in the pulse sequences to assist the analysis of multiple OP compounds in mixture samples. The use of the triple-resonance experiments in the analysis of a complex sample is shown with a test mixture containing typical scheduled OP compounds, including the characteristic degradation products of nerve agents sarin, soman, and VX. The viability of the approach in verification analysis is demonstrated in the analysis of the 30th OPCW Proficiency Test sample. PMID- 23084059 TI - Rapid, on-site identification of explosives in nanoliter droplets using a UV reflected fiber optic sensor. AB - A portable UV (190-400 nm) spectrophotometric based reflected fiber optic sensor system is presented for the on-site detection and identification of explosives. A reflected fiber optic sensor for explosives analysis was developed, with low sample consumption (20-100 nL) and a wide concentration quantification range (1.1 250 mg L(-1)). Seven common explosives [pentaerythritol tetranitrate (PETN), trinitrophenylmethylnitramine (CE), trinitrotoluene (TNT), dinitrotoluene (DNT), picric acid (PA), cyclotetramethylenetetranitramine (HMX), cyclotrimethylenetrinitramine (RDX)] and a PETN-RDX mixture (to simulate the Semtex used in many terrorist bombings) were quantitatively analyzed and identified by the proposed system in less than 3s per test, with limits of detection (LOD) of 0.3 mg L(-1). Due to chemical interference problems in the UV wavelengths range, a novel feature matching algorithm (FMA) was proposed for explosive identification, which was proved to have higher specificity and better anti-interference ability. Real post-blast debris samples were analyzed by the proposed method, and the results were validated against an LC/MS/MS method. The rapid, cost-effective detection with low sample consumption and wide applicability achieved by this system is highly suitable for homeland security on site applications, such as rapid sample screening in post-blast debris. PMID- 23084060 TI - A highly sensitive and selective immunoassay for the detection of tetrabromobisphenol A in soil and sediment. AB - Tetrabromobisphenol A is the most widely used brominated flame retardant. A sensitive and selective enzyme-linked immunosorbent assay (ELISA) for the detection of tetrabromobisphenol A was developed. The limit of detection and the inhibition half-maximum concentration of tetrabromobisphenol A in phosphate buffered saline with 10% methanol were 0.05 and 0.87 ng mL(-1), respectively. Cross-reactivity values of the ELISA with a set of important brominated flame retardants including tetrabromobisphenol A-bis(2,3-dibromopropylether), 2,2',6,6' tetrabromobisphenol A diallyl ether, hexabromocyclododecane, 1,2 bis(pentabromodiphenyl) ethane, 1,2-bis(2,4,6 tribromophenoxy) ethane, bis(2 ethylhexyl)-3,4,5,6-tetrabromophthalate, 2-ethylhexyl-2,3,4,5-tetrabromobenzoate, and polybrominated diphenyl ethers were <0.05%. Concentrations of tetrabromobisphenol A determined by ELISA in the soils from farmlands, the soils from an e-waste recycling site, and the sediments of a canal were in the range of non-detectable-5.6 ng g(-1), 26-104 ng g(-1) and 0.3-22 ng g(-1)dw, respectively, indicating the ubiquitous pollution of tetrabromobisphenol A. The results of this assay for 16 real world samples agreed well with those of the liquid chromatography-tandem mass spectrometry method, indicating this ELISA is suitable for screening of tetrabromobisphenol A in environmental matrices. PMID- 23084061 TI - A gel-based visual immunoassay for non-instrumental detection of chloramphenicol in food samples. AB - A gel-based non-instrumental immuno-affinity assay was developed for the rapid screening of chloramphenicol (CAP) in food samples with the limit of detection (LOD) of 1 MUg L(-1). The immuno-affinity test column (IATC) consisted of a test layer containing anti-CAP antibody coupled gel, and a control layer with anti-HRP antibody coupled gel. Based on the direct competitive immuno-reaction and the horseradish peroxidase enzymatic reaction, the test results could be evaluated visually. Basically, blue color development represented the negative results, while the absence of color development represented the positive results. In this study, CAP spiked samples of raw milk, pasteurized milk, UHT milk, skimmed milk powder, acacia honey, date honey, fish and shrimp were tested. Little or none sample pretreatment was required for this assay. The whole procedure was completed within 10min. In conclusion, the gel-based immuno-affinity test is a simple, rapid, and promising on-site screening method for CAP residues in food samples, with no instrumental requirement. PMID- 23084063 TI - Palladium@gold bimetallic nanostructures as peroxidase mimic for development of sensitive fluoroimmunoassay. AB - In this paper, gold nanoparticles coated with palladium dots (Pd@Au) bimetallic nanostructures have been reported to have a peroxidase like activity which is not found in their monometallic counterparts. Based on this finding, we have developed an immunoassay in which antibody-modified Pd@Au nanostructure catalyzes the dimerization of a fluorogenic substrate for peroxidase, 3-(4-dihydroxy phenyl) propionic acid (HPPA), to generate high fluorescence signal. Specific antibodies against bensulfuron-methyl were generated by using a well characterized bensulfuron-protein conjugate as an immunogen, and the assay was performed in a competitive immunoassay format where Pd@Au nanostructure was bound to secondary antibody to show the peroxidase like activity. The developed immunoassay exhibited an excellent sensitivity showing a dynamic response range from 0.001 to 100 ng mL(-1) for herbicide bensulfuron-methyl with a detection limit of 0.01 ng mL(-1) (n=3). The newly synthesized bimetallic nanostructure shows the advantages of low cost, easy synthesis and tunable catalytic activity, making it a promising substitution of enzyme peroxidase in different applications. PMID- 23084062 TI - A fluorescence reagent for the highly selective recognition and separation of lead ion (II) from aqueous solutions. AB - A new fluorescence reagent, N,N-bi[4(1-pyrene)-butyroyl]-lysine (1) was synthesized. The new fluorescence sensor showed high sensitivity (detection limit up to 20.7 MUg L(-1)) and specific selectivity for Pb(2+) over other metal ions examined in aqueous solutions. It could also be used to remove Pb(2+) from aqueous solutions by filtering the insoluble 1-Pb(2+) complex with sufficient reversibility. PMID- 23084064 TI - Multiplex detection platform for tumor markers and glucose in serum based on a microfluidic microparticle array. AB - We present a multiplex detection platform based on a microfluidic microparticle array to detect proteins and glucose in serum simultaneously. Multiplex detection of proteins and glucose was performed using biofunctionalized microparticles arrayed on gel-based microstructures integrated in microfluidics. The microparticles immobilized on these microstructures showed high stability under microfluidic flow conditions. With arrays of antibody-coated microbeads, microfluidic quantitative immunoassays for two protein tumor markers, human chorionic gonadotropin (hCG) and prostate specific antigen (PSA) were performed in serum samples with detection limits bellow the cut-off values for cancer diagnosis. Parallel to the immunoassays, quantitative enzymatic assays for glucose in the physiological concentration range were performed. Multiplex detection was achieved by using a spatially encoded microarray. By patterning antibody-coated microbeads and enzyme-containing microparticles on a novel mixed structure array, we successfully demonstrated simultaneous immunoassays (binding based assay) for proteins and an enzymatic assay (reaction kinetic based assay) for glucose. Our microparticle arrays could be potentially used for the detection of multiple categories of biomolecules (proteins, small metabolites and DNA) for clinical diagnostics and other biological applications. PMID- 23084065 TI - Droplet-based microscale colorimetric biosensor for multiplexed DNA analysis via a graphene nanoprobe. AB - The development of simple and inexpensive DNA detection strategy is very significant for droplet-based microfluidic system. Here, a droplet-based biosensor for multiplexed DNA analysis is developed with a common imaging device by using fluorescence-based colorimetric method and a graphene nanoprobe. With the aid of droplet manipulation technique, droplet size adjustment, droplet fusion and droplet trap are realized accurately and precisely. Due to the high quenching efficiency of graphene oxide (GO), in the absence of target DNAs, the droplet containing two single-stranded DNA probes and GO shows dark color, in which the DNA probes are labeled carboxy fluorescein (FAM) and 6-carboxy-X rhodamine (ROX), respectively. The droplet changes from dark to bright color when the DNA probes form double helix with the specific target DNAs leading to the dyes far away from GO. This colorimetric droplet biosensor exhibits a quantitative capability for simultaneous detection of two different target DNAs with the detection limits of 9.46 and 9.67*10(-8)M, respectively. It is also demonstrated that this biosensor platform can become a promising detection tool in high throughput applications with low consumption of reagents. Moreover, the incorporation of graphene nanoprobe and droplet technique can drive the biosensor field one more step to some extent. PMID- 23084066 TI - Towards an integrated biosensor array for simultaneous and rapid multi-analysis of endocrine disrupting chemicals. AB - In this paper we propose the construction and application of a portable multi purpose biosensor array for the simultaneous detection of a wide range of endocrine disruptor chemicals (EDCs), based on the recognition operated by various enzymes and microorganisms. The developed biosensor combines both electrochemical and optical transduction systems, in order to increase the number of chemical species which can be monitored. Considering to the maximum residue level (MRL) of contaminants established by the European Commission, the biosensor system was able to detect most of the chemicals analysed with very high sensitivity. In particular, atrazine and diuron were detected with a limit of detection of 0.5nM, with an RSD% less than 5%; paraoxon and chlorpyrifos were revealed with a detection of 5 MUM and 4.5 MUM, respectively, with an RSD% less than 6%; catechol and bisphenol A were identified with a limit of detection of 1 MUM and 35 MUM respectively, with an RSD% less than 5%. PMID- 23084067 TI - An acyclic, dansyl based colorimetric and fluorescent chemosensor for Hg(II) via twisted intramolecular charge transfer (TICT). AB - An efficient fluorescent chemosensor for Hg(2+) ion, based on 5-(dimethylamino)-N (2-mercaptophenyl)naphthalene-1-sulfonamide, has been developed. It exhibits Hg(2+)-selective on-off fluorescence quenching behavior via twisted intramolecular charge transfer (TICT) mechanism, which is rationalized by time dependent density functional theory (TD-DFT) calculations. The system exhibits visible color change from colorless to gray upon Hg(2+) binding with very high selectivity and sensitivity (as low as 5.0*10(-10)molL(-1)) over other metal ions such as K(+), Na(+), Ag(+), Mn(2+), Ca(2+), Ba(2+), Fe(2+), Zn(2+), Pb(2+), Cu(2+), Sn(2+), Cd(2+), Ni(2+) and Co(2+). The present sensing system is also successfully applied for the detection of Hg(2+) ion in real samples. PMID- 23084068 TI - Analysis of cytokinin nucleotides by capillary zone electrophoresis with diode array and mass spectrometric detection in a recombinant enzyme in vitro reaction. AB - A capillary zone electrophoresis (CZE) method for separation of adenosine and N(6)-isopentenyladenosine (cytokinin) nucleotides was developed, optimized and validated. Aqueous solutions of several amino acids were evaluated as the background electrolyte constituents. Separation of six nucleotides in less than 20 min with high theoretical plate number (up to 400000 for isopentenyladenosine triphosphate) was achieved using a 100 mM sarcosine/ammonia buffer at pH 10.0. The detection limits of the CZE-UV method are in the low micromolar range (0.69 1.27 MUmol L(-1)). Good repeatability of migration times (within 1.3%), peak areas (within 1.8%) and linearity (R(2)>0.999) was achieved over the concentration range 5-1000 MUmol L(-1). The method was used to assay the activity of the recombinant Arabidopsis thaliana isopentenyltransferase 1 (AtIPT1). Baseline separation of isopentenylated nucleotides by CE-ESI-MS using a volatile buffer (30 mM ammonium formate; pH 10.0) was accomplished. The identities of the reaction products - isopentenyladenosine di- and triphosphate were confirmed by HPLC-QqTOF-MS. Dephosphorylation of ATP was observed as a parallel reaction. PMID- 23084069 TI - Effectiveness of in-needle extraction device for liquid samples. AB - In this work in-needle technique as the method for liquid samples preparation which faces with the problem of high flow resistance produced by a sorbent layer is considered. The influence of parameters (needle size, sorbent particle size and length of sorbent layer) of in-needle device on the flow rate was examined. Acceptable sampling conditions were selected on the basis of experiments and their chemometric evaluation. Darcy law was used to describe flow velocity through sorbent in the needle. Kozeny-Carman model and Brinkman model led to results significantly different from those obtained experimentally. Baaren model gave the most realistic results. Diameter of grain, porosity and a constant termed C were taken into account in this model. Incorporation of an additional parameter - "constant C" provides the completion of the model and allows predicting effectively the permeability of the extraction system. The so-called "constant C" is not constant but characteristic for a given system. The range for geometrical characteristics of the sorbent has been determined, where the extraction system works properly. To estimate suitability of a given extraction system, a new parameter P(IN) expressing the geometry of the system was proposed. The usefulness of the range of P(IN) parameter was confirmed experimentally. This tool might be used in designing and preparation of a number of in-needle devices having similar ability of liquid transportation. PMID- 23084070 TI - Neutrophil/lymphocyte ratio is associated with thromboembolic stroke in patients with non-valvular atrial fibrillation. AB - BACKGROUND: Neutrophil/lymphocyte ratio (NLR) has been associated with poor outcomes in patients with cardiovascular diseases. However, little is known about the role of NLR in patients with thromboembolic stroke due to atrial fibrillation (AF). We aimed to compare the NLR ratios between non-valvular AF patients with or without thromboembolic stroke. METHODS: A total of 126 non-valvular AF patients with or without stroke were included in the study; 126 consecutive patients (52 males and 74 females), mean age, 70 +/- 10.2 years old. No patient had a recent history of an acute infection or an inflammatory disease. Baseline NLR was measured by dividing neutrophil count to lymphocyte count. WBC count>12.000 cells per MUL or <4.000 cells per MUL and high body temperature>38 o are excluded from the study. RESULTS: Mean NLR was significantly higher among persons with stroke compared to individuals without a stroke (5.6 +/- 3.4 vs. 3.1 +/- 2.1, p=0.001). There were no significant differences in RDW levels between the two groups (p>0.05). HAS-BLED and CHADS(2) scores were significantly higher in the stroke group. CONCLUSION: Higher NLR, an emerging marker of inflammation, is associated with thromboembolic stroke in non-valvular AF patients. PMID- 23084071 TI - Fresh fruit and vegetable purchases in an urban supermarket by low-income households. AB - OBJECTIVE: To investigate the predictors of fresh fruit and vegetable purchases in a low-income population and identify subgroups in which interventions to increase such purchases might prove useful. METHODS: Retrospective analysis of 209 shopping transactions from 30 households. Individual and household characteristics obtained from primary shopper. Data collected covered April 1 June 30, 2010. Primary outcome was number of servings of fresh produce purchased per week. Bivariate and multivariable analyses were conducted. RESULTS: Controlling for household size, the average number of servings of fresh produce per week was higher in families with more children (P = .008) and in families with a wider age range of children (P = .04). CONCLUSIONS AND IMPLICATIONS: Households with more children purchased more fresh produce. Purchase data combined with shopper household characteristics helped to distinguish relatively high from low purchasers of fresh produce among low-income families. PMID- 23084072 TI - Tips and techniques in breast MRI. AB - The standard breast MRI protocol includes T2 sequences (anatomy and signal analysis), T1 gradient-echo sequences which can detect markers placed after biopsy, and injected dynamic 3D sequences for performing volume and multiplanar reconstructions, which are particularly useful for locating lesions well. Good patient positioning is essential and is obtained by using foam wedges for small breasts, ensuring there are no folds, and the correct position of the nipples. These aspects limit movement artefacts which alter subtraction sequences, so that it must always be possible for reading these sequences to be assisted by comparing them with the native sequences. New functional imaging sequences are now appearing in an attempt to increase the specificity of MRI, which is one of its main limitations. Of these, magnetic resonance spectroscopy appears to be the most promising, highlighting an abnormal choline peak in malignant lesions. This molecular signature provides early information (24 hours after beginning neoadjuvant treatment) on the chemosensitivity of a breast tumour. PMID- 23084073 TI - Tips and traps in brain MRI: applications to vascular disorders. AB - The French Society of Radiology's guide to good use of medical imaging examinations recommends MRI as the first-line examination for exploring cerebrovascular events or disorders. This paper will discuss the main traps in the images when stroke is suspected and provide the technical tips or knowledge necessary for an optimal radiological report. PMID- 23084074 TI - The role of computed tomography in the exploration of Madura foot (pedal mycetoma). PMID- 23084075 TI - Food commodities from microalgae. AB - The prospect of sustainable production of food ingredients from photoautotrophic microalgae was reviewed. Clearly, there is scope for microalgal oils to replace functions of major vegetable oils, and in addition to deliver health benefits to food products. Furthermore, with a limited production surface, a substantial portion of the European Union market could be supplied with edible oils and proteins from microalgae. Yet, before microalgal ingredients can become genuinely sustainable and cost effective alternatives for current food commodities, major breakthroughs in production technology and in biorefinery approaches are required. Moreover, before market introduction, evidence on safety of novel microalgal ingredients, is needed. In general, we conclude that microalgae have a great potential as a sustainable feedstock for food commodities. PMID- 23084076 TI - Investigating transcriptional states at single-cell-resolution. AB - Gene expression analysis at single-cell-resolution is a powerful tool for uncovering individual cell differences within heterogeneous cell populations and complex tissues, which can provide invaluable insights into the extent of gene expression variability. Multi-dimensional information of gene expression at the level of the individual cell can help to identify distinct and rare molecular cell 'states' within populations and aid in unravelling genetic regulatory circuits. Gene expression analysis at the single-cell-level will also enhance our understanding of the molecular basis of aberrant cell states and disease development and holds great promise for the advancement of personalized medicine. We present approaches that provide large-scale views of gene expression at the level of the individual cell. PMID- 23084077 TI - The effects of a lutein-based supplement on objective and subjective measures of retinal and visual function in eyes with age-related maculopathy -- a randomised controlled trial. AB - Lutein and zeaxanthin are lipid-soluble antioxidants found within the macula region of the retina. Links have been suggested between increased levels of these carotenoids and reduced risk for age-related macular disease (ARMD). Therefore, the effect of lutein-based supplementation on retinal and visual function in people with early stages of ARMD (age-related maculopathy, ARM) was assessed using multifocal electroretinography (mfERG), contrast sensitivity and distance visual acuity. A total of fourteen participants were randomly allocated to either receive a lutein-based oral supplement (treated group) or no supplement (non treated group). There were eight participants aged between 56 and 81 years (65.50 (SD 9.27) years) in the treated group and six participants aged between 61 and 83 years (69.67 (SD 7.52) years) in the non-treated group. Sample sizes provided 80% power at the 5% significance level. Participants attended for three visits (0, 20 and 40 weeks). At 60 weeks, the treated group attended a fourth visit following 20 weeks of supplement withdrawal. No changes were seen between the treated and non-treated groups during supplementation. Although not clinically significant, mfERG ring 3 N2 latency (P=0.041) and ring 4 P1 latency (P=0.016) increased, and a trend for reduction of mfERG amplitudes was observed in rings 1, 3 and 4 on supplement withdrawal. The statistically significant increase in mfERG latencies and the trend for reduced mfERG amplitudes on withdrawal are encouraging and may suggest a potentially beneficial effect of lutein-based supplementation in ARM affected eyes. PMID- 23084078 TI - Neurophysiologic responses of peripheral nerve to anoxia: effects of hypothermia and age. AB - OBJECTIVE: Quantify how temperature and age modulate the effects of multiple periods of anoxia on peripheral nerve. METHODS: Nerve action potentials (NAP) recorded from rat sciatic nerve in vitro. Effects of multiple cycles of anoxia on the NAP are evaluated as functions of temperature and age. In some experiments, the nerve was held at constant temperature and others the nerve was hypothermic only during anoxia and returned to 36 degrees C with restoration of oxygen. RESULTS: Hypothermia mitigates the effect of anoxia on the NAP, an effect that increases with multiple cycles of anoxia. Preservation of the NAP waveform after 5 cycles of anoxia is best when hypothermia is delivered only during anoxia. Hypothermia reduces the rate at which the NAP disappears during anoxia but has a limited effect on the rate of recovery. With intermittent hypothermia the amplitude of the NAP is best preserved with temperatures of 15-22 degrees C. Velocity and duration are best preserved below 25 degrees C. The loss of the NAP during anoxia is slower in the older nerves. CONCLUSIONS: Lower temperatures improve the recovery of the NAP from anoxia and increase the time it takes for the NAP to disappear during anoxia as does increasing age. SIGNIFICANCE: Document the effects of hypothermia on the anoxia response as a step toward understanding its nerve protectant effect. PMID- 23084080 TI - The TLR4 gene polymorphisms and susceptibility to cancer: a systematic review and meta-analysis. AB - Growing studies revealed the association between polymorphisms in Toll-like receptor 4 (TLR4) and susceptibility to cancer, however, the results remained inconsistent. To assess the effect of six selected SNPs (rs1927914, rs4986790, rs4986791, rs11536889, rs1927911 and rs2149356) in TLR4 on cancer, we conducted a meta-analysis, up to February 2012, 22 case-control studies were available. Summary odds ratios (OR) and corresponding 95% confidence intervals (CIs) for polymorphisms in TLR4 and cancer risk were estimated. Our meta-analysis identified that two SNPs (rs4986790 and rs4986791) in TLR4 were associated with increased cancer risk (for rs4986790: OR=1.24, 95% CI=1.01-1.52 in dominant model; OR=1.24, 95% CI=1.02-1.52 in overdominant model; for rs4986791: OR=1.81, 95% CI=1.18-2.77 in allele comparison; OR=1.79, 95% CI=1.15-2.80 in dominant model; OR=1.70, 95% CI=1.09-2.67 in overdominant model) and one SNP (rs1927911) in TLR4 was associated with decreased cancer risk (for rs1927911: OR=0.63, 95% CI=0.41-0.99 in allele comparison; OR=0.57, 95% CI=0.35-0.95 in dominant model; OR=0.67, 95% CI=0.46-0.97 in codominant model). Moreover, in terms of stratified analyses by cancer type for SNP rs4986790, significantly elevated risk was observed to be associated with G allele in gastric cancer and 'other cancers'. These findings indicate that polymorphisms in TLR4 may play a role, although modest, in cancer development. PMID- 23084079 TI - On the nature of mycobacteriophage diversity and host preference. AB - The complete genome sequences of over 220 mycobacteriophages reveal them to be highly diverse, with numerous types sharing little or no nucleotide sequence identity with each other. We have determined the preferences of these phages for Mycobacterium tuberculosis and for other strains of Mycobacterium smegmatis, and find there is a correlation between genome type (cluster, subcluster, singleton) and host range. For many of the phages, expansion of host range occurs at relatively high frequencies, and we describe several examples in which host constraints occur at early stages of infection (adsorption or DNA injection), and phages have the ability to expand their host range through mutations in tail genes. We present a model in which phage diversity is a function of both the ability of phages to rapidly adapt to new hosts and the richness of the diversity of the bacterial population from which those phages are isolated. PMID- 23084081 TI - Determinants and interpretation of death certificate only proportions in the initial years of newly established cancer registries. AB - BACKGROUND: The proportion of cases notified by death certificate only (DCO) is a commonly used criterion to judge completeness of cancer registration even though it is affected by additional factors, particularly during initial years of newly established registries. METHODS: Based on cancer registry data from the United States, we provide model calculations to demonstrate the magnitude and time course of the impact of the following mechanisms on DCO proportions of "young" registries: registration of cancer deaths from patients diagnosed prior to the registration period and delayed registration by death certificate of patients diagnosed but not reported after initiation of registration. RESULTS: DCO proportions of up to >=30% can be expected from deaths of previously diagnosed patients during the first year of registration. Although this proportion is expected to gradually diminish over subsequent years, DCO proportions may be dominated for several years by this source, which may still be relevant after 10 or more years of cancer registration for cancers with relatively large proportions of late deaths. Otherwise, however, underreporting during patients' lifetime is expected to become the predominant source of DCO proportions in the long run. CONCLUSIONS: Our results may guide interpretation of DCO proportions of relatively "young" cancer registries. PMID- 23084082 TI - Case report: stimulation of puberty in a girl with chemo- and radiation therapy induced ovarian failure by transplantation of a small part of her frozen/thawed ovarian tissue. AB - AIM OF THE STUDY: To induce puberty by transplantation of frozen/thawed ovarian tissue collected prior to gonadotoxic treatment for a cancer. PATIENTS AND METHODS: A 9-year-old girl with Ewing sarcoma had one ovary excised and cryopreserved prior to chemo- and radiotherapy. Functional activity of the remaining ovary was destroyed during treatment. Four and a half years later the girl remained pre-pubertal with postmenopausal levels of FSH. Two of ten pieces of frozen/thawed cortex were transplanted to the remaining ovary in order to stimulate puberty. RESULTS: Four months after the transplantation FSH returned to low levels. During the following year puberty gradually progressed to Tanner stage B4 and P3 and regular menstrual cycles started. However, after 19 months the function of the graft ceased. CONCLUSIONS: We have shown for the first time in a girl treated for cancer that transplanted ovarian tissue can regain function and secrete estradiol in a sufficient amount to induce puberty. In addition, the majority of her ovarian tissue remains frozen with a possibility to support fertility in adult life. PMID- 23084083 TI - Age effect on the default mode network, inner thoughts, and cognitive abilities. AB - Age-related effects on the default mode network (DMN) connectivity as measured at rest using functional magnetic resonance imaging (fMRI) are now well described. Little is known however about the relationships between these changes and age related effects on cognition or on the unconstrained thoughts which occur during the resting-state scan, called inner experience. Brain resting-state activity, inner experience, and cognitive ability measurements were obtained in 70 participants aged 19-80 years. The anterior-posterior disruption of DMN activity with age reported in previous studies was recovered here. A significant effect of age was also found on cognitive abilities but not on inner experience. Finally, age-related changes in DMN connectivity were found to correlate with cognitive abilities, and more specifically with autobiographical memory performance. These findings provide new information to fuel the debate on the role of the brain default mode and more specifically on the effect of age-related changes in resting-state activity as measured with fMRI. PMID- 23084084 TI - The capillary dysfunction hypothesis of Alzheimer's disease. AB - It is widely accepted that hypoperfusion and changes in capillary morphology are involved in the etiopathogenesis of Alzheimer's disease (AD). This is difficult to reconcile with the hyperperfusion observed in young high-risk subjects. Differences in the way cerebral blood flow (CBF) is coupled with the local metabolic needs during different phases of the disease can explain this apparent paradox. This review describes this coupling in terms of a model of cerebral oxygen availability that takes into consideration the heterogeneity of capillary blood flow patterns. The model predicts that moderate increases in heterogeneity requires elevated CBF in order to maintain adequate oxygenation. However, with progressive increases in heterogeneity, the resulting low tissue oxygen tension will require a suppression of CBF in order to maintain tissue metabolism. The observed biphasic nature of CBF responses in preclinical AD and AD is therefore consistent with progressive disturbances of capillary flow patterns. Salient features of the model are discussed in the context of AD pathology along with potential sources of increased capillary flow heterogeneity. PMID- 23084086 TI - Engineering the immune system to cure genetic diseases, HIV, and cancer. PMID- 23084085 TI - Visual contrast sensitivity in Alzheimer's disease, mild cognitive impairment, and older adults with cognitive complaints. AB - Deficits in contrast sensitivity (CS) have been reported in Alzheimer's disease (AD). However, the extent of these deficits in prodromal AD stages, including mild cognitive impairment (MCI) or even earlier, has not been investigated. In this study, CS was assessed using frequency doubling technology in older adults with AD (n = 10), amnestic MCI (n = 28), cognitive complaints without performance deficits (CC; n = 20), and healthy controls (HC; n = 29). The association between CS and cognition was also evaluated. Finally, the accuracy of CS measures for classifying MCI versus HC was evaluated. CS deficits were found in AD and MCI, while CC showed intermediate performance between MCI and HC. Upper right visual field CS showed the most significant difference among groups. CS was also associated with cognitive performance. Finally, CS measures accurately classified MCI versus HC. The CS deficits in AD and MCI, and intermediate performance in CC, indicate that these measures are sensitive to early AD-associated changes. Therefore, frequency doubling technology-based measures of CS may have promise as a novel AD biomarker. PMID- 23084087 TI - Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib. AB - AIMS: Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas. METHODS: Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression free and overall survival. RESULTS: The patients underwent surgery after a median of 8 (range 1-55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2-30) cm and reduced to 6.2 (range 1-20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease. CONCLUSIONS: Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS. PMID- 23084088 TI - Spanish Pacemaker Registry. Ninth official report of the Spanish Society of Cardiology Working Group on Cardiac Pacing (2011). AB - INTRODUCTION AND OBJECTIVES: To describe the results of the analysis of pacemaker implantations reported to the Spanish Pacemaker Registry in 2011, with particular reference to the population distribution and the selection of pacing modes. METHODS: Information provided by the European Pacemaker Patient Identification Card was processed using a purpose-built computer application. RESULTS: Data from 115 hospitals were analyzed, totaling 13,373 cards, representing an estimated 38% of implantations. The number of pacemaker generators and resynchronization devices implanted was 738 and 56.2 units per million population, respectively. The mean age of the patients who received a device was 76.7 years. Overall, 57.2% of first implantations and 56.5% of replacements were performed in men. Most implantations (38.7%) and generator replacements (41.9%) were performed in patients aged between 80 and 89 years. Of the pacemaker leads used, 99.7% were bipolar and 63% used an active fixation system. Overall, 20% of the patients with atrioventricular block or sick sinus syndrome were paced in VVI/R mode despite being in sinus rhythm. CONCLUSIONS: With respect to previous years, the use of conventional pacemakers remained stable and the implantation of resynchronization devices has increased. The number of implantation procedures continues to be higher in men and in younger patients. Age and the degree of blockage remain as factors influencing the appropriate choice of pacing mode. PMID- 23084089 TI - Letter to the editor regarding manuscript entitled: T-category reflects the histopathologic characteristics of gallbladder cancer. PMID- 23084090 TI - Malignant peripheral nerve sheath tumors: prognostic impact of rhabdomyoblastic differentiation (malignant triton tumors), neurofibromatosis 1 status and location. AB - PURPOSE: The purpose of this study was to assess the impact of rhabdomyoblastic differentiation [malignant triton tumors (MTT)], neurofibromatosis 1 (NF1) status and location on the outcome of malignant peripheral nerve sheath tumors. METHODS: In this IRB-approved, HIPAA-compliant retrospective study medical records of 84 patients with pathologically confirmed MPNST from 1999 to 2011 were retrospectively reviewed. Patient and tumor characteristics including size, location, NF1 status, absence or presence of rhabdomyoblastic differentiation (MPNST versus MTT, respectively), recurrence and metastatic patterns and outcomes were evaluated. RESULTS: Of 84 patients, 62 were MPNST and 22 were MTT. MTT occurred in older patients than MPNST (50 years versus 40.7 years, p = 0.04) and were larger (12.3 cm versus 8.1 cm, p = 0.01). While there was no difference between the location, rate of recurrent or metastasis disease, and metastatic pattern between MTT and MPNST groups, MTT had shorter metastasis-free interval (median, 1 month versus 9 months, p = 0.02) and shorter survival (median, 10 months versus 43 months, p < 0.0001). NF1 status, while associated with earlier diagnosis (mean age, 35.1 years versus 46.5 years, p = 0.008), had no impact on rate of MTT or on prognosis. Patients with primary in the torso had shorter survival than those with extremity primary (median, 15 months versus 47 months, p = 0.0004). Multivariate analysis using the Cox proportional hazard regression model yielded age (p = 0.029), size (p = 0.0001), presence of rhabdomyoblastic differentiation (MTT) (p = 0.001), and location in the torso (p = 0.01) as independent predictors of survival. CONCLUSIONS: Among patients with malignant peripheral nerve sheath tumors, rhabdomyoblastic differentiation (MTT) and location in the torso are associated with poor prognosis. NF1 status has no impact on the prognosis. PMID- 23084091 TI - Efficacy of neoadjuvant chemotherapy in patients with FIGO stage IB1 to IIA cervical cancer: an international collaborative meta-analysis. AB - BACKGROUND: The efficacy of neoadjuvant chemotherapy before surgery (NCS) has not been well-established in FIGO stage IB1 to IIA cervical cancer when compared with primary surgical treatment (PST). Thus, we performed a meta-analysis to determine the efficacy of NCS in patients with FIGO stage IB1 to IIA cervical cancer when compared with PST. METHODS: We searched Pubmed, Embase and the Cochrane Library between January 1987 and September 2010. Since there was a relative lack of relevant randomized controlled trials (RCTs), we included 5 RCTs and 4 observational studies involving 1784 patients among 523 potentially relevant studies. RESULTS: NCS was related with lower rates of large tumor size (>=4 cm) (ORs, 0.22 and 0.10; 95% CI, 0.13-0.39 and 0.02-0.37) and lymph node metastasis (ORs, 0.61 and 0.38; 95% CI, 0.37-0.99 and 0.20-0.73) than PST in all studies and RCTs. Furthermore, NCS reduced the need of adjuvant radiotherapy (RT) in all studies (OR, 0.57; 95% CI, 0.33-0.98), and distant metastasis in all studies and RCTs (ORs, 0.61 and 0.61; 95% CI, 0.42-0.89 and 0.38-0.97). However, overall and loco-regional recurrences and progression-free survival were not different between the 2 treatments. On the other hand, NCS was associated with poorer overall survival in observational studies when compared with PST (HR, 1.68; 95% CI, 1.12-2.53). CONCLUSIONS: Although NCS reduced the need of adjuvant RT by decreasing tumor size and lymph node metastasis, and distant metastasis, it failed to improve survival when compared with PST in patients with FIGO stage IB1 to IIA cervical cancer. PMID- 23084092 TI - The Danish Twin Registry: linking surveys, national registers, and biological information. AB - Over the last 60 years, the resources and the research in the Danish Twin Registry (DTR) have periodically been summarized. Here, we give a short overview of the DTR and a more comprehensive description of new developments in the twenty first century. First, we outline our experience over the last decade of combining questionnaire and survey data with national demographic, social, and health registers in Statistics Denmark. Second, we describe our most recent data collection effort, which was conducted during the period 2008-2011 and included both in-person assessments of 14,000+ twins born 1931-1969 and sampling of biological material, hereby expanding and consolidating the DTR biobank. Third, two examples of intensively studied twin cohorts are given. The new developments in the DTR in the last decade have facilitated the ongoing research and laid the groundwork for new research directions. PMID- 23084093 TI - Pharmacokinetic properties and bioequivalence of two sulfadoxine/pyrimethamine fixed-dose combination tablets: a parallel-design study in healthy Chinese male volunteers. AB - BACKGROUND: Sulfadoxine/pyrimethamine fixed-dose combination (FDC) tablet is the long-acting portion of the antimalaria product Artecospe((r)), coblister containing artesunate tablets plus sulfadoxine/pyrimethamine FDC tablets. This study was conducted to support the efficacy and tolerability of the sulfadoxine/pyrimethamine FDC tablet in the World Health Organization's (WHO) Prequalification of Medicines Programme, as well as to obtain marketing authorization in China. OBJECTIVE: The aim of the present study was to compare the pharmacokinetic profiles between a new generic and the branded reference formulation of sulfadoxine/pyrimethamine FDC tablets, and to assess the bioequivalence of the 2 products in healthy Chinese volunteers. METHODS: This single-dose, open-label, randomized, parallel-group study was conducted in healthy Chinese male volunteers who were randomly assigned (1:1) to receive a single 1500/75-mg dose (3 * 500/25-mg tablets) of either the test or reference formulation after a 12-hour overnight fast. Seventeen blood samples were obtained over a 168-hour interval, and plasma concentrations of sulfadoxine and pyrimethamine were determined by 2 separate validated liquid chromatography isotopic dilution mass spectrometry methods. Pharmacokinetic properties (C(max), AUC(0-72), AUC(0-168), and T(max)) were calculated and analyzed statistically. The 2 formulations were to be considered bioequivalent if 90% CIs for the log transformed ratios of C(max) and AUC(0-72) were within the predetermined bioequivalence range of 80% to 125%, in accordance with the guidelines of WHO and China's Food and Drug Administration (FDA). Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12 lead ECGs, and subject interviews on adverse events (AEs). RESULTS: Forty-six healthy subjects completed the study. The mean values of sulfadoxine C(max) (183.07 and 165.15 mg/L), AUC(0-72) (11,036.52 and 10,536.78 mg/L/h), and AUC(0 168) (22,247.05 and 21,761.02 mg/L/h) were not significantly different between the test and reference formulations, respectively. The same was true for pyrimethamine (0.55 and 0.58 mg/L, 29.85 and 31.44 mg/L/h, and 56.18 and 59.27 mg/L/h, respectively). The 90% CIs for the log-transformed ratios of C(max), AUC(0-72), and AUC(0-168) of both sulfadoxine (105.4%-116.6%, 99.3%-110.6%, and 96.4%-108.1%) and pyrimethamine (88.8%-100.9%, 89.5%-101.0%, and 88.3%-101.6%) were within the acceptance limits for bioequivalence. A total of 7 mild AEs were reported in 7 subjects (15.2%). CONCLUSIONS: The findings from this single-dose (1500/75-mg) study suggest that the test and reference formulations of sulfadoxine/pyrimethamine FDC 500/25-mg tablet have similar pharmacokinetic profiles both in terms of rate and extent of absorption. The formulations met WHO's and China's FDA regulatory criteria for bioequivalence in these healthy Chinese volunteers under fasting conditions. Both formulations were generally well-tolerated. PMID- 23084094 TI - The influence of differences in the functioning of the neurocognitive attentional networks on drivers' performance. AB - Considerable research efforts are currently being devoted to analysing the role that the attentional system plays in determining driving behaviour, with the ultimate objective of reducing the number of attention-related accidents. The present study aims to assess the influence of differences in the functioning of the three attentional networks (executive control, attentional orienting and alerting) when drivers have to deal with some common hazardous situations, for example, when an oncoming car or a pedestrian unexpectedly crosses their trajectory. Multiple measures of participants' attentional functioning were obtained from a computer-based neurocognitive test: the Attention Networks Test for Interactions and Vigilance (ANTI-V). These measures were compared to performance in a driving simulator where different types of hazardous situations were presented. Correlation and linear regression analyses revealed significant associations between individual attentional measures and driving performance in specific traffic situations. In particular, a higher attentional orienting score on the ANTI-V was associated with safer driving in situations where a single precursor anticipated the hazard source, whereas in complex situations with multiple potential hazard precursors, higher attentional orienting scores were associated with delayed braking. Additionally, partial evidence of a relationship between crash occurrence and the functioning of the executive control and the alerting networks was found. Overall, the current research would be helpful to better understand the role that each attentional network (executive control, attentional orienting and alerting) play in safe driving, and thus to develop efficient countermeasures to reduce attention-related crashes. PMID- 23084096 TI - The influence of curbs on driver behaviors in four-lane rural highways--A driving simulator based study. AB - The speed limit of 55mph (88km/h) is typically used on rural highways in the U.S. For locations where curbs are installed along these roadways, some transportation agencies have suggested the use of a lower 45mph (72km/h) speed limit because, according to AASHTO, running into curbs at high speeds may cause significant vehicular damage and even severe injuries. However, it has also been argued that lowering the speed limit after the installation of curbs may cause confusion in drivers, who do not perceive the risk associated with the newly installed curbs and tend to operate their vehicles at the same speed as before. To better understand driver behavior on rural highways before and after curb installation, and with different speed limits, researchers at the University of Tennessee conducted a series of experiments in two-lane and four-lane highways on a high fidelity driving simulator. This paper mainly presents the findings from the four lane study, and compares the results from the previous two-lane study. The scenario matrix consists of several dimensions including posted speed limit (45 and 55mph, or 72 and 88km/h), curb installation, lateral clearance between the edge of travel lane and the curb (2ft, 6ft, and no-curb, or 0.6m, 1.8m, and no curb), weather (clear and fog), traffic conditions in the next lane (1400veh/h and 400veh/h), etc. For each subject under different experimental scenarios, detailed driving parameters, such as driving speed and vehicle position in the travel lane, were recorded and analyzed subsequently. Results of the study suggest that driver behaviors are influenced by the various factors in a complex and interrelated manner. It is likely that drivers do not perceive the risk from the curb in determining their speed on four-lane rural highways. However, it is found that curbs may provide certain guidance to drivers, especially in selecting lane position. Compared to the previous research in two-lane conditions, it is found that drivers are more likely to choose driving speeds according to posted speed limits, rather than lane configurations. It is also found that the relative speed between driver's vehicle and ambient traffic or curbs is an important factor determining drivers' perception of risk and thus their driving behavior. The influence of subjective effects of these factors to their driving behavior is also observed in the study. PMID- 23084095 TI - Inverse propensity weighting to adjust for bias in fatal crash samples. AB - BACKGROUND: The Fatality Analysis Reporting System (FARS) has data from all areas of the United States, but is limited to fatal crashes. The National Automotive Sampling System-General Estimates System (NASS-GES) includes all types of serious traffic crashes, but is limited to a few sampling areas. Combining the strengths of these two samples might offset their limitations. METHODS: Logistic regression (allowing for sample design, and conditional upon selected person-, event-, and geographic-level factors) was used to determine the propensity (P(FC)) for each injured person in 2002-2008 NASS-GES data to be in a fatal crash sample. NASS-GES subjects injured in fatal crashes were then reweighted by a factor of W(FC)=(1/P(FC)) to create a "pseudopopulation". The weights (W(FC)) derived from NASS-GES were also applied to injured subjects in 2007 FARS data to create another pseudopopulation. Characteristics and mortality predictions from these artificial pseudopopulations were compared to those obtained using the original NASS-GES sample. The sum of W(FC) for FARS cases was also used to estimate the number of crash injuries for rural and urban locations, and compared to independently reported data. RESULTS: Compared to regression results using the original NASS-GES sample, unadjusted models based on fatal crash samples gave inaccurate estimates of covariate effects on mortality for injured subjects. After reweighting using W(FC), estimates based upon the pseudopopulations were similar to results obtained using the original NASS-GES sample. The sum of W(FC) for FARS cases gave reasonable estimates for the number of crash injuries in rural and urban locations, and provided an estimate of the rural effect on mortality after controlling for other factors. CONCLUSIONS: Weights derived from analysis of NASS-GES data (the inverse propensity for selection into a fatal crash sample) allow appropriate adjustment for selection bias in fatal crash samples, including FARS. PMID- 23084097 TI - Postpartum haemorrhage associated with caesarean section and caesarean hysterectomy. AB - Excessive haemorrhage associated with caesarean section, commonly defined as blood loss in excess of 1000 ml, is frequently underestimated, but is documented as occurring in more than 5-10% of caesarean sections. Common causes are uterine atony, abnormal placentation, uterine trauma and sepsis. It is a major cause of maternal morbidity globally and of maternal mortality in low- and middle-income countries; however, many reports do not disaggregate it from postpartum haemorrhage in general. In this chapter, we outline preventive measures, including uterotonic agents, and provide treatment algorithms for managing excessive haemorrhage during and after caesarean section. Several management options, including uterotonic therapy, uterine compression sutures, balloon tamponade, blood-vessel ligation and uterine artery embolisation are described; each has a role for treating the different causes of caesarean section bleeding in different contexts. Caesarean hysterectomy is indicated when medical and conservative surgical measures are unsuccessful, and as first-line surgery for extensive uterine rupture and bleeding from morbidly adherent placentae. It has an incidence ranging from 1-4 per 1000 caesarean sections, significantly greater than that for vaginal delivery. Although it is a life-saving procedure, it is associated with significant morbidity, including massive blood transfusion and intensive care (10-48%), urological injury (8%) and the need for relook laparotomy (8-18%). PMID- 23084098 TI - Treatment of patients with small-cell lung cancer: from meta-analyses to clinical practice. AB - Despite decades of intensive biological and clinical research, there still remains a substantial lack of consensus regarding the appropriate therapeutic management of patients with small-cell lung cancer (SCLC). Many randomized studies have been performed to identify the most effective treatment strategy, the best agents or treatment duration, the most appropriate dose and timing of radiotherapy and thus providing more reliable evidence for clinical practice. Unfortunately most of these trials reported contrasting results, and in several meta-analyses have been performed, with the intent to clarify the strategic approach for each issue. This review focuses on the contribution of the main meta analyses in defining the standard approaches in the treatment of SCLC, discussing their real value and influence on every-day decision making. According to the results of available meta-analyses, platinum-based chemotherapy should be considered the standard of care for the treatment of SCLC. Cisplatin and carboplatin have shown similar efficacy, and the choice of the platinum compound for the treatment of patients with extensive stage SCLC should consider the expected toxicity profile, organ function, performance status, and comorbidities. Thoracic radiotherapy, administered early and in combination with chemotherapy, improves long-term results, although with higher toxicity. Prophylactic cranial irradiation in patients with limited disease obtaining response after induction treatment is a standard of care. Maintenance treatment, intensified chemotherapy and use of growth factors have not proven significant efficacy. Topotecan is effective as second-line treatment, although evidence on clinical benefit for patients relapsed after first-line is limited. PMID- 23084099 TI - Systems memory consolidation in Drosophila. AB - From an information processing perspective, memories need to be acquired, encoded, stored, maintained and retrieved. As time passes after training, memories become less easily retrieved, but also become progressively more stable in the face of experimental perturbations. This process is referred to as consolidation. But the term has been used to describe two different biological processes whose relationship is poorly understood [1,2]. The first, which we refer to as biochemical consolidation, involves cell-signaling events within a neuron. The second, which we call systems consolidation, involves ongoing communication between brain regions or cell types. Although systems consolidation was first thought to be at play only in complex brains, a number of recent studies reveal its importance in Drosophila. The ease of cell type specific genetic manipulations in flies provides a unique opportunity to forge an integrated mechanistic understanding of biochemical and systems consolidation. PMID- 23084100 TI - Should all moderate coronary lesions be grafted during primary coronary bypass surgery? An analysis of progression of native vessel disease during a randomized trial of conduits. AB - OBJECTIVE: Whether to graft a moderately stenosed coronary vessel remains debatable. We investigated whether grafting such vessels is warranted based on angiographic evidence of disease progression. METHODS: Of 619 patients who underwent on-pump coronary artery bypass grafting in an ongoing, randomized radial artery trial, 405 have at least 1 follow-up angiogram at a mean of 6.2 +/- 3.1 years (range, 0-14 years) after surgery. Percent diameter stenosis in each major native vessel was reported by 3 cardiac specialists and classified as either moderate (40%-69%) or severe (>=70%) stenosis. Progression of native vessel disease and graft patency were determined by comparison of pre- and postoperative angiography. RESULTS: A total of 3816 native vessels and 1242 bypass grafts were analyzed, of which 386 moderate preoperative lesions were identified, 323 of which were grafted. In all territories, grafted vessels had greater risk of disease progression than ungrafted equivalents (43.4% vs 10.5%, P < .001). Moderate lesions were more likely than severe lesions to remain unchanged on follow-up angiography (52.6% vs 31.1%, P < .001). Only 1 in 7 moderate lesions in the right coronary artery exhibited significant progression during follow-up if left ungrafted, whereas the likelihood of progression in left sided counterparts approached 50%. Arterial and vein grafts to left-sided moderately stenosed vessels had excellent patency (83% and 77% at 8 years, respectively), which was not matched by right-sided grafts (P = .051). Placement of a graft for a moderate lesion was associated with significantly greater incidence of disease progression, most marked in the right coronary territory. CONCLUSIONS: The greater risk of progression of left-sided moderate lesions, and high graft patency rates when bypassed, suggests that the balance of clinical judgment lies in favor of grafting moderate left-sided lesions. In the right coronary system, however, a lesion is likely to remain moderate if left ungrafted and, with a low risk of progression, it may be reasonable to leave these vessels undisturbed. PMID- 23084101 TI - Fate of the preserved aortic root after treatment of acute type A aortic dissection: 23-year follow-up. AB - OBJECTIVE: The objective of this study was to examine the fate of the native aortic root after replacement of the ascending aorta to treat acute type A aortic dissection. METHODS: Between June 1985 and January 2010, 319 consecutive patients (mean age, 63 +/- 11 years) with acute type A aortic dissection underwent replacement of the ascending aorta with preservation of the aortic root. The aortic valve was also replaced in 21 of these patients (7%). The intervention was extended to the aortic arch in 210 patients (66%), of whom 173 (54%) underwent hemiarch replacement, and 37 (12%), total arch replacement. RESULTS: There were 109 (34%) in-hospital deaths. Of the 210 discharged patients, survival was 95%, 58%, and 27% at 1, 10, and 23 years, respectively. Freedom from reoperation on the proximal aorta was reported by 97%, 92%, and 82% patients at 5, 10, and 23 years, respectively. Twelve patients were reoperated for aortic root dilatation and 2 died during reoperation. Univariate and multivariate Cox regression analyses revealed that significant risk factors for proximal reoperation were age <60 years (P = .005; relative risk, 1.94) and Marfan syndrome (P = .011; relative risk, 2.76). At follow-up, 15 patients (11%) had an aortic root diameter of >45 mm, but they were not reoperated. CONCLUSIONS: For acute type A aortic dissection, replacement of the ascending aorta with root preservation shows long term effectiveness with low reoperation and aortic root dilatation rates. PMID- 23084102 TI - Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium-2 consensus document. AB - OBJECTIVES: The aim of the current Valve Academic Research Consortium (VARC)-2 initiative was to revisit the selection and definitions of transcatheter aortic valve implantation (TAVI) clinical endpoints to make them more suitable to the present and future needs of clinical trials. In addition, this document is intended to expand the understanding of patient risk stratification and case selection. BACKGROUND: A recent study confirmed that VARC definitions have already been incorporated into clinical and research practice and represent a new standard for consistency in reporting clinical outcomes of patients with symptomatic severe aortic stenosis (AS) undergoing TAVI. However, as the clinical experience with this technology has matured and expanded, certain definitions have become unsuitable or ambiguous. METHODS AND RESULTS: Two in-person meetings (held in September 2011 in Washington, DC, and in February 2012 in Rotterdam, The Netherlands) involving VARC study group members, independent experts (including surgeons, interventional and noninterventional cardiologists, imaging specialists, neurologists, geriatric specialists, and clinical trialists), the US Food and Drug Administration (FDA), and industry representatives, provided much of the substantive discussion from which this VARC-2 consensus manuscript was derived. This document provides an overview of risk assessment and patient stratification that need to be considered for accurate patient inclusion in studies. Working groups were assigned to define the following clinical endpoints: mortality, stroke, myocardial infarction, bleeding complications, acute kidney injury, vascular complications, conduction disturbances and arrhythmias, and a miscellaneous category including relevant complications not previously categorized. Furthermore, comprehensive echocardiographic recommendations are provided for the evaluation of prosthetic valve (dys)function. Definitions for the quality of life assessments are also reported. These endpoints formed the basis for several recommended composite endpoints. CONCLUSIONS: This VARC-2 document has provided further standardization of endpoint definitions for studies evaluating the use of TAVI, which will lead to improved comparability and interpretability of the study results, supplying an increasingly growing body of evidence with respect to TAVI and/or surgical aortic valve replacement. This initiative and document can furthermore be used as a model during current endeavors of applying definitions to other transcatheter valve therapies (for example, mitral valve repair). PMID- 23084104 TI - A novel fluorescence technique for identification of the pulmonary segments by using the photodynamic diagnosis endoscope system: an experimental study in ex vivo porcine lung. AB - OBJECTIVE: Photodynamic diagnosis is a technique that has been proposed to enhance tumor detection and resection. We modified this technique to identify pulmonary segments and examine the feasibility of this technique in ex vivo porcine lungs. METHODS: The photodynamic diagnosis endoscope system consisted of the D-Light system as the excitation light source and a TRICAM camera as the fluorescence sensing endoscope (Karl Storz GmbH & Co, Tuttlingen, Germany). Vitamin B2 was used as the fluorescence substance. Two kinds of segmentectomy were performed in right porcine lung. After identification of the segmental bronchus, the fluorescent substance was injected transbronchially. The fluorescent segment was observed using the photodynamic diagnosis endoscope system, and the identified intersegmental plane was cut using scissors. The operative data collected were the success rate of accurately identifying the pulmonary segments. The duration and light intensity of fluorescence of the target segment were recorded to provide an objective measurement of success. The same parameters were also measured for the adjacent segment. RESULTS: Overall, 20 segmentectomies were performed, 10 of each kind--cranial segmentectomy and L2 segmentectomy. In all procedures, it was possible to identify the target segment by its yellow-green fluorescence. No unexpected injuries of the major segmental bronchi and vessels nor incorrect recognition of target segments occurred. The success rate of accurately identifying pulmonary segments was 100%. The duration and light intensity of this fluorescence technique was enough to perform pulmonary segmentectomy. CONCLUSIONS: This florescence technique using vitamin B2 and the photodynamic diagnosis endoscope system is useful to identify the target pulmonary segment easily and clearly in ex vivo porcine lung. PMID- 23084105 TI - Off-pump coronary artery bypass grafting attenuates morbidity and mortality for patients with low and high body mass index. AB - BACKGROUND: Patients at high and low body mass index have been shown to experience higher morbidity and mortality when undergoing coronary artery bypass grafting. The purpose of this research was to compare outcomes of patients at body mass index extremes who underwent coronary artery bypass grafting with or without cardiopulmonary bypass. METHODS: A retrospective review of 6801 patients with a body mass index <25 or >35 undergoing isolated, primary coronary artery bypass grafting from 1996 to 2009 at Emory Healthcare Hospitals was performed. Patients were compared by therapy either on-pump coronary artery bypass grafting (n = 3210) or off-pump coronary artery bypass grafting (n = 3591). Salvage patients or those with concomitant operations were excluded. Comparisons were made using multivariable regression analysis, using a propensity score covariate calculated from 41 preoperative risk factors. RESULTS: A total of 6801 patients, including 4312 with a body mass index <25 (off-pump coronary artery bypass grafting, n = 2083; on-pump coronary artery bypass grafting, n = 2229) and 2489 with a body mass index >35 (off-pump coronary artery bypass grafting, n = 1127; on-pump coronary artery bypass grafting, n = 1362) were included for analysis. Society of Thoracic Surgeons predicted risk of mortality was significantly higher for both body mass index strata in patients undergoing off-pump coronary artery bypass grafting (2.8% vs 3.1% for body mass index <25 [P = .043] and 1.7% vs 1.8% for body mass index >35 [P = .049]). For patients with a body mass index <25, multivariable analysis of outcomes showed a significant decrease in in-hospital mortality (adjusted odds ratio, 0.48; 95% confidence interval, 0.28-0.82), stroke (adjusted odds ratio, 0.31; 95% confidence interval, 0.18-0.56), new-onset renal failure (adjusted odds ratio, 0.59; 95% confidence interval, 0.36-0.96), and prolonged ventilation (adjusted odds ratio, 0.50; 95% confidence interval, 0.38 0.64). Long-term survival was unaffected by method of revascularization for either body mass index strata (P > .05). CONCLUSIONS: Patients with high and low body mass indices experience reduced morbidity and in-hospital mortality when undergoing off-pump coronary artery bypass grafting. Despite a higher risk profile, patients with a body mass index <25 who underwent off-pump coronary artery bypass grafting experienced a significant reduction in in-hospital mortality. PMID- 23084106 TI - Restraint to the left ventricle alone is superior to standard restraint. AB - OBJECTIVE: In standard ventricular restraint therapy, a single level of restraint is applied to the entire ventricular surface. We showed previously that at high restraint levels, cardiac tamponade develops because of the thin-walled right ventricle, even while the left ventricle remains unaffected. We now hypothesize that applying restraint exclusively to the left ventricle permits higher levels of restraint, resulting in increased benefit to the left ventricle. METHODS: The acute effect of restraint applied to the left ventricle alone was analyzed in healthy and cardiomyopathic sheep hearts. Restraint therapy was applied by fluid filled epicardial balloons placed solely around the left ventricle. Restraint level was defined by the measured balloon luminal pressure at end diastole. At incrementally higher restraint levels (0, 3, 5, 8, 10, 12, and 14 mm Hg), transmural myocardial left ventricular pressure (P(tm) = Left ventricle pressure Balloon pressure) and indices of myocardial oxygen consumption were measured in healthy sheep (n = 5) and in sheep with heart failure (n = 6). RESULTS: Increasing restraint from 0 to 14 mm Hg decreased transmural myocardial pressure by 48.8% (P <= .02) and the left ventricle tension-time index by 39.1% (P <= .01), and the pressure-volume area decreased by 58.4% (P <= .01). Similarly, stroke work decreased by 57.9% (P <= .03). Systemic hemodynamics were unchanged. There was no difference in the trend for all indices between animals that were healthy and those with heart failure. CONCLUSIONS: We showed previously that, with standard restraint, right ventricle tamponade develops at high restraint levels, limiting restraint therapy. We now show that restraint applied to the left ventricle alone permits increased restraint levels, without causing right ventricle or left ventricle tamponade, for greater therapeutic benefit. We conclude that partial left ventricle restraint may be more effective than standard restraint. PMID- 23084107 TI - Stanford type a aortic dissection in pregnancy: a diagnostic and management challenge. AB - BACKGROUND: In women under the age of 40, over 50% of type A aortic dissections occur in the obstetric population. This is a complex situation, with potential catastrophic outcomes for mother and child. Time to diagnosis is often delayed by a low degree of suspicion, atypical presentation and difficulties investigating pregnant women. Management requires early involvement of multiple teams and appreciation of potential complications. We report our experience (the largest series described) and describe our surgical strategy. METHODS: A retrospective search of the cardiothoracic surgical database at our centre from 2002 to 2010 identified five pregnant women with type A dissections. RESULTS: Median time to diagnosis was 18.5 h (range 5.5-150 h) and median time from diagnosis to arrival in the operating theatre was 1.5 h (range 0.5-54 h). Four patients underwent concomitant Caesarean section and dissection repair. There was one maternal death and one unrelated foetal death. CONCLUSION: Occurrence of type A aortic dissection in pregnant women is uncommon but potentially catastrophic. A high index of suspicion and timely investigations are necessary to expedite definitive management. Sound surgical strategies and collaboration with appropriate teams are necessary to optimise outcome. PMID- 23084108 TI - What is an acceptable risk of major adverse cardiac event in chest pain patients soon after discharge from the Emergency Department?: a clinical survey. PMID- 23084109 TI - Eosinophils and Kounis hypersensitivity associated syndrome as contributors to very late coronary stent thrombosis. PMID- 23084110 TI - Troponin levels after TAVI are related to the development of distinct electrocardiographic changes. PMID- 23084111 TI - Stent flexibility versus concertina effect: mechanism of an unpleasant trade-off in stent design and its implications for stent selection in the cath-lab. AB - The "concertina effect", longitudinal deformation of the proximal segments of a deployed stent when force is applied from a guide catheter or other equipment, is a recently recognised problem which seems to particularly affect more recent stent designs. Until now, flexibility and deliverability have been paramount aims in stent design. Developments have focussed on optimising these features which are commonly evaluated by clinicians and demanded by regulatory bodies. Contemporary stent designs now provide high flexibility by reducing the number of connecting links between stent segments and by allowing the connecting links to easily change their length. These design evolutions may, however, simultaneously reduce longitudinal strength and have the unintended effect of inducing some risk of longitudinal compression of the stent (the "concertina effect") during difficult clinical cases. Progress in stent design and elimination of restenosis by drug coating has improved PCI outcome and enabled new applications. Here we discuss design trade-offs that shaped evolution and improvement in stent design, from early bare metal designs to the latest generation of drug eluting stent (DES) platforms. Longitudinal strength was not recognised as a critical parameter by clinicians or regulators until recently. Measurements, only now becoming publically available, seem to confirm vulnerability of some modern designs to longitudinal deformation. Clinicians could be more guarded in their assumption that changes in technology are beneficial in all clinical situations. Sometimes a silent trade-off may have taken place, adopting choices that are favourable for the vast majority of patients but exposing a few patients to unintended hazard. PMID- 23084112 TI - Diagnosis, severity grading and prognosis of left ventricular non-compaction using cardiovascular magnetic resonance. PMID- 23084113 TI - Impact of a recent hospitalization on treatment and prognosis of ST-segment elevation myocardial infarction. PMID- 23084114 TI - Using risk difference as opposed to odds-ratio in meta-analysis. Response. PMID- 23084115 TI - Iodine deficiency among Belgian pregnant women not fully corrected by iodine containing multivitamins: a national cross-sectional survey. AB - Low iodine intake during pregnancy may cause thyroid dysfunction in pregnant women and their newborn. In the present study, iodine status among a nation-wide representative sample of Belgian pregnant women in the first and third trimester of pregnancy was determined, and determinants of iodine status were assessed 1 year after the introduction of bread fortified with iodised salt. The women were selected according to a multistage proportionate-to-size sampling design. Urine samples were collected and a general questionnaire was completed face to face with the study nurse. The median urinary iodine concentration (UIC) among pregnant women (n 1311) was 124.1mg/l and 122.6 mg/g creatinine when corrected for urinary creatinine. The median UIC in the first trimester (118.3 mg/l) was significantly lower than that in the third trimester (131.0 mg/l) but significantly higher than among non-pregnant women (84.8 mg/l). Iodine-containing supplement intake was reported by 60.8% of the women and 57.4% of the women took this supplement daily. The risk of iodine deficiency was significantly higher in younger women, in women not taking iodine-containing supplements, with low consumption of milk and dairy drinks and during autumn. Women with a higher BMI had a higher risk of iodine deficiency but the risk was lower in women who reported alcohol consumption. The median UIC during pregnancy indicates iodine deficiency in Belgium and some women are at a higher risk of deficiency. The current low iodine intake in women of childbearing age precludes the correction of iodine deficiency in pregnant women supplemented with multivitamins containing 150 mg iodine as recommended. PMID- 23084116 TI - Application of a Re-Pd bimetallic catalyst for treatment of perchlorate in waste ion-exchange regenerant brine. AB - Concentrated sodium chloride (NaCl) brines are often used to regenerate ion exchange (IX) resins applied to treat drinking water sources contaminated with perchlorate (ClO(4)(-)), generating large volumes of contaminated waste brine. Chemical and biological processes for ClO(4)(-) reduction are often inhibited severely by high salt levels, making it difficult to recycle waste brines. Recent work demonstrated that novel rhenium-palladium bimetallic catalysts on activated carbon support (Re-Pd/C) can efficiently reduce ClO(4)(-) to chloride (Cl(-)) under acidic conditions, and here the applicability of the process for treating waste IX brines was examined. Experiments conducted in synthetic NaCl-only brine (6-12 wt%) showed higher Re-Pd/C catalyst activity than in comparable freshwater solutions, but the rate constant for ClO(4)(-) reduction measured in a real IX waste brine was found to be 65 times lower than in the synthetic NaCl brine. Through a series of experiments, co-contamination of the IX waste brine by excess NO(3)(-) (which the catalyst reduces principally to NH(4)(+)) was found to be the primary cause for deactivation of the Re-Pd/C catalyst, most likely by altering the immobilized Re component. Pre-treatment of NO(3)(-) using a different bimetallic catalyst (In-Pd/Al(2)O(3)) improved selectivity for N(2) over NH(4)(+) and enabled facile ClO(4)(-) reduction by the Re-Pd/C catalyst. Thus, sequential catalytic treatment may be a promising strategy for enabling reuse of waste IX brine containing NO(3)(-) and ClO(4)(-). PMID- 23084117 TI - Fecal source tracking in water using a mitochondrial DNA microarray. AB - A mitochondrial-based microarray (mitoArray) was developed for rapid identification of the presence of 28 animals and one family (cervidae) potentially implicated in fecal pollution in mixed activity watersheds. Oligonucleotide probes for genus or subfamily-level identification were targeted within the 12S rRNA - Val tRNA - 16S rRNA region in the mitochondrial genome. This region, called MI-50, was selected based on three criteria: 1) the ability to be amplified by universal primers 2) these universal primer sequences are present in most commercial and domestic animals of interest in source tracking, and 3) that sufficient sequence variation exists within this region to meet the minimal requirements for microarray probe discrimination. To quantify the overall level of mitochondrial DNA (mtDNA) in samples, a quantitative-PCR (Q-PCR) universal primer pair was also developed. Probe validation was performed using DNA extracted from animal tissues and, for many cases, animal-specific fecal samples. To reduce the amplification of potentially interfering fish mtDNA sequences during the MI-50 enrichment step, a clamping PCR method was designed using a fish-specific peptide nucleic acid. DNA extracted from 19 water samples were subjected to both array and independent PCR analyses. Our results confirm that the mitochondrial microarray approach method could accurately detect the dominant animals present in water samples emphasizing the potential for this methodology in the parallel scanning of a large variety of animals normally monitored in fecal source tracking. PMID- 23084118 TI - Reduction of N-nitrosodimethylamine with zero-valent zinc. AB - N-Nitrosodimethylamine (NDMA) is known as the disinfection by-product and the pollutant in the source water. Reduction with zero-valent zinc (Zn(0)) was investigated as a potential technology to treat NDMA. The results showed that Zn(0) was effective for NDMA reduction at initial pH 7.0. There were lag period and rapid period during the process, the corresponding zero-order rate constant (k(zero)) was 2.968 +/- 0.245 MUg L(-1) h(-1) ([Zn(0)](0) = 10g L(-1)),the mass normalized pseudo-first-order rate (k(M)) was 0.1215 +/- 0.0171 L g(-1) h(-1). The reactivity of zinc on NDMA removal was consistent with the zinc corrosion rate. NDMA had little effect on the corrosion of zinc. Lower solution pH benefited the reduction of NDMA with Zn(0). The consumption of the oxygen and the localized acidification should be the cause of the shift from lag to rapid reaction period in the aerobic experiments. 1,1-dimethylhydrazine (unsymmetrical dimethylhydrazine, UDMH), dimethylamine (DMA) were detected as the products of NDMA degradation. The nitrogen mass balance at 24 h was 56%, the loss can be due to the formation of ammonium, the degradation of UDMH and other unmeasured products. DMA formed during the degradation of UDMH with Zn(0), the nitrogen loss could be caused by the formation of unmeasured products. Catalytic hydrogenation is proposed to be the mechanism based on the results and the redox properties of zinc and NDMA. One reduction process is: the active hydrogen atoms initially cleave and reduce the N=O bond in NDMA, generating UDMH. Then the N-N bond in UDMH is cleaved to form DMA and ammonium. PMID- 23084119 TI - [Primitive neuroectodermal tumour of soft tissue of the index finger in an adult. A case report]. AB - The primitive neuroectodermal tumours (PNET) of soft tissues belong to the Ewing's tumors family and affects particularly the child. The localization of the disease at the extremities is very rare within the adult population and raises the problem of differential diagnosis with others tumors of the soft tissues. We report the case of a 48-year-old patient with a localized tumor, at the level of the second right finger, of six months evolution. The biopsy showed the infiltrating nature of the tumour; and the diagnosis of (PNET) was confirmed after the histological and immunohistochemical study. The extension assessment was negative and the patient had an amputation of the second and third rays of the right hand. Four years afterwards, the patient showed no recurrence or metastases. PMID- 23084120 TI - Weaning from mechanical ventilation: why are we still looking for alternative methods? AB - Most patients who require mechanical ventilation for longer than 24 hours, and who improve the condition leading to the indication of ventilatory support, can be weaned after passing a first spontaneous breathing test. The challenge is to improve the weaning of patients who fail that first test. We have methods that can be referred to as traditional, such as the T-tube, pressure support or synchronized intermittent mandatory ventilation (SIMV). In recent years, however, new applications of usual techniques as noninvasive ventilation, new ventilation methods such as automatic tube compensation (ATC), mandatory minute ventilation (MMV), adaptive support ventilation or automatic weaning systems based on pressure support have been described. Their possible role in weaning from mechanical ventilation among patients with difficult or prolonged weaning remains to be established. PMID- 23084121 TI - Efficacy of HER2-targeted therapy in metastatic breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. AB - Therapies targeting the human epidermal growth factor receptor (HER) 2 are effective in metastatic breast cancer (MBC). We review the efficacy of HER2 directed therapies, focussing on monoclonal antibodies and tyrosine kinase inhibitors targeting HER2 that have been tested in phase II-III studies in MBC. Trastuzumab is an important component of first-line treatment of HER2-positive MBC. New anti-HER2 drugs have the potential to change clinical practice. The potential role of the different drugs and regimens is yet to be determined. The response rate for trastuzumab-DM1 of 26-64% is comparable to those obtained for capecitabine plus lapatinib (48%), continuing trastuzumab in combination with capecitabine (48%), pertuzumab plus trastuzumab (24%), and neratinib (24%). Strategies combining multiple HER2-directed therapies might yield additive or synergistic effects and lead to improved outcome. The future challenges include understanding HER2 functions, designing rational combinations and optimal selection of patients. PMID- 23084122 TI - Differential associations of myopia with major age-related eye diseases: the Singapore Indian Eye Study. AB - PURPOSE: To determine the associations of myopia and axial length (AL) with major age-related eye diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), age-related cataract, and primary open-angle glaucoma (POAG). DESIGN: Population-based, cross-sectional study. PARTICIPANTS: A total of 3400 Indians (75.6% response rate) aged 40 to 84 years in Singapore. METHODS: Refractive error was determined by subjective refraction, and AL was determined by noncontact partial coherence laser interferometry. Age-related macular degeneration and DR were defined from retinal photographs according to the Wisconsin Age-Related Maculopathy Grading System and Airlie House classification system, respectively. Age-related cataract was diagnosed clinically using the Lens Opacity Classification System (LOCS) III system. Glaucoma was defined according to International Society for Geographical and Epidemiological Ophthalmology criteria. MAIN OUTCOME MEASURES: Age-related macular degeneration, DR, age-related cataract, and POAG. RESULTS: Myopic eyes (spherical equivalent [SE] <-0.5 diopter [D]) were less likely to have AMD (early plus late AMD) (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.25-0.79) or DR (OR, 0.68; 95% CI, 0.46-0.98) compared with emmetropic eyes; each millimeter increase in AL was associated with a lower prevalence of AMD (OR, 0.76; 95% CI, 0.65-0.89) and DR (OR, 0.73; 95% CI, 0.63-0.86). Myopic eyes were more likely to have nuclear (OR, 1.57; 95% CI, 1.13-2.20) and posterior subcapsular (OR, 1.73; 95% CI, 1.10-2.72) cataract, but not cortical cataract (P = 0.64); each millimeter increase in AL was associated with a higher prevalence of posterior subcapsular cataract (PSC) (OR, 1.29; 95% CI, 1.07-1.55), but not nuclear (P = 0.77) or cortical (P = 0.39) cataract. Eyes with high myopia (SE <-6.0 D) were more likely to have POAG (OR, 5.90; 95% CI, 2.68-12.97); each millimeter increase in AL was associated with a higher prevalence of POAG (OR, 1.43; 95% CI, 1.13-1.80). CONCLUSIONS: Myopic eyes are less likely to have AMD and DR but more likely to have nuclear cataract, PSC, and POAG. The associations of myopia with AMD, DR, and POAG are mostly explained by longer AL. However, the association between myopia and nuclear cataract is explained by lens refraction rather than AL. PMID- 23084123 TI - Applicants' choice of an ophthalmology residency program. AB - OBJECTIVE: To determine the factors most important to applicants when selecting an ophthalmology residency program. DESIGN: Cross-sectional survey. PARTICIPANTS: All 595 applicants who submitted a rank list to the Ophthalmology Residency Matching Program for the 2012 match. METHODS: Participants anonymously completed a 25-item questionnaire after the submission of their rank lists. A multiple choice format and ordinal scale were used to query applicants on demographics, career plans, and the importance of factors related to program characteristics. One question allowed a free text response to identify factors that caused the applicant to rank a program lower than other programs or not at all (i.e., "red flag"). MAIN OUTCOME MEASURES: Factors important to applicants when creating their rank lists. RESULTS: The response rate was 37% (218/595). The 3 most important factors affecting rank lists were resident-faculty relationships, clinical and surgical volume, and diversity of training. The fourth most important was the interview experience with faculty; poor interview experience was the most frequently cited "red flag." Age, gender, and marital status did not affect how applicants rated factors. Applicants planning a post-residency fellowship or an academic career placed greater importance on opportunities for resident research and a program's prestige (P<0.0001). Female and ethnic minority applicants placed greater importance on the diversity of faculty and residents by gender or ethnicity (P<0.0001). CONCLUSIONS: Applicants rated educational and interpersonal factors as more important than geographic factors when selecting an ophthalmology residency program. Future career plans and demographic factors influenced the rating of specific factors. The results of this study provide a useful resource to programs preparing for the match. PMID- 23084124 TI - Anwar versus Melles deep anterior lamellar keratoplasty for keratoconus: a prospective randomized clinical trial. AB - PURPOSE: To compare the outcomes of 2 techniques (Anwar vs. Melles) of deep anterior lamellar keratoplasty (DALK) in patients with keratoconus. DESIGN: Randomized, double-blind clinical trial. PARTICIPANTS: Fifty-seven eyes of 57 patients 20 to 35 years of age were enrolled. METHODS: Patients with clinical diagnosis of keratoconus who were contact lens intolerant and whose corrected distance visual acuity (CDVA) was less than 20/80 were enrolled. Eligible eyes were allocated randomly into 2 groups: the Anwar technique (23 eyes) or the Melles technique (25 eyes). MAIN OUTCOME MEASURES: The primary outcome measure was CDVA. Secondary outcomes were spherical equivalent, contrast sensitivity, corneal aberrations, corneal biomechanical properties, endothelial cell count, and central corneal thickness. All outcomes were compared 15 months after surgery. RESULTS: The CDVA was 0.17 +/- 0.09 logarithm of the minimum angle of resolution (logMAR) units and 0.18 +/- 0.11 logMAR units in the Anwar and Melles groups, respectively (P = 0.803). Spherical equivalent was -1.82 +/- 2.7 diopters (D) and -2.69 +/- 3.94 D in the Anwar and Melles groups, respectively (P = 0.155). Overall, the difference in photopic and mesopic contrast sensitivity function between the 2 groups was statistically significant (P<0.05). There was no significant difference between 2 groups in total and higher-order aberrations up to the fifth order (P>0.05 for all parameters). Corneal hysteresis was not significantly different between the 2 groups (9.9 +/- 0.8 vs. 9.9 +/- 0.6; P = 0.606). The corneal resistance factor was 10.02 +/- 0.8 and 10.13 +/- 0.76 (P = 0.509). There was no significant difference in percentage of endothelial cell loss between the 2 groups (1 +/- 2% vs. 1 +/- 3% in the Anwar and Melles groups, respectively; P = 0.869). Mean central corneal thickness was 525.56 +/- 47.87 MUm versus 504.64 +/- 54.20 MUm in the Anwar and Melles groups, respectively (P = 0.155). CONCLUSIONS: The Anwar and Melles techniques of DALK have comparable visual acuity and refractive outcomes, aberrometric profiles, biomechanical properties, corneal thicknesses, and endothelial cell densities. However, patients who underwent the Anwar technique showed better contrast sensitivity. PMID- 23084125 TI - Endoscopic transcaruncular repair of large medial orbital wall fractures near the orbital apex. AB - PURPOSE: To study the suitability of an endoscopic transcaruncular approach (ETA) for repair of large medial orbital wall fractures (MOWFs) near the orbital apex. DESIGN: A retrospective, noncomparative case series with description of the surgical technique. PARTICIPANTS: Ninety-three consecutive patients (93 orbits) with large isolated MOWFs near the orbital apex. METHODS: The isolated MOWFs were determined by computed tomography (CT) scans of the orbit in all patients. All patients underwent fracture repair by an ETA, and the vertical and horizontal dimensions of the defects were measured during surgery. Porous polyethylene sheets (1.0 mm thick) were used to repair the bony defects. Patients were followed for 6 to 15 months. MAIN OUTCOME MEASURES: Size of vertical and horizontal fracture defects, rate of complete repair of the fracture defects, correction of enophthalmos, resolution of diplopia, and complications 6 months after surgery. RESULTS: All surgeries were completed uneventfully. The mean postoperative follow-up time was 9.7 +/- 3.0 months. Under direct endoscopic visualization, all entrapped and herniated orbital contents were released and reposited, the entire boundary of the fractures were exposed adequately, and the implants were placed to overlie all edges of the fracture stably in all cases. The vertical and horizontal fracture defects measured during surgeries ranged from 16 to 30 mm and from 25 to 34 mm, respectively. Six months after surgery, complete reconstruction of the bony defects was demonstrated by orbital CT scans, and symmetry of the both eyes was acquired in 92 of 93 patients (98.9%). Of 30 patients with significant preoperative enophthalmos of more than 2 mm, 29 (96.7%) were corrected, with a mean improvement of 3.37 +/- 0.77 mm. Diplopia within the 30 degrees visual field of the gaze was resolved in 40 of 43 patients (93.0%). Three patients (7.0%) had residual diplopia on medial gaze because of presumed paralysis of the medial rectus muscle. Intraorbital hemorrhage occurred in 1 patient the day after surgery and resolved with conservative treatment. CONCLUSIONS: The ETA seems to be a useful method for recovery of the normal anatomic features of the orbits for patients with large MOWFs near the orbital apex. PMID- 23084126 TI - Acute intraocular inflammation caused by endotoxin after intravitreal injection of counterfeit bevacizumab in Shanghai, China. AB - PURPOSE: To describe an outbreak of intraocular inflammation caused by endotoxin contaminated counterfeit bevacizumab in China. DESIGN: Retrospective, observational case series. PARTICIPANTS: Patients undergoing intravitreal injection at a public hospital in September 2010. METHODS: The medical records and microbiology results of patients who presented with intraocular inflammation after injection with intravitreal counterfeit bevacizumab were reviewed. MAIN OUTCOME MEASURES: The incidence of intraocular inflammation, results of pathogen cultures, and clinical features of inflammation. RESULTS: A total of 116 patients (70 men and 46 women) were injected from 3 vials of counterfeit bevacizumab. Intraocular inflammation developed in 80 patients. The estimated median incubation period was 12 hours (range, 2-24 hours), and the median duration of symptoms was 6 days (range, 3-22 days). All patients were treated initially with topical corticosteroid and antibiotics. Vitreous tap and intravitreal injection were performed on 43 patients. Twenty-one patients with hypopyon and significant vitreous inflammation underwent vitrectomy. Microscopic evaluations and microbiologic cultures of all ocular specimens were negative for bacterial and fungal contamination. The presence of endotoxin in specimens was confirmed by laboratory testing. We refer to this new clinical syndrome as "endotoxin-induced ocular toxic syndrome" (EOTS). The inflammation regressed rapidly after treatment, and 63 patients (78.8%) recovered their pre-injection vision. CONCLUSIONS: This study implicates endotoxin as the cause of intraocular inflammation after the intravitreal injection of counterfeit bevacizumab. The EOTS appeared clinically distinct from typical infectious endophthalmitis. PMID- 23084127 TI - Evaluation of inner retinal layers in patients with multiple sclerosis or neuromyelitis optica using optical coherence tomography. AB - PURPOSE: To evaluate the thickness of the inner retinal layers in the macula using frequency-domain optical coherence tomography (fd-OCT) in patients with demyelinating diseases. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 301 eyes of 176 subjects were evaluated. Subjects were divided in 5 different groups: controls, neuromyelitis optica (NMO), longitudinally extensive transverse myelitis (LETM), multiple sclerosis with a history of optic neuritis (MS-ON), and multiple sclerosis without a history of optic neuritis (MS non-ON). METHODS: The individual layers from macular fd-OCT cube scans were segmented with an automated algorithm and then manually hand-corrected. For each scan, we determined the thickness of the retinal nerve fiber layer (RNFL), the combined retinal ganglion cell and inner plexiform layers (RGCL+), and the inner nuclear layer (INL). MAIN OUTCOME MEASURES: Macular RNFL, RGCL+, and INL thickness. RESULTS: The RNFL was significantly thinner than in controls for all patient groups (P <= 0.01). Macular RGCL+ thickness was significantly thinner than in controls for the NMO, MS-ON, and MS non-ON groups (P<0.001 for the 3 groups). The INL thickness was significantly thicker than in controls for the patients with NMO (P = 0.003) and LETM (P = 0.006) but not for those with MS-ON or MS non-ON. Although the RNFL and RGCL+ were not significantly different between the NMO and MS-ON groups, the patients with NMO had a significantly thicker INL than the patients with MS-ON (P = 0.02). CONCLUSIONS: Macular RNFL and RGCL+ demonstrate axonal and neural loss in patients with MS, either with or without ON, and in patients with NMO. In addition, the INL thickening occurs in patients with NMO and patients with LETM, and study of this layer may hold promise for differentiating between NMO and MS. PMID- 23084128 TI - Cataract surgery in patients with nanophthalmos. AB - PURPOSE: To report the visual outcomes and complications of cataract surgery in a large series of patients with nanophthalmos. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Forty-three eyes with an axial length <= 20.5 mm of 32 adult patients who underwent cataract surgery in a tertiary clinic. METHODS: Medical records of patients undergoing cataract surgery between 1994 and 2010 were reviewed. MAIN OUTCOME MEASURES: Best-corrected visual acuity (BCVA) at 6 months after surgery and postoperative complications occurring during the entire follow-up period. RESULTS: Forty-three eyes of 32 patients (aged 19-87 years; median, 69 years) were included. Cataract surgery resulted in improvement of >= 3 Snellen lines in 19 eyes (44.2%). Two eyes (4.7%) lost >= 3 Snellen lines because of corneal decompensation in one and angle-closure glaucoma in the other. During the entire follow-up period, complications occurred in 12 eyes (27.9%). The most frequent complications were uveal effusion (9.3%) and cystoid macular edema (CME) (7.0%). CONCLUSIONS: Cataract surgery in patients with nanophthalmos remains a surgical challenge, and complications often occur in these high-risk eyes. PMID- 23084129 TI - Why patients in critical care do not receive adequate enteral nutrition? A review of the literature. AB - Enteral nutrition is frequently used to provide nutrients for critically ill patients. However, only about half of critically ill enterally fed patients receive their energy requirements. Underfeeding is associated with detrimental clinical outcomes including infection, pressure ulcers, impaired wound healing, prolonged hospital stays, and increased morbidity and mortality. This literature review was conducted to identify major barriers to adequate enteral nutrition intake in critically ill adults and to identify gaps in the research literature. Studies (n = 30) reviewed addressed adult patients in critical care, published since 1999, and written in English. Findings showed that factors that explain inadequate enteral nutritional intake include delayed initiation of enteral nutrition and slow advancement of infusion rate, underprescription, incomplete delivery of prescribed nutrition, and frequent interruption of enteral nutrition. Frequent interruption was caused by diagnostic tests, surgical procedures, gastrointestinal intolerance, feeding tube problems, and routine nursing procedures. There are no standardized protocols that address these barriers to receiving adequate enteral intake. Such protocols must be developed, implemented, and tested to address undernutrition and mitigate the negative consequences of inadequate enteral intake. PMID- 23084130 TI - Reasons underlying interhospital transfers to an academic medical intensive care unit. AB - PURPOSE: Interhospital critical care transfers are common, yet few studies address the underlying reasons for transfers. We examined clinician and patient/surrogate perceptions about interhospital transfers and assessed their agreement on these transfers. MATERIALS AND METHODS: This is a mixed-mode survey of 3 major stakeholders in interhospital transfers to an academic medical intensive care unit from August 2007 to April 2008. RESULTS: Sixty-two hospitals transferred 138 patients during the study period. Response rates varied among stakeholders (accepting physician, 90%; referring physicians, 20%; patients/surrogates, 33%). All 3 groups frequently endorsed quality of care and need for a specific test/procedure as important. Referring hospital reputation and quality were rarely endorsed. Accepting physicians and patients/surrogates substantially agreed on the need for a specific test (kappa = 0.70) and increased survival (kappa = 0.78) but, otherwise, had fair to poor agreement. Referring physicians and patients/surrogates rarely agreed and sometimes disagreed greater than expected by chance (kappa < 0). Physician pairs strongly agreed on the importance of accepting hospital experience (kappa = 0.96) but agreed less on patient satisfaction at the referring hospital (kappa = 0.37) and referring hospital reputation (kappa = 0.35). CONCLUSIONS: Stakeholders do not always agree on the reasons for critical care transfers. Efforts to improve communication are warranted to ensure informed patient choices. PMID- 23084131 TI - The impact of body mass index on the physiology of patients with polytrauma. AB - PURPOSE: Obesity is a growing problem in industrial nations. The aim was to test the hypothesis that overweight patients face early physiologic impairment. METHODS: A total of 651 patients were included in this retrospective study, with an injury severity score greater than 16 and 16 years or older. The sample was subdivided into 3 groups: body mass index (BMI) less than 25 kg/m(2), BMI of 25 to 30 kg/m(2), and BMI greater than 30 kg/m(2). Physiologic scores-Murray, Goris, Marshall and Sequential Organ Failure Assessment scores-were analyzed at admission and at the day of their maximum. Analysis of variance and chi(2) tests were used, and the significance level was set at P < .05. RESULTS: All 4 scores showed significant differences at their maxima according to the 3 BMI groups, respectively: Murray score (P < .001), Goris score (P < .05), Marshall score (P < .001), and Sequential Organ Failure Assessment score (P <.05). The injury severity score values of the 3 groups at admission were 27.6 +/- 12.0, 29.6 +/- 13.2, and 25.3 +/- 9.2, respectively (P < .05). The overall mortality rates in the 3 groups were 15.1%, 21.0%, and 20%, respectively (P < .001). CONCLUSIONS: Anticipating BMI-specific critical trauma problems will become mandatory for effective polytrauma treatment in industrialized nations given their increasing prevalence of obesity. PMID- 23084132 TI - Central venous pressure and shock index predict lack of hemodynamic response to volume expansion in septic shock: a prospective, observational study. AB - PURPOSE: Volume expansion is a common therapeutic intervention in septic shock, although patient response to the intervention is difficult to predict. Central venous pressure (CVP) and shock index have been used independently to guide volume expansion, although their use is questionable. We hypothesize that a combination of these measurements will be useful. METHODS: In a prospective, observational study, patients with early septic shock received 10-mL/kg volume expansion at their treating physician's discretion after brief initial resuscitation in the emergency department. Central venous pressure and shock index were measured before volume expansion interventions. Cardiac index was measured immediately before and after the volume expansion using transthoracic echocardiography. Hemodynamic response was defined as an increase in a cardiac index of 15% or greater. RESULTS: Thirty-four volume expansions were observed in 25 patients. A CVP of 8 mm Hg or greater and a shock index of 1 beat min(-1) mm Hg(-1) or less individually had a good negative predictive value (83% and 88%, respectively). Of 34 volume expansions, the combination of both a high CVP and a low shock index was extremely unlikely to elicit hemodynamic response (negative predictive value, 93%; P = .02). CONCLUSIONS: Volume expansion in patients with early septic shock with a CVP of 8 mm Hg or greater and a shock index of 1 beat min(-1) mm Hg(-1) or less is unlikely to lead to an increase in cardiac index. PMID- 23084133 TI - Early initiation of continuous renal replacement therapy improves patient survival in severe progressive septic acute kidney injury. AB - PURPOSE: The definition of "early" in terms of continuous renal replacement therapy (CRRT) initiation has not been uniformly used. Therefore, we tried to elucidate whether the timing of CRRT application, based on the interval between the start time of vasopressors infusion and CRRT initiation, was an independent predictor of mortality in the patients with septic acute kidney injury (AKI). MATERIALS AND METHODS: Progressive septic AKI patients, in whom the infusion doses of vasopressors were increased compared with the initial dose during the first 6 hours of vasopressor treatment and CRRT was performed, between 2009 and 2011, were collected and divided into 2 groups based on the median interval between the 2 points. RESULTS: A total of 210 patients were included. The mean age was 62.4 years, and 126 patients (60.0%) were male. The most common comorbid disease was malignancy (53.8%), followed by hypertension (35.7%) and diabetes mellitus (29.0%). The median interval between the start time of vasopressor infusion and CRRT commencement was 2.0 days. During the study period, 156 patients (74.3%) died within 28 days of CRRT application. The interval between 2 points was significantly shorter in the survivor compared with the death group (P < .001). Moreover, 28-day overall mortality rates in the early CRRT group were significantly lower than those in the late CRRT group (P = .034). Furthermore, early CRRT treatment was independently associated with a lower mortality rate even after adjustment for age, sex, causative organisms, and infection sites (P = .032). CONCLUSIONS: This retrospective cohort study suggests that early initiation of CRRT may be of benefit. Given the complex nature of this intervention, the ongoing controversies regarding early vs late initiation of therapy in acute and chronic situation, there is an urgent need to develop well designed clinical trials to answer the question definitely. PMID- 23084134 TI - The effects of hemodialysis on blood glutamate levels in chronic renal failure: implementation for neuroprotection. AB - PURPOSE: The purpose of the present study is to investigate whether hemodialysis (HD) is effective in lowering blood glutamate levels. In addition, we examined the effect of HD on glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate transaminase (GPT) levels in the blood and described the rate and pattern of blood glutamate clearance during HD. MATERIALS AND METHODS: Blood samples were taken from 45 patients with stage V chronic kidney disease immediately after initiation of HD and hourly, for a total of 5 blood samples. Samples were sent for determination of glutamate, glucose, GOT, GPT, hemoglobin, hematocrit, urea, and creatinine levels. A blood sample from 25 healthy volunteers without chronic renal failure was used as a control for the determination of baseline blood levels of glutamate, GOT, and GPT. RESULTS: Glutamate and GPT levels in patients on HD were higher at baseline compared with healthy controls (P < .001). In the first 3 hours after HD, there was a decrease in blood glutamate levels compared with baseline levels (P < .00001). At the fourth hour, there was an increase in blood glutamate levels compared with the third hour (P < .05). CONCLUSIONS: Hemodialysis may be a promising method of reducing blood glutamate levels. PMID- 23084135 TI - Systemic and microcirculatory effects of dobutamine in patients with septic shock. AB - PURPOSE: The aim of this study was to characterize the cardiovascular responses to dobutamine and their predictors. Our hypotheses were that dobutamine mainly produces tachycardia and vasodilation and fails to improve the microcirculation of patients with septic shock. MATERIALS AND METHODS: Systemic hemodynamics and sublingual microcirculation were evaluated with dobutamine (0, 2.5, 5.0, and 10.0 MUg kg(-1) min(-1)) in 23 patients with septic shock. RESULTS: Dobutamine increased heart rate, cardiac index, and stroke volume index (SVI). Mean blood pressure was unchanged, and systemic vascular resistance decreased. Individual responses were heterogeneous. Stroke volume index increased in 52% of the patients. These patients showed lower changes in mean blood pressure (3 +/- 16 mm Hg vs -10 +/- 6 mm Hg, P < .05) and higher increases in cardiac index (1.47 +/- 0.93 L m(-1) m(-2) vs 0.20 +/- 0.5 L m(-1) m(-2)) than did nonresponders. Changes in SVI significantly correlated with echocardiographic left ventricular ejection fraction (r = 0.55). In the whole group, perfused capillary density remained unchanged (14.0 +/- 4.3 mm/mm(2) vs 14.8 +/- 3.7 mm/mm(2)), but improved if basal values were 12 mm/mm(2) or less (9.1 +/- 4.3 mm/mm(2) vs 12.5 +/- 4.8 mm/mm(2)). CONCLUSIONS: Dobutamine produced variable hemodynamic effects. Systolic dysfunction was the only variable associated with increases in SVI. Finally, dobutamine only improved sublingual microcirculation when severe alterations were found at baseline. PMID- 23084137 TI - Genetic analysis of metabolome-phenotype interactions: from model to crop species. AB - The past decade has seen increased interest from the scientific community, and particularly plant biologists, in integrating metabolic approaches into research aimed at unraveling phenotypic diversity and its underlying genetic variation. Advances in plant metabolomics have enabled large-scale analyses that have identified qualitative and quantitative variation in the metabolic content of various species, and this variation has been linked to genetic factors through genetic-mapping approaches, providing a glimpse of the genetic architecture of the plant metabolome. Parallel analyses of morphological phenotypes and physiological performance characteristics have further enhanced our understanding of the complex molecular mechanisms regulating these quantitative traits. This review aims to illustrate the advantages of including assessments of phenotypic and metabolic diversity in investigations of the genetic basis of complex traits, and the value of this approach in studying agriculturally important crops. We highlight the ground-breaking work on model species and discuss recent achievements in important crop species. PMID- 23084136 TI - Diagnosis and treatment of post-extubation dysphagia: results from a national survey. AB - PURPOSE: This study sought to determine the utilization of speech-language pathologist (SLPs) for the diagnosis and treatment of post-extubation dysphagia in survivors of mechanical ventilation. METHODS: We designed, validated, and mailed a survey to 1,966 inpatient SLPs who routinely evaluate patients for post extubation dysphagia. RESULTS: Most SLP diagnostic evaluations (60%; 95% CI, 59% 62%) were performed using clinical techniques with uncertain accuracy. Instrumental diagnostic tests (such as fluoroscopy and endoscopy) are more likely to be available at university than community hospitals. After adjusting for hospital size and academic affiliation, instrumental test use varied significantly by geographical region. Treatments for post-extubation dysphagia usually involved dietary adjustment (76%; 95% CI, 73-79%) and postural changes/compensatory maneuvers (86%; 95% CI, 84-88%), rather than on interventions aimed to improve swallowing function (24%; 95% CI, 21-27%). CONCLUSIONS: SLPs frequently evaluate acute respiratory failure survivors. However, diagnostic evaluations rely mainly upon bedside techniques with uncertain accuracy. The use of instrumental tests varies by geographic location and university affiliation. Current diagnostic practices and feeding decisions for critically ill patients should be viewed with caution until further studies determine the accuracy of bedside detection methods. PMID- 23084138 TI - Ocular surface cell biology--from the light to the dark side. PMID- 23084139 TI - The origin of tears. III. The lipid component in the XIX and XX centuries. PMID- 23084140 TI - Wakayama Symposium: Current concepts of ocular surface cell biology. PMID- 23084141 TI - Wakayama Symposium: Epithelial-mesenchymal interactions in eyelid development. AB - Various congenital anomalies of the eyelids can result from abnormal tissue proliferation, fusion, and reopening of the eyelids. Therefore, it is important to study the molecular mechanisms underlying eyelid development, focusing on cell behaviors. Mammalian eyelid development occurs in four steps: specification, growth, epithelial fusion, and reopening. Epithelial-mesenchymal interactions are fundamental processes during eyelid formation, and epithelial factors functioning within the eyelid epithelium are also critical. Studies with mutant and genetically modified mice have revealed that various signaling pathways and transcriptional factors are involved in mouse eyelid development. In this review, eyelid morphogenetic factors or pathways are described, as revealed by their mutant phenotype, eye-open at birth (EOB). These include FGFR2b-FGF10, EGFR-ERK, MEKK-JNK, BMP, Shh, Wnt, GPR48, Jun, Forkhead, and Grainyhead. PMID- 23084142 TI - Wakayama Symposium: Epithelial-mesenchymal interaction regulates tissue formation and characteristics: insights for corneal development. AB - Epithelial-mesenchymal interactions and epithelial-to-mesenchymal transition (EMT) are essential during tissue formation and organ morphogenesis. The roles of Wnt/beta-catenin signaling have been studied in many organ systems. In this review, we describe the importance of Wnt/beta-catenin signaling by comparing skin and corneal development of Wnt/beta-catenin gain of function (GOF) mutant mice. In the skin, Wnt/beta-catenin signals have been suggested to play essential roles in regulating cell-cell interaction, cell proliferation and differentiation. Wnt signaling may be associated with basal cell carcinoma (BCC) of the skin. In the case of cornea, beta-catenin GOF mutation leads to epithelial hyperplasia. Investigation of the mechanisms of growth factor signaling as a reference to general organogenesis could provide profound insights for understanding corneal development and pathogenesis. PMID- 23084143 TI - Wakayama Symposium: Notch-FoxL2-alpha-SMA axis in eyelid levator muscle development and congenital blepharophimosis. AB - This review summarizes our recent findings regarding the Notch signaling pathway in regulating normal eyelid morphogenesis and its role in the pathogenesis of human congenital blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES). We used genetic and molecular biological approaches to investigate the mechanism by which Notch1 activation controls expression of FoxL2, which in turn activates smooth muscle actin gene expression in periocular mesenchyma to control eyelid levator smooth muscle formation. PMID- 23084145 TI - Analysis of meibum and tear lipids. AB - The meibum is a lipid-rich secretion that is the primary component of the external layer of the tear film. The meibomian glands produce the meibum, and meibomian gland dysfunction can lead to degradation of the tear film. Such dysfunction can result in ocular irritation, inflammation, and clinical disease. Understanding this relationship is critical to preventing ocular disease; therefore, a search of peer-reviewed literature focusing on the collection, quantification, and analysis of normal and abnormal meibum and tear lipids was conducted. Numerous collection and quantification techniques are described, including their advantages and disadvantages. Studies indicate that the meibum and tear lipids consist of a large array of polar and nonpolar lipids; individual lipids or their classes can be correlated to pathology. Significant amounts of lipids are deposited on contact lenses, depending on the nature of their polymer chemistry. These findings taken together indicate that normal meibum and tear lipids are essential for normal ocular health. Additional studies are required to provide a better understanding of the meibum and tear film biomolecules so that more effective treatments for blepharitis, dry eye disease, and tear film-related contact lens complications can be devised. PMID- 23084144 TI - Wakayama Symposium: Peroxisome proliferator-activated receptor-gamma (PPARgamma) and meibomian gland dysfunction. AB - Recently we have shown that mouse and human meibomian glands undergo specific age related changes, including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPARgamma) localization from cytoplasmic-vesicular/nuclear in young mice and humans to nuclear in old mice and humans. Since PPARgamma is a lipid-sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPARgamma may be involved in modulating meibomian gland differentiation during aging. Based on these findings, we propose that aging of the meibomian gland results in downregulation of PPARgamma, leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory meibomian gland dysfunction. PMID- 23084146 TI - Management of pigmented conjunctival lesions. AB - Pigmented conjunctival lesions primarily include melanoma, nevus, primary acquired melanosis (PAM), and complexion-associated melanosis. The incidence of conjunctival malignant melanoma (CMM) has significantly increased in the USA and Europe over the years, and it carries a very serious risk for metastasis and melanoma-related death. Conjunctival melanoma can arise de novo or from precursor lesions, nevus, and PAM. PAM is histologically separated into two distinct forms: PAM with atypia and without atypia. PAM with severe atypia progresses to malignant melanoma in up to 50% of cases and PAM without atypia virtually never progresses. Nevus is a benign melanocytic tumor that only rarely undergoes malignant transformation. Complexion-associated melanosis is frequently seen in more darkly pigmented individuals and does not progress to melanoma, although it can become very large. A detailed literature review on the various pigmented conjunctival lesions together with a schematic approach to diagnosis and management is presented. PMID- 23084147 TI - The benefit/risk of good therapeutics. PMID- 23084149 TI - Femoral cross-pin breakage and its effects on the results of anterior cruciate ligament reconstruction using a hamstring autograft. AB - PURPOSE: The primary aim was to determine the rate and risk factors of double biodegradable femoral cross-pin breakage after anterior cruciate ligament reconstruction using a hamstring autograft. In addition, we compared clinical outcomes and magnetic resonance imaging (MRI) findings related to grafts for knees with and without a broken cross-pin. METHODS: A retrospective review of 53 knees (53 patients) was performed. Cross-pin breakage was determined by follow-up MRI. Age, sex, weight, height, presence of a posterior transcortical cross-pin breach, time between surgery and follow-up MRI, graft diameter, and cross-pin position (superior or inferior) were included in the analysis. Differences in Lysholm knee scores, International Knee Documentation Committee grades, anterior laxity, and pivot-shift test results were examined in relation to cross-pin breakage. In addition, anterior cruciate ligament graft integrity and osseous graft integration by MRI were assessed and compared between knees with broken cross-pins and knees with intact cross-pins. RESULTS: A cross-pin was broken in 25 of 53 knees. A cross-pin posterior transcortical breach was the only factor found to be significantly correlated with cross-pin breakage (odds ratio, 6.117; P = .033) by univariate analysis. No significant differences in clinical outcomes were found to be related to cross-pin breakage, but femoral tunnel enlargement was more frequent in knees with breakage than in those without (P = .002). CONCLUSIONS: Breakage of biodegradable cross-pins used for femoral fixation is relatively common but did not affect clinical outcomes. However, femoral tunnel enlargement was found to be greater in knees with a broken cross-pin. The only significant relation found was between a cross-pin posterior transcortical breach and breakage, which suggests that pin breakage is related to a technical error. These findings should be borne in mind when a double biodegradable cross-pin is being considered for femoral fixation. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23084148 TI - The Twin Research Registry at SRI International. AB - The Twin Research Registry (TRR) at SRI International is a community-based registry of twins established in 1995 by advertising in local media, mainly on radio stations and in newspapers. As of August 2012, there are 3,120 same- and opposite-sex twins enrolled; 86% are 18 years of age or older (mean age 44.9 years, SD 16.9 years) and 14% less than 18 years of age (mean age 8.9 years, SD 4.5); 67% are female, and 62% are self-reported monozygotic (MZ). More than 1,375 twins have participated in studies over the last 15 years in collaboration with the University of California Medical Center in San Francisco, the University of Texas MD Anderson Cancer Center, and the Stanford University School of Medicine. Each twin completes a registration form with basic demographic information either online at the TRR Web site or during a telephone interview. Contact is maintained with members by means of annual newsletters and birthday cards. The managers of the TRR protect the confidentiality of twin data with established policies; no information is given to other researchers without prior permission from the twins; and all methods and procedures are reviewed by an Institutional Review Board. Phenotypes studied thus far include those related to nicotine metabolism, mutagen sensitivity, pain response before and after administration of an opioid, and a variety of immunological responses to environmental exposures, including second-hand smoke and vaccination for seasonal influenza virus and Varicella zoster virus. Twins in the TRR have participated in studies of complex, clinically relevant phenotypes that would not be feasible to measure in larger samples. PMID- 23084150 TI - Comparison of mini-open versus arthroscopic harvesting of osteochondral autografts in the knee: a cadaveric study. AB - PURPOSE: To prove that the assessment of osteochondral graft perpendicularity with magnetic resonance imaging (MRI) will allow for a precise measurement of graft perpendicularity and for an improved comparison of arthroscopic versus mini open harvest techniques. METHODS: Ten fresh cadaveric knees (mean age, 39.4 years) underwent harvest of 6-mm osteochondral plugs using the Osteochondral Autograft Transfer System (OATS; Arthrex, Naples, FL). A total of 8 plugs were harvested per knee from 3 donor sites: the lateral supracondylar ridge, the medial supracondylar ridge, and the lateral intercondylar notch. Two surgeons performed the graft harvest, alternating between mini-open (5 specimens) and arthroscopic (5 specimens) techniques to minimize bias. The osteochondral plugs were labeled and plated by a novel agar plating technique and then underwent MRI for measurement of graft perpendicularity. The data were analyzed to look for a significant difference in perpendicularity between the 2 harvest techniques, as well as overall graft acceptability. RESULTS: One specimen in the open harvest technique group was unable to undergo optimal MRI because of difficulties encountered with the novel agar plating system resulting in graft movement during imaging. When we compared the mini-open and arthroscopic harvest techniques, the mean angle of perpendicularity at the lateral intercondylar notch harvest site was 84.1 degrees and 84.2 degrees , respectively (P = .958). At the medial supracondylar ridge harvest site, the mean angle of perpendicularity for the mini open and arthroscopic techniques was 88.4 degrees and 81.0 degrees , respectively, with a mean difference of 7.4 degrees (P = .006). At the lateral supracondylar ridge harvest site, the mean angle of perpendicularity for the mini open and arthroscopic techniques was 85.7 degrees and 87.1 degrees , respectively (P = .237). CONCLUSIONS: A significant difference in osteochondral autograft perpendicularity was noted at the medial supracondylar ridge when we compared the mini-open and arthroscopic harvesting techniques. This suggests that when one is harvesting autologous osteochondral grafts from the medial supracondylar ridge, the mini-open technique may be preferred. CLINICAL RELEVANCE: When harvesting autologous osteochondral grafts from the medial supracondylar ridge of the knee, the mini-open technique will potentially allow for a more perpendicular graft for implantation. PMID- 23084151 TI - Arthroscopic reconstruction of isolated subscapularis tears: clinical results and structural integrity after 24 months. AB - PURPOSE: The purpose of this study was to evaluate the magnetic resonance imaging (MRI) and clinical results of arthroscopic repair of isolated subscapularis tears at 24 months' follow-up. METHODS: We prospectively followed up 20 patients with isolated subscapularis tears treated with arthroscopic repair with suture anchors in a 3-year period (January 2006 to December 2008) at our institution. Clinical examination of the patients and functional scores (Constant and University of California, Los Angeles [UCLA] scores) were obtained preoperatively and at 6 months, 12 months, and 24 months postoperatively. MRI and routine radiographs were obtained to evaluate the repair at the last follow-up. RESULTS: Of the patients (mean age, 42 years; age range, 31 to 56 years), 19 (95%) had complete follow-up. Constant and UCLA scores improved significantly after the repair at all postoperative examinations. The Constant score gained 39.7 points to a mean of 81 points (range, 61 to 95 points) at last follow-up, and the UCLA score improved from 16 points to 32 points (range, 25 to 35 points). Of the shoulders, 13 had a concomitant lesion of the long head of the biceps; 12 were treated with biceps tenodesis. At last follow-up, there were 2 retears detected by both MRI and examinations (positive belly-press and liftoff tests). Seventeen patients were satisfied with their results at 24 months postoperatively. CONCLUSIONS: Arthroscopic repair of isolated subscapularis tendon tears is an effective technique with good-to-excellent clinical and functional results. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23084152 TI - Histologic assessment of acetabular labrum healing. AB - PURPOSE: The purpose of this study was to histologically examine the human healing response of arthroscopically repaired acetabular labrum tears. METHODS: Biopsy specimens were retrieved from 6 patients during total hip arthroplasty after clinical failure of the index arthroscopic procedure. All patients were diagnosed as having femoroacetabular impingement with a concomitant labral tear. In all cases severe chondral damage was observed during arthroscopy (Beck grades 3 to 4). Despite successful technical repair of the labral tear, chondral damage in these patients was so advanced that the clinical progress after the procedure was unsatisfactory and arthroplasty of the joint was required. Biopsy specimens of the repaired acetabular labra were harvested during the arthroplasty surgery and processed for standard histologic evaluation. RESULTS: Macroscopically and histologically, all repaired labra kept their triangular shape more or less and appeared to have healed. All harvested biopsy specimens displayed a typical fibrocartilaginous appearance with limited vascular supply. Calcifications were present in only 1 biopsy specimen. In 3 cases neovascularization of the labral tissue was noticed in the proximity of the sutures. In the superficial and deep parts of the labral body, small clefts were observed in all cases. CONCLUSIONS: In this study the histologic aspects of arthroscopically repaired human labral tears were addressed. It was shown that human labral tears show healing potential after surgical repair. The surfaces of the labral tissues were intact, and neither remnants of the tear nor the presence of fibrovascular scar tissue was observed. However, some small clefts in the superior and deep parts of the repaired structures were noticed in all cases. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 23084153 TI - [The impact of early cranioplasty on cerebral blood flow and its correlation with neurological and cognitive outcome. Prospective multi-centre study on 24 patients]. AB - INTRODUCTION: Cranioplasty after decompressive craniectomy in patients suffering from severe head injury often leads to a functional improvement although, to date, the pathophysiology of this phenomenon remains unclear. A few hypotheses have been proposed. The impact of cranioplasty on cerebral perfusion could be one explanation. We have evaluated the impact of cranioplasty on the functional status of patients undergoing decompressive craniectomy for severe head injury with its influence on cerebral perfusion. MATERIALS AND METHODS: Twenty-four patients undergoing craniectomy for severe head injury were included in this multi-centric and prospective study. All of them had a cranioplasty within 12 weeks following decompressive craniectomy. A clinical and radiological evaluation was performed prior to and after cranioplasty. Neurological and cognitive evaluation was performed with the Glasgow Outcome Score (GOS), the Frontal Assessment Battery (FAB) and the Mini Mental State Examination (MMSE). Radiological evaluation was performed by perfusion CT scan and transcranial Doppler. RESULTS: A statistically significant neurological and cognitive improvement was observed in 92% of patients at 6 months follow-up (F-U). Brain perfusion was improved at 6 weeks F-U, predominantly in the affected hemisphere. Systolic and diastolic blood velocity flow were improved in both middle cerebral arteries. CONCLUSION: Cranioplasty after decompressive craniectomy for patients suffering from severe head injury probably improves the functional outcome of these patients, thanks to a global improvement of cerebral perfusion. PMID- 23084154 TI - Is level- and side-specific multifidus asymmetry a marker for lumbar disc pathology? AB - BACKGROUND CONTEXT: Several reports suggest that level- and side-specific multifidus atrophy or fat infiltration may be related to localized spinal pathology and symptoms. In particular, a study using a porcine model reported rapid level- and side-specific multifidus atrophy and adipocyte enlargement resulting from anterolateral disc or nerve root lesions. PURPOSE: To investigate asymmetry in cross-sectional area (CSA) and fat infiltration in multifidus and other paraspinal muscles in patients with acute or subacute unilateral symptoms of radiculopathy and concordant posterolateral disc herniation. If multifidus asymmetry is indeed related to local pathology, this may serve as a marker for helping to target the search for less clearly identifiable pathology responsible for low back-related symptoms, which currently remains elusive in approximately 85% of those seeking care. STUDY DESIGN: Cross-sectional observational study. PATIENT SAMPLE: Subjects were patients referred to magnetic resonance imaging (MRI) with unilateral leg symptoms of less than 6 weeks onset suggestive of radiculopathy, with a consistent posterolateral lumbar disc herniation verified on imaging. METHODS: Using T2-weighted axial MRI, measurements were obtained for total muscle CSA and signal intensity, functional (fat-free) CSA, and the ratio of functional CSA to total CSA. RESULTS: Forty-three subjects met the inclusion criteria. The ratio of functional CSA to total muscle CSA was smaller on the side of the herniation than on the unaffected side, both below (mean 0.69 vs. 0.72, p=.007) and at the level of herniation (mean 0.78 vs. 0.80, p=.031). Multifidus signal intensity (fat infiltration) was greater on the side of the herniation at the level below the herniation (p=.014). Contrary to expectation, greater total multifidus CSA was found ipsilateral to the pathology at the level of herniation (p=.033). No asymmetries were found at the level above the herniation or in any other paraspinal muscles, with the exception of higher signal in the erector spinae at the level and side of herniation. CONCLUSIONS: Multifidus may be particularly responsive to, or indicative of, localized lumbar disc or nerve root pathology within the first 6 weeks of symptoms as expressed through fat infiltration, but not through CSA asymmetry on MRI. However, such measurements are not reliable markers of lumbar pathology on an individual basis for use in clinical or research settings. PMID- 23084155 TI - Sentinel lymph node dissection only versus complete axillary lymph node dissection in early invasive breast cancer: a systematic review and meta analysis. AB - BACKGROUND: The Z0011-study, a landmark randomised controlled trial (RCT) challenged the benefits of complete axillary lymph node dissection (ALND) compared with sentinel lymph node dissection only (SLND) in breast cancer patients with positive sentinel nodes. The study, however, has been criticised for lack of power and low applicability. The aim of this review was to systematically assess the evidence on the comparative benefits and harms of ALND versus SLND for sentinel node positive breast cancer patients. METHODS: We systematically searched PubMed, Embase, the Cochrane Library, and reference lists of pertinent review articles from January 2006 to August 2011. We dually reviewed the literature and rated the risk of bias of each study. For effectiveness, we included RCTs and observational studies of at least 1 year follow-up. In addition, we considered studies conducted in sentinel node-negative women to assess the risk of harms. If data were sufficient, we conducted random effects meta-analysis of outcomes of interest. RESULTS: Meta-analysis of three studies with 50,120 patients indicated similar 5-year survival and regional recurrence rates between patients treated with ALND or SLND, although prognostic tumour characteristics varied among the 3 study-populations. Results from 6 studies on more than 11,500 patients reported a higher risk for harms for ALND than SLND. Long-term evidence on pertinent health outcomes is missing. CONCLUSION: The available evidence indicates that for some women with early invasive breast cancer SLND appears to be a justifiable alternative to ALND. Surgeons need to discuss advantages and disadvantages of both approaches with their patients. PMID- 23084156 TI - Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses: a rare case. AB - OBJECTIVE: We report a rare case of small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses with intracranial extension, and discuss the management of this rare tumour. RESULTS: Small cell neuroendocrine carcinoma involving the nasal cavity and paranasal sinuses with intracranial extension may be treated successfully with surgery alone, without development of local recurrence. CONCLUSION: Small cell neuroendocrine carcinoma is a locally aggressive tumour with a high rate of recurrence. Early and aggressive surgical excision with or without radiotherapy or chemotherapy can improve a patient's outcome and prognosis. Regular follow up is needed to detect any local or distant recurrence. PMID- 23084157 TI - Wavefront-optimized excimer laser in situ keratomileusis for myopia and myopic astigmatism: refractive outcomes and corneal densitometry. AB - PURPOSE: To determine the refractive outcomes of wavefront-optimized laser in situ keratomileusis (LASIK) treatments, in particular to measure corneal densitometry after LASIK using the densitometry function of the Pentacam Scheimpflug system. SETTING: Division of Ophthalmology and Visual Sciences, University of Nottingham, United Kingdom. DESIGN: Cohort study. METHODS: Changes in postoperative visual acuity, refraction, and contrast sensitivity were evaluated after wavefront-optimized laser treatment. Corneal densitometry was evaluated with the Scheimpflug system before and after LASIK. RESULTS: One year postoperatively, the uncorrected distance visual acuity was 6/6 or better in 92% of eyes and 6/9 or better in all eyes. Eighty-six percent of eyes had no change in the corrected distance visual acuity (CDVA); 4% gained 1 or more lines. Wavefront-optimized LASIK was stable over 1 year postoperatively. Eighty-nine percent of eyes were within +/-0.50 diopter (D) and 100% were within +/-1.00 D of the intended correction 1 year postoperatively. Contrast sensitivity showed a nonsignificant improvement (1.55 +/- 0.10 [SD] preoperatively to 1.57 +/- 0.09 12 months postoperatively) (P > .05). There was a nonsignificant increase in corneal densitometry 1 year postoperatively (from 12.72 +/- 2.43 to 13.04 +/- 2.58) (P > .05). No correlation was found between corneal densitometry and contrast sensitivity or CDVA. CONCLUSIONS: Wavefront-optimized LASIK gave excellent refractive and visual outcomes and did not seem to affect corneal densitometry significantly 1 year postoperatively. However, larger studies may show a masked effect on corneal densitometry. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23084158 TI - Ultrasound-promoted coating of silk yarn with different morphology of magnesium hydroxide nanostructures. AB - The growth of magnesium hydroxide nanostructures on silk yarn was achieved by sequential dipping steps in alternating bath of magnesium nitrate and potassium hydroxide under ultrasound irradiation. The effects of ultrasound irradiation, concentration, pH and sequential dipping steps on growth of the Mg(OH)(2) nanostructures have been studied. Morphology of the nanostructures, depending on pH and with decreasing pH from 13 to 8, changed from nanoparticle to nanoneedle. Results show a decrease in the particles size as the concentration and sequential dipping steps increased. The physicochemical properties of the nanostructures were determined by powder X-ray diffraction (XRD), scanning electron microscopy (SEM) and wavelength dispersive X-ray (WDX). PMID- 23084159 TI - The immediate and lasting effects of adolescent homelessness on suicidal ideation and behavior. PMID- 23084160 TI - Special requirements for electronic medical records in adolescent medicine. AB - Adolescents are a group likely to seek and, perhaps, most likely to benefit from electronic access to health information. Despite significant advances in technical capabilities over the past decade, to date neither electronic medical record vendors nor many health care systems have adequately addressed the functionality and process design considerations needed to protect the confidentiality of adolescent patients in an electronic world. We propose a shared responsibility for creating the necessary tools and processes to maintain the adolescent confidentiality required by most states: (1) system vendors must provide key functionality in their products (adolescent privacy default settings, customizable privacy controls, proxy access, and health information exchange compatibility), and (2) health care institutions must systematically address relevant adolescent confidentiality policies and process design issues. We highlight the unique technical and process considerations relevant to this patient population, as well as the collaborative multistakeholder work required for adolescent patients to experience the potential benefits of both electronic medical records and participatory health information technology. PMID- 23084161 TI - Children who run away from home: risks for suicidal behavior and substance misuse. AB - PURPOSE: The primary aim of this study is to examine the extent to which running away from home as a child is associated with behavioral problems and victimization during childhood and with suicidal behavior and substance abuse during early adulthood. METHODS: A random probability sample comprising 7,461 respondents was interviewed for the 2007 survey of psychiatric morbidity of adults in England. A subsample of 16- to 34-year-old individuals was selected for secondary analysis (N = 2,247). All survey respondents were asked whether they had run away from home and asked specific questions on being physically, emotionally and sexually abused as children. They were also asked about suicidal behavior and alcohol and drug dependence in early adulthood. RESULTS: Approximately 7% of 16- to 34-year-old individuals reported running away from home before the age of 16 years, with higher rates in women than in men (9.8% compared with 5.3%). Overall, 45.3% reported being bullied, 25.3% experienced violence at home, and 8.8% reported unwanted sexual intercourse. Runaways were far more likely than other children to have suffered victimization and family difficulties and to exhibit behavioral problems. Adults who reported running away from home were three times more likely than other adults to have thought about or attempted suicide, but the relationship with substance abuse was far less pronounced. CONCLUSIONS: Sexual, physical, and emotional abuse, along with family difficulties, can all impact children who run away from home. Running away from home was strongly associated with suicidal behavior in adulthood, regardless of other childhood adversities. PMID- 23084162 TI - YFHS-WHO+ Questionnaire: validation of a measure of youth-friendly primary care services. AB - PURPOSE: To develop and validate a research tool to measure the youth friendliness of primary care services from a client's perspective. METHODS: The questionnaire was initially developed in English, but as it was to be used in Bosnia and Herzegovina (BiH), it was validated in the language of this country. Items were adapted from two sources: a reproductive health services quality improvement questionnaire from the World Health Organization, and an Australian survey used to assess youth-friendly primary care services. An English-speaking international panel reviewed the list of items for face validity. After translation-back translation, the questionnaire was pretested with adolescent patients from a family practice in BiH. The stability and construct validation were then conducted with 60 young people from six different health services in BiH. Items for the final questionnaire were selected using item response theory. RESULTS: The validation and item response analysis led to a 49-item tool. Test retest stability at 1 week was excellent (mean kappa: .93). Construct validation was supported by the fact that services with the highest and the lowest scores on the questionnaire were also those that had many and few, respectively, youth friendly characteristics, as assessed by experts, on a predefined evaluation grid. Services seeing a higher proportion of adolescents also had higher scores on the questionnaire. CONCLUSIONS: This study supports the validity of the YFHS WHO+ questionnaire for assessing the level of youth friendliness of family medicine services for research purposes. Further validations in English and French will allow wider use of this tool in the future. PMID- 23084163 TI - "Coaching boys into men": a cluster-randomized controlled trial of a dating violence prevention program. AB - PURPOSE: Dating violence (DV)--physical, sexual, and psychological aggression in adolescent romantic relationships--is prevalent among youth. Despite broad calls for primary prevention, few programs with demonstrated effectiveness exist. This cluster-randomized trial examined the effectiveness of a DV perpetration prevention program targeting coaches and high school male athletes. METHODS: The unit of randomization was the high school (16 schools), and the unit of analysis was the athlete (N = 2,006 students). Primary outcomes were intentions to intervene, recognition of abusive behaviors, and gender-equitable attitudes. Secondary outcomes explored bystander behaviors and abuse perpetration. Regression models for clustered, longitudinal data assessed between-arm differences in over-time changes in mean levels of continuous outcomes in 1,798 athletes followed up at 3 months. RESULTS: Intervention athletes' changes in intentions to intervene were positive compared with control subjects, resulting in an estimated intervention effect of .12 (95% CI: .003, .24). Intervention athletes also reported higher levels of positive bystander intervention behavior than control subjects (.25, 95% CI: .13, .38). Changes in gender-equitable attitudes, recognition of abusive behaviors, and DV perpetration were not significant. Secondary analyses estimated intervention impacts according to intensity of program implementation. Compared with control subjects, athletes exposed to full-intensity implementation of the intervention demonstrated improvements in intentions to intervene (.16, 95% CI: .04, .27), recognition of abusive behaviors (.13, 95% CI: .003, .25), and positive bystander intervention (.28, 95% CI: .14, .41). CONCLUSION: This cluster-randomized controlled trial supports the effectiveness of a school athletics-based prevention program as one promising strategy to reduce DV perpetration. PMID- 23084164 TI - Older adolescents' views regarding participation in Facebook research. AB - PURPOSE: Facebook continues to grow in popularity among adolescents as well as adolescent researchers. Guidance on conducting research using Facebook with appropriate attention to privacy and ethics is scarce. To inform such research efforts, the purpose of this study was to determine older adolescents' responses after learning that they were participants in a research study that involved identification of participants using Facebook. METHODS: Public Facebook profiles of older adolescents aged 18-19 years from a large state university were examined. Profile owners were then interviewed. During the interview, participants were informed that they were identified by examining publicly available Facebook profiles. Participants were asked to discuss their views on this research method. RESULTS: A total of 132 participants completed the interview (70% response rate); the average age was 18.4 years (SD = .5); and our sample included 64 male participants (48.5%). Participant responses included endorsement (19.7%), fine (36.4%), neutral (28.8%), uneasy (9.1%), and concerned (6.1%). Among participants who were uneasy or concerned, the majority voiced confusion regarding their current profile security settings (p = .00). CONCLUSIONS: The majority of adolescent participants viewed the use of Facebook for research positively. These findings are consistent with the approach taken by many U.S. courts. Researchers may consider these findings when developing research protocols involving Facebook. PMID- 23084165 TI - Motivational subtypes of nonmedical use of prescription medications: results from a national study. AB - PURPOSE: Very little research has examined the heterogeneity associated with the nonmedical use of prescription medications (NUPM) in nationally representative samples of adolescents. The main objectives of this study were to (1) identify motivational subtypes of past-year NUPM among high school seniors in the United States using a person-centered approach, and (2) examine the associations among motivational subtypes and characteristics of substance abuse (i.e., route of administration, co-ingestion, and subjective high). METHODS: Self-administered questionnaires as part of the Monitoring the Future study were completed by nationally representative samples of high school seniors (modal age, 18 years). The sample consisted of five cohorts (senior years of 2002-2006) made up of 12,431 high school seniors in total, of which 53% were women. RESULTS: Approximately 75% of past-year nonmedical users of prescription opioids, stimulants, and tranquilizers endorsed more than one motive. Latent class analysis indicated five motivational subtypes associated with nonmedical use of prescription opioids (experiment, relax, get high, pain relief, and affect regulation), four subtypes of prescription stimulants (weight loss/enhance energy, enhance energy/awake/high, experiment, and affect regulation), and five subtypes of prescription tranquilizers (experiment, get high, relax/sleep, relax, affect regulation). Recreational subtypes were positively associated with characteristics of substance abuse, whereas self-treatment subtypes were associated with medical use before nonmedical use. CONCLUSIONS: Because multiple motives underlie NUPM, identifying subgroups of individuals who endorse combinations of motives, versus a single motive, will better inform intervention efforts to reduce nonmedical prescription medication use. PMID- 23084166 TI - A teacher-delivered intervention for adolescents exposed to ongoing and intense traumatic war-related stress: a quasi-randomized controlled study. AB - PURPOSE: For the past 8 years, the residents of Sderot-a town in southern Israel have been exposed to ongoing and intense war-related threat due to daily rocket attacks and mortar shelling from the adjacent Gaza region. This study first evaluates the prevalence of posttraumatic symptomatology in a sample of seventh- and eighth-grade students, and then assesses the efficacy of a universal teacher delivered skill-oriented and present-focused intervention in preventing and reducing adolescents' posttraumatic stress-related symptoms. METHOD: In a quasi randomized controlled trial, 154 seventh- and eighth-grade students with significant levels of war-related exposure were assigned to participate in either a manualized active 16-session intervention (Extended Enhancing Resiliency Amongst Students Experiencing Stress, ERASE-Stress) or a waiting-list control group. They were assessed using self-report measures before and after the intervention on posttraumatic stress-related symptoms, somatic complaints, functional impairment, and anxiety. RESULTS: At baseline, 43.5% were found to have a likely diagnosis of posttraumatic stress disorder. A month after the intervention ended, students in the active intervention showed statistically significant reduction on all outcome measures compared with those in the waiting list control group. CONCLUSIONS: Extended ERASE-Stress-a universal teacher delivered skill-oriented program not targeting traumatic memories and involving trained and supervised homeroom teachers-may help students suffering from significant war-related posttraumatic symptoms reduce their level of symptomatology and can serve as an important and effective component of a community mental health policy for communities affected by chronic trauma, such as war and terrorism. PMID- 23084167 TI - Short- and midterm effects of emotional intelligence training on adolescent mental health. AB - PURPOSE: To analyze the effects that an emotional intelligence (EI) educational program based on the EI ability model had on adolescent mental health immediately and 6 months after completion of the training. METHODS: A pretest-posttest quasi experimental design with a treatment and a control group was used; 479 Spanish adolescents (47.4% male, mean age of 13 years) were involved in the study. Adolescents were recruited through several schools in three Spanish cities. The 2 year training program involved 24 sessions lasting 1 hour each, conducted 'weekly during 6 months of 2009 and 2010. Data on psychological adjustment, mental health, and negative affect were collected at baseline, at the end of the training program, and 6 months later. Data were analyzed by multivariate analysis of covariance. RESULTS: Students who participated in the EI educational program reported fewer clinical symptoms compared with students in the control group, and these differences persisted 6 months after the conclusion of the program. CONCLUSIONS: These results suggest that EI programs created to develop skills in perceiving, facilitating, understanding, and managing emotions can be effective at promoting mental health in adolescents. PMID- 23084169 TI - Trajectories of psychosocial problems in adolescents predicted by findings from early well-child assessments. AB - PURPOSE: To describe trajectories of emotional and behavioral problems in adolescents and to identify early indicators of these trajectories using data from routine well-child assessments at ages 0-4 years. METHODS: Data from three assessment waves of adolescents (n = 1,816) of the TRAILS were used (ages: 11-17 years). Information on early indicators (at ages 0-4 years) came from the records of the well-child services. Trajectories of emotional and behavioral problems were based on the parent-reported Child Behavior Checklist and the adolescent reported Youth Self-Report, filled out at ages 11, 14, and 17 years. Multinomial logistic regression analysis was used to examine the predictive value of these early indicators on trajectories. RESULTS: For boys and girls, we found four trajectories for each outcome: one with high problem levels, and three with middle-high, middle-low, and low levels. For emotional problems, the type of trajectory was predicted by parental educational level and parental divorce or single parents, for both genders. Moreover, sleep problems were predictive in boys and language problems in girls (odds ratios between 1.53 and 7.42). For behavioral problems, the type of trajectory was predicted by maternal smoking during pregnancy, parental educational level, and parental divorce or single parents, for both genders. Moreover, for boys, early behavioral problems and attention hyperactivity problems were predictive (odds ratios between 1.64 and 5.43). CONCLUSIONS: Trajectories of emotional and behavioral problems during adolescence are rather stable and can be predicted by a parsimonious set of data from early well-child assessments. PMID- 23084168 TI - Self-weighing behaviors in young adults: tipping the scale toward unhealthy eating behaviors? AB - PURPOSE: This study examined associations between frequency of self-weighing and healthy weight-control behaviors (WCBs), unhealthy WCBs, muscle-enhancing behaviors (e.g., steroid use, protein powders), and psychological well-being (i.e., self-esteem, depression, body satisfaction) in a community sample of young adults. METHODS: Data were drawn from Project EAT-III (Eating and Activity in Teens and Young Adults), the third wave of a population-based study. Participants included young adults (n = 2,287, mean age = 25.3 years) from the Minneapolis/St. Paul metropolitan area. RESULTS: Self-weighing a few times per week or more frequently was reported by 18% of young adult women and 12% of young adult men. Linear regression models, adjusted for body mass index and demographic characteristics, indicated that in both women and men, more frequent self weighing was associated with a higher prevalence of dieting, both healthy and unhealthy WCBs, and muscle-enhancing behaviors. Additionally, young women who reported more frequent self-weighing were more likely to report binge eating. More frequent self-weighing was also associated with more depressive symptoms and lower self-esteem in women and lower body satisfaction in young men. CONCLUSIONS: More frequent self-weighing is associated with healthy and unhealthy weight control practices, muscle-enhancing behaviors, and poorer psychological well being in young adults. Young adults engaging in self-weighing behaviors should be screened for these health indicators and counseled as appropriate. Before recommending self-weighing as a weight-monitoring tool, health care providers should ensure that young adults are not at risk for an unhealthy preoccupation with body weight or shape. PMID- 23084170 TI - The relative odds of involvement in seven crash configurations by driver age and sex. AB - INTRODUCTION: Much is known about sex and age differences in collision types, but most studies have examined the effect of declining physical and mental capabilities on older drivers' performance. Fewer studies have focused on the relationship between younger driver's sex and crash type, and these studies have largely ignored the multidimensionality of crashes, have not consistently examined sex differences, and are based on outdated data. This study addressed these issues by examining differences in the likelihood of involvement in seven crash configurations between adolescent and adult male and female drivers. METHOD: Fatal crash data from the Fatality Analysis Reporting System and nonfatal crash data from the General Estimation System for years 2005-2009 were used. Crash configurations were identified using point of initial impact, manner of collision, and vehicle action (i.e., striking or struck). Logistic regression estimated relative odds ratios among four driver groups: male and female drivers aged 15-19 years, and male and female drivers aged 45-64 years. RESULTS: Crash likelihood varied dramatically by driver age and sex across crash configuration. Adolescent male drivers were most likely to be in single-vehicle and fatal head on crashes; adolescent drivers had a higher likelihood of front-to-rear crashes; adults had the highest likelihood of rear-end crashes; and female drivers had higher likelihoods of left- and right-side crashes. CONCLUSIONS: These findings may result from differences in driving experience, driving styles, or cognitive spatial abilities. Future research is needed to identify contributors to different crash configurations so that they can be directly addressed through tailored interventions and programs. PMID- 23084171 TI - Shared genetic effects between age at menarche and disordered eating. AB - PURPOSE: An early age at menarche is associated with disordered eating in women. However, it is unclear whether they share genetic factors. The goal of the current study was to delineate the genetic correlation between age at menarche and disordered eating. METHODS: Participants included 427 monozygotic and 329 dizygotic 16-17-year-old female twins from the Swedish Twin Study of Child and Adolescent Development. Disordered eating was assessed with the Eating Disorder Inventory-2. Age at menarche was assessed through self-report. A bivariate correlated factors model was used to delineate the genetic correlation between age at menarche and disordered eating. RESULTS: The analysis revealed a negative genetic correlation of -.18 in the best-fit model, indicating that the genetic factors that influence younger age at menarche are associated with increased liability for disordered eating. CONCLUSIONS: Future research should examine possible causes for this correlation, such as the estrogen system and gene environment interactions. PMID- 23084172 TI - Smoking initiation during young adulthood: a longitudinal study of a population based cohort. AB - PURPOSE: To examine the extent to which young adults initiate smoking between the ages of 18 and 21 years; to characterize the frequency and quantity of use among initiators; and to examine predictors of initiation. METHODS: Participants included youth who were part of the Minnesota Adolescent Community Cohort Study and had not smoked a whole cigarette before age of 18 (n = 2,034). Initiation in the present study was defined as having smoked a whole cigarette or more between the ages of 18 and 21. Predictors of initiation were measured at age 18 and included sociodemographic characteristics, social influences, and attitudes and beliefs about smoking. RESULTS: Twenty-five percent (n = 510) of participants initiated smoking between the ages of 18 and 21 years. Among those who initiated, the majority (64%) reported smoking during the past 30 days, and approximately one-quarter (24%) reported smoking 100 cigarettes or more. Predictors of young adult initiation included being male, living in a metropolitan area, having friends who smoke, and the belief that smoking can calm someone down when they are angry or nervous. CONCLUSIONS: This study indicates that smoking initiation during young adulthood is not uncommon. These results highlight the need for tobacco prevention programs that target young adults. PMID- 23084173 TI - Violent peers, network centrality, and intimate partner violence perpetration by young men. AB - PURPOSE: To measure the association between affiliation with violent peers in adolescence and intimate partner violence (IPV) perpetration by men in early adulthood, and how peer network structure influences the strength of this association. METHODS: Using the National Longitudinal Study of Adolescent Health, we analyzed a cohort of male subjects, originally in grades 7-12, reporting on sexual relationships 7 years later. At baseline, peer network violence was estimated as the average of network members' reports of their frequency of fighting during the past year, and centrality (number of friendships) was measured. Logistic regression was used to estimate associations between peer network violence, network centrality, and perpetration of IPV in recent intimate relationships. RESULTS: The probability of IPV perpetration was 37% for young men with a large number of friends (>13) engaging in an average of six to seven fights in the past year. However, young men in small- (<6 friends) or medium sized peer networks (6-13 friends) with these same levels of violence had probabilities of IPV perpetration between 5% and 7%. CONCLUSIONS: School-based interventions that target fighting by male subjects can reduce risk of IPV perpetration later in life. PMID- 23084174 TI - Cross-lagged effects between intimate partner violence victimization and suicidality from adolescence into adulthood. AB - PURPOSE: The current article extended previous research on the association between intimate partner violence (IPV) victimization and suicidality by longitudinally investigating their mutual impact from adolescence into early adulthood. METHODS: We analyzed data from a subsample (N= 4,675) of individuals with complete data on IPV victimization from Waves II (mean age = 16.41 years), III (mean age = 22.36 years), and IV (mean age = 28.85 years) of the National Longitudinal Study of Adolescent Health. Suicidality was measured through questions assessing suicidal thoughts and suicidal attempts during the past 12 months. IPV victimization was measured through a construct assessing whether individuals had experienced threat of violence, being pushed/shoved, or had something thrown at them during the past 12 (Waves III and IV) or 18 (Wave II) months. RESULTS: Using a path analysis framework, we found that IPV victimization and suicidality were highly stable across time. Suicidality was associated with IPV victimization prospectively, but IPV victimization did not predict suicidality prospectively. This longitudinal effect was limited to adolescent suicidality predicting IPV in early adulthood, and this effect was not qualified by gender. CONCLUSIONS: Although the findings from this study confirm the importance of considering concurrent IPV victimization in evaluating risk for suicidality, they also highlight the importance of considering a history of adolescent suicidality as an important risk marker for IPV victimization. PMID- 23084175 TI - The development of associations among body mass index, body dissatisfaction, and weight and shape concern in adolescent boys and girls. AB - PURPOSE: To examine how the associations among body mass index (BMI) and body dissatisfaction and weight and shape concern evolve from late childhood through late adolescence in boys and girls. METHODS: We analyze data from subjects aged 9 18 years from the Growing Up Today Study, a national prospective cohort of U.S. youth (n = 16,882, yielding 59,750 repeated-measures observations during five waves of data collection). Generalized additive models produced curves of association for body dissatisfaction and weight concern across BMI percentiles. Generalized estimating equations (adjusting for correlated within-subject repeated measures, sibling clusters, pubertal maturation, and region of residence) tested main and interactive effects of BMI, age, and gender. RESULTS: Girls above the 50th BMI percentile reported greater body dissatisfaction than girls below the 50th percentile. By contrast, boys who reported the most body dissatisfaction were either above the 75th BMI percentile (approaching overweight) or below the 10th percentile (approaching underweight). Body dissatisfaction increased with age for both girls and boys, but the gender specific patterns of BMI effects remained constant. Male and female participants in the overweight/obese BMI range reported the greatest weight concern, but among older adolescents (particularly girls), healthy weight became increasingly associated with greater weight and shape concern. CONCLUSIONS: Body dissatisfaction and weight and shape concern intensify across adolescence, but associations between the constructs and BMI remain gender specific. Findings have important implications for eating disorder risk assessment and prevention. PMID- 23084176 TI - Assessment of nutritional status and eating disorders in female adolescents with fibromyalgia. AB - PURPOSE: To assess eating disorders, nutritional status, body composition, and food intake in adolescents presenting with fibromyalgia. METHODS: In a cross sectional study, we evaluated the nutritional status (z score of body mass index [ZBMI]), waist circumference, body fat percentage by bioelectrical impedance analysis, symptoms of disordered eating, and possible eating disorders (Kids' Eating Disorders Survey [KEDS]) of 23 female adolescents with fibromyalgia and 23 matched healthy control subjects. RESULTS: Median age for both groups was 15 years. In the fibromyalgia group, the median time for diagnosis was 13.5 months. We did not observe a statistically significant difference between the control and fibromyalgia groups in relation to ZBMI, fat mass percentage, food intake, and symptoms of disordered eating (KEDS). In the fibromyalgia group, there was a significant correlation between fat mass percentage and the total KEDS score (r = .587, p = .003); the same correlation was observed for ZBMI (r = .0778, p < .001). CONCLUSIONS: This study verified an absence of nutritional and eating disorders in adolescents recently diagnosed with fibromyalgia that, in addition to the correlation between adiposity indexes and KEDS total score, emphasizes the importance of nutritional and body composition assessment, allowing an early and adequate nutritional intervention. PMID- 23084177 TI - Do young and older adults have different health care priorities? Evidence from a national survey of English inpatients. AB - PURPOSE: This article compares the inpatient experience of young versus older adults, and assesses the relative importance of different aspects of health care in these two groups. PARTICIPANTS: The study comprised adult inpatients in 161 English hospitals. METHODS: Standardized scores were calculated covering overall care and eight domains of patient experience (consistency, respect, involvement, nursing, doctors, cleanliness, pain control, and privacy). Values for young and older adults were compared. Additionally, Fisher r-to-z transformation was used to assess age differences in the strength of correlation between overall care and individual care domains. RESULTS: Young people reported a poorer experience across all aspects of inpatient care (p < .01). Compared with older adults, young men's overall care rating was more strongly correlated to pain control, and young women's to respect and doctors' characteristics (p < .05). CONCLUSIONS: These findings provide a quantitative national-level evidence base regarding young people's priorities in inpatient care. PMID- 23084178 TI - Using regression to measure holistic face processing reveals a strong link with face recognition ability. AB - Although holistic processing is thought to underlie normal face recognition ability, widely discrepant reports have recently emerged about this link in an individual differences context. Progress in this domain may have been impeded by the widespread use of subtraction scores, which lack validity due to their contamination with control condition variance. Regressing, rather than subtracting, a control condition from a condition of interest corrects this validity problem by statistically removing all control condition variance, thereby producing a specific measure that is uncorrelated with the control measure. Using 43 participants, we measured the relationships amongst the Cambridge Face Memory Test (CFMT) and two holistic processing measures, the composite task (CT) and the part-whole task (PW). For the holistic processing measures (CT and PW), we contrasted the results for regressing vs. subtracting the control conditions (parts for PW; misaligned congruency effect for CT) from the conditions of interest (wholes for PW; aligned congruency effect for CT). The regression-based holistic processing measures correlated with each other and with CFMT, supporting the idea of a unitary holistic processing mechanism that is involved in skilled face recognition. Subtraction scores yielded weaker correlations, especially for the PW. Together, the regression-based holistic processing measures predicted more than twice the amount of variance in CFMT (R(2)=.21) than their respective subtraction measures (R(2)=.10). We conclude that holistic processing is robustly linked to skilled face recognition. In addition to confirming this theoretically significant link, these results provide a case in point for the inappropriateness of subtraction scores when requiring a specific individual differences measure that removes the variance of a control task. PMID- 23084179 TI - [Pain in patients with opiates dependence]. AB - We have to trust the patient. Pain is undertreated. Inadequate treatment has adverse consequences. Over and under treatment are both liabilities. Opioid maintained patients do experience pain. These patients report higher pain scores. They experience both opioid tolerance and hyperalgesia. They are responsive to opioid analgesia. They need baseline opioids ("opioid debt"), mostly a well stabilized OST. They require higher doses, more frequent dosing and longer opioid administration. PMID- 23084180 TI - The development, implementation and evaluation of a cross organisational clinical guideline for the management and prevention of wound infection. AB - BACKGROUND: The Tissue Viability services in acute and primary care in Leeds had concerns about the increasing inappropriate use of topical antiseptic dressings for wound management and were aware that the use was disproportionate to the evidence supporting their prescribing. A scoping exercise of the use of topical antiseptics and systemic antibiotic usage in Leeds led to the identification of heterogeneous prescribing of systemic antibiotics and an almost L500,000 spend on topical antiseptics across Leeds community. METHODS: The project involved the following stages. 1- Local scoping of topical antiseptics and systemic antibiotic prescribing. 2- A cross organisational working group to develop and implement a clinical best practice guideline for the prevention, diagnosis and management of wound infection. 3- Development of a revised local dressings formulary. 4- The establishment of a new referral process to Tissue Viability for wounds requiring topical antiseptic treatments. 5- Evaluation of the new guideline through- monitoring prescribing- monitoring wound sampling- monitoring A & E admissions- collecting patient feedback through the 'Tell Tissue Viability' process. RESULTS: *Expenditure on topical antiseptic dressings for the period Oct 2009-Dec 2009 was L128,864 and this reduced to L65,604 for the period Nov 2011-Jan 2012. This demonstrates an overall saving of L63,260 with a projected annual saving of L237,584 within the community trust alone. *A reduction in the number of wound swabs sent to microbiology from inpatient locations by 1500/year comparing 2008/9 with 2010/11. *An increase in wound swabs sent from GPs by 100/year comparing 2008/9 with 2010/11. *A reduction in penicillin V and co-fluampicil prescriptions and an increase in flucloxacillin prescriptions in general practise suggesting greater concordance with local antibiotic prescribing recommendations. CONCLUSION: The implementation of a clinical guideline in association with support from the specialist team, for patients requiring topical antiseptics has resulted in a reduction in the inappropriate use of topical antiseptics in hospital and community. Wound sampling practises and prescribing practises have changed. No apparent increased risk for patients has been identified but it has not been easy to obtain details about admission to Accident and Emergency with cellulitis and optimising surveillance remains a challenge for the future. PMID- 23084181 TI - Unmet depression information needs in the community. AB - BACKGROUND: Despite the well acknowledged importance of consumer health information, little is known about the public's depression information needs. This study aimed to develop a formal measure of unmet need for depression information in the community, to investigate the level of this unmet need and to identify its predictors. METHODS: Data were collected as part of a survey of 12,319 Australian adults aged 18-65 years. This survey incorporated 21 questions targeting depression information need, together with measures of demographic status, self-reported current depression and personal stigma. The information needs data were subjected to principal components analysis followed by linear regression analyses to determine the demographic and other predictors of each of the resulting components. RESULTS: Between 50 and 75% of participants endorsed the need for more information on each of the 21 information need topics. The PCA yielded a 20-item Depression Information Needs Scale (DINS) of high reliability and factor validity comprising four subscales: General (facts about depression), Specific Treatments, Research and Policies, and Lived Experience. Controlling for other factors, those with self-reported current depression and those without tertiary education had greater information needs across all four factors. LIMITATIONS: The survey response rate was low and further research is required to establish the adequacy of the psychometric properties of the DINS. CONCLUSIONS: Given the high unmet need for depression information there is a need to develop and implement evidence-based strategies for ensuring the accessibility and uptake of depression information relevant to the needs of members of the community. PMID- 23084182 TI - Decreased hypothalamus volumes in generalized anxiety disorder but not in panic disorder. AB - BACKGROUND: The hypothalamus is a brain structure involved in the neuroendocrine aspect of stress and anxiety. Evidence suggests that generalized anxiety disorder (GAD) and panic disorder (PD) might be accompanied by dysfunction of the hypothalamus-pituitary-adrenal axis (HPA), but so far structural alterations were not studied. We investigated hypothalamic volumes in patients with either GAD or PD and in healthy controls. METHODS: Twelve GAD patients, 11 PD patients and 21 healthy controls underwent a 1.5T MRI scan. Hypothalamus volumes were manually traced by a rater blind to subjects' identity. General linear model for repeated measures (GLM-RM) was used to compare groups on hypothalamic volumes, controlling for total intracranial volume, age and sex. RESULTS: The hypothalamus volume was significantly reduced (p=0.04) in GAD patients, with significant reductions in both the left (p=0.02) and right side (p=0.04). Patients with PD did not differ significantly (p=0.73). Anxiety scores were inversely correlated with hypothalamic volumes. LIMITATIONS: The small sample size could reduce the generalizability of the results while the lack of stress hormone measurements renders functional assessment of the hypothalamus-pituitary-adrenal axis not feasible. CONCLUSIONS: The present study showed decreased hypothalamic volumes in GAD patients but not in those with PD. Future longitudinal studies should combine volumetric data with measurements of stress hormones to better elucidate the role of the HPA axis in GAD. PMID- 23084183 TI - Are childhood and adult life adversities differentially associated with specific symptom dimensions of depression and anxiety? Testing the tripartite model. AB - BACKGROUND: Different types of adverse events may have general or specific effects on depression and anxiety symptomatology. We examined the effects of adversities on the dimensions of the tripartite model: general distress, anhedonic depression and anxious arousal. METHODS: Data were from 2615 individuals from the Netherlands Study for Depression and Anxiety (NESDA), with or without depressive or anxiety disorders. We analysed associations of childhood trauma, childhood life events (childhood trauma interview), and recent life events (List of Threatening Events Questionnaire, LTE-Q) with anhedonic depression, anxious arousal, and general distress (assessed by the adapted Mood and Anxiety Symptoms Questionnaire, MASQ-D30). RESULTS: We controlled for co occurrence of adversities. Regarding childhood trauma, only emotional neglect was associated with all three symptom dimensions. Psychological and sexual abuse were associated with general distress and anxious arousal, whereas physical abuse was associated only with anxious arousal. Particularly strong associations were seen for emotional neglect with anhedonic depression and for sexual abuse with anxious arousal. Childhood life events showed no associations with symptom dimensions. The recent life events 'Serious problems with friend', 'Serious financial problems', and 'Becoming unemployed' were associated with all three dimensions. The recent life event 'death of parent/child/sibling' was associated with anxious arousal. Several associations remained significant when controlled for current diagnosis of depression or anxiety. LIMITATIONS: Our cross-sectional analyses do not allow for causal interpretation. CONCLUSIONS: Distinct childhood traumas had different effects on the symptom dimensions, whereas most recent adult life events were associated with all three symptom dimensions. Our observations help to understand the often reported associations of these adversities with depressive and anxiety symptomatology. In addition, symptom dimensions of the tripartite model were shown to capture effects of adverse events on top of those captured by diagnostic categories. PMID- 23084184 TI - Are subjects in treatment trials of panic disorder representative of patients in routine clinical practice? Results from a national sample. AB - BACKGROUND: Research on the generalizability of clinical trials in panic disorder is limited. The present study sought to quantify the generalizability of clinical trials' results of individuals with DSM-IV panic disorder (PD) to a large community sample. METHODS: Data were derived from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC), a large national representative sample of 43,093 adults of the United States population. We applied a standard set of eligibility criteria representative of PD clinical trials to all adults with past 12 months PD (n=907), and then to a subgroup of participants seeking treatment (n=105). Our aim was to determine the proportion of participants with PD who would have been excluded by typical eligibility criteria. RESULTS: We found that more than 8 out of ten participants (80.52%; 95% CI=77.13-83.52%) with PD were excluded by at least one criterion. In the subgroup of participants who sought treatment, the exclusion rate by at least one criterion was higher (92.40%; 95% CI=84.60-96.42%). For the full sample and the treatment-seeking subsample, having currently a depression and a diagnosis of alcohol or drug abuse/dependence were the criteria excluding the highest percentage of participants. Having a lifetime history of bipolar disorder and a current significant medical condition also excluded a substantial proportion of individuals in both samples. Exclusion rates were similar when considering panic disorder with and without agoraphobia. CONCLUSIONS: Clinical trials, that exclude a majority of adults with panic disorder, should carefully consider the impact of eligibility criteria on the generalizability of their results. As required by CONSORT guidelines, reporting exclusion rate estimate and reasons of eligibility should be mandatory in both clinical trials and meta-analyses. PMID- 23084185 TI - Fronto-occipital fasciculus, corpus callosum and superior longitudinal fasciculus tract alterations of first-episode, medication-naive and late-onset panic disorder patients. AB - OBJECTIVE: Because of limited knowledge about white matter (WM) tract in panic disorder, we designed this study to investigate alterations of WM tracts in first episode medication-naive panic disorder patients. METHODS: Thirty patients and 21 normal controls were enrolled into our study. They all received acquisitions of diffusion tensor imaging (DTI) in 30 directions. DTI images of patients and controls were preprocessed and analyzed to estimate differences of WM microintegrity between patients and controls. We obtained fractional anisotropy (FA) values from the DTI images. FA outputs of patients and controls were compared by non-parametric permutation-based method with global brain volume, age, gender and duration of illness as covariates. Correlations between severity of panic symptoms and FA values were also estimated. RESULTS: First-episode, medication-naive and late-onset panic disorder patients had altered integrity in WM tracts of right inferior fronto-occipital fasculi, left body of corpus callosum and left superior longitudinal fasciculus when compared to controls (corrected p<0.05). Negative correlations between PD symptoms and FA values were observed in corpus callosum of patient group (corrected p<0.05). CONCLUSIONS: WM tract alterations might represent structural pathophysiology in WM of first episode, medication-naive and late-onset panic disorder patients. PMID- 23084186 TI - Clinical feature of anaplastic lymphoma kinase-mutated neuroblastoma. AB - PURPOSE: Anaplastic lymphoma kinase (ALK) has recently been identified as a gene conferring a predisposition for neuroblastoma. We have analyzed tyrosine kinase domain mutations and amplification/expression of the ALK gene and focused on clinical features of neuroblastoma cases with ALK aberrations. METHODS: The frequency of ALK mutations, copy number gain, and expression were analyzed in 538 neuroblastoma tumors derived from 361 cases, including 161 cases detected by mass screening. These cases were analyzed according to clinicopathologic features including the International Neuroblastoma Staging System and patient outcomes. RESULTS: Three cases (0.8%) had ALK amplification, and 16 cases (5.2%) had missense mutations at positions F1174, F1245, D1249, and R1275. Among them, 7 cases were diagnosed at more than 14 months of age, and 11 cases were infants, including 9 cases detected by mass screening and 1 multiple neuroblastoma with a germline mutation. Of the 11 infants, 3 cases relapsed, and 1 case died of disease. Among cases detected by screening, activated ALK cases showed significantly worse prognosis (P = .002). Of 7 older cases, 5 had MYC amplifications, and 5 died of disease. The expression levels of ALK were up regulated in cases with unfavorable outcomes. In cases with activated ALK neuroblastoma, survival rates of patients detected by screening were significantly better than those in the clinically detected group (P = .025). CONCLUSIONS: The results of the present study support the hypothesis that activated ALK tumors represent a specific subset of neuroblastomas. These tumors usually develop in infants and may have a high capacity for recurrence. PMID- 23084187 TI - Micro-RNA-21 regulates the sensitivity to cisplatin in human neuroblastoma cells. AB - BACKGROUND/PURPOSE: Drug resistance often causes treatment failure in neuroblastomas. Increasing evidence has implicated that the micro-RNAs (miRNAs) are involved in the development of drug resistance. In this report, we aimed to investigate the role of miRNA in cisplatin resistance of neuroblastoma cells. MATERIALS AND METHODS: The cell viability of the neuroblastoma cells after cisplatin treatment was analyzed. The expression of the miRNAs and phosphatase and tensin homolog (PTEN) messenger RNA in the neuroblastoma cells was studied by real-time polymerase chain reaction. Overexpression of miRNA or suppression of miRNA expression by antagomir was used to investigate the effects of miRNA on the cisplatin-induced cell death or proliferation. RESULTS: The expression of miR-21 was increased in the cisplatin-resistant (CisR) neuroblastoma cells as compared with the parental cells, and the antagomir against miR-21 converted the resistant cells into sensitive ones. Ectopic expression of pre-miR-21 in parental cells resulted in decreased sensitivity to cisplatin treatment. In addition, overexpression of pre-miR-21 markedly increa sed the proliferation rate of neuroblastoma cells. The level of PTEN messenger RNA and protein in the CisR cells was lower than that in the parental cells. Transfection of pre-miR-21 into the parental cells reduced the PTEN expression, and transfection of anti-miR-21 into the CisR cells increased the PTEN expression. CONCLUSION: Micro-RNA-21 regulated the drug resistance and proliferation in neuroblastoma cells. PMID- 23084188 TI - Clinical management of Ewing sarcoma of the bones of the hands and feet: a retrospective single-institution review. AB - BACKGROUND/PURPOSE: Bones of the hands and feet are uncommon sites for Ewing sarcoma. In this study, we reviewed our experience in the management of these tumors. METHODS: We retrospectively reviewed clinical presentation, management, and outcome of patients with Ewing sarcoma of the bones of hands and feet treated at our institution (1981-2006). RESULTS: The cohort included 6 males and 3 females (8 white, 1 African American; median age at diagnosis, 15 years). Primary tumor site was the hand in 6 and the foot in 3 patients. Three patients had distant metastatic disease at diagnosis (lung [n = 2]; ipsilateral axillary lymph node[(n = 1]). All patients had painful swelling at the primary site, and 2 (22%) had pathological fracture. All patients received chemotherapy and local control measures (surgery [n = 6], radiation [n = 2], surgery and radiation [(n = 1]). Three patients received radiotherapy for distant metastases. Three patients had systemic recurrence (lungs [n = 2], lung and brain [n = 1]); none had local tumor recurrence. Median follow-up was 5 years. Five patients (55.6%) are alive at last follow-up. CONCLUSIONS: Chemotherapy and surgical excision of primary tumor are the mainstays of treatment. Radiotherapy is recommended for local control of lesions in the hand for patients declining excisional therapy. PMID- 23084189 TI - Assessment of early pulmonary function abnormalities in giant omphalocele survivors. AB - PURPOSE: Infants with giant omphalocele (GO) are at increased risk for persistent respiratory insufficiency, yet information regarding the systematic assessment of their lung function is limited. We performed a group of pulmonary function tests (PFTs) including spirometry, fractional lung volume measurements, assessment of bronchodilator responsiveness, and passive respiratory mechanics in GO survivors during infancy and early childhood to evaluate the nature and degree of pulmonary dysfunction. MATERIAL AND METHODS: Between July 2004 and June 2008, 30 consecutive GO survivors were enrolled in our interdisciplinary follow-up program. Forty-seven percent (14/30) underwent PFT during follow-up evaluation using the raised volume rapid thoracic compression technique to measure forced expiratory flows and bronchodilator responsiveness, body plethysmography to calculate lung volumes, and the single breath occlusion technique to measure passive mechanics of the respiratory system. RESULTS: The mean age at PFT assessment was 19.3 +/- 19.7 months (range, 1.0-58). Mean forced vital capacity and mean forced expiratory volume in the first 0.5 second were significantly reduced compared with published normative values (P = .03 and P < .01, respectively). Total lung capacity was significantly reduced (P < .001), whereas functional residual capacity, residual volume, and residual volume to total lung capacity ratio were within the normative range (P = .21, P = .34, and P = .48, respectively). Among the 46% who demonstrated significant bronchodilator responsiveness, there were greater increases in the mean percentage changes in flow at 25% to 75% (P = .01), flow at 75% (P < .001), and flow at 85% (P < .001) compared with those participants that did not respond. Specific compliance was reduced, whereas specific conductance increased, compared with published normal results. CONCLUSIONS: Abnormalities of pulmonary function in GO survivors include lung volume restriction without airway obstruction, an increased likelihood of airway hyperresponsivness, and reduced respiratory system specific compliance. Early recognition of pulmonary functional impairment in GO survivors could help to develop targeted treatment strategies to reduce the risk of subsequent pulmonary morbidity. PMID- 23084190 TI - Long-term orthopedic outcomes in patients with epispadias and bladder exstrophy. AB - BACKGROUND/PURPOSE: The aim of the study was to explore long-term orthopedic outcomes in patients with epispadias and bladder exstrophy (BE). METHODS: Sixty three adult patients with epispadias or BE were mailed the Modified Nordic Musculoskeletal Questionnaire, of which 33 (52%) responded. The patients were reviewed for possible pain in the lower back, hips, knees, and ankles, and their physical activity was scored, and the effect of possible pelvic osteotomy at the time of primary closure among patients with BE was evaluated. RESULTS: Patients with BE had more low-back pain during the last 12 months compared with patients with epispadias (84%/43%, P < .05). In terms of physical activity, the ability to run continuously without stopping was significantly reduced in patients with BE (P < .05). Patients with BE, especially women, who underwent pelvic osteotomy suffered more from hip pain compared with patients without pelvic osteotomy (45%/0%, P < .05). CONCLUSIONS: Patients with BE suffer more from low-back pain and have decreased running performance compared with patients with epispadias. Although pelvic osteotomy is widely used to achieve tension-free primary closure of abdominal wall, patients with osteotomy suffered more from hip pains, suggesting that pelvic osteotomy is indicated mainly when primary closure either is impossible or fails in BE reconstruction. PMID- 23084191 TI - Costal cartilage excision for the treatment of pediatric slipping rib syndrome. AB - BACKGROUND: Costal cartilage excision is an effective treatment of slipping rib syndrome (SRS), although the diagnosis of SRS may be elusive. We review our experience with SRS in the pediatric patient. METHODS: This is a retrospective review from 2000 to 2011 of patients presenting with symptoms of SRS before 18 years of age. RESULTS: Seven patients were identified who were diagnosed with SRS and underwent costal cartilage excision. All patients presented with unilateral chest pain that was exacerbated by activity. Five patients reported a popping or clicking sensation with activity that was associated with pain. On physical examination, all patients had reproducible pain with palpation over the affected cartilage. Four patients had a mobile or popping rib with palpation, and 4 also had chest wall asymmetry. Five patients underwent imaging, and 4 patients were referred to specialists. It was a median of 2 years (0-5 years) from onset of symptoms to resection. At resection, all cartilages were grossly abnormal. There were no postoperative complications. Follow-up was complete for all patients over a median 0.9 years (0.2-2.0 years). One patient had recurrence of pain in a different location; another had persistent pain, which was less severe. CONCLUSIONS: Slipping rib syndrome presents with costal cartilage pain that is reproducible on physical examination and commonly associated with a mobile rib. Excision of the affected cartilage(s) is an effective treatment and should be considered early to avoid unnecessary diagnostic tests and evaluation, which delay definitive therapy. PMID- 23084192 TI - Detection of hepatotropic viruses has no impact on the prognosis after Kasai procedure. AB - BACKGROUND/PURPOSE: A viral origin of biliary atresia (BA) is discussed, and several studies have demonstrated different viral strains in liver biopsies of patients undergoing Kasai portoenterostomy. We hypothesized that the presence of hepatotropic viruses in patients undergoing portoenterostomy contributes to the progression of the disease and negatively affect the outcome. METHODS: Liver biopsies were prospectively taken from 70 patients undergoing portoenterostomy in our department from April 1996 to April 2004. Samples were screened by polymerase chain reaction for all common hepatic viruses. Primary outcome parameter was survival with the native liver. Secondary parameters were postoperative serum activity of liver enzymes and serum bilirubin levels at different time points. Patients underwent regular follow-up until October 2008. RESULTS: Twenty-eight patients (40%) were positive for 1 or more hepatotropic viruses. Four patients were lost to follow-up. In the remaining 66 patients, there was no significant difference in survival with their native liver between virus-positive and virus negative patients. After a mean follow-up of 7.7 years (range, 4.6-16.1 years), 15 (23%) of 66 patients still lived with their native liver. There was no difference in liver enzymes, C-reactive protein, or bilirubin at any time point between both groups. CONCLUSION: A significant number of our patients tested positive for hepatotropic viruses in liver biopsies at the time of the Kasai procedure, but the presence of virus had no influence on the course of BA. This suggests that the ongoing inflammatory process of BA leading to liver cirrhosis in most Kasai-treated patients is not affected by hepatotropic viruses. Our data question the necessity to aggressively screen for and treat viral infections in patients with BA. PMID- 23084193 TI - Operative blunt duodenal injury in children: a multi-institutional review. AB - BACKGROUND/AIM: Operative blunt duodenal injury in children is rare. The purpose of this analysis is to describe the clinical presentation, current management, and outcome of children with operative blunt duodenal injury. METHODS: The American Pediatric Surgical Association Trauma Committee solicited data from its members on children with blunt intestinal injuries identified at autopsy or operation from January 2002 through August 2006. RESULTS: Fifty-four children from 16 hospitals with operative blunt duodenal injuries were identified: 0.67 patients per hospital per year. The most common mechanisms of injury were motor vehicle crashes (35%), bicycle crashes (22%), and nonaccidental trauma (20%). Forty-nine patients (90%) had positive physical examination findings on initial presentation, including peritonitis in 18 patients (33%). Twenty-five computed tomographic (CT) scans performed demonstrated free fluid, and 13 (52%), free air. Eleven CT scans used enteral contrast, and only 2 (18%) showed extravasation. Fifty-two patients (96%) survived to operation. The overall complication rate was 42%. CONCLUSION: Operative blunt duodenal injury occurs less than once per year in the typical pediatric trauma center. Most of the patients have pertinent physical examination findings on arrival. Computed tomographic scans with enteral contrast do not seem to be helpful in diagnosis of duodenal injuries. Postoperative complications are frequent, but most children survive. PMID- 23084194 TI - Treatment of lymphatic malformations: a more conservative approach. AB - BACKGROUND/PURPOSE: Lymphatic malformation is a benign disfiguring lesion of the neck and face in children. This study investigated the application and outcome of different modes of treatment. METHODS: The medical files of all children with lymphatic malformation of the head and neck attending a tertiary medical center in 1999 to 2010 were reviewed. Findings were compared by treatment: surgery, OK 432 sclerotherapy, or observation. RESULTS: The study group included 46 patients, most (65%) with macrocystic disease. Twenty were treated by OK-432 sclerotherapy, and 15, by surgery; 11 (with minor disfigurement) were observed only. Mean follow up time was 2.4 years. Complete removal or complete response to treatment was achieved in 67% of the surgery group and 45% of the OK-432 group; fair results (>50% reduction in swelling) were achieved in 20% and 50%, respectively. Sclerotherapy failure did not interfere with subsequent surgery. Complete spontaneous regression occurred in 5 patients under observation only. CONCLUSIONS: OK-432 sclerotherapy is associated with good aesthetic results in children with lymphatic malformation. Observation alone is sometimes sufficient. Surgery should be reserved for cases requiring a histologic diagnosis, microcystic disease, patients with an urgent clinical problem (eg, airway obstruction), and sclerotherapy failures. PMID- 23084195 TI - Treatment of persistent esophageal leaks in children with removable, covered stents. AB - Removable, fully covered, expandable metal esophageal stents are routinely used in adults for both malignant and benign esophageal disease. Several case reports have demonstrated the use of these stents in the management of caustic esophageal strictures in children. Most iatrogenic esophageal perforations and esophageal anastomotic leaks in children may be expected to heal with nonoperative treatment, although, in a small percentage, the leak may persist. We report 3 patients with complicated esophageal perforations refractory to nonoperative therapy who were successfully managed using covered esophageal stents. PMID- 23084196 TI - In vitro sensitivity of rat esophagus to agonists in different alkaline mediums. AB - AIM: An in vitro study was performed to determine the in vitro sensitivity of rat esophagi to contracting and relaxing agonists in different alkaline mediums. MATERIALS AND METHODS: Twenty-four Wistar rats weighing 200 to 250 g were included in the study. After inducing anesthesia with thiopental sodium (50 mg/kg), the rats were killed, and the distal esophagus (DE) and gastroesophageal junction (GEJ) were removed. Excised tissues were suspended under 0.6 g of resting tension in a tissue bath containing 10 mL of Tyrode solution at 37 degrees C. The esophageal segments were divided into 4 groups, each with a different pH medium: 7.4, 7.6, 7.8, and 8. To evaluate the smooth muscle activity of the rat esophagus in different alkaline mediums, cholinergic agonist carbachol (a cholinergic agonosit) and KCl (which acts on calcium channels) were added to the organ baths to obtain concentration-dependent contraction responses. Relaxation responses were obtained using an adrenergic agonist, isoproterenole. Data obtained from different pH mediums were analyzed using Kruskal-Wallis nonparametric analysis of variance and post hoc Dunn's test. RESULTS: The pH of the medium has no effect on the concentration-dependent contracting responses to carbachol in the DE, but responses obtained in pH 8 medium were significantly lower in the GEJ (P < .05). In pH 8 medium, concentration-dependent relaxation responses to isoproterenole were also significantly lower (P < .05). When contractile responses to KCl were evaluated, the groups with pH 7.6 and 7.8 medium were found to have higher responses in the DE segments than other groups (P < .05). However, the GEJ segments had lower contractile responses to KCl in pH 8 medium (P < .05). CONCLUSION: Although different alkaline mediums caused no alteration in esophageal smooth muscle responses to cholinergic stimulation, GEJ responses were lower in pH 8 medium. Relaxation responses, owing to increased adrenergic activity, decreased when the pH of the medium was increased to 8. Calcium-dependent contractions caused by KCl decreased in both segments in pH 8 medium but increased in the DE in pH 7.6 medium. PMID- 23084197 TI - Colorectal polyps in children: a retrospective study of clinical features and the value of ultrasonography in their diagnosis. AB - BACKGROUND: Colorectal polyps are common in children. The purpose of this report was to describe a clinical experience with colorectal polyps at the Beijing Children's Hospital and to evaluate the diagnostic value of ultrasonography in screening colorectal polyps in children. METHOD: This was a retrospective medical record review of 487 children with colorectal polyps managed at the Beijing Children's Hospital between August 2003 and April 2010. RESULTS: The mean age at presentation was 4.7 +/- 2.5 years, with a male predominance (M/F ratio, 1.9:1). Most children (n = 458, 94%) presented with hematochezia associated with other symptoms, such as recurrent abdominal pain (n = 42, 8.6%), prolapse of the polyp from the anus (n = 43, 8.8%), and diarrhea (n = 10, 2.1%). Anemia was observed in 33 (6.8%) children, 4 of whom required a blood transfusion before the colonoscopy. Among the 487 patients, 352 (72.3%) patients underwent ultrasonography before the colonoscopy. Polyps were detected on 345 of 352 ultrasonographic examinations in which patients subsequently underwent colonoscopy and were found to have colonic polyps. The most common polyp locations were the sigmoid colon (n = 212, 46.1%) and the rectum (n = 174, 37.8%). Solitary polyps were identified in 421 patients (88.4%), and multiple polyps were identified in 55 (11.6%) patients. Colonoscopy complications were rare, with colonic perforation observed in 2 patients and postcolonoscopy hemorrhage observed in 1 patient. The available pathology records showed that the most frequent histological type was juvenile polyps (n = 435, 91.8%), followed by Peutz-Jeghers polyps (n = 17, 3.6%), juvenile polyposis (n = 14, 3.0%), hamartomas (n = 6, 1.3%), familial adenomatous polyposis (n = 1, 0.2%), and inflammatory polyps (n = 1, 0.2%). CONCLUSION: Ultrasonic examination is a valid, accurate, and safe technique for screening colorectal polyps in children; and a full colonoscopy should be performed to remove the polyp(s) as soon as possible. PMID- 23084198 TI - Screening of the RET gene of Vietnamese Hirschsprung patients identifies 2 novel missense mutations. AB - BACKGROUND/PURPOSE: Hirschsprung disease (HSCR; megacolon, congenital aganglionosis) is a congenital disorder characterized by the absence of ganglion cells along variable segments of the gut. Both rare (RV) and common variants of the RET gene are associated with HSCR. The aim of this study is to assess, for the first time, the variation in the RET gene of Vietnamese HSCR patients. METHODS: We used Sanger sequencing to screen the coding sequence of the RET gene of 97 Vietnamese HSCR patients of Southern Chinese ancestry. The healthy population consisted of 250 Southern Chinese individuals with no diagnosis of HSCR. RESULTS: We detected 8 heterozygous RVs distributed among 13 patients (13.40%) and that were not present in healthy individuals. Among those variants, there were 2 novel and deleterious (R133C [c.397 C>T]; R144C [c.430 C>T]) missense amino acid substitutions, 2 novel silent variants (P667P [c.2001 A>T]; Y809Y [c.2427 C>T]), and 4 previously described missense substitutions (R114H [c.341 G>A]; V292M [c.874 G>A]; G533S [c.1597 G>A]; R982C [c.2944 C>T]). As expected, the common RET coding sequence variants rs1800858 (A45A [c.135 G>A]) and rs1800861 (L769L [c.2307 T>G]) were highly associated with the disease. CONCLUSIONS: The identification of novel deleterious variants together with the fact RET RVs are virtually unique to HSCR patients indicates that the RET gene is a target for mutations among Hirschsprung patients of any population. PMID- 23084200 TI - Late diagnosis of Hirschsprung disease--patient characteristics and results. AB - PURPOSE: The aim of the present study was to describe the characteristics and the postoperative results of children diagnosed as having Hirschsprung disease (HD) after the age of 3 years. METHODS: All patients with HD diagnosed after the age of 3 years in our hospital from 1998 to 2011 were included. Patient characteristics and postoperative results were prospectively registered. RESULTS: Eleven children were included. Age at diagnosis was 3.0 to 9.6 years. Ten patients had rectosigmoid disease, whereas 1 had total colonic aganglionosis. Three children were given a diverting ileostomy before the pull-through procedure, and all 3 had ileostomy-related complications. Early postoperative complications were seen in 5 children, of whom 2 had anastomotic leakage. At final follow-up, with a median of 3 years postoperatively, 7 had normal bowel function, 1 had frequent loose stools, and 3 were soiling. CONCLUSIONS: Early postoperative complications, especially anastomotic leakage, occurred frequently in children with late-diagnosed HD. Therefore, a diverting stoma should be considered in these patients. The long-term functional results were comparable with those seen in children operated on as neonates. PMID- 23084199 TI - Heparin-binding epidermal growth factor-like growth factor promotes murine enteric nervous system development and enteric neural crest cell migration. AB - BACKGROUND/PURPOSE: Developmental defects of the enteric nervous system lead to a variety of disorders including Hirschprung disease. We have previously shown that heparin-binding epidermal growth factor-like growth factor (HB-EGF) exerts neuroprotective effects on injured neurons. The goals of this study were to assess the role of HB-EGF in enteric nervous system development and to evaluate the effect of HB-EGF on enteric neural crest-derived cell (ENCC) migration in the developing gastrointestinal tract of mice. MATERIALS AND METHODS: HB-EGF immunohistochemistry was used to examine HB-EGF protein expression in the hindgut of embryonic mice. Gut specimens were stained for PGP9.5 (a neuronal cell marker) to examine the extent of ENCC migration in the intestine at different embryonic stages in HB-EGF knockout (KO) and wild-type (WT) mice. Embryonic gut organ cultures were established to examine the effect of HB-EGF on ENCC migration. RESULTS: The expression of HB-EGF was limited to the endodermal epithelium of the hindgut in early gestation, but rapidly involved the hindgut mesenchyme after ENCC migrated into this region. ENCC migration was significantly delayed in HB EGF KO compared with WT embryos, leading to defects in neural colonization of the distal gut in postnatal HB-EGF KO mice. Addition of HB-EGF to WT embryonic intestine significantly promoted ENCC migration, as demonstrated by a significant increase in the ratio of ENCC migration distance toward the distal hindgut/total colon length (78% +/- 4% vs 53% +/- 2%, P = .001). CONCLUSIONS: Deletion of the HB-EGF gene leads to enteric nervous system developmental defects. HB-EGF stimulates ENCC migration in the gut, supporting a potential role for administration of HB-EGF in the future for the treatment of patients with intestinal neuronal disorders. PMID- 23084201 TI - Long-term outcome of left- vs right-sided antegrade continence enema. AB - BACKGROUND/PURPOSE: This study compared long-term outcomes of left- vs right sided antegrade continence enema (ACE) procedures. METHODS: We retrospectively analyzed medical records and performed a follow-up telephone survey of patients who underwent the ACE procedure at Severance Children's Hospital between 1999 and 2011. RESULTS: A total of 49 patients underwent 51 ACE procedures. The procedures were left-sided ACE in 25 patients (group 1) and right-sided in 26 patients (group 2), including 2 patients who underwent left-sided procedures a few years earlier. Fecal soiling was more common in group 1 than in group 2 (8/25 [32.0%] vs 1/26 [3.9%], respectively; P = .0109). Seven patients (28.0%) in group 1 had abdominal pain unrelieved by ACEs. Stomal reflux of fecal material was more frequent in group 1 than in group 2 (13/25 [52.0%] vs 0/26 [0%], respectively; P < .0001). Nonuse or infrequent use of ACE was more common in group 1 than in group 2 (11/25 [44.0%] vs 0/26 [0%], respectively; P < .0001). Patient satisfaction was higher in group 2 (P = .0015). CONCLUSIONS: In our experience using the sigmoid colon for left-sided ACE, right-sided ACE was superior to left sided ACE in achieving fecal continence, resolving intractable constipation, and providing patient satisfaction. PMID- 23084202 TI - Advantages of abandoning abdominal cavity irrigation and drainage in operations performed on children with perforated appendicitis. AB - PURPOSE: This study evaluates the effect of peritoneal irrigation and drainage on postoperative morbidity when used together for perforated appendicitis. MATERIAL AND METHODS: This study was conducted on children undergoing open appendectomy for perforated appendicitis. Sixty-one children with perforated appendicitis operated on with irrigation and drainage between July 1998 and September 2001 (group DI) and 173 children with perforated appendicitis who underwent surgery without irrigation and drainage (group NDI) between October 2001 and November 2011 were retrospectively evaluated (a total of 234 patients). All patients were treated and followed up by the same pediatric surgeon using the same protocol. Both groups were compared in respect to postoperative complications, including wound infection, wound dehiscence, intraabdominal abscess, prolonged ileus, the presence of small bowel obstruction requiring surgery, operative time, and length of postoperative hospital stay. RESULTS: Of the total 234 patients, 151 were male and 83 were female with a mean age of 8.9 +/- 3.7 years (range, 1.5-15 years). The wound infection rates were 4.9% in group DI and 1.7% in group NDI (P = .184). Wound dehiscence was seen in 1.6% vs 0%, prolonged ileus in 8% vs 2.3%, intraabdominal abscess in 4.9% vs 1.7%, and small bowel obstruction requiring surgery in 1.6% vs 0.6% of the patients (P = .261, P = .054, P = .184, and P = .454, respectively). No statistically significant difference in postoperative infectious complications was found between both groups. The length of postoperative hospital stay was 9.9 +/- 4.1 days in group DI vs 6.3 +/- 2.4 days in group NDI (P < .001). The operation times were 39 +/- 8 and 31 +/- 11 minutes, respectively (P < .001). CONCLUSION: This study demonstrates that peritoneal irrigation and drainage in children with perforated appendicitis is not required, and in fact, these procedures cause an increase in operative time. PMID- 23084203 TI - Interstitial cell of Cajal loss correlates with the degree of inflammation in the human appendix and reverses after inflammation. AB - BACKGROUND: Normal gut motility relies on the complex interaction between the interstitial cell of Cajal (ICC) and the enteric nerve networks. Inflammation of the gastrointestinal tract adversely affects both ICC and enteric nerves. We aimed to determine the distribution of ICC and nerve networks in patients with appendicitis. METHODS: Specimens from controls and patients with appendicitis were examined with immunohistochemistry (c-Kit for ICC, beta III tubulin [Tuj-1] and neuronal nitric oxide synthase [histochemical diaphorase] for nitrergic neurons) and electron microscopy (EM). Data were quantified using image analysis. RESULTS: We found a profound decrease in c-Kit immunoreactivity (c-Kit IR) in the advanced inflammatory stages of appendicitis, which correlated with the severity of inflammation. Electron microscopy confirmed ultrastructural injury in both ICC and nerve fiber networks during acute inflammation. After the inflammation resolved, interval appendices displayed a recovery in ICC c-Kit IR to control levels and normal ultrastructure. The neuronal network also displayed ultrastructural recovery; however, neuronal nitric oxide synthase activity did not recover. CONCLUSIONS: Severe inflammation results in significant ultrastructural damage of nerves and ICC networks in appendicitis. The loss of c Kit IR is likely due to impaired ICC cytophysiology because ICC was still present under EM. After resolution of acute inflammation, ICC recovers their normal ultrastructure and c-Kit IR. PMID- 23084204 TI - Impact on family of management strategies for perforated appendicitis in children. AB - BACKGROUND/PURPOSE: The purpose of this study was to examine the impact on the family of immediate appendectomy compared with initial nonoperative management for perforated appendicitis in children. METHODS: Sixty-six prospectively identified families of children with perforated appendicitis completed a daily activity journal and the Impact on Family Scale at presentation and at completion of therapy. RESULTS: There were no significant differences in postoperative surgical site infections or number of missed school or employment days between the immediate appendectomy group (n = 40) and the initial nonoperative management group (n = 26). Impact on Family Scale total scores decreased over time for both groups, but this improvement over time was significant only in the initial nonoperative management group (P < .01). CONCLUSIONS: Immediate appendectomy or initial nonoperative management can effectively manage perforated appendicitis in children with no statistically significant differences in the number of missed school or employment days. Greater improvements in family impact are associated with initial nonoperative management as measured by the Impact on Family Scale at completion of therapy. PMID- 23084205 TI - Feasibility and safety of monopolar diathermy as an alternative to clip ligation in laparoscopic Fowler-Stephens orchiopexy. AB - PURPOSE: The aims of the study were to study the effect of Fowler-Stephens orchiopexy (FSO) on testicular histology and to assess the feasibility of using monopolar diathermy as an alternative to clip ligation during laparoscopic FSO. PATIENTS AND METHODS: The study included 20 patients with 20 intraabdominal testes and short vessels managed by laparoscopic-staged FSO. Biopsies were taken from intraabdominal testes during the first and second stages of the procedure for histologic comparison. The patients in the study were divided into 2 groups according to the method of dividing the testicular vessels in stage 1. The first 13 patients (group A) were managed by clip ligation of the vessels, whereas monopolar diathermy was used in the following 7 patients (group B). RESULTS: Biopsy findings at stage 2 revealed an overall reduction in both the total number of germ cells per tubule and mean diameter of seminiferous tubules, whereas there was no statistically significant difference between the results in groups A and B. CONCLUSION: The seminiferous cells can withstand (survive) dividing the main blood supply of the testis during FSO. The monopolar diathermy can be used as an alternative to clipping during laparoscopic procedures, having the advantages of lower expenses and using smaller instruments. PMID- 23084207 TI - Pott's puffy tumor: a forgotten differential diagnosis of frontal swelling of the forehead. AB - A 14-year-old adolescent boy experienced a nonsevere infection of the upper respiratory tract. After 10 days, he developed headache, intermittent vomiting, and fever. A sudden prominent swelling of the forehead occurred, and his general condition deteriorated. Cranial computed tomography showed a subdural empyema and subperiosteal abscess owing to osteomyelitis of the frontal bone. Surgical drainage of the subdural empyema and the subperiosteal abscess was performed, and appropriate long-term antibiotic therapy was initiated. The swelling of the forehead caused by a subperiosteal abscess with osteomyelitis of the frontal bone after frontal sinusitis or trauma is known as Pott's puffy tumor. This case demonstrates that swelling of the forehead in the presence of upper respiratory tract infection should lead to prompt evaluation for complications. PMID- 23084208 TI - A modified laparoscopic esophagogastric dissociation for severe bile reflux in a neurologically impaired child. AB - The clinical scenario of a neurologically impaired child with a prolonged history of gastroesophageal reflux disease that underwent open Roux-en-Y gastrojejunostomy with subsequent development of severe symptomatic bile reflux is reported. The presentation, evaluation, and surgical management by laparoscopic revision to a modified esophagogastric dissociation are discussed. PMID- 23084206 TI - Do hygienic factors affect labial fusion recurrence? A search for possible related etiologic factors. AB - BACKGROUND/PURPOSE: The purpose of our study was to define the factors related to recurrence of labial fusion. METHODS: The data of 110 patients diagnosed with labial fusion were gathered. The data collected and queried included age and body weight of the patient, season of presentation/occurrence, frequency of diaper change, frequency of diaper dermatitis, products used for hygiene, duration of breast milk feeding, infections, presence of allergy, thickness of the adhesion, mother's use of oral contraceptive drugs before pregnancy, mother's use of alcohol/drugs/cigarettes or presence of disease during pregnancy, the number of recurrences, treatment method, presence of labial fusion among maternal sisters or any relatives, and blood estrogen levels. RESULTS: Eighty-one patients (73.6%) with labial fusion were admitted for the first time, whereas 29 patients (26.4%) had been treated previously at least once. The adhesion was denser in patients with recurrence. There was no correlation between recurrence of labial fusion and age-based body weight percentile, frequency of diaper change, frequency of diaper dermatitis, hygiene products used, presence of infection, presence of allergy, mother's use of oral contraceptive drugs before pregnancy, or presence of any pathology in other family members. CONCLUSIONS: The products used for hygiene, frequency of diaper dermatitis, duration of breast milk feeding, presence of infection, and prenatal factors showed no correlation with the recurrence of labial fusion. PMID- 23084209 TI - Esophageal atresia associated with a rare vascular ring and esophageal duplication diverticulum: a case report and review of the literature. AB - Esophageal atresia with tracheoesophageal fistula (EA-TEF) associated with a right aortic arch poses a dilemma to the pediatric surgeon, often necessitating an operative approach via a left thoracotomy. A right aortic arch may be associated with a vascular ring, and EA-TEF, too, has been reported in association with a vascular ring. Rarely, esophageal atresia is associated with a second esophageal anomaly, such as a so-called "esophageal lung." To our knowledge, there is no report of all three in one patient. We report the first case of a patient with associated EA-TEF, vascular ring (diverticulum of Kommerell), and esophageal lung. The literature is reviewed for these rare entities. PMID- 23084210 TI - Juvenile fibroadenoma and granular cell tumor of the breast in an adolescent. AB - We describe a case of a 15-year-old girl who presented with 2 painful masses in her right breast. Ultrasound confirmed the presence of 2 lesions, both of which appeared noncharacteristic for fibroadenomas. Both lesions were surgically resected. One was found to be a fibroadenoma and the other a granular cell tumor, both benign upon further histologic evaluation. Breast masses are rare in the pediatric population. The finding of a concurrent fibroadenoma and granular cell tumor is unique and has not been previously reported. Granular cell tumors of the breast are relatively uncommon. Often, they are mistaken for a breast malignancy. The concerning clinical and radiographic findings in this patient warranted operative excision. PMID- 23084211 TI - Midline mature teratoma inside a ruptured meningomyelocele of lumbosacral region, a case report. AB - Meningomyelocele (MMC) is very rarely associated with teratoma. Only few reports on the concurrence of a teratoma within a meningomyelocele have been published. The hypotheses of a possible common aetiology for this association include a single dysembryogenic process and neoplastic transformation of heterotopic primordial elements incorporated in the defect. We report an unusual case of midline mature teratoma which presented inside a ruptured lumbar meningomyelocele. PMID- 23084212 TI - Type IV intestinal atresia, congenital bilateral perisylvian syndrome, and chronic pulmonary hypertension secondary to multiple vascular disruption syndrome in a monochorionic twin. AB - We describe a rare case of multiple intestinal atresias, congenital bilateral perisylvian polymicrogyria, and chronic pulmonary hypertension in a surviving monochorionic twin with co-twin demise. This constellation of congenital anomalies represents a multiple vascular disruption syndrome due to intrauterine vascular compromise in the setting of possible twin-to-twin transfusion syndrome. PMID- 23084213 TI - Clear cell sarcoma of the gastrointestinal tract after very low-dose therapeutic radiation therapy: a case report. AB - Childhood cancer survivors are at risk for developing second malignant neoplasms. Very-low-dose therapeutic radiation therapy (RT) may be used to treat infants with Stage 4S neuroblastoma. We report a case of a patient who subsequently developed clear cell sarcoma of the gastrointestinal tract nearly 15 years after treatment with very low-dose therapeutic RT (4.5 Gy) for Stage 4S neuroblastoma. PMID- 23084214 TI - A robotic-assisted laparoscopic approach for pediatric renal cell carcinoma allows for both nephron-sparing surgery and extended lymph node dissection. AB - Partial nephrectomy has been previously reported as safe and effective in appropriately selected children with renal cell carcinoma (RCC). However, there are limited reports of laparoscopic or robotic partial nephrectomy for oncologic surgery in children. Additionally, nodal involvement is common in pediatric RCC, and may present even with small primary tumors. Also, it is suggested that lymph node dissection may provide therapeutic benefit. We present a case of pediatric RCC and demonstrate how the risk of nodal involvement may impact the surgical approach. Robotic-assisted laparoscopy can permit excellent exposure for an oncologically-sound resection, in this case a partial nephrectomy, as well as an extended lymph node dissection. PMID- 23084215 TI - Prenatal detection and postnatal management of an intranasal glioma. AB - Nasal gliomas are rare benign congenital midline tumors composed of heterotopic neuroglial tissue. They have potential for intracranial extension through a bony defect in the skull base. Neuroimaging is essential for identifying nasal lesions and for determining their exact location and any possible intracranial extension. Computed tomography is often the initial imaging study obtained because it provides good visualization of the bony landmarks of the skull base; it is not, however, well suited for soft tissue imaging. Magnetic resonance imaging has better soft tissue resolution and may be the best initial study in patients seen early in life because the anterior skull base consists of an unossified cartilage and may falsely appear as if there is a bony dehiscence on computed tomography. A frontal craniotomy approach is recommended if intracranial extension is identified, followed by a transnasal endoscopic approach for intranasal glioma. A case is presented of a huge fetal facial mass that was shown by ultrasound that protruded through the left nostril at 33 weeks of gestation. Computed tomography of the neonate suggested a transethmoidal encephalocele. Magnetic resonance imaging showed a huge mass occupying the nasopharynx and the nasal cavity and protruding externally to the face but ruled out bony discontinuity in the skull base and, therefore, any intracranial connection. The infant underwent an endoscopic resection of the mass via oral and nasal routes and pathologic examination revealed intranasal glioma. PMID- 23084216 TI - Laparoscopic pyloroplasty for idiopathic non-hypertrophic pyloric stenosis in a child. AB - Acquired gastric outlet obstruction (GOO) during infancy and childhood represents an uncommon event. We describe a 6-year-old boy with GOO who did not respond to medical treatment or to endoscopic pyloric balloon dilatations. The stenosis was successfully treated with laparoscopic pyloroplasty which relieved the obstruction. PMID- 23084217 TI - Image-guided esophageal anastomosis in esophageal atresia. AB - Infants with tracheoesophageal fistulas may present with complex cardiac disease that may obviate or disrupt a safe operative repair. Here we present a case of an infant who developed cardiac instability during esophageal atresia repair, precluding formal anastomosis after approximation of the distal and proximal esophageal segments. Postoperatively, anastomosis of the esophagus was achieved using an image-guided technique with subsequent dilation. This approach may provide an alternative approach for establishment of esophageal continuity in patients who are high-risk operative candidates. PMID- 23084218 TI - Duhamel pull-through assisted by transrectal port: a hybrid natural orifice transluminal endoscopic surgery approach. AB - One of the latest surgical innovations is natural orifice transluminal endoscopic surgery (NOTES). We hypothesize that the principles of NOTES could be applied to the laparoscopic Duhamel procedure. Between March 2008 and May 2010, 3 children underwent the laparoscopic Duhamel procedure assisted by transrectal NOTES. Three 5-mm transabdominal trocars were combined with a 12-mm transrectal trocar. We were able to safely apply the principles of NOTES, improving the performance of laparoscopic Duhamel pull-through using current instruments and technology. This new approach avoids the need of an extra transabdominal 12-mm trocar for the endoscopic stapler, allows an easier creation of a smaller rectal stump, and offers the possibility of an extra working port. This hybrid concept can be seen as a transition into the emerging field of NOTES in colorectal surgery. PMID- 23084219 TI - Re: Novel use of glycopyrrolate (Robinul) in the treatment of anastomotic leak after repair of esophageal atresia and trachea-esophageal fistula. PMID- 23084221 TI - More patches or more lung in congenital diaphragmatic hernia? PMID- 23084222 TI - Hydrothorax following delayed extravascular migration of a totally implantable venous access device in a child. AB - Totally implantable venous access devices are widely used in pediatric oncology. The authors encountered a 10-year-old boy with implantation of the device at the age of 7 years owing to acute lymphoblastic leukemia. In the recent half-year, the device was not used except for regular heparin flushing. However, hydrothorax occurred when fluid therapy was required from the device during this admission. Thoracoscopic approach showed extravascular migration and intrapleural malposition of the catheter. Intrapleural migration of the extravascular portion of the catheter owing to irritation and pressure necrosis of the pleura and gradual shortening of intravascular portion of the catheter when the child grew up may be the pathogenesis of delayed extravascular migration of the catheter. PMID- 23084223 TI - Pelvic Wilms tumor in a child with an absent right kidney and spinal malformations. AB - Wilms tumor rarely occurs in other sites outside the kidney. Various congenital malformations often accompany Wilms tumor, but spinal deformations are rarely seen. We report a very rare association of multiple spinal malformations, right kidney absence, and pelvic Wilms tumor in a 21-month-old girl. The report includes a brief review of relevant literature. PMID- 23084224 TI - Colon perforation caused by a foreign body in Hirschsprung disease. AB - Accidental ingestion of foreign bodies is a common emergency in the pediatric population. The foreign body generally passes through the whole gastrointestinal system spontaneously without causing an obstruction. This is the first case report in the literature of Hirschsprung disease associated with a radio-opaque foreign body lodged at the site of a perforated sigmoid colon. This case highlights the fact that, in the case of an impacted radio-opaque foreign body in a child, the possibility of an obstructive congenital anomaly should be kept in mind in the differential diagnosis. PMID- 23084225 TI - Post-serial transverse enteroplasty bowel redilatation treated by longitudinal intestinal lengthening and tailoring procedure. AB - The serial transverse enteroplasty (STEP) is a safe and successful procedure to lengthen the small bowel. Several patients develop postoperative bowel redilatation with loss of bowel adaptation. We describe a 2-month-old male infant with short bowel syndrome who developed dilatation of the lengthened segment after STEP, which was successfully treated by a longitudinal intestinal lengthening and tailoring procedure. To the best of our knowledge, this is the first described case of longitudinal intestinal lengthening and tailoring procedure after STEP. PMID- 23084226 TI - Early diverting colostomy for perianal sepsis in children with acute leukemia. AB - Perineal sepsis is a life-threatening complication of acute leukemia. Although conservative management (antibiotics, incision, and drainage, alone or in combination) is considered the criterion standard, it provides an outcome that is not fully satisfactory, with an overall mortality of roughly 30%. This report presents a case series of 4 children who underwent early defunctioning colostomy for the treatment of perineal sepsis during leukemia. This management proved to be successful and allowed prompt reestablishment of chemotherapy, thus improving overall results. Routine application of this "aggressive" management in these cases will presumably increase overall survival of children with leukemia. PMID- 23084227 TI - Perinatal hemorrhage complicating neonatal hepatoblastoma: case report. AB - Hepatoblastoma is the most common malignant liver tumor of infancy and presents most frequently at a median age of 18 months. Presentation in the neonatal period is rare, and there are very few reports of an antenatal diagnosis of hepatoblastoma. We recently encountered a neonate who presented with hemoperitoneum after rupture of a congenital hepatoblastoma during vaginal delivery. After successful right hepatectomy and adjuvant cis-platinum-based chemotherapy, the child is doing well. We draw attention to rarity of this condition and difficulty in definitively establishing a diagnosis both in the antenatal and neonatal periods and discuss the management dilemmas in congenital presentations of hepatoblastoma. PMID- 23084228 TI - Bilateral xanthogranulomatous funiculitis and orchiepididymitis in a 13-year-old adolescent boy. AB - Xanthogranulomatous orchitis is an extremely rare inflammatory nonneoplastic lesion of the testis. We report a case of a 13-year-old adolescent boy who presented a painless left hemiscrotal swelling. The subsequent ultrasonography and magnetic resonance imaging revealed the presence of abnormal expanding tissue located in both testes and spermatic cord, reaching the internal inguinal ring. Testicular tumor markers were normal. The frozen section examination of the surgical specimen showed only inflammatory tissue and not neoplastic tissue. No orchiectomy was performed. Definitive histopathologic diagnosis was xanthogranulomatous inflammation. To our knowledge, this is the youngest case of xanthogranulomatous orchiepididymitis and funiculitis found in medical literature. PMID- 23084229 TI - Angiodysplasia (vascular malformations) of the colon presenting as an acute abdomen. AB - Angiodysplasia (vascular malformations) of the colon is extremely rare in children, and, as in adults, present with lower gastrointestinal hemorrhage. Here we report an unusual pediatric case of angiodysplasia of the terminal ileum and cecum presenting as an acute abdomen with radiological features suggestive of lymphoma. PMID- 23084230 TI - Intrapleural streptokinase for the treatment of complicated parapneumonic effusion and empyema in 2 newborns. AB - The management of complicated parapneumonic effusions by conventional first-line treatment with closed intercostal tube drainage and antibiotic therapy may fail because of thick viscous fluid and multiple pleural space loculations. Intrapleural fibrinolytic treatment is a non-invasive therapeutic option. In this report, we present successful use of intrapleural streptokinase for complicated parapneumonic effusion and empyema in 2 newborns. Intrapleural fibrinolytic therapy with streptokinase appears to be a safe and effective adjunctive therapy of choice and may have significant benefit even in newborns with complicated parapneumonic effusion and empyema, and thus, it can obviate surgical intervention. PMID- 23084231 TI - Benign cystic mesothelioma of the peritoneum in a male child. AB - The benign cystic mesothelioma of the peritoneum is a rare lesion that occurs predominatly in women of reproductive age and has a high propensity for local recurrence. It is very rare in childhood, especially in boys, being reported in only 4 cases. A new case of benign cystic mesothelioma of the peritoneum in an 11 year-old boy is reported. The lesion occupied the entire left abdomen, arising from the transverse mesocolon, and it was accompanied by 4 small cysts. The patient had a coexistent right-sided renal agenesis. The mesothelial nature of the cysts epithelial lining cells was confirmed by immunopositivity for calretinin, cytokeratin 5/6, HBME1, and epithelial membrane antigen (EMA). No recurrence of the lesion was noted in the 7-month follow-up. Pathologists and clinicians should be aware of the existence of this rare entity in childhood to establish an accurate diagnosis and provide close follow-up after the surgery. PMID- 23084232 TI - Intraosseous angioma: a rare cause of a rib mass in childhood. AB - Rib tumors are uncommon and represent 5% to 10% of all bony tumors. Regarding the benign rib lesions, costal angioma is very rare in childhood. We report a case of a rare angioma of a rib complicated by bone erosion in a young boy. PMID- 23084233 TI - Retroperitoneal lipoblastoma: a discussion of current management. AB - Retroperitoneal lipoblastomas are rare tumors found in young pediatric patients. Despite their large size at presentation, complete resection is usually achieved with minimal complications. Diagnosis is typically made after pathologic examination of the operative specimen, and cytogenetic analysis may be a key component in differentiating lipoblastoma from other lipomatous tumors. We present one such case of a large, retroperitoneal lipoblastoma and discuss the management of this uncommon entity. PMID- 23084234 TI - Management of postdural puncture headache with epidural saline patch in a 10-year old child after inguinal hernia repair: a case report. AB - Spinal anesthesia (SA) is becoming increasingly popular among pediatric anesthetists. Postdural puncture headache (PDPH) has been reported in children. PDPH generally spontaneously resolves within a few days with bed rest and nonopioid analgesics, but it may last for several days. If the symptoms persist, an epidural blood patch is considered as an effective treatment. We describe the successful use of an epidural saline patch in a 10 year-old child with PDPH who did not respond to conservative treatment. PMID- 23084235 TI - Congenital bronchopulmonary foregut malformation initially diagnosed as esophageal atresia type C: challenging diagnosis and treatment. AB - Communicating bronchopulmonary foregut malformations are extremely rare congenital malformations, characterized by a communicating fistula between an isolated part of the respiratory system and the esophagus or the stomach. In this article, we present a case of esophageal atresia type C, later diagnosed as a rare form of a communicating bronchopulmonary foregut malformation, an esophageal atresia combined with right main bronchus originating from the lower esophagus. Therapeutic resection of the right lung was complicated by postpneumonectomy syndrome. PMID- 23084236 TI - Extralobar pulmonary sequestration with an unusual venous drainage to the portal vein: preoperative diagnosis and excision by video-assisted thoracoscopy. AB - Pulmonary sequestration is an uncommon congenital malformation of the lung that can be classified as intralobar or extralobar (ELS). Approximately 90% of ELS occur in the left hemithorax. Approximately 10% of ELS may present below the diaphragm. Both types of sequestrations are characterized by pulmonary tissue that does not communicate with the bronchial tree. The arterial blood supply to 80% ELS is through a direct branch of the thoracic or abdominal aorta, in 15% via another systemic artery and 5% from the pulmonary artery. The venous drainage of ELS is variable, predominantly into the systemic circulation (via the azygos vein, hemiazygos vein, or inferior vena cava). Approximately 25% drain completely or partially through the pulmonary veins. We report an extremely rare case of ELS with unusual venous drainage to the portal vein. PMID- 23084237 TI - Flexible bronchoscopic cannulation of an isolated H-type tracheoesophageal fistula in a newborn. AB - Congenital isolated H-type tracheoesophageal fistula (H-TEF) is a rare malformation of the airways. Surgery should not be delayed once the diagnosis is established. Identification of the fistula during surgery is a prerequisite for a successful outcome. Intubation or cannulation of the H-TEF with a catheter can help the surgeon to identify the fistula. A rigid bronchoscope is generally used for cannulation of the fistula. Cannulation of an H-TEF in a newborn with a flexible bronchoscope has the merit of simplicity and safety. We report the insertion of a catheter in an isolated H-TEF in a newborn using a flexible bronchoscope and think that this method can be easily applied. PMID- 23084238 TI - Influences of cycloplegia with topical atropine on ocular higher-order aberrations. AB - PURPOSE: To investigate the influence of cycloplegia with topical atropine on higher-order aberrations (HOAs) of the eye in children. DESIGN: Prospective, noncomparative study. PARTICIPANTS: Twenty-three eyes of 23 subjects (11 boys and 12 girls) with hyperopia, ranging in age from 3 to 12 years (average, 5.74 years), were enrolled in this study. METHODS: Refraction and wavefront aberration were evaluated before and after cycloplegia with topical instillation of 1% atropine solution administered twice daily for 1 week. Ocular and corneal HOAs were measured simultaneously, and individual Zernike components were analyzed for a 6-mm pupil up to the 6th order. All these parameters were compared before and after cycloplegia. MAIN OUTCOME MEASURES: Ocular and corneal HOAs before and after cycloplegia. RESULTS: Cycloplegia with topical atropine significantly increased spherical equivalent refraction from +1.92+/-1.53 diopters (D) to +3.10+/-1.61 D (P<0.01, paired t test). Ocular HOAs significantly increased from 0.282+/-0.086 MUm to 0.316+/-0.087 MUm for coma-like aberrations (P=0.02), from 0.169+/-0.058 MUm to 0.192+/-0.076 MUm for spherical-like aberrations (P=0.02), and from 0.333+/-0.093 MUm to 0.377+/-0.095 MUm for total HOAs (P=0.01). Corneal HOAs did not change after cycloplegia. As for individual Zernike components, significant changes were found in C3(1) and C4(0) after cycloplegia (P<0.05). The induced changes in C4(0) were correlated significantly with those in spherical equivalent refraction (Pearson's correlation coefficient, R=0.45; P=0.03). CONCLUSIONS: Cycloplegia with atropine induced significant hyperopic shift and increases in ocular HOAs in children, leading to reduction in optical quality of the eye. It may be that physiologic tonic accommodation plays a role in improving retinal image quality by decreasing HOAs and refractive errors. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 23084241 TI - Difference-frequency generation in nonlinear scattering of acoustic waves by a rigid sphere. AB - In this paper, the partial-wave expansion method is applied to describe the difference-frequency pressure generated in a nonlinear scattering of two acoustic waves with an arbitrary wavefront by means of a rigid sphere. Particularly, the difference-frequency generation is analyzed in the nonlinear scattering with a spherical scatterer involving two intersecting plane waves in the following configurations: collinear, crossing at right angles, and counter-propagating. For the sake of simplicity, the plane waves are assumed to be spatially located in a spherical region which diameter is smaller than the difference-frequency wavelength. Such arrangements can be experimentally accomplished in vibro acoustography and nonlinear acoustic tomography techniques. It turns out to be that when the sphere radius is of the order of the primary wavelengths, and the downshift ratio (i.e. the ratio between the fundamental frequency and the difference-frequency) is larger than five, difference-frequency generation is mostly due to a nonlinear interaction between the primary scattered waves. The exception to this is the collinear scattering for which the nonlinear interaction of the primary incident waves is also relevant. In addition, the difference frequency scattered pressure in all scattering configurations decays as r(-1)lnr and 1/r, where r is the radial distance from the scatterer to the observation point. PMID- 23084239 TI - Visual improvement after cultivated oral mucosal epithelial transplantation. AB - PURPOSE: To report the effectiveness, disease-specific outcomes, and safety of cultivated oral mucosal epithelial sheet transplantation (COMET), with the primary objective of visual improvement. DESIGN: Noncomparative, retrospective, interventional case series. PARTICIPANTS: This study involved 46 eyes in 40 patients with complete limbal stem cell deficiency (LSCD) who underwent COMET for visual improvement. These LSCD disorders fell into the following 4 categories: Stevens-Johnson syndrome (SJS; 21 eyes), ocular cicatricial pemphigoid (OCP; 10 eyes), thermal or chemical injury (7 eyes), or other diseases (8 eyes). METHODS: Best-corrected visual acuity (BCVA) and ocular surface grading score were examined before surgery; at the 4th, 12th, and 24th postoperative week; and at the last follow-up. Data on COMET-related adverse events and postoperative management were collected. The outcomes in each disease category were evaluated separately. MAIN OUTCOME MEASURES: The primary outcome was the change in median logarithm of the minimum angle of resolution (logMAR) BCVA at the 24th postoperative week. The secondary outcome was the ocular surface grading score. RESULTS: Median logMAR BCVA at baseline was 2.40 (range, 1.10 to 3.00). In SJS, logMAR BCVA improved significantly during the 24 weeks after surgery. In contrast, the BCVA in OCP was improved significantly only at the 4th postoperative week. In 6 of the 7 thermal or chemical injury cases, logMAR BCVA improved after planned penetrating keratoplasty or deep lamellar keratoplasty. Grading scores of ocular surface abnormalities improved in all categories. Of 31 patients with vision loss (logMAR BCVA, >2) at baseline, COMET produced improvement (logMAR BCVA, <=2) in 15 patients (48%). Visual improvement was maintained with long-term follow-up (median, 28.7 months). Multivariate stepwise logistic regression analysis showed that corneal neovascularization and symblepharon were correlated significantly with logMAR BCVA improvement at the 24th postoperative week (P=0.0023 and P=0.0173, respectively). Although postoperative persistent epithelial defects and slight to moderate corneal infection occurred in the eyes of 16 and 2 patients, respectively, all were treated successfully with no eye perforation. CONCLUSIONS: Long-term visual improvement was achievable in cases of complete LSCD. Cultivated oral mucosal epithelial sheet transplantation offered substantial visual improvement even for patients with end-stage severe ocular surface disorders accompanying severe tear deficiency. Patients with corneal blindness such as SJS benefited from critical improvement of visual acuity. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in anymaterials discussed in this article. PMID- 23084240 TI - Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. AB - OBJECTIVE: Two similarly designed, phase-3 studies (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD [VIEW 1, VIEW 2]) of neovascular age-related macular degeneration (AMD) compared monthly and every-2-month dosing of intravitreal aflibercept injection (VEGF Trap-Eye; Regeneron, Tarrytown, NY, and Bayer HealthCare, Berlin, Germany) with monthly ranibizumab. DESIGN: Double masked, multicenter, parallel-group, active-controlled, randomized trials. PARTICIPANTS: Patients (n = 2419) with active, subfoveal, choroidal neovascularization (CNV) lesions (or juxtafoveal lesions with leakage affecting the fovea) secondary to AMD. INTERVENTION: Patients were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4), 2 mg monthly (2q4), 2 mg every 2 months after 3 initial monthly doses (2q8), or ranibizumab 0.5 mg monthly (Rq4). MAIN OUTCOME MEASURES: The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on Early Treatment Diabetic Retinopathy Study [ETDRS] chart). Other key end points included change in best corrected visual acuity (BCVA) and anatomic measures. RESULTS: All aflibercept groups were noninferior and clinically equivalent to monthly ranibizumab for the primary end point (the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1%, respectively, for VIEW 1, and 95.6%, 96.3%, and 95.6%, respectively, for VIEW 2, whereas monthly ranibizumab was 94.4% in both studies). In a prespecified integrated analysis of the 2 studies, all aflibercept regimens were within 0.5 letters of the reference ranibizumab for mean change in BCVA; all aflibercept regimens also produced similar improvements in anatomic measures. Ocular and systemic adverse events were similar across treatment groups. CONCLUSIONS: Intravitreal aflibercept dosed monthly or every 2 months after 3 initial monthly doses produced similar efficacy and safety outcomes as monthly ranibizumab. These studies demonstrate that aflibercept is an effective treatment for AMD, with the every-2-month regimen offering the potential to reduce the risk from monthly intravitreal injections and the burden of monthly monitoring. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 23084242 TI - Subject-specific finite element simulation of the human femur considering inhomogeneous material properties: a straightforward method and convergence study. AB - In numerical finite element (FE) simulations of human bones subject-specific models are necessary to reproduce the physiological conditions, which include the determination of inhomogeneous material properties from computed tomography (CT) scans and their implementation in the numerical model. In the present approach common software packages are directly used for the entire simulation process from segmentation of CT scans, surface reconstruction, mesh generation, calculation of mean element densities to FE simulation. The influence of the mesh discretisation level on the maximum displacement, the total system energy and the principal surface stress distribution of eight human femurs was analysed. Both the maximum displacement and the total system energy showed typical convergence behaviour towards an asymptotic value with decreasing element size. The principal surface stress distribution followed similar qualitative trends at all mesh discretisation levels studied for the same femur. However, the stress distributions did not converge with decreasing element size and still differed significantly between the two smallest element sizes studied of approximately 2mm and 1mm. The magnitude of convergence differed among the individual femurs. Thus, individual convergence studies in terms of local stress or strain distributions are necessary for accurately predicting local stress and strain values in subject specific FE bone models. PMID- 23084243 TI - A novel approach for preferential recovery of Sr from (Sr, Th)O2. AB - Quantitative leaching of Sr from homogeneous and calcined (Th,Sr) O(2) in dilute perchloric acid medium suggests the possibility of reducing the hazardousness of discharged nuclear fuel by separation of (90)Sr, a prominent fission product at dissolution stage itself rather than the conventional approach of its recovery from high level nuclear waste. Apart from mitigating the radiotoxicity of the nuclear waste, recovered (90)Sr can be employed as a compact heat source and as parent radionuclide for (90)Y (used in therapy radiopharmaceuticals), provided it can be made available at desired high purity. Leaching behavior of few other fission products was also investigated to quantify their contamination in leached Sr. Feasibility of employing extraction chromatography using Sr selective resin was explored in perchloric acid medium. In this context, the distribution coefficients of (85)Sr(II), Th (IV), Zr(IV), Y(III), Pd(II) as well as (152)Eu(III) and (137)Cs (I) were determined under varying nitric acid/perchloric acid concentration and under varying loading conditions of metal ions. Perchloric acid medium appears better than nitric acid medium for preferential leaching of Sr from (Th,Sr)O(2) as well as for uptake of Sr by Sr selective chromatographic resin. PMID- 23084244 TI - Disassembly and physical separation of electric/electronic components layered in printed circuit boards (PCB). AB - Although printed circuit boards (PCBs) contain various elements, only the major elements (i.e., those with content levels in wt% or over grade) of and precious metals (e.g., Ag, Au, and platinum groups) contained within PCBs can be recycled. To recover other elements from PCBs, the PCBs should be properly disassembled as the first step of the recycling process. The recovery of these other elements would be beneficial for efforts to conserve scarce resources, reuse electric/electronic components (EECs), and eliminate environmental problems. This paper examines the disassembly of EECs from wasted PCBs (WPCBs) and the physical separation of these EECs using a self-designed disassembling apparatus and a 3 step separation process of sieving, magnetic separation, and dense medium separation. The disassembling efficiencies were evaluated by using the ratio of grinding area (E(area)) and the weight ratio of the detached EECs (E(weight)). In the disassembly treatment, these efficiencies were improved with an increase of grinder speed and grinder height. 97.7% (E(area)) and 98% (E(weight)) could be accomplished ultimately by 3 repetitive treatments at a grinder speed of 5500 rpm and a grinder height of 1.5mm. Through a series of physical separations, most groups of the EECs (except for the diode, transistor, and IC chip groups) could be sorted at a relatively high separation efficiency of about 75% or more. To evaluate the separation efficiency with regard to the elemental composition, the distribution ratio (R(dis)) and the concentration ratio (R(conc)) were used. 15 elements could be separated with the highest R(dis) and R(conc) in the same separated division. This result implies that the recyclability of the elements is highly feasible, even though the initial content in EECs is lower than several tens of mg/kg. PMID- 23084245 TI - Basic studies on radioimmunotargeting of CD133-positive HCT116 cancer stem cells. AB - As cancer stem cells (CSCs) are postulated to play critical roles in cancer development, including metastasis and recurrence, CSC imaging would provide valuable information for cancer treatment and lead to CSC-targeted therapy. To assess the possibility of in vivo CSC targeting, we conducted basic studies on radioimmunotargeting of cancer cells positive for CD133, a CSC marker recognized in various cancers. Antibodies against CD133 were labeled with 125I, and their in vitro cell binding properties were tested. Using the same isotype IgG as a control, in vivo biodistribution of the labeled antibody retaining immunoreactivity was examined in mice bearing an HCT116 xenograft in which a population of the cancer cells expressed CD133. Intratumoral distribution of the labeled antibody was examined and compared to the CD133 expression pattern. The 125I-labeled anti-CD133 antibody showed a modest but significantly higher accumulation in the HCT116 xenograft compared to the control IgG. The intratumoral distribution of the labeled antibody mostly overlapped with the CD133 expression, whereas the control IgG was found in the area close to the necrotic tumor center. Our results indicate that noninvasive in vivo targeting of CSCs could be possible with radiolabeled antibodies against cell membrane markers. PMID- 23084246 TI - Tracking tumor cells in lymphatics in a mice xenograft model by magnetic resonance imaging. AB - To enrich our understanding of the mechanism of tumor lymphatic metastasis, we developed a model system for tracking metastatic tumor cells in the lymphatic system with cellular magnetic resonance imaging (MRI) in live mice to observe the interaction between tumor cells and the lymphatic system. Nude mice were inoculated subcutaneously with superparamagnetic iron oxide (SPIO)-labeled and unlabeled LOVO cells in the foot pad, groin, or axillary area. Serial 7 T MRI of the tumors and surrounding regions was performed in the following 2 weeks. After imaging, tumor tissues and regional lymph nodes were collected and subjected to immunohistologic analysis. T2/T2*-weighted MRIs showed the primary tumor growth and the draining lymphatic architecture, as well as the SPIO-labeled tumor cells metastasized into the regional lymph node at 8 days. MRIs also revealed information on sentinel lymph node mapping with high-resolution anatomic information. Histologic findings confirmed the in vivo MRI results and revealed lymphangiogenesis, angiogenesis, infiltration of macrophages, and expression of vascular endothelial growth factor C in tumor and draining lymph nodes as well. This technology provides a powerful tool for tracking SPIO-labeled cancer cells in the lymphatics by cellular MRI. There was a close relationship between tumor lymphatic metastasis and lymphangiogenesis. PMID- 23084247 TI - Temporal changes in phosphatidylserine expression and glucose metabolism after myocardial infarction: an in vivo imaging study in mice. AB - Positron emission tomography (PET) for in vivo monitoring of phosphatidylserine externalization and glucose metabolism can potentially provide early predictors of outcome of cardioprotective therapies after myocardial infarction. We performed serial [68Ga]annexin A5 PET (annexin-PET) and [18F]fluorodeoxyglucose PET (FDG-PET) after myocardial infarction to determine the time of peak phosphatidylserine externalization in relation to impaired glucose metabolism in infracted tissue. Annexin- and FDG-PET recordings were obtained in female (C57BL6/N) mice on days 1 to 4 after ligation of the left anterior descending (LAD) artery. [68Ga]annexin A5 uptake (%ID/g) in the LAD artery territory increased from 1.7 +/- 1.1 on day 1 to 5.0 +/- 3.3 on day 2 and then declined to 2.0 +/- 1.4 on day 3 (p = .047 vs day 2) and 1.6 +/- 1.4 on day 4 (p = .014 vs day 2). These results matched apoptosis rates as estimated by autoradiography and fluorescein staining. FDG uptake (%ID/g) declined from 28 +/- 14 on day 1 to 14 +/- 3.5 on day 4 (p < .0001 vs day 1). Whereas FDG-PET revealed continuous loss of cell viability after permanent LAD artery occlusion, annexin-PET indicated peak phosphatidylserine expression at day 2, which might be the optimal time point for therapy monitoring. PMID- 23084248 TI - Cellular immunogenicity of novel gene immunogens in mice monitored by in vivo imaging. AB - The efficient cell-mediated immune response clears cells expressing deoxyribonucleic acid (DNA) immunogens, but there are no methods to monitor this in vivo. We hypothesized that immune-mediated clearance can be monitored in vivo if DNA immunogens are coexpressed with reporter(s). To test this, we designed genes encoding human immunodeficiency virus 1 (HIV-1) reverse transcriptase (RT) fused via its N- or C-terminus to 30-amino acid-long Gly-Ala-repeat of Epstein Barr virus nuclear antigen 1 or via the N-terminus to the transport signal of invariant chain/Ii or inserted between the cytoplasmic and luminal domains of lysosome-associated membrane protein I (LAMP). DNA immunogens mixed with luciferase gene were injected into BALB/c mice with subsequent electroporation. Reporter expression seen as luminescence was monitored by in vivo imaging. When luminescence faded, mice were sacrificed, and their splenocytes were stimulated with RT-derived antigens. Fading of luminescence correlated with the RT-specific secretion of interferon-gamma and interleukin-2. Both immune and in vivo imaging techniques concordantly demonstrated an enhanced immunogenicity of RT-LAMP and of the N-terminal Gly-Ala-RT fusion genes. In vivo imaging performed as an animal sparing method to estimate the overall performance of DNA immunogens, predicting it early in the experiment. So far, in vivo imaging cannot be a substitute for conventional immune assays, but it is supplementary to them. Further experiments are needed to identify which arms of cellular immune response in vivo imaging monitors best. PMID- 23084249 TI - Multicellular tumor spheroids as an in vivo-like tumor model for three dimensional imaging of chemotherapeutic and nano material cellular penetration. AB - We present a flexible and highly reproducible method using three-dimensional (3D) multicellular tumor spheroids to quantify chemotherapeutic and nanoparticle penetration properties in vitro. We generated HeLa cell-derived spheroids using the liquid overlay method. To properly characterize HeLa spheroids, scanning electron microscopy, transmission electron microscopy, and multiphoton microscopy were used to obtain high-resolution 3D images of HeLa spheroids. Next, pairing high-resolution optical characterization techniques with flow cytometry, we quantitatively compared the penetration of doxorubicin, quantum dots, and synthetic micelles into 3D HeLa spheroid versus HeLa cells grown in a traditional two-dimensional culturing system. Our data revealed that 3D cultured HeLa cells acquired several clinically relevant morphologic and cellular characteristics (such as resistance to chemotherapeutics) often found in human solid tumors. These characteristic, however, could not be captured using conventional two dimensional cell culture techniques. This study demonstrated the remarkable versatility of HeLa spheroid 3D imaging. In addition, our results revealed the capability of HeLa spheroids to function as a screening tool for nanoparticles or synthetic micelles that, due to their inherent size, charge, and hydrophobicity, can penetrate into solid tumors and act as delivery vehicles for chemotherapeutics. The development of this image-based, reproducible, and quantifiable in vitro HeLa spheroid screening tool will greatly aid future exploration of chemotherapeutics and nanoparticle delivery into solid tumors. PMID- 23084250 TI - Influence of bioluminescence imaging dynamics by D-luciferin uptake and efflux mechanisms. AB - Bioluminescence imaging (BLI) detects light generated by luciferase-mediated oxidation of substrate and is used widely for evaluating transgene expression in cell-based assays and in vivo in relevant preclinical models. The most commonly used luciferase for in vivo applications is firefly luciferase (fLuc), for which D-luciferin serves as the substrate. We demonstrated previously that the expression of the ABCG2 efflux transporter can significantly reduce BLI signal output and that HhAntag-691 can inhibit the efflux of D-luciferin, thereby enhancing BLI signal. Here we show that an HhAntag-691-sensitive uptake mechanism facilitates the intracellular concentration of D-luciferin and that the BLI dynamics of different cell lines are coregulated by this uptake mechanism in conjunction with ABCG2-mediated efflux. After administration of D-luciferin, the HhAntag-691-sensitive uptake mechanism generates a rapid increase in BLI signal that decreases over time, whereas ABCG2-mediated efflux stably reduces signal output. We implicate SLC22A4 (OCTN1), a member of the organic cation/zwitterion uptake transporter family, as one potential mediator of the HhAntag-691-sensitive D-luciferin uptake. These findings provide insight into mechanisms that contribute to the cellular uptake kinetics and in vivo biodistribution of D luciferin. PMID- 23084252 TI - Volumetry of [11C]-methionine positron emission tomographic uptake as a prognostic marker before treatment of patients with malignant glioma. AB - The purpose of this positron emission tomography (PET) study was to compare the prognostic value of pretreatment volume of 11C]-methionine (MET) uptake and semiquantitative MET uptake ratio in patients with malignant glioma. The study population comprised 40 patients with malignant glioma. Pretreatment magnetic resonance imaging (MRI) and MET-PET imaging were performed before the initiation of glioma treatment in all patients. The pretreatment MET uptake ratios and volumes were assessed. To create prognostically homogeneous subgroups, patients' pretreatment prognostic factors were stratified according to the six classes of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA). Univariate and multivariate analyses were performed to determine significant prognostic factors. Survival analyses identified the pretreatment volume of MET uptake and a higher RTOG RPA class as significant predictors. In contrast, pretreatment maximum areas of contrast enhancement on MRI and semiquantitative MET uptake ratios could not be identified as significant prognostic factors. The patients' outcomes and Karnofsky Performance Scale scores were significantly correlated with pretreatment volume of MET uptake but not with semiquantitative MET uptake ratio. The data suggest that pretreatment volumetry of MET uptake but not the semiquantitative MET uptake ratio is a useful biologic prognostic marker in patients with malignant glioma. PMID- 23084251 TI - Molecular imaging of gastric neoplasia with near-infrared fluorescent activatable probes. AB - Gastric cancer is the second leading cause of cancer mortality worldwide and is projected to rise to tenth in all-cause mortality in the near term. Early detection requires improved sensitivity and specificity of endoscopic imaging with novel methods. The objective of this study was to evaluate the utility of activatable molecular probes for the detection of gastric cancer both in vivo and ex vivo in a preclinical model. Smad4+/- mice, which develop spontaneous gastric neoplasia, were compared to normal wild-type controls. Cathepsin-activatable and matrix metalloproteinase (MMP)-activatable molecular probes were injected 24 hours and 6 hours before imaging, respectively. In vivo imaging was performed using quantitative tomographic near-infrared fluorescence (NIRF) imaging. For validation, ex vivo imaging and histologic examination were performed. Molecular imaging in vivo of Smad4+/- gastric cancer murine models revealed intense activation of both cathepsin B and MMP probes. Ex vivo imaging and histology confirmed that the detected neoplasms were adenocarcinomas and hyperplastic lesions. This study provides proof of principle that the cathepsin- and MMP activatable molecular probes are activated in the Smad4+/- murine model of spontaneous gastric adenocarcinoma and can be imaged by both in vivo and ex vivo NIRF methods. The cathepsin probe also detects hyperplastic lesions. PMID- 23084254 TI - The effects of a six-week supervised multimodal exercise intervention during chemotherapy on cancer-related fatigue. AB - PURPOSE: Cancer related fatigue (CRF) is a common problem for cancer patients across diagnoses during chemotherapy and is associated with physical inactivity, lower functional level and lack of energy. Few RCT exercise intervention studies have included cancer patients undergoing chemotherapy. The objective of this study is to evaluate whether a six-week supervised multimodal exercise intervention, adjunct to chemotherapy and standard care, can reduce the patient's CRF level. METHODS: Data is based on analyses of a prospective randomised controlled trial 'The Body & Cancer Trial'. 213 cancer patients with different diagnoses were randomised into an intervention group or wait-list control group. The primary outcome, Fatigue score (CRF), was evaluated by the Functional Assessment of Cancer Therapy-Anaemia Questionnaire (FACT-An-) (FACT-G score & FACT-An Anemia subscale). INTERVENTION: Supervised exercise, comprising high intensity cardiovascular and heavy resistance training, relaxation- and body awareness training and massage, 9 h weekly for 6 weeks. RESULTS: CRF was significantly reduced in the intervention group, corresponding to a Fatigue score reduction of 3.04 (effect size of 0.44, 95% CI 0.17-0.72) (P = .002), the FACT-An score by 5.40 (P = .015), the FACT-An Toi score by 5.22 (P = .009) and the Anaemia-ANS by 3.76 (P = .002). There was no statistically significant effect on the General Quality of Life score (FACT-G) or on any of the individual wellbeing scores; Physical (P = .13), Emotional (P = .87), Social (P = .83) and Functional (P = .26). CONCLUSION: In summary, this six-week supervised multimodal exercise intervention can lead to significant reduction in self-reported CRF in cancer patients undergoing chemotherapy. PMID- 23084255 TI - Atrophic plaque of 8 years' duration on the scalp. PMID- 23084256 TI - Satisfactory response to narrowband UV-B therapy in generalized lichen amyloidosis. PMID- 23084257 TI - Lack of antibody protection against Porcine circovirus 2 and Porcine parvovirus in naturally infected dams and their offspring. AB - The aim of this study was to evaluate Porcine parvovirus (PPV) and Porcine circovirus 2 (PCV2) infection in dams and their offspring and the role of antibody protection on these infections. Sera were collected from gilts and sows by venipuncture and from umbilical cord of newborn pre-suckle piglets for the detection of PCV2 and PPV antibodies by immunoperoxidase monolayer and haemmaglutination inhibition assays, respectively. Gilts and sows sera were submitted to viral detection by PCR, as well as heart, lung, tonsil and lymph nodes samples from stillborn and mummified fetuses. High antibody titers before artificial insemination (AI) (>5.120 and >2.560 UHA for PCV2 and PPV, respectively), were found associated with viremia and fetal exposure for both PCV2 and PPV, respectively, in gilts and sows, regardless of pregnancy stage. These infections resulted in litters with mummified, stillborn, as well as seropositive and viable newborns. These findings bring new evidence about the lack of antibody protection against PCV2 and PPV infections in dams, indicating that more studies are necessary about the role of humoral response against both pathogens. PMID- 23084258 TI - [Primary biliary cirrhosis-autoimmune hepatitis overlap syndrome in a patient with chronic hepatitis B infection]. AB - We describe the case of a female patient with a previous diagnosis of primary biliary cirrhosis (PBC) and chronic hepatitis B in inactive phase who developed increased transaminase levels with no evidence of hepatitis B virus reactivation while receiving ursodeoxycholic acid treatment. A liver biopsy showed changes compatible with overlapping autoimmune hepatitis (AIH). Budesonide treatment achieved normalization of transaminase levels. We provide a review of PBC and AIH overlap syndrome and discuss the particular features of this case that led us to this diagnosis, as well as the treatment provided. PMID- 23084259 TI - Searching for a more sensitive earthworm species to be used in pesticide homologation tests - a meta-analysis. AB - Pesticide risk assessments include experiments designed to measure the effect of pesticides on earthworms using the Eisenia fetida fetida or Eisenia fetida andrei species. There is no clear consensus in the literature on the sensitivity of different earthworm species to pesticides. We performed a meta-analysis on the sensitivity of several earthworm species to pesticides to determine the most sensitive species, and to discuss their suitability for European homologation tests. A dataset including median lethal dose (LC50) values reported in 44 experimental treatments was constructed and then analyzed in order to compare the sensitivity levels of E. fetida with that of other earthworm species. Results showed that LC50 values reported for Lumbricus terrestris and Aporrectodea caliginosa were on average significantly lower than for E. fetida. Considering the relatively high LC50 values reported for E. fetida and the absence of this species from zones where pesticides are usually applied, the relevance of using E. fetida for pesticide homologation tests is questionable and we advise risk assessors to use A. caliginosa as model species. A new protocol based on this species could be proposed for European homologation tests but its implementation will require the definition of a new standard and take time. In the meantime, the results obtained with E. fetida should be interpreted with caution taking into account the low sensitivity of this species. Our study illustrates the value of the meta-analysis approach for comparing the sensitivity of different earthworm species to pesticides. It would be useful to extend the dataset presented in this paper in order to analyze the sensitivity of other aquatic or terrestrial organism groups used for pesticide homologation or ecotoxicology tests. PMID- 23084260 TI - Bioavailability-based toxicity endpoints of bifenthrin for Hyalella azteca and Chironomus dilutus. AB - Recent studies have determined that techniques, such as solid phase microextraction (SPME) fibers and Tenax beads, can predict bioaccumulation and potentially could predict toxicity for several compounds and species. Toxicity of bifenthrin was determined using two standard sediment toxicity tests with the benthic species Hyalella azteca and Chironomus dilutus in three reference sediments with different characteristics. The objectives of the current study were to establish bioavailability-based median lethal concentrations (LC50) and median effect concentrations (EC50) of the pyrethroid insecticide bifenthrin, compare their ability to assess toxicity to the use of whole sediment concentrations, as well as to make comparisons of the concentrations derived using each method in order to make assessments of accuracy and extrapolation potential. Four metrics were compared including SPME fiber concentration, pore water concentration derived using SPMEs, 6 h Tenax extractable concentration, and 24 h Tenax extractable concentration. The variation among the LC50s and EC50s in each sediment derived using bioavailability-based methods was comparable to variation among organic carbon normalized sediment concentrations, but improved over whole sediment concentrations. There was a significant linear relationship between SPME or Tenax and organic carbon normalized sediment concentrations. Additionally, there was a significant relationship between the SPME and Tenax concentrations across sediments. The significant linear relationship between SPME and Tenax concentrations further demonstrates that these bioavailability-based endpoints are interrelated. This study derived bioavailability-based benchmarks that may prove to be more accurate than sediment-based ones in predicting toxicity across sediment types. PMID- 23084261 TI - Prediction of rate constants for the gas phase reactions of triphenylene with OH and NO3 radicals using a relative rate method in CCl4 liquid phase-system. AB - The kinetics of CCl(4) liquid-phase reactions of ten kinds of polycyclic aromatic compounds (PACs) including triphenylene (TP) with NO(3) radicals have been investigated at 273K by a relative rate method using naphthalene (NA) as a reference compound. The obtained relative reaction rates of the tested PACs to NA in CCl(4) were as follows: 2.57+/-0.24 (acenaphthene), 2.11+/-0.30 (2,3 dimethylnaphthalene), 1.21+/-0.13 (fluoranthene), 0.56+/-0.07 (fluorene), 1.85+/ 0.19 (1-methylnaphthalene), 1.77+/-0.12 (2-methylnaphthalene), 0.11+/-0.03 (1 nitronaphthalene), 1.59+/-0.23 (phenanthrene), 2.40+/-0.29 (pyrene), 0.22+/-0.04 (TP). TP is a semi-volatile PAC with four aromatic rings and it is chemically changed into mutagenic 2-nitrotriphenylene (2-NTP) via the gas-phase OH or NO(3) radical-initiated reactions. On the basis of the relative reactivity of the PACs in the CCl(4) liquid phase-system, the rate constants of the gas-phase reactions of TP with OH and NO(3) radicals at 298 K were predicted to be (8.6+/-1.2)*10( 12) cm(3) molecule(-1) s(-1) and (6.6+/-1.5)*10(-29)[NO(2)] cm(3) molecule(-1) s( 1), respectively. Based on the ambient concentrations of TP and 2-NTP and the obtained rate constant for the reaction of TP with OH radicals, the atmospheric loss rate of 2-NTP was also evaluated. PMID- 23084263 TI - Computational methods for protein interaction and structural prediction. PMID- 23084262 TI - Cellular effects of metolachlor exposure on human liver (HepG2) cells. AB - Metolachlor is one of the most commonly used herbicides in the United States. Protein synthesis is inhibited when roots and shoots of susceptible plants absorb this synthetic herbicide. While quite effective in killing weeds, several studies have shown that exposure to metolachlor results in decreased cell proliferation, growth and reproductive ability of non-target organisms. However, the mode of metolachlor action in non-target organisms has not yet been elucidated. The current study assessed effects of metolachlor exposure on immortalized human liver (HepG2) cells. Results from cell proliferation assays showed that a 72-h exposure to 50 parts per billion (ppb) metolachlor significantly inhibited growth of these cells compared to untreated controls while a decrease in the cell division rate required exposure to 500 ppb metolachlor for 48 h. Flow cytometry analysis of cell cycle distribution revealed that 500 ppb metolachlor treatment resulted in fewer HepG2 cells in G2/M phase after 72 h. Real-time PCR analysis showed a significant decrease in the abundance of the cyclin A transcripts after 12h in cells exposed to 300 ppb metolachlor. These results suggest metolachlor may affect progression through the S phase of the cell cycle and entrance into the G2 phase. PMID- 23084264 TI - Anterior knee laxity measurement: comparison of passive stress radiographs Telos((r)) and "Lerat", and GNRB((r)) arthrometer. AB - INTRODUCTION: In patients with anterior cruciate ligament (ACL) tears, anterior laxity can be measured using stress radiographs or more recently introduced electronic measurement devices. HYPOTHESIS: The GNRB((r)) arthrometer offers a radiation-free method of measuring anterior knee laxity whose diagnostic value is identical to that of Telos((r)) or Lerat stress radiographs. PATIENTS AND METHODS: One hundred and fifty-seven patients (40 years [18-69]) scheduled for knee arthroscopy were evaluated using the GNRB((r)) and two series of stress radiographs of both knees, one obtained using a 250-N Telos((r)) device and the other using the technique described by Lerat (posterior translation of the femur/tibia under a 9-kg loading device). Arthroscopic evaluation of the ACL served as the reference standard for assessing the diagnostic performance of the radiological and instrumental laxity measurements. RESULTS: Under arthroscopic examination, the ACL was normal in 50.3%; "healed to roof of the notch" (partial tear) in 9.6%, "posterolateral bundle preserved" (partial tear) in 7.0%, "healed to the posterior cruciate ligament" (PCL) in 17.8%, and "empty notch" (complete tear) in 15.3%. In partial ACL tears, no significant differences in anterior laxity were found across the three measurement techniques. Telos((r)) and GNRB((r)) laxities were greater in the complete-tear group than in the normal ACL, partial-tear, and healed-to-PCL groups. With the Lerat technique, the only significant differences were between the complete-tear group and the normal-ACL and partial-tear groups. Telos((r)) and GNRB((r)) showed similar diagnostic performance (sensitivity>62%, specificity>75%), whereas the Lerat technique lacked sensitivity (sensitivity=43.2%, specificity=82.7%) at 3mm. DISCUSSION: Diagnostic performance was lower in our study than in earlier reports. The GNRB((r)) performed as well as Telos((r)). The non-irradiating nature of GNRB((r)) assessments allows repeated measurements for therapeutic or diagnostic purposes. LEVEL OF EVIDENCE: Level III, prospective case-control study. PMID- 23084265 TI - Ewing-like adamantinoma. AB - The Ewing-like variation of adamantinoma is a rare entity, leading to challenge its differential diagnosis, notably with Ewing's sarcoma. We are reporting a case of a 20-year-old male who presented with swelling in the left leg that had progressed over a 2-year period. X-rays revealed a tumour in the tibia that was intracortical, osteolytic, multilocular and invaded the soft tissues. A surgical biopsy was performed. Histopathology examination showed a tumour growth with small round cells expressing CD99. A diagnosis of Ewing's sarcoma was made. Since the patient declined surgical treatment, chemotherapy was administered. Two years later, the patient returned because the tumour had grown in size. A second biopsy was performed. Microscopic evaluation showed a tumour growth with osteofibrous and epithelial components, which expressed pankeratin and vimentin, but was negative for CD99. A diagnosis of Ewing-like adamantinoma was made. PMID- 23084266 TI - Preliminary results of the first human uterus transplantation from a multiorgan donor. AB - OBJECTIVE: To describe the first-year results of the first human uterus transplantation case from a multiorgan donor. DESIGN: Case study. SETTING: University hospital. PATIENT(S): A 21-year-old woman with complete mullerian agenesis who had been previously operated on for vaginal reconstruction. INTERVENTION(S): Uterus transplantation procedure consisting of orthotopic replacement and fixation of the retrieved uterus, revascularization, end to site anastomoses of bilateral hypogastric arteries and veins to bilateral external iliac arteries and veins was performed. MAIN OUTCOME MEASURE(S): Resumption of menstrual cycles. RESULT(S): The patient had menarche 20 days after transplant surgery. She has had 12 menstrual cycles since the operation. CONCLUSION(S): We have described the longest-lived transplanted human uterus to date with acquirement of menstrual cycles. PMID- 23084268 TI - Endometriosis: a consequence of varying injuries to pelvic autonomic nerves. PMID- 23084269 TI - Expression of survivin in human oocytes and preimplantation embryos. AB - OBJECTIVE: To determine whether [1] survivin is expressed in human oocytes and embryos; [2] embryos grown in vitro secrete survivin protein; and [3] survivin levels are correlated with embryo cleavage rates. DESIGN: Experimental. SETTING: University-affiliated IVF clinic. PATIENT(S): Couples undergoing IVF-ET cycles. INTERVENTION(S): Conventional reverse transcriptase-polymerase chain reaction (PCR), real-time PCR, immunohistochemistry, Western blot on oocytes, embryos and control choriocarcinoma JEG-3 cells, and ELISA analysis of conditioned culture media. MAIN OUTCOME MEASURE(S): Detection of survivin mRNA and protein in oocytes and preimplantation embryos and in JEG-3 cancer cells. Detection of survivin concentrations in embryo culture media. RESULT(S): Survivin mRNA and protein were expressed during human oocyte maturation, from germinal vesicle to metaphase II stage, and throughout embryo development, from pronuclear stage to blastocyst stage. Survivin was localized predominantly in the cytoplasm of all cells examined and in the oocytes on the chromatin of metaphase chromosomes and midbodies. Western blot analysis of human oocyte and cancer cell extracts detected a full-length (primary) survivin band of 16.5 kDa. Survivin was also detected in conditioned media samples from embryo cultures and showed a positive correlation with embryo cleavage rates. CONCLUSION(S): Our data have demonstrated for the first time that human oocytes/embryos not only express but also secret survivin, suggesting that survivin may play an important role in human oogenesis and embryogenesis. PMID- 23084267 TI - Pretreatment antimullerian hormone levels determine rate of posttherapy ovarian reserve recovery: acute changes in ovarian reserve during and after chemotherapy. AB - OBJECTIVE: To identify factors associated with ovarian reserve impairment during and immediately after chemotherapy. DESIGN: Prospective cohort study. SETTING: Four university hospitals. PATIENT(S): Forty-six adolescent and young adult women with a new diagnosis of cancer requiring chemotherapy. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Measurements of ovarian reserve via levels of serum follicle-stimulating hormone, luteinizing hormone, estradiol, inhibin B, and antimullerian hormone (AMH) as well as antral follicle counts and mean ovarian volume at 3-month intervals. RESULT(S): Changes in ovarian reserve were quantified for both the acute impact of treatment using linear regression and the longitudinal recovery after therapy using mixed-effects models adjusted for baseline ovarian reserve, use of alkylating agent, and hormone use. The women had at least one pretreatment and two posttreatment study visits (mean follow-up interval: 12 months). All measures of ovarian reserve demonstrated statistically significant changes during chemotherapy. Alkylating agent exposure and baseline ovarian reserve were acutely associated with the magnitude of impairment, and pretreatment AMH levels were associated with the rate of recovery of AMH after treatment. In adjusted models, participants with a pretreatment AMH level > 2 ng/mL recovered at a rate of 11.9% per month after chemotherapy, whereas participants with pretreatment AMH levels <= 2 ng/mL recovered at a rate of 2.6% per month after therapy. CONCLUSION(S): Baseline ovarian reserve and alkylating agent exposure effect the magnitude of acute changes in ovarian reserve from chemotherapy. The rate of recovery of AMH is impacted by pretreatment levels. This should be considered during pretreatment fertility preservation counseling. PMID- 23084270 TI - Quo vadis randomized controlled trials in infertility? PMID- 23084271 TI - An analysis of security price risk and return among publicly traded pharmacy corporations. AB - BACKGROUND: Community pharmacies have been subject to intense and increasing competition in the past several decades. OBJECTIVE: To determine the security price risk and rate of return of publicly traded pharmacy corporations present on the major U.S. stock exchanges from 1930 to 2009. METHODS: The Center of Research in Security Prices (CRSP) database was used to examine monthly security-level stock market prices in this observational retrospective study. The primary outcome of interest was the equity risk premium, with analyses focusing upon financial metrics associated with risk and return based upon modern portfolio theory (MPT) including: abnormal returns (i.e., alpha), volatility (i.e., beta), and percentage of returns explained (i.e., adjusted R(2)). Three equilibrium models were estimated using random-effects generalized least squares (GLS): 1) the Capital Asset Pricing Model (CAPM); 2) Fama-French Three-Factor Model; and 3) Carhart Four-Factor Model. RESULTS: Seventy-five companies were examined from 1930 to 2009, with overall adjusted R(2) values ranging from 0.13 with the CAPM to 0.16 with the Four-Factor model. Alpha was not significant within any of the equilibrium models across the entire 80-year time period, though was found from 1999 to 2009 in the Three- and Four-Factor models to be associated with a large, significant, and negative risk-adjusted abnormal returns of -33.84%. Volatility varied across specific time periods based upon the financial model employed. CONCLUSION: This investigation of risk and return within publicly listed pharmacy corporations from 1930 to 2009 found that substantial losses were incurred particularly from 1999 to 2009, with risk-adjusted security valuations decreasing by one-third. PMID- 23084272 TI - Does leaving a main pancreatic duct stent in place reduce the incidence of precut biliary sphincterotomy-associated pancreatitis? A randomized, prospective study. AB - BACKGROUND: Pancreatitis is the most common major complication of ERCP and precut endoscopic sphincterotomy (ES). Prophylactic pancreatic duct (PD) stent placement has been shown to reduce the incidence and severity of post-ERCP pancreatitis (PEP) in high-risk settings. OBJECTIVE: To determine whether leaving a main PD stent in place after precut ES would reduce the incidence and severity of PEP. DESIGN: Single-center, randomized, prospective study. SETTING: Tertiary care ERCP referral center. PATIENTS: Consecutive patients who underwent ERCP with a clear indication for biliary access and standard biliary ES whereby free cannulation of the bile duct was not possible and precut ES was undertaken. INTERVENTIONS: When free bile duct cannulation for ES was not possible and selective PD cannulation was achieved, a PD stent was placed. Using the PD stent as a guide, we used a needle-knife sphincterotome to perform precut ES. The patients were then randomized to either leaving the PD stent in place for 7 to 10 days (stent group) or immediate removal after the procedure (stent removed group). The remaining patients who did not undergo selective PD cannulation and stent placement were not randomized (no stent group) and had a free-hand needle-knife ES performed. MAIN OUTCOME MEASUREMENTS: Patients were prospectively followed for the development of complications. Standardized criteria were used to diagnose and grade the severity of PEP. RESULTS: A total of 151 patients were enrolled. The groups were similar with regard to patient demographics and patient and procedure risk factors for PEP. The overall incidence of PEP was 13.2% (20/151). It occurred in 4.3% (2/46), 21.3% (10/47), and 13.8% (8/58) of patients in the stent, stent removed, and no stent groups, respectively. The stent group had a significantly lower frequency and severity of PEP compared with the stent removed group (4.3% vs 21.3%; P = .027 for frequency and 0% vs 12.8%; P = .026 for moderate and severe pancreatitis). LIMITATIONS: Single center. Randomization scheme not optimal. CONCLUSIONS: These data suggest that placing and maintaining a PD stent for needle-knife precut ES reduces the frequency and severity of postprocedure pancreatitis. PMID- 23084273 TI - Effect of incinerator bottom-ash composition on the mechanical behavior of backfill material. AB - This study explores the influence of the chemical composition (SiO(2), CaO, Fe(2)O(3), and Al(2)O(3)) of incinerator bottom ash on its friction angle. Direct shear tests were performed to measure the strength of bottom ash with two distinctly different compositions. Then, an empirical equation was regressed to determine the correlation between each composition and the friction angle. The experimental results showed that the main constituent material of the incinerator bottom ash from general municipal wastes is SiO(2), and the friction angle is 48.04 degrees -52.66 degrees . The bottom ash from incineration plants treating both municipal wastes and general industrial wastes has a high content of iron aluminum oxides, and its friction angle is 44.60 degrees -52.52 degrees . According to the multivariate regression analysis result, the friction angle of bottom ash of any composition is influenced mainly by the Fe(2)O(3) and Al(2)O(3) contents. This study used the friction angle of the bottom ash from four different incineration plants to validate the empirical equation, and found that the error between actual friction angles and the predicted values was -1.36% to 5.34%. Therefore, the regressed empirical equation in this study can be employed in engineering applications to preliminarily identify the backfill quality of incinerator bottom ash. PMID- 23084274 TI - Endovenous laser ablation of the great saphenous vein using a bare fibre versus a tulip fibre: a randomised clinical trial. AB - OBJECTIVE: This clinical trial aimed to evaluate the clinical results of the use of a tulip fibre versus the use of a bare fibre for endovenous laser ablation. METHODS: In a multicentre prospective randomised trial 174 patients were randomised for the treatment of great saphenous vein reflux. A duplex scan was scheduled 1 month, 6 months and 1 year postoperatively. Ecchymosis was measured on the 5th postoperative day. In addition, pain, analgesics requirement, postoperative quality of life (CIVIQ 2) and patient satisfaction rate were noted. RESULTS: Patients treated with a tulip fibre had significantly less postoperative ecchymosis (0.04 vs. 0.21; p < 0.001) and pain (5th day) (1.00 vs. 2.00; p < 0.001) and had a better postoperative quality of life (27 vs. 32; p = 0.023). There was no difference in analgesic intake (p = 0.11) and patient satisfaction rate (p = 0.564). The total occlusion rate at 1 year was 97.02% and there was no significant difference between the two groups (p = 0.309). CONCLUSION: Using a tulip fibre for EVLA of the great saphenous vein results, when compared with the use of a bare fibre, in equal occlusion rates at 1 year but causes less postoperative ecchymosis and pain and in a better postoperative quality of life. PMID- 23084275 TI - Design, synthesis and evaluation of novel zwitterionic compounds as PPARalpha/gamma dual agonists (1). AB - We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) alpha/gamma dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR alpha/gamma dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR alpha/gamma dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR alpha/gamma dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model. PMID- 23084276 TI - Linear and cyclic dipeptides with antimalarial activity. AB - Several natural and synthetic polypeptides possess important antimalarial activity. Shorter peptides with potent antimalarial activity have also been described, among them linear di-, tri-, tetra- and pentapeptides and their cyclic analogs. In an attempt to find dipeptides with antimalarial activities we show that linear and cyclic dipeptides, the latter known as diketopiperazines, still retain the fundamental core to preserve antimalarial activity. Thirteen linear dipeptides and ten diketopiperazines were investigated. Eight linear dipeptides showed IC(50) values between 2.78 and 7.07 MUM, while eight diketopiperazines were also active with IC(50) values between 2.26 and 4.26 MUM on Plasmodium berghei schizont cultures. PMID- 23084277 TI - Kibdelomycin A, a congener of kibdelomycin, derivatives and their antibacterial activities. AB - Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family. PMID- 23084278 TI - Structure-activity relationship exploration of Kv1.3 blockers based on diphenoxylate. AB - Diphenoxylate, a well-known opioid agonist and anti-diarrhoeal agent, was recently found to block Kv1.3 potassium channels, which have been proposed as potential therapeutic targets for a range of autoimmune diseases. The molecular basis for this Kv1.3 blockade was assessed by the selective removal of functional groups from the structure of diphenoxylate as well as a number of other structural variations. Removal of the nitrile functional group and replacement of the C-4 piperidinyl substituents resulted in several compounds with submicromolar IC(50) values. PMID- 23084279 TI - Statistical models for spatially explicit biological data. AB - Existing algorithms for predicting species' distributions sit on a continuum between purely statistical and purely biological approaches. Most of the existing algorithms are aspatial because they do not consider the spatial context, the occurrence of the species or conditions conducive to the species' existence, in neighbouring areas. The geostatistical techniques of kriging and cokriging are presented in an attempt to encourage biologists more frequently to consider them. Unlike deterministic spatial techniques they provide estimates of prediction errors. The assumptions and applications of common geostatistical techniques are presented with worked examples drawn from a dataset of the bluetongue outbreak in northwest Europe in 2006. Emphasis is placed on the importance and interpretation of weights in geostatistical calculations. Covarying environmental data may be used to improve predictions of species' distributions, but only if their sampling frequency is greater than that of the species' or disease data. Cokriging techniques are unable to determine the biological significance or importance of such environmental data, because they are not designed to do so. PMID- 23084281 TI - Patients' experiences of adjusting insulin doses when implementing flexible intensive insulin therapy: a longitudinal, qualitative investigation. AB - AIM: To explore patients' experiences of using flexible intensive insulin therapy, a regimen requiring them to determine and adjust quick-acting and background/basal insulin doses and mealtime ratios. METHODS: Repeat, in-depth interviews with 30 type 1 diabetes patients converted to flexible intensive insulin therapy recruited from Dose Adjustment for Normal Eating (DAFNE) courses in the UK. RESULTS: While patients found determination of quick acting insulin doses relatively straightforward, many struggled, over time, to determine the correct mealtime ratios and adjust basal insulin doses independently. Reasons included: lack of confidence and poor analytical skills; deferential attitudes to health professionals; worries about hypoglycaemia; and, lack of record/diary keeping resulting in fixation on current readings and failure to spot patterns and problems. When health professional support was not sought and/or record keeping neglected, patients gradually developed over-reliance on corrective doses to attain blood glucose readings within target ranges. CONCLUSION: While patients are motivated to use flexible intensive insulin therapy, they expressed a need for on-going health professional input, particularly to support adjustment of background insulin doses and mealtime ratios. The need to sustain diary/record keeping should be emphasised to patients and provision of a dedicated glycaemic support service is recommended. PMID- 23084282 TI - A computational method for determining tissue material properties in ovine fracture calluses using electronic speckle pattern interferometry and finite element analysis. AB - For numerical simulations of biological processes the assignment of reliable material properties is essential. Since literature data show huge variations for each parameter, this study presents a method for determining tissue properties straight from the investigated specimens by combining electronic speckle pattern interferometry (ESPI) with finite element (FE) analysis in a two-step parameter analysis procedure. ESPI displacement data from two mid-sagittal ovine fracture callus slices under 5 N compressive load were directly compared to data from FE simulations of the respective experimental setup. In the first step a parameter sensitivity analysis quantified the influence of single tissues on the mechanical behavior of the callus specimens. In the second step, material properties (i.e. Young's moduli and Poisson's ratios) for the most dominant material of each callus specimen were determined through a parameter sampling procedure minimizing the mean local deviations between the simulated (FE) and measured (ESPI) equivalent element strains. The resulting material properties showed reasonable ranges downsizing the variability of previous published values, especially for Young's modulus which was 1881 MPa for woven bone and 16 MPa for cartilage in average. In conclusion, a numerical method was developed to determine material properties straight from independent fracture callus specimens based on experimentally derived local mechanical conditions. PMID- 23084280 TI - Improving diabetes care: multi-component cardiovascular disease risk reduction strategies for people with diabetes in South Asia--the CARRS multi-center translation trial. AB - AIMS: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in people with diabetes in South Asia. The CARRS Translation Trial tests the effectiveness, cost-effectiveness, and sustainability of a clinic-based multi-component CVD risk reduction intervention among people with diabetes in India and Pakistan. METHODS: We randomly assigned 1146 adults with diabetes recruited from 10 urban clinic sites, to receive usual care by physicians or to receive an integrated multi-component CVD risk reduction intervention. The intervention involves electronic health record management, decision-support prompts to the healthcare team, and the support of a care coordinator to actively facilitate patient and provider adherence to evidence-based guidelines. The primary outcome is a composite of multiple CVD risk factor control (blood glucose and either blood pressure or cholesterol, or all three). Other outcomes include control of the individual CVD risk factors, process and patient-centered measures, cost-effectiveness, and acceptability/feasibility. CONCLUSION: The CARRS Translation Trial tests a low-cost diabetes care delivery model in urban South Asia to achieve comprehensive cardio-metabolic disease case-management of high-risk patients (clinicaltrials.gov number: NCT01212328). PMID- 23084283 TI - Effects of intravenous low-dose recombinant human atrial natriuretic peptide on renal function in the perioperative management for gastrointestinal perforation or ileus: a retrospective single-center study. AB - PURPOSE: We studied the effectiveness of human atrial natriuretic peptide (hANP) on management of acute kidney injury. METHODS: This retrospective single-center study included 43 patients from January 2007 to February 2010 who had undergone non-elective abdominal surgery for gastrointestinal perforation and ileus. Patients were separated into 2 groups according to whether hANP was administered or not, and 4 subgroups according to whether or not baseline serum creatinine <1.2 mg/dL; normal cre/hANP (-) (n = 22), high cre/hANP (-) (n = 10), normal cre/hANP (+) (n = 4), and high cre/hANP (+) (n = 7). The administration of hANP was started during operation. RESULTS: The administration rate of hANP ranged between 0.02 and 0.05 MUg/kg per minute, except for one patient and the average postoperative administration time of hANP was 167 +/- 237 h (range, 8-888 h). There were no significant differences in characteristics of patients within four subgroups, except for patient's weight. Serum creatinine in high cre/hANP (+) got to decrease more than high cre/hANP (-). Outcomes such as 28-day mortality were not significantly different among four subgroups. No patients required renal replacement therapy in each subgroup. CONCLUSION: Intravenous low dose of hANP was useful as acute kidney injury management in gastrointestinal perforation and ileus patients undergoing non-elective surgery. PMID- 23084284 TI - A possible association between panic disorder and a polymorphism in the preproghrelingene. AB - The aim of the study was to investigate whether polymorphisms in the preproghrelin gene are associated with anxiety disorders, such as panic disorder, in humans. Panic disorder is a severe anxiety disorder, characterized by sudden attacks of intense fear or anxiety in combination with somatic symptoms. The preproghrelin gene codes for two gut-derived circulating peptides that have been linked to anxiety-like behaviour in rodents: ghrelin (an orexigenic, pro-obesity hormone) and obestatin. In the present study, we genotyped three missense mutations in the preproghrelin gene in 215 patients suffering from panic disorder and in 451 controls. The A allele of the rs4684677 polymorphism was significantly associated with panic disorder, while there were no significant associations with the two other polymorphisms studied. We conclude that the rs4684677 (Gln90Leu) polymorphism in the preproghrelin gene may be associated with increased risk of panic disorder. It will be important to confirm these findings in additional panic disorder patient groups. PMID- 23084285 TI - [The big questions of the medical chronobiology: why, how, when?]. PMID- 23084286 TI - Nocturnal evolution of heart rate variability indices in sleep apnea. AB - Heart rate variability (HRV) is a valuable clinical tool in diagnosing multiple diseases. This paper presents the results of a spectral HRV analysis conducted with 46 patients. HRV indices for the whole night show differences among patients with severe and mild apnea, and healthy subjects. These differences also appear when performing the analysis over 5-min intervals, regarding apneas being present or not in the intervals. Differences were also observed when analyzing the HRV nocturnal evolution. Results are consistent with the hypothesis that cardiovascular risk remains constant for OSA patients while it increases towards the end of the night for healthy subjects. PMID- 23084287 TI - Mycobacterium tuberculosis-secreted phosphatases: from pathogenesis to targets for TB drug development. AB - Mycobacterium tuberculosis (Mtb) infects human alveolar macrophages and relies on the inhibition of phagosome acidification and maturation. This is, in part, dependent on the disruption of host signaling networks within the macrophage. In recent years, Mtb-secreted protein- and lipid-phosphatases protein-tyrosine phosphatase A (PtpA), PtpB, and secreted acid phosphatase M (SapM) have been shown to contribute to Mtb pathogenicity. Here, we review the current knowledge on PtpA, PtpB, and SapM focusing on their ability to interfere with host functions. We further explore how these phosphatase-dependent host-pathogen interactions can be targeted for novel tuberculosis (TB) drug discovery and examine the ongoing development of inhibitors against these phosphatases. PMID- 23084288 TI - Subcellular localization and quantitation of the human papillomavirus type 16 E6 oncoprotein through immunocytochemistry detection. AB - Human papillomavirus (HPV) type 16 E6 is a viral oncoprotein essential for host cell transformation. Due to its role in HPV-induced cancers of the genital, head and neck epithelia, reliable protein-level determination of E6 expression would be an invaluable diagnostic tool. Immunocytochemical detection and subcellular localization of HPV16 E6 has been demonstrated with varying success and a comprehensive review of techniques is lacking. To address these issues, we used established monoclonal antibodies and optimized a standard immunocytochemical method for E6 protein detection inside the HPV16 positive cell lines, SiHa and CaSki. E6 oncoprotein was detected primarily in the nucleus. We also refined quantitative analysis with a software to objectively differentiate between HPV16 positive and negative cells. Our analysis was also able to differentiate expression differences between SiHa and CaSki on par with RT-qPCR. Thus, we provide a long-needed, robust protocol for antibody-mediated detection of the HPV16 E6 oncoprotein inside cultured cells. PMID- 23084289 TI - Microbial virus genome annotation-mustering the troops to fight the sequence onslaught. AB - The revolution in virus genome sequencing promises to effectively map the extant biological universe and reveal fundamental relationships between viral biology, genome structure, and evolution. Indeed, microbial virus genomes include large numbers of conserved coding sequences of unknown function as well as unique gene combinations, implying that that these viruses will be a significant source of novel protein biochemistry and genome architecture. Yet, making sense of the approaching phalanx of A's, G's, T's, and C's stretching across the genome sequencing horizon will require innovation and an unprecedented coordination of annotation efforts among stakeholders. PMID- 23084290 TI - A mutation in PNPT1, encoding mitochondrial-RNA-import protein PNPase, causes hereditary hearing loss. AB - A subset of nuclear-encoded RNAs has to be imported into mitochondria for the proper replication and transcription of the mitochondrial genome and, hence, for proper mitochondrial function. Polynucleotide phosphorylase (PNPase or PNPT1) is one of the very few components known to be involved in this poorly characterized process in mammals. At the organismal level, however, the effect of PNPase dysfunction and impaired mitochondrial RNA import are unknown. By positional cloning, we identified a homozygous PNPT1 missense mutation (c.1424A>G predicting the protein substitution p.Glu475Gly) of a highly conserved PNPase residue within the second RNase-PH domain in a family affected by autosomal-recessive nonsyndromic hearing impairment. In vitro analyses in bacteria, yeast, and mammalian cells showed that the identified mutation results in a hypofunctional protein leading to disturbed PNPase trimerization and impaired mitochondrial RNA import. Immunohistochemistry revealed strong PNPase staining in the murine cochlea, including the sensory hair cells and the auditory ganglion neurons. In summary, we show that a component of the mitochondrial RNA-import machinery is specifically required for auditory function. PMID- 23084291 TI - Mutation in PNPT1, which encodes a polyribonucleotide nucleotidyltransferase, impairs RNA import into mitochondria and causes respiratory-chain deficiency. AB - Multiple-respiratory-chain deficiency represents an important cause of mitochondrial disorders. Hitherto, however, mutations in genes involved in mtDNA maintenance and translation machinery only account for a fraction of cases. Exome sequencing in two siblings, born to consanguineous parents, with severe encephalomyopathy, choreoathetotic movements, and combined respiratory-chain defects allowed us to identify a homozygous PNPT1 missense mutation (c.1160A>G) that encodes the mitochondrial polynucleotide phosphorylase (PNPase). Blue-native polyacrylamide gel electrophoresis showed that no PNPase complex could be detected in subject fibroblasts, confirming that the substitution encoded by c.1160A>G disrupts the trimerization of the protein. PNPase is predominantly localized in the mitochondrial intermembrane space and is implicated in RNA targeting to human mitochondria. Mammalian mitochondria import several small noncoding nuclear RNAs (5S rRNA, MRP RNA, some tRNAs, and miRNAs). By RNA hybridization experiments, we observed a significant decrease in 5S rRNA and MRP related RNA import into mitochondria in fibroblasts of affected subject 1. Moreover, we found a reproducible decrease in the rate of mitochondrial translation in her fibroblasts. Finally, overexpression of the wild-type PNPT1 cDNA in fibroblasts of subject 1 induced an increase in 5S rRNA import in mitochondria and rescued the mitochondrial-translation deficiency. In conclusion, we report here abnormal RNA import into mitochondria as a cause of respiratory chain deficiency. PMID- 23084293 TI - Nonmelanoma skin cancer of the head and neck: current diagnosis and treatment. AB - An overview of where nonmelanoma cancers appear in the hierarchy of cancers is succinctly presented, as well as their incidence, etiology, and costs. The examination and treatment of these cancers are summarized. PMID- 23084292 TI - Unraveling multiple MHC gene associations with systemic lupus erythematosus: model choice indicates a role for HLA alleles and non-HLA genes in Europeans. AB - We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(*)03:01, HLA-DRB1(*)08:01, and HLA-DQA1(*)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000). PMID- 23084294 TI - Epidemiology and economic burden of nonmelanoma skin cancer. AB - The authors present a succinct summary of the incidence and costs of nonmelanoma skin cancers. They present incidence and health care costs for this disease from Australia, United States, and Europe, noting that NMSC care cost stands in fifth place after prostate, lung, colon, and breast carcinomas. PMID- 23084295 TI - Nonmelanoma skin cancer of the head and neck: clinical evaluation and histopathology. AB - Clinical and histopathologic features of nonmelanoma skin cancer, physical examination, and diagnostic methods (biopsy, dermoscopy, confocal microscopy) are summarized. A diagnostic algorithm provides a useful summarization of differential diagnosis of basal cell carcinoma, actinic keratosis, Bowen's disease, and squamous cell carcinoma. PMID- 23084296 TI - Nonmelanoma skin cancer of the head and neck: molecular mechanisms. AB - Histopathologic examination is the gold standard for the diagnosis of skin cancer. Because analysis of molecular parameters such as nucleic acids and DNA are also gaining importance in diagnosis, prognosis, and therapy, an understanding of the molecular mechanisms underlying the pathogenesis of nonmelanoma skin cancer of the head and neck is of growing importance for the diagnostician and surgeon alike. This article presents a description of the effect on cells and impact on DNA of ultraviolet radiation, with a discussion of squamous cell and basal cell carcinoma in terms of the effects of genetic pathways and apoptosis. PMID- 23084297 TI - Nonmelanoma skin cancer of the head and neck: nonsurgical treatment. AB - Nonmelanoma skin cancer (NMSC) is one of the most prevalent types of cancer worldwide, with basal cell carcinoma and squamous cell carcinoma being the most frequent histologic types. Surgical excision remains the mainstay of treatment, but nonsurgical treatment options may be indicated in specific cases. Nonsurgical treatment options for NMSC may be preferred as good alternatives under certain circumstances. This review provides a comprehensive overview of the nonsurgical treatment modalities for NMSCs, such as curettage and electrodesiccation, cryotherapy, radiotherapy, laser, photodynamic therapy, immunotherapy, and retinoid therapy. PMID- 23084298 TI - Nonmelanoma skin cancer of the head and neck: surgical treatment. AB - This article focuses on the surgical treatment of nonmelanoma skin cancers of the head and neck. The risk factors of nonmelanoma skin cancers for recurrence and metastases that are important for choosing the best treatment option are summarized. Surgical treatment options including surgical excision with standard margins, frozen section, staged surgery, and Mohs micrographic surgery are described. Indications, techniques, outcomes, and advantages and disadvantages of each approach are reviewed. Finally, management of incomplete excisions is discussed. PMID- 23084299 TI - Cutaneous squamous cell carcinoma of the head and neck: management of the parotid and neck. AB - Although the metastatic rate of cutaneous squamous cell carcinoma (SCC) is low, detailed examination for the presence of micro- and macrometastasis of lymph nodes is crucial in avoiding the devastating outcomes and in planning appropriate treatment. Cutaneous SCC of the head and neck can spread to parotid lymph nodes, cervical lymph nodes, or both, depending on the location of the primary tumor. Therefore, clinical and radiologic evaluation of the parotid and neck should be performed in patients with cutaneous SCC. Optimal treatment of metastatic cutaneous SCC of the head and neck should consist of complete surgical resection with adjuvant radiotherapy. PMID- 23084300 TI - Uncommon cutaneous neoplasms of the head and neck. AB - This article concentrates on the less-common cutaneous malignancies such as merkel cell, atypical fibroxanthoma, malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, microcystic adnexal carcinoma, and sebaceous carcinoma. The clinical and histopathologic descriptions of each, most current and emerging etiologies, diagnosis, staging, treatment, and prognosis are discussed. PMID- 23084301 TI - Nonmelanoma skin cancer of the head and neck: reconstruction. AB - Reconstruction of facial defects formed after resection of skin cancers is a challenging procedure. Achieving the best functional and aesthetic outcome depends on accurate preoperative planning. Reconstructive surgeons should perform a detailed analysis of the facial defect based on location, size, and depth and choose the most appropriate technique according to their experiences and patient preferences and expectations. This article reviews the preoperative analysis of facial defects, and the major principles and techniques of facial reconstruction. Discussed are reconstruction of the nose, lip, cheek, forehead, and eyelid, presenting for each technique the goals of the reconstruction, types of flaps and grafts, and surgical technique. PMID- 23084302 TI - Nonmelanoma skin cancer of the head and neck: prevention. AB - The importance and effectiveness of prevention efforts and strategies for skin cancers are reviewed. Topical sunscreens and their proper use are presented. Topical and ingested forms of natural, synthetic, or biologic chemical agents that are potentially efficacious for chemoprevention are listtdldted and discussed. PMID- 23084303 TI - Nonmelanoma skin cancer of the head and neck. PMID- 23084304 TI - A rare and unique case of aggressive IgE-lambda plasma cell myeloma in a 28-year old woman presented initially as an orbital mass. AB - A 28-year-old African-American woman presented with new onset of left exophthalmos and diplopia. Computed tomography of the head showed a solitary mass in the left orbit. Excisional biopsy revealed a diffuse infiltrate composed of exclusively lambda-restricted monotypic plasma cells based on morphology and immunohistochemistry, consistent with a plasma cell neoplasia. A subsequent staging bone marrow biopsy showed involvement of the bone marrow by lambda restricted monotypic plasma cells, consistent with a plasma cell myeloma. Serum protein electrophoresis and immunofixation studies on the peripheral blood showed a monoclonal band of IgE-lambda; thus, an IgE-lambda plasma cell myeloma was established. Additional clinical and radiologic workups showed multiple lytic bone lesions, diffuse lymphadenopathy, a pelvic mass, multiple mesenteric soft tissue nodules, and multiple pulmonary nodules, although none of the aforementioned sites was biopsied. The patient was treated with a combination of multiple chemotherapeutic agents and localized radiation due to the aggressive nature of the disease. To the best of our knowledge, this is the first case of an IgE plasma cell myeloma in a patient under the age of 30 years old presenting as a mass in an extramedullary site. PMID- 23084305 TI - Homicide among Indigenous South Australians: a forty-year study (1969-2008). AB - A retrospective review of homicide cases among Aboriginal people in South Australia examined at Forensic Science SA was undertaken over a 40-year period from 1969 to 2008. A total of 90 Indigenous homicide victims were identified compared to 599 non-Indigenous victims over the same time period. Although homicide rates have fallen, the Indigenous homicide rate (ranging from 73.5 to 223.97 per 100,000) significantly exceeded the non-Indigenous rate (ranging from 8.16 to 12.6 per 100,000) for all decades (p<0.001). The most common methods of homicide in the Indigenous population involved blunt force and sharp force trauma, with gunshot, strangulation and other forms of homicides being encountered less often. While lack of access to firearms may explain the lower numbers of gunshot deaths it would not explain the low numbers of deaths due to strangulation. Considerable variability may, therefore, exist in the types of unnatural deaths that may be found in different cultural and ethnic groups, even within the same community. PMID- 23084306 TI - Analysis of fatal road traffic accidents in a coastal township of South India. AB - Road traffic accidents (RTAs) are important causes of mortality and morbidity due to the increasing number of vehicles, changes in lifestyle and the risk behaviours among general population. With the aim of exploring various epidemiological characteristics of RTAs, this retrospective analysis of medico legal autopsies was conducted between January 2005 and December 2009 in the Department of Forensic Medicine, Kasturba Medical College, Manipal in Karnataka, South India. The information was collected from post-mortem registers and inquest documents received from the investigating police officers. The collected information was analysed using SPSS version 11.0. Out of the 879 autopsies conducted during the study period, 39% were due to RTAs. Among the victims, 89.8% were males and 10.2% were females. The mean age of victims was 38.7 years, which was slightly higher in females compared to males. Most of the male victims belonged to the age group 20-29 years. The head injuries were responsible for nearly 3/4th of deaths followed by abdominal injuries (6.7%). The mean duration of survival following road traffic accident was 6-7 days. Occupants of motorized two wheelers (43%) and pedestrians (33%) were the most common victims of RTAs followed by occupants of light motor vehicles (LMVs). The most common offending agents in road traffic accidents were heavy motor vehicles (35.2%) followed by light motor vehicles (31.7%). In view of the above finding, it is apt to conclude that RTAs are important public health hazards and should be addressed through strengthening of emergency healthcare, stricter enforcement of traffic laws and health education. PMID- 23084307 TI - Analysis of the hematological and biochemical parameters related to lead intoxication. AB - In parallel with industrial advancements, number of the occupational diseases secondary to chemical exposure is increasing. The chemical agents in the work places affect various organ and tissue systems, leading to chronic diseases. In this study, the cases diagnosed with occupational disease due to exposure to lead were studied and importance of the environmental forensic sciences on this issue was emphasized. A hundred and ninety patients diagnosed with occupational disease related to lead intoxication in Ankara Occupational Diseases Hospital between 01/01/2009 and 31/12/2009 were included in the study. Twenty cases were used as the controls. Sociodemographic characteristics, serum chemical parameters and hematological parameters of the patients were retrospectively assessed. Mean age of the cases included in the study was 35.3+/-8.69. Hemoglobin (Hb) (p=0.018) and Mean corpuscular volume (MCV) (p<0.001) values were found significantly lower in the patients with lead exposure than in the controls. Gamma glutamyl transferase (GGT) was significantly lower in the patients with lead exposure than in the controls (p=0.002), whereas alkaline phosphatase (ALP) was found higher (p<0.001). In thyroid function test (TFTs) panel, free triiodothyronine (fT3) levels were found significantly higher in the patients with lead exposure than in the control group (p=0.01), while Thyrotrophin-stimulating hormone (TSH) levels were lower (p<0.001). No significant difference was found in terms of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values. In the correlation analysis; serum level of serum lead (Pb) was correlated positively with ALP values and negatively with Hb, MCV and TSH. Considering its effects on the biochemical and hematological parameters, a detailed investigation should be carried out in the cases with lead exposure, which occupies an important place among the occupational diseases. PMID- 23084308 TI - A re-audit of the use of definitions of sudden infant death syndrome (SIDS) in peer-reviewed literature. AB - The use of different definitions of sudden infant death syndrome (SIDS) may make comparison of data among studies difficult. Fifty randomly selected papers dealing with SIDS that were published between 2010 and 2011 in peer-reviewed journals were reviewed to determine whether one of three internationally accepted definitions of SIDS had been either written in the text or referenced. A significant improvement in the use of definitions has occurred since 2005, with the percentage of papers either quoting or referencing a standard definition increasing by 26%, from 42 to 68%. The 1989 NICHD definition remained the most commonly used definition (35.1%) followed by the 2004 San Diego definition (26.3%). Although the percentage of papers where either no definition was provided or where an idiosyncratic or mis-cited definition was used fell 26%, from 58 to 32%, nearly one in three papers published on SIDS in peer-reviewed journals that were included in this study still did not cite a standard definition. PMID- 23084309 TI - Feasibility of screening for and treating vitamin D deficiency in forensic psychiatric inpatients. AB - Neuroleptic and anti-epileptic medication, inadequate vitamin D intake and limited solar exposure increase the risk of vitamin D deficiency in high security psychiatric environments. Of the 33 inpatients (40% selected; 21% of hospital population) completing this cross-sectional study, 36% had insufficient and 58% deficient vitamin D. Five patients with vitamin D deficiency had secondary hyperparathyroidism, two of whom had osteopenia on dual-emission X-ray absorptiometry. At 1-year follow up, of the 31 patients eligible, 15 had accepted and continued supplements. Systematic screening is therefore necessary due to mental health and consent issues. Implications of supplementation and grounds access are discussed. PMID- 23084310 TI - An analysis and report of custodial deaths in Nebraska, USA: Part II. AB - All medico-legal cases investigated by the Nebraska Institute of Forensic Sciences, Inc. in Lincoln, Nebraska, USA, between 2003 and 2009, were reviewed for deaths which occurred in custody (n = 38). The causes of death, in ranked order, were natural causes 37% (14/38), followed by homicide 21% (8/38), accident 21% (8/38), and suicide 21% (8/38). Each cause of death was then subdivided by age, race, and sex. The findings of this investigation are a continuation of a previous study of the same population from 1991 to 1996 (n = 51). This article also provided five case studies: two natural deaths, two suicides, and one homicide. PMID- 23084311 TI - Orbital aperture morphometry in Brazilian population by postero-anterior Caldwell radiographs. AB - Morphological variations of the orbital aperture measurements act as parameter for sexual and ethnic determination. The aim of this study evaluated the dimensions of the orbital aperture in Brazilian subjects to verify its relationship to gender. The orbital apertures of 97 individuals were examined through Caldwell radiographic technique. The maximum width and height of the orbits were measured. The inter-orbital distance, which is the minimum distance between the medial walls of the orbits, was also measured. Statistical analysis was performed through the Pearson test for correlation between measurements and Student t test with 5% significance level to verify the relation between the gender. Determination of significance attributed to non-parametric Kruskal-Wallis and Mann-Whitney tests (p<0.05). The test of intra-class correlation (ICC) showed satisfactory repeatability (ICC=0.9932, p<0.0001) between measurements performed, taken at different time periods. The ICC showed satisfactory repeatability (ICC=0.9932, p<0.0001) between measurements performed at different periods. In the t test, significant differences between the genders, the width, and area of the orbital aperture were obtained. In conclusion, if the area of orbital aperture is <8.5 cm2, the skull is likely to be a female; if it is >9.0 cm2, it is likely to be a male. If the width of orbital aperture is <3.5 cm the skull is likely to be a female; if it is >3.5 cm, it is likely to be a male. If the inter orbital distance is <2.4 cm the skull is likely to be a female; if it is >2.5 cm, it is likely to be a male. PMID- 23084312 TI - Why did the patient die? The relationship between ambulance accidents and death of patients: forensic medical issues. AB - This article's aim is investigating traumatic consequences of ambulance accident on patients and discussing difficulties to give a decision about the relation between death and accident at these cases. The cases were selected among the forensic medical reports concluded between 1996 and 2005 years. They were documented for age, sex, causes of urgent call, localization and extent of traumatic lesion, properties of events and board decisions. A total of 21 cases were found. 15 cases died on the day of the accident. Skin injuries at head (8 cases) and legs (6 cases) were most common traumatic lesions. Totally 6 deaths were found related with ambulance accident. Death of patient after ambulance accidents may not be associated easily to the accident. Delay due to accident or concomitant contributing medical conditions may also facilitate the death in this type of cases. Reliable medical records were needed for accurate medicolegal evaluation. PMID- 23084313 TI - The occurrence of acute subdural haematoma and diffuse axonal injury as two typical acceleration injuries. AB - Closed head injuries have already been classified into contact injuries and acceleration-deceleration injuries. Two typical acceleration-deceleration injuries and at the same time, the two worst head injuries are acute subdural haematoma (ASDH) and diffuse axonal injury (DAI), and that is where they got their medico-legal importance. Using experiments, it has been shown that acceleration with an impact time of more than 20-25 min (which occurs in traffic accidents in real life) causes DAI, whereas an impact time of 5-10 min is more likely to produce acute subdural haematoma. The aim of this research is to show that not all, but some types of traffic accidents are more typical for the occurrence of DAI, as well as that the ASDH is not a common feature for all types of fall. The analysis conveyed covered 80 cases of closed head injuries (traffic accidents, falls and assaults) where a complete forensic medical autopsy has been undertaken, followed by a complete forensic-neuropathological examination. For the purpose of diagnosing DAI, immunohistochemistry using antibody against beta amyloid precursor protein has been involved. Results show that ASDH is more likely to occur in cases of simple fall, assaults and cyclists and DAI is more typical for vehicular traffic accidents and cases of falling from a considerable height. The paper also comprises discussion about some open questions regarding the diagnosis of DAI in the medico-legal practice. PMID- 23084314 TI - Evaluation of coronary stenosis with the aid of quantitative image analysis in histological cross sections. AB - Coronary artery atherosclerosis is a hugely prevalent condition in the Western World and is often encountered during autopsy. Atherosclerotic plaques can cause luminal stenosis: which, if over a significant level (75%), is said to contribute to cause of death. Estimation of stenosis can be macroscopically performed by the forensic pathologists at the time of autopsy or by microscopic examination. This study compares macroscopic estimation with quantitative microscopic image analysis with a particular focus on the assessment of significant stenosis (>75%). A total of 131 individuals were analysed. The sample consists of an atherosclerotic group (n=122) and a control group (n=9). The results of the two methods were significantly different from each other (p=0.001) and the macroscopic method gave a greater percentage stenosis by an average of 3.5%. Also, histological examination of coronary artery stenosis yielded a difference in significant stenosis in 11.5% of cases. The differences were attributed to either histological quantitative image analysis underestimation; gross examination overestimation; or, a combination of both. The underestimation may have come from tissue shrinkage during tissue processing for histological specimen. The overestimation from the macroscopic assessment can be attributed to the lumen shape, to the examiner observer error or to a possible bias to diagnose coronary disease when no other cause of death is apparent. The results indicate that the macroscopic estimation is open to more biases and that histological quantitative image analysis only gives a precise assessment of stenosis ex vivo. Once tissue shrinkage, if any, is accounted for then histological quantitative image analysis will yield a more accurate assessment of in vivo stenosis. It may then be considered a complementary tool for the examination of coronary stenosis. PMID- 23084315 TI - Gas geyser--a cause of fatal domestic carbon monoxide poisoning. AB - Carbon monoxide is responsible for a large number of accidental domestic poisoning and deaths throughout the world. Domestic carbon monoxide poisoning is rarely reported in India and remains an under recognized problem. The diagnosis of carbon monoxide poisoning is usually based on autopsy findings, circumstantial evidence and estimation of carboxy-haemoglobin in blood. We report a case of fatal accidental carbon monoxide poisoning in a bathroom where an LPG gas water heater was installed recently. Cherry pink discolouration of the body and organs on autopsy suggested carbon monoxide poisoning. Laboratory analysis of blood by UV visible spectrophotometry revealed presence of dangerous levels of carboxy haemoglobin. Effective preventive measures can help in bringing down the mortality and morbidity associated with carbon monoxide poisoning. PMID- 23084316 TI - Autopsy diagnosis of a death due to scorpion stinging--a case report. AB - Post-mortem diagnosis of envenomation by a scorpion with or without a reliable history is a herculean task for any forensic pathologist. The challenge is compounded when stinging occurs at night, with the history remaining unreliable. The autopsy diagnosis is further complicated when the inflicted wound is small, and the mark is obliterated by healing within few days. As the venom of a scorpion is a mixture of enzymes, most of the forensic science laboratories in India fail to diagnose the poisoning. We present a case in which there was no external evidence of stinging, but the internal post-mortem findings along with histology of the organ systems pointed towards the diagnosis and were corroborated by the history. We reemphasise the importance of pathological sampling of organ systems, whenever there is death due to a suspicious, unknown insect bite. PMID- 23084317 TI - A case of adverse drug reaction induced by dispensing error. AB - OBJECTIVE: To report about a case of acute renal failure due to absence of communication between physician and patient. CASE SUMMARY: A 78 year old man with human immunodeficiency virus (HIV) accessed our hospital and was brought to our attention in August 2011 for severe renal failure. Clinical history revealed that he had been taking highly active antiretroviral therapy with lamivudine/abacavir and fosamprenavir since 2006. In April 2011 due to an augmentation in creatinine plasma levels, a reduction in lamivudine dosage to 100 mg/day and the prescription of abacavir 300 mg/day became necessary. Unfortunately, the patient took both lamivudine and abacavir therefore the association of the two medications (lamivudine/abacavir) lead to asthenia and acute renal failure within a few days. CONCLUSIONS: This case emphasizes the importance about how physicians must pay very careful attention during drug prescription, most particularly, as far as elderly patients are concerned. In fact, communication improvement between physicians and patients can prevent increase of adverse drug reactions related to drug dispensing, with consequential reduction of costs in the healthcare system. PMID- 23084318 TI - Intra and inter-tester reliability of the tuck jump assessment. AB - OBJECTIVE: To assess the inter-tester and intra-tester reliability of the tuck jump test. DESIGN: Repeated measures. SETTING: University Human Performance laboratory. PARTICIPANTS: Five male and 5 female athletes undertook the Tuck jump test which was then assessed by two independent assessors. MAIN OUTCOME MEASURES: Score from the video assessment of the tuck jump test by two independent assessors on two separate occasions. RESULTS: Average percentage of exact agreement (PEA) between the two testers across all scoring criteria for all subjects was 93% (range 80-100%). Both testers were in absolute 100% agreement in 5 out of 10 subjects for all of the scoring criteria. The kappa measure of agreement was k = 0.88 which is very good/excellent. The intra-tester PEA ranged 87.2%-100%, with kappa values of k = 0.86-1.0. CONCLUSION: The study showed very good-excellent intra-tester and inter-tester reliability for both examiners when comparing their individual scores of the tuck jump test across two analysis sessions. These findings indicate that the proposed tuck jump assessment is reliable to identify abnormal landing mechanics. PMID- 23084319 TI - [Timing of tourniquet release in total knee arthroplasty doesn't affect on transfusion needs]. AB - OBJECTIVE: To determine whether the removal of the ischaemia tourniquet to perform haemostasis during knee replacement surgery, reduces bleeding, the need for transfusions, the incidence of complications, the incidence of further surgery, and the hospital stay. PATIENTS AND METHOD: A non-randomised, prospective, descriptive and observational study was conducted on patients subjected to primary knee replacement with only one anaesthetist and 2 surgical teams. The same surgical technique and prosthesis model was used, with 2 schemes for ischaemia removal and drainage management. The patients were divided into 2 groups. In group i, the ischaemia tourniquet was released during the operation, before wound closure, and leaving the drainages without a vacuum. In group ii the tourniquet was released when the limb was bandaged and the drainages were connected to a vacuum. The parameters recorded were; bleeding during surgery, bleeding due to the drainages, monitoring the haemoglobin and haematocrit, incidence of complications and further surgery, transfusion needs, and hospital stay. RESULTS: The study included 100 patients. The mean bleeding during surgery was 230,0mL in group i and 2,0mL in group ii (P<.05). The bleeding due to the drainages in group i was 531,2mL and 601,6mL in Group ii (P>.05). The total bleeding was 754,3mL in group i and 621,6mL in group ii. There were statistically significant differences in both cases (P<.05). The transfusion incidence in both groups was 16,7%. There were no significant differences between either group as regards medical complications or further surgery. A longer hospital stay was observed in group ii. CONCLUSION: In this study, the need for transfusions in knee replacement surgery is not influenced by the time of releasing the ischaemia tourniquet. There is also no relationship between the incidence in postoperative complications and further surgery and the time of removing the tourniquet. The preoperative haemoglobin was the only predictive factor of transfusion in our study. PMID- 23084320 TI - Non-invasive cerebral stimulation for the upper limb rehabilitation after stroke: a review. AB - Numerous studies have recently been published on improving upper-limb motor function after stroke. There has been a particular interest in brain stimulation techniques, which could promote brain plasticity. In this review, transcranial Direct Current Stimulation (tDCS) and repetitive Transcranial Magnetic Stimulation (rTMS) are presented as techniques that could be relevant in Physical Medicine and Rehabilitation (PM&R) centers in the future. We are presenting a comprehensive literature review on the studies using tDCS or rTMS for upper-limb rehabilitation after a stroke. Both techniques have shown their ability to modify cortical excitability and to transitorily improve upper-limb function after one single stimulation session. The first placebo-controlled, blinded therapeutic trials, which included repeated daily sessions, seem quite promising, and deserve to be validated by further trials. PMID- 23084321 TI - Identification and management of prisoners with severe psychiatric illness by specialist mental health services. AB - BACKGROUND: The prevalence of mental disorders among prisoners is considerably higher than in the general population. This is an important public health issue as the vast majority of prisoners stay in custody for less than 9 months and, when not in prison, offenders' lifestyles are frequently chaotic, characterized by social exclusion, instability and unemployment. Multi-disciplinary mental health inreach services were introduced to target care towards prisoners with severe mental illness (SMI) in a similar way to that provided by Community Mental Health Teams outside prison. The aim was to establish the proportion of prisoners with SMI who were assessed and managed by prison mental health inreach services. Method A two-phase prevalence survey in six prisons in England measured SMI upon reception into custody. Case-note review established the proportion of those with SMI subsequently assessed and treated by inreach services. RESULTS: Of 3492 prisoners screened, 23% had SMI. Inreach teams assessed only 25% of these unwell prisoners, and accepted just 13% onto their caseloads. CONCLUSIONS: Inreach teams identified and managed only a small proportion of prisoners with SMI. Prison based services need to improve screening procedures and develop effective care pathways to ensure access to appropriate services. Improved identification of mental illness is needed in both the community and the Criminal Justice System to better engage with socially transient individuals who have chaotic lifestyles and complex needs. PMID- 23084322 TI - Cloning, characterization and differential expression of a Bowman-Birk inhibitor during progressive water deficit and subsequent recovery in peanut (Arachis hypogaea) leaves. AB - Bowman-Birk inhibitor (BBI) genes encode serine protease inhibitors well known for their anticarcinogenic properties and roles in plant defense against insects and pathogens. Here we investigated the expression of a BBI gene in response to water deficit, recovery and phytohormones. A full length cDNA encoding a novel BBI (AhBBI) was isolated from peanut (Arachis hypogaea L.) leaves. The deduced protein is a polypeptide of 11.5kDa containing a signal peptide of 20 amino acids which is missing from peanut seed full-length BBI. Sequence analysis showed that AhBBI presents the characteristic features of BBIs but its first inhibitory loop is unique among the Fabaceae species. Real-time PCR analyses indicated that in peanut leaves, AhBBI is upregulated by water deficit and exogenous jasmonic acid (JA) but repressed by abscissic acid (ABA) after 24h of treatment. The transcripts accumulation patterns during water deficit differed between two cultivars studied in relation to their tolerance levels to drought. AhBBI transcripts accumulated earlier and stronger in the tolerant cultivar (cv. Fleur11) compared to the susceptible one (cv. 73-30) suggesting that BBI genes are involved in drought stress tolerance. Subsequent rehydration reversed the accumulation of AhBBI transcripts in both cultivars but at different levels. The overall role of BBI in abiotic stress tolerance and the possible mechanisms of action are discussed. PMID- 23084323 TI - Utilization of intravascular ultrasound to accurately position stents in true aorto-ostial lesions. AB - Percutaneous coronary intervention of aorto-ostial lesions is associated with high rates of major adverse cardiovascular events. Precise implantation of coronary stents in the ostium is important in order to prevent adverse clinical outcomes. The presented case demonstrates a simple technique to accurately position a stent during aorto-ostial percutaneous coronary intervention. PMID- 23084324 TI - Health-related quality of life after coronary artery bypass grafting surgery and the role of gender. AB - OBJECTIVE: Heart disease is the leading cause of death for women. Previous studies suggest that women undergoing coronary artery bypass (CABG) surgery present with a higher severity of disease and that this may be an indicator of delays in treatment preceding diagnosis thus presenting challenges for recovery. The aim of this study was to examine gender differences in CABG morbidity and reported health-related quality of life (HRQL) at baseline and six months post surgery. It was hypothesized that female gender would be an independent predictor for lower HRQL at six months following CABG surgery. METHODS: Four hundred and ninety-six (n=496) adult patients who underwent a first-time, isolated CABG procedure with baseline and 6-month follow-up were included. Stepwise multivariate regressions were conducted to evaluate the factors predictive of 6 month HRQL scores. RESULTS: Females had more preoperative co-morbidities and scored significantly lower on HRQL compared to males at both baseline (p values<0.01) and six months (p values<0.01) on all ten domains. Gender was a significant predictor of 6-month HRQL in regression models for 8 out of 10 HRQL domains including Physical Component Summary score (B=-2.54, p=0.02). CONCLUSIONS: Female patients were at higher risk as reflected by their perioperative risk factors and baseline HRQL. These findings may reflect a delayed referral for surgery. Results indicated that female gender predicts lower HRQL 6-months post-CABG surgery, which can have an impact on recovery and outcomes. Efforts should be made to identify and treat female patients earlier to improve post-surgical outcomes. PMID- 23084325 TI - A complicated spontaneous left main coronary artery dissection. Is the initial conservative management safe in asymptomatic patients? AB - Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome. Knowledge of this condition is scarce and, at present, no consensus exists with regards to the aetiology, prognosis, and treatment. Among patients with SCAD, cases involving the left main (LM) and the left anterior descending (LAD) and circumflex (Cx) arteries bifurcation are even more exceptional. Furthermore, the treatment of asymptomatic patients with involvement of these major vessels poses a major challenge for the cardiologists and cardiac surgeons. We report a case of complicated spontaneous left main coronary artery dissection in which we question what is the best initial treatment in these asymptomatic patients: conservative or early aggressive. PMID- 23084326 TI - The effects on cardio-respiratory and acid-base variables of a constant rate infusion of alfaxalone-HPCD in sheep. AB - Alfaxalone in a 2-hydroxypropyl-beta-cyclodextrin (HPCD) formulation is an intravenous (IV) hypnotic agent characterised by the stability of cardiorespiratory effects after a single-bolus administration. The objective of this study was to investigate the cardiovascular, respiratory, and acid-base effects of alfaxalone-HPCD administered during a continuous rate infusion in six Ripollesa sheep. After instrumentation, a 2 mg/kg IV bolus of alfaxalone followed by a continuous infusion of 10 mg/kg/h was administered to the sheep. Heart rate, arterial blood pressure, respiratory rate and arterial blood gases were recorded. Occasional side effects and time to standing were also noted. No significant changes were observed in arterial blood pressure, but during the infusion and the initial stages of recovery, a significant increase in heart rate occurred during the last 120 min of the study. Significant respiratory depression was detected during the infusion period and the first 15 min of recovery. This study showed that a constant rate infusion alfaxalone in un-premedicated sheep produced clinically acceptable haemodynamic results and a mild respiratory depression that may require intermittent positive pressure ventilation. PMID- 23084327 TI - Pharmacokinetic and pharmacodynamic integration and modelling of marbofloxacin in calves for Mannheimia haemolytica and Pasteurella multocida. AB - The pharmacokinetics (PK) and pharmacodynamics (PD) of marbofloxacin were established in calves for six strains of each of the pneumonia pathogens Mannheimia haemolytica and Pasteurella multocida. The distribution of marbofloxacin into inflamed (exudate) and non-inflamed (transudate) tissue cage fluids allowed comparison with the serum concentration-time profile. To establish the PD profile, minimum inhibitory concentration (MIC) was determined in Mueller Hinton broth (MHB) and calf serum. Moderately higher MICs were obtained for serum compared to MHB. An initial integration of PK-PD data established C(max)/MIC ratios of 45.0 and AUC(24h)/MIC values of 174.7 h, based on serum MICs, for both bacterial species. Using bacterial time-kill curves, generated ex vivo for serum marbofloxacin concentrations, PK-PD modelling established three levels of growth inhibition: AUC(24 h)/MIC ratios for no reduction, 3 log(10) and 4 log(10) reductions in bacterial count from the initial inoculum count were 41.9, 59.5 and 68.0 h for M. haemolytica and 48.6, 64.9 and 74.8 h for P. multocida, on average respectively. Inter-strain variability for 3 log(10) and 4 log(10) reductions in bacterial count was smaller for P. multocida than for M. haemolytica. In conjunction with literature data on MIC(90) values, the present results allowed prediction of dosages for efficacy for each organism for the three levels of growth inhibition. PMID- 23084328 TI - The hidden effects of blinded, placebo-controlled randomized trials: an experimental investigation. AB - The knowledge of having only a 50% chance of receiving an active drug can result in reduced efficacy in blinded randomized clinical trials (RCTs) compared to clinical practice (reduced external validity). Moreover, minor onset sensations associated with the drug (but not with an inert placebo) can further challenge the attribution of group differences to drug-specific efficacy (internal validity). We used a randomized experimental study with inert placebos (inert substance) vs active placebos (inducing minor sensations), and different instructions about group allocation (probability of receiving drug: 0%, 50%, 100%). One hundred forty-four healthy volunteers were informed that a new application method for a well-known painkiller would be tested. Pain thresholds were assessed before and after receiving nasal spray. Half of the nasal sprays were inert placebos (sesame oil), while the other half were active placebos inducing prickling nasal sensations (sesame oil with 0.014% capsaicin). The major outcome was pain threshold after placebo application. A substantial expectation effect was found for the inert placebo condition, with participants who believed they had received an active drug reporting the highest pain thresholds. Active placebos show substantial differences to passive placebos in the 50% chance group. Therefore, patient expectations are significantly different in placebo controlled clinical trials (50% chance) vs clinical practice (100% chance). Moreover, minor drug onset sensations can challenge internal validity. Effect sizes for these mechanisms are medium, and can substantially compete with specific drug effects. For clinical trials, new study designs are needed that better control for these effects. PMID- 23084329 TI - Natural history of early, localized prostate cancer: a final report from three decades of follow-up. AB - BACKGROUND: Most localized prostate cancers are believed to have an indolent course. Within 15 yr of diagnosis, most deaths among men with prostate cancer (PCa) can be attributed to other competing causes. However, data from studies with extended follow-up are insufficient to determine appropriate treatment for men with localized disease. OBJECTIVE: To investigate the long-term natural history of untreated, early-stage PCa. DESIGN, SETTING, AND PARTICIPANTS: We conducted a population-based, prospective-cohort study using a consecutive sample of 223 patients with untreated, localized PCa from a regionally well-defined catchment area in central Sweden. All subjects were initially managed with observation. Androgen deprivation therapy was administered when symptomatic tumor progression occurred. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Based on >30 yr of follow-up, the main outcome measures were: progression-free, cause specific, and overall survival, and rates of progression and mortality per 1000 person-years. RESULTS AND LIMITATIONS: After 32 yr of follow-up, all but 3 (1%) of the 223 men had died. We observed 90 (41.4%) local progression events and 41 (18.4%) cases of progression to distant metastasis. In total, 38 (17%) men died of PCa. Cause-specific survival decreased between 15 and 20 yr, but stabilized with further follow-up. All nine men with Gleason grade 8-10 disease died within the first 10 yr of follow-up, five (55%) from PCa. Survival for men with well differentiated, nonpalpable tumors declined slowly through 20 yr, and more rapidly between 20 and 25 yr (from 75.2% [95% confidence interval, 48.4-89.3] to 25% [95% confidence interval, 22.0-72.5]). It is unclear whether these data are relevant for tumors detected by elevated prostate-specific antigen levels. CONCLUSIONS: Although localized PCa most often has an indolent course, local progression and distant metastasis can develop over the long term, even among patients considered low risk at diagnosis. PMID- 23084330 TI - Combination of diffusion-weighted magnetic resonance imaging and extended prostate biopsy predicts lobes without significant cancer: application in patient selection for hemiablative focal therapy. AB - BACKGROUND: Significant cancer in contralateral sides of the prostate that was missed on prostate biopsy (PBx) is a concern in hemiablative focal therapy (FT) of prostate cancer (PCa). However, extended PBx, a common diagnostic procedure, has a limited predictive ability for lobes without significant cancer. OBJECTIVE: To identify prostate lobes without significant cancer using extended PBx combined with diffusion-weighted imaging (DWI), which has the potential to provide pathophysiologic information on pretreatment assessment. DESIGN, SETTING, AND PARTICIPANTS: We conducted a prebiopsy DWI study between 2007 and 2012 that included 270 prostate lobes in 135 patients who underwent radical prostatectomy (RP) for clinically localized PCa. INTERVENTION: Participants underwent DWI and 14-core PBx; those with PBx-proven PCa and who were treated with RP were analyzed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Imaging and pathology were assessed in each side. Based on RP pathology, lobes were classified into lobes with no cancer (LNC), lobes with indolent cancer (LIC), and lobes with significant cancer (LSC). Predictive performance of DWI, PBx, and their combination in identifying lobes without significant cancer was examined. RESULTS AND LIMITATIONS: LNC, LIC, and LSC were identified in 23 (8.5%), 64 (23.7%), and 183 sides (67.8%), respectively. The negative predictive values (NPV) of DWI, PBx, and their combination were 22.1%, 27.8%, and 43.5%, respectively, for lobes with any cancer (ie, either LIC or LSC), and 68.4%, 72.2%, and 95.7%, respectively, for LSC. The NPV of PBx for LSC was improved by the addition of DWI findings (p=0.001), with no adverse influence on the positive predictive value. Limitations included a possible selection bias under which the decision to perform PBx might be affected by DWI findings. CONCLUSIONS: The combination of DWI and extended PBx efficiently predicts lobes without significant cancer. This procedure is applicable to patient selection for hemiablative FT. PMID- 23084331 TI - Novel immunotherapeutic strategies in development for renal cell carcinoma. AB - CONTEXT: The purpose of this report is to review immunotherapies under investigation for patients with renal cell carcinoma (RCC), the most common form of kidney cancer, for which the incidence and mortality rate continue to increase. OBJECTIVE: To summarize and evaluate current data on immunotherapies for RCC and discuss issues to be resolved before integration into the RCC treatment paradigm. EVIDENCE ACQUISITION: A search of Medline, clinicaltrials.gov, and congress abstracts/treatment guidelines was performed in May 2012 using the following terms (and variations): metastatic renal cell carcinoma, practice guidelines, response/resistance to current treatments, immunotherapy, novel immunotherapeutic strategies, T-cell modulation, immune priming, innate immunity, and combination therapy. EVIDENCE SYNTHESIS: Prior to the advent of novel agents targeting the vascular endothelial growth factor and mechanistic target of rapamycin pathways, interleukin-2 (IL-2) and interferon alpha were the mainstays of RCC treatment. IL-2 remains one of the only treatments capable of curing advanced RCC, albeit in few patients. Despite recent advances, unmet need still exists for patients in the adjuvant setting, those with poor prognostic factors, and those who have progressed on prior targeted therapies. Improved understanding of host-tumor immune interactions has led to development of novel immunotherapeutic agents, including antibodies against immune checkpoint proteins (eg, programmed death-1 and cytotoxic T-lymphocyte antigen-4), and various vaccines. Because many of these compounds are in development, clinical experience with them is limited, although some have demonstrated activity in preliminary studies. CONCLUSIONS: It is not yet clear where these new immunotherapies will fit into RCC treatment paradigms, but they may provide new options for patients whose current choices are limited. Furthermore, predictive biomarkers are needed to identify patients who will derive the greatest benefit from immunotherapy. PMID- 23084332 TI - How do we manage infected, obstructed hydronephrosis? PMID- 23084333 TI - Prolonged hypophosphatemia following parathyroidectomy in chronic hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Hypoparathyroidism in patients with functioning kidneys leads to hyperphosphatemia. This paper reviews data suggesting that hypoparathyroidism in patients on maintenance dialysis leads to hypophosphatemia. DESIGN: Clinical data in two patients on dialysis with hypoparathyroidism following parathyroid surgery; literature review of dialysis patients with hypoparathyroidism following parathyroid surgery. RESULTS: In the patients presented both here and in the literature, hypoparathyroidism in dialysis patients is associated with persistent hypophosphatemia or decrease in serum phosphorus from its pre-surgery level. CONCLUSION: In patients on maintenance dialysis, persistent hypoparathyroidism post-parathyroidectomy may lead to chronic hypophosphatemia, in contrast to the hyperphosphatemia usually associated with hypoparathyroidism. Proposed mechanisms for this paradoxical phenomenon include ongoing phosphorus deposition into bone (Hungry Bone Syndrome), phosphorus deposition into soft tissue and/or diminished intestinal phosphorus absorption or increased intestinal phosphorus loss. PMID- 23084334 TI - Recurrent posterior reversible encephalopathy syndrome in nephrotic syndrome: case report and review of the literature. AB - Sequential neuroimaging before and after seizures has not been reported in patients with nephrotic syndrome and recurrent posterior reversible encephalopathy syndrome (PRES). We report a 13-year-old nephrotic female patient with recurrent PRES during and after cessation of cyclosporine A (CyA). She had headache, visual disturbance and acute hypertension, followed by seizures. The brain magnetic resonance imaging (MRI) before seizures revealed a high signal intensity area on fluid-attenuated inversion recovery and diffusion-weighted images and a low signal intensity area on T1-weighted images in bilateral parieto occipital and left temporal lobes. Cessation of CyA resulted in clinical improvement. The follow-up MRI 2 months after the initial episode showed a complete resolution. Six months later, she had similar symptoms, edema, severe hypoalbuminemia, renal insufficiency, and acute pancreatitis before seizures. The brain MRI after seizures showed similar abnormalities in the same regions, which completely resolved 2 months later. Recurrence of acute severe hypertension, nephrotic state (edema/ hypoalbuminemia), and renal insufficiency may lead to recurrent PRES and thus early treatment of trigger factors, especially of hypertension, is important to reduce the episodes of PRES. PMID- 23084335 TI - Pharmacokinetic effect of voriconazole on cyclosporine in the treatment of aspergillosis after renal transplantation. AB - Azole antifungal agents are essential drugs in the treatment of fungal infections in renal transplant patients. As azoles, these antifungal agents are inhibitors of CYP3A4 and P-glycoprotein (P-gp); and thus therapeutic drug monitoring is important. We evaluated a patient with cutaneous and pulmonary aspergillosis who was successfully treated with voriconazole and a low cyclosporine trough level (3.2 - 27.9 ng/ml) for 3 months. During that period, the patient showed good allograft function with the co-administration of voriconazole and cyclosporine. We measured the patient's genotype of MDR1, CYP3A4, CYP3A5 and CYP2C19 enzymes in addition to the intracellular concentration of cyclosporine in peripheral blood mononuclear cells (PBMCs). The intracellular concentration of cyclosporine in PBMC is 3.2 times higher with no functionally defected alleles in MDR1, CYP3A4, CYP3A5 or CYP2C19 enzymes when cyclosporine is co-administered with voriconazole ex vivo. Although other confounding factors causing immunological modulation may exist, it is plausible that low serum and high intracellular cyclosporine concentrations, due to the inhibition of P-gp activity by voriconazole, also contribute to an immunosuppressive state. PMID- 23084336 TI - Autotransplantation for the treatment of severe renal artery stenosis in a solitary kidney after repeated percutaneous transluminal angioplasty: a case report. AB - A 66-year-old female suffering from massive atherosclerosis with a long history of renal artery stenosis in the left solitary kidney was admitted to reevaluate an in-stent restenosis. Advanced peripheral arterial disease had formerly been treated by aortobifemoral bypass surgery and a highly eccentric infrarenal abdominal aortic stenosis of 70 - 80% had been treated by patch angioplasty. In this patient several percutaneous transluminal renal angioplasties after a former stent deployment had resulted in recurrent in-stent restenoses. The renal artery stenosis was reevaluated and a re-angioplasty attempt was unsuccessful due to technical failure. Blood pressure remained difficult to manage. Renal function decreased as a result of presumed acute renal failure. A further progression of the renal artery stenosis was found. Autotransplantation to the left iliac fossa was done, because aortorenal bypass was considered impossible. Renal function normalized and follow-up Doppler ultrasonography examinations revealed a newly developed ostial anastomotic stenosis of 60 - 70%. While medical therapy and percutaneous transluminal angioplasty with stent deployment are common treatment options, surgical interventions are reserved for cases of complex stenoses. Autotransplantation as a complex option in the treatment of renal artery stenosis seems to be an adequate alternative in patients with severe, generalized atherosclerosis after failure of interventional procedures and the impossibility of standard surgical techniques. PMID- 23084337 TI - Letter to the editor concerning the article "Renal endarteritis with acute endocapillary proliferative glomerulonephritis" by Kawaguchi et al., Clin Nephrol. 2012; 77: 151-155 and authors response. PMID- 23084338 TI - Total organic iodine measurement: a new approach with UPLC/ESI-MS for off-line iodide separation/detection. AB - Total organic iodine (TOI) is a collective parameter and a toxicity indicator for all the iodinated disinfection byproducts in a water sample. The currently used TOI measurement method involves adsorption of organic iodine onto activated carbon, pyrolysis of adsorbed organic iodine to hydrogen iodide, absorption of hydrogen iodide into a solution, and off-line separation/detection of iodide in the absorption solution using ion chromatography coupled with conductivity detection. In this study, a new approach with ultra performance liquid chromatography/electrospray ionization-mass spectrometry (UPLC/ESI-MS) detection by setting selected ion recording of m/z 127 in the negative ion mode (instead of ion chromatography-conductivity detection) was developed for off-line iodide separation/detection in the TOI measurement. An obstacle with the new approach was found to be a series of adducts (with the same m/z value as iodide) formed in the mobile phase and at the ESI-MS sample cone, which were effectively eliminated by acidifying the absorption solution with formic acid and optimizing the instrumental parameters. By comparing the calibration curves of seven aliphatic and aromatic iodine-containing standard compounds, iodoacetic acid was determined to be an appropriate calibration standard for the TOI measurement. This new approach was found to be more sensitive, accurate and rapid. The quantitation limit of TOI was 5 MUg/L as I for a 40 mL water sample or 2.5 MUg/L as I for an 80 mL water sample. TOI recoveries were 94-103% for seven iodine-containing compounds and 91-108% for two wastewater and six tap water samples. The run duration for analyzing iodide in the absorption solution was only 4 min. With the new approach, TOI concentrations in various types of water samples were successfully analyzed and compared. This approach provides a sensitive tool for investigating the formation and control of iodinated DBPs in disinfected drinking water and wastewater. PMID- 23084339 TI - Aquatic photodegradation of sunscreen agent p-aminobenzoic acid in the presence of dissolved organic matter. AB - Dissolved organic matter (DOM) is an important photosensitizer for the phototransformation of organic contaminants in sunlit natural waters. This article focuses on the photolysis kinetics and mechanism of sunscreen agent p aminobenzoic acid (PABA) in the presence of four kinds of DOM; Suwannee River fulvic acid (SRFA), Suwannee River humic acid (SRHA), Nordic Lake fulvic acid (NOFA) and Nordic Lake humic acid (NOHA). It is evident that direct photolysis of PABA is highly pH-dependent because different species of PABA have different electrical densities on the ring system. The presence of four kinds of DOM inhibits the photolysis of PABA primarily due to their light screening effect. Meanwhile, a complex interaction involving energy transfer, triplet carbonyl group induced electron transfer, and amino acid induced proton abstraction between PABA and DOM is verified by competition kinetics experiments and density functional theory (DFT) computation. In addition, DOM-induced singlet oxygen ((1)O(2)) and hydroxyl radical (OH) are determined to play an insignificant role in PABA photolysis by competition dynamics method. Photoproducts identification using solid phase extraction-liquid chromatography-mass spectrometry (SPE-LC-MS) techniques reveals that the distribution of the photoproducts could not be affected by the addition of DOM. Two photodegradation pathways of PABA are temporarily proposed, in which the di(tri)-polymerization of intermediates are the dominant pathway whereas the oxidation of amino group to nitryl followed by hydroxylation is a minor process. Our findings reveal that direct photolysis is the dominant transformation pathway of PABA in natural sunlit waters, while the presence of DOM could evidently influence such process by light screening effect, energy transfer, electron transfer and proton abstraction mechanism. The findings in this study provide useful information for understanding of interaction between DOM and organic contaminants. PMID- 23084340 TI - Aqueous chlorination of levofloxacin: kinetic and mechanistic study, transformation product identification and toxicity. AB - The aim of this study was to gain further insight into the fate of levofloxacin during the chlorination process. First, a kinetic study was thus performed at pH 7.2, 20 degrees C and in the presence of an excess of total chlorine. A slower apparent removal of levofloxacin (k ~ 26 M(-1) s(-1)) was noted when sodium thiosulfate was used to stop the chlorination reaction compared to the degradation observed without using a reducing agent (k ~ 4400 M(-1) s(-1)). The formation of a chlorammonium intermediate which could be converted back into the parent compound through a reaction with thiosulfate was thus expected. This intermediate would result from an initial chlorine attack on the tertiary amine function of levofloxacin. Secondly, four chlorination transformation products were detected by LC/UV/MS analysis. The chemical structures of two of them are proposed. It was suggested that these compounds could come from a secondary reaction of the chlorammonium intermediate on levofloxacin. A reactional pathway is then proposed. Finally, a bioassay using Vibrio fisheri was carried out to study the toxicity pattern during levofloxacin chlorination. An increase in toxicity was observed during chlorination suggesting that the first transformations products formed were more toxic than the parent compound. PMID- 23084341 TI - The chemical and mechanical differences between alginate-like exopolysaccharides isolated from aerobic flocculent sludge and aerobic granular sludge. AB - This study aimed to investigate differences in the gel matrix of aerobic granular sludge and normal aerobic flocculent sludge. From both types of sludge that fed with the same municipal sewage, the functional gel-forming exopolysaccharides, alginate-like exopolysaccharides, were isolated. These two exopolysaccharides were chemically fractionated, and investigated by FT-IR spectroscopy. The isolated polymers were made into a gel by calcium addition and the mechanical properties of these reconstituted gels were measured by a low load compression tester. The viscoelastic behavior of the gels was described by a generalized Maxwell model. The alginate-like exopolysaccharides derived from aerobic granules had significantly higher amount of poly(guluronic acid) blocks but lower amount of poly(guluronic acid-manuronic acid) blocks in the chemical structure, while the alginate-like exopolysaccharides derived from aerobic flocculent sludge had equal amount of poly(guluronic acid) blocks and poly(guluronic acid-manuronic acid) blocks. These differences result in a perfect gel-forming capability of alginate-like exopolysaccharides derived from aerobic granules and bestowed this exopolysaccharides gel a stronger mechanical property as compared to alginate like exopolysaccharides derived from aerobic flocculent sludge. The different chemical and mechanical properties of these two exopolysaccharides contributed to the distinguished characteristics between aerobic granular sludge and aerobic flocculent sludge. PMID- 23084343 TI - Interactions between LPS moieties and macrophage pattern recognition receptors. AB - Mammalian host organisms live their life constantly interacting with pathogenic and non-pathogenic Gram-negative bacteria. Commensal/symbiont strains are tolerated in the gut, while pathogens are kept at bay by the immune system. In contrast both commensals and pathogenic bacteria are targets of the immune system outside of the digestive system. Immune cells are activated upon contact with different constituents of bacterial cells like peptidoglycan, outer membrane proteins, fimbriae, bacterial DNA, etc. One of the dominant molecular targets affecting the immune cells is the lipopolysaccharide (LPS), an essential molecule of the cell wall of Gram-negative bacteria. In this review we discuss interactions of macrophages with the main LPS moieties lipid A, core and O antigen regions. PMID- 23084342 TI - Analysis of the C9orf72 repeat in Parkinson's disease, essential tremor and restless legs syndrome. AB - The hexanucleotide expanded repeat (GGGGCC) in intron 1 of the C9orf72 gene is recognized as the most common genetic form of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, as part of the clinical phenotype, some patients present with parkinsonism. The present study investigated the potential expansion or association of the C9orf72 repeat length with susceptibility to Parkinson's disease and related disorders, essential tremor and restless legs syndrome. One restless legs syndrome patient was shown to harbor a repeat expansion, however on clinical follow-up this patient was observed to have developed frontotemporal dementia. There was no evidence of association of repeat length on disease risk or age-at-onset for any of the three disorders. Therefore the C9orf72 hexanucleotide repeat expansion appears to be specific to TDP-43 driven amyotrophic lateral sclerosis and dementia. PMID- 23084344 TI - Comparative in vitro toll-like receptor ligand induced cytokine profiles of Toda and Murrah buffaloes-Identification of tumour necrosis factor alpha promoter polymorphism. AB - The objective of this study was to assess cytokine production upon activation of pattern recognition receptors responsible for sensing bacterial and viral pathogen associated molecular patterns in two genetically diverse buffalo breeds, Toda and Murrah. A very limited molecular-epidemiological analysis showed a higher prevalence of Anaplasma and Theileria in Murrah than Toda buffaloes. Toda buffalo peripheral blood mononuclear cells (PBMC) produced significantly higher levels of IFN gamma and/or TNF alpha mRNAs in response to peptidoglycan, poly I:C, lipopolysaccharide, imiquimod and CpG. Flagellin stimulation did not result in any significant differences in the expression levels of the cytokines tested between these breeds. The levels of ligand induced IFN gamma and TNF alpha mRNA and proteins also correlated except when induced with CpG. The proximal promoter region of TNF alpha across these two breeds were also sequenced to detect SNPs and promoter assay performed to determine their role in altering the transcriptional activity. Two polymorphisms were identified at -737 (T/A) and 1092 (G/T) positions in Toda buffalo TNF alpha promoter and promoter assay revealed higher transcription activity in Toda buffalos than in Murrah. This suggests that disease tolerance of these buffalo breeds could be due to the differences in their cytokine transcription levels in response to the respective PAMPs that may be at least in part determined by polymorphisms in the cytokine promoter regions. PMID- 23084345 TI - Levetiracetam-loaded biodegradable polymer implants in the tetanus toxin model of temporal lobe epilepsy in rats. AB - Approximately one-third of people with epilepsy receive insufficient benefit from currently available anticonvulsant medication, and some evidence suggests that this may be due to a lack of effective penetration into brain parenchyma. The current study investigated the ability of biodegradable polymer implants loaded with levetiracetam to ameliorate seizures following implantation above the motor cortex in the tetanus toxin model of temporal lobe epilepsy in rats. The implants led to significantly shorter seizures and a trend towards fewer seizures for up to 1 week. The results of this study indicate that drug-eluting polymer implants represent a promising evolving treatment option for intractable epilepsy. Future research is warranted to investigate issues of device longevity and implantation site. PMID- 23084346 TI - A retrospective study of primary cerebellar glioblastoma multiforme in adults. AB - Primary cerebellar glioblastoma multiforme (GBM) is a rare tumour in adults that accounts for less than 1% of all patients with GBM. In view of their rarity, the pathogenesis and prognosis of cerebellar GBM are not yet completely understood. The aim of this study was to retrospectively analyse patients with primary cerebellar GBM treated in our institute over a period of 10 years. Data from the case records of five adult patients with cerebellar GBM was evaluated and their outcome was assessed. We observed local failure in patients who reported back with recurrence. The presence of brainstem infiltration was a significant factor influencing progression-free survival. The overall prognosis was worse than for patients with supratentorial GBM. In view of their rarity, a meta-analysis is required to assess the pathogenesis and prognostic factors affecting overall survival in patients with cerebellar GBM. PMID- 23084347 TI - Diffusion tensor imaging of acute inflammatory lesion evolution in multiple sclerosis. AB - The initiating events in multiple sclerosis (MS) plaque formation are poorly understood. Retrospective analysis of serial imaging data can improve the understanding of tissue changes characterising acute MS lesion evolution. This study aimed to assess lesion evolution using diffusion tensor imaging data from serially acquired scans from 22 patients with MS. Mean diffusivity (MD) and fractional anisotropy (FA) were measured from 13 suitable plaques from five patients and carefully matched regions of contralateral normal-appearing white matter. Measurement times were on average: 5 months and 1 month prior to, during, and 1 month and 2 months post gadolinium-enhancement. A significant increase in MD (7.25%) but no change in FA was observed in white matter areas that exhibited enhancement 5 months later. The pre-lesional MD increase was significantly correlated with the MD increase 2 months subsequent to enhancement (R=0.73, p=0.04) but not to the MD increase during enhancement (R=0.11). These results suggest that MD is sensitive to tissue changes that precede blood-brain barrier (BBB) breakdown by at least 5 months and that MD assessments may predict injury following BBB restoration. PMID- 23084348 TI - Racial disparities in Medicaid patients after brain tumor surgery. AB - The presence of healthcare-related disparities is an ongoing, widespread, and well-documented societal and health policy issue. We investigated the presence of racial disparities among post-operative patients either with meningioma or malignant, benign, or metastatic brain tumors. We used the Medicaid component of the Thomson Reuter's MarketScan database from 2000 to 2009. Univariate and multivariate analysis assessed death, 30-day post-operative risk of complications, length of stay, and total charges. We identified 2321 patients, 73.7% were Caucasian, 57.8% were women; with Charlson comorbidity scores of <3 (56.2%) and treated at low-volume centers (73.4%). Among all, 26.3% of patients were of African-American ethnicity and 22.1% had meningiomas. Mortality was 2.0%, mean length of stay (LOS) was 9 days, mean total charges were US$42,422, an adverse discharge occurred in 22.5% of patients, and overall 30-day complication rate was 23.4%. In a multivariate analysis, African-American patients with meningiomas had higher odds of developing a 30-day complication (p=0.05) and were significantly more likely to have longer LOS (p<0.001) and greater total charges (p<0.001) relative to Caucasian counterparts. The presence of one post-operative complication doubled LOS and nearly doubled total charges, while the presence of two post-operative complications tripled these outcomes. Patients of African American ethnicity had significantly higher post-operative complications than those of Caucasian ethnicity. This higher rate of complications seems to have driven greater healthcare utilization, including greater LOS and total charges, among African-American patients. Interventions aimed at reducing complications among African-American patients with brain tumor may help reduce post-operative disparities. PMID- 23084349 TI - High flow extracranial-to-intracranial brain bypass surgery. AB - High flow extracranial to intracranial (HF EC-IC) cerebral revascularisation may be necessary in the management of complex skull base tumours and intracranial aneurysms. Vascular reconstruction techniques, in addition to direct clip reconstruction, have been described since the first successful bypass more than 50 years ago. Bypass grafting can be considered high flow when a radial artery or the saphenous vein is interposed between the extracranial carotids arteries and intracranial vessels. The decision as to whether to use a low flow or high flow bypass is determined by the anticipated cerebral blood flow needed and the availability of a supply source. In this review, we consider the indications, diagnostic evaluation strategies and long-term graft patency of HF EC-IC bypass surgery. PMID- 23084350 TI - ALDH1 expression is correlated with pathologic grade and poor clinical outcome in patients with astrocytoma. AB - Aldehyde dehydrogenase 1 (ALDH1), a detoxifying enzyme, is a stem-like cell marker, but its expression pattern and clinical significance in astrocytoma remain unclear. In this study, we used immunohistochemical analysis to systematically investigate the expression of ALDH1 in 76 astrocytomas of different pathological grade and seven samples of normal brain tissues. We found that ALDH1 was expressed in some of the astrocytomas but was not detected in normal brain tissues. The proportion of ALDH1-expressing cells was positively correlated with the pathological grade of the astrocytomas, but not with patient age, sex or tumor size. We also collected detailed follow-up data and analyzed the correlation of ALDH1 expression with overall survival (OS) and progression free survival (PFS) using univariate and multivariate analysis. We found that the proportion of ALDH1-positive cells was an independent prognostic factor for PFS and OS. These results show that ALDH1 is expressed in astrocytoma, and that its expression is correlated with pathological grade and patient survival. PMID- 23084351 TI - Biomechanical performance of rigid compared to dynamic anterior cervical plating: analysis of adjacent upper and lower level compressive forces. AB - Dynamic anterior cervical plating is well established as a means of enhancing graft loading and subsequent arthrodesis. Current concerns center on the degree of adjacent-level stress induced by these systems. The aim of this study was to evaluate and compare the load transferred to adjacent levels for single-level anterior cervical discectomy and fusion utilizing rigid compared to dynamic anterior plating systems. Nine cadaveric adult human cervical spine specimens were subjected to range-of-motion testing prior to and following C5-C6 anterior cervical discectomy and fusion procedures. Interbody grafting was performed with human fibula tissue. Nondestructive biomechanical testing included flexion/extension and lateral bending loading modes. A constant displacement of 5mm was applied in each direction and the applied load was measured in newtons (N). Specimens were tested in the following order: intact, following discectomy, after rigid plating, then after dynamic plating. Adjacent level (C4-C5 [L(S)] and C6-C7 [L(I)]) compressive forces were measured using low profile load cells inserted into each disc space. The measured load values for plating systems were then normalized using values measured for the intact specimens. Mean loads transferred to L(S) and L(I) during forced flexion in specimens with rigid plating were 23.47 N and 8.76 N, respectively; while the corresponding values in specimens with dynamic plating were 18.55 N and 1.03 N, respectively. Dynamic plating yielded no significant change at L(I) and a 21.0% decrease in load at L(S) when compared with rigid plating, although the difference was not significant. The observed trend suggests that dynamic plating may diminish superior adjacent level compressive stresses. PMID- 23084352 TI - Striking similarity: GATA-3 regulates ILC2 and Th2 cells. AB - Innate lymphoid cells (ILCs) and T helper (Th) cells share similar effector functions. In this issue of Immunity, Hoyler et al. (2012) and Mjosberg et al. (2012) demonstrate that GATA-3, a Th2 regulator, controls ILC2 differentiation, maintenance, and function. PMID- 23084353 TI - New tricks from an old master. AB - In this issue of Immunity, Zhu et al. (2012) report a mouse reporter strain for the transcription factor T-bet. This reagent provides for the resolution of some longstanding issues in T helper cell development. PMID- 23084354 TI - The taming of the NF-kappaB: PP4R1 navigates while PP4c dephosphorylates. AB - The NF-kappaB signaling pathway is important in the regulation of physiological and malignant hematopoiesis. In this issue of Immunity, Brechmann et al. (2012) identify a phosphatase, PP4R1, that inhibits NF-kappaB activation in T cells and T cell lymphoma. PMID- 23084355 TI - Caught in the act: reprogramming of adipocytes into lymph-node stroma. AB - Interactions between stromal organizer cells and hematopoietic lymphoid inducer cells initiate lymph-node formation. In this issue of Immunity, Benezech et al. demonstrate that adipocyte precursors give rise to lymph-node stromal organizer cells, illuminating an important step in lymphoid-tissue development. PMID- 23084356 TI - Maintaining a competitive edge: new rules for peripheral T cell homeostasis. AB - The contraction of T cell populations after immune responses is poorly understood. In this issue of Immunity, Singh et al. show that "deletor" T cells regulate the frequency of antigen-specific T cells by competing for shared subthreshold ligands. PMID- 23084358 TI - A PP4 holoenzyme balances physiological and oncogenic nuclear factor-kappa B signaling in T lymphocytes. AB - Signal transduction to nuclear factor-kappa B (NF-kappaB) involves multiple kinases and phosphorylated target proteins, but little is known about signal termination by dephosphorylation. By RNAi screening, we have identified protein phosphatase 4 regulatory subunit 1 (PP4R1) as a negative regulator of NF-kappaB activity in T lymphocytes. PP4R1 formed part of a distinct PP4 holoenzyme and bridged the inhibitor of NF-kappaB kinase (IKK) complex and the phosphatase PP4c, thereby directing PP4c activity to dephosphorylate and inactivate the IKK complex. PP4R1 expression was triggered upon activation and proliferation of primary human T lymphocytes and deficiency for PP4R1 caused sustained and increased IKK activity, T cell hyperactivation, and aberrant NF-kappaB signaling in NF-kappaB-addicted T cell lymphomas. Collectively, our results unravel PP4R1 as a previously unknown activation-associated negative regulator of IKK activity in lymphocytes whose downregulation promotes oncogenic NF-kappaB signaling in a subgroup of T cell lymphomas. PMID- 23084357 TI - Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. AB - The mammalian intestine harbors trillions of beneficial commensal bacteria that are essential for the development of the immune system and for maintenance of physiologic processes in multiple organs. However, numerous chronic infectious, inflammatory, and metabolic diseases in humans have been associated with alterations in the composition or localization of commensal bacteria that result in dysregulated host-commensal bacteria relationships. The mammalian immune system plays an essential role in regulating the acquisition, composition, and localization of commensal bacteria in the intestine. Emerging research has implicated innate lymphoid cells (ILCs) as a critical immune cell population that orchestrates some of these host-commensal bacteria relationships that can impact immunity, inflammation, and tissue homeostasis in the intestine. This review will discuss reciprocal interactions between intestinal commensal bacteria and ILCs in the context of health and disease. PMID- 23084360 TI - Incidence of acute postoperative cystoid macular edema in clinical practice. AB - PURPOSE: To measure the incidence of acute postoperative cystoid macular edema (CME) in clinical practice. SETTING: Private clinical practice, Eugene, Oregon, USA. DESIGN: Retrospective chart review. METHODS: The electronic medical records database was searched for the charts of all patients having cataract surgery during a recent 5-year period. Each chart was then examined for a diagnosis of CME within the 3-month postoperative period. RESULTS: From March 1, 2007, through March 31, 2012, 2862 phacoemulsification cataract extraction and intraocular lens implantation procedures were performed. Of these, 3 cases (0.1%) of acute postoperative CME were confirmed by diagnosis within 90 days after surgery. CONCLUSIONS: This chart review found a 0.1% cumulative incidence of acute postoperative CME. Prophylaxis with topical steroidal and nonsteroidal agents may help reduce the incidence of CME. If the incidence of CME in this study applies generally, it would be harder to successfully and ethically perform a randomized trial of medical prophylaxis. FINANCIAL DISCLOSURE: Dr. Packer is a consultant to Advanced Medical Optics, Inc., Allergan, Inc., Bausch & Lomb Surgical, Inc., and Ista Pharmaceuticals, Inc. No other author has a financial or proprietary interest in any material or method mentioned. PMID- 23084359 TI - T cell affinity regulates asymmetric division, effector cell differentiation, and tissue pathology. AB - The strength of interactions between T cell receptors and the peptide-major histocompatibility complex (pMHC) directly modulates T cell fitness, clonal expansion, and acquisition of effector properties. Here we show that asymmetric T cell division is an important mechanistic link between increased signal strength, effector differentiation, and the ability to induce tissue pathology. Recognition of pMHC above a threshold affinity drove responding T cells into asymmetric cell division. The ensuing proximal daughters underwent extensive division and differentiated into short-lived effector cells expressing the integrin VLA-4, allowing the activated T cell to infiltrate and mediate destruction of peripheral target tissues. In contrast, T cells activated by below-threshold antigens underwent symmetric division, leading to abortive clonal expansion and failure to fully differentiate into tissue-infiltrating effector cells. Antigen affinity and asymmetric division are important factors that regulate fate specification in CD8(+) T cells and predict the potential of a self-reactive T cell to mediate tissue pathology. PMID- 23084361 TI - Recentration of a small-aperture corneal inlay. AB - We report 2 patients implanted with a small-aperture corneal inlay to correct presbyopia. After the surgery, both patients complained of visual symptoms and poor visual acuity. The distances from the center of the inlay to the corneal vertex center were 593 MUm nasally and 159 MUm superiorly in Case 1 and 72 MUm temporally and 17 MUm superiorly in Case 2. The 2 inlays were recentered at 2 weeks and 3 weeks postoperatively, resulting in significant improvement in the visual acuity and quality of vision. Accurate centration of a small-aperture corneal inlay seems to be an important factor in obtaining a satisfactory result. Recentration is possible and improves visual acuity if proper centration was not obtained after the first surgery. FINANCIAL DISCLOSURE: Dr. Saad is a consultant to Acufocus, Inc. Dr. Gatinel is an investigator for a clinical trial conducted with the small-aperture inlay. He does not have any financial interest in relation to this inlay. Neither of the other authors has a financial or proprietary interest in any material or method mentioned. PMID- 23084362 TI - Safety of nondominant-hand ophthalmic surgery. AB - PURPOSE: To establish the safety of nondominant-hand simulated intraocular surgery. SETTING: Horizon Suite Simulation Centre, South Devon Foundation NHS Trust, Devon, United Kingdom. DESIGN: Cohort study. METHODS: Physicians with no previous ophthalmic surgical experience completed an introductory program on the EyeSi ophthalmic surgical simulator to eliminate the learning curve. They then completed the validated level-4 forceps module 4 times with their dominant hand and then 4 times with their nondominant hand. Simulator total score, odometer movement, corneal injury, lens injury, and total time were recorded. Acuity (Snellen near) and stereoacuity (Frisby) were also recorded. RESULTS: All 30 physicians showed good acuity (6/6 and N6 or better) and stereopsis (mean 35 seconds of arc). The total score was lower (mean 60.8 versus 65.6; P=.019), operating times were longer (mean 71.6 versus 70.0; P=.026), and lens injury was greater (mean 0.93 versus 0.79, P=.021) when operating with the nondominant hand than with operating with the dominant hand. Those with higher scores with the dominant hand had higher scores with their nondominant hand. CONCLUSIONS: Simulated nondominant-hand ophthalmic surgery resulted in less efficient, less safe, and slower surgery. This observation was more marked in those with less skill with their dominant hand. This has practical implications for trainee and trainer if 1 surgeon is left handed and 1 right handed. It also suggests that a higher degree of competence with the dominant hand is required before performing nondominant-hand surgery. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23084363 TI - [A flagellate erythema]. PMID- 23084364 TI - [The hardest thing is to say no]. PMID- 23084365 TI - The first report of Rickettsia spp. in Amblyomma nodosum in the State of Mato Grosso do Sul, Brazil. AB - Ticks are vectors of various pathogens, including Rickettsia spp., which are responsible for causing an emerging disease of global significance. In the present study, an epidemiological survey was performed to identify Rickettsia spp. of the spotted fever group (SFG) in ticks and wild hosts in a native forest adjacent to livestock farming activity. The ticks and blood were evaluated by a hemolymph test and by PCR using the primers CS78 and CS323, which target a partial sequence of the enzyme citrate synthase (gltA) gene. Positive samples by PCR were further tested with the primers Rr190.70p and Rr190.602n, which target a 532-bp fragment of the rickettsial 190-kDa outer membrane protein gene (ompA). In addition, an indirect immunofluorescence assay (IFA) was performed to detect antibodies against Rickettsia spp. in horses that inhabited the same area. From the 43 animals that were captured, 192 ticks were collected; the ticks belonged to the species Amblyomma cajennense, A. ovale, and A. nodosum. All blood samples and hemolymph tests were negative. Four samples of A. nodosum that were collected from Tamandua tetradactyla were positive for Rickettsia spp. by PCR, and 8 samples of horse serum displayed titers greater than or equal to 1:64 by IFA. The phylogenetic analysis based on the DNA sequence of the ompACG gene demonstrated that Rickettsia spp. CG (the canadensis group) segregate in the same cluster as Rickettsia parkeri strain COOPERI, with a bootstrap value of 78%. These results indicate that Rickettsia spp. CG circulate among the tick population in the study area, which has a constant presence of livestock and humans. This may be the same species of Rickettsia that was recorded in A. nodosum throughout the Atlantic forest. PMID- 23084366 TI - High prevalence of genetically diverse Borrelia bavariensis-like strains in Ixodes persulcatus from Selenge Aimag, Mongolia. AB - In Mongolia, Lyme borreliosis was first reported in 2003. To determine which Borrelia species may contribute to the occurrence of Lyme borreliosis in Mongolia, real-time PCR was conducted on 372 adult Ixodes persulcatus ticks collected in Selenge Aimag, the province with the highest incidence of human Lyme borreliosis. 24.5% of ticks were identified to be positive for Borrelia burgdorferi sensu lato DNA. Species differentiation using an SNP-based real-time PCR and multi-locus sequence analysis revealed that strains phylogenetically closely related to B. bavariensis (previously known as B. garinii OspA serotype 4) is the most prevalent species, showing an unexpectedly high genetic diversity. PMID- 23084367 TI - New chronology for the Middle Palaeolithic of the southern Caucasus suggests early demise of Neanderthals in this region. AB - Neanderthal populations of the southern and northern Caucasus became locally extinct during the Late Pleistocene. The timing of their extinction is key to our understanding of the relationship between Neanderthals and anatomically modern humans (AMH) in Eurasia. Recent re-dating of the end of the Middle Palaeolithic (MP) at Mezmaiskaya Cave, northern Caucasus, and Ortvale Klde, southern Caucasus, suggests that Neanderthals did not survive after 39 ka cal BP (thousands of years ago, calibrated before present). Here we extend the analysis and present a revised regional chronology for MP occupational phases in western Georgia, based on a series of model-based Bayesian analyses of radiocarbon dated bone samples obtained from the caves of Sakajia, Ortvala and Bronze Cave. This allows the establishment of probability intervals for the onset and end of each of the dated levels and for the end of the MP occupation at the three sites. Our results for Sakajia indicate that the end of the late Middle Palaeolithic (LMP) and start of the Upper Palaeolithic (UP) occurred between 40,200 and 37,140 cal BP. The end of the MP in the neighboring site of Ortvala occurred earlier at 43,540-41,420 cal BP (at 68.2% probability). The dating of MP layers from Bronze Cave confirms that it does not contain LMP phases. These results imply that Neanderthals did not survive in the southern Caucasus after 37 ka cal BP, supporting a model of Neanderthal extinction around the same period as reported for the northern Caucasus and other regions of Europe. Taken together with previous reports of the earliest UP phases in the region and the lack of archaeological evidence for an in situ transition, these results indicate that AMH arrived in the Caucasus a few millennia after the Neanderthal demise and that the two species probably did not interact. PMID- 23084368 TI - [Review and update on the diagnosis and management of musculoskeletal tumors: introduction]. PMID- 23084370 TI - Plasticity of monocytes, macrophages and dendritic cells is reflected in distinct organs and tissues. PMID- 23084369 TI - Upper limb entheseal change with the transition to agriculture in the Southeastern United States: a view from Moundville and the central Tombigbee River valley. AB - We analyzed entheseal change in 159 skeletons from Moundville and surrounding settlements using primary fibrocartilaginous attachments of the upper limbs. Risk of entheseal change did not differ bilaterally, suggesting a wide variety of activities were used to exploit a diverse ecosystem. Consistent with predictions, Mississippian (1000-1500 CE) agriculturalists experienced greater risk of entheseal change than did Late Woodland (500-900 CE) hunter-gatherers. Attachments used in arm flexion were most affected, while rotator cuff entheses remained consistent over time. A temporal increase in muscular changes in males in concert with faunal evidence for resurgence of larger game (e.g., deer) is consistent with continued reliance on hunting alongside domestication of maize. Among Mississippians, younger males appear to have been carrying out the most strenuous tasks, contrary to earlier studies that suggested a decline in male activities with domestication. Mound centers consistently experienced the greatest upper body changes, in spite of faunal and botanical data supporting provisioning of elites by outlying sites. Center males, respectively, experienced more than 26 and 12 times greater changes at elbow extensors and brachialis than those from outlying settlements, with a significant decline from young to middle age among adults. Center females experienced increased risk at biceps insertions and common extensors of the humeri - trends that disappeared with age. Overall findings suggest increased upper body demands and shifting sex and age-dependent divisions of labor with maize intensification, but trends across settlements point to significant status-related body size selection in center males, with fewer differences among females. PMID- 23084371 TI - Fully human monoclonal antibodies from antibody secreting cells after vaccination with Pneumovax(r)23 are serotype specific and facilitate opsonophagocytosis. AB - B lymphocyte memory generates antibody-secreting cells (ASCs) that represent a source of protective antibodies that may be exploited for therapeutics. Here we vaccinated four donors with Pneumovax(r)23 and produced human monoclonal antibodies (hmAbs) from ASCs. We have cloned 137 hmAbs and the specificities of these antibodies encompass 19 of the 23 serotypes in the vaccine, as well as cell wall polysaccharide (CWPS). Although the majority of the antibodies are serotype specific, 12% cross-react with two serotypes. The Pneumovax(r)23 ASC antibody sequences are highly mutated and clonal, indicating an anamnestic response, even though this was a primary vaccination. Hmabs from 64% of the clonal families facilitate opsonophagocytosis. Although 9% of the total antibodies bind to CWPS impurity in the vaccine, none of these clonal families showed opsonophagocytic activity. Overall, these studies have allowed us to address unanswered questions in the field of human immune responses to polysaccharide vaccines, including the cross-reactivity of individual antibodies between serotypes and the percentage of antibodies that are protective after vaccination with Pneumovax(r)23. PMID- 23084373 TI - Feasibility of an early Alzheimer's disease immunosignature diagnostic test. AB - A practical diagnostic test is needed for early Alzheimer's disease (AD) detection. Immunosignaturing, a technology that employs antibody binding to a random-sequence peptide microarray, generates profiles that distinguish transgenic mice engineered with familial AD mutations (APPswe/PSEN1-dE9) from non transgenic littermates. It can also detect an AD-like signature in humans. Here, we assess the changes in the immunosignature at different time points of the disease in mice and humans. We also evaluate the accuracy of the late-stage signature as a test to discriminate between young mice with familial AD mutations from non-transgenic littermates. Plasma samples from AD patients were assayed 3 12 months apart, while APPswe/PSEN1-dE9 and non-transgenic controls supplied plasma at monthly intervals until they reached 15 months of age. Microarrays with 10,000 random-sequence peptides were used to compare antibody binding patterns. These patterns gradually changed over the life-span of mice. Strong, characteristic signatures were observed in transgenic mice at early, mid and late stages, but these profiles had minimal overlap. The signature of young transgenic mice had an error rate of 18% at classifying plasma samples from late-stage transgenic mice. Conversely, the late-stage transgenic mice signature discriminated between young transgenic mice and littermates with an error rate of 21%. Less distinctive profiles were recognizable throughout the transgenic mice lifespan, being detectable as early as 2 months. The human signature had minimal change on short-term follow-up. Our results call for a reappraisal of the way incipient AD is studied, as biomarkers seen in late-stages of the disease may not be relevant in earlier stages. PMID- 23084372 TI - Adjudin attenuates lipopolysaccharide (LPS)- and ischemia-induced microglial activation. AB - Neuroinflammation caused by microglial activation plays a key role in ischemia, neurodegeneration and many other CNS diseases. In this study, we found that Adjudin, a potential non-hormonal male contraceptive, exhibits additional function to reduce the production of proinflammatory mediators. Adjudin significantly inhibited LPS-induced IL-6 release and IL-6, IL-1beta, TNF-alpha expression in BV2 microglial cells. Furthermore, Adjudin exhibited anti inflammatory properties by suppression of NF-kappaB p65 nuclear translocation and DNA binding activity as well as ERK MAPK phosphorylation. To determine the in vivo effect of Adjudin, we used a permanent middle cerebral artery occlusion (pMCAO) mouse model and found that Adjudin could reduce ischemia-induced CD11b expression, a marker of microglial activation. Furthermore, Adjudin treatment attenuated brain edema and neurological deficits after ischemia but did not reduce infarct volume. Thus, our data suggest that Adjudin may be useful for mitigating neuroinflammation. PMID- 23084374 TI - Image analysis for retinopathy of prematurity: where are we headed? PMID- 23084375 TI - A 2-year prospective surveillance of pediatric traumatic optic neuropathy in the United Kingdom. AB - BACKGROUND: To report epidemiologic data on traumatic optic neuropathy (TON) in patients less than 18 years of age in the United Kingdom acquired by prospective population-based active surveillance through the British Ophthalmic Surveillance Unit. METHODS: Data were obtained from incident and 6-month follow-up questionnaires sent to reporting ophthalmologists over a period of 2 years. Main outcome measures were demographic data, clinical and visual function at presentation and follow-up, investigations, and treatments used. RESULTS: A total of 26 cases (21 males) were identified; follow-up data were available for 23 (88%). Minimum estimated annual incidence was 0.99 cases per million. Leading causes of TON included 6 sports injuries (23%), 5 falls (19%), and 4 traffic accidents (16%). Presenting best-corrected visual acuity was <= 6/60 in 15 cases (58%), with no light perception in 7 cases (27%). Associated injuries were as follows: nonpenetrating injuries, 8 (31%); adnexal injuries, 3 (11.5%); orbital fractures, 5 (19%); skull fractures, 3 (12%); intracranial bleeding, 1 (4%). Fourteen (54%) received no treatment, and 9 (35%) were treated with steroids. Final visual acuity improved in 7 of 21 patients (33%), with 13 of 23 (56%) achieving final visual acuity <= 6/60, 10 of whom (43%) had no light perception. Baseline visual acuity was associated with last follow-up visual acuity (P = 0.03), but treatment and improvement of visual acuity by at least 3 lines were not associated. Treatment was more common in children with poor presenting vision (P = 0.03). CONCLUSIONS: The incidence, natural history, poor presenting visual acuity, and male prevalence of TON in children appear similar to adults in adults in the UK. PMID- 23084376 TI - Newborn thyroid-stimulating hormone in children with optic nerve hypoplasia: associations with hypothyroidism and vision. AB - PURPOSE: To assess in children with optic nerve hypoplasia (ONH) whether newborn screening (NBS) thyroid-stimulating hormone (TSH) measurements can detect central hypothyroidism and whether newborn TSH or subsequent thyroidal status is associated with visual function. METHODS: From a registry of children with ONH at Children's Hospital Los Angeles, post-natal thyroidal status was retrospectively compared with NBS TSH levels in the subset of subjects born in California. The subset of subjects with outcome data at age 5 years was assessed for relationship of vision to NBS TSH levels and ultimate thyroidal status. RESULTS: A total of 135 subjects from the ONH registry were included in this study. Approximately 50% of subjects in each analysis were hypothyroid. Those diagnosed with hypothyroidism had lower median NBS TSH levels than did euthyroid subjects (3.2 vs 4.5 MUIU/mL; P = 0.006) and significantly worse quantitative vision outcomes (median visual acuity, logMAR 3.0 vs 1.0; P = 0.039). Receiver operating characteristic analysis suggested an optimal NBS TSH cut-point of 3.3 MUIU/mL. Serum TSH levels greater than this (30/43) were associated with relatively better vision outcomes (median visual acuity, logMAR 1.2 vs 3.3; P = 0.04). CONCLUSIONS: Children with ONH and lower NBS TSH levels are more likely to have central hypothyroidism and less likely to experience good vision than those with greater NBS TSH levels. PMID- 23084377 TI - Goniotomy versus circumferential trabeculotomy with an illuminated microcatheter in congenital glaucoma. AB - PURPOSE: To compare circumferential trabeculotomy performed with an illuminated microcatheter with standard goniotomy for the treatment of congenital glaucoma. METHODS: The short-term results of catheter-assisted trabeculotomy with an illuminated microcatheter were retrospectively compared with those of goniotomy in patients treated for congenital glaucoma. Success with either approach was defined as an intraocular pressure (IOP) <21 mm Hg with at least a 30% reduction from preoperative pressure levels at 12-month follow-up. Complete success was defined when the target IOP levels were reached without the use of antiglaucoma medication, and qualified success was defined when antiglaucoma drops were required to meet this level of IOP. RESULTS: A total of 24 eyes of 20 patients were included. Microcatheter-assisted circumferential trabeculotomy demonstrated a 91.6% qualified and 83.3% unqualified success rate with 12-month follow-up that exceeded the 53.8% qualified and 46.2% unqualified success rate of conventional goniotomy. CONCLUSIONS: In congenital glaucoma, during the first year after surgery, trabeculotomy performed with an illuminated microcatheter appears to be more effective than ab interno goniotomy. No complications were seen in either group; however, the follow-up was relatively short. PMID- 23084378 TI - A comparison between the amblyopic eye and normal fellow eye ocular architecture in children with hyperopic anisometropic amblyopia. AB - PURPOSE: To compare the anterior and posterior ocular architecture of amblyopic and normal fellow eyes in children with hyperopic anisometropic amblyopia. METHODS: Fourteen subjects with hyperopic anisometropic amblyopia were examined using the Pentacam and optical coherence tomography. For each participant, the amblyopic eye was compared to the fellow non-amblyopic eye. RESULTS: There were no significant differences (P > 0.05) in the anterior corneal curvature, posterior corneal curvature, central corneal thickness, corneal volume, anterior chamber depth, anterior chamber volume, peripapillary retinal nerve fiber layer, central macular thickness, and macular volume between the amblyopic eye and fellow eye of the study participants. CONCLUSIONS: The Pentacam and optical coherence tomography revealed no differences in the anterior and posterior ocular architecture between the amblyopic eye and fellow eye in children with hyperopic anisometropic amblyopia. PMID- 23084379 TI - The rate of change in retinal vessel width and tortuosity in eyes at risk for retinopathy of prematurity. AB - PURPOSE: To describe the rate of change in retinal vessel width and tortuosity in eyes that develop treatment-requiring, or type 1, retinopathy of prematurity (ROP) versus eyes that do not develop type 1 ROP. METHODS: Posterior poles of eyes of 41 infants at risk for ROP were imaged longitudinally with a 30 degrees fundus camera. Retinal vessel width and tortuosity were measured with computer assisted image analysis. The rate of change per day in width and tortuosity up to the development of most severe ROP was calculated from linear regression and eyes with (n = 10) and without type 1 ROP (n = 31) were compared. RESULTS: Eyes that developed type 1 ROP had a greater rate of change in width for venules and 3 widest vessels (P < 0.0001), and a greater rate of change in tortuosity for arterioles and 3 most tortuous vessels (P < 0.0001) than eyes that did not develop type 1 ROP. These vessel parameters discriminate the 2 groups well (area under the ROC curve, 0.79-0.90). A combination of venular width and arteriolar tortuosity had the best discriminative ability (area under the ROC curve, 0.96). CONCLUSIONS: In this pilot study, eyes that eventually developed type 1 ROP demonstrated a faster increase in width and tortuosity of retinal vessels compared with those that did not. Further study of the kinetics of retinal vascular change in a larger sample may allow for the earlier identification of vision-threatening ROP. PMID- 23084380 TI - Exotropia in children with high hyperopia. AB - PURPOSE: To describe the clinical characteristics, treatment, and subsequent clinical course of children with exotropia and high hyperopia. METHODS: The medical records of 26 patients seen between 1990 and 2009 who had an exotropia and >=4.00 D of hyperopia were retrospectively reviewed. We analyzed the clinical characteristics, treatments, and subsequent alignment outcomes. RESULTS: A total of 26 patients between the ages of 2.5 months and 9 years were included. Of these, 15 had associated medical conditions or developmental delay. Of 22 patients with measured visual acuities, 19 had amblyopia (10 unilateral, 9 bilateral). None of the patients demonstrated fine stereoacuity. Twenty-three exotropic children were treated with spectacles: 15 were fully corrected, 10 of whose exotropia improved; 8 received partial correction of their hyperopia, 3 of whose exotropia improved. Six patients who presented with large, poorly controlled exotropia and did not improve with spectacle correction required strabismus surgery. CONCLUSIONS: Children with high hyperopia and exotropia are likely to have developmental delay or other systemic diseases, amblyopia, and poor stereopsis. Treatment of high hyperopia in exotropic children with their full cycloplegic refraction can result in excellent alignment. PMID- 23084381 TI - Congenital cataract surgery with intracameral triamcinolone: pre- and postoperative central corneal thickness and intraocular pressure. AB - PURPOSE: To evaluate the change in intraocular pressure (IOP) and central corneal thickness (CCT) of children who underwent congenital cataract surgery with injection of triamcinolone acetonide into the anterior chamber at the end of the procedure. METHODS: Fifty-three eyes of 34 children <2 years of age who underwent congenital cataract surgery with injection of 1.2 mg/0.03 mL of preservative-free triamcinolone acetonide into the anterior chamber at the end of the procedure were included in this study. IOP and CCT were measured preoperatively and at a mean of 2 and 12 months' follow-up. RESULTS: The mean IOP was 8.7 +/- 0.4 mm Hg preoperatively, 8.4 +/- 0.6 mm Hg at the 2-month follow-up, and 8.1 +/- 0.3 mm Hg at the 12-month follow-up. The mean CCT was 562 +/- 11 MUm preoperatively, 563 +/ 10 MUm at the 2-month follow-up, and 570 +/- 10 MUm at the 12-month follow-up. There was no significant change in either pre- or postoperative IOP (P = 0.700) or CCT (P = 0.419) over the study period. CONCLUSIONS: Injection of 1.2 mg triamcinolone acetonide at the end of congenital cataract surgery in children <2 years of age did not significantly affect IOP or CCT in the first year after surgery. PMID- 23084382 TI - Surgical management of bilateral esotropic Duane syndrome. AB - PURPOSE: To describe the indications and outcomes of surgery for bilateral esotropic Duane syndrome. METHODS: The medical records of consecutive patients with bilateral esotropic Duane syndrome who underwent surgery from January 1999 to December 2008 were retrospectively reviewed. Data for surgical indications and outcomes were analyzed. Success was defined as postoperative orthotropia with eso or exodeviation <8(Delta). RESULTS: A total of 14 patients with esotropic bilateral Duane Syndrome underwent surgery: 12 had bilateral medial rectus muscle recession; 1 had unilateral medial rectus muscle recession; and 1 had bilateral asymmetrical medial rectus and lateral rectus muscle recessions. The mean preoperative esodeviation was 38.14(Delta) +/- 13.24(Delta), (range, 14(Delta) 70(Delta)). The mean medial rectus recession was 5.7 mm in the right eye and 5.5 mm in the left eye. The mean follow-up period was 11.7 months (range, 3-37 months). Success was achieved in 12 of 14 patients (85.71%); 2 patients had a residual esotropia of 15(Delta). In all patients who underwent surgery, there was satisfactory improvement in associated globe retraction and head turn. None of the patients developed consecutive exodeviation. CONCLUSIONS: Bilateral medial rectus muscle recession can provide a good outcome for patients with bilateral esotropic Duane syndrome. The mean amount of medial rectus muscle recession required may be greater than what is generally recommended for similar sized esodeviations in patients with infantile esotropia. PMID- 23084383 TI - Glaucoma in the Early Treatment for Retinopathy of Prematurity (ETROP) study. AB - PURPOSE: To report the clinical characteristics of infants with severe retinopathy of prematurity (ROP) and glaucoma-based on review of the Early Treatment for Retinopathy of Prematurity (ETROP) study. METHODS: All infants randomized in the ETROP trial were included. Each infant developed high-risk prethreshold ROP in at least one eye. Infants were examined until 6 years postnatal age. The following data were collected: corneal clarity, depth of the anterior chamber, status of the optic nerve and cup/disk ratio, retinal structure, and visual acuity. The diagnosis of glaucoma was based on the investigators best clinical judgment. All infants diagnosed with glaucoma were included in the study. RESULTS: A total of 12 of 718 eyes (1.67%) were diagnosed with glaucoma. Of these, 5 were first reported as having glaucoma at 9 months, 2 at 2 years, 1 each at 3 and 4 years, and 3 at 5 years. The anterior segment was shallow in 7 eyes. Three eyes had normal retinal structure, 1 had macular dragging, and 8 had retinal detachments involving the fovea (stage 4B or worse). At the 6-year follow-up examination only one eye with glaucoma had measurable vision. CONCLUSIONS: Although earlier treatment of significant ROP has resulted in better retinal structure and visual acuity outcomes, nearly 2% of the eyes with high-risk prethreshold ROP developed glaucoma at some point during the first 6 years of life. PMID- 23084384 TI - Outcomes of Harada-Ito surgery for acquired torsional diplopia. AB - PURPOSE: To evaluate the outcomes of Harada-Ito surgery in correcting various types of torsional diplopia. METHODS: The medical records of patients who underwent Harada-Ito surgery at two academic institutions were retrospectively reviewed. Data collected included etiology of torsional diplopia, strabismus and torsion measurements, reoperation rate, patient symptoms, and use of prism. Postoperative success was defined as a lack of diplopia in the primary position at distance and downgaze at near with or without prism. Failure was defined as persistent torsional diplopia; partial success was defined as surgical success but with restrictive strabismus in the secondary gaze positions. RESULTS: A total of 26 patients (mean age, 46 years; range, 13-89 years) were included. Of these, 17 had superior oblique palsy. The mean follow-up duration was 2 years (range, 2 60 months). The surgical outcome was success in 73% of patients, partial success in 7%, and failure in 19%. All patients with <=10 degrees of torsion preoperatively obtained surgical success. Patients in the failure group had higher amounts of preoperative torsion compared to the success group (P = 0.009). The reoperation rate was 23%, including four patients with additional surgery for downgaze esotropia or torsion. One-third of the patients wore a prism immediately after surgery. CONCLUSIONS: Harada-Ito surgery successfully treated torsional diplopia. Patients with <=10 degrees of preoperative torsion had a better outcome. Downgaze diplopia was a common reason for additional surgery. PMID- 23084385 TI - The use of self-inflating hydrogel expanders in pediatric patients with congenital microphthalmia in China. AB - PURPOSE: To report the results of enlarging orbital volume in consecutive cases of severe congenital microphthalmia by means of solid hydrophilic tissue expanders. METHODS: The medical records of consecutive patients with congenital microphthalmia who underwent the placement of a hydrogel expander were retrospectively reviewed. Main outcome measures were orbital tissue expansion, prosthetic retention, and patient family satisfaction. RESULTS: A total of 17 patients were included in the study. All patients were able to retain an ocular prosthesis. The horizontal palpebral length increased from 71.3% of the contralateral unaffected eye to 85.4% of the contralateral unaffected eye. The expansion of orbital volume was assessed in seven patients. The volume of the microphthalmic orbits was expanded from 74.7% of the contralateral unaffected orbits to 83.5% of the contralateral unaffected orbits. Aesthetic results were satisfactory to both physicians and patient families. The following complications were noted in two patients: inferior migration of a spherical expander occurred in one case; a hemispheric expander was removed by the patient in another case. CONCLUSIONS: Hydrogel implants can successfully expand the dimensions of the conjunctival sac and the orbit in cases of severe congenital microphthalmia. PMID- 23084386 TI - Computed tomographic dacryocystography in children undergoing balloon dacryoplasty. AB - PURPOSE: To ascertain whether the volume and circumference of the lacrimal sac and nasolacrimal duct as measured by contrast-enhanced computed tomographic dacryocystography (CT-DCG) before and after balloon dacryoplasty could be used to predict clinical success in children with congenital nasolacrimal obstruction. METHODS: Nasolacrimal ducts of children aged 2 to 6 years with clinical signs of congenital nasolacrimal duct obstruction undergoing balloon dilation were imaged with contrast-enhanced CT-DCG before and 5 minutes after the procedure. The circumference of the most dilated portion of the lacrimal sac was measured on the axial plane. The volume of contrast within the nasolacrimal duct and sac was also measured before and after the procedure. Clinical success was defined as the disappearance of signs of epiphora. RESULTS: A total of 18 nasolacrimal ducts of 13 children were included. The average circumference of the most dilated portion of the lacrimal sac was 1.30 +/- 0.45 cm (range, 0.64-2.50 cm) before the procedure. The average contrast volume was 0.12 +/- 0.08 cm(3) (range, 0.01-0.38 cm(3)) before and 0.07 +/- 0.06 cm(3) (range, 0.01-0.20 cm(3)) after (P = 0.01). Data were analyzed using multivariate logistic regression with a backward variable input model; a decrease in contrast volume before and after dilation (P = 0.04) was associated with clinical success, whereas the larger size of the most dilated portion of the lacrimal sac (P = 0.01) was associated with clinical failure. CONCLUSIONS: Contrast-enhanced CT-DCG provides useful information about nasolacrimal anatomy in children with congenital nasolacrimal duct obstruction. The decrease in contrast volume before and after balloon dilation was predictive of success; A larger size of the most dilated portion of the lacrimal sac was associated with clinical failure. PMID- 23084387 TI - Pushed monocanalicular intubation: an alternative stenting system for the management of congenital nasolacrimal duct obstructions. AB - PURPOSE: To present our experience with a "pushed" monocanalicular nasolacrimal intubation device in the management of nasolacrimal duct obstruction in children. METHODS: The cases of consecutive patients with nasolacrimal duct obstruction who were treated with primary probing and intubation with the Masterka were reviewed retrospectively. The Masterka includes a metal guide placed inside a silicone tube for "pushed" intubation as opposed to material attached at the distal end of the silicone for intranasal retrieval ("pulled" intubations). All procedures were accomplished with the patients receiving masked airway anesthesia; neither laryngeal mask airway nor endotracheal intubation was necessary. Only patients noted to have a membranous (mucosal) obstruction were considered for treatment with the Masterka. The duration of operation, duration of stent intubation, and severity of symptoms on follow-up were noted. Success was defined as absence of symptoms after stent removal or loss. RESULTS: A total of 110 eyes of 88 patients were included (average age, 2.4 years; range, 1-8 years). The average operating time was 3 minutes (range, 2-9 minutes). Persistent tearing on follow-up with the stent in place was noted in 26 eyes (24%); tearing resolved after stent removal in 19 eyes (73%). Success was achieved in 94 eyes (85%). with an average follow up of 33.7 weeks (range, 4-139). Keratitis was noted in 2 eyes (2%). Early stent loss occurred in 17 ducts (15%). CONCLUSIONS: The Masterka was an effective primary treatment for nasolacrimal duct obstruction associated with mucosal obstructions in this small series of patients. PMID- 23084388 TI - Bilateral anterior segment dysgenesis in an infant with partial trisomy 16q and partial monosomy 3p. AB - Anterior segment dysgenesis comprises a spectrum of malformations arising from faulty neural crest cell migration. We report a newborn boy with partial trisomy 16q and partial monosomy 3p who presented with anterior segment dysgenesis with iris hypoplasia on the right and glaucoma on the left in association with systemic anomalies. The anterior segment dysgenesis features observed in this case have not been previously associated with partial trisomy 16q or partial monosomy 3p. Our findings support the hypothesis that an additional anterior segment dysgenesis gene may reside on chromosome 3p or 16q. PMID- 23084389 TI - Toxic epidermal necrolysis in a 15-month-old girl successfully treated with amniotic membrane transplantation. AB - A 15-month-old girl presented with rash, fever, and vesicles around the mouth that worsened after erythromycin was administered. Subsequently, she was diagnosed with toxic epidermal necrolysis. Ocular involvement was treated with repeated complete corneal, conjunctival, and lid margin coverage with amniotic membrane. She recovered with minimal ocular sequelae despite persistent systemic symptoms. PMID- 23084390 TI - Detection of optic nerve disease in retinoblastoma by use of spectral domain optical coherence tomography. AB - We present the case of a child affected with retinoblastoma and evolving optic nerve pathology detected by spectral domain optical coherence tomography (SD-OCT) before magnetic resonance imaging. At 6 months of age, the patient was diagnosed with bilateral retinoblastoma, which was managed with systemic chemotherapy and focal therapy. Six months after the third and final cycle of systemic chemotherapy, the right optic disk clinically appeared progressively edematous, raising concerns of tumor infiltration of the optic nerve head. Images obtained via magnetic resonance imaging could not confirm the presence of a tumor at the optic nerve head, whereas findings on SD-OCT were suggestive of optic nerve head disease. Histopathologic findings after enucleation revealed viable tumor over the optic nerve head, supporting the OCT findings. PMID- 23084391 TI - Ocular tilt reaction, internuclear ophthalmoplegia, and torsional nystagmus following mitral commissurotomy. AB - Ocular tilt reaction, a type of skew deviation, and unilateral internuclear ophthalmoplegia with torsional nystagmus resulting from an ischemic event may result from unilateral disruption of otolithic pathways in the medial longitudinal fasciculus. A subset of skew deviations is known to simulate superior oblique palsy; however, none have been reported with a coexisting internuclear ophthalmoplegia. The present report documents the rare occurrence of an ocular tilt reaction simulating a left superior oblique palsy from involvement of left medial longitudinal fasciculus at the level of interstitial nucleus of Cajal. PMID- 23084392 TI - Acute idiopathic frosted branch angiitis in an 11-month-old infant treated with intravitreal triamcinolone acetonide. AB - An 11-month-old boy presented with bilateral vision loss following upper respiratory tract infection. Extensive perivascular sheathing resembling frosted branch angiitis and severe macular edema was noted in both eyes. All tests for etiological diagnosis were negative. Treatment with systemic corticosteroids and antibiotics caused resolution of perivascular infiltrates. Macular edema resolved with improvement in visual acuity following consecutive bilateral intravitreal triamcinolone acetonide injections. To our knowledge, this is the youngest reported case of frosted branch angiitis. PMID- 23084393 TI - Metastatic tumor to the extraocular muscles: report of 5 cases. AB - We report the findings in 5 patients with metastases to the extraocular muscles. Familiarity with this condition will aid ophthalmologists in differentiating it from thyroid ophthalmopathy, the most common form of muscle enlargement. Palliative treatment is effective in ameliorating visual symptoms. PMID- 23084394 TI - Nasolacrimal probing and intubation for children with nasolacrimal duct obstruction and history of dacryocystitis. PMID- 23084396 TI - Unilateral rectus muscle recession in the treatment of Duane syndrome. PMID- 23084397 TI - Toxoplasma gondii infection in Bactrian camel (Camelus bactrianus) in China. AB - Camel is important to the economy of many countries. We report Toxoplasma gondii infection in Bactrian camels (Camelus bactrianus), first for this host. Antibodies to T. gondii were found in sera of 7 of 234 C. bactrianus from Qinghai Province, northwestern China. Sera were tested by a commercial indirect hemagglutination test at a cut-off of 1:64. Age or the gender of the camel did not significantly affect the seroprevalence. Results are of public health and economic importance because camel milk and meat are used for human consumption in many countries, including China. PMID- 23084399 TI - Centralized and distributed control architectures under Foundation Fieldbus network. AB - This paper aims at discussing possible automation and control system architectures based on fieldbus networks in which the controllers can be implemented either in a centralized or in a distributed form. An experimental setup is used to demonstrate some of the addressed issues. The control and automation architecture is composed of a supervisory system, a programmable logic controller and various other devices connected to a Foundation Fieldbus H1 network. The procedures used in the network configuration, in the process modelling and in the design and implementation of controllers are described. The specificities of each one of the considered logical organizations are also discussed. Finally, experimental results are analysed using an algorithm for the assessment of control loops to compare the performances between the centralized and the distributed implementations. PMID- 23084398 TI - Interplay of DNA repair with transcription: from structures to mechanisms. AB - Many DNA transactions are crucial for maintaining genomic integrity and faithful transfer of genetic information but remain poorly understood. An example is the interplay between nucleotide excision repair (NER) and transcription, also known as transcription-coupled DNA repair (TCR). Discovered decades ago, the mechanisms for TCR have remained elusive, not in small part due to the scarcity of structural studies of key players. Here we summarize recent structural information on NER/TCR factors, focusing on bacterial systems, and integrate it with existing genetic, biochemical, and biophysical data to delineate the mechanisms at play. We also review emerging, alternative modalities for recruitment of NER proteins to DNA lesions. PMID- 23084400 TI - Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFbeta suppression. AB - ETS transcription factors ETV2, FLI1, and ERG1 specify pluripotent stem cells into induced vascular endothelial cells (iVECs). However, iVECs are unstable and drift toward nonvascular cells. We show that human midgestation c-Kit(-) lineage committed amniotic cells (ACs) can be reprogrammed into vascular endothelial cells (rAC-VECs) without transitioning through a pluripotent state. Transient ETV2 expression in ACs generates immature rAC-VECs, whereas coexpression with FLI1/ERG1 endows rAC-VECs with a vascular repertoire and morphology matching mature endothelial cells (ECs). Brief TGFbeta-inhibition functionalizes VEGFR2 signaling, augmenting specification of ACs into rAC-VECs. Genome-wide transcriptional analyses showed that rAC-VECs are similar to adult ECs in which vascular-specific genes are expressed and nonvascular genes are silenced. Functionally, rAC-VECs form stable vasculature in Matrigel plugs and regenerating livers. Therefore, short-term ETV2 expression and TGFbeta inhibition with constitutive ERG1/FLI1 coexpression reprogram mature ACs into durable rAC-VECs with clinical-scale expansion potential. Banking of HLA-typed rAC-VECs establishes a vascular inventory for treatment of diverse disorders. PMID- 23084401 TI - The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. AB - In addition to sculpting eukaryotic transcripts by removing introns, pre-mRNA splicing greatly impacts protein composition of the emerging mRNP. The exon junction complex (EJC), deposited upstream of exon-exon junctions after splicing, is a major constituent of spliced mRNPs. Here, we report comprehensive analysis of the endogenous human EJC protein and RNA interactomes. We confirm that the major "canonical" EJC occupancy site in vivo lies 24 nucleotides upstream of exon junctions and that the majority of exon junctions carry an EJC. Unexpectedly, we find that endogenous EJCs multimerize with one another and with numerous SR proteins to form megadalton sized complexes in which SR proteins are super stoichiometric to EJC core factors. This tight physical association may explain known functional parallels between EJCs and SR proteins. Further, their protection of long mRNA stretches from nuclease digestion suggests that endogenous EJCs and SR proteins cooperate to promote mRNA packaging and compaction. PMID- 23084402 TI - Familial disease predisposition impacts treatment outcome in patients with Waldenstrom macroglobulinemia. AB - Familial disease is common in Waldenstrom macroglobulinemia (WM). We examined the impact of familial disease status on treatment outcome in WM and observed that familial disease was associated with inferior outcomes. However patients with familial WM receiving a bortezomib-containing regimen showed improved treatment outcomes vs. those receiving non-bortezomib-containing regimens. Bortezomib containing regimens may therefore represent a more optimal treatment approach for patients with familial WM. BACKGROUND: We examined the impact of familial predisposition on treatment outcome in 135 patients with Waldenstrom macroglobulinemia (WM), 26.7% of whom had first- or second-degree relatives with a B-cell lymphoproliferative disorder. PATIENTS AND METHODS: All patients were rituximab naive and received a rituximab-containing regimen. There were no significant differences in baseline characteristics between cohorts. RESULTS: Overall response (93.9% vs. 75.0%; P = .029) and complete response/very good partial response (CR/VGPR) (23.2% vs. 16.7%; P < .0001), time to progression (TTP) (45.5 vs. 21 months; P = .015) and time to next therapy (TTNT) (50.0 vs. 33.0 months; P = .024) favored patients with sporadic WM. By multivariate analysis, familial predisposition was an independent marker for disease progression (hazard ratio, 0.554). Patients with familial but not sporadic disease exhibited better responses, including CR/VGPR attainment (P = .0006) and a trend for longer progression-free survival (> 33 vs. 20.6 months; P = .08), with bortezomib-containing therapy. CONCLUSION: The findings convey that familial predisposition is an important determinant of treatment outcome in WM. Prospective studies to confirm these observations are needed. PMID- 23084403 TI - Successful use of intrathecal carboxypeptidase G2 for intrathecal methotrexate overdose: a case study and review of the literature. PMID- 23084404 TI - Erectile dysfunction associated with bortezomib treatment in a patient with multiple myeloma and amyloidosis. PMID- 23084405 TI - Bortezomib administration with severe hyperbilirubinemia caused by hepatic plasma cell infiltration: a case report. PMID- 23084407 TI - Trainee satisfaction in surgery residency programs. PMID- 23084406 TI - [Prescribing of antibiotics in patients admitted from Emergency Departments: a multicenter study]. AB - INTRODUCTION: The infectious disease is the main source of care demand in Pediatric Emergency Departments (PED) and is a frequent cause of hospital admission with antibiotics. Our objectives are: 1) to determine the diseases that are seen in PED that required admission with antibiotics; 2) to determine the microbiological methods used and, 3) to analyze the characteristics of the indicated treatment. MATERIAL AND METHODS: A prospective multicenter study was conducted in 22 Spanish hospitals. We included patients younger than 18 years seen in PED on day 14 of each month between June 2009 and May 2010 who required hospitalization with systemic antibiotics. Patients admitted to Intensive Care Unit were excluded. RESULTS: There were 30,632 consultations in the PED during the study period. A total of 1,446 (4.7%) patients were hospitalized, 395 (27.3%) of them with antibiotics. Ninety-five patients (24.1%) had received antibiotics before admission. Three hundred twenty (81%) children underwent at least one microbiological test, with blood culture (69.9%) and urine culture (30.9%) being the most requested ones. The main diagnoses at admission were pneumonia (29.4%), urinary tract infection (15.4%), and fever without source (12.1%). Twenty five different antibiotics were prescribed, with cefotaxime (27.8%) and amoxicillin clavulanate (23.4%) being the most prescribed ones. A single antibiotic was prescribed to 80.8% of patients, and parenteral administration was the most indicated (93.7%). CONCLUSIONS: Antibiotic therapy was prescribed in one in every 4 patients who required admission to hospital. Pneumonia was the most common source. Blood culture was the most frequent microbiological test requested in the PED. A limited number of beta-lactam antibiotics represented the majority of antibiotic prescriptions. PMID- 23084408 TI - European surgical training: an opportunity for leadership. PMID- 23084409 TI - Surgical trainees like to be trained. PMID- 23084410 TI - Commentary on "trainee satisfaction in surgical residency programs: modern management tools ensure trainee motivation and success" by von Websky et al. PMID- 23084412 TI - A foot in 2 RVU canoes: the Massachusetts experiment-2012. PMID- 23084414 TI - Sequential in situ left internal thoracic artery grafting to the circumflex and right coronary artery areas. AB - BACKGROUND: Several bilateral internal thoracic artery (ITA) grafting patterns have been proposed to enhance 3-vessel coronary artery revascularization. We present the outcomes of sequential in situ left ITA grafting to the circumflex and right coronary artery (RCA) areas. METHODS: Between January 2001 and September 2007, 102 patients with 3-vessel coronary artery disease underwent arterial myocardial revascularization with bilateral in situ ITA grafts. The circumflex and distal RCA branches were revascularized sequentially with the left ITA. The left anterior descending artery area was grafted with the right ITA. RESULTS: Ninety-nine patients (97.0%) were monitored for 37.2 +/- 2.9 months, and 77 (75.4%) underwent postoperative coronary imaging after 27.8 +/- 5.8 months. The bilateral ITA grafts were 97.1% patent (FitzGibbon grade A+B) overall. The sequential anastomoses of the left ITA to the circumflex and RCA territories were 96.7% patent overall, with competitive flow (FitzGibbon grade B) in 3 patients. The patency rates of sequential anastomoses to the circumflex and RCA branches were 98.0% and 95.0%, respectively. The right posterolateral and right descending posterior artery anastomoses were 91.8% and 100% patent, respectively. The in situ right ITA grafts to the left anterior descending artery area were 98.0% (FitzGibbon grade A+B) patent overall. Angina recurred in 1 patient (0.9%) 6 months after the operation. Percutaneous coronary interventions were performed in 3 patients (3.8%). No cardiac deaths occurred during the follow-up period. CONCLUSIONS: Sequential in situ left ITA grafting to the circumflex and RCA areas yields acceptable midterm results in selected patients with 3-vessel disease. PMID- 23084413 TI - Decreased frontal lobe phosphocreatine levels in methamphetamine users. AB - BACKGROUND: Mitochondria-related mechanisms have been suggested to mediate methamphetamine (METH) toxicity. However, changes in brain energetics associated with high-energy phosphate metabolism have not been investigated in METH users. Phosphorus-31 ((31)P) magnetic resonance spectroscopy (MRS) was used to evaluate changes in mitochondrial high energy phosphates, including phosphocreatine (PCr) and beta-nucleoside triphosphate (beta-NTP, primarily ATP in brain) levels. We hypothesized that METH users would have decreased high-energy PCr levels in the frontal gray matter. METHODS: Study participants consisted of 51 METH (age=32.8+/ 6.7) and 23 healthy comparison (age=31.1+/-7.5) subjects. High-energy phosphate metabolite levels were compared between the groups and potential gender differences were explored. RESULTS: METH users had lower ratios of PCr to total pool of exchangeable phosphate (PCr/TPP) in the frontal lobe as compared to the healthy subjects (p=.001). The lower PCr levels in METH subjects were significantly associated with lifetime amount of METH use (p=.003). A sub analysis for gender differences revealed that female METH users, who had lower daily amounts (1.1+/-1.0g) of METH use than males (1.4+/-1.7g), had significantly lower PCr/TPP ratios than male METH users, controlling for the amount of METH use (p=.02). CONCLUSIONS: The present findings suggest that METH compromises frontal lobe high-energy phosphate metabolism in a dose-responsive manner. Our findings also suggest that the abnormality in frontal lobe high-energy phosphate metabolism might be more prominent in female than in male METH users. This is significant as decreased PCr levels have been associated with depressive symptoms, and poor responses to antidepressant treatment have been reported in those with decreased PCr levels. PMID- 23084415 TI - Differences in clinical characteristics, management, and outcomes of intraoperative versus spontaneous acute type A aortic dissection. AB - BACKGROUND: The clinical characteristics, management, and outcomes of patients who had intraoperative aortic dissection (IAD) have not been thoroughly investigated. This study compared early and late clinical outcomes in patients with IAD vs spontaneous (non-IAD) acute type A aortic dissection. METHODS: Between January 1, 2000, and July 1, 2008, 251 patients from 4 academic medical centers underwent repair of acute type A aortic dissection; of those, 11 had IAD. The mean age was 72 +/- 9 years for patients experiencing IAD and 59 +/- 13 years for those with non-IAD (p = 0.001). Patients with IAD were more likely to have coronary artery disease (p = 0.003) and a history of arrhythmia (p = 0.038). Rates for major morbidity, operative mortality, and 5-year actuarial survival were compared between groups. RESULTS: Operative mortality was not adversely influenced by IAD (27% IAD vs 17% non-IAD, p = 0.42). There were no differences in the rates of reoperation for bleeding (10% IAD vs 20% non-IAD, p = 0.69), stroke (18% IAD vs 18% non-IAD, p >= 0.99), or acute renal failure (9% IAD vs 22% non-IAD, p = 0.47) between the two groups. Actuarial 5-year survival was 64% for IAD patients vs 73% for non-IAD patients (p = 0.33). CONCLUSIONS: IAD does not adversely influence early outcomes and actuarial 5-year survival of patients with type A dissection. PMID- 23084416 TI - Prevention of postoperative pericardial adhesions with TachoSil. AB - BACKGROUND: The prevention of the pericardial adhesions largely accountable for the technical difficulty and risk of injury inherent to resternotomy continues to gain in importance with the increasing frequency of reoperations. The hemostatic sponge TachoSil (Nycomed Austria GmbH, Linz, Austria), has shown promising results in adhesion prevention in several regions of the body. This study was designed to evaluate its effectiveness in the prevention of pericardial adhesions in comparison with the Gore-Tex (W. L. Gore and Assoc, Flagstaff, AZ) surgical membrane and a control. METHODS: Twenty-four rabbits were distributed into 3 groups: TachoSil, Gore-Tex, or no barrier agent (control). After median sternotomy and pericardiotomy, the cardial surface was exposed to the aggravating effects of room air, irrigation, and gauze abrasion for one hour. A pericardial defect was created and repaired with one of the barrier agents, or left uncovered (control). Resternotomy was performed after 6 months for the evaluation of adhesion formation. RESULTS: Significantly fewer macroscopic adhesions were observed with TachoSil than Gore-Tex in all regions (p < 0.05) excluding the coronary arteries, where the difference in favor of TachoSil did not achieve significance (0.05< p-value <0.10). TachoSil also demonstrated significantly fewer retrosternal adhesions than the control, as well as a universal non significant trend of fewer adhesions in all regions. The limited lesions present in the TachoSil group were filmy in nature and removed with blunt dissection relatively easily. No significant differences were found between Gore-Tex and the control. Microscopically, the least pronounced fibrosis formation and inflammatory reaction was detected with TachoSil. CONCLUSIONS: TachoSil is effective in the prevention of pericardial adhesions. PMID- 23084417 TI - Endobronchial ultrasound and lymphoproliferative disorders: a retrospective study. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to have excellent diagnostic performance for mediastinal staging of lung cancer. The utility of EBUS-TBNA for the diagnosis of lymphoproliferative disorders involving the mediastinum or hila, or both, is unclear. METHODS: A retrospective analysis was completed of all patients diagnosed with a lymphoproliferative disorder involving the mediastinum or hila, or both, who underwent an EBUS-TBNA within 3 months of the diagnosis. RESULTS: Sixty-five patients with mediastinal or hilar lymph node, or both, involvement of their lymphoproliferative disorder underwent EBUS-TBNA within 3 months of their diagnosis. The initial EBUS-TBNA was nondiagnostic in 34 (52%), 11 were subsequently diagnosed by mediastinoscopy, and the remaining 23 were diagnosed by biopsy of a distant site, with involvement of the mediastinum or hilum assumed from preestablished radiographic criteria. A EBUS-TBNA specimen in 31 patients (48%) was interpreted as consistent with or suspicious for a lymphoproliferative disorder. The overall sensitivity of EBUS-TBNA for establishing a definitive diagnosis was 25 of 65 (38%). The sensitivity was lower for new patients, at 7 of 32 (22%), and better for patients with recurrence, at 18 of 33 (55%). CONCLUSIONS: Contrary to previous studies, our findings suggest that EBUS-TBNA does not provide sufficient diagnostic material for accurate lymphoproliferative disorder subtyping in a significant number of patients and performs especially poorly when evaluating new patients. Mediastinoscopy should still be considered as the initial diagnostic procedure of choice when the clinical suspicion for a lymphoproliferative disorder is high, unless the patient is being evaluated for a recurrence of prior disorder. PMID- 23084418 TI - Clarifying the surgical morphology of inlet ventricular septal defects. AB - BACKGROUND: Different types of ventricular septal defects (VSD) open to the inlet of the right ventricle. The atrioventricular conduction axis is markedly different within these subtypes, a feature of great surgical importance. To clarify these relationships, we have studied hearts with such VSDs from the Idriss archive at Ann and Robert H. Lurie Children's Hospital of Chicago. METHODS: We selected hearts from the archive showing the different variants of inlet VSD, photographing them to show the presumed disposition of the atrioventricular conduction axis as based on previous histology studies. We differentiated between perimembranous defects, muscular defects, perimembranous defects with straddling of the tricuspid valve, and atrioventricular septal defects with shunting confined at the ventricular level. RESULTS: The atrioventricular conduction axis is different in the four types of inlet VSDs. In perimembranous defects opening to the inlet of the right ventricle, the axis is positioned to the right hand of the surgeon operating through the tricuspid valve, whereas it is to the left hand with the muscular inlet defect. In patients with straddling tricuspid valve, the axis arises from an anomalous posteroinferior atrioventricular node, whereas in patients with atrioventricular septal defect with exclusive ventricular shunting, the axis arises at the crux of the heart from a node located in an inferiorly displaced nodal triangle. CONCLUSIONS: An appreciation of these relationships should help surgeons avoid the conduction system when closing inlet VSDs. PMID- 23084419 TI - [Fatigue and sleep disorders of patients with colorectal cancer]. AB - Fatigue and sleep disorders impact the quality of life of cancer patients. They do not put the vital prognosis at stake, but are debilitating and as a whole poorly treated. This article is oriented toward the fatigue and sleep disorders of patients with colorectal cancer. Special emphasis is put on the necessary clinical work up, on various available scales, indexes, inventories, questionnaires and on actigraphy and polysomnography, on the semiology of these disorders, on their mechanisms and on the recent therapeutic methods which are still insufficiently distributed. PMID- 23084421 TI - Identification of EPS-degrading activity within the tail spikes of the novel Pseudomonas putida phage AF. AB - We report the study of phage AF, the first member of the canonical lambdoid phage group infecting Pseudomonas putida. Its 42.6 kb genome is related to the "epsilon15-like viruses" and the "BPP-1-like viruses", a clade of bacteriophages shaped by extensive horizontal gene transfer. The AF virions display exopolysaccharide (EPS)-degrading activity, which originates from the action of the C-terminal domain of the tail spike (Gp19). This protein shows high similarity to the tail spike of the T7-like P. putida-infecting phage phi15. These unrelated phages have an identical host spectrum and EPS degradation characteristics, designating the C-terminal part of Gp19 as sole determinant for these functions. While intact AF particles have biofilm-degrading properties, Gp19 and non-infectious AF particles do not, emphasizing the role of phage amplification in biofilm degradation. PMID- 23084420 TI - Contribution of SUMO-interacting motifs and SUMOylation to the antiretroviral properties of TRIM5alpha. AB - Recent findings suggested that the SUMO-interacting motifs (SIMs) present in the human TRIM5alpha (TRIM5alpha(hu)) protein play an important role in the ability of TRIM5alpha(hu) to restrict N-MLV. Here we explored the role of SIMs in the ability of rhesus TRIM5alpha (TRIM5alpha(rh)) to restrict HIV-1, and found that TRIM5alpha(rh) SIM mutants IL376KK (SIM1mut) and VI405KK (SIM2mut) completely lost their ability to block HIV-1 infection. Interestingly, these mutants also lost the recently described property of TRIM5alpha(rh) to shuttle into the nucleus. Analysis of these variants revealed that they are unable to interact with the HIV-1 core, which might explain the reason that these variants are not active against HIV-1. Furthermore, NMR titration experiments to assay the binding between the PRYSPRY domain of TRIM5alpha(rh) and the small ubiquitin-like modifier 1(SUMO-1) revealed no interaction. In addition, we examined the role of SUMOylation in restriction, and find out that inhibition of SUMOylation by the adenoviral protein Gam1 did not alter the retroviral restriction ability of TRIM5alpha. Overall, our results do not support a role for SIMs or SUMOylation in the antiviral properties of TRIM5alpha. PMID- 23084423 TI - Ocean viruses: rigorously evaluating the metagenomic sample-to-sequence pipeline. AB - As new environments are studied, viruses consistently emerge as important and prominent players in natural and man-made ecosystems. However, much of what we know is built both upon the foundation of the culturable minority and using methods that are often insufficiently ground-truthed. Here, we review the modern culture-independent viral metagenomic sample-to-sequence pipeline and how next generation sequencing techniques are drastically altering our ability to systematically and rigorously evaluate them. Together, a series of studies quantitatively evaluate existing and new methods that allow-even for ultra-low DNA samples-the generation of replicable, near-quantitative datasets that maximize inter-comparability and biological inference. PMID- 23084422 TI - Comparison of novel MLB-clade, VA-clade and classic human astroviruses highlights constrained evolution of the classic human astrovirus nonstructural genes. AB - Eight serotypes of human astroviruses (the classic human astroviruses) are causative agents of diarrhea. Recently, five additional astroviruses belonging to two distinct clades have been described in human stool, including astroviruses MLB1, MLB2, VA1, VA2 and VA3. We report the discovery in human stool of two novel astroviruses, astroviruses MLB3 and VA4. The complete genomes of these two viruses and the previously described astroviruses VA2 and VA3 were sequenced, affording seven complete genomes from the MLB and VA clades for comparative analysis to the classic human astroviruses. Comparison of the genetic distance, number of synonymous mutations per synonymous site (dS), number of non-synonymous mutations per non-synonymous site (dN) and the dN/dS ratio in the protease, polymerase and capsid of the classic human, MLB and VA clades suggests that the protease and polymerase of the classic human astroviruses are under distinct selective pressure. PMID- 23084424 TI - Fully human broadly neutralizing monoclonal antibodies against influenza A viruses generated from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. AB - Whether the 2009 pandemic H1N1 influenza vaccine can induce heterosubtypic cross protective anti-hemagglutinin (HA) neutralizing antibodies is an important issue. We obtained a panel of fully human monoclonal antibodies from the memory B cells of a 2009 pandemic H1N1 influenza vaccine recipient. Most of the monoclonal antibodies targeted the HA protein but not the HA1 fragment. Among the analyzed antibodies, seven mAbs exhibited neutralizing activity against several influenza A viruses of different subtypes. The conserved linear epitope targeted by the neutralizing mAbs (FIEGGWTGMVDGWYGYHH) is part of the fusion peptide on HA2. Our work suggests that a heterosubtypic neutralizing antibody response primarily targeting the HA stem region exists in recipients of the 2009 pandemic H1N1 influenza vaccine. The HA stem region contains various conserved neutralizing epitopes with the fusion peptide as an important one. This work may aid in the design of a universal influenza A virus vaccine. PMID- 23084426 TI - Segmental disruption of the internal elastic lamina as a potential pathogenetic mechanism of a true posttraumatic femoral artery aneurysm, years after single blunt trauma. AB - We present an unusual case of a true posttraumatic aneurysm of the superficial femoral artery (SFAA) 7 years after a motorcycle accident including blunt trauma to the thigh. Surgical reconstruction was accomplished without any complications by aneurysm resection and interposition of an autologous reversed saphenous vein. Histopathological examination revealed a true aneurysm with segmental disruption and fragmentation of the internal elastic lamina (IEL) in van Gieson's stain. This is a first-time finding in context with SFAA and may represent the pathogenetic explanation for the rare formation of posttraumatic true aneurysms. PMID- 23084425 TI - An attenuating mutation in a neurovirulent Sindbis virus strain interacts with the IPS-1 signaling pathway in vivo. AB - The AR86 strain of Sindbis virus causes lethal neurologic disease in adult mice. Previous studies have identified a virulence determinant at nonstructural protein (nsP) 1 position 538 that regulates neurovirulence, modulates clearance from the CNS, and interferes with the type I interferon pathway. The studies herein demonstrate that in the absence of type I interferon signaling, the attenuated mutant exhibited equivalent virulence to S300 virus. Furthermore, both S300 and nsP1 T538I viruses displayed similar neurovirulence and replication kinetics in IPS-1-/- mice. TRIF dependent signaling played a modest role in protecting against disease by both S300 and nsP1 T538I, but did not contribute to control of nsP1 T538I replication within the CNS, while MyD88 played no role in the disease process. These results indicate that the control of the nsP1 T538I mutant virus is largely mediated by IPS-1-dependent RLR signaling, with TRIF-dependent TLR signaling also contributing to protection from virus-induced neurologic disease. PMID- 23084427 TI - Bioelectrochemical treatment of acid mine drainage dominated with iron. AB - Treatment of acid mine drainage (AMD) dominated with iron (Fe), the most common metal, is a long-term expensive commitment, the goal of which is to increase the pH and remove Fe. In the present study, a proton exchange membrane microbial fuel cell (MFC) showed promise for the efficient treatment of an AMD dominated with ferric iron (pH 2.4+/-0.1; 500 mg L(-1) Fe(3+)). Briefly, Fe(3+) was reduced to Fe(2+) at the cathode of the MFC, followed by Fe(2+) re-oxidation and precipitation as oxy(hydroxi)des. Oxygen reduction and cation transfer to the cathode of the MFC further caused a rise in pH. A linear relationship was observed between the charge transferred in the MFC and the performance of the system up to 880 C. Optimal conditions were found at a charge of 662 C, achieved within 7 d at an acetate concentration of 1.6 g L(-1) in a membrane MFC. This caused the pH to rise to 7.9 and resulted in a Fe removal of 99%. Treated effluent met the pH discharge limits of 6.5-9. The maximum power generation achieved under these conditions averaged 8.6+/-2.3 W m(-3), which could help reduce the costs of full-scale bioelectrochemical treatment of AMD dominated with Fe. PMID- 23084428 TI - Melatonin and cortisol rhythm in patients with extensive nasal polyposis. AB - PURPOSE: Extensive nasal polyposis is an inflammatory disease which effects 1%-4% of normal population. The mechanism of its formation and the circadian rhythm of cortisol and melatonin in ENP have not investigated. MATERIALS AND METHODS: Salivary levels of melatonin and cortisol were measured by radioimmunoassay in 31 patients with extensive nasal polyposis and in 27 control subjects matched for age and gender. In both groups none of the subjects did not have obstructive sleep apnea. RESULTS: The baseline and the peak levels of salivary melatonin in the extensive nasal polyposis group were significantly lower than in the control group (p<0.001). However, no differences were found in the acrophase and the peak duration of salivary melatonin between the study and control groups (p>0.05). The highest values of melatonin were recorded at 04:00 h in both the study and control groups. The amplitude and the 24 h mean levels of salivary cortisol in the extensive nasal polyposis group were significantly lower than in the control group (p<0.001). The acrophase was delayed by about 8 h in extensive nasal polyposis patients (p<0.001). CONCLUSION: The circadian rhythms of salivary melatonin and cortisol were found to be disrupted in patients with extensive nasal polyposis. These results may be applicable as therapeutic tools in the future and melatonin drugs might be useful in the therapy of nasal polyposis like cortisol drugs. PMID- 23084429 TI - A case of acquired tracheal diverticulum presenting with globus pharyngeus. AB - Acquired tracheal diverticulum is a rare pathology that has been associated with chronic cough and lung emphysema. A 72 year-old woman was referred to a tertiary Otorhinolaryngology Department for evaluation of chronic cough and globus pharyngeus. Computed tomography of the neck and chest revealed a diverticulum of the right posterolateral wall of the trachea. The patient underwent surgical excision of the diverticulum via a transcervical approach. Symptoms subsided after surgical treatment. PMID- 23084430 TI - Ultrasound characterization of middle ear effusion. AB - PURPOSE: To further enhance and assess the ability to characterize middle ear effusion (MEE) using non-invasive ultrasound technology. MATERIALS AND METHODS: This is a prospective unblinded comparison study. Fifty-six children between the ages of 6 months and 17 years scheduled to undergo bilateral myringotomy with pressure equalization tube placement were enrolled. With the child anesthetized, the probe was placed into the external ear canal after sterile water was inserted. Ultrasound recordings of middle ear contents were analyzed by computer algorithm. Middle ear fluid was collected during myringotomy and analyzed for bacterial culture and viscosity. RESULTS: Ultrasound waveforms yielded a computer algorithm interpretation of middle ear contents in 66% of ears tested. When a result was obtained, the sensitivity and specificity for successfully characterizing middle ear fluid content as either void of fluid, thick fluid (mucoid), or thin fluid (serous or purulent) were at least 94%. Mucoid effusions had higher measured viscosity values (P=.002). Viscosity measures were compared to culture result, and those with low viscosity (thin consistency) had a higher likelihood of having a positive culture (P=.048). CONCLUSION: The device sensitivity and specificity for fluid detection were 94% or greater among interpretable waveforms (66% of those tested). Although this technology provides important information of the middle ear effusion presence and characteristic, further technological improvements are needed. PMID- 23084432 TI - A new therapy for the reduction of axon and neuron loss and promotion of axon and oligodendrocyte regeneration through inhibition of death receptor 6 pathway after ischemic cerebral stroke. AB - Ischemic cerebral stroke may cause disability and rehabilitation is mainly dependent on long-term exercise. However, this needs many years of consistent application. Even then, it is not certain that patients will see satisfactory recovery of function. In the ischemic stroke, disability is attributed to neuron and axon loss resulting in injury to the nervous tract. In the nerve injury model, recovery of function is dependent on axon regeneration and rewiring of the nervous tract, which may be promoted and improved through appropriate drug intervention. Death receptor 6 (DR6), a member of the tumor necrosis factor (TNF) receptor superfamily, negatively regulates neuron, axon and oligodendrocyte survival and hinders axon and oligodendrocyte regeneration. Inhibition of DR6 has shown neuroprotection in nerve injury models. We hypothesized, therefore, that pharmacological inhibition of DR6 could be beneficial to the survival of axons and neurons, the regeneration of axons and oligodendrocytes, and the improvement of neurological function after ischemic cerebral stroke. PMID- 23084431 TI - Progressive hearing loss following acquired cytomegalovirus infection in an immunocompromised child. AB - We report a rare case of progressive hearing loss after acquired CMV infection in a child with Langerhans cell histiocytosis (LCH). A 5-month-old female was diagnosed as having LCH. When she was 14 months old, she received an unrelated donor umbilical cord blood transfusion for the treatment of intractable LCH. CMV infection was confirmed after the blood transfusion. Because her own umbilical cord had no CMV, the CMV infection was not congenital. When she was 7 years old, mixed hearing loss was noted with bilateral otitis media with effusion. After that time, the sensorineural hearing loss progressed to bilateral profound hearing loss over 3 years. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging with gadolinium contrast enhancement revealed a high intensity area in the inner ear that suggested bilateral labyrinthitis. This case demonstrates the possibility that, under the immunodeficiency, the acquired CMV infection causes progressive sensorineural hearing loss. PMID- 23084433 TI - Heparan sulfate and dermatan sulfate derived disaccharides are sensitive markers for newborn screening for mucopolysaccharidoses types I, II and III. AB - INTRODUCTION: Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders (LSDs) caused by a defect in the degradation of glycosaminoglycans (GAGs). The accumulation of GAGs in MPS patients results in extensive, severe and progressive disease. Disease modifying therapy is available for three of the MPSs and is being developed for the other types. Early initiation of treatment, before the onset of irreversible tissue damage, clearly provides a favorable disease outcome. However, early diagnosis is difficult due to the rarity of these disorders in combination with the wide variety of clinical symptoms. Newborn screening (NBS) is probably the optimal approach, and several screening techniques for different MPSs have been studied. Here we describe a relatively simple and sensitive method to measure levels of dermatan and heparan sulfate derived disaccharides in dried blood spots (DBS) with HPLC-MS/MS, and show that this reliably separates MPS I, II and MPS III newborns from controls and heterozygotes. METHODS: Newborn DBS of 11 MPS I, 1 MPS II, and 6 MPS III patients, with phenotypes ranging from severe to relatively attenuated, were collected and levels of dermatan and heparan sulfate derived disaccharides in these DBS were compared with levels in DBS of newborn MPS I and MPS III heterozygotes and controls. RESULTS: The levels of dermatan and heparan sulfate derived disaccharides were clearly elevated in all newborn DBS of MPS I, II and III patients when compared to controls. In contrast, DBS of MPS I and III heterozygotes showed similar disaccharide levels when compared to control DBS. CONCLUSIONS: Our study demonstrates that measurement of heparan and dermatan sulfate derived disaccharides in DBS may be suitable for NBS for MPS I, II and MPS III. We hypothesize that this same approach will also detect MPS VI, and VII patients, as heparan sulfate and/or dermatan sulfate is also the primary storage products in these disorders. PMID- 23084434 TI - Novel nitric oxide-releasing isochroman-4-one derivatives: Synthesis and evaluation of antihypertensive activity. AB - By coupling nitric oxide (NO)-donor moieties with a natural antihypertensive product (+/-)-7,8-dihydroxy-3-methyl-isochroman-4-one [(+/-)-XJP] and its analogue (+/-)-XJP-B, a series of novel NO-releasing isochroman-4-one derivatives were designed and synthesized. The NO-releasing assay indicated that compounds Ia, Id, IIIb and IIIe released the maximum amount of NO. The maximum reductions of blood pressure of Ia, IIIb and IIIe in SHRs were nearly 40%, which was obviously superior to that of the lead compounds and comparable to that of reference drug captopril. These results suggested that NO-donor/natural product hybrids may provide a promising approach for the discovery of novel antihypertensive agents. PMID- 23084435 TI - Synthesis of N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides as new selective ligands for sigma receptors. AB - Novel benzofuran-2-carboxamide ligands, which are selective for sigma receptors, have been synthesized via a microwave-assisted Perkin rearrangement reaction and a modified Finkelstein halogen-exchange used to facilitate N-alkylation. The ligands synthesized are the 3-methyl-N-phenyl-N-(3-(piperidin-1 yl)propyl)benzofuran-2-carboxamides (KSCM-1, KSCM-5 and KSCM-11). The benzofuran 2-carboxamide structure was N-arylated and N-alkylated to include both N-phenyl and N-(3-(piperidin-1-yl)propyl substituents, respectively. These new carboxamides exhibit high affinity at the sigma-1 receptor with K(i) values ranging from 7.8 to 34nM. Ligand KSCM-1 with two methoxy substituents at C-5 and C-6 of the benzofuran ring, and K(i)=27.5nM at sigma-1 was found to be more selective for sigma-1 over sigma-2. PMID- 23084436 TI - [Impact of cataract surgery on central macular thickness in diabetic patients without diabetic retinopathy]. AB - PURPOSE: To determine whether cataract surgery increases macular thickness in diabetic patients without preoperative retinopathy or macular edema. PATIENTS AND METHODS: In a prospective, non-controlled study, we compared preoperative macular thickness as measured by OCT to that measured 3 and 6 months after cataract surgery. RESULTS: Thirty-six eyes of 21 patients (ten men and 11 women) were included in the study from November 2008 to May 2009. Mean foveolar thickness measured preoperatively was 198 MUm (+/- 18.5 MUm) compared with 202 MUm (+/-17.2 MUm) 3 months postoperatively and 212 MUm (+/- 18.9 MUm) 6 months postoperatively. DISCUSSION: In our study, we do not show a significant increase in central foveolar thickness 3 months after cataract surgery; however, we do measure a significant increase at 6 months. This increase in thickness is similar to that found in the literature after cataract surgery in a non-diabetic population. CONCLUSION: Cataract surgery in diabetic patients without preoperative retinopathy does not appear to induce significant macular thickening compared to non-diabetic patients. The period prior to any diabetic retinopathy or maculopathy seems to be the most amenable to cataract surgery when necessary. PMID- 23084437 TI - [Angioid streaks complicated by choroidal neovascularization secondary to pseudoxanthoma elasticum: diagnosis and treatment. Case report]. AB - Angioid streaks represent linear breaks in Bruch's membrane secondary to a change in the elastic layer. They are often associated with pseudoxanthoma elasticum. We report the case of a 36-year-old man with no prior history who was seen for a macular problem in the left eye, eventually involving the right eye after 3 months. He was diagnosed with pseudoxanthoma elasticum, associated with angioid streaks, complicated by choroidal neovascularization in both eyes. He was treated with intravitreal ranibizumab injections (0.5 mg/0.05 mL). His course in the right eye was remarkable for stable improvement at 3 months after the final injection. In the left eye, after initial improvement, recurrence was noted 2.5 months after injection, with subfoveal progression of the choroidal neovascularisation, unresponsive to a fourth ranibizumab injection. Angioid streaks represent a degenerative retinal pathology of elastic tissue with the potential for ingrowth of choroidal neovascularization. Various therapeutic approaches such as photodynamic therapy or laser photocoagulation have been proposed, with variable and sometimes limited results. Intravitreal ranibizumab injections currently remain the best treatment and should be studied with a longer-term, larger series. PMID- 23084438 TI - Does telephone lactation counselling improve breastfeeding practices? A randomised controlled trial. AB - BACKGROUND: Exclusive breastfeeding rates in Malaysia remains low despite the implementation of the Baby Friendly Hospital Initiative (BFHI) policy in government hospitals. It has been suggested that any form of postnatal lactation support will lead to an increase in exclusive breastfeeding rates. OBJECTIVE: To study the effectiveness of telephone lactation counselling on breastfeeding practices. DESIGN: Single blinded, randomised controlled trial (RCT). SETTING: Maternity wards in a public hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: 357 mothers, each of whom had delivered a full term, healthy infant via spontaneous vaginal delivery. METHODS: Mothers were followed up for 6 months. The intervention group (n=179) received lactation counselling via telephone twice monthly by certified lactation counsellors in addition to receiving the current conventional care of postnatal breastfeeding support. The control group (n=178) received the current conventional care of postnatal breastfeeding support. Definitions of breastfeeding practices were according to World Health Organization (WHO) definitions. Participants answered a self-administered questionnaire during recruitment and were later followed up at one, four and 6 month intervals during the postpartum period via a telephone-based questionnaire. RESULTS: At 1 month, a higher percentage of mothers in the intervention group practiced exclusive breastfeeding, compared to the control group (84.3% vs. 74.7%, OR 1.825 95%, p=0.042, CI=1.054, 3.157). At 4 and 6 months postpartum, similar percentages of mothers from the two groups practiced exclusive breastfeeding (41.98% vs. 38.99%; 12.50% vs. 12.02%, no significant differences, both p>0.05). Slightly higher numbers of mothers in the control group had completely stopped breastfeeding at the 1, 4 and 6 month marks, compared to the intervention group (7.4% vs. 5.4%; 12.6% vs. 9.9%; 13.9% vs. 9.4%; all p>0.05). The reason cited by most mothers who had completely stopped breastfeeding during the early postpartum period was a low breast milk supply, while returning to work was the main reason for stopping breastfeeding later in the postpartum period. CONCLUSIONS: Telephone lactation counselling provided by certified lactation counsellors from the nursing profession was effective in increasing the rate of exclusive breastfeeding for the first postpartum month but not during the 4 and 6month postpartum intervals. PMID- 23084439 TI - Surgery: never too old to be treated. PMID- 23084440 TI - Our genomic future. PMID- 23084441 TI - 15 years of APOC--a lifetime of public health evidence. PMID- 23084443 TI - Jimmy Volmink: shaping the evidence base in South Africa. PMID- 23084444 TI - Magnesium for aneurysmal subarachnoid haemorrhage. PMID- 23084445 TI - Magnesium for aneurysmal subarachnoid haemorrhage. PMID- 23084447 TI - Epidemiology of multimorbidity. PMID- 23084449 TI - Epidemiology of multimorbidity. PMID- 23084450 TI - Physical activity for people with disabilities. PMID- 23084451 TI - Twin earthquakes in northwest Iran. PMID- 23084452 TI - Aboriginal infant mortality rate in Canada. PMID- 23084453 TI - International health regulations in the occupied Palestinian territory. PMID- 23084454 TI - Increase in serious ecstasy-related incidents in the Netherlands. PMID- 23084455 TI - In search of dignity. PMID- 23084456 TI - Making Alzheimer's and dementia research fit for populations. PMID- 23084457 TI - Persistent hiccups followed by cardiorespiratory arrest. PMID- 23084458 TI - Synapse dysfunction in autism: a molecular medicine approach to drug discovery in neurodevelopmental disorders. AB - Autism and autism spectrum disorders (ASDs) affect millions of individuals worldwide. Despite increased autism diagnoses over the past 30 years, therapeutic intervention is often 'trial and error'. This approach has identified some beneficial agents, but complex heterogeneous disorders require a more personalized treatment regimen. Many ASD risk factors are genetic, implicating impaired synaptic development and function. Monogenetic disorders (e.g., fragile X syndrome, Rett syndrome, and neurofibromatosis) that have phenotypic overlap with autism provide insights into ASD pathology through the identification novel drug targets (e.g., glutamatergic receptors). Encouragingly, some of these novel drug targets provide symptomatic improvement, even in patients who have lived with ASDs for protracted periods of time. Consequently, a targeted drug discovery approach is expected to deliver improved agents for the treatment and management of ASDs. Here, we review the opportunities and challenges in drug development for autism and provide insight into the neurobiology of ASDs. PMID- 23084459 TI - Refinements in osteotomy design to improve structural integrity: a finite element analysis study. AB - Osteotomy cuts are typically made using a saw, and the meeting point acts as a focus for the concentration of stress and failure. We have studied the impact of different designs of osteotomy cut. Cadaver sheep tibias were scanned by computed tomography (CT) and transformed into a computer-aided design (CAD) model. A standard marginal resection defect was created and then modified, and a finite element analysis made. The relative stress concentrations at the intersection of osteotomy cuts were recorded using principal stresses S1, S3, and von Mises stress, von Mises under both 4-point bending and torsion testing. The osteotomy designs studied were: right-angled and bevelled osteotomy end cuts, overcutting, and a stop drill hole. Peak stress values for 4-point bending and torsion were 24 30% greater at the right-angled osteotomy than the bevelled end cut. Overcutting dramatically increased peak stress values caused by bending and torsion by 48% and 71%, respectively. Substantially lower concentrations of stress were noted with a stop hole using both a 90 degrees (bending 38% and torsion 56%), and a tangential (bending 58% and torsion 60%) cut. A bevelled osteotomy has substantially lower concentrations of stress than a right-angled osteotomy. It is important to avoid creating an overcut as this causes an appreciable increase in the concentration of stress, while a stop drill hole substantially reduces the stress. The creation of a stop hole and the use of judicious bevelling techniques are modifications in the design of an osteotomy that are readily applicable to surgical practice. PMID- 23084460 TI - The associative-semantic network for words and pictures: effective connectivity and graph analysis. AB - Explicit associative-semantic processing of words and pictures activates a distributed set of brain areas that has been replicated across a wide range of studies. We applied graph analysis to examine the structure of this network. We determined how the left ventral occipitotemporal transition zone (vOT) was connected to word-specific areas. A modularity analysis discerned four communities: one corresponded to the classical perisylvian language system, including superior temporal sulcus (STS), middle temporal gyrus (GTm) and pars triangularis of the inferior frontal gyrus (GFi), among other nodes. A second subsystem consisted of vOT and anterior fusiform gyrus along with hippocampus and intraparietal sulcus. The two subsystems were linked through a unique connection between vOT and GTm, which were hubs with a high betweenness centrality compared to STS and GFi which had a high local clustering coefficient. Graph analysis reveals novel insights into the structure of the network for associative-semantic processing. PMID- 23084461 TI - Effect of intense functional task training upon temporal structure of variability of upper extremity post stroke. AB - STUDY DESIGN: Quasi-experimental design. INTRODUCTION: Although the effectiveness of constraint-induced movement therapy (CIMT) in upper extremity (UE) rehabilitation post stroke is well known, the efficacy of CIMT to enhance the temporal structure of variability in upper extremity movement is not known. PURPOSE: The purpose of this study was to investigate whether CIMT could enhance the temporal structure of variability in upper extremity movement in individuals with chronic stroke. METHODS: Six participants with chronic stroke underwent CIMT for 4 h/day for 2 weeks. Participants performed three trials of functional reach to-grasp before and after CIMT. Temporal structure of variability was determined by calculating approximate entropy (ApEn) in shoulder, elbow and wrist flexion/extension joint angles. RESULTS: ApEn increased post CIMT, however, statistical significance was not achieved (p > 0.0167). CONCLUSION: Future studies with larger sample size are warranted to investigate the effect of CIMT upon temporal structure of variability in UE movement. LEVEL OF EVIDENCE: 4. PMID- 23084462 TI - A critical evaluation and a search for the ideal colonoscopic preparation. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of various bowel preparations in accomplishing colonic cleansing for optimal mucosal visualization during colonoscopy. METHODS: The study included a cohort of 980 patients who underwent colonoscopy at our endoscopy center within the last 3 years. All of the study patients were subdivided into four groups. Each group included 245 patients, all receiving a different type of bowel preparation. The bowel preparations used in this study included: magnesium citrate (Group I), a combination of oral sodium phosphate (fleets) and powder PEG-3350 (Group II), powder polyethylene glycol-3350 (PEG-3350 powder for Group III), and oral sodium phosphate (fleets for Group IV). A Colon Prep Score (CPS) was devised to compare the quality of the different bowel preparations used. The colonoscopy results from all of these patients were tabulated and analyzed statistically and expressed as mean +/- 1 standard deviation. Statistical analysis was performed using a one way ANOVA with Holm-Sidak method for intergroup analysis. RESULTS: Group I patients received magnesium citrate and had a mean CPS +/- 1 SD of 3.11 +/- 0.91. Group II patients (fleets and powder PEG-3350 combination) achieved a CPS of 3.37 +/- 1.16. The patients in Group III (powder PEG-3350) actually showed the highest mean CPS of 3.44 +/- 1.12. Group IV patients who used oral sodium phosphate alone reached a mean CPS of 3.23 +/- 1.01. Group III patients (powder PEG-3350 only) demonstrated a statistically higher CPS (P<0.0006) in colon cleansing as compared to Group I patients (magnesium citrate). Similarly, Group II patients (oral sodium phosphate and powder PEG-3350 combination) also showed improved colon cleansing statistically (P<0.006) as compared to Group I patients (magnesium citrate). CONCLUSIONS: Overall, all four colon preparations achieved an average CPS greater than 3.0 indicating clinically adequate colonic cleansing. However, powder PEG-3350 alone and in combination with oral sodium phosphate was observed to be statistically superior to magnesium citrate, when used for colon preparation for colonoscopy. PMID- 23084463 TI - Correlation between interleukin-6 and ammonia in patients with overt hepatic encephalopathy due to cirrhosis. AB - OBJECTIVE: Previous studies have shown that elevated serum levels of interleukin 6 (IL-6) correlate with the severity of overt hepatic encephalopathy (OHE) in cirrhotic patients. However, the correlation between serum IL-6 levels and plasma ammonia levels in these patients remains unclear. Therefore, the present study investigated this correlation between both variables in cirrhotic patients with OHE. METHODS: Fifty-five cirrhotic patients with various grades of OHE, 29 cirrhotic patients without OHE, and 30 healthy controls were recruited. Concentrations of plasma ammonia and serum IL-6 were simultaneously measured. RESULTS: In cirrhotic patients with OHE, the severity of OHE, represented by the West Haven criteria, correlated with serum IL-6 levels (r=0.43, P<0.05) and plasma ammonia levels (r=0.59, P<0.05). IL-6 and ammonia were found to be significant independent predictors of OHE severity (P<0.05 for both variables). Furthermore, the severity of liver cirrhosis, determined by Child-Pugh scores, correlated with serum IL-6 levels (r=0.45, P<0.05) and plasma ammonia levels (r=0.68, P<0.05) in these patients. Moreover, there was a significant positive correlation between serum IL-6 levels and plasma ammonia levels (r=0.58, P<0.05) in cirrhotic patients with OHE, but not in patients without OHE (r=0.42, P>0.05) or healthy controls (r=0.27, P>0.05). The correlation between IL-6 and ammonia was independent of infectious precipitating factors. CONCLUSIONS: The results of the present study suggest that IL-6 might be involved in the mechanism by which ammonia contributes to the pathogenesis of OHE. There is also evidence of a potential synergistic interaction between proinflammatory cytokines and ammonia in the pathogenesis of OHE. PMID- 23084464 TI - Body dissatisfaction from adolescence to young adulthood: findings from a 10-year longitudinal study. AB - Given mixed findings regarding the unique trajectories of female and male adolescents' body dissatisfaction over time, comprehensive longitudinal examinations are needed. This 10-year longitudinal, population-based study, with 1902 participants from diverse ethnic/racial and socioeconomic backgrounds in the Minneapolis/St. Paul metropolitan area, examined changes in body dissatisfaction from adolescence to young adulthood. Results revealed that: (a) female and male participants' body dissatisfaction increased between middle and high school, (b) body dissatisfaction increased further during the transition to young adulthood, and (c) this increase was associated with an increase in BMI over time, such that the upward trend in body dissatisfaction became nonsignificant when BMI was controlled. These results highlight a trend in which diverse female and male youth are increasingly dissatisfied with their bodies as their BMI increases from middle school to young adulthood, and emphasize the need for targeted prevention efforts to intervene in this trajectory and mitigate potential harm. PMID- 23084465 TI - UV-B exposure, ROS, and stress: inseparable companions or loosely linked associates? AB - Ultraviolet-B (UV-B) radiation has long been perceived as a stressor. However, a conceptual U-turn has taken place, and UV-B damage is now considered rare. We question whether UV-stress and UV-B-induced reactive oxygen species (ROS) are still relevant concepts, and if ROS-mediated signaling contributes to UV-B acclimation. Measurements of antioxidants and of antioxidant genes show that both low and high UV-B doses alter ROS metabolism. Yet, there is no evidence that ROS control gene expression under low UV-B. Instead, expression of antioxidant genes is linked to the UV RESISTANCE LOCUS 8 pathway. We hypothesize that low UV-B doses cause 'eustress' (good stress) and that stimuli-specific signaling pathways pre-dispose plants to a state of low alert that includes activation of antioxidant defenses. PMID- 23084466 TI - Shade tolerance: when growing tall is not an option. AB - Two different plant strategies exist to deal with shade: shade avoidance and shade tolerance. All shade-exposed plants optimize photosynthesis to adapt to the decrease in light quality and quantity. When shaded, most species in open habitats express the shade-avoidance syndrome, a growth response to escape shade. Shade-tolerant species from forest understories cannot outgrow surrounding trees and adopt a tolerance response. Unlike shade avoidance, virtually nothing is known about regulation of shade tolerance. In this opinion article, we discuss potential modes of molecular regulation to adopt a shade-tolerance rather than a shade-avoidance strategy. We argue that molecular approaches using model and non model species should help identify the molecular pathways that underpin shade tolerance, thus providing knowledge for further crop improvement. PMID- 23084468 TI - Metagenomic insights into chlorination effects on microbial antibiotic resistance in drinking water. AB - This study aimed to investigate the chlorination effects on microbial antibiotic resistance in a drinking water treatment plant. Biochemical identification, 16S rRNA gene cloning and metagenomic analysis consistently indicated that Proteobacteria were the main antibiotic resistant bacteria (ARB) dominating in the drinking water and chlorine disinfection greatly affected microbial community structure. After chlorination, higher proportion of the surviving bacteria was resistant to chloramphenicol, trimethoprim and cephalothin. Quantitative real time PCRs revealed that sulI had the highest abundance among the antibiotic resistance genes (ARGs) detected in the drinking water, followed by tetA and tetG. Chlorination caused enrichment of ampC, aphA2, bla(TEM-1), tetA, tetG, ermA and ermB, but sulI was considerably removed (p < 0.05). Metagenomic analysis confirmed that drinking water chlorination could concentrate various ARGs, as well as of plasmids, insertion sequences and integrons involved in horizontal transfer of the ARGs. Water pipeline transportation tended to reduce the abundance of most ARGs, but various ARB and ARGs were still present in the tap water, which deserves more public health concerns. The results highlighted prevalence of ARB and ARGs in chlorinated drinking water and this study might be technologically useful for detecting the ARGs in water environments. PMID- 23084467 TI - Expression profile of drosomycin-like defensin in oral epithelium and oral carcinoma cell lines. AB - OBJECTIVE: Drosomycin-like defensin (DLD) is a recently discovered antimicrobial peptide mainly active against filamentous fungi. The present study investigated the expression profile of DLD in oral epithelium and oral squamous cell carcinoma (SCC) cell lines. METHODS: Tissue sections of human oral mucosa, keratinocytes derived from oral mucosa (NOK) and eight kinds of SCC cell lines were used. In situ hybridization was performed on tissue sections of oral mucosa. Expression levels of DLD in the cells were observed by reverse transcription polymerase chain reaction (RT-PCR) and real-time RT-PCR assays. The cells were treated with IL-1beta, IL-8 and TNF-alpha, and agonists for TLR2, TLR4 and beta-glucan. DLD expression in cells was increased and decreased by the DLD gene and its siRNA transfection, respectively. The proliferation rates were assessed by cell counting. RESULTS: By means of in situ hybridization, DLD mRNA positive staining was detected in the epithelial layer of the oral mucosa. An RT-PCR assay confirmed the expression of DLD mRNA in keratinocytes derived from oral epithelium. Expression of DLD in two out of eight cell lines was significantly lower than in NOK cells. The expression levels of DLD mRNA were not significantly changed in the cells stimulated with any cytokines or agonists. The cell proliferation rate where there was decreased expression of DLD was significantly lower than in the control. CONCLUSION: DLD may be partially involved in the defence against filamentous fungal infection in the oral mucosa, and may also serve other functions, such as contribution to cell growth. PMID- 23084469 TI - Recruitment of medically fragile children and adolescents: lessons learned from qualitative research. PMID- 23084470 TI - Can a complete fetal echocardiogram be performed at 12 to 16 weeks' gestation? AB - BACKGROUND: The aim of this study was to determine the feasibility of performing complete early fetal echocardiography (FE) at <17 weeks of gestation with comparison with standard FE in the midtrimester (17-23 weeks). METHODS: Fetal echocardiograms obtained in pregnancies studied at <17 weeks at the University of California, San Francisco, over a 5-year period were retrospectively reviewed. FE was considered complete if anatomic details could be assessed (systemic and pulmonary venous connections and atrial, ventricular, and septal [four-chamber sweeps], outflow and great artery, branch pulmonary artery, and arch anatomy) and if color and pulsed Doppler evaluations of the inferior vena cava, pulmonary veins, ventricular inflows and outflows, umbilical artery and vein, and ductus venosus were demonstrated. RESULTS: One hundred thirty-nine pregnancies were assessed by early FE at <17 weeks transabdominally during the study period (median gestational age, 14.0 weeks; range, 12-0/7-16-6/7 weeks). Additional transvaginal imaging was performed in 14 of 139 (10%) of early fetal echocardiographic studies. One hundred thirteen pregnancies were assessed using both early and later, standard (>17 weeks) FE. Of these, complete fetal echocardiograms were obtained in 27 early (24%; 95% confidence interval [CI], 17% 33%) and 76 later (67%; 95% CI, 58%-75%) exams. In most early exams, color and pulsed Doppler interrogation of the pulmonary veins was unsuccessful. If pulmonary vein Doppler assessment was excluded, complete studies were performed in 80 early exams (71%; 95% CI, 62%-78%) and 97 standard midtrimester exams (86%; 95% CI, 78%-91%). On early FE, heart disease was suspected in 20 pregnancies, and although no major congenital heart disease was missed, in four pregnancies, ventricular septal defects were found only on later FE or after birth. CONCLUSIONS: Early FE yields nearly complete information (exclusive of pulmonary venous interrogation) in the majority of patients. PMID- 23084471 TI - The role of intravenous catheters in cardiovascular implantable electronic device infections: identifying potential targets for prevention. AB - Infections related to cardiac implantable electronic devices (CIEDs) are increasing in prevalence and carry substantial morbidity and mortality. Complications involving peripheral intravenous catheters resulting in CIED infections have not yet been investigated and may pose an important risk factor. We report 5 cases of CIED infection related to documented complications of peripheral vascular devices. PMID- 23084472 TI - Chromobacterium violaceum: a potential nosocomial pathogen. PMID- 23084473 TI - Successful multifaceted intervention aimed to reduce short peripheral venous catheter-related adverse events: a quasiexperimental cohort study. AB - BACKGROUND: Data concerning the effectiveness of strategies implemented to reduce short peripheral vein catheter (PVC)-related adverse events are scarce. METHODS: A quasiexperimental study (2004-2011) was conducted to evaluate an intervention to reduce peripheral vein phlebitis (PVP) and PVC-related bloodstream infections (BSIs). Bundle intervention consisted of health care worker education and training, withdrawal of unnecessary catheters, exchange catheter policy, withdrawal of catheters at early stages of PVP, use of scales as a measuring tool, and repeated period-prevalence surveillance of PVC adverse events on wards. A Poisson exponentially weighted moving average control chart was used to assess time series analysis. RESULTS: One thousand six hundred thirty-one patients with 2,325 short catheters inserted were prospectively followed. PVP decreased by 48% (12.1% [95% confidence interval (CI): 10.7-13.2] during the intervention period versus 23.3% [95% CI: 16.4-30.1] in preintervention period; P < .05), and no reduction of PVP measured as 1,000 catheter-days was noted (48.6 [95% CI: 46.1 51.2] vs 37.9 [95% CI: 24.5-51.4], P > .05). A significant incidence reduction in PVC-related BSIs and health care-acquired Staphylococcus aureus BSIs was also achieved. CONCLUSION: A comprehensive multifaceted hospital approach was successful in reducing PVC-related adverse effects. Poisson exponentially weighted moving average control chart fits well as time series using Poisson data when very few events are present. PMID- 23084474 TI - Evaluation of a universal vs a targeted hepatitis C virus screening strategy among pregnant women at the Vienna University Hospital. AB - A universal vs a targeted hepatitis C virus (HCV) screening policy for identifying pregnant women with the virus were compared. Universal screening did not yield significantly more identification of patients with HCV than targeted screening. However, 14 of 67 (21%) women with confirmed HCV would not have been detected by targeted risk-based HCV screening. PMID- 23084475 TI - Reduced toxicity with intensity modulated radiation therapy (IMRT) for desmoplastic small round cell tumor (DSRCT): an update on the whole abdominopelvic radiation therapy (WAP-RT) experience. AB - PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare malignancy typically involving the peritoneum in young men. Whole abdominopelvic radiation therapy (WAP-RT) using conventional 2-dimensional (2D) radiation therapy (RT) is used to address local recurrence but has been limited by toxicity. Our objectives were to assess the benefit of intensity modulated radiation therapy (IMRT) on toxicity and to update the largest series on radiation for DSRCT. METHODS AND MATERIALS: The records of 31 patients with DSRCT treated with WAP-RT (22 with 2D RT and 9 with IMRT) between 1992 and 2011 were retrospectively reviewed. All received multi-agent chemotherapy and maximal surgical debulking followed by 30 Gy of WAP-RT. A further focal boost of 12 to 24 Gy was used in 12 cases. Boost RT and autologous stem cell transplantation were nearly exclusive to patients treated with 2D-RT. Toxicities were assessed with the Common Terminology Criteria for Adverse Events. Dosimetric analysis compared IMRT and simulated 2D-RT dose distributions. RESULTS: Of 31 patients, 30 completed WAP-RT, with a median follow up after RT of 19 months. Acute toxicity was reduced with IMRT versus 2D-RT: P=.04 for gastrointestinal toxicity of grade 2 or higher (33% vs 77%); P=.02 for grade 4 hematologic toxicity (33% vs 86%); P=.01 for rates of granulocyte colony stimulating factor; and P=.04 for rates of platelet transfusion. Post treatment red blood cell and platelet transfusion rates were also reduced (P=.01). IMRT improved target homogeneity ([D05-D95]/D05 of 21% vs 46%) and resulted in a 21% mean bone dose reduction. Small bowel obstruction was the most common late toxicity (23% overall). Updated 3-year overall survival and progression-free survival rates were 50% and 24%, respectively. Overall survival was associated with distant metastasis at diagnosis on multivariate analysis. Most failures remained intraperitoneal (88%). CONCLUSIONS: IMRT for consolidative WAP-RT in DSRCT improves hematologic toxicity in particular. Although the long-term efficacy of current treatment options remains disappointing, the improved therapeutic index of IMRT may aid in generalizing its use and allowing the addition of novel approaches such as intraperitoneal immunotherapy. PMID- 23084476 TI - Cytoplasmic STAT3 represses autophagy by inhibiting PKR activity. AB - In a screen designed to identify novel inducers of autophagy, we discovered that STAT3 inhibitors potently stimulate the autophagic flux. Accordingly, genetic inhibition of STAT3 stimulated autophagy in vitro and in vivo, while overexpression of STAT3 variants, encompassing wild-type, nonphosphorylatable, and extranuclear STAT3, inhibited starvation-induced autophagy. The SH2 domain of STAT3 was found to interact with the catalytic domain of the eIF2alpha kinase 2 EIF2AK2, best known as protein kinase R (PKR). Pharmacological and genetic inhibition of STAT3 stimulated the activating phosphorylation of PKR and consequent eIF2alpha hyperphosphorylation. Moreover, PKR depletion inhibited autophagy as initiated by chemical STAT3 inhibitors or free fatty acids like palmitate. STAT3-targeting chemicals and palmitate caused the disruption of inhibitory STAT3-PKR interactions, followed by PKR-dependent eIF2alpha phosphorylation, which facilitates autophagy induction. These results unravel an unsuspected mechanism of autophagy control that involves STAT3 and PKR as interacting partners. PMID- 23084477 TI - Automation synthesis modules review. AB - The introduction of (68)Ga labelled tracers has changed the diagnostic approach to neuroendocrine tumours and the availability of a reliable, long-lived (68)Ge/(68)Ga generator has been at the bases of the development of (68)Ga radiopharmacy. The huge increase in clinical demand, the impact of regulatory issues and a careful radioprotection of the operators have boosted for extensive automation of the production process. The development of automated systems for (68)Ga radiochemistry, different engineering and software strategies and post processing of the eluate were discussed along with impact of automation with regulations. PMID- 23084478 TI - Lower limbs composition and radiographic knee osteoarthritis (RKOA) in Chingford sample--a longitudinal study. AB - Our aim in this longitudinal study was to evaluate to what extent fat and lean tissue mass variations are associated and can predict RKOA in a large sample of British women followed-up over 10 years. Kellgren/Lawrence (K/L), joint space narrowing (JSN) and osteophyte (OSP) grades were scored from radiographs of both knees in 909 middle-aged women from the Chingford registry. Body composition components were assessed using the dual energy X-ray absorptiometry (DXA) method. In cross-sectional analysis, combined effect of age, BMI and leg tissue composition was required for best fitting model explaining variations of K/L scoring and osteophytes at lateral compartment. To explain medial osteophytes, age and BMI were sufficient to generate the best fitting model. In prediction analysis, leg lean mass was the more powerful predictor of K/L, medial osteophytes than BMI. In conclusion, BMI appears to influence the development of knee OA through both fat and/or lean mass, depending on RKOA phenotype. PMID- 23084479 TI - Pseudoxanthoma elasticum. PMID- 23084480 TI - Postoperative radiation for prostate cancer. PMID- 23084481 TI - Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911). AB - BACKGROUND: We report the long-term results of a trial of immediate postoperative irradiation versus a wait-and-see policy in patients with prostate cancer extending beyond the prostate, to confirm whether previously reported progression free survival was sustained. METHODS: This randomised, phase 3, controlled trial recruited patients aged 75 years or younger with untreated cT0-3 prostate cancer (WHO performance status 0 or 1) from 37 institutions across Europe. Eligible patients were randomly assigned centrally (1:1) to postoperative irradiation (60 Gy of conventional irradiation to the surgical bed for 6 weeks) or to a wait-and see policy until biochemical progression (increase in prostate-specific antigen >0.2 MUg/L confirmed twice at least 2 weeks apart). We analysed the primary endpoint, biochemical progression-free survival, by intention to treat (two-sided test for difference at alpha=0.05, adjusted for one interim analysis) and did exploratory analyses of heterogeneity of effect. This trial is registered with ClinicalTrials.gov, number NCT00002511. FINDINGS: 1005 patients were randomly assigned to a wait-and-see policy (n=503) or postoperative irradiation (n=502) and were followed up for a median of 10.6 years (range 2 months to 16.6 years). Postoperative irradiation significantly improved biochemical progression-free survival compared with the wait-and-see policy (198 [39.4%] of 502 patients in postoperative irradiation group vs 311 [61.8%] of 503 patients in wait-and-see group had biochemical or clinical progression or died; HR 0.49 [95% CI 0.41 0.59]; p<0.0001). Late adverse effects (any type of any grade) were more frequent in the postoperative irradiation group than in the wait-and-see group (10 year cumulative incidence 70.8% [66.6-75.0] vs 59.7% [55.3-64.1]; p=0.001). INTERPRETATION: Results at median follow-up of 10.6 years show that conventional postoperative irradiation significantly improves biochemical progression-free survival and local control compared with a wait-and-see policy, supporting results at 5 year follow-up; however, improvements in clinical progression-free survival were not maintained. Exploratory analyses suggest that postoperative irradiation might improve clinical progression-free survival in patients younger than 70 years and in those with positive surgical margins, but could have a detrimental effect in patients aged 70 years or older. FUNDING: Ligue Nationale contre le Cancer (Comite de l'Isere, Grenoble, France) and the European Organisation for Research and Treatment of Cancer (EORTC) Charitable Trust. PMID- 23084482 TI - Early onset prosthetic hip and knee joint infection: treatment and outcomes in Victoria, Australia. AB - BACKGROUND: Prosthetic joint infection (PJI) remains a devastating complication of arthroplasty. There are no internationally endorsed consensus management guidelines and treatment approaches differ widely. AIM: The aim of this multicentre study was to examine treatment approaches and predictors of treatment failure in patients with early PJI managed in hospitals in Victoria, Australia. METHODS: This cohort study was conducted across 10 hospitals over a three-year period (January 2006 to December 2008) and involved 147 patients who presented with early PJI. FINDINGS: Most patients (76%) were managed with debridement and retention of the prosthesis. Patients were followed for a median 20 months (interquartile range: 7-36). Overall 43 patients experienced treatment failure with a 12-month infection-free survival estimate of 76% [95% confidence interval (CI): 68-83%]. The following factors were associated with treatment failure: septic revision arthroplasty (hazard ratio: 7.5; 95% CI: 2.4-23.1; P < 0.0001), hypotension at presentation (4.9; 1.5-15.7; P = 0.007), one-stage exchange (3.1; 1.0-9.2; P = 0.048), total duration of antibiotic therapy <90 days: specifically <30 days (18.5; 5.4-63.1; P < 0.001), 30-60 days (8.0; 2.6-23.9; P < 0.001) and 60-90 days (7.3; 2.2-24.4; P = 0.001), respectively. Effective empiric antibiotic therapy was associated with a decreased risk of treatment failure (0.20; 0.09 0.47; P < 0.001). CONCLUSIONS: The management approach in Australia differs from that used elsewhere in the world. We have identified a number of clinically relevant risk factors for treatment failure that may impact on treatment recommendations. PMID- 23084483 TI - Impact of Port-A-Cath device management in cancer patients with candidaemia. AB - This study investigated the impact of management of a totally implantable central venous access port device, Port-A-Cath (Smith Medical, St. Paul, MN, USA), on the outcome of 98 cancer patients with candidaemia. Port-A-Cath retention was found to be significantly associated with poorer outcome, independent of other significant adverse factors [breakthrough candidaemia, Acute Physiology and Chronic Health Evaluation (APACHE) II score >= 21, and worse Eastern Cooperative Oncology Group (ECOG) performance score (3-4)]. However, retention of Port-A-Cath devices could be considered in patients who do not have definite catheter-related candidaemia, are not using total parenteral nutrition, do not have poor ECOG performance scores or APACHE II scores, and do not have septic shock. PMID- 23084484 TI - Synthesis and characterization of new generation open tubular silica capillaries for liquid chromatography. AB - The chromatographic performance gain of open tubular (OT) silica capillaries over packed beds has been demonstrated theoretically. However, experimental progress in the preparative realization of these columns is still lacking behind as thick films are required for a sufficient mass loadability. Here, silica sol-gel chemistry in confined spaces was applied to the preparation of thick-film OT capillaries comprising a mesoporous layer with a thickness of approximately 500 nm covalently attached to the capillary wall. Samples were synthesized varying both in length and inner diameter (ID) and the resulting layer morphology was investigated using scanning electron microscopy. The chromatographic performance of these first generation columns was evaluated by normal phase chromatography utilizing standard capillary-LC equipment. Separations of small molecules in a 15 MUm ID column provided high theoretical plate numbers (up to 170,000) and a good retention capacity within reasonable retention times (<1 h), bearing the unavoidable trade-off between column efficiency and analysis time. PMID- 23084485 TI - Electrophoretic analysis of cations using large-volume sample stacking with an electroosmotic flow pump using capillaries coated with neutral and cationic polymers. AB - To realize the high-performance and simple-operation analysis of cationic compounds in capillary electrophoresis, we investigated large-volume sample stacking with an electroosmotic flow pump (LVSEP) using capillaries with hydrophilic and weakly cationic inner surface. Three capillary modification methods were employed: thermally passivated physical coating with polymer mixture of poly(vinyl alcohol) and poly(allylamine); covalent modification with random copolymer of acryl amide and 3-(methacryloylamino)propyltrimethylammonium chloride; easily preparable physical coating with dimethyldioctadecylammonium bromide and polyoxyethylene stearate. In these capillaries, the electroosmotic flow (EOF) was well suppressed in the high ionic strength (I) electrolyte under the acidic and basic pH, whereas the EOF was enhanced in the low I electrolyte, indicating a suitable EOF property for the rapid LVSEP and following separation. In the LVSEP-capillary zone electrophoresis (CZE) analyses of benzylamine and 1 naphthylethylamine, up to 550-fold sensitivity increases were successfully obtained in the three capillaries without significantly reducing the repeatability and resolution. LVSEP-cyclodextrin-modified CZE of chlorpheniramine and brompheniramine was also carried out, resulting in up to 380-fold sensitivity enhancement with keeping the baseline separation for the enantiomers. Finally, we performed the LVSEP-CZE analysis of basic proteins, where up to 100-fold sensitivity increases were achieved, but a peak broadening was observed due to the sample adsorption in the low I sample matrix. PMID- 23084486 TI - Fast low-pressure microwave assisted extraction and gas chromatographic determination of polychlorinated biphenyls in soil samples. AB - A new technology equipment for low-pressure microwave assisted extraction (usually employed for organic chemistry reactions), recently launched in the market, is used for the first time in environmental analysis for the extraction of commercial technical Aroclor mixtures from soil. Certified reference materials of Aroclor 1260, Aroclor 1254 and Aroclor 1242 in transformer oils were used to contaminate the soil samples and to optimize the extraction method as well as the subsequent gas chromatographic electron capture detection (GC-ECD) analytical method. The study was performed optimizing the extraction, the purification and the gas chromatographic separation conditions to enhance the resolution of difficult pairs of congeners (C28/31 and C141/179). After optimization, the recovery yields were included within the range 79-84%. The detection limits, evaluated for two different commercial polychlorinated biphenyl (PCB) mixtures (Aroclor 1260 and Aroclor 1242) were 0.056 +/- 0.001 mg/kg and 0.290 +/- 0.006 mg/kg, respectively. The method, validated with certified soil samples, was used to analyze a soil sample after an event of failure of a pole-mounted transformer which caused the dumping of PCB contaminated oil in soil. Moreover, the method provides simple sample handling, fast extraction with reduced amount of sample and solvents than usually required, and simple purification step involving the use of solvent (cyclohexane) volumes as low as 5 mL. Reliability and reproducibility of extraction conditions are ensured by direct and continuous monitoring of temperature and pressure conditions. PMID- 23084487 TI - Evaluation of a new column backflushing set-up in the gas chromatographic-tandem mass spectrometric analysis of pesticide residues in dietary supplements. AB - This study evaluated the use of a new concurrent backflushing set-up in the multiresidue analysis of pesticides in dietary supplement matrices using gas chromatography-tandem mass spectrometry (GC-MS/MS). The backflushing configuration employed a purged union installed between a short, 5-m long capillary column and a 15-m analytical column of the same column diameter (0.25 mm i.d.), stationary phase type (HP-5MS UI) and film thickness (0.25 MUm). This set-up is more time- and cost-effective than the use of post-run or mid-column backflushing configurations because the backflushing starts as soon as the last analyte elutes from the short column, thus preventing the less volatile matrix components from reaching the longer analytical column and MS source. As opposed to the analysis without backflushing, the column does not need to be kept at a higher temperature for an extended period of time, resulting in about 50% increased sample throughput on the instrument (a run time of 20 min). Optimization of the GC-MS/MS method is discussed in detail, especially when it comes to the selection of MS/MS transitions, optimization of injection conditions using a programmable temperature vaporizer (PTV) inlet in solvent vent mode, and optimization of the backflushing parameters. The optimized method showed very good long-term performance, which was evaluated in a 2.5-day uninterrupted sequence (without any system maintenance) of repeated injections of various dietary supplement extracts containing over one hundred pesticides, mainly those with limits set for herbal drugs and preparations by the U.S. and European Pharmacopoeias. PMID- 23084488 TI - Management of comminuted but continuous mandible defects after gunshot injuries. AB - INTRODUCTION: Firearm injuries continue as a major public health problem, contributing significant morbidity, mortality, and expense to our society. There are four main steps in the management of patients with gunshot wounds to the face: securing an airway, controlling haemorrhage, identifying other injuries and definitive repair of the traumatic facial deformities. The objective of this study was to determine late outcome of two treatment options by open reduction and internal fixation versus closed reduction and maxillomandibular fixation (MMF) in the treatment of gunshot injuries of the mandible. METHODS: Sixty patients of gunshot injury were randomly allocated in two groups. In group A, 30 patients were treated by open reduction and internal fixation and in group B, 30 patients were treated by closed reduction and maxillomandibular fixation. Patients were discharged as the treatment completed and recalled for follow up. Up to 3 months after injury, fortnightly complications like infection, malocclusion, malunion of fractured fragments, facial asymmetry, sequestration of bone and exposed plates were evaluated and the differences between two groups were assessed. The follow-up period ranged from 3 months to 10 months. RESULTS: Patients treated by open reduction tended to have less complications as compared to closed reduction. CONCLUSION: Based on this study open reduction and internal fixation is the best available method for the treatment of gunshot mandible fractures without continuity defect. PMID- 23084489 TI - Congenital high scapula (Sprengel's deformity): four cases. AB - We report a series of four cases of congenital high scapula (or Sprengel's deformity) diagnosed and followed in our establishment. The main feature of this very rare congenital malformation of the pectoral girdle is an abnormally high, more or less dysmorphic scapula. A congenitally high scapula is often discovered in young children, when consequences for aesthetics, and sometimes functional difficulties, are brought to light. When surgical treatment is envisaged, imaging is recommended to diagnose a supernumerary structure, ossified (an omovertebral bone) or not (a fibrous and/or cartilaginous connection), extending from the scapula to the cervical spine. This needs to be resected. A CT scan is essential for detecting an omovertebral bone and the vertebral bone abnormalities that are often associated with it. MRI and ultrasound are very useful for assessing any fibrous and/or cartilaginous components. An ultrasound examination has the undeniable advantage of being quick and easy in these young children. PMID- 23084490 TI - Labour augmentation and fetal outcomes in relation to birth positions: a secondary analysis of an RCT evaluating birth seat births. AB - OBJECTIVE: the aim of this study was to compare the use of synthetic oxytocin for augmentation, duration of labour and birth and infant outcomes in nulliparous women randomised to birth on a birth seat or any other position. STUDY DESIGN: a randomised controlled trial in Sweden where 1002 women were randomised to birth on a birth seat (experimental group) or birth in any other position (control group). Data were collected between November 2006 and July 2009. The outcome measurements included synthetic oxytocin augmentation, duration of the second stage of labour and fetal outcome. Analysis was by intention to treat. SETTING: southern Sweden. FINDINGS: the main findings of this study were that women randomised to the experimental group had a statistically significant shorter second stage of labour than women randomised to the control group. There were no differences between the groups for use of synthetic oxytocin augmentation or for neonatal outcomes. CONCLUSIONS: women allocated to the birth seat had a significantly shorter second stage of labour despite similar numbers of women subjected to synthetic oxytocin augmentation in the study groups. The adverse neonatal outcomes did not differ between groups. The birth seat can be suggested as non-medical intervention used to reduce duration of second stage labour and birth. The birth seat can be suggested as a non-medical intervention that may facilitate reduced duration of the second stage of labour. Furthermore it is recommended that caregivers, both midwives and midwifery students, should learn skills to assist women in using a variety of birth positions. TRIAL REGISTRATION: unique Protocol ID: Dnr 2009/739 (register.clinicaltrials.gov). PMID- 23084491 TI - A qualitative study of women's lived experience after deinfibulation in the UK. AB - OBJECTIVE: to explore women's experiences of deinfibulation and its aftermath. DESIGN: a qualitative study using semi-structured interviews with data collection via audio-recording and field notes. The audio-recorded interviews were transcribed verbatim and analysed using Interpretive Phenomenological Analysis (IPA) method for qualitative data analysis. SETTING: recruitment for the study was carried out in an African Well Women Clinic in London, United Kingdom. PARTICIPANTS: there were nine women participants of Somali and Eritrean origin who had Female Genital Mutilation (FGM) type III previously and underwent deinfibulation between January 2008 and September 2009. FINDINGS: key themes identified were the cultural meaning and social acceptability of deinfibulation; the consequences of deinfibulation within marital relationships; feelings about the appearance of genitalia post deinfibulation and thoughts on reinfibulation. CONCLUSIONS: marital factors and stability of the relationship influence the experience of deinfibulation. Those women who said they had discussed deinfibulation with their husband in advance, and that he had agreed to the procedure, reported less problems afterwards. Single women who had deinfibulation before marriage may face more difficulties in terms of social acceptability within their community. IMPLICATIONS FOR PRACTICE: sensitivity to social consequences of deinfibulation is important as well as recognition that these consequences vary. When deinfibulation is carried out for medical purposes some women may appreciate the offer of an official letter from a health-care practitioner confirming the medical nature of the procedure. The data suggests that deinfibulated women may dislike the new appearance of their genitalia; therefore, the practicality of performing a concurrent minor cosmetic surgery with deinfibulation procedure may need to be examined. The need for further research conducted in women's primary language is pressing and should explore issues such as the situation of single women, men's knowledge of the complications associated with FGM and the benefits of deinfibulation for infibulated women. PMID- 23084492 TI - Clinical outcomes for anaplastic pancreatic cancer: a population-based study. AB - BACKGROUND: Anaplastic pancreatic cancer (APC) is a rare subtype of pancreatic ductal adenocarcinoma (PDA) that can carry a worse overall survival (OS) when compared with other variants. However, the presence of osteoclast-like giant cells (OCGCs) in APC specimens can predict improved OS. The aim of this study was to evaluate the OS of patients with APC (with and without OCGCs) compared with patients with other subtypes of PDA using a population-based registry. STUDY DESIGN: We identified all patients in the Surveillance, Epidemiology and End Results (SEER) database with pathologically confirmed APC and PDA diagnosed between 1988 and 2008. Overall survival was evaluated using Kaplan-Meier and Cox proportional hazard regression. RESULTS: The study cohort included 5,859 (94.3%) patients with PDA and 353 (5.7%) with APC. Overall survival for all patients with APC was significantly worse than for patients with PDA (hazard ratio [HR] = 1.9; 95% CI, 1.7-2.1; p < 0.001); however, in the subgroup of resected patients, APC (n = 81) had similar OS to PDA (n = 3,517) (HR = 0.9; 95% CI, 0.7-1.2; p = 0.37). Patients with APC tumors with OCGCs (n = 11) demonstrated improved OS when compared with all other APC variants without OCGCs (n = 342) (HR = 0.3; 95% CI, 0.1-0.7; p = 0.004), but this survival difference was not observed in the subgroup of resected patients (HR = 0.5; 95% CI, 0.2-1.4; p = 0.18). CONCLUSIONS: Anaplastic pancreatic cancer is a rare malignancy with poor OS. The diagnosis of APC with OCGCs is predictive of improved OS compared with other patients with APC. This survival benefit, however, is not observed in patients with resected disease. PMID- 23084493 TI - Does surgery improve outcomes for esophageal squamous cell carcinoma? An analysis using the surveillance epidemiology and end results registry from 1998 to 2008. AB - BACKGROUND: We examined survival associated with locally advanced esophageal squamous cell cancer (SCC) to evaluate if treatment without surgery could be considered adequate. STUDY DESIGN: Patients in the Surveillance, Epidemiology and End Results Registry (SEER) registry with stage II-III SCC of the mid or distal esophagus from 1998-2008 were grouped by treatment with definitive radiation versus esophagectomy with or without radiation. Information on chemotherapy is not recorded in SEER. Tumor stage was defined as first clinical tumor stage in case of neo-adjuvant therapy and pathological report if no neo-adjuvant therapy was performed. Cancer-specific (CSS) and overall survival (OS) were analyzed using the Kaplan-Meier approach and propensity-score adjusted Cox proportional hazard models. RESULTS: Of the 2,431 patients analyzed, there were 844 stage IIA (34.7%), 428 stage IIB (17.6%), 1,159 stage III (47.7%) patients. Most were treated with definitive radiation (n = 1,426, 58.7%). Of the 1,005 (41.3%) patients who underwent surgery, 369 (36.7%) had preoperative radiation, 160 (15.9%) had postoperative radiation, and 476 (47.4%) had no radiation. Five-year survival was 17.9% for all patients, and 22.1%, 18.5%, and 14.5% for stages IIA, IIB, and stage III, respectively. Compared to treatment that included surgery, definitive radiation alone predicted worse propensity-score adjusted survival for all patients (CSS Hazard Ratio [HR] 1.48, p < 0.001; OS HR 1.46, p < 0.001) and for stage IIA, IIB, and III patients individually (all p values <= 0.01). Compared to surgery alone, surgery with radiation predicted improved survival for stage III patients (CSS HR 0.62, p = 0.001, OS HR 0.62, p < 0.001) but not stage IIA or IIB (all p values > 0.18). CONCLUSIONS: Esophagectomy is associated with improved survival for patients with locally advanced SCC and should be considered as an integral component of the treatment algorithm if feasible. PMID- 23084495 TI - Assessing synoptic reports for pancreatic resection. PMID- 23084496 TI - General surgery resident perceptions. PMID- 23084497 TI - Field triage protocol in elderly trauma patients: what level of care? PMID- 23084498 TI - Board certification and medical school graduates. PMID- 23084501 TI - Appropriate management of flail chest needs proper injury classification. PMID- 23084503 TI - Review of automatic segmentation methods of multiple sclerosis white matter lesions on conventional magnetic resonance imaging. AB - Magnetic resonance (MR) imaging is often used to characterize and quantify multiple sclerosis (MS) lesions in the brain and spinal cord. The number and volume of lesions have been used to evaluate MS disease burden, to track the progression of the disease and to evaluate the effect of new pharmaceuticals in clinical trials. Accurate identification of MS lesions in MR images is extremely difficult due to variability in lesion location, size and shape in addition to anatomical variability between subjects. Since manual segmentation requires expert knowledge, is time consuming and is subject to intra- and inter-expert variability, many methods have been proposed to automatically segment lesions. The objective of this study was to carry out a systematic review of the literature to evaluate the state of the art in automated multiple sclerosis lesion segmentation. From 1240 hits found initially with PubMed and Google scholar, our selection criteria identified 80 papers that described an automatic lesion segmentation procedure applied to MS. Only 47 of these included quantitative validation with at least one realistic image. In this paper, we describe the complexity of lesion segmentation, classify the automatic MS lesion segmentation methods found, and review the validation methods applied in each of the papers reviewed. Although many segmentation solutions have been proposed, including some with promising results using MRI data obtained on small groups of patients, no single method is widely employed due to performance issues related to the high variability of MS lesion appearance and differences in image acquisition. The challenge remains to provide segmentation techniques that work in all cases regardless of the type of MS, duration of the disease, or MRI protocol, and this within a comprehensive, standardized validation framework. MS lesion segmentation remains an open problem. PMID- 23084504 TI - Segmentation with area constraints. AB - Image segmentation approaches typically incorporate weak regularity conditions such as boundary length or curvature terms, or use shape information. High-level information such as a desired area or volume, or a particular topology are only implicitly specified. In this paper we develop a segmentation method with explicit bounds on the segmented area. Area constraints allow for the soft selection of meaningful solutions, and can counteract the shrinking bias of length-based regularization. We analyze the intrinsic problems of convex relaxations proposed in the literature for segmentation with size constraints. Hence, we formulate the area-constrained segmentation task as a mixed integer program, propose a branch and bound method for exact minimization, and use convex relaxations to obtain the required lower energy bounds on candidate solutions. We also provide a numerical scheme to solve the convex subproblems. We demonstrate the method for segmentations of vesicles from electron tomography images. PMID- 23084505 TI - The clinical significance of Nicoletella semolina in horses with respiratory disorders and a screening of the bacterial flora in the airways of horses. AB - Nicoletella semolina, a member of the family Pasteurellaceae, can be isolated from the airways of horses with respiratory disorders. However, its role as a potential or opportunistic pathogen is not clear nor is its presence as part of the normal flora. We therefore investigated the presence and bacterial load of N. semolina in healthy and diseased horses. Samples from a healthy control group were compared with samples from the routine analysis of horses with a clinical history of respiratory disorders. A total of 1770 nose swabs and 1132 tracheal aspirate samples were analysed and subjected to conventional bacteriological examination. N. semolina was isolated from 12 (6%) of 207 nose samples from the healthy control group and from 42 (3%) of 1563 samples from horses with respiratory disorders. In tracheal aspirate, N. semolina was isolated from 7 (3%) of 211 samples from the control group and 49 (5%) of 921 samples from horses with respiratory disorders. Other bacteria were also isolated in laboratory analyses, the most commonly isolated bacterium in both the control group and the respiratory disorders group being Streptococcus equi subsp. zooepidemicus. It was isolated in 21% of tracheal aspirate from the control group and 33% of those from horses with respiratory disorders. In conclusion, N. semolina is not a primary pathogenic bacterium, as it was isolated at similar frequencies in horses with respiratory disorders and those in the healthy control group. PMID- 23084506 TI - Comparative study of the commonly used virulence tests for laboratory diagnosis of ovine footrot caused by Dichelobacter nodosus in Australia. AB - Footrot in sheep and goats is expressed as a spectrum of clinical entities ranging from benign, which is a self limiting interdigital dermatitis to highly virulent, in which severe under running of the horn of the hoof occurs. Interactions between the host, the virulence of the causative strain of Dichelobacter nodosus and environmental conditions determine the severity of the disease. Clinical diagnosis of virulent footrot, which a notifiable disease in some states of Australia, is not always straightforward. Therefore, the gelatin gel and elastase tests for protease activity, and the intA PCR test for an inserted genetic element in D. nodosus are commonly used to support or to confirm a clinical diagnosis. A comparative study of these laboratory tests with a large number of samples collected from 12 flocks of sheep with clinically virulent footrot was conducted. Based on the elastase test, 64% of the isolates tested were classified as virulent compared to 91% on the gelatin gel test and 41% according to the intA test. The agreement between the elastase and the gelatin gel test was low (kappa=0.12) as were the agreements between other tests. Only about 21% of the isolates were virulent in all 3 tests. Therefore these tests on their own may not provide standard and reliable results and are likely to remain as supplementary tests for clinical diagnosis of the disease. PMID- 23084507 TI - Disturbances of basic self and prodromal symptoms among non-psychotic help seeking adolescents. AB - BACKGROUND: The goal of this study was to explore the notion that anomalies of self-experience (ASE) are a core, 'not-yet-psychotic' clinical phenotype of emerging schizophrenia and its spectrum. Method To accomplish this goal, we examined the relationship between ASE and commonly accepted risk markers in a sample of 87 help-seeking, non-psychotic adolescents (aged 14-18 years). ASE were assessed with the Examination of Anomalous Self-Experience (EASE), subclinical psychotic symptoms were assessed with the Prodromal Questionnaire and the Structured Interview for Prodromal Syndromes, deterioration in psychosocial functioning was assessed with the Social and Role Functioning Scales, and level of distress with the Mood and Anxiety Symptoms Questionnaire. RESULTS: About 82 participants completed the entire EASE interview. The number of participants who reported ASE at a clinically meaningful level (n = 18, 22%) was smaller than that who met diagnostic criteria for a prodromal syndrome (n = 28, 34%). The degree of overlap between the two conditions was moderate but statistically significant (chi2 (1) = 7.01, p = 0.008). An exploratory factor analysis revealed that ASE load on a different factor than prodromal symptoms and deterioration in functioning, but that there is a moderate correlation between the three factors. CONCLUSIONS: These results suggest that ASE are prevalent among non-psychotic help-seeking adolescents, yet at a considerably lower rate than prodromal symptoms. In addition, they suggest that ASE and prodromal symptoms constitute distinct but moderately related dimensions of potential risk. Taken together, they provide preliminary support for the clinical usefulness of supplementing and refining the methods of early detection of risk with assessment of ASE. PMID- 23084508 TI - The older person in the emergency department: seeing beyond the frailty. PMID- 23084509 TI - During and beyond the triage encounter: chronically ill elderly patients' experiences throughout their emergency department attendances. AB - BACKGROUND: Chronically ill elderly patients are frequent users of care in emergency departments (EDs). Due to their presenting symptoms, these patients are often assessed on a low urgency level of priority by the triage nurse. AIM: The aim of the study was to explore and describe the experiences of a group of chronically ill elderly patients' during their triage encounter and subsequent ED stay. METHOD: The data consisted of 14 open-ended interviews with chronically ill patients aged between 71 and 90years. A lifeworld approach was used in order to describe the essence of patient experiences. The study was carried out with a descriptive phenomenological research perspective. CONCLUSION: The visit to the ED was experienced as contradictory. The triage encounter fostered confidence and set promising expectations, but during the rest of the visit, the patient felt abandoned and considered the staff to be uncommitted and reluctant. These ambiguous experiences of their ED visits indicate a need for exploring possible ways of improving the situation for the chronically ill older person in ED. PMID- 23084510 TI - Atrial fibrillation in the elderly -- not a benign condition. AB - Atrial fibrillation (AF) is the most commonly seen arrhythmia and its prevalence increases with age. In the general population, rates of 1-2% are reported but in older patients, the rates increase to over 10% (in those aged 85years or older). Many older patients present to the emergency department (ED) with complaints that could be caused or associated with AF including valvular heart disease, hypertension, heart failure, an underlying infection (urinary or chest) and thyroid disorder. The most devastating complication of AF is stroke and early detection of AF and initiation of treatment (specifically the use of anti coagulant medication) can significantly reduce the risk. AF is associated with high healthcare costs and has significant impacts on disability and quality of life especially if a stroke occurs. This review aims to describe the aetiology and treatment options for patients with newly diagnosed and previously diagnosed AF with an emphasis on how ED staff can manage older patients with AF and ensure optimal care is given. The treatment of AF has three main considerations (i) appropriateness for thromboembolic prophylaxis, (ii) rate control (including anti arrhythmics, cardiac glycosides, B blockers and calcium channel blockers) and (iii) rhythm control with traditional cardioversion (either electrically or pharmacologically) or utilising interventional means to maintain sinus rhythm with cardiac surgery and more recently radio-frequency ablation. As anti coagulation is widely implemented, the risks and benefits associated with warfarin and the newer agents will be described. Given that more than half of those with AF are over 75years and 30% of AF is diagnosed incidentally, there is an imperative for prompt diagnosis to reduce the risk of debilitating complications especially stroke. AF should not be viewed as yet another concomitant "benign" condition. Emergency staff are well placed to detect AF and ensure appropriate treatment is commenced to reduce the adverse events associated with it. PMID- 23084511 TI - Differentiating frailty in older people using the Swedish ambulance service: a retrospective audit. AB - The elderly population in Sweden is increasing. This will lead to an increased need for healthcare resources and put extra demands on healthcare professionals. Consequently, ambulance personnel will be faced with the challenge of meeting extra demands from increasing numbers of older people with complex and atypical clinical presentations. Therefore we highlight that great problems exist for ambulance personnel to understand and meet these patients' care needs. Using a caring science approach, we apply the patient's perspective, and the aim of this study is to identify and illuminate the conditions that affect elderly people assessed with the assessment category "general affected health condition". Thus, we have analyzed the characteristics belonging to this specific condition. The method is a retrospective audit, involving a qualitative content analysis of a total of 88 emergency service records. The conclusion is that by using caring science, the concept of frailty which is based on a comprehensive understanding of human life can clarify the state of "general affected health condition", as either illness or ill-health. This offers a new assessment category and outlines care and treatment that strengthen and support the health and wellbeing of the individual elderly person. Furthermore, the concept of frailty ought to be included in "The International Statistical Classification of Diseases and Related Health Problems" (ICD-10). PMID- 23084512 TI - Audit of standards of practice in suspected hip fracture. AB - BACKGROUND: Hip-fracture is a common orthopaedic injury presenting to the Emergency Department, particularly within the elderly population. Standards of practice dictating the care of these patients include the early administration of analgesia and an accurate clinical assessment. Once a hip-fracture has been confirmed with diagnostic-imaging, the patient should be transferred to an orthopaedic ward as soon as possible. These standards have been identified from a range of national policies and evidence-based literature. AIM: To identify standards of best-practice for the care of patients with a suspected hip-fracture in the Emergency Department and to audit compliance with these standards. METHOD: A retrospective-audit of 185 Emergency Department Information System records for adult patients admitted with a suspected hip-fracture was conducted using a purpose-designed data-extraction spread-sheet based on discrete standards of audit. FINDINGS: It was found that the Emergency Department performed well on some audit standards, such as the medical assessment of patients. However, some problems of assessment were identified in relation to pressure-care, the timely transfer of patients to a suitable ward and the delivery of pain-relief. CONCLUSIONS AND RECOMMENDATIONS: There were examples of good practice in this audit, but also areas that require improvement. We recommend that a care bundle be implemented to focus on improvements in pain-relief, pressure-care and fast tracking. PMID- 23084513 TI - The profile and follow-up of patients who attend the Emergency Department following a fall. AB - Falls in the older population are associated with increased morbidity and mortality especially in the absence of risk reduction measures. The study aims were to compare the characteristics of older people who present to the Emergency Department (ED) following a fall with the general older ED population and examine referral patterns following ED discharge. Face-to-face interviews were carried out with 306 people aged 65 years or older. Data was collected on demographic, socio-economic, health and social support factors. Descriptive and inferential statistics (Pearson chi-square test or independent t-test) were used to compare the falls and non-falls group. Falls occurred in 17% (53/306) of the study population and 43% sustained an injury requiring medical intervention. Patients in the falls group were significantly more likely to be female (68%), older (79 years (SD 6.6)) and living alone (59%). The physical and mental health profile of the falls and non-falls group was similar with 30-40% of people in both groups experiencing moderate to severe physical health impairment. A third of the falls group was discharged from the ED without evidence of referrals. CONCLUSION: The older population that present to the ED following a fall requires comprehensive risk factor assessment especially physical function and referrals that include falls prevention. Implications for staff: ED staff need to examine current practice within their ED in relation to falls assessment, management and referral pathways. PMID- 23084514 TI - Case report: a patient with dementia presenting with hip fracture in the emergency department -- challenges of acute pain assessment. AB - The purpose of this case report is to stimulate debate on the practicalities of detecting pain in patients with dementia in the emergency department (ED) - in this case, a patient who sustained a hip fracture subsequent to a fall in a nursing home. Although case reports are low in the hierarchy of evidence, they serve as useful glimpses into future possible detection and management of the pain status of the person with dementia in the ED who present with injuries such as hip fractures. Older patients with dementia, who are unable to provide a self report of pain post hip fracture in the ED are at risk for under-detection and under-treatment of acute pain. The utilisation of a specific pain assessment framework, based on best available evidence, will enable nurses to detect and manage acute pain for this vulnerable group in the emergency department. PMID- 23084516 TI - Silica nanoparticles capture atmospheric lead: implications in the treatment of environmental heavy metal pollution. AB - Lead (Pb) contamination in the air is a severe global problem, most notably in China. Removal of Pb from polluted air remains a significant challenge. It is unclear what potential effects silica nanoparticles (SiNPs) exposure can have on atmospheric Pb. Here we first characterized the features of SiNPs by measuring the particle size, zeta potential and the specific surface area of SiO(2) particles using a Nicomp 380/ZLS submicron particle sizer, the Brunauer-Emmett Teller (BET) method and transmission electronic microscopy (TEM). We measured the content of the metal Pb adsorbed by SiNPs exposed to two Pb polluted electric battery plants using inductively coupled plasma mass spectrometry (ICP-MS). It is found that SiNPs exposed to two Pb polluted electric battery plants absorb more atmospheric Pb compared to either blank control or micro-sized SiO(2) particles in a time-dependent manner. This is the first study demonstrating that SiNPs exposure can absorb atmospheric Pb in the polluted environment. These novel findings indicate that SiNPs have potential to serve as a significant adsorbent of Pb from industrial pollution, implicating a potentially novel application of SiNPs in the treatment of environmental heavy metal pollution. PMID- 23084515 TI - Enhanced cognitive behaviour therapy for adults with anorexia nervosa: a UK-Italy study. AB - Anorexia nervosa is difficult to treat and no treatment is supported by robust evidence. As it is uncommon, it has been recommended that new treatments should undergo extensive preliminary testing before being evaluated in randomized controlled trials. The aim of the present study was to establish the immediate and longer-term outcome following "enhanced" cognitive behaviour therapy (CBT-E). Ninety-nine adult patients with marked anorexia nervosa (body mass index <= 17.5) were recruited from consecutive referrals to clinics in the UK and Italy. Each was offered 40 sessions of CBT-E over 40 weeks with no concurrent treatment. Sixty-four percent of the patients were able to complete this outpatient treatment and in these patients there was a substantial increase in weight (7.47 kg, SD 4.93) and BMI (2.77, SD 1.81). Eating disorder features also improved markedly. Over the 60-week follow-up period there was little deterioration despite minimal additional treatment. These findings provide strong preliminary support for this use of CBT-E and justify its further evaluation in randomized controlled trials. As CBT-E has already been established as a treatment for bulimia nervosa and eating disorder not otherwise specified, the findings also confirm that CBT-E is transdiagnostic in its scope. PMID- 23084517 TI - Morphological, physiological, and genetic variation between metallicolous and nonmetallicolous populations of Dianthus carthusianorum. AB - Waste deposits produced by metal mining and smelting activities provide extremely difficult habitats for plant colonization and growth. Therefore, plants spontaneously colonizing such areas represent a very interesting system for studying evolution of plant adaptation and population differentiation between contaminated and noncontaminated environments. In this study, two populations of Dianthus carthusianorum, one originating from Zn-Pb waste deposit (a metallicolous population, M) and the other from unpolluted soil (a nonmetallicolous population, NM), were analyzed in respect of their morphological and physiological traits as well as genetic markers. It was found that the plants inhabiting the waste heap differed significantly from the NM plants in terms of leaf size and shape, and these differences were persistent between the first generation of the plants of both populations cultivated under uniform, controlled laboratory conditions. In contrast with the evident morphological differences, no significant differentiation between the populations regarding the physiological traits measured (accumulation of proline, anthocyanins, chlorophyll, carotenoids) was found. These traits can be regarded as neither population specific nor stress markers. The genetic variability was analyzed using 17 random amplified polymorphic DNA (RAPD) and four inter simple sequence repeat (ISSR) markers; this proved that the differentiation between the M and NM populations exists also at the genetic level. Analysis of molecular variance (AMOVA) showed that 24% of the total genetic diversity resided among populations, while 76% - within the populations. However, no significant differences in intrapopulation genetic diversity (Hj) between the M and NM populations of D. carthusianorum was found, which contradicts the theory that acquisition of adaptation mechanisms to adverse, isolated growth habitats is related to reduction in genetic diversity. Distinct genetic differences between the two populations in combination with evident morphological variation support the proposal to regard the M population of D. carthusianorum as a separate calamine ecotype. PMID- 23084518 TI - MDM2 inhibition in liposarcoma: a step in the right direction. PMID- 23084519 TI - Menarche, menopause, and breast cancer risk: individual participant meta analysis, including 118 964 women with breast cancer from 117 epidemiological studies. AB - BACKGROUND: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. METHODS: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. FINDINGS: Breast cancer risk increased by a factor of 1.050 (95% CI 1.044-1.057; p<0.0001) for every year younger at menarche, and independently by a smaller amount (1.029, 1.025-1.032; p<0.0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1.43, 1.33-1.52, p<0.001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0.006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0.01 for both comparisons). INTERPRETATION: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. FUNDING: Cancer Research UK. PMID- 23084520 TI - Menarche, menopause, and breast cancer risk. PMID- 23084521 TI - Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2 amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. AB - BACKGROUND: We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well differentiated or dedifferentiated MDM2-amplified liposarcoma who were eligible for resection. METHODS: Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m(2) per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 [MIC 1], and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10. RESULTS: Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4.86 times (IQR 4.38-7.97; p=0.0001) and 3.48 times (2.05-4.09; p=0.0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3.03 times (1.23-4.93; p=0.003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was -5.05% (IQR -12.55 to 0.05; p=0.01). Drug exposure correlated with blood concentrations of MIC-1 (p<0.0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients). DISCUSSION: MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2-amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma. FUNDING: F Hoffmann-La Roche. PMID- 23084522 TI - Biology of castration-recurrent prostate cancer. AB - Although androgen-deprivation therapy is the standard therapy for advanced and metastatic prostate cancer, this treatment is only palliative. Prostate cancer recurs then grows despite low circulating testicular androgens, using several mechanisms that remain dependent on androgen-receptor signaling in most cases. This article reviews the diversity of mechanisms used for growth by castration recurrent prostate cancer. PMID- 23084523 TI - Targeting the androgen receptor. AB - Androgen receptor (AR)-mediated signaling is critical to the growth and survival of prostate cancer. Although medical castration and antiandrogen therapy can decrease AR activity and lower PSA, castration resistance eventually develops. Recent work exploring the molecular structure and evolution of AR in response to hormonal therapies has revealed novel mechanisms of progression of castration resistant prostate cancer and yielded new targets for drug development. This review focuses on understanding the mechanisms of persistent AR signaling in the castrate environment, and highlights new therapies either currently available or in clinical trials, including androgen synthesis inhibitors and novel direct AR inhibitors. PMID- 23084524 TI - Immunotherapy for castration-resistant prostate cancer. AB - The improved survival with sipuleucel-T, an autologous antigen-presenting cell based agent, for the treatment of patients with metastatic asymptomatic and minimally symptomatic castration-resistant prostate cancer supports immunotherapy as a valid approach. Also, multiple novel immunotherapeutic approaches are undergoing vigorous investigation. T-lymphocyte checkpoint blockade and poxvirus based prime-boost approaches are in phase III evaluation. Other immunotherapeutic platforms undergoing early investigation include radioimmunoconjugates and adenovirus-based, DNA-based, and Listeria-based approaches. The development of predictive markers for immune response that translate into improved long-term outcomes is important. This article reviews the emerging data and the unique strengths and weaknesses of these approaches. PMID- 23084525 TI - Moving toward personalized medicine in castration-resistant prostate cancer. AB - Recent advances in research technologies have allowed improved molecular characterization of castration-resistant prostate cancer (CRPC). These efforts hold promise for development of therapies that target alterations unique to an individual patient's prostate cancer. Targets include androgens and the androgen receptor pathway, pathways associated with hormone-resistant disease, and the immune system. In aggregate, this will allow physicians to choose treatments based on a particular tumor profile. As these approaches are developed, CRPC treatment is becoming an example of truly personalized medicine. PMID- 23084526 TI - Palliative care in castrate-resistant prostate cancer. AB - Significant symptoms and suffering related to castrate-resistant prostate cancer (CRPC) are associated with the disease and its treatment. Increasingly, with advances in treatment efficacy, men can live with symptoms for long periods. Interdisciplinary palliative care teams (including physicians, nurses, social workers, chaplains, pharmacists, psychologists, physical therapists, and nutritionists) focused on symptom management and patients' goals of care can collaborate with prostate cancer surgeons, oncologists, and radiation oncologists to provide the best care for men at all stages of treatment, including end of life. This article reviews the benefits of palliative care in helping patients with CRPC manage symptoms and distress. PMID- 23084527 TI - Quality of life with advanced metastatic prostate cancer. AB - The health-related quality-of-life (HRQOL) implications of advanced metastatic prostate cancer are variable. There are several different HRQOL instruments that measure domains germane to patients with advanced metastatic disease. The burden of prostate cancer is inversely related to the magnitude of HRQOL declines. Treatment with androgen deprivation therapy commonly results in HRQOL declines that have served as the impetus for intermittent therapy. Conversely, chemotherapeutic agents have been associated with improvements in functional status for men with castrate-resistant disease. Emerging therapies may result in significant HRQOL improvements in this population, and careful prospective evaluation of patient-reported outcomes will be required. PMID- 23084528 TI - Targeted therapies in metastatic castration-resistant prostate cancer: beyond the androgen receptor. AB - Prostate cancer is the most common male cancer and one of the top causes of male cancer-related death in Western countries. Most patients with prostate cancer respond to initial androgen deprivation therapy but eventually progress to castration-resistant prostate cancer (CRPC). Although androgen receptor signaling remains the main driver in CRPC, a growing body of evidence suggests that other pathways are involved in this progression. This article reviews the preclinical data and current status of clinical trials therapeutically targeting tubulin, DNA repair, molecular chaperones such as CLU and Hsp27, tyrosine kinases, and DNA repair. PMID- 23084530 TI - Targeting angiogenesis as a promising modality for the treatment of prostate cancer. AB - Antiangiogenic therapy has been successful for the treatment of solid tumors. Several strategies have been used to target angiogenesis in prostate cancer. These strategies include blocking proangiogenic factors via monoclonal antibodies or small molecule inhibitors targeting downstream signaling effector pathways, or using agents with immune-modulatory effects. This review examines the general concepts of tumor angiogenesis and the key clinical trials that have used these agents and other novel biologics in prostate cancer. Targeting angiogenesis is still a promising treatment strategy in prostate cancer with a rational trial design and combination approach. PMID- 23084529 TI - Bone-targeted agents: preventing skeletal complications in prostate cancer. AB - In men, prostate cancer is the most common non-cutaneous malignancy and the second most common cause of cancer death. Skeletal complications occur at various points during the disease course, either due to bone metastases directly, or as an unintended consequence of androgen deprivation therapy (ADT). Bone metastases are associated with pathologic fractures, spinal cord compression, and bone pain and can require narcotics or palliative radiation for pain relief. ADT results in bone loss and fragility fractures. This review describes the biology of bone metastases, skeletal morbidity, and recent advances in bone-targeted therapies to prevent skeletal complications of prostate cancer. PMID- 23084531 TI - Advanced clinical states in prostate cancer. AB - The classification of clinical disease states within advanced prostate cancer is set apart from other solid tumors largely through measurement of prostate specific antigen in the blood. This testing has allowed the distinction between the castration-sensitive and the castration-resistant states, to complement radiographic distinction within advanced prostate cancer. This has paved the way for advances in prognostication and treatment of patients within a heterogeneous disease group. Currently used clinical classifications have limitations and continue to evolve. The authors define the current disease states and discuss implications for prognosis and treatment decisions, as well as the limitations of existing classifications and emerging discoveries. PMID- 23084532 TI - The experience with cytotoxic chemotherapy in metastatic castration-resistant prostate cancer. AB - This article reviews the initial experience with chemotherapy in metastatic castration-resistant prostate cancer (mCRPC) and outlines some of the ongoing clinical trials in this area. In addition, the authors outline current knowledge on outcomes of patients treated with taxane-based chemotherapy on retrospective analysis of randomized trials. These data are intended to provide physicians and patients with a general idea on the outcomes of men with mCRPC that may facilitate clinical decisions as well as the design and evaluation of clinical trials. PMID- 23084534 TI - Urologic Clinics of North America. Castrate-resistant prostate cancer. Foreword. PMID- 23084533 TI - Management of docetaxel failures in metastatic castrate-resistant prostate cancer. AB - The treatment of metastatic castration-resistant prostate cancer has evolved since the approval of docetaxel-based therapy. Since docetaxel approval, three new agents have gained approval for this indication: sipuleucel-T, cabazitaxel, and abiraterone. Recent Phase III trials have also demonstrated survival benefits for MDV-3100 and radium-223 though regulatory approval ispending. Practicing physicians face the challenge of determining the optimal sequencing of these new agents. This dilemma is particularly relevant to the post-docetaxel setting, in which the indication for several of these agents overlaps. This article details the efficacy and safety of these agents to provide a framework for their clinical use. PMID- 23084535 TI - Urologic Clinics of North America. Castrate-resistant prostate cancer. Preface. PMID- 23084536 TI - A review of the global prevalence, molecular epidemiology and economics of cystic echinococcosis in production animals. AB - Cystic echinococcosis (CE) is an important and widespread zoonotic infection caused by the larval stages of taeniid cestodes of the genus Echinococcus. The disease represents a serious animal health concern in many rural areas of the world, causing important economic losses derived from decreased productivity and viscera condemnation in livestock species. In this review we aim to provide a comprehensive overview on recent research progress in the epidemiology of CE in production animals from a global perspective. Particular attention has been paid to the discussion of the extent and significance of recent molecular epidemiologic data. The financial burden associated to CE on the livestock industry has also been addressed. Data presented are expected to improve our current understanding of the parasite's geographical distribution, transmission, host range, immunogenicity, pathogenesis, and genotype frequencies. This information should be also valuable for the design and implementation of more efficient control strategies against CE. PMID- 23084537 TI - Influence of apoptosis on the cutaneous and peripheral lymph node inflammatory response in dogs with visceral leishmaniasis. AB - In canine visceral leishmaniasis (CVL), the abnormalities most commonly observed in clinical examination on the animals are lymphadenomegaly and skin lesions. Dogs are the main domestic reservoir for the protozoon Leishmania (L.) chagasi and the skin is the main site of contamination by the vector insect. Some protozoa use apoptosis as an immunological escape mechanism. The aim of this study was to correlate the presence of apoptosis with the parasite load and with the inflammatory response in the skin and lymph nodes of dogs naturally infected with Leishmania (L.) chagasi. Thirty-three dogs from the municipality of Aracatuba (Sao Paulo, Brazil) were used, an endemic area for CVL. Muzzle, ear and abdominal skin and the popliteal, subscapular, iliac and mesenteric lymph nodes of symptomatic (S), oligosymptomatic (O) and asymptomatic (A) dogs were analyzed histologically. The parasite load and percentage apoptosis were evaluated using an immunohistochemical technique. Microscopically, the lymph nodes presented chronic lymphadenitis and the skin presented plasmacytic infiltrate and granulomatous foci in the superficial dermis, especially in the ear and muzzle regions. The inflammation was most severe in group S. The parasite load and apoptotic cell density were also greatest in this group. The cause of the lymphoid atrophy in these dogs was correlated with T lymphocyte apoptosis, thus leaving the dogs more susceptible to CVL. The peripheral lymph nodes presented the greatest inflammatory response. Independent of the clinical picture, the predominant inflammatory response was granulomatous and plasmacytic, both in the skin and in the peripheral lymph nodes. The ear skin presented the greatest intensity of inflammation and parasite load, followed by the muzzle skin, in group S. The ear skin area presented a non-significant difference in cell profile, with predominance of macrophages, and a significant difference from group A to groups O and S. It was seen that in these areas, there were high densities of parasites and cells undergoing apoptosis, in group S. The association between apoptosis and parasite load was not significant in the lymph nodes, but in the muzzle regions and at the ear tips, a positive correlation was seen between the parasite load and the density of cells undergoing apoptosis. The dogs in group S had the highest parasite load and the greatest number of apoptotic cells, thus suggesting that the parasite had an immune evasion mechanism, which could be proven statistically in the skin. PMID- 23084538 TI - Geohelminth egg contamination of children's play areas in the city of Lodz (Poland). AB - The contamination of soil and sand with helminth eggs in children's play areas in Lodz (Poland) was assessed over two seasons using the flotation method with saturated sodium nitrate solution. A total of 88 samples were examined from 7 children's playgrounds from various public parks, 6 sandpits situated in school or kindergarten areas and 9 school sports fields. The differences in the number of positive samples from these sites were significant (chi(2)=21.83, d.f.=2 and p<0.0001). The highest rate of contamination was found in the area around sports fields. (15.7%). There was a significant difference between the frequencies of positive samples from the surface and from the deeper layers of the examined sites (chi(2)=11.41, d.f.=1, and p=0.0007). The average density of geohelminth eggs in 100g of soil or sand was 1.1 from sports fields, 0.4 from playgrounds and 0.07 from fenced sandpits. Throughout the study, 4 genera of nematode eggs (Toxocara, Uncinaria/Ancylostoma, Ascaris, Trichuris) and 1 genus (Cystoisospora spp.) of oocysts were detected. A total of 62 eggs were recovered, and 43.5% were fully developed to embryonated egg stages. The contamination rate was different in autumn 2010 and spring 2011, but there was no significant difference in the number of positive findings between these seasons. The helminth eggs were found in 10.9% and 7.6% of samples collected in the spring and in the autumn, respectively. The most frequently seen eggs were from Toxocara sp., which were the most prevalent in both seasons. PMID- 23084539 TI - An updated meta-analysis on the association of TGF-beta1 gene promoter -509C/T polymorphism with colorectal cancer risk. AB - AIM: Published data on the association between transforming growth factor-beta1 (TGF-beta1) gene promoter-509C/T polymorphism and colorectal cancer (CRC) risk are inconsistent and inconclusive. To derive a more precise estimation of this association, a meta-analysis was carried out. METHODS: Meta-analysis was performed to evaluate reported studies of the relationship between TGF-beta1 gene promoter-509C/T polymorphism and colorectal cancer risk using fixed-effects model and random-effects model. RESULTS: We observed an increased colorectal cancer risk among subjects carrying TGF-beta1 gene promoter-509CC+CT genotype (odds ratio (OR)=1.18%, 95% confidence interval (95% CI): 1.06-1.32) using 4440/6785 cases/controls in total population. We observed an increased risk of the TGF beta1 gene promoter -509CC, CT and CC+CT polymorphisms for colorectal cancer in population-based study (OR=1.36, 95% CI: 1.19-1.56, OR=1.18, 95% CI: 1.03-1.34 and OR=1.26, 95% CI: 1.12-1.43, respectively) in stratified analysis. We observed an increased colorectal risk among CC and CC+CT carriers in European and American population (OR=1.22, 95% CI: 1.04-1.43 and OR=1.18, 95% CI: 1.02-1.38, respectively). We also observed an increased risk of colon cancer among subjects carrying CC+CT genotype (OR=1.31, 95% CI: 1.05-1.63). CONCLUSIONS: The present meta-analysis results suggest that TGF-beta1 gene promoter -509C allele variant is a possible risk factor for developing colorectal cancer. Recommendations for further studies include pooling of individual data to verify results from the study and to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental and lifestyle factors. PMID- 23084540 TI - Dedifferentiation and substitute strategy: deconstructing the processing-speed impairment in schizophrenia. AB - BACKGROUND: Recent research has identified impairment in processing speed, measured by the digit-symbol substitution task, as central to the cognitive deficit in schizophrenia. However, the underlying cognitive correlates of this impairment remain unknown. METHODS: A sample of cases (N=125) meeting DSM-IV criteria for schizophrenia and a sample of community controls (N=272) from the same geographical area completed a set of putative measures of processing-speed ability to which we implemented confirmatory factor and structural regression modelling in order to elucidate the latent structure of processing speed. Next, we tested the degree to which the structural and relational portions of the model were equal across groups. RESULTS: Processing-speed ability was best defined, in both controls and cases (chi(2)=38.59(26), p=0.053), as a multidimensional cognitive ability consisting of three latent factors comprising: psychomotor speed, sequencing and shifting, and verbal fluency. However, cases exhibited dedifferentiation (i.e., markedly stronger inter-correlations between factors; chi(2)=59.94(29), p<.01) and a reliance on an alternative ensemble of cognitive operations to controls when completing the digit-symbol substitution task. CONCLUSION: Dedifferentiation of processing-speed ability in schizophrenia and subsequent overreliance on alternative (and possibly less than optimal) cognitive operations underlies the marked deficit observed on the digit-symbol substitution task. PMID- 23084541 TI - Passive marker tracking via phase-only cross correlation (POCC) for MR-guided needle interventions: initial in vivo experience. AB - PURPOSE: In this work, a passive tracking sequence employing a phase-only cross correlation (POCC) algorithm was studied with a focus on the in vivo applicability of the technique. Therefore, MR-guided needle interventions were performed in a phantom and two animal experiments. METHODS: The targeting accuracy was quantified in an agarose phantom with 15 fiducials. For each fiducial, the distance between needle trajectory and target point was measured. In a first animal experiment at 3 T, the prostate of a pig was punctured under POCC guidance. Second, POCC-based tracking was performed during a laser-induced thermal therapy procedure in peripheral porcine muscle tissue at 1.5 T. RESULTS: In the phantom experiment, the 15 fiducials were penetrated with a mean accuracy of 1.5 +/- 0.9 mm (mean duration for one puncture about 2 min). In the first animal experiment, the center of the pig's right prostatic lobe was accurately punctured within 15 min. In the second, targeting and insertion of the needle could be performed within 5 min and a thermal lesion was successfully created. CONCLUSION: Our initial experience with the POCC-based tracking sequence indicates that this technique has the potential as an accurate and versatile tool for in vivo MR-guided needle interventions. PMID- 23084542 TI - Workplace justice and psychosocial work hazards in association with return to work in male workers with coronary heart diseases: a prospective study. PMID- 23084543 TI - Cachexia as major underestimated unmet medical need: facts and numbers. PMID- 23084545 TI - Prostate-specific antigen kallikrein, non-ST elevation myocardial infarction and a new-onset atrial fibrillation in hypertensive patients. PMID- 23084544 TI - Complex assessment of the temporal lability of repolarization. PMID- 23084546 TI - What did Avicenna (Ibn Sina, 980-1037A.D.) look like? AB - We present a reconstruction of Avicenna's face from the only photograph of his skull available today. The photograph is more than 50 years old, and was obtained during the exhumation of Avicenna's tomb in Hamadan for relocation. The reconstruction procedure was performed by the Centre for Anatomy and Human Identification at the University of Dundee, UK. This is probably the first scholarly attempt to reconstruct Avicenna's face. Historians and clinicians who are interested in the history of medicine may find the current craniofacial analysis of Avicenna and the final output interesting and worth recording. The life, achievements and contributions of Avicenna to medical sciences and the influence of his "Canon" on Renaissance medicine are discussed. PMID- 23084547 TI - Chronic kidney disease and percutaneous coronary interventions with drug-eluting stents: does the K/DOQI classification matter? PMID- 23084548 TI - Heme oxygenase-1: an important therapeutic target for protecting against myocardial ischemia and reperfusion injury. PMID- 23084549 TI - Circulating angiotensin-converting enzyme is associated with left ventricular dysfunction, but not with central aortic hemodynamics. PMID- 23084550 TI - Effect of additional treatment with EXenatide in patients with an Acute Myocardial Infarction: the EXAMI study. PMID- 23084551 TI - Relationship between high values of HOMA-IR and cardiovascular response to metformin. PMID- 23084552 TI - MUC-1 aptamer-conjugated dye-doped silica nanoparticles for MCF-7 cells detection. AB - In this work, we have prepared three types of aptamer-conjugated Rubpy-doped silica nanoparticles for Human breast carcinoma MCF-7 cells labeling. Probe A is prepared through covalent conjugation between amine-labeled MUC-1 aptamer and carboxyl-modified Rubpy-doped NPs (NPs-aptamer). Probe B is prepared based on the interaction between biotin-labeled MUC-1 aptamer and avidin-conjugated Rubpy doped NPs (NPs-avidin-biotin-aptamer). For Probe C, there is a PEG with flexible long chain as the bridge between avidin and the NPs (NPs-PEG-avidin-biotin aptamer). In addition, we further investigate the practical number of MUC-1 aptamers on an NP of each probe using hoechst33258 dye. The binding efficiency of MUC-1 aptamer on the three types of probes as follows: Probe A < Probe B < Probe C. In addition, microscopic fluorescence imaging shows that Probe C containing the PEG molecules can be effectively applied for the recognition of MUC-1 protein in human breast carcinoma MCF-7 cells thus demonstrates that the PEG with flexible long chain as the bridge between the aptamer and NP can greatly enhances the freedom of MUC-1 aptamer. Compared with common organic dyes, the dye-doped silica nanoparticles serve as a stable bioprobe because of their facile conjugation with the desirable biomolecules, and have exhibited great potential in bioanalysis. PMID- 23084555 TI - Extended trochanteric osteotomy followed by cemented impaction allografting in revision hip arthroplasty. AB - The aim of this study is to present the medium- to long-term results of all cases of femoral impaction allografting revision at our institution that required an extended trochanteric osteotomy (ETO) at the time of surgery. Eighteen patients with a mean age of 60 years were evaluated. Indication for revision was aseptic loosening in all cases. The mean follow-up was 123 months (51-170). Charnley D'Aubigne-Postel scores, stem length, ETO length, ETO healing, and complications were recorded. No patient was lost to follow-up. Signs of clinical healing were noted within the first 6 postoperative months. The difference between the preoperative and postoperative clinical scores was statistically significant. No nonunion of the ETO was observed in any case. These results give support to the combined use of these techniques. PMID- 23084554 TI - Medium-term follow-up of a modular tapered noncemented titanium stem in revision total hip arthroplasty: a single-surgeon experience. AB - We report a single-surgeon experience with a noncemented modular revision shaft (Modular Prosthesis; LINK, Hamburg, Germany) with clinical and radiographic results of 63 patients after 10 years. The Harris Hip Score improved from 51 to 84 points. Intraoperative complications included 11 fractures. Four patients had postoperative femoral fractures. Further shaft revisions were necessary: 1 subsidence, 1 late fracture, 1 late deep infection. Sixty-eight percent of cases showed revision defects as graded 3 degrees by Mallory; 95 % did not show signs of loosening or subsidence; 38 patients showed adequate bone remodeling in the shaft and proximal femur; 21 patients showed excellent recovery of preoperative osteolytic areas, and 5 patients did not show signs of remodeling. The Modular Prosthesis stem shows adequate fixation and tendency toward satisfactory bone remodeling after 10 years. PMID- 23084553 TI - The influence of hyaluronic acid hydrogel crosslinking density and macromolecular diffusivity on human MSC chondrogenesis and hypertrophy. AB - Hyaluronic acid (HA) hydrogels formed via photocrosslinking provide stable 3D hydrogel environments that support the chondrogenesis of mesenchymal stem cells (MSCs). Crosslinking density has a significant impact on the physical properties of hydrogels, including their mechanical stiffness and macromolecular diffusivity. Variations in the HA hydrogel crosslinking density can be obtained by either changes in the HA macromer concentration (1, 3, or 5% w/v at 15 min exposure) or the extent of reaction through light exposure time (5% w/v at 5, 10, or 15 min). In this work, increased crosslinking by either method resulted in an overall decrease in cartilage matrix content and more restricted matrix distribution. Increased crosslinking also promoted hypertrophic differentiation of the chondrogenically induced MSCs, resulting in more matrix calcification in vitro. For example, type X collagen expression in the high crosslinking density 5% 15 min group was ~156 and 285% higher when compared to the low crosslinking density 1% 15 min and 5% 5 min groups on day 42, respectively. Supplementation with inhibitors of the small GTPase pathway involved in cytoskeletal tension or myosin II had no effect on hypertrophic differentiation and matrix calcification, indicating that the differential response is unlikely to be related to force sensing mechanotransduction mechanisms. When implanted subcutaneously in nude mice, higher crosslinking density again resulted in reduced cartilage matrix content, restricted matrix distribution, and increased matrix calcification. This study demonstrates that hydrogel properties mediated through alterations in crosslinking density must be considered in the context of the hypertrophic differentiation of chondrogenically induced MSCs. PMID- 23084556 TI - Temperature impact on the sorption of selenium(VI) onto anatase. AB - The impact of temperature (298 K, 313 K, and 333 K) on the sorption of selenium(VI) onto anatase was investigated for the first time. At a macroscopic level, batch experiments showed a decrease of selenium(VI) retention with both increasing pH (3.5-7.0) and temperature. The thermodynamic parameters of the sorption reaction, i.e. the enthalpy Delta(R)H, entropy Delta(R)S, and the Gibbs free energy Delta(R)G, were determined from the temperature dependence sorption data using the van't Hoff equation. The sorption process was found to be exothermic. Neither significant phase transformation nor a significant increase of anatase solubility could be detected with increasing temperature by XRD and ICP-MS. However, electrophoretic mobility measurements showed that both the zeta potential as well as the isoelectric point (pH(IEP)) of anatase were shifted to lower values with increasing temperature, leading to a decreased selenium(VI) sorption. At a microscopic level, the sorption mechanism of selenium(VI) onto anatase was elucidated at the three investigated temperatures by means of in situ Attenuated Total Reflection Fourier-Transform Infrared spectroscopy (ATR FT-IR). Results evidenced the formation of outer-sphere surface complexes, with no significant structural changes within the investigated temperature range. PMID- 23084558 TI - Surface dilational moduli of latex-particle monolayers spread at air-water interface. AB - Latex particles prepared by radical dispersion polymerization of styrene and diacetone acrylamide (DAAM) in the presence of potassium persulfate as an initiator were spread as particle monolayers at the air-water interface. The surface pressure isotherms of the latex-particle monolayers are almost reversible during the compression-expansion cycles. The surface dilational moduli of the latex-particle monolayers at a fixed surface pressure of 20 mN/m and a fixed frequency of 10 mHz are almost independent of the strain. Moreover, at a fixed strain of 10% and fixed surface pressures of 10 or 15 mN/m the surface dilational moduli of the latex particle monolayers were measured as a function of frequency. The Lissajous orbits of the latex-particle monolayers exhibit positive hysteresis loops for all surface pressure ranges examined. The crossover between the magnitude of the surface elastic modulus and the magnitude of the surface viscous modulus occurs between the frequencies of 10 and 12 mHz and beyond the frequency of 12 mHz the former is larger than the latter. Such crossover indicates that the strain response of the latex-particle monolayers behave changes from liquid-like viscoelastic behavior to solid-like behavior with increasing frequency. PMID- 23084557 TI - Surface energy of phospholipid bilayers and the correlation to their hydration. AB - Supported lipid bilayers (SLBs) were prepared on glass and silicon slides grafted with polyethylene glycol (PEG) and covalently bound cholesteryl anchors to fix the lipid bilayer on the surface. Phospholipid bilayers and bilayers modified by addition of covalently bound PEG were investigated. Using contact angle measurements, the surface energy components of bilayer surfaces were analyzed using van Oss' and Owens-Wendt's methods. A quantitative correlation between the polar proton acceptor component of the surface energies and the respective hydration densities was proven for SLBs of pure lipids. We could show that the presence of PEG in the SLB produces a significant change of the proton acceptor component. Regarding the correlation between the surface energies and the hydration densities of SLBs with PEG, we were able to show a dependency on the PEG conformation. PMID- 23084559 TI - Fractional statistical theory of adsorption applied to protein adsorption. AB - Experimental adsorption isotherms of bovine serum albumin (BSA) adsorbed on sulfonated microspheres were described by means of two analytical models: the first is the well-known Langmuir-Freundlich model (LF), and the second, called fractional statistical theory of adsorption (FSTA), is a statistical thermodynamics model developed recently by Ramirez-Pastor et al. [Phys. Rev. Lett. 93 (2004) 186101]. The experimental data, obtained by Hu et al. [Biochem. Eng. J. 23 (2005) 259] for different concentrations of sulfonate group on the surface of the microspheres, were correlated by using a fitting algorithm based on least-squares statistics. The combination of LF and FSTA models, along with the choice of an adequate fitting procedure, allowed us to obtain several conclusions: (i) as previously reported in the literature, the maximum amount adsorbed increases as the amount of sulfonate group increases; (ii) the equilibrium constant does not appear as a sensitive parameter to the amount of sulfonate group on the surface of the microspheres; and (iii) the values of the fitting parameters obtained from FSTA may be indicative of a mismatch between the equilibrium separation of the intermolecular interaction and the distance between the adsorption sites. The exhaustive study presented here has shown that FSTA model is a good one considering the complexity of the physical situation, which is intended to be described and could be more useful in interpreting experimental data of adsorption of molecules with different sizes and shapes. PMID- 23084561 TI - Long-term results of prolapse recurrence and functional outcome after vaginal hysterectomy. AB - OBJECTIVE: To evaluate the incidence of prolapse and prolapse-related symptoms following vaginal hysterectomy. METHODS: Data were reviewed from women who underwent vaginal hysterectomy between 1988, and 1995, at St George's Hospital, London, UK, and attended long-term follow-up. Outcome measures included a questionnaire for prolapse, urinary, bowel, and sexual symptoms; and a vaginal examination. RESULTS: Among 94 women attending long-term evaluation, the mean follow-up time was 100.7 months (range 67.0-156.0 months). Before vaginal hysterectomy, urgency was noted among 23 (24.5%), urge incontinence among 11 (11.7%), and stress incontinence among 8 (8.5%) women. At follow-up, these symptoms were observed among 23 (24.5%), 13 (13.8%), and 6 (6.4%) women, respectively. De novo urge incontinence and de novo stress incontinence were observed among 3 (3.2%) and 2 (2.1%) women, respectively. Vaginal examination data were compared for 70 women, of whom 18 (25.7%) had grade 1, 40 (57.1%) had grade 2, and 6 (8.6%) had grade 3 uterine prolapsed before surgery. Postoperatively, vaginal vault prolapse occurred in 7 (10.0%) women and correlated with degree of posterior prolapse (P=0.007), but not with severity of uterine descent (P=0.205) or previous prolapse surgery (P=0.573). CONCLUSION: The incidence of post-hysterectomy vault prolapse correlated with the degree of preoperative rectocele. PMID- 23084560 TI - Colonization with Group B streptococcus and Ureaplasma urealyticum among parturient women in Poland and Ukraine. PMID- 23084562 TI - HIV seroconversion in a health care worker who underwent postexposure prophylaxis following needlestick injury. PMID- 23084563 TI - Betamethasone-enhanced vein graft conduit accelerates functional recovery in the rat sciatic nerve gap. AB - PURPOSE: The objective of the study was to assess the effect of topically administered betamethasone on peripheral nerve regeneration and functional recovery after sciatic nerve transection in the rat. MATERIALS AND METHODS: Forty five healthy male white Wistar rats were divided into 3 experimental groups (n = 15), randomly. In the treatment group, a 10-mm sciatic nerve defect was bridged by use of an inside-out vein graft filled with 10 MUL betamethasone (0.1 mg/kg) (IOVG/BETA group). In the control group, the vein was filled with phosphate buffered saline solution alone (IOVG group). In the sham surgery group, the sciatic nerve was exposed with no further deleterious manipulations (SHAM group). Each group was subdivided into 3 subgroups of 5 animals each, and the regenerated nerve fibers were studied 4, 8, and 12 weeks after surgery. RESULTS: Functional study confirmed faster recovery of regenerated axons in the IOVG/BETA group than in the IOVG group (P < .05). Gastrocnemius muscle mass in the IOVG/BETA group was found to be significantly greater than that in the IOVG group (P < .05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in the IOVG/BETA group than in the control group (P < .05). By use of immunohistochemistry, the location of reactions to S-100 in IOVG/BETA was clearly more positive than that in the IOVG group. CONCLUSIONS: When loaded in a vein graft, betamethasone resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. Topical application of this readily available agent offers the benefit of cost savings, as well as avoiding the complications associated with systemic administration. PMID- 23084564 TI - Bacterial genomes: next generation sequencing technologies for studies of bacterial ecosystems. PMID- 23084565 TI - Corifollitropin alfa followed by rFSH in a GnRH antagonist protocol for poor ovarian responder patients: an observational pilot study. AB - OBJECTIVE: To identify whether women with poor ovarian response may benefit from treatment with corifollitropin alfa in a GnRH antagonist protocol. DESIGN: Retrospective pilot study. SETTING: University-based tertiary care center. PATIENT(S): Poor ovarian responders fulfilling the Bologna criteria developed by European Society for Human Reproduction and Embryology Consensus Group. INTERVENTION(S): Corifollitropin alfa (150 MUg) followed by 300 IU rFSH in a GnRH antagonist protocol. MAIN OUTCOME MEASURE(S): Endocrinologic profile and ongoing pregnancy rates. RESULT(S): Among 43 women treated with corifollitropin alfa, mean E(2) levels showed an increasing pattern during the follicular phase, reaching 825 ng/L on the day of hCG administration, whereas FSH values showed a marked increase during the first 5 days, reaching a mean value of 35 IU/L and remaining above 20 IU/L during the late follicular phase. Cycle cancellation rate was 32.6% and embryo transfer rate 53.3%. Five patients (11.7%) had a positive hCG test and three (7%) had an ongoing pregnancy. Ongoing pregnancy rates were 11.1% per oocyte retrieval and 13% per embryo transfer. Ongoing pregnancy rates per patient did not significantly differ compared with a cohort of patients treated during 2011 with the standard protocol for poor responders in our center (short agonist-hMG) (7% vs. 6.3%). CONCLUSION(S): Treatment of poor ovarian responders, as described by the Bologna criteria, with corifollitropin alfa in a GnRH antagonist protocol results in low pregnancy rates, similarly to conventional stimulation with a short agonist protocol. PMID- 23084566 TI - Testosterone secretion in elite adolescent swimmers does not modify bone mass acquisition: a 1-year follow-up study. AB - OBJECTIVE: To investigate whether high plasma testosterone (T) levels affect areal bone mineral density (aBMD), bone geometry, and bone remodeling in young elite female swimmers (SW). DESIGN: Cross-sectional and 1-year follow-up study. SETTING: Pediatric endocrinology and gynecology units. PARTICIPANT(S): Twenty five SW and 21 control subjects (CON) with breast stages IV or V (mean age 15.3 +/- 1.3 y). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical and biologic parameters, aBMD, and bone geometry. RESULT(S): Two groups of SW were constituted on the basis of total T level. High T level SW (HSW; n = 15) presented higher T than SW with normal T (NSW; n = 10) and CON (0.63 +/- 0.17; 0.36 +/- 0.07, and 0.38 +/- 0.14 ng/mL, respectively). The SHBG level (62.1 +/- 18.7 vs. 43.3 +/- 19.8 nmol/L) and the LH/FSH ratio (1.7 +/- 1.1 vs. 0.9 +/- 0.5) were higher, and menstrual disorders (60% vs. 23.8%) were more frequent in HSW than CON, and no difference was observed between the three groups for other sex hormones and insulin-like growth factor (IGF) 1 or IGF-binding protein 3. SW presented lower fat mass in the whole body and higher lean mass in the upper limbs only. aBMD was only modestly increased in the upper limbs in the SW groups, but no other bone specific differences (aBMD, bone geometry, bone turnover markers) were demonstrated between SW and CON at baseline or for aBMD after 1 year in a subgroup of participants. CONCLUSION(S): High plasma T levels have no detectable effect on bone mass and bone geometry in SW during the period of peak bone mass acquisition. PMID- 23084567 TI - Endometriosis: ancient disease, ancient treatments. PMID- 23084568 TI - Effects of maternal and dietary selenium (Se-enriched yeast) on the expression of Sel P and apoER2 of germ cells of their offspring in goats. AB - In this experiment the effect of maternal dietary selenium on the expression of Sel P and apoER2 of goat offspring was studied. The experiment was conducted on 119 Taihang Black Goats randomly divided into 4 groups which were fed with a basal diet, supplemented with 0 (control), 0.5, 2 and 4 mg kg(-1) DM Se. Testis samples were collected from young male of each treatment group at the end of the study (30 d after weaning) for mRNA expression using real-time PCR and for protein expression by immunohistochemistry assay. A significant decrease was observed in mRNA expression of Sel P and apoER2 in the testis of the Se-deficient (Group 1) and the Se-excess (Group 4) compared with that in Groups 2 and 3. A similar trend of the protein expression of Sel P and apoER2 was also found. These data indicate that maternal and dietary selenium has an effect on the expression of Sel P and apoER2 in testis of their offspring. In addition, both groups were similar suggesting that the relationship between Sel P and apoER2, and apoER2 is a receptor of Sel P in the seminiferous epithelium to uptake the selenium. PMID- 23084569 TI - Single layer centrifugation (SLC) improves sperm quality of cryopreserved Blanca Celtiberica buck semen. AB - The aim of the present study was to evaluate the effect of sperm selection by means of single layer centrifugation (SLC) on sperm quality after cryopreservation, either when SLC is used before freezing or after thawing, using Blanca-Celtiberica buck semen collected by electroejaculation (EE). Ejaculates from six bucks were collected by EE and divided into two aliquots. One of them (unselected) was diluted with Biladyl((r)) by the two-step method and frozen over nitrogen vapor. The other aliquot was selected by the SLC technique and subsequently frozen in the same way as the unselected samples (SLC before freezing). In a further treatment, two unselected straws were thawed and SLC was carried out (SLC after thawing). At thawing, sperm motility of all samples ((i) unselected; (ii) selected before freezing and (iii) selected after thawing) was evaluated by CASA. In addition, integrity of the plasma membrane, mitochondrial membrane potential, ROS production and DNA fragmentation index were assessed by flow cytometry. Most of the sperm parameters were improved (P<=0.001) in samples selected by SLC after thawing in relation to unselected or selected by SLC before freezing. The percentage of progressive motile spermatozoa was greater (86%) for sperm samples selected after thawing compared with unselected (58%) or selected before freezing (54%). Moreover, percentages of spermatozoa with intact plasma membrane and spermatozoa with high mitochondrial membrane potential (hMMP) were also greater for sperm samples selected after thawing compared to sperm samples unselected or selected before freezing (spermatozoa with intact plasma membrane: 80% vs. 32% vs. 12%; spermatozoa with hMMP: 54% vs. 1% vs. 15%; respectively). Therefore, sperm quality after cryopreservation is improved in Blanca-Celtiberica buck ejaculates collected by EE when a sperm selection technique such as SLC is carried out after thawing. PMID- 23084570 TI - Joseph Barnett Kirsner, MD, PhD. PMID- 23084571 TI - How a practice chooses an electronic health record. PMID- 23084573 TI - Quorum sensing and the confusion about diffusion. AB - Two hypotheses, termed quorum sensing (QS) and diffusion sensing (DS), have been suggested as competing explanations for why bacterial cells use the local concentration of small molecules to regulate numerous extracellular behaviours. Here, we show that: (i) although there are important differences between QS and DS, they are not diametrically opposed; (ii) empirical attempts to distinguish between QS and DS are misguided and will lead to confusion; (iii) the fundamental distinction is not between QS and DS, but whether or not the trait being examined is social; (iv) empirical data are consistent with both social interactions and a role of diffusion; (v) alternate hypotheses, such as efficiency sensing (ES), are not required to unite QS and DS. More generally, work in this area illustrates how the use of jargon can obscure the underlying concepts and key questions. PMID- 23084572 TI - The function and evolution of the Aspergillus genome. AB - Species in the filamentous fungal genus Aspergillus display a wide diversity of lifestyles and are of great importance to humans. The decoding of genome sequences from a dozen species that vary widely in their degree of evolutionary affinity has galvanized studies of the function and evolution of the Aspergillus genome in clinical, industrial, and agricultural environments. Here, we synthesize recent key findings that shed light on the architecture of the Aspergillus genome, on the molecular foundations of the genus' astounding dexterity and diversity in secondary metabolism, and on the genetic underpinnings of virulence in Aspergillus fumigatus, one of the most lethal fungal pathogens. Many of these insights dramatically expand our knowledge of fungal and microbial eukaryote genome evolution and function and argue that Aspergillus constitutes a superb model clade for the study of functional and comparative genomics. PMID- 23084574 TI - Motor and cognitive outcome at school age of children with surgically treated intestinal obstructions in the neonatal period. AB - BACKGROUND: The motor and cognitive outcome at school age of newborn children with surgically treated intestinal obstructions is unknown. Physiological stress and anesthesia may potentially be harmful in the period of early brain development in newborn infants. OBJECTIVE: To determine motor and cognitive outcome at school age in children with surgically treated intestinal obstructions as newborns, and to identify clinical risk factors for adverse outcome. STUDY DESIGN: Cohort study of infants born between 1995 and 2002 with atresia, stenosis, or intestinal malrotation. At 6 to 13years we assessed their motor functions, intelligence, attention, visual perception, visuomotor integration, and verbal memory. RESULTS: Of 44 children three (7%) died. Twenty-seven survivors (66%) were included for follow-up (median gestational age 36.7weeks, birth weight 3000g). Motor outcome was abnormal (<5th percentile) in 22% of the children, which was significantly more than in the norm population (P<0.01). Scores on selective attention were abnormal in 15% of the children (P<0.01). Other cognitive functions were not affected. Lower birth weight and intestinal perforation were risk factors for poorer motor outcome (R(2)=53.0%), intrauterine growth restriction was a risk factor for poorer selective attention (R(2)=36.6%). CONCLUSIONS: Children treated surgically for intestinal obstructions in the neonatal period had an increased risk for poor motor functioning and selective attention at school age. Low birth weight, intrauterine growth restriction and intestinal perforation were risk factors for adverse outcome. We recommend to closely follow the motor and attentional development of these children. PMID- 23084575 TI - Elevated urinary NT-proBNP after pharmacological closure of patent ductus arteriosus in very low birth weight infants. AB - BACKGROUND: Hemodynamically significant patent ductus arteriosus (hsPDA) complicates the clinical course of preterm infants and contributes to increased morbidity and mortality. NT-proBNP is indicative of the effects of hsPDA on clinical and cardiac status of patients. AIMS: The aim of this study was to evaluate the value of urinary NT-proBNP and NT-proBNP/creatinine ratio in follow up of hsPDA. STUDY DESIGN: Urinary NT-proBNP and NT-proBNP/creatinine ratio (UNBCR) were measured and correlated with the presence of hsPDA. Measurements were performed in 92 neonates on postnatal days 14 and 28 by ELISA methodology. Of 92 neonates, 22 required therapeutic interventions. RESULTS: Infants treated for hsPDA showed significant higher levels of urinary NT-proBNP and UNBCR on postnatal day 14 whereas similar results were determined on postnatal day 28. Cut off level of NT-proBNP was 567pg/mL with a sensitivity of 79% and a specificity of 71%. CONCLUSION: Our data showed that NT-proBNP and UNBCR levels as non invasive and powerful methods in preterm infants may help clinicians to determine the effects of hsPDA on clinical and cardiac status of the patients even with first measurement on day 14. PMID- 23084577 TI - Evaluation of left ventricular diastolic function using tissue Doppler echocardiography and conventional doppler echocardiography in patients with subclinical hypothyroidism aged <60 years: a meta-analysis. AB - Studies have suggested that subclinical hypothyroidism (SCH) may have detrimental effects on left ventricular (LV) diastolic function. Whether SCH is a risk factor for LV diastolic dysfunction is controversial. Databases (MEDLINE, PubMed, EMBASE) were searched for cross-sectional studies evaluating LV diastolic function in SCH patients aged <60 years using tissue Doppler echocardiography (TDE) and conventional two-dimensional Doppler echocardiography (2D-DECG) published in the past 12 years. The weighted mean difference (WMD) and 95% confidence interval (CI) were calculated using fixed or random-effects models. We summarized the results of 14 cross-sectional studies with 675 participants. SCH patients had a significantly lower LV mitral annular E(a) peak velocity (WMD= 1.71 cm/s; 95%CI: -3.02 to -0.40; p<0.05), E(a)/A(a) ratio (WMD=-0.22; 95%CI: 0.40 to -0.05; p<0.05), and significantly higher mitral annular A(a) peak velocity (WMD=0.47 cm/s; 95%CI: 0.10-0.85; p<0.05) than euthyroid subjects using TDE. Subgroup analyses showed that statistical significance existed only in E(a) and E(a)/A(a) parameters when data from "women >= 90%" were used, and in the A(a) parameter when data from "women<90%" were used. No matter which subgroup of females was used, there were significant differences in LV peak transmitral A velocity (WMD=7.64 cm/s; 95%CI: 4.55-10.73; p<0.05), and E/A ratio (WMD=-0.22; 95%CI: -0.31 to -0.21; p<0.05) but no significant difference in peak transmitral E velocity (p>0.05) between SCH patients and euthyroid controls using 2D-DECG. Therefore, for those aged <60 years, SCH patients had significantly worse parameters of LV diastolic function than euthyroid controls. PMID- 23084576 TI - Prognostic impact of using drug-eluting-stents on outcome and strategy in multivessel PCI: data from the Frankfurt MV-PCI registry. AB - BACKGROUND: Drug-eluting-stents (DES) reduce clinical restenosis, but have mostly failed to demonstrate a reduction in death or myocardial infarction. The aim of this study was to evaluate the prognostic impact of the introduction of DES in patients undergoing multivessel percutaneous coronary intervention (MV-PCI). METHODS: Survival was assessed in 679 consecutive patients, who underwent PCI in at least two main vessels. Follow-up was available in 667 patients (98%) with a mean follow-up of 4.8 +/- 2.5 years. We compared several scenarios: firstly, patients receiving at least one DES (>= 1 DES group) vs. bare metal stent (BMS) only patients (BMS only); secondly, the population was divided into a pre-DES-era (2000-2003; N=257) and a DES-era (2004-2006; N=422). RESULTS: 316 patients (47%) were treated for acute myocardial infarction (MI; N=176 ST-elevation MI; N=140 non-ST-elevation MI). On average, 2.2 +/- 0.4 vessels were treated and 212 patients received at least one DES. The DES group showed a higher number of diseased (2.5 +/- 0.6 vs. 2.4 +/- 0.5; p=0.02) and treated vessels (2.2 +/- 0.5 vs. 2.1 +/- 0.3; p<0.01) and received more stents (3.3 +/- 1.4 vs. 3.0 +/- 1.1; p<0.01). The BMS group presented more frequently with acute MI (55% vs. 29%; p<0.01). The DES group showed more complex disease as evidenced by a higher SYNTAX-Score (17.4 +/- 8.5 vs. 14.5 +/- 8.3; p<0.01). Restricting the survival analysis to patients with stable coronary artery disease, a significant prognostic advantage was found for patients received at least one DES compared to the BMS group (hazard ratio 0.58, 95% confidence interval 0.34-0.99) in the multivariate cox-regression-analysis. CONCLUSION: The introduction of DES leads to extension of treatment to more complex patients. The use of DES is associated with improved survival in stable patients undergoing MV-PCI. PMID- 23084578 TI - Career preferences of nursing students. AB - This study investigates novice and experienced student nurses' attitudes about caring for patients across the lifespan. Students were also asked why they would enjoy or not enjoy caring for children and older adults. Both novice (n = 114) and advanced (n = 56) nursing students were relatively positive about caring for patients across the lifespan. However, novices were significantly more negative about working with older patients, particularly after experiencing a first clinical placement. In contrast, a significant quadratic effect was found for advanced students, indicating more negativity about working with both children and older adults. When giving reasons for why they would enjoy caring for older patients, novices were more likely than were advanced students to focus on stereotypical characteristics and on negative health outcomes of older adults as a group. Overall, results suggest that the attitudes driving career interests in nursing students change as training advances. PMID- 23084579 TI - Glypican 3 expression in tumors with loss of SMARCB1/INI1 protein expression. AB - Glypican 3 (GPC3), a membrane-bound heparin sulfate proteoglycan, is mutated in Simpson-Golabi-Behmel syndrome, characterized by tissue overgrowth and an increased risk of embryonal malignancies such as Wilms tumor. Malignant rhabdoid tumor (MRT), originally described as a rhabdomyosarcomatoid variant of Wilms tumor, is a tumor with loss of SMARCB1/INI1 protein expression. We analyzed the frequency of GPC3 protein expression, GPC3 mRNA, and serum-soluble GPC3 levels in 71 cases of tumors with loss of SMARCB1/INI1 protein expression, including 14 MRTs, 48 epithelioid sarcomas (ES) (proximal-type, 21; distal-type, 27), 4 extraskeletal myxoid chondrosarcomas, and 5 pediatric undifferentiated soft tissue sarcomas. We found that GPC3 overexpression of more than 10% of the labeling index was recognized in 6 (42.9%) MRTs, 1 (2.1%) proximal-type ES, and 3 (60%) pediatric undifferentiated soft-tissue sarcomas (MRT vs ES, P = .0003). All the remaining cases revealed GPC3-absent expression of less than 1% of the labeling index. The median values of GPC3 mRNA in the GPC3-absent expression group and overexpression group were 10.2 and 309, respectively, with a statistically significant difference between these 2 groups (P = .004). However, there was no statistically significant difference in the prognoses of these 2 groups of MRT (P = .99). In analyzable cases of small-number MRT and pediatric undifferentiated soft-tissue sarcoma, there is no significant correlation between GPC3 immunoreactivity and serum-soluble GPC3 level. Therefore, evaluation of GPC3 immunoexpression may be a useful diagnostic tool to distinguish ES from MRT, especially extrarenal MRT. It was suggested that MRTs with GPC3 overexpression may become a new target of GPC3 immunotherapy. PMID- 23084580 TI - Expression of p27, COX-2, MLH1, and MSH2 in young patients with colon carcinoma and correlation with morphologic findings. AB - Despite an overall decrease in colorectal carcinoma incidence, rates of colorectal carcinoma have increased substantially in patients aged less than 40 years. Several authors have characterized morphologic features of colorectal carcinoma in young patients, with variable results. To date, there has been 1 detailed molecular and immunohistochemical study in young patients with colorectal carcinoma. We sought to expand the data regarding young patients with colorectal carcinoma by a detailed assessment of morphologic features and by assaying expression of p27, COX-2, MLH1, and MSH2, markers with prognostic or therapeutic implications in colorectal carcinoma. We searched our pathology database from 1985 to 2009 and, after exclusion of cases with insufficient data or neoadjuvant therapy, identified a study population of 23 patients aged 40 or younger, 35 patients between 41 and 49 years of age, and a control group of 83 colorectal carcinoma patients aged 50 or older. Younger patients had higher tumor grade (P = .0085), with a trend toward mucinous differentiation and lymphovascular and perineural invasion. Loss of MSH2 was more prominent in younger patients (P = .02). Loss of p27 expression was not associated with age, but was associated with higher tumor stage (P = .0278), mucinous/signet ring differentiation (P = .0185), loss of either MLH1 or MSH2 (P = .0035), and larger tumor size (P = .0019). There was a trend toward lower COX-2 expression in younger patients, with less COX-2 expression relative to previously published data. Our findings support some prior reports regarding morphologic features in colorectal carcinoma in young patients and provide novel data on expression of several markers in this population. PMID- 23084581 TI - Chronic lymphocytic leukemia with t(14;18)(q32;q21). AB - The t(14;18)(q32;q21) is a cytogenetic hallmark of follicular lymphoma and also occurs in approximately 20% of diffuse large B-cell lymphomas of follicle center cell origin. Relatively few cases of chronic lymphocytic leukemia/small lymphocytic lymphoma with t(14;18) have been reported previously. We report the clinicopathologic, cytogenetic, and molecular genetic features of 12 patients with chronic lymphocytic leukemia associated with t(14;18). There were 9 men and 3 women, with a median age of 51 years at diagnosis. To date, 11 patients have required chemotherapy, 6 before coming to our institution. At last follow-up, 5 patients have died of disease. Karyotypic analysis showed that 10 cases had t(14;18) in the stemline and 2 cases in the sideline; t(14;18) was the sole abnormality in the stemline in 2 cases. In 11 cases, other abnormalities were identified in the stemline or sidelines, most commonly trisomy 12 in 6 cases. Trisomy 12 was associated with atypical morphology and immunophenotype. Of 8 cases tested, 7 showed somatically mutated immunoglobulin heavy chain variable region genes. We conclude that the t(14;18) in chronic lymphocytic leukemia is associated with relatively young age at diagnosis, mutated immunoglobulin heavy chain variable region genes, and a clinical course that usually requires chemotherapy. The cytogenetic findings, in particular, t(14;18) in the stemline in 10 cases and as the sole karyotypic abnormality in 2 cases, suggest that t(14;18) is an early pathogenetic event in this small subset of chronic lymphocytic leukemia cases. PMID- 23084582 TI - Salpingo-oophorectomy specimens for endometrial cancer staging: a comparative analysis of representative sampling versus whole tissue processing. AB - Involvement of the ovary and/or fallopian tube by an endometrial cancer is uncommon but clinically significant because this is one of the indications for adjuvant chemotherapy. The authors evaluated whether the routine microscopic evaluation of the adnexal organs in this setting should be of the entire specimen or of representative sections. Slides and reports were reviewed for 105 consecutive patients who underwent a staging salpingo-oophorectomy (205 ovaries, 210 tubes) for endometrial carcinoma/carcinosarcoma. The study period encompassed the periods before and after an institutional policy change from discretionary (predominantly representative) adnexal sampling to obligatory total processing. Ninety-four and 111 ovaries (and 92 and 118 tubes) were entirely and representatively processed, respectively. Even when using the most expansive definition of ovarian gross abnormality (definition with the highest sensitivity and lowest specificity for microscopically confirmed cancer), we still identified 4 (of 148; 2.7%) grossly normal ovaries and 3 (of 187; 1.6%) grossly normal tubes that were found to harbor microscopic cancers. There was no significant increase in the number of grossly occult cancers detected after the policy change, and 5 (71%) of the 7 grossly occult cancers were in the representatively sampled group. Approximately 3.76 more blocks per patient were required for total overrepresentative processing, and the total cost of these additional sections was estimated to be $25.57 per patient. In conclusion, the 1.6% to 2.7% of grossly normal adnexa that proved to be cancerous represents, at least theoretically, the risk for misdiagnosis and understaging that is associated with representative sampling, at relatively modest savings. However, the findings in this study do not provide direct evidentiary support for routine complete processing. PMID- 23084583 TI - In situ analysis of HER2 mRNA in gastric carcinoma: comparison with fluorescence in situ hybridization, dual-color silver in situ hybridization, and immunohistochemistry. AB - The importance of anti-HER2 therapy has focused attention on the ability of clinical assays to correctly assign HER2 amplification status. In the present study, we evaluated HER2 mRNA expression using a new mRNA in situ detection technique called RNAscope in 211 cases of formalin-fixed, paraffin-embedded gastric carcinoma. In addition, we compared the results with the conventional methods of immunohistochemistry, fluorescence in situ hybridization, and dual color silver in situ hybridization. RNA in situ hybridization (in situ hybridization) showed that 162 cases (76.8%) were score 0, 5 cases (2.4%) were score 1, 10 cases (4.7%) were score 2, 13 cases (6.2%) were score 3, and 21 cases (10.0%) were score 4. HER2 transcription levels were found to be significantly related to pT class, pN class, and tumor recurrence. mRNA expression was well correlated with protein overexpression and gene amplification; 20 cases out of 23 with DNA amplification showed a score of 4 in RNA in situ hybridization (P < .001). Three cases showed false negative and one case showed false positive results by in situ hybridization. More studies are needed to determine whether the in situ hybridization method can identify additional patients that may benefit from anti-HER2 therapy or exclude those who may be resistant to anti-HER2 therapy. PMID- 23084584 TI - Human epididymis protein 4 is up-regulated in gastric and pancreatic adenocarcinomas. AB - Upper gastrointestinal neoplasia in the esophagus, stomach, and pancreas is associated with the formation of preneoplastic metaplasias. We have previously reported the up-regulation of human epididymis protein 4 (HE4) in all metaplasias in the stomach of humans and mice. We have now sought to evaluate the expression of HE4 in metaplasias/preneoplastic precursors and cancers of the human stomach, pancreas, and esophagus. Tissue microarrays for gastric cancers, pancreatic cancers, and esophageal adenocarcinoma were stained with antibodies against HE4. Immunostaining was quantified by digital imaging, and the results were evaluated to assess the expression in metaplasias, the expression in cancer pathological subtypes, and the effects of expression on survival in patients with cancer. In patients with gastric cancer from Korea, HE4 was detected in 74% of intestinal and 90% of diffuse cancers, whereas in a gastric cancer cohort from Johns Hopkins, HE4 was detected in 74% of intestinal-type and 92% of diffuse cancers. Nevertheless, in both cohorts, there was no impact of HE4 expression on overall survival. In the esophagus, we observed the expression of HE4 in scattered endocrine cells within Barrett esophagus samples, but Barrett columnar metaplasias and HE4 were detected in only 2% of esophageal adenocarcinomas. Finally, in the pancreas, HE4 expression was not observed in pancreatic intraepithelial neoplasia lesions, but 46.8% of pancreatic adenocarcinomas expressed HE4. Still, we did not observe any influence of HE4 expression on survival. The results suggest that HE4 is up-regulated during gastric and pancreatic carcinogenesis. PMID- 23084585 TI - Desmoplastic spindle cell thymomas: a clinicopathologic and immunohistochemical study of 14 cases. AB - Fourteen cases of spindle cell thymoma with prominent desmoplastic changes are presented. The patients are 9 women and 5 men between the ages of 46 and 79 years. Clinically, the patients presented with symptoms of chest pain, shortness of breath, and dyspnea. Radiographic imaging showed the presence of an anterior mediastinal mass, and surgical resection of the tumor mass was accomplished in all of the cases. Grossly, all the tumors were described as ovoid tumor masses measuring between 4 and 9 cm in greatest dimension. At cut surface, the tumors were described as solid and light tan-brown in color. Necrosis and hemorrhage were not recorded in any of the cases. Histologically, 8 cases were invasive, and 6 were encapsulated tumors. Extensive areas of young fibrocollagen and a prominent fibroblastic proliferation characterized the tumors. Scattered areas of more conventional spindle cell thymoma were present in all cases but mitotic activity, necrosis, and/or hemorrhage were not identified. Immunohistochemical stains were performed in 9 cases, showing tumor cells positive for pancytokeratin, cytokeratin 5/6, Bcl-2, Pax8, and vimentin. Clinical follow-up in 8 patients showed that all are alive and well 1 to 8 years after diagnosis. The current growth pattern of spindle cell thymomas is unusual and should be kept in mind when evaluating mediastinoscopic biopsies. PMID- 23084586 TI - Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. AB - The distinction of hepatocellular adenoma from well-differentiated hepatocellular carcinoma (HCC) arising in noncirrhotic liver can be challenging, particularly when tumors histologically resembling hepatocellular adenoma occur in unusual clinical settings such as in a man or an older woman or show focal atypical morphologic features. In this study, we examine the morphologic, immunohistochemical, and cytogenetic features of hepatocellular adenoma-like neoplasms occurring in men, women 50 years or older or younger than 15 years, and/or those with focal atypia (small cell change, pseudogland formation, and/or nuclear atypia), designated atypical hepatocellular neoplasms, where the distinction of hepatocellular adenoma versus HCC could not be clearly established. Immunohistochemistry was performed for beta-catenin, glutamine synthetase, and serum amyloid A in 31 hepatocellular adenomas, 20 well differentiated HCCs, and 40 atypical hepatocellular neoplasms. Chromosomal gains/losses had previously been determined in 37 cases using comparative genomic hybridization or fluorescence in situ hybridization. beta-Catenin activation was observed in 35% of atypical hepatocellular neoplasms compared with 10% of typical hepatocellular adenomas (P < .05) and 55% of well-differentiated HCCs (P = .14). Cytogenetic changes typically observed in HCC were present in all atypical hepatocellular neoplasms with beta-catenin activation. beta-Catenin activation in atypical hepatocellular neoplasms was also associated with atypical morphologic features. Follow-up data were limited, but adverse outcome was observed in 2 atypical hepatocellular neoplasms with beta-catenin activation (1 recurrence, 1 metastasis); transition to areas of HCC was observed in 1 case. The similarity in morphologic and cytogenetic features of beta-catenin-activated hepatocellular adenoma-like tumors and HCC suggests that the former tumors represent an extremely well-differentiated variant of HCC. PMID- 23084588 TI - Sequence analysis of capsid coding region of foot-and-mouth disease virus type A vaccine strain during serial passages in BHK-21 adherent and suspension cells. AB - Sequence variability within the capsid coding region of the foot-and-mouth disease virus type A vaccine strain during serial in vitro passage was investigated. Specifically, two methods of virus propagation were utilized, a monolayer and suspension culture of BHK-21 cells. At three positions (VP2(131) E K in both monolayer and suspension passages, VP3(85) H-R in late monolayer passages and VP3(139) K-E in only suspension passages), all mapped to surface exposed loops, amino acid substitutions were apparently fixed without reversion till the end of the passage regime. Interestingly, VP2(131, 121) and VP3(85) which form part of the heparan sulphate binding pocket, showed a tendency to acquire positively charged amino acids in either monolayer or suspension environment probably to better interact with the negatively charged cell surface glycosaminoglycans. At three identified antigenically critical positions (VP2(79), VP3(139) and VP1(154)), amino acids substitutions even in the absence of immune pressure were noticed. Hence both random drift and adaptive mutations attributable to the strong selective pressure exerted by the proposed cell surface alternate receptors could play a role in modifying the capsid sequence of cell culture propagated FMDV vaccine virus, which in turn may alter the desired potency of the vaccine formulations. PMID- 23084587 TI - Overexpression of epithelial-mesenchymal transition-related markers according to cell dedifferentiation: clinical implications as an independent predictor of poor prognosis in cholangiocarcinoma. AB - Although increased evidence has suggested that epithelial-mesenchymal transition has been implicated in cancer invasion and is associated with poor prognosis, its significance in cholangiocarcinoma remains unclear. We evaluated the levels of expression of epithelial-mesenchymal transition-related genes and proteins in 2 established human cholangiocarcinoma cell lines with different morphological characteristics and performed transwell cell invasion assays. Furthermore, we investigated the association between altered expression of 6 epithelial mesenchymal transition-related proteins and clinical outcomes in human cholangiocarcinoma patients (n = 119) by immunohistochemistry using a tissue microarray approach. Comparative analysis of protein and messenger RNA expression revealed that the cell line with less differentiation (JCK) showed increased expression of mesenchymal markers and zinc-finger proteins and decreased expression of epithelial markers. The invasion activity of JCK cells was significantly higher than that of cells from OZ cell lines. Tissue microarray analysis revealed that the combined expression pattern of 6 epithelial mesenchymal transition-related proteins predicted shortened disease-free survival (13.0 versus 22.0 months, P = .033) and overall survival (23.0 versus 63.0 months, P = .003) and was confirmed as an independent unfavorable prognostic factor for survival in multivariate survival analysis (disease-free survival, P = .028 for the 3 epithelial-mesenchymal transition-related markers; overall survival, P = .010 for the 6 epithelial-mesenchymal transition-related markers). In conclusion, our results suggest that altered expression of a number of epithelial-mesenchymal transition-related genes in tumor cells with poor differentiation may explain their increased invasive ability. Our results also suggest that altered expression of a suite of epithelial-mesenchymal transition related proteins could be used as a tool to predict poor outcomes in human cholangiocarcinoma patients. PMID- 23084589 TI - Effects of polycyclic musks HHCB and AHTN on steroidogenesis in H295R cells. AB - 1,3,4,6,7,8-Hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-(gamma)-2-benzopyran (HHCB) and 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) are widely used in personal care products. Previous studies showed that HHCB and AHTN can be found in various environmental matrices and have potential endocrine disrupting effects. However, the effects on adrenocortical function of HHCB and AHTN are not fully understood. This study evaluated the influences of HHCB and AHTN on seven steroid hormones (progesterone, aldosterone, cortisol, 17alpha-OH progesterone, androstenedione, 17beta-estradiol, and testosterone) and 10 genes involved in steroidogenic pathways (HMGR, StAR, CYP11A1, 3betaHSD2, CYP17, CYP21, CYP11B1, CYP11B2, 17betaHSD, and CYP19) using the H295R cell line in the absence and presence of 8-Br-cAMP. MC2R transcription on the cell membrane was also examined to further investigate the effects of HHCB and AHTN on adrenal steroidogenesis. The results demonstrated that HHCB and AHTN could inhibit progesterone and cortisol production mainly by the suppression of 3betaHSD2 and CYP21. Meanwhile, high concentrations of AHTN can affect the sensitivity of H295R cells to ACTH by disrupting MC2R transcription. Overall, the results indicate that high concentrations of HHCB and AHTN can affect steroidogenesis in vitro using the H295R cell line. PMID- 23084590 TI - Biotransformation of 17alpha- and 17beta-estradiol in aerobic soils. AB - Considerable research has focused on the fate of 17beta-estradiol (17beta-E2) given its high estrogenic potency and frequent detection in the environment; however, little is known about the fate behavior of 17alpha-estradiol (17alpha E2) although it often dominates in some animal feces, and recently has been shown to have similar impacts as the beta-isomer. In this study, the aerobic biotransformation rates of 17alpha-E2 and 17beta-E2 applied at 50 MUg kg(-1) soil and metabolite trends were quantified in batch microcosms at ~21 degrees C and 70 85% field capacity using two soils with different taxonomic properties. Soils were extracted at designated times over a 3-week period and analyzed over time using negative electrospray ionization tandem mass spectrometry. For a given soil type, the two isomers degraded at the same rate with half lives across soils ranging between 4 and 12h. Estrone (E1) was the only metabolite detected and in all cases subsequent dissipation patterns of E1 are statistically different between isomers. Autoclaved-sterilized controls support that E2 dissipation is dominated by microbial processes. A first order exponential decay model that assumed sorption did not limit bioavailability was not able to accurately predict hormone residuals at later times, which indicates caution is required when trying to model fate and transport of hormones in the environment. PMID- 23084591 TI - The environmental photolysis of perfluorooctanesulfonate, perfluorooctanoate, and related fluorochemicals. AB - A field study on the photolysis of perfluoroalkyl substances (PFASs) was conducted at high altitudes in Mt. Mauna Kea (Hawaii, USA; 4200 m) and Mt. Tateyama (Toyama, Japan; 2500 m). Results of photolysis of PFASs in the field were further confirmed in laboratory studies. Perfluorooctanesulfonate (PFOS), which is perceived as a non-degradable chemical in the environment, can undergo photolysis. Long chain PFASs can be successively dealkylated to short chain compounds such as perfluorobutyric acid (PFBA) and perfluorobutane sulfonate (PFBS), but the short chain compounds were relatively more resistant to photodegradation. These results suggest that environmental levels of short chain PFASs would increase both due to their formation from photolysis of long chain PFASs and from direct releases. Earlier studies on photolysis of PFASs were focused on the formation of perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) from precursor compounds (such as fluorotelomer alcohols) under laboratory conditions. Our study suggests that PFSAs and PFCAs themselves can undergo photodegradation in the environment. PMID- 23084592 TI - Corrected QT interval during treatment with methadone and buprenorphine--relation to doses and serum concentrations. AB - BACKGROUND: Methadone and buprenorphine are widely used in the treatment of opioid addiction. Some study results suggest that methadone can be associated with QT interval prolongation and torsades de pointes ventricular arrhythmias, whereas no such risk has been observed for buprenorphine. The aim of this study is to determine the risk of corrected QT interval (QTc) increase among patients treated with these medications in an opioid maintenance treatment (OMT) programme, and to study possible associations between QTc changes and serum concentrations of methadone or buprenorphine. METHODS: Eighty patients enrolled in the OMT programme were followed after start of treatment with methadone (n=45) or buprenorphine (n=35). QTc interval was assessed by electrocardiography (ECG) at baseline and after 1 month (n=79) and 6 months (n=66) in the OMT programme. Blood samples were obtained for the analysis of serum concentrations of buprenorphine, (R)-methadone, (S)-methadone and total methadone. RESULTS: No patients had QTc prolongation (defined as a QTc value above 450 ms) at baseline or after 1 or 6 months. When analysed in a linear mixed effects model, QTc was not associated with the serum concentrations of buprenorphine or methadone. However, low serum potassium levels increased QTc significantly. CONCLUSIONS: These results support and extend previous findings that treatment with methadone in modest doses (i.e. below 100mg/d) is not associated with clinically significant QTc increases, and that buprenorphine in commonly used doses is a suitable alternative to methadone with regard to the risk of QTc prolongation. PMID- 23084593 TI - [Rizatriptan-induced liver toxicity. Report of a case]. AB - Triptans are a class of drugs with proven efficacy in the acute treatment of migraine headache. The first component of these drugs was sumatriptan, with various derivatives subsequently emerging. Until now, there has only been one reported case of liver toxicity with zolmitriptan. We now present a case of hepatotoxicity related to another drug in this group: rizatriptan. PMID- 23084594 TI - LuxS/AI-2 system is involved in antibiotic susceptibility and autolysis in Staphylococcus aureus NCTC 8325. AB - Current treatment for Staphylococcus aureus infections relies heavily upon the cell wall synthesis inhibitor antibiotics such as penicillin, oxacillin, vancomycin and teicoplanin. Increasing antibiotic resistance requires the development of new approaches to combating infection. Autoinducer-2 (AI-2) exists widely both in Gram-negative and Gram-positive pathogens and is suggested as a universal language for intraspecies and interspecies communication. This study demonstrates the association between AI-2 signalling and cell wall synthesis inhibitor antibiotic susceptibility in S. aureus. In addition, a luxS mutant exhibited decreased autolysis and upregulated vancomycin resistance-associated VraRS two-component regulatory system. This finding may provide novel clues for antimicrobial therapy in S. aureus infection. PMID- 23084595 TI - Chlorhexidine is a highly effective topical broad-spectrum agent against Candida spp. AB - The objective of this study was to compare the in vitro antifungal activities of chlorhexidine (CHX) and fluconazole (FLZ) against Candida isolates comprising eight different species associated with oral candidosis. A broth microdilution method as described in Clinical and Laboratory Standards Institute (CLSI) protocol M27-A3 was used to determine susceptibility. A total of 79 clinical isolates and reference strains belonging to eight different Candida spp. was tested. The minimum inhibitory concentration (MIC) was the lowest drug concentration that reduced growth by 50% for FLZ at 48 h and by 80% for CHX at 24h and 48 h. The geometric mean MIC (and MIC range) at 48 h for CHX was 3.03 mg/L (0.78-6.25mg/L) and for FLZ was 19.12 mg/L (<=0.125-256 mg/L). Of the 79 isolates, 14 (18%) were resistant to FLZ (MIC>=64 mg/L). All isolates were effectively inhibited by <=6.25mg/L CHX, and Candida CHX MICs are below the CHX levels found in saliva following normal dosing. No cross-resistance between CHX and FLZ was detected (r(s)=0.039, P=0.733). CLSI M27-A3 methodology proved to provide reproducible results with clear endpoints for CHX. In conclusion, the findings showed that CHX has excellent broad-spectrum antifungal activity in vitro. It was effective at concentrations detected in saliva when using standard dosing regimens. Moreover, no cross-resistance was detected between CHX and FLZ, even among Candida spp. highly resistant to FLZ. PMID- 23084596 TI - Compliance with therapeutic guidelines in Radiation Therapy Oncology Group prospective gastrointestinal clinical trials. AB - BACKGROUND: This report analyzes the adherence to radiation therapy protocol guidelines in contemporary Radiation Therapy Oncology Group (RTOG) gastrointestinal trials. We aim to provide insight into current standards and compliance of radiation therapy field design and administration. METHODS: From 1994 to 2006, the Gastrointestinal Cancer Committee of the RTOG initiated and completed 15 phase I-III clinical trials utilizing radiation therapy in the multimodality treatment of gastrointestinal cancers. In each protocol, details for planning and executing radiation therapy were outlined and each protocol contained scoring criteria for these components of radiation therapy, characterized according to per-protocol, variation acceptable and deviation unacceptable. Review of treatment planning and implementation was performed in all studies following therapy completion. RESULTS: Radiation therapy planning and implementation was reviewed in 2309 of 2312 (99.9%) patients. The mean rate of compliance over all for the 15 protocols was 65% (total of the 2309 analyzed patients). The mean variation acceptable rate was 21% whereas the mean deviation unacceptable rate was 5%. The mean "other" rate (no RT given or incomplete RT due to death, progression or refusal) was 8%. Two of the 15 trials (13%) had deviation unacceptable rates >10%. In four studies incorporating pre-treatment review of radiation therapy planning and treatment, compliance with protocol therapy was enhanced. CONCLUSIONS: The fidelity of radiation planning and execution detailed in protocol to actual therapy is heterogeneous, with a mean per-protocol rate of 65%. As clinical trials evolve, available technology should permit efficient pre-treatment review processes, thus facilitating compliance to protocol therapy. These analyses should also permit prospective analysis of outcome measures by compliance to therapy. PMID- 23084597 TI - Mental Illness: Clinicians' Attitudes (MICA) scale-psychometric properties of a version for healthcare students and professionals. AB - There are currently no published scales to assess the attitudes of students and professionals across a wide range of healthcare disciplines towards people with mental illness. Secondary analysis from a randomised controlled trial (RCT) of anti-stigma interventions was carried out to test the reliability, validity and acceptability of the Mental Illness: Clinicians' Attitudes (MICA) v4 scale, a modification of the MICA v2 scale in a sample of 191 nursing students. The MICA v4 was found to have good internal consistency (alpha=0.72) and item-total correlations. Principal component analysis produced a five-factor structure and the scale had acceptable convergent validity. A group of students and professionals within the healthcare discipline (n=5) reported that the MICA v4 had good face validity and suggested its use with students and professionals working in non-mental health settings. The scale had low rates of missing data, good readability and took less than 4min to complete. The MICA v4 scale was found to be a reliable, valid and acceptable measure of foundation year nursing students' attitudes towards mental illness. It has the potential for use with students and qualified staff across a range of healthcare professions and is available for use from the authors. PMID- 23084598 TI - Optimism and mental imagery: a possible cognitive marker to promote well-being? AB - Optimism is associated with a range of benefits not only for general well-being, but also for mental and physical health. The development of psychological interventions to boost optimism derived from cognitive science would have the potential to provide significant public health benefits, yet cognitive markers of optimism are little understood. The current study aimed to take a first step in this direction by identifying a cognitive marker for optimism that could provide a modifiable target for innovative interventions. In particular we predicted that the ability to generate vivid positive mental imagery of the future would be associated with dispositional optimism. A community sample of 237 participants completed a survey comprising measures of mental imagery and optimism, and socio demographic information. Vividness of positive future imagery was significantly associated with optimism, even when adjusting for socio-demographic factors and everyday imagery use. The ability to generate vivid mental imagery of positive future events may provide a modifiable cognitive marker of optimism. Boosting positive future imagery could provide a cognitive target for treatment innovations to promote optimism, with implications for mental health and even physical well-being. PMID- 23084599 TI - Risks factors and regression model for risk calculation of anesthesiologic intervention in topical and intracameral cataract surgery. AB - PURPOSE: To determine risk factors for anesthesiologist intervention during routine cataract surgery performed with topical and intracameral anesthesia and establish a regression model to identify high-risk patients. SETTING: Department of Ophthalmology, Clinica Universidad de Navarra, Pamplona, Spain. DESIGN: Prospective case series. METHODS: After cataract surgery at an ambulatory surgical center, anesthesia personnel completed a questionnaire to determine adverse medical events and risk factors related to anesthesiologist intervention. A Poisson regression model was used to calculate the interventional risks. Bootstrapping was performed for internal model validation. RESULTS: Of the 1010 cases, 50 (4.95%) required anesthesiologist intervention. Univariate analysis identified an association between anesthesiologist intervention and hypertension (P<.001), psychiatric history (P=.002), initial systolic blood pressure (P<.001), surgical duration (P=.001), and diabetes (P=.018). Scores were obtained using the following proposed regression model equation: (-8.68 + 0.33 * sex [men, 0; women, 1] + -0.02 * age [years] + 0.68 * hypertensive history [no, 0; yes, 1] + 1.18 * psychiatric background [no, 0; yes, 1] + 0.04 * initial systolic blood pressure [mm Hg]). The area under the receiver-operating curve was 0.803 (95% confidence interval [CI], 0.721-0.886). The area under the curve found in the validation method was 0.813 (95% CI, 0.727-0.887). CONCLUSION: Hypertension was the main risk factor for anesthesiologist intervention. The regression model discriminated between patients at lower and higher risk for intraoperative intervention for monitored anesthesia care. The probability of anesthesiologist intervention was 11.7 times higher when the model obtained a high score. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23084600 TI - Levels and correlates of implicit rationing of nursing care in Swiss acute care hospitals--a cross sectional study. AB - OBJECTIVES: (1) To describe the levels of implicit rationing of nursing care in Swiss acute care hospitals; (2) to explore the associations between nine selected potential rationing predictors and implicit rationing of nursing care. DESIGN: Cross sectional multi-center study. SETTINGS: A quota sample of 35 acute care hospitals from the German, French and Italian speaking regions of Switzerland participating in RN4CAST (Registered Nurse Forecasting) study. PARTICIPANTS: 1633 registered nurses working in randomly selected medical, surgical or medical surgical units. METHODS: Implicit rationing of nursing care, i.e., the withholding of any of 32 necessary nursing measures due to a lack of nursing resources, was measured using the revised Basel Extent of Rationing of Nursing Care (BERNCA) instrument. Nine potential rationing predictors, e.g., staffing and resource adequacy, patient-to-nurse ratio, nurse education, and confounding variables, e.g., nurse gender and age, hospital typology, were assessed with validated instruments or single items of the RN4CAST study. Descriptive statistical procedures were used as appropriate. Three level regression models were used to investigate the effect of the selected nine predictors on rationing at the nurse, unit and hospital levels. RESULTS: Ninety-eight percent of the participating nurses reported that, in their last seven working days, they had to ration at least one of the 32 nursing tasks listed in the BERNCA. The mean rationing level of 1.69 (SD=0.571) indicates that on average the nurses reported 'rarely' being unable to perform the nursing tasks listed in the BERNCA. Multilevel regression analysis confirmed two of the nine tested predictors: better unit level staff resource adequacy and a more favorable hospital level safety climate were both consistently significantly associated with lower rationing levels. Counter to our assumptions, the other two nurse practice environment dimensions, the three workload measures, nurse experience and nurse education were not associated with rationing. CONCLUSIONS: Rationing frequency varied among the 32 BERNCA items, indicating differing prioritizations of necessary nursing tasks. The identified rationing predictors, staff resource adequacy and safety climate, can determine starting points for interventions, i.e., proactive changes to improve staff resource adequacy when rationing exceeds predefined thresholds, increasing the risk of negative effects on patient outcomes. PMID- 23084601 TI - PESNPdb: a comprehensive database of SNPs studied in association with pre eclampsia. AB - Pre-eclampsia is a pregnancy specific disorder that can be life threatening for mother and child. Multiple studies have been carried out in an attempt to identify SNPs that contribute to the genetic susceptibility of the disease. Here we describe PESNPdb (http://bejerano.stanford.edu/pesnpdb), a database aimed at centralizing SNP and study details investigated in association with pre eclampsia. We also describe a Placenta Disorders ontology that utilizes information from PESNPdb. The main focus of PESNPdb is to help researchers study the genetic complexity of pre-eclampsia through a user-friendly interface that encourages community participation. PMID- 23084602 TI - Pedestrian and bicycle plans and the incidence of crash-related injuries. AB - This study examined the association between the presence of pedestrian and bicycle plans to pedestrian and bicyclist nonfatal and fatal injuries from 1997 to 2009 among 553 North Carolina (NC) municipalities. We considered all municipal plans (n=92; 49 pedestrian; 34 bicycle; and 9 combined plans featuring pedestrian and bicyclist components) published through 2009. Counts of pedestrian and bicyclist nonfatal and fatal injuries came from the NC Department of Transportation crash database, and the estimated number of pedestrian and bicycle trips per municipality in one year were used to calculate pedestrian and bicyclist nonfatal and fatal injury rates. In the 13-year study period, pedestrian/combined municipality plans and bicycle/combined municipality plans were present for 189 (2.6%) and 238 (3.3%) municipality-years, respectively. There were 11,795 nonfatal injuries, 9237 possible nonfatal injuries, and 1075 fatal injuries sustained by pedestrians in pedestrian-motor vehicle crashes. There were 4842 nonfatal injuries, 3666 possible nonfatal injuries, and 134 fatal injuries sustained by bicyclists in bicyclist-motor vehicle crashes. Although not statistically significant, unadjusted nonfatal and fatal injury rates among pedestrians and bicyclists were lower in those municipality-years in which plans had been published that year or in a year prior, compared to municipality-years lacking a plan. Adjusted rate ratios (RR) indicated that pedestrian nonfatal and fatal injury rates decreased in municipality-years with publication of pedestrian/combined plans (nonfatal injury RR: 0.75, 95% confidence interval (CI): 0.68, 0.82; fatal injury RR: 0.63, 95% CI: 0.46, 0.85). However, bicyclist nonfatal and fatal injury rates did not significantly change with publication of bicyclist/combined plans. Our research suggests that plan publication is associated with lower rates of nonfatal and fatal injury in pedestrians; this association was not observed for bicyclists. Further work must determine how the extent of implementation and quality of safety-related content within these plans affects changes in nonfatal and fatal injury rates. PMID- 23084603 TI - [Semiology for gluteal remodeling by lipofilling]. AB - INTRODUCTION: Gluteal augmentation is a consultation request for many patients. The most common surgical techniques performed for gluteal augmentation employ gluteal implants. However, the results can be frustrating. Liposuction is one of the most common surgical procedures in aesthetic surgery. This surgical procedure can provide some complications. Fat grafting is an effective and predictable way to remodel the buttocks. To get better results, it's important to understand gluteal compartments with a descriptive study. The aim of this study is to describe gluteal semiology for buttocks remodeling with fat grafting. METHODS AND TECHNIQUE: We have described gluteal semiology with our review of literature. We have analyzed fat compartments of gluteal region: volume, links between every compartments, connections with major gluteal muscle and with the skin. We have also analyzed shape and volume of the buttocks. RESULTS: We have described 11 aesthetic subunits, the volume and the shape of the buttocks, and the skin laxity. We did an important literature review to understand the most important gluteal zones to improve for patients' satisfaction. CONCLUSION: Our gluteal semiology description is very useful to understand liposuction/lipoinjection of gluteal areas. Fat grafting may be a reliable technique, simple and safe procedure. Surgery for correction of the buttocks may involve more than projection and volume. However, these must be in a balanced proportion with the rest of the body. PMID- 23084604 TI - [Acinetobacter baumannii: do they still deserve our attention?]. PMID- 23084605 TI - [The routine use of the Pneumonia Severity Index together with other criteria improves the management of community acquired pneumonia]. PMID- 23084606 TI - [Hemolytic anemia in a child with malaria treated with arthemeter]. PMID- 23084607 TI - Conflict resolution in end-of-life decisions in the neonatal unit. AB - End-of-life decisions are always stressful for families and professionals. As the decades pass, ethics and the law both change, even in one society, and cannot always provide perfect choices for each individual patient. Conflict should rarely arise in the neonatal unit. High-quality communication and compassion should allow professionals and families to build a team approach to the care of their child, even when the infant is imperilled. Each unit should have structures in place to deal with conflict, and every senior professional must be trained in conflict resolution so that the care of the family is outstanding. PMID- 23084608 TI - The DRD2 C957T polymorphism and the attentional blink--a genetic association study. AB - The attentional blink phenomenon (AB) describes a transient deficit in temporally selective visual attention regarding the processing of the second of two target stimuli in a rapid serial visual presentation (RSVP) task. The AB is a very prominent paradigm in the Cognitive Neurosciences that has been extensively studied by diverse psychophysiological techniques such as EEG or fMRI. Association studies from molecular genetics are scarce although the high heritability of higher cognitive functioning is proven. Only one seminal study reported an association between AB magnitude and the dopamine receptor D2 (DRD2) C957T polymorphism (Colzato et al., 2011). This functional polymorphism influences striatal D2 receptor binding affinity and thereby the efficacy of dopaminergic neurotransmission which is important for working memory and attentional processes. Colzato et al. (2011) reported that DRD2 C957T T/T carriers exhibit a significant smaller AB than C-allele carriers. In the present study this influence of the DRD2 SNP on the AB could not be replicated in N=211 healthy participants. However, a significantly larger lag 1 sparing was observed for homozygous T/T-carriers. Moreover, carriers of at least one T-allele showed a significantly poorer performance in the identification of T1. In general, these results support the notion of a role of the dopaminergic system on the AB. However, as our results do not parallel previous findings the exact nature of this influence and its dependence on task parameters will have to be examined in further genetic association studies. PMID- 23084609 TI - A 30-year perspective on psychosocial issues in lung cancer: how lung cancer "Came out of the Closet". AB - Psychological responses to lung cancer have changed over the past 30 years as perceptions of the disease have changed. Previously seen as a fatal diagnosis, it is now regarded as a cancer whose treatment is increasingly effective as the science of the disease advances. The stigma of smoking is diminishing as more is learned about genetic factors and as more nonsmokers are diagnosed. Support groups are now widely available. The increasing social support and greater knowledge of lung cancer provide a more supportive environment in which patients cope with lung cancer today compared with 30 years ago. PMID- 23084610 TI - Quality of life in pulmonary surgery: choosing, using, and developing assessment tools. AB - There is mounting recognition that, to aid surgical decision making, treatment efficacy needs to be measured in a variety of ways, with health-related quality of life now widely regarded as an important outcome in pulmonary surgical populations. The aim of this review is to provide a comprehensive overview of the key issues to consider if an investigator wishes to incorporate health-related quality of life assessment into trials and studies of pulmonary surgery, drawing on recent studies of lung cancer surgery as an example. PMID- 23084611 TI - Changes in quality of life after pulmonary resection. AB - This article assesses the impact of pulmonary resection on quality of life by means of a systematic quantitative review of the available literature. Perioperative changes in quality of life scales were measured by the Cohen's effect size method (mean change of the variable divided by its baseline standard deviation). After lobectomy, most quality-of-life scales differed slightly from preoperative values but tended to recover from the first evaluation time point up to 12 months after surgery. After pneumonectomy, most scales showed a stable or declining trend from the first evaluation up to 12 months after surgery. PMID- 23084612 TI - Minimally invasive lung surgery and postoperative quality of life. AB - Quality of life (QOL) after medical interventions is paramount to the patient considering treatment recommendations. To understand QOL in thoracic surgery patients, one must examine the outcomes patients prioritize (preferences) from successful surgical therapy, overall functional status of thoracic surgery patients, the literature addressing QOL after thoracic surgery (TS) and the possible benefit of minimally invasive TS, and, finally, future directions of TS postoperative QOL research. The primary focus of this article is lung cancer surgery with mention of other thoracic disease such as empyema, pneumothorax, or emphysema, as well. PMID- 23084613 TI - Quality of life in the high-risk candidate for lung resection. AB - Examination of the preferences of patients with lung cancer suggests that the ideal therapy may not be based on standard outcome measures such as survival, but should also consider the morbidity, adverse effects, and convenience of the treatment. Functional outcomes after lung resection have particular importance in guiding decision making in high-risk operative candidates. In this article, quality-of-life measures are reviewed in the context of guiding choices between operative and nonoperative therapies in a shared decision-making model for high risk candidates for lung resection. PMID- 23084614 TI - Surviving the intensive care: residual physical, cognitive, and emotional dysfunction. AB - Patients recovering from critical illness may suffer from physical, psychological, and cognitive problems that have a negative impact on their health related quality of life. To ensure that patients return as close as possible to their previous physical and mental health, their rehabilitation needs should be assessed and an appropriate program started. Both early mobilization and physical rehabilitation while the patient is still in the intensive care unit and manualized rehabilitation after discharge are beneficial. It is important to assess the rehabilitation needs of patients and target physiotherapy and counseling resources at those patients with the greatest need. PMID- 23084616 TI - The patient-surgeon relationship in the cyber era: communication and information. AB - From Laennec's invention of the stethoscope in 1816 to the recently introduced Sapien transcatheter aortic valve replacement, the increasing complexity of health care technology has altered the relationship between patients and physicians, usually for the better. Telemedicine, the provision of medical services through electronic media, has dramatically changed how the patient and physician interact and how medical care is delivered. Many studies of physicians' perceptions of electronic communication with patients have documented recognition of benefits as well as a consistent chorus of concerns about confidentiality, increased workload, inappropriate use, and medicolegal issues. PMID- 23084615 TI - Psychosocial issues facing lung transplant candidates, recipients and family caregivers. AB - Although lung transplantation is an accepted treatment for many individuals with severe lung disease, transplant candidates and recipients experience a range of psychosocial stressors that begin at the initiation of the transplant evaluation and continue throughout patients' wait for donor lungs, their perioperative recovery, and their long-term adjustment to posttransplant life. Transplant programs should strive to incorporate evidence-based interventions that aim to improve physical functioning, psychological distress, global quality of life, and medical adherence as well as to integrate symptom management and palliative care strategies throughout the pre- and posttransplantation course. PMID- 23084617 TI - Patients' perspective in the surgical decision-making process. AB - Barriers can arise if surgeons are unable to effectively convey information on benefits and risks or are unwilling to offer management choices based on patients' preferences. Facilitating shared decision making, allowing patients to carefully think and consider the alternatives, and empowering them to share in the decision-making process improve patient satisfaction and treatment adherence and represent the hallmark of an excellent clinician. PMID- 23084618 TI - Patient safety in the surgical setting. AB - Patient safety has been the subject of surgical investigation for the past century. A specific focus on safety and medical errors has incited public attention, government oversight, and research funding. Traditional efforts have been focused on the individual responsible for the "mistake," while current procedure focuses on a systems approach. A critical analysis of medical errors, their frequency and cause, and outcomes associated with their occurrence has allowed the identification of system-based issues and the implementation of corrective changes to improve these systems. Constant vigilance examining errors and how they occur will allow identification of strategies to reduce errors. PMID- 23084619 TI - Patients' satisfaction: customer relationship management as a new opportunity for quality improvement in thoracic surgery. AB - Clinical and nonclinical indicators of performance are meant to provide the surgeon with tools to identify weaknesses to be improved. The World Health Organization's Performance Evaluation Systems represent a multidimensional approach to quality measurement based on several categories made of different indicators. Indicators for patient satisfaction may include overall perceived quality, accessibility, humanization and patient involvement, communication, and trust in health care providers. Patient satisfaction is included among nonclinical indicators of performance in thoracic surgery and is increasingly recognized as one of the outcome measures for delivered quality of care. PMID- 23084620 TI - Patient perspectives in pulmonary surgery. Preface. PMID- 23084621 TI - Modeling Neanderthal clothing using ethnographic analogues. AB - Although direct evidence for Neanderthal clothing is essentially nonexistent, information about Paleolithic clothing could provide insights into the biological, technological, and behavioral capabilities of Neanderthals. This paper takes a new approach to understanding Neanderthal clothing through the collection and analysis of clothing data for 245 recent hunter-gatherer groups. These data are tested against environmental factors to infer what clothing humans tend to wear under different conditions. Beta regression is used to predict the proportion of the body covered by clothing according to a location's mean temperature of the coldest month, average wind speed, and annual rainfall. In addition, logistic regression equations predict clothing use on specific parts of the body. Neanderthal clothing patterns are modeled across Europe and over a range of Pleistocene environmental conditions, thereby providing a new appreciation of Paleolithic behavioral variability. After accounting for higher tolerances to cold temperatures, it is predicted that some Neanderthals would have covered up to 80% of their bodies during the winter, probably with non tailored clothing. It is also likely that some populations covered the hands and feet. In comparison with Neanderthals, Upper Paleolithic modern humans are found to have worn more sophisticated clothing. Importantly, these predictions shed new light on the relationship between Neanderthal extinction and their simple clothing. PMID- 23084622 TI - New discoveries of early Paleocene (Torrejonian) primates from the Nacimiento Formation, San Juan Basin, New Mexico. AB - Primates underwent a period of diversification following the extinction of non avian dinosaurs. Although the Order first appeared near the Cretaceous-Paleogene boundary, it is not until the Torrejonian (the second North American Land Mammal Age of the Paleocene) that a diversity of families began to emerge. One of the lithological units critical to understanding this first primate adaptive radiation is the early Paleocene Nacimiento Formation of the San Juan Basin (SJB; New Mexico). Primates previously described from this formation comprise six species of palaechthonid and paromomyid plesiadapiforms, all known from very limited material. Collecting has increased the sample of primate specimens more than fivefold. Included in the new sample is the first specimen of a picrodontid plesiadapiform from the Torrejonian of the SJB, referable to Picrodus calgariensis, and the first paromomyid specimen complete enough to allow for a species level taxonomic assignment, representing a new species of Paromomys. With respect to the 'Palaechthonidae', the current report describes large collections of Torrejonia wilsoni and Palaechthon woodi, and the first new specimens attributed to Plesiolestes nacimienti and Anasazia williamsoni since 1972 and 1994, respectively. These collections demonstrate previously unknown morphological variants, including the presence of a metaconid on the p4 of some specimens of T. wilsoni, a discovery that supports previous inferences about a close relationship between Torrejonia and Plesiolestes problematicus. This new sample considerably improves our knowledge of the poorly understood 'Palaechthonidae', and about the biostratigraphy, biogeography, and early evolution of North American primates. In particular, the rarity of paromomyids, the continuing absence of plesiadapid and carpolestid plesiadapiforms, and the presence of a number of endemic palaechthonid species in the SJB contrast with plesiadapiform samples from contemporaneous deposits to the north. Together, these data suggest that by the latter part of the early Paleocene primates had already developed not only an impressive diversity, but patterns of regional endemism. PMID- 23084623 TI - What are the most effective early response strategies and interventions to assess and address the immediate needs of children outside of family care? AB - OBJECTIVES: Children outside of family care face increased risk of threats to their well-being, have lower educational achievement, and experience adverse developmental outcomes. While it is generally accepted that early response and intervention is critical to reducing the risk of harm for children who have been separated from their families, it is not always clear what the most effective early response strategies are for assessing and addressing their immediate needs. The purpose of this review was to identify evidence-based early response strategies and interventions for improving the outcomes of children outside of family care, including children of and on the street, institutionalized children, trafficked children, children affected by conflict and disaster, and who are exploited for their labor. METHODS: A multi-phased, systematic evidence review was conducted on peer-reviewed and gray literature, which yielded a total of 101 documents that met the inclusion criteria and were reviewed. RESULTS: Overall there is a weak evidence base regarding assessment and early response interventions for children living outside of family care. Few studies included careful outcome measures or comparison groups. Although few proven interventions emerged, the review identified several promising early interventions and approaches. In emergency settings, family tracing and reunification is a highly effective response in regard to separated children, whereas placing children in institutional care is problematic, with the possible exception of time-limited placements of formerly recruited children in interim care centers. Livelihood supports are promising in regard to preventing and responding to children living outside family care. Other promising interventions include psychosocial support, including the use of traditional cleansing rituals as appropriate, educational supports such as Child Friendly Spaces, the maintenance of family connectedness for children of or on the streets, the use of community-based approaches that aid social integration, and approaches that enable meaningful child participation. A recurrent theme was that to be effective, all assessments and interventions must fit the context. CONCLUSION: A strong need exists for strengthening the evidence base regarding the effectiveness of early assessments and responses to children living outside family care and for using the evidence to guide operational policy and practice. Recommendations regarding policy, practices, and research emerged from the review process. PMID- 23084624 TI - Outcomes of contemporary use of rectangular titanium stand-alone cages in anterior cervical discectomy and fusion: cage subsidence and cervical alignment. AB - Cervical intervertebral disc replacement using a rectangular titanium stand-alone cage has become a standard procedure for anterior cervical discectomy and fusion (ACDF). We examined outcomes resulting from the contemporary use of rectangular titanium stand-alone cages for ACDF, particularly focusing on cage subsidence and subsequent kyphotic malalignment. Patient data were collected prospectively, and a total of 47 consecutive patients who underwent periodic follow-up of at least 1 year's duration after ACDF were studied retrospectively. Sixty-three rectangular titanium cages were implanted during 31 1-level and 16 2-level procedures. None of the patients developed surgery-related complications (including cage displacement or extrusion). Mean Neurosurgical Cervical Spine Scale scores were significantly improved at 1 year after surgery. Twelve of the 63 inserted cages (19.0%) were found to have cage subsidence, occurring in 11 of 47 patients (23.4%). There was no significant difference in functional recovery between patients with and without cage subsidence. Logistic regression analysis indicated that fusion level, cage size and cage position were significantly related to cage subsidence. The distraction ratio among patients with cage subsidence was significantly higher than that among patients without cage subsidence. Cage subsidence resulted in early deterioration of local angle and total alignment of the cervical spine. Although a longer follow-up is warranted, a good surgical outcome with negligible complications appears to justify the use of rectangular titanium stand-alone cages in 1- and 2-level ACDF. Excessive distraction at the fusion level should be avoided, and cage position should be adjusted to the anterior vertical line. PMID- 23084625 TI - Bovine innate and adaptive immune responses against Escherichia coli O157:H7 and vaccination strategies to reduce faecal shedding in ruminants. AB - Enterohaemorrhagic E. coli (EHEC) O157:H7 is a zoonotic pathogen of worldwide importance causing foodborne infections with possibly life-threatening consequences in humans, such as haemorrhagic colitis and in a small percentage of zoonotic cases, haemolytic-uremic syndrome (HUS). Ruminants are an important reservoir of EHEC and human infections are most frequently associated with direct or indirect contact with ruminant faeces. A thorough understanding of the host bacterium interaction in ruminants could lead to the development of novel interventions strategies, including innovative vaccines. This review aims to present the current knowledge regarding innate and adaptive immune responses in EHEC colonized ruminants. In addition, results on vaccination strategies in ruminants aiming at reduction of EHEC shedding are reviewed. PMID- 23084626 TI - Differentiation of F4 receptor profiles in pigs based on their mucin 4 polymorphism, responsiveness to oral F4 immunization and in vitro binding of F4 to villi. AB - F4(+) enterotoxigenic Escherichia coli (F4(+) ETEC) are an important cause of diarrhoea and mortality in piglets. F4(+) ETEC use their F4 fimbriae to adhere to specific receptors (F4Rs) on small intestinal brush borders, resulting in colonization of the small intestine. To prevent pigs from post-weaning diarrhoea, pigs should be vaccinated during the suckling period. Previously, we demonstrated that F4acR(+), but not F4acR(-) piglets could be orally immunized with purified F4 fimbriae resulting in a protective immunity against F4(+) ETEC infections, indicating that this immune response was F4R dependent. Recently, aminopeptidase N has been identified as a glycoprotein receptor important for this oral immune response. However, in some oral immunization experiments, a few F4acR(+) piglets did not show an antibody response upon oral immunization, suggesting additional receptors. Therefore, the binding profile of F4 to brush border membrane (glyco)proteins was determined for pigs differing in F4-specific antibody response upon oral immunization, in in vitro adhesion of F4(+)E. coli to small intestinal villi, and in Muc4 genotype. Six groups of pigs could be identified. Only two groups positive in all three assays showed two high molecular weight (MW) glycoprotein bands (>250kDa) suggesting that these high MW bands are linked to the MUC4 susceptible genotype. The fact that these bands were absent in the MUC4 resistant group which showed a positive immune response against F4 and was positive in the adhesion test confirm that at least one or perhaps more other F4Rs exist. Interestingly, two pigs that were positive in the villous adhesion assay did not show an immune response against F4 fimbriae. This suggests that a third receptor category might exist which allows the bacteria to adhere but does not allow effective immunization with soluble F4 fimbriae. Future research will be necessary to confirm or reveal the identity of these receptors. PMID- 23084627 TI - Immune response of turbot (Scophthalmus maximus L.) to a broad spectrum vaccine candidate, recombinant glyceraldehyde-3-phosphate dehydrogenase of Edwardsiella tarda. AB - Edwardsiella tarda is a Gram-negative pathogen which causes systemic infection in turbot. The increasing frequency of edwardsiellosis in turbot farming has stressed the need to understand the immune responses of fish, for the further development of prevention and control strategies. As a broad spectrum protective antigen, a recombinant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of E. tarda EIB202 has been proven to present remarkable protection against E. tarda, Aeromonas hydrophila, Vibrio anguillarum, Vibrio alginolyticus and Vibrio harvei in zebrafish. Here, the protection and immune responses of turbot vaccinated with this antigen were studied. Fish vaccinated with recombinant GAPDH via intraperitoneal injection exhibited a low cumulative mortality when challenged with E. tarda EIB202, while high levels of specific antibodies and enhanced bactericidal activities of the immunized sera were observed. In addition, significantly increased transcription levels of four immune-related genes including IL-1beta, MHC Ialpha and IIalpha, and IgM in the liver, spleen and kidney tissues of vaccinated fish showed that both humoral and cellular immune responses were soundly aroused in the vaccinated fish. Moreover, the IgM antibodies induced by recombinant GAPDH exhibited obvious cross-reactions with the other four pathogens. These results suggested that recombinant GAPDH could present effective protective immunity not only against E. tarda but also other extracellular pathogens, and would be a potential vaccine candidate against polymicrobial infections in the aquaculture industry. PMID- 23084628 TI - A directed intimin insertion mutant of a rabbit enteropathogenic Escherichia coli (REPEC) is attenuated, immunogenic and elicits serogroup specific protection. AB - We previously showed (Agin et al., 2005) that a truncated beta-intimin mutant of an O15 A/E REPEC strain, which does not contain the C terminal tir binding region of intimin but expresses the preceding immunodominant portion of the molecule in outer membranes, is attenuated, induces anti-intimin and anti whole cell antibody, and protects against challenge with a virulent strain of the same serogroup. Since the ability of this and other intimin mutants lacking the tir binding region to provide broad protection against challenge with REPEC strains of other serogroups is incompletely studied, we generated a targeted insertion/deletion intimin mutant in an O103 strain, immunized rabbit's orogastrically, then challenged them with the parent strain and a virulent strain of a different serogroup. We used lambda red recombinase to generate an eae mutation in the prototypic rabbit A/E Escherichia coli strain E22 (O103) by replacing the 81 C-terminal (860-939) tir-binding amino acids of intimin with an inserted kanamycin resistance gene. This mutant did not express intimin in its outer membranes. A range of increasing immunizing doses (10(4)-10(7)CFU) was used for the first immunization in 4 groups of 6 rabbits. All 4 groups received a 2nd immunization with 10(7)CFU after 2weeks. At 4weeks, half of the rabbits in each group, and 6 control rabbits, were challenged with the parent O103 strain or with the O15 strain RDEC-H19A. All unimmunized rabbits exhibited characteristic weight loss with diarrhea and shedding of the challenge strain after challenge with E22 or RDEC-H19A. Rabbits challenged with the parent O103 E22, but not with the O15 RDEC-H19A, were protected against clinical signs of disease, maintained normal weight gain, had reduced fecal shedding of challenge organism. At sacrifice, CFU of E22, but not RDECH19, were decreased in ileum, cecum and colon. Serum antibodies to E22 somatic antigens, but not intimin, were detected in rabbits immunized with E22 Deltaeae860-939 and correlated with protection. An intimin insertion mutation replacing the tir binding region of O103 REPEC strain E22 with an antibiotic resistance gene was attenuated, induced antibody to whole bacteria but not to intimin, and yielded protection against challenge with the WT strain from which it was prepared but not against a virulent strain of another serogroup. These results suggest that intimin expression in outer membranes may be necessary to confer cross serogroup protection by inducing anti-intimin immunity. PMID- 23084629 TI - Enhanced wound healing effect of canine adipose-derived mesenchymal stem cells with low-level laser therapy in athymic mice. AB - BACKGROUND: Adipose-derived mesenchymal stem cells (ASCs) are attractive cell source for skin tissue engineering. However, one obstacle to this approach is that the transplanted ASC population can decline rapidly in the recipient tissue. OBJECTIVE: The aim of this study was to investigate the effects of low-level laser therapy (LLLT) on transplanted canine ASCs in a skin wound animal model. METHODS: LLLT, ASC transplantation (ASCs) and ASC transplantation with LLLT (ASCs+LLLT) were applied to the wound bed in athymic mice. Wound healing was assessed by gross evaluation and by hematoxylin and eosin staining. The survival, differentiation and secretion of vascular endothelial growth factor and basic fibroblast growth factor of the ASCs were evaluated by immunohistochemistry and Western blotting. RESULTS: The ASCs and ASCs+LLLT groups stimulated wound closure and histological skin regeneration. The ASCs+LLLT group enhanced the wound healing, including neovascularization and regeneration of skin appendages, compared with the ASCs group. The ASCs contributed skin regeneration via differentiation and secretion of growth factors. In the ASCs+LLLT group, the survival of ASCs was increased by the decreased apoptosis of ASCs in the wound bed. The secretion of growth factors was stimulated in the ASCs+LLLT group compared with the ASCs group. CONCLUSION: These data suggest that LLLT is an effective biostimulator of ASCs in wound healing that enhances the survival of ASCs and stimulates the secretion of growth factors in the wound bed. PMID- 23084630 TI - Virulence and antimicrobial resistance genes in human MRSA ST398 isolates in Austria. AB - This study determined the genetic background of virulence and resistance genes of MRSA ST398 in Austria. From 2004 up to 2008 a total of 41 human isolates of MRSA ST398 were investigated for virulence and resistance gene patterns using DNA microarray chip analysis. Highly similar virulence gene profiles were found in 29 (70.7%) of the isolates but genes encoding Panton-Valentine leukocidin, enterotoxins, or toxic shock syndrome toxin were not detected. Genes conferring resistance to tetracycline and erythromycin-lincosamide were common as all but one of the isolates exhibited tetM and/or tetK, which are involved in tetracycline resistance, and 12 (29.9%) were positive for ermC, conferring resistance to erythromycin/lincosamide. SplitsTree analysis showed that 40 isolates were closely related. Changes in virulence and resistance gene patterns were minimal over the observed time period. PMID- 23084631 TI - Delayed wound healing in aged skin rat models after thermal injury is associated with an increased MMP-9, K6 and CD44 expression. AB - Age-related differences in wound healing have been documented but little is known about the wound healing mechanism after burns. Our aim was to compare histological features and immunohistochemical expression of matrix metalloproteinase-9 (MMP-9), collagen IV, K6 and CD44 in the burn wound healing process in aged and young rats. Following burns the appearance of the wound bed in aged rats had progressed but slowly, resulting in a delayed healing process compared to the young rats. At 21 days after injury, epithelial K6, MMP-9 and CD44 expression was significantly increased in aged rats with respect to young rats; moreover, in the aged rat group we observed a not fully reconstituted basement membrane. K6, MMP-9 and CD44 expression was significantly increased in wounded skin compared to unwounded skin both in young and aged rats. We hypothesise that delayed burn skin wound healing process in the aged rats may represent an age dependent response to injury where K6, MMP-9 and CD44 play a key role. It is therefore possible to suggest that these factors contribute to the delayed wound healing in aged skin and that modulation could lead to a better and faster recovery of skin damage in elderly. PMID- 23084632 TI - Work place electrical injury in construction workers. PMID- 23084633 TI - Mammaglobin expression in gynecologic adenocarcinomas. AB - Mammaglobin (MGB) has been proposed as a sensitive and specific immunohistochemical marker for adenocarcinoma of the breast. The differential diagnosis of breast adenocarcinoma versus a gynecologic primary frequently arises. We performed a semiquantitative survey of MGB immunoreactivity in 26 benign gynecologic tissues (6 ectocervices, 9 endocervices, 11 endometria), 86 ovarian adenocarcinomas, 70 endometrial adenocarcinomas, and 10 endocervical adenocarcinomas. Among ovarian tumors, MGB was present in 40% of endometrioid carcinomas; 36%, serous carcinomas; 21%, clear cell carcinomas; and 6%, mucinous carcinomas. Among endometrial cancers, MGB reactivity was present in 57% of endometrioid carcinomas, but only 30% of serous carcinomas and 6% of clear cell carcinomas. MGB was absent in endocervical adenocarcinomas. Across all tumor types with positive staining, MGB was focal or patchy (ie, less than diffuse) in 50 of 57 cases. Using a scale of 0 to 3+, the only 3 tumors with 3+ MGB reactivity were all serous carcinomas (1 ovarian and 2 endometrial). There were no cases with diffuse 3+ MGB expression. On the other hand, diffuse 2+ MGB was seen in 4 cases: 1 endometrioid carcinoma of ovary, 1 serous carcinoma of ovary, and 2 clear cell carcinomas of ovary. In conclusion, a diagnostically significant proportion of gynecologic carcinomas are immunoreactive for MGB. Gynecologic primaries should be considered in the differential diagnosis of MGB-positive malignancies of unknown origin. PMID- 23084634 TI - Dysregulation of mammalian target of rapamycin pathway in plasmacytoid variant of urothelial carcinoma of the urinary bladder. AB - Plasmacytoid urothelial carcinoma is a rare but aggressive variant of bladder cancer with no clear therapeutic guidelines. Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been linked to oncogenesis in conventional bladder cancer. Several antineoplastic agents targeting mTOR pathway are currently available. This study assesses mTOR pathway status as well as c-myc and p27 expression. We retrieved 19 archival cases of plasmacytoid urothelial carcinoma from two institutions. Whole tissue sections were evaluated for immunoexpression of phosphatase and tensin homolog (PTEN), phosphorylated mTOR, phosphorylated protein kinase B (AKT), phosphorylated S6, c-myc, and p27. We evaluated intensity (0 to 3+) and extent (0%-100%) of expression for all markers. An H score was calculated as the sum of products of intensity and extent for each marker and used during analysis. In addition, PTEN loss was defined as absence of expression in >10% of tumor cells. We encountered PTEN loss in 28%. Higher H score for nuclear phosphorylated AKT and a lower H score for phosphorylated S6 was encountered in muscle invasive tumors compared to non-muscle invasive tumors (P = .007 and P = .009, respectively). Although a trend for negative prognostic impact on overall survival for higher phosphorylated mTOR expression was noted (P = .051), markers expression levels failed to predict survival in our cohort. We found dysregulation of mTOR pathway members in urinary bladder plasmacytoid urothelial carcinoma, suggesting that the use of mTOR pathway inhibitors might be beneficial for patients with this aggressive tumor. PMID- 23084635 TI - A novel complex KIT mutation in a gastrointestinal stromal tumor of the vermiform appendix. AB - Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery. PMID- 23084636 TI - Potential mechanisms for the emerging link between obesity and increased intestinal permeability. AB - Recently, increased attention has been paid to the link between gut microbial composition and obesity. Gut microbiota is a source of endotoxins whose increase in plasma is related to obesity and insulin resistance through increased intestinal permeability in animal models; however, this relationship still needs to be confirmed in humans. That intestinal permeability is subject to change and that it might be the interface between gut microbiota and endotoxins in the core of metabolic dysfunctions reinforce the need to understand the mechanisms involved in these aspects to direct more efficient therapeutic approaches. Therefore, in this review, we focus on the emerging link between obesity and increased intestinal permeability, including the possible factors that contribute to increased intestinal permeability in obese subjects. We address the concept of intestinal permeability, how it is measured, and the intestinal segments that may be affected. We then describe 3 factors that may have an influence on intestinal permeability in obesity: microbial dysbiosis, dietary pattern (high-fructose and high-fat diet), and nutritional deficiencies. Gaps in the current knowledge of the role of Toll-like receptors ligands to induce insulin resistance, the routes for lipopolysaccharide circulation, and the impact of altered intestinal microbiota in obesity, as well as the limitations of current permeability tests and other potential useful markers, are discussed. More studies are needed to reveal how changes occur in the microbiota. The factors such as changes in the dietary pattern and the improvement of nutritional deficiencies appear to influence intestinal permeability, and impact metabolism must be examined. Also, additional studies are necessary to better understand how probiotic supplements, prebiotics, and micronutrients can improve stress-induced gastrointestinal barrier dysfunction and the influence these factors have on host defense. Hence, the topics presented in this review may be beneficial in directing future studies that assess gut barrier function in obesity. PMID- 23084637 TI - Resveratrol role in cardiovascular and metabolic health and potential mechanisms of action. AB - Resveratrol is a polyphenolic flavonoid found in a diversity of plants, especially berry fruits and is a popular nutritional supplement. It is known to have antioxidant, anti-inflammatory, and anticarcinogenic properties. Recently, additional evidence has been found that resveratrol is beneficial to metabolic and cardiovascular health and may increase the life expectancy of various organisms. These biological effects are widely believed to be due to the ability of resveratrol to activate silent mating-type information regulation 2 homolog 1, a nicotinamide adenine dinucleotide-dependent deacetylase. However, other research has shown that 5'-adenosine monophosphate-activated kinase and not silent mating-type information regulation 2 homolog 1 may be the target of resveratrol. A recent study reported that resveratrol directly inhibits cyclic adenosine monophosphate-specific phosphodiesterases and then activates 5' adenosine monophosphate-activated kinase. Therefore, the mechanism underlying the diverse nutritional and therapeutic activities of resveratrol needs to be further explored. Furthermore, the optimal dose and possible adverse effects of resveratrol in humans are completely clear. The purpose of this review is to present some of the newly discovered biological effects of resveratrol, including autophagy and stem cell regulation, and research opportunities for the application of resveratrol in cardiovascular and metabolic health. Described herein is the recent understanding of the mechanism of action of resveratrol and future research directions to ascertain the potential of this flavonoid that is present in food. PMID- 23084638 TI - Secondary analyses of data from 4 studies with fourth-grade children show that sex, race, amounts eaten of standardized portions, and energy content given in trades explain the positive relationship between body mass index and energy intake at school-provided meals. AB - Results from a 2012 article showed a positive relationship between children's body mass index (BMI) and energy intake at school-provided meals. To help explain that positive relationship, secondary analyses investigated (1) whether the relationship differed by sex and race and (2) the relationship between BMI and 6 aspects of school-provided meals--amounts eaten of standardized portions, energy content given in trades, energy intake received in trades, energy intake from flavored milk, energy intake from a la carte ice cream, and breakfast type. Data were from 4 studies conducted 1 per school year (1999-2000 to 2002-2003). Fourth grade children (n = 328; 50% female; 54% black) from 13 schools total were observed eating school-provided breakfast and lunch on 1 to 3 days per child for 1178 total meals (50% breakfast). Children were weighed and measured. Marginal regression models were fit using BMI as the dependent variable. For purpose 1, independent variables were energy intake at school-provided meals, sex, race, age, and study; additional models included interaction terms involving energy intake and sex/race. For purpose 2, independent variables were the 6 aspects of school-provided meals, sex, race, age, and study. The relationship between BMI and energy intake at school-provided meals differed by sex (P < .0001; stronger for females) and race (P = .0063; stronger for black children). BMI was positively related to amounts eaten of standardized portions (P < .0001) and negatively related to energy content given in trades (P = .0052). Explaining the positive relationship between BMI and energy intake at school-provided meals may contribute to school-based obesity prevention efforts. PMID- 23084639 TI - High levels of stearic acid, palmitoleic acid, and dihomo-gamma-linolenic acid and low levels of linoleic acid in serum cholesterol ester are associated with high insulin resistance. AB - The association of fatty acid composition with insulin resistance and type 2 diabetes has been reported in Western populations, but there is limited evidence of this association among the Japanese, whose populace consume large amounts of fish. To test the hypothesis that high palmitic, palmitoleic, and dihomo-gamma linolenic acids and low levels of linoleic and n-3 fatty acids are associated with higher insulin resistance among the Japanese, the authors investigated the relationship between serum fatty acid composition and serum C-peptide concentrations in 437 Japanese employees aged 21 to 67 years who participated in a workplace health examination. Serum cholesterol ester and phospholipid fatty acid compositions were measured by gas-liquid chromatography. Desaturase activity was estimated by fatty acid product-to-precursor ratios. A multiple regression was used to assess the association between fatty acid and C-peptide concentrations. C-peptide concentrations were associated inversely with linoleic acid levels in cholesterol ester and phospholipid (P for trend = .01 and .02, respectively) and positively with stearic and palmitoleic acids in cholesterol ester (P for trend =.02 and .006, respectively) and dihomo-gamma-linolenic acid in cholesterol ester and phospholipid (P for trend < .0001 for both). C-peptide concentrations were not associated with n-3 polyunsaturated fatty acids. C peptide concentrations significantly increased as delta-9-desaturase (16:1 n 7/16:0) and delta-6-desaturase (18:3 n-6/18:2 n-6) increased (P for trend = .01 and .03, respectively) and delta-5-desaturase (20:4 n-6/20:3 n-6) decreased (P for trend = .004). In conclusion, a fatty acid pattern with high levels of serum stearic, palmitoleic, or dihomo-gamma-linolenic acids; delta-9-desaturase (16:1 n 7/16:0) or delta-6-desaturase (18:3 n-6/18:2 n-6) activities; and low levels of serum linoleic acid or delta-5-desaturase (20:4 n-6/20:3 n-6) activity might be associated with higher insulin resistance in Japanese adults. PMID- 23084640 TI - Branched-chain amino acids reduce hindlimb suspension-induced muscle atrophy and protein levels of atrogin-1 and MuRF1 in rats. AB - Atrogin-1 and MuRF1, muscle-specific ubiquitin ligases, and autophagy play a role in protein degradation in muscles. We hypothesized that branched-chain amino acids (BCAAs) may decrease atrogin-1, MuRF1, and autophagy, and may have a protective effect on disuse muscle atrophy. To test this hypothesis, we selected hindlimb suspension (HS)-induced muscle atrophy as a model of disuse muscle atrophy because it is an established model to investigate the effects of decreased muscle activity. Sprague-Dawley male rats were assigned to 4 groups: control, HS (14 days), oral BCAA administration (600 mg/[kg day], 22.9% L isoleucine, 45.8% L-leucine, and 27.6% L-valine), and HS and BCAA administration. After 14 days of the treatment, muscle weights and protein concentrations, cross sectional area (CSA) of the muscle fibers, atrogin-1 and MuRF1 proteins, and microtubule-associated protein 1 light chain 3 II/I (ratio of LC3 II/I) were measured. Hindlimb suspension significantly reduced soleus muscle weight and CSA of the muscle fibers. Branched-chain amino acid administration partly but significantly reversed the HS-induced decrease in CSA. Hindlimb suspension increased atrogin-1 and MuRF1 proteins, which play a pivotal role in various muscle atrophies. Branched-chain amino acid attenuated the increase in atrogin-1 and MuRF1 in soleus muscles. Hindlimb suspension significantly increased the ratio of LC3 II/I, an indicator of autophagy, whereas BCAA did not attenuate the increase in the ratio of LC3 II/I. These results indicate the possibility that BCAA inhibits HS-induced muscle atrophy, at least in part, via the inhibition of the ubiquitin-proteasome pathway. Oral BCAA administration appears to have the potential to prevent disuse muscle atrophy. PMID- 23084641 TI - Green tea extract reverses endothelial dysfunction and reduces atherosclerosis progression in homozygous knockout low-density lipoprotein receptor mice. AB - The aim of this study was to evaluate the effects of green tea extract (GTE) administration on vascular reactivity and atherosclerosis progression in low density lipoprotein receptor knockout mice. We hypothesized that GTE intake may ameliorate atherosclerosis by improving endothelial dysfunction. Animals (n = 12 per group) were fed a hypercholesterolemic diet and received either water or GTE at a dose of 50, 100, or 300 mg/kg once a day by gavage (100 MUL/10 g weight). After 4 weeks, atherosclerosis extension and vascular reactivity were evaluated in the aorta, and the levels of lipids, monocyte chemotactic protein-1 (MCP-1), and tumor necrosis factor alpha were measured in the plasma. Administration of GTE at a dose of 50 mg/kg significantly decreased the area of atherosclerotic lesions by 35%, improved the vascular reactivity in the isolated thoracic aorta, and lowered the plasma levels of both MCP-1 and triglycerides. Delivery of 100 mg/kg of GTE only promoted vasocontraction and vasorelaxation (P < .05), whereas a dose of 300 mg/kg was ineffective. Maximum contraction and relaxation negatively correlated with the lesion area (r = -0.755 and -0.767, respectively), whereas the plasma levels of MCP-1 and triglycerides positively correlated with plaque size (r = 0.549 and 0.421, respectively). In summary, our results supported the hypothesis that administration of GTE at low doses may contribute to a decrease in atherosclerosis progression by reversing endothelial dysfunction. PMID- 23084642 TI - Soy protein with or without isoflavones failed to preserve bone density in gonadal hormone-deficient male rat model of osteoporosis. AB - Soy with its isoflavones has been shown to positively influence bone mineral density in female ovariectomized rats; hence, we hypothesized a similar effect in orchidectomized (ORX) male rats. Forty male Sprague-Dawley rats, aged 95 days, were divided into 4 groups and were either sham operated (Sham) or ORX. The ORX groups were fed a soy protein-based diet (SOY), an isoflavone-depleted soy protein diet (SOY-), or a casein based diet for 65 days after surgery. Orchidectomy increased the rate of bone turnover, resulting in reduced bone mineral density and bone mineral content by 3.5% and 14%, respectively, and compromised biomechanical properties. The mean femoral length of ORX animals was also significantly shorter than Sham animals, but ORX rats that were fed SOY diet did not experience this reduction in bone length, implicating a role for soy protein in bone growth (4.02 +/- 0.02, 3.93 +/- 0.01, 3.99 +/- 0.02, 3.91 +/- 0.01 for Sham, ORX, SOY, SOY-, respectively). The SOY and SOY- positively influenced the biomechanical properties of bone such as yield and ultimate force, the measures of bone elasticity, and plasticity. In terms of bone histomorphometry, the data indicate that SOY- tends to reduce ORX-induced increase in bone turnover as evidenced by suppressed bone formation rate/mineralized surface by about 9%. Overall, our results indicated that soy protein, regardless of its isoflavone content, was unable to prevent the ORX induced femoral decrease in bone density and mineral content. However, soy may enhance the quality of bone as indicated by increased yield force. PMID- 23084643 TI - Resveratrol up-regulates hepatic uncoupling protein 2 and prevents development of nonalcoholic fatty liver disease in rats fed a high-fat diet. AB - Obesity is associated with a markedly increased risk of nonalcoholic fatty liver disease. The anti-inflammatory polyphenol resveratrol possess promising properties in preventing this metabolic condition by dampening the pathological inflammatory reaction in the hepatic tissue. However, in the current study, we hypothesize that the beneficial effect of resveratrol is not solely attributable to its anti-inflammatory potential. Eight-week-old male Wistar rats were randomly distributed into 3 groups of 12 animals each: control diet (C), high-fat diet (HF), and HF supplemented with 100 mg resveratrol daily (HFR). After 8 weeks of dietary treatment, the rats were euthanized and relevant tissues were prepared for subsequent analysis. Resveratrol prevented the high fat-induced steatosis assessed by semiquantitative grading, which furthermore corresponded with a complete normalization of the hepatic triglyceride content (P < .001), despite no change in total body fat. In HFR, the hepatic uncoupling protein 2 expression was significantly increased by 76% and 298% as compared with HF and C, respectively. Moreover, the hepatic mitochondria content in HFR was significantly higher as compared with both C and HF (P < .001 and P = .004, respectively). We found no signs of hepatic inflammation, hereby demonstrating that resveratrol protects against fatty liver disease independently of its proposed anti-inflammatory potential. Our data might indicate that an increased number of mitochondria and, particularly, an increase in hepatic uncoupling protein 2 expression are involved in normalizing the hepatic fat content due to resveratrol supplementation in rodents fed a high-fat diet. PMID- 23084644 TI - Endurance training blocks uncoupling protein 1 up-regulation in brown adipose tissue while increasing uncoupling protein 3 in the muscle tissue of rats fed with a high-sugar diet. AB - The mitochondrial uncoupling proteins (UCPs) of interscapular brown adipose tissue (iBAT) and of muscles play important roles in energy balance. For instance, the expression of UCP1 and UCP3 are modulated by free fatty acid gradients induced by high-sugar diets and acute exercise that is dependent on sympathetic stimulation. However, the effects of endurance training in animals fed with high-sugar diets are unknown. This study aims to evaluate the long-term effects of diet and exercise on UCP1 and UCP3 levels and energy balance efficiency. Rats fed with standard or high-sugar (HSD) diets were simultaneously subjected to running training over an 8-week period. After the training period, the rats were decapitated, and the iBAT and gastrocnemius muscle tissues were removed for evaluation of the beta3-receptor, Ucp1, and Ucp3 mRNA and protein expression, which were analyzed by quantitative reverse transcriptase polymerase chain reaction and Western blot, respectively. Groups fed with an HSD displayed a higher adiposity index and iBAT weight (P < .05), whereas exhibited an up regulation of Ucp1 mRNA and protein levels (P < .05). Training increased beta3 receptor mRNA in iBAT and reduced the Ucp3 mRNA in muscle tissues. In association with an HSD, training restored the increasing beta3-receptor mRNA and greatly up regulated the levels of Ucp3 mRNA. Therefore, training blocked the HSD-induced up regulation of UCP1 expression in iBAT, whereas it up-regulated the expression of Ucp3 mRNA in muscle. These results suggest that training enhances the relationship between Ucp1/Ucp3 mRNA levels, which could result in higher energy efficiency, but not when HSD-induced elevated sympathetic activity is maintained. PMID- 23084645 TI - Panax ginseng reduces oxidative stress and restores antioxidant capacity in aged rats. AB - Nutritional antioxidants interact with cells in an active mode, including retrieving and sparing one another, to diminish oxidative stress. However, the intracellular balance of prooxidants and antioxidants becomes unbalanced, favoring prooxidants during the aging process. One hypothesis is that an aging associated increase in oxidative stress is the primary cause of aging. Hence, the research hypothesis for this study is that Korean red ginseng reduces oxidative stress in vivo. Therefore, we investigated the efficacy of Korean red ginseng water extract (GWE) in reducing aging-associated oxidative stress by measuring lipid peroxidation and antioxidant levels in older rats compared with young rats. We observed a significant increase in the markers for oxidative damage (eg, lipid peroxidation) and markers for vital organ damage (eg, aspartate aminotransferase, alanine aminotransferase, urea, and creatinine levels) in aged rats. The oxidative damage was accompanied by a significant decrease in enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione-S-transferase, and nonenzymatic antioxidants such as reduced glutathione, vitamin E, and vitamin C. Aged rats fed a diet supplemented with Korean red ginseng water extract had significantly less oxidative damage, possibly by enhancing the enzymatic and nonenzymatic antioxidants status. Our data suggest that consumption of Korean red ginseng reduces lipid peroxidation and restores antioxidant capacity by suppressing oxidative stress in rats. PMID- 23084646 TI - Perforator flap salvage using supermicrosurgical division and diversion of the pedicle. PMID- 23084647 TI - Natrelle Style 510 in breast augmentation surgery. PMID- 23084648 TI - Practical classification of columellar defects and surgical algorithm for their treatment. PMID- 23084649 TI - Clinical utility of CT angiography in DIEP breast reconstruction. AB - BACKGROUND: CT angiography has become the gold-standard imaging modality prior to DIEP flap breast reconstructions. Recent studies show excellent correlation between CTA and operative perforator location, but not their clinical significance. This study seeks to specifically evaluate the clinical utility of CTA in DIEP free flaps. METHODS: Preoperative CT angiography of the deep inferior epigastric system was obtained in 52 sequential DIEP free flaps involving 37 patients with dominant perforators marked by radiologist. Planned and used perforators were documented by the surgeon before and after the operation. RESULTS: A total of 62 out of 76 planned perforators were ultimately used (82%). Of those not used, 71% were abandoned due to inadequacy of preoperative CT. An additional 38 perforators were used that were not part of the initial preoperative plan, 60% of which were added due to inadequacy of the preoperative CT for planning. In total 23/52 flaps (44%) involved intraoperative changes due to features not appreciated on preoperative CT. CONCLUSION: CTA mapping of perforators prior to DIEP flap surgery increases surgeon confidence and reduces operative time; however, there are still a significant number of changes made based on clinical judgment. This study highlights the importance of surgeon review of CTA images. Caution is warranted in reliance on CTA mapping, and significant perforators should not be sacrificed until the anticipated perforator(s) have been exposed and evaluated. LEVEL OF EVIDENCE: Level 3. PMID- 23084650 TI - Ciprofloxacin-resistant Aeromonas hydrophila infection following leech therapy: a case report and review of the literature. AB - Compromised flap perfusion can lead to the use of leech therapy to aid in flap salvage. Aeromonas hydrophila, a symbiont of the leech, is a well-known bacterial pathogen that has the potential to cause infection in patients receiving leech therapy. Ciprofloxacin is commonly regarded as the antibiotic of choice for prophylaxis against this pathogen. We present patient who underwent leech therapy during salvage attempts for a venous congested flap. A resultant infection developed despite being on appropriate antibiotics. Culture sensitivities indicated that A. hydrophila was resistant to ciprofloxacin. PMID- 23084651 TI - Toxicity on the luminescent bacterium Vibrio fischeri (Beijerinck). II: Response to complex mixtures of heterogeneous chemicals at low levels of individual components. AB - The toxicity of eight complex mixtures of chemicals with different chemical structures and toxicological modes of action (narcotics, polar narcotics, herbicides, insecticides, fungicides) was tested on the luminescent bacterium Vibrio fischeri. There were maximum 84 individual chemicals in the mixtures. Suitable statistical approaches were applied for the comparison between experimental results and theoretical predictions. The results demonstrated that the two models of Concentration Addition (CA) and Independent Action (IA) are suitable to explain the effect of the mixtures.Even extremely lower concentrations of individual chemicals contributed to the effect of the mixtures. Synergistic effects were not observed in any of the tested mixtures. In particular, the CA approach well predicted the effects of six out of eight mixtures and slightly overestimated the effects of the remaining two mixtures. Therefore, the CA model can be proposed as a pragmatic and adequately protective approach for regulatory purposes. PMID- 23084652 TI - [Skin metastasis of lung carcinoma like Dupuytren's disease]. AB - Metastasis in the hand is uncommon. We report a case of metastasis of bronchial cancer to the hand mimicking Dupuytren's disease, which was operated using a skin graft with a good functional result. General prognosis is still very bad and the treatment should be palliative. PMID- 23084653 TI - [Permanent abduction of the little finger without ulnar nerve palsy: a case report]. AB - Wartenberg's sign, or permanent abduction of the little finger, occurs in the context of sequelae of ulnar nerve palsy. Its presence alone is rarely reported in the literature and is due to avulsion of the insertion of the third volar interosseous muscle. Several surgical techniques to correct this sign are reported in the literature. The authors report the case of a Wartenberg's sign without ulnar nerve palsy due to traumatic avulsion of the third volar interosseous muscle that was treated by a transfer of the extensor digiti minimi onto the radial side of the extensor digitorium communis according to technique of Bellan et al. After 1-year follow-up, result was good with no recurrence of any deformities and a normal active extension. PMID- 23084654 TI - A thematic review and a policy-analysis agenda of Electronic Health Records in the Greek National Health System. AB - The increasing pressure to improve healthcare outcomes and reduce costs is driving the current agenda of governments at worldwide level and calls for a fundamental reform of the status quo of health systems. This is especially the case with the Greek NHS (National Health System), a system in continuous crisis, and with the recent ongoing financial turbulence under intensive scrutiny. Technological innovations and Electronic Health Records (EHR) in particular, are recognised as key enablers in mitigating the existing burdens of healthcare. As a result, EHR is considered a core component in technology-driven reform processes. Nonetheless, the successful implementation and adoption of EHR proves to be a challenging task due to a mixture of technological, organisational and political issues. Drawing upon experiences within the European Union (EU) healthcare setting and the Greek NHS the paper proposes a conceptual framework as a policy analysis agenda for EHR interventions in Greece. While the context of discussion is Greece, the paper aims to also derive useful insights to healthcare policy makers around the globe. PMID- 23084655 TI - The value of a statistical life in Sweden: a review of the empirical literature. AB - Recent focus on cost-benefit/socio-economic assessment of government "life saving" programmes within public health, pharmaceutics, transport, and civil contingencies has spurred a wave of empirical research on the value of a statistical life (VSL) in Sweden. This paper provides an overview of the received evidence from a range of studies in one country and over a relatively short time period. A literature search was conducted in Econlit, Pubmed, Google Scholar and in bibliographies of published papers. Twelve studies on VSL with a total of 48 VSL estimates, published with data from Sweden from 1996 onwards, were identified. Among all estimates VSL varies from 9 to 1121 million SEK (?0.9-121 million). Based on a set of additional quality inclusion criteria, as used also in a recent global review of VSL studies, the sample is restricted to 9 studies with a total of 29 VSL estimates with VSL varying from 9 to 98 million SEK (?0.9 10.6 million). The raw mean among these estimates is 34.6 million SEK (?3.7 million) and the median is 23 million SEK (?2.5 million). Currently, official authorities in Sweden recommend a VSL of 22 million Swedish kronor (?2.4 million). We also point out important concerns regarding validity of these estimates: primarily the problem that VSL is significantly related to the size of the mortality risk reduction showing significant scale insensitivity, in contrast to theoretical assumptions but in line with previous empirical findings. PMID- 23084656 TI - [Considerations in the vaccination of adults with chronic kidney disease]. PMID- 23084657 TI - [The risk of nosocomial infection in informed consent documents]. PMID- 23084658 TI - [Bicycle helmet law in urban areas. Is it good for public health?]. PMID- 23084659 TI - Nonadherence to the isochrony principle in forged signatures. AB - Highly programmed skilled movements are executed in such a way that their kinematic features adhere to certain rules referred to as minimization principles. One such principle is the isochrony principle, which states that the duration of voluntary movement remains approximately constant across a range of movement distances; that is, movement duration is independent of movement extent. The concept of isochrony suggests that some information stored in the motor program is constant, thus reducing the storage demands of the program. The aim of the present study was to examine whether forged signatures can be distinguished from genuine signatures on the basis of isochrony kinematics. Sixty writers were asked to write their own signatures and to forge model signatures representing three different writing styles: text-based, stylized, and mixed. All signatures were digitized to enable high precision dynamic analyses of stroke kinematics. Vertical stroke duration and absolute amplitude were measured for each pen stroke of the signatures using MovAlyzeR((r)) software. Slope coefficients derived from simple regression models of the relationship between stroke duration and amplitude served as our measure of isochrony. The slope coefficient reflects the degree to which stroke duration increases in relation to stroke amplitude. Higher coefficients indicate greater increases in stroke duration for a given stroke amplitude and thus violate the isochrony principle. We hypothesized that the duration-amplitude coefficients for forged signatures would be significantly greater than for genuine signatures suggesting non-adherence to the isochrony principle. Results indicated that regardless of the style of the writer, genuine signatures were associated with low slope coefficients Pen strokes forming forged signatures had significantly greater duration-amplitude slope coefficients than genuine signatures. These findings suggest that when forging signatures, writers execute pen movements having steeper duration-amplitude relationships than for genuine signatures. PMID- 23084660 TI - Intratumoral tissue factor expression and risk of venous thromboembolism in brain tumor patients. AB - BACKGROUND: Brain tumor patients have an increased risk of venous thromboembolism (VTE). An important role in cancer-related VTE has been suggested for tissue factor (TF), the main initiator of the coagulation cascade. We conducted a prospective cohort study to determine whether expression levels of TF in brain tumors are associated with future VTE. PATIENTS AND METHODS: We immunohistochemically determined TF-expression in brain tumor specimens of 96 adult patients (8 low-grade and 82 high-grade gliomas, 6 embryonal tumors) that were included in the Vienna Cancer and Thrombosis Study (CATS). Each patient was prospectively followed until the occurrence of VTE and/or death within a period of two years or loss of follow-up. RESULTS: Fifteen brain tumor patients (15.6%) developed VTE during follow-up. Seventy-seven brain tumors (80.2%) stained positive for TF. Staining was strong in 13 (13.5%), moderate in 64 (66.7%) and negative in 19 (19.8%) tumors. No statistically significant association between TF-expression (negative, focal, widespread) and the occurrence of VTE was found. The hazard ratio (HR) for VTE was 1.30 (95% confidence interval [CI]: 054 - 3.14, p=0.567) when patients with negative-, focal- and widespread TF expression were compared and not statistically significant. Also when tumors were categorized into two groups (focal/widespread versus negative TF-expression), the HR for future VTE was not statistically significant (HR: 1.45, 95% CI: 0.44 - 7.37; p=0.578). An association can still not be definitely excluded, as this study was underpowered. CONCLUSIONS: Our data indicate that TF-expression levels in brain tumors are not strongly associated with future VTE. PMID- 23084661 TI - Neurophysiologic responses of peripheral nerve to repeated episodes of anoxia. AB - OBJECTIVE: Determine the effects of serial episodes of anoxia in an in vitro peripheral nerve preparation. METHODS: The nerve action potential (NAP) from rat sciatic nerve was recorded during 5 cycles of anoxia and reperfusion. Multiple NAP parameters were analyzed as well as stimulus response curves. RESULTS: The amplitude of the NAP declined to half baseline in 865 s on the first cycle of anoxia and recovered to half baseline during recovery in 470 s. These times increased with successive cycles of anoxia. The current required to produce a half maximal NAP showed a variable initial decrease before increasing with anoxia. The paired-pulse response showed a decline at 2-3 ms interstimulus interval during anoxia but was less dependent of interstimulus interval during recovery. NAP amplitude and velocity decrease over successive cycles of anoxia at a rate greater than in the absence of anoxia. CONCLUSIONS: The NAP declines slowly when peripheral nerve is exposed to anoxia but returns at least twice as quickly when re-exposed to oxygen. Short periods of anoxia produce long lasting changes in the nerve suggesting greater resistance to anoxia. With serial episodes of anoxia there is gradual NAP amplitude reduction and increase in duration and latency. SIGNIFICANCE: Anoxic-preconditioning appears in isolated peripheral nerve. PMID- 23084662 TI - A cloudy story: Guillain-Barre syndrome concealed by a spontaneous intracerebral haemorrhage. PMID- 23084663 TI - Evaluation of the current density in the brainstem during transcranial direct current stimulation with extra-cephalic reference electrode. PMID- 23084664 TI - A robust PID controller based on imperialist competitive algorithm for load frequency control of power systems. AB - A new PID controller for resistant differential control against load disturbance is introduced that can be used for load frequency control (LFC) application. Parameters of the controller have been specified by using imperialist competitive algorithm (ICA). Load disturbance, which is due to continuous and rapid changes of small loads, is always a problem for load frequency control of power systems. This paper introduces a new method to overcome this problem that is based on filtering technique which eliminates the effect of this kind of disturbance. The object is frequency regulation in each area of the power system and decreasing of power transfer between control areas, so the parameters of the proposed controller have been specified in a wide range of load changes by means of ICA to achieve the best dynamic response of frequency. To evaluate the effectiveness of the proposed controller, a three-area power system is simulated in MATLAB/SIMULINK. Each area has different generation units, so utilizes controllers with different parameters. Finally a comparison between the proposed controller and two other prevalent PI controllers, optimized by GA and Neural Networks, has been done which represents advantages of this controller over others. PMID- 23084665 TI - [Attitudes among Spanish and Latin American non-medical health professionals to living donor liver transplantation]. AB - INTRODUCTION: Hospital professionals are an opinion group that influences the general population. OBJECTIVE: To analyze attitudes to living donor liver transplantation (LDLT) among non-medical professionals working in Spanish and Latin American hospitals and to determine the variables that influence these attitudes. MATERIAL AND METHOD: A random sample, stratified by department, was selected from non-medical staff in the "International Donor Collaborative Project": there were three hospitals in Spain, five in Mexico and two in Cuba. Attitudes were evaluated through a validated, anonymous, self-administered questionnaire. RESULTS: There were 951 non-medical professionals: 277 from Spain, 632 from Mexico and 42 from Cuba. A total of 86% (n = 818) were in favor of related living donation and 31% (n = 299) were in favor of unrelated living donation. This attitude was associated with the following: country (Mexico 88%, Cuba 83%, Spain 81%) (p =0.016), female sex (p =0.026), having experience of donation and transplantation (p =0.001), having a favorable attitude to donation (P <0.001), considering the possibility of needing a transplant (P <0.001), being in favor of living kidney donation (P <0.001), being willing to accept a transplant from a living donor if necessary (P <0.001), discussing donation and transplantation with the family and partner (P <0.001), carrying out pro-social activities (P <0.001), believing that one's religion was in favor of donation and transplantation (P<0.001), and not worrying about bodily mutilation after donation (P <0.001). CONCLUSIONS: Attitudes toward related LDLT among non-medical staff in various Spanish, Mexican and Cuban hospitals are favorable. In 86% of those surveyed, this attitude was not influenced by classical psychosocial factors. PMID- 23084667 TI - "Tubal ostium sunshine": hysteroscopic sign of chronic salpingitis. PMID- 23084668 TI - Laparoscopic retrieval of a sheared epidural catheter segment more than a decade after cesarean section. PMID- 23084669 TI - Lesions of the umbilicus: what the minimally invasive gynecologic surgeon needs to know about the belly button. AB - The umbilicus is viewed as a portal by the laparoscopic surgeon, a doorway to the real business at hand. However, the umbilicus itself may be the site of a variety of lesional conditions. Some of these may be iatrogenic, caused by prior surgical interventions, such as endometriosis or seeding of a malignant neoplasm. Some may be the initial presenting complaint. This review discusses umbilical lesions that may be encountered by the minimally invasive gynecologic surgeon. PMID- 23084670 TI - Clinical observation of a modified surgical method: posterior vaginal mesh suspension of female rectocele with intractable constipation. AB - STUDY OBJECTIVE: To explore the feasibility and effectiveness of a modified posterior vaginal mesh suspension method in treating female rectocele with intractable constipation. DESIGN: Descriptive study (Canadian Task Force classification II-3). SETTING: The study was performed in the Study Center for Female Pelvic Dysfunction Disease, Department of Obstetrics and Gynecology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China. The Study Center includes 15 physicians, most of whom have received advanced training in pelvic floor dysfunctional disease and can skillfully perform many types of operations in patients with such disease. Almost 1500 operations to treat pelvic floor dysfunctional disease are performed every year at the center. PATIENTS: Thirty-six women with rectocele with intractable constipation. INTERVENTION: Posterior vaginal mesh suspension. MEASUREMENTS AND MAIN RESULTS: All patients were followed up for 15 to 36 months. In 29 patients, the condition was cured completely; in 5 patients it had improved; and in 2 patients, the intervention had no effect. Insofar as recovery and improved results, the overall effectiveness rate was 94.4%. CONCLUSION: Posterior vaginal mesh suspension is an effective, harmless, and convenient method for treatment of female rectocele with intractable constipation. It has positive short-term curative effects, with few complications and sequelae. However, the long-term effects of posterior vaginal mesh suspension should be evaluated. PMID- 23084671 TI - Outpatient laparoscopic hysterectomy for large uteri. AB - OBJECTIVE: To determine the incidence of perioperative complications associated with laparoscopic hysterectomies performed for very large uteri on an outpatient basis. METHODS: A retrospective chart review of consecutive women who underwent total laparoscopic (TLH) or supracervical laparoscopic (LSH) hysterectomy with uterine weight >= 500 grams. Clinical, demographic, and surgical characteristics were ascertained. Deviation from a normal intraoperative/perioperative course and readmission rate were assessed. Complications were graded by Dindo morbidity scale. Surgical characteristics and complications were compared between TLH and LSH groups using Chi2 tests for categorical and unpaired t tests for continuous variables. Logistic regressions were performed to identify specific risk factors. RESULTS: TLH and LSH were performed in 113 (25.3%) and 333 (74.7%) cases, respectively, with no differences in baseline characteristics between the groups. Median uterine weight was 786 gm (range: 500-4500). Mean operative time was 27 minutes longer in the TLH group: 186.5 +/- 58.6 vs. 159.6 +/- 53.8 minutes for LSH (P < 0.0001). Life threatening complications (Dindo's grade IV morbidity) occurred in 0.7%. Surgical intervention requiring general anesthesia (IIIB) occurred in 0.45% of cases. Visceral injury was limited to 6 (1.3%) cases of cystotomy. The rate of vascular injury was 0.22%. Conversion to laparotomy occurred in 3.4% of cases. 92.8% of patients were discharged on post-operative day zero, with 1.1% readmission rate. There was no association between perioperative morbidity and patient/surgical characteristics. CONCLUSION: Laparoscopic hysterectomy is a viable option for women with very large uteri. Same day discharge of clinically stable patients can be safely implemented. PMID- 23084672 TI - Laparoendoscopic single-site surgery (LESS) for treatment of benign adnexal disease: single-center experience over 3-years. AB - STUDY OBJECTIVE: To describe the effects of laparoendoscopic single-site (LESS) surgery performed over 3 consecutive years to treat adnexal disease and to report patient perioperative outcomes. DESIGN: Retrospective clinical study (Canadian Task Force classification III). SETTING: Tertiary care academic medical center. PATIENTS: Women undergoing LESS because of a benign gynecologic indication, from January 2009 through December 2011. INTERVENTIONS: Women with benign adnexal disease <=10 cm underwent LESS surgery through a single 1.5- to 2.0-cm umbilical incision. Intraoperative and postoperative outcomes were carefully recorded, including the need for postoperative rescue analgesia. MEASUREMENTS AND MAIN RESULTS: One hundred twenty-five patients were enrolled. Median patient age was 49 years, and median body mass index was 23. Surgical procedures included unilateral or bilateral salpingo-oophorectomy and unilateral or bilateral cyst enucleation. Median operative time was 48 minutes. Pain control was optimal, with an average visual analog score of 4/10. Both patients and surgeons were highly satisfied with the cosmetic result, and the cosmetic visual analog score was 9/10 at discharge and at 30 days after surgery. The number of women who underwent unilateral or bilateral salpingo-oophorectomy increased progressively and significantly yearly over the study period (16 vs 23 vs 40; p = .001). Median operative time for unilateral or bilateral salpingo-oophorectomy increased significantly from 2009 to 2010 and 2011 (34 vs 45 and 44 minutes; p = .001), together with median BMI (23 vs 23 vs 25; p = .04). CONCLUSION: LESS is a desirable surgical approach in patients with simple adnexal disease. PMID- 23084673 TI - Effect of extreme obesity on outcomes in laparoscopic hysterectomy. AB - STUDY OBJECTIVE: To estimate the effect of body mass index (BMI) on several outcomes in laparoscopic hysterectomy, in particular in the extremes of obesity. DESIGN: Retrospective cohort study (Canadian Task Force classification II-3). SETTING: Tertiary-care university-based teaching hospital. PATIENTS: Eight hundred thirty-four patients who underwent laparoscopic hysterectomy from January 2007 to October 2011. INTERVENTION: Laparoscopic hysterectomy for benign indications. MEASUREMENTS AND MAIN RESULTS: Demographic, operative, and postoperative data were abstracted from medical records. The primary outcome was a composite index score that took into account operative time, nonsurgical operating room time, estimated blood loss, length of hospital stay, number of complications, and severity of complications according to the Dindo-Clavien classification. We individually examined elements of the composite index as a secondary outcome. Models were developed to assess the association of BMI with the composite index score and the components of the index, controlling for age, presence of diabetes, tobacco use, surgeon, type of hysterectomy (total vs supracervical), use of robotics, uterine weight, number of additional procedures performed, presence of adhesions requiring lysis, and deeply infiltrating endometriosis as potential confounders. Mean (SD) BMI was 31.4 (8.1). Mean (SD) uterine weight was 345 (388) g. Mean operative time was 150 (61) minutes. Increasing BMI was associated with a worse composite score (p < .01); longer operative time (p = .03), nonsurgical operating room time (p = .02), and total operating room time (p < .01); greater estimated blood loss (p < .01); and complication severity (p = .01). CONCLUSION: These data suggest that there is a significant association of BMI with surgical outcomes in laparoscopic hysterectomy, and the effect is most pronounced in the morbidly obese. These patients may stand to gain the greatest differential benefit from a laparoscopic approach to surgery. However, they should be properly counseled about the challenge that obesity poses to the operation. PMID- 23084674 TI - Differences between adnexal torsion in pregnant and nonpregnant women. AB - STUDY OBJECTIVE: To compare the clinical manifestation, management, and outcome of adnexal torsion in pregnant and nonpregnant women. DESIGN: Retrospective case control study (Canadian Task Force classification II-3). SETTING: Tertiary care university hospital. PATIENTS: Sixty-four pregnant women and 198 nonpregnant women with episodes of adnexal torsion. INTERVENTIONS: Surgery to treat proved adnexal torsion. MEASUREMENTS AND MAIN RESULTS: The mean (SD) gestational age in the pregnant group was 11.5 (7.7) weeks. Thirty six episodes of adnexal torsion in the pregnant group (56%) developed after treatment for infertility, compared with only 14 such episodes (7%) in the nonpregnant group (p < .001). A repeated episode of torsion occurred more frequently in the pregnant group (14% vs 4%; p = .03). Sonographic demonstration of multicystic ovaries was more common in pregnant women with recurrent torsion than in women with a single episode of torsion (86% vs 31%; p = .009). Tissue preservation was achieved more frequently in pregnant than in nonpregnant patients (95% vs 77%; p < .001), and the duration of surgery was 15 minutes shorter in the pregnant women (p < .001). CONCLUSION: Pregnancy after treatment for infertility is a risk factor for adnexal torsion. Recurrence of ovarian torsion occurs more frequently in pregnant patients, and in particular in enlarged multicystic ovaries. PMID- 23084675 TI - Comparison of laparoscopic myomectomy using in situ morcellation with and without uterine artery ligation for treatment of symptomatic myomas. AB - STUDY OBJECTIVE: To evaluate the efficacy of laparoscopic uterine artery ligation (LUAL) before in situ morcellation (ISM) compared with ISM alone. DESIGN: Prospective study (Canadian Task Force classification II-1). SETTING: University affiliated hospital. PATIENTS: One hundred forty-four women with symptomatic uterine myomas, of whom 45 underwent LUAL and ISM and 99 underwent ISM only, from August 2007 through August 2009. INTERVENTIONS: Ligation or no ligation of the uterine arteries before ISM. MEASUREMENTS AND MAIN RESULTS: In the LUAL+ISM group compared with the ISM group, mean (SD) operative time was significantly longer (107 [34] minutes vs 93 [35] minutes; p = .03), and there was less intraoperative blood loss (84 [53] mL vs 137 [166] mL; p < .001). Eight patients in the ISM group (8.1%) required a blood transfusion, including 4 (4.0%) with excessive intraoperative bleeding and 4 (4.0%) with postoperative hematomas. Although myomas in the LUAL+ISM group weighed more (p < .001), none of the patients in that group had excessive intraoperative bleeding, postoperative hematomas, or required blood transfusion (p = .046). At 2 years of follow-up, in the LUAL+ISM group compared with the ISM group, the myoma recurrence rate was 7% vs 24%, and symptom improvement was reported by 98% of patients vs 86% (statistically significant). CONCLUSION: Laparoscopic myomectomy using an ISM technique with or without simultaneous LUAL may be used in the management of symptomatic uterine myomas; however, LUAL+ISM may result in a better surgical outcome. PMID- 23084676 TI - Hemostasis by bipolar coagulation versus suture after surgical stripping of bilateral ovarian endometriomas: a randomized controlled trial. AB - STUDY OBJECTIVE: To estimate whether the suture of the ovary is superior to bipolar coagulation in preserving ovarian reserve in infertile women undergoing laparoscopic stripping of bilateral endometriomas. DESIGN: Randomized controlled trial (Canadian Task Force classification I). SETTING: University teaching hospital. PATIENTS: 100 patients with bilateral endometriomas. INTERVENTIONS: Patients underwent stripping of bilateral endometriomas and were randomized to undergo hemostasis by use of either laparoscopic suturing (LS group) or bipolar coagulation (BC group). Changes in ovarian reserve were investigated by measuring the levels of anti-Mullerian hormone (AMH) and basal follicle-stimulating hormone (FSH) before surgery and at 3, 6 and 12 months from surgery. MEASUREMENTS AND MAIN RESULTS: At 3-month, 6-month, and 12-month follow-up, in both study groups, postsurgical AMH levels were significantly lower and basal FSH levels were significantly higher than before surgery. There was no significant difference in the mean percentage decrease of AMH levels in the BC group and LS group at 3-, 6 , and 12-month follow-up. The mean percentage increase in basal FSH was higher in the BC group than in the LS group at both 3-month (p = .023) and 6-month follow up (p = .029), but not at 12-month follow-up. Pregnancy rate, time to conception, and rate of endometrioma recurrence was similar in the 2 study groups. CONCLUSION: Laparoscopic stripping of ovarian endometriotic cyst significantly decreases serum AMH levels and increases basal FSH levels independent from the method used to obtain hemostasis on the ovarian tissue. PMID- 23084677 TI - A randomized, multi-center, clinical trial to assess the efficacy and safety of alginate carboxymethylcellulose hyaluronic acid compared to carboxymethylcellulose hyaluronic acid to prevent postoperative intrauterine adhesion. AB - STUDY OBJECTIVE: To estimate the efficacy of alginate carboxymethylcellulose hyaluronic acid (ACH) gel to prevent intrauterine adhesions after hysteroscopic surgery in comparison with carboxymethylcellulose hyaluronic acid (CH) gel, which is known as an effective adhesion inhibitor. DESIGN: Randomized, multicenter, single-blind, clinical trial (Canadian Task Force classification I). SETTING: Tertiary university hospital. PATIENTS: One hundred eighty-seven patients with a surgically treatable intrauterine lesion (myomas, polyps, septa, intrauterine adhesion, dysfunctional uterine bleeding). INTERVENTIONS: Patients were randomized to 2 groups: hysteroscopic surgery plus intrauterine application of ACH or CH. MEASUREMENTS AND RESULTS: The rate of adhesion formation and the adhesion severity score with type and extent were calculated 4 weeks after surgery. The ACH group had results that were comparable to the CH group in terms of the development of intrauterine adhesions at 4 weeks follow-up. The adhesion severities were not different between the 2 groups. In a subgroup without baseline intrauterine adhesion, the ACH group showed a lower intrauterine adhesion rate than the CH group (p = .016). CONCLUSIONS: ACH had a comparable efficacy to CH in terms of the adhesion rate and severity. In the case of no baseline intrauterine adhesion, intrauterine application of ACH after hysteroscopic surgery had a lower rate of intrauterine adhesion than application of CH. PMID- 23084678 TI - Anterior transobturator polypropylene mesh in the correction of cystocele: 2 point method vs 4-point method. AB - STUDY OBJECTIVE: To compare the effectiveness and safety of 2 anterior transobturator mesh methods for treating anterior vaginal wall prolapse. DESIGN: Randomized controlled study (Canadian Task Force classification I). SETTING: University hospital. PATIENTS: Eighty-seven women with anterior vaginal wall prolapse stage >=2 (Pelvic Organ Prolapse Quantification [POP-Q]) underwent an anterior transobturator mesh procedure using macropore polypropylene mesh. INTERVENTIONS: Forty-five patients underwent the operation via the conventional 4 point, full-sized mesh method, and 42 patients underwent the operation via a novel 2-point, half-sized mesh method. MEASUREMENTS AND MAIN RESULTS: Patient characteristics were comparable between the 2 groups. The anatomic cure rate was significantly lower in the 2-point group compared with the 4-point group at 12 months after surgery (87.2% vs 100%; p = .03). Healing abnormalities were significantly higher in the 2-point group than in the 4-point group (12.8% vs 0%; p = .03). Bladder perforation (2.6% vs 0%), stress urinary incontinence (23.1% vs 22.5%), urinary frequency (12.8% vs 22.5%), and voiding difficulty and dyspareunia (0% vs 0%) were not statistically different between the 2 groups. At linear regression analysis, mean (SD) operation time did not differ between the 2 groups (74.9 [32.7] minutes vs 87.8 [36.7] minutes; p = .11). CONCLUSION: Compared with the 4-point method, the 2-point anterior transobturator mesh method resulted in a lower rate of anatomic cure and a higher rate of healing abnormality. PMID- 23084679 TI - Thoracic endometriosis syndrome is strongly associated with severe pelvic endometriosis and infertility. AB - STUDY OBJECTIVE: To evaluate the clinical and surgical features of thoracic endometriosis syndrome (TES) represented by catamenial pneumothorax and pelvic endometriosis and to describe their association with infertility. DESIGN: Retrospective clinical study (Canadian Task Force classification: II-2). SETTING: Academic tertiary referral endometriosis center. PATIENTS: Seven patients who had undergone surgery because of thoracic and pelvic endometriosis between 2004 and 2010. INTERVENTIONS: Thoracic and pelvic exploration and treatment and fertility treatment. MEASUREMENTS AND MAIN RESULTS: Concurrently, thoracic and pelvic endometriosis, and subsequent fertility were determined during long-term follow up after combined surgical and pharmacologic interventions. The most frequent thoracic finding was diaphragmatic implants. Except for 1 patient with recurrent pleurodesis at 1 month after video-assisted thoracoscopy, no patients experienced recurrence of thoracic symptoms during a median (range) follow-up of 31.4 (1-61) months. Severe pelvic endometriosis was diagnosed in 6 patients with notable urologic and gastrointestinal tract involvement. Only 1 patient with catamenial pneumothorax had no macroscopic pelvic lesions. There was a considerable delay between the onset of pelvic symptoms and diagnosis. Median postoperative follow up was 31.5 (7-84) months. Most patients who tried to conceive had primary infertility. CONCLUSION: Thoracic endometriosis syndrome, represented by catamenial pneumothorax, was strongly associated with severe pelvic endometriosis and a high rate of infertility. Inasmuch as many patients with thoracic endometriosis syndrome are treated by thoracic surgeons using video-assisted thoracoscopy, it is desirable to involve an experienced gynecologist who can diagnose and treat concurrent pelvic endometriosis. PMID- 23084680 TI - Laparoscopic supracervical hysterectomy with transcervical morcellation and sacrocervicopexy: initial experience with a novel surgical approach to uterovaginal prolapse. AB - The objective of this retrospective study was to evaluate the feasibility, safety, and efficacy of a new laparoscopic technique for the treatment of uterovaginal prolapse using a transcervical access port to minimize the laparoscopic incision. From February 2008 through August 2010, symptomatic pelvic organ prolapse in 43 patients was evaluated and surgically treated using this novel procedure. Preoperative assessment included pelvic examination, the pelvic organ prolapse quantification scoring system (POP-Q), and complex urodynamic testing with prolapse reduction to evaluate for symptomatic or occult stress urinary incontinence. The surgical procedure consisted of laparoscopic supracervical hysterectomy with transcervical morcellation and laparoscopic sacrocervicopexy with anterior and posterior mesh extension. Concomitant procedures were performed as indicated. All procedures were completed laparoscopically using only 5-mm abdominal port sites, with no intraoperative complications. Patients were followed up postoperatively for pelvic examination and POP-Q at 6 weeks, 6 months, and 12 months. The median (interquartile range) preoperative POP-Q values for point Aa was 0 (-1.0 to 1.0), and for point C was 1.0 (-3.0 to 2.0). Postoperatively, median points Aa and C were significantly improved at 6 weeks, 6 months, and 12 months (all p < .001). One patient was found to have a mesh/suture exposure from the sacrocervicopexy, which was managed conservatively without surgery. We conclude that laparoscopic supracervical hysterectomy with transcervical morcellation and laparoscopic sacrocervicopexy is a safe and feasible surgical approach to treatment of uterovaginal prolapse, with excellent anatomic results at 6 weeks, 6 months, and 12 months. Potential advantages of the procedure include minimizing laparoscopic port site size, decreasing the rate of mesh exposure compared with other published data, and reducing the rate of postoperative cyclic bleeding in premenopausal women by removing the cervical core. Longer follow-up is needed to determine the durability and potential long-term sequelae of the procedure. PMID- 23084681 TI - Glutaraldehyde-induced bowel injury during gynecologic laparoscopy. AB - Glutaraldehyde is a widely used disinfectant, especially in developing countries, for rapid and effective disinfection of laparoscopic instruments that are not suitable for sterilization in an autoclave. This incident report demonstrates that even remarkably small residual amounts of glutaraldehyde on inadequately cleaned laparoscopic instruments can cause chemical burns during laparoscopic surgery. Our goal is to raise awareness of the possible hazardous effects of glutaraldehyde when necessary measures are not taken to properly sterilize laparoscopic instruments. PMID- 23084682 TI - CO2 laser total superficial vulvectomy: an outpatient treatment for wide multifocal vulvar intraepithelial neoplasia grade 3. AB - The ideal treatment of large multifocal vulvar intraepithelial neoplasia grade 3 (VIN 3) in young patients is still debated. The goal is to prevent development of invasive vulvar cancer while preserving normal vulvar anatomy and function. The authors describe the case of a 37-year-old woman affected by a biopsy-proven VIN 3 involving the entire external genitalia. A total superficial vulvectomy was carried out in 2 closer sessions by CO(2) laser used in an excisional way. Both procedures were performed in an outpatient setting with the patient under local anesthesia and without suturing stitches or skin flaps. Definitive pathologic analysis confirmed VIN 3 with free margins. No intraoperative and postoperative complications were documented. Functional and anatomic outcomes were optimal, and no relapse occurred after 12 months of follow-up. Use of CO(2) laser total superficial vulvectomy shows promise of a safe and adequate treatment in selected young patients with VIN 3 involving the entire external genitalia. PMID- 23084683 TI - Report of 7 uterine rupture cases after laparoscopic myomectomy: update of the literature. AB - The objective of this article is to report 7 previously unpublished uterine rupture cases in pregnancy after laparoscopic myomectomy and to update the medical literature. All cases were reported to the Board of Endoscopic Gynecologic Surgery (Athens, Greece) from 1998 to 2011. Myomas were single in 85.7% of patients, subserosal or pedunculated in 85.7%, and <=5 cm in 71.4%. Bipolar diathermy was the sole method used for hemostasis in 28.6%, and could be characterized as excessive in 85.7%. A 2-layer closure with stitches of the myometrium was performed in just 14.3% of cases. Mean (SD) time between surgery and pregnancy was 1.4 (0.5) years. Uterine rupture occurred at 34 weeks of gestation or later in 85.7%, and during labor in 14.3% of cases. All women survived. Fetal demise was reported in 1 twin pregnancy (both fetuses) with rupture at 24 weeks of gestation. Laparoscopic myomectomy should be performed by adequately trained and experienced surgeons. Excessive use of diathermy for hemostasis should be avoided, and multiple-layer suturing should always be used for repairing the myometrial defect in cases of intramural and subserosal myomas with deep intrusion. PMID- 23084684 TI - Remnant functioning cervical tissue after laparoscopic removal of cavitated noncommunicating rudimentary uterine horn. AB - Cavitated noncommunicating rudimentary uterine horn is managed via surgical removal. During the past 20 years this has been performed primarily via laparoscopy. At our multidisciplinary specialized center, this condition has been treated in 29 patients over 10 years. Three patients had pelvic pain and recurrent symptoms of menstrual obstruction at 2, 5, and 6 years after the initial operation. Magnetic resonance imaging revealed blood-filled pelvic masses at the site of the previous procedures. After laparoscopic removal of these masses, histologic analysis confirmed the presence of remnant functioning cervical tissue. This is the first report of long-term follow-up of patients with a history of obstructed rudimentary uterine horn to demonstrate that complications can occur several years after such operations. It is essential that any reports of recurrent pain should be considered seriously and investigated. PMID- 23084685 TI - Robot-assisted excision of a huge pararectal dermoid cyst via a totally transabdominal route. AB - Herein is reported the case of a 17-year-old adolescent with a huge cystic mass located between the vagina and the rectum, with extension into the gluteal region. The lesion caused compression and dislocation of the bladder, uterus, adnexae, and rectum. The patient underwent robot-assisted surgical excision of the mass via a totally transabdominal route. Postoperative recovery was uneventful, with excellent functional and cosmetic results. To our knowledge, this is the first case of a huge pelvic pararectal cyst reaching up to the gluteus and excised via a totally transabdominal approach with the aid of robotic assistance. Robot-assisted surgery seems to be appropriate for therapeutic management of huge pararectal tumors, the major advantages being minimum damage to contiguous structures, rapid postoperative recovery, and excellent cosmetic results. PMID- 23084686 TI - Conservative laparoscopic approach to a perforated pyomyoma after uterine artery embolization. AB - We describe a conservative laparoscopic approach to treatment of a perforated pyomyoma after uterine artery embolization. A 36-year-old woman came to our emergency department 8 weeks after undergoing uterine artery embolization. She reported painful abdominal cramps. Physical examination revealed fever, tachycardia, hypotension, abdominal pain with rebound tenderness and pain during bimanual examination. Ultrasonography showed a fundal/subserosal leiomyoma and a moderate amount of fluid in the abdominal cavity. Because the patient desired preservation of the uterus, a laparoscopic approach was used for drainage and lavage of a perforated pyomyoma. The patient had an uneventful recovery and remained well at follow-up visits. Second-look diagnostic laparoscopy enabled treatment of the adhesions formed and revealed patent fallopian tubes. Surgery has been the primary approach to pyomyoma. However, hysterectomy leads to irreversible sterility and myomectomy can be difficult to perform. Therefore, there is need for a less invasive intervention in women who seek conservative treatment. Recently, computed tomography-guided drainage was successfully performed in two patients with pyomyoma. To our knowledge, this is the first report of a successful conservative laparoscopic approach to pyomyoma. PMID- 23084687 TI - Uterine arteriovenous fistula treated with repetitive transcatheter embolization: case report. AB - Uterine arteriovenous fistula (AVF) is a rare entity, but may lead to life threatening hemorrhage. Although transcatheter embolization, surgical ligation, or hysterectomy would be considered for treatment of uterine AVF, there is poor knowledge as to how gynecologists can manage the uterine AVF with multiple large inflow arteries. Herein we report a uterine AVF successfully treated using multiple-step transcatheter embolization. The patient, a 58-year-old postmenopausal woman with a history of dilation and curettage, had intermittent massive uterine bleeding. Radiologic imaging revealed the presence of a large vasculature mass. The mass occupied the entire pelvis, and the source of hemorrhage was identified as an accompanying AVF. We thought that surgical intervention was contraindicated because of the potential risk of uncontrollable intraoperative bleeding. Multiple-step transcatheter embolization was performed, with complete resolution of the AVF. Thereafter, the patient had no further uterine bleeding. Multiple-step transcatheter embolization might be the most beneficial and efficient treatment option for a uterine AVF with multiple large inflow arteries. PMID- 23084688 TI - Laparoscopic management of uterine arteriovenous malformation via occlusion of internal iliac arteries. AB - Uterine arteriovenous malformation (AVM) can be congenital or acquired. When acquired (e.g., fistula), it results from abnormal arteriovenous communication between one or more uterine arteries and a myometrial and/or endometrial venous plexus, without the interposition of a vascular nidus. Arteriovenous malformation is composed of a tortuous net of fragile low-resistant arteriovenous shunts. Other arteries can be involved in fistulas, including ovarian arteries or those from the round ligaments of the uterus, in particular in congenital AVMs, which develop from failure in embryologic differentiation that leads to multiple abnormal vascular connections. In these cases, extension to pelvic vessels other than uterine arteries is frequent. Acquired AVMs often result in trauma to the uterus such as dilation and curettage in 85% of cases, gestational trophoblastic disease, or endometrial carcinoma. PMID- 23084689 TI - Malignant ovarian Sertoli-Leydig cell tumor localized with selective ovarian vein sampling. AB - Sertoli-Leydig cell tumors (SLCT) are rare, comprising less than 0.5% of ovarian neoplasms. They are most often diagnosed in premenopausal women and may produce androgens, resulting in hirsuitism, voice deepening, frontal balding, terminal hair growth, and clitoromegaly. SLCT are malignant in 15%-20% of cases. We discuss a 25-year-old patient with persistent hyperandrogenemia. Noninvasive imaging cannot conclusively differentiate between SCLT and other diagnoses such as polycystic ovary syndrome, ovarian hyperthecosis, idiopathic hyperandrogenism, idiopathic hirsuitism, and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Selective ovarian vein sampling revealed a 15-fold greater testosterone production from the right ovary compared with the left, which guided appropriate surgical management. PMID- 23084690 TI - Vesicovaginal fistula failing multiple surgical attempts salvaged laparoscopically without an interposition omental flap. AB - Failed vesicovaginal fistula repairs are often considered complicated and are thus relegated to an abdominal approach using an interposition omental flap. We report our successful laparoscopic approach without use of an omental flap in a patient with multiple recurrences of a vesicovaginal fistula. PMID- 23084691 TI - Onset of benign paroxysmal positional vertigo after total laparoscopic hysterectomy in the Trendelenburg position. AB - Herein is reported the case of a 51-year-old woman who underwent total laparoscopic hysterectomy in the steep Trendelenburg position who developed postoperative benign paroxysmal positional vertigo. The etiology of benign paroxysmal positional vertigo is examined and the Trendelenburg position during surgery as the triggering factor is explored. PMID- 23084693 TI - Hysterectomy subsequent to endometrial ablation. PMID- 23084694 TI - Adhesion prevention in endometriosis. PMID- 23084696 TI - Impact of the 7-valent pneumococcal conjugate vaccine on the incidence of childhood pneumonia. AB - In September 2006, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the UK immunization programme. We aimed to evaluate the impact of PCV7 on the incidence of all-cause community-acquired pneumonia (CAP) in children. A prospective survey was undertaken in 2008-2009 at 11 hospitals in North East England of children aged 0-16 years with radiologically confirmed pneumonia. Data were compared to those from a similar survey undertaken in the same hospitals in 2001-2002. A total of 542 children were enrolled, of which 74% were aged <5 years. PCV7 uptake was 90?7%. The incidence of pneumonia was 11?8/10,000 [95% confidence interval (CI) 10?9-12?9], and the hospitalization rate was 9?9/10,000 (95% CI 9?0-10?9). Compared to 2001, there was a 19% (95% CI 8-29) reduction in the rate of CAP in those aged <5 years, and in those <2 years a 33?1% (95% CI 20 45) reduction in the incidence of CAP and 38?1% (95% CI 24-50) reduction in hospitalization rates. However, for those unvaccinated aged >=5 years, there was no difference in the incidence of CAP and hospitalization rate between both surveys. Since 2001, the overall reduction in incidence was 17?7% (95% CI 8-26) and for hospitalization 18?5% (95% CI 8-28). For the <5 years age group there was a lower incidence of CAP in PCV7-vaccinated children (25?2/10,000, 95% CI 22?6 28?2) than in those that were not vaccinated (37?4/10,000, 95% CI 29?2-47?1). In conclusion, PCV7 has reduced both incidence and rate of hospitalization of pneumonia in children, particularly in the <2 years age group. PMID- 23084697 TI - Early detection of minor neurodevelopmental dysfunctions at age 6 months in prematurely born neonates. AB - OBJECTIVE: To investigate the 6-month neurodevelopmental outcomes of prematurely born neonates and find the determining neonatal factors of minor neurological dysfunctions (MNDs). STUDY DESIGN: We examined data collected prospectively on 151 infants born before 37th week of gestation in 2009-2010 who were assessed at 6 months corrected age with the Bayley Scales of Infant Development-2nd Edition (BSID-II) and the Denver Developmental Screening Test (DDST). RESULTS: Of 151 neonates born before 37 weeks, 20 (13.2%) had MNDs at 6 months corrected age. These proportions were 21.6%, 13.2%, and 8.2% for neonates born before 28 weeks, 29 weeks to 32 weeks, and 33 weeks to 36 weeks, respectively. Half of neonates with MNDs have a birth body weight of less than 1000g. BSID-II and DDST are highly correlated in assessing the MNDs of premature neonates at 6 months corrected age. MND was independently associated with postnatal corticosteroid use (odds ratio [OR], 11.2; 95% confidence interval [CI], 1.9-66.0, P=0.008) and cholestasis (OR, 6.2; 95% CI, 1.16-33.1, P=0.033). CONCLUSIONS: Premature neonates, even those born at 33 to 36 weeks, are found to have MNDs as early as 6 months corrected age by BSID-II and DDST, with risk increasing as gestation decreases. PMID- 23084698 TI - Fetal exposure to synthetic oxytocin and the relationship with prefeeding cues within one hour postbirth. AB - BACKGROUND: Prefeeding cues are oral-motor neurobehaviors that communicate feeding readiness, and the ability to self-comfort and regulate behavioral state. Intrapartum and newborn procedures have been associated with altered frequency and emergence of prefeeding cues soon after birth. Intrapartum synthetic oxytocin is commonly used for labor induction/augmentation in the US, yet there is little research on potential effects on infant neurobehavioral cues. AIMS: To explore whether fetal exposure to synthetic oxytocin was associated with the infant's level of prefeeding organization shortly after birth. STUDY DESIGN: Cohort. SUBJECTS: A convenience sample of 47 healthy full-term infants (36 exposed and 11 unexposed to intrapartum synthetic oxytocin) was studied. EXCLUSION CRITERIA: Fetal distress, vacuum/forceps, cesarean, and low Apgar. OUTCOME MEASURES: Videotapes of infants (45-50min postbirth) were coded for frequency of eight prefeeding cues, and analyzed by level of prefeeding organization. RESULTS: In general, fewer prefeeding cues were observed in infants exposed versus unexposed to synOT and differences were significant for brief and sustained hand to mouth cues [incidence rate ratio (95% CI)=0.6 (0.4, 0.9) and 0.5 (0.2, 0.9), respectively]. Forty-four percent of exposed infants demonstrated a low level of prefeeding organization, compared to 0% from the unexposed group. In contrast, 25% of exposed versus 64% of unexposed infants demonstrated high prefeeding organization. After adjusting for covariates, exposed infants were at 11.5 times (95% CI=1.8-73.3) the odds of demonstrating low/medium versus high levels of prefeeding organization compared to unexposed infants. CONCLUSIONS: Newborn neurobehavioral cues may be sensitive to intrapartum synthetic oxytocin. PMID- 23084699 TI - [Boxing-related cranial injury in children: a case report]. AB - No pediatric recommendations exist in France on the exercise of boxing by children and adolescents despite the risk of traumatic injury, sometimes serious. We report the case of a 15-year-old boy who participated in amateur boxing and had a subdural hematoma. Brain injuries and concussions are frequent and multiple. Severity is not always correlated with the intensity of the blows. There are age-related features. Several international medical organizations oppose boxing for children and adolescents. PMID- 23084701 TI - [Edema of the lower limb. Sickle cell disease revealed by venous thrombosis]. PMID- 23084702 TI - Synthesis and preliminary bioevaluation of novel E-ring modified acetal analog of camptothecin as cytotoxic agents. AB - In an effort to improve the metabolic stability of the E-ring and decrease the toxicity of camptothecin (CPT), a novel cytotoxic acetal analog with 21-alkoxy groups was designed and synthesized. The preliminary results revealed that this class of compounds showed superior antiproliferative activity in vitro and moderate in vivo activity, while their topoisomerase I (Topo I) inhibitory activity was weakened significantly. The implications of these results within the current understanding of the structure-activity relationship of camptothecin are analyzed in detail. The obtained information provides insight into the role of the 21-carbonyl group in the binding of CPT to Topo I-DNA complex. PMID- 23084703 TI - Association between early childhood otitis media and pediatric inflammatory bowel disease: an exploratory population-based analysis. AB - OBJECTIVE: To determine whether a diagnosis of otitis media in the first 5 years of childhood is associated with the development of pediatric inflammatory bowel disease (IBD). STUDY DESIGN: This was a nested case-control analysis of a population-based IBD database in Manitoba, Canada. A total of 294 children with IBD diagnosed between 1989 and 2008 were matched to 2377 controls, based on age, sex, and geographic region. The diagnosis of ottis media was based on physician claims. IBD status was determined based on a validated administrative database definition. Multivariate conditional logistic regression models were used to model the association between otitis media and IBD, adjusted for annual physician visits. RESULTS: Approximately 5% of the IBD cases and 12% of the controls did not have an otitis media diagnosis before that IBD case date. By age 5 years, 89% of the IBD cases had at least one diagnosis of otitis media, compared with 82% of the controls. In multivariate analyses, compared with cases and controls without an otitis media diagnosis, individuals with an otitis media diagnosis by age 5 years were 2.8-fold more likely to be an IBD case (95% CI, 1.5-5.2; P = .001). This association was detected in stratified models examining Crohn's disease and ulcerative colitis separately. CONCLUSION: Compared with controls, subjects diagnosed with IBD were more likely to have had at least one early childhood episode of otitis media before their diagnosis. We suspect that otitis media serves as a proxy measure of antibiotic use. PMID- 23084705 TI - Maternal life stress events in pregnancy link to children's school achievement at age 10 years. AB - OBJECTIVE: To test the hypothesis that maternal antenatal exposure to life stress events is associated with lower achievement in literacy and numeracy at age 10 years, with sex differences in this link. STUDY DESIGN: The Western Australian Pregnancy Cohort Study recruited 2900 women at 18 weeks' pregnancy, and 2868 children were followed up at birth and postnatally. At age 10 years, information on 1038 children was linked to their literacy and numeracy test scores. Multivariate regression models were used to test the foregoing hypotheses, adjusting for important confounders. RESULTS: In girls, maternal antenatal exposure to 4 or more maternal life stress events or death of the mother's friend and/or relative was associated with lower reading scores. In contrast, exposure to 3 or more life stress events or to a pregnancy or financial problem was associated with higher reading scores in boys. Furthermore, maternal exposure to 4 or more life stress events was associated with higher mathematic scores and a residential move was linked to higher writing scores in boys. CONCLUSION: Maternal antenatal exposure to life stress events has differing effects on the school performance of male and female offspring. Further research is needed to explore the reasons for this sex difference. PMID- 23084704 TI - Exercise improves behavioral, neurocognitive, and scholastic performance in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: To examine the effect of a single bout of moderate-intensity aerobic exercise on preadolescent children with attention-deficit/hyperactivity disorder (ADHD) using objective measures of attention, brain neurophysiology, and academic performance. STUDY DESIGN: Using a within-participants design, task performance and event-related brain potentials were assessed while participants performed an attentional-control task following a bout of exercise or seated reading during 2 separate, counterbalanced sessions. RESULTS: Following a single 20-minute bout of exercise, both children with ADHD and healthy match control children exhibited greater response accuracy and stimulus-related processing, with the children with ADHD also exhibiting selective enhancements in regulatory processes, compared with after a similar duration of seated reading. In addition, greater performance in the areas of reading and arithmetic were observed following exercise in both groups. CONCLUSION: These findings indicate that single bouts of moderately intense aerobic exercise may have positive implications for aspects of neurocognitive function and inhibitory control in children with ADHD. PMID- 23084706 TI - Effects of propranolol and exercise training in children with severe burns. AB - OBJECTIVES: To investigate whether propranolol administration blocks the benefits induced by exercise training in severely burned children. STUDY DESIGN: Children aged 7-18 years (n = 58) with burns covering >=30% of the total body surface area were enrolled in this randomized trial during their acute hospital admission. Twenty-seven patients were randomized to receive propranolol, whereas 31 served as untreated controls. Both groups participated in 12 weeks of in-hospital resistance and aerobic exercise training. Muscle strength, lean body mass, and peak oxygen consumption (VO2 peak) were measured before and after exercise training. Paired and unpaired Student t tests were used for within and between group comparisons, and chi(2) tests for nominal data. RESULTS: Age, length of hospitalization, and total body surface area burned were similar between groups. In both groups, muscle strength, lean body mass, and VO2 peak were significantly greater after exercise training than at baseline. The percent change in VO2 peak was significantly greater in the propranolol group than in the control group (P < .05). CONCLUSIONS: Exercise-induced enhancements in muscle mass, strength, and VO2 peak are not impaired by propranolol. Moreover, propranolol improves the aerobic response to exercise in massively burned children. PMID- 23084707 TI - Increasing prevalence of nonalcoholic fatty liver disease among United States adolescents, 1988-1994 to 2007-2010. AB - OBJECTIVE: To assess recent trends in nonalcoholic fatty liver disease (NAFLD) prevalence among US adolescents. STUDY DESIGN: Cross-sectional data from 12 714 12-19 year olds (exclusions: chronic hepatitis, hepatotoxic medications) in the National Health and Examination Survey between 1988-1994 and 2007-2010 were used to estimate trends in suspected NAFLD, defined as overweight (body mass index >=85th percentile) plus elevated alanine aminotransferase levels (boys >25.8 U/L; girls >22.1 U/L). Linear trends in prevalence and the independent effect of demographic indicators and adiposity on NAFLD risk were tested using regression models. Complex sampling methods and P values of <.05 were used to assess statistical significance. RESULTS: Suspected NAFLD prevalence (SE) rose from 3.9% (0.5) in 1988-1994 to 10.7% (0.9) in 2007-2010 (P < .0001), with increases among all race/ethnic subgroups, males and females, and those obese (P trend <=.0006 for all). Among those obese, the multivariate adjusted odds of suspected NAFLD were higher with increased age, body mass index, Mexican American race, and male sex; the adjusted odds in 2007-2010 were 2.0 times those in 1988-1994. In 2007 2010, 48.1% (3.7) of all obese males and 56.0% (3.5) of obese Mexican American males had suspected NAFLD. CONCLUSION: Prevalence of suspected NAFLD has more than doubled over the past 20 years and currently affects nearly 11% of adolescents and one-half of obese males. The rapid increase among those obese, independent of body mass index, suggests that other modifiable risk factors have influenced this trend. PMID- 23084708 TI - Validation of search filters for identifying pediatric studies in PubMed. AB - OBJECTIVE: To identify and validate PubMed search filters for retrieving studies including children and to develop a new pediatric search filter for PubMed. STUDY DESIGN: We developed 2 different datasets of studies to evaluate the performance of the identified pediatric search filters, expressed in terms of sensitivity, precision, specificity, accuracy, and number needed to read (NNR). An optimal search filter will have a high sensitivity and high precision with a low NNR. RESULTS: In addition to the PubMed Limits: All Child: 0-18 years filter (in May 2012 renamed to PubMed Filter Child: 0-18 years), 6 search filters for identifying studies including children were identified: 3 developed by Kastner et al, 1 developed by BestBets, one by the Child Health Field, and 1 by the Cochrane Childhood Cancer Group. Three search filters (Cochrane Childhood Cancer Group, Child Health Field, and BestBets) had the highest sensitivity (99.3%, 99.5%, and 99.3%, respectively) but a lower precision (64.5%, 68.4%, and 66.6% respectively) compared with the other search filters. Two Kastner search filters had a high precision (93.0% and 93.7%, respectively) but a low sensitivity (58.5% and 44.8%, respectively). They failed to identify many pediatric studies in our datasets. The search terms responsible for false-positive results in the reference dataset were determined. With these data, we developed a new search filter for identifying studies with children in PubMed with an optimal sensitivity (99.5%) and precision (69.0%). CONCLUSION: Search filters to identify studies including children either have a low sensitivity or a low precision with a high NNR. A new pediatric search filter with a high sensitivity and a low NNR has been developed. PMID- 23084709 TI - Multicenter study on season of birth and celiac disease: evidence for a new theoretical model of pathogenesis. AB - OBJECTIVE: To investigate whether season of birth is associated with celiac disease (CD). STUDY DESIGN: We performed a medical record review of 1964 patients with biopsy-proven CD at 3 teaching hospitals (2 pediatric centers and 1 adult center) between 2000 and 2010. The first positive small intestinal biopsy result defined age of diagnosis. The observed proportions of births in each season (spring [March-May], summer [June-August], fall [September-November], and winter [December-February]) were compared with the expected proportions using binomial probability tests. RESULTS: The mean age at diagnosis was 9.8 +/- 5.0 years in the 2 pediatric centers and 43.6 +/- 15.8 years in the adult center. The cohort was predominately female (69%). Overall, more patients were born in spring (27%) than in any other season: summer (25%), fall (25%), and winter (23%). In patients diagnosed before age 15 years, the spring birth excess was present in boys (33%; P = .0005), but not in girls (26%; P = .43). The sex difference in season of birth was less striking in patients with CD diagnosed at age >=15 years. CONCLUSION: Season of birth is an environmental risk factor for CD, particularly in boys diagnosed before age 15 years. The results are consistent with a new theoretical model that integrates potential environmental factors (eg, gluten introduction, ultraviolet-B exposure, vitamin D status) and acute viral gastrointestinal infections in early childhood. PMID- 23084711 TI - Palmitate induces RIP1-dependent necrosis in RAW 264.7 cells. AB - OBJECTIVE: The kinase receptor-interacting protein (RIP) 1, a serine/threonine protein kinase, is a key signaling molecule for necrosis. The possible involvement of RIP1 in palmitate-induced macrophage death and its underlying molecular mechanism was investigated in this study. METHODS: Cell viability was measured by an MTT reduction assay. The type of cell death was determined by staining with annexin V, propidium iodide (PI) and the APOPercentage dye, and by examining cell morphology using transmission electron microscopy. The down regulation of RIP1 was performed by siRNA transfection. Intracellular reactive oxygen species (ROS) were measured by staining with H(2)DCF-DA. RESULTS: Palmitate largely induced necrosis in RAW 264.7 cells, whereas C2-ceramide induced apoptosis. Palmitate-induced necrosis was inhibited by Necrostatin-1, an inhibitor of RIP1, and by RIP1 siRNA transfection, whereas ordinary cell death was not inhibited by z-VAD-fmk. In addition, the presence of palmitate caused a significant increase in intracellular ROS levels compared to control cells. Pre treatment with Tempol, a cell permeable ROS scavenger, and MnTBAP, an inhibitor of mitochondrial oxidative stress, protected cells from palmitate-induced cell death. Furthermore, the down-regulation of RIP1 by siRNA transfection significantly decreased palmitate-induced ROS generation compared to control cells. CONCLUSION: The findings reported herein indicate that palmitate induces necrotic cell death via RIP1-dependent ROS generation in RAW 264.7 cells. These findings may provide a new mechanism that explains the link between elevated levels of free fatty acids (FFAs) and macrophage death. PMID- 23084710 TI - Early life socioeconomic indicators and risk of type 1 diabetes in children and young adults. AB - OBJECTIVE: To examine the potential role of 2 early-life socioeconomic indicators, parental education, and crowding index, on risk of type 1 diabetes (T1DM) in patients up to age 29 years to test heterogeneity by age at onset according to the hygiene hypothesis. STUDY DESIGN: The study base was 330 950 individuals born from 1967 to 2006 who resided in the city of Turin at any time between 1984 and 2007. Data on their early life socioeconomic position were derived from the Turin Longitudinal Study; 414 incident cases of T1DM up to age 29 years were derived from the Turin T1DM registry. RESULTS: Socioeconomic indicators had opposing effects on risk of T1DM in different age at onset subgroups. In a Poisson regression model that included both socioeconomic indicators, there was a 3-fold greater risk of T1DM (relative risk 2.91, 95% CI 0.99-8.56) in children age 0-3 years at diagnosis living in crowded houses. In the 4- to 14-year subgroup, a low parental educational level had a protective effect (relative risk 0.50, 95% CI 0.29-0.84), and the effect of crowding nearly disappeared. In the 15- to 29-year subgroup, neither crowding nor parental educational level was clearly associated with the incidence of T1DM. CONCLUSIONS: We provide evidence of heterogeneity by age at onset of the association between early-life socioeconomic indicators and the risk of T1DM. This finding is consistent with the hypothesis that infectious agents in the perinatal period may increase the risk, whereas in the following years they may become protective factors (hygiene hypothesis). PMID- 23084713 TI - Letter to the editor: underestimation of the net present value of different sexed semen artificial insemination strategies in dairy heifers: a comment on Olynk and Wolf (2007). PMID- 23084712 TI - Sodium and potassium intake present a J-shaped relationship with arterial stiffness and carotid intima-media thickness. AB - OBJECTIVES: The purpose of this study was to analyse the relationship between sodium and potassium intake and vascular structure and function and to ascertain whether said relationship follows the pattern of a J-shaped curve. METHODS: A cross-sectional study was carried out in a primary care setting. Three hundred fifty-one subjects from the Vasorisk study were included and ranged in age from 30 to 80 years (mean 54.8, SD 11.7); 219 (62.4%) were females. Sodium and potassium intake were evaluated by means of a food frequency questionnaire. Arterial stiffness was assessed according to pulse wave velocity (PWV), ambulatory arterial stiffness index (AASI, AASI_BPVR), and central and peripheral augmentation index (AIx). Carotid intima-media thickness (C-IMT) was evaluated by ultrasonography. RESULTS: Age was lower in the quartiles with the highest sodium intake (p < 0.05), and no difference was observed between the sexes. Mean C-IMT, CAIx, AASI and AASI_BPVR were higher in the quartiles with higher sodium intake (p < 0.05 for both AASI and AASI_BPVR). Sodium intake was negatively correlated with C-IMT (r = -0.121, p < 0.05), PWV (r = -0.114, p < 0.05), AASI and AASI_BPVR (r = -0.155, p < 0.01). Potassium intake was positively correlated with Cornell VDP (r = 0.119, p < 0.05), CAIx (r = 0.178, p < 0.01) and PAIx (r = 0.202, p < 0.01). After adjustment, the morphology of the relationship between arterial stiffness parameters and C-IMT with quartiles of sodium intake resembles a J shaped curve. The relationship between central and peripheral AIx and C-IMT and potassium intake resembles a J-shaped curve. CONCLUSION: The relationship of sodium and potassium intake with vascular structure and function, as evaluated with C-IMT, PWV, AASI and peripheral and central AIx, resembles a J-shaped curve, which is similar to what has been proposed in the case of cardiovascular morbimortality. PMID- 23084715 TI - Effect of ultraviolet light on water- and fat-soluble vitamins in cow and goat milk. AB - The objective of this study was to investigate and compare the effects of UV light and heat treatment on vitamins A, B(2), C, and E in cow and goat milk. Vitamins were analyzed by reverse-phase high-pressure liquid chromatography. Ultraviolet and pasteurization treatments caused loss in vitamin C in milk. Pasteurization did not have any significant effect on vitamin B(2). However, UV light treatment decreased the amount of vitamin B(2) after several passes of milk through the UV system. In addition, UV light treatment decreased the amount of vitamins A and E. Vitamins C and E are more sensitive to UV light. UV light sensitivities of vitamins were C>E>A>B(2). These results show that UV light treatment decreases the vitamin content in milk. Also, the number of passes through the UV system and the initial amount of vitamins in milk are important factors affecting vitamin levels. PMID- 23084716 TI - Extending the respiratory care of children into long-term support. PMID- 23084717 TI - Patent ductus arteriosus in preterm infants. PMID- 23084718 TI - The burden of allergic asthma in children: a landscape comparison based on data from Lithuanian, Latvian, and Taiwanese populations. AB - Asthma is one of the most common chronic respiratory diseases with an increasing prevalence and financial burden worldwide. This disease affects individuals in all countries and all ethnic groups; however, prevalence rates of asthma have been reported to vary significantly between different regions. To understand the origin of asthma and to manage it effectively, it is necessary to analyze the genetic and environmental factors that cause these geographic differences. Therefore, we aimed to review published data from the investigations of asthma patients in Eastern Europe, represented by Latvia and Lithuania, and of patients from Eastern Asia represented by Taiwan. We hope that some of the common factors can be identified and different variants can be compared among these three countries for development of a new strategy to prevent childhood asthma. PMID- 23084719 TI - Urinary tract infection in infants: a single-center clinical analysis in southern Taiwan. AB - BACKGROUND: This study summarized the epidemiology, etiology, and susceptibility of pathogens to antibiotics, and specific characteristics in infants aged less than 4 months diagnosed with urinary tract infection in the past decade in Taiwan. METHODS: The medical charts of patients aged less than 4 months admitted for urinary tract infection to Kaohsiung Veterans General Hospital between January 2001 and December 2009 were retrospectively reviewed. RESULTS: A total of 132 patients, with male predominance (68.9%), were enrolled. The top three pathogens were similar to those identified in previous studies in Taiwan. The most common pathogen, Escherichia coli (85.3%), was resistant to ampicillin (75.9%), followed by sulfamethoxazole/trimethoprim (31.7%), and cefazolin (28.5%). Dimercaptosuccinic acid (DMSA) renal scan revealed 34.5% positive findings, while the vesicoureteral reflux (VUR) rate was 37.8% by direct radionuclide voiding cystography and/or voiding cysto-urethrography. Positive DMSA findings significantly correlated with VUR (p<0.001) and higher C-reactive protein level (p<0.05). CONCLUSIONS: E coli was the most common pathogen in the present cohort, and the top three pathogens were similar to those found in general pediatric population in Taiwan. VUR was the most common genitourinary tract anomaly in this age group. Positive DMSA was well correlated with VUR and higher C-reactive protein level. PMID- 23084720 TI - Laparoscopic versus open appendectomy in the management of all stages of acute appendicitis in children: a retrospective study. AB - BACKGROUND: We conducted this study in order to evaluate whether laparoscopic appendectomy was an alternative therapeutic tool to open appendectomy for all stages of pediatric appendicitis. MATERIALS AND METHODS: Between January 2000 and November 2004, the charts of 177 children who underwent appendectomy by a single surgeon were reviewed. The patients were divided into open and laparoscopic appendectomy groups. Each group was subdivided into three stages: simple appendicitis, perforated appendicitis, and appendicitis with abscess. The age, gender, white blood cell count, absolute neutrophil count, C-reactive protein, operating time, duration of postoperative hospital stay, minor and major complications, and use of intravenous analgesia were recorded. Fisher's exact and Student's t-test were used for statistical analysis. RESULTS: There were fewer minor complications (9/32 vs. 0/20, p = 0.009) in perforated appendicitis stage and fewer major complications (9/26 vs. 1/24, p = 0.011) in appendicitis with abscess stage between open and laparoscopic appendectomy group. But surgery for each laparoscopic appendectomy group took longer to perform than for the corresponding open appendectomy group in each stage (p < 0.05). There was no significant difference in other data between corresponding groups in each stage. CONCLUSION: Laparoscopic appendectomy may be considered a better alternative to open appendectomy for children with perforated appendicitis and appendicitis with abscess. PMID- 23084721 TI - Risk factors of respiratory failure in children with Guillain-Barre syndrome. AB - BACKGROUND: Respiratory failure is rarely associated with Guillain-Barre syndrome (GBS) in children. The aim of the study was to determine the risk factors of respiratory failure in children with GBS to advance management. METHODS: In this retrospective study, the variables that lead to respiratory failure were investigated in 40 children. The risk factors were compared for 4 children with intubation and 36 without. We also analyzed the specific treatments, including corticosteroids, intravenous immunoglobulin, plasmapheresis, and clinical status at discharge. RESULTS: Four (10.0%) of the 40 children with GBS required mechanical ventilation. The need for mechanical ventilation was significantly related to the Hughes score at nadir (p<0.001), respiratory distress (p<0.001), and hypotension (p<0.001). Atypical presentation of symptoms such as croup, hoarseness, vomiting, ataxia, consciousness disturbance, and previous event of diarrhea were more predominant in patients younger than 6 years. Disability grades >3 at discharge were found in 15 patients (37.5%), and there was no mortality in the present case series. CONCLUSIONS: Respiratory failure in childhood GBS was related to the Hughes score at nadir, respiratory distress, and hypotension. Atypical presentations of symptoms were more predominant in patients younger than 6 years. The prognosis in our series was good and not related to previous events. Understanding the risk factors of severe GBS will provide better treatment strategies and improve the outcomes. PMID- 23084722 TI - Recurrent Intussusception: when Should Surgical Intervention be performed? AB - OBJECTIVE: To determine the optimal timing of surgery for recurrent intussusception. METHODS: We retrospectively reviewed medical records of patients aged from 0 to 18 years old with diagnosis of intussusception in the Pediatric Department at Mackay Memorial Hospital between January 1995 and May 2010. RESULTS: During the study period, there were 686 children (divided into three age groups: 367 < 2 years, 289 aged 2 to 5 years, 30 > 5 years) with diagnoses of intussusception. Eighty-five of the 686 patients had recurrent intussusception, of whom 56 had two, 16 had three, 11 had four, and 2 had five episodes. The recurrence rate after the first, second, third, and fourth barium enema reductions were 15.7%, 37.7%, 68.4%, and 100.0%, respectively. The incidence of recurrence and failure rate of barium enema reduction did not differ significantly among these three age groups. Surgery was performed in 177 children (146 during the first episode and 31 in recurrent cases). The probability of eventual surgery after first enema reduction was 21.8%, after the second 35.7%, and after the third 70.0%. Lead points were found in 15 children, and all of them were found during surgery for the first episode of intussusception. CONCLUSION: The probability of recurrence was 100% after the fourth episode of intussusception in our study. After the third episode of intussusception, the probability of recurrence and eventual surgery were 68% and 70%, respectively. From this study, surgical intervention should be considered at the third episode of intussusception. PMID- 23084723 TI - Outcome of long-term mechanical ventilation support in children. AB - BACKGROUND: Improved technology and care in recent years have significantly improved the prognosis and quality of life for patients on long-term mechanical ventilation. This study examined the status of children on long-term mechanical ventilation (MV) support in Taiwan. METHODS: The medical records of patients between January 1998 and December 2006 were retrospectively reviewed, and the clinical factors were systematically reviewed. RESULTS: One hundred and thirty nine (139) patients aged 3 months to 18 years, with 53 (38.1%) girls and 86 (61.9%) boys, were enrolled. The common underlying disorders included neurologic/neuromuscular diseases (n=100, 71.9%) and airway/lung dysfunction (n=19, 13.7%). After instituting MV, the children returned to the medical center mainly for infection (n=157, 47.7%) and elective surgery or procedures (n=46, 13.9%). After long-term follow-up, 37 (26.6%) died, 81 (58.3%) were transferred to respiratory care wards in local hospitals, and 21 (15.1%) received home care support. CONCLUSIONS: There are now more children on long-term MV support in Taiwan and most are in respiratory care wards in local hospitals. The shift in underlying diagnoses from pulmonary disease to neurogenic respiratory insufficiency affects hospitalization. The main cause of respiratory insufficiency is neurologic insult. PMID- 23084724 TI - The impact of patent ductus arteriosus in neonates with late onset sepsis: a retrospective matched-case control study. AB - BACKGROUND: Late-onset sepsis (LOS) in neonates with patent ductus arteriosus (PDA) may predispose them to more complicated hospital courses. The objective of this study was to determine the incidence, the distribution of pathogens, and the clinical features of LOS in neonates with PDA and analyze their outcomes. METHODS: The medical records were reviewed retrospectively of infants with PDA and LOS who were hospitalized in NICUs of Chang Gung Children's Hospital between January 2003 and December 2009. The clinical features of these infants were compared with a group of gestational age and birth body weight-matched neonates with LOS during the same period. RESULTS: During this period, 224 neonates were found to have at least one event of blood-culture proven LOS and 79 (35.3%) were documented to have PDA. Although most LOS episodes (85/104, 81.7%) in neonates with PDA occurred after closure of PDA, neonates with PDA had a significantly higher rate of bronchopulmonary dysplasia (81.0% vs. 61.0%, p = 0.002) and a relatively higher rate of recurrent sepsis (25.3% vs. 15.2%, p = 0.079) than those without PDA. Longer durations of ventilator support and hospital stay were also noted in neonates with PDA as compared to those without (p = 0.001 and 0.005, respectively). CONCLUSION: In neonates with LOS, the presence of PDA, even though it is aggressively treated with indomethacin or surgical intervention, may still contribute to the complexity of hospitalization. Close monitoring and aggressive treatments are warranted in these neonates with PDA. PMID- 23084725 TI - Effective radiotherapy cured cauda equina syndrome caused by remitted intracranial germinoma depositing. AB - Cauda equina syndrome (CES) in children is very rare and can permanently disable. A remitted intracranial germinoma depositing on the spinal cord, leading to CES, has never been reported. We discuss the case of a 10-year-old girl who presented with sudden ataxia, low back pain, sensory deficits of the left lower extremity, and difficulty urinating and defecating 7 months after totally remitted intracranial germinoma postintracranial surgery and cranial irradiation. Magnetic resonance imaging (MRI) of the brain and spine showed multiple intradural extramedullary homogeneous masses from the cervical to lumbar levels, compressing the conus medullaris and cauda equina. After emergent craniospinal irradiation, the patient's neurologic symptoms dramatically subsided. A remitted intracranial germinoma depositing on her spinal cord could be the cause of CES. Early identification and a proper craniospinal irradiation may halt the progression of symptoms. PMID- 23084726 TI - Familial cases of Henoch-Schonlein purpura in Taiwanese Aborigines. AB - Henoch-Schonlein purpura (HSP) is a disorder whose cause and pathogenesis is unknown; some familial cases of this disease have been reported. The clinical heterogeneity in HSP may be conferred by a number of genetic loci, including the major histocompatibility complex. The racial and genetic factors responsible for the occurrence of the familial cases of HSP in Taiwan are unclear. The purpose of this study was to examine the racial and genetic factors in familial HSP cases in Taiwan. We retrospectively collected the HSP cases in our hospital during 2006 through 2010 and observed that familial HSP cases were only in Taroko Aborigines. Six cases of HSP in 3 Taroko families were found, and their human leukocyte antigens (HLA) were studied in the tissue typing laboratory of our hospital, to determine the possible association with familial HSP cases in Taiwanese Aborigines. Our results suggest an increased frequency of familial HSP cases with HLA-A24 in Taiwanese Taroko Aborigines. We concluded that racial and genetic predisposition was the possible cause for the familial occurrence of and renal involvement in HSP in Taiwanese Aborigines. PMID- 23084727 TI - Schizophrenia: metabolic aspects of aetiology, diagnosis and future treatment strategies. AB - Despite decades of research, the pathophysiology and aetiology of schizophrenia remains incompletely understood. The disorder is frequently accompanied by metabolic symptoms including dyslipidaemia, hyperinsulinaemia, type 2 diabetes and obesity. These symptoms are a common side effect of currently available antipsychotic medications. However, reports of metabolic dysfunction in schizophrenia predate the antipsychotic era and have also been observed in first onset patients prior to antipsychotic treatment. Here, we review the evidence for abnormalities in metabolism in schizophrenia patients, both in the central nervous system and periphery. Molecular analysis of post mortem brain tissue has pointed towards alterations in glucose metabolism and insulin signalling pathways, and blood-based molecular profiling analyses have demonstrated hyperinsulinaemia and abnormalities in secretion of insulin and co-released factors at first presentation of symptoms. Nonetheless, such features are not observed for all subjects with the disorder and not all individuals with such abnormalities suffer the symptoms of schizophrenia. One interpretation of these data is the presence of an underlying metabolic vulnerability in a subset of individuals which interacts with environmental or genetic factors to produce the overt symptoms of the disorder. Further investigation of metabolic aspects of schizophrenia may prove critical for diagnosis, improvement of existing treatment based on patient stratification/personalised medicine strategies and development of novel antipsychotic agents. PMID- 23084728 TI - Importance of epigenetic mechanisms in visceral pain induced by chronic water avoidance stress. AB - Epigenetic molecular mechanisms, which include DNA methylation and histone deacetylation, are implicated in the dysregulation of the hypothalamic-pituitary adrenal (HPA) axis. Previously, we demonstrated that repeated water avoidance stress (WAS), a validated model of chronic psychological stress, induces heightened visceral pain behaviors in rodents that resemble irritable bowel syndrome (IBS) sequelae. However, the involvement of epigenetic molecular mechanisms in the pathophysiology of stress-induced visceral pain has not been explored. Our hypothesis is that epigenetic mechanisms within the central nervous system (CNS) are important to chronic stress-induced visceral hypersensitivity. Adult male F-344 rats with intracerebroventricular (i.c.v.) cannulae were exposed to 7 days of repeated WAS. Controls received a SHAM stress. Following the daily 1h stressor, trichostatin A (TSA; 100 ng/ml), a potent histone deacetylase inhibitor, or vehicle (VEH; 0.1% DMSO/saline,) as control was administered via the i.c.v. cannula. Visceral sensitivity was assessed 24h after the final WAS and quantified the visceromotor response (VMR) by recording the number of abdominal contractions in response to graded pressures (20-60 mmHg) of colorectal distensions (CRD). From a separate group of rats that were exposed to repeated WAS or SHAM stress, the amygdala was isolated to assess the methylation status of glucocorticoid receptor (GR) and corticotropin releasing-factor (CRF) genes via bisulfite sequencing and verified by pyrosequencing. GR and CRF gene expression was quantified via qRT-PCR. Stressed rats exhibited visceral hypersensitivity that was significantly attenuated by TSA. Compared to SHAM controls, methylation of the GR gene was increased following WAS while expression of the GR gene was decreased. Methylation of the CRF promoter was decreased with WAS with a concomitant increase in CRF expression. This study demonstrates the involvement of central epigenetic mechanisms in regulating stress-induced visceral hypersensitivity and provides a foundation for exploring the epigenetic mechanisms that may contribute to IBS-like symptomatology. PMID- 23084729 TI - Does knee joint proprioception alter following medial patellofemoral ligament reconstruction? AB - BACKGROUND: This study firstly aimed to determine whether proprioception deficits, as measured by joint position sense (JPS), occur in people following recurrent patellar dislocations. Secondly, to determine whether JPS changes following medial patellofemoral ligament reconstruction (MPFL) reconstruction for patellar instability. METHODS: Thirty people following recurrent patellar dislocation were recruited. Pre-operative JPS was assessed using the passive angle reproduction test. Through this, an assessor moved a participant's limb to a target position. This was returned to neutral, before finally moving the limb again, whilst requiring the participant to indicate when they thought the target angle was reached. The actual angular error (AAE) was calculated as the difference between the perceived angle and target angle. Clinical outcomes included the Kujala Patellofemoral Disorder Score, the International Knee Documentation Committee (IKDC) form, pain, knee motion, extensor muscle strength and frequency of patellar dislocation. Outcomes were assessed pre-operative, 6 weeks, 3 and 12 months. RESULTS: Mean AAE was 2.2 degrees (inner range) to 3.9 degrees (mid-range); this was not clinically significant. There was no statistically significant difference between the baseline-and-6 week, 6 week-and 3 month or baseline-and-12 month AAE measures (p=0.38 to 1.00). There was a statistically significant improvement in functional outcomes as measured by the Kujala score, IKDC form, reduced pain and increased extension strength from baseline to 12 months (p<0.01). CONCLUSIONS: Following recurrent patellar dislocation, patients exhibit minimal deficits in JPS. Whilst MPFL reconstruction significantly improved clinical and functional outcomes for this population, this operation did not significantly alter JPS during the first post-operative year. PMID- 23084730 TI - Vascular injuries during anterior exposure of the thoracolumbar spine. AB - BACKGROUND: The aim of this study was to evaluate the vascular injuries, repairs, and complications encountered during anterior thoracolumbar spine exposures. METHODS: The medical records of patients undergoing anterior spine exposures from January 2004 to June 2010 were retrospectively analyzed. RESULTS: A total of 269 anterior exposures were performed in 260 patients. The average patient age was 50.1 years, and the average body mass index was 29.0. Female patients represented 146 (54.3%) cases. Previous spinal surgery was noted in 145 (53.9%) cases, and 19 (7.1%) had previous anterior exposure. The median estimated blood loss (EBL) was 300 mL, and there were no postoperative mortalities. A vascular injury occurred in 37 cases (13.8%), with redo anterior exposure (n = 19, 52% vs. 11%; P < 0.001), previous spinal surgery (n = 145, 19% vs. 7%; P = 0.01), and diagnosis of a tumor (n = 14, 36% vs. 12.5%; P = 0.03) being associated with increased vascular injury. A vascular injury resulted in greater EBL (median: 800 mL vs. 300 mL; P < 0.001) and longer hospitalization (median: 7 days vs. 5 days; P = 0.04). Most frequently injured was the left common iliac vein (in 21 of the 37 [52.5%] injured cases). A vascular surgeon performed the exposure in 159 (59.1%) cases. There was a decrease in EBL (250 mL vs. 500 mL; P < 0.001), total incision time (290 minutes vs. 404 minutes; P = 0.002), and length of stay (5 days vs. 6.5 days; P < 0.001) as compared with the operations where the vascular surgeon was not involved in the exposure. These cases also had an increased incidence of any vascular injury (28 vs. 9; P = 0.04). There were no differences between groups regarding vascular injury type, repair type, or the incidence of deep venous thrombosis. CONCLUSION: Collaboration between spine and vascular teams may result in decreased blood loss and consequently improved morbidity and length of hospital stay. PMID- 23084731 TI - Disparities in outcomes for Hispanic patients undergoing endovascular and open abdominal aortic aneurysm repair. AB - BACKGROUND: Previous studies have demonstrated racial and ethnic disparities associated with the outcomes of abdominal aortic aneurysm (AAA) repair, although little is known about the influence of race and ethnicity on the costs associated with these disparities. The current study was undertaken to examine the influence of race and ethnicity on the outcomes of endovascular (EVAR) and open repair (open AAA) of unruptured AAA and its effect on costs in contemporary practice. METHODS: The Nationwide Inpatient Sample (2005 to 2008) was queried using ICD-9 CM codes for unruptured AAA (441.4). The primary outcomes were mortality and total hospital charges. Multivariate analyses were performed adjusting for age, gender, race, comorbidities (Charlson index), year, insurance type, and hospital characteristics. RESULTS: A total of 62,728 patients underwent EVAR and 24,253 patients underwent open AAA. White patients (72%) were more likely to undergo EVAR than Hispanic (69%) or black patients (69%; P = 0.02). On univariate analysis, in-hospital mortality after EVAR was increased in Hispanic patients compared with white patients (1% vs 2%; P = 0.02). There were no differences in mortality after EVAR between white and black patients, and there were no racial or ethnic differences in mortality after open AAA. Hispanic ethnicity remained an independent risk factor for increased mortality after AAA repair on multivariate analysis (RR 1.64; 95% CI [1.05 to 2.57]; P = 0.03). Hispanic ethnicity was associated with increased hospital charges compared with white ethnicity after both EVAR ($108,886 vs $77,748; P < 0.001) and open AAA ($134,356 vs $85,536; P < 0.001) and for black patients after open AAA ($101,168 vs $85,536; P = 0.04). CONCLUSIONS: Hispanic ethnicity is an independent risk factor for mortality after AAA repair independent of insurance type or hospital characteristics. There were dramatic disparities in hospital costs for Hispanic patients undergoing either EVAR or open AAA and for black patients after open AAA compared with white patients. This observation seems unrelated to length of stay, postoperative complications, and admission status. Further studies are needed to determine whether these disparities extend beyond the primary hospitalization. PMID- 23084732 TI - Balance impairment, physical ability, and its link with disease severity in patients with intermittent claudication. AB - BACKGROUND: To determine whether increasing claudication severity is associated with impaired balance and physical functional ability. METHODS: A prospective observational study in claudicants was performed. Disease severity was determined according to Rutherford's criteria. Patient's balance was assessed objectively using computerized dynamic posturography (CDP-Sensory Organization Test [SOT]; NeuroCom). "Bedside" assessment of balance was performed using the Timed Up and Go (TUG) test (dynamic balance) and the Full Tandem Stance test (static balance). Physical function was assessed using the Summary Physical Performance Battery (SPPB) score. RESULTS: 185 claudicants were assessed (median age of 69 [IQR 63 74] years; 137 [74.1%] men). Fourteen claudicants were classified as Rutherford grade 0, 26 as grade I, 76 as grade II, and 69 as grade III. All Rutherford groups were comparable for age, gender, BMI, and comorbidities. Increasing Rutherford grade was associated with a significant deterioration in objective balance as determined by a failed SOT test: 3 (21.4%) in grade 0; 9 (34.6%) in grade I; 39 (52.7%) in grade II; and 41 (59.4%) in grade III (chi-squared 9.693, df 3, P = 0.021). A significant difference was also found with dynamic balance (TUG test), but not static balance (full tandem stance). Increasing claudication severity was also associated with significantly worse physical function: SPPB score. CONCLUSIONS: Specific objective tests demonstrate impaired balance and physical function are common in claudicants and become more frequent with increasing severity of claudication. Simple "bedside" measures may be sufficiently sensitive to detect this. PMID- 23084733 TI - Endovascular repair of mycotic aneurysm of the descending thoracic aorta. AB - BACKGROUND: Mycotic thoracic aortic aneurysms (MTAAs) are a rare yet life threatening disease. The current standard of care consists of surgical resection, in situ or extra-anatomic revascularization, and antibiotic therapy. Despite this treatment, mortality remains high (range, 5-40%). The endovascular repair of degenerative thoracic aortic aneurysms has been shown to be safe and effective, but its use in the treatment of MTAAs is still controversial. The purpose of this study is to review the use of endovascular repair for MTAAs. METHODS: A 10-year retrospective chart review was conducted of patients who underwent endovascular repair of MTAAs between March 2001 and March 2011. The surgical results of this single-institution review are reported. RESULTS: Seven patients underwent endovascular repair of MTAAs. One patient died 2 days postoperatively, which gave an in-hospital survival rate of 85.7%. The 1-year survival rate was 71.4%. The mean follow-up time was 25 months (range, 0-72 months), with a survival rate at that time of 57.1%. All patients were free of infection during their follow-up period. CONCLUSIONS: In this single-center case series, endovascular repair of MTAAs was associated with favorable perioperative and short-term mortality and morbidity. PMID- 23084734 TI - Chronic venous ulcer: minimally invasive treatment of superficial axial and perforator vein reflux speeds healing and reduces recurrence. AB - BACKGROUND: Chronic venous ulcer (CVU) is common and is responsible for significant health care expenditures worldwide. Compression is the mainstay of treatment, but long-term compliance with this therapy is often inconsistent, particularly in the elderly and infirm. Surgical ablation of axial and perforator reflux has been used as an adjunct to compression to reduce recurrence rates and assist healing. These surgical techniques are being replaced by minimally invasive procedures, such as thermal ablation and foam sclerotherapy, in the treatment of uncomplicated venous disease. The role for these techniques in the treatment of CVU is just beginning to be defined. METHODS: Eighty-six patients with CVU with 95 active ulcers (Clinical, Etiology, Anatomy, Physiology-CEAP clinical class 6) presenting to a multispecialty wound clinic were retrospectively reviewed and analyzed by leg. All patients underwent duplex scanning for venous insufficiency. Ulcer dimensions at each visit were recorded and used to calculate healing rates. Presence or absence of ulcer recurrence at 1 year follow-up was recorded. Ulcers treated with compression alone ("compression group") were compared with those treated with compression and minimally invasive interventions, such as thermal ablation of superficial axial reflux and ultrasound-guided foam sclerotherapy (UGFS) of incompetent perforating veins and varicosities ("intervention group"). RESULTS: The average age in the intervention and compression groups was 67 and 71 years, respectively (P = not significant [NS]). Body mass index was 32.4 +/- 9.5 and 33.6 +/- 11.8 kg/m(2), in the compression and intervention groups, respectively (P = not significant [NS]). Ulcers were recurrent in 42% of the intervention group and 26% of the compression group (P = NS). In the intervention group, 33% had radiofrequency ablation of axial reflux, 31% had UGFS of perforators, and 29% had both treatments. The only complication of intervention was a single case of cellulitis requiring hospitalization. Compared with the compression group, the ulcers in the intervention group healed faster (9.7% vs. 4.2% per week; P = 0.001) and showed fewer recurrences at 1-year follow-up (27.1% vs. 48.9 %; P < 0.015). Multivariate analysis showed use of intervention was the strongest determinant of healing with a coefficient of variation of 7.432, SE 2.406, P = 0.003. Analysis of just the intervention group before and after intervention using matched pairs showed acceleration of healing after intervention from ranging from a median of 1.2% (interquartile range [IQR], 14.3) to 9.7% (IQR, 11.3) per week (P <= 0.001). CONCLUSIONS: Minimally invasive ablation of superficial axial and perforator vein reflux in patients with active CVU is safe and leads to faster healing and decreased ulcer recurrence when combined with compression alone in the treatment of CVU. PMID- 23084735 TI - Presentation and treatment outcomes of patients with symptomatic inferior vena cava filters. AB - BACKGROUND: Use of inferior vena cava filters (IVCFs) has become more prevalent for the prevention of venous thromboembolism in part due to their ease of deployment and retrieval. Nonthrombotic complications of IVCFs are unusual but have been described. This study characterizes this cohort of patients and elucidates their clinical outcome. METHODS: Between January 1, 2006 and December 31, 2011, six patients were identified with nonthrombotic symptoms attributed to their IVCF. Symptoms included abdominal/back pain, hypertension from renal artery compression, and hydroureter from ureteral compression. RESULTS: The average age of the patients was 38.8 years (range 21 to 71 years) and all were female. Indication for IVCF placement included deep vein thrombosis (n = 2), deep vein thrombosis with pulmonary embolism (n = 1), and perioperative prophylaxis (n = 3). Filter types included the Ninitol Bard G2 (n = 3), Cook Celect (n = 1), Gunther Tulip (n = 1), and ALN (n = 1). The median time from IVCF placement to retrieval was 285 days (range 20 to 2091 days). At presentation, all IVCFs were tilted and had struts penetrating through the vena cava wall. Every IVCF was successfully removed: four by endovascular approach and two by open surgery. All patients had complete resolution of symptoms and there were no procedural complications. CONCLUSIONS: Symptomatic IVCFs occur in female patients, and are always associated with device strut erosion outside the inferior vena cava. Successful retrieval can be safely achieved by an endovascular or open surgical technique, resulting in symptom resolution. PMID- 23084736 TI - Postoperative renal function after juxtarenal aortic aneurysm repair with simple cross-clamping. AB - BACKGROUND: We report our 11-year experience of juxtarenal aortic aneurysm (JAA) repair with suprarenal aortic cross-clamping. METHODS: We retrospectively reviewed 51 consecutive JAA repairs performed between 2000 and 2010. In all 51 patients, aneurysms were replaced by prosthetic grafts with simple suprarenal aortic cross-clamping. No special renal protective measures (except inter-renal cross-clamping) were performed during interruption of perfusion to kidneys. For inter-renal cross-clamping, the aortic cross-clamp was placed from below one renal artery to above the other renal artery to maintain hemilateral renal perfusion. This technique was applied in 27 patients (54%). Postoperative complications, renal function, and survival were evaluated. RESULTS: There were no deaths. The average renal ischemia time was 28.9 +/- 9.7 minutes. Postoperatively, transient renal failure (defined as an estimated glomerular filtration rate of <30 mL/min/1.73 m(2)) occurred in 14% of the patients. The postoperative decrease of estimated glomerular filtration rate compared with the preoperative value was significantly smaller in the inter-renal clamp group (7.4% +/- 16%) than in the suprarenal clamp group (17.5% +/- 16%) (P < 0.05, unpaired t test). However, renal dysfunction was temporary and recovered to baseline before discharge with conservative therapy in all patients except one. In addition, renal function was generally preserved at 1 year after surgery. CONCLUSION: Surgical repair of JAA can be performed with simple cross-clamping and an acceptable renal ischemic time, achieving excellent results. Inter-renal cross clamping reduces renal damage compared with suprarenal cross-clamping. PMID- 23084737 TI - [Uterus transplantation. Current situation]. AB - Except adoption, absolute uterine factor infertility lacks solution in case of motherhood desire. Gestational surrogacy is still not approved in France. Over the last decade, uterus transplantation experimentation made advances. Data from animal research, progress in immunosuppressive treatment and knowledge about pregnancy after transplantation provide a scenario in which a human allotransplantation project can become reality. PMID- 23084738 TI - [Reproduction without a uterus? State of the art of ectogenesis]. AB - The concept of reproduction without uterus, or ectogenesis, has long been considered a myth. Nowadays, however, the in vitro conception (IVF) and embryo culture before implantation are largely used in humans with more than 50,000 IVF and ICSI procedures yearly in France, but also in ruminants where about 400,000 bovine embryos are produced in vitro worldwide each year. In order to proceed with gestation, a 3D structure enabling implantation is needed. Ex-vivo implantation of human embryos was obtained both in a perfused ex-vivo uterus and in a 3 dimensional culture of endometrial cells, but these experiments were stopped because of ethical concerns. The implantation of a mouse embryo in a similar 3D structure has been reported but did not lead to the production of a live pup. Another interest for an artificial uterus or placenta would be to use it for ex-vivo maturation of very premature fetuses. Extra-corporal membrane oxygenation (ECMO) was developed for many years but its use remains disappointing in preterm infants when compared to the important progress made with more classical clinical care. In any case, goat fetuses have been maintained alive up to 9 days in an artificial amniotic pouch, being oxygenated via ECMO. PMID- 23084739 TI - Towards safer and more effective analgesia. PMID- 23084740 TI - Population structure and genetic heterogeneity in popular dog breeds in the UK. AB - There is increasing concern that reproductive isolation related to breed specifications in dogs, while maintaining genetic differences among breeds, is likely to promote breed-specific genetic disorders. This study examined genetic diversity among 13 popular dog breed groups in the UK. Most breeds showed high levels of homozygosity when compared with crossbred animals. The Boxer and West Highland white terrier showed the lowest heterozygosity, while the Jack Russell terrier group (not a registered breed in the UK) had a level of heterozygosity comparable to crossbred dogs. Analysis of genetic distance between breeds showed significantly different inbreeding coefficients for pairwise comparisons among registered breeds, with the most divergent breeds being the Boxer and West Highland white terrier. The Rottweiler and Golden retriever showed the highest levels of inbreeding. The least distinct group contained crossbred dogs. The results show that the registered breeds are subject to a 'breed barrier' which promotes reduction in genetic diversity. PMID- 23084741 TI - Assessing the function of mesenchymal stromal cells: all that glitters is not gold. PMID- 23084743 TI - Innate immune messenger 2-5A tethers human RNase L into active high-order complexes. AB - 2',5'-linked oligoadenylates (2-5As) serve as conserved messengers of pathogen presence in the mammalian innate immune system. 2-5As induce self-association and activation of RNase L, which cleaves cytosolic RNA and promotes the production of interferons (IFNs) and cytokines driven by the transcription factors IRF-3 and NF kappaB. We report that human RNase L is activated by forming high-order complexes, reminiscent of the mode of activation of the phylogenetically related transmembrane kinase/RNase Ire1 in the unfolded protein response. We describe crystal structures determined at 2.4 A and 2.8 A resolution, which show that two molecules of 2-5A at a time tether RNase L monomers via the ankyrin-repeat (ANK) domain. Each ANK domain harbors two distinct sites for 2-5A recognition that reside 50 A apart. These data reveal a function for the ANK domain as a 2-5A sensing homo-oligomerization device and describe a nonlinear, ultrasensitive regulation in the 2-5A/RNase L system poised for amplification of the IFN response. PMID- 23084742 TI - Prevalence of obesity, abdominal obesity and associated factors in hypertensive adults aged 45-75 years. AB - BACKGROUND & AIMS: We aimed to examine the prevalence of obesity, abdominal obesity and associated factors in 17,656 Chinese hypertensive adults aged 45-75 years. METHODS: A cross-sectional investigation was carried out in Lianyungang, China. Overweight or obesity was defined as a body mass index of >=25 kg/m(2). Abdominal obesity was defined as a waist circumference >=90 cm for men and >=80 cm for women. RESULTS: The prevalence of overweight or obesity and abdominal obesity was 54.4% (women 59.3% and men 46.0%) and 59.4% (women 73.8% and men 35.1%), respectively. In the multivariable logistic-regression models, higher hypertension grades and standard of living, greater red meat consumption, lower physical activity levels, and antihypertensive treatment were independently associated with overweight or obesity and abdominal obesity in both sexes. Inland residence (versus coastal) was an independent associated factor for abdominal obesity in both sexes. Furthermore, a positive family history of diabetes in both sexes, a positive family history of hypertension, men with a positive family history of coronary heart disease, and men with inland residence were all independently associated with overweight or obesity. CONCLUSIONS: We found a high prevalence of overweight or obesity and abdominal obesity in Chinese hypertensive adults, particularly in inland areas. PMID- 23084744 TI - The microtubule plus-end tracking protein CLASP2 is required for hematopoiesis and hematopoietic stem cell maintenance. AB - Mammalian CLASPs are microtubule plus-end tracking proteins whose essential function as regulators of microtubule behavior has been studied mainly in cultured cells. We show here that absence of murine CLASP2 in vivo results in thrombocytopenia, progressive anemia, and pancytopenia, due to defects in megakaryopoiesis, in erythropoiesis, and in the maintenance of hematopoietic stem cell activity. Furthermore, microtubule stability and organization are affected upon attachment of Clasp2 knockout hematopoietic stem-cell-enriched populations, and these cells do not home efficiently toward their bone marrow niche. Strikingly, CLASP2-deficient hematopoietic stem cells contain severely reduced mRNA levels of c-Mpl, which encodes the thrombopoietin receptor, an essential factor for megakaryopoiesis and hematopoietic stem cell maintenance. Our data suggest that thrombopoietin signaling is impaired in Clasp2 knockout mice. We propose that the CLASP2-mediated stabilization of microtubules is required for proper attachment, homing, and maintenance of hematopoietic stem cells and that this is necessary to sustain c-Mpl transcription. PMID- 23084745 TI - A design principle for a posttranslational biochemical oscillator. AB - Multisite phosphorylation plays an important role in biological oscillators such as the circadian clock. Its general role, however, has been elusive. In this theoretical study, we show that a simple substrate with two modification sites acted upon by two opposing enzymes (e.g., a kinase and a phosphatase) can show oscillations in its modification state. An unbiased computational analysis of this oscillator reveals two common characteristics: a unidirectional modification cycle and sequestering of an enzyme by a specific modification state. These two motifs cause a substrate to act as a coupled system in which a unidirectional cycle generates single-molecule oscillators, whereas sequestration synchronizes the population by limiting the available enzyme under conditions in which substrate is in excess. We also demonstrate the conditions under which the oscillation period is temperature compensated, an important feature of the circadian clock. This theoretical model will provide a framework for analyzing and synthesizing posttranslational oscillators. PMID- 23084746 TI - Long-timescale dynamics and regulation of Sec-facilitated protein translocation. AB - We present a coarse-grained modeling approach that spans the nanosecond- to minute-timescale dynamics of cotranslational protein translocation. The method enables direct simulation of both integral membrane protein topogenesis and transmembrane domain (TM) stop-transfer efficiency. Simulations reveal multiple kinetic pathways for protein integration, including a mechanism in which the nascent protein undergoes slow-timescale reorientation, or flipping, in the confined environment of the translocon channel. Competition among these pathways gives rise to the experimentally observed dependence of protein topology on ribosomal translation rate and protein length. We further demonstrate that sigmoidal dependence of stop-transfer efficiency on TM hydrophobicity arises from local equilibration of the TM across the translocon lateral gate, and it is predicted that slowing ribosomal translation yields decreased stop-transfer efficiency in long proteins. This work reveals the balance between equilibrium and nonequilibrium processes in protein targeting, and it provides insight into the molecular regulation of the Sec translocon. PMID- 23084747 TI - An in vivo functional screen uncovers miR-150-mediated regulation of hematopoietic injury response. AB - Hematopoietic stem and progenitor cells are often undesired targets of chemotherapies, leading to hematopoietic suppression requiring careful clinical management. Whether microRNAs control hematopoietic injury response is largely unknown. We report an in vivo gain-of-function screen and the identification of miR-150 as an inhibitor of hematopoietic recovery upon 5-fluorouracil-induced injury. Utilizing a bone marrow transplant model with a barcoded microRNA library, we screened for barcode abundance in peripheral blood of recipient mice before and after 5-fluorouracil treatment. Overexpression of screen-candidate miR 150 resulted in significantly slowed recovery rates across major blood lineages, with associated impairment of bone marrow clonogenic potential. Conversely, platelets and myeloid cells from miR-150 null marrow recovered faster after 5 fluorouracil treatment. Heterozygous knockout of c-myb, a conserved target of miR 150, partially phenocopied miR-150-forced expression. Our data highlight the role of microRNAs in controlling hematopoietic injury response and demonstrate the power of in vivo functional screens for studying microRNAs in normal tissue physiology. PMID- 23084748 TI - Pleiotrophin regulates the retention and self-renewal of hematopoietic stem cells in the bone marrow vascular niche. AB - The mechanisms through which the bone marrow (BM) microenvironment regulates hematopoietic stem cell (HSC) fate remain incompletely understood. We examined the role of the heparin-binding growth factor pleiotrophin (PTN) in regulating HSC function in the niche. PTN(-/-) mice displayed significantly decreased BM HSC content and impaired hematopoietic regeneration following myelosuppression. Conversely, mice lacking protein tyrosine phosphatase receptor zeta, which is inactivated by PTN, displayed significantly increased BM HSC content. Transplant studies revealed that PTN action was not HSC autonomous, but rather was mediated by the BM microenvironment. Interestingly, PTN was differentially expressed and secreted by BM sinusoidal endothelial cells within the vascular niche. Furthermore, systemic administration of anti-PTN antibody in mice substantially impaired both the homing of hematopoietic progenitor cells to the niche and the retention of BM HSCs in the niche. PTN is a secreted component of the BM vascular niche that regulates HSC self-renewal and retention in vivo. PMID- 23084750 TI - RNAi screening reveals proteasome- and Cullin3-dependent stages in vaccinia virus infection. AB - A two-step, automated, high-throughput RNAi silencing screen was used to identify host cell factors required during vaccinia virus infection. Validation and analysis of clustered hits revealed previously unknown processes during virus entry, including a mechanism for genome uncoating. Viral core proteins were found to be already ubiquitinated during virus assembly. After entering the cytosol of an uninfected cell, the viral DNA was released from the core through the activity of the cell's proteasomes. Next, a Cullin3-based ubiquitin ligase mediated a further round of ubiquitination and proteasome action. This was needed in order to initiate viral DNA replication. The results accentuate the value of large scale RNAi screens in providing directions for detailed cell biological investigation of complex pathways. The list of cell functions required during poxvirus infection will, moreover, provide a resource for future virus-host cell interaction studies and for the discovery of antivirals. PMID- 23084749 TI - Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation. AB - The pentaspan membrane glycoprotein CD133 marks lineage-specific cancer progenitor cells and is associated with poor prognosis in a number of tumor types. Despite its utility as a cancer progenitor cell marker, CD133 protein regulation and molecular function remain poorly understood. We find that the deacetylase HDAC6 physically associates with CD133 to negatively regulate CD133 trafficking down the endosomal-lysosomal pathway for degradation. We further demonstrate that CD133, HDAC6, and the central molecule of the canonical Wnt signaling pathway, beta-catenin, can physically associate as a ternary complex. This association stabilizes beta-catenin via HDAC6 deacetylase activity, which leads to activation of beta-catenin signaling targets. Downregulation of either CD133 or HDAC6 results in increased beta-catenin acetylation and degradation, which correlates with decreased proliferation in vitro and tumor xenograft growth in vivo. Given that CD133 marks progenitor cells in a wide range of cancers, targeting CD133 may be a means to treat multiple cancer types. PMID- 23084752 TI - vacA genotypes of Helicobacter pylori in the oral cavity and stomach of patients with chronic gastritis and gastric ulcer. AB - INTRODUCTION: Helicobacter pylori adheres to various components of the human saliva. Therefore, the objective of this research was to simultaneously detect H. pylori in saliva and in gastric biopsy, and to determine the agreement between the vacA genotypes in both saliva and gastric biopsy. MATERIALS AND METHODS: A total of 162 patients with chronic gastritis and 34 with gastric ulcer were studied, and saliva and biopsy samples were collected from each patient. H. pylori DNA was detected by conventional PCR and nested PCR was used for vacA genotyping. RESULTS: In 24% of the patients (47/196) H. pylori DNA was found in saliva and in biopsy; 52.5% (103/196) were saliva(negative)/biopsy(positive) and 6.6% (13/196) were saliva(positive)/biopsy(negative). In either or both H. pylori vacAs1m1 or s1m2 genotypes were detected in saliva in 41.5% of the patients with chronic gastritis. Forty-seven percent had >1 genotype, and the s1m1/s1m2 combination was found in 36% of them. H. pylori vacAs1m1 and s1m2 were also found in the saliva and biopsy of patients with gastric ulcer. The genotypes found in saliva and biopsy of the same patient had 51.1% agreement. In 27.6% of the 47 patients saliva(positive)/biopsy(positive) two genotypes were found in saliva, and one or both in the stomach. CONCLUSIONS: The s1m1/s1m2 genotypes, alone or together, are found simultaneously in saliva and gastric biopsy of the same patient. These results suggest that H. pylori reaches the oral cavity by various ways, and that saliva can be the transmitting and re-infecting vector. PMID- 23084751 TI - Endogenous control of immunity against infection: tenascin-C regulates TLR4 mediated inflammation via microRNA-155. AB - Endogenous molecules generated upon pathogen invasion or tissue damage serve as danger signals that activate host defense; however, their precise immunological role remains unclear. Tenascin-C is an extracellular matrix glycoprotein that is specifically induced upon injury and infection. Here, we show that its expression is required to generate an effective immune response to bacterial lipopolysaccharide (LPS) during experimental sepsis in vivo. Tenascin-C enables macrophage translation of proinflammatory cytokines upon LPS activation of toll like receptor 4 (TLR4) and suppresses the synthesis of anti-inflammatory cytokines. It mediates posttranscriptional control of a specific subset of inflammatory mediators via induction of the microRNA miR-155. Thus, tenascin-C plays a key role in regulating the inflammatory axis during pathogenic activation of TLR signaling. PMID- 23084753 TI - Sensitive detection of glucose in human serum with oligonucleotide modified gold nanoparticles by using dynamic light scattering technique. AB - Dynamic light scattering based sensor for glucose was developed with oligonucleotide functionalized gold nanoparticles (Oligo-AuNPs). Oligonucleotide 5'-SH-(A)(12)-AGACAAGAGAGG-3' (Oligo 1) modified AuNPs and oligonucleotide 5' CAACAGAGAACG-(A)(12)-HS-3' (Oligo 2) modified AuNPs could hybridize with oligonulceotide 5'-CGTTCTCTGTTGCCTCTCTTGTCT-3' (Oligo 3), which resulted in the aggregation of Oligo-AuNPs probes, and triggered the increase of their average diameter. However, Oligo 3 could be cleaved into DNA fragments by the mixture of glucose, glucose oxidase (GOD) and Fe(2+), and the DNA fragments could not hybridize with Oligo-AuNPs probes. Under the conditions of 3.7 nM Oligo 1-AuNPs, 3.7 nM Oligo 2-AuNPs, 8.0 MUg/mL GOD, 100 nM Oligo 3 and 900 nM Fe(2+), the average diameter of Oligo-AuNPs probes decreased linearly with the increasing concentration of glucose over the range from 50 pmol/L to 5.0 nmol/L, with a detection limit of 38 pmol/L (3sigma/slope). Moreover, five sugars had no effect on the average diameter of mixture of Oligo-AuNPs probes, GOD and Fe(2+), which demonstrated the good selectivity of the assay. PMID- 23084754 TI - Frozen assembly of gold nanoparticles for rapid analysis of antifreeze protein activity. AB - We report the novel activity-based detection of antifreeze protein (AFP), also known as ice-binding protein (IBP), using freeze-labile gold nanoparticles (AuNPs) in order to overcome labor-intensive and low throughput issues of the current method based on thermal hysteresis (TH). Upon the addition of either CnAFP from the Antarctic diatom Chaetoceros neogracile or LeIBP from the Arctic yeast Leucosporidium sp. to mercaptosuccinic acid-capped AuNP, the self-assembly of AuNPs was highly inhibited after a freezing/thawing cycle, leading to no color change in the AuNP solution. As a result, the aggregation parameter (E(520)/E(650)) of AuNP presented the rapid detection of both the concentration dependent activity and stability of two AFPs with high sensitivity, where the detection range was 100-fold lower than that of the TH-based method. We suggest that our newly developed method is very suitable for simple and high-throughput measurement of AFP activity. PMID- 23084755 TI - Simultaneous and rapid detection of multiple pesticide and veterinary drug residues by suspension array technology. AB - Suspension array technology is proposed for the simultaneous quantitative determination of seven kinds of pesticide and veterinary drug residues, namely, atrazine, chloramphenicol, carbaryl, clenbuterol, 17-beta-estradiol, imidacloprid, and tylosin. The assay is simple and can be accomplished within 2h without repeated pumping and washing steps unlike conventional suspension arrays. The hapten-protein conjugate-coated beads bind to their complementary biotinylated antibodies using a competitive immunoassay format. The coefficients of determination R(2) for six targets were greater than 0.992, whereas that for atrazine was 0.961, which indicate good logistic correlations. The dynamic ranges for the seven targets in the 7-plex assay ranged from 2 log units to 4 log units(1.60*10(0)-1.64*10(3), 5.12*10(-2)-1.60*10(2), 1.00*10(0)-3.13*10(3), 4.00*10(-1)-4.10*10(2), 4.00*10(-1)-4.10*10(2), 5.12*10(-2)-1.60*10(2), and 2.00*10(0)-4.00*10(2)ngmL(-1)). The minimum detection concentrations of chloramphenicol, carbaryl, clenbuterol and 17-beta-estradiol in the suspension array (0.05, 1.00, 0.40 and 0.40 ng mL(-1)) were lower than the corresponding limits of detection (0.25, 6.60, 24.23 and 13.96 ng mL(-1)) of using an indirect competitive enzyme-linked immunosorbent assay. Environmental scanning electron microscope was employed to characterize the bead surface, which directly confirmed the reactions on the beads. The suspension array is more flexible and feasible than ELISA for the fast quantitative analysis of pesticide and veterinary drug residues. PMID- 23084757 TI - Dielectrophoretic responses of DNA and fluorophore in physiological solution by impedimetric characterization. AB - Characterization of the DNA's dielectrophoretic (DEP) behavior is the foundation of DNA manipulation by electric fields. This paper presents a label-free DNA differentiation technique by a combination of DEP response and impedimetric measurement on the microchip. In contrast to most of the recent studies on DEP manipulation of DNA that use deionized water or diluted DNA buffer where living biomolecules cannot survive, we used physiological solutions (PBS with 154 mM Na+) that are highly practical for pursuing DNA-based physical applications. The microchip, a commercial surface acoustic wave resonator, contains an array of interdigitated aluminum electrodes (1.4 MUm width, 1.1 MUm gap) on quartz substrate for DEP trap. Measurements were taken with a high precision impedance analyzer, which also acted as the excitation source to induce DEP response at 20 kHz, 50 kHz, 100 kHz, 300 kHz, 500 kHz, 1 MHz, 2 MHz and 5 MHz (N=3). To verify DEP response, fluorescence microscope images were captured before and after the electric excitation. Test results from the DEP experimentation after comparing with fluorescent images of pUC18 DNA show that a large change in impedance corresponds to positive DEP while little change corresponds to negative DEP. The strongest p-DEP and the maximum collection efficiency were observed around 300 kHz for supercoiled pUC18 and 100 kHz for linear lambdaDNA. This work yields real time impedimetric DEP response of DNA of different molecular conformations in practical settings. The technique can serve as the basis for submicron particle separation, disease diagnosis, cell life-circle research, and other applications in physiological surroundings. PMID- 23084756 TI - Parallel recording of neurotransmitters release from chromaffin cells using a 10*10 CMOS IC potentiostat array with on-chip working electrodes. AB - Neurotransmitter release is modulated by many drugs and molecular manipulations. We present an active CMOS-based electrochemical biosensor array with high throughput capability (100 electrodes) for on-chip amperometric measurement of neurotransmitter release. The high-throughput of the biosensor array will accelerate the data collection needed to determine statistical significance of changes produced under varying conditions, from several weeks to a few hours. The biosensor is designed and fabricated using a combination of CMOS integrated circuit (IC) technology and a photolithography process to incorporate platinum working electrodes on-chip. We demonstrate the operation of an electrode array with integrated high-gain potentiostats and output time-division multiplexing with minimum dead time for readout. The on-chip working electrodes are patterned by conformal deposition of Pt and lift-off photolithography. The conformal deposition method protects the underlying electronic circuits from contact with the electrolyte that covers the electrode array during measurement. The biosensor was validated by simultaneous measurement of amperometric currents from 100 electrodes in response to dopamine injection, which revealed the time course of dopamine diffusion along the surface of the biosensor array. The biosensor simultaneously recorded neurotransmitter release successfully from multiple individual living chromaffin cells. The biosensor was capable of resolving small and fast amperometric spikes reporting release from individual vesicle secretions. We anticipate that this device will accelerate the characterization of the modulation of neurotransmitter secretion from neuronal and endocrine cells by pharmacological and molecular manipulations of the cells. PMID- 23084758 TI - Amplified voltammetric detection of dopamine using ferrocene-capped gold nanoparticle/streptavidin conjugates. AB - Dopamine (DA) is one of the most important neurotransmitters present in brain tissues and body fluids of mammals. The change in the concentration levels has been associated with various diseases and disorders. Thus, sensitive and selective determination of DA is much preferred. In this work, sandwich-type electrochemical biosensor was developed, in which phenylboronic acid immobilized onto gold electrodes was used to capture DA. The anchored DA was then derivatized with biotin for the attachment of ferrocene-capped gold nanoparticle/streptavidin conjugates. The voltammetric responses were found to be proportional to the concentrations of DA ranging from 0.5 to 50 nM. A detection limit of 0.2 nM was achieved, which is 1~2 orders of magnitude lower than those achievable at various chemically modified electrodes. Analytical merits (e.g., dynamic range, reproducibility, detection level, selectivity and interference) were evaluated. The feasibility of the method for analysis of DA in artificial cerebrospinal fluid and dopamine hydrochloride injection has been demonstrated. PMID- 23084759 TI - Feed restriction as a biostimulant of the production of oocyte, their quality and GDF-9 gene expression in rabbit oocytes. AB - The use of short-term feed restriction (R) without or with subsequent refeeding (F) as biostimulant of rabbit fertility was examined in this study. A total of 40 mature, non-pregnant, non-lactating New Zealand white female rabbits were allocated to five treatments. The rabbits were individually caged and fed a complete pelleted diet (16.7% CP; 13.1 CF; 2490kcalDE/kg). Rabbits on the control (C) treatment received 150g/d of the diet. Two groups of 8 rabbits received 70% of the control daily feed intake (105g/d; moderate restriction; M) and the other two groups received 50% of the control feed intake (75g/d; severe restriction; S) for 21d. At the end of this period, one group each of M and S fed rabbits were slaughtered for oocyte recovery. Rabbits in the remaining three groups (C, MF and SF) were retained for a further 8d before slaughter and fed the control level of the diet during this period. The effects on body weight, oocyte number and quality, GDF-9 gene expression in oocytes, and changes in serum levels of leptin and IGF-1 were recorded. Initial mean body weights were not significantly different ranging from 2.50+/-0.33kg (S) to 2.58+/-0.24kg (C). After 3wk on treatment the C rabbits were significantly heavier (2.65+/-0.32kg; P<0.05) than rabbits on the M (2.26+/-0.33kg) or S (2.10+/-0.33kg) treatments. Following 8d of refeeding, the remaining group of S treated rabbits (SF) were still significantly lighter (2.40+/-0.21kg; P<0.05) than C (2.71+/-0.31kg) with MF rabbits having an intermediate weight (2.50+/-0.20kg). The number of mature grade A oocytes recovered per ovary was significantly lower for control (3.3+/-0.35) than the refed treatments (MF 4.0+/-0.30; SF 4.5+/-0.39; P<0.05). Semi-quantitative PCR analysis of GDF-9 expression showed that control mature grade A oocytes had significantly lower levels of expression (1.27+/-0.20; P<0.05) than those of refed rabbits (MF 1.60+/-0.10; SF 1.39+/-0.01). Leptin and IGF-1 values for refed rabbits were significantly higher (P<0.05) than at the end of feed restriction and the start point. It was concluded that this biostimulant method has the potential to improve the fertility of rabbits. PMID- 23084760 TI - Feasibility of salvaging genetic potential of post-mortem fawns: production of sperm in testis tissue xenografts from immature donor white-tailed deer (Odocoileus virginianus) in recipient mice. AB - The purpose of this study was to evaluate the long-term outcome of testis tissue xenografting from immature deer. Testis tissue was collected post-mortem from a 2 mo-old white-tailed deer fawn (Odocoileus virginianus) and small fragments of the tissue were grafted under the back skin of immunodeficient recipient mice (n = 7 mice; 8 fragments/mouse). Single xenograft samples were removed from representative recipient mice every 2 mo from grafting for up to 14 mo post grafting. The retrieved xenografts were evaluated for seminiferous tubular density (per mm(2)) and tubular diameter, as well as for seminiferous tubular morphology and identification of the most advanced germ cell type present in each tubule cross section. Overall, 63% of the grafted testis fragments were recovered as xenografts. Testis tissue xenografts showed a gradual testicular development starting with tubular expansion by 2 mo, presence of spermatocytes by 6 mo post grafting, round and elongated spermatids by 8 mo, followed by fully-formed sperm by 12 mo post-grafting. The timing of complete spermatogenesis generally corresponded to the reported timing of sexual maturation in white-tailed deer. This study demonstrated, for the first time, that testis tissue xenografting from immature deer donors into recipient mice can successfully result in testicular maturation and development of spermatogenesis in the grafts up to the stage of sperm production. These results may therefore provide a model for salvaging genetic material from immature male white-tailed deer that die before reaching sexual maturity. PMID- 23084761 TI - The percentage of spermatozoa lost during the centrifugation of brown bear (Ursus arctos) ejaculates is associated with some spermatozoa quality and seminal plasma characteristics. AB - Cryopreservation of brown bear (Ursus arctos) semen requires centrifugation to increase concentration and/or remove urine contamination. However, a percentage of the spermatozoa are lost in the process. This percentage varies considerably between males and ejaculates, and we have studied the effect of sperm quality and seminal plasma characteristics on the spermatozoa recovery rate after centrifugation. One hundred and thirty one sperm samples obtained from fifteen brown bear males by electroejaculation under general anaesthesia were used. The ejaculates were centrifuged 600 * g for 6 min. Motility was assessed by CASA, and acrosomal status (PNA-FITC) and viability (SYBR-14/propidium iodide) were determined by flow cytometry. Seminal plasma characteristics (albumin, alkaline phosphatase, calcium, cholesterol, creatine, glucose, glutamic oxaloacetic transaminase (GOT), lactate, lipase, magnesium, phosphate and total protein) were determined by a biochemical and gas analysis. Total motility (r = 0.26; P=0.005) and cell viability (r = 0.20; P = 0.033) were positively correlated with the percentage of recovered spermatozoa. Sperm recovery was correlated with the concentration of several components of seminal plasma: negatively with glucose concentration (r = -0.47; P = 0.005) and positively with the enzymes GOT (r = 0.36; P = 0.040) and lactate dehydrogenase (r = 0.36; P = 0.041). After sorting the data into classes according to sperm recovery (Low: 0-39, Medium: 40-69, High: 70-100), we observed that the samples with a lower recovery rate derived from ejaculates with lower values for TM, VAP and viability (P<0.05). Multiple regression analysis rendered two models to define the post-centrifugation spermatozoa recovery which included total motility and damaged acrosome or glucose, GOT and lactate dehydrogenase. We discuss these relationships and their implications in the electroejaculation procedure and the handling of the sample during centrifugation. PMID- 23084762 TI - Insights into tuberculosis from the zebrafish model. AB - Mycobacterium tuberculosis (MTB) continues to plague humanity because of significant gaps in our understanding of MTB infection, including the nature of a protective versus pathological host response, why antimicrobial cure is so difficult, and the ineffectiveness of vaccination. The development of a zebrafish model, utilizing infection with the natural fish pathogen Mycobacterium marinum (Mm), has yielded important insights into tuberculosis with immediate clinical applications. PMID- 23084764 TI - Improved edge delineation using a low-flow and delayed-phase contrast-enhanced protocol for computed tomography imaging of oral cavity and oropharyngeal malignancies. AB - AIM: To determine whether contrast-enhanced computed tomography (CT) performed with a high flow rate and short delay protocol or a lower flow rate and longer delay protocol resulted in better enhancement of the oral cavity and oropharyngeal tumour and tumour edge delineation. MATERIALS AND METHODS: Patients with squamous cell carcinomas of the upper aerodigestive tract (UAT) who underwent contrast-enhanced CT using 100 ml contrast material with 300 mg iodine/ml were selected for this comparison study. The protocols studied used a high flow rate and short scan delay (2 ml/s and 50 s) and a lower flow rate and longer delay (1 ml/s and 100 s). Contrast enhancement by radiodensity in Hounsfield units of the tumour site, poorest and clearest tumour boundaries and contralateral lateral pterygoid muscle were measured using a region of interest tool. A t-test statistical analysis was used to compare both protocols. RESULTS: The lower flow and longer delay protocol maximized contrast differences at both the poorest and clearest definition boundaries of the tumour (p <= 0.01 and p <= 0.05, respectively) and the pterygoid muscle (p <= 0.01). There was no significant difference in contrast enhancement within the central homogeneous tumour site. CONCLUSION: A lower flow and longer delay protocol (1 ml/s and 100 s) provided better enhancement of the delineation of the tumour edge and surrounding musculature than a high flow rate and short delay protocol (2 ml/s and 50 s). Both protocols achieved similar central tumour enhancement. PMID- 23084763 TI - Immune responses to Clostridium difficile infection. AB - Clostridium difficile is the causal agent of antibiotic-associated diarrhea and is a leading cause of hospital-acquired infections in the US. C. difficile has been known to cause severe diarrhea and colitis for more than 30 years, but the emergence of a newer, hypervirulent strain of C. difficile (BI/NAP1) has further compounded the problem, and recently both the number of cases and mortality associated with C. difficile-associated diarrhea have been increasing. One of the major drivers of disease pathogenesis is believed to be an excessive host inflammatory response. A better understanding of the host inflammation and immune mechanisms that modulate the course of disease and control host susceptibility to C. difficile could lead to novel (host-targeted) strategies for combating the challenges posed by this deadly infection. This review summarizes our current knowledge of the host inflammatory response during C. difficile infection. PMID- 23084765 TI - Modern cancer management and research in the Middle East. PMID- 23084766 TI - Tackling cancer burden in the Middle East: Qatar as an example. AB - Cancer prevalence is increasing in the Middle East, partly because of increased life expectancy and adoption of western lifestyle habits. Suboptimum delivery of health care also contributes to late diagnosis and poor survival of people with cancer. Public awareness of cancer risk is frequently low and misconceptions high, thereby preventing patients from seeking treatment early and constituting a substantial barrier to improvement of cancer outcomes. Screening programmes might have low uptake in Arab populations because of social and health beliefs about cancer. This review outlines the opportunities available to Middle Eastern countries and their emerging economies to learn from global experiences in cancer care, service provision, and research partnerships. The Middle East has begun to develop several health-care transformation programmes. Qatar, in particular, has published a National Health Strategy, in which cancer is one of the main commitments; this Strategy provides the focus of this review. The development of effective health-care strategies and evidence-based medicine directly linked to innovative cancer research is needed to improve cancer care. Although the full extent of the proposed solutions are not necessarily implementable in all Middle Eastern countries, wealthy states can lead derivation of population-specific approaches that could have effects throughout the region. Key challenges are outlined-namely, human capacity and training, subspecialisation of services, building on international cancer research initiatives, and the need for earlier diagnosis and awareness in the population. Countries in the Gulf Region (ie, countries bordering the Persian Gulf, including Iran, Iraq, Kuwait, Saudi Arabia, Bahrain, Qatar, UAE, and Oman) need to address these challenges to be at the forefront of integrated cancer care and research and ensure that the latest innovations and best possible care are delivered to their populations. PMID- 23084767 TI - Application of visualization techniques for cell and tissue engineering. AB - Visualization has been an indispensable technique in the biological field. The advantage of visualization is to perform non-disruptive analyses with high spatio and temporal resolution. Using these properties, visualization has been employed for cell and tissue engineering research, including therapeutic protein production, cell and organelle manipulation, and stem cell technology. For cell assessment and manipulation, two-photon microscopy based on femtosecond laser is becoming a major tool because of its high depth resolution, low cell damages, and depth of penetration into tick specimen. Non-disruptive and single cell observation/manipulation technique is a powerful tool for stem cell research. In this review, we discuss recent developments in cell and tissue engineering in relation to the revolution in visualization techniques. PMID- 23084768 TI - Volume changes of autogenous bone after sinus lifting and grafting procedures: a 6-year computerized tomographic follow-up. AB - OBJECTIVES: To evaluate long-term bone remodelling of autografts over time (annually, for 6 years), comparing the block and particulate bone procedures for sinus floor elevation, as well as to evaluate the survival of positioned dental implants. PATIENTS AND METHODS: Twenty-three sinus lift procedures with autogenous bone were performed: seven sinus lift procedures using particulate graft and 10 with block autogenous bone were performed in 17 patients. Employing a software program, pre- and post-surgical computerized tomography (CT) scans were used to compare the volume (V) and density (D) of inlay grafts over time (up to 6 years), and to determine the percentage of remaining bone (%R). All variable (V, D and %R) measurements were then compared statistically. RESULTS: At the 6 year survey for block form, a resorption of 21.5% was seen, whereas for particulate grafts there was a resorption of 39.2%. Both groups exhibited bone remodelling between the first and second follow-up which was significant regarding volume for the block form and regarding density for the particulate group. CONCLUSIONS: During the initial period of healing, the cortico-cancellous block bone grafted into the maxillary sinus underwent a negative remodelling of the volume, which is most probably due to graft cortex resorption, coupled with, primarily, an increase in density in the spongious area; for the particulate grafts, significant augmentations in density were obtained. The lack of significant differences among volumes was due to the wide degree of dispersion of the data. The rough data presented in this paper seem to support the use of a bone-block grafting procedure in maxillary sinus augmentation. PMID- 23084769 TI - Influence of age on the relative biological effectiveness of carbon ion radiation for induction of rat mammary carcinoma. AB - PURPOSE: The risk of developing secondary cancer after radiotherapy, especially after treatment of childhood cancers, remains a matter of concern. The high biological effects of carbon-ion radiation have enabled powerful radiotherapy, yet the approach is commonly restricted to the treatment of adults. Susceptibility of the fetus to particle radiation-induced cancer is also unclear. The present study is aimed to investigate the effect of carbon-ion irradiation in childhood on breast carcinogenesis. METHODS AND MATERIALS: We irradiated female Sprague-Dawley rats of various ages (embryonic days 3, 13, and 17 and 1, 3, 7, and 15 weeks after birth) with (137)Cs gamma rays or a 290-MeV/u monoenergetic carbonion beam (linear energy transfer, 13 keV/MUm). All animals were screened weekly for mammary carcinoma by palpation until they were 90 weeks old. RESULTS: Irradiation of fetal and mature (15-week-old) rats with either radiation source at a dose of 0.2 or 1 Gy did not substantially increase the hazard ratio compared with the nonirradiated group. Dose responses (0.2-2.0 Gy) to gamma rays were similar among the groups of rats irradiated 1, 3, and 7 weeks after birth. The effect of carbon ions increased along with the age at the time of irradiation, indicating relative biological effectiveness values of 0.2 (-0.3, 0.7), 1.3 (1.0, 1.6), and 2.8 (1.8, 3.9) (mean and 95% confidence interval) for animals that were 1, 3, and 7 weeks of age, respectively. CONCLUSIONS: Our findings imply that carbonion therapy may be associated with a risk of secondary breast cancer in humans, the extent of which may depend on the age of the patient at the time of irradiation. PMID- 23084770 TI - Live oral typhoid vaccine Salmonella Typhi Ty21a - a surrogate vaccine against non-typhoid salmonella? AB - BACKGROUND: Non-typhoid Salmonella (NTS) is a leading cause of food-borne illness with more than 90 million annual cases and an emerging antimicrobial resistance among the strains worldwide. Paradoxically, no vaccines are available against these pathogens. Numerous NTS strains share surface O-antigens with Salmonella enterica serotype Typhi. As intestinal antibodies against O-antigens have proven protective against NTS in animal experiments, it appears conceivable that the oral whole-cell typhoid vaccine, Salmonella Typhi Ty21a (Vivotif((r))), which effectively elicits intestinal antibodies against O-antigens, could exhibit cross protective efficacy against NTS. We sought immunological evidence in support of cross-protective efficacy of Ty21a against NTS. MATERIALS AND METHODS: 35 volunteers receiving Ty21a vaccine and five patients with enteric fever were investigated with ELISPOT for circulating plasmablasts secreting antibodies reactive with Salmonella Typhi and six different NTS serotypes. These plasmablasts were also analysed for homing receptor expressions. RESULTS: In all vaccinees and patients, a strong gut-directed cross-reactive plasmablast response was found against serotypes sharing the two O-antigens with Salmonella Typhi (O 9,12) (in vaccinees, mean: 95%CI 268: 228-508 and 363: 234-493 plasmablasts/10(6)PBMC against Salmonella Typhi and Enteritidis). Responses against strains sharing one O-antigen (O-12) were weaker (222: 105-338 against Salmonella Typhimurium), while no significant reactivity was detected against strains without typhoidal O-antigens. CONCLUSIONS: Intestinal antibodies against O-antigens protect against NTS in animal experiments. Ty21a was found to elicit intestinal immune responses cross-reactive with NTS strains sharing O-antigens with Ty21a. These include the most common NTS, Salmonella Enteritidis and Typhimurium. The data suggest that Ty21a may have cross-protective efficacy against numerous NTS strains. PMID- 23084771 TI - Improved protocols for histamine sensitization testing of acellular pertussis vaccines. AB - The histamine sensitization test is a widely used method for measuring the residual toxicity of pertussis toxin in acellular pertussis vaccines. Although it has been used as a routine assay for decades, the current protocols are difficult to standardize because the test results vary considerably and are based on several factors, including mouse strain, age and sex. In this study, we observed that mice of strains CD1, ddY and C57/BL6 were sufficiently sensitive to pertussis toxin among six mice strains tested and that aged male mice were more sensitive to pertussis toxin than younger or female mice. Using this animal model, we showed pertussis toxin dose-dependent responses in the two histamine sensitization test protocols based on either lethal end-point determination or mouse rectal temperature measurement. Sensitivity to pertussis toxin was further enhanced by the addition of lipopolysaccharide in both methods. With these improvements, pertussis toxin activity can be estimated more accurately and reproducibly using a reduced number of animals. PMID- 23084772 TI - The pendulum model for genome compositional dynamics: from the four nucleotides to the twenty amino acids. AB - The genetic code serves as one of the natural links for life's two conceptual frameworks-the informational and operational tracks-bridging the nucleotide sequence of DNA and RNA to the amino acid sequence of protein and thus its structure and function. On the informational track, DNA and its four building blocks have four basic variables: order, length, GC and purine contents; the latter two exhibit unique characteristics in prokaryotic genomes where protein coding sequences dominate. Bridging the two tracks, tRNAs and their aminoacyl tRNA synthases that interpret each codon-nucleotide triplet, together with ribosomes, form a complex machinery that translates genetic information encoded on the messenger RNAs into proteins. On the operational track, proteins are selected in a context of cellular and organismal functions constantly. The principle of such a functional selection is to minimize the damage caused by sequence alteration in a seemingly random fashion at the nucleotide level and its function-altering consequence at the protein level; the principle also suggests that there must be complex yet sophisticated mechanisms to protect molecular interactions and cellular processes for cells and organisms from the damage in addition to both immediate or short-term eliminations and long-term selections. The two-century study of selection at species and population levels has been leading a way to understand rules of inheritance and evolution at molecular levels along the informational track, while ribogenomics, epigenomics and other operationally-defined omics (such as the metabolite-centric metabolomics) have been ushering biologists into the new millennium along the operational track. PMID- 23084773 TI - Systems approaches to biology and disease enable translational systems medicine. AB - The development and application of systems strategies to biology and disease are transforming medical research and clinical practice in an unprecedented rate. In the foreseeable future, clinicians, medical researchers, and ultimately the consumers and patients will be increasingly equipped with a deluge of personal health information, e.g., whole genome sequences, molecular profiling of diseased tissues, and periodic multi-analyte blood testing of biomarker panels for disease and wellness. The convergence of these practices will enable accurate prediction of disease susceptibility and early diagnosis for actionable preventive schema and personalized treatment regimes tailored to each individual. It will also entail proactive participation from all major stakeholders in the health care system. We are at the dawn of predictive, preventive, personalized, and participatory (P4) medicine, the fully implementation of which requires marrying basic and clinical researches through advanced systems thinking and the employment of high-throughput technologies in genomics, proteomics, nanofluidics, single-cell analysis, and computation strategies in a highly-orchestrated discipline we termed translational systems medicine. PMID- 23084774 TI - Strand-biased gene distribution in bacteria is related to both horizontal gene transfer and strand-biased nucleotide composition. AB - Although strand-biased gene distribution (SGD) was described some two decades ago, the underlying molecular mechanisms and their relationship remain elusive. Its facets include, but are not limited to, the degree of biases, the strand preference of genes, and the influence of background nucleotide composition variations. Using a dataset composed of 364 non-redundant bacterial genomes, we sought to illustrate our current understanding of SGD. First, when we divided the collection of bacterial genomes into non-polC and polC groups according to their possession of DnaE isoforms that correlate closely with taxonomy, the SGD of the polC group stood out more significantly than that of the non-polC group. Second, when examining horizontal gene transfer, coupled with gene functional conservation (essentiality) and expressivity (level of expression), we realized that they all contributed to SGD. Third, we further demonstrated a weaker G dominance on the leading strand of the non-polC group but strong purine dominance (both G and A) on the leading strand of the polC group. We propose that strand biased nucleotide composition plays a decisive role for SGD since the polC bearing genomes are not only AT-rich but also have pronounced purine-rich leading strands, and we believe that a special mutation spectrum that leads to a strong purine asymmetry and a strong strand-biased nucleotide composition coupled with functional selections for genes and their functions are both at work. PMID- 23084775 TI - Putative chitin synthases from Branchiostoma floridae show extracellular matrix related domains and mosaic structures. AB - The transition from unicellular to multicellular life forms requires the development of a specialized structural component, the extracellular matrix (ECM). In Metazoans, there are two main supportive systems, which are based on chitin and collagen/hyaluronan, respectively. Chitin is the major constituent of fungal cell walls and arthropod exoskeleton. However, presence of chitin/chitooligosaccharides has been reported in lower chordates and during specific stages of vertebrate development. In this study, the occurrence of chitin synthases (CHSs) was investigated with a bioinformatics approach in the cephalochordate Branchiostoma floridae, in which the presence of chitin was initially reported in the skeletal rods of the pharyngeal gill basket. Twelve genes coding for proteins containing conserved amino acid residues of processive glycosyltransferases from GT2 family were found and 10 of them display mosaic structures with novel domains never reported previously in a chitin synthase. In particular, the presence of a discoidin (DS) and a sterile alpha motif (SAM) domain was found in nine identified proteins. Sequence analyses and homology modelling suggest that these domains might interact with the extracellular matrix and mediate protein-protein interaction. The multi-domain putative chitin synthases from B. floridae constitute an emblematic example of the explosion of domain innovation and shuffling which predate Metazoans. PMID- 23084776 TI - Novel adaptors of amyloid precursor protein intracellular domain and their functional implications. AB - Amyloid precursor protein intracellular domain (AICD) is one of the potential candidates in deciphering the complexity of Alzheimer's disease. It plays important roles in determining cell fate and neurodegeneration through its interactions with several adaptors. The presence or absence of phosphorylation at specific sites determines the choice of partners. In this study, we identified 20 novel AICD-interacting proteins by in vitro pull down experiments followed by 2D gel electrophoresis and MALDI-MS analysis. The identified proteins can be grouped into different functional classes including molecular chaperones, structural proteins, signaling and transport molecules, adaptors, motor proteins and apoptosis determinants. Interactions of nine proteins were further validated either by colocalization using confocal imaging or by co-immunoprecipitation followed by immunoblotting. The cellular functions of most of the proteins can be correlated with AD. Hence, illustration of their interactions with AICD may shed some light on the disease pathophysiology. PMID- 23084777 TI - Homepeptide repeats: implications for protein structure, function and evolution. AB - Analysis of protein sequences from Mycobacterium tuberculosis H37Rv (Mtb H37Rv) was performed to identify homopeptide repeat-containing proteins (HRCPs). Functional annotation of the HRCPs showed that they are preferentially involved in cellular metabolism. Furthermore, these homopeptide repeats might play some specific roles in protein-protein interaction. Repeat length differences among Bacteria, Archaea and Eukaryotes were calculated in order to identify the conservation of the repeats in these divergent kingdoms. From the results, it was evident that these repeats have a higher degree of conservation in Bacteria and Archaea than in Eukaryotes. In addition, there seems to be a direct correlation between the repeat length difference and the degree of divergence between the species. Our study supports the hypothesis that the presence of homopeptide repeats influences the rate of evolution of the protein sequences in which they are embedded. Thus, homopeptide repeat may have structural, functional and evolutionary implications on proteins. PMID- 23084778 TI - NSort/DB: an intranuclear compartment protein database. AB - Distinct substructures within the nucleus are associated with a wide variety of important nuclear processes. Structures such as chromatin and nuclear pores have specific roles, while others such as Cajal bodies are more functionally varied. Understanding the roles of these membraneless intra-nuclear compartments requires extensive data sets covering nuclear and compartment-associated proteins. NSort/DB is a database providing access to intra- or sub-nuclear compartment associations for the mouse nuclear proteome. Based on resources ranging from large-scale curated data sets to detailed experiments, this data set provides a high-quality set of annotations of non-exclusive association of nuclear proteins with structures such as promyelocytic leukaemia bodies and chromatin. The database is searchable by protein identifier or compartment, and has a documented web service API. The search interface, web service and data download are all freely available online at http://www.nsort.org/db/. Availability of this data set will enable systematic analyses of the protein complements of nuclear compartments, improving our understanding of the diverse functional repertoire of these structures. PMID- 23084779 TI - Wavelet analysis of DNA walks on the human and chimpanzee MAGE/CSAG-palindromes. AB - The palindrome is one class of symmetrical duplications with reverse complementary characters, which is widely distributed in many organisms. Graphical representation of DNA sequence provides a simple way of viewing and comparing various genomic structures. Through 3-D DNA walk analysis, the similarity and differences in nucleotide composition, as well as the evolutionary relationship between human and chimpanzee MAGE/CSAG-palindromes, can be clearly revealed. Further wavelet analysis indicated that duplicated segments have irregular patterns compared to their surrounding sequences. However, sequence similarity analysis suggests that there is possible common ancestor between human and chimpanzee MAGE/CSAG-palindromes. Based on the specific distribution and orientation of the repeated sequences, a simple possible evolutionary model of the palindromes is suggested, which may help us to better understand the evolutionary course of the genes and the symmetrical sequences. PMID- 23084780 TI - Hypoxia induces mucin expression and secretion in human bronchial epithelial cells. AB - The study objective was to investigate the role of hypoxia-inducible factor 1 (HIF-1) in the transcriptional activation of MUC5AC in human bronchial epithelial (HBE) 16 cells under hypoxia conditions and the effect of hypoxia on expression and secretion of MUC5AC. Cells were incubated in hypoxia medium. Serial deletions or mutations of the MUC5AC promoter were cloned in the reporter pGL3-basic plasmid (Promega Biotech Co, Ltd, Beijing, China). These reporter plasmids were cotransfected with HIF-1alpha small interfering RNA. Hypoxia markedly increased the level of MUC5AC secretion and the transcriptional activity of MUC5AC promoters. Western blot analysis showed that HIF-1alpha and MUC5AC proteins were strongly increased after HBE16 cells were exposed to hypoxic conditions. Treatment of HBE16 cells with HIF-1alpha inhibitor (YC-1) or HIF-1alpha small interfering RNA significantly inhibited the expression of HIF-1alpha and MUC5AC, and the secretion of MUC5AC. Depletion of the promoter sequence did not reduce the MUC5AC promoter activity to hypoxia. Luciferase assay indicated that HRE in the MUC5AC promoter was in the region from -120 to +54. Promoter sequence analysis showed that 1 HRE site at -65 plays an important role in hypoxia activation of the MUC5AC. The inactivation of the HRE site using site-directed mutagenesis led to the complete loss of induction by hypoxia, which further confirmed the key role of the HRE site. MUC5AC expression and secretion are upregulated in response to hypoxia. The HRE site at -65 in the MUC5AC promoter and the HIF-1alpha are the major regulators for the cellular response against hypoxia in human bronchial epithelial cells. PMID- 23084782 TI - Integral role of the I'-helix in the function of the "inactive" C-terminal domain of catalase-peroxidase (KatG). AB - Catalase-peroxidases (KatGs) have two peroxidase-like domains. The N-terminal domain contains the heme-dependent, bifunctional active site. Though the C terminal domain lacks the ability to bind heme or directly catalyze any reaction, it has been proposed to serve as a platform to direct the folding of the N terminal domain. Toward such a purpose, its I'-helix is highly conserved and appears at the interface between the two domains. Single and multiple substitution variants targeting highly conserved residues of the I'-helix were generated for intact KatG as well as the stand-alone C-terminal domain (KatG(C)). Single variants of intact KatG produced only subtle variations in spectroscopic and catalytic properties of the enzyme. However, the double and quadruple variants showed substantial increases in hexa-coordinate low-spin heme and diminished enzyme activity, similar to that observed for the N-terminal domain on its own (KatG(N)). The analogous variants of KatG(C) showed a much more profound loss of function as evaluated by their ability to return KatG(N) to its active conformation. All of the single variants showed a substantial decrease in the rate and extent of KatG(N) reactivation, but with two substitutions, KatG(C) completely lost its capacity for the reactivation of KatG(N). These results suggest that the I'-helix is central to direct structural adjustments in the adjacent N-terminal domain and supports the hypothesis that the C-terminal domain serves as a platform to direct N-terminal domain conformation and bifunctionality. PMID- 23084781 TI - Listen up: children with early identified hearing loss achieve age-appropriate speech/language outcomes by 3 years-of-age. AB - OBJECTIVES: Age-appropriate speech/language outcomes for children with early identified hearing loss are a possibility but not a certainty. Identification of children most likely to achieve optimal outcomes is complicated by the heterogeneity of the children involved in outcome research, who present with a range of malleable (e.g. age of identification and cochlear implantation, type of intervention, communication mode) and non-malleable (e.g. degree of hearing loss) factors. This study considered whether a homogenous cohort of early identified children (<= 12 months), with all severities of hearing loss and no other concomitant diagnoses could not only significantly outperform a similarly homogenous cohort of children who were later identified (>12 months to <5 years), but also achieve and maintain age-appropriate speech/language outcomes by 3, 4 and 5 years of age. METHODS: A mixed prospective/retrospective comparative study of a homogenous cohort of 45 early identified (<= 12 months) and 49 late identified (> 12 months to < 5 years) children with hearing loss was conducted. The children all attended the same oral auditory-verbal early intervention programme. Speech/language assessments standardized on typically developing hearing children were conducted at 3, 4 and 5 years of age. RESULTS: The early identified children significantly outperformed the late identified at all ages and for all severities of HL. By 3 years of age, 93% of all early identified participants scored within normal limits (WNL) for speech; 90% were WNL for understanding vocabulary; and 95% were WNL for receptive and expressive language. Progress was maintained and improved so that by 5 years of age, 96% were WNL for speech, with 100% WNL for language. CONCLUSIONS: This study found that most children with all severities of hearing loss and no other concomitant diagnosed condition, who were early diagnosed; received amplification by 3 months; enrolled into AV intervention by 6 months and received a cochlear implant by 18 months if required, were able to "keep up with" rather than "catch up to" their typically hearing peers by 3 years of age on measures of speech and language, including children with profound hearing loss. By 5 years, all children achieved typical language development and 96% typical speech. PMID- 23084783 TI - Influence of osteon area fraction and degree of orientation of HAp crystals on mechanical properties in bovine femur. AB - Cortical bone has a hierarchical structure, spanning from the macrostructure at several millimeters or whole bone level, the microstructure at several hundred micrometers level, to the nanostructure at hydroxyapatite (HAp) crystals and collagen fibrils levels. The aim of the study is to understand the relationship between the HAp crystal orientation and the elastic modulus and the relationship between the osteon area fraction and the deformation behavior of HAp crystals in cortical bone. In the experiments, five strip specimens (40*2*1mm(3)) aligned with the bone axis were taken from the cortical bone of a bovine femur. The degree of c-axis orientation of HAp crystals in the specimens was measured with the X-ray diffraction technique with the imaging plate. To measure the deformation behavior of HAp crystals in the specimens, tensile tests under X-ray irradiation were conducted. The specimens were cut at the X-ray measurement positions and osteon area fraction and porosity at the transverse cross-sections were observed. Further, the volume fraction of HAp of the specimens was measured. Results showed the degree of c-axis orientation of HAp crystals was positively correlated with the elastic modulus of the specimens (r=0.94). The volume fraction of HAp and the porosity showed no statistical correlation with the elastic modulus and the tensile strength. The HAp crystal strain epsilon(H) increased linearly with the bone tissue strain epsilon. The average value of epsilon(H)/epsilon was 0.69+/-0.13 and there was no correlation between the osteon area fraction and epsilon(H)/epsilon (r=-0.27, p=0.33). The results suggest that the degree of c-axis orientation of HAp crystals affects the elastic modulus and the magnitude of HAp crystal strain does not depend on the osteon area fraction. PMID- 23084784 TI - The natural medications for wound healing - Curcumin, Aloe-Vera and Ginger - do not induce a significant effect on the migration kinematics of cultured fibroblasts. AB - Curcumin, Aloe-vera and Ginger are popular natural medications (NMs) for treating wounds, however, the mechanisms by which these NMs apparently accelerate wound healing remain largely unknown. From a biomechanical perspective, it is specifically unclear whether fibroblast motility improves in the presence of any of these NMs. Here we use our recently developed quantitative high-precision automated assay for cell migration (Topman et al., 2012b) which is based on image processing of time lapse micrographs to determine whether kinematic parameters e.g. the maximum and average migration rates of en mass fibroblast colonies are influenced by treating the cells with the above NMs. We found no evidence that Curcumin, Aloe-vera and Ginger directly influence the en mass fibroblast migration kinematics in vitro post infliction of localized mechanical damage to the cultures. However, due to the complexity of a wound healing process in vivo, these NMs may still influence the healing through other pathways. PMID- 23084785 TI - Kinematic differences between optical motion capture and biplanar videoradiography during a jump-cut maneuver. AB - Jumping and cutting activities are investigated in many laboratories attempting to better understand the biomechanics associated with non-contact ACL injury. Optical motion capture is widely used; however, it is subject to soft tissue artifact (STA). Biplanar videoradiography offers a unique approach to collecting skeletal motion without STA. The goal of this study was to compare how STA affects the six-degrees-of-freedom motion of the femur and tibia during a jump cut maneuver associated with non-contact ACL injury. Ten volunteers performed a jump-cut maneuver while their landing leg was imaged using optical motion capture (OMC) and biplanar videoradiography. The within-bone motion differences were compared using anatomical coordinate systems for the femur and tibia, respectively. The knee joint kinematic measurements were compared during two periods: before and after ground contact. Over the entire activity, the within bone motion differences between the two motion capture techniques were significantly lower for the tibia than the femur for two of the rotational axes (flexion/extension, internal/external) and the origin. The OMC and biplanar videoradiography knee joint kinematics were in best agreement before landing. Kinematic deviations between the two techniques increased significantly after contact. This study provides information on the kinematic discrepancies between OMC and biplanar videoradiography that can be used to optimize methods employing both technologies for studying dynamic in vivo knee kinematics and kinetics during a jump-cut maneuver. PMID- 23084786 TI - Identification and location of the cocaine and amphetamine regulated transcript (CART) in the abomasum of cattle. AB - The cocaine and amphetamine regulated transcript (CART) belongs to the group of peptides with anorexigenic properties and is present in many areas of the central and peripheral nervous systems of numerous mammalian species. Research has suggested an effect on the feeling of appetite and satiety; however, there are no clear clues as to the role of CART in specific organs, including the stomach. Considering the specificity of cattle feeding and digestion, CART may play a highly significant role possibly associated with the option of administering greater amounts of high-volume feeds. Based on the results of immunohistochemical staining of abomasum samples prepared from hybrid bulls, the presence of CART positive structures and CART distribution were determined in the mucosa, submucosa and muscularis layers of the stomach. Abundant sites of CART were found in the myenteric plexus, nerve fibers innervating the myocytes of the myenteron, neuroendocrine cells of the diffuse neuroendocrine system and the submucous plexus. The preliminary stage of abomasal CART detection suggests that CART is an agent that strongly affects the regulation of motor activity involved in stomach emptying and in secretory functions of the stomach. However, further research is necessary to explain the relationship. PMID- 23084787 TI - Cochlin-tomoprotein (CTP) detection test identified perilymph leakage preoperatively in revision stapes surgery. AB - Perilymphatic fistula (PLF) is defined as an abnormal leakage between perilymph from the labyrinth to the middle ear. Symptoms include hearing loss, tinnitus, and vertigo. The standard mode of PLF detection is intraoperative visualization of perilymph leakage and fistula, which ostensibly confirms the existence of PLF. Other possible methods of diagnosis include confirmation of pneumolabyrinth via diagnostic imaging. Recently, a cochlin-tomoprotein (CTP) detection test has been developed that allows definitive diagnosis of PLF-related hearing loss. We report the case of a 45-year-old man who presented with right-sided tinnitus, hearing loss, and dizziness 30 years after stapes surgery. Middle ear lavage was performed after myringotomy. A preoperative diagnosis of PLF was reached using the CTP detection test. Intraoperative observations included a necrotic long process of the incus, displaced wire piston, and fibrous tissue in the oval window. Perilymph leakage was not evident. The oval window was closed with fascia, and vertigo disappeared within 2 weeks postoperatively. When PLF is suspected after stapes surgery, the CTP detection test can be a useful, highly sensitive, and less invasive method for preoperative diagnosis. PMID- 23084788 TI - Measurement of atropine and scopolamine in hair by LC-MS/MS after Datura stramonium chronic exposure. AB - BACKGROUND: Datura stramonium is an herbaceous annual plant. All parts of the plant contain tropane alkaloids such as atropine and scopolamine. We report the case of a 22-year-old man admitted to a general hospital for visual and aural hallucinations. One week after his admission, as the hallucinations remained, the patient was transferred to a psychiatric hospital. Neither blood nor urine was conserved during his hospitalization, so a hair analysis was requested in order to identify a possible consumption of a Datura seed infusion. METHODS: After decontamination and washing, hair strands were segmented into four pieces and grinded into a fine and homogeneous powder. We then incubated 20 mg for 10 min in 1 mL of phosphate buffer at pH 5.0 in the presence of 100 ng of ketamine-d4, used as internal standard (IS). Liquid-liquid extraction was performed with 4 mL of a mixture of hexane/ethyl acetate (1/1, v/v). The residue was reconstituted in 80 MUL of mobile phase. A further 10 MUL were injected into an 1.9 MUm Hypersil GOLD PFP column (100 mm*2.1 mm) eluted with a gradient of acetonitrile and 2 mmol/L 0.1% formate buffer at a flow rate of 300 MUL/min. Compounds were detected by a LCQ TSQ Vantage XP triple-quadripole mass spectrometer equipped with an electrospray ionization (ESI) source set in positive mode. SRM transitions m/z 290.2->124.1, m/z 304.2->138.1, and m/z 242.1->129.1 were optimized for atropine, scopolamine and IS, respectively. RESULTS: The assay was accurate and precise over the range of 1.0 (lower limit of quantification) to 1000.0 pg/mg (upper limit of quantification) in hair. Both atropine (from 8.4 to 15.0 pg/mg) and scopolamine (1.0-1.3 pg/mg) were identified in the four segment of the hair showing a regular consumption of Datura admitted by the patient himself. CONCLUSION: We report here the first description of atropine with scopolamine in a Caucasian dark man's hair after D. stramonium chronic exposure, using a validated LC-MS/MS method. PMID- 23084789 TI - The use of dehydroepiandrosterone in the treatment of hypoactive sexual desire disorder: a report of gender differences. AB - Data regarding the efficacy of dehydroepiandrosterone (DHEA) in the treatment of hypoactive sexual desire disorder (HSDD) are scarce and inconsistent. We aimed to determine possible gender differences in the efficacy of DHEA as a treatment for HDSS. Postmenopausal women (n=27), and men (n=21) with HSDD, were randomized to receive either DHEA 100 mg daily or placebo for 6 weeks in a controlled, double blind study. Primary outcome measures were sexual function questionnaires. Hormone serum levels of DHEAS, total and bioavailable testosterone, estradiol, and urine levels of DHEA and androsterone were also measured. Participants on active treatment showed a significant increase in circulating serum levels of DHEAS, while bioavailable testosterone levels increased in women only. In women only, significant interaction effects were observed for sexual arousal (p<0.05), satisfaction (p<0.05), and cognition (trend; p=0.06). For arousal, a significant improvement was observed for the DHEA treated group at 6 weeks (p=0.001). Significant correlations were observed between bioavailable T and sexual cognitions, arousal and orgasm, while DHEAS was correlated with satisfaction. In the men, significant correlations were observed between testosterone and arousal (r=.45), sexual drive (r=.50) and orgasm (r=.55). In women with HSDD, DHEA treatment had a significant beneficial effect on arousal, whereas no efficacy was demonstrated in men, indicating a possible gender difference. This improvement seems to be mediated via DHEA's metabolism to testosterone. Our positive results suggest that the neurosteroid DHEA may be effective as a treatment for women with HSDD if administered at a dose of at least 100 mg per day. PMID- 23084790 TI - Ultrasound-promoted solvent-free aza-Michael addition of p-toluenesulfonamide to fumaric esters by potassium carbonate: Synthesis of p-toluenesulfonamide derivatives. AB - An efficient, mild, inexpensive and eco-friendly protocol for the synthesis of p toluenesulfonamide derivatives by aza-Michael addition reaction of p toluenesulfonamide to fumaric esters using potassium carbonate under ultrasound irradiation was developed. This method is simple, convenient and the desired compounds are produced in good to excellent yield. The bulkiness of alkoxy group (-OR) of fumaric esters did not affect significantly on the yields and reaction times. This reaction worked well on linear and nonlinear alkyl fumarates. The reaction, surprisingly, was not successful on methyl fumarate. In this case methyl fumarate has been hydrolyzed to fumaric acid under reaction conditions. PMID- 23084791 TI - Sonoelectrochemical degradation of phenol in aqueous solutions. AB - The sonoelectrochemical degradation of phenol in aqueous solutions with stainless steel electrodes and high-frequency ultrasound (850kHz) was investigated. A 60% synergetic effect was obtained in the combined reaction system. High concentration of electrolyte (sodium sulfate) and a high electrical voltage are favorable conditions for the degradation of phenol. A nearly complete degradation of phenol was achieved with 4.26g/L Na(2)SO(4) and 30V electrical voltages at 25 degrees C in 1h. The degradation of phenol follows pseudo-first order kinetics. Considering costs and application, the energy efficiency of the reaction system with different reaction conditions was evaluated. PMID- 23084792 TI - Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease. AB - While decreased ATP production and redox imbalance are central to mitochondrial disease pathogenesis, efforts to develop effective treatments have been hampered by the lack of imaging markers of oxidative stress. In this study we wished to determine if Tc99m-HMPAO, a SPECT imaging marker of cerebral blood flow and glutathione/protein thiol content, could be used to monitor the effect(s) of EPI 743, an oral redox modulating, para-benzoquinone based therapeutic for mitochondrial disease. We hypothesized that treatment changes in HMPAO uptake would be inversely proportional to changes in oxidative stress within the brain and directly correlate to clinical response to EPI-743 therapy. Twenty-two patients with mitochondrial disease were treated with EPI-743. Each underwent baseline and 3-month Tc99m-HMPAO SPECT scanning along with clinical/neurologic evaluations. Diseases treated were: Leigh syndrome (n=7), polymerase gamma deficiency (n=5), MELAS (n=5), Friedreich ataxia (n=2), Kearns-Sayre syndrome, Pearson syndrome, and mtDNA depletion syndrome. Neuro-anatomic uptake analyses of HMPAO were performed with NeuroGamTM (Segami Corp.) statistical software and clinical response was assessed by the Newcastle Paediatric Mitochondrial Disease Scale or Newcastle Mitochondrial Disease Adult Scale depending on patient age. For all 22 patients there was a significant linear correlation between the change in cerebellar uptake of HMPAO and the improvement in Newcastle score (r=0.623, **p=0.00161). The MELAS subgroup showed a significant relationship of whole brain uptake (n=5, r=0.917, *p=0.028) to improvement in Newcastle score. We conclude that Tc99m-HMPAO SPECT scanning has promise as a general marker of the oxidative state of the brain and its response to redox modulating therapies. Further studies will be needed to confirm these findings in a more homogenous study population. PMID- 23084794 TI - Beliefs about depression and its treatments: associated variables and the influence of beliefs on adherence to treatment. AB - Beliefs and attitudes about treatment in patients with depression are significant factors related to treatment adherence. Despite their importance, few studies have evaluated the determining factors of these beliefs, and the positive or negative attitudes towards treatment. This review looks at areas such as, adherence to antidepressants and psychotherapy, influence of beliefs and attitudes on adherence to treatment, beliefs and attitudes about depression and its treatment, their assessment, variables associated with these beliefs, and limitations of available studies. Acknowledging the importance of patient beliefs about depression and treatment, and their assessment are essential to optimize the chances of success of therapy by identifying and addressing misconceptions, prejudices and negative attitudes, as well as the consideration of these aspects in order to improve treatment choice. PMID- 23084793 TI - Immune regulation toward immunomodulation for neuroprotection in glaucoma. AB - Although the immune system functions to preserve and restore tissue homeostasis, accumulating risk factors, prolonged glial activation, and sustained release of pro-inflammatory mediators in glaucoma may lead to a failure in the regulation of stress-induced immune response, and innate immune cells, autoreactive T cells, autoantibodies, and excess complement attack may exhibit potent stimuli that harm retinal ganglion cell somas, axons, and synapses. Identification of the cellular and molecular components of immune response pathways can provide immunomodulatory treatment strategies to attenuate neuroinflammation, protect neural tissue from collateral injury, and enhance endogenous recovery processes. This review highlights the current knowledge of molecular mechanisms regulating neuroinflammation in glaucoma. PMID- 23084795 TI - Differential diagnosis between obsessive compulsive disorder and restrictive and repetitive behavioural patterns, activities and interests in autism spectrum disorders. AB - INTRODUCTION: The obsessive compulsive disorder (OCD) and the restricted and repetitive patterns of behavior, interests and activities inherent to autism spectrum disorders (ASD) share a number of features that can make the differential diagnosis between them extremely difficult and lead to erroneous overdiagnosis of OCD in people with autism. DEVELOPMENT: In both cases there may appear to have a fixation on routine, ritualized patterns of verbal and nonverbal behavior, resistance to change, and highly restrictive interests, which becomes a real challenge for differentiating rituals, stereotypes and adherence to routines in ASD from obsessions and compulsions in OCD. This article provides key points to clarify this differential diagnosis through the analysis of emotional valence, content, function and psychological theories that explain the obsessions and compulsions in OCD, and the desire for sameness, stereotyped movements and limited interest in autism. CONCLUSION: The terms "obsession" and "compulsion" should no longer be used when referring to patterns of behavior, interests or restricted and repetitive activities in autism due to syntonic characteristics, low perception of personal responsibility and low neutralizing efforts. Treatment focuses on changing the environment, the use of socio-communicative compensatory strategies and behavioral modification techniques to improve cognitive and behavioral flexibility. When there is comorbidity between, exposure behavioral and response prevention techniques are then used, followed by others of more cognitive orientation if necessary. PMID- 23084796 TI - Theory of mind and functionality in bipolar patients with symptomatic remission. AB - INTRODUCTION: Functional deficits are commonly observed in bipolar disorder after symptomatic remission. Social cognition deficits have also been reported, which could contribute to dysfunction in patients with bipolar disorder in remission. MATERIAL AND METHODS: Twelve bipolar disorder patients in symptomatic remission (7 patients with bipolar disorder type I and 5 with bipolar disorder type II) and 12 healthy controls completed the Reading the Mind in the Eyes Test and the Faux Pas Test to evaluate theory of mind (ToM). Both groups also completed the Functional Assessment Short Test (FAST). RESULTS: The performance of the bipolar patients in the cognitive component of ToM was below normal, although the difference between the control group was not statistically significant (P=.078), with a trend to a worse performance associated with a higher number of depressive episodes (P=.082). There were no statistically significant differences between groups for the emotional component of ToM. Global functionality was significantly lower in bipolar patients compared to the control group (P=.001). Significant differences were also observed between both groups in five of the six dimensions of functionality assessed. No significant correlation was found between functionality and theory of mind. CONCLUSIONS: Bipolar patients in symptomatic remission exhibit impairments in several areas of functioning. Cognitive ToM appears more affected than emotional ToM. Deficits in ToM were not related to functional impairment. PMID- 23084797 TI - Cluster B maladaptive personality traits in Spanish adolescents. AB - INTRODUCCTION: The prevalence and expression of Cluster B personality disorders during adolescence have been poorly analyzed. The main aim of this research was to analyze the rate of Cluster B maladaptive personality traits in Spanish adolescents. We also examined dimensional structure underlying the influence of sex and age in its phenotypic expression, was also examined. METHOD: The sample consisted of a total of 1440 participants (Mean=15.9 years, SD=1.2). The self reporting questionnaire used was the Personality Diagnostic Questionnaire-4 + (PDQ-4 +). RESULTS: Maladaptative "dramatic" or "erratic" personality traits are common among adolescents, particularly antisocial and borderline facets. Using the PDQ-4+ cut-off points, 20.3% of the sample submitted had a Cluster B personality disorder. The analysis of the internal structure of the Cluster B items of the PDQ-4 + yielded a factorial solution centred on three interrelated factors, including: Antisocial, Borderline and Histrionic/Narcissistic. There were differences by gender in the subscales of Cluster B, but not in function of age. CONCLUSIONS: These data yield new insights that improve the understanding of the Cluster B personality disorders and traits in this sector of the population. Future studies should use measurement tools that take into account the concern, conviction and distress associated with such experiences. PMID- 23084798 TI - Burden of disease in adolescents and young people in Spain. AB - OBJECTIVE: This article analyses the burden of disease in adolescents and young people in Spain in 2008. MATERIAL AND METHODS: A cross-sectional population-based study. We estimated disability-adjusted life years (DALYs) by sex and cause for subjects aged 15-29 years. Data sources were used: 1) National death records by age, sex and cause; 2) Population data (both in July 2008); and 3) Estimates of the disability pattern for European countries with very low mortality. RESULTS: In 2008, adolescents and young people lost 786,479 DALYs (414,346 in males). Non communicable diseases generated 661,282 DALYs (84% of the total). The main specific causes of disease burden were: unipolar depression (16% of DALYs), alcohol use disorders (11%), migraine (9%), bipolar disorder (7%), schizophrenia (6%), road traffic accidents (5%) and drug addiction disorders (5%). CONCLUSIONS: The burden of disease expressed in DALYs can define the loss of health in adolescents and young people. At these ages, health promotion and protection are essential to prevent the onset of disease in adulthood. PMID- 23084799 TI - Translation and validation of the "Self-injurious thoughts and behaviors interview" in a Spanish population with suicidal behaviour. AB - INTRODUCTION: Most of the assesment tools used in our country examine a limited range of suicidal behaviours. In contrast, the Self-Injurious Thoughts and Behaviors Interview (SITBI), developed in the US, assesses a wider range of these behaviours: suicidal ideation, suicide attempt, suicidal gestures, and self harming behaviours. Given this lack, we think it is necessary to validate the Escala de Pensamientos y Conductas Autolesivas (EPCA), Spanish translation of the SITBI, in the Spanish population. MATERIAL AND METHODS: The EPCA interview was administered to 150 inpatients in the Psychiatry Unit- Fundacion Jimenez Diaz in order to examine its psychometric properties in a Spanish sample. To assess its test-retest reliability, the EPCA was again administered to those patients who were readmitted to hospital at least six months after the first assessment (n=50). To examine its construct validity, some of the most used assessment tools in this research field were also administered. RESULTS: [corrected] Inter-rater agreement ranged from k=.90 to k=1. Test-retest reliability was good in the case of suicidal ideation, suicide plans and suicide attempts; however, it was lower in the case of self-harming behaviours and suicidal gestures. Our results also support the construct validity of the scale. CONCLUSIONS: Our findings back the reliability (both inter-rater and test-retest) and construct validity of the EPCA in the Spanish population. PMID- 23084800 TI - The need to determine the best options for people with schizophrenia that is unresponsive to treatment. PMID- 23084801 TI - Should obesity be a limiting factor for clozapine treatment? AB - OBJECTIVE: Clozapine is the first choice in drug-resistant schizophrenia but also causes important weight changes. This might discourage clinicians concerned about the risk of developing health problems. To assess this issue we measured change in body mass index (cBMI) induced by clozapine at 18 and 56 weeks. METHODS: Baseline body weight and height were measured and weight weekly thereafter during the first 18 weeks of treatment. After that, measurements were made monthly. Steady clozapine dose, clozapine and norclozapine blood concentrations, concomitant medication, gender and age were recorded. RESULTS: At 18 weeks (n=76) mean cBMI was 1.83 kg/m(2). Baseline BMI was inversely correlated with cBMI. At 56 weeks (n=57) cBMI was 2.67 kg/m(2) and was inversely correlated with basal BMI. Multiple regression analysis replicated the results. When split with BMI categories, obese patients had lesser risk for further weight gain. CONCLUSIONS: Obesity should not discourage clinicians from starting clozapine in drug resistant patients. PMID- 23084802 TI - Salience and dysregulation of the dopaminergic system. AB - Psychosis is a subjective and experiential phenomenon of the mind, influenced by cognitive and socio-cultural patterns of the individual. The neurobiological correlate of this phenomenon is the dysfunction of brain dopaminergic pathways. This article reviews the scientific evidence on the theoretical approaches of the dopaminergic hypothesis of psychosis and its relationship with the reward and salience systems. The aberrant salience occurs when the dysregulation of dopamine transmission produces a mistaken interpretation of neutral or irrelevant stimuli as a source of reward or punishment. Advances in neuroscience achieved in the last decade have led to the conceptualization of the constructs of visual, social and emotional salience, to test the hypothesis of aberrant salience in psychosis. Psychosis appears, therefore, as a trans-nosological pathological process, relatively nonspecific, which alters the attribution system of reality. PMID- 23084803 TI - Personality dimensions and working alliance in subjects with borderline personality disorder. AB - BACKGROUND: As yet, the relation between personality traits and working alliance has not been investigated in subjects affected by Borderline Personality Disorder (BPD). METHOD: A sample of forty-nine BPD subjects who completed a module of Sequential Brief Adlerian Psychodynamic Psychotherapy (SB-APP) of 40 sessions has been recruited. Before the onset of psychotherapy an assessment was made with Clinical Global Impression (CGI), Global Assessment of Functioning (GAF), Symptom Checklist Revised 90 (SCL-R 90), and with Temperament and Character Inventory (TCI). At the end of their psychotherapy, patients were requested to rate the level of working alliance by means of the Working Alliance Inventory (WAI-S). RESULTS: Multiple linear regression analysis has identified three variables as independent predictors of WAI-S total score: subjects with lower Harm Avoidance, older patients, and subjects with a higher psychopathology level had a better WAIS total score. DISCUSSION: These preliminary results showed that the pattern of alliance with the therapist in subjects with BPD could be related not only to weakness of character, but also to a temperamental trait typical of inhibited and avoidant subjects. CONCLUSION: These results suggest that an assessment of temperament in subjects affected by BPD at intake could be useful to detect the subjects who have more difficulties in building a good working alliance and in order to improve the technical interventions and settings for psychotherapy of BPD subjects with higher Harm Avoidance. PMID- 23084804 TI - Cyclic psychosis and menstruation: presentation of a case. PMID- 23084805 TI - Lamotrigine rechallenge after a skin rash. A combined study of open cases and a meta-analysis. AB - OBJECTIVE: To determine the safety of lamotrigine rechallenge after a first episode of skin rash in bipolar patients. METHOD: An open cases prospective study was conducted with patients who, developed a skin rash when first treated with lamotrigine, were refractory to other treatments, and were offered lamotrigine rechallenge using a different dose titration. Additionally a review was performed on previous skin rash management strategies and lamotrigine rechallenge reports. RESULTS: Every 3 out of 10 lamotrigine rechallenge patients required drug interruption due to persistent rash. One of them was potentially serious and resolved by stopping the lamotrigine. The review of available literature identified several lamotrigine rechallenge studies with rates of positive results varying between 70% and 87% depending on the study. No patient developed Stevens Johnson syndrome or toxic epidermal necrolysis after rechallenge. The rate of rash was higher when rechallenge began between 4 weeks from initial rash (19% vs. 7%, P=.001) and decreased when first rash showed no potentially serious signs (0% vs.19%, P=.01). CONCLUSIONS: Rechallenge is a viable option after a benign lamotrigine-induced rash, and can even be rechallenged after rash with greater precautions when there exists one or two potentially serious signs. In cases of more serious rash there are no reliable data available on rechallenge safety and it may pose a significant risk. In those cases rechallenge should better be avoided between 4 weeks from first rash. PMID- 23084806 TI - After six months of anti-psychotic treatment: Is the improvement in mental health at the expense of physical health? AB - INTRODUCTION: The morbidity and mortality due to cardiovascular causes in patients with schizophrenia is higher than in the general population, a fact that has been observed more since second generation anti-psychotics came into general use. OBJECTIVES: To determine the incidence of metabolic syndrome in patients with a previously untreated first psychotic episode, as well as the prospective changes in the parameters that define the criteria of metabolic syndrome. METHOD: An observational study with a prospective cohort design including patients who were admitted to the Acute Unit of Donostia Hospital. RESULTS: A total of 21 patients were included in the study, of which 19 completed it. Just over one quarter (26.3%) of the patients developed a metabolic syndrome at six months. Statistically significant differences were observed in the following parameters: 1) abdominal perimeter measurement with an increase of 14.6 cm at six months (P=.001); 2) triglyceride levels with a mean increase over the initial measurement of 48.99 mg/dl (P=.039); and 3) fasting blood glucose levels with a mean increase of 10.72 mg/dl (P=.001). CONCLUSIONS: Significant changes were observed in metabolic parameters in a short period with the subsequent risk of associated cardiovascular events in a group of young patients. Actions are required directed at ensuring appropriate monitoring of these patients in order to measures to minimise the risks. PMID- 23084807 TI - Why people with fibromyalgia persist in activity despite the increasing pain? A Delphi Study of the content of the Clinic Scale of Persistence in Activity in Fibromyalgia. AB - BACKGROUND AND OBJECTIVE: There is evidence of the relevance of fear, anxiety and avoidance of activity in the maintenance of pain in fibromyalgia. Recently, an opposite pattern based on the persistence in activity has been described. To date, the cognitions that impede modifying this pattern are unknown. Therefore, the aim of this study is to reach consensus on the content of an instrument that assesses those cognitions. MATERIAL AND METHODS: A Delphi method was applied to reach consensus on the content of the Clinic Scale of Persistence in Activity in Fibromyalgia (CCAP-FM). RESULTS: After three rounds of consultation, an acceptable consensus was reached. Those items that received an average rating of relevance lower than 5/10 and that at least the 75% of experts recommended removing were excluded. The preliminary questionnaire of persistence in activity was composed of 30 items. CONCLUSIONS: The consensus on the content of the CCAP FM will allow advancing towards the assessment of the relation between the modification of the cognitions responsible for the maintenance of the persistence in activity and the clinical improvement in people with fibromyalgia. PMID- 23084808 TI - Health Canada/BIOTECanada Summit on regulatory and clinical topics related to subsequent entry biologics (biosimilars), Ottawa, Canada, 14 May 2012. AB - In May 2012, Health Canada and other participants held a National Summit on Subsequent Entry Biologics (SEBs). Health Canada released a guidance document in March 2010 describing policy positions and data requirements for approval of SEBs. While Health Canada and health agencies in other regulatory jurisdictions are aligned on many scientific principles related to biosimilar drugs, Health Canada's specific requirements may not be widely understood by many Canadian stakeholders. The Summit provided an opportunity for education and dialog among physicians who prescribe biologics, provincial payers, and industry on the following topics: preclinical and clinical comparability studies; manufacturing and other product differences; extrapolation of indications; substitution and interchangeability of SEBs with reference biologic drugs in clinical practice; payers' current perspective; pharmacovigilance and naming. It is anticipated that the consensus reached at this meeting will further educate Canadian healthcare professionals, provincial payers, and insurers about the appropriate use of SEBs, and may be of general interest to others internationally. PMID- 23084809 TI - Bovine maternal, fetal and neonatal responses to bovine viral diarrhea virus infections. AB - Due to the affinity of BVDV for the fetus and for cells of lymphatic organs of infected cattle, reproductive failure or immunosuppression, respectively, are likely consequences of BVDV infections of susceptible cattle. Infection of susceptible pregnant cattle with noncytopathic (ncp) BVDV results in transplacental infection with induction of maternal and fetal innate and adaptive immune responses. Differences in maternal innate and adaptive immune responses are evident in late gestation between cows carrying fetuses persistently-infected (PI) with BVDV and cows with fetuses transiently-infected with BVDV. Fetal innate and adaptive immune responses to ncp BVDV infection are defined by fetal age and developmental stage of the fetal immune system. Since a functional fetal adaptive immune response does not occur in the early fetus, immunotolerance to ncp BVDV is established, virus replicates unrestricted in fetal tissues and calves are born immunotolerant and PI with the virus. In the last trimester of gestation, the fetal immune system is adequately developed to respond in an efficacious manner, most commonly resulting in the birth of a clinically normal calf with pre colostral antibodies. Immunosuppression due to postnatal acute ncp BVDV infections of susceptible calves may contribute to the occurrence and severity of multi-factorial respiratory tract and enteric diseases. PMID- 23084810 TI - Regeneration and reprogramming. AB - Recent reprogramming studies indicate that mammalian, somatic cells have the potential to achieve pluripotent states and undergo cell type switching. Such cellular traits are observed under natural conditions in animals that regenerate complex organs. A number of invertebrates display the amazing trait of whole body regeneration. Underlying this trait is the maintenance of pluripotent cells in somatic tissue, and molecular studies indicate the use of common players associated with pluripotency and germ cell properties between these invertebrates and mammalian pluripotent cells. In regenerative vertebrates, heart regeneration, lens regeneration, and retinal regeneration provide good examples of dedifferentiation and transdifferentiation. The molecular factors associated with these phenomena are discussed. PMID- 23084811 TI - Cell reprogramming. PMID- 23084812 TI - Perceptual and acoustic outcomes of voice therapy for male-to-female transgender individuals immediately after therapy and 15 months later. AB - OBJECTIVES: The present study examined how effectively listeners' perceptions of gender could be changed from male to female for male-to-female (MTF) transgender (TG) clients based on the voice signal alone, immediately after voice therapy and at long-term follow-up. Short- and long-term changes in masculinity and femininity ratings and acoustic measures of speaking fundamental frequency (SFF) and vowel formant frequencies were also investigated. DESIGN: Prospective treatment study. METHOD: Five MTF TG clients, five control female speakers, and five control male speakers provided a variety of speech samples for later analysis. The TG clients then underwent 8 weeks of voice therapy. Voice samples were collected immediately at the termination of therapy and again 15 months later. Two groups of listeners were recruited to evaluate gender and provide masculinity and femininity ratings. RESULTS: Perceptual results revealed that TG subjects were perceived as female 1.9% of the time in the pretest, 50.8% of the time in the immediate posttest, and 33.1% of the time in the long-term posttest. The TG speakers were also perceived as significantly less masculine and more feminine in the immediate posttest and the long-term posttest compared with the pre-test. Some acoustic measures showed significant differences between the pretest and the immediate posttest and long-term posttest. CONCLUSIONS: It appeared that 8 weeks of voice therapy could result in vocal changes in MTF TG individuals that persist at least partially for up to 15 months. However, some TG subjects were more successful with voice feminization than others. PMID- 23084813 TI - Interpretation of the "obesity paradox": a 30-year study in patients with cardiovascular disease. AB - BACKGROUND: Several epidemiological reports indicate that the body mass index (BMI) is inversely related with mortality, in spite of the notion that obesity is a recognized cardio-metabolic risk factor. The aim of the study was to evaluate the independent impact of overweight and obesity on long-term mortality in a large cohort of patients with heart disease (HD). METHODS: The study included 10,446 patients hospitalized in the last three decades for ischemic (60%) or non ischemic HD and followed-up for 10 years. The relationship between BMI and total or cardiovascular mortality was analyzed in the whole cohort, and in age stratified categories (<= 65 and >65 years). Considering that survival in HD patients has improved after the introduction of revascularization, beta-blockers, ACE inhibitors, and statins, the relationship was re-examined separately in patients hospitalized before and after 1990. RESULTS: Diabetes, hyperuricemia, hypertension, glycaemia, and triglyceridemia increased across BMI groups. During follow-up (73 +/- 59 months) there were 1707 all-cause deaths (47% cardiac). Any relationship between BMI and mortality was lost in the <= 65 age category and in patients hospitalized before 1990, but it persisted in old patients hospitalized after 1990. Most significant independent predictors of mortality in all groups were hyperuricemia, diabetes and impaired ejection fraction. CONCLUSIONS: No independent relationship was found between BMI and mortality in subjects <= 65 years of age. This neutral relationship seems to be partly counteracted by treatment, particularly in old patients. A different effect of obesity onset in old vs. young age cannot be ruled out. PMID- 23084814 TI - Cigarette smoking induces vascular damage and persistent elevation of plasma serotonin unresponsive to 8 weeks of smoking cessation. PMID- 23084815 TI - Double transapical aortic and mitral valve-in-valve implant: an alternative for high risk and multiple reoperative patients. PMID- 23084816 TI - Platelet reactivity in diabetic patients undergoing coronary stenting for acute coronary syndrome treated with clopidogrel loading dose followed by prasugrel maintenance therapy. AB - BACKGROUND: Diabetes has been identified as a risk factor for impaired clopidogrel response, and these patients might have greater benefit with new P2Y12 blockers such as prasugrel. The present study was designed to assess response to thienopyridine in diabetic patients undergoing PCI for ACS. METHODS AND RESULTS: 107 diabetic patients undergoing PCI for ACS were included and treated by clopidogrel 600 mg loading dose and switched to prasugrel 10mg daily after PCI. Platelet reactivity was assessed by PRI VASP. High-on-treatment platelet reactivity (HTPR) was defined by PRI VASP>50% and Low-on-treatment platelet reactivity (LTPR) as PRI VASP below the 75th percentile (PRI VASP<20%). After clopidogrel, mean PRI VASP was 47 +/- 21% and 54 patients (50%) were non responders. At one month, mean PRI VASP on prasugrel 10mg daily was 31 +/- 13%, 9 patients (8%) had HTPR and 23 patients (22%) had LTPR. In multivariate analysis, factors associated with platelet reactivity were waist circumference for HTPR on clopidogrel and body weight for HTPR and LTPR on prasugrel. 10 patients (9%) suffered from BARC bleeding complications. Patients with bleeding complications had significantly lower PRI VASP values: 22 +/- 9 vs. 32 +/- 13, p=0.02 and ROC curves identified a cut-off value of VASP=28% to predict bleeding complications. CONCLUSION: The present study confirmed that many diabetic patients treated with clopidogrel for ACS have inadequate platelet inhibition. Switch to prasugrel is effective with acceptable safety in this specific population. We observed a significant relationship between on-treatment platelet reactivity and bleeding complications. PMID- 23084817 TI - Efficacy and safety of statins in the prevention of atherosclerosis in patients with systemic lupus erythematosus--a meta-analysis of randomized controlled trials. PMID- 23084818 TI - Acetylsalicylic acid prevents platelet-induced proarrhythmic effects on intracellular Ca2+ homeostasis in ventricular myocytes. PMID- 23084819 TI - B-type natriuretic peptide levels are decreased by reducing dietary salt intake in patients with permanent atrial fibrillation. PMID- 23084820 TI - Age may contribute to the negative cardiac effect of postconditioning on STEMI patients. PMID- 23084821 TI - Host targeting of virulence determinants and phosphoinositides in blood stage malaria parasites. AB - Blood stage malaria parasites target a 'secretome' of hundreds of proteins including virulence determinants containing a host (cell) targeting (HT) signal, to human erythrocytes. Recent studies reveal that the export mechanism is due to the HT signal binding to the lipid phosphatidylinositol-3-phosphate [PI(3)P] in the parasite endoplasmic reticulum (ER). An aspartic protease plasmepsin V which cleaves a specialized form of the HT signal was previously thought to be the export mechanism, but is now recognized as a dedicated peptidase that cleaves the signal anchor subsequent to PI(3)P binding. We discuss a model of PI(3)P dependent targeting and PI(3)P biology of a major human pathogen. PMID- 23084822 TI - Comparison of the selectivity of different sorbent phases for bar adsorptive microextraction--application to trace level analysis of fungicides in real matrices. AB - Bar adsorptive micro-extraction combined with liquid desorption followed by large volume injection-gas chromatography-mass spectrometry operating in the selected ion monitoring acquisition mode (BAMUE-LD/LVI-GC-MS(SIM)) was developed for the determination of trace levels of ten fungicides (azoxystrobin, difenoconazole, metalaxyl-M, myclobutanil, penconazole, tebuconazole, flusilazole, cyprodinil, procymidone and benalaxyl) in aqueous matrices. By comparing different sorbent coatings (two activated carbons, two styrene-divinylbenzene and one modified pyrrolidone polymers) through BAMUE, the latter phase showed much higher selectivity and capacity offering multiple mechanisms of interaction, even against polydimethylsiloxane by stir bar sorptive extraction. Assays performed on 25 mL of water samples spiked at the 0.8 MUg/L level, yielded recoveries ranging from 100.0 to 107.8%, under optimized experimental conditions; BAMUE(modified pyrrolidone) - equilibrium time: 4h (1000 rpm), pH 5.5; LD - solvent:methanol/acetonitrile (1/1), 15 min with sonification. The analytical performance showed convenient detection limits (4.0-30.0 ng/L) and excellent linear dynamic ranges (0.04-1.60 MUg/L) with remarkable correlation coefficients (r(2)>0.9980). Excellent repeatability was also achieved through intraday (RSD<13.7%) and interday (RSD<9.9%) assays. By using the standard addition methodology, the application of the present analytical approach on tap and ground water, as well as, wine samples revealed good sensitivity and absence of matrix effects. The proposed method operating under floating sampling technology proved to be a suitable sorption-based static microextraction alternative to monitor fungicides in real matrices, showing to be easy to implement, reliable, sensitive, requiring low sample volume and the possibility to choose the most selective sorbent coating according to the targets of interest. PMID- 23084823 TI - Doping control analysis of TB-500, a synthetic version of an active region of thymosin beta4, in equine urine and plasma by liquid chromatography-mass spectrometry. AB - A veterinary preparation known as TB-500 and containing a synthetic version of the naturally occurring peptide LKKTETQ has emerged. The peptide segment (17)LKKTETQ(23) is the active site within the protein thymosin beta(4) responsible for actin binding, cell migration and wound healing. The key ingredient of TB-500 is the peptide LKKTETQ with artificial acetylation of the N terminus. TB-500 is claimed to promote endothelial cell differentiation, angiogenesis in dermal tissues, keratinocyte migration, collagen deposition and decrease inflammation. In order to control the misuse of TB-500 in equine sports, a method to definitely identify its prior use in horses is required. This study describes a method for the simultaneous detection of N-acetylated LKKTETQ and its metabolites in equine urine and plasma samples. The possible metabolites of N acetylated LKKTETQ were first identified from in vitro studies. The parent peptide and its metabolites were isolated from equine urine or plasma by solid phase extraction using ion-exchange cartridges, and analysed by liquid chromatography-mass spectrometry (LC/MS). These analytes were identified according to their LC retention times and relative abundances of the major product ions. The peptide N-acetylated LKKTETQ could be detected and confirmed at 0.02 ng/mL in equine plasma and 0.01 ng/mL in equine urine. This method was successful in confirming the presence of N-acetylated LKKTETQ and its metabolites in equine urine and plasma collected from horses administered with a single dose of TB-500 (containing 10mg of N-acetylated LKKTETQ). To our knowledge, this is the first identification of TB-500 and its metabolites in post-administration samples from horses. PMID- 23084824 TI - Extended zones of operations in supercritical fluid chromatography. AB - The pressure and temperature ranges within which supercritical fluid chromatography is operated are generally decided based upon limitations imposed by the instrument or by the stationary phase. Because the maximum pump outlet pressure of most commercial instruments is near 400 bar and the maximum temperature at which most chiral stationary phases are stable is usually below 318 K, the possibility of performing analyses at sub-ambient temperatures (e.g., below 293 K) and under sub-critical pressures (i.e. below 73.8 bar) should be explored. This work investigates the performance of separations made in this unusual zone of operations, which might be attractive for some relevant SFC separations. PMID- 23084825 TI - Determination of polycyclic aromatic hydrocarbons in soil samples using flotation assisted homogeneous liquid-liquid microextraction. AB - In this study, flotation-assisted homogeneous liquid-liquid microextraction (FA HLLME) was developed as a fast, simple, and efficient method for extraction of four polycyclic aromatic hydrocarbons (PAHs) in soil samples followed by gas chromatography-flame ionization detector (GC-FID) analysis. A special home-made extraction cell was designed to facilitate collection of the low-density extraction solvent without a need for centrifugation. In this method, PAHs were extracted from soil samples into methanol and water (1:1, v/v) using ultrasound in two steps followed by filtration as a clean-up step. The filtrate was added into the home-made extraction cell contained mixture of 1.0 mL methanol (homogenous solvent) and 150.0 MUL toluene (extraction solvent). Using N(2) flotation, the dispersed extraction solvent was transferred to the surface of the mixture and was collected by means of a micro-syringe. Then, 2 MUL of the collected organic solvent was injected into the GC-FID for subsequent analysis. Under optimal conditions, linearity of the method was in the range of 40-1000 MUg kg(-1) soil (dry weight). The relative standard deviations in real samples varied from 5.9 to 15.2% (n=4). The proposed method was successfully applied to analyze the target PAHs in soil samples, and satisfactory results were obtained. PMID- 23084826 TI - Fast, high peak capacity separations in comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry. AB - Peak capacity production is substantially improved for two-dimensional gas chromatography coupled with time-of-flight mass spectrometry (GC*GC-TOFMS) and applied to the fast separation of a 28 component liquid test mixture, and two complex vapor samples (a 65 component volatile organic compound test mixture, and the headspace of warm ground coffee beans). A high peak capacity is achieved in a short separation time by selecting appropriate experimental conditions based on theoretical modeling of on-column band broadening, and by reducing the off-column band broadening by applying a narrow, concentrated injection pulse onto the primary column using high-speed cryo-focusing injection (HSCFI), referred to as thermal injection. A long, relatively narrow open tubular capillary column (20 m, 100 MUm inner diameter (i.d.) with a 0.4 MUm film thickness to benefit column capacity) was used as the primary column. The initial flow rate was 2 ml/min (60 cm/s average linear flow velocity) which is slightly below the optimal average linear gas velocity of 83 cm/s, due to the flow rate constraint of the TOFMS vacuum system. The oven temperature programming rate was 30 degrees C/min. The secondary column (1.8m, 100 MUm i.d. with a 0.1 MUm film thickness) provided a relatively high peak capacity separation, concurrent with a significantly shorter modulation period, P(M), than commonly applied with the commercial instrument. With this GC*GC-TOFMS instrumental platform, compounds in the 28 component liquid test mixture provided a ~7 min separation (with a ~6.5 min separation time window), producing average peak widths of ~600 ms full width half maximum (FWHM), resulting in a peak capacity on the primary column of ~400 peaks (at unit resolution). Using a secondary column with a 500 ms P(M), average peak widths of ~20 ms FWHM were achieved, thus providing a peak capacity of 15 peaks on the second dimension. Overall, an ideal orthogonal GC*GC peak capacity of ~6000 peaks (at unit resolution) was achieved (or a beta-corrected orthogonal peak capacity of ~4400, at an average modulation ratio, M(R), of ~2). This corresponds to an ideal orthogonal peak capacity production of ~1000 peaks/min (or ~700 peaks/min, beta-corrected). For comparison, standard split/split-less injection techniques with a 1:100 split, when combined with standard GC*GC conditions typically provide a peak capacity production of ~100 peaks/min, hence the instrumental platform we report provides a ~7-fold to 10-fold improvement. PMID- 23084827 TI - Different effects in tactile attention between the thumb and its metacarpus and the palm. AB - The aim of this study is to establish whether the thumb is represented independently of the palm. An exogenous spatial cueing paradigm was used, where participants had to detect a tactile stimulus that could appear on the proximal and distal phalanges or metacarpus of the thumb (thenar area; Experiment 1) and the metacarpus of the thumb or hypothenar area of the palm (Experiment 2) of the left hand. Our results suggest the thumb and its metacarpus share the same mental representation, which is distinct from the representation of the palm. PMID- 23084828 TI - Editorial comment. PMID- 23084830 TI - Impact of preoperative ureteral stenting on stone-free rates of ureteroscopy for nephroureterolithiasis: a matched-paired analysis of 286 patients. AB - OBJECTIVE: To determine the effect of preoperative ureteral stenting on success rates of ureteroscopy (URS) for nephroureterolithiasis. MATERIALS AND METHODS: We retrospectively evaluated patients who underwent URS for nephroureterolithiasis without preoperative indwelling ureteral stents. These patients were matched according to age, sex, body mass index, and stone side, size, site, and number of stones per patient, with patients who had been prestented before URS. Patient data, stone-free rates (SFRs), and complications were compared. RESULTS: The study included 286 patients (143 stented vs 143 nonstented). The mean stone size was 5.69 +/- 3 mm. The mean number of stones per patient was 1.35 +/- 0.7. The overall SFR after 1 URS procedure was 90.9% and higher in prestented than in nonstented patients (95.1% vs 86.7%, P <= .013). For ureteral stones, the SFR was 99% in prestented and 90% in nonstented patients (P <= .0048). The SFR did not differ between the groups for ureteral stones <5 mm, but was higher in prestented than in nonstented patients for ureteral calculi >= 5 mm (98.2% vs 83.3%, P <= .0105). For urinary calculi >= 5 mm, the overall SFR was higher in prestented than in nonstented patients (93.3 vs 78.3%, P <= .0054). Perioperative complications occurred in 27 patients (9.4%; Clavien I, 6.6%; Clavien IIIb, 2.8%) without differences between the groups. CONCLUSION: URS is a safe and efficacious procedure for the treatment of nephroureterolithiasis. Preoperative ureteral stent placement is associated with higher SFRs compared with nonstented patients for urinary calculi >= 5 mm. Nonstented patients with urinary calculi >= 5 mm should be informed about the risk for a second-look URS procedure. PMID- 23084831 TI - Malaria and lymphatic filariasis: the case for integrated vector management. AB - The global programmes to eliminate both malaria and lymphatic filariasis are facing operational and technical challenges. Available data show that the use of treated or untreated bednets and indoor residual spraying for malaria control concomitantly reduced filarial rates. In turn, mass drug administration campaigns against lymphatic filariasis can be combined with the distribution of insecticide treated bednets. Combining these disease control efforts could lead to more efficient use of resources, more accurate attribution of effects, and more effective control of both diseases. Systematic integration requires coordination at all levels, mapping of coendemic areas, and comprehensive monitoring and evaluation. PMID- 23084832 TI - Molecular basis for a protein-mediated DNA-bridging mechanism that functions in condensation of the E. coli chromosome. AB - The E. coli chromosome is condensed into insulated regions termed macrodomains (MDs), which are essential for genomic packaging. How chromosomal MDs are specifically organized and compacted is unknown. Here, we report studies revealing the molecular basis for Terminus-containing (Ter) chromosome condensation by the Ter-specific factor MatP. MatP contains a tripartite fold with a four-helix bundle DNA-binding motif, ribbon-helix-helix and C-terminal coiled-coil. Strikingly, MatP-matS structures show that the MatP coiled-coils form bridged tetramers that flexibly link distant matS sites. Atomic force microscopy and electron microscopy studies demonstrate that MatP alone loops DNA. Mutation of key coiled-coil residues destroys looping and causes a loss of Ter condensation in vivo. Thus, these data reveal the molecular basis for a protein mediated DNA-bridging mechanism that mediates condensation of a large chromosomal domain in enterobacteria. PMID- 23084834 TI - MSL2 combines sensor and effector functions in homeostatic control of the Drosophila dosage compensation machinery. AB - The process of dosage compensation (DC) in Drosophila counterbalances the monosomy of the X chromosome in male flies by increasing the transcription from this unique chromosome in the two-fold range. Upon exclusive expression of male specific lethal 2 (MSL2) in males, the dosage compensation machinery assembles on active X-chromosomal genes. Overexpression of MSL proteins leads to aberrant binding of complex components to autosomes. Accordingly, MSL levels have to be carefully regulated. Here we describe a new mechanism through which MSL2 can fulfill its role as the central regulator of the faithful biogenesis and functionality of the DC machinery. MSL2 is an E3 ligase that ubiquitylates itself and the other associated components when their stoichiometry is unbalanced, uncovering proteasome-dependent degradation as an additional layer of homeostatic control of MSL levels. Furthermore, systematic mapping of modification sites by mass spectrometry and chromatin interaction studies on the target protein MSL1 suggest that the role of MSL2-mediated ubiquitylation goes beyond proteolysis. PMID- 23084833 TI - A Tetrahymena Piwi bound to mature tRNA 3' fragments activates the exonuclease Xrn2 for RNA processing in the nucleus. AB - Emerging evidence suggests that Argonaute (Ago)/Piwi proteins have diverse functions in the nucleus and cytoplasm, but the molecular mechanisms employed in the nucleus remain poorly defined. The Tetrahymena thermophila Ago/Piwi protein Twi12 is essential for growth and functions in the nucleus. Twi12-bound small RNAs (sRNAs) are 3' tRNA fragments that contain modified bases and thus are attenuated for base pairing to targets. We show that Twi12 assembles an unexpected complex with the nuclear exonuclease Xrn2. Twi12 functions to stabilize and localize Xrn2, as well as to stimulate its exonuclease activity. Twi12 function depends on sRNA binding, which is required for its nuclear import. Depletion of Twi12 or Xrn2 induces a cellular ribosomal RNA processing defect known to result from limiting Xrn2 activity in other organisms. Our findings suggest a role for an Ago/Piwi protein and 3' tRNA fragments in nuclear RNA metabolism. PMID- 23084835 TI - Msl1-mediated dimerization of the dosage compensation complex is essential for male X-chromosome regulation in Drosophila. AB - The Male-Specific Lethal (MSL) complex regulates dosage compensation of the male X chromosome in Drosophila. Here, we report the crystal structure of its MSL1/MSL2 core, where two MSL2 subunits bind to a dimer formed by two molecules of MSL1. Analysis of structure-based mutants revealed that MSL2 can only interact with the MSL1 dimer, but MSL1 dimerization is MSL2 independent. We show that Msl1 is a substrate for Msl2 E3 ubiquitin ligase activity. ChIP experiments revealed that Msl1 dimerization is essential for targeting and spreading of the MSL complex on X-linked genes; however, Msl1 binding to promoters of male and female cells is independent of the dimer status and other MSL proteins. Finally, we show that loss of Msl1 dimerization leads to male-specific lethality. We propose that Msl1-mediated dimerization of the entire MSL complex is required for Msl2 binding, X chromosome recognition, and spreading along the X chromosome. PMID- 23084837 TI - Blindness caused by septic superior ophthalmic vein thrombosis in a Lemierre Syndrome variant. AB - A 65-year-old man presented with right facial cellulitis and right blindness. Enhanced CT and MRI showed right facial cellulitis involved with pterigopalatine fossa. Additionally, orbital cellulitis, superior ophthalmic vein thrombosis, and pulmonary multiple nodules were observed. (18)F-FDG PET/CT supported these findings. He was diagnosed with septic superior ophthalmic vein thrombosis accompanied with Lemierre Syndrome variant and was treated mainly by the administration of intravenous antibiotics. His symptoms and image findings improved after a few days of treatment, but the right visual loss has not recovered. Since septic superior ophthalmic vein thrombosis and Lemierre Syndrome both have life-threatening potential, early diagnosis and appropriate treatment are important and may contribute to reduce the incidence of severe complications. Septic superior ophthalmic vein thrombosis accompanied with Lemierre Syndrome is exceeding rare, and this case is the first report of blindness in Lemierre Syndrome. A literature review and discussion of septic superior ophthalmic vein thrombosis and Lemierre Syndrome are included. PMID- 23084836 TI - Epigenetic regulation of condensin-mediated genome organization during the cell cycle and upon DNA damage through histone H3 lysine 56 acetylation. AB - Complex genome organizations participate in various nuclear processes including transcription, DNA replication, and repair. However, the mechanisms that generate and regulate these functional genome structures remain largely unknown. Here, we describe how the Ku heterodimer complex, which functions in nonhomologous end joining, mediates clustering of long terminal repeat retrotransposons at centromeres in fission yeast. We demonstrate that the CENP-B subunit, Abp1, functions as a recruiter of the Ku complex, which in turn loads the genome organizing machinery condensin to retrotransposons. Intriguingly, histone H3 lysine 56 (H3K56) acetylation, which functions in DNA replication and repair, interferes with Ku localization at retrotransposons without disrupting Abp1 localization and, as a consequence, dissociates condensin from retrotransposons. This dissociation releases condensin-mediated genomic associations during S phase and upon DNA damage. ATR (ATM- and Rad3-related) kinase mediates the DNA damage response of condensin-mediated genome organization. Our study describes a function of H3K56 acetylation that neutralizes condensin-mediated genome organization. PMID- 23084838 TI - Listening to stories: valuing knowledge from patient experience. AB - This paper reports on a research project which explored students' perceptions of learning from listening to patient stories. There is a plethora of literature to support the value of learning from service users within professional education programmes and a growing body of literature suggesting that storytelling is an effective learning and teaching strategy. However, little evidence focuses on the process of learning from patients' stories during practice placements and this study was designed to address this knowledge gap. The study adopted a descriptive phenomenological approach employing in-depth, conversational interviews with a sample of twelve pre-qualifying nursing, midwifery and social work students. The findings confirm the value of service users as a resource for student learning and indicate that listening to patient stories was a strategy which all respondents adopted to access this source of knowledge. This paper recommends that educators should recognise and value this alternative form of knowledge; provide the space and opportunities for students to listen to stories during their placements and actively facilitate reflection on these learning experiences. PMID- 23084839 TI - Effect of choice of outcome measure on studies of the etiology of obesity in children. AB - PURPOSE: Epidemiologic studies of the etiology of childhood obesity often use proxies for adiposity as outcomes. This study aimed to compare the ability of a range of proxy measures to detect associations with sedentary behavior. METHODS: Longitudinal study of children in the Gateshead Millennium Study who were 7 years at baseline and 9 years at follow-up. Associations between 2-year changes in objectively measured sedentary behavior and changes in proxies for adiposity (waist circumference, waist Z score, body mass index, body mass index Z score) and measurement of body composition (fat mass index from bioelectric impedance) were examined. Associations were tested with linear regression. RESULTS: Associations between 2-year increases in sedentary behavior and increases in adiposity were detectable by using the fat mass index as the outcome, but not the simple proxy measures of adiposity, as outcomes. CONCLUSIONS: Proxy measures are inferior to measures of body composition as outcomes in epidemiologic studies. PMID- 23084840 TI - Income inequality and elderly self-rated health in Sao Paulo, Brazil. AB - PURPOSE: To test the association between income inequality and elderly self-rated health and to propose a pathway to explain the relationship. METHODS: We analyzed a sample of 2143 older individuals (60 years of age and over) from 49 distritos of the Municipality of Sao Paulo, Brazil. Bayesian multilevel logistic models were performed with poor self-rated health as the outcome variable. RESULTS: Income inequality (measured by the Gini coefficient) was found to be associated with poor self-rated health after controlling for age, sex, income and education (odds ratio, 1.19; 95% credible interval, 1.01-1.38). When the practice of physical exercise and homicide rate were added to the model, the Gini coefficient lost its statistical significance (P > .05). We fitted a structural equation model in which income inequality affects elderly health by a pathway mediated by violence and practice of physical exercise. CONCLUSIONS: The health of older individuals may be highly susceptible to the socioeconomic environment of residence, specifically to the local distribution of income. We propose that this association may be mediated by fear of violence and lack of physical activity. PMID- 23084841 TI - LIM and SH3 protein 1, a promoter of cell proliferation and migration, is a novel independent prognostic indicator in hepatocellular carcinoma. AB - LIM and SH3 protein 1 (LASP-1) plays a significant role in the formation of several malignant tumours. However, the biological and clinical significances of LASP-1 in hepatocellular carcinoma (HCC) remain largely unknown. Using immunohistochemistry, we analysed LASP-1 expression in 144 clinicopathologically characterised HCC cases. Using gene and transfection and RNA interference, we investigated the effects of LASP-1 overexpression and depletion on tumour cellular behaviour in vitro. LASP-1 expression was detected in not only cytoplasm and but also nucleus of HCC and liver cells. The positive rates of both cytosolic and nuclear LASP-1 expression in HCC were higher than adjacent non-tumourous tissues. Statistical analysis showed that heterogeneous LASP-1 expression is associated with hepatitis B surface antigen (HBsAg) and serum alpha-fetoprotein (AFP) level of HCC patients. A significant trend was identified between cytosolic LASP-1 overexpression in HCC and worsening clinical prognosis. Multivariate survival analysis showed that cytosolic LASP-1 expression was recognised as an independent prognostic factor of patient's survival. In vitro study showed LASP-1 promoted cell proliferation and migration, and resulted in aggressive phenotypes of cancer cells. LASP-1 is a valuable marker of HCC progression. High cytosolic LASP-1 expression is associated with poor overall survival in HCC patients. PMID- 23084842 TI - Ultrasmall superparamagnetic particles of iron oxide allow for the detection of metastases in normal sized pelvic lymph nodes of patients with bladder and/or prostate cancer. AB - AIM: Lymph node metastases influence prognosis and outcome in patients with bladder and prostate cancer. Cross sectional imaging criteria are limited in detecting metastases in normal sized lymph nodes. This prospective study assessed the diagnostic accuracy of ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced magnetic resonance imaging (MRI) for the detection of metastases in normal sized lymph nodes using extended pelvic lymph node dissection (ePLND) and histopathology as the reference standard. METHODS: Seventy-five patients (bladder cancer, n=19, prostate cancer n=48, both, n=8) were examined using 3T MR before and after USPIO-administration. A preoperative reading with two readers in consensus and a second postoperative reading with three independent blinded readers were performed. Results were correlated with histopathology and diagnostic accuracies were calculated for all readings. RESULTS: A total of 2993 lymph nodes were examined histopathologically. Fifty-four metastatic nodes were found in 20/75 patients (26.7%). The first reading had a sensitivity of 55.0%, specificity of 85.5%, positive predictive value (PPV) of 57.9%, negative predictive value (NPV) of 83.9%, and diagnostic accuracy (DA) of 77.3% on a per patient level. The second reading had a mean sensitivity of 58.3%, specificity of 83.0%, PPV of 58.0%, NPV of 84.4% and DA of 76.4% on a per patient level. The majority of missed metastases were smaller than 5mm in short axis diameter. CONCLUSIONS: USPIO-enhanced MRI in bladder and prostate cancer patients allows detection of metastases in normal sized lymph nodes and might guide the surgeon to remove suspicious lymph nodes not included in standard PLND. PMID- 23084844 TI - Bacillus spore display. PMID- 23084843 TI - Adverse childhood experiences and intimate partner violence: testing psychosocial mediational pathways among couples. AB - PURPOSE: Adverse childhood experiences (ACEs) are associated with an increased likelihood of intimate partner violence (IPV) in adulthood. We tested whether psychosocial factors, such as depression, anxiety, impulsivity, and problem drinking, mediate associations between ACEs and IPV. METHODS: Couple data from a cross-sectional sample of married/cohabiting couples residing in 50 medium-to large California cities (n = 1861 couples) were used. Hypothesized relationships among male and female ACE, male-to-female partner violence (MFPV) and female-to male partner violence (FMPV), frequency of intoxication, depression, impulsivity, and anxiety were tested with structural equation path models, and the significance of both individual direct paths and indirect associations was determined. RESULTS: Male and female partners had positive direct associations between ACEs and depression, anxiety, and impulsivity. Males' anxiety and impulsivity and females' depression were positively related to MFPV. Males' depression and frequency of intoxication and females' depression, were positively related to FMPV. Indirect associations between male ACEs and MPFV via depression; male ACEs and FMPV via anxiety and impulsivity; and female ACEs and MPFV and FMPV via depression were all positive and significant. CONCLUSIONS: Adverse childhood experiences impact IPV partially through psychosocial characteristics. Interventions targeted at reducing ACEs and subsequent psychosocial outcomes may help reduce adult IPV. PMID- 23084846 TI - Helicobacter pylori thiolperoxidase as a protective antigen in single- and multi component vaccines. AB - Helicobacter pylori is an important pathogen of the human stomach, and the development of a protective vaccine has been an enticing goal for many years. The H. pylori antioxidant enzymes superoxide dismutase (SOD) and catalase (KatA) have been shown to be protective as vaccine antigens in mice, demonstrating that the organism's antioxidant enzyme system is a fruitful target for vaccine development. The research described here demonstrates that an additional antioxidant enzyme, thiolperoxidase (Tpx), is effective as a prophylactic vaccine antigen via both systemic and mucosal routes. The functional relationship between SOD, KatA and Tpx also provided an opportunity to investigate synergistic or additive effects when the three antigens were used in combination. Although the antigens still provided equivalent protection when administered in combination, no additional protection was observed. Moreover a decrease in antibody titres to the individual antigens was observed when delivered in combination via the nasal route, though not when injected subcutaneously. The findings of this paper demonstrate that the antioxidant system of H. pylori presents a particularly rich resource for vaccine development. PMID- 23084845 TI - Outline of a general theory of behavior and brain coordination. AB - Much evidence suggests that dynamic laws of neurobehavioral coordination are sui generis: they deal with collective properties that are repeatable from one system to another and emerge from microscopic dynamics but may not (even in principle) be deducible from them. Nevertheless, it is useful to try to understand the relationship between different levels while all the time respecting the autonomy of each. We report a program of research that uses the theoretical concepts of coordination dynamics and quantitative measurements of simple, well-defined experimental model systems to explicitly relate neural and behavioral levels of description in human beings. Our approach is both top-down and bottom-up and aims at ending up in the same place: top-down to derive behavioral patterns from neural fields, and bottom-up to generate neural field patterns from bidirectional coupling between astrocytes and neurons. Much progress can be made by recognizing that the two approaches--reductionism and emergentism--are complementary. A key to understanding is to couch the coordination of very different things--from molecules to thoughts--in the common language of coordination dynamics. PMID- 23084847 TI - Effectiveness of the influenza vaccine at preventing hospitalization due to acute lower respiratory infection and exacerbation of chronic cardiopulmonary disease in Korea during 2010-2011. AB - BACKGROUND: Influenza epidemics are accompanied by a considerable increase in hospitalization due to acute lower respiratory infection and exacerbation of underlying medical conditions. We estimated the effectiveness of the influenza vaccine at preventing hospitalization due to acute lower respiratory infection and new onset or acute exacerbation of chronic cardiopulmonary disease. METHOD: During the peak influenza period in 2010-2011, we performed a multicenter, case control, retrospective cohort study of patients who were hospitalized due to newly developed pneumonia, bronchitis, and bronchiolitis, or new onset or acute exacerbation of asthma, COPD, ischemic heart disease, and CHF. Controls were selected from outpatients who visited study hospitals but who were not hospitalized during the same study period. Controls were matched 1:1 to cases based on age, gender, and date of hospital visit. Univariate and multivariate logistic regression analyses were used to determine the effectiveness of the influenza vaccine at decreasing hospitalization. RESULTS: Between December 2010 and February 2011, 556 hospitalized subjects were identified. Age, gender, and body mass index (BMI) were similar between case and control groups. The influenza vaccination rate of the hospitalized and non-hospitalized patients was 42.4% and 52.2%, respectively (p<0.001). The overall vaccine effectiveness for preventing hospitalization was 32.5% (odds ratio 0.675, 95% confidence interval [CI] 0.486 0.937; p=0.019). Multivariate logistic analysis showed that influenza vaccination significantly reduced the risk of hospitalization, especially due to new onset or acute exacerbation of ischemic heart disease and CHF in patients aged 65 years and older (OR 0.274, 95% CI 0.114-0.658, p=0.004). The estimated vaccine effectiveness in these patients was 72.6%. CONCLUSION: Influenza vaccination reduced the rate of hospitalization among patients with underlying chronic heart disease, particularly those patients 65 years old and greater. PMID- 23084848 TI - Adjuvants in influenza vaccines. AB - The effectiveness of influenza vaccines is still controversial, and the role of adjuvants in such vaccines is briefly reviewed in this paper. Inactivated whole virus vaccines may include components that function as adjuvants, meaning that additive adjuvants are often not required. MF59 and AS03 showed higher adjuvanticity than aluminum salts in several clinical studies. Recent research has suggested that immune cell recruitment is the main mechanism underlying adjuvant actions in general, and that aluminum salts induce this recruitment via inflammation at the injected site. The aspect of how oil-based adjuvants, such as MF59 and AS03, recruit immune cells remains to be clarified. PMID- 23084849 TI - The economic value of a quadrivalent versus trivalent influenza vaccine. AB - The recently licensed quadrivalent seasonal influenza vaccine (QIV) may provide better protection than the traditional trivalent influenza vaccine (TIV) as it includes one more influenza B strain. We developed a Monte Carlo simulation model to determine the economic value of a QIV compared to the TIV for 10 influenza seasons (1999-2009). The addition of the influenza B strain to convert the TIV into a QIV could result in substantial cost-savings to society (median of $3.1 billion) and third party payers (median of $292 million), even when the cost of QIV is significantly higher. PMID- 23084850 TI - The cost-effectiveness of a 13-valent pneumococcal conjugate vaccination for infants in England. AB - BACKGROUND: In the immunisation schedule in England and Wales, the 7-valent pneumococcal conjugate vaccine (PCV-7) was replaced by the 13-valent vaccine (PCV 13) in April 2010 after having been used since September 2006. The introduction of PCV-7 was informed by a cost effectiveness analysis using an infectious disease model which projected herd immunity and serotype replacement effects based on the post-vaccine experience in the United States at that time. AIM: To investigate the cost effectiveness of the introduction of PCV-13. METHOD: Invasive disease incidence following vaccination was projected from a dynamic infectious disease model, and combined with serotype specific disease outcomes obtained from a large hospital dataset linked to laboratory confirmation of invasive pneumococcal disease. The economic impact of replacing PCV-7 with PCV-13 was compared to stopping the use of pneumococcal conjugate vaccination altogether. RESULTS: Discontinuing PCV-7 would lead to a projected increase in invasive pneumococcal disease, costs and loss of quality of life compared to the introduction of PCV-13. However under base case assumptions (assuming no impact on non-invasive disease, maximal competition between vaccine and non-vaccine types, time horizon of 30 years, vaccine price of L49.60 a dose+L7.50 administration costs and discounting of costs and benefits at 3.5%) the introduction of PCV-13 is only borderline cost effective compared to a scenario of discontinuing of PCV-7. The intervention becomes more cost-effective when projected impact of non-invasive disease is included or the discount factor for benefits is reduced to 1.5%. CONCLUSION: To our knowledge this is the first evaluation of a transition from PCV-7 to PCV-13 based on a dynamic model. The cost-effectiveness of such a policy change depends on a number of crucial assumptions for which evidence is limited, particularly the impact of PCV-13 on non-invasive disease. PMID- 23084851 TI - Safety and vaccine efficacy of a glycoprotein G deficient strain of infectious laryngotracheitis virus delivered in ovo. AB - Infectious laryngotracheitis virus (ILTV), an alphaherpesvirus, causes respiratory disease in chickens and is commonly controlled by vaccination with conventionally attenuated vaccines. Glycoprotein G (gG) is a virulence factor in ILTV and a gG deficient strain of ILTV (DeltagG-ILTV) has shown potential for use as a vaccine. In the poultry industry vaccination via drinking water is common, but technology is now available to allow quicker and more accurate in ovo vaccination of embryos at 18 days of incubation. In this study DeltagG-ILTV was delivered to chicken embryos at three different doses (10(2), 10(3) and 10(4) plaque forming units per egg) using manual in ovo vaccination. At 20 days after hatching, birds were challenged intra-tracheally with wild type ILTV and protection was measured. In ovo vaccination was shown to be safe, as there were no developmental differences between birds from hatching up to 20 days of age, as measured by weight gain. The highest dose of vaccine was the most efficacious, resulting in a weight gain not significantly different from unvaccinated/unchallenged birds seven days after challenge. In contrast, birds vaccinated with the lowest dose showed weight gains not significantly different from unvaccinated/challenged birds. Gross pathology and histopathology of the trachea reflected these observations, with birds vaccinated with the highest dose having less severe lesions. However, qPCR results suggested the vaccine did not prevent the challenge virus replicating in the trachea. This study is the first to assess in ovo delivery of a live attenuated ILTV vaccine and shows that in ovo vaccination with DeltagG-ILTV can be both safe and efficacious. PMID- 23084852 TI - Prior infection of chickens with H1N1 avian influenza virus elicits heterologous protection against highly pathogenic H5N2. AB - Current vaccines for influenza are primarily killed whole virus vaccines that elicit antibody responses to the homologous virus but lack protection against heterologous viruses. Using chickens as a model we have explored the possibility of using a live low pathogenic avian influenza (LPAI) A/goose/AB/223/2005 H1N1 virus as a vaccine to generate protective immunity against heterologous highly pathogenic avian influenza (HPAI) A/chicken/Pensylvania/1370/1983 H5N2 virus challenge. Virus replicated in chickens infected with LPAI H1N1 but did not cause clinical disease. In addition, these chickens developed neutralizing antibodies to LPAI H1N1 virus, but not HPAI H5N2, 21 days post infection (DPI). Furthermore, peripheral blood mononuclear cells from H1N1-infected chickens at 20 DPI had antigen specific proliferation and IFN-gamma secretion following antigen stimulation to H5N2 indicating a heterologous HPAI H5N2 specific cell mediated immunity (CMI) following LPAI H1N1 infection. Following challenge with HPAI H5N2 virus, all control chickens developed clinical disease, while chickens previously infected with H1N1 did not develop clinical disease and shed significantly less virus by oral and cloacal routes. These results indicated that previous infection with LPAI virus can generate heterologous CMI capable of protecting against HPAI H5N2. PMID- 23084853 TI - Vaccination of piglets at 1 week of age with an inactivated Mycoplasma hyopneumoniae vaccine reduces lung lesions and improves average daily gain in body weight. AB - The field efficacy and safety of a single-dose inactivated Mycoplasma hyopneumoniae vaccine, Suvaxyn MH-One, was evaluated in 4-5-day-old piglets on a commercial farm with a history of Mycoplasma disease in Southern Germany. The piglets were injected intramuscularly with the vaccine or saline (control group) and raised under commercial conditions to slaughter weight. The efficacy of the vaccine was determined by comparing the lung lesions associated with infection by M. hyopneumoniae in control and vaccinated pigs post mortem. In this analysis the vaccinated pigs had the lower mean percentage lung lesion at 5% compared to 9% in controls. Of the vaccinated pigs 52.3% were shown to have low levels of lung lesions between 0% and 5% and no more than 5.4% were shown to have levels above 20%. In contrast, the pigs administered saline showed 36.5% in the lower category (0-5%), while 18.3% showed lesions greater than 20%. There were significant differences in the mean body weight of pigs at the final two weight measurements at approximately 21 weeks and 26 weeks of age, with those receiving Suvaxyn MH One being on average 5 kg heavier at each time point. There was also a significant increase in average daily gain in the vaccinated animals compared to the control group, particularly in the period from vaccination to the final two body weight measurements on day 138 and 166, from weaning at day 28 to the final two body measurements and from mid-way during finishing at day 84 to the final two body weight measurements. Vaccination had no adverse impact on appetite, although small numbers of vaccinated and control pigs did show mild signs of coughing, sneezing, respiratory distress or depression. There was no adverse impact on rectal temperatures and no signs of injection site reactions during the course of the study. We can conclude that vaccination with Suvaxyn MH-One to pigs at less than 1 week of age is effective in reducing lung lesions resulting from M. hyopneumoniae and also aids growth performance by reducing weight losses and improving average daily gain. PMID- 23084854 TI - Rabies virus vaccines: is there a need for a pan-lyssavirus vaccine? AB - All members of the lyssavirus genus are capable of causing disease that invariably results in death following the development of clinical symptoms. The recent detection of several novel lyssavirus species across the globe, in different animal species, has demonstrated that the lyssavirus genus contains a greater degree of genetic and antigenic variation than previously suspected. The divergence of species within the genus has led to a differentiation of lyssavirus isolates based on both antigenic and genetic data into two, and potentially a third phylogroup. Critically, from both a human and animal health perspective, current rabies vaccines appear able to protect against lyssaviruses classified within phylogroup I. However no protection is afforded against phylogroup II viruses or other more divergent viruses. Here we review current knowledge regarding the diversity and antigenicity of the lyssavirus glycoprotein. We review the degree of cross protection afforded by rabies vaccines, the genetic and antigenic divergence of the lyssaviruses and potential mechanisms for the development of novel lyssavirus vaccines for use in areas where divergent lyssaviruses are known to circulate, as well as for use by those at occupational risk from these pathogens. PMID- 23084855 TI - Acellular pertussis vaccines in China. AB - In China, whole-cell pertussis (Pw) vaccines were produced in the early 1960s and acellular pertussis (Pa) vaccines were introduced in 1995. Pa vaccines have now almost completely replaced Pw vaccines in the national immunization program. To strengthen the regulation of vaccines used in China, a vaccine lot release system was established in 2001 and Pa vaccines have been included in the system since 2006. This paper mainly described the current status of production and the quality control measures in place for Pa vaccines; and analyses quality control test data accumulated between 2006 and 2010. PMID- 23084857 TI - [Method of the peer review procedure]. PMID- 23084856 TI - Interrelationship between HIV-1 fitness and mutation rate. AB - Differences in replication fidelity, as well as mutator and antimutator strains, suggest that virus mutation rates are heritable and prone to natural selection. Human immunodeficiency virus type 1 (HIV-1) has many distinct advantages for the study of mutation rate optimization given the wealth of structural and biochemical data on HIV-1 reverse transcriptase (RT) and mutants. In this study, we conducted parallel analyses of mutation rate and viral fitness. In particular, a panel of 10 RT mutants-most having drug resistance phenotypes-was analyzed for their effects on viral fidelity and fitness. Fidelity differences were measured using single-cycle vector assays, while fitness differences were identified using ex vivo head-to-head competition assays. As anticipated, virus mutants possessing either higher or lower fidelity had a corresponding loss in fitness. While the virus panel was not chosen randomly, it is interesting that it included more viruses possessing a mutator phenotype rather than viruses possessing an antimutator phenotype. These observations provide the first description of an interrelationship between HIV-1 fitness and mutation rate and support the conclusion that mutator and antimutator phenotypes correlate with reduced viral fitness. In addition, the findings here help support a model in which fidelity comes at a cost of replication kinetics and may help explain why retroviruses like HIV-1 and RNA viruses maintain replication fidelity near the extinction threshold. PMID- 23084858 TI - [The peer review procedure and its place in medicine]. AB - Peer Review literally meaning "re-inspection by a peer" is a special form of external evaluation whose roots go back to Ancient Greece and which is widely employed in science to assess manuscripts submitted for publication. In the medical context the Peer Review process is defined as structured critical self reflection through dialogue with colleagues. Its prime objective is to improve the quality of patient care by identifying potentials for improvement and by deriving an action plan. Amongst other things, this includes medical standards and guidelines, indications and their traceability, the monitoring of the treatment process as well as the interdisciplinary cooperation and teamwork between different professional groups. The Peer Review practice in Germany has received strong impetus from comprehensive hospital operator projects like IQM, the "Initiative Qualitatsmedizin", and the Peer Review practice in intensive care. This practice, which has primarily been developed by practitioners for practitioners of their own accord, offers the chance to integrate medical quality with little bureaucratic effort and direct transfer of knowledge back into daily clinical work. Another important approach to promote peer reviewer qualifications is the curriculum "Medical Peer Review", which has been published by the German Medical Association since 2011. (As supplied by publisher). PMID- 23084859 TI - [Interview of Maria Eberlein-Gonska by Gunther Jonitz]. PMID- 23084860 TI - [The "Medical Peer Review" curriculum of the German Medical Association]. AB - Considering the increasing interest in peer review procedures over the past few years, the German Medical Association (Bundesarztekammer) published a curriculum document in 2011 titled "Medical Peer Review". This curriculum has been conceived to offer guidance for establishing this particularly promising voluntary instrument which links medical quality development with professional learning, focusing and promoting communication and knowledge transfer between experts. Therefore the peers' communicative and social competencies play a central role, including respect and appreciation for each other, the ability to create an atmosphere of trust, to reflect one's own role, to focus on concrete solutions and to constructively deal with conflicts, resistance and fear. For these reasons, the practice-oriented curriculum accentuates both the skills of designing, planning and conducting peer reviews and the necessary personal skills such as the techniques of solution-focused communication and conflict management. (As supplied by publisher). PMID- 23084861 TI - [The IQM peer review procedure - results of the "initiative qualitatsmedizin"]. AB - Between 2009 and 2011 67 IQM peer reviews were conducted. In 64 % of the cases potential could be identified for optimising processes and procedures, and the overall acceptance of the tool was high. The feedback from the visited clinics was positive and constructive. The general areas of interest with a very high optimisation potential include: documentation in the records; target-aimed treatment process; treatments being adequate and in time. It will not take long before data show improvement. PMID- 23084862 TI - [Peer review in ICU]. AB - Peer reviewing in intensive care medicine is an evaluation process that promotes a professional understanding of quality and the exchange of experience in intensive care. It will help integrate evidence-based knowledge into the treatment process at an earlier stage and thus improve the quality of intensive care and intensive nursing care. The process is a learning experience for all involved and is highly satisfying to the participants. The exchange of experience is an essential part of quality control. PMID- 23084863 TI - [Peer review procedures in pathology - more than ten years of experience in the free state of Saxony]. AB - The positive experiences regarding peer review practice go back to the 1990s and can be traced in the position paper of the German Medical Association concerning quality assurance in the field of pathology. This evolved into the initiative of pathologists in Saxony to implement the peer review practice within the remit of their State Medical Association. Since the 14(th) of May 1999 various institutes as well as medical group practices in pathology and cytology have joined forces to undertake voluntary inter-institutional quality control measures. The aim was to improve the process and especially the outcome quality by reviewing each other's quality (analysing samples) on the basis of defined criteria. A positive review outcome report, which will have to be unanimously agreed upon by all participants, will lead to a positive recommendation for a certificate issued by the Medical Association of Saxony. Between 1999 and 2011 a total of 56 peer review proceedings took place. The potentials for improvement concern the problem of "kitchen pathology" still being used in the context of macroscopic description, the quality of microscopic description including the use of correct nomenclature, the quality of tumour classification and immune histological investigations. Statements concerning the advantage of the peer review method in particular refer to the integration of resident pathologists. Due to the long period of implementation of the peer review system und the small number of proceedings, it is not possible to come to a clear conclusion about the improvement or deterioration of quality. During a period of more than 10 years three peer review proceedings were not successful. In this situation, it is appropriate to ask the question of how restrictive peer reviews should be. The three most important aspects for the pathologists in Saxony are: self determination, learning from each other, and a commitment to quality improvement. So this method set an example of how a quality management method can persist for more than 10 years through voluntary engagement. And the initiative of pathologists in Saxony has given an important impetus to the development of other peer review systems in various health care organisations or disciplines in Germany. PMID- 23084864 TI - [Case example: peer review in a stroke center]. PMID- 23084865 TI - [Case example: from trainee to peer - a physician executive reports]. PMID- 23084866 TI - [Quality management in implementing specialist pediatric palliative home care in Lower Saxony, Germany]. AB - BACKGROUND: To provide comprehensive high-quality health care is a great challenge in the context of high specialisation and intensive costs. This problem becomes further aggravated in service areas with low patient numbers and low numbers of specialists. Therefore, a multidimensional approach to quality development was chosen in order to optimise the care of children and adolescents with life-limiting conditions in Lower Saxony, a German federal state with a predominantly rural infrastructure. METHODS: Different service structures were implemented and a classification of service provider's specialisation was defined on the basis of existing references of professional associations. Measures to optimise care were implemented in a process-oriented manner. RESULTS: High quality health care can be facilitated by carefully worded requirements concerning the quality of structures combined with optimally designed processes. Parts of the newly implemented paediatric palliative care structures are funded by the statutory health insurance. PMID- 23084867 TI - Development and validation of the "FrOCK": Frankfurt observer communication checklist. AB - OBJECTIVES: Appropriate communication behaviour during medical consultations has been shown to improve doctor-patient relationships, and should therefore be an integral part of medical training. In Germany, though, there are almost no reliable and validated checklists for assessing communication skills during medical examinations. Our aim was to develop and validate the first German checklist to examine communication skills that can be used during examinations: the Frankfurt Observer Communication Checklist (FrOCK). METHODS: The checklist was developed according to a set of requirements that would need to be met by medical training checklists. It was pilot tested, revised and validated over several steps. Data analyses are provided for 371 assessments (371 students) by 17 examiners. After reviewing face validity and comprehensibility, we also checked for validity by comparing a trained and an untrained group of students and testing for both inter- and intrarater reliability. Interrater reliability was analysed by means of 37 interviews that were simultaneously assessed by five examiners. Intrarater reliability was calculated by having three examiners assess the same 37 students at two different points in time. RESULTS: The final version of FrOCK consists of 31 items for conducting medical interviews which can be broadly divided into four areas: "beginning and conclusion of the interview", "interview technique", "contact skills /empathy" and "history taking". Several aspects of validity could be demonstrated, and both intra- and interrater reliability were high. CONCLUSIONS: The results of this study have shown that FrOCK is a clear and concise checklist for assessing communication skills in medical examinations and one that satisfies psychometric requirements as well. It takes only 3 to 5minutes to complete and thus is particularly useful for assessing communication skills in medical examinations. PMID- 23084868 TI - Reduction in the size of layered double hydroxide nanoparticles enhances the efficiency of siRNA delivery. AB - Small interfering RNAs (siRNAs) are a potentially powerful new class of pharmaceutical drugs for many disease. However, the delivery of unprotected siRNAs is ineffective due to their susceptibility to degradation by ubiquitous nucleases under physiological conditions. Layered double hydroxide nanoparticles (LDHs) have been found to be efficient carriers of anionic drugs and nucleic acids. Our previous research has shown that LDHs (with the Z-average particle size of approximately 110 nm) can mediate siRNA delivery in mammalian cells, resulting in gene silencing. However, short double-stranded nucleic acids are mostly adsorbed onto the external surface and not well protected by LDHs. In order to enhance the intercalation of siRNA into the LDH interlayer and the efficiency of subsequent siRNA delivery, we prepared smaller LDHs (with the Z average particle size of approximately 45 nm) with an engineered non-aqueous method. We demonstrate here that dsDNA/siRNA is more effectively intercalated into these small LDH nanoparticles, more dsDNA/siRNA is transfected into HEK 293T cells, and more efficient silencing of the target gene is achieved using smaller LDHs. Thus, smaller LDH particles have greater potential as a delivery system for the application of RNA interference. PMID- 23084869 TI - CO2 adsorption on Santa Barbara Amorphous-15 (SBA-15) and amine-modified Santa Barbara Amorphous-15 (SBA-15) with and without controlled microporosity. AB - Mesoporous silica SBA-15 samples with and without controlled framework microporosity were prepared and used directly or impregnated with polymer amine as adsorbent for CO(2). These samples were evaluated for their ability to adsorb CO(2) by obtaining their equilibrium adsorption isotherms using volumetric adsorption at three different temperatures of 273 K, 278 K and 283 K. The data obtained were analyzed using Freundlich adsorption isotherm model while the isosteric heats of adsorption were estimated by the Clausius-Clapeyron equation. Under comparable conditions, the adsorption performance of silica SBA-15 was found to be strongly dependent upon the framework microporosity. However, the microporosity contribution to CO(2) adsorption in amine-modified SBA-15 was not obvious as amine blocked micropores and dominated CO(2) adsorption. The SBA-15 sample with higher microporosity displayed higher CO(2) uptake and the CO(2) uptake by amine-modified SBA-15 samples correlated with their total surface areas, as expected. These findings revealed the importance of surface area in designing an adsorbent for CO(2.). PMID- 23084870 TI - Validation of swept source optical coherence tomography (SS-OCT) for the diagnosis of smooth surface caries in vitro. AB - OBJECTIVE: An accurate evaluation of the extent of dental caries and possible progress of the lesion from enamel into dentin is very important in clinical dentistry. Dentists need an imaging technology that can noninvasively and reliably quantify the extent of caries. This study aimed to evaluate the effectiveness of non-polarized swept source optical coherence tomography (OCT) in evaluating the extent of caries on smooth enamel surfaces. METHODS: One-hundred and twenty-seven investigation sites on the enamel surfaces of 93 extracted teeth were selected randomly and examined visually. The presence and extent of caries were scored by experienced and inexperienced dentists using each observation method (0: no caries; 1: enamel demineralization without surface breakdown; 2: enamel breakdown due to caries; 3: deep caries involving the dentin). The same locations were then examined using OCT, following which the teeth were sectioned using a diamond saw and viewed directly under a confocal laser scanning microscope (CLSM). Sensitivity and specificity indices for OCT and VI were calculated and compared. The results were analysed statistically using receiver operating characteristic (ROC) curves. RESULTS: Enamel and dentin caries were outlined by a visible boundary on the cross-sectional OCT images. The modality showed superior results for the detection of dentinal caries; higher sensitivity and Az values could be obtained in the ROC curves, especially by experienced dentists. CONCLUSIONS: Cross-sectional imaging of the natural caries lesions on smooth enamel surface by OCT enables efficient diagnosis of the lesion type, extent and dentin involvement. CLINICAL SIGNIFICANCE: SS-OCT can demonstrate the cross-sectional image of smooth surface enamel caries as highlighted zone in tomogram. It is crucial to determine the extent of the lesion, whether it reaches beyond DEJ or not by a non-invasive and safe technique. OCT can give clinicians information about internal tooth structure and will help clinical decision making on surgical intervention. PMID- 23084871 TI - An experimentally validated finite element method for augmented vertebral bodies. AB - BACKGROUND: Finite element models of augmented vertebral bodies require a realistic modelling of the cement infiltrated region. Most methods published so far used idealized cement shapes or oversimplified material models for the augmented region. In this study, an improved, anatomy-specific, homogenized finite element method was developed and validated to predict the apparent as well as the local mechanical behavior of augmented vertebral bodies. METHODS: Forty nine human vertebral body sections were prepared by removing the cortical endplates and scanned with high-resolution peripheral quantitative CT before and after injection of a standard and a low-modulus bone cement. Forty-one specimens were tested in compression to measure stiffness, strength and contact pressure distributions between specimens and loading-plates. From the remaining eight, fourteen cylindrical specimens were extracted from the augmented region and tested in compression to obtain material properties. Anatomy-specific finite element models were generated from the CT data. The models featured element specific, density-fabric-based material properties, damage accumulation, real cement distributions and experimentally determined material properties for the augmented region. Apparent stiffness and strength as well as contact pressure distributions at the loading plates were compared between simulations and experiments. FINDINGS: The finite element models were able to predict apparent stiffness (R(2)>0.86) and apparent strength (R(2)>0.92) very well. Also, the numerically obtained pressure distributions were in reasonable quantitative (R(2)>0.48) and qualitative agreement with the experiments. INTERPRETATION: The proposed finite element models have proven to be an accurate tool for studying the apparent as well as the local mechanical behavior of augmented vertebral bodies. PMID- 23084872 TI - miRNA, development and disease. PMID- 23084875 TI - Potential of diffusion tensor MR imaging in the assessment of cognitive impairments in children with periventricular leukomalacia born preterm. AB - PURPOSE: To investigate MR diffusion tensor imaging (DTI) and fiber tractography (FT) in the assessment of altered major white matter fibers correlated with cognitive functions in preterm infants with periventricular leukomalacia (PVL), to explore the neural foundation for PVL children's cognitive impairments. MATERIALS AND METHODS: Forty six preterm infants (16 +/- 4.7 months) suffered from PVL and 16 age-matched normal controls were recruited. Developmental quotient (DQ) was recorded to evaluate PVL children's cognitive functions. According to the DQ scores, patients were divided into three groups: mild, moderate and severe cognitive impairment groups. DTI scan was performed. Fractional anisotropy (FA) values of major white matter fibers were measured and their correlation with cognitive levels was evaluated. RESULTS: Compared with the control group, the PVL group showed a significant mean FA reduction in bilateral corticospinal tract (CST), anterior/posterior limb of internal capsule (ICAL/ICPL), arcuate fasciculus (AF), corona radiate (CR), superior longitudinal fasciculus (SLF), splenium of corpus callosum (SCC) (p<0.05) and bilateral posterior thalamic radiation (PTR) (p<0.01). The FA values of left CST, bilateral AF, anterior cingulum (ACG), SLF, ICAL, ICPL, PTR, CR, genu of corpus callosum (GCC), SCC and middle cerebellar peduncle showed significant negative correlations with the cognitive levels. CONCLUSIONS: DTI can provide more information for understanding the pathophysiology of cognitive impairment in preterm infants with PVL. PMID- 23084876 TI - Middle longitudinal fasciculus delineation within language pathways: a diffusion tensor imaging study in human. AB - INTRODUCTION: The existence in the human brain of the middle longitudinal fasciculus (MdLF), initially described in the macaque monkey, is supported by diffusion tensor imaging studies. In the present work, we aim (1) to confirm that this fascicle is found constantly in control subjects with the use of DTI techniques and (2) to delineate the MdLF from the other fiber bundles that constitute the language pathways. MATERIALS AND METHODS: Tractography was realized in four right-handed healthy volunteers for the arcuate fascicle, uncinate fascicle, inferior fronto-occipital fascicle, inferior longitudinal fascicle and the middle longitudinal fascicle. The fiber tracts were characterized for their size, mean fractional anisotropy (FA), for their length, number of streamlines, and lateralization indices were calculated. RESULTS: The MdLF is found constantly and it is clearly delineated from the other fascicles that constitute the language pathways, especially the ventral pathway. It runs within the superior temporal gyrus white matter from the temporal pole, then it extends caudally in the upper part of the sagittal stratum and the posterior part of the corona radiata, to reach the inferior parietal lobule (angular gyrus). We found a leftward asymmetry for all fiber tracts when considering the mean FA. DISCUSSION: Using DTI methods, we confirm that the MdLF connects the angular gyrus and the superior temporal gyrus. On the basis of these findings, the role of the MdLF is discussed. CONCLUSION: The middle longitudinal fasciculus, connects the angular gyrus and the superior temporal gyrus and its course can be systematically differenciated from those of other fascicles composing both ventral and dorsal routes (IFOF, IFL, AF and UF). PMID- 23084877 TI - Carotid stenting with low-dose contrast medium for patients with moderate-to severe chronic renal insufficiency: keyhole carotid stenting. AB - Herein, we describe a new carotid stenting approach for four patients with moderate-to-severe chronic renal insufficiency, who have a glomerular filtration rate (GFR) between 15 and 59 mL/min/1.73 m(2), using a minimum dose of contrast medium (12 mL at a 50% dilution) and SmartMaskTM technology as an alternative to carotid endarterectomy. PMID- 23084878 TI - Translation of genetic findings to clinical practice in juvenile myoclonic epilepsy. AB - It has been estimated that JME (juvenile myoclonic epilepsy), when compared to other adult epilepsy syndromes, is most likely to have a genetic cause. However, decades of research have not brought us closer to finding a single 'JME gene' that is important on a population basis. Is this due in part to the genetic complexity of the syndrome, the cryptic nature of the genes of effect, or perhaps because JME is not one condition at all but many? Before we can begin to harness the power of next-generation sequencing techniques, we must first reduce JME down to lacunae of homogeneity--using increasingly more sophisticated phenotyping tools. The current technological advances in gene sequencing have been used to dramatic effect to identify single gene causes in rare syndromes and identify risk variants in malignancies. Filtering the variety of the human exome or genome down into a handful of biologically plausible candidates now relies on a pipeline of biostatistics, software, and functional analyses. It is simply unacceptable to return uncertain findings to the clinical domain and, therefore, it is crucial that pathogenicity is fully determined before families receive genetic counseling and test results. PMID- 23084879 TI - Evolution of hippocampal spatial representation over time in mice. AB - To investigate the intriguing and paradoxical contrast between the time-limited role of the hippocampus in memory consolidation and its permanent contribution to spatial memory as revealed by place cell activity, we carefully monitored the temporal evolution of the same set of place cells in normal naive mice throughout their familiarization to a spatial context and their consolidation of memory about space. Over six daily recording sessions, despite their widely reported stability, we observed gradual changes in hippocampal place fields and cell firing patterns. These changes were interpreted in terms of both improvement and impoverishment of spatial codes: improvement due to intrinsic place cell plasticity, and impoverishment as a consequence of attentional filtering of allocentric spatial information reaching the hippocampus due to the procedural behavioral requirements of the task, or to hippocampal disengagement as learning progresses. PMID- 23084873 TI - Precision editing of large animal genomes. AB - Transgenic animals are an important source of protein and nutrition for most humans and will play key roles in satisfying the increasing demand for food in an ever-increasing world population. The past decade has experienced a revolution in the development of methods that permit the introduction of specific alterations to complex genomes. This precision will enhance genome-based improvement of farm animals for food production. Precision genetics also will enhance the development of therapeutic biomaterials and models of human disease as resources for the development of advanced patient therapies. PMID- 23084880 TI - Can carotid bulb plaque assessment rule out significant coronary artery disease? A comparison of plaque quantification by two- and three-dimensional ultrasound. AB - BACKGROUND: Screening tools for the detection of coronary artery disease (CAD) are of considerable interest in light of skyrocketing risk factors. Recent work suggests that carotid plaque has a relatively unexplored role in CAD risk prediction but has previously been limited by the difficulty in quantifying its irregular architecture using two-dimensional (2D) ultrasound. The aim of this study was to investigate the utility of a novel automated three-dimensional (3D) ultrasound-based carotid plaque volume quantification technique as a negative predictor of CAD. METHODS: In this prospective study, 70 consecutive patients referred for coronary angiography underwent same-day 2D and 3D carotid ultrasound scans for the purpose of plaque quantification in the carotid bulbs. Two dimensional plaque thickness was measured in its maximal value perpendicular to the vessel wall. Total 3D plaque volume was quantified using a stacked-contour method. Luminal narrowing of coronary arteries was analyzed using the established 16-segment model for coronary arteries to produce an overall angiographic score. Receiver operating characteristic curves, negative predictive value, and sensitivity of 2D and 3D plaque quantification relative to coronary angiography were determined. RESULTS: The novel 3D carotid ultrasound method resulted in a higher negative predictive value and sensitivity relative to 2D carotid ultrasound at their optimal thresholds as determined by Youden indices of receiver operating characteristic curves. In particular, total 3D plaque volumes less than the threshold of 0.09 mL accurately predicted the absence of significant CAD in 93.3% of patients (98.0% sensitivity), whereas maximal 2D plaque thickness less than the threshold of 1.35 mm provided significantly lower negative predictability at 75% (93.9% sensitivity). CONCLUSIONS: Using the determined threshold of 0.09 mL for plaque volumes, this feasibility study suggests that automated 3D ultrasound-based carotid plaque quantification may serve as an important clinical screening tool to help identify patients who are at low risk for significant CAD. PMID- 23084874 TI - The genetic analysis of functional connectomics in Drosophila. AB - Fly and vertebrate nervous systems share many organizational features, such as layers, columns and glomeruli, and utilize similar synaptic components, such as ion channels and receptors. Both also exhibit similar network features. Recent technological advances, especially in electron microscopy, now allow us to determine synaptic circuits and identify pathways cell-by-cell, as part of the fly's connectome. Genetic tools provide the means to identify synaptic components, as well as to record and manipulate neuronal activity, adding function to the connectome. This review discusses technical advances in these emerging areas of functional connectomics, offering prognoses in each and identifying the challenges in bridging structural connectomics to molecular biology and synaptic physiology, thereby determining fundamental mechanisms of neural computation that underlie behavior. PMID- 23084882 TI - Dermoscopy of necrobiosis lipoidica. PMID- 23084881 TI - Judicial review of restrictions on gamete donation in Europe. AB - The decision of S.H. and Others v. Austria vindicates the right of governments to enact restrictions on gamete donation against claims that these restrictions violate the guarantees of the European Convention on Human Rights. Van Hoof and Pennings in this issue predict that legal diversity on the question of gamete donation will persist in the wake of this decision and discuss how the decision itself is insufficiently protective of the private and family interests of individuals who seek reproduction-assisting medical treatment. This commentary discusses the difficult balancing work of the European Court of Human Rights, its questionable expansion of the margin appreciation doctrine in S.H. and Others v. Austria and how the decision might influence national courts in the future. PMID- 23084883 TI - Transient myeloproliferative syndrome associated with Down syndrome. PMID- 23084884 TI - The effects of increasing doses of 2 preparations of long-acting insulin on short term plasma profiles of glucose and insulin in lactating dairy cows. AB - Two experiments were conducted to investigate effects of administering increasing doses of 2 different preparations of long-acting insulin on the 24-h profiles of plasma glucose and insulin concentrations in mid lactation dairy cows. The 2 separately analyzed experiments investigated the effects administering either Humulin N (H), a neutral protamine Hagedorn insulin, or insulin glargine (Lantus, L), an insulin analog, at doses of 0 (control), 0.1, 0.2, and 0.4 IU/kg of body weight in a randomized complete block design. Sixteen cows (237+/-11 d in milk for H; 213+/-10 d in milk for L; mean +/- SD) were used for each insulin preparation, resulting in n=4 for each dose within insulin preparation. Cows were fitted with a single jugular catheter on the day before the study. On the day of the study, cows were given treatments by subcutaneous injection of either sterile water or the designated insulin type and dose. Blood samples were taken hourly from the jugular catheter. Subcutaneous injection of both H and L resulted in linear decreases in plasma glucose concentrations, increased area under the curve, and decreased nadir for plasma glucose following administration of the insulin preparations. Plasma insulin concentration linearly increased with increasing dose of H. Though elevated concentrations of insulin were measurable in cows treated with H, they were not measurable in cows treated with L. Attempts to measure overall insulin concentrations and metabolites of L by a commercially available ELISA and a commercially available RIA kit were not successful and did not retrieve values that we felt truly represented the amount of insulin activity exhibited during this treatment. Both long-acting insulin preparations elicited insulin-like activity in lactating dairy cows, as evidenced by reduced plasma glucose concentrations. Given these results, the potential exists to use both H and L to study the effects of insulin in mid lactation dairy cows without the confounding effect of severe hypoglycemia (<20 mg/dL) or concurrent provision of glucose during treatment. PMID- 23084885 TI - Characterization by solid-phase microextraction-gas chromatography of the volatile profile of protected designation of origin Montasio cheese during ripening. AB - Montasio is a typical protected designation of origin (PDO) Italian semi-hard and semi-cooked cheese produced in northeast Italy from raw or thermized cow's milk. The PDO label implies that the product has distinctive characteristics that are connected to traditional production methods. The aim of this work was to precisely characterize the volatile fraction of this Italian cheese. The volatile profile can be considered a fingerprint because the flavor of a cheese variety is the result of a specific balance between the volatile compounds produced during the ripening process. Analysis of the volatile profile of Montasio cheese was performed by solid-phase microextraction-gas chromatography. Six cheesemaking trials were performed, each in a different dairy located within the Montasio cheese production area. Cheeses were analyzed at 5 stages of ripening (60, 90, 170, 300, and 365 d). Only 11 compounds were identified and measured: 5 fatty acids, 3 alcohols, 2 ketones, and 1 ester. The limited number of volatile compounds measured in the headspace of the Montasio cheese is probably due to the specific making process of this cheese, which affects evolution of the microflora and the biochemical processes of ripening. The total volatile fraction profile progressively increased from 60 to 170 d, after which time it remained almost steady. The most important contributors were found to be ethanol, short-chain fatty acids (C(2) to C(6)), diacetyl, and ethyl hexanoate. Ethanol and short chain fatty acids increased up to 170 d, diacetyl increased up to 300 d and then declined, and ethyl hexanoate increased until the final stage. PMID- 23084886 TI - Associations of housing, management, milking activity, and standing and lying behavior of dairy cows milked in automatic systems. AB - The objective of this cross-sectional study was to describe the housing, feeding management, and characteristics (parity and stage of lactation) of cows on commercial automatic milking system (AMS) dairies and their associations with the standing and lying behavior patterns and milking activity (frequency and yield) of lactating dairy cows. Thirteen AMS herds were enrolled in the study, with an average herd size of 71+/-30 (mean +/- SD; range: 34 to 131) lactating cows. All of the herds used freestall barns, each set up for free cow traffic to the AMS. On-farm measurements were taken to determine stocking density at the freestalls (0.9+/-0.1 cows/stall; mean +/- SD), feed bunk (0.66+/-0.17 m of feed bunk space/cow; mean +/- SD), and AMS units (55+/-11 cows/AMS; mean +/- SD). A random sample of 30 cows/herd was selected to monitor standing and lying behavior for 4d using electronic data loggers. Times of feed delivery and feed push-up were recorded daily by the herd managers. Milking times, frequency, and yield were automatically recorded by the AMS units. Data were analyzed in a multivariable mixed regression model to determine which herd-level (housing and feeding management) and cow-level (parity, DIM, and milk yield) factors were associated with behavior and milking activity measures. Lying bout lengths were found to be negatively associated with milk yield and tended to be positively associated with more space at the feed bunk. Increased lying duration was associated with cows of lower milk production, increased space at the feed bunk, and increased frequency of feed push-up. Longer postmilking standing durations were associated with cows of higher parity. An association existed between cows milking less frequently when they were further in lactation, were of higher parity, and as stocking density at the AMS (cows/AMS) increased. Milk yield was positively associated with increased space at the feed bunk and higher parity and negatively associated with DIM. From this study, it can be concluded that increased milking frequency may be achieved in AMS herds by reducing stocking density at the AMS unit. Further, in AMS systems, greater milk yield and lying duration may be achieved by ensuring that cows have ample feed bunk space and have their feed readily available to them in the bunk. PMID- 23084887 TI - Feeding behaviors of transition dairy cows fed glycerol as a replacement for corn. AB - Feed sorting is a natural behavior of dairy cows that can result in inconsistencies in the nutritive value of a total mixed ration (TMR). The objective of this study was to determine the effects of replacing high-moisture corn with glycerol on feed sorting and the feed intake pattern of transition dairy cows. Multiparous Holstein cows (n=26) were paired by expected calving date, housed in individual tie stalls, and fed diets containing either glycerol or high-moisture corn once daily from d -28 to +56 relative to calving. Glycerol was included at 11.5 and 10.8% of the ration dry matter for the pre- and postpartum diets, respectively. The feed consumption pattern was determined by measuring TMR disappearance during the intervals from 0 to 4 h, 4 to 8 h, 8 to 12 h, and 12 to 24 h relative to feed delivery. Feed sorting was determined on d 16, -9, 9, 16, and 51 relative to calving at 4, 8, 12 and 24 h after feeding. The TMR particle size profile was determined at feed delivery and at 4, 8, 12, and 24 after feed delivery by using the Penn State Particle Separator (Nasco, Fort Atkinson, WI) to yield long (>19 mm), medium (<19 mm, >8 mm), short (<8 mm, >1.18 mm), and fine (<1.18 mm) particles. Overall feed intake did not differ between diets and was 14.7+/-0.4 and 20.2+/-0.5 kg/d for the pre- and postpartum intervals, respectively. During the prepartum period, glycerol decreased the amount of feed consumed during the first 4h after feed delivery (7.22 vs. 5.59+/ 0.35 kg; control vs. glycerol, respectively) but increased feed consumed from 12 through 24 h after feed delivery (2.22 vs. 3.82+/-0.35 kg; control vs. glycerol, respectively). Similar effects on the feed consumption pattern were observed after calving. During the prepartum period, cows fed the control diet sorted against long particles, whereas cows fed glycerol did not sort against long particles (77.2 vs. 101.5+/-3.50% of expected intake for control vs. glycerol; significant treatment effect). The data indicate that addition of glycerol to the TMR alters the feed consumption pattern to increase feed consumption late in the day at the expense of feed consumed immediately after feeding, and it reduces sorting behavior against long particles. Together, these may reduce diurnal variations in the rumen environment to promote greater rumen health in transition cows. PMID- 23084888 TI - Calf birth weight, gestation length, calving ease, and neonatal calf mortality in Holstein, Jersey, and crossbred cows in a pasture system. AB - Holstein (HH), Jersey (JJ), and crosses of these breeds were mated to HH or JJ bulls to form purebreds, reciprocal crosses, backcrosses, and other crosses in a rotational mating system. The herd was located at the Center for Environmental Farming Systems in Goldsboro, North Carolina. Data for calf birth weight (CBW), calving ease (0 for unassisted, n=1,135, and 1 for assisted, n=96), and neonatal calf mortality (0 for alive, n=1,150, and 1 for abortions recorded after mid gestation, stillborn, and dead within 48 h, n=81) of calves (n=1,231) were recorded over 9 calving seasons from 2003 through 2011. Gestation length (GL) was calculated as the number of days from last insemination to calving. Linear mixed models for CBW and GL included fixed effects of sex, parity (first vs. later parities), twin status, and 6 genetic groups: HH, JJ, reciprocal F(1) crosses (HJ, JH), crosses >50% Holsteins (HX) and crosses >50% Jerseys (JX), where sire breed is listed first. The CBW model also included GL as a covariate. Logistic regression for calving ease and neonatal calf mortality included fixed effects of sex, parity, and genetic group. Genetic groups were replaced by linear regression using percentage of HH genes as coefficients on the above models and included as covariates to determine various genetic effects. Year and dam were included as random effects in all models. Female calves (27.57+/-0.54 kg), twins (26.39+/-1.0 kg), and calves born to first-parity cows (27.67+/-0.56 kg) had lower CBW than respective male calves (29.53+/-0.53 kg), single births (30.71+/-0.19 kg), or calves born to multiparous cows (29.43+/-0.52 kg). Differences in genetic groups were observed for CBW and GL. Increased HH percentage in the calf increased CBW (+9.3+/-0.57 kg for HH vs. JJ calves), and increased HH percentage in the dams increased CBW (+1.71+/-0.53 kg for calves from HH dams vs. JJ dams); JH calves weighed 1.33 kg more than reciprocal HJ calves. Shorter GL was observed for twin births (272.6+/-1.1 d), female calves (273.9+/-0.6 d), and for first-parity dams (273.8+/-0.6 d). Direct genetic effects of HH alleles shortened GL (-3.5+/-0.7 d), whereas maternal HH alleles increased GL (2.7+/-0.6 d). Female calves had lower odds ratio (0.32, confidence interval=0.10-0.99) for neonatal calf mortality in second and later parities than did male calves. Maternal heterosis in crossbred primiparous dams was associated with reduced calf mortality. PMID- 23084889 TI - The effect of NaCl substitution with KCl on proteinase activities of cell-free extract and cell-free supernatant at different pH levels and salt concentrations: Lactobacillus acidophilus and Lactobacillus casei. AB - The aim of this study was to investigate the effect of substitution of NaCl with KCl at different pH levels and salt concentrations on proteinase activity of cell free extract and cell-free supernatant of the probiotics Lactobacillus acidophilus and Lactobacillus casei. de Man, Rogosa, and Sharpe broth aliquots were mixed with 2 pure salts (NaCl and KCl) and 2 salt concentrations at 2 concentration levels (5 and 10%), inoculated with Lactobacillus acidophilus or Lactobacillus casei, and incubated aerobically at 37 degrees C for 22 h. The cultures were then centrifuged at 4,000*g for 30 min, and the collected cell pellets were used to prepare cell-wall proteinases and the supernatants used as a source of supernatant (extracellular) proteinases. The proteolytic activity and protein content of both portions were determined. After incubation of both portions with 3 milk caseins (alpha-, beta-, kappa-casein), the supernatants were individually subjected to analysis of angiotensin-converting enzyme (ACE) inhibitory activity and proteolytic activity using the o-phthalaldehyde method. Significant differences were observed in ACE-inhibitory and proteolytic activities between salt substitution treatments of cell-free extract and cell free supernatant from both probiotic strains at the same salt concentration and pH level. PMID- 23084890 TI - Random regression models using Legendre polynomials or linear splines for test day milk yield of dairy Gyr (Bos indicus) cattle. AB - Studies investigating the use of random regression models for genetic evaluation of milk production in Zebu cattle are scarce. In this study, 59,744 test-day milk yield records from 7,810 first lactations of purebred dairy Gyr (Bos indicus) and crossbred (dairy Gyr * Holstein) cows were used to compare random regression models in which additive genetic and permanent environmental effects were modeled using orthogonal Legendre polynomials or linear spline functions. Residual variances were modeled considering 1, 5, or 10 classes of days in milk. Five classes fitted the changes in residual variances over the lactation adequately and were used for model comparison. The model that fitted linear spline functions with 6 knots provided the lowest sum of residual variances across lactation. On the other hand, according to the deviance information criterion (DIC) and bayesian information criterion (BIC), a model using third-order and fourth-order Legendre polynomials for additive genetic and permanent environmental effects, respectively, provided the best fit. However, the high rank correlation (0.998) between this model and that applying third-order Legendre polynomials for additive genetic and permanent environmental effects, indicates that, in practice, the same bulls would be selected by both models. The last model, which is less parameterized, is a parsimonious option for fitting dairy Gyr breed test day milk yield records. PMID- 23084891 TI - A coupled kinematics-energetics model for predicting energy efficient flapping flight. AB - A new computational model based on an optimal power, wake-only aerodynamics method is presented to predict the interdependency of energetics and kinematics in bird and bat flight. The model is divided into offline, intermediate and online modules. In the offline module, a four-dimensional design space sweep is performed (lift, thrust, flapping amplitude and flapping frequency). In the intermediate stage, the physical characteristics of the animal are introduced (wing span, mass, wing area, aspect ratio, etc.), and a series of amplitude frequency response surfaces are constructed for all viable flight speeds. In the online component, the amplitude-frequency response surfaces are mined for the specific flapping motions being considered. The method is applied to several biological examples including a medium sized fruit bat (Cynopterus brachyotis), and two birds: a thrush nightingale (Luscinia luscinia) and a budgerigar (Melopsittacus undulatus). For each of these animals, the power and kinematics predictions are compared with available experimental data. These examples demonstrate that this new method can reasonably predict animal flight energetics and kinematics. PMID- 23084892 TI - Flow and anastomosis in vascular networks. AB - We analyze the effect that the geometrical place of anastomosis in the circulatory tree has on blood flow. We introduce an idealized model that consists of a symmetric network for the arterial and venous vascular trees. We consider that the network contains a viscoelastic fluid with the rheological characteristics of blood, and analyze the network hydrodynamic response to a time dependent periodic pressure gradient. This response is a measurement of the resistance to flow: the larger the response, the smaller the resistance to flow. We find that for networks whose vessels have the same radius and length, the outer the level of the branching tree in which anastomosis occurs, the larger the network response. Moreover, when anastomosis is incorporated in the form of bypasses that bridge vessels at different bifurcation levels, the further apart are the levels bridged by the bypass, the larger the response is. Furthermore, we apply the model to the available information for the dog circulatory system and find that the effect that anastomosis causes at different bifurcation levels is strongly determined by the structure of the underlying network without anastomosis. We rationalize our results by introducing two idealized models and approximated analytical expressions that allow us to argue that, to a large extent, the response of the network with anastomosis is determined locally. We have also considered the influence of the myogenic effect. This one has a large quantitative impact on the network response. However, the qualitative behavior of the network response with anastomosis is the same with or without consideration of the myogenic effect. That is, it depends on the structure that the underlying vessel network has in a small neighborhood around the place where anastomosis occurs. This implies that whenever there is an underlying tree-like network in an in vivo vasculature, our model is able to interpret the anastomotic effect. PMID- 23084893 TI - Specific interactions between adenosine and streptavidin/avidin. AB - The screening of ligands against proteins plays important role in drug discovery and biological research. Using a dye labelled Streptavidin binding aptamer (SBA) as a competitive reporter probe, we found that adenosine bound to streptavidin specifically. Fluorescence spectral analysis showed that adenosine bound to both avidin and streptavidin with the K(ds) in the range of 0.1-0.2 mM, and these bindings can be blocked by biotin. Although streptavidin and avidin are well known and widely used in bioanalysis, their biological role is still a riddle so far. Since adenosine is a ubiquitous physiological regulator present in cells, our finding provides new clues for the understanding of the functions of both proteins. PMID- 23084894 TI - Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain. AB - High throughput screening identified the pyridothienopyrimidinone 1 as a ligand for the metabotropic glutamate receptor 1 (mGluR1=10 nM). Compound 1 has an excellent in vivo profile; however, it displays unfavorable pharmacokinetic issues and metabolic stability. Therefore, using 1 as a template, novel analogues (10i) were prepared. These analogues displayed improved oral exposure and activity in the Spinal Nerve Ligation (SNL) pain model. PMID- 23084895 TI - Synthesis and antitrypanosomal activity of new 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles. AB - A series of novel 6,6,7-trisubstituted thiopyrano[2,3-d][1,3]thiazoles-based molecules have been synthesized and evaluated as potential antitrypanosomal agents. The most active analogue 3b inhibited Trypanosoma brucei brucei and Trypanosoma brucei gambiense with an IC(50) of 0.26 and 0.42 MUM, respectively. They could be considered as potent hits for further antitrypanosomal drug discovery efforts. PMID- 23084896 TI - Synthesis, characterization and potent DNA-cleaving activity of copper(II) complexed berberine carboxylate. AB - 9-O-(4-carboxybenzyl)berberine (CBB) 1 was synthesized from the reaction of berberrubine with methyl 4-(bromomethyl)benzoate and subsequent hydrolysis. Its Cu(II) complex 2 was prepared from the reaction with Cu(NO(3))(2).3H(2)O, and established as [Cu(CBB)(2)](NO(3))(2).2H(2)O by means of (1)H NMR, UV, IR, elemental analysis and TGA measurements. Agarose gel electrophoresis study on the cleavage of plasmid pBR322 DNA indicated that complex 2 was capable of efficiently cleaving DNA under physiological conditions, most probably via an oxidative mechanistic pathway involving the formation of singlet oxygen as the reactive species. Kinetic assay afforded the maximal first-order rate constant k(max) of 2.41 h(-1) and Michaelis constant K(M) of 2.64 mM, respectively, representing ca. 10(8)-fold acceleration in the cleavage. This catalytic efficacy is attributed to the Cu(II)-assisted formation of dimeric species, in which the two berberine subunits cooperatively bind to DNA, whereas the carboxylate coordinated Cu(II) moiety functions as the cleavage-active center. PMID- 23084897 TI - Aggregate formation and radiolytic degradation of amphiphilic DNA block copolymer possessing disulfide bond. AB - We have designed a novel aggregate of DNA block copolymer (DBC) that is sensitive to hypoxic X-irradiation. The DBC consists of tetrahydropyrane-protected 2 hydroxyethyl methacrylate as a hydrophobic unit and oligodeoxynucleotides as a hydrophilic unit, which are linked to a radiation-sensitive disulfide bond. The DBC self-assembled efficiently to form aggregates that encapsulated small molecules such as nile red and pyrene. Hypoxic X-irradiation could then induce reductive degradation of the DBC aggregates via an exchange reaction of the disulfide bond to release guest molecules. PMID- 23084898 TI - Structure-based bioisosterism design, synthesis and biological evaluation of novel 1,2,4-triazin-6-ylthioacetamides as potent HIV-1 NNRTIs. AB - The development of new HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) offers the possibility of generating novel chemical entities of increased potency. Previous investigations in our laboratory resulted in the discovery of several novel series of arylazolylthioacetanilides as potent NNRTIs. In this study, based on the structure-based bioisosterism strategy, novel 1,2,4 triazin-6-yl thioacetamide derivatives were designed, synthesized and evaluated for their anti-HIV activity in MT-4 cells. Among them, the most promising compound was 8b15 with double-digit nanomolar activity against wild-type HIV-1 (EC(50)=0.018+/-0.007 MUM) and moderate activity against the double mutant strain RES056 (EC(50)=3.3+/-0.1 MUM), which indicated that 1,2,4-triazin-6-yl thioacetamide can be used as a novel scaffold to develop a new class of potent NNRTIs active against both wild-type and drug-resistant HIV-1 strains. In addition, preliminary structure-activity relationship (SAR) and molecular modeling results are also briefly discussed, which provide some useful information for the further design of novel NNRTIs. PMID- 23084899 TI - 4-Phenyl tetrahydroisoquinolines as dual norepinephrine and dopamine reuptake inhibitors. AB - Novel 4-phenyl tetrahydroisoquinolines that inhibit both dopamine and norepinephrine transporters were designed and prepared. In this Letter, we describe the synthesis, in vitro activity and associated structure-activity relationships of this series. We also report the ex vivo NET occupancy of a representative compound, 41. PMID- 23084900 TI - Antibacterial activity of substituted 5-methylbenzo[c]phenanthridinium derivatives. AB - Antibiotic resistance has prompted efforts to discover antibiotics with novel mechanisms of action. FtsZ is an essential protein for bacterial cell division, and has been viewed as an attractive target for the development of new antibiotics. Sanguinarine is a benzophenanthridine alkaloid that prevents cytokinesis in bacteria by inhibiting FtsZ self-assembly. In this study, a series of 5-methylbenzo[c]phenanthridinium derivatives were synthesized and evaluated for antibacterial activity against Staphylococcus aureus and Enterococcus faecalis. The data indicate that the presence of a 1- or 12-phenyl substituent on 2,3,8,9-tetramethoxy-5-methylbenzo[c]phenanthridinium chloride significantly enhances antibacterial activity relative to the parent compound or sanguinarine. PMID- 23084901 TI - Prohormone-substrate peptide sequence recognition by peptidylglycine alpha amidating monooxygenase and its reflection in increased glycolate inhibitor potency. AB - The interactions of nineteen peptide substrates and fifteen analogous peptidomimetic glycolate inhibitors with human peptidylglycine alpha-amidating monooxygenase (PAM) have been investigated. The substrates and inhibitors are the prohormones of calcitonin and oxytocin and their analogues. PAM both secreted into the medium by and extracted from DMS53 small lung carcinoma cells has been studied. The results show that recognition of the prooxytocin and procalcitonin peptide sequences by the enzyme extends more than four and five amino acid residues, respectively, from their C-termini. This substrate sequence recognition is mirrored by increased inhibitor potency with increased peptide length in the glycolate peptidomimetics. Substitution of the C-terminal penultimate glycine and proline residues of prooxytocin and procalcitonin and their analogues with phenylalanine increases the enzyme binding affinity. However, this changes the binding mode from one that depends on peptide sequence recognition to another primarily determined by the phenylalanine moiety, for both the substrates and analogous glycolate inhibitors. PMID- 23084902 TI - Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement. AB - This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors. PMID- 23084903 TI - Synthesis, evaluation and structure-activity relationships of triazine dimers as novel antiviral agents. AB - This letter reports the synthesis and structure-activity relationship (SAR) study of a series of triazine dimers as novel antiviral agents. These compounds were obtained through a bivalent ligand approach in which two triazine moieties are covalently connected by suitable linkers. Several compounds showed submicromolar activity against wild-type HIV-1 and moderate activity against single mutant strains. PMID- 23084904 TI - Synthesis and antibiofilm activity of marine natural product-based 4 thiazolidinones derivatives. AB - 4-Thiazolidinones derivatives of marine bromopyrrole alkaloids were synthesized as potential antibiofilm compounds. Among the synthesized compounds, some showed promising antibiofilm activity. Biological data revealed that 1,3-thiazolidin-4 one derivatives are more potent antibiofilm agents compared to 1,3-thiazinan-4 ones. Antibiofilm activity of compound 4b, 4c (MIC=0.78 MUg/ml) was 3-fold superior than standard vancomycin (MIC=3.125 MUg/ml) while activity of compound 4d, 4f, 4g and 4h was 2-fold (MIC=1.56 MUg/ml) against Staphylococcus aureus biofilm. Compound 4b-4h showed equal antibiofilm activity against Staphylococcus epidermidis compared to standard Vancomycin (MIC=3.125 MUg/ml). PMID- 23084905 TI - Investigations into specificity of azepinomycin for inhibition of guanase: discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues. AB - In our long and broad program to explore structure-activity relationships of the natural product azepinomycin and its analogues for inhibition of guanase, an important enzyme of purine salvage pathway of nucleic acid metabolism, it became necessary to investigate if the nucleoside analogues of the heterocycle azepinomycin, which are likely to be formed in vivo, would be more or less potent than the parent heterocycle. To this end, we have resynthesized both azepinomycin (1) and its two diastereomeric nucleoside analogues (2 and 3), employing a modified, more efficient procedure, and have biochemically screened all three compounds against a mammalian guanase. Our results indicate that the natural product is at least 200 times more potent toward inhibition of guanase as compared with its nucleoside analogues, with the observed K(i) of azepinomycin (1) against the rabbit liver guanase=2.5 (+/-0.6)*10(-6) M, while K(i) of Compound 2=1.19 (+/-0.02)*10(-4) M and that of Compound 3=1.29 (+/-0.03)*10(-4) M. It is also to be noted that while IC(50) value of azepinomycin against guanase in cell culture has long been reported, no inhibition studies nor K(i) against a pure mammalian enzyme have ever been documented. In addition, we have, for the first time, determined the absolute stereochemistry of the 6-OH group of 2 and 3 using conformational analysis coupled with 2-D (1)H NMR NOESY. PMID- 23084907 TI - It's not all black and white. PMID- 23084906 TI - Development of macrocyclic inhibitors of HCV NS3/4A protease with cyclic constrained P2-P4 linkers. AB - A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker. PMID- 23084908 TI - Secreted bacterial vesicles as good samaritans. AB - Bacteriodes fragilis and polysaccharide A capsular antigen (PSA) produced by this commensal bacteria can mediate immune tolerance in the gastrointestinal (GI) tract. When looking for naturally secreted forms of PSA, Shen et al. (2012) suprisingly found that PSA is packaged in outer membrane vesicles (OMVs), bacterial blebs with a disreputable past. PMID- 23084909 TI - Where does innate immunity stop and adaptive immunity begin? AB - The regulation of alternative splicing in the immune effector Dscam reported by Dong et al. (2012) in this issue of Cell Host & Microbe raises important questions about the nature of immune responses. Can we clearly define "adaptive" as being different from "innate" immunity, or is it time for a more flexible description? PMID- 23084912 TI - Subversion of phagocytosis for pathogen survival. AB - Professional phagocytes, such as neutrophils and macrophages, effectively engulf and eliminate invading microorganisms. To survive this onslaught, pathogens have developed an astounding array of countermeasures aimed at avoiding detection, impairing signaling, or paralyzing the machinery that underlies phagocytosis. On the other hand, certain pathogens benefit from attaching to, entering, or traversing host cells to establish and spread infection. This is accomplished by yet other types of effectors that either co-opt or mimic host cell phagocytic components. Here, we briefly summarize the basic features of the phagocytic process and proceed to describe the types of strategies deployed by pathogens to either impair phagocytosis or to gain entry into cells where they can establish a safe survival niche. PMID- 23084910 TI - A Blueprint for HIV Vaccine Discovery. AB - Despite numerous attempts over many years to develop an HIV vaccine based on classical strategies, none has convincingly succeeded to date. A number of approaches are being pursued in the field, including building upon possible efficacy indicated by the recent RV144 clinical trial, which combined two HIV vaccines. Here, we argue for an approach based, in part, on understanding the HIV envelope spike and its interaction with broadly neutralizing antibodies (bnAbs) at the molecular level and using this understanding to design immunogens as possible vaccines. BnAbs can protect against virus challenge in animal models, and many such antibodies have been isolated recently. We further propose that studies focused on how best to provide T cell help to B cells that produce bnAbs are crucial for optimal immunization strategies. The synthesis of rational immunogen design and immunization strategies, together with iterative improvements, offers great promise for advancing toward an HIV vaccine. PMID- 23084911 TI - Innate immune sensing of HIV-1 by dendritic cells. AB - HIV-1-specific antibodies and CD8(+) cytotoxic T cells are detected in most HIV-1 infected people, yet HIV-1 infection is not eradicated. Contributing to the failure to mount a sterilizing immune response may be the inability of antigen presenting dendritic cells (DCs) to sense HIV-1 during acute infection, and thus the inability to effectively prime naive, HIV-1-specific T cells. Recent findings related to DC-expressed innate immune factors including SAMHD1, TREX1, and TRIM5 provide a molecular basis for understanding why DCs fail to adequately sense invasion by this deadly pathogen and suggest experimental approaches to improve T cell priming to HIV-1 in prophylactic vaccination protocols. PMID- 23084913 TI - IFN-inducible GTPases in host cell defense. AB - From plants to humans, the ability to control infection at the level of an individual cell-a process termed cell-autonomous immunity-equates firmly with survival of the species. Recent work has begun to unravel this programmed cell intrinsic response and the central roles played by IFN-inducible GTPases in defending the mammalian cell's interior against a diverse group of invading pathogens. These immune GTPases regulate vesicular traffic and protein complex assembly to stimulate oxidative, autophagic, membranolytic, and inflammasome related antimicrobial activities within the cytosol, as well as on pathogen containing vacuoles. Moreover, human genome-wide association studies and disease related transcriptional profiling have linked mutations in the Immunity-Related GTPase M (IRGM) locus and altered expression of guanylate binding proteins (GBPs) with tuberculosis susceptibility and Crohn's colitis. PMID- 23084914 TI - Innate lymphoid cells: balancing immunity, inflammation, and tissue repair in the intestine. AB - Innate lymphoid cells (ILCs) are a recently described group of innate immune cells that can regulate immunity, inflammation, and tissue repair in multiple anatomical compartments, particularly the barrier surfaces of the skin, airways, and intestine. Broad categories of ILCs have been defined based on transcription factor expression and the ability to produce distinct patterns of effector molecules. Recent studies have revealed that ILC populations can regulate commensal bacterial communities, contribute to resistance to helminth and bacterial pathogens, promote inflammation, and orchestrate tissue repair and wound healing. This review will examine the phenotype and function of murine and human ILCs and discuss the critical roles these innate immune cells play in health and disease. PMID- 23084916 TI - Host translation at the nexus of infection and immunity. AB - By controlling gene expression at the level of mRNA translation, organisms temporally and spatially respond swiftly to an ever-changing array of environmental conditions. This capacity for rapid response is ideally suited for mobilizing host defenses and coordinating innate responses to infection. Not surprisingly, a growing list of pathogenic microbes target host mRNA translation for inhibition. Infection with bacteria, protozoa, viruses, and fungi has the capacity to interfere with ongoing host protein synthesis and thereby trigger and/or suppress powerful innate responses. This review discusses how diverse pathogens manipulate the host translation machinery and the impact of these interactions on infection biology and the immune response. PMID- 23084915 TI - Chronic bystander infections and immunity to unrelated antigens. AB - Chronic infections with persistent pathogens such as helminths, mycobacteria, Plasmodium, and hepatitis viruses affect more than a third of the human population and are associated with increased susceptibility to other pathogens as well as reduced vaccine efficacy. Although these observations suggest an impact of chronic infections in modulating immunity to unrelated antigens, little is known regarding the underlying mechanisms. Here, we summarize evidence of the most prevalent infections affecting immunity to unrelated pathogens and vaccines, and discuss potential mechanisms of how different bystander chronic infections might impact immune responses. We suggest that bystander chronic infections affect different stages of host responses and may impact transmission and recognition of other pathogens, innate immune responses, priming and differentiation of adaptive effector responses, as well as the development and maintenance of immunological memory. Further understanding of the immunological effects of coinfection should provide opportunities to enhance vaccine efficacy and control of infectious diseases. PMID- 23084917 TI - Phytopathogen effectors subverting host immunity: different foes, similar battleground. AB - Phytopathogenic bacteria, fungi, and oomycetes invade and colonize their host plants through distinct routes. These pathogens secrete diverse groups of effector proteins that aid infection and establishment of different parasitic lifestyles. Despite this diversity, a comparison of different plant-pathogen systems has revealed remarkable similarities in the host immune pathways targeted by effectors from distinct pathogen groups. Immune signaling pathways mediated by pattern recognition receptors, phytohormone homeostasis or signaling, defenses associated with host secretory pathways and pathogen penetrations, and plant cell death represent some of the key processes controlling disease resistance against diverse pathogens. These immune pathways are targeted by effectors that carry a wide range of biochemical functions and are secreted by completely different pathogen groups, suggesting that these pathways are a common battleground encountered by many plant pathogens. PMID- 23084918 TI - Intestinal commensal microbes as immune modulators. AB - Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic strategy for many mucosal and nonmucosal immune-related conditions, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, diabetes, and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis. PMID- 23084919 TI - Anopheles NF-kappaB-regulated splicing factors direct pathogen-specific repertoires of the hypervariable pattern recognition receptor AgDscam. AB - Insects rely on innate immune responses controlled by the immune deficiency (IMD), Toll, and other immune signaling pathways to combat infection by a broad spectrum of pathogens. These pathways signal to downstream NF-kappaB family transcription factors that control specific antipathogen action via direct transcriptional control of immune effectors, hematopoiesis, and melanization. Here we show that in the Anopheles malaria vector, IMD and Toll pathways mediate species-specific defenses against Plasmodium and bacteria through the transcriptional regulation of splicing factors Caper and IRSF1 that, in turn, determine the production of pathogen-specific splice variant repertoires of the hypervariable pattern recognition receptor AgDscam. This mechanism represents an additional level of immune response regulation that may provide a previously unrecognized level of plasticity to the insect immune pathway-regulated antipathogen defenses. PMID- 23084921 TI - The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry. AB - Dengue viruses (DVs) are responsible for the most medically relevant arboviral diseases. However, the molecular interactions mediating DV entry are poorly understood. We determined that TIM and TAM proteins, two receptor families that mediate the phosphatidylserine (PtdSer)-dependent phagocytic removal of apoptotic cells, serve as DV entry factors. Cells poorly susceptible to DV are robustly infected after ectopic expression of TIM or TAM receptors. Conversely, DV infection of susceptible cells is inhibited by anti-TIM or anti-TAM antibodies or knockdown of TIM and TAM expression. TIM receptors facilitate DV entry by directly interacting with virion-associated PtdSer. TAM-mediated infection relies on indirect DV recognition, in which the TAM ligand Gas6 acts as a bridging molecule by binding to PtdSer within the virion. This dual mode of virus recognition by TIM and TAM receptors reveals how DVs usurp the apoptotic cell clearance pathway for infectious entry. PMID- 23084920 TI - Transcriptional pausing controls a rapid antiviral innate immune response in Drosophila. AB - Innate immune responses are characterized by precise gene expression whereby gene subsets are temporally induced to limit infection, although the mechanisms involved are incompletely understood. We show that antiviral immunity in Drosophila requires the transcriptional pausing pathway, including negative elongation factor (NELF) that pauses RNA polymerase II (Pol II) and positive elongation factor b (P-TEFb), which releases paused Pol II to produce full-length transcripts. We identify a set of genes that is rapidly transcribed upon arbovirus infection, including components of antiviral pathways (RNA silencing, autophagy, JAK/STAT, Toll, and Imd) and various Toll receptors. Many of these genes require P-TEFb for expression and exhibit pausing-associated chromatin features. Furthermore, transcriptional pausing is critical for antiviral immunity in insects because NELF and P-TEFb are required to restrict viral replication in adult flies and vector mosquito cells. Thus, transcriptional pausing primes virally induced genes to facilitate rapid gene induction and robust antiviral responses. PMID- 23084922 TI - Short-range exosomal transfer of viral RNA from infected cells to plasmacytoid dendritic cells triggers innate immunity. AB - Viral nucleic acids often trigger an innate immune response in infected cells. Many viruses, including hepatitis C virus (HCV), have evolved mechanisms to evade intracellular recognition. Nevertheless, HCV-permissive cells can trigger a viral RNA-, TLR7-, and cell-contact-dependent compensatory interferon response in nonpermissive plasmacytoid dendritic cells (pDCs). Here we report that these events are mediated by transfer of HCV-RNA-containing exosomes from infected cells to pDCs. The exosomal viral RNA transfer is dependent on the endosomal sorting complex required for transport (ESCRT) machinery and on Annexin A2, an RNA-binding protein involved in membrane vesicle trafficking, and is suppressed by exosome release inhibitors. Further, purified concentrated HCV-RNA-containing exosomes are sufficient to activate pDCs. Thus, vesicular sequestration and exosomal export of viral RNA may serve both as a viral strategy to evade pathogen sensing within infected cells and as a host strategy to induce an unopposed innate response in replication-nonpermissive bystander cells. PMID- 23084923 TI - Differential responses of immune cells to type I interferon contribute to host resistance to viral infection. AB - Type I interferons (IFNs) are central to antiviral defense, but how they orchestrate immune cell function is incompletely understood. We determined that IFNs produced during murine cytomegalovirus (MCMV) infection differentially affect dendritic cells (DCs) and natural killer (NK) cells. IFNs induce cell intrinsic responses in DCs, activating antiproliferative, antiviral, and lymphocyte-activating gene networks, consistent with high activity of the transcription factor STAT1 in these cells. By comparison, NK cells exhibit lower STAT1 expression and reduced IFN responsiveness. Rather, IFNs indirectly affect NK cells by inducing IL-15, which activates the transcription factor E2F and stimulates genes promoting cell expansion. IFN cell-intrinsic responses are necessary in DCs, but not NK cells, for MCMV resistance. Thus, sensitivity to IFN induced cytokines and differences in IFN receptor signaling program immune cells to mount distinct responses that promote viral control. PMID- 23084924 TI - Inhibition of HIV-1 particle assembly by 2',3'-cyclic-nucleotide 3' phosphodiesterase. AB - The expression of hundreds of interferon-stimulated genes (ISGs) causes the cellular "antiviral state" in which the replication of many viruses, including HIV-1, is attenuated. We conducted a screen for ISGs that inhibit HIV-1 virion production and found that 2',3'-cyclic-nucleotide 3'-phosphodiesterase (CNP), a membrane-associated protein with unknown function in mammals has this property. CNP binds to the structural protein Gag and blocks HIV-1 particle assembly after Gag and viral RNA have associated with the plasma membrane. Several primate lentiviruses are CNP-sensitive, and CNP sensitivity/resistance is determined by a single, naturally dimorphic, codon (E/K40) in the matrix domain of Gag. Like other antiretroviral proteins, CNP displays interspecies variation in antiviral activity. Mice encode an inactive CNP variant and a single amino acid difference in murine versus human CNP determines Gag binding and antiviral activity. Some cell types express high levels of CNP and we speculate that CNP evolved to restrict lentivirus replication therein. PMID- 23084925 TI - Evolution-guided identification of antiviral specificity determinants in the broadly acting interferon-induced innate immunity factor MxA. AB - MxA is an interferon-induced dynamin-like GTPase with wide-ranging antiviral activity, which hinges upon detection of unique viral structures that differ across virus families. Despite elucidation of its structure, the basis of MxA antiviral specificity remains enigmatic. We used an evolution-guided approach to identify the loop L4 of MxA as a hotspot for recurrent positive selection in primates. Further, we show that single amino acid changes in L4 are necessary and sufficient to explain dramatic differences in species-specific antiviral activity of primate MxA proteins against the orthomyxoviruses Thogoto virus and influenza A virus. Taken together, our findings identify a genetic determinant of MxA target recognition and suggest a model by which MxA achieves antiviral breadth without compromising viral specificity. PMID- 23084927 TI - Spurious hyperphosphatemia: a case for caution. PMID- 23084926 TI - PYK2: a calcium-sensitive protein tyrosine kinase activated in response to fertilization of the zebrafish oocyte. AB - Fertilization begins with binding and fusion of a sperm with the oocyte, a process that triggers a high amplitude calcium transient which propagates through the oocyte and stimulates a series of preprogrammed signal transduction events critical for zygote development. Identification of the pathways downstream of this calcium transient remains an important step in understanding the basis of zygote quality. The present study demonstrates that the calcium-calmodulin sensitive protein tyrosine kinase PYK2 is a target of the fertilization-induced calcium transient in the zebrafish oocyte and that it plays an important role in actin-mediated events critical for sperm incorporation. At fertilization, PYK2 was activated initially at the site of sperm-oocyte interaction and was closely associated with actin filaments forming the fertilization cone. Later PYK2 activation was evident throughout the entire oocyte cortex, however activation was most intense over the animal hemisphere. Fertilization-induced PYK2 activation could be blocked by suppressing calcium transients in the ooplasm via injection of BAPTA as a calcium chelator. PYK2 activation could be artificially induced in unfertilized oocytes by injection of IP3 at concentrations sufficient to induce calcium release. Functionally, suppression of PYK2 activity by chemical inhibition or by injection of a dominant-negative construct encoding the N terminal ERM domain of PKY2 inhibited formation of an organized fertilization cone and reduced the frequency of successful sperm incorporation. Together, the above findings support a model in which PYK2 responds to the fertilization induced calcium transient by promoting reorganization of the cortical actin cytoskeleton to form the fertilization cone. PMID- 23084928 TI - Successful resumption of peritoneal dialysis after Aspergillus fumigatus peritonitis. PMID- 23084929 TI - Characterization of an attenuated TE3L-deficient vaccinia virus Tian Tan strain. AB - An attenuated vaccinia virus (VACV), TE3L(-)VTT, was evaluated for virulence and safety to determine its potential use as a vaccine or as a recombinant virus vector to express foreign genes. The virulence of TE3L(-)VTT was compared with that of the wild-type VTT both in vivo and in vitro. The humoral and cellular immune responses were detected in a mouse model to test the vaccine efficacy of the TE3L mutant. The results suggested that deletion of the TE3L gene decreased the virulence and neurovirulence significantly in mice and rabbit models, yet retained the immunogenicity. Thus, the deletion of TE3L improved the safety of the VTT vector; this approach may yield a valuable resource for studies of recombinant VACV-vectored vaccines. PMID- 23084930 TI - When secondary comes first--the importance of non-canonical DNA structures. AB - Secondary structure-forming DNA motifs have achieved infamy because of their association with a variety of human diseases and cancer. The 3rd FASEB summer conference on dynamic DNA structures focused on the mechanisms responsible for the instabilities inherent to repetitive DNA and presented many exciting and novel aspects related to the metabolism of secondary structures. In addition, the meeting encompassed talks and posters on the dynamic structures that are generated during DNA metabolism including nicked DNA, Holliday junctions and RNA:DNA hybrids. New approaches for analysis and sequencing technologies put forth secondary structures and other DNA intermediates as vital regulators of a variety of cellular processes that contribute to evolution, polymorphisms and diseases. PMID- 23084931 TI - Methods for the study of endophytic microorganisms from traditional Chinese medicine plants. AB - Plant endophytes are very numerous and widely distributed in nature, their relationships being described as a balanced symbiotic continuum ranging from mutualism through commensalism to parasitism during a long period of coevolution. Traditional Chinese medicines have played a very important role in disease treatment in China and other Asian countries. Investigations show that these medicinal plants harbor endophytes with different kinds of ecological functions, and some of them have potential to produce bioactive small-molecule compounds. This chapter will focus on the selective isolation methods, the diversity of some endophytes (actinobacteria and fungi) isolated from Traditional Chinese Medicine (TCM) plants, and the bioactive compounds from selected endophytic actinobacteria reported in the past 3 years. PMID- 23084932 TI - Cyanobacteria as a source of natural products. AB - Cyanobacteria or blue-green algae from various environments have been recognized as sources of a variety of bioactive metabolites. Strategies of strain isolation from aquatic habitats, and cultivation and harvesting for metabolite production are described. Strategies for screening of compounds are discussed, including their direct MALDI-TOF mass spectrometric detection in whole cells. Genetic approaches including genomic mining, mutagenesis including transcriptional activation, heterologous expression, and in vitro reconstitution of pathways are presented. PMID- 23084933 TI - Isolating antifungals from fungus-growing ant symbionts using a genome-guided chemistry approach. AB - We describe methods used to isolate and identify antifungal compounds from actinomycete strains associated with the leaf-cutter ant Acromyrmex octospinosus. These ants use antibiotics produced by symbiotic actinomycete bacteria to protect themselves and their fungal cultivar against bacterial and fungal infections. The fungal cultivar serves as the sole food source for the ant colony, which can number up to tens of thousands of individuals. We describe how we isolate bacteria from leaf-cutter ants collected in Trinidad and analyze the antifungal compounds made by two of these strains (Pseudonocardia and Streptomyces spp.), using a combination of genome analysis, mutagenesis, and chemical isolation. These methods should be generalizable to a wide variety of insect-symbiont situations. Although more time consuming than traditional activity-guided fractionation methods, this approach provides a powerful technique for unlocking the complete biosynthetic potential of individual strains and for avoiding the problems of rediscovery of known compounds. We describe the discovery of a novel nystatin compound, named nystatin P1, and identification of the biosynthetic pathway for antimycins, compounds that were first described more than 60 years ago. We also report that disruption of two known antifungal pathways in a single Streptomyces strain has revealed a third, and likely novel, antifungal plus four more pathways with unknown products. This validates our approach, which clearly has the potential to identify numerous new compounds, even from well characterized actinomycete strains. PMID- 23084934 TI - Gamma-butyrolactone and furan signaling systems in Streptomyces. AB - Streptomyces bacteria produce different classes of diffusible signaling molecules that trigger secondary metabolite production and/or morphological development within the cell population. The biosynthesis of gamma-butyrolactones (GBLs) and 2 alkyl-4-hydroxymethylfuran-3-carboxylic acids (AHFCAs) signaling molecules is related and involves an essential AfsA-like butenolide synthase. This chapter first describes the catalytic role of AfsA-like enzyme then provides details about methods for the discovery and characterization of potentially novel signaling molecules. In section 4, one approach for establishing the biological role of these signaling molecules is presented. PMID- 23084935 TI - Old meets new: using interspecies interactions to detect secondary metabolite production in actinomycetes. AB - Actinomycetes, a group of filamentous, Gram-positive bacteria, have long been a remarkable source of useful therapeutics. Recent genome sequencing and transcriptomic studies have shown that these bacteria, responsible for half of the clinically used antibiotics, also harbor a large reservoir of gene clusters, which have the potential to produce novel secreted small molecules. Yet, many of these clusters are not expressed under common culture conditions. One reason why these clusters have not been linked to a secreted small molecule lies in the way that actinomycetes have typically been studied: as pure cultures in nutrient-rich media that do not mimic the complex environments in which these bacteria evolved. New methods based on multispecies culture conditions provide an alternative approach to investigating the products of these gene clusters. We have recently implemented binary interspecies interaction assays to mine for new secondary metabolites and to study the underlying biology of interactinomycete interactions. Here, we describe the detailed biological and chemical methods comprising these studies. PMID- 23084936 TI - Finding and analyzing plant metabolic gene clusters. AB - Plants produce an array of diverse secondary metabolites with important ecological functions, providing protection against pests, diseases, and abiotic stresses. Secondary metabolites are also a rich source of bioactive compounds for drug and agrochemical development. Despite the importance of these compounds, the metabolic diversity of plants remains largely unexploited, primarily due to the problems associated with mining large and complex genomes. It has recently emerged that genes for the synthesis of multiple major classes of plant-derived secondary metabolites (benzoxinones, diterpenes, triterpenes, and cyanogenic glycosides) are organized in clusters reminiscent of the metabolic gene clusters found in microbes. Many more secondary metabolic clusters are likely to emerge as the body of sequence information available for plants continues to grow, accelerated by high-throughput sequencing. Here, we describe approaches for the identification of secondary metabolic gene clusters in plants through forward and reverse genetics, map-based cloning, and genome mining and give examples of methods used for the analysis and functional confirmation of new clusters. PMID- 23084937 TI - Genomic approaches for interrogating the biochemistry of medicinal plant species. AB - Development of next-generation sequencing, coupled with the advancement of computational methods, has allowed researchers to access the transcriptomes of recalcitrant genomes such as those of medicinal plant species. Through the sequencing of even a few cDNA libraries, a broad representation of the transcriptome of any medicinal plant species can be obtained, providing a robust resource for gene discovery and downstream biochemical pathway discovery. When coupled to estimation of expression abundances in specific tissues from a developmental series, biotic stress, abiotic stress, or elicitor challenge, informative coexpression and differential expression estimates on a whole transcriptome level can be obtained to identify candidates for function discovery. PMID- 23084939 TI - Using a virus-derived system to manipulate plant natural product biosynthetic pathways. AB - A series of vectors (the pEAQ series) based on cowpea mosaic virus has been developed which allows the rapid transient expression of high levels of foreign protein in plants without the need for viral replication. The plasmids are small binary vectors, which are introduced into plant leaves by agroinfiltration. They are modular in design and allow the insertion of multiple coding sequences on the same segment of T-DNA. These properties make the pEAQ vectors particularly suitable for use in situations, such as the investigation and manipulation of metabolic pathways, where the coexpression of multiple proteins within a cell is required. PMID- 23084938 TI - Phylogenetic approaches to natural product structure prediction. AB - Phylogenetics is the study of the evolutionary relatedness among groups of organisms. Molecular phylogenetics uses sequence data to infer these relationships for both organisms and the genes they maintain. With the large amount of publicly available sequence data, phylogenetic inference has become increasingly important in all fields of biology. In the case of natural product research, phylogenetic relationships are proving to be highly informative in terms of delineating the architecture and function of the genes involved in secondary metabolite biosynthesis. Polyketide synthases and nonribosomal peptide synthetases provide model examples in which individual domain phylogenies display different predictive capacities, resolving features ranging from substrate specificity to structural motifs associated with the final metabolic product. This chapter provides examples in which phylogeny has proven effective in terms of predicting functional or structural aspects of secondary metabolism. The basics of how to build a reliable phylogenetic tree are explained along with information about programs and tools that can be used for this purpose. Furthermore, it introduces the Natural Product Domain Seeker, a recently developed Web tool that employs phylogenetic logic to classify ketosynthase and condensation domains based on established enzyme architecture and biochemical function. PMID- 23084940 TI - DNA assembler: a synthetic biology tool for characterizing and engineering natural product gene clusters. AB - The majority of existing antibacterial and anticancer drugs are natural products or their derivatives. However, the characterization and engineering of these compounds are often hampered by limited ability to manipulate the corresponding biosynthetic pathways. Recently, we developed a genomics-driven, synthetic biology-based method, DNA assembler, for discovery, characterization, and engineering of natural product biosynthetic pathways (Shao, Luo, & Zhao, 2011). By taking advantage of the highly efficient yeast in vivo homologous recombination mechanism, this method synthesizes the entire expression vector containing the target biosynthetic pathway and the genetic elements needed for DNA maintenance and replication in individual hosts in a single-step manner. In this chapter, we describe the general guidelines for construct design. By using two distinct biosynthetic pathways, we demonstrate that DNA assembler can perform multiple tasks, including heterologous expression, introduction of single or multiple point mutations, scar-less gene deletion, generation of product derivatives, and creation of artificial gene clusters. As such, this method offers unprecedented flexibility and versatility in pathway manipulations. PMID- 23084941 TI - Reassembly of functionally intact environmental DNA-derived biosynthetic gene clusters. AB - Only a small fraction of the bacterial diversity present in natural microbial communities is regularly cultured in the laboratory. Those bacteria that remain recalcitrant to culturing cannot be examined for the production of bioactive secondary metabolites using standard pure-culture approaches. The screening of genomic DNA libraries containing DNA isolated directly from environmental samples (environmental DNA (eDNA)) provides an alternative approach for studying the biosynthetic capacities of these organisms. One drawback of this approach has been that most eDNA isolation procedures do not permit the cloning of DNA fragments of sufficient length to capture large natural product biosynthetic gene clusters in their entirety. Although the construction of eDNA libraries with inserts big enough to capture biosynthetic gene clusters larger than ~40kb remains challenging, it is possible to access large gene clusters by reassembling them from sets of smaller overlapping fragments using transformation-associated recombination in Saccharomyces cerevisiae. Here, we outline a method for the reassembly of large biosynthetic gene clusters from captured sets of overlapping soil eDNA cosmid clones. Natural product biosynthetic gene clusters reassembled using this approach can then be used directly for functional heterologous expression studies. PMID- 23084942 TI - A toolkit for heterologous expression of metabolic pathways in Aspergillus oryzae. AB - Much has been learned about the activities of the key enzymes involved in eukaryotic natural product synthesis by isolating the relevant genes and expressing them in a suitable foreign host. Aspergillus oryzae has proved to be an amenable host for the functional analysis of megasynthases from other fungi, but secondary metabolites are often the products of suites of enzymes, and understanding their biosynthesis requires simultaneous expression of several genes. This chapter describes the development and use of a molecular toolkit that facilitates the rapid assembly of the genes constituting whole biosynthetic pathways in one or a few multiple gene expression plasmids designed to provide high-level expression in A. oryzae. Conventional DNA manipulation by restriction/ligation is replaced by homologous recombination in yeast and Gateway(r)-mediated site-specific recombination in vitro. The toolkit comprises an assembly vector used for the simple construction and modification of large genes from overlapping DNA fragments and three multigene expression vectors. Insertion of three tailoring enzyme genes by homologous recombination and one megasynthase gene by Gateway(r) transfer into each of the expression vectors can be achieved in a little more than 1 week, and alternative selection markers in the expression plasmids permit cotransformation of A. oryzae with up to 12 genes. PMID- 23084943 TI - De novo synthesis of high-value plant sesquiterpenoids in yeast. AB - Terpenoids comprise a structurally diverse group of natural products. Despite various and important uses of terpenoids (e.g., flavors, drugs, and nutraceuticals), most of them are, however, still extracted from plant sources, which suffer from high cost and low yield. Alternatively, terpenoids can be produced in microbes using their biosynthetic genes. With the explosion of sequence data, many genes for terpenoid metabolism can be characterized by biochemical approaches and used for the microbial production of terpenoids. However, substrates for in vitro studies of terpene synthases are costly, and the enzymatic synthesis of terpenoids in vitro using recombinant enzymes is insufficient to meet the chemical characterization need. Here, we describe the use of engineered yeast (EPY300) to evaluate in vivo production of sesquiterpenoids. Two sesquiterpene synthase genes (for valencene and 5-epi aristolochene synthases) were expressed in EPY300 in native and N-terminal thioredoxin fusion forms. By using the thioredoxin fusion, valencene biosynthesis was slightly decreased; however, the production of 5-epi-aristolochene was increased by 10-fold, producing 420 MUg mL(-1) of 5-epi-aristolochene. Accordingly, the thioredoxin-fused 5-epi-aristolochene was coexpressed with 5-epi aristolochene dihydroxylase (cytochrome P450 monooxygenase) and its reductase in EPY300. This combinatorial expression yielded hydroxylated sesquiterpene, capsidiol, at ~250 MUg mL(-1). Detailed experimental procedures and other considerations for this work are given. PMID- 23084944 TI - Streptomyces coelicolor as an expression host for heterologous gene clusters. AB - The expression of a gene or a set of genes from one organism in a different species is known as "heterologous expression." In actinomycetes, prolific producers of natural products, heterologous gene expression has been used to confirm the clustering of secondary metabolite biosynthetic genes, to analyze natural product biosynthesis, to produce variants of natural products by genetic engineering, and to discover new compounds by screening genomic libraries. Recent advances in DNA sequencing have enabled the rapid and affordable sequencing of actinomycete genomes and revealed a large number of secondary metabolite gene clusters with no known products. Heterologous expression of these cryptic gene clusters combined with comparative metabolic profiling provides an important means to identify potentially novel compounds. In this chapter, the methods and strategies used to heterologously express actinomycete gene clusters, including the techniques used for cloning secondary metabolite gene clusters, the Streptomyces hosts used for their expression, and the techniques employed to analyze their products by metabolic profiling, are described. PMID- 23084946 TI - Regulatory cross talk and microbial induction of fungal secondary metabolite gene clusters. AB - Filamentous fungi are well-known producers of a wealth of secondary metabolites with various biological activities. Many of these compounds such as penicillin, cyclosporine, or lovastatin are of great importance for human health. Genome sequences of filamentous fungi revealed that the encoded potential to produce secondary metabolites is much higher than the actual number of compounds produced during cultivation in the laboratory. This finding encouraged research groups to develop new methods to exploit the silent reservoir of secondary metabolites. In this chapter, we present three successful strategies to induce the expression of secondary metabolite gene clusters. They are based on the manipulation of the molecular processes controlling the biosynthesis of secondary metabolites and the simulation of stimulating environmental conditions leading to altered metabolic profiles. The presented methods were successfully applied to identify novel metabolites. They can be also used to significantly increase product yields. PMID- 23084945 TI - Toward awakening cryptic secondary metabolite gene clusters in filamentous fungi. AB - Mining for novel natural compounds is of eminent importance owing to the continuous need for new pharmaceuticals. Filamentous fungi are historically known to harbor the genetic capacity for an arsenal of natural compounds, both beneficial and detrimental to humans. The majority of these metabolites are still cryptic or silent under standard laboratory culture conditions. Mining for these cryptic natural products can be an excellent source for identifying new compound classes. Capitalizing on the current knowledge on how secondary metabolite gene clusters are regulated has allowed the research community to unlock many hidden fungal treasures, as described in this chapter. PMID- 23084947 TI - Waking up Streptomyces secondary metabolism by constitutive expression of activators or genetic disruption of repressors. AB - Streptomycete bacteria are renowned as a prolific source of natural products with diverse biological activities. Production of these metabolites is often subject to transcriptional regulation: the biosynthetic genes remain silent until the required environmental and/or physiological signals occur. Consequently, in the laboratory environment, many gene clusters that direct the biosynthesis of natural products with clinical potential are not expressed or at very low level preventing the production/detection of the associated metabolite. Genetic engineering of streptomycetes can unleash the production of many new natural products. This chapter describes the overexpression of pathway-specific activators, the genetic disruption of pathway-specific repressors, and the main strategy used to identify and characterize new natural products from these engineered Streptomyces strains. PMID- 23084948 TI - Use and discovery of chemical elicitors that stimulate biosynthetic gene clusters in Streptomyces bacteria. AB - Secondary metabolite production from Streptomyces bacteria is primarily controlled at the level of transcription. Under normal laboratory conditions, the majority of the biosynthetic pathways of Streptomyces coelicolor are transcriptionally silent. These are often referred to as "cryptic" pathways and it is thought that they may encode the biosynthesis of yet unseen natural products with novel structures that may be valuable leads for therapeutics and as bioactive compounds. Sequencing of microbial genomes has supported the notion that cryptic pathways are widely distributed and likely to be a source of new chemical diversity. Hence, techniques that can reverse the silencing will be valuable for natural product screening as well as giving access to interesting new biology. We have focused on the identification of chemical elicitors capable of inducing expression of secondary metabolic gene clusters and to do so have drawn a parallel with fungal biology where inhibitors of histone acetylation change chromatin structure to derepress biosynthetic pathways. Similarly, we find that the same chemicals can also modify the expression of pathways in S. coelicolor and other Streptomyces spp. They variously act to increase expression from known pathways as well as inducing cryptic pathways. We hypothesize that nucleoid structure may be playing an analogous role to fungal chromatin structure in controlling transcriptional programs. Further, we speculate that microbial natural product collections could themselves be a rich source of new histone deacetylase inhibitors that have many applications in human health, such as anticancer therapeutics, beyond their traditional use as antimicrobials. PMID- 23084949 TI - Persister eradication: lessons from the world of natural products. AB - Persisters are specialized survivor cells that protect bacterial populations from killing by antibiotics. Persisters are dormant phenotypic variants of regular cells rather than mutants. Bactericidal antibiotics kill by corrupting their targets into producing toxic products; tolerance to antibiotics follows when targets are inactive. Transcriptome analysis of isolated persisters points to toxin/antitoxin modules as a principle component of persister formation. Mechanisms of persister formation are redundant, making it difficult to eradicate these cells. In Escherichia coli, toxins RelE and MazF cause dormancy by degrading mRNA; HipA inhibits translation by phosphorylating Ef-Tu; and TisB forms an anion channel in the membrane, leading to a decrease in pmf and ATP levels. Prolonged treatment of chronic infections with antibiotics selects for hip mutants that produce more persister cells. Eradication of tolerant persisters is a serious challenge. Some of the existing antibiotics are capable of killing persisters, pointing to ways of developing therapeutics to treat chronic infections. Mitomycin is a prodrug which is converted into a reactive compound forming adducts with DNA upon entering the cell. Prolonged treatment with aminoglycosides that cause mistranslation leading to misfolded peptides can sterilize a stationary culture of Pseudomonas aeruginosa, a pathogen responsible for chronic, highly tolerant infections of cystic fibrosis patients. Finally, one of the best bactericidal agents is rifampin, an inhibitor of RNA polymerase, and we suggest that it "kills" by preventing persister resuscitation. PMID- 23084950 TI - Methods in Enzymology. Natural product biosynthesis by microorganisms and plants, part C. Preface. PMID- 23084952 TI - Giant spinal schwannoma: complete excision and one-step posterior spinal reconstruction. PMID- 23084951 TI - Development and evaluation of diclofenac sodium thermorevesible subcutaneous drug delivery system. AB - The objective of current work was to develop and evaluate thermoreversible subcutaneous drug delivery system for diclofenac sodium. The poloxamer 407, methyl cellulose, hydroxypropyl methyl cellulose and polyethylene glycol were used alone and in combination in different ratios to design the delivery system. The physical properties like Tsol-gel, viscosity, clarity of solution and gel were evaluated. The in vitro release of the drug delivery system was evaluated using membrane less method and the drug release kinetics and mechanism was predicted by applying various mathematical models to the in vitro dissolution data. Rabbits were used as in vivo model following subcutaneous injection to predict various pharmacokinetics parameters by applying Pk-Summit software. The in vitro and in vivo data revealed that the system consisting of the poloxamer 407 in concentration of 20% (DP20) was the most capable formulation for extending the drug release and maintaining therapeutic blood level of DS for longer duration (144 h). The data obtained for drug content after autoclaving the solutions indicate that autoclaving results in 6% degradation of DS. The data also suggested that the studied polymers poloxamer, MC and PG are good candidate to extend the drug release possessing a unique thermoreversible property. PMID- 23084953 TI - Osteoid osteoma of the lumbar spine. PMID- 23084954 TI - Malignant enterocutaneous fistula complicated by pneumorrhachis. PMID- 23084955 TI - Exercise and manual physiotherapy arthritis research trial (EMPART) for osteoarthritis of the hip: a multicenter randomized controlled trial. AB - OBJECTIVES: To determine the effectiveness of exercise therapy (ET) compared with ET with adjunctive manual therapy (MT) for people with hip osteoarthritis (OA); and to identify if immediate commencement of treatment (ET or ET+MT) was more beneficial than a 9-week waiting period for either intervention. DESIGN: Assessor blind randomized controlled trial with a 9-week and 18-week follow-up. SETTING: Four academic teaching hospitals in Dublin, Ireland. PARTICIPANTS: Patients (N=131) with hip OA recruited from general practitioners, rheumatologists, orthopedic surgeons, and other hospital consultants were randomized to 1 of 3 groups: ET (n=45), ET+MT (n=43), and waitlist controls (n=43). INTERVENTIONS: Participants in both the ET and ET+MT groups received up to 8 treatments over 8 weeks. Control group participants were rerandomized into either ET or ET+MT groups after 9 week follow-up. Their data were pooled with original treatment group data: ET (n=66) and ET+MT (n=65). MAIN OUTCOME MEASURES: The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical function (PF) subscale. Secondary outcomes included physical performance, pain severity, hip range of motion (ROM), anxiety/depression, quality of life, medication usage, patient-perceived change, and patient satisfaction. RESULTS: There was no significant difference in WOMAC PF between the ET (n=66) and ET+MT (n=65) groups at 9 weeks (mean difference, .09; 95% confidence interval [CI] -2.93 to 3.11) or 18 weeks (mean difference, .42; 95% CI, -4.41 to 5.25), or between other outcomes, except patient satisfaction with outcomes, which was higher in the ET+MT group (P=.02). Improvements in WOMAC, hip ROM, and patient-perceived change occurred in both treatment groups compared with the control group. CONCLUSIONS: Self-reported function, hip ROM, and patient perceived improvement occurred after an 8-week program of ET for patients with OA of the hip. MT as an adjunct to exercise provided no further benefit, except for higher patient satisfaction with outcome. PMID- 23084956 TI - Cord blood graft engineering. PMID- 23084957 TI - Review of multistate models in hematopoietic cell transplantation studies. PMID- 23084958 TI - Double haploidentical hematopoietic stem cell transplantation results in successful engraftment of bone marrow from both donors without graft-versus-host or graft-versus-graft effects. AB - We established double-haploidentical (DH) hematopoietic stem cell transplantation (HSCT) murine models to explore competitive engraftment, graft-versus-graft effect and graft-versus-host disease (GVHD). T cell-depleted (TCD) bone marrow (BM) cells from B6SJF1 (donor 1 [D1]) and B6D2F1 (donor 2 [D2]) mice achieved >90% donor engraftment when transplanted into B6CBAF1 mice. B6CBAF1 recipients survived without evidence of GVHD when undergoing HSCT with TCD-BM from 2 haploidentical donors, D1 and D2. DH-HSCT recipients had significantly higher leukocyte and neutrophil counts than single-haploidentical HSCT recipients from either D1 or D2. DH recipients consistently showed successful mixed chimerism in both BM and spleen. Two other DH-HSCT models, B6D2F1 + C3D2F1->B6C3F1 and B6CBAF1 + B6SJLF1->B6D2F1, showed similar engraftment patterns. Low-dose T cell infusion from both D1 and D2 increased the degree of early engraftment of the respective donors in BM and spleen; however, this early engraftment pattern did not determine long-term engraftment dominance. In the long term, minimally engrafted D1 BM recovered and comprised >50% of all donor- derived B, T, and natural killer cells. We conclude that early BM engraftment is determined by donor T cell immunodominance, but long-term engraftment is related to the engraftment potential of stem cells after DH-HSCT. PMID- 23084959 TI - HLA alloimmunization in Egyptian aplastic anemia patients receiving exclusively leukoreduced blood components. AB - BACKGROUND: The aim of the work was to detect the presence of anti-human leukocyte antigens (anti-HLAs) class I and II antibodies in sera of multitransfused aplastic anemia pediatric patients using two different techniques. The effect of the implemented transfusion practice on the frequency of these antibodies was studied as well as their effect on the patient's clinical condition. METHODS: Flowcytometry panel reactive antibodies (FlowPRAs) for HLA class I and II were determined and compared to the results obtained by Complement dependent-cytotoxicity (CDC) assay. RESULTS: Over the past 3years, 20 aplastic anemia patients received leukoreduced blood components, 5/20 patients received leukoreduced products exclusively throughout their disease (group1), 15/20 patients had received non-leukoreduced components previously (group2). None of the patients in group1 was FlowPRA positive. Six patients from group2 (40%) were FlowPRA positive, only four out of these six patients showed positive CDC test. Positive and negative predictive values of CDC were 44.4 and 81.4% respectively, with 65% accuracy. Platelet refractoriness was encountered in 13/20 patients; only 3 out of these 13 patients (23%) were FlowPRA I positive (38+/-18%). One refractory patient died from intracranial hemorrhage. His FlowPRA I was 65.7% and CDC assay failed to detect it. CONCLUSION: Leukoreduction of blood components minimizes the incidence of HLA alloimmunization. Further investigations for other immune causes of platelet refractoriness are recommended. FCM is a simple and reliable technique for detection of anti-HLA antibodies, while CDC assay lacks sensitivity and specificity. PMID- 23084960 TI - Costs of different follow-up strategies in early breast cancer: a review of the literature. AB - We reviewed the literature between January 1985 and June 2011 on the costs of different follow-up strategies for patients treated for early breast cancer. A total of 186 abstracts were retrieved of which eleven publications were considered relevant; 6 randomised clinical trials, 4 retrospective cohort studies and 1 'minisymposium'. The follow-up strategies, outcome measures and methods of analysis used in these studies vary widely, so no general conclusions can be drawn. However, from the results we infer that patient-led follow-up by a nurse practitioner, follow-up by a general practitioner, or telephone follow-up is feasible and cost-effective, without routine additional tests, except annual mammograms. In this era of increasing health care costs, cost-effectiveness, evaluated in a standardised way, should be taken into account in future clinical trials. PMID- 23084961 TI - Short commentaries on data published by Petit et al. on locoregional risk after lipofilling in breast cancer patients. AB - Lipofilling is becoming part of the breast reshaping after quadrantectomy or mastectomy in breast cancer patients, but there are open questions of its safety. PMID- 23084962 TI - Do primary mammary osteosarcoma and chondrosarcoma exist? A review of a large multi-institutional series of malignant matrix-producing breast tumours. AB - The existing literature describing the clinicopathological features and behaviour of matrix-producing (MP) malignant breast tumours presents conflicting results. As a consequence it remains uncertain whether these tumours should be treated as sarcoma and managed by a specialist sarcoma team or treated using the same principles as conventional ductal carcinoma, a dilemma that prompted this study. Improved understanding of the clinicopathological characteristics of primary mammary MP-sarcomas, namely osteosarcoma and chondrosarcoma, is required. METHODS: In this large international multicenter series of malignant MP-tumours of the breast (no = 101) with follow-up information has been assessed and their outcome is compared to other subtypes of metaplastic breast carcinoma (MBC) (no = 253) and to grade, lymph node and hormone receptor-matched ductal breast carcinomas (no = 258). RESULTS: The majority of MP-cancers were associated with epithelial features, which supports the concept that the majority of, if not almost all, primary MP breast sarcomas are of epithelial in origin (MBC). 21% showed nodal metastasis and the distribution of distant metastases resembled conventional mammary carcinoma. The prognosis of MP-MBC is comparable to matched ductal breast carcinoma and slightly better than other subtypes of MBC. Advanced stage (T3&T4) and development of recurrences were predictors of shorter survival in MP-MBC while grade and vascular invasion were not. CONCLUSION: Most malignant MP breast tumours are variants of MBC. MP-MBC with predominant mesenchymal components behaves similar to ductal carcinomas and although data on their response to systemic therapy is limited, there is no evidence that they should be managed differently from other forms of triple negative breast cancer. PMID- 23084963 TI - CpBir1 is required for conidiation, virulence and anti-apoptotic effects and influences hypovirus transmission in Cryphonectria parasitica. AB - Inhibitors of apoptosis proteins (IAPs) are critically important in the regulation of unicellular yeast and metazoan apoptosis. All IAPs contain one to three baculovirus IAP repeat (BIR) domains, which are essential for the anti apoptotic activity of the IAPs. A homolog of IAPs, CpBir1, which bears two BIR domains, was recently identified from the chestnut blight fungus Cryphonectria parasitica genome. CpIAP was deleted by gene replacement, and the phenotypes of DeltaIAP were characterized. CpBir1 was significantly down-regulated by hypovirus infection but up-regulated by H(2)O(2). Similar to Saccharomyces cerevisiae Bir1p, the Cpbir1 mutant was sensitive to H(2)O(2), and constitutive overexpression of CpBir1 increased resistance to H(2)O(2). The Cpbir1 mutant also showed defects in aerial hyphal formation, colony growth, mycelial morphology, conidiogenesis, pigmentation, resistance to stress conditions and virulence. Genetic complementation with native Cpbir1 fully recovered all these defective phenotypes. The CpBir1-eGFP fusion protein was localized to the nucleus in juvenile cultures, while it was found in the cytoplasm in old cultures, suggesting that the localization pattern of CpBir1 may correlate with the process of anti-apoptosis. Increased accumulation of reactive oxygen species (ROS) in the Cpbir1 deletion mutant further supports the anti-apoptotic function of CpBir1. Among five selected vegetative compatible (vc) types of C. parasitica, Cpbir1 deletion was found to block virus from transferring between Cpbir1 mutants. However, hypovirus infected Cpbir1 mutants showed a similar ability to transmit virus to other virus-free isolates compared with the infected wild-type strain. In summary, Cpbir1 encodes an IAP CpBir1 that is down-regulated by hypovirus infection and required for conidiation, virulence and anti-apoptosis, as well as affects hypovirus transmission in chestnut blight fungus C. parasitica. PMID- 23084964 TI - Clinical utility of transcranial direct current stimulation (tDCS) for treating major depression: a systematic review and meta-analysis of randomized, double blind and sham-controlled trials. AB - OBJECTIVE: tDCS is a promising novel therapeutic intervention for major depression (MD). However, clinical trials to date have reported conflicting results concerning its efficacy, which likely resulted from low statistical power. Thus, we carried out a systematic review and meta-analysis on randomized, double-blind and controlled trials of tDCS in MD with a focus on clinically relevant outcomes, namely response and remission rates. METHOD: We searched the literature for English language randomized, double-blind and sham-controlled trials (RCTs) on tDCS for treating MD from 1998 through July 2012 using MEDLINE, EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials and SCOPUS. We also consulted the Web of Science's Citations Index Expanded for the selected RCTs up to July 2012. The main outcome measures were response and remission rates. We used a random-effects model and Odds Ratios (OR). RESULTS: Data were obtained from 6 RCTs that included a total of 200 subjects with MD. After an average of 10.8 +/- 3.76 tDCS sessions, no significant difference was found between active and sham tDCS in terms of both response (23.3% [24/103] vs. 12.4% [12/97], respectively; OR = 1.97; 95% CI = 0.85-4.57; p = 0.11) and remission (12.2% [12/98] vs. 5.4% [5/92], respectively; OR = 2.13; 95% CI = 0.64-7.06; p = 0.22). Also, no differences between mean baseline depression scores and dropout rates in the active and sham tDCS groups were found. Furthermore, sensitivity analyses excluding RCTs that involved less than 10 treatment sessions or stimulus intensity of less than 2 mA did not alter the findings. However, tDCS used as monotherapy was associated with higher response rates when compared to sham tDCS (p = 0.043). Finally, the risk of publication bias in this meta-analysis was found to be low. CONCLUSIONS: The clinical utility of tDCS as a treatment for MD remains unclear when clinically relevant outcomes such as response and remission rates are considered. Future studies should include larger and more representative samples, investigate how tDCS compares to other therapeutic neuromodulation techniques, as well as identify optimal stimulation parameters. PMID- 23084965 TI - Comparing the differential effects of LPA on the barrier function of human pulmonary endothelial cells. AB - Lysophosphatidic acid (LPA) is a class of bioactive lyso-phospholipid that mediates most of its biological effects through a family of G protein-coupled receptors of which six have been identified. The role of the LPA pathway in driving chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) has gained considerable academic and industry attention. Modulation of the pulmonary artery endothelial barrier function by the LPA1 receptor has been shown to drive pulmonary fibrosis in murine models of disease. The purpose of this study was (i) to assess the effect of LPA on the barrier function of human pulmonary arterial (HPAEC) and microvascular (HMVEC) endothelial cells and (ii) to identify the LPA receptor subtype(s) responsible for changes in human pulmonary endothelial cell permeability using LPA receptor antagonists and siRNA technology. Analysis of the LPA receptor subtype expression demonstrated predominant expression of LPA2 and LPA6 receptor subtypes in both HPAECs and HMVECs. HPAECs also exhibit low expression of LPA1, LPA3, and LPA4 receptor subtypes. Treatment of cells with increasing concentrations of LPA caused loss of barrier function in HPAECs but not HMVECs, despite both cell types exhibiting very similar LPA receptor expression profiles. The LPA-mediated loss of barrier function in HPAECs appears to be independent of the LPA1 receptor and likely to be mediated via the LPA6 receptor although we cannot exclude an additional role for the LPA2 and LPA4 receptors in mediating these effects. These results suggest cell-specific mechanisms exist in human pulmonary endothelial cells to permit regulation of barrier function downstream of LPA receptors. More importantly, our data indicate that selective LPA1 receptor antagonism may be insufficient for therapeutic use in pulmonary diseases where impaired endothelial barrier function is related to disease initiation and progression. PMID- 23084967 TI - Carotenoid-protein interaction alters the S(1) energy of hydroxyechinenone in the Orange Carotenoid Protein. AB - The Orange Carotenoid Protein (OCP) is a photoactive water soluble protein that is crucial for photoprotection in cyanobacteria. When activated by blue-green light, it triggers quenching of phycobilisome fluorescence and regulates energy flow from the phycobilisome to the reaction center. The OCP contains a single pigment, the carotenoid 3'-hydroxyechinenone (hECN). Binding to the OCP causes a conformational change in hECN leading to an extension of its effective conjugation length. We have determined the S(1) energy of hECN in organic solvent and compared it with the S(1) energy of hECN bound to the OCP. In methanol and n hexane, hECN has an S(1) energy of 14,300cm(-1), slightly higher than carotenoids with shorter conjugation lengths such as zeaxanthin or beta-carotene; this is consistent with the proposal that the presence of the conjugated carbonyl group in hECN increases its S(1) energy. The S(1) energy of hECN in organic solvent is independent of solvent polarity. Upon binding to the OCP, the S(1) energy of hECN is further increased to 14,700cm(-1), underscoring the importance of protein binding which twists the conjugated carbonyl group into s-trans conformation and enhances the effect of the carbonyl group. Activated OCP, however, has an S(1) energy of 14,000cm(-1), indicating that significant changes in the vicinity of the conjugated carbonyl group occur upon activation. PMID- 23084966 TI - Human conjunctival microvasculature assessed with a retinal function imager (RFI). AB - The conjunctival and cerebral vasculatures share similar embryological origins, with similar structural and physiological characteristics. Tracking the conjunctival microvasculature may provide useful information for predicting the onset, progression and prognosis of both systemic and central nervous system (CNS) vascular diseases. The bulbar conjunctival vasculature was imaged using a retinal function imager (RFI, Optical Imaging Ltd, Rehovot, Israel). Hemoglobin in red blood cells was used as an intrinsic motion-contrast agent in the generation of detailed noninvasive capillary-perfusion maps (nCPMs) and the calculation of the blood flow velocity. Five healthy subjects were imaged under normal conditions and again under the stress condition of wearing a contact lens. The retina was also imaged in one eye of one subject for comparison. The nCPMs showed the conjunctival microvasculature in exquisite detail, which appeared as clear as the retinal nCPMs. The blood flow velocities in the temporal conjunctival microvasculature were 0.86+/-0.08 (mean+/-SD, mm/s) for the bare eye and 0.99+/-0.11 mm/s with contact lens wear. It is feasible to use RFI for imaging the conjunctival vasculature. PMID- 23084968 TI - Psb28 is involved in recovery of photosystem II at high temperature in Synechocystis sp. PCC 6803. AB - Psb28 is an extrinsic protein of photosystem II (PSII), which is conserved among photosynthetic organisms from cyanobacteria to higher plants. A unicellular cyanobacterium, Synechocystis sp. PCC 6803, has two homologs of Psb28, Psb28-1 and Psb28-2. However, the role of these proteins remains poorly understood. In this study, we disrupted the psb28-1 (sll1398) and psb28-2 (slr1739) genes in wild-type Synechocystis sp. PCC 6803 and examined their photosynthetic properties to elucidate the physiological role of Psb28 in photosynthesis. We also disrupted the psb28-1 gene in a dgdA mutant defective in the biosynthesis of digalactosyldiacylglycerol, in which Psb28-1 significantly accumulates in PSII. The disruption of the psb28-1 gene in the wild-type resulted in growth retardation under high-light conditions at high temperatures with a low rate of restoration of photodamaged photosynthetic machinery. Similar phenomena were observed at normal growth temperatures in the psb28-1/dgdA double mutant. In contrast, disruption of psb28-2 in the wild-type and dgdA mutant did not affect host strain phenotype, suggesting that Psb28-2 does not contribute to the recovery of PSII. In addition, protein analysis using strains expressing His tagged Psb28-1 revealed that Psb28-1 is mainly associated with the CP43-less PSII monomer. In the dgdA mutant, the CP43-less PSII monomer accumulated to a greater extent than in the wild-type, and its accumulation caused greater accumulation of Psb28-1 in PSII. These results demonstrate that Psb28-1 plays an important role in PSII repair through association with the CP43-less monomer, particularly at high temperatures. PMID- 23084969 TI - Invasive aspergillosis in patients with hematological malignancies in the Czech and Slovak republics: Fungal InfectioN Database (FIND) analysis, 2005-2009. AB - OBJECTIVES: To evaluate risk factors, diagnostic procedures, and treatment outcomes of invasive aspergillosis (IA) in patients with hematological malignancies. METHODS: A retrospective analysis of data from proven/probable IA cases that occurred from 2005 to 2009 at 10 hematology centers was performed. RESULTS: We identified 176 IA cases that mainly occurred in patients with acute leukemias (58.5%), mostly those on induction/re-induction treatments (39.8%). Prolonged neutropenia was the most frequent risk factor for IA (61.4%). The lungs were the most frequently affected site (93.8%) and computed tomography detected abnormalities in all episodes; however, only 53.7% of patients had findings suggestive of IA. Galactomannan (GM) detection in serum or bronchoalveolar lavage fluid (positive in 79.1% and 78.8% of episodes, respectively) played a crucial role in IA diagnosis. Neutrophil count and antifungal prophylaxis did not influence the GM positivity rate, but empirical therapy decreased this rate (in serum). Of the IA cases, 53.2% responded to initial antifungal therapy. The combination of voriconazole and echinocandin, even as initial or salvage therapy, did not perform better than voriconazole monotherapy (p=0.924 for initial therapy and p=0.205 for salvage therapy). Neutrophil recovery had a significant role in the response to initial (but not salvage) antifungal therapy. CONCLUSIONS: Our retrospective analysis identified key diagnostic and treatment characteristics, and this understanding could improve the management of hematological malignancy patients with IA. PMID- 23084970 TI - Emergence of the OXA-23 carbapenemase-encoding gene in multidrug-resistant Acinetobacter baumannii clinical isolates from the Principal Hospital of Dakar, Senegal. PMID- 23084971 TI - Early sensory cortex is activated in the absence of explicit input during crossmodal item retrieval: evidence from MEG. AB - Crossmodal associations form a fundamental aspect of our daily lives. In this study we investigated the neural correlates of crossmodal association in early sensory cortices using magnetoencephalography (MEG). We used a paired associate recognition paradigm in which subjects were tested after multiple training sessions over a span of four weeks. Subjects had to learn 12 abstract, nonlinguistic, pairs of auditory and visual objects that consisted of crossmodal (visual-auditory, VA; auditory-visual, AV) and unimodal (visual-visual, VV; auditory-auditory, AA) paired items. Visual objects included abstract, non nameable, fractal-like images, and auditory objects included abstract tone sequences. During scanning, subjects were shown the first item of a pair (S1), followed by a delay, then the simultaneous presentation of a visual and auditory stimulus (S2). Subjects were instructed to indicate whether either of the S2 stimuli contained the correct paired associate of S1. Synthetic aperture magnetometry (SAMspm), a minimum variance beamformer, was then used to assess source power differences between the crossmodal conditions and their corresponding unimodal conditions (i.e., AV-AA and VA-VV) in the beta (15-30 Hz) and low gamma frequencies (31-54 Hz) during the S1 period. We found greater power during S1 in the corresponding modality-specific association areas for crossmodal compared with unimodal stimuli. Thus, even in the absence of explicit sensory input, the retrieval of well-learned, crossmodal pairs activate sensory areas associated with the corresponding modality. These findings support theories which posit that modality-specific regions of cortex are involved in the storage and retrieval of sensory-specific items from long-term memory. PMID- 23084972 TI - Prevention of postoperative acute kidney injury: one step closer. PMID- 23084973 TI - Orientation of internal signal-anchor sequences at the Sec61 translocon. AB - Translocation and insertion of secretory and membrane proteins at the endoplasmic reticulum are mediated by the Sec61 translocon. Evidence from in vivo as well as in vitro experiments indicates that N-terminal signal-anchor sequences initially insert N-first before they invert their orientation to translocate the C terminus. Inversion is driven by flanking charges according to the positive inside rule and inhibited by increased signal hydrophobicity. Here, we show that upon extending the N-terminal hydrophilic domain preceding the signal core to more than ~20 residues, the insertion behavior changes. Apparent signal inversion and the effect of hydrophobicity are largely lost, suggesting that N-first insertion is limited to N-terminal signal anchors. Extended N-domains sterically hinder N-translocation in a length-dependent manner also for reverse signal anchors with inverted flanking charges. The results indicate a mechanistic difference in the insertion process of N-terminal and internal signal sequences. PMID- 23084974 TI - Loss of structure-gain of function. PMID- 23084975 TI - Protein quality control in the intermembrane space of mitochondria. PMID- 23084977 TI - Ovulation induction in the management of anovulatory polycystic ovary syndrome. AB - The aim of this brief review is to describe the management of anovulatory infertility in the polycystic ovary syndrome (PCOS). This has traditionally involved the use of clomiphene citrate (CC), and then gonadotropin therapy or laparoscopic ovarian surgery, in those who are clomiphene resistant (The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008). Recently developed therapeutic approaches include aromatase inhibitors and the potential use of in vitro maturation (IVM) of oocytes collected from unstimulated (or minimally stimulated) polycystic ovaries. Unfortunately the early promise of the insulin sensitizing drugs has not been translated into significant improvement in outcomes and therefore are not prescribed unless the patient has an impairment of glucose tolerance (The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008). There has been an unfortunate shift away from Mono-follicular ovulation induction remains the first line approach for the management of anovulatory PCOS, and in vitro fertilization treatment (IVF) should be reserved for those who fail to respond or who have additional infertility factors (The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, 2008). Superovulation for IVF presents significant risks for women with polycystic ovaries, namely the potentially life-threatening complication of ovarian hyperstimulation syndrome (OHSS). Carefully conducted and monitored ovulation induction can achieve good cumulative conception rates and furthermore, multiple pregnancy rates can be minimized with strict adherence to criteria that limit the number of follicles that are permitted to ovulate. PMID- 23084978 TI - Adipocyte biology in polycystic ovary syndrome. AB - Polycystic Ovary Syndrome (PCOS) is a common endocrinopathy that is associated with an adverse metabolic profile including insulin resistance. There is a clear association between obesity, the development of PCOS and the severity of its phenotypic, biochemical and metabolic features. Evidence to support this link includes data from epidemiological, pathophysiological and genetic studies. Given the importance of obesity in the development and manifestation of PCOS, ongoing research into the many facets of adipocyte biology in women with the condition is important and should continue to be a priority. In this review article, we discuss the existing literature on fat distribution, adipokines, adipocyte hypertrophy and adipocyte steroid metabolism in women with PCOS. PMID- 23084976 TI - Sheep models of polycystic ovary syndrome phenotype. AB - Polycystic ovary syndrome (PCOS) is a fertility disorder affecting 5-7% of reproductive-aged women. Women with PCOS manifest both reproductive and metabolic defects. Several animal models have evolved, which implicate excess steroid exposure during fetal life in the development of the PCOS phenotype. This review addresses the fetal and adult reproductive and metabolic consequences of prenatal steroid excess in sheep and the translational relevance of these findings to PCOS. By comparing findings in various breeds of sheep, the review targets the role of genetic susceptibility to fetal insults. Disruptions induced by prenatal testosterone excess are evident at both the reproductive and metabolic level with each influencing the other thus creating a self-perpetuating vicious cycle. The review highlights the need for identifying a common mediator of the dysfunctions at the reproductive and metabolic levels and developing prevention and treatment interventions targeting all sites of disruption in unison for achieving optimal success. PMID- 23084979 TI - HSP70 increases extracellular matrix production by human vascular smooth muscle through TGF-beta1 up-regulation. AB - The circulating levels of heat shock proteins (HSP) are increased in cardiovascular diseases; however, the implication of this for the fibrotic process typical of such diseases remains unclear. HSP70 can interact with the vascular smooth muscle cells (SMC), the major producer of extracellular matrix (ECM) proteins, through the Toll-like receptors 4 (TLR4). The transforming growth factor type-beta1 (TGF-beta1) is a well known vascular pro-fibrotic cytokine that is regulated in part by AP-1-dependent transcriptional mechanisms. We hypothesized that extracellular HSP70 could interact with SMCs, inducing TGF beta1 synthesis and subsequent changes in the vascular ECM. We demonstrate that extracellular HSP70 binds to human aorta SMC TLR4, which up-regulates the AP-1 dependent transcriptional activity of the TGF-beta1 promoter. This is achieved through the mitogen activated protein kinases JNK and ERK, as demonstrated by the use of specific blockers and the knockdown of TLR4 with specific small interfering RNAs. The TGF-beta1 upregulation increase the expression of the ECM proteins type I collagen and fibronectin. This novel observation may elucidate the mechanisms by which HSP70 contributes in the inflammation and fibrosis present in atherosclerosis and other fibrosis-related diseases. PMID- 23084980 TI - Epigenetics, autoimmunity and hematologic malignancies: a comprehensive review. AB - The relationships between immunological dysfunction, loss of tolerance and hematologic malignancies have been a focus of attention in attempts to understand the appearance of a higher degree of autoimmune disease and lymphoma in children with congenital immunodeficiency. Although multiple hypotheses have been offered, it is clear that stochastic processes play an important role in the immunopathology of these issues. In particular, accumulating evidence is defining a role of epigenetic mechanisms as being critical in this continuous spectrum between autoimmunity and lymphoma. In this review, we focus attention predominantly on the relationships between T helper 17 (Th17) and T regulatory populations that alter local microenvironments and ultimately the expression or transcription factors involved in cell activation and differentiation. Abnormal expression in any of the molecules involved in Th17 and/or Treg development alter immune homeostasis and in genetically susceptible hosts may lead to the appearance of autoimmunity and/or lymphoma. These observations have clinical significance in explaining the discordance of autoimmunity in identical twins. They are also particularly important in the relationships between primary immune deficiency syndromes, immune dysregulation and an increased risk of lymphoma. Indeed, defining the factors that determine epigenetic alterations and their relationships to immune homeostasis will be a challenge greater or even equal to the human genome project. PMID- 23084982 TI - Deciphering the impact of cerebellar and basal ganglia dysfunction in accuracy and variability of motor timing. AB - Studies in motor timing have shown that the basal ganglia and cerebellum play an important role in temporal processing. Timing studies in Cerebellar/ataxic Disorders (CD) and Parkinson's disease (PD) patients contrast the roles of the cerebellum and basal ganglia in motor timing. Here, we used a synchronization continuation task to compare accuracy and variability of motor timing during repetitive tapping. We compared data collected for the present study - from patients with CD and healthy controls - to data from a previous study with patients with PD. We asked participants to tap at Inter-stimulus Intervals (ISIs) of 250, 500, 1000, and 2000 ms. Using Linear Mixed Models (LMMs), we explored how ISI, Task Phase, and Diagnosis interacted to determine the (i) the accuracy and (ii) the variability of tapping. In our analysis of accuracy, we found evidence that during the synchronization phase, at ISI=250 ms, CD patients lagged 'behind the beat'; whereas our previous work has suggested that medicated PD patients hasten 'ahead of the beat'. In our analysis of variability, we observed that at ISIs below 1000 ms, CD patients showed greater variability in motor timing than the healthy controls, while PD patients showed less variability than CD patients and healthy controls during the synchronization phase at the 1000 ms ISI. These results highlight the differential performance on explicit motor timing between patients with disorders of the cerebellum and basal ganglia. Our results illustrate a novel approach to discerning cognitive control of motor timing. PMID- 23084983 TI - Food insecurity: its relationship to dietary intake and body weight among Somali refugee women in the United States. AB - OBJECTIVE: To examine the association between food insecurity, dietary intake, and body mass index among Somali refugee women living in the United States. METHODS: Cross-sectional study utilizing the snowball sampling method. RESULTS: Most (67%) participants experienced some level of food insecurity, which was common among recent arrivals and those who spoke only Somali at home (P < .05). Intake of meat and eggs was higher, whereas intake of fruits and vegetables was lower, among food insecure than secure participants. Food insecurity was positively related to overweight and obesity (odds ratio: 2.66; confidence interval: 1.25-5.69; P < .01). CONCLUSIONS AND IMPLICATIONS: Somali refugees experienced high levels of food insecurity upon resettlement. Poor dietary habits and the high overweight/obesity rate among insecure families call for future research in understanding what role family structure, cultural norms, and food preference play in predicting food security and dietary habits among Somali and overall African refugees in the United States. PMID- 23084981 TI - Oscillatory activity during maintenance of spatial and temporal information in working memory. AB - Working memory (WM) processes help keep information in an active state so it can be used to guide future behavior. Although numerous studies have investigated brain activity associated with spatial WM in humans and monkeys, little research has focused on the neural mechanisms of WM for temporal order information, and how processing of temporal and spatial information might differ. Available evidence indicates that similar frontoparietal regions are recruited during temporal and spatial WM, although there are data suggesting that they are distinct processes. The mechanisms that allow for differential maintenance of these two types of information are unclear. One possibility is that neural oscillations may differentially contribute to temporal and spatial WM. In the present study, we used scalp electroencephalography (EEG) to compare patterns of oscillatory activity during maintenance of spatial and temporal information in WM. Time-frequency analysis of EEG data revealed enhanced left frontal theta (5-8 Hz), enhanced posterior alpha (9-12 Hz), and enhanced left posterior beta (14-28 Hz) power during the delay period of correct temporal order trials compared to correct spatial trials. In contrast, gamma (30-50 Hz) power at right lateral frontal sites was increased during the delay period of spatial WM trials, as compared to temporal WM trials. The present results are consistent with the idea that neural oscillatory patterns provide distinct mechanisms for the maintenance of temporal and spatial information in WM. Specifically, theta oscillations are most critical for the maintenance of temporal information in WM. Possible roles of higher frequency oscillations in temporal and spatial memory are also discussed. PMID- 23084984 TI - Both acute and subchronic treatments with pindolol, a 5-HT(1A) and beta1 and beta2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: an autoradiographic study. AB - Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT(1A) and 5-HT(1B) autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5 HT(1A/1B,) beta1 and beta2 adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague-Dawley (SPD) rats (180-220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using alpha-[14C]methyl-L-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini-Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra--pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT(1A/1B) receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment. PMID- 23084985 TI - Aldo-keto reductases mediate constitutive and inducible protection against aldehyde toxicity in human neuroblastoma SH-SY5Y cells. AB - Reactive aldehydes including methyl glyoxal, acrolein and 4-hydroxy-2-nonenal (4 HNE) have been implicated in the progression of neurodegenerative diseases. The reduction of aldehydes to alcohols by the aldo-keto reductase (AKR) family of enzymes may represent an important detoxication route within neuronal cells. In this study, the ability of AKR enzymes to protect human neuroblastoma SH-SY5Y cells against reactive aldehydes was assessed. Using gene-specific RNA interference (RNAi), we report that AKR7A2 makes a significant contribution to the reduction of methyl glyoxal in SH-SY5Y cells, with its knockdown altering the IC(50) from 410 to 25.8MUM, and that AKR1C3 contributes to 4-HNE reduction, with its knockdown lowering the IC(50) from 1.25 to 0.58MUM. In addition, we have shown that pretreatment of cells with sub-lethal concentrations of 4-HNE or methyl glyoxal leads to a significant increase in IC(50) when cells are exposed to higher concentrations of the toxic aldehyde. The IC(50) for methyl glyoxal increased from 410MUM to 1.9mM, and the IC(50) for 4-HNE increased from 120 to 690nM. To investigate this protection, we show that pretreatment of cells with the AKR inhibitor sorbinil lead to decreased resistance to aldehydes. We show that AKR1C can be induced 8-fold in SH-SY5Y cells by treatment with sub-lethal concentrations of methyl glyoxal, and 5-fold by 4-HNE treatment. AKR1B is not induced by methyl glyoxal but is induced 10-fold by 4-HNE treatment. Furthermore, we have shown that this adaptive response can also be induced using the chemoprotective agent tert-butyl hydroquinone (t-BHQ), and that this also evokes an increase in the expression and activity of AKR1B and AKR1C. These findings highlight the potential for the interventional upregulation of AKR via non-toxic derivatives or natural compounds as a novel therapeutic approach towards the detoxication of aldehydes, with the aim of halting the progression of aldehyde dependent neurodegenerative diseases. PMID- 23084986 TI - Effects of acute and chronic low density lipoprotein exposure on neutrophil function. AB - Mounting evidence suggests that obesity and the metabolic syndrome have significant but often divergent effects on the innate immune system. These effects have been best established in monocytes and macrophages, particularly as a consequence of the hypercholesterolemic state. We have recently described defects in neutrophil function in the setting of both obesity and hypercholesterolemia, and hypothesized that exposure to elevated levels of lipoproteins, particularly LDL its oxidized forms, contributed to these defects. As a model of chronic cholesterol exposure, we examined functional responses of bone marrow neutrophils isolated from non-obese mice with diet-induced hypercholesterolemia compared to normal cholesterol controls. Chemotaxis, calcium flux, CD11b display, and F-actin polymerization were assayed in response to several chemoattractants, while neutrophil cytokine transcriptional response was determined to LPS. Following this, the acute effects of isolated LDL and its oxidized forms on normal neutrophils were assayed using the same functional assays. We found that neutrophils from non-obese hypercholesterolemic mice had blunted chemotaxis, altered calcium flux, and normal to augmented CD11b display with prolonged actin polymerization in response to stimuli. In response to acute exposure to lipoproteins, neutrophils showed chemotaxis to LDL which increased with the degree of LDL oxidation. Paradoxically, LDL oxidation yielded the opposite effect on LDL-induced CD11b display and actin polymerization, and both native and oxidized LDL were found to induce neutrophil transcription of the monocyte chemoattractant MCP-1. Together these findings suggest that chronic hypercholesterolemia impairs neutrophil functional responses, and these defects may be in part due to protracted signaling responses to LDL and its oxidized forms. PMID- 23084987 TI - [Pediatric Hodgkin disease in North Tunisia: clinical and therapeutic study]. AB - PURPOSE: To assess the epidemiological, clinical and therapeutic aspects of pediatric Hodgkin disease (HD) and to study prognosis factors. PATIENTS AND METHODS: We retrospectively reviewed the medical records of children (<=18 years) with HD treated between 1st January 1994 and 31st December 2004. Chemotherapy was undertaken in different departments of hematology and oncology in the North of the country and radiotherapy was centralized at the Salah-Azaiz National Cancer Institute. RESULTS: One hundred fourteen consecutively treated patients were collected. Median age was 12 years (4-18 years) and sex-ratio was 2.25. Peripheral lymphadenopathy was the predominant circumstance of HD detection (82.5%). The predominant histologic type was nodular sclerosing (56%). Treatment included chemotherapy and involved-field radiotherapy. With a mean follow-up of 23.5 months, relapse rate was 12.2%. Five-year overall survival (OS) and event free survival (EFS) rates were 95% and 76%, respectively. Five-year OS was 98.2% and 90.8% for early and advanced stages respectively. In multivariate analysis, stage IV (P=0.029) and early response to initial treatment (P=0.003) retained statistical significance for EFS whereas the only prognostic factor for OS was stage IV (P=0.002). The long-term side effects were rare. No secondary tumor was noted. CONCLUSION: Combined-modality therapy using chemotherapy and involved field radiotherapy was effective and well-tolerated in early stage pediatric HD. Stage IV patients should be referred to specialized units for intensive treatment. The short median follow-up in our study cannot allow considering long term effects. PMID- 23084988 TI - Rapid whisker movements in sleeping newborn rats. AB - Spontaneous activity in the sensory periphery drives infant brain activity and is thought to contribute to the formation of retinotopic and somatotopic maps. In infant rats during active (or REM) sleep, brainstem-generated spontaneous activity triggers hundreds of thousands of skeletal muscle twitches each day; sensory feedback from the resulting limb movements is a primary activator of forebrain activity. The rodent whisker system, with its precise isomorphic mapping of individual whiskers to discrete brain areas, has been a key contributor to our understanding of somatotopic maps and developmental plasticity. But although whisker movements are controlled by dedicated skeletal muscles, spontaneous whisker activity has not been entertained as a contributing factor to the development of this system. Here we report in 3- to 6-day-old rats that whiskers twitch rapidly and asynchronously during active sleep; furthermore, neurons in whisker thalamus exhibit bursts of activity that are tightly associated with twitches but occur infrequently during waking. Finally, we observed barrel-specific cortical activity during periods of twitching. This is the first report of self-generated, sleep-related twitches in the developing whisker system, a sensorimotor system that is unique for the precision with which it can be experimentally manipulated. The discovery of whisker twitching will allow us to attain a better understanding of the contributions of peripheral sensory activity to somatosensory integration and plasticity in the developing nervous system. PMID- 23084989 TI - Organelle size equalization by a constitutive process. AB - How cells control organelle size is an elusive problem. Two predominant models for size control can be distinguished: (1) induced control, where organelle genesis, maintenance, and disassembly are three separate programs that are activated in response to size change, and (2) constitutive control, where stable size results from the balance between continuous organelle assembly and disassembly. The problem has been studied in Chlamydomonas reinhardtii because the flagella are easy to measure, their size changes only in the length dimension, and the genetics are comparable to yeast. Length dynamics in Chlamydomonas flagella are quite robust: they maintain a length of about 12 MUm and recover from amputation in about 90 min with a growth rate that decreases smoothly to zero as the length approaches 12 MUm. Despite a wealth of experimental studies, existing data are consistent with both induced and constitutive control models for flagella. Here we developed novel microfluidic trapping and laser microsurgery techniques in Chlamydomonas to distinguish between length control models by measuring the two flagella on a single cell as they equilibrate after amputation of a single flagellum. The results suggest that cells equalize flagellar length by constitutive control. PMID- 23084990 TI - Localized tensional forces on PECAM-1 elicit a global mechanotransduction response via the integrin-RhoA pathway. AB - BACKGROUND: Mechanical forces regulate cell behavior and function during development, differentiation, and tissue morphogenesis. In the vascular system, forces produced by blood flow are critical determinants not only of morphogenesis and function, but also of pathological states such as atherosclerosis. Endothelial cells (ECs) have numerous mechanotransducers, including platelet endothelial cell adhesion molecule-1 (PECAM-1) at cell-cell junctions and integrins at cell-matrix adhesions. However, the processes by which forces are transduced to biochemical signals and subsequently translated into downstream effects are poorly understood. RESULTS: Here, we examine mechanochemical signaling in response to direct force application on PECAM-1. We demonstrate that localized tensional forces on PECAM-1 result in, surprisingly, global signaling responses. Specifically, force-dependent activation of phosphatidylinositol 3 kinase (PI3K) downstream of PECAM-1 promotes cell-wide activation of integrins and the small GTPase RhoA. These signaling events facilitate changes in cytoskeletal architecture, including growth of focal adhesions and adaptive cytoskeletal stiffening. CONCLUSIONS: Taken together, our work provides the first evidence of a global signaling event in response to a localized mechanical stress. In addition, these data provide a possible mechanism for the differential stiffness of vessels exposed to distinct hemodynamic force patterns in vivo. PMID- 23084991 TI - BLOC-3 mutated in Hermansky-Pudlak syndrome is a Rab32/38 guanine nucleotide exchange factor. AB - Hermansky-Pudlak syndrome (HPS) is a human disease characterized by partial loss of pigmentation and impaired blood clotting. These symptoms are caused by defects in the biogenesis of melanosomes and platelet dense granules, often referred to as lysosome-related organelles. Genes mutated in HPS encode subunits of the biogenesis of lysosome-related organelles complexes (BLOCs). BLOC-1 and BLOC-2, together with the AP-3 clathrin adaptor complex, act at early endosomes to sort components required for melanin formation and melanosome biogenesis away from the degradative lysosomal pathway toward early stage melanosomes. However the molecular functions of the Hps1-Hps4 complex BLOC-3 remain mysterious. Like other trafficking pathways, melanosome biogenesis and transport of enzymes involved in pigmentation involves specific Rab GTPases, in this instance Rab32 and Rab38. We now demonstrate that BLOC-3 is a Rab32 and Rab38 guanine nucleotide exchange factor (GEF). Silencing of the BLOC-3 subunits Hps1 and Hps4 results in the mislocalization of Rab32 and Rab38 and reduction in pigmentation. In addition, we show that BLOC-3 can promote specific membrane recruitment of Rab32/38. BLOC-3 therefore defines a novel Rab GEF family with a specific function in the biogenesis of lysosome-related organelles. PMID- 23084992 TI - Neuronal circuits underlying persistent representations despite time varying activity. AB - BACKGROUND: Our brains are capable of remarkably stable stimulus representations despite time-varying neural activity. For instance, during delay periods in working memory tasks, while stimuli are represented in working memory, neurons in the prefrontal cortex, thought to support the memory representation, exhibit time varying neuronal activity. Since neuronal activity encodes the stimulus, its time varying dynamics appears to be paradoxical and incompatible with stable network stimulus representations. Indeed, this finding raises a fundamental question: can stable representations only be encoded with stable neural activity, or, its corollary, is every change in activity a sign of change in stimulus representation? RESULTS: Here we explain how different time-varying representations offered by individual neurons can be woven together to form a coherent, time-invariant, representation. Motivated by two ubiquitous features of the neocortex-redundancy of neural representation and sparse intracortical connections-we derive a network architecture that resolves the apparent contradiction between representation stability and changing neural activity. Unexpectedly, this network architecture exhibits many structural properties that have been measured in cortical sensory areas. In particular, we can account for few-neuron motifs, synapse weight distribution, and the relations between neuronal functional properties and connection probability. CONCLUSIONS: We show that the intuition regarding network stimulus representation, typically derived from considering single neurons, may be misleading and that time-varying activity of distributed representation in cortical circuits does not necessarily imply that the network explicitly encodes time-varying properties. PMID- 23084993 TI - Longer life span evolves under high rates of condition-dependent mortality. AB - Aging affects nearly all organisms, but how aging evolves is still unclear. The central prediction of classic theory is that high extrinsic mortality leads to accelerated aging and shorter intrinsic life span. However, this prediction considers mortality as a random process, whereas mortality in nature is likely to be condition dependent. Therefore, the novel theory maintains that condition dependence may dramatically alter, and even reverse, the classic pattern. We present experimental evidence for the evolution of longer life span under high condition-dependent mortality. We employed an experimental evolution design, using a nematode, Caenorhabditis remanei, that allowed us to disentangle the effects of mortality rate (high versus low) and mortality source (random versus condition dependent). We observed the evolution of shorter life span under high random mortality, confirming the classic prediction. In contrast, high condition dependent mortality led to the evolution of longer life span, supporting a key role of condition dependence in the evolution of aging. This life-span extension was not the result of a trade-off with reproduction. By simultaneously corroborating the classic results [8-10] and providing the first experimental evidence for the novel theory, our study resolves apparent contradictions in the study of aging and challenges the traditional paradigm by demonstrating that condition-environment interactions dictate the evolutionary trajectory of aging. PMID- 23084994 TI - The first stalk-eyed phosphatocopine crustacean from the Lower Cambrian of China. AB - Exhibiting Orsten-type preservation, specimens of the phosphatocopine Dabashanella sp. from the Lower Cambrian Stage 3 (about 520 million years ago) of southern China possess a single-fold shield and a set of appendages of crustacean design. More significantly, a pair of stalked eyes-the earliest known visual structure in this group-is attached to an ocular segment analogous to the anterior sclerite of various stem-group arthropods. Accordingly, a unique visual system must have been present among some, if not all, early phosphatocopines. In comparison with the ground pattern of later members of this group, the new phosphatocopine, which with its unique head segmentation and limb design is unlikely to be embraced within the previously proposed Labrophora, demonstrates a remarkable modification and innovation in the appendages and visual system with time. Thus, this finding provides new data for the evaluation of the early evolutionary development and phylogenetics of the Crustacea and other related euarthropods. PMID- 23084996 TI - Improved patient-specific calibration for agent-based cancer modeling. PMID- 23084997 TI - On the relation between reactions and complexes of (bio)chemical reaction networks. AB - Robustness of biochemical systems has become one of the central questions in systems biology although it is notoriously difficult to formally capture its multifaceted nature. Maintenance of normal system function depends not only on the stoichiometry of the underlying interrelated components, but also on the multitude of kinetic parameters. Invariant flux ratios, obtained within flux coupling analysis, as well as invariant complex ratios, derived within chemical reaction network theory, can characterize robust properties of a system at steady state. However, the existing formalisms for the description of these invariants do not provide full characterization as they either only focus on the flux centric or the concentration-centric view. Here we develop a novel mathematical framework which combines both views and thereby overcomes the limitations of the classical methodologies. Our unified framework will be helpful in analyzing biologically important system properties. PMID- 23084995 TI - Lipid droplets control the maternal histone supply of Drosophila embryos. AB - BACKGROUND: Histones are essential for chromatin packing, yet free histones not incorporated into chromatin are toxic. While in most cells multiple regulatory mechanisms prevent accumulation of excess histones, early Drosophila embryos contain massive extranuclear histone stores, thought to be essential for development. Excess histones H2A, H2B, and H2Av are bound to lipid droplets, ubiquitous fat storage organelles especially abundant in embryos. It has been proposed that sequestration on lipid droplets allows safe transient storage of supernumerary histones. RESULTS: Here, we critically test this sequestration hypothesis. We find that histones are anchored to lipid droplets via the previously uncharacterized protein Jabba: Jabba localizes to droplets, coimmunoprecipitates with histones, and is necessary to recruit histones to droplets. Jabba mutants lack the maternal H2A, H2B, and H2Av deposits altogether; presumably, these deposits are eliminated unless sequestered on droplets. Jabba mutant embryos compensate for this histone deficit by translating maternal histone mRNAs. However, when histone expression is mildly compromised, the maternal histone protein deposits are essential for proper early mitoses and for viability. CONCLUSIONS: A growing number of proteins from other cellular compartments have been found to transiently associate with lipid droplets. Our studies provide the first insight into mechanism and functional relevance of this sequestration. We conclude that sequestration on lipid droplets allows embryos to build up extranuclear histone stores and provides histones for chromatin assembly during times of high demand. This work reveals a novel aspect of histone metabolism and establishes lipid droplets as functional storage sites for unstable or detrimental proteins. PMID- 23084998 TI - Renaissance model of an epidemic with quarantine. AB - Quarantine is one possible solution to limit the propagation of an emerging infectious disease. Typically, infected individuals are removed from the population by avoiding physical contact with healthy individuals. A key factor for the success of a quarantine strategy is the carrying capacity of the facility. This is often a known parameter, while other parameters such as those defining the population structure are more difficult to assess. Here we develop a model where we explicitly introduce the carrying capacity of the quarantine facility into a susceptible-infected-recovered (SIR) framework. We show how the model can address the propagation and control of contact and sexually transmitted infections. We illustrate this by a case study of the city of Zurich during the 16th century, when it had to face an epidemic of syphilis. After Swiss mercenaries came back from a war in Naples in 1495, the authorities of the city addressed subsequent epidemics by, among others, placing infected members of the population in quarantine. Our results suggest that a modestly sized quarantine facility can successfully prevent or reduce an epidemic. However, false detection can present a real impediment for this solution. Indiscriminate quarantine of individuals can lead to the overfilling of the facility, and prevent the intake of infected individuals. This results in the failure of the quarantine policy. Hence, improving the rate of true over false detection becomes the key factor for quarantine strategies. Moreover, in the case of sexually transmitted infections, asymmetries in the male to female ratio, and the force of infection pertaining to each sex and class of sexual encounter can alter the effectiveness of quarantine measures. For example, a heterosexually transmitted disease that mainly affects one sex is harder to control in a population with more individuals of the opposite sex. Hence an imbalance in the sex ratios as seen in situations such as mining colonies, or populations at war, can present impediments for the success of quarantine policies. PMID- 23084999 TI - Mutual inhibition through hybrid oligomer formation of daptomycin and the semisynthetic lipopeptide antibiotic CB-182,462. AB - Daptomycin is a clinically important lipopeptide antibiotic that kills Gram positive bacteria through membrane depolarization. Its activity requires calcium and the presence of phosphatidylglycerol in the target membrane. Calcium and phosphatidylglycerol also promote the formation of daptomycin oligomers, which have been assumed but not proven to be required for the bactericidal effect. Daptomycin shares substantial structural similarity with another lipopeptide antibiotic, A54145; the two have identical amino acid residues in 5 out of 13 positions and similar ones in 4 more positions. We here examined whether these conserved residues are sufficient for oligomer formation. To this end, we used fluorescence energy transfer and excimer fluorescence to detect hybrid oligomers of daptomycin and CB-182,462, a semisynthetic derivative of A54145. Mixtures of the two compounds indeed produced hybrid oligomers, but at the same time displayed a significantly less than additive antibacterial activity against Bacillus subtilis. The existence of functionally impaired oligomers indicates that oligomer formation is indeed important for antibacterial function. However, it also shows that oligomerization is not sufficient; once formed, the oligomers must take another step in order to acquire antibacterial activity. Thus, the amino acid residues shared between daptomycin and CB-182,462 suffice for formation of the oligomer, but not for its subsequent activation. PMID- 23085000 TI - The molecular organization of prenylated flavonoid xanthohumol in DPPC multibilayers: X-ray diffraction and FTIR spectroscopic studies. AB - Xanthohumol (XN) is the major prenylated flavonoid found in hop resin. It has attracted considerable attention in recent years due to its wide spectrum of biological activities and the beneficial effect on human health. Since lipid membrane is first target for biologically active compounds, we decided to investigate the influence of XN on the dipalmitoylphosphatidylcholine (DPPC) multibilayers. Interactions of XN with DPPC were investigated as a function of temperature and its concentration by using X-ray diffraction and the ATR-FTIR spectroscopy techniques. The aim of understanding the mechanisms of molecular interactions between XN and DPPC was to indicate the localization of the XN with respect to the membrane and the type of interaction with phospholipids. The results revealed that XN changes the physical properties of the DPPC multibilayers in the form of dry film. A new complex formation between XN and DPPC is reported. The detailed analysis of refraction effect indicates the changes in electron density ratio between hydrophobic and hydrophilic zones of lipid at phase transition. This is in compliance with reported changes in FTIR spectra where at pretransition XN moves from interface region between polar heads to the neighborhood of phosphate groups. PMID- 23085001 TI - Antimicrobial and cell-penetrating properties of penetratin analogs: effect of sequence and secondary structure. AB - Cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) show great potential as drug delivery vectors and new antibiotic drug entities, respectively. The current study deals with the properties of a variety of peptide analogs derived from the well-known CPP penetratin as well as octaarginine and different Tat sequences. The effects of peptide length, guanidinium content, and sequence of non-cationic residues were assessed in mammalian and bacterial cells. The arginine (Arg) content in the penetratin analogs was found to influence eukaryotic cell uptake efficiency, antimicrobial activity towards both Gram positive and Gram-negative bacteria as well as eukaryotic cell viability. All examined analogs retained the ability to cross eukaryotic membranes giving rise to a distribution within the vacuolar apparatus. Interestingly, a series of shuffled analogs of penetratin with the cationic residues in conserved positions, attain the same alpha-helical conformation as native penetratin in the presence of cholesterol-containing liposomes, while conformational differences were observed in the presence of highly anionic liposomes. While the antibacterial effect of the two groups of peptides was similar, the eukaryotic cellular uptake of the shuffled analogs was noticeably lower than for native penetratin. Moreover, a point substitution of Met to Leu in native penetratin had no influence on eukaryotic cellular uptake and antimicrobial effect, and only a minor effect on cytotoxicity, in contrast to the fact that the same substitution in the shuffled analog gave rise to reduced eukaryotic cellular uptake while increasing the antibacterial effect and cytotoxicity. PMID- 23085002 TI - The chondroprotective effects of dehydroepiandrosterone probably exerted by its conversion to estradiol. AB - The sex hormone precursor dehydroepiandrosterone (DHEA), which can be converted into estradiol by the enzyme aromatase, has a protective role against osteoarthritis (OA). To determine whether the protective effects of DHEA are dependent on its conversion to estradiol, the aromatase inhibitor letrozole and/or the estrogen receptor inhibitor fulvestrant were administered in the presence of DHEA in both interleukin 1beta (IL-1beta)-induced rabbit chondrocytes and a rabbit anterior cruciate ligament transaction (ACLT) model of OA. Expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase-1 (TIMP-1) were used to monitor these effects. Expression of MMP-3 and MMP-13 increased in both DHEA-treated chondrocytes and cartilage in the presence of letrozole and/or fulvestrant, while the expression of TIMP-1 and collagen type II (Col-II) decreased. Our findings suggest that the effects of DHEA may be mediated by its conversion to estradiol. PMID- 23085003 TI - Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson's Disease: a meta-analysis. AB - OBJECTIVES: To assess the efficacy and safety of istradefylline as an adjunct to levodopa in patients with Parkinson's Disease (PD). METHODS: In this study, we searched the Cochrane Library, MEDLINE, Embase, China Academic Journal Full-text Database (CNKI), China Biomedical Literature Database (CBM), Chinese Scientific Journals Database (VIP), and Wanfang Database. The quality of included studies was strictly evaluated. Data analyses were performed by the Cochrane Collaboration's RevMan5.0 software. RESULTS: Five randomized controlled trials (RCTs) were included. The result showed a significant reduction of the awake time per day spent in the OFF state and improvement of the Unified Parkinson's Disease Rating Scale (UPDRS) Part III in the ON state when receiving istradefylline compared with patients receiving placebo. There was no significant difference between the istradefylline 20mg and the istradefylline 40 mg groups in the UPDRS Part III in the ON state (WMD=1.27, 95% CI [-0.40, 2.95]). The results showed significant differences in dyskinesia (RR=1.63, 95% CI [1.16, 2.29]) compared to istradefylline 40 mg with placebo. There was no significant statistical difference with regard to other adverse events. CONCLUSIONS: The present study showed that istradefylline is safe and effective as an adjunct to levodopa in patients with PD. Future large-scale, higher-quality, long-treatment, and placebo controlled trials are needed. PMID- 23085004 TI - Depressive symptoms and disability in chagasic stroke patients: impact on functionality and quality of life. AB - INTRODUCTION: Chagas disease (CD) is associated with stroke, which can result in significant long-term disability. Stroke has also been associated with depressive symptoms, which affect functional performance and quality of life (QOL). Few data are available on the effect of chagasic stroke on functional performance and QOL. OBJECTIVES: This study aimed to investigate the correlation of stroke disability and depressive symptoms with functional performance and QOL in chagasic stroke patients. METHODS: In this cross-sectional study, stroke sequelae were assessed using the Modified Rankin Stroke Scale (MRSS), depressive symptoms using the Beck Depression Inventory (BDI), functional performance using the Barthel Index (BI), and QOL using the WHOQOL-BREF. RESULTS: Twenty-one patients with CD and a previous diagnosis of stroke were included. There was a correlation between the MRSS score and the BI score (r=-0.663, p=0.003), but not the scores of the WHOQOL BREF subscales. The BDI score was correlated with the WHOQOL-BREF subscale scores (Physical: r=-0.733, p=0.001; Psychological: r=-0.581, p=0.012; Social: r=-0.713, p=0.001; Environmental: r=-0.659, p=0.003). However, the BDI score was not associated with the BI score (r=0.279, p=0.262). CONCLUSIONS: QOL in patients with CD appears to be influenced more by depressive symptoms than by the motor associated consequences of stroke. Conversely, motor sequelae impair the functionality of the patient more than depressive symptoms. PMID- 23085005 TI - Efficient inhibition of cathepsin B by a secreted type 1 cystatin of Fasciola gigantica. AB - Cysteine proteases are important antigens in the liver fluke genus Fasciola, essential for infection, protection and nutrition. While their biochemistry, biological roles and application as vaccines have been thoroughly studied there is a lack of data concerning their regulation. In the present study we have continued our investigation of cysteine protease inhibitors in Fasciola gigantica and demonstrate, in comparison with FgStefin-1 and human cystatin C, that a second type 1 cystatin of the parasite, FgStefin-2, has been evolutionary adapted to block cathepsin B. The protein, which unusually for a type 1 cystatin carries a signal peptide, is expressed from the metacercarial to adult stage and located in the epithelial cells of the intestinal tract in all stages and in the prostate gland cells in adults. Both cell types may contribute to the released FgStefin-2 observed in the ES product of the parasite. Distinct isoforms of cathepsin B are essential for host tissue penetration during the early infection process and FgStefin-2 may act as key regulator, required to protect the minute juvenile from autoproteolysis. Expression in the prostate gland in the adult stage suggests an additional regulative role of cysteine protease activity in the reproductive system. PMID- 23085006 TI - Molecular characterization, functional expression, tissue localization and protective potential of a Taenia solium fatty acid-binding protein. AB - The fatty acid-binding proteins (FABPs) comprise a family of proteins that are widely expressed in animal cells and perform a variety of vital functions. Here, we report the identification, characterization, recombinant expression, tissue localization and protective potential of a Taenia solium FABP (TsFABP1). The TsFABP1 primary structure showed all the conserved residues characteristic of the subfamily iv of the intracellular Lipid-Binding Proteins (iLBPs), including those involved in the binding stabilization of the fatty acid molecule. Through a competitive binding assay we found that TsFABP1 is able to bind at least six different fatty acids with preference toward palmitic and stearic acid, suggesting that TsFABP1 is a member of the iLBP subfamily iv. Immunolocalization assays carried out on larval and adult tissues of four species of taeniids using anti-TsFABP1 hyperimmune sera produced in mice and rabbit, showed intense labeling in the tegument of the spiral canal and in subtegumental cytons of the larvae. These findings suggest that the spiral canal might be a major place for FA uptake in the developing scolex. In contrast, only subtegumental cytons in the adult worms stained positive. We propose that TsFABP1 is involved in the mechanism to mobilize fatty acids between compartments in the extensive syncytial tissue of taeniids. Protection assays carried out in a murine model of cysticercosis showed that subcutaneous immunization with TsFABP1 resulted in about 45% reduction of parasite load against an intraperitoneal challenge with Taenia crassiceps cysts. This reduction in parasite load correlated with the level of cellular and humoral immune responses against TsFABP1, as determined in spleen lymphocyte proliferation and ELISA testing. PMID- 23085007 TI - Effect of physical fatigue on the quality CPR: a water rescue study of lifeguards: physical fatigue and quality CPR in a water rescue. AB - PURPOSE: The purpose of the study is to analyze the influence of the fatigue caused by a water rescue on the cardiopulmonary resuscitation (CPR) performance. METHODS: The sample of our research is composed of a group of 60 lifeguards (30 men and 30 women) who have been trained at the Universities of A Coruna and Vigo. Two tests were conducted: the first test involved the execution of 5 min of CPR (rested), and the second one in performing water rescue and subsequent CPR (exhausted) for 5 minutes. The quality of the CPR at rest and at fatigue condition was compared. The recording instrument was the Laerdal Resusci Anne manikin. The time of the water rescue was also registered. RESULTS: Gender does not significantly influence CPR, either at rest or at fatigue condition. However, the fatigue caused by rescue has a significant influence on the total quantity of chest compressions: rested (380 +/- 38.64); exhausted (411 +/- 56.09; P < .001) and ventilations: rested (24 +/- 2.97); exhausted (26 +/- 3.92; P < .001). Also in correct chest compressions: rested (285 +/- 82.67); exhausted (246 +/- 122.08; P = .02) and ventilations: rested (14 +/- 7.09); exhausted (9 +/- 6.67; P < .001). As far as the water rescue is concerned, men are faster (261 +/- 34.58 s) when compared to women (326 +/- 99.87 seconds; P = .001). CONCLUSION: The accumulated fatigue during a water rescue performed by lifeguards reduces the quality of chest compressions and ventilations on the CPR. PMID- 23085008 TI - Dietary eicosapentaenoic acid supplementation accentuates hepatic triglyceride accumulation in mice with impaired fatty acid oxidation capacity. AB - Reduced mitochondrial fatty acid (FA) beta-oxidation can cause accumulation of triglyceride in liver, while intake of eicosapentaenoic acid (EPA) has been recommended as a promising novel therapy to decrease hepatic triglyceride content. However, reduced mitochondrial FA beta-oxidation also facilitates accumulation of EPA. To investigate the interplay between EPA administration, mitochondrial activity and hepatic triglyceride accumulation, we investigated the effects of EPA administration to carnitine-deficient mice with impaired mitochondrial FA beta-oxidation. C57BL/6J mice received a high-fat diet supplemented or not with 3% EPA in the presence or absence of 500 mg mildronate/kg/day for 10 days. Liver mitochondrial and peroxisomal oxidation, lipid classes and FA composition were determined. Histological staining was performed and mRNA level of genes related to lipid metabolism and inflammation in liver and adipose tissue was determined. Levels of pro-inflammatory eicosanoids and cytokines were measured in plasma. The results showed that mildronate treatment decreased hepatic carnitine concentration and mitochondrial FA beta oxidation and induced severe triglyceride accumulation accompanied by elevated systemic inflammation. Surprisingly, inclusion of EPA in the diet exacerbated the mildronate-induced triglyceride accumulation. This was accompanied by a considerable increase of EPA accumulation while decreased total n-3/n-6 ratio in liver. However, inclusion of EPA in the diet attenuated the mildronate-induced mRNA expression of inflammatory genes in adipose tissue. Taken together, dietary supplementation with EPA exacerbated the triglyceride accumulation induced by impaired mitochondrial FA beta-oxidation. Thus, further thorough evaluation of the potential risk of EPA supplementation as a therapy for NAFLD associated with impaired mitochondrial FA oxidation is warranted. PMID- 23085009 TI - Role of palmitate-induced sphingoid base-1-phosphate biosynthesis in INS-1 beta cell survival. AB - Sphingoid base-1-phosphates represent a very low portion of the sphingolipid pool but are potent bioactive lipids in mammals. This study was undertaken to determine whether these lipids are produced in palmitate-treated pancreatic beta cells and what role they play in palmitate-induced beta cell apoptosis. Our lipidomic analysis revealed that palmitate at low and high glucose supplementation increased (dihydro)sphingosine-1-phosphate levels in INS-1 beta cells. This increase was associated with an increase in sphingosine kinase 1 (SphK1) mRNA and protein levels. Over-expression of SphK1 in INS-1 cells potentiated palmitate-induced accumulation of dihydrosphingosine-1-phosphate. N,N dimethyl-sphingosine, a potent inhibitor of SphK, potentiated beta-cell apoptosis induced by palmitate whereas over-expression of SphK1 significantly reduced apoptosis induced by palmitate with high glucose. Endoplasmic reticulum (ER) targeted SphK1 also partially inhibited apoptosis induced by palmitate. Inhibition of INS-1 apoptosis by over-expressed SphK1 was independent of sphingosine-1-phosphate receptors but was associated with a decreased formation of pro-apoptotic ceramides induced by gluco-lipotoxicity. Moreover, over expression of SphK1 counteracted the defect in the ER-to-Golgi transport of proteins that contribute to the ceramide-dependent ER stress observed during gluco-lipotoxicity. In conclusion, our results suggest that activation of palmitate-induced SphK1-mediated sphingoid base-1-phosphate formation in the ER of beta cells plays a protective role against palmitate-induced ceramide dependent apoptotic beta cell death. PMID- 23085010 TI - Metabolic syndrome: a novel high-risk state for colorectal cancer. AB - Metabolic syndrome (MS) and related disorders, including cancer, are steadily increasing in most countries of the world. However, mechanisms underlying the link between MS and colon carcinogenesis have yet to be fully elucidated. In this review article we focus on the relationships between various individual associated conditions (obesity, dyslipidemia, diabetes mellitus type 2 and hypertension) and colon cancer development, and demonstrate probable related factors revealed by in vivo and in vitro studies. Furthermore, molecules suggested to be involved in cancer promotion are addressed, and the potential for cancer prevention by targeting these molecules is discussed. PMID- 23085011 TI - Antioxidant and prebiotic activities of selenium-containing green tea. PMID- 23085012 TI - Vitamin E content in fish oil emulsion does not prevent lipoperoxidative effects on human colorectal tumors. AB - OBJECTIVE: The anticancer action exerted by polyunsaturated fatty acid peroxidation may not be reproduced by commercially available lipid emulsions rich in vitamin E. Therefore, we evaluated the effects of fish oil (FO) emulsion containing alpha-tocopherol 0.19 g/L on human colorectal adenocarcinoma cells and tumors. METHODS: HT-29 cell growth, survival, apoptosis, and lipid peroxidation were analyzed after a 24-h incubation with FO 18 to 80 mg/L. Soybean oil (SO) emulsion was used as an isocaloric and isolipidic control. In vivo, nude mice bearing HT-29 tumors were sacrificed 7 d after an 11-d treatment with intravenous injections of FO or SO 0.2 g ? kg(-1) ? d(-1) FO or SO to evaluate tumor growth, necrosis, and lipid peroxidation. RESULTS: The FO inhibited cell viability and clonogenicity in a dose-dependent manner, whereas SO showed no significant effect compared with untreated controls. Lipid peroxidation and cell apoptosis after treatment with FO 45 mg/L were increased 2.0-fold (P < 0.01) and 1.6-fold (P = 0.04), respectively. In vivo, FO treatment did not significantly affect tumor growth. However, immunohistochemical analyses of tumor tissue sections showed a decrease of 0.6-fold (P < 0.01) in the cell proliferation marker Ki-67 and an increase of 2.3-fold (P = 0.03) in the necrotic area, whereas malondialdehyde and total peroxides were increased by 1.9-fold (P = 0.09) and 7.0-fold (P < 0.01), respectively, in tumors of FO-treated compared with untreated mice. CONCLUSION: These results suggest that FO but not SO has an antitumor effect that can be correlated with lipid peroxidation, despite its vitamin E content. PMID- 23085013 TI - High-fat diet blunts activation of the nuclear factor-kappaB signaling pathway in lipopolysaccharide-stimulated peritoneal macrophages of Wistar rats. AB - OBJECTIVE: The present study was designed to investigate the effect of a high-fat diet (HFD) on the inflammatory response of peritoneal macrophages. METHODS: Male Wistar rats were fed a control diet (n = 12) or an HFD (n = 12) for 12 wk. After euthanasia, peritoneal macrophages were collected and stimulated (or not) with lipopolysaccharide (LPS). Results from the assays using peritoneal macrophages were analyzed with one-way analysis of variance or an equivalent non-parametric test. The level of significance adopted was 0.05. RESULTS: Consumption of the HFD was associated with significant increases in weight gain and fat depots (P < 0.05). Despite having no influence in systemic markers of inflammation, such as interleukin (IL)-6, tumor necrosis factor-alpha, and plasminogen activator inhibitor-1, the HFD intake significantly decreased insulin sensitivity, as evaluated by the homeostasis model assessment index (P < 0.05). A decreased production of IL-1beta, IL-6, IL-10, and nitric oxide in response to the LPS stimulation was observed in peritoneal macrophages from the HFD group (P < 0.05). Also, in HFD-fed animals, LPS incubation did not increase IL-1beta and IL-6 mRNA expression (P < 0.05). These effects were associated with an attenuation of IkappaB inhibitor kinase-beta phosphorylation and nuclear factor-kappaB activation in response to LPS and with a failure to decrease IkappaB inhibitor alpha expression (P < 0.05). CONCLUSION: Chronic consumption of an HFD decreased the LPS-induced inflammatory response of peritoneal macrophages, which was associated with a downregulation of the nuclear factor-kappaB signaling pathway. PMID- 23085014 TI - Vitamin D: health panacea or false prophet? AB - Vitamin D deficiency, diagnosed when the serum 25-hydroxyvitamin D (25-OHD(3)) concentration is less than 20 ng/mL, has joined vitamin A deficiency as two of the most common nutrition-responsive medical conditions worldwide. There have been more scientific articles published about vitamin D in the 21st century than about any other vitamin, reflecting the massive expansion of the field of vitamin D research. Adequate vitamin D status has been linked to decreased risks of developing specific cancers, including cancers of the esophagus, stomach, colon, rectum, gallbladder, pancreas, lung, breast, uterus, ovary, prostate, urinary bladder, kidney, skin, thyroid, and hematopoietic system (e.g., Hodgkin's lymphoma, non-Hodgkin's lymphoma, multiple myeloma); bacterial infections; rheumatoid arthritis; Crohn's disease; periodontal disease; multiple sclerosis; asthma; type 2 diabetes; cardiovascular disease; stroke; peripheral artery disease; hypertension; chronic kidney disease; muscle weakness; cognitive impairment; Alzheimer's disease; clinical depression; and premature death. On the other hand, inadequate vitamin D status during human pregnancy may be associated with increased risk for the development of type 1 diabetes in the offspring. However, this point of view may be excessively optimistic. There also is evidence that despite the current heavy reliance on serum 25-OHD(3) concentration for the diagnosis of an individual's vitamin D status, local tissue vitamin D intoxication may be present in individuals with much lower serum 25-OHD(3) concentrations than are currently appreciated. Only rarely are the symptoms of local tissue vitamin D intoxication associated with vitamin D status or intake. An individual's serum 25-OHD(3) concentration may appear to be "low" for reasons totally independent of sunlight exposure or vitamin D intake. Serum 25-OHD(3) concentration is only poorly responsive to increases in vitamin D intake, and the prolonged routine consumption of thousands of international units of vitamin D may interfere with the regulation of phosphate homeostasis by fibroblast growth factor-23 (FGF23) and the Klotho gene product, with consequences that are detrimental to human health. In light of these counterbalancing observations, curbing excessive enthusiasm for universally increasing vitamin D intake recommendations may be in order. PMID- 23085015 TI - Efficacy of beta-hydroxy-beta-methylbutyrate supplementation in elderly and clinical populations. AB - Muscle loss is common during aging and chronic diseases, such as cancer and acquired immunodeficiency syndrome. Moreover, muscle loss has been correlated with decreased physical function, quality of life, and mortality in these populations. Therefore, interventions to counteract muscle loss in the elderly and clinical populations are needed. Recently, the efficacy of the leucine metabolite, beta-hydroxy-beta-methylbutyrate (HMB), to maintain muscle mass has been investigated in these populations. Many studies have found increases in lean mass and strength in the elderly and clinical populations when using HMB; however, not all studies have found beneficial effects of HMB supplementation. The present review summarizes published human studies investigating the efficacy of HMB supplementation in the elderly and clinical populations. In addition, the mechanisms by which HMB may exert its effects are summarized and future research directions are suggested. PMID- 23085016 TI - Bioactive compounds, antioxidant potential, and hepatoprotective activity of sea cucumber (Holothuria atra) against thioacetamide intoxication in rats. AB - OBJECTIVE: The identification of the active phenolic compounds in the mixed extract of sea cucumber (Holothuria atra) body wall by high-performance liquid chromatography and an assessment of its hepatoprotective activity against thioacetamide-induced liver fibrosis in rats. METHODS: Female Swiss albino rats were divided into four groups: normal controls; oral administration of a sea cucumber mixed extract (14.4 mg/kg of body weight) on days 2, 4, and 6 weekly for 8 consecutive weeks; intoxication with thioacetamide (200 mg/kg of body weight, intraperitoneally) on days 2 and 6 weekly for 8 wk; and oral administration of a sea cucumber extract and then intoxication with thioacetamide 2 h later for 8 wk. RESULTS: High-performance liquid chromatographic analysis of the sea cucumber mixed extract revealed the presence of some phenolic components, such as chlorogenic acid, pyrogallol, rutin, coumaric acid, catechin, and ascorbic acid. In vitro studies have shown that the extract has a high scavenging activity for the nitric oxide radical, a moderate iron-chelating activity, and a weak inhibitory effect of lipid peroxidation. The subchronic oral administration of sea cucumber extract to the rats did not show any toxic side effects but increased hepatic superoxide dismutase and glutathione peroxidase activities. The coadministration of sea cucumber extract and thioacetamide (protection modality) normalized serum direct bilirubin, alanine and aspartate aminotransferases, hepatic malondialdehyde, and hydroxyproline concentrations and antioxidant enzyme activities. In addition, the histologic examination of liver sections from the protection group that were stained with hematoxylin and eosin showed substantial attenuation of the degenerative cellular changes and regressions in liver fibrosis and necrosis induced by the thioacetamide intoxication. CONCLUSION: Sea cucumber mixed extract contains physiologically active phenolic compounds with antioxidant activity, which afforded a potential hepatoprotective activity against thioacetamide-induced liver injury in a rat model. PMID- 23085017 TI - Arginine-supplemented enteral nutrition in critically ill diabetic and obese rats: a dose-ranging study evaluating nutritional status and macrophage function. AB - OBJECTIVE: Critically ill diabetic and obese patients are at high risk of complications. Arginine availability is lowered in diabetes and in stress situations, yet arginine is necessary for immune response, mainly by its action through nitric oxide (NO). These facts argue for arginine-supplemented diets in critically ill patients. However, studies have raised concerns about possible adverse effects of such diets in intensive-care patients. We therefore analyzed the metabolic and immunologic effects of an arginine-enriched diet in stressed diabetic-obese rats. METHODS: Zucker Diabetic Fatty rats (fa/fa) were made endotoxemic by an intraperitoneal injection of lipopolysaccharide and then fed 4 d enteral nutrition enriched with arginine (ARG group) or a non-essential amino acid mix (NEAA group). The two groups each were subdivided into three subgroups: the ARG subgroups received 0.5 g (ARG0.5), 2 g (ARG2), and 5 g (ARG5) of arginine per kilogram daily, and the NEAA groups were made isonitrogenous with the corresponding ARG subgroups (NEAA0.5, NEAA2, and NEAA5). Plasma and urinary biomarkers were measured. Cytokine and NO production levels and inducible NO synthase and arginase protein levels were determined from peritoneal macrophages. RESULTS: The survival rate was lower in the ARG5 and NEAA5 subgroups than in all the other subgroups. The nitrogen balance was higher in the ARG5 group than in the NEAA5 group. Plasma triacylglycerol levels were lower in the ARG2 group than in the NEAA2 group. Interleukin-6, tumor necrosis factor-alpha, and NO production in the macrophages decreased and arginase-1 was upregulated in the ARG-treated rats. CONCLUSIONS: In this model, mortality was increased by the nitrogen burden rather than by arginine per se. Arginine improved nitrogen balance and had an anti-inflammatory action on macrophages by regulating NO production, probably through arginase-1 expression. PMID- 23085018 TI - Field-to-laboratory transport protocol impacts subsequent physiological biomarker response in the marine mussel, Perna canaliculus. AB - The transfer of mussels from field to laboratory, or transplantation between clean and contaminated field settings, is a common protocol in ecotoxicology. However, collection and transport of mussels could lead to stress that may impact biomarker responses, and thus confound interpretation of results. Physiological responses (clearance rate, absorption efficiency, excretion rate, respiration rate and scope-for-growth) of green-lipped mussels (Perna canaliculus) exposed to four different transportation protocols were investigated. These protocols included immersion in site seawater (SSW), immersion in artificial seawater (ASW), and emersion (aerial transport; EMS) at two temperatures (15 degrees C and 5 degrees C). Physiological measurements were conducted after a simulated 24h "transport" phase and a 48h "recovery" phase. Clearance rates were significantly inhibited by the EMS 5 degrees C and ASW protocols relative to SSW treatment, although the clearance rate of the latter recovered after 48h. A similar pattern was observed for excretion and respiration rates for ASW. Decreased excretion rates for EMS 15 degrees C and respiration rates for EMS 5 degrees C were also recorded relative to values for SSW following "recovery". Negative scope-for growth was observed for all treatments except EMS 15 degrees C. These data suggest transport emersed at ambient air temperatures is the best method to maintain physiological health of green-lipped mussels. PMID- 23085019 TI - Mitochondrial GCD1 dysfunction reveals reciprocal cell-to-cell signaling during the maturation of Arabidopsis female gametes. AB - Cell-to-cell communication in embryo sacs is thought to regulate the development of female gametes in flowering plants, but the details remain poorly understood. Here, we report a mitochondrial protein, GAMETE CELL DEFECTIVE 1 (GCD1), enriched in gametophytes that is essential for final maturation of female gametes. Using Arabidopsis gcd1 mutants, we found that final maturation of the egg and central cells is not required for double fertilization but is necessary for embryogenesis initiation and endosperm development. Furthermore, nonautonomous effects, observed when GCD1 or AAC2 function is disrupted, suggest that mitochondrial function influences reciprocal signaling between central and egg cells to regulate maturation of the partner (egg or central) cell. Our findings confirm that cell-to-cell communication is important in functional maturation of female gametic cells and suggest that both egg and central cells sense and transmit their mitochondrial metabolic status as an important cue that regulates the coordination of gamete maturation. PMID- 23085020 TI - The kinetochore-bound Ska1 complex tracks depolymerizing microtubules and binds to curved protofilaments. AB - To ensure equal chromosome segregation during mitosis, the macromolecular kinetochore must remain attached to depolymerizing microtubules, which drive chromosome movements. How kinetochores associate with depolymerizing microtubules, which undergo dramatic structural changes forming curved protofilaments, has yet to be defined in vertebrates. Here, we demonstrate that the conserved kinetochore-localized Ska1 complex tracks with depolymerizing microtubule ends and associates with both the microtubule lattice and curved protofilaments. In contrast, the Ndc80 complex, a central player in the kinetochore-microtubule interface, binds only to the straight microtubule lattice and lacks tracking activity. We demonstrate that the Ska1 complex imparts its tracking capability to the Ndc80 complex. Finally, we present a structure of the Ska1 microtubule-binding domain that reveals its interaction with microtubules and its regulation by Aurora B. This work defines an integrated kinetochore microtubule interface formed by the Ska1 and Ndc80 complexes that associates with depolymerizing microtubules, potentially by interacting with curved microtubule protofilaments. PMID- 23085021 TI - Ethnobotanical survey for potential anti-malarial plants in south-western Nigeria. AB - AIM OF STUDY: The ethnobotanical study surveyed the different types of medicinal plants used for the treatment of malaria in the south-western region of Nigeria. MATERIALS AND METHODS: Information was collected by interviewing indigenous people, using a semi-structured questionnaire. Collected plant samples were identified and authenticated in Forestry Research Institute of Nigeria, Ibadan, Nigeria. RESULTS: A total of 151 respondents were interviewed of which 64% were females and 36% males. This population comprised of herbal medicine sellers (39%), traditional doctors (15%), housewives (24%) and farmers (22%). Twenty two plants species used in the treatment of malaria belonging to 18 families were identified and compiled detailing information such as common and vernacular names, parts used, methods of preparation and previous scientific reports. Of the plants identified during the survey, Azadirachta indica (12.9%), Alstonia congensis (11.9%) and Cymbopogon citratus (11.3%) showed the highest incidence of encounter whereas Nauclea latifolia recorded the lowest incidence of encounter (0.2%). The traditional usage of Persea americana and Ludwigia peruviana in the treatment of malaria is reported here for the first time. CONCLUSION: Though a large number of traditionally used plants for the treatment of malaria were identified, scientific validation of the traditional claims of anti-malarial properties is imperative. This would establish their candidature for any possible future research for active principles and the possible development of new cheaper and more effective anti-malarial drugs, as well as in the conservation of this rich diversity of anti-malarial plants. PMID- 23085022 TI - Effects of Zuccagnia punctata extracts and their flavonoids on the function and expression of ABCB1/P-glycoprotein multidrug transporter. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zuccagnia punctata extracts (ZpE) are used in ethnomedicine as antimicrobial and anti-inflammatory drugs. The pharmacological properties of ZpE and their polyphenolic components suggest that they may be used as potential modulators on the P-glycoprotein (P-gp) multidrug transporter. P-gp is well known for its role in the acquired drug resistance by tumors following chemotherapy, causing a low drug bioavailability by extruding them out of the cells. AIM OF STUDY: To evaluate the effects of ZpE and three of their phenolic components: 7-hydroxyflavanone (HF), 3,7-dihydroxyflavone (DHF) and 2',4' dihydroxychalcone (DHC) on P-gp activity and expression. MATERIAL AND METHODS: The effects of natural products on ABCB1/P-gp function and expression were evaluated by R-123 accumulation assay and western blot analysis using HK-2 cells as experimental model. The ABCB1 mRNA content was determined by SQRT-PCR. RESULTS: The accumulation of R-123 in HK-2 cells was significantly increased by ZpE and DHF, and to a lesser extent by DHC, indicating their roles on the efflux transporter activity. However, HF did not show any effect. HK-2 cells maintained in the presence of ZpE or DHF for 72 h, showed an increase in P-gp expression whereas activity was unchanged or decreased. No changes were observed in ABCB1 mRNA content. Furthermore, in these assay conditions, more sensibility of HK-2 cells to the cytotoxic action of cyclosporine A (P-gp substrate) was observed. CONCLUSION: These results may suggest an impact of Zuccagnia punctata and some of its components on the pharmacokinetics of drugs that are P-gp substrates, as well as a potential role on multidrug resistance modulation. PMID- 23085023 TI - Oligopeptides derived from autophosphorylation sites of EGF receptor suppress EGF stimulated responses in human lung carcinoma A549 cells. AB - Epidermal growth factor (EGF) receptor plays a crucial role in the biology of human cancer, and is a highly appropriate target for anticancer agents. We have previously designed oligopeptides containing the amino acid sequences around autophosphorylation sites of EGF receptor to identify a specific inhibitor of this receptor. We found that Ac-ENAEYLR-NH(2) and Ac-NYQQN-NH(2) suppressed phosphorylation of purified EGF receptor in a non-ATP-competitive manner whereas Ac-QNAQYLR-NH(2) and Ac-DYQQD-NH(2) caused inhibition in an ATP-competitive manner. The aim of this study was to observe the effects of these peptides on the proliferation, cell death, and apoptosis of human lung carcinoma A549 cells. To facilitate transfer of these inhibitory peptides into A549 cells, the cell penetrating peptide, human immunodeficiency virus type 1-transactivator of transcription (Tat), was linked to the peptides. When A549 cells were treated with each Tat-conjugated peptide, the peptides penetrated the cells and EGF stimulated tyrosine phosphorylation of EGF receptor was significantly suppressed. These Tat-conjugated peptides played a suppressive role in EGF-stimulated A549 cell responses. In particular, Tat-epsilon-aminocaproic acid (acp)-ENAEYLR-NH(2) significantly inhibited proliferation and showed cytotoxicity, while Tat-acp NYQQN-NH(2) and Tat-acp-DYQQD-NH(2) suppressed the anti-apoptotic effect of EGF. In addition, we found that Tat-acp-ENAEYLR-NH(2) also inhibited the phosphorylation of epidermal growth factor receptor 2 (ErbB2) as well as EGF receptor in A549 cells. In conclusion, membrane-permeable synthetic peptides derived from EGF receptor autophosphorylation sites have the potential to suppress EGF receptor function in A549 cells and to be developed into novel and useful agents for cancer therapy. PMID- 23085024 TI - Participation of GABAA, GABA(B) receptors and neurosteroids in toluene-induced hypothermia: evidence of concentration-dependent differences in the mechanism of action. AB - Toluene is a misused substance that modifies gamma-aminobutyric acid (GABA) release and shares behavioral and molecular effects with GABA(A) and GABA(B) receptor agonists. GABAergic compounds are involved in thermoregulation processes and volatile substance users have reported that one of the reasons to inhale is to avoid feeling cold. At present, no studies have analyzed the effects of inhalants on body temperature and the mechanism of action involved. Thus, the main purpose of this study was to evaluate the effects of a (60 min) acute toluene inhalation (2000, 4000 and 6000 ppm) in core temperature. In addition, we tried to prevent the changes of temperature induced by toluene with the specific GABA(A) receptor blockers picrotoxin (0.01-0.1mg/kg), bicuculline (0.1-0.3mg/kg), and flumazenil (3-30 mg/kg); the GABA(B) receptor antagonist phaclofen (10-30 mg/kg) and the neurosteroid synthesis inhibitor finasteride (10-30 mg/kg). Results show that toluene reduced core temperature in mice in a concentration dependent manner. The hypothermia produced by 4000 ppm toluene was prevented by picrotoxin, bicuculline, phaclofen and finasteride but not by flumazenil. In contrast none of these antagonists tested blocked the effects of 6000 ppm toluene. In conclusion, toluene decreases core temperature, GABA receptors and neurosteroids participate in toluene's action at 4000 ppm; but other mechanisms of action are involved in the hypothermic effects of 6000 ppm toluene. PMID- 23085025 TI - Using cholinergic M1 receptor positive allosteric modulators to improve memory via enhancement of brain cholinergic communication. AB - Benzylquinolone carboxylic acid (BQCA) is a recently described cholinergic muscarinic M(1) receptor positive allosteric modulator having potential as cognitive enhancer in dementia. The present study focused on the characterisation of BQCA's mode of action in relation to positive effects on memory and side effects in an animal model. To get insight into this mode of action, in vitro receptor potency/left shift experiments in cells stably expressing the rat's M(1) receptor were performed. They revealed an inflection point value of BQCA corresponding to 306nM, and potentiation of the agonist response up to 47-fold in presence of 10MUM of BQCA. In vivo, brain microdialysis showed a maximal brain level of 270nM, 40min after i.p. administration at 10mg/kg. Based on in vitro data obtained with this dose, it can be concluded that BQCA reaches brain levels which should potentiate the agonist response about 4-fold. Behavioural data confirmed that BQCA used at 10mg/kg attenuated scopolamine-induced memory deficit in a spontaneous alternation task. Moreover, BQCA showed no side effect at 10mg/kg and above in spontaneous locomotion and salivation tests. The profile of BQCA observed in the present study displays a clear advantage over the M(1)-M(3) agonist cevimeline. The present data show the therapeutic potential of the M(1) receptor positive allosteric modulator BQCA for the treatment of memory deficits observed in Alzheimer's disease. PMID- 23085026 TI - Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy. AB - We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects. PMID- 23085027 TI - Effects of salvianolic acid B on survival, self-renewal and neuronal differentiation of bone marrow derived neural stem cells. AB - Our previous study has demonstrated the therapeutic potential of bone marrow derived-neural stem cells (BM-NSCs) in CNS disorders; however, the beneficial effects are modest due to the poor survival and low neural differentiation frequency. Here, we demonstrate that salvianolic acid B (Sal B), a potent aqueous of a well known Chinese medicine herb, Salvia miltiorrhiza, possesses the ability to promote BM-NSCs proliferation in a dose dependent manner as verified by growth curve and Bromodeoxyuridine (BrdU) incorporation assays; While in differentiation medium, Sal B promoted nestin(+) BM-NSCs differentiated into greater numbers of NF-M(+) neurons and NG2(+) oligodendrocyte precursors, but fewer GFAP(+) astrocytes as verified by triple immunostaining and quantitative analysis; upon exposure to H(2)O(2), Sal B facilitated the cells survival, reduced LDH leakage, and inhibited apoptosis, displaying a dose-dependent neuroprotective effect on BM NSCs. Sal B induced brain-derived neurotrophic factor (BDNF) production by BM NSCs, which may be beneficial for the cells survival and differentiation in unfavourable environment. The collective evidence indicates that Sal B may be a potential drug to upgrade the therapeutic efficiency of BM-NSCs in CNS diseases. PMID- 23085028 TI - Hypothermia reduces calcium entry via the N-methyl-D-aspartate and ryanodine receptors in cultured hippocampal neurons. AB - Hypothermia is a powerful neuroprotective method when induced following cardiac arrest, stroke, and traumatic brain injury. The physiological effects of hypothermia are multifaceted and therefore a better knowledge of its therapeutic targets will be central to developing innovative combination therapies to augment the protective benefits of hypothermia. Altered neuronal calcium dynamics have been implicated following stroke, status epilepticus and traumatic brain injury. This study was therefore initiated to evaluate the effect of hypothermia on various modes of calcium entry into a neuron. Here, we utilized various pharmacological agents to stimulate major routes of calcium entry in primary cultured hippocampal neurons. Fluorescent calcium indicator Fura-2AM was used to compare calcium ratio under normothermic (37 degrees C) and hypothermic (31 degrees C) conditions. The results of this study indicate that hypothermia preferentially reduces calcium entry through N-methyl-D-aspartate receptors and ryanodine receptors. Hypothermia, on the other hand, did not have a significant effect on calcium entry through the voltage-dependent calcium channels or the inositol tri-phosphate receptors. The ability of hypothermia to selectively affect both N-methyl-D-aspartate receptors and ryanodine receptors-mediated calcium systems makes it an attractive intervention for alleviating calcium elevations that are present following many neurological injuries. PMID- 23085029 TI - Comparative study of the quercetin, ascorbic acid, glutathione and superoxide dismutase for nitric oxide protecting effects in mouse gastric fundus. AB - The aim of this work was to compare the preventing capacity of quercetin with Cu/Zn superoxide dismutase (Cu/Zn SOD), ascorbic acid and glutathione on nitric oxide (NO)-induced relaxation in mouse gastric fundus. Furthermore, the effects of the quercetin on the tissue level of total oxidant and antioxidant was investigated. Nitrergic stimulation (4Hz, 25V, 0.1 ms, 10s-train) and exogenous NO (10 MUM) induced relaxation. Pyrogallol (10 MUM), hydroquinone (100 MUM) and LY83583 (6-Anilino-quinolin-5,8-quinone, 5 MUM) inhibited nitrergic relaxations. The inhibition observed with pyrogallol, hydroquinone and LY83583 was prevented by quercetin (0.1 MUM). Also, ascorbic acid (500 MUM), glutathione (100 MUM) and Cu/Zn SOD (100 U/ml) prevented the inhibitory effect of superoxide anion generators on the relaxation to nitrergic stimulation and NO. Diethyldithiocarbamic acid (DETCA; 8mM) inhibited nitrergic relaxations. DETCA induced inhibition on nitrergic stimulation and NO-induced relaxation was prevented by quercetin, ascorbic acid, glutathione or Cu/Zn SOD. DETCA plus pyrogallol, hydroquinone or LY83583 strengthened the inhibition on the relaxations. Also, pre-treatment with quercetin, ascorbic acid and glutathione prevented the inhibitory effect of DETCA plus LY-83583 on the relaxation to nitrergic stimulation and NO but Cu/Zn SOD did not prevent this inhibition. Also, quercetin increased tissue total antioxidant capacity and decreased tissue oxidant level and oxidative stress index in DETCA-treatment group. These results indicate that quercetin has antioxidant effect and protects NO from endogenous superoxide anion-driven inactivation and enhances its biological activity, suggesting that quercetin may scavenge superoxide anion in a Cu/Zn SOD, glutathione or ascorbic acid-inhibitable manner. PMID- 23085030 TI - Gene expression profiling and pathway analysis of human bronchial epithelial cells exposed to airborne particulate matter collected from Saudi Arabia. AB - Epidemiological studies have established a positive correlation between human mortality and increased concentration of airborne particulate matters (PM). However, the mechanisms underlying PM related human diseases, as well as the molecules and pathways mediating the cellular response to PM, are not fully understood. This study aims to investigate the global gene expression changes in human cells exposed to PM(10) and to identify genes and pathways that may contribute to PM related adverse health effects. Human bronchial epithelial cells were exposed to PM(10) collected from Saudi Arabia for 1 or 4 days, and whole transcript expression was profiled using the GeneChip human gene 1.0 ST array. A total of 140 and 230 genes were identified that significantly changed more than 1.5 fold after PM(10) exposure for 1 or 4 days, respectively. Ingenuity Pathway Analysis revealed that different exposure durations triggered distinct pathways. Genes involved in NRF2-mediated response to oxidative stress were up-regulated after 1 day exposure. In contrast, cells exposed for 4 days exhibited significant changes in genes related to cholesterol and lipid synthesis pathways. These observed changes in cellular oxidative stress and lipid synthesis might contribute to PM related respiratory and cardiovascular disease. PMID- 23085031 TI - Synthesis, evaluation of anti-HIV-1 and anti-HCV activity of novel 2',3'-dideoxy 2',2'-difluoro-4'-azanucleosides. AB - A series of 2',3'-dideoxy-2',2'-difluoro-4'-azanucleosides of both pyrimidine and purine nucleobases were synthesized in an efficient manner starting from commercially available L-pyroglutamic acid via glycosylation of difluorinated pyrrolidine derivative 15. Several 4'-azanucleosides were prepared as a separable mixture of alpha- and beta-anomers. The 6-chloropurine analogue was obtained as a mixture of N(7) and N(9) regioisomers and their structures were identified based on NOESY and HMBC spectral data. Among the 4'-azanucleosides tested as HIV-1 inhibitors in primary human lymphocytes, four compounds showed modest activity and the 5-fluorouracil analogue (18d) was found to be the most active compound (EC(50)=36.9MUM) in this series. None of the compounds synthesized in this study demonstrated anti-HCV activity. PMID- 23085034 TI - Effect of isoprenaline chronic stimulation on APD restitution and ventricular arrhythmogenesis. AB - BACKGROUND: Isoprenaline (ISO) acts through beta-adrenergic receptors to increase the intracellular Ca(2+), which has effects on action potential duration (APD) restitution and arrhythmogenesis. Thus, we investigated the effect of chronic stimulation with isoprenaline on APD restitution and ventricular tachyarrhythmias (VA) in the rabbit heart. METHODS AND RESULTS: Rabbits were randomly selected to receive an injection of isoprenaline (ISO group) or an equal volume of 0.9% saline (CTL group). The S(1)-S(2) protocol (n=15) and S(1) dynamic pacing (n=15) were performed to construct APD restitution and to induce APD alternans or arrhythmia in 10 sites of Langendorff-perfused hearts. Compared with the same sites in the control group, long-term ISO administration (7 days) shortened the APD(90) and the effective refractory period (ERP), and greatly increased the spatial dispersion of APD and ERP (p<0.01). Compared to CTL group, the APD restitution curves were significantly changed (p<0.01) and showed increased spacial dispersion of maximal slope (S(max)) among each site in the ISO group (p<0.05). In induction of VA and APD alternans, the threshold of VA and alternans was both decreased in each site of the ISO group. CONCLUSION: Chronic stimulation with ISO facilitated VA, possibly through the increased spatial dispersion of APD restitution. PMID- 23085035 TI - Estimated glomerular filtration rate and proteinuria are associated with persistent form of atrial fibrillation: analysis in Japanese patients. AB - BACKGROUND: Several reports have identified that decline in renal function and presence of proteinuria are closely associated with incidence of atrial fibrillation (AF). However, it is still unclear whether these kidney-related markers are associated with the progression of AF from paroxysmal to persistent form. METHODS AND RESULTS: Among the new patients who visited the Cardiovascular Institute Hospital between 2004 and 2010 (Shinken Database 2004-2010, n=15,227), both estimated glomerular filtration rate (eGFR) and proteinuria were measured in 1074 AF patients (paroxysmal/persistent 579/495, respectively), who were divided into tertiles of eGFR (the borderlines were 60.07 and 73.67 ml[min(-1)]1.73[m( 2)], respectively), and then further divided into the two categories with/without proteinuria. The average value of eGFR was lower (63.1 ml[min(-1)]1.73[m(-2)] vs. 68.8 ml[min(-1)]1.73[m(-2)], p<0.001) and the detection rate of proteinuria was higher (13.7% vs. 8.5%, p=0.006) in patients with persistent AF than in those with paroxysmal AF, respectively. In the multivariate analysis without parameters of echocardiography [left ventricular ejection fraction (LVEF) and left atrial dimension (LAD)], both eGFR and proteinuria were independently associated with persistent AF, but the association was abolished when the model included LAD and LVEF. CONCLUSIONS: In the present analysis with cross-sectional design, both eGFR and proteinuria were apparently linked to the persistent form of AF, but their role in the pathogenesis does not seem to exceed the atrial stretch and remodeling, represented by LAD and LVEF. PMID- 23085036 TI - Early use of granulocyte colony stimulating factor improves survival in a rabbit model of chronic myocardial ischemia. AB - BACKGROUND: Granulocyte colony stimulating factor (G-CSF) improves the survival of animals with myocardial infarction by inducing bone marrow stem cell mobilization and homing to infarcted areas. However, its precise mechanisms and direct effects on the ischemic myocardium remain unclear. In this study we investigated the direct effects and mechanisms of G-CSF in a rabbit model of chronic myocardial ischemia. METHODS: Myocardial ischemia models were created by partial ligation of the left anterior descending coronary artery in Japanese white male rabbits. Rabbits were subcutaneously injected with 10 MUg/kg of G-CSF (G-CSF group) or saline (control group) for 6 days after myocardial ischemia. Direct effects of G-CSF were analyzed by immunohistochemistry and terminal dUTP nick end-labeling (TUNEL). RESULTS: Rabbits in the G-CSF group exhibited 75% survival compared to 40% in the control group (p<0.05). Immunohistochemistry of the ischemic myocardium showed increased homing of CD34+ cells on day 7 post surgery and more vessels on day 28 post-surgery by anti-von Willebrand factor staining in the G-CSF group compared with the control group. Furthermore, an increased percentage of CD34+ cells were observed in peripheral blood and upregulation of vascular endothelial growth factor expression in ischemic tissue in the G-CSF group compared with the control group. TUNEL showed that the apoptotic index in the ischemic myocardium decreased in the G-CSF group compared with the control group on day 28 post-surgery. CONCLUSIONS: In addition to increasing stem cell mobilization and homing to ischemic myocardium, G-CSF treatment after myocardial ischemia improves survival by accelerating neovascularization and reducing apoptosis. PMID- 23085037 TI - Excision repair cross complementation group 1 and thymidylate synthase expression in patients with mesothelioma. AB - BACKGROUND: We hypothesized that in patients with malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), high expression of excision repair cross complementation group 1 (ERCC1) and low expression of thymidylate synthase (TS) are associated with prolonged survival. PATIENTS AND METHODS: Consecutive patients undergoing EPP at our institutions were reviewed. Tissue microarrays were constructed using five 1-mm cores per patient. TS and ERCC1 protein expression was evaluated by immunohistochemical techniques. The average percentage scores from evaluable cores were assessed and the median score was used to divide the group. Overall survival (OS) from the time of surgery was determined by the Kaplan-Meier method and results were compared by the log-rank test. RESULTS: Eighty patients were included: median age, 58 years; 79% men; 76% epithelial and 24% biphasic subtypes; 25% and pathologic stage I/II and 73% stage III/IV. The median OS was 18.2 months (80% deceased at the censor date). Nineteen patients received neoadjuvant chemotherapy; 2 patients received chemotherapy with adjuvant intent and 28 patients received palliative chemotherapy. The median score was 10.2% for TS and 35% for ERCC1. There was no correlation between TS expression and OS (13.7 vs. 21.6 months for low and high levels, respectively; P = .32). There was a trend between high ERCC1 expression and longer OS (27.6 vs. 10.3 months; P = .06). CONCLUSION: In this series of patients with MPM undergoing EPP, TS expression was not associated with prolonged survival, but there was a trend for longer survival in patients with high ERCC1 expression. PMID- 23085038 TI - Transglutaminase 2 facilitates or ameliorates HIF signaling and ischemic cell death depending on its conformation and localization. AB - Transglutaminase 2 (TG2) is a widely expressed and multifunctional protein that modulates cell death/survival processes. We have previously shown that TG2 binds to hypoxia inducible factor 1beta (HIF1beta) and decreases the upregulation of HIF responsive genes; however, the relationship between these observations was not investigated. In this study, we investigated whether endogenous TG2 is sufficient to suppress HIF activity and whether the interaction between TG2 and HIF1beta is required for this suppression. shRNA-mediated silencing of TG2 significantly enhanced HIF activation in response to hypoxia. In addition, nuclear localization of TG2 is required for its suppressive effect on HIF activity, with TG2 being recruited to HIF responsive promoters in hypoxic conditions. These observations suggest that TG2 directly regulates hypoxic transcriptional machinery; however, its interaction with HIF1beta was not required for this regulation. We also examined whether TG2's effect on cell death/survival processes in ischemia is due to its effects on HIF signaling. Our results indicate that TG2 mediated HIF suppression can be separated from TG2's effect on cell survival in hypoxic/hypoglycemic conditions. Lastly, here we show that nuclear TG2 in the closed conformation and non-nuclear TG2 in the open conformation have opposing effects on hypoxic/hypoglycemic cell death, which could explain previous controversial results. Overall, our results further clarify the role of TG2 in mediating the cellular response to ischemia and suggest that manipulating the conformation of TG2 might be of pharmacological interest as a therapeutic strategy for the treatment of ischemia-related pathologies. PMID- 23085039 TI - Cyclin-dependent kinase 5 is required for normal cerebellar development. AB - Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase, and its kinase activity is dependent upon its association with either of the activating subunits p35 or p39, which are mainly expressed in neurons. We previously reported that Cdk5 knockout (KO) mice exhibit perinatal lethality, defective neuronal migration, and abnormal positioning of neurons in the facial motor nucleus and inferior olive in the hindbrain and Purkinje cells (PCs) in the cerebellum. In this study, we focused on the analysis of the role of Cdk5 in cerebellar development. For this purpose we generated midbrain-hindbrain-specific Cdk5 conditional knockout (MHB-Cdk5 KO) mice because the cerebellum develops postnatally, whereas Cdk5 KO mice die perinatally. Histological analysis of the MHB-Cdk5 KO mice revealed a significant size reduction of the cerebellum. In addition, profound disturbance of inward migration of granule cells (GC) was observed in the developing cerebellum. A normal dendritic development of the Purkinje cells (PCs) was disturbed in MHB-Cdk5 KO mice. Cultured Cdk5-null PCs showed similar dendritic abnormalities. These results indicate that Cdk5/p35 plays an important role in neuronal migration of PCs and GCs and dendrite formation of PCs in cerebellar development. PMID- 23085040 TI - Implementation fidelity of Multidimensional Family Therapy in an international trial. AB - Implementation fidelity, a critical aspect of clinical trials research that establishes adequate delivery of the treatment as prescribed in treatment manuals and protocols, is also essential to the successful implementation of effective programs into new practice settings. Although infrequently studied in the drug abuse field, stronger implementation fidelity has been linked to better outcomes in practice but appears to be more difficult to achieve with greater distance from model developers. In the INternational CAnnabis Need for Treatment (INCANT) multi-national randomized clinical trial, investigators tested the effectiveness of Multidimensional Family Therapy (MDFT) in comparison to individual psychotherapy (IP) in Brussels, Berlin, Paris, The Hague, and Geneva with 450 adolescents with a cannabis use disorder and their parents. This study reports on the implementation fidelity of MDFT across these five Western European sites in terms of treatment adherence, dose and program differentiation, and discusses possible implications for international implementation efforts. PMID- 23085041 TI - Initiation of abstinence in adolescents treated for marijuana use disorders. AB - This study assessed the time to initiation of marijuana abstinence in an adolescent treatment-seeking sample, and identified variables that were predictive of abstinence. Adolescents (N=69), ages 14 to 18 were randomly assigned to one of two 14-week behavioral treatments. Abstinence was measured with twice-weekly urine toxicology plus teen and parent reports. Discrete-time survival and hazard functions were conducted. The majority of adolescents achieved at least 1 week of abstinence, and 51% achieved 6 weeks of abstinence. Initiation of abstinence occurred by the sixth treatment week for 94% of teens with any abstinence suggesting that alternative, clinical approaches should be considered for those not responding by week 6. Teens with a drug negative urinalysis at intake, and teens that had two parents participating in treatment were more likely to achieve at least 6 weeks of abstinence. These findings, if replicated, can be used to inform clinical and research strategies that might lead to enhanced treatment efficacy and cost effectiveness for substance abuse treatment programming. PMID- 23085042 TI - Endothelial safety of radiological contrast media: why being concerned. AB - Iodinated radiocontrast media have been the most widely used pharmaceuticals for intravascular administration in diagnostic and interventional angiographic procedures. Although they are regarded as relatively safe drugs and vascular biocompatibility of contrast media has been progressively improved, severe adverse reactions may occur, among which acute nephropathy is one of the most clinically significant complications after intravascular administration of contrast media and a powerful predictor of poor early and long-term outcomes. Since radiocontrast media are given through the arterial or the venous circulation in vascular procedures, morphological and functional changes of the microvascular and macrovascular endothelial cells substantially contribute to the pathogenesis of organ-specific and systemic adverse reactions of contrast media. Endothelial toxicity of contrast media seems to be the result of both direct proapoptotic effects and morphological derangements, as well as endothelial dysfunction and induction of inflammation, oxidative stress, thrombosis, and altered vasomotor balance, with predominant vasoconstrictive response in atherosclerotic coronary arteries and kidney microcirculation. Further understanding of pathogenetic mechanisms underlying contrast media-induced adverse reactions in cellular targets, including endothelial cells, will hopefully lead to the development of novel preventive strategies appropriately curbing the pathogenesis of contrast media vasotoxicity. PMID- 23085043 TI - A blood stage fraction of Plasmodium berghei induces protective and long lasting immune response in BALB/c mice. AB - Incorporation of the parasite's subcellular fractions in subunit vaccines can be a possible approach for formulation of vaccine against malaria. In this study, the immunogenicity and protective efficacy of 10,000g fraction of blood stage Plasmodium berghei was evaluated in mouse model. This fraction induced higher levels of anti-parasite antibodies and provided complete and long lasting protection as compared to whole parasite antigens. Antiserum raised against it was immunoadsorbed on CNBr activated sepharose-4B to elute antigens from this fraction. Eluted antigens were characterized electrophoretically, and after lyophilization these were designated as ML-I (having 55, 64, 66, and 74kDa proteins), ML-II (having 51, 64, 66, and 72kDa proteins) and ML-III (having only 47kDa protein) sub-fractions. Mice were immunized with these sub-fractions and immune responses induced by various immunization regimens were evaluated and compared with that of 10,000g fraction. These sub-fractions imparted partial protection except ML-III, which was non-protective. 10,000g fraction as a whole provided complete protection and generated significantly higher level of IL-2 and IFN-gamma in immune mice. ML-I produced significant amount of IL-1 and IL-4 as compared to ML-II. Enhanced level of malaria-specific IgG1 was produced by ML-II, but IgG2a was significantly higher in ML-I immunized mice. Conclusively, this study identifies 10,000g fraction as a promising blood stage vaccine candidate and suggests that a vaccine based upon multiple antigens may be more efficacious as compared to single antigen based formulations. PMID- 23085044 TI - Description and genetic characterisation of Hysterothylacium (Nematoda: Raphidascarididae) larvae parasitic in Australian marine fishes. AB - Nematodes belonging to the genus Hysterothylacium (family Raphidascarididae) infect various species of marine fish in both the larval and adult stages. Humans can be accidentally infected upon eating infected seafood. In spite of their importance, relatively little is known of their occurrence and systematics in Australia. An examination of various species of marine teleosts in Australian waters revealed a high prevalence of Hysterothylacium larval types. In the present study, seven previously undescribed Hysterothylacium larval morphotypes (V to VII and IX to XII) were discovered. In total we found 10 different morphotypes and we genetically characterised nine morphotypes identified. A morphological dichotomous identification key has been established to differentiate these morphotypes. Since some larvae of Hysterothylacium from marine fishes cannot be differentiated morphologically from other nematode larvae, such as Paraheterotyphlum, Heterotyphlum, Iheringascaris and Lapetascaris, the first and second internal transcribed spacers (ITS-1 and ITS-2) of nuclear ribosomal DNA (rDNA) of these larvae were characterised to confirm their taxonomic status. This genetic characterisation implied that some distinct morphotypes belong to different developmental stages of the same species. In addition, it revealed that some morphotypes can comprise distinct genotypes. No match was found between ITS-1 and ITS-2 sequences obtained from larvae in the present study and those from adults available in the GenBank, highlighting the lack of knowledge on occurrence of adult nematodes infecting Australian fish. PMID- 23085045 TI - Chemical and genetic blockade of HDACs enhances osteogenic differentiation of human adipose tissue-derived stem cells by oppositely affecting osteogenic and adipogenic transcription factors. AB - The human adipose-tissue derived stem/stromal cells (hASCs) are an interesting source for bone-tissue engineering applications. Our aim was to clarify in hASCs the role of acetylation in the control of Runt-related transcription factor 2 (Runx2) and Peroxisome proliferator activated receptor (PPAR) gamma. These key osteogenic and adipogenic transcription factors are oppositely involved in osteo differentiation. The hASCs, committed or not towards bone lineage with osteoinductive medium, were exposed to HDACs chemical blockade with Trichostatin A (TSA) or were genetically silenced for HDACs. Alkaline phosphatase (ALP) and collagen/calcium deposition, considered as early and late osteogenic markers, were evaluated concomitantly as index of osteo-differentiation. TSA pretreatment, useful experimental protocol to analyse pan-HDAC-chemical inhibition, and switch to osteogenic medium induced early-osteoblast maturation gene Runx2, while transiently decreased PPARgamma and scarcely affected late-differentiation markers. Time-dependent effects were observed after knocking-down of HDAC1 and 3: Runx2 and ALP underwent early activation, followed by late-osteogenic markers increase and by PPARgamma/ALP activity diminutions mostly after HDAC3 silencing. HDAC1 and 3 genetic blockade increased and decreased Runx2 and PPARgamma target genes, respectively. Noteworthy, HDACs knocking-down favoured the commitment effect of osteogenic medium. Our results reveal a role for HDACs in orchestrating osteo-differentiation of hASCs at transcriptional level, and might provide new insights into the modulation of hASCs-based regenerative therapy. PMID- 23085046 TI - A meta-metabolome network of carbohydrate metabolism: interactions between gut microbiota and host. AB - With the current knowledge of the multitude of microbes that inhabit the human body, it is increasingly clear that they constitute an integral component of the host. The gut microbiota community is principally involved in the metabolism of dietary constituents such as carbohydrates which account for majority of the energy intake from diet. Diet has gained an important role in shaping the composition of gut inhabitants. The quantity and type of food consumed is recognized as a causal factor for metabolic disorders such as obesity and diabetes. Analysis of host-microbe interactions can thus contribute to the understanding of such metabolic disorders. In this study, data from Kyoto Encyclopedia of Genes and Genomes and Carbohydrate Active EnZYmes Database was utilized as a starting point. Enzyme information from the host Homo sapiens coupled with details of the three predominant phyla of gut bacteria, namely Firmicutes, Bacteroidetes and Actinobacteria were used in the creation of a comprehensive metabolic network, which we refer to as 'meta-metabolome'. This 'meta-metabolome' provides a perspective of the degree to which microbes influence carbohydrate metabolism, in conjunction with host specific enzymes. Analysis of reactions in the network reveals the amplification of monosaccharide content brought about by microbial enzyme activity. The framework outlined in this study provides a holistic approach to assess host-microbe symbiosis. It also provides us with a means of analyzing how diet can be modulated to provide beneficial effects to the host or how probiotics can potentially be used to relieve certain metabolic disorders. PMID- 23085047 TI - Dibenzocyclooctadiene lignans, gomisins J and N inhibit the Wnt/beta-catenin signaling pathway in HCT116 cells. AB - Here, we report that gomisin J and gomisin N, dibenzocyclooctadiene type lignans isolated from Schisandra chinensis, inhibit Wnt/beta-catenin signaling in HCT116 cells. Gomisins J and N appear to inhibit Wnt/beta-catenin signaling by disrupting the interaction between beta-catenin and its specific target DNA sequences (TCF binding elements, TBE) rather than by altering the expression of the beta-catenin protein. Gomisins J and N inhibit HCT116 cell proliferation by arresting the cell cycle at the G0/G1 phase. The G0/G1 phase arrest induced by gomisins J and N appears to be caused by a decrease in the expression of Cyclin D1, a representative target gene of the Wnt/beta-catenin signaling pathway, as well as Cdk2, Cdk4, and E2F-1. Therefore, gomisins J and N, the novel Wnt/beta catenin inhibitors discovered in this study, may serve as potential agents for the prevention and treatment of human colorectal cancers. PMID- 23085048 TI - [Preimplantation genetic diagnosis--developments to expect?]. AB - Preimplantation genetic diagnosis (PGD) has been practiced for over 20 years. It prevents the birth of children with serious genetic diseases by selecting healthy embryos before pregnancy. In France, the initial indications of PGD have been extended in two directions: on the one hand, to allow identification of a mutation combined with embryo's HLA typing, to obtain, at birth, stem cells for therapeutic purposes, and on the other hand, to avoid transmission of late onset diseases without having to test the at-risk parent. Other applications are practiced worldwide but are not allowed in our country, such as social sexing. Technological developments can enable more complex diagnosis, research of several diseases or other genetic traits. It may be useful, for example, to use this possibility to add screening for Down's syndrome at any PDG in older women, when the risk is high. Other objectives were considered but presenting difficulties in their application, not only for regulatory and technical reasons, but also from an ethical point of view. PMID- 23085049 TI - [Present and future strategies for women at risk, or suffering from premature ovarian failure (POF)]. AB - The purpose of this review is to present the strategies for fertility preservation that are currently proposed to patients at risk from premature ovarian failure (POF) due to chemotherapy as well as some future solutions that could allow patients already affected by an IOP to recover their fertility. Today, cryo-preservation of pieces of ovarian cortex followed by orthotopic transplantation as well as in vitro maturation of oocytes (IVM) allow preservation of fertility in patients being to undergo an antitumor treatment. However, although promising results have been obtained, the pregnancy rate remains very low. Improvement of these techniques, but also stimulation of resting follicle activation, in vitro folliculogenesis, and culture of putative oogonia that may be present in the adult ovary, are all future opportunities for patients suffering from an IOP, and are currently the subject of intensive researches. PMID- 23085051 TI - Re: comparative effectiveness for survival and renal function of partial and radical nephrectomy for localized renal tumors: a systematic review and meta analysis: s. P. Kim, R. H. Thompson, s. A. Boorjian, C. J. Weight, L. C. Han, m. H. Murad, N. D. Shippee, p. J. Erwin, B. A. Costello, g. K. Chow and B. C. Leibovich j urol 2012; 188: 51-57. PMID- 23085053 TI - Demographics of stone disease--are they changing? PMID- 23085052 TI - Robot-assisted versus open radical prostatectomy: the differential effect of regionalization, procedure volume and operative approach. AB - PURPOSE: The use of robot-assisted radical prostatectomy has increased rapidly despite the absence of randomized, controlled trials showing the superiority of this approach. While recent studies suggest an advantage for perioperative complication rates, they fail to account for the volume-outcome relationship. We compared perioperative outcomes after robot-assisted and open radical prostatectomy, while considering the impact of this established relationship. MATERIALS AND METHODS: Using the NIS (Nationwide Inpatient Sample), we abstracted data on patients treated with radical prostatectomy in 2009. Univariable and multivariable logistic regression analyses were done to compare the rates of blood transfusion, intraoperative and postoperative complications, prolonged length of stay, increased hospital charges and mortality between robot-assisted and open radical prostatectomy overall and across volume quartiles. RESULTS: An estimated 77,616 men underwent radical prostatectomy, including a robot-assisted and an open procedure in 63.9% and 36.1%, respectively. Low volume centers averaged 26.2 robot-assisted and 5.2 open cases, while very high volume centers averaged 578.8 robot-assisted and 150.2 open cases. Overall, patients treated with the robot-assisted procedure experienced a lower rate of adverse outcomes than those treated with the open procedure for all measured categories. Across equivalent volume quartiles robot-assisted radical prostatectomy outcomes were generally favorable. However, the open procedure at high volume centers resulted in a lower postoperative complication rate (OR 0.59, 95% CI 0.46-0.75), elevated hospital charges (OR 0.75, 95% CI 0.64-0.87) and a comparable blood transfusion rate (OR 1.38, 95% CI 0.93-2.02) relative to the robot-assisted procedure at low volume centers. CONCLUSIONS: Regionalization has occurred to a greater extent for robot-assisted than for open radical prostatectomy with an associated benefit in overall outcomes. Nonetheless, low volume institutions experienced inferior outcomes relative to the highest volume centers irrespective of approach. These findings demonstrate the importance of accounting for hospital volume when examining the benefit of a surgical technique. PMID- 23085055 TI - Risk of febrile urinary tract infection after reflux surgery--does the type of procedure matter? PMID- 23085057 TI - Pathological features of lymph node metastasis for predicting biochemical recurrence after radical prostatectomy for prostate cancer. AB - PURPOSE: Subclassification of nodal stage may have prognostic value in men with lymph node metastasis at radical prostatectomy. We explored the role of extranodal extension, size of the largest metastatic lymph node and the largest metastasis, and lymph node density as predictors of biochemical recurrence. MATERIALS AND METHODS: We reviewed pathological material from 261 patients with node positive prostate cancer. We examined the predictive value when adding the additional pathology findings to a base model including extraprostatic extension, seminal vesicle invasion, radical prostatectomy Gleason score, prostate specific antigen and number of positive lymph nodes using the Cox proportional hazards regression and Harrell concordance index. RESULTS: The median number of lymph nodes removed was 14 (IQR 9, 20) and the median number of positive lymph nodes was 1 (IQR 1, 2). At a median followup of 4.6 years (IQR 3.2, 6.0) 155 of 261 patients experienced biochemical recurrence. The mean 5-year biochemical recurrence-free survival rate was 39% (95% CI 33-46). Median diameter of the largest metastatic lymph node was 9 mm (IQR 5, 16). On Cox regression radical prostatectomy specimen Gleason score (greater than 7 vs 7 or less), number of positive lymph nodes (3 or greater vs 1 or 2), seminal vesicle invasion and prostate specific antigen were associated with significantly increased risks of biochemical recurrence. On subset analysis metastasis size significantly improved model discrimination (base model Harrell concordance index 0.700 vs 0.655, p = 0.032). CONCLUSIONS: Our study confirms that the number of positive lymph nodes is a predictor of biochemical recurrence in men with node positive disease. The improvement in prognostic value of measuring the metastatic focus warrants further investigation. PMID- 23085058 TI - Simvastatin induces apoptosis in castrate resistant prostate cancer cells by deregulating nuclear factor-kappaB pathway. AB - PURPOSE: In castrate resistant prostate cancer cells we investigated the cytotoxic effect of simvastatin and the mechanism involved. MATERIALS AND METHODS: After treating PC3 and DU-145 cells with simvastatin, cell viability and apoptosis were determined using tetrazolium salt based colorimetric assay and annexin-V-fluorescein isothiocyanate/propidium iodide double staining assay, respectively. To determine whether simvastatin affects the nuclear factor-kappaB pathway, we assessed IkappaBalpha and phosphorylated IkappaBalpha expression, and p65 and phosphorylated p65 subcellular localization by Western blot analysis. Also, changes in nuclear factor-kappaB transcriptional activity were assessed using a luciferase reporter assay. RESULTS: After treating PC3 and DU-145 cells with 0, 20 or 40 MUM simvastatin for 24, 48 or 72 hours, the proportion of viable cells decreased and the proportion of apoptotic cells increased in a dose and time dependent manner. Western blot analysis showed that simvastatin inhibited IkappaBalpha phosphorylation and degradation. It also demonstrated that simvastatin increased p65 protein levels in cytoplasmic fractions and decreased phosphorylated p65 protein levels in nuclear fractions but did not change p65 protein levels in cytoplasm. Luciferase reporter assay showed that simvastatin dose dependently reduced nuclear factor-kappaB activity. Reverse transcriptase polymerase chain reaction and Western blot revealed that simvastatin inhibited nuclear factor-kappaB regulated cIAP-1 and 2, cFLIP-S and XIAP expression in dose and time dependent fashion. CONCLUSIONS: Simvastatin inhibited castrate resistant prostate cancer cell growth by inducing apoptosis. These effects were probably mediated by the inhibition of IkappaBalpha phosphorylation and nuclear translocation of p50/p65 dimer in the nuclear factor-kappaB pathway. PMID- 23085059 TI - Clinical effectiveness protocols for imaging in the management of ureteral calculous disease: AUA technology assessment. AB - PURPOSE: This technology assessment addresses the optimal use of imaging in the evaluation and treatment of patients with suspected or documented ureteral stones. MATERIALS AND METHODS: A comprehensive literature search addressing 4 guiding questions was performed for full text in English articles published between January 1990 and July 2011. The search focused on major subtopics associated with the imaging of ureteral calculi, and included specific imaging modalities used in the diagnosis and management of ureteral calculous disease such as unenhanced (noncontrast) computerized tomography, conventional radiography, ultrasound, excretory urography, magnetic resonance imaging and nuclear medicine studies. Protocols (in the form of decision tree algorithms) were developed based on this literature review and in some instances on panel opinion. The 4 questions addressed were 1) What imaging study should be performed for suspected ureteral calculous disease? 2) What information should be obtained? 3) After diagnosis of a ureteral calculus, what followup imaging should be used? 4) After treatment of a ureteral calculus, what followup imaging studies should be obtained? RESULTS: Based on these protocols, noncontrast computerized tomography is recommended to establish the diagnosis in most cases, with a low energy protocol advocated if body habitus is favorable. Conventional radiography and ultrasound are endorsed for monitoring the passage of most radiopaque stones as well as for most patients undergoing stone removal. Other studies may be indicated based on imaging findings, and patient, stone and clinical factors. CONCLUSIONS: The protocols generated assist the clinician in establishing the diagnosis of ureteral calculous disease, monitoring stone passage and following patients after treatment. The protocols take into account not only clinical effectiveness but also cost-effectiveness and risk/harm associated with the various imaging modalities. PMID- 23085060 TI - High grade prostatic intraepithelial neoplasia in prostate needle biopsy. PMID- 23085061 TI - Benign renal schwannoma. PMID- 23085062 TI - Urinary NGAL and KIM-1: biomarkers for assessment of acute ischemic kidney injury following nephron sparing surgery. AB - PURPOSE: Nephron sparing surgery is considered the treatment of choice in most patients with confined renal cancer. Interrupting renal blood flow is often necessary during such surgery, which can induce significant renal injury. We explored the possibility of using urinary NGAL and KIM-1 excretion as novel biomarkers to assess the extent of acute kidney injury after nephron sparing surgery. MATERIALS AND METHODS: The study group included 27 patients who underwent open nephron sparing surgery for enhancing solid renal tumors. During surgery the renal artery was clamped for between 6 and 47 minutes. Urine samples were collected before surgery, and 1, 3, 8, 24, 48 and 72 hours after renal pedicle clamp removal. Urinary levels of NGAL and KIM-1 were determined. RESULTS: Renal artery clamping induced renal injury, as reflected by increased urinary NGAL and KIM-1 in all participants. These increases in urinary NGAL excretion were evident after 1 hour of renal ischemia and lasted for 72 hours. Urinary NGAL correlated with the serum creatinine increase and ischemia duration. Compared with patients without significantly increased serum creatinine, those with significantly increased serum creatinine after nephron sparing surgery had a greater increase in urinary NGAL but not in KIM-1. CONCLUSIONS: Renal injury severity after nephron sparing surgery could be quantitatively assessed by measuring urinary NGAL and KIM-1. PMID- 23085064 TI - Comparative Effectiveness for Survival and Renal Function of Partial and Radical Nephrectomy for Localized Renal Tumors: A Systematic Review and Meta-Analysis. PMID- 23085065 TI - The 5' untranslated region of Apaf-1 mRNA directs translation under apoptosis conditions via a 5' end-dependent scanning mechanism. AB - We have previously shown that translation driven by the 5' UTR of Apaf-1 mRNA is relatively efficient in the absence of m7G-cap, but no IRES is involved. Nevertheless, it may be speculated that a "silent" IRES is activated under apoptosis conditions. Here, we show that translation of the mRNA with the Apaf-1 5' UTR is relatively resistant to apoptosis induced by etoposide when eIF4E is sequestered by 4E-BP and eIF4G is partially cleaved. However, translation under these conditions remains governed by 5' end-dependent scanning. We hypothesize that the observed phenomenon is based on the intrinsic low cap-dependence of the Apaf-1 5' UTR. PMID- 23085066 TI - Cyclisation of Lys48-linked diubiquitin in vitro and in vivo. AB - Ubiquitin (Ub) is able to form polymeric isopeptide-linked chains through condensation of any of its seven lysine (Lys) residues with the C-terminus of an adjacent Ub monomer. Electrospray ionisation mass spectrometry (ESI-MS) of commercial in vitro-generated Lys48-linked di-Ub (Lys48-Ub(2)) revealed a major population of cyclised dimer. The absence of a free C-terminus in this population was confirmed by an inability to bind the zinc finger ubiquitin-binding domain (ZnF-UBP) of USP5/isopeptidase-T. Endogenous Ub(2) purified from skeletal muscle and cultured mammalian cells was found to contain cyclic Lys48-Ub(2), demonstrating that cyclisation of poly-Ub can also occur in vivo. PMID- 23085067 TI - Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, inhibits human oral squamous carcinoma cells KB and KB/VCR: In vitro and in vivo studies. AB - BACKGROUND: Riccardin D-26, a synthesized macrocyclic bisbibenzyl compound, might possess anti-cancer properties. We aimed to evaluate the efficacy of Riccardin D 26 as a candidate compound for treatment of cancers with sensitive or drug resistant cells. METHODS: Experiments were performed on human oral squamous carcinoma KB cells and vincristin-selected MDR KB/VCR cells. The inhibition of cell growth was evaluated by colorimetric and clonogenic assays. The apoptotic cells were determined by the Annexin V-FITC/PI staining assay. JC-1 fluorescence probe was used to examine the mitochondria membrane potential (MMP). Further experiments were performed in nude mice bearing KB or KB/VCR xenografts. Riccardin D-26 was administered by injection for 2weeks. The specimens of KB and KB/VCR xenografts were removed for TUNEL staining and Western blotting analysis. RESULTS: Riccardin D-26 significantly inhibited cancer growth in both KB and KB/VCR cells. Riccardin D-26's activity in cancer cells was greater than that in human normal liver cells. In mice, Riccardin D-26 effectively prevented the growth of KB and KB/VCR xenografts without significant toxicity. Further studies suggested that Riccardin D-26 inhibited cancer growth by inducing apoptosis in the activation of mitochondria-mediated intrinsic apoptosis pathway. Riccardin D 26 also possessed this activity in regulation of mitogen-related protein kinases such as MAPK and PI3K/Akt, which is associated with its inhibitory effect on KB/VCR cells. CONCLUSIONS: Riccardin D-26 possessed an anti-proliferation activity against both sensitive KB and MDR KB/VCR cancer cells. GENERAL SIGNIFICANCE: Riccardin D-26 could be a promising agent for treatment of cancers with sensitive or drug resistant cells. PMID- 23085068 TI - CHK1 cleavage in programmed cell death is intricately regulated by both caspase and non-caspase family proteases. AB - BACKGROUND: CHK1 is an important effector kinase that regulates the cell cycle checkpoint. Previously, we showed that CHK1 is cleaved in a caspase (CASP) dependent manner during DNA damage-induced programmed cell death (PCD) and have examined its physiological roles. METHODS AND RESULTS: In this study, we investigated the behavior of CHK1 in PCD. Firstly, we found that CHK1 is cleaved at three sites in PCD, and all cleavages were inhibited by the co-treatment of a pan-CASP inhibitor or serine protease inhibitors. We also showed that CHK1 is cleaved by CASP3 and/or CASP7 recognizing at (296)SNLD(299) and (348)TCPD(351), and that the cleavage results in the enhancement of CHK1 kinase activity. Furthermore, as a result of the characterization of cleavage sites by site directed mutagenesis and an analysis performed using deletion mutants, we identified (320)EPRT(323) as an additional cleavage recognition sequence. Considering the consensus sequence cleaved by CASP, it is likely that CHK1 is cleaved by non-CASP family protease(s) recognizing at (320)EPRT(323). Additionally, the cleavage catalyzed by the (320)EPRT(323) protease(s) markedly and specifically increased when U2OS cells synchronized into G1 phase were induced to PCD by cisplatin treatment. CONCLUSION: CHK1 cleavage is directly and indirectly regulated by CASP and non-CASP family proteases including serine protease(s) and the "(320)EPRT(323) protease(s)." Furthermore, (320)EPRT(323) cleavage of CHK1 occurs efficiently in PCD which is induced at the G1 phase by DNA damage. GENERAL SIGNIFICANCE: CASP and non-CASP family proteases intricately regulate cleavage for up-regulation of CHK1 kinase activity during PCD. PMID- 23085069 TI - Lipoic acid prevents liver metabolic changes induced by administration of a fructose-rich diet. AB - BACKGROUND: To evaluate whether co-administration of R/S-alpha-lipoic acid can prevent the development of oxidative stress and metabolic changes induced by a fructose-rich diet (F). METHODS: We assessed glycemia in the fasting state and during an oral glucose tolerance test, triglyceridemia and insulinemia in rats fed with standard diet (control) and fructose without or with R/S-alpha-lipoic acid. Insulin resistance and hepatic insulin sensitivity were also calculated. In liver, we measured reduced glutathione, protein carbonyl groups, antioxidant capacity by ABTS assay, antioxidant enzymes (catalase and superoxide dismutase 1 and 2), uncoupling protein 2, PPARdelta and PPARgamma protein expressions, SREBP 1c, fatty acid synthase and glycerol-3-phosphate acyltransferase-1 gene expression, and glucokinase activity. RESULTS: R/S-alpha-lipoic acid co administration to F-fed rats a) prevented hyperinsulinemia, hypertriglyceridemia and insulin resistance, b) improved hepatic insulin sensitivity and glucose tolerance, c) decreased liver oxidative stress and increased antioxidant capacity and antioxidant enzymes expression, d) decreased uncoupling protein 2 and PPARdelta protein expression and increased PPARgamma levels, e) restored the basal gene expression of PPARdelta, SREBP-1c and the lipogenic genes fatty acid synthase and glycerol-3-phosphate acyltransferase, and f) decreased the fructose mediated enhancement of glucokinase activity. CONCLUSIONS: Our results suggest that fructose-induced oxidative stress is an early phenomenon associated with compensatory hepatic metabolic mechanisms, and that treatment with an antioxidant prevented the development of such changes. GENERAL SIGNIFICANCE: This knowledge would help to better understand the mechanisms involved in liver adaptation to fructose-induced oxidative stress and to develop effective strategies to prevent and treat, at early stages, obesity and type 2 diabetes mellitus. PMID- 23085070 TI - Determination of the duty cycle of WLAN for realistic radio frequency electromagnetic field exposure assessment. AB - Wireless Local Area Networks (WLANs) are commonly deployed in various environments. The WLAN data packets are not transmitted continuously but often worst-case exposure of WLAN is assessed, assuming 100% activity and leading to huge overestimations. Actual duty cycles of WLAN are thus of importance for time averaging of exposure when checking compliance with international guidelines on limiting adverse health effects. In this paper, duty cycles of WLAN using Wi-Fi technology are determined for exposure assessment on large scale at 179 locations for different environments and activities (file transfer, video streaming, audio, surfing on the internet, etc.). The median duty cycle equals 1.4% and the 95th percentile is 10.4% (standard deviation SD = 6.4%). Largest duty cycles are observed in urban and industrial environments. For actual applications, the theoretical upper limit for the WLAN duty cycle is 69.8% and 94.7% for maximum and minimum physical data rate, respectively. For lower data rates, higher duty cycles will occur. Although counterintuitive at first sight, poor WLAN connections result in higher possible exposures. File transfer at maximum data rate results in median duty cycles of 47.6% (SD = 16%), while it results in median values of 91.5% (SD = 18%) at minimum data rate. Surfing and audio streaming are less intensively using the wireless medium and therefore have median duty cycles lower than 3.2% (SD = 0.5-7.5%). For a specific example, overestimations up to a factor 8 for electric fields occur, when considering 100% activity compared to realistic duty cycles. PMID- 23085071 TI - Circular causality in integrative multi-scale systems biology and its interaction with traditional medicine. AB - This paper discusses the concept of circular causality in "biological relativity" (Noble, Interface Focus. 2, 56-64, 2012) in the context of integrative and multi scale systems approaches to biology. It also discusses the relationship between systems biology and traditional medicine (sometimes called scholarly medical traditions) mainly from East Asia and India. Systems biology helps illuminate circular processes identified in traditional medicine, while the systems concept of attractors in complex systems will also be important in analysing dynamic balance in the body processes that traditional medicine is concerned with. Ways of nudging disordered processes towards good attractors through the use of traditional medicines can lead to the development of new ways not only of curing disease but also of its prevention. Examples are given of cost-effective multi component remedies that use integrative ideas derived from traditional medicine. PMID- 23085072 TI - Anxiolytic effects of environmental enrichment attenuate sex-related anxiogenic effects of scopolamine in rats. AB - In groups of four same-sexed animals, PVG/c hooded rats were housed for 4.5 months in standard or enriched cages containing several objects that could be explored and manipulated. On separate occasions, each rat then experienced two consecutive daily trials in an open field, a light-dark box or a Y maze with arm inserts that enabled an acquisition trial comprising one black and one white arm to be changed for a retention trial consisting of two black arms. Before their trials in the open field and light-dark box, and following each acquisition trial in the Y maze, the rats received an intraperitoneal injection of 2 mg/kg scopolamine or isotonic saline. In the open field, enrichment led to higher levels of ambulation, walking, rearing and occupancy of the center of the apparatus and shorter emergence latencies from the dark into the light compartment of the light-dark box accompanied by more entries of this compartment. Enrichment also increased entries of and time spent in the changed (or novel) Y-maze arm only for male rats treated with scopolamine. The drug decreased rearing and increased grooming in the open field as well as increasing emergence latencies and decreasing entries of and the time spent on the light compartment of the light-dark box. The main results were interpreted as enrichment having attenuated anxiogenic effects of the behavioral testing and the action of scopolamine for male (but not female) rats in their choices of the novel arm in the Y maze. PMID- 23085073 TI - Adjunctive effects of aripiprazole on metabolic profiles: comparison of patients treated with olanzapine to patients treated with other atypical antipsychotic drugs. AB - Metabolic abnormalities are serious adverse effects of atypical antipsychotic treatment. This study aims to determine the effects of adjunctive aripiprazole on metabolic profiles among patients receiving treatment with atypical antipsychotics, and to examine whether these effects are different from that of pre-existing atypical antipsychotics. In the 8-week open-label trial, aripiprazole was added to patients who were receiving treatment with atypical antipsychotics and had experienced weight gain or dyslipidemia. The dosage of pre existing atypical antipsychotics was fixed, while the dosage of aripiprazole ranged from 5 to 20 mg/day during the study period. Metabolic profiles, including body weight, body mass index (BMI), plasma levels of fasting glucose, triglycerides, total cholesterol, high-density lipoprotein-cholesterol, low density lipoprotein-cholesterol, and adiponectin, were measured at baseline and week 8. As a result, 43 subjects (16 males and 27 females, mean age: 37.8+/-10.8 years) completed the study. The pre-existing antipsychotics were olanzapine (n=12), risperidone (n=19), quetiapine (n=6) and amisulpiride (n=6). The mean dosage of adjunctive aripiprazole was 9.9+/-3.2 mg/day. After the aripiprazole augmented regimen for 8 weeks, patients treated with olanzapine had significant decreases in body weight, BMI and triglyceride levels, and had significant increases in adiponectin levels. For patients treated with other atypical antipsychotics, none of the metabolic parameters significantly changed after administering aripiprazole. In conclusion, aripiprazole-augmented treatment might be beneficial for the metabolic regulation of patients being treated with a stable dose of olanzapine, but not for those treated with other atypical antipsychotics. A long-term, randomized, double-blind controlled design is suggested to confirm these findings. PMID- 23085074 TI - Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia. PMID- 23085075 TI - Structural and functional characterization of an SMC-like protein RecN: new insights into double-strand break repair. AB - Repair of DNA double-strand breaks (DSBs) is essential for cell survival and maintaining genome integrity. DSBs are repaired in a stepwise manner by homologous recombination. Here, we focused on the early steps of DSB repair, including DSB recognition, which is still only poorly understood. In prokaryotes, this process has been proposed to involve the RecN protein, a member of the structural maintenance of chromosome (SMC) protein family, which include key eukaryotic and prokaryotic proteins such as cohesin, condensin, and Rad50. An extensive high- and low-resolution structural analysis of Deinococcus radiodurans RecN using a combination of protein crystallography and small-angle X-ray scattering enabled us to assemble a quasi-atomic model of the entire RecN protein, representing the complete structure of a SMC-like protein. These results, together with a thorough biochemical and mutational study of RecN, allow us to propose a model for the role of RecN in DSB repair. PMID- 23085076 TI - Crystal structure of a Ba(2+)-bound gating ring reveals elementary steps in RCK domain activation. AB - RCK domains control activity of a variety of K(+) channels and transporters through binding of cytoplasmic ligands. To gain insight toward mechanisms of RCK domain activation, we solved the structure of the RCK domain from the Ca(2+) gated K(+) channel, MthK, bound with Ba(2+), at 3.1 A resolution. The Ba(2+) bound RCK domain was assembled as an octameric gating ring, as observed in structures of the full-length MthK channel, and shows Ba(2+) bound at several positions. One of the Ba(2+) sites, termed C1, overlaps with a known Ca(2+) activation site, determined by residues D184 and E210. Functionally, Ba(2+) can activate reconstituted MthK channels as observed in electrophysiological recordings, whereas Mg(2+) (up to 100 mM) was ineffective. Ba(2+) activation was abolished by the mutation D184N, suggesting that Ba(2+) activates primarily through the C1 site. Our results suggest a working hypothesis for a sequence of ligand-dependent conformational changes that may underlie RCK domain activation and channel gating. PMID- 23085078 TI - Structural basis of the PNRC2-mediated link between mrna surveillance and decapping. AB - Nonsense-mediated mRNA decay (NMD) is an important mRNA surveillance system, and human PNRC2 protein mediates the link between mRNA surveillance and decapping. However, the mechanism by which PNRC2 interacts with the mRNA surveillance machinery and stimulates NMD is unknown. Here, we present the crystal structure of Dcp1a in complex with PNRC2. The proline-rich region of PNRC2 is bound to the EVH1 domain of Dcp1a, while its NR-box mediates the interaction with the hyperphosphorylated Upf1. The mode of PNRC2 interaction with Dcp1a is distinct from those observed in other EVH1/proline-rich ligands interactions. Disruption of the interaction of PNRC2 with Dcp1a abolishes its P-body localization and ability to promote mRNA degradation when tethered to mRNAs. PNRC2 acts in synergy with Dcp1a to stimulate the decapping activity of Dcp2 by bridging the interaction between Dcp1a and Dcp2, suggesting that PNRC2 is a decapping coactivator in addition to its adaptor role in NMD. PMID- 23085077 TI - RecA-binding pilE G4 sequence essential for pilin antigenic variation forms monomeric and 5' end-stacked dimeric parallel G-quadruplexes. AB - Neisseria gonorrhoeae is an obligate human pathogen that can escape immune surveillance through antigenic variation of surface structures such as pili. A G quadruplex-forming (G4) sequence (5'-G(3)TG(3)TTG(3)TG(3)) located upstream of the N. gonorrhoeae pilin expression locus (pilE) is necessary for initiation of pilin antigenic variation, a recombination-based, high-frequency, diversity generation system. We have determined NMR-based structures of the all parallel stranded monomeric and 5' end-stacked dimeric pilE G-quadruplexes in monovalent cation-containing solutions. We demonstrate that the three-layered all parallel stranded monomeric pilE G-quadruplex containing single-residue double-chain reversal loops, which can be modeled without steric clashes into the 3 nt DNA binding site of RecA, binds and promotes E. coli RecA-mediated strand exchange in vitro. We discuss how interactions between RecA and monomeric pilE G-quadruplex could facilitate the specialized recombination reactions leading to pilin diversification. PMID- 23085079 TI - GAP-43 dependency defines distinct effects of netrin-1 on cortical and spinal neurite outgrowth and directional guidance. AB - Growth-associated protein-43 (GAP-43) is a major nervous system protein whose phosphorylation by protein kinase C regulates growth cone responses to extracellular guidance cues via F-actin. GAP-43 is essential for axon pathfinding in both cortical afferents and efferents: when it is genetically deleted, somatosensory, auditory and visual somatotopic maps fail to form, and telencephalic commissural axons fail to cross the midline. Here we investigated whether the midline guidance cue netrin-1 depends on GAP-43 for its functions in neurite growth and guidance. We used 3-dimensional collagen gel co-cultures to show that both endogenous netrin-1, expressed by the spinal cord floor plate, and recombinant netrin-1, expressed by transfected COS7 cells, stimulate neurite outgrowth and chemotropic guidance of neocortical callosal axons. In contrast both were significantly inhibited in GAP-43 (-/-) neocortical callosal axons, mimicking the in vivo phenotype. Conversely, neither netrin-1-stimulated neurite outgrowth nor guidance of dorsal spinal cord commissure axons were affected when GAP-43 was absent, again consistent with in vivo phenotype but suggesting fundamental differences in how neocortical and spinal cord axons respond to netrin-1. In addition, differences in GAP-43 dependency also distinguished how ventrolateral cortical efferents respond to netrin-1: in contrast to callosal neurites, in which netrin-1 required GAP-43 in order to stimulate both outgrowth and guidance, in ventrolateral efferents, netrin-1 required GAP-43 only to stimulate outgrowth, but not guidance. Moreover, netrin-1 increased the numbers of both types of cortical, but not spinal neurites. The results demonstrate previously unappreciated diversity in how different classes of neurons respond to the same guidance cue. PMID- 23085080 TI - Aberrant expression of collapsin response mediator proteins-1, -2 and -5 in the brain of intrauterine growth restricted rats. AB - Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity, higher incidence of neurodevelopmental defects and increased risk for adult metabolic syndrome manifestations. Altered protein expression profiles associated with IUGR may be informative on the pathological mechanisms of this condition and might reveal potential markers for postnatal complications. We hypothesized that nutrient manipulation of the pregnant rat might influence the expression of important neurodevelopmental proteins in the resultant IUGR offspring. Therefore, we aimed to determine in newborn rat brain tissue the expression of collapsin response mediator proteins (CRMPs)-1, -2 and -5, commonly referred to as dihydropyrimidinase-related proteins (DPYLs) - playing a role in axon guidance, invasive growth and cell migration - and compare it to the corresponding expression in control rats. Two-dimensional electrophoresis and mass spectrometry, as well as Western blot analysis were employed in brain tissue from 24 IUGR newborn rats and 24 controls. With both methods, CRMP-1, CRMP-2 and CRMP-5 were decreased in the brains of the IUGR group as compared to the control group at the time of delivery. In conclusion, IUGR rat offspring are born with a decreased expression of CRMPs, suggesting that these proteins may be implicated in fetal stress-induced programming. PMID- 23085081 TI - Transplantation of neural stem cells co-transfected with Nurr1 and Brn4 for treatment of Parkinsonian rats. AB - Neural stem cells (NSCs) tranplantation has great potential for the treatment of neurodegenerative disease such as Parkinson's disease (PD). However, the usage of NSCs is limited because the differentiation of NSCs into specific dopaminergic neurons has proven difficult. We have recently demonstrated that transgenic expression of Nurr1 could induce the differentiation of NSCs into tyrosine hydroxylase (TH) immunoreactive dopaminergic neurons, and forced co-expression of Nurr1 with Brn4 caused a dramatic increase in morphological and phenotypical maturity of these neurons. In this study, we investigated the effect of transplanted NSCs in PD model rats. The results showed that overexpression of Nurr1 promoted NSCs to differentiate into dopaminergic neurons in vivo, increased the level of dopamine (DA) neurotransmitter in the striatum, resulting in behavioral improvement of PD rats. Importantly, co-expression of Nurr1 and Brn4 in NSCs significantly increased the maturity and viability of dopaminergic neurons, further raised the DA amount in the striatum and reversed the behavioral deficit of the PD rats. Our findings provide a new potential and strategy for the use of NSCs in cell replacement therapy for PD. PMID- 23085082 TI - Glycogen synthase kinase-3beta regulates differentiation-induced apoptosis of human neural progenitor cells. AB - Glycogen synthase kinase-3beta is a multifunctional key regulator enzyme in neural developmental processes and a main component of the canonical Wnt signaling pathway. It is already known that the Wnt-driven differentiation of neural progenitor cells is accompanied by an increase of apoptosis at which the pro-apoptotic function of GSK-3beta is still discussed. The aim of the present study was to investigate whether the phosphorylation level of GSK-3beta at serine 9 is the primary regulatory mechanism of differentiation-induced apoptosis. Differentiating human neural ReNcell VM progenitor cells were treated with the specific GSK-3beta inhibitor SB216763 (10 MUM) and analyzed in respect to the intrinsic apoptosis pathway regulation using microscopy and protein expression analysis. Differentiation of ReNcell VM cells was accompanied by cell morphological changes, cytoskeleton rearrangement and apoptosis increase. Treatment of differentiating cells with SB216763 induced a significant dephosphorylation of GSK-3beta at serine 9 accompanied by a significant decrease of apoptosis of about 0.7+/-0.03% and reduced activation of caspase-3 as well as BAX and PARP cleavage during the first 12h of differentiation compared to untreated, differentiating cells. Dephosphorylation of GSK-3beta at serine 9 appears not solely to be responsible for its pro-apoptotic function, because we observed a decrease of intrinsic apoptosis after treatment of the cells with the specific GSK-3beta inhibitor SB216763. We assume that GSK-3beta drives neural progenitor cell apoptosis by direct interaction with pro-apoptotic BAX or by indirect influence on the canonical Wnt/beta-catenin target gene transcription. PMID- 23085083 TI - Mechanosensation and transduction in osteocytes. AB - The human skeleton is a miracle of engineering, combining both toughness and light weight. It does so because bones possess cellular mechanisms wherein external mechanical loads are sensed. These mechanical loads are transformed into biological signals, which ultimately direct bone formation and/or bone resorption. Osteocytes, since they are ubiquitous in the mineralized matrix, are the cells that sense mechanical loads and transduce the mechanical signals into a chemical response. The osteocytes then release signaling molecules, which orchestrate the recruitment and activity of osteoblasts or osteoclasts, resulting in the adaptation of bone mass and structure. In this review, we highlight current insights in bone adaptation to external mechanical loading, with an emphasis on how a mechanical load placed on whole bones is translated and amplified into a mechanical signal that is subsequently sensed by the osteocytes. PMID- 23085084 TI - Localized deferoxamine injection augments vascularity and improves bony union in pathologic fracture healing after radiotherapy. AB - BACKGROUND: Medically based efforts and alternative treatment strategies to prevent or remediate the corrosive effects of radiotherapy on pathologic fracture healing have failed to produce clear and convincing evidence of success. Establishing an effective pharmacologic option to prevent or treat the development of non-unions in this setting could have immense therapeutic potential. Experimental studies have shown that deferoxamine (DFO), an iron chelating agent, bolsters vascularity and subsequently enhances normal fracture healing when injected locally into a fracture callus in long bone animal models. Since radiotherapy is known to impede angiogenesis, we hypothesized that the pharmacologic addition of DFO would serve to mitigate the effects of radiotherapy on new vessel formation in vitro and in vivo. MATERIALS AND METHODS: In vitro investigation of angiogenesis was conducted utilizing HUVEC cells in Matrigel. Endothelial tubule formation assays were divided into four groups: Control, Radiated, Radiated+Low-Dose DFO and Radiated+High-Dose DFO. Tubule formation was quantified microscopically and video recorded for the four groups simultaneously during the experiment. In vivo, three groups of Sprague-Dawley rats underwent external fixator placement and fracture osteotomy of the left mandible. Two groups received pre-operative fractionated radiotherapy, and one of these groups was treated with DFO after fracture repair. After 40 days, the animals were perfused and imaged with micro-CT to calculate vascular radiomorphometrics. RESULTS: In vitro, endothelial tubule formation assays demonstrated that DFO mitigated the deleterious effects of radiation on angiogenesis. Further, high dose DFO cultures appeared to organize within 2h of incubation and achieved a robust network that was visibly superior to all other experimental groups in an accelerated fashion. In vivo, animals subjected to a human equivalent dose of radiotherapy (HEDR) and left mandibular fracture demonstrated quantifiably diminished MUCT metrics of vascular density, as well as a 75% incidence of associated non-unions. The addition of DFO in this setting markedly improved vascularity as demonstrated with 3D angiographic modeling. In addition, we observed an increased incidence of bony unions in the DFO treated group when compared to radiated fractures without treatment (67% vs. 25% respectively). CONCLUSION: Our data suggest that selectively targeting angiogenesis with localized DFO injections is sufficient to remediate the associated severe vascular diminution resulting from a HEDR. Perhaps the most consequential and clinically relevant finding was the ability to reduce the incidence of non-unions in a model where fracture healing was not routinely observed. PMID- 23085086 TI - Tracking EEG changes in response to alpha and beta binaural beats. AB - A binaural beat can be produced by presenting two tones of a differing frequency, one to each ear. Such auditory stimulation has been suggested to influence behaviour and cognition via the process of cortical entrainment. However, research so far has only shown the frequency following responses in the traditional EEG frequency ranges of delta, theta and gamma. Hence a primary aim of this research was to ascertain whether it would be possible to produce clear changes in the EEG in either the alpha or beta frequency ranges. Such changes, if possible, would have a number of important implications as well as potential applications. A secondary goal was to track any observable changes in the EEG throughout the entrainment epoch to gain some insight into the nature of the entrainment effects on any changes in an effort to identify more effective entrainment regimes. Twenty two healthy participants were recruited and randomly allocated to one of two groups, each of which was exposed to a distinct binaural beat frequency for ten 1-minute epochs. The first group listened to an alpha binaural beat of 10 Hz and the second to a beta binaural beat of 20 Hz. EEG was recorded from the left and right temporal regions during pre-exposure baselines, stimulus exposure epochs and post-exposure baselines. Analysis of changes in broad-band and narrow-band amplitudes, and frequency showed no effect of binaural beat frequency eliciting a frequency following effect in the EEG. Possible mediating factors are discussed and a number of recommendations are made regarding future studies, exploring entrainment effects from a binaural beat presentation. PMID- 23085085 TI - Histone deacetylase 3 is required for maintenance of bone mass during aging. AB - Histone deacetylase 3 (Hdac3) is a nuclear enzyme that removes acetyl groups from lysine residues in histones and other proteins to epigenetically regulate gene expression. Hdac3 interacts with bone-related transcription factors and co factors such as Runx2 and Zfp521, and thus is poised to play a key role in the skeletal system. To understand the role of Hdac3 in osteoblasts and osteocytes, Hdac3 conditional knockout (CKO) mice were created with the osteocalcin (OCN) promoter driving Cre expression. Hdac3 CKO(OCN) mice were of normal size and weight, but progressively lost trabecular and cortical bone mass with age. The Hdac3 CKO(OCN) mice exhibited reduced cortical bone mineralization and material properties and suffered frequent fractures. Bone resorption was lower, not higher, in the Hdac3 CKO(OCN) mice, suggesting that primary defects in osteoblasts caused the reduced bone mass. Indeed, reductions in bone formation were observed. Osteoblasts and osteocytes from Hdac3 CKO(OCN) mice showed increased DNA damage and reduced functional activity in vivo and in vitro. Thus, Hdac3 expression in osteoblasts and osteocytes is essential for bone maintenance during aging. PMID- 23085087 TI - Expression, purification and kinetic characterisation of human tissue transglutaminase. AB - The expression of soluble recombinant transglutaminase (TGase) has proven to be a challenge for many research groups. Herein, we report a complementary method for the expression, in BL21(DE3) Escherichia coli, of recombinant human tissue transglutaminase (hTG2) whose solubility is enhanced through N-terminal fusion to glutathione S-transferase (GST). Moreover, we report the cleavage of the GST tag using PreScissionTM Protease (PSP) and purification of hTG2 in its untagged form, distinctively suitable for subsequent studies of its remarkable conformational equilibrium. The effects of co-solvents and storage conditions on stability of purified hTG2 are also reported. Furthermore, we demonstrate for the first time the use of a convenient chromogenic assay to measure the activity of the human enzyme. The utility of this assay was demonstrated in the measurement of the kinetic parameters of a wide variety of substrates and inhibitors of both hTG2 and the extensively studied guinea pig liver TGase. Finally, comparison of these results provides further evidence for the functional similarity of the two enzymes. PMID- 23085088 TI - Expression of human heteromeric amino acid transporters in the yeast Pichia pastoris. AB - Human heteromeric amino acid transporters (HATs) play key roles in renal and intestinal re-absorption, cell redox balance and tumor growth. These transporters are composed of a heavy and a light subunit, which are connected by a disulphide bridge. Heavy subunits are the two type II membrane N-glycoproteins rBAT and 4F2hc, while L-type amino acid transporters (LATs) are the light and catalytic subunits of HATs. We tested the expression of human 4F2hc and rBAT as well as seven light subunits in the methylotrophic yeast Pichia pastoris. 4F2hc and the light subunit LAT2 showed the highest expression levels and yields after detergent solubilization. Co-transformation of both subunits in Pichia cells resulted in overexpression of the disulphide bridge-linked 4F2hc/LAT2 heterodimer. Two sequential affinity chromatography steps were applied to purify detergent-solubilized heterodimers yielding ~1mg of HAT from 2l of cell culture. Our results indicate that P. pastoris is a convenient system for the expression and purification of human 4F2hc/LAT2 for structural studies. PMID- 23085089 TI - Fear of pain in the context of intensive pain rehabilitation among children and adolescents with neuropathic pain: associations with treatment response. AB - Recent research has implicated pain-related fear in relation to functional outcomes in children with chronic pain. The current study examined fear of pain, disability, and depression within the context of an intensive pain rehabilitation program. One hundred forty-five children and adolescents who participated in an intensive interdisciplinary pediatric pain rehabilitation day program were assessed in this study. Patients completed measures of pain intensity, pain related fears, functional disability, and depressive symptoms at admission, discharge, and on average, 2 months postdischarge. After controlling for pain intensity, pain-related fear was significantly related to disability and depressive symptoms at all time points. As predicted, a decline in pain-related fear was significantly associated with a decrease in disability and depressive symptoms. Interestingly, high levels of pain-related fears at admission predicted less reduction in functional disability and depression at discharge, suggesting that high levels of pain-related fear may be a risk factor in relation to treatment outcomes. Overall, results indicate that the relationship between fear of pain and changes in disability and depressive symptoms are closely linked, with fear of pain playing an important role in treatment. PERSPECTIVE: This paper presents results underscoring the importance of pain-related fear in relation to treatment response for children and adolescents with chronic pain. These findings support the need to develop and implement interventions that target reductions in pain-related fear. PMID- 23085090 TI - Non-taxoid site microtubule-stabilizing drugs work independently of tau overexpression in mouse N2a neuroblastoma cells. AB - Microtubule-stabilizing drugs are useful in cancer therapy and show promise for treatment of neurodegenerative diseases. An overlapping binding site between tau and taxoid site drugs has led to a number of research papers investigating the competitive interaction between these drugs and the microtubule. This has implications for cancer treatment since increased tau could confer resistance to paclitaxel. Variations in the tau isoform ratio have also been reported in tauopathies, especially the rise in the levels of the four-repeat tau isoform. Therefore, in conditions of increased or altered expression of tau and its isoforms, a therapy that is not directly affected by changes in tau is desirable. Peloruside A and laulimalide are of particular interest in this respect because of their distinct binding site on the microtubule in relation to the clinically used drugs paclitaxel and ixabepilone. In the present study, we show that peloruside A and laulimalide stabilize microtubules independently of tau overexpression; whereas, the effects of paclitaxel and ixabepilone are masked by the presence of extra tau in the cell. PMID- 23085091 TI - Recent development in the effects of statins on cardiovascular disease through Rac1 and NADPH oxidase. AB - Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), are important lipid-lowering agents. After two decades of laboratory and clinical studies, their pleiotropic effects appear well-established. One of these effects is through the regulation of Rac1 and NADPH oxidases. Relatively few human trials have been carried out with regards to the action of statins on Rac1 and NADPH oxidases, but similar positive effects were also observed in blood vessels and myocardium of participants in the trials. Besides, more specific biomarkers for the antioxidation effects of statins have been developed in the recent two years; both monitoring of the progress of disease and the effects of medical therapy will be possible. Further development of the potency and specificity of statin may enhance their therapeutic potential on cardiovascular disease. PMID- 23085092 TI - A population-based case-control study on the association between rheumatoid arthritis and deep vein thrombosis. AB - OBJECTIVE: Chronic inflammation has been associated with endothelial dysfunction and altered coagulation status. However, at the present time, the data regarding the risk for developing deep vein thrombosis (DVT) in patients with rheumatoid arthritis (RA) is still scanty and conflicted. This study aimed to explore the frequency and association of DVT with RA using a population-based dataset. METHODS: This was a case-control study conducted in Taiwan. A total of 5193 patients with DVT were identified from the Longitudinal Health Insurance Database 2000 (LHID2000) database. In total, 20,772 controls matched with cases in terms of gender, age, and year of index date were randomly selected. We used conditional logistic regression to calculate the odds ratio (OR) for having been previously diagnosed with RA between cases and controls. RESULTS: Of the total 25,965 sampled subjects, 235 (0.9%) had been previously diagnosed with RA. Seventy-seven of these previous diagnoses were found among cases (1.5%) and 158 among controls (0.8%). Conditional logistic regression analysis revealed that cases were more likely to have had prior RA than controls (OR, 1.92; 95% confidence interval [CI], 1.46-2.53; P<.001). After adjusting for hospitalization history, pregnancy, fracture, surgery, cancer, inflammatory bowel disease, heart failure, hypertension, diabetes, coronary heart disease, hyperlipidemia, and renal disease, there was still a significant association between DVT and prior RA (OR, 1.88; 95% CI, 1.42-2.58; P<.001). CONCLUSIONS: We found RA to be significantly associated with DVT. Appropriate management should be taken to minimize the risk of DVT in patients with RA. Further study is needed to confirm our findings. PMID- 23085093 TI - Extinguishing intracellular calcium leak: a promising antiarrhythmic approach. PMID- 23085094 TI - Molecular analysis of point mutations in a barley genome exposed to MNU and gamma rays. AB - We present studies aimed at determining the types and frequencies of mutations induced in the barley genome after treatment with chemical (N-methyl-N nitrosourea, MNU) and physical (gamma rays) mutagens. We created M(2) populations of a doubled haploid line and used them for the analysis of mutations in targeted DNA sequences and over an entire barley genome using TILLING (Targeting Induced Local Lesions in Genomes) and AFLP (Amplified Fragment Length Polymorphism) technique, respectively. Based on the TILLING analysis of the total DNA sequence of 4,537,117bp in the MNU population, the average mutation density was estimated as 1/504kb. Only one nucleotide change was found after an analysis of 3,207,444bp derived from the highest dose of gamma rays applied. MNU was clearly a more efficient mutagen than gamma rays in inducing point mutations in barley. The majority (63.6%) of the MNU-induced nucleotide changes were transitions, with a similar number of G>A and C>T substitutions. The similar share of G>A and C>T transitions indicates a lack of bias in the repair of O(6)-methylguanine lesions between DNA strands. There was, however, a strong specificity of the nucleotide surrounding the O(6)-meG at the -1 position. Purines formed 81% of nucleotides observed at the -1 site. Scanning the barley genome with AFLP markers revealed ca. a three times higher level of AFLP polymorphism in MNU-treated as compared to the gamma-irradiated population. In order to check whether AFLP markers can really scan the whole barley genome for mutagen-induced polymorphism, 114 different AFLP products, were cloned and sequenced. 94% of bands were heterogenic, with some bands containing up to 8 different amplicons. The polymorphic AFLP products were characterised in terms of their similarity to the records deposited in a GenBank database. The types of sequences present in the polymorphic bands reflected the organisation of the barley genome. PMID- 23085095 TI - The exposure of highly toxic aconitine does not significantly impact the activity and expression of cytochrome P450 3A in rats determined by a novel ultra performance liquid chromatography-tandem mass spectrometric method of a specific probe buspirone. AB - Aconitum species are widely used to treat rheumatism, cardiovascular diseases, and tumors in China and other Asian countries. The herbs are always used with drugs such as paclitaxel. Aconitine (AC) is one of the main bioactive/high-toxic alkaloids of Aconitum roots. AC is metabolized by cytochrome P450 (CYP) 3A. However, whether AC inhibits/induces CYP3A, which causes drug-drug interaction (DDI) is unclear. Our study aims to explore the potent effects of AC, as a marker component of Aconitum, on CYP3A using the probe buspirone in rats. The effects of oral AC on pharmacokinetics of buspirone were evaluated. CYP3A activity and protein levels in rat liver microsomes pretreated with oral AC were also measured using in vitro buspirone metabolism and Western blot. Buspirone and its major metabolites 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone were determined using a newly validated UPLC-MS/MS method. Single dose and 7-day AC administration at 0.125mg/kg had no effect on CYP3A activity since no change in the formation of 1-(2-pyrimidinyl)piperazine and 6'-hydroxybuspirone. CYP3A activity and protein levels in liver microsomes were also not affected by 7-day AC pretreatment at 0.125mg/kg. Therefore, AC neither inhibits nor induces CYP3A in rats, indicating AC does not cause CYP3A-related DDI in the liver. PMID- 23085096 TI - Randomized trial of endoscopic sphincterotomy with balloon dilation versus endoscopic sphincterotomy alone for removal of bile duct stones. AB - BACKGROUND & AIMS: Limited endoscopic sphincterotomy with large balloon dilation (ESBD) is an alternative to endoscopic sphincterotomy (ES) for removing bile duct stones, but it is not clear which procedure is most effective. We compared the 2 techniques in removal of bile duct stones. METHODS: Between September 2005 and September 2011, 156 consecutive patients with suspected of having, or known to have, common bile duct stones were randomly assigned to groups that underwent ES or ESBD. Patients in the ESBD group underwent limited sphincterotomy (up to half of the sphincter) followed by balloon dilation to the size of the common bile duct or 15 mm, and patients in the ES group underwent complete sphincterotomy alone. Stones were then removed using standard techniques. The primary outcome was percentage of stones cleared, and secondary outcomes included procedural time, method of stone extraction, number of procedures required for stone clearance, morbidities and mortality within 30 days, and direct cost. RESULTS: There was no significant difference between groups in percentage of stones cleared (ES vs ESBD: 88.5% vs 89.0%). More patients in the ES group (46.2%) than the ESBD group (28.8%) required mechanical lithotripsy (P = .028), particularly for stones >=15 mm (90.9% vs 58.1%; P = .002). Morbidities developed in 10.3% of patients in the ES group and 6.8% of patients in the ESBD group (P = .46). The cost of the hospitalization was also significantly lower in the ESBD group (P = .034). CONCLUSIONS: ESBD and ES clear bile stones with equal efficacy. However, ESBD reduces the need for mechanical lithotripsy and is less expensive; ClinicalTrials.gov number, NCT00164853. PMID- 23085097 TI - Synaptic innervation to rat hippocampus by vasopressin-immuno-positive fibres from the hypothalamic supraoptic and paraventricular nuclei. AB - The neuropeptide arginine vasopressin (AVP) exerts a modulatory role on hippocampal excitability through vasopressin V(1A) and V(1B) receptors. However, the origin and mode of termination of the AVP innervation of the hippocampus remain unknown. We have used light and electron microscopy to trace the origin, distribution and synaptic relationships of AVP-immuno-positive fibres and nerve terminals in the rat hippocampus. Immuno-positive fibres were present in all areas (CA1-3, dentate gyrus) of the whole septo-temporal extent of the hippocampus; they had the highest density in the CA2 region, strongly increasing in density towards the ventral hippocampus. Two types of fibres were identified, both establishing synaptic junctions. Type A had large varicosities packed with immuno-positive large-granulated peptidergic vesicles and few small clear vesicles forming type I synaptic junctions with pyramidal neuron dendrites, dendritic spines and with axonal spines. Type B had smaller varicosities containing mostly small clear vesicles and only a few large-granulated vesicles and established type II synaptic junctions mainly with interneuron dendrites. The AVP-positive axons in stratum oriens appeared to follow and contact metabotropic glutamate receptor 1alpha (mGluR1alpha)-immuno-positive interneuron dendrites. Fluoro-Gold injection into the hippocampus revealed retrogradely labelled AVP positive somata in hypothalamic supraoptic and paraventricular nuclei. Hypothalamo-hippocampal AVP-positive axons entered the hippocampus mostly through a ventral route, also innervating the amygdala and to a lesser extent through the dorsal fimbria fornix, in continuation of the septal AVP innervation. Thus, it appears the AVP-containing neurons of the magnocellular hypothalamic nuclei serve as important sources for hippocampal AVP innervation, although the AVP-expressing neurons located in amygdala and bed nucleus of the stria terminalis reported previously may also contribute. PMID- 23085098 TI - False positivity of circumsporozoite protein (CSP)-ELISA in zoophilic anophelines in Bangladesh. AB - Circumsporozoite protein enzyme-linked immunosorbent assays (CSP-ELISAs) are widely used for malaria vector identification throughout the world. However, several studies have reported false-positive results when using this method. The present study was conducted to estimate the frequency of false positives among anopheline species in malaria endemic areas of Bangladesh. In total, 4724 Anopheles females belonging to 25 species were collected and tested for Plasmodium falciparum, Plasmodium vivax-210, and P. vivax-247 CSP. Initially, 144 samples tested positive using routine CSP-ELISA, but the number of positive results declined to 85 (59%) when the samples were tested after heating at 100 degrees C for 10min to remove false-positive specimens. Ten species, Anopheles annularis, Anopheles baimaii, Anopheles barbirostris, Anopheles jeyporiensis, Anopheles karwari, Anopheles kochi, Anopheles minimus s.l., Anopheles peditaeniatus, Anopheles philippinensis, and Anopheles vagus were CSP-positive. The highest and lowest infection rates were found in An. baimaii (4/25, 16.0%) and An. jeyporiensis (1/139, 0.67%), respectively. A significant correlation was found (regression analysis, R(2)=0.49, F=8.25, P<0.05) between human blood index results and the true CSP-positive ratios in 15 Anopheles species. We confirmed that false-positive reactions occurred more frequently in zoophilic species. The relatively high proportion of false positives (40%) that was found in this study should warn malaria epidemiologists working in the field to be cautious when interpreting ELISA results. PMID- 23085099 TI - A polyamine-deficient diet opposes hyperalgesia, tolerance and the increased anxiety-like behaviour associated with heroin withdrawal in rats. AB - In humans, hyperalgesia, tolerance and anxiety disorders are common symptoms during heroin withdrawal syndrome. Significant evidence supports a role of NMDA receptors in these phenomena. Because polyamines may positively modulate the functioning of NMDA receptors and mainly originate from dietary intake, one hypothesis is that a polyamine deficient diet (PD diet) may reduce withdrawal symptoms. To address this question, we investigated the ability of a PD diet to prevent or to alleviate some symptoms of withdrawal syndrome as hyperalgesia, and increased anxiety-like behaviour in rats receiving 14 once daily subcutaneous heroin injections. Here, we show that a PD diet has both preventive and curative properties for reducing certain signs of withdrawal such as hyperalgesia, tolerance and increased anxiety-like behaviour observed in rats fed with a standard diet. Moreover, in heroin-withdrawn rats which were returned to basal pain sensitivity level, hyperalgesia following acute analgesia induced by a single heroin dose was observed in heroin-treated rats fed with standard diet, not in rats fed with a PD diet. Similarly, a stress-induced hyperalgesia induced by a non-nociceptive environmental stress session was observed in heroin-treated rats fed with standard diet. In contrast, a stress-induced analgesia was observed in heroin-treated rats fed with a PD diet, as it was observed in non heroin treated rats. Since a PD diet for several weeks did not induce appreciable side effects in rats, these preclinical results suggest that a PD diet could be an effective strategy for improving the relief of certain negative emotional states of heroin withdrawal syndrome and to allow reducing other medications generally used, such as opioid maintenance drugs. PMID- 23085100 TI - Early evolution of eukaryote feeding modes, cell structural diversity, and classification of the protozoan phyla Loukozoa, Sulcozoa, and Choanozoa. AB - I discuss how different feeding modes and related cellular structures map onto the eukaryote evolutionary tree. Centrally important for understanding eukaryotic cell diversity are Loukozoa: ancestrally biciliate phagotrophic protozoa possessing a posterior cilium and ventral feeding groove into which ciliary currents direct prey. I revise their classification by including all anaerobic Metamonada as a subphylum and adding Tsukubamonas. Loukozoa, often with ciliary vanes, are probably ancestral to all protozoan phyla except Euglenozoa and Percolozoa and indirectly to kingdoms Animalia, Fungi, Plantae, and Chromista. I make a new protozoan phylum Sulcozoa comprising subphyla Apusozoa (Apusomonadida, Breviatea) and Varisulca (Diphyllatea; Planomonadida, Discocelida, Mantamonadida; Rigifilida). Understanding sulcozoan evolution clarifies the origins from them of opisthokonts (animals, fungi, Choanozoa) and Amoebozoa, and their evolutionary novelties; Sulcozoa and their descendants (collectively called podiates) arguably arose from Loukozoa by evolving posterior ciliary gliding and pseudopodia in their ventral groove. I explain subsequent independent cytoskeletal modifications, accompanying further shifts in feeding mode, that generated Amoebozoa, Choanozoa, and fungi. I revise classifications of Choanozoa, Conosa (Amoebozoa), and basal fungal phylum Archemycota. I use Choanozoa, Sulcozoa, Loukozoa, and Archemycota to emphasize the need for simply classifying ancestral (paraphyletic) groups and illustrate advantages of this for understanding step wise phylogenetic advances. PMID- 23085101 TI - Gut-derived serotonin is a multifunctional determinant to fasting adaptation. AB - Energy release from cellular storage is mandatory for survival during fasting. This is achieved through lipolysis and liver gluconeogenesis. We show here that in the mouse, gut-derived serotonin (GDS) is upregulated during fasting and that it favors both mechanisms. In adipocytes, GDS signals through the Htr2b receptor to favor lipolysis by increasing phosphorylation and activity of hormone sensitive lipase. In hepatocytes, GDS signaling through Htr2b promotes gluconeogenesis by enhancing activity of two rate-limiting gluconeogenic enzymes, FBPase and G6Pase. In addition, GDS signaling in hepatocytes prevents glucose uptake in a Glut2-dependent manner, thereby further favoring maintenance of blood glucose levels. As a result, inhibition of GDS synthesis can improve glucose intolerance caused by high-fat diet. Hence, GDS opposes deleterious consequences of food deprivation by favoring lipolysis and liver gluconeogenesis while preventing glucose uptake by hepatocytes. As a result, pharmacological inhibition of its synthesis may contribute to improve type 2 diabetes. PMID- 23085103 TI - In search of the neuroprotective mechanism of thiazolidinediones in Parkinson's disease. AB - The oral antidiabetic thiazolidinediones exert protective effects in models of Parkinson's disease and other neurological diseases. While the antidiabetic effect is due to activation of PPARgamma, the mechanisms underlying the neuroprotection are more controversial. It may involve activation of PPARgamma blocking inflammation and apoptosis. However, new evidence suggests an antioxidative PPARgamma-independent action. Here we discuss recent data on the mode of action of TZDs in models of PD and their implication for the translation into the clinic. PMID- 23085102 TI - Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1. AB - We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin. PMID- 23085104 TI - Synthesis of some novel 1-(2-naphthyl)-2-(imidazol-1-yl)ethanone oxime ester derivatives and evaluation of their anticonvulsant activity. AB - Twenty-three new oxime ester derivatives of nafimidone were synthesized with the prospect of potential anticonvulsant activities. MES and ScM tests were employed for their anticonvulsant activities and rotorod test for neurological deficits. Eighteen compounds were found to be protective against MES seizures. Alkyl (1-8) and arylalkyl (9, 10) oxime ester derivatives were found to be more active than aryl oxime ester derivatives (11-23). Five compounds (2, 3, 7, 9, 10), which were protective at 0.5 h at the doses of 30 mg/kg and higher in MES test, showed the highest activity. Compound 17 was the most active one in ScM test at all dose levels at 4 h. PMID- 23085105 TI - Synthesis and biological evaluation of imidazo[4,5-b]pyridine and 4-heteroaryl pyrimidine derivatives as anti-cancer agents. AB - A series of N-phenyl-imidazo[4,5-b]pyridin-2-amines, 4-indazolyl-N phenylpyrimidin-2-amines and N-phenyl-4-pyrazolo[3,4-b]pyridin-pyrimidin-2-amines have been synthesized. Their anti-proliferative activities were tested in HCT-116 human colon carcinoma and MCF-7 breast carcinoma cell lines. Many exhibited potent anti-proliferative and CDK9 inhibitory activities. A lead compound 18b demonstrated the ability to reduce the level of Mcl-1 anti-apoptotic protein, to activate caspase 3/7 and induce cancer cell apoptosis. PMID- 23085106 TI - Synthesis of novel pyrazolo[3,4-d]pyrimidine derivatives as potential anti-breast cancer agents. AB - A series of new 1-aryl-4-benzylidenehydrazinyl-3-methylsulphanyl-pyrazolo[3,4 d]pyrimidines 6a-p was synthesized. The cytotoxic activity of the newly synthesized compounds against human breast cancer cell line, MCF7 was investigated. Most of the test compounds showed potent antitumor activity comparable to that of doxorubicin. The 1-phenyl series (6a-i) exhibited better antitumor activity than 1-(4-methoxyphenyl) series (6j-p). 4-[2-(4 Fluorobenzylidene)hydrazinyl]-3-(methylsulphanyl)-1-phenyl-1H-pyrazolo[3,4 d]pyrimidine (6d) was the most active compound in this study with IC(50) equal to 7.5 nM. PMID- 23085107 TI - Frequency specific spatial interactions in human electrocorticography: V1 alpha oscillations reflect surround suppression. AB - Electrical brain signals are often decomposed into frequency ranges that are implicated in different functions. Using subdural electrocorticography (ECoG, intracranial EEG) and functional magnetic resonance imaging (fMRI), we measured frequency spectra and BOLD responses in primary visual cortex (V1) and intraparietal sulcus (IPS). In V1 and IPS, 30-120 Hz (gamma, broadband) oscillations allowed population receptive field (pRF) reconstruction comparable to fMRI estimates. Lower frequencies, however, responded very differently in V1 and IPS. In V1, broadband activity extends down to 3 Hz. In the 4-7 Hz (theta) and 18-30 Hz (beta) ranges broadband activity increases power during stimulation within the pRF. However, V1 9-12 Hz (alpha) frequency oscillations showed a different time course. The broadband power here is exceeded by a frequency specific power increase during stimulation of the area outside the pRF. As such, V1 alpha oscillations reflected surround suppression of the pRF, much like negative fMRI responses. They were consequently highly localized, depending on stimulus and pRF position, and independent between nearby electrodes. In IPS, all 3-25 Hz oscillations were strongest during baseline recording and correlated between nearby electrodes, consistent with large-scale disengagement. These findings demonstrate V1 alpha oscillations result from locally active functional processes and relate these alpha oscillations to negative fMRI signals. They highlight that similar oscillations in different areas reflect processes with different functional roles. However, both of these roles of alpha seem to reflect suppression of spiking activity. PMID- 23085108 TI - White-matter diffusion fMRI of mouse optic nerve. AB - Non-invasive assessment of white-matter functionality in the nervous system would be a valuable basic neuroscience and clinical diagnostic tool. Using standard MRI techniques, a visual-stimulus-induced 27% decrease in the apparent diffusion coefficient of water perpendicular to the axonal fibers (ADC(perpendicular)) is demonstrated for C57BL/6 mouse optic nerve in vivo. No change in ADC(||) (diffusion parallel to the optic nerve fibers) was observed during visual stimulation. The stimulus-induced changes are completely reversible. A possible vascular contribution was sought by carrying out the ADC(perpendicular) measurements in hypercapnic mice with and without visual stimulus. Similar effects were seen in room-air-breathing and hypercapnic animals. The in vivo stimulus-induced ADC(perpendicular) decreases are roughly similar to literature reports for ex vivo rat optic nerve preparations under conditions of osmotic swelling. The experimental results strongly suggest that osmotic after-effects of nerve impulses through the axonal fibers are responsible for the observed ADC decrease. PMID- 23085109 TI - A pitfall in the reconstruction of fibre ODFs using spherical deconvolution of diffusion MRI data. AB - Diffusion weighted (DW) MRI facilitates non-invasive quantification of tissue microstructure and, in combination with appropriate signal processing, three dimensional estimates of fibrous orientation. In recent years, attention has shifted from the diffusion tensor model, which assumes a unimodal Gaussian diffusion displacement profile to recover fibre orientation (with various well documented limitations), towards more complex high angular resolution diffusion imaging (HARDI) analysis techniques. Spherical deconvolution (SD) approaches assume that the fibre orientation density function (fODF) within a voxel can be obtained by deconvolving a 'common' single fibre response function from the observed set of DW signals. In practice, this common response function is not known a priori and thus an estimated fibre response must be used. Here the establishment of this single-fibre response function is referred to as 'calibration'. This work examines the vulnerability of two different SD approaches to inappropriate response function calibration: (1) constrained spherical harmonic deconvolution (CSHD)--a technique that exploits spherical harmonic basis sets and (2) damped Richardson-Lucy (dRL) deconvolution--a technique based on the standard Richardson-Lucy deconvolution. Through simulations, the impact of a discrepancy between the calibrated diffusion profiles and the observed ('Target') DW-signals in both single and crossing-fibre configurations was investigated. The results show that CSHD produces spurious fODF peaks (consistent with well known ringing artefacts) as the discrepancy between calibration and target response increases, while dRL demonstrates a lower over-all sensitivity to miscalibration (with a calibration response function for a highly anisotropic fibre being optimal). However, dRL demonstrates a reduced ability to resolve low anisotropy crossing-fibres compared to CSHD. It is concluded that the range and spatial-distribution of expected single-fibre anisotropies within an image must be carefully considered to ensure selection of the appropriate algorithm, parameters and calibration. Failure to choose the calibration response function carefully may severely impact the quality of any resultant tractography. PMID- 23085110 TI - Associating spontaneous with evoked activity in a neural mass model of visual cortex. AB - Spontaneous activity of the brain at rest frequently has been considered a mere backdrop to the salient activity evoked by external stimuli or tasks. However, the resting state of the brain consumes most of its energy budget, which suggests a far more important role. An intriguing hint comes from experimental observations of spontaneous activity patterns, which closely resemble those evoked by visual stimulation with oriented gratings, except that cortex appeared to cycle between different orientation maps. Moreover, patterns similar to those evoked by the behaviorally most relevant horizontal and vertical orientations occurred more often than those corresponding to oblique angles. We hypothesize that this kind of spontaneous activity develops at least to some degree autonomously, providing a dynamical reservoir of cortical states, which are then associated with visual stimuli through learning. To test this hypothesis, we use a biologically inspired neural mass model to simulate a patch of cat visual cortex. Spontaneous transitions between orientation states were induced by modest modifications of the neural connectivity, establishing a stable heteroclinic channel. Significantly, the experimentally observed greater frequency of states representing the behaviorally important horizontal and vertical orientations emerged spontaneously from these simulations. We then applied bar-shaped inputs to the model cortex and used Hebbian learning rules to modify the corresponding synaptic strengths. After unsupervised learning, different bar inputs reliably and exclusively evoked their associated orientation state; whereas in the absence of input, the model cortex resumed its spontaneous cycling. We conclude that the experimentally observed similarities between spontaneous and evoked activity in visual cortex can be explained as the outcome of a learning process that associates external stimuli with a preexisting reservoir of autonomous neural activity states. Our findings hence demonstrate how cortical connectivity can link the maintenance of spontaneous activity in the brain mechanistically to its core cognitive functions. PMID- 23085111 TI - Task-demands and audio-visual stimulus configurations modulate neural activity in the human thalamus. AB - Recent electrophysiological studies have reported short latency modulations in cortical regions for multisensory stimuli, thereby suggesting a subcortical, possibly thalamic origin of these modulations. Concurrently, there is an ongoing debate, whether multisensory interplay reflects automatic, bottom-up driven processes or relies on top-down influences. Here, we dissociated the effects of task set and stimulus configurations on BOLD-signals in the human thalamus with event-related functional magnetic resonance imaging (fMRI). We orthogonally manipulated temporal and spatial congruency of audio-visual stimulus configurations, while subjects judged either their temporal or spatial congruency. Voxel-based fMRI results revealed increased fMRI-signals for the temporal versus spatial task in posterior and central thalamus, respectively. A more sensitive region of interest (ROI)-analysis confirmed that the posterior thalamic nuclei showed a preference for the temporal task and central thalamic nuclei for the spatial task. Moreover, the ROI-analysis also revealed enhanced fMRI-signals for spatially incongruent stimuli in the central thalamus. Together, our results demonstrate that both audio-visual stimulus configurations and task related processing of spatial or temporal stimulus features selectively modulate thalamic processing and thus are in a position to influence cortical processing at an early stage. PMID- 23085113 TI - Protective role of IL-18 -137G/C polymorphism in a North Indian population with asthma: a pilot study. AB - BACKGROUND: IL-18, a pleiotropic, pro-inflammatory cytokine that plays a major role in innate as well as acquired immunity, has been implicated in asthma etiology and this is the first study investigating the role of IL-18 -137G/C (rs 187238) promoter polymorphism in asthma pathogenesis in a North Indian population. METHODS: A pilot study was conducted with a total of 824 subjects, out of which 410 were asthma patients including 323 patients suffering from allergic rhinitis and 414 healthy controls from regions of North India. Tetra Primer Amplification Refractory Mutation System Polymerase Chain Reaction (Tetra Primer ARMS PCR) was used for genotyping the IL-18 -137G/C polymorphism. RESULTS: While the homozygous wild (GG) genotype was equally prevalent in asthma patients as well as control subjects (70.0%), the homozygous mutant (CC) genotype was more prevalent among the controls (8.0%) than in asthma patients (3.4%), which yielded a significant protection or decreased risk towards asthma. Statistical analysis revealed Odds Ratio (OR)=0.43 (95% CI=0.21-0.85), Chi2 (chi2)=6.93 and p value=0.008 (p<0.005). Moreover, a few asthma phenotypic traits also revealed significant protective associations with the polymorphism. CONCLUSIONS: The IL-18 -137G/C polymorphism confers a significant protection from asthma in the studied North Indian population. This is the first study to report the protective association of the polymorphism with the disease. PMID- 23085114 TI - Dose-response relationship between in-hospital mortality and alcohol following acute injury. AB - Although the relationship between alcohol and injury incidence is well researched, there continues to be dispute about the relationship between alcohol and mortality following an injury. Findings from past studies have varied primarily because of methodological issues and have failed to characterize the dose-response relationship. The main objective of this study was to evaluate the dose response relationship of in-hospital mortality and blood alcohol concentration (BAC). This study was a retrospective analysis of traumatic injuries occurring between 1995 and 2009 as reported by all level 1 and 2 trauma units in the State of Illinois. The study includes all patients with blood alcohol toxicological examination levels ranging from zero to 500 mg/dl (N = 190,612). The Illinois trauma registry includes all patients sustaining traumatic injuries and admitted to a trauma center for >=12 h. A total of 6733 patients meeting the inclusion criteria died following admission. Patients that were dead on arrival and those that died during the initial assessment within the emergency room were excluded. In the adjusted multivariable model, a decrease in in hospital mortality was strongly associated with an increase in blood alcohol concentration (adjusted OR = 0.83 per 100 mg/dl units change in BAC; CI 95%: 0.80, 0.85; p < 0.001). The direction of the dose response relationship was consistent across the stratified models, with the exception of patients suffering burns. The largest reduction of in-hospital case fatality rates by blood alcohol concentration was observed among patients suffering penetrating or severe injuries (Injury Severity Score >= 16). In the clinical setting, it is important to understand not only how to recognize intoxicated patients, but also how alcohol may affect the course of treatment. The consistency of the findings across the multivariable models indicates that blood alcohol concentration is strongly associated with lower in-hospital mortality among those that survive long enough to receive treatment in specialized trauma units. PMID- 23085115 TI - Differential expression patterns and localization of glucocorticoid and mineralocorticoid receptor transcripts in the osmoregulatory organs of tilapia during salinity stress. AB - The glucocorticoid receptor (GR) plays an essential role during seawater (SW) acclimation. However, the regulation of GR isoforms 1 and 2 (GR1 and GR2) and the mineralocorticoid receptor (MR) during SW acclimation is poorly understood. To address this, we localized and examined the GR1, GR2 and MR transcripts in the tilapia gill, kidney and intestine. Our results indicated that the GR1, GR2 and MR levels were increased in the kidney and intestine on day 1 in seawater (SW) fish, which is in agreement with the recognized osmoregulatory role of the corticosteroid receptors. The SW transfer increased the GR2 and MR transcripts in the gill on day 1 and 4, respectively. Surprisingly, no significant difference was obtained for the GR1 mRNA level. Analysis of the plasma parameters in freshwater (FW) and SW tilapia showed that the plasma cortisol levels were significantly increased at day 1 in the SW fish compared to the FW fish. This is the first study that focused on the spatial distribution of GR1, GR2 and MR in the osmoregulatory organs of freshwater (FW)- and SW-acclimated tilapia by in situ hybridization. Consistent with the Q-PCR results, the expression levels of the GR1, GR2 and MR transcripts were increased or decreased in the SW-acclimated tilapia's gill, kidney and intestine compared to the FW fish. We observed that GR1, GR2 and MR were localized in the branchial epithelial cells and chloride cells of the gill, proximal tubules of the kidney and columnar cells of the intestine. Together, these results indicate that the mobilization of corticosteroid receptors is dependent on the target tissue, salinity and exposure time. PMID- 23085112 TI - Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses. AB - OBJECTIVE: Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients. METHODS: 410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA. RESULTS: SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli. CONCLUSIONS: MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ. PMID- 23085116 TI - A randomised controlled trial comparing graded exercise treatment and usual physiotherapy for patients with non-specific neck pain (the GET UP neck pain trial). AB - Evidence supports exercise-based interventions for the management of neck pain, however there is little evidence of its superiority over usual physiotherapy. This study investigated the effectiveness of a group neck and upper limb exercise programme (GET) compared with usual physiotherapy (UP) for patients with non specific neck pain. A total of 151 adult patients were randomised to either GET or UP. The primary measure was the Northwick Park Neck pain Questionnaire (NPQ) score at six weeks, six months and 12 months. Mixed modelling identified no difference in neck pain and function between patients receiving GET and those receiving UP at any follow-up time point. Both interventions resulted in modest significant and clinically important improvements on the NPQ score with a change score of around 9% between baseline and 12 months. Both GET and UP are appropriate clinical interventions for patients with non-specific neck pain, however preferences for treatment and targeted strategies to address barriers to adherence may need to be considered in order to maximise the effectiveness of these approaches. PMID- 23085117 TI - Stain-Free technology as a normalization tool in Western blot analysis. AB - Western blots are used to specifically measure the relative quantities of proteins of interest in complex biological samples. Quantitative measurements can be subject to error due to process inconsistencies such as uneven protein transfer to the membrane. These non-sample-related variations need to be compensated for by an approach known as normalization. Two approaches to data normalization are commonly employed: housekeeping protein (HKP) normalization and total protein normalization (TPN). In this study, we evaluated the performance of Stain-Free technology as a novel TPN tool for Western blotting experiments in comparison with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a representative of the HKP normalization strategy. The target protein (TP) used for this study was MCM7, a DNA licensing replication factor, which was shown previously to be down-regulated by 20% in irradiated lymphoblastoid cell lines (LCLs). We studied the regulation of MCM7 with a multiplex Western blotting approach based on fluorescently labeled secondary antibodies and found that Stain Free technology appears to be more reliable, more robust, and more sensitive to small effects of protein regulation when compared with HKP normalization with GAPDH. Stain-Free technology offers the additional advantages of providing checkpoints throughout the Western blotting process by allowing rapid visualization of gel separation and protein transfer. PMID- 23085118 TI - Assessment of stable isotope incorporation into recombinant proteins. AB - Stable isotope labeling combined with mass spectrometry has been widely used in a diverse set of applications in the biochemistry and biomedical fields. When stable isotope-labeled proteins are produced via metabolic labeling of cell culture, a comprehensive assessment of the labeling pattern is imperative. In this study, we present a set of mass spectrometry-based bioanalytical tools developed for quantitatively tracing the levels of the stable isotopes incorporated into the recombinant proteins (monoclonal antibodies and Fc fusion proteins expressed in different host systems) that include total mass analysis, peptide mapping analysis, and amino acid analysis. We show that these three mass spectrometry-based analytical methods have distinctive advantages and limitations and that they are mutually complementary in evaluating the quality of stable isotope-labeled proteins. In addition, we show that the analytical techniques developed here are powerful tools to provide valuable insights into studying cell metabolism and performing flux analysis during cell culture. PMID- 23085119 TI - Discrimination of coherent and incoherent motion by pigeons: an investigation using a same-different motion discrimination task. AB - We trained seven pigeons to discriminate arrays of 8 identical icons that made small random movements in the same direction (coherent movement) from arrays of 8 identical icons that made small random movements in different directions (incoherent movement), with each icon moving within its own cell in an invisible 4*4 grid. During initial training, one specific configuration of icons (a fixed array) was used. The pigeons learned this discrimination and were later trained with successively introduced novel fixed arrays, and finally with novel arrays of random spatial arrangements (random arrays). Four pigeons successfully learned the final version of the task and were tested with random arrays containing different numbers of icons (from 2 to 12). Discrimination accuracy rose as the number of icons increased. These and other findings suggested that the pigeons had discriminated the visual displays by relying on the relative motion of the icons. Nevertheless, motion signals from individual icons (i.e., absolute motion) did interfere with discriminative performance to arrays of coherently moving icons. These results were considered in light of findings from another experiment in which pigeons had to search for a static icon among identical icons that moved coherently or incoherently as in the present study. PMID- 23085120 TI - Bis(12)-hupyridone, a novel acetylcholinesterase inhibitor, protects against glutamate-induced neuronal excitotoxicity via activating alpha7 nicotinic acetylcholine receptor/phosphoinositide 3-kinase/Akt cascade. AB - Bis(12)-hupyridone (B12H), derived from the Chinese medicinal component huperzine A, was originally designed as a novel acetylcholinesterase (AChE) inhibitor. In this paper, we report that B12H (24-h pretreatment) effectively blocked glutamate induced neuronal excitotoxicity in cerebellar granule neurons (CGNs). However, the huge discrepancy between the EC50 value and IC50 value of B12H, to protect against neuronal toxicity (0.09 MUM) and to block the NMDA receptor (21.8 MUM) respectively, suggests that the neuroprotection of B12H might be not primarily due to the blockade of the NMDA receptor. Pretreatment by specific antagonists of alpha7-nicotinic acetylcholine receptor (alpha7nAChR), but not muscarinic acetylcholine receptor (mAChR) or alpha4beta2nAChR, decreased the neuroprotection of B12H. The neuroprotection of B12H could also be abolished by the pretreatment of specific PI3-K inhibitors. Furthermore, B12H restored the suppressed activation of the Akt pathway caused by glutamate as evidenced by the decreased expressions of pSer473-Akt and pSer9-GSK3beta. All these results suggest that B12H substantially protected CGNs against glutamate-induced neuronal excitotoxicity via activating alpha7nAChR/PI3-K/Akt cascade. PMID- 23085121 TI - Cholinesterase confabs and cousins: approaching forty years. AB - In the past four decades of cholinesterase (ChE) research, we have seen substantive evolution of the field from one centered around substrate and inhibitor kinetic profiles and compound characterizations to the analysis of ChE structure, first through the gene families and then by X-ray crystallographic determinations of the free enzymes and their complexes and conjugates. Indeed, these endeavors have been facilitated by recombinant DNA technologies, structure determinations and parallel studies in related proteins in the alpha/beta hydrolase fold family. This approach has not only contributed to a fundamental understanding of structure and function of a large family of hydrolase-like proteins possessing functions other than catalysis, but also has been used to develop new practical strategies for scavenging and antidotal activity in cases of organophosphate insecticide or nerve agent exposure. PMID- 23085122 TI - Timing of decontamination and treatment in case of percutaneous VX poisoning: a mini review. AB - Low volatile organophosphorous nerve agents such as VX, will most likely enter the body via the skin. The pharmacokinetics of drugs such as oximes, atropine and diazepam, are not aligned with the variable and persistent toxicokinetics of the agent. Repeated administration of these drugs showed to improve treatment efficacy compared to a single injection treatment. Because of the effectiveness of continuous treatment, it was investigated to what extent a subchronic pretreatment with carbamate (pyridostigmine or physostigmine combined with either procyclidine or scopolamine) would protect against percutaneous VX exposure. Inclusion of scopolamine in the pretreatment prevented seizures in all animals, but none of the pretreatments affected survival time or the onset time of cholinergic signs. These results indicate that percutaneous poisoning with VX requires additional conventional treatment in addition to the current pretreatment regimen. Decontamination of VX-exposed skin is one of the most important countermeasures to mitigate the effects of the exposure. To evaluate the window of opportunity for decontamination, the fielded skin decontaminant Reactive Skin Decontaminant Lotion (RSDL) was tested at different times in hairless guinea pigs percutaneously challenged with 4* LD50 VX in IPA. The results showed that RSDL decontamination at 15 min after exposure could not prevent progressive blood cholinesterase inhibition and therefore would still require additional treatment. A similar decontamination regimen with RSDL at 90 min showed that it still might effectively increase the time window of opportunity for treatment. In conclusion, the delay in absorption presents a window of opportunity for decontamination and treatment. The continuous release of VX from the skin presents a significant challenge for efficacious therapy, which should ideally consist of thorough decontamination and continuous treatment. PMID- 23085123 TI - African swine fever virus infection in Ornithodoros ticks. AB - African swine fever virus (ASFV) is an arbovirus which is vectored by soft ticks of the Ornithodoros spp. and in the sylvatic cycle infects wart hogs and bush pigs. ASFV infection of domestic swine causes a high mortality disease. On the other hand, ASFV infection of the tick can result in a high-titered and persistent infection depending upon the ASFV isolate and the tick combination. Recently, morphological, classical virology (titration) and recombinant ASFV have been used to study the cellular, molecular and genetic interactions that occur between ASFV and its host tick. PMID- 23085124 TI - The temporal dynamics of medial and lateral frontal neural activity related to proactive cognitive control. AB - The neural correlates of proactive cognitive control were examined in two experiments using the counting Stroop task and a computerized Blackjack task in combination with event-related brain potentials (ERPs). The primary objective of the study was to determine whether slow wave activity related to proactive control would be observed in the two tasks. Consistent with the existing literature, transient components of the ERPs (i.e., medial frontal negativity and feedback related negativity) were observed over the medial frontal region in both tasks that were related to stimulus congruency and feedback processing, respectively. The medial frontal ERPs in both tasks were modeled with a pair of equivalent current dipoles placed along the anterior to posterior axis of the cingulate. Most importantly, slow wave activity was observed that differentiated incongruent trials from congruent trials after the response in the counting Stroop task, and losses from wins and ties in the Blackjack task. In the Blackjack task, a pair of dipoles in the left lateral frontal and posterior regions modeled the slow wave activity. These data reveal that updating goal representations that support proactive cognitive control may require several 100 ms in contrast to conflict or outcome monitoring that is associated with transient medial frontal neural activity. PMID- 23085125 TI - How does the hippocampal formation mediate memory for stimuli processed by the magnocellular and parvocellular visual pathways? Evidence from the comparison of schizophrenia and amnestic mild cognitive impairment (aMCI). AB - Paired associates learning is impaired in both schizophrenia and amnestic mild cognitive impairment (aMCI), which may reflect hippocampal pathology. In addition, schizophrenia is characterized by the dysfunction of the retino geniculo-striatal magnocellular (M) visual pathway. The purpose of this study was to investigate the interaction between visual perceptual and memory dysfunctions. We administered a modified version of the CANTAB paired associates learning task to patients with schizophrenia (n=20), aMCI (n=20), and two groups of matched healthy controls (n=20 for each patient group). The stimuli in the paired associates learning task biased information processing toward the M pathways (low contrast, low spatial frequency) and parvocellular (P) pathways (high contrast, high spatial frequency). Results revealed that patients with schizophrenia exhibited a more pronounced learning deficit for M-biased relative to P-biased stimuli. In aMCI, there were similar memory deficits for both types of stimuli. Orientation discrimination for M- and P-biased stimuli was intact in both groups of patients. The number of errors in the M-biased memory condition significantly and inversely correlated with the volume of the right hippocampus in schizophrenia. These results suggest an interaction between M-biased perceptual processing and short-term relational memory in schizophrenia, which may be associated with the structural alteration of the right hippocampus. PMID- 23085126 TI - It is all in the timing: mechanical and electrical dyssynchrony in hypoplastic left heart syndrome. PMID- 23085127 TI - End stage of arrhythmogenic cardiomyopathy with severe involvement of the interventricular septum. AB - Detailed histopathologic, immunohistochemical, and ultrastructural analysis of the heart of a 56-year-old woman with end-stage arrhythmogenic cardiomyopathy with a pathogenic plakophilin-2 mutation is described. The explanted heart revealed severe fibrofatty replacement of nearly the entire right ventricular free wall. The left ventricle was severely affected, and, most remarkable, there was massive involvement of the interventricular septum. Immunohistochemical and electron microscopic findings of intercalated disks revealed areas with a heterogeneous distribution of connexin43 and focal electron microscopic abnormalities among these regions. This case illustrates that arrhythmogenic cardiomyopathy is not limited to the right ventricle but involves the entire myocardium, including the interventricular septum. PMID- 23085128 TI - Effect of defibrillation threshold testing on heart failure hospitalization or death in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy (MADIT-CRT). AB - BACKGROUND: Defibrillation threshold (DFT) testing is commonly practiced at the time of implantable cardioverter-defibrillator (ICD) implant. The clinical consequence of ICD shocks delivered during DFT testing is unknown. OBJECTIVE: The purpose of this study was to determine the impact of ICD shocks and ICD shock energy level delivered during DFT testing in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) on clinical outcomes. METHODS: Patients who underwent DFT testing within 1 month of device implant were categorized by the number of ICD shocks delivered during DFT testing (0, 1, 2, >=3 shocks) and according to high vs low (>20 J vs <=20 J) energy ICD shocks. Clinical outcomes consisting of heart failure (HF) or death, death alone, HF alone, and ventricular tachycardia or ventricular fibrillation were analyzed in each group. RESULTS: DFT testing was performed in 1,659 patients within 1 month of device implant (1 shock in 365 patients, 2 shocks in 896 patients, 3+ shocks in 398 patients). High-energy ICD shocks were delivered in 609 patients. Increasing number of ICD shocks during DFT testing was not associated with an increase risk for the primary end-point of HF or death or for any of the secondary end-points of HF alone, VT/VF alone, or death. Delivery of high vs low-energy ICD shocks was not associated with adverse clinical outcomes. CONCLUSIONS: In patients with mild symptoms of HF, increasing number of ICD shocks and delivery of high energy ICD shocks during DFT testing was not associated with increased risk for HF or death or future VT/VF episodes. PMID- 23085129 TI - The Purkinje fiber preparation: 60 years of progress culminating in the mouse preparation. PMID- 23085130 TI - Extinction of small-caliber transvenous ICD leads: downsizing in a race to a recall. PMID- 23085131 TI - Influence of cycle length variations on antitachycardia pacing effectiveness among ICD patients. AB - BACKGROUND: Antitachycardia pacing (ATP) fails to terminate 5% to 25% of ventricular tachycardias (VTs) occurring in implantable cardioverter defibrillator patients. We speculated that small fluctuations in VT cycle length (CL) may be related to the efficacy of subsequent ATP. OBJECTIVE: The purpose of this study was to determine the relationship between the R-R variations of the last 12 R-R intervals before ATP and the efficacy of the first ATP attempt. METHODS: We studied 551 VTs (CL 329+/-35 ms) occurring in 67 patients. We also analyzed the percentage of variation (P-RR), which was calculated by dividing the mean difference between each R-R interval and the next one by the CL (*100), and the acceleration index (AI), which was calculated by dividing the CL of the first 6 R-R intervals by the CL of the next 6. RESULTS: The effectiveness of the first ATP therapy was 81%, being higher in VTs with AI<1 (85% vs 64%; P<.001). After classifying the events according to the tertiles of P-RR, ATP efficiency was better in higher values of P-RR (VTs with AI<1): 99% (third tertile) vs 85% (second tertile) vs 76% (first tertile), P<.001; and for VTs with AI>=1: 94% vs 68% vs 42% (P<.001). By logistic regression, P-RR (%; odds ratio 2.37; P<.001), and AI<1 (odds ratio 4.17; P<.001) were found to be independent predictors of successful first ATP attempts. CONCLUSION: Small changes in CL increase the effectiveness of ATP significantly. VTs with lower degrees of R-R fluctuations, especially when the pattern is a progressive CL shortening, are infrequently terminated by ATP. PMID- 23085133 TI - Positive affect dimensions and their association with inflammatory biomarkers in patients with chronic heart failure. AB - BACKGROUND: In cardiac patients positive affect has found to be associated with improved clinical outcomes, with reduced inflammation being one of the potential mechanisms responsible. METHODS: Positive affect was assessed using The Global Mood Scale (GMS), Positive and Negative Affect Schedule (PANAS), and Hospital Anxiety and Depression Scale (HADS) in patient with chronic heart failure (N=210; 67 +/- 9 years, 79% men). Markers of inflammation (TNFalpha, sTNFr1, sTNFr2, IL-6 and CRP) were measured and averaged at three consecutive time points. RESULTS: The positive affect dimensions of the GMS and PANAS were significantly associated with lower averaged levels of sTNFr2, TNFalpha and IL-6 (p<.1), even after adjustment for clinical and lifestyle confounders. Positive affect of the HADS was significantly associated with lower averaged levels of hsCRP (p<.1), but was no longer significant after correction for lifestyle confounders and depressive symptoms. CONCLUSION: Positive affect is associated with reduced inflammation in patients with heart failure. PMID- 23085132 TI - The PAADRN study: a design for a randomized controlled practical clinical trial to improve bone health. AB - INTRODUCTION: To describe the rationale and design of an NIH funded randomized controlled trial: the Patient Activation after DXA Result Notification (PAADRN) study. The aim of this trial is to evaluate the effect that a direct mailing of Dual-Energy X-ray Absorptiometry (DXA) results from bone density testing centers to patients will have on patients' knowledge, treatment and self-efficacy. METHODS: We will enroll approximately 7500 patients presenting for DXA at three study sites, the University of Iowa, the University of Alabama at Birmingham, and Kaiser Permanente of Atlanta, Georgia. We will randomize providers (and their respective patients) to either the intervention arm or usual care. Patients randomized to the intervention group will receive a letter with their DXA results and an educational brochure, while those randomized to usual care will receive their DXA results according to standard practice. The seven discrete outcomes are changes from baseline to 12-weeks and/or 52-weeks post-DXA in: (1) guideline concordant pharmacologic and non-pharmacologic therapy; (2) knowledge of DXA results; (3) osteoporosis-specific knowledge; (4) general health-related quality of life; (5) satisfaction with bone-related health care, (6) patient activation; and, (7) osteoporosis-specific self-efficacy. CONCLUSION: This trial will offer evidence of the impact of a novel approach-direct-to-patient mailing of test results-to improve patient activation in their bone health care. The results will inform clinical practice for the communication of DXA and other test results. PMID- 23085135 TI - Phylogeny and biogeography of southern African spoon-winged lacewings (Neuroptera: Nemopteridae: Nemopterinae). AB - Nemopteridae are a charismatic family of lacewings characterised by uniquely extended hind wings. They are an ancient widespread group in the drier regions of the world. The family comprises two subfamilies, Crocinae (thread-wings) and Nemopterinae (spoon- and ribbon-wings). The present distribution of the family has been largely influenced by the vicariant events of plate tectonics, resulting in relict populations in some parts of the world and extensive evolutionary radiations in others, particularly southern Africa where the vast majority of the species are endemic to the Western and Northern Cape Provinces of South Africa. This study aimed to establish the validity of the 11 currently recognised genera and infer their biogeographic history using molecular sequence data from four gene regions. The hypothesis that the Cape nemopterines co-evolved with certain taxa in the Cape Floristic Region was also tested. Phylogenetic analysis supports seven of the 11 currently recognised genera. The crown age of the Nemopterinae is estimated to be at ca. 145.6 Mya, indicating that the group has been present since the late Jurassic. Most of the genera appear to have diversified during the middle Eocene and into the middle Miocene (ca. 44-11 Mya) with recent rapid radiation of several of the genera occurring during the late Miocene (ca. 6-4.5 Mya). While these data support an initial radiation with the Rushioideae (Aizoaceae) it is recommended that further study including observations and gut content be carried out. PMID- 23085134 TI - Beta adrenergic blockade reduces utilitarian judgement. AB - Noradrenergic pathways are involved in mediating the central and peripheral effects of physiological arousal. The aim of the present study was to investigate the role of noradrenergic transmission in moral decision-making. We studied the effects in healthy volunteers of propranolol (a noradrenergic beta-adrenoceptor antagonist) on moral judgement in a set of moral dilemmas pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person) in a double-blind, placebo-controlled, parallel group design. Propranolol (40 mg orally) significantly reduced heart rate, but had no effect on self-reported mood. Importantly, propranolol made participants more likely to judge harmful actions as morally unacceptable, but only in dilemmas where harms were 'up close and personal'. In addition, longer response times for such personal dilemmas were only found for the placebo group. Finally, judgments in personal dilemmas by the propranolol group were more decisive. These findings indicate that noradrenergic pathways play a role in responses to moral dilemmas, in line with recent work implicating emotion in moral decision-making. However, contrary to current theorising, these findings also suggest that aversion to harming is not driven by emotional arousal. Our findings are also of significant practical interest given that propranolol is a widely used drug in different settings, and is currently being considered as a potential treatment for post traumatic stress disorder in military and rescue service personnel. PMID- 23085136 TI - Dynamics of laser-excited stacked adenines: semiclassical simulations. AB - The nonradiative decay of a pi-stacked pair of adenine molecules, following laser excitation, was studied by semiclassical dynamics simulations. Two deactivation pathways were characterized. One pathway involves an ultrafast internal conversion within ~600 fs induced by an out-of-plane vibration of the H atom and deformation of the pyrimidine ring at the C(2) site. A slower process (~2400 fs) involves covalent bond formation between the stacked molecules, which lowers the excimer state energy and inhibits the deformation of the pyrimidine ring; the decay is also induced by an out-of-plane vibration of the H atom at the C(2) site of the pyrimidine ring. PMID- 23085137 TI - Thermoresponsive chitosan/N-isopropylacrylamide copolymer through atom transfer radical polymerization. AB - Regioseletive copolymerization of N-isopropylacrylamide (NIPAM) onto chitosan was achieved by atom transfer radical polymerization (ATRP) by using a regioselective 3,6-di-O-bromoisobutyryl-2-N-phthaloyl chitosan as a macroinitiator. The degree of polymerization (DP) of polyNIPAM onto the chitosan derivative changed by varying the ratio between NIPAM monomer, macroinitiator, ligand, and transition metal. ATRP successfully proceeded and a DP of polyNIPAM up to 110.5 was obtained. The thermal decomposition temperature of the 3,6-di-O-bromoisobutyryl-2 N-phthaloyl chitosan was significantly improved by increasing the DP of the NIPAM component. The polyNIPAM-g-chitosan derivative showed a thermoresponsive property. Although it formed a stable suspension in water at room temperature, it caused a hydrophilic-to-hydrophobic transition at around 32 degrees C, resulting in precipitate formation. PMID- 23085138 TI - Structure and immunology of a heteroglycan from somatic hybrid mushroom of Pleurotus florida and Calocybe indica var. APK2. AB - A water soluble polysaccharide was isolated from the aqueous extract of the fruit bodies of somatic hybrid mushroom PCH3FB, obtained through protoplast fusion between the strains Pleurotus florida and Calocybe indica var. APK2. On the basis of sugar analysis, methylation analysis, periodate oxidation, and NMR studies ((1)H, (13)C, DEPT-135, DQF-COSY, TOCSY, NOESY, ROESY, HMQC and HMBC), the structure of the repeating unit of the polysaccharide was established as: [formula, see text] This molecule showed macrophage, splenocyte and thymocyte activations. PMID- 23085139 TI - A system for the extraction and representation of summary of product characteristics content. AB - OBJECTIVE: Information about medications is critical in supporting decision making during the prescription process and thus in improving the safety and quality of care. In this work, we propose a methodology for the automatic recognition of drug-related entities (active ingredient, interaction effects, etc.) in textual drug descriptions, and their further location in a previously developed domain ontology. METHODS AND MATERIAL: The summary of product characteristics (SPC) represents the basis of information for health professionals on how to use medicines. However, this information is locked in free-text and, as such, cannot be actively accessed and elaborated by computerized applications. Our approach exploits a combination of machine learning and rule-based methods. It consists of two stages. Initially it learns to classify this information in a structured prediction framework, relying on conditional random fields. The classifier is trained and evaluated using a corpus of about a hundred SPCs. They have been hand-annotated with different semantic labels that have been derived from the domain ontology. At a second stage the extracted entities are added in the domain ontology corresponding concepts as new instances, using a set of rules manually-constructed from the corpus. RESULTS: Our evaluations show that the extraction module exhibits high overall performance, with an average F1-measure of 88% for contraindications and 90% for interactions. CONCLUSION: SPCs can be exploited to provide structured information for computer-based decision support systems. PMID- 23085140 TI - Design, Prins-cyclization reaction promoting diastereoselective synthesis of 10 new tetrahydropyran derivatives and in vivo antinociceptive evaluations. AB - We described in this article the very efficient 2,6-cis ou 2,4,6-cis diastereoselective synthesis (2 or 3 steps, 62-65% global yields) from Prins cyclization reaction as synthetic key-step to tetrahydropyran rings construction of 10 new congeners compounds (3-12) designed from Naproxen structure. These tetrahydropyran derivatives were in vivo bioevaluated on antinociceptive effect in the acetic acid-induced abdominal writhing test, the tail-flick test, the rota rod performance and open field tests. All new compounds showed greater antinociceptive activity compared to compound 1a, an analgesic tetrahydropyran derivative previously described by us. We can detach the high activity of tetrahydropyran derivative 10 which presented 87.5% inhibition (14% inhibition was presented by 1a) in the acetic acid-induced abdominal writhing test. Besides that the tail-flick tests indicate compounds 7 and 10 as the most actives. All these new compounds showed no toxicity in mice in all biologically studied models. PMID- 23085141 TI - Synthesis of novel octa-cationic and non-ionic 1,2-ethanediamine substituted zinc (II) phthalocyanines and their in vitro anti-cancer activity comparison. AB - Novel tetra-substituted zinc phthalocyanines (Pcs) bearing 1,2-ethanediamine group and the quaternized derivatives were synthesized and characterized. The photophysical and cellular properties of these Pcs were investigated. The results indicated that the quaternized ionic effect can greatly improve the water solubility of Pcs and reduce their aggregation degree in aqueous solution. Comparative studies with quaternized phthalocyanine and its unquaternized counterpart have also demonstrated that the quaternary action on the molecules significantly enhances the fluorescence quantum yields, fluorescence lifetimes, efficiency of singlet oxygen production and, thereby, the in vitro photodynamic therapy efficacy. PMID- 23085142 TI - Determinants of structural choice in visually situated sentence production. AB - Three experiments investigated how perceptual, structural, and lexical cues affect structural choices during English transitive sentence production. Participants described transitive events under combinations of visual cueing of attention (toward either agent or patient) and structural priming with and without semantic match between the notional verb in the prime and the target event. Speakers had a stronger preference for passive-voice sentences (1) when their attention was directed to the patient, (2) upon reading a passive-voice prime, and (3) when the verb in the prime matched the target event. The verb match effect was the by-product of an interaction between visual cueing and verb match: the increase in the proportion of passive-voice responses with matching verbs was limited to the agent-cued condition. Persistence of visual cueing effects in the presence of both structural and lexical cues suggests a strong coupling between referent-directed visual attention and Subject assignment in a spoken sentence. PMID- 23085143 TI - Episodic retrieval and decaying inhibition in the competitor-rule suppression phenomenon. AB - The Competitor Rule Suppression (CRS) effect is the performance impairment observed in task switching when the currently relevant task rule is the same rule that had generated a response conflict in the preceding trial. This effect could reflect (a) episodic tagging, in which a competitor rule is retrieved with relative difficulty in subsequent trials or (b) residual active inhibition of the competing rule. In order to help distinguishing between the two accounts, the authors manipulated the Response-Cue Interval (RCI), which may influence both processes. CRS increased with increasing temporal distinctiveness between the previous and current episode (operationalized by the ratio of the current RCI to the previous RCI, RCI/pRCI), thus supporting episodic tagging. CRS additionally decreased numerically with increasing RCI even when the RCI/pRCI ratio was fixed, thereby providing suggestive support for the decay account. PMID- 23085144 TI - False memories for missing aspects of traumatic events. AB - Can people come to remember an event as being more traumatic than they initially experienced? Participants watched a highly structured and emotionally disturbing film depicting a car accident in which five people, including a baby, are killed. We broke the film down into a series of short clips; some of which we removed. Later, we tested participants' memory for what they had and had not seen. While participants were highly accurate identifying what they had and definitely had not seen, they also falsely claimed to have seen 26% of the missing clips, clips that fitted with the film but were removed before screening. Moreover, participants were particularly likely to recall the missing clips that were considered to be the most critical and traumatic. Importantly, they did so with high confidence. We discuss both intentional and unintentional recall mechanisms that may promote the observed memory distortion. PMID- 23085145 TI - Effects of 5-fluorouracil chemotherapy on fatigue: role of MCP-1. AB - Chemotherapy has been known to cause severe side effects, including fatigue. While the mechanisms for chemotherapy induced fatigue (CIF) are likely to be multi-factorial in origin, it is thought that inflammation and anemia may play a role. The purpose of this study was to examine the effect of chemotherapy on fatigue in mice, and further, to begin to determine if inflammation and anemia may contribute to this response. For experiment 1, C57BL/6 mice were assigned to: vehicle (PBS), low (20 mg/kg), medium (40 mg/kg), or high (60 mg/kg) doses of 5 fluorouracil (5-FU). Voluntary physical activity (PA) was measured throughout the treatment period (day 1-5) as well as during the recovery period (day 6-14). In experiment 2, we examined the effects of 5-FU (60 mg/kg) on the inflammatory mediator MCP-1 and on markers of anemia (RBC, Hct and Hb). Finally, using MCP-1( /-) mice we examined the role of MCP-1 on CIF (experiment 3). 5-FU reduced voluntary PA in a dose response manner (p<0.05). Plasma MCP-1 was increased following 5-FU treatment on both days 5 (p=0.10) and 14 (p<0.05). In addition, RBCs, Hct and Hb were reduced with 5-FU on days 5 and 14 (p<0.05). Both C57BL/6 and MCP-1(-/-) mice saw similar decrements in PA through the duration of the treatment period (days 1-5), however the MCP-1(-/-) mice recovered much earlier than wildtype mice. This study provides evidence of the dose response effect of a standard chemotherapy agent on fatigue and demonstrates a potential role of MCP-1 and presumably inflammation, and anemia. PMID- 23085146 TI - Astrocyte-specific deficiency of interleukin-6 and its receptor reveal specific roles in survival, body weight and behavior. AB - Interleukin-6 (IL-6) is a major cytokine which controls not only the immune system but also exhibits many other functions including effects in the central nervous system (CNS). IL-6 is known to be produced by different cells in the CNS, and all the major CNS do respond to IL-6, which makes it difficult to dissect the specific roles of each cell type when assessing the role of IL-6 in the brain. We have produced for the first time floxed mice for IL-6 and have crossed them with GFAP-Cre mice to delete IL-6 in astrocytes (Ast-IL-6 KO mice), and have compared their phenotype with that of mice with deletion of IL-6 receptor in astrocytes (Ast-IL6R KO mice). Our results indicate a major prosurvival role of the astrocyte IL-6 system at early ages (intrauterine life), which was also involved to various degrees in the control of adult body weight, locomotor activity, anxiety and exploratory behaviors. In some occasions deleting IL-6R in astrocytes mimicked the phenotype of Ast-IL-6 KO mice (i.e. activity), while in others the opposite was observed (i.e. exploration), suggesting autocrine and paracrine (presumably on neurons) roles of astrocyte IL-6. Our results suggest important roles of the astrocyte IL-6 system on normal brain physiology, in some cases totally unexpected from previous results with total IL-6 KO mice. PMID- 23085147 TI - Lack of associations of alpha(+)-thalassemia with the risk of Plasmodium falciparum and Plasmodium vivax infection and disease in a cohort of children aged 3-21 months from Papua New Guinea. AB - Despite consistent evidence of a protective effect of alpha(+)-thalassemia against severe Plasmodium falciparum disease, the mechanisms underlying this protection remain unknown. An increase in risk of Plasmodium vivax malaria in early childhood resulting in a cross-species protection against severe P. falciparum malaria has been proposed as a possible mechanism in Melanesian children. The association of alpha(+)-thalassemia genotypes with a risk of P. falciparum and P. vivax infection and uncomplicated illness was reassessed in a cohort of 1,112 Papua New Guinean children, followed from 3 to 21 months of age. Three hundred and eighty-nine (35.0%) children were homozygous for alpha(+) thalassemia (-alpha/-alpha), 506 (45.5%) heterozygous (alphaalpha/-alpha) and 217 (19.5%) homozygous for the wild-type allele. No significant differences in the incidence of P. falciparum (Pf) or P. vivax (Pv) malaria were observed between alpha(+)-thalassemia homozygote (Pf: incidence rate ratio (IRR)=1.13, CI(95) (0.82, 1.56), P=0.45, Pv: IRR=1.15, CI(95) (0.88, 1.50), P=0.31), heterozygote (Pf: IRR=0.98, CI(95) (0.71, 1.34), P=0.93, Pv: IRR=1.14, CI(95) (0.88, 1.48), P=0.33) and wild-type children. The prevalence of infection with either species did not differ between alpha(+)-thalassemia genotypes, although densities of P. vivax (but not of P. falciparum) infections were significantly higher in alpha(+) thalassemia homozygote and heterozygote children. An excessive risk of moderate to-severe anemia (Hb<8 g/dl) was observed in alpha(+)-thalassemia homozygote children (IRR=1.54, CI(95) (1.12, 2.11), P=0.008). This study therefore failed to confirm an increased risk of P. vivax or P. falciparum malaria in very young, alpha(+)-thalassemic children without significant levels of acquired immunity. This confirms the lack of protection by alpha(+)-thalassemia against uncomplicated P. falciparum and challenges the hypothesis of immunological cross protection between P. falciparum and P. vivax as a mechanism underlying alpha(+) thalassemia protection against severe P. falciparum disease in Melanesian children. PMID- 23085148 TI - The trifecta outcome in 300 consecutive cases of robotic-assisted laparoscopic radical prostatectomy according to D'Amico risk criteria. AB - BACKGROUND: To analyze the trifecta outcome (continence, potency, and cancer control) in 300 cases of robotic-assisted laparoscopic radical prostatectomy (RARP). METHODS: A prospective assessment of outcomes in 300 consecutive patients that underwent a RARP performed by a single surgeon. Patients were grouped according to D'Amico risk criteria: Group I consisted of 'low-risk' cases (n = 64), Group II consisted of 'intermediate-risk' cases (n = 88), and Group III consisted of 'high-risk' cases (n = 148). Patients were evaluated for perioperative complications and the trifecta outcome. RESULTS: The operation time, blood loss, post-operative stay, duration of urethral catheterization, and perioperative complication rate were similar among all groups. The incidence of bilateral neurovascular bundle (NVB) preservation was significantly decreased with the increasing risk of cases (P < 0.001). The continence rates at the 1 week, 1-month, 3-month, 6-month, and 12-month follow-ups did not differ significantly between groups. The potency rates at the 12-month follow-up were not significantly different. The positive surgical margin and positive lymph node metastasis rate increased with the increasing risk of cases (P < 0.001). The biochemical recurrence rate (BCR, PSA >0.2 ng/mL) was 3.1, 11.36, and 19.59% in Groups I, II and III, respectively (P = 0.004). The trifecta outcome for RARP with bilateral NVB preservation showed no significant differences among groups. CONCLUSIONS: Undergoing a RARP is safe and feasible in high-risk prostate cancer patients. Compared to low-risk and intermediate-risk groups, the high-risk group had a significant higher incidence of positive surgical margin, positive lymph node metastasis, and BCR rate. PMID- 23085149 TI - Practical multigram-scale synthesis of 4,6- and 4,8-sphingadienes, chemopreventive sphingoid bases. AB - Sphingadienes are chemopreventive agents that act by blocking signaling pathways that are activated in cancer. A practical synthesis of 4,6- and 4,8-sphingadienes on a scale of gram quantities is reported here in order to allow evaluation of the biological properties of these sphingolipids. The key steps in the preparation of 4,6-sphingadiene (1a) are an intramolecular cyclization of N-Boc derivative 5a to oxazolidinone derivative 6a, followed by conversion to carbamate intermediate 7a and base-mediated hydrolysis to afford the product without further purification. 4,8-Sphingadiene (1b) was prepared in a similar fashion; the requisite trans-gamma,delta-unsaturated aldehyde 15 was prepared by an ester enolate Ireland-Claisen rearrangement. PMID- 23085151 TI - Polypeptide chain collapse and protein folding. AB - Polypeptide chain collapse is an integral component of a protein folding reaction. In this review, experimental characterization of the interplay of polypeptide chain collapse, secondary structure formation, consolidation of the hydrophobic core and the development of tertiary interactions, is scrutinized. In particular, the polypeptide chain collapse reaction is examined in the context of the three phenomenological models of protein folding - the hydrophobic collapse model, the framework model and the nucleation condensation model - which describe different ways by which polypeptide chains are able to fold in biologically relevant time-scales. PMID- 23085150 TI - Post-translational modifications of myofilament proteins involved in length dependent prolongation of relaxation in rabbit right ventricular myocardium. AB - The phosphorylation state of several cardiac myofilament proteins changes with the level of stretch in intact, twitch-contracting cardiac muscles. It remains unclear which kinases are involved in the length-dependent phosphorylation of these proteins. We set out to investigate which kinases are involved after a step wise change in cardiac muscle length. We hypothesize that myofilament protein phosphorylation by PKCbetaII and PKA alters contractile kinetics during length dependent activation. Right ventricular intact trabeculae were isolated from New Zealand White rabbit hearts and stimulated to contract at 1Hz. Twitch force recordings where taken at taut and optimal muscle lengths before and after administration of kinase inhibitors at 37 degrees C. PKCbetaII inhibition significantly decreased time from stimulation to peak force (TTP), time from peak force to 50% relaxation (RT50), and 90% relaxation (RT90) at optimal muscle length. This led to a loss in the length-dependent increase of RT50 and RT90 in the presence of the PKCbetaII inhibitor, whereas the length-dependent increase in RT50 and RT90 was seen in the controls. PKA inhibition using H-89 significantly decreased TTP at both taut and optimal muscle lengths. Detection of Ser/Thr phosphorylation with ProQ-diamond staining indicates a role for PKCbetaII in the phosphorylation of tropomyosin and myosin light chain-2 (MLC2) and PKA for tropomyosin, troponin-I, MLC2, myosin binding protein-C, troponin-T (TnT) 3 and TnT4. Our data provide evidence for two signaling kinases acting upon myofilament proteins during length-dependent activation, and provide further insight for length-dependent myofilament function. PMID- 23085152 TI - Constrained and UV-activatable cell-penetrating peptides for intracellular delivery of liposomes. AB - Herein we report on the development of a novel method of constraining a cell penetrating peptide, which can be used to trigger transport of liposomes into cells upon in this case radiation with UV-light. A cell-penetrating peptide, which was modified on both termini with an alkyl chain, was anchored to the liposomal surface in a constrained and deactivated form. Since one of the two alkyl chains was connected to the peptide via a UV-cleavable linker, disconnection of this alkyl chain upon irradiation led to the exposure of the cell-penetrating peptide, and mediated the transport of the entire liposome particle into cells. PMID- 23085153 TI - MAPPED study design: a 6 month randomised controlled study to evaluate the effect of dutasteride on prostate cancer volume using magnetic resonance imaging. AB - OBJECTIVE: To evaluate the percentage change in volume of prostate cancer, as assessed by T2-weighted MRI, following exposure to dutasteride (Avodart) 0.5mg daily for six months. PATIENTS AND METHODS: MRI in Primary Prostate cancer after Exposure to Dutasteride (MAPPED) is a double-blind, placebo-controlled trial, supported by GlaxoSmithKline (GSK). Men with prostate cancer suitable for active surveillance (low-intermediate risk prostate cancer on biopsy), and a visible lesion on T2-weighted MRI of at least 0.2 cc, were eligible for consideration. Forty-two men were randomised to 6 months of daily dutasteride 0.5mg or placebo. Multi-parametric MRI (mpMRI) scans were performed at baseline, 3 and 6 months. The percentage changes in cancer volume over time will be compared between the dutasteride and placebo groups. Planned analyses will examine the association between tumour volume and characteristics (perfusion and contrast washout) as seen on mpMRI, HistoScan ultrasound and biopsy histopathology in both groups. DISCUSSION: MAPPED is the first randomised controlled trial to use mpMRI to look at the effect of dutasteride on the volume of prostate cancer. If dutasteride is shown to reduce the volume of prostate cancer, it might be considered as an adjunct for men on active surveillance. Analysis of the placebo arm will allow us to comment on the short-term natural variability of the MR appearance in men who are not receiving any treatment. CONCLUSION: MAPPED will evaluate the short-term effect of dutasteride on prostate cancer volume, as assessed by mpMRI, in men undergoing active surveillance for low or intermediate risk prostate cancer. The study completed recruitment in January 2012. PMID- 23085154 TI - Construction of a reference plasmid containing ten targets for the detection of genetically modified crops. AB - Standard reference molecules play a significant role for the detection of genetically modified (GM) crops and products. The newest reference molecules should catch up with the rapid development of GM crops in the world. In this work, a reference plasmid containing ten targets from GM soybean, maize and cotton was constructed on the basis of the pTLE8 harboring eight targets only from GM soybean and cotton. Three target segments of the Bt176 event-specific 3' junction (Bt176G3'), MON810 event-specific 3'-junction (MON810G3') and the endogenous maize Hmg genes, were fused into the 890 bp fragment by overlap extension PCR. The CP4 EPSPS gene in the plasmid pTLE8 previously constructed in our laboratory was replaced with above fusion fragment, thus generating a new plasmid pTLH10 containing ten target genes from GM soybean, maize and cotton. The PCR efficiencies with pTLH10 as a calibrator ranged from 93.3% to 99.9% for the standard curves of the Bt176G3', MON810G3' and Hmg genes. The standard deviation (SD) values of repeatability were from 0.04 to 0.8 for three different days and from 0.12 to 1.14 for one day, respectively. These results indicated that the reference plasmid constructed in this work is also suitable for the identification of GM maize, and would be an important tool to establish a feasible identification management for various GM crops components. PMID- 23085155 TI - Solvent effect on halogen bonding: the case of the I?O interaction. AB - The solvent effect on the I?O halogen bonding in complexes of iodobenzene derivatives with formaldehyde has been investigated by systematically varying the substituents on the iodobenzene ring. Calculations have been performed at MP2 and DFT levels of theory, using the aug-cc-pVDZ basis set and the pseudopotential for iodine. Within the DFT approach, a series of the most widely used exchange correlation functionals have been considered, comprising PBE, PBE0, B3LYP, BH&HLYP, M06-2X and M06-HF. Results obtained in diethylether and in water using the conductor-like polarizable continuum model (CPCM) have been compared with in vacuo results. Though halogen bonding distances were found to systematically shorten when moving from vacuo to diethylether and then to water, the associated interaction energies showed a decrease in absolute value, indicating that solvent has a destabilizing effect on this interaction. By comparison with MP2 results, all the considered functionals, B3LYP excepted, have been found adequate to describe halogen bonding. As far as the interaction energies are concerned, the best performance was obtained with the M06-HF functional in vacuo and the PBE functional in solution. The geometrical parameters characterizing halogen bonds were better reproduced by the M06-2X functional. PMID- 23085156 TI - Phase transition study of confined water molecules inside carbon nanotubes: hierarchical multiscale method from molecular dynamics simulation to ab initio calculation. AB - In this study, the mechanism of the temperature-dependent phase transition of confined water inside a (9,9) single-walled carbon nanotube (SWCNT) was studied using the hierarchical multi-scale modeling techniques of molecular dynamics (MD) and density functional theory (DFT). The MD calculations verify the formation of hexagonal ice nanotubes at the phase transition temperature T(c)=275K by a sharp change in the location of the oxygen atoms inside the SWCNT. Natural bond orbital (NBO) analysis provides evidence of considerable intermolecular charge transfer during the phase transition and verifies that the ice nanotube contains two different forms of hydrogen bonding due to confinement. Nuclear quadrupole resonance (NQR) and nuclear magnetic resonance (NMR) analyses were used to demonstrate the fundamental influence of intermolecular hydrogen bonding interactions on the formation and electronic structure of ice nanotubes. In addition, the NQR analysis revealed that the rearrangement of nano-confined water molecules during the phase transition could be detected directly by the orientation of 17O atom EFG tensor components related to the molecular frame axes. The effects of nanoscale confinements in ice nanotubes and water clusters were analyzed by experimentally observable NMR and NQR parameters. These findings showed a close relationship between the phase behavior and orientation of the electronic structure in nanoscale structures and demonstrate the usefulness of NBO and NQR parameters for detecting phase transition phenomena in nanoscale confining environments. PMID- 23085157 TI - Homology modeling, docking and molecular dynamics of the Leishmania mexicana arginase: a description of the catalytic site useful for drug design. AB - The crystallographic structure of the Leishmania mexicana arginase, an attractive target for the design of leishmanicidal agents, is still unknown. For this reason, we report a computer-assisted homology study conducted to build its three dimensional structure based on the known sequence of amino acids of this enzyme. In this study, the amino acid sequence in the arginase of the parasite was compared with the sequence of the amino acids in the crystallographic structure of rat and human liver arginases. The best similarity was found with the rat liver arginase. The catalytic site of the three-dimensional arginase structure built for L. mexicana has important structural differences as compared with that of the human liver arginase with regard to reasonable design selective compounds against L. mexicana. With this information, a docking study was conducted to find the inhibitors of this enzyme. 1439 molecules were docked and 18 were selective to the L. mexicana arginase. Moreover, molecular dynamics were carried out to study the stability of the homologue protein (including manganeses) and the ligand-enzyme complex. The results indicated that the manganese remains inside the protein throughout the simulation. Besides, hydrogen bonds interactions between the ligand and the arginase were analyzed. These results provide important information for the design of new inhibitors. PMID- 23085158 TI - Substituent effects on zinc phthalocyanine derivatives: a theoretical calculation and screening of sensitizer candidates for dye-sensitized solar cells. AB - A series of unsymmetrical phthalocyanine sensitizer candidates with different donor and acceptor substituents, namely ZnPcBPh, ZnPcBOPh, ZnPcBtBu, ZnPcBN(Ph)2, ZnPcBNHPh, ZnPcBNH2, ZnPcBNHCH3 and ZnPcBN(CH3)2, were designed and calculated using density functional theory (DFT) and time-dependent DFT calculations. The molecular orbital energy levels, the molecular orbital spatial distributions and the electronic absorption spectra of the ZnPcB series molecules were compared with those of TT7 and TT8 to reveal the substituent effects of different donor and acceptor groups on the phthalocyanine compounds and select good sesitizer candidates. The results show that some of these compounds have considerably smaller orbital energy gaps, red-shifted absorption bands and better charge separated states, causing them to absorb photons in the lower energy region. Several new absorption bands emerge in the 400-600 nm region, which makes it possible for them to become panchromatic sensitizers. This characteristic is superior to the phthalocyanine sensitizers reported previously, including the current record holder, PcS6. The sensitizer candidates screened in the current work are very promising for providing good performance and might even challenge the photon-to-electricity conversion efficiency record of 4.6% for phthalocyanine sensitizers. PMID- 23085159 TI - Quantitative structure-activity relationships (QSARs) using the novel marine algal toxicity data of phenols. AB - The present study reports for the first time in its entirety the toxicity of 30 phenolic compounds to marine alga Dunaliella tertiolecta. Toxicity of polar narcotics and respiratory uncouplers was strongly correlated to hydrophobicity as described by the logarithm of the octanol/water partition coefficient (Log P). Compounds expected to act by more reactive mechanisms, particularly hydroquinones, were shown to have toxicity in excess of that predicted by Log P. A quality quantitative structure-activity relationship (QSAR) was obtained with Log P and a 2D autocorrelation descriptor weighted by atomic polarizability (MATS3p) only after the removal of hydroquinones from the data set. In an attempt to model the whole data set including hydroquinones, 3D descriptors were included in the modeling process and three quality QSARs were developed using multiple linear regression (MLR). One of the most significant results of the present study was the superior performance of the consensus MLR model, obtained by averaging the predictions from each individual linear model, which provided excellent prediction accuracy for the test set (Q(test)2=0.94). The four-parameter Counter Propagation Artificial Neural Network (CP ANN) model, which was constructed using four out of six descriptors that appeared in the linear models, also provided an excellent external predictivity (Q(test)2=0.93). The proposed algal QSARs were further tested in their predictivity using an external set comprising toxicity data of 44 chemicals on freshwater alga Pseudokirchneriella subcapitata. The two parameter global model employing a 3D descriptor (Mor24m) and a charge-related descriptor (C(ortho)) not only had high external predictivity (Q(ext)2=0.74), but it also had excellent external data set coverage (%97). PMID- 23085160 TI - Exploring the structure determinants of pyrazinone derivatives as PDE5 3HC8 inhibitors: an in silico analysis. AB - Phosphodiesterase type 5 (PDE5) inhibitors are clinically indicated for the treatment of erectile dysfunction, pulmonary hypertension and various other diseases. In this work, both ligand- and receptor-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 122 pyrazinone derivatives as PDE inhibitors. The resultant optimum 3D-QSAR model exhibits a proper predictive ability as indicated by the statistical results of Q2 of 0.584, R(ncv)2 of 0.884 and R(pre)2 of 0.817, respectively. In addition, docking analysis and molecular dynamics (MD) simulation were also applied to elucidate the probable binding modes of these inhibitors. Our main findings are: (1) Introduction of bulky, electropositive and hydrophobic substituents at 12- and 19-positions can increase the biological activities. (2) N atom at 8-position is detrimental to the inhibitor activity, and the effect of N atoms at 5- and 6-positions on compound activity is co-determined by both the hydrophobic force and the pi-pi stacking interaction. (3) Bulky and hydrophilic substitutions are favored at the 27 position of ring D. (4) Electronegative and hydrophilic substitutions around 5- and 6-positions increase the inhibitory activity. (5) Hydrophobic forces and pi pi stacking interaction with Phe786 and Phe820 are crucial in determining the binding of pyrazinone derivatives to PDE5. (6) Bulky substitutions around ring C favors selectivity against PDE11, while bulky groups near the 21-position disfavor the selectivity. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate future rational designs of novel PDE5 inhibitors with improved activity and selectivity. PMID- 23085161 TI - Novel descriptors from main and side chains of high-molecular-weight polymers applied to prediction of glass transition temperatures. AB - New descriptors of main and side chains for polymers with high molecular weight are presented in order to predict the glass-transition temperature (T(g)) by means of T(g)/M ratio. They were obtained by molecular modeling for the middle unit in a series of three repeating units (trimer). Taken together with other classic descriptors calculated for the entire trimeric structure, the ones that correlated better with the property were selected by using a variable selection method. Only three descriptors were chosen: main chain surface area (SA(MC)), side chain mass (M(SC)) and number of rotatable bonds (RBN), where the first two descriptors belong to the set of the new ones proposed. By means of a multi-layer perceptron (MLP) neural network a good prediction model (R2=0.953 and RMS=0.25 K mol/g) was achieved and internally (R2=0.964 and RMS=0.41 K mol/g) and externally (R2=0.933 and RMS =0.47 K mol/g) validated. The dataset included 88 polymers. The selected descriptors and the quality of the obtained model demonstrate the advantages of capturing through computational molecular modeling the structural characteristics of the polymers' main and side chains in the prediction of T(g)/M. PMID- 23085162 TI - Investigation of a predicted N-terminal amphipathic alpha-helix using atomistic molecular dynamics simulation of a complete prototype poliovirus virion. AB - The wild type 1 poliovirus capsid was first described in atomic detail in 1985 using X-ray crystallography. Numerous poliovirus capsid structures have been produced since, but none resolved the spatial positioning and conformation of a predicted N-terminal alpha-helix of the capsid protein VP1, which is considered critical to virus replication. We studied the helical structure under varying conditions using in silico reconstruction and atomistic molecular dynamics (MD) simulation methods based on the available poliovirus capsid atom coordinate data. MD simulations were performed on the detached N-terminal VP1 helix, the biologically active pentamer form of the pre-virion structure, reconstructed empty virus capsids and a full virion containing the poliovirus RNA genome in the form of a supercoiled structure. The N-terminal alpha-helix structure proved to be stable and amphipathic under all conditions studied. We propose that a combination of spatial disorder and proximity to the genomic RNA made this particular structure difficult to resolve by X-ray crystallography. Given the similarity of our in silico model of poliovirus compared to X-ray crystallography data, we consider computational methods to be a useful complement to the study of picornaviruses and other viruses that exhibit icosahedral symmetry. PMID- 23085163 TI - Molecular dynamics simulation of the interaction between protein tyrosine phosphatase 1B and aryl diketoacid derivatives. AB - The protein tyrosine phosphatase 1B (PTP-1B) is acknowledged as an outstanding therapeutic target for the treatment of diabetes, obesity and cancer. In this work, six aryl diketoacid compounds have been studied on the basis of molecular dynamics simulations. Hydrogen bonds, binding energies and conformation changes of the WPD loop have been analyzed. The results indicated that their activation model falls into two parts: the target region of the monomeric aryl diketoacid compounds is the active site, whereas the target region of the dimeric aryl diketoacid compounds is the WPD loop or the R loop. The van der Waals interactions exhibit stronger effects than the short-range electrostatic interactions. The van der Waals interaction energy and the IC50 values exhibit an approximately exponential relationship. Furthermore, the van der Waals interactions cooperate with the hydrogen bond interactions. This study provides a more thorough understanding of the PTP-1B inhibitor binding processes. PMID- 23085164 TI - Coupled motions during dynamics reveal a tunnel toward the active site regulated by the N-terminal alpha-helix in an acylaminoacyl peptidase. AB - Acylaminoacyl peptidase (AAP) subfamily belongs to the prolyl oligopeptidase (POP) family of serine-proteases. There is a great interest in the definition of molecular mechanisms related to the activity and substrate recognition of these complex multi-domain enzymes. The active site relies at the interface between the C-terminal catalytic domain and the beta-propeller domain, whose N-terminal region acts as a bridge to the hydrolase domain. In AAP, the N-terminal extension is characterized by a structurally conserved alpha1-helix, which is known to affect thermal stability and thermal dependence of the catalytic activity. In the present contribution, results from hundreds nanosecond all-atom molecular dynamics simulations, along with analyses of the networks of cross-correlated motions of a member of the AAP subfamily are discussed. The MD investigation identifies a tunnel that from the surrounding of the N-terminal alpha1-helix bring to the catalytic site. This cavity seems to be regulated by conformational changes of the alpha1-helix itself during the dynamics. The evidence here provided can be a useful guide for a better understanding of the mechanistic aspects related to AAP activity, but also for drug design purposes. PMID- 23085165 TI - Targeting essential cell wall lipase Rv3802c for potential therapeutics against tuberculosis. AB - Cell wall and lipid metabolism plays a vital role in the survival and infection of Mycobacterium tuberculosis. Increase in the incidences of life-threatening multidrug-resistant (MDR) and extreme drug-resistant (XDR) tuberculosis worsens the existing scenario and urge the need of new druggable targets and new drugs. Targeting Rv3802c, an essential cell wall lipase, can open up a new arsenal to fight the dreadful opportunistic pathogen. Our current study highlights the essentiality of Rv3802c. Its 3D structure is predicted for the first time which provides insight in identifying the ligand binding sites. Our analysis showed Rv3802c is highly conserved throughout mycobacterial species with no significant sequence homolog found in human proteome. Virtual screening followed by comparative docking studies of Rv3802c with its closest human structural homolog has been carried out to identify potential inhibitors effective towards mycobacterial proteins. Two diverse molecules from ZINC database, ZINC26726377 and ZINC43866786 have been identified as potential inhibitors effective towards Rv3802c based on the difference in predicted binding free energy of -3.99 and 3.28kcal/mol respectively. Rv3802c is a promising drug target and also a step towards understanding and targeting the pathogen's cell wall and lipid metabolism simultaneously to combat tuberculosis. PMID- 23085166 TI - Implementation of the force decomposition machine for molecular dynamics simulations. AB - We present the design and implementation of the force decomposition machine (FDM), a cluster of personal computers (PCs) that is tailored to running molecular dynamics (MD) simulations using the distributed diagonal force decomposition (DDFD) parallelization method. The cluster interconnect architecture is optimized for the communication pattern of the DDFD method. Our implementation of the FDM relies on standard commodity components even for networking. Although the cluster is meant for DDFD MD simulations, it remains general enough for other parallel computations. An analysis of several MD simulation runs on both the FDM and a standard PC cluster demonstrates that the FDM's interconnect architecture provides a greater performance compared to a more general cluster interconnect. PMID- 23085167 TI - Computational study: how redox affect the nonlinear optical properties of donor substituted heteroleptic bis-tridentate Ru(II) complexes? AB - Donor substituted heteroleptic bis-tridentate Ru(II) complexes with different deprotonated forms exhibit larger alterations of the first hyperpolarizabilities in oxidized process and are promising to become redox-switchable nonlinear optical (NLO) molecular materials. For systems with diprotonated form, the beta(vec) value of the two-electron-oxidized system 132+ is 5.3 and 178.6 times as large as those of the reduced parent 3 and the one-electron-oxidized system 3+ according to the DFT-FF results. For systems with mono-protonated form, the oxidization of the deprotonated benzimidazole anion is more helpful to enhance the beta(vec) value because of the increasing beta(x) component. For systems with fully deprotonated form, the largest ratio of |beta(vec)((1")+)/beta(vec)(1")| of the system without substituent is about 13.2 due to the dominant off-diagonal tensor beta(zxx). And the time-dependent density functional theory (TDDFT) results indicate that the charge transfer transition of the first excited state displays an indispensable role for larger off-diagonal tensor. Finally, the calculated frequency-dependent beta results exhibit a small dispersion effect at the low-frequency region. PMID- 23085168 TI - Comparative study on activation mechanism of carboxypeptidase A1, A2 and B: first insights from steered molecular dynamics simulations. AB - Different forms of procarboxypeptidases (PCPs) zymogens are observed experimentally to show different rates and modes of activation: PCPA1 shows a slow, biphasic, activation pathway compared to PCPA2 and PCPB which have a faster, monotonic activation behavior. Detailed mechanisms involved in activating these zymogen forms to the active enzymes are not well understood yet. In this work, three PCP zymogens (subtypes A1, A2 and B) were in silico converted into the primary cleavage state of zymogens using available X-ray structures. Based on these cleaved forms of zymogen, we are able to investigate their spontaneous dissociation process of the prosegment from its associated enzyme domain using steered molecular dynamics simulation. The simulations revealed the highest rupture force in PCPB followed by PCPA2 and PCPA1. We also found that the cleavage substantially destabilizes most of the hydrogen bonds at the prosegment enzyme interface in each zymogen structure. The mechanisms of the prosegment unbinding seem to be similar in both PCPA1 and PCPB but different in PCPA2: PCPA1 and PCPB show first rupture in the connecting segment followed by the globular domain, while PCPA2 conversely shows first rupture in the globular domain and then in the connecting segment. Our simulations have included the dynamic and long range conformational effects taking place after the first proteolytic cleavage in PCPs, providing first insights into the activation of carboxypeptidase A1, A2 and B. PMID- 23085169 TI - Toward panchromatic organic functional molecules: density functional theory study on the nature of the broad UV-Vis-NIR spectra of substituted tetra(azulene)porphyrins. AB - To achieve full solar spectrum absorption of organic dyes for organic solar cells and organic solar antenna collectors, a series of tetra(azulene)porphyrin derivatives including H2(TAzP), H2(alpha-F4TAzP), H2(beta-F4TAzP), H2(gamma F4TAzP), H2(delta-F4TAzP), H2(E-F4TAzP), H2(zeta-F4TAzP), H2[alpha-(NH2)4TAzP], H2[beta-(NH2)4TAzP], H2[gamma-(NH2)4TAzP], H2[delta-(NH2)4TAzP], H2[E (NH2)4TAzP], and H2[zeta-(NH2)4TAzP] were designed and their electronic absorption spectra were systematically studied on the basis of TDDFT calculations. The nature of the broad and intense electronic absorptions of H2(TAzP) in the range of 500-1450 nm is clearly revealed. In addition, different types of pi->pi* electronic transitions associated with different absorption bands are revealed to correspond to different electron density moving direction between peripherally-fused ten electron-pi-conjugated azulene units and the central eighteen electron-pi-conjugated porphyrin core. Introduction of electron donating groups onto the periphery of H2(TAzP) macrocycle is revealed to be able to lead to novel NIR dyes such as H2[alpha-(NH2)4TAzP] and H2[E-(NH2)4TAzP] with regulated UV-Vis-NIR absorption bands covering the full solar spectrum in the range of 300-2500 nm. In addition, the basic designing rules for panchromatic organic functional molecules based on tetrapyrrole derivatives are proposed together with the suggestions in experiments, including low molecular symmetry and narrow gap between HOMO and LUMO/LUMO+1, which will be helpful toward the design and synthesis of new panchromatic organic functional molecules. PMID- 23085170 TI - Quantitative analysis of molecular surface based on improved Marching Tetrahedra algorithm. AB - Quantitative analysis of molecular surface is a valuable technique for analyzing non-covalent interaction, studying molecular recognition mode, predicting reactive site and reactivity. An efficient way to realize the analysis was first proposed by Bulat et al. (J. Mol. Model., 16, 1679), in which Marching Tetrahedra (MT) approach commonly used in computer graphics is employed to generate vertices on molecular surface. However, it has been found that the computations of the electrostatic potential in the MT vertices are very expensive and some artificial surface extremes will be presented due to the uneven distribution of MT vertices. In this article, we propose a simple and reliable method to eliminate these unreasonably distributed surface vertices generated in the original MT. This treatment can save more than 60% of total analysis time of electrostatic potential, yet the loss in accuracy is almost negligible. The artificial surface extremes are also largely avoided as a byproduct of this algorithm. In addition, the bisection iteration procedure has been exploited to improve accuracy of linear interpolation in MT. The most appropriate grid spacing for surface analysis has also been investigated. 0.25 and 0.20 bohr are recommended to be used for surface analysis of electrostatic potential and average local ionization energy, respectively. PMID- 23085171 TI - Toward understanding the molecular basis for chemical allosteric modulator design. AB - Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient. Due to the wider receptor selectivity and lower target-based toxicity, compared with orthosteric ligands, allosteric modulators are expected to play a larger role in pharmaceutical research and development. However, current difficulties, such as a low affinity and unknown structural features of potential allosteric small-molecules, usually obstruct the discovery of allosteric modulators. In this study, we compared known allosteric modulators with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators generally contain more hydrophobic scaffolds and have a higher structural rigidity, i.e., less rotatable bonds and more rings. Based on this analysis, an empirical rule was defined to determine the structural requirements for an allosteric modulator. It was found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this "allosteric like" filter, which shows good discriminatory power in identifying allosteric modulators. Therefore, the study provides deeper insight into the chemical properties of allosteric modulators and has a good potential for the design or optimization of allosteric compounds. PMID- 23085172 TI - A theoretical study of structural and electronic properties of pentacene/Al(100) interface. AB - The first principle calculations within the framework of density functional theory have been performed for the pentacene molecule deposited on the aluminum Al(100) substrate to study the structural and electronic properties of the pentacene/Al(100) interface. The most stable configuration was found at bridge site with 45 degrees rotation of the pentacene molecule on Al(100) surface with a vertical distance of 3.4 A within LDA and 3.8 A within GGA functionals. The calculated adsorption energy reveals that the adsorption of pentacene molecule on Al(100) surface is physisorption. For the stable adsorption geometry the electronic properties such as density of states (DOS), partial density of states (PDOS), Mulliken population analysis and Schottky barrier height are studied. The analysis of atomic charge, DOS and PDOS show that the charge is transferred from the Al(100) surface to pentacene molecule, and the transferred charge is about 0.05 electrons. For the adsorbed system, the calculated Schottky barrier height for hole and electron transport is 0.27 and 1.55 eV, respectively. PMID- 23085173 TI - Identification of structural determinants of ligand selectivity in 5-HT2 receptor subtypes on the basis of protein-ligand interactions. AB - Drug selectivity is one of the most critical improvement steps in drug development. The 5-hydroxytryptamine 2 (5-HT2) receptor has 3 subtypes that exhibit different pharmacological functions. Because of their high amino acid sequence similarity, designing small molecules that selectively activate only 1 receptor among the 3 subtypes is difficult. We performed homology modeling of the 5-HT2 receptor subtypes using the beta2-adrenergic receptor as a template to identify differences in active sites that may influence 5-HT2 receptor agonist selectivity. A subset of selective 5-HT2 agonists was docked into the modeled protein structures to investigate their interactions with each receptor. Subtype specific active site residues at positions xl2.54, 5.39, and 5.46 interacted differently with each ligand. Molecular dynamics simulations revealed that position 5.46 of the 5-HT(2A) receptor interacted more favorably with selective 5 HT(2A) agonists than with selective 5-HT(2B) agonists. These computationally obtained insights provided clues to improving agonist selectivity for specific pharmacological action at 5-HT2 receptors. PMID- 23085174 TI - A DFT study on the interaction between adsorbed silver on C60 and disulfide bond. AB - Adsorption of a silver atom on the surface of Buckyball (C60) was investigated using density functional theory (DFT). The Ag atom tends to occupy the bridge site over C--C bond in pentagon-hexagon ring junction with the binding energy of 38.33 kcal mol-1. The capability of destroying S--S bond by both a single silver atom and the silver atom adsorbed on C60 was also investigated by DFT calculations using dimethyl disulfide as the molecular model. The results of the natural bond orbital (NBO) and population analysis indicate that the cleavage of the S--S bond effectively occurs by the silver atom adsorbed on C60. Since denaturation of disulfide bonds of envelope glycoprotein (gp) 120 is a key step in the prevention of the spread of HIV-1, the development of the proposed study is promised to HIV-1 research field. PMID- 23085175 TI - Teach-Discover-Treat (TDT): collaborative computational drug discovery for neglected diseases. AB - Teach-Discover-Treat (TDT) is an initiative to promote the development and sharing of computational tools solicited through a competition with the aim to impact education and collaborative drug discovery for neglected diseases. Collaboration, multidisciplinary integration, and innovation are essential for successful drug discovery. This requires a workforce that is trained in state-of the-art workflows and equipped with the ability to collaborate on platforms that are accessible and free. The TDT competition solicits high quality computational workflows for neglected disease targets, using freely available, open access tools. PMID- 23085176 TI - In silico studies toward the recognition of fluoride ion by substituted borazines. AB - The substituted borazines have been computationally investigated as new type of receptors for the recognition of fluoride ion. Fluorine, methyl and phenyl groups have been selected as electron-withdrawing, electron-releasing and aromatic substituents for the study employing DFT (B3LYP/6-311+G**) and ab initio (MP2/6 311+G**) levels of calculations. N-substituted borazines have shown higher fluoride ion affinity than their corresponding B-substituted borazines. In the case of fluorinated borazines, the binding affinity of fluoride is enhanced with the increasing number of substitutions. The F- and Cl- ions, generally, prefer to bind with the boron atom of substituted borazine rings, whereas, Br- ion prefers to bind with NH hydrogens of the borazine receptor units. Phenyl derivatives of borazine also showed analogous behavior with halide anions. The binding affinities of halides with fluorinated and phenyl derivatives of borazine have been found to be much higher than the simple borazine receptor molecule. The NBO analyses performed for the complexation of F- ion with fluorinated borazines suggest that the Lewis energy contribution in the total SCF energy enhanced with increasing the substitutions. However, in the case of methylated borazines, the delocalization energy is responsible for the stabilization of F- ion complexes. The N-trifluoroborazine showed much higher fluoride ion affinity (30.9 kcal/mol) in aqueous phase than the simple borazine. PMID- 23085177 TI - Comparative electronic structures and UV-vis spectra of tribenzosubporphyrin, tribenzomonoazasubporphyrin, tribenzodiazasubporphyrin, and subphthalocyanine: insight from DFT and TDDFT calculations. AB - Electronic structures, geometries, and vertical excitation energies of chloroboron subphthalocyanine, tribenzodiazasubporphyrin, tribenzomonoazasubporphyrin, and tribenzosubporphyrin were calculated using density functional theory (DFT) and time-dependent (TD) DFT coupled with polarized continuum model (PCM) approach. Molecular geometries calculated at the BP86/6-311G(d) level reveal bowl-shape, trigonal prismatic conformations for all compounds with a variable bowl-depth that depends on the number of meso-nitrogen atoms in corresponding molecule. TDDFT-PCM calculations predict that the Q-band should undergo gradual high-energy shift, while the B-band should undergo low energy shift upon stepwise substitution of the meso-nitrogen atoms in subphthalocyanine toward tribenzosubporphyrin. The TDDFT-PCM predicted trend was rationalized on the basis of electronic structures of target macrocycles. When comparison between theory and experiment is available, TDDFT-PCM calculations are in qualitative and quantitative agreement with experimental data. PMID- 23085178 TI - New statistical boundary conditions for argon-tungsten interactions. AB - In this study, scattering processes of argon beam impinging on tungsten surface are investigated numerically by applying molecular dynamics (MD) simulations. Energy transfer, momentum change, and scattering processes of argon gas atoms from W(110) surface are discussed. A new model of argon-tungsten (Ar-W) interaction is proposed. Based on the new proposed model, one can simplify the boundary conditions of this problem. The new boundary conditions are proved to be in line with previous experimental and theoretical results. This paper demonstrates how to proceed normalization and further conversion of the MD simulation results into boundary conditions. Application of the new proposed boundary conditions for Ar-W interactions provides a significant speedup of computations. PMID- 23085179 TI - Structure-based de novo design of Eya2 phosphatase inhibitors. AB - Although Eyes absent protein tyrosine phosphatases proved to be involved in various human cancers by a series of persuasive experimental evidence, only a very few number of small-molecule inhibitors have been reported so far. We have been able to identify 29 novel inhibitors of Eyes absent homologue 2 (Eya2) by means of a structure-based de novo design with the two known inhibitor scaffolds that contain a proper chelating group for the active-site Mg2+ ion. Because these newly found inhibitors were screened for having desirable physicochemical properties as a drug candidate and exhibited a moderate inhibitory activity with IC50 values ranging from 6 to 50 MUM, they deserve consideration for further investigation to develop new anticancer medicines. Structural features relevant to the stabilization of the identified inhibitors in the active site of Eya2 phosphatase are discussed in detail. PMID- 23085180 TI - Computational algorithms for fast-building 3D carbon nanotube models with defects. AB - Algorithms for generating defective carbon nanotubes have been developed and implemented in software. The algorithms were designed to create arrays of carbon atoms that form layers and interconnect. The parameters for construction were the following: Hamada indices that respond to topology (armchair, zigzag or chiral nanotubes) and diameter, the saturated or unsaturated nature of the nanotube, the length and, most importantly, the presence of defects that can be built individually or repetitively by rotating bonds, removing atoms, or adding additional carbon atoms. The output was written in a standard, exportable file format that contained atomic coordinates useful for further computational chemistry work. PMID- 23085181 TI - Partial physicochemical properties and relative stability of polyhydroxylated dibenzofurans: theoretical and experimental study. AB - Polyhydroxylated dibenzofuran (PHODF) is an important degradation product of polychlorinated dibenzofuran (PCDF). Four types of hydrogen bonds (the one between a hydroxyl and the oxygen atom in the matrix, between hydroxyls at ortho positions, between the oxygen atom of hydroxyl at position 1 and the hydrogen atom of the matrix at position 9, and between hydroxyls at positions 1 and 9) exist in PHODFs. The energies of the hydrogen bonds were ascertained by comparing the two configurational isomers as approximately 8-11 kJ mol-1, 16-21 kJ mol-1, 5 8 kJ mol-1 and 23-25 kJ mol-1, respectively. An experiment was designed to verify the bond energies, and the entrance geometry on main paths was studied by AIM 2000 program. The most stable in each group of configurational isomers was ascertained on the basis of evaluating the effect of hydrogen bonds. Their thermodynamic properties (standard state entropy S degrees , standard enthalpy Delta(f)H degrees and standard Gibbs energy of formation Delta(f)G degrees ) were calculated from the combination of density functional theory (DFT) at B3LYP/6-311G** level and isodesmic reactions. Octanol/water partition coefficients (log K(ow)) were calculated on line with molinspiration methodology based on group contributions. The number and position of hydroxyl substitution (N(PHOS)) can be a good indicator of these properties for all stable PHODF congeners. The configurations most likely to form are those with a hydrogen bond (Type IV). How intramolecular hydrogen bond influences ionization was also investigated and the first-order ionization constant for each stable conformation was obtained with the self-consistent reaction field (SCRF) method. PMID- 23085182 TI - Cognitive effects of diphenyl diselenide and estradiol treatments in ovariectomized mice. AB - This study investigated the effects of co-administration of diphenyl diselenide [(PhSe)(2)] and 17beta-estradiol (E(2)) on spatial reference, recognition, and working memories in ovariectomized (OVX) female mice. Sixty-day-old female adult Swiss mice were submitted to ovariectomy. From the 30th until 32nd day after ovariectomy, different doses of (PhSe)(2) (0.5-10mg/kg p.o.) were administrated to OVX mice 30min before each training of Morris Water Maze (MWM) test in order to find the highest subeffective dose for this drug. After that, OVX mice were divided into four groups: Oil, (PhSe)(2), E(2), and (PhSe)(2)+E(2). (PhSe)(2) (0.5mg/kg) and E(2) (0.1mg/kg) were administered to OVX mice from 30th to 32nd day after surgery, 30min before the training phases of behavioral tests (Open Field, MWM, Object Recognition, and T-maze). Our results demonstrated that 0.5mg/kg (PhSe)(2) plus 0.1mg/kg E(2) combined treatment improved spatial memory in the MWM test. By contrast, this same co-administration therapy was not effective in ameliorating neither delayed spontaneous alternation in the T-maze test nor object recognition memory deficits in OVX mice, although the dose of 0.5mg/kg (PhSe)(2) enhanced per se the object recognition memory in OVX mice. In conclusion, the current behavioral data suggest that a combination of (PhSe)(2) plus E(2) treatment seems to be a promising alternative to treat the cognitive decline related to menopause. Further studies should be conducted in order to determine an effective dose for (PhSe)(2) plus E(2) therapy on Object Recognition and T-maze tests. PMID- 23085183 TI - Structural studies of GDNF family ligands with their receptors-Insights into ligand recognition and activation of receptor tyrosine kinase RET. AB - RET is the receptor for glial cell line-derived neurotrophic factor family of ligands (GFLs). It is different from most other members in the receptor tyrosine kinase (RTK) family with the requirement of a co-receptor, GFRalpha, for ligand recognition and activation. Through the common signal transducer RET, GFLs are crucial for the development and maintenance of distinct sets of central and peripheral neurons, which has led to a series of studies towards understanding the structure, function and signaling mechanisms of GFLs with GFRalpha and RET receptors. Here I summarize our current understanding of the molecular basis underlying ligand recognition and activation of RET, focusing on the interactions of GFLs with their respective GFRalpha receptors, the recently determined crystal structure of RET extracellular region and a proposed GFL-GFRalpha-RET ternary complex model based on extensive structural, biochemical and functional data. This article is part of a Special Issue entitled: Emerging recognition and activation mechanisms of receptor tyrosine kinases. PMID- 23085185 TI - The "Arnold Schwarzenegger Effect": is strength of the "victim" related to misinterpretations of harm intrusions? AB - The present study used an in vivo paradigm to examine whether the victim's vulnerability in a harm-related intrusion affects beliefs about the importance of thoughts (i.e., Thought Action Fusion; TAF). Sixty-six undergraduate students at a large university were randomly assigned to imagine either a vulnerable (e.g., elderly man) or able-bodied individual (e.g., strong youthful male) they know getting into a car accident and provided in vivo ratings of anxiety, guilt, likelihood, moral wrongness, and urges to neutralize. Results indicated that thinking of car accident involving a vulnerable, compared to an able-bodied person, provoked more distress (anxiety and guilt), stronger feelings of moral wrongness, greater urges to cancel the effects of thinking such thoughts, and higher estimates of the likelihood that the collision would occur. The findings of our study broadly support Rachman's (1998) assertion that more significance and importance is attached to negative thoughts about vulnerable or helpless people. Current findings are discussed in terms of the cognitive-behavioral model of obsessions and clinical implications are addressed. PMID- 23085184 TI - Social-evaluative versus self-evaluative appearance concerns in Body Dysmorphic Disorder. AB - Body Dysmorphic Disorder (BDD) is characterised by significant preoccupation and distress relating to an imagined or slight defect in appearance. Individuals with BDD frequently report marked concerns relating to perceived negative evaluation of their appearance by others, but research specifically investigating such concerns remains limited. This study investigated the extent and nature of appearance-related social-evaluative and self-evaluative concerns in individuals with BDD and healthy controls. BDD participants, in comparison to controls, reported high levels of importance and anxiety associated with perceptions of others' views of their appearance, in addition to their own view. No differences were observed in the level of importance and anxiety associated with their self view in comparison to others' views. These findings support existing evidence indicating that appearance-related social-evaluative concerns are a central feature of BDD. Cognitive-behavioural treatment implications are discussed. PMID- 23085186 TI - Predicting return of fear following exposure therapy with an implicit measure of attitudes. AB - We sought to advance understanding of the processes underlying the efficacy of exposure therapy and particularly the phenomenon of return of fear (ROF) following treatment by drawing on a social psychological view of phobias as attitudes. Specifically, a dual process theory of attitude-related behavior predicts that a positive response to exposure therapy may reflect change in either the automatic (the attitude representation itself) or controlled (skills and confidence at coping with the fear) responses to the phobic stimulus, or both. However, if the attitude representation remains negative following treatment, ROF should be more likely. We tested this hypothesis in a clinical sample of individuals with public speaking phobia using a single-session exposure therapy protocol previously shown to be efficacious but also associated with some ROF. Consistent with predictions, a post-treatment implicit measure of attitudes toward public speaking (the Personalized Implicit Association Test [PIAT]) predicted ROF at 1-month follow-up. These results suggest that change in the automatically activated attitude toward the phobic stimulus is an important goal of exposure therapy and that an implicit measure like the PIAT can provide a useful measure of such change by which to gauge the adequacy of exposure treatment and predict its long-term efficacy. PMID- 23085187 TI - Accumulation and transfer of 137Cs and 90Sr in the plants of the forest ecosystem near the Ignalina Nuclear Power Plant. AB - The radioecological state of the forest ecosystem in the vicinity of the Ignalina Power Plant prior to decommissioning was analysed with specific emphasis on (137)Cs and (90)Sr activity concentrations in plant species growing in two reference sampling sites (Tilze and Grikiniskes). In the period of 1996-2008 the mean contamination of plants with (137)Cs was from 45 to 119 Bq/kg and with (90)Sr - from 3 to 42 Bq/kg. Measured (137)Cs TF values for soil-root transfer mainly ranged between 1.0-1.4, except for Calamagrostis arundinacea which had a TF value of 0.1. On average, the (137)Cs TF value from root to shoot was 1.7 fold higher than for soil to root transfer. (90)Sr TF values (soil-root) were in the range of 1.2-1.8 but for Calluna vulgaris it was 0.2. The mean root to shoot TF value for (90)Sr was 7.7 fold higher. These results indicate the higher (90)Sr bioavailability than that of (137)Cs in the forested area. The Grikiniskes reference site is located nearby the Ignalina NPP, specifically the heated water outlet channel, which results in altered microclimatic conditions. These specific microclimatic conditions result in relationships between (137)Cs TF (soil-root) values and pH, moisture and organic matter content in the soil at Grikiniskes which appear to be different to those at the Tilze reference sampling site. PMID- 23085188 TI - Airborne geophysical surveys in the north-central region of Goias (Brazil): implications for radiometric characterization of tropical soils. AB - Progress obtained in analysis aerogammaspectrometric and aeromagnetic survey data for the north-central region of the state of Goias (Brazil) are presented. The results obtained have allowed not only determination of the abundances of naturally radioactive elements but also new insights into the processes that determine the radiometric characteristics of the main soil types. There are indications that the radioelement abundances of soils are not only related to their physical properties, but also chemical characteristics of source rocks from which they are derived. For example, oxisol soils derived from the felsic source rocks of the Mara Rosa and Green stone belts have equivalent uranium (eU) values higher than 1.7 ppm, while those derived from source rocks of the relatively more basic Uruacu Group and sediment sequences of Proterozoic age are characterized by eU contents of less than 1 ppm. Oxisol soils of the Median massif, ultisol soils of the Paranoa, Canastra and Araxa Groups, cambisol soils of the Arai Group and plintosol soils of the Bambui Group constitute an intermediate class with eU contents in the range of 1-1.3 ppm. Equivalent thorium abundances of soil types display similar trends, the range of variation being 4-16 ppm. Potassium abundances on the other hand are rather uniform with values in the range of 1 1.3%, the only exception being the sedimentary sequences of Proterozoic age, which has a mean value of 0.7%. These observations have been considered as indicative of characteristic features of tropical soils in the study area. In this context, we point out the possibility of using results of aerogammaspectrometry surveys as a convenient complementary tool in identifying geochemical zoning of soils in tropical environments. The ratios of eU/K are found to fall in the range of 1-1.7, which is typical of common soils. The ratios of eTh/K exhibit a relatively wide interval, with values in the range of 4-16. The ratios of eTh/eU are found to have values in the range of 2-12. Also, there appears to be a rather reasonable association between the spatial distributions of positive anomalies of the radioelement ratios with the lineaments derived from the vertical derivative of the magnetic field. The map of the analytic signal of the magnetic field also reveals a similar association. Such associations imply that the processes which determine evolutionary trends of soil types are somehow related to the events that control the development of structural features in subsurface layers. PMID- 23085189 TI - Insulin-dependent diabetic patients with macrovascular complications suffer from many geriatric conditions. AB - BACKGROUND: Current diabetic care guidelines focus mainly on managing metabolic control and macro- and microvascular comorbidities. This focus may be too narrow given the number of geriatric conditions present in these often aged patients. METHODS: We studied the prevalence of multimorbidity, (undiagnosed) geriatric conditions and disabilities in diabetic patients with macrovascular complications. RESULTS: One hundred forty-three community dwelling, insulin dependent diabetic patients with macrovascular complications, aged 55 years and above, who were concurrently enrolled in the diabetes care clinic in a university hospital in the Netherlands, participated. Data on healthcare utilization, activities of daily living, geriatric conditions and quality of life were self reported using a systematic diagnostic questionnaire. Mean age was 66.9 years (8.5 years), 62% were male and 22% were of Surinamese-South Asian descent. Loneliness was reported by 47%. The majority rated their quality of life (QoL) from 'reasonable' (45%) to 'good' (31%). In patients without ADL impairments, 60% were in need of assistance, compared to 95% among those with more than one impairment (p<0.01). In total, 19% had cognitive impairment, and 63% perceived pain. 84% of patients with impairments experienced social problems compared to 32% of patients in the other group. CONCLUSIONS: This study demonstrates that the current focus of diabetes care may be too restricted given the high number of geriatric conditions that these patients present. PMID- 23085190 TI - Ts6 and Ts2 from Tityus serrulatus venom induce inflammation by mechanisms dependent on lipid mediators and cytokine production. AB - Inflammatory mediators are thought to be involved in the systemic and local immune response induced by the Tityus serrulatus scorpion envenomation. New functional aspects of lipid mediators have recently been described. Here, we examine the unreported role of lipid mediators in cell recruitment to the peritoneal cavity after an injection with Ts2 or Ts6 toxins isolated from the T. serrulatus scorpion venom. In this report, we demonstrate that following a single intraperitoneal (i.p.) injection of Ts2 or Ts6 (250 MUg/kg) in mice, there was an induction of leukocytosis with a predominance of neutrophils observed at 4, 24, 48 and 96 h. Moreover, total protein, leukotriene (LT)B(4), prostaglandin (PG)E(2) and pro-inflammatory cytokine levels were increased. We also observed an increase of regulatory cytokines, including interleukin (IL)-10, after the Ts2 injection. Finally, we observed that Ts2 or Ts6 injection in 5-lipoxygenase (LO) deficient mice and in wild type (WT) 129sv mice pre-treated with LTs and PGs inhibitors (MK-886 and celecoxib, respectively) a reduction the influx of leukocytes occurs in comparison to WT. The recruitment of these cells demonstrated a phenotype characteristic of neutrophils, macrophages, CD4 and CD8 lymphocytes expressing GR1+, F4/80+, CD3+/CD4+ and CD3+/CD8+, respectively. In conclusion, our data demonstrate that Ts2 and Ts6 induce inflammation by mechanisms dependent on lipid mediators and cytokine production. Ts2 may play a regulatory role whereas Ts6 exhibits pro-inflammatory activity exclusively. PMID- 23085191 TI - Gene construction, expression and functional testing of an inotropic peptide from the venom of the black scorpion Hottentotta judaicus. AB - Anti-insect depressant toxins represent a subfamily of scorpion venom-derived beta-toxins that are polypeptides composed of 61-65 amino acid residues stabilized by four disulfide bridges. These toxins affect the activation of voltage-sensitive sodium channels (NaScTx) and exhibit the preferential ability to induce flaccid paralysis in insect larvae. Here we demonstrate the recombinant expression of the novel cardiac inotropic peptide (Bj-IP) that was classified as an anti-insect depressant betaNaScTx isolated from the venom of Hottentotta judaicus. By using "splicing by overlap extension" (SOE)-PCR, allowing for the first time one step de novo synthesis of long-chain scorpion toxin genes, we generated a codon-optimized DNA fragment of Bj-IP for cloning into the Escherichia coli vector pQE30. Moreover, the gene of interest was fused to a 6xHis coding DNA sequence. Subsequent recombinant expression was performed in E. coli KRX. The purification of the polypeptide was achieved by a combination of NiNTA agarose columns and RP (C(18)) high-performance liquid chromatography. The purified fusion protein was digested with factor Xa resulting in the elution of Bj-IP. The yield of recombinant Bj-IP expression was approximately 4.5 mg per liter of culture. Mass spectrometry confirmed the theoretical total mass of Bj-IP (6608 Da). Tag-free Bj-IP was refolded in guanidine chloride buffer with a glutathione redox system which was supplemented with different additives at 16 degrees C. Supplementation with 10% glycerol produced Bj-IP folding forms that exhibited reproducible biological activity in mouse cardiomyocytes. Cell contractility was increased by almost 3-fold and decay kinetics were hasten by 47% after administration of Bj-IP. Taken together, here we show the recombinant expression of the functionally active cardiac inotropic peptide Bj-IP, a new betaNaScTx from H. judaicus, for promising pharmacological applications. Furthermore, our data suggest that the use of SOE-PCR may help to facilitate in future the high throughput of cloning and/or modification of scorpion toxin genes. PMID- 23085192 TI - Increased uracil insertion in DNA is cytotoxic and increases the frequency of mutation, double strand break formation and VSG switching in Trypanosoma brucei. AB - Deoxyuridine 5'-triphosphate pyrophosphatase (dUTPase) and uracil-DNA glycosylase (UNG) are key enzymes involved in the control of the presence of uracil in DNA. While dUTPase prevents uracil misincorporation by removing dUTP from the deoxynucleotide pool, UNG excises uracil from DNA as a first step of the base excision repair pathway (BER). Here, we report that strong down-regulation of dUTPase in UNG-deficient Trypanosoma brucei cells greatly impairs cell viability in both bloodstream and procyclic forms, underscoring the extreme sensitivity of trypanosomes to uracil in DNA. Depletion of dUTPase activity in the absence of UNG provoked cell cycle alterations, massive dUTP misincorporation into DNA and chromosomal fragmentation. Overall, trypanosomatid cells that lack dUTPase and UNG activities exhibited greater proliferation defects and DNA damage than cells deficient in only one of these activities. To determine the mutagenic consequences of uracil in DNA, mutation rates and spectra were analyzed in dUTPase-depleted cells in the presence of UNG activity. These cells displayed a spontaneous mutation rate 9-fold higher than the parental cell line. Base substitutions at A:T base pairs and deletion frequencies were both significantly enhanced which is consistent with the generation of mutagenic AP sites and DNA strand breaks. The increase in strand breaks conveyed a concomitant increase in VSG switching in vitro. The low tolerance of T. brucei to uracil in DNA emphasizes the importance of uracil removal and regulation of intracellular dUTP pool levels in cell viability and genetic stability and suggests potential strategies to compromise parasite survival. PMID- 23085193 TI - Tumor necrosis factor. AB - Tumor necrosis factor (TNF) is a critical cytokine, which contributes to both physiological and pathological processes. This mini-review will briefly touch the history of TNF discovery, its family members and its biological and pathological functions. Then, it will focus on new findings on the molecular mechanisms of how TNF triggers activation of the NF-kappaB and AP-1 pathways, which are critical for expression of pro-inflammatory cytokines, as well as the MLKL cascade, which is critical for the generation of ROS in response to TNF. Finally, this review will briefly summarize recent advances in understanding TNF-induced cell survival, apoptosis and necrosis (also called necroptosis). Understanding new findings and emerging concepts will impact future research on the molecular mechanisms of TNF signaling in immune disorders and cancer-related inflammation. PMID- 23085194 TI - The effect of intracerebroventricular infusions of ghrelin or short fasting on the gene expression and immunoreactivity of neuropeptide Y in the hypothalamic neurons in prepubertal female lambs: a morphofunctional study. AB - The role of exogenous ghrelin in the regulation of neuropeptide Y (NPY) neuronal system in the hypothalamus of intact lambs has not been yet determined. The aim of present study was to investigate the effects of intracerebroventricular infusion of ghrelin or short fasting on the secretory activity of the NPY neurons in the hypothalamus of prepubertal female sheep. Animals (n=30) were randomly divided into three groups, two groups were fed standard diet and one group was fasted for 72h. One group fed standard diet and fasted group were infused to the 3rd ventricle of the brain with vehicle, while the remaining group fed standard diet was infused with ghrelin (25MUg/120MUl/h) for 6h during three consecutive days. Immediately after the treatment, tissues were collected. Parts of the brains were fixed in situ for further immunohistochemical analysis, and remaining parts were frozen for RT-PCR analysis. Both, fasting and ghrelin infusion elicited the same kind of changes in the mRNA and intra-neuronal levels of the NPY hypothalamic neurons. Namely, the expression of NPY mRNA in the medial basal hypothalamus and immunoreactivity of NPY in the arcuate and periventricular nuclei increased in fasted and standard fed with ghrelin's infusion groups compared to standard fed sheep (P<0.05). These data demonstrate that ghrelin takes part in the mechanisms linking the nutritional status with an activity of the hypothalamic NPY at the level of the central nervous system by stimulating NPY secretion in sheep. PMID- 23085195 TI - Experimental evidence on actuation and performance of the elytron-to-body articulation in a diving beetle, Cybister laterimarginalis (Coleoptera, Dytiscidae). AB - Movements of the elytra and axillary sclerites were video recorded in tethered flying beetles and in manipulated mounts. Mesothoracic axillary plates are homologues of those in the metathorax. Two anterior axillaries (Ax1, Ax2) fuse together; they are hinged to the third axillary plate (Ax3). In turn, Ax3 is hinged with the elytron. During takeoff, a beetle abducts and highly elevates its elytra (1), then droops the elytra in a flatly spread position (2); closing is adduction in a horizontal plane (3). These steps have been simulated: (1) by pressing down the anterior horn; (2) occurred spontaneously after release of pressing; (3) the elytron closed flatly either by manual turn of the elytron or by manual elevation of the prothorax. Anterior axillaries rotated forward and down during (1), returned during (2) and remained immobile during closing. Ax3 is folded between the closed elytron and Ax1+Ax2; it unfolds during opening. Two hinges of Ax3 form a Z-configuration and provide a linked drive for complicated rotation of the elytron. Opening was impaired in vivo if tergal leg protractor and depressor were disabled, closing did not suffer. Closing was prevented by excision in the hind edge of the pronotum, not harmful for opening. Role of direct and indirect muscles in transient elytral movements is discussed. PMID- 23085196 TI - Cytochrome c produces pores in cardiolipin-containing planar bilayer lipid membranes in the presence of hydrogen peroxide. AB - Interaction of cytochrome c with cardiolipin in the presence of hydrogen peroxide induces peroxidase activity in cytochrome c and the ability to oxidize membrane lipids. These cytochrome c properties play a substantial role in the cytochrome c mediated apoptotic reactions. In the present study the electric properties (specific capacitance and integral conductance) of the cardiolipin-containing asolectin planar bilayer lipid membranes (pBLM) in the presence of cytochrome c and hydrogen peroxide were studied. Cytochrome c interaction with cardiolipin containing pBLM in the presence of hydrogen peroxide resulted in the dramatic increase of the conductance, pore production, their growth up to 3.5 nm diameter and subsequent membrane destruction. In the absence of hydrogen peroxide cytochrome c demonstrated almost no effect on the membrane capacitance and conductance. The data obtained prove the pivotal role of cytochrome c and membrane lipids in the permeabilization of pBLM. Correlation of apoptotic reactions and cytochrome c-mediated membrane permeability is discussed. PMID- 23085197 TI - Role of charge screening and delocalization for lipophilic cation permeability of model and mitochondrial membranes. AB - The effects of the mitochondria-targeted lipophilic cation dodecyltriphenylphosphonium (C12TPP, the charge is delocalized and screened by bulky hydrophobic residues) and those of lipophilic cations decyltriethylammonium bromide and cetyltrimethylammonium bromide (C10TEA and C16TMA, the charges are localized and screened by less bulky residues) on bilayer planar phospholipid membranes and tightly-coupled mitochondria from the yeast Yarrowia lipolytica have been compared. In planar membranes, C12TPP was found to generate a diffusion potential as if it easily penetrates these membranes. In the presence of palmitate, C12TPP induced H(+) permeability like plastoquinonyl decyltriphenilphosphonium that facilitates transfer of fatty acid anions (Severin et al., PNAS, 2010, 107, 663-668). C12TPP was shown to stimulate State 4 respiration of mitochondria and caused a mitochondrial membrane depolarization with a half-maximal effect at 6MUM. Besides, C12TPP profoundly potentiated the uncoupling effect of endogenous or added fatty acids. C10TEA and C16TMA inhibited State 4 respiration and decreased the membrane potential, though at much higher concentrations than C12TPP, and they did not promote the uncoupling action of fatty acids. These relationships were modeled by molecular dynamics. They can be explained by different membrane permeabilities for studied cations, which in turn are due to different availabilities of the positive charge in these cations to water dipoles. PMID- 23085199 TI - Computer-aided colorectal tumor classification in NBI endoscopy using local features. AB - An early detection of colorectal cancer through colorectal endoscopy is important and widely used in hospitals as a standard medical procedure. During colonoscopy, the lesions of colorectal tumors on the colon surface are visually inspected by a Narrow Band Imaging (NBI) zoom-videoendoscope. By using the visual appearance of colorectal tumors in endoscopic images, histological diagnosis is presumed based on classification schemes for NBI magnification findings. In this paper, we report on the performance of a recognition system for classifying NBI images of colorectal tumors into three types (A, B, and C3) based on the NBI magnification findings. To deal with the problem of computer-aided classification of NBI images, we explore a local feature-based recognition method, bag-of-visual-words (BoW), and provide extensive experiments on a variety of technical aspects. The proposed prototype system, used in the experiments, consists of a bag-of-visual words representation of local features followed by Support Vector Machine (SVM) classifiers. A number of local features are extracted by using sampling schemes such as Difference-of-Gaussians and grid sampling. In addition, in this paper we propose a new combination of local features and sampling schemes. Extensive experiments with varying the parameters for each component are carried out, for the performance of the system is usually affected by those parameters, e.g. the sampling strategy for the local features, the representation of the local feature histograms, the kernel types of the SVM classifiers, the number of classes to be considered, etc. The recognition results are compared in terms of recognition rates, precision/recall, and F-measure for different numbers of visual words. The proposed system achieves a recognition rate of 96% for 10-fold cross validation on a real dataset of 908 NBI images collected during actual colonoscopy, and 93% for a separate test dataset. PMID- 23085198 TI - Mitochondria: one of the destinations of miRNAs. AB - The cellular processes are controlled by a narrow range of mRNA and proteins levels, where small RNAs (sRNAs) known as miRNAs play a critical role. The spatial and temporal regulation of miRNA processing components and mature miRNA is emerging. The recent studies suggest that mitochondria are one of the destinations of pre as well as mature miRNAs. The role of mitochondria extends beyond energy metabolism to many other cellular processes like metabolism, cell death and inflammation. The new found destination of miRNAs suggest the role of mitochondria in monitoring site specific regulations of proteins as well as the function of mitochondria. The studies in this direction will decipher the novel role of mitochondria-associated miRNAs in different cellular processes. This review is focussed on the recent studies demonstrating the presence of miRNAs in mitochondria and its possible significance in different cellular and physiological conditions. PMID- 23085200 TI - Cyclic test comparison of all-inside device and inside-out sutures for radial meniscus lesion repair: an in vitro porcine model study. AB - PURPOSE: To compare biomechanical fixation and gapping characteristics of a new all-inside meniscus repair method for radial meniscus lesion repair versus conventional inside-out suture repair under submaximal cyclic loading and load-to failure test conditions. METHODS: Fresh-frozen porcine tibiae with attached lateral menisci and joint capsules were harvested and stored for 48 hours at -20 degrees C. After thawing for 12 hours, equivalent-size healthy specimens were randomly assigned to 2 groups of 8 specimens each. Standardized radial lesions were repaired with the Sequent device (ConMed Linvatec, Largo, FL) (group 1) or conventional inside-out suturing with No. 2-0 braided polyester suture (group 2). Repaired specimens were placed in custom clamps and mounted on a servohydraulic device. After a 2-N preload, specimens were cycled from 5 to 20 N (0.1 Hz), before undergoing 1,000 submaximal loading cycles between 5 and 20 N (0.5 Hz). A 40-second delay at 100, 500, and 1,000 cycles enabled digital photographs to be taken for gapping measurement determination. Specimens then underwent load-to failure testing (12.5 mm/s). Fixation failure mode was documented. RESULTS: Group displacement did not differ after 1, 100, 500, and 1,000 submaximal loading cycles. Group peak gapping did not differ at 100, 500, and 1,000 submaximal loading cycles. Load at failure and displacement and stiffness during load-to failure testing did not differ between groups. During load-to-failure testing, all-inside specimens failed by implant dislodgement from the meniscus periphery whereas the inside-out repaired specimens failed by suture rupture. CONCLUSIONS: Under controlled in vitro biomechanical test conditions, the all-inside device provided radial meniscus lesion fixation that was comparable, but not superior, to conventional inside-out suturing. CLINICAL RELEVANCE: The all-inside radial lateral meniscus lesion repair method may provide comparable fixation to conventional inside-out suturing without the need for additional incisions and their associated neurovascular injury risks. PMID- 23085201 TI - Heterogeneous patterns of health status among immigrants in Spain. AB - OBJECTIVES: (1) To analyse differences in the self-perceived health and mental health status between the Spanish population and immigrants from the seven leading countries in terms of number of immigrants; (2) to examine whether differences are accounted for by socio-economic characteristics, and (3) to determine whether the patterns of associations differ by gender. METHODS: Data come from the 2006 Spanish National Health Survey. The sample was composed of all 20-64 year old Spaniards and immigrants from the seven countries with most immigrants in Spain (Argentina, Bolivia, Colombia, Ecuador, Peru, Romania and Morocco) [n=20,731]. RESULTS: In both sexes, people from Bolivia had poorer health outcomes, above all Bolivian males. Conversely, people from Argentina and Colombia had the best health outcomes. For the rest of the countries varied results depending on gender, country and health indicator were found. CONCLUSIONS: Differences in health status between people born in Spain and foreign-born people depend on relationships between country of birth, characteristics of the migration process, gender, ethnicity and the health outcome analyzed. PMID- 23085203 TI - Association of severe autosomal recessive osteopetrosis and structural brain abnormalities: a case report and review of the literature. AB - We describe a fetus with severe osteopetrosis diagnosed on post-mortem radiographs following termination of pregnancy at 29 weeks for major brain malformations detected on ultrasound. SNP microarray confirmed loss of heterozygosity in 5% of the genome, consistent with parental consanguinity. Sequencing of the genes known to cause severe recessive osteopetrosis, TCIRG1, CLCN7, OSTM1 and SNX10, was negative. Brain malformations are not typically considered part of the phenotypic spectrum of osteopetrosis. We review the literature, and propose that this may represent a novel autosomal recessive variant of osteopetrosis. PMID- 23085204 TI - Spatial probability cuing and right hemisphere damage. AB - In this experiment we studied statistical learning, inter-trial priming, and visual attention. We assessed healthy controls and right brain damaged (RBD) patients with and without neglect, on a simple visual discrimination task designed to measure priming effects and probability learning. All participants showed a preserved priming effect for item color. Contrary to healthy controls and RBD participants without neglect, RBD participants with neglect did not show positional priming and both RBD groups learned the underlying spatial probability distribution of target locations to a lesser degree. To see if the latter deficiency could be improved, we tested a patient with long standing chronic spatial neglect on three separate days and observed improved identification times for left sided, high probability, targets. In summary, we found preservation of priming per se in people with spatial neglect. However, this was only clearly demonstrable for color priming and not for positional priming. Associated with this impairment was a difficulty in learning the overall statistical structure of target locations. In a patient with severe persistent neglect we were able to demonstrate that the deficit in statistical learning was not absolute, as this subject improved his identification times for targets appearing in high probability regions of the test display. PMID- 23085202 TI - Variety and quality of healthy foods differ according to neighbourhood deprivation. AB - This study addresses a gap in the food environment literature by investigating spatial differences in the inter relationship of price, variety and quality of food in southern England. We conducted a survey of all grocery stores (n=195) in the city of Southampton, UK, and ranked neighbourhoods according to national quintiles of deprivation. We found no difference in availability or cheapest price across neighbourhoods. However, the poorest neighbourhoods had less variety of healthy products and poorer quality fruit and vegetables than more affluent neighbourhoods. Dietary inequalities may be exacerbated by differences in the variety and quality of healthy foods sold locally; these factors may influence whether or not consumers purchase healthy foods. PMID- 23085206 TI - Simultaneous detection of diagnostic biomarkers of alkaptonuria, ornithine carbamoyltransferase deficiency, and neuroblastoma disease by high-performance liquid chromatography/tandem mass spectrometry. AB - BACKGROUND: Urinary homovanillic acid (HVA)/vanillylmandelic acid (VMA), orotic acid (OA), and homogentisic acid (HGA) are diagnostic biomarkers of neuroblastoma, ornithine carbamoyl transferase deficiency (OCTD), and alkaptonuria (AKU), respectively. In this study, a high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for simultaneous quantification of HVA, VMA, OA, and HGA in urine. METHODS: After sample preparation, which involved only the dilution procedure, samples were quantified by LC-MS/MS. Full-scan MS/MS mode enabled the urinary markers to be quantified with a high degree of specificity and sensitivity. Rather than using a separate enzymatic method to normalize the concentration of creatinine in urine, we quantified the level of creatinine in urine in one LC-MS run. RESULTS: The limits of detection were 10 MUg/l for HGA, 25 MUg/l for HVA/VMA, and 50 MUg/l for OA with a single-to-noise ratio of 3; the limits of quantification were 50 MUg/l for HVA and HGA, 100 MUg/l for VMA, and 250 MUg/l for OA. The linear dynamic range for quantification of the analytes covered 2 to 3 orders of magnitude, depending on the analyte. The relative standard deviation of the developed LC MS/MS method was less than 4% for the intra-day validation and 10% for the inter day validation. CONCLUSIONS: The results show that our LC-MS/MS technique is a highly sensitive and rapid method for screening for biomarkers that are diagnostic of three metabolic diseases. PMID- 23085207 TI - An improved candidate reference method for serum potassium measurement by inductively coupled plasma-mass spectrometry. AB - BACKGROUND: In 2002, the National Institute of Standards and Technology (NIST) established a reference method for serum potassium based on inductively coupled plasma-mass spectrometry (ICP-MS). The aim of this study was to develop an inexpensive and improved candidate reference method for accurate and precise determination of serum potassium. METHODS: Serum samples were diluted with 1% HNO3 supplemented with (59)Cobalt as isotope internal standard, and potassium was measured by ICP-MS. The new method was evaluated with NIST standard reference materials (SRMs), according to the Clinical and Laboratory Standard Institute's evaluation protocols. RESULTS: At 4.300 and 4.678 mmol/l levels, the present method demonstrated analytical imprecision of 0.09% and 0.14%, and recoveries of 99.67% to 99.88%, respectively. The bias between the target values of SRMs were 0.02% to +0.28%, respectively. This method was linear between 0.0000 and 6.87 mmol/l (R(2)=1.000). The method had an uncertainty (U95%) of 0.76%. CONCLUSIONS: The proposed ICP-MS method to measure serum potassium is precise and accurate, with high sensitivity and specificity. It may be considered as a candidate reference method for the determination of serum potassium. PMID- 23085205 TI - High throughput paper spray mass spectrometry analysis. AB - BACKGROUND: Fast analysis of chemicals in samples of complex mixtures is important for many analytical applications including therapeutic drug monitoring and food safety screening. METHODS: Based on the paper spray technology developed recently, a high throughput device was developed in this work and used for evaluation of the fast quantitative analysis using paper spray mass spectrometry. RESULTS: The performance of the method was characterized with bovine blood samples spiked with sunitinib and nicotine. At optimized condition, relatively fast analysis speed of 7s/sample was achieved with relatively good LOQs (1 ng/ml) and quantitation. CONCLUSION: In an application of the method for food screening, LODs better than 1 ng/g were achieved for clenbuterol in beef. PMID- 23085208 TI - Development and validation of a serum total testosterone liquid chromatography tandem mass spectrometry (LC-MS/MS) assay calibrated to NIST SRM 971. AB - BACKGROUND: At our institution, serum testosterone in adult males is measured by immunoassay while female and pediatric specimens are sent to a reference laboratory for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis due to low concentrations. As this is of significant cost, a testosterone LC MS/MS assay was developed in-house. METHODS: A 5500 QTRAP(r) using electrospray ionization and a Shimadzu Prominence with a C18 column were used. Gradient elution with formic acid, water and methanol:acetonitrile at 0.5 ml/min had a 7 min run-time. A liquid-liquid extraction with hexane:ethyl acetate was carried out on 200 MUl of serum. Multiple reaction monitoring was employed. RESULTS: Sample preparation took ~80 min for 21 samples. Six calibrators were used (0-1263 ng/dl; concentration assigned by NIST SRM 971) with 3 quality controls (9, 168 and 532 ng/dl). The limits of detection and quantitation were 1 and 2 ng/dl respectively. Extraction recovery was ~90% and ion suppression ~5%. Within-run and total precision studies yielded <15% CV at the limit of quantitation and <7% CV through the rest of the linear range. Isobaric interferences were baseline separated from testosterone. Method comparisons between this assay, an immunoassay, and another LC-MS/MS assay were completed. CONCLUSIONS: An accurate and sensitive LC-MS/MS assay for total testosterone was developed. Bringing this assay in-house reduces turnaround time for clinicians and patients and saves our institution funds. PMID- 23085209 TI - Gomisin N in the herbal drug gomishi (Schisandra chinensis) suppresses inducible nitric oxide synthase gene via C/EBPbeta and NF-kappaB in rat hepatocytes. AB - Gomishi is the dried fruit of Schisandra chinensis Baillon (Fructus Schisandrae chinensis, FSC) and has been used in Japanese Kampo medicine to treat inflammatory and liver diseases. However, it is unclear which constituent of FSC is primarily responsible for its pharmacological effects. FSC was extracted with methanol, fractionated by hydrophobicity, and further purified. We measured the effects of each fraction or constituent thereof on the induction of the inflammatory mediator nitric oxide (NO), which was induced by interleukin 1beta in primary cultured rat hepatocytes. The hydrophobic fraction markedly suppressed NO induction and reduced the expression of inducible nitric oxide syntheses (iNOS) in interleukin 1beta-treated hepatocytes. Gomisin N and gamma-schizandrin, two major constituents of the hydrophobic fraction, significantly reduced NO production and the levels of the iNOS protein, mRNA, and antisense transcript. Gomisin N and gamma-schizandrin also decreased the transcription of interleukin 1beta and inflammatory chemokines. The overexpression of the p65 subunit of nuclear factor kappaB or CCAAT/enhancer-binding protein beta increased the promoter activity of the iNOS gene in the firefly luciferase assay, whereas gomisin N decreased the promoter activity. The anti-inflammatory activity of FSC and its constituents were analysed, and we demonstrated that gomisin N and gamma schizandrin are involved in the hepatoprotective effect of the FSC extract, which has therapeutic potential for liver disease. PMID- 23085211 TI - Neuromodulation in Tourette syndrome: dopamine and beyond. AB - Almost since the beginning of research on Tourette syndrome (TS), tics have been linked to a dysfunction of the dopamine (DA) system. At first, this assumption was mainly based on clinical findings of DA antagonists being the most effective drug in treating tics, but in recent years nuclear imaging has enabled a much deeper understanding of DA neurotransmission in TS. Based on the findings of various PET and SPECT studies the first part of the review discusses four hypotheses on DA dysfunctions in TS: (i) DA hyperinnervation, (ii) supersensitive DA receptors, (iii) pre-synaptic DA abnormality and (iv) DA tonic-phasic dysfunction. According to the latter hypothesis, reduced levels of tonic DA in the extracellular space lead to higher concentrations of DA in the axon terminal and an increase of stimulus-dependent DA release. The second part of the review addresses the modulating role of DA in some major clinical features of TS, like the exacerbation with stress or infection and the association with deficient sensorimotor gating. PMID- 23085212 TI - CD4+ and CD8+ T lymphocytes in lung tissue of NSIP: correlation with T lymphocytes in BALF. AB - BACKGROUND: Nonspecific interstitial pneumonia (NSIP) is characterized by the interstitial infiltration T lymphocytes (TLs). Bronchoalveolar lavage fluid (BALF) has been used to analyze the inflammatory cells infiltrating in lung. The controversy about whether the BALF cellular profile reflects T lymphocytes in lung tissue still persists. Some studies found a positive correlation of cell composition between BALF and lung tissue, but others gave opposite conclusion. OBJECTIVE: To investigate CD4+ and CD8+ T lymphocytes distribution in lung tissue of NSIP and the relationship with T lymphocytes in bronchoalveolar lavage. METHODS: Thirty-seven patients diagnosed as NSIP were included. The pathological and BALF date were reviewed. The characteristics of TLs infiltration in different lung regions were investigated. RESULTS: The study included 28 women. The median age was 48 years. In lung tissue, CD4+ and CD8+ lymphocytes (counts/0.1mm2) were separately accounted in lymphoid follicle region (156.51 +/- 90.70 vs 85.30 +/- 43.75), small blood vessel region (66.58 +/- 31.99 vs 58.43 +/- 30.24), interstitial region (37.60 +/- 19.40 vs 47.12 +/- 33.42) and small airway region (26.59 +/- 17.04 vs 40.18 +/- 34.02). CD4+/CD8+ ratios in lymphoid follicle and small vessel > 1, in interstitium and small airway <1. The number of CD8+ lymphocytes in BALF was correlated with CD8+ lymphocytes around small airway (r = 0.360, p = 0.029) and in interstitial region (r = 0.451, p = 0.005). CD4+/CD8+ ratio in BALF was correlated with that in small airway region (r = 0.437, p = 0.007) and interstitial region (r = 0.468, p = 0.003). CONCLUSIONS: In NSIP, T lymphocytes were distributed in different regions of lung tissue. The CD8+ T lymphocytes and CD4+/CD8+ ratio in BALF reflect those in interstitium regions and around small airway of the lung. PMID- 23085213 TI - Relationship between daily physical activity and exercise capacity in patients with COPD. AB - BACKGROUND: Exercise training programmes for patients with COPD are effective in improving exercise capacity. The few trials that have investigated the effects of exercise programmes on daily physical activity show contradictory results. AIM: To investigate the relation between daily physical activity level and exercise capacity in patients with COPD using data of a randomised controlled trial in which the exercise intervention was aimed at improvement of both physical activity and exercise capacity (the COPE-II study). METHODS: These are secondary analyses of the COPE-II study, a randomised controlled trial in which a community based physiotherapeutic exercise programme was evaluated. Daily physical activity was measured with a pedometer (steps/day). Exercise capacity was measured with an incremental maximal cycle ergometer test, the incremental (ISWT) and endurance shuttle walk test (ESWT). Pearson correlation coefficients were calculated. RESULTS: At baseline, correlations between steps/day and VO(2peak), ISWT (m), ESWT (m) and ESWT (s) were 0.54, 0.59, 0.44, and 0.34, respectively (all p < 0.01). In the intervention group, correlations between change in steps/day over 7 months and change in ISWT (m), ESWT (m) and ESWT (s) were 0.47, 0.41, and 0.38, respectively (all p < 0.01). In the control group, these same correlations were weak to non-existent. CONCLUSIONS: A moderate to weak relationship was found between daily physical activity and exercise capacity. These results strengthen our beliefs that exercise interventions need to target not only exercise capacity but also behaviour change with regard to daily physical activity to achieve improvements in both parameters. PMID- 23085214 TI - Comparison of portable oxygen concentrators in a simulated airplane environment. AB - Portable oxygen concentrators (POC) are highly desirable for patients with lung disease traveling by airplane, as these devices allow theoretically much higher travel times if additional batteries can be used. However, it is unclear whether POCs produce enough oxygen in airplanes at cruising altitude, even if complying with aviation regulations. We evaluated five frequently used POCs (XPO2 (Invacare, USA), Freestyle (AirSep C., USA), Evergo (Philipps Healthcare, Germany), Inogen One (Inogen, USA), Eclipse 3 (Sequal, USA)) at an altitude of 2650 m (as simulated airplane environment) in 11 patients with chronic obstructive lung disease (COPD) and compared theses POCs with the standard oxygen system (WS120, EMS Ltd., Germany) used by Lufthansa. Oxygen was delivered by each POC for 30 min to each patient at rest, blood gases were then drawn from the arterialized ear lobe. All POCs were able to deliver enough oxygen to increase the PaO(2) of our subjects by at least 1.40 kPa (10 mmHg). However, to achieve this increase, the two most lightweight POCs (Freestyle and Invacare XPO2) had to be run at their maximum level. This causes a significant reduction of battery life. The three other POCs (EverGo, Inogen One, Eclipse 3) and the WS120 were able to increase the PaO(2) by more than 2.55 kPa (20 mmHg), which provides extra safety for patients with more severe basal hypoxemia. When choosing the right oxygen system for air travel in patients in COPD, not only weight, but also battery life and maximum possible oxygen output must be considered carefully. PMID- 23085210 TI - Neurosteroids, stress and depression: potential therapeutic opportunities. AB - Neurosteroids are potent and effective neuromodulators that are synthesized from cholesterol in the brain. These agents and their synthetic derivatives influence the function of multiple signaling pathways including receptors for gamma aminobutyric acid (GABA) and glutamate, the major inhibitory and excitatory neurotransmitters in the central nervous system (CNS). Increasing evidence indicates that dysregulation of neurosteroid production plays a role in the pathophysiology of stress and stress-related psychiatric disorders, including mood and anxiety disorders. In this paper, we review the mechanisms of neurosteroid action in brain with an emphasis on those neurosteroids that potently modulate the function of GABA(A) receptors. We then discuss evidence indicating a role for GABA and neurosteroids in stress and depression, and focus on potential strategies that can be used to manipulate CNS neurosteroid synthesis and function for therapeutic purposes. PMID- 23085215 TI - Chest physiotherapy effectiveness to reduce hospitalization and mechanical ventilation length of stay, pulmonary infection rate and mortality in ICU patients. AB - INTRODUCTION: Although physiotherapy is an integral part of the multiprofessional team in most ICUs there is only limited evidence concerning the effectiveness of its procedures. The objectives of this study were to verify if physiotherapy care provided within 24 h/day for hospitalized patients in the ICU reduce the length of stay, mechanical ventilation support, pulmonary infection and mortality compared to a physiotherapy care provided within 6 h/day. METHODS: A cohort study was designed to assess differences between one hospital where patients were given physiotherapy care for 24 h/day and another hospital with only 6 h/day. We considered the following as outcome measurements: clinical diagnosis, medication in use, presence of associated diseases, APACHE II and SOFA scores, ICU and mechanical ventilation length of stay, development of pulmonary infections and survival. RESULTS: One hundred and forty-six patients were enrolled. Patients admitted in the service A presented a lower length of stay in mechanical ventilation (p < 0.0001), ICU stay (p = 0.0003), respiratory infections (p = 0.0043) than patients admitted in service B. No difference was found for APACHE II score (p = 0.8) and SOFA scores (p = 0.2) between groups. The mortality risk was OR 1.3 (1.01-2.33) (p = 0.04) for patients in the service B. CONCLUSION: The presence of a physiotherapist in the intensive care unit contributes decisively to the early recovery of the patient, reducing mechanical ventilation support need, number of hospitalization days, incidence of respiratory infection and risk of mortality. PMID- 23085216 TI - High-mobility group box1 protein promotes neuroinflammation after intracerebral hemorrhage in rats. AB - High-mobility group box1 (HMGB1) protein is massively released into the cytoplasm and induces inflammation following various insults such as sepsis, acute cerebral ischemia, and pancreatitis. However, whether HMGB1 can act as an early proinflammatory cytokine to promote inflammation after intracerebral hemorrhage (ICH) is unclear. We explored this question using a rat model of collagenase induced ICH. We found that HMGB1 was released into the cytoplasm soon after ICH. Administration of ethyl pyruvate decreased the level of HMGB1 and microglia around the hematoma. Ethyl pyruvate also ameliorated ICH-induced neuronal apoptosis, cerebral edema, and neurological impairment. These findings suggest that HMGB1 may act as an early proinflammatory cytokine within the neurovascular unit to mediate inflammation during the acute phase of ICH. PMID- 23085218 TI - Sex differences and the role of estrogen in animal models of schizophrenia: interaction with BDNF. AB - Schizophrenia is a severe psychiatric disorder with a complex and variable set of symptoms. Both genetic and environmental mechanisms are involved in the development of the illness and lead to structural and neurochemical abnormalities in the brain. An intriguing facet of schizophrenia is sex differences, which have been described for nearly all features of the illness, including the peak age of onset, symptoms and treatment response. The ovarian hormone, estrogen, may be protective against schizophrenia and evidence is accumulating that estrogen may exert this effect via an interaction with brain-derived neurotrophic factor (BDNF). Both estrogen and BDNF have trophic effects on the developing brain and promote synaptic plasticity and maintain neurons well into adulthood. Major neurotransmitter systems including dopaminergic, serotonergic and glutamatergic pathways are modulated and supported by estrogen and BDNF. Despite their commonalities, estrogen and BDNF have mostly been examined independently but increasing evidence suggests an interaction between the two in brain regions pertinent to schizophrenia. This review will focus on the role of estrogen and BDNF in clinical and animal studies of schizophrenia. We include animal models of neurotransmitter dysfunction and genetic manipulation to show how estrogen may provide a protective effect in schizophrenia, including through mediating BDNF expression and activity. This posited estrogen-BDNF interaction could play a key role in modulating sex-dependent results reported in animal work as well as sex differences in clinical aspects of schizophrenia. PMID- 23085217 TI - Fast changes in direction during human locomotion are executed by impulsive activation of motor modules. AB - This study investigated the modular control of complex locomotor tasks that require fast changes in direction, i.e., cutting manoeuvres. It was hypothesized that such tasks are accomplished by an impulsive (burst-like) activation of a few motor modules, as observed during walking and running. It was further hypothesized that the performance in cutting manoeuvres would be associated to the relative timing of the activation impulses. Twenty-two healthy men performed 90 degrees side-step cutting manoeuvres while electromyography (EMG) activity from 16 muscles of the supporting limb and trunk, kinematics, and ground reaction forces were recorded. Motor modules and their respective temporal activations were extracted from the EMG signals by non-negative matrix factorization. The kinematic analysis provided the velocity of the centre of mass and the external work absorbed during the load acceptance (negative work, external work during absorption (W-Abs)) and propulsion phases (positive work, external work during propulsion (W-Prp)) of the cutting manoeuvres. Five motor modules explained the EMG activity of all muscles and were driven in an impulsive way, with timing related to the initial contact (M2), load acceptance (M3), and propulsion (M4). The variability in timing between impulses across subjects was greater for cutting manoeuvres than for running. The timing difference between M2 and M3 in the cutting manoeuvres was significantly associated to W-Abs (r(2)=0.45) whereas the timing between M3 and M4 was associated to W-Prp (r(2)=0.43). These results suggest that complex locomotor tasks can be achieved by impulsive activation of muscle groups, and that performance is associated to the specific timing of the activation impulses. PMID- 23085220 TI - In vitro investigations of alpha-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo[a]pyrene. AB - In vitro studies of alpha-amylase degradation of alpha-, beta- and gamma cyclodextrins and 2-hydroxypropyl-beta- and -gamma-cyclodextrins were investigated spectrophotometrically by measuring the formation of reducing sugars, the reaction products of alpha-amylase degradation. This was done to evaluate potential degradation and thereby biological conversion of the cyclodextrins if dosed orally, as the intestinal tract contains alpha-amylase for digestive purposes. The results demonstrated that only gamma- and 2-hydroxypropyl gamma-cyclodextrins can be degraded by alpha-amylase to a relevant extent, that is, gamma- and 2-hydroxypropyl-gamma-cyclodextrins have different biopharmaceutical behaviours than the other evaluated cyclodextrins. The rate of degradation was affected by the addition of the inclusion complex forming additives flurbiprofen, ibuprofen and benzo[a]pyrene. This effect between the degradation dynamics and the included additives was caused by a correlation between solubility of the additives and the stability of the complex. PMID- 23085219 TI - Acute N-methyl-D-aspartate receptor hypofunction induced by MK801 evokes sex specific changes in behaviors observed in open-field testing in adult male and proestrus female rats. AB - Schizophrenia is a complex constellation of positive, negative and cognitive symptoms. Acute administration of the non-competitive antagonist of the N-methyl d-aspartate receptor (NMDAR) dizocilpine (MK801) in rats is one of few preclinical animal models of this disorder that has both face and/or construct validity for these multiple at-risk behavioral domains and predictive power for the efficacy of therapeutic drugs in treating them. This study asked whether and to what extent the rat NMDAR hypofunction model also embodies the sex differences that distinguish the symptoms of schizophrenia and their treatment. Thus, we compared the effects of acute MK801, with and without pretreatment with haloperidol or clozapine, on seven discrete spontaneous open-field activities in adult male and female rats. These analyses revealed that MK801 was more effective in stimulating ataxia and locomotion and inhibiting stationary behavior in females while more potently stimulating stereotypy and thigmotaxis and inhibiting rearing and grooming in males. Haloperidol and clozapine pretreatments had markedly different efficacies in terms of behaviors but strong similarities in their effectiveness in male and female subjects. These results bear intriguing relationships with the complex male/female differences that characterize the symptoms of schizophrenia and suggest possible applications for acute NMDAR hypofunction as a preclinical model for investigating the neurobiology that underlies them. PMID- 23085222 TI - Indirect readout of DNA sequence by p22 repressor: roles of DNA and protein functional groups in modulating DNA conformation. AB - The repressor of bacteriophage P22 (P22R) discriminates between its various DNA binding sites by sensing the identity of non-contacted base pairs at the center of its binding site. The "indirect readout" of these non-contacted bases is apparently based on DNA's sequence-dependent conformational preferences. The structures of P22R-DNA complexes indicate that the non-contacted base pairs at the center of the binding site are in the B' state. This finding suggests that indirect readout and therefore binding site discrimination depend on P22R's ability to either sense and/or impose the B' state on the non-contacted bases of its binding sites. We show here that the affinity of binding sites for P22R depends on the tendency of the central bases to assume the B'-DNA state. Furthermore, we identify functional groups in the minor groove of the non contacted bases as the essential modulators of indirect readout by P22R. In P22R DNA complexes, the negatively charged E44 and E48 residues are provocatively positioned near the negatively charged DNA phosphates of the non-contacted nucleotides. The close proximity of the negatively charged groups on protein and DNA suggests that electrostatics may play a key role in the indirect readout process. Changing either of two negatively charged residues to uncharged residues eliminates the ability of P22R to impose structural changes on DNA and to recognize non-contacted base sequence. These findings suggest that these negatively charged amino acids function to force the P22R-bound DNA into the B' state and therefore play a key role in indirect readout by P22R. PMID- 23085221 TI - In vivo incorporation of an azide-labeled sugar analog to detect mammalian glycosylphosphatidylinositol molecules isolated from the cell surface. AB - N-Acetylgalactosamine (GalNAc) linked to the first mannose of glycosylphosphatidylinositol (GPI) core has been previously reported to be heterogeneously present on some mammalian GPI-anchored proteins. Here we present a method for profiling GalNAc-containing GPI-anchored proteins in mammalian cells by metabolic labeling with tetraacetylated N-azidoacetylgalactosamine (GalNAz) followed by biotinylation of the incorporated sugar analog. We have labeled both endogenous and recombinant GPI-anchored proteins with GalNAz, and demonstrated that the azide-activated sugar gets incorporated into the GPI glycan, likely as an unsubstituted side branch of the core structure. GalNAz was detected only on GPI molecules attached to proteins, and not on GPI precursors, indicating that GalNAc modification takes place after the GPI anchor is transferred to protein. We have highlighted the utility of this cell labeling approach by demonstrating the ability to examine specific GalNAc-containing GPI-anchored proteins isolated non-destructively from separate membrane domains (apical and basolateral) in polarized epithelial cells. This study represents the first demonstration of site specific in vivo labeling of a GPI moiety with a synthetic sugar analog. PMID- 23085223 TI - Inhibition of hepatic methionine adenosyltransferase by peroxides contaminating parenteral nutrition leads to a lower level of glutathione in newborn Guinea pigs. AB - Premature newborn infants on total parenteral nutrition (TPN) are at risk of oxidative stress because of peroxides contaminating TPN and low glutathione level. Low cysteine availability limits glutathione synthesis. In this population, the main source of cysteine derives from the hepatic conversion of methionine. The first enzyme of this conversion, methionine adenosyltransferase (MAT), contains redox-sensitive cysteinyl residues. We hypothesize that inhibition of MAT by peroxides contaminating TPN leads to a lower availability of cysteine for glutathione synthesis. At 3 days of life, animals were fitted with a jugular catheter for intravenous infusion. Four groups were compared by ANOVA (P<0.05): (1) Control, without surgery, fed regular chow; (2) Sham, fitted with an obstructed catheter, fed orally regular chow; (3) TPN, fed exclusively TPN (dextrose, amino acids, fat, vitamins) containing 350 MUM peroxides; (4) H2O2, fed regular chow orally and infused with 350 MUM H2O2. Four days later, MAT activity and glutathione in liver and blood were lower in TPN and H2O2 groups. The redox potential was more oxidized in blood and liver of the TPN group. In conclusion, peroxides generated in TPN inhibit methionine adenosyltransferase activity with, among consequences, a low level of glutathione and a more oxidized redox potential. PMID- 23085224 TI - Using multiple structural proteomics approaches for the characterization of prion proteins. AB - Structural proteomics approaches are valuable tools, particularly in cases where the exact mechanisms of protein conformational changes or the structures of proteins and protein complexes cannot be elucidated by traditional structural biology techniques like X-ray crystallography or NMR methods. Each structural proteomics method can provide a different set of data, all of which can be used as structural constraints for modeling the protein. We have applied a combination of limited proteolysis, surface modification, chemical crosslinking, and hydrogen/deuterium exchange for the characterization of structural differences in prion proteins in native monomeric and in the aggregated beta-oligomeric states. Data from these multiple proteomics approaches are in remarkable agreement in pointing to the rearrangement of the beta sheet 1-helix1-beta sheet 2-helix 2 (beta1-H1-beta2-H2) region as a major conformational change between the native and oligomeric prion protein forms. This data is also consistent with the beta1 H1-beta2 loop moving away from the H2-H3 core during the prion protein conversion. This is an example of how complementary data from multiple structural proteomics approaches can provide novel insights into the three-dimensional structures of proteins and protein complexes. This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23085225 TI - Proteomic identification of the macrophage-capping protein as a protein contributing to the malignant features of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide. We performed a proteomic study to understand the molecular mechanisms underlying metastasis in HCC. Among the 3491 protein spots observed by two-dimensional difference gel electrophoresis (2D-DIGE), we found that 197 and 88 protein spots had statistically significant differences in intensity between tumor and non tumor tissues and between the tumors with and without vascular invasion, respectively. Mass spectrometry was used to identify the proteins corresponding to those protein spots. We found that compared to tumor tissues without vascular invasion, those with vascular invasion showed markedly upregulated expression of the macrophage-capping protein (CapG). The association of increased CapG expression with vascular invasion in the tumor tissues was confirmed by western blotting. CapG expression levels were equal for non-tumor tissues and tumor tissues without venous invasion, as assessed by 2D-DIGE and western blotting. Silencing of CapG reduced tumor invasion without affecting the proliferation of the HCC cells. These observations suggested that CapG is involved in the process of metastasis by promoting the invasiveness of tumor cells. It may therefore be worth investigating the clinical usefulness of CapG as a biomarker in risk stratification therapy and as a therapeutic target in HCC. PMID- 23085226 TI - Proteomic analysis of endothelial cell secretome: a means of studying the pleiotropic effects of Hmg-CoA reductase inhibitors. AB - The clinical benefits of 3-hydroxy-3-methyl-3-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are closely related to their cholesterol-lowering properties. However, the inhibition of HMG-CoA reductase may also lead to pleiotropic effects due to the ability to inhibit the synthesis of non-steroidal isoprenoid compounds, thus exerting extra-beneficial effect in preventing atherosclerosis beyond their effect on the lipid profile. To identify new drug targets by means of which statins can promote some of their beneficial effects we used a global proteomic approach to analyse the secretome of endothelial cells, a major class of proteins that control a multitude of biological and physiological processes. Differentially expressed proteins were identified using a data independent, label-free, mass spectrometry-based method. A total of 273 proteins were identified, including 112 that were differentially expressed: 29 uniquely expressed in control cells, 14 uniquely expressed in statin-treated cells, 51 down-regulated by statin, and 18 up-regulated by statin. Gene ontology analysis revealed modulated biological processes related to proteolysis, cellular component organisation and biogenesis, and response to stress. The findings were validated by biochemical assays, thus confirming the effectiveness of our proteomic approach. In conclusion, this study underlines the role of proteomics for the discovery of novel and unpredictable targets of statins. PMID- 23085227 TI - Pyrroloquinoline quinone, a novel protein tyrosine phosphatase 1B inhibitor, activates insulin signaling in C2C12 myotubes and improves impaired glucose tolerance in diabetic KK-A(y) mice. AB - Insulin resistance is a pathological hallmark of type 2 diabetes mellitus and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling by tyrosine dephosphorylation of insulin receptor, and increased activity and expression of PTP1B is implicated in the pathogenesis of insulin resistance. Therefore, inhibition of PTP1B is anticipated to improve insulin resistance in type 2 diabetic subjects. Pyrroloquinoline quinone (PQQ), a redox cofactor for bacterial dehydrogenases, inhibits PTP1B to oxidatively modify the catalytic cysteine through its redox cycling activity. Here, we report that PQQ induces the ligand-independent activation of insulin signaling by inhibiting cellular PTP1B and enhances glucose uptake through the translocation of glucose transporter 4 in mouse C2C12 myotubes. Furthermore, we demonstrated that oral administration of PQQ improved impaired glucose tolerance in type 2 diabetic KK-A(y) mice. Our results strongly suggest that PQQ can be useful in anti-diabetic treatment for type 2 diabetic subjects. PMID- 23085228 TI - Stochastic differentiation into an osteoclast lineage from cloned macrophage-like cells. AB - Differentiation into osteoclasts is induced by a macrophage colony-stimulating factor and receptor activator of nuclear-factor kappaB ligand. The macrophage like cell line, C7 has the potential to differentiate into osteoclasts when it is cultured with both factors for 6 days. Although C7 is an established cell line, the frequency of differentiation into this lineage was less than 10%, and the ratio was maintained at a constant level, even after repeated cloning. In this study, to increase the differentiation of C7 cells to osteoclasts, C7 derivative treatments with several activators and/or inhibitors were performed for 3 days prior to setting osteoclast induction analysis; however, a reagent to significantly up-regulate the frequency of differentiation was not found. Only extended cultures for osteoclastogenesis exponentially increased the frequency of osteoclast precursors. It is likely that C7 cell differentiation into committed osteoclast precursors is on 'autopilot' rather than requiring specific signals to drive this process. PMID- 23085229 TI - Inorganic polyphosphates stimulate FGF23 expression through the FGFR pathway. AB - Polyphosphate (polyP) is composed of linear polymers of orthophosphate residues linked by high-energy phosphoanhydride bonds. It has been reported to improve osteoblastic differentiation, stimulate periodontal tissue regeneration, and accelerate bone repair. The aim of this study was to evaluate the effect of polyP on the expression of FGF23, a hormone secreted mostly be mature osteoblasts and osteocytes. In this study, different types of polyP were synthesized and co cultured with osteoblast-like UMR-106 cells. Real-time PCR and western blot were used to analyze the gene and protein expression of FGF23. We found that 1 mM polyP was able to increase FGF23 expression after 4 h, reaching a peak after 12 24 h, with expression decreasing by 48 h. We also found that polyP could activate the FGFR pathway, as evidenced by increased phosphorylation of FGFR, FRS2, and Erk1/2. When FGFR signaling was inhibited by the specific inhibitor SU5402, the effect of polyP on FGF23 expression was significantly reduced. Our results indicate that polyP is able to stimulate osteoblastic FGF23 expression and that this effect is associated with activation of the FGFR pathway. These findings provide support for the clinical use of polyP by indicating a mechanism for polyP in bone regeneration. PMID- 23085230 TI - 5-Fluorocytosine combined with Fcy-hEGF fusion protein targets EGFR-expressing cancer cells. AB - Human epithelial cancers account for approximately 50% of all cancer deaths. This type of cancer is characterized by excessive activation and expression of the epidermal growth factor receptor (EGFR). The EGFR pathway is critical for cancer cell proliferation, survival, metastasis and angiogenesis. The EGF-EGFR signaling pathway has been validated as an important anticancer drug target. Increasing numbers of targeted therapies against this pathway have been either approved or are currently under development. Here, we adopted a prodrug system that uses 5 fluorocytosine (5-FC) and human EGF (hEGF) fused with yeast cytosine deaminase (Fcy) to target EGFR-overexpressing cancer cells and to convert 5-FC to a significantly more toxic chemotherapeutic, 5-fluorouracil (5-FU). We cloned and purified the Fcy-hEGF fusion protein from Pichia pastoris yeast. This fusion protein specifically binds to EGFR with a similar affinity as hEGF, approximately 10 nM. Fcy-hEGF binds tightly to A431 and MDA-MB-468 cells, which overexpress EGFR, but it binds with a lower affinity to MDA-MB-231 and MCF-7, which express lower levels of EGFR. Similarly, the viability of EGFR-expressing cells was suppressed by Fcy-hEGF in the presence of increasing concentrations of 5-FC, and the IC(50) values for A431 and MDA-MB-468 were approximately 10-fold lower than those of MDA-MB-231 and MCF-7. This novel prodrug system, Fcy-hEGF/5-FC, might represent a promising addition to the available class of inhibitors that specifically target EGFR-expressing cancers. PMID- 23085231 TI - S100A4, frequently overexpressed in various human cancers, accelerates cell motility in pancreatic cancer cells. AB - S100A4, a member of the Ca(2+) dependent S100 protein family, is reported to associate with metastasis through regulation of the motility and invasiveness of cancer cells. A high level of S100A4 protein has been reported in a variety of cancers, including pancreatic cancer. However, its biological role in pancreatic carcinogenesis is largely unknown. We previously reported that S100A4 is frequently overexpressed and that RNAi-mediated knockdown induces apoptosis and suppression of cell growth, motility, and invasiveness. In this study, we analyzed the effects of forced expression of S100A4 in pancreatic cancer cell lines without S100A4-upregulation. We used two cell lines without upregulation of S100A4 (PCI-35 and PCI-43) as well as two cell lines with highly upregulated S100A4 as the control (MIA PaCa-2 and PAN-07-JCK). Cells did not show acceleration of their growth and invasiveness after forced expression of S100A4, but remarkable acceleration of cell motility was observed only in PCI-35 and PCI 43. We further performed microarray analyses using PCI-35 and PCI-43 with and without forced expression of S100A4 and identified 72 and 18 genes that were 2 fold or more upregulated or downregulated, respectively, in both cell lines after forced expression of S100A4. Our results suggest that S100A4 is crucial for cell motility in pancreatic cancer and that some downstream genes may play important roles in cell motility. PMID- 23085232 TI - Effects of matrix metalloproteinase-1 on the myogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. AB - Matrix metalloproteinase-1 (MMP-1) is a member of the family of zinc-dependent endopeptidases that are capable of degrading extracellular matrix (ECM) and certain non-matrix proteins. It has been shown that MMP-1 can enhance muscle regeneration by improving the differentiation and migration of myoblasts. However, it is still not known whether MMP-1 can promote the myogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). To address this question, we isolated BMSCs from C57BL/6J mice and investigated the effects of MMP-1 on their proliferation and myogenic differentiation. Our results showed that MMP-1 treatment, which had no cytotoxic effects on BMSCs, increased the mRNA and protein levels of MyoD and desmin in a dose-dependent manner, indicating that MMP 1 promoted myogenic differentiation of BMSCs in vitro. These results suggest that BMSCs may have a therapeutic potential for treating muscular disorders. PMID- 23085233 TI - Lipid A 3'-O-deacylation by Salmonella outer membrane enzyme LpxR modulates the ability of lipid A to stimulate Toll-like receptor 4. AB - Modification of lipopolysaccharides, including the membrane anchor portion lipid A, is essential for bacterial adaptation to its host. We examined whether lipid A 3'-O-deacylation by Salmonella lipid A deacylase LpxR affected the ability of lipid A to stimulate the Toll-like receptor 4 (TLR4) and MD-2 complex. Unmodified lipid A and 3'-O-deacylated lipid A were purified from Escherichia coli and E. coli expressing recombinant LpxR, respectively. Inactive lipid A species, palmitoylated lipid A and a lipid A biosynthetic precursor lacking the myristate moiety were purified from E. coli expressing recombinant Salmonella lipid A palmitoyltransferase PagP and E. coli mutant defective in lipid A biosynthesis, respectively. Mass spectrometric analysis of the purified lipid A preparations showed a spectra of single lipid A species and gave a single band on thin layer chromatography. An NF-kappaB-dependent reporter activation assay was used to determine the bioactivity of the lipid A species in a cell line that expressed human TLR4 and MD-2 complex. Deacylated lipid A was less active than unmodified lipid A, suggesting that lipid A 3'-O-deacylation by LpxR is beneficial for bacteria to evade host immune surveillance: On the other hand, deacylated lipid A was more active than palmitoylated lipid A and the lipid A precursor. Taken together, these results indicated that lipid A 3'-O-deacylation by LpxR significantly reduces the bioactivity of lipid A. PMID- 23085234 TI - Potential of telomerase activation in extending health span and longevity. AB - The progressive increase in the elderly population worldwide has resulted in higher numbers of individuals affected by age-associated diseases, such as neurodegenerative and heart diseases, metabolic impairment, or cancer, with the subsequent burden for national health systems. Therapeutic interventions aimed to increase the quality of life at advanced age are visualized as important demands for the future, both at the level of individuals and society. Novel advances in telomerase function from several independent laboratories have resulted in potential new therapeutic strategies which appear as promising new venues to prevent cellular and tissue dysfunction and organismal decline, thereby increasing the so-called "health span". Here, we analyze these recent advances. PMID- 23085235 TI - Generalized disruption of inherited genomic imprints leads to wide-ranging placental defects and dysregulated fetal growth. AB - Monoallelic expression of imprinted genes, including ones solely expressed in the placenta, is essential for normal placental development and fetal growth. To better understand the role of placental imprinting in placental development and fetal growth, we examined conceptuses developing in the absence of maternally derived DNA (cytosine-5-)-methyltransferase 1o (DNMT1o). Absence of DNMT1o results in the partial loss of methylation at imprinted differentially methylated domain (DMD) sequences in the embryo and the placenta. Mid-gestation E9.5 DNMT1o deficient placentas exhibited structural abnormalities of all tissue layers. At E17.5, all examined placentas had aberrant placental morphology, most notably in the spongiotrophoblast and labyrinth layers. Abnormalities included an expanded volume fraction of spongiotrophoblast tissue with extension of the spongiotrophoblast layer into the labyrinth. Many mutant placentas also demonstrated migration abnormalities of glycogen cells. Additionally, the volume fraction of the labyrinth was reduced, as was the surface area for maternal fetal gas exchange. Despite these placental morphologic abnormalities, approximately one-half of DNMT1o-deficient fetuses survived to late gestation (E17.5). Furthermore, DNMT1o-deficient placentas supported a broad range of fetal growth. The ability of some DNMT1o-deficient and morphologically abnormal placentas to support fetal growth in excess of wild type demonstrates the importance of differential methylation of DMDs and proper imprinting of discrete gene clusters to placental morphogenesis and fetal growth. PMID- 23085238 TI - Modelling Delta-Notch perturbations during zebrafish somitogenesis. AB - The discovery over the last 15 years of molecular clocks and gradients in the pre somitic mesoderm of numerous vertebrate species has added significant weight to Cooke and Zeeman's 'clock and wavefront' model of somitogenesis, in which a travelling wavefront determines the spatial position of somite formation and the somitogenesis clock controls periodicity (Cooke and Zeeman, 1976). However, recent high-throughput measurements of spatiotemporal patterns of gene expression in different zebrafish mutant backgrounds allow further quantitative evaluation of the clock and wavefront hypothesis. In this study we describe how our recently proposed model, in which oscillator coupling drives the propagation of an emergent wavefront, can be used to provide mechanistic and testable explanations for the following observed phenomena in zebrafish embryos: (a) the variation in somite measurements across a number of zebrafish mutants; (b) the delayed formation of somites and the formation of 'salt and pepper' patterns of gene expression upon disruption of oscillator coupling; and (c) spatial correlations in the 'salt and pepper' patterns in Delta-Notch mutants. In light of our results, we propose a number of plausible experiments that could be used to further test the model. PMID- 23085236 TI - Wnt3 function in the epiblast is required for the maintenance but not the initiation of gastrulation in mice. AB - The formation of the anteroposterior axis in mice requires a Wnt3-dependent symmetry-breaking event that leads to the formation of the primitive streak and gastrulation. Wnt3 is expressed sequentially in two distinct areas of the mouse embryo before the appearance of the primitive streak; first in the posterior visceral endoderm and soon after in the adjacent posterior epiblast. Hence, although an axial requirement for Wnt3 is well established, its temporal and tissue specific requirements remain an open question. Here, we report the conditional inactivation of Wnt3 in the epiblast of developing mouse embryos. Contrary to previous studies, our data shows that embryos lacking Wnt3 specifically in the epiblast are able to initiate gastrulation and advance to late primitive streak stages but fail to thrive and are resorbed by E9.5. At the molecular level, we provide evidence that Wnt3 regulates its own expression and that of other primitive streak markers via activation of the canonical Wnt signaling pathway. PMID- 23085237 TI - Distinct requirements for Sin3a in perinatal male gonocytes and differentiating spermatogonia. AB - Chromatin modifier Swi-independent 3a (SIN3A), together with associated histone deacetylases, influences gene expression during development and differentiation through a variety of transcription factors in a cell-specific manner. Sin3a is essential for the maintenance of inner cell mass cells of mouse blastocysts, embryonic fibroblasts, and myoblasts, but is not required for the survival of trophectoderm or Sertoli cells. To better understand how this transcriptional regulator modulates cells at different developmental stages within a single lineage, we used conditional gene targeting in mice to ablate Sin3a from perinatal quiescent male gonocytes and from postnatal differentiating spermatogonia. Mitotic germ cells expressing stimulated by retinoic acid gene 8 (Stra8) that lacked Sin3a exhibited increased DNA damage and apoptosis, yet collectively progressed through meiosis and spermiogenesis and generated epididymal sperm at approximately 50% of control levels, sufficient for normal fertility. In contrast, perinatal gonocytes lacking Sin3a underwent rapid depletion that coincided with cell cycle reentry, exhibiting 2.5-fold increased histone H3 phosphorylation upon cycling that suggested a prophase/metaphase block; germ cells were almost entirely absent two weeks after birth, resulting in sterility. Gene expression profiling of neonatal testes containing Sin3a-deleted gonocytes identified upregulated transcripts highly associated with developmental processes and pattern formation, and downregulated transcripts involved in nuclear receptor activity, including Nr4a1 (Nur77). Interestingly, Nr4a1 levels were elevated in testes containing Stra8-expressing, Sin3a-deleted spermatogonia. SIN3A directly binds to the Nr4a1 promoter, and Nr4a1 expression is diminished upon spermatogonial differentiation in vitro. We conclude that within the male germline, Sin3a is required for the mitotic reentry of gonocytes, but is dispensable for the maintenance of differentiating spermatogonia and subsequent spermatogenic processes. PMID- 23085239 TI - Detection of small orientation changes and the precision of visual working memory. AB - We investigated the precision of orientation representations with two tasks, change detection and recall. Previously change detection has been measured only with relatively large orientation changes compared to psychophysical thresholds. In the first experiment, we measured the observers' ability (d') to detect small changes in orientation (5-30 degrees ) with 1-4 Gabor items. With one item even a 10 degrees change was well detected (average d'=2.5). As the amount of change increased to 30 degrees , the d' increased to 5.2. When the number of items was increased, the d's gradually decreased. In the second experiment, we used a recall task and the observers adjusted the orientation of a probe Gabor to match the orientation of a Gabor held in the memory. The standard deviation (s.d.) of errors was calculated from the Gaussian distribution fitted to the data. As the number of items increased from 1 to 6, the s.d. increased from 8.6 degrees to 19.6 degrees . Even with six items, the observers did not make any random adjustments. The results show a square root relation between the d'/s.d. and the number of items. The d' in change detection is directly proportional to the square root of (1/n) and the orientation change. The increase of the s.d. in recall task is inversely proportional to square root of (1/n). The results suggest that limited resources and precision of representations, without additional assumptions, determine the memory performance. PMID- 23085240 TI - Dyspnea on exertion in obese men. AB - Recently, we reported that dyspnea on exertion is strongly associated with an increased oxygen cost of breathing in otherwise healthy obese women; the mechanism of dyspnea on exertion in obese men is unknown. Obese men underwent measurements of body composition, fat distribution, pulmonary function, steady state and maximal graded cycle ergometry, and oxygen cost of breathing. Nine men (34 +/- 8 years, 35 +/- 4 BMI) with ratings of perceived breathlessness of <=2 during cycling, and ten men (36 +/- 9 years, 38 +/- 5 BMI) with ratings of perceived breathlessness >=4 were studied (ratings of perceived breathlessness: 1.8 +/- 0.4 vs. 4.7 +/- 0.8, respectively; p<0.0001). Groups had only minor differences in fat distribution, pulmonary function, and steady state exercise. There was no association between ratings of perceived breathlessness and oxygen cost of breathing; but ratings of perceived breathlessness was strongly correlated with ratings of perceived exertion (RPE, rho=0.87, p<0.0001). The differences in exercise intensity, ventilatory demand, cardiovascular conditioning and/or the quality of respiratory sensation did not appear to play a role in the development of dyspnea on exertion. The mechanism of dyspnea on exertion in obese men seems unrelated to the oxygen cost of breathing. PMID- 23085242 TI - Who makes the rules? PMID- 23085241 TI - E3 ubiquitin ligase NKLAM is a macrophage phagosome protein and plays a role in bacterial killing. AB - Macrophages are a critically important component of the innate and adaptive immune systems. They are equipped with oxidative and non-oxidative mechanisms to kill ingested pathogens. Natural Killer Lytic-Associated Molecule (NKLAM) is an E3 ubiquitin ligase expressed in macrophages and natural killer cells. We show that NKLAM expression in macrophages was enhanced by Toll-like receptor agonists and pro-inflammatory cytokines. Using confocal microscopy, we found that NKLAM colocalized with ingested Escherichia coli. In assays using IgG-opsonized latex beads as targets, we demonstrated that NKLAM translocated to the phagosome early during maturation at a time that coincided with elevated levels of ubiquitinated phagosome proteins. In killing assays with bone marrow-derived macrophages from wild type and NKLAM-deficient mice, we found that NKLAM-deficient macrophages demonstrated less killing of E. coli than wild type macrophages. Collectively, our data show that NKLAM is a novel component of macrophage phagosomes and is involved in macrophage bactericidal functions. PMID- 23085243 TI - Effect of oral and intravenous heparin tetrasaccharide on allergic airway responses: critical role of N-sulfation. AB - We have shown that inhaled heparin (hep) oligosaccharides attenuate allergic airway responses in sheep and that this anti-allergic activity resides in a tetrasaccharide sequence. Here we determined: (a) the anti-allergic activity of oral and intravenous hep-tetrasaccharide on allergic airway responses in the sheep model of asthma; and (b) the role of N-sulfation in mediating this anti allergic activity. Ascaris suum-induced early (EAR) and Late (LAR) airway responses and airway hyperresponsiveness (AHR) to carbachol were measured in allergic sheep without and after treatment with different doses of oral or intravenous hep-tetrasaccharide. At doses of 0.06 mg/kg, 0.125 mg/kg, and 0.25 mg/kg, oral hep-tetrasaccharide caused a dose-dependent inhibition of EAR and LAR. Post-antigen AHR was also inhibited dose dependently. The same doses of intravenous hep-tetrasaccharide yielded comparable inhibition of EAR, LAR and AHR, confirming that orally delivered hep-tetrasaccharide has good bioavailability. The protection by hep-tetrasaccharide on EAR and LAR was dependent on N-sulfation, as N-desulfated/N-acetylated tetrasaccharide had a markedly reduced effect. However, inhibition of the post-antigen AHR was independent of N-sulfation. These results demonstrate that orally administered hep-tetrasaccharide inhibits allergic airway responses in the sheep model of asthma. Hep-tetrasaccharide has good oral bioavailability and its anti-allergic activity is critically dependent on N-sulfation of the glucosamine ring. PMID- 23085244 TI - Probing aggressive motivation during territorial contests in a group-living cichlid fish. AB - Many animals fight to win resources, repel competitors or establish dominance in a social group. Mutual-assessment of fighting ability, where competitors gather and compare information about their opponent's as well as their own fighting ability has been the dominant theoretical framework for understanding decision making during fights. However, self-assessment, where each individual has a cost threshold and fights up until that point, may be more common than previously appreciated. In this study, we attempted to discriminate between these two potential assessment mechanisms in a group-living cichlid fish, Neolamprologus pulcher by probing aggressive motivation during a territorial contest. We measured aggressive motivation, and used this metric to investigate assessment rules during an ongoing contest. We predicted that if these social fish use self assessment, we would observe a positive correlation between the fighting ability of the probed animal and its aggressive motivation. Alternatively, if mutual assessment is used then we predicted we would find a negative effect of the opponent's fighting ability on the aggressive motivation of the probed fish because fish should be less motivated to fight against formidable opponents. Our results did not support either of these predictions. In contrast we found that small individuals were more aggressively motivated regardless of their opponent's size. We discuss this result in the context of theoretical models of aggression in individuals of small body size. PMID- 23085246 TI - High incidence of viral co-infections and atypical bacterial detection in acute respiratory infections among hospitalized children in the Central Department of Paraguay, 2010-2011. PMID- 23085245 TI - Randomized clinical trial of lovastatin in HIV-infected, HAART naive patients (NCT00721305). AB - BACKGROUND: Evidence suggests that statins may modify the immune response against HIV. The aim was to evaluate the antiretroviral and immunomodulatory effects of lovastatin in HIV-infected patients, naive for antiretroviral therapy. METHODS: Randomized, double-blinded, placebo-controlled, phase-II clinical trial. Primary outcomes were plasma viral load and circulating CD4+ T cell count, after 6 and 12 months of treatment; secondary outcomes were CD8+ T cell count, expression of activation markers (CD38 and HLA-DR) on T cells, and clinical outcomes. With a power of 90% to detect both a decrease of 0.3 log10 in plasma HIV-1 RNA copies and an increase of 20% in the CD4+ T cell count, we estimated a required sample size of 110 HIV-infected patients (55 per group). The results were analyzed by a model of repeated measurements using Generalized Estimating Equations. RESULTS: Patients were randomized to receive either lovastatin (n = 55) or placebo (n = 57). During the 12-month follow-up, there was no effect of lovastatin either on viral load (estimated average change = 0.157 copies/mL; CI 95% = -0.099 to 0.414), or on the CD4+ T cell count (estimated average change = -26.1 cells/MUL; CI 95% = -89.8 to 37.6). Moreover, there were no significant differences in secondary outcomes. CONCLUSIONS: Daily administration of lovastatin (40 mg) for one year in HIV-infected patients, naive for antiretroviral therapy, had no significant effect on HIV replication, the CD4+ T cell count, or the activation level of T cells. (www.clinicaltrials.gov; ID NCT00721305). PMID- 23085247 TI - Epidemiology and prognostic determinants of bacteremic acute pyelonephritis in women. PMID- 23085248 TI - Response letter to rapid diagnosis of influenza: an evaluation of two commercially available RT-PCR assays. PMID- 23085250 TI - miR-122 acts as a tumor suppressor in hepatocarcinogenesis in vivo. PMID- 23085249 TI - The dynamic biliary epithelia: molecules, pathways, and disease. AB - Cholangiocytes, the cells lining bile ducts, are a heterogenous, highly dynamic population of epithelial cells. While these cells comprise a small fraction of the total cellular component of the liver, they perform the essential role of bile modification and transport of biliary and blood constituents. From a pathophysiological standpoint, cholangiocytes are the target of a diverse group of biliary disorders, collectively referred to as the cholangiopathies. To date, the cause of most cholangiopathies remains obscure. It is known, however, that cholangiocytes exist in an environment rich in potential mediators of cellular injury, express receptors that recognize potential injurious insults, and participate in portal tract repair processes following hepatic injury. As such, cholangiocytes may not be only a passive target, but are likely directly and actively involved in the pathogenesis of cholangiopathies. Here, we briefly summarize the characteristics of the reactive cholangiocyte and cholangiocyte responses to potentially injurious endogenous and exogenous molecules, and in addition, present emerging concepts in our understanding of the etiopathogenesis of several cholangiopathies. PMID- 23085251 TI - Accurate assessment of systemic iron status in cystic fibrosis will avoid the hazards of inappropriate iron supplementation. PMID- 23085252 TI - Eosinophilic esophagitis in cystic fibrosis: a case series and review of the literature. AB - Patients with cystic fibrosis (CF) frequently experience gastrointestinal symptoms including nausea, emesis, malnutrition and indigestion; diseases such as gastroesophageal reflux disease (GERD), distal intestinal obstructive syndrome, and cholelithiasis are commonly implicated. We have recently diagnosed eosinophilic esophagitis (EoE) in three patients with CF. EoE is a TH-2 driven, allergen-mediated disease which causes esophageal eosinophilia and presents with symptoms of nausea, feeding intolerance, regurgitation, and dysphagia. EoE is diagnosed when esophageal biopsies reveal greater than 15 eosinophils per high power field in the setting of the appropriate clinical scenario and after exclusion of other causes of esophageal eosinophilia. Although described with increasing frequently in the gastrointestinal literature, there have been no prior cases documenting the co-existence of EoE and CF. We speculate that this is related to lack of familiarity with EoE symptoms by CF providers. We present three patients with CF diagnosed with EoE and review the current literature regarding diagnosis and management, focusing on management issues in patients with CF. PMID- 23085253 TI - Pretreatment prognostic factors for overall survival in primary resistant acute myeloid leukemia. AB - AIM: Primary resistant acute myeloid leukemia has a very poor prognosis. We assessed pretreatment parameters for their significance as prognostic factors in the overall survival (OS) of 53 acute myeloid leukemia (AML) patients who had failed to achieve complete remission (CR) after first-line standard-dose remission-induction therapy. RESULTS: During the period January 2005-December 2009, 53 with acute myeloid leukemia received two cycles of the 3+7 protocol as a first-line standard-dose remission-induction therapy (ARA-C, days 1-7 and daunorubicin, days 1-3). The HiDAC (5 patients), MiDAC (7 patients), and FLAG-IDA protocols (3 patients) were given as salvage therapy. None of these patients achieved CR. There were 27 (51%) males and 26 (49%) females (median age, 55 years, range 28-76). The median white blood cell count was 53 (range 0.9 350)*10(9)/L, platelets 44 (range 3-856*10(9)/l) and bone marrow blasts 67%. HCT IC comorbidity scores were 3 in two (3.8%) patients, 2 in 11 (20.8%), 1 in 12 (22.6%) and 0 in 16 (30.2%) patients. Median OS was 3.9 months (range 1 -20 months). The hepatomegaly, white blood cell count, ECOG PS, serum level of lactate dehydrogenase, dysplastic changes, coexpression of CD64, CD15, CD11b, comorbidities and disease cytogenetics influenced survival. CONCLUSION: This single-center study evaluated the significance of pretreatment factors, and found that patient age, comorbidities, ECOG performance status, leukocytosis, hepatomegaly, LDH, and the disease cytogenetics were factors which influenced the outcomes of primary resistant patients with acute myeloid leukemia. An understanding of these factors may help to predict OS in cases where CR has not been achieved and may help when making further treatment decisions. PMID- 23085254 TI - Characterization of the gene expression profile of heterozygous liver-specific glucokinase knockout mice at a young age. AB - In the liver, glucokinase (GCK) facilitates hepatic glucose uptake during hyperglycemia and is essential for the regulation of a network of glucose responsive genes involved in glycolysis, glycogen synthesis, and lipogenesis. To better understand the consequences of changes in response to a liver-specific deficiency of GCK function, we examined the expression profiles of genes involved in glucose metabolism in the liver, pancreas, muscle and adipose tissue in heterozygous liver-specific Gck knockout (Gck(w/-)) mice. Our results showed that with the development of a liver GCK deficiency, significant decreases in the mRNA levels for insulin receptor and Glut2 were observed in the liver, and HkII in muscle, while glucagon mRNA increased markedly in the pancreas. The levels of circulating glucagon hormone levels increased with increased mRNA levels. Depite a decrease in muscle HkII levels, the hexokinase activity level did not change. Our findings suggest that in liver-specific Gck(w/-) mice, peripheral tissues use different strategies to tackle with hyperglycemia even at a young age. By identifying the specific changes that occur in different tissues at an early stage of glucokinase deficiency, potentially we can develop interventions to prevent further progression to diabetes. PMID- 23085256 TI - A simple k-word interval method for phylogenetic analysis of DNA sequences. AB - In this study, the normalized k-word average interval distance is proposed to extract phylogenetic information from DNA sequences. The phylogenetic trees of 30 mammalian species based on Euclidean distance measure are reconstructed with k ranging from 2 to 9. Comparison of our results with other methods shows that our method is efficient and powerful for phylogenetic analysis. In addition, for a fixed k, 4(k) distinct k-words are divided into n classes based on a new proposed indicator, where n is the number of DNA sequences. The effect of each k-word class on phylogeny is discussed. PMID- 23085257 TI - Design considerations for supervised consumption facilities (SCFs): preferences for facilities where people can inject and smoke drugs. AB - BACKGROUND: Supervised consumption facilities (SCFs) aim to improve the health and well-being of people who use drugs by offering safer and more hygienic alternatives to the risk environments where people typically use drugs in the community. People who smoke crack cocaine may be willing to use supervised smoking facilities (SSFs), but their facility design preferences and the views of other stakeholders have not been previously investigated in detail. METHODS: We consulted with people who use drugs and other stakeholders including police, fire and ambulance service personnel, other city employees and city officials, healthcare providers, residents, and business owners (N = 236) in two Canadian cities without SCFs and asked how facilities ought to be designed. All consultations were audio-recorded and transcribed. Thematic analyses were used to describe the knowledge and opinions of stakeholders. RESULTS: People who use drugs see SSFs as offering public health and safety benefits, while other stakeholders were more sceptical about the need for SSFs. People who use drugs provided insights into how a facility might be designed to accommodate supervised injection and supervised smoking. Their strongest preference would allow both methods of drug use within the same facility with some form of physical separation between the two based on different highs, comfort regarding exposure to different methods of drug administration, and concerns about behaviours often associated with smoking crack cocaine. Other stakeholders raised a number of SSF implementation challenges worthy of consideration. CONCLUSION: Decision-makers in cities considering SCF or SSF implementation should consider the opinions and preferences of potential clients to ensure that facilities will attract, retain, and engage people who use drugs. PMID- 23085258 TI - Estimating the economic value of British Columbia's domestic cannabis market: implications for provincial cannabis policy. AB - BACKGROUND: British Columbia (BC), Canada, is home to a large illegal cannabis industry that is known to contribute to substantial organized crime concerns. Although debates have emerged regarding the potential benefits of a legally regulated market to address a range of drug policy-related social problems, the value of the local (i.e., domestically consumed) cannabis market has not been characterized. METHODS: Monte Carlo simulation methods were used to generate a median value and 95% credibility interval for retail expenditure estimates of the domestic cannabis market in BC. Model parameter estimates were obtained for the number of cannabis users, the frequency of cannabis use, the quantity of cannabis used, and the price of cannabis from government surveillance data and studies of BC cannabis users. RESULTS: The median annual estimated retail expenditure on cannabis by British Columbians was $407 million (95% Credibility Interval [CI]: $169-948 million). Daily users accounted for the bulk of the cannabis revenue, with a median estimated expenditure of approximately $357 million (95% CI: $149 845 million), followed by weekly users ($44 million, 95% CI: $18-90 million), and monthly users ($6 million, 95% CI: $3-12 million). When under-reporting of cannabis use was adjusted for, the estimated retail expenditure ranged from $443 million (95% CI: $185-1 billion) to $564 million (95% CI: $236-1.3 billion). CONCLUSION: Based on local consumption patterns, conservative estimates suggest that BC's domestic illegal cannabis trade is worth hundreds of millions of dollars annually. Given the value of this market and the failure and harms of law enforcement efforts to control the cannabis market, policymakers should consider regulatory alternatives. PMID- 23085259 TI - DNA methylation: new therapeutic implications for hepatic fibrosis. AB - DNA methylation refers to a heritable alteration in the pattern of gene expression that is regulated by a mechanism specifically not owing to changes in the primary nucleotide sequence. The transcriptional silencing caused by DNA methylation affects genes involved in the main cellular pathways: cell cycle control, Ras signaling, apoptosis, and detoxification. Recent studies have shown that methylation modifications orchestrate the activation of hepatic stellate cells (HSCs) characterized by excessive accumulation of extracellular matrices (ECMs). The activation of HSCs is mediated by multiple signal transduction pathways and is generally regarded as the major ECM producer responsible for liver fibrosis. In addition, aberrant methylation of specific gene involved in the activation of multiple signal transduction pathways in liver fibrosis. The aim of this review is to compile recent information on aberrant DNA methylation in hepatic fibrosis and to highlight key genes and molecular pathways in hepatic fibrosis formation. PMID- 23085261 TI - Cutl1: a potential target for cancer therapy. AB - CDP, a key transcription regulator encoded by Cutl1 gene, has been demonstrated to be involved in repressing or promoting expression of target genes through its specific DNA-binding, meanwhile, the activity of CDP was influenced by some types of modifications including transcriptional, posttranscriptional, translational and posttranslational modifications. In this review, we systematically analyzed the role of CDP in normal development and tumor progression, and then emphasized its interactors and downstream molecules. Eventually, we concluded that Cut1 could promote cancer progression and its down-regulating expression will be a promising strategy for cancer therapy. PMID- 23085262 TI - Effects of carbogen on cochlear blood flow and hearing function following acute acoustic trauma in guinea pigs. AB - BACKGROUND AND AIMS: Disturbances of microcirculation and hemorheological changes in the inner ear are the results of noise-induced hearing loss (NIHL). Both the disturbances of microcirculation and hemorheological changes are the etiologies of NIHL development, but they are also the results. Although previous reports that inhalation of high concentration of CO(2) may increase cochlear blood flow (CoBF), the effects of carbogen on the cochlear microcirculation and NIHL remain unclear. METHODS: Changes induced by noise, carbogen and pure oxygen within the cochlear lateral wall microvasculature and in hearing thresholds were observed in guinea pigs using intravital microscopy and the auditory brainstem response. At the same time, arterial oxygen saturation and morphologic changes of cochlear hair cells were observed. RESULTS: Carbogen inhalation increased vessel diameters and blood flow velocities. Hearing thresholds elevation in the carbogen group was smaller than those in the control and oxygen group (p <0.05). Carbogen inhalation produced a trend toward less threshold shift after noise exposure, which reached statistical significance after day 3 (p <0.01). Respiratory acidosis was not found in our study. The segmented basal membranes of Corti in three groups indicated that no losses or discorders of hair cells were found. CONCLUSIONS: Carbogen inhalation can preserve hearing in animal models after acute acoustic trauma. PMID- 23085260 TI - CIKS (Act1 or TRAF3IP2) mediates high glucose-induced endothelial dysfunction. AB - Hyperglycemia-induced endothelial dysfunction is characterized by enhanced inflammatory cytokine and adhesion molecule expression, and endothelial-monocyte adhesion. The adapter molecule CIKS (connection to IKK and SAPK/JNK; also known as Act1 or TRAF3IP2) is an upstream regulator of NF-kappaB and AP-1, and plays a role in inflammation and injury. Here we show that high glucose (HG; 25mM vs. 5mM d-glucose)-induced endothelial-monocyte adhesion and inhibition of endothelial cell (EC) migration were both reversed by CIKS knockdown. In EC, HG induced CIKS mRNA and protein expression via DPI-inhibitable Nox4-dependent ROS generation. Further, HG induced CIKS transcription and enhanced CIKS promoter-dependent reporter gene activation via Nox4, ROS, AP-1 and C/EBP. Coimmunoprecipitation and immunoblotting revealed CIKS/IKKbeta/JNK physical association under basal conditions that was enhanced by HG treatment. Importantly, CIKS knockdown inhibited HG-induced (i) IKKbeta and JNK phosphorylation, (ii) p65 and c-Jun nuclear translocation, and (iii) NF-kappaB- and AP-1-dependent proinflammatory cytokine, chemokine, and adhesion molecule expression. Similar to HG, the deleterious metabolic products of chronic hyperglycemia, AGE-HSA, AOPPs-HSA and oxLDL, also induced CIKS-dependent endothelial dysfunction. Notably, aortas from streptozotocin-induced and the autoimmune type 1 diabetic NOD and Akita mice showed enhanced DPI-inhibitable ROS generation and CIKS expression. Since CIKS mediates high glucose-induced NF-kappaB and AP-1-dependent inflammatory signaling and endothelial dysfunction, targeting CIKS may delay progression of vascular diseases during diabetes mellitus and atherosclerosis. PMID- 23085263 TI - Prolactin and dehydroepiandrosterone sulfate: are they related to the severity of chronic urticaria? AB - BACKGROUND AND AIMS: Elevated prolactin and reduced dehydroepiandrosterone sulfate (DHEA-S) levels are associated with autoimmune diseases. A limited number of studies have investigated these hormones in chronic urticaria (CU). The autologous serum skin test (ASST) reaction has also been linked to autoimmune diseases, and a positive reaction is usually associated with a more severe disease. We aimed to compare serum prolactin and DHEA-S levels between female CU patients with positive and negative ASST reactions and healthy controls. METHODS: The study included 30 female CU patients with a positive ASST reaction, 30 female CU patients with a negative ASST reaction, and 30 healthy female controls. All identifiable causes of urticaria were excluded. Serum prolactin and DHEA-S levels were measured in all subjects. RESULTS: Prolactin was significantly higher among ASST positive patients than among ASST negative patients and controls but did not differ between ASST negative patients or controls. Higher prolactin levels were associated with increasing disease severity among ASST positive patients. DHEA-S levels did not differ between ASST positive or negative patients but were significantly lower among both patient subgroups than controls. DHEA-S levels did not differ according to the severity of disease among either of the patient subgroups. DHEA-S levels did not correlate with prolactin among any group. CONCLUSION: We demonstrate for the first time a possible role for prolactin in ASST-positive CU patients and its association with disease severity. We recommend larger prospective studies to assess changes in prolactin and DHEA-S levels after complete disease remission. PMID- 23085264 TI - Driving developmental and evolutionary change: A systems biology view. AB - Embryonic development is underpinned by ~50 core processes that drive morphogenesis, growth, patterning and differentiation, and each is the functional output of a complex molecular network. Processes are thus the natural and parsimonious link between genotype and phenotype and the obvious focus for any discussion of biological change. Here, the implications of this approach are explored. One is that many features of developmental change can be modeled as mathematical graphs, or sets of connected triplets of the general form . In these, the verbs (edges) are the outputs of the processes that drive change and the nouns (nodes) are the time-dependent states of biological entities (from molecules to tissues). Such graphs help unpick the multi-level complexity of developmental phenomena and may help suggest new experiments. Another comes from analyzing the effect of mutation that lead to tinkering with the dynamic properties of these processes and to congenital abnormalities; if these changes are both inherited and advantageous, they become evolutionary modifications. In this context, protein networks often represents what classical evolutionary genetics sees as genes, and the realization that traits reflect the output processes of complex networks, particularly for growth, patterning and pigmentation, rather than anything simpler clarifies some problems that the evolutionary synthesis of the 1950s has found hard to solve. In the wider context, most processes are used many times in development and cooperate to produce tissue modules (bones, branching duct systems, muscles etc.). Their underlying generative networks can thus be thought of as genomic modules or subroutines. PMID- 23085255 TI - Disengaging polymerase: terminating RNA polymerase II transcription in budding yeast. AB - Termination of transcription by RNA polymerase II requires two distinct processes: The formation of a defined 3' end of the transcribed RNA, as well as the disengagement of RNA polymerase from its DNA template. Both processes are intimately connected and equally pivotal in the process of functional messenger RNA production. However, research in recent years has elaborated how both processes can additionally be employed to control gene expression in qualitative and quantitative ways. This review embraces these new findings and attempts to paint a broader picture of how this final step in the transcription cycle is of critical importance to many aspects of gene regulation. This article is part of a Special Issue entitled: RNA polymerase II Transcript Elongation. PMID- 23085265 TI - Electron storage mediated dark antibacterial action of bound silver nanoparticles: smaller is not always better. AB - Size tunable silver nanoparticles (Ag NPs) are synthesized and incorporated into titanium oxide coatings (TOCs) by manipulating the atomic-scale heating effect of silver plasma immersion ion implantation (Ag PIII). The resulting Ag NPs/TOC composite coatings possess electron storage capability that gives rise to both controlled antibacterial activity and excellent compatibility with mammalian cells. The precipitation behavior of these Ag NPs is qualitatively constrained by the classical nucleation theory. Both photoluminescence (PL) spectra and fluorescence microscopy results demonstrate that larger Ag NPs (5-25 nm) are better at reserving electrons than smaller ones (~4 nm). The antibacterial activities of the as-sprayed and Ag PIII treated TOCs show that Ag NPs with a different size act distinctively to bacteria: large particles induce serious cytosolic content leakage and lysis of both Staphylococcus aureus and Escherichia coli cells while small ones do not. The excellent activity of larger Ag NPs against bacteria is highly related to their stronger electron storage capability, which can induce accumulation of adequate valence-band holes (h+) at the titanium oxide side, arousing oxidation reactions to bacterial cells in the dark. Moreover, the in vitro cell culture assay (using both MG63 and MC3T3 cells) reveals no significant cytotoxicity and even good cytocompatibility on the Ag PIII treated samples. Our results show that, by taking advantage of the boundary property between Ag NP and titanium oxide, the antibacterial activity of Ag NPs can be accurately controlled. This study provides a distinct criterion for the design of nanostructured surfaces such that their osteoblast functions and antibacterial activity are perfectly balanced. PMID- 23085266 TI - Zymosan induces NADPH oxidase activation in human neutrophils by inducing the phosphorylation of p47phox and the activation of Rac2: involvement of protein tyrosine kinases, PI3Kinase, PKC, ERK1/2 and p38MAPkinase. AB - Reactive oxygen species (ROS) production by the neutrophil NADPH oxidase plays a key role in host defense against pathogens, such as bacteria and fungi. Zymosan a cell-wall preparation from Saccharomyces cerevisiae is largely used to activate neutrophils in its opsonized form. In this study, we show that non-opsonized zymosan alone induced ROS production by human neutrophils. Zymosan-induced ROS production is higher than the formyl-methionyl-leucyl-phenylalanine (fMLF)- or the phorbol myristate acetate (PMA)-induced ROS production but is lower than the one induced by opsonized zymosan. Most of the zymosan-induced ROS production is intracellular. Interestingly, zymosan induced the phosphorylation of the NADPH oxidase cytosolic component p47phox on several sites which are Ser315, Ser328 and Ser345. Zymosan induced also the activation of the small G-protein Rac2. Phosphorylation of the p47phox as well as Rac2 activation were inhibited by genistein a broad range protein tyrosine kinase inhibitor and by wortmannin a PI3Kinase inhibitor. GF109203X a PKC inhibitor inhibited phosphorylation of p47phox on Ser315 and Ser328. SB203580 and UO126, inhibitors of p38MAPK and ERK1/2-pathway, respectively, inhibited phosphorylation of p47phox on Ser345. Zymosan-induced ROS production was completely inhibited by genistein and wortmannin and partially inhibited by SB203580, UO126 and GF109203X. These results show that zymosan alone is able to activate NADPH oxidase in human neutrophils via the phosphorylation of p47phox and Rac2 activation and that a protein tyrosine kinase, PI3Kinase, p38MAPK, ERK1/2 and PKC are involved in this process. These pathways could be potential pharmacological targets to treat zymosan- and S. cerevisiae-induced inflammation. PMID- 23085267 TI - A novel indole derivative compound GY3 improves glucose and lipid metabolism via activation of AMP-activated protein kinase pathway. AB - The AMP-activated protein kinase (AMPK) is a ubiquitously expressed serine/threonine protein kinase that functions as an intracellular fuel sensor. It has been demonstrated to mediate the activities of a number of pharmacological and physiological factors that exert beneficial effects on type2 diabetes mellitus. GY3 is a novel synthesized indole compound derived from indomethacin, a non-steroid anti-inflammatory drug. In a previous study, we found that GY3 could improve insulin resistance and lower glucose levels in db/db mice, although its mechanism of action is not yet clear. In this study, we demonstrate that in vivo administration of GY3 improved serum triglyceride levels and decreased lipid accumulation in the livers of db/db mice. In vitro studies show that GY3 increased glucose consumption in HepG2 cells and 3T3-L1 adipocytes, decreased free fatty acid (FFA)-induced lipid accumulation in HepG2 cells and lipid accumulation in 3T3-L1 adipocytes. In vitro studies further show that GY3 improved glucose and lipid metabolism through an AMPK-dependent pathway but not the PI3K pathway. These findings suggest that GY3 is an effective agent for the improvement of glucose and lipid metabolism through AMPK pathway activation. PMID- 23085268 TI - Effect of S-aspirin, a novel hydrogen-sulfide-releasing aspirin (ACS14), on atherosclerosis in apoE-deficient mice. AB - Hydrogen sulfide (H(2)S) is a novel gaseous mediator that plays important roles in atherosclerosis. The present study investigated the effect of a novel H(2)S releasing aspirin, ACS14 (2-acetyloxybenzoic acid 4-(3-thioxo-3H-1,2-dithiol-5 yl)phenyl ester), on atherosclerotic plaques in fat-fed apoE(-/-) mice and the underlying mechanism with respect to CX3C chemokine receptor 1 (CX3CR1) in macrophages. Mouse macrophage cell line RAW264.7 or mouse peritoneal macrophages were preincubated with aspirin (50, 100 or 200MUM), ACS14 (50, 100 or 200MUM) or vehicle for 6h, and then stimulated with interferon (IFN)-gamma (500U/ml) or lipopolysaccharide (LPS; 10MUg/ml) for 12h. ACS14, but not aspirin, dose dependently inhibited IFN-gamma or LPS-induced CX3CR1 expression and CX3CR1 mediated chemotaxis in macrophages. The inhibitory effect of ACS14 on CX3CR1 expression was abolished by pretreatment with GW9662, a selective peroxisome proliferator-activated receptor (PPAR)-gamma antagonist, suggesting that suppression of macrophage CX3CR1 expression by ACS14 is PPAR-gamma dependent. Eight-week-old male apoE(-/-) mice received intraperitoneal ACS14 (15 or 30MUmol/kg/day) or aspirin (15 or 30MUmol/kg/day) 4 weeks after fat feeding. Twelve weeks after ACS14 or aspirin treatment, mice were sacrificed to evaluate the extent of atherosclerosis and CX3CR1 expression in brachiocephalic artery (BCA). We found that ACS14, but not aspirin, significantly downregulated CX3CR1 expression in atherosclerotic plaques. ACS14 considerably impeded the formation and development of atherosclerosis as compared to a molar equivalent dose of aspirin. These data indicate that ACS14 may prevent the progression of atherosclerosis by downregulating macrophage CX3CR1 expression via a PPAR-gamma dependent mechanism. PMID- 23085269 TI - Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. AB - Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10MUl of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with cannabidiol (2.5, 5, or 10mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of cannabidiol at different doses reduced the TNF-alpha level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel. PMID- 23085270 TI - A novel carbazole derivative, MHY407, sensitizes cancer cells to doxorubicin-, etoposide-, and radiation treatment via DNA damage. AB - In this study, we synthesized a novel carbazole derivative, MHY407, as a sensitizer of cancer cells to increase DNA damage. We then evaluated the anticancer effects of MHY407 and identified the molecular mechanism for the sensitization of breast cancer cell lines. MHY407 significantly increased DNA damage as determined by DNA breakage, levels of damage-responsive proteins, and DNA foci. In addition, MHY407 increased p21 and decreased cyclin D1 protein levels. MHY407 also involved increased cell cycle arrest at the S phase. Furthermore, in doxorubicin and etoposide-treated breast cancer cells, co treatment with MHY407 reduced cell viability and increased apoptosis. Co treatment of MHY407 with doxorubicin or etoposide increased DNA damage-related proteins and foci formation, suggesting that increased DNA damage by MHY407 plays an important role in the sensitization. In addition, MHY407 also sensitized the cancer cells to DNA damaging radiation treatment. These results may contribute to the development of MHY407-based treatments for cancer patients receiving DNA damage therapy. PMID- 23085272 TI - MODY 2: mutation identification and molecular ancestry in a Brazilian family. AB - Maturity Onset Diabetes of the Young (MODY) is a heterogeneous group of genetic diseases characterized by a primary defect in insulin secretion and hyperglycemia, non-ketotic disease, monogenic autosomal dominant mode of inheritance, age at onset less than 25 years, and lack of auto-antibodies. It accounts for 2-5% of all cases of non-type 1 diabetes. MODY subtype 2 is caused by mutations in the glucokinase (GCK) gene. In this study, we sequenced the GCK gene of two volunteers with clinical diagnosis for MODY2 and we were able to identify four mutations including one for a premature stop codon (c.76C>T). Based on these results, we have developed a specific PCR-RFLP assay to detect this mutation and tested 122 related volunteers from the same family. This mutation in the GCK gene was detected in 21 additional subjects who also had the clinical features of this genetic disease. In conclusion, we identified new GCK gene mutations in a Brazilian family of Italian descendance, with one due to a premature stop codon located in the second exon of the gene. We also developed a specific assay that is fast, cheap and reliable to detect this mutation. Finally, we built a molecular ancestry model based on our results for the migration of individuals carrying this genetic mutation from Northern Italy to Brazil. PMID- 23085271 TI - Berberine suppresses high glucose-induced TGF-beta1 and fibronectin synthesis in mesangial cells through inhibition of sphingosine kinase 1/AP-1 pathway. AB - Sphingosine kinase 1 (SphK1) pathway is critical in the pathogenesis of diabetic nephropathy. Recently, we found that berberine suppressed the activation of SphK1 pathway in diabetic kidney, protecting against diabetic nephropathy. The potential molecular mechanism, however, is still unknown. Here, we showed that berberine prevented the expression of alpha-smooth muscle actin (alpha-SMA), transforming growth factor-beta1 (TGF-beta1) and fibronectin (FN) in mesangial cells cultured by high glucose. Furthermore, berberine suppressed the activation of SphK1 pathway via inhibition of the activity and expression of SphK1 in mesangial cells cultured by high glucose. Surprisingly, berberine blocked the increased activity and expression of SphK1 in mesangial cells transfected by wild type SphK1 under normal glucose condition. However, berberine had no inhibitory effect on the recombinant human SphK1 protein. Finally, berberine markedly attenuated the high glucose-induced activator protein-1 (AP-1) activity in mesangial cells. Altogether, these data not only demonstrate that berberine is an important agent against diabetic nephropathy through inhibition of SphK1/AP-1 pathway, but also indicate that the inhibition of SphK1/AP-1 by berberine is independent of ambient glucose concentration. PMID- 23085273 TI - Mutational analysis of TYR gene and its structural consequences in OCA1A. AB - Oculocutaneous albinism type 1A (OCA1A) is the most severe form of albinism characterized by a complete lack of melanin production throughout life and is caused by mutations in the TYR gene. TYR gene codes tyrosinase protein to its relation with melanin formation by knowing the function of these SNPs. Based on the computational approaches, we have analyzed the genetic variations that could change the functional behaviour by altering the structural arrangement in TYR protein which is responsible for OCA1A. Consequences of mutation on TYR structure were observed by analyzing the flexibility behaviour of native and mutant tyrosinase protein. Mutations T373K, N371Y, M370T and P313R were suggested as high deleterious effect on TYR protein and it is responsible for OCA1A which were also endorsed with previous in vivo experimental studies. Based on the quantitative assessment and flexibility analysis of OCA1A variants, T373K showed the most deleterious effect. Our analysis determines that certain mutations can affect the dynamic properties of protein and can lead to disease conditions. This study provides a significant insight into the underlying molecular mechanism involved in albinism associated with OCA1A. PMID- 23085275 TI - Mechanistic target of rapamycin in common carp: cDNA cloning, characterization, and tissue expression. AB - The mechanistic target of rapamycin (mTOR) plays a key role in growth and development. In the present study, a cDNA encoding mTOR protein was identified from common carp Cyprinus carpio muscle. The open reading frame of this cDNA encodes 2515 deduced amino acid residues that showed high sequence similarity with its zebrafish Danio rerio counterparts. Bioinformatic analysis showed that the protein belongs to the PI-3 kinase family. The putative protein has FAT, FRB, PI3Kc, and FATC domains, which are highly conserved among the vertebrate orthologs. Real-time quantitative PCR analysis revealed that the abundance of mTOR mRNA was the highest in the heart at 18-31 g and muscle at 31-75g of common carp. As the common carp grew (18-40 g), the mTOR expression gradually decreased in the hepatopancreas and heart, but increased in the muscle, hind kidney, spleen, gill, head kidney, foregut, midgut, and hindgut. Then the mTOR expression kept a constant in all examined tissues during the common carp grew (40-75g). The present study identified the mTOR gene and determined its gene expression profile in various tissues of the common carp with body weight increased. These findings will help better understand the biological role of mTOR in the juvenile fish. PMID- 23085274 TI - Mutation c.359_363delGTATTinsATAC in the COL4A5 causes Alport syndrome in a Chinese family. AB - The X-linked form of Alport syndrome is associated with mutations in the COL4A5 gene, which is located at Xq22.3 and encodes the alpha5 chain of type IV collagen. Here we clinically characterized a Chinese family with Alport Syndrome, but no ocular or hearing abnormalities have been observed in any patient in the family. Through Linkage analysis and direct DNA sequencing, a novel complex deletion/insertion mutation c.359_363delGTATTinsATAC in the COL4A5 gene was identified in the family. The mutation was found in all affected family members, but was not present in the unaffected family individuals or the 200 controls. The predicted mutant protein in the family is a truncated protein consisting of only 153 residues. Our report for the first time revealed that the frameshift mutation in the type IV collagen chain alpha5 causes only renal disease, without extrarenal lesion. Our study broadens genotypic and phenotypic spectrum of COL4A5 mutations associated with Alport syndrome. PMID- 23085276 TI - NOD2 gene mutations associate weakly with ulcerative colitis but not with Crohn's disease in Indian patients with inflammatory bowel disease. AB - BACKGROUND: Three mutations (two missense and one frameshift) in the NOD2 gene are associated with Crohn's disease (CD) in a proportion of patients with Crohn's disease in North America, Europe and Australia. These three mutations are not found in Indian patients with CD. We undertook new studies to identify polymorphisms in the NOD2 gene in the Indian population and to detect whether any of these were associated with inflammatory bowel disease (IBD) in this population. METHODS: Individual exons of the NOD2 gene were amplified by PCR and subjected to denaturing high performance liquid chromatography (DHPLC) to detect heteroduplex formation. All 12 exons of the NOD2 gene were amplified and Sanger sequenced to detect polymorphisms in the NOD2 gene. 310 patients with CD, 318 patients with ulcerative colitis (UC) and 442 healthy controls (HC) were recruited for association studies. DNA from these participants was evaluated for the identified eight polymorphisms by Sequenom analysis. RESULTS: Heteroduplex formation was noted by DHPLC in exons 2 and 4 of the NOD2 gene. Sequencing of the entire NOD2 gene data revealed eight polymorphisms - rs2067085, rs2066842, rs2066843, rs1861759, rs2111235, rs5743266, rs2076753, and rs5743291 - of which the latter four were described for the first time in Indians. None of these polymorphisms was associated with CD. The SNPs rs2066842 and rs2066843 were in significant linkage disequilibrium. Both SNPs showed a significant association with UC (P=0.03 and 0.04 respectively; odds ratio 1.44 and 1.41 respectively). CONCLUSION: Four NOD2 polymorphisms were identified for the first time in the Indian population. Of 8 NOD2 polymorphisms, none were associated with CD but two were weakly associated with UC. NOD2 polymorphisms do not play a major role in CD genesis in India. PMID- 23085277 TI - Protein and nucleic acid methylating enzymes: mechanisms and regulation. AB - Protein and nucleic acid methylating enzymes are implicated in myriad cellular processes. These enzymes utilize diverse chemical mechanisms ranging from nucleophilic substitution-displacement to a novel radical-based reaction found in bacterial iron-sulfur cluster proteins. Within the cell, methylation activity is governed by interactions with endogenous molecular machinery. Of particular interest are the observations that methylating enzyme activity can be allosterically controlled by regulatory binding partners. Recent advances and emerging trends in the study of methylating enzyme mechanisms and regulation highlight the importance of protein and nucleic acid methylation in cellular physiology and disease. PMID- 23085278 TI - Clustering of food and activity preferences in primary school children. AB - This study examined clustering of food and activity preferences in Dutch primary school children. It also explored whether the preference clusters are associated with child and parental background characteristics and with parenting practices. Data were used from 1480 parent-child dyads participating in the IVO Nutrition and Physical Activity Child cohort (INPACT). Children aged 8-11years reported their preferences for food (e.g. fruit and sweet snacks) and activities (e.g. biking and watching television) at school with a newly-developed, visual instrument designed for primary school children. Parents completed a questionnaire at home. Principal component analysis was used to identify preference clusters. Backward regression analyses were used to examine the relationship between child and parental characteristics with cluster scores. We found (1) a clustering of preferences for unhealthy foods and unhealthy drinks, (2) a clustering of preferences for various physical activity behaviours, and (3) a clustering of preferences for unhealthy drinks and sedentary behaviour. Boys had a higher cluster score than girls on all three preference clusters. In addition, physical activity-related parenting practices were negatively related to unhealthy preference clusters and positively to the physical-activity preference cluster. The next step is to relate our preference clusters to child dietary and activity behaviours, with special attention to gender differences. This may help in the development of interventions aimed at improving children's food and activity preferences. PMID- 23085279 TI - A weighted small world network measure for assessing functional connectivity. AB - There is a growing need to develop measures that can characterize complex patterns of functional connectivity among brain regions. Graph theoretic measures have emerged as an important way to characterize the multivariate connectivity between nodes in a network, which have been successfully applied to neurophysiologic activity. In this paper, we propose a new small-world measure based on advances in both the bivariate measures underlying the graph theoretic approach, as well as in the definition of the measure for weighted graphs. Specifically, we recently proposed a new bivariate time-frequency phase-synchrony (TFPS) measure, which quantifies the dynamic nature of the interactions between neuronal oscillations with a higher time-frequency resolution than previous approaches and is better at isolating relevant activity. The proposed graph theoretic measures, weighted clustering coefficient and path length, represent a new approach to the calculation of weighted graph measures based on this improved bivariate TFPS measure. The new graph theoretic measures are applied to two datasets. The first is a well-known social network, Zachary's Karate Club. The second application contains event-related potential (ERP) indexing the well-known error-related negativity (ERN) component related to cognitive control. Results indicate that the new measures outperform the previously published weighted graph measures, and produces expectable results for both applications. PMID- 23085280 TI - Frequency-based approach to the study of semantic brain networks connectivity. AB - The interactions among cerebral regions involved in semantic word generations are explored through connectivity analysis based on fMRI data through multivariate autoregressive model (MVAR). Connections among the pars triangularis of the left inferior frontal gyrus (L45), the lateral fusiform girus (LFG) and the left medial fusiform girus (MFG) were investigated. Ten healthy subjects were asked to covertly generate nouns belonging to two semantic categories (Animals and Tools). Time series for each voxel were derived from fMRI images, averaged within each area and concatenated over all subjects. The MVAR model allowed estimating spectral power, coherence and partial coherence between pairs of time series, and causality relations assessed through direct directed transfer function (dDTF). Spectral power is mostly concentrated in the frequency range of the imposed stimulus and the activation in the specific areas is modulated by conditions as well as coherence and partial coherence. dDTF values revealed stronger connections between L45 and LFG in "Tools" conditions, while a stronger causality was found between L45 and MFG in "Animals" conditions. In addition, comparing the same connections in the two conditions, a mirror reversal of the two weights was observed, with stronger causality L45-LFG in "Tools" vs "Animals" and stronger causality L45-MFG in "Animals" vs "Tools". The present study confirms and extends previous results obtained by structural equation modeling analysis, suggesting the suitability of a data-driven Granger causality approach in identifying condition-dependent effective connectivity from BOLD signals. The proposed methodology completes and integrates other analysis procedures providing new tools to explore brain functions. PMID- 23085281 TI - Raman study of the formation of beta silicomolybdic acid supported on silica, prepared by impregnation method. AB - Beta silicomolibdic acid/silica (beta-SMA, a metastable form of silicomolybdic acid - H(4)SiMo(12)O(40)) forms by the impregnation of fumed silica into molybdenum solution obtained by hydrolyzation of MoO(2)Cl(2.) beta-SMA/silica is found to be stable up to 300 degrees C after calcination for 1h due to the existence of an interlayer MoO(3) between silica surface and beta-SMA. Structures of molybdenum species in the preparation process (including precursor solution) were analyzed by Raman spectroscopy and XRD. PMID- 23085282 TI - Aluminium induced structural, metabolic alterations and protective effects of desferrioxamine in the brain tissue of mice: an FTIR study. AB - In this study, we intended to made a new approach to evaluate aluminium induced metabolic changes in mice brain tissue using Fourier transform infrared spectroscopy. Results demonstrate that FTIR can successfully indicate the molecular changes that occur in all groups. The overall findings demonstrate the alterations on the major biochemical constituents, such as lipids, proteins and nucleic acids of the brain tissues of mice. The significant decrease in the area value of amide A peak and Olefinic = CH stretching band suggests an alteration in the protein profile and lipid levels due to aluminium exposure, respectively. The significant shift in the amide I and amide II protein peaks may indicate the progression of aluminium induced Alzheimer's disease. Further the administration of DFO significantly improved the level of protein and brought back the amide I and II peaks nearer to the control value. Histopathological results also revealed impairment of Aluminium induced alterations in brain tissue. The results of the FTIR study were found to be in agreement with biochemical studies. PMID- 23085283 TI - Synthesis, growth and characterization of L-lysinium(+)...L-lysinium(2+) dichloride perchlorate (LLDP) single crystals by Sankaranarayanan-Ramasamy method. AB - L-lysinium(+)...L-lysinium(2+) dichloride perchlorate was synthesized at ambient temperature and bulk single crystals were grown by conventional and Sankaranarayanan-Ramasamy methods. Crystals grown by these methods were subjected to single crystal X-ray diffraction, Fourier transform infrared, high resolution X-ray diffraction, Vickers microhardness and thermogravimetric/differential scanning calorimetric/differential thermal analyses. Further, the cut-off wavelength and optical transmittance of the grown crystals were determined by UV vis-NIR spectrum. Linear refractive index (n(x)) of the crystal was measured using minimum deviation method for different wavelengths. Optical quality of the grown crystals was analyzed by conoscopic interference pattern and the birefringence was calculated using interferometric technique. Surface laser damage threshold of the crystal was determined using Nd:YAG laser. The nonlinear refractive index n(2) was measured through the Z-scan technique using low power continuous wave HeNe laser. Frequency and temperature dependent dielectric constant (epsilon(r)) and dielectric loss (tandelta) were measured. PMID- 23085284 TI - Structure and conformation studies from temperature dependent infrared spectra of xenon solutions and ab initio calculations of cyclobutylgermane. AB - The infrared spectra (3500-220 cm(-1)) of cyclobutylgermane, c-C(4)H(7)GeH(3) have been recorded of the gas. Also variable temperature (-65 to -100 degrees C) studies of the infrared spectra (3500-400 cm(-1)) of the sample dissolved in liquid xenon were recorded and both the equatorial and axial conformers were identified. The enthalpy difference has been determined from 10 band pairs 8 temperatures to give 112 +/- 11 cm(-1) (1.34 +/- 0.13 kJ mol(-1)) with the equatorial conformer the more stable form. The percentage of the axial conformer present at ambient temperature is estimated to be 37 +/- 1%. From ab initio calculations conformational stabilities have been predicted from both MP2(full) and density functional theory calculations from a variety of basic sets. The r(0) structure parameters have been obtained for both conformers from the previously reported rotational constants from the three isotopologues. The determined heavy atom distances for the equatorial [axial] form are (A) Ge-C(alpha)=1.952(3) [1.950(3)], [Formula: see text] , [Formula: see text] [1.551(3)] and angles in degrees ( degrees ) ?GeC(alpha)C(beta)=118.6(5) [113.4(5)], [Formula: see text] , ?C(alpha)C(beta)C(gamma)=87.8(5) [88.8(5)], [Formula: see text] and a puckering angle of 29.1(5) [25.1(5)]. Data from ab initio calculations were used to predict vibrational harmonic force constants, fundamental wavenumbers, infrared intensities, Raman activities and depolarization ratios for both conformers. The results are compared to the corresponding properties of some related molecules. PMID- 23085285 TI - CdSiO3:Pr3+ nanophosphor: synthesis, characterization and thermoluminescence studies. AB - A series of Pr(3+) (1-9 mol%) doped CdSiO(3) nanophosphors have been prepared for the first time by a low temperature solution combustion method using oxalyldihydrizide (ODH) as a fuel. The final product was characterized by Powder X-ray diffraction (PXRD), Fourier Transform Infrared Spectroscopy (FTIR), scanning electron microscopy (SEM), and UV-Vis spectroscopy. The average crystallite size was calculated using Debye-Scherrer's formula and Williamson Hall (W-H) plots and found to be in the range 31-37 nm. The optical energy band gap (E(g)) of undoped for Pr(3+) doped samples were estimated from Tauc relation which varies from 5.15-5.36 eV. Thermoluminescence (TL) properties of Pr(3+) doped CdSiO(3) nanophosphor has been investigated using gamma-irradiation in the dose range 1-6 kGy at a heating rate of 5 degrees C s(-1). The phosphor shows a well resolved glow peak at ~171 degrees C along with shouldered peak at 223 degrees C in the higher temperature side. It is observed that TL intensity increase with increase of Pr(3+) concentration. Further, the TL intensity at 171 degrees C is found to be increase linearly with increase in gamma-dose which is highly useful in radiation dosimetry. The kinetic parameters such as activation energy (E), frequency factor (s) and order of kinetics was estimated by Luschiks method and the results are discussed. PMID- 23085286 TI - Green upconversion emission in Nd3+-Yb3+-Zn2+:Y2O3 phosphor. AB - The Y(2)O(3) phosphor powder codoped with Nd(3+):Yb(3+) ions have been synthesized through optimized combustion route. Crystalline structures of the prepared samples have been investigated by powder X-ray diffraction technique. Efficient upconversion emission in the green region upon 980 nm NIR CW diode laser excitation has been reported. The maximal enhancement in the intensity of the green upconversion emission band has been observed on codoping with Zn(2+) ions in the Nd(3+):Yb(3+) codoped sample. The processes responsible for such an enhancement in the green upconversion emission band which can be used for the localization and diagnosis of cancer has been explained in detail. PMID- 23085287 TI - Biased competition in the global workspace: comment on "Consciousness, crosstalk and the mereological fallacy: an evolutionary perspective" by R. Wallace. PMID- 23085288 TI - Changes in lymphocyte oxidant/antioxidant parameters after carbonyl and antioxidant exposure. AB - During normal B- and T-cell life, processes including activation, proliferation, signaling pathways and apoptosis are markedly dependent on ROS generation. However, these cells can also suffer the effect of oxidant overproduction. Thus, the purpose of the present study was to examine the possible pro-oxidant effects of MGO/high glucose and antioxidant effects of astaxanthin associated with vitamin C on some oxidative and antioxidant parameters of human lymphocytes in vitro. Lymphocytes from healthy subjects were treated with 20mM of glucose and 30 MUM MGO followed or not by the addition of the antioxidants astaxanthin (2 MUM) and vitamin C (100 MUM) for up to 24h. We examined superoxide dismutase (SOD), catalase, glutathione peroxidase, glutathione reductase, and glucose-6-phosphate dehydrogenase (G6PDH) activities, GSH/GSSG ratio and total thiol and carbonyl content. Oxidative parameters included superoxide anion, hydrogen peroxide and nitric oxide production. The association of astaxanthin and vitamin C proved to be a powerful antioxidant in human lymphocytes as showed by the marked reduction in superoxide anion, and hydrogen peroxide production as well as increased GSH content, GSH/GSSG ratio, GPx and GR activities. The antioxidant association showed to be more potent than their individual application. High glucose and methylglyoxal did not promote oxidative stress in human lymphocytes, since neither the oxidative parameters nor the antioxidant defense system was altered. According to these results, new therapies with the association of astaxanthin and vitamin C may be helpful to improve the immune function of patients with exacerbated production of ROS. PMID- 23085289 TI - Sugar gustatory thresholds and sugar selection in two species of Neotropical nectar-eating bats. AB - Nectar-feeding bats play an important role in natural communities acting as pollinators; however, the characteristics that affect their food selection are unclear. Here we explore the role that sugar gustatory thresholds and sugar concentration play on sugar selection of Glossophaga soricina and Leptonycteris yerbabuenae. We offered bats paired feeders containing sugar solutions of sucrose (S), glucose (G) or fructose (F) vs. pure water, and sucrose vs. 1:1 equicaloric solutions of glucose-fructose at 5, 15 and 35% (wt./vol.). To see the effect of sweetness on sugar selection, we habituated the bats with a diet containing either sucrose or hexoses and subsequently evaluated sugar preferences. Sugar thresholds were S=24h) quantification of O(2)-consumption and studied the peripartum period from 5 weeks ante partum to 5 weeks postpartum. In addition, we determined cellular lactate production, DNA/RNA synthesis and cell size and zoo-technical parameters such as animal energy intake and milk yield were assessed, as well as selected plasma parameters, e.g. glucose concentration. The basal OCR of PBMC from pregnant, non-lactating cows (n=6, -5 weeks ante partum) was 1.19+/-0.15 nmol min(-1) (10(7)cells)(-1) and increased to maximum levels of 2.54+/-0.49 nmol min(-1) (10(7)cells)(-1) in phytohemagglutinin (PHA)-stimulated PBMC. The basal OCR did not change over the peripartum period. Whereas the activation indices, herein defined as the PHA-induced 24h-increase of OCR above baseline, amounted to 1.1+/-0.3, 4.2+/-0.3, 4.1+/-1.1, 2.1+/-0.3, and 2.7+/-0.5 at weeks -5, -1, +1, +2, and +5 relative to parturition, respectively. Because the activation index was positively correlated to plasma glucose levels and to energy balance during late pregnancy (week -5/week -1) and transition to lactation (week -1/week +2), we conclude that PBMC activation is modulated by energy/nutrient availability. In future studies, the activation index should aid the identification of causal mechanisms of disparity in PBMC activation, such as attenuated ion transport or macromolecule synthesis. PMID- 23085293 TI - Unique roles of glucagon and glucagon-like peptides: Parallels in understanding the functions of adipokinetic hormones in stress responses in insects. AB - Glucagon is conventionally regarded as a hormone, counter regulatory in function to insulin and plays a critical anti-hypoglycemic role by maintaining glucose homeostasis in both animals and humans. Glucagon performs this function by increasing hepatic glucose output to the blood by stimulating glycogenolysis and gluconeogenesis in response to starvation. Additionally it plays a homeostatic role by decreasing glycogenesis and glycolysis in tandem to try and maintain optimal glucose levels. To perform this action, it also increases energy expenditure which is contrary to what one would expect and has actions which are unique and not entirely in agreement with its role in protection from hypoglycemia. Interestingly, glucagon-like peptides (GLP-1 and GLP-2) from the major fragment of proglucagon (in non-mammalian vertebrates, as well as in mammals) may also modulate response to stress in addition to their other physiological actions. These unique modes of action occur in response to psychological, metabolic and other stress situations and mirror the role of adipokinetic hormones (AKHs) in insects which perform a similar function. The findings on the anti-stress roles of glucagon and glucagon-like peptides in mammalian and non-mammalian vertebrates may throw light on the multiple stress responsive mechanisms which operate in a concerted manner under regulation by AKH in insects thus functioning as a stress responsive hormone while also maintaining organismal homeostasis. PMID- 23085294 TI - [Policy and routine practice for smoking cessation in France]. AB - In France, daily tobacco consumption increased among adults between 18 and 75 years between 2005 and 2010, particularly women. At 17 age-old, it raised 10% between 2008 and 2011 (32.7% in boys and 30.2% in girls). The number of cigarettes smoked per day decreased between 2005 and 2010 in France, from 15.4 to 13.9 cigarettes smoked per day. But active exposition to cigarette smoke and consequently to cigarette toxins exposure did not change and even increased. Tobacco prevention should follow the World Health Organization Framework Convention on Tobacco Control, which was signed in 2004 by French representatives. Smoking cessation methods include: minimal counseling provided by general practitioners (when given during a medical visit for another motive than smoking cessation, one out of 50 smokers stops); minimal counseling given by any health professional; and the smoking cessation services framework. Evidence based medications associated with a non-pharmacologic support and with a regular follow-up significantly increase smoking cessation rates. Risk reduction by decreasing progressively tobacco consumption with the help of medications is only suggested nowadays. PMID- 23085295 TI - Molecular analyses of dinosaur osteocytes support the presence of endogenous molecules. AB - The discovery of soft, transparent microstructures in dinosaur bone consistent in morphology with osteocytes was controversial. We hypothesize that, if original, these microstructures will have molecular features in common with extant osteocytes. We present immunological and mass spectrometry evidence for preservation of proteins comprising extant osteocytes (Actin, Tubulin, PHEX, Histone H4) in osteocytes recovered from two non-avian dinosaurs. Furthermore, antibodies to DNA show localized binding to these microstructures, which also react positively with DNA intercalating stains propidium iodide (PI) and 4',6' diamidino-2-phenylindole dihydrochloride (DAPI). Each antibody binds dinosaur cells in patterns similar to extant cells. These data are the first to support preservation of multiple proteins and to present multiple lines of evidence for material consistent with DNA in dinosaurs, supporting the hypothesis that these structures were part of the once living animals. We propose mechanisms for preservation of cells and component molecules, and discuss implications for dinosaurian cellular biology. PMID- 23085297 TI - The sensitivity of initial transurethral resection or biopsy of bladder tumor(s) for detecting bladder cancer variants on radical cystectomy. AB - PURPOSE: We determined the ability of bladder biopsy and transurethral resection of the bladder to accurately predict bladder cancer variants on radical cystectomy since certain variants may affect prognosis and treatment. MATERIALS AND METHODS: We retrospectively evaluated the records of 302 patients who underwent biopsy and/or transurethral resection of the bladder followed by radical cystectomy from 2008 to 2010. The frequency of variant morphology and the sensitivity of the precystectomy material was determined using pathological findings at radical cystectomy as the final result. RESULTS: Bladder cancer variants were identified in 159 patients (53%) on initial biopsy/transurethral resection and/or final pathological evaluation at radical cystectomy. The most common variant was urothelial carcinoma with squamous differentiation in 72 of 159 patients (45%), followed by micropapillary urothelial carcinoma in 41 (26%). In 9 patients (6%) variant morphology was identified only on biopsy/transurethral resection bladder and not on final radical cystectomy pathological assessment. The remaining 150 patients (94%) showed variant morphology on radical cystectomy with (79 or 53%) or without (71 or 47%) variant morphology on the preceding biopsy/transurethral resection. The sensitivity of variant detection showed a broad range by variant subtype. Overall, initial biopsy/transurethral resection sensitivity was 39% for predicting variant morphology on radical cystectomy. CONCLUSIONS: Overall sensitivity for predicting bladder cancer variants from biopsy/transurethral resection of the bladder sampling is relatively low. This is likely due to sampling and tumor heterogeneity rather than to an inaccurate pathological diagnosis. Additional predictive markers of variant morphology may be useful to determine which tumors contain aggressive variants that may alter outcomes or therapy. PMID- 23085298 TI - Validation of online administration of the sexual health inventory for men. AB - PURPOSE: Previously we reported the development of a novel, inexpensive, online method to collect health related quality of life information to facilitate responses among patients and decrease loss to followup. We validated the practice by comparing responses to the SHIM (Sexual Health Inventory for Men), a representative validated instrument, when administered on line and in the traditional paper form. MATERIALS AND METHODS: Consented patients were administered validated health related quality of life instruments, including the SHIM, in office and via e-mail. Responses to the SHIM were compared between the administration formats. Paired sample testing was done to analyze test-retest reliability, concordance was assessed by intraclass analysis and a Bland-Altman plot, and the Cronbach alpha was used to examine internal reliability. Criterion validity was measured using SHIM defined erectile function categories and a dichotomized potency definition (SHIM 17 or greater). RESULTS: Of the 508 men who consented to participate 359 (71%) completed the SHIM in person, 277 (55%) completed the online form (p <0.001) and 116 (23%) contemporaneously completed each instrument. Comparison of scores revealed little variation and strong correlation (r(2) = 0.83, p <0.001). Intraclass and Bland-Altman analysis revealed strong agreement between the media. The Cronbach alpha was excellent (0.97) for the online tool. Erectile function classification was identical in 73% of patients with only 7% differing by more than 1 class. Dichotomized potency was consistently defined in 94% of patients. CONCLUSIONS: The online administered SHIM maintains validity and provides consistent responses. Online administration can capture patients who do not complete paper questionnaires and may serve as a reliable adjunct to paper administration for validated outcomes research. PMID- 23085299 TI - Infections versus penile implants: the war on bugs. AB - PURPOSE: Infection of an inflatable penile implant is the worst complication in prosthetic urology. This review summarizes the milestone advances that led to today's infection rates being the lowest ever, describes the current profile of the ever evolving bacteriology of device infections and suggests possible future research directions. MATERIALS AND METHODS: A comprehensive review of the relevant literature was performed and the data from that literature were summarized. RESULTS: Continual refinements in surgical technique and implant design combined with a greater understanding of bacterial virulence factors led to a dramatic decrease in inflatable penile prosthesis infections. CONCLUSIONS: Great strides have been made in decreasing the risk of inflatable penile prosthesis infections. The bacteriology of those infections is ever changing. Our continued success hinges on remaining attuned to those changes and adapting current approaches to meet them. PMID- 23085300 TI - Trends in renal surgery: robotic technology is associated with increased use of partial nephrectomy. AB - PURPOSE: Underuse of partial vs radical nephrectomy for renal tumors was noted in recent population based analyses. An explanation is the learning curve associated with laparoscopic partial nephrectomy. We analyzed state trends in renal surgery and their relationship to the introduction of robotic technology. MATERIALS AND METHODS: We used the Maryland HSCRC (Health Services Cost Review Commission) database to identify patients who underwent radical or partial nephrectomy, or renal ablation from 2000 to 2011. Utilization trends, and associated patient and hospital factors were analyzed using multivariate logistic regression. ICD-9 robotic modifier codes were established in October 2008. RESULTS: Of the 14,260 patients included in analysis 11,271 (79.0%), 2,622 (18.4%) and 367 (2.6%) underwent radical and partial nephrectomy, and renal ablation, respectively. Partial nephrectomy increased from 8.6% in 2000 to 27% in 2011. Open radical nephrectomy decreased by 33%, while minimally invasive radical nephrectomy increased by 15%. Robot-assisted laparoscopic partial nephrectomy increased from 2008 to 2011, attaining a 14% rate at university and 10% at nonuniversity hospitals (p = 0.03). It was associated with increased partial nephrectomy (OR 9.67, p <0.001). Younger age, male gender and low patient complexity predicted partial nephrectomy on overall analysis, while higher hospital volume and university status were predictors only in earlier years. CONCLUSIONS: Partial nephrectomy use increased in Maryland from 2001 to 2011, which was facilitated by robotic technology. Associations with hospital factors decreased with time. These data suggest that robotic technology may enable surgeons across practice settings to more frequently perform nephron sparing surgery. PMID- 23085301 TI - Effect of ibudilast on the reciprocal inhibitory visual-vestibular interaction closely related to dizziness after cerebral ischemia. AB - BACKGROUND: Many patients with chronic cerebrovascular diseases suffer dizziness. Our earlier findings suggested that prolonged terms of dizziness episodes may decrease the regional cerebral blood flow (CBF) in the occipital visual cortex via a remote effect from the vestibular cortex. METHODS: We studied 9 patients who suffered episodes of dizziness since the onset of chronic cerebral ischemia. Their at-rest CBF was measured at entry into the study and approximately 3 months after the start of ibudilast therapy when all patients reported the resolution of dizziness. RESULTS: After 3 months of ibudilast their at-rest CBF was significantly increased in the left occipital lobe (P = .02). CBF after acetazolamide (ACZ) loading was significantly increased in the bilateral occipital lobes (right, P = .049; left, P = .02) and in the bilateral parieto insular vestibular cortex (PIVC; right and left, P = .02). There were no significant CBF changes in any other areas. CONCLUSIONS: Our findings indicate that the occipital cortex and PIVC were implicated in their dizziness after cerebral ischemia. We discuss the underlying mechanism(s) and the relationship between dizziness and reciprocal inhibitory visual-vestibular interactions. PMID- 23085302 TI - Research focus on neuroethology. Editorial. PMID- 23085303 TI - Aetiology of childhood hearing loss in Cameroon (sub-Saharan Africa). AB - BACKGROUND: Severe hearing loss is a global problem affecting particularly developing countries. There is scarcity of recent published data on the epidemiology of childhood deafness in sub-Saharan Africa. OBJECTIVE: To determine the etiological profile of severe childhood deafness in Cameroon. METHODS: Prospective cross-sectional study of patients with a severe hearing loss that started before the age of 15 years. Detailed family and medical history was obtained; careful clinical, otological and audiological examinations were performed. RESULTS: A total of 582 patients with a severe hearing loss were examined. Prelingual deafness accounted for 75.1% (n = 437), with a mean age at medical diagnosis of 3.3 +/- 1.2 years. This late presentation may be explained by limited parental awareness of signs raising suspicion of hearing loss, poor access to health care and the absence of neonatal screening for hearing loss in Cameroon. Identified genetic causes accounted for 14.8% (n = 86), putative environmental causes for 52.6% (n = 306) and unknown causes for 32.6% (n = 190). Amongst Genetic causes, the syndromic hearing loss accounted for 13.1% (n = 12) of cases, the rest being non syndromic (n = 74). Consanguineous families accounted for 5.7% (n = 33) of the whole sample, and 15.1% (n = 13) of genetic cases. No union between deaf parents was observed. CONCLUSION: These data highlight the possible predominance of putative environmental causes of childhood deafness in Cameroon, and emphasize the need for improved policies for prevention of infectious diseases and for neonatal hearing screening. However, further molecular analyses and targeted CT scan investigations are required to more accurately gauge the contribution of genetics etiologies. PMID- 23085304 TI - 5p13 microduplication syndrome: a new case and better clinical definition of the syndrome. AB - Chromosome 5p13 duplication syndrome (OMIM #613174), a contiguous gene syndrome involving duplication of several genes on chromosome 5p13 including NIPBL (OMIM 608667), has been described in rare patients with developmental delay and learning disability, behavioral problems and peculiar facial dysmorphisms. 5p13 duplications described so far present with variable sizes, from 0.25 to 13.6 Mb, and contain a variable number of genes. Here we report another patient with 5p13 duplication syndrome including NIPBL gene only. Proband's phenotype overlapped that reported in patients with 5p13 microduplication syndrome and especially that of subjects with smaller duplications. Moreover, we better define genotype phenotype relationship associated with this duplication and confirmed that NIPBL was likely the major dosage sensitive gene for the 5p13 microduplication phenotype. PMID- 23085306 TI - Precious metals and rare earth elements in municipal solid waste--sources and fate in a Swiss incineration plant. AB - In Switzerland many kinds of waste, e.g. paper, metals, electrical and electronic equipment are separately collected and recycled to a large extent. The residual amount of municipal solid waste (MSW) has to be thermally treated before final disposal. Efforts to recover valuable metals from incineration residues have recently increased. However, the resource potential of critical elements in the waste input (sources) and their partitioning into recyclable fractions and residues (fate) is unknown. Therefore, a substance flow analysis (SFA) for 31 elements including precious metals (Au, Ag), platinum metal group elements (Pt, Rh) and rare earth elements (La, Ce, etc.) has been conducted in a solid waste incinerator (SWI) with a state-of-the-art bottom ash treatment according to the Thermo-Re(r) concept. The SFA allowed the determination of the element partitioning in the SWI, as well as the elemental composition of the MSW by indirect analysis. The results show that the waste-input contains substantial quantities of precious metals, such as 0.4 +/- 0.2mg/kg Au and 5.3 +/- 0.7 mg/kg Ag. Many of the valuable substances, such as Au and Ag are enriched in specific outputs (e.g. non-ferrous metal fractions) and are therefore recoverable. As the precious metal content in MSW is expected to rise due to its increasing application in complex consumer products, the results of this study are essential for the improvement of resource recovery in the Thermo-Re(r) process. PMID- 23085305 TI - A novel splice site mutation in ERLIN2 causes hereditary spastic paraplegia in a Saudi family. AB - Hereditary Spastic Paraplegias (HSP) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by insidiously progressive weakness and spasticity of the lower extremities. We describe a consanguineous Saudi family segregating a complicated form of HSP in an autosomal recessive pattern. The two affected siblings had early onset, cognitive, speech and motor involvement with spasticity of the lower extremities. Their upper extremities were mildly hypertonic. An intronic splice acceptor site mutation in ERLIN2 was found to be responsible for causing this disorder found in this family. ERLIN2 is a mediator of endoplasmic reticulum degradation pathway (ERAD) which helps to remove the aberrant proteins. Our results, in concurrence with previous studies suggest that alteration in ERLIN2 is one of the causes of complicated HSP, thereby increasing the spectrum of known mutations in SPG18. PMID- 23085307 TI - Assessment of plaque assay methods for alphaviruses. AB - Viruses from the Alphavirus genus are responsible for numerous arboviral diseases impacting human health throughout the world. Confirmation of acute alphavirus infection is based on viral isolation, identification of viral RNA, or a fourfold or greater increase in antibody titers between acute and convalescent samples. In convalescence, the specificity of antibodies to an alphavirus may be confirmed by plaque reduction neutralization test. To identify the best method for alphavirus and neutralizing antibody recognition, the standard solid method using a cell monolayer overlay with 0.4% agarose and the semisolid method using a cell suspension overlay with 0.6% carboxymethyl cellulose (CMC) overlay were evaluated. Mayaro virus, Una virus, Venezuelan equine encephalitis virus (VEEV), and Western equine encephalitis virus (WEEV) were selected to be tested by both methods. The results indicate that the solid method showed consistently greater sensitivity than the semisolid method. Also, a "semisolid-variant method" using a 0.6% CMC overlay on a cell monolayer was assayed for virus titration. This method provided the same sensitivity as the solid method for VEEV and also had greater sensitivity for WEEV titration. Modifications in plaque assay conditions affect significantly results and therefore evaluation of the performance of each new assay is needed. PMID- 23085309 TI - Transport properties of puerarin and effect of Radix Angelicae Dahuricae extract on the transport of puerarin in Caco-2 cell model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Angelicae Dahurica (Hoffm.)Benth.& Hook.f.ex Franch.&Sav combined with Pueraria labota (Willd.)Ohwi has been widely used as herb-pairs in traditional Chinese medicine (TCM) for utilization of antipyretic analgesic and anti-inflammatory drugs, and modern pharmacological studies have shown that application compatibility of the two drugs has the effects of cardiovascular disease treatment. The previous study has proved that Radix Angelicae Dahuricae extract could enhance the intestinal absorption of puerarin in Pueraria. But the underlying compatibility mechanism of the two herbs remains unknown. In this study we tried to further evaluate the improvement of Radix Angelicae Dahuricae extract on the puerarin using the Caco-2 cell model and explore the transport properties of puerarin through the above research to discuss the possible effect mechanism of Radix Angelicae Dahuricae extract on the transport of puerarin and the underlying compatibility mechanism of the two herbs. AIM OF STUDY: The aim of this work was to study the transport properties of puerarin in Radix Pueraria across Caco-2 cell membrane and to explore how the Radix Angelicae Dahuricae extract affected the transport of puerarin using the well-characterized, human-based intestinal Caco-2 cell model as a platform. MATERIALS AND METHODS: The bidirectional transport, and the effects of time, drug concentration, pH, P-gp inhibitors (Verapamil, Cyclosporin A), MRP inhibitor (MK 571) and EDTA-Na(2) (tight junction modulator) on the absorption of puerarin were observed. Then the influence of extract of Radix Angelicae Dahuricae on the transport of puerarin was studied. Drug concentration was measured by HPLC and the apparent permeability coefficients (Papp) and apparent permeability ratio (PDR) were calculated. RESULTS AND CONCLUSIONS: The results showed that the transport (Papp) of puerarin in Caco-2 cell monolayer model had time and concentration dependence, and the transport showed saturation characteristics with the time and concentration of puerarin to a certain degree. The Papp of puerarin transported on Caco-2 cell monolayer model was significantly changed when the specified inhibitors of P-gp were added to the model and the PDR decreased from 1.74 to 0.43. The absorption of puerarin was improved when combined with Radix Angelicae Dahuricae. The intestinal absorption of puerarin is by passive diffusion as the dominating process and active transportation was mediated by P-gp and MRP transporter in Caco-2 cell monolayer model, and Radix Angelicae Dahuricae could enhance the intestinal absorption of puerarin. PMID- 23085308 TI - The leaf and seed aqueous extract of Phyllanthus amarus improves insulin resistance diabetes in experimental animal studies. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Amongst the Yoruba tribe (Southwest Nigeria), water decoction of the leaf and seed of Phyllanthus amarus Schum. and Thonn. is reputably used for the local management of diabetes mellitus, obesity and hyperlipidemia. AIM OF THE STUDY: The present study seeks to evaluate the effectiveness and elucidate mechanism(s) of action of the aqueous leaf and seed extract of Phyllanthus amarus (PAE) in normal and 10% sucrose-induced hyperglycemia and dyslipidemia as an experimental model of insulin resistance diabetes mellitus. MATERIALS AND METHODS: In this study, the repeated oral antihyperglycemic action of 150-600 mg/kg/day of PAE was evaluated in normal and 10% sucrose-induced insulin resistance rats using indicators such as fasting blood glucose (FBG), insulin and insulin resistance indices. The extract's weight losing, antihyperlipidemic and anti-atherogenic effects were also evaluated by measuring the effect of the extract on the body weight, plasma levels of triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-c), low density lipoprotein cholesterol (LDL-c) and atherogenic indices. RESULTS: In normal rats, PAE caused significant (p<0.05, p<0.01 and p<0.001) and dose related decreases in body weight, FBG, TG, TC, LDL-c, and atherogenic indices. Repeated oral treatment with 10% sucrose drink for 30 days was associated with significant (p<0.001) weight gain, hyperglycemia, insulin resistance indices, hyperlipidemia and atherogenic indices. However, pre treatment with PAE significantly (p<0.05, p<0.01 and p<0.001) and dose dependently attenuated increase in any of these measured parameters. CONCLUSIONS: Overall, results of this study showed PAE to effectively control insulin resistance DM which was mediated via improvement in insulin resistance, thus, validating its ethnomedical use in the local management of DM. PMID- 23085310 TI - Salt induced thermodynamic instability, concentration heterogeneity and phase transitions in lysozyme solutions. AB - The ESR spin label method was used to estimate an average distance between spin labeled protein molecules at a concentration of 35mg/ml in solutions which contained 0 to 3M NaCl. Three NaCl concentration ranges, in which the distance between protein molecules varied markedly, were revealed: the distance increased in the range 0 to 0.15M NaCl, decreased in the range 0.3 M to 1.5 M NaCl and increased again in the range 1.5M to 3M NaCl. In lysozyme solutions, which contained 0.3 to 1.5M NaCl, solution heterogeneity was observed to increase gradually during 4 days because of the emergence of supramolecular organization in the form of clusters and aggregates. Viscous gel was formed immediately under salting-out conditions at 3M NaCl, and remained unchanged during 4 days. The results obtained are discussed on the basis of a theoretical and experimental phase diagram of lysozyme solution with an emphasis on analysis of continuous supercritical phase transitions which give rise to various types of dynamic and/or equilibrium protein clusters. PMID- 23085311 TI - Phenotype, genotype, and cellular physiology: need for clarity in characterization. PMID- 23085312 TI - MicroRNAs in HIV-associated nephropathy (HIVAN). AB - MicroRNAs (miRNAs) play a critical role in multiple biological and metabolic processes. Recent studies suggested that miRNAs are critical in the maintenance of glomerular homeostasis in both physiological and pathological states. However, the role of miRNAs in the pathogenesis of HIV-associated nephropathy (HIVAN) has not been studied. In the present study, we have used a microarray-based approach in combination with real-time PCR to profile the miRNA expression patterns in HIV 1 transgenic mice (Tg26). Our results showed that 13 miRNAs, which belong to 11 miRNA families, were downregulated in HIVAN when compared with control mice. These miRNAs were classified into 20 functional categories. In in vitro studies, we examined the expression of specific miRNAs in HIV-1 transduced human podocytes. Our results showed that HIV-1 downregulated miRNA expression, specifically of miR-200 and miR-33. These studies suggest that miRNAs contributed to the development of the proliferative phenotype of HIVAN. Further functional analysis of these miRNAs in HIVAN animal model will not only enhance understanding of the pathogenesis but would also lead to the development of therapeutic strategies for HIVAN patients. PMID- 23085313 TI - Effort-Based Reward (EBR) training enhances neurobiological efficiency in a problem-solving task: insights for depression therapies. AB - Effort-Based Reward (EBR) training strengthens associations between effort and rewards, leading to increased persistence in an unsolvable task when compared to control animals. EBR training involves placing animals in a test apparatus in which they are trained to dig in mounds to retrieve froot loop rewards (contingent group); these animals are compared to control animals that are given the same number of rewards, regardless of expended effort (noncontingent group). In the current study, the effect of EBR training on performance in a spatial task (Dry Land Maze) was explored to determine cognitive resilience during behavioral testing. Additionally, animals received BrdU injections during training to assess the role of neurogenesis on subsequent behavioral performance. Following the probe test, animals were perfused so that fos-immunoreactive (ir) cells in the hippocampus and cortical areas could be assessed. Behavioral results indicated that contingent rats were approximately 50% more efficient in locating and interacting with the previous baited well during the probe test than noncontingent animals, recruiting approximately 20% less c-fos ir-cells in the insular cortex, retrosplenial cortex, and dentate gyrus. A multidimensional scaling analysis grouped noncontingent animals together in a quadrant characterized by high latencies to find the previous baited well and higher ir cell activation in the aforementioned areas. Thus, our data support the hypothesis that the EBR training enhances both cognitive functioning and emotional regulation during challenging events. Considering the ongoing controversy about the efficacy of pharmacological interventions in treating depression, the EBR model provides a valuable alternative for the investigation of the neurobiology of mood disorders. PMID- 23085314 TI - Interleukin-1beta inhibits the differentiation of hippocampal neural precursor cells into serotonergic neurons. AB - Interleukin-1 beta (IL-1beta) is one of pro-inflammatory cytokines. Recent studies have shown that IL-1beta impairs hippocampal neurogenesis, mediates proliferation and differentiation of multipotent neural precursor cells (NPCs), and exerts effects of anti-proliferation, anti-neurogenesis, and pro-gliogenesis on embryonic hippocampal NPCs. The aim of this study was to examine the effect of IL-1beta on the differentiation of hippocampal NPCs into functional serotonergic neurons, which play important roles in the pathophysiology and treatment of depression. Hippocampal NPCs were prepared from the hippocampus of neonatal rats (within 24h after birth). After three passages and phenotyping, hippocampal NPCs were cultured in a differentiating medium with various concentrations (5, 10, and 20 ng/mL) of IL-1beta for 7 days. At the endpoint, the serotonergic differentiation of hippocampal NPCs in IL-1beta-treated cultures decreased in a dose-dependent manner and this effect was blocked by IL-1ra, an IL-1 receptor antagonist capable of blocking the effects of IL-1 by binding to the same receptor (IL-1R1) without triggering signaling; serotonin in the lysate of the differentiated hippocampal NPCs decreased in IL-1beta-treated cultures; and levels of Bcl-2 and phosphorylated extracellular-regulated kinase (pERK) were also lower in differentiated hippocampal NPCs with IL-1beta treatment. These results support the hypothesis that IL-1beta is an important factor in the stress associated neuropathology and psychopathology and has relevance to the treatment of depressive symptoms in patients with depression. PMID- 23085315 TI - [Oculocutaneous albinism 1B associated with a new mutation in the TYR gene]. PMID- 23085316 TI - [Diagnosis and management of iatrogenic pseudoaneurysm after percutaneous atrioseptostomy in a neonate]. PMID- 23085317 TI - [Ultrasound-guided suprapubic bladder aspiration increases the success of the technique in infants less than 4 months-old]. AB - INTRODUCTION: Suprapubic bladder aspiration (SBA) is a widely accepted technique used to collect uncontaminated urine samples from infants with suspected urinary tract infection (UTI). Ultrasound-based guidance improves the success rates. The standard measurements for a successful procedure, however, have been scarcely evaluated. OBJECTIVE: To assess the efficacy of ultrasound-guided SBA versus blind SBA, and to establish the bladder measurements associated with optimal results. PATIENTS AND METHOD: Ultrasound-guided SBA was performed in 50 infants<=4 months of age with suspected UTI, and the anteroposterior (APD) and transverse diameter of the bladder were determined using ultrasound equipment (Esaote MyLab(r) 25 Gold, and Hewlett Packard Sonos(r) 5500) with a 3.5MHz convex probe. The success rates and the total volumes of collected urine were compared to a control group of 50 patients of similar age and clinical characteristics, to whom conventional blind SBA was performed. RESULTS: The rate of successful ultrasound-guided SBA was 92.3% compared to 30.8% in the blind SBA group (P<.05). The collected urine volumes were 7.65+/-1.85ml and 6.1+/-2.13ml, respectively (P<.001). An APD>=2cm was associated with an optimal performance of the technique (97.8% success). No major complications were observed in either group. CONCLUSIONS: Ultrasound-guided SBA is significantly more successful than blind SBA in infants less than 4 months of age, with an APD>=2cm being optimal for conducting the procedure. PMID- 23085318 TI - [Neonatal cortical hyperostosis (Caffey disease)]. PMID- 23085319 TI - Exploiting genes and functional diversity of chlorogenic acid and luteolin biosyntheses in Lonicera japonica and their substitutes. AB - Chlorogenic acids (CGAs) and luteolin are active compounds in Lonicera japonica, a plant of high medicinal value in traditional Chinese medicine. This study provides a comprehensive overview of gene families involved in chlorogenic acid and luteolin biosynthesis in L. japonica, as well as its substitutes Lonicera hypoglauca and Lonicera macranthoides. The gene sequence feature and gene expression patterns in various tissues and buds of the species were characterized. Bioinformatics analysis revealed that 14 chlorogenic acid and luteolin biosynthesis-related genes were identified from the L. japonica transcriptome assembly. Phylogenetic analyses suggested that the function of individual gene could be differentiation and induce active compound diversity. Their orthologous genes were also recognized in L. hypoglauca and L. macranthoides genomic datasets, except for LHCHS1 and LMC4H2. The expression patterns of these genes are different in the tissues of L. japonica, L. hypoglauca and L. macranthoides. Results also showed that CGAs were controlled in the first step of biosynthesis, whereas both steps controlled luteolin in the bud of L. japonica. The expression of LJFNS2 exhibited positive correlation with luteolin levels in L. japonica. This study provides significant information for understanding the functional diversity of gene families involved in chlorogenic acid and the luteolin biosynthesis, active compound diversity of L. japonica and its substitutes, and the different usages of the three species. PMID- 23085320 TI - Global analysis of target genes of 21 members of the ZAD transcription factor family in Drosophila melanogaster. AB - The zinc-finger associated domain (ZAD) family is the largest transcription factor family in dipteran insects. Still, their functional significance is barely recognized in the literature due in part to their resistance to mutagenesis screens in genetic studies. Therefore, we employed in vitro techniques to identify the DNA-binding characteristics of several members of the Drosophila melanogaster ZAD family in an effort to study their target genes. In this comprehensive investigation, we constructed a panel of GST-Zinc finger (ZnF) array chimera from 21 selected ZAD proteins and used them to select binding sites from an oligonucleotide library by employing electrophoretic mobility shift assays (EMSA). Samples of the binding population were sequenced and used to derive DNA-binding consensus sequence for each member. These consensus sequences were tested for complex formation with their respective protein chimera and the specificity of binding ascertained by competition EMSA. Bioinformatics tools were used to identify potential genetic targets. The identified consensus sequences were distinct for each member and the putative genomic targets were clustered in the regulatory regions of specific genes. This appears to be consistent with a conservation of function between members and also suggests that the overlapping functions of ZAD proteins are the result of positive selection to maintain redundancy and not simply artifacts of recent expansion. Putative target genes suggest a major role of the ZAD family members in the regulation of several early developmental genes including homeobox transcription factors. PMID- 23085321 TI - Haplotype study of the CYP4A11 gene and coronary artery disease in Han and Uygur populations in China. AB - BACKGROUND: CYP4A11 converts arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE), which has a crucial role in the modulation of cardiovascular homeostasis. We assessed the association between the human CYP4A11 gene and coronary artery disease (CAD) in Han and Uygur populations in China. METHODS AND RESULTS: In the Han population, 361 CAD patients and 315 controls were genotyped for four single-nucleotide polymorphisms (SNPs) of the human CYP4A11 gene (rs9332978, rs4660980, rs3890011, rs1126742). In the Uygur population, 331 CAD patients and 182 controls were genotyped for the same four SNPs. Data were assessed via haplotype-based case-control studies. For the Han population, the significance of the recessive model of SNP3 (GG vs. CC+GC) between CAD patients and control subjects was retained after adjustment for EH, DM and smoking (for men, 95% CI: 1.173-3.013, P=0.009). The G-G-T haplotype in CAD was significantly higher than that in the control group (P=0.037). In the Uygur population, neither the distribution of genotypes and alleles for the four SNPs nor the distribution of haplotypes constructed with the same three SNPs showed a significant difference between CAD and control subjects. CONCLUSIONS: The GG genotype of rs3890011 and the G-G-T haplotype in the CYP4A11 gene could be a useful genetic marker of CAD in Han populations in China. PMID- 23085322 TI - Genetic control of infection-related development in Magnaporthe oryzae. AB - Diseases caused by various pathogenic fungi pose a serious threat to global food security. Despite their differences in life cycles, fungal pathogens use well conserved genetic mechanisms to regulate different developmental and infection processes. This review focuses on the key signaling pathways and recent advances in Magnaporthe oryzae, which is a model for studying fungal-plant interactions. In addition to the core components, a number of upstream genes and downstream targets of the cAMP-PKA and mitogen-activated protein (MAP) pathways have been identified. Recent advances in studies with cytoskeleton organization, effector biology, and ROS signaling in M. oryzae and future directions also are discussed. PMID- 23085323 TI - Dietary alpha-linolenic acid does not enhance accumulation of omega-3 long-chain polyunsaturated fatty acids in barramundi (Lates calcarifer). AB - This study examined the effects of substituting fish oil and fish meal with a blend of alpha-linolenic acid (ALA, 18:3 n-3) rich vegetable oils (14%, w/w) and defatted poultry meal (34%, w/w) in a formulated diet, on growth and tissue fatty acid profiles in barramundi fingerlings. Results indicated that on average, while the ALA levels of the barramundi liver and fillet increased with increasing dietary ALA, there was no corresponding increase in the levels of the omega-3 (n 3) long chain polyunsaturated fatty acid (LCPUFA). Compared to fish consuming a commercial feed, which contained fish meal and fish oil, fish on the ALA diets grew slower, had a lower feed intake and lower n-3 LCPUFA levels in the tissues. Hepatic mRNA expression of Delta6 desaturase (FADS2) and elongase (ELOVL5/2) was ~10 fold and ~3 fold higher, respectively, in all the ALA dietary groups, relative to those fed the commercial feed. However, the level of expression of the two genes was not different between fish fed differing ALA levels. These data demonstrate that increasing the ALA level of the diet is not an appropriate strategy for replacing marine sources of n-3 LCPUFA in barramundi. It was also noted, however, that within the different ALA dietary groups there was a large amount of variation between individual fish in their tissue DHA levels, suggesting a significant heterogeneity in their capacity for conversion of ALA and/or retention of n-3 LCPUFA. When dietary ALA intakes were greater than 0.8% en, tissue DHA levels were inversely related to ALA intake, suggesting that high intake of dietary ALA may inhibit DHA synthesis. PMID- 23085325 TI - [Pulmonary CT angiography in pulmonary embolism: beyond diagnosis]. PMID- 23085324 TI - Leptin and leptin receptor: analysis of a structure to function relationship in interaction and evolution from humans to fish. AB - Leptin is a circulating protein which regulates dietary intake through binding the leptin receptor. Numerous labs have used known structures and mutagenesis to study this binding process in common animal models (human, mouse and rat). Understanding this binding process in other vertebrate species will allow for a better understanding of leptin and leptin receptor function. The binding site between leptin and leptin receptor is highly conserved in mammals as confirmed through sequence alignments mapped onto structures of both leptin and leptin receptor. More variation in this interaction is found in lizard and frog sequences. Using our models, we show that the avian leptin sequences have far less variation in the binding site than does the leptin receptor. This analysis further suggests that avian leptins are artifactual. In fish, gene duplication events have led to the expression of multiple leptin proteins. These multiple leptin proteins have variation in the regions interacting with leptin receptor. In zebrafish and the Japanese rice fish, we propose that leptin A has a higher binding energy than does B. Differing binding energies are evidence of either divergent functions, different binding confirmations, or other protein partners of leptin B. PMID- 23085326 TI - Field evaluation of rapid diagnostic tests for malaria in Yaounde, Cameroon. AB - Rapid diagnostic tests (RDTs) are affordable, alternative diagnostic tools. The present study aimed to evaluate RDTs available in Cameroon and compare their characteristics to follow the parasitological response of patients for 28 days. Malaria diagnosis was assessed in 179 febrile patients using conventional microscopy as the reference method. Parascreen detects both Plasmodium falciparum specific histidine-rich protein 2 (Pf HRP-2) and Pan-specific plasmodial lactate dehydrogenase (pLDH) in all four human Plasmodium spp. Diaspot is based on the detection of Pf HRP-2. OptiMAL-IT (pLDH specific for P. falciparum and pLDH for all four human Plasmodium spp.) was assessed for comparison. The reliability of RDTs was evaluated by calculating the sensitivity, specificity, positive predictive value, negative predictive value, false-positive rate, false-negative rate, and likelihood ratio. The clinical outcome of 18 children treated with atovaquone-proguanil and followed for 28 days was evaluated using microscopy and RDTs. Of 179 samples, 133 (74.3%) were pure P. falciparum-positive smears, 4 (2.2%) pure P. malariae-positive smears, and 42 (23.5%) negative smears. Parascreen and Diaspot had high sensitivity (>92%) and positive predictive values (>94%). The specificities for Parascreen and Diaspot were 81.0% and 90.5%, respectively. The false-positive rates and the false-negative rates were 19.0% and 4.5% for Parascreen and 9.5% and 8.3% for Diaspot, respectively. Most false negatives occurred in samples with low parasitaemia (<500 asexual parasites/MUL). The performance of RDTs was better at higher parasitaemia (>500 asexual parasites/MUL). Four pure P. malariae were only detected by the pan-Plasmodium bands of Parascreen and OptiMAL-IT. In blood samples from patients treated and followed-up for 28 days, HRP2-based RDTs remained positive in most samples until Day 28. Despite negative smears, OptiMAL-IT remained positive in several patients until Day 7 but was negative in all patients from Day 14 onwards. RDTs can improve the management of febrile patients. The validity, ease of use, and cost of HRP2-based tests were comparable. However, one of the current weaknesses of the RDT-based strategy using the tests available in Cameroon is inadequate sensitivity for low parasitaemia. In some cases, RDT results may require correct interpretation based on clinical history, clinical examination, and microscopic diagnosis. PMID- 23085327 TI - Environmental epidemiology of intestinal schistosomiasis and genetic diversity of Schistosoma mansoni infections in snails at Bugoigo village, Lake Albert. AB - Intestinal schistosomiasis continues to be hyper-endemic in the fishing community of Bugoigo located on the eastern shore of Lake Albert, Uganda. Our study aimed to identify the factors that determine the local distribution and abundance of Biomphalaria, as well as infection(s) with Schistosoma mansoni inclusive of their genetic diversity. In addition, a DNA barcoding approach was taken to genotype schistosome cercariae, exploring the micro-epidemiology of infections. Over a 3 week period in June-July 2010, several hundred Biomphalaria spp. were collected, together with environmental information, from 10 selected sites, representative of both putative wave-exposed (n=5) and wave-sheltered shorelines (n=5). A Mann Whitney U-test and a generalized linear model were used to assess associations with snail abundance and parasite infections across the shoreline. Levels of local wave action were recorded over the 19-day period using digital accelerometers. The general absence of wave action on the sheltered shoreline likely helped to raise and focalize other environmental parameters, such as water conductivity by lack of mixing, that foster transmission of intestinal schistosomiasis. Over the study period, a total of 10 infected snails were encountered and a selection of schistosome cercariae from each infected snail was harvested for analysis by DNA barcoding. In total, 91 DNA barcodes were generated with 15 unique barcode types identified. Of these, 4 barcodes had been found previously in Lake Albert and (or) Victoria, the remaining 11 were newly encountered here and described. The distribution of DNA barcodes across infected snails and sampled locations revealed a complicated spatial sub-structuring. By shedding new light on the fine-scale patterning of infections, DNA barcoding has revealed a rather heterogeneous landscape of cercariae, likely inclusive of multi miracidial infections within the snail, which will in turn interplay with human water contact activities to shape the genetic diversity of worm populations within infected people. PMID- 23085328 TI - Outcomes after single lung transplantation in older patients with secondary pulmonary arterial hypertension. PMID- 23085329 TI - Fruit and vegetable intake and eating behaviors mediate the effect of a randomized text-message based weight loss program. AB - INTRODUCTION: We hypothesized that fruit/vegetable intake and eating behaviors mediate the relationship between experimental condition and weight loss in a randomized trial evaluating a text-message based weight loss program. METHODS: Overweight/obese individuals from San Diego, CA (N = 52 with complete data) were randomly assigned in 2007 into one of two groups for four months: 1) the intervention group that received 2-5 weight management text-messages p/day; 2) the usual-care comparison group. Three 24-hour recalls assessed fruit/vegetable intake change and the eating behavior inventory (EBI) measured change in eating behaviors. Regression path models tested intervention mediation. RESULTS: Direct effects of the intervention were found for change in body weight (b = -3.84, R(2) = 0.074), fruit/vegetable intake (b = 2.00, R(2) = 0.083), and EBI scores (b = 7.15, R(2) = 0.229) (ps < 0.05). The treatment group to weight change path was not statistically significant (b = -0.673, R(2) = 0.208) when fruit/vegetable intake change and EBI score change were specified as intervention mediators in the model. The total indirect effect was 3.17 lb indicating that the indirect paths explained 82.6% of the total effect on weight change. DISCUSSION: Fruit/vegetable intake and eating behaviors mediated the intervention's effect on weight change. The findings suggest that sending text-messages that promote healthy eating strategies resulted in moderate short-term weight loss. PMID- 23085330 TI - Solid dispersions for preparation of phototoxic supersaturated solutions for antimicrobial photodynamic therapy (aPDT): Studies on curcumin and curcuminoides L. AB - Curcumin is under investigation as a potential photosensitizer (PS) in antimicrobial photodynamic therapy (aPDT). The therapeutic potential of curcumin as a PS is limited by its low aqueous solubility, susceptibility to hydrolytic and photolytic degradation, and limited phototoxicity toward Gram negative (G-) bacteria. Supersaturated solutions of curcumin have demonstrated high phototoxicity toward several species of Gram positive (G+) bacteria as well as the G-Escherichia (E) coli. Thus, solid dispersions that can form supersaturated solutions of curcumin upon hydration may be beneficial in aPDT. In the present study, solid dispersions of curcumin have been prepared through lyophilization of concentrated solutions obtained from dissolution of hydroxypropyl-beta cyclodextrin (HPbetaCD)-curcumin co-precipitates. Hydroxypropyl methylcellulose (HPMC) was added to curcumin solutions prior to lyophilization. The resulting lyophilizates were porous, amorphous and hydrated and dissolved rapidly in contact with a model physiological salt solution. The detected drug load of the lyophilizates was in the range 0.5-1.0% (w/w) and was dependent on the selected ratio between HPbetaCD and curcumin in the co-precipitate. The lyophilizate with the highest drug load could easily be dissolved in aqueous medium to form curcumin solutions of relevant concentrations for aPDT (i.e., 10MUM). Selected solutions of the curcumin solid dispersions showed a pronounced decrease in curcumin concentration up to 90% after storage for 168h, which indicated that supersaturated curcumin solutions were initially formed upon dissolution of the lyophilizates. Both freshly prepared and 2days old solutions of one selected curcumin lyophilizate induced significant inactivation of E. coli (~1% bacterial survival) after exposure to a light dose of only 5J/cm(2). PMID- 23085331 TI - Effect of amorphization method on telmisartan solubility and the tableting process. AB - Telmisartan (TLM), a poorly water-soluble angiotensin II receptor antagonist in crystalline form, was transformed into the amorphous state by the melt quench technique, as well as a cryogenic grinding method, in order to improve its physiochemical properties. The chemical stability of TLM, that is, the tendency of the material to resist change or decomposition due to internal reaction, or due to the effects of air, heat, light, pressure, etc., during formation of the amorphous phase was assessed by monitoring high performance liquid chromatography. The existence of the amorphous state was confirmed by differential scanning calorimetry and X-ray powder diffraction. The glass transition occurred at T(g)=401K. In the next stage, the solubility of TLM in 0.1M HCl, phosphate buffer, pH=6.8, and water (25 degrees C and 37 degrees C) was determined. Both amorphous forms of TLM (vitrified and cryogrinded) had a higher solubility (MUg/ml) than their crystalline counterpart. An important and interesting problem of the study was to evaluate how the tableting process was affected by the choice of either a crystalline or an amorphous form of TLM. Eight different tablet formulations were evaluated using both the crystalline and the amorphous form of TLM. Measurements of the physical properties and dissolution tests of G4 formulations tablets with telmisartan in crystalline and amorphous form after different storage periods were also performed. PMID- 23085332 TI - Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel. AB - For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190+/-63.1ng/mLh for vs. 247+/-100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel. PMID- 23085333 TI - Two-photon fluorescence correlation spectroscopy as a tool for measuring molecular diffusion within human skin. AB - There is a need for tools enabling quantitative imaging of biological tissue for pharmaceutical applications. In this study, two-photon fluorescence microscopy (TPM) has been combined with fluorescence correlation spectroscopy (FCS), demonstrating proof-of-principle providing quantitative data of fluorophore concentration and diffusion in human skin. Measurements were performed on excised skin exposed to either rhodamine B (RB) or rhodamine B isothiocyanate (RBITC), chosen based on their similarity in fluorescence yield and molecular weight, but difference in chemical reactivity. The measurements were performed at tissue depths in the range 0 and 20 MUm, and the diffusion coefficients at skin depths 5 and 10 MUm were found to be significantly different (P<0.05). Overall median values for the diffusion coefficients were found to be 4.0*10(-13) m(2)/s and 2.0*10(-13) m(2)/s for RB and RBITC, respectively. These values correspond to the diffusion of a hard sphere with a volume eight times larger for RBITC compared to RB. This indicates that the RBITC have bound to biomolecules in the skin, and the measured signal is obtained from the RBITC-biomolecule complexes, demonstrating the potential of the TPM-FCS method to track molecular interactions in an intricate biological matrix such as human skin. PMID- 23085334 TI - Binding of Gq protein stabilizes the activated state of the muscarinic receptor type 1. AB - Activation of G protein coupled receptors (GPCRs) induces various cellular responses through interactions with G proteins. The key trigger of GPCR activation is agonist binding. It is reportedly known that the agonist-bound active conformation of the GPCRs, such as the muscarinic acetylcholine receptor type 1 (M(1)R), can be affected by the coupling of G proteins and by depolarization of the membrane potential. Here we aimed at investigating their effects on the structural rearrangements of the M(1)Rs between the active and quiescent states, using the fluorescence resonance energy transfer (FRET) technique. For this purpose, fluorescent M(1)R constructs that maintained intact activation of the Gq pathway and interaction with Gq were used. We captured the agonist-induced conformational changes of the M(1)R as the FRET decreases and found that the FRET decreases were enhanced by co-expression of the Gq subunits. In addition, co-expression of the Gq subunits decelerated the recovery of the declined FRET upon removal of the agonists, which was slower than the dissociation of the Gq subunits from the receptor. These results suggested that Gq binding stabilizes the agonist-induced activated conformation of the M(1)R. We also found that depolarization of the membrane potential slightly but significantly enhanced the agonist-induced FRET decrease, by accelerating the agonist-induced conformational changes. Thus, structural rearrangement analyses by FRET revealed that Gq coupling stabilizes the active conformation of the M(1)R and also suggested that depolarization accelerates the transition from quiescent to activation conformation. PMID- 23085335 TI - A critical review of the mechanism of action for the selective serotonin reuptake inhibitors: do these drugs possess anti-inflammatory properties and how relevant is this in the treatment of depression? AB - The selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed pharmacological treatment for depression. Since their introduction many have considered the primary mechanism by which the SSRIs produced therapeutic improvement in depression is their effect on monoaminergic signalling. In recent years, however, the credibility of the monoamine theory and the therapeutic efficacy of these compounds in the treatment of depression has been extensively criticized. In the current review the legitimacy of these criticisms is critically examined, in many instances the evidence base used to support these criticisms is found to be weak. Nevertheless, the apparent 'failure' of the monoamine theory has been of benefit in motivating research into alternative mechanisms through which the SSRIs may act. Given research demonstrating that depressive symptoms are intimately linked with disturbances in pro-inflammatory signalling, perhaps the most promising discovery has been the realisation that SSRIs posses significant anti-inflammatory properties. These recent findings are discussed and contextualised with respect to the neurogenic, neurotrophic and gluatamatergic effects that these drugs also possess. PMID- 23085336 TI - Creb is modulated in the mouse superior colliculus in developmental and experimentally-induced models of plasticity. AB - In the central nervous system long-term plastic processes need the activation of specific gene expression programs and the synthesis of new protein in order to occur. A transcription factor fundamental for several plasticity mechanisms in various CNS areas is the cAMP response element-binding protein, CREB. This factor is activated through phosphorylation at its Serine 133 residue by multiple signaling pathways. Little is known about CREB role in the superior colliculus, a midbrain area considered an experimentally useful model for the study of neuronal plasticity processes. In the present work we studied by Western blot analysis the modulation of CREB expression and activation in the mouse superior colliculus in three models of neuronal plasticity: (1) developmental plasticity; (2) lesion induced plasticity; (3) and fluoxetine-induced restored plasticity. We used an antibody that detects endogenous level of the total CREB protein (anti-TCREB) to identify possible modulations at CREB expression level, and a second antibody (anti-PCREB) that detects endogenous level of CREB only when it is phosphorylated at Ser133, to identify modifications of CREB activation state. The results showed that: (1) the expression and activation of CREB increase during the development of the superior colliculus in temporal correlation with the plastic process of refinement of retino-collicular projections; (2) the activation of CREB is induced by a monocular lesion performed during the critical period for plasticity in young animals but not when performed in less plastic juvenile mice; (3) the expression and activation of CREB increase in adult animals treated with fluoxetine, known to restore high levels of plasticity in adult animals. These results suggest that CREB transcription factor plays a fundamental role in plasticity processes also at the level of the mouse superior colliculus. PMID- 23085337 TI - Blocking GABA(C) receptors increases light responsiveness of retinal ganglion cells in a rat model of retinitis pigmentosa. AB - Previous studies in a mouse model of retinitis pigmentosa indicate that the GABAergic system in the retina may be overactive. GABA is known to act on GABA(C) receptors present on the axon terminals of bipolar cells to inhibit the release of excitatory neurotransmitter from these cells. The present study examined the effects of a GABA(C) receptor antagonist on the light-evoked responses of retinal ganglion cells (RGCs) in a rat model of retinitis pigmentosa. Extracellular recordings were made from RGCs in retinas isolated from P23H transgenic rats and non-dystrophic Sprague-Dawley (SD) rats. Spike activity of RGCs was measured in response to brief flashes of light over a range of light intensities. Intensity response curves were evaluated prior to and during bath application of the GABA(C) receptor antagonist TPMPA. I found that TPMPA consistently increased the sensitivity of P23H rat RGCs to light flashes. For ON-center RGCs (n = 21), the average increase in light sensitivity was 0.63 log unit. For OFF-center RGCs (n = 6), the average increase was 0.38 log unit. TPMPA increased the maximum peak response of ON-center RGCs by 22% and OFF-center RGCs by 11%. However, the increase in maximum peak response of OFF-center RGCs was not statistically significant. TPMPA had no significant effect on the dynamic operating range of either ON-center or OFF-center RGCs. Nine ON-center SD rat RGCs were also tested. In contrast to what was observed for P23H rat RGCs, TPMPA decreased the sensitivity of these RGCs to light flashes, on average by 0.20 log unit. In conclusion, GABA(C) receptors may be novel targets for therapeutic interventions aimed at increasing light responsiveness in patients with retinitis pigmentosa or other diseases involving degeneration of photoreceptors. PMID- 23085338 TI - A novel and effective human hepatocyte growth factor kringle 1 domain inhibits ocular neovascularization. AB - Neovascularization is the critical pathological process and the leading cause of blindness in a variety of clinical conditions. This angiogenesis process is still uncertain. Human hepatocyte growth factor 1 (HGFK1) is derived from the mature form of hepatocyte growth factor, which contains four kringle domains in its alpha-chain. This study aimed to investigate the antiangiogenic activity of HGFK1 using in vitro and in vivo assays. HGFK1 was added into the DMEM to test the proliferation and migration of human umbilical vascular endothelial cells (HUVEC), and it was intravitreously injected in laser photocoagulation-induced choroidal neovascularization (NV) model, oxygen-induced retinopathy model and rho/VEGF transgenic mice to test its antiangiogenic effect. The results showed that HGFK1 effectively inhibited VEGF-stimulated HUVEC proliferation and migration, and also had anti-NV activity in choroidal NV and retinal NV. It is suggested that HGFK1 has antiangiogenic activity in vitro and in vivo. It may lead to new potential drug discoveries and the development in addition to anti VEGF therapy in the future clinical anti-angiogenesis treatment. PMID- 23085339 TI - Rosmarinus officinalis polyphenols produce anti-depressant like effect through monoaminergic and cholinergic functions modulation. AB - Rosmarinus officinalis (R. officinalis), a culinary aromatic and medicinal plant, is very rich in polyphenols and flavonoids with high antioxidant properties. This plant was reported to exert multiple benefits for neuronal system and alleviate mood disorder. In our previous study, we demonstrated that R. officinalis and its active compounds, luteolin (Lut), carnosic acid (CA), and rosmarinic acid (RA), exhibited neurotrophic effects and improved cholinergic functions in PC12 cells in correlation with mitogen-activated protein kinase (MAPK), ERK1/2 signaling pathway. The current study was conducted to evaluate and understand the anti depressant effect of R. officinalis using tail suspension test (TST) in ICR mice and PC12 cells as in vitro neuronal model. Proteomics analysis of PC12 cells treated with R. officinalis polyphenols (ROP) Lut, CA, and RA revealed a significant upregulation of tyrosine hydroxylase (TH) and pyruvate carboxylase (PC) two major genes involved in dopaminergic, serotonergic and GABAergic pathway regulations. Moreover, ROP were demonstrated to protect neuronal cells against corticosterone-induced toxicity. These results were concordant with decreasing immobility time in TST and regulation of several neurotransmitters (dopamine, norepinephrine, serotonin and acetylcholine) and gene expression in mice brain like TH, PC and MAPK phosphatase (MKP-1). To the best of our knowledge this is the first evidence to contribute to the understanding of molecular mechanism behind the anti-depressant effect of R. officinalis and its major active compounds. PMID- 23085340 TI - A selective mGlu7 receptor antagonist MMPIP reversed antidepressant-like effects of AMN082 in rats. AB - Previous behavioural studies strongly indicated on potential antidepressant-like activity of mGlu7 positive allosteric modulator, AMN082 (N,N'-dibenzhydrylethane 1,2-diamine dihydrochloride). However, the mechanism of action of this drug was not clear. Some recent data, showing possible off-target activities of AMN082 and its metabolites casted doubt on the role of mGlu7 receptor activation in the antidepressant-like activity of this compound. In the present study we used a selective mGlu7 receptor antagonist, MMPIP (6-(4-methoxyphenyl)-5-methyl-3 pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one), to investigate the role of mGlu7 receptor blockade in the antidepressant action of AMN082 in the forced swim test (FST) in rats. We showed that MMPIP (10 mg/kg, i.p.) completely reversed AMN082 (8 mg/kg, i.p.)-induced behavioural effects, including decreased immobility time and increased swimming time, suggesting the crucial role of mGlu7 receptor activation in the antidepressant-like effects of AMN082 in the FST. On the other hand, our studies showed, that AMN082 (8 mg/kg, i.p.)-induced decrease in locomotor activity was not affected by MMPIP (10 mg/kg, i.p.), indicating on other, non-mGlu7 receptor-dependent mechanisms involved in changes in locomotor activity of rats after AMN082 administration. PMID- 23085341 TI - Individual differences in trait anxiety are associated with white matter tract integrity in fornix and uncinate fasciculus: preliminary evidence from a DTI based tractography study. AB - Trait anxiety, a personality dimension that measures an individual's higher disposition to anxiety, has been found to be associated with many functional consequences viz. increased distractibility, attentional bias in favor of threat related information etc. Similarly, volumetric studies have reported morphological changes viz. a decrease in the volume of left uncinate fasciculus (fiber connecting anterior temporal areas including the amygdala with prefrontal /orbitofrontal cortices) and an increase in the volume of the left amygdala and right hippocampus, to be associated with trait anxiety. The functional and morphological changes associated with trait anxiety might also be associated with the changes in the integrity of WM tracts in relation with the trait anxiety levels of the subjects. Therefore, in the present diffusion tensor tractography (DTT) study, we investigated the possible relationship between the diffusion tensor imaging (DTI) derived indices of a wide array of fiber tracts and the trait anxiety scores in our subject group. A positive correlation between trait anxiety scores and the mean fractional anisotropy (FA) value was obtained in fornix and left uncinate fasciculus. The study provides first account of a positive relation between sub-clinical anxiety levels of subjects and the FA of fornix thereby providing interesting insights into the biological foundation of sub-clinical anxiety. PMID- 23085342 TI - Sorption and retardation of strontium in saturated Chinese loess: experimental results and model analysis. AB - Geological burial and landfill have been widely practiced for disposal of nuclear wastes. However, radionuclides in the waste leachate from landfill facilities can contaminate soil and groundwater. Chinese loess is widely distributed in China and has been involved in large-scale disposal of nuclear wastes. Consequently, there has been an urgent need for understanding and predicting the fate and transport of contaminants in both vadose and saturated zones in the loess. In this paper, the distribution coefficient (K(d)) values of Strontium between a Chinese loess and groundwater were determined in batch experiments. The isotherm could be described with nearly linear isotherm model, which resulted in a K(d) value of 40.0 cm(3)/g. Based on this K(d) value, the retardation factor (R(d), the ratio of pore water velocity to solute transport velocity) value was calculated to be 112.6. As an alternative approach, the R(d) value was also determined through independent column experiments and transport modeling. Bromide (Br(-)) was used as a non-reactive tracer, and reagent SrCl(2) was used as a surrogate for the radioactive isotope ((99)Sr) in the experiment because they share the same adsorption and transportation characteristics. An equilibrium based model and a two-region non-equilibrium model were employed to interpret the column sorption data of Sr. The computer program, CXTFIT 2.1, was used to estimate the parameters by simulating the breakthrough and retention curves of Br and Sr, respectively. The resultant D (dispersion coefficient) value for Sr transport was much lower than that of Br(-), indicating the important effect of chemical non-equilibrium of Sr in the loess system. The observed Sr retention curves in the loess were best modeled by the two-site transport model. The R(d) value determined from batch equilibrium tests differed markedly from that determined from the column transport experiments, and the R(d) value decreased with increasing pore-water velocity. The relationship between D and pore water flow velocity (v) was determined as a D = 1.192v(1.26). The results from this work indicate that the strong flow and non-equilibrium effects on the transport parameters (R(d) and D) must be taken into account in Sr transport modeling. PMID- 23085343 TI - Leukemia specific loss of heterozygosity of MHC in a CLL patient: disease state impacts timing of confirmatory typing. AB - A 63 year old white male with refractory B-CLL presented for allogeneic HSCT evaluation; HLA typing was performed on PBL at time of WBC = 53K, ALC = 47K and revealed homozygosity at Class I locus and heterozygosity at Class II locus. Two siblings were full mismatches with the recipient and an unrelated search initiated. The patient was treated with Fludaribine and Rituxan complicated by aplastic anemia and bacteremia. Prior to transplant, confirmatory typing performed on PB revealed two full haplotypes at Class I and II. Sample identification error and the presence of third party lymphocyte engraftment as a result of prior red cell or granulocyte transfusion(s) were ruled out by STR analysis of 8 loci of all samples, T and B cells from cryopreserved PB at blast crisis were HLA typed independently. T cell typing yielded both complete haplotypes (genotype verified by offspring HLA typing); B cells typed for homozygous haplotype indicating loss of heterozygosity of MHC locus. Microarray based comparative genomic hybridization of tumor cells confirmed LOH at 6p. PMID- 23085344 TI - Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male. AB - We report a male with atypical severe combined immunodeficiency caused by heterozygous compound mutations c.256-257del and c.C1331T in RAG1 gene. The patient presents with recurrent bronchopneumonias with obstruction, chronic fibrosing alveolitis, complicated by respiratory failure, pulmonary hypertension and hepatosplenomegaly. He was diagnosed with agammaglobulinemia at the age of 9. His condition was complicated by granulomatous skin disease at the age of 12 despite regular IVIg substitution. Immunological presentation included profound hypogammaglobulinemia and absence of B cells. Under immunoglobulin substitution for 5 years patient has permanent lymphopenia, skewed phenotype of T cells and diminished number of recent thymic emigrants. PMID- 23085345 TI - Surface-associated GroEL facilitates the adhesion of Escherichia coli to macrophages through lectin-like oxidized low-density lipoprotein receptor-1. AB - The Escherichia coli homolog of GroEL, a 60 kDa heat shock protein (HSP), is a dominant protein produced not only in response to heat stress but also under in vitro growth condition. Beside its traditional cytoplasmic location, the surface exposures of GroEL have been observed in many pathogenic bacteria. To investigate the role of the surface-associated GroEL in the binding of E. coli to macrophages, we constructed a new strain of E. coli displaying GroEL on the outer membrane. We found that surface-associated GroEL increases the clearance ratio of E. coli by macrophages. It has been previously demonstrated that lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the receptor for Hsp60 from different species. Our present results showed that GroEL on E. coli was recognized by LOX-1 on macrophages, leading to the phagocytosis of pathogen by macrophages. In addition, surface-associated GroEL made mice more susceptible to E. coli-induced peritonitis. These findings add to the research that clarifies the factors mediating bacterial adherence to host cells. Our results suggest that GroEL is a novel therapeutic target for modulating the immune response in infectious and inflammatory conditions. PMID- 23085346 TI - Characterization of DNA topoisomerase I from Mycobacterium tuberculosis: DNA cleavage and religation properties and inhibition of its activity. AB - Type I DNA topoisomerases from bacteria catalyse relaxation of negatively supercoiled DNA in a Mg(2+) dependent manner. Although topoisomerases of distinct classes have been subjected for anti-cancer and anti-infective drug development, bacterial type I enzymes are way behind in this regard. Our studies with Mycobacterium smegmatis topoisomerase I (MstopoI) revealed several of its distinct properties compared to the well studied Escherichia coli topoisomerase I (EctopoI) suggesting the possibility of targeting the mycobacterial enzyme for inhibitor development. Here, we describe Mycobacterium tuberculosis topoisomerase I (MttopoI) and compare its properties with MstopoI and EctopoI. The enzyme cleaves DNA at preferred sites in a pattern similar to its ortholog from M. smegmatis. Oligonucleotides containing the specific recognition sequence inhibited the activity of the enzyme in a manner similar to that of MstopoI. Substitution of the acidic residues, D111 and E115 which are involved in Mg(2+) co-ordination, to alanines affected the DNA relaxation activity. Unlike the wild type enzyme, D111A was dependent on Mg(2+) for DNA cleavage and both the mutants were compromised in religation. The monoclonal antibody (mAb), 2F3G4, developed against MstopoI inhibited the relaxation activity of MttopoI. These studies affirm the characteristics of MttopoI to be similar to MstopoI and set a stage to target it for the development of specific small molecule inhibitors. PMID- 23085347 TI - Amelioration of uremic toxin indoxyl sulfate-induced endothelial cell dysfunction by Klotho protein. AB - Indoxyl sulfate (IS), a common kind of uremic toxin, is considered as a risk factor for aggravating endothelial function in CKD patients due to its oxidative activity. The anti-aging protein Klotho, which is produced by the kidneys and down-regulated in uremic conditions, has the ability to resist oxidative stress. Here, we carried out an in vitro study to investigate the deleterious effects of IS on endothelial cells and the protective role of Klotho protein. The cultured human umbilical vein endothelial cells (HUVECs) were incubated with IS in the presence or absence of Klotho protein. The release of reactive oxygen species (ROS) and the expression of monocyte chemoattractant protein-1 (MCP-1) were enhanced while the cell viability and production of nitric oxide (NO) were inhibited by IS in a concentration-dependent manner. Meanwhile, the phosphorylation of p38MAPK and the nuclear translocation of NF-kappaB were increased in HUVECs treated with IS. Pretreatment with Klotho protein resulted in remarkable increase of cell viability and decrease of ROS production in IS treated HUVECs. Like ROS scavenger, N-acetyl-l-cysteine (NAC), Klotho protein could inhibit the IS-induced activations of p38MAPK and NF-kappaB. Moreover, Klotho protein could also attenuate IS-induced reduction of NO production and up regulation of MCP-1 expression. These results suggest that IS can damage the functions of endothelial cells. Klotho protein has the ability to ameliorate the IS-induced endothelial dysfunction, which may be partly through inhibiting the ROS/p38MAPK and downstream NF-kappaB signaling pathways. PMID- 23085348 TI - Methyl group balance in brain and liver: role of choline on increased S-adenosyl methionine (SAM) demand by chronic arsenic exposure. AB - Arsenic toxicity has been related to its interference with one carbon metabolism, where a high demand of S-adenosylmethionine (SAM) for arsenic methylation as well as a failure of its regeneration would compromise the availability of methyl groups for diverse cellular functions. Since exposed animals show disturbances of methylated products such as methylated arginines, myelin and axon membranes, this work investigates whether alterations of SAM, choline and phosphatidylcholine (PC) in the brain of arsenic exposed rats are associated with myelin alterations and myelin basic protein (MBP) immunoreactivity. Also these metabolites, morphologic and biochemical markers of methyl group alterations were analyzed in the liver, the main site of arsenic methylation. In adult, life-long arsenic exposed rats through drinking water (3 ppm), no changes of SAM, choline and PC concentrations where found in the brain, but SAM and PC were severely decreased in liver accompanied by a significant increase of choline. These results suggest that choline plays an important role as methyl donor in arsenic exposure, which could underlie hepatic affections observed when arsenic exposure is combined with other environmental factors. Also, important myelin and nerve fiber alterations, accompanied by a 75% decrease of MBP immunoreactivity were not associated with a SAM deficit in the brain. PMID- 23085350 TI - Familial visceral myopathies: from symptom-based syndromes to actin-related diseases. PMID- 23085349 TI - Identifying safer anti-wear triaryl phosphate additives for jet engine lubricants. AB - Individuals aboard jet aircraft may be exposed to potentially toxic triaryl organophosphate anti-wear lubricant additives (TAPs) that are converted by cytochromes P450 into toxic metabolites. Consequences of exposure could be reduced by using less toxic TAPs. Our goal was to determine whether an in vitro assay for inhibition of butyrylcholinesterase (BChE) by bioactivated TAPs would be predictive of inhibition of serine active-site enzymes in vivo. The in vitro assay involved TAP bioactivation with liver microsomes and NADPH, followed by incubation with human BChE and measurement of BChE activity. Of 19 TAPs tested, tert-butylated isomers produced the least BChE inhibition. To determine the relevance of these results in vivo, mice were exposed to Durad 125 (D125; a commercial mixture of TAP esters) or to TAPs demonstrating low or no BChE inhibition when assayed in vitro. Inhibition of BChE by bioactivated TAPs in vitro correlated well with inhibition of other serine active-site enzymes in vivo, with the exception of brain acetylcholinesterase and neuropathy target esterase (NTE), which were not inhibited by any TAP tested following single exposures. A recombinant catalytic domain of NTE (rNEST) exhibited classical kinetic properties of NTE. The metabolite of tri-(o-cresyl) phosphate (ToCP), 2 (o-cresyl)-4H-1,3,2-benzodioxaphosphoran-2-one (CBDP), inhibited rNEST in vitro, but with an IC(50) value almost 6-times higher than for inhibition of BChE. Physiologically-relevant concentrations of the flavonoid naringenin dramatically reduced D125 bioconversion in vitro. The in vitro assay should provide a valuable tool for prescreening candidate TAP anti-wear additives, identifying safer additives and reducing the number of animals required for in vivo toxicity testing. PMID- 23085351 TI - An unusual cause of cholecystitis. PMID- 23085352 TI - Acute liver failure with lower extremity deep vein thrombosis. PMID- 23085353 TI - Epithelial and mesenchymal contribution to the niche: a safeguard for intestinal stem cell homeostasis. PMID- 23085354 TI - Hepatic failure during anabolic steroid therapy. PMID- 23085355 TI - Bile acid handling in cystic fibrosis: marked phenotypic differences between mouse models. PMID- 23085356 TI - Characterisation and tissue distribution of the PISCF allatostatin receptor in the red flour beetle, Tribolium castaneum. AB - The insect PISCF/allatostatins (ASTs) are pleiotropic peptides that are involved in the regulation of juvenile hormone biosynthesis, are myoinhibitory on the gut and the heart, and suppress feeding in various insects, but their roles in beetles are poorly understood. To provide further insight into the significance of PISCF/ASTs in beetles, the PISCF/AST receptor from Tribolium castaneum has been characterised and its tissue distribution determined. The biological activity of the T. castaneum PISCF/AST (Trica-AS) was also investigated. The Trica-AS receptor shows high sequence homology to other insect PISCF/AST receptors, which are related to the mammalian somatostatin/opioid receptors, a family of G protein-coupled receptors. The Trica-AS receptor was activated in a dose-dependent manner by both Trica-AS and T. castaneum allatostatin double C (Trica-ASTCC) as well as Manduca sexta-allatostatin (Manse-AS). Other allatoregulatory peptides (a FLG/AST, a MIP/AST and an allatotropin) and somatostatin(14) were inactive on this receptor. Receptor transcript levels in tissues, determined by qRT-PCR, were highest in the head and the gut, with variable amounts in the fat body and reproductive organs. There were measurable differences in receptor levels of the head, fat body and reproductive organs between males and females. There was also a widespread distribution of Trica-AS in various tissues of T. castaneum. The Trica-AS peptide precursor was most abundant in the head and there was a significant difference between levels in the heads and reproductive organs of males and females. Whole mount immunocytochemistry localised Trica-AS in the median and lateral neurosecretory cells of the brain, in the corpus cardiacum and throughout the ventral nerve cord. The peptide was also present in midgut neurosecretory cells, but no immunostaining was detected in the reproductive organs or Malpighian tubules. The widespread distribution of both Trica-AS and its receptor suggest this peptide may have multiple roles in beetles. However, Trica-AS had no effect on the spontaneous contractions of the gut or ovaries of T. castaneum but this peptide did stimulate the release of proteases from the anterior midgut of another beetle, Tenebrio molitor. The activation of the Trica-AS receptor by Trica-ASTCC implies a physiological role for this peptide in beetles, which remains to be identified. PMID- 23085357 TI - Expression and localization of glutamate-gated chloride channel variants in honeybee brain (Apis mellifera). AB - Due to its specificity to invertebrate species, glutamate-gated chloride channels (GluCls) are the target sites of antiparasitic agents and insecticides, e.g. ivermectin and fipronil, respectively. In nematodes and insects, the GluCls diversity is broadened by alternative splicing. GluCl subunits have been characterized according to their sensitivity to drugs, and to their anatomical localization. In the honeybee, the GluCl gene can encode different alpha subunits due to alternative splicing of exon 3. We examined mRNA expression in brain parts and we confirmed the existence of two GluCl variants with RT-PCR, Amel_GluCl A and Amel_GluCl B. Surprisingly, a mixed isoform not yet described in insect was obtained, we called it Amel_GluCl C. We determined precise immunolocalization of peptide sequence corresponding to Amel_GluCl A and Amel_GluCl B in the honeybee brain. Amel_GluCl A is mainly located in neuropils, whereas Amel_GluCl B is mostly expressed in cell bodies. Both proteins can also be co-localized. According to their anatomical localization, different GluCl variants might be involved in olfactory and visual modalities and in learning and memory. PMID- 23085359 TI - A subunit vaccine against hydropericardium syndrome using adenovirus penton capsid protein. AB - Hydropericardium syndrome (HPS) is a disease of poultry that is caused by fowl adenovirus-4. Inactivated liver homogenate from diseased birds is still the choice of vaccine in some countries which disseminates numerous pathogens along with inactivated virus. Moreover incomplete attenuation or inactivation, reversion to virulence and the oncogenic potential/genetic instability of the adenoviruses have prevented their use in routine vaccines. To address this problem an effort is made to develop a subunit vaccine. For this purpose penton base protein of HPS virus was expressed in Escherichia coli and used as subunit vaccine in broilers. Immunogenicity of the recombinant penton base protein and challenge protection test against pathogenic virus demonstrated the ability of recombinant penton base protein to confer (90%) protection. Results suggest that the recombinant penton base protein is a candidate for subunit vaccine against HPS. PMID- 23085358 TI - Cloning and functional characterization of inward-rectifying potassium (Kir) channels from Malpighian tubules of the mosquito Aedes aegypti. AB - Inward-rectifying K(+) (Kir) channels play critical physiological roles in a variety of vertebrate cells/tissues, including the regulation of membrane potential in nerve and muscle, and the transepithelial transport of ions in osmoregulatory epithelia, such as kidneys and gills. It remains to be determined whether Kir channels play similar physiological roles in insects. In the present study, we sought to 1) clone the cDNAs of Kir channel subunits expressed in the renal (Malpighian) tubules of the mosquito Aedes aegypti, and 2) characterize the electrophysiological properties of the cloned Kir subunits when expressed heterologously in oocytes of Xenopus laevis. Here, we reveal that three Kir subunits are expressed abundantly in Aedes Malpighian tubules (AeKir1, AeKir2B, and AeKir3); each of their full-length cDNAs was cloned. Heterologous expression of the AeKir1 or the AeKir2B subunits in Xenopus oocytes elicits inward rectifying K(+) currents that are blocked by barium. Relative to the AeKir2B expressing oocytes, the AeKir1-expressing oocytes 1) produce larger macroscopic currents, and 2) exhibit a modulation of their conductive properties by extracellular Na(+). Attempts to functionally characterize the AeKir3 subunit in Xenopus oocytes were unsuccessful. Lastly, we show that in isolated Aedes Malpighian tubules, the cation permeability sequence of the basolateral membrane of principal cells (Tl(+) > K(+) > Rb(+) > NH(4)(+)) is consistent with the presence of functional Kir channels. We conclude that in Aedes Malpighian tubules, Kir channels contribute to the majority of the barium-sensitive transepithelial transport of K(+). PMID- 23085360 TI - Consecutive CT in vivo lung imaging as quantitative parameter of influenza vaccine efficacy in the ferret model. AB - Preclinical vaccine efficacy studies are generally limited to certain read out parameters such as assessment of virus titers in swabs and organs, clinical signs, serum antibody titers, and pathological changes. These parameters are not always routinely applied and not always scheduled in a logical standardized way. We used computed tomography (CT) imaging as additional and novel read out parameter in a vaccine efficacy study by quantifying alterations in aerated lung volumes in ferrets challenged with the 2009 pandemic A/H1N1 influenza virus. Vaccination protected from marked variations in aerated lung volumes compared to naive controls. The vaccinated group showed a daily gradual mean reduction with a maximum of 7.8%, whereas the controls showed a maximum of 14.3% reduction. The pulmonary opacities evident on CT images were most pronounced in the placebo treated controls, and corresponded to significantly increased relative lung weights at necropsy. This study shows that consecutive in vivo CT imaging allows for a day to day read out of vaccine efficacy by quantification of altered aerated lung volumes. PMID- 23085361 TI - Prospects and challenges of using chicken cytokines in disease prevention. AB - Cytokines are soluble proteins secreted by a broad range of cell types that play pivotal roles in the regulation of inflammation and the immune response. Recent advances in avian genetics and immunology have explored the application of exogenous avian cytokines against infectious agents in poultry medicine. To use exogenous cytokines as novel therapeutics or as vaccine adjuvants in disease prevention, it is necessary to gain a comprehensive knowledge of their suitability as therapeutics, their direct effects on infection resistance, and the major barriers against their use. This review summarizes current knowledge on the functions and uses of chicken cytokines in disease prevention, the major obstacles hindering their application, and possible solutions that may circumvent these problems and ensure maximum efficiency. PMID- 23085362 TI - Vaccination in children with inborn errors of metabolism. AB - Inborn errors of metabolism (IEMs) are a large group of very heterogeneous diseases, and the impact of the available vaccines on children with IEMs may vary depending on the child's metabolic characteristics. The main aim of this review is to re-analyse the administration of vaccines to such children in the light of the most recent data. As a whole, these indicate that children with stable or slowly progressing IEMs can receive the recommended schedules of all of the recommended vaccinations. However, vaccines should be administered more cautiously to children with IEMs associated with a significant risk of morbidity and/or mortality with catabolic events: i.e. under strict medical supervision, and only when the children are clinically well and their metabolic condition is acceptably controlled. Furthermore, a number of IEMs have been associated with immune deficiency although, in most cases, the immunological abnormalities disappear or are significantly reduced when the metabolic defect is corrected. The response to vaccines is therefore unpredictable, but it is reasonable to think that it may be inadequate in children with the most severe immune defects. In addition to defective protection, vaccines administered to children with IEM and severe immunodeficiency can actually cause the disease they were meant to prevent. This explains why experts suggest that vaccines based on live attenuated viruses should not be given to such children, although all of the other vaccines can be administered without limitation regardless of the type of immune defect. Nevertheless, only specific multicentre studies will make it possible to say when and how to use vaccines in children with different types of IEM in order to protect them from vaccine-preventable diseases without any risk of worsening their metabolic situation. PMID- 23085364 TI - Effectiveness of an influenza A (H1N1) 2009 monovalent vaccine among Japanese pregnant women: a prospective observational study assessing antibody efficacy. AB - In order to estimate the effectiveness of an influenza A (H1N1) 2009 monovalent vaccine among pregnant women, we prospectively observed 135 Japanese pregnant women who received an influenza A (H1N1) 2009 monovalent vaccine during November 2009. We calculated an index of "antibody efficacy", in which the medical visits for respiratory illnesses were compared between those with and without post vaccination hemagglutination inhibition (HI) titer >=1:40. The product of antibody efficacy and achievement rate is theoretically equivalent to the vaccine effectiveness. Among all subjects, an inverse but non-significant relationship during the epidemic period was observed between post-vaccination HI titer >=1:40 and medical visits for respiratory illnesses. After stratification by trimester at recruitment, a significant inverse association during the epidemic period was found among subjects in the first or second trimester (antibody efficacy: 91%, vaccine effectiveness: 79%). The influenza A (H1N1) 2009 monovalent vaccine administered in the first or second trimester reduced medical visits for respiratory illnesses among Japanese pregnant women. PMID- 23085363 TI - Immune response to vaccine adjuvants during the first year of life. AB - Subunit vaccine formulations often include adjuvants that primarily stimulate innate immune cells. While young infants represent the major target population for vaccination, effective immunization in this age group remains a challenge. Many parameters of innate immune responses differ quantitatively and qualitatively from newborns to infants and adults, revealing a highly regulated developmental program. Herein, we discuss the potential implications of innate immune ontogeny for the activity of adjuvants contained in licensed infant vaccines, as well as future directions for rational design of adjuvanted vaccines for this age group. PMID- 23085365 TI - Reduced antibody responses against Plasmodium falciparum vaccine candidate antigens in the presence of Trichuris trichiura. AB - BACKGROUND: Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we assessed the influence of helminth infection on vaccine-induced immune responses in a phase I clinical trial of the malaria vaccine candidate GMZ2. METHODS: Twenty Gabonese preschool age children were vaccinated with GMZ2, a blood stage malaria vaccine candidate. Humoral immune response against the vaccine antigens and parasitological status were assessed. Vaccine-specific antibody concentrations and memory B-cell numbers were compared in worm infected and non-infected participants. RESULTS: Antibody response to GMZ2 was 3.4-fold (95% confidence interval: 1.6, 7.4) higher in Trichuris trichiura negative subjects compared to positive participants, whereas immunoglobulin subclass distribution was similar. Memory B-cell response was moderately increased in T. trichiura negative individuals, although the difference was not significant. CONCLUSIONS: Future malaria vaccine development programs need to account for worm-mediated hyporesponsiveness of immune reactions. PMID- 23085367 TI - Xanthohumol induces phase II enzymes via Nrf2 in human hepatocytes in vitro. AB - The aim of this study was to investigate whether xanthohumol may exert chemoprotective activity through the modulation of the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway in immortalized normal THLE-2 hepatocytes and a hepatocellular carcinoma HepG2 cell line. Cells were incubated in the presence of xanthohumol and the activation of Nrf2 and expression of genes controlled by this transcription factor were evaluated. Additionally, p53 level was assessed. Xanthohumol increased the expression and led to the activation of Nrf2 in both cell lines. However, in contrast to normal cells the expression of genes controlled by this transcription factor was not affected in HepG2 cells, except for GSTA and GSTP. Xanthohumol, beside the induction of GSTs and HO-1, significantly elevated NQO1 expression in concert with p53 level in normal hepatocytes. The activation of Nrf2 pathway and subsequently phase II enzymes in concert with p53 induction in normal hepatocytes may account for the molecular mechanism of the chemopreventive activity of xanthohumol. On the other hand its cytotoxicity towards HCC cells shown in this study indicates that it may also be considered as potentially chemotherapeutic. PMID- 23085366 TI - Humoral and cellular immune response generated by different vaccine programs before and after Salmonella Enteritidis challenge in chickens. AB - The poultry industry has a high demand for Salmonella vaccines in order to generate safer Salmonella-free food for consumers around the world. Vaccination against S. Enteritidis (SE) is vastly undertaken in many countries, although the criteria for the use of live vaccine (LV) or killed vaccine (KV) should also depend on the immune mechanisms triggered by each. In this study, a commercial bacterin (KV) and an attenuated SG mutant (LV) were used in four different vaccine programs (LV; LV+LV; KV; LV+KV). At 1 day before (dbi) and 1, 6 and 9 days after SE challenge (dpi), humoral (IgM, IgG and secretory IgA) and cellular (CD8(+) T cells) immune responses were evaluated along with the production of IL 10, IL-12 and IFN-gamma. Although after challenge, all birds from each group had an influx of CD8(+) T cells, birds which received KV had lower levels of these cells in organs and significantly higher levels of immunoglobulins. The expression of the cytokines was up-regulated in all groups post-vaccination, although, after challenge, cytokine expression decreased in the vaccinated groups, and increased in the unvaccinated group A. IL-10 levels were significantly higher at 1 day post-infection in the group that received KV, which may be involved in the weak cellular immune response observed within this group. In caecal tonsils, IFN-gamma expression at 1 dbi was higher in birds which received two vaccine doses, and after challenge, the population of CD8(+) T cells constantly increased in birds that were only vaccinated with the LV. This study demonstrated that the development of a mature immune response by CD8(+) T cells, provided by the use of the LV, had better efficacy in comparison to the high antibody levels in the serum stimulated by the KV. However, high secretory IgA levels in the intestinal lumen associated with influx CD8(+) T cells may be indicative of protection as noticed in group E (LV+KV). PMID- 23085368 TI - In vivo-in vitro comparison of acute respiratory tract toxicity using human 3D airway epithelial models and human A549 and murine 3T3 monolayer cell systems. AB - The usefulness of in vitro systems to predict acute inhalation toxicity was investigated. Nineteen substances were tested in three-dimensional human airway epithelial models, EpiAirwayTM and MucilAirTM, and in A549 and 3T3 monolayer cell cultures. IC(50) values were compared to rat four-hour LC(50) values classified according to EPA and GHS hazard categories. Best results were achieved with a prediction model distinguishing toxic from non-toxic substances, with satisfactory specificities and sensitivities. Using a self-made four-level prediction model to classify substances into four in vitro hazard categories, in vivo-in vitro concordance was mediocre, but could be improved by excluding substances causing pulmonary edema and emphysema in vivo. None of the test systems was outstanding, and there was no evidence that tissue or monolayer systems using respiratory tract cells provide an added value. However, the test systems only reflected bronchiole epithelia and alveolar cells and investigated cytotoxicity. Effects occurring in other cells by other mechanisms could not be recognised. Further work should optimise test protocols and expand the set of substances tested to define applicability domains. In vivo respiratory toxicity data for in vitro comparisons should distinguish different modes of action, and their relevance for human health effects should be ensured. PMID- 23085369 TI - Introducing 'Forensic cultures'. PMID- 23085371 TI - Repeated dose (14 days) rat intramuscular toxicology study of Her1 vaccine. AB - Our goal was to assess the toxicity of two strengths (200 and 400 MUg) of HER1 cancer vaccine (Center of Molecular Immunology, Cuba), presented in two different formulations, in Sprague Dawley rats after repeated intramuscular administration (14 days). Four groups (5 animals/sex) were established: Control, Placebo (adjuvant), and two Treated groups receiving a dose representing ten times of human total dose (10*), 28.6 and 57.1 MUg/kg. Clinical observations, body weight and rectal temperature were measured during the study. Clinical pathology analysis was performed, besides gross necropsy and histological examination of tissues on animals at the end of the assay. The assay ended with a 100% survival. Injection site damage, with the presence of cysts and granulomas, was observed in adjuvant and vaccine treated groups, with most severe cases predominating at higher strength. Administration of Placebo and Her1 vaccine induced increase in polymorphonuclear cells, with relative lymphopenia conditioned by primary neutrophilia. In summary, results suggest that Her1 immunization was capable of inducing an inflammatory effect at the injection site, leading to systemic alterations, more significant at higher strength (400 MUg, 57.1 MUg/kg), probably affected by the immunizations' schedule used. The vaccine was shown to be well tolerated without any obvious signs of systemic toxicity, with findings largely attributable to the adjuvant used. PMID- 23085370 TI - The anthelmintic effect of plumbagin on Schistosoma mansoni. AB - The anthelmintic effects of plumbagin (PB, 5-hydroxy-2-methyl-1,4-naphthoquinone) and praziquantel (PZQ) against adult Schistosoma mansoni in vitro were compared by estimating the relative motility (RM) values, survival indices (SI) and alterations of the tegument of flukes incubated in M-199 medium containing 1, 10 and 100 MUg/ml of the drugs, at 1, 3, 6, 12 and 24 h. For the parasites incubated in 10 MUg/ml, the RM values of the PB-treated group decreased at a more rapid rate than the PZQ-treated group. When incubated in 100 MUg/ml all PB-treated flukes appeared immobile from 1 to 24 h when 91-100% died, while in the PZQ treated group RM values were higher than that of PB and most flukes were still alive at 1-12 h, and at 24 h only 21% of flukes were killed. Furthermore, male parasites were more affected by PZQ than females as their RM values were significantly less than that of females at all doses. While in PB treatment, males and females showed less difference in response to the drug as their RM values were closer than those treated with PZQ. When observed by SEM, the tegument of untreated S. mansoni displayed no alteration, while in PB treated parasites it exhibited swelling, blebbing, loss of spines, disruption of tubercles and ridges, leading to erosion and lesion, exposure of the basal lamina, and sloughing of the tegument. PZQ induced similar tegumental changes as those observed in PB treatment but at longer incubation time and higher doses. These data indicated that PB had more anthelmintic effect on both sexes of adult S. mansoni than PZQ. PMID- 23085372 TI - Interaction analysis identifies semenogelin I fragments as new binding partners of PIP in human seminal plasma. AB - Identification of protein-protein interactions is vital for complete understanding of a biological process and for functional characterization of a protein in related biochemical pathways. In this study, we performed analysis of prolactin inducible protein (PIP) interactions in human seminal plasma. PIP and its interacting partners were co-immunoprecipitated, analyzed by SDS-PAGE and identified by MALDI-TOF mass spectrometry. Three major interacting partners were identified, viz. human serum albumin, zinc-alpha-2 glycoprotein and semenogelin I fragments. This is the first report of interaction between PIP and semenogelin I fragments in human seminal plasma or elsewhere with a suggestive role in reproductive physiology which might be helpful for spermatozoa to acquire their motility. PMID- 23085374 TI - Lyophilised wafers as vehicles for the topical release of chlorhexidine digluconate--release kinetics and efficacy against Pseudomonas aeruginosa. AB - There is a requirement to deliver accurate amounts of broad spectrum antimicrobial compounds locally to exuding wounds. Varying amounts of exudate complicates this process by limiting the residence and therefore efficacy of active substances. Minimum bactericidal concentrations (MBC) of antimicrobials are necessary to suppress infection and lessen the chances of resistant strains of potentially pathogenic bacteria from prevailing. Polysaccharide wafers can adhere to exudating wound beds, absorbing fluids and forming highly viscous gels that remain in situ for prolonged periods of time to release sustained amounts of antimicrobial. In this study, five different formulations were produced containing the antimicrobial, chlorhexidine digluconate (CHD). Absorption of simulated wound fluid, resultant rheological properties of gels and efficacy against plated cultures of Pseudomonas aeruginosa were measured and compared. CHD reduced the 'water uptake' of wafers by 11-50% (w/w) and decreased the rheological consistency of non-SA containing gels by 10-65%. Release studies indicated that karaya wafers gave the highest sustained release of CHD, >60 MUg/mL in 24 h, well in excess of the MBC for P. aeruginosa. Release kinetics indicated an anomalous diffusion mechanism according to Korsmeyer-Peppas, with diffusion exponents varying from 0.31 to 0.41 for most wafers except xanthan (0.65). PMID- 23085375 TI - Temporal orienting of attention is interfered by concurrent working memory updating. AB - A previous dual-task study (Capizzi, Sanabria, & Correa, 2012) showed that temporal orienting of attention was disrupted by performing a concurrent working memory task, while sequential effects were preserved. Here, we recorded event related potentials (ERPs) during single- and dual-task performance to investigate how this behavioural dissociation would be expressed in neural activity measures. The single-task condition required participants to respond to a visual target stimulus that could be anticipated on the basis of a highly predictive temporal cue. The dual-task condition introduced a concurrent working memory task, in which colour information had to be updated on every trial. The behavioural results replicated our previous findings of impaired temporal orienting, but preserved sequential effects, under dual-task relative to single-task conditions. The ERPs results showed that temporal orienting and sequential effects both modulated the cue-locked preparatory contingent negative variation (CNV) and the target-locked N2 amplitude and P3 latency under single-task, but not under dual task conditions. In contrast to temporal orienting, sequential effects were also observed at the early target-locked P1 and N1 potentials. Crucially, only the P1 modulation survived dual-task interference. These findings provide novel electrophysiological evidence that performance of a concurrent working memory task may interfere in a selective way with neural activity specifically linked to temporal orienting of attention. PMID- 23085376 TI - Development and evaluation of the activities measure for upper limb amputees. AB - OBJECTIVES: (1) To develop a measure of activities for adults with upper limb amputation: the Activities Measure for Upper Limb Amputees (AM-ULA); and (2) to conduct initial psychometric evaluation of the measure. DESIGN: This was a cohort study where the prototype measure was administered twice within 1 week. Tests were videotaped and graded by 2 independent raters. Interrater reliability, test retest reliability, internal consistency, and minimal detectable change were estimated. Known group validity was examined using analyses of variance comparing scores of transradial, transhumeral, and shoulder level amputees. Convergent validity was examined by correlating AM-ULA scores with dexterity tests and self reported function. SETTING: Hospital outpatient. PARTICIPANTS: Subjects (N=52) with upper limb amputation. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Not applicable. RESULTS: Intraclass correlation coefficients (ICCs) for test retest reliability were .88 to .91. ICCs for interrater reliability were .84 to .89. Cronbach alphas were .89 to .91. The minimal detectable change at the 90% confidence interval was 3.7 points. Subjects with more distal levels of limb loss had better scores than those with more proximal levels (P<.01). The AM-ULA was moderately correlated with most dexterity tests and self-reported function. CONCLUSIONS: The AM-ULA is a new measure of activity performance for adults with upper limb amputation that considers task completion, speed, movement quality, skillfulness of prosthetic use, and independence in its rating system. It has good interrater reliability, test-retest reliability, and demonstrated known group validity. PMID- 23085377 TI - Normalized knee-extension strength or leg-press power after fast-track total knee arthroplasty: which measure is most closely associated with performance-based and self-reported function? AB - OBJECTIVE: To investigate which of the 2 muscle-impairment measures for the operated leg, normalized knee extension strength or leg press power, was most closely associated with performance-based and self-reported measures of function shortly after total knee arthroplasty (TKA). DESIGN: Cross-sectional, exploratory study. SETTING: Laboratory at a regional hospital. PARTICIPANTS: Individuals (N=39) with an average age +/- SD of 65.5+/-10.3 years, who all had unilateral TKA 28 days prior. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The patients performed maximal isometric knee extensions and dynamic leg presses to determine their body-mass normalized knee extension strength and leg press power, respectively. The 10-meter fast speed walking- and 30-second chair stand tests were used to determine performance-based function, while the Western Ontario and McMaster Universities Osteoarthritis Index and Oxford Knee Scores were used to determine self-reported function. RESULTS: Normalized leg press power was more closely associated with both performance-based (r=.82, P<.001) and self-reported (r=.48, P=.002) measures of function compared with normalized knee extension strength (r=.51, P=.001 and r=.39, P=.015, respectively). CONCLUSIONS: Normalized leg press power was more closely associated with both performance-based and self reported function early after TKA than normalized knee extension strength. It may be explained by the fact that performance-based measures of function are typically closed kinetic chain tasks, such as walking or rising from a chair, and self-reported measures of function typically include questions that address perceived difficulty with performing these same tasks. PMID- 23085373 TI - Protein tyrosine kinase regulation by ubiquitination: critical roles of Cbl family ubiquitin ligases. AB - Protein tyrosine kinases (PTKs) coordinate a broad spectrum of cellular responses to extracellular stimuli and cell-cell interactions during development, tissue homeostasis, and responses to environmental challenges. Thus, an understanding of the regulatory mechanisms that ensure physiological PTK function and potential aberrations of these regulatory processes during diseases such as cancer are of broad interest in biology and medicine. Aside from the expected role of phospho tyrosine phosphatases, recent studies have revealed a critical role of covalent modification of activated PTKs with ubiquitin as a critical mechanism of their negative regulation. Members of the Cbl protein family (Cbl, Cbl-b and Cbl-c in mammals) have emerged as dominant "activated PTK-selective" ubiquitin ligases. Structural, biochemical and cell biological studies have established that Cbl protein-dependent ubiquitination targets activated PTKs for degradation either by facilitating their endocytic sorting into lysosomes or by promoting their proteasomal degradation. This mechanism also targets PTK signaling intermediates that become associated with Cbl proteins in a PTK activation-dependent manner. Cellular and animal studies have established that the relatively broadly expressed mammalian Cbl family members Cbl and Cbl-b play key physiological roles, including their critical functions to prevent the transition of normal immune responses into autoimmune disease and as tumor suppressors; the latter function has received validation from human studies linking mutations in Cbl to human leukemia. These newer insights together with embryonic lethality seen in mice with a combined deletion of Cbl and Cbl-b genes suggest an unappreciated role of the Cbl family proteins, and by implication the ubiquitin-dependent control of activated PTKs, in stem/progenitor cell maintenance. Future studies of existing and emerging animal models and their various cell lineages should help test the broader implications of the evolutionarily-conserved Cbl family protein mediated, ubiquitin-dependent, negative regulation of activated PTKs in physiology and disease. PMID- 23085378 TI - Testosterone protects female embryonic heart H9c2 cells against severe metabolic stress by activating estrogen receptors and up-regulating IES SUR2B. AB - A recent clinical study demonstrated that a testosterone supplementation improves functional capacity in elderly female patients suffering from heart failure. These findings prompted us to consider possible mechanisms of testosterone induced cardioprotection in females. To address this question we have used a pure female population of rat heart embryonic H9c2 cells. Pre-treatment of cells with testosterone for 24h significantly increased survival of H9c2 cells exposed to 2,4-dinitrophenol (DNP), an inhibitor of oxidative phosphorylation. These cells expressed low level of androgen receptors and the effect of testosterone was not modified by hydroxyflutamide, an antagonist of androgen receptor. In contrast, cyclohexamide, an inhibitor of protein biosynthesis, and tamoxifene, a partial agonist of estrogen receptors, abolished cardioprotection afforded by testosterone. In addition, finasteride, an inhibitor of 5alpha-reductase, and anastrazole, an inhibitor of alpha-aromatase, also blocked testosterone-induced cytoprotection. Real time RT-PCR revealed that testosterone did not regulate the expression of nine subunits and accessory proteins of sarcolemmal ATP-sensitive K(+) (K(ATP)) channels. On the other hand, testosterone, as well as 17beta estradiol, up-regulated a putative mitochondrial K(ATP) channel subunit, mitochondrial sulfonylurea receptor 2B intraexonics splice variant (IES SUR2B), without affecting expression of IES SUR2A. Tamoxifene inhibited testosterone induced up-regulation of IES SUR2B without affecting IES SUR2A. In conclusion, this study has shown that testosterone protect female embryonic heart H9c2 cells against severe metabolic stress by its conversion into metabolites that activate estrogen receptors and up-regulate IES SUR2B. PMID- 23085379 TI - Comparative analysis of semaphorin 3A in soleus and EDL muscle satellite cells in vitro toward understanding its role in modulating myogenin expression. AB - Resident myogenic stem cells, satellite cells, up-regulate a secreted multi functional modulator, semaphorin 3A (Sema3A), exclusively at the early differentiation phase in response to muscle-crush injury and treatment with hepatocyte growth factor (HGF) or basic fibroblast growth factor (FGF2). Here, we add evidence that the Sema3A expression and secretion induced by the growth factors is significantly higher in primary cultures from adult rat soleus than from the fast-twitch extensor digitorum longus (EDL) muscle. The higher Sema3A response, revealed by quantitative PCR and Western blotting of cell lysates and conditioned media, may account for the higher myogenin expression of soleus muscle satellite cells early in differentiation since addition of recombinant Sema3A stimulates myogenin expression in cultures. These experiments also showed that mRNA expression of plexin A2, which together with neuropilins, constitutes Sema3A composite-receptors, was higher in satellite cells from soleus than EDL with no difference in plexin A1 and A3 and neuropilin-1 and 2 levels. These comparative studies, therefore, highlight a possible Sema3A-plexin A2-myogenin signaling axis that may ensure promoting early differentiation by soleus muscle satellite cells. PMID- 23085380 TI - Implementation of liquid chromatography/mass spectrometry into the clinical laboratory. AB - BACKGROUND: For certain clinical chemistry and toxicology analytes, liquid chromatography (LC) coupled with tandem mass spectrometry (MS/MS) offers significant advantages over traditional testing by immunoassay. METHODS: Published reports comparing the performance of immunoassays against LC-MS/MS were reviewed. The tested analytes include testosterone, estradiol, thyroid hormones, vitamin D, immunosuppressants, steroids for newborn screening programs, and clinical and forensic toxicology. RESULTS: While immunoassays are widely used in the clinical laboratory, the analytical sensitivity and specificity are inferior for many of the analytes tested in routine clinical laboratories. Moreover, LC MS/MS can be multiplexed for high testing throughput and multiple analyte detection. The disadvantages of LC-MS/MS include the absence of Food and Drug Administration (FDA) and Conformite Europeenne (CE) Mark approved tests, the high cost of analytical instrumentation, and the technical expertise needed to operate and maintain analyzers. CONCLUSIONS: The implementation of LC-MS/MS will increase in the next few years as this technology continues to improve and the advantages become more well known. PMID- 23085381 TI - What have we learnt about high-density lipoprotein cholesterol measurements during 32 years? Experiences in Finland 1980-2012. AB - BACKGROUND: High-density lipoprotein cholesterol (HDL-C) is important in risk assessment for cardiovascular disease or metabolic syndrome; however, different direct HDL-C assays may lead to erroneous risk estimates and potentially misclassify people. METHODS: Data for 30-year HDL-C trends in Finland were obtained from the national FINRISK surveys during 1982-2012 (n=45766) taking into account biases from three external quality assessment programs (EQA). We also compared two different direct HDL-C and turbidimetric apolipoprotein A-I methods using 413 fresh serum samples. RESULTS: HDL-C concentrations in the Finnish population were on average 1.33 (+/-0.04) mmol/l for men and 1.62 (+/-0.05) mmol/l for women after bias-correction. Positive HDL-C trends were observed for both sexes with original data, but trends disappeared after bias-correction. Comparison of two direct HDL-C methods demonstrated concentration-dependent difference. When HDL-C concentrations were <1.0 mmol/l, the mean bias was -12.0% (95% CI -13.5 to -10.0) whereas HDL-C concentrations >1.55 mmol/l showed mean bias of 9.0% (95% CI 7.0-10.5). CONCLUSIONS: Accurate reporting of HDL-C concentrations at the population level requires proper and regular attendance to reliable EQA programs. We found evidence for a concentration-dependent difference between some direct HDL-C methods, which may cause misclassification of people in cardiovascular risk assessment. PMID- 23085382 TI - What is behind the non-antibiotic properties of minocycline? AB - Minocycline is a second-generation, semi-synthetic tetracycline that has been in use in therapy for over 30 years for its antibiotic properties against both Gram positive and Gram-negative bacteria. It displays antibiotic activity due to its ability to bind to the 30S ribosomal subunit of bacteria and thus inhibit protein synthesis. More recently, it has been described to exert a variety of biological actions beyond its antimicrobial activity, including anti-inflammatory and anti apoptotic activities, inhibition of proteolysis, as well as suppression of angiogenesis and tumor metastasis, which have been confirmed in different experimental models of non-infectious diseases. There are also many studies that have focused on the mechanisms involved in these non-antibiotic properties of minocycline, including anti-oxidant activity, inhibition of several enzyme activities, inhibition of apoptosis and regulation of immune cell activation and proliferation. This review summarizes the current findings in this topic, mainly focusing on the mechanisms underlying the immunomodulatory and anti-inflammatory activities of minocycline. PMID- 23085383 TI - Giant cell tumor of the tendon sheath in the foot and ankle: case series and review of the literature. AB - Giant cell tumor of tendon sheath (GCT-TS) in the foot and ankle has been reported as rare. The purpose of the present study was to describe 20 cases of GCT-TS in the foot and ankle treated in the orthopedic department of Huashan Hospital. From January 2007 to January 2012, a retrospective review was performed of 20 cases of GCT-TS in the foot and ankle, all of which were treated by local excision, including both arthroscopy and local excision. The follow-up of all cases was 3 months to 5 years. Of the 20 patients, 14 were female and 6 were male, with a mean age of 38.7 (range 15 to 59) years. Seventeen presented with a painless, solitary, well-defined soft tissue mass with good or poor mobility. Three had discomfort on weightbearing, because the mass was on the plantar aspect of the foot. One patient had neurologic symptoms. A correct preoperative diagnosis was made in only 5 cases. Magnetic resonance imaging proved to be the most useful noninvasive preoperative investigation, because GCT-TS has a characteristic appearance that allows for planned local excision to be performed. Four cases recurred after surgical excision, for a recurrence rate of 20%. After reviewing the published data and comparing them with our results, we concluded that a definite preoperative diagnosis of GCT-TS in the foot and ankle would help in planning the surgical treatment and that complete local excision is probably the only method to prevent recurrence. PMID- 23085384 TI - Endoscopic Achilles tenolysis for management of heel cord pain after repair of acute rupture of Achilles tendon. AB - Tendon pain after repair of an acute Achilles tendon rupture can result from suture granuloma formation, modification of the threshold of the pain receptors inside the tendon by scar tissue, expansion of the paratenon by tendon enlargement with secondary stimulation of mechanoreceptors, or underlying tendon degeneration. In the present technique report, an endoscopic technique of Achilles tenolysis for denervation and debulking is described that might be applicable in cases in which conservative treatment fails to alleviate the pain. PMID- 23085385 TI - Structural attributes of nucleotide sequences in promoter regions of supercoiling sensitive genes: how to relate microarray expression data with genomic sequences. AB - The level of supercoiling in the chromosome can affect gene expression. To clarify the basis of supercoiling sensitivity, we analyzed the structural features of nucleotide sequences in the vicinity of promoters for the genes with expression enhanced and decreased in response to loss of chromosomal supercoiling in Escherichia coli. Fourier analysis of promoter sequences for supercoiling sensitive genes reveals the tendency in selection of sequences with helical periodicities close to 10nt for relaxation-induced genes and to 11nt for relaxation-repressed genes. The helical periodicities in the subsets of promoters recognized by RNA polymerase with different sigma factors were also studied. A special procedure was developed for the study of correlations between the intensities of periodicities in promoter sequences and the expression levels of corresponding genes. Significant correlations of expression with the AT content and with AT periodicities about 10, 11, and 50nt indicate their role in regulation of supercoiling-sensitive genes. PMID- 23085386 TI - Changes on D2-like receptor induced Gi protein activation and hippocampal dopamine release in kindled rats. AB - The present study aimed to characterize dopamine release in the hippocampus and D2-like receptor-induced Gi protein activation in several brain areas of fully kindled rats. During the interictal period, kindled rats showed lower extracellular levels of dopamine when compared with those obtained in the control group under basal conditions, a situation that was not modified when an afterdischarge was evoked. Hippocampal perfusion of sulpiride, a D2 receptor antagonist, enhanced dopamine release, which was more evident when an afterdischarge was induced in kindled rats. In addition, sulpiride perfusion was associated with longer seizure duration. Functional autoradiography experiments revealed increased [(35)S]GTPgammaS incorporation as a consequence of D2-like receptor activation in different brain areas of fully kindled animals, including the ventral hippocampus. The present study reveals that hippocampal kindling is associated with alterations in dopamine release and D2-like receptor-induced neurotransmission. PMID- 23085388 TI - Persistent suppression of subthalamic beta-band activity during rhythmic finger tapping in Parkinson's disease. AB - OBJECTIVE: The function of synchronous oscillatory activity at beta band (15 30Hz) frequencies within the basal ganglia is unclear. Here we sought support for the hypothesis that beta activity has a global function within the basal ganglia and is not directly involved in the coding of specific biomechanical parameters of movement. METHODS: We recorded local field potential activity from the subthalamic nuclei of 11 patients with Parkinson's disease during a synchronized tapping task at three different externally cued rates. RESULTS: Beta activity was suppressed during tapping, reaching a minimum that differed little across the different tapping rates despite an increase in velocity of finger movements. Thus beta power suppression was independent of specific motor parameters. Moreover, although beta oscillations remained suppressed during all tapping rates, periods of resynchronization between taps were markedly attenuated during high rate tapping. As such, a beta rebound above baseline between taps at the lower rates was absent at the high rate. CONCLUSION: Our results demonstrate that beta desynchronization in the region of the subthalamic nucleus is independent of motor parameters and that the beta resynchronization is differentially modulated by rate of finger tapping, SIGNIFICANCE: These findings implicate consistent beta suppression in the facilitation of continuous movement sequences. PMID- 23085387 TI - Early life adversity reduces stress reactivity and enhances impulsive behavior: implications for health behaviors. AB - Altered reactivity to stress, either in the direction of exaggerated reactivity or diminished reactivity, may signal a dysregulation of systems intended to maintain homeostasis and a state of good health. Evidence has accumulated that diminished reactivity to psychosocial stress may signal poor health outcomes. One source of diminished cortisol and autonomic reactivity is the experience of adverse rearing during childhood and adolescence. The Oklahoma Family Health Patterns Project has examined a cohort of 426 healthy young adults with and without a family history of alcoholism. Regardless of family history, persons who had experienced high degrees of adversity prior to age 16 had a constellation of changes including reduced cortisol and heart rate reactivity, diminished cognitive capacity, and unstable regulation of affect, leading to behavioral impulsivity and antisocial tendencies. We present a model whereby this constellation of physiological, cognitive, and affective tendencies is consistent with altered central dopaminergic activity leading to changes in brain function that may foster impulsive and risky behaviors. These in turn may promote greater use of alcohol other drugs along with adopting poor health behaviors. This model provides a pathway from early life adversity to low stress reactivity that forms a basis for risky behaviors and poor health outcomes. PMID- 23085389 TI - History of exposure to dopaminergic medication does not affect motor cortex plasticity and excitability in Parkinson's disease. AB - OBJECTIVE: Little is known whether and how chronic exposure to dopaminergic treatment alters physiological mechanisms in Parkinson's disease (PD). METHODS: Two clinically similar groups of PD patients, one consisting of drug-naive patients and another of patients already on chronic dopaminergic medication (when off medication), were compared to each other and to a control group. Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. RESULTS: There was little difference between two patient groups, and both groups showed similar differences in comparison to controls: decreased facilitatory sensory motor plasticity (as measured by paired associative stimulation [PAS] protocol), impaired short-interval intracortical inhibition (SICI), and diminished slope of input-output curves at higher TMS intensities. The exception was that 30 min after PAS, intracortical facilitation (ICF) was significantly reduced in drug naive patients, whereas it changed much less in other two groups. CONCLUSIONS: Chronic exposure to dopaminergic drugs does not affect substantially the features of motor cortex excitability and plasticity in PD. There is little interaction between plasticity and excitability features of motor cortex in PD. SIGNIFICANCE: Reduced response to facilitatory PAS protocol, reduced SICI, and reduced slope of the input-output curve at higher TMS pulse intensities, seem to be physiological markers for the presence of the pathological disease process in PD. Long term treatment does not seem to change the underlying physiology of the disease. PMID- 23085390 TI - Stormy weather in the human basal ganglia. PMID- 23085391 TI - A comparison of relative-frequency and threshold-hunting methods to determine stimulus intensity in transcranial magnetic stimulation. AB - OBJECTIVE: Stimulation intensity (SI) in transcranial magnetic stimulation is commonly set in relation to motor threshold (MT), or to achieve a motor-evoked potential (MEP) of predefined amplitude (usually 1 mV). Recently, IFCN recommended adaptive threshold-hunting over the previously endorsed relative frequency method. We compared the Rossini-Rothwell (R-R) relative-frequency method to an adaptive threshold-hunting method based on parameter estimation by sequential testing (PEST) for determining MT and the SI to target a MEP amplitude of 1 mV (I(1) mV). METHODS: In 10 healthy controls we determined MT and I(1) mV with R-R and PEST using a blinded crossover design, and performed within-session serial PEST measurements of MT. RESULTS: There was no significant difference between methods for MT (52.6+/-2.6% vs. 53.7+/-3.1%; p=0.302; % maximum stimulator output; R-R vs. PEST, respectively) or I(1) mV (66.7+/-3.0% vs. 68.8+/ 3.8%; p=0.146). There was strong correlation between R-R and PEST estimates for both MT and I(1) mV. R-R required significantly more stimuli than PEST. Serial measurements of MT with PEST were reproducible. CONCLUSIONS: PEST has the advantage of speed without sacrificing precision when compared to the R-R method, and is adaptable to other SI targets. SIGNIFICANCE: Our results in healthy controls add to increasing evidence in favour of adaptive threshold-hunting methods for determining SI. PMID- 23085392 TI - Eliminating second-hand smoke from Mexican-American households: outcomes from Project Clean Air-Safe Air (CASA). AB - Exposure to second-hand smoke (SHS) is a major public health problem and a risk factor for morbidity and mortality. The objective of this randomized trial was to estimate the impact of a culturally-sensitive intervention to reduce SHS exposure in Mexican-American households. METHOD: A total of 91 households (with a child under 18 years of age and two adults, one of whom was a smoker) were recruited from a population-based cohort of Mexican-American households and randomized to receive the experimental intervention (EI; n=47) or standard care (SC; n=44). Of these, 74 households (83%) provided baseline, 6-month, and 12-month survey and nicotine monitor data (EI, n=39; SC, n=35). The EI materials, designed to increase the participants' likelihood of adopting a smoke-free indoor home air policy, included one culturally-appropriate bilingual comic book for children and two fotonovelas for adults. RESULTS: Ambient nicotine levels significantly decreased over the 12 study months (F=13.6, DF=147; p<0.001); with a significantly greater decrease in the EI households compared to the SC households (F=4.1, DF=72; p<0.05). At 12 months, 73% of EI households had banned smoking vs. 56% of SC households. Ambient nicotine levels, measured using nicotine air sampling monitors, were significantly associated with self-reported SHS exposure at the 12-month follow-up. Knowledge of the health effects of SHS increased from baseline to 6 and 12 months in the EI condition but not in the SC condition (F=6.0, DF=238; p<0.01), and smokers and quitters in the EI group reported an increased perception of health vulnerability compared to those in the SC group. CONCLUSION: Our low-cost intervention impacted SHS-related knowledge and exposure among Mexican Americans. This culturally-appropriate intervention has the potential to decrease SHS-related health problems in the target population substantially. PMID- 23085393 TI - SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice. AB - We identified urate oxidase (UOX) as a target of SIRT5 by comparing mitochondrial proteins in livers of SIRT5-overexpressing transgenic (SIRT5 Tg) and wild-type mice by using two-dimensional electrophoresis. Acetylation levels of UOX in liver of SIRT5 Tg mice were approximately half of those in wild-type mice, and UOX activity was significantly increased. Invitro-synthesized UOX protein was acetylated when incubated with mitochondria from wild-type mice liver but the levels were less when incubated with those from SIRT5 Tg mice liver. These results suggest that SIRT5 activates UOX through deacetylation in mouse liver mitochondria. PMID- 23085394 TI - Drosophila miR-5 suppresses Hedgehog signaling by directly targeting Smoothened. AB - Hedgehog (Hh) signaling plays many important roles in developmental processes and cancers. Smoothened (Smo) is an important signal transducer in the Hh pathway, and its expression is tightly regulated by several different post-transcriptional mechanisms. However, whether microRNAs (miRNAs) are involved in Smo regulation is still unclear. Here, we found that miR-5 acts as a suppressor of the Hh pathway by targeting Smo. Through in vivo sensor assay and in vitro luciferase assay, we found that miR-5 downregulates Smo through directly binding to its 3'UTR. Moreover, our data indicated Costal-2 (Cos2) and Fused (Fu) do not play a role in the reduction of Smo mediated by miR-5. Furthermore, we determined that miR-5 not involved in Notch or Dpp signaling pathways by detecting target gene expression. Together, our results indicate that miR-5 can specifically suppress Hh signaling by directly targeting Smo in Drosophila. PMID- 23085395 TI - Rooperol as an antioxidant and its role in the innate immune system: an in vitro study. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Biologically active rooperol is formed when the glucose subunits of the nontoxic glycoside, hypoxoside, are cleaved by beta glucosidase. Hypoxoside is isolated from Hypoxis, a medicinal plant genus frequently used by the indigenous people of South Africa as an immune system booster. The aim of this study was to investigate rooperol's antioxidant and anti inflammatory properties using the ferric reducing ability of plasma (FRAP) assay, NO and ROS production, and phagocytosis. MATERIALS AND METHODS: Differentiation of human promonocytic U937 leukemia cells to monocyte-macrophages was induced using 10-100 nM 1,25(OH)(2)D(3) and PMA over 72 h. Differentiation was confirmed by light microscopy and flow cytometry. Undifferentiated and/or differentiated cells were treated with DMSO (0.25 v/v%, vehicle control), hypoxoside (50 MUg/mL), rooperol (20 MUg/mL) or PMA (10/20 nM, positive control). ROS production was measured in undifferentiated and differentiated monocyte-macrophages using DCFH-DA and flow cytometry. Phagocytosis of pHrodoTM Escherichia coli BioParticles((r)) was measured using pre-treated monocyte-macrophage differentiated U937 cells. NO production was measured in monocyte-macrophage differentiated U937 cells using DAF-2 DA and flow cytometry. RESULTS: Rooperol was shown to have similar or greater antioxidant potential than ascorbic acid. Differentiation of human promonocytic U937 leukemia cells to monocyte-macrophages were confirmed morphologically (cell attachment, clump- and pseudopodia formation) and biochemically (CD11b and CD14 cell surface marker expression). Rooperol significantly increased ROS and NO production, and phagocytosis in undifferentiated and/or differentiated human promonocytic U937 leukemia cells. Hypoxoside had no or very little effect on ROS and NO production, and phagocytosis. CONCLUSION: This study confirms previous reports that hypoxoside has to be converted to rooperol to be biologically active. The FRAP assay confirms the antioxidant capacity of rooperol seen in previous studies, whereas rooperol's induction of ROS and NO production, and phagocytosis constitute novel findings. Possible mode(s) of action for the in vitro anti-inflammatory activities of rooperol may be explained by ROS and NO production, and phagocytosis. PMID- 23085396 TI - Analysis of the chemical composition, acute toxicity and skin sensitivity of essential oil from rhizomes of Ligusticum chuanxiong. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ligusticum chuanxiong Hort. (Umbelliferae) is a plant used as medicine and food in China. The essential oil (EO) extracted from its rhizomes possesses many pharmacological activities. However, there have been no scientific reports in the modern literature on the safety of EO. AIMS OF THE STUDY: The objective of this study was to conduct a chemical composition analysis and evaluate acute toxicity and skin sensitivity of EO from rhizomes of Ligusticum chuanxiong. MATERIALS AND METHODS: The chemical composition of hydrodistilled EO was analyzed by gas chromatography-mass spectrometry (GC-MS) and was evaluated in animals for acute toxicity, skin irritation and sensitization tests. RESULTS: Dozens of compounds were detected and the major components of EO were ligustilide and butylidenephthalide with relative contents of 67.46 and 5.06%, respectively. The oral and intra-peritoneal lethal doses of 50% (LD(50)) in mice were 7.23 g/kg (approximately 14,606 times of clinical dose used) and 2.25 g/kg (approximately 5091 times of clinical dose used), respectively. The doses of 0.115 and 0.23 g/kg EO (approximately 232.5 and 465 times of the respective clinical doses used) revealed slight irritation effects on rabbit skin, but 1g/kg EO (approximately 2020 times of clinical dose used) had no observable effect on guinea pig skin in the skin sensitization test. CONCLUSIONS: These experimental results indicate that short term application of EO is probably safe within the range of its clinical doses, but the dose should be controlled for external use due to its slight skin irritation. PMID- 23085397 TI - Acorus gramineus inhibits microglia mediated neuroinflammation and prevents neurotoxicity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Acorus gramineus Solander (Acoraceae, AG), is a widely distributed plant in Asian countries. Rhizome part of this plant has long been used as a traditional medicine for treating various symptoms including central nervous system (CNS) disorders. AIM OF STUDY: The anti-neuroinflammatory effect of AG aqueous extract was investigated using in vitro cellular and in vivo Parkinson's disease (PD) mouse model. MATERIALS AND METHODS: Lipopolysaccharide (LPS) is used to stimulate BV-2 microglial cells in vitro and the changes in neuroinflammatory expressional levels were measured using ELISA, Western blotting, RT-PCR and immunofluorescence techniques. In in vivo experiments, 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mouse model of PD was developed followed by immunohistochemical analysis of specific brain tissues. RESULTS: LPS-stimulation to BV-2 cells increased the production of nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-1beta. Pretreatment with AG extract inhibited the increased levels of NO and pro-inflammatory cytokines in LPS-stimulated BV-2 cells. Mechanistic study revealed that AG acts via the regulation of nuclear factor kappa B (NF-kappaB), mitogen-activated protein kinases (MAPKs) and TRIF dependent signaling pathways. Further, AG protected MPTP-induced neuronal cell death and inhibited neuroinflammation in vivo. CONCLUSION: Our results indicated that AG extract exerted anti-neuroinflammatory effects against activated microglia mediated insults through multiple signaling pathways and prevented in vivo neuronal cell death in mouse model of PD substantiating the traditional claims for its use in CNS disorders. PMID- 23085398 TI - Shaping chromatin for repair. AB - To counteract the adverse effects of various DNA lesions, cells have evolved an array of diverse repair pathways to restore DNA structure and to coordinate repair with cell cycle regulation. Chromatin changes are an integral part of the DNA damage response, particularly with regard to the types of repair that involve assembly of large multiprotein complexes such as those involved in double strand break (DSB) repair and nucleotide excision repair (NER). A number of phosphorylation, acetylation, methylation, ubiquitylation and chromatin remodeling events modulate chromatin structure at the lesion site. These changes demarcate chromatin neighboring the lesion, afford accessibility and binding surfaces to repair factors and provide on-the-spot means to coordinate repair and damage signaling. Thus, the hierarchical assembly of repair factors at a double strand break is mostly due to their regulated interactions with posttranslational modifications of histones. A large number of chromatin remodelers are required at different stages of DSB repair and NER. Remodelers physically interact with proteins involved in repair processes, suggesting that chromatin remodeling is a requisite for repair factors to access the damaged site. Together, recent findings define the roles of histone post-translational modifications and chromatin remodeling in the DNA damage response and underscore possible differences in the requirements for these events in relation to the chromatin context. PMID- 23085400 TI - Porcine reproductive and respiratory syndrome virus infection activates IL-10 production through NF-kappaB and p38 MAPK pathways in porcine alveolar macrophages. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is an emerging animal virus that has caused high economic losses for the swine industry worldwide. Previous in vitro and in vivo studies demonstrated that PRRSV infection induces significant production of interleukin 10 (IL-10), a pleiotropic cytokine with immuno-modulatory functions involved in host defense. However, the underlying regulatory mechanisms during PRRSV remain largely unknown. In the present study, we analyzed the expression kinetics of IL-10 in PRRSV-infected primary porcine alveolar macrophages (PAMs) and showed that PRRSV infection induced IL-10 mRNA and protein expression in a time- and dose-dependent manner. Inhibition of various molecules of the Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling pathways demonstrated that the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) has an important role in IL-10 induction during PRRSV infection. Furthermore, treatment with specific inhibitors or siRNA knockdown assays demonstrated that NF-kappaB and p38 MAPK (mitogen-activated protein kinase) are required for PRRSV-induced IL-10. Taken together, PRRSV infection significantly induced IL-10 expression and this induction depends on NF kappaB activation and p38 MAPK in PAMs. PMID- 23085402 TI - The function of the ATP-binding cassette (ABC) transporter ABCB1 is not susceptible to actin disruption. AB - Previously we have shown that the activity of the multidrug transporter ABCC1 (multidrug resistance protein 1), and its localization in lipid rafts, depends on cortical actin (Hummel I, Klappe K, Ercan C, Kok JW. Mol. Pharm. 2011 79, 229 40). Here we show that the efflux activity of the ATP-binding cassette (ABC) family member ABCB1 (P-glycoprotein), did not depend on actin, neither in ABCB1 over expressing murine National Institutes of Health (NIH) 3T3 MDR1 G185 cells nor in human SK-N-FI cells, which endogenously express ABCB1. Disruption of the actin cytoskeleton, upon treatment of the cells with latrunculin B or cytochalasin D, caused severe changes in cell and membrane morphology, and concomitant changes in the subcellular distribution of ABCB1, as revealed by confocal laser scanning and electron microscopy. Nevertheless, irrespective of actin perturbation, the cell surface pool of ABCB1 remained unaltered. In NIH 3T3 MDR1 G185 cells, ABCB1 is partly localized in detergent-free lipid rafts, which partitioned in two different density gradient regions, both enriched in cholesterol and sphingolipids. Interestingly, disruption of the actin cytoskeleton did not change the density gradient distribution of ABCB1. Our data demonstrate that the functioning of ABCB1 as an efflux pump does not depend on actin, which is due to its distribution in both cell surface-localized non-raft membrane areas and lipid raft domains, which do not depend on actin stabilization. PMID- 23085401 TI - PcLT, a novel C-type lectin from Procambarus clarkii, is involved in the innate defense against Vibrio alginolyticus and WSSV. AB - Lectins play important roles in the innate immunity. In this work, a C-type lectin, PcLT, was obtained from Procambarus clarkii which contained a carbohydrate recognition domain (CRD) with the ability to bind to Vibrio alginolyticus and white spot syndrome virus (WSSV). RT-PCR and qRT-PCR analyses demonstrated PcLT was specifically expressed in the hepatopancreas and the mRNA was markedly upregulated by V. alginolyticus and WSSV challenge, although a slight difference in timing was observed. The study also revealed upregulation of the mRNA expression and activity of immunological factors, peroxinectin, phenoloxidase, and superoxide dismutase in hemolymph in response to recombinant PcLT (rPcLT). Moreover, rPcLT also enhanced the phagocytosis, facilitated the subsequent clearance of V. alginolyticus and prolonged the survival of WSSV infected shrimp. These results suggested that PcLT not only served as a pathogen recognition receptor (PRR), but also functioned as an immune modulator, participating in host defense against invaders. PMID- 23085403 TI - The molecular basis of the cooperation between EGF, FGF and eCB receptors in the regulation of neural stem cell function. AB - Adult neurogenesis relies on EGF and FGF receptor (EGFR/FGFR) function and endocannabinoid (eCB) signalling. Here we have used a neural stem cell (NSC) line to determine how these systems cooperate to regulate neurogenesis. The results show the EGFR to be solely responsible for maintaining PI3K activation explaining its dominant role in promoting NSC survival. The EGFR and FGFR synergistically regulate the ERK/MAPK pathway, and this explains the requirement for both for optimal cell proliferation. The eCB receptors did not contribute to activation of the PI3K or ERK/MAPK pathways, highlighting the importance of another major proliferation pathway. The EGFR plays the dominant role in maintaining the transcriptome, with significant changes in the expression of over 3500 transcripts seen within hours of inhibition or activation of this receptor. The FGFR has a more modest effect on transcription with evidence for nodal integration with EGFR signalling at the level of the ERK/MAPK pathway. A common set of transcripts are regulated by the CB1 and CB2 receptors, with cooperation between these receptors and the EGFR apparent in the regulation of a pool of transcripts, most likely representing signal integration downstream from an as yet to be identified node. Finally, a first level molecular analysis of the transcriptional response shows regulation of a number of key growth factors, growth factor receptors and GPCRs to be under the control of the EGFR. PMID- 23085404 TI - Reduced in-hospital survival rates of out-of-hospital cardiac arrest victims with obstructive pulmonary disease. AB - AIM: Out-of-hospital cardiac arrest (OHCA) due to sustained ventricular tachycardia/fibrillation (VT/VF) is common and often lethal. Patient's co morbidities may determine survival after OHCA, and be instrumental in post resuscitation care, but are poorly studied. We aimed to study whether patients with obstructive pulmonary disease (OPD) have a lower survival rate after OHCA than non-OPD patients. METHODS: We performed a community-based cohort study of 1172 patients with non-traumatic OHCA with ECG-documented VT/VF between 2005 and 2008. We compared survival to emergency room (ER), to hospital admission, to hospital discharge, and at 30 days after OHCA, of OPD-patients and non-OPD patients, using logistic regression analysis. We also compared 30-day survival of patients who were admitted to hospital, using multivariate logistic regression analysis. RESULTS: OPD patients (n=178) and non-OPD patients (n=994) had comparable survival to ER (75% vs. 78%, OR 0.9 [95% CI: 0.6-1.3]) and to hospital admission (56% vs. 57%, OR 1.0 [0.7-1.4]). However, survival to hospital discharge was significantly lower among OPD patients (21% vs. 33%, OR 0.6 [0.4 0.9]). Multivariate regression analysis among patients who were admitted to hospital (OPD: n=100, no OPD: n=561) revealed that OPD was an independent determinant of reduced 30-day survival rate (39% vs. 59%, adjusted OR 0.6 [0.4 1.0, p=0.035]). CONCLUSION: OPD-patients had lower survival rates after OHCA than non-OPD patients. Survival to ER and to hospital admission was not different between both groups. However, among OHCA victims who survived to hospital admission, OPD was an independent determinant of reduced 30-day survival rate. PMID- 23085399 TI - Maternal high fat diet consumption during the perinatal period programs offspring behavior. AB - The environment that a developing offspring experiences during the perinatal period is markedly influenced by maternal health and diet composition. Evidence from both epidemiological studies and animal models indicates that maternal diet and metabolic status play a critical role in programming the neural circuitry that regulates behavior, resulting in long-term consequences for offspring behavior. Maternal diet and metabolic state influence the behavior of offspring directly by impacting the intrauterine environment and indirectly by modulating maternal behavior. The mechanisms by which maternal diet and metabolic profile shape the perinatal environment remain largely unknown, but recent research has found that increases in inflammatory cytokines, nutrients (glucose and fatty acids), and hormones (insulin and leptin) affect the environment of the developing offspring. Offspring exposed to maternal obesity and high fat diet consumption during development are more susceptible to developing mental health and behavioral disorders such as anxiety, depression, attention deficit hyperactivity disorder, and autism spectrum disorders. Recent evidence suggests that this increased risk for behavioral disorders is driven by modifications in the development of neural pathways involved in behavioral regulation. In particular, research indicates that the development of the serotonergic system is impacted by exposure to maternal obesity and high fat diet consumption, and this disruption may underlie many of the behavioral disturbances observed in these offspring. Given the high rates of obesity and high fat diet consumption in pregnant women, it is vital to examine the influence that maternal nutrition and metabolic profile have on the developing offspring. PMID- 23085405 TI - What hand position do untrained bystanders select during EMS-dispatcher-assisted CPR? PMID- 23085406 TI - Outcomes following military traumatic cardiorespiratory arrest: the role of surgery in resuscitation. PMID- 23085407 TI - Refractory acute disseminated encephalomyelitis with anti-galactocerebroside antibody. AB - Acute disseminated encephalomyelitis causes multifocal demyelination in the central nerve system. Although this disease generally responds well to steroid therapy, it is occasionally steroid-resistant, leading to poor outcomes. Serological markers of prognosis are currently unavailable. We measured anti glycolipid antibodies in 25 consecutive patients with acute disseminated encephalomyelitis, and found that four patients were positive for anti galactocerebroside antibodies. All four patients had a poor response to steroids. We summarize clinical information on these four patients and three similar patients reported previously. This is the first report to describe concomitant involvement of the central nerve system and peripheral nervous system in anti galactocerebroside antibody-associated acute disseminated encephalomyelitis, consistent with the location of galactocerebroside, and to document a dramatic response to repeated intravenous immunoglobulin therapy after unsuccessful steroid treatment in one patient. PMID- 23085408 TI - Benefit of overlapping reconstruction for improving the quantitative assessment of CT lung nodule volume. AB - RATIONALE AND OBJECTIVES: The aim of this study was to quantify the effect of overlapping reconstruction on the precision and accuracy of lung nodule volume estimates in a phantom computed tomographic (CT) study. MATERIALS AND METHODS: An anthropomorphic phantom was used with a vasculature insert on which synthetic lung nodules were attached. Repeated scans of the phantom were acquired using a 64-slice CT scanner. Overlapping and contiguous reconstructions were performed for a range of CT imaging parameters (exposure, slice thickness, pitch, reconstruction kernel) and a range of nodule characteristics (size, density). Nodule volume was estimated with a previously developed matched-filter algorithm. RESULTS: Absolute percentage bias across all nodule sizes (n = 2880) was significantly lower when overlapping reconstruction was used, with an absolute percentage bias of 6.6% (95% confidence interval [CI], 6.4-6.9), compared to 13.2% (95% CI, 12.7-13.8) for contiguous reconstruction. Overlapping reconstruction also showed a precision benefit, with a lower standard percentage error of 7.1% (95% CI, 6.9-7.2) compared with 15.3% (95% CI, 14.9-15.7) for contiguous reconstructions across all nodules. Both effects were more pronounced for the smaller, subcentimeter nodules. CONCLUSIONS: These results support the use of overlapping reconstruction to improve the quantitative assessment of nodule size with CT imaging. PMID- 23085409 TI - The effect of scan duration on the measurement of perfusion parameters in CT perfusion studies of brain tumors. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate the effect of scan duration on the measurement of blood flow (BF), blood volume (BV), and permeability-surface area product (PS) in patients undergoing computed tomography (CT) perfusion for brain tumors. MATERIALS AND METHODS: CT perfusion scans were performed in 14 patients with malignant glioma. Patients were scanned for 150 seconds, and BF, BV, and PS were assessed for scan durations of 150, 120, 90, and 60 seconds. Systematic, random, and percentage errors associated with shorter scan durations were calculated. Repeated-measures analyses of variance with paired t tests were used to compare the perfusion values measured from different scan durations. Systematic and random errors were correlated with scan duration. RESULTS: No effect of scan duration on BF and BV values was noted (P > .05). PS values were not affected by scan duration except in the tumor rim, in which they were significantly higher at 60 seconds (P < .01). Median percentage error was highest at 60 seconds for tumor core PS (median, 32.1%; interquartile range, 16.5%-43.0%). Tumor rim BV and PS and tumor core BF were correlated with scan durations (r = 0.42, -0.50, and -0.50, respectively; P < .01). Random errors were negatively correlated with scan durations for all tissue types (P <= .01) except for white matter BV. CONCLUSIONS: A scan duration of <=60 seconds is not warranted for the measurement of PS in brain tumors. A scan duration of >=90 seconds is recommended. PMID- 23085410 TI - Establishing a new radiology residency research track. AB - The authors describe the establishment of a radiology residency research track at their institution. Based on growing biomedical technology needs and the tremendous increase in imaging-based research, the importance of training and cultivating future clinical investigators continues to grow. Within the framework of a supportive environment, a residency research track exposes motivated radiologists-in-training to the tools, challenges, and successes of a career in academics. The authors describe their program's design, admissions process, curriculum, and expectations. Lastly, the authors share the insight of their experience and seek feedback from readers who have been involved in similar endeavors. PMID- 23085411 TI - Auto-initialized cascaded level set (AI-CALS) segmentation of bladder lesions on multidetector row CT urography. AB - RATIONALE AND OBJECTIVES: To develop a computerized system for segmentation of bladder lesions on computed tomography urography (CTU) scans for detection and characterization of bladder cancer. MATERIALS AND METHODS: We have developed an auto-initialized cascaded level set method to perform bladder lesion segmentation. The segmentation performance was evaluated on a preliminary dataset including 28 CTU scans from 28 patients collected retrospectively with institutional review board approval. The bladders were partially filled with intravenous contrast material. The lesions were located fully or partially within the contrast-enhanced area or in the non-contrast-enhanced area of the bladder. An experienced abdominal radiologist marked 28 lesions (14 malignant and 14 benign) with bounding boxes that served as input to the automated segmentation system and assigned a difficulty rating on a scale of 1 to 5 (5 = most subtle) to each lesion. The contours from automated segmentation were compared to three dimensional contours manually drawn by the radiologist. Three performance metric measures were used for comparison. In addition, the automated segmentation quality was assessed by an expert panel of two experienced radiologists, who provided quality ratings of the contours on a scale from 1 to 10 (10 = excellent). RESULTS: The average volume intersection ratio, the average absolute volume error, and the average distance measure were 67.2 +/- 16.9%, 27.3 +/- 26.9%, and 2.89 +/- 1.69 mm, respectively. Of the 28 segmentations, 18 were given quality ratings of 8 or above. The average rating was 7.9 +/- 1.5. The average quality ratings for lesions with difficulty ratings of 1, 2, 3, and 4 were 8.8 +/ 0.9, 7.9 +/- 1.8, 7.4 +/- 0.9, and 6.6 +/- 1.5, respectively. CONCLUSION: Our preliminary study demonstrates the feasibility of using the three-dimensional level set method for segmenting bladder lesions in CTU scans. PMID- 23085413 TI - Two distinct muscle progenitor populations coexist throughout amniote development. AB - During embryonic and fetal life, skeletal muscle growth is dependent upon the proliferation and the differentiation of a population of resident muscle progenitors, from which derive the muscle stem cells of the adult, the satellite cells. Under poorly defined extrinsic and intrinsic influences, muscle progenitors proliferate, differentiate or enter a quiescent state to become reserve satellite cells. Despite their primordial role, surprisingly little is known on the homeostasis of resident progenitors during embryogenesis. Preliminary studies in chick and mouse describing the key progenitor populations contributing to muscle growth during embryogenesis have led to differing results that could be due to technical issues or to fundamental differences between animal models. To address this question, we have undertaken a comprehensive analysis of the state of differentiation and proliferation of muscle progenitor cells from the time of their emergence within the dermomyotome until late fetal life, when they adopt a satellite cell-like position under the basal lamina. This was done by immunostaining against key players of myogenic differentiation, in muscles chosen from different regions of the body in two model organisms, the chick and mouse. This study identified two co-existing populations of progenitors during embryonic and fetal life in both chick and mouse: a minor, slow-cycling pool of undifferentiated resident progenitors which express Pax7, co-existing with a major fast-cycling population that co-express Pax7 and the early myogenic differentiation marker Myf5. We found that the overall proliferation rate of both progenitors drastically decreased with embryonic age, as an increasingly large portion of slow and fast-cycling progenitors entered quiescence during development. Together, this data suggests that the cellular strategies that drive muscle growth during embryonic and fetal life are remarkably conserved in amniotes throughout evolution. They rely on the tight regulation of proliferation, entry in quiescence, and modulation of the cell cycle's length for both of the co-existing populations of muscle progenitors to maintain the homeostasis of growing muscles during development. PMID- 23085412 TI - Spatiotemporal regulation of an Hcn4 enhancer defines a role for Mef2c and HDACs in cardiac electrical patterning. AB - Regional differences in cardiomyocyte automaticity permit the sinoatrial node (SAN) to function as the leading cardiac pacemaker and the atrioventricular (AV) junction as a subsidiary pacemaker. The regulatory mechanisms controlling the distribution of automaticity within the heart are not understood. To understand regional variation in cardiac automaticity, we carried out an in vivo analysis of cis-regulatory elements that control expression of the hyperpolarization activated cyclic-nucleotide gated ion channel 4 (Hcn4). Using transgenic mice, we found that spatial and temporal patterning of Hcn4 expression in the AV conduction system required cis-regulatory elements with multiple conserved fragments. One highly conserved region, which contained a myocyte enhancer factor 2C (Mef2C) binding site previously described in vitro, induced reporter expression specifically in the embryonic non-chamber myocardium and the postnatal AV bundle in a Mef2c-dependent manner in vivo. Inhibition of histone deacetylase (HDAC) activity in cultured transgenic embryos showed expansion of reporter activity to working myocardium. In adult animals, hypertrophy induced by transverse aortic constriction, which causes translocation of HDACs out of the nucleus, resulted in ectopic activation of the Hcn4 enhancer in working myocardium, recapitulating pathological electrical remodeling. These findings reveal mechanisms that control the distribution of automaticity among cardiomyocytes during development and in response to stress. PMID- 23085414 TI - Teaching techniques for the busy office practice. PMID- 23085415 TI - Correlation between actin content and laser phase shift of adhesive normal and malignant prostate epithelial cells. AB - Aiming to establish the noninvasive discrimination of cancer cells from normal cells in adherent culture, we examined in this study the reason why the laser phase shift, which is the product of refractive index and height of malignant cancer cells, was markedly smaller than that of normal cells. Both of the phase shift measured by phase-shifting laser microscopy (PLM) and the relative actin content of cells of the adhesive human prostatic carcinoma epithelial cell line (PC-3) were markedly lower than those of adhesive human prostate epithelial cells (PRECs), while there was almost no difference in morphology observed under a conventional inverted microscope, between them. The decrease in relative actin content by the addition of cytochalasin D resulted in the decrease in phase shift in both cell lines, and these cell lines showed a marked positive correlation between phase shift and relative actin content (r = 0.84). The height and refractive index of adhesive cells were determined using PLM and the height of PC 3 cells were apparently lower than those of PRECs, while there was no difference in refractive indices between PC-3 cells and PRECs. Consequently, the smaller height of PC-3 cells caused by lower actin content than of PRECs might be the reason for the lower phase shift of PC-3 cells. PMID- 23085416 TI - Assessment of change in biofilm architecture by nutrient concentration using a multichannel microdevice flow system. AB - A new multichannel microdevice flow system with stainless steel flow chamber was used for architecture visualization, development monitoring and structural quantification of GFP-labeled Pseudomonas aeruginosa PAO1 live biofilms. Direct in situ investigations using confocal laser scanning microscopy (CLSM) at 72 h revealed structural pattern differences as a result of nutrient concentration gradients. When grown in LB medium, round, dispersed cellular aggregates were formed whereas in 1/3-diluted LB medium, biofilms were mostly flat and compact. However, COMSTAT analyses showed no considerable differences in biomass and thickness between the two LB concentrations. Characterization of time-dependent development of biofilms grown in 1/3-diluted LB medium showed full maturation of colonies by 120 h reaching maximum biomass at 17.1 MUm(3)/MUm(2) and average thickness at 44.4 MUm. Consequent thinning and formation of openings through interior in colonies occurred by 168 h. These results suggest that the new system tested allowed a fast and thick biofilm development on the surface of the stainless steel flow chamber. These findings may provide better estimates of biofilm activity and systematic evaluation of the effects of different parameters on biofilm morphology and development in industrial and biomedical systems. PMID- 23085417 TI - Improved efficiency of butanol production by absorbed lignocellulose fermentation. AB - Alkali-treated steam-exploded corn stover (SECSAT) was used as solid substrate for acetone-butanol-ethanol (ABE) production by absorbed lignocellulose fermentation (ALF) using Clostridium acetobutylicum ATCC 824. The ABE concentration in ALF culture had increased by 47% compared with that in submerged culture. More surprisingly, the acetone production was promoted and ethanol production was lower in the presence of SECSAT than that in its absence. ALF was also successfully in cofermentation of glucose and xylose, although decreased fermentability with an increase in the proportion of xylose. An invariable chemical composition and dry weight of SECSAT was found in ALF. Partial simultaneous saccharification and fermentation of SECSAT using a certain amount of cellulase could not only enhance the ABE concentration by 71%, but also significantly increase the area proportion of fiber cells in SECSAT from 53% to 90%, which would be an excellent paper making material. PMID- 23085418 TI - Minimization of nitrous oxide emission from anoxic-oxic biological nitrogen removal process: effect of influent COD/NH4+ ratio and feeding strategy. AB - Nitrous oxide (N(2)O) is an important greenhouse gas and biological nitrogen removal process of wastewater treatment plant is one of its sources. Mechanisms of N(2)O emissions from anoxic-oxic biological nitrogen removal process were investigated and minimizations of N(2)O emissions were carried out from the aspect of organic carbon supplement, i.e., influent COD/NH4+ ratio (C/N ratio) and feeding strategy. Results showed that during anoxic-oxic biological nitrogen removal process, most of the N(2)O emissions occurred during the oxic phase, and both nitrifier denitrification and aerobic hydroxylamine oxidation pathways were possible mechanisms responsible for N(2)O emissions. N(2)O conversion rate decreased from 6.0% to 1.3% when the influent C/N ratio was increased from 7.5 to 14.5. This was mainly because of decrease in the abundance of Nitrosomonas-like ammonia oxidizing bacteria. Step feeding and external carbon source addition could reduce N(2)O conversion rate by 66.6% and 12.0%, respectively. Both of them were feasible methods for minimizing N(2)O emission from wastewater treatment process. The low N(2)O emission of step feeding was because of its high dissolved oxygen (DO) and low ammonium concentrations during the oxic phase, while the minimization effect of external carbon source addition was ascribed to its high nitrogen removal efficiency. PMID- 23085419 TI - Penicillium sp. strain that efficiently adsorbs lignosulfonate in the presence of sulfate ion. AB - Lignin is one of the major water insoluble substances that support the physical properties of plants and can be solubilized by sulfite or alkaline treatment in accordance with pulpification. The lignin derivatives produced by both the sulfite and the kraft processes are called lignosulfonate (LS) and kraft lignin (KL), respectively, and both derivatives show a broad spectrum of optical absorbance from ultraviolet to visible light. When the spore suspension of an isolated Penicillium sp., Penicillium sp. A, was inoculated to a medium containing 0.1% commercial LS, absorbance at 480 nm (A480) almost completely disappeared after 5 days of cultivation. Maximum decolorization of the culture broth was observed when the microbe was cultured in the 0.8% LS medium reaching 88%, and the amount of LS removed was calculated to be 7 g/L. In a similar assay with the dark-liquid containing KL, 80% of the A480 of a 20% (v/v) dark-liquid medium disappeared after 5 days of culturing and the amount of KL removed was calculated to be 2.9 g/L. These values significantly exceeded the previously reported amounts with respect to substrate concentration and decolorization. Furthermore, since similar results were obtained in the cases of both LS and KL, it is expected that the present strain is able to non-specifically adsorb a wide range of lignin derivatives, because most of the colored substances were recovered in the culture sediments. Thus, the strain can be used to clean up waste fluids containing water soluble lignin derivatives, adsorb lignin derivatives in waste fluids before dehydration. PMID- 23085420 TI - Inhibition of constitutive Akt (PKB) phosphorylation by docosahexaenoic acid in the human breast cancer cell line MDA-MB-453. AB - Many breast cancer cells express aberrantly activated receptor tyrosine kinases and are associated with deregulated phosphorylation of Akt (PKB). They are also often associated with a high level of free monounsaturated (MUFA) and saturated (SFA) fatty acids. We studied the effect of DHA and other polyunsaturated fatty acids (PUFAs) on these anomalies in a human breast cancer cell line, MDA-MB-453. Inhibitors of the Akt T308 kinase (PDK1) or S473 kinase (mTORC2, DNA-dependent protein kinase and integrin-linked kinase) and combinations of two of them incompletely inhibited, or even enhanced, the phosphorylation in this cell line. In contrast, it was found that DHA as well as other PUFAs inhibited Akt phosphorylation on T308 after 24h. These PUFAs also blocked phosphorylation of S473, although certain omega-6 PUFAs were ineffective. After 48h, only DHA inhibited Akt phosphorylation on the both residues. DHA, and other PUFAs though less efficiently, also elevated the expression of a mitochondrial enzyme, 2,4 dienoyl-CoA reductase, which catalyzes process necessary for beta-oxidation of PUFAs. These PUFAs were present in the cells at high concentrations and reduced the amount of free and phospholipid-bound MUFAs. DHA most efficiently blocked deregulated cell proliferation while the effects of other PUFAs were moderate. These results suggest that DHA suppressed the growth of the cancer cell through its specifically persistent block of Akt phosphorylation in conjunction with modulation of fatty acid metabolism. PMID- 23085421 TI - Biodegradation of cylindrospermopsin toxin by microcystin-degrading bacteria isolated from cyanobacterial blooms. AB - Cylindrospermopsin (CYN) is highly water soluble and stable cyanotoxin which can persist in water sources and pose health hazards to human, animals and plants. Consequently, there is a need to fully understand the fate of CYN in the aquatic environment, in particular, its biodegradation by endemic organisms. Although there is evidence of CYN degradation by microbial population, bacterial strains responsible for the toxin degradation are not yet identified. This study reports for the first time CYN degradation by Bacillus strain (AMRI-03) isolated from cyanobacterial blooms. In degradation batch experiment, the strain grew well in the presence of CYN without showing any lag period, and this growth increased with the initial CYN concentration. CYN degradation occurred rapidly, and the complete degradation was dependent on the initial CYN concentration. It occurred after 6 days at the highest concentration (300 MUg L(-1)) compared to 7 and 8 days at lower concentrations (10 & 100 MUg L(-1)). Also, the degradation rate correlated positively with the initial CYN concentration with maximum value (50 MUg L(-1) day(-1)) obtained at the highest CYN concentration. Furthermore, the biodegradation rate of CYN by this strain depended remarkably on temperature and pH. The highest biodegradation rates were obtained at 25 and 30 degrees C, and at pH 7 and pH 8. Taken that such microcystin-degrading strain can also degrade CYN, bacterial strains reported worldwide as microcystin degraders could be tested for their capability of CYN degradation. PMID- 23085422 TI - Synthesis, configuration assignment, and simultaneous quantification by liquid chromatography coupled to tandem mass spectrometry, of dihydroanatoxin-a and dihydrohomoanatoxin-a together with the parent toxins, in axenic cyanobacterial strains and in environmental samples. AB - We have synthesized cis- and trans-dihydroanatoxin-a and cis- and trans dihydrohomoanatoxin-a using a short synthetic route. The relative configuration of N-tert-butoxycarbonyl-cis-dihydroanatoxin-a was determined by X-ray crystallography, while that of N-tert-butoxycarbonyl-trans-dihydroanatoxin-a was confirmed by epimerization leading to the cis-diastereoisomer. The relative configuration of N-tert-butoxycarbonyl-trans- and cis-dihydrohomoanatoxin-a was inferred from their NMR spectra. Using an optimized LC-MS/MS analytical method and pure standards we have simultaneously determined anatoxin-a, homoanatoxin-a and their dihydroderivatives in axenic strains of cyanobacteria and in environmental samples from the Tarn River, France. However, in these analytical conditions, the cis- and trans-dihydroanatoxin-a and cis- and trans dihydrohomoanatoxin-a could not be separated. In axenic strains, the dihydroderivatives represented less than 3% of the total toxin content, while in field samples dihydroanatoxin-a represented from 17% to 90% of the total toxin content. Thus, the reduction of anatoxin-a to dihydroanatoxin-a is predominant in the environment. The ratio of anatoxin-a concentration over that of homoanatoxin a in axenic strains was variable, and among the eight strains studied we found three exclusive anatoxin-a producers and five producers of homoanatoxin-a and anatoxin-a, the latter representing from 0.5% to 2.0% of the total. In the strains studied, we have amplified by PCR, and sequenced the region of anaG coding for the methylation domain proposed to be responsible for the formation of homoanatoxin-a. The sequences showed at least 88% identity and we could not relate the toxin profile of the strains to the sequence of the methylation domain. PMID- 23085423 TI - Neurotoxicity of Penicillium crustosum secondary metabolites: tremorgenic activity of orally administered penitrem A and thomitrem A and E in mice. AB - Several cases of neurological disease in dogs after poisoning by food- and feed borne Penicillium toxins in Norway during the last years have uncovered a lack of knowledge regarding the toxicity and mechanism of action of neuroactive mycotoxins. In the present study, the lowest tremor-inducing dose after single oral administration of penitrem A to mice was 0.50 mg/kg bw. The estimated half maximal effective dose (ED(50)) in respect to the visual tremor scale was 2.74 mg/kg bw. Mice receiving the maximum penitrem A dose (8 mg/kg bw) suffered severe spontaneous tremors and even convulsions. Thomitrem A and E are penitrem analogues lacking the C-16-C-18 ether linkage and possessing an olefin at C-18-C 19. Compared with penitrem A, the lowest tremor-inducing dose of thomitrem A was 16-times higher (8 mg/kg bw) and thomitrem E was found to be non-tremorgenic at the highest dose tested (16 mg/kg bw). During a recovery phase of two weeks post administration animals appeared restored and no changes in feeding and other biological processes were observed. An initial dose-related weight reduction was observed 2 days after penitrem A administration. Penitrem A was absorbed and distributed to gastrointestinal tract, liver, kidneys and brain in the mice. Elimination of penitrem A appeared to be mainly hepatic and the highest concentration levels were found 1 h post administration for all investigated organs. The relationship between liver and gastrointestinal tract concentration levels showed time-dependent linear correlation and a doubling within 1.5 h. PMID- 23085424 TI - TLR4 signaling protects from excessive muscular damage induced by Bothrops jararacussu snake venom. AB - Immune cells and skeletal muscle express Toll-like receptors (TLRs) that participate as sensors of tissue injury triggering signals for activation of innate and adaptive immune responses. This study aimed to investigate the involvement of TLR4 in the process of skeletal muscle repair. Muscular injury was induced by injection of 0.6 mg/kg of Bothrops jararacussu snake venom in the gastrocnemius muscle of C3H/HeJ mice that express a non-functional TLR-4 receptor and C3H/HeN mice with functional receptor. TLR4-deficient mice had persistent muscular inflammation with few F4/80 macrophages at onset but increased MMP9 activity and collagen deposition during resolution of injury. Since such effect was not observed in the mouse strain with functional receptor it is concluded that TLR4 signaling exerts a protective role preventing from excessive muscular damage induced by B. jararacussu venom. PMID- 23085427 TI - Degradation and adhesive/cohesive strengths of a reservoir-based drug eluting stent. AB - This paper presents the results of loss of mechanical strengths due to the degradation that occurs in a model reservoir-based coronary stent, the NEVO(TM) Sirolimus-eluting Stent (NEVO(TM) SES). The adhesion of the formulation to the reservoir and cohesion within the formulation in the time course of hydrolysis were determined using a micro-testing system that was developed specifically for the measurements of the adhesive and cohesive strengths of suspended polymeric films. The strengths were measured after hydration, during degradation with gentle agitation, as well as degradation with pulsatile mechanical loading. The morphology and molecular weight changes in the time course of NEVO(TM) SES formulation degradation were also studied using Scanning Electron Microscopy (SEM) and Gel Permeation Chromatography (GPC) techniques. Morphological changes, such as pore formation, lagged behind the decrease in the molecular weight of the formulation. In contrast, the adhesion/cohesion strengths showed that the mechanical integrity of the stents dropped significantly within a few hours of hydration, before reaching a plateau. Despite the significant molecular weight decrease and morphological changes, the plateau mechanical strengths reached were essentially the same during degradation, under both, mechanically unloaded and loaded conditions. PMID- 23085426 TI - Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL. AB - Radiation therapy is an integral part of treatment for cancer patients; however, major side effects of this modality include aberrant bone remodeling and bone loss. Ionizing radiation (IR) is a major external factor that contributes to a significant increase in oxidative stress such as reactive oxygen species (ROS), has been implicated in osteoporotic phenotypes, and has been implicated in osteoporotic phenotypes, bone loss, and fracture risk. One of the major cellular defenses against heightened oxidative stress is mediated by nuclear factor (erythroid-derived 2)-like 2 (Nrf2), a master transcription factor that regulates induction of antioxidant gene expression and phase II antioxidant enzymes. Our objective was to test the hypothesis that loss of functional Nrf2 increases radiation-induced bone loss. We irradiated (single dose, 20Gy) the hindlegs of age- and sex-matched Nrf2(+/+) and Nrf2(-/-) mice. After 1 month, microCT analysis and histology revealed a drastic overall decrease in the bone volume after irradiation of mice lacking Nrf2. Although radiation exposure led to bone loss in mice with intact Nrf2, it was dramatically enhanced by loss of Nrf2. Furthermore, in the absence of Nrf2, a decrease in osteoblast mineralization was noted in calvarial osteoblasts compared with wild-type controls, and treatment with a common antioxidant, N-acetyl-l-cysteine (NAC), was able to rescue the mineralization. As expected, we observed a higher number of osteoclasts in Nrf2( /-) mice compared to Nrf2(+/+) mice, and after irradiation, the trend remained the same. RT-PCR analysis of calvarial osteoblasts revealed that in the absence of Nrf2, the expression of RANKL was increased after irradiation. Interestingly, RANKL expression was suppressed when the calvarial osteoblasts were treated with NAC before IR exposure. Taken together, our data suggest that loss of Nrf2 leads to heightened oxidative stress and increased susceptibility to radiation-induced bone loss. PMID- 23085428 TI - Evolving features in type 3 Gaucher disease on long-term enzyme replacement therapy. PMID- 23085429 TI - Pilot study using ambroxol as a pharmacological chaperone in type 1 Gaucher disease. AB - The purpose of this pilot was to assess the tolerability and efficacy of ambroxol as a pharmacological chaperone in patients with symptomatic, type 1 Gaucher disease who present with measurable disease parameters but are not receiving enzyme replacement therapy (ERT) in order to provide proof of concept and/or ascertain the suitability of ambroxol for a larger clinical trial. The Israeli Ministry of Health Form 29c was employed to prescribe ambroxol for off-label use. Twelve patients were dispensed 2 capsules of 75 mg of ambroxol daily for 6 months. There were 8 females (66.7%). Mean age at entry was 41.1 (range: 24-63) years. Mean body weight at entry was 66.4 (range: 46.5-100) kg. One patient withdrew because of a hypersensitivity reaction, one because of elective splenectomy. No patient experienced clinically relevant deterioration in disease parameters measured. One patient achieved a robust response relative to baseline: +16.2% hemoglobin; +32.9% platelets; -2.8% liver volume; and -14.4% spleen volume. Three patients, including the above one, elected to continue on ambroxol for a further 6 months: hemoglobin levels and liver volumes were relatively stable, but platelet counts further increased in the above patient (+52.6% from baseline) and spleen volumes decreased further in all three patients (-6.4%, 18.6%, and -23.4% from baseline). Thus, ambroxol may be a safe option for Gaucher disease patients with potential disease-specific efficacy and should be expanded into a clinical trial using higher doses and placebo-controlled design. PMID- 23085425 TI - Addiction-related gene regulation: risks of exposure to cognitive enhancers vs. other psychostimulants. AB - The psychostimulants methylphenidate (Ritalin, Concerta), amphetamine (Adderall), and modafinil (Provigil) are widely used in the treatment of medical conditions such as attention-deficit hyperactivity disorder and narcolepsy and, increasingly, as "cognitive enhancers" by healthy people. The long-term neuronal effects of these drugs, however, are poorly understood. A substantial amount of research over the past two decades has investigated the effects of psychostimulants such as cocaine and amphetamines on gene regulation in the brain because these molecular changes are considered critical for psychostimulant addiction. This work has determined in some detail the neurochemical and cellular mechanisms that mediate psychostimulant-induced gene regulation and has also identified the neuronal systems altered by these drugs. Among the most affected brain systems are corticostriatal circuits, which are part of cortico-basal ganglia-cortical loops that mediate motivated behavior. The neurotransmitters critical for such gene regulation are dopamine in interaction with glutamate, while other neurotransmitters (e.g., serotonin) play modulatory roles. This review presents (1) an overview of the main findings on cocaine- and amphetamine induced gene regulation in corticostriatal circuits in an effort to provide a cellular framework for (2) an assessment of the molecular changes produced by methylphenidate, medical amphetamine (Adderall), and modafinil. The findings lead to the conclusion that protracted exposure to these cognitive enhancers can induce gene regulation effects in corticostriatal circuits that are qualitatively similar to those of cocaine and other amphetamines. These neuronal changes may contribute to the addiction liability of the psychostimulant cognitive enhancers. PMID- 23085430 TI - A ridge-based framework for segmentation of 3D electron microscopy datasets. AB - Three-dimensional (3D) electron microscopy (EM) has become a major player in structural cell biology as it enables the analysis of subcellular architecture at an unprecedented level of detail. Interpretation of the resulting 3D volumes strongly depends on segmentation, which consists in decomposing the volume into their structural components. The computational approaches proposed so far have not turned out to be of general applicability. Thus, manual segmentation still remains a prevalent method. Here, a new computational framework for segmentation of 3D EM datasets is introduced. It relies on detection and characterization of ridges (i.e. local maxima). The detected ridges are modelled as asymmetric Gaussian functions whose parameters constitute ridge descriptors. This local information is then used to cluster the ridges, which leads to the ultimate segmentation. In this work we focus on membranes and locally planar structures in general. The performance of the framework is illustrated with its application to a number of complex 3D datasets and a quantitative analysis. PMID- 23085431 TI - Prospects and challenges for the development of new therapies for Ewing sarcoma. AB - The Ewing sarcoma family of tumors or Ewing sarcoma (ES) is the second most common malignant bone tumor of childhood. The prognosis for localized Ewing sarcoma has improved through the development of intense multimodal therapy over the past several decades. Unfortunately, patients with recurrent or metastatic disease continue to have a poor prognosis. Therefore, a number of complementary approaches are being developed in both the preclinical and clinical arenas to improve these outcomes. In this review, we will discuss efforts to directly target the biologic drivers of this disease and relate these efforts to the experience with several different agents both in the clinic and under development. We will review the data for compounds that have shown excellent activity in the clinic, such as the camptothecins, and summarize the biological data that supports this activity. In addition, we will review the clinical experience with IGF1 targeted agents, ET-743 and epigenetically targeted therapies, the substantial amount of literature that supports their activity in Ewing sarcoma and the challenges remaining translating these therapies to the clinic. Finally, we will highlight recent work aimed at directly targeting the EWS-FLI1 transcription factor with small molecules in Ewing tumors. PMID- 23085432 TI - Deriving an explicit hepatic clearance equation accounting for plasma protein binding and hepatocellular uptake. AB - High throughput in vitro biochemical and cell-based assays have the promise to provide more mechanism-based assessments of the adverse effects of large numbers of chemicals. One of the most challenging hurdles for interpreting in vitro toxicity findings is the need for reverse dosimetry tools that estimate the exposures that will give concentrations in vivo similar to the active concentrations in vitro. Recent experience using IVIVE approaches to estimate in vivo pharmacokinetics (Wetmore et al., 2012) identified the need to develop a hepatic clearance equation that explicitly accounted for a broader set of protein binding and membrane transport processes and did not depend on a well-mixed description of the liver compartment. Here we derive an explicit steady-state hepatic clearance equation that includes these factors. In addition to the derivation, we provide simple computer code to calculate steady-state extraction for any combination of blood flow, membrane transport processes and plasma protein-chemical binding rates. This expanded equation provides a tool to estimate hepatic clearance for a more diverse array of compounds. PMID- 23085433 TI - Target promiscuity and physicochemical properties contribute to pharmacologically induced ER-stress. AB - In vivo toxicity of drug candidates remains a major problem in the pharmaceutical industry, and is a significant cause of late stage attrition. As a consequence predictive in vitro assays are developed and put in place early in the discovery pipeline to aid compound selection. Endoplasmic reticulum stress (ER-stress) has been implicated in many disease states, as well as compound-induced organ toxicities. We explored the role of ER-stress as a general mechanism of toxicity by utilizing a high-throughput in vitro assay to screen 316 chemically diverse Pfizer proprietary compounds with known in vivo toxicity outcome for nuclear accumulation of spliced x-box binding protein 1 (XBP1s), a key transcription factor of the unfolded protein response (UPR). We examined the correlation between physicochemical properties, such as molecular weight, pKA, lipophilicity, topological polar surface area, and passive permeability, as well as target promiscuity, between XBP1s hits and non-hits and found that lipophilicity, target promiscuity and low passive permeability significantly contributed to ER-stress. In addition, we have shown that compounds which cause ER-stress in the form of XBP1s activation at concentrations below 40 MUM have a more than four times greater chance of causing in vivo toxicity at 10 MUM plasma exposure. PMID- 23085434 TI - Establishment of a cell line carrying single copy of an exogenous mutant reporter gene for assaying the biological activity of ZFNs. AB - In this study, in order to detect the genome-editing activities of ZFNs, a cell line carrying a single copy of mutant reporter eGFP or luciferase gene, with a ZFN target sequence inserted in the middle of the coding region, was built through AAVS1 ZFN mediated knock-in technique. Briefly, AAVS1 ZFN expression vector and donor vector expressing mutant eGFP or luciferase were co-transfected into HEK 293 cells followed by positive/negative selection and cloning procedure. The targeted insertion of a single copy of the exogenous gene was confirmed by PCR, sequencing and southern blot. To prove the principle, hVEGF ZFN was used to test this system. hVEGF ZFN expression vector and donor vector carrying a fragment of wild-type reporter gene corresponding to the mutation-disabled stretch were co-transfected into 293-eGFP-hVEGF-TSF or 293-luci-hVEGF-TSF cell lines. 4 days post transfection, 293-eGFP-hVEGF-TSF group showed increased eGFP positive clones with a correction efficiency of 0.11%, which was significantly higher than that of the control. Similar results were obtained for the 293-luci hVEGF-TSF group. The results indicated that the novel system, established by taking advantage of AAVS1 ZFN mediated knock-in technique, was useful for detecting the genome-editing activities of ZFNs. AAVS1 ZFN mediated knock-in was much easier to use than the current existing FLP-in technique. In addition, our donor vector system, featuring both positive and negative selection mechanisms, made it even more efficient to set up a system for assaying the biological activity of a new assembled ZFN. PMID- 23085435 TI - Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway. AB - Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP induced apoptosis. PMID- 23085436 TI - Chemical cholecystokinin receptor activation protects against obesity-diabetes in high fat fed mice and has sustainable beneficial effects in genetic ob/ob mice. AB - The current study has determined the ability of (pGlu-Gln)-CCK-8 to counter the development of diet-induced obesity-diabetes and examined persistence of beneficial metabolic effects in high fat and ob/ob mice, respectively. Twice daily injection of (pGlu-Gln)-CCK-8 in normal mice transferred to a high fat diet reduced energy intake (p < 0.001), body weight (p < 0.01), circulating insulin and LDL-cholesterol (p < 0.001) and improved insulin sensitivity (p < 0.001) as well as oral and intraperitoneal (p < 0.001) glucose tolerance. Energy intake, body weight, circulating insulin and glucose tolerance of (pGlu-Gln)-CCK-8 mice were similar to lean controls. In addition, (pGlu-Gln)-CCK-8 prevented the effect of high fat feeding on triacylglycerol accumulation in liver and muscle. Interestingly, (pGlu-Gln)-CCK-8 significantly (p < 0.001) elevated pancreatic glucagon content. Histological examination of the pancreata of (pGlu-Gln)-CCK-8 mice revealed no changes in islet number or size, but there was increased turnover of beta-cells with significantly (p < 0.001) increased numbers of peripherally located alpha-cells, co-expressing both glucagon and GLP-1. Beneficial metabolic effects were observed similarly in ob/ob mice treated twice daily with (pGlu-Gln)-CCK-8 for 18 days, including significantly reduced energy intake (p < 0.05), body weight (p < 0.05 to p < 0.01), circulating glucose (p < 0.05 to p < 0.01) and insulin (p < 0.05 to p < 0.001) and improved glucose tolerance (p < 0.05) and insulin sensitivity (p < 0.001). Notably, these beneficial effects were still evident 18 days following cessation of treatment. These studies emphasize the potential of (pGlu-Gln)-CCK-8 for the treatment of obesity-diabetes. PMID- 23085437 TI - Growth differentiation factor 15 stimulates rapamycin-sensitive ovarian cancer cell growth and invasion. AB - Identification of novel molecular markers and therapeutic targets may improve survival rates for patients with ovarian cancer. In the current study, immunohistochemical (IHC) analysis of two human ovarian tumor tissue arrays showed high staining for GDF15 in a majority of tissues. Exogenous stimulation of ovarian cancer cell lines with recombinant human GDF15 (rhGDF15) or stable over expression of a GDF15 expression plasmid promoted anchorage-independent growth, increased invasion, and up-regulation of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF). MMP inhibition suppressed GDF15 mediated invasion. In addition, IHC analysis of human ovarian tumor tissue arrays indicated that GDF15 expression correlated significantly with high MMP2 and MMP9 expression. Exogenous and endogenous GDF15 over-expression stimulated phosphorylation of p38, Erk1/2, and Akt. Pharmacologic inhibition of p38, MEK, or PI3K suppressed GDF15-stimulated growth. Further, proliferation, growth, and invasion of GDF15 stable clones were blocked by rapamycin. IHC analysis demonstrated significant correlation between GDF15 expression and phosphorylation of mTOR. Finally, knockdown of endogenous GDF15 or neutralization of secreted GDF15 suppressed invasion and growth of a GDF15-over-expressing ovarian cancer cell line. These data indicate that GDF15 over-expression, which occurred in a majority of human ovarian cancers, promoted rapamycin-sensitive invasion and growth of ovarian cancer cells. Inhibition of mTOR may be an effective therapeutic strategy for ovarian cancers that over-express GDF15. Future studies should examine GDF15 as a novel molecular target for blocking ovarian cancer progression. PMID- 23085438 TI - Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum. AB - Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19-46, 108-134 and 140-163. The regions covered by these residues are known to be functionally important for TCTP function. We conclude that interaction of artemisinin with TCTP may be at least in part explain the antimalarial activity of artemisinin. PMID- 23085439 TI - Mortality and the siesta, fact and fiction. PMID- 23085440 TI - Impact of beta(S)-globin haplotypes on oxidative stress in patients with sickle cell anemia in steady state. AB - BACKGROUND AND AIMS: In Brazil, sickle cell anemia (SCA) is one of the most common genetic disorders. The levels of fetal hemoglobin (HbF) may be influenced by the presence of genetic modifiers; among these are the beta(S)-globin haplotypes, associated with the clinical heterogeneity presented by the disease. Patients with SCA have an imbalance between the production of reactive oxygen species and antioxidant capacity, generating oxidative stress. Nitric oxide (NO) is a potent vasodilator and may be involved in the mechanism of HbF induction. The aim of this study was to evaluate the impact of beta(S)-globin haplotypes in oxidative stress in patients with SCA. METHODS: The study included 47 patients with SCA in steady state. The molecular diagnosis of SCA and characterization of the beta(S)-globin haplotype was performed by beta(S) chain polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). Concentration of HbF was determined by high-performance liquid chromatography (HPLC). Serum levels of nitrite/nitrate (NOx) and malondialdehyde were determined by spectrophotometry. RESULTS: The most prevalent haplotype in the study population was Bantu. The Benin/n group presented significantly higher HbF and nitrite levels as compared to the Bantu/n group. CONCLUSIONS: Our results confirm data reported in the literature where the Benin and Bantu haplotypes are respectively correlated to high levels and decreased HbF. In addition, haplotypes associated with high levels of HbF showed high levels of nitrite, demonstrating that as the HbF, serum levels of NOx may prove useful as a prognostic biomarker in patients with SCA. PMID- 23085441 TI - Focal lesion in upper part of brachial plexus can be detected by magnetic cervical motor root stimulation. AB - BACKGROUND: The utilities of magnetic cervical motor root stimulation are well known for lesions in the lower part of the brachial plexus, but not for lesions in the other parts. OBJECTIVE: The aim of paper is to show the utilities of magnetic cervical motor root stimulation for lesions in the upper part of the brachial plexus. METHODS: We analyzed the brachial plexus using both electrical stimulation at Erb's point and magnetic cervical motor root stimulation in a patient with brachial plexopathy caused by tumor invasion. RESULTS: On the fourth day after onset, magnetic cervical motor root stimulation revealed abnormal findings in the upper part of the brachial plexus. Two weeks after onset, needle electromyography supported the existence of the focal lesion. CONCLUSION: Magnetic cervical motor root stimulation is useful in detecting abnormal findings in the upper part of the brachial plexus, even at the acute phase. PMID- 23085442 TI - Transcranial direct current stimulation effects on the excitability of corticospinal axons of the human cerebral cortex. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) of the human cerebral cortex modulates cortical excitability non-invasively in a polarity-specific manner: anodal tDCS leads to lasting facilitation of motor cortex excitability. OBJECTIVE: To further elucidate the underlying physiological mechanisms of tDCS. METHODS: We recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation of the primary motor cortex before and after a 20 min period of anodal tDCS in a conscious patient who had electrode implanted in the cervical epidural space for the control of pain. We performed magnetic stimulation of the motor cortex using a direction of the induced current in the brain capable of activating both corticospinal axons, evoking D-wave activity, and cortico cortical axons projecting upon corticospinal cells, evoking I-wave activity. RESULTS: Anodal tDCS increased the excitability of cortical circuits generating both D and I-wave activity, with a more prolonged effect on D-wave activity. The changes in motor evoked potential recorded from hand muscles produced by tDCS were in agreement with the effects produced on intracortical circuitry. CONCLUSIONS: Epidural recordings of corticospinal activity in our patient indicate that anodal tDCS develops its facilitatory effects by an increase in the excitability of corticospinal axons and by an increase of activity in cortico cortical projections onto pyramidal tract neurones, modulating motor cortex excitability with both synaptic (I waves) and non-synaptic (D waves) mechanisms. PMID- 23085443 TI - Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia. AB - BACKGROUND AND OBJECTIVES: The development of more efficient treatment remains a major unmet need in the realm of schizophrenia disease. Using the maternal immune stimulation and the pubertal cannabinoid administration rat model of schizophrenia, the present study aimed at testing the hypothesis that deep brain stimulation (DBS) serves as a novel therapeutic technique for this disorder. METHODS: Adult offspring of dams, treated with the immune activating agent poly I:C (4 mg/kg, n = 50) or saline (n = 50), underwent bilateral stereotactic electrode implantation into one of the following brain regions: subthalamic nucleus (STN, n = 12/10), entopeduncularis nucleus (EP, n = 10/11), globus pallidus (GP, n = 10/10), medial prefrontal cortex (mPFC, n = 8/8), or dorsomedial thalamus (DM, n = 10/11). Adult rats treated with the CB1 receptor agonist WIN 55,212-2 (WIN, n = 16) or saline (n = 12) during puberty were bilaterally implanted with electrodes into either the mPFC (n = 8/6) or the DM (n = 8/6). After a post-operative recovery period of one week, all rats were tested on a well-established cross-species phenomenon that is disrupted in schizophrenia, the pre-pulse inhibition (PPI) of the acoustic startle reflex (ASR) under different DBS conditions. RESULTS: Poly I:C induced deficits in PPI of the ASR were normalized upon DBS. DBS effects depended on both stimulation target and stimulation parameters. Most prominent effects were found under DBS at high frequencies in the mPFC and DM. These effects were replicated in the pubertal WIN administration rat model of schizophrenia. CONCLUSIONS: Brain regions, in which DBS normalized PPI deficits, might be of therapeutic relevance to the treatment of schizophrenia. Results imply that DBS could be considered a plausible therapeutic technique in the realm of schizophrenia disease. PMID- 23085444 TI - Testosterone-dependency of male solo song in a duetting songbird--evidence from females. AB - For male songbirds of the temperate zone there is a tight link between seasonal song behaviour and circulating testosterone levels. Such a relationship does not seem to hold for tropical species where singing can occur year-round and breeding seasons are often extended. White-browed sparrow weavers (Plocepasser mahali) are cooperatively breeding songbirds with a dominant breeding pair and male and female subordinates found in eastern and southern Africa. Each group defends an all-purpose territory year-round. While all group members sing duets and choruses, the most dominant male additionally sings a solo song that comprises a distinct and large syllable repertoire. Previous studies suggested this type of song being associated with reproduction but failed to support a relationship with males' circulating testosterone levels. The present study aimed to investigate the steroid hormone sensitivity of the solo song in more detail. We found that dominant males had significantly higher circulating testosterone levels than subordinates during the early and late breeding seasons. No changes in solo song characteristics were found between both time points. Further, experimental implantation of captive adult females with exogenous testosterone induced solo singing within one week of treatment. Such females produced male-typical song regarding overall structure and syllable composition. Sex differences existed, however, concerning singing activity, repertoire size and temporal organisation of song. These results suggest that solo singing in white-browed sparrow weavers is under the control of gonadal steroid hormones. Moreover, the behaviour is not male-specific but can be activated in females under certain conditions. PMID- 23085446 TI - Classification systems of adult craniopharyngiomas: the need for an accurate definition of the hypothalamus-tumor relationships. PMID- 23085445 TI - Circulating Biomphalaria glabrata hemocyte subpopulations possess shared schistosome glycans and receptors capable of binding larval glycoconjugates. AB - Host lectin-like recognition molecules may play an important role in innate resistance in Biomphalaria glabrata snails to larval schistosome infection, thus implicating parasite-expressed glycans as putative ligands for these lectin receptors. While host lectins may utilize specific glycan structures for parasite recognition, it also has been hypothesized that the parasite may use this system to evade immune detection by mimicking naturally-expressed host glycans, resulting in reduced immunorecognition capacity. By employing immunocytochemical (ICC) and Western blot assays using schistosome glycan-specific monoclonal antibodies (mABs) we sought to identify specific glycan epitopes (glycotopes) shared in common between larval Schistosoma mansoni and B. glabrata hemocytes, the primary immune effector cells in snails. Results confirmed the presence of selected larval glycotopes on subpopulations of hemocytes by ICC and association with numerous hemocyte proteins by Western blot analyses, including a trimannosyl core N-glycan (TriMan), and two fucosylated lacdiNAc (LDN) variants, F-LDN and F LDN-F. Snail strain differences were seen in the prevalence of constitutively expressed F-LDN on hemocytes, and in the patterns of protein immunoreactivity with these mABs. In contrast, there was little to no hemocyte reactivity with mABs for Lewis X (LeX), LDN, LDN-F or LDN-DF. When intact hemocytes were exposed to larval transformation products (LTPs), distinct cell subpopulations displayed weak (LeX, LDN-DF) to moderate (LDN, LDN-F) glycotope reactivity by ICC, including snail strain differences in the prevalence of LDN-reactive cellular subsets. Far-Western blot analyses of the hemocytes following exposure to larval transformation proteins (LTPs) also revealed multiple mAB-reactive hemocyte protein bands for LeX, LDN, LDN-F, and LDN-DF. These results demonstrate the existence of complex patterns of shared larval glycan constitutively expressed on hemocytes and their proteins, as well as the ability of hemocytes to acquire shared glycans by the selective binding of parasite-released LTP. Unraveling the functional significance of these naturally expressed and acquired shared glycans on specific hemocyte populations represents an important challenge for future investigations. PMID- 23085447 TI - Diagnostic performances of hepatitis C virus-NS4 antigen in patients with different liver pathologies. AB - BACKGROUND AND AIMS: Hepatitis C virus (HCV) has emerged as the major pathogen of liver disease worldwide. The aim of this study was to quantitate and evaluate the performance of HCV-NS4 antigen as an alternative approach for confirmation of viremia. METHODS: Detection of HCV-NS4 was assessed in 883 patients with chronic hepatitis C. Areas under the ROC curves (AUC) were used to assess and compare diagnostic accuracy of ELISA for HCV-NS4 with quantitative HCV-RNA as a gold standard. RESULTS: HCV-NS4 was identified at 27 kDa using Western blot. AUC for HCV-NS4 detection was 0.95 for all patients with different liver pathologies: 0.93 for liver fibrosis (LF), 0.95 for liver cirrhosis (LC) and 0.98 for hepatocellular carcinoma (HCC). The mean +/- SD (MUg/mL) of HCV-NS4 in LF was 94.2 +/- 55.6; in LC was 99.3 +/- 64.8 and in HCC was 124.9 +/- 70.3. CONCLUSIONS: HCV-NS4 antigen detection using ELISA is a reliable test in the confirmation of HCV infection. PMID- 23085448 TI - Maternal/child seroprevalence of antibodies against Treponema pallidum at four general hospitals in the state of Morelos, Mexico. AB - BACKGROUND AND AIMS: Treponema pallidum can cause syphilis in pregnant women and congenital syphilis in the newborn. In Latin America, 330,000 pregnant women are diagnosed with syphilis every year. Adequate prenatal care to detect syphilis reduces maternal morbidity and fetal and neonatal mortality and morbidity. We undertook this study to determine T. pallidum seroprevalence among pregnant and puerperal women from Morelos, Mexico, as well as to evaluate the sexual behavior, demographic and clinical variables associated with the infection. METHODS: A cross-sectional study was carried out among pregnant and puerperal women from four general hospitals from Morelos, Mexico during 2005-2009. Women answered a questionnaire and provided a blood sample to detect antibodies against T. pallidum. RESULTS: A total of 2331 women were analyzed with 0.26% of T. pallidum seroprevalence. There were four cases with active syphilis and two cases with latent syphilis, as well as two cases of congenital syphilis. Illiterate women had 6.7 times higher risk of being infected. Women who did not undergo a urine test had a 5.3 times higher risk for infection and women who do not have piped water inside their household had a 5.0-fold higher risk of having anti-T. pallidum antibodies. All seropositive cases were from the same hospital (Cuautla General Hospital) with demographic, sexual behavior and medical care characteristics different from the other three hospitals. CONCLUSIONS: Syphilis during pregnancy and congenital syphilis are still present in Mexico. It may be that the more urban a population the higher the chance of the prevalence of maternal syphilis. It would be beneficial to reinforce the observance of the Official Mexican Norm and to implement rapid diagnostics tests to contend with this public health problem. PMID- 23085449 TI - Physical activity, brain plasticity, and Alzheimer's disease. AB - In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health. PMID- 23085450 TI - MicroRNA-34a modulates chemosensitivity of breast cancer cells to adriamycin by targeting Notch1. AB - BACKGROUND AND AIMS: MicroRNA-34a (miR-34a) as a tumor suppressor has been reported in many other studies. However, its role in modulating the sensitivity of breast cancer cells to adriamycin (ADR) remains unclear. The aim of this study is to evaluate the role of miR-34a in the sensitivity of breast cancer cells to ADR. METHODS: The role of miR-34a in breast cancer cells was detected using MTT assay, flow cytometry assay, real-time PCR and Western blot, etc. The association of miR-34a and Notch1 was analyzed by dual-luciferase reporter assay and Notch1 siRNA technology. Real-time PCR assay was performed to test the expression of miR 34a and Notch1 in 38 selective breast cancer tissue samples. RESULTS: Ectopic overexpression of miR-34a could sensitize MCF-7 breast cancer cells to ADR. MiR 34a mimic could inhibit the luciferase activity of the construct containing wild type 3' UTR of Notch1 in MCF-7/ADR cells. Notch1-siRNA could partially reverse the effect of miR-34a inhibitor in inducing chemoresistance of MCF-7 cells to ADR. Further, there was an inverse association between Notch1 and miR-34a expression in breast cancer. CONCLUSION: Dysregulation of miR-34a plays critical roles in the acquired ADR resistance of breast cancer, at least in part via targeting Notch1. PMID- 23085451 TI - Pathogenesis and disease-modifying therapy in Alzheimer's disease: the flat line of progress. AB - The lack of progress in the development of disease-modifying therapy in Alzheimer's disease (AD) was highlighted recently by the cessation of a phase 3 clinical trial studying the effects of bapineuzumab on mild to moderate disease. No treatment benefit was apparent, whereas several serious side effects occurred more commonly in the treatment group compared to placebo. This is the latest failure in a now long list of trials targeting lesional proteins believed to be fundamental drivers of the disease process. As the focus of the trial is directly tied to ostensible disease pathogenesis, objectivity compels us yet again to re examine the amyloid cascade hypothesis as even a marginally significant pathogenic mediator of disease and to perhaps revert back to traditional science where repeated negative data leads one to consider other ideas. In the case of AD, amyloid-beta metabolism and tau phosphorylation have been exhaustively studied, both to no avail. Oxidative stress has similarly been examined in detail by multiple mechanisms and targeted for treatment with a similar result. An appeal to the scientific community may be made to consider lesions in a different light. Have we been seduced by so-called hallmark lesions into believing that they are responsible for disease when in fact the reverse is true, and will we genuinely consider a systems biology approach to AD or instead continue on the path of the lesion, which has so far followed a flat line of progress? PMID- 23085453 TI - The macroeconomics of dementia--will the world economy get Alzheimer's disease? AB - BACKGROUND: Health is firmly on the economic radar. It is big business. In 2009, the proportion of the Gross Domestic Product spent on health care varied between 6.4% in Mexico and 17.4% in the U.S., with the UK at 9.8% and Germany, Switzerland and Canada ~11%. These are considerable amounts of money and they are growing. With all projections pointing to a growth in the numbers of older people, the pressure on budgets will only increase. In this paper we will consider the role of dementia in this. METHODS: Demographic and economic data were combined and policy implications developed. RESULTS: The costs of dementia dwarf those of the illnesses that are currently prioritized at a national and international level such as HIV, cancer, heart disease, stroke and diabetes. Based on simple demographics, the costs of dementia are set to increase by 85% by 2030, with developing countries bearing an increasing share of the economic burden. CONCLUSIONS: The data suggest that dementia is a clear and present economic challenge for the world from the macro level down to the individual. Before the crisis, governmental structural primary deficits were generally improving and this would have given time and resource to meet the challenges of ageing in general and dementia in particular. However, increasing government debt over the past 3 years has had the effect of our needing to implement reforms to contain the risks to sovereign budgets sooner rather than later. This is not an issue that can be ignored. Inaction will only lead to further debt accumulation in the medium term and the death of systems of care in the long term. Across the developed world, the main long-term fiscal challenges come from health care costs, and dementia is a major driver of those costs. There is a need for budgetary consolidation and pension reform more generally. But, given that dementia is the highest ticket health and social care item that we have, making up 60% of long term care spending according to some estimates, then targeted investment in early intervention and in research (into causes, cure and care) are likely to be of major value in personal, societal, political, and economic terms. PMID- 23085454 TI - Insight into estrogen receptor beta-beta and alpha-beta homo- and heterodimerization: A combined molecular dynamics and sequence analysis study. AB - Biological effects of estrogenic ligands are transduced by two estrogen receptors, ERalpha and ERbeta; they transactivate as dimers. Since ERbetabeta and ERalphabeta homo- and heterodimers are known to exhibit anti-proliferative effects, we characterized their dimerization interface in atomic details and explored their ligand induced conformational dynamics. ERalphabeta heterodimer is found to be relatively more stable than the ERbetabeta homodimer and the observed differences are mainly due to loop dynamics. The principal component analysis reveals that, in the essential subspace, the homo- and heterodimer dynamics are distinctively different. The core recognition groove of the dimer interface, formed by helix 9 and helix 10/11, remains unaltered in both homo- and heterodimers. The dimerization surfaces are found to be highly conserved in eukaryotic lineages. Phylogenetic patterns for ERalpha appear to be very much similar to that of ERbeta which signifies that the formation of functional heterodimer is evolutionary selected. PMID- 23085455 TI - Summarizing clinical pathways from event logs. AB - OBJECTIVE: Clinical pathway analysis, as a pivotal issue in ensuring specialized, standardized, normalized and sophisticated therapy procedures, is receiving increasing attention in the field of medical informatics. Research in clinical pathway analysis has so far mostly focused on looking at aggregated data seen from an external perspective, and only provide very limited insight into the pathways. In some recent work, process mining techniques have been studied in discovering clinical pathway models from data. While it is interesting, discovered models may provide too much detail to give a comprehensive summary of the pathway. Moreover, the number of patterns discovered can be large. Alternatively, this article presents a new approach to build a concise and comprehensive summary that describes the entire structure of a clinical pathway, while revealing essential/critical medical behaviors in specific time intervals over the whole time period of the pathway. METHODS: The presented approach summarizes a clinical pathway from the collected clinical event log, which regularly records all kinds of patient therapy and treatment activities in clinical workflow by various hospital information systems. The proposed approach formally defines the clinical pathway summarization problem as an optimization problem that can be solved in polynomial time by using a dynamic-programming algorithm. More specifically, given an input event log, the presented approach summarizes the pathway by segmenting the observed time period of the pathway into continuous and overlapping time intervals, and discovering frequent medical behavior patterns in each specific time interval from the log. RESULTS: The proposed approach is evaluated via real-world data-sets, which are extracted from Zhejiang Huzhou Central hospital of China with regard to four specific diseases, i.e., bronchial lung cancer, colon cancer, gastric cancer, and cerebral infarction, in two years (2007.08-2009.09). Although the medical behaviors contained in these logs are very diverse and heterogeneous, experimental results indicates that the presented approach is feasible to construct condensed clinical pathway summaries in polynomial time from the collected logs, and have a linear scalability against the increasing size of the logs. CONCLUSION: Experiments on real data-sets illustrate that the presented approach is efficient and discovers high-quality results: the observed time period of a clinical pathway is correctly segmented into a set of continuous and overlapping time intervals, in which essential/critical medical behaviors are well discovered from the event log to form the backbone of a clinical pathway. The experimental results indicate that the generated clinical pathway summary not only reveals the global structure of a pathway, but also provides a thorough understanding of the way in which actual medical behaviors are practiced in specific time intervals, which might be essential from the perspectives of clinical pathway analysis and improvement. PMID- 23085457 TI - TRAIL/MEKK4/p38/HSP27/Akt survival network is biphasically modulated by the Src/CIN85/c-Cbl complex. AB - Previously, we showed that mitogen-activated protein kinase/extracellular signal related kinase 4 (MEKK4) is responsible for p38 activation and that its activation during tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment also increases the catalytic activity of Akt. Here, we further investigated how the TRAIL-induced MEKK4/p38/heat shock protein (HSP27)/Akt survival network is modulated by the Src/c-Cbl interacting protein of 85kDa (CIN85)/c-Cbl complex. TRAIL-induced activation of Akt catalytic activity and phosphorylation were highly correlated with p38/HSP27 phosphorylation, whereas the phosphorylation of p38/HSP27 increased further during incubation with curcumin and TRAIL, which caused significant apoptotic cell death. CIN85, a c-Cbl binding protein, plays an essential role in connecting cell survival to cell death. The interaction of CIN85 with MEKK4 was increased during the late phase of TRAIL incubation, suggesting that sustained p38 and HSP27 phosphorylation protects cells by preventing further cell death. However, further increases in p38/HSP27 phosphorylation induced by cotreatment with curcumin and TRAIL converted cell fate to death. Taken together, these data demonstrate that phosphorylated p38/HSP27 as biphasic modulators act in conjunction with CIN85 to determine whether cells survive or die in response to apoptotic stress. PMID- 23085456 TI - TGF-beta inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system. AB - Over the past decades, the incidence of cutaneous melanoma in developed countries has increased faster than any other cancer. Although most patients have localized disease at the time of diagnosis and are cured by surgical excision of the primary tumor, melanoma can be highly malignant and the survival dramatically decreases for advanced stage melanomas. It is thus necessary to understand the progression of this disease. Cell migration and invasion promote tumor metastasis, the major cause of melanoma cancer morbidity and death. In this study, we investigated the role of the TGFbeta/Smad signaling pathway in melanoma tumor progression and found TGFbeta to potently inhibit both cell migration and invasion in human melanoma cell lines, established from different patients. Furthermore, we elucidated the molecular mechanisms by which TGFbeta exerts its effects and found the plasminogen activation system (PAS) to play a central role in the regulation of these effects. We found TGFbeta to strongly up-regulate the Plasminogen Activator Inhibitor-1 (PAI-1) in melanoma cells, leading to reduced plasmin generation and activity and, in turn to inhibition of cell migration and invasion. Together, our results define TGFbeta as a potent suppressor of tumor progression in cutaneous melanoma, inhibiting both cell migration and invasion. PMID- 23085458 TI - Preoperative biopsy and intraoperative tumor diameter predict lymph node dissemination in endometrial cancer. AB - OBJECTIVE: To determine whether preoperative biopsy (grade and histology) and intraoperative tumor diameter (TD) predict lymph node dissemination (LN+) and lymph node recurrence (LNRec) in endometrial cancer (EC). METHODS: Patients who underwent EC surgery from 2004 to 2008 were stratified into risk categories. Cases with preoperative grade 3 or non-endometrioid histology were classified as high risk (HR). Patients with preoperative FIGO grade 1 or 2, endometrioid histology or complex and/or atypical hyperplasia were classified based on intraoperative findings: (a) intraoperative macroscopic extrauterine disease classified as HR; (b) largest TD>2 cm classified as intermediate risk (IR) and (c) TD <= 2 cm classified as low risk (LR). LN+ and LNRec rates were determined. RESULTS: Of 704 patients evaluated, 188 were HR (27%), 350 IR (50%), and 166 LR (23%). P/PA lymphadenectomy was performed in 87% HR, 83% IR and 16% LR patients. LN+ and/or LNRec occurred in 51 HR patients (27%) and 39 IR patients (11%). Only 1 LR patient (0.6%) had LN+ and none had LNRec. Four LR patients (2%) required adjuvant therapy according to permanent section pathology. CONCLUSIONS: Preoperative biopsy and intraoperative TD can be used to effectively stratify patients into LR, IR or HR subgroups to tailor surgery. LR patients have a low probability (<1%) of LN+ and/or LNRec and lymphadenectomy can be omitted in this group. HR and IR patients combined (3/4 of population) have a substantial risk of LN+ or LNRec (17%). Lymphadenectomy is proposed to be advantageous in HR and IR patients if accurate frozen section is lacking. PMID- 23085459 TI - Sociodemographic factors associated with cervical cancer screening coverage and follow-up of high grade abnormal results in a population-based cohort. AB - INTRODUCTION: A cervical cytology based screening program is effective if there is regular screening of the 'at risk' population and close follow-up of those labeled abnormal. METHODS: This is a population cohort study of women between 20 69 year old who were eligible in Ontario from 2008-2010. We used administrative data to evaluate the rates of cervical cancer screening and follow-up of high grade Pap tests. Variation in cervical cytology coverage and follow-up of high grade abnormal results are associated with age, area level income and health region. Multivariate logistic regression was used to identify independent factors associated with screening and followup. RESULTS: 3.7million women were eligible for screening of which 72% had a Pap smear in the prior 3years. These rates varied by age, income and region (p<0.0001). Women residing in the lowest income neighborhoods were half as likely to be screened (p<0.0001). 83% of those with an high grade intraepithelial lesion Pap test result had follow-up with colposcopy or treatment within 6months and this varied by year, age, income and region (p<0.0001). CONCLUSIONS: Despite universal health coverage, cervical cancer screening rates are suboptimal with older and low income women being at greatest risk. Follow-up among women with high grade abnormal tests is mediocre at 3months and acceptable at 6months. Novel models of cervical cancer screening program implementation are needed to address these inadequacies. PMID- 23085460 TI - A multicenter evaluation of adjuvant therapy in women with optimally resected stage IIIC endometrial cancer. AB - OBJECTIVE: To determine if there is an advantage to combination chemotherapy and radiation for optimally resected stage IIIC endometrial cancer (EC). METHODS: A multicenter retrospective analysis of patients with EC from 1991 to 2008 was conducted. Inclusion criteria were lymph node assessment and optimally resected disease. Recurrence-free (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: 265 patients with optimally resected stage IIIC EC were identified. Postoperative therapies included radiotherapy in 17% (n=45), chemotherapy in 17% (n=46), and both chemotherapy and radiation in 61% (n=161). Three-year RFS was 56% for chemotherapy alone, compared to 73% for radiation alone, and 73% for combination therapy (p=0.12). Those receiving chemotherapy alone had the worst 3-year OS (78%) compared to either radiotherapy alone (95%) or combination therapy (90%) (p=0.005). After adjustment for stage and grade those treated with chemotherapy alone were at a 2.2 fold increased risk of recurrence (95% CI, 1.2 to 4.2; p=0.02) and 4.0 fold increased risk of death (95% CI, 1.6 to 10.0; p=0.004) compared to those treated with chemotherapy and radiation. In contrast there was no significant difference in RFS [HR=1.0 (95% CI, 0.5 to 2.0; p=0.92)] or OS [HR=1.1 (95% CI, 0.3 to 3.6; p=0.91)] for those treated with radiation alone compared to those treated with chemotherapy and radiation. CONCLUSION: Adjuvant therapy with either radiation alone or chemotherapy and radiation was associated with improved outcomes for patients with optimally resected stage IIIC EC compared to those treated with chemotherapy only. PMID- 23085461 TI - Transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR): a new method for sentinel lymph node detection in endometrial cancer. AB - OBJECTIVE: The objective of this prospective study was to determine the feasibility, safety and performance of a new method for sentinel lymph node (SLN) detection in endometrial cancer (EC) using transvaginal ultrasound-guided myometrial injection of radiotracer (TUMIR). METHODS: From 2006 to 2011, 74 patients with high-risk EC were included in the study. Twenty-four hours before surgery 148MBq of (99m)Tc-nanocolloid (8mL) was injected into two spots in the anterior and posterior myometrium using an ultrasound-guided transvaginal puncture. SLN was localized preoperatively by lymphoscintigraphy and intraoperatively with gamma probe. After SLN biopsy the patients underwent a complete laparoscopic pelvic and paraaortic lymphadenectomy. RESULTS: The TUMIR method was successfully achieved in 67/74 patients (90.5%). SLN was identified in 55 women (74.3%). No adverse effects were observed. Pelvic drainage was observed in 87.2% of women and paraaortic SLN was identified in 45.4%, with 12.8% of the patients draining only in this area. The mean number of SLN retrieved was 2.8 per patient (range 1 to 9). Metastatic disease was found in 13 (23.6%) patients. Metastatic involvement of the paraaortic lymph nodes was observed in 4 (30.7%) cases. All were identified by TUMIR. The sensitivity and negative predictive value of SLN detected by TUMIR to detect metastasis were 92.3% (95% CI 22.9-100) and 97.7% (95% CI 82.0-100), respectively. CONCLUSIONS: TUMIR is a safe, feasible method to detect SLN in patients with EC, has a good detection rate and provides representative information of the lymphatic drainage of EC. PMID- 23085462 TI - Replication-dependent irreversible topoisomerase 1 poisoning is responsible for FdUMP[10] anti-leukemic activity. AB - Previous studies have indicated that 5-Fluoro-2'-deoxyuridine-5'-O-monophosphate 10mer (FdUMP[10]) displays strong antileukemic activity through the dual targeting of thymidylate synthase (TS) and DNA topoisomerase 1 (Top1). The present studies were undertaken to clarify the relationship between the induction of a thymineless state and the formation of Top1 cleavage complexes (Top1CC) for inducing cell death and to clarify the role of DNA replication for induction of lethal DNA double-strand breaks (DSBs) in FdUMP[10]-treated acute myeloid leukemia (AML) cells. Human promyelocytic (HL60) and AML (KG1a, Molm13, THP-1) cells were synchronized by serum starvation and treated with FdUMP[10] with thymidine (Thy) rescue. Cells were assayed for TS inhibition, DNA DSBs, Top1CC, and apoptosis to clarify the interrelationship of TS inhibition and Top1CC for cell death. FdUMP[10] induced a thymineless state in AML cells and exogenous Thy administered within the first 18 hours of treatment rescued FdUMP[10]-induced Top1CC formation, gammaH2AX phosphorylation, and apoptosis induction. Exogenous Thy was not effective after cells had committed to mitosis and undergone cell division in the presence of FdUMP[10]. FdUMP[10] treatment resulted in Chk1 activation, and Chk1 inhibition enhanced FdUMP[10]-induced DNA damage and apoptosis. Jnk-signaling was required for FdUMP[10]-induced apoptosis in promyelocytic HL60 cells and in THP1 cells, but was antiapoptotic in Molm13 and to a lesser extent KG1a AML cells. The results are consistent with FdUMP[10] inducing a thymineless state, leading to misincorporation of FdU into genomic DNA of proliferating cells. Top1CC form in cells upon re-entry into S-phase, resulting in DNA double-strand breaks, and initiating apoptotic signaling that can be either muted or enhanced by Jnk-signaling depending on cell type. PMID- 23085463 TI - Postallograft lenalidomide induces strong NK cell-mediated antimyeloma activity and risk for T cell-mediated GvHD: Results from a phase I/II dose-finding study. AB - Lenalidomide may prevent relapses after allogeneic stem cell transplantation by promoting the immune-mediated graft-versus-tumor effect. We performed a prospective phase I/II study to define the dose-limiting toxicity and the immunologic effects of lenalidomide given early (day 100-180) after allograft for four cycles in patients with multiple myeloma. According to the Fibonacci design, 24 patients with a median age of 53 years were included. Dose-limiting toxicity was organ toxicity owing to graft-versus-host disease, and the maximum tolerable dose was 5 mg. The incidence of graft-versus-host disease after lenalidomide was 38%, occurring after a median of 22 days, and was beside organ toxicity, a leading cause to discontinue the study in 29% of the patients. Immune monitoring revealed a significant increase in peripheral gamma-interferon-secreting CD4(+) and CD8(+) T cells within the first week of lenalidomide treatment followed by a delayed increase in T regulatory cells. Furthermore, natural killer (NK) cells isolated from the peripheral blood of patients evidenced a significantly improved antimyeloma activity after lenalidomide treatment. The immune effect might have contributed to the increased CR rate from 24-42% after lenalidomide treatment because nonresponding patients showed significantly less natural killer and T cell activation. (Study registered under: NCT 00778752.). PMID- 23085464 TI - Effects of azacitidine on matrix metalloproteinase-9 in acute myeloid leukemia and myelodysplasia. AB - Matrix metalloprotease-9 (MMP9) plays a critical role in acute myeloid leukemia (AML) by increasing the invasive properties of malignant myeloblasts. The role of this enzyme in high-risk myelodysplastic diseases (MDS) and the effect of azacitidine on its expression in MDS and AML have not been studied in detail. In this work, we have analyzed the effect of different concentrations of azacitidine in two well-established, MDS-derived, acute myeloid leukemic cell lines: MOLM-13 and SKM-1. We have demonstrated that 1 MUmol/L azacitidine decreases MMP9 DNA methylation levels and that this is correlated with a significant increase in messenger RNA expression in both cell lines. Surprisingly, changes in protein levels were minor. This paradoxic effect is explained by the drug-dependent induction of apoptosis that reduces the amount of active secreting cells. A balance between induced expression and apoptosis was established at an azacitidine concentration of 0.2 MUmol/L in MOLM-13 cells. This dose significantly increased the invasive capacity of viable cells, as measured in the Matrigel assay. To evaluate the clinical relevance of this observation, we have examined the effect of azacitidine on MMP9 expression in bone marrow from five patients with MDS, with the finding that this drug significantly increased MMP9 protein levels in all analyzed patients after six cycles of treatment. Based on these results, we conclude that azacitidine increases MMP9 expression and may enhance invasiveness in vitro. Because all five patients relapsed, these findings might explain, at least partially, the clinical failure of the drug and the progression to a more aggressive disease. PMID- 23085465 TI - Effects of DNA methyltransferase inhibitors (DNMTIs) on MDS-derived cell lines. AB - DNA methyltransferase inhibitors (DNMTIs), including decitabine (DAC) and azacitidine (AZA), have recently been highlighted for the treatment of high-risk myelodysplastic syndrome (MDS); however, their action mechanisms have not been clearly defined. Therefore, we investigated the effects of DNMTIs on MDS-derived cell lines in vitro. An MDS-derived cell line MDS92 and its blastic subline MDS-L and HL-60 were used. All three cell lines were sensitive to DNMTIs, but MDS-L was the most susceptible. DAC-induced cell death in MDS-L was preceded by DNA damage induced G2 arrest via a p53-independent pathway. AZA did not influence the pattern of cell cycle, although it induced DNA damage response. The IC(50) of DAC or AZA on MDS-L cells was associated with the dose inducing the maximal hypomethylation in long interspersed nuclear elements-1 (LINE-1) methylation assay. AZA suppressed the level of methylation in a time-dependent manner (days 4, 7, and 10), whereas DAC maintained the level of methylation from day 4 to 11. The protein expression of DNMT1 and DNMT3a decreased with the suppression of growth and methylation. We conclude that this study provides in vitro models for understanding the effects of DNMTIs on cell growth and gene regulation, including differences in the possible action mechanism of DAC and AZA. PMID- 23085466 TI - Use of time-of-flight mass spectrometry for large screening of organic pollutants in surface waters and soils from a rice production area in Colombia. AB - The irrigate district of Usosaldana, an important agricultural area in Colombia mainly devoted to rice crop production, is subjected to an intensive use of pesticides. Monitoring these compounds is necessary to know the impact of phytosanitary products in the different environmental compartments. In this work, surface water and soil samples from different sites of this area have been analyzed by applying an analytical methodology for large screening based on the use of time-of-flight mass spectrometry (TOF MS) hyphenated to liquid chromatography (LC) and gas chromatography (GC). Several pesticides were detected and unequivocally identified, such as the herbicides atrazine, diuron or clomazone. Some of their main metabolites and/or transformation products (TPs) like deethylatrazine (DEA), deisopropylatrazine (DIA) and 3,4-dichloroaniline were also identified in the samples. Among fungicides, carbendazim, azoxystrobin, propiconazole and epoxiconazole were the most frequently detected. Insecticides such as thiacloprid, or p,p'-DDT metabolites (p,p'-DDD and p,p'-DDE) were also found. Thanks to the accurate-mass full-spectrum acquisition in TOF MS it was feasible to widen the number of compounds to be investigated to other families of contaminants. This allowed the detection of emerging contaminants, such as the antioxidant 3,5-di-tertbutyl-4-hydroxy-toluene (BHT), its metabolite 3,5-di-tert butyl-4-hydroxy-benzaldehyde (BHT-CHO), or the solar filter benzophenone, among others. PMID- 23085467 TI - Regional land salinization assessment and simulation through cellular automaton Markov modeling and spatial pattern analysis. AB - Land salinization and desalinization are complex processes affected by both biophysical and human-induced driving factors. Conventional approaches of land salinization assessment and simulation are either too time consuming or focus only on biophysical factors. The cellular automaton (CA)-Markov model, when coupled with spatial pattern analysis, is well suited for regional assessments and simulations of salt-affected landscapes since both biophysical and socioeconomic data can be efficiently incorporated into a geographic information system framework. Our hypothesis set forth that the CA-Markov model can serve as an alternative tool for regional assessment and simulation of land salinization or desalinization. Our results suggest that the CA-Markov model, when incorporating biophysical and human-induced factors, performs better than the model which did not account for these factors when simulating the salt-affected landscape of the Yinchuan Plain (China) in 2009. In general, the CA-Markov model is best suited for short-term simulations and the performance of the CA-Markov model is largely determined by the availability of high-quality, high-resolution socioeconomic data. The coupling of the CA-Markov model with spatial pattern analysis provides an improved understanding of spatial and temporal variations of salt-affected landscape changes and an option to test different soil management scenarios for salinity management. PMID- 23085468 TI - Assessment of legacy and emerging persistent organic pollutants in Weddell seal tissue (Leptonychotes weddellii) near McMurdo Sound, Antarctica. AB - Muscle samples were collected from pup, juvenile and adult Weddell seals (Leptonychotes weddellii) near McMurdo Sound, Antarctica during the austral summer of 2006. Blubber samples were collected from juvenile and adult seals. Samples were analyzed for emerging and legacy persistent organic pollutants (POPs) including current and historic-use organochlorine pesticides, polychlorinated biphenyls (PCBs), and polybrominated diphenyl ethers (PBDEs). Of the 41 target analytes, 28 contaminants were recovered from the Weddell seal blubber, in this order of prevalence: p,p'-DDE, p,p'-DDT, trans-nonachlor, mirex, cis-nonachlor, PCB 153, PCB 138, dieldrin, heptachlor epoxide, nonachlor III, PCB 187, oxychlordane, cis-chlordane, PCB 118, PBDE 47, PCB 156, PCB 149, PCB 180, PCB 101, PCB 170, PCB 105, o,p'-DDT, PCB 99, trans-chlordane, PCB 157, PCB 167, PCB 189, and PCB 114. Fewer POPs were found in the muscle samples, but were similar in the order of prevalence to that of the blubber: p,p'-DDE, o,p'-DDT, trans-nonachlor, nonachlor III, oxychlordane, p,p'-DDT, dieldrin, mirex, cis nonachlor, PCB 138, and PCB 105. Besides differences in toxicant concentrations reported between the muscle and blubber, we found differences in POP levels according to age class and suggest that differences in blubber storage and/or mobilization of lipids result in age class differences in POPs. To our knowledge, such ontogenetic associations are novel. Importantly, data from this study suggest that p,p'-DDT is becoming less prevalent temporally, resulting in an increased proportion of its metabolite p,p'-DDE in the tissues of this top predator. In addition, this study is among the first to identify a PBDE congener in Weddell seals near the McMurdo Station. This may provide evidence of increased PBDE transport and encroachment in Antarctic wildlife. PMID- 23085469 TI - Temporal trends of polychlorinated biphenyls and organochlorine pesticides in Great Lakes fish, 1999-2009. AB - Temporal trend analysis of the latest Great Lake Fish Monitoring and Surveillance Program (GLFMSP) data showed statistically significant decreases in persistent bioaccumulative and toxic (PBT) contaminant (polychlorinated biphenyls (PCBs), dichloro-diphenyl-trichlorethane and its metabolites (DDTs), dieldrin, cis chlordane, oxychlordane, cis-nonachlor) concentrations in Lakes Huron, Ontario, and Michigan lake trout over the period of 1999 to 2009. In contrast, for most contaminants, no statistically significant concentration trends were found in top predator fish in Lakes Superior and Erie during the same period. For Lakes Huron, Ontario, and Michigan 5.0 +/- 2.6% average annual concentration decreases were found for PCBs, DDTs, dieldrin, and other organochlorine pesticides (OCs) decreased at a faster rate, ranging from 10 +/- 4.3% to 20 +/- 7.1% per year. For these three lakes, with the exception of PCBs, these current decreases are greater than were shown by an earlier trend analysis that estimated an annual contaminant decrease of about 2-5% for the period of 1980 to 2003. For Lakes Superior and Erie, the finding of no statistically significant trend is in agreement with previously reported results for these lakes. PMID- 23085470 TI - Valuation of environmental improvements in a specially protected marine area: a choice experiment approach in Gocek Bay, Turkey. AB - Although the Gocek Bay area was declared as a specially protected area by General Directorate of Natural Assets Protection, the region is threatened because of pollution resulting from increased boat tourism and lack of efficient policies. Extensive measures are being planned in order to protect the region. Coastal management requires the use of technical, social political and economic tools to create a comprehensive management strategy. For environmental investments, it is necessary that benefits and the costs of environmental improvements should be identified in monetary terms in order to determine the feasibility of the investments. The aim of this study is to determine the benefits of the management alternatives to improve environmental quality in Gocek Bay to aid decision makers. In this study, the environmental benefits that can be obtained with improved water quality and restored marine ecosystem were calculated using the Choice Experiment Method, a non-market valuation technique. Data were analyzed using Multinomial Logit Model and the results showed that, local residents and tourists are willing to pay 18TL/month and 16.6TL/tour, respectively for improvements in water quality. For improvements in marine life, local residents are willing to pay 14.8TL/month and tourists are willing to pay 11.2TL/tour. With this study, it has been seen that the results obtained will pave the way for new policies and measures against the deterioration of the marine environment of Gocek Bay. PMID- 23085471 TI - Assessing the occurrence of the dibromide radical (Br2-*) in natural waters: measures of triplet-sensitised formation, reactivity, and modelling. AB - The triplet state of anthraquinone-2-sulphonate (AQ2S) is able to oxidise bromide to Br(*)/Br(2)(-*), with rate constant (2-4)?10(9)M(-1)s(-1) that depends on the pH. Similar processes are expected to take place between bromide and the triplet states of naturally occurring chromophoric dissolved organic matter ((3)CDOM*). The brominating agent Br(2)(-*) could thus be formed in natural waters upon oxidation of bromide by both (*)OH and (3)CDOM*. Br(2)(-*) would be consumed by disproportionation into bromide and bromine, as well as upon reaction with nitrite and most notably with dissolved organic matter (DOM). By using the laser flash photolysis technique, and phenol as model organic molecule, a second-order reaction rate constant of ~3?10(2)L(mg C)(-1)s(-1) was measured between Br(2)(-*) and DOM. It was thus possible to model the formation and reactivity of Br(2)(-*) in natural waters, assessing the steady-state [Br(2)(-*)]~10(-13)-10(-12)M. It is concluded that bromide oxidation by (3)CDOM* would be significant compared to oxidation by (*)OH. The (3)CDOM*-mediated process would prevail in DOM-rich and bromide-rich environments, the latter because elevated bromide would completely scavenge (*)OH. Under such conditions, (*)OH-assisted formation of Br(2)(-*) would be limited by the formation rate of the hydroxyl radical. In contrast, the formation rate of (3)CDOM* is much higher compared to that of (*)OH in most surface waters and would provide a large (3)CDOM* reservoir for bromide to react with. A further issue is that nitrite oxidation by Br(2)(-*) could be an important source of the nitrating agent (*)NO(2) in bromide-rich, nitrite-rich and DOM-poor environments. Such a process could possibly account for significant aromatic photonitration observed in irradiated seawater and in sunlit brackish lagoons. PMID- 23085472 TI - Characterization of complement 1q binding protein of tiger shrimp, Penaeus monodon, and its C1q binding activity. AB - The receptor for the globular heads of C1q, C1qBP/gC1qR/p33, is a multicompartmental, multifunctional cellular protein with an important role in infection and in inflammation. In the present study, we identified and characterized the complement component 1q subcomponent binding protein (C1qBP) from the tiger shrimp Penaeus monodon (designated as PmC1qBP). The open reading frame of PmC1qBP encodes 262 amino acid residues with a conserved MAM33 domain, an arginine-glycine-aspartate cell adhesion motif, and a mitochondrial targeting sequence in the first 53 amino acids. PmC1qBP shares 32%-81% similarity with known C1qBPs and clusters with lobster gC1qR under phylogenetic analysis. The temporal PmC1qBP mRNA expression in the hepatopancreas was significantly enhanced at 9 h after Vibrio vulnificus challenge. The native PmC1qBP was expressed in the gills, hepatopancreas, ovaries, and intestines as a precursor (38 kDa) and the active peptide (35 kDa). The recombinant PmC1qBP protein was expressed in Escherichia coli BL21, and was purified using nickel-nitrilotriacetic acid agarose. A complement 1q binding assay indicated that the rC1qBP protein competitively binds to C1q in mouse serum. The data reveal that PmC1qBP is not only involved in shrimp immune responses to pathogenic infections, but also cross binding to the mouse C1q. PMID- 23085473 TI - DREADDing the lateral habenula: a review of methodological approaches for studying lateral habenula function. AB - The lateral habenula (LHb) is part of the habenular complex in the dorsal diencephalon. The LHb is an important regulator of several neurotransmitter systems in the midbrain; disturbances in this regulation may contribute to mood disorders, abnormalities in cognition, drive, and addiction. Owing to the critical role this nucleus plays in modulating activity of midbrain nuclei, there has been a rapid increase in studies targeting the LHb in the recent years. In this review, we describe studies using traditional approaches to elucidate the function of this brain region, such as lesion, electrical and chemical stimulation, electrophysiology and in vivo microdialysis. We have selected a variety of illustrative studies to discuss each of these methods. Next, we describe studies using methods that are based upon recent advances in molecular biology techniques including recent results from our laboratory using the Designer Receptor Exclusively Activated by Designer Drug (DREADD) technology. Using a Gi/o-coupled DREADD, we found that inhibition of the LHb reduces depression-like behavior in the forced swim test in a manner that suggests enhanced serotonergic activity. The emerging picture reveals that the LHb is likely to be a critical node in the network of subcortical nuclei that regulate aversive learning, motivation, stress responses, etc. We describe how recently developed methods have advanced the study of the LHb and are leading research of this brain region in promising new directions. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID- 23085474 TI - Jaw muscle spindle afferents coordinate multiple orofacial motoneurons via common premotor neurons in rats: an electrophysiological and anatomical study. AB - Jaw muscle spindle afferents (JMSA) in the mesencephalic trigeminal nucleus (Vme) project to the parvocellular reticular nucleus (PCRt) and dorsomedial spinal trigeminal nucleus (dm-Vsp). A number of premotor neurons that project to the trigeminal motor nucleus (Vmo), facial nucleus (VII) and hypoglossal nucleus (XII) are also located in the PCRt and dm-Vsp. In this study, we examined whether these premotor neurons serve as common relay pool for relaying JMSA to multiple orofacial motoneurons. JMSA inputs to the PCRt and dm-Vsp neurons were verified by recording extracellular responses to electrical stimulation of the caudal Vme or masseter nerve, mechanical stimulation of jaw muscles and jaw opening. After recording, biocytin in recording electrode was inotophorized into recording sites. Biocytin-Iabeled fibers traveled to the Vmo, VII, XII, and the nucleus ambiguus (Amb). Labeled boutons were seen in close apposition with Nissl-stained motoneurons in the Vmo, VII, XII and Amb. In addition, an anterograde tracer (biotinylated dextran amine) was iontophorized into the caudal Vme, and a retrograde tracer (Cholera toxin B subunit) was delivered into either the VII or Xll to identify VII and XII premotor neurons that receive JMSA input. Contacts between labeled Vme neuronal boutons and premotor neurons were observed in the PCRt and adjacent dm-Vsp. Confocal microscopic observations confirmed close contacts between Vme boutons and VII and XII premotor neurons. This study provides evidence that JMSA may coordinate activities of multiple orofacial motor nuclei, including Vmo, VII, XII and Amb in the brainstem via a common premotor neuron pool. PMID- 23085475 TI - Fruit for dessert. How people compose healthier meals. AB - The present study assessed whether factual nutritional information on portion sizes helps consumers to select healthier meals. 124 people were invited to serve themselves lunch from a 'fake food buffet' containing 55 replica food items. Participants in the control group were instructed to serve themselves a meal, as they would normally eat from the given selections (control). Participants in the second condition were asked to select a healthy, balanced meal (instruction). People in the third group were also instructed to select a healthy meal, but in addition, they received nutrition information (instruction+information). The results suggest that participants in the instruction and instruction+information condition chose fewer sweets and desserts (F((2,121))=6.91, P<.05) but more fruits (F((2,121))=5.16, P<.05). This led to overall healthier meals than in the control group. All other food categories, including vegetables, were not altered. No difference was found between the two experimental groups. The results indicate that factual nutrition information does not help consumers compose healthier meals. PMID- 23085476 TI - Meal support using mobile technology in Anorexia Nervosa. Contextual differences between inpatient and outpatient settings. AB - The aim of this study was to examine the impact of a "supported eating" intervention using mobile technology in patients with Anorexia Nervosa (AN). Twenty Inpatients and 18 Outpatients with AN underwent a test meal on two occasions, whilst listening to either a short video-clip ('vodcast'), or music delivered on an MP4 player. Self-report and behavioural measures were collected before and after each test meal. Differences were found between the inpatient and outpatient settings. Inpatients drank more of the test meal and had increased levels of vigilance to food after the test meal, in both conditions. When the support conditions (Vodcast vs. Music) were compared, inpatients seemed to benefit more from listening to music (reduced distress and more smoothie drunk), whereas outpatients benefitted more from using the vodcast (reduced distress, more smoothie drunk, and reduced vigilance to food). The context in which the intervention was delivered had an impact on self-report and behavioural measures collected during the test meal. This suggests that the form of meal support in AN needs to match the context. PMID- 23085477 TI - Alterations in expression and phosphorylation of GluA1 receptors following cocaine-cue extinction learning. AB - Brain regional analyses of total GluA1 and GluA1-pSer(845) were used to delineate plasticity of the AMPA receptor in conjunction with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a 2-s light cue and later underwent a single 2 h extinction session for which cocaine was withheld but response-contingent cues were presented. Control groups received yoked-saline sessions or received cocaine self-administration training without undergoing extinction training. Extinction-related increases and decreases, respectively, in total GluA1 were observed in the ventromedial prefrontal cortex (vmPFC) and basolateral amygdala (BLA). Phosphorylation of GluA1 at Ser(845) was increased in the vmPFC and nucleus accumbens (NAc). Though total GluA1 did not change in NAc, there was a positive association between the number of responses during extinction training and the magnitude of total GluA1 in NAc. No significant changes were evident in the dorsal hippocampus. We conclude that the BLA and vmPFC, in particular, appear to be loci for the inhibition of learned behavior induced via extinction training, but each site may have different signaling functions for cocaine-cue extinction learning. PMID- 23085478 TI - Tetrandrine exerts antidepressant-like effects in animal models: role of brain derived neurotrophic factor. AB - The present study focused on investigating the antidepressant potential of tetrandrine and its possible mechanisms of action. Forced swimming test (FST) and tail suspension test (TST) were used to reveal the antidepressant-like effect of tetrandrine. Potential mechanisms were explored applying reserpine-induced ptosis and hypothermia in mice, as well as using the chronic unpredictable mild stress (CUMS) induced depression model in rats. Tetrandrine reduced immobility time in both the FST and TST and antagonized reserpine-induced ptosis and hypothermia in mice. The concentrations of 5-hydroxytryptamine (5-HT) and norepinephrine (NE) in mice hippocampi decreased after the administration of reserpine. However, pre treatments with tetrandrine significantly increased the concentrations of 5-HT and NE in mice hippocampi. In the CUMS-induced depressive rats, bodyweight, 1% sucrose consumption and the concentrations of 5-HT and NE in hippocampi decreased significantly compared with the normal control group. However, these changes could be significantly reversed by tetrandrine application. Furthermore, the levels of the brain-derived neurotrophic factor (BDNF) in hippocampi increased in the tetrandrine-treated rats exposed to CUMS. In summary, our findings suggest that the antidepressant-like effect of tetrandrine is involved in the regulation of the central monoaminergic neurotransmitter system and the levels of BDNF. PMID- 23085480 TI - Anabolic-androgenic steroids induce apoptosis and NOS2 (nitric-oxide synthase 2) in adult rat Leydig cells following in vivo exposure. AB - Anabolic-androgenic steroids (AAS) are synthetic derivatives of testosterone (T) predominantly taken as drugs of abuse. Using in vivo treatment of adult male rats we investigated the effects of testosterone enanthate (TE) a widely abused AAS, on apoptosis of Leydig cells. Increased T and decreased luteinizing hormone levels in serum and decreased intra-testicular T values were found in 2 and 10 weeks treated groups. Two weeks of TE-treatment stimulated the expression of inducible nitric oxide synthase (NOS2) followed by increased NO production, decreased mitochondrial membrane potential and increased prevalence of Leydig cell apoptosis. This was prevented by in vivo administration of androgen receptor blocker. The induced NOS2 level and apoptosis returned to control levels after 10 weeks of TE-treatment but testes contained fewer Leydig cells. Overall, AAS in addition to reduced steroidogenesis induce transient increase of Leydig cells apoptotic rate through mechanism associated with androgen receptor, most likely involving NOS2 induction. PMID- 23085481 TI - An analysis of dinoflagellate metabolism using EST data. AB - The dinoflagellates are an important group of eukaryotic, single celled algae. They are the sister group of the Apicomplexa, a group of intracellular parasites and photosynthetic algae including the malaria parasite Plasmodium. Many apicomplexan mitochondria have a number of unusual features, including the lack of a pyruvate dehydrogenase and the existence of a branched TCA cycle. Here, we analyse dinoflagellate EST (expressed sequence tag) data to determine whether these features are apicomplexan-specific, or if they are more widespread. We show that dinoflagellates have replaced a key subunit (E1) of pyruvate dehydrogenase with a subunit of bacterial origin and that transcripts encoding many of the proteins that are essential in a conventional ATP synthase/Complex V are absent, as is the case in Apicomplexa. There is a pathway for synthesis of starch or glycogen as a storage carbohydrate. Transcripts encoding isocitrate lyase and malate synthase are present, consistent with ultrastructural reports of a glyoxysome. Finally, evidence for a conventional haem biosynthesis pathway is found, in contrast to the Apicomplexa, Chromera and early branching dinoflagellates (Perkinsus, Oxyrrhis). PMID- 23085479 TI - Impulsive choice behavior in four strains of rats: evaluation of possible models of Attention-Deficit/Hyperactivity Disorder. AB - Several studies have examined impulsive choice behavior in spontaneously hypertensive rats (SHRs) as a possible pre-clinical model for Attention Deficit/Hyperactivity Disorder (ADHD). However, this strain was not specifically selected for the traits of ADHD and as a result their appropriateness as a model has been questioned. The present study investigated whether SHRs would exhibit impulsive behavior in comparison to their control strain, Wistar Kyoto (WKY) rats. In addition, we evaluated a strain that has previously shown high levels of impulsive choice, the Lewis (LEW) rats and compared them with their source strain, Wistar (WIS) rats. In the first phase, rats could choose between a smaller-sooner (SS) reward of 1 pellet after 10 s and a larger-later (LL) reward of 2 pellets after 30 s. Subsequently, the rats were exposed to increases in LL reward magnitude and SS delay. These manipulations were designed to assess sensitivity to magnitude and delay within the choice task to parse out possible differences in using the strains as models of specific deficits associated with ADHD. The SHR and WKY strains did not differ in their choice behavior under either delay or magnitude manipulations. In comparison to WIS, LEW showed deficits in choice behavior in the delay manipulation, and to a lesser extent in the magnitude manipulation. An examination of individual differences indicated that the SHR strain may not be sufficiently homogeneous in their impulsive choice behavior to be considered as a viable model for impulse control disorders such as ADHD. The LEW strain may be worthy of further consideration for their suitability as an animal model. PMID- 23085482 TI - Connexins and the atrioventricular node. AB - The structure and functioning of the atrioventricular (AV) node has remained mysterious owing to its high degree of complexity. In this review article, we integrate advances in knowledge regarding connexin expression in the AV node. Complex patterning of 4 different connexin isoforms with single channel conductances ranging from ultralow to high explains the dual pathway electrophysiology of the AV node, the presence of 2 nodal extensions, longitudinal dissociation in the penetrating bundle, and, most importantly, how the AV node maintains slow conduction between the atria and the ventricles. It is shown that the complex patterning of connexins is the consequence of the embryonic development of the cardiac conduction system. Finally, it is argued that connexin dysregulation may be responsible for AV node dysfunction. PMID- 23085483 TI - p.D1690N Nav1.5 rescues p.G1748D mutation gating defects in a compound heterozygous Brugada syndrome patient. AB - BACKGROUND: We identified 2 compound heterozygous mutations (p.D1690N and p.G1748D) in the SCN5A gene encoding cardiac Na(+) channels (Nav1.5) in a proband diagnosed with Brugada syndrome type 1. Furthermore, in the allele encoding the p.D1690N mutation, the p.H558R polymorphism was also detected. OBJECTIVE: The purpose of this study was to analyze the functional properties of the mutated channels as well as the putative modulator effects produced by the presence of the polymorphism. METHODS: Wild-type and mutated human Nav1.5 channels were expressed in Chinese hamster ovary cells and recorded using whole-cell patch clamp technique. RESULTS: Separately, both p.D1690N and p.G1748D mutations produced a marked reduction in peak Na(+) current density (>80%), mainly due to their limited trafficking toward the membrane. Furthermore, p.G1748D mutation profoundly affected channel gating. Both p.D1690N and p.G1748D produced a marked dominant negative effect when cotransfected with either wild-type or p.H558R channels. Conversely, p.H558R was able to rescue defective trafficking of p.D1690N channels toward the membrane when both polymorphism and mutation were in the same construct. Surprisingly, cotransfection with p.D1690N, either alone or together with the polymorphism (p.H558R-D1690N), completely restored the profound gating defects exhibited by p.G1748D channels but only slightly rescued their trafficking. CONCLUSIONS: Our results add further support to the hypothesis that Nav1.5 subunits interact among them before trafficking toward the membrane and suggest that a missense mutation can "rescue" the defective gating produced by another missense mutation. PMID- 23085484 TI - Physalin B inhibits Trypanosoma cruzi infection in the gut of Rhodnius prolixus by affecting the immune system and microbiota. AB - Physalin B is a natural secosteroidal, extracted from the Solanaceae plant, Physalis angulata, and it presents immune-modulator effects on the bloodsucking bug, Rhodnius prolixus. In this work, R. prolixus was treated with physalin B at a concentration of 1 mg/ml of blood meal (oral application), or 20 ng/insect (applied topically) or 57 ng/cm(2) of filter paper (contact treatment), and infected with Trypanosoma cruzi Dm28c clone (2*10(6) epimastigotes/insect). The three types of applications significantly decreased the number of T. cruzi Dm28c in the gut comparing with the non-treated infected insects (controls). All groups of infected insects treated with physalin B had higher numbers of bacterial microbiota in the gut than the non-treated controls infected with T. cruzi. We observed that the infected physalin B insects with topical and contact treatments had a lower antibacterial activity in the gut when compared with control infected insects. Furthermore, infected insects with the physalin B oral treatment produced higher levels of nitrite and nitrate in the gut than control infected insects. These results demonstrate that physalin B decreases the T. cruzi transmission by inhibiting the parasite development in the insect vector R. prolixus. Herein the importance of physalin B modulation on the immune system and microbiota population in terms of parasite development and transmission are discussed. PMID- 23085485 TI - Insights into dyssynchrony in hypoplastic left heart syndrome. AB - BACKGROUND: Cardiac resynchronization therapy has been proposed for treatment of hypoplastic left heart syndrome (HLHS) patients with right ventricular (RV) failure. The role of dyssynchrony, however, is poorly understood in this population. OBJECTIVE: The purpose of this study was to better understand the relationship between electrical and mechanical dyssynchrony in HLHS using 3 dimensional electrical mapping, tissue Doppler indices of wall motion, and vector velocity imaging. METHODS: Eleven HLHS subjects with normal RV function and ten normal subjects (age 3-18 years) were studied. Electrical and mechanical activation times and dyssynchrony indices (electrical dyssynchrony index, mechanical dyssynchrony index) were calculated using 3-dimensional electrical mapping, tissue Doppler indices, and vector velocity imaging. RESULTS: No differences in measures of electrical dyssynchrony were seen when comparing HLHS patients and normal patients (electrical activation time 63.3 +/- 22.8 ms vs 56.2 +/- 11.2 ms, P = .38; electrical dyssynchrony index 13.7 +/- 6.3 ms vs 11.6 +/- 3.0 ms, P = .34). However, measures of mechanical dyssynchrony were markedly abnormal in HLHS patients despite normal RV function (mechanical activation time 16 +/- 11.3 ms vs 0.9+/-1.9 ms, P = .01; mechanical dyssynchrony index 7.5 +/- 5.5 vs 0.4 +/- 0.8, P<.01). CONCLUSION: Patients with HLHS and preserved RV systolic function have normal electrical activation when compared to patients with normal right and left ventricles. In contrast, these patients demonstrate mechanical dyssynchrony compared to patients with normal right and left ventricles. This finding raises important questions about the indications for cardiac resynchronization therapy in this patient population. PMID- 23085486 TI - Optical imaging of periostin enables early endoscopic detection and characterization of esophageal cancer in mice. AB - Imaging strategies that detect early stage esophageal squamous cell carcinoma (ESCC) could improve clinical outcomes, when combined with endoscopic approaches. Periostin is an integrin-binding protein that is important in the tumor microenvironment. We created a fluorescent-labeled antibody that recognizes periostin and binds specifically to ESCC xenograft tumors in mice. In L2 cre;p120ctnLoxP/LoxP mice, which develop squamous cell cancers that resemble human ESCC, we visualized the probe in preneoplastic and neoplastic esophageal lesions using near-infrared fluorescent imaging with upper-gastrointestinal endoscopy. Periostin might be a biomarker of the esophageal tumor microenvironment that can be used to detect preneoplastic lesions. PMID- 23085487 TI - Autologous stem cell transplantation for multiple myeloma: identification of prognostic factors. AB - INTRODUCTION: The purpose of this study was to evaluate the effect of prognostic factors on the outcome of patients with MM after ASCT. PATIENTS AND METHODS: We analyzed results of 170 consecutive patients (121 male and 49 female) of MM who underwent ASCT. Patients' median age was 52 years (range, 26-68 years). High dose melphalan (200 mg/m(2)) was used for conditioning. One hundred thirty-two patients (77.6%) had evidence of chemosensitive disease before transplant. Response was assessed using European Group for Blood and Bone Marrow Transplantation criteria. RESULTS: Post ASCT 44.7% of patients achieved CR, 24.7% had very good partial response (VGPR), and 21.2% had partial response (PR). Presence of pretransplant chemosensitive disease (CR, VGPR, and PR) and transplant within 12 months of diagnosis for years before 2006 were associated with higher response rates on multivariate analysis. At a median follow-up of 84 months, median overall (OS) and event-free survival (EFS) is 85.5 and 41 months, respectively. Estimated OS and EFS at 60 months is 62 +/- 0.04% and 41 +/- 0.04%, respectively. Patients who responded to transplant (CR, VGPR, and PR) had a longer OS (P < .001) and EFS (P < .001). Additionally, patients who achieved CR post transplant had a longer OS (P < .001) and EFS (P < .001). Patients who received novel agents for induction pretransplant had a longer OS (P < .001) and EFS (P < .002). CONCLUSION: Outcome after ASCT is better for myeloma patients with pretransplant chemosensitive disease and those who achieve CR after transplant. PMID- 23085488 TI - Anticancer activity of chemically prepared shrimp low molecular weight chitin evaluation with the human monocyte leukaemia cell line, THP-1. AB - In the present study, anticancer activities of chitin, chitosan and low molecular weight chitin were evaluated using a human tumour cell line, THP-1. A molecular weight-activity relationship and an electrostatic interaction-activity relationship were determined. The cytotoxic effects of chitin and derivatives were also evaluated using a normal human foetal lung fibroblastic cell line, MRC 5 and the specific cytotoxicity of chitin and derivatives to tumour cell lines was demonstrated. The high antitumour effect of low molecular weight of chitin was established. PMID- 23085489 TI - Introduction of a unique tryptophan residue into various positions of Bacillus licheniformis DnaK. AB - Site-directed mutagenesis together with biochemical and biophysical techniques were used to probe effects of single-tryptophan-incorporated mutations on a bacterial molecular chaperone, Bacillus licheniformis DnaK (BlDnaK). Specifically, five phenylalanine residues (Phe(120), Phe(174), Phe(186), Phe(378) and Phe(396)) of BlDnaK were individually replaced by single tryptophans, thus creating site-specific probes for the fluorescence analysis of the protein. The steady-state ATPase activity for BlDnaK, F120W, F174W, F186W, F378W, and F396W was determined to be 76.01, 52.82, 25.32, 53.31, 58.84, and 47.53 nmol Pi/min/mg, respectively. Complementation test revealed that the single mutation at codons 120, 186, and 378 of the dnaK gene still allowed an Escherichia coli dnaK756-Ts strain to grow at a stringent temperature of 44 degrees C. Simultaneous addition of co-chaperones and NR-peptide did not synergistically stimulate the ATPase activity of F174W and F396W, and these two proteins were unable to assist the refolding of GdnHCl-denatured luciferase. The heat-induced denaturation of all variants could be fitted adequately to a three-state model, in agreement with the observation for the wild-type protein. By CD spectral analysis, GdnHCl-induced unfolding transition for BlDnaK was 1.51 M corresponding to DeltaG(N-U) of 1.69 kcal/mol; however, the transitions for mutant proteins were 1.07-1.55 M equivalent to DeltaG(N-U) of 0.94-2.93 kcal/mol. The emission maximum of single tryptophan-incorporated variants was in the range of 333.2-335.8 nm. Acrylamide quenching analysis showed that the mutant proteins had a dynamic quenching constant of 3.0-4.2 M(-1). Taken together, these results suggest that the molecular properties of BlDnaK have been significantly changed upon the individual replacement of selected phenylalanine residues by tryptophan. PMID- 23085490 TI - Effect of nitrogen source on curdlan production by Alcaligenes faecalis ATCC 31749. AB - This study aims to investigate the effect of nitrogen source on curdlan production by Alcaligenes faecalis ATCC 31749. Curdlan production fell when excess nitrogen source was present, while biomass accumulation increased as the level of nitrogen source raised. Curdlan production and biomass accumulation were greater with urea compared with those with other nitrogen sources. The highest production of curdlan and biomass accumulation by A. faecalis ATCC 31749 was 28.16 g L(-1) and 9.58 g L(-1), respectively, with urea, whereas those with NH(4)Cl were 15.17 g L(-1) and 6.25 g L(-1), respectively. The optimum fermentation time for curdlan production was also affected by the nitrogen source in the medium. PMID- 23085491 TI - The hereditary spastic paraplegia protein strumpellin: characterisation in neurons and of the effect of disease mutations on WASH complex assembly and function. AB - Mutations in the gene encoding strumpellin cause autosomal dominant hereditary spastic paraplegia (HSP), in which there is degeneration of corticospinal tract axons. Strumpellin is a component of the WASH complex, an actin-regulating complex that is recruited to endosomes by interactions with the retromer complex. The WASH complex and its relationship to retromer have not been fully characterised in neurons, and the molecular pathological mechanism of strumpellin mutation is unclear. Here we demonstrate that the WASH complex assembles in the brain, where it interacts with retromer. Members of both complexes co-localise with each other and with endosomes in primary cortical neurons, and are present in somato-dendritic and axonal compartments. We show that strumpellin is not required for normal transferrin receptor traffic, but is required for the correct subcellular distribution of the beta-2-adrenergic receptor. However, strumpellin disease mutations do not affect its incorporation into the WASH complex or its subcellular localisation, nor do they have a dominant effect on functions of the WASH complex, including regulation of endosomal tubulation, transferrin receptor traffic or beta-2-adrenergic receptor localisation. Models of the WASH complex indicate that it contains a single strumpellin molecule, so in patients with strumpellin mutations, complexes containing wild-type and mutant strumpellin should be present in equal numbers. In most cell types this would provide sufficient functional WASH to allow normal cellular physiology. However, owing to the demands on membrane traffic imposed by their exceptionally long axons, we suggest that corticospinal neurons are especially vulnerable to reductions in functional WASH. PMID- 23085492 TI - FTIR spectroscopy: a new valuable tool to classify the effects of polyphenolic compounds on cancer cells. AB - Polyphenolic compounds are an important part of human diet and regular consumption of fruits, vegetables and tea is associated with reduced risk of cancer. Dietary polyphenols display a vast array of cellular effects but the large number of data published in the literature makes it difficult to determine the main mechanisms of action associated and to identify molecules with original mechanisms. Therefore, there is an increasing demand for more systemic approaches in order to obtain a global insight of the biochemical processes mediated by polyphenols. Here, we used Fourier transform infrared (FTIR) spectroscopy to analyze cancer cells exposed in vitro to 6 polyphenols: 3 natural well documented polyphenols (curcumin, epigallocatechin gallate (EGCG) and quercetin) and 3 synthetic molecules with a very closely related chemical structure. Statistical analyses on FTIR spectra allowed the comparison of global effects of the 6 compounds and evidenced some common or different features in the cell perturbations among natural and synthetic molecules. Interestingly, marked metabolic changes induced by polyphenols closely related from a chemical point of view were identified. Furthermore, many metabolic changes could be detected as early as after 2h incubation with the drugs. PMID- 23085493 TI - A novel imidazopyridine derivative, HS-106, induces apoptosis of breast cancer cells and represses angiogenesis by targeting the PI3K/mTOR pathway. AB - Abnormal activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is an essential step for the formation and growth of tumors in humans. HS-106 is an imidazopyridine derivative that inhibits the kinase activity of PI3K by binding to the ATP-binding cleft. We found that this compound suppressed breast cancer cell proliferation and induced apoptosis by specifically inhibiting the activity of target proteins in the PI3K/Akt/mTOR signaling pathway. Cell cycle analysis revealed that treatment with HS-106 resulted in cell cycle arrest at the G(2)/M phase due to up-regulation of p-cdc25 and down-regulation of cyclin B1. Also, HS 106 induced apoptosis by increasing the levels of cleaved caspase-3 and cleaved PARP. In addition, chromatin condensation and apoptotic bodies were detected in HS-106-treated breast cancer cells. Furthermore, HS-106 decreased the expression of hypoxia-inducible factor 1alpha (HIF-1alpha), and inhibited tube formation and migration of human umbilical vein endothelial cells (HUVECs) in vitro and blood vessel formation in an in vivo Matrigel plug assay. These results show that HS 106 may be an effective novel therapeutic candidate in clinical trials as a potential treatment for human breast cancers or other advanced malignancies with aberrant PI3K/Akt/mTOR signaling. PMID- 23085494 TI - Simultaneous quantification of urine flunitrazepam, nimetazepam and nitrazepam by using liquid chromatography tandem mass spectrometry. AB - BACKGROUND: Benzodiazepines are used in hypnotics, sedation, and anti-anxiety. Recently liquid chromatography tandem mass spectrometry (LC-MS/MS) has been vastly developed for drug analysis in biological samples. METHODS: We developed and validated a LC-MS/MS method for simultaneous quantification of flunitrazepam (FM2), nimetazepam and nitrazepam levels in 87 benzodiazepine positive human urine specimens by enzyme immunoassay. Deuterated analogues were used as internal standard. RESULTS: The limits of quantification were found to be 0.25, 2.5, 5, 5 and 1ng/ml for FM2, 7-aminoFM2, nimetazepam, 7-amino-nimetazepam and nitrazepam, respectively. The intraday and inter-day CVs ranged from 0.6 to 4.6% and 1.2 9.4%, respectively. The within-day accuracy ranged from 80.8 to 108.7% and the between-day accuracy ranged from 80.5 to 118.0%. The recovery rate ranged from 70.5 to 96.7% for five different analytes. A group of 34 urine samples previously gas chromatography-mass spectrometry determined to contain 7-aminoFM2 was analyzed by this new LC-MS/MS approach. Quantitative data produced by both methods agreed well. CONCLUSIONS: The LC-MS/MS method has proved to be robust and specific for the quantification of FM2, nimetazepam and nitrazepam in urine samples. This study also confirmed that nitrazepam and 7-aminonimetazepam are the metabolic products of nimetazepam. PMID- 23085495 TI - Changes in women's feelings about their romantic relationships across the ovulatory cycle. AB - According to the dual mating hypothesis, women possess two overlapping suites of mate-choice mechanisms: one leading to preferences for sexually desirable men who have high-fitness genes and one leading to preferences for men who are able to invest in a woman and her children. Evidence increasingly demonstrates that women's preference for sexual desirability (but not investment attractiveness) increases when women are most fertile within the ovulatory cycle. Little is known, however, about the implications of these preference shifts for women's relationships with their long-term partners. Using luteinizing hormone tests to verify ovulation, across two studies (Samples 1 and 2), we found that women whose partners were relatively low in sexual desirability felt less close to their partner (Samples 1 and 2) and were more critical of their partner's faults (Sample 2) on high-fertility days of the cycle just prior to ovulation compared with low-fertility days of the cycle. Women whose partners were relatively high in sexual desirability felt closer to their partner (Sample 1) and more satisfied with their relationship (Sample 2) on high- than low-fertility days of the cycle. There were no such shifts in women's commitment to their relationship. Therefore, partner sexual desirability predicts women's high-fertility assessments of relationship quality but not their intentions to stay in their relationship, consistent with the dual mating hypothesis. These findings suggest that variations across the ovulation cycle in women's reproductive hormones play an important role in relationship dynamics. PMID- 23085496 TI - Lower sexual interest in postpartum women: relationship to amygdala activation and intranasal oxytocin. AB - During the postpartum period, women experience significant changes in their neuroendocrine profiles and social behavior compared to before pregnancy. A common experience with motherhood is a decrease in sexual desire. Although the lifestyle and peripheral physiological changes associated with parturition might decrease a woman's sexual interest, we hypothesized that there are also hormone mediated changes in women's neural response to sexual and infant stimuli with altered reproductive priorities. We predicted that amygdala activation to sexually arousing stimuli would be suppressed in postpartum versus nulliparous women, and altered with intranasal oxytocin administration. To test this, we measured amygdala activation using fMRI in response to sexually arousing pictures, infant pictures, and neutral pictures in 29 postpartum and 30 nulliparous women. Half of the women received a dose of exogenous oxytocin before scanning. As predicted, nulliparous women subjectively rated sexual pictures to be more arousing, and infant pictures to be less arousing, than did postpartum women. However, nulliparous women receiving the nasal oxytocin spray rated the infant photos as arousing as did postpartum women. Right amygdala activation was lower in postpartum versus nulliparous women in response to sexual, infant, and neutral images, suggesting a generalized decrease in right amygdala responsiveness to arousing images with parturition. There was no difference in right amygdala activation with nasal spray application. Postpartum women therefore appear to experience a decrease in sexual interest possibly as a feature of a more generalized decrease in amygdala responsiveness to arousing stimuli. PMID- 23085497 TI - Toward reliable characterization of functional homogeneity in the human brain: preprocessing, scan duration, imaging resolution and computational space. AB - While researchers have extensively characterized functional connectivity between brain regions, the characterization of functional homogeneity within a region of the brain connectome is in early stages of development. Several functional homogeneity measures were proposed previously, among which regional homogeneity (ReHo) was most widely used as a measure to characterize functional homogeneity of resting state fMRI (R-fMRI) signals within a small region (Zang et al., 2004). Despite a burgeoning literature on ReHo in the field of neuroimaging brain disorders, its test-retest (TRT) reliability remains unestablished. Using two sets of public R-fMRI TRT data, we systematically evaluated the ReHo's TRT reliability and further investigated the various factors influencing its reliability and found: 1) nuisance (head motion, white matter, and cerebrospinal fluid) correction of R-fMRI time series can significantly improve the TRT reliability of ReHo while additional removal of global brain signal reduces its reliability, 2) spatial smoothing of R-fMRI time series artificially enhances ReHo intensity and influences its reliability, 3) surface-based R-fMRI computation largely improves the TRT reliability of ReHo, 4) a scan duration of 5 min can achieve reliable estimates of ReHo, and 5) fast sampling rates of R-fMRI dramatically increase the reliability of ReHo. Inspired by these findings and seeking a highly reliable approach to exploratory analysis of the human functional connectome, we established an R-fMRI pipeline to conduct ReHo computations in both 3-dimensions (volume) and 2-dimensions (surface). PMID- 23085498 TI - Anatomical connectivity and the resting state activity of large cortical networks. AB - This paper uses mathematical modelling and simulations to explore the dynamics that emerge in large scale cortical networks, with a particular focus on the topological properties of the structural connectivity and its relationship to functional connectivity. We exploit realistic anatomical connectivity matrices (from diffusion spectrum imaging) and investigate their capacity to generate various types of resting state activity. In particular, we study emergent patterns of activity for realistic connectivity configurations together with approximations formulated in terms of neural mass or field models. We find that homogenous connectivity matrices, of the sort of assumed in certain neural field models give rise to damped spatially periodic modes, while more localised modes reflect heterogeneous coupling topologies. When simulating resting state fluctuations under realistic connectivity, we find no evidence for a spectrum of spatially periodic patterns, even when grouping together cortical nodes into communities, using graph theory. We conclude that neural field models with translationally invariant connectivity may be best applied at the mesoscopic scale and that more general models of cortical networks that embed local neural fields, may provide appropriate models of macroscopic cortical dynamics over the whole brain. PMID- 23085499 TI - Full body gait analysis may improve diagnostic discrimination between hereditary spastic paraplegia and spastic diplegia: a preliminary study. AB - Hereditary spastic paraplegia (HSP) and spastic diplegia (SD) patients share a strong clinical resemblance. Thus, HSP patients are frequently misdiagnosed with a mild form of SD. Clinical gait analysis (CGA) has been highlighted as a possible tool to support the differential diagnosis of HSP and SD. Previous analysis has focused on the lower-body but not the upper-body, where numerous compensations during walking occur. The aim of this study was to compare the full body movements of HSP and SD groups and, in particular, the movement of the upper limbs. Ten HSP and 12 SD patients were evaluated through a CGA (VICON 460 and Mx3+; ViconPeak((r)), Oxford, UK) between 2008 and 2012. The kinematic parameters were computed using the ViconPeak((r)) software (Plug-In-Gait). In addition, the mean amplitude of normalised (by the patient's height) arm swing was calculated. All patients were asked to walk at a self-selected speed along a 10-m walkway. The mean kinematic parameters for the two populations were analysed with Mann Whitney comparison tests, with a significant P-value set at 0.05. The results demonstrated that HSP patients used more spine movement to compensate for lower limb movement alterations, whereas SD patients used their arms for compensation. SD patients had increased shoulder movements in the sagittal plane (Flexion/extension angle) and frontal plane (elevation angle) compared to HSP patients. These arm postures are similar to the description of the guard position that toddlers exhibit during the first weeks of walking. To increase speed, SD patients have larger arm swings in the sagittal, frontal and transversal planes. Upper-body kinematics, and more specifically arm movements and spine movements, may support the differential diagnosis of HSP and SD. PMID- 23085500 TI - Gender differences in the prevalence of metabolic syndrome and its components among adults with disabilities based on a community health check up data. AB - Metabolic syndrome is highly prevalent in society gradually and has important implications for public health in recent years. The present study aims to examine the gender effect on the prevalence of metabolic syndrome among adults with disabilities. A cross-sectional study was conduct to analyze annual health check up chart of 419 people with disabilities whose age >= 20 years in east Taiwan. We used to diagnose the metabolic syndrome was defined by the Taiwan Bureau of Health Promotion as the presence of three or more of the following five components: abdominal obesity, high blood pressure, high fasting glucose level, high triglyceride level, and low high-density lipoprotein cholesterol level. The results showed that the prevalence of metabolic syndrome was 19.3% in the study subjects (16.8% in men and 23.1% in women; p = 0.110). Our study also indicated that the genders were significantly different in the followings (men vs. women): abdominal obesity (33.2% vs. 50.9%; p<0.001), high blood pressure (36.4% vs. 23.7%; p = 0.006), high fasting glucose level (18.4 vs. 14.8%; p = 0.334), high triglyceride level (24.0% vs. 14.2%; p = 0.014) and HDL-C (21.6% vs. 35.5%; p = 0.002) among the sample. To prevent the metabolic syndrome occurrence and consequences, the study suggests that the health authorities should put greater efforts to address the metabolic syndrome components, particularly in higher rates of obesity-related health conditions to avoid significant health and health care costs in the future. PMID- 23085501 TI - Patterns of multimorbidity in an older population of persons with an intellectual disability: results from the intellectual disability supplement to the Irish longitudinal study on aging (IDS-TILDA). AB - Multimorbidity (2 or more chronic conditions) is being widely studied in older populations and this study explores both the relevance of emerging conceptualizations and the extent to which multimorbidity is a feature of aging in persons with an intellectual disability. METHODS: Data was generated from wave one of the intellectual disability supplement to the Irish longitudinal study on aging (IDS-TILDA) which included 753 persons with an ID aged 40 years and over. Information on the presence of 12 chronic conditions was collected using a standardized protocol administered in face to face interviews with persons with ID and/or their caregivers. Prevalence of multimorbidity was established and patterns were examined using logistic regression models. The patterns of multimorbidity for people with ID that emerged were then compared with those reported for other older adults. RESULTS: Multimorbidity was established for 71% of the IDS-TILDA sample with women at highest risk and rates of multimorbidity was high (63%) even among those aged 40-49 years. Eye disease and mental health problems were most often associated with a second condition and the most prevalent multimorbidity pattern was mental health/neurological disease. DISCUSSION: Further investigation, attention to mental health issues and the development of treatment guidelines that recognize chronic condition disease load are critical to mitigating the negative impact of multiple chronic conditions and preventing additional disability in adults with ID as they age. PMID- 23085502 TI - Occupational therapy home program for children with intellectual disabilities: a randomized, controlled trial. AB - This study aimed to investigate the effectiveness of a proposed occupational therapy home program (OTHP) for children with intellectual disabilities (ID). Children with ID were randomly and equally assigned to OTHP or to no OTHP groups. The primary outcome measures were Canadian Occupational Performance, Bruininks Oseretsky Test of Motor Proficiency-Second Edition, and The Children's Assessment of Participation and Enjoyment scores at 10 and 20 weeks. The 20-week OTHP produced significant difference in fine motor function, activity participation, and parent satisfaction with performance, compared to those of no OTHP. Pediatricians can advise families to implement 20 weeks of OTHP with an average 15 min per session to facilitate functional changes of children with ID. PMID- 23085504 TI - Vitamin D analog EB1089 inhibits aromatase expression by dissociation of comodulator WSTF from the CYP19A1 promoter-a new regulatory pathway for aromatase. AB - The enzyme aromatase, encoded by the CYP19A1 gene, catalyzes the production of estrogens and inhibition of aromatase has therefore become one of the key strategies in breast cancer treatment. We have studied the effects of the vitamin D analog EB1089 on aromatase gene expression and enzyme activity in breast cancer cells. We found that EB1089 was able to decrease the gene expression and enzyme activity as well as inhibit aromatase-dependent cell growth. Furthermore, a low dose of EB1089 combined with low doses of clinically used aromatase inhibitors such as anastrozole, letrozole and exemestane were able to effectively inhibit aromatase-dependent growth of breast cancer cells. The molecular mechanism for this effect of EB1089 on the aromatase gene expression was investigated and we found that it is mediated by the vitamin D receptor (VDR), vitamin D receptor interacting repressor (VDIR) and Williams syndrome transcription factor (WSTF). ChIP and Re-ChIP assays revealed that EB1089 mediates dissociation of WSTF from the CYP19A1 promoter and thereby decreases the gene expression. Regulation of aromatase via WSTF has not been reported previously. Furthermore, gene silencing of WSTF results in decreased gene expression of CYP19A1 and aromatase activity, showing that WSTF is an interesting drug target for development of new anti cancer drugs. In summary, we report that the vitamin D analog EB1089 is able to decrease the gene expression and enzyme activity of aromatase via a novel regulatory pathway for aromatase and suggest that EB1089 may be a new treatment option for estrogen dependent breast cancer. PMID- 23085503 TI - Rationale and design of the Chronic Kidney Disease Antidepressant Sertraline Trial (CAST). AB - Major Depressive Disorder (MDD) affects one in five patients with Chronic Kidney Disease (CKD) and is an independent risk factor for hospitalization and death before and after dialysis initiation. However, it remains an under-recognized and under-treated problem, in part due to the lack of well-controlled studies that support or refute the efficacy and safety of antidepressant medications in CKD patients. Major trials of antidepressant treatment excluded patients with stages 3-5 CKD, precisely those at higher risk for both depression and increased mortality. The Chronic Kidney Disease Antidepressant Sertraline Trial (CAST) is a randomized, double-blinded, placebo-controlled trial of sertraline, a selective serotonin reuptake inhibitor (SSRI). It will enroll 200 adults with stages 3-5 CKD and MDD excluding kidney transplant and chronic dialysis patients. Sertraline will be administered at an initial dose of 50mg once daily or matching placebo followed by a dose escalation strategy consisting of 50mg increments at 2week intervals (as tolerated) to a maximum dose of 200mg. The primary outcome is improvement in depression symptom severity measured by the Quick Inventory of Depressive Symptomatology scale. Secondary outcomes include safety endpoints and improvement in quality of life. Changes in cognitive function, adherence to medications, nutritional status, inflammation, and platelet function will be explored as potential mechanisms by which depression may mediate poor outcomes. We discuss the rationale and design of the CAST study, the largest placebo controlled trial aimed to establish safety and efficacy of a SSRI in the acute phase treatment of CKD patients with MDD. PMID- 23085505 TI - Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission. AB - Neuronal activity and energy metabolism are tightly coupled processes. Previously, we found that nuclear respiratory factor 1 (NRF-1) transcriptionally co-regulates energy metabolism and neuronal activity by regulating all 13 subunits of the critical energy generating enzyme, cytochrome c oxidase (COX), as well as N-methyl-d-aspartate (NMDA) receptor subunits 1 and 2B, GluN1 (Grin1) and GluN2B (Grin2b). We also found that another transcription factor, nuclear respiratory factor 2 (NRF-2 or GA-binding protein) regulates all subunits of COX as well. The goal of the present study was to test our hypothesis that NRF-2 also regulates specific subunits of NMDA receptors, and that it functions with NRF-1 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation of mouse neuroblastoma cells and rat visual cortical tissue, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate Grin1 and Grin2b genes, but not any other NMDA subunit genes. Grin1 and Grin2b transcripts were up-regulated by depolarizing KCl, but silencing of NRF-2 prevented this up-regulation. On the other hand, over-expression of NRF-2 rescued the down-regulation of these subunits by the impulse blocker TTX. NRF-2 binding sites on Grin1 and Grin2b are conserved among species. Our data indicate that NRF 2 and NRF-1 operate in a concurrent and parallel manner in mediating the tight coupling between energy metabolism and neuronal activity at the molecular level. PMID- 23085506 TI - Poly(ADP-ribose) polymerase 1 inhibition protects against low shear stress induced inflammation. AB - BACKGROUND: Atherosclerosis begins as local inflammation of vessels at sites of disturbed flow, where low shear stress (LSS) leads to mechanical irritation and plaque development and progression. Nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1) is associated with the inflammation response during atherosclerosis. We investigated the role and underlying mechanism of PARP-1 in LSS-induced inflammation in human umbilical vein endothelial cells (HUVECs). METHODS AND RESULTS: HUVECs were simulated by LSS (0.4Pa). PARP-1 expression was inhibited by ABT888 or siRNA. The inducible nitric oxide synthase (iNOS) and intercellular adhesion molecular-1 (ICAM-1) expression was regulated by LSS in a time dependent manner. LSS could increase superoxide production and 3-nitrotyrosine formation. LSS induced DNA damage as assessed by H2A.X phosphorylation and comet assay. Compared with cells under static, LSS increased PARP-1 expression and PAR formation via MEK/ERK signaling pathway. PARP-1 inhibition increased Sirt1 activity through an increased intracellular nicotinamide adenine dinucleotide (NAD(+)) level. Moreover, PARP-1 inhibition attenuated LSS-induced iNOS and ICAM 1 upregulation by inhibiting nuclear factor kappa B (NF-kappaB) nuclear translocation and activity, with a reduced NF-kappaB phosphorylation. CONCLUSIONS: LSS induced oxidative damage and PARP-1 activation via MEK/ERK pathway. PARP-1 inhibition restored Sirt1 activity by increasing NAD(+) level and decreased iNOS and ICAM-1 expression by inhibiting NF-kappaB nuclear translocation and activity as well as NF-kappaB phosphorylation. PARP-1 played a fundamental role in LSS induced inflammation. Inhibition of PARP-1 might be a mechanism for treatment of inflammation response during atherosclerosis. PMID- 23085507 TI - Immune system and glucose metabolism interaction in schizophrenia: a chicken-egg dilemma. AB - Impaired glucose metabolism and the development of metabolic syndrome contribute to a reduction in the average life expectancy of individuals with schizophrenia. It is unclear whether this association simply reflects an unhealthy lifestyle or whether weight gain and impaired glucose tolerance in patients with schizophrenia are directly attributable to the side effects of atypical antipsychotic medications or disease-inherent derangements. In addition, numerous previous studies have highlighted alterations in the immune system of patients with schizophrenia. Increased concentrations of interleukin (IL)-1, IL-6, and transforming growth factor-beta (TGF-beta) appear to be state markers, whereas IL 12, interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and soluble IL-2 receptor (sIL-2R) appear to be trait markers of schizophrenia. Moreover, the mononuclear phagocyte system (MPS) and microglial activation are involved in the early course of the disease. This review illustrates a "chicken egg dilemma", as it is currently unclear whether impaired cerebral glucose utilization leads to secondary disturbances in peripheral glucose metabolism, an increased risk of cardiovascular complications, and accompanying pro-inflammatory changes in patients with schizophrenia or whether immune mechanisms may be involved in the initial pathogenesis of schizophrenia, which leads to disturbances in glucose metabolism such as metabolic syndrome. Alternatively, shared underlying factors may be responsible for the co-occurrence of immune system and glucose metabolism disturbances in schizophrenia. PMID- 23085508 TI - Oxytocin in postnatally depressed mothers: its influence on mood and expressed emotion. AB - BACKGROUND: Postnatal depression is common and negatively affects the mother-baby relationship; oxytocin has been found to have positive effects on parenting behavior. We hypothesize that intranasal administration of oxytocin to mothers with depression will influence their parenting related expressed emotion, creating a better basis for sensitive parenting. METHODS: Twenty-five postnatally depressed mothers with infants less than one year participated in a randomized, double-blind, placebo controlled within-subject clinical study in 2011. Mothers attended an out-patient perinatal psychiatry setting in NSW, Australia. They received 24 IU of oxytocin alternating with placebo approximately one week apart in random order, prior to completing outcome measures. The outcome measures were the Five Minute Speech Sample, the Self-Assessment Manikin and the Controlled Oral Word Association Test. RESULTS: In the oxytocin condition mothers were sadder (p=.01), and they more often initially described their babies as difficult (p=.038), but they reported that the quality of their relationship with their infant was more positive (p=.036). LIMITATIONS: Despite an adequate sample size to answer our central hypothesis, a larger sample may have elucidated a moderating effect of childhood trauma. CONCLUSION: Oxytocin did not make depressed mothers happier but their perception of the relationship with their baby improved. Treatment with intranasal oxytocin might show some unwanted side effects in depressed individuals. PMID- 23085509 TI - Immune changes and neurotransmitters: possible interactions in depression? AB - A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro inflammatory cytokine interferon-gamma stimulates the biosynthesis of 5,6,7,8 tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-gamma triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients. PMID- 23085510 TI - Diagnosis and antimicrobial therapy of Mycoplasma hominis meningitis in adults. AB - Meningitis in adults due to infection with Mycoplasma hominis is rarely reported. Here, we document the third case of M. hominis meningitis in an adult individual, developed upon neurosurgery following a subarachnoid haemorrhage. Our findings are noteworthy, because the presence of M. hominis in cerebrospinal fluid cannot be identified by standard culturing, Gram-staining, or matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Importantly, however, 16S rDNA sequencing did lead to an unambiguous diagnosis and guided successful antimicrobial therapy. Based on our present findings and a review of the respective literature, we conclude that M. hominis should be considered as a candidate causative agent of infections of the central nervous system following neurosurgical procedures, especially if there is no response to standard antimicrobial therapy, and routine culturing yields negative results. PMID- 23085511 TI - Mechanism of TNF-alpha autocrine effects in hypoxic cardiomyocytes: initiated by hypoxia inducible factor 1alpha, presented by exosomes. AB - Excessive tumor necrosis factor-alpha (TNF-alpha) expression is increasingly thought to be detrimental to cardiomyocytes in acute myocardial infarction. During myocardial ischemia, TNF-alpha is mainly released from macrophages, but with persistent ischemia, it can originate from cardiomyocytes and contribute to cardiac remodeling. The initiating factor and exact molecular mechanism of TNF alpha release from cardiomyocytes is presently unclear. In this study, we investigated direct effects of hypoxia on TNF-alpha expression of cardiomyocytes, the role of hypoxia inducible factor-1alpha (HIF-1alpha) in TNF-alpha regulation and potential secretory pathway of TNF-alpha. Elevated TNF-alpha expression and HIF-1alpha activation in primary cultured cardiomyocytes under hypoxia were detected by real-time PCR, Western blotting and immunofluorescence. TNF-alpha mRNA elevation and protein secretion were obviously inhibited by nucleofection of HIF-1alpha small interfering RNA (siRNA) and treatment with 2-methoxyestradiol (inhibitor of HIF-1alpha protein). Similar results were observed in HEK293 and HepG2 cells. Putative hypoxia response elements were identified in the human TNF alpha gene promoter. Deletion analysis and site-directed mutagenesis demonstrated that HIF consensus binding sites spanning bp-1295 to bp-1292 relative to the transcription start site were functional for activation of the TNF-alpha promoter which was confirmed by electrophoretic mobility-shift assay (EMSA) and chromatin immunoprecipitation (ChIP) analysis. Exosomes (vesicles mediating a non-classical route of protein secretion) in supernatants from hypoxic cardiomyocytes were identified by an anti-CD63 antibody in Western blot and observed by electron microscopy. The presence of TNF-alpha within exosomes precipitated from supernatants of hypoxic cardiomyocytes was verified by immunoelectron microscopy and immunoblotting. Results of this study indicate that under hypoxia, HIF-1alpha initiates expression of TNF-alpha, mediated by exosomes in cardiomyocytes. PMID- 23085512 TI - Overexpression of TNNI3K, a cardiac-specific MAPKKK, promotes cardiac dysfunction. AB - Cardiac troponin I-interacting kinase (TNNI3K) is a cardiac-specific kinase whose biological function remains largely unknown. We have recently shown that TNNI3K expression greatly accelerates cardiac dysfunction in mouse models of cardiomyopathy, indicating an important role in modulating disease progression. To further investigate TNNI3K kinase activity in vivo, we have generated transgenic mice expressing both wild-type and kinase-dead versions of the human TNNI3K protein. Importantly, we show that the increased TNNI3K kinase activity induces mouse cardiac remodeling, and its kinase activity promotes accelerated disease progression in a left-ventricular pressure overload model of mouse cardiomyopathy. Using an in vitro kinase assay and proteomics analysis, we show that TNNI3K is a dual-function kinase with Tyr and Ser/Thr kinase activity. TNNI3K expression induces a series of cellular and molecular changes, including a reduction of sarcomere length and changes in titin isoform composition, which are indicative of cardiac remodeling. Using antisera to TNNI3K, we show that TNNI3K protein is located at the sarcomere Z disc. These combined data suggest that TNNI3K mediates cell signaling to modulate cardiac response to stress. PMID- 23085513 TI - Oxidative regulation of the Na(+)-K(+) pump in the cardiovascular system. AB - The Na(+)-K(+) pump is an essential heterodimeric membrane protein, which maintains electrochemical gradients for Na(+) and K(+) across cell membranes in all tissues. We have identified glutathionylation, a reversible posttranslational redox modification, of the Na(+)-K(+) pump's beta1 subunit as a regulatory mechanism of pump activity. Oxidative inhibition of the Na(+)-K(+) pump by angiotensin II- and beta1-adrenergic receptor-coupled signaling via NADPH oxidase activation demonstrates the relevance of this regulatory mechanism in cardiovascular physiology and pathophysiology. This has implications for dysregulation of intracellular Na(+) and Ca(2+) as well as increased oxidative stress in heart failure, myocardial ischemia-reperfusion, and regulation of vascular tone under conditions of elevated oxidative stress. Treatment strategies that are able to reverse this oxidative inhibition of the Na(+)-K(+) pump have the potential for cardiovascular-protective effects. PMID- 23085515 TI - Thioredoxin-1 functions as a molecular switch regulating the oxidative stress induced activation of MST1. AB - The mammalian STE20-like kinase-1 (MST1), a multifunctional serine-threonine kinase in mammalian cells, has been recently implicated in the mediation of oxidative stress-induced signaling processes that lead to cell death. However, the molecular mechanism by which oxidative stress induces the stimulation of MST1 remains unclear. In this study, we found that thioredoxin-1 was physically associated with MST1 in intact cells and that this interaction was abolished by H2O2. Thioredoxin-1, by binding to the SARAH domain of MST1, inhibited the homodimerization and autophosphorylation of MST1, thereby preventing its activation. Furthermore, TNF-alpha prevented the physical interaction between thioredoxin-1 and MST1 and promoted the homodimerization and activation of MST1. The effect of TNF-alpha on MST1 activation was reversed by the reducing agent N acetyl-l-cysteine. Taken together, our results suggest that thioredoxin-1 functions as a molecular switch to turn off the oxidative stress-induced activation of MST1. PMID- 23085516 TI - Cadmium as an endocrine disruptor: correlation with anterior pituitary redox and circadian clock mechanisms and prevention by melatonin. AB - To examine the effect of a low dose of cadmium (Cd) as an endocrine disruptor, male Wistar rats received CdCl2 (5ppm Cd) in drinking water or drinking water alone. After 1 month, the rats were euthanized at one of six time intervals around the clock and the 24-h pattern of adenohypophysial prolactin (PRL) synthesis and release, lipid peroxidation, and redox enzyme and metallothionein (MT) gene expression was examined. Cd suppressed 24-h rhythmicity in expression of the PRL gene and in circulating PRL by increasing them at early photophase only, in correlation with an augmented pituitary lipid peroxidation and redox enzyme expression. CdCl2 treatment effectively disrupted the 24-h variation in expression of every pituitary parameter tested except for MT-3. In a second experiment the effect of melatonin (3MUg/ml in drinking water) was assessed at early photophase, the time of maximal endocrine-disrupting effect of Cd. Melatonin treatment blunted the effect of Cd on PRL synthesis and release, decreased Cd-induced lipid peroxidation, and counteracted the effect of Cd on expression of most redox enzymes. A third experiment was performed to examine whether melatonin could counteract Cd-induced changes in the 24-h pattern of pituitary circadian clock gene expression and plasma PRL, luteinizing hormone (LH), thyrotropin (TSH), and corticosterone levels. Rats receiving CdCl2 exhibited a suppressed daily rhythm of Clock expression and a significant disruption in daily rhythms of pituitary Bmal1, Per1, Per2, Cry1, and Cry2. The coadministration of melatonin restored rhythmicity in Clock and Bmal1 expression but shifted the maxima in pituitary Per1, Cry1, and Cry2 expression to the scotophase. Melatonin also counteracted the effect of Cd on 24-h rhythmicity of circulating PRL, LH, TSH, and corticosterone. The results highlight the occurrence of a significant endocrine disruptor effect of a low dose of Cd. Generally melatonin counteracted the effects of Cd and ameliorated partially the circadian disruption caused by the pollutant. PMID- 23085517 TI - A nitrogen dioxide delivery system for biological media. AB - Nitrogen dioxide is formed endogenously via the oxidation of NO by O(2) or O(2)( ) and from NO(2)(-) via peroxidases, among other pathways. This radical has many potential biological targets and its concentration, like that of NO and other reactive nitrogen species, is thought to be elevated at sites of inflammation. To investigate the specific cytotoxic or mutagenic effects of NO(2), it is desirable to be able to maintain its concentration at constant, predictable, and physiological levels in cell cultures, in the absence of NO. To do this, a delivery system was constructed in which NO(2)-containing gas mixtures contact a liquid within a small (110 ml) stirred reactor. In such gas mixtures NO(2) is present in equilibrium with its dimer, N(2)O(4). The uptake of NO(2) and N(2)O(4) was characterized by measuring the accumulation rates of NO(2)(-) and NO(3)(-), the stable products of N(2)O(4) hydrolysis, in buffered aqueous solutions. In some experiments NO(2)-reactive 2,2'-azino-bis(3-ethyl-benzothiazoline-6 sulfonate) (ABTS) was included and formation of the stable ABTS radical was measured. A reaction-diffusion model was developed that predicts the accumulation rates of all three products to within 15% for gas-phase concentrations of NO(2) spanning 3 orders of magnitude. The model also provides estimates for the NO(2) concentration in the liquid. This system should be useful for exposing cells to NO(2) concentrations similar to those in vivo. PMID- 23085514 TI - Redox regulation of stem/progenitor cells and bone marrow niche. AB - Bone marrow (BM)-derived stem and progenitor cell functions including self renewal, differentiation, survival, migration, proliferation, and mobilization are regulated by unique cell-intrinsic and -extrinsic signals provided by their microenvironment, also termed the "niche." Reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2)), play important roles in regulating stem and progenitor cell functions in various physiologic and pathologic responses. The low level of H(2)O(2) in quiescent hematopoietic stem cells (HSCs) contributes to maintaining their "stemness," whereas a higher level of H(2)O(2) within HSCs or their niche promotes differentiation, proliferation, migration, and survival of HSCs or stem/progenitor cells. Major sources of ROS are NADPH oxidase and mitochondria. In response to ischemic injury, ROS derived from NADPH oxidase are increased in the BM microenvironment, which is required for hypoxia and hypoxia-inducible factor-1alpha expression and expansion throughout the BM. This, in turn, promotes progenitor cell expansion and mobilization from BM, leading to reparative neovascularization and tissue repair. In pathophysiological states such as aging, atherosclerosis, heart failure, hypertension, and diabetes, excess amounts of ROS create an inflammatory and oxidative microenvironment, which induces cell damage and apoptosis of stem and progenitor cells. Understanding the molecular mechanisms of how ROS regulate the functions of stem and progenitor cells and their niche in physiological and pathological conditions will lead to the development of novel therapeutic strategies. PMID- 23085518 TI - T63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through activation of the reactive oxygen species-FOXO3a pathway in lung cancer cells. AB - Curcumin (diferuloylmethane) is a natural polyphenol product of the plant Curcuma longa and has a diversity of antitumor activities. T63, a new 4-arylidene curcumin analogue, was reported to inhibit proliferation of lung cancer cells. However, its precise molecular antitumor mechanisms have not been well elucidated. Here, we showed that T63 could significantly inhibit the proliferation of A549 and H460 human lung cell lines via induction of G0/G1 cell cycle arrest and apoptosis. We found that the reactive oxygen species (ROS) activated FOXO3a cascade plays a central role in T63-induced cell proliferation inhibition. Mechanistically, enhancement of ROS production by T63 induced FOXO3a expression and nuclear translocation through activation of p38MAPK and inhibition of AKT, subsequently elevating the expression of FOXO3a target genes, including p21, p27, and Bim, and then increased the levels of activated caspase-3 and decreased the levels of cyclin D1. Moreover, the antioxidant N-acetylcysteine markedly blocked the above effects, and small interfering RNA-mediated knockdown of FOXO3a also significantly decreased T63-induced cell cycle arrest and apoptosis. In vivo experiments showed that T63 significantly suppressed the growth of A549 lung cancer xenograft tumors, associated with proliferation suppression and apoptosis induction in tumor tissues, without inducing any notable major organ-related toxicity. These data indicated that the novel curcumin analogue T63 is a potent antitumor agent that induces cell cycle arrest and apoptosis and has significant therapeutic potential for lung cancer. PMID- 23085520 TI - Reactive oxygen species-dependent wound responses in animals and plants. AB - Animals and plants evolved sophisticated mechanisms that regulate their responses to mechanical injury. Wound response in animals mainly promotes wound healing processes, nerve cell regeneration, and immune system responses at the vicinity of the wound site. In contrast, wound response in plants is primarily directed at sealing the wound site via deposition of various compounds and generating systemic signals that activate multiple defense mechanisms in remote tissues. Despite these differences between animals and plants, recent studies have shown that reactive oxygen species (ROS) play very common signaling and coordination roles in the wound responses of both systems. This review provides an update on recent findings related to ROS-regulated coordination of intercellular communications and signal transduction during wound response in plants and animals. In particular, differences and similarities in H2O2-dependent long distance signaling between zebrafish and Arabidopsis thaliana are discussed. PMID- 23085519 TI - Real-time monitoring of superoxide accumulation and antioxidant activity in a brain slice model using an electrochemical cytochrome c biosensor. AB - The overproduction of reactive oxygen species and the resulting damage are central to the pathology of many diseases. The study of the temporal and spatial accumulation of reactive oxygen species has been limited because of the lack of specific probes and techniques capable of continuous measurement. We demonstrate the use of a miniaturized electrochemical cytochrome c (Cyt c) biosensor for real time measurements and quantitative assessment of superoxide production and inactivation by natural and engineered antioxidants in acutely prepared brain slices from mice. Under control conditions, superoxide radicals produced from the hippocampal region of the brain in 400-MUm-thick sections were well within the range of detection of the electrode. Exposure of the slices to ischemic conditions increased the superoxide production twofold and measurements from the slices were stable over a 3- to 4-h period. The stilbene derivative and anion channel inhibitor 4,4'-diisothiocyano-2,2'-disulfonic stilbene markedly reduced the extracellular superoxide signal under control conditions, suggesting that a transmembrane flux of superoxide into the extracellular space may occur as part of normal redox signaling. The specificity of the electrode for superoxide released by cells in the hippocampus was verified by the exogenous addition of superoxide dismutase (SOD), which decreased the superoxide signal in a dose dependent manner. Similar results were seen with the addition of the SOD mimetic cerium oxide nanoparticles (nanoceria), in that the superoxide anion radical scavenging activity of nanoceria with an average diameter of 15 nm was equivalent to 527 U of SOD for each 1 MUg/ml of nanoceria added. This study demonstrates the potential of electrochemical biosensors for studying real-time dynamics of reactive oxygen species in a biological model and the utility of these measurements in defining the relative contribution of superoxide to oxidative injury. PMID- 23085521 TI - Enhanced expression of cystine/glutamate transporter in the lung caused by the oxidative-stress-inducing agent paraquat. AB - In mammalian cultured cells, the activity of a cystine/glutamate transporter, designated System xc(-), has been shown to be essential for maintaining intracellular glutathione levels and the extracellular cystine/cysteine redox balance. The substrate-specific subunit of this transporter, xCT, is strongly induced by various stimuli, including oxidative stress, which suggests that xCT is one of the adaptive cellular defense systems against these types of stress. Embryonic fibroblasts from xCT-deficient mice fail to survive unless a cysteine precursor, N-acetylcysteine, is present. However, it is unclear whether xCT has similar functions in vivo because xCT-deficient mice are apparently normal. In this study, we investigated the phenotype of the xCT-deficient mice under paraquat-induced oxidative stress. At a paraquat dose of 45mg/kg, the survival rate of the xCT-deficient mice was significantly lower than that of the wild-type mice. Under this condition, total glutathione (the reduced form of glutathione (GSH)+the oxidized form of GSH) levels in the lungs of the xCT-deficient mice were lower than those in the lungs of the wild-type mice. Histopathological examinations showed that paraquat administration worsened the alveolar structure of the xCT-deficient mice compared with the wild-type mice. After paraquat treatment, obvious 8-hydroxy-2'-deoxyguanosine and 4-hydroxy-2-nonenal reactivity was detected in the lungs of the xCT-deficient mice. Although xCT expression was slightly detectable in the lungs of the normal wild-type mice, paraquat administration induced xCT mRNA expression in the lung. Constitutive expression of xCT mRNA was detected in alveolar macrophages isolated from the pulmonary lavage fluid of the wild-type mice, and paraquat administration strongly enhanced xCT mRNA expression in these cells. GSH levels in bronchoalveolar lavage fluid were significantly higher in the paraquat-treated wild-type mice than in the paraquat-treated xCT-deficient mice. These results suggest that xCT contributes to the maintenance of glutathione levels in lungs and the glutathione redox state as a protective system against paraquat toxicity in vivo. PMID- 23085522 TI - Evaluating the neurotoxic effects of lactational exposure to persistent organic pollutants (POPs) in Spanish children. AB - Although the brain continues developing in the postnatal period, epidemiological studies on the effects of postnatal exposure to neurotoxic POPs through breast feeding remain mostly inconclusive. Failure to detect associations between postnatal exposure and health outcomes may stem from the limitations of commonly employed approaches to assess lactational exposure. The aim of the present study was to assess whether lactational exposure to polychlorinated biphenyl-153 (PCB 153), dichlorodiphenyldichloroethylene (DDE), or hexachlorobenzene (HCB) as estimated with a physiologically based pharmacokinetic (PBPK) model, is associated with decrements in mental and psychomotor development scores of the Bayley Scales of Infant Development (BSID) test in children aged around 14-months of a subsample (N=1175) of the Spanish INMA birth cohort, and to compare this with the effects of prenatal exposure. Although in the present study population PCB-153, DDE and HCB exposure increased within the first months of postnatal life, no associations were found between different periods of postnatal exposure to these compounds and mental or psychomotor scores. Increasing prenatal PCB-153 concentrations were associated with worse mental and psychomotor scores, although significance was only reached for psychomotor development (beta [95%CI]=-1.36 [ 2.61, -0.11]). Indeed, the association between exposure and effects observed during prenatal life weakened gradually across periods of postnatal life. Results of the present study suggest that, although breastfeeding increases children's blood persistent organic pollutants (POPs) levels during postnatal life, deleterious effects of PCB-153 on neuropsychological development are mainly attributable to prenatal exposure. PMID- 23085523 TI - Chemical toxins that cause seizures. AB - Seizurogenic chemicals include a variety of toxic agents, including chemical warfare agents, toxic industrial chemicals, and natural toxins. Chemical weapons such as sarin and VX, and pesticides such as parathion and carbaryl cause hyperstimulation of cholinergic receptors and an increase in excitatory neurotransmission. Glutamatergic hyperstimulation can occur after exposure to excitatory amino acid toxins such as the marine toxin domoic acid. Other pesticides such as lindane and strychnine do not affect excitatory neurotransmission directly, but rather, they block the inhibitory regulation of neurotransmission by antagonism of inhibitory GABA and glycine synapses. In this paper, chemicals that cause seizures by a variety of molecular mechanisms and pathways are discussed. PMID- 23085524 TI - Primary cilia and forebrain development. AB - With a microtubule-based axoneme supporting its plasma membrane-ensheathed projection from the basal body of almost all cell types in the human body, and present in only one copy per cell, the primary cilium can be considered an organelle sui generis. Although it was first observed and recorded in histological studies from the late 19th century, the tiny structure was essentially forgotten for many decades. In the past ten years, however, scientists have turned their eyes once again upon primary cilia and realized that they are very important for the development of almost all organs in the mammalian body, especially those dependent upon the signaling from members Hedgehog family, such as Indian and Sonic hedgehog. In this review, we outline the roles that primary cilia play in forebrain development, not just in the crucial transduction of Sonic hedgehog signaling, but also new results showing that cilia are important for cell cycle progression in proliferating neural precursors. We will focus upon cerebral cortex development but will also discuss the importance of cilia for the embryonic hippocampus, olfactory bulb, and diencephalon. PMID- 23085525 TI - Peripheral nerve injury decreases the expression of metabolic glutamate receptor 7 in dorsal root ganglion neurons. AB - Group II and III metabolic glutamate receptors (mGluRs) are responsible for the glutamate-mediated postsynaptic excitation of neurons. Previous pharmacological evidences show that activation of mGluR7 could inhibit nociceptive reception. However, the distribution and expression patterns of mGluR7 after peripheral injury remain unclear. Herein we found that mGluR7 was expressed in the rat peptidergic dorsal root ganglion (DRG) neurons and large neurons, but rarely in isolectin B4 positive neurons. Sciatic nerve ligation experiment showed that mGluR7 was anterogradely transported from cell body to the peripheral site. Furthermore, after peripheral nerve injury, mGluR7 expression was down-regulated in both peptidergic and large DRG neurons. Our work suggests that mGluR7 might be involved in the regulation of pathological pain after peripheral nerve injury. PMID- 23085526 TI - Effect of dietary zinc deficiency on ischemic vulnerability of the brain. AB - Deficiency of zinc, which modulates glutamate release, might increase ischemic vulnerability of the brain. We examined effects of dietary zinc deficiency for 2 weeks on ischemic vulnerability in several brain regions using dynamic positron autoradiography technique and [18F]2-fluoro-2-deoxy-d-glucose with rat brain slices. In the normal diet group, the cerebral glucose metabolic rate (CMRglc) was not significantly different from that of the ischemia-unloaded control even after the loading of ischemia for 45 min. However, in the zinc-deficient diet group, CMRglc was significantly lower than that of the ischemia-unloaded control after loading of ischemia for 45 min. With treatment of MK-801 (NMDA receptor antagonist) from the start of ischemia loading, CMRglc was not significantly different from that of the ischemia-unloaded control. These findings, obtained for all analyzed brain regions, suggest that dietary zinc deficiency increased ischemic vulnerability in the brain, and that glutamate might contribute to this effect through activation of the NMDA receptor. PMID- 23085527 TI - Cryopreservation with a twist - towards a sterile, serum-free surface-based vitrification of hESCs. AB - Human embryonic stem cells (hESCs) play an important role in the fields of regenerative medicine, basic scientific research, tissue engineering and toxicology. Their unique morphology however makes them very sensitive to cryopreservation procedures. We recently introduced a surface dependent, enzyme- and serum-free method for the effective cryopreservation of bulk quantities of hESC colonies using direct immersion into liquid nitrogen (Beier et al., 2011 [5]). However, direct contact with liquid nitrogen risks contamination and cell infection and severely limits clinical application. This work introduces a modified method and a new combined cultivation and cryopreservation device to facilitate the surface dependent vitrification without contact with (possibly unsterile) liquid nitrogen. The technique allows the culture, cryopreservation, storage and post-thawing cultivation in the same device without detaching cell samples from the cultivation surface. Successful vitrification of bulk quantities of hESCs without direct liquid nitrogen contact is an important step towards automated cryopreservation processes for clinical applications of stem cells and other colony forming cell types. PMID- 23085528 TI - Gender, weight status and socioeconomic differences in psychosocial correlates of physical activity in schoolchildren. AB - OBJECTIVES: This study sought to assess differences in attraction to physical activity, perceived physical competence and parental socialization influences across gender, body mass index and socioeconomic status in Portuguese children. DESIGN: Cross-sectional study. METHODS: 683 children, aged 8-10 years, from elementary schools were participants. Attraction to physical activity, perceived physical competence, parental socialization influences and socioeconomic status were assessed via standardized questionnaires. The prevalence of overweight and obesity was calculated using body mass index, based on the international cut-off points. MANOVA and ANOVA models were conducted. RESULTS: Boys reported greater enjoyment of games and sports participation than did girls. Boys and normal weight children perceived themselves as being more successful and physically competent than did girls and obese children. Normal-weight girls enjoyed participation in vigorous physical activity more than did overweight and obese girls. Obese children felt less accepted by their peers in games and sports than did normal-weight and overweight children. High and medium socioeconomic status children perceived physical activity participation as of greater importance than did low-socioeconomic status children. High-socioeconomic status girls reported greater liking of the exertional aspects of physical activity compared to low socioeconomic status girls. High socioeconomic status children were more likely to perceive their parents as positive role models and perceived that they had greater enjoyment of physical activity than did lower socioeconomic status children. CONCLUSIONS: These results suggest that physical activity promotion interventions should focus on girls, obese children and lower socioeconomic status children as these individuals tend to have lower levels of attraction to physical activity, lower perceived physical competence and less parent physical activity support, which puts them at greater risk of being physically inactive. PMID- 23085529 TI - TRAIL protein localization in human primary T cells by 3D microscopy using 3D interactive surface plot: a new method to visualize plasma membrane. AB - The apoptotic ligand TNF-related apoptosis ligand (TRAIL) is expressed on the membrane of immune cells during HIV infection. The intracellular stockade of TRAIL in human primary CD4(+) T cells is not known. Here we investigated whether primary CD4(+) T cells expressed TRAIL in their intracellular compartment and whether TRAIL is relocalized on the plasma membrane under HIV activation. We found that TRAIL protein was stocked in intracellular compartment in non activated CD4(+) T cells and that the total level of TRAIL protein was not increased under HIV-1 stimulation. However, TRAIL was massively relocalized on plasma membrane when cells were cultured with HIV. Using three dimensional (3D) microscopy we localized TRAIL protein in human T cells and developed a new method to visualize plasma membrane without the need of a membrane marker. This method used the 3D interactive surface plot and bright light acquired images. PMID- 23085530 TI - Invasive African nontyphoidal Salmonella requires high levels of complement for cell-free antibody-dependent killing. AB - Nontyphoidal isolates of Salmonella (NTS), particularly Salmonella Typhimurium, are a major cause of invasive bacteremia in Africa. Despite this, no vaccine against NTS is currently available for use in humans. If a NTS vaccine is to be developed in a timely manner, there is a need to develop assays to assess its in vivo efficacy. Assessment of potential efficacy of candidate vaccines in preclinical models is important for proof-of-concept and reduces attrition of vaccines in clinical trials. Serum bactericidal assays (SBA) are often used to assess the functional activity of vaccine-induced antibody responses targeted against Gram-negative bacteria with results given as the maximum dilution of serum that can effect bacterial killing. Previously we have found evidence for a protective role for antibody-induced complement-mediated killing of NTS in African children using an undiluted whole serum SBA. However, endogenous complement in diluted human sera is limiting and insufficient to effect bactericidal activity against S. Typhimurium beyond two two-fold dilutions. In the current study, we examined the requirements for SBA against NTS using baby rabbit serum (BRS) as an exogenous source of complement. We found that the amount of complement required for antibody-mediated bactericidal activity is much higher for the invasive African S. Typhimurium isolate D23580, compared with the laboratory S. Typhimurium LT2 and Salmonella Paratyphi A CVD1901. While 20% BRS was sufficient to kill LT2 and CVD1901, 75% BRS was needed to kill D23580. Our findings demonstrate that one concentration of exogenous complement is not suitable for SBA against all Salmonella isolates. To develop SBA to assess the in vivo efficacy of Salmonella vaccines, it is necessary to optimize the assay for the Salmonella isolates against which the vaccine is targeted. PMID- 23085531 TI - Purification of functional eosinophils from human bone marrow. AB - Eosinophils are granulocytic leukocytes that are best known for their involvement in host immune defense and pathologic states. More recently, they have also been shown to play a role in regulation of murine plasma cell homeostasis in the bone marrow, which prompted our investigation of human bone marrow eosinophils. However, effective methods to isolate eosinophils from human bone marrow thereby allowing comparisons with circulating eosinophils have not yet been described. Herein we describe the development of a novel, cost effective protocol for the purification of eosinophils from human bone marrow that allows us to obtain bone marrow eosinophils of near 100% purity after an 8-day culture system. Furthermore, we demonstrate that bone marrow eosinophils have characteristics similar to blood eosinophils, including the expression of IL-5Ralpha, the presence of eosinophil-specific granules, and similar activation kinetics upon phorbol myristate acetate and high-dose IL-5 stimulation. While migratory responses toward the chemokine CXCL12 differed between purified bone marrow and freshly isolated blood eosinophils, migratory responses were similar upon comparison of bone marrow eosinophils with blood eosinophils cultured ex vivo for 8 days prior to assay. Interestingly, a concurrent upregulation of CXCR4 expression was not observed in these cultured blood eosinophils. Taken together, we have overcome the existing challenges to the study of bone marrow eosinophils through our novel strategy for cell purification and have thus enabled future investigations of these cells and their role(s) in human health and disease. PMID- 23085533 TI - Noise-free accurate count of microbial colonies by time-lapse shadow image analysis. AB - Microbial colonies in food matrices could be counted accurately by a novel noise free method based on time-lapse shadow image analysis. An agar plate containing many clusters of microbial colonies and/or meat fragments was trans-illuminated to project their 2-dimensional (2D) shadow images on a color CCD camera. The 2D shadow images of every cluster distributed within a 3-mm thick agar layer were captured in focus simultaneously by means of a multiple focusing system, and were then converted to 3-dimensional (3D) shadow images. By time-lapse analysis of the 3D shadow images, it was determined whether each cluster comprised single or multiple colonies or a meat fragment. The analytical precision was high enough to be able to distinguish a microbial colony from a meat fragment, to recognize an oval image as two colonies contacting each other, and to detect microbial colonies hidden under a food fragment. The detection of hidden colonies is its outstanding performance in comparison with other systems. The present system attained accuracy for counting fewer than 5 colonies and is therefore of practical importance. PMID- 23085532 TI - A multi-center ring trial of allergen analysis using fluorescent multiplex array technology. AB - BACKGROUND: Consistent performance of allergen assays is essential to ensure reproducibility of exposure assessments for investigations of asthma and occupational allergic disease. This study evaluated intra- and inter-laboratory reproducibility of a fluorescent multiplex array, which simultaneously measures eight indoor allergens in a single reaction well. METHODS: A multi-center study was performed in nine laboratories in the US and Europe to determine the inter laboratory variability of an 8-plex array for dust mite, cat, dog, rat, mouse and cockroach allergens. Aliquots of 151 dust extract samples were sent to participating centers and analyzed by each laboratory on three separate occasions. Agreement within and between laboratories was calculated by the concordance correlation coefficient (CCC). RESULTS: Results were obtained for over 32,000 individual allergen measurements. Levels covered a wide range for all allergens from below the lower limit of detection (LLOD = 0.1-9.8 ng/ml) to higher than 6800 ng/ml for all allergens except Mus m 1, which was up to 1700 ng/ml. Results were reproducible within as well as between laboratories. Within laboratories, 94% of CCC were >= 0.90, and 80% of intra-laboratory results fell within a 10% coefficient of variance (CV%). Results between laboratories also showed highly significant positive correlations for all allergens (~0.95, p<0.001). Overall means of results were comparable, and inter-laboratory CV% for all allergens except Rat n 1 ranged between 17.6% and 26.6%. CONCLUSION: The data indicate that performance criteria for fluorescent multiplex array technology are reproducible within and between laboratories. Multiplex technology provides standardized and consistent allergen measurements that will streamline environmental exposure assessments in allergic disease. PMID- 23085534 TI - Signature-tagging of a bacterial isolate demonstrates phenotypic variability of the progeny in vivo in the absence of defined mutations. AB - Awareness of the high degree of redundancy that occurs in several nutrient uptake pathways of Haemophilus influenzae led us to attempt to develop a quantitative STM method that could identify both null mutants and mutants with decreased fitness that remain viable in vivo. To accomplish this task we designed a modified STM approach that utilized a set of signature tagged wild-type (STWT) strains (in a single genetic background) as carriers for mutations in genes of interest located elsewhere in the genome. Each STWT strain differed from the others by insertion of a unique, Q-PCR-detectable, seven base pair tag into the same redundant gene locus. Initially ten STWTs were created and characterized in vitro and in vivo. As anticipated, the STWT strains were not significantly different in their in vitro growth. However, in the chinchilla model of otitis media, certain STWTs outgrew others by several orders of magnitude in mixed infections. Removal of the predominant STWT resulted in its replacement by a different predominant STWT on retesting. Unexpectedly we observed that the STWT exhibiting the greatest proliferation was animal dependent. These findings identify an inherent inability of the signature tag methodologies to accurately elucidate fitness in this animal model of infection and underscore the subtleties of H. influenzae gene regulation. PMID- 23085535 TI - Molecular phylogeny of the harvestmen genus Sabacon (Arachnida: Opiliones: Dyspnoi) reveals multiple Eocene-Oligocene intercontinental dispersal events in the Holarctic. AB - We investigated the phylogeny and biogeographic history of the Holarctic harvestmen genus Sabacon, which shows an intercontinental disjunct distribution and is presumed to be a relatively old taxon. Molecular phylogenetic relationships of Sabacon were estimated using multiple gene regions and Bayesian inference for a comprehensive Sabacon sample. Molecular clock analyses, using relaxed clock models implemented in BEAST, are applied to date divergence events. Biogeographic scenarios utilizing S-DIVA and Lagrange C++ are reconstructed over sets of Bayesian trees, allowing for the incorporation of phylogenetic uncertainty and quantification of alternative reconstructions over time. Four primary well-supported subclades are recovered within Sabacon: (1) restricted to western North America; (2) eastern North American S. mitchelli and sampled Japanese taxa; (3) a second western North American group and taxa from Nepal and China; and (4) eastern North American S. cavicolens with sampled European Sabacon species. Three of four regional faunas (wNA, eNA, East Asia) are thereby non monophyletic, and three clades include intercontinental disjuncts. Molecular clock analyses and biogeographic reconstructions support nearly simultaneous intercontinental dispersal coincident with the Eocene-Oligocene transition. We hypothesize that biogeographic exchange in the mid-Tertiary is likely correlated with the onset of global cooling, allowing cryophilic Sabacon taxa to disperse within and among continents. Morphological variation supports the divergent genetic clades observed in Sabacon, and suggests that a taxonomic revision (e.g., splitting Sabacon into multiple genera) may be warranted. PMID- 23085536 TI - Knockdown of NYGGF4 (PID1) rescues insulin resistance and mitochondrial dysfunction induced by FCCP in 3T3-L1 adipocytes. AB - NYGGF4 is a recently identified gene that is involved in obesity-associated insulin resistance. Previous data from this laboratory have demonstrated that NYGGF4 overexpression might contribute to the development of insulin resistance (IR) and to mitochondrial dysfunction. Additionally, NYGGF4 knockdown enhanced insulin sensitivity and mitochondrial function in 3T3-L1 adipocytes. We designed this study to determine whether silencing of NYGGF4 in 3T3-L1 adipocytes could rescue the effect of insulin sensitivity and mitochondrial function induced by the cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP), a mitochondrion uncoupler, to ascertain further the mechanism of NYGGF4 involvement in obesity-associated insulin resistance. We found that 3T3-L1 adipocytes, incubated with 5MUM FCCP for 12h, had decreased levels of insulin-stimulated glucose uptake and had impaired insulin-stimulated GLUT4 translocation. Silencing also diminished insulin stimulated tyrosinephosphorylation of IRS-1 and serine phosphorylation of Akt. This phenomenon contrasts with the effect of NYGGF4 knockdown on insulin sensitivity and describes the regulatory function of NYGGF4 in adipocytes insulin sensitivity. We next analyzed the mitochondrial function in NYGGF4-silenced adipocytes incubated with FCCP. NYGGF4 knockdown partly rescued the dissipation of mitochondrial mass, mitochondrial DNA, intracellular ATP synthesis, and intracellular reactive oxygen species (ROS) production occurred following the addition of FCCP, as well as inhibition of mitochondrial transmembrane potential (DeltaPsim) in 3T3-L1 adipocytes incubated with FCCP. Collectively, our results suggested that addition of silencing NYGGF4 partly rescued the effect of insulin resistance and mitochondrial dysfunction in NYGGF4 silenced 3T3-L1 adipocytes incubated with FCCP, which might explain the involvement of NYGGF4-induced IR and the development of NYGGF4 in mitochondrial function. PMID- 23085537 TI - Is mitochondrial DNA content a potential biomarker of mitochondrial dysfunction? AB - Mitochondrial dysfunction is central to numerous diseases of oxidative stress. Changes in mitochondrial DNA (MtDNA) content, often measured as mitochondrial genome to nuclear genome ratio (Mt/N) using real time quantitative PCR, have been reported in a broad range of human diseases, such as diabetes and its complications, obesity, cancer, HIV complications, and ageing. We propose the hypothesis that MtDNA content in body fluids and tissues could be a biomarker of mitochondrial dysfunction and review the evidence supporting this theory. Increased reactive oxygen species resulting from an external trigger such as hyperglycaemia or increased fat in conditions of oxidative stress could lead to enhanced mitochondrial biogenesis, and increased Mt/N. Altered MtDNA levels may contribute to enhanced oxidative stress and inflammation and could play a pathogenic role in mitochondrial dysfunction and disease. Changes in Mt/N are detectable in circulating cells such as peripheral blood mononuclear cells and these could be used as surrogate to predict global changes in tissues and organs. We review a large number of studies reporting changes in MtDNA levels in body fluids such as circulating blood cells, cell free serum, saliva, sperm, and cerebrospinal fluid as well as in tumour and normal tissue samples. However, the data are often conflicting as the current methodology used to measure Mt/N can give false results because of one or more of the following reasons (1) use of mitochondrial primers which co-amplify nuclear pseudogenes (2) use of nuclear genes which are variable and/or duplicated in numerous locations (3) a dilution bias caused by the differing genome sizes of the mitochondrial and nuclear genome and (4) template preparation protocols which affect the yields of nuclear and mitochondrial genomes. Development of robust and reproducible methodology is needed to test the hypothesis that MtDNA content in body fluids is biomarker of mitochondrial dysfunction. PMID- 23085538 TI - The effect of prefabricated and proprioceptive foot orthoses on plantar pressure distribution in patients with flexible flatfoot during walking. AB - BACKGROUND: Previous studies have suggested that orthoses with different constructions could alter gait parameters in flexible flatfoot. However, there is less evidence about the effect of insoles with proprioceptive mechanism on plantar pressure distribution in flatfoot. OBJECTIVES: To assess the effect of orthoses with different mechanisms on plantar pressure distribution in subjects with flexible flatfoot. STUDY DESIGN: Quasi-experimental. METHODS: In total, 12 flatfoot subjects were recruited for this study. In-shoe plantar pressure in walking was measured by Pedar-X system under three conditions including wearing the shoe only, wearing the shoe with a proprioceptive insole, and wearing the shoe with a prefabricated foot insole. RESULTS: Using the proprioceptive insoles, maximum force was significantly reduced in medial midfoot, and plantar pressure was significantly increased in the second and third rays (0.94 +/- 0.77 N/kg, 102.04 +/- 28.23 kPa) compared to the shoe only condition (1.12 +/- 0.88 N/kg and 109.79 +/- 29.75 kPa). For the prefabricated insole, maximum force was significantly higher in midfoot area compared to the other conditions (p < 0.05). CONCLUSIONS: Construction of orthoses could have an effect on plantar pressure distribution in flatfeet. It might be considered that insoles with sensory stimulation alters sensory feedback of plantar surface of foot and may lead to change in plantar pressure in the flexible flatfoot. CLINICAL RELEVANCE: Based on the findings of this study, using orthoses with different mechanisms such as proprioceptive intervention might be a useful method in orthotic treatment. Assessing plantar pressure can also be an efficient quantitative outcome measure for clinicians in evidence-based foot orthosis prescription. PMID- 23085540 TI - Methionine biosynthesis in Agrobacterium tumefaciens: study of the first enzyme. AB - Here we characterize the first step in methionine biosynthesis in Agrobacterium tumefaciens, an alpha-proteobacterium. We explored the metA gene and its products and found several unique properties. Although the gene was annotated as a homoserine transsuccinylase, based upon sequence similarity to characterized homologs in other bacteria, including Escherichia coli, the enzyme uses acetyl CoA as a substrate and therefore is functionally a transacetylase. Moreover, the protein is thermolabile and the gene is under regulation of heat shock transcriptional activator sigma32. 3. The gene has a SAM-riboswitch, which shuts off transcription by sigma-32 as well as by the vegetative sigma-70. PMID- 23085541 TI - Long reach cantilevers for sub-cellular force measurements. AB - Maneuverable, high aspect ratio poly(3,4-ethylene dioxythiophene) (PEDOT) fibers are fabricated for use as cellular force probes that can interface with individual pseudopod adhesive contact sites without forming unintentional secondary contacts to the cell. The straight fibers have lengths between 5 and 40 MUm and spring constants in the 0.07-23.2 nN MUm(-1) range. The spring constants of these fibers were measured directly using an atomic force microscope (AFM). These AFM measurements corroborate determinations based on the transverse vibrational resonance frequencies of the fibers, which is a more convenient method. These fibers are employed to characterize the time dependent forces exerted at adhesive contacts between apical pseudopods of highly migratory D. discoideum cells and the PEDOT fibers, finding an average terminal force of 3.1 +/- 2.7 nN and lifetime of 23.4 +/- 18.5 s to be associated with these contacts. PMID- 23085542 TI - Dynamic and distinct histone modifications modulate the expression of key adipogenesis regulatory genes. AB - Histone modifications and their modifying enzymes are fundamentally involved in the epigenetic regulation of adipogenesis. This study aimed to define the roles of various histone modifications and their "division of labor" in fat cell differentiation. To achieve these goals, we examined the distribution patterns of eight core histone modifications at five key adipogenic regulatory genes, Pref-1, C/EBPbeta, C/EBPalpha, PPARgamma2 and aP2, during the adipogenesis of C3H 10T1/2 mouse mesenchymal stem cells (MSCs) and 3T3-L1 preadipocytes. We found that the examined histone modifications are globally stable throughout adipogenesis but show distinct and highly dynamic distribution patterns at specific genes. For example, the Pref-1 gene has lower levels of active chromatin markers and significantly higher H3 K27 tri-methylation in MSCs compared with committed preadipocytes; the C/EBPbeta gene is enriched in active chromatin markers at its 3'-UTR; the C/EBPalpha gene is predominantly marked by H3 K27 tri-methylation in adipogenic precursor cells, and this repressive marker decreases dramatically upon induction; the PPARgamma2 and aP2 genes show increased histone acetylation on both H3 and H4 tails during adipogenesis. Further functional studies revealed that the decreased level of H3 K27 tri-methylation leads to de-repression of Pref 1 gene, while the increased level of histone acetylation activates the transcription of PPARgamma2 and aP2 genes. Moreover, the active histone modification-marked 3'-UTR of C/EBPbeta gene was demonstrated as a strong enhancer element by luciferase assay. Our results indicate that histone modifications are gene-specific at adipogenic regulator genes, and they play distinct roles in regulating the transcriptional network during adipogenesis. PMID- 23085543 TI - Epigenetic silencing of Notch signaling in gastrointestinal cancers. AB - The Notch signaling pathway drives proliferation, differentiation, apoptosis, cell fate choices and maintenance of stem cells during embryogenesis and in self renewing tissues of the adult. In addition, aberrant Notch signaling has been implicated in several tumors, where Notch can function both as an oncogene or a tumor-suppressor gene, depending on the context. This Extra View aims to review what is currently known about Notch signaling, in particular in gastrointestinal tumors, providing a summary of our data on Notch1 signaling in gastric cancer with results obtained in colorectal cancer (CRC). We have already reported that the epigenetic regulation of the Notch ligand DLL1 controls Notch1 signaling activation in gastric cancer, and that Notch1 inhibition is associated with the diffuse type of gastric cancer. Here, we describe additional data showing that in CRC cell lines, unlike gastric cancer, DLL1 expression is not regulated by promoter methylation. Moreover, in CRC, Notch1 receptor is not affected by any mutation. These data suggest a different regulation of Notch1 signaling between gastric cancer and CRC. PMID- 23085544 TI - The neurobiology of abnormal manifestations of aggression--a review of hypothalamic mechanisms in cats, rodents, and humans. AB - Aggression research was for long dominated by the assumption that aggression related psychopathologies result from the excessive activation of aggression promoting brain mechanisms. This assumption was recently challenged by findings with models of aggression that mimic etiological factors of aggression-related psychopathologies. Subjects submitted to such procedures show abnormal attack features (mismatch between provocation and response, disregard of species specific rules, and insensitivity toward the social signals of opponents). We review here 12 such laboratory models and the available human findings on the neural background of abnormal aggression. We focus on the hypothalamus, a region tightly involved in the execution of attacks. Data show that the hypothalamic mechanisms controlling attacks (general activation levels, local serotonin, vasopressin, substance P, glutamate, GABA, and dopamine neurotransmission) undergo etiological factor-dependent changes. Findings suggest that the emotional component of attacks differentiates two basic types of hypothalamic mechanisms. Aggression associated with increased arousal (emotional/reactive aggression) is paralleled by increased mediobasal hypothalamic activation, increased hypothalamic vasopressinergic, but diminished hypothalamic serotonergic neurotransmission. In aggression models associated with low arousal (unemotional/proactive aggression), the lateral but not the mediobasal hypothalamus is over-activated. In addition, the anti-aggressive effect of serotonergic neurotransmission is lost and paradoxical changes were noticed in vasopressinergic neurotransmission. We conclude that there is no single 'neurobiological road' to abnormal aggression: the neural background shows qualitative, etiological factor-dependent differences. Findings obtained with different models should be viewed as alternative mechanisms rather than conflicting data. The relevance of these findings for understanding and treating of aggression-related psychopathologies is discussed. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'. PMID- 23085545 TI - Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors. AB - Excessive activation of N-methyl-D-aspartate receptors (NMDARs) has been implicated in the pathophysiology of chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and Huntington's disease. Some studies reported that NR2A and NR2B play different roles in the central nervous system (CNS). The NR2A subunit is primarily found in the synapses and is required for glutamate-mediated neuronal survival. On the other hand, the NR2B subunit is primarily found in the extrasynaptic sites and is required for glutamate-mediated neuronal death in both in vitro and in vivo experiments. Estrogen is a steroid hormone well known for its widespread effects such as neuroprotection in the brain. Classically, estrogen can bind to two kinds of nuclear receptors, namely, estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta), and produce physiological and neuroprotective effects. Aside from nuclear receptors, estrogen has one membrane receptor, which can either be G-protein-coupled receptor 30 (GPR30), Gq-mER, or ER-X. NMDA exposure clearly promotes NR2B subunit phosphorylation at Ser-1303 and causes neuronal cell death. GPR30 mediates rapid non-genomic effects to protect neurons against injury by inhibiting p-DAPK1 dephosphorylation, which inhibits NR2B subunit phosphorylation at Ser-1303. In addition, NMDA exposure and global ischemia activate the autophagy pathway and induce cell death, which are markedly blocked by the NR2B antagonist Ro 25-6981. Thus, NR2B signaling, autophagy induction and cell death may be closely related. Ro 25-6981 inhibits the dissociation of the NR2B-Beclin-1 signaling complex and delays autophagy in vivo, thus confirming the link between NR2B signaling and autophagy. In short, ERalpha, ERbeta, and GPR30 are involved in the neuroprotection of estrogen in the CNS. Additional research must be conducted to reveal the mechanism of estrogen action fully and to identify better targets for the development of more effective drugs. This article is part of a Special Issue entitled 'Extrasynaptic ionotropic receptors'. PMID- 23085546 TI - Solid-state dependent dissolution and oral bioavailability of piroxicam in rats. AB - The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus(r) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus(r) was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug. PMID- 23085547 TI - Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. AB - Wet media milling by top down method has proved to be an effective method to prepare nanosuspension of poorly soluble drugs/APIs. Few or no attempts have been made so far to understand the feasibility of nanosuspension formulation in terms of the mechanism of stabilization as a function of drug properties. The objective of this study was to understand the effect of drug substance and stabilizer properties to form a successful nanosuspension product. From this study, logP and enthalpy were concluded to have a direct correlation on the feasibility of formation of a stable nanosuspension. The most likely candidate for media milling was a drug substance with a high enthalpy and hydrophobicity which can be stabilized either electrostatically or sterically. The least likely candidate will be one that is hydrophilic and having a very low enthalpy value. Also the choice of an ideal stabilizer/surfactant was found to be influenced by the degree of hydrophobicity of the drug itself. Finally the morphology of the starting drug was found to significantly affect the milling time required to produce submicron particles. PMID- 23085548 TI - Production of pure samples of 131mXe and 135Xe. AB - Pure samples of (131m)Xe, (133m)Xe, (133)Xe and (135)Xe facilitate the calibration and testing of noble gas sampler stations and related laboratory instrumentation. We have earlier reported a Penning trap-based production method for pure (133m)Xe and (133)Xe samples. Here we complete the work by reporting the successful production of pure (131m)Xe and (135)Xe samples using the same technique. In addition, we present data on xenon release from graphite. PMID- 23085539 TI - Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascade inhibitors: how mutations can result in therapy resistance and how to overcome resistance. AB - The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Targeting these pathways is often complex and can result in pathway activation depending on the presence of upstream mutations (e.g., Raf inhibitors induce Raf activation in cells with wild type (WT) RAF in the presence of mutant, activated RAS) and rapamycin can induce Akt activation. Targeting with inhibitors directed at two constituents of the same pathway or two different signaling pathways may be a more effective approach. This review will first evaluate potential uses of Raf, MEK, PI3K, Akt and mTOR inhibitors that have been investigated in pre-clinical and clinical investigations and then discuss how cancers can become insensitive to various inhibitors and potential strategies to overcome this resistance. PMID- 23085549 TI - An improved non-destructive method of potassium determination. AB - The simplest non-destructive method of potassium determination is to co-relate the fixed abundance of naturally occurring (40)K with the total amount of potassium. Earlier this relationship was applied by measuring the beta(-) activity of (40)K in a sample by Geiger counter. However, merely this simple linear relationship has been applied through gamma spectrometric measurement of (40)K activity, might be due to the huge interference of the (40)K background. We have demonstrated that heavily shielded Compton Suppressor System reduces the background in such extent that the total amount of K in a sample can be measured by measuring the area of the (40)K photo peak (at 1460.82 keV). The developed method requires neither chemical treatment of the sample like dissolution or digestion, nor irradiation of the sample in a nuclear reactor and therefore truly follows green chemistry principles, minimizing the chemicals and hazards. The method has been validated using NIST SRMs. The developed method was compared with WDXRF and ICPOES measurement. PMID- 23085551 TI - A rapid microfluidic synthesis of [18F]fluoroarenes from nitroarenes. AB - Microfluidic radiofluorodenitrations have been successfully performed using a commercially available microfluidic synthesis system. Reactions of nitroarenes with para-substituted electron withdrawing groups provide incorporation yields ranging from 43 to 97%. Ortho- and meta-substituted nitroarenes provided incorporation yields up to 35%. The reactions were conducted using dry, no carrier-added [(18)F]-fluoride and K(2)CO(3)/K(222) dissolved in N,N dimethylformamide or dimethyl sulfoxide with total synthesis times of less than five min. The methodology developed in these studies can be applied to the synthesis of a variety of fluorine-18 labeled radiotracers and radiolabeled prosthetic groups from nitroarene precursors. PMID- 23085550 TI - Automated synthesis of [18F]Florbetaben as Alzheimer's disease imaging agent based on a synthesis module system. AB - An automated synthesis procedure of [(18)F]Florbetaben ([(18)F]BAY94-9172), a radiolabeled imaging agent in phase III study for in vivo mapping of fibrillar amyloid beta (Abeta) with PET, was developed using the commercial PET-MF-2V-IT-1 synthesizer. The automated radiosynthesis was carried out via a one-step nucleophilic fluorination of methanesulfonic acid 2-[2-(2-{4-[2-(4-methylamino phenyl)-vinyl]-phenoxy}-ethoxy)-ethoxy]-ethyl ester, as a new precursor, and separation with semi-preparative high performance liquid chromatography (HPLC). The total synthesis time amounted to 50 min with 20-25% yield (uncorrected for decay) and radiochemical purities of more than 95% in all runs. The described automated radiosynthesis allows the production of [(18)F]Florbetaben using a commercial radiosynthesis module and enables clinical trials of this compound. PMID- 23085553 TI - Posttransplant malignancies in solid organ adult recipients: an analysis of the U.S. National Transplant Database. AB - BACKGROUND: De novo posttransplant malignancy (PTM) is a serious complication of transplantation. Incidences may vary among solid organ transplantations (SOTs) and may take to particular screening recommendations and posttransplantation care. METHODS: Adult recipients, from the U.S. Organ Procurement Transplant Network/United Network for Organ Sharing database (data as of September 3, 2010), of a primary kidney transplantation (KT), liver transplantation (LT), heart transplantation (HT) or lung transplantation (LuT) performed in the United States between 1999 and 2008 were selected. Multiple-organ recipients and those whose grafts failed within 2 weeks after transplantation were excluded. The incidence of PTM (in 1000 person-years) was estimated using the Kaplan-Meier product-limit method and compared with SOT and the general population. RESULTS: The cohort included 193,905 recipients (123,380 KT; 43,106 LT; 16511 HT; and 10,908 LuT). PTM incidence was 8.03, 11.0, 14.3, and 19.8 in KT, LT, HT, and LuT, respectively. In general, PTM recipients were 3 to 5 years older, mostly whites, and are males in all SOTs. In KT, the type of cancer with the highest incidence was posttransplant lymphoproliferative disorder (PTLD, 1.58%), followed by lung (1.12%), prostate (0.82%), and kidney (0.79%) cancers; in LT, PTLD (2.44%), lung and bronchial (2.18%), primary hepatic (0.91%), and prostate (0.88%) cancers; in HT, lung and bronchial (3.24%) and prostate (3.07%) cancers, and PTLD (2.24%); and in LuT, lung and bronchial cancers (5.94%), PTLD (5.72%), and colorectal cancer (1.38%). PTLD, Kaposi sarcoma, and lung and bronchial cancers were increased in all SOTs, when compared with an older (55- to 59-year-old) population. CONCLUSIONS: Cancer incidence is different among solid organ transplantations, and ratios may be higher than those in the 55- to 59-year-old population. PMID- 23085552 TI - 3,3'-Diindolylmethane alleviates oxazolone-induced colitis through Th2/Th17 suppression and Treg induction. AB - The T cell is pivotal in orchestrating and promoting an immune response during ulcerative colitis (UC). The aryl hydrocarbon receptor (AhR) is involved in the regulation of T cell responses, and 3,3'-diindolylmethane (DIM) is a known ligand of AhR. The aim of this study was to examine the therapeutic effects of DIM in experimental colitis and to investigate the possible mechanisms underlying its effects on mucosal T cell responses. The therapeutic effects of DIM were studied in an oxazolone-induced colitis model. The pathologic markers of colitis were measured, moreover, T-helper cell (Th)- and regulatory T cell (Treg)-related transcription factor expression and associated colonic cytokine production were determined. The impact of DIM on T cell differentiation was further investigated in cultures of naive Th cells that were stimulated with anti-CD3/CD28 monoclonal antibodies (mAbs). The administration of DIM attenuated experimental colitis, as determined by pathological indices. DIM may affect signaling pathways downstream of AhR, leading to decreased Th2/Th17 cells and increased Tregs. Ultimately, this could result in the alleviation of experimental colitis. DIM has shown anti-UC activity in animal models via inhibition of Th2/Th17 cells and promotion of Tregs and may thus offer potential treatments for UC patients. PMID- 23085554 TI - The spike generator in the labellar taste receptors of the blowfly is differently affected by 4-aminopyridine and 5-hydroxytryptamine. AB - In taste chemoreception of invertebrates the interaction of taste stimuli with specific membrane receptors and/or ion channels located in the apical membrane of taste receptor cells results in the generation of a receptor potential which, in turn, activates the 'encoder' region to produce action potentials which propagate to the CNS. This study investigates, in the labellar chemosensilla of the blowfly, Protophormia terraenovae, the voltage-gated K(+) currents involved in the action potential repolarization and repetitive firing of the neurons by way of the K(v) channel inhibitors, 4-aminopyridine and 5-hydroxytryptamine. The receptor potential and the spike activity were simultaneously recorded from the 'salt', 'sugar' and 'deterrent' cells, by means of the extracellular side-wall technique, in response to 150 mM NaCl, 100 mM sucrose and 1 mM quinine HCl, before, 0/10 min after apical administration of 4-AP (0.01-10 mM) or 5-HT (0.1 100 mM). The results show that the receptor potential in all three cells is neither affected by 4-AP nor by 5-HT. Instead, spike activity is significantly decreased, by way of blocking different K(v) channel types: an inactivating A type K(+) current (KA) modulating repetitive firing of the cells and responsible for the after hyperpolarization, and a sustained K(+) current that resembles the delayed rectifier (DKR) and contributes to action potential repolarization. PMID- 23085555 TI - Bactridine's effects on DUM cricket neurons under voltage clamp conditions. AB - We describe the effects of six bactridines (150 nM) on cricket dorsal unpaired median (DUM) neurons. The addition of bactridine 2 to DUM neurons induced a large current component with a reversal potential more negative than -30 mV, most evident at the end of the pulses. This current was completely suppressed when 1 MUM amiloride was applied before adding the bactridines. Since the amiloride sensitive current is able to distort the aim of our study, i.e. the effect of bactridines on sodium channels, all experiments were done in the presence of 1 MUM amiloride. Most bactridines induced voltage shifts of V(1/2) of the Boltzmann inactivation voltage dependency curves in the hyperpolarizing direction. Bactridines 1, 4 and 6 reduced Na current peak by 65, 80 and 24% of the control, respectively. The sodium conductance blockage by bactridines was voltage independent at potentials >20 mV. Bactridines effect on cricket DUM neurons does not correspond to neither alpha- nor beta-toxins. Most bactridines shifted the inactivation curves in the hyperpolarizing direction without any effects on the activation m(infinity)-like curves. Also bactridines differ from other NaScpTx in that they increased an amiloride-sensitive conductance in DUM neurons. Our result suggest that the alpha/beta classification of sodium scorpion toxins is not all encompassing. The present work shows that bactridines target more than one site: insect voltage dependent Na channels and an amiloride-sensitive ionic pathway which is under study. PMID- 23085556 TI - Experience of mating rivals causes males to modulate sperm transfer in the fly Drosophila pseudoobscura. AB - Male responses to risk of sperm competition play an important role in sexual selection, sexual conflict, and the evolution of mating systems. Such responses can combine behavioural and physiological processes, and can be mediated through different components of the ejaculate such as sperm numbers and seminal proteins. An additional level of ejaculate complexity is sperm heteromorphism, with the inclusion of non-fertilising parasperm in the ejaculate. We now test the response to rivals in a sperm heteromorphic species, Drosophila pseudoobscura, measuring the behavioural response and sperm transfer and, crucially, relating these to short-term fitness. Males respond to exposure to conspecific rivals by increasing mating duration, but do not respond to heterospecific rivals. In addition, after exposure to a conspecific rival, males increased the transfer of fertilising eusperm, but not non-fertilising parasperm. Males exposed to a conspecific rival also achieve higher offspring production. This suggests that the evolution of parasperm in flies was not driven by sperm competition and adds to the increasing evidence that males can make extremely sophisticated responses to mating competition. PMID- 23085557 TI - Evaluating interventions aimed at reducing occupational exposure to latex and rubber glove allergens. AB - OBJECTIVE: Concerns over occupational exposures to blood-borne viruses resulted in increased protective glove use; consequentially latex allergy became a hazard for some occupational groups. Interventions aimed at managing this problem included substitution measures (eg, non-powdered/non-latex gloves), but such changes may not occur simultaneously across occupational sectors. This study evaluated whether the incidence of occupational dermatoses fell after interventions aiming to reduce exposure to 'latex and rubber glove allergens' ('latex') were introduced, and whether these interventions were more effective for healthcare workers (HCWs), compared with non-HCWs. METHODS: Incidence rate ratios (IRRs) comparing cases reported to EPIDERM (a UK-wide surveillance scheme) during post versus pre-intervention periods were calculated, both where 'latex' was cited and for cases associated with other exposures ('controls'). RESULTS: Among HCWs, cases of contact urticaria and allergic contact dermatitis (ACD) where 'latex' was cited showed significant downward trends post-intervention, with IRRs of 0.72, 95% CI; 0.52 to 1.00 and 0.47, 95% CI; 0.35 to 0.64 respectively. For HCWs, this fall in 'latex' associated ACD was significantly greater (p=0.02) than for other exposures ('controls') IRR=0.85, 95% CI; 0.57 to 1.28, and greater than that among non-HCWs (IRR 0.75, 95% CI; 0.61 to 0.93). Increases over time were seen for irritant contact dermatitis (ICD) reporting for HCWs, both for cases associated with 'latex' (IRR 1.47, 95% CI: 1.02 to 2.13) and for other exposures ('controls') IRR 1.36, 95% CI 1.06 to 1.76, but not for non HCWs. CONCLUSIONS: A reduction in overall ACD, particularly in HCWs, coincided with interventions aimed at managing workplace contact dermatoses associated with 'latex' exposure. A coincidental rise in ICD reporting is also important, both for hand care and for infection control strategies. PMID- 23085558 TI - Asian dust and daily all-cause or cause-specific mortality in western Japan. AB - OBJECTIVE: Desert dust, which is included in course particles, is considered to have potential toxicity. The effect modification of desert dust on associations between anthropogenic air pollution and mortality has been evaluated. However, the independent effects of Asian dust are less clear. Thus, we evaluated the effects of Asian dust on mortality independent of particulate matter (PM) in western Japan. METHODS: We obtained daily mean concentrations of Asian dust using Light Detection and Ranging measurements and suspended particulate matter (SPM) concentrations (approximately PM(8)) during March 2005 to December 2010. We then evaluated city-specific associations of Asian dust and SPM with daily mortality using a time-series analysis targeting 1 379 052 people aged 65 or above living in 47 cities. The city-specific results were then combined with a Bayesian hierarchical model. RESULTS: Asian dust did not modify the effects of SPM on mortality. Meanwhile, Asian dust was adversely associated with mortality independent of SPM. The excess risk following a 10 MU/m(3) increase in mean of the current to the previous 2 days Asian dust concentration was 0.6% (95% CI 0.1 to 1.1) for heart disease, 0.8% (95% CI 0.1 to 1.6) for ischaemic heart disease, 2.1% (95% CI 0.3 to 3.9) for arrhythmia and 0.5% (95% CI 0.2 to 0.8) for pneumonia mortality. Furthermore, the effects of Asian dust were stronger in northern areas close to the Eurasian continent (source of Asian dust). CONCLUSIONS: Asian dust had adverse effects on circulatory and respiratory mortality independent of PM. PMID- 23085559 TI - A computer based asthma hazard prediction model and new molecular weight agents in occupational asthma. PMID- 23085560 TI - Chondrocytes extract from patients with osteoarthritis induces chondrogenesis in infrapatellar fat pad-derived stem cells. AB - OBJECTIVE: Infrapatellar fat pad of patients with osteoarthritis (OA) contains multipotent and highly clonogenic adipose-derived stem cells that can be isolated by low invasive methods. Moreover, nuclear and cytoplasmic cellular extracts have been showed to be effective in induction of cell differentiation and reprogramming. The aim of this study was to induce chondrogenic differentiation of autologous mesenchymal stem cells (MSCs) obtained from infrapatellar fat pad (IFPSCs) of patients with OA using cellular extracts-based transdifferentiation method. DESIGN: IFPSCs and chondrocytes were isolated and characterized by flow cytometry. IFPSCs were permeabilized with Streptolysin O and then exposed to a cell extract obtained from chondrocytes. Then, IFPSCs were cultured for 2 weeks and chondrogenesis was evaluated by morphologic and ultrastructural observations, immunologic detection, gene expression analysis and growth on 3-D poly (dl-lactic co-glycolic acid) (PLGA) scaffolds. RESULTS: After isolation, both chondrocytes and IFPSCs displayed similar expression of MSCs surface makers. Collagen II was highly expressed in chondrocytes and showed a basal expression in IFPSCs. Cells exposed to chondrocyte extracts acquired a characteristic morphological and ultrastructural chondrocyte phenotype that was confirmed by the increased proteoglycan formation and enhanced collagen II immunostaining. Moreover, chondrocyte extracts induced an increase in mRNA expression of chondrogenic genes such as Sox9, L-Sox5, Sox6 and Col2a1. Interestingly, chondrocytes, IFPSCs and transdifferentiated IFPSCs were able to grow, expand and produce extracellular matrix (ECM) on 3D PLGA scaffolds. CONCLUSIONS: We demonstrate for the first time that extracts obtained from chondrocytes of osteoarthritic knees promote chondrogenic differentiation of autologous IFPSCs. Moreover, combination of transdifferentiated IFPSCs with biodegradable PLGA 3D scaffolds can serve as an efficient system for the maintenance and maturation of cartilage tissue. These findings suggest its usefulness to repair articular surface in OA. PMID- 23085561 TI - Microstructural analysis of collagen and elastin fibres in the kangaroo articular cartilage reveals a structural divergence depending on its local mechanical environment. AB - OBJECTIVE: To assess the microstructure of the collagen and elastin fibres in articular cartilage under different natural mechanical loading conditions and determine the relationship between the microstructure of collagen and its mechanical environment. METHOD: Articular cartilage specimens were collected from the load bearing regions of the medial femoral condyle and the medial distal humerus of adult kangaroos. The microstructure of collagen and elastin fibres of these specimens was studied using laser scanning confocal microscopy (LSCM) and the orientation and texture features of the collagen were analysed using ImageJ. RESULTS: A zonal arrangement of collagen was found in kangaroo articular cartilage: the collagen fibres aligned parallel to the surface in the superficial zone and ran perpendicular in the deep zone. Compared with the distal humerus, the collagen in the femoral condyle was less isotropic and more clearly oriented, especially in the superficial and deep zones. The collagen in the femoral condyle was highly heterogeneous, less linear and more complex. Elastin fibres were found mainly in the superficial zone of the articular cartilage of both femoral condyle and distal humerus. CONCLUSIONS: The present study demonstrates that the collagen structure and texture of kangaroo articular cartilage is joint-dependent. This finding emphasizes the effects of loading on collagen development and suggests that articular cartilage with high biochemical and biomechanical qualities could be achieved by optimizing joint loading, which may benefit cartilage tissue engineering and prevention of joint injury. The existence of elastin fibres in articular cartilage could have important functional implications. PMID- 23085563 TI - Human recombinant elastin-like protein coatings for muscle cell proliferation and differentiation. AB - Recombinant proteins represent a new and promising class of polymeric materials in the field of biomaterials research. An important model for biomaterial design is elastin, the protein accounting for the elasticity of several tissues. Human elastin-like polypeptides (HELPs) have been developed as recombinant versions of elastin with the purpose of enhancing some peculiar characteristics of the native protein, like self-assembling. In this paper, we report on a comparative study of rat myoblasts response to coatings based on two different HELP macromolecules, with respect to control cultures on bare cell culture polystyrene and on a standard collagen coating. Cell behavior was analyzed in terms of adhesion, proliferation and differentiation. The collected data strongly suggest the use of HELPs as excellent biomaterials for tissue engineering and regenerative medicine applications. PMID- 23085562 TI - Organized nanofibrous scaffolds that mimic the macroscopic and microscopic architecture of the knee meniscus. AB - The menisci are crescent-shaped fibrocartilaginous tissues whose structural organization consists of dense collagen bundles that are locally aligned but show a continuous change in macroscopic directionality. This circumferential patterning is necessary for load transmission across the knee joint and is a key design parameter for tissue engineered constructs. To address this issue we developed a novel electrospinning method to produce scaffolds composed of circumferentially aligned (CircAl) nanofibers, quantified their structure and mechanics, and compared them with traditional linearly aligned (LinAl) scaffolds. Fibers were locally oriented in CircAl scaffolds, but their orientation varied considerably as a function of position (P<0.05). LinAl fibers did not change in orientation over a similar length scale (P>0.05). Cell seeding of CircAl scaffolds resulted in a similar cellular directionality. Mechanical analysis of CircAl scaffolds revealed significant interactions between scaffold length and region (P<0.05), with the tensile modulus near the edge of the scaffolds decreasing with increasing scaffold length. No such differences were detected in LinAl specimens (P>0.05). Simulation of the fiber deposition process produced "theoretical" fiber populations that matched the fiber organization and mechanical properties observed experimentally. These novel scaffolds, with spatially varying local orientations and mechanics, will enable the formation of functional anatomic meniscus constructs. PMID- 23085564 TI - Comparing parametric and nonparametric methods for detecting phase synchronization in EEG. AB - Detecting significant periods of phase synchronization in EEG recordings is a non trivial task that is made especially difficult when considering the effects of volume conduction and common sources. In addition, EEG signals are often confounded by non-neural signals, such as artifacts arising from muscle activity or external electrical devices. A variety of phase synchronization analysis methods have been developed with each offering a different approach for dealing with these confounds. We investigate the use of a parametric estimation of the time-frequency transform as a means of improving the detection capability for a range of phase analysis methods. We argue that such an approach offers numerous benefits over using standard nonparametric approaches. We then demonstrate the utility of our technique using both simulated and actual EEG data by showing that the derived phase synchronization estimates are more robust to noise and volume conduction effects. PMID- 23085565 TI - Tanshinone IIA inhibits TNF-alpha-mediated induction of VCAM-1 but not ICAM-1 through the regulation of GATA-6 and IRF-1. AB - The goal of this study was to investigate the differential effect of tanshinone IIA on the induction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) by TNF-alpha and the possible molecular mechanisms by which it regulates ICAM-1 and VCAM-1 expression differentially. Stimulation of human umbilical vein endothelial cells (HUVEC) with TNF-alpha increased ICAM-1 and VCAM-1 expressions, and the pretreatment with tanshinone IIA concentration dependently inhibited VCAM-1 expression but not ICAM-1 expression. In previous study, PI3K/Akt, PKC and Jak/STAT-3 pathways were involved in the TNF alpha-mediated induction of VCAM-1 but not ICAM-1. Thus, we examined the effect of tanshinone IIA on TNF-alpha-mediated activations of PI3K/Akt, PKC and Jak/STAT 3 pathways. Tanshinone IIA efficiently inhibited the phosphorylations of Akt, PKC and STAT-3 by TNF-alpha. Moreover, we determined the effect of tanshinone IIA on IRF-1 or GATAs induction and binding activity to VCAM-1 promoter since the upstream promoter region of VCAM-1 but not ICAM-1 contains IRF-1 and GATA binding motifs. Western blot analysis and ChIP assay showed that tanshinone IIA efficiently inhibited TNF-alpha-increased nuclear level of IRF-1 and GATA-6 and their binding affinity to VCAM-1 promoter region. Taken together, tanshinone IIA selectively inhibits TNF-alpha-mediated expression of VCAM-1 but not ICAM-1 through modulation of PI3/Akt, PKC and Jak/STAT-3 pathway as well as IRF-1 and GATA-6 binding activity. PMID- 23085566 TI - Long-range interlayer alignment of intralayer domains in stacked lipid bilayers. AB - Liquid-crystalline phases of stacked lipid bilayers represent a pervasive motif in biomolecular assemblies. Here we report that, in addition to the usual smectic order, multicomponent multilayer membranes can exhibit columnar order arising from the coupling of two-dimensional intralayer phase separation and interlayer smectic ordering. This coupling propagates across hundreds of membrane lamellae, producing long-range alignment of phase-separated domains. Quantitative analysis of real-time dynamical experiments reveals that there is an interplay between intralayer domain growth and interlayer coupling, suggesting the existence of cooperative multilayer epitaxy. We postulate that such long-range epitaxy is solvent-assisted, and that it originates from the surface tension associated with differences in the network of hydrogen-bonded water molecules at the hydrated interfaces between the domains and the surrounding phase. Our findings might inspire the development of self-assembly-based strategies for the long-range alignment of functional lipid domains. PMID- 23085567 TI - Design of zeolite by inverse sigma transformation. AB - Although the search for new zeolites has traditionally been based on trial and error, more rational methods are now available. The theoretical concept of inverse sigma transformation of a zeolite framework to generate a new structure by removal of a layer of framework atoms and contraction has for the first time been achieved experimentally. The reactivity of framework germanium atoms in strong mineral acid was exploited to selectively remove germanium-containing four ring units from an UTL type germanosilicate zeolite. Annealing of the leached framework through calcination led to the new all-silica COK-14 zeolite with intersecting 12- and 10-membered ring channel systems. An intermediate stage of this inverse sigma transformation with dislodged germanate four-rings still residing in the pores could be demonstrated. Inverse sigma transformation involving elimination of germanium-containing structural units opens perspectives for the synthesis of many more zeolites. PMID- 23085568 TI - Quantized thermal transport across contacts of rough surfaces. AB - Heat transport across interfaces is often discussed in terms of the transmission probability of the heat-carrying phonons through the contact zone. Although interface roughness influences the true contact area and affects phonon scattering within the contact zone, its effect on nanoscale heat transport remains poorly understood. Here, we report experimental data on the pressure dependence of thermal transport across polished nanoscale contacts. The data can be quantitatively explained by a model of thermal conductance across interfaces that incorporates the effect of nanoscale roughness through the quantized thermal conductance across individual atomic-scale contacts within the contact zone. PMID- 23085569 TI - Atomic-scale determination of surface facets in gold nanorods. AB - It is widely accepted that the physical properties of nanostructures depend on the type of surface facets. For Au nanorods, the surface facets have a major influence on crucial effects such as reactivity and ligand adsorption and there has been controversy regarding facet indexing. Aberration-corrected electron microscopy is the ideal technique to study the atomic structure of nanomaterials. However, these images correspond to two-dimensional (2D) projections of 3D nano objects, leading to an incomplete characterization. Recently, much progress was achieved in the field of atomic-resolution electron tomography, but it is still far from being a routinely used technique. Here we propose a methodology to measure the 3D atomic structure of free-standing nanoparticles, which we apply to characterize the surface facets of Au nanorods. This methodology is applicable to a broad range of nanocrystals, leading to unique insights concerning the connection between the structure and properties of nanostructures. PMID- 23085570 TI - Tuning the catalytic activity of Ag(110)-supported Fe phthalocyanine in the oxygen reduction reaction. AB - A careful choice of the surface coverage of iron phthalocyanine (FePc) on Ag (110) around the single monolayer allows us to drive with high precision both the long-range supramolecular arrangement and the local adsorption geometry of FePc molecules on the given surface. We show that this opens up the possibility of sharply switching the catalytic activity of FePc in the oxygen reduction reaction and contextual surface oxidation in a reproducible way. A comprehensive and detailed picture built on diverse experimental evidence from scanning tunnelling microscopy, X-ray photoelectron spectroscopy and X-ray absorption spectroscopy, coupled with density functional theory calculations, sheds new light on the nature of the catalytically active molecule-surface coordination and on the boundary conditions for its occurrence. The results are of relevance for the improvement of the catalytic efficiency of metallo-macrocycles as viable substitutes for platinum in the cathodic compartment of low-temperature fuel cells. PMID- 23085571 TI - Reactivation of codogenic endogenous retroviral (ERV) envelope genes in human endometrial carcinoma and prestages: Emergence of new molecular targets. AB - Endometrial carcinoma (EnCa) is the most common invasive gynaecologic carcinoma. Over 85% of EnCa are classified as endometrioid, expressing steroid hormone receptors and mostly involving pathological prestages. Human endogenous retroviruses (ERV) are chromosomally integrated genes, account for about 8% of the human genome and are implicated in the etiology of carcinomas. The majority of ERV envelope (env) coding genes are either not present or not consistently represented between common gene expression microarrays. The aim of this study was to analyse the absolute gene expression of all known 21 ERV env genes including 19 codogenic and two env genes with premature stop codons in EnCa, endometrium as well as in hyperplasia and polyps. For EnCa seven env genes had high expression with >200 mol/ng cDNA (e.g. envH1-3, Syncytin-1, envT), two middle >50 mol/ng cDNA (envFc2, erv-3) and 12 low less than 50 mol/ng cDNA (e.g. Syncytin-2, envV2). Regarding tumor parameters, Syncytin-1 and Syncytin-2 were significantly over-expressed in advanced stage pT2 compared to pT1b. In less differentiated EnCa Syncytin-1, erv-3, envT and envFc2 were significantly over-expressed. Syncytin-1, Syncytin-2 and erv-3 were specific to glandular epithelial cells of polyps, hyperplasia and EnCa using immunohistochemistry. An analysis of 10 patient-matched EnCa with endometrium revealed that the ERV-W 5' long terminal repeat regulating Syncytin-1 was hypomethylated, including the ERE and CRE overlapping MeCP2 sites. Functional analyses showed that 10 env genes were regulated by methylation in EnCa using the RL95-2 cell line. In conclusion, over expressed env genes could serve as indicators for pathological pre-stages and EnCa. PMID- 23085572 TI - Glutamate attenuates IGF-1 receptor tyrosine phosphorylation in mouse brain: possible significance in ischemic brain damage. AB - We have previously reported that glutamate acting on NMDA receptors attenuated IGF-1 pro-survival signaling and its protective effect in cultured neurons. In this study, we investigate whether IGF-1 signaling was suppressed by glutamate in vivo, and whether this effect of glutamate was implicated in ischemic brain damage. Our results showed that exogenous glutamate injected by i.c.v. decreased phosphorylation of IGF-1 receptors and Akt, and this effect of glutamate was reversed by NMDA antagonist MK-801 but not by non-NMDA antagonist DNQX. NMDA exhibited similar effects of glutamate. Endogenous glutamate, which was induced by focal cerebral ischemia, gradually reduced the phosphorylation of IGF-1 receptors and Akt in a time-dependent manner. Moreover, IGF-1 injected by i.c.v. failed to stimulate phosphorylation of IGF-1 receptors and Akt after 180 min MCAO, and the protective effect was abolished. Pre-treatment of MK-801 restored the phosphorylation of IGF-1 receptors and Akt by IGF-1. In parallel, IGF-1 successfully rescued infarct area after 180 min MCAO. These findings suggest that glutamate interferes with IGF-1 signaling in vivo by activating NMDA receptors, and thereby shorten the therapeutic window of IGF-1 against focal cerebral ischemia. PMID- 23085573 TI - Enhancing the efficiency of polymerase chain reaction using graphene nanoflakes. AB - The effect of the recently developed graphene nanoflakes (GNFs) on the polymerase chain reaction (PCR) has been investigated in this paper. The rationale behind the use of GNFs is their unique physical and thermal properties. Experiments show that GNFs can enhance the thermal conductivity of base fluids and results also revealed that GNFs are a potential enhancer of PCR efficiency; moreover, the PCR enhancements are strongly dependent on GNF concentration. It was found that GNFs yield DNA product equivalent to positive control with up to 65% reduction in the PCR cycles. It was also observed that the PCR yield is dependent on the GNF size, wherein the surface area increases and augments thermal conductivity. Computational fluid dynamics (CFD) simulations were performed to analyze the heat transfer through the PCR tube model in the presence and absence of GNFs. The results suggest that the superior thermal conductivity effect of GNFs may be the main cause of the PCR enhancement. PMID- 23085574 TI - Heterotrimeric G protein signaling governs the cortical stability during apical constriction in Drosophila gastrulation. AB - During gastrulation in Drosophila melanogaster, coordinated apical constriction of the cellular surface drives invagination of the mesoderm anlage. Forces generated by the cortical cytoskeletal network have a pivotal role in this cellular shape change. Here, we show that the organisation of cortical actin is essential for stabilisation of the cellular surface against contraction. We found that mutation of genes related to heterotrimeric G protein (HGP) signaling, such as Gbeta13F, Ggamma1, and ric-8, results in formation of blebs on the ventral cellular surface. The formation of blebs is caused by perturbation of cortical actin and induced by local surface contraction. HGP signaling mediated by two Galpha subunits, Concertina and G-ialpha65A, constitutively regulates actin organisation. We propose that the organisation of cortical actin by HGP is required to reinforce the cortex so that the cells can endure hydrostatic stress during tissue folding. PMID- 23085575 TI - Peripheral intrahepatic cholangiocarcinoma occurring in patients without cirrhosis or chronic bile duct diseases: epidemiology and histopathology of distant nontumoral liver in 57 White patients. AB - BACKGROUND/AIM: Peripheral intrahepatic cholangiocarcinoma (ICC) occurring mainly in the absence of cirrhosis represents an increasing subgroup of primary liver tumors in Western countries. Histopathologic changes in the non-neoplastic liver in this context are not well characterized. PATIENTS AND METHODS: We assessed the clinical characteristics and histopathologic changes in the distant nontumoral liver of 57 consecutive White patients (34 men, mean age 59 years) referred to one medical and one surgical liver institution over a 16-year period who developed a peripheral ICC in the absence of cirrhosis or bile duct disease. RESULTS: High alcohol consumption was observed in 11 patients (20%), 38 patients (66%) had a BMI of 25 kg/m or more, 22 patients (40%) had diabetes, two patients had hepatitis B virus infection, two others had hepatitis C virus infection, three patients had genetic hemochromatosis, and two patients had cutaneous porphyria tarda. The distant nontumoral liver was normal in 10 patients (18%). The two main histopathologic changes observed were macrovesicular steatosis (>10% of hepatocytes) in 38 patients (66%), including 11 patients (19%) with steatohepatitis, and moderate or intense hepatocyte iron overload in 22 patients (38%). CONCLUSION: This study shows a high prevalence of macrovesicular steatosis associated or not with steatohepatitis and iron overload in patients who develop peripheral ICC in the absence of cirrhosis or bile duct disease. PMID- 23085576 TI - Evaluation of early atherosclerosis markers in patients with nonalcoholic fatty liver disease. AB - OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is characterized by the excessive accumulation of fat in the liver cells. It is strongly associated with cardiovascular risk factors for atherosclerosis. Flow-mediated dilation (FMD) and carotid intima-media thickness (CIMT) are noninvasive methods for the evaluation of endothelium. They are considered early markers of atherogenesis. The aim of this study was to evaluate early atherosclerosis markers in patients with NAFLD. METHODS: We examined 161 patients. All the patients underwent hepatic ultrasonography, transthoracic echocardiography, and brachial artery and carotid artery imaging. Fasting blood samples were drawn from all patients for the determination of lipids, insulin, C-peptide, and fasting blood glucose. HOMA-IR was calculated. RESULTS: Among the 161 patients, 44 had normal hepatic ultrasonography, 42 had stage 1 hepatosteatosis, 53 had stage 2 hepatosteatosis and 22 had stage 3 hepatosteatosis. FMD was reduced in patients with NAFLD as compared with the healthy controls (5.9 +/- 3.1 vs. 9.6 +/- 2.7%, P<0.001). There was a significant negative moderate correlation between ultrasonographic hepatosteatosis grade and FMD (r=-0.556, P<0.001). The mean CIMT was significantly increased in patients with NAFLD as compared with the controls (0.40 +/- 0.19 vs. 0.27 +/- 0.18, P<0.001). There was a significant positive weak correlation between ultrasonographic hepatosteatosis grade and mean CIMT (r=0.376, P<0.001). CONCLUSION: This study showed that NAFLD is associated with impaired CIMT and FMD, which are early markers of atherosclerosis. These findings may play a crucial role in understanding the pathophysiology of the atherosclerotic process in patients with NAFLD. PMID- 23085577 TI - Significance of histopathological features in differentiating autoimmune liver disease from nonautoimmune chronic liver disease in children. AB - OBJECTIVES: Autoimmune liver disease (AILD) requires a constellation of clinical, serological, biochemical, and histological findings for diagnosis. Liver biopsy forms the cornerstone for the definite diagnosis of AILD, despite histological features not being pathognomonic. Liver biopsies of AILD and nonautoimmune chronic liver disease (NACLD) were reviewed blindly to assess the role of typical histological findings in differentiating AILD from NACLD in a pediatric population. PARTICIPANTS AND METHODS: Twenty-five liver biopsies of AILD and 34 liver biopsies of NACLD were reviewed retrospectively without knowledge of the final diagnosis. RESULTS: The typical histology comprising all four features, interface hepatitis, portal lymphoplasmacytic infiltrate, rosette formation, and emperipolesis, was observed in 56% of AILD. Rosette formation and emperipolesis were associated significantly with the diagnosis of AILD. Rosette formation alone or in combination with emperipolesis or lymphoplasmacytic infiltrate had high specificity (96.2% each) but low sensitivity (68, 60, and 60%, respectively) for AILD. The diagnostic accuracy of typical histology comprising of a combination of at least three of four features, rosette formation, emperipolesis, and lymphoplasmacytic infiltrate, was 76.9%, with a positive predictive value of 93.3% and a negative predictive value of 70.2%. CONCLUSION: Characteristic patterns of liver injury comprising typical histological features on liver biopsy may strongly suggest the diagnosis of AILD irrespective of other laboratory parameters in children. Rosette formation was the only independent significant histological factor to predict AILD. High specificity and predictability of typical histological features may be helpful in diagnosing seronegative AILD among cases of cryptogenic liver disease in the absence of other supportive findings. PMID- 23085578 TI - The effect of smoking on the risk of gallbladder cancer: a meta-analysis of observational studies. AB - BACKGROUND: Cigarette smoking has been shown to cause many nonpulmonary cancers, including those of liver, pancreas and bladder. However, results of epidemiologic studies examining the association between smoking and gallbladder cancer (GBC) have been mixed. To clarify the association of cigarette smoking and GBC, we performed a meta-analysis of observational studies. METHODS: A literature search was performed using Medline (from 1 January 1966) and Embase (from 1 January 1974), through 31 January 2012, and by manually searching the reference lists of pertinent articles. Summary relative risks (SRRs) with corresponding 95% confidence intervals (CIs) were calculated with a random-effects model. RESULTS: A total of 11 articles (10 case-control and one prospective cohort studies) were used in this meta-analysis, which is based on a total of 1178 GBC cases. Analysis of 11 studies found that smokers had an increased risk of GBC development, compared with nonsmokers (SRRs 1.45, 95% CIs, 1.11-1.89). There was moderate heterogeneity among studies (Q=18.15, P=0.052, I2 =44.9%). These increased risks were independent of alcohol use and a history of gallstones. No significant publication bias was found. CONCLUSION: Although the current evidence supports a positive link between cigarette smoking and risk of gallbladder cancer, additional population-based studies, particularly cohort studies, are needed before definitive conclusions can be drawn. PMID- 23085579 TI - Novel upstream and downstream sequence elements contribute to polyadenylation efficiency. AB - Polyadenylation is a 3' mRNA processing event that contributes to gene expression by affecting stability, export and translation of mRNA. Human polyadenylation signals (PAS) have core and auxiliary elements that bind polyadenylation factors upstream and downstream of the cleavage site. The majority of mRNAs do not have optimal upstream and downstream core elements and therefore auxiliary elements can aid in polyadenylation efficiency. Auxiliary elements have previously been identified and studied in a small number of mRNAs. We previously used a global approach to examine auxiliary elements to identify overrepresented motifs by a bioinformatic survey. This predicted information was used to direct our in vivo validation studies, all of which were accomplished using both a tandem in vivo polyadenylation assay and using reporter protein assays measured as luciferase activity. Novel auxiliary elements were placed in a test polyadenylation signal. An in vivo polyadenylation assay was used to determine the strength of the polyadenylation signal. All but one of the novel auxiliary elements enhanced the test polyadenylation signal. Effects of these novel auxiliary elements were also measured by a luciferase assay when placed in the 3' UTR of a firefly luciferase reporter. Two novel downstream auxiliary elements and all of the novel upstream auxiliary elements showed an increase in reporter protein levels. Many well known auxiliary polyadenylation elements have been found to occur in multiple sets. However, in our study, multiple copies of novel auxiliary elements brought reporter protein levels as well as polyadenylation choice back to wild type levels. Structural features of these novel auxiliary elements may also affect the role of auxiliary elements. A MS2 structure placed upstream of the polyadenylation signal can affect polyadenylation in both the positive and negative direction. A large change in RNA structure by using novel complementary auxiliary element also decreased polyadenylation choice and reporter protein levels. Therefore, we conclude that RNA structure has an important role in polyadenylation efficiency. PMID- 23085580 TI - Expression of macrophage migration inhibitory factor by osteoblastic cells: protection against cadmium toxicity. AB - Exposition to cadmium (Cd) has been linked to bone metabolism alterations and occurrence of osteoporosis. Despite its known renal toxicity which indirectly disrupts bone metabolism through impairment of vitamin D synthesis, increasing evidence argues for the direct action of Cd on bone-forming osteoblasts. Indeed, accumulation of Cd in osteoblasts and metal-induced cell death has been documented but little is known about the intracellular mechanisms of protection against this stress. In this work, we investigated the protection afforded by thiol-containing proteins against Cd cytotoxicity in MC3T3 osteoblastic cells. Viability of MC3T3 cells was reduced by Cd in a concentration-dependent manner with a LC(50) of 7.6+/-1.1MUM. Depletion of glutathione by l-buthionine sulphoximine (BSO) increased cell sensitivity to Cd cytotoxicity, suggesting the involvement of thiol-containing peptides as a mechanism of protection. Accordingly, Cd was shown to promote progressive depletion of reduced thiol content and to stimulate the production of reactive oxygen species (ROS). Interestingly, low non cytotoxic concentrations of Cd increased the gene expression of macrophage migration inhibitory factor (MIF), also a thiol containing protein. Inhibition of the transcription factor NFkappaB prevented Cd dependent upregulation of MIF expression and consequently, increased Cd cytotoxicity in osteoblasts. Moreover, MIF deficient mouse osteoblasts were more sensitive to Cd cytotoxicity than the corresponding control cells. By gel filtration chromatography, we demonstrated that MIF acts as a thiol-containing protein and thereby promotes Cd complexation. In accordance with its binding ability, addition of recombinant MIF to the culture medium reduced Cd cytotoxicity. Overall, upregulation of MIF expression by Cd may protect against the cytotoxicity of this metal in the osteoblasts. PMID- 23085581 TI - The topography of electrospun nanofibers and its impact on the growth and mobility of keratinocytes. AB - Despite a lot of intensive research in the field of polymer nanofibers as wound healing and tissue-regeneration materials, the behavior of cells in contact with nanofibers in vitro as well as in vivo is still not well understood. However, this knowledge is crucial for the design of nanofibrillar materials that are suitable for biomedical applications. Therefore, in this study, we present the preparation of poly(vinyl alcohol) (PVA) nanofibers from a physico-chemically characterized polymer solution by electrospinning together with a stabilization method to preserve the morphology of the nanofibers in aqueous conditions. An investigation of the effects of a nanofibrillar scaffold on the growth of human keratinocytes showed that randomly oriented PVA nanofibers delay the keratinocytes' adhesion but improve their strength, greatly alter their morphology, increase their metabolic activity, and limit their mobility. We have shown that due to the small interfiber pores, the whole cells are unable to penetrate into nanofibrillar network efficiently. However, flexible cell parts can penetrate into the nanofibrillar network, whereas the cell nuclei stay on the surface of electrospun scaffold. Additional reason for poor cell mobility is random orientation of nanofibers, which does not provide continuous routes for successful cell infiltration. Therefore, nanofibrillar support with nanosized interfiber pores could potentially be used to enable an efficient cell proliferation and accelerate surface-wound healing, but not for three-dimensional tissue regeneration. Finally, we showed that aligned nanofibers can successfully direct the migration and proliferation of cells, which is a crucial property of nanomaterials for the successful regeneration of tissues with a highly organized structure. PMID- 23085582 TI - Bioavailability and foam cells permeability enhancement of Salvianolic acid B pellets based on drug-phospholipids complex technique. AB - This study investigated phospholipids complex (PC) loaded pellets of poorly permeable Salvianolic acid B (SalB), in which PC was to improve the liposolubility and permeability of SalB. Transmission electron microscopy observation, differential scanning calorimetry measurement, infrared spectroscopy analysis, n-octanol/water partition coefficient study, and foam cell permeability research were employed to prove the complex formation. Pellets containing SalB phospholipids complex (SalB-PC) were prepared via extrusion/spheronization technique. The optimal pellets obtained with 30% SalB-PC, 15% Kollidon(r)CL-SF, 15% Flowlac(r)100, and 40% MCC exhibited a very homogeneous size distribution, the shortest disintegration time, highest crushing force, appreciable spherical shape, and a fast drug release behavior. Following hydration, the droplet size distribution of SalB-PC pellets was nearly same to its PC (85.4+/-16 and 73.5+/ 12nm). In vivo performance showed SalB-PC pellets presented significantly larger AUC(0-)(t), which was 0.58 times more than that of physical mixtures (PMs) and 1.57 times more than that of SalB pellets. C(max) of SalB-PC pellets were also increased by 0.26-fold and 0.80-fold as that of PMs and SalB pellets, respectively. In conclusion, extrusion/spheronization could be a suitable technique to prepare PC loaded pellets, which could effectively preserve the properties of PC to improve the permeability and bioavailability of highly water soluble drug. PMID- 23085583 TI - Tetracycline-ferrite nanocomposites formed via high-energy ball milling and the influence of milling conditions. AB - High-energy ball milling was used to mediate the formation of nanocomposites containing tetracycline and magnetic nanoparticles. Tetracycline-HCl was ball milled for 1, 3, 5, 15, and 30 h under argon or air atmosphere with preformed Mg 0.5 Zn 0.5 Fe2O4 nanoferrites prepared by glycolthermal method. The structural, thermal, and magnetic properties of these novel materials and the effect of milling atmosphere on composition, crystallinity and cation distribution were then characterized by ICP-OES, DSC/TGA, XRPD, ATR-IR, UV-Vis and Mossbauer spectroscopy. Tetracycline underwent rapid and consecutive metal coordination events in the milling process to yield complexes characterized by bathochromic shifts in its electronic spectra and suppression of electronic absorbance at 365 nm. Changes in stretching vibrations due to the A-ring carbonyl (1616 cm(-1)), amide II nitrogen (1602 cm(-1)), and CO bond (1039 cm(-1)) indicate Mg-type interactions imposed on the metals. Exothermic oxidation of the drug at 235 degrees C disappeared after 5h milling with the nanoferrites, and the composites formed remained thermostable up to 500 degrees C. Tetracycline-nanoferrites (Tet NF) are magnetic-ordered materials with a well-defined spinel-type structure. Analysis of the Mossbauer data suggests that the milling time and atmosphere have significant influence on cation distributions in Tet-NF composites. PMID- 23085584 TI - Neutral lipid accumulation at elevated temperature in conditional mutants of two microalgae species. AB - Triacylglycerols, an energy storage compound in microalgae, are known to be accumulated after nitrogen starvation of microalgae cells. Microalgae could be of importance for future biodiesel production due to their fast growth rate and high oil content. In collections of temperature sensitive mutants of Chlamydomonas reinhardtii and Chlorella vulgaris, nine out of fourty-one mutants in C. reinhardtii and eleven out of fifty-three mutants in C. vulgaris contained increased amounts of neutral lipids, predominantly as triacylglycerols. Upon temperature induced cell-cycle arrest, these mutants showed enlarged cellular volume compared with the wild type. The C. reinhardtii mutants were analyzed further and one type of mutants displayed a shift in lipid composition from polar membrane lipids to neutral lipids after a temperature up-shift, while the second type of mutants accumulated more total lipid per cell, predominantly as neutral lipids as compared with the wild type. Three C. reinhardtii mutants were analyzed further and found to be arrested after DNA synthesis but prior to cell division in the cell cycle. These mutants will be useful in order to further understand neutral lipid accumulation in microalgae and suggest possibilities for biodiesel production by specific induction of lipid accumulation in miroalgal cultures by cell-cycle inhibition. PMID- 23085585 TI - A unique caleosin serving as the major integral protein in oil bodies isolated from Chlorella sp. cells cultured with limited nitrogen. AB - Accumulation of oil bodies was successfully induced in a microalga, Chlorella sp., cultured in a nitrogen-limited medium. The oil bodies were initially assembled as many small entities (mostly 0.1-1 MUm), and lately found as a major irregular compartment (>3 MUm) occupying more than half of the cell space. Approximately, two thirds of oil bodies isolated from Chlorella cells were broken and formed a transparent oil layer on top of the milky compact layer of the remaining stable oil bodies after being washed with 0.1% triton X-100. The stable oil bodies mainly comprised triacylglycerols as examined by thin layer chromatography analysis and confirmed by both Nile red and BODIPY stainings. Integrity of these stable oil bodies was maintained via electronegative repulsion and steric hindrance possibly provided by their surface proteins. Immunological cross-recognition revealed that a major protein of 29 kDa, tentatively identified as caleosin, was exclusively present in Chlorella oil bodies. Mass spectrometric analysis showed that the putative caleosin possessed a trypic fragment of 13 residues matching to that of a hypothetical caleosin in Picea sitchensis. With the aid of a degenerate primer designed according to the tryptic peptide, a complete cDNA fragment encoding this putative caleosin was obtained by PCR. Phylogenetic tree analysis supports that Chlorella caleosin is the most primitive caleosin found in oil bodies to date. PMID- 23085586 TI - Differential regulation of two sucrose transporters by defoliation and light conditions in perennial ryegrass. AB - Sucrose transport between source and sink tissues is supposed to be a key-step for an efficient regrowth of perennial rye-grass after defoliation and might be altered by light conditions. We assessed the effect of different light regimes (high vs low light applied before or after defoliation) on growth, fructans and sucrose mobilization, as well as on sucrose transporter expression during 14 days of regrowth. Our results reported that defoliation led to a mobilization of C reserves (first sucrose and then fructans), which was parallel to an induction of LpSUT1 sucrose transporter expression in source and sink tissues (i.e. leaf sheaths and elongating leaf bases, respectively) irrespective to light conditions. Light regime (high or low light) had little effects on regrowth and on C reserves mobilization during the first 48 h of regrowth after defoliation. Thereafter, low light conditions, delaying the recovery of photosynthetic capacities, had a negative effect on C reserves re-accumulation (especially sucrose). Surprisingly, high light did not enhance sucrose transporter expression. Indeed, while light conditions had no effect on LpSUT1 expression, LpSUT2 transcripts levels were enhanced for low light grown plants. These results indicate that two sucrose transporter currently identified in Lolium perenne L. are differentially regulated by light and sucrose. PMID- 23085587 TI - MicroRNAs deciding cardiac stem cell fate. PMID- 23085589 TI - (Dipyrido[3,2-a:2',3'-c]phenazine)(glycinato)copper(II) perchlorate: a novel DNA intercalator with anti-proliferative activity against thyroid cancer cell lines. AB - A novel copper(II) heteroleptic complex of dipyrido[3,2-a:2',3'-c]phenazine (dppz) and glycinato (gly) as chelating ancillary ligand, [Cu(dppz)(gly)]ClO(4) (1), was synthesized and characterized. X-ray crystallography revealed that the coordination geometry of the cationic [Cu(dppz)(gly)](+) unit is hexacoordinated and shows a distorted octahedral coordination geometry in the solid state, with the N,N and N,O chelating atoms of dppz and glycinato, respectively, in the square plane and in which the planar units are connected in a monodimensional polymeric array by the apical copper coordination of the second carboxylic oxygen atom. Biological assays showed that 1 exhibits a remarkable anti-proliferative activity against the two human anaplastic thyroid cancer cell lines 8505c (BrafV600E/V600E) and SW1736 (BrafWT/V600E), in a dose- and time-dependent manner. In details, the IC(50) after 48 h of drug exposure was 2.86 +/- 0.54 MUM for SW1736 and 1.05 +/- 0.48 MUM for 8505c. On the other hand, the IC(50) shown by cis-diamminedichloroplatinum(II) (cisplatin) against the same cell lines was 2.50 +/- 0.40 MUM and 6.03 +/- 0.78 MUM, respectively. Optical microscopy observations, after 48 h of treatment, showed morphological cell changes typical of apoptosis, confirmed by DNA ladder assays. DNA interaction studies, performed by UV absorption spectrophotometry, circular dichroism and viscosimetry, clearly showed that [Cu(dppz)(gly)]ClO(4) is a DNA-intercalator, with a DNA-binding constant, K(b), of 2.1 * 10(6) M(-1), suggesting that the mechanism of the cytotoxic activity can be related to its DNA-binding. PMID- 23085590 TI - The synthesis and spectral investigation of a novel highly water-soluble, aggregation-free antimony(V)-phthalocyanine absorbing light in optical therapeutical window. AB - A novel antimony-phthalocyanine, [Sb(H(3)tsppc)(OH)(2)], where H(3)tsppc denotes monodeprotonated tetrakis{(2',6'-dimethyl-4'-sulfonic acid)phenoxyl}phthalocyaninate, has been synthesized through sulfonation of [Sb(tppc)(OH)(2)](+) (tppc denotes tetrakis{(2',6' dimethyl)phenoxyl}phthalocyaninate) in concentrated sulfuric acid. This compound is highly soluble in water (ca. 4 * 10(-2) M) without surfactant or alcohol. Moreover, it has been found free from aggregation in water up to almost 10(-4) M, unlike its copper and metal-free analogues, and show an intense optical absorption and emission band in optical therapeutical window (700-800 nm). The axial hydroxyl groups play a crucial role in disaggregation of the antimony derivative in water. PMID- 23085588 TI - New concepts of endoplasmic reticulum function in the heart: programmed to conserve. AB - Secreted and membrane proteins play critical roles in myocardial health and disease. Studies in non-myocytes have shown that the peri-nuclear ER is the site for synthesis, folding, and quality control of most secreted and membrane proteins, as well as a nexus of a signal transduction system, called the ER stress response, which informs the cell about the status of ER protein folding. Moreover, the dynamic physical and functional association of the ER with mitochondria is a key site responsible for integrating ER function and mitochondrial metabolism, but is only just beginning to be understood in the myocardium. Although a great deal is known about roles played by the sarcoplasmic reticulum (SR) in contractile calcium handling in the heart, little is known about the relative locations and functions of the peri-nuclear ER and the SR in terms of secreted and membrane protein synthesis and folding. In this review we will explore the current state of knowledge of the location of secreted and membrane protein synthesis, folding, and quality control machinery in cardiac myocytes, as well as our understanding of the functional consequences of ER stress and the unfolded protein response in the heart in terms of protein synthesis, cell growth, and metabolic regulation. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". PMID- 23085591 TI - Pro-oxidant activity of aluminum: promoting the Fenton reaction by reducing Fe(III) to Fe(II). AB - The possibility for an Al-superoxide complex to reduce Fe(III) to Fe(II), promoting oxidative damage through the Fenton reaction, is investigated using highly accurate ab initio methods and density functional theory in conjunction with solvation continuum methods to simulate bulk solvent effects. It is found that the redox reaction between Al-superoxide and Fe(III) to produce Fe(II) is exothermic. Moreover, the loss of an electron from the superoxide radical ion in the Al-superoxide complex leads to a spontaneous dissociation of molecular oxygen from aluminum, recovering therefore an Al(3+) hexahydrated complex. As demonstrated in previous studies, this complex is again prone to stabilize another superoxide molecule, suggesting a catalytic cycle that augments the concentration of Fe(II) in the presence of Al(III). Similar results are found for Al(OH)(2+) and Al(OH)(2)(+) hydrolytic species. Our work reinforces the idea that the presence of aluminum in biological systems could lead to an important pro oxidant activity through a superoxide formation mechanism. PMID- 23085592 TI - Trivalent chromium and aluminum affect the thermostability and conformation of collagen very differently. AB - Ultrasensitive differential scanning calorimetry (US-DSC) was used to directly measure the thermal transition temperature and energy change of acid soluble collagen in the presence of Cr(3+) and Al(3+) sulfates. The behavior of Cr(3+) was analogous to kosmotropes in the cation Hofmeister series and increased the stability of collagen in dilute solutions. Meanwhile, the denaturational enthalpy change (DeltaH) of collagen was substantially reduced with change to increasing Cr(3+) concentration. This is likely due to the uni-point binding of Cr(3+) with carboxyl groups of collagen side chains that could decrease the hydrogen-bonding in collagen and result in the increase of protein hydrophobicity. In the case of Al(3+), the interactions between the ions and collagen showed very different properties: at low and medium ion concentrations, the stability of the collagen was decreased; however, a further increase of Al(3+) concentration led to a salting-out effect of collagen, indicating the Al(3+) is a typical chaotropic ion. This striking difference of the two ions in the stabilization of collagen can be explained in terms of the different interactions between the cations and the carboxyl groups of collagen side chains. Additionally, we studied metal ion induced conformational change by the combination of circular dichroism (CD) and atomic force microscopy (AFM). CD measurements revealed that neither metal ion interactions of collagen with Cr(3+) nor Al(3+) ions destroyed the triple-helical backbone structure of collagen in the solution. AFM results further confirmed that the dehydration of collagen by Cr(3+) is more significant than Al(3+), thus inducing the aggregation of collagen fibrils. PMID- 23085593 TI - Zinc(II) complexes with dithiocarbamato derivatives: structural characterisation and biological assays on cancerous cell lines. AB - Zinc is one of the most important trace elements in the body and it is essential as a cofactor for the structure and function of a number of cellular molecules including enzymes, transcription factors, cellular signalling proteins and DNA repair enzymes. On the other hand, recent studies have shown that zinc could play a role both in the development of various cancers and in the induction of apoptosis in some cell types, however, no established common relationships of zinc with cancer development and progression have been identified. To date, in our research group different metal-dithiocarbamato complexes have been designed that were expected to resemble the main features of cisplatin together with higher activity, improved selectivity and bioavailability, and lower side effects. On the basis of the obtained encouraging achievements with other metals (such as gold and copper) we have decided to enlarge the studies to the complexes of zinc(II) using the same ligands. Hereby, we report the results on the synthesis and characterisation of ZnL(2) complexes with five different dithiocarbamato derivatives, such as dimethyl-(DMDT), pyrrolidine-(PyDT), methyl (MSDT), ethyl-(ESDT) and tert-butyl-(TSDT) sarcosinedithiocarbamate. All the obtained compounds have fully been characterised by means of several spectroscopic techniques. In addition, the crystal structure of [Zn(MSDT)(2)](2) dinuclear complex is also reported. In order to evaluate the in vitro cytotoxic properties, some biological assays have been carried out on a panel of human tumour cell lines sensible and resistant to cisplatin. Some of the tested compounds show cytotoxicity levels comparable or even greater than the reference drug (cisplatin). PMID- 23085594 TI - Bis(L-cysteinato)zincate(lI) as a coordination compound that induces metallothionein gene transcription without inducing cell-stress-related gene transcription. AB - Zinc is an essential micronutrient, deficiency of which results in growth retardation, immunodeficiency, and neurological diseases such as dysgeusia. Several zinc coordination compounds are used for zinc supplementation; however, supplemented zinc ions have no specificity and interact with various groups of molecules. Here, we found that, from a library of 30 zinc coordination compounds, bis(L-cysteinato)zincate(II), designated Z01, functioned as a metallothionein (MT) inducer. Z01 induced MT expression mediated by the transcription factor MTF 1, without inducing cell-stress-related heme oxygenase-1 gene expression at specific concentration. The zinc ion was necessary for the MT induction. (65)Zn incorporation following treatment with (65)Zn-labeled Z01 suggested that Z01 did not act as zinc ionophore despite its hydrophilicity. Electrophoretic mobility shift assays revealed that Z01 facilitates MTF-1-MRE complex formation, and, by inference, transfer of zinc from Z01 to MTF-1. Phosphorylated ERK levels were increased by ZnSO(4) treatment but not by Z01. Although our data do not definitely prove that Z01 is an MTF-1-specific activator, our observations suggest that zinc coordination compounds can regulate zinc distribution and act as zinc donors for specific molecules. PMID- 23085595 TI - Redox-active cytotoxic diorganotin(IV) cycloalkylhydroxamate complexes with different ring sizes: reduction behaviour and theoretical interpretation. AB - Two series of new diorganotin(IV) cycloalkylhydroxamate complexes with different ring sizes (cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), formulated as the mononuclear [R(2)Sn(HL)(2)] (1:2) (a, R=(n)Bu and Ph) and the polymeric [R(2)SnL](n) (1:1) (b, R=(n)Bu) compounds, were prepared and fully characterized. Single crystal X-ray diffraction for [(n)Bu(2)Sn{C(5)H(9)C(O)NHO}(2)] (3a) discloses the cis geometry and strong intermolecular NH?O interactions. The in vitro cytotoxic activities of the complexes were evaluated against HL-60, Bel 7402, BGC-823 and KB human tumour cell lines, the greater activity concerning [(n)Bu(2)Sn(HL)(2)] [HL=C(3)H(5)C(O)NHO (1a), C(6)H(11)C(O)NHO (4a)] towards BGC 823. The complexes undergo, by cyclic voltammetry and controlled-potential electrolysis, one irreversible overall two-electron cathodic process at a reduction potential that does not appear to correlate with the antitumour activity. The electrochemical behaviour of [R(2)Sn{C(5)H(9)C(O)NHO}(2)] [R=(n)Bu (3a), Ph (7a)] was also investigated using density functional theory (DFT) methods, showing that the ultimate complex structure and the mechanism of its formation are R dependent: for the aromatic (R=Ph) complex, the initial reduction step is centred on the phenyl ligands and at the metal, being followed by a second reduction with SnO and SnC ruptures, whereas for the alkyl (R=(n)Bu) complex the first reduction step is centred on one of the hydroxamate ligands and is followed by a second reduction with SnO bond cleavages and preservation of the alkyl ligands. In both cases, the final complexes are highly coordinative unsaturated Sn(II) species with the cis geometry, features that can be of biological significance. PMID- 23085596 TI - CH/pi interactions in metal-porphyrin complexes with pyrrole and chelate rings as hydrogen acceptors. AB - CH/pi interactions in metal porphyrinato complexes were studied by analyzing data in crystal structures from the Cambridge Structural Database (CSD) and by quantum chemical calculations. The analysis of the data in the CSD shows that both five membered pyrrole and six-membered chelate rings form CH/pi interactions. The interactions occur more frequently with five-membered rings. The analysis of distances in crystal structures and calculated energies show stronger interactions with six-membered chelate rings, indicating that a larger number of interactions with five-membered rings are not the consequence of stronger interactions, but better accessibility of five-membered pyrrole rings. The calculated energies of the interactions with positions in six-membered rings are 2.09 to -2.83 kcal/mol, while the energies with five-membered rings are -2.05 to 2.26 kcal/mol. The results reveal that stronger interactions of six-membered rings are the consequence of stronger electrostatic interactions. Substituents on the porphyrin ring significantly strengthen the interactions. Substituents on the six-membered ring strengthen the interaction energy by about 20%. The results show that CH/pi interactions play an important role in molecular recognition of metalloporphyrins. The significant influence of the substituents on interaction energies can be very important for the design of model systems in bioinorganic chemistry. PMID- 23085597 TI - Temporal behavior of DNA thermal stability in the presence of platinum compounds. Role of monofunctional and bifunctional adducts. AB - Penetrating into cell nuclei, antitumor drug cisplatin sequentially forms various intermediate and final adducts destroying local DNA structure. The demonstrated disappearance of the fine structure of melting curve of long DNAs along with a strong decrease in melting enthalpy conforms to the structural impact. However, the negative thermal effect (deltaT(m)) caused by cisplatin is relatively small if neutral medium is used in melting experiments. Cisplatin's inactive analogs transplatin and diethylenetriaminechloroplatinum {Pt[(dien)Cl]Cl} also distort DNA structure but their thermal effect is even positive. We have found that the use of alkaline medium in melting experiments strengthens the negative thermal effect for cisplatin. For transplatin and Pt[(dien)Cl]Cl, the thermal effect becomes negative that makes it qualitatively consistent with structural distortions. Those changes are explained by elimination of nonspecific electrostatic stabilization of DNA under platination. Additionally, alkaline medium fixes intermediate states of DNA platination and makes them stable against heating. These results allowed us to monitor deltaT(m) under binding of platinum compounds to DNA and their further transformation. The kinetic and thermal characteristics of monofunctional and bifunctional adducts were evaluated. It has been demonstrated that monofunctional adducts of cisplatin, transplatin and Pt[(dien)Cl]Cl produce approximately the same thermal destabilization. Cisplatin intrastrand crosslinks cause a two-fold stronger thermal destabilization than its monofunctional adducts. The value of deltaT(m) for cisplatin's final adducts is ten times larger than for transplatin. This difference mainly comes from the much stronger thermal destabilizing power of cisplatin's intrastrand crosslinks, which are responsible for antitumor activity of this compound. PMID- 23085598 TI - Preparation of new half sandwich ruthenium arene complexes with aminophosphines as potential chemotherapeutics. AB - Aminophosphines 2-(diphenylphosphino)-1-methylimidazole (dpim) and diphenyl-2 pyridylphosphine (PPh(2)py) have been used to prepare two series of Ru(II) arene complexes of formulae [(eta(6)-p-cymene)Ru(kappa(2)-O,O'-X)(kappa(1)-P-dpim)]Y (series a: 1a.Y-3a.Y) and [(eta(6)-p-cymene)Ru(kappa(2)-O,O'-X)(kappa(1)-P PPh(2)py)]Y (series b: 1b.Y-3b.Y) (where X=acac, acetylacetonate; bzac, benzoyl acetonate; dbzm, dibenzoyl methanoate; Y=BF(4), BPh(4)). The structures of 1a.BF(4), 1a.BPh(4), 3a.BF(4), 1b.BPh(4) and 3b.BPh(4) were determined by X-ray diffraction. The tetrafluoroborate derivatives are more soluble in organic solvents than their tetraphenylborate counterparts. Five BF(4)(-) derivatives (all except the unstable 1b.BF(4)) were selected to evaluate the cytotoxic behavior in vitro against the human cancer cell lines MCF-7 (breast cancer) and CAPAN-1 (pancreatic cancer). 2b.BF(4) and 3b.BF(4) exhibited IC(50) values similar to those of cisplatin. Electrophoresis and AFM studies showed good correspondence between the biological activity levels of 2b.BF(4) and 3b.BF(4) and their ability to modify the DNA structure. Hydrolytic studies indicate that aquation could be involved in the activation mechanism of these complexes and confirm that the hydrolysis rate of 3b.BF(4) is higher than that of 3a.BF(4). Thus, the cytotoxic activity trends are explained in terms of the higher reactivity of derivatives from series b, which in turn is rationalized as being the result of the electronic features of dpim and PPh(2)py established by cyclic voltammetry measurements. PMID- 23085600 TI - The 2013 educational supplement on hematopoietic cell transplantation. PMID- 23085599 TI - Chimeric antigen receptor--modified T cells: clinical translation in stem cell transplantation and beyond. PMID- 23085601 TI - National marrow donor program session: donor issues. PMID- 23085602 TI - Hematopoietic stem cell transplantation in unique pediatric populations: adolescents, infants, and children with down syndrome. PMID- 23085603 TI - Cloning and characterization of a COMMD4 gene from amphioxus (Branchiostoma belcheri): an insight into the function and evolution of COMMD4. AB - The recently discovered COMM domain-containing (COMMD) protein family has ten members (COMMD1-10). A COMMD protein contains a carboxyl-terminal COMM (copper metabolism gene MURR1) domain which provides an interface for protein-protein interactions. However, no COMMD4 gene has been identified in amphioxus. In this study, we report the identification and characterization of a COMMD4 gene from the amphioxus (designated as AmphiCOMMD4). First, we cloned the full length of AmphiCOMMD4 gene and found that the deduced amino acid sequence of AmphiCOMMD4 has 55.5-82.5% similarity and 38.8-64.0% identity to those from other species. Second, the genomic structure analysis of AmphiCOMMD4 gene showed that COMMD4 underwent intron loss in amphioxus. Third, we found that the AmphiCOMMD4 was ubiquitously and differentially expressed in five investigated tissues (muscles, gills, intestine, hepatic cecum and gonad). Finally, we found that the expression level of AmphiCOMMD4 gene was induced by LPS stimulation. In conclusion, our study elaborates the COMMD4 in amphioxus and provides an insight into the innate immunity and the evolution of the COMMD family. PMID- 23085604 TI - Qa-2 associated lipid rafts are indispensable in the final maturation of CD4+CD8- thymocytes. AB - Lipid rafts have been shown to play significant roles in thymocyte development. However, the exact role of lipid rafts in single positive (SP) thymocyte differentiation is poorly characterized. We previously defined a developmental program (SP1->SP4) for CD4SP thymocytes. In this study, we found that lipid raft components were up-regulated during CD4SP maturation. Qa-2, a unique marker for the most mature SP4 subset, was localized to lipid rafts and heterogeneously expressed in SP4 cells. Functional assays showed that the proliferation capacity of SP4 cells correlated with the expression of Qa-2. Raft-disruption on both CD4SP and epithelial cells by cholesterol extraction or cholesterol oxidation in a medullary thymic epithelial cell (mTEC)-supported co-culture system impaired the transition from SP3 to SP4. This result was further confirmed in fetal thymic organ culture system. Collectively, these studies suggest that raft-associated signaling between mTECs and thymocytes drives the differentiation of CD4SP thymocytes and lipid rafts are involved in the final maturation of SP4 thymocytes. PMID- 23085605 TI - Different domains of glycoprotein 96 influence HPV16 E7 DNA vaccine potency via electroporation mediated delivery in tumor mice model. AB - DNA vaccines have emerged as a promising approach for generating antigen-specific immunotherapy. However, due to their low immunogenicity, there is a need to enhance DNA-based vaccine potency. Two main strategies to increase DNA-based vaccine potency are the employment of immuno-adjuvants such as heat shock proteins (HSPs) and a method of improving the delivery of naked plasmid DNA by electroporation. In the current study, we evaluated the effects of linkage of human papillomavirus (HPV) type 16 E7 as a model antigen to N-terminal and C terminal of glycoprotein 96 (NT-/CT-gp96) on the potency of E7-specific immunity generated by DNA vaccines. We found that subcutaneous DNA injection with E7-CT (gp96) followed by electroporation generates the significant E7-specific IFN gamma immune responses as well as the best protective effects in vaccinated mice as compared to E7 or E7-NT (gp96) DNA vaccines. Therefore, our data indicate that subcutaneous administration of E7 DNA linked to CT (gp96) fragment followed by electroporation can significantly enhance the potency of DNA vaccines. Indeed, the structural domains of immuno-chaperones show the potential of generating effective immune responses against different clinical disorders such as cancer. Altogether, our results show that comparable regions of gp96 (N-/C-terminal fragments of gp96) may have qualitatively different immunological effects in vaccine design. PMID- 23085606 TI - A monoclonal antibody for the detection of SNAP/CLIP-tagged proteins. AB - SNAP/CLIP-tag technology is a novel approach that allows tagged proteins to be covalently coupled to diverse labels, such as fluorochromes and particles, using a convenient and specific enzymatic reaction. A monoclonal antibody (mAb) that binds to the SNAP/CLIP-tag would be useful to determine labeling efficiency, and to achieve reproducible detection in a variety of experimental formats. We therefore generated the murine mAb M2D11 by standard immunization and hybridoma technology. M2D11 binds to both the SNAP- and the CLIP-tag in either the coupled or uncoupled configurations and can be detected in the context of ELISA, flow cytometry, immunohistochemistry and western blot. The new antibody increases the versatility of the SNAP-tag technology by enabling the detection of tagged proteins using conventional immunological methods and widely available secondary antibodies. PMID- 23085607 TI - Benchmarking stable isotope labeling based quantitative proteomics. AB - Several quantitative mass spectrometry based technologies have recently evolved to interrogate the complexity, interconnectivity and dynamic nature of proteomes. Currently, the most popular methods use either metabolic or chemical isotope labeling with MS based quantification or chemical labeling using isobaric tags with MS/MS based quantification. Here, we assess the performance of three of the most popular approaches through systematic independent large scale quantitative proteomics experiments, comparing SILAC, dimethyl and TMT labeling strategies. Although all three methods have their strengths and weaknesses, our data indicate that all three can reach a similar depth in number of identified proteins using a classical (MS2 based) shotgun approach. TMT quantification using only MS2 is heavily affected by co-isolation leading to compromised precision and accuracy. This issue may be partly resolved by using an MS3 based acquisition; however, at the cost of a significant reduction in number of proteins quantified. Interestingly, SILAC and chemical labeling with MS based quantification produce almost indistinguishable results, independent of which database search algorithm used. PMID- 23085608 TI - Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. AB - BACKGROUND: Data from racially and ethnically diverse US boys are needed to determine ages of onset of secondary sexual characteristics and examine secular trends. Current international studies suggest earlier puberty in boys than previous studies, following recent trend in girls. METHODS: Two hundred and twelve practitioners collected Tanner stage and testicular volume data on 4131 boys seen for well-child care in 144 pediatric offices across the United States. Data were analyzed for prevalence and mean ages of onset of sexual maturity markers. RESULTS: Mean ages for onset of Tanner 2 genital development for non Hispanic white, African American, and Hispanic boys were 10.14, 9.14, and 10.04 years and for stage 2 pubic hair, 11.47, 10.25, and 11.43 years respectively. Mean years for achieving testicular volumes of >= 3 mL were 9.95 for white, 9.71 for African American, and 9.63 for Hispanic boys; and for >= 4 mL were 11.46, 11.75, and 11.29 respectively. African American boys showed earlier (P < .0001) mean ages for stage 2 to 4 genital development and stage 2 to 4 pubic hair than white and Hispanic boys. No statistical differences were observed between white and Hispanic boys. CONCLUSIONS: Observed mean ages of beginning genital and pubic hair growth and early testicular volumes were 6 months to 2 years earlier than in past studies, depending on the characteristic and race/ethnicity. The causes and public health implications of this apparent shift in US boys to a lower age of onset for the development of secondary sexual characteristics in US boys needs further exploration. PMID- 23085609 TI - Antibody generation and immunoassay development in diverse formats for pyrimethanil specific and sensitive analysis. AB - Immunochemical techniques are complementary tools to modern analytical requirements. These methods rely on the production of immunoreagents with adequate binding properties. In the present study, a rationally designed and functionalized derivative of pyrimethanil--a modern anilinopyrimidine fungicide- was synthesized in order to generate for the first time high-affinity and selective antibodies to this xenobiotic. A single coupling procedure--based on hapten activation using N,N'-disuccinimidyl carbonate and purification of the active ester--was followed to prepare both immunizing and assay conjugates. Polyclonal antibodies were produced and characterized by enzyme-linked immunosorbent assay (ELISA) in four alternative formats: one indirect and three direct competitive procedures. The selected immunoassay displayed a limit of detection of 0.024 MUg L(-1), far lower than the official maximum residue limits and close to the sensitivity of regular instrumental assays. This ELISA was shown to be robust to buffer changes and tolerant to the presence of little amounts of methanol, ethanol and acetonitrile. Finally, the developed assay was applied to the analysis of pyrimethanil in carrot juice samples, and a limit of quantification of 0.040 mg L(-1) was determined. PMID- 23085610 TI - Synthesis and plant growth promoting activity of dinorcholanic lactones bearing the 5alpha-hydroxy-6-oxo moiety. AB - The naturally occurring dinorcholanic lactone vespertilin and two other non natural derivatives bearing the 5alpha-hydroxy-6-oxo moiety were synthesized starting from the readily available steroid sapogenin diosgenin. The obtained compounds showed plant growth promoting activity in the bean's second internode elongation assay. PMID- 23085611 TI - Genetic diversity analyses reveal novel recombination events in Grapevine leafroll-associated virus 3 in China. AB - Grapevine leafroll-associated virus 3 (GLRaV-3) is the most prevalent causal agent of grapevine leafroll disease (GLD). Of the 75 grapevine samples collected from three regions in China, 46.7% and 94.7% of samples tested positive for GLRaV 3 in reverse transcription-PCR (RT-PCR) and reverse transcription nested PCR (RT nPCR), respectively. The SSCP analysis for the clones of complete CP gene from 16 GLRaV-3 isolates showed that 15 isolates contained one predominant haplotype and one isolate had no predominant haplotype. The sequences of the CP genes showed 89.9-100% identities at the nucleotide level. Phylogenetic analysis of the CP gene sequences revealed the existence of four well defined variant groups, which corresponded to previously reported phylogenetic groups (1, 2, 3, and 5). Two new sub-groups designated as sub-group 1B and sub-group 3B in groups 1 and 3, respectively, were identified in the Chinese GLRaV-3 population. Recombination analyses illustrated that those two new sub-groups (1B and 3B) were emerged as a result of recombination events between variants in groups 1 and 2, and variants in groups 1 and 3, respectively. These results further indicated that the variants in those new sub-groups are viable and evolutionary successful. Recombinants with highly similar coat protein structure to variants of group 1 were abundantly found in the viral population. In addition, these analyses provided evidence about CP gene as one of the recombination hotspots in GLRaV-3 genome. The population genetic parameters of all available CP sequences suggested that the recombinants might have emerged due to population bottlenecks during transmission. The results provide new insights into the variability and evolution of GLRaV-3. PMID- 23085613 TI - Staining and embedding the whole mouse brain for electron microscopy. AB - The development of methods for imaging large contiguous volumes with the electron microscope could allow the complete mapping of a whole mouse brain at the single axon level. We developed a method based on prolonged immersion that enables staining and embedding of the entire mouse brain with uniform myelin staining and a moderate preservation of the tissue's ultrastructure. We tested the ability to follow myelinated axons using serial block-face electron microscopy. PMID- 23085614 TI - Membrane-protein binding measured with solution-phase plasmonic nanocube sensors. AB - We describe a solution-phase sensor of lipid-protein binding based on localized surface plasmon resonance (LSPR) of silver nanocubes. When silica-coated nanocubes are mixed in a suspension of lipid vesicles, supported membranes spontaneously assemble on their surfaces. Using a standard laboratory spectrophotometer, we calibrated the LSPR peak shift due to protein binding to the membrane surface and then characterized the lipid-binding specificity of a pleckstrin homology domain protein. PMID- 23085615 TI - Proposed silicone hydrogel contact lens grouping system for lens care product compatibility testing. PMID- 23085616 TI - Strategies to optimize conditions for testing multipurpose contact lens solution efficacy against Acanthamoeba. AB - OBJECTIVES: To optimize the growth, culture, and life cycle conditions for testing multipurpose solutions (MPS) against Acanthamoebatrophozoites and cysts to better inform the development of an appropriate test protocol. METHODS: Two strains of Acanthamoeba castellanii were grown using 2 different methods, bacterized and axenic. Amoebae grown from both methods and from both strains were treated with 4 different MPS as trophozoites and cysts, which were generated using 4 encystment methods. Experiments were run in triplicate with controls. A 5 tube most probable number method was used to enumerate the survivors and to determine the log kills. Statistical analysis was performed using effect screening. RESULTS: There was a marked difference in effectiveness among solutions, which varied with growth conditions (P<0.0001) and encystment method. Growth medium affected survival. In addition, there was a significant difference in cyst survival, which was dependent on encystment method (P=0.0013). The strain used was less of a factor in trophozoite resistance to MPS. Cyst resistance to MPS varied depending on which strain was used, but it was not a significant factor. CONCLUSIONS: When designing a contact lens solution efficacy testing protocol for Acanthamoeba, care should be taken to control for variables that may distort results. An appropriate protocol should include growing Acanthamoeba bacterized and allowing them to encyst naturally. By choosing optimized testing conditions, a more realistic efficacy of contact lens solutions can be determined which will result in better and safer products on the market. PMID- 23085617 TI - The effects of contact lens materials on a multipurpose contact lens solution disinfection activity against Staphylococcus aureus. AB - OBJECTIVES: To determine the effect of 8 different lens materials on polyhexamethylene biguanide (PHMB) concentration in multipurpose solution (MPS) levels over time and to determine the effect of lenses on lens solution microbial efficacy over time. METHODS: Silicone hydrogel lenses and conventional hydrogel lenses were soaked in polypropylene lens cases filled with contact lens MPS containing 1 ppm PHMB for 6, 12, 24, 72, and 168 hours. Cases filled with the same solution without lenses were controls. After each time period, solutions from cases with the 8 types of lenses and controls were assayed for activity against Staphylococcus aureus according to International Organization for Standardization-14729 with modifications. Solutions were analyzed for PHMB concentration at each time point. RESULTS: Some of the different lens materials significantly affected the PHMB concentration (P<0.0001) and the biocidal efficacy. Etafilcon A lenses significantly decreased PHMB levels after only 6 hours of lens soak time. The product lot of MPS used was also significant (P<0.0001). Enfilcon A, senofilcon A, and lotrafilcon B lenses did not significantly decrease PHMB levels. CONCLUSIONS: The efficacy of MPS was affected by some lens materials and PHMB concentration. Lens materials differ in their effect on PHMB concentration and the subsequent efficacy of the MPS. Over time, some lens materials can significantly reduce the PHMB concentration and the MPS's microbial activity against S. aureus. PMID- 23085618 TI - Impact of contact lens materials on multipurpose contact lens solution disinfection activity against Fusarium solani. AB - OBJECTIVE: To investigate the effects of eight different soft contact lenses on disinfection efficacy of a multipurpose solution (MPS) containing polyhexamethylene biguanide (PHMB) against Fusarium solani. METHODS: Six silicone hydrogel lenses (galyfilcon A, senofilcon A, comfilcon A, enfilcon A, balafilcon A, and lotrifilcon B) and two conventional hydrogel lenses (polymacon and etafilcon A) were placed in polypropylene lens cases filled with MPS containing 0.0001% PHMB and soaked for 6, 12, 24, 72, and 168 hours. After each interval, depleted MPS from lens cases were removed and assayed for activity against F. solani according to International Organization for Standardization (ISO) 14729 stand-alone procedure. A portion was aliquoted for chemical analysis. RESULTS: Soaking etafilcon A, balafilcon A, and polymacon lenses for 6 hours reduced the concentration of PHMB in MPS by more than half the stated labeled concentration, with concentrations below the limit of detection for etafilcon A-depleted and balafilcon A-depleted solutions after 12 and 72 hours of soaking, respectively. Except for comfilcon A-depleted solutions, all others failed to consistently obtain one log reduction of F. solani. The solutions soaked with etafilcon A, balafilcon A, and polymacon lenses for 24 hours or more lost all or almost all fungicidal activity against F. solani. CONCLUSIONS: Over time, the disinfectant uptake by some lenses can significantly reduce the PHMB concentration and the fungicidal activity of the MPS against F. solani. Current ISO methodology does not address the reduction in microbiocidal efficacy when lenses are soaked in MPS. The ISO committee should consider adding "soaking experiments" to quantify the effect that contact lens materials have on the performance of MPSs. PMID- 23085619 TI - Material properties that predict preservative uptake for silicone hydrogel contact lenses. AB - OBJECTIVES: To assess material properties that affect preservative uptake by silicone hydrogel lenses. METHODS: We evaluated the water content (using differential scanning calorimetry), effective pore size (using probe penetration), and preservative uptake (using high-performance liquid chromatography with spectrophotometric detection) of silicone and conventional hydrogel soft contact lenses. RESULTS: Lenses grouped similarly based on freezable water content as they did based on total water content. Evaluation of the effective pore size highlighted potential differences between the surface treated and non-surface-treated materials. The water content of the lens materials and ionic charge are associated with the degree of preservative uptake. CONCLUSIONS: The current grouping system for testing contact lens-solution interactions separates all silicone hydrogels from conventional hydrogel contact lenses. However, not all silicone hydrogel lenses interact similarly with the same contact lens solution. Based upon the results of our research, we propose that the same material characteristics used to group conventional hydrogel lenses, water content and ionic charge, can also be used to predict uptake of hydrophilic preservatives for silicone hydrogel lenses. In addition, the hydrophobicity of silicone hydrogel contact lenses, although not investigated here, is a unique contact lens material property that should be evaluated for the uptake of relatively hydrophobic preservatives and tear components. PMID- 23085620 TI - Photoconductivity and enhanced memory effects in hybrid C60-graphene transistors. AB - We describe the observation of photoconductivity and enhanced memory effects in graphene devices functionalized with clusters of alkylated C(60) molecules. The alkylated C(60) clusters were adsorbed on chemical vapor deposition-grown graphene devices from an aprotic medium. The resulting alkylated C(60)-graphene hybrid devices showed reproducible photoconductive behavior originating from the electron-accepting nature of the C(60) molecules. Significantly enhanced gate hysteresis was observed upon illumination with visible light, thereby enabling the use of C(60)-graphene hybrid devices in three-terminal photo-memory applications. PMID- 23085621 TI - Formation of chiral fluoroalkyl products through copper-free enantioselective allylic alkylation catalyzed by an NHC ligand. AB - A valuable Cu-free protocol is reported where an NHC ligand has been employed to form quaternary carbon centers bearing fluoroalkyl units. The results obtained, from this allylic substitution, are better in terms of enantioselectivity and regioselectivity compared to the copper catalyzed system. PMID- 23085622 TI - A step toward solving the long-term care dilemma for living kidney donors. AB - Living kidney donor transplantation, universally recognized as the best current option in care for patients with end-stage renal disease, has shown a static growth in application in the United States despite continued expansion of the prevalent number of patients sustained by dialysis. Whether insurance providers' deficient payment to transplantation facilities for long-term costs generated by living kidney donors contributes to the problem was examined by the facility. Precise focus on all coding and billing for services rendered during care beyond 6 months effectively increased reimbursement from insurance providers for a living kidney donor from 47% to 85% of the amount billed. Although the sample of 82 donors was small and predominantly white (81.7%), it seems reasonable to suggest that centers with a low rate of payment consider an examination of their own billing and coding practices. The extent of donor resistance to participate in a continuing posttransplantation relationship with the transplantation center previously linked to financial issues borne by the donor remains unaddressed and could be explored in a subsequent study. PMID- 23085623 TI - Identification of collagen binding domain residues that govern catalytic activities of matrix metalloproteinase-2 (MMP-2). AB - An innovative approach to enhance the selectivity of matrix metalloproteinase (MMP) inhibitors comprises targeting these inhibitors to catalytically required substrate binding sites (exosites) that are located outside the catalytic cleft. In MMP-2, positioning of collagen substrate molecules occurs via a unique fibronectin-like domain (CBD) that contains three distinct modular collagen binding sites. To characterize the contributions of these exosites to gelatinolysis by MMP-2, seven MMP-2 variants were generated with single, or concurrent double and triple alanine substitutions in the three fibronectin type II modules of the CBD. Circular dichroism spectroscopy verified that recombinant MMP-2 wild-type (WT) and variants had the same fold. Moreover, the MMP-2 WT and variants had the same activity on a short FRET peptide substrate that is hydrolyzed independently of CBD binding. Among single-point variants, substitution in the module 3 binding site had greatest impact on the affinity of MMP-2 for gelatin. Simultaneous substitutions in two or three CBD modules further reduced gelatin binding. The rates of gelatinolysis of MMP-2 variants were reduced by 20-40% following single-point substitutions, by 60-75% after double point modifications, and by >90% for triple-point variants. Intriguingly, the three CBD modules contributed differentially to cleavage of dissociated alpha 1(I) and alpha-2(I) collagen chains. Importantly, kinetic analyses (k(cat)/K(m)) revealed that catalysis of a triple-helical FRET peptide substrate by MMP-2 relied primarily on the module 3 binding site. Thus, we have identified three collagen binding site residues that are essential for gelatinolysis and constitute promising targets for selective inhibition of MMP-2. PMID- 23085624 TI - Primary cilium-dependent sensing of urinary flow and paracrine purinergic signaling. AB - During the last 10 years or so, the renal research community has set the primary cilium into the lime light. From being viewed as a possible evolutionary rudiment, today the primary cilium has achieved the noble status of a physiologically relevant and necessary cellular structure. Its prime function in renal epithelium appears to be its ability to sense urinary flow. Much is still lacking to understand how the primary cilium senses flow. Transducer proteins, such as specific mechano-sensory ion channels, have been identified and are necessary for flow-dependent increases of epithelial [Ca(2+)](i). Other ciliary receptor proteins have been suggested, which may open the field of primary cilia sensing to become an even more dynamic topic of research. A flow-induced increase of [Ca(2+)](i) has been observed in all renal and other ciliated epithelial cells. Work over the last 5 years has addressed the mechanism underlying the flow induced increase of [Ca(2+)](i). It has become apparent that an initial Ca(2+) influx triggers a global increase of epithelial [Ca(2+)](i). Eventually, it also became clear that mechanical stimulation of the epithelial cells triggers the release of ATP. Intriguingly, ATP is an auto- and paracrine signaling molecule that regulates electrolyte and water transport in the nephron by binding to apical and basolateral purinergic receptors. ATP inhibits transport at almost all sites from the proximal to the distal tubule and thus elicits a diuretic response. In the perspective of this review, the primary cilium is a sensory structure and the adequate stimulus is the mechanical deflection. The output signal is the released ATP, a paracrine factor that ultimately modulates the main function of the kidney, i.e. the enormous task of absorbing some 180 L of filtrate every day. PMID- 23085625 TI - Functional diversification of taste cells in vertebrates. AB - Tastes are senses resulting from the activation of taste cells distributed in oral epithelia. Sweet, umami, bitter, sour, and salty tastes are called the five "basic" tastes, but why five, and why these five? In this review, we dissect the peripheral gustatory system in vertebrates from molecular and cellular perspectives. Recent behavioral and molecular genetic studies have revealed the nature of functional taste receptors and cells and show that different taste qualities are accounted for by the activation of different subsets of taste cells. Based on this concept, the diversity of basic tastes should be defined by the diversity of taste cells in taste buds, which varies among species. PMID- 23085627 TI - Systems biology approach for in vivo photodynamic therapy optimization of ruthenium-porphyrin compounds. AB - Two arene ruthenium porphyrin compounds showing interesting photodynamic activity in vitro, [Ru(eta(6)-p-Pr(i)C(6)H(4)Me)(PMP)Cl(2)] (PMP=5-(3-pyridyl)-10,15,20 triphenylporphyrin) and [Ru(4)(eta(6)-p-Pr(i)C(6)H(4)Me)(4)(PTP)Cl8] (PTP=5,10,15,20-tetra(3-pyridyl)porphyrin) coined Rut1 and Rut4 respectively, have been evaluated in vivo. Porphyrins alone and the arene ruthenium porphyrin derivatives (Rut1 and Rut4) showed comparable spectroscopic and photophysical properties. The in vivo study consisted in selecting the optimal arene ruthenium porphyrin photosensitizer by using an original experimental design approach on mice bearing an ectopic human oral carcinoma xenograft. The model of experimental design demonstrated to be well suited to the empirical model-building of photodynamic therapy (PDT) response. Arene ruthenium porphyrins concentration and fluence level demonstrated no statistically significant influence on the tumor growth. On the contrary, the presence of ruthenium groups improved the in vivo photodynamic efficiency. By optical fiber fluorimetry, we demonstrated that both compounds exhibited enhanced accumulation in KB tumors from 24h to 96 h post intravenous injection. These experiments were completed by inductively coupled plasma mass spectrometry quantification of ruthenium in different organs including tumor tissue. Despite a statistically significant in vivo photodynamic efficiency for Rut4, cellular localization in human oral carcinoma KB cells using fluorescence microscopy demonstrated that both conjugates Rut1 and Rut4 accumulated only in cytoplasm of KB cells but not in the nucleus. PMID- 23085626 TI - Epithelial stem cells and implications for wound repair. AB - Activation of epithelial stem cells and efficient recruitment of their proliferating progeny plays a critical role in cutaneous wound healing. The reepithelialized wound epidermis has a mosaic composition consisting of progeny that can be traced back both to epidermal and several types of hair follicle stem cells. The contribution of hair follicle stem cells to wound epidermis is particularly intriguing as it involves lineage identity change from follicular to epidermal. Studies from our laboratory show that hair follicle-fated bulge stem cells commit only transient amplifying epidermal progeny that participate in the initial wound re-epithelialization, but eventually are outcompeted by other epidermal clones and largely disappear after a few months. Conversely, recently described stem cell populations residing in the isthmus portion of hair follicle contribute long-lasting progeny toward wound epidermis and, arguably, give rise to new interfollicular epidermal stem cells. The role of epithelial stem cells during wound healing is not limited to regenerating stratified epidermis. By studying regenerative response in large cutaneous wounds, our laboratory uncovered that epithelial cells in the center of the wound can acquire greater morphogenetic plasticity and, together with the underlying wound dermis, can engage in an embryonic-like process of hair follicle neogenesis. Future studies should uncover the cellular and signaling basis of this remarkable adult wound regeneration phenomenon. PMID- 23085628 TI - Single step detection of HIV-1 proviral DNA and housekeeping beta-actin gene from dried blood spots by a monoplex polymerase chain reaction. AB - There is a growing need for developing a simple, rapid, reliable and cost effective method for detection of HIV-1 for early diagnosis of the infection especially in developing countries and in resource limited settings. A method for simultaneous detection of the HIV-1 p17 gene and the house keeping human beta actin gene from dried blood spots (DBS) by a monoplex polymerase chain reaction (PCR) is described. Genomic DNA was extracted from 40 HIV-1 positive and 40 HIV-1 negative DBS and used as templates to amplify both the HIV-1 p17 and beta-actin genes simultaneously under the same cycling condition by a single round PCR. This method of detection of HIV-1 may provide a simple, rapid and cost effective alternative in resource limited settings; however, it would require testing a larger number of samples before widespread use. PMID- 23085630 TI - Growing new kidneys from embryonic cell suspensions: fantasy or reality? PMID- 23085629 TI - Characterization of an early passage Merkel cell polyomavirus-positive Merkel cell carcinoma cell line, MS-1, and its growth in NOD scid gamma mice. AB - Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high mortality rate. The majority of MCC (70-80%) harbor clonally integrated Merkel cell polyomavirus (MCV) in the tumor genome and express viral T antigen oncoproteins. The characterization of an early passage MCV-positive MCC cell line MS-1 is described, and its cellular, immunohistochemical, and virological features to MCV negative (UISO, MCC13, and MCC26) and MCV-positive cell lines (MKL-1 and MKL-2) were compared. The MS-1 cellular genome harbors integrated MCV, which preserves an identical viral sequence from its parental tumor. Neither VP2 gene transcripts nor VP1 protein are detectable in MS-1 or other MCV-positive MCC cell lines tested. Mapping of viral and cellular integration sites in MS-1 and MCC tumor samples demonstrates no consistent viral or cellular gene integration locus. All MCV-positive cell lines show cytokeratin 20 positivity and grow in suspension. When injected subcutaneously into NOD scid gamma (NSG) mice, MS-1 forms a discrete macroscopic tumor. Immunophenotypic analysis of the MS-1 cell line and xenografts in mice show identical profiles to the parental tumor biopsy. Hence, MS-1 is an early passage cell line that provides a useful in vitro model to characterize MCV-positive MCC. PMID- 23085632 TI - Parathyroid hormone-independent role for the calcium-sensing receptor in the control of urinary calcium excretion. PMID- 23085631 TI - In vivo maturation of functional renal organoids formed from embryonic cell suspensions. AB - The shortage of transplantable organs provides an impetus to develop tissue engineered alternatives. Producing tissues similar to immature kidneys from simple suspensions of fully dissociated embryonic renal cells is possible in vitro, but glomeruli do not form in the avascular environment. Here, we constructed renal organoids from single-cell suspensions derived from E11.5 kidneys and then implanted these organoids below the kidney capsule of a living rat host. This implantation resulted in further maturation of kidney tissue, formation of vascularized glomeruli with fully differentiated capillary walls, including the slit diaphragm, and appearance of erythropoietin-producing cells. The implanted tissue exhibited physiologic functions, including tubular reabsorption of macromolecules, that gained access to the tubular lumen on glomerular filtration. The ability to generate vascularized nephrons from single cell suspensions marks a significant step to the long-term goal of replacing renal function by a tissue-engineered kidney. PMID- 23085633 TI - Activation of liver X receptor inhibits osteopontin and ameliorates diabetic nephropathy. AB - Osteopontin is a proinflammatory cytokine and monocyte chemoattractant implicated in the pathogenesis of diabetic nephropathy. Synthetic agonists for liver X receptors (LXRs) suppress the expression of proinflammatory genes, including osteopontin, but whether LXR activation modulates diabetic nephropathy is unknown. We administered the LXR agonist T0901317 to mice with streptozotocin induced diabetes and evaluated its effects on diabetic nephropathy. The LXR agonist decreased urinary albumin excretion without altering blood glucose levels and substantially attenuated macrophage infiltration, mesangial matrix accumulation, and interstitial fibrosis. LXR activation suppressed the gene expression of inflammatory mediators, including osteopontin, in the kidney cortex. In vitro, LXR activation suppressed osteopontin expression in proximal tubular epithelial cells by inhibiting AP-1-dependent transcriptional activation of the osteopontin promoter. Taken together, these results suggest that inhibition of renal osteopontin by LXR agonists may have therapeutic potential for diabetic nephropathy. PMID- 23085634 TI - Uromodulin, inflammasomes, and pyroptosis. PMID- 23085636 TI - Modulation of innate immune responses in Atlantic salmon by chronic hypoxia induced stress. AB - Atlantic salmon post-smolts were exposed to either chronic hypoxic (Hy) or normal oxygen (No) conditions in seawater tanks for 58 days, mimicking conditions typical of sea cages for farmed salmon at some periods of the year. By day 29 head kidney macrophages were isolated and subjected to in vitro poly I:C stimulation to simulate viral infection, and samples were collected over 48 h. By day 58 fish were subjected to in vivo stimulation using poly I:C or a Vibrio water-based vaccine to simulate viral or bacterial infection, respectively. The fish were monitored for stress responses and expression of several pro inflammatory genes in head kidney and intestinal tissue up to five days post injection. Stress load was monitored by plasma cortisol estimation at days 29 and 58, and on days 1, 2, 3 and 5 post-injection in the in vivo trial. Hy exposure resulted in elevated plasma cortisol levels on day 29 compared to No, while on day 58 cortisol levels were higher in the control group. Additionally, both poly I:C and the Vibrio vaccine gave significantly increased cortisol levels one day post-injection compared to PBS treated controls, irrespective of previous oxygen exposure. In vitro stimulation of macrophages with poly I:C revealed higher IFNalpha mRNA levels at 6, 12 and 24 h and for Mx at 12 and 24 h post stimulation, for both No and Hy individuals. Moreover, IFNalpha levels were higher in No than in Hy individuals at all time points, and a similar difference was seen in Mx at 48 h. In vivo stimulation with poly I:C elicited strong elevation of the IL-1beta, IFNgamma, Mx and IP10 mRNA transcripts in head kidney, while TNFalpha1 and IFNalpha were found unaffected. The Vibrio vaccine elicited a strong up regulation of IL-1beta, IFNgamma and IP10 mRNA, whereas Mx, TNFalpha1 and IFNalpha appeared unchanged. Significant differences in expression between different oxygen exposure groups were found for all genes and both stimuli. The overall trend suggests that long-term hypoxia either reduces or delays the expression of these genes in head kidney. Expression of IFNgamma and Mx in intestinal tissues also showed a strong up regulation of the genes following poly I:C stimulation, and also here the overall trend suggests that chronic hypoxia results in a lower or delayed expression of the measured genes. In summary, our results indicate that chronic hypoxia modulates the expression of important immune related genes putatively altering the immune response. As the effect is present in isolated macrophages as well as head kidney and intestinal tissue the modulation appears to be affecting local as well as systemic responses. PMID- 23085635 TI - Damage of the endothelial glycocalyx in dialysis patients. AB - Damage to the endothelial glycocalyx, which helps maintain vascular homeostasis, heightens the sensitivity of the vasculature to atherogenic stimuli. Patients with renal failure have endothelial dysfunction and increased risk for cardiovascular morbidity and mortality, but the state of the endothelial glycocalyx in these patients is unknown. Here, we used Sidestream Darkfield imaging to detect changes in glycocalyx dimension in dialysis patients and healthy controls from in vivo recordings of the sublingual microcirculation. Dialysis patients had increased perfused boundary region and perfused diameters, consistent with deeper penetration of erythrocytes into glycocalyx, indicating a loss of glycocalyx barrier properties. These patients also had higher serum levels of the glycocalyx constituents hyaluronan and syndecan-1 and increased hyaluronidase activity, suggesting the shedding of these components. Loss of residual renal function had no influence on the imaging parameters but did associate with greater shedding of hyaluronan in blood. Furthermore, patients with higher levels of inflammation had more significant damage to the glycocalyx barrier. In conclusion, these data suggest that dialysis patients have an impaired glycocalyx barrier and shed its constituents into blood, likely contributing to the sustained endothelial cell activation observed in ESRD. PMID- 23085638 TI - Correlation between In content and emission wavelength of In(x)Ga(1-x)N/GaN nanowire heterostructures. AB - GaN nanowire ensembles with axial In(x)Ga(1-x)N multi-quantum-wells (MQWs) were grown by molecular beam epitaxy. In a series of samples we varied the In content in the MQWs from almost zero to around 20%. Within the nanowire ensemble, the MQWs fluctuate strongly in composition and size. Statistical information about the composition was obtained from x-ray diffraction and Raman spectroscopy. Photoluminescence at room temperature was obtained in the range of 2.2 to 2.5 eV, depending on In content. Contrary to planar MQWs, the intensity increases with increasing In content. We compare the observed emission energies with transition energies obtained from a one-dimensional model, and conclude that several mechanisms for carrier localization affect the luminescence of these three dimensional structures. PMID- 23085639 TI - Attitude is everything? The impact of workload, safety climate, and safety tools on medical errors: a study of intensive care units. AB - BACKGROUND: Hospitals face an increasing pressure toward efficiency and cost reduction while ensuring patient safety. This warrants a closer examination of the trade-off between production and protection posited in the literature for a high-risk hospital setting (intensive care). PURPOSES: On the basis of extant literature and concepts on both safety management and organizational/safety culture, this study investigates to which extent production pressure (i.e., increased staff workload and capacity utilization) and safety culture (consisting of safety climate among staff and safety tools implemented by management) influence the occurrence of medical errors and if/how safety climate and safety tools interact. METHODOLOGY/APPROACH: A prospective, observational, 48-hour cross sectional study was conducted in 57 intensive care units. The dependent variable is the incidence of errors affecting those 378 patients treated throughout the entire observation period. Capacity utilization and workload were measured by indicators such as unit occupancy, nurse-to-patient/physician-to-patient ratios, levels of care, or NEMS scores. The safety tools considered include Critical Incidence Reporting Systems, audits, training, mission statements, SOPs/checklists, and the use of barcodes. Safety climate was assessed using a psychometrically validated four-dimensional questionnaire.Linear regression was employed to identify the effects of the predictor variables on error rate as well as interaction effects between safety tools and safety climate. FINDINGS: Higher workload has a detrimental effect on safety, whereas safety climate-unlike the examined safety tools-has a virtually equal opposite effect. Correlations between safety tools and safety climate as well as their interaction effects on error rate are mostly nonsignificant. PRACTICE IMPLICATIONS: Increased workload and capacity utilization increase the occurrence of medical error, an effect that can be offset by a positive safety climate but not by formally implemented safety procedures and policies. PMID- 23085640 TI - How do you learn to walk? Thousands of steps and dozens of falls per day. AB - A century of research on the development of walking has examined periodic gait over a straight, uniform path. The current study provides the first corpus of natural infant locomotion derived from spontaneous activity during free play. Locomotor experience was immense: Twelve- to 19-month-olds averaged 2,368 steps and 17 falls per hour. Novice walkers traveled farther faster than expert crawlers, but had comparable fall rates, which suggests that increased efficiency without increased cost motivates expert crawlers to transition to walking. After walking onset, natural locomotion improved dramatically: Infants took more steps, traveled farther distances, and fell less. Walking was distributed in short bouts with variable paths--frequently too short or irregular to qualify as periodic gait. Nonetheless, measures of periodic gait and of natural locomotion were correlated, which indicates that better walkers spontaneously walk more and fall less. Immense amounts of time-distributed, variable practice constitute the natural practice regimen for learning to walk. PMID- 23085641 TI - Does this recession make me look black? The effect of resource scarcity on the categorization of biracial faces. PMID- 23085642 TI - Emergent filling in induced by motion integration reveals a high-level mechanism in filling in. AB - The visual system is intelligent--it is capable of recovering a coherent surface from an incomplete one, a feat known as perceptual completion or filling in. Traditionally, it has been assumed that surface features are interpolated in a way that resembles the fragmented parts. Using displays featuring four circular apertures, we showed in the study reported here that a distinct completed feature (horizontal motion) arises from local ones (oblique motions)-we term this process emergent filling in. Adaptation to emergent filling-in motion generated a dynamic motion aftereffect that was not due to spreading of local motion from the isolated apertures. The filling-in motion aftereffect occurred in both modal and amodal completions, and it was modulated by selective attention. These findings highlight the importance of high-level interpolation processes in filling in and are consistent with the idea that during emergent filling in, the more cognitive symbolic processes in later areas (e.g., the middle temporal visual area and the lateral occipital complex) provide important feedback signals to guide more isomorphic processes in earlier areas (V1 and V2). PMID- 23085643 TI - Shared visual attention reduces hindsight bias. AB - Hindsight bias is the tendency to retrospectively think of outcomes as being more foreseeable than they actually were. It is a robust judgment bias and is difficult to correct (or "debias"). In the experiments reported here, we used a visual paradigm in which performers decided whether blurred photos contained humans. Evaluators, who saw the photos unblurred and thus knew whether a human was present, estimated the proportion of participants who guessed whether a human was present. The evaluators exhibited visual hindsight bias in a way that matched earlier data from judgments of historical events surprisingly closely. Using eye tracking, we showed that a higher correlation between the gaze patterns of performers and evaluators (shared attention) is associated with lower hindsight bias. This association was validated by a causal method for debiasing: Showing the gaze patterns of the performers to the evaluators as they viewed the stimuli reduced the extent of hindsight bias. PMID- 23085644 TI - The nanomechanical signature of breast cancer. AB - Cancer initiation and progression follow complex molecular and structural changes in the extracellular matrix and cellular architecture of living tissue. However, it remains poorly understood how the transformation from health to malignancy alters the mechanical properties of cells within the tumour microenvironment. Here, we show using an indentation-type atomic force microscope (IT-AFM) that unadulterated human breast biopsies display distinct stiffness profiles. Correlative stiffness maps obtained on normal and benign tissues show uniform stiffness profiles that are characterized by a single distinct peak. In contrast, malignant tissues have a broad distribution resulting from tissue heterogeneity, with a prominent low-stiffness peak representative of cancer cells. Similar findings are seen in specific stages of breast cancer in MMTV-PyMT transgenic mice. Further evidence obtained from the lungs of mice with late-stage tumours shows that migration and metastatic spreading is correlated to the low stiffness of hypoxia-associated cancer cells. Overall, nanomechanical profiling by IT-AFM provides quantitative indicators in the clinical diagnostics of breast cancer with translational significance. PMID- 23085645 TI - Photoresponse of a strongly correlated material determined by scanning photocurrent microscopy. AB - The generation of a current by light is a key process in optoelectronic and photovoltaic devices. In band semiconductors, depletion fields associated with interfaces separate long-lived photo-induced carriers. However, in systems with strong electron-electron and electron-phonon correlations it is unclear what physics will dominate the photoresponse. Here, we investigate photocurrent in VO(2), an exemplary strongly correlated material known for its dramatic metal insulator transition at T(c) ~ 68 degrees C, which could be useful for optoelectronic detection and switching up to ultraviolet wavelengths. Using scanning photocurrent microscopy on individual suspended VO(2) nanobeams we observe a photoresponse peaked at the metal-insulator boundary but extending throughout both insulating and metallic phases. We determine that the response is photothermal, implying efficient carrier relaxation to a local equilibrium in a manner consistent with strong correlations. Temperature-dependent measurements reveal subtle phase changes within the insulating state. We further demonstrate switching of the photocurrent by optical control of the metal-insulator boundary arrangement. Our work shows the value of applying scanning photocurrent microscopy to nanoscale crystals in the investigation of strongly correlated materials, and the results are relevant for designing and controlling optoelectronic devices employing such materials. PMID- 23085646 TI - Focus. PMID- 23085647 TI - Improvement of serum alkaline phosphatase to <1.5 upper limit of normal predicts better outcome and reduced risk of cholangiocarcinoma in primary sclerosing cholangitis. AB - BACKGROUND & AIMS: Normalization of serum alkaline phosphatase (SAP) was recently shown to correlate with better prognosis in Primary Sclerosing Cholangitis (PSC). We aimed at evaluating the impact of SAP improvement to below 1.5 the upper limit of normal (ULN) on the prognosis of this cholestatic liver disease. METHODS: Oxford PSC database was screened for cases diagnosed between 1980 and 2004. Cases which met the inclusion criteria were retrospectively examined for clinical parameters, laboratory values, and clinical end points (liver decompensation, liver transplantation, and liver-related deaths including cholangiocarcinoma). Cases were followed-up to 31/12/2010. RESULTS: 139 patients were included, (87 males). Improvement of SAP to below 1.5 ULN was achieved by 55 (40%) patients in a median time of 2 years, compared to 84 (60%) who did not. 3/55 (6%) patients with SAP improvement reached an end point compared to 32/84 (38%) patients with no SAP improvement (p <0.0001). 13/84 (15%) patients with no SAP improvement developed cholangiocarcinoma compared to no cholangiocarcinoma in the group with SAP improvement (p = 0.002). The end point free survival was significantly longer in patients with SAP improvement (p <0.0001). The significance of SAP improvement as a predictor of prognosis persisted after controlling for other clinical and laboratory variables. Improvement of SAP to below 1.5 ULN was comparable to complete normalization of SAP in terms of prognosis. CONCLUSIONS: Improvement in SAP to below 1.5 ULN is associated with better outcome and reduced risk of CCA in PSC. This was comparable to the achievement of complete normalization of SAP. PMID- 23085648 TI - Hepatic and serum levels of miR-122 after chronic HCV-induced fibrosis. AB - BACKGROUND & AIMS: The progression of liver fibrosis in patients with chronic hepatitis C (CHC) is important to decide on the treatment of the virus. As liver biopsy and liver stiffness measurement for staging of fibrosis present limitations, circulating levels of miR-122 have been suggested as a novel biomarker to predict the extent of liver injury. We evaluated the potential of miR-122 as an indicator of fibrosis progression in CHC infection and performed, for the first time, a comprehensive analysis of hepatic and circulating miR-122 levels in patients with CHC. METHODS: Patients with well-documented CHC infection were selected from the database of HepNet, the German-Competence-Network on Viral Hepatitis. All patients underwent blood sampling and liver biopsy with grading of inflammation and staging of fibrosis. RNA was extracted from 84 liver biopsies and 164 serum samples of CHC patients. miR-122 levels in liver and serum samples were quantified by real-time PCR normalized to RNU6 or spiked-in RNA, respectively. RESULTS: Hepatic levels of miR-122 decreased significantly with the severity of fibrosis (p = 0.001). In addition, circulating miR-122 levels correlated negatively with increasing stages of fibrosis, although the inverse correlation was moderate due to a two-phase miR-122 pattern during fibrosis progression. Thus, circulating miR-122 levels decreased in patients with severe fibrosis (F3, F4), while at early stages with distinct fibrotic structures (F2) and high inflammatory activity, miR-122 serum levels were elevated. CONCLUSIONS: We conclude that during progression of fibrosis less miR-122 is released into the blood stream due to the loss of liver cells and the decrease of hepatic miR-122 levels. Although the release of circulating miR-122 possibly mirrors acute liver injury, in chronic liver disease and fibrosis, the loss of liver cells and the decreased hepatocellular miR-122 expression render miR-122 an inappropriate marker, when exclusively used for interpretation of fibrosis progression. PMID- 23085649 TI - A practical synthesis of betulonic acid using selective oxidation of betulin on aluminium solid support. AB - The room temperature oxidation of betulin by Cr(VI) compounds in aqueous acetone on solid supports such as alumina, zeolites and silica gel has been studied. The oxidation on alumina support leaded to a single product--betulonic acid--in quantitative yield. One hundred percent selective oxidation during 30 min of betulin up to betulonic aldehyde was determined when silica gel support was used. The oxidation of betulin using zeolites as a support gives a mixture of betulonic acid and aldehyde in a 2:1 ratio. It is proposed the selective oxidation up to betulonic acid is due to the influence of Al3+-ions. PMID- 23085650 TI - In vitro and in vivo metabolism of verproside in rats. AB - Verproside, a catalpol derivative iridoid glycoside isolated from Pseudolysimachion rotundum var. subintegrum, is a biologically active compound with anti-inflammatory, antinociceptic, antioxidant, and anti-asthmatic properties. Twenty-one metabolites were identified in bile and urine samples obtained after intravenous administration of verproside in rats using liquid chromatography-quadrupole Orbitrap mass spectrometry. Verproside was metabolized by O-methylation, glucuronidation, sulfation, and hydrolysis to verproside glucuronides (M1 and M2), verproside sulfates (M3 and M4), picroside II (M5), M5 glucuronide (M7), M5 sulfate (M9), isovanilloylcatalpol (M6), M6 glucuronide (M8), M6 sulfate (M10), 3,4-dihydroxybenzoic acid (M11), M11 glucuronide (M12), M11 sulfates (M13 and M14), 3-methyoxy-4-hydroxybenzoic acid (M15), M15 glucuronides (M17 and M18), M15 sulfate (M20), 3-hydroxy-4-methoxybenzoic acid (M16), M16 glucuronide (M19), and M16 sulfate (M21). Incubation of verproside with rat hepatocytes resulted in thirteen metabolites (M1-M11, M13, and M14). Verproside sulfate, M4 was a major metabolite in rat hepatocytes. After intravenous administration of verproside, the drug was recovered in bile (0.77% of dose) and urine (4.48% of dose), and O-methylation of verproside to picroside II (M5) and isovanilloylcatalpol (M6) followed by glucuronidation and sulfation was identified as major metabolic pathways compared to glucuronidation and sulfation of verproside in rats. PMID- 23085651 TI - Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues. AB - More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC50 = 220 and 175 nM, respectively) while 1a and b demonstrated good activity (IC50 = 4 and 5 MUM, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC50 of 4 MUM and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s). PMID- 23085652 TI - Nukuhivensiums, indolo[2,3-a]quinoliziniums from the Marquesan plant Rauvolfia nukuhivensis. AB - The first phytochemical inspection of the Marquesan endemic plant Rauvolfia nukuhivensis led to the isolation and structure characterization of two new indolo[2,3-a]quinolizinium derivatives named nukuhivensium and N12-methyl nukuhivensium. They feature an aromatic indolo[2,3-a]quinolizinium core, substituted at C-2 by a n-propyl group, which is unusual in this family of alkaloid derivatives. The structure elucidation was performed on the basis of NMR spectroscopy and especially by interpretation of 2D HMBC correlations. A biosynthetic pathway is proposed on the basis of known enzymatic transformations for this family of natural products. These compounds exhibited low antimicrobial activities. PMID- 23085653 TI - Synergistic antibacterial activity of the essential oil of aguaribay (Schinus molle L.). AB - Schinus molle L. (aguaribay, aroeira-falsa, "molle", family Anacardiaceae), a native of South America, produces an active antibacterial essential oil extracted from the leaves and fruits. This work reports a complete study of its chemical composition and determines the antibacterial activity of Schinus molle L. essential oil and its main components. The results showed that the crude extract essential oil has a potent antibacterial effect on Staphylococcus aureus ATCC 25923, a strong/moderate effect on Escherichia coli ATCC 25922 and moderate/weak one on Pseudomonas aeruginosa ATCC 27853. PMID- 23085654 TI - MiR-15a decreases bovine mammary epithelial cell viability and lactation and regulates growth hormone receptor expression. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that regulate the expression of target genes at the post-transcriptional level by transcript degradation or translational inhibition. The role of bta-miR-15a in bovine mammary gland hasn’t been reported. Using miRNAs prediction software, GHR gene was predicted to be a potential target of bta-miR-15a. In this study, bovine mammary epithelial cell line was used as an in vitro cell model to address the function of bta-miR-15a on bovine mammary epithelial cells. The expression changes of bta-miR-15a and Ghr after bta-miR-15a transfection were detected by qRT-PCR; the expression of GHR protein and casein was detected by western blotting. To determine whether bta-miR-15a can affect cell viability, cells were examined using an electronic Coulter counter (CASY-TT). In conclusion, bta-miR 15a inhibited the expression of casein of bovine mammary epithelial cells, and cell number and viability were reduced by bta-miR-15a expression. Bta-miR-15a inhibited the viability of mammary epithelial cells as well as the expression of GHR mRNA and protein level, therefore suggesting that bta-miR-15a may play an important role in mammary gland physiology. PMID- 23085655 TI - Identification of insecticidal constituents of the essential oil of Curcuma wenyujin rhizomes active against Liposcelis bostrychophila Badonnel. AB - The aim of this research was to determine the chemical composition and insecticidal activity of the essential oil of Curcuma wenyujin Y.H. Chen et C. Ling rhizomes against the booklouse Liposcelis bostrychophila Badonnel and to isolate any insecticidal constituents from the essential oil. The essential oil of C. wenyujin rhizomes was obtained by hydrodistillation and analyzed by GC-MS. A total of 43 components of the essential oil were identified and the principal compounds in the essential oil were 1,8-cineole (15.26%), camphor (10.12%), germacrone (6.86%), beta-elemene (6.33%), curzerene (6.70%), and beta-elemenone (5.23%). followed by curzerenone (4.52%), curdione (4.45%) and linalool (4.43%). Based on bioactivity-guided fractionation, the two main active constituents were isolated from the essential oil and identified as 1,8-cineole and camphor. The essential oil of C. wenyujin rhizomes exhibited contact toxicity against L. bostrychophila with an LD50 value of 208.85 ug/cm2. Camphor (LD50 = 207.26 ug/cm2) exhibited stronger contact toxicity than 1,8-cineole (LD50 = 1048.75 ug/cm2) against booklouse. The essential oil of C. wenyujin (LC50 = 2.76 mg/L air) also possessed fumigant toxicity against L. bostrychophila, while the two constituents, camphor and 1,8-cineole had LC50 values of 1.03 mg/L air and 1.13 mg/L air, respectively. The results indicate that the essential oil of C. wenyujin rhizomes and its constituent compounds have potential for development as natural insecticides or fumigants for control of insects in stored grains. PMID- 23085656 TI - Synthesis and photophysical study of 2'-deoxyuridines labeled with fluorene derivatives. AB - We examined microenvironment-sensitive fluorescent 2'-deoxyuridines labeled with fluorene derivatives that exhibited solvent-dependent photophysical properties. The high sensitivity of the fluorescence shift and the nucleoside intensity dependence on solvent polarity provided information useful for estimating the polarity of the environment surrounding the fluorescent nucleoside. PMID- 23085657 TI - A novel class of selective acetylcholinesterase inhibitors: synthesis and evaluation of (E)-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles. AB - (E)-2-(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles are described as a new class of selective inhibitors of acetylcholinesterase (AChE). The most potent compound in the series exhibited good AChE inhibitory activity (IC50 = 64 uM). Compound 7f was found to be more selective than galanthamine in inhibiting AChE and it showed a moderate selectivity index. Kinetic studies on AChE indicated that a competitive type of inhibition pattern exist for these acrylonitrile derivates. Molecular docking models of the ligand-AChE complexes suggest that compound 7 g is located on the periphery of the AChE active site. PMID- 23085658 TI - c-IAP1 binds and processes PCSK9 protein: linking the c-IAP1 in a TNF-alpha pathway to PCSK9-mediated LDLR degradation pathway. AB - Recent genetic studies have shown that PCSK9, one of the key genes in cholesterol metabolism, plays a critical role by controlling the level of low-density lipoprotein receptor. However, how PCSK9 mediates LDLR degradation is still unknown. By combining a shotgun proteomic method and differential analysis of natural occurring mutations of the PCSK9 gene, we found that an E3 ubiquitin ligase c-IAP1 binds and processes PCSK9 protein. One of the 'gain-of-function' mutations, S127R, is defective with respect to binding to c-IAP1, and thus has defective autocatalytic activity. Knockdown of c-IAP1 impairs PCSK9 processing and autocatalytic cleavage. In c-IAP1 null mouse embryonic fibroblasts (MEFs), there is a dramatic decrease in secreted mature PCSK9 protein accompanied by a significant increase in LDLR protein levels compared with matched wild-type MEF cells. c-IAP1 also acts as an E3 ligase for ubiquitination of PCSK9. Ubiquitin containing only lysine-27 mediated PCSK9 ubiquitination by c-IAP1. Given K27 linked polyubiquitination promotes lysosomal localization, the finding indicates the c-IAP1 acts on both secretion of PCSK9 and its lysosomal localization. The novel pathway described here will open new avenues for exploring novel disease treatments. PMID- 23085659 TI - Acetylated and methylated beta-cyclodextrins as viable soluble supports for the synthesis of short 2'-oligodeoxyribo-nucleotides in solution. AB - Novel soluble supports for oligonucleotide synthesis 11a-c have been prepared by immobilizing a 5'-O-protected 3'-O-(hex-5-ynoyl)thymidine (6 or 7) to peracetylated or permethylated 6-deoxy-6-azido-beta-cyclodextrins 10a or 10b by Cu(I)-promoted 1,3-dipolar cycloaddition. The applicability of the supports to oligonucleotide synthesis by the phosphoramidite strategy has been demonstrated by assembling a 3'-TTT-5' trimer from commercially available 5'-O-(4,4' dimethoxytrityl)thymidine 3'-phosphoramidite. To simplify the coupling cycle, the 5'-O-(4,4'-dimethoxytrityl) protecting group has been replaced with an acetal that upon acidolytic removal yields volatile products. For this purpose, 5'-O-(1 methoxy-1-methylethyl)-protected 3'-(2-cyanoethyl-N,N-diisopropyl phosphoramidite)s of thymidine (5a), N4-benzoyl-2'-deoxycytidine (5b) and N6 benzoyl-2'-deoxyadenosine (5c) have been synthesized and utilized in synthesis of a pentameric oligonucleotide 3'-TTCAT-5' on the permethylated cyclodextrin support 11c. PMID- 23085660 TI - Suzuki-Miyaura reactions catalyzed by C2-symmetric Pd-multi-dentate N heterocyclic carbene complexes. AB - Suzuki-Miyaura coupling reactions are promoted by Pd complexes ligated with C2 symmetric multi-dentate N-heterocyclic carbenes derived in situ from Pd(OAc)2 and imidazolium salts. Good to excellent yields were obtained for aryl bromides as substrates. Turnover numbers of up to 105 could be achieved with 5 * 10-4 mol% of Pd(OAc)2/1 * 10-3 mol% NHC precatalyst in 24 h. PMID- 23085661 TI - Synthesis and field evaluation of the sex pheromone analogues to soybean pod borer Leguminivora glycinivorella. AB - In order to develop efficient lures for soybean pod borer Leguminivora glycinivorella (Matsumura) in China, (E,E)-8,10-dodecadienyl acetate (EE-8,10 12:Ac), the main component of the pheromone of L. glycinivorella, and 12 structurally-related compounds were synthesised in good overall yields, regiospecificities, and stereo-selectivities via coupling reactions catalysed by Li2CuCl4. The effect of different synthetic compounds, alone or in combination with EE-8,10-12:Ac, on numbers of captured L. glycinivorella males was evaluated. EE-8,10-12:Ac, (E)-10-dodecenyl acetate (E-10-12:Ac), (E)-8-dodecenol (E-8 12:OH), tetradecyl acetate (14:Ac), and (Z)-9-tetradecenyl acetate (Z-9-14:Ac) alone displayed different attractiveness to L. glycinivorella males. 14:Ac, E-8 12:OH, E-10-12:Ac, (E,E)-8,10-dodecadienal (EE-8,10-12:Ald), (E)-8-dodecenal (E-8 12:Ald), (E)-10-dodecenal (E-10-12:Ald) and Z-9-14:Ac all showed a synergistic effect to EE-8,10-12:Ac at certain dosages. The binary mixtures of EE-8,10-12:Ac and E-10-12:Ald, Z-9-14:Ac,14:Ac, E-8-12:Ald, EE-8,10-12:Ald, E-8-12:OH, or E-10 12:Ac in suitable ratios give 17.00-, 10.98-, 10.67-, 6.73-, 5.54-, 4.30- and 4.50-fold increases in trap catch, respectively, over the standard pheromone lure, and as novel pheromone blends, demonstrated potential use in pheromone traps to monitor or control L. glycinivorella populations in China. PMID- 23085662 TI - Side-chain modifications of highly functionalized 3(2H)-furanones. AB - A series of 3(2H)-furanones, based on side-chain modifications of a parent 3(2H) furanone, was synthesized in good yield. The parent compound was prepared by hydrogenolysis, and subsequent acid hydrolysis, of isoxazole derivatives. The isoxazole was prepared by a [3+2] 1,3-dipolar cycloaddition reaction between 3 butyn-2-ol and nitrile oxide. PMID- 23085663 TI - Synthesis and characterization of new thieno[3,2-b]thiophene derivatives. AB - Three derivatives of thieno[3,2-b]thiophene end-capped with phenyl units have been synthesized and characterized by MALDI TOF mass spectroscopy, elemental analysis, UV-vis absorption spectroscopy and thermogravimetric analysis (TGA). All compounds were prepared using Pd-catalyzed Stille or Suzuki coupling reactions. Optical measurements and thermal analysis revealed that these compounds are promising candidates for p-type organic semiconductor applications. PMID- 23085664 TI - Interaction profile of diphenyl diselenide with pharmacologically significant thiols. AB - Diphenyl diselenide has shown interesting biological activities in various free radical-induced damage models and can be considered as a potential candidate drug against oxidative stress. Apart from its anti-oxidant activity, this compound can oxidize various thiols. However there are no detailed studies in the literature about the thiol oxidase-like activity of this compound against biologically significant mono and di-thiols with respect to various pH conditions. Keeping in mind the scarcity of data in this area of organochalcogen chemistry, we report for the first time the kinetics of thiol oxidation by diphenyl diselenide, which was carried out in a commonly used phosphate buffer, not only at physiological pH, but also at a number of acidic values. The relative reactivities of the different thiols with diphenyl diselenide were independent of the pKa of the thiol group, such that at pH 7.4, cysteine and dithiothreitol were the most reactive, while 2,3-dimercapto-1-propanesulfonic acid and glutathione were weakly reactive and extremely low reactivity was observed with dimercaptosuccinic acid. Rate of oxidation was dependent on the pH of the incubation medium. The results obtained will help us in the design of rational strategies for the safe pharmacological use of diphenyl diselenide. PMID- 23085665 TI - TLC screening for antioxidant activity of extracts from fifteen bamboo species and identification of antioxidant flavone glycosides from leaves of Bambusa. textilis McClure. AB - Interest in the antioxidant activity of bamboo leaves is growing. To discover new sources of natural antioxidants, a TLC bioautography method combined with a new image processing method was developed to evaluate the antioxidant activity of leaf extracts from 15 different species of bamboo. The results showed that the methanolic extract of Bambusa. textilis McClure possessed the highest antioxidant activity among the selected bamboo species. To rapidly identify the antioxidant compounds, the crude extract of B. textilis McClure was analysed by HPLC-UV, and HPLC-micro-fractionation of the extract was carried out. Based on TLC bioautography-guided fractionation, three antioxidant fractions were isolated from B. textilis McClure by preparative chromatography. These three antioxidant compounds were identified as isoorientin 4''-O beta-D-xylopyranoside, isoorientin 2''-O-alpha-L-rhamnoside and isoorientin according to their UV, MS, and NMR data. The proposed TLC screening method could therefore be an easy way to evaluate the antioxidant activity of bamboo leaves, and the results achieved should prove very helpful for promoting their utilization, as B. textilis McClure can be considered a promising plant source of natural antioxidants. PMID- 23085666 TI - Bioassays against pinewood nematode: assessment of a suitable dilution agent and screening for bioactive essential oils. AB - Acetone was investigated and found to be an appropriate alternative to Triton X 100 as a solvent of essential oils in bioassays aimed to investigate their effects on pinewood nematode (Bursaphelenchus xylophilus) mortality. Therefore it was used as dilution agent to screen the effectiveness of fifty two essential oils against this pest. Thirteen essential oils were highly effective, resulting in more than 90% pinewood nematode mortality at 2 mg/mL, with six of them resulting in 100% mortality. LC100 values ranged between 0.50 mg/mL and 0.83 mg/mL for the essential oils of Origanum vulgare and Satureja montana, respectively. Essential oils were submitted to gas chromatography and gas chromatography-mass spectrometry analysis and their chemical composition established. Data from essential oils with 100% mortality at 2 mg/mL and other essential oils previously found to have LC100 <= 2 mg/mL was combined, their chemical profiles investigated by correspondences analysis plus automatic classification. PMID- 23085668 TI - Comparison of the phenolic compounds, carotenoids and tocochromanols content in wheat grain under organic and mineral fertilization regimes. AB - A field study was performed to evaluate the effect of mineral (NPK) and organic based fertilizers such as compost (C), manure (FYM) and meat and bone meal (MBM) on the appearance (dimensions and color) of spring wheat kernels and on the total content in grain of main its phytochemicals (polyphenols, carotenoids and tocochromanols) and phenolic acids composition. Total phenolic compounds were determined using the Folin-Ciocalteu assay after alkaline hydrolysis of grain and carotenoids were analyzed spectrophotometrically. Composition of tocochromanols and phenolic acids was determined using RP-HPLC techniques. Only insignificant differences in the appearance of kernels and small changes in the content and composition of grain phytochemicals were noted between the studied fertilization systems. Among the analyzed phytochemicals the greatest variation was observed in the group of polyphenol compounds, with a stated increase of their total content of 6.7 and 11.2% in grain fertilized with MBM and compost, respectively. Simultaneously the grain from organic fertilization contained significantly less phenolic acids, and the decrease in their content ranged from 10.0% for FYM to 24.8% for MBM+EM-1. Organically and conventionally fertilized grain had similar amounts of tocochromanols and carotenoids. Comparison of MBM and MBM+EM-1 variants showed that application of effective microorganisms decreased carotenoids and tocochromanols content by 8.5 and 9.7%, respectively. PMID- 23085667 TI - Phenolic and lignan glycosides from the butanol extract of Averrhoa carambola L. root. AB - Fifteen compounds, which included six chiral lignans and nine phenolic glycosides, were separated from the butanol fraction of Averrhoa carambola L. root and identified. All of the compounds, namely 3,4,5-trimethoxyphenol-1-O-beta D-glucopyranoside, benzyl-1-O-beta-D-glucopyranoside, (+)-5' methoxyisolariciresinol 3alpha-O-beta-D-gluco-pyranoside, (+)-isolariciresinol 3alpha-O-beta-D-glucopyranoside, koaburaside, (+)-lyoniresinol 3alpha-O-beta-D glucopyranoside, (-)-lyoniresinol 3alpha-O-beta-D-glucopyranoside, (-)-5' methoxyisolariciresinol 3alpha-O-beta-D-glucopyranoside, (-)-isolariciresinol 3alpha-O-beta-D-glucopyranoside, 3,5-dimethoxy-4-hydroxyphenyl 1-O-beta apiofuranosyl (1''->6')-O-beta-D-glucopyranoside, 3,4,5-trimethoxyphenyl 1-O-beta apiofuranosyl (1''->6')-beta-gluco-pyranoside, methoxyhydroquinone-4-beta-D glucopyranoside, (2S)-2-O-beta-D-gluco-pyranosyl-2-hydroxyphenylacetic acid, 3 hydroxy-4-methoxyphenol 1-O-beta-D-apio-furanosyl-(1''->6')-O-beta-D glucopyranoside and 4-hydroxy-3-methoxyphenol 1-O-beta-D-apiofuranosyl-(1''->6') O-beta-D-glucopyranoside were isolated from this plant for the first time. PMID- 23085669 TI - The effect of broadleaf woodland on aluminium speciation in stream water in an acid-sensitive area in the UK. AB - Acidification can result in the mobilisation and release of toxic inorganic monomeric aluminium (Al) species from soils into aquatic ecosystems. Although it is well-established that conifer trees enhance acidic atmospheric deposition and exacerbate soil and water acidification, the effect of broad-leaved woodland on soil and water acidification is less clear. This study investigated the effect of broadleaf woodland cover on the acid-base chemistry and Al species present in stream water, and processes controlling these in the acid-sensitive area around Loch Katrine, in the central Highlands, Scotland, UK, where broadleaf woodland expansion is occurring. A nested sampling approach was used to identify 22 stream sampling locations, in sub-catchments of 3.2-61 ha area and 0-45% broadleaf woodland cover. In addition, soils sampled from 68 locations were analysed to assess the influence of: (i) broadleaf woodland cover on soil characteristics and (ii) soil characteristics on stream water chemistry. Stream water pH was negatively correlated with sub-catchment % woodland cover, indicating that woodland cover is enhancing stream water acidification. Concentrations of all stream water Al species (monomeric total, organic and inorganic) were positively correlated with % woodland cover, although not significantly, but were below levels that are toxic to fish. Soil depth, O horizon depth and soil chemistry, particularly of the A horizon, appeared to be the dominant controls on stream water chemistry rather than woodland cover. There were significant differences in soil acid-base chemistry, with significantly lower O horizon pH and A horizon base saturation and higher A horizon exchangeable Al in the wooded catchments compared to the control. This is evidence that the mobile anion effect is already occurring in the study catchments and suggests that stream water acidification arising from broadleaf woodland expansion could occur, especially where tree density is high and acid deposition is predominantly in dry or occult forms. PMID- 23085670 TI - Ego depletion results in an increase in spontaneous false memories. AB - The primary aim of the current study was to examine whether depleted cognitive resources might have ramifications for the formation of neutral and negative spontaneous false memories. To examine this, participants received neutral and negative Deese/Roediger-McDermott false memory wordlists. Also, for half of the participants, cognitive resources were depleted by use of an ego depletion manipulation (solving difficult calculations while being interfered with auditory noise). Our chief finding was that depleted cognitive resources made participants more vulnerable for the production of false memories. Our results shed light on how depleted cognitive resources affect neutral and negative correct and errant memories. PMID- 23085672 TI - N-acetylcysteine-pretreated human embryonic mesenchymal stem cell administration protects against bleomycin-induced lung injury. AB - INTRODUCTION: The transplantation of mesenchymal stem cells (MSCs) has been reported to be a promising approach in the treatment of acute lung injury. However, the poor efficacy of transplanted MSCs is one of the serious handicaps in the progress of MSC-based therapy. Therefore, the purpose of this study was to investigate whether the pretreatment of human embryonic MSCs (hMSCs) with an antioxidant, namely N-acetylcysteine (NAC), can improve the efficacy of hMSC transplantation in lung injury. METHODS: In vitro, the antioxidant capacity of NAC-pretreated hMSCs was assessed using intracellular reactive oxygen species (ROS) and glutathione assays and cell adhesion and spreading assays. In vivo, the therapeutic potential of NAC-pretreated hMSCs was assessed in a bleomycin-induced model of lung injury in nude mice. RESULTS: The pretreatment of hMSCs with NAC improved antioxidant capacity to defend against redox imbalances through the elimination of cellular ROS, increasing cellular glutathione levels, and the enhancement of cell adhesion and spreading when exposed to oxidative stresses in vitro. In addition, the administration of NAC-pretreated hMSCs to nude mice with bleomycin-induced lung injury decreased the pathological grade of lung inflammation and fibrosis, hydroxyproline content and numbers of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid and apoptotic cells, while enhancing the retention and proliferation of hMSCs in injured lung tissue and improving the survival rate of mice compared with results from untreated hMSCs. CONCLUSIONS: The pretreatment of hMSCs with NAC could be a promising therapeutic approach to improving cell transplantation and, therefore, the treatment of lung injury. PMID- 23085673 TI - Predictive value of brachial-ankle pulse wave velocity for cardiovascular events. AB - BACKGROUND: The aim of this study was to determine the association of pulse wave velocity or left ventricular diastolic function with the development of cardiovascular (CV) events. METHODS: Brachial-ankle pulse wave velocity (baPWV) and E/E' were analyzed in 185 patients. The primary end point was CV events including ischemic stroke, coronary arterial disease (CAD), peripheral arterial disease and aortic dissection. RESULTS: There were 30 CV events during a mean follow-up period of 19.8 months. When the baPWV cutoff level was set to 1704 cm/s using the receiver operating characteristic curve, the sensitivity was 70/92% and the specificity 63/62% for differentiating between the group with and without CV events or ischemic stroke. In univariate analysis with the Cox proportional hazard model, higher baPWV was a predictor for CV events and ischemic stroke events. However, high E/E' (>15) was not a predictor for CV, ischemic stroke events or CAD. A higher baPWV was an independent predictor for CV and ischemic stroke risk after adjusting for age, sex, hypertension and diabetes in the Cox proportional hazard analysis. In subgroup analysis, diabetic patients with a baPWV >1704 cm/s had a high CV event and ischemic stroke risk. CONCLUSIONS: The results of this study show that higher baPWV was a predictive marker for CV events, especially ischemic stroke. The subgroup analysis suggests that antiplatelet therapy may be needed in diabetic patients with a high baPWV for prevention of ischemic stroke. PMID- 23085674 TI - Railroad track sign: a radiographic clue to the cause of pulmonary hypertension. PMID- 23085675 TI - Herpes zoster ophthalmicus masked by hymenoptera stings. PMID- 23085676 TI - Pulsion diverticulae of the esophagus. PMID- 23085677 TI - Phylogeography of Fischer's blue, Tongeia fischeri, in Japan: Evidence for introgressive hybridization. AB - The widespread lycaenid butterfly Tongeia fischeri is distributed from eastern Europe to northeastern Asia and represented by three geographically isolated populations in Japan. In order to clarify the phylogeographic history of the species, we used sequences of three mitochondrial (COI, Cyt b and ND5) and two nuclear (Rpl5 and Ldh) genes of 207 individuals collected from 55 sites throughout Japan and five sites on the Asian continent. Phylogenetic trees and the median-joining network revealed six evolutionary mitochondrial haplotype clades, which corresponded to the geographic distribution of the species. Common ancestors of Japanese T. fischeri might have come to Japan during the mid Pleistocene by multiple dispersals of continental populations, probably via a land bridge or narrow channel between western Japan and the Korean Peninsula. The geographical patterns of variation of mitochondrial and nuclear markers are discordant in northeastern Kyushu, possibly as a result of introgressive hybridization during the ancient contact between the Kyushu and Shikoku populations in the last glacial maximum. The phylogeographic pattern of T. fischeri in Japan are probably related to the geological history, Pleistocene climatic oscillations and distribution of the host plant. PMID- 23085678 TI - Asymmetric trifluoromethylation of aromatic aldehydes by cooperative catalysis with (IPr)CuF and quinidine-derived quaternary ammonium salt. AB - A general enantioselective trifluoromethylation of aldehydes has been developed using (IPr)CuF and quinidine-derived quaternary ammonium salt as the cooperative catalyst. Thus, a wide range of aromatic aldehydes have been converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading. The greatly enhanced activity and enantioselectivity result from the initiative generation of active [(IPr)CuCF(3)] as well as additional coordination activation of other copper species. PMID- 23085679 TI - Hydrocarbon biomarkers responses in the bivalve, Tivela mactroides, exposed to polluted sediments. AB - The objective of this work was to evaluate the potential use of the bivalve Tivela mactroides, as a Caribbean sentinel species. Organisms were collected from a relatively clean sandy beach, and were exposed to a gradient of petroleum hydrocarbon-polluted sediments for periods of 3, 4 and 6 days, after which their activity levels of biotransformation enzymes were measured. NADPH-cytochrome c reductase, glutathione transferase and cytochrome b5 activities increased according to total hydrocarbon concentration, whereas NADH-cytochrome ferricyanide reductase activity decreased. Catalase activity was constant while superoxide dismutase activity was inhibited. The results indicated that T. mactroides may serve as a sentinel species. However, further studies are recommended on the influence of biotic and abiotic variables on basal activities of enzymes, and their responses to other pollutants. PMID- 23085680 TI - Fabrication of nanoscale zero-mode waveguides using microlithography for single molecule sensing. AB - We present a novel approach to the fabrication of zero-mode waveguides (ZMWs) using inexpensive processing techniques. Our method is capable of rapid fabrication of circular nanoapertures with diameters ranging from 70 nm to 2 MUm, allowing us to perform a detailed characterization of the dependence of the fluorescence emission on the waveguide diameter. We also validated the use of the fabricated ZMWs by detecting single molecule binding events with a signal-to noise ratio of ten. PMID- 23085681 TI - Cyclization of RGD peptide sequences via the macrocyclic chelator DOTA for integrin imaging. AB - Two bicyclic compounds containing Arg-Gly-Asp (RGD) motifs (RGDf and RGD) were synthesized by cyclizing the peptide sequence across the macrocyclic ring of DOTA via two non-adjacent carboxylate pendent arms. The Lu(3+) or Cu(2+) complexes of these compounds, c(DOTA-RGDf) and c(DOTA-RGD), showed a metal dependent affinity towards integrin alpha(v)beta(3)in vitro and the (177)Lu(3+) or (64)Cu(2+) labelled derivatives showed specific tumour uptake in MCF7 and U87MG tumour bearing mice. PMID- 23085682 TI - Food characteristics, long-term habituation and energy intake. Laboratory and field studies. AB - Greater food variety is related to increased energy intake, and one approach to reduce food intake is to reduce food variety. The effects of varying the variety of foods at the dinner meal to reduce energy intake was assessed in laboratory and field experiments. Experiment 1 randomly assigned 31 overweight children to one of three conditions that provided one laboratory meal per day over a week. Conditions were the SAME macaroni and cheese, SIMILAR types of macaroni and cheese, or a VARIETY of high-energy-dense foods. On days 1 and 5 all children consumed the same macaroni and cheese meal. Results showed significant differences in energy consumed between SAME and SIMILAR versus VARIETY from day 1 to 5, with SAME and SIMILAR decreasing and VARIETY increasing energy intake. Trials to habituation, a potential mechanism for the variety effect, showed the same pattern of between group differences as energy intake. Experiment 2 randomly assigned 30 overweight children to conditions that provided the SAME, SIMILAR or VARIETY of high-energy-dense entrees along with a variety of low-energy-dense dinner entrees to eat in their homes for 4 weeks. Results showed significant between group differences in energy intake across weeks, with significant decreases over weeks for the SAME and SIMILAR versus VARIETY groups. The pattern of results across the experiments shows the same pattern of reduction in energy intake if children eat the same or similar characteristics of foods (types of macaroni and cheese), which may provide ideas about how to develop dietary variety prescriptions that can reduce intake and be tested in clinical trials. PMID- 23085683 TI - Texture and savoury taste influences on food intake in a realistic hot lunch time meal. AB - BACKGROUND: Previous studies with model foods have shown that softer textures lead to higher eating rates and higher ad libitum food intake and higher intensity of salt taste has been shown to result in a lower ad libitum food intake. These observations have yet to be replicated in the context of realistic solid hot meal components. AIM: The objective of the present study was to assess the effect of texture and taste on the ad libitum intake of a realistic hot lunchtime meal. METHODS: The meals consisted of potatoes, carrots, steak and gravy varied according to a 2 (texture: mashed vs. whole) * 2 (taste: standard taste vs. strong taste) design. The texture dimension referred to mashed potatoes, mashed carrots and pieces of steak vs. whole boiled potatoes, whole boiled carrots and whole steak. The taste was varied by manipulating the taste intensity of the gravy to be either standard or high intensity savoury taste. The current study used a between groups, single course ad libitum design whereby subjects were recruited for a one off meal study, during which their food intake was measured. The four groups consisted of about 40 subjects (mashed, standard, n=37; mashed, savoury n=39; whole, standard n=40; and whole, savoury n=41) matched for age (average age=44.8 +/- 5.3), gender (on average 19 males and 20 females), normal BMI (average 22.6 +/- 1.7) and dietary restraint score (DEBQ score=1.74 +/- 0.6). RESULTS: The results showed that the estimated means of the intake of the two mashed conditions was 563.2 +/- 20.3g and intake of whole meal was 527.5 +/- 20.0 g (p=0.23). The texture effect was significant in the higher savoury condition with an average of 91 g less food consumed in the solid-savoury meal than in the mashed-savoury meal. This effect was not replicated in the standard gravy condition, with no significant difference between solid and mashed textures. This was reflected in an interaction effect that was approaching significance (p=0.051). The estimated mean eating rate in the two mashed conditions was 57.0 +/- 2.5 g and was significantly higher than the whole meal condition (47.2 +/- 2.5g (p<0.05), with no difference in eating rate between the standard and savoury gravy conditions. DISCUSSION: Although interpretation was made difficult by the between groups design and the interaction between taste*texture, the results nonetheless confirm the effect of texture on eating rate and ad libitum intake for solid savoury meal components. The impact of taste on ad libitum intake of a solid meal remains unclear. We conclude that people consumed more of the meal when the food was simultaneously mashed and savoury. Food texture may be used to produce slower eating rates that result in a reduced overall energy intake within a realistic hot lunchtime meal. PMID- 23085684 TI - Highly efficient double-carbonylation of amines to oxamides using gold nanoparticle catalysts. AB - Hydrotalcite-supported gold nanoparticles (Au/HT) catalyzed the highly efficient double-carbonylation of amines to oxamides under mild reaction conditions. Various amines were selectively converted to the corresponding oxamides. The cooperation between gold nanoparticles and basic sites of HT plays a key role in the reaction. PMID- 23085685 TI - Mechanistic insights into nanotoxicity determined by synchrotron radiation-based Fourier-transform infrared imaging and multivariate analysis. AB - Our ability to identify the mechanisms by which carbon-based nanomaterials (CBNs) exert toxicity in cells is constrained by the lack of standardized methodologies to assay endpoint effects. Herein we describe a method of mechanistically identifying the effects of various CBN types in both prokaryotic and eukaryotic cells using multi-beam synchrotron radiation-based Fourier-transform infrared imaging (SR-FTIRI) at diffraction-limited resolution. This technique overcomes many of the inherent difficulties of assaying nanotoxicity and demonstrates exceptional sensitivity in identifying the effects of CBNs in cells at environmentally-relevant concentrations. We identify key mechanisms of nanotoxicity as the alteration of Amide and lipid biomolecules, but propose more specific bioactivity of CBNs occurs as a result of specific interactions between CBN structural conformation and cellular characteristics. PMID- 23085686 TI - Charge transport at the metal oxide and organic interface. AB - This review focuses on electron transfer at the interfaces between metal oxides and dye molecules within the context of the chemical nature of the anchoring functional groups, the structure of the dye molecules and the morphology of the metal oxides. In dye-sensitized metal oxides, the efficiency of interfacial charge separation and hence photon-to-current conversion may be sensitively manipulated by the interfacial bonding interactions whereby the dye molecules are adsorbed onto the oxide surface, as well as by the oxide surface morphologies. In these studies, it has been found that upon photoirradiation, the electron injection from the excited dye molecules into the conduction band of metal oxides and electron transport in the metal oxide are two of the most important steps. Therefore, a fundamental understanding of how the interfacial electron transfer dynamics is impacted by these structural parameters is critical for the design and optimization of dye-sensitized photocatalysis and photovoltaics. PMID- 23085687 TI - Nanoscale adhesion, friction and wear of proteins on polystyrene. AB - Protein layers are routinely deployed on biomaterials and biological micro/nanoelectromechanical systems (bioMEMS/NEMS) as a functional layer allowing for specific molecular recognition, binding properties or to facilitate biocompatibility. In addition, uncoated biomaterial surfaces will have uncontrolled protein layers adsorbing to the surface within seconds of implantation, so a pre-defined protein layer will improve the host response. Implanted biomaterials also experience micromotion over time which may degrade any surface protein layers. Degradation of these protein layers may lead to system failure or an unwanted immune response. Therefore, it is important to characterize the interfacial properties of proteins on biomaterial surfaces. In this study, the nanoscale adhesion, friction and wear properties of proteins adsorbed to a spin coated polystyrene surface were measured using atomic force microscopy (AFM) in deionized (DI) water and phosphate buffered saline. Adhesion, friction and wear have been measured for bovine serum albumin (BSA), collagen, fibronectin and streptavidin (STA) in DI water and PBS as a function of protein concentration. These proteins were chosen due to their importance and widespread application in the biotechnology field. Adhesion and friction were also measured for BSA and STA at two different temperatures and different pH values to simulate a biological environment. Based on this study, adhesion, friction and wear mechanisms of the different proteins are discussed. PMID- 23085688 TI - Impact of anxiety parameters on prospective and experienced pain intensity in implant surgery. AB - PURPOSE: To investigate the relationship between anxiety and pain perception in the context of implant surgery and to examine the impact of factors such as gender and surgery duration on anxiety and pain levels. METHODS: One hundred twenty-one patients undergoing implant surgery evaluated their anxiety and pain levels by completing a set of 2 questionnaires at different points in time. RESULTS: Both anxiety and pain levels were highest on the day of surgery and showed a significant decrease when evaluated retrospectively (P < 0.01; P < 0.05). Correlations were found between preoperative anxiety and expected pain levels (r = 0.19), pain peak and duration of pain (r = 0.79), and a nearly significant correlation between preoperative anxiety and duration of pain (r = 0.18). Women showed significantly higher levels of preoperative anxiety (P < 0.05) and expected pain (P < 0.05) than men. CONCLUSION: The results confirm a strong negative impact of increased preoperative anxiety levels on pain perception and the recovery process. Therefore, future research should focus on individual patient's sources of dental anxiety to reduce its negative consequences. PMID- 23085689 TI - Three-dimensional Raman spectroscopic imaging of protein crystals deposited on a nanodroplet. AB - Confocal Raman spectroscopic imaging has been used to find the location of protein crystals deposited in a nanodroplet. The depth of the protein crystal has been clearly identified by comparing the three-dimensional Raman spectroscopic images of the protein with those of water. Additionally, the low concentration region around a growing protein crystal in the nanodroplet was visualized using two-dimensional Raman spectroscopic imaging. PMID- 23085690 TI - [Where is gynecological cytology in Germany going from here?]. PMID- 23085691 TI - [Bone marrow diagnostics: integrative evaluation of results is a duty]. PMID- 23085692 TI - [Bone marrow biopsy: processing and use of molecular techniques]. AB - The rapid technological development in diagnostic pathology, especially of immunohistochemical and molecular techniques, also has a significant impact on diagnostic procedures for the evaluation of bone marrow trephine biopsies. The necessity for optimal morphology, combined with preservation of tissue antigens and nucleic acids on one hand and the wish for short turnaround times on the other hand require careful planning of the workflow for fixation, decalcification and embedding of trephines. Although any kind of bone marrow processing has its advantages and disadvantages, formalin fixation followed by EDTA decalcification can be considered a good compromise, which does not restrict the use of molecular techniques. Although the majority of molecular studies in haematological neoplasms are routinely performed on bone marrow aspirates or peripheral blood cells, there are certain indications, in which molecular studies such as clonality determination or detection of specific mutations need to be performed on the trephine biopsy. Especially, the determination of B- or T-cell clonality for the diagnosis of lymphoid malignancies requires stringent quality controls and knowledge of technical pitfalls. In this review, we discuss technical aspects of bone marrow biopsy processing and the application of diagnostic molecular techniques. PMID- 23085693 TI - [Bone marrow histology from the clinical point of view]. AB - Bone marrow diagnostics is an essential tool in routine hematological clinical practice. Not only conventional cytological and histological approaches but also more modern techniques, such as immunohistochemistry, cytogenetics and molecular diagnostics are used. The molecular basis of more and more hematological disorders is being discovered and makes its way not only into routine diagnostics but also into daily clinical practice. Recurrent genomic aberrations associated with the individual patient prognosis are well characterized and are being applied in differential therapeutic decisions. In addition, understanding deregulated biochemical pathways have led to the development of targeted therapeutic approaches. This review outlines the value of bone marrow diagnostics in hematological diseases with a focus on the currently emerging molecular diagnostic possibilities. PMID- 23085694 TI - [Myeloproliferative neoplasms: histopathological and molecular pathological diagnosis]. AB - Myeloproliferative neoplasms (chronic myeloproliferative disorders according to former nomenclature) comprise chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia and systemic mastocytosis. All disorders have excessive proliferation of one or more hematopoietic lineages in common and progress with different probability to blast crisis or fibrosis. A further common feature is provided by the activating mutation of tyrosin kinases and associated pathways of signal transduction (BCR-ABL, JAK2(V617F), MPL(W515L/K), KIT(D816V) and FIP1L1-PDGFRA) causative for the abnormal proliferation. With regard to diagnosis and therapy these mutations are of utmost importance because they enable the exclusion of reactive processes, contribute with varying specificity to subtyping of MPN and are at least partly sensitive to targeted therapy. The molecular mechanisms of blastic and fibrotic progression are not yet understood. PMID- 23085695 TI - [Lymphomas and lymphatic leukemias in the bone marrow]. AB - A bone marrow biopsy in a patient with a diagnosis of lymphoma is often performed as part of the staging procedures, i.e. to find out whether or not the bone marrow harbors infiltrates of an already diagnosed tumor. On the other hand, occasionally changes in the peripheral blood count or an M-protein in the serum lead to a bone marrow biopsy in which the first diagnosis of a malignant lymphoma is established. In either case, the diagnosis of lymphomas and lymphatic leukemias in the bone marrow requires an integration of clinical data, cytomorphology, the topographic distribution of the infiltrate and immunohistochemical as well as molecular techniques, where required. This may particularly be the case when confirmation or exclusion of conventionally barely detectable infiltrates (e.g. hairy cell leukemia, hepatosplenic T-cell lymphoma, plasma cell infiltrates) is required. PMID- 23085696 TI - [Diagnostics of acute leukemias: interaction of phenotypic and genetic methods]. AB - Due to the heterogeneity of these disorders, the diagnosis of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) requires a broad spectrum of laboratory techniques: cytomorphology, immunophenotyping, chromosome banding analysis, fluorescence in situ hybridization, and molecular genetics. The cytomorphological leukemia subtypes can be indicative for distinct genetic alterations and contribute to the guidance of the further diagnostic process. Immunophenotyping allows to define the hematological lineage and to characterize the leukemia-associated immunophenotype as basis for follow up investigation. Cytogenetic alterations and molecular mutations are essential for the correct classification of cases and for prognostication. Molecular markers are helpful to define the minimal residual disease load after the achievement of hematological complete remission. In cases of hypocellular AML or in case of bone marrow necrosis, histopathology in combination with immunohistochemistry is of importance. Hierarchies between the different techniques catalyze the workflow in the laboratory and allow a rapid diagnosis and classification of the leukemia cases. PMID- 23085697 TI - [Mastocytosis and eosinophilic leukemia: diagnostics and classification]. AB - Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update. PMID- 23085703 TI - The ReWalk powered exoskeleton to restore ambulatory function to individuals with thoracic-level motor-complete spinal cord injury. AB - OBJECTIVE: The aim of this study was to assess the safety and performance of ReWalk in enabling people with paraplegia due to spinal cord injury to carry out routine ambulatory functions. DESIGN: This was an open, noncomparative, nonrandomized study of the safety and performance of the ReWalk powered exoskeleton. All 12 subjects have completed the active intervention; three remain in long-term follow-up. RESULTS: After training, all subjects were able to independently transfer and walk, without human assistance while using the ReWalk, for at least 50 to 100 m continuously, for a period of at least 5 to 10 mins continuously and with velocities ranging from 0.03 to 0.45 m/sec (mean, 0.25 m/sec). Excluding two subjects with considerably reduced walking abilities, average distances and velocities improved significantly. Some subjects reported improvements in pain, bowel and bladder function, and spasticity during the trial. All subjects had strong positive comments regarding the emotional/psychosocial benefits of the use of ReWalk. CONCLUSIONS: ReWalk holds considerable potential as a safe ambulatory powered orthosis for motor-complete thoracic-level spinal cord injury patients. Most subjects achieved a level of walking proficiency close to that needed for limited community ambulation. A high degree of performance variability was observed across individuals. Some of this variability was explained by level of injury, but other factors have not been completely identified. Further development and application of this rehabilitation tool to other diagnoses are expected in the future. PMID- 23085704 TI - Exercise adherence during home-based functional electrical stimulation cycling by individuals with spinal cord injury. AB - OBJECTIVE: The typically sedentary spinal cord injured population has limited physical activity options because of muscle paralysis, difficulties in transportation, and barriers to access rehabilitation/wellness facilities. It is important to investigate physical activity alternatives to increase physical activity levels and decrease the risk of inactivity-derived diseases. The goal of this study was to determine the effects of a home-based functional electrical stimulation cycling program on exercise adherence of those with spinal cord injury. DESIGN: Seventeen Veterans with posttraumatic C4-T11 American Spinal Injury Association Impairment Scale A-C spinal cord injury participated in two 8 wk exercise periods of home-based functional electrical stimulation lower extremity cycling. Exercise adherence and the effects of six factors thought to influence exercise adherence were studied during both exercise periods. RESULTS: Exercise adherence rates for exercise periods 1 and 2 were 71.7% and 62.9%, respectively. Age, history of exercise, and pain not associated with the exercise activity were determined to have significant impact on exercise adherence rates. CONCLUSIONS: Exercise adherence rates were well above the reported 35% in the able-bodied population, which provides evidence for the feasibility of a home based functional electrical stimulation lower extremity cycling program. Younger adults with a history of being physically active have the highest potential for exercise adherence. PMID- 23085705 TI - The electrically assisted bicycle: an alternative way to promote physical activity. AB - OBJECTIVE: The aim of this study was to analyze the physiologic demand of pedaling on an electrically assisted bicycle to test its potential as an alternative method to perform exercise. DESIGN: Twenty participants (ten trained vs. ten untrained in endurance) novice in the electrically assisted bicycle performed the same cycling protocol composed of nine 5-min submaximal cycling periods without electrical support (NO), with a light support (S1), or with a high support (S4). The cycling conditions were tested at two different imposed speeds (16 and 21 km.hr(-1)) and one freely chosen speed (mean [SD], 18.1 [0.7] km.h(-1)). RESULTS: Mean power output, intensity, and energy expenditure were significantly lowered by the use of an electrical support, in similar proportions between the groups. For all subjects, the intensity of the electrically assisted bicycle in all measured conditions (S1 or S4) was sufficiently high to achieve the standards for moderate-intensity health-enhancing physical activity for adults (>3 metabolic equivalents). However, a vigorous intensity (>6 metabolic equivalents) was reached with the NO and S1 supports in the untrained group whatever the cycling speed and only at 21 km.hr(-1) with the light support (S1) in the endurance-trained group. CONCLUSIONS: By reducing the perceived sensation of effort while maintaining a sufficiently high energy expenditure, the electrically assisted bicycle has a great potential to promote physical activity in industrialized societies. PMID- 23085706 TI - Botulinum toxin type A injection into the gastrocnemius muscle for spastic equinus in adults with stroke: a randomized controlled trial comparing manual needle placement, electrical stimulation and ultrasonography-guided injection techniques. AB - OBJECTIVE: The aim of this study was to compare the clinical outcomes of manual needle placement, electrical stimulation, and ultrasonography-guided techniques for botulinum toxin injection into the gastrocnemius of adults with spastic equinus after stroke. DESIGN: After randomization into three groups, each patient received the same dose of botulinum toxin type A into the lateral and medial head of the gastrocnemius muscle (OnabotulinumtoxinA, 100U per head) of the affected leg. The manual needle placement group (n = 15) underwent injections using anatomic landmarks and palpation; the electrical stimulation group (n = 15) received injections with electrical stimulation guidance; and the ultrasonography group (n = 17) was injected under sonographic guidance. The modified Ashworth scale, the Tardieu scale, and the ankle passive range of motion were measured at baseline and 1 mo after injection. Nonparametric statistical analysis was used. RESULTS: One month after injection, the modified Ashworth scale improved better in the ultrasonography group than in the manual needle placement group (P = 0.008). The ankle passive range of motion improved better in the ultrasonography group than in the electrical stimulation (P = 0.004) and manual needle placement (P < 0.001) groups. No difference was found between groups for the Tardieu scale. CONCLUSIONS: Ultrasonography-guided injection technique could improve the clinical outcome of botulinum toxin injections into the gastrocnemius of adults with spastic equinus. PMID- 23085707 TI - Using Lean principles to manage throughput on an inpatient rehabilitation unit. AB - Performance improvement is a mainstay of operations management and maintenance of certification. In this study at a University Hospital inpatient rehabilitation unit, Lean management techniques were used to manage throughput of patients into and out of the inpatient rehabilitation unit. At the start of this process, the average admission time to the rehabilitation unit was 5:00 p.m., with a median time of 3:30 p.m., and no patients received therapy on the day of admission. Within 8 mos, the mean admission time was 1:22 p.m., 50% of the patients were on the rehabilitation unit by 1:00 p.m., and more than 70% of all patients received therapy on the day of admission. Negative variance from this performance was evaluated, the identification of inefficient discharges holding up admissions as a problem was identified, and a Lean workshop was initiated. Once this problem was tackled, the prime objective of 70% of patients receiving therapy on the date of admission was consistently met. Lean management tools are effective in improving throughput on an inpatient rehabilitation unit. PMID- 23085708 TI - Tandem allylic substitution-5-exo-dig-carbocyclization: a [4 + 1]-annulation approach to arylidene cyclopentenes from MBH-acetates of acetylenic aldehydes. AB - A new entry for the synthesis of functionalized arylidene cyclopentenes under metal-free reaction conditions is disclosed via the base-promoted [4 + 1] annulation of Morita-Baylis-Hillman acetates of acetylenic aldehydes with active methylene derivatives involving tandem allylic substitution followed by 5-exo-dig carbocyclization. PMID- 23085709 TI - Matrix-associated autologous chondrocyte transplantation in a compartmentalized early stage of osteoarthritis. AB - OBJECTIVE: Cartilage restoration in joints with an early stage of osteoarthritis (OA) is an important clinical challenge. In this study, a compartmentalized, early-stage OA was generated surgically in sheep stifle joints, and this model was used to evaluate a matrix-associated cell transplantation approach for cartilage repair. METHOD: Eighteen sheep were operated twice. During the first operation, a unicompartmental OA in a stable joint was induced by creating a critical-size defect. The second operation served as a regeneration procedure. The eighteen sheep were divided into three groups. One group was treated with spongialization (SPONGIO), while the two others had spongialization followed by implantation of a hyaluronan matrix with (MACT) or without chondrocytes (MATRIX). The follow-up took place 4 months after the second operation. Gross Assessment of Joint Changes score and Brittberg score were used for the macroscopic evaluation, Mankin score, O'Driscoll score, and immunohistochemistry for collagen type I and type II for histological evaluation. RESULTS: The MACT group achieved significantly better results in both macroscopic and histological examinations. In the regeneration area, a Mankin score of 7.88 (6.20; 9.55) [mean (upper 95% confidence interval; lower 95% confidence interval)] was reached in the MACT group, 10.38 (8.03; 12.72) in the MATRIX group, and 10.33 (8.80; 11.87) in the SPONGIO group. The O'Driscoll score revealed a highly significant difference in the degree of defect repair: 15.92 (14.58; 17.25) for the MACT group compared to the two other groups [5.04 (1.21; 8.87) MATRIX and 6.58 (5.17; 8.00) SPONGIO; P < 0.0001]. CONCLUSION: This study demonstrates promising results toward the development of a biological regeneration technique for early-stage OA. PMID- 23085710 TI - Clinicopathological evaluation of 164 dental follicles and dentigerous cysts with emphasis on the presence of odontogenic epithelium in the connective tissue. The hypothesis of "focal ameloblastoma". AB - OBJECTIVES: Some ameloblastomas presumably originate from odontogenic epithelium within the connective tissue of dental follicles and dentigerous cysts. Therefore, it would seem reasonable to discuss as whether odontogenic epithelium proliferations, frankly displaying ameloblastomatous features ("focal ameloblastoma"), should be considered as an "early" ameloblastoma. STUDY DESIGN: Histopathological reports from 164 dental follicles and dentigerous cysts from the Department of Oral and Maxillofacial Surgery/Oral Pathology of the VU Free University medical center in Amsterdam, The Netherlands, were reviewed. Histopathological slides from 39 cases reporting the presence of odontogenic epithelium within the connective tissue were re-evaluated in order to assess the possible presence of focal ameloblastomas. RESULTS: Focal ameloblastomas were detected in one dental follicle and in two dentigerous cysts. During a follow-up period of 6, 8 and 22 years, respectively, no clinical signs of (recurrent) ameloblastoma have occurred in these patients. CONCLUSIONS: Focal ameloblastoma possibly represents the early stage of ameloblastoma development. PMID- 23085711 TI - The relevance of uniform reporting in oral leukoplakia: definition, certainty factor and staging based on experience with 275 patients. AB - The aim of the present study was to evaluate the definition of oral leukoplakia, proposed by the WHO in 2005 and taking into account a previously reported classification and staging system, including the use of a Certainty factor of four levels with which the diagnosis of leukoplakia can be established. In the period 1997-2012 a hospital-based population of 275 consecutive patients with a provisional diagnosis of oral leukoplakia has been examined. In only 176 patients of these 275 patients a firm diagnosis of leukoplakia has been established based on strict clinicopathological criteria. The 176 patients have subsequently been staged using a classification and staging system based on size and histopathologic features. For use in epidemiological studies it seems acceptable to accept a diagnosis of leukoplakia based on a single oral examination (Certainty level 1). For studies on management and malignant transformation rate the recommendation is made to include the requirement of histopathologic examination of an incisional or excisional biopsy, representing Certainty level 3 and 4, respectively. This recommendation results in the following definition of oral leukoplakia: "A predominantly white lesion or plaque of questionable behaviour having excluded, clinically and histopathologically, any other definable white disease or disorder". Furthermore, we recommend the use of strict diagnostic criteria for predominantly white lesions for which a causative factor has been identified, e.g. smokers' lesion, frictional lesion and dental restoration associated lesion. PMID- 23085712 TI - Cytological changes in the oral mucosa after use of a mouth rinse with alcohol. A prospective double blind control study. AB - AIM: The aim of this preliminary study was to detect cytological changes in the oral mucosa after using a mouth wash with alcohol. MATERIAL AND METHODS: A prospective double-blind, controlled study was performed, for 6 months. Group 1 consisted of 30 subjects who used a mouth rinse with 26.9% of alcohol [Listerine] and Group 2 consisted of 30 subjects who used a mouth rinse with the same ingredients but with no alcohol. We obtained three cytological samples from the oral mucosa. The presence of cytological atypia, binucleation and karyorrhesis, and type of cells were studied. We also used a fluorescent in situ hybridization technique (FISH) in 15 samples in each group, for the micronucleus. RESULTS: We found no clinical mucosal alteration after using the mouth wash at the end of the study in either group. We observed no cytological differences between the groups at the end of the study (p>0.05). Regarding the study of the micronucleus by FISH, we observed no significant difference between the groups (p>0.05). CONCLUSIONS: Our results showed no cytological alteration in patients using a mouth rinse with alcohol, but these findings should be considered preliminary results, to be confirmed in a greater sample of patients. PMID- 23085713 TI - Histone H2A.Z inheritance during the cell cycle and its impact on promoter organization and dynamics. AB - Although it has been clearly established that well-positioned histone H2A.Z containing nucleosomes flank the nucleosome-depleted region (NDR) at the transcriptional start site (TSS) of active mammalian genes, how this chromatin based information is transmitted through the cell cycle is unknown. We show here that in mouse trophoblast stem cells, the amount of histone H2A.Z at promoters decreased during S phase, coinciding with homotypic (H2A.Z-H2A.Z) nucleosomes flanking the TSS becoming heterotypic (H2A.Z-H2A). To our surprise these nucleosomes remained heterotypic at M phase. At the TSS, we identified an unstable heterotypic histone H2A.Z-containing nucleosome in G1 phase that was lost after DNA replication. These dynamic changes at the TSS mirror a global expansion of the NDR at S and M phases, which, unexpectedly, is unrelated to transcriptional activity. Coincident with the loss of histone H2A.Z at promoters, histone H2A.Z is targeted to the centromere when mitosis begins. PMID- 23085714 TI - Multimodal microtubule binding by the Ndc80 kinetochore complex. AB - The Ndc80 complex is a key site of kinetochore-microtubule attachment during cell division. The human complex engages microtubules with a globular 'head' formed by tandem calponin-homology domains and an 80-amino-acid unstructured 'tail' that contains sites of phosphoregulation by the Aurora B kinase. Using biochemical, cell biological and electron microscopy analyses, we dissected the roles of the tail in binding of microtubules and mediation of cooperative interactions between Ndc80 complexes. Two segments of the tail that contain Aurora B phosphorylation sites become ordered at interfaces; one with tubulin and the second with an adjacent Ndc80 head on the microtubule surface, forming interactions that are disrupted by phosphorylation. We propose a model in which Ndc80's interaction with either growing or shrinking microtubule ends can be tuned by the phosphorylation state of its tail. PMID- 23085717 TI - Complexation and thermodynamics of Cm(III) at high temperatures: the formation of [Cm(SO4)(n)](3-2n) (n = 1, 2, 3) complexes at T = 25 to 200 degrees C. AB - The formation of [Cm(SO(4))(n)](3-2n) complexes (n = 1, 2, 3) in an aquatic solution is studied by time resolved laser fluorescence spectroscopy as a function of the ligand concentration, the ionic strength (NaClO(4)) and the temperature (25 to 200 degrees C). The experiments are performed in a custom built high temperature cell for spectroscopic measurements at high pressures and temperatures. The single component spectra of the individual species are identified by slope analysis at every studied temperature and their molar fractions are determined by peak deconvolution of the emission spectra. The results show a strong shift of the chemical equilibrium towards the complexed species at increased temperatures. With the determined speciation, the conditional stepwise stability constants are calculated and extrapolated to zero ionic strength, using the specific ion interaction theory (SIT). The log K(0)(n)(T) values increase by several orders of magnitude in the studied temperature range. The fitting of the temperature dependency of the first and second stability constant (log K(0)(1) and log K(0)(2)) requires an extended van't Hoff equation, taking into account a constant heat capacity of the reaction (Delta(r)C(0)(p,m) = const.). Contrarily, the temperature dependency of the log K(0)(3) is very well described by the linear van't Hoff equation, assuming Delta(r)C(0)(p,m) = 0. Thus, the thermodynamic standard state data (Delta(r)H(0)(m), Delta(r)S(0)(m), Delta(r)C(0)(p,m)) of the stepwise complexation of Cm(III) with SO(4)(2-) are determined. Additionally, the ion interaction coefficients of the stepwise complexation reactions (Deltaepsilon(n)) are determined as a function of the temperature. The fluorescence lifetimes of Cm(III) are recorded at different sulphate concentrations as a function of the temperature. The results give a strong indication that at T > 100 degrees C the first excited state of Cm(III) ((6)D'(7/2)) is effectively quenched by a temperature dependent enhancement of the energy transfer from the metal ion to OH vibrations of first shell water molecules. PMID- 23085716 TI - CLIP-seq of eIF4AIII reveals transcriptome-wide mapping of the human exon junction complex. AB - The exon junction complex (EJC) is a central effector of the fate of mRNAs, linking nuclear processing to mRNA transport, translation and surveillance. However, little is known about its transcriptome-wide targets. We used cross linking and immunoprecipitation methods coupled to high-throughput sequencing (CLIP-seq) in human cells to identify the binding sites of the DEAD-box helicase eIF4AIII, an EJC core component. CLIP reads form peaks that are located mainly in spliced mRNAs. Most expressed exons harbor peaks either in the canonical EJC region, located ~24 nucleotides upstream of exonic junctions, or in other noncanonical regions. Notably, both of these types of peaks are preferentially associated with unstructured and purine-rich sequences containing the motif GAAGA, which is a potential binding site for EJC-associated factors. Therefore, EJC positions vary spatially and quantitatively between exons. This transcriptome wide mapping of human eIF4AIII reveals unanticipated aspects of the EJC and broadens its potential impact on post-transcriptional regulation. PMID- 23085718 TI - Electromagnetic interference shielding effectiveness of monolayer graphene. AB - We report the first experimental results on the electromagnetic interference (EMI) shielding effectiveness (SE) of monolayer graphene. The monolayer CVD graphene has an average SE value of 2.27 dB, corresponding to ~40% shielding of incident waves. CVD graphene shows more than seven times (in terms of dB) greater SE than gold film. The dominant mechanism is absorption rather than reflection, and the portion of absorption decreases with an increase in the number of graphene layers. Our modeling work shows that plane-wave theory for metal shielding is also applicable to graphene. The model predicts that ideal monolayer graphene can shield as much as 97.8% of EMI. This suggests the feasibility of manufacturing an ultrathin, transparent, and flexible EMI shield by single or few layer graphene. PMID- 23085715 TI - Genome-wide nucleosome positioning during embryonic stem cell development. AB - We determined genome-wide nucleosome occupancies in mouse embryonic stem cells and their neural progenitor and embryonic fibroblast counterparts to assess features associated with nucleosome positioning during lineage commitment. Cell type- and protein-specific binding preferences of transcription factors to sites with either low (Myc, Klf4 and Zfx) or high (Nanog, Oct4 and Sox2) nucleosome occupancy as well as complex patterns for CTCF were identified. Nucleosome depleted regions around transcription start and transcription termination sites were broad and more pronounced for active genes, with distinct patterns for promoters classified according to CpG content or histone methylation marks. Throughout the genome, nucleosome occupancy was correlated with certain histone methylation or acetylation modifications. In addition, the average nucleosome repeat length increased during differentiation by 5-7 base pairs, with local variations for specific regions. Our results reveal regulatory mechanisms of cell differentiation that involve nucleosome repositioning. PMID- 23085719 TI - Silver metallization engineered conformational switch of G-quadruplex for fluorescence turn-on detection of biothiols. AB - In this work, we demonstrate a novel fluorescent method for the construction of the label-free detection of biothiols by utilization of a silver metallization engineered conformational switch of G-quadruplex. PMID- 23085720 TI - A survey of the supportive care needs of informal caregivers of adult bone marrow transplant patients. AB - PURPOSE: This study aims to describe the supportive care needs of informal caregivers (ICG) of adult bone marrow transplant (BMT) patients. In addition, we explored relationships between levels of unmet need, psychological morbidity and patient and ICG characteristics. METHODS AND SAMPLE: We invited patients within 24 months of BMT to participate in a cross-sectional survey. Consenting patients asked their ICG to complete and return the questionnaire booklet. Measures included the Supportive Care Needs Survey Partners and Carers and General Health Questionnaire. KEY RESULTS: Two hundred patients were approached, and 98 completed questionnaires were received (response rate = 49 %). We found high unmet need and psychological morbidity among ICGs and an association between ICG unmet need and psychological morbidity. Patient functioning, particularly anxiety and depression, sexual dysfunction and resumption of usual activities impacted on ICG unmet need and psychological morbidity. No associations were found between ICG unmet need and psychological morbidity and the following variables: type of BMT, time from BMT, ICG gender, number of dependents and patient age. CONCLUSION: ICG of BMT patients have high levels of unmet need and psychological morbidity in the months that follow a BMT. This highlights the importance of thorough needs assessment to ensure limited resources are targeted to those most in need. PMID- 23085721 TI - Validation of a COPD diagnosis from the Swedish Inpatient Registry. AB - AIMS: The Swedish National Inpatient Registry is an important source of data for numerous epidemiological studies, amongst them studies on chronic obstructive pulmonary disease (COPD). General validation studies indicate that in general 85 95% of diagnoses reported are correct, but this is not true for all groups of diseases, why specific validation studies are of great importance. METHODS: Charts from 374 individuals discharged with a COPD diagnosis between 2000-07 from two central hospitals and two university hospitals in the county of Skane were validated against the original medical files. Criteria for the degree of certainty of the COPD diagnosis were predefined and the association between predictors of diagnostic probability and the level of certainty was assessed using an ordinal logistic regression model. RESULTS: According to the Global Initiative for Chronic Obstructive Lung Disease criteria, 21.7% of the diagnosis were classified as proven COPD, 35.5% were classified as probable, another 34.0% as possible COPD, 2.1% were classified as having an uncertain diagnosis, and 7.0% as an unlikely COPD diagnosis. Age category (adjusted ORs: 60-79 years, 2.6, 95% CI 1.2-5.4; >=80 years, 1.6, 95% CI 0.7-3.3) and discharge from a non-surgical department (adjusted OR: 1.7, 95% CI 1.1-2.8) were significantly associated with higher level of diagnostic certainty. CONCLUSIONS: A COPD diagnoses from the Swedish Inpatient Registry is of acceptable validity for epidemiological research. The degree of certainty of the diagnosis varies but less than 10% were considered as misclassified or having an uncertain COPD diagnosis. PMID- 23085722 TI - Timing and outcome of renal replacement therapy in patients with congenital malformations of the kidney and urinary tract. AB - BACKGROUND AND OBJECTIVES: Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of ESRD in children, but the proportion of patients with individual CAKUT entities progressing to ESRD during adulthood and their long-term clinical outcomes are unknown. This study assessed the age at onset of renal replacement therapy (RRT) and patient and renal graft survival in patients with CAKUT across the entire age range. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CAKUT were compared with age-matched patients who were undergoing RRT for other renal disorders on the basis of data from the European Renal Association-European Dialysis and Transplant Association Registry. Competing risk and Cox regression analyses were conducted. RESULTS: Of 212,930 patients commencing RRT from 1990 to 2009, 4765 (2.2%) had renal diagnoses consistent with CAKUT. The proportion of incident RRT patients with CAKUT decreased from infancy to childhood and then increased until age 15-19 years, followed by a gradual decline throughout adulthood. Median age at RRT start was 31 years in the CAKUT cohort and 61 years in the non-CAKUT cohort (P<0.001). RRT was started earlier (median, 16 years) in patients with isolated renal dysplasia than in those with renal hypoplasia and associated urinary tract disorders (median, 29.5-39.5 years). Patients with CAKUT survived longer than age- and sex matched non-CAKUT controls because of lower cardiovascular mortality (10-year survival rate, 76.4% versus 70.7%; P<0.001). CONCLUSIONS: CAKUT leads to ESRD more often at adult than pediatric age. Treatment outcomes differ from those of acquired kidney diseases and vary within CAKUT subcategories. PMID- 23085723 TI - Effect of red cell transfusions on future kidney transplantation. AB - Red cell transfusions, erythropoiesis-stimulating agents (ESAs), and intravenous iron therapy all have a place in the treatment of anemia associated with CKD. Their relative merits and uses are subject to many clinical and nonclinical factors. New concerns associated with the use of ESA therapy make it likely that the use of blood transfusions will increase, refueling previous debates about their associated risks. Data on whether red cell transfusions increase sensitization to HLA antigens, rendering subsequent transplantation more problematic, are mainly derived from older literature. Older data suggested that women were more at risk of HLA sensitization than men, particularly those with previous multiple pregnancies, although recent U.S. Renal Data System data have challenged this. HLA sensitization prolongs the waiting time for transplantation and reduces graft survival. Leukocyte depletion of red cells does not appear to reduce the risk of HLA sensitization. This review summarizes much of the data on these issues, as well as highlighting the need for further research on the potential risks for blood transfusion in patients with CKD. PMID- 23085724 TI - Pregnancy in renal transplant recipients: a UK national cohort study. AB - BACKGROUND AND OBJECTIVES: Most reports of pregnancy outcome in women with kidney transplants are single-center, retrospective, and include small numbers and few are compared with controls. The aim of this study was to collect information about pregnancy outcomes among all kidney transplant recipients in the United Kingdom, managed with current antenatal and nephrologic care, and to compare these data with a contemporaneous control group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Pregnant women with a kidney transplant were identified through the UK Obstetric Surveillance System (UKOSS) between January 1, 2007 and December 31, 2009. Data on a comparison cohort were obtained from the UKOSS database, containing information on comparison women identified in previous studies. Outcomes were also compared with national data. RESULTS: There were 105 pregnancies identified in 101 recipients. Median prepregnancy creatinine was 118 MUmol/L. Preeclampsia developed in 24% compared with 4% of the comparison group. Median gestation at delivery was 36 weeks, with 52% of women delivering at <37 weeks, significantly higher than the national rate of 8%. Twenty-four infants (24%) were small for gestational age (<10th centile). There were two (2%) cases of acute rejection. Potential predictive factors for poor pregnancy outcome included >1 previous kidney transplant (P=0.03), first trimester serum creatinine >125 MUmol/L (P=0.001), and diastolic BP >90 mmHg in the second (P=0.002) and third trimesters (P=0.05). CONCLUSIONS: Most pregnancies in the United Kingdom in women with kidney transplants are successful but rates of maternal and neonatal complications remain high. PMID- 23085725 TI - Early dialysis initiation and rates and timing of withdrawal from dialysis in Canada. AB - BACKGROUND AND OBJECTIVES: The number of elderly patients and those with higher estimated GFR (eGFR) initiating dialysis have recently increased. This study sought to determine rates of withdrawal from dialysis and variables associated with withdrawal. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Canadian Organ Replacement Registry data were used to examine withdrawal rate and identify variables associated with withdrawal among the total cohort, patients age < 75 years, and patients age >= 75 years, along with those with early (eGFR > 10.5 ml/min per 1.73 m(2)) and those with late (eGFR <= 10.5 ml/min per 1.73 m(2)) initiation of dialysis, using a Cox proportional hazard model in patients starting dialysis between 2001 and 2009, with follow-up to December 31, 2009. RESULTS: Median follow-up duration was 23.0 (interquartile range [IQR], 34.3) months. Rate of withdrawal per 100 patient-years doubled from 1.5 to 3.0, and withdrawal as cause of death increased from 7.9% to 19.5% between 2001 and 2009. Early initiation of dialysis was associated with increased withdrawal risk (hazard ratio, 1.17; 95% confidence interval, 1.06-1.30; P=0.002), as were older age, female sex, white race, and late referral to nephrologist. Patients age >= 75 years withdrew earlier after dialysis initiation (median, 15.9 [IQR, 27.9] months) compared to those age < 75 years (21.6 [IQR, 35.2] months). Early-start patients withdrew earlier (median, 15.6 [IQR, 28.5] months) compared with late start patients (20.2 [IQR, 32.9] months). CONCLUSIONS: In Canada, withdrawal from dialysis has increased significantly over recent years, especially among patients starting with higher eGFRs and in the elderly. PMID- 23085726 TI - Factors associated with CKD in the elderly and nonelderly population. AB - BACKGROUND AND OBJECTIVES: The risk factors for CKD in different age groups remain unknown. This community-based study aimed to identify the risk factors for CKD in elderly and nonelderly patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A multistage sampling survey for CKD was conducted in 2007 in Kaohsiung County, an area with the highest prevalence of dialysis in the world. CKD was defined as proteinuria in at least the microalbuminuric stage or an estimated GFR (eGFR) of <60 ml/min per 1.73 m(2). The factors for CKD in elderly and nonelderly patient groups were identified (with age 60 years as a cutoff value). RESULTS: The analyses included 3352 participants, of whom 687 had CKD. The weighted prevalence of CKD was 19.4% (95% confidence interval [CI], 18.0% 20.7%). Elderly patients typically presented with low eGFR and nonelderly patients, with proteinuria. Age, annual income, use of oral analgesics, metabolic syndrome, hyperuricemia, and hemoglobin were risk factors for CKD in both age groups. In elderly patients, risk factors were medical history of diabetes mellitus, CKD, stroke, and not using analgesic injection (odds ratios [95% CIs], 3.58 [2.06-6.22], 3.66 [1.58-8.43], 3.89 [1.09-13.87], 2.27 [1.21-4.17], respectively). In nonelderly patients, associated risk factors for CKD were gout, hepatitis B virus infection, and use of the Chinese herbal medicine Long Dan Xie Gan Tang (odds ratios [95% CIs], 3.15 [1.96-5.07], 1.66 [1.09-2.53], and 8.86 [1.73-45.45], respectively). CONCLUSIONS: The risk factors for CKD vary by age. PMID- 23085727 TI - Interaction between GFR and risk factors for morbidity and mortality in African Americans with CKD. AB - BACKGROUND AND OBJECTIVES: The African American Study of Kidney Disease Trial identified risk factors for CKD progression and suggested that GFR level may modify the association between these risk factors and CKD progression or death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment in the African American Study of Kidney Disease Trial occurred between June of 1995 and September of 2001, with median follow-up of 48.6 months. Among 1094 patients with hypertensive kidney disease in the trial, this study tested whether the association between six previously identified risk factors for CKD progression (or death) and a composite clinical outcome (progression of CKD, ESRD, or death) depends on level of GFR. Multivariate Cox regression was used to control for other baseline risk factors. RESULTS: After controlling for baseline risk factors, only proteinuria was more closely associated with the composite clinical outcome at lower levels of GFR (P value for interaction term=0.002); increased hazards of the clinical composite outcome associated with a doubling of proteinuria ranged from 30% (95% confidence interval=21%-39%) with a GFR of 50 to 55% (95% confidence interval=40% 72%) with a GFR of 25. CONCLUSIONS: The magnitude of the association between proteinuria and CKD progression, ESRD, or death in the African American Study of Kidney Disease Trial cohort depends on the level of GFR; proteinuria is a stronger independent predictor of the composite clinical outcome at lower levels of GFR. This finding reinforces that African Americans with proteinuria and lower GFR represent a population at particularly high risk for adverse outcomes. PMID- 23085728 TI - Association of circulating fibroblast growth factor-23 with renal phosphate excretion among hemodialysis patients with residual renal function. AB - BACKGROUND AND OBJECTIVES: High serum levels of fibroblast growth factor-23 (FGF 23) are associated with mortality in patients with ESRD, but whether it still acts as a phosphaturic factor is unknown. This study aimed to explore the role of circulating FGF-23 on urinary phosphate excretion and phosphate balance in maintenance hemodialysis (MHD) patients with residual renal function (RRF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: There were 134 MHD patients enrolled in this cross-sectional study from June to July 2010. Demographics, laboratory data, and excretion capacity of phosphate were recorded. Multivariable linear regression was used to analyze the relationship of serum phosphate and the tubular reabsorption rate of phosphate with other factors. RESULTS: The median age of the patients was 61.0 years and 47.8% were male. Thirty percent of the patients had high urinary output (>200 ml/d) accompanied by lower serum levels of phosphate, calcium, intact parathyroid hormone, and FGF-23 compared with those with low urine output (<=200 ml/d). The independent predictors of serum phosphate were normalized protein nitrogen appearance, intact parathyroid hormone, and FGF 23 in the low urine output group and female sex and GFR in the high urine output group. The tubular reabsorption rate of phosphate decreased to 50% of the normal level in patients with RRF. Elevated circulating FGF-23 was significantly associated with lower tubular phosphate reabsorption after adjusting for GFR. CONCLUSIONS: RRF is associated with significant capacity to excrete phosphate in MHD patients and high levels of serum FGF-23 may promote phosphate excretion by remnant nephrons. PMID- 23085729 TI - Association between oral nutritional supplementation and clinical outcomes among patients with ESRD. AB - BACKGROUND AND OBJECTIVES: Oral nutritional supplementation (ONS) was provided to ESRD patients with hypoalbuminemia as part of Fresenius Medical Care Health Plan's (FMCHP) disease management. This study evaluated the association between FMCHP's ONS program and clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Analyses included FMCHP patients with ONS indication (n=470) defined as 2-month mean albumin <3.8 g/dl until reaching a 3-month mean >=3.8 g/dl from February 1, 2006 to December 31, 2008. Patients did not receive ONS if deemed inappropriate or refused. Patients on ONS were compared with patients who were not, despite meeting ONS indication. Patients with ONS indication regardless of use were compared with Medicare patients with similar serum albumin levels from the 2007 Centers for Medicare and Medicaid Services Clinical Performance Measures Project (CPM). Cox models calculated adjusted hospitalization and mortality risks at 1 year. RESULTS: Among patients with indication for ONS, 276 received supplements and 194 did not. ONS use was associated with 0.058 g/dl higher serum albumin overall (P=0.02); this difference decreased by 0.001 g/dl each month (P=0.05) such that the difference was 0.052 g/dl (P=0.04) in month 6 and the difference was no longer significant in month 12 . In analyses based on ONS use, ONS patients had lower hospitalization at 1 year (68.4%; P<0.01) versus patients without ONS (88.7%), but there was no significant reduction in mortality risk (P=0.29). In analyses based on ONS indication, patients with indication had lower mortality at 1 year (16.2%) compared with CPM patients (23.4%; P<0.01). CONCLUSIONS: These findings suggest that ONS use was associated with significantly lower hospitalization rates but had no significant effect on mortality in a disease management setting. PMID- 23085730 TI - L-carnitine for anemia in hemodialysis patients: a last resort. PMID- 23085731 TI - Association of epitope spreading of antiglomerular basement membrane antibodies and kidney injury. AB - BACKGROUND AND OBJECTIVES: Antiglomerular basement membrane autoantibodies are pathogenic in antiglomerular basement membrane disease with two major epitopes, E(A) and E(B), on alpha3 chain of type IV collagen. This study investigated the epitope spectrum of antiglomerular basement membrane autoantibodies, aiming to identify the association between epitope specificity and kidney injury. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: All 108 patients with antiglomerular basement membrane disease and complete clinical data were divided into three groups according to renal dysfunction: mild group (n=20) with serum creatitine<=1.5 mg/dl; moderate group (n=22) with serum creatinine=1.5-6.8 mg/dl; severe group (n=66) with serum creatitine>=6.8 mg/dl. Epitope spectrums of antibodies were determined by ELISA, and their associations with kidney damage were analyzed. Sequential serum samples in 40 patients were examined during disease courses. RESULTS: E(A) and E(B) were recognized in 79.6% and 72.2% of patients, respectively. E(A) and E(B) reactions were the lowest in the mild group and higher in the moderate group (E(A): 35.0% versus 81.8%, P=0.002; E(B): 15.0% versus 68.2%, P=0.001). They were the highest in the severe group (E(A): 92.4%, P=0.31; E(B): 90.9%, P=0.02). Close association was observed between renal injury and E(A) and E(B) reactions. Multivariate Cox regression analysis showed that E(B) reaction was an independent risk factor for renal failure (hazard ratio=6.91, P=0.02). The recognition for non-E(AB) remained low among groups. No augmentation of epitope spectrum was shown in serial serum samples. CONCLUSIONS: Intramolecular epitope spreading might occur before the onset of human antiglomerular basement membrane disease. The autoimmunity to E(A) and E(B), especially E(B), was crucial for kidney dysfunction. PMID- 23085734 TI - Different methods for tritium determination in surface water by LSC. AB - The main aim of this paper was to compare different methods of preparing water samples for tritium analysis by ultra-low-level background liquid scintillation counter, Quantulus 1220. Three methods of sample preparation for low-level tritium measurement have been implemented in the Nuclear Physics Laboratory in Novi Sad: electrolytic enrichment, direct method without electrolytic enrichment and sample Oxidizer 307 method. The examined fresh water samples were rainfall collected during 6 months and water from a stream in the Vinca nuclear research center collected over 3 months. The obtained results using these three methods showed satisfying agreement. The appropriate measuring time by LSC for each sample prepared according to different methods has been determined. PMID- 23085735 TI - Diameter and chiral angle distribution dependencies on the carbon precursors in surface-grown single-walled carbon nanotubes. AB - Carbon nanotubes grown from discrete Fe-containing nanoparticles dispersed on a silicon nitride transmission electron microscope grid were systematically studied. The (n,m) indices of produced single-walled carbon nanotubes (SWNTs) were deduced from their electron diffraction patterns. Relatively small diameter SWNTs with a narrow diameter distribution (0.7-1.6 nm) were produced using CO as the carbon source at 800 degrees C, while large diameter SWNTs ranging from 1.0 nm to 4.7 nm were synthesized when using CH(4) as the carbon source. The chiral angle distributions of the SWNTs produced from different carbon sources are also different, which are attributed to the preferred cap nucleation associated with the carbon feed rate on the catalyst instead of carbon nanotube growth kinetics. Furthermore, growth of carbon laminar nanoclusters inside carbon nanotubes was achieved at a higher growth temperature, suggesting that dissociated carbon diffuses across the nanoparticle during the nanotube growth process. PMID- 23085732 TI - The Arabidopsis thylakoid ADP/ATP carrier TAAC has an additional role in supplying plastidic phosphoadenosine 5'-phosphosulfate to the cytosol. AB - 3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is the high-energy sulfate donor for sulfation reactions. Plants produce some PAPS in the cytosol, but it is predominantly produced in plastids. Accordingly, PAPS has to be provided by plastids to serve as a substrate for sulfotransferase reactions in the cytosol and the Golgi apparatus. We present several lines of evidence that the recently described Arabidopsis thaliana thylakoid ADP/ATP carrier TAAC transports PAPS across the plastid envelope and thus fulfills an additional function of high physiological relevance. Transport studies using the recombinant protein revealed that it favors PAPS, 3'-phosphoadenosine 5'-phosphate, and ATP as substrates; thus, we named it PAPST1. The protein could be detected both in the plastid envelope membrane and in thylakoids, and it is present in plastids of autotrophic and heterotrophic tissues. TAAC/PAPST1 belongs to the mitochondrial carrier family in contrast with the known animal PAPS transporters, which are members of the nucleotide-sugar transporter family. The expression of the PAPST1 gene is regulated by the same MYB transcription factors also regulating the biosynthesis of sulfated secondary metabolites, glucosinolates. Molecular and physiological analyses of papst1 mutant plants indicate that PAPST1 is involved in several aspects of sulfur metabolism, including the biosynthesis of thiols, glucosinolates, and phytosulfokines. PMID- 23085733 TI - Spatio-temporal cellular dynamics of the Arabidopsis flagellin receptor reveal activation status-dependent endosomal sorting. AB - The activity of surface receptors is location specific, dependent upon the dynamic membrane trafficking network and receptor-mediated endocytosis (RME). Therefore, the spatio-temporal dynamics of RME are critical to receptor function. The plasma membrane receptor flagellin sensing2 (FLS2) confers immunity against bacterial infection through perception of flagellin (flg22). Following elicitation, FLS2 is internalized into vesicles. To resolve FLS2 trafficking, we exploited quantitative confocal imaging for colocalization studies and chemical interference. FLS2 localizes to bona fide endosomes via two distinct endocytic trafficking routes depending on its activation status. FLS2 receptors constitutively recycle in a Brefeldin A (BFA)-sensitive manner, while flg22 activated receptors traffic via ARA7/Rab F2b- and ARA6/Rab F1-positive endosomes insensitive to BFA. FLS2 endocytosis required a functional Rab5 GTPase pathway as revealed by dominant-negative ARA7/Rab F2b. Flg22-induced FLS2 endosomal numbers were increased by Concanamycin A treatment but reduced by Wortmannin, indicating that activated FLS2 receptors are targeted to late endosomes. RME inhibitors Tyrphostin A23 and Endosidin 1 altered but did not block induced FLS2 endocytosis. Additional inhibitor studies imply the involvement of the actin myosin system in FLS2 internalization and trafficking. Altogether, we report a dynamic pattern of subcellular trafficking for FLS2 and reveal a defined framework for ligand-dependent endocytosis of this receptor. PMID- 23085736 TI - Self-assembly of well-defined ferrocene triblock copolymers and their template synthesis of ordered iron oxide nanoparticles. AB - Well-defined ferrocene-containing triblock copolymers were synthesized by atom transfer radical polymerization and self-assembled into highly ordered hexagonal arrays of cylinders via solvent annealing. The thin films were further used as a template and converted into highly ordered iron oxide nanoparticles (alpha-Fe2O3) by UV/ozonolysis and thermal pyrolysis. PMID- 23085737 TI - A phase I study on pharmacokinetics and pharmacodynamics of higenamine in healthy Chinese subjects. AB - AIM: To investigate the pharmacokinetics, pharmacodynamics, and safety of higenamine, an active ingredient of Aconite root, in healthy Chinese volunteers. METHODS: Ten subjects received continuous, intravenous infusion of higenamine at gradually escalating doses from 0.5 to 4.0 MUg.kg(-1).min(-1), each dose was given for 3 min. Blood and urine samples were collected at designated time points to measure the concentrations of higenamine. Pharmacodynamics was assessed by measuring the subject's heart rate. A nonlinear mixed-effect modeling approach, using the software Phoenix NLME, was used to model the plasma concentration-time profiles and heart rate. RESULTS: Peak concentrations (C(max)) of higenamine ranged from 15.1 to 44.0 ng/mL. The half-life of higenamine was 0.133 h (range, 0.107-0.166 h), while the area under concentration-time curve (AUC), extrapolated to infinity, was 5.39 ng.h.mL(-1) (range, 3.2-6.8 ng.h.mL(-1)). The volume of distribution (V) was 48 L (range, 30.8-80.6 L). The total clearance (CL) was 249 L/h (range, 199-336 L/h). Within 8 h, 9.3% (range, 4.6%-12.4%) of higenamine was recovered in the urine. The pharmacokinetics of higenamine was successfully described using a two-compartment model with nonlinear clearance. In the pharmacodynamic model, heart rates were related to the plasma drug concentrations using a simple direct effect model with baseline. The E(0), E(max), and EC(50) were 68 bpm, 73 bpm and 8.1 MUg/L, respectively. CONCLUSION: Higenamine has desirable pharmacokinetic and pharmacodynamic characteristics. The results provide important information for future clinical studies on higenamine. PMID- 23085738 TI - Pharmacokinetics and pharmacodynamics of single and multiple doses of prasugrel in healthy native Chinese subjects. AB - AIM: To characterize the pharmacokinetics (PKs), pharmacodynamics (PDs), and tolerability of different dose regimens of prasugrel in healthy Chinese subjects. METHODS: This was a single-centered, open-label, parallel-design study. Subjects received a single loading dose (LD) of prasugrel followed by once-daily maintenance dose (MD) for 10 d. They were enrolled into 3 groups: 60 mg LD/10 mg MD; 30 mg LD/7.5 mg MD; 30 mg LD/5 mg MD. Blood samples were collected after the first and last dose. The serum concentration of the active metabolite of prasugrel was determined using a LC/MS/MS method. Platelet aggregation was assessed using the VerifyNow-P2Y(12) assay. RESULTS: Thirty-six healthy native Chinese subjects (19 males) aged 18-45 were enrolled; mean age and body weight were similar across the treatment groups (n=12 for each). The metabolite AUC(0-4) and C(max) increased dose-proportionally across the dose range of 5 mg to 60 mg. The median T(max) was 0.5 h in all groups. The PD parameters, indicated by the inhibition of ADP-induced platelet aggregation, were met more rapidly in the 60 mg group than the 30 mg group after the LD (94%-98%). This high degree of inhibition of platelet aggregation was maintained following the 10 mg MD (87% 90%) and was lower in the 7.5 mg and 5 mg MD groups (79%-83% and 64%-67%, respectively). Prasugrel was well tolerated in healthy Chinese subjects for single doses up to 60 mg and a MD of 10 mg for 10 d. CONCLUSION: The PKs and PDs of the active metabolite of prasugrel were similar to those in Chinese subjects reported by a previous bridging study, which demonstrated that the exposure to the active metabolite in Chinese subjects was higher than in Caucasians. PMID- 23085739 TI - Simulation of the pharmacokinetics of bisoprolol in healthy adults and patients with impaired renal function using whole-body physiologically based pharmacokinetic modeling. AB - AIM: To develop and evaluate a whole-body physiologically based pharmacokinetic (WB-PBPK) model of bisoprolol and to simulate its exposure and disposition in healthy adults and patients with renal function impairment. METHODS: Bisoprolol dispositions in 14 tissue compartments were described by perfusion-limited compartments. Based the tissue composition equations and drug-specific properties such as log P, permeability, and plasma protein binding published in literatures, the absorption and whole-body distribution of bisoprolol was predicted using the 'Advanced Compartmental Absorption Transit' (ACAT) model and the whole-body disposition model, respectively. Renal and hepatic clearances were simulated using empirical scaling methods followed by incorporation into the WB-PBPK model. Model refinements were conducted after a comparison of the simulated concentration-time profiles and pharmacokinetic parameters with the observed data in healthy adults following intravenous and oral administration. Finally, the WB PBPK model coupled with a Monte Carlo simulation was employed to predict the mean and variability of bisoprolol pharmacokinetics in virtual healthy subjects and patients. RESULTS: The simulated and observed data after both intravenous and oral dosing showed good agreement for all of the dose levels in the reported normal adult population groups. The predicted pharmacokinetic parameters (AUC, C(max), and T(max)) were reasonably consistent (<1.3-fold error) with the observed values after single oral administration of doses ranging from of 5 to 20 mg using the refined WB-PBPK model. The simulated plasma profiles after multiple oral administration of bisoprolol in healthy adults and patient with renal impairment matched well with the observed profiles. CONCLUSION: The WB-PBPK model successfully predicts the intravenous and oral pharmacokinetics of bisoprolol across multiple dose levels in diverse normal adult human populations and patients with renal insufficiency. PMID- 23085740 TI - Association of CYP3A polymorphisms with the pharmacokinetics of cyclosporine A in early post-renal transplant recipients in China. AB - AIM: To evaluate retrospectively the association of cytochrome P450 3A (CYP3A) and ATP-binding cassette sub-family B member 1 (ABCB1) gene polymorphisms with the pharmacokinetics of cyclosporine A (CsA) in Chinese renal transplant patients. METHODS: One hundred and twenty-six renal transplant patients were recruited. Blood samples were collected, and corresponding clinical indices were recorded on the seventh day after the procedure. The patients were genotyped for CYP3A4*1G, CYP3A5*3C, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T polymorphisms. Whole blood trough concentrations of CsA at time zero (C(0)) were measured before the drug administration. A multiple regression model was developed to analyze the effects of genetic factors on the CsA dose-adjusted C(0) (C(0)/dose) based on several clinical indices. RESULTS: The CYP3A5*3C polymorphism influenced the C(0) and C(0)/dose of CsA, which were significantly higher in patients with the GG genotype than in patients with the AA or GA genotypes. No significant differences were detected for other SNPs (CYP3A4*1G, ABCB1 1236 C>T, ABCB1 2677 G>T/A, and ABCB1 3435 C>T). In a univariate analysis using Pearson's correlation test, age, hemoglobin, blood urea nitrogen and blood creatinine levels were significantly correlated with the log-transformed CsA C(0)/dose. In the multiple regression model, CYP3A5*3C, age, hemoglobin and blood creatinine level were associated with the log-transformed CsA C(0)/dose. CONCLUSION: CYP3A5*3C correlates with the C(0)/dose of CsA on the seventh day after renal transplantation. The allele is a putative indicator for the optimal CsA dosage in the early phase of renal transplantation in the Chinese population. PMID- 23085741 TI - Nuclear translocation of cysteinyl leukotriene receptor 1 is involved in oxygen glucose deprivation-induced damage to endothelial cells. AB - AIM: Cysteinyl leukotriene receptor 1 (CysLT(1) receptor) is located in epithelial cells, and translocates from the plasma membrane to the nucleus in a ligand-dependent manner. Here, we investigated whether CysLT(1) receptors translocated to the nucleus in endothelial cells after ischemic insult in vitro and whether it was involved in ischemic injury to endothelial cells. METHODS: EA.hy926 cell line, derived from human umbilical vein endothelial cells, was subjected to oxygen-glucose deprivation (OGD). The expression and distribution of CysLT(1) receptors were detected by immunofluorescent staining, immunogold labeling and immunoblotting analyses. Cell viability was evaluated using MTT reduction assay. Necrosis and apoptosis were determined by double fluorescent staining with propidium iodide and Hoechst 33342. RESULTS: CysLT(1) receptors were primarily distributed in the cytoplasm and nucleus in EA.hy926 cells, and few was found in the cell membrane. OGD induced the translocation of CysLT(1) receptors from the cytoplasm to the nucleus in a time-depen dent manner, with a peak reached at 6 h. OGD-induced nuclear translocation of CysLT(1) receptors was inhibited by pretreatment with the CysLT(1) receptor antagonist pranlukast (10 MUmol/L), or by preincubation with NLS-pep, a peptide corresponding to the nuclear localization sequence of CysLT(1) receptor (10 MUg/mL). However, zileuton, an inhibitor of 5-lipoxygenase that was a key enzyme in cysteinyl leukotriene generation, did not inhibit the nuclear translocation of CysLT(1) receptors. Moreover, preincubation with NLS-pep (0.4 MUg/mL) significantly ameliorated OGD-induced cell viability reduction and necrosis. CONCLUSION: CysLT(1) receptors in endothelial cells translocate to the nucleus in a ligand independent manner after ischemic insult in vitro, and it is involved in the ischemic injury. PMID- 23085742 TI - Clinical efficacy of long-acting neuraminidase inhibitor laninamivir octanoate hydrate in postmarketing surveillance. AB - Laninamivir octanoate hydrate (laninamivir) is a long-acting neuraminidase inhibitor which requires only a single inhaled dose to fully treat infection by the influenza virus. In Japan, this drug was launched in October 2010 as a new treatment for the influenza virus. A postmarketing surveillance study was conducted in the 2010/2011 influenza season to assess the efficacy of this drug in clinical settings. For 3542 patients evaluated for efficacy (type A, n = 3179; type B, n = 342, unknown type, n = 3), including the day of drug administration, the median duration to fever resolution was three days, and the median duration to relief from influenza symptoms was four days. Based on the judgment of participating physicians, the efficacy rate was 97.6 % for type A influenza, 93.3 % for type B influenza, and 100 % in unknown types. "Treatment failure," as judged by participating physicians, was most closely correlated with the inhalation status of laninamivir. Despite laninamivir requiring only the administration of a single dose, it was confirmed to be an effective treatment in more than 90 % of patients with type A or type B influenza virus infections. This drug was considered to be useful for the treatment of influenza infections due to ease of use and its improvement of compliance. It became clear that the efficacy of laninamivir depended strongly on the status of inhalation, and thus careful and detailed instructions on the correct method of inhalation were considered to be important in order to obtain reliable therapeutic effects. PMID- 23085744 TI - Band gap engineering of silicene zigzag nanoribbons with perpendicular electric fields: a theoretical study. AB - The electronic properties of silicene zigzag nanoribbons with the presence of perpendicular fields are studied by using first-principles calculations and the generalized nearest neighboring approximation method. In contrast to the planar graphene, in silicene the Si atoms are not coplanar. As a result, by applying perpendicular fields to the two-dimensional silicene sheet, the on-site energy can be modulated and the band gap at the Dirac point is open. The buckled structure also creates a height difference between the two edges of the silicene zigzag nanoribbons. We find that the external fields can modulate the energies of spin-polarized edge states and their corresponding band gaps. Due to the polarization in the plane, the modulation effect is width dependent and becomes much more significant for narrow ribbons. PMID- 23085743 TI - Efficacy and safety of intravenous daptomycin in Japanese patients with skin and soft tissue infections. AB - Daptomycin is a lipopeptide antibiotic active against gram-positive organisms and recently approved for marketing in Japan. This study investigates the efficacy and safety of daptomycin in Japanese patients with skin and soft tissue infections (SSTIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) for regulatory filing in Japan. Overall, 111 Japanese patients with SSTI were randomized in this open-label, randomized, active-comparator controlled, parallel group, multicenter, phase III study. Patients received intravenous daptomycin 4 mg/kg once daily or vancomycin 1 g twice daily for 7-14 days. Efficacy was determined by a blinded Efficacy Adjudication Committee. Among patients with SSTIs caused by MRSA, 81.8 % (95 % CI, 69.1-90.9) of daptomycin recipients and 84.2 % (95 % CI, 60.4-96.6) of vancomycin recipients achieved a successful clinical response at the test-of-cure (TOC) visit. The microbiological success rate against MRSA at the TOC visit was 56.4 % (95 % CI, 42.3-69.7) with daptomycin and 47.4 % (95 % CI, 24.4-71.1) with vancomycin. Daptomycin was generally well tolerated; most adverse events were of mild to moderate severity. The measurement of daptomycin concentration in plasma revealed that patients with mild or moderate impaired renal function showed similar pharmacokinetics profiles to patients with normal renal function. Clinical and microbiological responses, stratified by baseline MRSA susceptibility, suggested that patients infected with MRSA of higher daptomycin MIC showed a trend of lower clinical success with a P value of 0.052 by Cochran-Armitage test. Daptomycin was clinically and microbiologically effective for the treatment of MRSA-associated SSTIs in Japanese patients. PMID- 23085745 TI - A bacteriophage endolysin-based electrochemical impedance biosensor for the rapid detection of Listeria cells. AB - The objective of this study was to develop a biosensor using the cell wall binding domain (CBD) of bacteriophage-encoded peptidoglycan hydrolases (endolysin) immobilized on a gold screen printed electrode (SPE) and subsequent electrochemical impedance spectroscopy (EIS) for a rapid and specific detection of Listeria cells. The endolysin was amine-coupled to SPEs using EDC/NHS chemistry. The CBD-based electrode was used to capture and detect the Listeria innocua serovar 6b from pure culture and 2% artificially contaminated milk. In our study, the endolysin functionalized SPEs have been characterized using X-ray photoelectron spectroscopy (XPS). The integration of endolysin-based recognition for specific bacteria and EIS can be used for direct and rapid detection of Listeria cells with high specificity against non-Listeria cells with a limit of detection of 1.1 * 10(4) and 10(5) CFU mL(-1) in pure culture and 2% milk, respectively. PMID- 23085746 TI - The Neurospora crassa chr-1 gene is up-regulated by chromate and its encoded CHR 1 protein causes chromate sensitivity and chromium accumulation. AB - The ChrA membrane protein belongs to the CHR superfamily of chromate ion transporters, which includes homologues from bacteria, archaea and eukaryotes. Bacterial ChrA homologues confer chromate resistance by exporting chromate ions from the cell's cytoplasm. The Neurospora crassa strain 74-A chr-1 gene encodes a putative CHR-1 protein of 507 amino acid residues, which belongs to the CHR superfamily. RT-PCR assays showed that expression of the chr-1 gene was up regulated by chromate exposure of N. crassa cultures. Introduction in N. crassa of sense and antisense fragments of the chr-1 gene, as part of a silencing module within the pSilent-1 vector, produced transformants with a phenotype of resistance to chromate and diminished accumulation of chromium, as compared with the control strain containing only the vector. A chromate-resistance phenotype was also observed in N crassa strains deleted in the genomic chr-1 gene, thus confirming that the absence of CHR-1 protein confers chromate resistance to the fungus. The cDNA from N. crassa chr-1 gene (Ncchr-1) was cloned into the pYES2 vector under the control of a GAL promoter and the resulting recombinant plasmid was transferred to the yeast Saccharomyces cerevisiae. Galactose-induced S. cerevisiae transformants expressing Ncchr-1 were more sensitive to chromate and accumulated 2.5 times more chromium than the induced strain containing only the vector. Excess sulfate, a chromate analog, was unable to protect S. cerevisiae chr-1 transformants from chromate toxicity. These data indicate that the N. crassa CHR-1 protein functions as a transporter that takes up chromate; it also appears that this transport occurs in a sulfate-independent fashion. This is the first report assigning a role as a chromate transporter to a nonbacterial CHR protein. PMID- 23085747 TI - Changes in plasma and cerebrospinal fluid biomarkers in aged patients with early postoperative cognitive dysfunction following total hip-replacement surgery. AB - PURPOSE: We hypothesized that different patterns of biomarkers of brain injury and inflammation exist in aged patients with postoperative cognitive dysfunction (POCD) after total hip-replacement with spinal anesthesia. METHODS: Eighty-three patients older than 65 years undergoing elective total hip-replacement surgery were enrolled in this prospective observational study. The CSF levels of Tau, phosphorylated-tau (pTau), amyloidbeta1-42 (Abeta1-42), Tau/Abeta1-42, pTau/Abeta1-42, BDNF, IL-6, and IL-1beta were measured preoperatively. Perioperative plasma levels of IL-1beta, IL-6, brain-derived neurotrophic factor (BDNF), C-reactive protein (CRP), and malonaldehyde (MDA) as well as neurocognitive tests were determined preoperatively and seven days postoperatively. RESULTS: Sixty-one patients completed both the CSF and blood samples collection and the neurocognitive tests. POCD occurred in 24.6 % of patients at seven days after surgery. Patients with POCD had significantly higher IL-1beta, Tau/Abeta1-42, pTau/Abeta1-42, and a lower level of Abeta1-42 in CSF when compared with the Non-POCD group (P < 0.05). Furthermore, POCD patients displayed significantly higher plasma levels of MDA when compared with Non-POCD patients at seven days after surgery (P < 0.05). There was no difference in preoperative CSF levels of Tau, IL-6, and pTau as well as plasma levels of IL 1beta, IL-6, BDNF and CRP between POCD and Non-POCD groups (P > 0.05). CONCLUSION: The POCD patients were associated with higher postoperative plasma levels of MDA, and higher IL-1beta and lower Abeta1-42 levels in preoperative CSF that might predispose the development of POCD in aged patients following total hip-replacement surgery with spinal anesthesia. PMID- 23085748 TI - Classical and non-classical phosphine-Ru(II)-hydrides in aqueous solutions: many, various, and useful. AB - Hydrogenation of the water-soluble [{RuCl(2)(mtppms)(2)}(2)] (mtppms = monosulfonated triphenylphosphine) was studied in aqueous solutions in the presence of excess mtppms both with H(2) and with aqueous HCOONa. Depending on the reductant, the pH and H(2) pressure altogether nine hydride species were identified. In acidic solutions at 1 bar H(2) pressure the known [RuHCl(mtppms)(3)] (1) and [{RuHCl(mtppms)(2)}(2)] (3) were formed, however, elevated pressure led to the formation of trans-[RuH(2)(mtppms)(4)] (11). In basic solutions at atmospheric pressure cis-fac-[RuH(2)(H(2)O)(mtppms)(3)] (12) was observed which was readily replaced by [RuH(2)(eta(2)-H(2))(mtppms)(3)] (13) at higher H(2) pressures. 13 is the first water-soluble and stable eta(2)-H(2) Ru(II)-complex stabilized only by monodentate phosphine ligands. [RuHBr(mtppms)(3)] (9) and [RuHI(mtppms)(3)] (10) were obtained analogously to 1. In concentrated aqueous HCOONa solutions (often used in H-transfer hydrogenations) the major species was trans-[RuH(2)(HCOO)(mtppms)](-) (14) while in dilute solutions trans-[RuH(2)(H(2)O)(mtppms)(3)] (15) could be observed. Formation of these various hydride species offers an explanation for the earlier observed pH and pressure dependence of the rates and selectivities in hydrogenation of unsaturated aldehydes catalyzed by [{RuCl(2)(mtppms)(2)}(2)] + mtppms. PMID- 23085749 TI - A mechanistic study of the photodegradation of herbicide 2,4,5 trichlorophenoxyacetic acid in aqueous solution. AB - Photodegradation of herbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) in aqueous solution was investigated by stationary (254 nm) and nanosecond laser (266 nm) flash photolysis techniques. It was shown that in the primary photochemical step both photoionization (which generates a hydrated electron radical cation pair) and heterolytic cleavage of a C-Cl bond takes place. The major products of substitution of one of the chlorine atoms in the 2-, 4- or 5 position by a hydroxyl group as well as the products of hydroxylation of the benzene ring in 3- and 6-positions were identified by HPLC and LC-MS methods. The complexation of 2,4,5-T with beta- and gamma-cyclodextrins (beta(gamma)CD) was investigated. The influence of such complexation on the quantum yield of herbicide photolysis and on the ratio of photodegradation products was determined. PMID- 23085750 TI - GSK3beta phosphorylation of the KLF6 tumor suppressor promotes its transactivation of p21. AB - KLF6, a ubiquitously expressed Kruppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several cancer-derived KLF6 mutants lead to the loss of p21-mediated growth suppression through an unknown mechanism. Because several colorectal cancer and hepatocellular carcinoma-derived KLF6 mutations affect a glycogen synthase kinase 3beta (GSK3beta) phosphorylation consensus site, we investigated the role of GSK3beta in the regulation of KLF6 function. Based on transient transfection, GSK3beta augments the transactivation of a p21 promoter luciferase by KLF6. Reciprocal co-immunoprecipitation of hemagglutinin (HA)-GSK3beta and Flag-KLF6 validated the interaction between these two proteins. KLF6 phosphorylation is augmented in the presence of GSK3beta based on in vitro and in vivo (32)P incorporation assays. Site-directed mutagenesis of the candidate phosphorylation sites to alanines ('KLF6-4A' phosphomutant) eliminated a higher molecular weight phosphorylated isoform of KLF6 based on western blot. GSK3beta augmented the transactivation by wild-type KLF6, but not KLF6-4A, towards the p21 promoter, and increased p21 protein. Functionally, GSK3beta enhanced KLF6-mediated growth suppression, which was abrogated by the KLF6-4A phosphomutant. These data establish that GSK3beta directly phosphorylates KLF6, which augments its induction of p21 and resultant growth suppression. This interaction may account for the growth-promoting effects of cancer-derived KLF6 mutants that lack tumor suppressor activity. PMID- 23085751 TI - Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia. AB - The term myelodysplastic syndrome (MDS) identifies a heterogeneous group of clonal disorders originating from bone marrow stem cells that often progress to acute myeloid leukemia (AML). The reference treatments for MDS include the DNA methyltransferase inhibitors azacytidine and decitabine. Recently, the epidermal growth factor receptor (EGFR) inhibitor erlotinib has been shown to exert antileukemic activity in vitro and in vivo, independent of the EGFR. Thanks to this feature, erlotinib is currently being tested as an antileukemic drug in clinical trials. Here, we report that azacytidine and erlotinib mediate synergistic antineoplastic effects in several primary or secondary (post-MDS) AML cell lines. The combination of azacytidine and erlotinib blocked cell-cycle progression and induced caspase-dependent apoptosis more consistently than either of the two agents alone. These effects were not a consequence of cellular differentiation and could be discriminated from each other, as the former depended on caspases whereas the latter did not. The synergy between azacitidine and erlotinib, which involved the proteasomal degradation of the anti-apoptotic Bcl-2 family members MCL-1 and BCL2L10 and the upregulation of their pro apoptotic counterpart PUMA, was abolished when azacytidine was replaced by decitabine but persisted when erlotinib was substituted with gefitinib, another EGFR inhibitor. Of note, the intracellular accumulation of azacytidine was exacerbated by both erlotinib and gefitinib, pointing to a pharmacokinetic mechanism of synergy. In approximately half of the cases studied, marrow and circulating blasts from MDS and AML patients, respectively, exhibited hyperadditive cytotoxic responses to the combination of azacytidine and erlotinib. These results strongly suggest that the combination of azacytidine and erlotinib may exert clinically relevant antileukemic effects. PMID- 23085752 TI - Disruption of epithelial architecture caused by loss of PTEN or by oncogenic mutant p110alpha/PIK3CA but not by HER2 or mutant AKT1. AB - Genetic changes in HER2, PTEN, PIK3CA and AKT1 are all common in breast cancer and lead to the elevated phosphorylation of downstream targets of the PI3K/AKT signalling pathway. Changes in HER2, PTEN, PIK3CA and AKT have all been reported to lead to both enhanced proliferation and failures in hollow lumen formation in three dimensional epithelial culture models, but it is not clear whether these failures in lumen formation are caused by any failure in the spatial coordination of lumen formation (hollowing) or purely a failure in the apoptosis and clearance of luminal cells (cavitation). Here, we use normal murine mammary gland (NMuMG) epithelial cells, which form a hollow lumen without significant apoptosis, to compare the transformation by these four genetic changes. We find that either mutant PIK3CA expression or PTEN loss, but not mutant AKT1 E17K, cause disrupted epithelial architecture, whereas HER2 overexpression drives strong proliferation without affecting lumen formation in these cells. We also show that PTEN requires both lipid and protein phosphatase activity, its extreme C-terminal PDZ binding sequence and probably Myosin 5A to control lumen formation through a mechanism that does not correlate with its ability to control AKT, but which is selectively lost through mutation in some tumours. These findings correlate AKT-independent signalling activated by mutant PIK3CA or PTEN loss, but not strongly by HER2, with disrupted epithelial architecture and tumour formation. PMID- 23085754 TI - ATR controls cellular adaptation to hypoxia through positive regulation of hypoxia-inducible factor 1 (HIF-1) expression. AB - Tumor cells adaptation to severe oxygen deprivation (hypoxia) plays a major role in tumor progression. The transcription factor HIF-1 (hypoxia-inducible factor 1), whose alpha-subunit is stabilized under hypoxic conditions is a key component of this process. Recent studies showed that two members of the phosphoinositide 3 kinase-related kinases (PIKKs) family, ATM (ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase), regulate the hypoxic-dependent accumulation of HIF-1. These proteins initiate cellular stress responses when DNA damage occurs. In addition, it has been demonstrated that extreme hypoxia induces a replicative stress resulting in regions of single-stranded DNA at stalled replication forks and the activation of ATR (ataxia telangiectasia and Rad3 related protein), another member of the PIKKs family. Here, we show that even less severe hypoxia (0.1% O2) also induces activation of ATR through replicative stress. Importantly, in using either transiently silenced ATR cells, cells expressing an inactive form of ATR or cells exposed to an ATR inhibitor (CGK733), we demonstrate that hypoxic ATR activation positively regulates the key transcription factor HIF-1 independently of the checkpoint kinase Chk1. We show that ATR kinase activity regulates HIF-1alpha at the translational level and we find that the elements necessary for the regulation of HIF-1alpha translation are located within the coding region of HIF-1alpha mRNA. Finally, by using three independent cellular models, we clearly show that the loss of ATR expression and/or kinase activity results in the decrease of HIF-1 DNA binding under hypoxia and consequently affects protein expression levels of two HIF-1 target genes, GLUT-1 and CAIX. Taken together, our data show a new function for ATR in cellular adaptation to hypoxia through regulation of HIF-1alpha translation. Our work offers new prospect for cancer therapy using ATR inhibitors with the potential to decrease cellular adaptation in hypoxic tumors. PMID- 23085753 TI - HIF-independent role of prolyl hydroxylases in the cellular response to amino acids. AB - Hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are alpha-ketoglutarate (alphaKG)-dependent dioxygenases that function as cellular oxygen sensors. However, PHD activity also depends on factors other than oxygen, especially alphaKG, a key metabolic compound closely linked to amino-acid metabolism. We examined the connection between amino-acid availability and PHD activity. We found that amino-acid starvation leads to alphaKG depletion and to PHD inactivation but not to HIF stabilization. Furthermore, pharmacologic or genetic inhibition of PHDs induced autophagy and prevented mammalian target of rapamycin complex 1 (mTORC1) activation by amino acids in a HIF-independent manner. Therefore, PHDs sense not only oxygen but also respond to amino acids, constituting a broad intracellular nutrient-sensing network. PMID- 23085755 TI - Mesenchymal stem cells promote growth and angiogenesis of tumors in mice. AB - Though the early integration of mesenchymal stem cells (MSCs) into tumor associated stroma of cancer has been demonstrated, the functional contributions and underlying mechanisms of these cells to tumor growth and angiogenesis remain to be clarified. Using a xenograft model, human colorectal cancer cells, MSCs, and their cell mixture were introduced to a subcutaneous site of immunodeficient mice. The tumor growth rate and angiogenesis of each transplantation was then compared. We demonstrate that a variety of colorectal cancer cells, when mixed with otherwise non-tumorigenic MSCs, increase the tumor growth rate and angiogenesis more than that when mixed with carcinoma-associated fibroblasts or normal colonic fibroblasts. The secretion of interleukin-6 (IL-6) from MSCs increases the secretion of endothelin-1 (ET-1) in cancer cells, which induces the activation of Akt and ERK in endothelial cells, thereby enhancing their capacities for recruitment and angiogenesis to tumor. The IL-6/ET-1/Akt or ERK pathway of tumor-stroma interaction can be targeted by an antibody against IL-6 or Lentiviral-mediated RNAi against IL-6 in MSCs, by inhibition or knockdown of ET-1 in cancer cells, or by inhibition of ERK and Akt in host endothelial cells. These demonstrate that attempts to interrupt the interaction of MSCs and cancer cells help to abrogate angiogenesis and inhibit tumor growth in tumors formed by cancer cells admixed with MSCs. These data demonstrate that the tumor microenvironment, namely, MSCs-secreted IL-6, may enrich the proangiognic factors secreted by cancer cells to increase angiogenesis and tumor growth and that targeting this interaction may lead to novel therapeutic and preventive strategies. PMID- 23085756 TI - Metabotropic glutamate receptor 1 (Grm1) is an oncogene in epithelial cells. AB - Non-neuronal expression of components of the glutamatergic system has been increasingly observed, and our laboratory previously had demonstrated the etiological role of ectopically expressed metabotropic glutamate receptor 1 (Grm1/mGluR1) in mouse models of melanoma. We hypothesize that inappropriate glutamatergic signaling in other cell types can dysregulate growth leading to transformation and tumorigenesis. As most cancers are carcinomas, we selected an immortalized primary baby mouse kidney (iBMK) cell model to assess whether Grm1 can transform epithelial cells. These iBMK cells, engineered to be immortal yet nontumorigenic and retaining normal epithelial characteristics, were used as recipients for exogenous Grm1 cDNA. Several stable Grm1-expressing clones were isolated and the Grm1-receptors were shown to be functional, as evidenced by the accumulation of second messengers in response to Grm1 agonist. Additionally activated by agonist were mitogen-activated protein kinase (MAPK) and AKT/protein kinase B signaling cascades, the major intracellular pathways shown by many investigators to be critical in melanomagenesis and other neoplasms. These Grm1 iBMK cells exhibited enhanced cell proliferation in in vitro methylthiazolyldiphenyl-tetrazolium bromide (MTT) assays and significant tumorigenicity in in vivo allografts. Persistent Grm1 expression was required for the maintenance of the in vivo tumorigenic phenotype as demonstrated by an inducible Grm1-silencing RNA. These are the first results that indicate that Grm1 can be an oncogene in epithelial cells. In addition, relevance to human disease in the corresponding tumor type of renal cell carcinoma (RCC) may be suggested by observed expression of GRM1/mGluR1 in a number of RCC tumor biopsy samples and cell lines, and the effects of GRM1 modulation on tumorigenicity therein. Moreover, RCC cell lines exhibited elevated levels of extracellular glutamate, and some lines responded to drugs, which modulate the glutamatergic system. These findings imply a possible role for glutamate signaling apparatus in RCC cell growth, and that the glutamatergic system may be a therapeutic target in RCC. PMID- 23085757 TI - miR-30d, miR-181a and miR-199a-5p cooperatively suppress the endoplasmic reticulum chaperone and signaling regulator GRP78 in cancer. AB - GRP78, a major endoplasmic reticulum chaperone and signaling regulator, is commonly overexpressed in cancer. Moreover, induction of GRP78 by a variety of anti-cancer drugs, including histone deacetylase inhibitors, confers chemoresistance to cancer, thereby contributing to tumorigenesis. Thus, therapies aimed at decreasing GRP78 levels, which results in the inhibition of tumor cell proliferation and resensitization of tumor cells to chemotherapeutic drugs may hold promise for cancer treatment. Despite advances in our understanding of GRP78 actions, little is known about endogenous inhibitors controlling its expression. As endogenous regulators, microRNAs (miRNAs) play important roles in modulating gene expression; therefore, we sought to identify miRNA(s) that target GRP78, under the hypothesis that these miRNAs may serve as therapeutic agents. Here, we report that three miRNAs (miR-30d, miR-181a, miR-199a-5p) predicted to target GRP78 are down-regulated in prostate, colon and bladder tumors, and human cancer cell lines. We show that in C42B prostate cancer cells, these miRNAs down regulate GRP78 and induce apoptosis by directly targeting its 3' untranslated region. Importantly, we demonstrate that the three miRNAs act cooperatively to decrease GRP78 levels, suggesting that multiple miRNAs may be required to efficiently control the expression of some genes. In addition, delivery of multiple miRNAs by either transient transfection or lentivirus transduction increased the sensitivity of cancer cells to the histone deacetylase inhibitor, trichostatin A, in C42B, HCT116 and HL-60 cells. Together, our results indicate that the delivery of co-transcribed miRNAs can efficiently suppress GRP78 levels and GRP78-mediated chemoresistance, and suggest that this strategy holds therapeutic potential. PMID- 23085758 TI - Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/beta-catenin signalling thresholds for tumourigenesis. AB - Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/beta-catenin signalling levels 'just right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/beta-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers. PMID- 23085759 TI - The Cul4A-DDB1 E3 ubiquitin ligase complex represses p73 transcriptional activity. AB - The Cullin4A (cul4A)-dependent ligase (CDL4A) E3 has been implicated in a variety of biological processes, including cell cycle progression and DNA damage response. Remarkably, CDL4A exerts its function through both proteolytic and non proteolytic events. Here, we show that the p53 family member p73 is able to interact with the CDL4A complex through its direct binding to the receptor subunit DNA-binding protein 1 (DDB1). As a result, the CDL4A complex is able to monoubiquitylate p73. Modification of p73 by CDL4A-mediated ubiquitylation does not affect p73 protein stability, but negatively regulates p73-dependent transcriptional activity. Indeed, genetic or RNA interference-mediated depletion of DDB1 induces the expression of several p73 target genes in a p53-independent manner. In addition, by exploiting a bioinformatic approach, we found that elevated expression of Cul4A in human breast carcinomas is associated with repression of p73 target genes. In conclusion, our findings add a novel insight into the regulation of p73 by the CDL4A complex, through the inhibition of its transcriptional function. PMID- 23085760 TI - The novel tumor suppressor NOL7 post-transcriptionally regulates thrombospondin-1 expression. AB - Thrombospondin-1 (TSP-1) is an endogenous inhibitor of angiogenesis whose expression suppresses tumor growth in vivo. Like many angiogenesis-related genes, TSP-1 expression is tightly controlled by various mechanisms, but there is little data regarding the contribution of post-transcriptional processing to this regulation. NOL7 is a novel tumor suppressor that induces an antiangiogenic phenotype and suppresses tumor growth, in part through upregulation of TSP-1. Here we demonstrate that NOL7 is an mRNA-binding protein that must localize to the nucleoplasm to exert its antiangiogenic and tumor suppressive effects. There, it associates with the RNA-processing machinery and specifically interacts with TSP-1 mRNA through its 3'UTR. Reintroduction of NOL7 into SiHa cells increases luciferase expression through interaction with the TSP-1 3'UTR at both the mRNA and protein levels. NOL7 also increases endogenous TSP-1 mRNA half-life. Further, NOL7 post-transcriptional stabilization is observed in a subset of angiogenesis related mRNAs, suggesting that the stabilization of TSP-1 may be part of a larger novel mechanism. These data demonstrate that NOL7 significantly alters TSP-1 expression and may be a master regulator that coordinates the post transcriptional expression of key signaling factors critical for the regulation of the angiogenic phenotype. PMID- 23085762 TI - Hepatic hydrothorax. AB - Hepatic hydrothorax is defined as a pleural effusion in patients with liver cirrhosis in the absence of cardiopulmonary disease. The estimated prevalence among patients with liver cirrhosis is approximately 5-6%. The pathophysiology involves the passage of ascitic fluid from the peritoneal cavity to the pleural space through diaphragmatic defects. The diagnosis is made from clinical presentation and confirmed by diagnostic thoracentesis with pleural fluid analysis. The initial medical management is sodium restriction and diuretics, but liver transplantation provides the only definitive therapy. For patients who are not transplant candidates and those who await organ availability, other therapeutic modalities that are to be considered include transjugular intrahepatic portosystemic shunt placement, videoassisted thoracoscopic surgery repair, pleurodesis, and vasoconstrictors (eg, octreotide and terlipressin). The primary therapeutic goals are to reduce ascitic fluid production and improve symptoms to bridge the time for liver transplantation. PMID- 23085761 TI - NANOG modulates stemness in human colorectal cancer. AB - NANOG is a stem cell transcription factor that is essential for embryonic development, reprogramming normal adult cells and malignant transformation and progression. The nearly identical retrogene NANOGP8 is expressed in multiple cancers, but generally not in normal tissues and its function is not well defined. Our postulate is that NANOGP8 directly modulates the stemness of individual human colorectal carcinoma (CRC) cells. Stemness was measured in vitro as the spherogenicity of single CRC cells in serum-free medium and the size of the side population (SP) and in vivo as tumorigenicity and experimental metastatic potential in NOD/SCID mice. We found that 80% of clinical liver metastases express a NANOG with 75% of the positive metastases containing NANOGP8 transcripts. In all, 3-62% of single cells within six CRC lines form spheroids in serum-free medium in suspension. NANOGP8 is translated into protein. The relative expression of a NANOG gene increased 8- to 122-fold during spheroid formation, more than the increase in OCT4 or SOX2 transcripts with NANOGP8 the more prevalent family member. Short hairpin RNA (shRNA) to NANOG not only inhibits spherogenicity but also reduces expression of OCT4 and SOX2, the size of the SP and tumor growth in vivo. Inhibition of NANOG gene expression is associated with inhibition of proliferation and decreased phosphorylation of G2-related cell cycle proteins. Overexpression of NANOGP8 rescues single-cell spherogenicity when NANOG gene expression is inhibited and increases the SP in CRC. Thus, NANOGP8 can substitute for NANOG in directly promoting stemness in CRC. PMID- 23085763 TI - Temperature-dependent electrical property transition of graphene oxide paper. AB - Reduction of graphene oxide is primarily important because different reduction methods may result in graphene with totally different properties. For systematically exploring the reduction of graphene oxide, studies of the temperature-dependent electrical properties of graphene oxide (GO) are urgently required. In this work, for the first time, broadband dielectric spectroscopy was used to carry out an in situ investigation on the transition of the electrical properties of GO paper from -40 to 150 degrees C. The results clearly reveal a very interesting four-stage transition of electrical properties of GO paper with increasing temperature: insulator below 10 degrees C (stage 1), semiconductor at between 10 and 90 degrees C (stage 2), insulator at between 90 and 100 degrees C (stage 3), and semiconductor again at above 100 degrees C (stage 4). Subsequently, the transition mechanism was discussed in combination with detailed dielectric properties, microstructure and thermogravimetric analyses. It is suggested that the temperature-dependent transition of electronic properties of GO is closely associated with the ion mobility, water molecules removal and the reduction of GO in the GO paper. Most importantly, the present work clearly demonstrates the reduction of GO paper starts at above 100 degrees C. PMID- 23085764 TI - Through the lens of culture: quality of life among Latina breast cancer survivors. AB - Latinas have lower quality of life than Caucasian cancer survivors but we know little about factors associated with quality of life in this growing population. Bilingual staff conducted interviews with a national cross-sectional sample of 264 Latina breast cancer survivors. Quality of life was measured using the Functional Assessment of Cancer Therapy-Breast (FACT-B). Regression models evaluated associations between culture, social and medical context and overall quality of life and its subdomains. Latina survivors were 1-5 years post diagnosis and reported a lower mean quality of life score compared to other published reports of non-Latina survivors (M = 105; SD = 19.4 on the FACT-B). Culturally based feelings of breast cancer-related stigma and shame were consistently related to lower overall quality of life and lower well-being in each quality of life domain. Social and medical contextual factors were independently related to quality of life; together cultural, social and medical context factors uniquely accounted for 62 % of the explained model variance of overall quality of life (Adjusted R (2) = 0.53, P < 0.001). Similar relationships were seen for quality of life subdomains in which cultural, social, and medical contextual variables independently contributed to the overall variance of each final model: physical well-being (Adjusted R (2) = 0.23, P < .001), social well being (Adjusted R (2) = 0.51, P < 0.001), emotional well-being (Adjusted R (2) = 0.28, P < 0.001), functional well-being (Adjusted R (2) = 0.41, P < 0.001), and additional breast concerns (Adjusted R (2) = 0.40, P < 0.001). Efforts to improve Latinas' survivorship experiences should consider cultural, social, and medical contextual factors to close existing quality of life gaps between Latinas and other survivors. PMID- 23085766 TI - Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. AB - Aberrant activation of the mammalian target of rapamycin (mTOR) signaling plays an important role in breast cancer progression and represents a potential therapeutic target for breast cancer. In this study, we report the impact of the investigational drug MLN0128, a potent and selective small molecule active-site TORC1/2 kinase inhibitor, on tumor growth and metastasis using human breast cancer xenograft models. We assessed in vitro antiproliferative activity of MLN0128 in a panel of breast cancer cell lines. We next evaluated the impact of MLN0128 on tumor growth, angiogenesis and metastasis using mammary fat pad xenograft models of a non-VEGF (ML20) and a VEGF-driven (MV165) MCF-7 sublines harboring PIK3CA mutations. MLN0128 potently inhibited cell proliferation in various breast cancer cell lines harboring PIK3CA (IC(50): 1.5-53 nM), PTEN (IC(50): 1-149 nM), KRAS, and/or BRAF mutations (IC(50): 13-162 nM), and in human endothelial cells (IC(50): 33-40 nM) in vitro. In vivo, MLN0128 decreased primary tumor growth significantly in both non-VEGF (ML20; p = 0.05) and VEGF-driven MCF 7 (MV165; p = 0.014) xenograft models. MLN0128 decreased the phosphorylation of Akt, S6, 4E-BP1, and NDRG1 in both models. In contrast, rapamycin increased Akt activity and failed to reduce the phosphorylation of 4E-BP1, PRAS40, and NDRG1. VEGF-induced lung metastasis in MV165 is inhibited by MLN0128 and rapamycin. In conclusion, MLN0128 inhibits TORC1/2-dependent signaling in preclinical models of breast cancer. MLN0128 appears to be superior in blocking mTORC1/2 signaling in contrast to rapamycin. Our findings support the clinical research of MLN0128 in patients with breast cancer and metastasis. PMID- 23085767 TI - Associations between TCF7L2 polymorphisms and risk of breast cancer among Hispanic and non-Hispanic white women: the Breast Cancer Health Disparities Study. AB - The transcription factor 7-like 2 (TCF7L2) gene is part of the Wnt/beta-catenin signaling pathway and plays a critical role in cell development and growth regulation. TCF7L2 variants rs12255372 and rs7903146 have been associated with risk of Type 2 diabetes. Few epidemiological studies have examined the association between TCF7L2 and breast cancer risk. We investigated the associations between 25 TCF7L2 single nucleotide polymorphisms (SNPs) and breast cancer in Hispanic and non-Hispanic white (NHW) women from the 4-Corner's Breast Cancer Study, the San Francisco Bay Area Breast Cancer Study, and the Mexico Breast Cancer Study. A total of 4,703 Hispanic (2,093 cases, 2,610 controls) and 3,031 NHW (1,431 cases, 1,600 controls) women were included. Odds ratios (OR) and 95 % confidence intervals (CI) were calculated using logistic regression to estimate the association between the TCF7L2 SNPs and breast cancer risk. We also examined effect modification by self-reported ethnicity, genetic admixture, and diabetes history. After adjusting for multiple comparisons, four TCF7L2 SNPs were significantly associated with breast cancer overall: rs7903146 (OR(TT) 1.24; 95 % CI 1.03-1.49), rs3750805 (OR(AT/TT) 1.15; 95 % CI 1.03-1.28), rs7900150 (OR(AA) 1.23; 95 % 1.07-1.42), and rs1225404 (OR(CC) 0.82; 95 % 0.70-0.94). Among women with a history of diabetes, the TT genotype of rs3750804 increased breast cancer risk (OR, 2.46; 95 % CI 1.28-4.73). However, there was no association among women without a diabetes history (OR, 1.06; 95 % CI 0.85-1.32). We did not find significant interactions by ethnicity or by genetic admixture. Findings support an association between TCF7L2 and breast cancer and history of diabetes modifies this association for specific variants. PMID- 23085768 TI - Insulin-like growth factor-1, insulin-like growth factor-binding protein-3, growth hormone, and mammographic density in the Nurses' Health Studies. AB - Higher circulating insulin-like growth factor I (IGF-1) levels have been associated with higher mammographic density among women in some, but not all studies. Also, few studies have examined the association between mammographic density and circulating growth hormone (GH) in premenopausal women. We conducted a cross-sectional study among 783 premenopausal women and 436 postmenopausal women who were controls in breast cancer case-control studies nested in the Nurses' Health Study (NHS) and NHSII. Participants provided blood samples in 1989 1990 (NHS) or in 1996-1999 (NHSII), and mammograms were obtained near the time of blood draw. Generalized linear models were used to assess the associations of IGF 1, IGF-binding protein-3 (IGFBP-3), IGF-1:IGFBP-3 ratio, and GH with percent mammographic density, total dense area, and total non-dense area. Models were adjusted for potential confounders including age and body mass index (BMI), among others. We also assessed whether the associations varied by age or BMI. In both pre- and postmenopausal women, percent mammographic density was not associated with plasma levels of IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 ratio. In addition, GH was not associated with percent density among premenopausal women in the NHSII. Similarly, total dense area and non-dense area were not significantly associated with any of these analytes. In postmenopausal women, IGF-1 was associated with higher percent mammographic density among women with BMI <25 kg/m(2), but not among overweight/obese women. Overall, plasma IGF-1, IGFBP-3, and GH levels were not associated with mammographic density in a sample of premenopausal and postmenopausal women. PMID- 23085769 TI - Exercise efficiency is reduced by mitochondrial uncoupling in the elderly. AB - A reduction in exercise efficiency accompanies ageing in humans. Here we evaluated the impact of changes in the contractile-coupling and mitochondrial coupling efficiencies on the reduction in exercise efficiency in the elderly. Nine adult (mean, 38.8 years old) and 40 elderly subjects (mean, 68.8 years old) performed a cycle ergometer test to measure O2 uptake and leg power output up to the aerobic limit ( ). Reduced leg power output per unit O2 uptake was reflected in a drop in delta efficiency (epsilonD) from 0.27 +/- 0.01 (mean +/- SEM) in adults to 0.22 +/- 0.01 in the elderly group. Similar declines with age were apparent for both the leg power output at and the ATP generation capacity (ATPmax) determined in vivo using (31)P magnetic resonance spectroscopy. These similar declines resulted in unchanged contractile-coupling efficiency values (epsilonC) in the adult (0.50 +/- 0.05) versus the elderly group (0.58 +/- 0.04) and agreed with independent measures of muscle contractile-coupling efficiency in human quadriceps (0.5). The mitochondrial-coupling efficiency calculated from the ratio of delta to contractile-coupling efficiencies in the adults (epsilonD/epsilonC = 0.58 +/- 0.08) corresponded to values for well-coupled mitochondria (0.6); however, epsilonD/epsilonC was significantly lower in the elderly subjects (0.44 +/- 0.03). Conversion of ATPmax per mitochondrial volume (ATPmax/Vv[mt,f]) reported in these groups into thermodynamic units confirmed this drop in mitochondrial-coupling efficiency from 0.57 +/- 0.08 in adults to 0.41 +/- 0.03 in elderly subjects. Thus, two independent methods revealed that reduced mitochondrial-coupling efficiency was a key part of the drop in exercise efficiency in these elderly subjects and may be an important part of the loss of exercise performance with age. PMID- 23085771 TI - Anticancer activity of small amphipathic beta2,2-amino acid derivatives. AB - We report the anticancer activity from screening of a series of synthetic beta(2,2)-amino acid derivatives that were prepared to confirm the pharmacophore model of short cationic antimicrobial peptides with high anti-Staphylococcal activity. The most potent derivatives against human Burkitt's lymphoma (Ramos) cells displayed IC(50) values below 8 MUM, and low toxicity against human red blood cells (EC(50) > 200 MUM). A more than 5-fold preference for Ramos cancer cells compared to human lung fibroblasts (MRC-5 cells) was also obtained for the most promising beta(2,2)-amino acid derivative 3-amino-N-(2-aminoethyl)-2,2 bis(naphthalen-2-ylmethyl)propanamide (5c). Screening of 5c at the National Cancer Institute (NCI, USA) confirmed its anticancer potency and revealed a very broad range of anticancer activity with IC(50) values of 0.32-3.89 MUM against 59 different cancer cell lines. Highest potency was obtained against the colon cancer cell lines, a non-small cell lung cancer, a melanoma, and three leukemia cell lines included in the NCI screening panel. The reported beta(2,2)-amino acid derivatives constitute a promising new class of anticancer agents based on their high anticancer potency, ease of synthesis, mode-of-action, and optimized pharmacokinetic properties compared to much larger antimicrobial peptides. PMID- 23085772 TI - Investigations on the 4-quinolone-3-carboxylic acid motif. 6. Synthesis and pharmacological evaluation of 7-substituted quinolone-3-carboxamide derivatives as high affinity ligands for cannabinoid receptors. AB - Within our studies on structure-activity relationships of 4-quinolone-3 carboxamides as cannabinoid ligands, a new series of compounds characterized by a fluoro or phenylthio group at 7-position and different substituents at N1 and carboxamide nitrogen were synthesized and evaluated for their binding ability to cannabinoid type 1 (CB1) and type 2 (CB2) receptors. Most of the compounds showed affinity for one or both cannabinoid receptors at nanomolar concentration, with K(i)(CB1) and K(i)(CB2) values ranging from 2.45 to >10,000 nM and from 0.09 to 957 nM, respectively. The N-(3,4-dichlorobenzyl)amide derivatives 27 and 40 displayed relatively low affinity, but high selectivity towards the CB1 receptor. Compounds 4 and 40, a CB2 and a CB1 ligand, respectively, behaved as partial agonists in the [(35)S]GTPgammaS assay. They showed very low permeability through (MDCK-MDR1) cells and might, therefore, represent possible lead structures for further optimization in the search for cannabinoid ligands unable to cross the blood-brain barrier. PMID- 23085773 TI - Microwave-assisted synthesis of hydroxyphenyl nitrones with protective action against oxidative stress. AB - Oxidative stress plays an important role in neuronal death in neurodegenerative disorders such as Parkinson's disease (PD). Hydroxyphenyl nitrones, derivatives of the nitrone spin trap alpha-phenyl-N-tert-butylnitrone (PBN), were synthesized and their antioxidant, anti-inflammatory and neuroprotective activity in neural cells evaluated. These hydroxyphenyl nitrones 5-7 were synthesized by reaction of the corresponding hydroxybenzaldehyde with N-tert-butyl hydroxylamine under microwave irradiation. They showed good peroxyl free radical scavenger capacities, analyzed by oxygen radical absorbance capacity (ORAC). Also inhibited peroxynitrite-mediated tyrosine nitration of alpha-synuclein in vitro and protected human neuroblastoma (SH-SY5Y) cells against SIN-1 and 6-OHDA toxicity when micromolar concentrations were used. Besides, the hydroxyphenyl nitrones evaluated showed anti-inflammatory activity modulating nitrite production in primary neural cell cultures of astrocytes and microglia treated with lipopolysaccharide (LPS), a potent inflammatory agent. These experimental data suggest a potential therapeutic use of these hydroxyphenyl nitrones against oxygen and nitrogen reactive species involved in neurodegenerative pathology. PMID- 23085774 TI - Ring-opening polymerization reaction of polyhedral oligomeric silsesquioxanes (POSSs) for preparation of well-controlled 3D skeletal hybrid monoliths. AB - A novel, facile, highly flexible process was developed for the first preparation of well-controlled 3D skeletal polyhedral oligomeric silsesquioxane (POSS)-based functionalizable porous hybrid monoliths via ring-opening polymerization. This approach represents an ideal pathway for easy access to a series of hybrid monoliths with high separation efficiency in cLC. PMID- 23085776 TI - Pharmacokinetics of 400 mg of raltegravir once daily in combination with atazanavir/ritonavir plus two nucleoside/nucleotide reverse transcriptase inhibitors. PMID- 23085770 TI - Secreted and transmembrane wnt inhibitors and activators. AB - Signaling by the Wnt family of secreted glycoproteins plays important roles in embryonic development and adult homeostasis. Wnt signaling is modulated by a number of evolutionarily conserved inhibitors and activators. Wnt inhibitors belong to small protein families, including sFRP, Dkk, WIF, Wise/SOST, Cerberus, IGFBP, Shisa, Waif1, APCDD1, and Tiki1. Their common feature is to antagonize Wnt signaling by preventing ligand-receptor interactions or Wnt receptor maturation. Conversely, the Wnt activators, R-spondin and Norrin, promote Wnt signaling by binding to Wnt receptors or releasing a Wnt-inhibitory step. With few exceptions, these antagonists and agonists are not pure Wnt modulators, but also affect additional signaling pathways, such as TGF-beta and FGF signaling. Here we discuss their interactions with Wnt ligands and Wnt receptors, their role in developmental processes, as well as their implication in disease. PMID- 23085775 TI - Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance. AB - OBJECTIVES: To determine whether pan-protease inhibitor (PI)-resistant virus populations are composed predominantly of viruses with resistance to all PIs or of diverse virus populations with resistance to different subsets of PIs. METHODS: We performed deep sequencing of plasma virus samples from nine patients with high-level genotypic and/or phenotypic resistance to all licensed PIs. The nine virus samples had a median of 12 PI resistance mutations by direct PCR Sanger sequencing. RESULTS: For each of the nine virus samples, deep sequencing showed that each of the individual viruses within a sample contained nearly all of the mutations detected by Sanger sequencing. Indeed, a median of 94.9% of deep sequence reads had each of the PI resistance mutations present as a single chromatographic peak in the Sanger sequence. A median of 5.0% of reads had all but one of the Sanger mutations that were not part of an electrophoretic mixture. CONCLUSIONS: The collinearity of PI resistance mutations in the nine virus samples demonstrated that pan-PI-resistant viruses are able to replicate in vivo despite their highly mutated protease enzymes. We hypothesize that the marked collinearity of PI resistance mutations in pan-PI-resistant virus populations results from the unique requirements for multi-PI resistance and the extensive cross-resistance conferred by many of the accessory PI resistance mutations. PMID- 23085777 TI - Treatment of Candida famata bloodstream infections: case series and review of the literature. AB - OBJECTIVES: Candida famata (also known as Debaryomyces hansenii and Torulopsis candida) is a commensal yeast found in cheese, dairy products and the environment. C. famata accounts for 0.2%-2% of invasive candidiasis. The purpose of this study was to provide an overview of the treatment of C. famata bloodstream infections. METHODS: The clinical course of two hospitalized patients who developed C. famata fungaemia within 2 weeks of each other was summarized along with available data regarding in vitro susceptibility patterns, genotyping and clinical outcomes of these cases compared with the published literature. RESULTS AND CONCLUSIONS: C. famata appears to exhibit reduced susceptibility to echinocandins and azoles, particularly in the setting of prior antifungal exposure. The removal of indwelling central venous catheters and prompt initiation of therapy with liposomal amphotericin B is recommended for successful treatment of C. famata fungaemia, particularly in immunocompromised patients. These cases also help provide justification for routine antifungal susceptibility testing in patients with candidaemia to guide optimal antifungal therapy. PMID- 23085778 TI - The structure and low-energy phonons of the nonferroelectric mixed perovskite: BaMg1/3Ta2/3O3. AB - The structure of BaMg(1/3)Ta(2/3)O(3) (BMT) has been studied using x-ray scattering. The phonons have been measured and the results are similar to those of other materials with a perovskite structure such as PbMg(1/3)Nb(2/3)O(3) (PMN). The acoustic and lowest energy optic branches were measured but it was not possible to measure the branches of higher energy, possibly this is because they largely consist of oxygen motions. High-resolution inelastic measurements also showed that the diffuse scattering was strictly elastic and not directly related to the phonon spectra. Diffuse scattering was observed in BMT near the (H +/- 1/2, K +/- 1/2, L +/- 1/2) points in the Brillouin zone and these had a characteristic cube shape. This arises from ordering of the B-site ions in BMT. Additional experiments revealed the diffuse scattering in BMT similar in shape to Bragg reflections at wavevectors of the form (H +/- 1/3, K +/- 1/3, L +/- 1/3). Such reflections were also observed by Lufaso (2004 Chem. Mater. 16 2148) from powders and suggest that this structure of BMT consists of four differently oriented domains of a trigonal structure and results from a different ordering of the B-site ions from that responsible for the scattering at the (H +/- 1/2, K +/- 1/2, L +/- 1/2) points. The results lead us to suggest that for BMT single crystals the bulk has the properties of a cubic perovskite, whereas the surface may have quite different structure from that of the bulk. This difference resembles the behaviour of cubic relaxors like PMN and PMN doped by PbTiO(3), where significant surface effects have been reported. PMID- 23085779 TI - Functionalized gold magic clusters: Au25(SPhNH2)17. AB - New Au(25) nanoclusters stabilized by heterotopic 4-aminothiophenolate ligands (HSPhNH(2)) have been isolated with a yield of ~70%. The nanoclusters formula determined by ESI-MS is Au(25)(SPhNH(2))(17), with the 18(th) position occupied by an amine or DMF molecules to close their electronic shell. PMID- 23085780 TI - Managing chronic myeloid leukemia patients intolerant to tyrosine kinase inhibitor therapy. AB - The outcomes for patients with chronic myeloid leukemia have improved dramatically with the development and availability of BCR-ABL1 tyrosine kinase inhibitors (TKIs) over the past decade. TKI therapy has a superior safety profile compared with the previous standard of care, interferon-alpha, and most adverse events (AEs) observed with front-line and second-line TKI treatment are managed with supportive care. However, some patients are intolerant to TKI therapy and experience AEs that cannot be managed through dose reduction or symptomatic treatment. Careful management of AEs helps patients to remain adherent with treatment and increases their chances for successful outcomes. Proactive vigilance for potential AEs and treatment strategies that reduce symptom burden will help to minimize patient intolerance. This review discusses the most common AEs associated with intolerance to TKI therapy and treatment strategies to help manage patients at risk for or experiencing these events. PMID- 23085781 TI - Clinical characteristics and predictors of progression of chronic kidney disease in autosomal dominant polycystic kidney disease: a single center experience. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. The course and progression of the disease is highly variable. In this study, we aimed to investigate the impact of clinical characteristics and basic biochemical parameters on progression of chronic kidney disease (CKD) in ADPKD patients. MATERIALS AND METHODS: A total of 323 consecutive patients with ADPKD were enrolled into the study and followed with a mean duration of 100 +/- 38 months. Patients were grouped as rapid progressors (RP) and slow progressors (SP) according to median rates of decline in glomerular filtration rate (DeltaGFR) per year, namely 1 ml/min/year. RESULTS: History of macroscopic hematuria, urinary stone and smoking were more common in male patients; hepatic and other organ cysts were more common in female patients. ?GFR/year was similar between males and females [0.95 (0-3.02) vs. 1.11 (0.10 2.74) ml/min/year, p = 0.21]. History of smoking and pack-year of cigarettes smoked were significantly higher in the RP compared to the SP group (36 vs. 18%, p = 0.01 and 5.24 +/- 1.20 vs. 3 +/- 1.32 pack-year, p = 0.02, respectively). Baseline 24 h-proteinuria was found to be significantly correlated with the percent decline of GFR (?%GFR) per year (r = 0.303, 0.001). In Cox regression analysis for predicting the progression of CKD, age, hypertension, urinary stone and proteinuria were retained as the significant independent factors predicting progression of CKD in the model. CONCLUSION: Baseline proteinuria was significantly correlated with ?%GFR per year. Hypertension and proteinuria were found to be the major treatable risk factors for the progression of CKD in ADPKD patients. PMID- 23085782 TI - Is the estimation of daily urinary sodium excretion in patients with chronic kidney disease sufficiently accurate in clinical practice? PMID- 23085785 TI - Invited lectures related to patient-centered outcomes research. AB - The third PANDA symposium on Anesthesia and Neurodevelopment in Children included a session on Patient Centered Outcomes Research. Three speakers were invited to discuss SmartTots, a private-public partnership between IARS and FDA, Wake Up Safe, a patient safety organization and lastly, NICHD/NIH funding for training in research. The session provided information related to ongoing efforts to improve outcome and safety of anesthesia care in children and introduced potential sources and mechanisms of federal and non-federal funding for research related to anesthetic neurotoxicity in the developing brain. PMID- 23085784 TI - Anesthetics interfere with the polarization of developing cortical neurons. AB - Numerous studies from the clinical and preclinical literature indicate that general anesthetic agents have toxic effects on the developing brain, but the mechanism of this toxicity is still unknown. Previous studies have focused on the effects of anesthetics on cell survival, dendrite elaboration, and synapse formation, but little attention has been paid to possible effects of anesthetics on the developing axon. Using dissociated mouse cortical neurons in culture, we found that isoflurane delays the acquisition of neuronal polarity by interfering with axon specification. The magnitude of this effect is dependent on isoflurane concentration and exposure time over clinically relevant ranges, and it is neither a precursor to nor the result of neuronal cell death. Propofol also seems to interfere with the acquisition of neuronal polarity, but the mechanism does not require activity at GABAA receptors. Rather, the delay in axon specification likely results from a slowing of the extension of prepolarized neurites. The effect is not unique to isoflurane as propofol also seems to interfere with the acquisition of neuronal polarity. These findings demonstrate that anesthetics may interfere with brain development through effects on axon growth and specification, thus introducing a new potential target in the search for mechanisms of pediatric anesthetic neurotoxicity. PMID- 23085786 TI - Elective procedures and anesthesia in children: pediatric surgeons enter the dialogue on neurotoxicity questions, surgical options, and parental concerns. AB - The Pediatric Anesthesia NeuroDevelopment Assessment research group at Columbia University Medical Center Department of Anesthesiology has conducted biannual national Symposia since 2008 to evaluate study data and invigorate continued thinking about unresolved issues of pediatric anesthesia neurotoxicities. The third Symposium extended the dialogue between pediatric anesthesiologists and surgeons in panel presentations and discussions by four surgical specialists. This paper reports the prevailing opinions expressed by a pediatric general surgeon, urologist, plastic surgeon and ophthalmologist and explores factors related to delayed operative intervention, need for multiple procedures, and parental concerns. PMID- 23085788 TI - [Overweight and obesity in Peru: urgent need to have a public health policy for their control]. PMID- 23085789 TI - [Revista Peruana de Medicina Experimental y Salud Publica: generating a publication culture in Peru]. PMID- 23085787 TI - Which symptoms matter? Self-report and observer discrepancies in repressors and high-anxious women with metastatic breast cancer. AB - Clinicians working with cancer patients listen to them, observe their behavior, and monitor their physiology. How do we proceed when these indicators do not align? Under self-relevant stress, non-cancer repressors respond with high arousal but report low anxiety; the high-anxious report high anxiety but often have lower arousal. This study extends discrepancy research on repressors and the high-anxious to a metastatic breast cancer sample and examines physician rating of coping. Before and during a Trier Social Stress Test (TSST), we assessed affect, autonomic reactivity, and observers coded emotional expression from TSST videotapes. We compared non-extreme (N = 40), low-anxious (N = 16), high-anxious (N = 19), and repressors (N = 19). Despite reported low anxiety, repressors expressed significantly greater Tension or anxiety cues. Despite reported high anxiety, the high-anxious expressed significantly greater Hostile Affect rather than Tension. Physicians rated both groups as coping significantly better than others. Future research might productively study physician-patient interaction in these groups. PMID- 23085790 TI - [Overweight and obesity: prevalence and determining social factors of overweight in the Peruvian population (2009-2010)]. AB - OBJECTIVES: Estimate the prevalence of overweight, obesity and the determining social factors of overweight in the Peruvian population. MATERIALS AND METHODS: A cross-cut study was conducted which included family members from homes in the sample of the National Household Survey, 2009-2010. Stratified random and multistage sampling was used. The sample included 69 526 members; the anthropometric measurements were done based on the international methodology. To evaluate overweight and obesity, weight-for-height (children <5 years), BMI for age (children and teenagers from 5 to 19 years old), and BMI for adults were used. An analysis of complex samples was made in SPSS and the weighting factor was adjusted. Descriptive statistics and logistic regression were calculated with a 95% confidence interval. RESULTS: Overweight and obesity were higher in young adults (62.3%) and lower in children <5 years old (8.2%). The determining social factors for overweight according to age group were: not being poor (child <5 years old, children 5-9 years old, teenagers and the elderly), living in urban areas (child <5 years old, teenagers, young adults, adults and the elderly) and being a woman (children 5-9 years old, adults and the elderly). CONCLUSIONS: Overweight and obesity are indeed a public health issue in Peru. Not being poor and living in urban areas are determining social factors of overweight among Peruvian people. PMID- 23085791 TI - [Consumption of chispitas(r) multimicronutrient supplements and anemia in 6 - 35 month-old children: cross-cut study in the context of a populational health intervention in Apurimac, Peru]. AB - OBJECTIVES: To assess the implementation of the Universal "Chispitas(r)" Multimicronutrient Supplement Program in Apurimac by determining the quantity and quality of sachets consumed and their connection with anemia, in 6 - 35-month-old children. MATERIALS AND METHODS: A crosscut study was conducted by using a multistage sample in 2010. Anemia was considered to be related to altitude adjusted hemoglobin values below 110 g/L. The consumption of multimicronutrients was classified as follows: less than 30; 30 to 59, and 60 or more sachets. The quality of consumption was considered to be adequate when the mother indicated that the child ate all his food with the supplement. The rationale for prevalence (RPa) adjusted by Poisson regression was calculated. RESULTS: 714 participants were included, 25.3% of which lived in poor houses and 59.2% in extreme poverty; 52.6% lived at over 3000 m of altitude. The prevalence of anemia was 51.3% (CI95%: 47.1-55.4%), 5.4% did not receive intervention; 60.3% consumed 60 or more sachets and 49.0% consumed them adequately. No association between the number of sachets received or consumed and anemia (p<0.05) was found. Children who consumed the supplement adequately showed lower prevalence of anemia than those who did not (RPa: 0.81; CI95%: 0.68-0.96) CONCLUSIONS: In order to reduce the prevalence of anemia, attention should not only focus on giving or consuming the necessary quantity of multimicronutrients, but also on ensuring that the consumption process is adequate, and work needs to be done in this area in order to improve this intervention. PMID- 23085792 TI - [Change in nutritional status over the course of antituberculosis treatment in current and past beneficiaries of the program PANTBC]. AB - OBJECTIVES: Analyze the nutritional changes among current and old beneficiaries of the Food and Nutrition Program for Outpatients with Tuberculosis and their Family (PANTBC, Spanish acronym). MATERIALS AND METHODS: A secondary analysis was conducted based on the anthropometric measurements with the body mass index (BMI) in current and old beneficiaries of the PANTBC program. The measurements were taken at the baseline, second and fifth or sixth month, and the distribution of the nutritional status was analyzed at baseline as compared to the endpoint (McNemar-Bowker test). RESULTS: Information about 409 current beneficiaries and 110 old beneficiaries were included. A progressive decline in low weight as well as an increase in overweight were observed in both current and old beneficiaries (IMC<18.5). The results of the third measurement showed that 57.7% of current beneficiaries who started with low weight ended up with normal weight, while 20.7% of those who started with normal weight ended up with overweight. The analysis of the nutritional status at baseline compared to the endpoint showed changes in distribution (p<0.05). CONCLUSIONS: Across the PANTBC program, there is a variation of beneficiaries' nutritional status, showing a tendency to go from a lower level to a higher level of BMI. PMID- 23085793 TI - [Hemoglobin levels in pregnant women seen in health care centers of the Peruvian Ministry of Health, 2011]. AB - OBJECTIVES: Determine hemoglobin levels and prevalence of anemia in pregnant women seen in health care centers of the Ministry of Health at national level. MATERIALS AND METHODS: Cross-cut study where the database of the Information System on the Nutritional Health of Children under 5 and Pregnant Women (SIEN) were analyzed. 287 691 records of pregnant women examined at the health care centers of the Peruvian Ministry of Health in 2011 were included, hemoglobin levels corrected by height, age, gestational age, altitude and prevalence of anemia (light, moderate and serious) were analyzed. Descriptive statistics and the chi-square method were used. RESULTS: Nationwide prevalence of anemia in pregnant women was 28.0%, with mild anemia being at 25.1%, moderate anemia at 2.6% and severe anemia at 0.2%. Hemoglobin levels are higher in older and younger women during the first months of pregnancy, prevalence of anemia decreases with altitude. Furthermore, prevalence is higher in the Highland regions. Huancavelica was the region with higher prevalence of anemia (53.6%), followed by Puno with 51.0%. CONCLUSIONS: Hemoglobin levels get higher as the mother gets older, and they go down in keeping with the gestation trimester and altitude. Huancavelica has the highest prevalence of anemia in pregnant women. PMID- 23085794 TI - [Identification of tachypnea and subcostal retractions as clinical signs for the diagnosis of community-acquired pneumonia among children: systematic review and meta-analysis]. AB - OBJECTIVES: Determine whether tachypnea and subcostal retractions can be efficient predictors for the diagnosis of Community-Acquired Pneumonia (CAP) among children. MATERIALS AND METHODS: These were the databases used: PubMed, LILACS, The African Journal Database and The Cochrane Central Library. Original studies were included which assessed the diagnostic performance of the clinical criteria for tachypnea or subcostal retraction defined in accordance with the criteria of the World Health Organization (OMS) for CAP diagnosis in children <= 5 with cough and fever. The likelihood ratio (LR), the diagnosis odds ratio (DOR), and their respective confidence intervals at 95% (IC95%) were estimated for each clinical test. RESULTS: 975 studies were found, eight were included in the review. 4740 patients were enrolled and 3584 (75%) were analyzed, 916 (19%) of which had a CAP diagnosis. When data were combined, tachypnea had a positive LR of 3.16, (95% CI 2.11-4.73) and a negative LR of 0.36 (95% CI 0.23-0.57). The DOR was 10.63 (95% CI 4.4-25.66, I2=93%). When subcostal retractions were analyzed, a positive LR of 2.49 (95%CI 1.41-4.37) and a negative LR of 0.59 (95%CI 0.4-0.87) were obtained. The DOR was 5.32 (95%CI 1.88-15.05, I2=89%). CONCLUSIONS: The presence or absence of tachypnea and subcostal retractions can be used in CAP diagnosis; it is worth considering the relative uncertainty in its diagnostic power and relatively modest LR. The confidence of these results is low due to the inadequate quality of the related evidence. PMID- 23085795 TI - [Overweight and obesity in indigenous nahuas from Ixtaczoquitlan, Veracruz, Mexico]. AB - The study was aimed at determining the prevalence of overweight and obesity in indigenous nahuas from Ixtaczoquitlan, Veracruz, Mexico. For this purpose, a cross-cut study was conducted between 2010 and 2011, in which the body mass index (BMI) was calculated. To define overweight and obesity, the categories of the World Health Organization (WHO) and the Mexican Official Standard (NOM, Spanish acronym) were used. 227 nahuas (77,5% women) were included. According to WHO?s guidelines, the rate for overweight among nahuas was 41%, and 36.5% for obesity; according to NOM, it was 11.4 and 69.2% respectively. In conclusion, the prevalence of overweight and obesity among indigenous nahuas is high. Studies should be conducted to determine the prevalence and risk factors in order to develop prevention strategies based on this information to improve the health quality of these populations. PMID- 23085796 TI - [Use of resources and costs associated to fractures in Spanish women]. AB - The objective of the study was to determine the use of resources and costs due to bone fractures in Spanish women above 50 years of age in the population scope. An observational and retrospective study was conducted in six primary care centers and two urban hospitals in Spain. Socio-demographic and co-morbidity data, use of resources (primary care consultations, complementary tests, medications, specialized care, hospitalizations, visits, urgencies), costs and productivity losses were registered. Records of 19 022 women were included, 7% showed some type of fracture between 2003 and 2007. Fractures were mostly associated with osteoporosis (OR: 3.2), fibromyalgia (OR: 2.4) and thyroid changes (OR: 2.2). In the corrected model, the total cost for patients who had a fracture was USD 3727 compared to USD 2705.5 (p<0.001) for those who did not have it. Patients with a fracture generate a greater use of resources, sanitation costs and work productivity losses. PMID- 23085797 TI - [Consequences of obesity in children and teenagers: a problem that requires attention]. AB - Obesity is a worldwide pandemic and children are a vulnerable group. In America, it was estimated that in 2010, 15.2% of 18 year-old children could suffer from this. Obesity in children and teenagers has a negative impact on health and on the load of diseases at this stage of life, and later on in adulthood, having a negative impact on the economy of a country due to the rise of risks of chronic diseases, health expenses and indirect costs as a result of the disease. Peru is going through an epidemiological transition, with unsolved malnutrition problems and high child obesity rates (10% of children under five), thus being one of the countries with a higher increase of child obesity in recent years in Latin America. Childhood and adolescence are considered critical periods because eating habits and physical activity start at this point; and because most obese children and teenagers will maintain those habits until they reach adulthood. For this reason, it is essential to seek strategies and interventions that prevent overweight and obesity among children and teenagers in order to improve the health conditions of a country. PMID- 23085798 TI - [Determining factors of overweight and obesity in children at school age in Peru]. AB - Obesity in children at school age is an increasing problem in Peru. It concentrates in urban areas, mainly in Lima where one out of three children is overweight. An initial study in 80 schools in Lima showed that the lack of physical activity would have a greater impact on overweight and obesity in school children than the amount of food intake. More detailed studies are required. In spite of the limited information available regarding its determining factors, it is necessary to implement culturally-sensitive measures to fight this problem as part of the current nutritional policies, and prevent the problem from spreading, making sure the sustainability of the health system is not affected. PMID- 23085799 TI - [Transitions in context: findings related to rural-to-urban migration and chronic non-communicable diseases in Peru]. AB - In order to better understand the emergence of chronic non-communicable diseases in low- and middle-income countries this article seeks to present, in context, different transitional processes which societies and populations are currently undergoing. Relevant factors for specific contexts such as Peru are described, including internal migration, urbanization and profiles of adversity in early life, all of them linked to chronic non-communicable diseases, including obesity and overweight. The capacity-load model, which considers chronic disease risk in adulthood as a function of two generic traits, metabolic capacity and metabolic load, is described. The contribution of rural-to-urban migration to this problem is also presented. Finally, these topics are framed within pending challenges for public health in Peru. PMID- 23085800 TI - [How to feed children? Healthy eating behaviors starting at childhood]. AB - Interventions to prevent malnutrition or overweight in children focus on the diet, and give little attention to the behaviors of their caretakers. In their first two years of life, children adopt practices that are embedded in their environment and the behaviors of their caretakers, thus turning into nutrition patterns that will persist during their lifetimes. Therefore, children and caretakers establish a relationship in which they recognize, construe and respond to verbal and non verbal communication signs. Feeding a child by adopting a "responsive" behavior in which caretakers provide guidance and structure, and respond to children's signs of hunger and satiety promotes self-regulation and children's awareness of healthy nutrition. In this article, we give recommendations to include responsive nutrition and model healthy eating behaviors in nutritional interventions. PMID- 23085801 TI - [Food and diet factors associated to child obesity: recommendations for preventing it in children under two years of age]. AB - Several factors leading to obesity have been identified, which start at very early stages of life. Although there are genetic contributors and socioeconomic and racial disparities in the prevalence of overweight and obesity, the problem is universal. Children's weight has been associated to multiple specific diet factors and these, in turn, are associated to specific "parent feeding practices" (PAPP, Spanish abbreviation). Parents or caretakers determine patterns that are set at an early stage in life, and the weight before the first two years of age already predicts future overweight and obesity. Absence of breastfeeding and low food quality, consumption patterns and food preferences in the first two years of life are highly associated to PAPP and can, therefore, be modified. In this article, we will examine the diet factors and the diet-related practices that have been associated to child obesity, and are potentially modifiable, so that they can be used as a potential guide for intervention goals in the prevention of child obesity. PMID- 23085802 TI - [Secondary vasculitis to infection by Fasciola hepatica]. AB - There is a case of a 38 year-old male patient coming from an area where hepatic fascioliasis is endemic in Peru. He was hospitalized because he showed 4 weeks of symptoms like fever, intense myalgias, erythematous and painful injuries on limb extensions. The electromyography and nerve conduction velocity showed a global inflammatory myopathy. A skin biopsy showed polyarteritis nodosa-type vasculitis. During the evaluation process prior to the immunosuppressive therapy, hepatic Fasciola eggs were found in the parasitological examination of stools. The fascioliasis diagnosis was confirmed by fas2-ELISA: 0.46 (VN <0.20). Clinical symptoms started to subside after treatment with ticlabendazol. Contact with the patient was maintained for a year and there was no evidence of disease recurrence, and he was asymptomatic. PMID- 23085803 TI - [Hantavirus pulmonary syndrome (Rio Mamore virus) in the Peruvian Amazon region]. AB - Hantavirus infection is a viral zoonotic infection borne by rodents which most letal form clinical is the Hantavirus Pulmonary Syndrome (SPH, Spanish abbreviation). The Mamore River variant originates in South America and was found in rodents without any association to human diseases. Two cases of SPH were identified in the Peruvian Amazon region in November 2011. In both cases, a molecular diagnostic testing was conducted by the Instituto Nacional de Salud from Peru. A phylogenetic analysis of a viral genome fragment and a histopathological evaluation were conducted. Both patients developed adult respiratory distress syndrome and refractory shock. A patient died and another one recovered 12 days later. PMID- 23085804 TI - [Potential use of snake venom components in cancer treatment]. AB - Cancer can develop to the extent tumor cells grow, divide and grow into other body tissues. Integrins are a family of cell-surface heterodimeric receptors that play an important role in the development of tumor angiogenesis, growth and metastasis, thus being recognized as an attractive therapeutic target. Snake venom contains low-molecular weight peptides known as "disintegrins" that bind to integrins with high affinity, and prevent their action in cancer. In the next article, we go over the results of investigations, both in vitro and in vivo, which have shown promising results, thus revealing that the use of disintegrins could be a promising alternative for the treatment of different neoplasias. PMID- 23085805 TI - [Evolution of chronic malnutrition in children under five in Peru]. AB - Child chronic malnutrition is one of the main problems of Public Health in Peru, according to WHO's reference values, national prevalence is 19.5% in children under five. Child chronic malnutrition has a negative impact on people throughout their lives, limits the development of society and hinders poverty eradication. To attain the goal of reducing chronic malnutrition in children to 10% by 2016, the Peruvian government will continue to strengthen, mainly, the efficient use of economic resources, the assessment of interventions, the implementation of investigations that help define causal relations and provide information for the design of public policies, health capacity building and the articulation of different government levels. This article goes over the main interventions implemented in the country. PMID- 23085806 TI - [Native food: Peruvian plants]. PMID- 23085807 TI - [Food in ancient Peru: Haku mikumusum (let's go to eat!)]. AB - The Andean region is one of the eight world centers where plant and animal domestication originated. Given that food is a structural factor of social reality, a description is given of the close relationship that Andean men developed with their geographic surroundings, and the plants and animals they domesticated, giving rise to a remarkable culture that united the extraordinary nutritional richness of their traditional food with a food production, conservation and distribution system that led to a civilization who never experienced hunger. Some foods of ancient Peru are briefly described in the following review. PMID- 23085808 TI - [Hantavirus infection: some considerations of this new infection in Peru]. PMID- 23085809 TI - [Assaults against health workers in Tacna, Peru]. PMID- 23085810 TI - [National health investigation priorities as categories in the 2012 Scientific Congress of Medicine Students]. PMID- 23085811 TI - Tobacco consumption and genetic susceptibility to nasopharyngeal carcinoma (NPC) in Thailand. AB - BACKGROUND: The incidence of nasopharyngeal carcinoma (NPC) varies substantially worldwide, with an endemic pocket in Southeast Asia. METHOD: We assessed lifestyle and genetic factors in relation to NPC risk among 681 NPC cases and 1,078 controls from Thailand. Evaluated lifestyle factors included traditionally preserved foods, tobacco smoking, betel quid chewing, and alcohol consumption. Genetic factors included six variants implicated in a previous a genome-wide association study (GWAS) of NPC and three variants residing near the CHRNA3 and TERT genes that were linked to lung cancer risk in Asian populations. Odds ratios (OR) and 95 % confidence intervals (95 % CI) were estimated using unconditional logistic regression. RESULTS: Frequent consumption of fermented vegetables was associated with increased NPC risk (OR of consumption >=weekly vs. <=rare 1.78, 95 % CI 1.24-2.55, p (trend) = 0.005), as was tobacco smoking (p (trend) < 0.001), former and current smokers displaying OR of 1.57 (95 % CI 1.10-2.30) and 2.00 (95 % CI 1.48-2.71) compared to never smokers, respectively. Four out of six genetic variants implicated in the recent NPC GWAS were associated with NPC risk (p (trend) <= 0.03), as well as two variants (rs402710 and rs2736098) on the TERT locus at 5p15.33 (p = 0.004 and p = 0.04, respectively). CONCLUSIONS: These results strengthen our previous observation that tobacco smoking is an important risk factor of NPC in this population. Four out of six genetic variants identified in a recent NPC GWAS were confirmed, and the association noted with variants on 5p15.33 suggests that this locus is involved in NPC susceptibility, representing a novel finding in NPC epidemiology. PMID- 23085812 TI - Cohort study of workers employed in an Italian tire manufacturing plant, 1962 2004. AB - PURPOSE: To investigate mortality and bladder cancer incidence among workers of a tire manufacturing plant where antioxidants severely contaminated by beta naphthylamine were never used. METHODS: Mortality follow-up was performed of 9,501 workers first hired between 1962 when the plant started operations and 2000. Person-years of observation from 1962 to 2004, expected deaths, and standardized mortality ratios (SMR) were calculated. Follow-up for bladder cancer incidence from 1988 to 2003 was carried out, and standardized incidence ratios (SIR) were calculated. Multivariable (Poisson) analyses of bladder cancer incidence and mortality by duration of employment (DOE) and time since first employment (TSFE) were performed. RESULTS: Among men, SMRs were significantly reduced for all causes, all cancers, lung cancer, cardiovascular, and ischemic heart diseases. Bladder cancer mortality and leukemia mortality were close to expectation but increased with TSFE. Seventy-two incident cases of bladder cancer were observed (SIR = 1.15; 95 % confidence interval 0.90-1.44), and multivariable analysis suggested a possible increase in rate ratios with DOE. Among women, mortality was close to expectation, but the limited number of observed deaths prevented detailed analyses. CONCLUSIONS: No significant cancer excess was observed. A suggestion of increased risks of bladder cancer and leukemias after extended TSFE was present in men, deserving consideration as exposure to carcinogens possibly occurred early in plant operation. Furthermore, this cohort of workers is still relatively young and less than 10 % have died. There was, thus, limited power to detect small increases in risk at rare cancer sites. Further epidemiological surveillance of this cohort is planned. PMID- 23085813 TI - Relationship between anthropometric factors, radiation exposure, and colon cancer incidence in the Life Span Study cohort of atomic bomb survivors. AB - PURPOSE: We examined colon cancer risk in atomic bomb survivors to investigate whether excess body weight after the bombings alters sensitivity to radiation effects. METHODS: Of the 56,064 Japanese atomic bomb survivors with follow-up through 2002 with self-reported anthropometric data obtained from periodic mail surveys, 1,142 were diagnosed with colon cancer. We evaluated the influence of body mass index (BMI) and height on radiation-associated colon cancer risk using Poisson regression. RESULTS: We observed a similar linear dose-response relationship for the 56,064 subjects included in our analysis and the entire cohort of Japanese atomic bomb survivors [excess relative risk (ERR) per Gray (Gy) = 0.53, 95 % confidence interval (CI) 0.25-0.86]. Elevation in earliest reported BMI, BMI reported closest to colon cancer diagnosis, and time-varying BMI were associated with an elevated risk of colon cancer [relative risk (RR) per 5 kg/m(2) increase in BMI = 1.14, 95 % CI 1.03-1.26; RR = 1.16, 95 % CI 1.05 1.27; and RR = 1.15, 95 % CI 1.04-1.27, respectively]. Height was not significantly related to colon cancer risk. Inclusion of anthropometric variables in models had little impact on radiation risk estimates, and there was no evidence that sensitivity to the effect of radiation on colon cancer risk depended on BMI. CONCLUSIONS: Radiation exposure and BMI are both risk factors for colon cancer. BMI at various times after exposure to the atomic bombings does not significantly influence the relationship between radiation dose and colon cancer risk, suggesting that BMI and radiation impact colon cancer risk independently of each other. PMID- 23085814 TI - Insulin-like growth factors (IGFs) and IGF-binding proteins in active monitoring of localized prostate cancer: a population-based observational study. AB - PURPOSE: Active monitoring of prostate cancer requires the selection of low-risk cancers and subsequent identification of disease progression. Our objective was to determine whether serum insulin-like growth factor (IGF)-I, IGF-II, IGF binding protein (IGFBP)-2 or IGFBP-3 at diagnosis (potential biomarkers of prognosis), and repeated measures of IGFBP-2 (potential biomarker of tumour growth), were associated with annual change in PSA and PSA doubling time (PSADT), proxies for disease progression. METHODS: We investigated associations of circulating IGFs and IGFBPs with PSA measures using multilevel models, in 909 men (recruited between 1999 and 2009) with PSA-detected clinically localized prostate cancer undergoing active monitoring in the United Kingdom. Each man had an average of 14 measurements of PSA during a mean of 4-year follow-up. RESULTS: IGF I, IGF-II, IGFBP-2, and IGFBP-3 were not associated with baseline PSA. There was weak evidence that IGF-I at diagnosis was positively associated with a rapid post diagnosis PSADT (<=4 years vs. >4 years): OR 1.34 (95 % CI 0.98, 1.81) per SD increase in IGF-I. IGFBP-2 increased by 2.1 % (95 % CI 1.4, 2.8) per year between 50 and 70 years, with no association between serial IGFBP-2 levels and PSADT. There was no evidence that serum IGF-II, IGFBP-2, or IGFBP-3, or post-diagnosis IGFBP-2, were associated with PSA kinetics in men with PSA-detected localized prostate cancer. CONCLUSIONS: The weak association of IGF-I with PSADT requires replication in larger datasets, and more definitive evidence will be provided on the maturity of long-term active monitoring cohorts with relevant clinical outcomes (metastasis and prostate cancer mortality). PMID- 23085815 TI - Prevalence of complications in neuromuscular scoliosis surgery: a literature meta analysis from the past 15 years. AB - PURPOSE: Our objectives were primarily to review the published literature on complications in neuromuscular scoliosis (NMS) surgery and secondarily, by means of a meta-analysis, to determine the overall pooled rates (PR) of various complications associated with NMS surgery. METHODS: PubMed and Embase databases were searched for studies reporting the outcomes and complications of NMS surgery, published from 1997 to May 2011. We focused on NMS as defined by the Scoliosis Research Society's classification. We measured the pooled estimate of the overall complication rates (PR) using a random effects meta-analytic model. This model considers both intra- and inter-study variation in calculating PR. RESULTS: Systematic review and meta-analysis were performed for 68 cohort and case-control studies with a total of 15,218 NMS patients. Pulmonary complications were the most reported (PR = 22.71 %) followed by implant complications (PR = 12.51 %), infections (PR = 10.91 %), neurological complications (PR = 3.01 %) and pseudoarthrosis (PR = 1.88 %). Revision, removal and extension of implant had highest PR (7.87 %) followed by malplacement of the pedicle screws (4.81 %). Rates of individual studies have moderate to high variability. The studies were heterogeneous in methodology and outcome types, which are plausible explanations for the variability; sensitivity analysis with respect to age at surgery, sample size, publication year and diagnosis could also partly explain this variability. In regard to surgical complications affiliated with various surgical techniques in NMS, the level of evidence of published literature ranges between 2+ to 2-; the subsequent recommendations are level C. CONCLUSION: NMS patients have diverse and high complication rates after scoliosis surgery. High PRs of complications warrant more attention from the surgical community. Although the PR of all complications are affected by heterogeneity, they nevertheless provide valuable insights into the impact of methodological settings (sample size), patient characteristics (age at surgery), and continual advances in patient care on complication rates. PMID- 23085816 TI - Ultrasensitive on-column laser-induced fluorescence in capillary electrophoresis using multiparameter confocal detection. AB - We report a simple method to efficiently couple on-column, standard Capillary Electrophoresis with Confocal MultiParameter Fluorescence detection (CE-CMPF) using only commercially available components. A molecular collection of 13% and a concentration limit of detection of 1.5 pM fluorescein are achieved in our instrument by gating the arrival time of individual photons in order to reduce the scattering contribution. The proposed scheme allows for amplification-free detection and separation of three different microRNAs from the MCF-7 cell lysate. The limit of detection is approximately 500 times smaller and the separation time is 3 times shorter compared to protocols based on commercial CE instrumentation. Although the optical design can be further improved, it is shown that the current CE-CMPF prototype is already capable of analyzing the microRNA content of single cells. In addition, all CE protocols previously developed for commercial instruments can be performed with our CE-CMPF without modification but with nearly 3 orders of magnitude better limit of detection. PMID- 23085817 TI - Effects of combination therapy using hypothermia and erythropoietin in a rat model of neonatal hypoxia-ischemia. AB - BACKGROUND: Hypoxic-ischemic (HI) injury to the developing brain remains a major cause of morbidity. Hypothermia is effective but does not provide complete neuroprotection, prompting a search for adjunctive therapies. Erythropoietin (Epo) has been shown to be beneficial in several models of neonatal HI. This study examines combination hypothermia and treatment with erythropoietin in neonatal rat HI. METHODS: Rats at postnatal day 7 were subjected to HI (Vannucci model) and randomized into four groups: no treatment, hypothermia alone, Epo alone, or hypothermia and Epo. Epo (1,000 U/kg) was administered in three doses: immediately following HI, and 24 h and 1 wk later. Hypothermia consisted of whole body cooling for 8 h. At 2 and 6 wk following HI, sensorimotor function was assessed via cylinder-rearing test and brain damage by injury scoring. Sham treated animals not subjected to HI were also studied. RESULTS: Differences between experimental groups, except for Epo treatment on histopathological outcome in males, were not statistically significant, and combined therapy had no adverse effects. CONCLUSION: No significant benefit was observed from treatment with either hypothermia or combination therapy. Future studies may require older animals, a wider range of functional assays, and postinsult assessment of injury severity to identify only moderately damaged animals for targeted therapy. PMID- 23085818 TI - Lack of severe long-term outcomes of acute, subclinical B1 deficiency in 216 children in Israel exposed in early infancy. AB - BACKGROUND: A vitamin B(1)-deficient soy-based infant formula was marketed in Israel in 2003, exposing infants to clinical or subclinical B(1) deficiency. We investigated whether subclinical B(1) deficiency in early infancy had medical, neurodevelopmental, or cognitive effects at 3-5 y of age. METHODS: A historical prospective cohort study was conducted consisting of four groups: "exposed," consuming a B(1)-deficient soy-based formula exclusively for four consecutive weeks or longer; "control," consuming no soy-based formula; "mixed," consuming the formula nonexclusively or exclusively for less than four consecutive weeks; and "other," consuming soy-based formulas other than Remedia. Participants were evaluated by medical examination, Stanford-Binet (SB) intelligence test, sensory profile evaluation, and Conners scales (attention deficit disorder/attention deficit and hyperactivity disorder (ADD/ADHD)). RESULTS: Following adjustment for gender, age, and maternal education, there were no significant differences among the four groups on the mean SB scores, on the verbal and nonverbal scores, or in the proportion of children in each group with scores <90. A significantly higher proportion of exposed children as compared with control children had an impaired sensory profile and scores on the Conners scales (ADD/ADHD), but these proportions were also high in the "other" and "mixed" groups. CONCLUSION: The results do not support an association between subclinical B(1) deficiency in infancy and long-term development. PMID- 23085819 TI - Hypothermia and erythropoietin for neuroprotection after neonatal brain damage. AB - BACKGROUND: Both hypothermia and erythropoietin (EPO) are reported to have neuroprotective effects after perinatal hypoxia-ischemia (HI). We investigated a possible additive effect of the use of a combination of hypothermia-EPO in a rat model of neonatal HI. METHODS: At postnatal day 7, rats were subjected to HI and then randomized to 3 h of hypothermia, EPO, or both. Sensorimotor function was assessed by the cylinder-rearing test (CRT) at 2 and 5 wk after HI. Brain lesion volume and white matter loss were determined by hematoxylin-eosin and luxol fast blue staining, respectively. RESULTS: Multivariable analysis using general linear modeling showed that hypothermia, EPO, and the interaction hypothermia * gender were determinants of sensorimotor function, both at 2 and 5 wk after HI. Neuroprotective effects of hypothermia at 5 wk were more pronounced in females, showing 52% improvement in the CRT. Maximal improvement in males was 26% after combined treatment with hypothermia and EPO. Histological outcome was improved by hypothermia only with no additional effect of EPO or gender. CONCLUSION: Hypothermia after HI improved sensorimotor function in females more than in males. There was a borderline additive effect of EPO when combined with hypothermia. Histology of brain lesion volume and white matter damage was improved only by hypothermia. PMID- 23085820 TI - The effect of roots and media constituents on trichomes and artemisinin production in Artemisia annua L. AB - KEY MESSAGE : Rooting of Artemisia annua increases trichome size on leaves and helps drive the final steps of the biosynthesis of the sesquiterpene antimalarial drug, artemisinin. Artemisia annua produces the antimalarial drug, artemisinin (AN), which is synthesized and stored in glandular trichomes (GLTs). In vitro grown A. annua shoots produce more AN when they form roots. This may be a function not of the roots, but rather media components such as the phytohormones, alpha-naphthaleneacetic acid (NAA) and 6-benzylaminopurine (BAP), or salts and sucrose used to maintain either rooted or unrooted shoot cultures. We investigated how three main media components altered artemisinic metabolite production, pathway gene transcripts, and GLT formation in both mature and developing leaves in rooted and unrooted cultures. Although transcript levels of AN biosynthetic genes were not altered, AN levels were significantly different, and there were major differences in both artemisinic metabolite levels and trichomes in mature versus developing leaves. For example, NAA induced higher AN production in rooted shoots, but only in mature leaves. In developing leaves, BAP increased GLT density on the leaf surface. When both phytohormones were present, GLTs were larger on young developing leaves, but smaller on mature leaves. Furthermore, although other media components increased GLT density, their size decreased on young leaves, but there was no effect on mature leaves. Roots also appeared to drive conversion of artemisinic precursors towards end products. These results suggest that, while the presence of roots affects AN and trichome production, phytohormones and other media constituents used for in vitro culture of A. annua also exert an influence. PMID- 23085821 TI - The effect of tibio-femoral over-distraction in primary knee arthroplasty. AB - PURPOSE: Overstuffing the patellofemoral joint has been associated with poor post operative outcomes. No study has assessed the effect of over-distracting the tibio-femoral joint in the vertical plane and its effects on function and quality of life. The purpose of this study is to assess the effect of tibio-femoral joint distraction on function and quality of life after total knee arthroplasty. METHODS: Measurements of knee joint distraction were devised using long-leg alignment radiographs. Seventy-three patients were prospectively recruited and their joint distraction measured post-operatively. A comparison was made between the level of joint distraction and functional outcomes as measured by the International Knee Society score and its components, such as pain and flexion, and the Knee injury and Osteoarthritis Outcome Score and quality of life as measured by the Short-Form 12 score. Twelve-month follow-up was achieved. RESULTS: Knee joint over-distraction post-arthroplasty correlated significantly with Knee Society score (p = 0.041), flexion (p = 0.005) and pain (p = 0.002). Those knees that were over-distracted post-operatively suffered more pain, less flexion and a lower International Knee Society score compared with their counterparts. No correlation was found between over-distracting the knee joint and quality of life. CONCLUSION: Over-distracting the tibio-femoral joint during arthroplasty is a significant predictor of reduction in function and increase in pain in the short to medium term. When between sizes of tibial inserts, the surgeon should consider using the thinner option. PMID- 23085822 TI - Methods to diagnose acute anterior cruciate ligament rupture: a meta-analysis of physical examinations with and without anaesthesia. AB - PURPOSE: The aims of this meta-analysis were to determine the sensitivity and specificity of the Lachman, pivot shift and anterior drawer test for acute complete ACL rupture in the office setting and under anaesthesia. It was hypothesized that the Lachman test is the most sensitive and the pivot shift test the most specific. Secondly, it was hypothesized that the sensitivity and specificity of all three exams increases when the examination is performed under anaesthesia. METHODS: An electronic database search was performed using MEDLINE and EMBASE. All cross-sectional and cohort studies comparing one or more physical examination tests for diagnosing acute complete ACL rupture to an accepted reference standard such as arthroscopy, arthrotomy and MRI were included. RESULTS: Twenty studies were identified and included. The overall sensitivity of the Lachman test was 0.81 and the specificity 0.81; with anaesthesia, the sensitivity was 0.91 and the specificity 0.78. For the anterior drawer test, the sensitivity was 0.38 and the specificity 0.81; with anaesthesia, the sensitivity was 0.63 and the specificity 0.91. The sensitivity of the pivot shift test was 0.28 and the specificity 0.81; with anaesthesia, the sensitivity was 0.73 and the specificity 0.98. CONCLUSION: In the office setting, the Lachman test has the highest sensitivity for diagnosing an acute, complete ACL rupture, while all three tests had comparable specificity. When the examination was performed under anaesthesia, the Lachman test still obtained the highest sensitivity, but the pivot shift test was the most specific. LEVEL OF EVIDENCE: Meta-analysis of diagnostic test accuracy, Level II. PMID- 23085823 TI - Interaction of dislocations with carbon-decorated dislocation loops in bcc Fe: an atomistic study. AB - Properties of ferritic Fe-based alloys are highly sensitive to the carbon content dissolved in the matrix because interstitial carbon is known to strongly interact with lattice point defects and dislocations. As a result, the accumulation of radiation defects and its impact on the change of mechanical properties is also affected by the presence of dissolved interstitial carbon. This work contributes to an understanding of how interstitial carbon atoms influence the properties of small dislocation loops, which form directly in collision cascades upon neutron or ion irradiation and are 'invisible' to (i.e. undetectable by) standard experimental techniques applied to reveal nano-structural damage in metals. We have carried out MD simulations to investigate how the trapping of 1/2 inner product 111 dislocation loops at thermally stable carbon-vacancy complexes, known to form under irradiation, affects the interaction of these dislocation loops with dislocations in bcc Fe. We have considered loops of size 1 and 3.5 nm, which represent experimentally invisible and visible defects, respectively. The obtained results point at the strong suppression of the drag of carbon-decorated loops by dislocations. In the case of direct interaction between dislocation and carbon-decorated loops, invisible loops are found to act as obstacles whose strength is at least twice as high compared to that of undecorated ones. Additional strengthening due to the carbon decoration on the visible loops was also regularly registered. The reasons for the additional strengthening have been rationalized and discussed. It is demonstrated that carbon decoration/segregation at dislocation loops affects not only accumulation of radiation damage under prolonged irradiation but also alters the post-irradiation plastic deformation mechanisms. For the first time, we provide evidence that undetectable dislocation loops decorated by carbon do contribute to the radiation hardening. PMID- 23085824 TI - Direct 'in situ', low VOC, high yielding, CO2 expanded phase catalytic chain transfer polymerisation: towards scale-up. AB - The successful application of catalytic chain transfer polymerisation (CCTP) by adopting an 'in situ' catalyst preparation methodology in several polymerisation media is described. More specifically, this study is focused on reporting the development of 'in situ' CCTP within a CO(2) expanded phase polymerisation process, which achieved high yields of polymer whilst minimising both VOC footprint and CO(2) compression costs. The 'in situ' method is shown to be effective in controlling polymerisations conducted in both conventional solvents and bulk under inert atmosphere, delivering molecular weight reductions and a Cs value of appropriate similar magnitude to those achieved by the benchmark, commercially sourced CoPhBF catalyst. The 'in situ' effect has been achieved with equal efficiency when both using catalysts with different axial ligands and where the complex is required to undergo a facile ligand dissociation in order to create the required catalyst necessary to achieve CCTP control. Furthermore, both catalysts are shown to effectively control polymerisations in a CO(2) expanded phase process, in which a small amount of compressed CO(2) is introduced to reduce the viscosity of the reaction mixture, allowing for easy heat transfer and good catalyst diffusion during reaction. In this way, yield limitations imposed to avoid the Trommsdorff effect required in bulk processing and the need for post precipitation have been successfully overcome. Both of these factors further improve the sustainability of such a polymerisation process. However, the 'in situ', high pressure expanded phase environment was observed to retard the ligand dissociation required for catalyst activation. PMID- 23085825 TI - Delayed graft-versus-mast-cell effect on systemic mastocytosis with associated clonal haematological non-mast cell lineage disease after allogeneic transplantation. PMID- 23085826 TI - GVHD after allogeneic haematopoietic SCT for AML: angiogenesis, vascular endothelial growth factor and VEGF receptor expression in the BM. AB - There is increasing evidence suggesting that both angiogenesis and endothelial injury are involved in GVHD. To study the dynamics of angiogenesis, we examined 26 patients with AML who had undergone allogeneic haematopoietic SCT. All were in CR and had either acute GVHD (aGVHD) or chronic GVHD (cGVHD). We performed immunohistochemical studies of BM microvessel density (MVD) using Abs against vascular-endothelial (VE)-cadherin, CD34 and CD105, and expression of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. At the time of diagnosis, the MVD in AML patients was higher than that in the normal controls, and the MVD decreased after induction chemotherapy. Patients with aGVHD had a significantly higher MVD than patients without aGVHD. Conversely, patients with cGVHD did not have a significantly different MVD. In previous aGVHD, we also found more VEGF+ megakaryocytes. XY FISH in sex-mismatched patients showed that the BM blood vessels consisted mainly of recipient endothelial cells. Taken together, these results suggest that new vessel formation and the VEGF/VEGFR system are involved in aGVHD. PMID- 23085827 TI - Clinical factors affecting engraftment and transfusion needs in SCT: a single center retrospective analysis. AB - Successful utilization of SCT modalities often requires utilization of both red cell and platelet transfusions. In this retrospective evaluation of clinical factors affecting transplant engraftment and transfusion utilization at a single transplant center in 505 patients from 2005 through 2009, we found that graft type, donor type and the conditioning regimen intensity significantly affected both the neutrophil engraftment time (P<0.001) and the platelet engraftment time (P<0.001). SCT patients required an average of 6.2 red cell units, and 7.9 platelet transfusions in the first 100 days with a wide s.d. Among auto-SCT patients, 5% required neither RBC nor platelet transfusions. Some reduced intensity transplants were also associated with no transfusion need, and in allogeneic transplants, conditioning regimen intensity was positively correlated with platelet transfusion events as assessed by multivariate analysis. Other patient characteristics such as gender, graft type, donor type, underlying disease and use of TBI were all independently associated with transfusion needs in SCT patients. Further studies are required to understand the means to minimize transfusions and potential related complications in SCT patients. PMID- 23085828 TI - Safety and efficacy of rituximab in steroid-refractory chronic GVHD. PMID- 23085829 TI - 5-day/5-drug myeloablative outpatient regimen for resistant neuroblastoma. AB - 5-day/5-drug (5D/5D) is a novel high-dose regimen administered with autologous hematopoietic SCT (HSCT). It was designed to maximize cytoreduction via high dosing of synergistically interacting agents, while minimizing morbidity in patients with resistant neuroblastoma (NB) and ineligible for clinical trials due to myelosuppression from previous therapy. 5D/5D comprises carboplatin 500 mg/m(2)/day on days 1-2, irinotecan 50 mg/m(2)/day on days 1-3, temozolomide 250 mg/m(2)/day on days 1-3, etoposide 200 mg/m(2)/day on days 3-5 and cyclophosphamide 70 mg/kg/day on days 4-5. HSCT is on day 8. Sixteen patients received 21 courses. Treatment was in the outpatient clinic. Responses were noted against progressive disease (PD) that had developed while patients were off, or receiving only low-dose, chemotherapy but not against PD that emerged despite high-dose chemotherapy. Responses were also seen in patients with PD or stable disease after (131)I-metaiodobenzylguanidine therapy. Grade 3 toxicities were limited to transient elevations in liver enzymes (three courses) and hyponatremia (one course). Bacteremia occurred in 2/21 (10%) courses. Hematological recovery allowed patients to be enrolled on clinical trials. In conclusion, 5D/5D (including HSCT) spares vital organs, entails modest morbidity, shows activity against resistant NB and helps patients meet eligibility requirements for formal clinical trials. PMID- 23085831 TI - Fludarabine-induced severe necrotizing leukoencephalopathy in pediatric hematopoietic cell transplantation. PMID- 23085830 TI - Outcomes of second allogeneic hematopoietic stem cell transplantation for patients with acute lymphoblastic leukemia. AB - For patients with ALL who relapse following allo-SCT, only a second SCT provides a realistic chance for long-term disease remission. We retrospectively analyzed the outcomes of 31 patients with relapsed ALL after a prior allo-SCT, who received a second SCT (SCT2) at our center. With a median follow-up of 3 years, 1 and 3-year PFS was 23 and 11% and 1- and 3 year OS rates were 23 and 11%. Twelve patients (39%) were transplanted with active disease, of whom 75% attained a CR. We found a significant relationship between the time to treatment failure following first allograft (SCT1) and PFS following SCT2 (P=0.02, hazard ratio=0.93/month). In summary, a second transplant remains a potential treatment option for achieving response in a highly refractory patient population. While long-term survival is limited, a significant proportion of patients remains disease-free for up to 1 year following SCT2, providing a window of time to administer preventive interventions. Notably, our four long-term survivors received novel therapies with their second transplant underscoring the need for a fundamental change in the methods for SCT2 to improve outcome. PMID- 23085832 TI - Long-term follow-up of children conditioned with Treosulfan: German and Austrian experience. AB - We report the long-term follow-up of children transplanted with Treosulfan (TREO) based conditioning in Germany and Austria. Nine centres reported a total of 109 transplantations. Patients were stratified according to the paediatric TRM risk score derived from the paediatric BMT registry (PRST) and compared with the historical transplant population of this registry. Underlying diseases were malignancies, immunodeficiencies, and haematologic and metabolic disorders. TREO total dose ranged from 21-42 g/m(2). Additional conditioning drugs included fludarabine, thiotepa, melphalan, CY and/or TBI. EFS at 3 years for non-malignant and malignant diseases was 88% and 49%, respectively. Leukaemia patients in remission had a survival of 51% at 3 years; nonremission patients relapsed and died within 18 months. TRM and OS in the low-risk groups 0 and 1 were similar to PRST controls. TRM in the high-risk groups 2 and 3 was markedly lower (9% vs 28% and 13% vs 53%, respectively) than in the PRST group, but OS was similar. In conclusion, TREO-based conditioning regimens in children resulted in excellent engraftment and long-term survival in nonmalignant disease. In high-risk malignancy, low acute toxicity was followed by low TRM but it did not translate into increased survival. PMID- 23085834 TI - Layered semiconductor molybdenum disulfide nanomembrane based Schottky-barrier solar cells. AB - We demonstrate Schottky-barrier solar cells employing a stack of layer-structured semiconductor molybdenum disulfide (MoS(2)) nanomembranes, synthesized by the chemical-vapor-deposition method, as the critical photoactive layer. An MoS(2) nanomembrane forms a Schottky-barrier with a metal contact by the layer-transfer process onto an indium tin oxide (ITO) coated glass substrate. Two vibrational modes in MoS(2) nanomembranes, E(1)(2g) (in-plane) and A(1g) (perpendicular-to plane), were verified by Raman spectroscopy. With a simple stacked structure of ITO-MoS(2)-Au, the fabricated solar cell demonstrates a photo-conversion efficiency of 0.7% for ~110 nm MoS(2) and 1.8% for ~220 nm MoS(2). The improvement is attributed to a substantial increase in photonic absorption. The MoS(2) nanomembrane exhibits efficient photo-absorption in the spectral region of 350-950 nm, as confirmed by the external quantum efficiency. A sizable increase in MoS(2) thickness results in only minor change in Mott-Schottky behavior, indicating that defect density is insensitive to nanomembrane thickness attributed to the dangling-bond-free layered structure. PMID- 23085833 TI - Decellularized ear tissues as scaffolds for stem cell differentiation. AB - Permanent sensorineural hearing loss is a major medical problem and is due to the loss of hair cells and subsequently spiral ganglion neurons in the cochlea. Since these cells lack the capacity of renewal in mammals, their regeneration would be an optimal solution to reverse hearing loss. In other tissues, decellularized extracellular matrix (ECM) has been used as a mechanical and biochemical scaffold for the induction of stem and other cells toward a target tissue phenotype. Such induced cells have been used for tissue and organ transplants in preclinical animal and human clinical applications. This paper reports for the first time the decellularization of the cochlea and identification of remaining laminin and collagen type IV as a first step in preparing an ECM scaffold for directing stem cells toward an auditory lineage. Fresh ear tissues were removed from euthanized mice, a rat and a human and processed for decellularization using two different detergent extraction methods. Cochleas were imaged with scanning thin-sheet laser imaging microscopy (sTSLIM) and brightfield microscopy. Detergent treatment of fresh tissue removed all cells as evidenced by lack of H&E and DNA staining of the membranous labyrinth while preserving components of the ECM. The organ of Corti was completely removed, as were spiral ganglion neurons, which appeared as hollow sheaths and tubes of basal lamina (BL) material. Cells of the stria vascularis were removed and its only vestige left was its laterally linking network of capillary BL that appeared to "float" in the endolymphatic space. Laminin and type IV collagen were detected in the ECM after decellularization and were localized in vascular, neural and epithelial BL. Further work is necessary to attempt to seed neural and other stem cells into the decellularized ECM to hopefully induce differentiation and subsequent in vivo engraftment into damaged cochleas. PMID- 23085835 TI - Determinants of outcomes after resection of renal cell carcinoma with venous involvement. AB - PURPOSE: To determine the outcomes and to identify prognostic variables determining mortality and recurrence after surgery for renal cell cancer (RCC) with venous involvement. METHODS: Retrospective evaluation of the medical records of 132 patients with RCC and tumor thrombi treated at Johns Hopkins Hospital (1997-2008) was done. Kaplan-Meier analysis was used to determine survivals. Uni- and multivariate Cox proportional analysis was done to identify predictors for recurrence, all-cause mortality (ACM) and cancer-specific mortality (CSM). RESULTS: Mean follow-up was 30.3 (0.03-159.5) months. Sixty-four (48.5%) patients had renal vein thrombus (Group 1), 55 (41.7%) had subdiaphragmatic inferior vena cava (IVC) tumor thrombus (Group 2), while 13 (9.8%) had involvement of IVC above diaphragm or atrial extension (Group 3). IVC thrombus was more common from the right-sided tumors. Patients with higher thrombus levels had more blood loss and complicated and longer hospital stay. Thrombus level was not found to be a predictor of recurrence, ACM and CSM. One- and three-year recurrence-free survivals for non-metastatic patients were 69 and 53%. Tumor size (p=0.015), grade (p=0.007) and venous wall invasion (p=0.027) were predictors for recurrence. Five-year overall survival was 48, 35 and 13% for 3 groups, respectively. Presence of distant metastasis (p=0.032), size (p=0.002), histology (p=0.020) and grade (p=0.013) were predictors of ACM. Five-year cancer-specific survival was 65, 43 and 36 for 3 groups, respectively. Tumor size (p=0.001) and distant metastasis at presentation (p=0.025) were the predictors of CSM. CONCLUSIONS: Tumor thrombus level does not predict recurrence or mortality in RCC with venous involvement. Survival is determined by inherent aggressiveness of the cancer manifested by tumor size, grade and distant metastasis at presentation. PMID- 23085836 TI - Automated region mask for four-chamber fetal heart biometry. AB - This letter proposes an automated region mask for the detection of cardiac chambers from ultrasonic fetal heart biometry. The fetal biometry consists of two dimensional ultrasonic cine-loop sequences of apical four chamber view of fetal heart, which are comparatively The clinical motion information of individual frame is extracted by keeping a constant frame rate of 25 frames per second (fps). The region mask is designed based on the superimposition of motion information from a set of consecutive frames that belong to one cardiac cycle followed by connected component labelling. The borders and edges of all four chambers are thus recognized leading to formation of binary region mask. Experimental study based on second trimester cine-loop sequences confirms the suitability of the proposed technique for detection of heart chambers. PMID- 23085837 TI - SERS substrate for detection of explosives. AB - A novel gold coated femtosecond laser nanostructured sapphire surface - an "optical nose" - based on surface-enhanced Raman spectroscopy (SERS) for detecting vapours of explosive substances was investigated. Four different nitroaromatic vapours at room temperature were tested. Sensor responses were unambiguous and showed response in the range of 0.05-15 MUM at 25 degrees C. The laser fabricated substrate nanostructures produced up to an eight-fold increase in Raman signal over that observed on the unstructured portions of the substrate. This work demonstrates a simple sensing system that is compatible with commercial manufacturing practices to detect taggants in explosives which can undertake as part of an integrated security or investigative mission. PMID- 23085838 TI - LCAA, a novel factor required for magnesium protoporphyrin monomethylester cyclase accumulation and feedback control of aminolevulinic acid biosynthesis in tobacco. AB - Low Chlorophyll Accumulation A (LCAA) antisense plants were obtained from a screen for genes whose partial down-regulation results in a strong chlorophyll deficiency in tobacco (Nicotiana tabacum). The LCAA mutants are affected in a plastid-localized protein of unknown function, which is conserved in cyanobacteria and all photosynthetic eukaryotes. They suffer from drastically reduced light-harvesting complex (LHC) contents, while the accumulation of all other photosynthetic complexes per leaf area is less affected. As the disturbed accumulation of LHC proteins could be either attributable to a defect in LHC biogenesis itself or to a bottleneck in chlorophyll biosynthesis, chlorophyll synthesis rates and chlorophyll synthesis intermediates were measured. LCAA antisense plants accumulate magnesium (Mg) protoporphyrin monomethylester and contain reduced protochlorophyllide levels and a reduced content of CHL27, a subunit of the Mg protoporphyrin monomethylester cyclase. Bimolecular fluorescence complementation assays confirm a direct interaction between LCAA and CHL27. 5-Aminolevulinic acid synthesis rates are increased and correlate with an increased content of glutamyl-transfer RNA reductase. We suggest that LCAA encodes an additional subunit of the Mg protoporphyrin monomethylester cyclase, is required for the stability of CHL27, and contributes to feedback-control of 5 aminolevulinic acid biosynthesis, the rate-limiting step of chlorophyll biosynthesis. PMID- 23085839 TI - Deciphering systemic wound responses of the pumpkin extrafascicular phloem by metabolomics and stable isotope-coded protein labeling. AB - In cucurbits, phloem latex exudes from cut sieve tubes of the extrafascicular phloem (EFP), serving in defense against herbivores. We analyzed inducible defense mechanisms in the EFP of pumpkin (Cucurbita maxima) after leaf damage. As an early systemic response, wounding elicited transient accumulation of jasmonates and a decrease in exudation probably due to partial sieve tube occlusion by callose. The energy status of the EFP was enhanced as indicated by increased levels of ATP, phosphate, and intermediates of the citric acid cycle. Gas chromatography coupled to mass spectrometry also revealed that sucrose transport, gluconeogenesis/glycolysis, and amino acid metabolism were up regulated after wounding. Combining ProteoMiner technology for the enrichment of low-abundance proteins with stable isotope-coded protein labeling, we identified 51 wound-regulated phloem proteins. Two Sucrose-Nonfermenting1-related protein kinases and a 32-kD 14-3-3 protein are candidate central regulators of stress metabolism in the EFP. Other proteins, such as the Silverleaf Whitefly-Induced Protein1, Mitogen Activated Protein Kinase6, and Heat Shock Protein81, have known defensive functions. Isotope-coded protein labeling and western-blot analyses indicated that Cyclophilin18 is a reliable marker for stress responses of the EFP. As a hint toward the induction of redox signaling, we have observed delayed oxidation-triggered polymerization of the major Phloem Protein1 (PP1) and PP2, which correlated with a decline in carbonylation of PP2. In sum, wounding triggered transient sieve tube occlusion, enhanced energy metabolism, and accumulation of defense-related proteins in the pumpkin EFP. The systemic wound response was mediated by jasmonate and redox signaling. PMID- 23085840 TI - Growth of transplastomic cells expressing D-amino acid oxidase in chloroplasts is tolerant to D-alanine and inhibited by D-valine. AB - Dual-conditional positive/negative selection markers are versatile genetic tools for manipulating genomes. Plastid genomes are relatively small and conserved DNA molecules that can be manipulated precisely by homologous recombination. High yield expression of recombinant products and maternal inheritance of plastid encoded traits make plastids attractive sites for modification. Here, we describe the cloning and expression of a dao gene encoding D-amino acid oxidase from Schizosaccharomyces pombe in tobacco (Nicotiana tabacum) plastids. The results provide genetic evidence for the uptake of D-amino acids into plastids, which contain a target that is inhibited by D-alanine. Importantly, this nonantibiotic based selection system allows the use of cheap and widely available D-amino acids, which are relatively nontoxic to animals and microbes, to either select against (D-valine) or for (D-alanine) cells containing transgenic plastids. Positive/negative selection with d-amino acids was effective in vitro and against transplastomic seedlings grown in soil. The dual functionality of dao is highly suited to the polyploid plastid compartment, where it can be used to provide tolerance against potential D-alanine-based herbicides, control the timing of recombination events such as marker excision, influence the segregation of transgenic plastid genomes, identify loci affecting dao function in mutant screens, and develop D-valine-based methods to manage the spread of transgenic plastids tagged with dao. PMID- 23085841 TI - Natural variation for seed longevity and seed dormancy are negatively correlated in Arabidopsis. AB - Dormancy is a state of metabolic arrest that facilitates the survival of organisms during environmental conditions incompatible with their regular course of life. Many organisms have deep dormant stages to promote an extended life span (increased longevity). In contrast, plants have seed dormancy and seed longevity described as two traits. Seed dormancy is defined as a temporary failure of a viable seed to germinate in conditions that favor germination, whereas seed longevity is defined as seed viability after dry storage (storability). In plants, the association of seed longevity with seed dormancy has not been studied in detail. This is surprising given the ecological, agronomical, and economic importance of seed longevity. We studied seed longevity to reveal its genetic regulators and its association with seed dormancy in Arabidopsis (Arabidopsis thaliana). Integrated quantitative trait locus analyses for seed longevity, in six recombinant inbred line populations, revealed five loci: Germination Ability After Storage1 (GAAS1) to GAAS5. GAAS loci colocated with seed dormancy loci, Delay Of Germination (DOG), earlier identified in the same six recombinant inbred line populations. Both GAAS loci and their colocation with DOG loci were validated by near isogenic lines. A negative correlation was observed, deep seed dormancy correlating with low seed longevity and vice versa. Detailed analysis on the collocating GAAS5 and DOG1 quantitative trait loci revealed that the DOG1 Cape Verde Islands allele both reduces seed longevity and increases seed dormancy. To our knowledge, this study is the first to report a negative correlation between seed longevity and seed dormancy. PMID- 23085842 TI - The prevalence and impact of depression in self-referred clients attending an employee assistance program. AB - OBJECTIVE: To determine the prevalence and characteristics of clients with depression attending an employee assistance program (EAP). METHODS: Anonymized data were obtained from 10,794 consecutive clients, including 9105 employees, self-referred to PPC Canada, a large, external EAP. Assessment measures included the self-rated nine-item Patient Health Questionnaire (PHQ-9). Clinical characteristics of depressed clients (PHQ-9 score >= 10) were compared with those of nondepressed clients. RESULTS: Thirty-seven percent of the employee sample met PHQ-9 criteria for clinically significant depression. Compared with clients without depression, they had significantly higher rates of anxiety, psychotropic medication use, problem substance use, global problems with functioning, absenteeism, impairment in work-related tasks, and low job satisfaction. CONCLUSIONS: A large proportion of EAP clients were clinically depressed with associated negative effects on personal and occupational functioning. PMID- 23085843 TI - Factors associated with health-related quality of life among operating engineers. AB - BACKGROUND: Because health-related quality of life among blue-collar workers has not been well studied, the purpose of this study was to determine factors associated with health-related quality of life among Operating Engineers. METHODS: With cross-sectional data from a convenience sample of 498 Operating Engineers, personal and health behavioral factors associated with health-related quality of life were examined. RESULTS: Multivariate linear regression analysis revealed that personal factors (older age, being married, more medical comorbidities, and depression) and behavioral factors (smoking, low fruit and vegetable intake, low physical activity, high body mass index, and low sleep quality) were associated with poor health-related quality of life. CONCLUSIONS: Operating Engineers are at risk for poor health-related quality of life. Underlying medical comorbidities and depression should be well managed. Worksite wellness programs addressing poor health behaviors may be beneficial. PMID- 23085844 TI - Association between pulmonary dysfunction as a result of occupational exposures and risk of developing cancer. AB - BACKGROUND: Cohen's hypothesis states that pulmonary dysfunction is the underlying unifying factor that leads to numerous health risks of inhaled toxicants. OBJECTIVE: To test the idea postulated by Cohen. METHODS: We compiled a retrospective cohort (n = 8024) composed of participants in eight population based research and occupational studies conducted between 1977 and 1989. Smoking history, occupational exposures, health indicators, and demographic information were obtained by questionnaire. Pulmonary function was assessed by spirometry. RESULTS: Cox proportional hazards models were utilized to test the Cohen's hypothesis. Risk of developing cancer increased (hazard ratio, 1.31; 95% confidence interval, 1.02 to 1.67) if a subject had an obstructive pulmonary disease at baseline. CONCLUSION: Impaired lung function caused by environmental and occupational exposures is one of the risk factors for the incidence of cancer. PMID- 23085845 TI - Single-molecule photon stamping FRET spectroscopy study of enzymatic conformational dynamics. AB - The fluorescence resonant energy transfer (FRET) from a donor to an acceptor via transition dipole-dipole interactions decreases the donor's fluorescent lifetime. The donor's fluorescent lifetime decreases as the FRET efficiency increases, following the equation: E(FRET) = 1 - tau(DA)/tau(D), where tau(D) and tau(DA) are the donor fluorescence lifetime without FRET and with FRET. Accordingly, the FRET time trajectories associated with single-molecule conformational dynamics can be recorded by measuring the donor's lifetime fluctuations. In this article, we report our work on the use of a Cy3/Cy5-labeled enzyme, HPPK to demonstrate probing single-molecule conformational dynamics in an enzymatic reaction by measuring single-molecule FRET donor lifetime time trajectories. Compared with single-molecule fluorescence intensity-based FRET measurements, single-molecule lifetime-based FRET measurements are independent of fluorescence intensity. The latter has an advantage in terms of eliminating the analysis background noise from the acceptor fluorescence detection leak through noise, excitation light intensity noise, or light scattering noise due to local environmental factors, for example, in a AFM-tip correlated single-molecule FRET measurements. Furthermore, lifetime-based FRET also supports simultaneous single-molecule fluorescence anisotropy. PMID- 23085846 TI - Modeling the radiation ionization energy and energy resolution of trigonal and amorphous selenium from first principles. AB - Advances in the development of amorphous selenium-based direct conversion photoconductors for high-energy radiation critically depend on the improvement of its sensitivity to ionizing radiation, which is directly related to the pair production energy. Traditionally, theories for the pair production energy have been based on the parabolic band approximation and do not provide a satisfactory agreement with experimental results for amorphous selenium. Here we present a calculation of the pair creation energy in trigonal and amorphous selenium based on its electronic structure. In indirect semiconductors, such as trigonal selenium, the ionization threshold energy can be as low as the energy gap, resulting in a lower pair creation energy, which is a favorable factor for sensitivity. Also, the statistics of photogenerated charge carriers is studied in order to evaluate the theoretical value of the Fano factor and its dependence on recombination processes. We show that recombination can significantly compromise the detector's energy resolution as a result of an increase in the Fano factor. PMID- 23085847 TI - VEGF and Notch in tip and stalk cell selection. AB - Sprouting angiogenesis is a dynamic process in which endothelial cells collectively migrate, shape new lumenized tubes, make new connections, and remodel the nascent network into a hierarchically branched and functionally perfused vascular bed. Endothelial cells in the nascent sprout adopt two distinct cellular phenotypes--known as tip and stalk cells--with specialized functions and gene expression patterns. VEGF and Notch signaling engage in an intricate cross talk to balance tip and stalk cell formation and to regulate directed tip cell migration and stalk cell proliferation. In this article, we summarize the current knowledge and implications of the tip/stalk cell concepts and the quantitative and dynamic integration of VEGF and Notch signaling in tip and stalk cell selection. PMID- 23085849 TI - In vitro investigation of efficient photodynamic therapy using a nonviral vector; hemagglutinating virus of Japan envelope. AB - Photodynamic therapy (PDT) is a photochemical modality approved for cancer treatment. PDT has demonstrated efficacy in early stage lung cancer and esophageal cancer. The accumulation of photosensitizers in cancer cells is necessary to enhance the therapeutic benefits of PDT; however, photosensitizers have low uptake efficiency. To overcome this limitation, a drug delivery system, such as the hemagglutinating virus of Japan envelope (HVJ-E) vector, is required. In this study, the combination of PDT and HVJ-E was investigated for enhancing the efficacy of PDT. The photosensitizers that were evaluated included 5 aminolaevulinic acid (5-ALA), protoporphyrin IX (PPIX), and HVJ-PPIX. The uptake of the photosensitizers as increased twenty-fold with the addition of HVJ-E. The cytotoxicity of conventional 5-ALA was enhanced by the addition of HVJ-E vector. In conclusion, HVJ-E vector improved the uptake of photosensitizers and the PDT effect. PMID- 23085848 TI - The central amygdala and alcohol: role of gamma-aminobutyric acid, glutamate, and neuropeptides. AB - Alcohol dependence is a chronically relapsing disorder characterized by compulsive drug seeking and drug taking, loss of control in limiting intake, and the emergence of a withdrawal syndrome in the absence of the drug. Accumulating evidence suggests an important role for synaptic transmission in the central amygdala (CeA) in mediating alcohol-related behaviors and neuroadaptative mechanisms associated with alcohol dependence. Acute alcohol facilitates gamma aminobutyric acid-ergic (GABAergic) transmission in CeA via both pre- and postsynaptic mechanisms, and chronic alcohol increases baseline GABAergic transmission. Acute alcohol inhibits glutamatergic transmission via effects at N methyl-d-aspartate (NMDA) and AMPA receptors in CeA, whereas chronic alcohol up regulates N-methyl-d-aspartate receptor (NMDAR)-mediated transmission. Pro- (e.g., corticotropin-releasing factor [CRF]) and anti-stress (e.g., NPY, nociceptin) neuropeptides affect alcohol- and anxiety-related behaviors, and also alter the alcohol-induced effects on CeA neurotransmission. Alcohol dependence produces plasticity in these neuropeptide systems, reflecting a recruitment of those systems during the transition to alcohol dependence. PMID- 23085855 TI - Cross-kingdom effects of plant-plant signaling via volatile organic compounds emitted by tomato (Solanum lycopersicum) plants infested by the greenhouse whitefly (Trialeurodes vaporariorum). AB - Volatile organic compounds (VOCs) emitted from plants in response to insect infestation can function as signals for the attraction of predatory/parasitic insects and/or repulsion of herbivores. VOCs also may play a role in intra- and inter-plant communication. In this work, the kinetics and composition of VOC emissions produced by tomato (Solanum lycopersicum) plants infested with the greenhouse whitefly Trialeurodes vaporariorum was determined within a 14 days period. The VOC emission profiles varied concomitantly with the duration of whitefly infestation. A total of 36 different VOCs were detected during the experiment, 26 of which could be identified: 23 terpenoids, plus decanal, decane, and methyl salicylate (MeSA). Many VOCs were emitted exclusively by infested plants, including MeSA and 10 terpenoids. In general, individual VOC emissions increased as the infestation progressed, particularly at 7 days post-infestation (dpi). Additional tunnel experiments showed that a 3 days exposure to VOC emissions from whitefly-infested plants significantly reduced infection by a biotrophic bacterial pathogen. Infection of VOC-exposed plants induced the expression of a likely tomato homolog of a methyl salicylate esterase gene, which preceded the expression of pathogenesis-related protein genes. This expression pattern correlated with reduced susceptibility in VOC-exposed plants. The observed cross-kingdom effect of plant-plant signaling via VOCs probably represents a generalized defensive response that contributes to increased plant fitness, considering that resistance responses to whiteflies and biotrophic bacterial pathogens in tomato share many common elements. PMID- 23085856 TI - Targeting the Ras-ERK pathway in pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PAC) stands as the poorest prognostic tumor of the digestive tract with limited therapeutic options. PAC carcinogenesis is associated with the loss of function of tumor suppressor genes such as INK4A, TP53, BRCA2, and DPC4, and only a few activated oncogenes among which K-RAS mutations are the most prevalent. The K-RAS mutation occurs early in PAC carcinogenesis, driving downstream activation of MEK and ERK1/2 which promote survival, invasion, and migration of cancer cells. In PAC models, inhibition of members of the Ras-ERK pathway blocks cellular proliferation and metastasis development. As oncogenic Ras does not appear to be a suitable drug target, inhibitors targeting downstream kinases including Raf and MEK have been developed and are currently under evaluation in clinical trials. In this review, we describe the role of the Ras-ERK pathway in pancreatic carcinogenesis and as a new therapeutic target for the treatment of PAC. PMID- 23085858 TI - One-stage surgical management for tuberculosis of the upper cervical spine by posterior debridement, short-segment fusion, and posterior instrumentation in children. AB - PURPOSE: To evaluate the clinical study efficacy and feasibility of 11 children with tuberculosis of the upper cervical spine treated by one-stage posterior debridement, short-segment fusion, and posterior instrumentation. METHODS: Eleven children who suffered from tuberculosis of the upper cervical spine were admitted to our hospital between June 2005 and December 2010. All of them were treated by one-stage posterior debridement, short-segment fusion, and posterior instrumentation. Then, the clinical efficacy was evaluated using statistical analysis based on the materials about the visual analogue scale (VAS) scores of pain, JOA scores of nerve function and erythrocyte sedimentation rate (ESR), which were collected at certain time. RESULTS: The average follow-up period was 28.1 +/- 10.5 months (13-42 months). In the 11 cases, no postoperative complications related to instrumentation occurred and neurologic function was improved in various degrees. The average pretreatment ESR was 58.4 +/- 4.9 mm/h (53-69 mm/h), which got normal (8.9 +/- 6.5 mm/h) within 3 months in all patients. The average preoperative VAS was 7.4 +/- 2.2, which decreased to 1.6 +/ 1.8 postoperatively. Mean preoperative JOA was 11.2 +/- 3.8, and the JOA at the last visit was 16.3 +/- 1.0. All patients got bony fusion within 3-8 months after surgery. CONCLUSIONS: One-stage posterior debridement, short-segment fusion, and posterior instrumentation can be an effective treatment method for the treatment of tuberculosis of the upper cervical spine in children. PMID- 23085857 TI - What underlies the diversity of brain tumors? AB - Glioma and medulloblastoma represent the most commonly occurring malignant brain tumors in adults and in children, respectively. Recent genomic and transcriptional approaches present a complex group of diseases and delineate a number of molecular subgroups within tumors that share a common histopathology. Differences in cells of origin, regional niches, developmental timing, and genetic events all contribute to this heterogeneity. In an attempt to recapitulate the diversity of brain tumors, an increasing array of genetically engineered mouse models (GEMMs) has been developed. These models often utilize promoters and genetic drivers from normal brain development and can provide insight into specific cells from which these tumors originate. GEMMs show promise in both developmental biology and developmental therapeutics. This review describes numerous murine brain tumor models in the context of normal brain development and the potential for these animals to impact brain tumor research. PMID- 23085859 TI - Mediterranean diet and incidence of hip fractures in a European cohort. AB - Prevention of hip fractures is of critical public health importance. In a cohort of adults from eight European countries, evidence was found that increased adherence to Mediterranean diet, measured by a 10-unit dietary score, is associated with reduced hip fracture incidence, particularly among men. INTRODUCTION: Evidence on the role of dietary patterns on hip fracture incidence is scarce. We explored the association of adherence to Mediterranean diet (MD) with hip fracture incidence in a cohort from eight European countries. METHODS: A total of 188,795 eligible participants (48,814 men and 139,981 women) in the European Prospective Investigation into Cancer and nutrition study with mean age 48.6 years (+/-10.8) were followed for a median of 9 years, and 802 incident hip fractures were recorded. Diet was assessed at baseline through validated dietary instruments. Adherence to MD was evaluated by a MD score (MDs), on a 10-point scale, in which monounsaturated were substituted with unsaturated lipids. Association with hip fracture incidence was assessed through Cox regression with adjustment for potential confounders. RESULTS: Increased adherence to MD was associated with a 7 % decrease in hip fracture incidence [hazard ratio (HR) per 1 unit increase in the MDs 0.93; 95 % confidence interval (95 % CI) = 0.89-0.98]. This association was more evident among men and somewhat stronger among older individuals. Using increments close to one standard deviation of daily intake, in the overall sample, high vegetable (HR = 0.86; 95 % CI = 0.79-0.94) and high fruit (HR = 0.89; 95 % CI = 0.82-0.97) intake was associated with decreased hip fracture incidence, whereas high meat intake (HR = 1.18; 95 % CI = 1.06-1.31) with increased incidence. Excessive ethanol consumption (HR high versus moderate = 1.74; 95 % CI = 1.32-2.31) was also a risk factor. CONCLUSIONS: In a prospective study of adults, increased adherence to MD appears to protect against hip fracture occurrence, particularly among men. PMID- 23085860 TI - Early diffuse recurrence of hepatocellular carcinoma after percutaneous radiofrequency ablation: analysis of risk factors. AB - OBJECTIVE: To evaluate the risk factors affecting early diffuse recurrence within 1 year of percutaneous ultrasound-guided radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC). METHODS: Out of 146 patients who received transcatheter arterial chemoembolisation (TACE) for treatment of recurrent HCC after percutaneous ultrasound-guided RFA, we selected 23 patients with early diffuse recurrence. Early diffuse recurrence was defined as three or more new recurrent HCCs within 1 year of initial RFA. As a control group, we selected 23 patients, matched exactly for age and sex, in which there was no local tumour progression or new recurrence after RFA. To analyse the risk factors, we examined patient factors and tumour factors. RESULTS: Recurrent tumours occurred from 30 to 365 days after RFA (median time, 203 days). Univariate analysis indicated that larger tumour size and poorly defined margin were significant risk factors (P < 0.05). Multivariate analysis indicated that poorly defined margin was a significant risk factor (P < 0.05). CONCLUSION: Larger tumour size and poorly defined margin may be risk factors for early diffuse recurrence of HCC within 1 year of RFA. Tumours with such risk factors should be treated with a combination of TACE to minimise the potential for therapeutic failure. PMID- 23085861 TI - Variability of 18F-FDG-positive lung lesion volume by thresholding. AB - OBJECTIVES: To assess the variability of (18)F-FDG-positive volume measurements in lung cancer patients, obtained with different fixed percentages of maximum standard uptake value (SUVmax) thresholds. METHODS: PET dynamic acquisition involving ten frames was performed within 60-110 min post-injection in eight patients. In each lesion (n = 11), volume was automatically outlined in each frame with fixed 40-50-60-70 % of the SUVmax thresholds. Thus, ten volume values for each threshold (V40-50-60-70) were available to calculate relative SD (SDr), and hence relative measurement error (MEr) and repeatability (R). Dependence on SUVmax variability was also assessed. RESULTS: Mean SDr (; %) of volume estimates was found to strongly correlate with threshold value (T; %): = 1.626 * exp(0.044 * T) (r = 0.999; P < 0.01). MEr and R for V40 were found to be (95 % CL) 18.9 % and 26.7 %. For all fixed thresholds, in successive frames of an arbitrary lesion, volume estimate inversely correlated with SUVmax (P <= 0.02). CONCLUSIONS: A formula allows estimation of the variability of (18)F-FDG-positive volumes provided by any fixed percentage of SUVmax threshold, and hence by any thresholding method. It only necessitates conversion of the threshold value into the SUVmax percentage in order to aid quick estimation of volume variability magnitude in current clinical practice. PMID- 23085862 TI - Investigation of viewing procedures for interpretation of breast tomosynthesis image volumes: a detection-task study with eye tracking. AB - OBJECTIVES: To evaluate the efficiency of different methods of reading breast tomosynthesis (BT) image volumes. METHODS: All viewing procedures consisted of free scroll volume browsing and three were combined with initial cine loops at three different frame rates (9, 14 and 25 fps). The presentation modes consisted of vertically and horizontally orientated BT image volumes. Fifty-five normal BT image volumes in mediolateral oblique view were collected. In these, simulated lesions were inserted, creating four unique image sets, one for each viewing procedure. Four observers interpreted the cases in a free-response task. Time efficiency, visual attention and search were investigated using eye tracking. RESULTS: Horizontally orientated BT image volumes were read faster than vertically when using free scroll browsing only and when combined with fast cine loop. Cine loops at slow frame rates were ruled out as inefficient. CONCLUSIONS: In general, horizontally oriented BT image volumes were read more efficiently. All viewing procedures except for slow frame rates were promising when assuming equivalent detection performance. PMID- 23085863 TI - Albumin-binding MR blood pool contrast agent improves diagnostic performance in human brain tumour: comparison of two contrast agents for glioblastoma. AB - OBJECTIVE: We qualitatively and quantitatively compared MRI enhancement obtained with gadofosveset, an albumin-binding blood-pool contrast agent, and with gadobutrol, an extracellular contrast agent, in patients with glioblastoma. METHODS: Thirty-five patients (25 men; 64 +/- 14 years) with histologically proven glioblastoma underwent MRI including pre- and post-contrast T1-weighted SE images acquired 5 min after gadobutrol (0.1 mmol/kg) and, 48 h later, images acquired with identical parameters 5 min and 3, 6, and 24 h after gadofosveset (0.03 mmol/kg). Lesion extent, delineation, internal morphology, multifocality, and global diagnostic preference were evaluated quantitatively for the signal-to noise ratio (SNR), contrast-to-noise ratio (CNR), and contrast enhancement (CE). RESULTS: Mean values of SNR, CNR, and tumour CE were highest 6 h after gadofosveset. Multifocality was seen in 17 (48.6 %) patients; additional lesions had stronger enhancement 6 h after gadofosveset in 12 patients (70.6 %). In 21 (60 %) patients, radiologists' global preference was highest in images acquired 6 h after gadofosveset (kappa = 0.764). In 22 patients (62.8 %), all qualitative endpoints were better at 5 min after gadobutrol than in images acquired 5 min after gadofosveset injection. CONCLUSIONS: Gadobutrol gives significant tumour enhancement in early postcontrast imaging. However, images acquired 6 h after gadofosveset injection have significantly better diagnostic information endpoints and contrast enhancement. PMID- 23085864 TI - Miss rate of colorectal cancer at CT colonography in average-risk symptomatic patients. AB - OBJECTIVES: Computed tomographic colonography (CTC) is a less burdensome alternative to colonoscopy in excluding colorectal cancer (CRC) in symptomatic patients. We evaluated the proportion of patients who underwent CTC in whom CRC was missed. METHODS: Patients who had undergone CTC in the period 1 January 2007 to 1 January 2011 were merged with all cases of CRC recorded in the Cancer Registry between 1 January 2007 and 1 July 2011 to identify all patients who had undergone CTC less than 2 years before CRC had been diagnosed. RESULTS: In 53 out of 1,855 patients who had undergone CTC, CRC was diagnosed. Of these, 40 patients had suspected CRC and 5 had large polyps at CTC. In five patients with an indeterminate mass, further investigation confirmed malignancy. One cancer in the caecum was missed because of poor distension. Two cancers were missed: one in the distal rectum and one in the ascending colon. Sensitivity of CTC for CRC was 94.3 % (95 % CI 88-100 %). The true miss rate, excluding the inadequate distended study, was 2 out of 53 (3.8 %). CONCLUSION: This study shows that the miss rate for CTC is low, which means that CTC is accurate in excluding CRC in symptomatic patients at a relatively low risk of CRC. PMID- 23085865 TI - Impact of breast mass size on accuracy of ultrasound elastography vs. conventional B-mode ultrasound: a meta-analysis of individual participants. AB - OBJECTIVES: To conduct an individual patient data meta-analysis comparing the diagnostic performance of ultrasound elastography (USE) versus B-mode ultrasound (USB) across size ranges of breast masses. METHODS: An extensive literature search of PubMed and other medical/general purpose databases from inception through August 2011 was conducted. Corresponding authors of published studies that reported a direct comparison of the diagnostic performance of USE using the elasticity score versus USB for characterisation of focal breast masses were contacted for their original patient-level data set. Summary diagnostic performance measures were compared for each test within and across three mass size groups (<10 mm, 10-19 mm, and >19 mm). RESULTS: The patient-level data sets were received from five studies, providing information on 1,412 breast masses. For breast masses <10 mm (n = 543; 121 malignant), the sensitivity/specificity of USE and USB were 76 %/93 % and 95 %/68 %, respectively. For masses 10-19 mm of size (n = 528; 247 malignant), sensitivity/specificity of USE and USB were 82 %/90 % and 95 %/67 %, respectively. For masses >19 mm of size (n = 325; 162 malignant), sensitivity/specificity of USE and USB were 74 %/94 % and 97 %/55 %, respectively. CONCLUSION: Regardless of the mass size, USE has higher specificity and lower sensitivity compared to USB in characterising breast masses. The performance of each of these two tests does not vary significantly by mass size. PMID- 23085866 TI - Reliability and responsiveness of the Juvenile Arthritis MRI Scoring (JAMRIS) system for the knee. AB - OBJECTIVES: To assess the reliability and responsiveness of a new Juvenile Arthritis MRI Scoring (JAMRIS) system for evaluating disease activity of the knee. METHODS: Twenty-five juvenile idiopathic arthritis (JIA) patients with clinical knee involvement were studied using open-bore 1-T MRI. MRI features of synovial hypertrophy, bone marrow changes, cartilage lesions and bone erosions were independently scored by five readers using the JAMRIS system. In addition, the JAMRIS system was determined to be a follow-up parameter by two readers to evaluate the response to therapy in 15 consecutive JIA patients. RESULTS: Inter reader (ICCs 0.86-0.95) and intra-reader reliability (ICCs 0.92-1.00) for the scoring of JAMRIS features was good. Reliability of the actual scores and changes in scores over time was good for all items: ICCs 0.89-1.00, 0.87-1.00, respectively. Concerning therapy response, the mean synovial hypertrophy scores decreased significantly (mean 1.1 point; P < 0.001, SRM = -0.65). No change was observed with respect to bone marrow change, cartilage lesion and bone erosion scores. CONCLUSIONS: The JAMRIS proved to be a simple and highly reliable assessment score in the evaluation of JIA disease activity of the knee. The JAMRIS system may serve as an objective and accurate outcome measure in future research and clinical trials. PMID- 23085867 TI - Differentiation of benign from malignant solid breast masses: comparison of two dimensional and three-dimensional shear-wave elastography. AB - OBJECTIVES: To prospectively compare the diagnostic performances of two dimensional (2D) and three-dimensional (3D) shear-wave elastography (SWE) for differentiating benign from malignant breast masses. METHODS: B-mode ultrasound and SWE were performed for 134 consecutive women with 144 breast masses before biopsy. Quantitative elasticity values (maximum and mean elasticity in the stiffest portion of mass, Emax and Emean; lesion-to-fat elasticity ratio, Erat) were measured with both 2D and 3D SWE. The area under the receiver operating characteristic curve (AUC), sensitivity and specificity of B-mode, 2D, 3D SWE and combined data of B-mode and SWE were compared. RESULTS: Sixty-seven of the 144 breast masses (47 %) were malignant. Overall, higher elasticity values of 3D SWE than 2D SWE were noted for both benign and malignant masses. The AUC for 2D and 3D SWE were not significantly different: Emean, 0.938 vs 0.928; Emax, 0.939 vs 0.930; Erat, 0.907 vs 0.871. Either 2D or 3D SWE significantly improved the specificity of B-mode ultrasound from 29.9 % (23 of 77) up to 71.4 % (55 of 77) and 63.6 % (49 of 77) without a significant change in sensitivity. CONCLUSION: Two-dimensional and 3D SWE performed equally in distinguishing benign from malignant masses and both techniques improved the specificity of B-mode ultrasound. PMID- 23085869 TI - Thiacalix[4]crown based optical chemosensor for Fe3+, Li+ and cysteine: a Fe3+/Li+ ion synchronized allosteric regulation. AB - A heteroditopic chemosensor 2 based on a thiacalix[4]crown with a 1,3-alternate conformation has been synthesized and shows a selective fluorescence turn-off response with Fe(3+) ions in mixed aqueous media. Furthermore, the 2-Fe(3+) complex can be used as a chemosensing system for the detection of Li(+) and cysteine based on two different approaches. Moreover, the sequence addition of Fe(3+) and Li(+) triggers an Fe(3+)/Li(+) switchable on-off-on fluorescence chemosensor with negative allosteric regulations. PMID- 23085868 TI - Diagnostic performance of regional DTI-derived tensor metrics in glioblastoma multiforme: simultaneous evaluation of p, q, L, Cl, Cp, Cs, RA, RD, AD, mean diffusivity and fractional anisotropy. AB - OBJECTIVES: Almost a dozen diffusion tensor-imaging (DTI) variables have been used to evaluate brain tumours with scarce information about their diagnostic ability. We aimed to perform a comprehensive evaluation of tensor metrics reported in the last decade. METHODS: Retrospective case control study performed in 14 patients with glioblastoma multiforme (GBM) and 28 controls. Conventional brain MR sequences and image postprocessing of DTI allowed the calculation of: MD, FA, p, q, L, Cl, Cp, Cs, RA, RD and AD, classified into five regions: normal appearance white matter (NAWM), immediate and distant oedema, enhancing rim and cystic cavity. ANOVA and AUROC analyses were performed. RESULTS: ANOVA depicted a significant difference among all metrics (p < 0.05). RA had the highest performance in the NAWM and cystic cavity; immediate and distant zones of oedema were best diagnosed by RD and Cp respectively; q was the best biomarker of the enhancing rim zone; p < 0.001 for all metrics. CONCLUSIONS: FA and MD, accepted biomarkers of brain injury, were surpassed by other metrics. RA, together with Cs, Cl and CP, might be the new leaders in the evaluation of brain tumours. DTI tensor metrics depict different clinical applicability at each tumour region. PMID- 23085870 TI - Simple suppression of radiation damping. AB - Radiation damping is known to cause line-broadening and frequency shifts of strong resonances in NMR spectra. While several techniques exist for the suppression of these effects, many require specialized hardware, or are only compatible with the presence of few strong resonances. We describe a simple pulse sequence for radiation damping suppression in spectra with many strong resonances. The sequence can be used as-is to generate simple spectra or as a signal excitation part in more advanced experiments. PMID- 23085872 TI - Drug trafficking: recent advances in therapeutics and disease. AB - Drug transporter proteins are of ever-increasing interest because of their role both in processes regulating pharmacokinetic properties of drugs (absorption, distribution, and elimination) and in the development of cellular drug resistance through decreased uptake or increased efflux of drugs in the target organ or tumor. Further understanding of the role of transporters in drug-drug interactions and identification of these proteins as possible therapeutic targets could contribute to improved treatment of a wide variety of diseases. PMID- 23085873 TI - Advancing pharmacometrics and systems pharmacology. AB - Pharmacometrics and systems pharmacology are emerging as principal quantitative sciences within drug development and experimental therapeutics. In recognition of the importance of pharmacometrics and systems pharmacology to the discipline of clinical pharmacology, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), in collaboration with Nature Publishing Group and Clinical Pharmacology & Therapeutics, has established CPT: Pharmacometrics & Systems Pharmacology to inform the field and shape the discipline. PMID- 23085876 TI - The UCSF-FDA TransPortal: a public drug transporter database. AB - Drug transporters play a key role in the absorption, distribution, and elimination of many drugs, and they appear to be important determinants of therapeutic and adverse drug activities. Although a large body of data pertaining to drug transporters is available, there are few databases that inform drug developers, regulatory agencies, and academic scientists about transporters that are important in drug action and disposition. In this article, we inform the scientific community about the UCSF-FDA TransPortal, a new and valuable online resource for research and drug development. PMID- 23085877 TI - Prediction of transporter-mediated drug-drug interactions using endogenous compounds. AB - Therapy with two or more drugs is more the rule than the exception, particularly in aging societies. Drug-drug interactions are frequently undesirable and may lead to increased toxicity and mortality. Inhibition of transporters is one major mechanism underlying drug-drug interactions. The myriad of potential drug combinations makes it very challenging to predict drug-drug interactions. This Commentary discusses potential advantages and limitations of endogenous compounds for predicting transporter-mediated drug-drug interactions. PMID- 23085879 TI - A step closer to personalized chemotherapy: consideration of the influence of genetic variation in hepatic uptake transporters on the metabolism of CYP3A substrates. AB - Understanding the metabolic, transporter, and genetic influences on the disposition of drugs used in chemotherapy is critical to individualization of drug therapy. Recognition of the importance of transporter-enzyme interplay, in which genetic variants of drug uptake transporters can change drug metabolism when the enzymes are unchanged, is an important advance in predicting appropriate drug dosage regimens for the individual patient. PMID- 23085878 TI - Models of excellence: improving oncology drug development. AB - Simulations based on disease-progression models and phase II trial results can predict phase III results and have the potential to improve oncology drug development by informing end-of-phase II decisions (EOP2Ds). Many barriers impede effective use of modeling and simulation (M&S) for EOP2Ds in oncology: concerns about model validity, lack of access to M&S results and patient-level data, limited awareness of M&S among academic oncologists, and inexperience fitting M&S into the drug development timeline. PMID- 23085880 TI - Highlights from the International Transporter Consortium second workshop. AB - The Second International Transporter Consortium (ITC) Workshop was held with the purpose of expanding on previous white-paper recommendations, discussing recent regulatory draft guidance documents on transporter-drug interactions, and highlighting transporter-related challenges in drug development. Specific goals were to discuss additional clinically relevant transporters (MATEs, MRP2, BSEP) and best-practice methodologies and to re-evaluate ITC decision trees based on actual case studies. The outcome of the workshop will be a series of white papers targeted for publication in 2013. PMID- 23085882 TI - Guidance on the use of canakinumab in patients with cryopyrin-associated periodic syndrome in Japan. AB - Cryopyrin-associated periodic syndrome (CAPS) is an orphan disease with incidence of about one in 1,000,000 persons. This autoinflammatory disease develops in the neonatal period or early childhood, with various inflammatory symptoms occurring repeatedly throughout the patient's lifetime. It is caused by abnormality of the NLRP3 protein which mediates the intracellular signal transduction mechanism of inflammatory processes, resulting in continuous overproduction of interleukin (IL)-1beta, which induces chronic inflammation and progressive tissue damage. Definitive diagnosis of CAPS is difficult, and treatment has also been difficult because of a lack of effective medications in Japan. Clinical studies of human anti-human IL-1beta monoclonal antibody (canakinumab) treatment were conducted in Japan, and approval was granted for therapeutic use of canakinumab for CAPS in September 2011. Similar to other biological drugs, canakinumab is clinically highly effective. However, sufficient attention to the method of use and adverse drug reactions is necessary. This guidance describes the use of canakinumab in Japan for CAPS in relation to exclusion criteria, method of use, evaluation criteria, and adverse drug reactions. PMID- 23085883 TI - Clinical features of patients with anti-neutrophil cytoplasmic autoantibodies targeting native myeloperoxidase antigen. AB - OBJECTIVES: Anti-neutrophil cytoplasmic autoantibodies (ANCA) are useful diagnostic markers in systemic vasculitic disorders with small-vessel involvement, but depending on the particular test used, the myeloperoxidase (MPO) ANCA results are variable. In the present study, we performed a comparative analysis between our originally developed nMPO-ANCA assay that targets the native MPO antigen and other commercially available assays using sera of patients with clinical features of ANCA-associated vasculitis (AAV). METHODS: Sera of 24 patients strongly suspected of having AAV were examined for the presence of MPO ANCAs by our nMPO-ANCA assay and by other commercial-based MPO-ANCA assays. These results were correlated to indirect immunofluorescence microscopy staining patterns and patient clinical parameters. RESULTS: Eighteen out of 24 patients (75 %) were positive for nMPO-ANCA, compared with 13 out of 24 patients (54 %) by one of the most frequently used commercial-based MPO-ANCA enzyme-linked immunosorbent assays (ELISAs) in Japan. Interestingly, the patients who tested positive with our nMPO-ANCA assay alone showed clinical features of AAV marked by continuous fever, polyarthritis, and mild nephritis. The titers of nMPO-ANCA decreased in association with clinical improvement after treatment. CONCLUSIONS: Our data suggest that a positive nMPO-ANCA result, which identifies antibodies to human native MPO antigen, correlates with AAV disease activity. Moreover, the nMPO-ANCA test has clinical utility in detecting AAV-affected patients who have tested negative using commercially available assays. PMID- 23085884 TI - Identification and genetic characterization of new bovine viral diarrhea virus genotype 2 strains in pigs isolated in China. AB - Classical swine fever (CSF)-like symptoms in pigs regarded as free from CSF has been reported previously. From sick pigs with CSF-like symptoms, and who had been inoculated with the hog cholera vaccine, samples were collected and subjected to RT-PCR using specific primers. Twelve bovine viral diarrhea virus 2 (BVDV-2) strains were screened and isolated. Homology comparison showed that the E2 genes of the twelve isolates were highly conserved. The genome of the one of the BVDV-2 isolates (named as SH-28) from the sick pigs, which showed a noncytopathic effect in MDBK cell cultures and strong reactivity with monoclonal antibody (MAb) Bz-53 raised against BVDV-2, was sequenced. The genome of SH-28 comprises 12,279 nucleotides and contains a large open reading frame beginning at nucleotide 386 and ending at nucleotide 12,073. Genomic comparison and phylogenetic analyzes showed that SH-28 fall into BVDV-2 subtype and was most similar to XJ-04 (nucleotide and amino acid homologies were 89.9-93.8 % and 91.1-96.9 %, respectively), but was genetically divergent from ZM-95 (pig BVDV-1). PMID- 23085885 TI - Introduction of East African cassava mosaic Zanzibar virus to Oman harks back to "Zanzibar, the capital of Oman". AB - Cassava mosaic disease (CMD) is the most devastating disease of the subsistence crop cassava (Manihot esculenta) across Africa and the Indian subcontinent. The disease is caused by viruses of the genus Begomovirus (family Geminiviridae) seven species have been identified so far. The Sultanate of Oman is unusual among countries in Arabia in growing cassava on a small scale for local consumption. During a recent survey in A'Seeb wilayat of Muscat governorate, Oman, cassava plants were identified with symptoms typical of CMD. A begomovirus, East African cassava mosaic Zanzibar virus (EACMZV), was isolated from symptomatic plants. This virus was previously only known to occur in Zanzibar and Kenya. During the 19th Century, Zanzibar was governed by Oman and was so important that the Sultan of Oman moved his capital there from Muscat. After a period of colonial rule, the governing Arab elite was overthrown, following independence in the 1960s, and many expatriate Omanis returned to their homeland. Having gained a liking for the local Zanzibar cuisine, it appears that returning Omanis did not wish to do without dishes made from one particular favorite, cassava. Consequently, they carried planting material back to Oman for cultivation in their kitchen gardens. The evidence suggests that this material harbored EACMZV. Recently, Oman has been shown to be a nexus for geminiviruses and their associated satellites from diverse geographic origins. With their propensity to recombine, a major mechanism for evolution of geminiviruses, and the fact that Oman (and several other Arabian countries) is a major hub for trade and travel by air and sea, the possibility of onward spread is worrying. PMID- 23085886 TI - Orbital upper critical field and its anisotropy of clean one- and two-band superconductors. AB - The Helfand-Werthamer (HW) scheme (Helfand and Werthamer 1966 Phys. Rev. 147 288; another part of this work published as a separate paper by Werthamer et al 1966 Phys. Rev. 147 295) of evaluating the orbital upper critical field is generalized to anisotropic superconductors in general, and to two-band clean materials, in particular. Our formal procedure differs from those in the literature; it reproduces not only the isotropic HW limit but also the results of calculations for the two-band superconducting MgB(2) (Miranovic et al 2003 J. Phys. Soc. Japan 72 221, Dahm and Schopohl 2003 Phys. Rev. Lett. 91 017001) along with the existing data on H(c2)(T) and its anisotropy gamma(T) = H(c2,ab)(T)/H(c2,c)(T) (a, c are the principal directions of a uniaxial crystal). Using rotational ellipsoids as model Fermi surfaces we apply the formalism developed to study gamma(T) for a few different anisotropies of the Fermi surface and of the order parameters. We find that even for a single band d-wave order parameter gamma(T) decreases on warming; however, relatively weakly. For order parameters of the form Delta(k(z)) = Delta(0)(1 + eta cos k(z)a) (Xu et al 2011 Nature Phys. 7 198), according to our simulations gamma(T) may either increase or decrease on warming even for a single band depending on the sign of eta. Hence, the common belief that the multi-band Fermi surface is responsible for the temperature variation of gamma is proven incorrect. For two s-wave gaps, gamma decreases on warming for all Fermi shapes examined. For two order parameters of the form Delta(k(z)) = Delta(0)(1 + eta cos k(z)a), presumably relevant for pnictides, we obtain gamma(T) increasing on warming provided both eta(1) and eta(2) are negative, whereas for eta > 0, gamma(T) decreases. We study the ratio of the two order parameters at H(c2)(T) and find that the ratio of the small gap to the large one does not vanish at any temperature, even at H(c2)(T), an indication that this does not happen at lower fields. PMID- 23085887 TI - Microwave-assisted synthesis of CdSe quantum dots: can the electromagnetic field influence the formation and quality of the resulting nanocrystals? AB - Microwave-assisted syntheses of colloidal nanocrystals (NCs), in particular CdSe quantum dots (QDs), have gained considerable attention due to unique opportunities provided by microwave dielectric heating. The extensive use of microwave heating and the frequently suggested specific microwave effects, however, pose questions about the role of the electromagnetic field in both the formation and quality of the produced QDs. In this work a one-pot protocol for the tunable synthesis of monodisperse colloidal CdSe NCs using microwave dielectric heating under carefully controlled conditions is introduced. CdSe QDs are fabricated using selenium dioxide as a selenium precursor, 1-octadecene as a solvent and reducing agent, cadmium alkyl carboxylates or alkyl phosphonates as cadmium sources, 1,2-hexadecanediol to stabilize the cadmium complex and oleic acid to stabilize the resulting CdSe QDs. Utilizing the possibilities of microwave heating technology in combination with accurate online temperature control the influence of different reaction parameters such as reaction temperature, ramp and hold times, and the timing and duration of oleic acid addition have been carefully investigated. Optimum results were obtained by performing the reaction at 240 degrees C applying a 5 min ramp time, 2 min hold time before oleic acid addition, 90 s for oleic acid addition, and a 5 min hold time after oleic acid addition (8.5 min overall holding at 240 degrees C). By using different cadmium complexes in the microwave protocol CdSe QDs with a narrow size distribution can be obtained in different sizes ranging from 0.5-4 nm by simply changing the cadmium source. The QDs were characterized by TEM, HRTEM, UV-Vis, and photoluminescence methods and the size distribution was monitored by SAXS. Control experiments involving conventional conductive heating under otherwise identical conditions ensuring the same heating and cooling profiles, stirring rates, and reactor geometries demonstrate that the electromagnetic field has no influence on the generated CdSe QDs. The resulting CdSe NCs prepared using either conductive or microwave dielectric heating exhibited the same primary crystallite size, shape, quantum yield and size distribution regardless of the heating mode. PMID- 23085888 TI - In situ noninvasive Raman microspectroscopic investigation of polychrome plasterworks in the Alhambra. AB - A totally non-invasive in situ investigation in one of the main halls of the Palace of the Lions in the Alhambra (Granada, Spain) has been carried out. Analyses were made with a fiber-optic portable Raman microspectrometer placed on scaffolding platforms at a height of ca. 12 m above the ground level during the period of conservation works. The objects of this study are the decorated plasterworks in the seven vaults of the Hall of the Kings. Together with the results, the different practical problems related to the positioning of the instrumental setup and the influence of the local environment during the analysis are discussed. In general, high quality spectra were obtained despite difficulties for micro-probe head positioning and sometimes the vibrations of the corresponding scaffold. Different typical antiquity pigments have been identified: cinnabar, minium, carbon black and lapis lazuli. Furthermore, the luminescence pattern from lapis lazuli found in most blue decorations has allowed the establishment of the natural origin and provenance of the pigment. Apart from this natural lapis lazuli, synthetic ultramarine blue was also found in one of the vaults showing up a recent restoration. In addition, some degradation products of cinnabar and minium were identified, with the major advantage of providing real-time information to the conservators during their work. PMID- 23085889 TI - A structural change in Ca3Co4O9 associated with enhanced thermoelectric properties. AB - Temperature dependent electrical resistivity, crystal structure and heat capacity measurements reveal a resistivity drop and electrical transport behavior change corresponding to a structural change near 400 K in Ca(3)Co(4)O(9). The lattice parameter c varies smoothly with increasing temperature while anomalies in a, b(1) and b(2) lattice parameters occur near 400 K. The Ca site in the Ca(2)CoO(3) block becomes distorted and a change in electrical transport behavior is found above 400 K. Resistivity and heat capacity measurements as a function of temperature under magnetic field combined with Co L-edge x-ray absorption spectra reveal only a weak spin contribution to this change. Reduced resistivity associated with the structural change enhances the thermoelectric properties at moderately high temperatures and points to the electrical transport behavior change as a mechanism for improved ZT in this thermoelectric oxide. PMID- 23085890 TI - Coeliac disease: time for a new diagnostic approach in symptomatic children. PMID- 23085892 TI - Human leukocyte antigen DQ2.2 and celiac disease. AB - Patients with celiac disease (CD) lacking both human leukocyte antigen (HLA) DQ2.5 in cis (DQA1*05:01, DQB1*02:01) or trans (DQA1*05:05, DQB1*02:02) configuration and HLA-DQ8 (DQA1*03:01, DQB1*03:02) are considered to be rare. Therefore, absence of these genotypes is commonly used to exclude the diagnosis of CD. To investigate whether this approach is justified, the HLA-distribution in 155 children with CD was studied. A total of 139 (89.7%) patients carried HLA DQ2.5. Of the remaining patients, 7 (4.5%) carried HLA-DQ8. Interestingly, the 9 (5.8%) patients lacking HLA-DQ2.5 and HLA-DQ8 carried HLA-DQA1*02:01 and DQB1*02:02 (HLA-DQ2.2). Therefore, HLA-DQ2.2 should be included as an important HLA-type related to CD. PMID- 23085893 TI - Kawasaki disease and the pediatric gastroenterologist: a diagnostic challenge. AB - BACKGROUND AND OBJECTIVES: Gastrointestinal symptoms and signs are rarely the main clinical presentation of Kawasaki disease (KD). In the present study, we report a series of patients with KD in whom a gastroenterology consult was obtained before consideration of the diagnosis of KD. METHODS: We retrospectively reviewed all patients with KD admitted to Children's Hospital Colorado from January 2009 through February 2011 with prominent gastrointestinal symptoms, resulting in gastrointestinal service consultation before their diagnosis of KD. RESULTS: We identified 7 of 118 (6%) patients with KD who met our criteria. All 7 patients were males, and the median age at admission was 9.7 years. All patients had abdominal pain and fever at presentation. Vomiting, diarrhea, and clinical jaundice were present in 70%, 50%, and 43% of patients, respectively. Aminotransferases and/or gamma-glutamyl transpeptidase abnormalities were observed in 6 (89%) patients. All of the patients had fever and rash on admission, and 86% had nonexudative conjunctivitis and 71% had mucosal changes. Median duration of illness at gastroenterology consultation was 5 days, whereas median duration of illness at infectious disease consultation was 6 days. One patient developed coronary artery dilation and 2 patients had intravenous immunoglobulin-resistant KD. CONCLUSIONS: Gastroenterologists should be aware of gastrointestinal presentations of KD. Unexplained gastrointestinal symptoms in the presence of fever, and 1 or 2 of the major clinical signs of KD, should prompt consideration of KD in the differential diagnosis. PMID- 23085891 TI - Monotonous diets protect against acute colitis in mice: epidemiologic and therapeutic implications. AB - OBJECTIVES: Multiple characteristics of industrialization have been proposed to contribute to the global emergence of inflammatory bowel diseases (IBDs: Crohn disease and ulcerative colitis). Major changes in eating habits during the last decades and the effectiveness of exclusive enteral nutrition in the treatment of Crohn disease indicate the etiologic importance of dietary intake in IBDs. A uniform characteristic of nutrition in developing countries (where the incidence of IBD is low) and exclusive enteral nutrition is their consistent nature for prolonged periods; however, the potentially beneficial effect of dietary monotony in respect to mammalian intestinal inflammation has not been examined. METHODS: The association between alternating (2 different complete chows) and persistent regular diets, and dextran sulfate sodium colitis susceptibility in C57BL/6J mice was studied. Colonic mucosal microbiota changes were investigated by high throughput pyrosequencing of the 16S rRNA gene. RESULTS: The severity of colitis increased upon dietary alternation compared with consistent control feeding. The microbiota of the alternating nutritional group clustered discretely from both control groups. CONCLUSIONS: Our findings highlight that monotonous dietary intake may decrease mammalian vulnerability against colitis in association with microbiota separation. The epidemiologic and therapeutic implications of our results are also discussed. PMID- 23085894 TI - Percutaneous endoscopic gastrostomy tubes in pediatric bone marrow transplant patients. AB - BACKGROUND AND OBJECTIVES: Nourishing a child undergoing bone marrow transplant (BMT) is essential, but the optimal method to achieve this is not established. The objectives of the study were to investigate the incidence and risk factors for complications of gastrostomy tubes in patients with BMT. METHODS: A retrospective chart review was conducted of pediatric patients who received a percutaneous endoscopic gastrostomy (PEG) either for BMT or for other indications during a 3-year period. Occurrences of complications, absolute neutrophil count (ANC) at time of PEG placement, and ANC at time of complication were reviewed for both BMT and the comparison group. RESULTS: Of the 11 subjects in the BMT group, 4 (36%) had a major complication of infection related to PEG and 3 of those required PEG removal. Two of the 4 subjects who developed a major complication were moderately neutropenic at the time of PEG placement and all subjects were neutropenic at the time of complication. Of the 30 subjects in the comparison group, only 1 (2.8%) had a major complication with cellulitis. There were no statistically significant differences between the 2 groups before PEG placement for age, weight, albumin, or white blood cell count. The incidence of complication in BMT compared with the comparison group was significant (P=0.01). CONCLUSIONS: Our findings support that ANC should be considered before placement of PEG, significant neutropenia may be a contraindication for PEG placement in BMT patients, and other modalities for nutrition support might need to be considered. PMID- 23085895 TI - Clinical features distinguish eosinophilic and reflux-induced esophagitis. AB - BACKGROUND AND OBJECTIVES: Diagnosing eosinophilic esophagitis (EoE) depends on intraepithelial eosinophil count of >=15 eosinophils per high-power field (HPF); however, differentiating EoE from gastroesophageal reflux disease (GERD) continues to be a challenge because no true "criterion standard" criteria exist. Identifying clinical and endoscopic characteristics that distinguish EoE could provide a more comprehensive diagnostic strategy than the present criteria. The aim of the study was to determine symptoms and signs that can be used to distinguish EoE from reflux esophagitis. METHODS: Adult and pediatric patients with EoE were identified by present diagnostic guidelines including an esophageal biopsy finding of >=15 eosinophils/HPF. Patients with GERD were age-matched one to one with patients with EoE. Clinical, endoscopic, and histologic information at the time of diagnosis was obtained from the medical record and compared between pairs by McNemar test. A conditional logistic regression model was created using 6 distinguishing disease characteristics. This model was used to create a nomogram to differentiate EoE from reflux-induced esophagitis. RESULTS: Patients with EoE were 75% men and 68% had a history of atopy. Many aspects of EoE were statistically distinct from GERD when controlling for age. Male sex, dysphagia, history of food impaction, absence of pain/heartburn, linear furrowing, and white papules were the distinguishing variables used to create the logistic regression model and scoring system based on odds ratios. The area under the curve of the receiver-operator characteristic curve for this model was 0.858. CONCLUSIONS: EoE can be distinguished from GERD using a scoring system of clinical and endoscopic features. Prospective studies will be needed to validate this model. PMID- 23085896 TI - Comprehensive evaluation of the effects of enalapril on matrix metalloproteinases levels in hypertension. AB - PURPOSE: Angiotensin-converting enzyme inhibitors (ACEi) may downregulate matrix metalloproteinases (MMPs). We examined whether enalapril affects MMP-2, MMP-8, and MMP-9 levels and activity, and their endogenous inhibitors (tissue inhibitors of MMPs, TIMP-1 and TIMP-2) levels in hypertensive patients. Moreover, we assessed the effects of enalaprilat on MMP-9 and TIMP-1 secretion by human endothelial cells (HUVECs). METHODS: Thirty-eight hypertensive patients received enalapril for 8 weeks and were compared with thirty-eight normotensive controls. Blood samples were collected at baseline and after treatment. Plasma ACE activity was determined by a fluorimetric assay. Plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 were measured by ELISA and gelatin zymography. A fluorogenic peptide cleavage assay was used to measure MMP activity. HUVECs cells were stimulated by phorbol-12-myristate-13-acetate (PMA) and the effects of enalaprilat (10(-10) to 10(-6) M) on MMP-9 and TIMP-1 levels were determined. RESULTS: Enalapril decreased blood pressure and ACE activity in hypertensive patients (P < 0.05), but had no effects on plasma MMP-2, MMP-8, MMP-9, TIMP-1, and TIMP-2 levels, or MMP activity. Enalaprilat had no effects on PMA-induced increases in MMP-9 and TIMP-1 secretion by HUVECs or on MMP activity. CONCLUSIONS: We show consistent evidence, both in vivo and in vitro, that enalapril does not affect MMPs and TIMPs levels in hypertensive patients. PMID- 23085897 TI - The management of subacute bacterial endocarditis superimposed on rheumatic heart disease in the immediate pre-penicillin era: the case of Pasquale Imperato. AB - Subacute bacterial endocarditis (SBE) was invariably a fatal disease in the pre penicillin era. The availability of sulfonamide antibiotics beginning in the mid 1930s raised hopes that they would be effective in SBE. Unfortunately, except in rare instances, they were not. This paper reviews the clinical experience with sulfonamides in the pre-penicillin period in treating patients with SBE. It presents in detail the case of Pasquale Imperato, who died from the disease at the age of 72 years on 30 November 1942. In so doing, it focuses on the medical management measures then available to treat patients with SBE and on the inevitable course of the illness once it began. Also discussed is the relationship of acute rheumatic fever and its sequela, rheumatic heart disease, to predisposing people to SBE and possible genetic factors. The well-known case of Alfred S. Reinhart, a Harvard Medical School student who died from SBE in 1931 and who kept a detailed chronicle of his disease, is also discussed and contrasted with Pasquale Imperato's case. PMID- 23085898 TI - Scattering anisotropy-weighted mesoscopic imaging. AB - We report that when tissue images are formed via a small solid angle in the backward direction (i.e., back-directional gating), the image intensity is dominantly determined by tissue scattering anisotropy. Thus, this configuration allows for scattering anisotropy-weighted imaging that can provide an intrinsic contrast by capturing tissue structures and organizations. To demonstrate the immediate feasibility, we apply scattering anisotropy-weighted imaging to tissue blocks including basal-cell carcinomas as a pilot study. The main feature of our imaging approach is the high sensitivity to tumor locations and the simplicity for large-area visualization. We further envision that scattering anisotropy weighted imaging could potentially be used to visualize tissue microenvironments in a mesoscopic (between microscopic and macroscopic) imaging setting. PMID- 23085899 TI - Noninvasive Raman spectroscopy of rat tibiae: approach to in vivo assessment of bone quality. AB - We report on in vivo noninvasive Raman spectroscopy of rat tibiae using robust fiber-optic Raman probes and holders designed for transcutaneous Raman measurements in small animals. The configuration allows placement of multiple fibers around a rat leg, maintaining contact with the skin. Bone Raman data are presented for three regions of the rat tibia diaphysis with different thicknesses of overlying soft tissue. The ability to perform in vivo noninvasive Raman measurement and evaluation of subtle changes in bone composition is demonstrated with rat leg phantoms in which the tibia has carbonated hydroxylapatite, with different carbonate contents. Our data provide proof of the principle that small changes in bone composition can be monitored through soft tissue at anatomical sites of interest in biomedical studies. PMID- 23085900 TI - Quantitative analysis of angle-resolved scattering properties of ovarian tissue using optical coherence tomography. AB - Angle-resolved optical scattering properties of ovarian tissue, on different optical coherence tomography (OCT) imaging planes, were quantitatively measured by fitting the compounded OCT A-lines into a single scattering model. Higher cross correlation value of angle-resolved scattering coefficients between different OCT imaging planes was found in normal ovaries than was present in malignant ovaries. The mean cross correlation coefficient (MCC) was introduced in this pilot study to characterize and differentiate normal, n=6, and malignant, n=4, ovaries. A specificity of 100 percent and a sensitivity of 100 percent were achieved by setting MCC threshold at 0.6. Collagen properties, within the OCT imaging penetration depth, were also qualitatively studied in terms of their content, structure and directivity. The homogeneous three-dimensional collagen fiber network, observed in the normal ovary, effectively explains the stronger cross correlation of angle-resolved scattering properties on different imaging planes while the heterogeneity, observed in the malignant ovary, suggests a weaker correlation. PMID- 23085901 TI - Peer-to-peer Monte Carlo simulation of photon migration in topical applications of biomedical optics. AB - In the framework of further development of the unified approach of photon migration in complex turbid media, such as biological tissues we present a peer to-peer (P2P) Monte Carlo (MC) code. The object-oriented programming is used for generalization of MC model for multipurpose use in various applications of biomedical optics. The online user interface providing multiuser access is developed using modern web technologies, such as Microsoft Silverlight, ASP.NET. The emerging P2P network utilizing computers with different types of compute unified device architecture-capable graphics processing units (GPUs) is applied for acceleration and to overcome the limitations, imposed by multiuser access in the online MC computational tool. The developed P2P MC was validated by comparing the results of simulation of diffuse reflectance and fluence rate distribution for semi-infinite scattering medium with known analytical results, results of adding-doubling method, and with other GPU-based MC techniques developed in the past. The best speedup of processing multiuser requests in a range of 4 to 35 s was achieved using single-precision computing, and the double-precision computing for floating-point arithmetic operations provides higher accuracy. PMID- 23085902 TI - Optical properties of human skin. AB - A survey of the literature is presented that provides an analysis of the optical properties of human skin, with particular regard to their applications in medicine. Included is a description of the primary interactions of light with skin and how these are commonly estimated using radiative transfer theory (RTT). This is followed by analysis of measured RTT coefficients available in the literature. Orders of magnitude differences are found within published absorption and reduced-scattering coefficients. Causes for these discrepancies are discussed in detail, including contrasts between data acquired in vitro and in vivo. An analysis of the phase functions applied in skin optics, along with the remaining optical coefficients (anisotropy factors and refractive indices) is also included. The survey concludes that further work in the field is necessary to establish a definitive range of realistic coefficients for clinically normal skin. PMID- 23085903 TI - Retinal safety of near-infrared lasers in cataract surgery. AB - Femtosecond lasers have added unprecedented precision and reproducibility to cataract surgery. However, retinal safety limits for the near-infrared lasers employed in surgery are not well quantified. We determined retinal injury thresholds for scanning patterns while considering the effects of reduced blood perfusion from rising intraocular pressure and retinal protection from light scattering on bubbles and tissue fragments produced by laser cutting. We measured retinal damage thresholds of a stationary, 1030-nm, continuous-wave laser with 2.6-mm retinal spot size for 10- and 100-s exposures in rabbits to be 1.35 W (1.26 to 1.42) and 0.78 W (0.73 to 0.83), respectively, and 1.08 W (0.96 to 1.11) and 0.36 W (0.33 to 0.41) when retinal perfusion is blocked. These thresholds were input into a computational model of ocular heating to calculate damage threshold temperatures. By requiring the tissue temperature to remain below the damage threshold temperatures determined in stationary beam experiments, one can calculate conservative damage thresholds for cataract surgery patterns. Light scattering on microbubbles and tissue fragments decreased the transmitted power by 88% within a 12 deg angle, adding a significant margin for retinal safety. These results can be used for assessment of the maximum permissible exposure during laser cataract surgery under various assumptions of blood perfusion, treatment duration, and scanning patterns. PMID- 23085904 TI - Dynamic contrast-enhanced optical imaging of in vivo organ function. AB - Conventional approaches to optical small animal molecular imaging suffer from poor resolution, limited sensitivity, and unreliable quantitation, often reducing their utility in practice. We previously demonstrated that the in vivo dynamics of an injected contrast agent could be exploited to provide high-contrast anatomical registration, owing to the temporal differences in each organ's response to the circulating fluorophore. This study extends this approach to explore whether dynamic contrast-enhanced optical imaging (DyCE) can allow noninvasive, in vivo assessment of organ function by quantifying the differing cellular uptake or wash-out dynamics of an agent in healthy and damaged organs. Specifically, we used DyCE to visualize and measure the organ-specific uptake dynamics of indocyanine green before and after induction of transient liver damage. DyCE imaging was performed longitudinally over nine days, and blood samples collected at each imaging session were analyzed for alanine aminotransferase (ALT), a liver enzyme assessed clinically as a measure of liver damage. We show that changes in DyCE-derived dynamics of liver and kidney dye uptake caused by liver damage correlate linearly with ALT concentrations, with an r2 value of 0.91. Our results demonstrate that DyCE can provide quantitative, in vivo, longitudinal measures of organ function with inexpensive and simple data acquisition. PMID- 23085905 TI - Parallel multigrid solver of radiative transfer equation for photon transport via graphics processing unit. AB - A graphics processing unit-based parallel multigrid solver for a radiative transfer equation with vacuum boundary condition or reflection boundary condition is presented for heterogeneous media with complex geometry based on two dimensional triangular meshes or three-dimensional tetrahedral meshes. The computational complexity of this parallel solver is linearly proportional to the degrees of freedom in both angular and spatial variables, while the full multigrid method is utilized to minimize the number of iterations. The overall gain of speed is roughly 30 to 300 fold with respect to our prior multigrid solver, which depends on the underlying regime and the parallelization. The numerical validations are presented with the MATLAB codes at https://sites.google.com/site/rtefastsolver/. PMID- 23085906 TI - Extracting cardiac shapes and motion of the chick embryo heart outflow tract from four-dimensional optical coherence tomography images. AB - Recent advances in optical coherence tomography (OCT), and the development of image reconstruction algorithms, enabled four-dimensional (4-D) (three dimensional imaging over time) imaging of the embryonic heart. To further analyze and quantify the dynamics of cardiac beating, segmentation procedures that can extract the shape of the heart and its motion are needed. Most previous studies analyzed cardiac image sequences using manually extracted shapes and measurements. However, this is time consuming and subject to inter-operator variability. Automated or semi-automated analyses of 4-D cardiac OCT images, although very desirable, are also extremely challenging. This work proposes a robust algorithm to semi automatically detect and track cardiac tissue layers from 4-D OCT images of early (tubular) embryonic hearts. Our algorithm uses a two dimensional (2-D) deformable double-line model (DLM) to detect target cardiac tissues. The detection algorithm uses a maximum-likelihood estimator and was successfully applied to 4-D in vivo OCT images of the heart outflow tract of day three chicken embryos. The extracted shapes captured the dynamics of the chick embryonic heart outflow tract wall, enabling further analysis of cardiac motion. PMID- 23085907 TI - In vivo functional imaging of blood flow and wall strain rate in outflow tract of embryonic chick heart using ultrafast spectral domain optical coherence tomography. AB - During cardiac development, the cardiac wall and flowing blood are two important cardiac tissues that constantly interact with each other. This dynamic interaction defines appropriate biomechanical environment to which the embryonic heart is exposed. Quantitative assessment of the dynamic parameters of wall tissues and blood flow is required to further our understanding of cardiac development. We report the use of an ultrafast 1310-nm dual-camera spectral domain optical coherence tomography (SDOCT) system to characterize/image, in parallel, the dynamic radial strain rate of the myocardial wall and the Doppler velocity of the underlying flowing blood within an in vivo beating chick embryo. The OCT system operates at 184-kHz line scan rate, providing the flexibility of imaging the fast blood flow and the slow tissue deformation within one scan. The ability to simultaneously characterize tissue motion and blood flow provides a useful approach to better understand cardiac dynamics during early developmental stages. PMID- 23085908 TI - Optical mapping at increased illumination intensities. AB - Voltage-sensitive fluorescent dyes have become a major tool in cardiac and neuro electrophysiology. Achieving high signal-to-noise ratios requires increased illumination intensities, which may cause photobleaching and phototoxicity. The optimal range of illumination intensities varies for different dyes and must be evaluated individually. We evaluate two dyes: di-4-ANBDQBS (excitation 660 nm) and di-4-ANEPPS (excitation 532 nm) in the guinea pig heart. The light intensity varies from 0.1 to 5 mW/mm2, with the upper limit at 5 to 10 times above values reported in the literature. The duration of illumination was 60 s, which in guinea pigs corresponds to 300 beats at a normal heart rate. Within the identified duration and intensity range, neither dye shows significant photobleaching or detectable phototoxic effects. However, light absorption at higher intensities causes noticeable tissue heating, which affects the electrophysiological parameters. The most pronounced effect is a shortening of the action potential duration, which, in the case of 532-nm excitation, can reach ~30%. At 660-nm excitation, the effect is ~10%. These findings may have important implications for the design of optical mapping protocols in biomedical applications. PMID- 23085909 TI - Feasibility of in vivo intravascular photoacoustic imaging using integrated ultrasound and photoacoustic imaging catheter. AB - Pilot studies of in vivo combined intravascular ultrasound (IVUS) and intravascular photoacoustic (IVPA) imaging are reported. A recently introduced prototype of an integrated IVUS/IVPA imaging catheter consisting of a single element ultrasound transducer and a light delivery system based on a single optical fiber was adapted and used for in vivo imaging of a coronary stent deployed in a rabbit's thoracic aorta in the presence of luminal blood. The results suggest that in vivo IVUS/IVPA imaging is feasible using the integrated IVUS/IVPA imaging catheter. The challenges of in vivo combined IVUS/IVPA imaging are discussed, and further improvements on the design of the catheter and the clinical imaging system are proposed. PMID- 23085910 TI - Infrared microscopic imaging of cutaneous wound healing: lipid conformation in the migrating epithelial tongue. AB - Infrared microscopic imaging has been utilized to analyze for the first time the spatial distribution of lipid structure in an ex vivo human organ culture skin wound healing model. Infrared images were collected at zero, two, four, and six days following wounding. Analysis of lipid infrared spectral properties revealed the presence of a lipid class with disordered chains within and in the vicinity of the migrating epithelial tongue. The presence of lipid ester C=O bands colocalized with the disordered chains provided evidence for the presence of carbonyl-containing lipid species. Gene array data complemented the biophysical studies and provided a biological rationale for the generation of the disordered chain species. This is the first clear observation, to our knowledge, of disordered lipid involvement in cutaneous wound healing. Several possibilities are discussed for the biological relevance of these observations. PMID- 23085911 TI - Mapping lipid and collagen by multispectral photoacoustic imaging of chemical bond vibration. AB - Photoacoustic microscopy using vibrational overtone absorption as a contrast mechanism allows bond-selective imaging of deep tissues. Due to the spectral similarity of molecules in the region of overtone vibration, it is difficult to interrogate chemical components using photoacoustic signal at single excitation wavelength. Here we demonstrate that lipids and collagen, two critical markers for many kinds of diseases, can be distinguished by multispectral photoacoustic imaging of the first overtone of C-H bond. A phantom consisting of rat-tail tendon and fat was constructed to demonstrate this technique. Wavelengths between 1650 and 1850 nm were scanned to excite both the first overtone and combination bands of C-H bonds. B-scan multispectral photoacoustic images, in which each pixel contains a spectrum, were analyzed by a multivariate curve resolution alternating least squares algorithm to recover the spatial distribution of collagen and lipids in the phantom. PMID- 23085912 TI - Towards pH-sensitive imaging of small animals with photon-counting difference diffuse fluorescence tomography. AB - The importance of cellular pH has been shown clearly in the study of cell activity, pathological feature, and drug metabolism. Monitoring pH changes of living cells and imaging the regions with abnormal pH-values, in vivo, could provide invaluable physiological and pathological information for the research of the cell biology, pharmacokinetics, diagnostics, and therapeutics of certain diseases such as cancer. Naturally, pH-sensitive fluorescence imaging of bulk tissues has been attracting great attentions from the realm of near infrared diffuse fluorescence tomography (DFT). Herein, the feasibility of quantifying pH induced fluorescence changes in turbid medium is investigated using a continuous wave difference-DFT technique that is based on the specifically designed computed tomography-analogous photon counting system and the Born normalized difference image reconstruction scheme. We have validated the methodology using two dimensional imaging experiments on a small-animal-sized phantom, embedding an inclusion with varying pH-values. The results show that the proposed approach can accurately localize the target with a quantitative resolution to pH-sensitive variation of the fluorescent yield, and might provide a promising alternative method of pH-sensitive fluorescence imaging in addition to the fluorescence lifetime imaging. PMID- 23085913 TI - Approximation error method can reduce artifacts due to scalp blood flow in optical brain activation imaging. AB - Diffuse optical tomography can image the hemodynamic response to an activation in the human brain by measuring changes in optical absorption of near-infrared light. Since optodes placed on the scalp are used, the measurements are very sensitive to changes in optical attenuation in the scalp, making optical brain activation imaging susceptible to artifacts due to effects of systemic circulation and local circulation of the scalp. We propose to use the Bayesian approximation error approach to reduce these artifacts. The feasibility of the approach is evaluated using simulated brain activations. When a localized cortical activation occurs simultaneously with changes in the scalp blood flow, these changes can mask the cortical activity causing spurious artifacts. We show that the proposed approach is able to recover from these artifacts even when the nominal tissue properties are not well known. PMID- 23085914 TI - Photoacoustic tomography to identify inflammatory arthritis. AB - Identifying neovascularity (angiogenesis) as an early feature of inflammatory arthritis can help in early accurate diagnosis and treatment monitoring of this disease. Photoacoustic tomography (PAT) is a hybrid imaging modality which relies on intrinsic differences in the optical absorption among the tissues being imaged. Since blood has highly absorbing chromophores including both oxygenated and deoxygenated hemoglobin, PAT holds potential in identifying early angiogenesis associated with inflammatory joint diseases. PAT is used to identify changes in the development of inflammatory arthritis in a rat model. Imaging at two different wavelengths, 1064 nm and 532 nm, on rats revealed that there is a significant signal enhancement in the ankle joints of the arthritis affected rats when compared to the normal control group. Histology images obtained from both the normal and the arthritis affected rats correlated well with the PAT findings. Results support the fact that the emerging PAT could become a new tool for clinical management of inflammatory arthritis. PMID- 23085915 TI - Digital parallel frequency-domain spectroscopy for tissue imaging. AB - Near-infrared (NIR) (650 to 1000 nm) optical properties of turbid media can be quantified accurately and noninvasively using methods based on diffuse reflectance or transmittance, such as frequency-domain photon migration (FDPM). Conventional FDPM techniques based on white-light steady-state (SS) spectral measurements in conjunction with the acquisition of frequency-domain (FD) data at selected wavelengths using laser diodes are used to measure broadband NIR scattering-corrected absorption spectra of turbid media. These techniques are limited by the number of wavelength points used to obtain FD data and by the sweeping technique used to collect FD data over a relatively large range. We have developed a method that introduces several improvements in the acquisition of optical parameters, based on the digital parallel acquisition of a comb of frequencies and on the use of a white laser as a single light source for both FD and SS measurements. The source, due to the high brightness, allows a higher penetration depth with an extremely low power on the sample. The parallel acquisition decreases the time required by standard serial systems that scan through a range of modulation frequencies. Furthermore, all-digital acquisition removes analog noise, avoids the analog mixer, and does not create radiofrequency interference or emission. PMID- 23085916 TI - Intravascular optical coherence tomography to characterize tissue deformation during angioplasty: preliminary experiments with artery phantoms. AB - We explored the potential of intravascular optical coherence tomography (IVOCT) to assess deformation during angioplasty balloon inflation. Using a semi compliant balloon and artery phantoms, we considered two experimental scenarios. The goal for the first scenario was to investigate if variation in the elasticity of the structure surrounding the balloon could be sensed by IVOCT monitoring. In this scenario, we used three single-layer phantoms with various mechanical properties. Image analysis was performed to extract the inner and outer diameters of the phantoms at various pressures. The goal for the second scenario was twofold. First, we investigated the IVOCT capability to monitor a more complex balloon inflation process. The balloon was in a folded state prior to inflation. This allowed studying two stages of deformation: during balloon unfolding and during balloon expansion. Second, we investigated IVOCT capability to monitor the deformation in a three-layer phantom used to better mimic a true artery. So, not only were the IVOCT images processed to provide the inner and outer diameters of the phantom, but the layer thicknesses were also determined. In both scenarios, IVOCT monitoring revealed to be very efficient in providing relevant information about the phantom deformation during balloon inflation. PMID- 23085917 TI - Acoustic and photoacoustic characterization of micron-sized perfluorocarbon emulsions. AB - Perfluorocarbon droplets containing nanoparticles (NPs) have recently been investigated as theranostic and dual-mode contrast agents. These droplets can be vaporized via laser irradiation or used as photoacoustic contrast agents below the vaporization threshold. This study investigates the photoacoustic mechanism of NP-loaded droplets using photoacoustic frequencies between 100 and 1000 MHz, where distinct spectral features are observed that are related to the droplet composition. The measured photoacoustic spectrum from NP-loaded perfluorocarbon droplets was compared to a theoretical model that assumes a homogenous liquid. Good agreement in the location of the spectral features was observed, which suggests the NPs act primarily as optical absorbers to induce thermal expansion of the droplet as a single homogenous object. The NP size and composition do not affect the photoacoustic spectrum; therefore, the photoacoustic signal can be maximized by optimizing the NP optical absorbing properties. To confirm the theoretical parameters in the model, photoacoustic, ultrasonic, and optical methods were used to estimate the droplet diameter. Photoacoustic and ultrasonic methods agreed to within 1.4%, while the optical measurement was 8.5% higher; this difference decreased with increasing droplet size. The small discrepancy may be attributed to the difficulty in observing the small droplets through the partially translucent phantom. PMID- 23085918 TI - Impact of the optical depth of field on cytogenetic image quality. AB - In digital pathology, clinical specimen slides are converted into digital images by microscopic image scanners. Since random vibration and mechanical drifting are unavoidable on even high-precision moving stages, the optical depth of field (DOF) of microscopic systems may affect image quality, in particular when using an objective lens with high magnification power. The DOF of a microscopic system was theoretically analyzed and experimentally validated using standard resolution targets under 60* dry and 100* oil objective lenses, respectively. Then cytogenetic samples were imaged at in-focused and off-focused states to analyze the impact of DOF on the acquired image qualities. For the investigated system equipped with the 60* dry and 100* oil objective lenses, the theoretical estimation of the DOF are 0.855 MUm and 0.703 MUm, and the measured DOF are 3.0 MUm and 1.8 MUm, respectively. The observation reveals that the chromosomal bands of metaphase cells are distinguishable when images are acquired up to approximately 1.5 MUm or 1 MUm out of focus using the 60* dry and 100* oil objective lenses, respectively. The results of this investigation provide important designing trade-off parameters to optimize the digital microscopic image scanning systems in the future. PMID- 23085919 TI - Improved intravital microscopy via synchronization of respiration and holder stabilization. AB - A major challenge in high-resolution intravital confocal and multiphoton microscopy is physiologic tissue movement during image acquisition. Of the various physiological sources of movement, respiration has arguably the largest and most wide-ranging effect. We describe a technique for achieving stabilized microscopy imaging using a dual strategy. First, we designed a mechanical stabilizer for constraining physical motion; this served to simultaneously increase the in-focus range over which data can be acquired as well as increase the reproducibility of imaging a certain position within each confocal imaging plane. Second, by implementing a retrospective breathing-gated imaging modality, we performed selective image extraction gated to a particular phase of the respiratory cycle. Thanks to the high reproducibility in position, all gated images presented a high degree of correlation over time. The images obtained using this technique not only showed significant improvements over images acquired without the stabilizer, but also demonstrated accurate in vivo imaging during longitudinal studies. The described methodology is easy to implement with any commercial imaging system, as are used by most biological imaging laboratories, and can be used for both confocal and multiphoton laser scanning microscopy. PMID- 23085920 TI - Sensing dynamic cytoplasm refractive index changes of adherent cells with quantitative phase microscopy using incorporated microspheres as optical probes. AB - The intracellular refractive index is an important parameter that describes the optical density of the cytoplasm and the concentration of the intracellular solutes. The refractive index of adherently grown cells is difficult to access. We present a method in which silica microspheres in living cells are used to determine the cytoplasm refractive index with quantitative phase microscopy. The reliability of our approach for refractive index retrieval is shown by data from a comparative study on osmotically stimulated adherent and suspended human pancreatic tumor cells. Results from adherent human fibro sarcoma cells demonstrate the capability of the method for sensing of dynamic refractive index changes and its usage with microfluidics. PMID- 23085921 TI - Extraction of effective parameters of turbid media utilizing the Mueller matrix approach: study of glucose sensing. AB - An analytical technique based on Stokes polarimetry and the Mueller matrix method is proposed for extracting the effective linear birefringence, linear dichroism, circular birefringence, circular dichroism, linear depolarization, and circular depolarization properties of turbid media. In contrast to existing analytical models, the model proposed extracts the effective parameters in a decoupled manner and considers not only the circular dichroism properties of the sample, but also the depolarization properties. The results show that the proposed method enables all of the effective parameters to be measured over the full range. Moreover, it is shown that the extracted value of the depolarization index is unaffected by the order in which the depolarizing Mueller matrix is decomposed during the extraction procedure. Finally, a method is proposed for calibrating the optical rotation angle of a polystyrene microsphere suspension containing dissolved D-glucose (C6H12O6) powder in accordance with the distance between the sample and the detector. The experimental results show that the sensitivity of the resulting D-glucose measurement is equal to approximately 1.73 deg/M. PMID- 23085922 TI - Diffuse correlation spectroscopy with a fast Fourier transform-based software autocorrelator. AB - Diffuse correlation spectroscopy (DCS) is an emerging noninvasive technique that probes the deep tissue blood flow, by using the time-averaged intensity autocorrelation function of the fluctuating diffuse reflectance signal. We present a fast Fourier transform (FFT)-based software autocorrelator that utilizes the graphical programming language LabVIEW (National Instruments) to complete data acquisition, recording, and processing tasks. The validation and evaluation experiments were conducted on an in-house flow phantom, human forearm, and photodynamic therapy (PDT) on mouse tumors under the acquisition rate of ~400 kHz. The software autocorrelator in general has certain advantages, such as flexibility in raw photon count data preprocessing and low cost. In addition to that, our FFT-based software autocorrelator offers smoother starting and ending plateaus when compared to a hardware correlator, which could directly benefit the fitting results without too much sacrifice in speed. We show that the blood flow index (BFI) obtained by using a software autocorrelator exhibits better linear behavior in a phantom control experiment when compared to a hardware one. The results indicate that an FFT-based software autocorrelator can be an alternative solution to the conventional hardware ones in DCS systems with considerable benefits. PMID- 23085923 TI - Absorption spectroscopy of single red blood cells in the presence of mechanical deformations induced by optical traps. AB - The electronic properties of single human red blood cells under mechanical deformations were investigated using a combination of dual beam optical tweezers and UV-vis absorption spectroscopy. The mechanical deformations were induced by two near-infrared optical traps with different trapping powers and trap configurations. The deformations were applied in two ways: locally, due to the mechanical forces around the traps, and by stretching the cell by moving the traps in opposite directions. In the presence of local deformations, the single cell undergoes a transition from an oxygenated state to a partially deoxygenated state. This process was found to be reversible and strongly power-dependent. Stretching the cell caused an opposite effect, indicating that the electronic response of the whole cell is dominated by the local interaction with the trapping beams. Results are discussed considering light-induced local heating, the Stark effect, and biochemical alterations due to mechanical forces, and are compared with reports of previous Raman spectroscopy studies. The information gained by the analysis of a single red blood cell's electronic response facilitates the understanding of fundamental physiological processes and sheds further light on the cell's mechanochemistry. This information may offer new opportunities for the diagnosis and treatment of blood diseases. PMID- 23085924 TI - Noninvasive fluorescence excitation spectroscopy for the diagnosis of oral neoplasia in vivo. AB - Fluorescence excitation spectroscopy (FES) is an emerging approach to cancer detection. The goal of this pilot study is to evaluate the diagnostic potential of FES technique for the detection and characterization of normal and cancerous oral lesions in vivo. Fluorescence excitation (FE) spectra from oral mucosa were recorded in the spectral range of 340 to 600 nm at 635 nm emission using a fiberoptic probe spectrofluorometer to obtain spectra from the buccal mucosa of 30 sites of 15 healthy volunteers and 15 sites of 10 cancerous patients. Significant FE spectral differences were observed between normal and well differentiated squamous cell carcinoma (WDSCC) oral lesions. The FE spectra of healthy volunteers consists of a broad emission band around 440 to 470 nm, whereas in WDSCC lesions, a new primary peak was seen at 410 nm with secondary peaks observed at 505, 540, and 580 nm due to the accumulation of porphyrins in oral lesions. The FE spectral bands of the WDSCC lesions resemble the typical absorption spectra of a porphyrin. Three potential ratios (I410/I505, I410/I540, and I410/I580) were calculated from the FE spectra and used as input variables for a stepwise linear discriminant analysis (SLDA) for normal and WDSCC groups. Leave-one-out (LOO) method of cross-validation was performed to check the reliability on spectral data for tissue characterization. The diagnostic sensitivity and specificity were determined for normal and WDSCC lesions from the scatter plot of the discriminant function scores. It was observed that diagnostic algorithm based on discriminant function scores obtained by SLDA-LOO method was able to distinguish WDSCC from normal lesions with a sensitivity of 100% and specificity of 100%. Results of the pilot study demonstrate that the FE spectral changes due to porphyrin have a good diagnostic potential; therefore, porphyrin can be used as a native tumor marker. PMID- 23085925 TI - Assessment of corneal hydration sensing in the terahertz band: in vivo results at 100 GHz. AB - Terahertz corneal hydration sensing has shown promise in ophthalmology applications and was recently shown to be capable of detecting water concentration changes of about two parts in a thousand in ex vivo corneal tissues. This technology may be effective in patient monitoring during refractive surgery and for early diagnosis and treatment monitoring in diseases of the cornea. In this work, Fuchs dystrophy, cornea transplant rejection, and keratoconus are discussed, and a hydration sensitivity of about one part in a hundred is predicted to be needed to successfully distinguish between diseased and healthy tissues in these applications. Stratified models of corneal tissue reflectivity are developed and validated using ex vivo spectroscopy of harvested porcine corneas that are hydrated using polyethylene glycol solutions. Simulation of the cornea's depth-dependent hydration profile, from 0.01 to 100 THz, identifies a peak in intrinsic reflectivity contrast for sensing at 100 GHz. A 100 GHz hydration sensing system is evaluated alongside the current standard ultrasound pachymetry technique to measure corneal hydration in vivo in four rabbits. A hydration sensitivity, of three parts per thousand or better, was measured in all four rabbits under study. This work presents the first in vivo demonstration of remote corneal hydration sensing. PMID- 23085926 TI - Effects of enamel abrasion, salivary pellicle, and measurement angle on the optical assessment of dental erosion. AB - The present study assessed the effects of abrasion, salivary proteins, and measurement angle on the quantification of early dental erosion by the analysis of reflection intensities from enamel. Enamel from 184 caries-free human molars was used for in vitro erosion in citric acid (pH 3.6). Abrasion of the eroded enamel resulted in a 6% to 14% increase in the specular reflection intensity compared to only eroded enamel, and the reflection increase depended on the erosion degree. Nevertheless, monitoring of early erosion by reflection analysis was possible even in the abraded eroded teeth. The presence of the salivary pellicle induced up to 22% higher reflection intensities due to the smoothing of the eroded enamel by the adhered proteins. However, this measurement artifact could be significantly minimized (p<0.05) by removing the pellicle layer with 3% NaOCl solution. Change of the measurement angles from 45 to 60 deg did not improve the sensitivity of the analysis at late erosion stages. The applicability of the method for monitoring the remineralization of eroded enamel remained unclear in a demineralization/remineralization cycling model of early dental erosion in vitro. PMID- 23085927 TI - Fluorescence spectra of blood and urine for cervical cancer detection. AB - In the current study, the fluorescence emission spectra (FES) and Stokes shift spectra (SSS) of blood and urine samples of cervical cancer patients were obtained and compared to those of normal controls. Both spectra showed that the relative intensity of biomolecules such as porphyrin, collagen, Nicotinamide adenine dinucleotide, and flavin were quite out of proportion in cervical cancer patients. The biochemical mechanism for the elevation of these fluorophores is not yet definitive; nevertheless, these biomolecules could serve as tumor markers for diagnosis, screening, and follow-up of cervical cancers. To the best of our knowledge, this is the first report on FES and SSS of blood and urine of cervical cancer patients to give a sensitivity of 80% and specificity of 78%. PMID- 23085928 TI - Optical property measurements establish the feasibility of photodynamic therapy as a minimally invasive intervention for tumors of the kidney. AB - We measured the optical properties of freshly excised kidneys with renal parenchymal tumors to assess the feasibility of photodynamic therapy (PDT) in these patients. Kidneys were collected from 16 patients during surgical nephrectomies. Spatially resolved, white light, steady-state diffuse reflectance measurements were performed on normal and neoplastic tissue identified by a pathologist. Reflectance data were fit using a radiative transport model to obtain absorption (MUa) and transport scattering coefficients (MUs'), which define a characteristic light propagation distance, delta. Monte Carlo (MC) simulations of light propagation from cylindrical diffusing fibers were run using the optical properties extracted from each of the kidneys. Interpretable spectra were obtained from 14 kidneys. Optical properties of human renal cancers exhibit significant inter-lesion heterogeneity. For all diagnoses, however, there is a trend toward increased light penetration at longer wavelengths. For renal cell carcinomas (RCC), mean values of delta increase from 1.28 to 2.78 mm as the PDT treatment wavelength is increased from 630 to 780 nm. MC simulations of light propagation from interstitial optical fibers show that fluence distribution in tumors is significantly improved at 780 versus 630 nm. Our results support the feasibility of PDT in selected renal cancer patients, especially with photosensitizers activated at longer wavelengths. PMID- 23085930 TI - Endothelial nitric oxide synthase gene polymorphism and type 2 diabetic retinopathy among Asian Indians. AB - Endothelial nitric oxide synthase (eNOS) has been shown to play an essential role in retinal vascular function, and disequilibrium in its production can lead to diabetic retinopathy (DR). Genetic polymorphisms of eNOS gene have been suggested to play a role in nitric oxide (NO) abnormalities which may contribute to the development and progression of DR. In view of the variable results that have been reported for the association between eNOS gene polymorphisms and DR, the present study was designed to study the association and interaction between eNOS gene polymorphisms and the development and progression of DR in Asian Indian type 2 diabetes mellitus patients (T2DM). We screened 1,720 T2DM patients, belonging to two independently ascertained cohorts out of which 1,446 were genotyped for three polymorphisms of eNOS (two SNPs: T-786C, G894T and one 27-bp repeat polymorphism in intron 4 (27VNTR)) using validated PCR-RFLP assays. In both the cohorts, consistently lower prevalence and decreased risk of DR was observed in patients with ba, aa and ba + aa genotype of 27VNTR (a/b), C-a-G and C-a-T haplotype (allele of T-786C, 27VNTR a/b and G894T) carrying "C" allele of T-786C and "a" allele of 27VNTR (a/b). Also, mean NO levels in T2DM subjects carrying ba + aa genotype were higher as compared to bb genotype. Our results suggest that eNOS genotypes 27VNTR carrying "aa" genotype is an independent protective factor for DR and is associated with low risk of DR. PMID- 23085931 TI - Sleep stage sequence analysis of sleep onset REM periods in the hypersomnias. AB - BACKGROUND: The Multiple Sleep Latency Test (MSLT) remains an important diagnostic tool in the diagnosis of hypersomnias. However, a positive MSLT may be found in other sleep disorders, such as behaviourally induced inadequate sleep syndrome (BIISS). It has been demonstrated that in sleep onset rapid eye movement (SOREM) periods in BIISS, REM sleep tends to arise from stage 2 sleep (non-REM (NREM) 2), rather than stage 1 sleep (NREM1), as in narcolepsy. METHODS: We performed sleep stage sequence analysis on 127 patients with nocturnal polysomnography and MSLT, including 25 with narcolepsy with cataplexy (N+C), 41 with narcolepsy without cataplexy (N-C), 21 with idiopathic hypersomnia with long sleep time (IHL), 20 with BIISS and 20 with periodic limb movement disorder (PLMD). 537 naps were recorded, containing 176 SOREM periods. RESULTS: All SOREM periods in the IHL, BIISS and PLMD groups arose from NREM2 sleep, 75% of those in N+C arose from NREM1 and in N-C only 52% arose from NREM1. Within the N-C group, those with SOREM periods all arising from stage 1 had a shorter MSL (p=0.02). CONCLUSIONS: These results suggest that SOREM periods arising from NREM1 have high sensitivity for the diagnosis of narcolepsy and that SOREM periods from NREM1 are a marker of severity, either of sleepiness or REM instability. Sleep stage sequence analysis of SOREM periods may also aid more accurate phenotyping of the hypersomnias and in particular clarify heterogeneity among patients with narcolepsy without cataplexy. PMID- 23085932 TI - The venous angioarchitecture of sporadic cerebral cavernous malformations: a susceptibility weighted imaging study at 7 T MRI. AB - BACKGROUND AND PURPOSE: To test the hypothesis that sporadic cerebral cavernous malformations (CCMs) are systematically associated with venous malformations (VMs) using susceptibility weighted imaging (SWI) at 7 Tesla (T) field MRI. METHODS: A prospective unselected series of 20 patients with symptomatic or asymptomatic sporadic CCM diagnosed using 1.5 T MRI was additionally scanned using high resolution (250 um(2) in-plane) SWI at 7 T MRI. Imaging data were analysed to examine the presence and formation of CCM associated venous vessel structures. Interobserver agreement was assessed using kappa statistics. RESULTS: In the 20 patients harbouring 23 CCMs, a solitary or multiple venous drainage was found in all lesions. A 'typical' VM was found in seven lesions. In the other cases, associated abnormal venous structures were also depicted although they appeared structurally different. Excellent interobserver agreement was achieved (95% confidence interval 0.92 to 0.99). CONCLUSIONS: Our data support previous assumptions that sporadic CCMs are systematically associated with local venous abnormalities involving larger outflow vessels. However, the typical appearance of a VM was not confirmed in all cases. The role of the venous environment in the pathomechanism of CCMs remains unclear. PMID- 23085933 TI - Grey matter correlates of clinical variables in amyotrophic lateral sclerosis (ALS): a neuroimaging study of ALS motor phenotype heterogeneity and cortical focality. AB - BACKGROUND: Body region of onset and functional disability are key components of disease heterogeneity in amyotrophic lateral sclerosis (ALS). OBJECTIVES: To evaluate patterns of grey matter pathology in the motor cortex and correlate focal structural changes with functional disability. METHODS: We conducted a single-centre neuroimaging study of a cohort of 33 cognitively normal patients with amyotrophic lateral sclerosis (ALS) and 44 healthy controls. A voxel-wise generalised linear model was used to investigate the distribution of disease burden within the motor cortex in relation to clinical disability. RESULTS: Patients with bulbar onset have bilateral focal atrophy in the bulbar segment of the motor homunculus compared with patients with limb onset who have focal cortical changes in the limb segment of their motor strip. Furthermore, the extent to which different body regions are affected in ALS corresponds to the extent of focal grey matter loss in the primary motor cortex. Cortical ALS pathology also extends beyond the motor cortex affecting frontal, occipital and temporal regions. CONCLUSIONS: Focal grey matter atrophy within the motor homunculus corresponds with functional disability in ALS. The findings support the existing concepts of cortical focality and motor phenotype heterogeneity in ALS. PMID- 23085934 TI - Rates and predictors of risk of stroke and its subtypes in diabetes: a prospective observational study. AB - BACKGROUND: Small vessel disease is reported to be a more common cause of ischaemic stroke in people with diabetes than in others. However, population based studies have shown no difference between those with and those without diabetes in the subtypes of stroke. We determined the rates and predictors of risk of stroke and its subtypes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. METHODS: 9795 patients aged 50-75 years with type 2 diabetes were followed up for a median of 5 years. Annual rates were derived by the Kaplan-Meier method and independent predictors of risk by Cox proportional hazards regression analyses. RESULTS: The annual rate of stroke was 6.7 per 1000 person years; 82% were ischaemic and caused by small artery disease (36%), large artery disease (17%) and embolism from the heart (13%); 10% were haemorrhagic. Among the strongest baseline predictors of ischaemic or unknown stroke were age (60-65 years, HR 1.98; >65 years, HR 2.35) and a history of stroke or transient ischaemic attack (TIA) (HR 2.06). Other independent baseline predictors were male sex, smoking, history of hypertension, ischaemic heart disease, nephropathy, systolic blood pressure and blood low density lipoprotein (LDL) cholesterol, HbA(1c) and fibrinogen. A history of peripheral vascular disease, low high density lipoprotein, age and history of hypertension were associated with large artery ischaemic stroke. A history of diabetic retinopathy, LDL cholesterol, male sex, systolic blood pressure, smoking, diabetes duration and a history of stroke or TIA were associated with small artery ischaemic stroke. CONCLUSIONS: Older people with a history of stroke were at highest risk of stroke, but the prognosis and prognostic factors of subtypes were heterogeneous. The results will help clinicians quantify the absolute risk of stroke and its subtypes for typical diabetes patients. PMID- 23085935 TI - Regional brain volume differences in symptomatic and presymptomatic carriers of familial Alzheimer's disease mutations. AB - BACKGROUND: Mutations in the presenilin (PSEN1, PSEN2) and amyloid precursor protein (APP) genes cause familial Alzheimer's disease (FAD) in a nearly fully penetrant, autosomal dominant manner, providing a unique opportunity to study presymptomatic individuals who can be predicted to develop Alzheimer's disease (AD) with essentially 100% certainty. Using tensor-based morphometry (TBM), we examined brain volume differences between presymptomatic and symptomatic FAD mutation carriers and non-carrier (NC) relatives. METHODS: Twenty-five mutation carriers and 10 NC relatives underwent brain MRI and clinical assessment. Four mutation carriers had dementia (MUT-Dem), 12 had amnestic mild cognitive impairment (MUT-aMCI) and nine were cognitively normal (MUT-Norm). TBM brain volume maps of MUT-Norm, MUT-aMCI and MUT-Dem subjects were compared to NC subjects. RESULTS: MUT-Norm subjects exhibited significantly smaller volumes in the thalamus, caudate and putamen. MUT-aMCI subjects had smaller volumes in the thalamus, splenium and pons, but not in the caudate or putamen. MUT-Dem subjects demonstrated smaller volumes in temporal, parietal and left frontal regions. As non-demented carriers approached the expected age of dementia diagnosis, this was associated with larger ventricular and caudate volumes and a trend towards smaller temporal lobe volume. CONCLUSIONS: Cognitively intact FAD mutation carriers had lower thalamic, caudate and putamen volumes, and we found preliminary evidence for increasing caudate size during the predementia stage. These regions may be affected earliest during prodromal stages of FAD, while cortical atrophy may occur in later stages, when carriers show cognitive deficits. Further studies of this population will help us understand the progression of neurobiological changes in AD. PMID- 23085936 TI - Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. AB - BACKGROUND: Crossover in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) has been described but is poorly understood. A GGGGCC hexanucleotide repeat expansion of C9ORF72 has recently been identified in a significant proportion of patients with ALS. METHODS: In approximately 650 patients diagnosed with ALS from the North of England we identified seven patients who initially presented with MS. DNA obtained from five patients with MS-ALS and 215 patients with MS alone was screened for the C9ORF72 expansion. Post-mortem material was examined from two patients with MS-ALS. Gene expression profiling was performed on lymphoblastoid cells and levels of CXCL10 were measured in cerebrospinal fluid (CSF) from patients with ALS with and without the C9ORF72 expansion and controls. RESULTS: Concurrence of MS and ALS is higher than expected in our population. The C9ORF72 expansion was identified in 80% of patients with MS-ALS but not in those with MS alone. In the presence of preceding MS, C9ORF72-ALS was more rapidly progressive. MetaCore analysis identified alteration of the NF-kB pathway in C9ORF72-ALS and non-C9ORF72-ALS. NF kB activation is associated with increased expression of the neuroprotective cytokine CXCL10 but, in C9ORF72-ALS, CXCL10 is downregulated and CSF levels are reduced. CONCLUSIONS: We propose that MS-associated neuroinflammation may affect penetrance and progression of the C9ORF72 expansion. In particular, the NF-kB pathway is activated in MS and appears to be dysfunctional in C9ORF72-ALS. Aberrant downregulation of CXCL10 may explain the predisposition of C9ORF72 expansion carriers to develop ALS in the context of MS and NF-kB activation, and offers a potential therapeutic target. PMID- 23085938 TI - Determinants and spatial patterns of adult overweight and hypertension in a high HIV prevalence rural South African population. AB - We conducted a large population-based survey among adults measuring weight, height, and blood pressure nested within an HIV survey in rural KwaZulu-Natal, South Africa, to identify and characterize clusters of overweight and hypertension in a typical rural African population and to explore whether geographic clusters can be accounted for by established individual-level risk factors. 58.4% of the participants were overweight and 22.6% were hypertensive. One cluster of high prevalence of overweight (RR=1.50, p<0.001) was identified using Kulldorff spatial scan statistic as the most likely cluster, whereas a low risk cluster was identified in the nearby high-density settlement area (RR=0.62, p<0.05). No geographic clusters of hypertension were identified. After controlling for age, sex, educational attainment, household wealth, marital status, place of residence, and HIV status, no spatial clustering of overweight remained. The results provided clear evidence for the localized clustering of overweight. Identification of clustering of chronic disease could provide additional insights into the prevention and control for the rural South African population. PMID- 23085939 TI - Street connectivity and obesity in Glasgow, Scotland: impact of age, sex and socioeconomic position. AB - This study investigated associations of street connectivity with body mass index (BMI), and whether these associations varied by sex, age and socioeconomic position, amongst adults in Glasgow, Scotland. Data on socio-demographic variables, height and weight were collected from 1062 participants in the Greater Glasgow Health and Well-being Study, and linked with neighbourhood-level census and geo-referenced data on area level deprivation and street connectivity. Results of multilevel models showed that, after adjustment for individual level covariates, street connectivity was not significantly associated with either BMI or BMI category; nor were there any significant interactions between age, sex or socioeconomic position and street connectivity. PMID- 23085937 TI - Therapeutic strategies for tau mediated neurodegeneration. AB - Based on the amyloid hypothesis, controlling beta-amyloid protein (Abeta) accumulation is supposed to suppress downstream pathological events, tau accumulation, neurodegeneration and cognitive decline. However, in recent clinical trials, Abeta removal or reducing Abeta production has shown limited efficacy. Moreover, while active immunisation with Abeta resulted in the clearance of Abeta, it did not prevent tau pathology or neurodegeneration. This prompts the concern that it might be too late to employ Abeta targeting therapies once tau mediated neurodegeneration has occurred. Therefore, it is timely and very important to develop tau directed therapies. The pathomechanisms of tau mediated neurodegeneration are unclear but hyperphosphorylation, oligomerisation, fibrillisation and propagation of tau pathology have been proposed as the likely pathological processes that induce loss of function or gain of toxic function of tau, causing neurodegeneration. Here we review the strategies for tau directed treatments based on recent progress in research on tau and our understanding of the pathomechanisms of tau mediated neurodegeneration. PMID- 23085940 TI - The unusual stabilization of the Ni2+ and Cu2+ complexes with NSFRY. AB - The binding mode provided by an unprotected peptide with non-coordinating side chains is simple and well understood. However, when particular residues are inserted into the peptide sequence, they can have a significant impact on the stability of the formed complexes. The presence of non-bonding side chains of amino acids close to the metal binding centre in the peptide/protein can provide special interactions which result in increasing the stabilization of the formed species. Moreover, these interactions can play a crucial role in generating particular protein structures and in influencing biological activity. In the present paper it is shown how peptides with no specific predisposition for metal binding, like ANF peptides, can form metal complexes with a very high thermodynamic stability. For better understanding this peculiar behavior, a combined pH-metric and spectroscopic method was used to determine the stability and the solution structure of Cu(2+) and Ni(2+) complexes with NSFRY-NH(2) (ANF peptide) and a series of analogue peptides. All obtained data support the hypothesis that the complex-formation process is very similar for both metal ions and all the ligands, involving some intramolecular interactions among the different side chains. The two-dimensional NMR analysis of nickel complexes showed the occurrence of many inter-residue correlations and suggested the presence of a direct interaction between the d electrons of the metal ion and the pi-ring system of the aromatic side-chains of the ligand. PMID- 23085941 TI - Plutonium-238: an ideal power source for intracorporeal ventricular assist devices? AB - Ventricular assist devices emerged as a widely used modality for treatment of end stage heart failure; however, despite significant advances, external energy supply remains a problem contributing to significant patient morbidity and potential mortality. One potential solution is using the nuclear radioisotope Plutonium-238 as a power source. Given its very high energy density and long half life, Plutonium-238 could eventually allow a totally intracorporeal ventricular assist system that lasts for the patient's lifetime. Risks, such as leakage and theft identified decades ago, still remain. However, it is possible that newer technologies could be used to overcome the system complexity and unreliability of the previous generations of nuclear-powered mechanical assist systems. Were it not for the remaining safety risks, Plutonium-238 would be an ideal energy source for this purpose. PMID- 23085942 TI - Physiologic response to a simplified venovenous perfusion-induced systemic hyperthermia system. AB - Our original venovenous perfusion-induced systemic hyperthermia (vv-PISH) system appeared to significantly improve the survival of patients with lung cancer, but was too complex with numerous dialysis problems. We tested a simplified vv-PISH circuit that includes the Avalon Elite (Avalon Laboratories, LLC, Rancho Dominguez, CA) double lumen cannula, a modified heat exchanger, a water heater/cooler, and a centrifugal pump. The purpose of this study was to evaluate this simplified vv-PISH system (without hemodialyzer) and to investigate the physiologic response to whole-body hyperthermia in pigs. We tested our vv-PISH circuit in healthy adult female swine (n = 7, 55-68 kg). The therapeutic core temperature (42 degrees C), calculated as mean of rectal, bladder, and esophageal temperatures, was achieved in six swine. A maximum difference of 0.5 degrees C was observed between the individual temperature sensor readings, indicating homogeneous heat distribution. Heart rate and mean arterial pressure were transiently altered, but were safely managed. A significant elevation in pulmonary artery pressure occurred during the heating phase, resulting in death of one pig. In all other pigs, pulmonary artery pressure returned to physiologic values during the therapeutic phase. Arterial blood electrolytes were maintained without the need of a dialyzer. Major organ function was within normal parameters. The simplified vv-PISH circuit reliably delivered the hyperthermic dose with no need of dialysis. PMID- 23085943 TI - Mechanisms underlying lineage commitment and plasticity of human gammadelta T cells. AB - Phenotypic and functional heterogeneity are the hallmarks of effector and memory T cells. Upon antigen stimulation, gammadelta T cells differentiate into two major types of memory T cells: central memory cells, which patrol the blood and secondary lymphoid organs, and effector memory cells, which migrate to peripheral tissues. gammadelta T cells display in vitro a certain degree of plasticity in their function that is reminiscent of that which is observed in conventional CD4 T cells. Similar to CD4 T cells, in which a plethora of specialized subsets affect the host response, gammadelta T cells may readily and rapidly assume distinct Th1-, Th2-, Th17-, T(FH) and T regulatory-like effector functions, suggesting that they profoundly influence cell-mediated and humoral immune responses. In addition to differences in cytokine repertoire, gammadelta T cells exhibit diversity in homing, such as migration to lymph node follicles, to help B cells versus migration to inflamed tissues. Here, we review our current understanding of gammadelta T-cell lineage heterogeneity and flexibility, with an emphasis on the human system, and propose a classification of effector gammadelta T cells based on distinct functional phenotypes. PMID- 23085944 TI - Induction of M2-like macrophages in recipient NOD-scid mice by allogeneic donor CD4(+)CD25(+) regulatory T cells. AB - CD4(+)CD25(+) regulatory T cells (Tregs) play an important role in maintaining host immune tolerance via regulation of the phenotype and function of the innate and adaptive immune cells. Whether allogeneic CD4(+)CD25(+) Tregs can regulate recipient mouse macrophages is unknown. The effect of allogeneic donor CD4(+)CD25(+) Tregs on recipient mouse resident F4/80(+)macrophages was investigated using a mouse model in which allogeneic donor CD4(+)CD25(+) Tregs were adoptively transferred into the peritoneal cavity of host NOD-scid mice. The phenotype and function of the recipient macrophages were then assayed. The peritoneal F4/80(+) macrophages in the recipient mice that received the allogeneic CD4(+)CD25(+) Tregs expressed significantly higher levels of CD23 and programmed cell death-ligand 1(PD-L1) and lower levels of CD80, CD86, CD40 and MHC II molecules compared to the mice that received either allogeneic CD4(+)CD25( ) T cells (Teffs) or no cells. The resident F4/80(+) macrophages of the recipient mice injected with the allogeneic donor CD4(+)CD25(+) Tregs displayed significantly increased phagocytosis of chicken red blood cells (cRBCs) and arginase activity together with increased IL-10 production, whereas these macrophages also showed decreased immunogenicity and nitric oxide (NO) production. Blocking arginase partially but significantly reversed the effects of CD4(+)CD25(+) Tregs with regard to the induction of the M2 macrophages in vivo. Therefore, the allogeneic donor CD4(+)CD25(+) Tregs can induce the M2 macrophages in recipient mice at least in part via an arginase pathway. We have provided in vivo evidence to support the unknown pathways by which allogeneic donor CD4(+)CD25(+) Tregs regulate innate immunity in recipient mice by promoting the differentiation of M2 macrophages. PMID- 23085945 TI - Inhibition of Pim2-prolonged skin allograft survival through the apoptosis regulation pathway. AB - Recently, apoptosis has been considered to be an important regulator for allograft survival. The serine/threonine kinase Pim2 has been implicated in many apoptotic pathways. In a previous study, we found that pim2 was highly expressed in CD4(+) T cells in an allograft model. Here, we further investigated the effects of Pim2 on allograft survival and the underlying mechanisms associated with apoptosis. The results showed that pim2 was overexpressed in grafts and spleens, particularly in spleen CD4(+) T cells when acute allorejection occurred, and correlated positively with the extent of rejection. In T cells from the spleens of naive BALB/c mice treated with 5 uM 4a (a specific inhibitor of Pim2) for 24 h, the apoptosis rate increased and the phosphorylation of BAD was decreased. Furthermore, adoptive transfer of CD4(+) T cells treated with 4a in vitro to allografted severe combined immunodeficiency (SCID) mice effectively prolonged allograft survival from 19.5+/-1.7 days to 31+/-2.3 days. Moreover, the results demonstrated that the CD4(+)CD25(-) effector T-cell subset was the predominate expresser of the pim2 gene as compared with the CD4(+)CD25(+) regulatory T (Treg) cell subset. Alloantigen-induced CD4(+)CD25(+) T cells displayed less Foxp3 expression and a low suppression of apoptosis compared with effector CD4(+)CD25(-) T cells treated with 4a. Collectively, these data revealed that Pim2 facilitated allograft rejection primarily by modulating the apoptosis of effector T cells and the function of Treg cells. These data suggested that Pim2 may be an important target for in vivo anti-rejection therapies and for the ex vivo expansion of CD4(+)CD25(+) T cells. PMID- 23085946 TI - Diversity of gammadelta T-cell antigens. AB - In the last two decades, it has become clear that gammadelta T cells recognize a diverse array of antigens including self and foreign, large and small, and peptidic and non-peptidic molecules. In this respect, gammadelta antigens as a whole resemble more the antigens recognized by antibodies than those recognized by alphabeta T cells. Because of this antigenic diversity, no single mechanism such as the major histocompatibility complex (MHC) restriction of alphabeta T cells-is likely to provide a basis for all observed T-cell antigen receptor (TCR) dependent gammadelta T-cell responses. Furthermore, available evidence suggests that many individual gammadelta T cells are poly-specific, probably using different modes of ligand recognition in their responses to unrelated antigens. While posing a unique challenge in the maintenance of self-tolerance, this broad reactivity pattern might enable multiple overlapping uses of gammadelta T-cell populations, and thus generate a more efficient immune response. PMID- 23085948 TI - Pre-treatment with IL-1beta enhances the efficacy of MSC transplantation in DSS induced colitis. AB - Mesenchymal stem cells (MSCs) have been used experimentally for treating inflammatory disorders, partly due to their immunosuppressive properties. Although interleukin-1beta (IL-1beta) is one of the most important inflammatory mediators, growing evidence indicates that IL-1beta signaling elicits the immunosuppressive properties of MSCs. However, it remains unclear how IL-1beta signaling accomplishes this activity. Here, we focus on the therapeutic efficacy of IL-1beta-primed MSCs in the dextran sulfate sodium (DSS)-induced colitis model, in addition to the underlining mechanisms. We first found that IL-1beta primed MSCs, without any observable phenotype change in vitro, significantly attenuated the development of DSS-induced murine colitis. Moreover, IL-1beta primed MSCs modulated the balance of immune cells in the spleen and the mesenteric lymph nodes (MLNs) through elevating cyclooxygenase-2 (COX-2), IL-6 and IL-8 expression and influencing the polarization of peritoneal macrophages. Importantly, IL-1beta-primed MSCs possessed an enhanced ability to migrate to the inflammatory site of the gut via upregulation of chemokine receptor type 4 (CXCR4) expression. In summary, IL-1beta-primed MSCs have improved efficacy in treating DSS-induced colitis, which at least partly depends on their increased immunosuppressive capacities and enhanced migration ability. PMID- 23085947 TI - Defining the nature of human gammadelta T cells: a biographical sketch of the highly empathetic. AB - The elusive task of defining the character of gammadelta T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the alpha and beta T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, gammadelta T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and alphabeta T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm gammadelta T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human gammadelta T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. PMID- 23085950 TI - Type I interferon: the mediator of bacterial infection-induced necroptosis. PMID- 23085949 TI - The equivalents of human blood and spleen dendritic cell subtypes can be generated in vitro from human CD34(+) stem cells in the presence of fms-like tyrosine kinase 3 ligand and thrombopoietin. AB - Dendritic cells (DCs) are immune cells specialized to capture, process and present antigen to T cells in order to initiate an appropriate adaptive immune response. The study of mouse DC has revealed a heterogeneous population of cells that differ in their development, surface phenotype and function. The study of human blood and spleen has shown the presence of two subsets of conventional DC including the CD1b/c(+) and CD141(+)CLEC9A(+) conventional DC (cDC) and a plasmacytoid DC (pDC) that is CD304(+)CD123(+). Studies on these subpopulations have revealed phenotypic and functional differences that are similar to those described in the mouse. In this study, the three DC subsets have been generated in vitro from human CD34(+) precursors in the presence of fms-like tyrosine kinase 3 ligand (Flt3L) and thrombopoietin (TPO). The DC subsets so generated, including the CD1b/c(+) and CLEC9A(+) cDCs and CD123(+) pDCs, were largely similar to their blood and spleen counterparts with respect to surface phenotype, toll-like receptor and transcription factor expression, capacity to stimulate T cells, cytokine secretion and cross-presentation of antigens. This system may be utilized to study aspects of DC development and function not possible in vivo. PMID- 23085951 TI - TLR8: the forgotten relative revindicated. AB - The endosomal Toll-like receptors (TLRs) TLR3, TLR7, TLR8 and TLR9 are important in sensing foreign nucleic acids encountered by phagocytes. Because TLR8 was initially thought to be non-functional in mice, less is known about TLR8 than the genetically and functionally related TLR7. Originally associated with the recognition of single-stranded RNA of viral origin, there is now evidence that human TLR8 is also able to sense bacterial RNA released within phagosomal vacuoles, inducing the production of both nuclear factor (NF)-kappaB-dependent cytokines and type I interferons (IFNs), such as IFN-beta. The functions of TLR8 extend beyond the recognition of foreign pathogens and include cross-talk with other endosomal TLRs, a process that may also have a role in the generation of autoimmunity. PMID- 23085953 TI - Exiguobacterium oxidotolerans, a halotolerant plant growth promoting rhizobacteria, improves yield and content of secondary metabolites in Bacopa monnieri (L.) Pennell under primary and secondary salt stress. AB - Brahmi (Bacopa monnieri), an integral component of Indian Ayurvedic medicine system, is facing a threat of extinction owing to the depletion of its natural populations. The present study investigates the prospective of exploitation of halotolerant plant growth promoting rhizobacteria (PGPR) in utilising the salt stressed soils for cultivation of B. monnieri. The effects of two salt tolerant PGPR, Bacillus pumilus (STR2) and Exiguobacterium oxidotolerans (STR36) on the growth and content of bacoside-A, an important pharmaceutical compound in B. monnieri, were investigated under primary and secondary salinity conditions. The herb yields of un-inoculated plants decreased by 48 % under secondary salinization and 60 % under primary salinization than the non salinised plants. Among the rhizobacteria treated plants, E. oxidotolerans recorded 109 and 138 %, higher herb yield than non-inoculated plants subjected to primary and secondary salinity respectively. E. oxidotolerans inoculated plants recorded 36 and 76 % higher bacoside-A content under primary and secondary salinity respectively. Higher levels of proline content and considerably lower levels of lipid peroxidation were noticed when the plants were inoculated with PGPR under all salinity regimes. From the results of this investigation, it can be concluded that, the treatments with salt tolerant PGPR can be a useful strategy in the enhancement of biomass yield and saponin contents in B. monnieri, as besides being an eco-friendly approach; it can also be instrumental in cultivation of B. monnieri in salt stressed environments. PMID- 23085954 TI - Biosynthesis of nicotinic acid from 3-cyanopyridine by a newly isolated Fusarium proliferatum ZJB-09150. AB - In this study, nitriles were used as sole sources of nitrogen in the enrichments to isolate nitrile-converting microorganisms. A novel fungus named ZJB-09150 possessing nitrile-converting enzymes was obtained with 3-cyanopyridine as sole source of nitrogen, which was identified by morphology, biology and 18S rDNA gene sequence as Fusarium proliferatum. It was found that F. proliferatum had ability to convert nitriles to corresponding acids or amides and showed wide substrate specificity to aliphatic nitriles, aromatic nitriles and ortho-substituted heterocyclic nitriles. The nitrile converting enzymes including nitrilase and nitrile hydratase in ZJB-09150 were induced by epsilon-caprolactam. Nitrilase obtained in this study showed high activity toward 3-cyanopyridine. It was active within pH 3.0-12.0 and temperature ranging from 25 to 65 degrees C with optimal at pH 9.0 and temperature 50-55 degrees C. The enzyme was thermostable and its half-life was 12.5 and 6 h at 45 and 55 degrees C, respectively. Under optimized reaction conditions, 60 mM 3-cyanopyridine was converted to nicotinic acid in 15 min, which indicated ZJB-09150 has potentials of application in large scale production of nicotinic acid. PMID- 23085955 TI - Enhanced production of (+)-terrein in fed-batch cultivation of Aspergillus terreus strain PF26 with sodium citrate. AB - (+)-Terrein is a fungal metabolite with multiple biological activities, especially with great value in medicine. However, the mass production of single configuration terrein is still a big challenge. In this study, the effects of acetic acid, sodium acetate, citric acid and sodium citrate on the (+)-terrein production by Aspergillus terreus strain PF26 derived from marine sponge Phakellia fusca were investigated. Sodium citrate was selected for fed-batch cultivation because it showed the best effect on (+)-terrein production among the four regulators tested. As a result, 5.38 g/L (+)-terrein production was achieved by feeding 10 mM sodium citrate on the 3rd day in shake flask, which was 33.8 % higher than the control and represented the highest yield of (+)-terrein. In a 7.5-L stirred bioreactor, 2.58 g/L of (+)-terrein production was achieved by the feeding of 10 mM sodium citrate on the 8th day. The results from this study lay a basis for the high-yield production of (+)-terrein by fermentation. PMID- 23085956 TI - Stuck in traffic: Patterns of powder adhesion. AB - The adhesion of fine particles to surfaces is important for applications ranging from drug delivery to fouling of solar cells. In this letter, we show that powder adhesion can occur in unexpected patterns, concentrating particular grain types in some locations and clearing them from others, and we propose a straightforward traffic model that appears to reproduce many of the behaviors seen. The model predicts different patterns depending on inter-particle cohesion, and we find in both experiment and model that adhesion occurs in three distinct stages. PMID- 23085958 TI - Role of autophagy in COPD skeletal muscle dysfunction. AB - Chronic obstructive pulmonary disease (COPD) is a debilitating disease caused by parenchymal damage and irreversible airflow limitation. In addition to lung dysfunction, patients with COPD develop weight loss, malnutrition, poor exercise performance, and skeletal muscle atrophy. The latter has been attributed to an imbalance between muscle protein synthesis and protein degradation. Several reports have confirmed that enhanced protein degradation and atrophy of limb muscles of COPD patient is mediated in part through activation of the ubiquitin proteasome pathway and that this activation is triggered by enhanced production of reactive oxygen species. Until recently, the importance of the autophagy lysosome pathway in protein degradation of skeletal muscles has been largely ignored, however, recent evidence suggests that this pathway is actively involved in recycling of cytosolic proteins, organelles, and protein aggregates in normal skeletal muscles. The protective role of autophagy in the regulation of muscle mass has recently been uncovered in mice with muscle-specific suppression of autophagy. These mice develop severe muscle weakness, atrophy, and decreased muscle contractility. No information is yet available about the involvement of the autophagy in the regulation of skeletal muscle mass in COPD patients. Pilot experiments on vastus lateralis muscle samples suggest that the autophagy lysosome system is induced in COPD patients compared with control subjects. In this review, we summarize recent progress related to molecular structure, regulation, and roles of the autophagy-lysosome pathway in normal and diseased skeletal muscles. We also speculate about regulation and functional importance of this system in skeletal muscle dysfunction in COPD patients. PMID- 23085957 TI - Functional classification of skeletal muscle networks. II. Applications to pathophysiology. AB - In our preceding companion paper (Wang Y, Winters J, Subramaniam S. J Appl Physiol. doi: 10.1152/japplphysiol.01514.2011), we used extensive expression profile data on normal human subjects, in combination with legacy knowledge to classify skeletal muscle function into four models, namely excitation-activation, mechanical, metabolic, and signaling-production model families. In this paper, we demonstrate how this classification can be applied to study two well characterized myopathies: amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD). Using skeletal muscle profile data from ALS and DMD patients compared with that from normal subjects, normal young in the case of DMD, we delineate molecular mechanisms that are causative and consequential to skeletal muscle dysfunction. In ALS, our analysis establishes the metabolic role and specifically identifies the mechanisms of calcium dysregulation and defects in mitochondrial transport of materials as important for muscle dysfunction. In DMD, we illustrate how impaired mechanical function is strongly coordinated with other three functional networks, resulting in transformation of the skeletal muscle into hybrid forms as a compensatory mechanism. Our functional models also provide, in exquisite detail, the mechanistic role of myriad proteins in these four families in normal and disease function. PMID- 23085960 TI - Reduced motor unit discharge rates of maximal velocity dynamic contractions in response to a submaximal dynamic fatigue protocol. AB - Fatigability is highly task dependent wherein motor unit (MU) discharge rates and recruitment thresholds are affected differently depending on whether contractions are performed at maximal or submaximal intensities. Although much is described for isometric tasks, the behavior of MU properties during the production of maximal velocity dynamic contractions following submaximal fatiguing contractions is unknown. In seven young men, we evaluated changes in MU recruitment thresholds and MU discharge rates of the anconeus muscle during both submaximal and maximal dynamic elbow extensions following a submaximal dynamic fatiguing protocol of moderate intensity to velocity task failure. Velocity and power of the maximal dynamic contractions declined ~45 and ~55%, respectively, but these variables were unchanged for the submaximal target velocity contractions. Discharge rates of the 12 MUs at task failure were unchanged for submaximal dynamic contractions, but were decreased ~20% for maximal dynamic and ballistic isometric contractions at task failure. MU recruitment thresholds of submaximal dynamic contractions decreased 52% at task failure, but were similar throughout the fatiguing protocol for maximal contractions. These findings support the concept of a common neural mechanism responsible for the relative declines in MU discharge rate associated with submaximal fatigability in both isometric and dynamic contractions. PMID- 23085961 TI - Viewpoint: On the hysteresis in the human Achilles tendon. PMID- 23085959 TI - Functional classification of skeletal muscle networks. I. Normal physiology. AB - Extensive measurements of the parts list of human skeletal muscle through transcriptomics and other phenotypic assays offer the opportunity to reconstruct detailed functional models. Through integration of vast amounts of data present in databases and extant knowledge of muscle function combined with robust analyses that include a clustering approach, we present both a protein parts list and network models for skeletal muscle function. The model comprises the four key functional family networks that coexist within a functional space; namely, excitation-activation family (forward pathways that transmit a motoneuronal command signal into the spatial volume of the cell and then use Ca(2+) fluxes to bind Ca(2+) to troponin C sites on F-actin filaments, plus transmembrane pumps that maintain transmission capacity); mechanical transmission family (a sophisticated three-dimensional mechanical apparatus that bidirectionally couples the millions of actin-myosin nanomotors with external axial tensile forces at insertion sites); metabolic and bioenergetics family (pathways that supply energy for the skeletal muscle function under widely varying demands and provide for other cellular processes); and signaling-production family (which represents various sensing, signal transduction, and nuclear infrastructure that controls the turn over and structural integrity and regulates the maintenance, regeneration, and remodeling of the muscle). Within each family, we identify subfamilies that function as a unit through analysis of large-scale transcription profiles of muscle and other tissues. This comprehensive network model provides a framework for exploring functional mechanisms of the skeletal muscle in normal and pathophysiology, as well as for quantitative modeling. PMID- 23085962 TI - Physically based principles of cell adhesion mechanosensitivity in tissues. AB - The minimal structural unit that defines living organisms is a single cell. By proliferating and mechanically interacting with each other, cells can build complex organization such as tissues that ultimately organize into even more complex multicellular living organisms, such as mammals, composed of billions of single cells interacting with each other. As opposed to passive materials, living cells actively respond to the mechanical perturbations occurring in their environment. Tissue cell adhesion to its surrounding extracellular matrix or to neighbors is an example of a biological process that adapts to physical cues. The adhesion of tissue cells to their surrounding medium induces the generation of intracellular contraction forces whose amplitude adapts to the mechanical properties of the environment. In turn, solicitation of adhering cells with physical forces, such as blood flow shearing the layer of endothelial cells in the lumen of arteries, reinforces cell adhesion and impacts cell contractility. In biological terms, the sensing of physical signals is transduced into biochemical signaling events that guide cellular responses such as cell differentiation, cell growth and cell death. Regarding the biological and developmental consequences of cell adaptation to mechanical perturbations, understanding mechanotransduction in tissue cell adhesion appears as an important step in numerous fields of biology, such as cancer, regenerative medicine or tissue bioengineering for instance. Physicists were first tempted to view cell adhesion as the wetting transition of a soft bag having a complex, adhesive interaction with the surface. But surprising responses of tissue cell adhesion to mechanical cues challenged this view. This, however, did not exclude that cell adhesion could be understood in physical terms. It meant that new models and descriptions had to be created specifically for these biological issues, and could not straightforwardly be adapted from dead matter. In this review, we present physical concepts of tissue cell adhesion and the unexpected cellular responses to mechanical cues such as external forces and stiffness sensing. We show how biophysical approaches, both experimentally and theoretically, have contributed to our understanding of the regulation of cellular functions through physical force sensing mechanisms. Finally, we discuss the different physical models that could explain how tissue cell adhesion and force sensing can be coupled to internal mechanosensitive processes within the cell body. PMID- 23085963 TI - A novel fluorescence method for determination of pFe3+. AB - The fluorescence intensity of probe CP645 in the presence of iron and a competing ligand is associated with pFe(3+) of the competing ligand. A linear correlation was found to exist between the fluorescence and pFe(3+) values. The pFe(3+) values of well studied ligands calculated from the standard curve are consistent with reported values. This novel fluorescence method can be used to determine the pFe(3+) values of ligands which are difficult to measure using conventional spectrophotometric or potentiometric methods. PMID- 23085964 TI - Multi-vortical flow inducing electrokinetic instability in ion concentration polarization layer. AB - In this work, we investigated multiple vortical flows inside the ion concentration polarization (ICP) layer that forms due to a coupling of applied electric fields and the semipermeable nanoporous junction between microchannels. While only a primary vortex near perm-selective membrane is traditionally known to lead to electrokinetic instability, multiple vortexes induced by the primary vortex were found to play a major role in the electrokinetic instability. The existence of multiple vortexes was directly confirmed by experiments using particle tracers and interdigitated electrodes were used to measure the local concentration profile inside the ICP layer. At larger applied electric fields, we observed aperiodic fluid motion due to electrokinetic instabilities which develop from a coupling of applied electric fields and electrical conductivity gradients induced by the ICP. The electrokinetic instability at micro-nanofluidic interfaces is important in the development of various electro-chemical-mechanical applications such as fuel cells, bio-analytical preconcentration methods, water purification/desalination and the fundamental study of ion electromigration through nanochannels and nonporous perm-selective membranes. PMID- 23085965 TI - A unified model exploring parenting practices as mediators of marital conflict and children's adjustment. AB - We examined positive and negative parenting practices and psychological control as mediators of the relations between constructive and destructive marital conflict and children's internalizing and externalizing problems in a unified model. Married mothers of 121 children between the ages of 6 and 12 completed questionnaires measuring marital conflict, parenting practices, and child adjustment. Analyses revealed significant direct paths from destructive marital conflict to negative parenting practices, psychological control, and both children's internalizing and externalizing behavior. In addition, psychological control was found to partially mediate relations between destructive marital conflict and children's internalizing and externalizing behavior. PMID- 23085966 TI - Summarizing phenotype evolution patterns from report cases. AB - The need to represent and manage time is implicit in several reasoning processes in medicine. However, this is predominantly obvious in the field of many neurodegenerative disorders, which are characterized by insidious onsets, progressive courses and variable combinations of clinical manifestations in each patient. Therefore, the availability of tools providing high level descriptions of the evolution of phenotype manifestations from patient data is crucial to promote early disease recognition and optimize the diagnostic process. Although many case reports published in the literature do not provide exhaustive temporal information except only key time references, such as disease onset, diagnosis or monitoring time, automatically comparing cases described by temporal clinical manifestation sequences can provide valuable knowledge about the data evolution. In this paper, we demonstrate the usefulness of representing patient case reports of a neurodegenerative disorder as a set of temporal clinical manifestations semantically annotated with a domain phenotype ontology and registered with a time-stamped value. Novel techniques are presented to query and match sets of different manifestation sequences from multiple patient cases, with the aim of automatically inferring phenotype evolution patterns of generic patients for clinical studies. The method was applied to 25 patient report cases from a Spanish study of the domain of cerebrotendinous xanthomatosis. Five evolution patterns were automatically generated to analyze the patient data. The results were evaluated against 49 relevant conclusions drawn from the study, with a precision of 93 % and a recall of 70 %. PMID- 23085967 TI - Prognostic factors in patients undergoing complete resection of pulmonary metastases of colorectal cancer: a multi-institutional cumulative follow-up study. AB - PURPOSE: The aim of this retrospective study was to establish the prognostic factors for overall survival after pulmonary resection for lung metastases of colorectal carcinoma (CRC). METHODS: The baseline characteristics and outcomes of 266 CRC patients undergoing complete pulmonary resection were collected from 19 institutions by the Japanese Society for Cancer of the Colon and Rectum (JSCCR) Study Group. We used the Cox proportional hazard regression to identify independent prognostic factors for OS. RESULTS: The 5-year overall survival rate of patients undergoing complete resection of isolated pulmonary metastases was 56.5 %. The independent unfavorable prognostic factors after pulmonary resection included stage T4 (p = 0.0004) and N2 (p = 0.0082) as primary cancer-related factors, and more than three metastases (p = 0.0342), bilateral distribution (p = 0.0450), metastatic disease-free interval (DFI) of less than 2 years (p = 0.0257), and a preoperative carcinoembryonic antigen (CEA) level greater than 5.0 ng/mL (p = 0.0209) as pulmonary metastases-related factors. CONCLUSIONS: This retrospective analysis suggested that the indications for pulmonary resection of CRC metastases should be decided not only by the status of lung metastases, but also by pulmonary-related factors such as the T and N stage of the primary lesion, preoperative CEA level, and the DFI. PMID- 23085969 TI - Relationships among performance of lateral cutting maneuver from lateral sliding and hip extension and abduction motions, ground reaction force, and body center of mass height. AB - Basketball players have to move laterally and quickly change their movement directions, especially during defensive moves. This study aimed to investigate how frontal and sagittal plane hip movements relate to fastness and quickness of lateral cutting maneuvers from sliding. Three-dimensional biomechanical data were obtained for 28 female college basketball players while they performed lateral cutting maneuvers using their left leg after 2 lateral sliding steps. The lateral cutting index (LCIndex) expressing fastness and quickness of lateral cutting maneuvers, peak hip abduction and extension velocities immediately before foot contact, hip abduction and extension velocities at foot contact, peak horizontal ground reaction force, frontal plane ground reaction force angle, and sacrum center of mass position were calculated. Simple and stepwise regression analyses were conducted to predict LCIndex. The former showed that greater maximum hip extension velocity (p = 0.03) and lesser hip abduction velocity (p = 0.04) as well as smaller ground reaction force angle (p = 0.001) and lower sacrum center of mass position (p = 0.001) at foot contact led to better LCIndex. The latter showed that sacrum center of mass position at foot contact and hip extension velocity explained 35.3% (p < 0.01) and 7.3% (p = 0.088) of variance in LCIndex, respectively. Our results did not suggest that hip abductor function is important for lateral sliding moves, instead suggesting that faster hip extension motions to kick the ground and lowering the body center of mass are crucial for better lateral deceleration-acceleration motions. PMID- 23085968 TI - Predictors of intraoperative blood loss in patients undergoing hepatectomy. AB - PURPOSE: Despite recent advances in surgical techniques, blood loss can still determine the postoperative outcome of hepatectomy. Thus, the preoperative identification of risk factors predicting increased blood loss is important. METHODS: We studied retrospectively the clinical records of 482 patients who underwent elective hepatectomy for liver disease, and analyzed the clinicopathological and surgical parameters influencing intraoperative blood loss. RESULTS: Red cell transfusion was required for 165 patients (35 %). Based on blood transfusion requirement and hepatic failure, we estimated predictive cut off values at 850 and 1500 ml. The factors found to be significantly associated with increased blood loss were as follows: male gender, obstructive jaundice, non metastatic liver carcinoma, Child-Pugh B disease, decreased uptake ratio on liver scintigraphy, platelet count, or prothrombin activity, longer hepatic transection time, operating time, the surgeon's technique, J-shape or median incision, major hepatectomy, and not using hemostatic devices (p < 0.05). Multivariate analysis identified male gender, low prothrombin activity, longer transection time, longer operation time, and not using hemostatic devices as factors independently associated with increased blood loss (p < 0.05). CONCLUSIONS: Male gender and low prothrombin activity represent risk factors for increased blood loss during hepatectomy. Moreover, every effort should be made to reduce the transection and operating times using the latest hemostatic devices. PMID- 23085970 TI - Different loading schemes in power training during the preseason promote similar performance improvements in Brazilian elite soccer players. AB - The present study investigated the effects of 2 different power training loading schemes in Brazilian elite soccer players. Thirty-two players participated in the study. Maximum dynamic strength (1RM) was evaluated before (B), at midpoint (i.e., after 3 weeks; T1), and after 6 weeks (T2) of a preseason strength/power training. Muscle power, jumping, and sprinting performance were evaluated at B and T2. Players were randomly allocated to 1 of 2 training groups: velocity-based (VEL: n = 16; age, 19.18 +/- 0.72 years; height, 173 +/- 6 cm; body mass, 72.7 +/ 5.8 kg) or intensity-based (INT: n = 16; age, 19.11 +/- 0.7 years; height, 172 +/- 4.5 cm; body mass, 71.8 +/- 4.6 kg). After the individual determination of the optimal power load, both groups completed a 3-week traditional strength training period. Afterward, the VEL group performed 3 weeks of power-oriented training with increasing velocity and decreasing intensity (from 60 to 30% 1RM) throughout the training period, whereas the INT group increased the training intensity (from 30 to 60% 1RM) and thus decreased movement velocity throughout the power-oriented training period. Both groups used loads within +/-15% (ranging from 30 to 60% 1RM) of the measured optimal power load (i.e., 45.2 +/- 3.0% 1RM). Similar 1RM gains were observed in both groups at T1 (VEL: 9.2%; INT: 11.0%) and T2 (VEL: 19.8%; INT: 22.1%). The 2 groups also presented significant improvements (within-group comparisons) in all of the variables. However, no between-group differences were detected. Mean power in the back squat (VEL: 18.5%; INT: 20.4%) and mean propulsive power in the jump squat (VEL: 29.1%; INT: 31.0%) were similarly improved at T2. The 10-m sprint (VEL: -4.3%; INT: -1.6%), jump squat (VEL: 7.1%; INT: 4.5%), and countermovement jump (VEL: 6.7%; INT: 6.9%) were also improved in both groups at T2. Curiously, the 30-m sprint time (VEL: -0.8%; INT: 0.1%) did not significantly improve for both groups. In summary, our data suggest that male professional soccer players can achieve improvements in strength- and power-related abilities as a result of 6 weeks of power-oriented training during the preseason. Furthermore, similar performance improvements are observed when training intensity manipulation occurs around only a small range within the optimal power training load. PMID- 23085971 TI - Effects of load-volume on EPOC after acute bouts of resistance training in resistance-trained men. AB - Recent investigations have shown excess postexercise oxygen consumption (EPOC) to be elevated for up to 48 hours in both untrained and trained subjects after resistance training (RT). The purpose of this study was to investigate the effect of load-volume on EPOC. Eight trained men (aged 22 +/- 3 years) participated in 2 randomized RT bouts separated by at least 1 week with total load-volumes of 10,000 and 20,000 kg, respectively. Intensity of RT (85% 1 repetition maximum) did not differ between trials. Exercise energy expenditure and resting metabolic rate (RMR) were measured by indirect calorimetry at 8.5 hours before, 1.5 hours before, and during RT bouts and 12, 24, 36, and 48 hours after exercise. Creatine kinase (CK) was measured before and after RT, and 12, 24, 36, and 48 hours postexercise; ratings of perceived muscle soreness were measured on a similar time course save the immediate postexercise time point. Analysis of variance with repeated measures was used to analyze dependent variables. During the 20,000 kg trial, subjects expended significantly (p < 0.01) more energy (484 +/- 29 kcal) than the 10,000 kg lift (247 +/- 18 kcal). After the 20,000 kg lift, 12 hours postexercise, CK (1,159 +/- 729 U.L) was significantly elevated (p < 0.05) as compared with baseline (272 +/- 280 U.L) and immediately postexercise (490 +/- 402 U.L). No significant time or trial differences were found in RMR between the 10,000 and 20,000 kg trials. In conclusion, high-intensity RT with load-volumes of up to 20,000 kg using resistance-trained men does not significantly increase EPOC above baseline RMR. PMID- 23085972 TI - Whole-body vibration applied during upper body exercise improves performance. AB - Whole-body vibration (WBV) training has exercisers perform static and dynamic resistance training exercises on a ground-based platform. Exposure to WBV exposure has demonstrated benefits and no effect on lower body strength, power, and performance. The aim of this study was to determine if WBV exposure (50 Hz, 2.51 mm) has any potentiating effects postexercise by measuring the kinematic variables of a set of upper body elbow-extensor exercise (70% one-repetition maximum [1RM]) to volitional exhaustion. Sixteen recreationally active students (12 male and 4 female) performed 3 different experimental conditions on separate days. Each condition had the subjects perform 1 set of elbow-extension exercise to fatigue with 1 of 3 WBV treatments: WBV simultaneously during the set (AE); 60 seconds after application of WBV for 30 seconds (RE); and no WBV (CTRL). Kinematic parameters of each repetition were monitored by linking a rotary encoder to the highest load plate. The mean velocity and acceleration throughout the set and perceived exertion were analyzed. A significant increase (p < 0.05) was observed in the mean velocity for the whole set in the AE condition vs. the CTRL condition. The mean acceleration was significantly higher (p < 0.05) in the AE condition in comparison with RE (increased by 45.3%) and CTRL (increased by 50.4%) conditions. The positive effect induced by WBV on upper-limb performance is only achieved when the stimulus is applied during the exercise. However, WBV applied 60 seconds before upper body exercise results in no benefit. PMID- 23085973 TI - Influence of rest intervals after assisted jumping on bodyweight vertical jump performance. AB - Assisted jumping (an overspeed concept) is a method used to improve vertical jump performance. However, research is lacking on the optimal program design to maximize performance outcomes. The purpose of this study was to determine the influence of rest intervals after assisted jumping on bodyweight (BW) vertical jumps. Twenty healthy recreationally trained men (age: 22.85 +/- 1.84 years; height: 179.44 +/- 5.99 cm; mass: 81.73 +/- 9.51 kg) attended 5 sessions. For all sessions, subjects performed the same dynamic warm-up and then executed 1 set of 5 consecutive assisted jumps at 30% BW reduction. They then rested for 30 seconds (C30), 1 minute (C1), 2 minutes (C2), or 4 minutes (C4), followed by 3 BW jumps with no assistance. Baseline (CB) jump height was measured without preceding assisted jumps. Analyses of variance revealed a main effect for takeoff velocity, with 1 and 4 minutes being greater than baseline (C1: 3.36 +/- 0.40 m.s(-1); C4: 3.27 +/- 0.41 m.s(-1); CB: 3.13 +/- 0.32 m.s(-1)). Relative peak power also demonstrated a main effect, with 1 minute being greater than all other conditions (C1: 75.22 +/- 10.83 W.kg(-1)). Jump height and relative ground reaction force demonstrated no differences between conditions. These results indicate overspeed jumping acutely enhances explosive BW jumping velocity and power. This acute performance enhancement is probably a result of increased motor neuron excitability and motor unit synchronization. PMID- 23085974 TI - Strength, power, and muscular endurance exercise and elite rowing ergometer performance. AB - Knowledge of the relationship between weight room exercises and various rowing performance measures is limited; this information would prove useful for sport specific assessment of individual needs and exercise prescription. The purpose of this study was to establish strength, power, and muscular endurance exercises for weight room training, which are strong determinants of success in specific performance measures used to assess elite rowers. Nineteen heavyweight elite males determined their repetition maximum (RM) loads for exercises using a Concept 2 DYNO [5, 30, 60 and 120RM leg pressing and seated arm pulling (in Joules)] and free weights [1RM power clean (in kilograms) and 6RM bench pull (in kilograms and watts)]. Rowing performance measures included a 7-stage blood lactate response ergometer test (aerobic condition), time trials (500, 2000, and 5000 m), a peak stroke power test, and a 60-minute distance trial. Pearson correlation moments (r >= 0.7) and stepwise multiple linear regression calculations (R >= 50%) were used to establish strong common variances between weight room exercises and rowing ergometer performance (p <= 0.05). Weight room exercises were strong predictors of 2000-m, 500-m time (in seconds), and peak stroke power performance measures only. Bench pull power (in watts) and 1RM power clean (in kilograms) were the best 2-factor predictors of peak stroke power (R = 73%; standard error of the estimates [SEE] = 59.6 W) and 500 m (R = 70%; SEE = 1.75 seconds); while 5RM leg pressing (in Joules) and either 6RM bench pull (kg) or 60RM seated arm pulling (in Joules) the best predictors of 2000 m (R = 59%; SEE = 6.3 seconds and R = 57%; SEE = 6.4 seconds, respectively). Recommended exercises for weight room training include a 1RM power clean, 6RM bench pull, 5RM leg press, and 60RM seated arm pulling. PMID- 23085975 TI - Effect of local cooling on short-term, intense exercise. AB - The widespread belief that local cooling impairs short-term, strenuous exercise performance is controversial. Eighteen original investigations involving cooling before and intermittent cooling during short-term, intensive exercise are summarized in this review. Previous literature examining short-term intensive exercise and local cooling primarily has been limited to the effects on muscle performance immediately or within minutes following cold application. Most previous cooling studies used equal and longer than 10 minutes of pre-cooling, and found that cooling reduced strength, performance and endurance. Because short duration, high intensity exercise requires adequate warm-up to prepare for optimal performance, prolonged pre-cooling is not an effective method to prepare for this type of exercise. The literature related to the effect of acute local cooling immediately before short duration, high intensity isotonic exercise such as weight lifting is limited. However, local intermittent cooling during short term, high intense exercise may provide possible beneficial effects; first, by pain reduction, caused by an "irritation effect" from hand thermal receptors which block pain sensation, or second, by a cooling effect, whereby stimulation of hand thermal receptors or a slight lowering of blood temperature might alter central fatigue. PMID- 23085976 TI - Influence of dorsiflexion shoes on neuromuscular fatigue of the plantar flexors after combined tapping-jumping exercises in volleyball players. AB - Dorsiflexion shoes could be useful to increase jumping performance. The aim of the present study was to investigate the impact of wearing shoes inducing moderate dorsiflexion (2 degrees ) on neuromuscular fatigue induced by volleyball exercises involving multiple stretch-shortening cycles. Squat jump (SJ) and countermovement jump (CMJ) performance, and plantar flexors isometric voluntary and evoked contractile properties were assessed in 10 unfamiliarized trained volleyball players before and after a 10-minute intensive combined tapping jumping volleyball exercise performed, in blinded randomized conditions, with neutral (0 degrees ) or moderate dorsiflexion (2 degrees ). No significant difference was observed on SJ performance in neutral and moderate dorsiflexion conditions. However, CMJ height was initially lower with 2 degrees dorsiflexion compared with 0 degrees (p < 0.05). Height in CMJ was increased after exercise with 2 degrees dorsiflexion shoes and remained unchanged in neutral 0 degrees condition. Combined tapping-jumping volleyball exercise also induced a significant decrease in maximal voluntary contraction (p < 0.001), peak-twitch torque (p = 0.009), contraction time (p < 0.001) and twitch relaxation rate (p = 0.001) values without any significant difference between neutral and dorsiflexion conditions. Voluntary activation level (p = 0.014) and rate of force development (p = 0.05) were also decreased in both conditions. In conclusion, acute moderate dorsiflexion had no effect on jumping performance and neuromuscular fatigue in unfamiliarized trained subjects and altered the elastic energy store in plyometric condition (CMJ). Future studies are necessary to investigate the chronic effect of moderate dorsiflexion on jumping performance and neuromuscular fatigue in trained volleyball players. PMID- 23085978 TI - Aging and sequential resistance exercise bout effects on housekeeping gene messenger RNA expression in human skeletal muscle. AB - The purpose of this study was to investigate how age and 1 week of conventional resistance exercise affects commonly used housekeeping gene (HKG) messenger RNAs (mRNAs) in skeletal muscle. Ten college-aged (18-25 years) and 10 older (60-76 years) men completed 3 lower-body resistance exercise bouts on Monday, Wednesday, and Friday, and muscle samples were obtained before bout 1 (T1), 48 hours after the first (T2) and second bouts (T3), and 24 hours after the third bout (T4). Raw Ct values indicated that beta-actin and cyclophilin were more highly expressed in older vs. younger males (p < 0.01) at T1. When normalizing each HKG mRNA to the other 4 HKG mRNAs, CYC increased at T3 and glyceraldehyde-3-phosphate dehydrogenase decreased at T2 (p < 0.05) in younger men. This is one of the few studies to suggest that explicit HKG mRNAs should be used depending upon age group and resistance exercise intervention. PMID- 23085977 TI - Knee joint kinetics in relation to commonly prescribed squat loads and depths. AB - Controversy exists regarding the safety and performance benefits of performing the squat exercise to depths beyond 90 degrees of knee flexion. Our aim was to compare the net peak external knee flexion moments (pEKFM) experienced over typical ranges of squat loads and depths. Sixteen recreationally trained men (n = 16; age, 22.7 +/- 1.1 years; body mass, 85.4 +/- 2.1 kg; height, 177.6 +/- 0.96 cm; mean +/- SEM) with no previous lower-limb surgeries or other orthopedic issues and at least 1 year of consistent resistance training experience while using the squat exercise performed single-repetition squat trials in a random order at squat depths of above parallel, parallel, and below parallel. Less than 1 week before testing, 1RM values were found for each squat depth. Subsequent testing required the subjects to perform squats at the 3 depths with 3 different loads: unloaded, 50% 1RM, and 85% 1RM (9 total trials). Force platform and kinematic data were collected to calculate pEKFM. To assess the differences among loads and depths, a 2-factor (load and depth) repeated measures analysis of variance with significance set at the p < 0.05 level was used. Squat 1RM significantly decreased 13.6% from the above-parallel to the parallel squat and another 3.6% from the parallel to the below-parallel squat (p < 0.05). Net peak external knee flexion moments significantly increased as both squat depth and load were increased (p <= 0.02). Slopes of pEKFM were greater from unloaded to 50% 1RM than when progressing from 50% to 85% 1RM (p < 0.001). The results suggest that typical decreases in squat loads used with increasing depths are not enough to offset increases in pEKFM. PMID- 23085979 TI - Aryl hydrocarbon receptor-mediated disruption of contact inhibition is associated with connexin43 downregulation and inhibition of gap junctional intercellular communication. AB - The aryl hydrocarbon receptor (AhR) contributes to the control of cell-to-cell communication, cell adhesion, migration or proliferation. In the present study, we investigated the regulation of connexin43 (Cx43) and Cx43-mediated gap junctional intercellular communication (GJIC) during the AhR-dependent disruption of contact inhibition in non-tumorigenic liver epithelial cells. The contact inhibition of cell proliferation is a process restricting the cell division of confluent non-transformed cells, which is frequently abolished in cancer cells; however, the mechanisms contributing to its disruption are still only partially understood. Disruption of contact inhibition, which was induced by toxic AhR ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons in epithelial WB-F344 cells, reduced Cx43 protein levels, possibly via enhanced proteasomal degradation, significantly decreased the amount of gap junction plaques and downregulated GJIC, in an AhR-dependent manner. Although both intracellular and membrane Cx43 pools were markedly reduced in cells released from contact inhibition by TCDD, siRNA-mediated Cx43 knock-down was not sufficient to stimulate proliferation in contact-inhibited cells. Our data suggest that downregulation of Cx43/GJIC in non-transformed epithelial cells is an inherent part of disruption of contact inhibition, which occurs at the post transcriptional level. This process runs in parallel with alterations of other forms of cell-to-cell communication, thus suggesting that toxic AhR agonists may simultaneously abrogate contact inhibition and reduce GJIC, two essential mechanisms linked to deregulation of cell-to-cell communication during tumor promotion and progression. PMID- 23085980 TI - Kidney injury biomarkers in hypertensive, diabetic, and nephropathy rat models treated with contrast media. AB - Contrast-induced nephropathy (CIN) refers to a decline in renal function following exposure to iodinated contrast media (CM). The present study was initiated to explore the role of known human risk factors (spontaneous hypertension, diabetes, protein-losing nephropathy) on CIN development in rodent models and to determine the effect of CM administration on kidney injury biomarkers in the face of preexisting kidney injury. Spontaneously hypertensive rats (hypertension), streptozotocin-treated Sprague Dawley rats (diabetes), and Dahl salt-sensitive rats (protein-losing nephropathy) were given single intravenous injections of the nonionic, low osmolar contrast medium, iohexol. Blood urea nitrogen (BUN), serum creatinine (sCr), and urinary biomarkers; albumin, lipocalin 2 (Lcn-2), osteopontin (Opn), kidney injury molecule 1 (Kim 1), renal papillary antigen 1 (Rpa-1), alpha-glutathione S-transferase (alpha Gst), u-glutathione S-transferase (u-Gst), and beta-2 microglobulin (beta2m) were measured in disease models and appropriate controls to determine the response of these biomarkers to CM administration. Each disease model produced elevated biomarkers of kidney injury without CM. Preexisting histopathology was exacerbated by CM but little or no significant increases in biomarkers were observed. When 1.5-fold or greater sCr increases from pre-CM were used to define true positives, receiver-operating characteristic curve analysis of biomarker performance showed sCr was the best predictor of CIN across disease models. beta2m, Lcn-2, and BUN were the best predictors of histopathology defined kidney injury. PMID- 23085981 TI - DNA reactivity as a mode of action and its relevance to cancer risk assessment. AB - The ability of a chemical to induce mutations has long been a driver in the cancer risk assessment process. The default strategy has been that mutagenic chemicals demonstrate linear cancer dose responses, especially at low exposure levels. In the absence of additional confounding information, this is a reasonable approach, because risk assessment is appropriately considered as being protective of human health. The concept of mode of action has allowed for an opportunity to move off this default position; mutagenicity is now not considered as the driver but rather the mode of action is. In a more precise way, it is the set of key events that define a mode of action that is fundamental in defining the shape of a cancer dose response. A key event is an informative bioindicator of the cancer response and as such should be predictive of the tumor response, at least in a qualitative way. A clear example of the use of key events in cancer risk assessment is for DNA reactive chemicals. A series of such key events is initiated by the production of DNA damage in target cells from direct interaction of the chemical with DNA leading to the production of mutations by misreplication that results in enhanced cell replication. This enhanced cell replication eventually leads to the development of preneoplastic cells and ultimately overt neoplasms. The response of each of these key events to dose of the chemical can inform the cancer dose-response curve shape. Thus, the dose-response curve for any DNA-reactive chemical can be predicted from knowledge of its mode of action and the behavior of the induced key events. PMID- 23085982 TI - On-target and off-target-based toxicologic effects. AB - Adverse toxicologic effects are categorized as chemical-based, on-target, or off target effects. Chemical-based toxicity is defined as toxicity that is related to the physicochemical characteristics of a compound and its effects on cellular organelles, membranes, and/or metabolic pathways. On-target refers to exaggerated and adverse pharmacologic effects at the target of interest in the test system. Off-target refers to adverse effects as a result of modulation of other targets; these may be related biologically or totally unrelated to the target of interest. Both the risk assessment and development strategies used for xenobiotics are influenced by the understanding of the mechanism of toxicity. It is imperative that the toxicologic pathologist use the toxicologic and biologic data at hand and literature information on the target to form testable hypotheses related to whether a toxicity is chemical-based, on-target, or off-target. The objective of this session at the 2012 Society of Toxicologic Pathologists Symposium in Boston, Massachusetts, was to discuss chemical-based, on-target, and off-target-based effects and the scientific approaches used to aid in their human risk assessment. PMID- 23085983 TI - Diffuse near-infrared reflectance spectroscopy during heatstroke in a mouse model: pilot study. AB - Heatstroke, a form of hyperthermia, is a life-threatening condition characterized by an elevated core body temperature that rises above 40 degrees C (104 degrees F) and central nervous system dysfunction that results in delirium, convulsions, or coma. Without emergency treatment, the victim lapses into a coma and death soon follows. The study presented was conducted with a diffuse reflectance spectroscopy (DRS) setup to assess the effects of brain dysfunction that occurred during heatstroke in mice model (n=6). It was hypothesized that DRS can be utilized in small animal studies to monitor change in internal brain tissue temperature during heatstroke injury since it induces a sequence of pathologic changes that change the tissue composition and structure. Heatstroke was induced by exposure of the mice body under general anesthesia, to a high ambient temperature. A type of DRS in which the brain tissue was illuminated through the intact scalp with a broadband light source and diffuse reflected spectra was employed, taking in the spectral region between 650 and 1000 nm and acquired at an angle of 90 deg at a position on the scalp ~12 mm from the illumination site. The temperature at the onset of the experiment was ~34 degrees C (rectal temperature) with increasing intervals of 1 degrees C until mouse death. The increase in temperature caused optical scattering signal changes consistent with a structural alteration of brain tissue, ultimately resulting in death. We have found that the peak absorbance intensity and its second derivative at specific wavelengths correlate well with temperature with an exponential dependence. Based on these findings, in order to estimate the influence of temperature on the internal brain tissue a reflectance-temperature index was established and was seen to correlate as well with measured temperature. Overall, results indicate variations in neural tissue properties during heatstroke and the feasibility to monitor and assess internal temperature variations using DRS. Although several approaches have described the rise in temperature and its impact on tissue, to the best of our knowledge no information is available describing the ability to monitor temperature during heatstroke with DRS. The motivation of this study was to successfully describe this ability. PMID- 23085984 TI - In vivo spatial frequency domain spectroscopy of two layer media. AB - Monitoring of tissue blood volume and local oxygen saturation can inform the assessment of tissue health, healing, and dysfunction. These quantities can be estimated from the contribution of oxyhemoglobin and deoxyhemoglobin to the absorption spectrum of the dermis. However, estimation of blood related absorption in skin can be confounded by the strong absorption of melanin in the epidermis and epidermal thickness and pigmentation varies with anatomic location, race, gender, and degree of disease progression. Therefore, a method is desired that decouples the effect of melanin absorption in the epidermis from blood absorption in the dermis for a large range of skin types and thicknesses. A previously developed inverse method based on a neural network forward model was applied to simulated spatial frequency domain reflectance of skin for multiple wavelengths in the near infrared. It is demonstrated that the optical thickness of the epidermis and absorption and reduced scattering coefficients of the dermis can be determined independently and with minimal coupling. Then, the same inverse method was applied to reflectance measurements from a tissue simulating phantom and in vivo human skin. Oxygen saturation and total hemoglobin concentrations were estimated from the volar forearms of weakly and strongly pigmented subjects using a standard homogeneous model and the present two layer model. PMID- 23085985 TI - Heteropolyhedral silver compounds containing the polydentate ligand N,N,O-E-[6 (hydroxyimino)ethyl]-1,3,7-trimethyllumazine. Preparation, spectral and XRD structural study and AIM calculations. AB - The oxime derived from 6-acetyl-1,3,7-trimethyllumazine (1) ((E-6 (hydroxyimino)ethyl)-1,3,7-trimethylpteridine-2,4(1H,3H)-dione, DLMAceMox) has been prepared and its molecular and crystal structure determined from spectral and XRD data. The oxime ligand was reacted with silver nitrate, perchlorate, thiocyanate, trifluoromethylsulfonate and tetrafluoroborate to give complexes with formulas [Ag(2)(DLMAceMox)(2)(NO(3))(2)](n) (2), [Ag(2)(DLMAceMox)(2)(ClO(4))(2)](n) (3), [Ag(2)(DLMAceMox)(2)(SCN)(2)] (4), [Ag(2)(DLMAceMox)(2)(CF(3)SO(3))(2)(CH(3)CH(2)OH)].CH(3)CH(2)OH (5) and [Ag(DLMAceMox)(2)]BF(4) (6). Single-crystal XRD studies show that the asymmetrical residual unit of complexes 2, 3 and 5 contains two quite different but connected silver centers (Ag1-Ag2, 2.9-3.2 A). In addition to this, the Ag1 ion displays coordination with the N5 and O4 atoms from both lumazine moieties and a ligand (nitrato, perchlorato or ethanol) bridging to another disilver unit. The Ag2 ion is coordinated to the N61 oxime nitrogens, a monodentate and a (O,O) bridging nitrato/perchlorato or two monodentate O-trifluoromethylsulfonato anions. The coordination polyhedra can be best described as a strongly distorted octahedron (around Ag1) and a square-based pyramid (around Ag2). The Ag-N and Ag O bond lengths range between 2.22-2.41 and 2.40-2.67 A, respectively. Although the structure of 4 cannot be resolved by XRD, it is likely to be similar to those described for 2, 3 and 5, containing Ag-Ag units with S-thiocyanato terminal ligands. Finally, the structure of the tetrafluoroborate compound 6 is mononuclear with a strongly distorted tetrahedral AgN(4) core (Ag-N, 2.27-2.43 A). Always, the different Ag-N distances found clearly point to the more basic character of the oxime N61 nitrogen atom when compared with the pyrazine N5 one. A topological analysis of the electron density within the framework provided by the quantum theory of atoms in molecules (QTAIM) using DFT(M06L) levels of theory has been performed. Every Ag-Ag and Ag-ligand interaction has been characterized in terms of Laplacian of the electron density, [nabla](2)rho(r), and the total energy density, H(r). PMID- 23085986 TI - The acoustic effect of vocal tract adjustments in zebra finches. AB - Vocal production in songbirds requires the control of the respiratory system, the syrinx as sound source and the vocal tract as acoustic filter. Vocal tract movements consist of beak, tongue and hyoid movements, which change the volume of the oropharyngeal-esophageal cavity (OEC), glottal movements and tracheal length changes. The respective contributions of each movement to filter properties are not completely understood, but the effects of this filtering are thought to be very important for acoustic communication in birds. One of the most striking movements of the upper vocal tract during vocal behavior in songbirds involves the OEC. This study measured the acoustic effect of OEC adjustments in zebra finches by comparing resonance acoustics between an utterance with OEC expansion (calls) and a similar utterance without OEC expansion (respiratory sounds induced by a bilateral syringeal denervation). X-ray cineradiography confirmed the presence of an OEC motor pattern during song and call production, and a custom built Hall-effect collar system confirmed that OEC expansion movements were not present during respiratory sounds. The spectral emphasis during zebra finch call production ranging between 2.5 and 5 kHz was not present during respiratory sounds, indicating strongly that it can be attributed to the OEC expansion. PMID- 23085987 TI - Wig1 prevents cellular senescence by regulating p21 mRNA decay through control of RISC recruitment. AB - Premature senescence, a key strategy used to suppress carcinogenesis, can be driven by p53/p21 proteins in response to various stresses. Here, we demonstrate that Wig1 plays a critical role in this process through regulation of p21 mRNA stability. Wig1 controls the association of Argonaute2 (Ago2), a central component of the RNA-induced silencing complex (RISC), with target p21 mRNA via binding of the stem-loop structure near the microRNA (miRNA) target site. Depletion of Wig1 prohibited miRNA-mediated p21 mRNA decay and resulted in premature senescence. Wig1 plays an essential role in cell proliferation, as demonstrated in tumour xenografts in mice, and Wig1 and p21 mRNA levels are inversely correlated in human normal and cancer tissues. Together, our data indicate a novel role of Wig1 in RISC target accessibility, which is a key step in RNA-mediated gene silencing. In addition, these findings indicate that fine tuning of p21 levels by Wig1 is essential for the prevention of cellular senescence. PMID- 23085988 TI - Molecular basis for SNX-BAR-mediated assembly of distinct endosomal sorting tubules. AB - Sorting nexins (SNXs) are regulators of endosomal sorting. For the SNX-BAR subgroup, a Bin/Amphiphysin/Rvs (BAR) domain is vital for formation/stabilization of tubular subdomains that mediate cargo recycling. Here, by analysing the in vitro membrane remodelling properties of all 12 human SNX-BARs, we report that some, but not all, can elicit the formation of tubules with diameters that resemble sorting tubules observed in cells. We reveal that SNX-BARs display a restricted pattern of BAR domain-mediated dimerization, and by resolving a 2.8 A structure of a SNX1-BAR domain homodimer, establish that dimerization is achieved in part through neutralization of charged residues in the hydrophobic BAR dimerization interface. Membrane remodelling also requires functional amphipathic helices, predicted to be present in all SNX-BARs, and the formation of high order SNX-BAR oligomers through selective 'tip-loop' interactions. Overall, the restricted and selective nature of these interactions provide a molecular explanation for how distinct SNX-BAR-decorated tubules are nucleated from the same endosomal vacuole, as observed in living cells. Our data provide insight into the molecular mechanism that generates and organizes the tubular endosomal network. PMID- 23085989 TI - AgRP neurons: a switch between peripheral carbohydrate and lipid utilization. PMID- 23085990 TI - The FUS about arginine methylation in ALS and FTLD. PMID- 23085991 TI - Properties of hot liquid cerium by LDA + U molecular dynamics. AB - We present ab initio simulations of liquid cerium in the framework of the LDA + U formulation. The liquid density has been determined self-consistently by searching for the zero pressure equilibrium state at 1320 K with the same set of parameters (U and J) and occupation matrices as those optimized for the gamma phase. We have computed static and transport properties. The liquid produced by the simulations appears more structured than the available measurements. This raises questions regarding the ability of the theory to describe such a complex liquid. Conductivity calculations and temperature dependences are nevertheless in reasonable agreement with data. PMID- 23085992 TI - Structural characterization of titanium-doped Bioglass using isotopic substitution neutron diffraction. AB - Melt quenched silicate glasses containing calcium, phosphorus and alkali metals have the ability to promote bone regeneration and to fuse to living bone. Of these glasses 45S5 Bioglass(r) is the most widely used being sold in over 35 countries as a bone graft product for medical and dental applications; particulate 45S5 is also incorporated into toothpastes to help remineralize the surface of teeth. Recently it has been suggested that adding titanium dioxide can increase the bioactivity of these materials. This work investigates the structural consequences of incorporating 4 mol% TiO(2) into Bioglass(r) using isotopic substitution (of the Ti) applied to neutron diffraction and X-ray Absorption Near Edge Structure (XANES). We present the first isotopic substitution data applied to melt quench derived Bioglass or its derivatives. Results show that titanium is on average surrounded by 5.2(1) nearest neighbor oxygen atoms. This implies an upper limit of 40% four-fold coordinated titanium and shows that the network connectivity is reduced from 2.11 to 1.97 for small quantities of titanium. Titanium XANES micro-fluorescence confirms the titanium environment is homogenous on the micron length scale within these glasses. Solid state magic angle spinning (MAS) NMR confirms the network connectivity model proposed. Furthermore, the results show the intermediate range order containing Na-O, Ca-O, O-P-O and O-Si-O correlations are unaffected by the addition of small quantities of TiO(2) into these systems. PMID- 23085993 TI - Homocysteine induces serum amyloid A3 in osteoblasts via unlocking RGD-motifs in collagen. AB - Hyperhomocysteinemia is a risk factor for osteoporotic fractures. Homocysteine (Hcys) inhibits collagen cross-linking and consequently decreases bone extracellular matrix (ECM) quality. Serum amyloid A (A-SAA), an acute-phase protein family, plays an important role in chronic and inflammatory diseases and up-regulates MMP13, which plays an important role in bone development and remodeling. Here, we investigate the effect of Hcys on expression of SAA3, a member of the A-SAA gene family, in osteoblasts characterizing underlying mechanisms and possible consequences on bone metabolism. MC3T3-E1 osteoblast-like cells were cultured up to 21 d with Hcys (low millimolar range) or reseeded onto ECM resulting from untreated or Hcys-treated MC3T3-E1 cells. Fourier-transformed infrared spectroscopy and a discriminative antibody were used to characterize the resulting ECM. Gene expression and signaling pathways were analyzed by gene chip, quantitative RT-PCR, and immunoblotting. Transcriptional regulation of Saa3 was studied by promoter transfection assays, chromatin immunoprecipitation, and immunofluorescence microscopy. Hcys treatment resulted in reduced collagen cross linking, uncovering of RGD-motifs, and activation of the PTK2-PXN-CTNNB1 pathway followed by RELA activation. These signaling events led to increased SAA3 expression followed by the production of MMP13 and several chemokines, including Ccl5, Ccl2, Cxcl10, and Il6. Our data suggest Saa3 as link between hyperhomocysteinemia and development of osteoporosis. PMID- 23085994 TI - Actinin-4 in keratinocytes regulates motility via an effect on lamellipodia stability and matrix adhesions. AB - During wound repair, epidermal cells at the edge of an injury establish front rear polarity through orchestrated changes in their cytoskeleton and adhesion structures. The polarity and directed migration of such cells is determined by the assembly, extension, and stabilization of a lamellipodium. Actinin-4 associates with lamellipodia and has been implicated in regulating lamellipodial structure, function and assembly. To study the functions of actinin-4 in human keratinocytes, we used shRNA to generate knockdown cells and compared their motility behavior and matrix adhesion assembly to scrambled shRNA treated control keratinocytes. Actinin-4 knockdown keratinocytes lack polarity, assemble multiple lamellipodia with a 2* increased area over controls, display reduced activity of the actin remodeling protein cofilin, and fail to migrate in a directional manner. This motility defect is rescued by plating knockdown cells on preformed laminin-332 matrix. In actinin-4-knockdown keratinocytes, focal contact area is increased by 25%, and hemidesmosome proteins are mislocalized. Specifically, alpha6beta4 integrin localizes to large lamellipodial extensions, displays reduced dynamics, and fails to recruit its bullous pemphigoid antigen binding partners. Together, our data indicate a role for actinin-4 in regulating the steering mechanism of keratinocytes via profound effects on their matrix adhesion sites. PMID- 23085995 TI - Effect of Caenorhabditis elegans age and genotype on horizontal gene transfer in intestinal bacteria. AB - Horizontal gene transfer (HGT) between bacteria occurs in the intestinal tract of their animal hosts and facilitates both virulence and antibiotic resistance. A model in which both the pathogen and the host are genetically tractable facilitates developing insight into mechanistic processes enabling or restricting the transfer of antibiotic resistance genes. Here we develop an in vivo experimental system to study HGT in bacteria using Caenorhabditis elegans as a model host. Using a thermosensitive conjugative system, we provide evidence that conjugation between two Escherichia coli strains can take place in the intestinal lumen of N2 wild-type worms at a rate of 10(-3) and 10(-2) per donor. We also show that C. elegans age and genotype are important determinants of the frequency of conjugation. Whereas ~1 transconjugant for every 100 donor cells could be recovered from the intestine of N2 C. elegans, for the age-1 and tol-1 mutants, the detected rate of transconjugation (10(-3) and 10(-4) per donor cell, respectively) was significantly lower. This work demonstrates that increased recombination among lumenal microbial populations is a phenotype associated with host aging, and the model provides a framework to study the dynamics of bacterial horizontal gene transfer within the intestinal environment. PMID- 23085996 TI - Pharmacological inhibition of calpain-1 prevents red cell dehydration and reduces Gardos channel activity in a mouse model of sickle cell disease. AB - Sickle cell disease (SCD) is a globally distributed hereditary red blood cell (RBC) disorder. One of the hallmarks of SCD is the presence of circulating dense RBCs, which are important in SCD-related clinical manifestations. In human dense sickle cells, we found reduced calpastatin activity and protein expression compared to either healthy RBCs or unfractionated sickle cells, suggesting an imbalance between activator and inhibitor of calpain-1 in favor of activator in dense sickle cells. Calpain-1 is a nonlysosomal cysteine proteinase that modulates multiple cell functions through the selective cleavage of proteins. To investigate the relevance of this observation in vivo, we evaluated the effects of the orally active inhibitor of calpain-1, BDA-410 (30 mg/kg/d), on RBCs from SAD mice, a mouse model for SCD. In SAD mice, BDA-410 improved RBC morphology, reduced RBC density (D(20); from 1106 +/- 0.001 to 1100 +/- 0.001 g/ml; P<0.05) and increased RBC-K(+) content (from 364 +/- 10 to 429 +/- 12.3 mmol/kg Hb; P<0.05), markedly reduced the activity of the Ca(2+)-activated K(+)channel (Gardos channel), and decreased membrane association of peroxiredoxin-2. The inhibitory effect of calphostin C, a specific inhibitor of protein kinase C (PKC), on the Gardos channel was eliminated after BDA-410 treatment, which suggests that calpain-1 inhibition affects the PKC-dependent fraction of the Gardos channel. BDA-410 prevented hypoxia-induced RBC dehydration and K(+) loss in SAD mice. These data suggest a potential role of BDA-410 as a novel therapeutic agent for treatment of SCD. PMID- 23085998 TI - Functional segregation and emerging role of cilia-related cytosolic carboxypeptidases (CCPs). AB - Recent experimental data indicating axonal regeneration, axogenesis, dendritogenesis, and ciliary axoneme assembly and wellness have linked the role of cytosolic metallocarboxypeptidase 1 (CCP1/AGTPBP1/Nna1) to the microtubule network. In addition, 5 of the 6 mammalian ccp genes have been shown to participate in post-translational modifications of tubulin, which occur in the microtubules of neurons, mitotic spindles, cilia, and basal bodies. Here, we compile evidence for the idea that the occurrence of CCPs strongly correlates with the presence of cilia, suggesting that CCP functions might be primarily related to cilia and basal bodies (CBBs). In agreement with this hypothesis, CCPs were localized in centrioles, basal bodies, and mitotic spindles in HeLa cells by confocal microscopy. By reconstructing the evolutionary history of CCPs, we show their presence in the last eukaryotic common ancestor and relate each group of CCP orthologs to specific roles in CBBs. The clues presented in this study suggest that during the evolution of eukaryotes, mechanisms mediated by CCPs through tubulin post-translational modifications controlling assembly, trafficking, and signaling in the microtubules, were transferred from cilia to cell and axon microtubules. PMID- 23085997 TI - MicroRNA 339 down-regulates MU-opioid receptor at the post-transcriptional level in response to opioid treatment. AB - MU-Opioid receptor (MOR) level is directly related to the function of opioid drugs, such as morphine and fentanyl. Although agonist treatment generally does not affect transcription of mor, previous studies suggest that morphine can affect the translation efficiency of MOR transcript via microRNAs (miRNAs). On the basis of miRNA microarray analyses of the hippocampal total RNA isolated from mice chronically treated with MU-opioid agonists, we found a miRNA (miR-339-3p) that was consistently and specifically increased by morphine (2-fold) and by fentanyl (3.8-fold). miR-339-3p bound to the MOR 3'-UTR and specifically suppressed reporter activity. Suppression was blunted by adding miR-339-3p inhibitor or mutating the miR-339-3p target site. In cells endogenously expressing MOR, miR-339-3p inhibited the production of MOR protein by destabilizing MOR mRNA. Up-regulation of miR-339-3p by fentanyl (EC(50)=0.75 nM) resulted from an increase in primary miRNA transcript. Mapping of the miR-339-3p primary RNA and its promoter revealed that the primary miR-339-3p was embedded in a noncoding 3'-UTR region of an unknown host gene and was coregulated by the host promoter. The identified promoter was activated by opioid agonist treatment (10 nM fentanyl or 10 MUM morphine), a specific effect blocked by the opioid antagonist naloxone (10 MUM). Taken together, these results suggest that miR-339 3p may serve as a negative feedback modulator of MOR signals by regulating intracellular MOR biosynthesis. PMID- 23085999 TI - Molecular structure, vibrational, UV, NMR, hyperpolarizability, NBO and HOMO-LUMO analysis of Pteridine2,4-dione. AB - The FTIR and FT-Raman spectra of Pteridine2,4-dione has been recorded in the region 4000-450 and 4000-100 cm(-1), respectively. The tautomeric stability, optimized geometry, frequency and intensity of the vibrational bands of Pteridine2,4-dione were obtained by the density functional theory (DFT) using 6 311++G(d,p) basis set. The harmonic vibrational frequencies were calculated and the scaled values have been compared with experimental FTIR and FT-Raman spectra. The observed and the calculated frequencies are found to be in good agreement. The (1)H and(13)C NMR spectra chemical shifts of the molecule were also calculated using the gauge independent atomic orbital (GIAO) method. The theoretical UV-Vis spectrum of the compound using CIS method and the electronic properties, such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. The calculated HOMO and LUMO energies show that charge transfer occurs within molecule. The first order hyperpolarizability (beta(0)) of these novel molecular system and related properties (beta, alpha(0) and Deltaalpha) of Pteridine2,4-dione are calculated using DFT/6-311++G (d,p) method on the finite-field approach. The Mulliken charges, the values of electric dipole moment (MU) of the molecule were computed using DFT calculations. The change in electron density (ED) in the sigma(*) antibonding orbitals and stabilization energies E(2) have been calculated by natural bond (NBO) analysis to give clear evidence of stabilization originating in the hyper conjugation of hydrogen-bonded interactions. PMID- 23086001 TI - Prospective one-year treatment outcomes of tortured refugees: a psychiatric approach. AB - The treatment of torture survivors from diverse cultures has been a difficult task involving issues of loss, massive trauma, cultural style, and adjusting to a new country. Research on treatment outcomes has shown inconsistent results. This report presents a prospective one year treatment outcome of 22 severely tortured patients from Ethiopia, Somalia, Iran and Afghanistan. Treatment was provided by psychiatrists and counselors with interpreters from each culture involved. The specific treatment included psychiatric evaluation, medicine, education, supportive psychotherapy and assisting some social needs. All 22 were diagnosed with depression and 17 of these also had posttraumatic stress disorder (PTSD). Twenty of 22 patients showed marked significant improvement on all of the scales for depression, PTSD, disability, and quality of life. Medicine was particularly useful in treating depression and the symptoms of flashbacks, nightmares and irritability. Standard psychiatric treatment with evaluation, diagnosis, appropriate medicine, supportive psychotherapy and counseling by ethnic counselors provided good outcomes. PMID- 23086000 TI - Rab5 regulates internalisation of P2X4 receptors and potentiation by ivermectin. AB - The P2X4 receptor is an ATP-gated ion channel expressed in neurons, endothelia and immune cells. Plasma membrane expression of P2X4 is regulated by dynamin dependent endocytosis, and this study identifies a Rab5-dependent pathway of receptor internalisation. Expression of Rab5 constructs altered the distribution of P2X4 in HEK-293 cells, and both constitutive internalisation and agonist induced desensitisation of P2X4 were increased by co-expression of wild-type Rab5 or constitutively active Rab5 (Q79L). Expression of inactive dynamin K44A and Rab5 S34N constructs abolished agonist-induced desensitisation, suggesting internalisation as the underlying mechanism. Blocking P2X4 internalisation in this way also abolished potentiation of ATP-induced currents by the allosteric modulator ivermectin. This suggests that the dynamin-Rab5 internalisation pathway is essential for the ivermectin potentiation effect. In agreement with this hypothesis, the co-expression of wild-type dynamin, wild-type Rab5 or active Rab5 (Q79L) could increase the potentiation of the ATP-induced P2X4 response by ivermectin. These findings highlight Rab5 GTPase as a key regulator of P2X4 receptor cell surface expression and internalisation. PMID- 23086002 TI - Social support, coping and posttraumatic stress symptoms in young refugees. AB - Young refugees from the former Yugoslavia commonly testify to having been exposed to multiple, traumatic experiences, which may contribute to the development of serious mental health problems such as posttraumatic stress disorder (PTSD), anxiety, and depression. Using selfreport scales the present study investigated the prevalence of PTSD as well as factors associated with PTSD in a group of 119 Bosnian refugee youths (mean age 18.5). The group was special in that they had no right to seek asylum in the host country for the first couple of years of their stay. It is suspected that this circumstance had an effect on their wellbeing. Between 35-43% of the youth were found to be in the clinical range for a PTSD diagnosis. Female gender, problem-focused, and avoidant coping strategies, were significant predictors of PTSD. The protective effects of social support were, however, not observed for this group. There is a need for more studies, which address the factors that mediate and moderate effects of social support and effectiveness of different coping strategies in refugee youth dealing with different circumstances of the refugee experience. PMID- 23086003 TI - Rape as a weapon of war in the Democratic Republic of the Congo. AB - The Democratic Republic of the Congo has been appropriately acknowledged as "the rape capital of the world." While the country has been trapped in conflict, the use of rape as a weapon of war has been rampant and unyielding. The sexual violence inflicted upon women has been nothing less than brutal and destructive, physically, socially, and psychologically. This paper analyzes the use of rape as a weapon of war in the Congo, taking into context the ongoing war, cultural and social situations that facilitate its existence, and the many consequences the victims are forced to endure. Drawing information from various academic journals, articles, and field research from international organizations, this paper paints a concise picture of the sexual atrocities occurring in the Democratic Republic of the Congo. PMID- 23086004 TI - Complementary and alternative medicine in the treatment of refugees and survivors of torture: a review and proposal for action. AB - Survivors of torture and refugee trauma often have increased needs for mental and physical healthcare. This is due in part to the complex sequelae of trauma, including chronic pain, major depressive disorder, posttraumatic stress disorder (PTSD) and somatization. This article reviews the scientific medical literature for the efficacy and feasibility of some complementary and alternative medicine (CAM) modalities including meditation, Ayurveda, pranayama/yogic breathing, massage/body-work, dance/movement, spirituality, yoga, music, Traditional Chinese Medicine and acupuncture, qigong, t'ai chi, chiropractic, homeopathy, aromatherapy and Reiki specifically with respect to survivors of torture and refugee trauma. We report that preliminary research suggests that the certain CAM modalities may prove effective as part of an integrated treatment plan for survivors of torture and refugee trauma. Further research is warranted. PMID- 23086005 TI - Reconciliation in Cambodia. PMID- 23086006 TI - Presenting evidence of torture at immigration tribunals in the United Kingdom. PMID- 23086007 TI - Contributory torture. PMID- 23086008 TI - Wash-less and highly sensitive assay for prostate specific antigen detection. AB - A novel, simple and facile biosensor for prostate specific antigen (PSA) detection was constructed. In this method, proteolytically active PSA is capable of cleaving PSA substrate-magnetic carrier complexes. Electrochemical analysis of the sensor layer showed a significant decrease in impedance signal after proteolysis has occurred, whereas a positive change in impedance was observed using a negative control substrate, indicating the specificity of our detection mechanism. The biosensor has the ability to monitor PSA concentrations ranging from 1 pg ml(-1) to 1 MUg ml(-1) with a detection limit as low as 1 pg ml(-1). The sensor offers the possibility of developing a wash-less and cost-effective point-of-care device due to the simplicity of the probe immobilization process and the elimination of labeling and reporter molecules during the biosensing step. PMID- 23086009 TI - Post-inpatient attrition from care "as usual" in veterans with multiple psychiatric admissions. AB - Disengagement from outpatient care following psychiatric hospitalization is common in high-utilizing psychiatric patients and contributes to intensive care utilization. To investigate variables related to treatment attrition, a range of demographic, diagnostic, cognitive, social, and behavioral variables were collected from 233 veterans receiving inpatient psychiatric services who were then monitored over the following 2 years. During the follow-up period, 88.0 % (n = 202) of patients disengaged from post-inpatient care. Attrition was associated with male gender, younger age, increased expectations of stigma, less short-term participation in group therapy, and poorer medication adherence. Of those who left care, earlier attrition was predicted by fewer prior-year inpatient psychiatric days, fewer lifetime psychiatric hospitalizations, increased perceived treatment support from family, and less short-term attendance at psychiatrist appointments. Survival analyses were used to analyze the rate of attrition of the entire sample as well as the sample split by short-term group therapy attendance. Implications are discussed. PMID- 23086011 TI - Intramedullary spinal cord cavernous malformations presenting with unexplained chest pain: case report and review of the literature. AB - INTRODUCTION: Intramedullary spinal cord cavernous malformations are very uncommon in pediatric age, with only 26 cases reported within the available literature to date. The diagnosis of such lesions is often difficult and delayed because of their rarity and bizarre clinical presentation. CASE REPORT: We report a case of intramedullary spinal cord cavernous malformation in a girl, in which sudden onset chest pain was the only presenting symptom, followed by appearance of neurological deficits after 5 days. We review the available literature discussing clinical features and principles of management of these lesions in children. PMID- 23086010 TI - Differential lung uptake of 99mTc-hexamethylpropyleneamine oxime and 99mTc duramycin in the chronic hyperoxia rat model. AB - Noninvasive radionuclide imaging has the potential to identify and assess mechanisms involved in particular stages of lung injury that occur with acute respiratory distress syndrome, for example. Lung uptake of (99m)Tc hexamethylpropyleneamine oxime (HMPAO) is reported to be partially dependent on the redox status of the lung tissue whereas (99m)Tc-duramycin, a new marker of cell injury, senses cell death via apoptosis or necrosis. Thus, we investigated changes in lung uptake of these agents in rats exposed to hyperoxia for prolonged periods, a common model of acute lung injury. METHODS: Male Sprague-Dawley rats were preexposed to either normoxia (21% O(2)) or hyperoxia (85% O(2)) for up to 21 d. For imaging, the rats were anesthetized and injected intravenously with either (99m)Tc-HMPAO or (99m)Tc-duramycin (both 37-74 MBq), and planar images were acquired using a high-sensitivity modular gamma-camera. Subsequently, (99m)Tc-macroagreggated albumin (37 MBq, diameter 10-40 MUm) was injected intravenously, imaged, and used to define a lung region of interest. The lung-to background ratio was used as a measure of lung uptake. RESULTS: Hyperoxia exposure resulted in a 74% increase in (99m)Tc-HMPAO lung uptake, which peaked at 7 d and persisted for the 21 d of exposure. (99m)Tc-duramycin lung uptake was also maximal at 7 d of exposure but decreased to near control levels by 21 d. The sustained elevation of (99m)Tc-HMPAO uptake suggests ongoing changes in lung redox status whereas cell death appears to have subsided by 21 d. CONCLUSION: These results suggest the potential use of (99m)Tc-HMPAO and (99m)Tc-duramycin as redox and cell-death imaging biomarkers, respectively, for the in vivo identification and assessment of different stages of lung injury. PMID- 23086013 TI - A fond farewell to JTI case reports. PMID- 23086014 TI - IASLC/ATS/ERS International Multidisciplinary Classification of Lung Adenocarcinoma: novel concepts and radiologic implications. AB - In 2011, the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society proposed a new classification for lung adenocarcinoma that included a number of changes to previous classifications. This classification now considers resection specimens, small biopsies, and cytology specimens. Two former histopathologic terms, bronchioloalveolar carcinoma and mixed subtype adenocarcinoma, are no longer to be used. For resection specimens, the new terms of adenocarcinoma in situ and minimally invasive adenocarcinoma are introduced for small adenocarcinomas showing pure lepidic growth and predominantly lepidic growth, with invasion <=5 mm, respectively. Invasive adenocarcinomas are now classified by their predominant pattern as lepidic, acinar, papillary, and solid; a micropapillary pattern is newly added. This classification also provides guidance for small biopsies and cytology specimens. For adenocarcinomas that include both an invasive and a lepidic component, it is suggested that for T staging the size of the T-factor may be best measured on the basis of the size of the invasive component rather than on the total size of tumors including lepidic components, both on pathologic and computed tomography assessment. This suggestion awaits confirmation in clinical-radiologic trials. An implication for M staging is that comprehensive histologic subtyping along with other histologic and molecular features can be very helpful in determining whether multiple pulmonary nodules are separate primaries or intrapulmonary metastases. In this review article, we provide an illustrated overview of the proposed new classification for lung adenocarcinoma with an emphasis upon what the radiologist needs to know in order to successfully contribute to the multidisciplinary strategic management of patients with this common histologic subtype of lung cancer. PMID- 23086012 TI - Minimally invasive surgery for esophageal epiphrenic diverticulum: the results of 133 patients in 25 published series and our experience. AB - Esophageal epiphrenic diverticula are uncommon. Traditionally, thoracotomy has been the preferred surgical approach. Recently, minimally invasive approaches have been reported in a few series. However, the best surgical approach remains uncertain. In this study, we review the results of 25 articles discussing laparoscopic or thoracoscopic surgery. From January 1995 to December 2008, there were a total of 133 patients reported in English-language journals in PubMed. Nineteen patients (14 %) underwent thoracoscopic surgery, 112 (84 %) laparoscopic surgery and two patients (2 %) were treated using a combination approach. The diverticulectomy was performed using an endostapler device in all patients. A myotomy was added in 103 patients (83 %). A fundoplication was added in 106 patients (85 %). There were two deaths during surgery (2 %). The post-operative morbidity rate was 21 %. The most severe complication was suture-line leakage, which occurred in 20 patients (15 %). Recently, we successfully treated a patient with an epiphrenic esophageal diverticulum by performing a minimally invasive laparoscopic transhiatal resection and Heller myotomy with Dor fundoplication after observing its enlargement on radiological and endoscopic examinations over 2 years. We believe laparoscopic transhiatal resection and Heller myotomy with Dor fundoplication may therefore become the standard treatment modality for minimally invasive surgery for esophageal epiphrenic diverticulum. PMID- 23086015 TI - The association between forms of aggression, leadership, and social status among urban youth. AB - While much prior research has documented the negative associations between aggression, peer relationships, and social skills, other research has begun to examine whether forms of aggression also may be associated with prosocial skills and increased social status. However, few studies have examined these associations within diverse samples of elementary aged youth. The current study examined the associations between aggression, popularity, social preference, and leadership among 227 urban, ethnic minority (74 % African American, 9 % bi-racial including African American, 12 % other ethnic minorities, and 5 % European American) elementary school youth (average age 9.5 years, 48.5 % female). Results indicated that in an urban, high risk environment, displaying aggressive behaviors was associated with increased perceived popularity, decreased social preference, and, in some cases, increased perceived leadership. The results also suggested gender differences in the association between the forms of aggression (i.e. relational and overt) and popularity. The current study underscores the importance of examining youth leadership along with forms of aggression and social status among urban minority youth. Implications for future research and aggression prevention programming are highlighted. PMID- 23086016 TI - The physiological expression of living in disadvantaged neighborhoods for youth. AB - Evidence suggests that the consequences of chronic exposure to stressors extend beyond psychological effects, and that adolescents living in socio-economically disadvantaged neighborhoods may experience an accumulation of exposure to stressors that wears down the physical systems in the body, resulting in hyper activation of the stress response. This research examines the relationship between exposure to neighborhood stressors and salivary cortisol reactivity in a sample of 163 at-risk African American adolescents (average age 21; 50% female) living in disadvantaged urban neighborhoods. More specifically, the relationship between neighborhood stressors and physiological stress, measured by baseline cortisol and cortisol reactivity is assessed. This research also examines several moderating pathways between exposure to neighborhood disadvantage and cortisol reactivity including substance use, high effort coping, psychological stress and social support. Results indicate that both individual and neighborhood-level factors influence adolescent cortisol. High effort coping and psychological stress were associated with cortisol in the sample, and exposure to neighborhood socio-economic disadvantage resulted in an atypical cortisol response. In addition, neighborhood disadvantage interacted with intra- and interpersonal factors to affect cortisol indirectly. Thus, living in disadvantaged neighborhoods may take a psychological and physiological toll on adolescents, and it also may exert synergistic effects through individual coping and vulnerabilities. PMID- 23086019 TI - Lanthanide upconversion within microstructured optical fibers: improved detection limits for sensing and the demonstration of a new tool for nanocrystal characterization. AB - We investigate a powerful new sensing platform based on the excitation of upconversion luminescence from NaYF(4):Yb/Er nanocrystals loaded in solution within a suspended-core microstructured optical fiber. We demonstrate a substantial improvement in the detection limit that can be achieved in a suspended-core fiber sensor for solution-based measurements using these nanocrystals as an alternative to more traditional fluorophores, with sensing of concentrations as low as 660 fM demonstrated compared with the 10 pM obtained using quantum dots. This nanocrystal loaded suspended core fiber platform also forms the basis for a novel and robust nanoscale spectrometry device capable of capturing power-dependent spectra over a large dynamic range from 10(3) W cm(-2) to 10(6) W cm(-2) using a laser diode. This serves as a useful tool to study the multiple energy levels of rare earth luminescent nano-materials, allowing the two sharp emission bands to be studied in detail over a large dynamic range of excitation powers. Thus, in addition to demonstrating a highly sensitive dip sensor, we have devised a powerful new approach for characterizing upconversion nanoparticles. PMID- 23086017 TI - MauG: a di-heme enzyme required for methylamine dehydrogenase maturation. AB - Methylamine dehydrogenase (MADH) requires the cofactor tryptophan tryptophylquinone (TTQ) for activity. TTQ is a posttranslational modification that results from an 8-electron oxidation of two specific tryptophans in the MADH beta-subunit. The final 6-electron oxidation is catalyzed by an unusual c-type di heme enzyme, MauG. The di-ferric enzyme can react with H(2)O(2), but atypically for c-type hemes the di-ferrous enzyme can react with O(2) as well. In both cases, an unprecedented bis-Fe(IV) redox state is formed, composed of a ferryl heme (Fe(IV)=O) with the second heme as Fe(IV) stabilized by His-Tyr axial ligation. Bis-Fe(IV) MauG acts as a potent 2-electron oxidant. Catalysis is long range and requires a hole hopping electron transfer mechanism. This review highlights the current knowledge and focus of research into this fascinating system. PMID- 23086020 TI - Guanfacine modulates the influence of emotional cues on prefrontal cortex activation for cognitive control. AB - RATIONALE: Functional interactions between limbic regions that process emotions and frontal networks that guide response functions provide a substrate for emotional cues to influence behavior. Stimulation of postsynaptic alpha2 adrenoceptors enhances the function of prefrontal regions in these networks. However, the impact of this stimulation on the emotional biasing of behavior has not been established. OBJECTIVES: This study tested the effect of the postsynaptic alpha2 adrenoceptor agonist guanfacine on the emotional biasing of response execution and inhibition in prefrontal cortex. METHODS: Fifteen healthy young adults were scanned twice with functional magnetic resonance imaging while performing a face emotion go/no-go task following counterbalanced administration of single doses of oral guanfacine (1 mg) and placebo in a double-blind, cross over design. RESULTS: Lower perceptual sensitivity and less response bias for sad faces resulted in fewer correct responses compared to happy and neutral faces but had no effect on correct inhibitions. Guanfacine increased the sensitivity and bias selectively for sad faces, resulting in response accuracy comparable to happy and neutral faces, and reversed the valence-dependent variation in response related activation in left dorsolateral prefrontal cortex (DLPFC), resulting in enhanced activation for response execution cued by sad faces relative to happy and neutral faces, in line with other frontoparietal regions. CONCLUSIONS: These results provide evidence that guanfacine stimulation of postsynaptic alpha2 adrenoceptors moderates DLPFC activation associated with the emotional biasing of response execution processes. The findings have implications for the alpha2 adrenoceptor agonist treatment of attention-deficit hyperactivity disorder. PMID- 23086023 TI - Pathogenesis of severe dengue infection. PMID- 23086021 TI - The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. AB - RATIONALE: Behavioral-economic demand curve analysis offers several useful measures of drug self-administration. Although generation of demand curves previously required multiple days, recent within-session procedures allow curve construction from a single 110-min cocaine self-administration session, making behavioral-economic analyses available to a broad range of self-administration experiments. However, a mathematical approach of curve fitting has not been reported for the within-session threshold procedure. OBJECTIVES: We review demand curve analysis in drug self-administration experiments and provide a quantitative method for fitting curves to single-session data that incorporates relative stability of brain drug concentration. METHODS: Sprague-Dawley rats were trained to self-administer cocaine, and then tested with the threshold procedure in which the cocaine dose was sequentially decreased on a fixed ratio-1 schedule. Price points (responses/mg cocaine) outside of relatively stable brain cocaine concentrations were removed before curves were fit. Curve-fit accuracy was determined by the degree of correlation between graphical and calculated parameters for cocaine consumption at low price (Q(0)) and the price at which maximal responding occurred (P(max)). RESULTS: Removing price points that occurred at relatively unstable brain cocaine concentrations generated precise estimates of Q(0) and resulted in P (max) values with significantly closer agreement with graphical P(max) than conventional methods. CONCLUSION: The exponential demand equation can be fit to single-session data using the threshold procedure for cocaine self-administration. Removing data points that occur during relatively unstable brain cocaine concentrations resulted in more accurate estimates of demand curve slope than graphical methods, permitting a more comprehensive analysis of drug self-administration via a behavioral-economic framework. PMID- 23086022 TI - Effects of mood stabilizers on marble-burying behavior in mice: involvement of GABAergic system. AB - RATIONALE: Obsessive-compulsive disorder (OCD) is characterized by recurrent unwanted thoughts (obsessions), usually accompanied by repetitive behaviors (compulsions) intended to alleviate anxiety. Marble-burying behavior is a pharmacological model for study of OCD. OBJECTIVES: In the present study, we examined the effects of mood stabilizers on marble-burying behavior in mice, as well as the role of GABA receptors in this behavior. METHODS: The effects of treatment with valproate, carbamazepine, lithium carbonate, lamotrigine, muscimol and baclofen on marble-burying behavior in mice were evaluated. RESULTS: Valproate (10, 30 and 100 mg/kg, i.p.) and carbamazepine (30 and 100 mg/kg, p.o.) significantly reduced marble-burying behavior without affecting total locomotor activity in ICR mice. Lamotrigine (30 mg/kg, i.p.) also significantly reduced marble-burying behavior in ddY mice. On the other hand, lithium carbonate (10, 30 and 100 mg/kg, i.p.) reduced total locomotor activity without affecting marble burying behavior in ddY mice. The selective GABA(A) receptor agonist muscimol (1 mg/kg) significantly reduced marble-burying behavior without affecting total locomotor activity, whereas the selective GABA(B) receptor agonist baclofen (3 mg/kg) reduced total locomotor activity without affecting marble-burying behavior. Moreover, the selective GABA(A) receptor antagonist bicuculline (3 mg/kg) significantly counteracted the decrease in marble-burying induced by the administration of muscimol (1 mg/kg) and valproate (100 mg/kg). CONCLUSIONS: These results suggest that GABAergic mechanism is involved in marble-burying behavior, and that valproate, carbamazepine and lamotrigine reduce marble-burying behavior. Moreover, valproate reduces marble-burying behavior via a GABA(A) receptor-dependent mechanism. PMID- 23086024 TI - Anaemia in pregnancy in the district of Anuradhapura, Sri Lanka--need for updating prevalence data and screening strategies. AB - OBJECTIVES: To determine the prevalence of anaemia during pregnancy in Anuradhapura district and evaluate present screening methods for anaemia. METHODS: Modified WHO 30 cluster sampling method with increased precision was used to estimate the prevalence of anaemia in the Anuradhapura district, Sri Lanka. Serum haemoglobin was measured using methemoglobin method. Clinical examination was carried out to evaluate the conjunctival method in anaemia screening. Values recorded from haemoglobin colour scale method used in the field antenatal clinics were collected. RESULTS: A total of 990 pregnant women participated in the study. In the first, second and third trimesters, prevalence of anaemia was 7.6%, 19.7% and 19.3% respectively. Gestational age adjusted anaemia prevalence among pregnant women in this study population was 14.1% (95% CI 12.0-16.4%). Mean and median haemoglobin concentration of the study sample was 11.8g/dL (SD 1.02g/dl and IQR 11.2-12.5g/dl). Among anaemic pregnant women, average values for Mean Corpuscular Volume (MCV), Mean Corpuscular Haemoglobin (MCH), and Mean Corpuscular Haemoglobin Concentration (MCHC) were, 82.9 fl (SD 11.5), 27.6 (SD-3.6) pg/cell and 32.9g/dl (SD 1.8) respectively. Sensitivity and specificity of haemoglobin colour scale method was 50% (95% CI 29.0-71.0%) and 76.3% (95% CI 66.9-83.7%) respectively. Sensitivity and specificity of conjunctival method in detecting anaemia during pregnancy was 18.8% (95% CI 11.9 28.4) and 69.3% (95% CI 58.2- 78.6%). CONCLUSIONS: Prevalence of anaemia in the district of Anuradhapura was less than 50% of the estimated prevalence for Sri Lanka. Both haemoglobin colour scale and conjunctival method were having low validity in detecting anaemia in pregnancy. PMID- 23086025 TI - Risk behaviour of street children in Colombo. AB - INTRODUCTION: Sri Lankan street children live in insecure and disadvantaged environments and have disrupted and poorly functioning families resulting in their poor socialisation. In this backdrop they are at high risk of adopting delinquent and antisocial behaviour and becoming victims of abuse. Despite recognition of this as a social problem, an in-depth exploration of their behaviour and its correlates has not been attempted. OBJECTIVES: To describe risk behaviour among street children in Colombo city and the determinants of such behaviour. METHODS: A cross sectional qualitative study in Colombo Fort, Pettah, Slave Island, and Maradana areas was conducted using focus group discussions (FGDs) with street children and semi-structured interviews (SSIs) with street children and key informants in their environment. Data generated were used to profile 283 children identified through referral sampling. An observation study was conducted to validate data generated through FGDs and SSIs. Semi-structured questionnaires, a moderator guide, an interviewer-administered questionnaire, and an observational checklist were used for SSIs, FGDs, profiling, and observational study, respectively. RESULTS: Majority of street children were boys and were aged 14 years or less. Nearly 18% lived alone without a guardian. Two thirds had never enrolled in a school. Many children were used for begging, neglecting their health vulnerabilities. Occupational risk behaviour included heavy manual labour, transportation and sale of illicit alcohol and narcotics, robbing/pick-pocketing, commercial sex work, and pimping. Recreational risk behaviour included abuse of alcohol/narcotics, smoking, sexual promiscuity, and patronising commercial sex workers. CONCLUSIONS: Increased awareness and strategies are required to minimise threats to street children and society. PMID- 23086026 TI - Physical, chemical and microbial analysis of bottled drinking water. AB - INTRODUCTION: People rely on the quality of the bottled drinking water, expecting it to be free of microbial contamination and health hazards. OBJECTIVES: To evaluate the quality of bottled drinking water sold in Jaffna peninsula by analysing the physical, chemical and microbial contents and comparing with the recommended Sri Lankan Standard (SLS) values. METHODS: All bottled water samples sold in Jaffna peninsula were collected. Electrical conductivity, total dissolved solid, pH, calcium, nitrate, total aerobic and anaerobic count, coliform bacterial count and faecal contamination were checked. RESULTS: These are 22 brands of bottled drinking water sold in Jaffna peninsula. The sample had very low electrical conductivity when compared with SLS (750 MUS/ cm) and varied from 19 to 253 MUS/cm with the mean of 80.53 (+/-60.92) MUS/cm. The pH values of the bottled drinking water brands varied from 4.11 to 7.58 with a mean of 6.2 (+/ 0.75). The total dissolved solid content of the bottled drinking water brands varied from 9 to 123.67 mg/l with a mean of 39.5 (+/-30.23) mg/l. The calcium content of the bottled drinking water brands varied from 6.48 to 83.77 mg/l with a mean of 49.9 (+/-25.09) mg/l. The nitrate content of the bottled drinking water brands varied from 0.21 to 4.19 mg/l with the mean of 1.26 (+/-1.08) mg/l. Aerobic bacterial count varied from 0 to 800 colony forming unit per ml (cfu/ml) with a mean of 262.6 (+/-327.50) cfu/ml. Among the 22 drinking bottled water brands 14 and 9% of bottled drinking water brands showed fungal and coliform bacterial contaminants respectively. The water brands which contained faecal contamination had either Escherichia coli or Klebsiella spp. CONCLUSIONS: The bottled drinking water available for sale do not meet the standards stipulated by SLS. PMID- 23086027 TI - The prevalence of autoimmune thyroiditis after universal salt iodisation in Sri Lanka. AB - INTRODUCTION: Sri Lanka is endemic for goiters. Iodine deficiency is thought to be the main cause. The global iodisation programme was implemented in the country in 1995. Several studies done in school children have shown a reduction in the goiter prevalence (3.8%) in the initial post iodisation period. An island wide, community based study was carried out to study the prevalence of goiters. METHODS: A multistage cluster sampling method was used. Examination of goiters was done by two trained investigators and graded according to the WHO grading. Fine needle aspiration cytology of the goitres was also undertaken in the field. A sample of urine was collected from all participants. In a random sample of 153 individuals with a goiter, serum was checked for anti thyroid peroxidase antibodies. RESULTS: Out of 5200 individuals screened, 426 had a clinically detectable goiter. Adjusted prevalence rate was 6.8%. Both serological and cytological evidence of autoimmune thyroiditis was seen in 19.6% of goiters. Mean urinary iodine concentration was 235 MUg/l range 11.1 - 425 MUg/l). Association between elevated antithyroperoxidase antibodies and median urinary iodine concentration was significant. CONCLUSION: Goiter prevalence in Sri Lanka has increased after an initial drop following the iodisation. A significant proportion of goiters is due to AIT. Urinary excretion of Iodine in the community is high and has a positive correlation with the prevalence of aTPO anti vodies. Increase in AIT due to a high Iodine intake may account for the rise in goiter prevalence. PMID- 23086028 TI - A desk review of Sri Lankan migrant worker deaths in 2009. AB - OBJECTIVES: A desk review and indirect standardisation techniques are used to describe the mortality risk for Sri Lankan migrant workers. METHODS: Annonymised data were extracted from Sri Lanka Bureau of Foreign Employment case files recording deaths during 2009. Indirect standardisation is used to compare death rates taking into account age-sex distribution of the groups. As the actual age death distribution of the departures for 2009 was not available, estimates were derived using departure for 2007, 2008 and 2009. RESULTS: Out of 333 deaths reported in 2009, 328 were analysed. The mortality rates for males and females based on 2007, 2008 and 2009 estimates were consistent for all age groups. Females aged 25-29 years were at an increased risk of death relative to their counterparts in Sri Lanka. CONCLUSIONS: Although information from the country of death is inaccessible, data available locally can be analysed systematically to highlight pertinent migrant workers' issues. PMID- 23086029 TI - Aortic patch reconstruction of superior mesenteric and celiac axis in a deceased donor liver transplantation. PMID- 23086030 TI - Thrombocytopenia in dyschromatosis universalis hereditaria. PMID- 23086031 TI - Partial ptosis, dilated pupils and ataxia following abamectin poisoning. PMID- 23086032 TI - A patient with spotted fever group rickettsiosis mimicking connective tissue disease. PMID- 23086033 TI - Two siblings with cerebrotendinous xanthomatosis. PMID- 23086034 TI - Splenic infarction and spontaneous rupture in a patient with paratyphoid. PMID- 23086035 TI - PGC-1alpha improves glucose homeostasis in skeletal muscle in an activity dependent manner. AB - Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC 1alpha) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1alpha in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1alpha in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1alpha and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1alpha and exercise constitutes a promising approach for the treatment of metabolic disorders. PMID- 23086036 TI - Altered response of skeletal muscle to IL-6 in type 2 diabetic patients. AB - Interleukin-6 (IL-6) has a dual role in modulating insulin sensitivity, with evidence for this cytokine as both an enhancer and inhibitor of insulin action. We determined the effect of IL-6 exposure on glucose and lipid metabolism in cultured myotubes established from people with normal glucose tolerance or type 2 diabetes. Acute IL-6 exposure increased glycogen synthesis, glucose uptake, and signal transducer and activator of transcription 3 (STAT3) phosphorylation in cultured myotubes from normal glucose tolerant subjects. However, in type 2 diabetic patients, IL-6 was without effect on glucose metabolism and STAT3 signaling, concomitant with increased suppressor of cytokine signaling 3 (SOCS3) expression. IL-6 increased fatty acid oxidation in myotubes from type 2 diabetic and normal glucose tolerant subjects. Expression of IL-6, IL-6 receptor (IL-6R), or glycoprotein 130, as well as IL-6 secretion, was unaltered between cultured myotubes from normal glucose tolerant or type 2 diabetic subjects. Circulating serum IL-6 concentration was unaltered between normal glucose tolerant and type 2 diabetic subjects. In summary, skeletal muscle cells from type 2 diabetic patients display selective IL-6 resistance for glucose rather than lipid metabolism. In conclusion, IL-6 appears to play a differential role in regulating metabolism in type 2 diabetic patients compared with normal glucose tolerant subjects. PMID- 23086037 TI - Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. AB - Despite the recent attention focused on the roles of the nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of type 2 diabetes, little is known about the ex vivo profile of inflammasome activation in type 2 diabetic patients. In this study, we investigated patterns of NLRP3 inflammasome activation in monocyte derived macrophages (MDMs) from drug-naive patients with newly diagnosed type 2 diabetes. Type 2 diabetic subjects had significantly increased mRNA and protein expression of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), and proinflammatory cytokines in MDMs cultured with autologous sera compared with healthy controls. Upregulated interleukin (IL)-1beta maturation, IL 18 secretion, and caspase-1 cleavage were observed in MDMs from type 2 diabetic patients after stimulation with various danger molecules (ATP, high-mobility group protein B1, free fatty acids, islet amyloid polypeptide, and monosodium uric acid crystals). Mitochondrial reactive oxygen species and NLRP3 were required for IL-1beta synthesis in MDMs. Finally, 2 months of therapy with the antidiabetic drug metformin significantly inhibited the maturation of IL-1beta in MDMs from patients with type 2 diabetes through AMP-activated protein kinase (AMPK) activation. Taken together, these data suggest that NLRP3 inflammasome activation is elevated in myeloid cells from type 2 diabetic patients and that antidiabetic treatment with metformin contributes to modulation of inflammasome activation in type 2 diabetes. PMID- 23086038 TI - PAQR3 modulates insulin signaling by shunting phosphoinositide 3-kinase p110alpha to the Golgi apparatus. AB - Phosphoinositide 3-kinase (PI3K) mediates insulin actions by relaying signals from insulin receptors (IRs) to downstream targets. The p110alpha catalytic subunit of class IA PI3K is the primary insulin-responsive PI3K implicated in insulin signaling. We demonstrate here a new mode of spatial regulation for the p110alpha subunit of PI3K by PAQR3 that is exclusively localized in the Golgi apparatus. PAQR3 interacts with p110alpha, and the intracellular targeting of p110alpha to the Golgi apparatus is reduced by PAQR3 downregulation and increased by PAQR3 overexpression. Insulin-stimulated PI3K activity and phosphoinositide (3,4,5)-triphosphate production are enhanced by Paqr3 deletion and reduced by PAQR3 overexpression in hepatocytes. Deletion of Paqr3 enhances insulin stimulated phosphorylation of AKT and glycogen synthase kinase 3beta, but not phosphorylation of IR and IR substrate-1 (IRS-1), in hepatocytes, mouse liver, and skeletal muscle. Insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake are enhanced by Paqr3 ablation. Furthermore, PAQR3 interacts with the domain of p110alpha involved in its binding with p85, the regulatory subunit of PI3K. Overexpression of PAQR3 dose-dependently reduces the interaction of p85alpha with p110alpha. Thus, PAQR3 negatively regulates insulin signaling by shunting cytosolic p110alpha to the Golgi apparatus while competing with p85 subunit in forming a PI3K complex with p110alpha. PMID- 23086040 TI - Adipose tissue TCF7L2 splicing is regulated by weight loss and associates with glucose and fatty acid metabolism. AB - We investigated the effects of obesity surgery-induced weight loss on transcription factor 7-like 2 gene (TCF7L2) alternative splicing in adipose tissue and liver. Furthermore, we determined the association of TCF7L2 splicing with the levels of plasma glucose and serum free fatty acids (FFAs) in three independent studies (n = 216). Expression of the short mRNA variant, lacking exons 12, 13, and 13a, decreased after weight loss in subcutaneous fat (n = 46) and liver (n = 11) and was more common in subcutaneous fat of subjects with type 2 diabetes than in subjects with normal glucose tolerance in obese individuals (n = 54) and a population-based sample (n = 49). Additionally, there was a positive correlation between this variant and the level of fasting glucose in nondiabetic individuals (n = 113). This association between TCF7L2 splicing and plasma glucose was independent of the TCF7L2 genotype. Finally, this variant was associated with high levels of serum FFAs during hyperinsulinemia, suggesting impaired insulin action in adipose tissue, whereas no association with insulin secretion or insulin-stimulated whole-body glucose uptake was observed. Our study shows that the short TCF7L2 mRNA variant in subcutaneous fat is regulated by weight loss and is associated with hyperglycemia and impaired insulin action in adipose tissue. PMID- 23086039 TI - Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. AB - Adult non-insulin requiring diabetes includes latent autoimmune diabetes of adults (LADA), distinguished from type 2 diabetes by the presence of islet autoantibodies. LADA China determined the characteristics of Chinese LADA. This nationwide, multicenter, clinic-based cross-sectional study was conducted in 46 university-affiliated hospitals in 25 Chinese cities. All 4,880 ketosis-free diabetic patients (<1 year postdiagnosis, without insulin therapy for >6 months, aged >=30 years) had GAD antibody (GADA) and HLA-DQ genotype measured centrally with clinical data collected locally. GADA-positive subjects were classified as LADA. Of the patients, 5.9% were GADA positive with LADA. LADA showed a north south gradient. Compared with GADA-negative type 2 diabetes, LADA patients were leaner, with lower fasting C-peptide and less metabolic syndrome. Patients with high GADA titers are phenotypically different from those with low GADA titers, while only a higher HDL distinguished the latter from those with type 2 diabetes. HLA diabetes-susceptible haplotypes were more frequent in LADA, even in those with low-titer GADA. HLA diabetes-protective haplotypes were less frequent in LADA. Our study implicates universal immunogenetic effects, with some ethnic differences, in adult-onset autoimmune diabetes. Autoantibody positivity and titer could be important for LADA risk stratification and accurate therapeutic choice in clinical practice. PMID- 23086042 TI - Gate-controlled transitions in triple dots with interdot repulsion and magnetic field. AB - We study the quantum phase transition (QPT) and electronic transport in triple quantum dots for a wide range of the gate voltage epsilon. We focus on the effect of the interdot repulsion V and the magnetic field B. In the case of particle hole (p-h) symmetry and B = 0, we find the local quadruplet-doublet transition of first order when V increases to a critical point V(c) ~ U, where U is the on-site repulsion. Beyond the p-h symmetry, the sequence of the QPTs depends on epsilon. For small epsilon, a first order doublet-singlet transition is observed. For middle epsilon, we find the quadruplet-triplet transition of first order at V(c1) and the triplet-singlet transition of the Kosterlitz-Thouless type at V(c2). For large epsilon, there are two kinds of first order QPT with phase sequence quadruplet-triplet-doublet. The magnetic field B compensates for the effect of V. For V > U, as B increases we find a first order or second order QPT from a low spin state to a high-spin state. The restoring of the Kondo effect and a perfect spin filtering is realized in the appropriate regime of the magnetic field. PMID- 23086041 TI - Gold coatings on polymer laser induced periodic surface structures: assessment as substrates for surface-enhanced Raman scattering. AB - We report on the fabrication of gold coated nanostructured polymer thin films and on their characterization as substrates for surface enhanced Raman spectroscopy (SERS). Laser induced periodic surface structures (LIPSS) were obtained on thin polymer films of poly(trimethylene terephthalate) (PTT) upon laser irradiation with the fourth harmonic of a Nd:YAG laser (266 nm, pulse duration 6 ns) resulting in a period close to the incident wavelength. The nanostructured polymer substrates were coated with a nanoparticle assembled gold layer by pulsed laser deposition using the fifth harmonic of a Nd:YAG laser (213 nm, pulse duration 15 ns). Different deposition times resulted in thicknesses from a few nanometres up to several tens of nanometres. Analysis by atomic force microscopy and grazing incident small angle X-ray scattering showed that gold coating preserved the LIPSS relief. The capabilities of the produced nanostructures as substrates for SERS have been investigated using benzenethiol as a test molecule. The SERS signal is substantially larger than that observed for a gold-coated flat substrate. Advantages of this new type of SERS substrates are discussed. PMID- 23086043 TI - Certificates of confidentiality: legal counsels' experiences with and perspectives on legal demands for research data. AB - The certificate of confidentiality (Certificate) is an important tool for protecting identifiable, sensitive human subjects research data in the United States. However, little is known about the Certificate's effectiveness in protecting identifiable data. We interviewed 24 legal counsel representing U.S. research institutions about their experiences with legal demands for research data. Our respondents reported few, if any, legal demands over the course of their tenure, but two-thirds had experience with legal demands for data protected by a Certificate. They reported such demands often were resolved without disclosure of identifiable research data, typically without court intervention. While our respondents reported similar success protecting identifiable data in court, they often did not rely on the Certificate to do so. PMID- 23086044 TI - Opportunities, ethical challenges, and lessons learned from working with peer research assistants in a multi-method HIV community-based research study in Ontario, Canada. AB - We discuss ethical challenges and opportunities experienced by peer research assistants (PRAs) in a multi-method HIV community-based research study in Ontario, Canada. We review lessons learned and best practices based on our experience conducting a qualitative investigation of research priorities with diverse women living with HIV (WLWH) and implementation of a cross-sectional survey with African, Caribbean, and Black WLWH. While some opportunities were similar across research phases for PRAs (e.g., skill building), distinct challenges emerged in qualitative and quantitative phases. For example, our training did not adequately prepare PRAs with focus group facilitation skills; at times, survey implementation became counseling sessions. Researchers should assess how best to support PRAs as part of multi-method research processes. PMID- 23086045 TI - Navigating risks and professional roles: research with lesbian, gay, bisexual, trans, and queer young people with intellectual disabilities. AB - We examine ethical issues that emerged during a community-based participatory research (CBPR) study in Toronto, Canada, exploring sexual health attitudes and practices among lesbian, gay, bisexual, trans, queer, and questioning (LGBTQ) young people (ages 17-26) labeled with intellectual disabilities. These ethical concerns included: (1) managing the risk of coercion, (2) consent to participate in the study, (3) issues of confidentiality and disclosure, (4) balancing beneficence with self-determination, and (5) role conflict for researcher practitioners who participate in CBPR projects. Incorporating critical disability perspectives and a heightened awareness of professional role conflict into CBPR practices has the potential to foster development of more inclusive and accessible sexual health initiatives and research environments. PMID- 23086046 TI - Photovoice as a community-based participatory research method among women living with HIV/AIDS: ethical opportunities and challenges. AB - Photovoice is a method in which participants use photography to identify, express, and disseminate their experiences. We conducted photovoice projects with women living with HIV/AIDS (N=21) to explore opportunities and challenges associated with the method. Photovoice provided a means to achieve two key principles of ethical public health practice: It gives participants opportunities to define their health priorities, and facilitates participant empowerment. Ethical challenges that were encountered related to exposing, through photographs, one's identity as living with HIV/AIDS, illicit activities, and other people. We discuss lessons learned for future practice to maximize the ethical opportunities and manage the challenges associated with using photovoice as an HIV-related CBPR strategy. PMID- 23086047 TI - Community perspectives on research consent involving vulnerable children in Western Kenya. AB - Involving vulnerable pediatric populations in international research requires culturally appropriate ethical protections. We sought to use mabaraza, traditional East African community assemblies, to understand how a community in western Kenya viewed participation of children in health research and informed consent and assent processes. Results from 108 participants revealed generally positive attitudes towards involving vulnerable children in research, largely because they assumed children would directly benefit. Consent from parents or guardians was understood as necessary for participation while gaining child assent was not. They felt other caregivers, community leaders, and even community assemblies could participate in the consent process. Community members believed research involving orphans and street children could benefit these vulnerable populations, but would require special processes for consent. PMID- 23086049 TI - Readability of informed consent documents (1987-2007) for clinical trials: a linguistic analysis. AB - We investigated the readability of informed consent documents linguistically and compared old and new ICDs. Twenty ICDs (ten from 1987-1992 and ten from 2006 2007) were included. The Evaluative Linguistic Framework (ELF) was used to analyze the texts. The ELF evaluates the following items: main themes, order of themes, rhetorical functions, the relationship between reader and writer, metadiscourse, headings, expert terminology, and visual aspects. An ICD is considered readable if it achieves the goal of inviting the reader to participate and explaining the implication of participation. The new ICDs were more readable than the old ones, as they were more oriented towards research, contained instructions about how to consent, and provided clear contact information. Aspects that reduced the readability of the new ICDs were the large number of topics, details, and actors presented. The readability of the old ICDs was enhanced by fewer topics, a clear presentation of the involved actors, and brevity. However, their readability was reduced by the inclusion of a vast amount of information about the reader's diagnosis and treatment. PMID- 23086048 TI - The vulnerabilities of orphaned children participating in research: a critical review and factors for consideration for participation in biomedical and behavioral research. AB - Orphans are a subpopulation with a unique set of additional vulnerabilities. Increasing focus on children's rights, pediatric global health, and pediatric research makes it imperative to recognize and address unique vulnerabilities of orphaned children. This paper describes the unique vulnerabilities of the orphaned pediatric population and offers a structured set of factors that require consideration when including orphans in biomedical research. Pediatric orphans are particularly vulnerable due to decreased economic resources, psychosocial instability, increased risk of abuse, and delayed/decreased access to healthcare. These vulnerabilities are significant. By carefully considering each issue in a population in a culturally specific and study-specific manner, researchers can make valuable contributions to the overall health and well-being of this uniquely vulnerable population. PMID- 23086050 TI - An investigation of case-based instructional strategies on learning, retention, and ethical decision-making. AB - Case-based instruction has been successfully employed by educators across various fields; however, little is known about how individuals work with cases during the learning process. We examined two well-established instructional strategies: elaboration and self-development of narratives. Participants were randomly assigned to (1) elaborate on a given case, (2) develop their own case, (3) elaborate on a self-developed case, or (4) a control condition. Findings indicated that those who elaborated on a given case and the control group outperformed the other treatment groups in terms of case-based knowledge acquisition, execution of sensemaking processes, utilization of ethical decision making (EDM) strategies, and performance on two EDM measures. Implications for use of instructional strategies in ethics training programs are discussed. PMID- 23086054 TI - Assessing the accuracy of template-based structure prediction metaservers by comparison with structural genomics structures. AB - The explosion of the size of the universe of known protein sequences has stimulated two complementary approaches to structural mapping of these sequences: theoretical structure prediction and experimental determination by structural genomics (SG). In this work, we assess the accuracy of structure prediction by two automated template-based structure prediction metaservers (genesilico.pl and bioinfo.pl) by measuring the structural similarity of the predicted models to corresponding experimental models determined a posteriori. Of 199 targets chosen from SG programs, the metaservers predicted the structures of about a fourth of them "correctly." (In this case, "correct" was defined as placing more than 70 % of the alpha carbon atoms in the model within 2 A of the experimentally determined positions.) Almost all of the targets that could be modeled to this accuracy were those with an available template in the Protein Data Bank (PDB) with more than 25 % sequence identity. The majority of those SG targets with lower sequence identity to structures in the PDB were not predicted by the metaservers with this accuracy. We also compared metaserver results to CASP8 results, finding that the models obtained by participants in the CASP competition were significantly better than those produced by the metaservers. PMID- 23086055 TI - Once is not enough: effective strategies for medical student education on intimate partner violence. AB - Training in intimate partner violence (IPV) improves health professionals' knowledge and comfort regarding IPV; the optimal training frequency and format is unknown. We assessed how various types and amounts of IPV education for medical students affected knowledge and attitudes. Medical students at a large, urban university completed a survey concerning IPV-related knowledge and attitudes and participation in didactic and experiential IPV training activities. This was a one-time assessment. Of 586 students, 279 (48%) completed the survey. IPV-related knowledge increased with increased number of training activities. Knowledge and attitude scores were higher (p < .001) for respondents with experiential, versus only didactic, activities. PMID- 23086056 TI - Joining forces: nurses caring for military veterans. PMID- 23086057 TI - Keep the family dog. PMID- 23086058 TI - Slaying the dragon of curriculum review. AB - This column provides information on accreditation for nursing programs of all types. Readers may submit questions to the National League for Nursing Accrediting Commission. General questions of interest to a wide audience will be addressed in this column, whereas more specific questions or those requiring confidentiality will be answered directly. PMID- 23086059 TI - Interprofessional and interdisciplinary collaboration in nursing. AB - Many new nursing leaders assuming deanships, assistant deanships, or interim deanships have limited education, experience, or background to prepare them for the job. To assist new deans and those aspiring to be deans, the authors of this department offer survival tips based on their experiences and insights. They address common issues, challenges, and opportunities that face academic executive teams, such as negotiating an executive contract, obtaining faculty lines, building effective work teams, managing difficult employees, and creating nimble organizational structure to respond to changing consumer, healthcare delivery, and community needs. The authors welcome counterpoint discussions with readers. PMID- 23086061 TI - Motivating underrepresented students to pursue faculty roles. PMID- 23086060 TI - Who is in control of social networks? PMID- 23086062 TI - Supporting nursing students' critical thinking with a mobile web learning environment. AB - The use of mobile technology has the potential of revolutionizing and transforming the way clinical practicums are conducted in nursing training. Our Web-based implementation suggested that incorporating technology, specifically with Internet and mobile devices, to promote nursing students' critical thinking is feasible and showed dramatic results. As our environment was tailored for the psychiatric nursing practicum, future studies should delineate the context in which they are to be delivered. PMID- 23086063 TI - Answering the joining forces call: integrating woman veteran care into nursing simulations. AB - Joining Forces is a national undertaking asking for a commitment from nurses to serve military members, veterans, and their family members. However, given the content saturation concerns so common in nursing curricula, how can educators ensure this content is in their curricula without overburdening their faculty or students? The authors provide suggestions on how to modify existing simulations to incorporate veteran care. These suggestions can easily be incorporated into simulations for nursing schools, hospitals, or outpatient care settings. PMID- 23086065 TI - Ethical reasoning and online social media. AB - Undergraduate nursing students are frequent users of social media sites; however, the ethical or professional implications surrounding the use of online social networking sites are ambiguous and understudied. Faculty guidance is needed if students are to gain the necessary skills and values to appropriately use social media while maintaining professional accountability. The authors discuss the outcomes of a study that assessed their students' sensitivity to posting clinical information on social media sites. PMID- 23086066 TI - Resources for the healthy nurse. PMID- 23086067 TI - Storytelling in the digital world: achieving higher-level learning objectives. AB - Nursing students are not passive media consumers but instead live in a technology ecosystem where digital is the language they speak. To prepare the next generation of nurses, educators must incorporate multiple technologies to improve higher-order learning. The author discusses the evolution and use of storytelling as part of the digital world and how digital stories can be aligned with Bloom's Taxonomy so that students achieve higher-level learning objectives. PMID- 23086068 TI - Questioning the safe status of those nasty tarballs. PMID- 23086069 TI - Using the generative nursing model to reframe nursing student transition to practice. AB - New nurses are leaving hospitals in record numbers after fulfilling their initial employment obligations. Reasons for turnover relate to job dissatisfaction in the form of stressful working conditions, disempowerment, insufficient resources, difficult working relationships, and poor management. The authors discuss an approach for preparing students to manage factors that lead to burnout and new nurse turnover using the Generative Leadership Model as a framework. PMID- 23086070 TI - Meet me for lunch at the "repair cafe". PMID- 23086071 TI - Using technology to promote mobile learning: engaging students with cell phones in the classroom. AB - Advancements in cell phone technology have impacted every aspect of society. Individuals have instant access to social networks, Web sites, and applications. Faculty need to consider using these mobile devices to enrich the classroom. The authors discuss how they successfully designed and incorporated cell phone learning activities into their classrooms. Teaching-learning strategies using cell phone technology and recommendations for overcoming challenges associated with cell phone use in the classroom are discussed. PMID- 23086072 TI - The Idaho dedicated education unit model: cost-effective, high-quality education. AB - Faculty face many challenges in delivering clinical education, including faculty availability, the complexity of the faculty role, and limited clinical placements. Dedicated education units (DEUs) are being explored as alternatives to traditional clinical placement models. The authors describe the successful development of a DEU that resulted in positive student outcomes at reduced cost to both the school and the medical center. PMID- 23086073 TI - Infusing environmental health concepts into an existing nursing course. AB - The updated American Nurses Association Nursing: Scope and Standards of Practice's 16th standard delineates that the practice of RNs be environmentally healthy. This makes explicit the need to incorporate learning activities about environmental health into nursing education courses. The authors describe a simple yet very rewarding undergraduate educational intervention that helped nursing students explore environmental health concepts and related nursing implications. PMID- 23086074 TI - Carbon-riveted Pt catalyst supported on nanocapsule MWCNTs-Al2O3 with ultrahigh stability for high-temperature proton exchange membrane fuel cells. AB - Pt catalyst supported on nanocapsule MWCNTs-Al(2)O(3) (multi-walled carbon nanotubes, MWCNTs) catalyst has been prepared by microwave-assisted polyol process (MAPP). The results of electrochemical measurements show that the nanocapsule Pt/MWCNTs-Al(2)O(3) catalyst has higher activity due to more uniform dispersion and smaller size of Pt nanoparticles, and higher stability ascribed to the stronger metal-support interaction (SMSI) between Pt nanoparticles and nanocapsule support than in Pt/MWCNTs. Furthermore, the carbon-riveted nanocapsule Pt/MWCNTs-Al(2)O(3) catalyst has been designed and synthesized on the basis of in situ carbonization of glucose. The physical characteristics such as X ray diffraction (XRD), energy dispersive analysis of X-ray (EDAX), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) have indicated that alpha-Al(2)O(3) indeed entered into the inside of the MWCNTs and formed a nanocapsule support of MWCNTs with alpha-Al(2)O(3) as stuffing. The accelerated potential cycling tests (APCT) show that carbon-riveted nanocapsule Pt/MWCNTs-Al(2)O(3) possesses 10 times the stability of Pt/C and has 4.5 times the life-span of carbon-riveted Pt/TiO(2)-C reported in our previous work. The significantly enhanced stability for carbon-riveted nanocapsule Pt/MWCNTs Al(2)O(3) catalyst is attributed to the reasons as follows: the inherently excellent mechanical resistance and stability of alpha-Al(2)O(3) and MWCNTs in acidic and oxidative environments; SMSI between Pt nanoparticles and the nanocapsule support; the anchoring effect of the carbon layers formed during the carbon-riveting process (CRP); the increase of Pt(0) composition during CRP. PMID- 23086075 TI - Solid-phase extraction, sample stacking and capillary zone electrophoresis for the analysis of urinary polycyclic aromatic hydrocarbon metabolites. AB - A capillary zone electrophoresis method is presented for the analysis of six biomarkers of polycyclic aromatic hydrocarbons in urine samples. Baseline resolution of 2-hydroxyfluorene, 2-hydroxynaphthalene, 1-hydroxypyrene, 9 hydroxyphenanthrene, 3-hydroxybenzo[a]pyrene, 4-hydroxybenzo[a]pyrene and 5 hydroxybenzo[a]pyrene was achieved in approximately 17 min with a 20 mM borate buffer prepared in 50% methanol-water (volume/volume). Competitive limits of detection were obtained for all the studied metabolites using commercial instrumentation equipped with an ultraviolet-visible absorption detector. Detection at the sub-parts-per-billion concentration levels was made possible via sample pre-concentration based on solid-phase extraction and sample stacking. Solid-phase extraction was performed with the aid of a twelve port vacuum manifold. Sample stacking was carried out in methanol, i.e. the eluting solvent from the solid-phase extraction procedure. To the extent of our literature search, this is the first application of sample stacking to the analysis of monohydroxy-polycyclic aromatic hydrocarbons in urine samples. Metabolite recoveries varied from 93.2 +/- 7.7% (5-hydroxybenzo[a]pyrene) to 108.7 +/- 7.8% (2-hydroxynaphthalene). Limits of detection were at the trace level ranging from 0.99 ng mL(-1) (3-hydroxybenzo[a]pyrene) to 8.54 ng mL(-1) (2 hydroxynaphthalene). The new method was found to be free of interference from four pharmacological drugs - naproxen, ibuprofen, diclofenac and amoxicillin - that might be found in urine samples of unhealthy individuals. PMID- 23086076 TI - Synthesis and engineering porosity of a mixed metal Fe2Ni MIL-88B metal-organic framework. AB - A new rational approach has been developed for the synthesis of a mixed metal MIL 88B metal-organic framework based on a neutral mixed metal cluster, such as Fe(2)Ni(MU(3)-O). Unlike the conventional negative charged single metal cluster, the use of the neutral mixed metal cluster as nodes in the framework avoids the need of a compensating anion inside the porous MIL-88B system; thus the mixed metal MIL-88B becomes porous. The flexibility of the mixed metal MIL-88B can be controlled by terminal ligands with different steric hindrance. This allows us to reversibly customize the porosity of the MIL-88B structure at three levels of specific surface area as well as the pore volume. PMID- 23086077 TI - Can we deliver both population-based and personalized approaches to cancer care? PMID- 23086078 TI - Correcting critical imbalance. PMID- 23086079 TI - Changes in quality of life among prostate cancer patients after surgery. AB - BACKGROUND: Quality of life (QoL) often is impacted after radical prostatectomy (RP) procedures. Although patients' QoL scores gradually improve after RP, changes in the QoL score over time after different RP procedures must be examined. OBJECTIVE: The aim of this study was to compare the changes in QoL over time of prostate cancer patients who were treated with open RP (ORP) or laparoscopic RP (LRP) procedures. METHODS: A longitudinal study design was used. A convenient sample of 67 prostate cancer patients was recruited after RP (ORP = 34, LRP = 33). QoL scores were assessed at 1, 3, and 6 months after RP using the University of California, Los Angeles, Prostate Cancer Index (UCLA-PCI). RESULTS: With respect to the PCI mean score between the ORP and LRP groups, there were significant differences in overall PCI and urinary function at time 1 (1 month after RP). However, a mixed-design analysis of covariance on the overall PCI of the 2 groups over time indicated that, after controlling for nerve sparing, there were significant differences in the main effects for group and time, but no interaction effect. CONCLUSION: Results indicated that all patients' QoL scores improved over time. Laparoscopic RP patients' overall scores were better than ORP patients' scores, but this may be due to unmeasured preoperative differences in this nonrandom sample, and thus, these findings cannot be attributed to treatment differences alone. IMPLICATIONS FOR PRACTICE: Patients' QoL after either RP surgery is likely to drop but is regained by 6 months. This information should be given to patients undergoing RP who are deciding between various RP procedures. PMID- 23086080 TI - Repair of hand defects by transfer of free tissue flaps from toes. AB - INTRODUCTION: There are very few reports on the use of a free composite flap from the toe to repair small tissue defects in the hand. Here, we describe our experience using a free composite flap from the great toe and second toe. METHOD: Fifteen patients sought surgical treatment for tissue defects of the hand at our medical institution from July 2008 to December 2010. These defects included: dorsal defect of the distal thumb, dorsal-radialis defect of the proximal thumb, degloving injury of distal index finger, pulp defect of the middle finger and these were repaired with toe side pulp flaps. In five subjects, treatment of the metatarsophalangeal joint (MPJ) or proximal interphalangeal joint (PIPJ) involved a combined extensor tendon defect with a composite flap with MPJs and PIPJs and the extensor tendon of the second toe. All flaps were transferred as free flaps. RESULTS: All flaps survived. At 34.8 months of follow-up, the average subjective satisfaction score was 8. Eleven patients (73.3 %) experienced cold intolerance, and one patient (6.7 %) dysesthesia. The Semmes-Weinstein Sensitivity Score was 3.48-4.71 at the flap and 0-4.21 at the donor site. The mean two-point discrimination was 7.13 mm. Grip strength was 10 % less than in the unaffected hand. Mobility loss in the MPJ and PIPJ was <10 degrees . No patients had complications at the donor sites. CONCLUSION: Based on the unique characteristics of the free flap from toes, we consider them to be good options for reconstruction of small tissue defects in the hand according to various sizes, shapes, and sites. PMID- 23086081 TI - Distal radius fracture fixation with volar locking plates and additional bone augmentation in osteoporotic bone: a biomechanical study in a cadaveric model. AB - BACKGROUND: Fractures of the distal radius represent the most common fractures in adults. Volar locked plating has become a popular method for treating these fractures, but has been subject to several shortcomings in osteoporotic bone, such as loss of reduction and screw purchase. In order to overcome these shortcomings, cement augmentation has been proposed. METHODS: AO-type 23-A3.3 fractures were made in 8 pairs of fresh frozen osteoporotic cadaveric radial bones. All specimens were treated with volar plating, and divided into cement augmentation or non-augmentation groups (n = 8/group). Constructs were tested dynamically and load to failure, construct-stiffness, fracture gap movement and screw cutting distance were measured. RESULTS: Cement augmentation resulted in a significant increase in cycles and load to failure, as well as construct stiffness at loads higher than 325 N. When compared to the non-augmented group, fracture gap movement decreased significantly at this load and higher, as did screw cutting distance at the holes of the ulnar column. The cycles to failure depend on the BMD in the distal region of the radius. CONCLUSION: Cement augmentation improves biomechanical properties in volar plating of the distal radius. PMID- 23086082 TI - New strategies for teaching maths to chemistry students. PMID- 23086083 TI - Characterization of in vitro transcription amplification linearity and variability in the low copy number regime using External RNA Control Consortium (ERCC) spike-ins. AB - Using spike-in controls designed to mimic mammalian mRNA species, we used the quantitative reverse transcription polymerase chain reaction (RT-qPCR) to assess the performance of in vitro transcription (IVT) amplification process of small samples. We focused especially on the confidence of the transcript level measurement, which is essential for differential gene expression analyses. IVT reproduced gene expression profiles down to approximately 100 absolute input copies. However, a RT-qPCR analysis of the antisense RNA showed a systematic bias against low copy number transcripts, regardless of sequence. Experiments also showed that noise increases with decreasing copy number. First-round IVT preserved the gene expression information within a sample down to the 100 copy level, regardless of total input sample amount. However, the amplification was nonlinear under low total RNA input/long IVT conditions. Variability of the amplification increased predictably with decreasing input copy number. For the small enrichments of interest in typical differential gene expression studies (e.g., twofold changes), the bias from IVT reactions is unlikely to affect the results. In limited cases, some transcript-specific differential gene expression values will need adjustment to reflect this bias. Proper experimental design with reasonable detection limits will yield differential gene expression capability even between low copy number transcripts. PMID- 23086084 TI - Application of PM-IRRAS to study thin films on industrial and environmental samples. AB - Polarization modulation-infrared reflection absorption spectroscopy (PM-IRRAS) was employed to analyze two unique samples: (1) an industrially prepared alkoxysilane-pretreated aluminum alloy (AA6111) in the absence and presence of a ~600-nm-thick lubricant coating and (2) a chemical warfare agent simulant, triethyl phosphate (TEP), on glass. For the pretreated aluminum samples, PM-IRRAS spectra were analyzed for three distinct regions; the SiO stretching vibration around 1120 cm(-1), the NH(2) bending mode at ~1600 cm(-1) and the CH stretching region around 2900 cm(-1). Our results showed that increasing the curing temperature (from 55 to 100 degrees C) improved the overall extent of cross linking within the siloxane network. In addition, the spectra of lubricant (top coating) and the underlying siloxane layer for the aluminum samples with lubricant were collected for the same sample. Our results show that the nature of the siloxane film remains intact and unaltered after deposition of the lubricant top-coat. For detection of TEP on glass, the band at 1268 cm(-1), corresponding to the P?O vibration, was monitored. A droplet of TEP solution in dichloromethane was deposited on glass. After solvent evaporation had occurred, the intensity of the P?O vibration band was used to construct calibration curves to determine the experimental limit of detection, which was found to be ~200 MUg for TEP on glass. PMID- 23086085 TI - Glycated hemoglobin (HbA1c) measurement in frozen whole blood depends on baseline values of fresh samples. AB - Glycated hemoglobin (HbA1c) has been recently adopted as a diagnostic marker of type 2 diabetes. However, its usage is currently limited to fresh blood samples. To allow retrospective HbA1c measurement in blood banks developed in large epidemic studies, here, we contribute to validate HbA1c assessment in frozen versus fresh blood samples from a cohort of diabetic/nondiabetic adult subjects. HbA1c was measured by HPLC in 237 fresh whole blood samples and on the same samples after a 12-month storage and a further 6-month-refrozen storage. Mean HbA1c +/- SD in fresh, frozen, and refrozen samples was 6.9 +/- 1.2, 6.6 +/- 1.1, and 6.4 +/- 1.0% for the Diabetes Control and Complications Trial and 52 +/- 13, 49 +/- 12, and 46 +/- 11 mmol/mol for the International Federation of Clinical Chemistry and Laboratory Medicine reference, respectively. A significant correlation was found between fresh/frozen and fresh/refrozen (R = 0.994 and 0.993, P < 0.001) samples. HbA1c relative error ratio (%RER) between frozen/refrozen and fresh samples significantly correlated with HbA1c and depended on fresh value range, increasing in the five HbA1c classes (<6.0, 6.0 6.5, 6.5-7, 7-8, >=8%, corresponding to <42, 42-48, 48-53, 53-64, >=64 mmol/mol, P < 0.001). In particular, the 6.5% (48 mmol/mol) HbA1c diagnostic cutoff of fresh samples identified two classes reflecting significant differences in %RER (2.8 +/- 2.0 and 3.3 +/- 1.7; P < 0.05) between frozen and fresh samples. In conclusion, our results demonstrate a high correlation between data from fresh and frozen samples, with a very limited %RER between the two measurements, which increases with baseline HbA1c levels. Accordingly, when analyzing biobank frozen specimens for diagnostic purpose, the effect of the HbA1c range should be taken into account. PMID- 23086086 TI - Analysis of carbamazepine and its five metabolites in serum by large-volume sample stacking-sweeping capillary electrophoresis. AB - This study establishes a method, using different buffer conductivities and large volume sample stacking (LVSS)-sweeping capillary electrophoresis, for analysis of carbamazepine (CBZ) and its five metabolites in serum. The capillary (50/60 cm) was filled with a high concentration of background electrolyte (150 mM phosphate, pH 3.5, containing 15 % methanol), followed by a large volume of samples (10 psi, 20 s) with low-concentration buffers (5 mM phosphate, pH 3.5, with 5 % methanol). When high voltage was applied (-20 kV), the sodium dodecyl sulfate (SDS) started to sweep the analytes to an outlet. Meanwhile, the analytes decelerated at the boundary between low- and high-conductivity buffers. Finally, a narrow sample zone was formed. The procedure of sweeping and separation was simultaneously carried out by a sweeping buffer (150 mM phosphate, pH 3.5) with 15% methanol and 50 mM SDS added, and the detection was performed by UV at 214 nm. The method was validated for linearity (r >/= 0.997), precision, and accuracy. The calibration curves were established for CBZ and its five metabolites between 0.03-25 and 0.03 3 MUg/mL. The limits of detection (S/N = 3) were 0.01 MUg/mL for each analyte. Compared with simple MEKC (0.5 psi, 5 s), this system can improve the sensitivity about 300-fold. Finally, this method was successfully applied to five patients, who had taken 200 mg CBZ daily, and CBZ levels were found to be from 3.72 to 5.82 MUg/mL. PMID- 23086087 TI - Stable isotopic labelling-assisted untargeted metabolic profiling reveals novel conjugates of the mycotoxin deoxynivalenol in wheat. AB - An untargeted screening strategy for the detection of biotransformation products of xenobiotics using stable isotopic labelling (SIL) and liquid chromatography high resolution mass spectrometry (LC-HRMS) is reported. The organism of interest is treated with a mixture of labelled and non-labelled precursor and samples are analysed by LC-HRMS. Raw data are processed with the recently developed MetExtract software for the automated extraction of corresponding peak pairs. The SIL-assisted approach is exemplified by the metabolisation of the Fusarium mycotoxin deoxynivalenol (DON) in planta. Flowering ears were inoculated with 100 MUg of a 1 + 1 (v/v) mixture of non-labelled and fully labelled DON. Subsequent sample preparation, LC-HRMS measurements and data processing revealed a total of 57 corresponding peak pairs, which originated from ten metabolites. Besides the known DON and DON-3-glucoside, which were confirmed by measurement of authentic standards, eight further DON-biotransformation products were found by the untargeted screening approach. Based on a mass deviation of less than +/-5 ppm and MS/MS measurements, one of these products was annotated as DON-glutathione (GSH) conjugate, which is described here for the first time for wheat. Our data further suggest that two DON-GSH-related metabolites, the processing products DON S-cysteine and DON-S-cysteinyl-glycine and five unknown DON conjugates were formed in planta. Future MS/MS measurements shall reveal the molecular structures of the detected conjugates in more detail. PMID- 23086088 TI - On-line solid-phase microextraction of triclosan, bisphenol A, chlorophenols, and selected pharmaceuticals in environmental water samples by high-performance liquid chromatography-ultraviolet detection. AB - A method using on-line solid-phase microextraction (SPME) on a carbowax-templated fiber followed by liquid chromatography (LC) with ultraviolet (UV) detection was developed for the determination of triclosan in environmental water samples. Along with triclosan, other selected phenolic compounds, bisphenol A, and acidic pharmaceuticals were studied. Previous SPME/LC or stir-bar sorptive extraction/LC UV for polar analytes showed lack of sensitivity. In this study, the calculated octanol-water distribution coefficient (log D) values of the target analytes at different pH values were used to estimate polarity of the analytes. The lack of sensitivity observed in earlier studies is identified as a lack of desorption by strong polar-polar interactions between analyte and solid-phase. Calculated log D values were useful to understand or predict the interaction between analyte and solid phase. Under the optimized conditions, the method detection limit of selected analytes by using on-line SPME-LC-UV method ranged from 5 to 33 ng L( 1), except for very polar 3-chlorophenol and 2,4-dichlorophenol which was obscured in wastewater samples by an interfering substance. This level of detection represented a remarkable improvement over the conventional existing methods. The on-line SPME-LC-UV method, which did not require derivatization of analytes, was applied to the determination of TCS including phenolic compounds and acidic pharmaceuticals in tap water and river water and municipal wastewater samples. PMID- 23086089 TI - The effect of a provider-enhanced clinical decision support tool for guiding venous thromboembolism pharmacoprophylaxis in low-risk patients. AB - BACKGROUND: Computer-based tools to assess venous thromboembolism (VTE) risk have been shown to increase VTE pharmacoprophylaxis rates and decrease VTE incidence in high-risk hospitalized patients. However, VTE risk may be underestimated using computer-based tools alone. We tested the effect of a provider-enhanced clinical decision support (CDS) tool on VTE pharmacoprophylaxis and VTE incidence in patients who would have been deemed "low risk" using a computer-based risk assessment tool alone. METHODS: The study sample was adult patients hospitalized during a 13-month period who were determined to be at low risk for VTE with a computer-based risk-assessment tool. The provider-enhanced CDS tool was implemented 4 months into the study period and required providers to stratify patients as being at high, moderate, or low risk for VTE. We compared rates of VTE pharmacoprophylaxis and VTE incidence before and after implementation of the provider-enhanced CDS tool. RESULTS: There were 1322 patients in the 4-month pre implementation period and 3347 patients in the 9-month post-implementation period who were determined to be at low risk for VTE based on a computer-based risk assessment tool. Using the provider-enhanced CDS tool, providers stratified 31% of these computer-assigned low-risk patients as being at moderate risk for VTE and 7% as being at high risk for VTE. The rate of VTE pharmacoprophylaxis increased from 27% to 34% (P < 0.01). The venous thromboprophylaxis rate decreased from 0.98% to 0.42% after implementation of the provider-enhanced CDS tool (P < 0.02). CONCLUSION: Patients identified as being at low risk for VTE solely by computer-based algorithms may include patients whom providers determine to be at risk for VTE. Provider-enhanced CDS tools may outperform computer-based VTE risk-stratification algorithms. PMID- 23086090 TI - Statins for the prevention of venous thromboembolism? a narrative review. AB - Venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is a substantial public health problem. The majority of VTE events are associated with transient periods of heightened risk, such as prolonged hospitalization, undergoing major surgery, experiencing trauma or lower extremity immobility, use of oral contraceptives, or having active cancer. Although pharmacologic thromboprophylaxis agents (eg, unfractionated heparin, low molecular-weight heparins, warfarin, and novel oral anticoagulants) are effective, they remain underused, with concerns about increased bleeding risk often cited as a reason. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (ie, statins), although used primarily for lipid lowering and arterial thrombosis risk reduction, have pleiotrophic effects that affect coagulation and inflammation, and do not increase bleeding risk. There is emerging evidence to suggest that through these pleiotrophic effects, statins may be effective in reducing the incidence of VTE. This article summarizes the literature with regard to statins' effect on VTE and suggests that additional investigations are needed to assess a potential adjunctive role for primary VTE thromboprophylaxis. PMID- 23086091 TI - New options for anticoagulation following total hip arthroplasty and total knee arthroplasty: new oral agents on the horizon. AB - Patients undergoing surgery for total hip arthroplasty (THA) or total knee arthroplasty (TKA) are at particularly high risk for developing venous thromboembolism (VTE). Despite the existence of effective therapies for VTE prevention, THA/TKA patients remain at risk for developing thrombi. Furthermore, the incidence of VTE is predicted to increase as an aging and increasingly obese population experiences joint damage necessitating THA and TKA. Current guidelines recommend the use of a wide range of antithrombotic agents in patients undergoing THA and TKA. These agents include vitamin K antagonists, low-molecular-weight heparins, fondaparinux, and the new oral anticoagulants. However, adherence to guidelines in clinical practice is disappointingly low. The limitations of traditional anticoagulants present management challenges following orthopedic surgery. Vitamin K antagonists present a number of drawbacks, including a narrow therapeutic window and unpredictable pharmacokinetics and pharmacodynamics. The subcutaneous route of administration of fondaparinux and low-molecular-weight heparins may make them unacceptable to patients in the outpatient setting. The introduction of a new generation of anticoagulants promises to address many of the drawbacks associated with the traditional agents. Clinical studies have shown the new oral anticoagulants to be as effective as traditional thromboprophylaxis, with good tolerability profiles. Clinical knowledge of these new agents will be essential to ensure that patients receive appropriate care following orthopedic surgery. This article will discuss the prevention of VTE after THA and TKA based on current evidence-based practice guidelines, the limitations of conventional anticoagulants, and the promise of new therapeutics. PMID- 23086092 TI - Clinical decision support systems to improve utilization of thromboprophylaxis: a review of the literature and experience with implementation of a computerized physician order entry program. AB - OBJECTIVE: A literature review was conducted of studies investigating the effectiveness of paper- and computer-based clinical decision support systems (CDSS) used with or without educational programs designed to increase the use of venous thromboembolism (VTE) prophylaxis. METHODS: Medline was searched on August 9, 2010, without limits on publication year, but with restrictions to English language articles only. The search terms used were "venous thromboembolism," "deep vein thrombosis," "pulmonary embolism," "prophylaxis," "thromboprophylaxis," "computerized," "computerised," "decision support," "alerts," "reminder," "paper system," "risk assessment," and "risk score." All types of studies regarding the effects of CDSS on VTE prophylaxis rates were included. Studies were included if >= 1 post-implementation outcome was measured, such as rates of VTE, rates of prophylaxis prescribing, or guideline-adherence measures. RESULTS: Studies evaluating paper-based CDSS used different strategies, including risk-assessment forms with prophylaxis recommendations, standard order sets, and preprinted sticker reminders on patient notes. Paper-based systems consistently improved prophylaxis rates; however, in most studies, there was still room for improvement. Furthermore, the effect of paper-based CDSS on VTE rates was not conclusively established. Studies evaluating computer-based systems used approaches including risk-assessment models integrated in the computerized physician order entry system, with or without alerts, and automatic reminders on operating schedules. CONCLUSION: Computerized systems are associated with substantial improvements in the prescribing of appropriate prophylaxis and reductions in VTE events, particularly in medical patients. More robust systems can be established with computer-based rather than paper-based CDSS. A drawback of computerized systems is that some hospitals may not have adequate information technology system resources. PMID- 23086093 TI - Periprocedural anticoagulant management. AB - Approximately 6 million Americans are treated with chronic anticoagulation. Of these, 10% of patients will require temporary anticoagulation interruption for an invasive procedure each year. Anticoagulation management during this period requires a formal strategy in order to limit both bleeding and thromboembolic complications. This article will give health care providers a stepwise approach to this process. The first step is to determine whether warfarin discontinuation is necessary for the planned procedure. For procedures requiring warfarin discontinuation, the second step is to determine the appropriate timing. The third step is to identify the patient-specific thromboembolic risk in order to determine which patients require bridging therapy with parenteral anticoagulants. The fourth step is both the most complicated and most critical step in this management strategy. This decision-making step involves choosing the appropriate anticoagulant regimen, dose, and timing of reinitiation that is best tailored to a specific patient, as well as determining procedural variables, in order to limit bleeding and thrombotic complications. PMID- 23086094 TI - Target-specific oral anticoagulants for stroke prevention in patients with atrial fibrillation: real-world considerations. AB - Target-specific oral anticoagulants are now available for the prevention of stroke in patients with atrial fibrillation. These medications have many advantages, including fixed dosing, predictable anticoagulation without the need for monitoring, and few food or drug interactions. On the down side, their anticoagulant effects cannot be readily measured in clinical practice, and there are no known antidotes to reverse their anticoagulant effects. Clinical trials have shown superiority or noninferiority of these anticoagulants when compared with warfarin for reduction in incidence of stroke or systemic embolism, major bleeding, and mortality rates. Based on these findings, recent guidelines have supported the use of dabigatran compared with warfarin (other agents were not included in the guideline). Yet, there are concerns that these new agents may not be appropriate for all patients. Patients who are on warfarin and have stable and therapeutic anticoagulation may see no improvement in outcomes if changed to one of the new anticoagulants. Patients with decreased renal function may be at increased risk for bleeding if deterioration in renal function occurs. Management of bleeding events is complicated by the inability to reverse the new medications' anticoagulant effects. Medication noncompliance may result in more adverse outcomes due to the short half-life of these agents compared with warfarin. Prescribers need to be aware of these limitations as these medications are incorporated into clinical practice. Patients and clinicians need to understand the risk and benefits, and patients need to be engaged with their health care providers in decision making. PMID- 23086095 TI - Venous thromboembolism: diagnosis and current anticoagulation strategies for deep vein thrombosis and pulmonary embolism. AB - The diagnosis and treatment of venous thromboembolic events represents a significant source of medical spending, both domestically and worldwide. Advances in medical imaging and pharmacology continue to alter and improve established treatment paradigms. In this article, we discuss venous thromboembolism etiology, diagnosis, and rationale for current and future treatment strategies. PMID- 23086096 TI - Chronic thromboembolic pulmonary hypertension: an underdiagnosed entity? AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is the only cause of pulmonary hypertension for which there is a potential cure, which is in the form of pulmonary endarterectomy. There is a strong link between pulmonary embolism (PE) and the development of CTEPH. Although CTEPH was initially believed to be a rare complication, this belief has been reconsidered following several studies suggesting that up to 8.8% of patients develop CTEPH within the 2 years after PE. However, considering the incidence of PE, there is a significant discrepancy in the number of patients who are diagnosed, referred, and treated for CTEPH. Potential reasons for this include its often vague clinical presentation, the variable association of CTEPH with PE, and discrepancies when interpreting imaging studies. Underdiagnosis of CTEPH is preventing patients from accessing potentially curative therapy. Increased awareness about this condition is an important initial step to improving diagnostic rates and treatment. PMID- 23086097 TI - Pancreatectomy and autologous islet transplantation for painful chronic pancreatitis: indications and outcomes. AB - Total pancreatectomy with intrahepatic autoislet transplantation (TP/IAT) is a definitive treatment for relentlessly painful chronic pancreatitis. Pain relief is reported to be achieved in approximately 80% of patients. Overall, 30% to 40% achieve insulin independence, and 70% of recipients remain insulin independent for > 2 years, sometimes longer if > 300 000 islets are successfully transplanted. Yet, this approach to chronic pancreatitis is underemphasized in the general medical and surgical literature and vastly underused in the United States. This review emphasizes the history and metabolic outcomes of TP/IAT and considers its usefulness in the context of other, more frequently used approaches, such as operative intervention with partial pancreatectomy and/or lateral pancreaticojejunostomy (Puestow procedure), as well as endoscopic retrograde cholangiopancreatography with pancreatic duct modification and stent placement. Distal pancreatectomy and Puestow procedures compromise isolation of islet mass, and adversely affect islet autotransplant outcomes. Therefore, when endoscopic measures fail to relieve pain in severe chronic pancreatitis, we recommend early intervention with TP/IAT. PMID- 23086098 TI - Hyperbaric medicine for the hospital-based physician. AB - Hyperbaric oxygen (HBO2) is the inhalation of 100% oxygen at pressures > 1.4 times atmospheric pressure. Hyperbaric oxygen can be delivered in monoplace (single person) or multiplace (multi-person) chambers. Most clinical HBO2 exposures are between 2 and 2.4 atm abs for approximately 2 hours. Hyperbaric oxygen causes the blood and tissue oxygen levels to increase, reduces the volume of intravascular and tissue bubbles (to treat decompression sickness [DCS] and arterial gas embolism [AGE]), and accelerates wash-out of other gases, such as nitrogen or carbon monoxide (CO), which is important for DCS, AGE, and CO poisoning. Hyperbaric oxygen favorably modulates ischemia-reperfusion injury by transiently inhibiting neutrophil-endothelial interactions, which is important for patients with DCS, AGE, CO poisoning, and potentially other acute ischemic conditions. Because of enhanced oxygen delivery, HBO2 is used for acute crush injury, ischemic flaps and grafts, acute central retinal arterial occlusion, other acute arterial occlusions, and idiopathic sudden sensorineural hearing loss. Hyperbaric oxygen has antimicrobial effects and is offered for patients with limb- or life-threatening infections, such as clostridial gas gangrene and necrotizing fasciitis. The most common US indication for HBO2 is the treatment of ischemic wounds (eg, diabetic lower extremity wounds, late effects of radiation, and refractory osteomyelitis). In ischemic wounds, HBO2 can deliver sufficient oxygen to the nonhealing wound to stimulate angiogenesis and healing through multiple mechanisms, including increased collagen production, increased growth factor receptor numbers, upregulation of vascular endothelial growth factor, increased circulating endothelial progenitor cells, and improvement in neutrophil mediated host defense. Clinical trials support efficacy of HBO2 for acute CO poisoning, diabetic lower extremity wounds, crush injury, and radiation necrosis. Most hyperbaric chambers are associated with wound care centers and may be hospital based or nonhospital based. We review some of the disorders treated with HBO2 that hospital-based clinicians may be asked to evaluate. PMID- 23086099 TI - Diabetic foot ulcers: evaluation and management. AB - Diabetic foot ulcers (DFUs) are a common complication of diabetes and present a significant health risk to patients, as well as impose a large economic burden. Evaluation for contributory factors that may impact general health or healing, such as hyperglycemia, peripheral artery disease, neuropathy, and nutritional status, is of the utmost importance. Management of DFUs requires involvement of a multidisciplinary team and a standardized approach to patient care. Standard therapy for DFUs includes offloading and debridement. Assessment and control of infection are critical, including determining the severity of the infection, which may drive therapeutic approaches. For recalcitrant ulcers, adjuvant therapies are used to hasten the healing process, and newer therapies are under investigation. PMID- 23086100 TI - Managing inpatient hyperglycemia in a resource-constrained county hospital: the Parkland Memorial Hospital experience. AB - Diabetes is a common comorbidity among hospitalized patients and has been linked to increased length of stay, morbidity, and mortality. In addition, multiple pathophysiological factors contribute to incident hyperglycemia in a sizable proportion of inpatients without previously diagnosed diabetes. Insulin is the mainstay of therapy for inpatient management of diabetes and hyperglycemia. In this article, we discuss initial treatment planning and insulin initiation for established and treatment-naive patients with diabetes who are being treated with human and analog-based insulin therapy. As a publicly funded and cost-conscious hospital, we rely on human insulin for first-line therapy and generally find good results, reserving more costly insulin analogs for patients with type 1 diabetes. We also describe a novel continuous insulin-infusion protocol, the Parkland glucose insulin infusion protocol, which controls severe hyperglycemia safely and effectively in hospitalized patients who are unable to tolerate oral nutrition or are in other complicated clinical situations. We outline transitions from intravenous to subcutaneous insulin and other planning and diabetes education necessary to facilitate discharge. Lastly, we discuss steps for the development and implementation of a continuous intravenous insulin-infusion protocol at the institutional level. PMID- 23086101 TI - The new oral anticoagulants: a challenge for hospital formularies. AB - Introduction Over the past 60 years, clinicians have used vitamin K antagonists, primarily warfarin, as the sole oral anticoagulants for managing a variety of thrombotic disorders. Warfarin, which requires frequent monitoring, has a variable dose response, a narrow therapeutic index, and numerous drug and dietary interactions. However, intravenous and subcutaneous agents, such as unfractionated heparin, low-molecular-weight heparin, direct thrombin inhibitors, and pentasaccharide, have been introduced over the past 30 years for managing thromboembolic disorders. Recently, 5 new oral anticoagulants, dabigatran, rivaroxaban, apixaban, endoxaban, and betrixaban, have been introduced into clinical trials. Apixaban, rivaroxaban, endoxaban, and betrixaban are specific direct inhibitors of factor Xa, while dabigatran inhibits factor IIa. These drugs have a pharmacological profile that does not require monitoring in order to adjust therapy, which is the mainstay of warfarin management. In addition, these new medications have not shown any major issues regarding food interactions; rather, they demonstrate the potential for limited drug-drug interactions due to their limited metabolism through the cytochrome P450 system. This unique pharmacokinetic profile may provide clinicians with a new era of managing thromboembolic disorders. Two of these agents, dabigatran and rivaroxaban, have been approved by the US Food and Drug Administration (FDA) for stroke prevention in patients with nonvalvular atrial fibrillation (AF); in addition, rivaroxaban can be used in the prevention of venous thromboembolism (VTE) in total hip and knee arthroplasty during the acute and extended periods of risk. However, the challenge for hospital formularies will be the appropriate use and management of these new medications as they become integrated into outpatient care. In order to better understand the issues that pharmacy and therapeutics committees will encounter, a review of the 2 FDA-approved oral anticoagulants will be evaluated. PMID- 23086102 TI - Explaining length of stay variation of episodes of care in the Netherlands. AB - OBJECTIVES: Diagnosis Related Group (DRG) systems aim to classify patients into mutually exclusive groups of patients, with the patients in each group having the same expected length of stay (LOS). We examined the ability of current classification variables to explain LOS variation between DRG-like Diagnosis Treatment Combination (DBC)s for ten episodes of care in the Netherlands, including breast cancer, stroke and inguinal hernia repair. Additionally, we assessed the predictive ability of some other classification variables. METHODS: For each episode of care, the relevant DBC codes of all hospitalizations in 2008 were identified and all available determinants that may serve as classification variables were acquired from the national database. Ordinary least squares regression was used to examine the predictive ability of these classification variables. RESULTS: The current classification variables are not sufficiently distinct to classify patients into mutually exclusive groups of patients. ICU admissions and hospital type may serve as valuable classification variables. Additionally, episode-specific variables may improve the Dutch grouping algorithm. CONCLUSIONS: Although it may not be feasible in the short term, grouping algorithms would benefit greatly from the introduction of classification variables tailored to the needs of specific episodes of care. A first step would be to focus on 'general' classification variables meaningful for specific episodes of care. PMID- 23086104 TI - The effect of the Wyckoff position of the K atom on the crystal structure and electronic properties of the compound KFe2Se2. AB - By means of first-principles electronic structure calculations, we study the effect of the Wyckoff position of the K atom on the crystal and electronic structures of the compound KFe(2)Se(2). When the K atoms take up the Wyckoff positions 2a, 2b and 4c (the related structures of KFe(2)Se(2) are referred to as Struc-2a, Struc-2b and Struc-4c), the calculated lattice constants c lie in the ranges 13.5-14.5, 15.5-16.7 or 18.6-19.1 A respectively. Three concentric cylinder-like Fermi surfaces emerge around Gamma-Z in the Brillouin zone for Struc-2b in the nonmagnetic state, unlike the cases for Struc-2a and Struc-4c. The Fe-Se-Fe angles are 107.8 degrees , 108.8 degrees and 110.7 degrees respectively in the collinear antiferromagnetic state, and the superexchange interactions J(2) between two next neighbor Fe moments are 13.08 meV S(-2), 20.75 meV S(-2) and 11.86 meV S(-2) for the Struc-2a, Struc-2b and Struc-4c structures respectively. Struc-2b and Struc-4c have good correspondence with the newly discovered superconducting phases with T(c) = 40 and 30 K in KFe(2)Se(2). Our findings suggest a reasonable approach for achieving an understanding of the existence of multiple superconducting phases in alkali metal intercalated FeSe superconductor. PMID- 23086103 TI - Quiescent leukaemic cells account for minimal residual disease in childhood lymphoblastic leukaemia. PMID- 23086105 TI - Higher incidence of epilepsy in meningiomas located on the premotor cortex: a voxel-wise statistical analysis. AB - BACKGROUND: A substantial number of patients with brain tumors develop recurrent seizures, known as tumor-associated epilepsy. It is important to identify specific subgroups of brain tumor patients with higher incidences of epilepsy because a meta-analysis failed to certify the effectiveness of prophylactic anti epileptic drugs (AEDs) to abort tumor-associated epilepsy as a whole. METHODS: To investigate the relationship between tumor location and incidence of epilepsy, we performed voxel-wise comparison between 3D MRI scans obtained from patients with meningioma-associated epilepsy and those from control patients using spatial normalization techniques on neuroimaging data. Variables such as age, tumor size, the degree of edema, and pathological diagnosis were also compared between the two groups. RESULTS: Our results showed the highest incidence of epilepsy when the tumor was located on the premotor cortex in the frontal lobe (Z-scores >2.0, Liebermeister's quasi-exact test). The stepwise multiple regression analysis on the clinical data revealed that the tumor diameter (p < 0.001) and the patient's age (p = 0.024) were positive and negative predictors, respectively, for the onset of epilepsy. CONCLUSIONS: The incidence of epilepsy was higher in meningiomas located on the premotor cortex than on the other cortex. Larger volume also contributed to the onset of epilepsy. We suggest that variations of epilepsy incidence dependent on tumor characteristics can be considered when treating tumor-associated epilepsy. PMID- 23086106 TI - Vagus nerve stimulation in drug-resistant epilepsies. Analysis of potential prognostic factors in a cohort of patients with long-term follow-up. AB - BACKGROUND: The results of vagus nerve stimulation (VNS) for the treatment of drug-resistant epilepsies are highly variable due to the lack of defined patient's selection criteria and a follow-up of published studies being generally too short. Here we report the outcome of VNS in a series with long-term follow-up and try to identify subgroups of patients who could be better candidates for this procedure. METHOD: We studied 53 patients (33 male, 20 female) with a prospectively recorded follow-up (mean, 55.96 +/- 43.53 months). The monthly average seizure frequency for each patient at baseline, 3, 6, 12 months, and each year until the latest follow-up after implant was measured and the percentage of "responders" and response time (RT) were calculated. We investigated the following potential prognostic role of these factors: age of onset of epilepsy, pre-implant epilepsy duration, etiology, and age at implant. RESULTS: Globally, 40 % of patients responded to VNS (mean RT, 14.85 +/- 16.85 months). Lesional etiology (p = 0.0179, logrank test), particularly ischemia (p = 0.011, Fisher exact test) and tuberous sclerosis (p = 0.0229, Fisher exact test), and age at implant <18 years (p = 0.0242, logrank test) were associated to better response to VNS. In the lesional subgroup the best results were observed in patients with a pre-implant epilepsy duration <15 years (p = 0.0204, logrank test) and an age at implant <18 years (p = 0.0187 logrank test). CONCLUSIONS: The best candidate to VNS seems to be a patient with lesional etiology epilepsy (particularly post ischemic and tuberous sclerosis) and a short duration of epilepsy who undergo VNS younger than 18 years. PMID- 23086107 TI - MU-PADs for detection of chemical warfare agents. AB - Conventional methods of detection of chemical warfare agents (CWAs) based on chromogenic reactions are time and solvent intensive. The development of cost, time and solvent effective microfluidic paper based analytical devices (MU-PADs) for the detection of nerve and vesicant agents is described. The detection of analytes was based upon their reactions with rhodamine hydroxamate and para nitrobenzyl pyridine, producing red and blue colours respectively. Reactions were optimized on the MU-PADs to produce the limits of detection (LODs) as low as 100 MUM for sulfur mustard in aqueous samples. Results were quantified with the help of a simple desktop scanner and Photoshop software. Sarin achieved a linear response in the two concentration ranges of 20-100 mM and 100-500 mM, whereas the response of sulfur mustard was found to be linear in the concentration range of 10-75 mM. Results were precise enough to establish the MU-PADs as a valuable tool for security personnel fighting against chemical terrorism. PMID- 23086108 TI - Multiple aneurysms of thoracic spinal cord arteries presenting with spinal infarction and subarachnoid hemorrhage: case report and literature review. AB - BACKGROUND AND IMPORTANCE: Arterial aneurysms of the spinal cord are rare. Their pathogenesis is variable, and the therapeutic strategies remain controversial, because their natural history is unclear. We report a case of multiple dissecting aneurysms of radiculomedullary and radiculopial arteries presenting with spinal infarction and subarachnoid hemorrhage, which spontaneously resolved. CLINICAL PRESENTATION: A 67-year-old woman was hospitalized owing to sudden onset of severe back pain with discomfort in the lower extremities. Two days later, she again experienced sudden back pain accompanied by paraparesis and sphincter disturbance. Magnetic resonance imaging of the thoracic spinal cord showed 2 intradural masses of heterogeneous intensity at the levels of T-8 and T-10, spinal infarction, and subarachnoid hemorrhage. Spinal angiography revealed a "pearls and strings" aspect of a radiculomedullary artery arising from the left T 11 and a fusiform aneurysm of a radiculopial artery arising from the left T-8. Infectious and immunological evaluations failed to show any anomaly. Spontaneous dissections were suspected. Conservative treatment was proposed, and the patient's clinical course remained uneventful. Follow-up magnetic resonance imaging and spinal angiography performed 2 months after onset showed disappearance of both arterial lesions. CONCLUSION: Arterial dissections of spinal radicular arteries can resolve spontaneously and be managed conservatively. We propose a classification of the pathogenesis of spinal arterial aneurysm to clarify appropriate treatment strategies by a literature review. PMID- 23086109 TI - Direct observation of aluminium ions produced via pulsed laser ablation in liquid: a 'turn-on' fluorescence study. AB - An Al metal plate was ablated by a pulsed Nd-YAG laser to produce nano-structured Al and gamma-Al(2)O(3) in deionized water without any surfactants or catalysts. In this study, direct evidence for the production of Al(3+) ions from the plasma plume is presented for the first time by characterizing the absorption and emission spectra of their [Al(salophen)](+) complex. Very interestingly, a remarkable increase in the fluorescence intensity was observed when the Al(3+) ions, produced via the pulsed laser ablation, complexed with the salophen ligand. This fluorescence 'turn-on' behaviour of [Al(salophen)](+) was investigated by DFT/TD-DFT calculations. Based on these results, mechanisms for the production of aluminium and alumina nanoparticles in the pulsed laser ablation in liquid (PLAL) process are proposed. PMID- 23086110 TI - Overlap syndromes of autoimmune hepatitis: an open question. AB - The headword "overlap syndromes" of liver diseases includes the coexistence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. These syndromes often represent a diagnostic and therapeutic challenge for hepatologists; it remains unclear whether these overlap syndromes form distinct entities or they are only variants of the major autoimmune liver diseases. The most frequent reported association occurs between autoimmune hepatitis and primary biliary cirrhosis, whereas the overlap between autoimmune hepatitis and primary sclerosing cholangitis is less frequent, typically at young age and often attendant with an inflammatory bowel disease. The choice therapy is based on ursodeoxycholic acid and immunosuppressive drugs, used at the same time or consecutively, according to the course of disease. The diagnostic scores for autoimmune hepatitis can help for diagnosis, even though their definitive soundness is lacking. PMID- 23086111 TI - The economic burden of inflammatory bowel disease: clear problem, unclear solution. PMID- 23086112 TI - Making sense of racial disparities in gastrointestinal cancer mortality. PMID- 23086113 TI - Methanogenesis in irritable bowel syndrome: a lot of hot air? PMID- 23086115 TI - Automated identification of surveillance colonoscopy in inflammatory bowel disease using natural language processing. AB - BACKGROUND: Differentiating surveillance from non-surveillance colonoscopy for colorectal cancer in patients with inflammatory bowel disease (IBD) using electronic medical records (EMR) is important for practice improvement and research purposes, but diagnosis code algorithms are lacking. The automated retrieval console (ARC) is natural language processing (NLP)-based software that allows text-based document-level classification. AIMS: The purpose of this study was to test the feasibility and accuracy of ARC in identifying surveillance and non-surveillance colonoscopy in IBD using EMR. METHODS: We performed a split validation study of electronic reports of colonoscopy pathology for patients with IBD from the Michael E. DeBakey VA Medical Center. A gastroenterologist manually classified pathology reports as either derived from surveillance or non surveillance colonoscopy. Pathology reports were randomly split into two sets: 70 % for algorithm derivation and 30 % for validation. An ARC generated classification model was applied to the validation set of pathology reports. The performance of the model was compared with manual classification for surveillance and non-surveillance colonoscopy. RESULTS: A total of 575 colonoscopy pathology reports were available on 195 IBD patients, of which 400 reports were designated as training and 175 as testing sets. Within the testing set, a total of 69 pathology reports were classified as surveillance by manual review, whereas the ARC model classified 66 reports as surveillance for a recall of 0.77, precision of 0.80, and specificity of 0.88. CONCLUSIONS: ARC was able to identify surveillance colonoscopy for IBD without customized software programming. NLP based document-level classification may be used to differentiate surveillance from non-surveillance colonoscopy in IBD. PMID- 23086114 TI - Screening for gastric premalignant lesions with narrow band imaging, white light and updated Sydney protocol or both? AB - BACKGROUND: Narrow band imaging (NBI) can accurately discriminate gastritis but premalignant lesions (PMLs) are difficult to detect. AIMS: The purpose of this study was to compare white light endoscopy (WLE) and histopathologic findings using the updated Sydney protocol (USP) with NBI and targeted biopsies (TB). METHODS: One hundred nineteen symptomatic patients referred for upper GI endoscopy were included in this prospective open study. All patients were assessed for gastritis and PMLs using WLE and NBI by two endoscopists selected in a random manner. Biopsies were taken according to USP and targeted from any area suspicious for PML. Imaging and histological findings between protocols were compared. RESULTS: In total 45 patients (38 %) had atrophy of whom 39 (32.7 %) were detected with WLE-USP and 28 (23.5 %) with NBI-TB (p = 0.03), 25 (21 %) had intestinal metaplasia (IM) of whom 19 (16 %) were detected with WLE-USP and 18 (15.1 %) with NBI-TB (p = 0.7) and 14 (12 %) had dysplasia of whom 12 (10 %) were detected with WLE-USP and 7 (7 %) with NBI-TB (p = 0.5), and 1 (0.8 %) case of gastric cancer only detected with WLE-USP. Accuracies for atrophy and IM were 93 and 90 % for the WLE-USP and 80 and 82 % for NBI-TB. The NBI-TB detected six cases of atrophy (13 %), 5 (20 %) of IM, and 2 (14 %) of dysplasia missed by WLE USP as agreement was moderate. Accuracies of the NBI patterns for body and antral gastritis were 80 and 84 %. CONCLUSIONS: In a non high-risk population NBI-TB has less accuracy in detecting premalignant lesions compared to WLE-USP. However, it may be used as an important and easy-to-use complementary method which increases overall detectability for gastric premalignant lesions. PMID- 23086116 TI - Insulin sensitivity and variability in hepatitis C virus infection using direct measurement. AB - BACKGROUND AND AIMS: Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement. METHODS: One hundred two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady state plasma glucose (SSPG) concentration during the insulin suppression test. RESULTS: Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95 % CI 37-96), BMI (Coef 19 per 5 kg/m(2), 95 % CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95 % CI 0.2-2.5), male gender (Coef -48, 95 % CI -80 to -16), and HDL (Coef -16, 95 % CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95 % CI 19 90), steatosis (Coef -44, 95 % CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m(2), 95 % CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95 % CI 0.3-6.7) predicted change in SSPG. CONCLUSIONS: There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV. PMID- 23086117 TI - Needle size has only a limited effect on outcomes in EUS-guided fine needle aspiration: a systematic review and meta-analysis. AB - BACKGROUND: Several recent studies have investigated the utility of 19-, 22-, and 25-gauge needles in endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic and peri-pancreatic tumors. AIM: The objective of this study was to summarize data from these studies and estimate the effect of needle size on reported outcomes such as accuracy, adequacy, and complications. METHODS: Systematic review and meta-analysis comparing the effect of needle size (19, 22, and 25G) on diagnostic accuracy, adequacy, number of needle passes, and complications. RESULTS: 25G appear to confer an advantage in adequacy rates relative to 22G needles (risk difference = 0.12 %, 95 % CI 0.01, 0.25). There was no significant difference in accuracy with an overall sensitivity and specificity for 22G being 0.78 (95 % CI 0.74-0.81) and 1.00 (95 % CI 0.98-1.00) and an overall sensitivity and specificity for 25G being 0.91 (95 % CI 0.87-0.94) and 1.00 (95 % CI 0.97-1.00). There was no difference in number of passes or complications between 25 and 22G. The limited data available regarding 19G needles do not show evidence of improved outcomes with these devices. CONCLUSIONS: In the evaluation of pancreatic and peri-pancreatic lesions by EUS FNA, 25G needles may confer an advantage in adequacy relative to 22G needles but confer no advantages with respect to accuracy, number of passes, or complications. PMID- 23086118 TI - Potential factors dedicated to postoperative liver dysfunction in patients with normal preoperative ICG-15 clearance rate. PMID- 23086119 TI - Cirrhosis and gastrointestinal bleeding. PMID- 23086120 TI - Mechanisms behind the increased vulnerability of the aging stomach to NSAID related injury: perhaps not as simple as we may think. PMID- 23086121 TI - Long-term efficacy of enteral nutrition for patients with Crohn's disease. PMID- 23086122 TI - Can cap-assisted colonoscopy be a savior for right side interval cancer? PMID- 23086123 TI - MRI prediction of islet yield for autologous transplantation after total pancreatectomy for chronic pancreatitis. AB - OBJECTIVE: The relationship between magnetic resonance imaging (MRI), histopathology, and islet yield was examined for chronic pancreatitis patients undergoing total pancreatectomy and autologous islet cell transplant (TP-AIT) to determine if the yield can be predicted by pre-operative MRI. METHODS: MRI sequences and histopathology were scored and compared for patients from whom <=2,500 islet equivalents/kg were obtained with those from whom >2,500 islet equivalents/kg were obtained. RESULTS: Twenty patients, 14 female, mean age 40.20 +/- 12.5 years, (range 19-63) underwent MRI before TP-AIT; mean 3,724 +/- 891 islet equivalents/kg body weight, median 2,970, (range 76-17,770) were procured. There was no correlation between islet cell numbers and pancreas weight, HgbA1c, or c-peptide. The most common MRI sequence abnormality was the delayed interstitial phase, 14/18 (78 %). The other common MRI sequence abnormalities were, precontrast T1W 3D GRE sequence, 13/19 (68 %), and the arterial perfusion phase, 11/18 (61 %). The pancreatic duct was dilated in 10/20 (50 %). Parenchymal atrophy was noted in 10/20 (50 %). Median scores for individual MRI sequences were greater in patients with an islet cell yield of <=2,500 islet equivalents/kg; for the delayed interstitial phase the difference was significant (median 2.5, range 1-3 versus median 0.5, range 0-3, P = 0.034). Histologically the most common feature was fibrosis, (17/17, 100 %); the score for fibrosis was greater for patients with an islet cell yield of <=2,500 islet equivalents/kg (median 6.0, range 5-7 versus median 4.0, range 3-7, P = 0.024). CONCLUSION: A diminished islet yield may be predicted on the basis of the delayed interstitial phase MRI sequence. PMID- 23086124 TI - Thrombocytopenia in patients with chronic liver disease: what's in a name? PMID- 23086125 TI - Diagnosis of iron deficiency anemia in the elderly: when to say "uncle". PMID- 23086126 TI - Incidence and survival of colorectal cancer among Hispanics in the United States: a population-based study. AB - BACKGROUND: Hispanics are the largest and fastest growing ethnic group in the United States (US). AIMS: We evaluated the incidence and survival of colorectal cancer (CRC) among this population. METHODS: Data from the surveillance, epidemiology, and end results program were used to calculate CRC age-adjusted and age-specific incidence rates in Hispanics during 1993-2007. Temporal trends in CRC incidence were examined using annual percent change (APC) and Poisson regression. The 1- and 5-year survival rates were calculated. RESULTS: The annual age-adjusted incidence rates for CRC in Hispanics of all ages declined from 47.4 per 100,000 in 1993-1997 to 43.8 per 100,000 in 2003-2007, with an APC during 1993-2007 equal to -0.8/year. However, there was a 45 % increase in CRC incidence among Hispanic men and women aged 20-49 years that affected both the right and left colon. The proportions of CRC cases with regional (+37 %) and distant (+18 %) spread increased, now constituting 72 % of cases diagnosed at that age. The Poisson model confirmed the increasing CRC incidence in Hispanics aged 20-49 years during 1993-2007 while adjusting for sex and geographic region. The 1-year survival improved in younger Hispanics from approximately 86 % in 1993-1997 to 91 % in 2003-2007 with no significant improvement in 5-year survival. In Hispanics aged >50 years, no significant improvements in survival were observed. CONCLUSIONS: The incidence of CRC in young Hispanic men and women has increased in the US. Most are diagnosed with regional or distant disease. No significant improvement in long-term survival was observed in young Hispanics with CRC. PMID- 23086127 TI - Up-regulation of Toll-like receptors 2 and 4 on peripheral monocytes after major abdominal surgical operation. AB - BACKGROUND: This study is to investigate the time-course expression of TLR2 and TLR4 on peripheral monocytes in patients receiving major abdominal surgical operation. METHODS: Blood samples were obtained from peripheral vein before and after an operation in 30 patients with gastrointestinal or pancreatic surgery. The mRNA expression of TLR2, TLR4, TNF-alpha and IL-6 on peripheral blood mononuclear cells (PBMC) was analyzed by real-time PCR. The expressions of TLR2, TLR4, HLA-DR, CD80, and CD86 on monocytes were analyzed by flow cytometry. The expressions of TLR2 and TLR4 on monocytes responding to each agonist (zymosan and lipopolysaccharide) were also measured by flow cytometry. RESULTS: TLR2 and TLR4 mRNA showed significant up-regulation after the completion of the operation when compared with those before the operation. TLR2 expression reached its peak level on day 1 and TLR4 on days 1 and 3. There was no significant difference between pre- and post-operation in the expressions of HLA-DR, CD80 and CD86. Stimulation with zymosan, increased the expression of TLR2 significantly after the operation and reached its highest value on day 3. Similarly, after stimulation with lipopolysaccharide, the expression of TLR4 was also increased and the highest level was observed on day 1. The expression of TNF-alpha and IL-6 mRNA decreased after completion of the operation and gradually returned to basal level. CONCLUSIONS: The expressions of TLR2 and TLR4 on monocytes were up-regulated during the early period after a major abdominal surgical operation in patients, which might be related to the activation of innate immunity. PMID- 23086129 TI - Mixed-valence state of symmetric diruthenium complexes: synthesis, characterization, and electron transfer investigation. AB - Complexes of the type {[(pyS)Ru(NH(3))(4)](2)-MU-L}(n), where pyS = 4 mercaptopyridine, L = 4,4'-dithiodipyridine (pySSpy), pyrazine (pz) and 1,4 dicyanobenzene (DCB), and n = +4 and +5 for fully reduced and mixed-valence complexes, respectively, were synthesized and characterized. Electrochemical data showed that there is electron communication between the metal centers with comproportionation constants of 33.2, 1.30 * 10(8) and 5.56 * 10(5) for L = pySSpy, pz and DCB, respectively. It was also observed that the electronic coupling between the metal centers is affected by the pi-back-bonding interaction toward the pyS ligand. Raman spectroscopy showed a dependence of the intensity of the vibrational modes on the exciting radiations giving support to the assignments of the electronic transitions. The degree of electron communication between the metal centers through the bridging ligands suggests that these systems can be molecular wire materials. PMID- 23086128 TI - Profiles of gene polymorphisms in cytokines and Toll-like receptors with higher risk for gastric cancer. AB - BACKGROUND: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. AIMS: The purpose of this study was to investigate the combined effect of the pro- and anti inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. METHODS: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL 1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. RESULTS: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A 857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL 10-592A/TLR4 + 896G, IL-10-592A/TLR2del/TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8 845C/TLR2del. CONCLUSIONS: Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together. PMID- 23086130 TI - Determining the experimental leachability of copper, lead, and zinc in a harbor sediment and modeling. AB - The potential leaching of pollutants present in harbor sediments has to be evaluated in order to choose the best practices for managing them. Little is known about the speciation and mobility of heavy metals in these specific solid materials. The objective of this paper is to determine and model the leachability of copper, lead, and zinc present in harbor sediments in order to obtain essential new data. The mobility of inorganic contaminants in a polluted harbor sediment collected in France was investigated as a function of physicochemical conditions. The investigation relied mainly on the use of leaching tests performed in combination with mineralogical analysis and thermodynamic modeling using PHREEQC. The modeling phase was dedicated to both confirm the hypothesis formulated to explain the experimental results and improve the determination of the main physico-chemical parameters governing mobility. The experimental results and modeling showed that the release of copper, lead, and zinc is very low with deionized water which is due to the stability of the associated solid phases (organic matter, carbonate minerals, and/or iron sulfides) at natural slightly basic conditions. However, increased mobilization is observed under pH values below 6.0 and above 10.0. This methodology helped to consistently obtain the geochemical parameters governing the mobility of the contaminants studied. PMID- 23086132 TI - Iron phthalocyanine and nitrogen-doped graphene composite as a novel non-precious catalyst for the oxygen reduction reaction. AB - We develop a facile method for the synthesis of an iron phthalocyanine (FePc) and nitrogen-doped graphene (NG) composite as a novel and efficient non-precious catalyst in the oxygen reduction reaction (ORR). The resulting product exhibits superior ORR catalytic activity, excellent tolerance to methanol crossover, and comparable stability to commercial Pt/C, which leads to the invention of a new non-precious catalyst for ORR in fuel cells. PMID- 23086131 TI - Structural basis of bacterial defense against g-type lysozyme-based innate immunity. AB - Gram-negative bacteria can produce specific proteinaceous inhibitors to defend themselves against the lytic action of host lysozymes. So far, four different lysozyme inhibitor families have been identified. Here, we report the crystal structure of the Escherichia coli periplasmic lysozyme inhibitor of g-type lysozyme (PliG-Ec) in complex with Atlantic salmon g-type lysozyme (SalG) at a resolution of 0.95 A, which is exceptionally high for a complex of two proteins. The structure reveals for the first time the mechanism of g-type lysozyme inhibition by the PliG family. The latter contains two specific conserved regions that are essential for its inhibitory activity. The inhibitory complex formation is based on a double 'key-lock' mechanism. The first key-lock element is formed by the insertion of two conserved PliG regions into the active site of the lysozyme. The second element is defined by a distinct pocket of PliG accommodating a lysozyme loop. Computational analysis indicates that this pocket represents a suitable site for small molecule binding, which opens an avenue for the development of novel antibacterial agents that suppress the inhibitory activity of PliG. PMID- 23086133 TI - Hopelessness and complementary therapy use in patients with ovarian cancer. AB - BACKGROUND: Hopelessness negatively affects ovarian cancer patients' quality of life (QOL). Research validating the effects of complementary and alternative medicine (CAM) use on QOL and hope is scarce, even though QOL and hope are reasons that patients cite for using CAM therapy. Clinicians need effective, evidence-based interventions to improve QOL and reduce hopelessness. OBJECTIVE: The objectives of this study were to examine factors influencing hopelessness in patients with newly diagnosed disease, long-term survivors, and patients experiencing ovarian cancer recurrence and to examine the effects of CAM on hopelessness in the same population. METHODS: Surveys of ovarian cancer patients (N = 219) undergoing treatment at a comprehensive cancer center in the United States were analyzed. Descriptive, correlation, and multivariate analyses described variables and demonstrated the effects of sociodemographics, disease state, psychological distress, QOL, CAM use, and faith on hopelessness. RESULTS: Patients ages 65 years or older (-0.95, P = .03), with strong faith (-0.28, P = .00), and good QOL (0.11, P = .00) directly reduced hopelessness scores (mean, 3.37). Massage therapy substantially reduced hopelessness scores (-1.07, P = .02); holding age constant, employed patients were twice as likely to use massage (odds ratio, 2.09; P = .04). Patients who had newly diagnosed and recurrent ovarian cancer were more hopeless because of greater distress from symptoms and adverse effects of treatment. CONCLUSION: Patients who used massage therapy were significantly less hopeless, as were those with strong faith and well-controlled disease symptoms and treatment for adverse effects. IMPLICATIONS FOR PRACTICE: Support of spiritual needs and symptom management are important interventions to prevent and/or reduce hopelessness, especially for patients with newly diagnosed and recurrent ovarian cancer. Further research testing the positive effect of massage interventions on hopelessness is needed. PMID- 23086135 TI - German guidelines for psychosocial counselling in the area of "cross border reproductive services". AB - An increasing number of couples and individuals with a desire for a child travel abroad for assisted reproductive technologies that are not available in their home country. This trend has been coined "cross border reproductive services" (CBRS), often comprising third party reproduction. In order to respect the welfare of all parties involved, the German Society for Fertility Counselling has developed guidelines for psychosocial counselling in this area in 2010. The following article raises some of the controversies in CBRS and introduces these guidelines. PMID- 23086134 TI - What is the success of drug treatment in urge urinary incontinence? What should be measured? AB - PURPOSE: The aim of this study is to evaluate the efficacy and the tolerability of three classic antimuscarinic drugs used in the treatment of over active bladder syndrome using clinical data and quality of life tests, and to evaluate the parameters affecting the success of these drugs. METHODS: A total of 90 patients with urge urinary incontinence were randomly allocated into three groups either to receive tolterodine (group A), trospium chloride (group B) or oxybutynin (group C). Urogenital distress inventory short form (UDI-6) and Incontinence impact questionnaire short form (IIQ-7) of the Turkish Urogynecology and Pelvic Reconstructive Surgery Association were performed to each patient before and after treatment to evaluate the effectiveness and tolerability of the antimuscarinic drugs. Adverse events were also recorded during treatment. RESULTS: Improved urodynamic test values were recorded after 6 weeks of treatment in each group. Similarly, statistically significant differences were observed in UDI-6 and IIQ-7 test scores before and after treatment. Complete cure was achieved in 86 % of patients in group A; however, complete cure rates were 67 and 80 % in group B and C, respectively. Although, patients reported comparable tolerability against trospium chloride (77 %) and tolterodine (80 %), only 23 % of patients using oxybutynin considered the drug as tolerable. The most common side effect was dry mouth, followed by insomnia. Both dry mouth and insomnia was highest in group C (50 %). One patient (0.3 %) in group B and two patients (0.7 %) in group C reported that they did not want to continue to use the drug. CONCLUSION: Antimuscarinic medications are very successful in the treatment of urge urinary incontinence; however, the success of treatment is not only limited to clinical improvement. Patients do not regard a drug as successful unless it is tolerable, easy to adapt to the daily life and improve the quality of life even it has very successful clinical outcomes. PMID- 23086136 TI - Obstructive sleep apnea screening and perinatal outcomes in Korean pregnant women. AB - PURPOSE: This study was intended to evaluate the attributable risk of obstructive sleep apnea (OSA) by a sleep questionnaire to adverse pregnancy outcomes. METHODS: This was a prospective, cohort study in Korean pregnant women. Berlin questionnaire was employed for symptom-based OSA screening during the third trimester and obstetric outcome data were obtained in 276 deliveries. The relationship between symptom-based OSA and outcomes were explored using SPSS version 18.0 and stratified by obesity (BMI strata <30 and >=30). Our primary outcome was the compound occurrence of SGA (fetal) or preeclampsia (maternal). Multivariate models were applied in controlling for potential confounders. RESULTS: The overall prevalence of OSA was 32.2 % and it was significantly related with the higher maternal BMI, more body weight at delivery, and weight gain during pregnancy (p = 0.007, p = 0.003, p = 0.005, respectively). There were no significant differences in the primary outcomes according to the positivity of OSA by screening, regardless of the stratification by obesity. The cesarean delivery rate was significantly higher in the OSA positive group (36.0 vs 22.5 %, p = 0.018), but it was not significant in the each strata of obesity. In multivariate analysis, the outcomes of birth weight, preeclampsia, cesarean delivery, and small for gestational age were also not different according to the positivity of OSA. CONCLUSIONS: It seems that the prevalence of OSA by a sleep questionnaire is overestimating OSA in Korean pregnant women. Polysomnography might be needed to diagnose OSA and to evaluate the relationship between OSA and the occurrence of SGA or preeclampsia. PMID- 23086137 TI - Interaction between surface shape and intra-surface viscous flow on lipid membranes. AB - The theory of intra-surface viscous flow on lipid bilayers is developed by combining the equations for flow on a curved surface with those that describe the elastic resistance of the bilayer to flexure. The model is derived directly from balance laws and augments an alternative formulation based on a variational principle. Conditions holding along an edge of the membrane are emphasized, and the coupling between flow and membrane shape is simulated numerically. PMID- 23086138 TI - Randomized, double-blind, dose-ranging study of TAK-875, a novel GPR40 agonist, in Japanese patients with inadequately controlled type 2 diabetes. AB - OBJECTIVE: Assessment of the efficacy and safety of TAK-875 (a novel GPR40 agonist) in Japanese patients with type 2 diabetes inadequately controlled by diet/exercise. RESEARCH DESIGN AND METHODS: This was a phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled, 12-week dose ranging evaluation of TAK-875 (6.25-200 mg once daily) with the primary end point of change in A1C at week 12. A nonblinded group received 1 mg glimepiride once daily as an active control. RESULTS: A total of 396 patients were randomized to receive TAK-875 (n = 299), placebo (n = 48), or glimepiride (n = 49). The least square mean changes in A1C at week 12 from baseline were as follows: 0.09% in the placebo group; -0.54, -0.67, -0.88, -1.27, -1.29, and -1.40% in the 6.25-, 12.5-, 25-, 50-, 100-, and 200-mg TAK-875 groups, respectively; and -1.32% in the 1-mg glimepiride group. All TAK-875 groups had statistically significant reductions in A1C compared with placebo (P < 0.0001), and those receiving >=50 mg TAK-875 achieved reductions in A1C equivalent to those with glimepiride. Results for other glycemic parameters, including improvements during a meal tolerance test, mirrored these positive findings with TAK-875. There were no significant differences in incidence of adverse events among the groups and no dose-dependent changes in tolerability. Hypoglycemic episodes were reported in 0.7% of patients in the TAK-875 groups and in 4.1% of the glimepiride group. CONCLUSIONS: TAK-875 produced clinically and statistically significant improvements in glycemic control in patients with type 2 diabetes inadequately controlled by diet and exercise, and it was well tolerated with a lower propensity to cause hypoglycemia. PMID- 23086139 TI - Metabolism of insulin glargine after repeated daily subcutaneous injections in subjects with type 2 diabetes. AB - OBJECTIVE: To investigate concentration of plasma insulin glargine after its subcutaneous dosing compared with concentration of its metabolites 1 (M1) and 2 (M2) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: Nine subjects underwent a 32-h euglycemic glucose clamp study (0.4 units/kg glargine after 1 week of daily glargine administration). Glargine, M1, and M2 were measured by a specific liquid chromatography-tandem mass spectrometry assay. RESULTS: Glargine was detected in only five of the nine subjects, at few time points, and at negligible concentrations. M1 was detected in all subjects and exhibited the same pattern as traditional radioimmunoassay-measured plasma insulin. M2 was not detected at all. CONCLUSIONS: After subcutaneous injection, glargine was minimally detectable in blood, whereas its metabolite M1 accounted for most (>90%) of the plasma insulin concentration and metabolic action of the injected glargine. PMID- 23086140 TI - Decreased glycolytic and tricarboxylic acid cycle intermediates coincide with peripheral nervous system oxidative stress in a murine model of type 2 diabetes. AB - Diabetic neuropathy (DN) is the most common complication of diabetes and is characterized by distal-to-proximal loss of peripheral nerve axons. The idea of tissue-specific pathological alterations in energy metabolism in diabetic complications-prone tissues is emerging. Altered nerve metabolism in type 1 diabetes models is observed; however, therapeutic strategies based on these models offer limited efficacy to type 2 diabetic patients with DN. Therefore, understanding how peripheral nerves metabolically adapt to the unique type 2 diabetic environment is critical to develop disease-modifying treatments. In the current study, we utilized targeted liquid chromatography-tandem mass spectrometry (LC/MS/MS) to characterize the glycolytic and tricarboxylic acid (TCA) cycle metabolomes in sural nerve, sciatic nerve, and dorsal root ganglia (DRG) from male type 2 diabetic mice (BKS.Cg-m+/+Lepr(db); db/db) and controls (db/+). We report depletion of glycolytic intermediates in diabetic sural nerve and sciatic nerve (glucose-6-phosphate, fructose-6-phosphate, fructose-1,6 bisphosphate (sural nerve only), 3-phosphoglycerate, 2-phosphoglycerate, phosphoenolpyruvate, and lactate), with no significant changes in DRG. Citrate and isocitrate TCA cycle intermediates were decreased in sural nerve, sciatic nerve, and DRG from diabetic mice. Utilizing LC/electrospray ionization/MS/MS and HPLC methods, we also observed increased protein and lipid oxidation (nitrotyrosine; hydroxyoctadecadienoic acids) in db/db tissue, with a proximal-to distal increase in oxidative stress, with associated decreased aconitase enzyme activity. We propose a preliminary model, whereby the greater change in metabolomic profile, increase in oxidative stress, and decrease in TCA cycle enzyme activity may cause distal peripheral nerves to rely on truncated TCA cycle metabolism in the type 2 diabetes environment. PMID- 23086142 TI - The synergistic character of the defect-induced magnetism in diluted magnetic semiconductors and related magnetic materials. AB - In this work, we introduce a new perspective in explaining the origin of magnetism in dilute magnetic semiconductors, carbon-based materials and other related materials. According to our proposal, the magnetism in these materials is the result of the synergistic action of defect-induced electronic processes mostly of local character which can provide magnetic moments and develop a ferromagnetic coupling among them. This synergy is realizable via appropriate codoping which appears as a general and generic approach. In the present report, we use ab initio results to demonstrate that in a diverse sample of systems including codoped ZnO, GaN, TiO(2) and carbon-based materials, the ferromagnetic coupling that is developed among the doped (or defect-induced) magnetic moments results from the interaction of spin-polarized neighborhoods centered at the defect sites. Our results also give evidence that bipartite codopant configurations can further enhance the ferromagnetic features of these systems significantly. PMID- 23086141 TI - Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress. AB - The neuropeptide apelin is expressed in hypothalamic paraventricular and supraoptic nuclei and mediates its effects via activation of the apelin receptor (APJ). Evidence suggests a role for apelin and APJ in mediating the neuroendocrine response to stress. To understand the physiological role of APJ in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, we measured ACTH and corticosterone (CORT) plasma levels in male and female mice lacking APJ (APJ knockout, APJ KO) and in wild-type controls, in response to a variety of acute stressors. Exposure to mild restraint, systemic injection of lipopolysaccharide (LPS), insulin-induced hypoglycaemia and forced swim (FS) stressors, elevated plasma ACTH and CORT levels in wild-type mice. Acute mild restraint significantly increased plasma ACTH and CORT to a similar level in APJ KO mice as in wild-type mice. However, an intact APJ was required for a conventional ACTH, but not CORT, response to LPS administration in male mice and to insulin-induced hypoglycaemia in male and female mice. In contrast, APJ KO mice displayed an impaired CORT response to acute FS stress, regardless of gender. These data indicate that APJ has a role in regulation of the HPA axis response to some acute stressors and has a gender-specific function in peripheral immune activation of the HPA axis. PMID- 23086143 TI - Structural insight into the type-II mitochondrial NADH dehydrogenases. AB - The single-component type-II NADH dehydrogenases (NDH-2s) serve as alternatives to the multisubunit respiratory complex I (type-I NADH dehydrogenase (NDH-1), also called NADH:ubiquinone oxidoreductase; EC 1.6.5.3) in catalysing electron transfer from NADH to ubiquinone in the mitochondrial respiratory chain. The yeast NDH-2 (Ndi1) oxidizes NADH on the matrix side and reduces ubiquinone to maintain mitochondrial NADH/NAD(+) homeostasis. Ndi1 is a potential therapeutic agent for human diseases caused by complex I defects, particularly Parkinson's disease, because its expression restores the mitochondrial activity in animals with complex I deficiency. NDH-2s in pathogenic microorganisms are viable targets for new antibiotics. Here we solve the crystal structures of Ndi1 in its substrate-free, NADH-, ubiquinone- and NADH-ubiquinone-bound states, to help understand the catalytic mechanism of NDH-2s. We find that Ndi1 homodimerization through its carboxy-terminal domain is critical for its catalytic activity and membrane targeting. The structures reveal two ubiquinone-binding sites (UQ(I) and UQ(II)) in Ndi1. NADH and UQ(I) can bind to Ndi1 simultaneously to form a substrate-protein complex. We propose that UQ(I) interacts with FAD to act as an intermediate for electron transfer, and that NADH transfers electrons through this FAD-UQ(I) complex to UQ(II). Together our data reveal the regulatory and catalytic mechanisms of Ndi1 and may facilitate the development or targeting of NDH-2s for potential therapeutic applications. PMID- 23086144 TI - BTB-ZF factors recruit the E3 ligase cullin 3 to regulate lymphoid effector programs. AB - The differentiation of several T- and B-cell effector programs in the immune system is directed by signature transcription factors that induce rapid epigenetic remodelling. Here we report that promyelocytic leukaemia zinc finger (PLZF), the BTB-zinc finger (BTB-ZF) transcription factor directing the innate like effector program of natural killer T-cell thymocytes, is prominently associated with cullin 3 (CUL3), an E3 ubiquitin ligase previously shown to use BTB domain-containing proteins as adaptors for substrate binding. PLZF transports CUL3 to the nucleus, where the two proteins are associated within a chromatin modifying complex. Furthermore, PLZF expression results in selective ubiquitination changes of several components of this complex. CUL3 was also found associated with the BTB-ZF transcription factor BCL6, which directs the germinal centre B cell and follicular T-helper cell programs. Conditional CUL3 deletion in mice demonstrated an essential role for CUL3 in the development of PLZF- and BCL6 dependent lineages. We conclude that distinct lineage-specific BTB-ZF transcription factors recruit CUL3 to alter the ubiquitination pattern of their associated chromatin-modifying complex. We propose that this new function is essential to direct the differentiation of several T- and B-cell effector programs, and may also be involved in the oncogenic role of PLZF and BCL6 in leukaemias and lymphomas. PMID- 23086145 TI - Lower satellite-gravimetry estimates of Antarctic sea-level contribution. AB - Recent estimates of Antarctica's present-day rate of ice-mass contribution to changes in sea level range from 31 gigatonnes a year (Gt yr(-1); ref. 1) to 246 Gt yr(-1) (ref. 2), a range that cannot be reconciled within formal errors. Time varying rates of mass loss contribute to this, but substantial technique-specific systematic errors also exist. In particular, estimates of secular ice-mass change derived from Gravity Recovery and Climate Experiment (GRACE) satellite data are dominated by significant uncertainty in the accuracy of models of mass change due to glacial isostatic adjustment (GIA). Here we adopt a new model of GIA, developed from geological constraints, which produces GIA rates systematically lower than those of previous models, and an improved fit to independent uplift data. After applying the model to 99 months (from August 2002 to December 2010) of GRACE data, we estimate a continent-wide ice-mass change of -69 +/- 18 Gt yr( 1) (+0.19 +/- 0.05 mm yr(-1) sea-level equivalent). This is about a third to a half of the most recently published GRACE estimates, which cover a similar time period but are based on older GIA models. Plausible GIA model uncertainties, and errors relating to removing longitudinal GRACE artefacts ('destriping'), confine our estimate to the range -126 Gt yr(-1) to -29 Gt yr(-1) (0.08-0.35 mm yr(-1) sea-level equivalent). We resolve 26 independent drainage basins and find that Antarctic mass loss, and its acceleration, is concentrated in basins along the Amundsen Sea coast. Outside this region, we find that West Antarctica is nearly in balance and that East Antarctica is gaining substantial mass. PMID- 23086146 TI - Structure of the chemokine receptor CXCR1 in phospholipid bilayers. AB - CXCR1 is one of two high-affinity receptors for the CXC chemokine interleukin-8 (IL-8), a major mediator of immune and inflammatory responses implicated in many disorders, including tumour growth. IL-8, released in response to inflammatory stimuli, binds to the extracellular side of CXCR1. The ligand-activated intracellular signalling pathways result in neutrophil migration to the site of inflammation. CXCR1 is a class A, rhodopsin-like G-protein-coupled receptor (GPCR), the largest class of integral membrane proteins responsible for cellular signal transduction and targeted as drug receptors. Despite its importance, the molecular mechanism of CXCR1 signal transduction is poorly understood owing to the limited structural information available. Recent structural determination of GPCRs has advanced by modifying the receptors with stabilizing mutations, insertion of the protein T4 lysozyme and truncations of their amino acid sequences, as well as addition of stabilizing antibodies and small molecules that facilitate crystallization in cubic phase monoolein mixtures. The intracellular loops of GPCRs are crucial for G-protein interactions, and activation of CXCR1 involves both amino-terminal residues and extracellular loops. Our previous nuclear magnetic resonance studies indicate that IL-8 binding to the N-terminal residues is mediated by the membrane, underscoring the importance of the phospholipid bilayer for physiological activity. Here we report the three dimensional structure of human CXCR1 determined by NMR spectroscopy. The receptor is in liquid crystalline phospholipid bilayers, without modification of its amino acid sequence and under physiological conditions. Features important for intracellular G-protein activation and signal transduction are revealed. The structure of human CXCR1 in a lipid bilayer should help to facilitate the discovery of new compounds that interact with GPCRs and combat diseases such as breast cancer. PMID- 23086148 TI - Ecology: Bumblebees and pesticides. PMID- 23086147 TI - A bimodular mechanism of calcium control in eukaryotes. AB - Calcium ions (Ca(2+)) have an important role as secondary messengers in numerous signal transduction processes, and cells invest much energy in controlling and maintaining a steep gradient between intracellular (~0.1-micromolar) and extracellular (~2-millimolar) Ca(2+) concentrations. Calmodulin-stimulated calcium pumps, which include the plasma-membrane Ca(2+)-ATPases (PMCAs), are key regulators of intracellular Ca(2+) in eukaryotes. They contain a unique amino- or carboxy-terminal regulatory domain responsible for autoinhibition, and binding of calcium-loaded calmodulin to this domain releases autoinhibition and activates the pump. However, the structural basis for the activation mechanism is unknown and a key remaining question is how calmodulin-mediated PMCA regulation can cover both basal Ca(2+) levels in the nanomolar range as well as micromolar-range Ca(2+) transients generated by cell stimulation. Here we present an integrated study combining the determination of the high-resolution crystal structure of a PMCA regulatory-domain/calmodulin complex with in vivo characterization and biochemical, biophysical and bioinformatics data that provide mechanistic insights into a two-step PMCA activation mechanism mediated by calcium-loaded calmodulin. The structure shows the entire PMCA regulatory domain and reveals an unexpected 2:1 stoichiometry with two calcium-loaded calmodulin molecules binding to different sites on a long helix. A multifaceted characterization of the role of both sites leads to a general structural model for calmodulin-mediated regulation of PMCAs that allows stringent, highly responsive control of intracellular calcium in eukaryotes, making it possible to maintain a stable, basal level at a threshold Ca(2+) concentration, where steep activation occurs. PMID- 23086149 TI - Structure and mechanism of a bacterial sodium-dependent dicarboxylate transporter. AB - In human cells, cytosolic citrate is a chief precursor for the synthesis of fatty acids, triacylglycerols, cholesterol and low-density lipoprotein. Cytosolic citrate further regulates the energy balance of the cell by activating the fatty acid-synthesis pathway while downregulating both the glycolysis and fatty-acid beta-oxidation pathways. The rate of fatty-acid synthesis in liver and adipose cells, the two main tissue types for such synthesis, correlates directly with the concentration of citrate in the cytosol, with the cytosolic citrate concentration partially depending on direct import across the plasma membrane through the Na(+) dependent citrate transporter (NaCT). Mutations of the homologous fly gene (Indy; I'm not dead yet) result in reduced fat storage through calorie restriction. More recently, Nact (also known as Slc13a5)-knockout mice have been found to have increased hepatic mitochondrial biogenesis, higher lipid oxidation and energy expenditure, and reduced lipogenesis, which taken together protect the mice from obesity and insulin resistance. To understand the transport mechanism of NaCT and INDY proteins, here we report the 3.2 A crystal structure of a bacterial INDY homologue. One citrate molecule and one sodium ion are bound per protein, and their binding sites are defined by conserved amino acid motifs, forming the structural basis for understanding the specificity of the transporter. Comparison of the structures of the two symmetrical halves of the transporter suggests conformational changes that propel substrate translocation. PMID- 23086150 TI - Combined pesticide exposure severely affects individual- and colony-level traits in bees. AB - Reported widespread declines of wild and managed insect pollinators have serious consequences for global ecosystem services and agricultural production. Bees contribute approximately 80% of insect pollination, so it is important to understand and mitigate the causes of current declines in bee populations . Recent studies have implicated the role of pesticides in these declines, as exposure to these chemicals has been associated with changes in bee behaviour and reductions in colony queen production. However, the key link between changes in individual behaviour and the consequent impact at the colony level has not been shown. Social bee colonies depend on the collective performance of many individual workers. Thus, although field-level pesticide concentrations can have subtle or sublethal effects at the individual level, it is not known whether bee societies can buffer such effects or whether it results in a severe cumulative effect at the colony level. Furthermore, widespread agricultural intensification means that bees are exposed to numerous pesticides when foraging, yet the possible combinatorial effects of pesticide exposure have rarely been investigated. Here we show that chronic exposure of bumblebees to two pesticides (neonicotinoid and pyrethroid) at concentrations that could approximate field level exposure impairs natural foraging behaviour and increases worker mortality leading to significant reductions in brood development and colony success. We found that worker foraging performance, particularly pollen collecting efficiency, was significantly reduced with observed knock-on effects for forager recruitment, worker losses and overall worker productivity. Moreover, we provide evidence that combinatorial exposure to pesticides increases the propensity of colonies to fail. PMID- 23086151 TI - [World Health Organization document "water safety in buildings": Italian translation]. AB - A working group of the Italian Society of Hygiene, Preventive Medicine and Public Health (SItI) has translated into Italian the World Health Organization (WHO) guidance document "Water safety in buildings" published in 2011. The document is intended to provide guidance on implementing the WHO Guidelines for drinking water quality. In the present article, the authors describe the framework of the WHO document and summarize the main points discussed. PMID- 23086152 TI - Healthcare providers' knowledge, attitudes and counselling on injury prevention for preschool children in Croatia. AB - Injuries are the leading cause of death for children and young adults in Croatia. Research has indicated that health care providers can be effective in reducing the risk for traumatic injury through anticipatory guidance, but successful guidance requires that providers have injury knowledge and informed safety attitudes. This is the first study in Croatia to identify health care provider's knowledge, attitudes, and practices regarding anticipatory guidance on injury prevention for children. A stratified, random sample of licensed Croatian healthcare providers was mailed a survey, with a response of rate of 39.5 %. Participants included pediatricians, family physicians, gynecologists, each with a focus on primary care, and community nurses. Participants filled out a 15 minute paper-and-pencil survey that tested their knowledge of injury risks and prevention strategies, assessed their safety-prone attitudes, and measured the extent to which they counselled their patients on injury prevention. Pediatricians had the highest knowledge of injury risks and intervention approaches, with an average correct score of six out of ten (significantly higher than all other provider types). Knowledge was highest regarding infant fall risk and lowest for safe sleep positions. Pediatricians and community nurses had the highest safety-prone attitudes. Safety prone attitudes were strongest for transportation safety and weakest for safe sleeping position for all providers. Community nurses reported the highest level of patient counselling, followed by pediatricians. Both factual education and support in translating knowledge into everyday practice are necessary for health care providers. Implementing anticipatory guidance for child safety is a promising approach in Croatia. PMID- 23086153 TI - Receipt of preventive oral health care by U.S. children: a population-based study of the 2005-2008 medical expenditure panel surveys. AB - This study provides estimates of the annual use of preventive oral health care by U.S. children ages 6 months-17 years. We estimated the annual use of preventive oral health care with data from the Medical Expenditure Panel Survey for the years 2005 through 2008 (n = 18,218). Additionally, we tested associations between use of preventive oral health care and predisposing factors, enabling factors and health need within three age groups: young children, school-age children and youth. Overall, 21 % of the sample was reported to have received preventive oral health care in the prior year. More school-age children received preventive care than did young children or youth regardless of gender, race/ethnicity, health status, residence, or family size. Among the youngest children, low parental education and lack of health insurance were associated with lower odds of receiving preventive care. School-age children of racial and ethnic minority groups had a higher odds of receiving preventive care than did non-Hispanic Whites. Youth with special health care needs were less likely to receive care than their peers. Within each age group, use of preventive care increased significantly from 2005 to 2008. In the U.S. there has been an increase in use of pediatric preventive dental care. Continued effort is needed to achieve primary prevention. Outreach and education should include all parents and especially parents with low levels of education, parents of children with special health care needs and those without health insurance. PMID- 23086154 TI - Moutan Cortex Radicis inhibits inflammatory changes of gene expression in lipopolysaccharide-stimulated gingival fibroblasts. AB - Moutan Cortex Radicis (MCR), the root bark of Paeonia suffruticosa Andrews (Paeoniaceae), is found in the traditional Chinese medicinal formulae which were used to treat periodontal diseases. This study investigated the changes in gene expression by MCR treatment when stimulated with lipopolysaccharide (LPS) in cultured human gingival fibroblasts (HGFs). A genome-wide expression GeneChip was used for the gene array analysis, and real-time reverse transcription polymerase chain reaction (RT-PCR) analysis was also performed to confirm the gene expression. It was shown that 42 of the 643 genes up-regulated by LPS, when compared to the control, were down-regulated by the MCR treatment. Of these 42 genes, the inflammation and immune response-related genes were especially noted, which indicates that MCR inhibits the induction of inflammation by LPS stimulation. In addition, 33 of the 519 genes down-regulated by LPS, when compared to the control, were up-regulated by the MCR treatment. The expression patterns of some representative genes by real-time RT-PCR correlated with those of the genes shown in the microarray. In addition, the MCR extract contained paeonol and paeoniflorin, which are known to have the anti-inflammatory effect as the major phenolic components of MCR. This study showed that the MCR extract could comprehensively inhibit a wide variety of activations of inflammation related genes, which may be due to paeonol and paeoniflorin. It is, thus, suggested that MCR may be applied to alleviate the inflammation of periodontal diseases. PMID- 23086155 TI - Discrimination of the Thai rejuvenating herbs Pueraria candollei (White Kwao Khruea), Butea superba (Red Kwao Khruea), and Mucuna collettii (Black Kwao Khruea) using PCR-RFLP. AB - The tuberous roots of Pueraria candollei (White Kwao Khruea), Butea superba (Red Kwao Khruea) and Mucuna collettii (Black Kwao Khruea), which belong to the family Leguminosae, are used as rejuvenating herbs in traditional Thai medicine. Although all of these species have an indication for rejuvenation, each differs in its medicinal properties. Two varieties of P. candollei, var. mirifica and var. candollei, affect females, whereas B. superba and M. collettii exhibit effects on males. However, the identification of these roots according to the name "Kwao Khruea" is confusing due to the similarity in their features. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was utilised to identify plant origin. The partial matK gene was amplified and subjected to restriction enzyme digestion with DdeI and TaqI. The restriction fragments generated differed in number and size. To test the reliability of the method, an admixture of the different Kwao Khruea species containing equal amounts of DNA was tested. The results showed combined restriction patterns, and each species could be detected in the background of the others. The method was also used to authenticate eight different crude drugs sold as various types of Kwao Khruea in Thai markets. The results showed that the misidentification of commercial drugs remains a problem in crude drug markets. The PCR-RFLP analysis developed here provides a simple and accurate discrimination of these rejuvenating "Kwao Khruea" species. PMID- 23086156 TI - Management of prosthetic heart valve complications. AB - OPINION STATEMENT: With greater awareness and treatment of valvular heart disease, there are now an increasing number of patients with prosthetic heart valves. However, replacement of a diseased valve with a prosthetic valve creates the opportunity for new and unique complications that once diagnosed require specific treatments. Complications which may occur depend not only on the type of prosthesis but also are influenced by clinical factors that are important to understand and may affect treatment strategies. Tissue prostheses tend to deteriorate over time while mechanical prostheses require anticoagulation with its attendant risks. The rate of serious prosthetic heart valve complications is approximately 3 % per year. They include bleeding, systemic embolization, obstruction due to thrombus or pannus formation, patient-prosthesis mismatch, infective endocarditis, structural deterioration, prosthetic and peri-prosthetic regurgitation, and hemolysis. Importantly, the risk of prosthetic heart valve complications can be reduced by appropriate choices made at the time of surgery such as utilization of the correct prosthesis size and type. In addition, adherence to current guidelines for anticoagulation, endocarditis prophylaxis, and the timing of clinical and echocardiographic surveillance is also important to prevent complications. Should complications occur, rapid diagnosis, usually with echocardiography, is pivotal and can provide important hemodynamic as well as anatomic information critical to determining appropriate treatment and timing of surgical re-intervention if necessary. Optimal treatment of prosthetic heart valve complications remains a challenge and new treatment strategies continue to evolve. PMID- 23086157 TI - Current and Future Options for Anticoagulant Therapy in the Acute Management of ACS. AB - OPINION STATEMENT: Anticoagulation with a parenteral (intravenous or subcutaneous) antithrombin agent is foundational to the early management of acute coronary syndrome (ACS). While indications for, the timing of, and the choice among agents (other than aspirin) that provide antiplatelet effects are all subject to discussion, the need for acute anticoagulation is beyond question. There are a number of agents that can be used for anticoagulation in ACS, depending upon the intended near-term management of the patient (medical vs interventional), the patient's ischemic risk, and the patient's hemorrhagic risk. It is usually appropriate for therapy to be initiated in the emergency department (ED), which in turn supports close collaboration between "upstream" providers and interventional cardiologists. Clinical trial data suggest that "switching" agents during ACS care affords no efficacy advantage and may increase bleeding risk. At least 1 potential new agent (otamixaban) that can be used in all ACS care settings is on the near-term horizon, with the drug currently in late Phase III testing. PMID- 23086161 TI - Multifunctional cantilever-free scanning probe arrays coated with multilayer graphene. AB - Scanning probe instruments have expanded beyond their traditional role as imaging or "reading" tools and are now routinely used for "writing." Although a variety of scanning probe lithography techniques are available, each one imposes different requirements on the types of probes that must be used. Additionally, throughput is a major concern for serial writing techniques, so for a scanning probe lithography technique to become widely applied, there needs to be a reasonable path toward a scalable architecture. Here, we use a multilayer graphene coating method to create multifunctional massively parallel probe arrays that have wear-resistant tips of uncompromised sharpness and high electrical and thermal conductivities. The optical transparency and mechanical flexibility of graphene allow this procedure to be used for coating exceptionally large, cantilever-free arrays that can pattern with electrochemical desorption and thermal, in addition to conventional, dip-pen nanolithography. PMID- 23086163 TI - Tactical deception reduces predation on birds' eggs. PMID- 23086162 TI - Role of prefrontal cortex and the midbrain dopamine system in working memory updating. AB - Humans are adept at switching between goal-directed behaviors quickly and effectively. The prefrontal cortex (PFC) is thought to play a critical role by encoding, updating, and maintaining internal representations of task context in working memory. It has also been hypothesized that the encoding of context representations in PFC is regulated by phasic dopamine gating signals. Here we use multimodal methods to test these hypotheses. First we used functional MRI (fMRI) to identify regions of PFC associated with the representation of context in a working memory task. Next we used single-pulse transcranial magnetic stimulation (TMS), guided spatially by our fMRI findings and temporally by previous event-related EEG recordings, to disrupt context encoding while participants performed the same working memory task. We found that TMS pulses to the right dorsolateral PFC (DLPFC) immediately after context presentation, and well in advance of the response, adversely impacted context-dependent relative to context-independent responses. This finding causally implicates right DLPFC function in context encoding. Finally, using the same paradigm, we conducted high resolution fMRI measurements in brainstem dopaminergic nuclei (ventral tegmental area and substantia nigra) and found phasic responses after presentation of context stimuli relative to other stimuli, consistent with the timing of a gating signal that regulates the encoding of representations in PFC. Furthermore, these responses were positively correlated with behavior, as well as with responses in the same region of right DLPFC targeted in the TMS experiment, lending support to the hypothesis that dopamine phasic signals regulate encoding, and thereby the updating, of context representations in PFC. PMID- 23086166 TI - Leading into the future. PMID- 23086164 TI - Negative blood oxygenation level dependent homunculus and somatotopic information in primary motor cortex and supplementary motor area. AB - A crucial attribute in movement encoding is an adequate balance between suppression of unwanted muscles and activation of required ones. We studied movement encoding across the primary motor cortex (M1) and supplementary motor area (SMA) by inspecting the positive and negative blood oxygenation level dependent (BOLD) signals in these regions. Using periodic and event-related experiments incorporating the bilateral/axial movements of 20 body parts, we report detailed mototopic imaging maps in M1 and SMA. These maps were obtained using phase-locked analysis. In addition to the positive BOLD, significant negative BOLD was detected in M1 but not in the SMA. The negative BOLD spatial pattern was neither located at the ipsilateral somatotopic location nor randomly distributed. Rather, it was organized somatotopically across the entire homunculus and inversely to the positive BOLD, creating a negative BOLD homunculus. The neuronal source of negative BOLD is unclear. M1 provides a unique system to test whether the origin of negative BOLD is neuronal, because different arteries supply blood to different regions in the homunculus, ruling out blood stealing explanations. Finally, multivoxel pattern analysis showed that positive BOLD in M1 and SMA and negative BOLD in M1 contain somatotopic information, enabling prediction of the moving body part from inside and outside its somatotopic location. We suggest that the neuronal processes underlying negative BOLD participate in somatotopic encoding in M1 but not in the SMA. This dissociation may emerge because of differences in the activity of these motor areas associated with movement suppression. PMID- 23086167 TI - Disruptive innovation and the changing face of healthcare. PMID- 23086168 TI - Hands-on BCMA education for direct care nurses. PMID- 23086169 TI - Leading change with emotional intelligence. PMID- 23086171 TI - Tier one alert! A psychiatric rapid response team. PMID- 23086172 TI - Classifying psychiatric inpatient pediatric populations. PMID- 23086173 TI - Rapid cycle improvement: avoid the pitfalls. PMID- 23086174 TI - Step away from your comfort zone. PMID- 23086175 TI - In vitro digestion of fish oils rich in n-3 polyunsaturated fatty acids studied in emulsion and at the oil-water interface. AB - The in vitro digestion of beta-lactoglobulin stabilized emulsions rich in the n-3 polyunsaturated fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), was studied using several physicochemical techniques. Artificial media for the mouth, stomach and small intestine were used in a sequential static in vitro digestion method. Different sizing techniques were compared to follow the droplet size during the digestion steps, including diffusing wave spectroscopy (DWS) which allowed direct measurements on undiluted emulsions. Titration of fatty acids confirmed that the digestion of such emulsified fish oils is partial. The study of the digestion at the oil-water interface using tensiometry revealed specific affinities between lipids and proteins. These could explain the emulsion and the single droplet lipolysis. Nevertheless, by comparing our results to a previous study on fish oil lipolysis, we identified two other important factors. Those were the aqueous solubility and the rate of hydrolysis of the individual fatty acids, the emulsion with the most soluble and hydrolysable ones being digested more quickly. PMID- 23086176 TI - Ictal autoscopic phenomena and near death experiences: a study of five patients with ictal autoscopies. AB - Autoscopic phenomena in general may-among other conditions-occur during epileptic seizures and near death experiences. We set the hypothesis that ictal autoscopic phenomena and near death experiences have a similar semiology as measured by the Near Death Experience Questionnaire. We also investigated whether patients with aura before temporal lobe seizures with or without autoscopic phenomena could be distinguished by this questionnaire. For these purposes, we examined five patients with ictal autoscopy and 12 patients with aura before temporal lobe seizures without ictal autoscopy as controls. We used a cut-off of 7 points or higher on the Near Death Experience Questionnaire for indicating the semiology of a near death experience and for distinguishing patients with ictal autoscopy from controls. This cut-off separated patients with ictal autoscopic phenomena from aura before temporal lobe seizures without autoscopy (p = 0.0002, two-sided, exact Fisher's Test; specificity: 100 % [CI95 % 77.9 and 100 %], sensitivity: 100 % [CI95 % 54.9 and 100 %]). Furthermore, all autoscopic patients (range 7-10) and none of the controls (range 0-5) had scores of 7 points or higher. Thus, the individual experiences during simple partial autoscopic seizures and near death experiences are similar, at least in some prominent aspects. These findings might be of particular interest for the pathophysiology of near death experiences, as all patients with ictal autoscopic phenomena had an epileptic dysfunction at the temporo-parietal junction or its neighboring regions. Therefore, a malfunction of this brain region might also be involved in near death experiences of other origins especially during states which could cause a near death experience and a cerebral excitability. PMID- 23086178 TI - Aphasia: early classification, evaluation of existing therapy, and novel therapeutics. PMID- 23086179 TI - Effects of cerebellar infarcts on cortical processing of saccades. AB - The objective of the present study was to investigate cerebellar influences on cortical components of saccadic eye movement programming in human subjects. In 24 patients with a localized cerebellar lesion, saccadic eye movements were recorded in different reflexive (step, gap, overlap) and intentional (anti, memory, short memory sequences) tasks and compared to 23 healthy controls. The cerebellar lesions led to impairments in different saccade parameters. Cerebellar patients tended to show hypermetria and increased latencies compared to the control group. In particular, they executed significantly more erroneous saccades specifically in the memory task (suppression errors) but not in the anti task (pro-saccade errors). Moreover, while reproducing short sequences of saccades from memory, patients with cerebellar infarcts made more errors with regard to the sequence order than controls. The influence of cerebellar hemispheric lesions on the saccade latency, the task-specific lesion effects on the frequency of suppression errors, and the effects on the number of order errors suggest that the cerebellum is involved in cortical processes such as target selection and sequence reproduction. PMID- 23086180 TI - Deep brain stimulation as a treatment for chorea-acanthocytosis. PMID- 23086181 TI - Central nervous system demyelinating diseases and recombinant hepatitis B vaccination: a critical systematic review of scientific production. AB - The etiology of multiple sclerosis has not yet been fully described. A potential link between the recombinant hepatitis B vaccine and an increased risk of onset or exacerbation of multiple sclerosis emerged in the mid-1990s, leading to several spontaneous reports and studies investigating this association. We conducted a critical systematic review aimed at assessing whether hepatitis B vaccination increases the risk of onset or relapse of multiple sclerosis and other central nervous system demyelinating diseases. MEDLINE and EMBASE were used as data sources, and the search covered the period between 1981 and 2011. Twelve references met the inclusion criteria. No significant increased risk of onset or relapse of the diseases considered was associated with hepatitis B vaccination, except in one study. Most studies included in this review displayed methodological limitations and heterogeneity among them, which rendered it impossible to draw robust conclusions about the safety of hepatitis B vaccination in healthy subjects and patients with multiple sclerosis. Therefore, on the basis of current data there is no need to modify the vaccination recommendations; however, there is a need to improve the quality of observational studies with emphasis on certain considerations that are discussed in this review. PMID- 23086182 TI - Assessing bioavailability and toxicity of permethrin and DDT in sediment using matrix solid phase microextraction. AB - Matrix solid phase microextraction (matrix-SPME) was evaluated as a surrogate for the absorbed dose in organisms to estimate bioavailability and toxicity of permethrin and dichlorodiphenyltrichloroethane (DDT) in laboratory-spiked sediment. Sediments were incubated for 7, 28, and 90 days at room temperature to characterize the effect of aging on bioavailability and toxicity. Sediment toxicity was assessed using two freshwater invertebrates, the midge Chironomus dilutus and amphipod Hyalella azteca. Disposable polydimethylsiloxane fibers were used to estimate the absorbed dose in organisms and to examine bioavailability and toxicity. The equilibrium fiber concentrations substantially decreased with an increase in sediment aging time, indicating a reduction in bioavailability. Based on median lethal fiber concentrations (fiber LC50), toxicity of permethrin was not significantly different among the different aging times. Due to the substantial degradation of DDT to dichlorodiphenyldichloroethane (DDD) in sediment, sediment toxicity to C. dilutus increased, while it decreased for H. azteca with extended aging times. A toxic unit-based fiber LC50 value represented the DDT mixture (DDT and DDD) toxicity for both species. Significant linear relationships were found between organism body residues and the equilibrium fiber concentrations for each compound, across aging times. The study suggested that the matrix-SPME fibers mimicked bioaccumulation in the organisms, and enabled estimation of body residues, and could potentially be used in environmental risk assessment across matrices (e.g. sediment and water) to measure bioavailability and toxicity of hydrophobic pesticides. PMID- 23086183 TI - 2'-F-ANA-guanosine and 2'-F-guanosine as powerful tools for structural manipulation of G-quadruplexes. AB - Here we demonstrate the applicability of 2'-F-ANA-guanosine and 2'-F-guanosine as powerful tools for manipulating G-quadruplex folding by anti-position-favoring substitutions. A single guanine to 2'-F-ANA-guanine substitution can favor a single (3+1) hybrid conformation from a mixture of conformers. Rational substitutions of either type of 2'-F-modified nucleotide enable conformational switching from a (3+1) hybrid to a parallel folding topology. PMID- 23086185 TI - Making sense of posaconazole therapeutic drug monitoring: a practical approach. AB - PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) may be an important adjunct to optimizing the use of posaconazole. RECENT FINDINGS: Limited clinical studies suggest that an exposure-response relationship for posaconazole exists for the treatment of established invasive fungal diseases (IFDs), with emerging but less compelling data supporting its role in prophylaxis. The high prevalence of subtherapeutic levels has not translated to high prophylactic failure rates perhaps because of preferential uptake by effector cells important in the front line defence against Aspergillus species. Nevertheless, TDM would appear prudent in patients deemed at highest risk for IFD with correction of patient modifiable factors and attention to drug administration important in optimizing drug exposure. TDM performed within a few days after commencing posaconazole may be predictive of steady-state levels, thus minimizing the delay in obtaining results in addition to identifying a subset of patients who may remain persistently subtherapeutic and also resistant to dose-escalation. Trough levels may be supplanted by untimed levels at steady state, thereby expanding the practicalities of TDM. We propose that TDM becomes one of the several measures in an integrated approach to IFD prevention combining screening of high-risk haematology patients for invasive aspergillosis at presentation, together with prospective surveillance for IFD, explicit criteria for switching to an alternative prophylactic agent and adherence to infection control practices. SUMMARY: Growing evidence supports the value of TDM for posaconazole to identify patients who may benefit from correction of modifiable factors impacting bioavailability, dosage adjustment or switch to an alternative agent. PMID- 23086186 TI - Benefit and harm from immunity to respiratory syncytial virus: implications for treatment. AB - PURPOSE OF REVIEW: Human respiratory syncytial virus (RSV) infection is a major cause of morbidity in children and of morbidity and mortality in elderly or immunocompromised adults. Given prophylactically, antibody can protect against infection, but natural levels are poorly protective. Vaccination may enhance disease, and there is no well tolerated and effective vaccine or antiviral treatment. Despite over 50 years of research, therapy remains nonspecific and supportive. RECENT FINDINGS: Experimental human challenge in adult volunteers is beginning to elucidate the dynamics of viral shedding and causes of disease, but investigations of naturally infected children remain logistically challenging. RSV was known to bind several surface ligands, but the recent demonstration that nucleolin acts as a receptor for the RSV fusion protein was unexpected. Recent studies increasingly emphasize the relevance of innate immune responses and the dysregulation of inflammation as key factors in causing the pathological effects of infection. Studies in both human infants and mice indicate that interleukin-17 plays a role in some forms of RSV disease and regulatory T cells may be important in controlling inflammation. SUMMARY: Improved understanding of the human immune response to RSV infection continues to be needed in order to accelerate the development of vaccines and new treatments for bronchiolitis. PMID- 23086187 TI - Emerging patterns and implications of HIV-1 integrase inhibitor resistance. AB - PURPOSE OF REVIEW: This review highlights recent data on the pathways of resistance that impact the clinical activity of first-generation and second generation integrase inhibitors. RECENT FINDINGS: Raltegravir (RAL) and elvitegravir (EVG) are highly efficacious in first-line antiretroviral therapy, with small numbers of virological failures observed in clinical trials. Durable activity in treatment-experienced patients requires a fully supportive background regimen. RAL and EVG show a low-to-moderate genetic barrier to resistance and extensive cross-resistance, which preclude their sequential use. Resistance to dolutegravir (DTG) is not selected as readily in vitro and has not emerged in studies of treatment-naive patients to date. Both in vitro and in vivo, DTG retains activity against several RAL and EVG resistant strains, but susceptibility is variably impaired by multiple mutations within the G148 pathway, which are common after RAL or EVG failure. Cross-resistance can be partially overcome by doubling DTG dosing to twice daily, but durability of responses remains dependent on a supportive background regimen. There is variability in the integrase gene of circulating HIV strains, which does not appear to reduce drug activity, although it may influence the emergence and evolution of integrase resistance. Transmission of integrase resistance remains rare but surveillance is required. SUMMARY: Integrase inhibitors provide a potent option for the treatment of HIV infection. Drug resistance remains a challenge, which may be partially overcome by the introduction of second-generation compounds. Prompt management of RAL and EVG failure is required to prevent the accumulation of multiple resistance mutations that reduce DTG susceptibility. PMID- 23086188 TI - Knockdown of MMP-7 inhibits cell proliferation and enhances sensitivity to 5 Fluorouracil and X-ray irradiation in colon cancer cells. AB - The role of matrix metalloproteinase-7 (MMP-7) in the pathogenesis of colon cancer is not understood thoroughly. Previous studies from our group have shown that the expression levels of MMP-7 were highly elevated in colorectal cancer patient specimens and were correlated with Dukes Staging, histological differentiation grade and CEA level. The goal of this study was to investigate the cellular impact of MMP-7 in colon cancer. In this study, we used the SW480 colon cancer cell lines of MMP-7 knockdown by lentivirus-mediated RNA interference as a model system to investigate the impact of MMP-7 on cell proliferation and sensitivity to 5-Fluorouracil (5-FU) and X-ray irradiation (IR). Cell proliferation and sensitivity to 5-FU and IR were measured by MTT assay and colony formation assay. Cell cycle was evaluated by flow cytometry. We showed that the down regulation of MMP-7 inhibits colon cancer cell proliferation and sensitizes tumour cells to 5-FU and IR (P < 0.05). Decreased MMP-7 expression in SW480 cells by RNA interference triggered cell cycle arrest at G1 phase (P < 0.05). Down regulation of MMP-7 may inhibit the cell proliferation of colon cancer cells and increase tumour cells sensitivity to radiotherapy and chemotherapy. RNAi-mediated silencing of MMP-7 may represent a powerful therapeutic approach for controlling human colorectal cancer growth. PMID- 23086189 TI - The impact of gestational age on resource utilization after open heart surgery for congenital cardiac disease from birth to 1 year of age. AB - The impact of gestational age on perioperative morbidity was examined using a novel construct, the resource utilization index (RUI). The medical records of subjects from birth to 1 year of age entered into a pediatric cardiothoracic surgery database from a major academic medical center between 2007 and 2011 were reviewed. The hypothesis tested was that infants born at 37-38 weeks (early-term infants) experience greater resource utilization after open heart surgery than those born at 39 completed weeks and that this association can be observed until 1 year of age. The results support the premise that resource utilization increases linearly with declining gestational age among infants at 0-12 months who undergo cardiac surgery. Five of the six variables comprising the RUI showed statistically significant linear associations with gestational age in the predicted direction. Multivariate linear regression analysis showed that gestational age was a significant predictor of an increased RUI composite. Further investigation is needed to test the concept and to expand on these findings. PMID- 23086190 TI - Accessory pathway ablation in a 6-year-old girl using remote magnetic navigation as an alternative to cryoablation. AB - A 6-year-old girl with evidence of a parahisian accessory pathway on a baseline electrocardiogram underwent successful catheter ablation using magnetic navigation. Magnetic remote controlled ablation eliminated the parahisian pathway with the first radiofrequency application. A second anterolaterally located concealed pathway was successfully ablated in the same session, resulting in exclusively atrioventricular nodal conduction bidirectionally (total fluoroscopy, 4 min; 25 MUGy). PMID- 23086191 TI - A one-step screening process for optimal alignment of (soft) colloidal particles. AB - We developed nanostructured gradient wrinkle surfaces to establish a one-step screening process towards optimal assembly of soft and hard colloidal particles (microgel systems and silica particles). Thereby, we simplify studies on the influence of wrinkle dimensions (wavelength, amplitude) on particle properties and their alignment. In a combinatorial experiment, we optimize particle assembly regarding the ratio of particle diameter vs. wrinkle wavelength and packing density and point out differences between soft and hard particles. The preparation of wrinkle gradients in oxidized top layers on elastic poly(dimethylsiloxane) (PDMS) substrates is based on a controlled wrinkling approach. Partial shielding of the substrate during plasma oxidation is crucial to obtain two-dimensional gradients with amplitudes ranging from 7 to 230 nm and wavelengths between 250 and 900 nm. PMID- 23086193 TI - Complex magnetic order in Pr2Pd3Ge5: a single crystal study. AB - We have investigated the magnetic and electronic transport properties of single crystal Pr(2)Pd(3)Ge(5) grown by the Czochralski method. Complex magnetic behaviour (multiple magnetic transitions) is clearly seen in this compound from the magnetic susceptibility chi(T), isothermal magnetization M(H) and electrical resistivity rho(T) data. For the magnetic field applied along the crystallographic c-axis (H || [001]) the chi(T) data exhibit two sharp transitions at 6.9 and 6.3 K and a broad hump near 8 K. Four anomalies at 8.0, 7.3, 6.2 and 4.9 K are observed for the magnetic field along both a- and b directions (H || [100] and H || [010]). Further, the ordered state chi(T) presents a large anisotropy with an easy axis along the c-axis. The presence of magnetocrystalline anisotropy is also inferred from the isothermal M(H) data. The M(H) data measured at 1.9 K for H || [001] exhibit a step-like increase due to field-induced metamagnetic transitions at [Formula: see text] T and [Formula: see text] T. For H || [100] and H || [010] sharp step-like field-induced metamagnetic transitions occur at [Formula: see text] T and [Formula: see text] T which are accompanied by a weak S-shaped spin-flop metamagnetic transition at [Formula: see text] T. We have extracted the H-T phase diagram from the M(H) data collected at different temperatures in the magnetically ordered state which shows the existence of three magnetic phases below T(N) for H || [100] and H || [010], and two magnetic phases for H || [001]. A sharp transition due to the onset of long range antiferromagnetic order is also seen in the rho(T) data which also exhibit anisotropic behaviour. The observation of an upturn near T(N) in the rho(T) data suggests the formation of a super-zone gap and hence the existence of incommensurate magnetic structure. Further, in the ordered state, the rho(T) data present a gap in the excitation spectrum of magnons with a characteristic energy gap Delta ~ 0.23 meV. PMID- 23086192 TI - Are sex-selective abortions a characteristic of every poor region? Evidence from Brazil. AB - OBJECTIVES: Introduction of ultrasound equipment has been associated with higher sex ratio (number of male live births divided by female live births) for some developing countries. So far, studies have solely focused in regions with a cultural preference for males, which may introduce misleading conclusions about the association between poverty and sex-selective abortions. METHODS: We analyzed poor Brazilian municipalities that either (a) did not have ultrasound equipment, or (b) had the introduction of ultrasound equipment for the first time. Propensity score matching was performed, resulting in 155 pairs of comparable municipalities. RESULTS: We found a sex ratio of 1.039 for municipalities that had the introduction of ultrasound equipment and of 1.047 for those that did not. The difference between the two groups was not statistically significant. The use of the propensity score matching approach was successful in reducing bias. CONCLUSIONS: Concerns about an association between local poverty and sex selective abortions should not be a barrier against access to maternal technology. While sex-selective abortions are an important concern for some developing countries, they are not a specific characteristic of poverty. PMID- 23086194 TI - Editorial: Special issue on mobile and wireless technologies for healthcare delivery. PMID- 23086195 TI - SoM: a smart sensor for human activity monitoring and assisted healthy ageing. AB - This paper presents the hardware and software design and implementation of a low cost, wearable, and unobstructive intelligent accelerometer sensor for the monitoring of human physical activities. In order to promote healthy lifestyles to elders for an active, independent, and healthy ageing, as well as for the early detection of psychomotor abnormalities, the activity monitoring is performed in a holistic manner in the same device through different approaches: 1) a classification of the level of activity that allows to establish patterns of behavior; 2) a daily activity living classifier that is able to distinguish activities such as climbing or descending stairs using a simple method to decouple the gravitational acceleration components of the motion components; and 3) an estimation of metabolic expenditure independent of the activity performed and the anthropometric characteristics of the user. Experimental results have demonstrated the feasibility of the prototype and the proposed algorithms. PMID- 23086196 TI - Wireless design of a multisensor system for physical activity monitoring. AB - Real-time monitoring of human physical activity (PA) is important for assessing the intensity of activity and exposure to environmental pollutions. A wireless wearable multisenor integrated measurement system (WIMS) has been designed for real-time measurement of the energy expenditure and breathing volume of human subjects under free-living conditions. To address challenges posted by the limited battery life and data synchronization requirement among multiple sensors in the system, the ZigBee communication platform has been explored for energy efficient design. Two algorithms have been developed (multiData packaging and slot-data-synchronization) and coded into a microcontroller (MCU)-based sensor circuitry for real-time control of wireless data communication. Experiments have shown that the design enables continued operation of the wearable system for up to 68 h, with the maximum error for data synchronization among the various sensor nodes (SNs) being less than 24 ms. Experiment under free-living conditions have shown that the WIMS is able to correctly recognize the activity intensity level 86% of the time. The results demonstrate the effectiveness of the energy efficient wireless design for human PA monitoring. PMID- 23086197 TI - NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. AB - This is a report on a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics and held at the Experimental Biology 2012 meeting in San Diego, California, on April 25, 2012. The symposium speakers summarized and critically evaluated our current understanding of the physiologic, pharmacological, and toxicological roles of NADPH-cytochrome P450 oxidoreductase (POR), a flavoprotein involved in electron transfer to microsomal cytochromes P450 (P450), cytochrome b(5), squalene mono-oxygenase, and heme oxygenase. Considerable insight has been derived from the development and characterization of mouse models with conditional Por deletion in particular tissues or partial suppression of POR expression in all tissues. Additional mouse models with global or conditional hepatic deletion of cytochrome b(5) are helping to clarify the P450 isoform- and substrate-specific influences of cytochrome b(5) on P450 electron transfer and catalytic function. This symposium also considered studies using siRNA to suppress POR expression in a hepatoma cell-culture model to explore the basis of the hepatic lipidosis phenotype observed in mice with conditional deletion of Por in liver. The symposium concluded with a strong translational perspective, relating the basic science of human POR structure and function to the impacts of POR genetic variation on human drug and steroid metabolism. PMID- 23086198 TI - Importance of UDP-glucuronosyltransferases 2A2 and 2A3 in tobacco carcinogen metabolism. AB - UDP-glucuronosyltransferase A1 (UGT2A1) is expressed in the lung and exhibits activity against polycyclic aromatic hydrocarbons (PAHs), suggesting UGT2A1 involvement in the local metabolism of PAH tobacco carcinogens. The goal of the present study was to investigate the importance of two additional UGT2A enzymes, UGT2A2 and UGT2A3, in tobacco carcinogen metabolism. Real-time polymerase chain reaction suggested that wild-type UGT2A2 had the highest expression in the breast, followed by trachea > larynx > kidney. A novel splice variant of UGT2A2 lacking exon 3 (termed UGT2A2Deltaexon3) was investigated, with UGT2A2Deltaexon3 expression determined to be 25-50% that of wild-type UGT2A2 in all tissues examined. UGT2A3 was determined to be well expressed in the liver and colon, followed by pancreas > kidney > lung > tonsil > trachea > larynx. Cell homogenates prepared from human embryonic kidney (HEK)293 cells overexpressing wild-type UGT2A2 (termed UGT2A2_i1) exhibited glucuronidation activity, as observed by reverse-phase ultra-pressure liquid chromatography, against 1-hydroxy (OH)-pyrene, 1-naphthol, and hydroxylated benzo(a)pyrene metabolites, whereas homogenates prepared from HEK293 cells overexpressing UGT2A3 only showed activity against simple PAHs like 1-OH-pyrene and 1-naphthol. Activity assays showed the UGT2A2Deltaexon3 protein (termed UGT2A2_i2) exhibited no detectable glucuronidation activity against all substrates examined; however, coexpression studies suggested that UGT2A2_i2 negatively modulates UGT2A2_i1 activity. Both UGT2A2 and UGT2A3 exhibited no detectable activity against complex PAH proximate carcinogens, tobacco-specific nitrosamines, or heterocyclic amines. These data suggest that, although UGT2A1 is the only UGT2A enzyme active against PAH proximate carcinogens (including PAH diols), both UGTs 2A1 and 2A2 play an important role in the local detoxification of procarcinogenic monohydroxylated PAH metabolites. PMID- 23086199 TI - Parkinsonism in cirrhosis: pathogenesis and current therapeutic options. AB - Acquired hepatolenticular degeneration, also known as "Parkinsonism in cirrhosis" is characterized by extrapyramidal symptoms including hypokinesia, dystonia and rigidity that are rapidly progressive and may be independent of the severity of cognitive dysfunction. Magnetic resonance imaging reveals T1-weighted hyperintense signals in both globus pallidus and substantia nigra. Estimates of the prevalence of Parkinsonism in cirrhosis have been reported as high as 21 %. The cause of Parkinsonism in cirrhosis has been attributed to manganese deposition in basal ganglia structures, leading to the dysfunction of the dopaminergic neurotransmitter system. In particular, there is evidence from both spectroscopic and biochemical investigations for damage to (or dysfunction of) presynaptic dopamine transporters together with a loss of post-synaptic dopamine receptors in basal ganglia of affected patients. Therapeutic options are limited; ammonia-lowering strategies are without substantial benefit, and an effective manganese chelator is not available. In many patients, L-Dopa replacement therapy and the dopamine receptor agonist bromocriptine are beneficial, and liver transplantation is generally effective. However, reports of post-transplant residual extrapyramidal symptoms suggest an element of irreversibility in some cases. PMID- 23086201 TI - Hybrid density functional study of band alignment in ZnO-GaN and ZnO-(Ga(1 x)Zn(x))(N(1-x)O(x))-GaN heterostructures. AB - The band alignment in ZnO-GaN and related heterostructures is crucial for uses in solar harvesting technology. Here, we report our density functional calculations of the band alignment and optical properties of ZnO-GaN and ZnO-(Ga(1 x)Zn(x))(N(1-x)O(x))-GaN heterostructures using a Heyd-Scuseria-Ernzerhof (HSE) hybrid functional. We found that the conventional GGA functionals underestimate not only the band gap but also the band offset of these heterostructures. Using the hybrid functional calculations, we show that the (Ga(1-x)Zn(x))(N(1-x)O(x)) solid solution has a direct band gap of about 2.608 eV, in good agreement with the experimental data. More importantly, this solid solution forms type-II band alignment with the host materials. A GaN-(Ga(1-x)Zn(x))(N(1-x)O(x))-ZnO core shell solar cell model is presented to improve the visible light absorption ability and carrier collection efficiency. PMID- 23086200 TI - Decrease of glutathione content in the prefrontal cortical mitochondria of rats with acute hepatic encephalopathy: prevention by histidine. AB - Mitochondrial glutathione (mGSH) is a critical factor in the cell defense against oxidative and nitrosative stress (ONS), and ONS is a key pathogenic event in hepatic encephalopathy (HE). Acute HE in the thioacetamide (TAA) model caused a 54 % decrease of mGSH content in the rat prefrontal cortex (pfc), but not in the striatum (str), nor did it affect the GSH content in the pfc or str homogenate. In the pfc, treatment with L- histidine (His), which is known to alleviate ONS related symptoms in HE animals, attenuated the decrease of mGSH, and increased the GSH content in pfc and str homogenates and pfc microdialysates of control animals. His increased the expression of mRNA coding for the GSH synthesizing enzyme, glutamate cysteine ligase (GCL) and decreased that of the GSH-degrading enzyme gamma-glutamyltranspeptidase (gammaGT). The results suggest that the decrease of mGSH may be an important contributing factor to mitochondrial dysfunction in HE, and delineate a new mechanistic aspect of the therapeutic potential of His in HE. PMID- 23086202 TI - Engineering a thermoregulated intein-modified xylanase into maize for consolidated lignocellulosic biomass processing. AB - Plant cellulosic biomass is an abundant, low-cost feedstock for producing biofuels and chemicals. Expressing cell wall-degrading (CWD) enzymes (e.g. xylanases) in plant feedstocks could reduce the amount of enzymes required for feedstock pretreatment and hydrolysis during bioprocessing to release soluble sugars. However, in planta expression of xylanases can reduce biomass yield and plant fertility. To overcome this problem, we engineered a thermostable xylanase (XynB) with a thermostable self-splicing bacterial intein to control the xylanase activity. Intein-modified XynB (iXynB) variants were selected that have <10% wild type enzymatic activity but recover >60% enzymatic activity upon intein self splicing at temperatures >59 degrees C. Greenhouse-grown xynB maize expressing XynB has shriveled seeds and low fertility, but ixynB maize had normal seeds and fertility. Processing dried ixynB maize stover by temperature-regulated xylanase activation and hydrolysis in a cocktail of commercial CWD enzymes produced >90% theoretical glucose and >63% theoretical xylose yields. PMID- 23086203 TI - Engineered ascorbate peroxidase as a genetically encoded reporter for electron microscopy. AB - Electron microscopy (EM) is the standard method for imaging cellular structures with nanometer resolution, but existing genetic tags are inactive in most cellular compartments or require light and can be difficult to use. Here we report the development of 'APEX', a genetically encodable EM tag that is active in all cellular compartments and does not require light. APEX is a monomeric 28 kDa peroxidase that withstands strong EM fixation to give excellent ultrastructural preservation. We demonstrate the utility of APEX for high resolution EM imaging of a variety of mammalian organelles and specific proteins using a simple and robust labeling procedure. We also fused APEX to the N or C terminus of the mitochondrial calcium uniporter (MCU), a recently identified channel whose topology is disputed. These fusions give EM contrast exclusively in the mitochondrial matrix, suggesting that both the N and C termini of MCU face the matrix. Because APEX staining is not dependent on light activation, APEX should make EM imaging of any cellular protein straightforward, regardless of the size or thickness of the specimen. PMID- 23086204 TI - 18F-FDG-PET evaluation of pathological tumour response to neoadjuvant therapy in patients with NSCLC. AB - OBJECTIVES: The ability to identify potential responders to neoadjuvant treatment may improve patient selection or surgery and may help in the development of response criteria suitable for routine monitoring of response. The aim of this study was to evaluate the value of PET in predicting the pathological tumour response of non-small-cell lung cancer (NSCLC) to neoadjuvant therapy using a meta-analysis. METHODS: All available published studies investigating the value of PET in predicting the pathological response of NSCLC to neoadjuvant therapy were collected. Pooled sensitivity and specificity data were obtained using statistical software. Subgroup analysis was performed to explore the sources of heterogeneity. RESULTS: A total of 13 studies comprising 414 patients with NSCLC were included in the meta-analysis. Pooled sensitivity, specificity, positive predictive value and negative predictive value for PET-predicted response was 83% [95% confidence interval (CI); 76-89%], 84% (95% CI; 79-88%), 74% (95% CI; 67 81%) and 91% (95% CI; 87-94%), respectively. Significant heterogeneity (P<0.05) was observed. On the basis of our subgroup analyses, methodological quality could be responsible for this heterogeneity in our metaregression. The predictive value of PET in NSCLC patients with pathological response (considered the gold standard) was significantly higher than that of computed tomography (P<0.05). CONCLUSION: PET scanning has an important role in predicting nonresponders to neoadjuvant therapy in cases of NSCLC, and the predictive value of PET for evaluating pathologically documented responses is superior to that of computed tomography. However, additional evaluations using prospective clinical trials will be required to assess the clinical benefit of this strategy. PMID- 23086205 TI - Geometry-based optimization of radio-frequency coils for powering neuroprosthetic implants. AB - Biomedical implants powered by inductive links have several advantages over batteries or percutaneous power linkages. The inductive link power transfer efficiency must be optimized to realize the full advantage over other power delivery technologies. Optimization is also important to reduce the electromagnetic radiation exposure, reduce secondary heating effects and improve power efficiency, so that large primary side storage batteries are not required. Geometric constraints, i.e., size and shape, of biomedical implants are a primary concern of device design. In this paper, we present a novel coil optimization strategy driven by geometric constraints. By considering the relationship between wire diameter, number of turns, quality factor, coupling coefficient and shape of coil, we can optimize the inductively coupled coils to maximize the power transfer efficiency under stringent geometric constraints. This new approach is verified using a design example targeted for an intraocular visual prosthesis. In this example, we demonstrate an experimental power transfer efficiency of 52% by co-optimization of the primary and secondary coils. PMID- 23086206 TI - AglS, a novel component of the Haloferax volcanii N-glycosylation pathway, is a dolichol phosphate-mannose mannosyltransferase. AB - In Haloferax volcanii, a series of Agl proteins mediates protein N-glycosylation. The genes encoding all but one of the Agl proteins are sequestered into a single gene island. The same region of the genome includes sequences also suspected but not yet verified as serving N-glycosylation roles, such as HVO_1526. In the following, HVO_1526, renamed AglS, is shown to be necessary for the addition of the final mannose subunit of the pentasaccharide N-linked to the surface (S) layer glycoprotein, a convenient reporter of N-glycosylation in Hfx. volcanii. Relying on bioinformatics, topological analysis, gene deletion, mass spectrometry, and biochemical assays, AglS was shown to act as a dolichol phosphate-mannose mannosyltransferase, mediating the transfer of mannose from dolichol phosphate to the tetrasaccharide corresponding to the first four subunits of the pentasaccharide N-linked to the S-layer glycoprotein. PMID- 23086207 TI - Identification and characterization of a highly conserved crenarchaeal protein lysine methyltransferase with broad substrate specificity. AB - Protein lysine methylation occurs extensively in the Crenarchaeota, a major kingdom in the Archaea. However, the enzymes responsible for this type of posttranslational modification have not been found. Here we report the identification and characterization of the first crenarchaeal protein lysine methyltransferase, designated aKMT, from the hyperthermophilic crenarchaeon Sulfolobus islandicus. The enzyme was capable of transferring methyl groups to selected lysine residues in a substrate protein using S-adenosyl-l-methionine (SAM) as the methyl donor. aKMT, a non-SET domain protein, is highly conserved among crenarchaea, and distantly related homologs also exist in Bacteria and Eukarya. aKMT was active over a wide range of temperatures, from ~25 to 90 degrees C, with an optimal temperature at ~60 to 70 degrees C. Amino acid residues Y9 and T12 at the N terminus appear to be the key residues in the putative active site of aKMT, as indicated by sequence conservation and site directed mutagenesis. Although aKMT was identified based on its methylating activity on Cren7, the crenarchaeal chromatin protein, it exhibited broad substrate specificity and was capable of methylating a number of recombinant Sulfolobus proteins overproduced in Escherichia coli. The finding of aKMT will help elucidate mechanisms underlining extensive protein lysine methylation and the functional significance of posttranslational protein methylation in crenarchaea. PMID- 23086208 TI - CspR, a cold shock RNA-binding protein involved in the long-term survival and the virulence of Enterococcus faecalis. AB - By coprecipitation, we identified RNA-binding proteins in the Gram-positive opportunistic pathogen Enterococcus faecalis known to be deficient of the RNA chaperone Hfq. In particular, we characterized one belonging to the cold shock protein (Csp) family (Ef2925) renamed CspR for cold shock protein RNA binding. Compared to the wild-type strain, the DeltacspR mutant was less virulent in an insect infection model (Galleria mellonella) and exhibited a decreased persistence in mouse kidneys and a low survival rate in peritoneal macrophages. As expected, we found that the DeltacspR mutant strain was more impaired in its growth than the parental strain under cold conditions and in its long-term survival under nutrient starvation. All these phenotypes were restored after complementation of the DeltacspR mutant. In addition, Western blot analysis showed that CspR was overexpressed under cold shock conditions and in the stationary phase. Since CspR may act as an RNA chaperone, putative targets were identified using a global proteomic approach completed with transcriptomic assays. This study revealed that 19 proteins were differentially expressed in the DeltacspR strain (9 upregulated, 10 downregulated) and that CspR mainly acted at the posttranscriptional level. These data highlight for the first time the role of the RNA-binding protein CspR as a regulator in E. faecalis and its requirement in stress response and virulence in this important human pathogen. PMID- 23086210 TI - The Sakaguchi reaction product quenches phycobilisome fluorescence, allowing determination of the arginine concentration in cells of Anabaena strain PCC 7120. AB - The filamentous cyanobacterium Anabaena fixes nitrogen in specialized cells called heterocysts. The immediate product of fixation, ammonia, is known to be assimilated by addition to glutamate to make glutamine. How fixed nitrogen is transported along the filament to the 10 to 20 vegetative cells that separate heterocysts is unknown. N-fixing heterocysts accumulate an insoluble polymer containing aspartate and arginine at the cell poles. Lockau's group has proposed that the polymer is degraded at the poles to provide a mobile carrier, arginine, to the vegetative cells (R. Richter, M. Hejazi, R. Kraft, K. Ziegler, and W. Lockau, Eur. J. Biochem. 263:163-169, 1999). We wished to use the Sakaguchi reaction for arginine to determine the relative cellular concentration of arginine along the filament. At present, the methods for measuring absorption of the Sakaguchi reaction product at 520 nm are insufficiently sensitive for that purpose. However, that product quenches the fluorescence of phycobiliproteins, which we have adapted to a determination of arginine. Our results are consistent with the proposal that arginine is a principal nitrogen carrier from heterocysts to vegetative cells in Anabaena. PMID- 23086209 TI - New functions for the ancient DedA membrane protein family. AB - The DedA protein family is a highly conserved and ancient family of membrane proteins with representatives in most sequenced genomes, including those of bacteria, archaea, and eukarya. The functions of the DedA family proteins remain obscure. However, recent genetic approaches have revealed important roles for certain bacterial DedA family members in membrane homeostasis. Bacterial DedA family mutants display such intriguing phenotypes as cell division defects, temperature sensitivity, altered membrane lipid composition, elevated envelope related stress responses, and loss of proton motive force. The DedA family is also essential in at least two species of bacteria: Borrelia burgdorferi and Escherichia coli. Here, we describe the phylogenetic distribution of the family and summarize recent progress toward understanding the functions of the DedA membrane protein family. PMID- 23086211 TI - Transcription factor family-based reconstruction of singleton regulons and study of the Crp/Fnr, ArsR, and GntR families in Desulfovibrionales genomes. AB - Accurate detection of transcriptional regulatory elements is essential for high quality genome annotation, metabolic reconstruction, and modeling of regulatory networks. We developed a computational approach for reconstruction of regulons operated by transcription factors (TFs) from large protein families and applied this novel approach to three TF families in 10 Desulfovibrionales genomes. Phylogenetic analyses of 125 regulators from the ArsR, Crp/Fnr, and GntR families revealed that 65% of these regulators (termed reference TFs) are well conserved in Desulfovibrionales, while the remaining 35% of regulators (termed singleton TFs) are species specific and show a mosaic distribution. For regulon reconstruction in the group of singleton TFs, the standard orthology-based approach was inefficient, and thus, we developed a novel approach based on the simultaneous study of all homologous TFs from the same family in a group of genomes. As a result, we identified binding for 21 singleton TFs and for all reference TFs in all three analyzed families. Within each TF family we observed structural similarities between DNA-binding motifs of different reference and singleton TFs. The collection of reconstructed regulons is available at the RegPrecise database (http://regprecise.lbl.gov/RegPrecise/Desulfovibrionales.jsp). PMID- 23086212 TI - Inactivation of the transcriptional regulator-encoding gene sdiA enhances rice root colonization and biofilm formation in Enterobacter cloacae GS1. AB - Enterobacter cloacae GS1 is a plant growth-promoting bacterium which colonizes rice roots. In the rhizosphere environment, N-acyl homoserine lactone (NAHL)-like quorum-sensing signals are known to be produced by host plants and other microbial inhabitants. E. cloacae GS1 was unable to synthesize NAHL quorum sensing signals but had the NAHL-dependent transcriptional regulator-encoding gene sdiA. This study was aimed at understanding the effects of SdiA and NAHL dependent cross talk in rice root colonization by E. cloacae GS1. Pleiotropic effects of sdiA inactivation included substantial increases in root colonization and biofilm formation, suggesting a negative role for SdiA in bacterial adhesion. We provide evidence that sdiA inactivation leads to elevated levels of biosynthesis of curli, which is involved in cellular adhesion. Extraneous addition of NAHLs had a negative effect on root colonization and biofilm formation. However, the sdiA mutant of E. cloacae GS1 was insensitive to NAHLs, suggesting that this NAHL-induced inhibition of root colonization and biofilm formation is SdiA dependent. Therefore, it is proposed that NAHLs produced by both plant and microbes in the rice rhizosphere act as cross-kingdom and interspecies signals to negatively impact cellular adhesion and, thereby, root colonization in E. cloacae GS1. PMID- 23086213 TI - Surgical technique: Endoscopic gluteus maximus tendon release for external snapping hip syndrome. AB - BACKGROUND: While many authors have recommended surgery for patients with persistent symptoms of external snapping hip, it is unclear which one best relieves symptoms. Concerns with iliotibial band (ITB)-modifying techniques include altering the shape of the lateral thigh and overload of the contralateral abduction mechanism. We describe a new endoscopic technique that decreases the tension of the ITB complex by releasing the femoral insertion of the gluteus maximus tendon (GMT). DESCRIPTION OF TECHNIQUE: Via an endoscopic approach, we tenotomize the GMT near its insertion at the linea aspera through two trochanteric portals, developing a space beneath the ITB. METHODS: We reviewed eight patients (nine hips) with external snapping hip nonresponsive to nonoperative treatment treated by endoscopic GMT release. There were seven women (one bilateral) and one man, with a mean +/- SD age of 35 +/- 13.1 years (range, 18-55 years). Mean symptom duration was 36 +/- 20.3 months (range, 16-84 months). Minimum followup was 22 months (mean, 32 +/- 9.3 months; range, 22-45 months). RESULTS: Snapping and pain resolved in seven patients after the initial procedure. We performed one revision procedure with complete relief of symptoms. All eight patients returned to their previous level of activity. Average modified Harris hip score was 61 points (range, 45-70 points) preoperatively and 78 points (range, 62-93 points) at latest followup. We observed no neurovascular complications. CONCLUSIONS: Our small series suggests endoscopic release of the GMT resolves pain and snapping symptoms in most patients. PMID- 23086214 TI - Editorial: Richard A. Brand MD, editor-in-chief 2002-2012. PMID- 23086215 TI - Endothelial differentiation of mesenchymal stromal cells: when traditional biology meets mechanotransduction. AB - In the last few years, scientists have focused their attention on adult stem cells. It has long been known that stem cells are capable of renewing themselves and can generate multiple cell types. Today, it is demonstrated that stem cells are present in far more tissues and organs than once thought and that they are capable of developing into more kinds of cells than previously imagined. Adult human mesenchymal stromal cells (h-MSC) are prime candidates for many cell-based tissue-engineering applications thanks to their plasticity and easy accessibility. Despite such potential, their use in therapeutic application is still restricted because there are some open issues, which need to be deeply investigated. In this review, we focus on endothelial differentiation of h-MSCs. We comment on some controversies and show how these might arise from h-MSCs heterogeneity and morpho-functional variability. Finally, we highlight the role of extracellular mechanical cues and report on the mechanotransduction pathways activated by micro-/nanotopographies as promising alternative differentiation inducers. PMID- 23086216 TI - Family Support and Colorectal Cancer Screening among Urban African Americans. AB - Colorectal cancer (CRC) is the third leading cause of cancer death among African Americans. Less than 50% of African Americans have had CRC screening. This study examined the relationships between family support and influence, cultural identity, CRC beliefs, and a screening informed decision among 129 urban African Americans. Family support (p < .01) significantly predicted CRC beliefs and CRC beliefs significantly predicted informed decision (p < .01). Based on study results, practitioners should routinely assess family support and CRC beliefs with African Americans patients. This may improve patient-provider shared decision-making satisfaction and CRC screening adherence among African American patients. PMID- 23086217 TI - Multiple-trait genomic selection methods increase genetic value prediction accuracy. AB - Genetic correlations between quantitative traits measured in many breeding programs are pervasive. These correlations indicate that measurements of one trait carry information on other traits. Current single-trait (univariate) genomic selection does not take advantage of this information. Multivariate genomic selection on multiple traits could accomplish this but has been little explored and tested in practical breeding programs. In this study, three multivariate linear models (i.e., GBLUP, BayesA, and BayesCpi) were presented and compared to univariate models using simulated and real quantitative traits controlled by different genetic architectures. We also extended BayesA with fixed hyperparameters to a full hierarchical model that estimated hyperparameters and BayesCpi to impute missing phenotypes. We found that optimal marker-effect variance priors depended on the genetic architecture of the trait so that estimating them was beneficial. We showed that the prediction accuracy for a low heritability trait could be significantly increased by multivariate genomic selection when a correlated high-heritability trait was available. Further, multiple-trait genomic selection had higher prediction accuracy than single-trait genomic selection when phenotypes are not available on all individuals and traits. Additional factors affecting the performance of multiple-trait genomic selection were explored. PMID- 23086218 TI - Genetic basis of a violation of Dollo's Law: re-evolution of rotating sex combs in Drosophila bipectinata. AB - Phylogenetic analyses suggest that violations of "Dollo's law"--that is, re evolution of lost complex structures--do occur, albeit infrequently. However, the genetic basis of such reversals has not been examined. Here, we address this question using the Drosophila sex comb, a recently evolved, male-specific morphological structure composed of modified bristles. In some species, sex comb development involves only the modification of individual bristles, while other species have more complex "rotated" sex combs that are shaped by coordinated migration of epithelial tissues. Rotated sex combs were lost in the ananassae species subgroup and subsequently re-evolved, ~12 million years later, in Drosophila bipectinata and its sibling species. We examine the genetic basis of the differences in sex comb morphology between D. bipectinata and D. malerkotliana, a closely related species with a much simpler sex comb representing the ancestral condition. QTL mapping reveals that >50% of this difference is controlled by one chromosomal inversion that covers ~5% of the genome. Several other, larger inversions do not contribute appreciably to the phenotype. This genetic architecture suggests that rotating sex combs may have re evolved through changes in relatively few genes. We discuss potential developmental mechanisms that may allow lost complex structures to be regained. PMID- 23086219 TI - More than the sum of its parts: a complex epistatic network underlies natural variation in thermal preference behavior in Caenorhabditis elegans. AB - Behavior is a complex trait that results from interactions among multiple genes and the environment. Both additive and nonadditive effects are expected to contribute to broad-sense heritability of complex phenotypes, although the relative contribution of each of these mechanisms is unknown. Here, we mapped genetic variation in the correlated phenotypes of thermal preference and isothermal dispersion in the nematode Caenorhabditis elegans. Genetic variation underlying these traits is characterized by a set of linked quantitative trait loci (QTL) that interact in a complex epistatic network. In particular, two loci located on the X chromosome interact with one another to generate extreme thermophilic behavior and are responsible for ~50% of the total variation observed in a cross between two parental lines, even though these loci individually explain very little of the among-line variation. Our results demonstrate that simultaneously considering the influence of a quantitative trait locus (QTL) on multiple scales of behavior can inform the physiological mechanism of the QTL and show that epistasis can explain significant proportions of otherwise unattributed variance within populations. PMID- 23086221 TI - Surprising differences in the variability of Y chromosomes in African and cosmopolitan populations of Drosophila melanogaster. AB - The nonrecombining Drosophila melanogaster Y chromosome is heterochromatic and has few genes. Despite these limitations, there remains ample opportunity for natural selection to act on the genes that are vital for male fertility and on Y factors that modulate gene expression elsewhere in the genome. Y chromosomes of many organisms have low levels of nucleotide variability, but a formal survey of D. melanogaster Y chromosome variation had yet to be performed. Here we surveyed Y-linked variation in six populations of D. melanogaster spread across the globe. We find surprisingly low levels of variability in African relative to Cosmopolitan (i.e., non-African) populations. While the low levels of Cosmopolitan Y chromosome polymorphism can be explained by the demographic histories of these populations, the staggeringly low polymorphism of African Y chromosomes cannot be explained by demographic history. An explanation that is entirely consistent with the data is that the Y chromosomes of Zimbabwe and Uganda populations have experienced recent selective sweeps. Interestingly, the Zimbabwe and Uganda Y chromosomes differ: in Zimbabwe, a European Y chromosome appears to have swept through the population. PMID- 23086223 TI - Pain assessment in neonates and infants in the post-operative period following cardiac surgery. AB - PURPOSE: We aimed to test the convergent validity of the COMFORT scale and the Cardiac Analgesic Assessment Scale (CAAS) and to evaluate changes in physiological parameters over time in response to a painful procedure in neonates and infants following cardiac surgery. METHODS: From October 2006 to May 2008, 16 children were prospectively evaluated over 1-3 days after cardiac surgery while they remained on mechanical ventilation and received infusions of sedatives and analgesics. Pain was assessed by the COMFORT scale and CAAS before and during endotracheal tube suctioning. Heart rate, systemic systolic blood pressure, pulmonary artery pressure, oxygen saturation and pupil size were recorded at the same times. RESULTS: During endotracheal suctioning on the first day, there was a significant increase in COMFORT and CAAS scores, systemic systolic blood pressure tended to decrease, pulmonary artery pressure significantly increased and there was a significant reduction in oxygen saturation. Heart rate and pupil size did not change significantly during the painful procedure throughout the study. COMFORT scores significantly correlated with CAAS scores on all days. Nevertheless, agreement for the detection of pain between both scales was weak (kappa<0.5). The COMFORT scale detected more patients with pain. CONCLUSIONS: There was poor agreement between the COMFORT scale and CAAS for detection of pain in neonates and infants who had undergone cardiac surgery. A reduction in systemic systolic blood pressure and a rise in pulmonary artery pressure were observed during painful stimulation on the first post-operative day. For this population, a pain scale scoring physiological parameters according to their variation to higher and lower values should be developed. PMID- 23086220 TI - Dispensable, redundant, complementary, and cooperative roles of dopamine, octopamine, and serotonin in Drosophila melanogaster. AB - To investigate the regulation of Drosophila melanogaster behavior by biogenic amines, we have exploited the broad requirement of the vesicular monoamine transporter (VMAT) for the vesicular storage and exocytotic release of all monoamine neurotransmitters. We used the Drosophila VMAT (dVMAT) null mutant to globally ablate exocytotic amine release and then restored DVMAT activity in either individual or multiple aminergic systems, using transgenic rescue techniques. We find that larval survival, larval locomotion, and female fertility rely predominantly on octopaminergic circuits with little apparent input from the vesicular release of serotonin or dopamine. In contrast, male courtship and fertility can be rescued by expressing DVMAT in octopaminergic or dopaminergic neurons, suggesting potentially redundant circuits. Rescue of major aspects of adult locomotion and startle behavior required octopamine, but a complementary role was observed for serotonin. Interestingly, adult circadian behavior could not be rescued by expression of DVMAT in a single subtype of aminergic neurons, but required at least two systems, suggesting the possibility of unexpected cooperative interactions. Further experiments using this model will help determine how multiple aminergic systems may contribute to the regulation of other behaviors. Our data also highlight potential differences between behaviors regulated by standard exocytotic release and those regulated by other mechanisms. PMID- 23086222 TI - Age-related changes in parietal lobe activation during an episodic memory retrieval task. AB - The crucial role of lateral parietal regions in episodic memory has been confirmed in previous studies. While aging has an influence on retrieval of episodic memory, it remains to be examined how the involvement of lateral parietal regions in episodic memory changes with age. We investigated episodic memory retrieval in two age groups, using faces as stimuli and retrieval success as a measure of episodic memory. Young and elderly participants showed activation within a similar network, including lateral and medial parietal as well as prefrontal regions, but elderly showed a higher level of brain activation regardless of condition. Furthermore, we examined functional connectivity in the two age groups and found a more extensive network in the young group, including correlations of parietal and prefrontal regions. In the elderly, the overall stronger activation related to memory performance may indicate a compensatory process for a less extensive functional network. PMID- 23086224 TI - Preface: geochemistry of road dusts, dusts generated in bushfires. PMID- 23086226 TI - [Arterial hypertension]. PMID- 23086225 TI - Adherence to ranibizumab treatment for neovascular age-related macular degeneration in real life. AB - BACKGROUND: To identify factors and problems influencing treatment adherence in patients undergoing anti-VEGF therapy for neovascular age-related macular degeneration (AMD) under real-life conditions. METHODS: Cross-sectional study was conducted of 95 patients receiving ranibizumab therapy on a pro re nata (PRN) regimen with monthly controls in a tertiary health care clinic. Monthly controls included best corrected visual acuity, slit-lamp examination and spectral-domain optical coherence tomography. Adherence was measured using Kaplan-Meier time-to discontinuation analysis. Patients were asked to respond to a 16-item questionnaire covering items such as anxiety, subjective benefit, and financial issues of therapy. RESULTS: Forty-two men and 53 women were included. After a mean follow-up time of 675 days (range 63-1008), adherence was 81.1% (77/95). The mean number of follow-up visits was 19 (3-30), the mean number of intravitreal injections was ten (3-23). Seven patients withdrew from treatment due to subjective dissatisfaction with benefit. Other reasons for loss to follow-up were death in one case, serious general disease in three patients, and treatment options closer to home in five cases. Two patients cancelled further follow-up after treatment cessation due to terminal fibrosis. 62.1% of patients were afraid of a negative examination result, whereas 19.0% were afraid of intravitreal injections. A major problem was travel to and from the hospital (46.3%), with 61.5% of patients requiring escort. CONCLUSION: Despite necessary monthly visits, patients showed a high adherence to therapy. The major problem was travel to and from the hospital. From the patients' point of view, anxiety of a negative examination result was more pronounced than fear of intraocular injections, which would be an argument for continuous injections rather than for a PRN regimen. PMID- 23086227 TI - Microporous metal-organic frameworks for storage and separation of small hydrocarbons. AB - Hydrocarbons are very important energy resources and raw materials for some industrially important products and fine chemicals. There is a need for the discovery of better materials that offer enhanced capacities for safe storage of hydrocarbons. Furthermore, the development of improved separation technologies will lead to significant reduction in energy requirements and costs. In this feature article, we provide an overview of the current status of the emerging microporous metal-organic frameworks for the storage and separation of small hydrocarbons. PMID- 23086228 TI - LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria. AB - Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve defects in the intrinsic/mitochondrial apoptotic pathway. The bioactive sphingolipid ceramide is a critical mediator of apoptosis initiated by a number of therapeutic modalities. It is noteworthy that insufficient ceramide accumulation has been linked to gemcitabine resistance in multiple cancer types, including pancreatic cancer. Taking advantage of the fact that cancer cells frequently have more negatively charged mitochondria, we investigated a means to circumvent resistance to gemcitabine by targeting delivery of a cationic ceramide (l-t-C6-CCPS [LCL124: ((2S,3S,4E)-2-N-[6'-(1"-pyridinium)-hexanoyl-sphingosine bromide)]) to cancer cell mitochondria. LCL124 was effective in initiating apoptosis by causing mitochondrial depolarization in pancreatic cancer cells but demonstrated significantly less activity against nonmalignant pancreatic ductal epithelial cells. Furthermore, we demonstrate that the mitochondrial membrane potentials of the cancer cells were more negative than nonmalignant cells and that dissipation of this potential abrogated cell killing by LCL124, establishing that the effectiveness of this compound is potential-dependent. LCL124 selectively accumulated in and inhibited the growth of xenografts in vivo, confirming the tumor selectivity and therapeutic potential of cationic ceramides in pancreatic cancer. It is noteworthy that gemcitabine-resistant pancreatic cancer cells became more sensitive to subsequent treatment with LCL124, suggesting that this compound may be a uniquely suited to overcome gemcitabine resistance in pancreatic cancer. PMID- 23086229 TI - Interruption of the ionic lock in the bradykinin B2 receptor results in constitutive internalization and turns several antagonists into strong agonists. AB - The DRY motif with the highly conserved R3.50 is a hallmark of family A G protein coupled receptors (GPCRs). The crystal structure of rhodopsin revealed a salt bridge between R135(3.50) and another conserved residue, E247(6.30), in helix 6. This ionic lock was shown to maintain rhodopsin in its inactive state. Thus far, little information is available on how interruption of this ionic bond affects signaling properties of nonrhodopsin GPCRs, because the focus has been on mutations of R3.50, although this residue is indispensable for G protein activation. To investigate the importance of an ionic lock for overall receptor activity in a nonrhodopsin GPCR, we mutated R128(3.50) and E238(6.30) in the bradykinin (BK) B(2) receptor (B(2)R) and stably expressed the constructs in HEK293 cells. As expected, mutation of R3.50 resulted in lack of G protein activation. In addition, this mutation led to considerable constitutive receptor internalization. Mutation of E6.30 (mutants E6.30A and E6.30R) also caused strong constitutive internalization. Most intriguingly, however, although the two E6.30 mutants displayed no increased basal phosphatidylinositol hydrolysis, they gave a response to three different B(2)R antagonists that was almost comparable to that obtained with BK. In contrast, swapping of R3.50 and E6.30, thus allowing the formation of an inverse ionic bond, resulted in rescue of the wild type phenotype. These findings demonstrate for the first time, to our knowledge, that interruption of the ionic lock in a family A GPCR can have distinctly different effects on receptor internalization and G protein stimulation, shedding new light on its role in the activation process. PMID- 23086230 TI - Fetal muscle-type nicotinic acetylcholine receptor activation in TE-671 cells and inhibition of fetal movement in a day 40 pregnant goat model by optical isomers of the piperidine alkaloid coniine. AB - Coniine is an optically active toxic piperidine alkaloid and nicotinic acetylcholine receptor (nAChR) agonist found in poison hemlock (Conium maculatum L.). Coniine teratogenicity is hypothesized to be attributable to the binding, activation, and prolonged desensitization of fetal muscle-type nAChR, which results in the complete inhibition of fetal movement. However, pharmacological evidence of coniine actions at fetal muscle-type nAChR is lacking. The present study compared (-)-coniine, (+)-coniine, and nicotine for the ability to inhibit fetal movement in a day 40 pregnant goat model and in TE-671 cells that express fetal muscle-type nAChR. Furthermore, alpha-conotoxins (CTx) EI and GI were used to antagonize the actions of (+)- and (-)-coniine in TE-671 cells. (-)-Coniine was more effective at eliciting electrical changes in TE-671 cells and inhibiting fetal movement than was (+)-coniine, suggesting stereoselectivity by the receptor. The pyridine alkaloid nicotine did not inhibit fetal movement in a day 40 pregnant goat model, suggesting agonist specificity for the inhibition of fetal movement. Low concentrations of both CTxs potentiated the TE-671 cell response and higher concentrations of CTx EI, and GI antagonized the actions of both coniine enantiomers demonstrating concentration-dependent coagonism and selective antagonism. These results provide pharmacological evidence that the piperidine alkaloid coniine is acting at fetal muscle-type nAChR in a concentration-dependent manner. PMID- 23086231 TI - C-type natriuretic peptide protects the retinal pigment epithelium against advanced glycation end product-induced barrier dysfunction. AB - In diabetic retinopathy, vision loss is usually secondary to macular edema, which is thought to depend on the functional integrity of the blood-retina barrier. The levels of advanced glycation end products in the vitreous correlate with the progression of diabetic retinopathy. Natriuretic peptides (NP) are expressed in the eye and their receptors are present in the retinal pigment epithelium (RPE). Here, we investigated the effect of glycated-albumin (Glyc-alb), an advanced glycation end product model, on RPE-barrier function and the ability of NP to suppress this response. Transepithelial electrical resistance (TEER) measurements were used to assess the barrier function of ARPE-19 and human fetal RPE (hfRPE) monolayers. The monolayers were treated with 0.1-100 MUg/ml Glyc-alb in the absence or presence of 1 pM to 100 nM apical atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), or C-type natriuretic peptide (CNP). Glyc-alb induced a significant reduction in TEER within 2 hours. This response was concentration-dependent (EC(50)= 2.3 MUg/ml) with a maximal reduction of 40 +/- 2% for ARPE-19 and 27 +/- 7% for hfRPE at 100 MUg/ml 6 hours post-treatment. One hour pretreatment with ANP, BNP, or CNP blocked the reduction in TEER induced by Glyc-alb (100 MUg/ml). The suppression of the Glyc-alb response by NP was dependent on the generation of cyclic guanosine monophosphate and exhibited a rank order of agonist potency consistent with the activation of natriuretic peptide-receptor-2 (NPR2) subtype (CNP >> BNP >= ANP). Our data demonstrate that Glyc-alb is effective in reducing RPE-barrier function, and this response is suppressed by NP. Moreover, these studies support the idea that NPR2 agonists can be potential candidates for treating retinal edema in diabetic patients. PMID- 23086234 TI - Hierarchical structures consisting of SiO2 nanorods and p-GaN microdomes for efficiently harvesting solar energy for InGaN quantum well photovoltaic cells. AB - We experimentally and theoretically demonstrated the hierarchical structure of SiO(2) nanorod arrays/p-GaN microdomes as a light harvesting scheme for InGaN based multiple quantum well solar cells. The combination of nano- and micro structures leads to increased internal multiple reflection and provides an intermediate refractive index between air and GaN. Cells with the hierarchical structure exhibit improved short-circuit current densities and fill factors, rendering a 1.47 fold efficiency enhancement as compared to planar cells. PMID- 23086232 TI - Effect of auxin physiological analogues on rapeseed (Brassica napus) cold hardening, seed yield and quality. AB - The effect of the auxin physiological analogues analogues 1-[2 chloroethoxycarbonylmethyl]-4-naphthalenesulfonic acid calcium salt (TA-12) and 1 [2-dimethylaminoethoxicarbonylmethyl]naphthalene chlormethylate (TA-14) TA-14 on different winter rapeseed cultivars were studied with regard to their autumnal growth, cold hardening, accumulation of the stress-protective metabolites proline and saccharide in plant organs: apical bud and root collum, winter survival and productivity formation. The test cultivars were the very early 'Libea' medium resistant to wintering, the medium-early 'Sunday' resistant to wintering, the medium-early 'Valesca' less than medium resistant to wintering, and the early 'Hornet' (hybrid) tolerant to stress growth conditions. During the period of cold hardening in natural field conditions, the test compounds TA-12 (2 mM) and TA-14 (4 mM), applied to different winter rapeseed cultivars at the 4th-5th leaf stage, stimulate accumulation proline and saccharides (sucrose and glucose) in the root collum and apical bud tissues, influence plants acclimation to cold, overwintering and productivity formation. Compounds TA-12 and especially TA-14 produced a stable effect on seed and crude fat yield in cvs. 'Hornet', 'Sunday' and 'Libea'. The genotypic peculiarities of a cultivar and the meteorological conditions of the plant vegetation period were the factors that mostly determined fatty acid content in seed oil. PMID- 23086235 TI - The anomalous Hall effect in epitaxial face-centered-cubic cobalt films. AB - The anomalous Hall effect in epitaxial face-centered-cubic Co film grown by molecular beam epitaxy on MgO(001) is investigated. The intrinsic anomalous Hall conductivity is separated from the scattering-related extrinsic contributions and determined to be 727 Omega(-1) cm(-1) and temperature independent. This result provides well defined experimental data for further theoretical justification. PMID- 23086237 TI - Subdiffraction imaging of centrosomes reveals higher-order organizational features of pericentriolar material. AB - The centrosome is the main microtubule organization centre of animal cells. It is composed of a centriole pair surrounded by pericentriolar material (PCM). Traditionally described as amorphous, the architecture of the PCM is not known, although its intricate mode of assembly alludes to the presence of a functional, hierarchical structure. Here we used subdiffraction imaging to reveal organizational features of the PCM. Interphase PCM components adopt a concentric toroidal distribution of discrete diameter around centrioles. Positional mapping of multiple non-overlapping epitopes revealed that pericentrin (PCNT) is an elongated molecule extending away from the centriole. We find that PCM components occupy separable spatial domains within mitotic PCM that are maintained in the absence of microtubule nucleation complexes and further implicate PCNT and CDK5RAP2 in the organization and assembly of PCM. Globally, this work highlights the role of higher-order PCM organization in the regulation of centrosome assembly and function. PMID- 23086238 TI - Elf5 inhibits the epithelial-mesenchymal transition in mammary gland development and breast cancer metastasis by transcriptionally repressing Snail2. AB - The epithelial-mesenchymal transition (EMT) is a complex process that occurs during organogenesis and in cancer metastasis. Despite recent progress, the molecular pathways connecting the physiological and pathological functions of EMT need to be better defined. Here we show that the transcription factor Elf5, a key regulator of mammary gland alveologenesis, controls EMT in both mammary gland development and metastasis. We uncovered this role for Elf5 through analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary tumour progression and clinical breast cancer samples. Furthermore, we demonstrate that Elf5 suppresses EMT by directly repressing the transcription of Snail2, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish Elf5 not only as a key cell lineage regulator during normal mammary gland development, but also as a suppressor of EMT and metastasis in breast cancer. PMID- 23086240 TI - 2012 American Pancreatic Association presidential address: Fostering translation. PMID- 23086241 TI - 2012 International Association of Pancreatology presidential address: A time for change. PMID- 23086239 TI - Subdiffraction-resolution fluorescence microscopy reveals a domain of the centrosome critical for pericentriolar material organization. AB - As the main microtubule-organizing centre in animal cells, the centrosome has a fundamental role in cell function. Surrounding the centrioles, the pericentriolar material (PCM) provides a dynamic platform for nucleating microtubules. Although the importance of the PCM is established, its amorphous electron-dense nature has made it refractory to structural investigation. By using SIM and STORM subdiffraction-resolution microscopies to visualize proteins critical for centrosome maturation, we demonstrate that the PCM is organized into two main structural domains: a layer juxtaposed to the centriole wall, and proteins extending farther away from the centriole organized in a matrix. Analysis of Pericentrin-like protein (PLP) reveals that its carboxy terminus is positioned at the centriole wall, it radiates outwards into the matrix and is organized in clusters having quasi-nine-fold symmetry. By RNA-mediated interference (RNAi), we show that PLP fibrils are required for interphase recruitment and proper mitotic assembly of the PCM matrix. PMID- 23086242 TI - American Pancreatic Association: the Vay Liang and Frisca Go Award for lifetime achievement. PMID- 23086243 TI - Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference. AB - Pancreatic and peripancreatic necrosis may result in significant morbidity and mortality in patients with acute pancreatitis. Many recommendations have been made for management of necrotizing pancreatitis, but no published guidelines have incorporated the many recent developments in minimally invasive techniques for necrosectomy. Hence, a multidisciplinary conference was convened to develop a consensus on interventions for necrotizing pancreatitis. Participants included most international experts from multiple disciplines. The evidence for efficacy of interventions was reviewed, presentations were given by experts, and a consensus was reached on each topic. In summary, intervention is primarily indicated for infected necrosis, less often for symptomatic sterile necrosis, and should ideally be delayed as long as possible, preferably 4 weeks or longer after the onset of disease, for better demarcation and liquefaction of the necrosis. Both the step-up approach using percutaneous drainage followed by minimally invasive video-assisted retroperitoneal debridement and per-oral endoscopic necrosectomy have been shown to have superior outcomes to traditional open necrosectomy with respect to short-term and long-term morbidity and are emerging as treatments of choice. Applicability of these techniques depends on the availability of specialized expertise and a multidisciplinary team dedicated to the management of severe acute pancreatitis and its complications. PMID- 23086244 TI - Prevention of severe acute pancreatitis with octreotide in obese patients: a prospective multi-center randomized controlled trial. AB - OBJECTIVES: To evaluate the efficacy of octreotide in preventing severe acute pancreatitis (SAP) in obese patients. METHODS: A prospective multi-center partly randomized control trial was conducted in patients with mild acute pancreatitis (AP). Nonobese patients received conventional management (nonobese-C, n = 82), whereas obese patients (body mass index >= 25 kg/m(2)) were randomized into 2 groups: obese-C (n = 79), who received conventional management, and obese-C+O (n = 82), who received conventional management plus intravenous infusion of octreotide, 50 MUg/h for 72 hours. RESULTS: The risk ratio and relative risk reduction in the development of SAP in the obese-C+O group were 0.27 (95% confidence interval, 0.10-0.69) and 0.73 (95% confidence interval, 0.31-0.90), respectively. The number of cases developing local complications in the obese-C+O group was significantly smaller than that in the obese-C group: 4.9% vs 19%, P = 0.006. The plasma level of somatostatin in the obese-C+O group was significantly higher than that in the obese-C group: 165.5 +/- 42.6 vs 112.1 +/- 24.86 pg/mL, P < 0.05. Supplement of octreotide also accompanied with reduction in plasma levels of tumor necrosis factor alpha and IL-6. CONCLUSIONS: Intravenous administration of octreotide (50 MUg/h) for 72 hours in the early stage of AP could prevent the development of SAP effectively in obese patients by raising plasma somatostatin to a normal level and reducing circulating cytokines. PMID- 23086245 TI - Smoking and the course of recurrent acute and chronic alcoholic pancreatitis: a dose-dependent relationship. AB - OBJECTIVES: Smoking has been shown to affect the course of alcoholic chronic pancreatitis (ACP). However, a dose-dependent relationship between ACP course and the amount of tobacco consumption has not been studied. METHODS: All consecutive smokers with ACP were included prospectively. Thresholds were defined at 10, 15, 20, and 30 pack-years (p.y.) to assess the relationship between tobacco intake and ACP complications. Statistical adjustment on alcohol intake was performed. RESULTS: One hundred eight patients (male, 86%) were included. The median tobacco intake was 30 p.y. (range, 3-90 p.y.) Pancreatic calcifications and duct abnormalities were observed in 70% and 73%, respectively. Pancreatic exocrine insufficiency and diabetes mellitus were observed in 36% and 30%, respectively. No differences in ACP outcome were seen at 10-p.y. threshold. At a 15-p.y. threshold, ACP diagnosis was made earlier (36 versus 46 years; P = 0.0036). At a 20-p.y. threshold, ACP occurred earlier (P = 0.0002), and the patients had more often calcifications (P = 0.05). Similar results were observed at the 30-p.y. threshold, but additionally pancreatic exocrine insufficiency occurred earlier (P = 0.04). CONCLUSION: Tobacco intake accelerates the course of ACP in a dose dependent fashion, apart from the amount of alcohol intake. A major threshold effect is seen in 20 p.y. PMID- 23086246 TI - Usefulness of brush cytology combined with pancreatic juice cytology in the diagnosis of pancreatic cancer: significance of pancreatic juice cytology after brushing. AB - OBJECTIVES: Pancreatic juice cytology (PJC) and brush cytology (BC) performed during endoscopic retrograde cholangiopancreatography could make a definite diagnosis of pancreatic cancer. The aim of this study was to improve the diagnostic value of cytology performed during endoscopic retrograde cholangiopancreatography in the diagnosis of pancreatic cancer. METHODS: The subjects comprised 127 patients with pancreatic ductal adenocarcinoma (PDAC) and 74 with benign pancreatic duct stricture mimicking PDAC. Final diagnosis was confirmed based on histopathology by resection or on more than 1 year of follow up. Pancreatic juice cytology was examined before and after BC. And the sensitivity of PJC combined with BC was examined. RESULTS: No malignancy was detected by PJC or by BC in patients with benign pancreatic duct strictures (specificity, 100%). In those with PDAC, the sensitivity of PJC before and after brushing was 21.3% and 40.9%, respectively; that of BC was 48.8%. Of 65 patients with PDAC, in whom neither PJC before brushing nor BC indicated malignancy, 16 were diagnosed with pancreatic cancer using PJC after brushing. Brush cytology combined with PJC after brushing significantly raised the diagnostic sensitivity for PDAC to 61.4%. CONCLUSIONS: Diagnosis of pancreatic cancer based on BC combined with PJC after brushing was more reliable than PJC before brushing or BC. PMID- 23086247 TI - The amendment of the Clinical Diagnostic Criteria in Japan (JPS2011) in response to the proposal of the International Consensus of Diagnostic Criteria (ICDC) for autoimmune pancreatitis. PMID- 23086250 TI - Examination of weight control practices in a non-clinical sample of college women. AB - The current study examined healthy weight control practices among a sample of college women enrolled at an urban university (N=715; age=19.87+/-1.16; 77.2% Caucasian; 13.4% African American, 7.2% Asian, 2.2% other races). Participants completed measures as part of an on-line study about health habits, behaviors, and attitudes. Items from the Three Factor Eating Questionnaire were selected and evaluated with exploratory factor analysis to create a healthy weight control practices scale. Results revealed that college women, regardless of weight status, used a comparable number (four of eight) of practices. Examination of racial differences between Caucasian and African American women revealed that normal weight African American women used significantly fewer strategies than Caucasian women. Of note, greater use of healthy weight control practices was associated with higher cognitive restraint, drive for thinness, minutes of physical activity, and more frequent use of compensatory strategies. Higher scores on measures of binge and disinhibited eating, body dissatisfaction, negative affect, and depressive symptoms were associated with greater use of healthy weight control practices by underweight/normal weight but not by overweight/obese college women. Results suggest that among a sample of college females, a combination of healthy and potentially unhealthy weight control practices occurs. Implications of the findings suggest the need for effective weight management and eating disorder prevention programs for this critical developmental life stage. Such programs should be designed to help students learn how to appropriately use healthy weight control practices, as motivations for use may vary by weight status. PMID- 23086251 TI - Academic examination stress increases disordered eating symptomatology in female university students. AB - BACKGROUND: It is well documented that stress and anxiety can affect eating behaviour and food intake in humans. The purpose of the current study was to explore the possible effect of academic examination stress on disordered eating attitudes, emotional eating, restraint eating, body image, anxiety levels and self-esteem in a group of female university students. The interrelationships of the above parameters were also examined. METHODS: Sixty Greek female university students, 18-25 years old, have been recruited and completed, on two separate occasions: a) during an examination stress period, and b) during a control period, the following questionnaires: the Eating Attitudes Test (EAT-26), the Dutch Eating Behavior Questionnaire (DEBQ), the State-Trait Anxiety Inventory (STAI), the Rosenberg Self- Esteem Scale, the Body Image Pictorial Instrument Scale (COLLINS) and a specially designed General Background Questionnaire. RESULTS: Subjects reported significantly higher levels of disordered eating attitudes (EAT-26, p=0.01), higher levels of anxiety (p=0.000) and lower levels of self-esteem (p=0.016) during the examination stress period compared to the control period. Disordered eating attitudes (EAT-26) were significantly positively correlated with emotional eating (p=0.04) and restrained eating (p=0.010) and negatively correlated with levels of self-esteem (p=0.05) and perceived desired body image (p=0.008) during the exam stress period. Finally, EAT-26 was significantly positively correlated with levels of anxiety in both study periods. CONCLUSION: Academic examination stress seems to increase disordered eating symptomatology in female university students and is associated with lower levels of self-esteem, an important finding which warrants further investigation. PMID- 23086252 TI - Clinical outcomes of a novel, family-centered partial hospitalization program for young patients with eating disorders. AB - AIM: Eating disorders (ED) in children and younger adolescents are becoming more evident, but there is a small evidence base for their management in this population. We hypothesized that a new family-centered partial hospital program for young patients would be effective in promoting weight gain, as well as improvement in psychiatric symptoms. METHODS: A retrospective chart review of 56 patients treated in the program between August 2008 and November 2009 was performed. Historical data, anthropometric variables and scores from psychological instruments [Children's Eating Attitudes Test (ChEAT), Children's Depression Inventory (CDI), and Revised Children's Manifest Anxiety Scale (RCMAS)] were collected on admission and at discharge. After exclusion, 30 patients were available for statistical analysis, using paired t-tests. The primary outcome variables were improvement in weight and change in total ChEAT score. Secondary outcomes included improvements in the CDI and RCMAS scores. Multivariate analysis included linear regression models that controlled for patient-specific fixed effects. RESULTS: The cohort was 87% female with a mean age of 12.8+/-2 years; 60% were diagnosed with ED not otherwise specified. Two thirds had a co-morbid depressive and/or anxiety disorder. Change in weight was significant (p<0.0001), as were improvements on total ChEAT (p<0.0001), CDI (p=0.0002), and RCMAS (p<0.0001) scores. No historical factors were correlated with improvement, nor was use of psychotropic medications. Length of stay in weeks significantly predicted greater weight gain (p=0.004, R2=0.26). CONCLUSIONS: Patients treated in a family-centered partial hospital program had significant improvements in weight and psychological parameters. This approach holds significant promise for the management of young ED patients. PMID- 23086253 TI - Perceptions of underweight images: are women with anorexia nervosa perceived as attractive and healthy? AB - The current study examined the impact of receiving information about a woman's eating disorder status on perceptions of the woman's health and attractiveness. A total of 99 females and 84 males viewed a photo of a model who had disclosed her diagnosis of anorexia nervosa. Participants were randomly divided into three groups: model (M) group (those who were informed that the photo showed a model), eating disorders (ED) group (those who were informed that the photo showed a woman with an eating disorder), and no description control (C) group. Male and female participants in the ED group rated the woman in the photo as less healthy than did participants in the M and C groups. However, there were no differences between groups for ratings of attractiveness or the participants' desire to achieve a similar look (for females). Additionally, male participants rated the photo as less attractive than female participants had predicted. Finally, internalization of the thin ideal was a significant predictor of ratings of health and attractiveness of the woman in the photo. PMID- 23086254 TI - Lifetime and recent DSM and ICD psychiatric comorbidity of inpatients engaging in different eating disorder behaviours. AB - OBJECTIVE: Previous studies investigating psychiatric comorbidity in eating disorder (ED) patients compared groups according to ED diagnoses. The current paper compared groups according to ED behaviours: self-induced vomiting, objective binge eating, excessive exercising, and to body mass index (BMI, kg/m(2)) for selected psychiatric comorbidity using two systems: Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) and International Classification of Diseases - Tenth Revision (ICD-10) diagnoses. METHOD: Two hundred and twenty-six patients admitted for treatment in a specialised Eating Disorders Unit completed the Composite International Diagnostic Interview (CIDI). Lifetime and recent (12 months) psychiatric diagnoses were produced according to DSM-IV and ICD-10. Associations between presence of ED behaviours or BMI and psychiatric comorbidity were investigated. RESULTS: Eighty-eight percent of patients had a lifetime history (72% recent history) of at least one comorbid diagnosis (regardless of diagnostic system). Agreement between the systems was high for mood (affective) disorders and moderate for anxiety/somatoform disorders. Significantly more patients who vomit had lifetime and recent mood (affective) disorders (DSM-IV and ICD-10). Significantly more 'vomiters' had recent anxiety disorders (DSM-IV) and neurotic, stress-related and somatoform disorders (ICD-10) including post-traumatic stress disorder (PTSD; DSM-IV and ICD-10). More patients with BMI >17.5 kg/m(2) had lifetime and recent mood (affective) disorders and lifetime PTSD (DSM-IV and ICD 10). The results for 'excessive exercisers' varied and appeared inconsistent. There were no differences in any disorders for objective binge eaters. DISCUSSION: Patients who induce vomiting have more psychiatric comorbidity than 'non-vomiters', both lifetime and recent, and may benefit from diagnostic recognition as a separate group, for example 'vomiting' or 'purging' ED, who can then receive specialist treatment for their comorbidity and associated problems. PMID- 23086255 TI - Tumour necrosis factor alpha and oxidative stress as maintaining factors in the evolution of anorexia nervosa. AB - OBJECTIVE: Aim of the study was to evaluate tumour necrosis factor alpha (TNF alpha) axis and oxidative status in patients with anorexia nervosa (AN) seeking a possible correlation with both nutritional status and evolution of the disease. SUBJECTS AND METHODS: Thirty-nine consecutive women with AN and an age-matched healthy control group were studied. Patients were 26+/-9 yr, with a body mass index (BMI) of 13.9+/-2 kg/m(2). TNF-alpha, its receptors TNF-R55 and TNF-R75, and oxidative status markers (selenium, ascorbic/ dehydroascorbic acid, retinol, alpha-tocopherol, selenium-dependent gluthatione peroxidase, reduced/oxidated gluthatione) were measured. A correlation with both nutritional indexes (body weight, BMI, albumin, prealbumin, transferrin, lymphocyte count) and disease duration was investigated. Pearson's correlation and unpaired Student's t-test were used to compare patients and controls. RESULTS: TNF-alpha and oxidative status markers were significantly higher in patients than controls and TNF-alpha was directly related to dehydroascorbic acid (p<0.05). Both TNF-R55 and TNF-R75 were higher in patients with duration of disease longer than one year as compared to controls and patients with shorter duration. Receptors inversely correlated with BMI (p<0.05 and p<0.01) and directly with disease duration (p<0.05). Inverse correlation between disease duration and BMI was present (p<0.01). CONCLUSIONS: The study showed activation of TNF-alpha axis and oxidative stress in AN patients, as well as correlation between the two systems. Due to the correlation between TNF receptors and both BMI and disease duration, a possible role of pro inflammatory cytokines in the evolution of the eating disorder is suggested. PMID- 23086256 TI - Gender differences in binge eating and behavioral correlates among college students. AB - PURPOSE: The purpose of this study was to investigate gender differences in binge eating and associated behavioral correlates in college students. METHODS: A webbased survey was conducted with 2073 students (mean age 19.8 yr; range 18-23 yr). Multiple logistic regression was used to calculate odds ratios and 95% confidence intervals for the factors associated with binge eating. RESULTS: Twenty-nine percent of students reported recent bingeing. Factors associated with binge eating included being female, having a higher body mass index, current tobacco use, and exercising to lose weight. Women were more likely to binge eat (73.8%; chi(2)=32.3; p<=0.001), report loss of control (45%; chi(2)=16.3; p<=0.001), self induced vomiting (20.7%; chi(2)=15.9; p<=0.001), and laxative use (6.7%; chi(2)=8.93; p<=0.001). CONCLUSIONS: Results generated from this study suggest that gender-disparate behaviors are potential targets for future tailored interventions. PMID- 23086257 TI - Classical Stroop effect in bulimia nervosa. AB - Bulimia nervosa (BN) is a distressing condition. Its pathogenesis is not fully understood. Neurocognitive functioning, and particularly inhibitory control, is a potential biomarker that may improve our understanding of BN. A few small-scale studies have used the classical Stroop Colour Word Test (SCWT) in BN with contradictory findings. We examined SCWT performance in a large sample of people with BN (N=72), eating disorder not otherwise specified--bulimic type (N=43) and healthy controls (N=50). The results found no difference between groups on Stroop interference effect. These findings question the utility of the classical SCWT as an assessment tool in examining executive functioning in BN. PMID- 23086258 TI - Anorexia nervosa in a Thai adolescent. AB - In Thailand, anorexia nervosa (AN) has rarely been reported. We report a 13- year old female adolescent with AN restrictive type, the first from Thailand to meet all Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition - Text Revision (DSM IVTR) criteria for AN. The emergence of a patient with AN in Khon Kaen, a province from the region with the lowest gross domestic product, accentuates the existence of eating disorders in adolescents beyond Thailand capital. Future studies considering sociocultural issues on normal eating attitudes, eating behaviors and body image in Thailand should be conducted. PMID- 23086259 TI - Improving electronic transport of zigzag graphene nanoribbons by ordered doping of B or N atoms. AB - Using an ab initio method, we explored electronic structures and transport properties of zigzag graphene nanoribbons (ZGNRs) with ordered doping of B or N atoms. We find B or N atoms doping can increase significantly the conductance of the ZGNRs with an even number of zigzag chains due to additional conducting channels being induced and the breakdown of parity limitation. The higher the doping concentration, the larger the current amplification factor obtained. For the nanojunctions with one row B (or N) atoms, the current amplification factor can be larger when the doping position is near to the center, while for the junction with two rows, the trend is subtle due to the interactions between the two rows of B (or N) atoms. Negative differential resistive phenomena are found for the case of B doping at low concentrations and the case for N doping. The conductance of the ZGNR with odd numbers of zigzag chains can also be increased by doping of B or N atoms. More interestingly, the B or N doping can almost completely remove the even-odd effect on electronic transport of the ZGNRs. Our studies provide avenues to drastically improve the electronic transport of ZGNRs, helpful for graphene applications. PMID- 23086261 TI - Dynamic real-time magnetic resonance imaging for the analysis of voice physiology. AB - PURPOSE OF REVIEW: For a number of years, it has been possible to use dynamic real-time magnetic resonance imaging (MRI) to analyse the dynamic processes which occur in the human body. In the fields of laryngology and phoniatrics, such dynamic processes are found not only in swallowing, but also in voice and speech production. This article aims to present an overview of how the use of MRI might add to our current understanding of the dynamic processes involved in voice production. RECENT FINDINGS: It is shown that up to now the analysis of vocal fold oscillations has been limited by MRI's relatively low sampling rate of up to 50 Hz. Nevertheless, more detailed analysis does seem possible with regard to the modulation of the power source and vocal tract. SUMMARY: Dynamic real-time MRI offers a great opportunity for the analysis of voice production in all stages of the voice production system. PMID- 23086260 TI - Identification and characterization of superoxide dismutase in Phytophthora cinnamomi. AB - Superoxide dismutase (SOD) activities of the oomycete Phytophthora cinnamomi were examined. Five polypeptides with manganese superoxide dismutase (MnSOD) activity were found in mycelium growing in liquid culture with relative molecular weights ranging from approximately 25 to 100 kDa. Comparison with characterized avocado SODs showed no evidence for the presence of either iron or copper/zinc SODs in P. cinnamomi. The level of activity of the MnSOD polypeptides decreased in the presence of avocado root or cell wall components. Growth of P. cinnamomi, measured as dry weight, increased when the mycelium was grown in the presence of superoxide anion (O(2) (-)), which was added exogenously. Our results suggest that the metabolism of O(2) (-) has an important role in the development of P. cinnamomi. PMID- 23086262 TI - Multidetector computed tomography in nonmalignant laryngeal disease. AB - PURPOSE OF REVIEW: Multidetector computed tomography (MDCT) is the examination of choice for laryngeal imaging in benign and malignant lesions. This review gives an overview of the MDCT scanning technique and discusses the advantages and disadvantages in investigation of benign lesions of the larynx. RECENT FINDINGS: MDCT is not the primary diagnostic method for benign lesions on the vocal folds. However, CT is indispensable for the diagnostic investigation of immobility of the vocal fold, for laryngoceles, and for laryngeal trauma, and may allow the exact delineation of extension and nature of benign laryngeal disease. The improved spatial resolution with consecutive high-quality two-dimensional (2D) and three-dimensional (3D) reconstructions using thin-slice MDCT allows a better detection of laryngeal anatomic structures and benign pathologies. SUMMARY: The investigation of choice in diagnosing the cause of hoarseness is laryngoscopy and/or laryngostroboscopy, respectively. Nevertheless, thin-slice MDCT with multiplanar 2D and 3D volume-rendered reconstructions is essential for exact anatomic definition and extension and diagnosis of subtle benign laryngeal diseases. PMID- 23086263 TI - Two aircraft carriers' perspectives: a comparative of control measures in shipboard H1N1 outbreaks. AB - BACKGROUND: The USS George Washington (GW) and the USS Ronald Reagan (RR), 2 US Navy aircraft carriers, experienced almost simultaneous outbreaks of novel H1N1 influenza A in the summer of 2009. We compared the respective epidemic control measures taken and subsequent lessons learned. METHODS: Data were collated from both outbreaks to assess various elements including attack rate, isolation/quarantine protocols, and treatment methods. The respective duration of each outbreak was compared with survival curve analysis. The number of personnel affected in each outbreak was compared using chi2 analysis. RESULTS: Differences were found in the protocols used on the 2 ships. The GW treated about two-thirds of the patients with oseltamivir through day 14 and quarantined all patients meeting case definition throughout the outbreak. Face masks were used throughout. The RR used oseltamivir and quarantined many fewer patients (through days 5 and 3, respectively). No face masks were used after day 5. The outbreaks were similar in duration (GW = 25 days, RR = 27 days, P = .38), but the RR had significantly more cases (n = 253 vs 142, P < .0001). A portion of each group had samples that were confirmed H1N1 by polymerase chain reaction. CONCLUSIONS: GW's protocol, including aggressive oseltamivir treatment of two-thirds of the cases and quarantine throughout the duration decreased the overall number of personnel affected, likely reducing the overall control reproduction number. Both outbreaks were similar in duration. Even though the GW expended significantly more resources than the RR, if the 2009 pandemic H1N1 strain had been as clinically severe as the 1918 pandemic, a more stringent treatment protocol may have been the only way to prevent significant operational impact. PMID- 23086264 TI - Complete mitochondrial genome sequence of Catla catla and its phylogenetic consideration. AB - Complete nucleotide sequence of mitochondrial genome (mitogenome) of the Catla catla (Ostariophysi: Cypriniformes: Cyprinidae) was determined in the present study. Its length is 16,594 bp and contains 13 protein coding genes, 22 transfer RNAs, two ribosomal RNAs and one non-coding control region. Most of the genes were encoded on the H-strand, while the ND6 and eight tRNA (Gln, Ala, Asn, Cys, Tyr, Ser (UCN), Glu and Pro) genes were encoded on the L-strand. The reading frames of two pair of genes overlapped: ATPase 8 with 6 and ND4L with ND4 by seven nucleotides each. The main non-coding region was 929 bp, with three conserved sequence blocks (CSB-I, CSB-II, and CSB-III) and an unusual simple sequence repeat, (TA)(7). Phylogenetic analyses based on complete mitochondrial genome sequences were in favor of the traditional taxonomy of family Cyprinidae. In conclusion present mitogenome of Catla catla adds more information to our understanding of diversity and evolution of mitogenome in fishes. PMID- 23086265 TI - Genetic diversity study of some medicinal plant accessions belong to Apiaceae family based on seed storage proteins patterns. AB - Cumin (Cuminum cyminum L.), Fennel (Foeniculum vulgare L.) and Longleaf (Falcaria vulgaris Bernh) that all belong to Apiaceae family as medicinal plants are very important in many countries. Study of genetic diversity for medicinal plant is important for researches in future. One of the methods to evaluate plant genetic diversity and classification of them is the electrophoresis of seed storage proteins. This research was conducted in order to evaluate seed protein variability in different Iranian Cumin, Fennel and Longleaf accessions and grouping them based on these proteins as a biochemical marker. For this purpose, the samples were first powdered in liquid nitrogen and seed protein was extracted with extraction buffer. Then total soluble proteins were resolved on 12.5 % sodium dodecyl sulphate polyacrylamide gel electrophoresis gels. The electrophoretic protein pattern showed 38 bands that were low polymorphism among the accessions. The result of cluster analysis showed that the accessions were classified in three groups (all 29 Cumin accessions in the first group, three Fennel ecotypes in second group and three Longleaf accessions in the last one). PMID- 23086266 TI - Allelic variation in ovine fatty acid-binding protein (FABP4) gene. AB - The fatty acid-binding protein 4 (FABP4) plays a role in lipid metabolism and has been implicated in intra-cellular lipid transport. While FABP4 variation has been reported in some species, variation in the coding sequence has not been reported in sheep. In this study two regions of ovine FABP4 were analysed using PCR-SSCP and sequencing. Five different PCR-SSCP patterns, representing five specific sequences (A ( 1 )-E ( 1 )) were detected in region 1 (exon 2-intron 2) with sequence analysis revealing three nucleotide substitutions and one deletion in the intron. In region 2 (exon 3-intron 3), four different PCR-SSCP patterns (A ( 2 )-D ( 2 )) were observed and four nucleotide substitutions were revealed. In total, fourteen haplotypes through both regions were defined. There was a difference (P < 0.001) in allele frequencies between two selection lines of Coopworth sheep that have been bred over many generations to be lean or fat. In region 1, A ( 1 ) and B ( 1 ) were most common (at a frequency of 50 and 30 % respectively) in the fat line, whereas these two variants were absent or rare in the lean line in which C ( 1 ) predominated (89 %). In region 2, C ( 2 ) was the most common variant (59 %) in the lean line but was absent in the fat line, whereas B ( 2 ) was predominant (83 %) in the fat line but was rare (3 %) in the lean line. These results indicate that ovine FABP4 is polymorphic and suggest further analysis is required to see if the variation detected affects fat deposition in sheep. PMID- 23086267 TI - Euphorbia mauritanica and Kedrostis hirtella extracts can induce anti proliferative activities in lung cancer cells. AB - Cancer is a public health problem in the world accounting for most of the deaths. Currently, common treatment of cancer such as chemotherapy works by killing fast growing cancer cells. Unfortunately, chemotherapy cannot tell the difference between cancer cells and fast-growing healthy cells, including red and white blood cells. As a result, one of the most serious potential side effects of some types of chemotherapy is a low white blood cell count that makes it unreliable (Parkin et al. [34]; Pauk et al. [3]). Even though intense research has been going on in recent years, successful therapeutic targets against this disease have been elusive. In this study, we evaluate the anti-proliferative activity of Euphorbia mauritanica and Kedrostis hirtella in lung cancer. In our assessment it was observed that E. mauritanica and K. hirtella were able to induce cell death at 5 MUg/ml in A549 cells over 22 h and at 10 MUg/ml over 24 h in the Lqr1 cell line. Molecular analysis of DNA fragmentation and Annexin V were used to examine the type of cell death induced by E. mauritanica and K. hirtella extracts. These results showed an increase in necrotic and apoptotic characteristics with both nuclear DNA fragmentation and smear. Therefore, these results suggest that E. mauritanica and K. hirtella may play a role in inducing cell death in lung cancer cells. However, further studies need to be conducted to ascertain these results. PMID- 23086268 TI - Association of glutathione S-transferase omega gene polymorphisms with progression of head and neck cancer. AB - This study investigated the influence of glutathione S-transferase omega 1 (GSTO1) and GSTO2 gene polymorphisms on susceptibility and aggressiveness of head and neck squamous cell carcinoma (HNSCC). A case-control study consisting of 300 HNSCC cases and 299 age and sex- matched normal control was performed. Genotyping of GSTO1*A140D and GSTO2*N142D polymorphisms was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Our results revealed that the frequencies of GSTO1 and GSTO2 genotypes were not significantly different between HNSCC cases and controls. No significant differences were found in smoking or drinking status between cases and controls. However, HNSCC individuals with the GSTO1*D140 varient were significantly associated with nodal metastasis (OR = 0.53, 95 %CI = 0.31-0.91, P = 0.020) and advanced pathological stage (OR = 0.33,95 %CI = 0.15-0.70, P = 0.032), while no significant association was observed between GSTO2 genotype and clinicopathological features. Therefore, our findings suggest that the GSTO1*D140 variant genotype in individuals might play a protective role against the aggressiveness of HNSCC. PMID- 23086269 TI - Genome-wide transcriptome profiling of ROS scavenging and signal transduction pathways in rice (Oryza sativa L.) in response to different types of ionizing radiation. AB - Ionizing radiation directly and indirectly affects gene expression within the plant genome. To access the antioxidant response of rice to different types of ionizing radiation, rice seeds were exposed to gamma-ray, cosmic-ray and ion beam radiation. Exposure to ionizing radiation dramatically decreased the shoot length in all plants but not the root length compared with a non-irradiated plant. Electron spin resonance, confirmed that the number of free radicals in cell was greatly increased by different types of ionizing radiation. The measurement of the MDA, chlorophyll, carotenoids contents and activity of antioxidant enzymes revealed that gamma-ray and cosmic-ray, but not ion beam, ionization deceased chlorophyll and carotenoids contents, while all three ionization treatments increased the activities of peroxidase, ascorbate peroxidase, and superoxide dismutase compared with the non-irradiated plants. Microarray analysis using Affymetrix GeneChip was used to establish the gene transcript profiles of rice genes regarding ROS scavenging and signal transduction pathways after ionization treatment. Many of the rice genes involved in ROS scavenging and signal transduction pathways showed induction or repression that had increased more than twofold after ionization treatment. In particular, genes associated with electron transport, such as NADPH oxidase-like and alternative oxidase, were often down regulated by more than twofold in response to the ionization treatments. In our transcriptomic profile analysis, we confirmed that the expression of rice genes associated with ROS scavenging and signal transduction pathways was induced or repressed to different degrees by the different types of ionizing radiations, as in other environmental stresses. PMID- 23086270 TI - Different methylation patterns in BWS/SRS cases clarified by MS-MLPA. AB - Molecular abnormalities in the 11p15.5 imprinted gene cluster lead to two different growth diseases: Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). They are mainly caused by epigenetic alterations in one of the two imprinting 11p15 control regions (ICR1 and ICR2). These CpG-rich regions are differentially methylated on the maternally and paternally derived chromosomes. We report four different methylation patterns along the BWS/SRS critical region, clarified by methylation-specific multiplex ligation-dependent probe amplification. The mathematical processing of the data provides information about alterations in the methylation status: from hypo- to almost complete demethylation of KvDMR, hypo- and hypermethylation of H19DMR and combined results from both regions provide information on paternal uniparental disomy (patUPD). The study concerns two BWS cases with KvDMR hypomethylation and almost complete loss of methylation, respectively; two patUPD11p15 cases with H19DMR hypermethylation/KvDMR hypomethylation, and one SRS case with H19DMR demethylation. In some cases KvDMR hypomethylation in patUPD11p15 can be difficult to assess, which requires combination with STR analysis or alternative method. The STR analysis provides also information on complete or segmental coverage and iso- or heterodisomy. Following this systematic approach, the precise diagnosis can be clarified in a few days and different methylation patterns could be detected. PMID- 23086272 TI - Association between 9p21.3 genomic markers and coronary artery disease in East Asians: a meta-analysis involving 9,813 cases and 10,710 controls. AB - Recently, genome-wide association studies on coronary artery disease (CAD) identified a series of associated single-nucleotide polymorphisms (SNPs) in an intergenic region of chromosome 9p21.3, near the CDKN2A and CDKN2B genes. We investigated the association of this locus with CAD in 12 case-control studies of East Asians and undertook a meta-analysis for effect size, heterogeneity, publication bias, and strength of evidence. English and Chinese language articles were tested for 9p21.3 SNPs with coronary heart/artery disease or myocardial infarction as primary outcomes. Included articles also provided race, numbers of participants, and data to compute an odds ratio (OR). Articles were excluded if reporting other outcomes (e.g., stroke). Thirty-five articles were initially identified and 12 were included. Independent extraction was performed by two reviewers and consensus was reached. SNP rs1333049, rs2383206 and rs10757278 representing the 9p21.3 locus, were genotyped in 12 case-control studies involving a total of 9,813 patients and 10,710 controls. For rs1333049 (8 data sets), using a fixed-effects model, the summary OR was 1.29 (95 % CI, 1.23-1.36, P = 0.001). For rs2383206 (6 data sets), using a fixed-effects model, the summary OR was 1.24 (95 % CI, 1.18-1.31, P = 0.001). For rs10757278 (6 data sets), using a random-effects model, the summary OR was 1.34 (95 % CI, 1.21-1.50, P = 0.001). In addition, we defined the haploblock structure of SNPs within the region of 9p21.3 in China population in one study. This broad replication provides unprecedented evidence for association between genetic variants at chromosome 9p21.3 and risk of CAD in East Asians. PMID- 23086271 TI - The significance of epigenetic alterations in lung carcinogenesis. AB - Lung cancer is recognized as a leading cause of cancer-related death worldwide and its frequency is still increasing. The prognosis in lung cancer is poor and limited by the difficulties of diagnosis at early stage of disease, when it is amenable to surgery treatment. Therefore, the advance in identification of lung cancer genetic and epigenetic markers with diagnostic and/or prognostic values becomes an important tool for future molecular oncology and personalized therapy. As in case of other tumors, aberrant epigenetic landscape has been documented also in lung cancer, both at early and late stage of carcinogenesis. Hypermethylation of specific genes, mainly tumor suppressor genes, as well as hypomethylation of oncogenes and retrotransposons, associated with histopathological subtypes of lung cancer, has been found. Epigenetic aberrations of histone proteins and, especially, the lower global levels of histone modifications have been associated with poorer clinical outcome in lung cancer. The recently discovered role of epigenetic modifications of microRNA expression in tumors has been also proven in lung carcinogenesis. The identified epigenetic events in lung cancer contribute to its specific epigenotype and correlated phenotypic features. So far, some of them have been suggested to be cancer biomarkers for early detection, disease monitoring, prognosis, and risk assessment. As epigenetic aberrations are reversible, their correction has emerged as a promising therapeutic target. PMID- 23086274 TI - Expression of PiABP19, Picdc2 and PiSERK3 during induction of somatic embryogenesis in leaflets of Prunus incisa (Thunb.). AB - Somatic embryogenesis is a useful tool of plant breeding. In this context, a procedure for inducing somatic embryogenesis in Prunus incisa leaf explants had been previously developed. The original in vitro protocol relies on picloram treatments and exposure to darkness as inductive conditions, the best frequency of embryogenesis being obtained on the second leaf (F(2)) exposed to 4 MUM picloram during 30 days. The morphological and biochemical changes observed during somatic embryogenesis occur in response to alterations in gene expression regulation patterns. A molecular study was conducted in order to provide deeper insight into the fundamental biological factors involved in the induction of this process using a gene candidate strategy and semi-quantitative reverse transcription polymerase chain reaction analysis. So far, no sequence data related to somatic embryogenesis has been available in cherry. In the present study, we cloned and sequenced cDNA fragments of putative genes encoding auxin binding protein, cell cycle regulator and somatic embryogenesis receptor kinase. Time-course differential transcript accumulations were observed for all investigated genes in leaves or derived callus tissues during the observation period (first month of culture). Their possible involvement in the sequential steps of the embryogenic pathway (dedifferentiation, cell proliferation, differentiation through somatic embryogenesis) is presented and discussed. PMID- 23086273 TI - Determination of GABA(Aalpha1) and GABA (B1) receptor subunits expression in tissues of gilts during the late gestation. AB - GABA(Aalpha1) and GABA(B1) receptor subunits are responsible for most behavioral, physiological and pharmacological effects of GABA receptors. We investigated the expression of GABA(Aalpha1) and GABA(B1) receptor subunits in different tissues of gilts during late pregnancy in hot summer. The mRNA abundance of GABA(Aalpha1) receptor subunit in different tissues of gilts at d 90 and d 110 of gestation was as follows: d 90: brain > lung > liver > ovary > spleen > kidney > heart; d 110: brain > lung > spleen > liver > ovary > kidney > heart. And, the mRNA abundance of GABA(B1) receptor subunit was as follows: d 90: spleen > lung > brain > kidney > ovary > liver > heart; d 110: spleen > lung > kidney > brain > ovary > liver > heart. The results in this trial indicated that the GABA(Aalpha1) receptor subunit was abundantly expressed in brain, while GABA(B1) receptor subunit was abundant in spleen and lung of gilts during late gestation. There were no gestation stage-dependent effects on GABA(Aalpha1) and GABA(B1) receptor subunits expression in all tissues. PMID- 23086276 TI - Development and multiplex PCR amplification of microsatellite markers in the commercial clam Venerupis rhomboides (Mollusca: Bivalvia). AB - Venerupis rhomboides is a commercial clam whose production could be enhanced through effective management of natural and hatchery stocks. This study provides the first panel of microsatellite markers for the exploitation of this species according to genetic criteria. A total of 22 polymorphic microsatellite loci were isolated and characterized from two genomic libraries enriched for different motifs. The number of alleles per locus ranged from 2 to 14 in a sample of 20 clams from Spain, and the observed and expected heterozygosity from 0 to 0.95 and 0.05-0.901, respectively. Sixteen loci were in agreement with Hardy-Weinberg equilibrium after sequential Bonferroni correction and linkage disequilibrium between loci pairs was not detected. To reduce the cost of the genotyping process, tri- and pentaplex PCRs, amplifying a total of 13 microsatellites loci were optimized. The microsatellites developed here represent the first nuclear markers described in V. rhomboides and will be useful tools for genetic studies involving assessment of genetic variation and population structure of natural and cultivated populations, assignment testing, construction of genetic linkage maps and dissection of production traits. PMID- 23086275 TI - High FLT3 expression and IL10 (G1082A) polymorphism in poor overall survival in calla acute lymphoblastic leukemia. AB - Patients with acute lymphoblastic leukemia presenting the immunophenotypic marker CD10+ (calla), usually has treatment profile good. The FLT3 molecular marker is listed as a prognostic factor, an important leukaemogenic marker in acute leukemias, also the polymorphism (G1082A) of the IL10 interleukin can to present pleiotropic effects in many diseases and could is associated to development of ALL. However, the FLT3 expression is variability among patients with calla-ALL. The aim of this study was to determine the FLT3 expression, to associate with the genotypes and allelic of G1082A (IL10) in 50 patients with calla-ALL and assess the overall survival at 98 months follow-up. The expression was assessed by quantitative real time PCR (RT-PCR), the G1082A polymorphism was identified by allele-specific PCR and for immunophenotypic classification was used specific markers of B lineage-calla. We observed that patients who died showed higher FLT3 expression (p = 0.005), worse survival (p = 0.0137) and the IL10G allele may favor the survival, because the IL10 GG and IL10 GA genotypes showed a low FLT3 expression (p < 0.05). PMID- 23086277 TI - Hypoglycemic dipeptide cyclo (His-Pro) significantly altered plasma proteome in streptozocin-induced diabetic rats and genetically-diabetic (ob/ob) mice. AB - The proteins in plasma perform many important functions in the body, and the protein profiles of the plasma vary under different physiological and pathological conditions. In an attempt to identify novel marker proteins for diabetes prognosis, we examined the effect of hypoglycemic dipeptide cyclo (His Pro) (CHP) on the differential regulation of plasma proteins in streptozocin induced diabetic rats and genetically-diabetic (ob/ob) mice. The orally administrated CHP produced an excellent hypoglycemic effect in both animal models, lowering the average plasma glucose level by over 50 %. In the 2-DE analysis of the plasma, a total of 23 spots among 500 visualized spots were found to be differentially regulated, and they were identified by MALDI/TOF mass spectrometry. These proteins include the down-regulation of Apo E and the up regulation of FGA, Apo A-I, Apo A-IV, and A1M in STZ-induced diabetic rats. Moreover, CHP significantly reduced the plasma protein levels of FGB, FGC, F12, C1QTNF5, and SPA3K, as well as increased the abundance of A1M, A2M, Apo E, and TTR in genetically-diabetic mice. In conclusion, alteration in the regulation of these proteins indicates that this treatment may be successful in overcoming the diabetic state. The present proteomic data can serve as the basis for the development of specific evidence-based interventions allowing for the prevention and treatment of diabetes. PMID- 23086278 TI - Microsatellite-based evidences of genetic bottlenecks in the cryptic species "Andrographis paniculata Nees": a potential anticancer agent. AB - Andrographis paniculata (AP) is a medicinal plant species introduced into Malaysia. To address the genetic structure and evolutionary connectedness of the Malaysian AP with the Indian AP, a DNA sequence analysis was conducted based on 24 microsatellite markers. Out of the 24 primer sets, seven novel microsatellite primers were designed and amplified intra-specifically according to the available Indian AP sequences at the National Centre for Biotechnology Information (NCBI), where 17 of them were amplified using the cross-species strategy by employing the primers belonging to Acanthus ilicifolius Linn (Acanthaceae) and Lumnitzera racemosa Wild (Combretaceae). The primers were then applied on the Malaysian AP accessions. Sixteen of the new microsatellite loci were amplified successfully. Analysis of these microsatellite sequences, revealed some significant differences between the Indian and Malaysian AP accessions in terms of the size and type of the repeat motifs. These findings depicted the cryptic feature of this species. Despite identifying several heterozygous alleles no polymorphism was observed in the detected loci of the selected accessions. This situation was in concordance with the presence of "fixed heterozygosity" phenomenon in the mentioned loci. Accordingly, this was fully consistent with the occurrence of the genetic bottleneck and founder effect within Malaysian AP population. Apart from the amplification of new microsatellites in this species, our observations could be in agreement with the risk of genetic depletion and consequently extinction of this precious herb in Malaysia. This issue should be taken into consideration in the future studies. PMID- 23086279 TI - Genome-wide identification and analysis of late embryogenesis abundant (LEA) genes in Prunus mume. AB - Late embryogenesis abundant (LEA) proteins play important roles in plant desiccation tolerance. In this study, 30 LEA genes were identified from Chinese plum (Prunus mume) through genome-wide analysis. The PmLEA genes are distributed on all Chinese plum chromosomes except chromosome 3. Twelve (40 %) and five PmLEA genes are arranged in tandem and segmental duplications, respectively. The PmLEA genes could be divided into eight groups (LEA_1, LEA_2, LEA_3, LEA_4, LEA_5, PvLEA18, dehydrin and seed maturation protein). Ten gene conversion events were observed and most of them (70 %) were identified in dehydrin group. Most PmLEA genes were highly expressed in flower (22/30) and up-regulated by ABA treatment (19/30). PMID- 23086281 TI - Siderophore-mediated iron uptake promotes yeast-bacterial symbiosis. AB - In the present study, siderophore produced by the marine yeast Aureobasidium pullulans was characterized as hydroxamate by chemical and bioassays. The hydroxamate assignment was supported by the appearance of peaks at 1,647.21 1,625.99 cm(-1) and at 1,435.04 cm(-1) in the infrared spectrum. The purified siderophore exhibited specific growth-promoting activity under iron-limited conditions for siderophore auxotrophic probiotic bacteria. Cross-utilization of siderophore indicates a symbiotic relationship between the yeast A. pullulans and the selected probiotic bacterial strains. Statistical optimization of medium components for improved siderophore production in A. pullulans was depicted by response surface methodology. The shift in UV-Vis spectroscopy indicates the photoreactive property and subsequent oxidative cleavage of purified siderophore on exposure to sunlight. PMID- 23086280 TI - Comparison of splenic transcriptome activity of two rainbow trout strains differing in robustness under regional aquaculture conditions. AB - The spleen plays a crucial role in innate and adaptive immunity in bony fish. Consequently, this organ is well suited to assess the immune competence of an organism and hence provides useful information for comparison and classification of production traits of food fish, such as robustness and susceptibility. To gain information about differences in the basal splenic transcriptome activity, healthy rainbow trout of the commercially important strain TCO and the local selection strain BORN have been compared in a holistic expression analysis using the GRASP 16K cDNA microarray. Nearly all differentially expressed genes (n = 807) in the spleen were on a lower expression level (n = 802) in BORN trout compared to the TCO strain. Global gene ontology analysis revealed that most genes are involved in fundamental biological processes like cellular growth, vesicular trafficking and energy metabolism. Surprisingly, only 7 % of splenic differentially expressed genes are associated with functions of the immune system like TLR signaling, acute phase response and complement system. MARCH3 is one lower expressed gene of interest in BORN trout. This gene, coding for an E3 ubiquitin ligase, is involved in three metabolic functions: immune system, vesicular trafficking and ubiquitination. Since MARCH genes are furthermore differently regulated in the two strains after viral infection and assumed to be potentially active in regulation of immune receptors in fish, MARCH3 was chosen for a closer structural analysis. In concert with the data interpretation of the achieved comparative transcriptome analysis for the involved rainbow trout strains, we provide the full mRNA sequence of trout MARCH3 and its hypothetical protein structure. PMID- 23086282 TI - ATP regulation of the ligand-binding properties in temperate and cold-adapted haemoglobins. X-ray structure and ligand-binding kinetics in the sub-Antarctic fish Eleginops maclovinus. AB - The major haemoglobin of the sub-Antarctic fish Eleginops maclovinus was structurally and functionally characterised with the aim to compare molecular environmental adaptations in the O(2)-transport system of sub-Antarctic fishes of the suborder Notothenioidei with those of their high-latitude relatives. Ligand binding kinetics of the major haemoglobin of E. maclovinus indicated strong stabilisation of the liganded quaternary T state, enhanced in the presence of the physiological allosteric effector ATP, compared to that of high-Antarctic Trematomus bernacchii. The activation enthalpy for O(2) dissociation was dramatically lower than that in T. bernacchii haemoglobin, suggesting remarkable differences in temperature sensitivity and structural changes associated with O(2) release and exit from the protein. The haemoglobin functional properties, together with the X-ray structure of the CO form at 1.49 A resolution, the first of a temperate notothenioid, strongly support the hypothesis that in E. maclovinus, whose life-style varies according to changes in habitat, the mechanisms that regulate O(2) affinity and the ATP-induced Root effect differ from those of high-Antarctic Notothenioids. PMID- 23086284 TI - Survival from breast cancer in relation to access to tertiary healthcare, body mass index, tumor characteristics and treatment: a Hellenic Cooperative Oncology Group (HeCOG) study. AB - Apart from tumour, treatment and patient characteristics at diagnosis, access to healthcare delivery may as well play a significant role in breast cancer prognosis. This study aimed to assess the additional impact exerted on survival by travel burden-a surrogate indicator of limited access to healthcare- expressed as geographical distance and/or time needed to reach the tertiary healthcare center from the patient's residence. Between 1997 and 2005, 2,789 women participated in therapeutic clinical trials conducted by the Hellenic Cooperative Oncology Group. The effect of geographical distance and travel time between patient's residence and treating hospital on survival was estimated using Cox proportional hazards regression adjusting for age, menopausal status, tumour size/grade, positive nodes (number), hormonal receptor status, HER2 overexpression, surgery type/treatment protocol as well as for body mass index>30 kg/m2. More aggressive tumour features, older treatment protocols and modifiable patient characteristics, such as obesity (HR: 1.27) adversely impacted on breast cancer survival. In addition, less studied indicators of access to healthcare, such as geographic distance>350 km and travel time>4 h were independently and significantly associated with worse outcomes (HR=1.43 and 1.34 respectively). In conclusion, to address inequalities in breast cancer survival, improvements in access to healthcare services related to increased travel burden especially for patients of lower socioeconomic status should be considered, more than ever at times of financial crisis and independently of already known modifiable patient characteristics. PMID- 23086285 TI - Publication biases in probiotics. PMID- 23086283 TI - The Generation R Study: design and cohort update 2012. AB - The Generation R Study is a population-based prospective cohort study from fetal life until adulthood. The study is designed to identify early environmental and genetic causes and causal pathways leading to normal and abnormal growth, development and health during fetal life, childhood and adulthood. The study focuses on six areas of research: (1) maternal health; (2) growth and physical development; (3) behavioural and cognitive development; (4) respiratory health and allergies; (5) diseases in childhood; and (6) health and healthcare for children and their parents. Main exposures of interest include environmental, endocrine, genetic and epigenetic, lifestyle related, nutritional and socio demographic determinants. In total, n = 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. Response at baseline was 61 %, and general follow-up rates until the age of 6 years exceed 80 %. Data collection in mothers, fathers and children include questionnaires, detailed physical and ultrasound examinations, behavioural observations, and biological samples. A genome and epigenome wide association screen is available in the participating children. From the age of 5 years, regular detailed hands-on assessments are performed in a dedicated research center including advanced imaging facilities such as Magnetic Resonance Imaging. Eventually, results forthcoming from the Generation R Study contribute to the development of strategies for optimizing health and healthcare for pregnant women and children. PMID- 23086287 TI - Analysis and simulation of division- and label-structured population models : a new tool to analyze proliferation assays. AB - In most biological studies and processes, cell proliferation and population dynamics play an essential role. Due to this ubiquity, a multitude of mathematical models has been developed to describe these processes. While the simplest models only consider the size of the overall populations, others take division numbers and labeling of the cells into account. In this work, we present a modeling and computational framework for proliferating cell populations undergoing symmetric cell division, which incorporates both the discrete division number and continuous label dynamics. Thus, it allows for the consideration of division number-dependent parameters as well as the direct comparison of the model prediction with labeling experiments, e.g., performed with Carboxyfluorescein succinimidyl ester (CFSE), and can be shown to be a generalization of most existing models used to describe these data. We prove that under mild assumptions the resulting system of coupled partial differential equations (PDEs) can be decomposed into a system of ordinary differential equations (ODEs) and a set of decoupled PDEs, which drastically reduces the computational effort for simulating the model. Furthermore, the PDEs are solved analytically and the ODE system is truncated, which allows for the prediction of the label distribution of complex systems using a low-dimensional system of ODEs. In addition to modeling the label dynamics, we link the label-induced fluorescence to the measure fluorescence which includes autofluorescence. Furthermore, we provide an analytical approximation for the resulting numerically challenging convolution integral. This is illustrated by modeling and simulating a proliferating population with division number-dependent proliferation rate. PMID- 23086286 TI - Complementation contributes to transcriptome complexity in maize (Zea mays L.) hybrids relative to their inbred parents. AB - Typically, F(1)-hybrids are more vigorous than their homozygous, genetically distinct parents, a phenomenon known as heterosis. In the present study, the transcriptomes of the reciprocal maize (Zea mays L.) hybrids B73*Mo17 and Mo17*B73 and their parental inbred lines B73 and Mo17 were surveyed in primary roots, early in the developmental manifestation of heterotic root traits. The application of statistical methods and a suitable experimental design established that 34,233 (i.e., 86%) of all high-confidence maize genes were expressed in at least one genotype. Nearly 70% of all expressed genes were differentially expressed between the two parents and 42%-55% of expressed genes were differentially expressed between one of the parents and one of the hybrids. In both hybrids, ~10% of expressed genes exhibited nonadditive gene expression. Consistent with the dominance model (i.e., complementation) for heterosis, 1124 genes that were expressed in the hybrids were expressed in only one of the two parents. For 65 genes, it could be shown that this was a consequence of complementation of genomic presence/absence variation. For dozens of other genes, alleles from the inactive inbred were activated in the hybrid, presumably via interactions with regulatory factors from the active inbred. As a consequence of these types of complementation, both hybrids expressed more genes than did either parental inbred. Finally, in hybrids, ~14% of expressed genes exhibited allele specific expression (ASE) levels that differed significantly from the parental inbred expression ratios, providing further evidence for interactions of regulatory factors from one parental genome with target genes from the other parental genome. PMID- 23086288 TI - Magnetic resonance imaging in patients with granulomatosis with polyangiitis (Wegener's) and subglottic stenosis. AB - OBJECTIVE: To evaluate the ability of MRI to detect subglottic stenosis and to differentiate between active and inactive subglottic inflammation in patients with granulomatosis with polyangiitis (GPA). MATERIALS AND METHODS: MRI studies of the larynx of 18 GPA patients with suspected SGS were included. The MRI protocol included T1- and T2-weighted and STIR-sequences, dynamic contrast enhancement (DCE) and diffusion weighted imaging (DWI). Two independent observers reviewed the MR images. SGS were identified and quantified, inflammatory activity was assessed using edema imaging, DCE and DWI. Final MRI diagnoses were compared to the clinical, laryngoscopic and histopathologic results. RESULTS: MRI confirmed SGS in all GPA patients with significant narrowing of the airway lumen and thickening of subglottic wall. Assessing the subglottic inflammatory activity, MRI showed a sensitivity of 87.5 % and a specificity of 60.0 %. Interrater agreement was kappa = 0.769. Of the different MR technical approaches tested, edema imaging was most sensitive and specific. DWI led to significant differences in the apparent diffusion coefficient between active and inactive subglottic inflammation. No significant differences were found with DCE imaging. CONCLUSION: MR imaging has shown the ability to detect and grade SGS in patients with GPA. It non-invasively assesses the status of inflammatory activity utilizing edema sensitive sequences and DWI. PMID- 23086289 TI - A facile synthetic route to diazepinone derivatives via ring closing metathesis and its application for human cytidine deaminase inhibitors. AB - A variety of diazepinone derivatives were prepared from alpha-amino acids and amino alcohols by a new synthetic methodology based on ring closing metathesis as a key step. The diazepinones were coupled with ribose derivatives to afford novel diazepinone nucleosides. Among them, (4R)-1-ribosyl-4-methyl-3,4-dihydro-1H-1,3 diazepin-2(7H)-one (3) showed a potent inhibitory effect (K(i) = 145.97 +/- 4.87 nM) against human cytidine deaminase. PMID- 23086291 TI - The nature and stability of the Au(110)/electrochemical interface produced by flame annealing. AB - It is shown using reflection anisotropy spectroscopy (RAS) that following flame annealing and immersion in pure water, the Au(110) surface adopts a (1*1) structure and that this structure is preserved in a 0.1 M H(2)SO(4) environment. The surface transforms to the (1*2) reconstruction following the application of a potential of 0.0 V versus SCE (a saturated calomel electrode). This surface is unstable and the RAS profile changes over periods of 15 min and 1 h in a manner which suggests that changes are occurring in the structure and distribution of [11(-)0] steps. Over longer periods the RAS transforms towards a profile attributed to a surface associated with the specific adsorption of anions. PMID- 23086292 TI - Enhancement of photo/thermal stability of organic bulk heterojunction photovoltaic devices via gold nanoparticles doping of the active layer. AB - This study focuses on the crucial problem of the stability of organic photovoltaic (OPV) devices, aiming to shed light on the photo and thermal degradation mechanisms during prolonged irradiation under ambient conditions. For this purpose, the stability enhancement of bulk heterojunction OPV devices upon embedding surfactant free Au nanoparticles (NPs) into the photoactive layer is investigated by in situ time-resolved energy dispersive X-ray reflectometry (EDXR), photoluminescence (PL) and Raman spectroscopy as well as device degradation electrical measurements. It is shown that besides the improved cell efficiency attributed to plasmon absorption and scattering effects, the embedded NPs act as performance stabilizers, giving rise to enhanced structural stability and, in turn, to reduced photodegradation rate of the respective OPV devices. It is particularly clarified that, in addition to further stabilization of the polymer-fullerene blend, the observed improvement can be ascribed to a NP mediated mitigation of the photooxidation effect at the cathode-active layer interface. Our work suggests the exploitation of surfactant free NPs to be a successful approach to address aging effects in OPV devices. PMID- 23086293 TI - [Positioning of patients with acute respiratory failure]. AB - The collapse of lung tissue, edema and intrapulmonary shunt are the main symptoms in patients with acute respiratory insufficiency. The techniques of ventilation in a prone position and continuous lateral rotational therapy (CLRT) are based on these pathophysiological changes. Ventilation in a prone position was found to improve ventilation and perfusion relationships and reduction in the pleural pressure gradient. In hypoxemic lung failure (PaO(2)/FIO(2) <100) a prone position was found to improve oxygenation as a rescue measure and to improve survival. In contrast CLRT is considered to be an early therapeutic or prophylactic measure aimed at prevention of ventilation-associated complications. In trauma patients these beneficial effects were demonstrated in several studies. Positioning therapy can be accompanied by potentially serious complications (e.g. face and skin ulceration, accidental loss of tubes and catheters and cardiac arrhythmias) and its use requires routine management and exact knowledge of indications and risks. PMID- 23086294 TI - Rationalization of stereospecific binding of propranolol to cytochrome P450 2D6 by free energy calculations. AB - Cytochrome P450 2D6 is a major drug-metabolising enzyme with a wide substrate range. A single-point mutation introduced in this enzyme induces stereoselective binding of R and S-propranolol whereas the wild type has no preference. The system has previously been studied both experimentally and computationally (de Graaf et al. in Eur Biophys J 36:589-599, 2007a). The in silico study reported hysteresis and significant deviations from closure of thermodynamic cycles, probably because of lack of sampling. Here, we focus on the effect of prolonged simulation time and enhanced sampling methods, such as Hamiltonian replica exchange, to reduce these problems and to improve the precision of free energy calculations. Finally we rationalize the results at a molecular level and compare data with experimental findings and previously estimated free energies. PMID- 23086296 TI - Big claims for big weights but with little evidence. PMID- 23086295 TI - Combined whole-body vibration, resistance exercise, and sustained vascular occlusion increases PGC-1alpha and VEGF mRNA abundances. AB - We previously reported that high load resistance exercise with superimposed whole body vibration and sustained vascular occlusion (vibroX) markedly improves cycling endurance capacity, increases capillary-to-fibre ratio and skeletal muscle oxidative enzyme activity in untrained young women. These findings are intriguing, since increases in oxidative muscle phenotype and endurance capacity are typically induced by endurance but not heavy resistance exercise. Here, we tested the hypothesis that vibroX activates genes associated with mitochondrial biogenesis and angiogenesis. Eight healthy, recreationally resistance-trained young men performed either vibroX or resistance exercise (RES) in a randomised, cross-over design. Needle biopsies (M. vastus lateralis) were obtained at rest and 3 h post-exercise. Changes in relative gene expression levels were assessed by real-time quantitative PCR. After vibroX, vascular endothelial growth factor and peroxisome proliferator-activated receptor-gamma coactivator 1alpha mRNA abundances increased to 2- and 4.4-fold, respectively, but did not significantly change above resting values after RES. Other genes involved in mitochondrial biogenesis were not affected by either exercise modality. While vibroX increased the expression of hexokinase II, xanthine dehydrogenase, and manganese superoxide dismutase mRNA, there were no changes in these transcripts after RES. This study demonstrates that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion activates metabolic and angiogenic gene programs, which are usually activated after endurance but not resistance exercise. Thus, targeted modification of high load resistance exercise by vibration and vascular occlusion might represent a novel strategy to induce endurance-type muscle adaptations. PMID- 23086297 TI - The ydaO motif is an ATP-sensing riboswitch in Bacillus subtilis. AB - We report what is to our knowledge the first natural RNA that regulates gene expression in response to intracellular ATP. Using a biochemical screen, we found that several putative riboswitches bind ATP in vitro. The ydaO motif specifically bound ATP and regulated expression of endogenous and reporter genes in response to ATP concentrations in Bacillus subtilis. This discovery demonstrates a role for RNAs in regulating gene expression in response to energy balance in bacteria. PMID- 23086299 TI - Systems biology analysis unravels the complementary action of combined rosuvastatin and ezetimibe therapy. AB - AIMS: Combination-drug therapy takes advantage of the complementary action of their individual components, thereby potentiating its therapeutic effect. Potential disadvantages include side effects that are not foreseen on basis of the data available from drug monotherapy. Here, we used a systems biology approach to understand both the efficacy and the side effects of a cholesterol lowering drug-combination therapy on the basis of the biological pathways and molecular processes affected by each drug alone or in combination. METHODS AND RESULTS: ApoE*3Leiden transgenic mice, a mouse model with human-like cholesterol lowering drug responses, were treated with rosuvastatin and ezetimibe, alone and in combination. Analyses included functional responses, viz. effects on cardiovascular risk factors, inflammation, and atherosclerosis, and measurement of global gene expression, and identification of enriched biological pathways and molecular processes. Combination therapy reduced plasma cholesterol, plasma inflammation markers, and atherosclerosis stronger than the single drugs did. Systems biology analysis at the level of biological processes shows that the therapeutic benefit of combined therapy is largely the result of additivity of the complementary mechanisms of action of the two single drugs. Importantly, combination therapy also exerted a significant effect on 16 additional and mostly NF-kappaB-linked signaling processes, 11 of which tended to be regulated in a similar direction with monotherapy. CONCLUSION: This study shows that gene expression analysis together with bioinformatics pathway analysis has the potential to help predict and identify drug combination-specific complementary and side effects. PMID- 23086298 TI - Divergent allosteric control of the IRE1alpha endoribonuclease using kinase inhibitors. AB - Under endoplasmic reticulum stress, unfolded protein accumulation leads to activation of the endoplasmic reticulum transmembrane kinase/endoRNase (RNase) IRE1alpha. IRE1alpha oligomerizes, autophosphorylates and initiates splicing of XBP1 mRNA, thus triggering the unfolded protein response (UPR). Here we show that IRE1alpha's kinase-controlled RNase can be regulated in two distinct modes with kinase inhibitors: one class of ligands occupies IRE1alpha's kinase ATP-binding site to activate RNase-mediated XBP1 mRNA splicing even without upstream endoplasmic reticulum stress, whereas a second class can inhibit the RNase through the same ATP-binding site, even under endoplasmic reticulum stress. Thus, alternative kinase conformations stabilized by distinct classes of ATP competitive inhibitors can cause allosteric switching of IRE1alpha's RNase- either on or off. As dysregulation of the UPR has been implicated in a variety of cell degenerative and neoplastic disorders, small-molecule control over IRE1alpha should advance efforts to understand the UPR's role in pathophysiology and to develop drugs for endoplasmic reticulum stress-related diseases. PMID- 23086300 TI - An integrated pathway system modeling of Saccharomyces cerevisiae HOG pathway: a Petri net based approach. AB - Biochemical networks comprise many diverse components and interactions between them. It has intracellular signaling, metabolic and gene regulatory pathways which are highly integrated and whose responses are elicited by extracellular actions. Previous modeling techniques mostly consider each pathway independently without focusing on the interrelation of these which actually functions as a single system. In this paper, we propose an approach of modeling an integrated pathway using an event-driven modeling tool, i.e., Petri nets (PNs). PNs have the ability to simulate the dynamics of the system with high levels of accuracy. The integrated set of signaling, regulatory and metabolic reactions involved in Saccharomyces cerevisiae's HOG pathway has been collected from the literature. The kinetic parameter values have been used for transition firings. The dynamics of the system has been simulated and the concentrations of major biological species over time have been observed. The phenotypic characteristics of the integrated system have been investigated under two conditions, viz., under the absence and presence of osmotic pressure. The results have been validated favorably with the existing experimental results. We have also compared our study with the study of idFBA (Lee et al., PLoS Comput Biol 4:e1000-e1086, 2008) and pointed out the differences between both studies. We have simulated and monitored concentrations of multiple biological entities over time and also incorporated feedback inhibition by Ptp2 which has not been included in the idFBA study. We have concluded that our study is the first to the best of our knowledge to model signaling, metabolic and regulatory events in an integrated form through PN model framework. This study is useful in computational simulation of system dynamics for integrated pathways as there are growing evidences that the malfunctioning of the interplay among these pathways is associated with disease. PMID- 23086301 TI - Overexpression of the oil palm (Elaeis guineensis Jacq.) TAPETUM DEVELOPMENT1 like Eg707 in rice affects cell division and differentiation and reduces fertility. AB - The functional analysis of the TAPETUM DEVELOPMENT1-like analog Eg707 of oil palm was carried out in rice by over-expressing Eg707 under the control of a double cauliflower mosaic virus 35S promoter. Ectopic expression of Eg707 in rice induced dark green and matured compact brownish calli compared to pale wild type and negative control calli. Regenerated transgenic rice plants exhibited a reduction in organ size and plant height, rolled, erect leaves, less tillers, increased chlorophyll content, and reduced fertility with smaller green seeds. At the molecular level Eg707 overexpression caused an increase in the transcription of SAPK9, a SnRK2 protein kinase family member that is activated by ABA and hyperosmotic stress. Together, the results show that ectopic Eg707 expression influences cell division and differentiation, presumably via altered hormone homeostasis. PMID- 23086302 TI - HER2 Ile655Val and PTEN IVS4 polymorphisms in patients with breast cancer. AB - Although HER2/PTEN pathway is commonly disrupted in cancer, association of HER2 and PTEN polymorphisms with breast cancer (BC) remains controversial. We investigated the HER2 Ile655 Val and PTEN IVS4 polymorphisms in patients with BC in Turkish population. HER2 Ile655Val (rs 1136201) and PTEN IVS4 (rs 3830675) polymorphisms were determined using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) in blood samples of 118 BC patients and 118 age-matched healthy controls. We found that the frequency of the Ile/Val genotype of HER2 Ile655Val gene was significantly higher in BC patients (p < 0.009; OR: 1,983 95 % CI: 1.181-3.328). The presence of ATCTT insertion (+/+) genotype at downstream of exon 4 in intron 4 of PTEN IVS4 gene was also associated with 1.83 fold decreased risk of BC development (p < 0.033; OR: 1.83, 95 % CI: 1.11-3.03). Analysis on clinico-pathological parameters showed neither HER2 Ile655Val nor PTEN IVS4 genotypes were not associated with any of the variables (p > 0.05).In conclusion, our findings suggest that the Ile/Val genotype of HER2 and ATCTT insertion (+/+) genotype of PTEN IVS4 gene may play an important role as genetic markers for breast cancer risk, but both genes genotypes may not be useful for predicting tumor prognosis in Turkish population. PMID- 23086303 TI - Association of the apolipoprotein M gene polymorphisms and serum lipid levels. AB - The association of rs707921 and rs707922 SNPs in the apolipoprotein M (APOM) gene and serum lipid levels is still controversial. This study aimed to detect the association of the APOM rs707921 and rs707922 SNPs and several environmental factors with serum lipid profiles. Genotyping of rs707921 and rs707922 was performed in 703 of Mulao's and 707 of Han's participants. The serum levels of TG in Mulao, and TG and HDL-C in Han were different between the A and C allele carriers of rs707921 (P < 0.05-0.01); while the serum levels of TG in both Mulao and Han were different between the T and G allele carriers of rs707922 (P < 0.05 0.01). According to the gender-subgroup analysis, the levels of TC in Mulao females, TG and ApoB in Han males, and HDL-C in Han females were associated with the genotypes of rs707921 (P < 0.05 for each); whereas the levels of TG in Mulao males, and TG and ApoB in Han males were correlated with the genotypes of rs707922 (P < 0.05 for each). Serum lipid parameters were also associated with several environmental factors (P < 0.05-0.001). The APOM gene rs707921 and rs707922 SNPs are associated with some serum lipid parameters in the two ethnic groups, but the trends of association suggest that the two SNPs might have racial/ethnic- and/or gender- specificity. PMID- 23086304 TI - Association of CAST gene polymorphisms with carcass and meat quality traits in Yanbian cattle of China. AB - Bovine calpastatin (CAST) gene polymorphisms have been associated with meat tenderness traits; however, little is known about how the CAST gene affects beef quality traits. In this study, 25 single nucleotide polymorphisms were detected in the CAST gene using polymerase chain reaction with single-strand conformation polymorphism and gene sequencing. Different preponderant genotypes were found at the corresponding gene locus. The E1-1, E1-2, and C3-1 loci were correlated with meat tenderness height and highly correlated with the fatty acid content and the amino acid content. The E4-2 locus was not correlated with meat tenderness, but it was correlated with cooking loss, brightness, and yellowness, among others. The CAST gene is a potential marker for these meat quality traits, but further research is required. PMID- 23086306 TI - Facilitators and barriers to teamworking and patient centeredness in multidisciplinary cancer teams: findings of a national study. AB - BACKGROUND: Multidisciplinary teams (MDTs) are the standard means of making clinical decisions in surgical oncology. The aim of this study was to explore the views of MDT members regarding contribution to the MDT, representation of patients' views, and dealing with disagreements in MDT meetings-issues that affect clinical decision making, but have not previously been addressed. METHODS: Responses to open questions from a 2009 national survey of MDT members about effective MDT working in the United Kingdom were analyzed for content. Emergent themes were identified and tabulated, and verbatim quotes were extracted to validate and illustrate themes. RESULTS: Free-text responses from 1,636 MDT members were analyzed. Key themes were: (1) the importance of nontechnical skills, organizational support, and good relationships between team members for effective teamworking; (2) recording of disagreements (potentially sharing them with patients) and the importance of patient-centered information in relation to team decision making; (3) the central role of clinical nurse specialists as the patient's advocates, complementing the role of physicians in relation to patient centeredness. CONCLUSIONS: Developing team members' nontechnical skills and providing organizational support are necessary to help ensure that MDTs are delivering high-quality, patient-centered care. Recording dissent in decision making within the MDT is an important element, which should be defined further. The question of how best to represent the patient in MDT meetings also requires further exploration. PMID- 23086305 TI - The molecular mechanism for human metallothionein-3 to protect against the neuronal cytotoxicity of Abeta(1-42) with Cu ions. AB - Aggregation and cytotoxicity of Abeta with redox-active metals in neuronal cells have been implicated in the progression of Alzheimer disease. Human metallothionein (MT) 3 is highly expressed in the normal human brain and is downregulated in Alzheimer disease. Zn(7)MT3 can protect against the neuronal toxicity of Abeta by preventing copper-mediated Abeta aggregation, abolishing the production of reactive oxygen species (ROS) and the related cellular toxicity. In this study, we intended to decipher the roles of single-domain proteins (alpha/beta) and the alpha-beta domain-domain interaction of Zn(7)MT3 to determine the molecular mechanism for protection against the neuronal cytotoxicity of Abeta(1-42) with copper ions. With this in mind, the alpha and beta single-domain proteins, heterozygous beta(MT3)-alpha(MT1), and a linker truncated mutant ?31-34 were prepared and characterized. In the presence/absence of various Zn(7)MT3 proteins, the Abeta(1-42)-Cu(2+)-mediated aggregation, the production of ROS, and the cellular toxicity were investigated by transmission electron microscopy, ROS assay by means of a fluorescent probe, and SH-SY5Y cell viability, respectively. The beta domain cannot abolish Abeta(1-42)-Cu(2+) induced aggregation, and neither the beta domain nor the alpha domain can quench the production of ROS because of the redox cycling of Abeta-Cu(2+). Similarly to wild-type Zn(7)MT3, the heterozygous beta(MT3)-alpha(MT1) possesses the characteristic of alleviating Abeta(1-42) aggregation and oxidative stress to neuronal cells. Therefore, the two domains through the linker Lys-Lys-Ser form a cooperative unit, and each of them is indispensable in conducting its bioactivity. The alpha domain plays an important role in modulating the stability of the metal-thiolate cluster, and the alpha-beta domain-domain interaction through the linker is critical for its protective role in the brain. PMID- 23086307 TI - C-phycocyanin modulates selenite-induced cataractogenesis in rats. AB - The present investigation is aimed to evaluate the anticataractogenic potential of C-phycocyanin (C-PC), extracted and purified from Spirulina platensis. Enucleated rat lenses were maintained in vitro in Dulbecco's modified Eagle medium (DMEM). Group I contained DMEM, Group II and Group III contained 100 MUM of sodium selenite, Group III was subdivided into three viz IIIa, IIIb, IIIc supplemented with 100, 150, 200 MUg of C-PC respectively. In the in vivo study, on tenth day post partum: Group I rat pups received an intraperitoneal injection of saline, Group II, IIIa, IIIb, and IIIc rat pups received a subcutaneous injection of sodium selenite (19 MUmol/kg bodyweight) Group IIIa, IIIb, IIIc also received an intraperitoneal injection of 100, 150, 200 mg/kg body weight of C-PC, respectively, from postpartum days 9-14. On termination of the experiment, the lenses from both in vitro and in vivo studies were subjected to morphological examination and subsequently processed to estimate the activities of antioxidant enzymes namely superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, levels of reduced glutathione and lipid peroxidation products. Sodium selenite-exposed, C-PC-treated rat lenses (Group IIIc), showed significant restoration of antioxidant enzyme activity (p < 0.05) when compared to their counterpart Group II. Group IIIc conserved the levels of GSH and lipid peroxidation products at near to normal levels as compared with Group II. Results conclude the possible role of C-PC in modulating the antioxidant enzyme status, thereby retarding sodium selenite-induced cataract incidence both in vitro and in vivo. PMID- 23086308 TI - Prenatal and lactational lead exposure enhanced oxidative stress and altered apoptosis status in offspring rats' hippocampus. AB - Oxidative stress and apoptosis facilitation in the developing central nervous system (CNS) have been inferred as two mechanisms related to lead's neurotoxicity, and excessive reactive oxygen species (ROS) can promote oxidative stress and apoptosis facilitation. Few studies systematically investigated the potential relationship among oxidative stress, ROS generation, and apoptosis facilitation after lead exposure in earlier life as a whole. To better understand the adverse effect on the developing central nervous system (CNS) after lead exposure during pregnancy and lactation, the indexes of oxidative stress, apoptosis status, and Bax and Bcl-2 expression of offspring rats' hippocampus were determined. Pregnant rats were randomly divided into four groups and given free access to drinking water which contained 0 %, 0.05 %, 0.1 %, and 0.2 % Pb(AC)(2) respectively from gestation day 0 to postnatal day 21 (PND21). Results showed that ROS and malondialdehyde level of either PND7 or PND21 pups' hippocampus were significantly raised; reduced glutathione level and superoxide dismutase activity were obviously decreased following the increase of blood and brain lead level. Similar to apoptotic indexes, Bax/Bcl-2 ratio increased after 0.1 % and 0.2 % Pb(AC)(2) exposure, especially for the pups on PND7. Comparing with cortex, the hippocampus seemed much more sensitive to damage induced by lead. We concluded that the disruption of pro-oxidant and antioxidant balance and apoptosis facilitation could be associated with the mechanisms of neurotoxicity after lead exposure in earlier life. PMID- 23086309 TI - Autophagic dysfunction in a lysosomal storage disorder due to impaired proteolysis. AB - Alterations in macroautophagy (hereafter referred to as "autophagy") are a common feature of lysosomal storage disorders, and have been hypothesized to play a major role in the pathogenesis of these diseases. We have recently reported multiple defects in autophagy contributing to the lysosomal storage disorder Niemann-Pick type C (NPC). These include increased formation of autophagosomes, slowed turnover of autophagosomes secondary to impaired lysosomal proteolysis, and delivery of stored lipids to the lysosome via autophagy. The study summarized here describes novel methods for the interrogation of individual stages of the autophagic pathway, and suggests mechanisms by which lipid storage may result in broader lysosomal dysfunction. PMID- 23086310 TI - Metallization of the potassium overlayer on the beta-SiC(100) c(4 * 2) surface. AB - We present new data on the potassium-induced semiconducting to metallic transition of the silicon-terminated beta-SiC(100) c(4 * 2) surface, resulting from density functional theory simulations. We have analysed many different SiC(100)-K surface topologies, corresponding to K coverages ranging from 0.08 to 1.25 monolayers (ML), paying special attention to the 2/3 ML and 1 ML cases where a metal-insulator transition has been reported to occur. We find that the SiC(100)-K surface is metallic in all the cases. In spite of that, the potassium layer shows a very low density of states in the semiconductor gap up to potassium coverages of ~1 ML, beyond which the potassium layer undergoes a transition to metallic behaviour, explaining the experimental observation. We propose a new atomic model for the surface reconstruction of the 1 ML case which is lower in total energy than the previously suggested model based on linear potassium chains. PMID- 23086311 TI - Modification of calcium carbonate based gene and drug delivery systems by a cell penetrating peptide. AB - In this study, a facile strategy to effectively improve the gene and drug delivery efficiencies of calcium carbonate based nanoparticles was developed by introducing a cell-penetrating peptide, KALA, into the delivery systems. To evaluate the effect of KALA on the gene delivery efficiency, luciferase reporter gene plasmid was encapsulated in CaCO(3)-KALA-DNA nanoparticles. The measurements of a Zetasizer showed that the size and the zeta potential of CaCO(3)-KALA-DNA nanoparticles increased with increasing KALA amount because of the addition of positively charged KALA. Due to the existence of KALA, the gene expressions could be significantly enhanced in both HeLa and 293T cells. Confocal microscopy observation showed that the cellular uptake of CaCO(3)-KALA-DNA nanoparticles was obviously enhanced compared to CaCO(3)-DNA nanoparticles. To investigate the gene and drug co-delivery property, p53 expression plasmid and doxorubicin hydrochloride (DOX) were loaded in CaCO(3)-KALA-p53-DOX nanoparticles. The in vitro cell growth inhibition effect of CaCO(3)-KALA-p53-DOX nanoparticles was evaluated by MTT assay. Compared with CaCO(3)-p53-DOX nanoparticles, CaCO(3)-KALA p53-DOX nanoparticles exhibited enhanced delivery efficiency, which led to a stronger inhibition effect on HeLa cells. These results indicated that the addition of KALA, which facilitated the cellular uptake of various agents, could improve both gene and drug delivery efficiencies. The KALA modified CaCO(3) based nanoparticles have promising applications in cancer treatments. PMID- 23086312 TI - Preparation of enantioenriched iodinated pyrrolinones by iodocyclization of alpha amino-ynones. AB - The unprecedented electrophilic iodo-mediated cyclization of alpha-amino-ynones afforded enantiomerically enriched beta-iodopyrrolin-4-ones in excellent yields under mild conditions. The starting substituted alpha-amino-ynones were obtained from the chiral pool by selective mono-addition of an organolithium to optically pure N-protected carboxyanhydrides of amino acids (UNCAs). PMID- 23086313 TI - Diffusional kurtosis imaging of normal-appearing white matter in multiple sclerosis: preliminary clinical experience. AB - PURPOSE: We evaluated diffusional changes in normal-appearing white matter (NAWM) regions remote from multiple sclerosis (MS) plaques by using diffusional kurtosis imaging (DKI) to investigate the non-Gaussian behavior of water diffusion. MATERIALS AND METHODS: Participants were 11 MS patients and 6 age-matched healthy volunteers. DKI was performed on a 3-T MR imager. Fractional anisotropy (FA), apparent diffusion coefficient (ADC), and diffusional kurtosis (DK) maps were computed. Regions of interest (ROIs) were compared in 24 cerebral regions, including the frontal, parietal, and temporal lobe white matter (WM) in controls and NAWM in MS patients. RESULTS: The mean FA of all ROIs was 0.468 +/- 0.014 (SD) (controls) or 0.431 +/- 0.029 (MS group) (P = 0.016). Mean ADC was 0.785 +/- 0.034 * 10(-3) mm(2)/s (controls) or 0.805 +/- 0.041 * 10(-3) mm(2)/s (MS group). The mean DK of all ROIs was 0.878 +/- 0.020 (controls) or 0.823 +/- 0.032 (MS group) (P = 0.002). Analysis of individual ROIs revealed significant differences in DK in 3 ROIs between normal WM and NAWM, but significant differences in ADC and FA in only one ROI each. CONCLUSION: DKI may be a new sensitive indicator for detecting tissue damage in MS patients in addition to conventional diffusional evaluations, for example diffusion tensor imaging. PMID- 23086315 TI - Affective disorder associated with pontocerebellar hypoplasia. PMID- 23086316 TI - Metabolic syndrome in an adolescent psychiatric unit. PMID- 23086318 TI - Will we ever have enough psychiatric registrars? PMID- 23086317 TI - Online, blended learning materials in psychiatry for medical students and trainees. PMID- 23086319 TI - Walking on thin ice: who are we afraid will drown? PMID- 23086329 TI - Chromoblastomycosis in Mainland China: a systematic review on clinical characteristics. AB - Chromoblastomycosis is one of the most frequent chronic infections caused by melanized fungi. In order to evaluate the clinical characteristics of chromoblastomycosis in Mainland China, we performed an evidence-based review of published literature. PubMed and Chinese-language database of CNKI, VIP and Wanfang data during January 1990-August 2011 were searched. Epidemiology, clinical features, laboratory findings, therapy and prognosis were analyzed. Cladophialophora carrionii was the most common causative agent in the north of the Mainland China, and Fonsecaea monophora and F. pedrosoi were the most common agents in the southern part of the Mainland China. Infection commonly initiated after the etiologic agents gain entrance through puncture wounds and more common involved extremities of the males. Skin lesions were found in different sites, like the extremities, buttocks, trunk and face, and presented diversity morphology. There were about seven different clinical types found in Mainland China: plaque type, tumoral type, cicatricial type, verrucous type, pseudo vacuole type, eczymatous type and mixed type of lesions. The success of treatment for chromoblastomycosis was related to the causative agent, the clinical form and severity of the lesions. Most of the patients could be treated successfully with the physical treatment, chemotherapy and/or combination therapy. The itraconazole, terbinafine or a combination of both were commonly medication for these mycosis patients. Physical methods were usually indicated to support chemotherapy with some severe forms and long-lasting cases. Photodynamic therapy has been extended from the oncological field to that of antimicrobial chemotherapy in these years. We applied it on some recalcitrant cases of chromoblastomycosis and found its good clinical response, and hopeful it could be a promising therapy in near future. PMID- 23086331 TI - A universal immunosensing strategy based on regulation of the interaction between graphene and graphene quantum dots. AB - We provide a novel and versatile signaling transduction strategy in the fluoroimmunoassay through regulating the interaction between graphene (Gr) and graphene quantum dots (GQDs), and demonstrate its feasibility in sensitive detection of human immunoglobulin G (IgG). PMID- 23086333 TI - Accuracy of digital and conventional impression techniques and workflow. AB - OBJECTIVES: Digital impression techniques are advertised as an alternative to conventional impressioning. The purpose of this in vitro study was to compare the accuracy of full ceramic crowns obtained from intraoral scans with Lava C.O.S. (3M ESPE), CEREC (Sirona), and iTero (Straumann) with conventional impression techniques. MATERIALS AND METHODS: A model of a simplified molar was fabricated. Ten 2-step and 10 single-step putty-wash impressions were taken using silicone impression material and poured with type IV plaster. For both techniques 10 crowns were made of two materials (Lava zirconia, Cera E cast crowns). Then, 10 digital impressions (Lava C.O.S.) were taken and Lava zirconia crowns manufactured, 10 full ceramic crowns were fabricated with CEREC (Empress CAD) and 10 full ceramic crowns were made with iTero (Copran Zr-i). The accessible marginal inaccuracy (AMI) and the internal fit (IF) were measured. RESULTS: For AMI, the following results were obtained (mean +/- SD): overall groups, 44 +/- 26 MUm; single-step putty-wash impression (Lava zirconia), 33 +/- 19 MUm; single step putty-wash impression (Cera-E), 38 +/- 25 MUm; two-step putty-wash impression (Lava zirconia), 60 +/- 30 MUm; two-step putty-wash impression (Cera E), 68 +/- 29 MUm; Lava C.O.S., 48 +/- 25 MUm; CEREC, 30 +/- 17 MUm; and iTero, 41 +/- 16 MUm. With regard to IF, errors were assessed as follows (mean +/- SD): overall groups, 49 +/- 25 MUm; single-step putty-wash impression (Lava zirconia), 36 +/- 5 MUm; single-step putty-wash impression (Cera-E), 44 +/- 22 MUm; two-step putty-wash impression (Lava zirconia), 35 +/- 7 MUm; two-step putty-wash impression (Cera-E), 56 +/- 36 MUm; Lava C.O.S., 29 +/- 7 MUm; CEREC, 88 +/- 20 MUm; and iTero, 50 +/- 2 MUm. CONCLUSIONS: Within the limitations of this in vitro study, it can be stated that digital impression systems allow the fabrication of fixed prosthetic restorations with similar accuracy as conventional impression methods. CLINICAL RELEVANCE: Digital impression techniques can be regarded as a clinical alternative to conventional impressions for fixed dental restorations. PMID- 23086332 TI - Bonding and sealing ability of a new self-adhering flowable composite resin in class I restorations. AB - OBJECTIVES: The aim of this study is to assess by means of shear bond strength tests (SBS), microleakage analysis (MULKG), and scanning electron microscopy (SEM) the bonding potential and sealing ability of a new self-adhering composite resin. MATERIALS AND METHODS: SBS and MULKG of Vertise Flow (VF, Kerr) were measured and compared to the all-in-one adhesive systems G-Bond (GB, GC), AdheSE One (AO, Ivoclar Vivadent), Adper Easy Bond (EB, 3M ESPE), Xeno V (XV, Dentsply), and iBOND (iB, Heraeus Kulzer). For each system, 20 molars were tested for SBS on dentin (n = 10) and enamel (n = 10). For MULKG assessment, 12 premolars per group were selected and small, box-shaped cavities were made. After restoration, the teeth were immersed in 50 wt% silver nitrate solution for 24 h. For each group, 10 randomly selected specimens were processed for leakage calculations, while two of the specimens were examined under SEM. Between-group differences in SBS to dentin and MULKG were assessed using Kruskal-Wallis analysis of variance followed by the Dunn's Multiple Range test. Enamel SBS data were analyzed with one-way ANOVA, followed by the Tukey test. RESULTS: On dentin and enamel, VF recorded the lowest SBS values that were statistically comparable to those measured by GB, iB, and AO. MULKG analysis showed the lowest percentage of stained interface for VF. Significantly greater extent of infiltration was seen for iB and EB. CONCLUSIONS: Although VF resulted in lower bond strengths values on either dental substrate, better marginal sealing ability was visualized in comparison with all-in-one adhesive systems. CLINICAL RELEVANCE: The results of the present study demonstrated satisfactory in vitro outcome of the self-adhering flowable composite resin VF when used to restore class I cavities. PMID- 23086334 TI - Neural progenitor cells regulate microglia functions and activity. AB - We found mouse neural progenitor cells (NPCs) to have a secretory protein profile distinct from other brain cells and to modulate microglial activation, proliferation and phagocytosis. NPC-derived vascular endothelial growth factor was necessary and sufficient to exert at least some of these effects in mice. Thus, neural precursor cells may not only be shaped by microglia, but also regulate microglia functions and activity. PMID- 23086335 TI - Reorganization of cortical population activity imaged throughout long-term sensory deprivation. AB - Sensory maps are reshaped by experience. It is unknown how map plasticity occurs in vivo in functionally diverse neuronal populations because activity of the same cells has not been tracked over long time periods. Here we used repeated two photon imaging of a genetic calcium indicator to measure whisker-evoked responsiveness of the same layer 2/3 neurons in adult mouse barrel cortex over weeks, first with whiskers intact, then during continued trimming of all but one whisker. Across the baseline period, neurons displayed heterogeneous yet stable responsiveness. During sensory deprivation, responses to trimmed whisker stimulation globally decreased, whereas responses to spared whisker stimulation increased for the least active neurons and decreased for the most active neurons. These findings suggest that recruitment of inactive, 'silent' neurons is part of a convergent redistribution of population activity underlying sensory map plasticity. Sensory-driven responsiveness is a key property controlling experience-dependent activity changes in individual neurons. PMID- 23086336 TI - Divergence of visual channels in the inner retina. AB - Bipolar cells form parallel channels that carry visual signals from the outer to the inner retina. Each type of bipolar cell is thought to carry a distinct visual message to select types of amacrine cells and ganglion cells. However, the number of ganglion cell types exceeds that of the bipolar cells providing their input, suggesting that bipolar cell signals diversify on transmission to ganglion cells. We explored in the salamander retina how signals from individual bipolar cells feed into multiple ganglion cells and found that each bipolar cell was able to evoke distinct responses among ganglion cells, differing in kinetics, adaptation and rectification properties. This signal divergence resulted primarily from interactions with amacrine cells that allowed each bipolar cell to send distinct signals to its target ganglion cells. Our findings indicate that individual bipolar cell-ganglion cell connections have distinct transfer functions. This expands the number of visual channels in the inner retina and enhances the computational power and feature selectivity of early visual processing. PMID- 23086338 TI - Sulfate-reducing bacteria inhabiting natural corrosion deposits from marine steel structures. AB - In the present study, investigations were conducted on natural corrosion deposits to better understand the role of sulfate-reducing bacteria (SRB) in the accelerated corrosion process of carbon steel sheet piles in port environments. We describe the abundance and diversity of total and metabolically active SRB within five natural corrosion deposits located within tidal or low water zone and showing either normal or accelerated corrosion. By using molecular techniques, such as quantitative real-time polymerase chain reaction, denaturing gel gradient electrophoresis, and sequence cloning based on 16S rRNA, dsrB genes, and their transcripts, we demonstrated a clear distinction between SRB population structure inhabiting normal or accelerated low-water corrosion deposits. Although SRB were present in both normal and accelerated low-water corrosion deposits, they dominated and were exclusively active in the inner and intermediate layers of accelerated corrosion deposits. We also highlighted that some of these SRB populations are specific to the accelerated low-water corrosion deposit environment in which they probably play a dominant role in the sulfured corrosion product enrichment. PMID- 23086337 TI - [Aspects of perioperative care in patients with diabetes]. AB - Diabetes is a common disease in Germany. Due to diabetes-associated end-organ disease, such as large and small vessel disease and neuropathy, diabetic patients require more intense anesthesia care during the perioperative phase. An in-depth and comprehensive medical history focusing on hemodynamic alterations, gastroparesis, neuropathy and stiff joint syndrome is a cornerstone of perioperative care and may affect outcome of diabetes patients more than specific anesthetic medications or the anesthetic procedure. Intraoperative anesthetic care needs to focus on preservation of hemodynamic stability, perioperative infection control and maintenance of glucose homeostasis. Whereas some years ago strict glucose control by aggressive insulin therapy was adamantly advocated, the results of recent studies have put the risk of such therapeutic algorithms into perspective. Therefore, optimized perioperative care of diabetic patients consists of setting a predefined targeted blood glucose level, evidence-based therapeutic approaches to reach that goal and finally adequate and continuous monitoring and amendment of the therapeutic approach if required. PMID- 23086339 TI - Development and validation of qualitative SYBR(r)Green real-time PCR for detection and discrimination of Listeria spp. and Listeria monocytogenes. AB - A combination of four qualitative SYBR(r)Green qPCR screening assays targeting two levels of discrimination: Listeria genus (except Listeria grayi) and Listeria monocytogenes, is presented. These assays have been developed to be run simultaneously using the same polymerase chain reaction (PCR) programme. The paper also proposes a new validation procedure to specifically validate qPCR assays applied to food microbiology according to two guidelines: the ISO 22118 norm and the "Definition of minimum performance requirements for analytical methods of GMO testing". The developed assays target the iap, prs and hlyA genes that belong to or neighbour the virulence cluster of Listeria spp. The selected primers were designed to amplify short fragments (60 to 103 bp) in order to obtain optimal PCR efficiency (between 97 and 107 % efficiency). The limit of detection of the SYBR(r)Green qPCR assays is two to five copies of target genes per qPCR reaction. These assays are highly accurate (98.08 and 100 % accuracy for the Listeria spp. and L. monocytogenes assays, respectively). PMID- 23086340 TI - STAT1 activation by venous malformations mutant Tie2-R849W antagonizes VEGF-A mediated angiogenic response partly via reduced bFGF production. AB - A missense mutation from arginine to tryptophan at residue 849 in the kinase domain of Tie2 (Tie2-R849W) is commonly identified in familial venous malformations. The mechanistic action of Tie2-R849W variant expression on angiogenic cascades including smooth muscle cell recruitment, however, remains elusive. To avoid confounding factors from endogenous Tie2 expression, Tie2 depleted endothelial cells (ECs) were used to study the effects of ectopic shRNA resistant Tie2 variant expression, Tie2-WT* and Tie2-R849W*, on vascular cell proliferation, migration, tube formation, and smooth muscle cell (SMC) recruitment. Tie2-R849W* induced STAT1 phosphorylation at Tyr701. Tie2-R849W* expressing cells had reduced ability to migrate and form tubes on Matrigel than their wildtype counterparts. STAT1 phosphorylation attenuated VEGF-A-induced STAT3 tyrosine phosphorylation in Tie2-R849W*-expressing HUVECs. The induced STAT1 activation also decreased VEGF-A-induced bFGF mRNA expression by competing with activated STAT3 for a direct binding to the consensus STAT-binding site at positions -997 to -989 bp from transcription start site in the bFGF promoter. Depleting STAT1 expression rescued the inability of Tie2-R849W expression to mediate angiogenesis. Moreover, bFGF neutralization or constitutive STAT1 activation, reminiscence of Tie2-R849W* expression, suppressed the smooth muscle cell recruiting ability of endothelial conditioned medium. This work reveals an anti-angiogenic role of STAT1 activation that acts in Tie2-R849W-expressing ECs to impair VEGF-A-mediated STAT3 signaling, bFGF production, and smooth muscle cell recruitment. A balancing activity of STAT1 and STAT3 may be important for Tie2-mediated vascular homeostasis. PMID- 23086341 TI - Molecular dynamics simulations of oxygen vacancy diffusion in SrTiO3. AB - A classical force-field model with partial ionic charges was applied to study the behaviour of oxygen vacancies in the perovskite oxide strontium titanate (SrTiO(3)). The dynamical behaviour of these point defects was investigated as a function of temperature and defect concentration by means of molecular dynamics (MD) simulations. The interaction between oxygen vacancies and an extended defect, here a Sigma3(111) grain boundary, was also examined by means of MD simulations. Analysis of the vacancy distribution revealed considerable accumulation of vacancies in the envelope of the grain boundary. The possible clustering of oxygen vacancies in bulk SrTiO(3) was studied by means of static lattice calculations within the Mott-Littleton approach. All binary vacancy vacancy configurations were found to be energetically unfavourable. PMID- 23086345 TI - Comparing safety in surface landmarks versus ultrasound-guided peripheral nerve blocks: an observational study of a practice in transition. PMID- 23086342 TI - Control of STN7 transcript abundance and transient STN7 dimerisation are involved in the regulation of STN7 activity. AB - Reversible phosphorylation of LHCII, the light-harvesting complex of photosystem II, controls its migration between the two photosystems (state transitions), and serves to adapt the photosynthetic machinery of plants and green algae to short term changes in ambient light conditions. The thylakoid kinase STN7 is required for LHCII phosphorylation and state transitions in vascular plants. Regulation of STN7 levels occurs at the post-translational level, depends on the thylakoid redox state, and might involve reversible autophosphorylation. Here, we have analysed the effects of different light conditions and chemical inhibitors on the abundance of STN7 transcripts and their products. This analysis was performed in wild-type Arabidopsis thaliana plants, in several photosynthetic mutants, and in lines overexpressing STN7 (oeSTN7) or expressing mutant variants of STN7 carrying single or double cysteine-serine exchanges. It was found that accumulation of the STN7 protein is also controlled at the level of transcript abundance. Under certain conditions, exposure to high light or far-red light treatment, the relative decreases in LHCII phosphorylation can be attributed to decreases in STN7 abundance. Nevertheless, inhibitor experiments showed that redox control of LHCII kinase activity persists in oeSTN7 plants. STN7 dimers were found in oeSTN7 plants and in lines with single cysteine-serine exchanges, indicating that dimerisation involves disulphide bridges. We speculate that transient STN7 dimerisation is required for STN7 activity, and that the altered dimerisation behaviour of oeSTN7 plants might be responsible for the unusually high phosphorylation of LHCII in the dark found in this genotype. PMID- 23086343 TI - Induction of a ricinosomal-protease and programmed cell death in tomato endosperm by gibberellic acid. AB - Several examples of programmed cell death (PCD) in plants utilize ricinosomes, organelles that appear prior to cell death and store inactive KDEL-tailed cysteine proteinases. Upon cell death, the contents of ricinosomes are released into the cell corpse where the proteinases are activated and proceed to degrade any remaining protein for use in adjacent cells or, in the case of nutritive seed tissues, by the growing seedling. Ricinosomes containing pro-SlCysEP have been observed in anther tissues prior to PCD and ricinosome-like structures have been observed in imbibed seeds within endosperm cells of tomato. The present study confirms that the structures in tomato endosperm cells contain pro-SlCysEP making them bona fide ricinosomes. The relative abundance of pro- versus mature SlCysEP is suggested to be a useful indicator of the degree of PCD that has occurred in tomato endosperm, and is supported by biochemical and structural data. This diagnostic tool is used to demonstrate that a sub-region of the micropylar endosperm surrounding the emerged radical is relatively long-lived and may serve to prevent loss of mobilized reserves from the lateral endosperm. We also demonstrate that GA-induced reserve mobilization, SlCysEP accumulation and processing, and PCD in tomato endosperm are antagonized by ABA. PMID- 23086346 TI - Meta-analysis: somewhere between mega-silliness and the final word, but where? PMID- 23086347 TI - Local anesthetics in diabetic rats (and patients): shifting from a known slippery slope toward a potentially better multimodal perineural paradigm? PMID- 23086349 TI - Education in regional anesthesia: caseloads, simulation, journals, and politics: 2011 Carl Koller Lecture. AB - This special article is an essay version of the European Society of Regional Anaesthesia and Pain Therapy 2011 Carl Koller Award lecture. Historically, evaluations of a trainee's regional anesthesia learning focused on caseload numbers. The deficiency of this unidimensional approach is that case numbers alone say little about the resident's mastery of the nontechnical aspects of regional anesthesiology. Simulation can refine technical skills, but also expands the teaching paradigm to include management of rare complications. Teachers are further challenged by requirements to incorporate systems-based practice topics, including the optimization of operating room efficiency and patient safety. Journals play an important role in regional anesthesia education for both trainees and mature anesthesiologists. Editorial boards build valuable educational foundations by providing critical analysis of new technologies and sponsoring practice advisories. Subspecialty societies such as European Society of Regional Anaesthesia and Pain Therapy and the American Society of Regional Anesthesia and Pain Medicine foster regional anesthesia education through their efforts to define curricula, produce guidelines, and promote international collaboration. PMID- 23086350 TI - American Society of Regional Anesthesia and Pain Medicine 2011 John J. Bonica Award Lecture: the evolution of the field of pain medicine. PMID- 23086351 TI - Novel ultrasound-guided suprascapular nerve block. PMID- 23086353 TI - Ultrasound-guided eye blocks. PMID- 23086354 TI - Getting to the core of platinum drug bio-distributions: the penetration of anti cancer platinum complexes into spheroid tumour models. AB - Elemental mapping and fluorescence imaging techniques are frequently employed to probe the distribution of platinum-based chemotherapeutics within biological systems. Although useful, these techniques have unique limitations: elemental mapping methods, such as those that use particle beams, typically require rigorous sample preparation that can alter chemical distributions, whilst in situ visible fluorescence studies require fluorescent-tagging of the platinum component and may be confounded by factors such as ligand loss. The present study aimed to establish reliable methods for accurately probing the bio-distribution of platinum compounds within the model tumour micro-environment of the well characterised DLD-1 colorectal cancer cell spheroids. 3D X-ray fluorescence computed micro-tomography (XRF-CT) was performed on intact untreated spheroids to determine the effect of physical sectioning and chemical fixation on elemental distributions. It was revealed for the first time that cisplatin can readily penetrate through DLD-1 spheroids and accumulate in the central hypoxic and necrotic regions of the spheroids. Furthermore, formalin fixing was shown to cause significant changes to the distributions and concentrations of the elements, particularly in the cases of platinum and zinc. This effect was not observed in the cryo-fixed and cryo-sectioned samples. X-ray fluorescence microscopy (XFM) was used to re-examine the fate of platinum in the previously reported fluorescence distribution studies of platinum(ii) complexes tagged with fluorescent anthraquinone moieties. In contrast to the fluorescence distributions, in which fluorescence was observed predominantly around the periphery of the spheroids, the XFM revealed a high level of platinum in the spheroid centre, indicating that ligand exchange occurred within the peripheral cell layers. Both the platinum maps and the fluorescence images exhibit similar diffusion trends, supporting the conclusion that charge on the compound can slow cellular uptake can enhance tumour penetration. PMID- 23086355 TI - Isoliquiritigenin enhances radiosensitivity of HepG2 cells via disturbance of redox status. AB - Redox balance plays an important role in the maintenance of cell growth and survival. Disturbance of this equilibrium can alter normal cellular processes. Excessive reactive oxygen species (ROS) are often found in cancer cells. However, cancer cells have an efficient antioxidant system to counteract the increased generation of ROS. This high antioxidant capacity also favors resistance to drugs and radiation. Here, we show that isoliquiritigenin (ISL), a natural antioxidant, effectively decreased ROS in HepG2 cells in a time-dependant manner at 0.5, 1, and 2 h of treatment. The decreased ROS caused redox imbalance and reductive stress. To adapt to this state, nuclear factor erythroid-2-related factor 2, which regulates the antioxidant enzyme system, was significantly decreased. Antioxidant enzymes reached their lowest level at 6 h after ISL treatment. Endogenous ROS were still being generated so after 6 h of ISL treatment, ROS were clearly higher than before ISL treatment, causing redox imbalance in the HepG2 cells which changed from reductive to oxidative stress. At this stage, cells were irradiated with X-rays. The excess ROS induced serious oxidative stress, resulting in radiosensitization. Therefore, we concluded that ISL induced oxidative stress by disturbing the redox status and ultimately enhancing the radiosensitivity of HepG2 cells. PMID- 23086356 TI - Osteopontin promotes mesenchymal stem cell migration and lessens cell stiffness via integrin beta1, FAK, and ERK pathways. AB - The use of mesenchymal stem cells (MSCs) for therapeutic applications has attracted great attention because MSCs home to and engraft to injured tissues after in vivo administration. The expression of osteopontin (OPN) is elevated in response to injury and inflammation, and its role on rat bone marrow-derived mesenchymal stem cells (rMSCs)-directed migration has been elucidated. However, the signaling pathways through the activation of which OPN promotes rMSCs migration and the involvement of cell mechanics during OPN-mediating rMSCs migration have not been well studied. In this study, we found that OPN activated focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK) signaling pathways by the ligation of integrin beta1 in rMSCs. Inhibitors of FAK and ERK pathways inhibited OPN-induced rMSCs migration, indicating the possible involvement of FAK and ERK activation in OPN-induced migration in rMSCs. In addition, atomic force microscopy analysis showed that OPN reduced cell stiffness in rMSCs via integrin beta1, FAK, and ERK pathways, suggesting that the promotion of rMSCs migration might partially be contributing to the decrease in cell stiffness stimulated by OPN. To further examine the role of OPN on cell motility and stiffness, actin cytoskeleton of rMSCs was observed. The reduced well-defined F-actin filaments and the promoted formation of pseudopodia in rMSCs induced by OPN explained the reduction in cell stiffness and the increase in cell migration. The current study data have shown for the first time that OPN binding to integrin beta1 promotes rMSCs migration through the activation of FAK and ERK pathways, which may be attributed to the change in cell stiffness caused by the reduction in the amount of organized actin cytoskeleton. PMID- 23086357 TI - Prospective study of corneal collagen cross-linking efficacy and tolerance in the treatment of keratoconus and corneal ectasia: 3-year results. AB - PURPOSE: To assess the efficacy and tolerance of corneal collagen cross-linking with corneal epithelium debridement in the stabilizing treatment of primary or secondary corneal ectasia. METHODS: Prospective, comparative, single-center study of patients presenting with progressive primary or secondary corneal ectasia. The control group, comprising the fellow eye of patients with bilateral involvement, was followed up for 6 months and then treated. The parameters examined were the biomicroscopic examination, visual acuity [best spectacle-corrected visual acuity (BSCVA) and uncorrected visual acuity (UCVA)], keratometry of the central 3 mm, intraocular pressure, central pachymetry, endothelial density, and macular profile. RESULTS: Fifty-five eyes of 39 patients were treated; the mean follow-up period was 20.8 +/- 6.8 months (range, 12-36 months). The control group comprised 16 eyes. UCVA and BSCVA were significantly improved between 3 and 12 months, reaching their minimum at 6 months, varying from 0.12 UCVA to 0.07 BSCVA (P < 0.05). These values and the keratometry values did not vary significantly after 36 months of follow-up. In contrast, analysis of the control group revealed significant keratometric deterioration of +1.2 diopters at 6 months (P < 0.05), with no further significant variation after treatment. Analysis of the subgroups of patients with post-laser in situ keratomileusis ectasia confirmed these results. At the end of the study, intraocular pressure, pachymetry, and endothelial density were not significantly modified, and no macular profile modification was observed. CONCLUSION: This study shows that corneal collagen cross-linking can stabilize progressive corneal ectasia, both primary and secondary, with no induced iatrogenic effects. PMID- 23086358 TI - One-year experience in presbyopia correction with biaspheric multifocal central presbyopia laser in situ keratomileusis. AB - PURPOSE: To analyze simultaneous vision (distance and near) 1-year after biaspheric multifocal central presbyLASIK treatments for hyperopia and myopia with or without astigmatism. METHODS: Patients were treated to correct distance ametropias and alleviating presbyopic symptoms simultaneously. All patients have been treated in Presby aberration-free mode using FemtoLASIK for Sphere from 7.00 to +3.25 diopters (D), astigmatism up to 3.00 D, and addition up to +2.75 D. No eye had previous corneal refractive surgery. Preoperative corneal curvature ranged between 40 and 48 D, with pachymetry thicker than 500 MUm. Preoperative corrected distance visual acuity was 0.1 logarithm of the minimum angle of resolution (logMAR) or better, with near vision of 0.2 logRAD or better with addition up to +2.50 D. RESULTS: Sixty-six eyes treated bilaterally using PresbyMAX software were reviewed. For 31 patients (94%), 1-year follow-up was completed. At 1 year, 70% of patients achieved uncorrected distance visual acuity 0.1 logMAR or better, 84% patients obtained uncorrected near visual acuity 0.1 logRAD or better, and 83% of eyes were within 0.75 D of defocus. Postoperative mean spherical equivalent refraction was -0.47 +/- 0.44 D. Stability was achieved from the 6-week follow-up. Eighty-five percent of patients achieved simultaneously uncorrected distance visual acuity 0.2 logMAR or better and uncorrected near visual acuity 0.2 logRAD or better. CONCLUSION: Patient selection and expectation management is essential to achieve patient satisfaction. Even though optically the results are predictable and good, some patients find it difficult to adapt to the compromise and others are dissatisfied by the minor loss of distance visual acuity. Certain individuals are best suited for PresbyMAX. A test with multifocal contact lenses or trial frames that creates slightly defocused images can be used to simulate postoperative visual impressions and verify patient acceptance. PMID- 23086359 TI - Deep intrastromal injection of bevacizumab for the management of corneal neovascularization. PMID- 23086360 TI - The role of host endothelial cell proliferation in descemet membrane endothelial transfer. PMID- 23086361 TI - Dissection plane of the clear margin big-bubble in deep anterior lamellar keratoplasty. PMID- 23086362 TI - Reply to "Descemet stripping automated endothelial keratoplasty: effect of intraoperative lenticule thickness on visual outcome and endothelial cell density". PMID- 23086363 TI - Reply: To PMID 22257863. PMID- 23086364 TI - Tear osmolarity and dry eye symptoms in women using oral contraception and contact lenses. AB - PURPOSE: The aim of this study was to examine the relationship among oral contraceptive pill (OCP) use, contact lens wear, and dry eye signs and symptoms in healthy young women. METHODS: Fifty-two women using OCPs and 45 women not using any form of hormonal contraception were enrolled. Medical, menstrual, and contact lens histories were obtained and dry eye symptoms assessed using the Ocular Surface Disease Index (OSDI) and Symptom Assessment iN Dry Eye (SANDE) questionnaires. Tear osmolarity testing was performed using the TearLab Osmolarity System. RESULTS: The mean age of all subjects was 26.0 +/- 3.7 years. There were no significant differences in any of the measurements between the follicular and luteal phases. Although SANDE scores were significantly higher in subjects with OCP and recent contact lens use (P < 0.01), there were no significant differences in OSDI and tear osmolarity among the same subject groups. Subjects who reported both OCP and recent contact lens use had significantly higher OSDI and SANDE scores (P = 0.015 and P < 0.001, respectively). CONCLUSIONS: There were no differences between the phases of the menstrual cycle. Tear osmolarity was not affected by OCP or contact lens use in young women. However, the combination of OCP use and contact lens wear may increase the severity of dry eye symptoms. PMID- 23086365 TI - Validation of cooling effect of insulated containers for the shipment of corneal tissue and recommendations for transport. AB - PURPOSE: To determine the cooling effect of generic insulated shipping containers in ambient and high-temperature environments. METHODS: Twenty-seven shipping containers were packed with wet ice according to industry standards. The ice in each container was weighed. Ambient temperatures were recorded by data loggers affixed to the exterior. Internal temperatures were recorded by data loggers packed inside the containers, for as long as the data loggers remained at <=8 degrees C. The cooling effect, or minutes per gram of ice a data logger maintained a temperature of <=8 degrees C, was calculated using linear regression; 8 similar containers were subjected to elevated summer temperatures. RESULTS: Small, medium, and large containers held mean masses of wet ice of 685, 1929, and 4439 g, respectively. The linear regression equation for grams of ice to duration of time at <=8 degrees C was y = 0.1994x + 385.13 for small containers, y = 0.1854x + 1273.3 for medium, and y = 0.5892x + 1410.3 for large containers, resulting in a cooling effect of 25.1 hours for small, 58.9 hours for medium, and 85.7 hours for large containers at ambient temperature. The duration of cooling effect in the summer profile group was consistent with that of the ambient temperature group. CONCLUSIONS: All of the container sizes successfully maintained proper cooling when packed with the appropriate grams of wet ice for the needed time interval. This study validates current practice for the shipment of corneal tissue in inexpensive, generic containers that can maintain effective cooling for the duration required for local, national, and international shipment. PMID- 23086366 TI - Graft rejection and graft failure after penetrating keratoplasty or posterior lamellar keratoplasty for fuchs endothelial dystrophy. AB - PURPOSE: To compare the frequency of rejection episodes and graft failure because of surgical complications or rejection after Descemet stripping automated endothelial keratoplasty (DSAEK) and penetrating keratoplasty (PK) for Fuchs endothelial dystrophy. METHODS: A total of 201 eyes of 201 consecutive patients with Fuchs endothelial dystrophy undergoing keratoplasty were included. One hundred two patients underwent DSAEK and 99 PK in the period January 1, 2000, to December 31, 2010. Postoperative topical steroid treatment was similar in the 2 groups. Most patients in the PK group received a short course of oral prednisolone, which was not prescribed for patients undergoing DSAEK. Patient records were retrospectively reviewed; rejection episodes and causes of graft failures were recorded, and Kaplan-Meier survival curves up to 5 years after surgery were computed and compared. RESULTS: All rejection episodes and most graft failures occurred during the first 2 years after surgery. In this period, rejection episodes were noted in 16% of PK and in 5% of DSAEK-treated eyes (P = 0.03). During the first 5 years, significantly more DSAEK grafts than PK grafts had failed (P = 0.04) but only 2 PK-treated and no DSAEK-treated grafts failed because of rejection. CONCLUSION: The frequency of graft rejection episodes is higher after PK than DSAEK for primary endothelial disease, despite the use of oral prednisolone in the PK group. Early graft failure is more common after DSAEK than after PK, whereas graft failure because of previous rejection episodes is uncommon after DSAEK and PK. PMID- 23086368 TI - Effects of chalazion excision on ocular aberrations. AB - PURPOSE: The goal of this study was to compare higher-order aberrations before and after upper lid chalazion excision. METHODS: Fourteen eyes from 12 patients (8 females, mean age: 28.7 +/- 2.7 years) with upper lid chalazion were enrolled in this prospective interventional case series. Chalazia were excised by standard transconjunctival vertical incision. Ocular aberrations were evaluated by aberrometry (ZyWave) before and 2 months after chalazion excision. RESULTS: Root mean square of total higher-order aberrations decreased from 0.67 +/- 0.12 to 0.43 +/- 0.15 MUm (P = 0.012) after excision. The root mean square of Zernike orders in the vertical and horizontal trefoil and horizontal coma were decreased after excision. Orbscan IIz tomography showed a statistically significant decrease in 5 mm zone irregularity (P = 0.027) and an increase in minimum simulated keratometry after surgery (P = 0.046). CONCLUSIONS: Chalazion increases higher-order aberrations, as measured by the Hartmann-Shack aberrometer, which could affect the preoperative evaluation and results of refractive surgery, especially wavefront-guided approaches. Chalazion excision could reduce ocular aberrations and is recommended before refractive surgeries. PMID- 23086369 TI - Viral HCV RNA reactivity of corneal cells in plasma HCV nucleic acid-positive eye donors. AB - PURPOSE: Hepatitis C virus (HCV) infection is a worldwide health concern according to the World Health Organization, and a positive serology test for HCV is currently one of the most common reasons for tissue rejection for transplantation. Demonstrating the presence or absence of viral RNA or DNA in corneal cells, a privileged avascular site, verifies the importance of screening and testing protocols, which eliminate individual donor tissue from potential release for transplantation. METHODS: Improved tests such as nucleic acid test (NAT) have added a significant advantage in the arsenal of measures employed to determine donor eligibility. Standard testing for blood using nucleic acid technology was applied to aliquots of corneal cells obtained by scraping pooled epithelial and endothelial cells from individual donor corneas. RESULTS: Results of the current study further confirm and extend the importance of NAT blood tests by the demonstration of a high percentage (77%) of corneal cells that test positive with HCV NAT in conjunction with concomitant serum-positive ocular tissue donor samples. CONCLUSIONS: These data provide important support for Center for Disease Control and Prevention reports that state that 3 of 4 seropositive individuals were also viremic, and reemphasize the importance of routine NAT blood testing in assuring safe tissue transplants. PMID- 23086370 TI - Elevated immunoglobulin to tissue KLK11 in patients with Sjogren syndrome. AB - PURPOSE: We have previously reported that mouse kallikrein (KLK) 22 in the lacrimal and salivary glands is an autoantigen that can induce primary Sjogren syndrome (SS) in rats. In this study, we determine whether the production of antibodies against tissue KLK is specific for SS and whether the antibody can be used as a biomarker for the diagnosis in humans. METHODS: Sera from 11 patients diagnosed with SS, 8 patients with dry eye disease (DED), and 8 normal age/sex matched controls (NL) were collected for detecting antibodies against tissue KLK1, KLK11, KLK12, and KLK13 by capture enzyme-linked immunosorbent assay. RESULTS: Anti-KLK11 antibody was significantly higher in the SS than in the DED (P = 0.05) and NL (P < 0.01) groups, with no difference in the level of this antibody between the DED and NL groups. In addition, receiver operating characteristic analysis revealed that, at or above an optical density cutoff point of 0.2695, anti-KLK11 antibody has a sensitivity of 82% and a specificity of 94% to distinguish the SS group from the other groups. CONCLUSIONS: Our results suggest that anti-KLK11 might be a novel biomarker for SS in humans. Further investigation is required to confirm this finding and to establish the exact role of KLK11 in the pathogenesis of SS. PMID- 23086371 TI - Surgical resection and amniotic membrane transplantation for treatment of refractory giant papillae in vernal keratoconjunctivitis. AB - PURPOSE: The aim of this study was to evaluate the outcome of surgical resection and amniotic membrane transplantation (AMT) for treatment of refractory symptomatic giant papillae in vernal keratoconjunctivitis (VKC). METHODS: This is a retrospective study of 13 eyes of 9 patients with refractory giant papillae associated with corneal shield ulcer and/or punctate epithelial erosions who underwent surgical resection of the papillae combined with AMT to cover the tarsal conjunctival defect. RESULTS: During 14.2 +/- 4.2 months of postoperative follow-up, smooth tarsal conjunctival surface was achieved in all cases, with no recurrence of the giant papillae in any eye. Corneal shield ulcers and punctate epithelial erosions healed within 2 weeks after surgery and did not recur during the follow-up. Best-corrected visual acuity improved from 0.26 +/- 0.21 logarithm of the minimum angle of resolution preoperatively to 0.02 +/- 0.04 logarithm of the minimum angle of resolution postoperatively (P = 0.01). Three patients experienced recurrence of VKC symptoms, but without giant papillae, which could be well controlled by topical medications. CONCLUSIONS: Surgical resection combined with AMT is an effective procedure for treatment of refractory giant papillae in patients with VKC. PMID- 23086372 TI - Evidence suggesting that the keratinized portions of the upper and lower lid margins do not make complete contact during deliberate blinking. AB - PURPOSE: To investigate whether the keratinized portions of the upper and lower eyelid margins make complete contact during deliberate blinking. METHODS: Ten asymptomatic subjects (21.7 +/- 1.5 years) with healthy eyelids were enrolled. A 0.1-MUL drop of unpreserved 2% fluorescein placed in the temporal (T) third of the keratinized lower lid margin was observed for 10 deliberate blinks, under 16* magnification. If 10 complete blinks did not alter the drop, the subject squeezed their lids shut. The number of lid squeezes to alter the drop appearance was recorded and repeated for the central (C) and nasal (N) sections. Meibomian gland (MG) functionality was assessed with standardized diagnostic expression. Liquid fluorescein was used to assess the proximity of the line of Marx (LOM) to the lower lid MG orifices. RESULTS: In all cases, 10 complete deliberate blinks did not alter the drop. The mean numbers of lid squeezes to alter the drop was: T = 1.5 +/- 1.3, C = 1.9 +/- 1.8, and N = 1.2 +/- 0.8. The mean number of functional MGs per lid section was as follows: T = 0.8 +/- 2.2, C = 4.3 +/- 2.3, and N = 4.4 +/- 0.8. The LOM relative to the MG orifices was as follows-T: LOM in 30% of eyes was posterior to the MG orifices and in 70% of eyes was mixed (a combination of the LOM posterior, touching, bisecting, or anterior to the MG orifices); C: 70% posterior, 30% mixed; and N: 90% posterior, 10% mixed. CONCLUSIONS: Counterintuitively, the keratinized portions of the upper and lower eyelid margins frequently do not make full contact during what appears to be complete blinking. PMID- 23086373 TI - Prevalence and associated factors for pterygium in a rural adult population (the Southern Harbin Eye Study). AB - PURPOSE: To estimate the prevalence of pterygium and identify associated risk factors in a Southern Harbin population at low altitude in a cold climate. METHODS: A prospective population-based survey was conducted in 2006. A stratified, clustered, randomized sampling procedure was used to select 5057 subjects aged 50 years and older. Pterygia were diagnosed and graded, and the association between pterygium and astigmatism was investigated. Risk factors associated with pterygium were evaluated with logistic regression models. RESULTS: A total of 5057 persons aged 50 to 96 years (91.0% of the eligible population) who were residents of Southern Harbin, Heilongjiang Province, China, participated in the study, and 323 (6.4%) had at least 1 pterygium. The prevalence of pterygium in the unilateral and bilateral eyes of the participants was 3.7% and 2.6%, respectively. The presence of a pterygium was significantly associated with the presence of astigmatism (cylinder >= +/- 0.5 diopters, P < 0.001). Pterygium was independently associated with male sex (odds ratio 1.73; 95% confidence interval, 1.37-2.19) and smoking (odds ratio 1.90; 95% confidence interval, 1.51-2.35) (P < 0.001). CONCLUSIONS: This study details pterygium in a rural population of Harbin at low altitude in a cold climate. The prevalence of pterygium in the population is lower than that reported in other regions of the world. The primary causative factors were related to male sex and smoking, the latter of which is easily preventable. Public health schemes to address this serious health issue are urgently needed. PMID- 23086374 TI - Management and outcomes of descemet stripping automated endothelial keratoplasty with intraocular lens exchange, aphakia, and anterior chamber intraocular lens. AB - PURPOSE: To compare outcomes and complications of Descemet stripping automated endothelial keratoplasty (DSAEK) in complicated cases with intraocular lens (IOL) exchange, aphakia, or anterior chamber intraocular lens (ACIOL) implants with a group of noncomplicated DSAEK cases. METHODS: Of the 30 complicated DSAEK cases, 14 eyes underwent concurrent IOL exchange, 5 ACIOLs were not removed, 5 eyes remained aphakic, and 5 eyes had IOL exchange done before or after DSAEK. One eye had an iris-supported phakic IOL removed, followed by cataract extraction with IOL implantation at the time of DSAEK. The comparison group included 109 consecutive DSAEK cases with a history of Fuchs dystrophy or pseudophakic bullous keratopathy. RESULTS: In the complicated group with significant ocular comorbidities, 27.6% achieved best-corrected visual acuity (BCVA) >=20/40 and 60% had a final BCVA >=20/70. In the comparison group of patients without visually significant comorbidities, 94.4% of eyes achieved BCVA >=20/40 with no complication of graft detachments. Of the 30 complicated eyes, 5 (16.7%) had graft detachments and 5 (16.7%) developed IOL dislocations. All grafts remained clear at the last follow-up visit, except 3 cases (10%) in the complicated group, 2 of which were because of primary graft failure and required penetrating keratoplasty. CONCLUSIONS: In comparison with uncomplicated DSAEK cases, higher graft and IOL dislocations were observed in cases involving IOL exchanges, ACIOLs, or aphakia. PMID- 23086375 TI - Corneal cross-linking for the treatment of fungal keratitis. PMID- 23086376 TI - Corneal cross-linking combined with intrastromal corneal ring implantation for progressive keratoconus. PMID- 23086377 TI - Molecular neuropathogenesis of Alzheimer's disease: an interaction model stressing the central role of oxidative stress. AB - Alzheimer's disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic physiological and clinical entity. Other significant psychiatric conditions, such as depression and schizophrenia, may also present with complex and concurrent clinical and/or molecular phenotypes. These neuropsychiatric pathologies also originate from both environmental and genetic factors. We analyzed the molecular phenotypes of AD and discuss them with respect to the classical theories, which we integrated into mechanisms that share molecular and/or anatomical connections. Based on these mechanisms, we propose an interaction model and discuss the model in light of studies that refute or support it. Given the spectrum of AD phenotypes, we limit the scope of our discussion to a few, which facilitates concrete analysis. In addition, the study of specific, individual pathogenic phenotypes may be critical to defining the complex mechanisms leading to AD, thereby improving strategies for developing novel therapies. PMID- 23086379 TI - Selective detection of ATP and ADP in aqueous solution by using a fluorescent zinc receptor. AB - We report on the successful use of a new zinc complex for the selective fluorescent detection of ADP and ATP in water. This is achieved by the complementary coordination of the phosphate groups to the metal centre and hydrogen bonding of the adenosine with the coordinated ligand. PMID- 23086378 TI - Development of embryonic stem cells in recombinant kidneys. AB - Embryonic stem cells (ESC) are self-renewing and can generate all cell types during normal development. Previous studies have begun to explore fates of ESCs and their mesodermal derivatives after injection into explanted intact metanephric kidneys and neonatal kidneys maturing in vivo. Here, we exploited a recently described recombinant organ culture model, mixing fluorescent quantum dot labeled mouse exogenous cells with host metanephric cells. We compared abilities of undifferentiated ESCs with ESC-derived mesodermal or non-mesodermal cells to contribute to tissue compartments within recombinant, chimeric metanephroi. ESC-derived mesodermal cells downregulated Oct4, a marker of undifferentiated cells, and, as assessed by locations of quantum dots, contributed to Wilms' tumor 1-expressing forming nephrons, synaptopodin expressing glomeruli, and organic ion-transporting tubular epithelia. Similar results were observed when labeled native metanephric cells were recombined with host cells. In striking contrast, non-mesodermal ESC-derived cells strongly inhibited growth of embryonic kidneys, while undifferentiated ESCs predominantly formed Oct4 expressing colonies between forming nephrons and glomeruli. These findings clarify the conclusion that ESC-derived mesodermal cells have functional nephrogenic potential, supporting the idea that they could potentially replace damaged epithelia in diseased kidneys. On the other hand, undifferentiated ESCs and non-mesodermal precursors derived from ESCs would appear to be less suitable materials for use in kidney cell therapies. PMID- 23086381 TI - Comorbid anxiety and neurocognitive dysfunctions in children with ADHD. AB - Previous research established that children with ADHD and comorbid anxiety have a later age of ADHD onset, show less off-task and hyperactive behavior, and have more school problems than children with ADHD alone. Comorbid anxiety appears to ameliorate behavioral inhibition deficits, worsen working memory problems, and lengthen reaction times in ADHD. This study investigated the effect of comorbid anxiety on a broad range of neurocognitive functions and includes child-, parent- and teacher reports of anxiety. The sample consisted of 509 children in the age range 5-19 years, including 238 children with a diagnosis of ADHD combined subtype and 271 normal control children. Children were tested on a broad battery of neurocognitive tasks that proved highly sensitive to ADHD in previous work. Linear Structural Equation Modeling (SEM) was used to estimate the effect of comorbid anxiety on the neurocognitive functions. Child reported anxiety was associated with slower motor speed and response speed and better behavioral inhibition. Teacher reported anxiety was related to worse time production. Parent reported anxiety was not significantly associated with any of the neurocognitive functions. Compared to parent and teacher reports of anxiety, child reported comorbid anxiety shows foremost the largest associations with the neurocognitive dysfunctions observed in children with ADHD. This stresses the importance of including child self-reported anxiety assessments in clinical and research practice. PMID- 23086382 TI - Frailty: a review of the first decade of research. AB - Frailty is an emerging geriatric syndrome that refers to a state of increased vulnerability to adverse events including mortality, morbidity, disability, hospitalization, and nursing home admission. Despite its long conceptual and operational history in research and publications, frailty and mechanisms of frailty development are still poorly understood. In this review, we describe a number of conceptual models-reliability, allostatic load, and complexity-that have been put forward to explain the dynamic nature of frailty. We illustrate a consolidated pathophysiological model of frailty, taking into consideration the large and exponentially growing body of studies regarding predictors, indicators, and outcomes of frailty. The model addresses cellular (e.g., oxidative damage and telomere length) and systemic mechanisms (e.g., endocrinal, inflammatory, coagulatory, and metabolic deficiencies) of frailty, moderating or risk factors (e.g., ethnicity, lifestyle, and comorbidities), and outcomes (morbidity, disability, and cognitive decline). Finally, we identify the weaknesses of traditional epidemiological approaches for studying complex phenomena related to frailty and propose areas for future methodological and physiological inquiry. PMID- 23086383 TI - Pseudomembranous candidiasis in HIV/AIDS patients in Cali, Colombia. AB - Candida albicans is the most frequently isolated yeast from the oral cavity of HIV/AIDS individuals. The use of fluconazole has increased the number of resistant or less-sensitive Candida species different than C. albicans. The purpose of this study was to identify the Candida species producing pseudomembranous candidiasis in patients suffering from AIDS, their relationship with CD4(+) counts and their sensitivity to fluconazole and itraconazole. We studied 71 patients at a hospital in the city of Cali. Samples of white plaque were seeded on CHROMagar Candida, yeast identification was done with API 20C Aux, and susceptibility testing was determined by E test. Ninety-three yeast isolates were obtained, 52 single and 41 mixed. C. albicans was the most isolated, followed by C. glabrata. An increased frequency of isolates and variety of Candida species occurred in patients with a CD4(+) cell count <=100 cells/mm(3) without significant differences (p = 0.29). The susceptibility study showed that 8 (8.6%) isolates were resistant to fluconazole and 11 (11.8%) to itraconazole, while 6 (8.8%) C. albicans were simultaneously resistant. No association was found between the isolates of C. albicans or Candida species different than C. albicans and the use of fluconazole (p = 0.21). The results of this study indicate that in the tested population, fluconazole continues to be the best treatment option for oropharyngeal candidiasis in patients suffering from AIDS (HIV/AIDS); however, susceptibility tests are necessary in patients who present therapeutic failure. PMID- 23086384 TI - Synthesis of an activated phosphonated bifunctional chelate with potential for PET imaging and radiotherapy. AB - The synthesis of a phosphonated acyclic bifunctional chelate L* for the labeling of biomaterial is described. L* is based on a pyridine backbone, functionalized in ortho positions by aminomethyl-bis-methylphosphonic acids, and, in the para position, by a side chain containing a reactive NHS carbamate function. The stability of L* in aqueous solutions at different pH values was studied by mass spectrometry, showing the activated function to be sensitive to hydrolysis above neutral pH. The reactivity of L* towards amine functions was tested using ethylamine under different conditions of pH and concentrations, and by the labeling of two reference peptides containing both an N-terminal amino function and a epsilon-amino group of a lysine residue in the backbone, and a supplementary thiol group of a cysteine residue for one of these two peptides. The results showed the coupling to be efficient at pH 8.0, with a total selectivity for the terminal amine function with respect to lysine and cysteine. The labeling was further performed on B28-13, a mouse monoclonal antibody specifically recognizing tenascin-C protein in human cancer. The labeled antibody was characterized by means of mass spectrometry and spectrofluorimetry, unraveling a labeling ratio of one chelate per antibody. Finally, the affinity of the labeled antibody towards its target was controlled by immunofluorescence staining experiments on human colon cancer biopsies, confirming the affinity of the labeled peptide for tenascin-C. PMID- 23086385 TI - Hormone therapy not recommended for chronic disease prevention in menopausal women. PMID- 23086386 TI - Lack of association between proton pump inhibitors and adverse events in patients taking clopidogrel and aspirin. PMID- 23086387 TI - Lung cancer screening with low-dose CT: benefits and potential risks. PMID- 23086388 TI - Confirming the value of pulse oximetry screening for diagnosing critical congenital heart disease. PMID- 23086389 TI - An enormous Jurassic turtle bone bed from the Turpan Basin of Xinjiang, China. AB - A spectacular new terrestrial Konzentratlagerstatte is introduced from the Turpan Basin of Xinjiang, China that probably belongs to the late Middle Jurassic Qigu Formation. It contains a mass accumulation of "xinjiangchelyid" turtles preliminarily identified as Annemys sp. In the zone with the highest turtle concentration, complete and articulated turtle skeletons are tightly packed at a density of up to 36 turtles per square meter. The fossiliferous layer is thickened here and shows an erosional base. This high concentration zone outcrops approximately 10 m in length and shows no decrease in turtle density after exposing 2 m of the layer into the hillside. Adjacent is a more expansive zone of at least 10 m by 30 m. In this region, the fossiliferous layer is evenly thick, and approximately five, fully disarticulated turtles are present per square meter. A conservatively estimated 1,800 turtles may, therefore, have been deposited at this site. It is likely that these aquatic turtles gathered in a retreating water hole in a riverine environment during a drought, much as some aquatic turtles will do today, but perished when the habitat dried up completely. A following catastrophic rainfall event caused a debris flow, possibly channelized in a dry river bed, which transported complete turtles, disarticulated turtles, and mudstone clasts and deposited them after a short distance. This taphonomic model is consistent with previous environmental reconstructions of the Turpan Basin during the late Middle Jurassic in predicting the episodic breakdown of regional monsoonal circulation resulting in a seasonally dry climate with severe episodic droughts. PMID- 23086390 TI - Skimming behaviour and spreading potential of Stenus species and Dianous coerulescens (Coleoptera: Staphylinidae). AB - Rove beetles of the genus Stenus Latreille and the genus Dianous Leach possess pygidial glands containing a multifunctional secretion of piperidine and pyridine derived alkaloids as well as several terpenes. One important character of this secretion is the spreading potential of its different compounds, stenusine, norstenusine, 3-(2-methyl-1-butenyl)pyridine, cicindeloine, alpha-pinene, 1,8 cineole and 6-methyl-5-heptene-2-one. The individual secretion composition enables the beetles to skim rapidly and far over the water surface, even when just a small amount of secretion is emitted. Ethological investigations of several Stenus species revealed that the skimming ability, skimming velocity and the skimming behaviour differ between the Stenus species. These differences can be linked to varied habitat claims and secretion saving mechanisms. By means of tensiometer measurements using the pendant drop method, the spreading pressure of all secretion constituents as well as some naturally identical beetle secretions on the water surface could be established. The compound 3-(2-methyl-1 butenyl)pyridine excelled stenusine believed to date to be mainly responsible for skimming relating to its surface activity. The naturally identical secretions are not subject to synergistic effects of the single compounds concerning the spreading potential. Furthermore, evolutionary aspects of the Steninae's pygidial gland secretion are discussed. PMID- 23086391 TI - Resource competition between two fungal parasites in subterranean termites. AB - Subterranean termites live in large groups in underground nests where the pathogenic pressure of the soil environment has led to the evolution of a complex interaction among individual and social immune mechanisms in the colonies. However, groups of termites under stress can show increased susceptibility to opportunistic parasites. In this study, an isolate of Aspergillus nomius Kurtzman, Horn & Hessltine was obtained from a collapsed termite laboratory colony. We determined that it was primarily a saprophyte and, secondarily, a facultative parasite if the termite immunity is undergoing a form of stress. This was determined by stressing individuals of the Formosan subterranean termite Coptotermes formosanus Shiraki via a co-exposure to the virulent fungal parasite Metarhizium anisopliae (Metch.) Sorokin. We also examined the dynamics of a mixed infection of A. nomius and M. anisopliae in a single termite host. The virulent parasite M. anisopliae debilitated the termite immune system, but the facultative, fast growing parasite A. nomius dominated the mixed infection process. The resource utilization strategy of A. nomius during the infection resulted in successful conidia production, while the chance for M. anisopliae to complete its life cycle was reduced. Our results also suggest that the occurrence of opportunistic parasites such as A. nomius in collapsing termite laboratory colonies is the consequence of a previous stress, not the cause of the stress. PMID- 23086392 TI - Chronotype differences in Drosophila are enhanced by semi-natural conditions. AB - Morning and evening chronotypes of sleep/wake cycles in humans are often metaphorically termed as 'larks' and 'owls'. We derived Drosophila populations early and late, displaying lark- and owl-like emergence chronotypes by imposing selection for adult emergence during morning and evening hours. Preference for morning and evening emergence in these populations was accompanied by divergence in their circadian period (tau) and photic phase response curve. To test if lark- and owl-like emergence chronotypes displayed by these flies under weak environmental cycles of the laboratory would also persist in nature where several zeitgebers are present in the strongest form, we examined the emergence rhythm of early and late flies under semi-natural conditions. The early and late flies not only continued to exhibit divergent emergence waveforms under semi-natural conditions, the differences became even more prominent. However, phases of early and late emergence waveforms did not match natural morning and evening transitions, unlike that observed under laboratory conditions. These results thus provide evidence consistent with the notion that chronotypes are the result of interactions between circadian clocks and natural environmental cycles. PMID- 23086393 TI - Regional collapse of symbiotic specificity between lucanid beetles and canestriniid mites. AB - The intensity of interspecific interactions between hosts and symbionts varies among populations of each organism because of differences in the biotic and abiotic environment. We found geographic mosaics in associations between lucanid beetles (Dorcus rectus and Dorcus striatipennis) and symbiotic mites (Haitlingeria sp. and Sandrophela sp., respectively) that were caused by the collapse of host specificity in the northern part of Japan. Haitlingeria sp. was only collected from the surface of the exoskeleton of D. rectus in south and central Japan. Sandrophela sp. showed host specificity in southern to central Japan but was found on both beetle species in areas where Haitlingeria sp. was not found. Because Haitlingeria sp. was able to reproduce on D. rectus collected from Haitlingeria-free regions and no significant differences were observed in average temperature between the host-specific and nonspecific regions bordering on each other, we suggest that the expansion of Haitlingeria sp. in the north has been limited for unknown reasons. When both mites were placed together on D. rectus, only Haitlingeria sp. reproduced, probably because it killed Sandrophela sp., especially juveniles. Thus, we conclude that Sandrophela sp. has expanded its host use to include D. rectus in areas where Haitlingeria sp. is absent. We hypothesise that false host specificity in the canestriniids has been maintained by habitat isolation and/or aggressive behaviour toward competitors. We suggest that host-specific canestriniids provide benefits to hosts that do not develop countermeasures to exclude micro- or macroparasites from their surfaces. PMID- 23086394 TI - Visual prey detection by near-infrared cues in a fish. AB - Many animal species are able to perceive light wavelengths beyond those visible to humans. While numerous species are additionally sensitive to short wavelengths (UV), long wavelengths such as the near-infrared spectrum (NIR) are supposed to be unsuitable for visual perception. Here, we experimentally show that under exclusive NIR illumination, the cichlid fish Pelvicachromis taeniatus displays a clear foraging response towards NIR reflecting prey. Additional control experiments without prey indicate that the observed behavior is not a mere response to the NIR environment. These results give first evidence for NIR visual sensitivity in a functional context and thus challenge the current view about NIR perception. PMID- 23086395 TI - Offspring sex in a TSD gecko correlates with an interaction between incubation temperature and yolk steroid hormones. AB - We incubated eggs of the Japanese gecko Gekko japonicus at three temperatures, and measured yolk testosterone (T) and 17beta-estradiol (E2) levels at three time points in embryonic development (oviposition, 1/3 of incubation, and 2/3 of incubation), to examine whether maternal influence on offspring sex via yolk steroid hormone deposition is significant in the species. Eggs incubated at 24 degrees C and 32 degrees C produced mostly females, and eggs incubated at 28 degrees C almost a 50:50 sex ratio of hatchlings. Female-producing eggs were larger than male-producing eggs. Clutches in which eggs were incubated at the same temperature produced mostly same-sex siblings. Yolk T level at laying was negatively related to eggs mass, and yolk E2/T ratio was positively related to egg mass. Results of two-way ANOVA with incubation temperature and stage as the factors show that: yolk E2 level was higher at 32 degrees C than at 24 degrees C; yolk T level was higher, whereas yolk E2/T ratio was smaller, at 28 degrees C than at 24 degrees C; yolk E2 and T levels were higher at 2/3 than at 1/3 of incubation. Our data in G. japonucus show that: (1) maternal influence on offspring sex via yolk steroid hormone deposition is significant; (2) incubation temperature affects the dynamics of developmental changes in yolk steroid hormones; (3) influences of yolk steroid hormones on offspring sex are secondary relative to incubation temperature effects; and (4) offspring sex correlates with an interaction between incubation temperature and yolk steroid hormones. PMID- 23086396 TI - Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. AB - We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies. PMID- 23086398 TI - Medical education: a particularly complex intervention to research. AB - Previous debate has explored whether medical education research should become more like health services research in terms of frameworks, collaborations and methodologies. Notable recent changes in health services research include an increasing emphasis on complex interventions, defined as interventions that involve more than one component. The purpose of this study was to explore the extent of thinking about medical education as a complex intervention and to analyse medical education research to determine whether its collaborations and methodologies are becoming more like health services research. Research articles published in three journals over 2 years were analysed to determine the purpose of the research in relation to a framework for evaluating complex interventions, the degree of collaboration, and the methodology. Most studies aimed to develop theory or assess effectiveness and many categories of the complex interventions framework were not represented in the medical education research literature. Studies usually involved only one research site and were predominantly quantitative but not experimental or quasi-experimental. Whilst medical education research has not moved significantly in the direction of health services research over recent years, the complex interventions lens provided insights into why this might be so (namely the significant challenges associated with researching medical education). We recommend that medical education researchers work within a complex interventions framework and look to research fields with similar challenges (e.g. the study of chronic illness in a changing context) for ideas about theories, frameworks, methodologies and collaborations that can illuminate the field of medical education research. PMID- 23086397 TI - De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. AB - Malignant migrating partial seizures of infancy (MMPSI) is a rare epileptic encephalopathy of infancy that combines pharmacoresistant seizures with developmental delay. We performed exome sequencing in three probands with MMPSI and identified de novo gain-of-function mutations affecting the C-terminal domain of the KCNT1 potassium channel. We sequenced KCNT1 in 9 additional individuals with MMPSI and identified mutations in 4 of them, in total identifying mutations in 6 out of 12 unrelated affected individuals. Functional studies showed that the mutations led to constitutive activation of the channel, mimicking the effects of phosphorylation of the C-terminal domain by protein kinase C. In addition to regulating ion flux, KCNT1 has a non-conducting function, as its C terminus interacts with cytoplasmic proteins involved in developmental signaling pathways. These results provide a focus for future diagnostic approaches and research for this devastating condition. PMID- 23086399 TI - Studies on agri-environmental measures: a survey of the literature. AB - Agri-environmental measures (AEM) are incentive-based instruments in the European Union (EU) that provide payments to farmers for voluntary environmental commitments related to preserving and enhancing the environment and maintaining the cultural landscape. We review the AEM literature and provide an overview of important research topics, major research results and future challenges as discussed in the available literature concerning these measures. This review contributes to the existing literature by attempting to equally consider ecological and economic perspectives. The reviewed articles are analyzed regarding their regional focus, topics and methods. The analytical section of the article seeks to discuss commonly asked questions about AEM on the basis of results from reviewed studies. The vast amount of available literature provides valuable insights into specific cases and reveals a complex picture with few general conclusions. The existing research is usually either biased toward ecological or economic perspectives and fails to provide a holistic picture of the problems and challenges within agri-environmental programming (e.g., multiple measures, multiple target areas, legal aspects, financial constraints, transaction costs). Most empirical studies provide detailed insights into selected individual measures but are incapable of providing results at a level relevant to decision-making, as they neglect the role of farmers and the available AEM budget. Predominantly economic approaches often only consider rough assumptions of ecological and economic processes and are also not suitable for decision-making. Decision-support tools that build on these disciplinary results and simultaneously consider scheme factors and environmental conditions at high spatial resolution for application by the responsible authorities are rare and require further research. PMID- 23086400 TI - A review of the main driving factors of forest fire ignition over Europe. AB - Knowledge of the causes of forest fires, and of the main driving factors of ignition, is an indispensable step towards effective fire prevention policies. This study analyses the factors driving forest fire ignition in the Mediterranean region including the most common human and environmental factors used for modelling in the European context. Fire ignition factors are compared to spatial and temporal variations of fire occurrence in the region, then are compared to results obtained in other areas of the world, with a special focus on North America (US and Canada) where a significant number of studies has been carried out on this topic. The causes of forest fires are varied and their distribution differs among countries, but may also differ spatially and temporally within the same country. In Europe, and especially in the Mediterranean basin, fires are mostly human-caused mainly due arson. The distance to transport networks and the distance to urban or recreation areas are among the most frequently used human factors in modelling exercises and the Wildland-Urban Interface is increasingly taken into account in the modelling of fire occurrence. Depending on the socio economic context of the region concerned, factors such as the unemployment rate or variables linked to agricultural activity can explain the ignition of intentional and unintentional fires. Regarding environmental factors, those related to weather, fuel and topography are the most significant drivers of ignition of forest fires, especially in Mediterranean-type regions. For both human and lightning-caused fires, there is a geographical gradient of fire ignition, mainly due to variations in climate and fuel composition but also to population density for instance. The timing of fires depends on their causes. In populated areas, the timing of human-caused fires is closely linked to human activities and peaks in the afternoon whereas, in remote areas, the timing of lightning-caused fires is more linked to weather conditions and the season, with most such fires occurring in summer. PMID- 23086401 TI - Modulation of charge conduction in ZnO nanowires through selective surface molecular functionalization. AB - Two-terminal devices were fabricated using unintentionally doped Zinc Oxide (ZnO) nanowires (NW) grown via a chemical vapor deposition technique to study the influence of surface functionalization on their transport properties. Organic molecules with differing functional groups demonstrated contrasting effects on the charge transport of the nanowires depending on the polarity and orientation of the molecules. PMID- 23086403 TI - Hepatitis C in Punjab--peeping into Pandora's box! PMID- 23086402 TI - Review and discussion of tubular biomarkers in the diagnosis and management of diabetic nephropathy. AB - The prevalence of diabetic nephropathy has tremendously increased with the relentless rise in the incidence of diabetes over the last couple decades. Diabetic nephropathy is a leading cause of morbidity and mortality, and it invariably leads to an end-stage renal disease (ESRD). In an effort to delay the onset of ESRD systematic screening and appropriate management are needed to evaluate the progression of renal damage in diabetic nephropathy. The reliability of current tests in predicting the onset, progression and response to various regimens for diabetic nephropathy is still under debate; and it has engendered a search for more sensitive and specific urinary biomarkers, especially those reflective of tubular dysfunctions. It is well-known that there is a good correlation between the degree of damage to the tubulo-interstitial compartment and the deterioration of renal functions. In view of this, the utility of urinary biomarkers, reflective of tubular injury, reported in the literature is discussed in this brief review. PMID- 23086405 TI - Graphene as a carbon source effects the nanometallurgy of nickel in Ni,Mn layered double hydroxide-graphene oxide composites. AB - Thermal treatment of the hybrid material formed by the spontaneous precipitation of graphene oxide and Ni,Mn layered double hydroxide leads to the segregation of nickel metal nanoparticles (Ni NPs) and the decomposition of graphene to CO(2). Increasing the temperature increases the Ni NP size and results in the complete disappearance of graphene. PMID- 23086404 TI - Histological characteristics of the human femoral head in patients with femoral neck fracture. AB - The reparative reaction including angiogenesis and osteogenesis in human bone after an ischemic event remains unknown. To investigate the reparative reaction in human bone, the distribution of tartrate resistant acid phosphatase (TRAP) positive cells and the expressions of hypoxia inducible factor-1alpha (HIF 1alpha), vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and CD31 were observed around the fracture site in 101 hips in 100 patients with femoral neck fracture. These 17 men and 83 women had a mean age of 80 years (range, 58-97 years). Of the hips, 17 were Garden stage 3, and 84 were Garden stage 4. The mean duration from fracture to surgery was 6.3 days (range, 1 14 days). Hematoxylin-eosin staining, TRAP staining, and immunohistochemistry using anti-HIF-1alpha, anti-VEGF anti-FGF-2, and anti-CD31 antibodies were performed for the coronal section of the retrieved whole femoral heads. TRAP positive cells were detected near the trabecular bone around the fracture site in ten hips (10 %). HIF-1alpha expression was detected in 41 hips (41 %), mainly in the endothelial cells of the vessels. VEGF showed diffuse cytoplasmic staining of the mononuclear cells in the edematous area in 39 hips (39 %) while FGF-2 was detected in the cytoplasm of mononuclear cells in the bone marrow in 82 hips (82 %). CD31 was expressed in the bone marrow vessels in 35 hips (35 %). There were significant differences in HIF-1alpha expression relative to the duration between the fracture and the surgery, and in CD31 expression relative to Garden stage. HIF-1alpha expression was detected around the fracture site in the early period after fracture and CD31 expression was detected more frequently in Garden 3 hips while VEGF and FGF-2 expressions were detected regardless of Garden classification. PMID- 23086407 TI - Physical activity in students of the Medical University of Silesia in Poland. AB - BACKGROUND: Medical students and other health care professionals have substantial knowledge of the benefits of regular physical activity. Furthermore, as they have an ethical obligation to prescribe suitable exercises, they can influence their patients' attitude toward physical activity and can become role models for their patients. Physical therapists, who are primary care practitioners, have great potential for promoting physical activity; however, their role is still underestimated by patients and health care professionals. OBJECTIVE: The objectives of this study were to evaluate physical activity level in students of the Medical University of Silesia in Poland and to focus on the role of physical therapist students in promoting physical activity. DESIGN: This was a cross sectional study. METHODS: The final analysis included 300 students from the schools of physical therapy, midwifery, nursing, pharmacy, cosmetology, and medicine at the Medical University of Silesia. The short form of the International Physical Activity Questionnaire (IPAQ) was used to evaluate physical activity level. RESULTS: Physical therapist students demonstrated the highest level of physical activity, with 46% demonstrating a high level of physical activity, 54% a moderate level of physical activity, and none a low level of physical activity. The largest group of students with a low level of physical activity comprised students from the school of medicine (26%). LIMITATIONS: The number of respondents was relatively small. The main study limitations included its cross-sectional nature and the possibility of self report biases. Further research is warranted to expand the study nationally and determine which factors influence physical activity. CONCLUSIONS: There was a large group of medical students who, despite being aware of benefits of physical activity, did not meet the recommended level of physical activity. Physical therapist students are well trained and qualified to promote healthy habits and encourage individuals to undertake regular physical activity. PMID- 23086406 TI - Autophagy restricts Chlamydia trachomatis growth in human macrophages via IFNG inducible guanylate binding proteins. AB - Interferon gamma (IFNG) is a key host response regulator of intracellular pathogen replication, including that of Chlamydia spp The antichlamydial functions of IFNG manifest in a strictly host, cell-type and chlamydial strain dependent manner. It has been recently shown that the IFNG-inducible family of immunity-related GTPases (IRG) proteins plays a key role in the defense against nonhost adapted chlamydia strains in murine epithelial cells. In humans, IFN inducible guanylate binding proteins (hGBPs) have been shown to potentiate the antichlamydial effect of IFNG; however, how hGBPs regulate this property of IFNG is unknown. In this study, we identified hGBP1/2 as important resistance factors against C. trachomatis infection in IFNG-stimulated human macrophages. Exogenous IFNG reduced chlamydial infectivity by 50 percent in wild-type cells, whereas shRNA hGBP1/2 knockdown macrophages fully supported chlamydial growth in the presence of exogenous IFNG. hGBP1/2 were recruited to bacterial inclusions in human macrophages upon stimulation with IFNG, which triggered rerouting of the typically nonfusogenic bacterial inclusions for lysosomal degradation. Inhibition of lysosomal activity and autophagy impaired the IFNG-mediated elimination of inclusions. Thus, hGBP1/2 are critical effectors of antichlamydial IFNG responses in human macrophages. Through their capacity to remodel classically nonfusogenic chlamydial inclusions and stimulate fusion with autophagosomes, hGBP1/2 disable a major chlamydial virulence mechanism and contribute to IFNG-mediated pathogen clearance. PMID- 23086408 TI - Undetected pectoralis major tendon rupture in a patient referred to a physical therapist in a combat environment: a case report. AB - BACKGROUND AND PURPOSE: This case report describes a patient who was referred to a physical therapist for treatment of a shoulder strain and was eventually diagnosed with a rupture of the pectoralis major tendon that required surgical repair. The purpose of this case report is to highlight the management of this injury within the unique constraints of a combat environment. CASE DESCRIPTION: A 29-year-old man, currently serving as an active duty soldier in the U.S. Army in Iraq, had a sudden onset of right shoulder pain during the concentric portion of a bench press. He was seen by a physician immediately after the injury, diagnosed with a shoulder strain, and referred to a physical therapist for a sling and exercise instruction. On the basis of the history and physical examination findings, which were consistent with a pectoralis major tendon rupture, the physical therapist placed a consult to an orthopedic surgeon in the United States through teleconsultation because orthopedic surgeons were not easily accessible in Iraq for nonemergency musculoskeletal referrals. Subsequently, the orthopedic surgeon advised evacuating the patient out of Iraq for surgical treatment. OUTCOMES: By means of magnetic resonance imaging, the patient was diagnosed as having a rupture of the pectoralis major tendon at the musculotendinous junction near its insertion into the greater tubercle of the humerus that required surgical repair. At 3 months after surgery, the patient had full pain-free shoulder active range of motion and had progressed well through his strengthening program in a manner that allowed return to full duty. At 6 months after surgery, the patient maintained full duty status, was performing a routine of strength training 3 times per week, and had met all of his rehabilitation and personal goals. DISCUSSION: Successful treatment of this patient depended on analysis of the history and physical examination findings by the physical therapist to form an accurate diagnosis. In addition, timely medical evacuation and referral to an orthopedic surgeon for surgical treatment were coordinated in a combat environment. Completion of a progressive rehabilitation program after pectoralis major tendon repair also contributed to this patient's full recovery and return to duty. Had the physical therapist only followed the initial referral request, given this patient's military duties and sports and recreational activities, this case probably would have resulted in suboptimal outcomes. PMID- 23086409 TI - Ankle joint mobilization affects postoperative pain through peripheral and central adenosine A1 receptors. AB - BACKGROUND: Physical therapists frequently use joint mobilization therapy techniques to treat people with musculoskeletal dysfunction and pain. Several studies suggest that endogenous adenosine may act in an analgesic fashion in various pain states. OBJECTIVE: The purpose of this study was to investigate the contribution of the adenosinergic system on the antihyperalgesic effect of ankle joint mobilization (AJM). DESIGN: This was a experimental study. METHODS: To test the hypothesis that the adrenosinergic system is involved in the antihyperalgesic effect of AJM, mice (25-35 g) submitted to plantar incision surgery were used as a model of acute postoperative pain. The mice were subjected to AJM for 9 minutes. Withdrawal frequency to mechanical stimuli was assessed 24 hours after plantar incision surgery and 30 minutes after AJM, adenosine, clonidine, or morphine treatments. The adenosinergic system was assessed by systemic (intraperitoneal), central (intrathecal), and peripheral (intraplantar) administration of caffeine. The participation of the A1 receptor was investigated using a selective adenosine A1 receptor subtype antagonist. In addition, previous data on the involvement of the serotonergic and noradrenergic systems in the antihyperalgesic effect of AJM were confirmed. RESULTS: Ankle joint mobilization decreased mechanical hyperalgesia, and this effect was reversed by pretreatment of the animals with caffeine given by intraperitoneal, intraplantar, and intrathecal routes. In addition, intraplanar and intrathecal administrations of 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, a selective adenosine A1 subtype receptor antagonist) or systemic administration of yohimbine or rho chlorophenylalanine methyl ester hydrochloride (PCPA) blocked the antihyperalgesia induced by AJM. LIMITATIONS: The results are limited to animal models and cannot be generalized to acute pain in humans. CONCLUSIONS: This study demonstrated the involvement of the adenosinergic system in the antihyperalgesic effect of AJM in a rodent model of pain and provides a possible mechanism basis for AJM-induced relief of acute pain. PMID- 23086410 TI - The hypothesis-oriented pediatric focused algorithm: a framework for clinical reasoning in pediatric physical therapist practice. AB - Pediatric physical therapist practice presents unique challenges to the clinical reasoning processes of novice clinicians and physical therapist students. The purpose of this article is to present the Hypothesis-Oriented Pediatric Focused Algorithm (HOP-FA), a clinical framework designed to guide the clinical reasoning process in pediatric physical therapist practice. The HOP-FA provides a systematic, stepwise guide to the patient/client management process wherein the therapist is asked to consider various factors and issues that may affect the clinical reasoning process for a particular child and family. The framework provided by the HOP-FA is not built upon a specific therapeutic philosophy and may be useful as a tool in clinical education, in the classroom, and for clinicians who are new to or re-entering pediatric practice. PMID- 23086411 TI - An introduction to phosphoinositides. AB - Phosphoinositides (PIs) are minor components of cellular membranes that play critical regulatory roles in several intracellular functions. This chapter describes the main enzymes regulating the turnover of each of the seven PIs in mammalian cells and introduces to some of their intracellular functions and to some evidences of their involvement in human diseases. Due to the complex interrelation between the distinct PIs and the plethora of functions that they can regulate inside a cell, this chapter is not meant to be a comprehensive coverage of all aspects of PI signalling but rather an introduction to this complex signalling field. For more details of their regulation/functions and extensive description of their intracellular roles, more detailed reviews are suggested on each single topic. PMID- 23086412 TI - Phosphoinositides and cardiovascular diseases. AB - Phosphoinositides (PIs), a family of phosphorylated derivatives of the membrane lipid phosphatidylinositol, are established regulators of multiple cellular functions. An increasing amount of evidence has highlighted potential links between PI-mediated signaling pathways and the etiology of many human diseases, including cardiovascular pathologies. This chapter will provide a detailed overview of the peculiar functions of the major cardiovascular PIs in the pathogenesis of atherosclerosis, heart failure, and arrhythmias. PMID- 23086413 TI - Phosphoinositides in insulin action and diabetes. AB - Phosphoinositides play an essential role in insulin signaling, serving as a localization signal for a variety of proteins that participate in the regulation of cellular growth and metabolism. This chapter will examine the regulation and localization of phosphoinositide species, and will explore the roles of these lipids in insulin action. We will also discuss the changes in phosphoinositide metabolism that occur in various pathophysiological states such as insulin resistance and diabetes. PMID- 23086414 TI - Phosphoinositides in neuroexocytosis and neuronal diseases. AB - Phosphoinositides (PIs) are a family of phospholipids derived from phosphatidylinositol (PtdIns), whose location, synthesis, and degradation depend on specific PI kinases and phosphatases. PIs have emerged as fundamental regulators of secretory processes, such as neurotransmitter release, hormone secretion, and histamine release in allergic responses. In neurons and neuroendocrine cells, regulated secretion requires the calcium-dependent fusion of transmitter-containing vesicles with the plasma membrane. The role played by PIs in exocytosis is best exemplified by the Ca2+-dependent binding of vesicular Synaptotagmin1 to the plasma membrane PtdIns(4,5)P2, and the recently demonstrated role of PtdIns(4,5)P2 in the mobilization of secretory vesicles to the plasma membrane. New evidence has also recently emerged of an alternative PI pathway that can control exocytosis positively (via PtdIn3P) or negatively (via PtdIns(3,5)P2). However, the positive or negative effectors for these pathways remain to be established. Reducing PtdIns(3,5)P2 potentiates neuroexocytosis but leads to neuronal degeneration and has been linked to certain forms of Charcot Marie-Tooth disease and amyotrophic lateral sclerosis. The goal of this review is to describe the role of PIs in neuroexocytosis and explore the current hypotheses linking these effects to human diseases. PMID- 23086415 TI - Effects of phosphoinositides and their derivatives on membrane morphology and function. AB - Currently, one of the fundamental problems in the study of membrane function and morphology is that the roles of proteins and lipids are usually investigated separately. In most cases proteins are predominant, with lipids taking a subsidiary role. This polarised view is in part due to the more straightforward and familiar techniques used to investigate proteins. Here, we summarise how phospholipids can be studied in cells with new tools that can acutely (rapidly and specifically) modify phospholipid composition of membranes in subcellular compartments. We point out some of the important physical effects that phosphoinositides in particular can have in altering membrane bilayer morphology, and provide specific examples to illustrate the roles that these phospholipids may play in maintaining the geometry of endomembranes. PMID- 23086417 TI - PIKfyve and its Lipid products in health and in sickness. AB - PIKfyve, a phosphoinositide 5-kinase synthesizing PtdIns(3,5)P2 and PtdIns5P in a cellular context, belongs to an evolutionarily ancient gene family of PtdIns(3,5)P2-synthesizing enzymes that, except for plants, are products of a single-copy gene across species. In the dozen years after its discovery, enormous progress has been made in characterizing the numerous PIKfyve cellular functions and the regulatory mechanisms that govern these functions. It became clear that PIKfyve does not act alone but, rather, it engages the scaffolding regulator ArPIKfyve and the phosphatase Sac3 to make a multiprotein "PAS" complex, so called for the first letters of the protein names. This complex relays antagonistic signals, one for synthesis, another for turnover of PtdIns(3,5)P2, whose dysregulated coordination is linked to several human diseases. The physiological significance for each protein in the PAS complex is underscored by the early lethality of the mouse models with disruption in any of the three genes. This chapter summarizes our current knowledge of the diverse and complex functionality of PIKfyve and PtdIns(3,5)P2/PtdIns5P products with particular highlights on recent discoveries of inherited or somatic mutations in PIKfyve and Sac3 linked to human disorders. PMID- 23086418 TI - Class I phosphoinositide 3-kinases in normal and pathologic hematopoietic cells. AB - Class I phosphoinositide 3-kinases which produce the D3-phosphoinositide second messenger phosphatidylinositol 3,4,5-trisphosphate in response to membrane receptors activation play a critical role in cell proliferation, survival, metabolism, and motility. These lipid kinases and the phosphatases regulating the level of D3-phosphoinositides have been an intense area of research these last two decades. The class I phosphoinositide 3-kinases signaling is found aberrantly activated in numerous human cancers, including in malignant hemopathies, and are important therapeutic targets for cancer therapy. Haematopoiesis is an ongoing process which generates the distinct blood cell types from a common hematopoietic stem cell through the action of a variety of cytokines. In the human adult hematopoiesis occurs primarily in the bone marrow, and defects in hematopoiesis result in diseases, such as anemia, thrombocytopenia, myeloproliferative syndromes, or leukemia. Here we give a brief overview of the role of class I phosphoinositide 3-kinases in hematopoietic stem cells, in hematopoietic lineage development and in leukemia, particularly in acute myeloid leukemia and summarize the potential therapeutic implications. PMID- 23086416 TI - Molecular analysis of protein-phosphoinositide interactions. AB - Diverse biological processes including cell growth and survival require transient association of proteins with cellular membranes. A large number of these proteins are drawn to a bilayer through binding of their modular domains to phosphoinositide (PI) lipids. Seven PI isoforms are found to concentrate in distinct pools of intracellular membranes, and this lipid compartmentalization provides an efficient way for recruiting PI-binding proteins to specific cellular organelles. The atomic-resolution structures and membrane docking mechanisms of a dozen PI effectors have been elucidated in the last decade, offering insight into the molecular basis for regulation of the PI-dependent signaling pathways. In this chapter, I summarize the mechanistic aspects of deciphering the 'PI code' by the most common PI-recognizing domains and discuss similarities and differences in the membrane anchoring mechanisms. PMID- 23086419 TI - The diverse functions of phosphatidylinositol transfer proteins. AB - Phosphatidylinositol transfer proteins (PITPs), comprising five members in the human genome are implicated in the non-vesicular traffic of phosphatidylinositol (PI) between intracellular membranes and the plasma membrane. Three members of the PITP family (PITPalpha, PITPbeta, and RdgBbeta (retinal degeneration type B) alt. name PITPNC1) are present as single domain proteins and two (RdgBalphaI and RdgBalphaII alt. name PITPNM1 and PITPNM2) are present as multi-domain proteins with the PITP domain located at the N-terminus. The hallmark of PITP proteins is to extract PI molecules from a membrane, sequester in its binding pocket and deposit the lipid to membranes. PITPs regulate the synthesis of phosphoinositides (PPIs) either by delivery of the substrate, PI to specific membrane compartments or by potentiating the activities of the lipid kinases, or both. In the light of recent studies, we propose that PITPs are regulators of phosphoinositide pathways by recruitment to membranes through specific protein interactions to promote molecular exchange between closely opposed membranes i.e., at membrane contact sites. Individual PITP proteins play highly specific roles in many biological processes including neurite outgrowth, membrane traffic, cytokinesis, and sensory transduction in mammals as well as in the model organisms, Drosophila, Caenorhabditis elegans, and zebrafish. The common requirement for the diverse functions for all PITPs is their ability to bind PI and coupling its function to phosphoinositide-dependent pathways. PMID- 23086420 TI - Myotubularin phosphoinositide phosphatases in human diseases. AB - The level and turnover of phosphoinositides (PIs) are tightly controlled by a large set of PI-specific enzymes (PI kinases and phosphatases). Mammalian PI phosphatases are conserved through evolution and among this large family the dual specificity phosphatase (PTP/DSP) are metal-independent enzymes displaying the amino acid signature Cys-X5-Arg-Thr/Ser (CX5RT/S) in their active site. Such catalytic site characterizes the myotubularin 3-phosphatases that dephosphorylate PtdIns3P and PtdIns(3,5)P2 and produce PtdIns5P. Substrates of myotubularins have been implicated in endocytosis and membrane trafficking while PtdIns5P may have a role in signal transduction. As a paradox, 6 of the 14 members of the myotubularin family lack enzymatic activity and are considered as dead phosphatases. Several myotubularins have been genetically linked to human diseases: MTM1 is mutated in the congenital myopathy X-linked centronuclear or myotubular myopathy (XLCNM) and MTMR14 (JUMPY) has been linked to an autosomal form of such disease, while MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth (CMT) neuropathies. Furthermore, recent evidences from genetic association studies revealed that several other myotubularins could be associated to chronic disorders such as cancer and obesity, highlighting their importance for human health. Here, we discuss cellular and physiological roles of myotubularins and their implication in human diseases, and we present potential pathological mechanisms affecting specific tissues in myotubularin-associated diseases. PMID- 23086421 TI - Nuclear PI-PLC beta1 and Myelodysplastic syndromes: from bench to clinics. AB - Myelodysplastic syndromes (MDS), clonal hematopoietic stem-cell disorders mainly affecting older adult patients, show ineffective hematopoiesis in one or more of the lineages of the bone marrow. A number of MDS progresses to acute myeloid leukemia (AML) with the involvement of genetic and epigenetic mechanisms affecting PI-PLC beta1. The molecular mechanisms underlying the MDS evolution to AML are still unclear, even though it is now clear that the nuclear signaling elicited by PI-PLC beta1, Cyclin D3, and Akt plays an important role in the control of the balance between cell cycle progression and apoptosis in both normal and pathologic conditions. Moreover, a correlation between other PI-PLCs, such as PI-PLC beta3, kinases and phosphatases has been postulated in MDS pathogenesis. Here, we review the findings hinting at the role of nuclear lipid signaling pathways in MDS, which could become promising therapeutic targets. PMID- 23086422 TI - Inositol polyphosphate phosphatases in human disease. AB - Phosphoinositide signalling molecules interact with a plethora of effector proteins to regulate cell proliferation and survival, vesicular trafficking, metabolism, actin dynamics and many other cellular functions. The generation of specific phosphoinositide species is achieved by the activity of phosphoinositide kinases and phosphatases, which phosphorylate and dephosphorylate, respectively, the inositol headgroup of phosphoinositide molecules. The phosphoinositide phosphatases can be classified as 3-, 4- and 5-phosphatases based on their specificity for dephosphorylating phosphates from specific positions on the inositol head group. The SAC phosphatases show less specificity for the position of the phosphate on the inositol ring. The phosphoinositide phosphatases regulate PI3K/Akt signalling, insulin signalling, endocytosis, vesicle trafficking, cell migration, proliferation and apoptosis. Mouse knockout models of several of the phosphoinositide phosphatases have revealed significant physiological roles for these enzymes, including the regulation of embryonic development, fertility, neurological function, the immune system and insulin sensitivity. Importantly, several phosphoinositide phosphatases have been directly associated with a range of human diseases. Genetic mutations in the 5-phosphatase INPP5E are causative of the ciliopathy syndromes Joubert and MORM, and mutations in the 5-phosphatase OCRL result in Lowe's syndrome and Dent 2 disease. Additionally, polymorphisms in the 5-phosphatase SHIP2 confer diabetes susceptibility in specific populations, whereas reduced protein expression of SHIP1 is reported in several human leukaemias. The 4-phosphatase, INPP4B, has recently been identified as a tumour suppressor in human breast and prostate cancer. Mutations in one SAC phosphatase, SAC3/FIG4, results in the degenerative neuropathy, Charcot-Marie-Tooth disease. Indeed, an understanding of the precise functions of phosphoinositide phosphatases is not only important in the context of normal human physiology, but to reveal the mechanisms by which these enzyme families are implicated in an increasing repertoire of human diseases. PMID- 23086423 TI - Effects of lexical characteristics and demographic factors on mandarin chinese open-set word recognition in children with cochlear implants. AB - OBJECTIVE: The purpose of this study was to examine the open-set word recognition performance of Mandarin Chinese-speaking children who had received a multichannel cochlear implant (CI) and examine the effects of lexical characteristics and demographic factors (i.e., age at implantation and duration of implant use) on Mandarin Chinese open-set word recognition in these children. DESIGN: Participants were 230 prelingually deafened children with CIs. Age at implantation ranged from 0.9 to 16.0 years, with a mean of 3.9 years. The Standard-Chinese version of the Monosyllabic Lexical Neighborhood test and the Multisyllabic Lexical Neighborhood test were used to evaluate the open-set word identification abilities of the children. A two-way analysis of variance was performed to delineate the lexical effects on the open-set word identification, with word difficulty and syllable length as the two main factors. The effects of age at implantation and duration of implant use on open-set, word-recognition performance were examined using correlational/regressional models. RESULTS: First, the average percent-correct scores for the disyllabic "easy" list, disyllabic "hard" list, monosyllabic "easy" list, and monosyllabic "hard" list were 65.0%, 51.3%, 58.9%, and 46.2%, respectively. For both the easy and hard lists, the percentage of words correctly identified was higher for disyllabic words than for monosyllabic words, Second, the CI group scored 26.3%, 31.3%, and 18.8 % points lower than their hearing-age-matched normal-hearing peers for 4, 5, and 6 years of hearing age, respectively. The corresponding gaps between the CI group and the chronological-age-matched normal-hearing group were 47.6, 49.6, and 42.4, respectively. The individual variations in performance were much greater in the CI group than in the normal-hearing group, Third, the children exhibited steady improvements in performance as the duration of implant use increased, especially 1 to 6 years postimplantation. Last, age at implantation had significant effects on postimplantation word-recognition performance. The benefit of early implantation was particularly evident in children 5 years old or younger. CONCLUSIONS: First, Mandarin Chinese-speaking pediatric CI users' open set word recognition was influenced by the lexical characteristics of the stimuli. The score was higher for easy words than for hard words and was higher for disyllabic words than for monosyllabic words, Second, Mandarin-Chinese speaking pediatric CI users exhibited steady progress in open-set word recognition as the duration of implant use increased. However, the present study also demonstrated that, even after 6 years of CI use, there was a significant deficit in open-set, word-recognition performance in the CI children compared with their normal-hearing peers. Third, age at implantation had significant effects on open-set, word-recognition performance. Early implanted children exhibited better performance than children implanted later. PMID- 23086424 TI - Acoustic experience alters the aged auditory system. AB - OBJECTIVES: Presbyacusis, one of the most common ailments of the elderly, is often treated with hearing aids, which serve to reintroduce some or all of those sounds lost to peripheral hearing loss. However, little is known about the underlying changes to the ear and brain as a result of such experience with sound late in life. The present study attempts to model this process by rearing aged CBA mice in an augmented acoustic environment (AAE). DESIGN: Aged (22-23 months) male (n = 12) and female (n = 9) CBA/CaJ mice were reared in either 6 weeks of low-level (70 dB SPL) broadband noise stimulation (AAE) or normal vivarium conditions. Changes as a function of the treatment were measured for behavior, auditory brainstem response thresholds, hair cell cochleograms, and gamma aminobutyric acid neurochemistry in the key central auditory structures of the inferior colliculus and primary auditory cortex. RESULTS: The AAE-exposed group was associated with sex-specific changes in cochlear pathology, auditory brainstem response thresholds, and gamma aminobutyric acid neurochemistry. Males exhibited significantly better thresholds and reduced hair cell loss (relative to controls) whereas females exhibited the opposite effect. AAE was associated with increased glutamic acid decarboxylase (GAD67) levels in the inferior colliculus of both male and female mice. However, in primary auditory cortex AAE exposure was associated with increased GAD67 labeling in females and decreased GAD67 in males. CONCLUSIONS: These findings suggest that exposing aged mice to a low-level AAE alters both peripheral and central properties of the auditory system and these changes partially interact with sex or the degree of hearing loss before AAE. Although direct application of these findings to hearing aid use or auditory training in aged humans would be premature, the results do begin to provide direct evidence for the underlying changes that might be occurring as a result of hearing aid use late in life. These results suggest the aged brain retains significantly anatomical, electrophysiological, and neurochemical plasticity. PMID- 23086425 TI - Identity-related growth and loss in a sample of HIV-positive gay and bisexual men: initial scale development and psychometric evaluation. AB - Past examinations of the impact of chronic illness on identity have focused primarily on positive adaptation (i.e., benefit finding or posttraumatic growth). Given that associations between these constructs and psychosocial wellbeing are equivocal, greater investigation is needed into interactions among perceived positive and negative identity changes pursuant to illness. A cross-sectional study was conducted between 2006 and 2007 with an ethnically diverse sample of 129 HIV-positive gay and bisexual men. Participants completed a brief quantitative survey, including a new measure, the Impact on Self-Concept Scale (ISCS), as well as gay-related stigma, quality of life, and regulatory focus. Factor analysis supported the existence of two ISCS subscales: self-growth and self-loss. Both subscales demonstrated strong internal consistency and were weakly but positively correlated. Preliminary assessment of construct validity indicated distinct patterns of association, with self-loss being more strongly associated with stigma and quality of life than self-growth. In multivariate models, associations between self-loss and both quality of life and regulatory focus were moderated by self-growth. The ISCS demonstrated preliminary reliability and validity in this sample. Findings suggest that self-growth and self-loss are meaningfully distinct constructs that may interact to produce important implications for understanding the experience of chronic illness. PMID- 23086426 TI - HIV-positive and in jail: race, risk factors, and prior access to care. AB - Black individuals represent 13 % of the US population but 46 % of HIV positive persons and 40 % of incarcerated persons. The national EnhanceLink project evaluated characteristics of HIV-positive jail entrants at ten sites and explored associations between race and HIV disease state. Between 1/2008 and 10/2011, 1,270 study participants provided demographic and clinical data. Adjusted odds ratios (aORs) were calculated for advanced HIV disease (CD4 < 200 cells/mm(3)) and uncontrolled viremia (viral load > 400 copies/ml) for Black (n = 807) versus non-Black (n = 426) participants. Sixty-five percent of HIV-positive jail participants self-identified as Black. Among all participants, fewer than half had a high school diploma or GED, the median number of lifetime arrests was 15, and major mental illness and substance abuse were common. Black participants were more likely to be older than non-Black participants, and less likely to have health insurance (70 vs 83 %) or an HIV provider (73 vs 81 %) in the prior 30 days. Among all male study participants (n = 870), 20 % self-identified as homosexual or bisexual. Black male participants were more likely to be homosexual or bisexual (22 vs 16 %) and less likely to have a history of injection drug use (20 vs 50 %) than non-Black male participants. Advanced HIV disease was associated with self-identification as Black (aOR = 1.84, 95 % CI 1.16-2.93) and time since HIV diagnosis of more than two years (aOR = 3.55, 95 % CI 1.52-8.31); advanced disease was inversely associated with age of less than 38 years (aOR = 0.41, 95 % CI 0.24-0.70). Uncontrolled viremia was inversely associated with use of antiretroviral therapy (ART) in the prior 7 days (aOR = 0.25, 95 % CI 0.15 0.43) and insurance coverage in the prior 30 days (aOR = 0.46, 95 % CI 0.26 0.81). CONCLUSIONS: The racial disparities of HIV and incarceration among Black individuals in the US are underscored by the finding that 65 % of HIV-positive jail participants self-identified as Black in this ten-site study. Our study also found that 22 % of Black male participants self-identified as men who have sex with men (MSM). We believe these findings support jails as strategic venues to reach heterosexual, bisexual, and homosexual HIV-positive Black men who may have been overlooked in the community. Among HIV-positive jail entrants, Black individuals had more advanced HIV disease. Self-identification as Black was associated with a lower likelihood of having health insurance or an HIV provider prior to incarceration. HIV care and linkage interventions are needed within jails to better treat HIV and to address these racial disparities. PMID- 23086427 TI - Routine depression screening in an HIV clinic cohort identifies patients with complex psychiatric co-morbidities who show significant response to treatment. AB - This study described characteristics, psychiatric diagnoses and response to treatment among patients in an outpatient HIV clinic who screened positive for depression. Depressed (25 %) were less likely to have private insurance, less likely to have suppressed HIV viral loads, had more anxiety symptoms, and were more likely to report current substance abuse than not depressed. Among depressed, 81.2 % met diagnostic criteria for a depressive disorder; 78 % for an anxiety disorder; 61 % for a substance use disorder; and 30 % for co-morbid anxiety, depression, and substance use disorders. Depressed received significantly more treatment for depression and less HIV primary care than not depressed patients. PHQ-9 total depression scores decreased by 0.63 from baseline to 6-month follow-up for every additional attended depression treatment visit. HIV clinics can routinely screen and treat depressive symptoms, but should consider accurate psychiatric diagnosis as well as co-occurring mental disorders. PMID- 23086428 TI - Bringing your baggage to bed: associations of previous relationship experiences with sexual risk. AB - Delaying sexual intercourse after initiating a relationship (i.e., increasing the presexual period) and delaying unprotected sex can reduce HIV/STI risk. Past relationship and risk experiences may influence sexual decisions in a current relationship. We examined how past relationship and risk experiences of both members of 296 young pregnant couples influenced length of presexual period and time to unprotected sex. Forty-six percent of couples had sex within the first month of seeing each other and had unprotected sex within 1 month of having sex. Length of presexual period and time to unprotected sex were significantly shorter in their current relationship than their previous relationship for both men and women (all p < 0.05). Female past relationship and risk factors were more strongly associated with length of presexual relationship than male past relationship and risk factors. Both male and female past relationship and risk factors were associated with time to unprotected sex. PMID- 23086429 TI - Food insecurity and risky sexual behaviors among homeless and marginally housed HIV-infected individuals in San Francisco. AB - Food insecurity is common among HIV-infected populations in resource-rich and resource-poor countries. We hypothesized that food insecurity would be associated with risky sexual behaviors. We examined this hypothesis among all sexually active participants (n = 154) in the Research on Access to Care in the Homeless (REACH) cohort in San Francisco. The outcomes were unprotected vaginal or anal sex and multiple sexual partners during the prior 90 days. Associations were examined using repeated measures multivariable logistic regression analyses. Food insecurity was independently associated with unprotected sexual activity (AOR = 2.01 for each five point increase in HFIAS scale, 95 % CI 1.31-3.10) and multiple sexual partners (AOR = 1.54 for each five-point increase in HFIAS scale, 95 % CI 1.05-2.29). Food insecurity is a risk factor for unprotected sexual activity and multiple sexual partners among homeless and marginally housed HIV-infected individuals in San Francisco. Measures to alleviate food insecurity may play a role in decreasing secondary HIV transmission. PMID- 23086431 TI - The role of LAT1 in (18)F-DOPA uptake in malignant gliomas. AB - Positron emission tomography (PET) imaging with the amino acid tracer 6-(18)F fluoro-L-3,4-dihydroxy-phenylalanine ((18)F-DOPA) may provide better spatial and functional information in human gliomas than CT or MRI alone. The L-type amino acid transporter 1 (LAT1) is responsible for membrane transport of large neutral amino acids in normal cells. This study assessed the relationship between LAT1 expression and (18)F-DOPA uptake in human astrocytomas. Endogenous LAT1 expression was measured in established glioblastoma (GBM) cell lines and primary GBM xenografts using Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR). Uptake of (18)F-DOPA was approximated in vitro using (3)H-L-DOPA as an analog. Uptake of (3)H-L-DOPA was assessed in cells expressing LAT1 shRNA or LAT1 siRNA and compared to non-targeted (NT) control shRNA or siRNA sequences, respectively. To demonstrate the clinical relevance of these findings, LAT1 immunofluorescence staining was compared with corresponding regions of (18)F-DOPA PET uptake in patients with newly diagnosed astrocytomas. LAT1 mRNA and protein expression varies in GBM, and the extent of (3)H-L-DOPA uptake was positively correlated with endogenous LAT1 expression. Stable shRNA mediated LAT1 knockdown in T98 and GBM28 reduced (3)H-L-DOPA uptake relative to NT shRNA by 57 (P < 0.0001) and 52 % (P < 0.001), respectively. Transient siRNA mediated LAT1 knockdown in T98 reduced (3)H-L-DOPA uptake relative to NT siRNA up to 68 % (P < 0.01). In clinical samples, LAT1 expression positively correlated with (18)F-DOPA PET uptake (P = 0.04). Expression of LAT1 is strongly associated with (3)H-L-DOPA uptake in vitro and (18)F-DOPA uptake in patient biopsy samples. These results define LAT1 as a key determinant of (18)F-DOPA accumulation in GBM. PMID- 23086432 TI - A phase II study of conventional radiation therapy and thalidomide for supratentorial, newly-diagnosed glioblastoma (RTOG 9806). AB - The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma. PMID- 23086433 TI - Continuous daily sunitinib for recurrent glioblastoma. AB - Bevacizumab ((BEV) has become a mainstay of treating recurrent glioblastoma, but eventual tumor resistance is expected. Targeting multiple growth-associated signaling pathways may result in more effective treatment than targeting VEGF alone. Patients with recurrent glioblastoma were stratified by prior BEV exposure and treated with sunitinib 37.5 mg daily in this phase II study. Response evaluations were performed at baseline and at the end of every 4 week cycle. Six month progression-free survival (PFS6) was the primary endpoint for both arms of the study. Secondary endpoints included health related quality of life measures and FDG-PET correlatives with patient outcomes. Sixty-three patients were accrued to this study; thirty-two were BEV-naive, 31 were BEV-resistant. PFS6 was 10.4 % [95 % CI 3.2-33.8] in the BEV-naive cohort and 0 % in the BEV-resistant cohort. Median overall survival was 9.4 months [95 % CI 6.15-21.90] in the BEV-naive cohort and 4.37 months [95 % CI 3.02-6.21] in the BEV-resistant cohort. 3/29 patients (10 %) of the BEV-naive, and 0/27 BEV-resistant patients achieved radiographic response. Thrombocytopenia, leukopenia, and neutropenia were the most common drug-associated adverse events and occurred with higher frequency than expected. Sunitinib treatment in BEV-naive patients did not appear to affect outcomes with subsequent BEV therapy. Continuous daily sunitinib did not prolong progression-free survival in BEV-naive nor BEV-resistant patients with recurrent glioblastoma. PMID- 23086434 TI - EGFR mutation status in brain metastases of non-small cell lung carcinoma. AB - Brain metastases are a frequent and grave complication of non-small cell lung carcinoma (NSCLC). The prognosis is generally poor, despite standard therapy based on surgery and radiotherapy. A degree of understanding of the molecular basis of tumors has led to the development of targeted agents with promising initial findings for the treatment of NSCLC. EGFR mutations have been identified which are associated with significant sensitivity to EGFR tyrosine kinase inhibitors (TKI) and correlate with improved outcome in patients with NSCLC who are treated with these agents. The adoption of treatment tailored to the genetic make-up of individual tumors could lead to substantial therapeutic improvements, and such targeted therapy might be considered as a therapeutic option for brain metastases in the future. We review current knowledge about EGFR mutation status in the specific context of brain metastasis: its association with the response of brain metastases to TKI, its prevalence in brain metastases, and the correlation between mutation status in metastases as compared to the corresponding primary lung carcinoma. PMID- 23086435 TI - Epilepsy in the end-of-life phase in patients with high-grade gliomas. AB - Epilepsy is common in patients with brain tumors. Patients presenting seizures as the first sign of a malignant glioma are at increased risk of recurrent seizures despite treatment with antiepileptic drugs. However, little is known about the incidence of epilepsy in the last stage of disease and in the end-of-life phase of brain tumor patients. We retrospectively analyzed the incidence of seizures in the last months of life in a series of patients affected by high-grade gliomas who were assisted at home during the whole course of the disease until death. A total of 157 patients were available for analysis. Of these patients, 58 (36.9 %) presented seizures in the last month before death. The risk of seizures in the end-of-life phase is higher in patients presenting previous history of epilepsy, particularly in patients with late-onset epilepsy. Out of the 58 patients presenting seizures in the last month of life, 86.2 % had previously had seizures and 13.8 % were seizure free. Most patients may encounter swallowing difficulties in taking anticonvulsants orally due to dysphagia and disturbances of consciousness, thus anticonvulsant treatment needs to be modified in advance. Loss of seizure control in the end-of-life phase may influence the quality of life of patients and their caregivers. PMID- 23086436 TI - Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model. AB - Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy. PMID- 23086437 TI - Direct deposition of gold nanoplates and porous platinum on substrates through solvent-free chemical reduction of metal precursors with ethylene glycol vapor. AB - Deposition of nanostructured metals on substrates is important for the fundamental study and practical application, such as in optics and catalysis. In this paper, we report the deposition of gold (Au) nanoplates and porous platinum (Pt) structures on substrates through solvent-free chemical reductions of chloroauric acid (HAuCl(4)) and chloroplatinic acid (H(2)PtCl(6)) with ethylene glycol (EG) vapor at temperatures below 200 degrees C. The process includes two steps. The first step is the formation of a thin layer of a metal precursor on substrates by coating solution of a metal precursor. The thin metal precursor layer is subsequently dried by annealing. The second step is the chemical reduction of the metal precursor with EG vapor at 160 or 180 degrees C in the absence of solvent. Both the Au and Pt nanostructures deposited by this method have good adhesion to substrates, but they have different morphologies. The Au nanostructures appear as separate two-dimensional islands on the substrates, and up to 70% of them can be triangular nanoplates with the (111) crystal plane as the basal plane. In contrast, the reduction of H(2)PtCl(6) gives rise to a 3 dimensional porous Pt structure on substrates. The different morphologies of nanostructured Au and Pt are tentatively related to the different surface energies of Au and Pt. PMID- 23086438 TI - Synthesis and high-pressure transformation of metastable wurtzite-structured CuGaS2 nanocrystals. AB - The metastable wurtzite nanocrystals of CuGaS(2) have been synthesized through a facile and effective one-pot solvothermal approach. Through the Rietveld refinement on experimental X-ray diffraction patterns, we have unambiguously determined the structural parameters and the disordered nature of this wurtzite phase. The metastability of wurtzite structure with respect to the stable chalcopyrite structure was testified by a precise theoretical total energy calculation. Subsequent high-pressure experiments were performed to establish the isothermal phase stability of this wurtzite phase in the pressure range of 0-15.9 GPa, above which another disordered rock salt phase crystallized and remained stable up to 30.3 GPa, the highest pressure studied. Upon release of pressure, the sample was irreversible and intriguingly converted into the energetically more favorable and ordered chalcopyrite structure as revealed by the synchrotron X-ray diffraction and the high-resolution transmission electron microscopic measurements. The observed phase transitions were rationalized by first principles calculations. The current research surely establishes a novel phase transition sequence of disorder -> disorder -> order, where pressure has played a significant role in effectively tuning stabilities of these different phases. PMID- 23086439 TI - [Course of trauma sequelae in ex-political prisoners in the GDR: a 15-year follow up study]. AB - BACKGROUND: In a sample of ex-political prisoners in the GDR examined in the middle of the 1990s, a follow-up examination carried out 15 years later investigated alterations in the diagnosis and symptom prevalence of post traumatic stress syndrome PTSS) as well as other psychiatric disorders. The diagnosis course given by the clinicians was compared with the retrospective subjective estimations by participants. METHODS: A total of 93 ex-political prisoners participated in the follow-up study (85 %) with an average age of 64 years. Diagnoses and symptoms were collated using structured clinical interviews and questionnaires. The retrospective subjective estimation of progression of the participants was calculated using a PTSS symptom index based on four symptom groups (intrusions, avoidance, numbing and hyperarousal). RESULTS: At the time of follow-up PTSS was present in 33 % of participants (in 1997 it was 29 %). In 1994 this was present in only approximately 50 % of cases and in the other 50 % it concerned newly incident or remission cases. The next most common diagnoses were major depression episodes (26 %), panic (with or without agoraphobia 24 %) and somatoform disorders (19 %). In the PTSS symptom profile intrusions, flashbacks and alienation feelings decreased with time but in contrast irritability and shock reactions increased. The subjective self-estimation of the course of PTSS symptoms by the participants often gave a resilient (never PTSS) or delayed and rarely a remission course pattern in comparison to the diagnosing clinicians. CONCLUSIONS: The results indicate a trauma-related long-term morbidity which is, however less stable than previously assumed. PMID- 23086440 TI - [The neurobiology of anhedonia. The pathophysiology of an important symptom in depressive disorders]. AB - The phenomenon of anhedonia, the inability to experience pleasure, is one of the essential elements for the diagnosis of depressive disorders. According to the criteria of both the ICD-10 and the DSM-IV, the presence of this symptom is crucial for the diagnosis of depressive disorders. In recent years scientific approaches using animal studies and projects of functional imaging have allowed the development of a new concept of the pathophysiology of anhedonia. The hypothesis that functional changes within the mesolimbic reward system could represent the neural correlate of anhedonia has contributed to a new concept of depressive disorders and allows testing of new therapeutic options for patients suffering from very resistant forms of depression. By using the method of deep brain stimulation present clinical studies try to ascertain whether the symptom of anhedonia can be alleviated by influencing the neural activity of the reward system. This article will give a critical overview about the background for new therapeutic approaches and illuminates the results of these studies. PMID- 23086441 TI - Frequency distribution of hard ticks (Acari: Ixodidae) infesting bubaline population of district Toba Tek Singh, Punjab, Pakistan. AB - The current research was conducted to define the epidemiological parameters related to the prevalence and associated risk factors of tick infestation in buffaloes in the Toba Tek Singh District of central Punjab, Pakistan. The prevalence of ticks on buffaloes was 31.21 % (352/1,128). Among the species of ticks, the prevalence of Hyalomma marginatum (75.56 %; 266/352) was higher (P < 0.05; odd's ratios (OR) = 3.09) than Rhipicephalus microplus (24.44 %; 86/352). Female buffaloes (69.60 %; 245/352) and younger animals (59.09 %; 208/352) were more heavily infested than males (30.40 %; 107/352) and adult animals (40.91 %; 144/352), respectively, whereas breed was not a determinant (P > 0.05). With regard to management and husbandry practices, the prevalence of ticks was higher in animals kept on uncemented flooring (54.55 %; 192/352; OR = 1.90) followed in order by partially cemented (28.69 %; 101/352; OR = 1.71) and fully cemented flooring (16.76 %; 59/352). With regard to feeding systems, grazing animals (64.20 %; 226/352) were more burdened compared to stall-fed animals (35.80 %; 126/352). The highest tick prevalence was recorded in closed housing systems (52.27 %; 184/352), followed by semi-closed (34.09 %; 120/352; OR = 1.53), and open housing systems (13.64 %; 48/352). Rope-tied animals (70.73 %; 249/352) were more parasitized (P > 0.05) than open (29.27 %; 103/352). Prevalence in the study district was highest in tehsil Kamalia followed in order by T.T. Singh and Gojra. The primary body area of infestation by ticks (head, neck, ear, dewlap, back, abdomen, foreleg, shoulder, hind leg, congenital areas, and tail) ranged from highest at inside thigh (17 %) to lowest at rump. In the present survey, the highest prevalence was recorded in July and lowest in December. Comparison of hematological changes showed remarkable differences between infested and non infested animals, in the form of low values of infested animals, whereas an increment in biochemical parameter values was observed in tick-infested animals. The present study provides significant data to enhance planning for tick control program in the study area. PMID- 23086442 TI - Antimycobacterial and antileishmanial effects of microfungi isolated from tropical regions in Mexico. AB - A total of 82 fungal extracts were selected and screened against Mycobacterium tuberculosis and promastigotes of Leishmania mexicana strains. Results showed inhibitory activity in 29 % of the fungal strains against at least one of the targets tested. The most significant antituberculosis (antiTB) effects were presented by Cylindrocarpon sp. XH9B, Fusarium sp. TA54, Fusarium XH1Ga, Gliocladium penicillioides TH04 and TH21, Gliocladium sp. TH16, Kutilakesa sp. MR46, and Verticillium sp. TH28 strains (minimal inhibition concentration (MIC) = 1.56-25 MUg/ml). Mortality of L. mexicana promastigotes was displayed by only four strains, Fusarium sp. TA50, Fusarium sp. TA54, Verticillium sp. TH28, and the unidentified 2TA2 strain (IC(50) = 14.23-100 MUg/ml and IC(100) = 50-100 MUg/ml). Seven of these most active strains were defatted and their corresponding fractions evaluated again. The results showed the best antiTB activity in Gliocladium sp. TH16 (MIC = 1.56 MUg/ml) and the highest leishmanicidal potential in Fusarium sp. TA54 (IC(50) = 6.36 MUg/ml). These results show that fungi living in the tropical regions of Mexico have the ability to produce bioactive metabolites that could be used in the near future as natural products to control neglected tropical diseases. PMID- 23086443 TI - Effects of Enteromyxum leei (Myxozoa) infection on gilthead sea bream (Sparus aurata) (Teleostei) intestinal mucus: glycoprotein profile and bacterial adhesion. AB - The intestinal myxosporean parasite Enteromyxum leei causes severe desquamative enteritis in gilthead sea bream (Sparus aurata) (Teleostei) that impairs nutrient absorption causing anorexia and cachexia. In fish, as in terrestrial vertebrates, intestinal goblet cells are responsible for the adherent mucus secretion overlying epithelial cells, which constitutes a first line of innate immune defense against offending microorganisms but serves also as substrate and nutrient source for the commensal microflora. The secreted intestinal mucus of parasitized (n = 6) and unexposed (n = 8) gilthead sea bream was isolated, concentrated, and subjected to downward gel chromatography. Carbohydrate and protein contents (via PAS and Bradford stainings), terminal glycosylation (via lectin ELISA), and Aeromonas hydrophila and Vibrio alginolyticus adhesion were analyzed for the isolated intestinal mucins. Parasitized fish, compared with unexposed fish, presented intestinal mucus mucins with a lower glycoprotein content and glycosylation degree at the anterior and middle intestine, whereas both glycoprotein content and glycosylation degree increased at the posterior intestine section, though only significantly for the total carbohydrate content. Additionally, a slight molecular size increase was detected in the mucin glycoproteins of parasitized fish. Terminal glycosylation of the mucus glycoproteins in parasitized fish pointed to an immature mucin secretion (N acetyl-alpha-D-galactosamine increase, alpha-L-fucose, and neuraminic-acid-alpha 2-6-galactose reduction). Bacterial adhesion to large-sized mucus glycoproteins (>2,000 kDa) of parasitized fish was significantly lower than in unexposed fish. PMID- 23086445 TI - Rhipicephalus sanguineus (Acari: Ixodidae) female ticks exposed to castor oil (Ricinus communis): an ultrastructural overview. AB - Tick control has been accomplished through the use of synthetic acaricides, which has created resistant individuals, as well as contaminating the environment and nontarget organisms. Substances of plant origin, such as oils and extracts of eucalyptus and neem leaves, have been researched as an alternative to replace the synthetic acaricides. Ricinoleic acid esters from castor oil have recently been shown as a promising alternative in eliminating bacterial contamination during ethanol fermentation, by acting as an effective biocide. The same positive results have been observed when these esters are added to the food given to tick infested rabbits. This study tested the effect of these substance on the reproductive system of Rhipicephalus sanguineus females, added to rabbit food, more specifically on oogenesis. For this, four groups were established: four control groups (CG1, CG2, CG3, and CG4) and four treatment groups (TG1, TG2, TG3, and TG4) with one rabbit in each (New Zealand White), used as hosts. After full 4 days feeding (semi-engorgement), the females were collected and had their ovaries extracted. In this study, it was observed that R. sanguineus females exposed to esters had their ovaries modified, which was demonstrated through transmission electron microscopy techniques. The addition of ricinoleic esters to the diet of tick-infested rabbits revealed how toxic such substances are for the cytoplasmic organelles of oocytes and pedicel cells. These compounds can change the morphophysiology of germ and somatic cells, consequently influencing their viability and, therefore, confirming that the ricinoleic acid esters from castor oil are a promising substance in the control of R. sanguineus. PMID- 23086444 TI - Anthelmintic activity of carvacryl acetate against Schistosoma mansoni. AB - Blood flukes of the genus Schistosoma are the causative agents of human schistosomiasis, a debilitating disease that afflicts over 200 million people worldwide. Praziquantel is the drug of choice but concerns over praziquantel resistance have renewed interest in the search for alternative drug therapies. Carvacrol, a naturally occurring monoterpene phenol and food additive, has been shown high medicinal importance, including antimicrobials activities. The aim of this study was to evaluate in vitro effect of carvacryl acetate, a derivative of carvacrol, on Schistosoma mansoni adult worms. We demonstrated that carvacryl acetate at 6.25 MUg/mL has antischistosomal activity, affecting parasite motility and viability. Additionally, confocal laser scanning microscopy pictures revealed morphological alterations on the tegumental surface of worms, where some tubercles appeared to be swollen with numerous small blebs emerging from the tegument around the tubercles. Furthermore, experiments performed using carvacryl acetate at sub-lethal concentrations (ranging from 1.562 to 6.25 MUg/mL) showed an inhibitory effect on the daily egg output of paired adult worms. Thus, carvacryl acetate is toxic at high doses, while at sub-lethal doses, it significantly interferes with the reproductive fitness of S. mansoni adult worms. Due to its safety and wide use in the industry, carvacryl acetate is a promising natural product-derived compound and it may represent a step forward in the search for novel anthelmintic agents, at a time when there is an urgent need for novel drugs. PMID- 23086446 TI - In vitro protoscolicidal effects of high-intensity focused ultrasound enhanced by a superabsorbent polymer. AB - Echinococcus granulosus, the etiologic agent of cystic echinococcosis in humans and other animal hosts, is distributed worldwide. Echinococcosis is an increasing public health and socioeconomic concern. The present work evaluated whether or not a superabsorbent polymer (SAP) could enhance the damage efficacy of high intensity focused ultrasound (HIFU) on the viability of E. granulosus protoscolices in vitro. HIFU of 100 W acoustic power and 0.01 g superabsorbent polymer were used to treat 5,000 protoscolices in 2-ml protoscolices suspension. After different HIFU exposure time (5, 10, 20, 30, 40, 50, and 60 s, respectively), the temperature of protoscolices suspension was taken, and the treated protoscolices were stained by trypan-blue exclusion assay, and their structures were observed by light microscopy. To better understand the biological mechanisms responsible for the deaths of protoscolices, the activity of succinate dehydrogenase (SDH) of the protoscolices treated with HIFU was examined. The temperature of protoscolices suspension treated with HIFU rose slowly, and the death rate of protoscolices was 73.7 % in the group of HIFU treatment time of 40 s; however, with the same HIFU treatment time of 40 s, the temperature of protoscolices suspension in the group of HIFU combined with SAP rose quickly, and the death rate of protoscolices was 100 %. The same protoscolicidal effect (100 %) of HIFU of 100 W acoustic power combined with SAP was also observed in the groups of HIFU treatment time of 50 and 60 s, respectively. The dead protoscolices were stained to blue, shrunken and black calcareous corpuscles, and disordered and decreasing hooks though of intact membrane, as well as some protoscolices lost hooks and tore open on membrane were observed. In the group of HIFU combined with SAP, it was found that the superabsorbent polymer was surrounded by the spoiled, and the destruction of protoscolices was much stronger than in the group of HIFU. The dead protoscolices exhibited the reduction or absence of SDH staining intensity in the parenchymal cell and calcareous corpuscles after HIFU irradiation, where a large number of necrotic cells were evident. These results suggested that HIFU could induce the damage and loss of viability of protoscolices; SAP could enhance the HIFU energy focused and cause more severe destruction efficacy on protoscolices; and mitochondrial energetic function is involved in the regulation of cell-death pathways of protoscolices. PMID- 23086447 TI - Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-kappaB pathways. AB - The NF-kappaB protein RelB controls dendritic cell (DC) maturation and may be targeted therapeutically to manipulate T cell responses in disease. Here we report that RelB promoted DC activation not as the expected RelB-p52 effector of the noncanonical NF-kappaB pathway, but as a RelB-p50 dimer regulated by canonical IkappaBs, IkappaBalpha and IkappaBE. IkappaB control of RelB minimized spontaneous maturation but enabled rapid pathogen-responsive maturation. Computational modeling of the NF-kappaB signaling module identified control points of this unexpected cell type-specific regulation. Fibroblasts that we engineered accordingly showed DC-like RelB control. Canonical pathway control of RelB regulated pathogen-responsive gene expression programs. This work illustrates the potential utility of systems analyses in guiding the development of combination therapeutics for modulating DC-dependent T cell responses. PMID- 23086449 TI - Indeterminate pulmonary nodules represent lung metastases in a significant portion of patients undergoing liver resection for malignancy. AB - INTRODUCTION: Despite detection on imaging before resection of hepatic malignancies, the natural history of indeterminate pulmonary nodules (IPN) is unknown. The objective of this study is to determine how often IPN detected on imaging before surgery for hepatic malignancies represent lung metastases. METHODS: Demographics, comorbidities, tumor characteristics, and surgical treatments of patients with pre-operative IPN who underwent liver resection and/or radiofrequency ablation for malignant diagnoses were reviewed. RESULTS: From 2000 to 2010, 90 patients with at least one IPN underwent liver resection or radiofrequency ablation for malignancy. Of these, 44 (48.9 %), 32 (35.6 %), and 14 (15.6 %) patients had colorectal cancer liver metastases (CRCLM), primary hepatobiliary malignancies (HB), and other cancers, respectively. The median number of IPN was 1. The median size was 4 mm. Twenty (22 %) patients had isolated lung recurrence after hepatic surgical therapy. Eighty percent occurred in the exact location of the pre-operative IPN. Isolated lung recurrence was more common among patients with CRCLM compared to those with HB and other cancers (42.9 vs. 9.4 vs. 14.3 %, p = 0.004). CONCLUSION: Pre-operatively detected IPN represent lung metastases in a substantial portion of patients undergoing surgery for hepatic malignancy. IPN are more likely to represent lung metastases in patients with CRCLM compared to those with primary HB and other cancers. PMID- 23086448 TI - The CD46-Jagged1 interaction is critical for human TH1 immunity. AB - CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-gamma (IFN-gamma)-secreting effector T helper type 1 (T(H)1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-gamma and switching to IL-10. Notably, CD4(+) T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate T(H)1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients. PMID- 23086450 TI - Systematic review and meta-analysis of haemostatic and biliostatic efficacy of fibrin sealants in elective liver surgery. AB - BACKGROUND: Fibrin sealants are frequently used in liver surgery to achieve intraoperative haemostasis and reduce post-operative haemorrhage and bile leak. This meta-analysis aimed to review the haemostatic and biliostatic capacity of fibrin sealants in elective liver surgery. METHODS: An electronic search was performed on the MEDLINE, Embase and PubMed databases using both subject headings and truncated word searches to identify all published articles that are related to this topic. Pooled risk ratios were calculated for categorical outcomes, and mean differences for secondary continuous outcomes, using the fixed-effects and random-effects models for meta-analysis. RESULTS: Ten randomised controlled trials encompassing 1,225 patients were analysed to achieve a summated outcome. Pooled data analysis showed the use of fibrin sealants resulted in reduced time to haemostasis (mean difference -3.45 min [-3.78, -3.13] (P < 0.00001)) and increased numbers of patients with complete haemostasis (risk ratio 1.56, 95 % confidence interval 1.04-2.34, p = 0.03) when compared to controls. The use of fibrin sealants did not influence perioperative blood transfusion requirements, bile leak rates, post-operative haemorrhage, intra-abdominal collections and overall morbidity and mortality compared with controls. CONCLUSIONS: There is no solid evidence that the routine use of fibrin sealants reduces the incidence of post-operative haemorrhage or bile leak compared with other treatments. The use of fibrin sealants may reduce the time to haemostasis, but this does not translate to improved perioperative outcomes. PMID- 23086451 TI - Predicting recurrence of C. difficile colitis using bacterial virulence factors: binary toxin is the key. AB - BACKGROUND: Recurrent Clostridium difficile colitis is common, yet the ability to predict recurrence is poorly developed. METHODS: Patients >=18 years of age treated at our institution for C. difficile of any severity were consecutively enrolled. C. difficile colitis was defined as symptoms of colitis with a positive PCR stool test. Each bacterial isolate was studied for virulence factors: tcdC mutations via PCR; the presence of genes for toxins A, B, and binary toxin using restriction fragment length polymorphism; and identification of ribotype 027 by PCR. Chi-squared tests, t tests, and logistic and linear regression were used to determine which virulence factors predicted recurrence. RESULTS: Sixty-nine patients (male, 57 %) were studied, with a mean age of 64 +/- 13 years. Twenty one (30 %) patients were initially diagnosed as outpatients. There was no difference (p > 0.05) between virulence factors among inpatients and outpatients. The presence of a binary toxin gene was the single virulence factor independently associated with recurrence (p = 0.02). The combination of a tcdC mutation with binary toxin gene resulted in the highest odds of recurrence (OR, 5.3; 95 % CI, 3.52-6.09). CONCLUSION: Binary toxin gene is a predictor of recurrent infection. Its presence may require longer antibiotic regimens in an effort to lower already elevated recurrence rates. PMID- 23086452 TI - Does mechanical thrombectomy in acute embolic stroke have long-term side effects on intracranial vessels? An angiographic follow-up study. AB - PURPOSE: Mechanical thrombectomy (mTE) proved to be effective treating acute vessel occlusions with an acceptable rate of procedural complications. Potential long-term side effects of the vessel wall trauma caused by mechanical irritation of the endothelium are unknown up to now. METHODS: From a retrospectively established database of 640 acute stroke treatments, we selected 261 patients with 265 embolic vessel occlusions treated successfully by mTE without permanent implantation of a stent. Analysis comprised the type of devices used and the number of passes performed. Digital subtraction angiography immediately after treatment was evaluated for vasospasm, dissection, and extravasation. Control angiographic images were evaluated for any morphological change compared to the immediate posttreatment angiographic run. RESULTS: Recanalization was achieved with a median of one (range 1-10) mTE maneuvers. Vasospasm occurred in 69 territories (26.0 %) and was treated with glyceroltrinitrate in three. Dissection was observed in one vessel (0.4 %). Intraprocedural hemorrhage in two patients (0.8 %) was either wire or device induced. Follow-up digital subtraction angiography was available for 117 territories after a median of 107 days, revealing target vessel occlusion in one segment (0.9 %) and a de novo stenosis of four segments (3.4 %). All findings were clinically asymptomatic. Posttreatment vasospasm was more frequent in patients with de novo stenosis and occlusion (p = 0.038). CONCLUSION: De novo stenoses and occlusions occur in a small proportion of patients after mTE. Because all lesions were clinically asymptomatic, this finding does not affect the overall benefit of the treatment. Vasospasm may predict late vessel wall changes. PMID- 23086453 TI - Overexpression of Camellia sinensis thaumatin-like protein, CsTLP in potato confers enhanced resistance to Macrophomina phaseolina and Phytophthora infestans infection. AB - Thaumatin-like proteins (TLPs), a class of pathogenesis related proteins are induced in response to pathogens and exhibit antifungal property when overexpressed in transgenic plants. In the present study, we have raised transgenic potato plants overexpressing TLP gene of Camellia sinensis (CsTLP). Fungal resistance assays of transgenic potato elucidated the potential role of CsTLP in imparting tolerance to fungal pathogens, Macrophomina phaseolina (necrotrophic) and Phytophthora infestans (hemi-biotrophic). Transgenic tubers with higher resistance to M. phaseolina, showed a concomitant and significant increase in transcripts of StPAL, StLOX, and StTLP genes involved in phenylpropanoid, lipoxygenase, and general defense response pathway, respectively after infection. Importantly, leaves of CsTLP transgenic lines inoculated with P. infestans spores under in vitro conditions also showed a resistant phenotype. The resistant phenotype recorded for the two important fungal pathogens by CsTLP transgenic potato plants is remarkable, since no effective control methods and no resistant cv. against M. phaseolina has been identified so far in potato. PMID- 23086455 TI - Study of substrate dependence on the chemoselectivity of the gold-catalysed cycloisomerisation of aryl substituted 1,7-enynes. AB - The effects of starting material substitution patterns on reaction selectivity for the gold(I)-catalysed cycloisomerisations of aryl substituted 1,7-enynes were investigated. The results indicated the chemoselectivity of the reaction to be highly substrate and catalyst dependent. Either the piperidine or the tetrahydro 1H-azepine product was obtained in moderate to excellent yields depending on the steric and/or electronic nature of the substrate and the gold(I) catalyst. Overall, six-membered nitrogen ring formation was found to be favoured in reactions with 1,7-enyne derivatives containing a disubstituted alkene moiety or not bearing a sterically bulky substituent or a gold(I) catalyst with a pendant sterically unencumbered phosphine ligand. Formation of the seven-membered nitrogen heterocycle was observed in reactions where the substrate contained a tetrasubstituted alkene unit or a sterically demanding substituent. PMID- 23086454 TI - A novel nuclear protein phosphatase 2C negatively regulated by ABL1 is involved in abiotic stress and panicle development in rice. AB - Type 2C protein phosphatase plays an important role in the signal transduction of stress response in plants. In this paper, we identified a novel stress-induced type 2C protein phosphatase gene OsSIPP2C1 from rice. OsSIPP2C1 contains a complete open reading frame of 1,074 bp, encoding a protein with 357 amino acids. OsSIPP2C1 expression was up-regulated by high salt, PEG6000 and exogenous ABA, and enhanced in the abl1 mutant under normal, salt, or drought condition. Interestingly, OsSIPP2C1 expression was increased during the early panicle development. Subcellular localization assay using rice protoplast cells indicated that OsSIPP2C1 was predominantly located in the nucleus. Together, it is suggested that a nuclear PP2C protein OsSIPP2C1 negatively regulated by ABL1 is involved in abiotic stress and panicle development in rice. PMID- 23086456 TI - Ab-initio study of anisotropic and chemical surface modifications of beta-SiC nanowires. AB - The electronic band structure and electronic density of states of cubic SiC nanowires (SiCNWs) in the directions [001], [111], and [112] were studied by means of Density Functional Theory (DFT) based on the generalized gradient approximation and the supercell technique. The surface dangling bonds were passivated using hydrogen (H) atoms and OH radicals in order to study the effects of this passivation on the electronic states of the SiCNWs. The calculations show a clear dependence of the electronic properties of the SiCNWs on the quantum confinement, orientation, and chemical passivation of the surface. In general, surface passivation with either H or OH radicals removes the dangling bond states from the band gap, and OH saturation appears to produce a smaller band gap than H passivation. An analysis of the atom-resolved density of states showed that there is substantial charge transfer between the Si and O atoms in the OH-terminated case, which reduces the band gap compared to the H-terminated case, in which charge transfer mainly occurs between the Si and C atoms. PMID- 23086457 TI - The density per particle can be used as the fundamental descriptor for systems with rapidly decaying external potentials. AB - For systems of electrons bound by potentials that decay faster than 1/r asymptotically, the density per particle determines the number of electrons and therefore the electron density. The density per particle, commonly called the shape function, can thus be used as the fundamental descriptor of systems with rapidly decaying external potentials. This result is analogous to a result that is known for Coulomb potentials. Possible extensions of the result to include broader classes of external potentials and alternative density-like descriptors are discussed. PMID- 23086458 TI - Partial activation of alpha7 nicotinic acetylcholine receptors: insights from molecular dynamics simulations. AB - Nicotinic acetylcholine receptors (nAChRs) are drug targets for neuronal disorders and diseases. Partial agonists for nAChRs are currently being developed as drugs for the treatment of neurological diseases for their relative safety originated from reduced excessive stimulation. In the current study, molecular docking, molecular dynamics simulations and binding energy calculations were performed to theoretically investigate the interactions between the partial agonists, 4-OH-DMXBA and tropisetron with alpha7-nAChR. The results suggest that the partial agonists 4-OH-DMXBA and tropisetron bind with alpha7-nAChR in a binding mode similar to that with AChBP. The non-conserved residues in the binding sites contribute to the orientation deviation of these partial agonists from their orientation in AChBP. Energy calculation and decomposition using MM GB/SA suggests that the van der Waals term (DeltaE(VDW)) is the main driving force for the binding of the partial agonists to alpha7-nAChR. The molecular dynamics simulations showed that the opening of the C-loop binding with the partial agonists is in-between the openings for the binding with the full agonist and in the apo state. This conformation difference for the C-loop sheds light on the partial agonism of nAChR. PMID- 23086460 TI - Molecular dynamics and QM/MM-based 3D interaction analyses of cyclin-E inhibitors. AB - Abnormal expression of cyclin-dependent kinase 2 (CDK2)/cyclin-E is detected in colorectal, ovarian, breast and prostate cancers. The study of CDK2 with a bound inhibitor revealed CDK2 as a potential therapeutic target for several proliferative diseases. Several highly selective inhibitors of CDK2 are currently undergoing clinical trials, but possibilities remain for the identification and development of novel and improved inhibitors. For example, in silico targeting of ATP-competitive inhibitors of CDKs is of special interest. A series of 3,5 diaminoindazoles was studied using molecular docking and comparative field analyses. We used post-docking short time molecular dynamics (MD) simulation to account for receptor flexibility. The three types of structures, i.e., the highest energy, lowest energy and the structure most resembling the X-ray structure (three complexes) were identified for all ligands. QM/MM energy calculations were performed using a DFT b3lyp/6-31 g* and MM OPLS-2005 force field. Conceptual DFT properties such as the interaction energy of ligand to protein, global hardness (eta), HOMO density, electrostatic potential, and electron density were calculated and related to inhibitory activity. CoMFA and CoMSIA were used to account for steric and electrostatic interactions. The results of this study provide insight into the bioactive conformation, interactions involved, and the effect of different drug fragments over different biological activities. PMID- 23086459 TI - The investigations on HIV-1 gp120 bound with BMS-488043 by using docking and molecular dynamics simulations. AB - BMS-488043, like its predecessor BMS-378806, is a small molecule that can block the interactions between gp120 and CD4, and has shown good clinical efficacy. However, the crystal structure of drug-gp120 complexes or the full-length gp120 free of bound ligand is unpublished until now. Docking combined with molecular dynamics simulation is used to investigate the binding mode between BMS-488043 and gp120. On the basis of the analysis of the simulated results, the plausible binding mode is acquired, such as the changes of binding mode in the trajectory and the calculated binding free energy. Subsequently, a number of residues which make contacts with the small molecule are studied by binding free energy decomposition to understand the mutation experiments, such as Trp427, Ser375, and Thr257 residues with the help of the acquired binding mode above. Especially, the importance of the hydrophobic groove formed by residues Ile371 and Gly472 which bind BMS-488043 is elaborated, which has not been explored much. In addition, theoretical investigations on the dynamics behavior of the gp120 associated with BMS-488043 enhanced binding are performed; the results indicate that the BMS 488043 may be more deeply inserted into the Phe43 cavity compared with the previous binding mode acquired by docking. PMID- 23086461 TI - Density functional conformational study of 2-O-sulfated 3,6 anhydro-alpha-D galactose and of neo-kappa- and iota-carrabiose molecules in gas phase and water. AB - We examined the conformational preferences of the 2-O-sulfated-3,6-alpha-D anhydrogalactose (compound I) and two 1,3 linked disaccharides constituting-kappa or iota-carrageenans using density functional and ab initio methods in gas phase and aqueous solution. Systematic modifications of two torsion angles leading to 324 and 144 starting geometries for the compound I and each disaccharide were used to generate adiabatic maps using B3LYP/6-31G(d). The lower energy conformers were then fully optimized using B3LYP, B3PW91 and MP2 with several basis sets. Overall, we discuss the impact of full relaxation on the energy and structure of the dominant conformations, present the performance comparison with previous molecular mechanics calculations if available, and determine whether our results are impacted, when polarization and diffuse functions are added to the 6-31G(d) basis set, or when the MP2 level of theory is used. PMID- 23086462 TI - Vibrational spectra of an RDX film over an aluminum substrate from molecular dynamics simulations and density functional theory. AB - We report calculated vibrational spectra in the range of 0-3,500 cm(-1) of RDX (hexahydro-1,3,5-trinitro-1,3,5-triazine) molecules adsorbed on a model aluminum surface. A molecular film was modeled using two approaches: (1) density functional theory (DFT) was used to optimize a single RDX molecule interacting with its periodic images, and (2) a group of nine molecules extracted from the crystal structure was deposited on the surface and interacted with its periodic images via molecular dynamics (MD) simulations. In both cases, the molecule was initialized in the AAA conformer geometry having the three nitro groups in axial positions, and kept that conformation in the DFT examination, but some molecules were found to change to the AAE conformer (two nitro groups in axial and one in equatorial position) in the MD analysis. The vibrational spectra obtained from both methods are similar to each other, except in the regions where collective RDX intermolecular interactions (captured by MD simulations) are important, and compare fairly well with experimental findings. PMID- 23086463 TI - DFT and MP2 study of the interaction between corannulene and alkali cations. AB - Corannulene is an unsaturated hydrocarbon composed of fused rings, with one central five-membered ring and five peripheral six-membered rings. Its structure can be considered as a portion of C60. Corannulene is a curved pi surface, but unlike C60, it has two accessible different faces: one concave (inside) and one convex (outside). In this work, computational modeling of the binding between alkali metal cations (Li(+), Na(+), and K(+)) and corannulene has been performed at the DFT and MP2 levels. Different corannulene...M(+) complexes have been studied and the transition states interconnecting local minima were located. The alkali cations can be bound to a five or six membered ring in both faces. At the DFT level, binding to the convex face (outside) is favored relative to the concave face for the three alkali cations studied, as it was previously published. This out preference was found to decrease as cation size increases. At the MP2 level, although a similar trend is found, some different conclusions related to the in/out preference were obtained. According to our results, migration of cations can take place on the convex or on the concave face. Also, there are two ways to transform a concave complex in a convex complex: migration across the edge of corannulene and bowl-to-bowl inversion. PMID- 23086464 TI - Global and local reactivity indexes applied to understand the chemistry of graphene oxide and doped graphene. AB - At the density functional theory level, the electronic reactivity of oxidized and doped (with N, B, and P) graphene (G) has been analyzed. Molecular hardness and electrophilicity were used as global reactivity descriptors, while those at the local level, Fukui functions, Mulliken charges and molecular electrostatic potential were used in the order to characterize the intramolecular and intermolecular reactivity. These descriptors show that in GO, the global and local reactivity of the basal plane is improved mainly by hydroxyl groups, which improve besides the physisorption of small molecules, while, the active carbon atoms around the functional group would allow enhancement of the consecutively chemisorption. Furthermore, epoxide, carbonyl and carboxyl groups allow mainly enhancement of intermolecular non-covalent interactions. On the other hand, doping with N and B atoms increases the electrophilic character and the reactivity in the bulk. Specifically, in N-doped G, N and around carbon atoms would be able to serve as active sites of detection by frontier-controlled processes, explaining the improvement in electrochemical sensing; in addition, electron-deficient carbon atoms around N enhance the physisorption. Respecting the B-doped G, dopant and carbon atoms adjacent to B act as donor sites, suggesting that adsorption of cations on B-doped G is a frontier-controlled process; moreover, positively-charged B atoms enhance charge-controlled interactions with polarized molecules, and consecutively, in a frontier controlled step, chemisorption is possible. Finally, P-doping increases the electrophilic reactivity in the bulk; also, P atoms enhance the physisorption of chemical species with negatively-charged centers or lone-pair electrons, and consecutively, chemisorption on P is possible. PMID- 23086465 TI - Palladium-catalyzed tandem reaction of o-aminophenols, bromoalkynes and isocyanides to give 4-amine-benzo[b][1,4]oxazepines. AB - A robust route to 4-amine-benzo[b][1,4]oxazepines relying upon a palladium catalyzed tandem reaction of o-aminophenols, bromoalkynes and isocyanides has been developed. This chemistry presumably proceeds through the migratory insertion of isocyanides into the vinyl-palladium intermediate as a key step. PMID- 23086466 TI - Emergency department short-stay ward for dengue management. PMID- 23086467 TI - Prevalence of beta-thalassemia and other haemoglobinopathies in six cities in India: a multicentre study. AB - The population of India is extremely diverse comprising of more than 3,000 ethnic groups who still follow endogamy. Haemoglobinopathies are the commonest hereditary disorders in India and pose a major health problem. The data on the prevalence of beta-thalassemias and other haemoglobinopathies in different caste/ethnic groups of India is scarce. Therefore the present multicentre study was undertaken in six cities of six states of India (Maharashtra, Gujarat, West Bengal, Assam, Karnataka and Punjab) to determine the prevalence of haemoglobinopathies in different caste/ethnic groups using uniform methodology. Fifty-six thousand seven hundred eighty individuals (college students and pregnant women) from different caste/ethnic groups were screened. RBC indices were measured on an automated haematology counter while the percentage of HbA(2), HbF and other abnormal Hb variants were estimated by HPLC on the Variant Hemoglobin Testing System. The overall prevalence of beta-thalassemia trait was 2.78 % and varied from 1.48 to 3.64 % in different states, while the prevalence of beta-thalassemia trait in 59 ethnic groups varied from 0 to 9.3 %. HbE trait was mainly seen in Dibrugarh in Assam (23.9 %) and Kolkata in West Bengal (3.92 %). In six ethnic groups from Assam, the prevalence of HbE trait varied from 41.1 to 66.7 %. Few subjects with deltabeta-thalassemia, HPFH, HbS trait, HbD trait, HbE homozygous and HbE beta-thalassemia as well as HbS homozygous and HbS-beta thalassemia (<1 %) were also identified. This is the first large multicentre study covering cities from different regions of the country for screening for beta-thalassemia carriers and other haemoglobinopathies where uniform protocols and methodology was followed and quality control ensured by the co-ordinating centre. This study also shows that establishment of centres for screening for beta-thalassemia and other haemoglobinopathies is possible in medical colleges. Creating awareness, screening and counselling can be done at these centres. This experience will help to formulate a national thalassemia control programme in India. PMID- 23086468 TI - Examining the family-centred approach to genetic testing and counselling among UK Pakistanis: a community perspective. AB - WHO advice suggests a family-centred approach for managing the elevated risk of recessively inherited disorders in consanguineous communities, whilst emerging policy recommends community engagement as an integral component of genetic service development. This paper explores the feasibility of the family-centred approach in the UK Pakistani origin community. The study took place within a context of debate in the media, professional and lay circles about cousin marriage causing disability in children. Using qualitative methods, a total of six single-sex focus group discussions (n = 50) were conducted in three UK cities with a high settlement of people of Pakistani origin. Tape-recorded transcripts were analysed using framework analysis. Kinship networks within Pakistani origin communities are being sustained and marriage between close blood relatives continues to take place alongside other marriage options. Study participants were critical of what was perceived as a prevalent notion that cousin marriage causes disability in children. They were willing to discuss cousin marriage and disability, share genetic information and engage with genetic issues. A desire for accurate information and a public informed about genetic issues was articulated whilst ineffective communication of genetic risk information undermined professionals in their support role. This study suggests a community that is embracing change, one in which kinship networks are still active and genetic information exchange is taking place. At the community level, these are conditions supportive of the family-centred approach to genetic testing and counselling. PMID- 23086469 TI - Genetics and public health: the experience of a reference center for diagnosis of 22q11.2 deletion in Brazil and suggestions for implementing genetic testing. AB - Considering the prevalence of 22q11.2 deletion syndrome (22q11.2 DS) of around 1:4,000 and of palatal abnormalities in 70 % of the cases of 22q11.2 DS and taking into account the Brazilian health system and its current situation of medical genetic services, this study aims to contribute to establish strategies for genetic diagnosis. The access to genetic testing at 11 services was investigated and samples from 100 patients with palatal abnormalities and suspicion of 22q11.2 DS were sent to a reference center. Laboratorial techniques included karyotyping, fluorescence in situ hybridization (FISH), and multiplex ligation-dependent probe amplification. Costs were also calculated. Disparities among centers for genetic diagnosis were evident, with remarkable regional differences. Some of the obstacles encountered were difficulties for families to show up for medical appointments, complementary evaluations, and for the clinics to send the samples to the reference center. A conclusive diagnosis was reached for 38 % of patients. Combination of karyotyping and FISH had better laboratorial cost-effectiveness. These results might represent the reality for the investigation of other genetic conditions. Clinical and laboratorial approaches herein presented could be adapted for use under different genetic conditions in the Brazilian health system, which has relatively limited financial and human resources. Suggestions for the rational implementation of genetic testing in developing countries are presented. PMID- 23086471 TI - Reactivity of 2-chalcogenopyridines with palladium-phosphine complexes: isolation of different complexes depending on the nature of chalcogen atom and phosphine ligand. AB - Reactions of either Pd(0) phosphine complexes with dipyridyldichalcogenides or [PdCl2(P?P)] (P?P = dppe, dppp) with pyridylchalcogenolate ions have been examined and a variety of Pd(II) complexes have been isolated and characterized. Oxidative addition of {SeC5H3(3-R)N}2 (R = H or Me) to [Pd(P?P)2] (P?P = dppe, dppp) gave either a mononuclear complex, [Pd{2-Se-C5H3(3-R)N}2(P?P)] (for P?P/R: dppe/H or Me; dppp/H) or a cationic binuclear complex, [Pd2{MU-SeC5H3(3 Me)N}2(dppp)2]2+ (4b) (R = Me) whereas reactions involving the tellurium analogue exclusively afforded trinuclear complexes, [Pd3(MU-Te)2(P?P)3]Cl2 (P?P = dppe (2) or dppp (6)). The latter was also obtained in the substitution reaction between [PdCl2(P?P)] and NaTeC5H3(3-R)N. The substitution reactions between [PdCl2(dppe)] and Pb{EC5H3(3-R)N}2 yielded mononuclear complexes, [Pd{2-E-C5H3(3-R)N}2(dppe)] (1a-1e) (E = S, Se or Te) while in the case of [PdCl2(dppp)], the reactions resulted in the formation of mono-, bi- and tri- nuclear complexes depending on the nature of the chalcogen atom (E = S, Se or Te) and the substituent on the pyridyl ring (R = H or Me). Treatment of dipyridyl ditellurides, {TeC5H3(3-R)N}2 (R = H or Me), with [Pd(PPh3)4] gave expected tellurolate complexes, [Pd{2 TeC5H3(3-R)N}2(PPh3)2] (7a, 7b) which on prolonged standing in CDCl3 solution gave green crystals of [PdCl{2-Te(Cl)2C5H3(3-Me)N}(PPh3)] (9). The molecular structures of {TeC5H3(3-Me)N}2, [Pd2{MU-TeC5H3(3-Me)N}2(dppp)2]Cl2.3H2O (5.3H2O), [Pd3(MU-Te)2(dppp)3]Cl2.3CHCl3 (6.3CHCl3) and [PdCl{2-Te(Cl)2C5H3(3-Me)N}(PPh3)] (9) were established by single crystal X-ray diffraction analyses. PMID- 23086472 TI - Evaluation of the possible epileptogenic activity of ciprofloxacin: the role of Nigella sativa on amino acids neurotransmitters. AB - The neuroprotective effect of Nigella sativa (NS) on amino acid neurotransmitters alteration in pentylenetetrazole (PTZ) and ciprofloxacin (CFX) treated rats in different brain regions was examined. The oral administration of NS induced an elevation in aspartate and glutamate contents, whereas the levels of GABA and glycine were decreased. Furthermore, the treated groups with PTZ and CFX caused a decrease in aspartate, glutamate and total antioxidant capacity levels, while the concentrations of GABA and glycine were increased after 14 days. Moreover, the pre- and post-treatment with NS in PTZ and CFX treated rats return the levels of these parameters near control values. So, it could be concluded that the treatment with CFX induced imbalance between the excitatory and the inhibitory amino acids which may lead to the initiation of epileptic seizures and the treatment with NS was found to ameliorate these neurological defects which reflect its potent antiepileptic activity. PMID- 23086473 TI - Enhanced expression of glia maturation factor correlates with glial activation in the brain of triple transgenic Alzheimer's disease mice. AB - We previously demonstrated that glia maturation factor (GMF), a brain specific protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokines and chemokines in the central nervous system. We also reported that the up-regulation of GMF in astrocytes leads to the destruction of neurons suggesting a novel pathway of GMF-mediated cytotoxicity of brain cells, and implicated its involvement in the pathogenesis of inflammatory neurodegenerative diseases. In the present study, we examined the expressions of GMF in triple-transgenic Alzheimer's disease (3xTg-AD) mice. Our results show a 13-fold up-regulation of GMF and 8-12-fold up-regulation of proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), IL 1beta, interferon gamma (IFN-gamma), and chemokine (C-C motif) ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10/IP-10) mRNA as determined by quantitative real-time RT-PCR in the brain of 3xTg-AD mice as compared to non-transgenic (Non Tg) mice. In conclusion, the increase in GMF and cytokine/chemokine expression was correlated with reactive glial fibrillary acidic protein positive astrocytes and ionized calcium binding adaptor molecule 1 (Iba-1)-positive microglia in 3xTg AD mice. PMID- 23086474 TI - Not all protein-mediated single-wall carbon nanotube dispersions are equally bioactive. AB - Single-wall carbon nanotubes (SWCNTs) have been dispersed with proteins to increase biocompatibility and specificity, but examinations of dispersion parameters on functional cellular uptake are required for utilization of SWCNTs in biological applications. Here we correlate conditions of SWCNT dispersion with various proteins to uptake these SWCNTs in NIH-3T3 fibroblasts and J774A.1 macrophage-like cells. We varied protein types (bovine serum albumin - BSA, lysozyme - LSZ, and gamma-globulins - gammaG), protein : SWCNT ratio and sonication time. Each protein created stable, high yield (~25%) dispersions in water while preserving intrinsic SWCNT fluorescence, but SWCNT-LSZ flocculated in media and SWCNT-gammaG formed clusters in both water and media, drastically altering cellular internalization. Dispersion quality and yield improved with increased protein : SWCNT - without substantial effects from depletion attraction, even at 100 : 1 protein : SWCNT - and slightly increased internalized SWCNTs for both NIH-3T3 and J774A.1 cells. Longer sonication time (12 versus 2 h) improved the dispersion yield and quality but caused minor damage to SWCNTs and altered protein structure. Cell association of SWCNT-BSA was homogenous and unaltered by sonication time. Bulk assay showed that cell association of SWCNT LSZ and SWCNT-gammaG was altered with 12 versus 2 h sonication, but imaging of individual cells showed that these differences are likely from precipitation of clusters of SWCNT-LSZ and SWCNT-gammaG in media onto cells. Hence, the quality of SWCNT-protein dispersions in water does not necessarily correlate with bulk cellular uptake, and quantification at the level of individual cells is required to determine delivery efficacy. PMID- 23086475 TI - Evolution of an HIV glycan-dependent broadly neutralizing antibody epitope through immune escape. AB - Neutralizing antibodies are likely to play a crucial part in a preventative HIV-1 vaccine. Although efforts to elicit broadly cross-neutralizing (BCN) antibodies by vaccination have been unsuccessful, a minority of individuals naturally develop these antibodies after many years of infection. How such antibodies arise, and the role of viral evolution in shaping these responses, is unknown. Here we show, in two HIV-1-infected individuals who developed BCN antibodies targeting the glycan at Asn332 on the gp120 envelope, that this glycan was absent on the initial infecting virus. However, this BCN epitope evolved within 6 months, through immune escape from earlier strain-specific antibodies that resulted in a shift of a glycan to position 332. Both viruses that lacked the glycan at amino acid 332 were resistant to the Asn332-dependent BCN monoclonal antibody PGT128 (ref. 8), whereas escaped variants that acquired this glycan were sensitive. Analysis of large sequence and neutralization data sets showed the 332 glycan to be significantly under-represented in transmitted subtype C viruses compared to chronic viruses, with the absence of this glycan corresponding with resistance to PGT128. These findings highlight the dynamic interplay between early antibodies and viral escape in driving the evolution of conserved BCN antibody epitopes. PMID- 23086476 TI - Vascular niche E-selectin regulates hematopoietic stem cell dormancy, self renewal and chemoresistance. AB - The microenvironment, or niche, surrounding a stem cell largely governs its cellular fate. Two anatomical niches for hematopoietic stem cells (HSCs) have been reported in the bone marrow, but a distinct function for each of these niches remains unclear. Here we report a new role for the adhesion molecule E selectin expressed exclusively by bone marrow endothelial cells in the vascular HSC niche. HSC quiescence was enhanced and self-renewal potential was increased in E-selectin knockout (Sele(-/-)) mice or after administration of an E-selectin antagonist, demonstrating that E-selectin promotes HSC proliferation and is a crucial component of the vascular niche. These effects are not mediated by canonical E-selectin ligands. Deletion or blockade of E-selectin enhances HSC survival threefold to sixfold after treatment of mice with chemotherapeutic agents or irradiation and accelerates blood neutrophil recovery. As bone marrow suppression is a severe side effect of high-dose chemotherapy, transient blockade of E-selectin is potentially a promising treatment for the protection of HSCs during chemotherapy or irradiation. PMID- 23086479 TI - Intra-peritoneal sRAGE treatment induces alterations in cellular distribution of CD19(+), CD3 (+) and Mac-1 (+) cells in lymphoid organs and peritoneal cavity. AB - Receptor for advanced glycation end products (RAGE) is a pattern recognition receptor that binds a variety of pro-inflammatory ligands. Its soluble form, sRAGE, can compete for ligand binding and thereby have an anti-inflammatory effect. We have recently reported that sRAGE also exerts pro-inflammatory and chemotactic properties suggesting a dual role for sRAGE in immune modulation. Our present aim was to analyse the immunomodulatory properties of sRAGE in vivo with respect to acquired immunity. Naive mice were treated intra-peritoneally with sRAGE and cells from peritoneal lavage, spleens and bone marrow were examined. Mice treated with sRAGE displayed an increased leucocyte count in the peritoneal cavity, enlarged spleens and increased cellularity compared with vehicle-treated animals. Furthermore, sRAGE-treated mice had a significantly increased frequency and number of CD19(+) B cells in spleen and a reduced frequency of CD19(+) B cells in bone marrow compared with controls. Functionally, splenocytes from sRAGE treated mice showed elevated IgG production and up to a four-fold increased IgM secretion compared with control animals and produced significantly higher levels of interleukin-10, interferon-gamma and interleukin-6 in response to lipopolysaccharide stimulation. Our results suggest that sRAGE has immunomodulatory properties, since intra-peritoneal administration of sRAGE into healthy mice leads to rearrangements in cellular composition in the bone marrow and spleen. Moreover, the administration of sRAGE directs B cells into the spleen and towards differentiation. Our novel findings indicate that sRAGE exerts an effect on the cells of adaptive immunity. PMID- 23086478 TI - NOTCH1 promotes T cell leukemia-initiating activity by RUNX-mediated regulation of PKC-theta and reactive oxygen species. AB - Reactive oxygen species (ROS), a byproduct of cellular metabolism, damage intracellular macromolecules and, when present in excess, can promote normal hematopoietic stem cell differentiation and exhaustion. However, mechanisms that regulate the amount of ROS in leukemia-initiating cells (LICs) and the biological role of ROS in these cells are largely unknown. We show here that the ROS(low) subset of CD44(+) cells in T cell acute lymphoblastic leukemia (T-ALL), a malignancy of immature T cell progenitors, is highly enriched in the most aggressive LICs and that ROS accumulation is restrained by downregulation of protein kinase C theta (PKC-theta). Notably, primary mouse T-ALLs lacking PKC theta show improved LIC activity, whereas enforced PKC-theta expression in both mouse and human primary T-ALLs compromised LIC activity. We also show that PKC theta is regulated by a new pathway in which NOTCH1 induces runt-related transcription factor 3 (RUNX3), RUNX3 represses RUNX1 and RUNX1 induces PKC theta. NOTCH1, which is frequently activated by mutation in T-ALL and required for LIC activity in both mouse and human models, thus acts to repress PKC-theta. These results reveal key functional roles for PKC-theta and ROS in T-ALL and suggest that aggressive biological behavior in vivo could be limited by therapeutic strategies that promote PKC-theta expression or activity, or the accumulation of ROS. PMID- 23086477 TI - The sirtuin SIRT6 blocks IGF-Akt signaling and development of cardiac hypertrophy by targeting c-Jun. AB - Abnormal activation of insulin-like growth factor (IGF)-Akt signaling is implicated in the development of various diseases, including heart failure. However, the molecular mechanisms that regulate activation of this signaling pathway are not completely understood. Here we show that sirtuin 6 (SIRT6), a nuclear histone deacetylase, functions at the level of chromatin to directly attenuate IGF-Akt signaling. SIRT6-deficient mice developed cardiac hypertrophy and heart failure, whereas SIRT6 transgenic mice were protected from hypertrophic stimuli, indicating that SIRT6 acts as a negative regulator of cardiac hypertrophy. SIRT6-deficient mouse hearts showed hyperactivation of IGF signaling related genes and their downstream targets. Mechanistically, SIRT6 binds to and suppresses the promoter of IGF signaling-related genes by interacting with c-Jun and deacetylating histone 3 at Lys9 (H3K9). We also found reduced SIRT6 expression in human failing hearts. These findings disclose a new link between SIRT6 and IGF-Akt signaling and implicate SIRT6 in the development of cardiac hypertrophy and failure. PMID- 23086480 TI - Inflammatory effects of resistin on human smooth muscle cells: up-regulation of fractalkine and its receptor, CX3CR1 expression by TLR4 and Gi-protein pathways. AB - In the atherosclerotic plaque, smooth muscle cells (SMC) acquire an inflammatory phenotype. Resistin and fractalkine (CX3CL1) are found in human atheroma and not in normal arteries. CX3CL1 and CX3CR1 are predominately associated with SMC. We have questioned whether resistin has a role in the expression of CX3CL1 and CX3CR1 in SMC thus contributing to the pro-inflammatory status of these cells. Cultured human aortic SMC were stimulated with 100 ng/ml resistin for 4, 6, 12, and 24 h, and then CX3CL1 and CX3CR1 expression was assessed by quantitative reverse transcription with the polymerase chain reaction and Western blot. We found that resistin up-regulated CX3CL1 and CX3CR1 in SMC and induced the phosphorylation of p38MAPK and STAT3. Inhibitors of p38MAPK, JAK-STAT, NF-kB, and AP-1 significantly reduced CX3CL1 and CX3CR1 expression. Knockdown of STAT1 and STAT3 with decoy oligodeoxinucleotides and the silencing of p65 and cjun with short interfering RNA decreased CX3CL1 and CX3CR1 expression. Anti-TLR4 antibody and pertussis toxin also reduced CX3CL1 and CX3CR1 protein expression. xCELLigence experiments revealed that resistin probably uses Gi-proteins for its effect on SMC. The CX3CL1 induced by resistin exhibited a chemotactic effect on monocyte transmigration. Thus, (1) resistin contributes to the pro-inflammatory state of SMC by the up-regulation of CX3CL1 and CX3CR1 expression via a mechanism involving NF-kB, AP-1, and STAT1/3 transcription factors, (2) resistin employs TLR4 and Gi-protein signaling for its effect on SMC, (3) CX3CL1 induced by resistin is functional in monocyte chemotaxis. The data reveal new mechanisms by which resistin promotes the inflammatory phenotype of SMC. PMID- 23086482 TI - [Placement of percutaneous nephrostomy by open magnetic resonance imaging: clinical results and current status in urology]. AB - BACKGROUND: Percutaneous nephrostomy (PCN) tube placement under combined ultrasound and fluoroscopic guidance is a standard procedure in urology. The use of a 1 Tesla open magnetic resonance imaging (MRI) scanner enables PCN placement under real-time guidance. METHOD: In the present series 51 patients underwent a total of 79 MRI-guided procedures between 2008 and 2012 and 52 interventions were performed after failure of conventional urological manipulation. Of the procedures 55 involved only a minor urine transport disorder (UTD) or none at all. RESULTS: Puncture and subsequent PCN tube placement were successful in all patients. Extravasation was found in four patients and renal pelvic clots in three. All complications healed without sequelae or further interventions. CONCLUSION: The MRI-guided PCN tube placement is an optimal alternative, particularly in cases of limited conventional imaging. PMID- 23086483 TI - [The GeSRU in the ESRU]. PMID- 23086484 TI - A new strategy in drug design of Chinese medicine: theory, method and techniques. AB - The research and development (R&D) process of Chinese medicine, with one notable feature, clinical application based, is significantly different from which of chemical and biological medicine, from laboratory research to clinics. Besides, compound prescription is another character. Therefore, according to different R&D theories between Chinese and Western medicine, we put forward a new strategy in drug design of Chinese medicine, which focuses on "combination-activity relationship (CAR)", taking prescription discovery, component identification and formula optimization as three key points to identify the drugs of high efficacy and low toxicity. The method of drug design of Chinese medicine includes: new prescription discovery based on clinical data and literature information, component identification based on computing and experimental research, as well as formula optimization based on system modeling. This paper puts forward the concept, research framework and techniques of drug design of Chinese medicine, which embodies the R&D model of Chinese medicine, hoping to support the drug design of Chinese medicine theoretically and technologically. PMID- 23086485 TI - Systematic review of beta-elemene injection as adjunctive treatment for lung cancer. AB - OBJECTIVE: To evaluate the effectiveness and safety of beta-elemene Injection as an adjunctive treatment for lung cancer by systematic review. METHODS: We retrieved randomized controlled clinical trials related to the use of beta elemene Injection as an adjunctive treatment for lung cancer from Chinese Biomedical (CBMweb), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), ChinaInfo, Cochrane Central Register of Controlled Trials; MEDLINE, EMBASE, OVID and TCMLARS. We also referred to an unpublished conference proceeding titled Clinical Use and Basic: Elemene Injection. We then divided the studies into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) subgroups by RevMan 5.1 software. RESULTS: A total of 21 source documents (1,467 patients) matched pre-specified criteria for determining the effectiveness and safety of beta-elemene Injection as an adjunctive treatment for lung cancer. Five studies involving 285 NSCLC patients reported a higher 24-month survival rate (39.09%) with the adjunctive treatment than with chemotherapy alone (26.17%; RR, 1.51; 95% CI, 1.03 to 2.21). Four studies involving 445 patients reported that the increased probability for improved performance status for patients treated with elemene-based combinations was higher than that of patients treated with chemotherapy alone (RR, 1.82; 95% CI, 1.45 to 2.29). The results from a subgroup analysis on 12 studies involving 974 NSCLC patients and 9 studies involving 593 patients with both SCLC and NSCLC showed that the tumor control rate for NSCLC improved more in the elemene-based combinations treatment group (78.70%) than in the chemotherapy alone control group (71.31%; RR, 1.06; 95% CI, 1.00 to 1.12). The tumor response rate for NSCLC also improved more among patients treated with elemenebased combinations (50.71%) than among patients treated with chemotherapy alone (38.04%; RR, 1.34; 95%CI, 1.17 to 1.54). In addition, the main adverse reaction to beta-elemene Injection was phlebitis, but usually only to a mild degree. An Egger's test showed no publication bias in our study (P=0.7030). CONCLUSIONS: The effectiveness of chemotherapy for the treatment of lung cancer may improve when combined with beta elemene injection as an adjunctive treatment. The combined treatment can result in an improved quality of life and prolonged survival. However, these results require confirmation by rigorously controlled trials. PMID- 23086486 TI - Qianliening capsule () inhibits human prostate cell growth via induction of mitochondrion-dependent cell apoptosis. AB - OBJECTIVE: To investigate the molecular mechanisms by which Qianliening Capsule (, QC) treats benign prostatic hyperplasia (BPH). METHODS: Human prostate stromal cell line WPMY-1 was treated with 0, 1, 3 and 5 mg/mL of QC for 24, 48 and 72 h, respectively, in the presence of 10 ng/mL basic fibroblast growth factor (bFGF). The viability of WPMY-1 cells was determined by 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Cell morphology was observed by phase contrast microscopy. 4',6-diamidino-2-phenylindole (DAPI) staining and fluorescence activated cell sorting (FACS) analysis with Annexin-V/propidium iodide (PI) staining were performed to determine cell apoptosis. The loss of mitochondrial membrane potential was examined by FACS analysis with 5,5',6,6' tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyarine iodide (JC-1) staining. Activation of caspase-3 and -9 was evaluated by colorimetric assay. The mRNA and protein expression levels of Bcl-2 and Bax were measured by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting, respectively. RESULTS: Upon bFGF stimulation, the viability of WPMY-1 cells was increased to 122%-118% compared with the control cells (P <0.05). However, treatment with 1-5 mg/mL of QC for 24, 48 and 72 h decreased the viability of bFGF-stimulated cells to 80%-92%, 59%-82%, 36%-62% compared with the untreated cells (P <0.05). In addition, QC treatment reduced WPMY-1 cell density in a dose dependent manner. Moreover, QC treatment dose-dependently induced the loss of plasma membrane asymmetry, the nuclear condensation and fragmentation, collapse of mitochondrial membrane potential, activation of caspase-9 and caspase-3, and increase of pro-apoptotic Bax/Bcl-2 ratio. CONCLUSION: Promoting mitochondrion dependent apoptosis of prostate stromal cells might be one of the mechanisms by which QC treats BPH. PMID- 23086487 TI - Changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha naphthylisothiocyanate-induced experimental hepatic injury after Yinchenhao Decoction () treatment. AB - OBJECTIVE: To study the changes of pharmacokinetics of 6,7-dimethoxycoumarin in a rat model of alpha-naphthylisothiocyanate (ANIT)-induced experimental hepatic injury after oral administration of Yinchenhao Decoction (, YCHD) using an ultra pressure liquid chromatography (UPLC) method. METHODS: Rats were divided into a normal group and a model group, after modeled by 4% ANIT (75 mg/kg) for 48 h, they were orally administrated with YCHD extract at the dose of 0.324 g/kg, and then blood was collected from their orbital sinus after different intervals. Changes in liver function were monitored by the levels of liver enzymes [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] and bilirubins [total bilirubin (TBIL), direct bilirubin (DBIL)], the concentration of 6,7 dimethoxycoumarin in plasma were measured by UPLC, and the pharmaceutical parameters were calculated with DAS2.1.1 software. RESULTS: The concentration time curve of both normal and modeled rats after oral administration of YCHD was obtained. Their time to maximum plasma concentration (t(max)) were both 0.25 h, the maximum concentration (C(max)) were 4.533 MUg/mL and 6.885 MUg/mL, and their area under concentration-time curve (AUC)(0->24h) were 16.272 and 32.981, respectively. There was a 51.88% and 100.46% increase in C(max) and AUC(0-t) (P<0.05), but there showed a 45.52% and 92.93% reduction in clearance of drug and volum of distribution (P<0.05), respectively. CONCLUSIONS: Hepatic injury could significantly influence the pharmacokinetics of 6,7-dimethoxycoumarin after oral administration of YCHD, the absorption and distribution process was accelerated in liver injured rats, but the metabolism and elimination process was slowed. And this may lead to a significant accumulation of 6,7-dimethoxycoumarin in the body. PMID- 23086488 TI - Neutroprotective efficacy of sodium tanshinone B on hippocampus neuron in a rat model of focal cerebral ischemia. AB - OBJECTIVE: To investigate the protective effects of sodium tanshinone B (STB) on brain damage following focal ischemia-reperfusion (I/R) injury through interfering with N-methyl-D-aspartic acid receptor (NMDAR) and excitatory and inhibitory amino acids, and evaluate the potential mechanisms of the neuroprotective activity of STB. METHODS: Transient forebrain ischemia was induced by middle cerebral artery occlusion (MCAO). The rats were randomized into a sham operated group, a model group (I/R) and three STB different dose groups. Rats were pretreated with STB at the doses of 4, 8, 16 mg/kg (STB(1), STB(2), STB(3)) for 3 days before MCAO. The expression of NMDAR1 was detected by immunohistochemistry and Western blotting. The concentrations of glutamate and gamma-aminobutyric acid (GABA) were analyzed using high performance liquid chromatography. RESULTS: STB treatment reduced neurological defect scores, cerebral infarction volume and brain water content. The levels of NMDAR1 were significantly higher in the l/R and STB(1) groups than that of the sham and the STB(3) groups (P<0.01). Optical density of NMDAR1 was significantly increased in cornu ammonis (CA)1 region of the l/R group (P<0.05). STB treatment reduced NMDAR1 optical density in the CA1 region (P<0.01). The levels of glutamate were significantly lower in the hippocampus in the STB(3) group than that of the l/R, STB(1) and STB(2) groups (P<0.01). CONCLUSION: Preconditioning with STB appears to be a simple and promising strategy to reduce or even prevent cerebral l/R injury and has potential for future clinical application. PMID- 23086489 TI - Effects of Er'zhi Tiangui Granule () on sequential expressions of integrin beta 3 and its ligand osteopontin in mouse endometrium during controlled ovarian hyperstimulation. AB - OBJECTIVE: To investigate the effects of Er'zhi Tiangui Granule (, ETG) on sequential expressions of integrinbeta3 and its ligand osteopontin in the mouse endometrium during controlled ovarian hyperstimulation (COH) and implantation period. METHODS: Seventy-five Mature female Kunming mice were randomly divided into 3 groups, a normal control group, a model group, and a treatment group administrated with ETG for 10 days, 25 in each group. After mated with male mice, every 5 mice were sacrified in each group at the 0, 2nd, 4th, 6th, and 8th days to take their endometrium. In-situ hybridization was used to detect the expressions of integrinbeta3 and osteopontin in the endometrium. RESULTS: mRNA expressions of integrinbeta3 and osteopontin in the endometrium during implantation period showed similar time sequence rules in the treatment group to those in the normal control group; the peak values of them were a little lower in the treatment group than the normal control without significant differences. In the model group, integrinbeta3 mRNA expression was higher at the 2nd day, obviously lower at the 4th and 6th days, and insignificantly lower at the 8th day; and osteopontin expression was remarkably lower at the 4th, 6th, and 8th days, compared with the normal control and the treatment groups (P<0.05, P<0.01). CONCLUSIONS: COH might influence the sequential expressions of integrinbeta3 and its ligand osteopontin, bring forward the integrinbeta3 expression peak, impact on the cooperation of integrinbeta3 and osteopontin, so as to damage the endometrial receptivity. ETG could regulate the sequential expressions of integrinbeta3 and its ligand osteopontin to improve the mouse endometrial receptivity during COH. PMID- 23086490 TI - A review on pharmacological significance of genus Jatropha (Euphorbiaceae). AB - A number of herbs belonging to the genus Jatropha of Euphorbiaceae family are noted for their medicinal benefits. The genus Jatropha is one of the prospective biodiesel yielding crops. The plants which have been so far explored include J. curcas, J. gossypifolia, J. glandulifera, J. multifida and J. podagrica. Although, the plants of this genus are widely distributed, there is an exiguity of scientific literature proclaiming the medicinal benefits of the plants belonging to genus Jatropha. The present paper is a pragmatic approach to accrue the findings on this very significant genus. PMID- 23086492 TI - Expert approaches to common bleeding and thrombotic problems-part I. PMID- 23086493 TI - NHC Bronsted base-catalyzed transformations of isochromene derivatives: regulation of products by the structures of carbene catalysts. AB - Two different transformations of alpha-(isochromen-1-yl)ketones catalyzed by NHC Bronsted bases are reported. In the presence of a triazole carbene, alpha (isochromen-1-yl)ketones isomerized into beta-(2-(aroylmethylene)phenyl) alpha,beta-unsaturated ketones in 38-88% yields, while the same reaction catalyzed by an imidazole carbene produced 1-aroylnaphthalene derivatives in 90 99% yields. This work not only provides a new method for the synthesis of a novel type of alpha,beta-unsaturated ketone and multi-substituted naphthalene derivatives, but also advances the application of NHC catalysts in the field of Bronsted base-catalysis. PMID- 23086491 TI - Recent advances in plant-virus interaction with emphasis on small interfering RNAs (siRNAs). AB - Regulation of several biological functions in plants has now been known to involve diverse RNA silencing pathways. These vital pathways involve various components such as dsRNA, Dicer, RNA-dependent RNA polymerase and Argonaute proteins, which lead to the production of several small RNAs (sRNAs) varying in their sizes. These sRNAs have significant role in the regulation of gene expression at transcriptional and translational levels. Among them, small interfering RNAs (siRNAs; majorly 21, 22 and 24 nt) have been shown to play an important role in plants' resistance against many viruses by inhibiting the viral gene expression. Furthermore, it has also been highlighted that siRNA-mediated methylation of viral DNA confers resistance to various plant DNA viruses. In this review, we have outlined the recent advances made using the siRNA-mediated antiviral strategy, along with methylation-based epigenetic defensive mechanisms as a protective measure against diverse plant viruses. PMID- 23086494 TI - Improvement of eustachian tube function by tissue-engineered regeneration of mastoid air cells. AB - OBJECTIVES/HYPOTHESIS: Most cases of chronic otitis media (OMC) are associated with poor development of the mastoid air cells (MACs) and poor Eustachian tube (ET) function. We have previously reported that MAC regeneration can effectively eliminate intractable OMC. In this study, we assessed the ability of regenerated MACs to restore normal gas exchange function and contribute to improved ET function. STUDY DESIGN: Clinical trial with control. SETTING: General hospitals. MATERIALS AND METHODS: Seventy-six patients with OMC, including cholesteatoma and adhesive otitis media, received tympanoplasty and MAC regeneration therapy. At the first-stage of tympanoplasty, artificial pneumatic bones and/or autologous bone fragments were implanted into the opened mastoid cavity. At the 2nd-stage operation, a nitrous oxide (N2O) gas study was performed in 10 patients to measure middle ear pressure (MEP). For the control group, MEP was measured in five patients with good MAC development during cochlear implantation or facial nerve decompression. ET function was measured twice in each patient, once before the 1st operation and 6 months after the second operation. RESULTS: At the 2nd stage operation, in all cases with regenerated MACs and in the normal control group, MEP changed after administration of N2O. In contrast, no change in MEP was observed in cases with unregenerated MACs. In 70% (n = 37/53) of the regenerated MAC group, ET function was improved, whereas improvement of ET function was observed in only 13% (n = 3/23) of the unregenerated MAC group. CONCLUSIONS: Tissue-engineered regeneration of MACs improves ET function and gas exchange in the middle ear. PMID- 23086495 TI - [Parietal complications of hydatid cyst of the liver. Report of two cases in Tunisia]. AB - The aim of this study is to consider the parietal complications of the hydatid cyst of the liver: the subcutaneous rupture of the cyst and spontaneous cutaneous fistula of liver hydatid cyst. 1(st) case: A 24-year-old woman, who underwent surgery 10 years ago for hydatid cyst of the liver, was admitted for a right hypochondrium mass and a fistula draining clear liquid containing cystic elements. Computed tomography (CT) showed a large cystic lesion in the subcutaneous tissue communicating with another cystic mass in the liver. The diagnosis of a cyst-cutaneous fistula due to a peritoneal hydatid cyst was established. The patient underwent surgical treatment and recovered uneventfully. 2(nd) case: A 40-year-old woman presented with a mass in her right hypochondrium. The diagnosis of subcutaneous rupture of a hydatid cyst of liver was established by ultrasonography and CT-scan. The patient underwent surgical treatment and recovered uneventfully. Parietal complications of hydatid cyst of the liver are extremely rare, clinical presentation can be derailing. The diagnosis is usually established by ultrasonography and CT-scan. PMID- 23086496 TI - Fabrication and design equation of film-type large-scale interdigitated supercapacitor chips. AB - We report large-scale interdigitated supercapacitor chips based on pseudo capacitive metal oxide electrodes. A novel method is presented, which provides a powerful fabrication technology of interdigitated supercapacitors operated by a pseudo-capacitive reaction. Also, we empirically develop an equation that describes the relationship between capacitance, mass, and sweep rate in an actual supercapacitor system. PMID- 23086497 TI - A zinc-binding citrus protein metallothionein can act as a plant defense factor by controlling host-selective ACR-toxin production. AB - Metallothionein is a small cysteine-rich protein known to have a metal-binding function. We isolated three different lengths of rough lemon cDNAs encoding a metallothionein (RlemMT1, RlemMT2 and RlemMT3), and only RlemMT1-recombinant protein had zinc-binding activity. Appropriate concentration of zinc is an essential micronutrient for living organisms, while excess zinc is toxic. Zinc also stimulates the production of host-selective ACR-toxin for citrus leaf spot pathogen of Alternaria alternata rough lemon pathotype. Trapping of zinc by RlemMT1-recombinant protein or by a zinc-scavenging agent in the culture medium caused suppression of ACR-toxin production by the fungus. Since ACR-toxin is the disease determinant for A. alternata rough lemon pathotype, addition of RlemMT1 to the inoculum suspension led to a significant decrease in symptoms on rough lemon leaves as a result of reduced ACR-toxin production from the zinc trap around infection sites. RlemMT1-overexpression mutant of A. alternata rough lemon pathotype also produced less ACR-toxin and reduced virulence on rough lemon. This suppression was caused by an interruption of zinc absorption by cells from the trapping of the mineral by RlemMT1 and an excess supplement of ZnSO(4) restored toxin production and pathogenicity. Based on these results, we propose that zinc adsorbents including metallothionein likely can act as a plant defense factor by controlling toxin biosynthesis via inhibition of zinc absorption by the pathogen. PMID- 23086498 TI - Dual targeting of a mature plastoglobulin/fibrillin fusion protein to chloroplast plastoglobules and thylakoids in transplastomic tobacco plants. AB - Plastoglobules (PG) are lipid droplets in chloroplasts and other plastid types having important functions in lipid metabolism. Plastoglobulins (PGL) also known as fibrillins (FBN) are evolutionary conserved proteins present at the PG surface but also to various extents at the thylakoid membrane. PGLs are thought to have structural functions in PG formation and maintenance. The targeting of an Arabidopsis PGL (PGL34) to PG required the full protein sequence with the exception of a short C-terminal stretch. This indicated that PGL targeting relies on correct folding rather than a discrete sequence. PGLs lack strongly hydrophic regions and may therefore extrinsically associate with PG and thylakoid membranes via interaction with hydrophilic headgroups of surface lipids. Here, we report on the expression of the Arabidopsis plastoglobulin of 35kD (PGL35 or FBN1a) expressed as a mature protein fused to HIVp24 (human immunodeficiency virus capsid particle p24) or HCV (hepatitis C virus core protein) in transplastomic tobacco. A PGL35-HIVp24 fusion targeted in part to plastoglobules but a larger proportion was recovered in the thylakoid fraction. The findings indicate that transplastomic PGL35-HIVp24 folded correctly after its synthesis inside the chloroplast and then dually targeted to plastoglobules as well as thylakoid membranes. PMID- 23086499 TI - Therapist perspectives on training in a package of evidence-based practice strategies for children with autism spectrum disorders served in community mental health clinics. AB - Therapist perspectives regarding delivery of evidence-based practice (EBP) strategies are needed to understand the feasibility of implementation in routine service settings. This qualitative study examined the perspectives of 13 therapists receiving training and delivering a package of EBPs to children with autism spectrum disorders (ASDs) in community mental health clinics. Therapists perceived the training and intervention delivery as effective at improving their clinical skills, the psychotherapy process, and child and family outcomes. Results expand parent pilot study findings, and add to the literature on training community providers and limited research on training providers to deliver EBPs to children with ASD. PMID- 23086500 TI - Experimental heart rate regulation in cycle-ergometer exercises. AB - The heart rate can be effectively used as a measure of the exercise intensity during long duration cycle-ergometer exercises: precisely controlling the heart rate (HR) becomes crucial especially for athletes or patients with cardiovascular/obesity problems. The aim of this letter is to experimentally show how the nonlocal and nonswitching nonlinear control that has been recently proposed in the literature for the HR regulation in treadmill exercises can be effectively applied to cycle-ergometer exercises at constant cycling speed. The structure of the involved nonlinear model for the HR dynamics in cycle-ergometer exercises is mathematically inspired by the structure of a recently identified and experimentally validated nonlinear model for the HR dynamics in treadmill exercises: the role played by the treadmill speed is played here by the work load while the zero speed case for the treadmill exercise is here translated into the cycling operation under zero work load. Experimental results not only validate the aforementioned nonlinear model but also demonstrate the effectiveness--in terms of precise HR regulation--of an approach which simply generalizes to the nonlinear framework the classical proportional-integral control design. The possibility of online modifying the HR reference on the basis of the heart rate variability (HRV) is also suggested and experimentally motivated. PMID- 23086501 TI - The use of ensemble empirical mode decomposition with canonical correlation analysis as a novel artifact removal technique. AB - Biosignal measurement and processing is increasingly being deployed in ambulatory situations particularly in connected health applications. Such an environment dramatically increases the likelihood of artifacts which can occlude features of interest and reduce the quality of information available in the signal. If multichannel recordings are available for a given signal source, then there are currently a considerable range of methods which can suppress or in some cases remove the distorting effect of such artifacts. There are, however, considerably fewer techniques available if only a single-channel measurement is available and yet single-channel measurements are important where minimal instrumentation complexity is required. This paper describes a novel artifact removal technique for use in such a context. The technique known as ensemble empirical mode decomposition with canonical correlation analysis (EEMD-CCA) is capable of operating on single-channel measurements. The EEMD technique is first used to decompose the single-channel signal into a multidimensional signal. The CCA technique is then employed to isolate the artifact components from the underlying signal using second-order statistics. The new technique is tested against the currently available wavelet denoising and EEMD-ICA techniques using both electroencephalography and functional near-infrared spectroscopy data and is shown to produce significantly improved results. PMID- 23086502 TI - Surface electrocardiogram reconstruction from intracardiac electrograms using a dynamic time delay artificial neural network. AB - This study proposes a method to facilitate the remote follow up of patients suffering from cardiac pathologies and treated with an implantable device, by synthesizing a 12-lead surface ECG from the intracardiac electrograms (EGM) recorded by the device. Two methods (direct and indirect), based on dynamic time delay artificial neural networks (TDNNs) are proposed and compared with classical linear approaches. The direct method aims to estimate 12 different transfer functions between the EGM and each surface ECG signal. The indirect method is based on a preliminary orthogonalization phase of the available EGM and ECG signals, and the application of the TDNN between these orthogonalized signals, using only three transfer functions. These methods are evaluated on a dataset issued from 15 patients. Correlation coefficients calculated between the synthesized and the real ECG show that the proposed TDNN methods represent an efficient way to synthesize 12-lead ECG, from two or four EGM and perform better than the linear ones. We also evaluate the results as a function of the EGM configuration. Results are also supported by the comparison of extracted features and a qualitative analysis performed by a cardiologist. PMID- 23086503 TI - Natural product synthesis as a challenging test of newly developed methodology. AB - This article describes the examination of several synthetic methodologies that have been developed in our laboratories, by application to the construction of a variety of natural product targets. PMID- 23086504 TI - Doubly robust estimators of causal exposure effects with missing data in the outcome, exposure or a confounder. AB - We consider the estimation of the causal effect of a binary exposure on a continuous outcome. Confounding and missing data are both likely to occur in practice when observational data are used to estimate this causal effect. In dealing with each of these problems, model misspecification is likely to introduce bias. We present augmented inverse probability weighted (AIPW) estimators that account for both confounding and missing data, with the latter occurring in a single variable only. These estimators have an element of robustness to misspecification of the models used. Our estimators require two models to be specified to deal with confounding and two to deal with missing data. Only one of each of these models needs to be correctly specified. When either the outcome or the exposure of interest is missing, we derive explicit expressions for the AIPW estimator. When a confounder is missing, explicit derivation is complex, so we use a simple algorithm, which can be applied using standard statistical software, to obtain an approximation to the AIPW estimator. PMID- 23086505 TI - Individual and spatio-temporal variations in the home range behaviour of a long lived, territorial species. AB - Despite the fact that investigations of home range behaviour have exponentially evolved on theoretical, analytical and technological grounds, the factors that shape animal home range behaviour still represent an unsolved question and a challenging field of research. However, home range studies have recently begun to be approached under a new integrated conceptual framework, considering home range behaviour as the result of the simultaneous influences of temporal, spatial and individual-level processes, with potential consequences at the population level. Following an integrated approach, we studied the influence of both external and internal factors on variations in the home range behaviour of 34 radiotagged eagle owl (Bubo bubo) breeders. Home range behaviour was characterised through complementary analysis of space use, movement patterns and rhythms of activity at multiple spatio-temporal scales. The effects of the different phases of the biological cycle became considerably evident at the level of movement patterns, with males travelling longer distances than females during incubation and nestling periods. Both external (i.e. habitat structure and composition) and internal (i.e. sex and health state) factors explained a substantial amount of the variation in home range behaviour. At the broader temporal scale, home range and core area size were negatively correlated with landscape heterogeneity. Males showed (1) smaller home range and core area sizes, (2) more complex home range internal structure and (3) higher rates of movement. The better the physiological condition of the individuals, the simpler the internal home range structure. Finally, inter- and intra-individual effects contributed to shaping space use and movement patterns during the biological cycle. Because of the plurality of behavioural and ecological processes simultaneously involved in home range behaviour, we claim that an integrative approach is required for adequate investigation of its temporal and spatial variation. PMID- 23086506 TI - Biotic interactions as a structuring force in soil communities: evidence from the micro-arthropods of an Antarctic moss model system. AB - Current meta-community theories postulate that the structure of local communities depends on dispersal, environmental filtering, and biotic interactions. However, disentangling the relative effects of these factors in the field and for diverse assemblages is a major challenge. A solution is to address natural but simple communities (i.e. with low numbers of species in few trophic levels), wherein one of these factors is predominant. Here, we analyse the micro-arthropod community of a moss-turf habitat typical of the Antarctic Peninsula region, and test the widely accepted hypothesis that this system is abiotically driven. In the austral summers 2006/7 and 2007/8, we sampled nearly 80 units of moss from four islands in the Argentine Islands. Using variance partitioning, we quantified the relative contribution of: (1) multiple scale spatio-temporal autocorrelation; (2) environmental effects; (3) the island effect. Little variance (1 %) was accounted for by sources 1 (1 %, significant) and 2 (<1 %, not significant). The island effect significantly accounted for the largest amount of variation (8 %). There was a relatively large effect of spatially structured environmental variation (7 %). Null models demonstrated that species co-occurred less frequently than expected by chance, suggesting the prevalence of negative interactions. Our data support the novel hypothesis that negative biotic interactions are the most important structuring force of this micro-arthropod community. The analysed system is a good proxy for more complex communities in terms of taxonomic composition and the functional groups present. Thus, biotic interaction might be a predominant factor in soil meta-community dynamics. PMID- 23086507 TI - Nocturnal loss of body reserves reveals high survival risk for subordinate great tits wintering at extremely low ambient temperatures. AB - Winter acclimatization in birds is a complex of several strategies based on metabolic adjustment accompanied by long-term management of resources such as fattening. However, wintering birds often maintain fat reserves below their physiological capacity, suggesting a cost involved with excessive levels of reserves. We studied body reserves of roosting great tits in relation to their dominance status under two contrasting temperature regimes to see whether individuals are capable of optimizing their survival strategies under extreme environmental conditions. We predicted less pronounced loss of body mass and body condition and lower rates of overnight mortality in dominant great tits at both mild and extremely low ambient temperatures, when ambient temperature dropped down to -43 degrees C. The results showed that dominant great tits consistently maintained lower reserve levels than subordinates regardless of ambient temperature. However, dominants responded to the rising risk of starvation under low temperatures by increasing their body reserves, whereas subdominant birds decreased reserve levels in harsh conditions. Yet, their losses of body mass and body reserves were always lower than in subordinate birds. None of the dominant great tits were found dead, while five young females and one adult female were found dead in nest boxes during cold spells when ambient temperatures dropped down to -43 degrees C. The dead great tits lost up to 23.83 % of their evening body mass during cold nights while surviving individuals lost on average 12.78 % of their evening body mass. Our results show that fattening strategies of great tits reflect an adaptive role of winter fattening which is sensitive to changes in ambient temperatures and differs among individuals of different social ranks. PMID- 23086509 TI - Limitation in the assessment of baseline lymphomatous bone marrow involvement by FDG-PET/CT scan. PMID- 23086508 TI - Efficacy and safety of deferasirox at low and high iron burdens: results from the EPIC magnetic resonance imaging substudy. AB - The effect of deferasirox dosing tailored for iron burden and iron loading based on liver iron concentration (LIC) was assessed over 1 year in less versus more heavily iron-overloaded patients in a substudy of the Evaluation of Patients' Iron Chelation with Exjade(r). Deferasirox starting dose was 10-30 mg/kg/day, depending on blood transfusion frequency, with recommended dose adjustments every 3 months. Therapeutic goals were LIC maintenance or reduction in patients with baseline LIC <7 or >=7 mg Fe/g dry weight (dw), respectively. Changes in LIC (R2 magnetic resonance imaging) and serum ferritin after 1 year were assessed. Adverse events (AEs) and laboratory parameters were monitored throughout. Of 374 patients, 71 and 303 had baseline LIC <7 and >=7 mg Fe/g dw, respectively; mean deferasirox doses were 20.7 and 27.1 mg/kg/day (overall average time to dose increase, 24 weeks). At 1 year, mean LIC and median serum ferritin levels were maintained in the low-iron cohort (-0.02 +/- 2.4 mg Fe/g dw, -57 ng/mL; P = not significant) and significantly decreased in the high-iron cohort (-6.1 +/- 9.1 mg Fe/g dw, -830 ng/mL; P < 0.0001). Drug-related gastrointestinal AEs, mostly mild to moderate, were more frequently reported in the <7 versus >=7 mg Fe/g dw cohort (39.4 versus 20.8 %; P = 0.001) and were not confounded by diagnosis, dosing, ethnicity, or hepatitis B and/or C history. Reported serum creatinine increases did not increase in low- versus high-iron cohort patients. Deferasirox doses of 20 mg/kg/day maintained LIC <7 mg Fe/g dw and doses of 30 mg/kg/day were required for net iron reduction in the high-iron cohort, with clinically manageable safety profiles. The higher incidence of gastrointestinal AEs at lower iron burdens requires further investigation. PMID- 23086510 TI - Remission of primary cutaneous anaplastic large cell lymphoma after a brief course of brentuximab vedotin. PMID- 23086511 TI - Cross-talk between amino acid residues and flavonoid derivatives: insights into their chemical recognition. AB - Currently, there is a general consensus that flavonoids exert their antioxidant activity through their ability to interact with a broad range of proteins, enzymes and transcription factors rather than acting as conventional hydrogen donating antioxidants. For this, the effect of different chemical groups of the conjugated flavonoid metabolites is apparently playing a pivotal role. Yet, many questions concerning the relevant molecular mechanisms still remain open. It is therefore crucial to gain a deeper insight into the amino acid residue-flavonoid interaction. Here we show extensive theoretical thermodynamic data and structural characteristics of the interaction of chalcone, genistein, epigallocatechin gallate, and quercetin and some of its metabolites with amino acid residues. By correlating (a) the binding energies of flavonoids-amino acid residues, (b) the hydrophobicity of amino acids, and (c) the abundance of amino acid residues in the binding sites of proteins, we can conclude that flavonoids appear to be strongly bonded to only few charged hydrophilic amino acids in the protein pockets, and rather weakly bonded to the majority of amino acid residues in the binding sites. This finding strongly impacts the understanding of the chemical recognition of flavonoids and their metabolites in their interaction with proteins and would contribute to a better design of further experimental studies. Particularly, the amino acids Phe, Leu, Ile and Trp seem to play a crucial role in the dynamics of flavonoid ligands in the binding sites of proteins. PMID- 23086513 TI - LiCl-effect on asymmetric intramolecular hydroamination catalyzed by binaphthylamido yttrium complexes. AB - Chiral alkyl or amido yttrium complexes were prepared from N-silyl- or N cyclopentyl-substituted binaphthylamido ligands. According to the synthetic procedure, these complexes could be obtained in their neutral form or as heterobimetallic complexes in the presence of 1 equiv. LiCl. These new species were characterized by IR and NMR spectroscopies, elemental analyses and some of them by X-ray diffraction studies. Their efficiency as catalysts for the asymmetric intramolecular hydroamination was then evaluated with several substrates towards the synthesis of two pyrrolidines and a piperidine derivative. A cooperative effect between the lithium and the yttrium atoms was undoubtedly revealed. LiCl-containing complexes afforded indeed higher enantioselectivities than their salt-free counterparts and according to the structure of the chiral ligand, they were also the most active species. PMID- 23086512 TI - Rapid development of molecular markers by next-generation sequencing linked to a gene conferring phomopsis stem blight disease resistance for marker-assisted selection in lupin (Lupinus angustifolius L.) breeding. AB - Selection for phomopsis stem blight disease (PSB) resistance is one of the key objectives in lupin (Lupinus angustifolius L.) breeding programs. A cross was made between cultivar Tanjil (resistant to PSB) and Unicrop (susceptible). The progeny was advanced into F(8) recombinant inbred lines (RILs). The RIL population was phenotyped for PSB disease resistance. Twenty plants from the RIL population representing disease resistance and susceptibility was subjected to next-generation sequencing (NGS)-based restriction site-associated DNA sequencing on the NGS platform Solexa HiSeq2000, which generated 7,241 single nucleotide polymorphisms (SNPs). Thirty-three SNP markers showed the correlation between the marker genotypes and the PSB disease phenotype on the 20 representative plants, which were considered as candidate markers linked to a putative R gene for PSB resistance. Seven candidate markers were converted into sequence-specific PCR markers, which were designated as PhtjM1, PhtjM2, PhtjM3, PhtjM4, PhtjM5, PhtjM6 and PhtjM7. Linkage analysis of the disease phenotyping data and marker genotyping data on a F(8) population containing 187 RILs confirmed that all the seven converted markers were associated with the putative R gene within the genetic distance of 2.1 CentiMorgan (cM). One of the PCR markers, PhtjM3, co segregated with the R gene. The seven established PCR markers were tested in the 26 historical and current commercial cultivars released in Australia. The numbers of "false positives" (showing the resistance marker allele band but lack of the putative R gene) for each of the seven PCR markers ranged from nil to eight. Markers PhtjM4 and PhtjM7 are recommended in marker-assisted selection for PSB resistance in the Australian national lupin breeding program due to its wide applicability on breeding germplasm and close linkage to the putative R gene. The results demonstrated that application of NGS technology is a rapid and cost effective approach in development of markers for molecular plant breeding. PMID- 23086514 TI - Effectiveness of a simulated training model for procedural skill demonstration in neonatal circumcision. AB - INTRODUCTION: Although existing evidence is insufficient to recommend routine neonatal male circumcision, it is a procedure commonly performed in the United States. There are no commercially available infant penile models available for circumcision training. We improved the design of a low-fidelity penile model constructed of cocktail wieners following the one by Brill and Wallace (Fam Med 2007;39:241-243) and attached it to a high-fidelity infant simulator. Providing simulated movement and crying similar to what is encountered in routine newborn circumcisions create a more realistic training scenario.The study objectives were to (1) evaluate the educational experience of a simulated skill training program as perceived by participants based on a comparison scale and (2) evaluate the fidelity of the simulated model. METHODS: Standardized workshops were held for family medicine (n = 23) and obstetrics/gynecology (n = 6) residents (n = 29). Residents evaluated the realism of the simulation, the realistic adequacy of the model, and the overall educational effectiveness of the workshop. RESULTS: Using a Likert scale where 1 was the lowest and 4 was the highest, the average participant ratings were 3.96 for educational experience and improved medical knowledge and 3.89 for improved technical ability for both Mogen and Gomco clamps. The model was evaluated for anatomic landmarks (3.7), anesthesia administration (3.9), dorsal crush and slit (3.9), and breaking adhesions (3.5). Qualitative comments for perceived fidelity of the model were summarized. CONCLUSIONS: This project demonstrated successful development of a low-cost, easy to-construct penile model combined with a high-fidelity infant simulator that, according to the responses of the participants in this study, enhances the simulated neonatal circumcision training. A tutorial for model construction and investigator-developed skill assessment checklists for Gomco and Mogen techniques are included in this technical report. PMID- 23086515 TI - Using software-based simulation for resident physician training in the management of temporary pacemakers. AB - INTRODUCTION: An understanding of epicardial pacing is essential for the postoperative management of patients having cardiac surgery. By developing a software-based epicardial pacing program to be used with the existing patient simulator, resident physicians may be exposed to various clinical scenarios that might be encountered while caring for a postoperative heart patient. This experience will assist junior residents with no prior experience to become familiar and competent in the management of epicardial pacemakers. METHODS: The simulation session used the human patient simulator in combination with an internally developed computer program using Flash animation to present arrhythmias and various epicardial pacing interventions commonly used in the postoperative period. By modeling the Flash animation software after a pulse generator, the user is able to make adjustments (type of pacing, rate of pacing, and chamber output) as if using an actual pulse generator. A group of 15 anesthesiology residents who had minimal or no epicardial pacing experience underwent the simulation training. Feedback was obtained by an anonymous postscenario questionnaire. RESULTS: A detailed description of the scenario and computer program is provided. All participants provided positive feedback and have strongly agreed that the simulation session improved their understanding and management of epicardial pacemakers. CONCLUSIONS: Our experience with epicardial pacing simulation was demonstrated to be effective in increasing the confidence of junior anesthesiology residents with little or no prior experience with regard to the management of temporary pacemakers. PMID- 23086516 TI - Rheumatoid arthritis: what do we mean by early? PMID- 23086517 TI - A study of baseline prevalence and cumulative incidence of comorbidity and extra articular manifestations in RA and their impact on outcome. AB - OBJECTIVES: To study the prevalence at diagnosis and cumulative incidence of comorbidity in RA, associations with clinical features and impact on outcome. METHODS: Standard clinical, laboratory and radiological measures of RA, and details of comorbidity and extra-articular features were recorded at baseline and yearly in an inception cohort of 1460 patients with recently diagnosed RA from nine regions in the UK. The General Practice Research Database was used to compare the incidence of common comorbid conditions (International Classification for Disease-10 codes). RESULTS: Baseline prevalence was 31.6% and 8.6% for all comorbidities and extra-articular features, respectively, and 15-year cumulative incidence was 81% and 53%, respectively. Rates of hypertension [standardized incidence ratio (SIR) = 1.61; 95% CI 1.43, 1.79] and ischaemic heart disease (SIR = 1.60; 95% CI 1.35, 1.84) were raised compared with figures for the general population, as was stroke in females (SIR = 1.34; 95% CI 1.02, 1.77) and chronic obstructive pulmonary disorder in males (SIR = 1.63; 95% CI 1.17, 2.26). Comorbidity was associated with risk of both all-cause and cardiovascular mortality (hazard ratio = 1.09; 95% CI 1.02, 1.17) and increased rates of functional decline over 10 years (b = 0.011; 95% CI 0.004, 0.019). Comorbidity was not related to disease activity or structural damage. CONCLUSION: Significant comorbidity was present at the outset of RA, increasing with follow-up, mainly in cardiovascular, non-cardiac vascular and respiratory systems. Specific conditions (e.g. hypertension) occurred more frequently than in the general population. Comorbidity was related to mortality and functional decline, and more intensive therapies may need consideration in these patients. As many co-existent conditions are amenable to preventative/therapeutic measures, comorbidity needs earlier detection and management in order to reduce its impact on outcome in RA. PMID- 23086518 TI - Health care quality indicators on the management of rheumatoid arthritis and osteoarthritis: a literature review. AB - OBJECTIVE: To make an inventory of quality and content of currently available and published sets of health care quality indicators (HCQIs) for RA and OA. METHODS: A systematic review was performed for documents on the development and/or a description of HCQIs for the management of patients with RA and/or OA, using the PubMed, EMBASE, Web of Science, Cochrane and CINAHL databases up to 1 December 2010 and official websites of arthritis organizations. The following data were extracted: general characteristics, contents and quality of developmental process (six aspects related to the definition of target, target group and stakeholders, patient involvement, description of development and test of validity). RESULTS: The search yielded 498 potentially eligible references and two websites, with ultimately six original HCQI sets for RA and/or OA being identified (one for RA and OA, two for OA and three for RA). The number of HCQI ranged from 7 to 27, with the majority being process indicators. No conflicting indicators between the HCQI sets for one condition were seen. Concerning the quality of the developmental process, all six sets lacked patient involvement. CONCLUSION: Only a limited number of HCQI sets for the management of OA and RA are available, mainly including process indicators. The developmental process was methodologically suboptimal in all cases. As improvement of health care quality is an ongoing process, there is a need for development of HCQIs covering different aspects of health care quality (structure, process and outcome) and using appropriate methodology. PMID- 23086520 TI - Graph-based multi-surface segmentation of OCT data using trained hard and soft constraints. AB - Optical coherence tomography (OCT) is a well-established image modality in ophthalmology and used daily in the clinic. Automatic evaluation of such datasets requires an accurate segmentation of the retinal cell layers. However, due to the naturally low signal to noise ratio and the resulting bad image quality, this task remains challenging. We propose an automatic graph-based multi-surface segmentation algorithm that internally uses soft constraints to add prior information from a learned model. This improves the accuracy of the segmentation and increase the robustness to noise. Furthermore, we show that the graph size can be greatly reduced by applying a smart segmentation scheme. This allows the segmentation to be computed in seconds instead of minutes, without deteriorating the segmentation accuracy, making it ideal for a clinical setup. An extensive evaluation on 20 OCT datasets of healthy eyes was performed and showed a mean unsigned segmentation error of 3.05 +/-0.54 MUm over all datasets when compared to the average observer, which is lower than the inter-observer variability. Similar performance was measured for the task of drusen segmentation, demonstrating the usefulness of using soft constraints as a tool to deal with pathologies. PMID- 23086519 TI - Cortical surface reconstruction via unified Reeb analysis of geometric and topological outliers in magnetic resonance images. AB - In this paper we present a novel system for the automated reconstruction of cortical surfaces from T1-weighted magnetic resonance images. At the core of our system is a unified Reeb analysis framework for the detection and removal of geometric and topological outliers on tissue boundaries. Using intrinsic Reeb analysis, our system can pinpoint the location of spurious branches and topological outliers, and correct them with localized filtering using information from both image intensity distributions and geometric regularity. In this system, we have also developed enhanced tissue classification with Hessian features for improved robustness to image inhomogeneity, and adaptive interpolation to achieve sub-voxel accuracy in reconstructed surfaces. By integrating these novel developments, we have a system that can automatically reconstruct cortical surfaces with improved quality and dramatically reduced computational cost as compared with the popular FreeSurfer software. In our experiments, we demonstrate on 40 simulated MR images and the MR images of 200 subjects from two databases: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and International Consortium of Brain Mapping (ICBM), the robustness of our method in large scale studies. In comparisons with FreeSurfer, we show that our system is able to generate surfaces that better represent cortical anatomy and produce thickness features with higher statistical power in population studies. PMID- 23086521 TI - Correction for collimator-detector response in SPECT using point spread function template. AB - Compensating for the collimator-detector response (CDR) in SPECT is important for accurate quantification. The CDR consists of both a geometric response and a septal penetration and collimator scatter response. The geometric response can be modeled analytically and is often used for modeling the whole CDR if the geometric response dominates. However, for radionuclides that emit medium or high energy photons such as I-131, the septal penetration and collimator scatter response is significant and its modeling in the CDR correction is important for accurate quantification. There are two main methods for modeling the depth dependent CDR so as to include both the geometric response and the septal penetration and collimator scatter response. One is to fit a Gaussian plus exponential function that is rotationally invariant to the measured point source response at several source-detector distances. However, a rotationally-invariant exponential function cannot represent the star-shaped septal penetration tails in detail. Another is to perform Monte-Carlo (MC) simulations to generate the depth dependent point spread functions (PSFs) for all necessary distances. However, MC simulations, which require careful modeling of the SPECT detector components, can be challenging and accurate results may not be available for all of the different SPECT scanners in clinics. In this paper, we propose an alternative approach to CDR modeling. We use a Gaussian function plus a 2-D B-spline PSF template and fit the model to measurements of an I-131 point source at several distances. The proposed PSF-template-based approach is nearly non-parametric, captures the characteristics of the septal penetration tails, and minimizes the difference between the fitted and measured CDR at the distances of interest. The new model is applied to I-131 SPECT reconstructions of experimental phantom measurements, a patient study, and a MC patient simulation study employing the XCAT phantom. The proposed model yields up to a 16.5 and 10.8% higher recovery coefficient compared to the results with the conventional Gaussian model and the Gaussian plus exponential model, respectively. PMID- 23086522 TI - FoxO3a negatively regulates nerve growth factor-induced neuronal differentiation through inhibiting the expression of neurochondrin in PC12 cells. AB - Forkhead box O3 (FoxO3a) is a forkhead family transcription factor playing important roles in non-neuronal differentiation, metabolism, proliferation, and survival, but its role in neuronal differentiation remains unclear. In the present study, we investigated the role of FoxO3a in neuronal differentiation and its underlying mechanisms. Our results showed that overexpression of FoxO3a inhibited neuronal differentiation of PC12 cells induced by nerve growth factor (NGF) while knockdown of FoxO3a by siRNA enhanced NGF-induced differentiation. DNA microarray analysis and quantitative reverse transcription PCR (RT-PCR) showed that the overexpression of FoxO3a significantly attenuated expression of neurochondrin (NCDN), a neurite outgrowth-related protein, in PC12 cells, while knocking down the expression of FoxO3a had the opposite effect. Bioinformatic studies found that the regulatory region of NCDN promoter contained multiple FoxO3a binding sites. Dual-luciferase reporter assay with report gene containing NCDN promoter showed that FoxO3a significantly decreased the transcription activity of NCDN promoter. These results indicate that NCDN is a direct downstream target of FoxO3a which negatively regulates the expression of NCDN. Interestingly, NGF-induced NCDN expression and cell differentiation was blocked by the inhibition of phosphatidylinositol-3-kinase (PI3K)-protein kinase B (PKB, Akt) signal pathway (activation of FoxO3a) and overexpression of FoxO3a. Moreover, knockdown of NCDN by siRNA blocked NGF-induced neuronal differentiation of PC12 cells while overexpression of NCDN significantly promoted neurite outgrowth. These results put together demonstrate that NCDN plays an important role in NGF-induced neuronal differentiation and suggest that FoxO3a inhibits NGF induced neuronal differentiation, at least in part, by suppressing the expression of NCDN. PMID- 23086525 TI - Modeling thermoelectric transport in organic materials. AB - Thermoelectric energy converters can directly convert heat to electricity using semiconducting materials via the Seebeck effect and electricity to heat via the Peltier effect. Their efficiency depends on the dimensionless thermoelectric figure of merit of the material, which is defined as zT = S(2)sigmaT/kappa with S, sigma, kappa, and T being the Seebeck coefficient, electrical conductivity, thermal conductivity, and absolute temperature respectively. Organic materials for thermoelectric applications have attracted great attention. In this review, we present our recent progress made in developing theories and computational schemes to predict the thermoelectric figure of merit at the first-principles level. The methods have been applied to model thermoelectric transport in closely packed molecular crystals and one-dimensional conducting polymer chains. The physical insight gained in these studies will help in the design of efficient organic thermoelectric materials. PMID- 23086524 TI - Rapid weight loss is associated with preoperative hypovolemia in morbidly obese patients. AB - BACKGROUND: In morbidly obese patients (MO), adequate levels of venous return (VR) and left ventricular filling pressures (LVFP) are crucial in order to augment perioperative safety. Rapid weight loss (RWL) preparation with very low calorie diet is commonly used aiming to facilitate bariatric surgery. However, the impact of RWL on VR and LVFP is poorly studied. METHODS: In this prospective, controlled, single-center study, we hypothesized that RWL-prepared MO prior to bariatric surgery can be hypovolemic (i.e., low VR) and compared MO to lean controls with conventional overnight fasting. Twenty-eight morbidly obese patients were scheduled consecutively for bariatric surgery and 19 lean individuals (control group, CG) for elective general surgery. Preoperative assessment of VR, LVFP, and biventricular heart function was performed by a transthoracic echocardiography (TTE) protocol to all patients in the awake state. Assessment of VR and LVFP was made by inferior vena cava maximal diameter (IVCmax) and inferior vena cava collapsibility index- (IVCCI) derived right atrial pressure estimations. RESULTS: A majority of MO (71.4 %) were hypovolemic vs. 15.8 % of lean controls (p < 0.001, odds ratio = 13.3). IVCmax was shorter in MO than in CG (p < 0.001). IVCCI was higher in MO (62.1 +/- 23 %) vs. controls (42.6 +/- 20.8; p < 0.001). Even left atrium anterior-posterior diameter was shorter in MO compared to CG. CONCLUSIONS: Preoperative RWL may induce hypovolemia in morbidly obese patients. Hypovolemia in MO was more common vs. lean controls. TTE is a rapid and feasible tool for assessment of preload even in morbid obesity. PMID- 23086523 TI - Unconjugated bilirubin restricts oligodendrocyte differentiation and axonal myelination. AB - High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). Impairments in myelination and white matter damage were observed at autopsy in kernicteric infants. We have recently reported that UCB reduces oligodendrocyte progenitor cell (OPC) survival in a pure OPC in vitro proliferative culture. Here, we hypothesized that neonatal hyperbilirubinemia may also impair oligodendrocyte (OL) maturation and myelination. We used an experimental model of hyperbilirubinemia that has been shown to mimic the pathophysiological conditions leading to brain dysfunction by unbound (free) UCB. Using primary cultures of OL, we demonstrated that UCB delays cell differentiation by increasing the OPC number and reducing the number of mature OL. This finding was combined with a downregulation of Olig1 mRNA levels and upregulation of Olig2 mRNA levels. Addition of UCB, prior to or during differentiation, impaired OL morphological maturation, extension of processes and cell diameter. Both conditions reduced active guanosine triphosphate (GTP)-bound Rac1 fraction. In myelinating co-cultures of dorsal root ganglia neurons and OL, UCB treatment prior to the onset of myelination decreased oligodendroglial differentiation and the number of myelinating OL, also observed when UCB was added after the onset of myelination. In both circumstances, UCB decreased the number of myelin internodes per OL, as well as the myelin internode length. Our studies demonstrate that increased concentrations of UCB compromise myelinogenesis, thereby elucidating a potential deleterious consequence of elevated UCB. PMID- 23086526 TI - Structural stabilization of DNA-templated nanostructures: crosslinking with 2,5 bis(2-thienyl)pyrrole monomers. AB - Ordered 2,5-bis(2-thienyl)pyrrole (SNS) zipper arrays are formed by hybridization of complementary DNA oligomers each containing covalently bound SNS monomers. Upon oxidation with HRP/H(2)O(2), these SNS arrays are converted to oligomers having specific lengths and conformation. As a consequence of this reaction the two SNS-containing strands are permanently crosslinked. PMID- 23086528 TI - A novel artificial bee colony algorithm based on modified search equation and orthogonal learning. AB - The artificial bee colony (ABC) algorithm is a relatively new optimization technique which has been shown to be competitive to other population-based algorithms. However, ABC has an insufficiency regarding its solution search equation, which is good at exploration but poor at exploitation. To address this concerning issue, we first propose an improved ABC method called as CABC where a modified search equation is applied to generate a candidate solution to improve the search ability of ABC. Furthermore, we use the orthogonal experimental design (OED) to form an orthogonal learning (OL) strategy for variant ABCs to discover more useful information from the search experiences. Owing to OED's good character of sampling a small number of well representative combinations for testing, the OL strategy can construct a more promising and efficient candidate solution. In this paper, the OL strategy is applied to three versions of ABC, i.e., the standard ABC, global-best-guided ABC (GABC), and CABC, which yields OABC, OGABC, and OCABC, respectively. The experimental results on a set of 22 benchmark functions demonstrate the effectiveness and efficiency of the modified search equation and the OL strategy. The comparisons with some other ABCs and several state-of-the-art algorithms show that the proposed algorithms significantly improve the performance of ABC. Moreover, OCABC offers the highest solution quality, fastest global convergence, and strongest robustness among all the contenders on almost all the test functions. PMID- 23086529 TI - Ln(3+)-doped nanoparticles for upconversion and magnetic resonance imaging: some critical notes on recent progress and some aspects to be considered. AB - In this feature article we will critically discuss the synthesis and characterisation aspects of Ln(3+)-doped nanoparticles (NPs) that show upconversion, upon 980 nm excitation. Upconversion is a non-linear process that converts two or more low-energy photons, often near-infrared photons, into one of higher energy, e.g. blue and 800 nm from Tm(3+) and green and red from Er(3+) or Ho(3+). Nearly all researchers use the absorption of 980 nm light by Yb(3+) as the sensitiser for the co-doped emissive Ln(3+) ions. The focus will be on LnF(3) and MLnF(4) (M = alkali metal) as the host matrix, because most progress has been made with these. In particular we will argue that a detailed understanding of how the dopant ions and the host Ln(3+) ions are distributed (in the core) and how (doped) shell growth occurs is not well understood. Moreover, their use as optical and magnetic resonance imaging contrast agents will be discussed. We will argue that deep-tissue imaging beyond 600 MUm with retention of optical resolution, i.e. to see fine structure such as blood capillaries in brain tissues, has not yet been achieved. Three key parameters have been identified as impediments: (i) the low absorption efficiency of the Yb(3+) sensitiser, (ii) the low quantum yield of upconversion, and (iii) the long-lived excited states. On the other hand, there are very encouraging results that suggest that these nanoparticles could be developed into very potent magnetic resonance imaging (MRI) contrast agents. PMID- 23086530 TI - An inverse-Warburg effect and the origin of Alzheimer's disease. AB - Glycolysis and oxidative phosphorylation (OxPhos) are the two major mechanisms involved in brain energetics. In this article we propose that the sporadic forms of Alzheimer's disease (AD) are driven by age-related damage to macromolecules and organelles which results in the following series of dynamic processes. (1) Metabolic alteration: Upregulation of OxPhos activity by dysfunctional neurons. (2) Natural selection: Competition for the limited energy substrates between neurons with normal OxPhos activity [Type (1)] and dysfunctional neurons with increased OxPhos [Type (2)]. (3) Propagation, due to the fact that Type (1) neurons are outcompeted for limited substrate by Type (2) neurons which, because of increased ROS production, eventually become dysfunctional and die. Otto Warburg, in his studies of the origin of cancer, discovered that most cancer cells are characterized by an increase in glycolytic activity-a property which confers a selective advantage in oncologic environments. Accordingly, we propose the term "inverse-Warburg effect" to describe increased OxPhos activity--a property which we propose confers a selective advantage in neuronal environments, and which we hypothesize to underlie the shift from normal to pathological aging and subsequent AD. PMID- 23086531 TI - A new framework architecture for next generation e-Health services. AB - The challenge for fast and low-cost deployment of ubiquitous personalized e Health services has prompted us to propose a new framework architecture for such services. We have studied the operational features and the environment of e Health services and we led to a framework structure that extends the ETSI/Parlay architecture, which is used for the deployment of standardized services over the next generation IP networks. We expanded the ETSI/Parlay architecture with new service capability features as well as sensor, profiling and security mechanisms. The proposed framework assists the seamless integration, within the e-Health service structure, of diverse facilities provided by both the underlying communication and computing infrastructure as well as the patient's bio and context sensor networks. Finally, we demonstrate the deployment of a tele monitoring service in smart home environment based on the proposed framework architecture. PMID- 23086532 TI - Automatic detection of atrial fibrillation in cardiac vibration signals. AB - We present a study on the feasibility of the automatic detection of atrial fibrillation (AF) from cardiac vibration signals (ballistocardiograms/BCGs) recorded by unobtrusive bedmounted sensors. The proposed system is intended as a screening and monitoring tool in home-healthcare applications and not as a replacement for ECG-based methods used in clinical environments. Based on BCG data recorded in a study with 10 AF patients, we evaluate and rank seven popular machine learning algorithms (naive Bayes, linear and quadratic discriminant analysis, support vector machines, random forests as well as bagged and boosted trees) for their performance in separating 30 s long BCG epochs into one of three classes: sinus rhythm, atrial fibrillation, and artifact. For each algorithm, feature subsets of a set of statistical time-frequency-domain and time-domain features were selected based on the mutual information between features and class labels as well as first- and second-order interactions among features. The classifiers were evaluated on a set of 856 epochs by means of 10-fold cross validation. The best algorithm (random forests) achieved a Matthews correlation coefficient, mean sensitivity, and mean specificity of 0.921, 0.938, and 0.982, respectively. PMID- 23086533 TI - Quantitative deconvolution of human thermal infrared emittance. AB - The bioheat transfer models conventionally employed in etiology of human thermal infrared (TIR) emittance rely upon two assumptions; universal graybody emissivity and significant transmission of heat from subsurface tissue layers. In this work, a series of clinical and laboratory experiments were designed and carried out to conclusively evaluate the validity of the two assumptions. Results obtained from the objective analyses of TIR images of human facial and tibial regions demonstrated significant variations in spectral thermophysical properties at different anatomic locations on human body. The limited validity of the two assumptions signifies need for quantitative deconvolution of human TIR emittance in clinical, psychophysiological and critical applications. A novel approach to joint inversion of the bioheat transfer model is also introduced, levering the deterministic temperature-dependency of proton resonance frequency in low-lipid human soft tissue for characterizing the relationship between subsurface 3D tissue temperature profiles and corresponding TIR emittance. PMID- 23086535 TI - An investigation of the construct validity of the ICECAP-A capability measure. AB - PURPOSE: To investigate the construct validity of the ICECAP-A capability wellbeing measure. METHODS: A face-to-face interview-administered survey was conducted with 418 members of the UK general population, randomly sampled from the Postcode Address File. Pre-specified hypotheses were developed about the expected associations between individuals' ICECAP-A responses and their socio economic circumstances, health and freedom. The hypotheses were investigated using statistical tests of association. RESULTS: The ICECAP-A responses and scores reflected differences across different health and socioeconomic groups as anticipated, but did not distinguish individuals by the level of local deprivation. Mean ICECAP-A scores reflected individuals' perceived freedom slightly more closely than did measures of health and happiness. CONCLUSION: This study suggests that the ICECAP-A measure can identify expected differences in capability wellbeing in a general population sample. Further work could establish whether self-reported capabilities exhibit desirable validity and acceptability in sub-groups of the population such as patients, social care recipients and informal carers. PMID- 23086534 TI - Systematic review reveals limitations of studies evaluating health-related quality of life after potentially curative treatment for esophageal cancer. AB - PURPOSE: To (1) assess the quality of studies evaluating Health-Related Quality of Life (HRQL) after potentially curative treatment for esophageal cancer, and (2) to identify high-quality studies that provide robust HRQL results. METHODS: A systematic literature search is to identify studies evaluating HRQL with a validated multidimensional patient-reported outcome measure. Study quality focused on study design, risk of bias, HRQL outcome reporting, and additional issues of reporting and methodology. A study was deemed high-quality if criteria for robust study methodology and robust HRQL outcome reporting were met. RESULTS: Six RCTs, 12 cohort studies, 13 case-series, and 31 cross-sectional studies were identified. Overall risk of bias was high. Reporting of HRQL concept (e.g., a priori hypothesis), methodology (e.g., reasons for missing data), and interpretation (e.g., clinical significance) was often absent or unclear. Additional issues of reporting (e.g., unclear treatment descriptions) and methodology (e.g., no control for multiple testing) were identified. Four studies (6%) met the criteria for robust study methodology, and 26 studies (42%) met the criteria for robust HRQL outcome reporting. We identified three high-quality studies (5%)--two RCTs and one case-series--capable of providing robust results. CONCLUSIONS: Current evidence is restricted in its ability to inform practice on HRQL after potentially curative treatment for esophageal cancer. PMID- 23086536 TI - American Indian perceptions of colorectal cancer screening: viewpoints from adults under age 50. AB - Colorectal cancer (CRC) mortality rates have decreased in the general US population; however, CRC mortality rates are increasing among American Indians (AI). AI CRC screening rates remain low when compared to other ethnic groups. Our team investigated CRC screening education prior to recommended age for screening to better understand screening perceptions among AI community members. Our research team conducted 11 focus groups with AI men and women aged 30-49 (N = 39 men and N = 31 women) in Kansas and Missouri. The results revealed that community members (1) have little knowledge of CRC, (2) do not openly discuss CRC, and (3) want additional CRC education. Variations existed among men and women's groups, but they agreed that preventive measures need to be appropriate for AI communities. Thus, AI CRC screening interventions should be culturally tailored to better meet the needs of the population. PMID- 23086539 TI - Enhanced solar cell performance by replacing benzodithiophene with naphthodithiophene in diketopyrrolopyrrole-based copolymers. AB - Replacing benzodithiophene (BDT) with a naphthodithiophene (NDT) building block, PNDTDPP exhibited enhanced photovoltaic performance with a PCE of 5.37% when compared with BDT-based copolymer PBDDPP, which gave a PCE of 2.91% in conventional device structures. Encouragingly, the obtained inverted PSC with PBDDPP achieved an impressively high PCE of 6.92%. PMID- 23086537 TI - Evaluation of the potential antimicrobial resistance transfer from a multi-drug resistant Escherichia coli to Salmonella in dairy calves. AB - Previous research conducted in our laboratory found a significant prevalence of multi-drug resistant (MDR) Salmonella and MDR Escherichia coli (MDR EC) in dairy calves and suggests that the MDR EC population may be an important reservoir for resistance elements that could potentially transfer to Salmonella. Therefore, the objective of the current research was to determine if resistance transfers from MDR EC to susceptible strains of inoculated Salmonella. The experiment utilized Holstein calves (approximately 3 weeks old) naturally colonized with MDR EC and fecal culture negative for Salmonella. Fecal samples were collected for culture of Salmonella and MDR EC throughout the experiment following experimental inoculation with the susceptible Salmonella strains. Results initially suggested that resistance did transfer from the MDR E. coli to the inoculated strains of Salmonella, with these stains demonstrating resistance to multiple antibiotics following in vivo exposure to MDR EC. However, serogrouping and serotyping results from a portion of the Salmonella isolates recovered from the calves post challenge, identified two new strains of Salmonella; therefore transfer of resistance was not demonstrated under these experimental conditions. PMID- 23086538 TI - Characterisation of two bifunctional cellulase-xylanase enzymes isolated from a bovine rumen metagenome library. AB - Ruminant digestive tract microbes hydrolyse plant biomass, and the application of metagenomic techniques can provide good coverage of their glycosyl hydrolase enzymes. A metagenomic library of circa 70,000 fosmids was constructed from bacterial DNA isolated from bovine rumen and subsequently screened for cellulose hydrolysing activities on a CMC agar medium. Two clones were selected based on large clearance zones on the CMC agar plates. Following nucleotide sequencing, translational analysis and homology searches, two cellulase encoding genes (cel5A and cel5B) belonging to the glycosyl hydrolyse family 5 were identified. Both genes encoded pre-proteins of about 62 kDa, containing signal leader peptides which could be cleaved to form mature proteins of about 60 kDa. Biochemical characterisation revealed that both enzymes showed alkaline pH optima of 9.0 and the temperature optima of 65 degrees C. Substrate specificity profiling of the two enzymes using 1,4-beta-D-cello- and xylo-oligosaccharides revealed preference for longer oligosaccharides (n >= 3) for both enzymes, suggesting that they are endo-cellulases/xylanases. The bifunctional properties of the two identified enzymes render them potentially useful in degrading the beta-1,4 bonds of both the cellulose and hemicellulose polymers. PMID- 23086540 TI - Massive posttraumatic bleeding: epidemiology, causes, clinical features, and therapeutic management. AB - Bleeding typically results as a consequence of derangements of primary hemostasis, secondary hemostasis, or both, and can be dramatically amplified by the presence of other predisposing conditions, especially inherited bleeding disorders. Life-threatening hemorrhages are, however, almost exclusively caused by penetrating wounds, blunt traumas of chest and abdomen, suicide attempts, amputations, bone fractures with concomitant injury to internal organs and blood vessels, and shearing forces from sudden rotation, violent flexion, extension, or deceleration injuries. The pathogenesis of posttraumatic bleeding is complex and multifaceted. The most dramatic phenomenon that always accompanies major hemorrhages is the abrupt and considerable loss of intravascular volume, that further leads to hypovolemic shock, also known as hemorrhagic shock, culminating with peripheral ischemia, especially in those tissues where oxygen delivery is more critical (i.e., central nervous system and myocardium). The mortality rate of severe posttraumatic bleeding can be as high as 50%, especially when an appropriate treatment is not established in a timely manner. The damage control sequence basically entails a four-step approach including damage control surgery, damage control resuscitation with fluid restoration, and hemocomponents administration, as well as correction of the coagulopathy with platelets, antifibrinolytic (e.g., tranexamic acid), and/or procoagulant agents such as fresh frozen plasma, prothrombin complex concentrate, or recombinant-activated Factor VII. PMID- 23086541 TI - Underreporting of hemorrhagic and thrombotic complications of pharmaceuticals to the U.S. Food and Drug Administration: empirical findings for warfarin, clopidogrel, ticlopidine, and thalidomide from the Southern Network on Adverse Reactions (SONAR). AB - The U.S. Food and Drug Administration's (FDA) Adverse Event Reporting System (AERS), familiarly known as "MedWatch," is the nation's primary tool for postmarket pharmaceutical safety surveillance. This system relies on adverse events voluntarily reported by health care providers and consumers either directly to the FDA or to drug manufacturers, which are required to prepare and forward the information to the agency. Little is known about how frequently adverse events are reported. Previous estimates range from 1 to 31% depending on the event, drug, and time period. We used published incidence studies to calculate reporting rates for hemorrhage, emergency hospitalization, and venous thromboembolism (VTE) associated with four drugs. We estimated annual reporting rates of 1.07% for 33,171 emergency hospitalizations of patients older than 65 years associated with warfarin, 0.9% for 13,363 hospitalizations of clopidogrel and ticlopidine, and 1.02% for an estimated 67,200 hemorrhage cases associated with warfarin. We also estimated a 9-year reporting rate of 2.3% for VTE associated with thalidomide. The incidence of these hematologic adverse drug events is high and reporting rates are low, and near the lower boundary of the 1 to 15% range seen for other events. PMID- 23086542 TI - Risk assessment for sustainable food security in China according to integrated food security--taking Dongting Lake area for example. AB - Integrated food security covers three aspects: food quantity security, food quality security, and sustainable food security. Because sustainable food security requires that food security must be compatible with sustainable development, the risk assessment of sustainable food security is becoming one of the most important issues. This paper mainly focuses on the characteristics of sustainable food security problems in the major grain-producing areas in China. We establish an index system based on land resources and eco-environmental conditions and apply a dynamic assessment method based on status assessments and trend analysis models to overcome the shortcomings of the static evaluation method. Using fuzzy mathematics, the risks are categorized into four grades: negligible risk, low risk, medium risk, and high risk. A case study was conducted in one of China's major grain-producing areas: Dongting Lake area. The results predict that the status of the sustainable food security in the Dongting Lake area is unsatisfactory for the foreseeable future. The number of districts at the medium-risk range will increase from six to ten by 2015 due to increasing population pressure, a decrease in the cultivated area, and a decrease in the effective irrigation area. Therefore, appropriate policies and measures should be put forward to improve it. The results could also provide direct support for an early warning system-which could be used to monitor food security trends or nutritional status so to inform policy makers of impending food shortages-to prevent sustainable food security risk based on some classical systematic methods. This is the first research of sustainable food security in terms of risk assessment, from the perspective of resources and the environment, at the regional scale. PMID- 23086543 TI - Assessing heavy metal pollution using Great Tits (Parus major): feathers and excrements from nestlings and adults. AB - Passerine species have been increasingly used as bioindicators of metal bioaccumulation especially by taking benefit of non-invasive procedures, such as collecting feathers and excrements. In 2009, metal (As, Cd, Cu, Hg, Ni, Pb, Se and Zn) concentrations were determined in feathers and excrements of nestling and adult female great tits (Parus major) in industrial (a paper mill) and rural sites in maritime pine forests on the west coast of Portugal. The aim of this study was to compare the levels of metals between the areas but also between sampling methods (feather vs. excrement) and age classes (nestling vs. adult). Although excrements and feathers of nestling great tits showed different concentrations, similar patterns of accumulation were detected in both study areas. There was a significantly higher concentration of mercury in the industrial area and significantly higher concentrations of arsenic in the rural area in both sample types. Metal levels in adult females had quite different results when compared to nestlings, and only nickel presented significantly higher levels near the paper mill. Since metal levels showed a consistent pattern in feathers and excrements of nestling great tits, we conclude that both represent good and non-invasive methods for the evaluation of these elements in polluted areas. PMID- 23086544 TI - The current status of an FDG-PET cancer screening program in Japan, based on a 4 year (2006-2009) nationwide survey. AB - OBJECTIVE: The aim of this study was to survey the 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) cancer screening program conducted in Japan. METHODS: The "FDG-PET cancer screening program" included both FDG-PET and positron emission tomography with computed tomography (PET/CT) with or without other combined screening tests that were performed for cancer screening in asymptomatic subjects. A total of 155,456 subjects who underwent the FDG-PET cancer screening program during 2006-2009 were analyzed. RESULTS: Of the 155,456 subjects, positive findings suggesting possible cancer were noted in 16,955 (10.9 %). The number of cases with detected cancer was 1,912 (1.23 % of the total screened cases, annual range 1.14-1.30 %). Of the 1,912 cases of detected cancer, positive findings on FDG-PET were present in 1,491 cases (0.96 % of the total number of screened cases). According to the results of further examinations, the true positive rate for subjects with suggested possible cancer (positive predictive value) was 32.3 % with FDG-PET. Cancers of the colon/rectum, thyroid, lung, and breast were most frequently found (396, 353, 319, and 163 cases, respectively) with high PET sensitivity (85.9, 90.7, 86.8, 84.0 %, respectively). Prostate cancer and gastric cancer (165 and 124 cases, respectively) had low PET sensitivity (37.0 and 37.9 %, respectively). The Union for International Cancer Control (UICC) clinical stage of cancer found with the FDG-PET cancer screening program was mainly Stage I. CONCLUSIONS: The FDG-PET screening program in Japan has detected a variety of cancers at an early stage. However, several cancers were found in repeated FDG-PET cancer screening program, indicating the limitation of a one-time FDG-PET cancer screening program. The value of the FDG PET cancer screening program is left to the judgment of individuals with regard to its potentials and limitations. PMID- 23086545 TI - Iodine-123 metaiodobenzylguanidine imaging can predict future cardiac events in Japanese patients with Parkinson's disease. AB - OBJECTIVES: Iodine-123 metaiodobenzylguanidine (123I-MIBG) myocardial scintigraphy provides useful diagnostic information in differentiating Parkinson's disease (PD) from other neurological diseases. Moreover, a number of studies have reported that 123I-MIBG imaging provides powerful diagnostic and prognostic information in congestive heart failure (HF) patients. The aim of the present study was to investigate the cardiovascular predictive value of cardiac 123I-MIBG imaging in patients with PD. METHODS: Seventy-eight patients with PD were retrospectively studied. All patients underwent 123I-MIBG imaging at 30 min (early) and 240 min (delayed) after the tracer injection, and clinical parameters were also investigated. RESULTS: During a mean follow-up of 27 +/- 12 months, 5 patients required hospitalization for HF. There were no occurrences of myocardial infarction, fatal arrhythmia or sudden death. There was no significant coronary artery stenosis, significant valvular heart disease, or cardiomyopathy in the HF patients. The left ventricular ejection fraction (LVEF) was normal in the HF patients. (123)I-MIBG delayed heart to mediastinal ratio (delayed H/M) was lower and washout rate (WR) was higher in HF patients than non-HF patients (1.62 +/- 0.21 vs. 1.34 +/- 0.08, p = 0.019; 31.9 +/- 5.5 vs. 38.2 +/- 3.3, p = 0.005, respectively). Both WR and delayed H/M did not correlate with Hoehn and Yahr stage. The WR showed a weak negative correlation with delayed H/M (R = -0.357, p < 0.001) upon simple linear regression analysis. A multivariate Cox regression analysis revealed that WR and delayed H/M were independently associated with HF (p = 0.014, p = 0.029, respectively). Kaplan-Meier analysis revealed that patients with abnormal WR (> 37%) and delayed H/M (< 1.48) had a higher incidence of HF than those with normal WR and delayed H/M (p = 0.014, p = 0.04, respectively). CONCLUSIONS: WR showed stronger predictive power than delayed H/M in Kaplan-Meier analysis. WR has more useful cardiovascular predictive value than delayed H/M in Japanese patients with PD. Further studies are needed to clarify the significance of abnormal MIBG uptake in PD patients. PMID- 23086547 TI - 18F labeling of arenes. AB - Molecular imaging has witnessed an upsurge in growth, with positron emission tomography leading the way. This trend has encouraged numerous synthetic chemists to enter the field of (18) F-radiochemistry and provide generic solutions to address the well-recognized challenges of late-stage fluorination. This Minireview focuses on recent developments in the (18)F-labeling of aromatic substrates. PMID- 23086548 TI - Mixing characteristics and liquid circulation in a new multi-environment bioreactor. AB - The theoretical and experimental aspects of the hydrodynamics and mixing in a new multi-environment bioreactor that uses the air-lift design were investigated. This study focused on the mixing characteristics, residence time distribution, liquid circulation between three zones of aerobic, microaerophilic and anoxic, and liquid displacement in the bioreactor at influent flow rates of 720-1,450 L/day and air flow rates of 15-45 L/min. The theoretical analysis of liquid displacement led to the estimation of the specific rate of liquid discharge from the bioreactor at any given influent flow rate, and the number of liquid circulations between various bioreactor zones before the discharge of a given quantity of wastewater. The ratio of mean residence time to the overall hydraulic retention time (t m/HRT) decreased with the increase of air flow rate at any given influent flow rate, and approached unity at higher air flow rates. Mixing was characterized in terms of the axial dispersion coefficient and Bodenstein number, demonstrating a linear relationship with the superficial gas velocity. A correlation was developed between the Bodenstein number and the Froude number. The study of liquid circulation between the zones showed that less than 1.5 % of the circulating liquid escapes circulation at each cycle and flows towards the outer clarifier, while the percentage of escaped liquid decreases with increasing air flow rate at a given influent flow rate. The specific rate of liquid discharge from the bioreactor increased from 0.19 to 0.69 h-1 with the increase of air and influent flow rates from 15 to 45 L/min and 500 to 1,450 L/day, respectively. Under the examined operating conditions, mixed liquor circulates between 364 and 1,698 times between the aerobic, microaerophilic and anoxic zones before 99 % of its original volume is replaced by the influent wastewater. PMID- 23086549 TI - Sperm cells manipulation employing dielectrophoresis. AB - Infertility studies are an important growing field, where new methods for the manipulation, enrichment and selection of sperm cells are required. Microfluidic techniques offer attractive advantages such as requirement of low sample volume and short processing times in the range of second or minutes. Presented here is the application of insulator-based dielectrophoresis (iDEP) for the enrichment and separation of mature and spermatogenic cells by employing a microchannel with cylindrical insulating structures with DC electric potentials in the range of 200 1500 V. The results demonstrated that iDEP has the potential to concentrate sperm cells and distinguish between mature and spermatogenic cells by exploiting the differences in shape which lead to differences in electric polarization. Viability assessments revealed that a significant percentage of the cells are viable after the dielectrophoretic treatment, opening the possibility for iDEP to be developed as a tool in infertility studies. PMID- 23086550 TI - Hydrogen sulfide formation as well as ethanol production in different media by cysND- and/or cysIJ-inactivated mutant strains of Zymomonas mobilis ZM4. AB - Many bacteria reduce inorganic sulfate to sulfide to satisfy their need for sulfur, one of the most important elements for biological life. But little is known about the metabolic pathways involving hydrogen sulfide (H2S) in mesophilic bacteria. By genomic sequence analysis, a complete set of genes for the assimilatory sulfate reduction pathway has been identified in the ethanologen Zymomonas mobilis. In this study, the first ATP sulfurylase- and final sulfite reductase-encoding genes cysND and cysIJ, respectively, in the putative pathway from sulfate to sulfite in Z. mobilis ZM4 was singly or doubly inactivated by homologous recombination and a site-specific FLP-FRT recombination. The resultant mutants, ?cysND, ?cysIJ and ?cysND-cat?cysIJ, were unable to produce detectable H2S in glucose or sucrose-containing rich medium and sweet sorghum juice, in which the wild-type ZM4 produced detectable H2S. While adding sulfite (SO32-) into media impaired the growth of the mutants and ZM4 to varying degrees, the sulfite restored the H2S formation in the ?cysND in the above media, but not in the ?cysIJ and ?cysND-cat?cysIJ mutants. Although it seemed that the inactivation of cysND and cysIJ did not exert a significant negative effect on the cell growth at least in glucose or sucrose medium, the ethanol production of all mutants was inferior to that of ZM4 in sucrose medium and sweet sorghum juice. In addition, adding L-cysteine to glucose-containing rich media restored H2S formation of all mutants, indicating the existence of another pathway for producing H2S in Z. mobilis. All these results would help to further elucidate the metabolic pathways involving H2S in Z. mobilis and exploit the biotechnological applications of this industrially important bacterium. PMID- 23086551 TI - Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acid differentially modulate rat neutrophil function in vitro. AB - Fish oils are used as therapeutic agents in chronic inflammatory diseases. The omega-3 fatty acids (FA) found in these oils are mainly eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids. The anti-inflammatory properties of fish oils are attributed to both omega-3 fatty acids. However, it is unknown whether such effects are due to either EPA or DHA. In this study, the effects of EPA and DHA on rat neutrophil function in vitro were compared. Both EPA and DHA increased the production of H2O2 when cells were stimulated or not with lipopolysaccharides (LPS). However, EPA was more potent than DHA in triggering an increase in superoxide release by cells in the basal condition or when stimulated with phorbol myristate acetate (PMA) or zymosan. Only DHA increased the phagocytic capacity and fungicidal activity of neutrophils. Both FA increased the release of tumor necrosis factor-alpha (TNF-alpha) in nonstimulated cells, but only EPA increased the production of cytokine-inducing neutrophil chemoattractant-2 (CINC 2) in the absence or presence of LPS, whereas production of interleukin-1 beta (IL-1beta) was only increased by DHA in the presence of LPS. In addition, there was no alteration in the production of nitric oxide. In conclusion, we show herein that EPA and DHA can differently modulate aspects of the neutrophil response, which may be relevant for the development of therapies rich in one or other FA depending on the effect required. PMID- 23086552 TI - Dietary fat composition influences tissue lipid profile and gene expression in Fischer-344 rats. AB - The AIN-76A diet causes fatty liver in rodents when fed for long periods of time. The aim of this study was to utilize fatty acid analysis and transcriptomics to investigate the effects of different fat sources in the AIN-76A diet on tissue lipid profiles and gene expression in male, weanling Fischer-344 rats. Animals were fed isocaloric diets that differed only in the fat source: (1) corn oil (CO) (2) anhydrous milk fat (AMF), and (3) AMF supplemented with 10% phospholipids from the milk fat globule membrane (AMF-MFGM). There were no differences in food intake, body weight, growth rate, or body fat composition among the groups, and the fatty acid compositions of red blood cells (RBC), plasma, muscle, and visceral adipose tissues reflected the dietary fat sources. Modifying the fat source resulted in 293 genes differentially regulated in skeletal muscle, 1,124 in adipose, and 831 in liver as determined by analysis of variance (ANOVA). Although tissue fatty acid profiles mostly reflected the diet, there were several quantitative differences in lipid classes in the liver and plasma. The AMF diet resulted in the highest level of hepatic triacylglycerols, but the lowest level in plasma. The CO diet resulted in significant accumulation of hepatic unesterified fatty acids and decreased DGAT expression and activity, a potential trigger for steatohepatitis. These results indicate that the fatty acid composition and presence of polar lipids in the AIN-76A diets have significant effects on lipid partitioning, gene expression, and potentially the development of liver pathology. PMID- 23086553 TI - Vitamin C enhances vitamin E status and reduces oxidative stress indicators in sea bass larvae fed high DHA microdiets. AB - Docosahexaenoic acid (DHA) is an essential fatty acid necessary for many biochemical, cellular and physiological functions in fish. However, high dietary levels of DHA increase free radical injury in sea bass (Dicentrarchus labrax) larvae muscle, even when vitamin E (alpha-tocopherol, alpha-TOH) is increased. Therefore, the inclusion of other nutrients with complementary antioxidant functions, such as vitamin C (ascorbic acid, vitC), could further contribute to prevent these lesions. The objective of the present study was to determine the effect of vitC inclusion (3,600 mg/kg) in high DHA (5% DW) and alpha-TOH (3,000 mg/kg) microdiets (diets 5/3,000 and 5/3,000 + vitC) in comparison to a control diet (1% DHA DW and 1,500 mg/kg of alpha-TOH; diet 1/1,500) on sea bass larvae growth, survival, whole body biochemical composition and thiobarbituric acid reactive substances (TBARS) content, muscle morphology, skeletal deformities and antioxidant enzymes, insulin-like growth factors (IGFs) and myosin expression (MyHC). Larvae fed diet 1/1,500 showed the best performance in terms of total length, incidence of muscular lesions and ossification degree. IGFs gene expression was elevated in 5/3,000 diet larvae, suggesting an increased muscle mitogenesis that was confirmed by the increase in the mRNA copies of MyHC. vitC effectively controlled oxidative damages in muscle, increased alpha-TOH larval contents and reduced TBARS content and the occurrence of skull deformities. The results of the present study showed the antioxidant synergism between vitamins E and C when high contents of DHA are included in sea bass larvae diets. PMID- 23086554 TI - The use of an audience response system in an elementary school-based health education program. AB - BACKGROUND: The audience response system (ARS) allows students to respond and interact anonymously with teachers via small handheld wireless keypads. Despite increasing popularity in classroom settings, the application of these devices to health education programming has not been studied. We assessed feasibility, engagement, and learning among children using an ARS compared with traditional pencil-paper formats, (ARS) for a stroke health education program. METHOD: We compared outcome data generated via an ARS-based intervention to pencil-paper controls, including test scores and missing data rates among 265 schoolchildren 9 to 11 years old participating in stroke education. Among 119 children, we evaluated the feasibility of ARS use and explored student motivation with a 10 item questionnaire. We assessed facilitator experience with both methods. RESULTS: ARS use is feasible. Students reported having more fun (p < .001), increased attention (p < .001), participation (p < .001), and perceived learning outcomes (p < .001) compared with pencil-paper controls. Test scores showed highly positive improvement for both ARS and paper without additional benefits of ARS on learning. There was no difference in missing data rates (p < .001). Educators preferred the ARS. CONCLUSION: The use of an ARS among children is feasible and improves student and facilitator engagement without additional benefits on stroke learning. PMID- 23086555 TI - User preferences for a text message-based smoking cessation intervention. AB - Younger adults are more likely to smoke and less likely to seek treatment than older smokers. They are also frequent users of communication technology. In the current study, we conducted focus groups to obtain feedback about preferences for a text message-based smoking cessation program from potential users. Participants (N = 21, M age = 25.6 years, age range = 20-33 years) were current or recently quit smokers (M cigarettes/day = 12.8) who used text messaging. Participants completed questionnaires and participated in a 2-hour focus group. Focus groups were conducted using an a priori semistructured interview guide to promote discussion of the content and functionality of the intervention. Major themes from analysis of the focus groups included support for the acceptability of a text-based cessation program, suggestions for a more technologically broad-based program, and adjustments to the program structure. Participants recommended including social networking functions, user control of program output through an online profile, and text message features to promote interaction with the system. Interestingly, many participants suggested the program should begin on individuals' identified quit day, challenging the procedures used in most cessation programs, which begin by preparing participants for a future quit date. Overall, younger adult smokers appear to be interested in participating in a smoking cessation program that uses text messages and web-based elements. Qualitative feedback regarding the perceived optimal features and structure of a technology-based intervention challenged traditional methods of implementing smoking cessation interventions and will inform the development of future programs. PMID- 23086556 TI - Identifying barriers to colonoscopy screening for nonadherent African American participants in a patient navigation intervention. AB - African Americans have a higher rate of colorectal cancer (CRC) mortality than other racial/ethnic groups. This disparity is alarming given that CRC is largely preventable through the use of endoscopy (screening colonoscopy or sigmoidoscopy), yet rates of CRC screening among African Americans is suboptimal. Only 48.9% of African Americans are screened for CRC through endoscopy or fecal occult blood testing. As such, researchers have focused their efforts on the prevention of CRC through patient navigation (PN) services for colonoscopy screening. Although PN has been successful in increasing colonoscopy screening rates, screening rates of navigated participants could still be improved. Thus, the purpose of this exploratory study was to understand why patients, who received PN services, did not complete a colonoscopy. Sixteen participants were interviewed to identify salient themes related to noncompletion of the colonoscopy procedure. Major themes identified included the following: a lack of knowledge about CRC; fear/anxiety about the procedure, including unknown expectations, fear of pain, and fear of cancer diagnosis; inadequate physician communication about CRC and the colonoscopy exam; and believing that cancer leads to death. Participants felt that greater communication and explanation from their physician might help allay their fears. Our findings also suggest that a universal approach to PN, even within culturally targeted interventions, may not be appropriate for all individuals. Future interventions should consider gender specific navigation and combining PN with nonmedical interventions to address other identified barriers. PMID- 23086557 TI - Synthesis and X-ray structures of cyclometalated iridium complexes including the hydrides. AB - Cyclometalation of [Cp*IrCl(2)](2) with ketimine ligands generated very active catalysts for transfer hydrogenation of imines as well as reductive amination. The synthesis and X-ray diffraction structures of three such complexes are disclosed in this paper. The hydrides of two complexes, key intermediates in hydrogenation, have been isolated and their structures determined by X-ray diffraction as well. PMID- 23086558 TI - Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial. AB - AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH. PMID- 23086559 TI - A urinary peptide biomarker set predicts worsening of albuminuria in type 2 diabetes mellitus. AB - AIMS/HYPOTHESIS: Microalbuminuria is considered the first clinical sign of kidney dysfunction and is associated with a poor renal and cardiovascular prognosis in type 2 diabetes. Detection of patients who are prone to develop micro- or macroalbuminuria may represent an effective strategy to start or optimise therapeutic intervention. Here we assessed the value of a urinary proteomic-based risk score (classifier) in predicting the development and progression of microalbuminuria. METHODS: We conducted a prospective case-control study. Cases (n = 44) and controls (n = 44) were selected from the PREVEND (Prevention of Renal and Vascular End-stage Disease) study and from the Steno Diabetes Center (Gentofte, Denmark). Cases were defined by transition from normo- to microalbuminuria or from micro- to macroalbuminuria over a follow-up of 3 years. Controls with no transitions in albuminuria were pair-matched for age, sex and albuminuria status. A model for the progression of albuminuria was built using a proteomic classifier based on 273 urinary peptides. RESULTS: The proteomic classifier was independently associated with transition to micro- or macroalbuminuria (OR 1.35 [95% CI 1.02, 1.79], p = 0.035). The classifier predicted the development and progression of albuminuria on top of albuminuria and estimated GFR (eGFR, area under the receiver operating characteristic [ROC] curve increase of 0.03, p = 0.002; integrated discrimination index [IDI]: 0.105, p = 0.002). Fragments of collagen and alpha-2-HS-glycoprotein showed significantly different expression between cases and controls. CONCLUSIONS/INTERPRETATION: Although limited by the relatively small sample size, these results suggest that analysis of a urinary biomarker set enables early renal risk assessment in patients with diabetes. Further work is required to confirm the role of urinary proteomics in the prevention of renal failure in diabetes. PMID- 23086561 TI - Oral egg immunotherapy is effective for desensitisation but not for inducing sustained tolerance in the majority of egg allergic children. PMID- 23086560 TI - Bimonthly regimen of high-dose leucovorin, infusional 5-fluorouracil, docetaxel, and cisplatin (modified DCF) in advanced gastric adenocarcinoma. AB - BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (DCF) is an effective but highly toxic regimen for the treatment of advanced gastric cancer. To improve tolerability while maintaining the efficacy of the DCF regimen, we developed a modified DCF regimen including an infusional 5 fluorouracil administration according to the de Gramont regimen. METHODS: In this study, 70 patients with advanced gastric cancer were treated. Each 2-week cycle consisted of docetaxel (60 mg/m(2)), cisplatin (50 mg/m(2)), a 5-fluorouracil (400 mg/m(2)) i.v. bolus, and 5-fluorouracil (2,400 mg/m(2)) i.v. over 46 h plus leucovorin (400 mg/m(2)) i.v. over 2 h. RESULTS: The median progression-free survival and overall survival were 9.0 months (95% CI, 7.1-10.9) and 10.8 months (95% CI, 7.4-14.2), respectively; the 1-year and 2-year overall survival rates were 46.3 and 18.4%, respectively. Twenty-nine (41.4%) partial responses, 19 (27.1%) stable disease, and 22 (31.4%) progression of disease were observed. Grade 3-4 toxicities included neutropenia (37.1%), febrile neutropenia (15.7%), thrombocytopenia (10.0%), anemia (8.6%), nausea and vomiting (10.0%), stomatitis (5.7%), infection (8.6%), and diarrhea (2.9%). CONCLUSIONS: Our results show that a de Gramont-based DCF regimen may have tolerable toxicities and be an effective and convenient palliative treatment for advanced gastric cancer. PMID- 23086562 TI - Elective induction of labour is associated with decreased perinatal mortality and lower odds of caesarean section at 40 and 41 weeks. PMID- 23086563 TI - Danish patients with alcoholic cirrhosis have a low risk of hepatocellular carcinoma thus raising questions about the utility of screening. PMID- 23086564 TI - Zinc supplementation for probable serious bacterial infection in early infancy may reduce the need for antibiotic change. PMID- 23086565 TI - Adequate enteral feeding in the pediatric intensive care unit may be associated with fewer nosocomial infections and deaths. PMID- 23086566 TI - Elective delivery of twins at 37 weeks gestation decreases infant complications. PMID- 23086567 TI - Radical prostatectomy does not improve survival compared to observation for localised prostate cancer in a prospective randomised trial. PMID- 23086568 TI - Can serum procalcitonin levels help interpret indeterminate chest radiographs in patients hospitalized with acute respiratory illness? AB - BACKGROUND: Clinical diagnosis of pneumonia is difficult and chest radiographs often indeterminate, leading to incorrect diagnoses and antibiotic overuse. OBJECTIVE: To determine if serum procalcitonin (ProCT) could assist in managing patients with respiratory illness and indeterminate radiographs. DESIGN: Subjects were prospectively enrolled during 2 consecutive winters. SETTING: A 520-bed hospital in Rochester, NY. PATIENTS: Five hundred twenty-eight adults admitted with acute respiratory illness were enrolled. MEASUREMENTS: Serum ProCT, admission diagnoses, and chest radiographic findings were used to derive receiver operating characteristics curves to assess predictive accuracy of ProCT for the presence of infiltrates. RESULTS: Subjects with pneumonia had higher ProCT (median 0.27 ng/ml) than those with exacerbations of chronic obstructive pulmonary disease (0.08 ng/ml), acute bronchitis (0.09 ng/ml), or asthma (0.06 ng/ml). ProCT had moderate accuracy for the presence of infiltrates (area under curve [AUC] 0.72), when indeterminate radiographs were independently classified as infiltrates by a pulmonologist evaluating patients. CONCLUSIONS: ProCT may be useful in diagnosing pneumonia when chest radiographs are indeterminate. PMID- 23086569 TI - Energy consumption and greenhouse gas emissions from enzyme and yeast manufacture for corn and cellulosic ethanol production. AB - Enzymes and yeast are important ingredients in the production of ethanol, yet the energy consumption and emissions associated with their production are often excluded from life-cycle analyses of ethanol. We provide new estimates for the energy consumed and greenhouse gases (GHGs) emitted during enzyme and yeast manufacture, including contributions from key ingredients such as starch, glucose, and molasses. We incorporated these data into Argonne National Laboratory's Greenhouse Gases, Regulated Emissions, and Energy Use in Transportation model and observed that enzymes and yeast together contribute 1.4 and 27 % of farm-to-pump GHG emissions for corn and cellulosic ethanol, respectively. Over the course of the entire corn ethanol life cycle, yeast and enzymes contribute a negligible amount of GHG emissions, but increase GHG emissions from the cellulosic ethanol life cycle by 5.6 g CO(2)e/MJ. PMID- 23086570 TI - Step-up/step-down perfusion approach for increased mAb 520C9 production by a hybridoma cell line. AB - The hybridoma cell line, HB-8696, produces a monoclonal antibody, 520C9 (mouse IgG(1)) that recognizes the breast cancer oncoprotein, c-erbB2. The effect of perfusion rate (volume of fresh feed/working volume of reactor/day) on cell growth and mAb production was investigated but perfusion at a constant rate and at an arbitrarily increased rate could not maintain exponential cell growth or a higher specific mAb production rate. An optimum step-up/step-down perfusion strategy is therefore proposed for maintaining a steady state production phase at high cell density for ten days. The optimum step-up perfusion could achieve fast cell growth by avoiding any nutrient limited condition and the following optimum step-down perfusion could potentially maintain high live cell density and reduced product dilution as well. The maximum viable cell achieved under optimum perfusion strategy was 2.3 * 10(7) cells/ml which was 19-fold higher than in optimum batch culture. The mAb yield and volumetric productivity were significantly improved to 52 and 50 mg/l day compared to 25 and 3.8 mg/l day in optimum batch, respectively, and could be maintained for up to ten days. PMID- 23086571 TI - Enhanced-acceptor fluorescence-based single cell ATP biosensor monitors ATP in heterogeneous cancer populations in real time. AB - Current methods to monitor cellular ATP do not provide spatial or temporal localization of ATP in single cells in real time or they display imperfect specificity to ATP. Here, we have developed a single cell, Enhanced Acceptor Fluorescence (EAF)-based ATP biosensor to visualize ATP in real time. This biosensor utilizes a modified mimic of the epsilon-subunits of the Bacillus subtilis F(0)F(1) synthase and is coupled to the EAF fluorophores pairs, GFP and YFP. The sensor was then used to monitor ATP in a heterogeneous glioblastoma multiform cancer cell population. We anticipate that this innovative technology and our better understanding of the ATP machinery will have substantial influence on future translational studies. PMID- 23086573 TI - Cell-free protein synthesis: the state of the art. AB - Cell-free protein synthesis harnesses the synthetic power of biology, programming the ribosomal translational machinery of the cell to create macromolecular products. Like PCR, which uses cellular replication machinery to create a DNA amplifier, cell-free protein synthesis is emerging as a transformative technology with broad applications in protein engineering, biopharmaceutical development, and post-genomic research. By breaking free from the constraints of cell-based systems, it takes the next step towards synthetic biology. Recent advances in reconstituted cell-free protein synthesis (Protein synthesis Using Recombinant Elements expression systems) are creating new opportunities to tailor the reactions for specialized applications including in vitro protein evolution, printing protein microarrays, isotopic labeling, and incorporating nonnatural amino acids. PMID- 23086575 TI - Characterization of H3K9me3- and H4K20me3-associated circulating nucleosomal DNA by high-throughput sequencing in colorectal cancer. AB - Modified histone tails in nucleosomes circulating in the blood bear the potential as cancer biomarkers. Recently, using chromatin immunopecipitation (ChIP)-related quantitative PCR, we described reduced plasma levels of the two pericentric heterochromatin-specific histone methylation marks H3K9me3 and H4K20me3 in patients with colorectal cancer (CRC). Here, by utilizing ChIP-related high throughput sequencing, we further characterized these modifications in circulation. Plasma DNA from nucleosomes immunoprecipitated by H3K9me3- and H4K20me3-specific antibodies from patients with CRC (N = 15) and healthy subjects (N = 15) was subjected to the Roche 454 FLX sequencing, and the generated array of ChIP-enriched sequences were compared to the human reference genome. The total number of nucleosomes, of sequence reads and of diverse DNA repetitive elements were statistically compared between the study groups. Total nucleosome amount was not different in both groups. Concerning both histone modifications, lower numbers of sequence reads were detected in CRC patients as compared with healthy controls (medians in H3K9me3: 32 vs. 61; p < 0.01; in H4K20me3: 54 vs. 88; p < 0.01). Size of fragments was not different in both groups. Most abundant sequences were repetitive LINE and SINE elements while simple repeats, LTR, DNA, SAT, and low complexity elements were less frequent. Best discrimination between both groups was achieved by total number of H3K9me3 reads (AUC 0.90) and H3K9me3 LINE elements L1 (AUC 0.93) und L2 (AUC 0.91). The present results confirm earlier findings of lower H3K9me3 levels in CRC and show LINE elements to be the most frequent and best discriminative markers on modified histones. PMID- 23086574 TI - Density of mast cells and microvessels in minor salivary gland tumors. AB - The aim of this study was to investigate the density of mast cells and microvessels in minor salivary gland tumors. Forty-one cases of minor salivary gland tumors (pleomorphic adenoma, n = 10; adenoid cystic carcinoma, n = 11; mucoepidermoid carcinoma, n = 10; and polymorphous low-grade adenocarcinoma) were investigated using immunohistochemistry for mast cell tryptase and von-Willebrand factor. Density of mast cells was higher in mucoepidermoid carcinoma; however, no differences in the number of these cells were observed between the different types of tumors (p > 0.05). The number of mast cells was higher in periparenchymal areas in all tumors, but the difference was not significant (p > 0.05). Mucoepidermoid carcinoma showed the largest number of periparenchymal mast cells, whereas pleomorphic adenomas showed the smallest number of intraparenchymal mast cells (p > 0.05). The highest microvessel density was observed in mucoepidermoid carcinomas, being this difference statistically significant when mucoepidermoid carcinoma was compared to pleomorphic adenoma (p = 0.0034) and polymorphous low-grade adenocarcinoma (p = 0.004). Microvessel density was significantly higher in adenoid cystic carcinoma when compared to pleomorphic adenoma (p = 0.0406) and polymorphous low-grade adenocarcinoma (p = 0.0123). Comparison of mast cells and microvessel densities showed no significant difference between tumors. A quantitative difference in mast cells and microvessels was observed, particularly in mucoepidermoid carcinoma, a finding supporting the aggressive behavior of malignant salivary gland tumors without myoepithelial differentiation. Further studies are needed to determine the role of mast cells in angiogenesis, as well as in the development and biological behavior of these tumors. PMID- 23086576 TI - Significant alterations in the expression pattern of kallikrein-related peptidase genes KLK4, KLK5 and KLK14 after treatment of breast cancer cells with the chemotherapeutic agents epirubicin, docetaxel and methotrexate. AB - Given that 1.3 million new cases of breast cancer are universally registered among women and approximately 36 % of the patients die annually, the revelation of new predictive markers for treatment efficiency is of vital importance. Recently, our group has depicted that KLK4, KLK5, and KLK14 are differentially expressed in breast carcinoma. The objective of this study was to determine and investigate the expression pattern of the KLK4, KLK5, and KLK14 genes in breast cancer cells after treatment with established chemotherapeutic agents. We evaluated these genes' expression after treatment of the BT-20 cells with epirubicin, docetaxel and methotrexate, determining their cytotoxic effect by MTT and trypan blue assays. The relative quantification of genes' mRNA levels was performed by using the SYBR Green(r) chemistry, and the HPRT1 served as an endogenous control gene. The drugs triggered apoptosis in treated cells and induced deregulations in the expression of the above KLKs. The most significant alterations were a 12-fold and tenfold increase of KLK5 in docetaxel and methotrexate-treated cells, respectively, while the KLK4 levels decreased by ten fold in epirubicin, five-fold in docetaxel and twenty-fold in methotrexate treated-cells, compared to the untreated ones. In the case of KLK14 levels, a twofold increase in epirubicin and threefold decrease in methotrexate-treated cells were observed. Present significant alterations in the expression pattern of KLK4, KLK5, and KLK14 could comprise an initial stage for predicting chemotherapy response in breast cancer and should be further investigated as predictive markers in the future. PMID- 23086577 TI - Blood pressure changes and chemical constituents of particulate air pollution: results from the healthy volunteer natural relocation (HVNR) study. AB - BACKGROUND: Elevated blood pressure (BP) has been associated with particulate matter (PM) air pollution, but associations with PM chemical constituents are still uncertain. OBJECTIVES: We investigated associations of BP with various chemical constituents of fine PM (PM2.5) during 460 repeated visits among a panel of 39 university students. METHODS: Resting BP was measured using standardized methods before and after the university students relocated from a suburban campus to an urban campus with different air pollution contents in Beijing, China. Air pollution data were obtained from central monitors close to student residences. We used mixed-effects models to estimate associations of various PM2.5 constituents with systolic BP (SBP), diastolic BP (DBP), and pulse pressure. RESULTS: An interquartile range increase of 51.2 MUg/m3 in PM2.5 was associated with a 1.08-mmHg (95% CI: 0.17, 1.99) increase in SBP and a 0.96-mmHg (95% CI: 0.31, 1.61) increase in DBP on the following day. A subset of PM2.5 constituents, including carbonaceous fractions (organic carbon and elemental carbon), ions (chloride and fluoride), and metals/metalloid elements (nickel, zinc, magnesium, lead, and arsenic), were found to have robust positive associations with different BP variables, though robust negative associations of manganese, chromium, and molybdenum with SBP or DBP also were observed. CONCLUSIONS: Our results support relationships between specific PM2.5 constituents and BP. These findings have potential implications for the development of pollution abatement strategies that maximize public health benefits. PMID- 23086578 TI - Organocatalytic asymmetric biomimetic transamination of aromatic ketone to optically active amine. AB - An asymmetric biomimetic transamination of aromatic ketones to optically active amines with o-HOPhCH(2)NH(2) as amine source catalyzed by hydroquinine-derived chiral base is described. Up to 85% ee was obtained. PMID- 23086579 TI - Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease. AB - Altered fibrin clot structure has been reported both in patients with coronary artery disease (CAD) and those with type 2 diabetes mellitus (DM2). The aim of the present study was to evaluate plasma fibrin clot permeability and susceptibility to lysis in patients with DM2 and CAD. We studied 132 consecutive CAD patients, including 67 subjects with DM2, scheduled for elective coronary artery bypass grafting surgery. Ex vivo plasma fibrin clot permeability (K(s)) and lysis time (t(50%)) induced by 1 MUg/mL recombinant tissue plasminogen activator (tPA), along with plasma levels of plasminogen activator inhibitor-1 (PAI-1), thrombin activatable fibrinolysis inhibitor (TAFI), tPA, von Willebrand factor (vWF), P-selectin, soluble CD40 ligand (sCD40L), were measured. Diabetic and non-diabetic patients did not differ in regard to demographics and remaining cardiovascular risk factors. Concomitant DM2 was associated with higher glucose (+24.3%, p < 0.001), fibrinogen (+9.0%, p = 0.037), PAI-1 (+58.7%, p < 0.001), tPA (+24.0%, p < 0.001) and P-selectin (+12.2%, p < 0.001). Compared with the non diabetic group, the CAD patients with DM2 had lower K(s) (-6.1%, p = 0.02) and prolonged t(50%) (+5.1%, p = 0.04). Multiple regression analysis of the whole study group showed that vWF, PAI-1, fibrinogen and DM2 were the independent predictors of t(50%) (R(2) = 0.58, p < 0.001), while only vWF was an independent predictor of K(s) (R(2) = 0.22, p < 0.001). This study indicates that DM2 is potent enough to unfavorably affect plasma fibrin clot characteristics despite abnormal clot phenotype typically observed in CAD. Of note, platelet and endothelial markers appear to contribute to fibrin clot properties in CAD concomitant with DM2. PMID- 23086580 TI - Microwave-assisted synthesis of 1,3-benzothiazol-2(3H)-one derivatives and analysis of their antinociceptive activity. AB - A rapid and efficient method was developed for synthesis of 6-acyl-1,3 benzothiazol-2(3H)-one derivatives under microwave irradiation (MWI) conditions. The reaction times were shortened compared to conventional heating. Additionally, we synthesized acetic acid and acetamide derivatives of 1,3-benzothiazol-2(3H) one, 6-acyl-1,3-benzothiazol-2(3H)-one, 5-chloro-1,3-benzothiazol-2(3H)-one and 6 acyl-5-chloro-1,3-benzothiazol-2(3H)-one with the microwave-assisted method and analyzed their antinociceptive activity with the tail flick, tail clip, hot plate and writhing tests. Among the synthesized compounds, 3-[2-(4-ethylpiperazin-1-yl) 2-oxoethyl]-1,3-benzothiazol-2(3H)-one (6a), 5-chloro-3-{2-oxo-2-[4-(propan-2-yl) piperazin-1-yl]ethyl}-1,3-benzothiazol-2(3H)-one (7e) and 3-[2-(4-butylpiperazin 1-yl)-2-oxoethyl]-5-chloro-1,3-benzothiazol-2(3H)-one (8e) showed significant antinociceptive activity in the tail clip, tail flick, hot plate and writhing tests. Supporting Information available online at http://www.thieme connect.de/ejournals/toc/amf. PMID- 23086581 TI - Antimicrobial and cytotoxicity potential of acetamido, amino and nitrochalcones. AB - Chalcones constitute one of the major classes of natural products belonging to the flavonoid family, and they have been reported as having a range of important therapeutic activities, including some chalcones are effective as antimicrobial agents. Currently, the search for new structures with antimicrobial activity has been intensified due to the emergence of many strains resistant to antibiotics currently used to treat infectious diseases.3 chalcone series (amino, acetamido and nitrochalcones) were prepared (23 compounds) and evaluated for their antimicrobial and cytotoxic potential. The effects of substituents on their respective activities also was evaluated.The results showed that 4 aminochalcones (2, 4, 8, 9), 3 acetoamidochalcones (10, 14, 18) and 3 nitrochalcones (20, 22, 23), exhibited antifungal effects. The aminochalcones were more toxic than the acetamidochalcones, while the nitrochalcones did not present any toxic effect. It was verified that there seems to be structure-activity correlation in some electron-donating and withdrawing substituents groups in rings A and B of the synthetized chalcone analogues and its antifungal and cytotoxic activity. PMID- 23086582 TI - A validated biomarker panel to identify peripheral artery disease. AB - Current guidelines recommend obtaining an ankle-brachial index (ABI) to screen for peripheral artery disease (PAD) in subjects at risk. Previous work demonstrated that a combination of beta(2)-microglobulin, cystatin C, high sensitivity C-reactive protein and glucose was associated with PAD. This study evaluated the ability of these biomarkers combined with clinical parameters to predict PAD in at-risk subjects. This study enrolled 1025 subjects from 99 primary care clinics who were smokers and/or diabetics >= 50 years or any individual >= 70 years. Consented subjects underwent a clinical assessment, fasting blood draw, and an ABI measurement with PAD defined as an ABI < 0.90 in either leg. The biomarkers and their interactions were evaluated using logistic regression and performance was evaluated at a cut point of the biomarker panel selected to maximize sensitivity while minimizing the false positive rate of the test. Of the 1025 subjects enrolled, 46 did not meet the ABI or other criteria for inclusion in the analysis. Among the evaluable subjects (n = 979), PAD was detected in 83 (8.5%). The model had a C-statistic of 0.73 (95% CI 0.67-0.79). There were 20 patients with PAD who were judged to be at low to moderate risk for cardiovascular events by clinical assessment; the model correctly identified 17 of these 20 patients. The model also performed well in subjects with no prior history of PAD. Thus, a biomarker panel may have a role for identifying PAD. PMID- 23086583 TI - Absence of loss of heterozygosity of BRCA1 in a renal tumor from a BRCA1 germline mutation carrier. AB - BRCA1 functions as a tumor suppressor gene and germline and somatic mutations in this gene have been shown to be associated with many types of cancer. We report the first tumor study of renal cell carcinoma in a carrier of the deleterious BRCA1 mutation-c.68_69delAG. PMID- 23086584 TI - Feasibility evaluation of an online tool to guide decisions for BRCA1/2 mutation carriers. AB - Women with BRCA1 or BRCA2 (BRCA1/2) mutations face difficult decisions about managing their high risks of breast and ovarian cancer. We developed an online tool to guide decisions about cancer risk reduction (available at: http://brcatool.stanford.edu ), and recruited patients and clinicians to test its feasibility. We developed questionnaires for women with BRCA1/2 mutations and clinicians involved in their care, incorporating the System Usability Scale (SUS) and the Center for Healthcare Evaluation Provider Satisfaction Questionnaire (CHCE-PSQ). We enrolled BRCA1/2 mutation carriers who were seen by local physicians or participating in a national advocacy organization, and we enrolled clinicians practicing at Stanford University and in the surrounding community. Forty BRCA1/2 mutation carriers and 16 clinicians participated. Both groups found the tool easy to use, with SUS scores of 82.5-85 on a scale of 1-100; we did not observe differences according to patient age or gene mutation. General satisfaction was high, with a mean score of 4.28 (standard deviation (SD) 0.96) for patients, and 4.38 (SD 0.89) for clinicians, on a scale of 1-5. Most patients (77.5 %) were comfortable using the tool at home. Both patients and clinicians agreed that the decision tool could improve patient-doctor encounters (mean scores 4.50 and 4.69, on a 1-5 scale). Patients and health care providers rated the decision tool highly on measures of usability and clinical relevance. These results will guide a larger study of the tool's impact on clinical decisions. PMID- 23086585 TI - A dismantling study of assertive outreach services: comparing activity and outcomes following replacement with the FACT model. AB - PURPOSE: Financial constraints and some disappointing research evaluations have seen English assertive outreach (AO) teams subject to remodelling, decommissioning and integration into standard care. We tested a specific alternative model of integrating the AO function from two AO teams into six standard community mental health teams (CMHT). The Flexible Assertive Community Treatment model (FACT) was adopted from the Netherlands (Van Veldhuizen, Commun Mental Health J 43(4):421-433, 2007; Bond and Drake, Commun Mental Health J 43(4):435-438, 2007). We aimed to demonstrate non-inferiority in clinical effectiveness and thereby show cost efficiencies associated with FACT. METHODS: Outcomes were compared in a mirror-image study of the 12 months periods pre- and post-service change with eligible individuals from the AO teams' caseloads (n = 112) acting as their own controls. We also conducted a cost-consequence analysis of the changes. Outcome data regarding admissions, use of crisis and home treatment, frequency of contact and DNA rate were extracted from the electronic patient record. RESULTS: The results show AO patients (n = 112) transferred to standard CMHTs with FACT had significantly fewer admissions and a halving of bed use (21 fewer admission and 2,394 fewer occupied bed days) whilst being in receipt of a less intensive service (2,979 fewer contacts). This was offset by significantly poorer engagement but not by increased use of crisis and home treatment services. CONCLUSIONS: Enhancing multi-disciplinary CMHTs with FACT provides a clinically effective alternative to AO teams. FACT offers a cost effective model compared to AO. PMID- 23086586 TI - The importance of both workplace and private life factors in psychological distress: a large cross-sectional survey of French railway company employees. AB - PURPOSE: The psychological well-being of employees is a priority in occupational health. This study aimed to estimate the prevalence of psychological distress among employees of a large French company, to calculate the associations between distress and stressors in the workplace and private life domains, and to explore confounding across stressor domains. METHODS: 8,058 employees of the French national railways company completed a nation-wide survey in 2006 (94.3 % participation). Psychological distress was measured by the 12-item General Health Questionnaire and 21 potential stressors and socio-demographic factors by a self administered questionnaire. Stressors were summarized in scores for work pressure, workplace conflict, and personal life domains. Risk ratios (RRs) between psychological distress and stressors were calculated using robust variance Poisson regression. RESULTS: The prevalence of psychological distress was 32.8 % (95 % CI 31.8-33.9 %), higher among women (48.9 %, 95 % CI 46.5-51.7 %) than men (30.1 %, 95 % CI 29.0-31.2 %). Each stressor domain was associated with distress in the final model containing likely confounders and all three domains (RR highest vs. lowest level-work pressure: men 1.55, 95 % CI 1.42-1.70, women 1.42, 95 % CI 1.23-1.63; work conflict: men 2.63, 95 % CI 2.38-2.91, women 1.98, 95 % CI 1.70-2.30; life concerns: men 2.04, 95 % CI 1.86-2.23, women 1.53, 95 % CI 1.32-1.78). The mutually adjusted RRs for the stressor domains were smaller than the unadjusted RRs. CONCLUSIONS: Almost one-third of all employees and one-half of female employees experienced psychological distress. All three stressor domains were associated with psychological distress and adjustment reduced the association size, suggesting possible over-estimation if one or more domains are omitted from the survey. PMID- 23086588 TI - Aortic arch replacement for degenerative aneurysms: advances during the last decade. AB - During the last decade, treatment paradigm for degenerative aortic arch aneurysms has been changed by a better understanding of the pathophysiology of brain complication and introduction of endovascular technologies. To avoid neurocognitive dysfunction, safe duration of deep hypothermic circulatory arrest is now considered <25 min, and retrograde cerebral perfusion became less frequently used. Selective cerebral perfusion (SCP) is not associated with neurocognitive decline unless profound hypothermia (<20 degrees C) is used, which may suggest profound hypothermic SCP is not advantageous but may be detrimental. Attempts have been made to use mild to moderate hypothermia during SCP, and safe duration of distal circulatory arrest seems <60 min at 28 degrees C to avoid ischemic spinal cord injury. Three-vessel perfusion seems advantageous to provide adequate brain and spinal cord protection. To avoid aortogenic brain atheroembolism in the high risk patients, we previously proposed the "isolation" technique, where SCP is established before systemic perfusion. This technique has subsequently been modified to use both axillary and left carotid arteries for systemic arterial return, so that aortogenic emboli may not enter the brain circulation. In the TEVAR (thoracic endovascular aortic repair) era, hybrid operations such as the frozen elephant trunk or TEVAR completion after the elephant trunk are increasingly performed for extensive or distal arch aneurysms. It should be noted, however, that the frozen elephant trunk operation for extensive aneurysms carries an increased risk of paraplegia, and for distal arch aneurysms its outcome is not better than that after the standard open repair in Japan. PMID- 23086587 TI - Modelling the cost-effectiveness of pregabalin versus usual care in daily practice in the treatment of refractory generalised anxiety disorder in Spain. AB - PURPOSE: To model the cost-effectiveness (CEA) of the use of pregabalin versus usual care (UC) in outpatients with refractory generalised anxiety disorder (GAD) treated in daily practice in mental health settings in Spain. METHODS: This CEA model used data extracted from a 6-month prospective non-interventional trial: the Amplification of Definition of ANxiety (ADAN) study, which was conducted to determine the cost-of-illness in GAD subjects. Refractory subjects were those who reported persistent symptoms of anxiety and showed suboptimal response in the Hamilton-anxiety scale (HAM-A >= 16) after a standard dose regimen of anxiolytics other than pregabalin, alone or in combination, over 6 months. The pregabalin arm was documented with data extracted from patients who received pregabalin in the study for the first time, added or replacing the existing therapy. In the UC arm, treatment might include one or more of the following: a serotonin selective reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, other anti depressants, a benzodiazepine or an anti-epileptic drug other than pregabalin. The time horizon of the modelling was 6 months in the base-case scenario, and the National Health System perspective was chosen to calculate costs. Effectiveness was expressed as quality-adjusted life years (QALYs) gained, which were derived using the EQ-5D questionnaire, at baseline and end-of-trial visits. Results of the CEA model was expressed as an incremental cost-effectiveness ratio (ICER) per QALY gained. Probabilistic sensitivity analysis using bootstrapping techniques was also carried out to obtain the cost-effectiveness plane and the corresponding acceptability curve. RESULTS: Data from a total of 429 subjects per arm (mean HAM A score 25.7) meeting eligible criteria for inclusion in CEA modelling were extracted from the original trial. Compared with UC, pregabalin (average dose 218 mg/day) was associated with significantly higher QALY gain; 0.1209 +/- 0.1030 versus 0.0994 +/- 0.0979 (P = 0.003), but increased healthcare costs as well; 1,272 +/- 1,240 versus 1,070 +/- 1,177 (P < 0.069) and drug costs 525 +/- 252 versus 219 +/- 211 (P < 0.001), resulting in an ICER of 15,804/QALY (95 % CI 6,661; 37,186) for healthcare costs and 15,165/QALY (7,947; 31,754) when drug costs were considered alone. A total of 94 % of re-samples fell below the threshold of 30,000 per QALY. CONCLUSIONS: This evaluation modelling suggests that pregabalin may be cost effective in comparison with UC in outpatients with refractory GAD treated in mental healthcare settings in daily practice in Spain. PMID- 23086589 TI - Outcomes from a diabetes self-management intervention for Native Hawaiians and Pacific People: Partners in Care. AB - BACKGROUND: Culturally adapted interventions are needed to reduce diabetes related morbidity and mortality among Native Hawaiian and Pacific People. PURPOSE: The purpose of this study is to pilot test the effectiveness of a culturally adapted diabetes self-management intervention. METHODS: Participants were randomly assigned in an unbalanced design to the Partners in Care intervention (n = 48) or wait list control group (n = 34). Assessments of hemoglobin A1c, understanding of diabetes self-management, performance of self care activities, and diabetes-related distress were measured at baseline and 3 months (post intervention). Analysis of covariance was used to test between-group differences. The community steering committee and focus group data informed the cultural adaptation of the intervention. RESULTS: There were significant baseline adjusted differences at 3 months between the Partners in Care and wait list control group in intent-to-treat (p < 0.001) and complete case analyses (p < 0.0001) for A1c, understanding (p < 0.0001), and performing diabetes self management (p < 0.0001). CONCLUSIONS: A culturally adapted diabetes self management intervention of short duration was an effective approach to improving glycemic control among Native Hawaiian and Pacific Islanders. PMID- 23086590 TI - Pathways linking socioeconomic status and postpartum smoking relapse. AB - BACKGROUND: Low socioeconomic status (SES) exacerbates the high rate of smoking relapse in women following childbirth. PURPOSE: This study examined multiple models of potential mechanisms linking SES and postpartum smoking relapse among women who quit smoking due to pregnancy. METHODS: Participants were 251 women enrolled in a randomized clinical trial of a new postpartum smoking relapse prevention intervention. Four models of the prepartum mechanisms linking SES and postpartum smoking relapse were evaluated using a latent variable modeling approach. RESULTS: Each of the hypothesized models were a good fit for the data. As hypothesized, SES indirectly influenced postpartum smoking relapse through increased prepartum negative affect/stress, reduced sense of agency, and increased craving for cigarettes. However, the model that included craving as the sole final pathway between SES and relapse demonstrated superior fit when compared with all other models. CONCLUSIONS: Findings have implications for future interventions that aim to reduce postpartum relapse. PMID- 23086591 TI - Nutritional vitamin D use in chronic kidney disease: a survey of pediatric nephrologists. AB - BACKGROUND: Vitamin D deficiency may contribute to risk of cardiovascular disease, diabetes, and infections, in addition to known effects on mineral metabolism. Controversy remains regarding the use of nutritional vitamin D supplementation in chronic kidney disease (CKD), and the supplementation practices of pediatric nephrologists are unknown. METHODS: An electronic survey containing eight vignettes was sent to physician members of the International Pediatric Nephrology Association in 2011 to identify physician and patient characteristics that influence nephrologists to supplement CKD patients with nutritional vitamin D. Vignettes contained patient characteristics including light vs dark skin, CKD stage, cause of renal disease, parathyroid hormone (PTH), and 25(OH) vitamin D levels. Multivariate logistic generalized estimating equation regression was used to identify predictors of supplementation. RESULTS: Of 1,084 eligible physicians, 504 (46%) completed the survey. Supplementation was recommended in 73% of cases overall (ranging from 91% of those with vitamin D levels <10 ng/mL to 35% with levels >30). Greater CKD severity was associated with greater recommendation of supplementation, especially for patients with higher vitamin D levels (test for interaction p < 0.0001). PTH level above target for CKD stage was associated with greater recommendation to supplement in pre dialysis CKD, but did not have an impact on recommendations in dialysis patients (test for interaction p < 0.0001). Skin color, cause of CKD, and albumin levels were not associated with supplementation recommendation. CONCLUSIONS: Recommending nutritional vitamin D is common worldwide, driven by CKD stage and vitamin D and PTH levels. Future studies are needed to establish the risks and benefits of supplementation. PMID- 23086593 TI - Can postpyelonephritic renal scarring be prevented? AB - Pyelonephritis in childhood may, in the worst cases, lead to long-term cardiovascular morbidity due to tubulointerstitial renal scarring. Renal damage is the end result of an interplay between (1) urinary tract anatomy and function, (2) bacterial virulence factors, and (3) the host innate immune system, which on the one hand manages bacterial clearance, but on the other causes tubulointerstitial inflammation, which underlies the renal scarring. It is unclear how common postpyelonephritic scarring is, and how many of the "scars" in fact represent congenital renal hypoplasia. We do, however, know that some situations have an increased risk for scars, i.e., large renal-uptake defects on initial renal scintigraphy or pyelonephritis in young girls with dilating vesicoureteral reflux. It seems logical that antiinflammatory or antioxidant therapy given concomitantly with antibiotics should lower the risk of postpyelonephritic scarring. Animal studies give some support to this idea, but research on humans has been surprisingly scant. In this issue of Pediatric Nephrology, we publish a study that indicates that antioxidant therapy with vitamin A or E given to children with pyelonephritis may indeed lower the risk for renal scarring. This is a track that needs to be pursued further. PMID- 23086594 TI - A new arsenate reductase involved in arsenic detoxification in Anabaena sp. PCC7120. AB - In silico analysis followed by experimental validation leads us to propose that the predicted protein All0195 of Anabaena sp. PCC7120 showing enhanced expression under sodium arsenate (Na2HAsO4) stress belongs to the thioredoxin superfamily with structural similarity to bacterial arsenate reductase. The All0195 protein demonstrated C-X-TC-X-K, NTSG-X2-YR, and D-X2-L-X-KRP as functional motifs that show similarity to seven known bacterial arsenate reductase family protein homologs with Cys, Arg, and Pro as conserved residues. In view of physicochemical properties, such as aliphatic index, ratio of Glu + Lys to Gln + His, and secondary structure, it was evident that All0195 was also a thermostable protein. The predicted three-dimensional structure on molecular docking with arsenate oxyanion ([Formula: see text]) revealed its interaction with conserved Cys residue as also known for other bacterial arsenate reductase. In silico derived properties were experimentally attested by cloning and heterologous expression of all0195. Furthermore, this protein functionally complemented the arsenate reductase-deficient sodium arsenate-hypersensitive phenotype of Escherichia coli strainWC3110 (DeltaarsC) and depicted arsenate reductase activity on purification. In view of the above properties, All0195 appears to be a new arsenate reductase involved in arsenic detoxification in Anabaena sp. PCC7120. PMID- 23086595 TI - The barley UNICULM2 gene resides in a centromeric region and may be associated with signaling and stress responses. AB - Vegetative axillary meristem (AXM) activity results in the production of branches. In barley (Hordeum vulgare L.), vegetative AXM develop in the crown and give rise to modified branches, referred to as tillers. Mutations in the barley low-tillering mutant uniculm2 block vegetative AXM development and prevent tiller development. The objectives of this work were to examine gene expression in wild type and cul2 mutant plants, fine map the CUL2 gene, and to examine synteny in the CUL2 region in barley with rice. RNA profiling experiments using two near isogenic line pairs carrying either the cul2 mutant allele or wild-type CUL2 allele in different genetic backgrounds detected 28 unique gene transcripts exhibiting similar patterns of differential accumulation in both genetic backgrounds, indicating that we have identified key genes impacted by the CUL2 gene. Twenty-four genes had higher abundance in uniculm2 mutant tissues, and nearly half of the annotated genes likely function in stress-response or signal transduction pathways. Genetic mapping identified five co-segregating markers in 1,088 F2 individuals. These markers spanned the centromere region on chromosome 6H, and coincided with a 50-cM region on rice chromosome 2, indicating that it may be difficult to positionally clone CUL2. Taken together, the results revealed stress response and signal transduction pathways that are associated with the CUL2 gene, isolating CUL2 via positional cloning approaches that may be difficult, and the remnants of barley-rice synteny in the CUL2 region. PMID- 23086597 TI - Hypoglycaemia and neonatal brain injury. PMID- 23086596 TI - Structure-activity differences of chlorogenic acid and its isomers on sensitization via intravenous exposure. AB - Chlorogenic acid (CGA) is found in many plants that are used as medicinal substances in traditional Chinese medicine injectables (TCMIs). However, to date, there is controversy as to whether CGA is the major cause of TCMIs-related hypersensitivity administered intravenously. Therefore, the aim of this study was to evaluate the potential sensitization of CGA and structure-activity differences between its isomers using an intravenous exposure mouse model. The results showed that popliteal lymph nodes proliferation was significantly induced by CGA and its isomers. Both CGA and isochlorogenic acid A (iso-CGA A) significantly enhanced the secretion of trinitrophenyl (TNP) ovalbumin-specific immunoglobulin (Ig)G1; and iso-CGA B significantly induced TNP-specific IgG1, IgM, and IgG2b secreting. Furthermore, the results of quantitative structure-activity relationship analysis suggested that chemical structure factors, including atomic mass, electronegativity, atom shape and size, atom distribution, atomic weight, and atomic polarizabilities, the ionic currents, were significantly correlated with the potential sensitization of CGA and its isomers. In summary, when administered intravenously, the strength and type of sensitization may be correlated with structure differences in the CGA family. PMID- 23086598 TI - A furan Diels-Alder cycloaddition approach to scyphostatin analogues. AB - The synthesis of two diastereoisomers of the epoxycyclohexenone core of scyphostatin, a naturally occurring sphingomyelinase inhibitor, has been achieved via a common oxabicyclic intermediate. The diastereomeric intermediates are accessed by stereodivergent oxidative functionalisation processes, followed by a Lewis acid mediated ring opening rearrangement reaction. PMID- 23086599 TI - Characterizing the next-generation matrix and basic reproduction number in ecological epidemiology. AB - We address the interaction of ecological processes, such as consumer-resource relationships and competition, and the epidemiology of infectious diseases spreading in ecosystems. Modelling such interactions seems essential to understand the dynamics of infectious agents in communities consisting of interacting host and non-host species. We show how the usual epidemiological next generation matrix approach to characterize invasion into multi-host communities can be extended to calculate R0, and how this relates to the ecological community matrix. We then present two simple examples to illustrate this approach. The first of these is a model of the rinderpest, wildebeest, grass interaction, where our inferred dynamics qualitatively matches the observed phenomena that occurred after the eradication of rinderpest from the Serengeti ecosystem in the 1980s. The second example is a prey-predator system, where both species are hosts of the same pathogen. It is shown that regions for the parameter values exist where the two host species are only able to coexist when the pathogen is present to mediate the ecological interaction. PMID- 23086600 TI - Phenothiazine-based organic dyes with two anchoring groups on TiO2 for highly efficient visible light-induced water splitting. AB - New phenothiazine-based organic dyes with two anchoring groups at 3,7 positions and systematic alkyl chains on nitrogen were prepared. Their TiO(2)-Pt composites showed excellent photo-catalytic activities in visible light-induced water splitting. Interestingly, phenothiazine dyes with longer alkyl chains showed better stability in catalytic systems. PMID- 23086601 TI - Phenotypic and genetic parameter estimates for reproductive traits in Zandi sheep. AB - This study reports on the phenotypic and genetic (co)variance components for reproductive traits in Zandi sheep, using between 1,859 and 2,588 records obtained from 577 ewes. The data were collected from the Khojir Breeding Station of Zandi sheep in Tehran, Iran from 1994 to 2008. The basic traits were litter size at birth (LSB), litter size at weaning (LSW), litter mean weight per lamb born (LMWLB), and litter mean weight per lamb weaned (LMWLW), and the composite traits were total litter weight at birth (TLWB) and total litter weight at weaning (TLWW). Genetic analyses were carried out using the restricted maximum likelihood method that was explored by fitting the additive direct genetic effects and permanent environmental effects of the ewes as random effects and the ewe age at lambing and lambing year as fixed effects for all of the investigated traits. Akaike's information criterion was used to choose the most appropriate model. LSB, LSW, LMWLB, LMWLW, TLWB, and TLWW direct heritability estimates were 0.07, 0.05, 0.12, 0.10, 0.08, and 0.14, respectively. The estimated fractions of variance due to the permanent environmental effects of the ewe ranged from 0.03 for LMWLB to 0.08 for LMWLW and TLWW. Corresponding repeatability estimates ranged from 0.10 for LSW to 0.22 for TLWW. Direct genetic correlations varied from -0.61 for LSB-LMWLB to 0.88 for LSB-LSW and LSB-TLWB. Results indicate that genetic change depends not only on the heritability of traits, but also on the observed phenotypic variation; therefore, improvement of non-genetic factors should be included in the breeding programs. PMID- 23086602 TI - Characteristics of two duck farming systems in the Mekong Delta of Viet Nam: stationary flocks and moving flocks, and their potential relevance to the spread of highly pathogenic avian influenza. AB - Ducks are considered to play a major role in the spread of highly pathogenic avian influenza (HPAI) H5N1 in Viet Nam, but detailed information on their management is limited. We distinguished two different systems (1) stationary duck flocks that are not commonly driven to rice fields beyond village boundaries and that are confined overnight on farms and (2) moving duck flocks that are intentionally driven to rice fields beyond village boundaries, that are not returning to home farms for extended periods and that are housed overnight in temporary enclosures in rice paddies. A total of 115 stationary and 22 moving flock farmers were interviewed in 2007 in the Mekong Delta of Viet Nam. Moving duck flocks are larger than stationary flocks, which is indicative of their more commercial production. Moving flock farmers apparently are more aware of HPAI risks than stationary flock farmers, as their flocks are more likely fully vaccinated and have less contact with chickens during scavenging. On the other hand, the spread of HPAI virus between birds might be promoted by moving duck flocks as they repeatedly use transport vehicles and numerous rice paddies for scavenging and are often visited by hatchery owners in the field for purchasing duck eggs. In addition, long distances travelled by moving duck flocks might also result in widespread dissemination of HPAI virus. Further studies are necessary to describe HPAI prevalence and travel patterns of moving duck flocks and to explore the moving duck flock network in detail. PMID- 23086604 TI - Can we consider plasma alkyresorcinols as a potential biomarker of whole-grain food? PMID- 23086603 TI - Diffuse large B cell lymphoma: molecular targeted therapy. AB - Diffuse large B cell lymphoma (DLBCL) is a biologically heterogeneous disease and the most common subtype of B cell non-Hodgkin's lymphoma in the USA. Even though it is a curable lymphoma in advanced stages, up to 40 % of patients eventually relapse or fail to achieve remission. Improved understanding of the biologic complexity of DLBCL reveals a diverse range of oncogenic driver mutations and signaling pathways that are essential for growth and survival of malignant cells. Since many of these signaling pathways can be targeted by small-molecule inhibitors, the therapy for DLBCL is currently undergoing a paradigm shift away from conventional chemotherapy and toward targeted agents that capitalize on an improved biologic understanding of the subsets with the highest risk of treatment failure. Participation in well-conducted and rationally designed clinical trials will be essential to realize the potential of these targeted agents and realize the goal of improving overall outcomes in the most common B cell lymphoma in the world. PMID- 23086605 TI - Comparison of vitamin D(2) and vitamin D(3) supplementation in increasing serum 25-hydroxyvitamin D status: a systematic review and meta-analysis. PMID- 23086608 TI - Peptide mapping of polymorphic myosin heavy chain isoforms in different muscle types of some freshwater teleosts. AB - A modified SDS-PAGE system has been employed to resolve polymorphic myosin heavy chain (MyHC) isoforms in different muscle types of three freshwater teleosts displaying different modes of respiration, adaptive features and life styles. Investigated species include accessory air-breather Channa punctata along with exclusive aquatic breather major carps Labeo rohita and Catla catla. All the selected species show specificity and expressivity of at least three MyHC isoforms, one each in red, head and pectoral muscles. Chymotryptic peptide maps unambiguously support substructural individuality of each MyHC isoforms with the type-specific dispersal of chymotryptic cleavage sites. Specific Ca(2+)- and Mg(2+)-ATPase activities of natural actomyosin (NAM) of lateral line red muscle of C. punctata were low and less sensitive to pH, but sensitive to KCl concentrations between 0.05 and 0.15 M. In comparison, the specific enzymatic activities of NAM of red muscle from the carps (L. rohita and C. catla) were substantially high with prominent peaks at pH 7.5 and near insensitivity to 0.05 0.15 M KCl, while C. punctata had shown a different response at these molarities. Thus, the data favor a correlation between breathing modes and life style and the differences in pH or ionic strength sensitivities of ATPases. Unique profiles of peptide maps and the dispersal patterns of hydrophobic residues (cleavage sites of chymotrypsin) in MyHC of different muscle types further reflect individuality of their evolutionary histories. PMID- 23086609 TI - Cadmium and copper reduce hematopoietic potential in common carp (Cyprinus carpio L.) head kidney. AB - The effects of cadmium and copper on activity of common carp head kidney hematopoietic tissue were evaluated. The fish were subjected to short-term (3 h, Cd-s and Cu-s) or long-term (4 weeks, Cd-l and Cu-l) exposures to 100% 96hLC50 or 10% 96hLC50, respectively. Head kidneys were isolated weekly from 5 fish of each group for 4 weeks (post-short-term exposure and during long-term exposure). Percentage of early blast cells among the hematopoietic precursors was calculated. Proliferative and apoptotic activity were evaluated using immunocytochemical staining for proliferating cell nuclear antigen (PCNA) and caspase 3, respectively. Hematopoietic activity was calculated as the ratio of proliferating to apoptotic cells. All metal exposures induced an increase in frequency of early blast cells. The frequency of proliferating (PCNA-positive) cells also significantly increased. A considerable and significant increase in the frequency of apoptotic cells was the most pronounced effect of metal exposures. Both short-term and long-term treatments caused similar effects, but in case of Cd exposures, the reaction was more pronounced. All metal exposures reduced hematopoietic potential of fish measured as the ratio of proliferating to apoptotic precursor cell frequency. However, in all cases, hematopoietic activity was higher than 1 showing that the rate of repair of hematopoietic tissue prevailed over destruction. PMID- 23086610 TI - Isolation and selection of suitable reference genes for real-time PCR analyses in the skeletal muscle of the fine flounder in response to nutritional status: assessment and normalization of gene expression of growth-related genes. AB - In the present study, different reference genes were isolated, and their stability in the skeletal muscle of fine flounder subjected to different nutritional states was assessed using geNorm and NormFinder. The combinations between 18S and ActB; Fau and 18S; and Fau and Tubb were chosen as the most stable gene combinations in feeding, long-term fasting and refeeding, and short term refeeding conditions, respectively. In all periods, ActB was identified as the single least stable gene. Subsequently, the expression of the myosin heavy chain (MYH) and the insulin-like growth factor-I receptor (IGF-IR) was assessed. A large variation in MYH and IGF-IR expression was found depending on the reference gene that was chosen for normalizing the expression of both genes. Using the most stable reference genes, mRNA levels of MYH decreased and IGF-IR increased during fasting, with both returning to basal levels during refeeding. However, the drop in mRNA levels for IGF-IR occurred during short-term refeeding, in contrast with the observed events in the expression of MYH, which occurred during long-term refeeding. The present study highlights the vast differences incurred when using unsuitable versus suitable reference genes for normalizing gene expression, pointing out that normalization without proper validation could result in a bias of gene expression. PMID- 23086611 TI - Heavy metal lead exposure, osteoporotic-like phenotype in an animal model, and depression of Wnt signaling. AB - BACKGROUND: Exposure to lead (Pb) from environmental and industrial sources remains an overlooked serious public health risk. Elucidating the effect of Pb on bone cell function is therefore critical for understanding its risk associated with diseases of low bone mass. OBJECTIVES: We tested the hypothesis that Pb negatively affects bone mass. We also assessed the underlying mechanisms of Pb on bone signaling pathways. METHODS: We used a model of low-level Pb exposure in a rodent beginning before conception and continuing over 18 months. We characterized the effect of Pb on bone quality using dual-energy X-ray absorptiometry (DXA), micro-computed tomography, Raman spectroscopy, and histology. We assessed the effect of Pb on bone and adipocyte formation by mineral deposition, lipid droplet formation, and Western blot and RNA analysis. RESULTS: Pb-exposed animals had decreased bone mass that resulted in bones that were more susceptible to fracture. Pb decreased osteoblastic cell number leading to a depression of bone formation. Accompanying this, Pb exposure elevated sclerostin protein levels in the skeleton, and correspondingly reduced levels of beta-catenin and Runx2 in stromal precursor cells. Pb also increased skeletal expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These results indicate a shift in mesenchymal differentiation wherein Pb promoted enhanced adipogenesis and decreased osteoblastogenesis. Substantial differences in bone marrow composition were observed, highlighted by an increase in adipocytes. CONCLUSIONS: The disruption Pb has on bone mass and bone homeostasis is principally explained by inhibition of the Wnt/beta-catenin pathway, which may provide a molecular basis for novel therapeutic strategies to combat Pb-induced bone pathologies. PMID- 23086612 TI - An unexpected mortality following cardiac surgery: a post-mortem diagnosis of cardiac amyloidosis. AB - Amyloidosis is a rare systemic disease that is notoriously difficult to diagnose early. Cardiac involvement is associated with a poor prognosis. We present the case of a 72-year-old gentleman who underwent elective coronary artery bypass grafting and mitral valve repair. While initially making a good post-operative recovery, a sudden deterioration on post-operative day 3 led to an unexpected mortality. Post-mortem examination demonstrated previously undiagnosed severe systemic amyloidosis, which particularly affected his heart, due to underlying multiple myeloma. It is important to emphasise that due to the absence of the typical findings on routine pre-operative investigations suggestive of cardiac amyloidosis in this patient, cardiac surgeons should be aware that symptoms inconsistent with angiography findings should prompt consideration of amyloidosis. Diagnostic tools including cardiac MRI and ultimately endomyocardial biopsy could then facilitate earlier recognition of this enigmatic disease process. PMID- 23086614 TI - Clinical characteristics of children with cochlear nerve dysplasias. AB - OBJECTIVES/HYPOTHESIS: To describe the clinical and audiometric characteristics of children with cochlear nerve dysplasia (CND). STUDY DESIGN: Retrospective chart review of clinical database of children with inner ear anomalies treated at a tertiary care children's hospital. METHODS: Institutional review board-approved retrospective review from June 30, 2006, to July 1, 2011; 18 children were identified with magnetic resonance imaging (MRI) evidence of CND defined as a cochlear nerve 50% smaller than the adjacent facial nerve. RESULTS: Of the 18 patients, nine were girls and nine were boys. Average age at time of MRI diagnosis of CND was 4.6 years. Twelve children had cochlear nerve aplasia, and six had hypoplasia. Three were affected bilaterally: two with aplasia and one with hypoplasia. Unilateral dysplasia was found in 15 children; of these, 60% occurred on the left side. Other inner ear anomalies were found in 50%, including all patients with bilateral CND. Severe-to-profound hearing loss was found in the involved ear(s) in 14 of 18 patients, including all bilateral patients. Of the 18 patients tested, 13 (72%) had an audiometric profile of auditory neuropathy/dys synchrony syndrome (auditory neuropathy spectrum disorder [ANSD]). Comorbid conditions were present in 56% of patients. Two patients were syndromic. Family history of hearing loss was present in 11% of patients. CONCLUSIONS: Many patients with CND have ANSD, and more than half have comorbidities. Approximately half of affected patients have other inner ear anomalies in the involved ears. Unilateral CND may be more common on the left side. PMID- 23086613 TI - Male fertility versus sterility, cytotype, and DNA quantitative variation in seed production in diploid and tetraploid sea lavenders (Limonium sp., Plumbaginaceae) reveal diversity in reproduction modes. AB - The genus Limonium Miller, a complex taxonomic group, comprises annuals and perennials that can produce sexual and/or asexual seeds (apomixis). In this study, we used diverse cytogenetic and cytometric approaches to analyze male sporogenesis and gametogenesis for characterizing male reproductive output on seed production in Limonium ovalifolium and Limonium multiflorum. We showed here that the first species is mostly composed of diploid cytotypes with 2n = 16 chromosomes and the latter species by tetraploid cytotypes with 2n = 32, 34, 35, 36 chromosomes and had a genome roughly twice as big as the former one. In both species, euploid and aneuploid cytotypes with large metacentric chromosomes having decondensed interstitial sites were found within and among populations, possibly involved in chromosomal reconstructions. L. ovalifolium diploids showed regular meiosis resulting in normal tetrads, while diverse chromosome pairing and segregation irregularities leading to the formation of abnormal meiotic products are found in balanced and non-balanced L. multiflorum tetraploids. Before anther dehiscence, the characteristic unicellular, bicellular, or tricellular pollen grains showing the typical Limonium micro- or macro-reticulate exine ornamentation patterns were observed in L. ovalifolium using scanning electron microscopy. Most of these grains were viable and able to produce pollen tubes in vitro. In both balanced and unbalanced L. multiflorum tetraploids, microspores only developed until the "ring-vacuolate stage" with a collapsed morphology without the typical exine patterns, pointing to a sporophytic defect. These microspores were unviable and therefore never germinated in vitro. L. ovalifolium individuals presented larger pollen grains than those of L. multiflorum, indicating that pollen size and ploidy levels are not correlated in the Limonium system. Cytohistological studies in mature seeds from both species revealed that an embryo and a residual endosperm were present in each seed. Flow cytometric seed screens using such mature seeds showed quantitative variations in seeds ploidy level. It is concluded that male function seems to play an important role in the reproduction modes of Limonium diploids and tetraploids. PMID- 23086615 TI - Hydrogen-bonded complexes between 4-alkoxystilbazoles and fluorophenols: solid state structures and liquid crystallinity. AB - 48 new hydrogen-bonded complexes have been prepared by combining 16 fluorophenols of general formula C(6)F(n)H(5-n)OH with three different alkoxystilbazoles (butyloxy-, octyloxy- and dodecyloxy-). Single-crystal X-ray structures were obtained for 10 of the 16 complexes of octyloxystilbazole from which it was found that most of the structures could be collected into one of two groups according to both the motif shown by the complex and by the solid-state packing. Because all but one crystallised in the P1 space group, meaningful comparisons could be drawn and it was observed that six structures were extremely close in nature so that significant molecular overlap was found. On this basis, doubt is cast on the significance of some of the weaker intermolecular contacts found in the solid state. 40 of the new complexes showed liquid-crystal properties and it was found that although complexes of butyloxystilbazole were all nematic, almost all of those with dodecyloxystilbazole showed a smectic A (SmA) phase. Complexes of octyloxystilbazole showed a mixture of both. Structure/property correlations showed that clearing points were independent of the pK(a) of the phenol. The most stable mesophases were found when the fluorophenol contained a fluorine at the 2 position, which was interpreted in terms of the formation of an intramolecular H???F hydrogen bond to give a six-membered ring linking the two components into a stable, coplanar conformation. The least stable mesophases were found when no such ring formation was possible and the phenol was relatively free to move. PMID- 23086616 TI - A decade of EEG Theta/Beta Ratio Research in ADHD: a meta-analysis. AB - OBJECTIVE: Many EEG studies have reported that ADHD is characterized by elevated Theta/Beta ratio (TBR). In this study we conducted a meta-analysis on the TBR in ADHD. METHOD: TBR data during Eyes Open from location Cz were analyzed from children/adolescents 6-18 years of age with and without ADHD. RESULTS: Nine studies were identified with a total of 1253 children/adolescents with and 517 without ADHD. The grand-mean effect size (ES) for the 6-13 year-olds was 0.75 and for the 6-18 year-olds was 0.62. However the test for heterogeneity remained significant; therefore these ESs are misleading and considered an overestimation. Post-hoc analysis found a decreasing difference in TBR across years, explained by an increasing TBR for the non-ADHD groups. CONCLUSION: Excessive TBR cannot be considered a reliable diagnostic measure of ADHD, however a substantial sub-group of ADHD patients do deviate on this measure and TBR has prognostic value in this sub-group, warranting its use as a prognostic measure rather than a diagnostic measure. PMID- 23086617 TI - U13C cell extract of Pichia pastoris--a powerful tool for evaluation of sample preparation in metabolomics. AB - Quantitative metabolic profiling is preceded by dedicated sample preparation protocols. These multistep procedures require detailed optimization and thorough validation. In this work, a uniformly (13)C-labeled (U(13)C) cell extract was used as a tool to evaluate the recoveries and repeatability precisions of the cell extraction and the extract treatment. A homogenous set of biological replicates (n = 15 samples of Pichia pastoris) was prepared for these fundamental experiments. A range of less than 30 intracellular metabolites, comprising amino acids, nucleotides, and organic acids were measured both in monoisotopic (12)C and U(13)C form by LC-MS/MS employing triple quadrupole MS, reversed phase chromatography, and HILIC. Recoveries of the sample preparation procedure ranging from 60 to 100% and repeatability precisions below 10% were obtained for most of the investigated metabolites using internal standardization approaches. Uncertainty budget calculations revealed that for this complex quantification task, in the optimum case, total combined uncertainty of 12% could be achieved. The optimum case would be represented by metabolites, easy to extract from yeast with high and precise recovery. In other cases the total combined uncertainty was significantly higher. PMID- 23086618 TI - Computer-assisted screening of ordered crystalline nanoporous adsorbents for separation of alkane isomers. PMID- 23086619 TI - VWF, WM, and angiogenesis: is there a link? PMID- 23086620 TI - A mismatched life in the stem cell pool. PMID- 23086621 TI - Diversifying the MHC peptide portfolio. PMID- 23086622 TI - SF3B1 and the riddle of the ring sideroblast. PMID- 23086623 TI - Bregging rights in ITP. PMID- 23086624 TI - Characteristics and outcomes of patients with V299L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. PMID- 23086625 TI - Prognostic implications of cumulative dosing in total therapy 3. PMID- 23086626 TI - Activation of neutrophil respiratory burst by fungal particles requires phosphatidylinositol 3-phosphate binding to p40(phox) in humans but not in mice. PMID- 23086627 TI - Dynamic prediction by landmarking in competing risks. AB - We propose an extension of the landmark model for ordinary survival data as a new approach to the problem of dynamic prediction in competing risks with time dependent covariates. We fix a set of landmark time points tLM within the follow up interval. For each of these landmark time points tLM , we create a landmark data set by selecting individuals at risk at tLM ; we fix the value of the time dependent covariate in each landmark data set at tLM . We assume Cox proportional hazard models for the cause-specific hazards and consider smoothing the (possibly) time-dependent effect of the covariate for the different landmark data sets. Fitting this model is possible within the standard statistical software. We illustrate the features of the landmark modelling on a real data set on bone marrow transplantation. PMID- 23086628 TI - Dispersal and noise: various modes of synchrony in ecological oscillators. AB - We use the theory of noise-induced phase synchronization to analyze the effects of dispersal on the synchronization of a pair of predator-prey systems within a fluctuating environment (Moran effect). Assuming that each isolated local population acts as a limit cycle oscillator in the deterministic limit, we use phase reduction and averaging methods to derive a Fokker-Planck equation describing the evolution of the probability density for pairwise phase differences between the oscillators. In the case of common environmental noise, the oscillators ultimately synchronize. However the approach to synchrony depends on whether or not dispersal in the absence of noise supports any stable asynchronous states. We also show how the combination of partially correlated noise with dispersal can lead to a multistable steady-state probability density. PMID- 23086629 TI - A feasibility study on reduction of the entrance-surface dose to neonates by use of a new digital mobile X-ray system. AB - We investigated the neonatal entrance-surface dose (ESD) and doses of scattered radiation emitted by a digital mobile X-ray system. The system is equipped with a novel flat-panel detector and is used in the neonatal intensive care unit. In the present study, the following three experiments were performed on frequently used X-ray-imaging condition: (1) the digital characteristics of the FPD were evaluated; (2) the ESD to a water-equivalent phantom was measured with a patient skin dosimeter (PSD); and (3) the scattered radiation around the incubator was measured with an ionization chamber survey meter. The digital characteristic curve showed that the system had excellent linearity and that the contrast characteristics were not affected by the tube voltage in the range of 50-110 kV. The ESD was 51-52 MUGy with an 8-cm-thick phantom and 33-34 MUGy with a 4.5-cm phantom, for one exposure. The doses measured around the incubator were 0.1-0.6 MUSv or below measurable limits. Use of the new device demonstrates the potential of reducing the ESD to the patient and operator. PMID- 23086630 TI - Readiness for change and job satisfaction in a case of lean management application - a comparative study. AB - OBJECTIVES: This current study investigates the effect of lean management system on work attitudes of workers of two manufacturing companies. "Lean management" is a concept of work processes and human relations that determines company's productivity and profitability. Workers of two enterprises, the first one with lean production and the second one with old mass production, were compared for their readiness for change and job satisfaction (both emotional and cognitive aspect). MATERIALS AND METHODS: The sample of 102 employees completed a battery of instruments such as: the Job Description Inventory by Neuberger and Allerbeck, the Job Affect Scale by Burke et al. and the Change-Readiness Scale by Kriegel and Brandt. RESULTS: Individuals from the lean manufacturing company were characterized by higher level of readiness for change, positive affect at work, and cognitive job satisfaction. CONCLUSIONS: In this approach the introduction of lean production positively affected company's human resource attitudes. PMID- 23086631 TI - Exposure to environmental and lifestyle factors and attention-deficit / hyperactivity disorder in children - a review of epidemiological studies. AB - Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in children. Although the mechanisms that lead to the development of ADHD remain unclear, genetic and environmental factors have been implicated. These include heavy metals and chemical exposures, nutritional and lifestyle/psychosocial factors. The aim of this review was to investigate the association between ADHD or ADHD-related symptoms and widespread environmental factors such as phthalates, bisphenol A (BPA), tobacco smoke, polycyclic aromatic hydrocarbons (PAHs), polyfluoroalkyl chemicals (PFCs) and alcohol. Medline, PubMed and Ebsco search was performed to identify the studies which analyze the association of prenatal and postnatal child exposure to environmental toxicants and lifestyle factors and ADHD or ADHD-related symptoms. The review is restricted to human studies published since 2000 in English in peer reviewed journals. Despite much research has been done on the association between environmental risk factors and ADHD or ADHD symptoms, results are not consistent. Most studies in this field, focused on exposure to tobacco smoke, found an association between that exposure and ADHD and ADHD symptoms. On the other hand, the impact of phthalates, BPA, PFCs, PAHs and alcohol is less frequently investigated and does not allow a firm conclusion regarding the association with the outcomes of interest. PMID- 23086632 TI - A new quantitative approach to measure perceived work-related stress in Italian employees. AB - OBJECTIVE: We propose a method for a reliable quantitative measure of subjectively perceived occupational stress applicable in any company to enhance occupational safety and psychosocial health, to enable precise prevention policies and intervention and to improve work quality and efficiency. MATERIALS AND METHODS: A suitable questionnaire was telephonically administered to a stratified sample of the whole Italian population of employees. Combined multivariate statistical methods, including principal component, cluster and discriminant analyses, were used to identify risk factors and to design a causal model for understanding work-related stress. RESULTS: The model explained the causal links of stress through employee perception of imbalance between job demands and resources for responding appropriately, by supplying a reliable U shaped nonlinear stress index, expressed in terms of values of human systolic arterial pressure. Low, intermediate and high values indicated demotivation (or inefficiency), well-being and distress, respectively. Costs for stress-dependent productivity shortcomings were estimated to about 3.7% of national income from employment. CONCLUSIONS: The method identified useful structured information able to supply a simple and precise interpretation of employees' well-being and stress risk. Results could be compared with estimated national benchmarks to enable targeted intervention strategies to protect the health and safety of workers, and to reduce unproductive costs for firms. PMID- 23086633 TI - Work-related health emergency cases due to hydrofluoric acid exposures reported to Texas poison centers. AB - OBJECTIVES: Hydrofluoric acid is used in a number of industries. Work-related accidents involving hydrofluoric acid can result in serious injury and death. The intent of this investigation was to describe work-related hydrofluoric acid exposures in Texas. MATERIALS AND METHODS: Work-related hydrofluoric acid exposures reported to Texas poison centers during 2000-2010 were identified. The distribution of exposures was determined for various demographic and clinical factors. RESULTS: There were 409 work-related hydrofluoric acid exposures in years 2000-2010. The number of work-related exposures declined from 69 in 2000 to 18 in 2010. The patients were 85.3% male and 96.6% age 20 years or older. The distribution of cases by route of exposure was 69.4% dermal contact, 21.0% inhalation, 12.0% ocular, and 3.7% ingestion. At the time of reporting to Texas poison centers, the patient was already at or en route to a health care facility in 71.9% of the cases and referred to a healthcare facility in 20.5% of the cases. The medical outcome was known or expected to be not serious in 51.6% of the cases. CONCLUSIONS: Hydrofluoric acid exposures reported to Texas poison centers decreased over the eleven-year period. The patients were almost all adults and primarily male. Most of the exposures occurred by dermal contact followed by inhalation. The majority of patients were managed at healthcare facilities. Slightly over half of the exposures were known or expected to not result in serious outcomes. PMID- 23086634 TI - High-energy liquid jet technology - risk assessment in practice. AB - OBJECTIVES: The contribution deals with a risk assessment in practical applications of the high-energy liquid jet technology from the point of view of the risk identification, estimation and evaluation. MATERIALS AND METHODS: Differences between three different types of workplaces are highlighted and analysed - the indoor, the outdoor and the research ones. Theoretical analyses are supported by particular application of the method for the risk assessment in the Laboratory of Liquid Jets at the VSB - Technical University of Ostrava. This laboratory is primarily oriented to research. Nevertheless, the conclusions can be used also for predominantly commercial workplaces. RESULTS: Some new considerations and evaluations concerning health and safety are presented. CONCLUSIONS: Failure Mode and Effect Analysis (FMEA) procedures were applied and their limitations in risk assessment of water jet-based technologies are explained. PMID- 23086636 TI - [Prospects for research on small molecular targeted drugs in treatment of acute myeloid leukemia]. PMID- 23086635 TI - Octabromodiphenyl ether - porphyrogenicity after repeated administration to rats. AB - OBJECTIVES: Octabromodiphenyl ether (OctaBDE) is a flame retardant which has been withdrawn from common use due to its negative effect on the environment. The literature data regarding its toxicity addresses its effect on liver function, the endocrine and reproductive systems, as well as its developmental toxicology aspects. The aim of this study was to investigate the effect of repeated administration of OctaBDE on heme biosynthesis in rats. MATERIALS AND METHODS: The study was performed on female Wistar rats. OctaBDE was administered intragastrically at four different doses (2, 8, 40 or 200 mg/kg/day) for 7, 14, 21 or 28 days. The following measures of heme synthesis disturbance were used: urinary excretion of porphyrins, liver concentration of porphyrins, the activity of delta-aminolevulinate synthase (ALA-S) and delta-aminolevulinate dehydratase (ALA-D) in the liver. RESULTS: After 28 days of exposure, lower ALA-S and ALA-D activity was observed in the liver. Additionally, increased concentrations of high carboxylated porphyrins (octa- and heptacarboxyporphyrins) were found in the liver: from 2- to 10-fold after the 2 mg/kg/day doses and from 4- to 14-fold after the 8-200 mg/kg/day doses. The porphyrogenic effect of OctaBDE was also evidenced by augmented, dose-dependent and exposure time-dependent, concentrations of total porphyrins in urine (2-7.5-fold increase) and their urinary excretion (2-9-fold increase). Tetracarboxyporphyrins predominated in the urine; their concentrations increased 2.5-10 fold. CONCLUSIONS: The study revealed that repeated exposure to OctaBDE affects heme biosynthesis and the levels of porphyrins. The lowest effective level which induced changes in porphyrin concentration was 2 mg/kg/day. PMID- 23086637 TI - [Synergistic effect of histone deacetylase inhibitor suberoylanilide hydroxamic acid with imatinib on K562 cells]. AB - OBJECTIVE: To investigate synergistically killing effect of histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) combined with imatinib on human chronic myeloid leukemia (CML) cell line. METHODS: K562 cells were co treated with SAHA and imatinib. Cell growth was measured by MTT assay. Apoptosis was determined using Hoechst staining apoptosis detection kit and flow cytometric analysis. Activation of Caspase pathway, expression of Bcr-Abl and its downstream target genes, and expression of anti-apoptotic proteins were detected by Western blot. RESULTS: SAHA synergized the cytotoxicity of imatinib against leukemia K562 cells, concomitantly with increased apoptosis and enhanced activation of Caspase 3, -8 and PRAP. The combination therapy resulted in significantly lower levels of Bcr-Abl,phosphorylated Bcr-Abl compared to treatment with either SAHA or imatinib alone. Furthermore,the co-treatment resulted in down-regulation of anti-apoptotic protein Mcl-1 expression. Also,marked down-regulated expression of JAK2,STAT5,and phosphorylated STAT5 was detected in the combination therapy. CONCLUSION: Combining HDAC inhibitor SAHA with imatinib can kill CML cells synergistically by inhibiting cell growth and inducing apoptosis, which is associated with activation of Caspase pathway and regulation of anti-apoptotic proteins. PMID- 23086638 TI - [Killing effect of aurora kinase inhibitor ENMD-2076 on acute myelogenous leukemia cells]. AB - OBJECTIVE: To investigate the effect of aurora kinase inhibitor ENMD-2076 on human acute myelogenous leukemia (AML) cell lines. METHODS: AML THP-1 and Kasumi 1 cells were treated with ENMD-2076 for 24 h and 48 h,respectively. Cell growth was measured by MTT assay. Apoptosis was determined using Hoechst staining apoptosis detection kit. Activation of Caspase pathway and expression of apoptosis regulator proteins were detected by Western blot. RESULTS: ENMD-2076 significantly induced growth arrest and apoptosis in THP-1 and Kasumi-1 cells. Enhanced apoptosis was observed in ENMD-2076 group evidenced by strong activation of Caspase-9,Caspase-3 and PARP. Furthermore,the ENMD-2076 treatment resulted in down-regulation of anti-apoptotic protein Mcl-1 expression. Also,up-regulated expression of pro-apoptotic protein Bak,Bad and Bax was detected after ENMD-2076 treatment. CONCLUSION: ENMD-2076 can kill effectively AML cells by inhibiting cell growth and inducing apoptosis,which is associated with activation of Caspase pathway and regulation of pro-apoptotic and anti-apoptotic proteins. PMID- 23086639 TI - [Cytotoxicity of homoharringtonine on leukemic stem-like cells in AML cell line KG-1]. AB - OBJECTIVE: To investigate the effect of homoharringtonine (HHT) on leukemic stem like cells (LSC) in human acute myeloid leukemia (AML) cell lines. METHODS: The phenotypes of AML cell lines U937,Kasumi-1,and KG-1 cells were analyzed by flow cytometry (FACS). The effect of HHT on leukemia stem-like cells with immunophenotype of CD34(+)CD38(-)CD96(+) was detected with FACS. Cell growth was measured by MTT assay. Activation of Caspase pathway and expression of apoptosis related regulator proteins were examined by Western blotting. RESULTS: FACS demonstrated that the 69% of KG-1 cells expressed LSC phenotype CD34(+)CD38( )CD96(+), while 26.7% on Kasumi-1 cells expressed this marker. In contrast,U937 cells showed CD96 negative. HHT significantly inhibited cell growth of KG-1 cells with an IC(50) of 16.9 ng/ml at 48 h. The ratio of CD34(+)CD38(-)CD96(+) cells decreased from 63.6% to 17.1% after HHT treatment. Enhanced apoptosis was demonstrated in HHT group evidenced by strong activation of Caspase-9,Caspase-3 and PARP.HHT treatment resulted in down-regulation of expression of anti apoptotic protein BCL-2 and phosphorylated-Akt. CONCLUSION: HHT can effectively kill the leukemic stem-like cells in human AML cell line KG1 by inhibiting cell growth and inducing apoptosis which is associated with activation of Caspase pathway and down-regulation of anti-apoptotic proteins and phosphorylated-Akt. PMID- 23086640 TI - [Antitumor activity of histone deacetylase inhibitor suberic bishydroxamate on acute myeloid leukemia cell lines]. AB - OBJECTIVE: To investigate the effect of histone deacetylase inhibitor suberic bishydroxamate (SBHA) on human acute myeloid leukemia (AML) cell lines. METHODS: AML U937, KG-1 and Kasumi-1 cells were treated with SBHA. Cell growth was measured by MTT assay. Apoptosis was determined using flow cytometry. Activation of Caspase pathway and expression of apoptosis regulator proteins were detected by Western blot. RESULTS: SBHA significantly induced growth arrest and apoptosis in U937, KG-1 and Kasumi-1 cells. Enhanced apoptosis was observed in SHBA group evidenced by strong activation of Caspase-9, Caspase-8 and Caspase-3. SHBA treatment resulted in down-regulation of anti-apoptotic protein Bcl-2 and Bcl-xl expression; down-regulated expression of antiapoptotic proteins survivin, XIAP and cIAP was also detected after SBHA treatment. CONCLUSION: SBHA can effectively kill AML cells by inhibiting cell growth and inducing apoptosis, which is associated with the activation of Caspase pathway and regulation of apoptotic related proteins. PMID- 23086642 TI - [Establishment of a transgenic cell line with stable expression of human CD14]. AB - OBJECTIVE: To establish a transgenic cell line with stable expression of CD14. METHODS: Total RNA extracted from peripheral blood mononuclear cells was treated with RNAase-free DNAase, the human CD14 gene was cloned and sequenced through the RT-PCR, T-A clone techniques and ABI PRISM377 machine. Eukaryotic expression vector pcDNA3.1(+)/CD14 was constructed by cleaving with double restriction endonucleases EcoR I/Xba I and ligating with T4 ligase. The human cervical cancer cell line Hela was transfected with the positive recombinant plasmid pcDNA3.1(+)/CD14 using superfect transfection reagent. Positive clones were selected by G418 at a concentration of 0.5 MUg/MUl and the expression of human CD14 on the transfected Hela cells was confirmed by quantitative PCR and immunofluorescent assay. RESULTS: There was significantly difference om expression of CD14 mRNA between the blank pcDNA3.1(+) transfected cells and pcDNA3.1(+)/CD14 transfected cells (P<0.01). The fluorescence was significantly stronger on the stable cell line Hela-CD14 than that on the transiently transfected Hela cells,and no visible fluorescence was observed in blank vector transfected cells. CONCLUSION: The transfectant cell line Hela-CD14 with stable expression of human CD14 has been successfully established, which can be used to study human CD14 molecular and CD14-associated monocyte/macrophage cell diseases. PMID- 23086641 TI - [Effect of Evn-50 on cell growth and apoptosis in tamoxifen-resistance human breast cancer cell line MCF-7/TAM-R]. AB - OBJECTIVE: To investigate the effect of Evn-50 extracted from Vitex negundo on human breast cancer cell line MCF-7 and MCF-7/TAM-R cells in vitro. METHODS: MCF 7 and tamoxifen-resistant MCF-7/TAM-R cells were treated with Evn-50,tamoxifen or combination of Evn-50 and tamoxifen. Cell proliferation inhibition rates were determined by MTT assay. The apoptosis rate and the change of cell cycle were detected by PI staining flow cytometry. Protein expression of phospho-MAPK 44/42 (Thr202/Tyr204),MAPK P44/42, phospho-AKT (Ser473) and AKT were detected with Western blotting. RESULTS: The viability of MCF-7 cells was decreased in combination group [(28.65 +/-11.43)%] and Evn-50 group [(53.02 +/-15.14)%] compared with TAM group (P<0.01). The cell viability of MCF-7/TAM-R in combination group [(42.11 +/-14.30)%] was significantly lower than that in TAM group [(92.18 +/-13.16)%] (P<0.01). The cell apoptosis rate was dependent on the time of treatment in all groups,the effects on apoptosis and G2/M phase cells were most prominent at 72 h (P<0.01). Western blotting revealed that protein levels of phosphorylated AKT and p-MAPK44/42 decreased,while the expression of total AKT and MAPK44/42 was stable. In MCF-7/TAM-R cells,the expression of phosphorylation of AKT and MAPK44/42 protein was not changed in Evn-50 or TAM alone group,but significantly inhibited in the combination group at 72 h. CONCLUSION: Evn-50 can inhibit cell growth and induce apoptosis in MCF-7 and MCF 7/TAM-R cells,it can reverse tamoxifen-resistance of MCF-7/TAM-R cells.The mechanisms may be related to the down-regulation of phosphorylated ERK1/2 in MAPK signal pathway and phosphorylated AKT in AKT signal pathway. PMID- 23086643 TI - [A case-control study on risk factors of female breast cancer in Zhejiang province]. AB - OBJECTIVE: To investigate the risk factors on female breast cancer in Zhejiang province. METHODS: A case-control study was conducted in 200 cases of female breast cancer with histopathological diagnosis and 200 matched controls from Zhejiang province. RESULTS: Univariate conditional logistic regression showed that family history of malignant tumor and breast cancer, housing decoration in last 10 years, mammary hyperplasia, adverse life events, bra with steel rings, sleeping with bra, high fat and pickle intake, poor sleep were positively related to breast cancer; whereas environmental friendly decoration materials, long decoration time interval, workplace condition, more lactation and parity, high fruits intake, sufficient sleep were negatively related to breast cancer. Multivariate conditional logistic regression analysis showed that the risk factors included family history of other tumors [odds ratio (OR)= 1.571,95% confidence interval(CI):1.029-2.396],mammary hyperplasia (OR=3.066,95%CI:1.834 5.126), job-related life events (OR=4.575,95%CI:1.690-12.390),the death of a loved one (OR=2.555,95%CI:1.475-4.424), wearing bra at night (OR=1.902,95%CI:1.177-3.072),high fat intake (OR=2.709,95%CI:1.546-4.749) and salted food (OR=2.460,95%CI:1.300-4.653). Factors as environmental friendly decoration materials (OR=0.517,95%CI:0.339-0.789),workplaces condition (OR=0.430,95%CI:0.243-0.762),more lactation (OR=0.109,95%CI:0.013-0.896),enough sleep (OR=0.424,95%CI:0.205-0.880) were protective factors. CONCLUSION: Hereditary,psychological factors,lifestyle,environment and diet related factors are significantly associated with risk of breast cancer. PMID- 23086644 TI - [Construction of pBIFC-VN173-CXCR4 and pBIFC-VC155-NT21MP eukaryotic expression plasmids and their interaction in living cells]. AB - OBJECTIVE: To construct pBIFC-VN173-CXCR4 and pBIFC-VC155-NT21MP eukaryotic expression plasmids and to investigate the interaction of chemokine receptor 4 (CXCR4) and viral macrophage inflammatory protein-II(vMIP-II) N terminal 21 peptides (NT21MP) in living cells. METHODS: DNA fragment encoding NT21MP was chemically synthesized and inserted into BiFC eukaryotic expression vector pBIFC VC155. The full length of CXCR4 DNA fragment was amplified by RT-PCR from SKBR (3) cells and inserted into BiFC eukaryotic expression plasmid pBIFC-VN173. Two recombinant vectors were identified by restriction enzyme digestion and DNA sequencing. The recombinant vectors were cotransfected into Africa green monkey kidney fibroblast COS-7 cells by using Lipofectamine 2000. The interaction of NT21MP and CXCR4 was detected by bimolecular fluorescence complementation (BiFC) assay. RESULTS: The restriction enzyme digestion and DNA sequences and open read frames of two vectors were consistent with experiment design. The BiFC plasmids were successfully cotransfected into the target cells and expressed. The strong BiFC signals were detected in pBIFC-VN173-CXCR4 and pBIFC-VC155-NT21MP cotransfected cells and the fluorescence signal was located in the cytoplasm. CONCLUSION: The eukaryotic expression plasmids for BiFC assay are successfully constructed. The interaction of NT21MP and CXCR4 in living cells can be detected by using this technology. PMID- 23086645 TI - [Effects of snakegourd root polysaccharide on apoptosis of MCF-7 cells]. AB - OBJECTIVE: To investigate the effects of snakegourd root polysaccharide on apoptosis of human breast cancer cells (MCF-7 cells). METHODS: Colorimetric MTT assay was used to measure the inhibition of snakegourd root polysaccharide on MCF 7 cells. The morphological changes of MCF-7 cells were observed by fluorescence microscope after DAPI staining and transmission electron microscope. The apoptosis of MCF-7 cells was examined by DNA agarose gel electrophoresis analysis of DNA fragmentation amd flow cytometry. The activity of Caspase-3 and Caspase-8 was detected by colorimetric assay. RESULTS: Polysaccharide of snakegourd root significantly inhibited MCF-7 cells in a dose-and time-dependent manner. The nuclear condensation and marginalization were observed by DAPI staining and transmission electron microscope. The characteristic ladder of apoptosis in DNA electrophoresis was detected in MCF-7 cells treated with 10.0 MUmol/L polysaccharide of snakegourd root at d 2. The activities of Caspase-3 and Caspase 8 were increased in a time-dependent manner. The rates of apoptosis in MCF-7 cells were (5.2 +/-1.3)%, (13.1 +/-4.7)%, (27.6 +/-6.8)% and (43.8 +/-9.8)% treated with 1.0,5.0,10.0 and 20.0 MUmol/L snakegourd root polysaccharide at d 2,respectively. The maximal activities of intracellular Caspase-3 and Caspase-8 were (2.32 +/-0.12)U/MUg and (1.92 +/-0.11)U/MUg at d 2 and d 1, respectively when MCF-7 cells were treated with 10.0 MUmol/L. CONCLUSION: The polysaccharide of snakegourd root can induce the apoptosis of MCF-7 cells,which is associated with the activation of intracellular Caspase-3 and Caspase-8. PMID- 23086646 TI - [Diagnosis value of serum NKX2-1 for primary lung cancer]. AB - OBJECTIVE: To evaluate serum Nkx2-1 (NKX homeobox-1) levels in diagnosis of primary lung cancer. METHODS: The serum NKX2-1 and CEA (carcinoma embryonic antigen) levels were measured in 61 patients with primary lung cancer admitted from May 2009 to December 2010 and 49 healthy individuals served as controls. The receiver operating characteristic curve (ROC) of NKX2-1 in diagnosis for primary lung cancer was analyzed. The value of serum NKX2-1 in diagnosing primary lung cancer was compared with that of CEA by X(2) test and Kappa test. RESULTS: The serum Nkx2-1 levels in lung cancer were significantly higher than those in controls [(1.4206 +/-0.1257)ng/ml compared with (0.7646 +/-0.0734)ng/ml,P<0.01]. ROC analysis showed the area under the curve of serum NKX2-1 was 0.859. The Kappa value of NKX2-1 was higher than that of CEA (0.586 compared with 0.396,P<0.05). Combination of serum NKX2-1 with CEA improved the Kappa value to 0.704, and also had high sensitivity (83.6%) and specificity (87.0%) for diagnosis of primary lung cancer. CONCLUSION: Serum NKX2-1 protein can be used as a marker for diagnosis of lung cancer, the combination of NKX2-1 with CEA may further improve the diagnostic value. PMID- 23086647 TI - [Expression of RRM1 and ERCC1 genes in tumor tissues and peripheral blood lymphocytes of advanced non-small cell lung cancer]. AB - OBJECTIVE: To investigate the expression of RRM1 and ERCC1 genes in tumor tissues and peripheral blood lymphocytes of advanced non-small cell lung cancer (NSCLC). METHODS: Tissue and peripheral blood samples were collected from 49 advanced NSCLC patients treated with gemcitabine plus carboplatin. The expressions of RRM1 and ERCC1 mRNA in tumor tissue and peripheral lymphocytes were detected by real time fluorescent quantitative PCR. The relationship of gene expression with clinical characteristics,chemotherapy response and prognosis was analyzed. RESULTS: The RRM1 expression in tumor tissues was positively correlated with that in peripheral blood lymphocytes,while no significant correlation was observed between ERCC1 expression in tumor tissues and that in peripheral blood (rs=0.332 and 0.258; P=0.020 and 0.073, respectively). The expression of RRM1 and ERCC1 in tumor tissues peripheral lymphocytes was synchronous (rs=0.634 and 0.351; P<0.001 and 0.013, respectively). There was no significant correlation of gene expression with gender, age, smoking status, performance status, clinical stages and histological types of patients (P>0.05). Significant difference was found in response rate to chemotherapy (P<0.05,P<0.01,P<0.05),median survival time (P<0.05,P<0.01,P<0.05) and 1-year survival rate (P<0.01,<0.05,P<0.05) between patients with low RRM1 and ERCC1 expression levels in tumor tissues or low RRM1 expression levels in peripheral blood and those with high RRM1 and ERCC1 expression levels. The patients with low ERCC1 expression levels in tumor tissues gained higher 2-year survival rate (P<0.05). There was no correlation of the expression of ERCC1 in peripheral blood with the response to chemotherapy and prognosis (P>0.05). CONCLUSION: The expression of RRMI and ERCC1 genes in tumor tissues and RRM1 in peripheral blood lymphocytes is closely correlated with the response to chemotherapy and prognosis of patients with advanced NSCLC treated with gemcitabine plus carboplatin. PMID- 23086648 TI - [Effect of Helicobacter pylori infection on platelet activation and coagulation function in patients with acute cerebral infarction]. AB - OBJECTIVE: To investigate the effect of Helicobacter pylori (Hp) on platelet activation and coagulation function in patients with acute cerebral infarction. METHODS: Sixty-six patients with acute cerebral infarction and 50 health individuals were enrolled in the study. Hp antibody,expression of CD62p on platelets and clotting indexes were measured and compared between two groups. RESULTS: The positive rate of Hp-IgG and Hp-CagA in cerebral infarction patients were higher than that in controls (P<0.05). The positive rate of CD62p in patients with positive Hp-IgG and Hp-CagA was significantly higher than that in negative patients and also controls (P<0.05). The APTT and TT were lower and FIB was higher in patients with positive Hp antibody than those in patients with negative Hp antibody (P<0.05),but there was no difference in PT,PTR and INR (P>0.05). CONCLUSION: Hp infection can activate platelets and affect coagulation function,which may be involved in the development of cerebral infarction. PMID- 23086649 TI - [Sevoflurane preconditioning produces delayed cardioprotection effect through up regulation of inducible nitric oxide synthase in rats]. AB - OBJECTIVE: To investigate whether inhaled sevoflurane is capable of producing delayed cardioprotection effect in rats and its underlying mechanisms. METHODS: Male Sprague-Dawley rats inhaled 1.0 minimum alveolar concentration (MAC) sevoflurane, 1.5 MAC sevoflurane,or O(2) for 1 h. After 24 h and 48 h the left coronary artery of rats was occluded for 30 min,followed by 120 min of reperfusion. Hemodynamics was continuously recorded and myocardial infarct size was determined by Evans blue and triphenyltetrazolium chloride staining. The expression of nitric oxide synthase (NOS) was assessed by immunoblotting. RESULTS: 1.0 MAC sevoflurane and 1.5 MAC sevoflurane improved cardiac pump function after reperfusion and reduced myocardial infarct size with the increased iNOS expression (P<0.05). However,the expression of eNOS and p-eNOS was not affected (P>0.05). A selective iNOS inhibitor 1400 W abolished the cardioprotection effect induced by inhalation of 1.0 MAC sevoflurane for 24 h. CONCLUSION: Sevoflurane produces delayed cardioprotection through the up regulation of iNOS expression. PMID- 23086650 TI - [Effects of hydrogen sulfide preconditioning on myocardial ischemia reperfusion injury in rats]. AB - OBJECTIVE: To investigate the effects of hydrogen sulfide preconditioning on myocardial ischemia reperfusion injury in rats. METHODS: Sprague-Dawley male rats were divided into 4 groups with 10 in each group: in S group rats received sham operation; in IR group rats were given with NS (1.0 ml/kg iv) 24 h before ischemia; in H group rats were treated with NaHS (0.05 mg/kg iv) 24 h before ischemia; and in D group, NaHS-treated rats received 5-hydroxydecanoate (5-HD) 15 min before ischemia. Rats in IR group,H group and D group were subjected to ischemia by occlusion of coronary artery for 30 min followed by 2 h of reperfusion. At the end of the reperfusion,myocardial infarct size was measured. SAM-s was measured by Western blotting. Plasma SOD activity and MDA were determined at the end of reperfusion. RESULTS: The infarct size was significantly lesser in H group (25.40 % +/- 3.54%) than that in IR group (38.27% +/ 5.64%,P<0.05). The SAM-s protein expression in myocardium was significantly lower in H group than that in IR group. The plasma MDA content was significantly lower and SOD activity was higher in H group than those in IR group,but there was no difference between IR group and D group. CONCLUSION: The hydrogen sulfide preconditioning attenuates myocardial IR injury possibly through down-regulating SAM-s expression,reducing the production of oxygen free radicals and enhancing anti-oxidize effect in rats. PMID- 23086651 TI - [Corbrin shugan capsule for treatment of alcoholic hepatic fibrosis in rats]. AB - OBJECTIVE: To investigate the therapeutic effect of Corbrin shugan capsule for treatment of alcoholic hepatic fibrosis in rats. METHODS: The rat model of alcoholic hepatic fibrosis was induced by intragastric administration of alcohol repeatedly. The serum procollagen III (PC III), laminin (LN) and tissue inhibitors of metalloproteinase-1 (TIMP-1) levels were measured with ELISA, and the content of hydroxyproline (Hyp) in liver tissue were determined with colorimetric method. Collagen deposition in liver tissue was observed with Masson's staining, and the fibrosis area was measured with digital medical image analysis system (Motic Med 6.0). RESULTS: Compared with the model control group, the serum TIMP-1 and LN levels and hepatic fibrosis area in liver tissue significantly decreased in Corbrin shugan capsule groups with doses of 0.09,0.27 and 0.45 g*kg(-1), and the serum PC III and the Hyp contents in liver tissue also decreased of Corbrin shugan capsule groups with doses of 0.27 and 0.45g*kg(-1). CONCLUSION: Corbrin shugan capsule can decrease serum PC III, TIMP-1 and LN levels and Hyp levels in liver tissue and hepatic fibrosis area in rats, indicating it may have therapeutic effect on alcoholic hepatic fibrosis. PMID- 23086652 TI - [Extraction and purification of acidic polysaccharide from Moerella iridescens]. AB - OBJECTIVE: To optimize extraction and purification methods of acidic polysaccharide from Moerella iridescens (MIAP). METHODS: With alkali extraction process and orthogonal experiment,the time consumption,temperature,pH value of the solution and alcohol concentration during the extraction were optimized. The crude products were deprived of protein,pigment and ion,then were purified with DEAE-cellulose ion-exchange chromatography and verified with Sephadex G-100 and cellulose acetate membrane electrophoresis,and examined with infrared spectrum. RESULTS: The optimized extraction conditions were as follows: extraction time 6 h,extraction temperature 70 degree,the solution pH 8.0 and the concentration of alcohol precipitation 70%. Intuitive features showed that the MIAP was pure white crystalline granular with slight dark brown color. The purification results demonstrated that the target MIAP was eluted and identified as a homogeneous components by DEAE-cellulose ion exchange column,Sephadex G-100 and cellulose acetate membrane electrophoresis. Infrared spectral scanning suggested that MIAP was alpha-D-type terminated glucopyranose. Intuitive features showed that MIAP was soft and cottony white. CONCLUSION: The extraction process with orthogonal test has been optimized and the acidic polysaccharide from Moerella iridescens is successfully isolated. PMID- 23086653 TI - [Research advances on mechanisms of chemoresistance in acute myeloid leukemia]. AB - Acute myeloid leukemia (AML) is a common type of hematopoietic malignancies seriously threatening human life. Resistance to chemotherapy is one of the main reasons for recurrence and refractoriness of acute myeloid leukemia. The mechanisms of chemoresistance are complex. This article reviews the mechanisms of chemoresistance in acute myeloid leukemia,the current research advances and the possible approach for reverse of drug resistance. PMID- 23086654 TI - [Research progress of protein tyrosine phosphatase SHP-2]. AB - The Src homology-2 domain-containing phosphatase SHP-2 encoded by PTPN11 is an essential component in several signaling pathways.Different types of mutation in SHP-2 have been confirmed in several types of leukemia and solid tumors. Elucidation of the events underlying Shp2-evoked transformation may provide new insights into the novel targets for anti-cancer therapy. PMID- 23086655 TI - [Ubiquitination of recombinant adeno-associated viral vector and its application]. AB - Recombinant adeno-associated virus (rAAV) has been widely used as vector for gene therapy. However, the effectiveness of gene therapy based on rAAV needs to be further improved. Enhancement of the transduction efficiency is one of the most important fields for rAAV-based gene therapy. Recent results have showed that the ubiquitin-proteasome system plays an important role in the trafficking of rAAV vector in cytoplasm, and regulation of its function may significantly improve the transduction efficiency of rAAV vector in various types of cells and tissues. PMID- 23086656 TI - Antinociceptive effects of radon inhalation on formalin-induced inflammatory pain in mice. AB - Radon therapy is clinically useful for the treatment of inflammatory diseases. The mechanisms of pain relief remain to be fully elucidated. In this study, we investigated the antinociceptive effects of radon inhalation in a mouse model of formalin-induced inflammatory pain. Immediately, after radon inhalation at a concentration of background level (ca. 19 Bq/m(3)), 1,000 or 2,000 Bq/m(3) for 24 h, 1.35 % formalin (0.5 % formaldehyde in saline, 20 MUl) was subcutaneously injected into the hind paw of mice, and we measured licking response time. Radon inhalation inhibited the second phase of response in formalin test. Formalin administration induced nociception and increased tumor necrosis factor alpha (TNF alpha) and nitric oxide (NO) levels in serum and leukocyte migration in paws. Concurrently, formalin injection decreased antioxidative functions. Radon inhalation produced antinociceptive effects, i.e., lowered serum TNF-alpha and NO levels, and restored antioxidative functions. The results showed that radon inhalation inhibited formalin-induced inflammatory pain. PMID- 23086657 TI - Retinol suppresses the activation of Toll-like receptors in MyD88- and STAT1 independent manners. AB - Dysregulation of Toll-like receptor (TLR) activation is well known to be linked to development and aggravation of inflammatory diseases and immune disorders. Retinol is reported to participate in regulation of immune responses. However, it has not been fully understood how retinol regulates TLR activation in macrophages. Our results showed that retinol suppressed the expression of various inflammatory cytokines in bone marrow-derived macrophages stimulated with ligands of TLR2, TLR3, or TLR4. These demonstrate that inhibitory effect of retinol is not limited to a single TLR. Inhibitory effect of retinol on lipopolysaccharide induced target gene expression was still observed in myeloid differentiation primary-response protein 88 (MyD88)- or signal transducer and activator of transcription 1 (STAT1)-deficient macrophages, indicating that MyD88 and STAT1 are dispensable for retinol-mediated blockade of TLRs. Together, the results demonstrate that retinol suppresses the activation of TLRs in macrophages resulting in downregulation of inflammatory gene expression and further suggest that beneficial effect of retinol is mediated through regulation of TLR-mediated inflammatory responses. PMID- 23086658 TI - Brief communication: the effects of disuse on the mechanical properties of bone: what unloading tells us about the adaptive nature of skeletal tissue. AB - The intricate link between load environment and skeletal health is exemplified by the severe osteopenia that accompanies prolonged periods of immobilization, frequently referred to as disuse osteoporosis. Investigating the effects disuse has on the structural properties of bone provides a unique opportunity to better understand how mechanical loads influence the adaptation and maintenance of skeletal tissue. Here, we report results from an examination of multiple indicators of bone metabolism (e.g., mean osteon density, mean osteon size, bone mass, and bone area distribution) within the major long bones of individuals with distinct activity level differences. Results are based on a sample comprising two subjects that suffered from long-term quadriplegia and 28 individuals of comparable age that had full limb mobility. Although limited in sample size, our findings suggest bones associated with long-term disuse have lower osteon densities and larger osteon areas compared to individuals of normal mobility, reflecting dramatically lower remodeling rates potentially related to reduced strain levels. Moreover, immobilized skeletal elements demonstrate a reduced percentage of cortical area present resulting from endosteal resorption. Differences between mobility groups in the percentage of cortical area present and bone distribution of all skeletal elements, suggests bone modeling activity is negligible in the unloaded adult skeleton. Additional histomorphometric comparisons reveal potential intraskeletal differences in bone turnover rates suggesting remodeling rates are highest within the humeri and femora. Addition of more immobilized individuals in the future will allow for quantitative statistical analyses and greater consideration of human variation within and between individuals. PMID- 23086659 TI - Dual lag screw cephalomedullary nail versus the classic sliding hip screw for the stabilization of intertrochanteric fractures. A prospective randomized study. AB - This study is a randomized prospective study comparing two fracture fixation implants, the extramedullary sliding hip screw (SHS) and the dual lag screw cephalomedullary nail, in the treatment of intertrochanteric femoral fractures in the elderly. One hundred and sixty-five patients with low-energy intertrochanteric fractures, classified as AO/OTA 31A, were prospectively included during a 2-year period (2005-2006). Patients were randomized into two groups: group A included 79 hip fractures managed with sliding hip screws and group B included 86 fractures treated with cephalomedullary nails. Delay to surgery, duration of surgery, time of fluoroscopy, total hospital stay, implant related complications, transfusion requirements, re-operation details, functional recovery, and mortality were recorded. The mean follow-up was 36 months (24-56 months). The mean surgical time was statistically significantly shorter and fluoroscopy time longer for the group B. No intraoperative femoral shaft fractures occurred. There was no statistically significant difference in the functional recovery score, reoperation, and mortality rates between the 2 groups. A new type of complication, the so-called Z-effect phenomenon, was noticed in the cephalomedullary nail group. There are no statistically significant differences between the two techniques in terms of type and rate of complications, functional outcome, reoperation and mortality rates when comparing the SHS and the cephalomedullary nail for low-energy AO/OTA 31A intertrochanteric fractures. Our data do not support recommendations for the use of one implant over the other. PMID- 23086660 TI - Tibial plateau fractures: compared outcomes between ARIF and ORIF. AB - The purpose of this study is to compare arthroscopic assisted reduction internal fixation (ARIF) treatment with open reduction internal fixation (ORIF) treatment in patients with tibial plateau fractures. We studied 100 patients with tibial plateau fractures (54 men and 46 women) examined by X-rays and CT scans, divided into 2 groups. Group A with associated meniscus tear was treated by ARIF technique, while in group B ORIF technique was used. The follow-up period ranged from 12 to 116 months. The patients were evaluated both clinically and radiologically according to the Rasmussen and HSS (The Hospital for Special Surgery knee-rating) scores. In group A, the average Rasmussen clinical score is 27.62 +/- 2.60 (range, 19-30), while in group B is 26.81 +/- 2.65 (range, 21-30). HSS score in group A was 76.36 +/- 14.19 (range, 38-91) as the average clinical result, while in group B was 73.12 +/- 14.55 (range, 45-91). According to Rasmussen radiological results, the average score for group A was 16.56 +/- 2.66 (range, 8-18), while in group B was 15.88 +/- 2.71 (range, 10-18). Sixty-nine of 100 patients in our study had associated intra-articular lesions. We had 5 early complications and 36 late complications. The study suggests that there are no differences between ARIF and ORIF treatment in Schatzker type I fractures. ARIF technique may increase the clinical outcome in Schatzker type II-III-IV fractures. In Schatzker type V and VI fractures, ARIF and ORIF techniques have both poor medium- and long-term results but ARIF treatment, when indicated, is the best choice for the lower rate of infections. PMID- 23086661 TI - Driving and arrhythmia: a review of scientific basis for international guidelines. AB - In patients with arrhythmias, the most feared complication while driving is of driver incapacity resulting in a road traffic accident. Patients with implantable cardioverter-defibrillators (ICDs) may suffer incapacity as a result of device therapy itself. The aim of this review article was to examine the types of arrhythmia that occur while driving, the impact of arrhythmia on driving as well as evidence to support that driving itself can precipitate arrhythmias. We will also review the postulated mechanisms by which driving can precipitate arrhythmias. Finally, we will compare guidelines from the USA, Europe, and UK in fitness to drive in patients with arrhythmias and ICDs. PMID- 23086662 TI - Endoscopic cold incision, balloon dilation, mitomycin C application, and steroid injection for adult laryngotracheal stenosis. AB - OBJECTIVES/HYPOTHESIS: To describe the presentation, stenosis characteristics, etiological differences, and outcomes of adult laryngotracheal stenosis treated with endoscopic cold incision, balloon dilation, topical mitomycin C application, and steroid injection. STUDY DESIGN: Retrospective chart review. METHODS: Demographic and clinical data were extracted for patients treated between March 2000 and December 2010. Prolonged intubation and idiopathic patient data were utilized for comparative analysis. RESULTS: Eighty patients (65 females; 15 males; 220 procedures; 2.9 years mean follow-up) presented with dyspnea (81%) and/or exercise intolerance (40%). Most commonly, etiologies were idiopathic (53 of 80; 66%) or prolonged intubation (14 of 80; 18%). Mean procedures per patient and interval between procedures were 2.8 procedures and 405 days, respectively. Mean stenosis length and distance from the caudal phonating edge of the true vocal folds were 9 mm and 19 mm. Complication, tracheotomy, and open-procedure rates were 1.8%, 1.4%, and 10.0%, respectively. Patients with more than two procedures demonstrated a mean 4-mm reduction in stenosis length and a 2-mm cephalad progression of stenosis over time. More caudal stenoses required more frequent procedures. Procedures were less frequent as more procedures were performed. Stenosis characteristics, interval between procedures, and total procedures were similar between idiopathic patients with or without intubation histories, but different between idiopathic and prolonged intubation patients. CONCLUSIONS: This procedure was shown to be a viable option in adult laryngotracheal stenosis. Repeat dilation was likely, but was performed without adversely affecting stenosis characteristics. Stenoses farther from the vocal folds required procedures more frequently. Idiopathic patients with a history of brief, elective intubation had stenosis characteristics and responses to therapy similar to idiopathic patients without an intubation history. Both idiopathic groups together demonstrated stenosis characteristics and responses to therapy dissimilar to patients with a history of prolonged intubation. PMID- 23086663 TI - Triflumizole is an obesogen in mice that acts through peroxisome proliferator activated receptor gamma (PPARgamma). AB - BACKGROUND: Triflumizole (TFZ) is an imidazole fungicide used on many food and ornamental crops. TFZ is not thought to be particularly toxic or carcinogenic, but little is known about its effect on development. TFZ is identified as a peroxisome proliferator activated receptor gamma (PPARgamma) activator in ToxCast. Because PPARgamma is a master regulator of adipogenesis, we hypothesized that TFZ would activate PPARgamma, thereby inducing adipogenesis and weight gain in vivo. OBJECTIVES: We sought to test the ability of TFZ to activate PPARgamma and promote adipogenesis in vitro and in vivo. METHODS: We used transient transfection to test the ability of TFZ to activate PPARgamma, and we used 3T3-L1 preadipocytes and human multipotent mesenchymal stromal stem cells (MSCs) to study the adipogenic capacity of TFZ in culture. We treated pregnant mice with three doses of TFZ and evaluated the effects on body weight, adipose depot weight, and MSC programming in the prenatally exposed offspring. DISCUSSION: TFZ induced adipogenesis in MSCs and in mouse 3T3-L1 preadipocytes. Prenatal exposure to levels of TFZ at approximately 400-fold below the reported no observed adverse effect level increased adipose depot weight. All doses of TFZ tested increased adipogenic gene expression in MSCs while inhibiting expression of osteogenic genes. CONCLUSIONS: TFZ acts through a PPARgamma-dependent mechanism to induce adipogenic differentiation in MSCs and preadipocytes at low nanomolar concentrations. Prenatal TFZ exposure increases adipose depot weight and diverts MSC fate toward the adipocyte lineage; therefore, we conclude that TFZ is an obesogen in vivo. PMID- 23086664 TI - Efficient synthesis and first regioselective C-3 direct arylation of imidazo[1,2 b]pyrazoles. AB - Highly regioselective: An efficient synthesis of the imidazo[1,2-b]pyrazole core has been developed, and the first regioselective palladium-catalyzed direct arylation of the C-3 position is described (see scheme). Good to excellent yields were obtained for a wide range of aryl partners with electron-rich and electron poor substituents. This methodology allows rapid access to a large variety of imidazo[1,2-b]pyrazole products and could open the way to the design of new biologically active compounds. PMID- 23086665 TI - Optimization of a refolding step for a therapeutic fusion protein in the quality by design (QbD) paradigm. AB - Production of biotech therapeutics in Escherichia coli involves protein expression as insoluble inclusion bodies that need to be denatured and the resulting protein refolded into the native structure. In this paper, we apply a Quality by Design approach using Design of Experiments for optimization of the refolding process for a recombinant biotech therapeutic, granulocyte colony stimulating factor. First, risk analysis was performed to identify process parameters that require experimental examination. Next, the chosen parameters were examined using a fractional factorial screening design. Based on the results of this study, parameters that have significant effect on refold yield and product quality were identified and examined using a full factorial Design of Experiments for their interactions. The final model was statistically significant and delivered a refolding yield of 77%. Further, kinetics of refolding was evaluated under optimal conditions and was found to be of first order with a rate constant of 0.132/min. Design space was established for the three parameters for a given permissible range of yield, protein concentration, and purity. The primary objective of this paper is to provide a roadmap for implementing Quality by Design for development of a protein refolding step. PMID- 23086666 TI - Rhodium(III) and hexabromobenzene-a catalyst system for the cross-dehydrogenative coupling of simple arenes and heterocycles with arenes bearing directing groups. AB - C(6)Br(six) & drugs! C(6)Br(6) can be used as the cooxidant/catalyst modifier for the [Rh(III)Cp*]-catalyzed (Cp*=C(5)Me(5)) dehydrogenative cross-coupling of benzamides with simple benzene derivatives (see scheme, DG=directing group). Similarly, heterocycles can be coupled and druglike structures formed. Mechanistic studies suggest a unique and multiple role of the Cu(OAc)(2)/C(6)Br(6) system and a nonchelate-assisted C-H activation as the rate determing step. PMID- 23086667 TI - The contribution of smoking to black-white differences in U.S. mortality. AB - Smoking has significantly impacted American mortality and remains a major cause of morbidity and mortality. No previous study has systematically examined the contribution of smoking-attributable deaths to mortality trends among blacks or to black-white mortality differences at older ages over time in the United States. In this article, we employ multiple methods and data sources to provide a comprehensive assessment of this contribution. We find that smoking has contributed to the black-white gap in life expectancy at age 50 for males, accounting for 20 % to 48 % of the gap between 1980 and 2005, but not for females. The fraction of deaths attributable to smoking at ages above 50 is greater for black males than for white males; and among men, current smoking status explains about 20 % of the black excess relative risk in all-cause mortality at ages above 50 without adjustment for socioeconomic characteristics. These findings advance our understanding of the contribution of smoking to contemporary mortality trends and differences and reinforce the need for interventions that better address the needs of all groups. PMID- 23086669 TI - The relation between habitual sleep duration and blood pressure values in Japanese male subjects. AB - BACKGROUND: Previous studies have demonstrated that sleep duration is closely associated with metabolic risk factors. However, the relationship between habitual sleep duration and blood pressure values in Japanese population has not been fully established. METHODS: We performed a cross-sectional study of 1,670 Japanese male subjects to clarify the relationship between habitual sleep duration and blood pressure values. The study subjects were divided into four groups (<6, 6-, 7-, and >=8 h) according to their nightly habitual sleep duration. RESULTS: The rate of subjects with <6, 6-, 7-, and >=8 h sleep duration was 12.0, 37.6, 38.2, and 12.2 %, respectively. Compared with the group with 7-h sleep duration (referent), the <6 and >=8 h groups had significantly greater systolic and diastolic blood pressure values. The rate of hypertensive subjects, defined as systolic blood pressure >=140 mmHg and/or diastolic blood pressure >=90 mmHg, with sleep duration of <6, 6-, 7-, and >=8 h was 13.4, 5.7, 7.5, and 13.8 %, respectively. Compared with the group with 7-h sleep duration (referent), the multivariate odds ratios (95 % confidence interval) of the groups with <6 and >=8 h for hypertension was 2.43 (1.40-4.20, P < 0.01) and 2.28 (1.31-3.95, P < 0.01), respectively, adjusted for conventional cardiovascular risk factors. CONCLUSION: The present study demonstrates that both long and short habitual sleep duration were significantly associated with high blood pressure values and hypertension occurrence in Japanese male subjects. PMID- 23086671 TI - Reviving neuroprotection using a new approach: targeting postsynaptic density-95 to arrest glutamate excitotoxicity. PMID- 23086672 TI - Registry report on kinetics of rescue antiplatelet treatment to abolish cerebral microemboli after carotid endarterectomy. AB - BACKGROUND AND PURPOSE: Cerebral microemboli signals (MES) are associated with increased risk of acute stroke syndromes. We compared the effects on cerebral microemboli after carotid endarterectomy of tirofiban with dextran-40. METHODS: We used transcranial Doppler ultrasound to study transient MES acutely after carotid endarterectomy between August 2000 and December 2010 in 128 subjects refractory to preoperative antiplatelet treatment. Antithrombotic treatment was given for MES >=50 hour(-1) (tirofiban: 40 patients [age 74 +/- 1 {SEM}, males 27, and white 38]; dextran-40: 34 patients [age 69 +/- 2, males 22, white 30]). In 54 patients with MES <50 hour(-1) (age 71 +/- 1, male 36, white 52), MES were monitored during their spontaneous resolution (controls). Data are median (interquartile range). RESULTS: The time to 50% reduction in MES (tirofiban 23 minutes [15-28]; dextran-56 [43-83]; controls 30 [22-38]; P<0.001, Kruskal-Wallis analysis) and for complete MES resolution (tirofiban 68 minutes [53-94]; dextran 113 [79-146]; controls 53 [49-68]; P<0.001, Kruskal-Wallis analysis) were shorter with tirofiban. The early cardiovascular event rate was similar with tirofiban compared with controls but increased in patients who received dextran. CONCLUSIONS: These findings suggest that transcranial Doppler-directed tirofiban therapy is more effective than dextran-40 in suppression of cerebral microemboli after carotid endarterectomy. PMID- 23086673 TI - A randomized controlled trial of prophylactic intra-aortic balloon counterpulsation in high-risk aneurysmal subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: To assess whether prophylactic postoperative intraaortic balloon counterpulsation (IABC) reduces the risk of poor outcome because of vasospasm following aneurysmal subarachnoid haemorrhage relative to conventional hypervolemic therapy (HT). METHODS: This was a single-center, parallel group randomized controlled trial. Patients suffering a subarachnoid hemorrhage at high risk of vasospasm were eligible. Patients were randomly allocated to receive prophylactic IABC (n=35) or HT (n=36). The primary end point was Glasgow Outcome and SF-36 scores assessed at 6 months by a blinded and independent observer and analyzed by intention to treat. Secondary analysis of physiological parameters was by treatment performed. RESULTS: Twenty-seven patients in each arm had a good outcome (P=0.55). There was no statistical difference in mean SF-36 score (t=0.39, P=0.70). There were no long-term complications secondary to IABC. There were no differences in preload (pulmonary artery wedge pressure, P=0.97) or afterload (mean arterial pressure, P=0.97). IABC was associated with a lower cardiac output (P=0.002) and higher systemic vascular resistance (P=0.005), although for both groups mean cardiac output was >6 L/min. Cerebral blood flow was not different between groups: HT=41.5 (SD 7.2), IABP=44.9 (SD 8.6) mL/100 g/min (P=0.14). CONCLUSIONS: In this study, prophylactic IABC did not improve perfusion indices or confer any clinical benefit following subarachnoid haemorrhage in patients with normal cardiac function. The study was small, however, and cannot be extrapolated to patients with cardiac failure and medically refractory symptomatic cerebral vasospasm. Clinical Trial Registration This trial was not registered because enrolment began prior to July 1, 2005. PMID- 23086674 TI - Evidence for a strong genetic influence on carotid plaque characteristics: an international twin study. AB - BACKGROUND AND PURPOSE: Few family studies reported moderate genetic impact on the presence and scores of carotid plaques. However, the heritability of carotid plaque characteristics remains still unclear. Twin studies more reliably estimate the relative contribution of genes to these traits in contrast to family study design. METHODS: One hundred ninety-two monozygotic and 83 dizygotic adult twin pairs (age 49+/-15 years) from Italy, Hungary, and the United States underwent B mode and color Doppler ultrasound of bilateral common, internal, and external carotid arteries. RESULTS: Age-, sex-, and country-adjusted heritability was 78% for the presence of carotid plaque (95% CI, 55%-90%), 74% for plaque echogenicity (hypoechoic, hyperechoic, or mixed; 95% CI, 38%-87%), 69% for plaque size (area in mm2 in longitudinal plane; 50 percentile; 95% CI, 16%-86%), 74% for plaque sidedness (unilateral or bilateral; 95% CI, 25%-90%), 74% for plaque numerosity (95% CI, 26%-86%), 68% (95% CI, 40%-84%), and 66% (95% CI, 32%-90%) for the presence of plaque in carotid bulbs and proximal internal carotid arteries. No role of shared environmental factors was found. Unique environmental factors were responsible for the remaining variance (22%-34%). Controlling for relevant covariates did not change the results significantly. CONCLUSIONS: The heritability of ultrasound characteristics of carotid plaque is high. Unshared environmental effects account for a modest portion of the variance. Our findings should stimulate the search for genes responsible for these traits. PMID- 23086675 TI - Glucocorticoid-induced fetal brain growth restriction is associated with p73 gene activation. AB - Fetal exposure to excessive amounts of glucocorticoids (GCs) hampers proper brain development. The molecular mechanism(s) underlying these GCs effects are not well understood. We explored the impact of fetal exposure to maternal GCs on fetal brain expression of p63 and p73 transactivation (TA) and dominant negative (DeltaN) gene variants that promote neural cell death (TA) and cell survival programs (DeltaN). The fetoplacental enzyme 11beta-hydroxysteroid dehydrogenase 2, which shields fetuses from maternal glucocorticoids, was inhibited throughout pregnancy by daily injection of carbenoxolone to pregnant dams. The expression of p63 and p73 gene variants and proteins was monitored by real-time rtPCR and Western blot in the brains of male and female fetuses. Carbenoxolone administration led to an overall enhanced level of corticosterone in the amniotic fluid of both male and female fetuses at late pregnancy. These enhanced corticosterone levels were associated with a significant reduction in fetal brain weights and a significant increase in TAp73 mRNA and p73 protein levels. However, the expression levels of TAp63 mRNA and p63 proteins were either suppressed or unaffected. The pro-neural survival gene variant DeltaNp73 was significantly reduced in female and enhanced in male fetal brains, whereas DeltaNp63 was significantly reduced in the brains of both genders. These data suggest that the GCs-induced negative impact on fetal brain development likely is due, at least in part, to their action of the pro-neural cell death gene variant TAp73 and to the modulation of the pro-survival DeltaNp63 and DeltaNp73 gene variants in a gender dependent fashion. PMID- 23086677 TI - Lower income cancer patients not as involved in clinical trials. PMID- 23086676 TI - Providers search for ways to help cancer patients with psychosocial challenges: Increasing numbers of hospitals are exploring methods beyond group support. PMID- 23086678 TI - Mammograms decline after US Preventive Services Task Force recommendation. PMID- 23086679 TI - The efficacy of Cutanplast nasal packing after endoscopic sinus surgery: a prospective, randomized, controlled trial. AB - OBJECTIVES/HYPOTHESIS: Absorbable packing materials are commonly used after endoscopic sinus surgery (ESS). Cutanplast is a novel gelatin sponge with a powerful hemostatic effect that is rapidly absorbed. The purpose of this study was to investigate the efficacy of Cutanplast in patients following ESS. STUDY DESIGN: A multicenter, prospective, randomized, double-blind, paired, controlled trial. METHODS: One hundred adult patients with chronic sinusitis requiring the same extent of ESS were included. Patients were excluded if they were undergoing septoplasty, turbinate surgery, revision surgery, and taking anticoagulants. Following surgery, one nasal cavity was packed with Cutanplast and the other one with Merocel. Hemostatic properties, patient discomfort while the packing was in situ, patient pain on removal, degree of bleeding on removal, time required to control bleeding after removal, the cost of the pack, and postoperative wound healing were evaluated. RESULTS: Both packs were effective at preventing postoperative hemorrhage. However, Cutanplast was significantly more comfortable while in situ (mean difference, 0.90; 95% confidence interval [CI], 0.75-1.25) and less painful on removal of the pack (mean difference, 1.36; 95% CI, 0.85 1.71). The Merocel pack was associated with significantly more bleeding on removal (mean difference, 1.23; 95% CI, 0.61-2.29), therefore much time was needed to control hemorrhage (mean difference, 1.05; 95% CI, 0.31-1.45). There was no significant difference in the cost of the pack used and outcome measure of wound healing. CONCLUSIONS: Cutanplast nasal pack results in significantly less pain and less bleeding compared to Merocel pack. PMID- 23086680 TI - Molecular modeling of polymeric adsorbent media: the effects of counter-ions on ligand immobilization and pore structure. AB - Molecular dynamics modeling and simulations are employed to study the immobilization of ligands on the surface of the pores of a base porous polymeric matrix. The results show the significant effects that the counter-ions have on the spatial distribution of the density of immobilized ligands as well as on the pore size and pore connectivity distributions of the porous adsorbent medium being constructed. The results for the systems studied in this work indicate that by using doubly charged counter-ions whose numbers during ligand immobilization are half to those of singly charged counter-ions, the ligand immobilization process proceeds faster and the magnitude of local nonelectroneutrality becomes smaller. More importantly, the pore structures of the adsorbent media resulting from the system using doubly charged counter-ions have porous structures that are characterized by more mid-sized pores and higher pore connectivity than the porous adsorbent structures generated by the system employing singly charged counter-ions and, furthermore, the density distribution of the immobilized ligands in the porous structures where doubly charged counter-ions are employed tends to be more uniform laterally and the ligands are surrounded by fewer counter-ions. These characteristics affected by the use of doubly charged counter ions could provide important advantages with respect to the transport and adsorption of adsorbate biomolecules of interest. Furthermore, the results of this work indicate that the type of counter-ions being used in the ligand immobilization process could represent an additional control variable for affecting the ligand density distribution as well as the pore size and pore connectivity distributions of the porous structure of the adsorbent medium being constructed. PMID- 23086681 TI - Transition-metal-free synthesis of aryl-substituted tert-butyl ynol ethers through addition/elimination substitution at an sp centre. AB - Nucleophilic attack of an alkoxide on an alkynyl sulfonamide leads to displacement of the sulfonamide at the sp centre and isolation of the ynol ether in good yield in a single operation. The mechanistic pathway has been probed by the use of coordinating additives, (13)C-labelling experiments and ab initio calculations, which indicated that an addition/elimination mechanism is in operation. PMID- 23086682 TI - Syntheses of xanthofulvin and vinaxanthone, natural products enabling spinal cord regeneration. PMID- 23086683 TI - Overexpression of NEDD9 is associated with altered expression of E-Cadherin, beta Catenin and N-Cadherin and predictive of poor prognosis in non-small cell lung cancer. AB - Neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) is overexpressed in multiple tumor types, where it is thought to regulate tumor cell metastasis and act as a trigger of the epithelial-mesenchymal transition (EMT). Loss of E-cadherin/beta-catenin and upregulation of N-cadherin are hallmarks of the EMT. The expression and correlation of NEDD9 with E-cadherin, beta-catenin and N-cadherin in lung cancer are poorly characterized. We examined NEDD9, E cadherin, beta-catenin and N-cadherin protein expression in 105 cases of non small cell lung carcinoma (NSCLC), including 43 cases of squamous cell carcinoma and 62 cases of lung adenocarcinoma, and the corresponding normal lung tissues using immunohistochemistry. NEDD9 was overexpressed in 56.2 % (59/105) of the NSCLC samples compared to normal lung tissue. Overexpression of NEDD9 correlated with abnormal expression of E-cadherin, beta-catenin and N-cadherin (P < 0.001, P = 0.008 and P = 0.027, respectively). Additionally, overexpression of NEDD9 correlated positively with lymph node metastasis in NSCLC (Chi-square test; P = 0.015). The mean overall survival of NSCLC patients overexpressing NEDD9 (39.10 +/- 6.49 months) was markedly shorter than patients with normal NEDD9 expression (56.67 +/- 7.44 months; Log-Rank, P = 0.001). Moreover, for patients with adenocarcinoma or squarmous cell carcinoma, the survival is also dramatically poorer upon overexpression of NEDD9. In multivariate analysis, overexpression of NEDD9 (P = 0.013) and TNM stage (P = 0.001) were significant independent prognostic factors for overall survival in NSCLC. In conclusion, overexpression of NEDD9 correlates with altered expression of EMT markers, increased lymph node metastasis and poorer survival in lung cancer. PMID- 23086684 TI - Infection control: point prevalence study versus incidence study in Polish long term care facilities in 2009-2010 in the Malopolska Region. AB - OBJECTIVE: The objective of this study was to evaluate the epidemiology of infection in Polish long-term care facilities (LTCFs) and to analyse the capabilities and legitimacy of implementing continuous targeted surveillance. METHODS: The study investigated the relationship between the presence of infection and health status, tested using a point prevalence study (PPS) and incidence study. A 1-day PPS was carried out in October 2009, with prospective continuous surveillance between December 2009 and November 2010. Infections were defined according to McGeer's criteria. RESULTS: The surveillance encompassed 193 people. The prevalence was 14.0 % in residential homes (RHs) and 18.7 % in the nursing home (NH). Various types of infections (in the PPS) were observed significantly more frequently in patients with asthma, wounds, atherosclerosis of lower extremities, tracheotomy tubes and conditions in patients hospitalised in intensive care units (ICUs) up to 1 year before the PPS day. The incidence rate was 2.7/1,000 patient days (pds). CONCLUSIONS: The factors determined to be important for the risk of infection (in the continuous study) include the general status of patients, expressed using Barthel, abbreviated mental and Katz scales, as well as limited physical activity, stool incontinence and urinary catheterisation. In the PPS study, only a slight relationship was shown between the general status of residents and the risk of infection. None of the general status scales used clinically were shown to be helpful in estimating that risk, similarly to the five-point physical activity scale. Prospective continuous surveillance shows a possibility of limiting the range of infection control in the LTCFs within targeted surveillance in a population of patients that requires intensive nursing procedures. As a marker, one could point to the low score in the Barthel or Katz scales or low physical activity/bedridden persons. PMID- 23086685 TI - Brief report: Stony Brook Guidelines on the ethics of the care of people with autism and their families. AB - The increased prevalence of autism spectrum disorders (ASD), with associated societal and clinical impacts, calls for a broad community-based dialogue on treatment related ethical and social issues. The Stony Brook Guidelines, based on a community dialogue process with affected individuals, families and professionals, identify and discuss the following topics: treatment goals and happiness, distributive justice, managing the hopes for a cure, sibling responsibilities, intimacy and sex, diagnostic ethics, and research ethics. Our guidelines, based not on "top-down" imposition of professional expertise but rather on "bottom-up" grass roots attention to the voices of affected individuals and families speaking from experience, can inform clinical practice and are also meaningful for the wider social conversation emerging over the treatment of individuals with ASD. PMID- 23086692 TI - Pain-ameliorating effects of minocycline: an emerging treatment modality. PMID- 23086693 TI - Camptothecin-7-yl-methanthiole: semisynthesis and biological evaluation. AB - The introduction of a methylenthiol group at position 7 of camptothecin was carried out in four steps. This preparation also yielded the corresponding disulfide, which behaves as a prodrug due to its reactivity with glutathione. Assessment of their antiproliferative activities, investigations of their mechanism of action, and molecular modeling analysis indicated that the 7 modified camptothecin derivatives described herein maintain the biological activity and drug-target interactions of the parent compound. PMID- 23086691 TI - Are we ready to stratify treatment for diffuse large B-cell lymphoma using molecular hallmarks? AB - The division of the heterogeneous entity of diffuse large B-cell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-kappaB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as next-generation sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence. PMID- 23086694 TI - Toxicokinetic modeling of persistent organic pollutant levels in blood from birth to 45 months of age in longitudinal birth cohort studies. AB - BACKGROUND: Despite experimental evidence that lactational exposure to persistent organic pollutants (POPs) can impact health, results from epidemiologic studies are inconclusive. Inconsistency across studies may reflect the inability of current methods to estimate children's blood levels during specific periods of susceptibility. OBJECTIVES: We developed a toxicokinetic model to simulate blood POP levels in children from two longitudinal birth cohorts and aimed to validate it against blood levels measured at 6, 16, and 45 months of age. METHODS: The model consisted of a maternal and a child lipid compartment connected through placental diffusion and breastfeeding. Simulations were carried out based on individual physiologic parameters; duration of breastfeeding; and levels of POPs measured in maternal blood at delivery, cord blood, or breast milk. Model validity was assessed through regression analyses of simulated against measured blood levels. RESULTS: Simulated levels explained between 10% and 83% of measured blood levels depending on the cohort, the compound, the sample used to simulate children's blood levels, and child's age when blood levels were measured. Model accuracy was highest for estimated blood POP levels at 6 months based on maternal or cord blood levels. However, loss in model precision between the 6th and the 45th month was small for most compounds. CONCLUSIONS: Our validated toxicokinetic model can be used to estimate children's blood POP levels in early to mid childhood. Estimates can be used in epidemiologic studies to evaluate the impact of exposure during hypothesized postnatal periods of susceptibility on health. PMID- 23086695 TI - Nuclear epidermal growth factor receptor and p16 expression in head and neck squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: Epidermal growth factor receptor (EGFR) and p16 (a surrogate marker of human papillomavirus [HPV] infection) expression are strong prognostic factors in patients with head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: We examined expression levels of total and nuclear EGFR as well as p16 status based on evidence that nuclear EGFR may have a role in DNA damage repair. METHODS: An HPV-negative (SQ20B) and an HPV-positive (UMSCC47) HNSCC cell line were examined for EGFR and gammaH2AX expression. A tissue microarray containing 123 cores obtained from 101 HNSCC tumors was analyzed for EGFR expression by automated quantitative analysis and p16 expression by immunohistochemical staining, and these results were correlated with available clinical data. RESULTS: SQ20B had higher EGFR expression than UMSCC47. Nuclear localization of EGFR on activation with transforming growth factor-alpha was observed in SQ20B, but not in UMSCC47. SQ20B also had increased gammaH2AX foci compared to UMSCC47, suggesting that SQ20B has more DNA damage compared to UMSCC47. Total and nuclear EGFR was reliably obtained from 80 of 101 patients. p16 levels were determined in 87 of 101 patients. p16 levels were strongly associated with the oropharyngeal subsite and poorly differentiated histology. Expression of total and nuclear EGFR was higher in p16-negative tumors compared to p16-positive tumors (Wilcoxon rank test, P = .038 and P = .014, respectively). CONCLUSIONS: Further studies are required to determine a mechanistic link between these two prognostic factors and the significance of EGFR localization to nucleus in DNA damage repair pathway activation. PMID- 23086696 TI - Characteristics and clinical implications of the pharmacokinetic profile of ibuprofen in patients with knee osteoarthritis. AB - BACKGROUND AND OBJECTIVE: Ibuprofen is a non-selective cyclo-oxygenase (COX) 1/COX-2 inhibitor used to treat pain conditions and inflammation. Limited data have been published concerning the pharmacokinetic profile and clinical effects of ibuprofen in patients with osteoarthritis (OA). In this paper we compared the pharmacokinetic and clinical profile of ibuprofen (at a dosage of from 800 mg/day to 1800 mg/day) administered in patients affected by severe knee OA. METHODS: Ibuprofen was administered for 7 days to patients who were scheduled to undergo knee arthroplasty due to OA. After 7 days, the ibuprofen concentration in plasma and synovial fluid was measured through both high-performance liquid chromatography (HPLC)-UV and gas chromatography-mass spectroscopy (GC/MS), while clinical effects were evaluated through both visual analogue scale (VAS) and Western Ontario and McMaster Universities (WOMAC) scores. The Naranjo scale and the WHO causality assessment scale were used for estimating the probability of adverse drug reactions (ADRs). The severity of ADRs was assessed by the modified Hartwig and Siegel scale. RESULTS: Ibuprofen showed a dose-dependent diffusion in both plasma and synovial fluid, which was related to the reduction of pain intensity and improvement of health status, without the development of ADRs. CONCLUSION: Ibuprofen at higher dosages can be expected to provide better control of OA symptoms as a result of higher tissue distribution. PMID- 23086697 TI - A genuine two-dimensional Ising ferromagnet with magnetically driven re-entrant transition. PMID- 23086698 TI - Comparison of conventional and automated breast volume ultrasound in the description and characterization of solid breast masses based on BI-RADS features. AB - PURPOSE: To compare the performance of radiologists in the use of conventional ultrasound (US) and automated breast volume ultrasound (ABVU) for the characterization of benign and malignant solid breast masses based on breast imaging and reporting data system (BI-RADS) criteria. MATERIALS AND METHODS: Conventional US and ABVU images were obtained in 87 patients with 106 solid breast masses (52 cancers, 54 benign lesions). Three experienced radiologists who were blinded to all examination results independently characterized the lesions and reported a BI-RADS assessment category and a level of suspicion of malignancy. The results were analyzed by calculation of Cohen's kappa coefficient and by receiver operating characteristic (ROC) analysis. RESULTS: Assessment of the agreement of conventional US and ABVU indicated that the posterior echo feature was the most discordant feature of seven features (kappa = 0.371 +/- 0.225) and that orientation had the greatest agreement (kappa = 0.608 +/- 0.210). The final assessment showed substantial agreement (kappa = 0.773 +/- 0.104). The areas under the ROC curves (Az) for conventional US and ABVU were not statistically significant for each reader, but the mean Az values of conventional US and ABVU by multi-reader multi-case analysis were significantly different (conventional US 0.991, ABVU 0.963; 95 % CI -0.0471 to -0.0097). The means for sensitivity, specificity, positive predictive value, and negative predictive value of conventional US and ABVU did not differ significantly. CONCLUSION: There was substantial inter-observer agreement in the final assessment of solid breast masses by conventional US and ABVU. ROC analysis comparing the performance of conventional US and ABVU indicated a marginally significant difference in mean Az, but not in mean sensitivity, specificity, positive predictive value, or negative predictive value. PMID- 23086699 TI - Dyslexia laws in the USA. AB - Throughout the various states of the USA, the appropriate identification of dyslexia and the timely provision of interventions are characterized by variability and inconsistency. Several states have recognized the existence of this disorder and the well-established need for services. These states have taken proactive steps to implement laws and regulations for both identification and treatment, and the provision of equal access to students who are diagnosed with dyslexia. The majority of states, however, have not developed such laws and guidelines. The purposes of this article are to review the present status and content of these dyslexia laws, highlight some differences among the laws and regulations across states, and suggest strategies for initiating such laws. PMID- 23086700 TI - Primary cervicothoracic thyroid paraganglioma. PMID- 23086701 TI - Clinicopathological features of thymic carcinomas and the impact of histopathological agreement on prognostical studies. AB - OBJECTIVES: Thymic carcinomas have wide ranges of reported survival. Interobserver agreement on diagnosis might affect prognostical studies. Clinicopathological features of thymic carcinomas were compared with thymic epithelial neoplasms in which pathologists disagreed upon. METHODS: Patients treated with thymic epithelial neoplasms were reviewed. Three thoracic pathologists independently classified all cases according to the World Health Organization classification. The study group comprised cases in which all pathologists agreed independently on thymic carcinomas. A disagreement group included cases in which pathologists disagreed upon the diagnosis. Tumours were staged according to the modified Masaoka and tumour-node metastasis (TNM) stages. Time-to-death was estimated with the Kaplan-Meier method. Survival outcomes were assessed with the Cox proportional-hazards regression. RESULTS: In the study group, 25 of 29 patients presented with symptoms but no autoimmune diseases. Masaoka stage III (18 of 29) and TNM stage III (13 of 24) were most common. Complete tumour resection was achieved in 17 of 29. Four patients had metastasis at diagnosis, and 12 developed metastasis/recurrence post-treatment. The estimated 5-year survival was 35.6%, and recurrence/metastasis-free survival was 34.2%. Overall survival was associated with weight loss (P = 0.02) and metastasis/recurrence with morphology (P = 0.009). In the disagreement group, most disagreements occurred between type B3 thymomas and carcinomas (21 of 29). Twenty-four of the 29 patients presented with symptoms, including autoimmune disorders (12 of 29). Masaoka stage III (10 of 29) and TNM stage IV (10 of 17) were most common. Twenty-one of the 29 underwent complete tumour resection. The estimated 5-year survival was 64.9%. Two patients had metastasis at diagnosis and eight developed metastasis/recurrence post-treatment. The study group had significantly more patients with chest pain and additional treatment than the disagreement group (P = 0.005 and 0.044, respectively). The disagreement group had more patients with myasthenia gravis and a higher TNM stage (P = 0.0003 and 0.025, respectively). The risks of death and recurrence/metastasis were significantly higher in the study group than the disagreement group [P = 0.025, hazard ratio (HR) = 2.44 and P = 0.012, HR = 3.23, respectively]. CONCLUSIONS: Thymic carcinomas were diagnosed at high stages and the overall prognosis appeared relatively poor. Autoimmune disease was not a manifestation of thymic carcinomas. Weight loss was associated with survival. The disagreement group in contrast had more patients with autoimmune syndrome and, despite a higher stage, had a better survival, suggesting that interobserver variability in the histopathological classification of thymic carcinomas vs thymomas leads to prognostical variability. PMID- 23086702 TI - Training old rats selectively modulates synaptosomal protein synthesis. AB - We have previously shown that the local synthesis of two synaptic proteins of 66.5-kDa and 87.6-kDa is selectively enhanced in male adult rats trained for a two-way active avoidance task. We report here that a comparable but not identical response occurs in 2-year-old male rats trained for the same task. In the latter age group, the local synthesis of the 66.5-kDa protein markedly increases in cerebral cortex, brainstem, and cerebellum, with a somewhat lower increment in synthesis of the 87.6-kDa protein. On the other hand, the newly synthesized 87.6 kDa protein correlates with avoidances and escapes and inversely correlates with freezings in cerebral cortex and brainstem, whereas the correlations of the newly synthesized 66.5-kDa protein remain below significance. These correlative patterns are sharply at variance with those present in trained adult rats. Our data confirm that the local system of synaptic protein synthesis is selectively modulated by training and show that the synaptic response of old rats differs from that of adult rats as reflected in behavioral responses. PMID- 23086703 TI - Low-molecular-weight CXCR4 ligands with variable spacers. AB - Low-molecular-weight CXCR4 ligands based on known lead compounds including the 14 mer peptide T140, the cyclic pentapeptide FC131, peptide mimetics, and dipicolylamine-containing compounds were designed and synthesized. Three types of aromatic spacers, 1,4-phenylenedimethanamine, naphthalene-2,6-diyldimethanamine, and [1,1'-biphenyl]-4,4'-diyldimethanamine, were used to build four pharmacophore groups. As pharmacophore groups, 2-pyridylmethyl and 1-naphthylmethyl are present in all of the compounds, and several aromatic groups and a cationic group from 1 propylguanidine and 1,1,3,3-tetramethyl-2-propylguanidine were also used. Several compounds showed significant CXCR4 binding affinity, and zinc(II) complexation of bis(pyridin-2-ylmethyl)amine moieties resulted in a remarkable increase in CXCR4 binding affinity. PMID- 23086704 TI - MILD ovarian stimulation with GnRH-antagonist vs. long protocol with low dose FSH for non-PCO high responders undergoing IVF: a prospective, randomized study including thawing cycles. AB - OBJECTIVE: To compare the effectiveness of two stimulation protocols in non polycystic ovary (PCO) high responders undergoing in vitro fertilization (IVF). DESIGN: Prospective randomized trial. SETTING: A Reproductive Medicine and IVF Unit of a University Hospital and a private IVF Clinic. METHODS: Four hundred-and twelve normoovulatory women with good ovarian responsiveness were randomized to receive either the "mild" (FSH 150 IU/day from day 4 of a spontaneous cycle followed by GnRH-antagonist from day 8; n = 205) or the "long" (FSH 150 IU/day; n = 207) stimulation protocol. The outcome of these two regimens was compared including "fresh" and thawing cycles. RESULTS: The total FSH dose and the peak estradiol level were significantly lower in the "mild" protocol, whereas the retrieved oocytes, fertilization rate, number and quality of embryos, pregnancy and implantation rates, cumulative "fresh plus thaw" success rate, and incidence of severe ovarian hyperstimulation syndrome were comparable with the two regimens. CONCLUSIONS: In young, normoovulatory patients with good ovarian responsiveness undergoing IVF the "mild" stimulation protocol has effectiveness and risks comparable to the "long" protocol with low FSH starting dose, even when thawing cycles are included in the comparison. PMID- 23086707 TI - An introduction to journal club in The Cerebellum. PMID- 23086706 TI - HLA-DR3-DQ2 mice do not develop ataxia in the presence of high titre anti-gliadin antibodies. AB - Recently, it has been suggested that anti-gliadin antibodies (alphaGAb) may produce "gluten ataxia", even in the absence of celiac disease enteropathy. alphaGAb are reportedly present in 12-50 % of patients with sporadic ataxia, but also in 12 % of the general population, such that the importance of alphaGAb as a cause of sporadic ataxia is not conclusively settled. We aimed to determine whether mice transgenic for HLA-DR3-DQ2 and immunised with gliadin to achieve high titres of alphaGAb would develop ataxia and/or cerebellar damage. From 6 weeks of age, HLA-DR3-DQ2 transgenic mice were immunised fortnightly with gliadin (n = 10) or a saline control (n = 6) in adjuvant. Serum titres were measured by alphaGAb enzyme-linked immunosorbent assay. At 24 weeks of age, mice were tested for locomotor function using the accelerating rotarod, ledged beam, ink-paw gait, and several neurological severity score subtests. Brains were then collected and processed for immunohistochemistry. Sections were analysed for lymphocytic infiltration, changes in morphology and Purkinje cell (PC) dendritic volume and the number of PCs counted via unbiased stereology. Gliadin-immunised mice developed high alphaGAb titres while controls did not. There was no statistically significant difference between the gliadin and sham-immunised HLA-DR3-DQ2 mice on any of the tests of motor coordination, in lymphocytic infiltration, PC number or in dendritic volume. High levels of alphaGAb are not sufficient to produce ataxia or cerebellar damage in HLA-DR3-DQ2 transgenic mice. PMID- 23086708 TI - Catalytic hydrogen/deuterium exchange of unactivated carbon-hydrogen bonds by a pentanuclear electron-deficient nickel hydride cluster. PMID- 23086705 TI - Addressing human variability in next-generation human health risk assessments of environmental chemicals. AB - BACKGROUND: Characterizing variability in the extent and nature of responses to environmental exposures is a critical aspect of human health risk assessment. OBJECTIVE: Our goal was to explore how next-generation human health risk assessments may better characterize variability in the context of the conceptual framework for the source-to-outcome continuum. METHODS: This review was informed by a National Research Council workshop titled "Biological Factors that Underlie Individual Susceptibility to Environmental Stressors and Their Implications for Decision-Making." We considered current experimental and in silico approaches, and emerging data streams (such as genetically defined human cells lines, genetically diverse rodent models, human omic profiling, and genome-wide association studies) that are providing new types of information and models relevant for assessing interindividual variability for application to human health risk assessments of environmental chemicals. DISCUSSION: One challenge for characterizing variability is the wide range of sources of inherent biological variability (e.g., genetic and epigenetic variants) among individuals. A second challenge is that each particular pair of health outcomes and chemical exposures involves combinations of these sources, which may be further compounded by extrinsic factors (e.g., diet, psychosocial stressors, other exogenous chemical exposures). A third challenge is that different decision contexts present distinct needs regarding the identification-and extent of characterization-of interindividual variability in the human population. CONCLUSIONS: Despite these inherent challenges, opportunities exist to incorporate evidence from emerging data streams for addressing interindividual variability in a range of decision making contexts. PMID- 23086709 TI - Noninvasive management of cochlear implant's inner magnet displacement after magnetic resonance. AB - MRI is a widespread and greatly helpful diagnostic tool, yet its use on cochlear implant patients is restricted by the presence of an inner magnet. We report on a case of magnet dislodgment after 1.5T MRI in a 31-year-old female with a Hi-Res 90K cochlear implant. In this case, it was possible to implement an alternative, totally noninvasive approach based on an external manual repositioning rather than a surgical procedure of the displaced magnet. PMID- 23086710 TI - Sampling requirements in DCE-MRI based analysis of high grade gliomas: simulations and clinical results. AB - PURPOSE: To investigate the effect of variations in temporal resolution and total measurement times on the estimations of kinetic parameters derived from dynamic contrast-enhanced (DCE) MRI in patients with high-grade gliomas (HGGs). MATERIALS AND METHODS: DCE-MRI with high temporal resolution (dynamic sampling time (T(s)) = 2.1 s and 3.4 s) and total sampling time (T(acq)) of 5.2 min was acquired in 101 examinations from 15 patients. Using the modified Tofts model K(trans), k(ep) v(e) and v(p) were estimated. The effects of increasing T(s) and reducing T(acq) on the estimated kinetic parameters were estimated through down-sampling and data truncation, and the results were compared with numerical simulations. RESULTS: There was an overall dependence of all four kinetic parameters on T(s) and T(acq). Increasing T(s) resulted in under-estimation of K(trans) and over estimation of V(p), whereas k(ep) and V(e) varied in a less predictable manner. Reducing T(acq) resulted in over-estimation of K(trans) and k(ep) and under estimation of v(p) and v(e). Increasing T(s) and reducing T(acq) resulted in increased relative error for all four parameters. CONCLUSION: Estimated K(trans), K(ep), and V(e) in HGGs were within 15% of the high sampling rate reference values for T(s) <20 s. Increasing T(s) and reducing T(acq) leads to reduced precision of the estimated values. PMID- 23086712 TI - A synthetic amino acid residue containing a new oligopeptide-based photosensitive fluorescent organogel. AB - A synthetic amino acid (with a stilbene residue in the main chain) containing a tripeptide-based organogelator has been discovered. This peptide-based synthetic molecule 1 self-assembles in various organic solvents to form an organogel. The gel has been thoroughly characterized by using various microscopic techniques including field-emission scanning electron microscopy (FESEM), atomic force microscopy (AFM), X-ray diffraction (XRD), UV-visible and fluorescence spectroscopy, and rheology. Morphological investigations using FESEM and AFM show a nanofibrillar network structure. Interestingly, the organogel is photoresponsive and a gel-sol transition occurred by irradiating the gel with UV light of 365 nm for 2 h as shown by the UV and fluorescence study. This photoresponsive fluorescent gel holds promise for new peptide-based soft materials with interesting applications. PMID- 23086711 TI - Polyomavirus JC infection inhibits differentiation of oligodendrocyte progenitor cells. AB - Reactivation of the human polyomavirus JC (JCV) in the CNS results in a fatal demyelinating disease, progressive multifocal leukoencephalopathy (PML). The lytic destruction of oligodendrocytes, which occurs at the terminal stage of the viral infection cycle, is considered a critical factor in the development of demyelination and the pathogenesis of PML. However, knowledge is limited about interaction of JCV with oligodendrocytes and its impact on the denudation of axons at the early stage of viral reactivation and prior to the destruction of the infected cells. We have developed an in vitro neuroprogenitor cell culture using human fetal brain that can be differentiated to the oligodendrocyte lineage to investigate interactions of JCV with its host cells. Results show that infection with JCV delays oligodendrocyte maturation as shown by reduced levels of oligodendrocytic markers, including myelin basic protein, proteolipid protein, and platelet-derived growth factor receptor-alpha. Furthermore, replication of JCV in these cells caused substantial dysregulation of several chemokines, including CCL5/RANTES, GRO, CXCL1/GROalpha, CXCL16, CXCL8/IL-8, CXCL5/ENA-78, and CXCL10/IP-10, all of which play a role in cell growth and differentiation. PMID- 23086713 TI - Accuracy and precision of protein-ligand interaction kinetics determined from chemical shift titrations. AB - NMR-monitored chemical shift titrations for the study of weak protein-ligand interactions represent a rich source of information regarding thermodynamic parameters such as dissociation constants (K ( D )) in the micro- to millimolar range, populations for the free and ligand-bound states, and the kinetics of interconversion between states, which are typically within the fast exchange regime on the NMR timescale. We recently developed two chemical shift titration methods wherein co-variation of the total protein and ligand concentrations gives increased precision for the K ( D ) value of a 1:1 protein-ligand interaction (Markin and Spyracopoulos in J Biomol NMR 53: 125-138, 2012). In this study, we demonstrate that classical line shape analysis applied to a single set of (1)H (15)N 2D HSQC NMR spectra acquired using precise protein-ligand chemical shift titration methods we developed, produces accurate and precise kinetic parameters such as the off-rate (k ( off )). For experimentally determined kinetics in the fast exchange regime on the NMR timescale, k ( off ) ~ 3,000 s(-1) in this work, the accuracy of classical line shape analysis was determined to be better than 5 % by conducting quantum mechanical NMR simulations of the chemical shift titration methods with the magnetic resonance toolkit GAMMA. Using Monte Carlo simulations, the experimental precision for k ( off ) from line shape analysis of NMR spectra was determined to be 13 %, in agreement with the theoretical precision of 12 % from line shape analysis of the GAMMA simulations in the presence of noise and protein concentration errors. In addition, GAMMA simulations were employed to demonstrate that line shape analysis has the potential to provide reasonably accurate and precise k ( off ) values over a wide range, from 100 to 15,000 s(-1). The validity of line shape analysis for k ( off ) values approaching intermediate exchange (~100 s(-1)), may be facilitated by more accurate K ( D ) measurements from NMR-monitored chemical shift titrations, for which the dependence of K ( D ) on the chemical shift difference (Deltaomega) between free and bound states is extrapolated to Deltaomega = 0. The demonstrated accuracy and precision for k ( off ) will be valuable for the interpretation of biological kinetics in weakly interacting protein-protein networks, where a small change in the magnitude of the underlying kinetics of a given pathway may lead to large changes in the associated downstream signaling cascade. PMID- 23086714 TI - Is "black geode" sign a characteristic MRI finding for extracranial schwannomas? AB - PURPOSE: To evaluate whether the "black geode" sign is a characteristic magnetic resonance imaging (MRI) finding for extracranial schwannomas. MATERIALS AND METHODS: Forty-three patients with pathologically confirmed extracranial schwannomas underwent preoperative gadolinium-enhanced MRI. The black geode sign was defined as the appearance of enhanced outer and inner rings. MR images were retrospectively reviewed for size, configuration, and signal intensity of the lesions in addition to the presence of the black geode sign. RESULTS: Gadolinium enhanced T1-weighted images revealed the black geode sign in seven of 43 patients (16%). The thickness of inner rings (mean 0.6 cm, range 0.3-0.8 cm) was significantly greater than that of outer rings (mean 0.2 cm, range 0.1-0.3 cm) (P < 0.01). While outer rings were circular or elliptical in shape with smooth contours, inner rings had a lobular configuration with irregular thickness and contours. The degrees of enhancement were significantly stronger with inner rings than with outer rings (P < 0.01). In histopathological correlation of five patients who underwent total excision, inner and outer rings corresponded to peridegenerative areas and fibrous capsules, respectively. CONCLUSION: The black geode sign may be fairly specific to extracranial schwannomas on gadolinium enhanced MR images. PMID- 23086715 TI - Changes in the surface roughness and friction coefficient of orthodontic bracket slots before and after treatment. AB - In this study, we tested the surface roughness of bracket slots and the friction coefficient between the bracket and the stainless steel archwire before and after orthodontic treatment. There were four experimental groups: groups 1 and 2 were 3M new and retrieved brackets, respectively, and groups 3 and 4 were BioQuick new and retrieved brackets, respectively. All retrieved brackets were taken from patients with the first premolar extraction and using sliding mechanics to close the extraction space. The surface roughness of specimens was evaluated using an optical interferometry profilometer, which is faster and nondestructive compared with a stylus profilometer, and provided a larger field, needing no sample preparation, compared with atomic force microscopy. Orthodontic treatment resulted in significant increases in surface roughness and coefficient of friction for both brands of brackets. However, there was no significant difference by brand for new or retrieved brackets. These retrieval analysis results highlight the necessity of reevaluating the properties and clinical behavior of brackets during treatment to make appropriate treatment decisions. PMID- 23086716 TI - Negative affect differentiation and adherence during treatment for thalassemia. AB - BACKGROUND: Although research has demonstrated the detrimental effects of excessive negative affect on treatment adherence and morbidity in chronic illness, rarely have researchers investigated the benefits of awareness of negative emotional experiences during treatment. PURPOSE: In this investigation, we examined the association of negative affect differentiation (the ability to report negative emotional experiences as separate and distinct from each other,) to treatment adherence in adult patients with the congenital blood disorder thalassemia. METHOD: Negative affect differentiation was assessed during a 12-16 week treatment-based diary and adherence was operationalized as attendance at routine screenings over 12 months. Participants were adult patients (n = 32; age M = 31.63, SD = 7.72; 72 % female) with transfusion-dependent thalassemia in treatment in a large metropolitan hospital in the Northeastern USA. RESULTS: The results indicate that negative affect differentiation is significantly associated with greater adherence to treatment, even when controlling for disease burden and level of psychological distress. CONCLUSION: Although preliminary, this investigation suggests that differentiated processing of negative emotional experiences during illness can lead to adaptive treatment-related behavior. As such, it may present a new avenue for research and intervention targeting the improvement of adherence during treatment for chronic illness. PMID- 23086717 TI - Identification and functional characterization of zebrafish Gas7 gene in early development. AB - Growth arrest-specific 7 (Gas7) is preferentially expressed in the nervous system and plays an important role during neuritogenesis in mammals. However, the structure and function of Gas7 homologs have not been studied in nonmammalian vertebrates used as models. In this report, we identify a Gas7 gene in zebrafish that we termed zfGas7. The transcript of this gene was produced by canonical splicing, and its protein product contained a Fes/CIP4 homology and a coiled-coil domain. In early zebrafish embryos, RT-PCR analyses revealed that zfGas7 was initially expressed at 5.3 hr postfertilization (hpf), followed by an increase of expression at 10 hpf and further accumulation during somitogenesis at 48 hpf. Spatiotemporal analyses further showed that Gas7 mRNA was detected in the brain, somite, and posterior presomitic mesoderm regions during somitogenesis. At 36 hpf, zfGas7 mRNA was detected in the brain and somite but was later found only in neuronal clusters of the brain at 52 hpf. Gas7 knockdown with morpholino antisense oligonucleotides (Gas7MO) reduced the number of HuC-positive neurons in the trigeminal and statoacoustic ganglions and produced deformed phenotypes, such as flattening of the top of the head. Notably, the neuron reduction and deformed phenotypes observed in Gas7MO embryos were partially rescued by ectopic expression of Gas7. Because altered somitogenesis and pigmentation were also found in the morphants, the neuronal phenotypes observed likely are due to a general developmental delay of embryogenesis. These results indicate that Gas7 is expressed in neuronal cells but is not specifically required for neuronal development in vertebrates. PMID- 23086718 TI - General information to obtain spherical particles with ordered mesoporous structures. AB - Conditions for the synthesis of aluminum organophosphonate (AOP) and aluminophosphate (AlPO) spheres containing periodic mesopores were optimized and demonstrated to be general morphological controls for the surfactant-assisted synthesis of mesoporous materials. High-quality AOP and AlPO spheres with uniform mesopores were obtained at low and high temperatures, respectively. The aerosol assisted synthesis of materials with uniform mesopores was categorized by using the difference in relative density of soluble AOP and AlPO oligomers that interact with ethylene oxide (EO) units in EO(n)PO(m)EO(n) triblock copolymer (PO=propylene oxide). Then, ordered mesoporous structures are constructed with the adequate amount of species in resultant frameworks, and the number of interactive points in soluble species determines the resultant density of the frameworks after self-assembly. Consequently, temperature-dependent synthesis, which allows controlled infiltration of soluble species to match the density of resultant frameworks, is required for the formation of ordered mesoporous structures under morphological control. PMID- 23086719 TI - Long echo time proton magnetic resonance spectroscopy for estimating relative measures of lipid unsaturation at 3 T. AB - PURPOSE: To examine the behavior of lipid olefinic and diallylic resonances as a function of PRESS (point resolved spectroscopy) echo time (TE) to determine an optimal long TE value for their measurement at 3 T. MATERIALS AND METHODS: Experiments were conducted on nine oils (almond, canola, cod liver, corn, linseed, peanut, sesame, sunflower, and walnut oil) and on vertebral and tibial bone marrow in vivo at 3 T. The methylene (or methyl + methylene), diallylic, and olefinic resonances were measured with PRESS with multiple TEs. RESULTS: J coupling evolution effects on the olefinic and diallylic peaks appeared to be minimized when TE = 200 msec. The TE = 200 msec olefinic/methylene and diallylic/methylene peak area ratios calculated for each oil correlated well with ratios deduced from oil compositions in the literature (R(2) = 0.92 and 0.98 for the olefinic and diallylic protons, respectively). In addition, the relative amounts of bone marrow unsaturation of vertebral and tibial bone marrow inferred from the TE = 200 msec olefinic/(methyl + methylene) peak area ratio agreed with values estimated from the literature. CONCLUSION: A PRESS sequence with a long TE value of 200 msec is suitable for determining relative amounts of lipid unsaturation at 3 T. PMID- 23086720 TI - Segmented field OFFGEL(r) electrophoresis. AB - A multielectrode setup for protein OFFGEL electrophoresis that significantly improves protein separation efficiency has been developed. Here, the electric field is applied by segments between seven electrodes connected in series to six independent power supplies. The aim of this strategy is to distribute evenly the electric field along the multiwell system, and as a consequence to enhance electrophoresis in terms of separation time, resolution, and protein collection efficiency, while minimizing the overall potential difference and therefore the Joule heating. The performances were compared to a standard two-electrode setup for OFFGEL fractionation of a protein mixture, using UV-Vis spectroscopy for quantification and MALDI-MS for identification. The electrophoretic separation process was simulated, and optimized by solving the time-dependent Nernst-Planck differential equation. PMID- 23086721 TI - A rare variation of posterior cord brachial plexus branching coexisting with the intercalated ectopic muscle. AB - During a dissection of the brachial plexus we found a rare variation of left posterior cord branching coexisting with an unusual intercalated ectopic muscle. This muscle originated from the shoulder joint capsule at the lesser tubercle on insertion of the subscapularis then pierced between the brachial plexus, enclosed by two roots of the radial nerve, and inserted into the upper part of the latissimus dorsi muscle. The variant posterior cord divided into two roots; a thin lateral and thick medial root. The lateral root gave off the thoracodorsal nerve that penetrated and also innervated the ectopic muscle. The medial root gave off five nerve branches; two upper subscapular, one lower subscapular, one axillary and one terminal branch. A terminal branch fused with the lateral root to form a loop enclosing the ectopic muscle then continued as the radial nerve. This type of variation may be useful to interpret unexplained clinical signs and symptoms and provided additional knowledge to surgeons who perform brachial plexus surgery. PMID- 23086722 TI - Habenula and the asymmetric development of the vertebrate brain. AB - Habenula is a relay nucleus connecting the forebrain with the brain stem and plays a pivotal role in cognitive behaviors by regulating serotonergic and dopaminergic activities. The mammalian habenula is divided into the medial and lateral habenulae, each of which consists of a heterogeneous population of neurons. Recent comparative analyses of zebrafish and rodent habenulae have provided molecular insights into the developmental mechanism of the habenula. Hodological and gene expression analyses revealed that these two habenular pathways are conserved phylogenetically between fish and mammals. The anatomical information make the zebrafish and rodent model animals amenable to the genetic analysis of the development and physiological role of the vertebrate habenula. Intriguingly, habenula has also attracted interest as a model for brain asymmetry, since many vertebrates show left-right differences in habenular size and neural circuitry. Left-right asymmetry is a common feature of the central nervous system in vertebrates. Despite its prevalence and functional importance, few studies have addressed the molecular mechanism for generation of the asymmetric brain structure, probably due to the absence of genetically accessible model animals showing obvious asymmetry. The results from recent studies on zebrafish habenula suggest that development of habenular asymmetry is mediated by differential regulation of the neurogenetic period for generating specific neuronal subtypes. Since the orientation and size ratio of the medial and lateral habenulae differs across species, evolution of those subregions within the habenula may also reflect changes in neurogenesis duration for each habenular subdivision according to the evolutionary process. PMID- 23086723 TI - Reverse regioselectivity in the palladium(II) thiourea catalyzed intermolecular Pauson-Khand reaction. PMID- 23086724 TI - Assessment of corticospinal tract (CST) damage in acute stroke patients: comparison of tract-specific analysis versus segmentation of a CST template. AB - PURPOSE: To compare two techniques to assess corticospinal tract (CST) damage in stroke patients: tract-specific analysis by probabilistic tractography and segmentation using a CST template. MATERIALS AND METHODS: We extracted fractional anisotropy (FA) values, the FA ratio, and mean diffusivity (MD) in 18 stroke patients and 21 healthy volunteers matched for age and sex. We compared the two methods in order to determine their ability to detect 1) differences between diffusion tensor imaging (DTI) parameters of healthy volunteers and stroke patients, 2) the correlation between DTI parameters and clinical scores, and 3) the correlation between DTI parameters and blood oxygen level-dependent (BOLD) signals in a fist-closure task. RESULTS: FA values were higher with the tractography approach than with the segmentation method, but differences between the ipsilesional CST and the homologous region in healthy subjects were detected using both methods. In patients, clinical scores were significantly correlated with FA values and FA ratios with both methods. The BOLD signal was positively correlated with FA values for CST with the segmentation but not with the tractography approach. CONCLUSION: CST damage in stroke patients can be assessed by either probabilistic tractography or segmentation of a CST template. Although each method has advantages and limitations, both are sensitive enough to detect differences among stroke patients and identify specific correlations with clinical scores. PMID- 23086725 TI - Effect of electrolyte pH on CIEF with narrow pH range ampholytes. AB - CIEF of components following sequential injection of ampholytes and the sample zone offers unique advantages for analysis. The most important one of these is the efficient separation of amphoteric compounds having pIs outside the pH range of the ampholytes applied, but the resolution of the components can be increased by an adequate setup in the injection protocol. In this study, the effect of the pH of the anolyte and catholyte on the selectivity and speed of the isoelectric focusing was investigated. Changes in the pH values significantly influenced the resolution and the length of the pH gradient, while changes in the charge state of components were also observed. Three ampholyte solutions (from different suppliers) covering only two pH units were used for the analyses of substituted nitrophenol dyes in uncoated capillary. With appropriate setup, the components, with pIs not covered by the ampholyte pH range, migrated in charged state outside the pH gradient. This phenomenon is preferable for coupling isoelectric focusing to MS detection, by evading the undesirable ion suppression effect of ampholytes. PMID- 23086727 TI - A10LaCdSb9 (A=Ca, Yb): a highly complex Zintl system and the thermoelectric properties. AB - Two new Zintl compounds A(10)LaCdSb(9) (A=Ca, Yb), namely, Ca(9.81(1))La(0.97(1))Cd(1.23(1))Sb(9) and Yb(9.78(1))La(0.97(1))Cd(1.24(1))Sb(9), have been designed and synthesized by applying the Zintl concept. Although both compounds are isoelectronic with their Ca(11)InSb(9) and Yb(11)InSb(9) analogues, they crystallize in a new structure type with the orthorhombic space group Ibam (No.72) and feature very complex anion structures, which are composed of unique [Cd(2)Sb(6)](12-) clusters, dumbbell-shaped [Sb(2)](4-) dimers, and isolated [Sb](3-) anions. For Yb(9.78(1))La(0.97(1))Cd(1.24(1))Sb(9), an extremely low lattice thermal conductivity of 0.29 W m(-1) K(-1) was observed at 875 K, which almost approaches the lowest reported limit of nonglassy or nonionically conducting bulk materials. According to thermogravimetric (TG) and differential scanning calorimetry (DSC) analyses, both compounds show very good thermal stability and no melting or phase transition processes were found below 1173 K. Although related thermoelectric property studies on Yb(9.78(1))La(0.97(1))Cd(1.24(1))Sb(9) only present a maximum ZT of 0.11 at 920 K, owing to its low Seebeck coefficients, these materials are still very promising for their high temperature stability and low thermal conductivity. Furthermore, as mixed cations exist with different charges, it makes this system very flexible in tuning the related electrical properties. PMID- 23086726 TI - The missing link between long-term stimulation of nicotinic receptors and the increases of acetylcholine release and vasodilation in the cerebral cortex of aged rats. AB - In adult rats (4-9 months), chronic nicotine infusion increases the basal level of acetylcholine (ACh) release in the cerebral cortex and enhances responses of cortical ACh release and cortical vasodilation elicited by nucleus basalis of Meynert (NBM) stimulation. In the present study, we examined whether these effects of nicotine are detected in aged rats. Aged rats (27-30 months) received sustained subcutaneous nicotine (100 MUg/kg/h) or saline for 14 days. Under urethane anesthesia, ACh release and regional blood flow in the parietal cortex were measured. The basal level of ACh release in the cerebral cortex was not changed by chronic nicotine. In addition, the magnitudes of ACh release and vasodilation by NBM stimulation were similar between the saline-treated and nicotine-treated groups. The lack of an effect of chronic nicotine in aged rats may be due to a decrease in nicotinic receptors in the cerebral cortex during aging (Nordberg et al., J Neurosci Res 31:103-111, 1992). PMID- 23086728 TI - Diffusion-weighted imaging of the healthy pancreas: ADC values are age and gender dependent. AB - PURPOSE: To investigate the healthy pancreas with diffusion-weighted imaging (DWI) for characterization of age and gender-related differences in apparent diffusion coefficient (ADC) values. MATERIALS AND METHODS: Sixty six volunteers were prospectively enrolled (33 male, 33 female; range 1.4 to 83.7 years of age) and echo-planar DWI of the pancreas was performed. ADC values were measured in the pancreas head, body, and tail using a pixel-by-pixel approach. Effects of age and gender on ADC values were analyzed using a two-factorial multivariate analysis of variance (MANOVA). RESULTS: ADC values correlated inversely with the age of the volunteers. The mean global pancreatic ADC values (* 10(-3) mm(2)/s) in the age groups 0-20 years, 21-40 years, and > 40 years were 1.18 +/- 0.19, 1.07 +/- 0.13, and 0.99 +/- 0.18, respectively. Female individuals had higher mean global ADC values than male (1.13 +/- 0.14 versus 1.02 +/- 0.18 * 10(-3) mm(2)/s). MANOVA showed significant effects of age (P value 0.022, eta(2) = 0.13) and gender (P value 0.001, eta(2) = 0.28) on ADC values. CONCLUSION: Pancreatic ADC values decline with ageing and show significant gender differences with higher mean values in females. The awareness of baseline values adjusted to age and gender will be important for correct interpretation of individual cases and design of future studies. PMID- 23086729 TI - Sample preconcentration in open microchannels combined with MALDI-MS. AB - In this work, a method for preconcentrating samples in 1 cm long, 50-150 MUm wide open microchannels is presented. Platinum electrodes were positioned at the channel ends, voltage was applied, and charged analyte was preconcentrated at the oppositely charged side during continuous supply of sample. The preconcentration was initially studied in a closed system, where an influence on the analyte position from a pH gradient, generated by water electrolysis, was observed. In the open channel, the analyte distribution after preconcentration was evaluated using MALDI-MS with the channel as MALDI target. MALDI matrix was applied with an airbrush or by electrospray matrix deposition and by using the latter technique higher degrees of crystallization in the channels were obtained. After preconcentrating a 1 nM cytochrome c solution for 5 min, corresponding to a supplied amount of 1.25 fmol, a signal on the cathodic channel end could be detected. When a solution of cytochrome c trypsin digest was supplied, the peptides were preconcentrated at different positions along the channel depending on their charge. PMID- 23086730 TI - Cell-free metabolic engineering: production of chemicals by minimized reaction cascades. AB - The limited supply of fossil resources demands the development of renewable alternatives to petroleum-based products. Here, biobased higher alcohols such as isobutanol are versatile platform molecules for the synthesis of chemical commodities and fuels. Currently, their fermentation-based production is limited by the low tolerance of microbial production systems to the end products and also by the low substrate flux into cell metabolism. We developed an innovative cell free approach, utilizing an artificial minimized glycolytic reaction cascade that only requires one single coenzyme. Using this toolbox the cell-free production of ethanol and isobutanol from glucose was achieved. We also confirmed that these streamlined cascades functioned under conditions at which microbial production would have ceased. Our system can be extended to an array of industrially relevant molecules. Application of solvent-tolerant biocatalysts potentially allows for high product yields, which significantly simplifies downstream product recovery. PMID- 23086731 TI - qMRI relaxometry of mandibular bone marrow: a monomodal distribution in sickle cell disease. AB - PURPOSE: To identify and characterize sickle cell disease (SCD)-related changes in the composition of mandibular bone marrow using qMRI relaxometry histograms. MATERIALS AND METHODS: Thirteen SCD patients and 17 controls underwent brain MR imaging with the mixed turbo spin-echo (TSE) pulse sequence at 1.5T. The mandible was manually segmented and divided into body, angle, ramus, and condyle. T1 and T2 histograms of each mandible were modeled with Gaussian functions. The relaxation time histogram peaks were calculated, and the number of monomodal versus bimodal curves was compared. RESULTS: SCD patients exhibited monomodal distributions on both T1 and T2 histograms, consistent with a composition of predominantly red hematopoietic marrow. Eighty-eight percent of mandibles in control subjects exhibited a bimodal distribution in T1 and all showed a bimodal distribution in T2, indicating mixed but predominantly yellow marrow composition. The second peak in control subjects was shorter in T1 and longer in T2, consistent with yellow marrow composition. CONCLUSION: Instead of physiological fatty replacement, SCD patients exhibit red marrow persistence in the mandible, likely due to the increased demand for hematopoiesis. This phenomenon can be manifested by a monomodal curve in both T1 and T2 relaxometric histograms. PMID- 23086732 TI - Sputum analysis: non-invasive early lung cancer detection. AB - Lung cancer is the leading cause of cancer-related deaths over the world, characterized by a very high mortality rate. Molecular technique development tries to focus on early detection of cancers by studying molecular alterations that characterize cancer cells. Worldwide lung cancer research has focused on an ever-increasing number of molecular elements of carcinogenesis at genetic, epigenetic and protein levels. The non-invasiveness is the characteristic that all clinical trials on cancer detection should have. Abnormal chest imaging and/or non-specific symptoms are initial signals of lung cancer that appear in an advanced stage of disease. This fact represents the cause of the low 5-year survival rate: over 90% of patients dying within 5 years of diagnosis. Since smokers have higher quantity of sputum containing exfoliated cells from the bronchial tree, and the sputum represents the most easily accessible biological fluid and its collection is non-invasive, analysis of this sample represents a good area of research in early lung cancer diagnosis. Continued cigarette smoking is the cause of chronic obstructive pulmonary disease (COPD), with an estimated attributable risk factor exceeding 80% in smoking affected individuals. Lung cancer is found in 40-70% of patients with COPD, particularly in severe disease, and it is a common cause of death in these patients. A large prospective trial of almost half a million non-smokers showed as lung cancer is also common in patients with COPD who have never smoked. This review describes issues related to early lung cancer screening using non-invasive methods. PMID- 23086733 TI - Normal phase LC coupled with direct analysis in real time MS for the chiral analysis of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and jasmonic acid. AB - Normal phase chiral LC (NPLC) has been proved to be powerful and efficient for chiral separation. However, the combination of NPLC with ESI or atmospheric pressure chemical ionization MS is restricted by the poor ionization efficiency and thermal fragmentations of analytes to some extent. Direct analysis in real time MS (DART-MS) is an ambient ionization technique that shows high ionization efficiency of the analytes in the normal phase mobile phase. In this work, we coupled chiral NPLC to DART-MS for the chiral qualitative and quantitative analysis of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol and jasmonic acid enantiomers. Satisfactory results for the enantiomers of 4-(methylnitrosamino)-1 (3-pyridyl)-1-butanol operating in the positive mode were obtained in terms of linearity (2.5-250 MUg/mL, R(2) , 0.999-1.000) and repeatability (25 MUg/mL, RSDs, 4.7-5.6%). Moreover, chiral NPLC-DART-MS resulted in the simultaneous chiral separation and detection of jasmonic acid enantiomers, which are very difficult to be analyzed by NPLC-ESI-MS and NPLC-APCI-MS. Compared with the coupled techniques of NPLC-ESI-MS and NPLC-APCI-MS, NPLC-DART-MS showed advantages in increasing the ionization efficiency and reducing the in-source thermal fragmentation of analytes. PMID- 23086734 TI - Changes in surface chemistry of carbon materials upon electrochemical measurements and their effects on capacitance in acidic and neutral electrolytes. AB - Four porous carbon samples with very similar porosities but visible differences in their surface chemistry are investigated as supercapacitor electrodes in 1 M H2SO4 and 3 M NaCl. The key objective is to monitor the changes to the oxygen- and nitrogen-containing functionalities in oxygen- and nitrogen+oxygen-rich carbons upon a three-electrode test and the effect of these changes on the energy storage capacity in a real two-electrode supercapacitor setup. The carbon samples are thoroughly characterized by nitrogen sorption measurements, Raman spectroscopy, potentiometric titrations, elemental analysis, and synchrotron XPS. The findings presented in this work imply that the pretreatment of the oxygen- and nitrogen+oxygen-rich carbons under the conditions of the three-electrode test in an acidic electrolyte are beneficial to the overall energy storage capacity as the pores become more accessible to the electrolyte ions and the contribution of pseudocapacitive oxygen-containing groups increases in the oxygen-rich carbons, whereas favorable changes to the electronic structure take place in the nitrogen+oxygen-rich carbons. Thus, the total capacitance increases as a result of the improved double-layer capacitance as well as pseudocapacitance. Greater capacitance after the three-electrode test is also measured in a neutral electrolyte for both sets of samples, which is a result of improved double-layer capacitance upon the removal of some oxygen-containing functional groups that leads to better accessibility of the pores. PMID- 23086736 TI - Assessing liver function using dynamic Gd-EOB-DTPA-enhanced MRI with a standard 5 phase imaging protocol. AB - PURPOSE: To evaluate liver function obtained by tracer-kinetic modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data acquired with a routine gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB DTPA)-enhanced protocol. MATERIALS AND METHODS: Data were acquired from 25 cases of nonchronic liver disease and 94 cases of cirrhosis. DCE-MRI was performed with a dose of 0.025 mmol/kg Gd-EOB-DTPA injected at 2 mL/sec. A 3D breath-hold sequence acquired 5 volumes of 72 slices each: precontrast, double arterial phase, portal phase, and 4-minute postcontrast. Regions of interest (ROIs) were selected semiautomatically in the aorta, portal vein, and whole liver on a middle slice. A constrained dual-inlet two-compartment uptake model was fitted to the ROI curves, producing three parameters: intracellular uptake rate (UR), extracellular volume (Ve), and arterial flow fraction (AFF). RESULTS: Median UR dropped from 4.46 10(-2) min(-1) in the noncirrhosis to 3.20 in Child-Pugh A (P = 0.001), and again to 1.92 in Child-Pugh B (P < 0.0001). Median Ve dropped from 6.64 mL 100 mL(-1) in the noncirrhosis to 5.80 in Child-Pugh A (P = 0.01). Other combinations of Ve and AFF changes were not significant for any group. CONCLUSION: UR obtained from tracer kinetic analysis of a routine DCE-MRI has the potential to become a novel index of liver function. PMID- 23086737 TI - Role of NF-kappaB activation in matrix metalloproteinase 9, vascular endothelial growth factor and interleukin 8 expression and secretion in human breast cancer cells. AB - The aims of this study were to assess the effects and potential mechanisms of parthenolide on the expression of vascular endothelial growth factor (VEGF), interleukin 8 (IL-8) and matrix metalloproteinase 9 (MMP-9) in human breast cancer cell line MDA-MB-231. After incubation with different concentrations of parthenolide for 24 h, MDA-MB-231 cells were collected, and the expressions of VEGF, IL-8 and MMP-9 were measured by real-time PCR and Western blot. The secretions of VEGF, IL-8 and MMP-9 in culture supernatant of MDA-MB-231 cells were then measured with ELISA assays. The NF-kappaB DNA-binding activity of breast cancer cells treated with parthenolide was analyzed using electrophoretic mobility assays. The real-time PCR and Western blot data showed that the expressions of VEGF, IL-8 and MMP-9 were significantly inhibited by parthenolide at both transcription level and protein level in MDA-MB-231 cells. ELISA results also confirmed these effects at a secretion level. The electrophoretic mobility assay results demonstrated that parthenolide can inhibit NF-kappaB DNA-binding activity of the breast cancer cells. Hence, the expression of VEGF, IL-8 and MMP 9 may be suppressed by parthenolide through the inhibition of NF-kappaB DNA binding activity in MDA-MB-231 cells. PMID- 23086738 TI - Therapeutic use of electrical stimulation of peripheral nerves to modulate lower urinary tract function and symptoms. PMID- 23086739 TI - Total synthesis of the triglycosyl phenolic glycolipid PGL-tb1 from Mycobacterium tuberculosis. PMID- 23086740 TI - Is unconventional secretion inhibited during cell division by Cdk1 activity? AB - A process of unconventional secretion that is dependent on the Golgi stacking protein GRASP and multiple components of the autophagy machinery has recently been documented for several cytoplasmic and membrane protein. Classical secretion via the exocytic pathway is inhibited during cell division in animal cells, as key membrane compartments, particularly the Golgi, are disassembled and fragmented. The question as to whether unconventional secretion is likewise inhibited during mitosis has not been explored. This mode of secretion supposedly bypasses the Golgi. However, GRASP and Vps34 (a key autophagy protein) are both substrates of the cell cycle regulating cyclin-dependent kinase 1 (Cdk1), and their activities are apparently inhibited by Cdk1 phosphorylation. Is unconventional secretion therefore similarly inhibited during cell division like conventional secretion? The story may yet turn out to be more complicated. PMID- 23086741 TI - Batchwise and continuous nanofiltration of POSS-tagged Grubbs-Hoveyda-type olefin metathesis catalysts. AB - New molecular-weight-enlarged metathesis catalysts, which bear polyhedral oligomeric silsesquioxane (POSS) tags, were synthesized and characterized. The catalysts can be recovered from the reaction mixture by using nanofiltration techniques and can be reused. It was found that the membranes Starmem 228 and PuraMem 280 successfully separate the catalyst from the post-reaction mixtures to below 3 ppm. The application of these POSS-tagged catalysts in a continuous metathesis reaction was also investigated. PMID- 23086742 TI - Human mesenchymal stromal cells are mechanosensitive to vibration stimuli. AB - Low-magnitude high-frequency (LMHF) vibrations have the ability to stimulate bone formation and reduce bone loss. However, the anabolic mechanisms that are mediated by vibration in human bone cells at the cellular level remain unclear. We hypothesized that human mesenchymal stromal cells (hMSCs) display direct osteoblastic responses to LMHF vibration signals. Daily exposure to vibrations increased the proliferation of hMSCs, with the highest efficiency occurring at a peak acceleration of 0.3 g and vibrations at 30 to 40 Hz. Specifically, these conditions promoted osteoblast differentiation through an increase in alkaline phosphatase activity and in vitro matrix mineralization. The effect of vibration on the expression of osteogenesis-related factors differed depending on culture method. hMSCs that underwent vibration in a monolayer culture did not exhibit any changes in the expressions of these genes, while cells in three-dimensional culture showed increased expression of type I collagen, osteoprotegerin, or VEGF, and VEGF induction appeared in 2 different hMSC lines. These results are among the first to demonstrate a dose-response effect upon LMHF stimulation, thereby demonstrating that hMSCs are mechanosensitive to LMHF vibration signals such that they could facilitate the osteogenic process. PMID- 23086743 TI - Parthenogenesis in a Brazilian rainbow boa (Epicrates cenchria cenchria). AB - A 22-year-old captive Brazilian rainbow boa (Epicrates cenchria cenchria) gave birth to four offspring after being housed with a vasectomized male. Sexual reproduction as a result of failed prior vasectomy, recanalization of the vas deferens, or prolonged sperm storage was ruled out using the clinical history, histopathology, and gross necropsy. Short tandem repeat (STR) DNA markers were genotyped in the male, female, and four offspring. None of the offspring possessed a diagnostic STR allele present in the potential sire. In addition, all offspring were homozygous at each STR locus evaluated, supporting parthenogenetic reproduction. This is the first report of parthenogenesis in a Brazilian rainbow boa and has implications for the conservation of reptiles maintained in captive breeding programs. PMID- 23086744 TI - Mechanisms of formation of structural variation in a fully sequenced human genome. AB - Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1 kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10 kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10 kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions. PMID- 23086746 TI - Hyaluronan in cytosol--microinjection-based probing of its existence and suggested functions. AB - Hyaluronan (HA) is a large glycosaminoglycan produced by hyaluronan synthases (HAS), enzymes normally active at plasma membrane. While HA is delivered into the extracellular space, intracellular HA is also seen, mostly in vesicular structures, but there are also reports on its presence in the cytosol and specific locations and functions there. We probed the possibility of HA localization and functions in cytosol by microinjecting fluorescent HA binding complex (fHABC), HA fragments and hyaluronidase (HYAL) into cytosol. Microinjection of fHABC did not reveal HA-specific intracellular binding sites. Likewise, specific cytosolic binding sites for HA were not detected, as microinjected fluorescent HA composed of 4-8 monosaccharide units (HA4-HA8) were evenly distributed throughout the cells, including the nucleus, but excluded from membrane-bound organelles. The largest HA tested (~HA120 or ~25 kDa) did not enter the nucleus, and HA10-HA28 were progressively excluded from parts of nuclei resembling nucleoli. In contrast, HA oligosaccharides endocytosed from medium remained in vesicular compartments. The activity of HA synthesis was estimated by measuring the HA coat on green fluorescent protein (GFP)-HAS3-transfected MCF-7 cells. Microinjection of HA4 reduced coat size at 4 h, but increased at 24 h after injection, while larger HA-oligosaccharides and HYAL had no influence. As a positive control, microinjection of glucose increased coat size. In summary, no evidence for the presence or function of HA in cytosol was obtained. Also, the synthesis of HA and the active site of HAS were not accessible to competition, binding and degradation by cytosolic effectors, while synthesis responded to increased substrate supply. PMID- 23086745 TI - PKCdelta knockdown inhibits free fatty acid induction of endothelial cell apoptosis. AB - The mechanisms whereby free fatty acids induce endothelial cell apoptosis are not yet understood. The present study aimed to investigate the role of PKCdelta in free fatty acid-induced endothelial cell apoptosis. In addition, we looked for evidence of apoptosis-related interactions between PKCdelta and Fas signal pathway. Human umbilical vein endothelial cells were treated with various concentrations of free fatty acids and transiently transfected with PKCdelta siRNA or Fas siRNA to inhibit PKCdelta or Fas expression. Cell proliferation was determined through colorimetric assays, and apoptosis was quantified using flow cytometry. Protein expression was determined from cell lysates using Western blots with antibodies against p-PKCdeltaTyr512, PKCdelta, and Fas. Statistical analyses were performed. Free fatty acids had multiple effects on human umbilical vein endothelial cells, including concentration-dependent inhibition of cell proliferation, induction of apoptosis, increased Fas expression, and increased PKCdelta expression and phosphorylation. Inhibition of PKCdelta mRNA expression by PKCdelta siRNA led to a reduction in both free fatty acid-induced apoptosis and Fas expression. However, Fas siRNA treatment inhibited Fas, but not PKCdelta, expression in human umbilical vein endothelial cells. The free fatty acid-induced apoptosis in endothelial cells are possibly mediated by PKCdelta and may involve upregulation of its downstream Fas. PMID- 23086747 TI - Effects of DMSA-coated Fe3O4 nanoparticles on the transcription of genes related to iron and osmosis homeostasis. AB - In this article, we checked the effect of 2,3-dimercaptosuccinic acid-coated Fe(3)O(4) nanoparticles on gene expression of mouse macrophage RAW264.7 cells and found that the transcription of several important genes related to intracellular iron homeostasis were significantly changed. We thus speculated that the cellular iron homeostasis might be disturbed by this nanoparticle through releasing iron ion in cells. To verify this speculation, we first confirmed the transcriptional changes of several key iron homeostasis- related genes, such as Tfrc, Trf, and Lcn2, using quantitative PCR, and found that an iron ion chelator, desferrioxamine, could alleviate the transcriptional alterations of two typical genes, Tfrc and Lcn2. Then, we designed and validated a method based on centrifugation for assaying intracellular irons in ion and nanoparticle state. After extensive measures of intracellular iron in two forms and total iron, we found that the intracellular iron ion significantly increased with intracellular total iron and nanoparticle iron, demonstrating degradation of this nanoparticle into iron ion in cells. We next mimicked the intralysosomal environment in vitro and verified that the internalized iron nanoparticle could release iron ion in lysosome. We found that as another important compensatory response to intracellular overload of iron ion, cells significantly downregulated the expressions of genes belonging to solute carrier family which are responsible for transferring many organic solutes into cells, such as Slc5a3 and Slc44a1, in order to prevent more organic solutes into cells and thus lower the intracellular osmosis. Based on these findings, we profiled a map of gene effects after cells were treated with this iron nanoparticle and concluded that the iron nanoparticles might be more detrimental to cell than iron ion due to its intracellular internalization fashion, nonspecific endocytosis. PMID- 23086748 TI - Effects of silver nanoparticles on the liver and hepatocytes in vitro. AB - With the increasing use and incorporation of nanoparticles (NPs) into consumer products, screening for potential toxicity is necessary to ensure customer safety. NPs have been shown to translocate to the bloodstream following inhalation and ingestion, and such studies demonstrate that the liver is an important organ for accumulation. Silver (Ag) NPs are highly relevant for human exposure due to their use in food contact materials, dietary supplements, and antibacterial wound treatments. Due to the large number of different NPs already used in various products and being developed for new applications, it is essential that relevant, quick, and cheap methods of in vitro risk assessment suitable for these new materials are established. Therefore, this study used a simple hepatocytes model combined with an in vivo injection model to simulate the passage of a small amount of NPs into the bloodstream following exposure, e.g., via ingestion or inhalation, and examined the potential of Ag NPs of 20 nm diameter to cause toxicity, inflammation, and oxidative stress in the liver following in vivo exposures of female Wistar rats via iv injection to 50 MUg of NPs and in vitro exposures using the human hepatocyte cell line C3A. We found that Ag NPs were highly cytotoxic to hepatocytes (LC(50) lactate dehydrogenase: 2.5 MUg/cm(2)) and affected hepatocyte homeostasis by reducing albumin release. At sublethal concentrations with normal cell or tissue morphology, Ag NPs were detected in cytoplasm and nuclei of hepatocytes. We observed similar effects of Ag NPs on inflammatory mediator expression in vitro and in vivo with increase of interleukin-8 (IL-8)/macrophage inflammatory protein 2, IL-1RI, and tumor necrosis factor-alpha expression in both models and increased IL-8 protein release in vitro. This article presents evidence of the potential toxicity and inflammogenic potential of Ag NPs in the liver following ingestion. In addition, the similarities between in vitro and in vivo responses are striking and encouraging for future reduction, refinement, and replacement of animal studies by the use of hepatocyte cell lines in particle risk assessment. PMID- 23086749 TI - Bacteria differentially induce degradation of Bcl-xL, a survival protein, by human platelets. AB - Bacteria can enter the bloodstream in response to infectious insults. Bacteremia elicits several immune and clinical complications, including thrombocytopenia. A primary cause of thrombocytopenia is shortened survival of platelets. We demonstrate that pathogenic bacteria induce apoptotic events in platelets that include calpain-mediated degradation of Bcl-x(L), an essential regulator of platelet survival. Specifically, bloodstream bacterial isolates from patients with sepsis induce lateral condensation of actin, impair mitochondrial membrane potential, and degrade Bcl-x(L) protein in platelets. Bcl-x(L) protein degradation is enhanced when platelets are exposed to pathogenic Escherichia coli that produce the pore-forming toxin alpha-hemolysin, a response that is markedly attenuated when the gene is deleted from E coli. We also found that nonpathogenic E coli gain degrading activity when they are forced to express alpha-hemolysin. Like alpha-hemolysin, purified alpha-toxin readily degrades Bcl-x(L) protein in platelets, as do clinical Staphylococcus aureus isolates that produce alpha toxin. Inhibition of calpain activity, but not the proteasome, rescues Bcl-x(L) protein degradation in platelets coincubated with pathogenic E coli including alpha-hemolysin producing strains. This is the first evidence that pathogenic bacteria can trigger activation of the platelet intrinsic apoptosis program and our results suggest a new mechanism by which bacterial pathogens might cause thrombocytopenia in patients with bloodstream infections. PMID- 23086750 TI - The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. AB - NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP 70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value. PMID- 23086751 TI - The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. AB - Delta-like 4 (DLL4), a membrane-bound ligand belonging to the Notch signaling family, plays a fundamental role in vascular development and angiogenesis. We identified a conserved microRNA family, miR-30, which targets DLL4. Overexpression of miR-30b in endothelial cells led to increased vessel number and length in an in vitro model of sprouting angiogenesis. Microinjection of miR-30 mimics into zebrafish embryos resulted in suppression of dll4 and subsequent excessive sprouting of intersegmental vessels and reduction in dorsal aorta diameter. Use of a target protector against the miR-30 site within the dll4 3'UTR up-regulated dll4 and synergized with Vegfa signaling knockdown to inhibit angiogenesis. Furthermore, restoration of miR-30b or miR-30c expression during Kaposi sarcoma herpesvirus (KSHV) infection attenuated viral induction of DLL4. Together these results demonstrate that the highly conserved molecular targeting of DLL4 by the miR-30 family regulates angiogenesis. PMID- 23086753 TI - Classification of non-Hodgkin lymphoma in Central and South America: a review of 1028 cases. AB - The distribution of non-Hodgkin lymphoma (NHL) subtypes differs around the world but a systematic study of Latin America has not been done. Therefore, we evaluated the relative frequencies of NHL subtypes in Central and South America (CSA). Five expert hematopathologists classified consecutive cases of NHL from 5 CSA countries using the WHO classification and compared them to 400 cases from North America (NA). Among the 1028 CSA cases, the proportions of B- and T-cell NHL and the sex distribution were similar to NA. However, the median age of B cell NHL in CSA (59 years) was significantly lower than in NA (66 years; P < .0001). The distribution of high-grade (52.9%) and low-grade (47.1%) mature B cell NHL in CSA was also significantly different from NA (37.5% and 62.5%; P < .0001). Diffuse large B-cell lymphoma was more common in CSA (40%) than in NA (29.2%; P < .0001), whereas the frequency of follicular lymphoma was similar in Argentina (34.1%) and NA (33.8%), and higher than the rest of CSA (17%; P < .001). Extranodal NK/T-cell NHL was also more common in CSA (P < .0001). Our study provides new objective evidence that the distribution of NHL subtypes varies significantly by geographic region and should prompt epidemiologic studies to explain these differences. PMID- 23086752 TI - Identification of key regulatory pathways of myeloid differentiation using an mESC-based karyotypically normal cell model. AB - Understanding the process of myeloid differentiation offers important insights into both normal and abnormal developmental processes but is limited by the dearth of experimental models. Here we show that myeloid progenitors can be derived from embryonic stem cells, immortalized, and applied to the study of the mechanisms underlying myeloid differentiation. The embryonic stem cell-derived myeloid progenitors, when immortalized with estrogen-regulated Hoxb8 protein, demonstrate normal karyotyping, are genetically tractable, and can be differentiated into functional neutrophils. Using this model, we identified mammalian target of rapamycin complex 1 as a critical regulator of myeloid differentiation. Together, our studies led to a convenient, karyotypically normal, and genetically manipulatable cellular system, which can be used to shed new light on the mechanisms for myeloid differentiation. PMID- 23086754 TI - Matrix metalloproteases and PAR1 activation. AB - Cardiovascular diseases, including atherothrombosis, are the leading cause of morbidity and mortality in the United States, Europe, and the developed world. Matrix metalloproteases (MMPs) have recently emerged as important mediators of platelet and endothelial function, and atherothrombotic disease. Protease activated receptor-1 (PAR1) is a G protein-coupled receptor that is classically activated through cleavage of the N-terminal exodomain by the serine protease thrombin. Most recently, 2 MMPs have been discovered to have agonist activity for PAR1. Unexpectedly, MMP-1 and MMP-13 cleave the N-terminal exodomain of PAR1 at noncanonical sites, which result in distinct tethered ligands that activate G protein signaling pathways. PAR1 exhibits metalloprotease-specific signaling patterns, known as biased agonism, that produce distinct functional outputs by the cell. Here we contrast the mechanisms of canonical (thrombin) and noncanonical (MMP) PAR1 activation, the contribution of MMP-PAR1 signaling to diseases of the vasculature, and the therapeutic potential of inhibiting MMP-PAR1 signaling with MMP inhibitors, including atherothrombotic disease, in-stent restenosis, heart failure, and sepsis. PMID- 23086756 TI - Systemic delivery of a TLR7 agonist in combination with radiation primes durable antitumor immune responses in mouse models of lymphoma. AB - Passive immunotherapy with monoclonal antibodies has improved outcome for patients with B-cell malignancies, although many still relapse and little progress has been made with T-cell malignancies. Novel treatment approaches are clearly required in this disease setting. There has been much recent interest in developing therapeutic approaches to enhance antitumor immune responses using novel immunomodulatory agents in combination with standard of care treatments. Here we report that intravenous administration of the Toll-like receptor 7 (TLR7) agonist, R848 in combination with radiation therapy (RT), leads to the longstanding clearance of tumor in T- and B-cell lymphoma bearing mice. In combination, TLR7/RT therapy leads to the expansion of tumor antigen-specific CD8(+) T cells and improved survival. Furthermore, those mice that achieve long term clearance of tumor after TLR7/RT therapy are protected from subsequent tumor rechallenge by the generation of a tumor-specific memory immune response. Our findings demonstrate the potential for enhancing the efficacy of conventional cytotoxic anticancer therapy through combination with a systemically administered TLR7 agonist to improve antitumor immune responses and provide durable remissions. PMID- 23086757 TI - Substitution of two fluorine atoms in a trifluoromethyl group: regioselective synthesis of 3-fluoropyrazoles. PMID- 23086755 TI - Platelet secretion is kinetically heterogeneous in an agonist-responsive manner. AB - Platelets release numerous bioactive molecules stored in their granules enabling them to exert a wide range of effects on the vascular microenvironment. Are these granule cargo released thematically in a context-specific pattern or via a stochastic, kinetically controlled process? Here we sought to describe the platelet exocytosis using a systematic examination of platelet secretion kinetics. Platelets were stimulated for increasing times with different agonists (ie, thrombin, PAR1-agonist, PAR4-agonist, and convulxin) and micro-ELISA arrays were used to quantify the release of 28 distinct alpha-granule cargo molecules. Agonist potency directly correlated with the speed and extent of release. PAR4 agonist induced slower release of fewer molecules, whereas thrombin rapidly induced the greatest release. Cargo with opposing actions (eg, proangiogenic and antiangiogenic) had similar release profiles, suggesting limited thematic response to specific agonists. From the release time-course data, rate constants were calculated and used to probe for underlying patterns. Probability density function and operator variance analyses were consistent with 3 classes of release events, differing in their rates. The distribution of cargo into these 3 classes was heterogeneous, suggesting that platelet secretion is a stochastic process potentially controlled by several factors, such as cargo solubility, granule shape, and/or granule-plasma membrane fusion routes. PMID- 23086758 TI - Interleukin-27 expression modifies prostate cancer cell crosstalk with bone and immune cells in vitro. AB - Prostate cancer is frequently associated with bone metastases, where the crosstalk between tumor cells and key cells of the bone microenvironment (osteoblasts, osteoclasts, immune cells) amplifies tumor growth. We have explored the potential of a novel cytokine, interleukin-27 (IL-27), for inhibiting this malignant crosstalk, and have examined the effect of autocrine IL-27 on prostate cancer cell gene expression, as well as the effect of paracrine IL-27 on gene expression in bone and T cells. In prostate tumor cells, IL-27 upregulated genes related to its signaling pathway while downregulating malignancy-related receptors and cytokine genes involved in gp130 signaling, as well as several protease genes. In both undifferentiated and differentiated osteoblasts, IL-27 modulated upregulation of genes related to its own signaling pathway as well as pro-osteogenic genes. In osteoclasts, IL-27 downregulated several genes typically involved in malignancy and also downregulated osteoclastogenesis-related genes. Furthermore, an osteogenesis-focused real-time PCR array revealed a more extensive profile of pro-osteogenic gene changes in both osteoblasts and osteoclasts. In T-lymphocyte cells, IL-27 upregulated several activation-related genes and also genes related to the IL-27 signaling pathway and downregulated several genes that could modulate osteoclastogenesis. Overall, our results suggest that IL-27 may be able to modify interactions between prostate tumor and bone microenvironment cells and thus could be used as a multifunctional therapeutic for restoring bone homeostasis while treating metastatic prostate tumors. PMID- 23086759 TI - Sequential identification of a degradable phosphate glass scaffold for skeletal muscle regeneration. AB - Tissue engineering has the potential to overcome limitations associated with current management of skeletal muscle defects. This study aimed to sequentially identify a degradable phosphate glass scaffold for the restoration of muscle defects. A series of glass compositions were investigated for the potential to promote bacterial growth. Thereafter, the response of human craniofacial muscle derived cells was determined. Glass compositions containing Fe4- and 5 mol% did not promote greater Staphylococcus aureus and Staphylococcus epidermidis growth compared to the control (p > 0.05). Following confirmation of myogenicity, further studies assessed the biocompatibility of glasses containing Fe5 mol%. Cells seeded on collagen-coated disks demonstrated comparable cellular metabolic activity to control. Upregulation of genes encoding for myogenic regulatory factors (MRFs) confirmed myofibre formation and there was expression of developmental MYH genes. The use of 3-D aligned fibre scaffolds supported unidirectional cell alignment and upregulation of MRF and developmental MYH genes. Compared to the 2-D disks, there was also expression of MYH2 and MYH7 genes, indicating further myofibre maturation on the 3-D scaffolds and confirming the importance of key biophysical cues. PMID- 23086760 TI - Maximal expansion capacity with current DES platforms: a critical factor for stent selection in the treatment of left main bifurcations? AB - AIMS: Left main stenting is increasingly performed and often involves deployment of a single stent across vessels with marked disparity in diameters. Knowing stent expansion capacity is critical to ensure adequate strut apposition after post-dilatation of the stent has been performed. Coronary stents are usually manufactured in only two or three different model designs with each design having a different maximal expansion capacity. Information about the different workhorse designs and their maximal achievable diameter is not commonly provided by manufacturers but, in the absence of this critically important information, stents implanted in segments with major changes in vessel diameter have the potential to become grossly overstretched and to remain incompletely apposed. METHODS AND RESULTS: We examined the differences in workhorse designs of six commercially available drug-eluting stents (DES): the PROMUS Element, Taxus Liberte, XIENCE Prime, Resolute Integrity, BioMatrix Flex and Cypher Select stents. Using micro-computed tomography, we tested oversizing capabilities above nominal pressures for the different workhorse designs of the six DES using 4.0, 5.0 and 6.0 mm post-dilatation balloons inflated to 14 atmospheres. MLD could be increased significantly in all stents, only restricted by workhorse design limitations. Minimal inner lumen diameter (MLD) achieved after two successive 6.0 mm post-dilatations of the largest design (4.0 mm stent) was 5.7 mm for the Element, 5.6 mm for the XIENCE Prime, 6.0 mm for the Taxus, 5.4 mm for the Resolute Integrity, 5.9 mm for the BioMatrix and 5.8 mm for the Cypher stent. Significant deformations were observed during stent oversizing with large changes in terms of cell opening and crowns expansion. These are affected by design structure and reveal important differences among all stents tested. Such extensive deformations may alter the functional ability of an individual stent to scaffold a lesion and prevent restenosis. CONCLUSIONS: Stent selection based on stent model design may be critical, particularly for treatment of large artery and left main bifurcations where overexpansion is normally required to optimise results and ensure full expansion of the stent. PMID- 23086761 TI - Factors influencing microsurgical skill acquisition during a dedicated training course. AB - BACKGROUND: Proficient microsurgical skills are considered essential in plastic and reconstructive surgery. Specialized courses offer trainees opportunity to improve their technical skills. Trainee aptitude may play an important role in the ability of a trainee to acquire proficient skills as individuals have differing fundamental abilities. We delivered an intensive 5-day microsurgical training course. We objectively assessed the impact of the course on microsurgical skill acquisition and whether aptitudes as assessed with psychometric tests were related to surgical performance. METHODS: Sixteen surgical trainees (male = 10 and female = 6) participated in the courses. Trainees' visual spatial, perceptual, and psychomotor aptitudes were assessed on day 1 of the course. The trainees' performance of an end-to-end arterial anastomosis was assessed on days 2 and 5. Surgical performance was assessed with objective structured assessment of technical skills(OSATS) and time to complete the task. RESULTS: The trainees showed a significant improvement in OSATS scores from days 2 to 5 (P < 0.001) and the time taken to complete the anastomosis (P < 0.001). Aptitude scores correlated strongly with objectively assessed microsurgical skill performance for male trainees but not for females. CONCLUSIONS: We demonstrated that participating in a microsurgical training course results in significant improvement in objectively assessed microvascular surgical skills. The degree of skills improvement was strongly correlated with psychomotor aptitude assessments scores for male trainees. PMID- 23086762 TI - Should intraoperative frozen section evaluation of breast lumpectomy margins become routine practice? PMID- 23086763 TI - Laboratory quality control for all. Can this be achieved? PMID- 23086764 TI - Soluble transferrin receptor (sTfR) and sTfR/log ferritin index for the diagnosis of iron-deficiency anemia. A meta-analysis. AB - Determination of serum soluble transferrin receptor (sTfR) is proposed to distinguish between iron-deficiency anemia and anemia of chronic disease. Here we conducted a meta-analysis of the literature to evaluate the diagnostic efficacy of sTfR and sTfR/log ferritin index. The meta-analysis included 18 sTfR and 10 sTfR index studies. Three sTfR index studies were, however, eliminated as outliers. The odds ratio was significant for both sTfR (22.9, 95% confidence interval [CI], 9.6-55.0) and sTfR index (9.5, 95% CI, 5.0-18.1) in a heterogeneous set of studies. Meta-analysis for sensitivity, specificity, and likelihood ratios (LRs) was performed only in a subset of 10 sTfR studies. The overall sensitivity, specificity, and positive and negative LRs were 86%, 75%, 3.85, and 0.19, respectively, with an area under summary receiver operating characteristic curve of 0.912 (standard error, 0.039). Additional studies are needed to define the overall diagnostic accuracy of sTfR. PMID- 23086765 TI - CINtec PLUS immunocytochemistry as a tool for the cytologic diagnosis of glandular lesions of the cervix uteri. AB - Cytologic findings of glandular lesions of the cervix uteri are often difficult to evaluate. We studied the usefulness of CINtec PLUS p16/Ki-67 double stain (mtm laboratories, Heidelberg, Germany) for the diagnosis of glandular lesions. The study included 47 abnormal results on liquid-based cytologic tests with a subsequent histologic diagnosis of adenocarcinoma in situ or with early invasion, and 16 samples with negative results on follow-up. All samples were stained with CINtec PLUS p16/Ki-67 double stain. Of the neoplastic samples, 7 were excluded because of insufficient residual cellularity or loss of neoplastic cells. Of the samples that were adequate, 92.5% were stained with CINtec PLUS, whereas 7.5% were judged inconclusive. All inconclusive cases were at least 3 years old. Of the 16 negative samples, 15 (93.8%) stained negative and only 1 (6.2%) showed several positive clusters of cells. Our study shows that CINtec PLUS is a robust and useful tool for the diagnosis of glandular lesions of the cervix uteri. PMID- 23086767 TI - Molecular diagnostics of melanoma fine-needle aspirates: a cytology-histology correlation study. AB - Patients with advanced-stage melanoma harboring a BRAF mutation are candidates for BRAF inhibition as a therapeutic strategy. The use of fine-needle aspiration (FNA) to diagnose metastatic melanoma is increasing. Studies examining the predictive value of BRAF mutation analysis on melanoma FNAs via correlation with follow-up excision findings are lacking. We examined 37 consecutive FNA cases of metastatic melanoma in which the aspirated lesion was subsequently excised. DNA was purified from Diff-Quik-stained FNA smears and tissue blocks from corresponding excisions in parallel. BRAF mutation status was successfully obtained from both specimen types in 34 (92%) of 37 cases. BRAF mutations were detected in 12 (35%) of 34 cases-11 V600E and 1 V600K. Results of BRAF mutational analysis were concordant in all 34 FNA smear/tissue excision pairs. Thus, melanoma FNA for molecular diagnostics represents a rapid, minimally invasive, and effective management strategy in this era of precision medicine. PMID- 23086766 TI - Intraoperative frozen section analysis of margins in breast conserving surgery significantly decreases reoperative rates: one-year experience at an ambulatory surgical center. AB - Intraoperative frozen section (FS) margin evaluation is not common practice for patients undergoing breast conservation therapy (BCT), but offers a significant reduction in reoperation. In this study, a technique to allow for more effective freezing of breast tissue was developed to perform FS evaluation of lumpectomy margins (FSM) for all patients undergoing BCT at an ambulatory surgery center. FS evaluation of sentinel lymph node biopsy specimens was performed concurrently. One hundred eighty-one study and 188 control patients, with and without FS evaluation, were compared. Reexcision was reduced 34% (from 48.9% to 14.9%) and reoperation was reduced 36% (from 55.3% to 19.3%) with FS evaluation. Most of the decrease in reoperative rate was because of a decrease in the need for margin reexcision. The number of patients requiring 1, 2, or 3 operations to complete therapy was 84, 92, and 12, respectively, in the control group, and 146, 33, and 2, respectively, in the study group. Lobular subtype, multifocal disease, and larger tumor size (>=2 cm) were significantly associated with failure of FSM to prevent reoperation, but reoperation rates were still significantly decreased in this subgroup of patients (from 75.5% to 43.8%) with FSM. This study highlights an innovative yet simple and adaptable FS approach that resulted in a nearly 3 fold reduction in reoperation for patients undergoing BCT. PMID- 23086768 TI - Utility of PAX2 as a marker for diagnosis of endometrial intraepithelial neoplasia. AB - Diagnosis of endometrial intraepithelial neoplasia (EIN) requires learning new criteria. Two trainees rendered diagnoses based on biopsy findings, and then measured the effect of reviewing PAX2 on their interpretation. Fifty-two endometrial biopsy specimens diagnosed as having EIN were evaluated using EIN criteria. Background endometrial pattern, altered differentiation, and any features complicating diagnosis were noted. PAX2 stains were scored as confusing, helpful, or noncontributory. Fifty-two cases generated 104 passes; 82% were rediagnosed as EIN. The diagnosis was complicated because of altered differentiation (14%), EIN and background separation (13%), large lesions lacking background (11%), and secretory background (8%). PAX2 was most helpful in cases with secretory backgrounds and when EIN lacked adjacent normal tissue, and most confusing when scoring was ambiguous (14%). The diagnosis of EIN can be difficult when: (1) the lesion cannot be easily compared with background; (2) there is a confounding process; and (3) gland differentiation is altered. PAX2 can be of assistance in delimiting EIN lesions. PMID- 23086770 TI - Comparison of anti-estrogen receptor antibodies SP1, 6F11, and 1D5 in breast cancer: lower 1D5 sensitivity but questionable clinical implications. AB - We compared the anti-estrogen receptors (ER) SP1, 6F11, and 1D5 antibodies in breast carcinoma cases with different ranges of positive cells to evaluate whether this could generate different therapies for patients. We selected 66 cases of breast cancer, each of which was immunostained with the 3 antibodies. 1D5 was less sensitive than SP1 and 6F11, as seen in 26, 20, and 21 negative cases, respectively. Nine cases showed differences in endocrine-therapy indications, of which 8 1D5-negative cases showed low positivity for SP1 and/or 6F11. However, these cases were prevalently G3, progesterone receptor-negative or low-positive, with high Ki-67 and positive HER-2 findings, all biological features associated with endocrine resistance. Finally ER values obtained with these 3 antibodies had no implications for chemotherapy. PMID- 23086771 TI - Comparison of monoclonal napsin A, polyclonal napsin A, and TTF-1 for determining lung origin in metastatic adenocarcinomas. AB - Thyroid transcription factor 1 (TTF-1) is currently the best immunohistochemical marker for carcinomas of lung origin. Our aim was to compare napsin A to TTF-1 for identifying pulmonary origin in metastatic adenocarcinoma and its mimics. One hundred fifty-five metastatic carcinomas (55 pulmonary, 100 nonpulmonary) were stained with monoclonal napsin A and TTF-1, and most also with polyclonal napsin A. The sensitivity of monoclonal napsin A, polyclonal napsin A, and TTF-1 for metastatic adenocarcinomas of pulmonary origin was 76%, 81%, and 82%, respectively. Two lung carcinomas were diffusely positive for monoclonal napsin A, but negative or equivocal for TTF-1. TTF-1 stained 9 of 100 nonpulmonary carcinomas (all thyroid), monoclonal napsin A stained 12 of 100 (4 sites), and polyclonal napsin A stained 27 of 91 (8 sites). Napsin A is expressed in a wider variety of metastatic nonpulmonary carcinomas than TTF-1, and the monoclonal antibody is more specific. Napsin A is a useful adjunct to TTF-1, because occasional lung adenocarcinomas are TTF-1 negative but napsin A positive. PMID- 23086772 TI - Morphologic and clinicopathologic features of lung squamous cell carcinomas expressing Sox2. AB - Sox2 amplification was recently reported as a common event in squamous cell carcinomas (SCCs) occurring at different anatomic sites including the lung. The objective of the study was to determine morphologic and clinicopathologic characteristics of lung SCCs with respect to Sox2 protein expression and gene amplification. One hundred forty-seven surgically treated non-small cell lung carcinomas were analyzed for Sox2 gene amplification by using fluorescence in situ hybridization and protein expression using immunohistochemical analysis. SCC showed more frequent Sox2 protein expression (52/66; 79%) than adenocarcinomas (ADC) (14/76; 18%) (P < .0001). Similarly, Sox2 amplification was more frequent in SCCs (52/70; 72%) than in ADCs (6/77; 8%) (P < .0001). Sox2 protein expression was associated with better overall survival in SCC (66 vs 14 months; P =.048). SCC with basaloid differentiation and severe nuclear atypia exhibited more intense Sox2 protein expression than other tumors. Sox2 appears to be an important gene in lung squamous cell carcinogenesis that in particular drives the development of poorly differentiated tumors. PMID- 23086769 TI - Correlation of urine TMPRSS2:ERG and PCA3 to ERG+ and total prostate cancer burden. AB - ERG rearrangements (most commonly transmembrane protease, serine 2 [TMPRSS2]:ERG [T2:ERG] gene fusions) have been identified in approximately 50% of prostate cancers . Quantification of T2:ERG in postdigital rectal examination urine, in combination with PCA3, improves the performance of serum prostate-specific antigen for prostate cancer prediction on biopsy. Here we compared urine T2:ERG and PCA3 scores with ERG+ (determined with immunohistochemical analysis) and total prostate cancer burden in 41 mapped prostatectomies. Prostatectomies had a median of 3 tumor foci (range, 1-15) and 2.6 cm of summed linear tumor dimension (range, 0.6-7.1 cm). Urine T2:ERG score correlated most with summed linear ERG+ tumor dimension and number of ERG+ foci (r(s) = 0.68 and 0.67, respectively, both P < .001). Urine PCA3 score showed weaker correlation with both number of tumor foci (r(s) = 0.34, P = .03) and summed linear tumor dimension (r(s) = 0.26, P = .10). In summary, we demonstrate a strong correlation between urine T2:ERG score and total ERG+ prostate cancer burden at prostatectomy, consistent with high tumor specificity. PMID- 23086773 TI - External quality assurance performance of clinical research laboratories in sub saharan Africa. AB - Patient Safety Monitoring in International Laboratories (JHU-SMILE) is a resource at Johns Hopkins University that supports and monitors laboratories in National Institutes of Health-funded international clinical trials. To determine the impact of the JHU-SMILE quality assurance scheme in sub-Saharan African laboratories, we reviewed 40 to 60 months of external quality assurance (EQA) results of the College of American Pathologists (CAP) in these laboratories. We reviewed the performance of 8 analytes: albumin, alanine aminotransferase, creatinine, sodium, WBC, hemoglobin, hematocrit, and the human immunodeficiency virus antibody rapid test. Over the 40- to 60-month observation period, the sub Saharan laboratories had a 1.63% failure rate, which was 40% lower than the 2011 CAP-wide rate of 2.8%. Seventy-six percent of the observed EQA failures occurred in 4 of the 21 laboratories. These results demonstrate that a system of remote monitoring, feedback, and audits can support quality in low-resource settings, even in places without strong regulatory support for laboratory quality. PMID- 23086774 TI - Determination of turnaround time in the clinical laboratory: "accessioning-to result" time does not always accurately reflect laboratory performance. AB - Laboratories often focus on computer-generated components of turnaround time (TAT) reports that capture time from sample accessioning to reporting of results, and use this indicator to determine performance. This study assesses limitations of "accessioning-to-results" times and details ways in which to evaluate laboratory-controlled TAT. Samples were sent via pneumatic tube and times from arrival to accessioning were determined. Staffing was increased and the delay between sample arrival and accessioning was measured again. Significant delays were seen between specimen arrival and accessioning, which were not captured with computer-generated TAT reports. When TAT was calculated to include these delays, the TAT goal was not achieved. Increasing the number of employees significantly decreased delays. Laboratories must ensure that TAT reports encompass all laboratory-controlled parts of the testing processes. Analysis of causes for discrepancies between computer reports and clinician perceptions, combined with targeted measurements and well-designed interventions, can decrease TAT and improve service. PMID- 23086775 TI - Diagnostic potential of CD34+ cell antigen expression in myelodysplastic syndromes. AB - The World Health Organization introduced flow cytometry as an additional criterion for diagnosis of myelodysplastic syndromes (MDS). Aberrant antigen expression on bone marrow (BM) blasts may identify "low-grade MDS." This study aimed to examine differences in antigen expression on CD34+ BM cells between patients with MDS and those with secondary cytopenia. BM aspirates of 175 patients with cytopenia were classified as MDS or secondary cytopenia. Expression of stem cell antigens (CD34, CD133), myeloid antigens (CD13, CD33), B-cell antigens (CD19, CD10), growth factor receptors (CD117, CD123), and chemokine receptor (CD184) was examined. Thirty-two normal adults and 49 patients with CD34+ acute myeloid leukemia (AML) were also examined. High percentage of CD34+ cells, CD117 and CD123 overexpression, and abnormal CD45 expression on these cells are the best markers for MDS. These phenotypic aberrancies correlate with number of blasts and degree of dysplasia, and were similar to those in CD34+ AML, thus reflecting the relationship between these disorders. PMID- 23086776 TI - Usefulness of CD11a and CD18 in flow cytometric immunophenotypic analysis for diagnosis of acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is an aggressive disease that requires prompt diagnosis and therapy. Flow cytometry immunophenotyping can serve as a screening test for APL before the results of cytogenetic or molecular testing for t(15;17)(q22;q21)/PML-RARalpha are often dimly expressed or absent in APL. We used flow cytometry immunophenotyping with an antibody panel including CD11a and CD18 to assess 36 APL and 33 other AML cases. HLA-DR, CD11a, and CD18 were absent in 81% of APL and 12% of other AML cases (specificity, 88%). By further including combinations of HLA-DR-, CD2+, and either CD11a- or CD18-, we identified 92% of APL cases with 85% specificity. These data compare favorably with the combination of HLA-DR-, CD34-, and CD117+ for APL diagnosis, which had a sensitivity of 64% in this study. PMID- 23086777 TI - Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP-BEZ235 in renal cell carcinoma cells. AB - The PI3K/AKT/mTOR pathway plays a key role in the development of the hypervascular tumor renal cell carcinoma (RCC). NVP-BEZ235 (NVP), a novel dual PI3K/mTOR inhibitor, showed great antitumor benefit and provided a treatment strategy in RCC. In this study, we test the effect of NVP on survival rate, apoptosis and autophagy in the RCC cell line, 786-0. We also explore the hypothesis that NVP, in combination with autophagy inhibitors, leads to apoptosis enhancement in 786-0 cells. The results showed that the PI3K/AKT/mTOR pathway proteins p-AKT and p-P70S6K were highly expressed in RCC tissue. We also showed that NVP inhibited cell growth and induced apoptosis and autophagy in RCC cells. The combination treatment of NVP with autophagy inhibitors enhanced the effect of NVP on suppressing 786-0 growth and induction of apoptosis. This study proposes a novel treatment paradigm where combining PI3K/AKT/mTOR pathway inhibitors and autophagy inhibitors lead to enhanced RCC cell apoptosis. PMID- 23086779 TI - Rhodium(III)-catalyzed oxidative C-H functionalization of azomethine ylides. PMID- 23086780 TI - What is the "what": reflections on language after PCR London Valves. PMID- 23086781 TI - Radiation exposure as an occupational hazard. PMID- 23086778 TI - Kohlschutter-Tonz syndrome: mutations in ROGDI and evidence of genetic heterogeneity. AB - Kohlschutter-Tonz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschutter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease. PMID- 23086782 TI - Renal denervation for resistant hypertension treatment: a novel team approach. PMID- 23086783 TI - The occupational effects of interventional cardiology: results from the WIN for Safety survey. AB - AIMS: Interventional cardiologists are amongst the most intensive radiation users within medicine. To assess the implications of this usage, the "Women In Innovation" Group (WIN) created a web-based survey called "WIN for Safety" distributed through the European Association of Percutaneous Coronary Intervention (EAPCI) to all catheterisation laboratory healthcare professionals, enquiring about radiation protection measures, compliance with monitoring, health (orthopaedic issues), radiation-associated problems (cataracts and cancer) and restrictions imposed upon the pregnant female. METHODS AND RESULTS: In total, there were 615 participants: 72.8% were interventional cardiologists. Most (73.5%) of them were male and 63.3% were aged 31-50 years. A radiation collar badge was used by the majority (64.4%) and the most frequently utilised protective measure was the thyroid shield (87.2%). Potential illnesses related to radiation exposure included 19.5% orthopaedic problems (back/neck/hip pain), 5.5% varicose veins, 2.4% blood count problems and 2.0% cataracts. Notably, an association between orthopaedic problems and years of exposure was found (p=0.001). Overall, only 2.2% had ever been diagnosed with a cancer, with a trend for more females to be affected (4.4% vs. 1.8%; p=0.067). Finally, 62.1% have restrictions imposed upon the pregnant female in the working environment. CONCLUSIONS: Awareness of radiation in the field of interventional cardiology is essential. The main risk is orthopaedic problems and measures should be taken for prevention. Cancer has not been demonstrated to be a direct consequence; however, we should remain vigilant and monitor individuals. PMID- 23086784 TI - Triple antithrombotic therapy following an acute coronary syndrome: prevalence, outcomes and prognostic utility of the HAS-BLED score. AB - AIMS: The aim of this study was to evaluate the prevalence of triple antithrombotic therapy (TT) (warfarin, aspirin and clopidogrel) in patients following an acute coronary syndrome (ACS), the bleeding risk compared to double antiplatelet therapy (DAPT) (aspirin and clopidogrel) and evaluate the accuracy of the HAS-BLED risk score in predicting serious bleeding events in TT patients. METHODS AND RESULTS: We retrospectively identified all ACS patients on TT upon discharge from the Coronary Care Unit at Skane University Hospital between 2005 and 2010. TT patients were compared to age- and sex-matched control patients discharged with DAPT. Major bleeding was defined in accordance with the HAS-BLED derivation study. A total of 2,423 patients were screened, of whom 159 (6.6%) were on TT. The mean age was 67.2 (+/-0.9) years. The most common indication for TT was atrial fibrillation (n=63, 39.6%) followed by apical akinesia (n=60, 37.8%), and the mean duration of TT was 3.7 (+/-0.3) months. Upon termination of TT, warfarin was discontinued in 82 (52.2%) patients and clopidogrel in 57 (36.3%) patients. The cumulative incidence of spontaneous bleeding events was significantly higher with TT compared to DAPT at one year (10.2% vs. 3.2%; p=0.01). The HAS-BLED score significantly predicted spontaneous bleeding events in TT patients (area under the receiver operating characteristic [ROC] curve 0.67; 95% CI=0.54-0.79; p=0.048). CONCLUSIONS: TT was relatively common following acute coronary syndrome and was associated with a threefold increase in major bleeding compared to DAPT at one year. The HAS-BLED risk score predicted bleeding events with moderate accuracy. PMID- 23086785 TI - Patient radiation exposure during transcatheter aortic valve replacement procedures. AB - AIMS: To describe patient radiation utilisation during transcatheter aortic valve replacement (TAVR) on a series of consecutive patients. METHODS AND RESULTS: Data on radiation exposure were prospectively collected for consecutive patients undergoing TAVR and percutaneous coronary interventions at our centre. Radiation dose during the procedure was recorded using the US Food and Drug Administration (FDA) reference point (Ka,r) and the dose area product (PKA). In addition to quantifying overall radiation doses during TAVR, radiation exposure during transfemoral (TF) (n=79) and transapical (TA) (n=26) cases was compared. The median radiation dose during TAVR was 1,639 mGy (983-2,420), or 188 (106-321) Gy*cm2. Radiation dose was significantly lower among TA patients using either the reference point (TA: 946 [777-1,261] vs. TF: 1,932 [1,383-2,614] mGy; p<0.001) or the dose area product (TA: 89 [60-115] vs. TF: 236 [164-338] Gy*cm2; p<0.001). Fluoroscopy time was lower for TA patients (TA: 10 [8-11] vs. TF: 30 [24-34] minutes; p<0.001). Operators experience did not affect radiation exposure for TF cases. CONCLUSIONS: Radiation exposure during TAVR appears similar to other percutaneous coronary interventions of moderate complexity. Radiation doses were significantly lower for TA procedures. A higher dose of radiation in TF patients may be related to additional imaging requirements to optimise percutaneous vascular access and closure. PMID- 23086786 TI - Right subclavian approach as a feasible alternative for transcatheter aortic valve implantation with the CoreValve ReValving System. AB - AIMS: Arterial access selection is crucial during transcatheter aortic valve implantation. When traditional femoral access has been deemed unfeasible the left subclavian artery has been used successfully. In cases where even the latter was ineligible, we opted, despite the lack of any data, for the right subclavian approach. We hereby present the results of the first series available. Our aim was to evaluate the feasibility and performance of the CoreValve ReValving System (CRS) implantation via the right subclavian artery in patients with contraindication to femoral and left subclavian accesses. METHODS AND RESULTS: Among 300 patients who have undergone CRS implantation, 70 (23%) have been treated via the subclavian approach, 10 via the right subclavian artery and 60 via the left. Demographic features were quite similar except for the presence of significant left subclavian disease in all patients treated via the right subclavian artery. The success rate was 100% for both groups. At 30-day follow up, there was no significant difference in terms of all-cause mortality and cardiac mortality between right vs. left subclavian approach (0% vs. 6.6% and 0% vs. 6.6%, respectively). Consistent results were observed at a mean follow-up of 12+/-7.9 months (all-cause mortality: 10% vs. 15%). Incidences of new AV block requiring PM implantation were also statistically equivalent. CONCLUSIONS: CRS implantation via the right subclavian artery was as feasible and safe as the left subclavian approach. It poses very particular technical issues but should be considered when more conventional approaches are inadequate in order to provide patients with a further chance to be treated effectively. PMID- 23086787 TI - Simultaneous kissing drug-eluting stents to treat unprotected left main stem bifurcation disease: medium term outcome in 150 consecutive patients. AB - AIMS: Percutaneous coronary intervention (PCI) is increasingly being used to treat left main stem (LMS) coronary artery disease. Disease at the LMS bifurcation is technically challenging to treat, and there is no consensus as to the best method. We previously described experimental and initial clinical results with the simultaneous kissing stents (SKS) technique in a small series using drug-eluting stents (DES). We now report our results in a larger cohort with long-term follow-up. METHODS AND RESULTS: We treated 150 consecutive, unselected patients with unprotected bifurcation LMS with SKS using DES. The patients' mean age was 67 years, 70% were male, 45% were non-elective and 35% were not surgical candidates. The New York Risk Score estimate of in-hospital mortality was (median) 0.7% (IQR 0.3-3.9%), logistic EuroSCORE 3.3% (1.3-11.9%) and angiographic SYNTAX score 20 (15-27). SKS were deployed in 99.3% of cases, and DES in 97%. There was no emergency CABG. The mortality rate at one year was 11.3% and at two years 12.7%. The (ischaemia-driven) target lesion revascularisation rate was 4.3% at one year and 6.2% at two years. CONCLUSIONS: The SKS technique for treating ULMS bifurcation disease is simple, feasible, effective and durable in treating "all-comers" with LMS bifurcation disease. It is a two-stent technique worthy of consideration at the LMS bifurcation. PMID- 23086788 TI - Angiographic and clinical outcome of percutaneous coronary intervention for in stent restenosis of bifurcated lesions. AB - AIMS: Restenosis and bifurcated lesions represent technically challenging lesions for percutaneous coronary interventions (PCI). Data regarding procedural and clinical outcome of re-PCI for restenosis of stented bifurcated lesions are lacking. Our aims were to evaluate angiographic and procedural results and one year clinical outcome of PCI for restenosis of stented bifurcated lesions. METHODS AND RESULTS: Consecutive patients undergoing PCI for restenosis of one bifurcated lesion previously treated by stent implantation at our centre entered the study. The primary endpoint was angiographic and procedural success, defined as final residual stenosis <=30% in the main vessel with TIMI 3 flow in both MV and side branch, and stenosis <=50% in the SB without death, myocardial infarction or target vessel revascularisation during hospitalisation. The secondary endpoint was the incidence of major adverse cardiac events at one-year clinical follow-up. The study population included 64 patients treated by PCI on a single restenotic bifurcated lesion. Angiographic and procedural success was achieved in 61 cases (95.3%) whereas the three cases of failure were due to SB residual stenosis >50%. At one year, MACE rate was 18.7% (12/64) with rates of cardiac death, MI and TVR of 1.6% (1/64), 6.2% (4/64) and 18.7% (12/64), respectively. No cases of stent thrombosis occurred. Patients treated by a single drug-eluting stent (DES) on main vessel (MV) had a significant lower rate of MACE at one year as compared to patients treated with balloon only PCI or by double stenting technique or with a BMS, irrespective of the strategy adopted: 4/37 (10.8%) vs. 8/27 (29.6%); p=0.04. CONCLUSIONS: PCI in restenotic bifurcated lesions can be a good treatment option with high rates of angiographic and procedural success and an acceptable rate of long-term MACE. The use of a single DES implantation may be a promising strategy as it is associated with lower rates of MACE in the long term. PMID- 23086789 TI - Plaque distribution patterns in left main trunk bifurcations: prediction of branch vessel compromise by multidetector row computed topography after percutaneous coronary intervention. AB - AIMS: We investigated the mechanism and predictors of jailed branch vessel (BV) compromise during the stenting of left main trunk (LMT) bifurcation lesions from a multidetector row computed tomography (MDCT) analysis. METHODS AND RESULTS: Eighty patients who underwent MDCT and stenting for LMT bifurcation lesions were examined. The patients were retrospectively classified into a BV stenosis (BVS; n=38) group and a non-BV stenosis (NBVS; n=42) group according to a coronary angiography obtained just after crossover stent deployment for the target vessel (TV). The angle between the LMT and TV was significantly wider in the BVS group than in the NBVS group (140.2+/-10.3 degree vs. 132.6+/-14.2 degree, p=0.0076), and the frequency of carina side plaque at the TV in the long and short axis was significantly higher in the BVS group than in the NBVS group (50.0% vs. 16.7%; p=0.0012, 63.2% vs. 38.1%; p=0.0251, respectively). In a multivariate analysis, the presence of carina side plaque at the TV in the long and short axis were independent predictors of BVS (odds ratio: 5.15, p=0.0086, odds ratio: 3.83, p=0.0231, respectively). CONCLUSIONS: The plaque distribution and morphology assessed by MDCT may provide useful information that can predict the potential compromise of the BV during treatment for an LMT bifurcation lesion. PMID- 23086790 TI - Percutaneous closure of the patent foramen ovale using the HELEX(r) Septal Occluder: acute and long-term results in 405 patients. AB - AIMS: Although routinely used, limited data are available regarding the long-term outcome after patent foramen ovale (PFO) closure using the HELEX(r) Occluder system. The aim of this study was therefore the examination of the acute and long term outcome after transcatheter PFO closure using this system. METHODS AND RESULTS: All (n=407) patients included had undergone PFO closure with the HELEX(r) Occluder system for secondary prevention of stroke, transient ischaemic attack (TIA) or peripheral embolism at a single centre. Primary endpoints were residual shunts at six or 12 months (assessed by transoesophageal echocardiography) and the number of neurological and other adverse events during follow-up. Device implantation was successful in 99% of patients. Complete closure at six months was achieved in 81%. During follow-up of 1,695 patient years, 10 neurologic events occurred (four TIA, six strokes). The annual incidence of stroke was 1.2%. Other adverse events were wire frame fractures requiring no further intervention in five (1%), device-associated thrombus formation in one (0.25%), and paroxysmal atrial fibrillation in nine patients (2%). CONCLUSIONS: PFO closure using the HELEX(r) Occluder system is feasible and safe. Complications and adverse events during long-term follow-up are rare. The safety profile and efficacy in prevention of recurrent events compare well to that reported with other closure devices. PMID- 23086791 TI - Comparison of vascular response to the everolimus-eluting stent versus the paclitaxel-eluting stent: intravascular ultrasound results from the SPIRIT III trial. AB - AIMS: The purpose of this study was to investigate the vascular response of the everolimus-eluting stent (EES) compared with the paclitaxel-eluting stent (PES) using serial intravascular ultrasound (IVUS). METHODS AND RESULTS: Data were obtained from the SPIRIT III trial, a multicentre, 2:1 randomised, controlled study comparing EES and PES in de novo native coronary artery lesions. IVUS images were eligible for volumetric analysis at eight-month follow-up in 158 lesions (EES: 113, PES: 45). At eight months, EES had a smaller neointimal volume index (VI: mm3/mm) (EES: 0.4+/-0.4 vs. PES: 0.8+/-0.8 mm3/mm, p=0.002) and also a smaller % neointimal obstruction (EES: 7.1+/-6.7% vs. PES: 11.1+/-10.5%, p=0.005) compared with PES. While there was no significant change in vessel VI with EES, there was a significant increase in vessel VI in PES during eight-month follow-up (EES: 0.1+/-1.2 vs. PES: 1.2+/-0.8 mm3/mm, p=0.001). There were no statistical differences in the frequency of edge dissection or incomplete stent apposition between the two groups. CONCLUSIONS: Detailed IVUS analysis confirmed significantly less neointimal hyperplasia with EES compared with PES. While there was no increase in vessel volume with EES during the eight-month follow-up period, vessel enlargement was seen at the stented segment in PES. PMID- 23086792 TI - Percutaneous, transendocardial injection of bone marrow-derived mononuclear cells in heart failure patients following acute ST-elevation myocardial infarction: ALSTER-Stem Cell trial. AB - AIMS: Patients with symptomatic heart failure following acute ST-elevation myocardial infarction (STEMI) received transendocardial application of bone marrow-derived mononuclear cells (BMC) to improve left ventricular (LV) function and clinical outcome. METHODS AND RESULTS: Patients (n=12) with LV ejection fraction (EF) <45% and NYHA Class >=II received NOGA-guided transendocardial injection of BMC into the infarction border zone 17.5+/-0.8 days following successful interventional revascularisation after STEMI. A matched control group (n=11) was generated from the source data of the previously published LIPSIAbciximab-STEMI trial. Primary and secondary endpoints were derived from comparisons of baseline vs. six-month follow-up cardiac magnetic resonance imaging (CMR) measurements and clinical assessments. Following cell therapy we observed a significant increase of EF (+7.9+/-1.5%, p=0.001) while the control group showed no change. This effect was driven by a reduction of LV end-systolic volume (ESV) by -27.5+/-6.5 ml (p=0.001); LV end-diastolic volume (EDV) and scar volu-me remained unchanged. A significant decrease of NYHA Class was found only in the cell therapy group (-0.75 vs. -0.18, p=0.04). Findings were also translated into enhancement of clinical assessments (rehospitalisation for decompensated heart failure, six-minute walk test, NT-proBNP levels). CONCLUSION: The data suggest transendocardial injection of BMC can be used safely in patients with sympto-matic heart failure following acute STEMI. These prospective, preliminary data of a well-characterised, small cohort suggest efficiency compared to routine treatment. PMID- 23086793 TI - Vascular responses to a biodegradable polymer (polylactic acid) based biolimus A9 eluting stent in porcine models. AB - AIMS: The time-dependent changes in endothelial and healing properties of coronary arteries implanted with a biodegradable polymer-based biolimus A9 eluting stent (BioPol-BES) have not been investigated. We evaluated the short term and the long-term in vivo response of BioPol-BES, as compared to a permanent polymer-based sirolimus-eluting stent (PermPol-SES), and a bare metal stent (BMS). METHODS AND RESULTS: Overlapping stents were placed in 33 swine (n=11 for BES, SES, and BMS, respectively) for two and four weeks and single stents in 30 miniature pigs (n=18 for BES, n=9 for SES, n=3 for BMS) for three, nine and 15 month evaluations. The vessel patency, arterial healing and endothelialisation were assessed by angiography, histopathology and scanning electron microscopy. At four weeks, the endothelialisation at overlapping stent regions was greater with BioPol-BES (87.8+/-3.7%) and BMSs (98.0+/-0.4%) than with PermPol-SES (66.4+/ 3.2%). The inflammation score in vessels implanted with single BioPol-BES increased slightly from three to 15 months (0.00+/-0.00 to 0.28+/-0.14), while this increase was more pronounced with PermPol-SES (0.11+/-0.07 to 1.56+/-0.68). Compared to BMS moderate lymphocyte infiltration was seen with BioPol-BES, and marked granulomatous formation with PermPol-SES. CONCLUSIONS: The level of endothelial coverage in BioPol-BES was comparable to BMS at four weeks, with no significant increase of inflammatory reaction up to 15 months. PMID- 23086794 TI - Vascular healing in drug-eluting stents: differential drug-associated response of limus-eluting stents in a preclinical model of stent implantation. AB - AIMS: We aimed to assess the influence of different sirolimus analogues released from a uniform stent platform on re-endothelialisation and vascular healing responses. METHODS AND RESULTS: Bare metal stents (BMS) were coated with a fluoropolymer containing everolimus (EES), sirolimus (SES) or zotarolimus (ZES) to generate drug-eluting stents (DES) with identical stent backbones, drug loads and release kinetics. DES constructs and control BMS were implanted into the iliac arteries of rabbits and were analysed at 14 days by scanning electron microscopy (SEM) and confocal microscopy for en face evaluation of endothelialisation (n=6 for each stent), or at 28 days to determine histomorphometric characteristics (n=11 for each stent). SEM analysis revealed low degrees of strut re-endothelialisation within the DES without differences among groups, while the BMS control showed almost complete endothelialisation. Percent stenosis was significantly reduced in all DES compared to BMS. Strut based fibrin analysis revealed significantly greater deposition in the DES compared to BMS, with EES showing maximum fibrin deposition among the DES groups. CONCLUSIONS: Sirolimus and its derivatives have similar effects on endothelial regrowth and neointimal thickening. The observation of greatest fibrin deposition in the experimental EES group indicates that everolimus may affect vascular healing differently. PMID- 23086795 TI - Giant coronary aneurysm in Churg-Strauss syndrome. PMID- 23086796 TI - Anterograde-retrograde method for harvest of distally based sural fasciocutaneous flap: report of results from 154 patients. AB - Distally based sural fasciocutaneous flap is traditionally raised by the retrograde method. This article introduces the anterograde-retrograde method for harvest of the flap and describes our experience on altering the flap plan. A total of 159 flaps in 154 patients were elevated by the anterograde-retrograde approach that harvest of the flap began with exploring the peroneal artery perforators nearby the pivot point before the upper and bilateral edges of the flap were incised. Partial necrosis occurred in 16 (10.1%) flaps, and marginal necrosis developed in 10 flaps. Nine flaps were redesigned with adjusted pivot point and skin island. The anterograde-retrograde approach for harvest of the flap can accurately locate the perforator, readily adjust both the pivot point and skin island if necessary, and thus improve reliability of the flap. This approach is particularly applicable for elevation of the flap without preoperative localization of the perforators by means of the Doppler. PMID- 23086797 TI - Hepatic differentiation of human embryonic stem cells on growth factor-containing surfaces. AB - Embryonic stem cells (ESCs) hold considerable promise in tissue engineering and regenerative medicine as a source of tissue-specific cells. Hepatocytes derived from ESCs will be useful for therapies, bioartificial liver assistance devices and drug discovery. In traditional stem cell cultivation/differentiation experiments, growth factors (GFs) are added in soluble form in order to provide signals for tissue-specific differentiation. In contrast, we investigated differentiation of hESCs cultured on top of GFs. In these experiments, glass substrates were imprinted with a mixture of ECM and GF molecules to form 500 um diameter spots. hESCs were cultured onto these GF-containing ECM spots for up to 12 days to induce differentiation towards the hepatic lineage. The dynamics of differentiation were examined by quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and immunocytochemistry. Stem cells cultured on GF containing surfaces stained positive for the endoderm markers SOX17 and FOXA2, as well as early liver markers such as alpha-fetoprotein and albumin. qRT-PCR confirmed that pluripotency, endoderm and liver gene expression of hESCs cultured on GF-containing surfaces was consistent with hepatic differentiation. In comparison, hESCs cultured on ECM spots without GFs showed less pronounced loss of pluripotency and lower levels of liver gene expression. In summary, our study demonstrates that hESCs receive differentiation-inducing signals from GF containing surfaces and may be pushed along the hepatic lineage when cultured on such surfaces. Compared to traditional approaches, the advantages of GF immobilization include reduction in the cost of experiments, stronger and longer stimulation and the possibility of screening GF-stem cell interactions in a multiplexed manner. PMID- 23086798 TI - Hospital volume, proportion resected and mortality from oesophageal and gastric cancer: a population-based study in England, 2004-2008. AB - OBJECTIVE: This study assessed the associations between hospital volume, resection rate and survival of oesophageal and gastric cancer patients in England. DESIGN: 62,811 patients diagnosed with oesophageal or gastric cancer between 2004 and 2008 were identified from a national population-based cancer registration and Hospital Episode Statistics-linked dataset. Cox regression analyses were used to assess all-cause mortality according to hospital volume and resection rate, adjusting for case-mix variables (sex, age, socioeconomic deprivation, comorbidity and type of cancer). HRs and 95% CIs, according to hospital volume, were evaluated for three predefined periods following surgery: <30, 30-365, and >365 days. Analysis of mortality in relation to resection rate was performed among all patients and among the 13 189 (21%) resected patients. RESULTS: Increasing hospital volume was associated with lower mortality (p trend=0.0001; HR 0.87, 95% CI 0.79 to 0.95 for hospitals resecting 80+ and compared with <20 patients a year). In relative terms, the association between increasing hospital volume and lower mortality was particularly strong in the first 30 days following surgery (p trend<0.0001; HR 0.52, (0.39 to 0.70)), but a clinically relevant association remained beyond 1 year (p trend=0.0011; HR 0.82, (0.72 to 0.95)). Increasing resection rates were associated with lower mortality among all patients (p trend<0.0001; HR 0.86, (0.84 to 0.89) for the highest, compared with the lowest resection quintile). CONCLUSIONS: With evidence of lower short-term and longer-term mortality for patients resected in high-volume hospitals, this study supports further centralisation of oesophageal and gastric cancer surgical services in England. PMID- 23086799 TI - alpha-2-Macroglobulin: a physiological guardian. AB - Alpha macroglobulins are large glycoproteins which are present in the body fluids of both invertebrates and vertebrates. Alpha-2-macroglobulin (alpha2 M), a key member of alpha macroglobulin superfamily, is a high-molecular weight homotetrameric glycoprotein. alpha2 M has many diversified and complex functions, but it is primarily known by its ability to inhibit a broad spectrum of proteases without the direct blockage of the protease active site. alpha2 M is also known to be involved in the regulation, transport, and a host of other functions. For example, apart from inhibiting proteinases, it regulates binding of transferrin to its surface receptor, binds defensin and myelin basic protein, etc., binds several important cytokines, including basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), interleukin 1beta (IL-1beta), and interleukin-6 (IL-6), and modify their biological activity. alpha2 M also binds a number of hormones and regulates their activity. alpha2 M is said to protect the body against various infections, and hence, can be used as a biomarker for the diagnosis and prognosis of a number of diseases. However, this multipurpose antiproteinse is not "fail safe" and could be damaged by reactive species generated endogenously or exogenously, leading to various pathophysiological conditions. PMID- 23086800 TI - Pharmacoresistant Cav 2.3 (E-type/R-type) voltage-gated calcium channels influence heart rate dynamics and may contribute to cardiac impulse conduction. AB - Voltage-gated Ca(2+) channels regulate cardiac automaticity, rhythmicity and excitation-contraction coupling. Whereas L-type (Cav 1.2, Cav 1.3) and T-type (Cav 3.1, Cav 3.2) channels are widely accepted for their functional relevance in the heart, the role of Cav 2.3 Ca(2+) channels expressing R-type currents remains to be elucidated. We have investigated heart rate dynamics in control and Cav 2.3 deficient mice using implantable electrocardiogram radiotelemetry and pharmacological injection experiments. Autonomic block revealed that the intrinsic heart rate does not differ between both genotypes. Systemic administration of isoproterenol resulted in a significant reduction in interbeat interval in both genotypes. It remained unaffected after administering propranolol in Cav 2.3(-|-) mice. Heart rate from isolated hearts as well as atrioventricular conduction for both genotypes differed significantly. Additionally, we identified and analysed the developmental expression of two splice variants, i.e. Cav 2.3c and Cav 2.3e. Using patch clamp technology, R-type currents could be detected in isolated prenatal cardiomyocytes and be related to R-type Ca(2+) channels. Our results indicate that on the systemic level, the pharmacologically inducible heart rate range and heart rate reserve are impaired in Cav 2.3 (-|-) mice. In addition, experiments on Langendorff perfused hearts elucidate differences in basic properties between both genotypes. Thus, Cav 2.3 does not only contribute to the cardiac autonomous nervous system but also to intrinsic rhythm propagation. PMID- 23086801 TI - A novel regulatory defect in the branched-chain alpha-keto acid dehydrogenase complex due to a mutation in the PPM1K gene causes a mild variant phenotype of maple syrup urine disease. AB - This article describes a hitherto unreported involvement of the phosphatase PP2Cm, a recently described member of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, in maple syrup urine disease (MSUD). The disease causing mutation was identified in a patient with a mild variant phenotype, involving a gene not previously associated with MSUD. SNP array-based genotyping showed a copy-neutral homozygous pattern for chromosome 4 compatible with uniparental isodisomy. Mutation analysis of the candidate gene, PPM1K, revealed a homozygous c.417_418delTA change predicted to result in a truncated, unstable protein. No PP2Cm mutant protein was detected in immunocytochemical or Western blot expression analyses. The transient expression of wild-type PPM1K in PP2Cm deficient fibroblasts recovered 35% of normal BCKDH activity. As PP2Cm has been described essential for cell survival, apoptosis and metabolism, the impact of its deficiency on specific metabolic stress variables was evaluated in PP2Cm deficient fibroblasts. Increases were seen in ROS levels along with the activation of specific stress-signaling MAP kinases. Similar to that described for the pyruvate dehydrogenase complex, a defect in the regulation of BCKDH caused the aberrant metabolism of its substrate, contributing to the patient's MSUD phenotype--and perhaps others. PMID- 23086802 TI - Robot assisted surgery in gynaecologic oncology - starting a program and initial learning curve from a UK tertiary referral centre: the Guildford perspective. AB - BACKGROUND: The paper discusses the setup and evaluation of early data following the establishment of a robotic surgery programme in a UK gynaecological oncology cancer centre. METHODS: Prospective data were collected between December 2009 and December 2011 for all women undergoing robotic assisted procedures within the gynaecological oncology department. Patient demographics, intra, peri and post operative data were collected at a single institution, which is a tertiary referral centre for gynaecological oncology and minimal access surgery. RESULTS: In total, 104 robotically assisted cases were performed within the gynaecological oncology team. The procedures undertaken included simple and radical hysterectomy, radical trachelectomy, BSO following previous hysterectomy, pelvic and para-aortic node dissection and omentectomy. The mean blood loss was 155.24 mL and the mean hospital stay was 3 days with more than half the women being discharged on day 1 post surgery. CONCLUSIONS: These data suggest that robotic assisted surgery is well suited to treating women with principally endometrial and cervical cancers and selected cases of ovarian cancer, enabling surgical staging to be completed with many more patients benefitting from a minimal access surgery approach. Thorough preparation, appropriate case selection and preceptorship in robotic surgery is essential to minimize the associated risks associated with adopting new surgical techniques. PMID- 23086803 TI - Effect of family history of type-2 diabetes on coronary flow reserve and it's relationship with insulin resistance: an observational study. AB - OBJECTIVE: Coronary microvascular function among offspring of patients with diabetes mellitus might be compromised when compared to persons with no first degree relative with diabetes mellitus. The aim of the study was to evaluate effect of family history of type-2 diabetes on coronary flow reserve. METHODS: In this observational study, we evaluated coronary flow reserve (CFR) via echocardiography of 95 subjects having a biological parent with type-2 diabetes and 34 healthy volunteers without any biological parent with type-2 diabetes. We have analyzed possible association with CFR and homeostasis model assessment - insulin resistance (HOMA-IR). Comparison analyses were made using independent samples t test, Chi-square test and one-way ANOVA. Association of independent variables with CFR was obtained by correlation analysis and stepwise linear regression model including potential confounders. RESULTS: CFR was significantly lower in the positive family history group than in the controls. Moreover, when compared with controls, the subgroup of insulin-sensitive subjects in the positive family history group also had significantly reduced CFR (2.67+/-0.28 vs. 2.83+/-0.19; p=0.01). Correlation analysis revealed that CFR was inversely correlated with HOMA-IR, (r=-0.433), fasting glucose (r=-0.331), fasting insulin (r=-0.396), and hemoglobin (Hb)A1c (r=-0.405). When the positive family history group was divided into tertiles of insulin resistance (HOMA-IR <1.3, 1.3-2.6, and >2.6; Groups 1-2, and 3), there was a significant difference in CFR between Groups 1 and 2 and between Groups 1 and 3 (p<0.05 for all). Though statistically not significant, there was also a difference in CFR between Groups 2 and 3. In a linear regression model, only fasting glucose level was independent predictor of CFR (beta=-677; p value =0.001, 95% CI: -0.061 and -0.019). CONCLUSION: Nondiabetic first-degree relatives of patients with type-2 diabetes are at increased risk of developing coronary microvascular dysfunction. PMID- 23086804 TI - Predictive value of mean platelet volume in young patients with non-ST-segment elevation acute coronary syndromes: a retrospective observational study. AB - OBJECTIVE: Platelets play an important role in both initiation and propagation of acute coronary syndromes. We sought to evaluate the predictive value of mean platelet volume (MPV) in young patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS). METHODS: This is a retrospective observational study; evaluating the MPV values of 79 NSTE-ACS patients aged under 45 years and 45 control subjects having normal coronary anatomy. NSTE-ACS group was composed of 41 non-ST elevation myocardial infarction (NSTEMI) and 38 unstable angina pectoris (USAP) patients. MPV was measured using an automated hematologic analyzer called Coulter counter. The predictive value of MPV was evaluated using logistic regression analysis and comparison of MPV between NSTE-ACS and control groups was performed by Mann-Whitney U test. RESULTS: The MPV was found to be significantly higher in the NSTE-ACS compared with control group (8.49+/-1.22 versus 7.78+/-0.65 fL, p=0.001). In logistic regression analysis, MPV was found to be an independent predictor of NSTE-ACS (OR=3.1, 95% CI 1.2-8.2, p=0.022). The MPV values of NSTEMI group were not significantly different from USAP group (8.78+/-1.38 versus 8.17+/-0.95 fL, p=0.66). Similarly, the MPV values of the 3 groups (Control, USAP and NSTEMI) were found to be significantly different (7.78+/-0.65, 8.18+/-0.95, 8.78+/-1.38 fL respectively, p=0.001). CONCLUSION: In conclusion, MPV was found to be elevated in NSTE-ACS patients compared with control subjects in young population. In addition, increased MPV was established to be an independent predictor of NSTE-ACS. PMID- 23086805 TI - Heart disease in patients with thyroid dysfunction: hyperthyroidism, hypothyroidism and beyond. AB - The thyroid and the cardiovascular system are closely related, both in physiological and pathological conditions. The adverse consequences on the heart of overt thyroid disease are well-known and even subclinical forms of both hyperthyroidism and hypothyroidism are associated with increased cardiovascular mortality. In recent years, attention has shifted towards milder forms of thyroid disease, such as the so-called "low T3 syndrome", which is characterized by an isolated reduction in circulating levels of the biologically active form of thyroid hormone, triiodothyronine (T3). Furthermore, variations of T3 within the physiological range have been linked to coronary artery disease, one of the leading causes of morbidity and mortality worldwide. The present manuscript provides an overview of thyroid physiology and pathophysiology, with a particular focus on cardiovascular disease in patients with milder forms of thyroid dysfunction. PMID- 23086806 TI - Diurnal variation in acute thrombotic cardiovascular events. AB - Circadian clocks affect cardiovascular system and thought to be responsible for the increased vascular events during certain periods. Determination of the diurnal variation of acute vascular thrombotic events might help us for protection of patients during vulnerable periods. In this review, we investigate diurnal variation in acute thrombotic vascular events in the light of recent information. PMID- 23086807 TI - Kidney injury molecule-1: more than just an injury marker of tubular epithelial cells? AB - Regardless of the original causes and etiology, the progression to renal function declines follows a final common pathway associated with tubulointerstitial injury, in which the proximal tubular epithelial cells (PTEC) are instrumental. Kidney injury molecule-1 (KIM-1) is an emerging biomarker, and its expression and release are induced in PTEC upon injury. KIM-1 plays the role as a double-edged sword and implicates in the process of kidney injury and healing. Expression of KIM-1 is also associated with tubulointerstitial inflammation and fibrosis. More importantly, KIM-1 expressing PTEC play the role as the residential phagocytes, contribute to the removal of apoptotic cells and facilitate the regeneration of injured tubules. The precise mechanism of KIM-1 and its sheded ectodomain on restoration of tubular integrity after injury is not fully understood. Other than PTEC, macrophages (Mo) also implicate in tubular repair. Understanding the crosstalk between Mo and the injured PTEC is essential for designing appropriate methods for controlling the sophisticated machinery in tubular regeneration and healing. This article will review the current findings of KIM-1, beginning with its basic structure, utility as a biomarker, and possible functions, with focus on the role of KIM-1 in regeneration and healing of injured PTEC. PMID- 23086808 TI - E-ADA activity in lymphocytes of an experimental model of pythiosis treated with immunotherapy. AB - Pythiosis is a life-threatening disease caused by the oomycete Pythium insidiosum. Some authors have suggested the involvement of a Th2-like immune response in the infected host, which leads to extensive tissue damage. The switch from a Th2 to a Th1 response pattern is one hypothesis to explain the curative properties of immunotherapy. Taking into account the importance of immunotherapy for pythiosis treatment and the contribution of adenine nucleotides in the immunoregulation of the host, we evaluated the ecto-adenosine deaminase (E-ADA; EC 3.5.4.4) activity in lymphocytes from rabbits inoculated with P. insidiosum. Rabbits were inoculated with 1 milliliter of zoospores subcutaneously injected into the lateral thorax; after developing lesions, the rabbits received eight doses of immunotherapy. E-ADA activity was measured in lymphocytes and the adenine nucleotides and adenosine levels were quantitatively determined in serum. Rabbits with characteristic lesions of pythiosis showed a decreased E-ADA activity (82.36%), a decreased adenosine triphosphate concentration (54.04%) and a higher adenosine concentration (2.51 fold), when compared with controls, after 28 days of inoculation. However, after the immunotherapy, the rabbits showed an increase in the E-ADA activity when compared with control (78.62%), contributing for the change in the immune response. Our results reinforce the hypothesis that the change from a Th2 to a Th1 immune response with the participation of the purinergic system could be responsible for the curative properties of immunotherapy. PMID- 23086809 TI - Effects of chitosan and bioactive glass modifications of knitted and rolled polylactide-based 96/4 L/D scaffolds on chondrogenic differentiation of adipose stem cells. AB - The performance of biodegradable knitted and rolled 3-dimensional (3D) polylactide-based 96/4 scaffolds modified with bioactive glass (BaG) 13-93, chitosan and both was compared with regard to the viability, proliferation and chondrogenic differentiation of rabbit adipose stem cells (ASCs). Scaffold porosities were determined by micro-computed tomography (MUCT). Water absorption and degradation of scaffolds were studied during 28-day hydrolysis in Tris buffer. Viability, number and differentiation of ASCs in PLA96/4 scaffolds were examined in vitro. The dimensions of the scaffolds were maintained during hydrolysis and mass loss was detected only in the BaG13-93 containing scaffolds. ASCs adhered and proliferated on each scaffold type. Cell aggregation and expression of chondral matrix components improved in all scaffold types in chondrogenic medium. Signs of hypertrophy were detected in the modified scaffolds but not in the plain PLA96/4 scaffold. Chondrogenic differentiation was most enhanced in the presence of chitosan. These findings indicate that the plain P scaffold provided a good 3D-matrix for ASC proliferation whereas the addition of chitosan to the PLA96/4 scaffold induced chondrogenic differentiation independent of the medium. Accordingly, a PLA96/4 scaffold modified by chitosan could provide a functional and bioactive basis for tissue-engineered chondral implants. PMID- 23086810 TI - A gene expression analysis of cell wall biosynthetic genes in Malus x domestica infected by 'Candidatus Phytoplasma mali'. AB - Apple proliferation (AP) represents a serious threat to several fruit-growing areas and is responsible for great economic losses. Several studies have highlighted the key role played by the cell wall in response to pathogen attack. The existence of a cell wall integrity signaling pathway which senses perturbations in the cell wall architecture upon abiotic/biotic stresses and activates specific defence responses has been widely demonstrated in plants. More recently a role played by cell wall-related genes has also been reported in plants infected by phytoplasmas. With the aim of shedding light on the cell wall response to AP disease in the economically relevant fruit-tree Malus * domestica Borkh., we investigated the expression of the cellulose (CesA) and callose synthase (CalS) genes in different organs (i.e., leaves, roots and branch phloem) of healthy and infected symptomatic outdoor-grown trees, sampled over the course of two time points (i.e., spring and autumn 2011), as well as in in vitro micropropagated control and infected plantlets. A strong up-regulation in the expression of cell wall biosynthetic genes was recorded in roots from infected trees. Secondary cell wall CesAs showed up-regulation in the phloem tissue from branches of infected plants, while either a down-regulation of some genes or no major changes were observed in the leaves. Micropropagated plantlets also showed an increase in cell wall-related genes and constitute a useful system for a general assessment of gene expression analysis upon phytoplasma infection. Finally, we also report the presence of several 'knot'-like structures along the roots of infected apple trees and discuss the occurrence of this interesting phenotype in relation to the gene expression results and the modalities of phytoplasma diffusion. PMID- 23086812 TI - Selenium-containing amino acids as direct and indirect antioxidants. AB - Selenium is a trace element essential for normal physiological processes. Organic selenium-containing amino acids, such as selenocysteine (Sec) / selenocystine and selenomethionine (SeMet, the major dietary form), can provide antioxidant benefits by acting both as direct antioxidants as well as a source of selenium for synthesis of selenium-dependent antioxidant and repair proteins (e.g., glutathione peroxidases, thioredoxin reductases, methionine sulfoxide reductases). The direct antioxidant actions of these amino acids arise from the nucleophilic properties of the ionized selenol (RSe(-), which predominates over the neutral form at physiological pH values) and the ease of oxidation of Sec and SeMet. This results in higher rate constants for reaction with multiple oxidants, than for the corresponding thiols/thioethers. Furthermore, the resulting oxidation products are more readily and rapidly reversed by both enzyme and nonenzymatic reactions. The antioxidant effects of these seleno species can therefore be catalytic. Seleno amino acids may also chelate redox-active metal ions. The presence of Sec in the catalytic site of selenium-dependent antioxidant enzymes enhances the kinetic properties and broadens the catalytic activity of antioxidant enzymes against biological oxidants when compared with sulfur containing species. However, while normal physiological selenium levels afford protection, when compared with deficiency, excessive selenium may induce damage and adverse effects, with this being manifest, for example, as an increased incidence of type 2 diabetes. Further studies examining the availability of redox active selenium species and their mechanisms and kinetics of action are therefore of critical importance in the potential development of seleno species as a therapeutic strategy. PMID- 23086811 TI - Genetic transformation of European chestnut somatic embryos with a native thaumatin-like protein (CsTL1) gene isolated from Castanea sativa seeds. AB - The availability of a system for direct transfer of antifungal candidate genes into European chestnut (Castanea sativa Mill.) would offer an alternative approach to conventional breeding for production of chestnut trees tolerant to ink disease caused by Phytophthora spp. For the first time, a chestnut thaumatin like protein gene (CsTL1), isolated from chestnut cotyledons, has been overexpressed in three chestnut somatic embryogenic lines. Transformation experiments have been performed using an Agrobacterium tumefaciens Smith and Townsend vector harboring the neomycin phosphotransferase (NPTII) selectable and the green fluorescent protein (EGFP) reporter genes. The transformation efficiency, determined on the basis of the fluorescence of surviving explants, was clearly genotype dependent and ranged from 32.5% in the CI-9 line to 7.1% in the CI-3 line. A total of 126 independent transformed lines were obtained. The presence and integration of chestnut CsTL1 in genomic DNA was confirmed by polymerase chain reaction (PCR) and Southern blot analyses. Quantitative real time PCR revealed that CsTL1 expression was up to 13.5-fold higher in a transgenic line compared with its corresponding untransformed line. In only one of the 11 transformed lines tested, expression of the CsTL1 was lower than the control. The remaining 115 transformed lines were successfully subjected to cryopreservation. Embryo proliferation was achieved in all of the transgenic lines regenerated and the transformed lines showed a higher mean number of cotyledonary stage embryos and total number of embryos per embryo clump than their corresponding untransformed lines. Transgenic plants were regenerated after maturation and germination of transformed somatic embryos. Furthermore, due to the low plantlet conversion achieved, axillary shoot proliferation cultures were established from partially germinated embryos (only shoot development), which were multiplied and rooted according to procedures already established. Transgenic plants were acclimatized and grown in a greenhouse. No phenotypic differences were found with control plants, suggesting no potential cytotoxic effects of the green fluorescent protein. The results reported in the present work could be considered as a first step toward the production of fungal-disease tolerant cisgenic chestnut plants. PMID- 23086813 TI - GA/GB fold switching may modulate fatty acid transfer from human serum albumin to bacteria. AB - Human serum albumin (HSA) accounts for most of the functions of plasma. Among others, HSA serves as a carrier and a solubilizer for many endogenous and exogenous ligands, including fatty acids (FAs) as well as peptides and proteins such as the GA module of the bacterial poly(A)-binding (PAB) protein. Although the biological function(s) of the GA module of the bacterial PAB protein is unknown, the acquisition of the GA module adds selective advantages to the bacterium in terms of growth rate and increase in virulence, probably by providing the bacteria with FAs and, possibly, other nutrients transported by HSA. Here, we hypothesize that the GA module may undergo a structural transition from the all-alpha form to the 4beta+alpha form typical of the GB domains upon binding of a FA molecule, as part of the mechanism which allows the bacterial PAB protein to extract FAs from HSA. PMID- 23086815 TI - FHL family members suppress vascular endothelial growth factor expression through blockade of dimerization of HIF1alpha and HIF1beta. AB - Four and a half LIM domain (FHL) proteins belong to a family of LIM-only proteins that have been implicated in the development and progression of various types of cancers. However, the role of FHL proteins in tumor angiogenesis remains to be elucidated. Herein, we demonstrate that FHL1-3 decrease the promoter activity and expression of vascular endothelial growth factor (VEGF), the key regulator of angiogenesis in cancer growth and progression as well as an important target gene of the transcription factor hypoxia-inducible factor 1 (HIF1alpha/HIF1beta). FHL1 3 interacted with HIF1alpha both in vitro and in vivo. A single LIM domain of FHL1 was sufficient for its interaction with HIF1alpha. FHL1 interacted with the HIF1alpha region containing basic helix-loop-helix (bHLH) motif and PER-ARNT-SIM domain, both of which aid in dimerization with HIF1beta and DNA binding. FHL1-3 inhibited HIF1 transcriptional activity and HIF1-mediated VEGF expression in a hypoxia-independent manner. Moreover, FHL1 blocked HIF1alpha-HIF1beta heterodimerization and HIF1alpha recruitment to the VEGF promoter. These data suggest that FHL proteins are involved in negative regulation of VEGF possibly by interfering with the dimerization and DNA binding of HIF1 subunits and may play an important role in tumor angiogenesis. PMID- 23086814 TI - Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer. AB - CD73, an ecto-enzyme overexpressed in breast-cancer cells, catalyzes the dephosphorylation of adenosine monophosphates into adenosine. Anti-CD73 slows breast cancer growth and its spread both in vivo and in vitro. In this study, we investigated the relation of CD73 to epidermal growth factor receptor (EGFR) expression using tissue array and breast cancer cell lines. We found that CD73 expression correlated positively to EGFR expression in vivo (n = 80, r = 0.425, P < 0.01) and in vitro. EGFR expression can be decreased by suppressing CD73 with an inhibitor or small shRNA, and this effect was reversed by adenosine and NECA (adenosine A2 receptor agonist), which suggested that adenosine is involved in EGFR expression regulated by CD73 (P < 0.01). We also showed that CD73 regulates EGFR phosphorylation by Src (P < 0.01). By transcription factor (TF) assay, CD73 was found to regulate some associated TFs activity such as PPARgamma, which mediates EGFR expression, although whether PPARgamma mediates the effect of CD73 on EGFR expression needs further study. The Kaplan-Meier recurrence-free survival curves for CD73 were also plotted in www.kmplot.com. The curves show that CD73 expression separates the cases into significantly different prognostic groups among the estrogen receptor-negative cancers (P < 0.01). Our results suggest that CD73 may be a potential prognostic biomarker associated with coexpression of EGFR in human breast cancer. PMID- 23086817 TI - [Salute to Ors Peter Horvath]. PMID- 23086818 TI - [The role of neoadjuvant therapy in the treatment of locally advanced squamous cell cancer of the cervical oesophagus]. AB - INTRODUCTION: Cervical oesophagus represents a critical location for squamous cell carcinoma, which usually requires extensive surgery (pharyngo-laryngo oesophagectomy). In the last decade, neoadjuvant chemo-radiotherapy was reported to be beneficial in the treatment of locally advanced squamous cell oesophageal cancer. METHODS: Between November 1997 and January 2012, 55 patients with locally advanced (T3-4) squamous cell oesophageal cancer received preoperative chemo radiotherapy, where the tumour was localized in the upper third. Patients received preoperative irradiation of 3960 cGy in 180 cGy fractions and simultaneously Cisplatin and 5-FU chemotherapy. Restaging was carried out after four weeks and patients considered operable were underwent surgery. RESULTS: In patients with cervical oesophageal cancer 35 of 55 (64%) underwent oesophageal resection or pharyngo-laryngectomy. In 16 out of 35 resected specimens (46%) complete histopathological remission (pCR) was observed. Perioperative mortality and anastomotic leaks were the same: 5/35 (14%). R0 resection rate was 82% and the 2- and 5 years survival rates were 41% and 18%. In 19 cases a larynx preserving pharyngo-oesophagectomy was performed and a free jejunal graft was used for reconstruction after a pharyngo-laryngectomy in 11 cases. CONCLUSION: The high rate of pCR (46%) confirmed that upper third oesophageal cancer has superior sensitivity to multimodal treatment. In 30 cases neoadjuvant chemo radiotherapy was able to achieve tumour regression and render pharyngo-laryngo oesophagectomy unnecessary. PMID- 23086819 TI - [Reconstruction of the esophagus with plastic surgery techniques]. AB - INTRODUCTION: Various plastic surgery techniques were applied for oesophageal reconstruction in complicated cases. Myocutaneous flaps that are suitable to cover soft tissue defects of the neck may also be transferred and used for partial defects of the cervical oesophagus or securing a vulnerable suture line. Application of microsurgical techniques may also be useful in certain situations. PATIENTS AND METHODS: Pectoralis major myocutaneous flap was used in 5 cases in our department between 1998 and 2012. Microsurgical techniques were used in 38 cases of esophageal reconstruction, which were 34 free jejunal grafts and 4 supercharged colon grafts. RESULTS: 23 patients underwent primary reconstruction after pharyngolaryngectomy, while 15 patients had secondary reconstruction after failed previous operations or recurrence. When more experienced was gained free jejunal grafts were used for the cervical as well as thoracic oesophagus. Three grafts were lost, two of them were due to anastomotic thrombosis and one was due to severe MRSA wound infection. CONCLUSION: Complicated cases of oesophagus reconstructions may be successfully treated by the cooperation of oesophagus and plastic surgeons, which may result in an acceptable complication rate. PMID- 23086821 TI - [Experiences with central pancreatectomy]. AB - INTRODUCTION: The authors report their experience with central pancreatectomy and also summarize relevant literature data. MATERIAL AND METHODS: Central pancreatectomies were performed in 7 patients for benign or low-grade malignant pancreatic neoplasms, or pancreatic rupture in one patient. Most frequently applied anastomosis was between the distal part of the pancreas and a Roux-en-Y limb, while the proximal cut surface was closed with sutures, and the suture line was covered with a limb. RESULTS: There were three complications (37%), but reoperation didn't need to be performed and none of the patients died. We did not detect any deterioration in the exocrine or endocrine function during the follow up period. CONCLUSIONS: Central pancreatectomy is a safe procedure with excellent functional results, if both the indication and the applied technique are chosen appropriately. PMID- 23086820 TI - [Chest trauma: who, how and what?]. AB - A chest-trauma management system, tagged as the "Pecs model" in a tertiary referral center is described with extensive references to the state of the art in thoracic trauma. Chest drainage has utmost importance in primary therapy as well as in surgical decision making (diagnosis). Thoracotomy is a general surgical competence, just as damage control is. Definitive treatment and management of sequelae, however, requires competence in thoracic surgery. Multidisciplinarity is underscored. PMID- 23086822 TI - [Minimally invasive technique as the gold standard of adrenal surgery]. AB - INTRODUCTION: Minimal invasive surgery of the adrenal gland is a "gold standard" procedure worldwide. Authors compare operative data to a historical control group retrospectively analyzing an almost 15 years period. MATERIAL AND METHODS: Between 1997 and 2011, 175 transabdominal laparoscopic adrenalectomies were performed with the lateral approach. On the left side, a new "suprasplenic" approach was introduced with the superior mobilization of the spleen, and transection of the short gastric vessels. For larger lesions (above 7 cm) hand assisted laparoscopic method was applied. RESULTS: Average operative time of laparoscopic surgery was 77 minutes, compared to 115 minutes of open surgery. The average size of the tumor was 3.1 cm in the laparoscopic, and 4.9 cm in the open group. The largest tumors were similar in both groups, however the rate of smaller sized lesions was higher in the laparoscopic one. Conversion was required in 15 cases (8.6%) mostly due to bleeding. Complication rate was 10.8% in the laparoscopic and 24.6% in the conventional group. Hospital stay was significantly shorter with the laparoscopic technique (4.5 vs. 8.1 days). Among laparoscopic cases unexpected primary malignancy was reported in 3 cases (1.7%). CONCLUSIONS: The laparoscopic technique is the procedure of choice in case of benign adrenal tumors, which offer many advantages. Most metastasis localized to the adrenals can also be removed laparoscopically with expertise and self-restraint, without oncologic compromise. To assure the quality of pre- and postoperative care, cooperation with an endocrinologist is indispensable. PMID- 23086823 TI - [Functional proctology at the University of Pecs]. AB - INTRODUCTION: Functional proctological investigations have been introduced at Pecs University of Sciences 15 years ago. The Pelvic Floor Multidisciplinary Team has been re-launched after many years of pause in 2010. Experience of the team in the treatment of faecal incontinence and obstructed defecation syndrome is discussed. PATIENTS: In the past 3 years 9 patients underwent sphincter reconstruction for faecal incontinence. The Pelvic Floor Team in the past 1.5 year consulted 31 patients with constipation, who were considered by the referee for surgical intervention. Following investigations 10 patients underwent surgery, the rest of them were treated conservatively. Seven patients underwent perineal reconstruction with mesh, three patients had ventral rectopexy with additional levatoro-pexy. RESULTS: 78% of patients operated on for faecal incontinence reported full continence, 88% improvement. We invented a new symptom score with a maximum of 20 points to evaluate results of treatment of patients with Obstructed Defecation Syndrome. Patients who underwent perineal repair were interviewed pre and postoperatively. They scored 14 +/- 2.83 and 5.4 +/- 4.62 points, respectively (p = 0.0075). CONCLUSION: Functional proctological patients require a specialist approach from history taking through investigation to treatment. Majority of patients benefit from conservative treatment. Adequate patient selection is essential for successful surgical treatment. Symptom scores applied pre and postoperatively facilitate proper patient selection for various surgical methods. PMID- 23086824 TI - [Bilateral thoracoscopic sympathectomy in treatment of palmar and axillary hyperhydrosis - a summary of 22 cases. A role for one day surgery in thoracic surgery?]. AB - INTRODUCTION: The procedure of the ETS is carried out by two ports, a videothoracoscop and a diathermy instrument are introduced into the pleural cavity. After the identification of the sympathetic chain, the relevant ganglia are divided or excised. MATERIALS AND METHODS: 22 patient underwent bilateral video assisted thoracoscopic T2-T4 sympathectomy in a half-way sitting position for palmar and axillary hyperhydrosis between December 2008 and January 2011. RESULTS: 5 male and 17 female patients with a mean age of 39.9 years, (19-63) underwent the above procedure. The mean operation time was 36 minutes, (30-61 minutes). CONCLUSION: No postoperative complications were detected. The authors believe that two port VATS sympathectomy is a safe and effective method for the treatment of hyperhydrosis even as one day surgical procedure. PMID- 23086825 TI - [Surgical treatment of acute descending necrotising mediastinitis]. AB - INTRODUCTION: Acute descending necrotizing mediastinitis (DNM) is a severe septic inflammation of the mediastinum with necrosis, which progrediates rapidly and leads to death without adequate surgical treatment in 80% of cases. PATIENTS AND METHOD: 17 patients were treated with acute DNM between 1999 and 2012 at the Thoracic Surgical Department of Koranyi National Institute and Semmelweis University of Hungary. The infection source was primarily in the head-neck region with dental infections in eight cases, retro/parapharyngeal abscess in four patients, primary collar phlegmone and abscess in one case and two retrotonsillar abscesses. Further, in one case there was a previous operation (mediastinoscopy) in the history and in another case there was "difficult intubation process" (not recognized trachea-laesion) mentioned during abdominal operation. Primary exploration was performed from the neck in nine cases, thoracotomies plus collar incisions were carried out in four cases, athoracotomy only was done in one and orofacial exploration in further three patients. Disease progression could be evaluated by computer tomography which had to be followed by immediate surgery. RESULTS: Four patients needed two operations, five patients underwent exploration three times, while three patients needed 4 interventions four times. More than one anatomical region was explored in 70% of the cases. Based on our experience prognosis is affected by the time elapsed between detection and surgical intervention, age of the patient and comorbidites such as diabetes mellitus. We lost nine patients (53%), eight patients recovered and symptom free (47%). CONCLUSIONS: Successful treatment is based on early diagnosis, urgent elimination of the primary source, adequate exploration of the cervico-facial region, debridement, collar and upper mediastinal drainage. If the inflammation spreads below the azygos vein or the aortic arch, a right thoracotomy should be performed with wide mediastinal exploration, debridement, and thoracic suction-lavage drainage. Treatment should be completed with broad spectrum and targeted antibiotics as well as organ support. Mortality and morbidity can be reduced with prompt and aggressive therapy. PMID- 23086826 TI - [Perineal soft-tissue reconstruction with vertical rectus abdominis myocutan (VRAM) flap following extended abdomino-perineal resection for cancer]. AB - Perineal wound healing problems following extended abdomino-perineal resection of ano-rectal cancer represent a great challenge to the surgeon. Perineal soft tissue reconstruction with a myocutan flap was thought to reduce surgical wound healing complications. A review of the relevant literature was carried out on perineal soft-tissue reconstruction with rectus abdominis myocutan (VRAM) flap following extended abdomino-perineal rectal resection for cancer. The more commonly used neoadjuvant chemo- and radiotherapy as well as extended surgical radicality resulted in increased perioperative risks, therefore combined procedures between the colorectal and plastic surgical teams are inevitable. This case report illustrates the above trend. PMID- 23086829 TI - Glucagon-like peptide-1 as a treatment for chemotherapy-induced mucositis. AB - BACKGROUND: Glucagon-like peptide-2 (GLP-2) has been suggested for the treatment of mucositis, but the peptide has also been shown to accentuate colonic dysplasia in carcinogen-treated mice. Recently, an effect on intestinal growth was discovered for glucagon-like peptide-1 (GLP-1), OBJECTIVE: To determine whether endogenous GLP-1 contributes to the healing processes and if exogenous GLP-1 has a potential role in treating mucositis. METHODS: Mice were injected with 5 fluorouracil (5-FU) or saline to induce mucositis and were then treated with GLP 1, GLP-2, GLP-2 (3-33), exendin (9-39) or vehicle. The mice were sacrificed 48 or 96 h after the 5-FU injections. The end points were intestinal weight, villus height, proliferation and histological scoring of mucositis severity. Rats were injected with 5-FU or saline, and after 48 h, blood was drawn and analysed for GLP-1 and GLP-2 concentration. RESULTS: GLP-1 and GLP-2 significantly prevented the loss of mucosal mass and villus height and significantly decreased the mucositis severity score in the duodenum and jejunum 48 h after chemotherapy. The effect was equivalent. Exendin (9-39) reduced the intestinal weight 96 h after chemotherapy. The GLP-1 levels in blood were increased more than 10-fold, and GLP 2 levels were increased sevenfold. CONCLUSIONS: GLP-1 and GLP-2 were secreted after intestinal injury, and recovery was delayed after treatment with exendin (9 39), indicating an important role for the peptides in the protection of the intestine from injury. GLP-1 treatment ameliorated mucositis, which suggests that mucositis and other acute intestinal disorders might benefit from treatment with GLP-1 analogues. PMID- 23086830 TI - Exercise-induced SPARC prevents tumorigenesis of colon cancer. PMID- 23086831 TI - Matrix metalloproteinase and cytokine expression in Tenon fibroblasts during scar formation after glaucoma filtration or implant surgery in rats. AB - Failure of surgery for glaucoma is usually due to post-surgical scarring (fibrosis), a process in which fibroblasts play a prominent role. We investigated the molecular mechanisms of such scarring by examining the expression of matrix metalloproteinases and cytokines in Tenon fibroblasts isolated from rats after glaucoma surgery. Filtration surgery was performed in one eye and implant surgery in the other; and Tenon fibroblasts were isolated from the tissue surrounding the bleb after surgery. The cells were cultured and examined for the expression of matrix metalloproteinases (MMPs) by reverse transcription-polymerase chain reaction, immunoblot and gelatin zymographic analyses. Culture supernatants were also assayed for cytokines with a multiplex array. The amounts of MMP-1 and MMP-3 mRNAs and proteins were greater in cells isolated after implant surgery than in those isolated after filtration surgery, with the progression of scar formation being more complete after the former surgery. The secretion of interleukin-6 (IL 6) by cells isolated after filtration surgery was greater than that for cells isolated after implant surgery. Depletion of IL-6 by RNA interference in cells isolated after filtration surgery increased the expression of MMP-1 and MMP-3 in these cells. These results thus suggest that the expression of MMP-1 and MMP-3 in Tenon fibroblasts is regulated by IL-6 during, and may play an important role in, scar formation after glaucoma surgery. PMID- 23086833 TI - Functional recovery guided by an electrospun silk fibroin conduit after sciatic nerve injury in rats. AB - The aim of this study was to evaluate the regenerative capacity of a newly developed nerve guidance conduit using electrospun silk fibroin (SFNC) implanted in a 10-mm defect of the sciatic nerve in rats. After evaluating the physical properties and cytocompatibility of SFNC in vitro, rats were randomly allocated into three groups: defect only, autograft and SFNC. To compare motor function and abnormal sensation among groups, ankle stance angle (ASA) and severity of autotomy were observed for 10 weeks after injury. Immunostaining with axonal neurofilament (NF) and myelin basic protein (MBP) antibodies were performed to investigate regenerated nerve fibres inside SFNC. ASA increased significantly in the SFNC group at 1, 7 and 10 weeks after injury compared to the defect only group (p<0.05). At one week, mean ASA of the SFNC group was significantly higher than that of the autograft group (p<0.05). Onset and severity of autotomy decreased significantly in the SFNC group compared to other groups (p<0.05). Autotomy in the SFNC group started at 4 weeks and maximally reached toe level. However, the defect only and autograft groups first showed autotomy at 2 and 1 weeks following injury, respectively, and then reached the sole level. Well myelinated nerve fibres stained with NF and MBP were found inside SFNC. In conclusion, SFNC could be helpful in restoring motor function and preventing abnormal sensations after nerve injury. PMID- 23086835 TI - Methods for building QSARs. AB - Structure-activity relationship (SAR) and quantitative structure-activity relationship (QSAR) models are increasingly used in toxicology, ecotoxicology, and pharmacology for predicting the activity of the molecules from their physicochemical properties and/or their structural characteristics. However, the design of such models has many traps for unwary practitioners. Consequently, the purpose of this chapter is to give a practical guide for the computation of SAR and QSAR models, point out problems that may be encountered, and suggest ways of solving them. Attempts are also made to see how these models can be validated and interpreted. PMID- 23086834 TI - eHealth program to empower patients in returning to normal activities and work after gynecological surgery: intervention mapping as a useful method for development. AB - BACKGROUND: Full recovery after gynecological surgery takes much longer than expected regardless of surgical technique or the level of invasiveness. After discharge, detailed convalescence recommendations are not provided to patients typically, and postoperative care is fragmented, poorly coordinated, and given only on demand. For patients, this contributes to irrational beliefs and avoidance of resumption of activities and can result in a prolonged sick leave. OBJECTIVE: To develop an eHealth intervention that empowers gynecological patients during the perioperative period to obtain timely return to work (RTW) and prevent work disability. METHODS: The intervention mapping (IM) protocol was used to develop the eHealth intervention. A literature search about behavioral and environmental conditions of prolonged sick leave and delayed RTW in patients was performed. Patients' needs, attitudes, and beliefs regarding postoperative recovery and resumption of work were identified through focus group discussions. Additionally, a literature search was performed to obtain determinants, methods, and strategies for the development of a suitable interactive eHealth intervention to empower patients to return to normal activities after gynecological surgery, including work. Finally, the eHealth intervention was evaluated by focus group participants, medical doctors, and eHealth specialists through questionnaires. RESULTS: Twenty-one patients participated in the focus group discussions. Sufficient, uniform, and tailored information regarding surgical procedures, complications, and resumption of activities and work were considered most essential. Knowing who to contact in case of mental or physical complaints, and counseling and tools for work reintegration were also considered important. Finally, opportunities to exchange experiences with other patients were a major issue. Considering the determinants of the Attitude-Social influence-self Efficacy (ASE) model, various strategies based on a combination of theory and evidence were used, resulting in an eHealth intervention with different interactive functionalities including tailored convalescence recommendations and a video to communicate the most common pitfalls during the perioperative period to patients and employers. Fifteen patients in the focus groups, 11 physicians, and 3 eHealth specialists suggested points for improvement to optimize the usability of the eHealth intervention and judged it an approachable, appropriate, and attractive eHealth intervention to empower gynecological patients. CONCLUSIONS: The IM protocol was a useful method to develop an eHealth intervention based on both theory and evidence. All patients and stakeholders judged the eHealth intervention to be a promising tool to empower gynecological patients during the perioperative period and to help them to return to normal activities and work. PMID- 23086836 TI - Accessing and using chemical databases. AB - Computer-based representation of chemicals makes it possible to organize data in chemical databases-collections of chemical structures and associated properties. Databases are widely used wherever efficient processing of chemical information is needed, including search, storage, retrieval, and dissemination. Structure and functionality of chemical databases are considered. The typical kinds of information found in a chemical database are considered-identification, structural, and associated data. Functionality of chemical databases is presented, with examples of search and access types. More details are included about the OASIS database and platform and the Danish (Q)SAR Database online. Various types of chemical database resources are discussed, together with a list of examples. PMID- 23086838 TI - Mutagenicity, carcinogenicity, and other end points. AB - Aiming at understanding the structural and physical chemical basis of the biological activity of chemicals, the science of structure-activity relationships has seen dramatic progress in the last decades. Coarse-grain, qualitative approaches (e.g., the structural alerts), and fine-tuned quantitative structure activity relationship models have been developed and used to predict the toxicological properties of untested chemicals. More recently, a number of approaches and concepts have been developed as support to, and corollary of, the structure-activity methods. These approaches (e.g., chemical relational databases, expert systems, software tools for manipulating the chemical information) have dramatically expanded the reach of the structure-activity work; at present, they are powerful and inescapable tools for computer chemists, toxicologists, and regulators. This chapter, after a general overview of traditional and well-known approaches, gives a detailed presentation of the latter more recent support tools freely available in the public domain. PMID- 23086837 TI - From QSAR to QSIIR: searching for enhanced computational toxicology models. AB - Quantitative structure activity relationship (QSAR) is the most frequently used modeling approach to explore the dependency of biological, toxicological, or other types of activities/properties of chemicals on their molecular features. In the past two decades, QSAR modeling has been used extensively in drug discovery process. However, the predictive models resulted from QSAR studies have limited use for chemical risk assessment, especially for animal and human toxicity evaluations, due to the low predictivity of new compounds. To develop enhanced toxicity models with independently validated external prediction power, novel modeling protocols were pursued by computational toxicologists based on rapidly increasing toxicity testing data in recent years. This chapter reviews the recent effort in our laboratory to incorporate the biological testing results as descriptors in the toxicity modeling process. This effort extended the concept of QSAR to quantitative structure in vitro-in vivo relationship (QSIIR). The QSIIR study examples provided in this chapter indicate that the QSIIR models that based on the hybrid (biological and chemical) descriptors are indeed superior to the conventional QSAR models that only based on chemical descriptors for several animal toxicity endpoints. We believe that the applications introduced in this review will be of interest and value to researchers working in the field of computational drug discovery and environmental chemical risk assessment. PMID- 23086839 TI - Classification models for safe drug molecules. AB - Frequent failure of drug candidates during development stages remains the major deterrent for an early introduction of new drug molecules. The drug toxicity is the major cause of expensive late-stage development failures. An early identification/optimization of the most favorable molecule will naturally save considerable cost, time, human efforts and minimize animal sacrifice. (Quantitative) Structure Activity Relationships [(Q)SARs] represent statistically derived predictive models correlating biological activity (including desirable therapeutic effect and undesirable side effects) of chemicals (drugs/toxicants/environmental pollutants) with molecular descriptors and/or properties. (Q)SAR models which categorize the available data into two or more groups/classes are known as classification models. Numerous techniques of diverse nature are being presently employed for development of classification models. Though there is an increasing use of classification models for prediction of either biological activity or toxicity, the future trend will naturally be towards the development of classification models capable of simultaneous prediction of biological activity, toxicity, and pharmacokinetic parameters so as to accelerate development of bioavailable safe drug molecules. PMID- 23086840 TI - QSAR and metabolic assessment tools in the assessment of genotoxicity. AB - In this chapter, a range of computational tools for applying QSAR and grouping/read-across methods are described, and their integrated use in the computational assessment of genotoxicity is illustrated through the application of selected tools to two case-study compounds-2-amino-9H-pyrido[2,3-b]indole (AalphaC) and 2-aminoacetophenone (2-AAP). The first case study compound (AalphaC) is an environment pollutant and a food contaminant that can be formed during the cooking of protein-rich food. The second case study compound (2-AAP) is a naturally occurring compound in certain foods and also proposed for use as a flavoring agent. The overall aim is to describe and illustrate a possible way of combining different information sources and software tools for genotoxicity and metabolism prediction by means of a simple stepwise approach. The chapter is aimed at researchers and assessors who have a basic knowledge of computational toxicology and some familiarity with the practical use of computational tools. The emphasis is on how to evaluate the data generated by multiple tools, rather than the practical use of any specific tool. PMID- 23086841 TI - Gene expression networks. AB - With the advent of microarrays and next-generation biotechnologies, the use of gene expression data has become ubiquitous in biological research. One potential drawback of these data is that they are very rich in features or genes though cost considerations allow for the use of only relatively small sample sizes. A useful way of getting at biologically meaningful interpretations of the environmental or toxicological condition of interest would be to make inferences at the level of a priori defined biochemical pathways or networks of interacting genes or proteins that are known to perform certain biological functions. This chapter describes approaches taken in the literature to make such inferences at the biochemical pathway level. In addition this chapter describes approaches to create hypotheses on genes playing important roles in response to a treatment, using organism level gene coexpression or protein-protein interaction networks. Also, approaches to reverse engineer gene networks or methods that seek to identify novel interactions between genes are described. Given the relatively small sample numbers typically available, these reverse engineering approaches are generally useful in inferring interactions only among a relatively small or an order 10 number of genes. Finally, given the vast amounts of publicly available gene expression data from different sources, this chapter summarizes the important sources of these data and characteristics of these sources or databases. In line with the overall aims of this book of providing practical knowledge to a researcher interested in analyzing gene expression data from a network perspective, the chapter provides convenient publicly accessible tools for performing analyses described, and in addition describe three motivating examples taken from the published literature that illustrate some of the relevant analyses. PMID- 23086842 TI - Construction of cell type-specific logic models of signaling networks using CellNOpt. AB - Mathematical models are useful tools for understanding protein signaling networks because they provide an integrated view of pharmacological and toxicological processes at the molecular level. Here we describe an approach previously introduced based on logic modeling to generate cell-specific, mechanistic and predictive models of signal transduction. Models are derived from a network encoding prior knowledge that is trained to signaling data, and can be either binary (based on Boolean logic) or quantitative (using a recently developed formalism, constrained fuzzy logic). The approach is implemented in the freely available tool CellNetOptimizer (CellNOpt). We explain the process CellNOpt uses to train a prior knowledge network to data and illustrate its application with a toy example as well as a realistic case describing signaling networks in the HepG2 liver cancer cell line. PMID- 23086843 TI - Regulatory networks. AB - The usefulness of mathematical models for the biological regulatory networks relies on the predictive capability of the models in order to suggest interesting hypotheses and suitable biological experiments. All mathematical frameworks dedicated to biological regulatory networks must manage a large number of abstract parameters, which are not directly measurable in the cell. The cornerstone to establish predictive models is the identification of the possible parameter values. Formal frameworks involve qualitative models with discrete values and computer-aided logic reasoning. They can provide the biologists with an automatic identification of the parameters via a formalization of some biological knowledge into temporal logic formulas. For pedagogical reasons, we focus on gene regulatory networks and develop a qualitative model of the detoxification of benzo[a]pyrene in human cells to illustrate the approach. PMID- 23086844 TI - Computational reconstruction of metabolic networks from KEGG. AB - Reconstruction of metabolic networks from metabolites, enzymes, and reactions is the foundation of the network-based study on metabolism. In this chapter, we describe a practical method for reconstructing metabolic networks from KEGG. This method makes use of organism-specific pathway data in the KEGG/PATHWAY database to reconstruct metabolic networks on pathway level, and the pathway hierarchy data in the KEGG/ORTHOLOGY database to guide the network reconstruction on higher levels. By calling upon the KEGG Web services, this method ensures the data used in the reconstruction are correct and up-to-date. The incorporation of a local relational database allows caching of pathway data improves performance and speeds up network reconstruction. Some applications of reconstructed networks on network alignment and network topology analysis are exampled and notes are stated in the end. PMID- 23086845 TI - Biomarkers. AB - Biomarkers are characteristics objectively measured and evaluated as indicators of: normal biologic processes, pathogenic processes, or pharmacologic response(s) to a therapeutic intervention. In environmental research and risk assessment, biomarkers are frequently referred to as indicators of human or environmental hazards. Discovering and implementing new biomarkers for toxicity caused by exposure to a chemical either from a therapeutic intervention or accidentally through the environment continues to be pursued through the use of animal models to predict potential human effects, from human studies (clinical or epidemiologic) or biobanked human samples, or the combination of all such approaches. The key to discovering or inferring biomarkers through computational means involves the identification or prediction of the molecular target(s) of the chemical(s) and the association of these targets with perturbed biological pathways. Two examples are given in this chapter: (1) inferring potential human biomarkers from animal toxicogenomics data, and (2) the identification of protein targets through computational means and associating these in one example with potential drug interactions and in another case with increasing the risk of developing certain human diseases. PMID- 23086846 TI - Biomonitoring-based environmental public health indicators. AB - This chapter discusses the use ofbiomonitoring-based indicators of exposure to environmental pollutants in environmental health information systems. Matrices for biomonitoring, organization and standardization of surveillance programs, the use of intake and body burden data, and the interpretation of surveillance data are discussed. The concept of environmental public health indicators is demonstrated using the "Persistent organic pollutants in human milk" indicator implemented in the Environment and Health Information System (ENHIS) of the WHO Regional Office for Europe. This indicator is based on the data from the WHO coordinated surveillance of persistent organic pollutants in human milk as well as data from selected national studies. The WHO survey data demonstrate a steady decline in breast milk concentrations of dioxins across Europe. The data from biomonitoring surveys in Sweden also show a steady decline of breast milk concentrations of most persistent organic pollutants since 1970s with the exception of polybrominated diphenyl ethers (PBDEs) which increased rapidly until the late 1990s and then started to decline after the implementation of policy measures aiming at reducing exposures. The application of human biomonitoring data in support of environmental public health policy actions requires carefully designed standardized and sustainable surveillance, comprehensive interpretation of the data, and an effective communication strategy based on credible information presented in the form of indicator factsheets. PMID- 23086847 TI - Modeling for regulatory purposes (risk and safety assessment). AB - Chemicals provide many key building blocks that are converted into end-use products or used in industrial processes to make products that benefit society. Ensuring the safety of chemicals and their associated products is a key regulatory mission. Current processes and procedures for evaluating and assessing the impact of chemicals on human health, wildlife, and the environment were, in general, designed decades ago. These procedures depend on generation of relevant scientific knowledge in the laboratory and interpretation of this knowledge to refine our understanding of the related potential health risks. In practice, this often means that estimates of dose-response and time-course behaviors for apical toxic effects are needed as a function of relevant levels of exposure. In many situations, these experimentally determined functions are constructed using relatively high doses in experimental animals. In absence of experimental data, the application of computational modeling is necessary to extrapolate risk or safety guidance values for human exposures at low but environmentally relevant levels. PMID- 23086848 TI - Developmental toxicity prediction. AB - Developmental toxicity may be estimated using commercial and noncommercial software that is already available in the market and/or literature, or models may be built from scratch using both commercial and noncommercial software packages. In this chapter, commonly available software programs that can predict the developmental toxicity of chemicals are described. In addition, a method for developing qualitative structure-activity relationship (SAR) models to predict the developmental toxicity of chemicals qualitatively (yes/no prediction) and quantitative structure-activity relationship (QSAR) models to predict quantitative estimates (e.g., LOAEL) of developmental toxicants is also described in this chapter. Additional information described in this chapter include methods to predict physicochemical properties of chemicals that can be used as descriptor variables in the model building process, statistical methods that be used to build QSAR models as well as methods to validate the models that are developed. Most of the methods described in this chapter can be used to develop models for health endpoints other than developmental toxicity as well. PMID- 23086849 TI - Predictive computational toxicology to support drug safety assessment. AB - Use of predictive technologies is an important aspect of many efforts in today's research, development, and regulatory landscapes. Computational methods as predictive tools for supporting drug safety assessments is of widespread interest as the field of in silico assessments rapidly changes with emerging technologies and the large amount of existing data available for modeling. There are challenges associated with application of in silico analyses for drug toxicity predictions and need for strategies and harmonization to enable an acceptable in silico evaluation for prediction of specific toxicity assay outcomes. This chapter will provide an overview focused on computational tools using structure activity relationships and will highlight initiatives for use of computational assessments and realistic applications for predictive modeling in evaluating potential toxicities of drug-related molecules. PMID- 23086850 TI - Developing a practical toxicogenomics data analysis system utilizing open-source software. AB - Comprehensive gene expression analysis has been applied to investigate the molecular mechanism of toxicity, which is generally known as toxicogenomics (TGx). When analyzing large-scale gene expression data obtained by microarray analysis, typical multivariate data analysis methods performed with commercial software such as hierarchical clustering or principal component analysis usually do not provide conclusive outputs by themselves. To best utilize the TGx data for toxicity evaluation in the drug development process, fit-for-purpose customization of the analytical algorithm with user-friendly interface and intuitive outputs are required to practically address the toxicologists' demands. However, commercial software is usually not very flexible in the customization of their functions or outputs. Owing to the recent advancement and accumulation of open-source software contributed by bioinformaticians all over the world, it becomes easier for us to develop practical and fit-for-purpose analytical software by ourselves with fairly low cost and efforts. The aim of this article is to present an example of developing an automated TGx data processing system (ATP system), which implements gene set-level analysis toxicogenomic profiling by D-score method and generates straightforward output that makes it easy to interpret the biological and toxicological significance of the TGx data. Our example will provide basic clues for readers to develop and customize their own TGx data analysis system which complements the function of existing commercial software. PMID- 23086851 TI - Systems toxicology from genes to organs. AB - This unique overview of systems toxicology methods and techniques begins with a brief account of systems thinking in biology over the last century. We discuss how systems biology and toxicology continue to leverage advances in computational modeling, informatics, large-scale computing, and biotechnology. Next, we chart the genesis of systems toxicology from previous work in physiologically based models, models of early development, and more recently, molecular systems biology. For readers interested in further details this background provides useful linkages to the relevant literature. It also lays the foundations for new ideas in systems toxicology that could translate laboratory measurements of molecular responses from xenobiotic perturbations to adverse organ level effects in humans. By providing innovative solutions across disciplinary boundaries and highlighting key scientific gaps, we believe this chapter provides useful information about the current state, and valuable insight about future directions in systems toxicity. PMID- 23086852 TI - Agent-based models of cellular systems. AB - Software agents are particularly suitable for engineering models and simulations of cellular systems. In a very natural and intuitive manner, individual software components are therein delegated to reproduce "in silico" the behavior of individual components of alive systems at a given level of resolution. Individuals' actions and interactions among individuals allow complex collective behavior to emerge. In this chapter we first introduce the readers to software agents and multi-agent systems, reviewing the evolution of agent-based modeling of biomolecular systems in the last decade. We then describe the main tools, platforms, and methodologies available for programming societies of agents, possibly profiting also of toolkits that do not require advanced programming skills. PMID- 23086853 TI - Linear algebra. AB - This chapter is a short review of linear algebra leading to a discussion of the singular value decomposition. PMID- 23086854 TI - Ordinary differential equations. AB - In this chapter we provide an overview of the basic theory of ordinary differential equations (ODE). We give the basics of analytical methods for their solutions and also review numerical methods. The chapter should serve as a primer for the basic application of ODEs and systems of ODEs in practice. As an example, we work out the equations arising in Michaelis-Menten kinetics and give a short introduction to using Matlab for their numerical solution. PMID- 23086855 TI - On the development and validation of QSAR models. AB - The fundamental and more critical steps that are necessary for the development and validation of QSAR models are presented in this chapter as best practices in the field. These procedures are discussed in the context of predictive QSAR modelling that is focused on achieving models of the highest statistical quality and with external predictive power. The most important and most used statistical parameters needed to verify the real performances of QSAR models (of both linear regression and classification) are presented. Special emphasis is placed on the validation of models, both internally and externally, as well as on the need to define model applicability domains, which should be done when models are employed for the prediction of new external compounds. PMID- 23086856 TI - Principal components analysis. AB - Principal components analysis (PCA) is a standard tool in multivariate data analysis to reduce the number of dimensions, while retaining as much as possible of the data's variation. Instead of investigating thousands of original variables, the first few components containing the majority of the data's variation are explored. The visualization and statistical analysis of these new variables, the principal components, can help to find similarities and differences between samples. Important original variables that are the major contributors to the first few components can be discovered as well.This chapter seeks to deliver a conceptual understanding of PCA as well as a mathematical description. We describe how PCA can be used to analyze different datasets, and we include practical code examples. Possible shortcomings of the methodology and ways to overcome these problems are also discussed. PMID- 23086857 TI - Partial least squares methods: partial least squares correlation and partial least square regression. AB - Partial least square (PLS) methods (also sometimes called projection to latent structures) relate the information present in two data tables that collect measurements on the same set of observations. PLS methods proceed by deriving latent variables which are (optimal) linear combinations of the variables of a data table. When the goal is to find the shared information between two tables, the approach is equivalent to a correlation problem and the technique is then called partial least square correlation (PLSC) (also sometimes called PLS-SVD). In this case there are two sets of latent variables (one set per table), and these latent variables are required to have maximal covariance. When the goal is to predict one data table the other one, the technique is then called partial least square regression. In this case there is one set of latent variables (derived from the predictor table) and these latent variables are required to give the best possible prediction. In this paper we present and illustrate PLSC and PLSR and show how these descriptive multivariate analysis techniques can be extended to deal with inferential questions by using cross-validation techniques such as the bootstrap and permutation tests. PMID- 23086858 TI - Maximum likelihood. AB - The maximum likelihood method is a popular statistical inferential procedure widely used in many areas to obtain the estimates of the unknown parameters of a population of interest. This chapter gives a brief description of the important concepts underlying the maximum likelihood method, the definition of the key components, the basic theory of the method, and the properties of the resulting estimates. Confidence interval and likelihood ratio test are also introduced. Finally, a few examples of applications are given to illustrate how to derive maximum likelihood estimates in practice. A list of references to relevant papers and software for a further understanding of the method and its implementation is provided. PMID- 23086859 TI - Bayesian inference. AB - This chapter provides an overview of the Bayesian approach to data analysis, modeling, and statistical decision making. The topics covered go from basic concepts and definitions (random variables, Bayes' rule, prior distributions) to various models of general use in biology (hierarchical models, in particular) and ways to calibrate and use them (MCMC methods, model checking, inference, and decision). The second half of this Bayesian primer develops an example of model setup, calibration, and inference for a physiologically based analysis of 1,3 butadiene toxicokinetics in humans. PMID- 23086860 TI - Laparoscopic surgery for colorectal cancer. AB - BACKGROUND: Laparoscopic surgery for colorectal cancer has undergone tremendous advancement in the last two decades, with maturation of techniques and integration into current practice. SOURCES OF DATA: Worldwide English-language literature on laparoscopic surgery for the management of colon and rectal cancer was reviewed. AREAS OF AGREEMENT: A large body of evidence has attested to the improved short-term outcomes and long-term oncological safety of laparoscopic surgery for colon cancer. Laparoscopic colectomy can be recommended to suitable patients where expertise is available. Laparoscopic resection for rectal cancer is feasible, with good evidence of faster post-operative recovery and adequate surgical quality, but requires more data on long-term oncological outcomes. This review examines the evidence and current practice of laparoscopic surgery for colorectal cancer. AREAS OF CONTROVERSY: Does laparoscopic surgery confer a survival advantage for colorectal cancer patients? GROWING POINTS: The role of single-incision laparoscopic surgery and robotic surgery in colorectal cancer. AREAS TIMELY FOR DEVELOPING RESEARCH: Barriers to the adoption of the laparoscopic technique. PMID- 23086861 TI - PC12 neuron-like cell response to electrospun poly( 3-hydroxybutyrate) substrates. AB - In the last decade, the importance of topographic properties of extracellular environments has been shown to be essential to addressing cell response, especially when replacing damaged tissues with functional constructs obtained in vitro. In the current study, densely packed sub-micron poly(3-hydroxybutyrate) (PHB) fibres were electrospun with random and parallel orientations. PC12 pheochromocytoma cells that mimic central dopaminergic neurons and represent a model for neuronal differentiation were cultured on collagen-coated fibres to evaluate cell response dependence on substrate topography. Cell adhesion, viability and proliferation, as well as dopamine production were evaluated after three days since seeding. Cell differentiation was examined in terms of neurite number, orientation and length 6 days after administration of nerve growth factor (NGF). Results showed that proliferating PC12 cells secreted a higher quantity of dopamine on fibres with respect to control cultures and as a result, a possible use of PHB fibres was considered for cell transplantation in the central nervous system when local production of dopamine is impaired. Differentiated PC12 cells were characterized by highly aligned and longer neurites on parallel PHB fibres with respect to random fibres, thereby demonstrating the suitability of parallel PHB fibres for further studies in peripheral nervous system regeneration. PMID- 23086862 TI - Germ-like cell differentiation from induced pluripotent stem cells (iPSCs). AB - Historically, our understanding of molecular genetic aspects of germ cell development has been limited. Recently, results demonstrated that the derivation of pluripotent stem cells may provide the necessary genetic system to study germ cell development. Here, we characterized an induced pluripotent stem cell (iPSC) line, which can spontaneously differentiate into embryonic bodies (EBs) after 3 days of suspension culture, expressing specific markers of three germ layers. Then, we induced the iPSCs to differentiate into germ cells by culturing adherent EBs in retinoic acid (RA) and porcine follicular fluid (PFF) differentiation medium or seminiferous tubule transplantation. Our results indicated that RA and PFF were beneficial for the derivation of germ cells and oocyte-like cells from iPSCs, and iPSCs transplantation could make a contribution to repairing the testis of infertile mice. Our study offers an approach for further study on the development and the differentiation of germ cells derived from iPSCs. PMID- 23086863 TI - Comparison of drug-induced sleep endoscopy and lateral cephalometry in obstructive sleep apnea. AB - OBJECTIVES/HYPOTHESIS: To evaluate the association between findings from drug induced sleep endoscopy (DISE) and lateral cephalometry in obstructive sleep apnea (OSA) STUDY DESIGN: Cross-sectional. METHODS: This was a consecutive series of subjects with OSA who underwent DISE and lateral cephalometry. DISE findings were characterized according to the region/degree of obstruction as well as the VOTE classification (velum, oropharyngeal lateral walls, tongue, and epiglottis). The primary measurements from lateral cephalometry images were sella-nasion-point A angle, sella-nasion-point B angle, distance from the posterior nasal spine-tip of palate, posterior airway space, and mandibular plane to hyoid (MPH) distance, although additional airway measurements were taken. Descriptive statistics summarized DISE and lateral cephalometry findings, and chi(2) and t tests examined potential associations between their findings. RESULTS: Among the 55 subjects, most demonstrated velum-related obstruction, although obstruction related to other structures was also common. Lateral cephalometry findings were within population norms with the exception of an increased MPH and decreased airway 4 and airway 5 measurements. There was little association between DISE and lateral cephalometry findings, although significant associations were identified between tongue-related obstruction and airway measurements posterior to the tongue base. CONCLUSIONS: DISE and lateral cephalometry are largely distinct airway evaluation techniques in OSA. The use of these techniques remains complementary. PMID- 23086865 TI - Twenty-four years after liver transplantation, the recipient becomes a body donor. PMID- 23086866 TI - Introduction: nanoimaging techniques in biology. AB - To dissect the astonishing complexity of the biomolecular machinery functioning within a cell, imaging has been an integral tool in biology, allowing researches to "view" the detailed molecular biology responsible for coordinating cellular life. To visualize the molecular components of cellular structures requires, in particular, imaging techniques capable of reaching nanoscale spatial resolutions. Such nanoimaging techniques are the focus of this volume. Chapters in the current volume are divided into four parts and include specialized techniques in the areas of light, electron, and scanning probe microscopy, as well as methodologies employing combinatorial and complementary imaging approaches. PMID- 23086864 TI - Effects of isoflurane anesthesia on hyperpolarized (13)C metabolic measurements in rat brain. AB - PURPOSE: Commonly used anesthetic agents such as isoflurane are known to be potent cerebral vasodilators, with reported dose-dependent increase in cerebral blood flow and cerebral blood volume. Despite the widespread use of isoflurane in hyperpolarized (13)C preclinical research studies, a quantitative assessment of its effect on metabolic measurements is limited. This work investigates the effect of isoflurane anesthesia dose on hyperpolarized (13)C MR metabolic measurements in rat brain for [1-(13)C]pyruvate and 2-keto[1-(13)C]isocaproate. METHODS: Dynamic 2D and 3D spiral chemical shift imaging was used to acquire metabolic images of rat brain as well as kidney and liver following bolus injections of hyperpolarized [1-(13)C]pyruvate or 2-keto[1-(13)C]isocaproate. The impact of a "low dose" vs. a "high dose" of isoflurane on cerebral metabolite levels and apparent conversion rates was examined. RESULTS: The cerebral substrate signal levels, and hence the metabolite-to-substrate ratios and apparent conversion rates, were found to depend markedly on isoflurane dose, while signal levels of metabolic products and their ratios, e.g. bicarbonate/lactate, were largely insensitive to isoflurane levels. No obvious dependence on isoflurane was observed in kidney or liver for pyruvate. CONCLUSION: This study highlights the importance of careful attention to the effects of anesthesia on the metabolic measures for hyperpolarized (13)C metabolic imaging in brain. PMID- 23086867 TI - Live-cell imaging of vesicle trafficking and divalent metal ions by total internal reflection fluorescence (TIRF) microscopy. AB - Total internal reflection fluorescence (TIRF) microscopy is an especially powerful tool for visualizing live cellular events. Fluorescent molecules alone provide broad information about the expression and localization of proteins and other molecules; however, the temporal and spatial resolution is confounded by signal from outside the area of interest and the intensity of the illumination required. TIRF overcomes this limitation by using the reflective properties of a laser beam to illuminate a narrow (<100 nm) strip at the surface of a cell with a relatively low powered evanescent wave, thus making it possible to measure events occurring specifically at the plasma membrane such as exocytosis, single molecule interactions, and ionic changes during signal transduction. Here we describe some of the methods for using TIRF microscopy to study the processes involved in exocytosis from excitable cells (i.e., neurons, endocrine, neuroendocrine, and exocrine cells) and the release of physiologically active substances (i.e., neurotransmitters, hormones, and mucus).The failure of regulated exocytosis is associated with various diseases such as allergy, brain dysfunction, and endocrine illness. Diabetes mellitus, which is due to an absolute (type I) or relative (type II) deficiency of insulin secretion from pancreatic beta-cells, is a major area of therapeutic interest. Insulin is stored in dense core vesicles with Zn(2+) ions in pancreatic beta-cells. Insulin secretion is regulated by plasma glucose concentration which acts through intracellular metabolism to influence intracellular [Ca(2+)]. However, the precise molecular mechanisms controlling insulin granule movement towards, and fusion at, the plasma membrane remain only partially understood. To tackle this problem, we have used live cell imaging techniques to image regulated exocytosis in single living beta-cells alongside intracellular Ca(2+) and Zn(2+) concentrations. PMID- 23086868 TI - 4Pi Microscopy. AB - Optical microscopy has become a key technology in the life sciences today. Its noninvasive nature provides access to the interior of intact and even living cells, where specific molecules can be precisely localized by fluorescent tagging. However, the attainable 3D resolution of an optical microscope has long been hampered by a comparatively poor resolution along the optic axis. By coherent focusing through two objective lenses, 4Pi microscopy improves the axial resolution by three- to fivefold. This primer is intended as a starting point for the design and operation of a 4Pi microscope of type A. PMID- 23086869 TI - Fluorescence in situ hybridization applications for super-resolution 3D structured illumination microscopy. AB - Fluorescence in situ hybridization on three-dimensionally preserved cells (3D FISH) is an efficient tool to analyze the subcellular localization and spatial arrangement of targeted DNA sequences and RNA transcripts at the single cell level. 3D reconstructions from serial optical sections obtained by confocal laser scanning microscopy (CLSM) have long been considered the gold standard for 3D FISH analyses. Recent super-resolution techniques circumvent the diffraction limit of optical resolution and have defined a new state-of-the-art in bioimaging. Three-dimensional structured illumination microscopy (3D-SIM) represents one of these technologies. Notably, 3D-SIM renders an eightfold improved volumetric resolution over conventional imaging, and allows the simultaneous visualization of differently labeled target structures. These features make this approach highly attractive for the analysis of spatial relations and substructures of nuclear targets that escape detection by conventional light microscopy. Here, we focus on the application of 3D-SIM for the visualization of subnuclear 3D-FISH preparations. In comparison with conventional fluorescence microscopy, the quality of 3D-SIM data is dependent to a much greater extent on the optimal sample preparation, labeling and acquisition conditions. We describe typical problems encountered with super-resolution imaging of in situ hybridizations in mammalian tissue culture cells and provide optimized DNA-/(RNA)-FISH protocols including combinations with immunofluorescence staining (Immuno-FISH) and DNA replication labeling using click chemistry. PMID- 23086870 TI - Two-color STED imaging of synapses in living brain slices. AB - STED microscopy is a novel fluorescence microscopy technique that breaks the classic diffraction barrier of optical microscopy. It offers the chance to investigate dynamic processes inside living cells with a spatial resolution well below 100 nm, possibly even down to a few nanometers, essentially without forgoing the benefits of conventional light microscopy, such as labeling specificity, sensitivity, and contrast. STED microscopy has already been exploited for several important neurobiological experiments. Given the tremendous potential as a transforming technology, it is important to understand how it works, and what its scope and limitations are. Here, we present a primer on STED microscopy, its basic principles and practical implementation, presenting a how to guide on building and operating a STED microscope. PMID- 23086871 TI - Super-resolution imaging by localization microscopy. AB - Photoactivated localization microscopy (PALM) and the related technique of Stochastic optical reconstruction microscopy (STORM) are super-resolution imaging methods based on the precise localization of single molecules. Instruments based on these techniques are now commercially available and are capable of generating images with lateral resolutions in the tens of nanometers range. Here, we give an overview of the current state of this technology including live-cell and 3D PALM and provide an in-depth protocol for performing PALM experiments in a fixed cell monolayer. This includes both the instrumentation/acquisition aspects and the data analysis required for generating quantitative, super-resolution data of molecular distributions. In this example, the system under investigation will be fixed HeLa cells transfected with the photo-switchable fluorescent protein PS CFP2 targeted to the plasma membrane by fusion to the N-terminus of the protein kinase Lck. PMID- 23086873 TI - Super-resolution fluorescence imaging with blink microscopy. AB - Recently, a new approach for super-resolution microscopy has emerged which is based on the successive localization of single molecules. The majority of molecules are prepared to reside in a nonfluorescent dark state, leaving only a few single molecules fluorescing. The single molecules can subsequently be localized on the camera image. Successive localization of all molecules allows reconstruction of a super-resolved image of the labeled structure. A variety of ways for limiting the number of locatable molecules have been developed recently which expand this current field of imaging. Here we describe a super-resolution microscopy method that employs the use of reversible, generic dark states, for example radical ion states. This method requires only a single laser source and can be carried out with many fluorescent dyes, in some cases, even in living cells. We provide a step-by-step procedure for this method, which we have called Blink Microscopy. PMID- 23086872 TI - High-content super-resolution imaging of live cell by uPAINT. AB - In this chapter, we present the uPAINT method (Universal Point Accumulation Imaging in Nanoscale Topography), a simple single-molecule super-resolution method which can be implemented on any wide field fluorescence microscope operating in oblique illumination. The key feature of uPAINT lies in recording high numbers of single molecules at the surface of a cell by constantly labeling while imaging. In addition to generating super-resolved images, uPAINT can provide dynamical information on a single live cell with large statistics revealing localization-specific diffusion properties of membrane biomolecules. Interestingly, any membrane biomolecule that can be labeled with a fluorescent ligand can be studied, making uPAINT an extremely versatile method. PMID- 23086874 TI - Photoswitchable fluorophores for single-molecule localization microscopy. AB - Over the past decade, fluorescence microscopy has been revolutionized by the development of novel techniques that allow near-molecular resolution. Many such methods-collectively referred to as "single-molecule localization microscopy" (SMLM)-are based upon the repeated imaging of sparse stochastic subsets of the fluorophores in a sample. Active fluorophores are localized by finding the centers of their point spread functions, and a super-resolution image is constructed.Key to this strategy is the use of fluorophores that can be switched "on" and "off" in a controllable manner. Here we review the strengths and weaknesses of the wide variety of SMLM-compatible photoswitchable fluorophores and labeling strategies currently available. We also discuss their suitability for live-cell and multicolor imaging, as well as molecular counting. PMID- 23086875 TI - Single-molecule tracking of mRNA in living cells. AB - Some mRNAs localize to specific regions within eukaryotic cells to express their functions. The movement and localization of mRNA molecules provides valuable information about how they concentrate to particular regions. Recent technical advances in optical microscopy and image analysis algorithms enable real-time tracking of single mRNA molecules in living cells. This chapter presents the methods to visualize and track single beta-actin mRNA molecules that localize at the leading edge of chicken embryo fibroblasts. Furthermore, this chapter presents an analysis approach for single-molecule tracking data to extract quantitative information about the microenvironments of the mRNA molecules. PMID- 23086876 TI - Semiautomatic, high-throughput, high-resolution protocol for three-dimensional reconstruction of single particles in electron microscopy. AB - In this chapter we describe the steps needed for reconstructing the three dimensional structure of a macromolecular complex starting from its projections collected in electron micrographs. The concepts are shown through the use of Xmipp 3.0, a software suite specifically designed for the image processing of biological structures imaged with electron or X-ray microscopy. We illustrate the image processing workflow by applying it to the images of Bovine Papilloma virus published in Wolf et al. (Proc Natl Acad Sci USA 107:6298-6303, 2010). We show that in the case of high-quality, homogeneous datasets with a priori knowledge about the initial volume, we can have a high-resolution 3D reconstruction in less than 1 day using a computer cluster with only 32 processors. PMID- 23086877 TI - Mass mapping of amyloid fibrils in the electron microscope using STEM imaging. AB - Scanning transmission electron microscopy (STEM) in the dark-field mode of operation is a technique regularly used to record high-contrast images from isolated macromolecular assemblies at nanometer resolution. Dark-field STEM images are unique in that they can be readily quantified to provide information on the mass of individual molecular complexes. Importantly, because STEM images contain simultaneous mass and overall molecular shape information, the concept of "mass mapping" can be realized to provide distinctive measurements of the mass per area of planar assemblies or the mass per length of filamentous structures. In this chapter we describe how the STEM technique can be applied to generate characteristic measurements of mass per length from isolated Alzheimer's amyloid fibrils. PMID- 23086878 TI - Elemental mapping by electron energy loss spectroscopy in biology. AB - Over the past decades there have been significant advances in transmission electron microscopy for biological applications, including in energy filtering and spectrum imaging, which are techniques based on the principles of electron energy loss spectroscopy. These imaging modalities allow quantitative mapping of specific chemical elements with high sensitivity and spatial resolution. This chapter describes the experimental and computational procedures for elemental mapping in two dimensions as well as a more recent extension to three dimensions, which can reveal quantitative distributions of elements in cells on a macromolecular scale. PMID- 23086879 TI - Cellular nanoimaging by cryo electron tomography. AB - Cryo electron tomography is a technique that allows visualization of biological specimens in three dimensions with nanometer resolution. For cryo immobilized life sciences samples it can reveal cellular morphology, the shape of membranous structures, and depict internal macromolecular arrangements and large proteins. Cryo electron tomography is a unique technique in structural biology research because it is the only tool that enables direct visualization of the cellular space at molecular resolution. Here we present the methods that we apply in our lab to perform cellular cryo electron tomography, which require expertise on cell biology for cell growth, physics for electron microscopy, and image processing for reconstruction and 3D visualization. We define the instrumentation, materials, and protocols for cryo electron tomography of whole cells, including cell growth, specimen vitrification, microscope alignments, data acquisition, tomographic image reconstruction, and 3D visualization techniques. PMID- 23086880 TI - Large-volume reconstruction of brain tissue from high-resolution serial section images acquired by SEM-based scanning transmission electron microscopy. AB - With recent improvements in instrumentation and computational tools, serial section electron microscopy has become increasingly straightforward. A new method for imaging ultrathin serial sections is developed based on a field emission scanning electron microscope fitted with a transmitted electron detector. This method is capable of automatically acquiring high-resolution serial images with a large field size and very little optical and physical distortions. In this chapter, we describe the procedures leading to the generation and analyses of a large-volume stack of high-resolution images (64 MUm * 64 MUm * 10 MUm, or larger, at 2 nm pixel size), including how to obtain large-area serial sections of uniform thickness from well-preserved brain tissue that is rapidly perfusion fixed with mixed aldehydes, processed with a microwave-enhanced method, and embedded into epoxy resin. PMID- 23086881 TI - 3D imaging of cells and tissues by focused ion beam/scanning electron microscopy (FIB/SEM). AB - Integration of a scanning electron microscope (SEM) and focused ion beam (FIB) technology into a single FIB/SEM system permits use of the FIB as a nano-scalpel to reveal site-specific subsurface microstructures which can be examined in great detail by SEM. The FIB/SEM technology is widely used in the semiconductor industry and material sciences, and recently its use in the life sciences has been initiated. Samples for FIB/SEM investigation can be either embedded in a plastic matrix, the traditional means of preparation of transmission electron microscopy (TEM) specimens, or simply dried as in samples prepared for SEM imaging. Currently, FIB/SEM is used in the life sciences for (a) preparation by the lift-out technique of lamella for TEM analysis, (b) tomography of samples embedded in a matrix, and (c) in situ site-specific FIB milling and SEM imaging using a wide range of magnifications. Site-specific milling and imaging has attracted wide interest as a technique in structural research of single eukaryotic and prokaryotic cells, small animals, and different animal tissue, but it still remains to be explored more thoroughly. In the past, preparation of samples for site-specific milling and imaging by FIB/SEM has typically adopted the embedding techniques used for TEM samples, and which have been very well described in the literature. Sample preparation protocols for the use of dried samples in FIB/SEM have been less well investigated. The aim of this chapter is to encourage application of FIB/SEM on dried biological samples. A detailed description of conventional dried sample preparation and FIB/SEM investigation of dried biological samples is presented. The important steps are described and illustrated, and direct comparison between embedded and dried samples of same tissues is provided. The ability to discover links between gross morphology of the tissue or organ, surface characteristics of any selected region, and intracellular structural details on the nanometer scale is an appealing application of electron microscopy in the life sciences and merits further exploration. PMID- 23086882 TI - Preparation of gold nanocluster bioconjugates for electron microscopy. AB - In this chapter, we describe types of gold nanoparticle-biomolecule conjugates and their use in electron microscopy. Included are two detailed protocols for labeling an IgG antibody with gold monolayer protected clusters. The first approach is a direct bonding approach that utilizes the ligand place exchange reaction. The second approach describes NHS-EDC coupling of Au(144)(pMBA)(60) with IgG. Also included are various characterization techniques for determining labeling efficiency. PMID- 23086883 TI - Atomic force microscopy imaging of macromolecular complexes. AB - This chapter reviews amplitude modulation (AM) AFM in air and its applications to high-resolution imaging and interpretation of macromolecular complexes. We discuss single DNA molecular imaging and DNA-protein interactions, such as those with topoisomerases and RNA polymerase. We show how relative humidity can have a major influence on resolution and contrast and how it can also affect conformational switching of supercoiled DNA. Four regimes of AFM tip-sample interaction in air are defined and described, and relate to water perturbation and/or intermittent mechanical contact of the tip with either the molecular sample or the surface. Precise control and understanding of the AFM operational parameters is shown to allow the user to switch between these different regimes: an interpretation of the origins of topographical contrast is given for each regime. Perpetual water contact is shown to lead to a high-resolution mode of operation, which we term SASS (small amplitude small set-point) imaging, and which maximizes resolution while greatly decreasing tip and sample wear and any noise due to perturbation of the surface water. Thus, this chapter provides sufficient information to reliably control the AFM in the AM AFM mode of operation in order to image both heterogeneous samples and single macromolecules including complexes, with high resolution and with reproducibility. A brief introduction to AFM, its versatility and applications to biology is also given while providing references to key work and general reviews in the field. PMID- 23086884 TI - Imaging of transmembrane proteins directly incorporated within supported lipid bilayers using atomic force microscopy. AB - Structural analysis of transmembrane proteins remains a challenge in biology, mainly due to their difficulty in being overexpressed and the required use of detergents that impair different steps of biochemistry classically used to obtain 3D crystals. In this context, we have developed a new technique for protein incorporation within supported lipid bilayers that only requires a few picomoles of protein per assay. Proteins are directly inserted into a detergent destabilized bilayer that can be imaged in buffer with atomic force microscopy (AFM) allowing structural analysis down to sub-nanometer lateral resolution. In this chapter, we describe the main guidelines for this technique, from the choice of detergent to the requirements for AFM high-resolution imaging. PMID- 23086885 TI - Functional AFM imaging of cellular membranes using functionalized tips. AB - The real-time visualization of specific binding sites on biological samples with high spatial resolution, in order of several nanometers, is an important undertaking in many fields of biology. During the past 5 years, simultaneous topography and recognition imaging (TREC) has become a powerful tool to quickly obtain local receptor nanomaps on complex heterogeneous biosurfaces, such as cells and membranes. In this chapter, we present the TREC technique and explain how to unravel the nano-landscape of cells of the immune system, such as macrophages. We describe the procedures for all steps of the experiment including tip functionalization with Fc fragments via flexible PEG-linker, sample preparation, and localization of Fcgamma receptors on macrophages. PMID- 23086886 TI - Near-field scanning optical microscopy for high-resolution membrane studies. AB - The desire to directly probe biological structures on the length scales that they exist has driven the steady development of various high-resolution microscopy techniques. Among these, optical microscopy and, in particular, fluorescence based approaches continue to occupy dominant roles in biological studies given their favorable attributes. Fluorescence microscopy is both sensitive and specific, is generally noninvasive toward biological samples, has excellent temporal resolution for dynamic studies, and is relatively inexpensive. Light based microscopies can also exploit a myriad of contrast mechanisms based on spectroscopic signatures, energy transfer, polarization, and lifetimes to further enhance the specificity or information content of a measurement. Historically, however, spatial resolution has been limited to approximately half the wavelength due to the diffraction of light. Near-field scanning optical microscopy (NSOM) is one of several optical approaches currently being developed that combines the favorable attributes of fluorescence microscopy with superior spatial resolution. NSOM is particularly well suited for studies of both model and biological membranes and application to these systems is discussed. PMID- 23086887 TI - Correlative fluorescence and EFTEM imaging of the organized components of the mammalian nucleus. AB - The cell nucleus contains many distinct subnuclear compartments, domains, and bodies that vary in their composition, structure, and function. While the cellular constituents that occupy the subnuclear regions may be well known, defining the structural details of the molecular assembly of the constituents has been more difficult. A correlative fluorescence and energy-filtering transmission electron microscopy (EFTEM) imaging method has the ability to provide these details. The correlative microscopy method described here allows the tracking of subnuclear structures from specific cells by fluorescence microscopy and then, using electron energy loss imaging in the transmission electron microscope, reveals the ultrastructural features of the nuclear components along with endogenous elemental information that relates directly to the biochemical composition of the structure. The ultrastructural features and composition of well-characterized PML bodies and interchromatin granule clusters are compared to those of ligand-activated glucocorticoid receptor (GR) foci, with GR foci containing fibrogranular nucleic acid-containing features and PML bodies being devoid of nucleic acid. PMID- 23086888 TI - High data output method for 3-D correlative light-electron microscopy using ultrathin cryosections. AB - Investigation of intracellular dynamics requires a detailed description of the molecular topography and ultrastructural morphology of the cell, for example, the position of a protein in relation to a given compartment of the cell and the morphology of the compartment. Standard fluorescence light microscopy (FLM) localizes proteins in living or fixed cells with a resolution of few hundreds of nanometers, but the unlabeled cellular context is partially missing. Electron microscopy (EM) techniques, such as immuno-EM, reveal protein topology with a few tens of nanometer resolution and retain the cellular context. However, EM analysis shows shortcomings compared to FLM, such as, lower statistical output, applicability only to fixed cells, and higher technical difficulties. To bridge the gap between fluorescent cell imaging and EM, several laboratories have developed methods for correlative light-electron microscopy (CLEM). In CLEM, a limited number of fluorescently labeled cell compartments are first imaged by light microscopy and then visualized and analyzed by EM. Recently, two different CLEM approaches using the EM cryo-immunogold method have been developed to extend the analysis to a high number of regions of interest and to correlate the topology of specific antigens. In this chapter, we describe one of these methods, the High Data Output CLEM (HDO-CLEM) approach. The major benefits of HDO-CLEM are the possibility to (1) correlate several hundreds of events at the same time, (2) perform three-dimensional (3D) correlation, (3) immunolabel both endogenous and recombinantly tagged proteins at the same time, and (4) combine the high data analysis capability of FLM with the high precision-accuracy of transmission electron microscopy in a CLEM hybrid morphometric analysis. We have identified and optimized critical steps in sample preparation, defined routines for sample analysis and retracing of regions of interest, developed software for semi/fully automatic 3D FLM reconstruction and defined preliminary conditions for a hybrid light/electron microscopy morphometry approach. PMID- 23086889 TI - Correlative optical and scanning probe microscopies for mapping interactions at membranes. AB - Innovative approaches for real-time imaging on molecular-length scales are providing researchers with powerful strategies for characterizing molecular and cellular structures and dynamics. Combinatorial techniques that integrate two or more distinct imaging modalities are particularly compelling as they provide a means for overcoming the limitations of the individual modalities and, when applied simultaneously, enable the collection of rich multi-modal datasets. Almost since its inception, scanning probe microscopy has closely associated with optical microscopy. This is particularly evident in the fields of cellular and molecular biophysics where researchers are taking full advantage of these real time, in situ, tools to acquire three-dimensional molecular-scale topographical images with nanometer resolution, while simultaneously characterizing their structure and interactions though conventional optical microscopy. The ability to apply mechanical or optical stimuli provides an additional experimental dimension that has shown tremendous promise for examining dynamic events on sub-cellular length scales. In this chapter, we describe recent efforts in developing these integrated platforms, the methodology for, and inherent challenges in, performing coupled imaging experiments, and the potential and future opportunities of these research tools for the fields of molecular and cellular biophysics with a specific emphasis on the application of these coupled approaches for the characterization of interactions occurring at membrane interfaces. PMID- 23086890 TI - Nanoimaging cells using soft X-ray tomography. AB - Soft X-ray microscopy is ideally suited to visualizing and quantifying biological cells. Specimens, including eukaryotic cells, are imaged intact, unstained and fully hydrated, and therefore visualized in a near-native state. The contrast in soft X-ray microscopy is generated by the differential attenuation of X-rays by the molecules in the specimen-water is relatively transmissive to this type of illumination compared to carbon and nitrogen. The attenuation of X-rays by the specimen follows the Beer-Lambert law, and therefore both linear and a quantitative measure of thickness and chemical species present at each point in the cell. In this chapter, we will describe the procedures and computational methods that lead to 50 nm (or better) tomographic reconstructions of cells using soft X-ray microscope data, and the subsequent segmentation and analysis of these volumetric reconstructions. In addition to being a high-fidelity imaging modality, soft X-ray tomography is relatively high-throughput; a complete tomographic data set can be collected in a matter of minutes. This new modality is being applied to imaging cells that range from small prokaryotes to stem cells obtained from mammalian tissues. PMID- 23086891 TI - Secondary ion mass spectrometry imaging of biological membranes at high spatial resolution. AB - Characterization of the distributions of specific proteins and lipids within cellular membranes is currently a major challenge. Advances in secondary ion mass spectrometry (SIMS) now enable the distributions of isotopically labeled lipids within cellular or model membranes to be imaged with chemical specificity and high (>=50 nm) lateral resolution. Here, methods to image the distributions of sphingolipids within the membranes of intact cells with a Cameca NanoSIMS are described. For NanoSIMS detection, the incorporation of distinct stable isotopes into the lipid species of interest is essential. Metabolic labeling, cell preservation, imaging conditions, and data analysis are critical factors. The methods and principles described here can be extended to studying other membrane lipids or cholesterol. PMID- 23086892 TI - Reconstruction of hepatic stellate cell-incorporated liver capillary structures in small hepatocyte tri-culture using microporous membranes. AB - In liver sinusoids, hepatic stellate cells (HSCs) locate the outer surface of microvessels to form a functional unit with endothelia and hepatocytes. To reconstruct functional liver tissue in vitro, formation of the HSC-incorporated sinusoidal structure is essential. We previously demonstrated capillary formation of endothelial cells (ECs) in tri-culture, where a polyethylene terephthalate (PET) microporous membrane was intercalated between the ECs and hepatic organoids composed of small hepatocytes (SHs), i.e. hepatic progenitor cells, and HSCs. However, the high thickness and low porosity of the membranes limited heterotypic cell-cell interactions, which are essential to form HSC-EC hybrid structures. Here, we focused on the effective use of the thin and highly porous poly( d, l lactide-co-glycolide) (PLGA) microporous membranes in SH-HSC-EC tri-culture to reconstruct the HSC-incorporated liver capillary structures in vitro. First, the formation of EC capillary-like structures was induced on Matrigel-coated PLGA microporous membranes. Next, the membranes were stacked on hepatic organoids composed of small SHs and HSCs. When the pore size and porosity of the membranes were optimized, HSCs selectively migrated to the EC capillary-like structures. This process was mediated in part by platelet-derived growth factor (PDGF) signalling. In addition, the HSCs were located along the outer surface of the EC capillary-like structures with their long cytoplasmic processes. In the HSC incorporated capillary tissues, SHs acquired high levels of differentiated functions, compared to those without ECs. This model will provide a basis for the construction of functional, thick, vascularized liver tissues in vitro. PMID- 23086893 TI - Statistical analysis of missense mutation classifiers. PMID- 23086894 TI - Urban-rural contrasts in fitness, physical activity, and sedentary behaviour in adolescents. AB - Research considering physical activity (PA), physical inactivity and health outcomes among urban and rural youth has produced equivocal findings. This study examined PA, physical inactivity, sedentary behaviours and cardiorespiratory fitness (CRF) in adolescents from urban and rural communities in the Portuguese Midlands. The sample included 362 adolescents (165 males, 197 females) of 13-16 years of age. CRF was assessed by the PACER test. A GT1M accelerometer was used to record 5 consecutive days of PA and time spent sedentary. Analyses of covariance (chronological age as co-variate) were performed to test the effect of the area of residence on sedentary behaviour, PA and CRF. Urban youth of both sexes spent less time in sedentary activities than rural youth. Urban males were more active than rural peers at the weekend, whereas urban females were significantly less active than rural females on week days and across all days assessed. Rural youth of both sexes had higher levels of CRF than urban youth. Area of residence was related to aerobic fitness, PA and time spent in sedentary behaviours among Portuguese youth. Interventions seeking to enhance health and active lifestyles in Portuguese youth should consider the potential impact of socio-geographic factors. PMID- 23086895 TI - The integration of information and communication technology into community pharmacists practice in Barcelona. AB - The study aims to identify community pharmacists' (CPs) utilization of information and communication technology (ICT); to develop and characterize a typology of CPs' utilization of ICT and to identify factors that can enhance or inhibit the use of these technologies. An online survey of the 7649 members of the Pharmacist Association of Barcelona who had a registered email account in 2006 was carried out. Factor analysis, cluster analysis and binomial logit modelling were undertaken. Multivariate analysis of the CPs' responses to the survey (648) revealed two profiles of adoption of ICT. The first profile (40.75%) represents those CPs who place high emphasis on ICT within their practice. This group is therefore referred to as 'integrated CPs'. The second profile (59.25%) represents those CPs who make less use of ICT and so are consequently labelled 'non-integrated CPs'. Statistical modelling was used to identify variables that were important in predisposing CPs to integrate ICT with their work. From the analysis it is evident that responses to questions relating to 'recommend patients going on line for health information'; 'patients discuss or share their Internet health information findings'; 'emphasis on the Internet for communication and dissemination' and 'Pharmacists Professional Association information' play a positive and significant role in the probability of being an 'integrated CP'. The integration of ICT within CPs' practices cannot be adequately understood and appreciated without examining how CPs are making use of ICT within their own practice, their organizational context and the nature of the pharmacists-client relationship. PMID- 23086897 TI - Center competition and outcomes following liver transplantation. AB - In the United States, livers for transplantation are distributed within donation service areas (DSAs). In DSAs with multiple transplant centers, competition among centers for organs and recipients may affect recipient selection and outcomes in comparison with DSAs with only 1 center. The objective of this study was to determine whether competition within a DSA is associated with posttransplant outcomes and variations in patients wait-listed within the DSA. United Network for Organ Sharing data for 38,385 adult cadaveric liver transplant recipients undergoing transplantation between January 1, 2003 and December 31, 2009 were analyzed to assess differences in liver recipients and donors and in posttransplant survival by competition among centers. The main outcome measures that were studied were patient characteristics, actual and risk-adjusted graft and patient survival rates after transplantation, organ quality as quantified by the donor risk index (DRI), wait-listed patients per million population by DSA, and competition as quantified by the Hirschman-Herfindahl index (HHI). Centers were stratified by HHI levels as no competition or as low, medium (or mid), or high competition. In comparison with DSAs without competition, the low-, mid-, and high-competition DSAs (1) performed transplantation for patients with a higher risk of graft failure [hazard ratio (HR) = 1.24, HR = 1.26, and HR = 1.34 (P < 0.001 for each)] and a higher risk of death [HR = 1.21, HR = 1.23, and HR = 1.34 (P < 0.001 for each)] and for a higher proportion of sicker patients as quantified by the Model for End-Stage Liver Disease (MELD) score [10.0% versus 14.8%, 20.1%, and 28.2% with a match MELD score of 31-40 (P < 0.001 for each comparison)], (2) were more likely to use organs in the highest risk quartile as quantified by the DRI [18.3% versus 27.6%, 20.4%, and 31.7% (P <= 0.001 for each)], and (3) listed more patients per million population [18 (median) versus 34 (P = not significant), 37 (P = 0.005), and 45 (P = 0.0075)]. Significant variability in patient selection for transplantation is associated with market variables characterizing competition among centers. These findings suggest both positive and negative effects of competition among health care providers. PMID- 23086898 TI - Emotional exhaustion and cognitive performance in apparently healthy teachers: a longitudinal multi-source study. AB - We investigate how emotional exhaustion (EE), the core component of burnout, relates to cognitive performance, job performance and health. Cognitive performance was assessed by self-rated cognitive stress symptoms, self-rated and peer-rated cognitive impairments in everyday tasks and a neuropsychological test of learning and memory (LGT-3); job performance and physical health were gauged by self-reports. Cross-sectional linear regression analyses in a sample of 100 teachers confirm that EE is negatively related to cognitive performance as assessed by self-rating and peer-rating as well as neuropsychological testing (all p < .05). Longitudinal linear regression analyses confirm similar trends (p < .10) for self-rated and peer-rated cognitive performance. Executive control deficits might explain impaired cognitive performance in EE. In longitudinal analyses, EE also significantly predicts physical health. Contrary to our expectations, EE does not affect job performance. When reversed causation is tested, none of the outcome variables at Time 1 predict EE at Time 2. This speaks against cognitive dysfunctioning serving as a vulnerability factor for exhaustion. In sum, results underpin the negative consequences of EE for cognitive performance and health, which are relevant for individuals and organizations alike. In this way, findings might contribute to the understanding of the burnout syndrome. PMID- 23086899 TI - Comment on real-time observation on dynamic growth/dissolution of conductive filaments in oxide-electrolyte- based ReRAM. AB - Filament formation and dissolution in the system Ag(Cu)/ZrO(2) /Pt were observed by Liu et al. [Adv. Mater. 2012, 24, 1844]. Their explanation of the phenomena is shown here to be inappropriate. Various situations, including the "bipolar electrode" shown in the figure, are considered and the difference between the behavior in electrochemical metallization memories (ECMs) and valence change memories (VCMs) outlined. Of crucial importance for distinguishing ECM from VCM behavior, that is, the effects of cation and anion migration, is the choice of the solid materials used to transport metal cations. A possible explanation of the phenomena is proposed. PMID- 23086900 TI - A synthetic polypeptide conjugate from a 42-residue polypeptide and salicylhydroxamic acid binds human myeloperoxidase with high affinity. AB - Myeloperoxidase (MPO) is a 150 kD tetrameric heme protein consisting of two heavy chains and two light chains, which is present in neutrophils, white blood cells, at concentrations between 2% and 5% and plays an important role in the innate immune system. The MPO concentration in serum or plasma has been shown to be linked to the risk for cardiovascular diseases, and MPO is considered to be a high potential diagnostic biomarker. To develop a molecule that binds MPO, salicylhydroxamic acid (SHA), a substrate analog inhibitor of MPO with a KD=2 MUM, was conjugated to a designed set of 42-residue polypeptide scaffolds via 9- and 11-carbon atom aliphatic spacers to form 20 different protein binder candidates, and their interactions with MPO were evaluated by surface plasmon resonance analysis. The polypeptide conjugate 4C37L34C11SHA was found to bind to MPO with an affinity that could be estimated to have a dissociation constant of around 400 pM, nearly four orders of magnitude higher than that of SHA. Inhibition of binding to MPO by free SHA was observed in competition experiments demonstrating that the binding of the polypeptide conjugate is dominated by the interactions of SHA with the heme cavity. Although still in the future, the discovery of these new synthetic binders for MPO suggests a route to clinical diagnostic tests in vivo or in vitro, independent of antibodies. PMID- 23086901 TI - Are better sleepers more engaged workers? A self-regulatory approach to sleep hygiene and work engagement. AB - Previous research has emphasized facets of both the organizational environment and individual differences as predictors of work engagement. This study explored sleep hygiene as another important behavioural factor that may be related to work engagement. With a sample of 328 adult workers, we tested a multiple mediator model in which sleep hygiene predicts work engagement through one's appraisals of resource depletion stemming from demands (psychological strain) and general self regulatory capacity (self-control). Results indicated that individuals who frequently engaged in poor sleep hygiene behaviours had lower self-regulatory capacity, experienced higher subjective depletion and were less engaged at work. Additionally, the path from poor sleep hygiene to decreased work engagement was attributed to perceptions of personal resources that are needed to exert self regulatory energy at work. This is consistent with current self-regulatory theories suggesting that individuals have a limited amount of resources to allocate to demands and that the depletion of these resources can lead to stress and lower self-regulatory functioning in response to other demands. Specifically, poor sleep hygiene results in the loss of self-regulatory resources needed to be engaged in work tasks by impairing the after-work recovery process. Practical and research implications regarding sleep hygiene interventions for well-being and productivity improvement are discussed. PMID- 23086902 TI - Anti-ferrodistortive-like oxygen-octahedron rotation induced by the oxygen vacancy in cubic SrTiO3. AB - New insights into the atomistic and electronic structure of the oxygen vacancy in SrTiO(3) are presented through first-principles calculations. The oxygen vacancy induces a local anti-ferrodistortive-like oxygen-octahedron rotation, even in the cubic phase. This feature leads to localized electronic states in the bandgap, giving an excellent explanation to the thermal ionization and optical transition observed experimentally. PMID- 23086903 TI - Interaction of polypeptide antibiotic gramicidin S with platelets. AB - Gramicidin S (GS) is a cyclic decapeptide antibiotic active against both Gram positive and Gram-negative bacteria as well as against several pathogenic fungi. However, clinical application of GS is limited because of GS hemolytic activity. The large number of GS analogues with potentially attenuated hemolytic activity has been developed over the last two decades. For all new GS derivatives, the antimicrobial test is accompanied with the hemolytic activity assay. At the same time, neither GS nor its analogues were tested against other blood cells. In the present work, the effects of GS on platelets and platelet aggregates have been studied. GS interaction with platelets is concentration dependent and leads either to platelet swelling or platelet shape change. Effect of GS on platelets is independent of platelet aggregation mechanism. GS induces disaggregation of platelet aggregates formed in the presence of aggregation agonists. The rate of the GS interaction with platelet membranes depends on membrane lipid mobility and significantly increases with temperature. The interaction of GS with the platelet membranes depends strongly on the state of the membrane lipids. Factors affecting the membrane lipids (temperature, lipid peroxidation and ionising irradiation) modify GS interaction with platelets. Our results show that GS is active not only against erythrocytes but also against other blood cells (platelets). The estimated numbers of GS molecules per 1 um2 of a blood cell required to induce erythrocyte hemolysis and disaggregation of platelet aggregates are comparable. This must be considered when developing new antimicrobial GS analogues with improved hemolytic properties. PMID- 23086904 TI - Unconscious fearful priming followed by a psychosocial stress test results in higher cortisol levels. AB - Human perception of stress includes an automatic pathway that processes subliminal presented stimuli below the threshold of conscious awareness. Subliminal stimuli can therefore activate the physiologic stress system. Unconscious emotional signals were shown to significantly moderate reactions and responses to subsequent stimuli, an effect called 'priming'. We hypothesized that subliminal presentation of a fearful signal during the Stroop task compared with an emotionally neutral one will prime stress reactivity in a subsequently applied psychosocial stress task, thereby yielding a significant increase in salivary cortisol. Half of 36 participants were repeatedly presented either a fearful face or a neutral one. After this, all underwent a psychosocial stress task. The fearful group showed a significant increase in cortisol levels (p = 0.022). This change was not affected by sex, age and body mass index, and it also did not change when taking resting cortisol levels into account. Post-hoc analyses showed that the increase in cortisol in the fearful group started immediately after the psychosocial stress test. Hence, subliminal exposure to a fearful signal in combination with the Stroop and followed by a psychosocial stress test leads to an increase in stress reactivity. PMID- 23086905 TI - Axial view radiograph of the shoulder. PMID- 23086906 TI - Canada's Supreme Court ruling on HIV disclosure is unjust, say HIV advocacy groups. PMID- 23086907 TI - WHO annual report finds world at a crossroad on tuberculosis. PMID- 23086908 TI - NHS Gloucestershire keeps L80m community services in public hands. PMID- 23086909 TI - Website can charge fees for "matching" people wanting a transplant with donors, regulator says. PMID- 23086910 TI - Response to "comment on real-time observation on dynamic growth/dissolution of conductive filaments in oxide-electrolyte-based ReRAM". PMID- 23086911 TI - Herceptin-decorated salinomycin-loaded nanoparticles for breast tumor targeting. AB - The use of conventional chemotherapeutic drugs was emerged as challenging for breast cancer therapy, because breast cancer stem cells cannot be destroyed due to their great nature of drug resistance. In this study, a novel nanoparticulate system of Herceptin (HER)-immobilized salinomycin (SAL)-encapsulated poly(lactic co-glycolic acid) (PLGA) (HER-SAL-PLGA) nanoparticles were constructed and investigated for breast cancer targeting. SAL-encapsulated PLGA nanoparticles were characterized for their particle size, morphology, structural and thermal properties, and drug-encapsulation efficiency. HER-SAL-PLGA nanoparticles were characterized via particle size, surface chemistry, and herceptin-immobilization efficiency. In vitro release studies were performed for both nontargeting and targeting SAL-PLGA nanoparticles, which demonstrated a controlled release of SAL from nanoparticles. Cellular uptake of the HER-SAL-PLGA nanoparticles was assessed by fluorescence and optical microscopy and flow cytometry, which showed that the HER-SAL-PLGA nanoparticles were successfully uptaken by MCF7 cells. In conclusion, this novel drug-delivery system, HER-SAL-PLGA, was suggested as a promising targeting system for breast cancer therapy. PMID- 23086912 TI - Chemical biology of glycosylphosphatidylinositol anchors. AB - Glycosylphosphatidylinositols (GPIs) are complex glycolipids that are covalently linked to the C-terminus of proteins as a posttranslational modification. They anchor the attached protein to the cell membrane and are essential for normal functioning of eukaryotic cells. GPI-anchored proteins are structurally and functionally diverse. Many GPIs have been structurally characterized but comprehension of their biological functions, beyond the simple physical anchoring, remains largely speculative. Work on functional elucidation at a molecular level is still limited. This Review focuses on the roles of GPI unraveled by using synthetic molecules and summarizes the structural diversity of GPIs, as well as their biological and chemical syntheses. PMID- 23086913 TI - Lactobacillus acidophilus upregulates intestinal NHE3 expression and function. AB - A major mechanism of electroneutral NaCl absorption in the human ileum and colon involves coupling of Na(+)/H(+) and Cl(-)/HCO(3)(-) exchangers. Disturbances in these mechanisms have been implicated in diarrheal conditions. Probiotics such as Lactobacillus have been indicated to be beneficial in the management of gastrointestinal disorders, including diarrhea. However, the molecular mechanisms underlying antidiarrheal effects of probiotics have not been fully understood. We have previously demonstrated Lactobacillus acidophilus (LA) to stimulate Cl( )/HCO3- exchange activity via an increase in the surface levels and expression of the Cl(-)/HCO3- exchanger DRA in vitro and in vivo. However, the effects of LA on NHE3, the Na(+)/H(+) exchanger involved in the coupled electroneutral NaCl absorption, are not known. Current studies were, therefore, undertaken to investigate the effects of LA on the function and expression of NHE3 and to determine the mechanisms involved. Treatment of Caco2 cells with LA or its conditioned culture supernatant (CS) for 8-24 h resulted in a significant increase in Na(+)/H(+) exchange activity, mRNA, and protein levels of NHE3. LA-CS upregulation of NHE3 function and expression was also observed in SK-CO15 cells, a human colonic adenocarcinoma cell line. Additionally, LA treatment increased NHE3 promoter activity, suggesting involvement of transcriptional mechanisms. In vivo, mice gavaged with live LA showed significant increase in NHE3 mRNA and protein expression in the ileum and colonic regions. In conclusion, LA-induced increase in NHE3 expression may contribute to the upregulation of intestinal electrolyte absorption and might underlie the potential antidiarrheal effects of probiotics. PMID- 23086914 TI - The novel growth factor, progranulin, stimulates mouse cholangiocyte proliferation via sirtuin-1-mediated inactivation of FOXO1. AB - Progranulin (PGRN), a secreted growth factor, regulates the proliferation of various epithelial cells. Its mechanism of action is largely unknown. Sirtuin 1 (Sirt1) is a protein deacetylase that is known to regulate the transcriptional activity of the forkhead receptor FOXO1, thereby modulating the balance between proapoptotic and cell cycle-arresting genes. We have shown that PGRN is overexpressed in cholangiocarcinoma and stimulates proliferation. However, its effects on hyperplastic cholangiocyte proliferation are unknown. In the present study, the expression of PGRN and its downstream targets was determined after bile duct ligation (BDL) in mice and in a mouse cholangiocyte cell line after stimulation with PGRN. The effects of PGRN on cholangiocyte proliferation were assessed in sham-operated (sham) and BDL mice treated with PGRN or by specifically knocking down endogenous PGRN expression using Vivo-Morpholinos or short hairpin RNA. PGRN expression and secretion were upregulated in proliferating cholangiocytes isolated after BDL. Treatment of mice with PGRN increased biliary mass and cholangiocyte proliferation in vivo and in vitro and enhanced cholangiocyte proliferation observed after BDL. PGRN treatment decreased Sirt1 expression and increased the acetylation of FOXO1, resulting in the cytoplasmic accumulation of FOXO1 in cholangiocytes. Overexpression of Sirt1 in vitro prevented the proliferative effects of PGRN. Conversely, knocking down PGRN expression in vitro or in vivo inhibited cholangiocyte proliferation. In conclusion, these data suggest that the upregulation of PGRN may be a key feature stimulating cholangiocyte proliferation. Modulating PGRN levels may be a viable technique for regulating the balance between ductal proliferation and ductopenia observed in a variety of cholangiopathies. PMID- 23086915 TI - Angiotensin-(1-7) reduces the perfusion pressure response to angiotensin II and methoxamine via an endothelial nitric oxide-mediated pathway in cirrhotic rat liver. AB - Recent studies have shown that, in cirrhosis, portal angiotensin-(1-7) [Ang-(1 7)] levels are increased and hepatic expression of angiotensin converting enzyme 2 (ACE2) and the Mas receptor are upregulated, but the effects of Ang-(1-7) on hepatic hemodynamics in cirrhosis have not been studied. This study investigated the effects of Ang-(1-7) on vasoconstrictor-induced perfusion pressure increases in cirrhotic rat livers. Ang II or the alpha 1 agonist methoxamine (MTX) were injected in the presence or absence of Ang-(1-7), and the perfusion pressure response was recorded. Denudation of vascular endothelial cells with sodium deoxycholate was used to investigate the contribution of endothelium to the effects of Ang-(1-7). Ang-(1-7) alone had no effect on perfusion pressure. However, it reduced the maximal vasoconstriction response and area under the pressure response curve to Ang II and MTX by >50% (P < 0.05). This effect of Ang (1-7) was not blocked by Mas receptor inhibition with A779 or by Ang II type 1 and type 2 receptor and bradykinin B(2) receptor blockade and was not reproduced by the Mas receptor agonist AVE0991. D-Pro(7)-Ang-(1-7), a novel Ang-(1-7) receptor antagonist, completely abolished the vasodilatory effects of Ang-(1-7), as did inhibition of endothelial nitric oxide synthase (eNOS) with N(G)-nitro-L arginine methyl-ester, guanylate cyclase blockade with ODQ and endothelium denudation. The functional inhibition by D-Pro(7)-Ang-(1-7) was accompanied by significant (P < 0.05) inhibition of eNOS phosphorylation. This study shows that Ang-(1-7) significantly inhibits intrahepatic vasoconstriction in response to key mediators of increased vascular and sinusoidal tone in cirrhosis via a receptor population present on the vascular endothelium that is sensitive to D-Pro(7)-Ang (1-7) and causes activation of eNOS and guanylate cyclase-dependent NO signaling pathways. PMID- 23086916 TI - TRPV4 activation in mouse submandibular gland modulates Ca2+ influx and salivation. AB - Transient receptor potential vanilloid subtype 4 (TRPV4) is a ligand-gated nonselective cation channel that participates in the transduction of mechanical and osmotic stimuli in different tissues. TRPV4 is activated by endogenous arachidonic acid metabolites, 4alpha-phorbol-12,13 didecanoate, GSK1016790A, moderate heat, and mechanical stress. TRPV4 is expressed in the salivary glands, but its expression pattern and function are poorly understood. The aim of this study was to evaluate the functional role of TRPV4 channels in the mouse submandibular gland. Using RT-PCR and Western blot analysis, we detected expression of TRPV4 message and protein, respectively, in the submandibular gland. Immunolocalization studies showed that TRPV4 targeted to the basolateral membrane of mouse submandibular gland acinar cells. Pharmacological TRPV4 activation using the selective agonist GSK1016790A caused Ca(2+) influx in isolated acinar cells in a basal-to-apical wave. Consistent with these observations, GSK1016790A elicited salivation in the perfused submandibular gland that was dependent on extracellular Ca(2+). In summary, we report that activation of TRPV4 channels induced Ca(2+) influx and salivation and, thus, may contribute a novel nonadrenergic, noncholinergic secretion pathway in the mouse submandibular gland. PMID- 23086917 TI - 3-D imaging and illustration of mouse intestinal neurovascular complex. AB - Because of the dispersed nature of nerves and blood vessels, standard histology cannot provide a global and associated observation of the enteric nervous system (ENS) and vascular network. We prepared transparent mouse intestine and combined vessel painting and three-dimensional (3-D) neurohistology for joint visualization of the ENS and vasculature. Cardiac perfusion of the fluorescent wheat germ agglutinin (vessel painting) was used to label the ileal blood vessels. The pan-neuronal marker PGP9.5, sympathetic neuronal marker tyrosine hydroxylase (TH), serotonin, and glial markers S100B and GFAP were used as the immunostaining targets of neural tissues. The fluorescently labeled specimens were immersed in the optical clearing solution to improve photon penetration for 3-D confocal microscopy. Notably, we simultaneously revealed the ileal microstructure, vasculature, and innervation with micrometer-level resolution. Four examples are given: 1) the morphology of the TH-labeled sympathetic nerves: sparse in epithelium, perivascular at the submucosa, and intraganglionic at myenteric plexus; 2) distinct patterns of the extrinsic perivascular and intrinsic pericryptic innervation at the submucosal-mucosal interface; 3) different associations of serotonin cells with the mucosal neurovascular elements in the villi and crypts; and 4) the periganglionic capillary network at the myenteric plexus and its contact with glial fibers. Our 3-D imaging approach provides a useful tool to simultaneously reveal the nerves and blood vessels in a space continuum for panoramic illustration and analysis of the neurovascular complex to better understand the intestinal physiology and diseases. PMID- 23086918 TI - Innate immune responses involving natural killer and natural killer T cells promote liver regeneration after partial hepatectomy in mice. AB - To clarify the roles of innate immune cells in liver regeneration, here, we investigated the alteration in regenerative responses after partial hepatectomy (PH) under selective depletion of natural killer (NK) and/or NKT cells. Male, wild-type (WT; C57Bl/6), and CD1d-knockout (KO) mice were injected with anti NK1.1 or anti-asialo ganglio-N-tetraosylceramide (GM1) antibody and then underwent the 70% PH. Regenerative responses after PH were evaluated, and hepatic expression levels of cytokines and growth factors were measured by real-time RT PCR and ELISA. Phosphorylation of STAT3 was detected by Western blotting. Depletion of both NK and NKT cells with an anti-NK1.1 antibody in WT mice caused drastic decreases in bromodeoxyuridine uptake, expression of proliferating cell nuclear antigen, and cyclin D1, 48 h after PH. In mice given NK1.1 antibody, increases in hepatic TNF-alpha, IL-6/phospho-STAT3, and hepatocyte growth factor (HGF) levels following PH were also blunted significantly, whereas IFN-gamma mRNA levels were not different. CD1d-KO mice per se showed normal liver regeneration; however, pretreatment with an antiasialo GM1 antibody to CD1d-KO mice, resulting in depletion of both NK and NKT cells, also blunted regenerative responses. Collectively, these observations clearly indicated that depletion of both NK and NKT cells by two different ways results in impaired liver regeneration. NK and NKT cells most likely upregulate TNF-alpha, IL-6/STAT3, and HGF in a coordinate fashion, thus promoting normal regenerative responses in the liver. PMID- 23086919 TI - Butyrate increases IL-23 production by stimulated dendritic cells. AB - The gut microbiota is essential for the maintenance of intestinal immune homeostasis and is responsible for breaking down dietary fiber into short-chain fatty acids (SCFAs). Butyrate, the most abundant bioactive SCFA in the gut, is a histone deacetylase inhibitor (HDACi), a class of drug that has potent immunomodulatory properties. This characteristic of butyrate, along with our previous discovery that conventional dendritic cells (DCs) are required for the development of experimental colitis, led us to speculate that butyrate may modulate DC function to regulate gut mucosal homeostasis. We found that butyrate, in addition to suppressing LPS-induced bone marrow-derived DC maturation and inhibiting DC IL-12 production, significantly induced IL-23 expression. The upregulation of mRNA subunit IL-23p19 at the pretranslational level was consistent with the role of HDACi on the epigenetic modification of gene expression. Furthermore, the mechanism of IL-23p19 upregulation was independent of Stat3 and ZBP89. Coculture of splenocytes with LPS-stimulated DCs pretreated with or without butyrate was performed and showed a significant induction of IL 17 and IL-10. We demonstrated further the effect of butyrate in vivo using dextran sulfate sodium (DSS)-induced colitis and found that the addition of butyrate in the drinking water of mice worsened DSS-colitis. This is in contrast to the daily intraperitoneal butyrate injection of DSS-treated mice, which mildly improved disease severity. Our study highlights a novel effect of butyrate in upregulating IL-23 production of activated DCs and demonstrates a difference in the host response to the oral vs. systemic route of butyrate administration. PMID- 23086921 TI - Use of the ecosystem services concept in ecological risk assessment of chemicals. AB - The reason for expressing ecological protection goals in terms of ecosystem services is to make a connection between ecosystems and what people get out of them in terms of marketed goods and nonmarketed welfare. Here our focus will be on how the ecosystem services framework is and can be applied to the ecological risk assessment (ERA) of chemicals. We provide 2 contrasting examples of how the ecosystem services framework is currently being applied in regulatory risk assessment, and we discuss the challenges and knowledge gaps that need to be addressed if such a framework is to substantially improve ERAs and their ability to inform management decisions. We make the point that formulating protection goals in terms of ecosystem services only makes sense if they can be used in managing environmental impacts and if they are useful in informing the risk assessments behind these. Ecosystem services can make a contribution to management by connecting ecosystem structure and process to what is valued, and analyzing risk in this context is a way of making risk assessment more policy- and value-relevant. Using an ecosystem services framework to its fullest potential to support ERA will require the successful development of a suite of coupled Valuation Methods, Ecological Production Functions, and Mechanistic Effect Models that will require the establishment of strong multidisciplinary collaborations among ecologists, computer scientists, social scientists, and possibly others. In addition, buy-in from environmental decision makers and other stakeholders will be crucial. Some progress is being made on the research front, and the implementation of new legislation is providing incentives for developing risk assessment outputs that are much more directly related to environmental protection goals than those used currently. PMID- 23086920 TI - Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons. AB - Xenin-25 (Xen) is a 25 amino acid neurotensin-related peptide reportedly produced with glucose-dependent insulinotropic polypeptide (GIP) by a subset of K cells in the proximal gut. We previously showed exogenously administered Xen, with GIP but not alone, increases insulin secretion in humans and mice. In mice, this effect is indirectly mediated via a central nervous system-independent cholinergic relay in the periphery. Xen also delays gastric emptying, reduces food intake, induces gall bladder contractions, and increases gut motility and secretion from the exocrine pancreas, suggesting that some effects of Xen could be mediated by myenteric neurons (MENs). To determine whether Xen activates these neurons, MENs were isolated from guinea pig proximal small intestines. Cells expressed neuronal markers and exhibited typical neuron-like morphology with extensive outgrowths emanating from cell bodies. Cytosolic free Ca(2+) levels ([Ca(2+)](i)) were measured using Fura-2. ATP/UTP, KCl, and forskolin increased [Ca(2+)](i) in 99.6%, 92%, and 23% of the MENs imaged, respectively, indicating that they are functional and activated by nucleotide receptor signaling, direct depolarization, and cAMP. [Ca(2+)](i) increased in only 12.7% of MENs treated with Xen. This rise was blocked by pretreatment with EGTA, diazoxide, SR48692, and neurotensin. Thus the Xen-mediated increase in [Ca(2+)](i) involves influx of extracellular Ca(2+) and activation of neurotensin receptor-1 (NTSR1). Xen also increased acetylcholine release from MENs. Amylin, produced by beta-and enteroendocrine cells, delays gastric emptying and increased [Ca(2+)](i) almost exclusively in Xen-responsive MENs. Immunohistochemistry demonstrated NTSR1 expression in human duodenal MENs. Thus myenteric rather than central neurons could mediate some effects of Xen and amylin. PMID- 23086922 TI - From home range dynamics to population cycles: validation and realism of a common vole population model for pesticide risk assessment. AB - Despite various attempts to establish population models as standard tools in pesticide risk assessment, population models still receive limited acceptance by risk assessors and authorities in Europe. A main criticism of risk assessors is that population models are often not, or not sufficiently, validated. Hence the realism of population-level risk assessments conducted with such models remains uncertain. We therefore developed an individual-based population model for the common vole, Microtus arvalis, and demonstrate how population models can be validated in great detail based on published data. The model is developed for application in pesticide risk assessment, therefore, the validation covers all areas of the biology of the common vole that are relevant for the analysis of potential effects and recovery after application of pesticides. Our results indicate that reproduction, survival, age structure, spatial behavior, and population dynamics reproduced from the model are comparable to field observations. Also interannual population cycles, which are frequently observed in field studies of small mammals, emerge from the population model. These cycles were shown to be caused by the home range behavior and dispersal. As observed previously in the field, population cycles in the model were also stronger for longer breeding season length. Our results show how validation can help to evaluate the realism of population models, and we discuss the importance of taking field methodology and resulting bias into account. Our results also demonstrate how population models can help to test or understand biological mechanisms in population ecology. PMID- 23086923 TI - Crystal structure of the primary piRNA biogenesis factor Zucchini reveals similarity to the bacterial PLD endonuclease Nuc. AB - Piwi-interacting RNAs (piRNAs) are a gonad-specific class of small RNAs that associate with the Piwi clade of Argonaute proteins and play a key role in transposon silencing in animals. Since biogenesis of piRNAs is independent of the double-stranded RNA-processing enzyme Dicer, an alternative nuclease that can process single-stranded RNA transcripts has been long sought. A Phospholipase D like protein, Zucchini, that is essential for piRNA processing has been proposed to be a nuclease acting in piRNA biogenesis. Here we describe the crystal structure of Zucchini from Drosophila melanogaster and show that it is very similar to the bacterial endonuclease, Nuc. The structure also reveals that homodimerization induces major conformational changes assembling the active site. The active site is situated on the dimer interface at the bottom of a narrow groove that can likely accommodate single-stranded nucleic acid substrates. Furthermore, biophysical analysis identifies protein segments essential for dimerization and provides insights into regulation of Zucchini's activity. PMID- 23086924 TI - Neuron-restrictive silencer factor (NRSF) represses cocaine- and amphetamine regulated transcript (CART) transcription and antagonizes cAMP-response element binding protein signaling through a dual NRSE mechanism. AB - Cocaine- and amphetamine-regulated transcript (CART) peptide plays a pivotal role in neuroprotection against stroke-related brain injury. However, the regulatory mechanism on CART transcription, especially the repression mechanism, is not fully understood. Here, we show that the transcriptional repressor neuron restrictive silencer elements (NRSF, also known as REST) represses CART expression through direct binding to two NRSF-binding elements (NRSEs) in the CART promoter and intron 1 (named pNRSE and iNRSE, respectively). EMSA show that NRSF binds to pNRSE and iNRSE directly in vitro. ChIP assays show that NRSF recruits differential co-repressor complexes including CoREST and HDAC1 to these NRSEs. The presence of both NRSEs is required for efficient repression of CART transcription as indicated by reporter gene assays. NRSF overexpression antagonizes forskolin-mediated up-regulation of CART mRNA and protein. Ischemia insult triggered by oxygen-glucose deprivation (OGD) enhances NRSF mRNA levels and then NRSF antagonizes the CREB signaling on CART activation, leading to augmented cell death. Depletion of NRSF in combination with forskolin treatment increases neuronal survival after ischemic insult. These findings reveal a novel dual NRSE mechanism by which NRSF represses CART expression and suggest that NRSF may serve as a therapeutic target for stroke treatment. PMID- 23086925 TI - Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. AB - Transcriptional elongation by RNA polymerase II (Pol II) is regulated by positive transcription elongation factor b (P-TEFb) in association with bromodomain containing protein 4 (BRD4). We used genome-wide chromatin immunoprecipitation sequencing in primary human CD4+ T cells to reveal that BRD4 co-localizes with Ser-2-phosphorylated Pol II (Pol II Ser-2) at both enhancers and promoters of active genes. Disruption of bromodomain-histone acetylation interactions by JQ1, a small-molecule bromodomain inhibitor, resulted in decreased BRD4 binding, reduced Pol II Ser-2, and reduced expression of lineage-specific genes in primary human CD4+ T cells. A large number of JQ1-disrupted BRD4 binding regions exhibited diacetylated H4 (lysine 5 and -8) and H3K27 acetylation (H3K27ac), which correlated with the presence of histone acetyltransferases and deacetylases. Genes associated with BRD4/H3K27ac co-occupancy exhibited significantly higher activity than those associated with H3K27ac or BRD4 binding alone. Comparison of BRD4 binding in T cells and in human embryonic stem cells revealed that enhancer BRD4 binding sites were predominantly lineage-specific. Our findings suggest that BRD4-driven Pol II phosphorylation at serine 2 plays an important role in regulating lineage-specific gene transcription in human CD4+ T cells. PMID- 23086927 TI - Human mismatch repair protein hMutLalpha is required to repair short slipped-DNAs of trinucleotide repeats. AB - Mismatch repair (MMR) is required for proper maintenance of the genome by protecting against mutations. The mismatch repair system has also been implicated as a driver of certain mutations, including disease-associated trinucleotide repeat instability. We recently revealed a requirement of hMutSbeta in the repair of short slip-outs containing a single CTG repeat unit (1). The involvement of other MMR proteins in short trinucleotide repeat slip-out repair is unknown. Here we show that hMutLalpha is required for the highly efficient in vitro repair of single CTG repeat slip-outs, to the same degree as hMutSbeta. HEK293T cell extracts, deficient in hMLH1, are unable to process single-repeat slip-outs, but are functional when complemented with hMutLalpha. The MMR-deficient hMLH1 mutant, T117M, which has a point mutation proximal to the ATP-binding domain, is defective in slip-out repair, further supporting a requirement for hMLH1 in the processing of short slip-outs and possibly the involvement of hMHL1 ATPase activity. Extracts of hPMS2-deficient HEC-1-A cells, which express hMLH1, hMLH3, and hPMS1, are only functional when complemented with hMutLalpha, indicating that neither hMutLbeta nor hMutLgamma is sufficient to repair short slip-outs. The resolution of clustered short slip-outs, which are poorly repaired, was partially dependent upon a functional hMutLalpha. The joint involvement of hMutSbeta and hMutLalpha suggests that repeat instability may be the result of aberrant outcomes of repair attempts. PMID- 23086926 TI - Genome-wide identification and quantitative analysis of cleaved tRNA fragments induced by cellular stress. AB - Certain stress conditions can induce cleavage of tRNAs around the anticodon loop via the use of the ribonuclease angiogenin. The cellular factors that regulate tRNA cleavage are not well known. In this study we used normal and eIF2alpha phosphorylation-deficient mouse embryonic fibroblasts and applied a microarray based methodology to identify and compare tRNA cleavage patterns in response to hypertonic stress, oxidative stress (arsenite), and treatment with recombinant angiogenin. In all three scenarios mouse embryonic fibroblasts deficient in eIF2alpha phosphorylation showed a higher accumulation of tRNA fragments including those derived from initiator-tRNA(Met). We have shown that tRNA cleavage is regulated by the availability of angiogenin, its substrate (tRNA), the levels of the angiogenin inhibitor RNH1, and the rates of protein synthesis. These conclusions are supported by the following findings: (i) exogenous treatment with angiogenin or knockdown of RNH1 increased tRNA cleavage; (ii) tRNA fragment accumulation was higher during oxidative stress than hypertonic stress, in agreement with a dramatic decrease of RNH1 levels during oxidative stress; and (iii) a positive correlation was observed between angiogenin-mediated tRNA cleavage and global protein synthesis rates. Identification of the stress specific tRNA cleavage mechanisms and patterns will provide insights into the role of tRNA fragments in signaling pathways and stress-related disorders. PMID- 23086928 TI - Ubiquitination of retinoblastoma family protein 1 potentiates gene-specific repression function. AB - The retinoblastoma (RB) tumor suppressor family functions as a regulatory node governing cell cycle progression, differentiation, and apoptosis. Post translational modifications play a critical role in modulating RB activity, but additional levels of control, including protein turnover, are also essential for proper function. The Drosophila RB homolog Rbf1 is subjected to developmentally cued proteolysis mediated by an instability element (IE) present in the C terminus of this protein. Paradoxically, instability mediated by the IE is also linked to Rbf1 repression potency, suggesting that proteolytic machinery may also be directly involved in transcriptional repression. We show that the Rbf1 IE is an autonomous degron that stimulates both Rbf1 ubiquitination and repression potency. Importantly, Rbf1 IE function is promoter-specific, contributing to repression of cell cycle responsive genes but not to repression of cell signaling genes. The multifunctional IE domain thus provides Rbf1 flexibility for discrimination between target genes embedded in divergent cellular processes. PMID- 23086929 TI - Identification of amino acid residues required for the substrate specificity of human and mouse chondroitin sulfate hydrolase (conventional hyaluronidase-4). AB - Human hyaluronidase-4 (hHYAL4), a member of the hyaluronidase family, has no hyaluronidase activity, but is a chondroitin sulfate (CS)-specific endo-beta-N acetylgalactosaminidase. The expression of hHYAL4 is not ubiquitous but restricted to placenta, skeletal muscle, and testis, suggesting that hHYAL4 is not involved in the systemic catabolism of CS, but rather has specific functions in particular organs or tissues. To elucidate the function of hyaluronidase-4 in vivo, mouse hyaluronidase-4 (mHyal4) was characterized. mHyal4 was also demonstrated to be a CS-specific endo-beta-N-acetylgalactosaminidase. However, mHyal4 and hHYAL4 differed in the sulfate groups they recognized. Although hHYAL4 strongly preferred GlcUA(2-O-sulfate)-GalNAc(6-O-sulfate)-containing sequences typical in CS-D, where GlcUA represents d-glucuronic acid, mHyal4 depolymerized various CS isoforms to a similar extent, suggesting broad substrate specificity. To identify the amino acid residues responsible for this difference, a series of human/mouse HYAL4 chimeric proteins and HYAL4 point mutants were generated, and their preference for substrates was investigated. A combination of the amino acid residues at 261-265 and glutamine at 305 was demonstrated to be essential for the enzymatic activity as well as substrate specificity of mHyal4. PMID- 23086930 TI - Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-beta-induced pulmonary fibrosis. AB - Dysregulated amphiregulin (AR) expression and EGR receptor (EGFR) activation have been described in animal models of pulmonary fibrosis and in patients with idiopathic pulmonary fibrosis. However, the exact role of AR in the pathogenesis of pulmonary fibrosis has not been clearly defined. Here, we show that a potent profibrogenic cytokine TGF-beta1 significantly induced the expression of AR in lung fibroblasts in vitro and in murine lungs in vivo. AR stimulated NIH3T3 fibroblast cell proliferation in a dose-dependent manner. Silencing of AR expression by siRNA or chemical inhibition of EGFR signaling, utilizing AG1478 and gefitinib, significantly reduced the ability of TGF-beta1 to stimulate fibroblast proliferation and expression of alpha-smooth muscle actin, collagen, and other extracellular matrix-associated genes. TGF-beta1-stimulated activation of Akt, ERK, and Smad signaling was also significantly inhibited by these interventions. Consistent with these in vitro findings, AR expression was impressively increased in the lungs of TGF-beta1 transgenic mice, and either siRNA silencing of AR or chemical inhibition of EGFR signaling significantly reduced TGF-beta1-stimulated collagen accumulation in the lung. These studies showed a novel regulatory role for AR in the pathogenesis of TGF-beta1-induced pulmonary fibrosis. In addition, these studies suggest that AR, or AR-activated EGFR signaling, is a potential therapeutic target for idiopathic pulmonary fibrosis associated with TGF-beta1 activation. PMID- 23086931 TI - Sertoli cell-specific expression of metastasis-associated protein 2 (MTA2) is required for transcriptional regulation of the follicle-stimulating hormone receptor (FSHR) gene during spermatogenesis. AB - BACKGROUND: Desensitization of FSH response by down-regulation of FSHR transcription is critical for FSH action. RESULTS: Chromatin modifier MTA2 participates in the down-regulation of FSHR transcription. CONCLUSION: The FSH/Ar/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate FSH transduction events in Sertoli cells. SIGNIFICANCE: Our findings provide new insights into mechanisms by which FSH is deregulated in male infertile patients. The effect of follicle-stimulating hormone (FSH) on spermatogenesis is modulated at a fundamental level by controlling the number of competent receptors present at the surface of Sertoli cells (SCs). One underlying mechanism is the down-regulation of the expression levels of the FSH receptor (FSHR) gene after exposure to FSH. Here we report that metastasis-associated protein 2 (MTA2), a component of histone deacetylase and nucleosome-remodeling complexes, as a gene product induced directly by testosterone or indirectly by FSH, is exclusively expressed in SCs. Stimulation of SCs with FSH is accompanied by up-regulation of MTA2 expression and enhancement of deacetylase activity. This effect requires the integrity of functional androgen receptor. Furthermore, MTA2 is a potent corepressor of FSHR transcription, because it can recruit histone deacetylase-1 onto the FSHR promoter and participates in the down-regulation of FSHR expression upon FSH treatment. Abolishment of endogenous MTA2 by siRNA treatment disrupted the desensitization of the FSH response and thereafter impaired the FSH-dependent secretory function of SCs. From a clinical standpoint, deregulated expression of MTA2 in SCs of human pathological testes negatively correlates to the deregulated level of serum FSH. Overall, our present results provide the first evidence that the FSH/androgen receptor/MTA2 cascade may serve as an indispensable negative feedback mechanism to modulate the transduction events of SCs in response to FSH. These data also underscore an unexpected reproductive facet of MTA2, which may operate as a novel integrator linking synergistic actions of FSH and androgen signaling in SCs. PMID- 23086932 TI - NAD(P)H:quinone oxidoreductase 1 (NQO1) competes with 20S proteasome for binding with C/EBPalpha leading to its stabilization and protection against radiation induced myeloproliferative disease. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that protects cells against radiation and chemical-induced oxidative stress. Disruption of NQO1 gene in mice leads to increased susceptibility to myeloproliferative disease. In this report, we demonstrate that NQO1 controls the stability of myeloid differentiation factor C/EBPalpha against 20S proteasomal degradation during radiation exposure stress. Co-immunoprecipitation studies showed that NQO1, C/EBPalpha, and 20S all interacted with each other. C/EBPalpha interaction with 20S led to the degradation of C/EBPalpha. NQO1 in presence of its cofactor NADH protected C/EBPalpha against 20S degradation. Deletion and site-directed mutagenesis demonstrated that NQO1 and 20S competed for the same binding region (268)SGAGAGKAKKSV(279) in C/EBPalpha. Mutagenesis studies also revealed that NQO1Y127/Y129 required for NADH binding is essential for NQO1 stabilization of C/EBPalpha. Exposure of mice and HL-60 cells to 3 Grays of gamma-radiation led to increased NQO1 that stabilized C/EBPalpha against 20S proteasomal degradation. This mechanism of NQO1 regulation of C/EBPalpha may provide protection to bone marrow against adverse effects of radiation exposure. The studies have significance for human individuals carrying hetero- or homozygous NQO1P187S mutation and are deficient or lack NQO1 protein. PMID- 23086933 TI - beta-Catenin and peroxisome proliferator-activated receptor-delta coordinate dynamic chromatin loops for the transcription of vascular endothelial growth factor A gene in colon cancer cells. AB - Vascular endothelial growth factor A (VEGFA) mRNA is regulated by beta-catenin and peroxisome proliferator activated receptor delta (PPAR-delta) activation in colon cancer cells, but the detailed mechanism remains to be elucidated. As chromatin loops are generally hubs for transcription factors, we tested here whether beta-catenin could modulate chromatin looping near the VEGFA gene and play any important role for PPAR-delta activated VEGFA transcription. First, we identified the far upstream site as an important site for VEGFA transcription by luciferase assay and chromatin immunoprecipitation in colorectal carcinoma HCT116 cells. Chromatin conformation capture analysis also revealed the chromatin loops formed by the beta-catenin bindings on these sites near the VEGFA gene. Dynamic association and dissociation of beta-catenin/TCF-4/PPAR-delta on the far upstream site and beta-catenin/NF-kappaB p65 on the downstream site were also detected depending on PPAR-delta activation. Interestingly, beta-catenin-mediated chromatin loops were relieved by PPAR-delta activation, suggesting a regulatory role of beta-catenin for VEGFA transcription. Based on these data, we propose a model for PPAR-delta-activated VEGFA transcription that relies on beta-catenin mediated chromatin looping as a prerequisite for the activation. Our findings could extend to other beta-catenin regulated target genes and could provide a general mechanism and novel paradigm for beta-catenin-mediated oncogenesis. PMID- 23086934 TI - The organization of a CSN5-containing subcomplex of the COP9 signalosome. AB - The COP9 signalosome (CSN) is an evolutionarily conserved multi-protein complex that interfaces with the ubiquitin-proteasome pathway and plays critical developmental roles in both animals and plants. Although some subunits are present only in an ~320-kDa complex-dependent form, other subunits are also detected in configurations distinct from the 8-subunit holocomplex. To date, the only known biochemical activity intrinsic to the complex, deneddylation of the Cullin subunits from Cullin-RING ubiquitin ligases, is assigned to CSN5. As an essential step to understanding the structure and assembly of a CSN5-containing subcomplex of the CSN, we reconstituted a CSN4-5-6-7 subcomplex. The core of the subcomplex is based on a stable heterotrimeric association of CSN7, CSN4, and CSN6, requiring coexpression in a bacterial reconstitution system. To this heterotrimer, we could then add CSN5 in vitro to reconstitute a quaternary complex. Using biochemical and biophysical methods, we identified pairwise and combinatorial interactions necessary for the formation of the CSN4-5-6-7 subcomplex. The subcomplex is stabilized by three types of interactions: MPN-MPN between CSN5 and CSN6, PCI-PCI between CSN4 and CSN7, and interactions mediated through the CSN6 C terminus with CSN4 and CSN7. CSN8 was also found to interact with the CSN4-6-7 core. These data provide a strong framework for further investigation of the organization and assembly of this pivotal regulatory complex. PMID- 23086935 TI - Poly-small ubiquitin-like modifier (PolySUMO)-binding proteins identified through a string search. AB - Polysumoylation is a crucial cellular response to stresses against genomic integrity or proteostasis. Like the small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligase RNF4, proteins with clustered SUMO-interacting motifs (SIMs) can be important signal transducers downstream of polysumoylation. To identify novel polySUMO-binding proteins, we conducted a computational string search with a custom Python script. We found clustered SIMs in another RING domain protein Arkadia/RNF111. Detailed biochemical analysis of the Arkadia SIMs revealed that dominant SIMs in a SIM cluster often contain a pentameric VIDLT ((V/I/L/F/Y)(V/I)DLT) core sequence that is also found in the SIMs in PIAS family E3s and is likely the best-fitted structure for SUMO recognition. This idea led to the identification of additional novel SIM clusters in FLASH/CASP8AP2, C5orf25, and SOBP/JXC1. We suggest that the clustered SIMs in these proteins form distinct SUMO binding domains to recognize diverse forms of protein sumoylation. PMID- 23086936 TI - The role of heme binding by DNA-protective protein from starved cells (Dps) in the Tolerance of Porphyromonas gingivalis to heme toxicity. AB - The widely expressed DNA-protective protein from starved-cells (Dps) family proteins are considered major contributors to prokaryotic resistance to stress. We show here that Porphyromonas gingivalis Dps (PgDps), previously described as an iron-storage and DNA-binding protein, also mediates heme sequestration. We determined that heme binds strongly to PgDps with an apparent K(d) of 3.7 * 10( 8) m and is coordinated by a single surface-located cysteine at the fifth axial ligand position. Heme and iron sequestered in separate sites by PgDps provide protection of DNA from H(2)O(2)-mediated free radical damage and were found to be important for growth of P. gingivalis under excess heme as the only iron source. Conservation of the heme-coordinating cysteine among Dps isoforms from the Bacteroidales order suggests that this function may be a common feature within these anaerobic bacteria. PMID- 23086937 TI - The F-box protein FBXO44 mediates BRCA1 ubiquitination and degradation. AB - BRCA1 mutations account for a significant proportion of familial breast and ovarian cancers. In addition, reduced BRCA1 protein is associated with sporadic cancer cases in these tissues. At the cellular level, BRCA1 plays a critical role in multiple cellular functions such as DNA repair and cell cycle checkpoint control. Its protein level is regulated in a cell cycle-dependent manner. However, regulation of BRCA1 protein stability is not fully understood. Our earlier study showed that the amino terminus of BRCA1 harbors a degron sequence that is sufficient and necessary for conferring BRCA1 degradation. In the current study, we used mass spectrometry to identify Skp1 that regulates BRCA1 protein stability. Small interfering RNA screening that targets all human F-box proteins uncovered FBXO44 as an important protein that influences BRCA1 protein level. The Skp1-Cul1-F-box-protein44 (SCF(FBXO44)) complex ubiquitinates full-length BRCA1 in vitro. Furthermore, the N terminus of BRCA1 mediates the interaction between BRCA1 and FBXO44. Overexpression of SCF(FBXO44) reduces BRCA1 protein level. Taken together, our work strongly suggests that SCF(FBXO44) is an E3 ubiquitin ligase responsible for BRCA1 degradation. In addition, FBXO44 expression pattern in breast carcinomas suggests that SCF(FBXO44)-mediated BRCA1 degradation might contribute to sporadic breast tumor development. PMID- 23086938 TI - The assembly of nonadhesive fibrinogen matrices depends on the alphaC regions of the fibrinogen molecule. AB - Adsorption of fibrinogen on fibrin clots and other surfaces strongly reduces integrin-mediated adhesion of platelets and leukocytes with implications for the surface-mediated control of thrombus growth and blood compatibility of biomaterials. The underlying mechanism of this process is surface-induced aggregation of fibrinogen, resulting in the assembly of a nanoscale multilayered matrix. The matrix is extensible, which makes it incapable of transducing strong mechanical forces via cellular integrins, resulting in insufficient intracellular signaling and weak cell adhesion. To determine the mechanism of the multilayer formation, the physical and adhesive properties of fibrinogen matrices prepared from human plasma fibrinogen (hFg), recombinant normal (rFg), and fibrinogen with the truncated alphaC regions (FgAalpha251) were compared. Using atomic force microscopy and force spectroscopy, we show that whereas hFg and rFg generated the matrices with a thickness of ~8 nm consisting of 7-8 molecular layers, the deposition of FgAalpha251 was terminated at two layers, indicating that the alphaC regions are essential for the multilayer formation. The extensibility of the matrix prepared from FgAalpha251 was 2-fold lower than that formed from hFg and rFg. In agreement with previous findings that cell adhesion inversely correlates with the extensibility of the fibrinogen matrix, the less extensible FgAalpha251 matrix and matrices generated from human fibrinogen variants lacking the alphaC regions supported sustained adhesion of leukocytes and platelets. The persistent adhesiveness of matrices formed from fibrinogen derivatives without the alphaC regions may have implications for conditions in which elevated levels of these molecules are found, including vascular pathologies, diabetes, thrombolytic therapy, and dysfibrinogenemia. PMID- 23086939 TI - Characterization of streptokinases from group A Streptococci reveals a strong functional relationship that supports the coinheritance of plasminogen-binding M protein and cluster 2b streptokinase. AB - Group A streptococcus (GAS) strains secrete the protein streptokinase (SK), which functions by activating host human plasminogen (hPg) to plasmin (hPm), thus providing a proteolytic framework for invasive GAS strains. The types of SK secreted by GAS have been grouped into two clusters (SK1 and SK2) and one subcluster (SK2a and SK2b). SKs from cluster 1 (SK1) and cluster 2b (SK2b) display significant evolutionary and functional differences, and attempts to relate these properties to GAS skin or pharynx tropism and invasiveness are of great interest. In this study, using four purified SKs from each cluster, new relationships between plasminogen-binding group A streptococcal M (PAM) protein and SK2b have been revealed. All SK1 proteins efficiently activated hPg, whereas all subclass SK2b proteins only weakly activated hPg in the absence of PAM. Surface plasmon resonance studies revealed that the lower affinity of SK2b to hPg served as the basis for the attenuated activation of hPg by SK2b. Binding of hPg to either human fibrinogen (hFg) or PAM greatly enhanced activation of hPg by SK2b but minimally influenced the already effective activation of hPg by SK1. Activation of hPg in the presence of GAS cells containing PAM demonstrated that PAM is the only factor on the surface of SK2b-expressing cells that enabled the direct activation of hPg by SK2b. As the binding of hPg to PAM is necessary for hPg activation by SK2b, this dependence explains the coinherant relationship between PAM and SK2b and the ability of these particular strains to generate the proteolytic activity that disrupts the innate barriers that limit invasiveness. PMID- 23086940 TI - Structural characterization of a unique interface between carbohydrate response element-binding protein (ChREBP) and 14-3-3beta protein. AB - Carbohydrate response element-binding protein (ChREBP) is an insulin-independent, glucose-responsive transcription factor that is expressed at high levels in liver hepatocytes where it plays a critical role in converting excess carbohydrates to fat for storage. In response to fluctuating glucose levels, hepatic ChREBP activity is regulated in large part by nucleocytoplasmic shuttling of ChREBP protein via interactions with 14-3-3 proteins. The N-terminal ChREBP regulatory region is necessary and sufficient for glucose-responsive ChREBP nuclear import and export. Here, we report the crystal structure of a complex of 14-3-3beta bound to the N-terminal regulatory region of ChREBP at 2.4 A resolution. The crystal structure revealed that the alpha2 helix of ChREBP (residues 117-137) adopts a well defined alpha-helical conformation and binds 14-3-3 in a phosphorylation-independent manner that is different from all previously characterized 14-3-3 and target protein-binding modes. ChREBP alpha2 interacts with 14-3-3 through both electrostatic and van der Waals interactions, and the binding is partially mediated by a free sulfate or phosphate. Structure-based mutagenesis and binding assays indicated that disrupting the observed 14-3-3 and ChREBP alpha2 interface resulted in a loss of complex formation, thus validating the novel protein interaction mode in the 14-3-3beta.ChREBP alpha2 complex. PMID- 23086941 TI - LIM kinase 1 (LIMK1) interacts with tropomyosin-related kinase B (TrkB) and Mediates brain-derived neurotrophic factor (BDNF)-induced axonal elongation. AB - BDNF/TrkB signaling plays critical roles in axonal outgrowth of neurons, the process of which requires the remodeling of the cytoskeleton structure, including microtubules and filamentous actin. However, the mechanism by which BDNF/TrkB signaling regulates cytoskeleton reorganization is still unclear. Here, we identified a novel interaction between LIMK1 and TrkB, which is required for the BDNF-induced axonal elongation. We demonstrated that BDNF-induced TrkB dimerization led to LIMK1 dimerization and transphosphorylation independent of TrkB kinase activity, which could further enhance the activation and stabilization of LIMK1. Moreover, activated LIMK1 translocated to the membrane fraction and phosphorylated its substrate cofilin, thus promoting actin polymerization and axonal elongation. Our findings provided evidence of a novel mechanism for the BDNF-mediated signal transduction leading to axonal elongation. PMID- 23086942 TI - Intracellular endothelin type B receptor-driven Ca2+ signal elicits nitric oxide production in endothelial cells. AB - Endothelin-1 exerts its actions via activation of ET(A) and ET(B) G(q/11) protein coupled receptors, located in the plasmalemma, cytoplasm, and nucleus. Although the autocrine/paracrine nature of endothelin-1 signaling has been extensively studied, its intracrine role has been largely attributed to interaction with receptors located on nuclear membranes and the nucleoplasm. Because ET(B) receptors have been shown to be targeted to endolysosomes, we used intracellular microinjection and concurrent imaging methods to test their involvement in Ca(2+) signaling and subsequential NO production. We provide evidence that microinjected endothelin-1 produces a dose-dependent elevation in cytosolic calcium concentration in ET(B)-transfected cells and endothelial cells; this response is sensitive to ET(B) but not ET(A) receptor blockade. In endothelial cells, the endothelin-1-induced Ca(2+) response is abolished upon endolysosomal but not Golgi disruption. Moreover, the effect is prevented by inhibition of microautophagy and is sensitive to inhibitors of the phospholipase C and inositol 1,4,5-trisphosphate receptor. Furthermore, intracellular endothelin-1 increases nitric oxide via an ET(B)-dependent mechanism. Our results indicate for the first time that intracellular endothelin-1 activates endolysosomal ET(B) receptors and increase cytosolic Ca(2+) and nitric oxide production. Endothelin-1 acts in an intracrine fashion on endolysosomal ET(B) to induce nitric oxide formation, thus modulating endothelial function. PMID- 23086943 TI - Ligand directed signaling differences between rodent and human kappa-opioid receptors. AB - KOR activation of Gbetagamma dependent signaling results in analgesia, whereas the dysphoric effects of KOR agonists are mediated by a different pathway involving G protein receptor kinase and non-visual arrestin. Based on this distinction, a partial KOR agonist that does not efficiently activate arrestin dependent biased signaling may produce analgesia without dysphoria. No KOR selective partial agonists are currently available, and preclinical assessment is complicated by sequence differences between rodent (r) and human (h) KOR. In this study, we compared the signaling initiated by the available partial agonists. Pentazocine was significantly more potent at activating p38 MAPK in hKOR than rKOR expressed in HEK293 cells but equally potent at arrestin-independent activation of ERK1/2 in hKOR and rKOR. Similarly, butorphanol increased phospho p38-ir in hKOR-expressing cells but did not activate p38 in rKOR-HEK293. Like pentazocine, butorphanol was equally efficacious at activating ERK1/2 in rKOR and hKOR. In contrast, levorphanol, nalorphine, and U50,488 did not distinguish between hKOR and rKOR in p38 MAPK activation. Consistent with its low potency at p38 activation, pentazocine did not produce conditioned place aversion in mice. hKOR lacks the Ser-369 phosphorylation site in rKOR required for G protein receptor kinase/arrestin-dependent p38 activation, but mutation of the Ser-358 to asparagine in hKOR blocked p38 activation without affecting the acute arrestin independent activation of ERK1/2. This study shows that hKOR activates p38 MAPK through a phosphorylation and arrestin-dependent mechanism; however, activation differs between hKOR and rKOR for some ligands. These functional selectivity differences have important implications for preclinical screening of partial KOR agonists. PMID- 23086944 TI - Post-translational modification of serine/threonine kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity. AB - Oxidative stress is pathogenic in a variety of diseases, but the mechanism by which cellular signaling is affected by oxidative species has yet to be fully characterized. Lipid peroxidation, a secondary process that occurs during instances of free radical production, may play an important role in modulating cellular signaling under conditions of oxidative stress. 4-Hydroxy-trans-2 nonenal (HNE) is an electrophilic aldehyde produced during lipid peroxidation that forms covalent adducts on proteins, altering their activity and function. One such target, LKB1, has been reported to be inhibited by HNE adduction. We tested the hypothesis that HNE inhibits LKB1 activity through adduct formation on a specific reactive residue of the protein. To elucidate the mechanism of the inhibitory effect, HEK293T cells expressing LKB1 were treated with HNE (10 MUm for 1 h) and assayed for HNE-LKB1 adduct formation and changes in LKB1 kinase activity. HNE treatment resulted in the formation of HNE-LKB1 adducts and decreased LKB1 kinase activity by 31 +/- 9% (S.E.) but had no effect on the association of LKB1 with its adaptor proteins sterile-20-related adaptor and mouse protein 25. Mutation of LKB1 lysine residue 97 reduced HNE adduct formation and attenuated the effect of HNE on LKB1 activity. Taken together, our results suggest that adduction of LKB1 Lys-97 mediates the inhibitory effect of HNE. PMID- 23086945 TI - Interaction of antidepressants with the serotonin and norepinephrine transporters: mutational studies of the S1 substrate binding pocket. AB - The serotonin transporter (SERT) and the norepinephrine transporter (NET) are sodium-dependent neurotransmitter transporters responsible for reuptake of released serotonin and norepinephrine, respectively, into nerve terminals in the brain. A wide range of inhibitors of SERT and NET are used as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis for SERT/NET selectivity. Mutational analyses have suggested that a central substrate binding site (denoted the S1 pocket) also harbors an inhibitor binding site. In this study, we determine the effect of mutating six key S1 residues in human SERT (hSERT) and NET (hNET) on the potency of 15 prototypical SERT/NET inhibitors belonging to different drug classes. Analysis of the resulting drug sensitivity profiles provides novel information on drug binding modes in hSERT and hNET and identifies specific S1 residues as important molecular determinants for inhibitor potency and hSERT/hNET selectivity. PMID- 23086946 TI - Minireview series on sirtuins: from biochemistry to health and disease. PMID- 23086947 TI - Sirtuin catalysis and regulation. AB - Sirtuins are a family of NAD(+)-dependent protein deacetylases/deacylases that dynamically regulate transcription, metabolism, and cellular stress response. Their general positive link with improved health span in mammals, potential regulation of pathways mediated by caloric restriction, and growing links to human disease have spurred interest in therapeutics that target their functions. Here, we review the current understanding of the chemistry of catalysis, biological targets, and endogenous regulation of sirtuin activity. We discuss recent efforts to generate small-molecule regulators of sirtuin activity. PMID- 23086948 TI - Calcium, bioenergetics, and neuronal vulnerability in Parkinson's disease. AB - The most distinguishing feature of neurons is their capacity for regenerative electrical activity. This activity imposes a significant mitochondrial burden, especially in neurons that are autonomously active, have broad action potentials, and exhibit prominent Ca(2+) entry. Many of the genetic mutations and toxins associated with Parkinson's disease compromise mitochondrial function, providing a mechanistic explanation for the pattern of neuronal pathology in this disease. Because much of the neuronal mitochondrial burden can be traced to L-type voltage dependent channels (channels for which there are brain-penetrant antagonists approved for human use), a neuroprotective strategy to reduce this burden is available. PMID- 23086949 TI - Structural basis for sirtuin activity and inhibition. AB - Sir2 proteins, or sirtuins, are a family of enzymes that catalyze NAD(+) dependent deacetylation reactions and can also process ribosyltransferase, demalonylase, and desuccinylase activities. More than 40 crystal structures of sirtuins have been determined, alone or in various liganded forms. These high resolution architectural details lay the foundation for understanding the molecular mechanisms of catalysis, regulation, substrate specificity, and inhibition of sirtuins. In this minireview, we summarize these structural features and discuss their implications for understanding sirtuin function. PMID- 23086950 TI - Identification of functionally critical residues in the channel domain of inositol trisphosphate receptors. AB - We have combined alanine mutagenesis and functional assays to identify amino acid residues in the channel domain that are critical for inositol 1,4,5-trisphosphate receptor (IP(3)R) channel function. The residues selected were highly conserved in all three IP(3)R isoforms and were located in the cytosolic end of the S6 pore lining helix and proximal portion of the C-tail. Two adjacent hydrophobic amino acids (Ile-2588 and Ile-2589) at the putative cytosolic interface of the S6 helix inactivated channel function and could be candidates for the channel gate. Of five negatively charged residues mutated, none completely eliminated channel function. Of five positively charged residues mutated, only one inactivated the channel (Arg-2596). In addition to the previously identified role of a pair of cysteines in the C-tail (Cys-2610 and Cys-2613), a pair of highly conserved histidines (His-2630 and His-2635) were also essential for channel function. Expression of the H2630A and H2635A mutants (but not R2596A) produced receptors with destabilized interactions between the N-terminal fragment and the channel domain. A previously unrecognized association between the cytosolic C-tail and the TM 4,5-loop was demonstrated using GST pulldown assays. However, none of the mutations in the C-tail interfered with this interaction or altered the ability of the C-tail to assemble into dimers. Our present findings and recent information on IP(3)R structure from electron microscopy and crystallography are incorporated into a revised model of channel gating. PMID- 23086951 TI - Mitochondrial protein acylation and intermediary metabolism: regulation by sirtuins and implications for metabolic disease. AB - The sirtuins are a family of NAD(+)-dependent protein deacetylases that regulate cell survival, metabolism, and longevity. Three sirtuins, SIRT3-5, localize to mitochondria. Expression of SIRT3 is selectively activated during fasting and calorie restriction. SIRT3 regulates the acetylation level and enzymatic activity of key metabolic enzymes, such as acetyl-CoA synthetase, long-chain acyl-CoA dehydrogenase, and 3-hydroxy-3-methylglutaryl-CoA synthase 2, and enhances fat metabolism during fasting. SIRT5 exhibits demalonylase/desuccinylase activity, and lysine succinylation and malonylation are abundant mitochondrial protein modifications. No convincing enzymatic activity has been reported for SIRT4. Here, we review the emerging role of mitochondrial sirtuins as metabolic sensors that respond to changes in the energy status of the cell and modulate the activities of key metabolic enzymes via protein deacylation. PMID- 23086952 TI - Human and pneumococcal cell surface glyceraldehyde-3-phosphate dehydrogenase (GAPDH) proteins are both ligands of human C1q protein. AB - C1q, a key component of the classical complement pathway, is a major player in the response to microbial infection and has been shown to detect noxious altered self substances such as apoptotic cells. In this work, using complementary experimental approaches, we identified the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a C1q partner when exposed at the surface of human pathogenic bacteria Streptococcus pneumoniae and human apoptotic cells. The membrane-associated GAPDH on HeLa cells bound the globular regions of C1q as demonstrated by pulldown and cell surface co-localization experiments. Pneumococcal strains deficient in surface-exposed GAPDH harbored a decreased level of C1q recognition when compared with the wild-type strains. Both recombinant human and pneumococcal GAPDHs interacted avidly with C1q as measured by surface plasmon resonance experiments (K(D) = 0.34-2.17 nm). In addition, GAPDH-C1q complexes were observed by transmission electron microscopy after cross linking. The purified pneumococcal GAPDH protein activated C1 in an in vitro assay unlike the human form. Deposition of C1q, C3b, and C4b from human serum at the surface of pneumococcal cells was dependent on the presence of surface exposed GAPDH. This ability of C1q to sense both human and bacterial GAPDHs sheds new insights on the role of this important defense collagen molecule in modulating the immune response. PMID- 23086953 TI - The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses. AB - Cytokine secretion by cancer cells contributes to cancer-induced symptoms and angiogenesis. Studies show that the sirtuin SIRT6 promotes inflammation by enhancing TNF expression. Here, we aimed to determine whether SIRT6 is involved in conferring an inflammatory phenotype to cancer cells and to define the mechanisms linking SIRT6 to inflammation. We show that SIRT6 enhances the expression of pro-inflammatory cyto-/chemokines, such as IL8 and TNF, and promotes cell migration in pancreatic cancer cells by enhancing Ca(2+) responses. Via its enzymatic activity, SIRT6 increases the intracellular levels of ADP ribose, an activator of the Ca(2+) channel TRPM2. In turn, TRPM2 and Ca(2+) are shown to be involved in SIRT6-induced TNF and IL8 expression. SIRT6 increases the nuclear levels of the Ca(2+)-dependent transcription factor, nuclear factor of activated T cells (NFAT), and cyclosporin A, a calcineurin inhibitor that reduces NFAT activity, reduces TNF and IL8 expression in SIRT6-overexpressing cells. These results implicate a role for SIRT6 in the synthesis of Ca(2+)-mobilizing second messengers, in the regulation of Ca(2+)-dependent transcription factors, and in the expression of pro-inflammatory, pro-angiogenic, and chemotactic cytokines. SIRT6 inhibition may help combat cancer-induced inflammation, angiogenesis, and metastasis. PMID- 23086955 TI - Serine 363 is required for nociceptin/orphanin FQ opioid receptor (NOPR) desensitization, internalization, and arrestin signaling. AB - We determined the role of carboxyl-terminal regulation of NOPR (nociceptin, orphanin FQ receptor) signaling and function. We mutated C-terminal serine and threonine residues and examined their role in NOPR trafficking, homologous desensitization, and arrestin-dependent MAPK signaling. The NOPR agonist, nociceptin, caused robust NOPR-YFP receptor internalization, peaking at 30 min. Mutation of serine 337, 346, and 351, had no effect on NOPR internalization. However, mutation of C-terminal threonine 362, serine 363, and threonine 365 blocked nociceptin-induced internalization of NOPR. Furthermore, point mutation of only Ser-363 was sufficient to block NOPR internalization. Homologous desensitization of NOPR-mediated calcium channel blockade and inhibition of cAMP were also shown to require Ser-363. Additionally, NOPR internalization was absent when GRK3, and Arrestin3 were knocked down using siRNA, but not when GRK2 and Arrestin2 were knocked down. We also found that nociceptin-induced NOPR-mediated JNK but not ERK signaling requires Ser-363, GRK3, and Arrestin3. Dominant positive Arrestin3 but not Arrestin2 was sufficient to rescue NOPR-S363A internalization and JNK signaling. These findings suggest that NOPR function may be regulated by GRK3 phosphorylation of Ser-363 and Arrestin3 and further demonstrates the complex nature of G-protein-dependent and -independent signaling in opioid receptors. PMID- 23086954 TI - From sirtuin biology to human diseases: an update. AB - Originally rising to notoriety for their role in the regulation of aging, sirtuins are a family of NAD(+)-dependent enzymes that have been connected to a steadily growing set of biological processes. In addition to regulating aging, sirtuins play key roles in the maintenance of organismal metabolic homeostasis. These enzymes also have primarily protective functions in the development of many age-related diseases, including cancer, neurodegeneration, and cardiovascular disease. In this minireview, we provide an update on the known roles for each of the seven mammalian sirtuins in these areas. PMID- 23086956 TI - Nontruncating SCN1A mutations associated with severe myoclonic epilepsy of infancy impair cell surface expression. AB - Mutations in SCN1A, encoding the voltage-gated sodium channel Na(V)1.1, are the most common cause of severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome. SMEI is most often associated with premature truncations of Na(V)1.1 that cause loss of function, but nontruncating mutations also occur. We hypothesized that some nontruncating mutations might impair trafficking of Na(V)1.1 to the plasma membrane. Here we demonstrated that seven nontruncating missense or in-frame deletion mutations (L986F, delF1289, R1648C, F1661S, G1674R, and G1979E) exhibited reduced cell surface expression relative to wild type (WT) Na(V)1.1 consistent with impaired trafficking. We tested whether two commonly prescribed antiepileptic drugs (phenytoin, lamotrigine), as well as the cystic fibrosis transmembrane conductance regulator (CFTR) trafficking corrector VRT 325, could rescue cell surface and functional expression of two representative Na(V)1.1 mutants (R1648C, G1674R). Treatment of cells with phenytoin increased cell surface expression of WT-Na(V)1.1 and both mutant channels, whereas lamotrigine only increased surface expression of R1648C. VRT-325 did not alter surface expression of WT-Na(V)1.1 or mutant channels. Although phenytoin increased surface expression of G1674R, channel function was not restored, suggesting that this mutation also causes an intrinsic loss of function. Both phenytoin and lamotrigine increased functional expression of R1648C, but lamotrigine also increased persistent sodium current evoked by this mutation. Our findings indicate that certain nontruncating SCN1A mutations associated with SMEI have impaired cell surface expression and that some alleles may be amenable to pharmacological rescue of this defect. However, rescue of dysfunctional Na(V)1.1 channels to the plasma membrane could contribute to exacerbating rather than ameliorating the disease. PMID- 23086957 TI - The mitochondrial amidoxime-reducing component (mARC1) is a novel signal-anchored protein of the outer mitochondrial membrane. AB - The mitochondrial amidoxime-reducing component (mARC) was recently discovered as the fifth eukaryotic molybdenum cofactor-containing enzyme. The human genome encodes two mARC proteins, mARC1 and mARC2, sharing significant homologies with respect to sequence and function. Whereas mARC2 was identified as a mitochondrial enzyme, the subcellular localization of mARC1 has remained uncharacterized, although the similarity of both proteins suggested identical subcellular localizations. In addition, neither mARC1 nor mARC2 could be attributed unambiguously to one of the four mitochondrial subcompartments. Accordingly, mechanisms triggering the subcellular distribution of both enzymes have been unexplored so far. Here, we shed light on the subcellular localization of mARC1 and demonstrate that it is integrated into the outer mitochondrial membrane. The C-terminal catalytic domain of the protein remains exposed to the cytosol and confers an N((in))-C((out)) membrane orientation of mARC1. This localization is triggered by the N terminus of the enzyme, being composed of a weak N-terminal mitochondrial targeting signal and a downstream transmembrane helix. We demonstrate the transmembrane domain of mARC1 to be sufficient for mitochondrial targeting and the N-terminal targeting signal to function as a supportive receptor for the outer mitochondrial membrane. According to its localization and targeting mechanism, we classify mARC1 as a novel signal-anchored mitochondrial protein. During mitochondrial import, mARC1 is not processed, and membrane integration proceeds membrane potential independently but requires external ATP, which finally results in the assembly of mARC1 into high oligomeric protein complexes. PMID- 23086959 TI - Medical students still suffer mistreatment by faculty, resident doctors, and nurses, US report says. PMID- 23086960 TI - WMA says doctors must not prescribe drugs for execution. PMID- 23086958 TI - Dynamic adaptation of liver mitochondria to chronic alcohol feeding in mice: biogenesis, remodeling, and functional alterations. AB - Liver mitochondria undergo dynamic alterations following chronic alcohol feeding to mice. Intragastric alcohol feeding to mice resulted in 1) increased state III respiration (109% compared with control) in isolated liver mitochondria, probably due to increased levels of complexes I, IV, and V being incorporated into the respiratory chain; 2) increased mitochondrial NAD(+) and NADH levels (~2-fold), with no change in the redox status; 3) alteration in mitochondrial morphology, with increased numbers of elongated mitochondria; and 4) enhanced mitochondrial biogenesis in the liver, which corresponded with an up-regulation of PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator-1alpha). Oral alcohol feeding to mice, which is associated with less liver injury and steatosis, slightly enhanced respiration in isolated liver mitochondria (30.8% compared with control), lower than the striking increase caused by intragastric alcohol feeding. Mitochondrial respiration increased with both oral and intragastric alcohol feeding despite extensive N-acetylation of mitochondrial proteins. The alcohol-induced mitochondrial alterations are probably an adaptive response to enhance alcohol metabolism in the liver. Isolated liver mitochondria from alcohol-treated mice had a greater rate of acetaldehyde metabolism and respiration when treated with acetaldehyde than control. Aldehyde dehydrogenase-2 levels were unaltered in response to alcohol, suggesting that the greater acetaldehyde metabolism by isolated mitochondria from alcohol-treated mice was due to increased mitochondrial respiration that regenerated NAD(+), the rate limiting substrate in alcohol/acetaldehyde metabolism. Overall, our work suggests that mitochondrial plasticity in the liver may be an important adaptive response to the metabolic stress caused by alcohol intake and could potentially play a role in many other vital functions performed by the liver. PMID- 23086961 TI - NHS changes in England are likely to cost more than L1.5bn. PMID- 23086962 TI - Government announces start of revalidation. PMID- 23086963 TI - More US citizens die from meningitis as scope of inquiry widens. PMID- 23086964 TI - Researchers promise to be more open about use of animals in their work. PMID- 23086965 TI - Hybrid myocardial perfusion SPECT/CT coronary angiography and invasive coronary angiography in patients with stable angina pectoris lead to similar treatment decisions. AB - OBJECTIVES: To evaluate to what extent treatment decisions for patients with stable angina pectoris can be made based on hybrid myocardial perfusion single photon emission CT (SPECT) and CT coronary angiography (CCTA). It has been shown that hybrid SPECT/CCTA has good performance in the diagnosis of significant coronary artery disease (CAD). The question remains whether these imaging results lead to similar treatment decisions as compared to standalone SPECT and invasive coronary angiography (CA). METHODS: We prospectively included 107 patients (mean age 62.8+/-10.0 years, 69% male) with stable anginal complaints and an intermediate to high pre-test likelihood for CAD. Hybrid SPECT/CCTA was performed prior to CA in all patients. The study outcome was the treatment decision categorised as: no revascularisation, percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Treatment decisions were made by two interventional cardiologists and one cardiothoracic surgeon in two steps: first, based on the results of hybrid SPECT/CCTA; second, based on SPECT and CA. RESULTS: Revascularisation (PCI or CABG) was indicated in 54 (50%) patients based on SPECT and CA. Percentage agreement of treatment decisions in all patients based on hybrid SPECT/CCTA versus SPECT and CA on the necessity of revascularisation was 92%. Percentage agreement of treatment decisions in patients with matched, unmatched and normal hybrid SPECT/CCTA findings was 95%, 84% and 100%, respectively. CONCLUSIONS: Panel evaluation shows that patients could be accurately indicated for and deferred from revascularisation based on hybrid SPECT/CCTA. PMID- 23086967 TI - Considering a possible application to prevent or to treat arterial stiffness. PMID- 23086966 TI - Thromboprophylaxis of elderly patients with AF in the UK: an analysis using the General Practice Research Database (GPRD) 2000-2009. AB - OBJECTIVE: To assess use of thromboprophylaxis in UK general practise among patients with atrial fibrillation (AF); to investigate whether elderly patients are less likely to receive anticoagulation therapy than younger patients. DESIGN: Retrospective cohort study SETTING: UK General Practice Research Database (GPRD) PATIENTS: Aged >=60 years with a new diagnosis of AF (2000-2009). INTERVENTIONS: None. MAIN OUTCOME MEASURES: The main outcome measure was initiation of warfarin in the first year following diagnosis. Patients were categorised by stroke risk (CHADS(2) score) and bleeding risk (HAS-BLED score). RESULTS: 81 381 patients were identified (21% aged 60-69 years, 37% aged 70-79 years, 42% aged 80+ years). Patients aged 80+ years were significantly less likely to be initiated on warfarin than younger patients, adjusted for gender, practice and comorbidities; 32% of patients aged 80+ years received warfarin compared with 57% aged 60-69 years (p<0.0001), and 55% aged 70-79 years (p<0.0001). For all strata of CHADS(2)/HASBLED scores, patients aged 80+ years were significantly less likely to be treated with warfarin than younger patients. Logistic regression showed that female sex, low Basal Metabolic Index (BMI), age over 80 years, increasing HAS-BLED score and dementia were independently associated with reduced use of warfarin. Stroke/Transient Ischaemic Attack (TIA), hypertension, heart failure and left ventricular systolic dysfunction were associated with increased use. Patients with HAS-BLED>CHADS(2) were less likely to be initiated on warfarin. Higher CHADS(2) scores were associated with increased anticoagulation use. CONCLUSIONS: Anticoagulation is being under-used in patients with AF aged 80+ years, even after taking into account increased bleeding risk in this age group. PMID- 23086968 TI - Surgery for rheumatic mitral valve disease and the forgotten role of concomitant organic tricuspid valve impairment. PMID- 23086969 TI - COURAGE or FAME...? Who should have percutaneous coronary intervention in stable coronary artery disease? PMID- 23086970 TI - The perennial quest for an ideal prosthetic valve. PMID- 23086971 TI - Differential effects of heart rate reduction by atenolol or ivabradine on peripheral endothelial function in type 2 diabetic patients. AB - OBJECTIVE: To assess whether reduction of heart rate (HR) has beneficial effects on endothelial function in patients with type 2 diabetes mellitus (T2DM). DESIGN: Randomised, double-blind, placebo-controlled study. SETTING: University hospital. PATIENTS: 66 T2DM patients without overt cardiovascular disease. INTERVENTIONS: Patients were randomised to receive for 4 weeks, in addition to their standard therapy, one of the following treatments: atenolol (25 mg twice daily), ivabradine (5 mg twice daily) or placebo (1 tablet twice daily). MAIN OUTCOME MEASURES: Systemic endothelial function, assessed by flow-mediated dilation (FMD); endothelium-independent vasodilation, assessed by nitrate-mediated dilation (NMD); cardiac autonomic function, assessed by HR variability (HRV). RESULTS: 61 patients completed the study (19, 22 and 20 patients in atenolol, ivabradine and placebo groups, respectively). Compared with baseline, HR was similarly reduced by atenolol (87+/-13 vs 69+/-9 bpm) and ivabradine (86+/-12 to 71+/-9 bpm), but not by placebo (82+/-10 vs 81+/-9 bpm) (p<0.001). FMD improved at follow-up in the atenolol group (4.8+/-1.7 vs 6.4+/-1.9%), but not in the ivabradine group (5.2+/-2.5 vs 4.9+/-2.2%) and in the placebo group (4.8+/-1.5 vs 4.7+/-1.7%) (p<0.01). NMD did not change significantly in any group. HRV parameters did not change in the placebo group; they, instead, consistently increased in the atenolol, whereas a mild increase in SDNNi was only observed in the ivabradine group. A significant correlation was found in the atenolol group between HR and FMD changes (r=-0.48; p=0.04). CONCLUSIONS: Despite a comparable reduction in HR, atenolol, but not ivabradine, improved FMD in T2DM patients suggesting that changes in HR are by themselves unlikely to significantly improve endothelial function. PMID- 23086972 TI - Steroids for Kawasaki disease: the devil is in the detail. PMID- 23086973 TI - Syphilitic coronary artery ostial stenosis presenting with acute myocardial infarction. PMID- 23086974 TI - Long-term follow-up of older patients with Mobitz type I second degree atrioventricular block. AB - OBJECTIVE: To examine the long-term survival of older patients with Mobitz I second degree atrioventricular (AV) block. DESIGN: Retrospective cohort study. Propensity score adjustment for requiring a cardiac implantable electronic device (CIED) was performed. Multivariable Cox regression analysis was used. SETTING: Tertiary care referral centre. PATIENTS: We examined 299 older patients (age >45 years) with Mobitz I second degree AV block on ECG at the Minneapolis Veterans Affairs Medical Center from 1992 to 2010. MAIN OUTCOME MEASURE: Survival. RESULTS: The average age of patients was 75+/-9 years; 99% were male; 59% had coronary heart disease; 44% had heart failure. 141 (47%) patients required CIED, of which 17 were implantable cardioverter-defibrillators (ICDs). CIEDs were implanted a median of 110 days after the ECG for symptomatic bradycardia, high degree AV block or prevention of sudden cardiac death. Patients with CIED had greater cardiac co-morbidity than those without CIED. After a median 3.3 years of follow-up (range 3 days to 19 years), 190 (64%) patients died. Patients with CIED had longer survival than those without CIED (p=0.001). In propensity-adjusted multivariable Cox regression analysis, CIED implantation was associated with a 46% reduction in mortality (HR 0.54, 95% CI 0.35 to 0.82; p=0.004). Excluding 17 patients with ICDs did not alter the results. CONCLUSIONS: In this retrospective cohort study of older male patients with Mobitz I AV block on ECG, CIED implantation was associated with longer survival. PMID- 23086975 TI - Altered cardiovascular autonomic regulation in overweight children engaged in regular physical activity. AB - Overweight (OW) and obesity in children are important forerunners of cardiovascular risk, possibly through autonomic nervous system (ANS) dysregulation, while physical exercise exerts a beneficial influence. In this observational study we hypothesise that OW might influence ANS profile even in a population performing high volume of supervised exercise. We study 103 young soccer players, homogeneous in terms of gender (all male), cultural background, school, age (11.2 +/- 1 years) and exercise routine, since they all belong to the same soccer club, thus guaranteeing equality of supervised training and similar levels of competitiveness. ANS is evaluated by autoregressive spectral analysis of heart rate and systolic arterial pressure (SAP) variabilities. We estimate also the accumulated weekly Metabolic Equivalents and time spent in sedentary activities. We subdivide the entire population in two subgroups (normal weight and OW) based on the International Obesity Task Force criteria. In OW soccer players (10.7% of total group) we observe an altered profile of autonomic cardiovascular regulation, characterised by higher values of SAP (113 +/- 4 vs 100 +/- 1 mm Hg, 39.7 +/- 3 vs 66.2 +/- 10%), higher Low Frequency variability power of SAP (an index of vasomotor sympathetic regulation) (12 +/- 3 vs 4.5 mm Hg(2)) and smaller spontaneous baroreflex gain (an index of cardiac vagal regulation) (19 +/- 3 vs 33 +/- 3 ms/mm Hg) (all (p < 0.02)). Moreover Correlation analysis on the entire study population shows a significant link between anthropometric and autonomic indices. These data show that OW is associated to a clear autonomic impairment even in children subjected to an intense aerobic training. PMID- 23086976 TI - Human Rap1 interacts directly with telomeric DNA and regulates TRF2 localization at the telomere. AB - The TRF2-Rap1 complex suppresses non-homologous end joining and interacts with DNAPK-C to prevent end joining. We previously demonstrated that hTRF2 is a double strand telomere binding protein that forms t-loops in vitro and recognizes three- and four-way junctions independent of DNA sequence. How the DNA binding characteristics of hTRF2 to DNA is altered in the presence of hRap1 however is not known. Here we utilized EM and quantitative gel retardation to characterize the DNA binding properties of hRap1 and the TRF2-Rap1 complex. Both gel filtration chromatography and mass analysis from two-dimensional projections showed that the TRF2-Rap1 complex exists in solution and binds to DNA as a complex consisting of four monomers each of hRap1 and hTRF2. EM revealed for the first time that hRap1 binds to DNA templates in the absence of hTRF2 with a preference for double strand-single strand junctions in a sequence independent manner. When hTRF2 and hRap1 are in a complex, its affinity for ds telomeric sequences is 2-fold higher than TRF2 alone and more than 10-fold higher for telomeric 3' ends. This suggests that as hTRF2 recruits hRap1 to telomeric sequences, hRap1 alters the affinity of hTRF2 and its binding preference on telomeric DNA. Moreover, the TRF2-Rap1 complex has higher ability to re-model telomeric DNA than either component alone. This finding underlies the importance of complex formation between hRap1 and hTRF2 for telomere function and end protection. PMID- 23086977 TI - Influence of bilirubin photoisomers on unbound bilirubin measurement in clinical settings. AB - BACKGROUND: Measured unbound bilirubin concentration is influenced by bilirubin photoisomers. Bilirubin photoisomers are produced even with only a slight light exposure, and clinical samples are inevitably exposed to light. The objective of the study was to evaluate the influence of bilirubin photoisomers on the measurement of unbound bilirubin using serum of jaundiced neonates during blue light phototherapy. METHODS: Five neonates treated with phototherapy for hyperbilirubinaemia were enrolled. The samples were taken 12 h after initiation of phototherapy. Samples were processed by irradiation with blue light, by indoor ceiling light, by both blue light and indoor ceiling light or shaded. Bilirubin subfractions, total bilirubin and unbound bilirubin were measured. RESULTS: Compared with the non-irradiated samples, the (EZ)-cyclobilirubin concentration and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the blue light irradiated samples, the (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the indoor ceiling light-irradiated samples, and the (EZ) cyclobilirubin, (EZ)-bilirubin and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the samples irradiated with both lights. No change was noted in unbound bilirubin in any group. CONCLUSIONS: We consider that changes in bilirubin photoisomers induced by light exposure during clinical practice do not influence the measured unbound bilirubin concentration. PMID- 23086978 TI - 'Sweet Dreams', 'Happy Days' and elevated 24-h urine 5-hydroxyindoleacetic acid excretion. AB - We report two patients with markedly elevated 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) excretion due to over-the-counter (OTC) self-medication with 5 hydroxytryptophan (5-HTP). It is important to recognize that OTC medication may cause increased 'false-positive' 5-HIAA excretion to prevent undue patient anxiety and unnecessary further investigation for carcinoid disease. Discordance between chromogranin A and 24-h urine 5-HIAA results should alert to the possibility of false-positive or -negative laboratory results. PMID- 23086979 TI - Acupuncture and brain imaging: what do we have to consider? PMID- 23086980 TI - A teledermatology care management protocol for tracking completion of teledermatology recommendations. AB - In July 2009 we implemented a 3-year store-and-forward teledermatology project to provide dermatology care to veterans living in rural and underserved areas of the US Pacific Northwest. We also developed a follow-up protocol and tracking system. Information about all completed teledermatology consultations was entered into a database, and major procedures and select medications were tracked. In the first 21 months, 8202 dermatology conditions in 5232 veterans were treated and 3370 major procedures carried out. Ninety-five percent of conditions were associated with no more than two teledermatology consultations, and no condition required more than ten consultations. In total, 1454 conditions were reviewed for clinical pathological correlation, and in 310 (21%) there was a subsequent clinical pathological correlation conference, resulting in a change in final diagnosis for 93 conditions. The follow-up was important in ensuring high quality patient care. PMID- 23086981 TI - Hospital and emergency department resource usage: a cost analysis from a home telehealth project in Kansas. PMID- 23086982 TI - Validity and reliability of the assessment and diagnosis of musculoskeletal elbow disorders using telerehabilitation. AB - We examined the validity and reliability of a physiotherapy examination of the elbow, using telerehabilitation. The patho-anatomical diagnoses, systems diagnosis and physical examination findings of face-to-face physiotherapy examinations were compared with telerehabilitation examinations. Ten participants attended a single session, during which they were interviewed, a face-to-face physical examination was performed and a remote physical examination was conducted, guided by an examiner at a different location via a telerehabilitation system. Conventional face-to-face physiotherapy physical examination test results, diagnoses and systems diagnoses were compared to those produced by an examiner using the telerehabiliation system. There was substantial agreement for systems diagnosis (73%; P = 0.013) for validity and almost perfect agreement for intra-rater reliability (90%; P = 0.001). The inter-rater reliability had a weaker and non-significant agreement (64%; P = 0.11). Physical examination data demonstrated >68% agreement across all three datasets, between the examination methods. Performing a telerehabilitation physical examination to determine a musculoskeletal diagnosis of the elbow joint complex is both valid and reliable. PMID- 23086983 TI - The incidence, pathology of trauma and victim profiles of homicidal deaths in Pretoria, South Africa (2007-2008). AB - This study aimed to establish the incidence of homicide, associated pathology of trauma and victim profiles in cases admitted to or managed as homicidal deaths at the Pretoria Medico-Legal Laboratory (PMLL) over the period of 2007-2008. A total of 1088 cases were reviewed. Homicides accounted for 22.7% of all cases admitted to the PMLL. The majority of homicide victims were male individuals (87.0%). The most common cause of death was gunshot wounds (42.6%), followed by blunt force trauma (25.1%). Homicides are most likely to occur at the victim's place of residence (28.5%) and only 37.4% of victims survive long enough to receive hospital care. The results of this study seem to concur with international findings for the most part, with a few interesting deviations. Highlighting at risk groups, as well as dangerous locations and incident times, creates the potential to decrease the occurrence of unnecessary deaths by generating an awareness of the trends. PMID- 23086985 TI - Cell-based interventions for therapeutic angiogenesis: review of potential cell sources. AB - Alternative therapies are currently being developed to treat patients with chronic limb ischemia who are unable to be revascularized in order to avoid amputation. Cell-based therapy using mononuclear cells is gaining attention as many clinical trials are currently underway. We review cell differentiation along with the different potential cell sources for use in therapeutic angiogenesis. PMID- 23086986 TI - Stem cell therapy for critical limb ischemia: what can we learn from cell therapy for chronic wounds? AB - Although much progress has been made regarding our knowledge of stem cells and their potential applications for therapeutic angiogenesis, there has been less success with the clinical application of this knowledge to patients with critical limb ischemia (CLI). Patients with CLI often have chronic wounds and newer cell based therapies for chronic wounds show interesting parallels to stem cell therapy for CLI. Several human-derived wound care products and therapies, including human neonatal fibroblast-derived dermis (Dermagraft(r)), bilayered bioengineered skin substitute (Apligraf(r)), recombinant human platelet-derived growth factor and autologous platelet-rich plasma may provide insight into the mechanisms through which differentiated cells can be used as therapy for chronic wounds, and, analogously, by which stem cells might function therapeutically in CLI. PMID- 23086987 TI - A randomized trial comparing in person and electronic interventions for improving adherence to oral medications in schizophrenia. AB - Poor adherence to medication leads to symptom exacerbation and interferes with the recovery process for patients with schizophrenia. Following baseline assessment, 142 patients in medication maintenance at a community mental health center were randomized to one of 3 treatments for 9 months: (1) PharmCAT, supports including pill containers, signs, alarms, checklists and the organization of belongings established in weekly home visits from a PharmCAT therapist; (2) Med-eMonitor (MM), an electronic medication monitor that prompts use of medication, cues the taking of medication, warns patients when they are taking the wrong medication or taking it at the wrong time, record complaints, and, through modem hookup, alerts treatment staff of failures to take medication as prescribed; (3) Treatment as Usual (TAU). All patients received the Med eMonitor device to record medication adherence. The device was programmed for intervention only in the MM group. Data on symptoms, global functioning, and contact with emergency services and police were obtained every 3 months. Repeated measures analyses of variance for mixed models indicated that adherence to medication was significantly better in both active conditions than in TAU (both p<0.0001). Adherence in active treatments ranged from 90-92% compared to 73% in TAU based on electronic monitoring. In-person and electronic interventions significantly improved adherence to medication, but that did not translate to improved clinical outcomes. Implications for treatment and health care costs are discussed. PMID- 23086988 TI - H2O2-induced endothelial NO production contributes to vascular cell apoptosis and increased permeability in rat venules. AB - Although elevated levels of H(2)O(2) have been implicated to play important roles in the pathogenesis of various cardiovascular diseases, the underlying mechanisms remain unclear. This study aims to examine the effect of H(2)O(2) on endothelial nitric oxide (NO) production in intact venules, and elucidate the role and mechanisms of NO in H(2)O(2)-induced increases in microvessel permeability. Experiments were conducted on individually perfused rat mesenteric venules. Microvessel permeability was determined by measuring hydraulic conductivity (Lp), and endothelial [Ca(2+)](i) was measured on fura-2-loaded vessels. Perfusion of H(2)O(2) (10 MUM) caused a delayed and progressively increased endothelial [Ca(2+)](i) and Lp, a pattern different from inflammatory mediator-induced immediate and transient response. Under the same experimental conditions, measuring endothelial NO via DAF-2 and the spatial detection of cell apoptosis by fluorescent markers revealed that H(2)O(2) induced two phases of NO production followed by caspase activation, intracellular Ca(2+) accumulation, and vascular cell apoptosis. The initial NO production was correlated with increased endothelial NO synthase (eNOS) Ser(1177) phosphorylation in the absence of elevated endothelial [Ca(2+)](i), whereas the second phase of NO depended on increased [Ca(2+)](i) and was associated with Thr(495) dephosphorylation without increased Ser(1177) phosphorylation. Inhibition of NOS prevented H(2)O(2)-induced caspase activation, cell apoptosis, and increases in endothelial [Ca(2+)](i) and Lp. Our results indicate that H(2)O(2) at micromolar concentration is able to induce a large magnitude of NO in intact venules, causing caspase activation mediated endothelial Ca(2+) accumulation, cell apoptosis, and increases in permeability. The mechanisms revealed from intact microvessels may contribute to the pathogenesis of oxidant-related cardiovascular diseases. PMID- 23086989 TI - Melatonin inhibits nitric oxide signaling by increasing PDE5 phosphorylation in coronary arteries. AB - Melatonin inhibits nitric oxide (NO)-induced relaxation of coronary arteries. We tested the hypothesis that melatonin increases the phosphorylation of phosphodiesterase 5 (PDE5), which increases the activity of the enzyme and thereby decreases intracellular cGMP accumulation in response to NO and inhibits NO-induced relaxation. Sodium nitroprusside (SNP) and 8-Br-cGMP caused concentration-dependent relaxation of isolated coronary arteries suspended in organ chambers for isometric tension recording. In the presence of melatonin, the concentration-response curve to SNP, but not 8-Br-cGMP, was shifted to the right. The effect of melatonin on SNP-induced relaxation was abolished in the presence of the PDE5 inhibitors zaprinast and sildenafil. Melatonin markedly inhibited the SNP-induced increase in intracellular cGMP in coronary arteries, an effect that was also abolished by zaprinast. Treatment of coronary arteries with melatonin caused a nearly fourfold increase in the phosphorylation of PDE5, which increased the catalytic activity of the enzyme and thereby increased the degradation of cGMP to inactive 5'-GMP. Melatonin-induced PDE5 phosphorylation was markedly attenuated in the presence of the PKG1 inhibitors DT-2 or Rp-8-Br-PET-cGMPS and in those arteries in which PKG1 expression was first downregulated by 24-h incubation with SNP before exposure to melatonin. The selective MT(2) receptor antagonist 4-phenyl-2-propionamidotetralin completely blocked the stimulatory effect of melatonin on PDE5 phosphorylation as well as the inhibitory effect of melatonin on SNP-induced relaxation and intracellular cGMP. Thus, in coronary arteries, melatonin acts via MT(2) receptors and PKG1 to increase PDE5 phosphorylation, resulting in decreased cGMP accumulation in response to NO and impaired NO-induced vasorelaxation. PMID- 23086990 TI - Left atrial and ventricular function during dobutamine and glycopyrrolate stress in healthy young and elderly as evaluated by cardiac magnetic resonance. AB - The aim of this study is to describe phasic volume changes of the left atrium (LA) in healthy young and elderly subjects at rest and during pharmacological stress (PS). LA maximum size is related to cardiovascular mortality. LA has passive, active, and conduit function for left ventricular (LV) filling. We hypothesized that changes in LV compliance from normal aging are reflected in LA volume changes and that PS will augment these differences. We enrolled twenty young (20-30 yr) and twenty elderly (60-70 yr) healthy subjects and measured their LV and LA volumes by cardiac magnetic resonance imaging at rest and during dobutamine and glycopyrrolate stress. We identified LA minimum, maximum, and middiastolic volumes and the volume before atrial contraction. LA emptying volumes were calculated as LA passive and active emptying volumes and LA conduit volume. We also calculated LV peak filling rates (LVPFRs). Both at rest and during PS, LA maximum and minimum volumes were similar in the groups, whereas middiastolic volume was higher in the elderly. During PS, a marked decrease in LA passive emptying function and a corresponding increase in LA active emptying function were seen in the elderly but not in the young. At rest, LVPFR was lower in the elderly, and during PS this difference was augmented. The aging heart has reduced LVPFR, which is reflected in reduced LA passive and compensatory increased LA active volumetric contribution to LV stroke volume. These age related differences are evident at rest and highly augmented during both dobutamine and glycopyrrolate stress. PMID- 23086992 TI - Oxidative stress exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation in rats with hypertension induced by angiotensin II. AB - Muscle contraction stimulates thin fiber muscle afferents and evokes reflex sympathoexcitation. In hypertension, this reflex is exaggerated. ANG II, which is elevated in hypertension, has been reported to trigger the production of superoxide and other reactive oxygen species. In the present study, we tested the hypothesis that increased ANG II in hypertension exaggerates skeletal muscle contraction-evoked reflex sympathoexcitation by inducing oxidative stress in the muscle. In rats, subcutaneous infusion of ANG II at 450 ng.kg(-1).min(-1) for 14 days significantly (P < 0.05) elevated blood pressure compared with sham-operated (sham) rats. Electrically induced 30-s hindlimb muscle contraction in decerebrate rats with hypertension evoked larger renal sympathoexcitatory and pressor responses [+1,173 +/- 212 arbitrary units (AU) and +35 +/- 5 mmHg, n = 10] compared with sham normotensive rats (+419 +/- 103 AU and +13 +/- 2 mmHg, n = 11). Tempol, a SOD mimetic, injected intra-arterially into the hindlimb circulation significantly reduced responses in hypertensive rats, whereas this compound had no effect on responses in sham rats. Tiron, another SOD mimetic, also significantly reduced reflex renal sympathetic and pressor responses in a subset of hypertensive rats (n = 10). Generation of muscle superoxide, as evaluated by dihydroethidium staining, was increased in hypertensive rats. RT-PCR and immunoblot experiments showed that mRNA and protein for gp91(phox), a NADPH oxidase subunit, in skeletal muscle tissue were upregulated in hypertensive rats. Taken together, hese results suggest that increased ANG II in hypertension induces oxidative stress in skeletal muscle, thereby exaggerating the muscle reflex. PMID- 23086993 TI - The scanning ion conductance microscope for cellular physiology. AB - The quest for nonoptical imaging methods that can surmount light diffraction limits resulted in the development of scanning probe microscopes. However, most of the existing methods are not quite suitable for studying biological samples. The scanning ion conductance microscope (SICM) bridges the gap between the resolution capabilities of atomic force microscope and scanning electron microscope and functional capabilities of conventional light microscope. A nanopipette mounted on a three-axis piezo-actuator, scans a sample of interest and ion current is measured between the pipette tip and the sample. The feedback control system always keeps a certain distance between the sample and the pipette so the pipette never touches the sample. At the same time pipette movement is recorded and this generates a three-dimensional topographical image of the sample surface. SICM represents an alternative to conventional high-resolution microscopy, especially in imaging topography of live biological samples. In addition, the nanopipette probe provides a host of added modalities, for example using the same pipette and feedback control for efficient approach and seal with the cell membrane for ion channel recording. SICM can be combined in one instrument with optical and fluorescent methods and allows drawing structure function correlations. It can also be used for precise mechanical force measurements as well as vehicle to apply pressure with precision. This can be done on living cells and tissues for prolonged periods of time without them loosing viability. The SICM is a multifunctional instrument, and it is maturing rapidly and will open even more possibilities in the near future. PMID- 23086991 TI - Modulation of cardiac Na+,K+-ATPase cell surface abundance by simulated ischemia reperfusion and ouabain preconditioning. AB - Na(+),K(+)-ATPase and cell survival were investigated in a cellular model of ischemia-reperfusion (I/R)-induced injury and protection by ouabain-induced preconditioning (OPC). Rat neonatal cardiac myocytes were subjected to 30 min of substrate and coverslip-induced ischemia followed by 30 min of simulated reperfusion. This significantly compromised cell viability as documented by lactate dehydrogenase release and Annexin V/propidium iodide staining. Total Na(+),K(+)-ATPase alpha(1)- and alpha(3)-polypeptide expression remained unchanged, but cell surface biotinylation and immunostaining studies revealed that alpha(1)-cell surface abundance was significantly decreased. Na(+),K(+) ATPase-activity in crude homogenates and (86)Rb(+) transport in live cells were both significantly decreased by about 30% after I/R. OPC, induced by a 4-min exposure to 10 MUM ouabain that ended 8 min before the beginning of ischemia, increased cell viability in a PKCepsilon-dependent manner. This was comparable with the protective effect of OPC previously reported in intact heart preparations. OPC prevented I/R-induced decrease of Na(+),K(+)-ATPase activity and surface expression. This model also revealed that Na(+),K(+)-ATPase-mediated (86)Rb(+) uptake was not restored to control levels in the OPC group, suggesting that the increased viability was not conferred by an increased Na(+),K(+)-ATPase mediated ion transport capacity at the cell membrane. Consistent with this observation, transient expression of an internalization-resistant mutant form of Na(+),K(+)-ATPase alpha(1) known to have increased surface abundance without increased ion transport activity successfully reduced I/R-induced cell death. These results suggest that maintenance of Na(+),K(+)-ATPase cell surface abundance is critical to myocyte survival after an ischemic attack and plays a role in OPC-induced protection. They further suggest that the protection conferred by increased surface expression of Na(+),K(+)-ATPase may be independent of ion transport. PMID- 23086994 TI - Ventricular tachyarrhythmias in rats with acute myocardial infarction involves activation of small-conductance Ca2+-activated K+ channels. AB - In vitro experiments have shown that the upregulation of small-conductance Ca(2+) activated K(+) (SK) channels in ventricular epicardial myocytes is responsible for spontaneous ventricular fibrillation (VF) in failing ventricles. However, the role of SK channels in regulating VF has not yet been described in in vivo acute myocardial infarction (AMI) animals. The present study determined the role of SK channels in regulating spontaneous sustained ventricular tachycardia (SVT) and VF, the inducibility of ventricular tachyarrhythmias, and the effect of inhibition of SK channels on spontaneous SVT/VF and electrical ventricular instability in AMI rats. AMI was induced by ligation of the left anterior descending coronary artery in anesthetized rats. Spontaneous SVT/VF was analyzed, and programmed electrical stimulation was performed to evaluate the inducibility of ventricular tachyarrhythmias, ventricular effective refractory period (VERP), and VF threshold (VFT). In AMI, the duration and episodes of spontaneous SVT/VF were increased, and the inducibility of ventricular tachyarrhythmias was elevated. Pretreatment in the AMI group with the SK channel blocker apamin or UCL 1684 significantly reduced SVT/VF and inducibility of ventricular tachyarrhythmias (P < 0.05). Various doses of apamin (7.5, 22.5, 37.5, and 75.0 MUg/kg iv) inhibited SVT/VF and the inducibility of ventricular tachyarrhythmias in a dose-dependent manner. Notably, no effects were observed in sham-operated controls. Additionally, VERP was shortened in AMI animals. Pretreatment in AMI animals with the SK channel blocker significantly prolonged VERP (P < 0.05). No effects were observed in sham-operated controls. Furthermore, VFT was reduced in AMI animals, and block of SK channels increased VFT in AMI animals, but, again, this was without effect in sham-operated controls. Finally, the monophasic action potential duration at 90% repolarization (MAPD(90)) was examined in the myocardial infarcted (MI) and nonmyocardial infarcted areas (NMI) of the left ventricular epicardium. Electrophysiology recordings showed that MAPD(90) in the MI area was shortened in AMI animals, and pretreatment with SK channel blocker apamin or UCL-1684 significantly prolonged MAPD(90) (P < 0.05) in the MI area but was without effect in the NMI area or in sham-operated controls. We conclude that the activation of SK channels may underlie the mechanisms of spontaneous SVT/VF and susceptibility to ventricular tachyarrhythmias in AMI. Inhibition of SK channels normalized the shortening of MAPD(90) in the MI area, which may contribute to the inhibitory effect on spontaneous SVT/VF and inducibility of ventricular tachyarrhythmias in AMI. PMID- 23086996 TI - Improving the treatment of atherosclerosis by linking anti-inflammatory and lipid modulating strategies. PMID- 23086995 TI - Passive limb movement: evidence of mechanoreflex sex specificity. AB - Previous studies have determined that premenopausal women exhibit an attenuated metaboreflex; however, little is known about sex specificity of the mechanoreflex. Thus, we sought to determine if sex differences exist in the central and peripheral hemodynamic responses to passive limb movement. Second-by second measurements of heart rate, stroke volume, cardiac output (CO), mean arterial pressure, and femoral artery blood flow (FBF) were recorded during 3 min of supine passive knee extension in 24 young healthy subjects (12 women and 12 men). Normalization of CO and stroke volume to body surface area, expressed as cardiac index and stroke index, eliminated differences in baseline central hemodynamics, whereas, peripherally, basal FBF and femoral vascular conductance were similar between the sexes. In response to passive limb movement, women displayed significantly attenuated peak central hemodynamic responses compared with men (heart rate: 9.0 +/- 1 vs. 14.8 +/- 2% change, stroke index: 4.5 +/- 0.6 vs. 7.8 +/- 1.2% change, cardiac index: 9.6 +/- 1 vs. 17.2 +/- 2% change, all P < 0.05), whereas movement induced similar increases in peak FBF (167 +/- 32 vs. 193 +/- 17% change) and femoral vascular conductance (172 +/- 31 vs. 203 +/- 16% change) in both sexes (women vs. men, respectively). Additionally, there was a significant positive relationship between individual peak FBF and peak CO response to passive movement in men but not in women. Thus, although both sexes exhibited similar movement-induced hyperemia and peripheral vasodilatory function, the central hemodynamic response was blunted in women, implying an attenuated mechanoreflex. Therefore, this study reveals that, as already recognized with the metaboreflex, there is likely a sex-specific attenuation of the mechanoreflex in women. PMID- 23086998 TI - Structural basis of transcription initiation. AB - During transcription initiation, RNA polymerase (RNAP) binds and unwinds promoter DNA to form an RNAP-promoter open complex. We have determined crystal structures at 2.9 and 3.0 A resolution of functional transcription initiation complexes comprising Thermus thermophilus RNA polymerase, sigma(A), and a promoter DNA fragment corresponding to the transcription bubble and downstream double-stranded DNA of the RNAP-promoter open complex. The structures show that sigma recognizes the -10 element and discriminator element through interactions that include the unstacking and insertion into pockets of three DNA bases and that RNAP recognizes the -4/+2 region through interactions that include the unstacking and insertion into a pocket of the +2 base. The structures further show that interactions between sigma and template-strand single-stranded DNA (ssDNA) preorganize template-strand ssDNA to engage the RNAP active center. PMID- 23086999 TI - SAICAR stimulates pyruvate kinase isoform M2 and promotes cancer cell survival in glucose-limited conditions. AB - Pyruvate kinase isoform M2 (PKM2) plays an important role in the growth and metabolic reprogramming of cancer cells in stress conditions. Here, we report that SAICAR (succinylaminoimidazolecarboxamide ribose-5'-phosphate, an intermediate of the de novo purine nucleotide synthesis pathway) specifically stimulates PKM2. Upon glucose starvation, cellular SAICAR concentration increased in an oscillatory manner and stimulated PKM2 activity in cancer cells. Changes in SAICAR amounts in cancer cells altered cellular energy level, glucose uptake, and lactate production. The SAICAR-PKM2 interaction also promoted cancer cell survival in glucose-limited conditions. SAICAR accumulation was not observed in normal adult epithelial cells or lung fibroblasts, regardless of glucose conditions. This allosteric regulation may explain how cancer cells coordinate different metabolic pathways to optimize their growth in the nutrient-limited conditions commonly observed in the tumor microenvironment. PMID- 23087000 TI - Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. AB - Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor in humans. Here we show that gliomas can originate from differentiated cells in the central nervous system (CNS), including cortical neurons. Transduction by oncogenic lentiviral vectors of neural stem cells (NSCs), astrocytes, or even mature neurons in the brains of mice can give rise to malignant gliomas. All the tumors, irrespective of the site of lentiviral vector injection (the initiating population), shared common features of high expression of stem or progenitor markers and low expression of differentiation markers. Microarray analysis revealed that tumors of astrocytic and neuronal origin match the mesenchymal GBM subtype. We propose that most differentiated cells in the CNS upon defined genetic alterations undergo dedifferentiation to generate a NSC or progenitor state to initiate and maintain the tumor progression, as well as to give rise to the heterogeneous populations observed in malignant gliomas. PMID- 23087002 TI - Less is more - fluid therapy for kidney disease. PMID- 23087001 TI - Tricking the guard: exploiting plant defense for disease susceptibility. AB - Typically, pathogens deploy virulence effectors to disable defense. Plants defeat effectors with resistance proteins that guard effector targets. We found that a pathogen exploits a resistance protein by activating it to confer susceptibility in Arabidopsis. The guard mechanism of plant defense is recapitulated by interactions among victorin (an effector produced by the necrotrophic fungus Cochliobolus victoriae), TRX-h5 (a defense-associated thioredoxin), and LOV1 (an Arabidopsis susceptibility protein). In LOV1's absence, victorin inhibits TRX-h5, resulting in compromised defense but not disease by C. victoriae. In LOV1's presence, victorin binding to TRX-h5 activates LOV1 and elicits a resistance-like response that confers disease susceptibility. We propose that victorin is, or mimics, a conventional pathogen virulence effector that was defeated by LOV1 and confers virulence to C. victoriae solely because it incites defense. PMID- 23087003 TI - Feline acute kidney injury: 1. Pathophysiology, etiology and etiology-specific management considerations. AB - PRACTICAL RELEVANCE: Acute kidney injury (AKI) is a frequently recognized disease process in cats that requires immediate and aggressive intervention. A thorough understanding of the pathophysiologic processes underlying AKI and familiarity with the most common etiologies are essential for providing the most effective and timely therapy. Possessing this knowledge will also allow a more accurate prognosis to be given, and afford the best chance of a favorable outcome. CLINICAL CHALLENGES: Feline patients often present with vague signs of AKI, which may delay treatment and adversely affect the prognosis. Their response to injury and treatment is often different to that of other species. AUDIENCE: This two part review article is directed at small animal practitioners as well as specialists. Part 1 reviews mechanisms underlying AKI in the cat, as well as etiologies and treatments related to some specific causes of AKI. EVIDENCE BASE: The veterinary literature is limited with regards to the pathophysiology of AKI unique to the cat. However, there are numerous feline studies evaluating causes of AKI. PMID- 23087004 TI - Feline acute kidney injury: 2. Approach to diagnosis, treatment and prognosis. AB - PRACTICAL RELEVANCE: Feline acute kidney injury (AKI) is a commonly recognized problem in small animal practice that requires prompt diagnosis and directed therapy. There are many treatment methods with which practitioners should be familiar, including medical options, surgical interventions and renal replacement therapy (dialysis). It is important to know which option is most appropriate for each cause and stage of AKI to deliver the most effective therapy. CLINICAL CHALLENGES: AKI can cause vague clinical signs, but a vast array of life threatening sequelae. Rapid recognition of potential complications and knowledge of treatment options is imperative for successful management. Feline patients also require an understanding of their unique physiology as it relates to the therapeutic plan. AUDIENCE: This two-part review article is directed at small animal practitioners as well as specialists. Part 2 discusses the diagnosis of AKI in cats using physical examination findings, clinicopathologic results and imaging modalities. The treatment of AKI and its sequelae is also reviewed, with information on recent advances in this area. EVIDENCE BASE: While there is very limited data comparing the outcomes of various treatment options, there is literature addressing the use of several medications, as well as renal replacement therapy, in cats. PMID- 23087005 TI - Ultrasonography of the feline kidney: Technique, anatomy and changes associated with disease. AB - PRACTICAL RELEVANCE: Ultrasonography is an important tool for the detection of kidney disorders, which are among the most common health problems suffered by cats. It is more accurate than radiography for this purpose and is considered to be the reference modality for imaging the feline kidney, providing excellent visualisation of renal size, shape and internal architecture. Compared with more advanced imaging modalities, such as computed tomography or magnetic resonance imaging, ultrasonography is more accessible, less expensive, does not require general anaesthesia and allows real-time procedures to be performed. CLINICAL CHALLENGES: On ultrasound examination, focal or multifocal disorders may be readily identified, but diffuse changes are more challenging. B-mode ultrasonography is of limited use for differentiating between benign and malignant focal lesions. However, based on the presence and pattern of vascularity as an indicator of malignancy, contrast-enhanced ultrasonography allows distinction between benign and malignant focal renal lesions. AUDIENCE: This review provides a framework for the ultrasonographic approach to feline renal and perirenal disorders for the general practitioner. EVIDENCE BASE: Drawing on current literature relating to ultrasonographic examination of feline kidneys, the aim is to summarise ultrasonographic technique, anatomy and changes associated with renal and perirenal diseases. PMID- 23087006 TI - Hyperthyroidism in cats: what's causing this epidemic of thyroid disease and can we prevent it? AB - PRACTICAL RELEVANCE: Since first being reported in the late 1970s, there has been a dramatic increase in the prevalence of hyperthyroidism in cats. It is now recognized worldwide as the most common feline endocrine disorder. PATIENT GROUP: Hyperthyroidism is an important cause of morbidity in cats older than 10 years of age. It is estimated that over 10% of all senior cats will develop the disorder. CLINICAL CHALLENGES: Despite its frequency, the underlying cause(s) of this common disease is/are not known, and no one has suggested a means to prevent the disorder. Because of the multiple risk factors that have been described for feline hyperthyroidism, it is likely that more than one factor is involved in its pathogenesis. Continuous, lifelong exposure to environmental thyroid disruptor chemicals or goitrogens in food or water, acting together in an additive or synergistic manner, may first lead to euthyroid goiter and then to autonomous adenomatous hyperplasia, thyroid adenoma and hyperthyroidism. EVIDENCE BASE: This review draws on published research studies to summarize the available evidence about the risk factors for feline hyperthyroidism. Based on the known goitrogens that may be present in the cat's food, drinking water or environment, it proposes measures that cat owners can implement that might prevent, or reduce the prevalence of, thyroid tumors and hyperthyroidism in their cats. PMID- 23087007 TI - Carotid artery pseudoaneurysm in a cat. AB - CLINICAL SUMMARY: A 4-month-old female intact domestic shorthair cat presented to Kansas State University Veterinary Medical Teaching Hospital for investigation of a large, firmly adhered mass in the left mid-cervical region that developed after phlebotomy performed at the referring veterinarian's clinic. Ultrasound examination of the mass revealed a cystic structure in communication with the left carotid artery, with bidirectional blood flow through the area. A diagnosis of pseudoaneurysm secondary to accidental needle penetration of the carotid artery during jugular venepuncture was made. OUTCOME: Strict cage rest and pain management resulted in complete resolution of clinical and ultrasonographic signs in this cat. PMID- 23087008 TI - Feline focus. PMID- 23087009 TI - Age and educational inequalities in smoking cessation due to three population level tobacco control interventions: findings from the International Tobacco Control (ITC) Netherlands Survey. AB - This study aimed to examine age and educational inequalities in smoking cessation due to the implementation of a tobacco tax increase, smoke-free legislation and a cessation campaign. Longitudinal data from 962 smokers aged 15 years and older were used from three survey waves of the International Tobacco Control (ITC) Netherlands Survey. The 2008 survey was performed before the implementation of the interventions and the 2009 and 2010 surveys were performed after the implementation. No significant age and educational differences in successful smoking cessation were found after the implementation of the three tobacco control interventions, although smokers aged 15-39 years were more likely to attempt to quit. Of the three population-level tobacco control interventions that were implemented simultaneously in the Netherlands, only the smoke-free legislation seemed to have increased quit attempts. The price increase of cigarettes may have been only effective in stimulating smoking cessation among younger smokers. Larger tax increases, stronger smoke-free legislation and media campaigns about the dangers of (second-hand) smoking are needed in the Netherlands. PMID- 23087010 TI - Rheumatic heart disease: pilot study for a population-based evaluation of prevalence and cardiovascular outcomes among schoolchildren in Nepal. AB - OBJECTIVES: To evaluate a protocol for a population-based programme targeting the prevention of rheumatic heart disease (RHD) progression by early echocardiographic diagnosis of valvular lesions and timely implementation of secondary prevention. DESIGN: Observational survey with a subsequent prospective cohort study. SETTING: Private boarding school in the urban area of the Sunsari district situated on the foothills of the Lower Himalayan Range in Eastern Nepal. PARTICIPANTS: Fifty-four unselected school-going children 5-15 years of age, 24 girls and 30 boys. PRIMARY OUTCOME MEASURE: Logistic feasibility of a large-scale population-based screening study using the echocardiographic criteria formulated by the World Heart Federation, with longitudinal follow-up of children with definite or borderline RHD in a prospective cohort study. RESULTS: Standardised interview, physical examination and screening echocardiography were performed in a three-staged process and took approximately 6 min per child. Socio-economic status was assessed using surrogate markers such as the occupation of the primary caregiver, numbers of rooms at home, car, television, cell phone and internet connection. Physical examination was focused on cardiac auscultation and signs of acute rheumatic fever and targeted echocardiography was performed by an independent examiner without knowledge of the clinical findings. Two children with evidence of borderline RHD were re-examined at B.P. Koirala Institute of Health Sciences and the indication for secondary antibiotic prevention was discussed with the parents and the children. At 6 months of follow-up, echocardiographic findings were stable in both children. Implementation of secondary antibiotic prevention was challenged by impaired awareness of subclinical RHD among parents and inadequate cooperation with family physicians. CONCLUSIONS: This pilot study shows that the methods outlined in the protocol can be translated into a large-scale population-based study. We learned that education and collaboration with teachers, parents and family physicians/paediatricians will be of key importance in order to establish a sustainable programme. PMID- 23087011 TI - Three-year follow-up of a randomised clinical trial of intravenous versus oral iron for anaemia in pregnancy. AB - BACKGROUND: To date, there are no data available concerning the impact of iron therapy on the long-term well-being and health-related quality of life (HRQoL) in pregnancy. OBJECTIVE: To assess the long-term effect of iron therapy on HRQoL in pregnancy. DESIGN: This is a follow-up study conducted between January 2010 and January 2011 of an earlier randomised open-label clinical trial of intravenous and oral iron versus oral iron for pregnancy-related iron deficiency anaemia. We used a modified version of the SF-36 questionnaire together with the original prospective HRQoL data collected during and after pregnancy. PARTICIPANTS AND INTERVENTIONS: Of the original evaluable 183 pregnant Caucasian women randomised to receive oral iron or a single intravenous iron polymaltose infusion followed by oral iron maintenance, 126 women completed the follow-up HRQoL study. METHODS: The participants were followed up 4 weeks after treatment, predelivery and postdelivery for a median period of 32 months (range, 26-42) with a well-being and HRQoL questionnaire using a modified SF-36 QoL-survey and child growth charts as set by the Australasian Paediatric Endocrine Group (APEG). RESULTS: Patients who received intravenous iron demonstrated significantly higher haemoglobin and serum ferritin levels (p<0.001). There were strong associations between iron status and a number of the HRQoL parameters, with improved general health (p<0.001), improved vitality (physical energy) (p<0.001), less psychological downheartedness (p=0.005), less clinical depression (p=0.003) and overall improved mental health (p<0.001). The duration of breastfeeding was longer (p=0.046) in the intravenous iron group. The babies born in both groups recorded similarly on APEG growth chart assessments. CONCLUSIONS: Our data suggest that HRQoL is improved until after pregnancy in anaemic pregnant women by repletion of their iron stores during pregnancy. About 80% of the intravenous iron group showed a maintained normal ferritin until delivery with long-term benefits. Further studies to confirm these findings are warranted. PMID- 23087012 TI - Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. AB - BACKGROUND: Despite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents. OBJECTIVE: To assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. DATA SOURCES: MEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers. INCLUSION CRITERIA: Randomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy. METHODS: Systematic review. Quality assessment used the Cochrane risk of bias score. RESULTS: Seven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to 2.3 kg compared to placebo). LIMITATIONS: Long-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers. CONCLUSIONS: Dapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed. PMID- 23087013 TI - Frequency and consequences of violence and aggression towards employees in the German healthcare and welfare system: a cross-sectional study. AB - OBJECTIVES: In this study, the frequency and consequences of aggressive assaults on employees in the German healthcare and welfare system were investigated. DESIGN: A retrospective cross-sectional study. SETTING: Employees in the German healthcare system and their experiences of violence and aggression were examined in this study. PARTICIPANTS: The sample consisted of 1973 employees from 39 facilities (6 facilities for the disabled, 6 hospitals and 27 outpatient and inpatient geriatric care facilities) who have regular contact with patients or clients. MAIN OUTCOME MEASURES: The frequency of physical and verbal violence towards employees and the consequences of aggressive assaults were analysed. RESULTS: 56% of respondents had experienced physical violence and 78% verbal aggression. The highest frequency of physical violence was in inpatient geriatric care (63%) (p=0.000). Younger workers run a higher risk of being affected by physical violence than older colleagues (OR 1.8, 95% CI 1.3 to 2.4). There is also an increased risk of experiencing physical violence in inpatient geriatric care (OR 1.6, 95% CI 1.2 to 2.0). Around a third of workers feel seriously stressed by the violence experienced. The better the facility trained employees for dealing with aggressive and violent clients, the less risk employees ran of experiencing either verbal aggression (OR 0.5, 95% CI 0.4 to 0.7) or physical violence (OR 0.7, 95% CI 0.6 to 0.9). Training by the facility has a positive effect on experienced stress (OR 0.6, 95% CI 0.4 to 0.8). CONCLUSIONS: Violence towards nursing and healthcare personnel occurs frequently. Every third respondent feels severely stressed by violence and aggression. Occupational support provisions to prevent and provide aftercare for cases of violence and aggression reduce the risk of incidents and of perceived stress. Research is needed on occupational support provisions that reduce the risk of staff experiencing verbal and physical violence and the stress that is associated with it. PMID- 23087015 TI - Type 2 diabetes: a cohort study of treatment, ethnic and social group influences on glycated haemoglobin. AB - OBJECTIVES: To assess whether in people with poorly controlled type 2 diabetes (HbA1c>7.5%) improvement in HbA1c varies by ethnic and social group. DESIGN: Prospective 2-year cohort of type 2 diabetes treated in general practice. SETTING AND PARTICIPANTS: All patients with type 2 diabetes in 100 of the 101 general practices in two London boroughs. The sample consisted of an ethnically diverse group with uncontrolled type 2 diabetes aged 37-71 years in 2007 and with HbA1c recording in 2008-2009. OUTCOME MEASURE: Change from baseline HbA1c in 2007 and achievement of HbA1c control in 2008 and 2009 were estimated for each ethnic, social and treatment group using multilevel modelling. RESULTS: The sample consisted of 6104 people; 18% were white, 63% south Asian, 16% black African/Caribbean and 3% other ethnic groups. HbA1c was lower after 1 and 2 years in all ethnic groups but south Asian people received significantly less benefit from each diabetes treatment. After adjustment, south Asian people were found to have 0.14% less reduction in HbA1c compared to white people (95% CI 0.04% to 0.24%) and white people were 1.6 (95% CI 1.2 to 2.0) times more likely to achieve HbA1c controlled to 7.5% or less relative to south Asian people. HbA1c reduction and control in black African/Caribbean and white people did not differ significantly. There was no evidence that social deprivation influenced HbA1c reduction or control in this cohort. CONCLUSIONS: In all treatment groups, south Asian people with poorly controlled diabetes are less likely to achieve controlled HbA1c, with less reduction in mean HbA1c than white or black African/Caribbean people. PMID- 23087014 TI - HIV among people who inject drugs in Central and Eastern Europe and Central Asia: a systematic review with implications for policy. AB - BACKGROUND AND OBJECTIVES: HIV among people who inject drugs (PWID) is a major public health concern in Eastern and Central Europe and Central Asia. HIV transmission in this group is growing and over 27 000 HIV cases were diagnosed among PWID in 2010 alone. The objective of this systematic review was to examine risk factors associated with HIV prevalence among PWID in Central and Eastern Europe and Central Asia and to describe the response to HIV in this population and the policy environments in which they live. DESIGN: A systematic review of peer-reviewed and grey literature addressing HIV prevalence and risk factors for HIV prevalence among PWID and a synthesis of key resources describing the response to HIV in this population. We used a comprehensive search strategy across multiple electronic databases to collect original research papers addressing HIV prevalence and risk factors among PWID since 2005. We summarised the extent of key harm reduction interventions, and using a simple index of 'enabling' environment described the policy environments in which they are implemented. STUDIES REVIEWED: Of the 5644 research papers identified from electronic databases and 40 documents collected from our grey literature search, 70 documents provided unique estimates of HIV and 14 provided multivariate risk factors for HIV among PWID. RESULTS: HIV prevalence varies widely, with generally low or medium (<5%) prevalence in Central Europe and high (>10%) prevalence in Eastern Europe. We found evidence for a number of structural factors associated with HIV including gender, socio-economic position and contact with law enforcement agencies. CONCLUSIONS: The HIV epidemic among PWID in the region is varied, with the greatest burden generally in Eastern Europe. Data suggest that the current response to HIV among PWID is insufficient, and hindered by multiple environmental barriers including restricted access to services and unsupportive policy or social environments. PMID- 23087016 TI - Screening for HIV among tuberculosis patients: a cross-sectional study in Sindh, Pakistan. AB - OBJECTIVE: To describe feasibility and results of systematic screening of tuberculosis (TB) patients for HIV. DESIGN: Cross-sectional study. SETTING: Six selected sentinel sites (public DOTS clinics) in the province of Sindh, Pakistan. PARTICIPANTS: All TB patients aged 16-60 years registered for treatment from April 2008 to March 2012. MEASUREMENT: Demographic information of registered TB patients, screening for HIV through rapid testing and confirmation by referral lab of Sindh AIDS Control Program, according to national guidelines. RESULTS: Of a total of 18 461 registered TB patients, 12 882 fulfilled the inclusion criteria and were given education and counselling. Of those counselled 12 552 (97.4%) were screened for HIV using a rapid test. Men made up 48% of the sample and 76.5% of patients had pulmonary TB. Of the total patients tested, 42 (0.34%) were HIV positive after confirmatory testing at the Sindh AIDS Control Program Laboratory. Prevalence of HIV among male patients was 0.67% whereas prevalence among female patients was 0.03% (p value <0.001). Prevalence of HIV among pulmonary TB patients was 0.29% and among extrapulmonary TB patients was 0.48% (p value=0.09). CONCLUSION: In public DOTS clinics in Pakistan it is feasible to test TB patients for HIV. Prevalence of HIV is three times higher among TB patients as compared with the general population in Pakistan. Although the results are not representative of Pakistan or Sindh province they cover a large catchment area and closely match WHO estimate for the country. Routinely screening all TB patients for HIV infection, especially targeting men and ensuring antiretroviral therapy, can significantly improve TB/HIV collaborative activities in Pakistan and identify many cases of HIV, improve health outcomes and save lives. PMID- 23087017 TI - High pulsatility flow stimulates smooth muscle cell hypertrophy and contractile protein expression. AB - Proximal arterial stiffening is an important predictor of events in systemic and pulmonary hypertension, partly through its contribution to downstream vascular abnormalities. However, much remains undetermined regarding the mechanisms involved in the vascular changes induced by arterial stiffening. We therefore addressed the hypothesis that high pulsatility flow, caused by proximal arterial stiffening, induces downstream pulmonary artery endothelial cell (EC) dysfunction that in turn leads to phenotypic change of smooth muscle cells (SMCs). To test the hypothesis, we employed a model pulmonary circulation in which upstream compliance regulates the pulsatility of flow waves imposed onto a downstream vascular mimetic coculture composed of pulmonary ECs and SMCs. The effects of high pulsatility flow on SMCs were determined both in the presence and absence of ECs. In the presence of ECs, high pulsatility flow increased SMC size and expression of the contractile proteins, smooth muscle alpha-actin (SMA) and smooth muscle myosin heavy chain (SM-MHC), without affecting proliferation. In the absence of ECs, high pulsatility flow decreased SMC expression of SMA and SM MHC, without affecting SMC size or proliferation. To identify the molecular signals involved in the EC-mediated SMC responses, mRNA and/or protein expression of vasoconstrictors [angiotensin-converting enzyme (ACE) and endothelin (ET)-1], vasodilator (eNOS), and growth factor (TGF-beta1) in EC were examined. Results showed high pulsatility flow decreased eNOS and increased ACE, ET-1, and TGF beta1 expression. ACE inhibition with ramiprilat, ET-1 receptor inhibition with bosentan, and treatment with the vasodilator bradykinin prevented flow-induced, EC-dependent SMC changes. In conclusion, high pulsatility flow stimulated SMC hypertrophy and contractile protein expression by altering EC production of vasoactive mediators and cytokines, supporting the idea of a coupling between proximal vascular stiffening, flow pulsatility, and downstream vascular function. PMID- 23087018 TI - Site-specific dynamics of CD11b+ and CD103+ dendritic cell accumulations following ozone exposure. AB - Pulmonary dendritic cells (DCs) are among the first responders to inhaled environmental stimuli such as ozone (O(3)), which has been shown to activate these cells. O(3) reacts with epithelial lining fluid (ELF) components in an anatomically site-specific manner dictated by O(3) concentration, airway flow patterns, and ELF substrate concentration. Accordingly, the anatomical distribution of ELF reaction products and airway injury are hypothesized to produce selective DC maturation differentially within the airways. To investigate how O(3) affects regional airway DC populations, we utilized a model of O(3) induced pulmonary inflammation, wherein C57BL/6 mice were exposed to 0.8 ppm O(3) 8 h/day for 1, 3, and 5 days. This model induced mild inflammation and no remarkable epithelial injury. Tracheal, but not more distant airway sites, and mediastinal lymph node (MLN) DC numbers were increased significantly after the third exposure day. The largest increase in each tissue was of the CD103(+) DC phenotype. After 3 days of exposure, fewer DCs expressed CD80, CD40, and CCR7, and, at this same time point, total MLN T cell numbers increased. Together, these data demonstrate that O(3) exposure induced site-specific and phenotype changes in the pulmonary and regional lymph node DC populations. Possibly contributing to ozone-mediated asthma perturbation, the phenotypic changes to DCs within pulmonary regions may alter responses to antigenic stimuli. Decreased costimulatory molecule expression within the MLN suggests induction of tolerance mechanisms; increased tracheal DC number may raise the potential for allergic sensitization and asthmatic exacerbation, thus overcoming O(3)-induced decrements in costimulatory molecule expression. PMID- 23087019 TI - Insufficient autophagy in idiopathic pulmonary fibrosis. AB - Autophagy, a process that helps maintain homeostatic balance between the synthesis, degradation, and recycling of organelles and proteins to meet metabolic demands, plays an important regulatory role in cellular senescence and differentiation. Here we examine the regulatory role of autophagy in idiopathic pulmonary fibrosis (IPF) pathogenesis. We test the hypothesis that epithelial cell senescence and myofibroblast differentiation are consequences of insufficient autophagy. Using biochemical evaluation of in vitro models, we find that autophagy inhibition is sufficient to induce acceleration of epithelial cell senescence and myofibroblast differentiation in lung fibroblasts. Immunohistochemical evaluation of human IPF biospecimens reveals that epithelial cells show increased cellular senescence, and both overlaying epithelial cells and fibroblasts in fibroblastic foci (FF) express both ubiquitinated proteins and p62. These findings suggest that insufficient autophagy is an underlying mechanism of both accelerated cellular senescence and myofibroblast differentiation in a cell-type-specific manner and is a promising clue for understanding the pathogenesis of IPF. PMID- 23087020 TI - A mutation in the beta-subunit of ENaC identified in a patient with cystic fibrosis-like symptoms has a gain-of-function effect. AB - In some patients with atypical cystic fibrosis (CF), only one allele of the CF transmembrane conductance regulator (CFTR) gene is affected. Mutations of the epithelial sodium channel (ENaC) may contribute to the pathophysiology of the disease in these patients. To functionally characterize a mutation in the beta subunit of ENaC (betaV348M) recently identified in a patient with severe CF-like symptoms (Mutesa et al. 2009), we expressed wild-type (wt) alphabetagammaENaC or mutant alphabetaV348MgammaENaC in Xenopus laevis oocytes. The betaV348M mutation stimulated amiloride-sensitive whole-cell current (DeltaI(ami)) by ~40% but had no effect on surface expression or single-channel conductance of ENaC. Instead the mutation increased channel open probability (P(o)). Proteolytic activation of mutant ENaC by chymotrypsin was reduced compared with that of wt ENaC (~3.0-fold vs. ~4.2-fold), which is consistent with the increased baseline P(o) of mutant ENaC. Similarly, the ENaC activator S3969 stimulated mutant ENaC currents to a lesser degree (by ~2.6-fold) than wt ENaC currents (by ~3.5-fold). The gain-of function effect of the betaV348M mutation was confirmed by whole-cell current measurements in HEK293 cells transiently transfected with wt or mutant ENaC. Computational channel modeling in combination with functional expression of different betaV348 mutants in oocytes suggests that the betaV348M mutation increases channel P(o) by destabilizing the closed channel state. Our findings indicate that the gain-of-function effect of the betaV348M mutation may contribute to CF pathophysiology by inappropriately increasing sodium and fluid absorption in the respiratory tract. PMID- 23087021 TI - Changes in Purkinje cell firing and gene expression precede behavioral pathology in a mouse model of SCA2. AB - Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited disorder, which is caused by a pathological expansion of a polyglutamine (polyQ) tract in the coding region of the ATXN2 gene. Like other ataxias, SCA2 most overtly affects Purkinje cells (PCs) in the cerebellum. Using a transgenic mouse model expressing a full-length ATXN2(Q127)-complementary DNA under control of the Pcp2 promoter (a PC-specific promoter), we examined the time course of behavioral, morphologic, biochemical and physiological changes with particular attention to PC firing in the cerebellar slice. Although motor performance began to deteriorate at 8 weeks of age, reductions in PC number were not seen until after 12 weeks. Decreases in the PC firing frequency first showed at 6 weeks and paralleled deterioration of motor performance with progression of disease. Transcription changes in several PC-specific genes such as Calb1 and Pcp2 mirrored the time course of changes in PC physiology with calbindin-28 K changes showing the first small, but significant decreases at 4 weeks. These results emphasize that in this model of SCA2, physiological and behavioral phenotypes precede morphological changes by several weeks and provide a rationale for future studies examining the effects of restoration of firing frequency on motor function and prevention of future loss of PCs. PMID- 23087022 TI - Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish. AB - Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans. PMID- 23087023 TI - Birthweight discordant female twins and their offspring: is the intergenerational influence on birthweight due to genes or environment? AB - STUDY QUESTION: Does the intergenerational influence on birthweight and birth length remain within female dizygotic and monozygotic twin pairs? SUMMARY ANSWER: The intergenerational influence on birthweight and birth length remained within dizygotic but not within monozygotic twin pairs. WHAT IS KNOWN ALREADY: Low birthweight is associated with increased morbidity and mortality in both the short and long term; therefore it is important to understand determinants of fetal growth. There is a known intergenerational association between parents' and offspring's size at birth. STUDY DESIGN, SIZE, DURATION: This is a register-based cohort study with a nested within-twin-pair comparison. The study is retrospective, but based on prospectively collected information. The study population included 8685 monozygotic and like-sexed dizygotic female twins born in Sweden from 1926 to 1985, who had given birth to their first infant between 1973 and 2009. PARTICIPANTS/MATERIALS, SETTING, METHODS: This study is set in Sweden and used data from the Swedish Twin Register and the Swedish Medical Birth Register. We used generalized estimating equations to obtain regression coefficients with 95% confidence intervals (CI) for the outcomes: offspring birthweight and birth length. To control for genetic and shared environmental factors, we performed within-twin-pair analyses in 1479 dizygotic and 1526 monozygotic twin pairs. MAIN RESULTS AND THE ROLE OF CHANCE: In the cohort of both dizygotic and monozygotic twins, there was an association between mother's and offspring's size at birth. Within-dizygotic twin pairs, a 500-g increase from the twin pair's mean birthweight was associated with increased offspring birthweight [70 g (95% CI: 35-106)] and birth length [0.22 cm (95% CI: 0.07 0.38)]. The corresponding increase in birth length of 1 cm was estimated to increase offspring's birthweight by 26 g (95% CI: 12-40) and birth length by 0.11 cm (95% CI: 0.04-0.17). Within-monozygotic twin pairs there were no such associations. LIMITATIONS, REASONS FOR CAUTION: This study is limited to twins who themselves or whose co-twin voluntarily responded to questionnaires. WIDER IMPLICATIONS OF THE FINDINGS: The intergenerational influence on size at birth is suggested to be due to direct or indirect genetic factors. PMID- 23087025 TI - Practice recommendations in the diagnosis, management, and prevention of carbon monoxide poisoning. AB - Carbon monoxide (CO) poisoning is common in modern society, resulting in significant morbidity and mortality in the United States annually. Over the past two decades, sufficient information has been published about carbon monoxide poisoning in the medical literature to draw firm conclusions about many aspects of the pathophysiology, diagnosis, and clinical management of the syndrome, along with evidence-based recommendations for optimal clinical practice. This article provides clinical practice guidance to the pulmonary and critical care community regarding the diagnosis, management, and prevention of acute CO poisoning. The article represents the consensus opinion of four recognized content experts in the field. Supporting data were drawn from the published, peer-reviewed literature on CO poisoning, placing emphasis on selecting studies that most closely mirror clinical practice. PMID- 23087024 TI - Imatinib attenuates hypoxia-induced pulmonary arterial hypertension pathology via reduction in 5-hydroxytryptamine through inhibition of tryptophan hydroxylase 1 expression. AB - RATIONALE: Whether idiopathic, familial, or secondary to another disease, pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, neointimal hyperplasia, medial hypertrophy, and adventitial fibrosis. Imatinib, a potent receptor tyrosine kinase inhibitor, reverses pulmonary remodeling in animal models of PAH and improves hemodynamics and exercise capacity in selected patients with PAH. OBJECTIVES: Here we use both imatinib and knockout animals to determine the relationship between platelet-derived growth factor receptor (PDGFR) and serotonin signaling and investigate the PAH pathologies each mediates. METHODS: We investigated the effects of imatinib (100 mg/kg) on hemodynamics, vascular remodeling, and downstream molecular signatures in the chronic hypoxia/SU5416 murine model of PAH. MEASUREMENTS AND MAIN RESULTS: Treatment with imatinib reduced all measures of PAH pathology observed in hypoxia/SU5416 mice. In addition, 5-hydroxytryptamine (5-HT) and tryptophan hydroxylase 1 (Tph1) expression were reduced compared with the normoxia/SU5416 control group. Imatinib attenuated hypoxia-induced increases in Tph1 expression in pulmonary endothelial cells in vitro via inhibition of the PDGFR-beta pathway. To better understand the consequences of this novel mode of action for imatinib, we examined the development of PAH after hypoxic/SU5416 exposure in Tph1 deficient mice (Tph1(-/-)). The extensive changes in pulmonary vascular remodeling and hemodynamics in response to hypoxia/SU5416 were attenuated in Tph1(-/-) mice and further decreased after imatinib treatment. However, imatinib did not significantly further impact collagen deposition and collagen 3a1 expression in hypoxic Tph1(-/-) mice. Post hoc subgroup analysis suggests that patients with PAH with greater hemodynamic impairment showed significantly reduced 5-HT plasma levels after imatinib treatment compared with placebo. CONCLUSIONS: We report a novel mode of action for imatinib, demonstrating TPH1 down-regulation via inhibition of PDGFR-beta signaling. Our data reveal interplay between PDGF and 5-HT pathways within PAH, demonstrating TPH1-dependent imatinib efficacy in collagen-mediated mechanisms of fibrosis. PMID- 23087026 TI - High levels of virus-specific CD4+ T cells predict severe pandemic influenza A virus infection. AB - RATIONALE: T-cell responses have been implicated in control and exacerbation of lung injury during influenza A virus (IAV) infection. OBJECTIVES: To examine the breadth and magnitude of influenza-specific CD4(+) and CD8(+) T-cell responses during acute phase of infection. METHODS: Influenza-specific T-cell response to the entire pandemic H1N1/09 IAV proteome and T cell-related cytokine levels were measured in blood from previously healthy individuals with mild (n = 32) and severe (n = 16) IAV infection during the 2009 influenza pandemic. Virus-specific T-cell response in lung and blood was also performed in two acutely infected, severely ill patients using fluorescent-conjugated pdmH1N1/09 Matrix-MHC-I tetrameric complexes. MEASUREMENTS AND MAIN RESULTS: Strong and broad CD4(+) but not CD8(+) T-cell responses were observed in the blood, and were higher in those with severe disease. Antigen-specific CD8(+) T cells in the lungs were on average 45-fold higher compared with blood in severely ill patients. Paradoxically, in patients with severe disease, IL-17, IL-2, IL-4, and IFN-gamma levels were significantly decreased. CONCLUSIONS: High levels of circulating virus-specific CD4(+) T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection are associated with subsequent development of severe IAV infection. This finding could be an early and specific marker for ensuing clinical deterioration. Contrasting levels of antigen-specific CD8(+) T cells in lungs and blood have implications on design and analysis of clinical trials for T cell vaccines because measurements of T cells in the periphery may not reflect events in the lungs. PMID- 23087027 TI - Genotype MTBDRsl line probe assay shortens time to diagnosis of extensively drug resistant tuberculosis in a high-throughput diagnostic laboratory. AB - RATIONALE: Conventional culture-based drug susceptibility testing (DST) for the second-line antituberculosis drugs is slow, leading to diagnostic delay with associated exacerbation of transmission, amplification of resistance, and increased mortality. OBJECTIVES: To assess the diagnostic performance of the GenoType MTBDRsl line probe assay (LPA) for the rapid detection of mutations conferring resistance to ofloxacin (OFX), amikacin (AMK), and ethambutol and to determine the impact of implementation on the turnaround time in a high throughput diagnostic laboratory. METHODS: Six hundred and fifty-seven direct patient acid-fast bacilli smear-positive specimens resistant to isoniazid, rifampin, or both according to the GenoType MTBDRplus assay were consecutively tested, using the GenoType MTBDRsl LPA. The diagnostic performance was assessed relative to the "gold standard" culture-based method, and the laboratory turnaround times for both methods were determined. MEASUREMENTS AND MAIN RESULTS: A total of 516 of 657 patient specimens had valid results for both tests. The sensitivity for detecting OFX, AMK, and extensive drug resistance, using the GenoType MTBDRsl LPA, was 90.7% (95% confidence interval [CI], 80.1-96.0%), 100% (95% CI, 91.8-100%), and 92.3% (95% CI, 75.9-97.9%), respectively, and the specificity for detection was 98.1% (95% CI, 96.3-99.0%), 99.4% (95% CI, 98.2 99.8%), and 99.6% (95% CI, 98.5-99.9%), respectively. Implementation of this test significantly reduced the turnaround time by 93.3% (P < 0.001), calculated from the date that the specimen was received at the laboratory to reporting second line results. In addition, a significant increase in diagnostic yield of 20.1% and 19.3% (P < 0.001) for OFX and AMK resistance, respectively, was obtained for isolates that were either contaminated or had lost viability. CONCLUSIONS: The GenoType MTBDRsl LPA is a rapid and reliable DST that can be easily incorporated into the diagnostic algorithm. This assay significantly improved diagnostic yield (P < 0.001) while simultaneously decreasing diagnostic delay for reporting second line DST. The rapid dissemination of second-line DST results will guide initiation of appropriate treatment, thereby reducing transmission and improving treatment outcome. PMID- 23087028 TI - Severe sepsis in pre-hospital emergency care: analysis of incidence, care, and outcome. AB - RATIONALE: Severe sepsis is common and highly morbid, yet the epidemiology of severe sepsis at the frontier of the health care system-pre-hospital emergency care-is unknown. OBJECTIVES: We examined the epidemiology of pre-hospital severe sepsis among emergency medical services (EMS) encounters, relative to acute myocardial infarction and stroke. METHODS: Retrospective study using a community based cohort of all nonarrest, nontrauma King County EMS encounters from 2000 to 2009 who were transported to a hospital. MEASUREMENTS AND MAIN RESULTS: Overall incidence rate of hospitalization with severe sepsis among EMS encounters, as well as pre-hospital characteristics, admission diagnosis, and outcomes. Among 407,176 EMS encounters, we identified 13,249 hospitalizations for severe sepsis, of whom 2,596 died in the hospital (19.6%). The crude incidence rate of severe sepsis was 3.3 per 100 EMS encounters, greater than for acute myocardial infarction or stroke (2.3 per 100 and 2.2 per 100 EMS encounters, respectively). More than 40% of all severe sepsis hospitalizations arrived at the emergency department after EMS transport, and 80% of cases were diagnosed on admission. Pre hospital care intervals, on average, exceeded 45 minutes for those hospitalized with severe sepsis. One-half or fewer of patients with severe sepsis were transported by paramedics (n = 7,114; 54%) or received pre-hospital intravenous access (n = 4,842; 37%). CONCLUSIONS: EMS personnel care for a substantial and increasing number of patients with severe sepsis, and spend considerable time on scene and during transport. Given the emphasis on rapid diagnosis and intervention for sepsis, the pre-hospital interval may represent an important opportunity for recognition and care of sepsis. PMID- 23087029 TI - Co-occurring anammox, denitrification, and codenitrification in agricultural soils. AB - Anammox and denitrification mediated by bacteria are known to be the major microbial processes converting fixed N to N(2) gas in various ecosystems. Codenitrification and denitrification by fungi are additional pathways producing N(2) in soils. However, fungal codenitrification and denitrification have not been well investigated in agricultural soils. To evaluate bacterial and fungal processes contributing to N(2) production, molecular and (15)N isotope analyses were conducted with soil samples collected at six different agricultural fields in the United States. Denitrifying and anammox bacterial abundances were measured based on quantitative PCR (qPCR) of nitrous oxide reductase (nosZ) and hydrazine oxidase (hzo) genes, respectively, while the internal transcribed spacer (ITS) of Fusarium oxysporum was quantified to estimate the abundance of codenitrifying and denitrifying fungi. (15)N tracer incubation experiments with (15)NO(3)(-) or (15)NH(4)(+) addition were conducted to measure the N(2) production rates from anammox, denitrification, and codenitrification. Soil incubation experiments with antibiotic treatments were also used to differentiate between fungal and bacterial N(2) production rates in soil samples. Denitrifying bacteria were found to be the most abundant, followed by F. oxysporum based on the qPCR assays. The potential denitrification rates by bacteria and fungi ranged from 4.118 to 42.121 nmol N(2)-N g(-1) day(-1), while the combined potential rates of anammox and codenitrification ranged from 2.796 to 147.711 nmol N(2)-N g(-1) day(-1). Soil incubation experiments with antibiotics indicated that fungal codenitrification was the primary process contributing to N(2) production in the North Carolina soil. This study clearly demonstrates the importance of fungal processes in the agricultural N cycle. PMID- 23087030 TI - Gray mold populations in german strawberry fields are resistant to multiple fungicides and dominated by a novel clade closely related to Botrytis cinerea. AB - The gray mold fungus Botrytis cinerea is a major threat to fruit and vegetable production. Strawberry fields usually receive several fungicide treatments against Botrytis per season. Gray mold isolates from several German strawberry growing regions were analyzed to determine their sensitivity against botryticides. Fungicide resistance was commonly observed, with many isolates possessing resistance to multiple (up to six) fungicides. A stronger variant of the previously described multidrug resistance (MDR) phenotype MDR1, called MDR1h, was found to be widely distributed, conferring increased partial resistance to two important botryticides, cyprodinil and fludioxonil. A 3-bp deletion mutation in a transcription factor-encoding gene, mrr1, was found to be correlated with MDR1h. All MDR1h isolates and the majority of isolates with resistance to multiple fungicides were found to be genetically distinct. Multiple-gene sequencing confirmed that they belong to a novel clade, called Botrytis group S, which is closely related to B. cinerea and the host-specific species B. fabae. Isolates of Botrytis group S genotypes were found to be widespread in all German strawberry-growing regions but almost absent from vineyards. Our data indicate a clear subdivision of gray mold populations, which are differentially distributed according to their host preference and adaptation to chemical treatments. PMID- 23087031 TI - Specific detection and localization of microsporidian parasites in invertebrate hosts by using in situ hybridization. AB - We designed fluorescence in situ hybridization probes for two distinct microsporidian clades and demonstrated their application in detecting, respectively, Nosema/Vairimorpha and Dictyoceola species. We used them to study the vertical transmission of two microsporidia infecting the amphipod Gammarus duebeni. PMID- 23087032 TI - Development of quantitative PCR assays targeting the 16S rRNA genes of Enterococcus spp. and their application to the identification of enterococcus species in environmental samples. AB - The detection of environmental enterococci has been determined primarily by using culture-based techniques that might exclude some enterococcal species as well as those that are nonculturable. To address this, the relative abundances of enterococci were examined by challenging fecal and water samples against a currently available genus-specific assay (Entero1). To determine the diversity of enterococcal species, 16S rRNA gene-based group-specific quantitative PCR (qPCR) assays were developed and evaluated against eight of the most common environmental enterococcal species. Partial 16S rRNA gene sequences of 439 presumptive environmental enterococcal strains were analyzed to study further the diversity of enterococci and to confirm the specificities of group-specific assays. The group-specific qPCR assays showed relatively high amplification rates with targeted species (>98%), although some assays cross-amplified with nontargeted species (1.3 to 6.5%). The results with the group-specific assays also showed that different enterococcal species co-occurred in most fecal samples. The most abundant enterococci in water and fecal samples were Enterococcus faecalis and Enterococcus faecium, although we identified more water isolates as Enterococcus casseliflavus than as any of the other species. The prevalence of the Entero1 marker was in agreement with the combined number of positive signals determined by the group-specific assays in most fecal samples, except in gull feces. On the other hand, the number of group-specific assay signals was lower in all water samples tested, suggesting that other enterococcal species are present in these samples. While the results highlight the value of genus- and group-specific assays for detecting the major enterococcal groups in environmental water samples, additional studies are needed to determine further the diversity, distributions, and relative abundances of all enterococcal species found in water. PMID- 23087033 TI - Relationship between abundance and specific activity of bacterioplankton in open ocean surface waters. AB - Marine microbial communities are complex and dynamic, and their ecology impacts biogeochemical cycles in pelagic ecosystems. Yet, little is known about the relative activities of different microbial populations within genetically diverse communities. We used rRNA as a proxy for activity to quantify the relative specific activities (rRNA/ribosomal DNA [rDNA or rRNA genes]) of the eubacterial populations and to identify locations or clades for which there are uncouplings between specific activity and abundance. After analyzing 1.6 million sequences from 16S rDNA and rRNA (cDNA) libraries from two euphotic depths from a representative site in the Pacific Ocean, we show that although there is an overall positive relationship between the abundances (rDNAs) and activities (rRNAs) among populations of the bacterial community, for some populations these measures are uncoupled. Different ecological strategies are exemplified by the two numerically dominant clades at this site: the cyanobacterium Prochlorococcus is abundant but disproportionately more active, while the heterotrophic SAR11 is abundant but less active. Other rare populations, such as Alteromonas, have high specific activities in spite of their low abundances, suggesting intense population regulation. More detailed analyses using a complementary quantitative PCR (qPCR)-based approach of measuring relative specific activity for Prochlorococcus populations in the Pacific and Atlantic Oceans also show that specific activity, but not abundance, reflects the key drivers of light and nutrients in this system; our results also suggest substantial top-down regulation (e.g., grazing, viruses, or organismal interactions) or transport (e.g., mixing, immigration, or emigration) of these populations. Thus, we show here that abundance and specific activity can be uncoupled in open ocean systems and that describing both is critical to characterizing microbial communities and predicting marine ecosystem functioning and responses to change. PMID- 23087034 TI - Biochemical properties and crystal structure of a beta-phenylalanine aminotransferase from Variovorax paradoxus. AB - By selective enrichment, we isolated a bacterium that can use beta-phenylalanine as a sole nitrogen source. It was identified by 16S rRNA gene sequencing as a strain of Variovorax paradoxus. Enzyme assays revealed an aminotransferase activity. Partial genome sequencing and screening of a cosmid DNA library resulted in the identification of a 1,302-bp aminotransferase gene, which encodes a 46,416-Da protein. The gene was cloned and overexpressed in Escherichia coli. The recombinant enzyme was purified and showed a specific activity of 17.5 U mg( 1) for (S)-beta-phenylalanine at 30 degrees C and 33 U mg(-1) at the optimum temperature of 55 degrees C. The beta-specific aminotransferase exhibits a broad substrate range, accepting ortho-, meta-, and para-substituted beta-phenylalanine derivatives as amino donors and 2-oxoglutarate and pyruvate as amino acceptors. The enzyme is highly enantioselective toward (S)-beta-phenylalanine (enantioselectivity [E], >100) and derivatives thereof with different substituents on the phenyl ring, allowing the kinetic resolution of various racemic beta-amino acids to yield (R)-beta-amino acids with >95% enantiomeric excess (ee). The crystal structures of the holoenzyme and of the enzyme in complex with the inhibitor 2-aminooxyacetate revealed structural similarity to the beta-phenylalanine aminotransferase from Mesorhizobium sp. strain LUK. The crystal structure was used to rationalize the stereo- and regioselectivity of V. paradoxus aminotransferase and to define a sequence motif with which new aromatic beta-amino acid-converting aminotransferases may be identified. PMID- 23087035 TI - Colonization of Campylobacter spp. in broiler chickens and laying hens reared in tropical climates with low-biosecurity housing. AB - The onset and prevalence of Campylobacter colonization in broilers and layers at commercial farms with low biosecurity in tropical climates were tested. Despite the presence of positive animals at the same farms, the broiler flocks tested negative until, on average, 21 days. Prelaying flocks showed a higher prevalence than laying flocks. PMID- 23087036 TI - Identification of a residue affecting fatty alcohol selectivity in wax ester synthase. AB - The terminal enzyme in the bacterial wax ester biosynthetic pathway is the bifunctional wax ester synthase/acyl-coenzyme A:diacylglycerol acyltransferase (WS/DGAT), which utilizes a fatty alcohol and a fatty acyl-coenzyme A (CoA) to synthesize the corresponding wax ester. In this report, we identify a specific residue in WS/DGAT enzymes obtained from Marinobacter aquaeolei VT8 and Acinetobacter baylyi that alters fatty alcohol selectivity and kinetic parameters when modified to alternative residues. PMID- 23087037 TI - Development and evaluation of EPA method 1615 for detection of enterovirus and norovirus in water. AB - The U.S. EPA developed a sample concentration and preparation assay in conjunction with the total culturable virus assay for concentrating and measuring culturable viruses in source and drinking waters as part of the Information Collection Rule (ICR) promulgated in 1996. In an effort to improve upon this method, the U.S. EPA recently developed Method 1615: Measurement of Enterovirus and Norovirus Occurrence in Water by Culture and RT-qPCR. Method 1615 uses a culturable virus assay with reduced equipment and labor costs compared to the costs associated with the ICR virus method and introduces a new molecular assay for the detection of enteroviruses and noroviruses by reverse transcription quantitative PCR. In this study, we describe the optimization of several new components of the molecular assay and examine virus recovery from ground, reagent grade, and surface water samples seeded with poliovirus type 3 and murine norovirus. For the culturable virus and molecular assays, mean poliovirus recovery using the complete method was 58% and 20% in groundwater samples, 122% and 39% using low-titer spikes in reagent-grade water, 42% and 48% using high titer spikes in reagent-grade water, and 11% and 10% in surface water with high turbidity, respectively. Murine norovirus recovery by the molecular assay was 30% in groundwater samples, less than 8% in both low- and high-titer spikes in reagent-grade water, and 6% in surface water with high turbidity. This study demonstrates the effectiveness of Method 1615 for use with groundwater samples and highlights the need for further research into its effectiveness with surface water. PMID- 23087038 TI - Behavior of different Shiga toxin-producing Escherichia coli serotypes in various experimentally contaminated raw-milk cheeses. AB - Shiga toxin-producing Escherichia coli (STEC) is an important cause of food-borne illness. The public health implication of the presence of STEC in dairy products remains unclear. Knowledge of STEC behavior in cheeses would help to evaluate the human health risk. The aim of our study was to observe the growth and survival of experimentally inoculated STEC strains in raw-milk cheeses manufactured and ripened according to five technological schemes: blue-type cheese, uncooked pressed cheese with long ripening and with short ripening steps, cooked cheese, and lactic cheese. Cheeses were contaminated with different STEC serotypes (O157:H7, O26:H11, O103:H2, and O145:H28) at the milk preparation stage. STEC growth and survival were monitored on selective media during the entire manufacturing process. STEC grew (2 to 3 log(10) CFU . g(-1)) in blue-type cheese and the two uncooked pressed cheeses during the first 24 h of cheese making. Then, STEC levels progressively decreased in cheeses that were ripened for more than 6 months. In cooked cheese and in lactic cheese with a long acidic coagulation step (pH < 4.5), STEC did not grow. Their levels decreased after the cooking step in the cooked cheese and after the coagulation step in the lactic cheese, but STEC was still detectable at the end of ripening and storage. A serotype effect was found: in all cheeses studied, serotype O157:H7 grew less strongly and was less persistent than the others serotypes. This study improves knowledge of the behavior of different STEC serotypes in various raw-milk cheeses. PMID- 23087040 TI - Improved recovery of Bacillus spores from nonporous surfaces with cotton swabs over foam, nylon, or polyester, and the role of hydrophilicity of cotton in governing the recovery efficiency. AB - Evaluating different swabbing materials for spore recovery efficiency (RE) from steel surfaces, we recorded the maximum RE (71%) of 10(7) Bacillus subtilis spores with Tulips cotton buds, followed by Johnson's cotton buds and standard Hi Media cotton, polyester, nylon, and foam (23%) swabs. Among cotton swabs, instant water-absorbing capacity or the hydrophilicity index appeared to be the major indicator of RE, as determined by testing three more brands. Tulips swabs worked efficiently across diverse nonporous surfaces and on different Bacillus spp., registering 65 to 77% RE. PMID- 23087039 TI - Polycyclovorans algicola gen. nov., sp. nov., an aromatic-hydrocarbon-degrading marine bacterium found associated with laboratory cultures of marine phytoplankton. AB - A strictly aerobic, halotolerant, rod-shaped bacterium, designated strain TG408, was isolated from a laboratory culture of the marine diatom Skeletonema costatum (CCAP1077/1C) by enrichment with polycyclic aromatic hydrocarbons (PAHs) as the sole carbon source. 16S rRNA gene sequence analysis placed this organism within the order Xanthomonadales of the class Gammaproteobacteria. Its closest relatives included representatives of the Hydrocarboniphaga-Nevskia-Sinobacter clade (<92% sequence similarity) in the family Sinobacteraceae. The strain exhibited a narrow nutritional spectrum, preferring to utilize aliphatic and aromatic hydrocarbon compounds and small organic acids. Notably, it displayed versatility in degrading two- and three-ring PAHs. Moreover, catechol 2,3-dioxygenase activity was detected in lysates, indicating that this strain utilizes the meta-cleavage pathway for aromatic compound degradation. Cells produced surface blebs and contained a single polar flagellum. The predominant isoprenoid quinone of strain TG408 was Q-8, and the dominant fatty acids were C(16:0), C(16:1) omega7c, and C(18:1) omega7c. The G+C content of the isolate's DNA was 64.3 mol% +/- 0.34 mol%. On the basis of distinct phenotypic and genotypic characteristics, strain TG408 represents a novel genus and species in the class Gammaproteobacteria for which the name Polycyclovorans algicola gen. nov., sp. nov., is proposed. Quantitative PCR primers targeting the 16S rRNA gene of this strain were developed and used to show that this organism is found associated with other species of marine phytoplankton. Phytoplankton may be a natural biotope in the ocean where new species of hydrocarbon-degrading bacteria await discovery and which contribute significantly to natural remediation processes. PMID- 23087042 TI - Form and function of Clostridium thermocellum biofilms. AB - The importance of bacterial adherence has been acknowledged in microbial lignocellulose conversion studies; however, few reports have described the function and structure of biofilms supported by cellulosic substrates. We investigated the organization, dynamic formation, and carbon flow associated with biofilms of the obligately anaerobic cellulolytic bacterium Clostridium thermocellum 27405. Using noninvasive, in situ fluorescence imaging, we showed biofilms capable of near complete substrate conversion with a characteristic monolayered cell structure without an extracellular polymeric matrix typically seen in biofilms. Cell division at the interface and terminal endospores appeared throughout all stages of biofilm growth. Using continuous-flow reactors with a rate of dilution (2 h(-1)) 12-fold higher than the bacterium's maximum growth rate, we compared biofilm activity under low (44 g/liter) and high (202 g/liter) initial cellulose loading. The average hydrolysis rate was over 3-fold higher in the latter case, while the proportions of oligomeric cellulose hydrolysis products lost from the biofilm were 13.7% and 29.1% of the total substrate carbon hydrolyzed, respectively. Fermentative catabolism was comparable between the two cellulose loadings, with ca. 4% of metabolized sugar carbon being utilized for cell production, while 75.4% and 66.7% of the two cellulose loadings, respectively, were converted to primary carbon metabolites (ethanol, acetic acid, lactic acid, carbon dioxide). However, there was a notable difference in the ethanol-to-acetic acid ratio (g/g), measured to be 0.91 for the low cellulose loading and 0.41 for the high cellulose loading. The results suggest that substrate availability for cell attachment rather than biofilm colonization rates govern the efficiency of cellulose conversion. PMID- 23087041 TI - Depth-related differences in organic substrate utilization by major microbial groups in intertidal marine sediment. AB - Stable isotope probing of magnetic-bead-captured rRNA (Mag-SIP) indicated clear differences in in situ organic substrate utilization by major microbial groups between the more oxidized (0 to 2 cm) and sulfate-reducing (2 to 5 cm) horizons of marine intertidal sediment. We also showed that cyanobacteria and diatoms may survive by glucose utilization under dark anoxic conditions. PMID- 23087043 TI - Structure and ecological roles of a novel exopolysaccharide from the arctic sea ice bacterium Pseudoalteromonas sp. Strain SM20310. AB - The structure and ecological roles of the exopolysaccharides (EPSs) from sea ice microorganisms are poorly studied. Here we show that strain SM20310, with an EPS production of 567 mg liter(-1), was screened from 110 Arctic sea ice isolates and identified as a Pseudoalteromonas strain. The EPS secreted by SM20310 was purified, and its structural characteristics were studied. The predominant repeating unit of this EPS is a highly complicated alpha-mannan with a molecular mass greater than 2 * 10(6) Da. The backbone of the EPS consists of 2-alpha-, 6 alpha-mannosyl residues, in which a considerable part of the 6-alpha-mannosyl residues are branched at the 2 position with either single t-mannosyl residues or two mannosyl residues. The structure of the described EPS is different from the structures of EPSs secreted by other marine bacteria. Analysis of the ecological roles of the identified EPS showed that the EPS could significantly enhance the high-salinity tolerance of SM20310 and improve the survival of SM20310 after freeze-thaw cycles. These results suggest that the EPS secreted by strain SM20310 enables the strain to adapt to the sea ice environment, which is characterized by low temperature, high salinity, and repeated freeze-thaw cycles. In addition to its functions in strain SM20310, this EPS also significantly improved the tolerance of Escherichia coli to freeze-thaw cycles, suggesting that it may have a universal impact on microorganism cryoprotection. PMID- 23087044 TI - Immunohistochemical analysis of IA-2 family of protein tyrosine phosphatases in rat gastrointestinal endocrine cells. AB - Islet-associated protein-2 (IA-2) and IA-2beta (also known as phogrin) are unique neuroendocrine-specific protein tyrosine phosphatases (PTPs). The IA-2 family of PTPs was originally identified from insulinoma cells and discovered to be major autoantigens in type 1 diabetes. Despite its expression in the neural and canonical endocrine tissues, data on expression of the IA-2 family of PTPs in gastrointestinal endocrine cells (GECs) are limited. Therefore, we immunohistochemically investigated the expression of the IA-2 family of PTPs in the rat gastrointestinal tract. In the stomach, IA-2 and IA-2beta were expressed in GECs that secrete serotonin, somatostatin, and cholecystokinin/gastrin-1. In addition to these hormones, secretin, gastric inhibitory polypeptide (also known as the glucose-dependent insulinotropic peptide), glucagon-like peptide-1, and glucagon, but not ghrelin were coexpressed with IA-2 or IA-2beta in duodenal GECs. Pancreatic islet cells that secrete gut hormones expressed the IA-2 family of PTPs. The expression patterns of IA-2 and IA-2beta were comparable. These results reveal that the IA-2 family of PTPs is expressed in a cell type-specific manner in rat GECs. The extensive expression of the IA-2 family of PTPs in pancreo-gastrointestinal endocrine cells and in the enteric plexus suggests their systemic contribution to nutritional control through a neuroendocrine signaling network. PMID- 23087046 TI - Scale, nature, preventability and causes of adverse events in hospitalised older patients. AB - OBJECTIVE: to gain insight into the scale, nature, preventability and causes of adverse events in hospitalised older patients. DESIGN: a three-stage retrospective, structured, medical record review study of 7,917 records of patients admitted in 21 Dutch hospitals in 2004. MAIN OUTCOME MEASURES: incidence, preventability, clinical process category, consequences and causes of adverse events in hospitalised patients of 65 years and older, compared with patients younger than 65. RESULTS: adverse events and preventable adverse events occur significantly more often in older patients [6.9% (95% CI: 5.9-8.0%) and 2.9% (95% CI: 2.3-3.7%), respectively] than in younger patients [4.8% (95% CI: 4.0-5.7%) and 1.8% (95% CI: 1.3-2.4%), respectively]. In older patients, the adverse events were more often related to medication (20.1 versus 9.6%) (P < 0.01). An exploration of the causes revealed that the inability to apply existing knowledge to a new and complex situation contributes more often to the occurrence of adverse events in older patients than in younger patients (36.4 versus 24.3%) (P < 0.05). CONCLUSION: to reduce the number of adverse events in older patients in the future, more particular training of hospital staff in geriatric medicine is required, with a specific focus on medication. PMID- 23087045 TI - Inhibition of rho kinase enhances survival of dopaminergic neurons and attenuates axonal loss in a mouse model of Parkinson's disease. AB - Axonal degeneration is one of the earliest features of Parkinson's disease pathology, which is followed by neuronal death in the substantia nigra and other parts of the brain. Inhibition of axonal degeneration combined with cellular neuroprotection therefore seem key to targeting an early stage in Parkinson's disease progression. Based on our previous studies in traumatic and neurodegenerative disease models, we have identified rho kinase as a molecular target that can be manipulated to disinhibit axonal regeneration and improve survival of lesioned central nervous system neurons. In this study, we examined the neuroprotective potential of pharmacological rho kinase inhibition mediated by fasudil in the in vitro 1-methyl-4-phenylpyridinium cell culture model and in the subchronic in vivo 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Application of fasudil resulted in a significant attenuation of dopaminergic cell loss in both paradigms. Furthermore, dopaminergic terminals were preserved as demonstrated by analysis of neurite network in vitro, striatal fibre density and by neurochemical analysis of the levels of dopamine and its metabolites in the striatum. Behavioural tests demonstrated a clear improvement in motor performance after fasudil treatment. The Akt survival pathway was identified as an important molecular mediator for neuroprotective effects of rho kinase inhibition in our paradigm. We conclude that inhibition of rho kinase using the clinically approved small molecule inhibitor fasudil may be a promising new therapeutic strategy for Parkinson's disease. PMID- 23087047 TI - Benign breast disease and the risk of subsequent breast cancer in African American women. AB - Benign breast disease (BBD) is an established risk factor for breast cancer among Caucasian women but less is known about BBD in African American women. As African American women suffer from disproportionate mortality due to breast cancer, special focus on pathologic characteristics that may influence disease risk is warranted. Benign breast biopsies from African American women were identified by the University Pathology Group (Detroit, MI). African American women of ages 20 to 84 years, who underwent a breast biopsy from 1997 to 2000, were eligible for the study. Subsequent breast cancers were identified through a linkage with the Detroit Surveillance Epidemiology and End Results (SEER) program. The first biopsy was reviewed by the pathologist, and lesions were classified following Dupont and Page criteria along with involution and other histologic features. Logistic regression was used to estimate the risk of developing a subsequent breast cancer with the histologic characteristics of BBD. A total of 1,406 BBD biopsies from African American women were included in this study with a median follow-up of 10.1 years. The majority (68%) showed nonproliferative disease, 29% had proliferative disease without atypia, and 3% had proliferative disease with atypia. Subsequent incident breast cancers occurred in 55 women (3.9%). Women whose biopsies showed proliferative disease with atypia were more than three-fold more likely to develop breast cancer as compared with women who had nonproliferative disease [relative risk (RR) 3.29, 95% confidence interval (CI) 1.21-8.93]. Better characterization of the risk of breast cancer among women with BBD, considering both ethnicity and detailed molecular findings, can lead to better surveillance, earlier diagnosis, and potentially improved survival. PMID- 23087048 TI - Characterizing the molecular spatial and temporal field of injury in early-stage smoker non-small cell lung cancer patients after definitive surgery by expression profiling. AB - Gene expression alterations in response to cigarette smoke have been characterized in normal-appearing bronchial epithelium of healthy smokers, and it has been suggested that adjacent histologically normal tissue displays tumor associated molecular abnormalities. We sought to delineate the spatial and temporal molecular lung field of injury in smoker patients with early-stage non small cell lung cancer (NSCLC; n = 19) who were accrued into a surveillance clinical trial for annual follow-up and bronchoscopies within 1 year after definitive surgery. Bronchial brushings and biopsies were obtained from six different sites in the lung at the time of inclusion in the study and at 12, 24, and 36 months after the first time point. Affymetrix Human Gene 1.0 ST arrays were used for whole-transcript expression profiling of airways (n = 391). Microarray analysis identified gene features (n = 1,165) that were nonuniform by site and differentially expressed between airways adjacent to tumors relative to more distant samples as well as those (n = 1,395) that were significantly altered with time up to 3 years. In addition, gene interaction networks mediated by phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK)1/2 were modulated in adjacent compared with contralateral airways and the latter network with time. Furthermore, phosphorylated AKT and ERK1/2 immunohistochemical expression were significantly increased with time (nuclear pAKT, P = 0.03; cytoplasmic pAKT, P < 0.0001; pERK1/2, P = 0.02) and elevated in adjacent compared with more distant airways (nuclear pAKT, P = 0.04; pERK1/2, P = 0.03). This study highlights spatial and temporal cancer-associated expression alterations in the molecular field of injury of patients with early-stage NSCLCs after definitive surgery that warrant further validation in independent studies. PMID- 23087049 TI - Raf-1, actin dynamics, and abelson tyrosine kinase in human airway smooth muscle cells. AB - Raf-1 is a serine/threonine protein kinase that has an essential role in cell proliferation. The mechanisms that regulate Raf-1 in airway smooth muscle are not well understood. In this study, treatment with platelet-derived growth factor (PDGF) induced spatial redistribution of Raf-1 from the cytoplasm to the periphery of human airway smooth muscle cells. Moreover, a pool of Raf-1 was found in F-actin of human airway smooth muscle cells. Activation with PDGF led to an increase in the association of Raf-1 with cytoskeletal actin. Treatment of cells with the actin polymerization inhibitor latrunculin A (LAT-A), but not the microtubule depolymerizer nocodazole, inhibited the interaction of Raf-1 with actin in response to PDGF activation. Because abelson tyrosine kinase (Abl) is known to specifically regulate actin dynamics in smooth muscle, the role of Abl in modulating the coupling of Raf-1 with actin was also evaluated. Abl knockdown by RNA interference attenuated the association of Raf-1 with actin, which is recovered by Abl rescue. Treatment with LAT-A, but not nocodazole, inhibited the spatial redistribution of Raf-1 during PDGF activation. However, treatment with both LAT-A and nocodazole attenuated smooth muscle cell proliferation. Finally, Abl knockdown attenuated the redistribution of Raf-1 and cell proliferation, which were restored by Abl reexpression. The results suggest a novel mechanism that the interaction of Raf-1 with cytoskeletal actin is critical for Raf-1 redistribution and airway smooth muscle cell proliferation during activation with the growth factor. PMID- 23087050 TI - High Mobility Group Box-1 mediates hyperoxia-induced impairment of Pseudomonas aeruginosa clearance and inflammatory lung injury in mice. AB - Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, a significant number of patients on ventilators exhibit enhanced susceptibility to infections and develop ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most common species of bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AMs), an essential part of the innate immunity, to phagocytose PA. This study sought to investigate the potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a murine model of PA pneumonia. Here, we show that exposure to hyperoxia (>= 99% O2) led to a significant elevation in concentrations of airway high mobility group box-1 (HMGB1) and increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with a neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and numbers of neutrophils in the lungs, and an increase in leukocyte phagocytic activity compared with mice receiving control mAb. This improved phagocytic function was associated with reduced concentrations of airway HMGB1. The correlation between phagocytic activity and concentrations of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment with regard to a host's ability to clear bacteria and inflammatory lung injury. Thus, HMGB1 may provide a novel molecular target for improving hyperoxia-compromised innate immunity in patients with VAP. PMID- 23087051 TI - Retinoic acid rescues alveolar hypoplasia in the calorie-restricted developing rat lung. AB - Infants born with intrauterine growth retardation (IUGR) are at increased risk of adverse pulmonary outcomes at birth, including meconium aspiration and persistent pulmonary hypertension. Preterm infants with IUGR are at especially high risk of developing bronchopulmonary dysplasia (BPD), a disease hallmarked by alveolar hypoplasia. Although vitamin A supplementation has been shown to decrease the incidence of BPD or death in preterm very low birth weight infants, its potential to reduce BPD or death in preterm infants with IUGR remains unknown. We used a well-characterized rat model of caloric restriction to mimic IUGR and determine the impact of IUGR on lung development. We hypothesized that retinoic acid treatment would preserve alveolar formation through increases in key signaling molecules of the retinoic acid signaling pathway. Our results showed that alveolar hypoplasia caused by caloric restriction can be reversed with refeeding, and that retinoic acid prevents the alveolar hypoplasia coincident with the increased expression of elastin and retinoic acid receptor-alpha and decreased transforming growth factor-beta activity in developing rat lungs. These findings suggest that alveolar hypoplasia attributable to caloric restriction is reversible, and raises the possibility that retinoic acid therapy may prove a useful strategy to prevent adverse pulmonary sequelae such as BPD in preterm infants with IUGR. PMID- 23087053 TI - Hypoxia-induced inflammation in the lung: a potential therapeutic target in acute lung injury? AB - Acute lung injury (ALI) is a severe form of hypoxic lung disease responsible for a large number of deaths worldwide. Despite recent advances in supportive care, no reduction in mortality has been evident since the introduction of a standard consensus definition almost two decades ago. New strategies are urgently required to help design effective therapies for this condition. A key pathological feature of ALI involves regional alveolar hypoxia. Because alveolar hypoxia in isolation, such as that encountered at high altitude, causes an inflammatory pulmonary phenotype in the absence of any other pathogenic stimuli, these regions may not be passive bystanders but may actually contribute to the pathogenesis and progression of lung injury. Unique transcriptional responses to hypoxia in the lung apparently allow it to express an inflammatory phenotype at levels of hypoxia that would not produce such a response in other organs. We will review recent advances in our understanding of these unique transcriptional responses to moderate levels of alveolar hypoxia, which may provide new insights into the pathogenesis of ALI. PMID- 23087052 TI - Humoral immunity and the development of obliterative bronchiolitis after lung transplantation: is there a link? AB - Lung transplantation is considered the definitive treatment for many end-stage lung diseases. However, the lung is rejected more commonly than other solid organ allografts. Obliterative bronchiolitis (OB) is the leading cause of chronic allograft dysfunction, and the key reason why the 5-year survival of lung transplant recipients is only 50%. The pathophysiology of OB is incompletely understood. Although a clear role for the immune response to donor antigens has been observed (also known as anti-human leukocyte antigens), evidence is emerging about the role of autoimmunity to self-antigens. This review highlights the current understanding of humoral immunity in the development of OB after lung transplantation. PMID- 23087054 TI - Radical-containing ultrafine particulate matter initiates epithelial-to mesenchymal transitions in airway epithelial cells. AB - Environmentally persistent free radicals (EPFRs) in combustion-generated particulate matter (PM) are capable of inducing pulmonary pathologies and contributing to the development of environmental asthma. In vivo exposure of infant rats to EPFRs demonstrates their ability to induce airway hyperresponsiveness to methacholine, a hallmark of asthma. However, the mechanisms by which combustion-derived EPFRs elicit in vivo responses remain elusive. In this study, we used a chemically defined EPFR consisting of approximately 0.2 MUm amorphrous silica containing 3% cupric oxide with the organic pollutant 1,2-dichlorobenzene (DCB-230). DCB-230 possesses similar radical content to urban-collected EPFRs but offers several advantages, including lack of contaminants and chemical uniformity. DCB-230 was readily taken up by BEAS-2B and at high doses (200 MUg/cm(2)) caused substantial necrosis. At low doses (20 MUg/cm(2)), DCB-230 particles caused lysosomal membrane permeabilization, oxidative stress, and lipid peroxidation within 24 hours of exposure. During this period, BEAS-2B underwent epithelial-to-mesenchymal transition (EMT), including loss of epithelial cell morphology, decreased E cadherin expression, and increased alpha-smooth muscle actin (alpha-SMA) and collagen I production. Similar results were observed in neonatal air-liquid interface culture (i.e., disruption of epithelial integrity and EMT). Acute exposure of infant mice to DCB-230 resulted in EMT, as confirmed by lineage tracing studies and evidenced by coexpression of epithelial E-cadherin and mesenchymal alpha-SMA proteins in airway cells and increased SNAI1 expression in the lungs. EMT in neonatal mouse lungs after EPFR exposure may provide an explanation for epidemiological evidence supporting PM exposure and increased risk of asthma. PMID- 23087056 TI - Kinase pathway dependence in primary human leukemias determined by rapid inhibitor screening. AB - Kinases are dysregulated in most cancers, but the frequency of specific kinase mutations is low, indicating a complex etiology in kinase dysregulation. Here, we report a strategy to rapidly identify functionally important kinase targets, irrespective of the etiology of kinase pathway dysregulation, ultimately enabling a correlation of patient genetic profiles to clinically effective kinase inhibitors. Our methodology assessed the sensitivity of primary leukemia patient samples to a panel of 66 small-molecule kinase inhibitors over 3 days. Screening of 151 leukemia patient samples revealed a wide diversity of drug sensitivities, with 70% of the clinical specimens exhibiting hypersensitivity to one or more drugs. From this data set, we developed an algorithm to predict kinase pathway dependence based on analysis of inhibitor sensitivity patterns. Applying this algorithm correctly identified pathway dependence in proof-of-principle specimens with known oncogenes, including a rare FLT3 mutation outside regions covered by standard molecular diagnostic tests. Interrogation of all 151 patient specimens with this algorithm identified a diversity of kinase targets and signaling pathways that could aid prioritization of deep sequencing data sets, permitting a cumulative analysis to understand kinase pathway dependence within leukemia subsets. In a proof-of-principle case, we showed that in vitro drug sensitivity could predict both a clinical response and the development of drug resistance. Taken together, our results suggested that drug target scores derived from a comprehensive kinase inhibitor panel could predict pathway dependence in cancer cells while simultaneously identifying potential therapeutic options. PMID- 23087055 TI - Modulation of the ATPase and transport activities of broad-acting multidrug resistance factor ABCC10 (MRP7). AB - The cell surface molecule ABCC10 is a broad-acting transporter of xenobiotics, including cancer drugs, such as taxanes, epothilone B, and modulators of the estrogen pathway. Abcc10(-/-) mice exhibit increased tissue sensitivity and lethality resulting from paclitaxel exposure compared with wild-type counterparts, arguing ABCC10 functions as a major determinant of taxane sensitivity in mice. To better understand the mechanistic basis of ABCC10 action, we characterized the biochemical and vectorial transport properties of this protein. Using crude membranes in an ABCC10 overexpression system, we found that the ABCC10 transport substrates estrogen estradiol-glucuronide (E(2)17betaG) and leukotriene C4 (LTC(4)) significantly stimulated ABCC10 beryllium fluoride (BeFx) sensitive ATPase activity. We also defined the E(2)17betaG antagonist, tamoxifen, as a novel substrate and stimulator of ABCC10. In addition, a number of cytotoxic substrates, including docetaxel, paclitaxel, and Ara-C, increased the ABCC10 basal ATPase activity. We determined that ABCC10 localizes to the basolateral cell surface, using transepithelial well assays to establish that ABCC10 overexpressing LLC-PK1 cells exported [(3)H]-docetaxel from the apical to the basolateral side. Importantly, we found that the clinically valuable multikinase inhibitor sorafenib, and a natural alkaloid, cepharanthine, inhibited ABCC10 docetaxel transport activity. Thus, concomitant use of these agents might restore the intracellular accumulation and potency of ABCC10-exported cytotoxic drugs, such as paclitaxel. Overall, our work could seed future efforts to identify inhibitors and other physiologic substrates of ABCC10. PMID- 23087057 TI - Loss of PPP2R2A inhibits homologous recombination DNA repair and predicts tumor sensitivity to PARP inhibition. AB - Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G(1) to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high fidelity homologous recombination repair pathway and sensitized cells to small molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non-small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic. PMID- 23087059 TI - VMD decides to ban advertising of antimicrobials to animal keepers. PMID- 23087058 TI - Targeting CD4(+) T-helper cells improves the induction of antitumor responses in dendritic cell-based vaccination. AB - To evaluate the relevance of directing antigen-specific CD4(+) T helper cells as part of effective anticancer immunotherapy, we investigated the immunologic and clinical responses to vaccination with dendritic cells (DC) pulsed with either MHC class I (MHC-I)-restricted epitopes alone or both MHC class I and II (MHC I/II)-restricted epitopes. We enrolled 33 stage III and IV HLA-A*02:01-positive patients with melanoma in this study, of whom 29 were evaluable for immunologic response. Patients received intranodal vaccinations with cytokine-matured DCs loaded with keyhole limpet hemocyanin and MHC-I alone or MHC-I/II-restricted tumor-associated antigens (TAA) of tyrosinase and gp100, depending on their HLA DR4 status. In 4 of 15 patients vaccinated with MHC-I/II-loaded DCs and 1 of 14 patients vaccinated with MHC-I-loaded DCs, we detected TAA-specific CD8(+) T cells with maintained IFN-gamma production in skin test infiltrating lymphocyte (SKIL) cultures and circulating TAA-specific CD8(+) T cells. If TAA-specific CD4(+) T-cell responses were detected in SKIL cultures, it coincided with TAA specific CD8(+) T-cell responses. In 3 of 13 patients tested, we detected TAA specific CD4(+)CD25(+)FoxP3(-) T cells with high proliferative capacity and IFN gamma production, indicating that these were not regulatory T cells. Vaccination with MHC-I/II-loaded DCs resulted in improved clinical outcome compared with matched control patients treated with dacarbazine (DTIC), median overall survival of 15.0 versus 8.3 months (P = 0.089), and median progression-free survival of 5.0 versus 2.8 months (P = 0.0089). In conclusion, coactivating TAA-specific CD4(+) T-helper cells with DCs pulsed with both MHC class I and II-restricted epitopes augments TAA-specific CD8(+) T-cell responses, contributing to improved clinical responses. PMID- 23087061 TI - Developing a test to screen drugs for their emetic potential. PMID- 23087063 TI - Drop-in ID scheme for horses. PMID- 23087062 TI - Concerns expressed about badger cull. PMID- 23087064 TI - Wild dog conservation project gets vaccine boost. PMID- 23087065 TI - Changing mindsets on production animal health. PMID- 23087066 TI - Sharing responsibility for tackling antibiotic resistance. PMID- 23087067 TI - Advising on optimal vaccination practices. PMID- 23087068 TI - Equine disease surveillance: quarterly summary. PMID- 23087069 TI - Vets asked to help with surveillance for equine influenza. PMID- 23087070 TI - Going for gold in the detection of honeybee pathogens. PMID- 23087071 TI - Bovine TB and badger culling. PMID- 23087072 TI - Canine trombiculosis and seasonal canine illness. PMID- 23087073 TI - Grain prices and food wastage. PMID- 23087074 TI - National control programme for Salmonella in pigs. PMID- 23087075 TI - Practical experience for students. PMID- 23087077 TI - VBF bungalows. PMID- 23087078 TI - Geocoding coronial data: tools and techniques to improve data quality. AB - Clinical, administrative and demographic health information is fundamental to understanding the nature of health and evaluating the effectiveness of efforts to reduce morbidity and mortality of the population. The demographic data item 'location' is an integral part of any injury surveillance tool or injury prevention strategy. The true value of location data can only be realised once these data have been appropriately classified and quality assured. Geocoding as a means of classifying location is increasingly used in various health fields to enable spatial analysis of data. This article reports on research carried out in Australia at the National Coroners Information System (NCIS). Trends in the use of NCIS location-based data by researchers were identified. The research also aimed to establish the factors that impacted on the quality of geocoded data and the extent of this impact. A systematic analysis of the geocoding process identified source documentation, data cleaning, and software settings as key factors impacting on data quality. Understanding and application of these processes can improve data quality and therefore inform the analysis and interpretation of these data by researchers. PMID- 23087079 TI - Sustainability of health information systems in developing countries: the case of Fiji. AB - This paper examines the future sustainability of the Fijian Ministry of Health's (MoH) information and communication technology (ITC) system for patient management (PATIS). PATIS was developed with AusAID funding and, as the owner of the system, AusAID has no commercial competence or interest in further development of the system. Thus, the question that arises is: should Fiji adopt a commercially available patient administration system or retain the existing PATIS? In-depth consultations with senior executives and line managers of units that were major users of PATIS were undertaken. Semi-structured interviews and focus group discussion approaches were utilised. The consensus or majority views of the users were that the existing PATIS performed more than adequately. The future sustainability of the system is threatened by the lack of investment in resources (e.g. hardware maintenance and human resources) required to keep the system operating at its optimum. It was found that PATIS provides Fiji with a satisfactory patient administration system. The identified problems with the system are not related to the application per se but rather to an under investment in resources for its utilisation. PMID- 23087080 TI - Information support for health information management in regional Sri Lanka: health managers' perspectives. AB - Good management, supported by accurate, timely and reliable health information, is vital for increasing the effectiveness of Health Information Systems (HIS). When it comes to managing the under-resourced health systems of developing countries, information-based decision making is particularly important. This paper reports findings of a self-report survey that investigated perceptions of local health managers (HMs) of their own regional HIS in Sri Lanka. Data were collected through a validated, pre-tested postal questionnaire, and distributed among a selected group of HMs to elicit their perceptions of the current HIS in relation to information generation, acquisition and use, required reforms to the information system and application of information and communication technology (ICT). Results based on descriptive statistics indicated that the regional HIS was poorly organised and in need of reform; that management support for the system was unsatisfactory in terms of relevance, accuracy, timeliness and accessibility; that political pressure and community and donor requests took precedence over vital health information when management decisions were made; and use of ICT was unsatisfactory. HIS strengths included user-friendly paper formats, a centralised planning system and an efficient disease notification system; weaknesses were lack of comprehensiveness, inaccuracy, and lack of a feedback system. Responses of participants indicated that HIS would be improved by adopting an internationally accepted framework and introducing ICT applications. Perceived barriers to such improvements were high initial cost of educating staff to improve computer literacy, introduction of ICTs, and HIS restructure. We concluded that the regional HIS of Central Province, Sri Lanka had failed to provide much-needed information support to HMs. These findings are consistent with similar research in other developing countries and reinforce the need for further research to verify causes of poor performance and to design strategic reforms to improve HIS in regional Sri Lanka. PMID- 23087081 TI - Long-term outcomes of postoperative septic arthritis after anterior cruciate ligament reconstruction. AB - BACKGROUND: Septic arthritis is a rare but potentially devastating complication of anterior cruciate ligament (ACL) reconstruction surgery. Several studies, including one by this group, have reported short- and medium-term outcomes, but to our knowledge there are no long-term follow-up studies. HYPOTHESIS: Postoperative septic arthritis after ACL reconstruction surgery will lead to diminished long-term outcomes compared with surgery without infectious complications, likely related to the development of arthritis. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Four of 831 consecutive patients undergoing arthroscopically guided ACL reconstruction surgeries performed by 1 surgeon were previously reported on by this group at an average follow-up of 36 months. These same patients were contacted and reevaluated. Each patient underwent a physical examination, functional testing, and subjective evaluations with the SF-36, Lysholm, International Knee Documentation Committee (IKDC), and Tegner activity scale scores. Plain film radiographs and magnetic resonance imaging (MRI) scans were analyzed by 2 musculoskeletal radiologists. RESULTS: Average follow-up time for this study was 17.9 years, and average age was 44.3 years. No other injuries or surgeries had occurred from the time of the previous study. Each patient had a decline in SF-36, Lysholm, and IKDC score, and the average Tegner score was unchanged. Average vertical hop test performance and Biodex dynamometry were both improved. The average side-to-side displacement measured via the KT-1000 arthrometer was increased. Radiographic and MRI studies revealed progression of arthritis in all patients and ACL graft rupture in 1 patient. CONCLUSION: Patients who develop septic arthritis as a complication of ACL reconstruction surgery have diminished long-term subjective, functional, and radiographic outcomes compared with historical reports of uncomplicated cases, likely related to pain from advanced arthritis. As compared with their own earlier follow-up, these patients had declines in pain-related subjective measures but remained stable or improved in both functional testing and activity related subjective scales. PMID- 23087082 TI - The BH3-mimetic ABT-737 sensitizes human melanoma cells to apoptosis induced by selective BRAF inhibitors but does not reverse acquired resistance. AB - Although the introduction of selective v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilization of disease or no response at all. This study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. We examined the influence of the BH3-mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 in melanoma cells with or without BRAF V600E mutation. Included were cell lines established from four patients before and during treatment with selective BRAF inhibitors and 3D spheroids derived from these cell lines. Cell lines with no or low sensitivity to PLX4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT 737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following small interfering RNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors and in 3D spheroids derived from these cell lines. These results suggest that combination of selective BRAF inhibitors with ABT-737 or the related orally available compound ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents. PMID- 23087084 TI - miR-106b downregulates adenomatous polyposis coli and promotes cell proliferation in human hepatocellular carcinoma. AB - Aberrant activation of the Wnt/beta-catenin signal pathway is frequently observed in hepatocellular carcinoma (HCC). beta-Catenin is the major cellular effector of Wnt signaling and inactivation of adenomatous polyposis coli (APC) results in nuclear accumulation of beta-catenin. Therefore, it was speculated that APC inhibition could play important roles in activating the Wnt/beta-catenin pathway and in HCC progression. In this study, we report that miR-106b expression is markedly upregulated in hepatoma cells and hepatoma tissues compared with immortalized normal liver epithelial cells and normal hepatic tissues. Ectopic expression of miR-106b induces the proliferation and anchorage-independent growth of hepatoma cells, whereas inhibition of miR-106b reduced this effect. Furthermore, miR-106b upregulation in hepatoma cells modulated entry into the G(1)/S transitional phase by upregulating cyclin D1 and downregulating APC. Moreover, we demonstrated that miR-106b downregulates APC expression by directly targeting the 3'-untranslated region of APC messenger RNA. Taken together, our results suggest that miR-106b plays an important role in promoting the proliferation of human hepatoma cells and presents a novel mechanism of micro RNA mediated direct suppression of APC expression in cancer cells. PMID- 23087085 TI - Contribution of serotonin type 3 receptors in the successful extinction of cued or contextual fear conditioned responses: interactions with GABAergic signaling. AB - The changes in serotonin type 3 (5-HT) receptor activity influence memory and emotional regulation,the two essential components underlying the successful extinction of conditioned fear. These studies determined if blocking 5-HT3 receptors with granisetron influences the extinction of fear in male Sprague Dawley rats. In Experiment 1, preextinction granisetron (0.5 or 1.0 mg/kg intraperitoneally) d~d not affect cued extinction learning but enhanced memory for the extinction session on retention test given 24 and 48 h later. In Experiment 2, granisetron injections given on days 1 and 4 during 6 days of extinction training reduced fear produced by contextual fear conditioning. Experiments 3 and 4 examined if 5-HT3 antagonists influence extinction memory by interactions with y-aminobutyric acid (GABA). The expression of the GABA receptor clustering protein gephyrin was significantly A elevated in the amygdala after cued fear extinction training and a subsequent extinction retention test given 24 h later. Gephyrin expression in the hippocampus but not in the amygdala or the medial prefrontal cortex was significantly reduced after contextual fear extinction sessions given 1 or 5 days after training. The current studies reveal the beneficial effects of 5-HT3 receptor activity in improving new learning associated with extinction of fearful memories and suggest that these actions could be mediated through influences on central GABAergic systems. PMID- 23087083 TI - Recruitment of NCOR1 to VDR target genes is enhanced in prostate cancer cells and associates with altered DNA methylation patterns. AB - The current study investigated transcriptional distortion in prostate cancer cells using the vitamin D receptor (VDR) as a tool to examine how epigenetic events driven by corepressor binding and CpG methylation lead to aberrant gene expression. These relationships were investigated in the non-malignant RWPE-1 cells that were 1alpha,25(OH)(2)D(3) responsive (RWPE-1) and malignant cell lines that were 1alpha,25(OH)(2)D(3) partially responsive (RWPE-2) and resistant (PC 3). These studies revealed that selective attenuation and repression of VDR transcriptional responses in the cancer cell lines reflected their loss of antiproliferative sensitivity. This was evident in VDR target genes including VDR, CDKN1A (encodes p21( (waf1/cip1) )) and GADD45A; NCOR1 knockdown alleviated this malignant transrepression. ChIP assays in RWPE-1 and PC-3 cells revealed that transrepression of CDKN1A was associated with increased NCOR1 enrichment in response to 1alpha,25(OH)(2)D(3) treatment. These findings supported the concept that retained and increased NCOR1 binding, associated with loss of H3K9ac and increased H3K9me2, may act as a beacon for the initiation and recruitment of DNA methylation. Overexpressed histone methyltransferases (KMTs) were detectable in a wide panel of prostate cancer cell lines compared with RWPE-1 and suggested that generation of H3K9me2 states would be favored. Cotreatment of cells with the KMT inhibitor, chaetocin, increased 1alpha,25(OH)(2)D(3)-mediated induction of CDKN1A expression supporting a role for this event to disrupt CDKN1A regulation. Parallel surveys in PC-3 cells of CpG methylation around the VDR binding regions on CDKN1A revealed altered basal and VDR-regulated DNA methylation patterns that overlapped with VDR-induced recruitment of NCOR1 and gene transrepression. Taken together, these findings suggest that sustained corepressor interactions with nuclear-resident transcription factors may inappropriately transform transient repressive histone states into more stable and repressive DNA methylation events. PMID- 23087086 TI - Identification of circulating microRNAs as biomarkers in cancers: what have we got? AB - During the past few years there has been great interest in the development of circulating microRNAs (miRNAs) as stable blood-based biomarkers for cancer detection. Deregulation of miRNAs in blood samples has shown considerable clinical utilities in cancers. Due to poorly characterized preanalytical and analytical variables and the lack of a standardized measurement protocol, the application of these miRNA fingerprints is hindered by conflicting results. In this review,we outline our current understanding of preanalytically and analytically confounding factors. We believe that great consideration should be taken in the development of circulating miRNA as tumor biomarkers. PMID- 23087087 TI - Most of the benefits from genomic selection can be realized by genotyping a small proportion of available selection candidates. AB - We reasoned that marginal returns from genomic selection diminish as the proportion of genotyped selection candidates increases and breeding values (BV) based on a priori information are used to choose candidates that are genotyped. We tested this premise by stochastic simulation of breeding schemes that resembled those used for pigs. We estimated rates of genetic gain and inbreeding realized by genomic selection in breeding schemes where candidates were phenotyped before genotyping and 0 to 100% of the candidates were genotyped based on predicted BV. Genotyping was allocated to male and female candidates at ratios of 100:0, 75:25, 50:50, 25:75, and 0:100. For genotyped candidates, a direct genomic value (DGV) was sampled with reliabilities 0.10, 0.50, and 0.90. Ten sires and 300 dams with the largest BV after genotyping were selected at each generation. Selection was for a single trait with heritability 0.20. We found that the marginal returns did diminish as genotyping proportion was increased, while the rate at which the returns diminished slowed as DGV became more reliable. With DGV reliability 0.10, genotyping as little as 5% of the selection candidates realized 86% of the additional genetic gain and 67% of the reduction in inbreeding that was realized by genotyping 100% of the candidates. All of the genetic gain and reduction in inbreeding was realized by genotyping 40 and 50% of the candidates. When the reliability was increased to 0.90, genotyping 20% of the candidates was required to realize 76% of the genetic gain and 85% of the reduction in inbreeding. Genotyping 50% of the selection candidates with DGV reliability 0.90 realized 91% of the genetic gain and 94% of the reduction in inbreeding. Regardless of DGV reliability, returns at small genotyping proportions of 0.5 to 10% were maximized when only male candidates were genotyped. At the large genotyping proportions of 20 to 50%, returns were maximized by genotyping both males and females. Our findings indicate that, provided a priori information is available, only 5 to 20% of the selection candidates need to be genotyped to realize most of the benefits from genomic selection. At these genotyping proportions, it is best to target males in schemes when selection intensity for males is greater than females. Our findings should benefit breeders because they suggest that large investments in genotyping are not required to reap most of the benefits from genomic selection. PMID- 23087088 TI - Intestinal permeability and fecal eosinophil-derived neurotoxin are the best diagnosis tools for digestive non-IgE-mediated cow's milk allergy in toddlers. AB - BACKGROUND: Food allergy is a common problem in France involving 4%-6% of toddlers. As opposed to IgE-mediated cow's milk allergy (CMA), delayed-onset CMA, mostly, non-IgE-mediated, remains difficult to diagnose in toddlers. Our study assessed the diagnostic performances of intestinal permeability and of fecal markers, in comparison with the standard allergic work-up in children referred for CMA diagnosis. METHODS: Twenty-five consecutive children, mean age (standard deviation) 6.3 months (4.8) with digestive and/or extra-digestive manifestations suggesting CMA, were prospectively studied based on a standardized allergic work up (specific cow's protein IgE and IgG, skin prick test, atopy patch test and oral open cow's milk challenge) and digestive work-up including fecal microbiota analysis, intestinal permeability determination (urinary lactitol/mannitol ratio) and fecal markers measurement, i.e., alpha(1)-antitrypsin, tumor necrosis factor alpha, calprotectin, beta-defensin2, secretory IgA and eosinophil-derived neurotoxin (EDN). Receiver operating characteristic (ROC) curves were calculated for all markers in order to define cut-off levels. RESULTS: The cow's milk challenge was positive in 11 children and negative in 14. The global test performances, i.e., the number of true positive+negative cases/the total number of cases, were 76% for intestinal permeability; 72% for fecal EDN; contrasting with atopy patch test, 68%; IgE, 60%; skin prick test, 55% and IgG, 52%. CONCLUSIONS: In this routine diagnosis allergy work-up for CMA in toddlers, the best efficacy was seen for intestinal permeability compared to IgE, IgG, skin prick test and atopy patch test. Moreover, fecal EDN in a single spot sample displayed a similar performance. PMID- 23087089 TI - The congenital database and the Streif in Kitzbuhel. PMID- 23087090 TI - Results of reparative surgery for tetralogy of Fallot: data from the European Association for Cardio-Thoracic Surgery Congenital Database. AB - OBJECTIVES: Right ventricular (RV) dysfunction and pulmonary insufficiency (PI) after tetralogy of Fallot (TOF) repair may contribute to early and late morbidity and mortality. RV dysfunction may be related to the ventriculotomy employed in the transventricular repair technique, particularly when it is combined with a transannular patch (TAP). Transatrial/transpulmonary (TA/TP) repair without ventriculotomy has been advocated as a method potentially diminishing such adverse events. However, the prevalence and early as well as the late results of these different surgical approaches in Europe have not been studied. To ascertain 'the current prevalence and associated early mortality' of various surgical approaches for repair of TOF, relevant data in the European Association for Cardio-Thoracic Surgery Congenital Database were analysed. METHODS: The study population was all types of reparative operations (n = 6654) for patients with primary diagnosis of TOF reported between 1999 and 2011. RESULTS: Overall hospital mortality (HM) was 2.58% (172 of 6654). Repair via ventriculotomy with TAP was the most prevalent technique (n = 3827, 57.5%), with HM 3.11%. Repair via ventriculotomy with non-TAP was performed in 1309 patients (19.7%, HM = 1.53%). Repair without ventriculotomy was performed in 1214 patients (18.2%, HM = 1.48%). Logistic regression analysis showed statistically significant association between HM risk and the type of surgery. In particular, ventriculotomy with TAP is associated with increased mortality risk significantly compared with ventriculotomy with non-TAP (crude odds ratio [OR] 2.13 (95% confidence interval [CI]: 1.33-3.63). Similar results were obtained by analysing for operative mortality risk (30-day mortality, OM). Operations that have been performed before 2005 have resulted in increased surgical risk compared with those performed after 2005 (ORs for OM 1.45, 95% CI: 1.03-2.013). CONCLUSIONS: Overall HM for TOF repair is low. TOF repair by means of ventriculotomy with TAP is the most prevalent approach and is associated with higher mortality. Repair with ventriculotomy but no TAP and repair without ventriculotomy are both less prevalent and with lower mortality. Surgical risk appears to be decreasing over time. PMID- 23087091 TI - Editorial comment: Know-how transfer from east- to west-perventricular closure of perimembranous ventricular septal defects. PMID- 23087092 TI - Editorial comment: Revisions to the 7th edition of TNM for lung cancer: data are good but prospective data are better! PMID- 23087093 TI - Solitary pericardial hydatid cyst encompassing the heart. PMID- 23087094 TI - Route of reconstruction after total oesophagectomy. PMID- 23087095 TI - Factors increasing blood transfusion in open heart surgery. PMID- 23087097 TI - In memory of Ian Beecroft. PMID- 23087098 TI - Simvastatin attenuates pulmonary vascular remodelling by down-regulating matrix metalloproteinase-1 and -9 expression in a carotid artery-jugular vein shunt pulmonary hypertension model in rats. AB - OBJECTIVES: It remains controversial as to whether simvastatin has a beneficial effect on pulmonary artery hypertension. This study aimed to explore the efficacy of simvastatin on haemodynamic changes, pulmonary vascular remodelling and expression of matrix metalloproteinase-1 and -9 (MMP-1,9) in a carotid artery jugular vein (CA-JV) shunt pulmonary artery hypertension (PAH) model in rats. METHODS: Thirty-six Sprague-Dawley rats were randomized into three groups: Control group, CA-JV group, and Treatment group. A pre-tricuspid systemic pulmonary shunt from the left common carotid artery to the external jugular vein was established on the CA-JV and Treatment groups, but only ligations of both vessels were performed in Control group. Simvastatin (4 mg/kg/d) was administered to the Treatment group, and placebo to the CA-JV group. Twelve weeks later, the animals underwent a haemodynamic evaluation, followed by pulmonary tissue sampling for morphometry, quantitative real-time PCR and Western blot analysis. RESULTS: By week 12, rats in the CA-JV group had higher right ventricular systolic pressure (RVSP), medial area/total area (MA/TA) and percentage of fibrous tissue (F%) than those in the Control group. These changes were associated with up-regulation of MMP-1,9 mRNA and increased expression of MMP-1,9 proteins. Pretreatment with simvastatin decreased the shunt-induced RVSP, MA/TA and F% in pulmonary arteries. In addition, lung MMP-1,9 mRNA and proteins levels decreased toward normal levels in simvastatin-treated rats. CONCLUSIONS: Simvastatin ameliorated the structural and functional derangements of pulmonary arterioles caused by the CA-JV shunt, partly associated with the suppression of up-regulated MMP-1, as well as MMP-9. Simvastatin may play a role in the treatment of systemic-pulmonary shunt-induced PAH diseases, such as congenital heart disease. PMID- 23087101 TI - Cellular microcompartments constitute general suborganellar functional units in cells. AB - All cells are compartmentalized to facilitate enzymatic reactions or cellular dynamics. In eukaryotic cells, organelles differ in their protein/lipid repertoire, luminal ion composition, pH, and redox status. In addition, organelles contain specialized subcompartments even within the same membrane or within its lumen. Moreover, the bacterial plasma membrane reveals a remarkable degree of organization, which is recapitulated in eukaryotic cells and often linked to cell signaling. Finally, protein-based compartments are also known in the bacterial and eukaryotic cytosol. As the organizing principle of such cellular subcompartments is likely similar, previous definitions like rafts, microdomains, and all kinds of '-somes' fall short as a general denominator to describe such suborganellar structures. Within this review, we will introduce the term cellular microcompartment as a general suborganellar functional unit and discuss its relevance to understand subcellular organization and function. PMID- 23087099 TI - Pre-emptive hypoxia-regulated HO-1 gene therapy improves post-ischaemic limb perfusion and tissue regeneration in mice. AB - AIMS: Haem oxygenase-1 (HO-1) is a haem-degrading enzyme that generates carbon monoxide, bilirubin, and iron ions. Through these compounds, HO-1 mitigates cellular injury by exerting antioxidant, anti-apoptotic, and anti-inflammatory effects. Here, we examined the influence of HO-1 deficiency and transient hypoxia/ischaemia-induced HO-1 overexpression on post-injury hindlimb recovery. METHODS AND RESULTS: Mice lacking functional HO-1 (HO-1(-/-)) showed reduced reparative neovascularization in ischaemic skeletal muscles, impaired blood flow (BF) recovery, and increased muscle cell death compared with their wild-type littermates. Human microvascular endothelial cells (HMEC-1) transfected with plasmid vector (pHRE-HO-1) carrying human HO-1 driven by three hypoxia response elements (HREs) and cultured in 0.5% oxygen demonstrated markedly increased expression of HO-1. Such upregulated HO-1 levels were effective in conferring protection against H(2)O(2)-induced cell death and in promoting the proangiogenic phenotype of HMEC-1 cells. More importantly, when delivered in vivo, pHRE-HO-1 significantly improved the post-ischaemic foot BF in mice subjected to femoral artery ligation. These effects were associated with reduced levels of pro inflammatory cytokines (IL-6 and CXCL1) and lower numbers of transferase-mediated dUTP nick-end labelling-positive cells. Moreover, HO-1 delivered into mouse skeletal muscles seems to influence the regenerative potential of myocytes as it significantly changed the expression of transcriptional (Pax7, MyoD, myogenin) and post-transcriptional (miR-146a, miR-206) regulators of skeletal muscle regeneration. CONCLUSION: Our results suggest the therapeutic potential of HO-1 for prevention of adverse effects in critical limb ischaemia. PMID- 23087102 TI - Possible role of a septin, SEPT1, in spreading in squamous cell carcinoma DJM-1 cells. AB - We performed biochemical, histochemical and cell biological characterization of septins by focusing on SEPT1 in human skin tissues and a squamous cell carcinoma (SCC) cell line DJM-1. In immunoblotting, SEPT1, together with other septins, was detected in normal human epidermis, SCC and DJM-1. In immunohistochemical analyses, SEPT1 was detected diffusely in the cytoplasm of human epidermal cells and eccrine gland epithelial cells, and the protein level was increased in some skin tumors. In DJM-1 cells, SEPT1 together with other members of SEPT2-subgroup, SEPT4 and SEPT5, was enriched in lamellipodia and the localization was dependent on the cortical actin structure. SEPT1 distribution at lamellipodia was also observed in melanoma B16 cells. SEPT9, SEPT11 and SEPT14, in contrast, were localized along with microtubules in DJM-1 cells. In immunoprecipitation assays, SEPT1 and SEPT5 were found to form a complex in DJM-1 cells, whereas SEPT9, SEPT11 and SEPT14 formed a distinct complex with other septins including SEPT7, SEPT8 and SEPT10, in which SEPT5 was not included. When SEPT1 was silenced in DJM 1 cells, cell spreading was inhibited. These results suggest that SEPT1 may participate in cell-cell and/or cell-substrate interaction in DJM-1 and exert its function in a coordinated manner with other septins. PMID- 23087103 TI - cCMP, cUMP, cTMP, cIMP and cXMP as possible second messengers: development of a hypothesis based on studies with soluble guanylyl cyclase alpha(1)beta(1). AB - Adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate are second messengers that regulate multiple physiological functions. The existence of additional cyclic nucleotides in mammalian cells was postulated many years ago, but technical problems hampered development of the field. Using highly specific and sensitive mass spectrometry methods, soluble guanylyl cyclase has recently been shown to catalyze the formation of several cyclic nucleotides in vitro. This minireview discusses the broad substrate-specificity of soluble guanylyl cyclase and the possible second messenger roles of cyclic nucleotides other than adenosine 3',5'-cyclic monophosphate and guanosine 3',5'-cyclic monophosphate. We hope that this article stimulates productive and critical research in an area that has been neglected for many years. PMID- 23087104 TI - Complete genome sequences of novel rat noroviruses in Hong Kong. AB - We report two genome sequences of novel noroviruses isolated from fecal swab specimens of brown rats in Hong Kong. The complete genome is approximately 7.5 kb in length and consists of 3 overlapping open reading frames encoding ORF1 polyprotein, VP1, and VP2, respectively. Sequence analysis suggested that these noroviruses should be classified in genogroup V, but they are distinct from other known rodent noroviruses and represent a novel cluster within the genogroup. PMID- 23087105 TI - Complete genome sequence of the podoviral bacteriophage YMC/09/02/B1251 ABA BP, which causes the lysis of an OXA-23-producing carbapenem-resistant Acinetobacter baumannii isolate from a septic patient. AB - The emergence of carbapenem-resistant Acinetobacter baumannii, responsible for causing nosocomial infections, has been becoming a significant global health issue. In this article, we report the complete genome sequence of bacteriophage B B1251 (YMC/09/02/B1251 ABA BP), which causes lysis of a carbapenem-resistant A. baumannii strain. The bacteriophage belongs to the family Podoviridae and has a double-stranded circular DNA genome with a length of 45,364 bp and a 39.05% G+C content. Genome analysis showed that it had no similarity to other previously reported bacteriophages capable of infecting A. baumannii. PMID- 23087106 TI - Complete genome sequence of the bacteriophages ECBP1 and ECBP2 isolated from two different Escherichia coli strains. AB - Escherichia coli is recognized as one of the most abundant avian bacterial pathogens. In this study, we report the sequencing by the traditional Sanger method of ECBP1 and ECBP2: bacteriophages that infected two different E. coli strains which might be used as therapeutic agents in combination with alternative antibiotics. PMID- 23087107 TI - Genome sequence of human adenovirus type 55, a re-emergent acute respiratory disease pathogen in China. AB - Human adenovirus type 55 (HAdV-B55) is an acute respiratory disease (ARD) pathogen first completely characterized in China (2006). This is a unique Trojan horse microbe with the virus neutralization attribute of a renal pathogen and the cell tropism and clinical attributes of a respiratory pathogen, bypassing herd immunity. It appeared to be an uncommon pathogen, with earlier putative, sporadic occurrences in Spain (1969) and Turkey (2004); these isolates were incompletely characterized using only two epitopes. Reported here is the genome of a second recent isolate (China, 2011), indicating that it may occur more frequently. The availability of this HAdV-B55 genome provides a foundation for studying adenovirus molecular evolution, the dynamics of epidemics, and patterns of pathogen emergence and re-emergence. These data facilitate studies to predict genome recombination between adenoviruses, as well as sequence divergence rates and hotspots, all of which are important for vaccine development and because HAdVs are used for epitope and/or gene delivery vectors. PMID- 23087108 TI - Complete genome sequence of a novel reassortant H11N2 avian influenza virus isolated from a live poultry market in eastern China. AB - A/chicken/Nanjing/908/2009(H11N2) (CK908) was isolated from a live poultry market in Nanjing, China. Using PCR and sequencing analysis, we obtained the complete genome sequences of the CK908 virus. The sequence analysis demonstrated that this H11N2 virus was a novel reassortant AIV whose PB1, PB2, PA, HA, NP, NA, M, and NS genes originated from H9N2, H7N7, H5N2, H11N8, H3N6, H6N2, H1N1, and H5N1, respectively. Knowledge regarding the complete genome sequences of the CK908 virus will be useful for epidemiological surveillance. PMID- 23087109 TI - Genome sequence of a novel Hobi-like pestivirus in China. AB - Hobi-like pestivirus is a novel pestivirus species first isolated in 2004. Here, we report the genome sequence of a Hobi-like pestivirus strain isolated from contaminated MDBK cells in China. The sequence information is important for surveillance of this emerging animal infectious disease worldwide. PMID- 23087110 TI - Complete genomic sequence of a new Muscovy duck-origin reovirus from China. AB - The complete genomic sequence of a new Muscovy duck-origin reovirus (N-MDRV), strain J18 from China, was determined. The virus has a tricistronic S1 genome segment that is distinct from the originally described MDRV, which possesses a bicistronic S4 genome segment. Pairwise comparisons and phylogenetic analyses suggest that N-MDRV J18 is a new isolate within the species Avian orthoreovirus. PMID- 23087111 TI - The genome sequence of an isolate of Indian citrus ringspot virus infecting the sweet orange in India. AB - Whole-genome sequencing of an isolate of Mandarivirus infecting the sweet orange [Citrus sinensis (L) Blanco] in the western part of India (Pune) was done. The single-stranded positive-sense RNA genome of Indian citrus ringspot virus (ICRSV) Pune has 7,560 nucleotides (nt), excluding a poly(A) tail, comprised of 27.98% (2,115 nt) A, 32.12% (2,428 nt) C, 19.68% (1,488 nt) G, and 20.22% (1,529 nt) T residues. The genome, organized into six open reading frames (ORFs), shares 97.7% sequence identity with the complete genome of the ICRSV K1 isolate (AF406744.1) infecting the kinnow (Citrus reticulate Blanco, a hybrid between King and Willow mandarins) in north India. The ICRSV Pune genome formed a complex secondary structure with a large number of unpaired cytosine-rich regions, and recombination analysis highlighted potential recombination in the ICRSV genome. PMID- 23087112 TI - Complete genome sequence of a variant porcine epidemic diarrhea virus strain isolated in China. AB - Since October 2010, an outbreak of porcine epidemic diarrhea (PED) has been observed in some provinces of China. Here we report the complete genome sequence of porcine epidemic diarrhea virus (PEDV) strain LC, which was recently isolated from sucking piglets that suffered from severe watery diarrhea in Guangdong. It will help in understanding the epidemiological and molecular characteristics of PEDV in China. PMID- 23087113 TI - Complete genome sequence of a novel bovine norovirus: evidence for slow genetic evolution in genogroup III genotype 2 noroviruses. AB - A new genogroup III genotype 2 bovine norovirus, B309/2003/BE, was entirely sequenced and genetically compared to the original Newbury2/1976/UK strain and to Dumfries/1994/UK, detected in 1976 and 1994, respectively. Interestingly, except in well-defined coding regions (N-terminal protein, 3A-like protease, hypervariable region of the capsid protein, and C-terminal part of the minor structural protein), very low genetic differences were noted between the entire genomes of these three strains along a 30-year-long period. It allowed some hypotheses of hotspots of genetic evolution through a low genetic evolution background in genotype 2 genogroup III bovine noroviruses. PMID- 23087114 TI - Complete genome sequence of Central Africa human T-cell lymphotropic virus subtype 1b. AB - Human T-lymphotropic virus type 1 (HTLV-1) has a global spread, and it is estimated that around 20 million persons are infected. Seven major genetic subtypes are recognized. However, there are complete genomes only from the HTLV 1a (cosmopolitan) and HTLV-1c (Melanesian) subtypes. Here, the first full-length genome of an HTLV-1b strain, a subtype so far restricted to Central African countries, is revealed. The genome size of HTLV-1b SF26, a strain isolated in Brazil, was determined to be 8,267 bp. The genomic analysis showed that all characteristic regions and genes of a prototypic HTLV-1 virus are conserved. This genome can provide information for further studies on the evolutionary history and pathogenic potential of this human oncovirus. PMID- 23087115 TI - Complete genome sequence of temperate bacteriophage AcaML1 from the extreme acidophile Acidithiobacillus caldus ATCC 51756. AB - Development of reproducible genetic tools in the industrially important acidithiobacilli is urgently required. Inducible temperate phages which may be modified in vitro, propagated in suitable hosts, and used to transduce relevant genetic information to other strains and/or species are potentially valuable tools in this field of research. In order to address these current limitations, the genome sequence of an inducible temperate Myoviridae-like bacteriophage from the Acidithiobacillus caldus type strain was annotated and analyzed bioinformatically. Here, we announce the genome sequence of AcaML1 and report major findings from its annotation. PMID- 23087117 TI - Complete genome sequence of a porcine orthoreovirus from southern China. AB - Porcine orthoreoviruses belong to the family Reoviridae and cause mainly mild enteritis in piglets. We present here the complete genome sequence of a novel porcine orthoreovirus strain (GD-1) isolated from a piglet in southern China. Our data will facilitate future investigations of the molecular characteristics and epidemiology of porcine orthoreoviruses. PMID- 23087116 TI - Complete genome sequence of a highly virulent rabies virus isolated from a rabid pig in south China. AB - A virulent rabies virus (RABV) strain, GD-SH-01, was isolated from brain tissue of a rabid pig in China. This report describes the first complete genome sequence of a swine-origin RABV strain, and this information will provide important insights into the transmission cycle and genetic diversity of RABV from different hosts in China. PMID- 23087118 TI - Complete genome sequence of porcine circovirus 2d strain GDYX. AB - Porcine circovirus type 2 (PCV2) is the etiologic agent of porcine circovirus associated disease, and it is mainly divided into five genotypes. Here, we report the complete genome sequence of PCV2 strain GDYX, which belongs to PCV2d and has a unique amino acid variation at position 169 (S to G). PMID- 23087119 TI - Complete genome sequence of a mammalian species-infectious and -pathogenic H6N5 avian influenza virus without evidence of adaptation. AB - An H6N5 avian influenza virus (AIV) strain, designated A/aquatic bird/Korea/CN5/2009 (H6N5), was isolated from fecal swabs of aquatic birds in 2009, and surprisingly, it showed infectivity and pathogenicity in mammalian species without evidence of adaptation. In this study, we report the first complete genome sequence containing 3' and 5' noncoding regions (NCRs) of a mammalian species-infectious and pathogenic H6N5 AIV, which will help provide important insights into the molecular basis of pathogenesis, transmission, and evolution of AIV. PMID- 23087120 TI - Complete genome sequence of a Newcastle disease virus strain isolated from broiler breeder flocks in China. AB - In 2010 and 2011, several devastating Newcastle disease (ND) outbreaks occurred in China, affecting broilers, layers, and breeders. The CK-JSX1-201005 virus was isolated from broiler breeder flocks vaccinated with the classical ND virus (NDV) vaccine program, but laying rate decreased from 80% to 30 to 40% in the clinic. Here, we report the complete genome sequence and molecular characteristic of the CK-JSX1-201005 NDV. These findings provide additional insights into the genetic variation of NDV circulating in China and are useful for vaccine development for NDV. PMID- 23087121 TI - Genome sequence of a natural reassortant H5N2 avian influenza virus from domestic mallard ducks in eastern China. AB - Here, we report the genomic sequence of a Chinese reassortant H5N2 avian influenza virus which possessed the polybasic motif PLREKRRK-R/GL at the hemagglutinin cleavage site. Phylogenetic analysis showed that all eight genes were of the Eurasian lineage, five of which were highly homologous to the endemic clade 2.3.4 H5N1 viruses and their H5N5 reassortant descendants. These data suggested that novel multisubtypic NA reassortants bearing the H5N1 backbone could be generated through genetic reassortment in H5N1 circulating regions, which will help in understanding the evolution and segment reassortment mechanism of H5 subtype avian influenza viruses. PMID- 23087122 TI - Complete genome sequences of highly divergent Torque teno virus type II from swine herds. AB - Through routine and nested PCR amplifications, four complete genome sequences of porcine Torque teno virus (TTV) type II were obtained from swine herds. By comparison with the TTV genome sequences deposited in GenBank, we found the most divergent types so far described. The level of genetic diversity between these genomes is higher than would be expected within a single virus species. A nucleotide and amino acid phylogenetic tree was constructed. PMID- 23087123 TI - Complete genome sequence of a reovirus isolated from grass carp, indicating different genotypes of GCRV in China. AB - A widespread grass carp hemorrhagic disease (GCHD) caused by grass carp reovirus (GCRV) has been known in China since 1983. A virulent reovirus strain, HZ08, was isolated from diseased grass carp in Zhejiang Province, China. We sequenced and analyzed the complete genome of strain HZ08 and compared it with published GCRV genome sequences, contributing to the evidence of several genotypes of GCRV in China. PMID- 23087124 TI - Genomic sequence of Heliothis virescens ascovirus 3g isolated from Spodoptera exigua. AB - Heliothis virescens ascovirus 3a (HvAV-3a), a member of the family Ascoviridae, has the highest diversity among ascovirus species that have been reported in Australia, Indonesia, China, and the United States. To understand the diversity and origin of this important ascovirus, the complete genome of the HvAV Indonesia strain (HvAV-3g), isolated from Spodoptera exigua, was determined to be 199,721 bp, with a G+C content of 45.9%. Therefore, HvAV-3g has the largest genome among the reported ascovirus genomes to date. There are 194 predicted open reading frames (ORFs) encoding proteins of 50 or more amino acid residues. In comparison to HvAV-3e reported from Australia, HvAV-3g has all the ORFs in HvAV-3e with 6 additional ORFs unique to HvAV-3g, including 1 peptidase C26 gene with the highest identity to Drosophila spp. and 2 gas vesicle protein U (GvpU) genes with identities to Bacillus megaterium. The five unique homologous regions (hrs) and 25 baculovirus repeat ORFs (bro) of HvAV-3g are highly variable. PMID- 23087125 TI - Complete genome sequence of a novel porcine circovirus type 2b variant present in cases of vaccine failures in the United States. AB - Two genomes of a new porcine circovirus type 2 (PCV2) strain associated with cases of perceived failure of PCV2 vaccination were sequenced and analyzed. Based on the genome, this is the first report of this mutant of PCV2b in the United States. The genomic knowledge of this mutant PCV2b will improve understanding of the epidemiology of PCV and potentially inform the development of new and more effective vaccines for PCV2. PMID- 23087127 TI - Cytogenetic evidence of mixed disomic and polysomic inheritance in an allotetraploid (AABB) Musa genotype. AB - BACKGROUND AND AIMS: Edible bananas originated mainly from two wild species, Musa acuminata Colla (AA) and Musa balbisiana Colla (BB), and triploid cultivars with an AAA, AAB or ABB genome are the most widely used. In the present study, chromosome pairing affinities are investigated in a sterile AB Indian variety and in its fertile colchicine-induced allotetraploid (AABB) derivative to determine the inheritance pattern of the tetraploid genotype. The potential implications of interspecific recombination and chromosomal composition of diploid gametes for Musa improvement are presented. METHODS: The pairing of different chromosome sets at diploid and tetraploid levels was investigated through a combination of conventional cytogenetic and genomic in-situ hybridization (GISH) analyses of meiotic chromosomes, leading to a likelihood model of the pairing behaviour. GISH analysis of mitotic chromosomes was also conducted to reveal the chromosome constitution of hybrids derived from crosses involving the allotetraploid genotype. KEY RESULTS: Analysis of chromosome associations at both ploidy levels suggested that the newly formed allotetraploid behaves as a 'segmental allotetraploid' with three chromosome sets in a tetrasomic pattern, three sets in a likely disomic pattern and the five remaining sets in an intermediate pattern. Balanced and unbalanced diploid gametes were detected in progenies, with the chromosome constitution appearing to be more homogenous in pollen than in ovules. CONCLUSIONS: Colchicine-induced allotetraploids in Musa provide access to the genetic background of natural AB varieties. The segmental inheritance pattern exhibited by the AABB allotetraploid genotype implies chromosome exchanges between M. acuminata and M. balbisiana species and opens new horizons for reciprocal transfer of valuable alleles. PMID- 23087126 TI - Long-term outcome in patients with acromegaly: analysis of 1344 patients from the German Acromegaly Register. AB - BACKGROUND: Acromegaly is a rare disease with significant morbidity and increased mortality. Epidemiological data about therapeutic outcome under 'real life' conditions are scarce. OBJECTIVE: To describe biochemical long-term outcome of acromegaly patients in Germany. DESIGN AND METHODS: Retrospective data analysis from 1344 patients followed in 42 centers of the German Acromegaly Register. Patients' data were collected 8.6 (range 0-52.6) years after diagnosis. Controlled disease was defined by an IGF1 within the center-specific reference range. RESULTS: Nine hundred and seventeen patients showed a normalized IGF1 (157 (range 25-443) ng/ml). In patients with a diagnosis dated back >2 years (n=1013), IGF1 was normalized in 76.9%. Of the patients, 19.5% had an elevated IGF1 and a random GH >=1 ng/ml, 89% of the patients had at least one surgical intervention, 22% underwent radiotherapy, and 43% received medical treatment. After surgery 38.8% of the patients were controlled without any further therapy. The control rates were higher in surgical centers with a higher caseload (P=0.034). Of the patients with adjunctive radiotherapy 34.8% had a normal IGF1 8.86 (0-44.9) years post irradiation, 65.2% of the medically treated patients were controlled, and 47.2% of the patients with an elevated IGF1 received no medical therapy. CONCLUSION: The majority of acromegaly patients were controlled according to their IGF1 status. Long-term outcome could be improved by exploiting medical treatment options especially in patients who are not controlled by surgery and/or radiotherapy. PMID- 23087128 TI - DNA replication stress induces deregulation of the cell cycle events in root meristems of Allium cepa. AB - BACKGROUND AND AIMS: Prolonged treatment of Allium cepa root meristems with changing concentrations of hydroxyurea (HU) results in either premature chromosome condensation or cell nuclei with an uncommon form of biphasic chromatin organization. The aim of the current study was to assess conditions that compromise cell cycle checkpoints and convert DNA replication stress into an abnormal course of mitosis. METHODS: Interphase-mitotic (IM) cells showing gradual changes of chromatin condensation were obtained following continuous 72 h treatment of seedlings with 0.75 mm HU (without renewal of the medium). HU treated root meristems were analysed using histochemical stainings (DNA DAPI/Feulgen; starch-iodide and DAB staining for H(2)O(2) production), Western blotting [cyclin B-like (CBL) proteins] and immunochemistry (BrdU incorporation, detection of gamma-H2AX and H3S10 phosphorylation). KEY RESULTS: Continuous treatment of onion seedlings with a low concentration of HU results in shorter root meristems, enhanced production of H(2)O(2), gamma-phosphorylation of H2AX histones and accumulation of CBL proteins. HU-induced replication stress gives rise to axially elongated cells with half interphase/half mitotic structures (IM cells) having both decondensed and condensed domains of chromatin. Long-term HU treatment results in cell nuclei resuming S phase with gradients of BrdU labelling. This suggests a polarized distribution of factors needed to re initiate stalled replication forks. Furthermore, prolonged HU treatment extends both the relative time span and the spatial scale of H3S10 phosphorylation known in plants. CONCLUSIONS: The minimum cell length and a threshold level of accumulated CBL proteins are both determining factors by which the nucleus attains commitment to induce an asynchronous course of chromosome condensation. Replication stress-induced alterations in an orderly route of the cell cycle events probably reflect a considerable reprogramming of metabolic functions of chromatin combined with gradients of morphological changes spread along the nucleus. PMID- 23087129 TI - The phylogenetic distribution of extrafloral nectaries in plants. AB - BACKGROUND AND AIMS: Understanding the evolutionary patterns of ecologically relevant traits is a central goal in plant biology. However, for most important traits, we lack the comprehensive understanding of their taxonomic distribution needed to evaluate their evolutionary mode and tempo across the tree of life. Here we evaluate the broad phylogenetic patterns of a common plant-defence trait found across vascular plants: extrafloral nectaries (EFNs), plant glands that secrete nectar and are located outside the flower. EFNs typically defend plants indirectly by attracting invertebrate predators who reduce herbivory. METHODS: Records of EFNs published over the last 135 years were compiled. After accounting for changes in taxonomy, phylogenetic comparative methods were used to evaluate patterns of EFN evolution, using a phylogeny of over 55 000 species of vascular plants. Using comparisons of parametric and non-parametric models, the true number of species with EFNs likely to exist beyond the current list was estimated. KEY RESULTS: To date, EFNs have been reported in 3941 species representing 745 genera in 108 families, about 1-2 % of vascular plant species and approx. 21 % of families. They are found in 33 of 65 angiosperm orders. Foliar nectaries are known in four of 36 fern families. Extrafloral nectaries are unknown in early angiosperms, magnoliids and gymnosperms. They occur throughout monocotyledons, yet most EFNs are found within eudicots, with the bulk of species with EFNs being rosids. Phylogenetic analyses strongly support the repeated gain and loss of EFNs across plant clades, especially in more derived dicot families, and suggest that EFNs are found in a minimum of 457 independent lineages. However, model selection methods estimate that the number of unreported cases of EFNs may be as high as the number of species already reported. CONCLUSIONS: EFNs are widespread and evolutionarily labile traits that have repeatedly evolved a remarkable number of times in vascular plants. Our current understanding of the phylogenetic patterns of EFNs makes them powerful candidates for future work exploring the drivers of their evolutionary origins, shifts, and losses. PMID- 23087131 TI - Potential pitfalls of propofol target controlled infusion delivery related to its pharmacokinetics and pharmacodynamics. AB - Target controlled infusion (TCI) devices are increasingly used in clinical practice. These devices unquestionably aid optimization of drug dosage. However, it still remains to be determined if they sufficiently address differences in pharmacological make up of individual patients. The algorithms guiding TCI pumps are based on pharmacological data obtained from a relatively small number of healthy volunteers, which are then extrapolated, on the basis of sophisticated pharmacokinetic and pharmacodynamic modeling, to predict plasma concentrations of the drug and its effect on general population. One has to realize the limitation of this approach: these models may be less accurate when applied to patients in extreme clinical conditions: in intensive care units, with a considerable loss of blood, severe hypothermia or temporary changes in the composition of plasma, e.g., hypoalbuminemia. In the future, data obtained under these "extreme" clinical circumstances, may be used to modify the dosage algorithms of propofol TCI systems to match the clinical scenario. PMID- 23087130 TI - Prediction of enzyme activity with neural network models based on electronic and geometrical features of substrates. AB - BACKGROUND: Artificial Neural Networks (ANNs) are introduced as robust and versatile tools in quantitative structure-activity relationship (QSAR) modeling. Their application to the modeling of enzyme reactivity is discussed, along with methodological issues. Methods of input variable selection, optimization of network internal structure, data set division and model validation are discussed. The application of ANNs in the modeling of enzyme activity over the last 20 years is briefly recounted. METHODS: The discussed methodology is exemplified by the case of ethylbenzene dehydrogenase (EBDH). Intelligent Problem Solver and genetic algorithms are applied for input vector selection, whereas k-means clustering is used to partition the data into training and test cases. RESULTS: The obtained models exhibit high correlation between the predicted and experimental values (R(2) > 0.9). Sensitivity analyses and study of the response curves are used as tools for the physicochemical interpretation of the models in terms of the EBDH reaction mechanism. CONCLUSIONS: Neural networks are shown to be a versatile tool for the construction of robust QSAR models that can be applied to a range of aspects important in drug design and the prediction of biological activity. PMID- 23087132 TI - Antidepressant-like activity of ellagic acid in unstressed and acute immobilization-induced stressed mice. AB - BACKGROUND: The aim of present study was to evaluate antidepressant-like activity of ellagic acid in Swiss young male albino mice; and to explore the possible underlying mechanisms for this activity. METHODS: Mice were immobilized for 150 min once only for induction of stress. Ellagic acid (8.75, 17.5, 35 mg/kg, po) and fluoxetine (20 mg/kg, ip) per se were administered to unstressed and stressed mice; and immobility periods were recorded using tail suspension test and forced swim test. The plasma nitrite levels were also estimated in unstressed and stressed mice. Effects of 7-nitroindazole (nNOS inhibitor), aminoguanidine (iNOS inhibitor), prazosin (alpha(1)-adrenoceptor antagonist), sulpiride (selective D(2)-receptor antagonist), and p-chlorophenylalanine (p-CPA - tryptophan hydroxylase inhibitor) on antidepressant-like activity of ellagic acid were also evaluated. RESULTS: Ellagic acid (17.5 and 35 mg/kg, po) and fluoxetine per se significantly decreased immobility periods of unstressed and stressed mice, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice. Ellagic acid significantly decreased the plasma nitrite levels in stressed mice only. Aminoguanidine significantly potentiated antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid (35 mg/kg) in stressed mice. 7-Nitroindazole did not enhance antidepressant-like activity and plasma nitrite decreasing effect of ellagic acid in unstressed mice. Prazosin and p-CPA significantly attenuated antidepressant like effect of ellagic acid (35 mg/kg) in unstressed mice only. CONCLUSION: Thus, ellagic acid showed antidepressant-like activity in unstressed mice probably by interaction through adrenergic and serotonergic systems. On the other hand, antidepressant-like activity of ellagic acid in stressed mice might be through inhibition of inducible NOS. PMID- 23087133 TI - Influence of long-term administration of rutin on spatial memory as well as the concentration of brain neurotransmitters in aged rats. AB - BACKGROUND: The present study was designed to investigate the behavioral and neurochemical effects of long-term oral rutin administration to old male WAG rats (100 and 200 mg/kg b.w./day). Rutin is a well-known dietary flavonol glycoside with antioxidant and anti-inflammatory properties. METHODS: First, spatial memory was assessed in the water maze and then the levels of neurotransmitters in selected brain regions were estimated. RESULTS: There was enhanced spatial memory in aged rats pretreated with the smaller dose of rutin in the probe trial of the water maze, nevertheless, augmented levels of noradrenaline in the hippocampi of these animals were not correlated with improved spatial memory. The increased dopamine levels in the hypothalami of the same group of animals may suggest effects other than behavioral. CONCLUSION: Long-term rutin pre-treatment may cause behavioral and neurochemical changes in aged WAG male rats. PMID- 23087134 TI - Synthesis and pharmacological properties of new GABA uptake inhibitors. AB - BACKGROUND: gamma-Aminobutanoic acid (GABA) is the principal inhibitory neurotransmitter in the mammalian central nervous system. The identification and subsequent development of the GABA transport inhibitors which enhance the GABA ergic transmission has shown the important role that GABA transporters play in the control of numerous functions of the nervous system. Compounds which inhibit GABA uptake are used as antiepileptic drugs (tiagabine - a selective GAT1 inhibitor), they are also being investigated for other indications, including treatment of psychosis, general anxiety, sleep disorders, drug addiction or acute and chronic pain. METHODS: In this paper, the synthesis of 2-substituted-4-(1,3 dioxoisoindolin-2-ylo)-butanamides and 2-substituted-4-aminobutanoic acids derivatives is described. These compounds were tested in vitro for their ability to inhibit GABA uptake. The inhibitory potency towards murine plasma membrane GABA transporters (mGAT1-4) was performed as [(3)H]GABA uptake assay based on stably transfected HEK cells. Compound 18, which demonstrated the highest affinity for mGAT1-4 (pIC(50) ranged from 4.42 for mGAT1 to 5.07 for mGAT3), was additionally investigated in several behavioral tests in mice. RESULTS: Compound 18 increased the locomotor activity (14-38%) and had anxiolytic-like properties in the four-plate test (ED(50) = 9.3 mg/kg). It did not show analgesic activity in acute pain model, namely the hot plate test, however, it was antinociceptive in the acetic acid-induced writhing test (ED(50) = 15.3 mg/kg) and in the formalin model of tonic pain. In the latter assay, it diminished nocifensive behavior in both phases and in the first (neurogenic) phase of this test the obtained ED(50) value (5.3 mg/kg) was similar to morphine (3.0 mg/kg). CONCLUSION: Compound 18 exhibited significant anxiolytic-like properties and was antinociceptive in some models of pain in mice. Moreover, it did not impair animals' motor coordination in the chimney test. Some of the described pharmacological activities of compound 18 can be partly explained based on its affinity for plasma membrane GABA transporters. PMID- 23087135 TI - Effect of benzothiazole/piperazine derivatives on intracerebroventricular streptozotocin-induced cognitive deficits. AB - BACKGROUND: In this study, benzothiazole-piperazine compounds were synthesized by condensing the functional groups of donepezil (DNP), FK-960, and sabeluzole, which are known to have therapeutic potential against Alzheimer's disease, with the aim of obtaining new and potent anti-Alzheimer agents. METHODS: Initially, acetylcholinesterase/butyrylcholinesterase enzyme inhibition activities of the synthesized test compounds were investigated by Ellman's method. Effects of the compounds on a streptozotocin (STZ) model of Alzheimer's disease (SMAD) were investigated in rats. SMAD was established by intracerebroventricular (icv) injection of STZ (3 mg/kg), bilaterally. The elevated plus maze, Morris water maze, and active avoidance tests were used to examine the effects of test compounds (1, 5, and 10 mg/kg) on learning and memory parameters of icv STZ injected rats. Effects of the test compounds on spontaneous locomotor activities of rats were examined with the activity cage test. RESULTS: The compounds B2-B5 and DNP exhibited significant selective inhibitory potencies against acetylcholinesterase. Compounds B2 and B3 at 10 mg/kg doses and compounds B4 and B5 at 5 and 10 mg/kg doses, as well as the reference drug DNP (1 and 3 mg/kg), significantly improved the learning and memory parameters of animals in all cognition tests. None of the test compounds changed spontaneous locomotor activities. CONCLUSION: Results of the present study revealed that compounds B2 B5 repaired the parameters related to the learning and memory deficits of icv STZ injected rats. Potencies of these test compounds were comparable to the activity of DNP. PMID- 23087136 TI - Mangiferin ameliorates 6-hydroxydopamine-induced cytotoxicity and oxidative stress in ketamine model of schizophrenia. AB - BACKGROUND: Accumulating evidence indicates that mangiferin (MGF), a natural xanthone, by virtue of its antioxidant and antiinflammatory properties is neuroprotective. Here we sought to verify the cytoprotective role of MGF on cultured rat primary mesencephalic cells exposed to 6-hydroxydopamine (6-OHDA) in vitro, and the MGFs anti-inflammatory potential in mouse model of ketamine induced schizophrenia in vivo. METHODS: 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT)-assay was performed tomeasure cell viability inmesencephalic cell cultures exposed to neurotoxin (6-OHDA, 40 MUM). Schizophrenia was induced in mice by ketamine (50 mg/kg, ip, twice a day, for 7 days). The treatment effects of MGF (50 mg/kg, po, for 7 days) were verified on locomotor behavioral changes in open-field test, and on the oxidant stress related increase in lipid-peroxidation (malondialdehyde) and interleukin-6 (IL-6) levels in brain tissues. RESULTS: MGF (10-100 MUM) produced no per se effect on cell viability as measured by MTT assay, but significantly prevented the 6-OHDA induced cell death in a concentration-dependent manner. Acridine orange/ethidium bromide (AO/EtBr) staining confirmed the absence of 6-OHDA-induced morphological changes characteristic of apoptosis/necrosis. In open-field test, ketamine induced impaired locomotor activity and behavioral changes such as grooming and stereotyped but not rearing were effectively ameliorated by MGF pretreatment. Also, ketamine-associated increase in brain tissue levels of IL-6 and MDA were significantly lowered in MGF-pretreated mice. CONCLUSION: Mangiferin has a neurocytoprotective role related, at least in part, to an antioxidant and anti inflammatory mechanism, which could be explored for more effective therapies of schizophrenia and other neurodegenerative diseases. PMID- 23087137 TI - Comparative behavioral and neurochemical studies of R- and S-1-methyl-1,2,3,4 tetrahydroisoquinoline stereoisomers in the rat. AB - BACKGROUND: 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) is present in human and mammalian brain as a racemate (R,S) of two stereoisomers: R- and S-1MeTIQ. The racemate is a mixture of the endogenous, synthesized in the brain dextrorotary R-1MeTIQ, and the exogenous, levorotary form, S-1MeTIQ. METHODS: In this study, we compared the effect of these two stereoisomers of 1MeTIQ with the racemate in the context of their influence on dopamine metabolism and in vivo dopamine release in the rat striatum. Additionally, a behavioral study was used to examine the influence of both enantiomers R- and S-1MeTIQ on locomotor activity of rats. RESULTS: The behavioral studies showed that both R- and S 1MeTIQ enantiomers, like the racemate, produced biphasic effects: a slight decrease in the exploratory locomotor activity, and then an increase in the basal locomotor activity. Biochemical ex vivo experiments showed that S-1MeTIQ produced a much stronger inhibition of MAO-dependent dopamine oxidation than the racemate. R-1MeTIQ, in opposite to S-isoform and racemate, did not block dopamine oxidation in the structures which contain dopamine nerve endings (striatum, nucleus accumbens), and in fact did not suppress the level of its intraneuronal metabolite, DOPAC in these brain regions. However , an in vivo microdialysis study demonstrated that the racemate and both stereoisomers (R-1MeTIQ to a lesser extent) significantly elevated the concentration of dopamine in the extraneuronal space in the rat striatum. What is more, the concentration of an extraneuronal dopamine metabolite 3-methoxytyramine (3-MT), which is an indicator of its release, was considerably increased by all the compounds. CONCLUSIONS: In summary of the results, it can be stated that S-1MeTIQ, like the racemate and in contrast to R-stereoisomer, inhibits MAO-dependent dopamine oxidation in all investigated brain structures. In addition, both these substances potentiated COMT-dependent O methylation in the brain, however, also R-1MeTIQ produced such effect but to a lesser extent. In conclusion, we suggest that R- and S-1MeTIQ enantiomers like the racemate may demonstrate neuroprotective properties in the brain via the activation of dopamine O-methylation catabolic pathway and elevation of its methylated product - 3-MT. PMID- 23087138 TI - Decreased analgesic effect of morphine, but not buprenorphine, in patients with advanced P-glycoprotein(+) cancers. AB - BACKGROUND: P-glycoprotein (P-gp) is expressed on the blood-brain barrier (BBB) and acts as a transporter regulating the analgesic effect of morphine. The P-gp is also expressed by different types of tumors. The aim of this study was to determine the potential association of the P-gp expression in malignant tumors with analgesic effects in patients. METHODS: The P-gp expression in 120 malignant tumors was examined by immunohistochemistry. The analgesic responses of individual patients to morphine and buprenorphine (BNP) were evaluated by visual analog scale (VAS). The levels of plasma morphine and BNP were determined by HPLC. RESULTS: We found that there was no significant difference in the values of VAS between patients with P-gp(+) and P-gp(-) malignant tumors in responses to 0.000025 g x kg(-2) of BNP administered by patient-controlled intravenous analgesia (PCIA), accompanied by similar levels of plasma BNP in those patients. In contrast, the values of VAS in response to 0.00075 g x kg(-2) of morphine in patients with P-gp(+) tumors were significantly greater than those in the patients with P-gp(-) tumors, although similar levels of plasma morphine were detected in both groups of patients. Furthermore, treatment with a higher dose (0.0011 g x kg(-2)) of morphine effectively controlled pain in those with P-gp(+) tumors. CONCLUSION: Our data indicated that patients with P-gp(+) tumors required a higher dose of morphine to achieve an analgesic effect and that the P-gp expression in tumors may be valuable for predicting the analgesic responses of patients with severe pain to morphine. PMID- 23087139 TI - Effect of angiotensin II type 1 receptor blocker on osteoporotic rat femurs. AB - BACKGROUND: Osteoblasts and osteoclasts are known to express Ang II type I (AT1) receptor in cell cultures, suggesting the existence of local renin-angiotensin system (RAS) in bone. This study was designed to investigate the effects of losartan as AT1 receptor blocker on ovariectomized rats' femur. METHODS: Losartan (5 mg/kg/day) was administered via oral gavage for 8 weeks. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry, while tensile and three-point bending tests were performed for evaluation of biomechanical properties of bone. The trabecular porosity was analyzed by scanning electron microscopy. RESULTS: There was a significant decrease in BMD values of ovariectomized rats' femurs which were reversed by losartan treatment. According to tensile test results, ultimate tensile strength and strain values of losartan treated ovariectomized rats' femurs increased and decreased, respectively, when compared to that of ovariectomized animals. Losartan treatment also caused a significant recovery in flexural strength and modulus parameters regarding respective control values, which mean losartan treated ovariectomized rats' femur had more force tolerance until break than ovariectomized rats' femur. Quantitative microscopic analysis showed larger trabecular porosity in ovariectomized rats than control rat femurs and it was significantly decreased after losartan treatment. CONCLUSION: Blockage of AT1 receptor increased strength, mass and trabecular connections of ovariectomized rat femurs. Therefore, it is tempting to speculate that drugs, including AT1 receptor blockers, may be used for the treatment of osteoporosis or reduction of its detrimental effects in the future. PMID- 23087140 TI - Berberine inhibits dyslipidemia in C57BL/6 mice with lipopolysaccharide induced inflammation. AB - BACKGROUND: Inhibiting the action of proprotein convertase subtilisin/kexin type 9 (PCSK9) on the low-density lipoprotein receptor (LDLR) has emerged as a novel therapeutic target for hypercholesterolemia. Here we investigated the effect of berberine, natural plant extracts, on PCSK9-LDLR pathway in C57BL/6 mice with lipopolysaccharide (LPS) induced inflammation. METHODS: Forty female mice were divided into four groups (n =10): control, LPS (5 mg/kg), LPS + berberine 10 (5 mg/kg LPS plus 10 mg/kg berberine), and LPS + berberine 30 (5 mg/kg LPS plus 30 mg/kg berberine). Changes in the levels of blood lipids [total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C)]; pro-inflammatory cytokines [interferon-gamma (IFNgamma), tumor necrosis factor alpha (TNFalpha), and interleukin-1alpha (IL 1alpha)], 8-isoprostane, hepatic expressions of PCSK9 and LDLR were determined. RESULTS: Berberine pretreatment reduced the expression of hepatic PCSK9, decreased the plasma TC, TG, LDL-C, IFNgamma, TNFalpha, IL-1alpha, and 8 isoprostane concentrations; increased HDL-C level and LDLR expression in mice. CONCLUSION: The present results suggest that berberine inhibits dyslipidemia in C57BL/6 mice with LPS induced inflammation through regulating PCSK9-LDLR pathway. PMID- 23087141 TI - Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex. AB - BACKGROUND: This study was performed to investigate expression and distribution of glucocorticoid receptor (GR) in the rat adrenal cortex, acute effect of ethanol on its expression and possible role of endogenous nitric oxide (NO) in this phenomenon. METHODS: Adult female Wistar rats showing diestrus day 1 were treated with: a) ethanol (2 or 4 g/kg body weight (b.w.), ip), b) N(omega)-nitro L-arginine methyl ester (L-NAME), well-known competitive inhibitor of all isoforms of NO synthase (NOS), (30 mg/kg b.w., sc) followed by ethanol (4 g/kg, ip) 3 h later and c) L-NAME (30 mg/kg b.w., sc) followed by saline (ip) 3 h later. Untreated rats were used as controls. Adrenocortical expression of GR was estimated by immunohistochemistry. RESULTS: Strong nuclear GR staining was observed throughout the cortex of control rats. Acute ethanol treatment significantly decreased the expression of GR in the zona fasciculata and zona reticularis. Blockade of NO formation had no influence on this effect of ethanol, whereas L-NAME itself induced significant decline in GR immunoreactivity. CONCLUSIONS: Obtained findings are the first to demonstrate localization and distribution of the GR throughout the rat adrenal cortex and to suggest that ethanol as well as endogenous NO may modulate adrenocortical expression of this steroid receptor. PMID- 23087142 TI - Effect of exposure to fluoride and acetaminophen on oxidative/nitrosative status of liver and kidney in male and female rats. AB - BACKGROUND: This study was undertaken to investigate, the effect of 6 weeks treatment with acetaminophen (AAP) and fluoride (F), administered either separately or together, on nitric oxide generation, lipid and protein peroxidation, total antioxidant status and level of reduced glutathione in the liver and kidney of male and female Wistar Han rats. Also, the influence of AAP on F excretion in urine was determined. METHODS: Thirty adult male and female rats were divided into five equal groups of six each: (I) controls drinking tap water; (II) controls drinking tap water and receiving 1 ml of tap water intragastrically; (III) animals receiving 12 mg F/L in drinking water; (IV) animals receiving 150 mg AAP /kg b.w./day; (V) animals receiving 12 mg F/L in drinking water and 150 mg AAP /kg b.w./day. RESULTS: F and AAP given separately and both together enhanced oxidative and nitrosative stress in investigated tissues. No gender differences were observed in oxidative/nitrosative stress parameters during treatment with F and/or AAP. Interestingly, the combined exposure to F and AAP resulted in an enhancement of oxidative/nitrosative stress in kidney of male and female rats compared to the group treated separately with F and AAP. No additive effect in the measured parameters in the liver during co exposure to both xenobiotics was noticed. CONCLUSIONS: As expected, the urinary F excretion increased in an exposure time-dependent manner in rats receiving F or a combination of F and AAP. The study also showed that AAP significantly decreased urinary F. PMID- 23087143 TI - Epigallocatechin-3-gallate inhibits angiotensin II and interleukin-6-induced C reactive protein production in macrophages. AB - BACKGROUND: Consumption of green tea has been associated with health benefits against multiple diseases including cardiovascular diseases. However, the action mechanisms of green tea and its major ingredient epigallocatechin-3-gallate (EGCG) against cardiovascular diseases are still unclear. Emerging evidence has suggested a common role for C-reactive protein (CRP) in the pathogenesis of inflammation and atherosclerosis. Therefore, the effect of EGCG on angiotensin II (Ang II)- and interleukin-6 (IL-6)-induced CRP production in U937 macrophages and the possible mechanisms were observed. METHODS: U937 macrophages were cultured, and Ang II and IL-6 were used as stimulants for generation of CRP. U937 macrophages were preincubated with EGCG at 1, 3, 10 MUM for 1 h prior to the stimulation. mRNA expression and protein level were determined by RT-PCR and ELISA, respectively. ROS production was observed by a fluorescence microscope. RESULTS: Pretreatment of macrophages with EGCG prior to the stimulation concentration-dependently inhibited Ang II- and IL-6-induced expression of CRP both in protein and mRNA levels. Meanwhile, EGCG reduced Ang II- and IL-6 stimulated generation of ROS in macrophages. CONCLUSION: EGCG is able to inhibit Ang II- and IL-6-stimulated CRP expression in macrophages to produce an anti inflammation by interfering with ROS generation. The finding is helpful to update understanding of anti-atherosclerotic effects of EGCG. PMID- 23087144 TI - Epicutaneous immunization with hapten-conjugated protein antigen alleviates contact sensitivity mediated by three different types of effector cells. AB - BACKGROUND: Allergic contact dermatitis (ACD) is a common clinical condition in industrialized countries and often causes occupational diseases. Animal model of contact sensitivity (CS) is commonly used to study ACD in mice and can be induced by skin application of haptens. It has been previously shown that CS is mediated by CD4(+) or CD(8+) T effector cells. More recently it was found that also liver NK cells can play a role of CS effector cells in mice. METHODS: The aim of the present study was to test whether skin-induced suppression could inhibit CS response in vivo. RESULTS: Here we show that EC immunization of normal mice with hapten conjugated protein antigen prior to hapten sensitization suppresses Th1, Tc1 and NK mediated CS responses. CONCLUSIONS: These data strongly suggest that maneuver of EC immunization may have important implications for designing therapeutic schemes aimed at modulating unwanted immune responses in contact hypersensitivity. PMID- 23087145 TI - Expression of genes involved in xenobiotic metabolism and transport in end-stage liver disease: up-regulation of ABCC4 and CYP1B1. AB - BACKGROUND: Expression of drug-metabolizing enzymes and drug transporters in liver is mainly regulated by a system of nuclear receptors. The aim of the current study was to investigate the expression of nuclear receptors, as well as these enzymes and transporters, in liver samples from patients suffering from end stage liver disease of various etiologies (HCV infection, alcohol liver disease, and primary sclerosis cholangitis). METHODS: Gene expression was measured using quantitative real-time PCR with surgical specimens from livers of patients with end-stage liver disease, and non-tumoral liver tissue that served as control. RESULTS: Our study confirmed that the expression of most phase I enzymes is suppressed in end-stage liver disease, and is correlated with a decrease in NR1I2 and NR1I3, the main regulators of xenobiotic metabolism. While mRNA levels of phase II enzymes were generally unchanged, some ABC transporters were up regulated. The most spectacular increases in expression were observed with ABCC4 (MRP4) - at the mRNA level, and CYP1B1 - at both the mRNA and protein levels. We also demonstrated that IL-6 can induce CYP1B1 expression independently of CYP1A1, in a human hepatocellular liver carcinoma cell line. CONCLUSIONS: As CYP1B1 is an enzyme which converts various substrates into carcinogenous metabolites, its overexpression in liver may be one of the factors increasing the risk of hepatic cancers in patients with liver disease. CYP1A1 and CYP1B1 are often referred to as model AHR target genes, but CYP1A1 was down-regulated in diseased liver samples. This points to the existence of differences in regulation of these two genes. PMID- 23087146 TI - In vivo and in vitro evaluation of the estrogenic properties of the 17beta (butylamino)-1,3,5(10)-estratrien-3-ol (buame) related to 17beta-estradiol. AB - BACKGROUND: Buame [17beta-(butylamino)-1,3,5(10)-estratrien-3-ol] possesses anticoagulant and antiplatelet activities that are potentially antithrombotic. Since its estrogenicity is unknown, it was evaluated by established methods. METHODS: Buame (10, 100, 500, and 1,000 MUg/kg), 17beta-estradiol (E(2)) (100 MUg/kg), or propylene glycol (10 ml/kg) were subcutaneously (sc) administered for three days to immature Wistar female rats (21 days old). The relative uterotrophic effect to E(2) was 78 (E(2) = 100) with a relative uterotrophic potency of 1.48 (E(2) = 100). Adult ovariectomized Wistar rats received an sc injection at 8:00 h (reversed cycle) of: 7.5 MUg of E(2) (~ 30 MUg/kg), buame (~ 750, 1,500, 3,000 MUg/kg), or corn oil (~ 1.2 ml/kg). After 24 h, progesterone (4 5 mg/kg) was administered. Sexual receptivity was assessed 5 to 7 h later, and the lordosis quotient (LQ; number lordosis/number mounts x 100) was evaluated. RESULTS: Buame induced lordosis (LQmax 85 +/- 9; ED50 952 +/- 19 MUg/kg) and E(2) LQmax 56 +/- 8; ED50 10 +/- 2 MUg/kg; the relative LQ-potency was 0.51 (E(2) = 100). Buame competed with [(3)H]E(2) for the estrogen receptor (Buame RBA= 0.15 and Ki = 5.9 x 10(-7) M; E(2) RBA= 100;Ki = 6.6 x 10(-9) M). Buame increased MCF 7 cells proliferation, from 10(-11) to 10(-)9 M, its proliferative effect was 1.73-1.79 (E(2) = 3.0-3.9); its relative proliferative effect to E(2) was 33-40% (E(2) = 100%) and relative potency 10.4-10.7 (E(2) = 100). Tamoxifen and fulvestrant (ICI 182,780) inhibited buame's proliferation indicating mediation through estrogen receptors in this response. CONCLUSION: Buame is therefore an estrogen partial agonist with a weak estrogenic activity. PMID- 23087147 TI - Modulation of ghrelin axis influences the growth of colonic and prostatic cancer cells in vitro. AB - BACKGROUND: The risk of different cancers seems to be associated with obesity. Moreover, low ghrelin levels observed in obese people may be implicated in cancer development and progression. The aim of this study was to examine the direct effects of both forms of ghrelin (acylated and unacylated) and ghrelin receptor type 1a antagonist (D-Lys-GHRP-6) on the growth of murine colon cancer MC38 and human prostate cancer DU145 cell lines in vitro. METHODS: The cells were cultured for 72 h in the presence of rat or human acylated ghrelin (rG, hG), human unacylated ghrelin (hUAG), D-Lys-GHRP-6 (GHS-RA) applied either alone or jointly. The cell line growth was assessed by the colorimetric Mosmann method. RESULTS: hUAG (10(-6), 10(-7) and 10(-10) M) inhibited MC38 cancer cell growth and, at some concentrations (10(-8), 10(-9), 10(-10) M), enhanced the antineoplastic effect of GHS-RA(10(-4) M). In turn, GHS-RA evoked a biphasic effect on MC38 cancer growth: inhibitory at 10(-4) M and stimulatory at 10(-5) and 10(-6) M. Moreover, GHS-RA at the highest examined concentration (10(-4) M) enhanced the cytostatic effect of FU. Human acylated and unacylated ghrelin and GHS-RA inhibited DU145 cancer growth with moderate and different potencies. A dose response effect was observed for the inhibitory action of hG together with the synergistic effect of hUAG and GHS-RA. CONCLUSION: The obtained results indicate an involvement of the ghrelin axis in the growth regulation of colon and prostate cancers and may suggest new therapeutic options for these neoplasms. PMID- 23087148 TI - Wheel running decreases the positive reinforcing effects of heroin. AB - BACKGROUND: The purpose of this study was to examine the effects of voluntary wheel running on the positive reinforcing effects of heroin in rats with an established history of drug self-administration. METHODS: Rats were assigned to sedentary (no wheel) and exercise (wheel) conditions and trained to self administer cocaine under positive reinforcement contingencies. Rats acquiring cocaine self-administration were then tested with various doses of heroin during daily test sessions. RESULTS: Sedentary rats self-administered more heroin than exercising rats, and this effect was greatest at low and moderate doses of heroin. CONCLUSION: These data suggest that voluntary wheel running decreases the positive reinforcing effects of heroin. PMID- 23087149 TI - Influence of acute and subchronic oral administration of dehydroepiandrosterone (DHEA) on nociceptive threshold in rats. AB - BACKGROUND: Dehydroepiandrosterone (DHEA), a neurosteroid, is known to be the most abundant hormone in the human body. Its role in the central nervous system has not been well defined. Previous studies indicate that DHEA is synthesized in the spinal cord and plays an important role in pain modulation. In the present study, we investigated the effect of DHEA on pain threshold in rats after both acute and subchronic treatment. METHOD: Rats were orally administered with DHEA at a dose of 10 mg/kg once daily and the pain threshold was measured with mechanical and thermal stimuli. RESULTS: After acute treatment, DHEA exhibited pronociceptive effects which lasted up to 150 min. After subchronic administration, DHEA showed an opposite effect by elevating the pain threshold. CONCLUSION: The results suggest that DHEA could be indicated as a drug to improve treatment of chronic pain disorders. PMID- 23087150 TI - Influence of 5-(3-chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole 3-thione on the anticonvulsant action of 4 classical antiepileptic drugs in the mouse maximal electroshock-induced seizure model. AB - BACKGROUND: The aim of this study was to determine the effects of 5-(3 chlorophenyl)-4-(4-methylphenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP10) on the protective action of 4 classical antiepileptic drugs - carbamazepine, phenobarbital, phenytoin and valproate - against maximal electroshock-induced seizures in mice. METHODS: Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by an electric current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Acute adverse-effect profiles with respect to motor performance, long-term memory and skeletal muscular strength were measured, together with total brain antiepileptic drug concentrations. RESULTS: TP10 administered intraperitoneally at 10 mg/kg significantly elevated the threshold for electroconvulsions in mice. TP10 at doses of 2.5 and 5 mg/kg had no impact on the threshold for electroconvulsions in mice. Moreover, TP10 (5 mg/kg) significantly enhanced the anticonvulsant activity of valproate, but not that of carbamazepine, phenobarbital or phenytoin in the maximal electroshock seizure test in mice. Pharmacokinetic experiments revealed that TP10 significantly elevated total brain concentrations of valproate in mice. CONCLUSIONS: The enhanced anticonvulsant action of valproate by TP10 in the mouse maximal electroshock-induced seizure model was associated with a pharmacokinetic increase in total brain valproate concentrations in mice. The combinations of TP10 with carbamazepine, phenobarbital and phenytoin were neutral from a preclinical viewpoint. PMID- 23087151 TI - In vitro effects of serotonin and noradrenaline reuptake inhibitors on human platelet adhesion and coagulation. AB - BACKGROUND: Although several studies show that there is an increased risk of bleeding events during antidepressant treatment with selective serotonin reuptake inhibitors (SSRIs), few studies show direct effects in vitro of SSRIs on hemostasis. METHODS: This study was undertaken to investigate the effects on platelet adhesion and plasma coagulation (APTT and PT) of two common SSRIs, citalopram and sertraline, the selective noradrenaline reuptake inhibitor reboxetine, and the serotonin and noradrenaline reuptake inhibitor venlafaxine. RESULTS: None of the compounds affected plasma coagulation significantly but all compounds except for venlafaxine inhibited platelet adhesion by approximately 50% or more at the highest concentration (100 MUg/l, p < 0.01). The potency of respective compound to inhibit platelet adhesion to both collagen and fibrinogen surfaces was in the following order; citalopram > sertraline > reboxetine. In contrast, venlafaxine caused a weak but statistically significant increased platelet adhesion to fibrinogen. CONCLUSION: This study showed that sertraline, citalopram and reboxetine direct and acutely decrease platelet adhesion to both collagen and fibrinogen in vitro. These results also indicate that increased risk for bleeding complications in antidepressant users may not only be explained by depletion of serotonin in platelets. PMID- 23087152 TI - Comparative study of the anti-edematogenic effects of anethole and estragole. AB - BACKGROUND: Anethole and estragole are monoterpene position isomers and constituents of essential oils from aromatic plants and were used in this study with the aim of analyzing their anti-inflammatory activity. METHODS: The anti edematogenic effects of anethole and estragole were evaluated through plethysmometry in Swiss mice. RESULTS: Anethole inhibited carrageenan-induced edema at doses of 3, 10 and 30 mg/kg from 60 to 240 min after induction. However, the inhibitory effects of estragole were observed only from 60 to 120 min at the two highest doses. Anethole and estragole similarly inhibited edema elicited by substance P, bradykinin, histamine and TNF-alpha but were different in the inhibition of serotonin-elicited edema. In addition, only estragole inhibited sodium nitroprusside-induced edema. CONCLUSIONS: Anethole and estragole showed different profiles in the anti-inflammatory response to substance P, bradykinin, histamine, serotonin and TNF-alpha NO is involved only in the inhibition mechanism of estragole. PMID- 23087153 TI - Verapamil-induced autophagy-like process in colon adenocarcinoma COLO 205 cells; the ultrastructural studies. AB - BACKGROUND: Verapamil (Ver) is a well known, worldwide used drug to correct cardiac arrhythmias. The main Ver target is the L-type calcium channel. Modulation of calcium homeostasis vaulted Ver into use in medical applications. METHODS: To examine COLO 205 cells morphology after Ver treatment, an electron microscopy technique was used. RESULTS: This study shows ultrastructural evidence that Ver initiates autophagy-like process in human colon adenocarcinoma COLO 205 cells. TEM photographs revealed the presence of differently developed autophagic vacuoles in response to Ver administration. Furthermore, extensive ultrastructural cell alterations confirmed that cancer cells died via necrosis or apoptosis, as demonstrated by ruptured plasma membrane or condensed chromatin, respectively. CONCLUSIONS: It is the evidence that apoptosis resistant COLO 205 cells are overruled by autophagy-like process. Autophagy-like cell death could be a promising venue to delete cancer cells. Ver appears to be a new potentially effective anticancer compound. PMID- 23087154 TI - Ezetimibe - a new approach in hypercholesterolemia management. PMID- 23087156 TI - Making a black box transparent. PMID- 23087155 TI - High cytidine deaminase expression in the liver provides sanctuary for cancer cells from decitabine treatment effects. AB - We document for the first time that sanctuary in an organ which expresses high levels of the enzyme cytidine deaminase (CDA) is a mechanism of cancer cell resistance to cytidine analogues. This mechanism could explain why historically, cytidine analogues have not been successful chemotherapeutics against hepatotropic cancers, despite efficacy in vitro. Importantly, this mechanism of resistance can be readily reversed, without increasing toxicity to sensitive organs, by combining a cytidine analogue with an inhibitor of cytidine deaminase (tetrahydrouridine). Specifically, CDA rapidly metabolizes cytidine analogues into inactive uridine counterparts. Hence, to determine if sheltering/protection of cancer cells in organs which express high levels of CDA (e.g., liver) is a mechanism of resistance, we utilized a murine xenotransplant model of myeloid cancer that is sensitive to epigenetic therapeutic effects of the cytidine analogue decitabine in vitro and hepato-tropic in vivo. Treatment of tumor bearing mice with decitabine (subcutaneous 0.2mg/kg 2X/week) doubled median survival and significantly decreased extra-hepatic tumor burden, but hepatic tumor burden remained substantial, to which the animals eventually succumbed. Combining a clinically-relevant inhibitor of CDA (tetrahydrouridine) with a lower dose of decitabine (subcutaneous 0.1mg/kg 2X/week) markedly decreased liver tumor burden without blood count or bone marrow evidence of myelotoxicity, and with further improvement in survival. In conclusion, sanctuary in a CDA-rich organ is a mechanism by which otherwise susceptible cancer cells can resist the effects of decitabine epigenetic therapy. This protection can be reversed without increasing myelotoxicity by combining tetrahydrouridine with a lower dose of decitabine. PMID- 23087158 TI - Incorporating video modeling into a school-based intervention for students with autism spectrum disorders. AB - PURPOSE: Video modeling is an intervention strategy that has been shown to be effective in improving the social and communication skills of students with autism spectrum disorders, or ASDs. The purpose of this tutorial is to outline empirically supported, step-by-step instructions for the use of video modeling by school-based speech-language pathologists (SLPs) serving students with ASDs. METHOD: This tutorial draws from the many reviews and meta-analyses of the video modeling literature that have been conducted over the past decade, presenting empirically supported considerations for school-based SLPs who are planning to incorporate video modeling into their service delivery for students with ASD. The 5 overarching procedural phases presented in this tutorial are (a) preparation, (b) recording of the video model, (c) implementation of the video modeling intervention, (d) monitoring of the student's response to the intervention, and (e) planning of the next steps. CONCLUSION: Video modeling is not only a promising intervention strategy for students with ASD, but it is also a practical and efficient tool that is well-suited to the school setting. This tutorial will facilitate school-based SLPs' incorporation of this empirically supported intervention into their existing strategies for intervention for students with ASD. PMID- 23087159 TI - Autism spectrum disorders: experience, training, and confidence levels of school based speech-language pathologists. AB - PURPOSE: To investigate the graduate training experiences of school-based speech language pathologists (SLPs) working with children with autism spectrum disorders (ASDs). Comparisons were made between recent graduates (post 2006) and pre-2006 graduates to determine if differences existed in their academic and clinical experiences or their confidence in working with children with ASDs. METHOD: A 46 item, web-based, national survey was used. Participants were recruited through e mail and listservs for American Speech-Language-Hearing Association Special Interest Divisions 1 (Language, Learning, and Education) and 16 (School-Based Issues). RESULTS: Recent graduates reported a greater amount of graduate coursework relating to ASDs than pre-2006 graduates. However, the pre-2006 graduates reported significantly greater confidence in the areas of counseling parents of children who exhibit "red flags" of ASDs and addressing social communication, literacy, and academics in intervention. CONCLUSION: Results of the current survey indicated an increase in the amount of preprofessional training that SLPs receive relating to ASDs. Nonetheless, the majority of SLPs reported that they could have benefitted from additional clinical experience and training working with children with ASDs. The greater degree of confidence reported by the pre-2006 graduates highlights the importance of experience and continuing education for professionals in the field of speech-language pathology. PMID- 23087160 TI - Identification of cargo proteins specific for the nucleocytoplasmic transport carrier transportin by combination of an in vitro transport system and stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative proteomics. AB - The human importin-beta family consists of 21 nucleocytoplasmic transport carrier proteins that carry proteins and RNAs across the nuclear envelope through nuclear pores in specific directions. These transport carriers are responsible for the nucleocytoplasmic transport of thousands of proteins, but the cargo allocation of each carrier, which is necessary information if one wishes to understand the physiological context of transport, is poorly characterized. To address this issue, we developed a high-throughput method to identify the cargoes of transport carriers by applying stable isotope labeling by amino acids in cell culture to construct an in vitro transport system. Our method can be outlined in three steps. (1) Cells are cultured in a medium containing a stable isotope. (2) The cell membranes of the labeled cells are permeabilized, and proteins extracted from unlabeled cells are transported into the nuclei of the permeabilized cells. In this step, the reaction system is first depleted of all importin-beta family carriers and then supplemented with a particular importin-beta family carrier of interest. (3) Proteins in the nuclei are extracted and analyzed quantitatively via LC-MS/MS. As an important test case, we used this method to identify cargo proteins of transportin, a representative member of the importin-beta family. As expected, the identified candidate cargo proteins included previously reported transportin cargoes as well as new potential cargoes, which we corroborated via in vitro binding assays. The identified cargoes are predominately RNA-interacting proteins, affirming that cargoes allotted to the same carrier share functional characteristics. Finally, we found that the transportin cargoes possessed at least two classes of signal sequences: the well characterized PY-nuclear localization signals specific for transportin, and Lys/Arg-rich segments capable of binding to both transportin and importin-beta. Thus, our method will be useful for linking a carrier to features shared among its cargoes and to specific nuclear localization signals. PMID- 23087161 TI - Putting public health back into the global cancer agenda. PMID- 23087162 TI - Public health oncology: a framework for progress in low- and middle-income countries. AB - BACKGROUND: The problems of cancer are increasing in low- and middle-income countries (LMCs), which now have significant majorities of the global case and mortality burdens. The professional oncology community is being increasingly called upon to define pragmatic and realistic approaches to these problems. PATIENTS AND METHODS: Focusing on mortality and case burden outcomes defines public health oncology or population-affecting cancer medicine. We use this focus to consider practical approaches. RESULTS: The greatest cancer burdens are in Asia. A public health oncology perspective mandates: first, addressing the major and social challenges of cancer medicine for populations: human rights, health systems, corruption, and our limited knowledge base for value-conscious interventions. Second, adoption of evolving concepts and models for sustainable development in LMCs. Third, clear and realistic statements of action and inaction affecting populations, grounded in our best cancer science, and attention to these. Finally, framing the goals and challenges for population-affecting cancer medicine requires a change in paradigm from historical top-down models of technology transfer, to one which is community-grounded and local-evidence based. CONCLUSION: Public health oncology perspectives define clear focus for much needed research on country-specific practical approaches to cancer control. PMID- 23087163 TI - Cardiac tamponade caused by migration of ingested metallic wire. PMID- 23087164 TI - Litorisediminicola beolgyonensis gen. nov., sp. nov., isolated from a coastal sediment. AB - A Gram-negative, non-spore-forming, aerobic, non-flagellated and rod- or oval shaped bacterial strain, BB-MW24(T), was isolated from a coastal sediment in South Korea. Strain BB-MW24(T) grew optimally at 30-37 degrees C, at pH 7.0-7.5 and in the presence of 2.0-3.0% (w/v) NaCl. A neighbour-joining phylogenetic tree based on 16S rRNA gene sequences revealed that strain BB-MW24(T) clustered with Ponticoccus litoralis CL-GR66(T) and Roseivivax lentus S5-5(T), with which it exhibited 96.0 and 96.2% 16S rRNA gene sequence similarity, respectively. Strain BB-MW24(T) exhibited 85.2% gyrB sequence similarity with Sagittula stellata DSM 11524(T) and 83.3 and 83.2% gyrB sequence similarity with P. litoralis DSM 18986(T) and R. lentus S5-5(T), respectively. Strain BB-MW24(T) contained Q-10 as the predominant ubiquinone and C18:1omega7c as the predominant fatty acid. The polar lipid profile in strain BB-MW24(T) was similar to those of members of the genera Ponticoccus and Roseivivax, but one unidentified phospholipid was found as a major polar lipid only in strain BB-MW24(T). The DNA G+C content was 68.9 mol%. The phylogenetic data and differential chemotaxonomic and phenotypic properties revealed that strain BB-MW24(T) represents a novel species in a new genus within the class Alphaproteobacteria, for which the name Litorisediminicola beolgyonensis gen. nov., sp. nov. is proposed; the type strain of Litorisediminicola beolgyonensis is BB-MW24(T) (=KCTC 32139(T) =CCUG 62953(T)). PMID- 23087165 TI - Sinobacterium caligoides gen. nov., sp. nov., a new member of the family Oceanospirillaceae isolated from the South China Sea, and emended description of Amphritea japonica. AB - A taxonomic study was carried out on strain SCSWE24(T), isolated from a seawater sample collected from the South China Sea. Cells of strain SCSWE24(T) were Gram negative, rod-shaped, non-motile, moderately halophilic and capable of reducing nitrate to nitrite. Growth was observed at salinities from 1.5 to 4.5% and at 4 37 degrees C; it was unable to degrade gelatin. The dominant fatty acids (>15%) were summed feature 3 (C16:1omega7c and/or C16:1omega6c; 50.4%) and C16:0 (21.1%). The G+C content of the chromosomal DNA was 58.8 mol%. 16S rRNA gene sequence comparisons showed that strain SCSWE24(T) was most closely related to an uncultured bacterium clone Tun3b.F5 (98%; GenBank accession no. FJ169216), and showed 92% similarity to an endosymbiont bacterium from the bone-eating worm Osedax mucofloris (clone Omu 9 c4791; FN773233). Levels of similarity between strain SCSWE24(T) and type strains of recognized species in the family Oceanospirillaceae were less than 93%; the highest similarity was 92%, to both Amphritea japonica JAMM 1866(T) and 'Oceanicoccus sagamiensis' PZ-5. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain SCSWE24(T) formed a distinct evolutionary lineage within the family Oceanospirillaceae. Strain SCSWE24(T) was distinguishable from members of phylogenetically related genera by differences in several phenotypic properties. On the basis of the phenotypic and phylogenetic data, strain SCSWE24(T) represents a novel species of a new genus, for which the name Sinobacterium caligoides gen. nov., sp. nov. is proposed. The type strain of Sinobacterium caligoides is SCSWE24(T) (=CCTCC AB 209289(T) =LMG 25705(T) =MCCC 1F01088(T)). An emended description of Amphritea japonica is also provided. PMID- 23087166 TI - Sagittula marina sp. nov., isolated from seawater and emended description of the genus Sagittula. AB - A novel bacterium, designated strain F028-2(T), was isolated from seawater at Damupo beach in Pohang, Korea, and investigated in a taxonomic study using a polyphasic approach. This novel strain was strictly aerobic, non-motile, Gram stain-negative and rod-shaped, and occasionally formed aggregates. The temperature, pH and NaCl ranges for growth were 4-30 degrees C, pH 6.5-9.0 and 1 7% (w/v), respectively. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain F028-2(T) formed a lineage within the family Rhodobacteraceae of the class Alphaproteobacteria, and was closely related to members of the genera Sagittula and Antarctobacter with 96.3-96.4% sequence similarities. The polar lipid profile of strain F028-2(T) comprised diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids, one unidentified phospholipid and six unidentified lipids. The predominant cellular fatty acids were C18:1omega7c and C12:1 3-OH. The genomic DNA G+C content of strain F028-2(T) was 61.6 mol% and the major respiratory quinone was Q-10. Based on phenotypic, phylogenetic and genotypic data, strain F028-2(T) is considered to represent a novel species in the genus Sagittula, for which the name Sagittula marina sp. nov. is proposed. The type strain is F028-2(T) (=KCTC 23543(T)=JCM 17627(T)). An emended description of the genus Sagittula is also proposed. PMID- 23087167 TI - Burkholderia grimmiae sp. nov., isolated from a xerophilous moss (Grimmia montana). AB - A Gram-staining-negative, rod-shaped, non-spore-forming bacterium, designated strain R27(T), was isolated from the moss Grimmia montana, collected from Beijing Songshan National Nature Reserve, China, and characterized by using a polyphasic taxonomic approach. The predominant fatty acids of strain R27(T) were C18:1omega7c (33.6%), C16:0 (16.3%), summed feature 3 (C16:1omega7c and/or C16:1omega6c; 15.8%) and C17:0 cyclo (8.7%) and its major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, three uncharacterized aminolipids and an unknown phospholipid. Strain R27(T) contained Q-8 as the dominant isoprenoid quinone and the G+C content of its genomic DNA was 64.6 mol%. On the basis of 16S rRNA gene sequence comparison, strain R27(T) showed 99.1% similarity to the closest related type strain, Burkholderia zhejiangensis OP-1(T), and 97.6% similarity to Burkholderia glathei ATCC 29195(T). However, the DNA-DNA relatedness between strain R27(T) and B. zhejiangensis CCTCC AB 2010354(T) and B. glathei ATCC 29195(T) was 10.2 and 14.9%, respectively. Based on 16S rRNA and rpoB gene sequence similarities and phenotypic and chemotaxonomic data, strain R27(T) is considered to represent a novel species of the genus Burkholderia, for which the name Burkholderia grimmiae sp. nov. is proposed. The type strain is R27(T) (=CGMCC 1.11013(T) =DSM 25160(T)). PMID- 23087168 TI - Leptochlorella corticola gen. et sp. nov. and Kalinella apyrenoidosa sp. nov.: two novel Chlorella-like green microalgae (Trebouxiophyceae, Chlorophyta) from subaerial habitats. AB - The diversity of green microalgae in subaerial habitats remains largely unexplored and a number of new genus- and species-level lineages have been discovered recently. The traditional green algal genus, Chlorella, which accommodated coccoid unicellular green algal species with globular to oval cells, reproducing entirely by autospores, has been found to be polyphyletic. In this study, we provide a detailed characterization of two strains of microalgae isolated from tree bark in the Mediterranean. These algae share the general Chlorella-like morphology and their 18S rRNA and rbcL gene sequences place them in the Trebouxiophyceae. Strain CAUP H8401 forms an independent trebouxiophycean lineage, together with three previously published 18S rRNA gene environmental sequences of undescribed microalgae, which were retrieved from profoundly different habitats. In contrast, strain CAUP H7902 is related to Kalinella bambusicola in the Watanabea clade of the Trebouxiophyceae on the basis of its 18S rRNA gene sequence. This relationship is also supported by the rbcL gene sequence, acquired from the type strain of K. bambusicola. The investigated strains are described as representatives of a novel species in a new genus, Leptochlorella corticola gen. et sp. nov., and a novel species, Kalinella apyrenoidosa sp. nov., according to the International Code of Nomenclature for Algae, Fungi and Plants. PMID- 23087169 TI - Parvularcula dongshanensis sp. nov., isolated from soft coral. AB - A taxonomic study was carried out on strain SH25(T), which was isolated from soft coral collected from Dongshan Island, China. The isolate was a heterotrophic organism to the soft coral, and was a Gram-reaction-negative, short rod that was motile by a polar flagellum. Growth was observed at salinities from 0 to 12% and at temperatures from 10 to 41 degrees C. It was unable to reduce nitrate to nitrite. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SH25(T) belonged to the genus Parvularcula, with highest sequence similarity to Parvularcula lutaonensis CC-MMS-1(T) (96.1%) and Parvularcula bermudensis HTCC2503(T) (94.3%); 16S rRNA gene sequence similarities to other taxa were below 90.0%. The dominant fatty acids were C16:0 and summed feature 8 (C18:1omega7c/omega6c,). The G+C content of the chromosomal DNA was 61.8 mol%. The major quinone was Q10. These combined genotypic and phenotypic data show that strain SH25(T) represents a novel species of the genus Parvularcula, for which the name Parvularcula dongshanensis sp. nov. is proposed. The type strain is SH25(T) (=CCTCC AB 2010355(T)=LMG 26158(T)=MCCC 1A06534(T)). PMID- 23087170 TI - Massilia lurida sp. nov., isolated from soil. AB - A bacterial isolate, designated strain D5(T), was isolated from a soil sample collected from the Inner Mongolia Autonomous Region, China, and subjected to a taxonomic investigation using a polyphasic approach. Strain D5(T) was aerobic, Gram-stain-negative, rod-shaped and motile. Strain D5(T) fell within the evolutionary radius of the genus Massilia in the phylogenetic tree based on 16S rRNA gene sequences and was most closely related to Massilia plicata 76(T) with 97.3% 16S rRNA gene sequence similarity. The predominant quinone of strain D5(T) was Q-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. The major fatty acids were summed feature 3 (comprising C16:1omega7c and/or iso-C15:0 2-OH) and C16:0. These chemotaxonomic data supported the affiliation of strain D5(T) to the genus Massilia. The genomic DNA G+C content was 65.9 mol%. Mean DNA-DNA relatedness values between strain D5(T) and the phylogenetically most closely related species of the genus Massilia, Massilia plicata KCTC 12344(T) and Massilia dura KCTC 12342(T), were 26 and 21%, respectively. Strain D5(T) could be differentiated from recognized species of the genus Massilia by several phenotypic characteristics. It is clear from the data presented that strain D5(T) represents a novel species of the genus Massilia, for which the name Massilia lurida sp. nov. is proposed. The type strain is D5(T) (=CGMCC 1.10822(T)=KCTC 23880(T)). PMID- 23087172 TI - Relaxin regulates hyaluronan synthesis and aquaporins in the cervix of late pregnant mice. AB - Cervical ripening is associated with loss of structural integrity and tensile strength, thus enabling the cervix to dilate at term. It is characterized by changes in glycosaminoglycan composition, increased water content, and a progressive reorganization of the collagen network. The peptide hormone relaxin via interaction with its receptor, relaxin family peptide receptor 1 (RXFP1), promotes tissue hydration and increases cervical hyaluronan (HA) concentrations, but the mechanisms that regulate these effects are not known. This study in relaxin mutant (Rln(-/-)) mice tested the hypothesis that relaxin regulates HA synthase and aquaporin (AQP) expression in the cervix. We also assessed expression of the RXFP1 protein by immunohistochemistry. Pregnant Rln(-/-) mice had lower Has2 and Aqp3 expression on d 18.5 of pregnancy and decreased cervical HA compared with wild-type Rln(+/+) mice. Chronic infusion of relaxin for 4 or 6 d in pregnant Rln(-/-) mice reversed these phenotypes and increased Has2 and Aqp3 compared with placebo controls. Relaxin-treated mice also had lower Has1 and Aqp5. Changes in gene expression were paralleled by increases in cervical HA and variations in AQP3 and AQP5 protein localization in epithelial cells of Rln(-/-) cervices. Our findings demonstrate that relaxin alters AQP expression in the cervix and initiates changes in glycosaminoglycan composition through increased HA synthesis. These effects are likely mediated through RXFP1 localized to subepithelial stromal cells and epithelial cells. We suggest these actions of relaxin collectively promote water recruitment into the extracellular matrix to loosen the dense collagen fiber network. PMID- 23087171 TI - Thyroid hormone receptor agonists reduce serum cholesterol independent of the LDL receptor. AB - The majority of cholesterol reduction therapies, such as the statin drugs, work primarily by inducing the expression of hepatic low-density lipoprotein receptors (LDLRs), rendering these therapeutics only partially effective in animals lacking LDLRs. Although thyroid hormones and their synthetic derivatives, often referred to as thyromimetics, have been clearly shown to reduce serum cholesterol levels, this action has generally been attributed to their ability to increase expression of hepatic LDLRs. Here we show for the first time that the thyroid hormone T(3) and the thyroid hormone receptor-beta selective agonists GC-1 and KB2115 are capable of markedly reducing serum cholesterol in mice devoid of functional LDLRs by inducing Cyp7a1 expression and stimulating the conversion and excretion of cholesterol as bile acids. Based on this LDLR-independent mechanism, thyromimetics such as GC-1 and KB2115 may represent promising cholesterol lowering therapeutics for the treatment of diseases such as homozygous familial hypercholesterolemia, a rare genetic disorder caused by a complete lack of functional LDLRs, for which there are limited treatment options because most therapeutics are only minimally effective. PMID- 23087174 TI - Mamld1 deficiency significantly reduces mRNA expression levels of multiple genes expressed in mouse fetal Leydig cells but permits normal genital and reproductive development. AB - Although mastermind-like domain containing 1 (MAMLD1) (CXORF6) on human chromosome Xq28 has been shown to be a causative gene for 46,XY disorders of sex development with hypospadias, the biological function of MAMLD1/Mamld1 remains to be elucidated. In this study, we first showed gradual and steady increase of testicular Mamld1 mRNA expression levels in wild-type male mice from 12.5 to 18.5 d postcoitum. We then generated Mamld1 knockout (KO) male mice and revealed mildly but significantly reduced testicular mRNA levels (65-80%) of genes exclusively expressed in Leydig cells (Star, Cyp11a1, Cyp17a1, Hsd3b1, and Insl3) as well as grossly normal testicular mRNA levels of genes expressed in other cell types or in Leydig and other cell types. However, no demonstrable abnormality was identified for cytochrome P450 17A1 and 3beta-hydroxysteroid dehydrogenase (HSD3B) protein expression levels, appearance of external and internal genitalia, anogenital distance, testis weight, Leydig cell number, intratesticular testosterone and other steroid metabolite concentrations, histological findings, in situ hybridization findings for sonic hedgehog (the key molecule for genital tubercle development), and immunohistochemical findings for anti-Mullerian hormone (Sertoli cell marker), HSD3B (Leydig cell marker), and DEAD (Asp-Glu-Ala Asp) box polypeptide 4 (germ cell marker) in the KO male mice. Fertility was also normal. These findings imply that Mamld1 deficiency significantly reduces mRNA expression levels of multiple genes expressed in mouse fetal Leydig cells but permits normal genital and reproductive development. The contrastive phenotypic findings between Mamld1 KO male mice and MAMLD1 mutation positive patients would primarily be ascribed to species difference in the fetal sex development. PMID- 23087173 TI - Expression and function of thyroid hormone transporters in the microvillous plasma membrane of human term placental syncytiotrophoblast. AB - The transplacental passage of thyroid hormones (THs) from mother to fetus in humans has been deduced from observational clinical studies and is important for normal fetoplacental development. To investigate the transporters that regulate TH uptake by syncytiotrophoblast (the primary barrier to maternal-fetal exchange, which lies in direct contact with maternal blood), we isolated the microvillous plasma membrane (MVM) of human term syncytiotrophoblasts. We have demonstrated that MVM vesicles express plasma membrane TH transporter proteins, including system-L (L-type amino acid transporter 1 and CD98), monocarboxylate transporters (MCTs) 8 and 10, organic anion-transporting polypeptides 1A2 and 4A1. We provide the first definitive evidence that the human syncytiotrophoblast MVM is capable of rapid, saturable T(4) and T(3) uptake at similar rates and in a Na(+) independent manner. These two major forms of THs could not significantly inhibit each others' uptake, suggesting that each is mediated by largely different transporters. No single transporter was noted to play a dominant role in either T(4) or T(3) uptake. Using combinations of transporter inhibitors that had an additive effect on TH uptake, we provide evidence that 67% of saturable T(4) uptake is facilitated by system-L and MCT10 with a minor role played by organic anion-transporting polypeptides, whereas 87% of saturable T(3) uptake is mediated by MCT8 and MCT10. Our data demonstrate that syncytiotrophoblast may control the quantity and forms of THs taken up by the human placenta. Thus, syncytiotrophoblast could be critical in regulating transplacental TH supply from the mother to the fetus. PMID- 23087175 TI - Wnt inhibitory factor 1 (Wif1) is regulated by androgens and enhances androgen dependent prostate development. AB - Fetal prostate development from urogenital sinus (UGS) epithelium requires androgen receptor (AR) activation in UGS mesenchyme (UGM). Despite growing awareness of sexually dimorphic gene expression in the UGS, we are still limited in our knowledge of androgen-responsive genes in UGM that initiate prostate ductal development. We found that WNT inhibitory factor 1 (Wif1) mRNA is more abundant in male vs. female mouse UGM in which its expression temporally and spatially overlaps androgen-responsive steroid 5alpha-reductase 2 (Srd5a2). Wif1 mRNA is also present in prostatic buds during their elongation and branching morphogenesis. Androgens are necessary and sufficient for Wif1 expression in mouse UGS explant mesenchyme, and testicular androgens remain necessary for normal Wif1 expression in adult mouse prostate stroma. WIF1 contributes functionally to prostatic bud formation. In the presence of androgens, exogenous WIF1 protein increases prostatic bud number and UGS basal epithelial cell proliferation without noticeably altering the pattern of WNT/beta-catenin responsive Axin2 or lymphoid enhancer binding factor 1 (Lef1) mRNA. Wif1 mutant male UGSs exhibit increased (Sfrp)2 and (Sfrp)3 expression and form the same number of prostatic buds as the wild-type control males. Collectively our results reveal Wif1 as one of the few known androgen-responsive genes in the fetal mouse UGM and support the hypothesis that androgen-dependent Wif1 expression is linked to the mechanism of androgen-induced prostatic bud formation. PMID- 23087177 TI - PD-1 is a novel regulator of human B-cell activation. AB - The outcome of the adaptive immune response is determined by the integration of both positive and negative signals, respectively, induced upon the triggering of co-signaling receptors. One of them, programmed cell death 1 (PDCD1/PD-1) has largely been shown to be involved in the negative regulation of T-cell activation. However, PD-1 is also expressed on human B cells, and its role(s) in the process of human B-cell activation remains uncertain thus far. In this study, we describe the expression of PD-1 on the major human B-cells subsets isolated from peripheral blood and lymph nodes. We showed that PD-1 was expressed on naive B cells, was differentially expressed on peripheral IgM memory as compared with memory B cells and was lost on germinal center B cells. Expression of PD-1 ligands (PD-Ls) was induced by TLR9 activation. Finally, we showed that PD-1 was recruited to the B-cell receptor upon triggering. We determined that during TLR9 activation, blockade of PD-1/PD-Ls pathways indeed increased B-cell activation, proliferation and the production of inflammatory cytokines. Altogether, our results show, that, as reported in T cells, PD-1/PD-Ls complexes acted as inhibitors of the B-cell activation cascade and highlight the importance of devising future therapies able to modulate lymphocyte activation through the targeting of the PD-1/PD-Ls pathways. PMID- 23087178 TI - Progression to rheumatoid arthritis in early inflammatory arthritis is associated with low IL-7 serum levels. AB - OBJECTIVE: Early diagnosis of rheumatoid arthritis (RA) remains a challenge. Interleukin (IL)-7 is a pleiotropic cytokine that plays a central role in the development and maintenance of T-cells and has been associated with T-cell dysfunction in RA. Serum levels of IL-7 are reduced in both early and established disease. The aim of this study was to determine whether serum IL-7 can identify patients with very early inflammatory joint symptoms who will progress to RA, and to examine whether IL-7 levels predict disease persistence and radiographic progression. METHODS: Patients with inflammatory joint symptoms<6 months followed over 5 years for progression to RA and 80 healthy controls were studied. Baseline IL-7 levels were measured by ELISA. RESULTS: Of 250 patients, 108 developed RA (ACR 1987- criteria). IL-7 at inclusion was reduced significantly in RA compared with non-RA patients (p=0.009). IL-7 was categorised using the lower limit of the healthy control distribution (10 pg/ml). In multivariate analysis, independent predictors of RA development were: antibodies against citrullinated peptides (ACPA) positivity (p=0.001), IL-7<10 pg/ml (p=0.003) and swollen joint count (p=0.050). In the ACPA-negative subgroup (n=199), the only predictors were: DAS 44 (p=0.001), IL-7<10 pg/ml (p=0.010) and radiographic erosions (p=0.050). At 1 year follow-up, remission (DAS<1.6) was only predicted by ACPA negativity (p=0.019) and IL-7>17 pg/ml at recruitment (p=0.013). CONCLUSION: These data demonstrate that low IL-7 levels in patients with recent onset of symptoms may have value as a diagnostic biomarker predicting the progression to RA, particularly in ACPA-negative disease, as well as being related to RA progression. PMID- 23087176 TI - Angiotensin receptor blockade recovers hepatic UCP2 expression and aconitase and SDH activities and ameliorates hepatic oxidative damage in insulin resistant rats. AB - Metabolic syndrome (MetS) is commonly associated with elevated renin-angiotensin system, oxidative stress, and steatohepatitis with down-regulation of uncoupling proteins (UCPs). However, the mechanisms linking renin-angiotensin system, steatosis, and UCP2 to hepatic oxidative damage during insulin resistance are not described. To test the hypothesis that angiotensin receptor activation contributes to decreased hepatic UCP2 expression and aconitase activity and to increased oxidative damage after increased glucose intake in a model of MetS, lean and obese Long Evans rats (n = 10/group) were randomly assigned to the following groups: 1) untreated Long Evans Tokushima Otsuka (lean, strain control), 2) untreated Otsuka Long Evans Tokushima Fatty (OLETF) (MetS model), 3) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg.d * 6 wk), 4) OLETF + high glucose (HG) (5% in drinking water * 6 wk), and 5) OLETF + ARB + HG (ARB/HG * 6 wk). HG increased body mass (37%), plasma triglycerides (TGs) (35%), plasma glycerol (87%), plasma free fatty acids (28%), and hepatic nitrotyrosine (74%). ARB treatment in HG decreased body mass (12%), plasma TG (15%), plasma glycerol (23%), plasma free fatty acids (14%), and hepatic TG content (42%), suggesting that angiotensin receptor type 1 (AT1) activation and increased adiposity contribute to the development of obesity-related dyslipidemia. ARB in HG also decreased hepatic nitrotyrosine and increased hepatic UCP2 expression (59%) and aconitase activity (40%), as well as antioxidant enzyme activities (50 120%), suggesting that AT1 activation also contributes to protein oxidation, impaired lipid metabolism, and antioxidant metabolism in the liver. Thus, in addition to promoting obesity-related hypertension, AT1 activation may also impair lipid metabolism and antioxidant capacity, resulting in steatosis via decreased UCP2 and tricarboxylic acid cycle activity. PMID- 23087179 TI - Sustained efficacy of the monoclonal anti-interleukin-1 beta antibody canakinumab in a 9-month trial in Schnitzler's syndrome. AB - OBJECTIVES: Schnitzler's syndrome is a chronic disabling autoinflammatory disorder, characterised by chronic urticaria, paraproteinemia and systemic inflammation. The interleukin (IL) 1 receptor antagonist anakinra is a very effective treatment, but requires daily injection and blocks both IL-1alpha and IL-1beta. Canakinumab is a selective human monoclonal anti-IL-1beta antibody with a long half-life. We investigated the long-term efficacy and safety of canakinumab in Schnitzler's syndrome. METHODS: In an open-label, single-treatment arm trial, eight patients with Schnitzler's syndrome received monthly injections with 150 mg canakinumab subcutaneously for 6 months, followed by a 3-month observation period. Primary outcome was complete or clinical remission at day 14. Secondary outcome measures included inflammatory markers, quality of life, time to relapse, safety and tolerability. RESULTS: After stopping anakinra, patients developed moderate to severe clinical symptoms. Canakinumab induced complete or clinical remission at day 14 in all eight patients. Median C-reactive protein concentrations decreased from 169 mg/l at baseline to less than 10 mg/l on day 14 and remained low or undetectable. One patient discontinued participation on day 39 because of return of symptoms while all others remained in complete or clinical remission during the 6-month treatment period. Relapse after last canakinumab dose occurred within 3 months in four patients. For two patients, remission continued several months post-study. Five patients reported at least one adverse event, predominantly mild upper respiratory tract infections. One patient died in a traffic accident. CONCLUSIONS: In this 9-month study, monthly 150 mg canakinumab injection was an effective and well-tolerated treatment for Schnitzler's syndrome. Our data demonstrate that IL-1beta plays a pivotal role in this disease. CLINICALTRIALS.GOV: NCT01276522. PMID- 23087180 TI - Granulocyte colony stimulating factor exacerbates antineutrophil cytoplasmic antibody vasculitis. AB - OBJECTIVES: Granulocyte colony stimulating factor (GCSF) is important in mobilising neutrophils from the bone marrow but also has a range of proinflammatory effects. We therefore decided to investigate the role of GCSF in antineutrophil cytoplasmic antibody (ANCA) vasculitis. METHODS: We measured GCSF levels in the serum of 38 patients with active ANCA vasculitis compared with 31 age-matched controls, and assessed the effect of GCSF priming on the response of human neutrophils to ANCA. We also examined the effect of exogenous GCSF administration in a murine model of antimyeloperoxidase (anti-MPO) vasculitis, and the effect of GCSF on murine neutrophil activation. RESULTS: The serum levels of GCSF in patients with active ANCA vasculitis were significantly higher than those of age matched healthy controls (mean 38.04 vs 18.35 pg/ml, p<0.001). Furthermore, we demonstrated that GCSF primed human neutrophils in vitro for a respiratory burst in response to anti-MPO ANCA. In an anti-MPO antibody transfer model, mice given GCSF had more crescents (mean 29.1% vs 5.8% per glomerular cross section, p<0.05), more macrophages (mean 3.2 vs 1.2 per glomerular cross section, p<0.01), higher serum creatines (mean 13.6 vs 8.3 MUmol/l, p<0.05) and more haematuria (p<0.05) compared with controls. In vivo administration of GCSF with lipopolysaccharide (LPS), but not LPS alone, led to upregulation of CD11c on murine neutrophils. CONCLUSIONS: These data suggest that GCSF, which is raised in patient serum, may play an important role in exacerbating disease in ANCA vasculitis. In addition, GCSF therapy for neutropenia should be used with caution in these patients. PMID- 23087181 TI - Serological changes in the course of traditional and biological disease modifying therapy of rheumatoid arthritis. AB - OBJECTIVE: To investigate changes of rheumatoid factor (RF) and antibodies against citrullinated peptides (ACPA) during therapy with disease modifying antirheumatic drugs. METHODS: We obtained clinical and serological data of patients from the treatment start and after 6 months of therapy. With non parametric tests, we analysed changes of ACPA and RF levels between the two visits and the influence of treatment response. Furthermore, we analysed potential influential factors as disease chronicity, different therapeutics and the trend over 18 months. RESULTS: 143 ACPA and RF positive patients were included. The median (25th/75th percentile) relative changes after 6 months were 35.6% (-63.3; -8.3) for RF and -15.2% (-40.0; 10.0) for ACPA (p<0.001 for both). Changes of RF levels were significantly greater than those seen for ACPA (p<0.001). The decrease of ACPA and RF was significantly higher in treatment responders (p=0.034 and p=0.01, respectively). Aside from changes in disease activity, only a short disease duration showed an independent effect on changes of RF levels (p=0.087). CONCLUSIONS: ACPA and RF levels decreased significantly after 6 months of therapy. Reductions of both autoantibodies were closely linked to a reduction of disease activity. RF declined faster, to a larger extent and in greater numbers of patients than ACPA. PMID- 23087182 TI - MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. AB - OBJECTIVE: To evaluate whether miR-20a belonging to the cluster miR-17-92 is a negative regulator of inflammation in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) by modulating expression of apoptosis signal-regulating kinase (ASK) 1, a key component of the toll-like receptors 4 pathway, upstream of p38 mitogen-activated protein kinase. METHODS: Evaluation of miR-20a and ASK1 mRNA was performed by RT-qPCR. ASK1 protein expression was assessed by western blotting. Overexpression of miR-20a was performed by transfection of RA FLS and THP-1 cells with miR-20a mimics. Interleukin (IL)-6, CXCL-10, IL-1beta and TNF alpha release were measured by ELISA. The role of miR-20a in vivo was assessed by IL-6 release from macrophages obtained from mice injected intraperitoneally with vectorised miR-20a mimics. RESULTS: We showed that stimulation of RA FLS with lipopolysacharide (LPS) and bacterial lipoproteins (BLP) induces a drop in expression of miR-20a and that this decrease is associated with an upregulation of ASK1 expression. Using transfection of Ask1 3'UTR reporters, we demonstrate that Ask1 is a direct target of miR-20a. Overexpression of miR-20a led to a global decrease in ASK1 protein in BLP- and LPS-activated cells indicating that miR-20a regulates the expression of ASK1 at the translational level. Transfection of miR-20a mimics decreases IL-6 and CXCL10 release by RA FLS and IL-1beta and TNF-alpha by activated THP-1 cells but only in response to LPS. Last, injection of vectorised miR-20a mimics to mice led to a global decrease in ASK1 protein expression and IL-6 secretion in LPS-activated macrophages. CONCLUSIONS: Our data point toward an important role for miR-20a in the regulation of pro-inflammatory cytokines release, by controlling ASK1 expression in RA FLS. PMID- 23087183 TI - Efficacy of anti-IL-1 treatment in Majeed syndrome. AB - BACKGROUND AND OBJECTIVE: Majeed syndrome is an autosomal recessive disorder characterised by the triad of chronic recurrent multifocal osteomyelitis, congenital dyserythropoietic anaemia and a neutrophilic dermatosis that is caused by mutations in LPIN2. Long-term outcome is poor. This is the first report detailing the treatment of Majeed syndrome with biological agents and demonstrates clinical improvement with IL-1blockade. METHODS: We describe the clinical presentation, genetic analysis, cytokine profiles and response to biological therapy in two brothers with Majeed syndrome. RESULTS: Both boys were homozygous for a novel 2-base pair deletion in LPIN2 (c.1312_1313delCT; p.Leu438fs+16X), confirming the diagnosis. Their bone disease and anaemia were refractory to treatment with corticosteroids. Both siblings had elevated proinflammatory cytokines in their serum, including tumour necrosis factor alpha (TNF-alpha), however a trial of the TNF inhibitor etanercept resulted in no improvement. IL-1 inhibition with either a recombinant IL-1 receptor antagonist (anakinra) or an anti-IL-1beta antibody (canakinumab) resulted in dramatic clinical and laboratory improvement. CONCLUSIONS: The differential response to treatment with TNF-alpha or IL-1 blocking agents sheds light into disease pathogenesis; it supports the hypothesis that Majeed syndrome is an IL-1beta dependent autoinflammatory disorder, and further underscores the importance of IL 1 in sterile bone inflammation. PMID- 23087184 TI - Why the findings of published multiple treatment comparison meta-analyses of biologic treatments for rheumatoid arthritis are different: an overview of recurrent methodological shortcomings. AB - OBJECTIVES: To evaluate the quality of published multiple treatment comparison (MTC) meta-analyses on biologic disease modifying antirheumatic drugs (bDMARDs) for rheumatoid arthritis (RA), and to identify methodological issues that can explain the discrepancies in the findings of these MTCs. METHODS: We searched MEDLINE for MTCs of bDMARDs for RA. Following the PRISMA guidelines, we extracted a large set of methodological items. These comprised of inclusion/exclusion criteria, information sources, reported results and outcomes measures, approaches to dealing with differing response profiles to available treatments, monotherapies versus combination therapies, and potential sources of heterogeneity. RESULTS: We identified 13 published MTCs, of which nine were published since 2009. Despite similar stated eligibility criteria and objectives across MTCs, we identified major discrepancies in the estimated treatment effects, the inclusion of trials and analytic approaches. The number of included trials was typically much smaller than the number of eligible trials at the time of publication. Three out of six MTCs including patients of differing response profiles inappropriately combined DMARD-naive and DMARD-inadequate responder patients in the analyses. Four out of eight MTCs that considered both monotherapy and combination therapy (ie, concomitant DMARD) did not adjust for the potential effect modification. Half of the identified MTCs did not explore potential sources of heterogeneity, and the explored sources varied considerably. Last, most MTCs only included one or two efficacy outcomes (eg, ACR50) and only two considered health related quality of life outcomes (eg, HAQ). CONCLUSIONS: The identified methodological shortcomings and inconsistencies most likely explain the observed discrepancies in findings across MTCs. PMID- 23087185 TI - The NHS and market forces in healthcare: the need for organisational ethics. AB - The NHS in England is an organisation undergoing substantial change. The passage of the Health and Social Care Act 2012, consolidates and builds on previous health policies and introduces further 'market-style' reforms of the NHS. One of the main aspects of these reforms is to encourage private and third sector providers to deliver NHS services. The rationale for this is to foster a more competitive market in healthcare to encourage greater efficiency and innovation. This changing healthcare environment in the English NHS sharpens the need for attention to be paid to the ethical operation of healthcare organisations. All healthcare organisations need to consider the ethical aspects of their operation, whether state or privately run. However, the changes in the type of organisations used to provide healthcare (such as commercial companies) can create new relationships and ethical tensions. This paper will chart the development of organisational ethics as a concern in applied ethics and how it arose in the USA largely owing to changes in the organisation of healthcare financing and provision. It will be argued that an analogous transition is happening in the NHS in England. The paper will conclude with suggestions for the development of organisational ethics programmes to address some of the possible ethical issues raised by this new healthcare environment that incorporates both private and public sector providers. PMID- 23087186 TI - Commentary by Janet Radcliffe-Richards on Simon Rippon's 'Imposing options on people in poverty: the harm of a live donor organ market'. PMID- 23087188 TI - Recognition of viruses in the cytoplasm by RLRs and other helicases--how conformational changes, mitochondrial dynamics and ubiquitination control innate immune responses. AB - Mammalian cells possess multiple sensors for recognition of invasion by a broad range of microbes. This recognition occurs through specific molecular signatures found across various pathogens. Toll-like receptors (TLRs), retinoic acid inducible gene-I (RIG-I)-like receptors (RLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) and C-type lectin receptors (CLRs) are the major cellular pathogen-recognition receptors (PRRs) responsible for this recognition. TLRs are transmembrane sensors, whereas other PRRs mainly localize in the cytoplasm for the activation of type I interferons and pro inflammatory cytokines. Among these PRRs, RLRs are well known for their indispensable role in sensing the invasion of RNA viruses. This review summarizes recent advances in knowledge about viral recognition by RLRs and their signalling pathways, and introduces newly emerging RNA helicases involved in innate immune responses. PMID- 23087187 TI - Bone marrow-induced Mef2c deficiency delays B-cell development and alters the expression of key B-cell regulatory proteins. AB - The Mef2 family transcriptional regulator Mef2c (myocyte enhancer factor 2c) is highly expressed in maturing bone marrow and peripheral mature B-cells. To evaluate the role of this transcription factor in B-cell development, we generated a B-cell-specific conditional deletion of Mef2c using the Mb-1-Cre transgene that is expressed during the early stages of immunoglobulin rearrangement. Young mice possessing this defect demonstrated a significant impairment in B-cell numbers in bone marrow and spleen. This phenotype was evident in all B-cell subsets; however, as the animals mature, the deficit in the peripheral mature B-cell compartments was overcome. The absence of Mef2c in mature B-cells led to unique CD23+ and CD23- subsets that were evident in Mef2c knockout primary samples as well as Mef2c-deficient cultured, differentiated B cells. Genome-wide expression analysis of immature and mature B-cells lacking Mef2c indicated altered expression for a number of key regulatory proteins for B cell function including Ciita, CD23, Cr1/Cr2 and Tnfsf4. Chromatin immunoprecipitation analysis confirmed Mef2c binding to the promoters of these genes indicating a direct link between the presence (or absence) of Mef2c and altered transcriptional control in mature B-cells. PMID- 23087189 TI - Low prevalence of behavioural and emotional problems among Swiss paediatric patients with inflammatory bowel disease. AB - OBJECTIVES: Whether behavioural and emotional maladjustment is more prevalent in children with inflammatory bowel disease (IBD) than in healthy controls remains controversial. The aim of this study was to assess paediatric IBD patients for problems with emotional and behavioural adjustment and to examine associations with clinical and demographic variables. METHODS: Data from paediatric patients with IBD enrolled in the Swiss IBD Cohort Study and the results of both the parent-rated Strengths and Difficulties Questionnaire (SDQ) and the self-reported Child Depression Inventory (CDI) were analysed. Of the 148 registered patients, 126 had at least one questionnaire completed and were included. RESULTS: The mean age of 71 patients with Crohn's disease (44 males, 27 females) was 13.4 years, and 12.8 years for the 55 patients with ulcerative or indeterminate colitis. The mean duration of disease was 1.2 and 2.7 years, respectively. The total score of the SDQ was abnormal in 11.4% of cases compared to 10% in the normal population. Abnormal sub-scores were found in 20.2% of subjects for the domain of emotional problems and in 17.1% for problems with peers. The total CDI T score indicated a significantly lower prevalence of clinical depression in IBD patients than in normal youth. No correlation between the total SDQ scores or the CDI T scores and gender, type or duration of IBD, inflammatory markers or disease scores was found. CONCLUSIONS: The prevalence of problems with behavioural and emotional adjustment among Swiss paediatric IBD patients is low and comparable to that of the normal population. PMID- 23087190 TI - S100 A8/A9 protein as a marker for early diagnosis of necrotising enterocolitis in neonates. PMID- 23087192 TI - In support of the evidence. PMID- 23087191 TI - Parental height in relation to offspring coronary heart disease: examining transgenerational influences on health using the west of Scotland Midspan Family Study. AB - BACKGROUND: Adult height is known to be inversely related to coronary heart disease (CHD) risk. We sought to investigate transgenerational influence of parental height on offspring's CHD risk. METHODS: Parents took part in a cardiorespiratory disease survey in two Scottish towns during the 1970s, in which their physical stature was measured. In 1996, their offspring were invited to participate in a similar survey, which included an electrocardiogram recording and risk factor assessment. RESULTS: A total of 2306 natural offspring aged 30-59 years from 1456 couples were subsequently flagged for notification of mortality and followed for CHD-related hospitalizations. Taller paternal and/or maternal height was associated with socio-economic advantage, heavier birthweight and increased high-density lipoprotein cholesterol in offspring. Increased height in fathers, but more strongly in mothers (risk ratio for 1 SD change in maternal height = 0.85; 95% confidence interval: 0.76 to 0.95), was associated with a lower risk of offspring CHD, adjusting for age, sex, other parental height and CHD risk factors. CONCLUSION: There is evidence of an association between taller parental, particularly maternal, height and lower offspring CHD risk. This may reflect an influence of early maternal growth on the intrauterine environment provided for her offspring. PMID- 23087193 TI - Breastfeeding and telehealth. PMID- 23087194 TI - Establishing an online and social media presence for your IBCLC practice. AB - Women of childbearing age, especially in industrialized nations, are using social media in record numbers and are seeking information about pregnancy, birth, and breastfeeding online. Social media is a form of communication that enables online communities to share ideas, information, and personal messages. Those providing support to breastfeeding mothers are uniquely equipped to share information, guidance, and encouragement with new mothers. Lactation professionals, advocates, and volunteers should be aware that mothers are using Web-based communication to gain information about breastfeeding. Those who support breastfeeding mothers can also learn to use these methods to engage with the breastfeeding community online. Regardless of the chosen platform, social media is most successful when it promotes engagement with a target audience. Facebook, Twitter, blogs, and Pinterest are identified as useful platforms for connecting with breastfeeding mothers. PMID- 23087195 TI - New insights into the risk of feeding infants by bottle. PMID- 23087196 TI - Transfer of carboplatin and paclitaxel into breast milk. AB - Carboplatin is an alkylating agent that is FDA approved for the treatment of advanced ovarian cancer. Paclitaxel is a plant taxane mitotic inhibitor approved for primary or salvage treatment of ovarian and breast cancer. This is a case report of a 40-year-old woman who was exclusively breastfeeding prior to being treated for papillary thyroid cancer with intravenous carboplatin (233 mg) and intravenous paclitaxel (30 mg/m(2)) for 6 consecutive weeks. Breast milk samples were collected during the sixth chemotherapy session. Carboplatin had a relative infant dose of 2.0% and remained measurable after 316 hours. Paclitaxel had a relative infant dose of 16.7% but was eliminated before 316 hours. The potential side effects of infant exposure of these medications include myelosuppression, hypersensitivity reactions, nephrotoxicity, and neurotoxicity. It would be inadvisable for a mother to breastfeed while undergoing therapy with these 2 medications. PMID- 23087197 TI - Infant feeding attitudes of women in the United Kingdom during pregnancy and after birth. AB - BACKGROUND: To address the recognized low rates of breastfeeding in the United Kingdom (UK), a change in fundamental attitudes toward infant feeding might be required. This paper reports an exploration of women's attitudes toward breastfeeding at different time points in the perinatal period, undertaken as part of a larger breastfeeding evaluation study. OBJECTIVES: To measure women's infant feeding attitudes at 3 stages during the perinatal period to see whether, on average, they differed over time. METHODS: Using the 17-item Iowa Infant Feeding Attitudes Scale (IIFAS), this cross-sectional study measured the infant feeding attitudes of 866 UK women at 3 perinatal stages (20 and 35 weeks antenatally and 6 weeks postpartum). RESULTS: Mean IIFAS scores were very similar, which shows that discrete groups of women at different time points in pregnancy and postpartum appear to have the same attitudes toward infant feeding. The predominance of scores lay in the mid-range at each of the time points, which may indicate women's indecision or ambivalent feelings about infant feeding during pregnancy and the postpartum period. CONCLUSIONS: Action must be undertaken to target the majority of women with mid-range scores whose ambivalence may respond positively to intervention programs. The challenge is to understand what would be appropriate and acceptable to this vulnerable group of women. PMID- 23087198 TI - Concern about advertisement. PMID- 23087200 TI - Expecting the unexpected: planning for a baby with medical problems. PMID- 23087202 TI - Immune thrombocytopenic purpura: a presentation of HIV infection. AB - About 5% to 10% of HIV-infected patients develop thrombocytopenia during the course of the disease, and immune thrombocytopenic purpura (ITP) may be the sole clinical manifestation of HIV infection. The clinical picture is indistinguishable from the classic auto-ITP. Treatment is the same as that given for classic ITP as the pathogenesis is in many ways similar. Steroids, intravenous immunoglobulins (IVIGs), and antiretroviral therapy (ART) have all been tried with varied results but have been associated with fall in platelet count on withdrawal of therapy. We report a case of a 13-year-old girl who presented with thrombocytopenic purpura and had no response to ART but had normalization of platelet count while on steroids, which immediately fell below the normal range on withdrawing the steroids. PMID- 23087203 TI - Frequent coinfection with hepatitis among HIV-positive patients in Urumqi, China. AB - OBJECTIVE: To analyze the epidemiology and outcome for patients with HIV coinfected with hepatitis in comparison with monoinfected patients. METHODS: At the First Affiliated Hospital at Xinjiang Medical University in Urumqi, China, 395 patients were diagnosed with HIV between 2001 and 2010. The main routes of transmission were sexual (30%) and intravenous drug use (33%). The patient records were studied retrospectively. RESULTS: A total of 135 patients had markers of viral hepatitis (34.2%). Abnormal liver function was seen among 48.9% of these patients. Hepatitis B surface antigen was positive in 24 patients (6.1%), with 15 (3.8%) being hepatitis B virus (HBV)-DNA positive, none on tenofovir treatment, because it is still not provided free in Xinjiang. Hepatitis C antibodies were found in 98 patients (24.8%), 46 (11.6%) were hepatitis C virus (HCV)-RNA positive. Only 1 patient had been treated with interferon and ribavirin. Both HBV and HCV were found in 13 (3.3%) of the patients. CONCLUSIONS: Nearly half of the HIV patients in Urumqi had markers of hepatitis. Only antiretroviral treatment is provided free, and most of the patients cannot afford the hepatitis treatment they need, which has to be addressed in the treatment programs. PMID- 23087205 TI - Towards standardised evaluation tools. PMID- 23087206 TI - RhoD regulates cytoskeletal dynamics via the actin nucleation-promoting factor WASp homologue associated with actin Golgi membranes and microtubules. AB - The Rho GTPases have mainly been studied in association with their roles in the regulation of actin filament organization. These studies have shown that the Rho GTPases are essential for basic cellular processes, such as cell migration, contraction, and division. In this paper, we report that RhoD has a role in the organization of actin dynamics that is distinct from the roles of the better studied Rho members Cdc42, RhoA, and Rac1. We found that RhoD binds the actin nucleation-promoting factor WASp homologue associated with actin Golgi membranes and microtubules (WHAMM), as well as the related filamin A-binding protein FILIP1. Of these two RhoD-binding proteins, WHAMM was found to bind to the Arp2/3 complex, while FILIP1 bound filamin A. WHAMM was found to act downstream of RhoD in regulating cytoskeletal dynamics. In addition, cells treated with small interfering RNAs for RhoD and WHAMM showed increased cell attachment and decreased cell migration. These major effects on cytoskeletal dynamics indicate that RhoD and its effectors control vital cytoskeleton-driven cellular processes. In agreement with this notion, our data suggest that RhoD coordinates Arp2/3 dependent and FLNa-dependent mechanisms to control the actin filament system, cell adhesion, and cell migration. PMID- 23087207 TI - The two human centrin homologues have similar but distinct functions at Tetrahymena basal bodies. AB - Centrins are a ubiquitous family of small Ca(2+)-binding proteins found at basal bodies that are placed into two groups based on sequence similarity to the human centrins 2 and 3. Analyses of basal body composition in different species suggest that they contain a centrin isoform from each group. We used the ciliate protist Tetrahymena thermophila to gain a better understanding of the functions of the two centrin groups and to determine their potential redundancy. We have previously shown that the Tetrahymena centrin 1 (Cen1), a human centrin 2 homologue, is required for proper basal body function. In this paper, we show that the Tetrahymena centrin 2 (Cen2), a human centrin 3 homologue, has functions similar to Cen1 in basal body orientation, maintenance, and separation. The two are, however, not redundant. A further examination of human centrin 3 homologues shows that they function in a manner distinct from human centrin 2 homologues. Our data suggest that basal bodies require a centrin from both groups in order to function correctly. PMID- 23087208 TI - Taxol-stabilized microtubules promote the formation of filaments from unmodified full-length Tau in vitro. AB - Tau is a neuronal protein that stabilizes the microtubule (MT) network, but it also forms filaments associated with Alzheimer's disease. Understanding Tau-MT and Tau-Tau interactions would help to establish Tau function in health and disease. For many years, literature reports on Tau-MT binding behavior and affinity have remained surprisingly contradictory (e.g., 10-fold variation in Tau MT affinity). Tau-Tau interactions have also been investigated, but whether MTs might affect Tau filament formation is unknown. We have addressed these issues through binding assays and microscopy. We assessed Tau-MT interactions via cosedimentation and found that the measured affinity of Tau varies greatly, depending on the experimental design and the protein concentrations used. To investigate this dependence, we used fluorescence microscopy to examine Tau-MT binding. Strikingly, we found that Taxol-stabilized MTs promote Tau filament formation without characterized Tau-filament inducers. We propose that these novel Tau filaments account for the incongruence in Tau-MT affinity measurements. Moreover, electron microscopy reveals that these filaments appear similar to the heparin-induced Alzheimer's model. These observations suggest that the MT-induced Tau filaments provide a new model for Alzheimer's studies and that MTs might play a role in the formation of Alzheimer's-associated neurofibrillary tangles. PMID- 23087209 TI - The kinesin-14 Klp2 is negatively regulated by the SIN for proper spindle elongation and telophase nuclear positioning. AB - In Schizosaccharomyces pombe, a late mitotic kinase pathway called the septation initiation network (SIN) triggers cytokinesis. Here we show that the SIN is also involved in regulating anaphase spindle elongation and telophase nuclear positioning via inhibition of Klp2, a minus end-directed kinesin-14. Klp2 is known to localize to microtubules (MTs) and have roles in interphase nuclear positioning, mitotic chromosome alignment, and nuclear migration during karyogamy (nuclear fusion during mating). We observe SIN-dependent disappearance of Klp2 from MTs in anaphase, and we find that this is mediated by direct phosphorylation of Klp2 by the SIN kinase Sid2, which abrogates loading of Klp2 onto MTs by inhibiting its interaction with Mal3 (EB1 homologue). Disruption of Klp2 MT localization is required for efficient anaphase spindle elongation. Furthermore, when cytokinesis is delayed, SIN inhibition of Klp2 acts in concert with microtubules emanating from the equatorial microtubule-organizing center to position the nuclei away from the cell division site. These results reveal novel functions of the SIN in regulating the MT cytoskeleton and suggest that the SIN may have broader functions in regulating cellular organization in late mitosis than previously realized. PMID- 23087210 TI - SNAP-23 regulates phagosome formation and maturation in macrophages. AB - Synaptosomal associated protein of 23 kDa (SNAP-23), a plasma membrane-localized soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE), has been implicated in phagocytosis by macrophages. For elucidation of its precise role in this process, a macrophage line overexpressing monomeric Venus tagged SNAP-23 was established. These cells showed enhanced Fc receptor-mediated phagocytosis. Detailed analyses of each process of phagocytosis revealed a marked increase in the production of reactive oxygen species within phagosomes. Also, enhanced accumulation of a lysotropic dye, as well as augmented quenching of a pH sensitive fluorophore were observed. Analyses of isolated phagosomes indicated the critical role of SNAP-23 in the functional recruitment of the NADPH oxidase complex and vacuolar-type H(+)-ATPase to phagosomes. The data from the overexpression experiments were confirmed by SNAP-23 knockdown, which demonstrated a significant delay in phagosome maturation and a reduction in uptake activity. Finally, for analyzing whether phagosomal SNAP-23 entails a structural change in the protein, an intramolecular Forster resonance energy transfer (FRET) probe was constructed, in which the distance within a TagGFP2 TagRFP was altered upon close approximation of the N-termini of its two SNARE motifs. FRET efficiency on phagosomes was markedly enhanced only when VAMP7, a lysosomal SNARE, was coexpressed. Taken together, our results strongly suggest the involvement of SNAP-23 in both phagosome formation and maturation in macrophages, presumably by mediating SNARE-based membrane traffic. PMID- 23087211 TI - The microtubule-binding protein Cep170 promotes the targeting of the kinesin-13 depolymerase Kif2b to the mitotic spindle. AB - Microtubule dynamics are essential throughout mitosis to ensure correct chromosome segregation. Microtubule depolymerization is controlled in part by microtubule depolymerases, including the kinesin-13 family of proteins. In humans, there are three closely related kinesin-13 isoforms (Kif2a, Kif2b, and Kif2c/MCAK), which are highly conserved in their primary sequences but display distinct localization and nonoverlapping functions. Here we demonstrate that the N-terminus is a primary determinant of kinesin-13 localization. However, we also find that differences in the C-terminus alter the properties of kinesin-13, in part by facilitating unique protein-protein interactions. We identify the spindle localized proteins Cep170 and Cep170R (KIAA0284) as specifically associating with Kif2b. Cep170 binds to microtubules in vitro and provides Kif2b with a second microtubule-binding site to target it to the spindle. Thus the intrinsic properties of kinesin-13s and extrinsic factors such as their associated proteins result in the diversity and specificity within the kinesin-13 depolymerase family. PMID- 23087212 TI - Sequestration of G3BP coupled with efficient translation inhibits stress granules in Semliki Forest virus infection. AB - Dynamic, mRNA-containing stress granules (SGs) form in the cytoplasm of cells under environmental stresses, including viral infection. Many viruses appear to employ mechanisms to disrupt the formation of SGs on their mRNAs, suggesting that they represent a cellular defense against infection. Here, we report that early in Semliki Forest virus infection, the C-terminal domain of the viral nonstructural protein 3 (nsP3) forms a complex with Ras-GAP SH3-domain-binding protein (G3BP) and sequesters it into viral RNA replication complexes in a manner that inhibits the formation of SGs on viral mRNAs. A viral mutant carrying a C terminal truncation of nsP3 induces more persistent SGs and is attenuated for propagation in cell culture. Of importance, we also show that the efficient translation of viral mRNAs containing a translation enhancer sequence also contributes to the disassembly of SGs in infected cells. Furthermore, we show that the nsP3/G3BP interaction also blocks SGs induced by other stresses than virus infection. This is one of few described viral mechanisms for SG disruption and underlines the role of SGs in antiviral defense. PMID- 23087215 TI - A threat to national security. PMID- 23087220 TI - Nobel Prize in chemistry. Receptor scientists to receive chemistry Nobel. PMID- 23087213 TI - G9a mediates Sharp-1-dependent inhibition of skeletal muscle differentiation. AB - Sharp-1, a basic helix-loop-helix transcription factor, is a potent repressor of skeletal muscle differentiation and is dysregulated in muscle pathologies. However, the mechanisms by which it inhibits myogenesis are not fully understood. Here we show that G9a, a lysine methyltransferase, is involved in Sharp-1 mediated inhibition of muscle differentiation. We demonstrate that G9a directly interacts with Sharp-1 and enhances its ability to transcriptionally repress the myogenin promoter. Concomitant with a differentiation block, G9a-dependent histone H3 lysine 9 dimethylation (H3K9me2) and MyoD methylation are apparent upon Sharp-1 overexpression in muscle cells. RNA interference-mediated reduction of G9a or pharmacological inhibition of its activity erases these repressive marks and rescues the differentiation defect imposed by Sharp-1. Our findings provide new insights into Sharp-1-dependent regulation of myogenesis and identify epigenetic mechanisms that could be targeted in myopathies characterized by elevated Sharp-1 levels. PMID- 23087221 TI - Nobel Memorial Prize in economic sciences. Economics Nobel honors matchmaking finesse. PMID- 23087214 TI - Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system. AB - The endoplasmic reticulum (ER)-resident enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyzes the rate-limiting step in sterol production and is the therapeutic target of statins. Understanding HMG-CoA reductase regulation has tremendous implications for atherosclerosis. HMG-CoA reductase levels are regulated in response to sterols both transcriptionally, through a complex regulatory loop involving the ER Insig proteins, and posttranslationally, by Insig-dependent protein degradation by the ubiquitin-proteasome system. The ubiquitin ligase (E3) gp78 has been implicated in the sterol-regulated degradation of HMG-CoA reductase and Insig-1 through ER-associated degradation (ERAD). More recently, a second ERAD E3, TRC8, has also been reported to play a role in the sterol-accelerated degradation of HMG-CoA reductase. We interrogated this network in gp78(-/-) mouse embryonic fibroblasts and also assessed two fibroblast cell lines using RNA interference. Although we consistently observe involvement of gp78 in Insig-1 degradation, we find no substantive evidence to support roles for either gp78 or TRC8 in the robust sterol-accelerated degradation of HMG-CoA reductase. We discuss factors that might lead to such discrepant findings. Our results suggest a need for additional studies before definitive mechanistic conclusions are drawn that might set the stage for development of drugs to manipulate gp78 function in metabolic disorders. PMID- 23087222 TI - Genetics. New company pushes the envelope on pre-conception testing. PMID- 23087223 TI - Evolution. Gene duplication's role in evolution gets richer, more complex. PMID- 23087224 TI - Bioinformatics. New way to look at life. PMID- 23087225 TI - Contraception research. Reinventing the pill: male birth control. PMID- 23087227 TI - Nuclear physics. Primordial matter comes into focus in many tiny big bangs. PMID- 23087226 TI - Cell biology. Looking for a sugar rush. PMID- 23087228 TI - Violence: finding peace. PMID- 23087229 TI - Violence: clarified. PMID- 23087233 TI - Research funding. Toward variable funding for international science. PMID- 23087231 TI - Comment on "Restoring voluntary control of locomotion after paralyzing spinal cord injury". AB - Van den Brand et al. (Reports, 1 June 2012, p. 1182) claim to have restored voluntary control of locomotion after paralyzing spinal cord injury. They have not considered recent findings that their upright posture paradigm contributes to locomotor capability after such injuries. We propose that postural adjustments that activate the locomotor central pattern generator in the upright posture, rather than direct voluntary control of locomotion, account for their results. PMID- 23087234 TI - Astronomy. Galactic archaeology. PMID- 23087235 TI - Systems biology. How information theory handles cell signaling and uncertainty. PMID- 23087236 TI - Geochemistry. Life in the Early Triassic ocean. PMID- 23087237 TI - Atmospheric science. Refining the radiocarbon time scale. PMID- 23087238 TI - Circadian surprise--it's not all about transcription. PMID- 23087239 TI - Chemistry. Unconventional chemistry for unconventional natural gas. PMID- 23087240 TI - Neuroscience. Preventable forms of autism? PMID- 23087241 TI - Anticipating critical transitions. AB - Tipping points in complex systems may imply risks of unwanted collapse, but also opportunities for positive change. Our capacity to navigate such risks and opportunities can be boosted by combining emerging insights from two unconnected fields of research. One line of work is revealing fundamental architectural features that may cause ecological networks, financial markets, and other complex systems to have tipping points. Another field of research is uncovering generic empirical indicators of the proximity to such critical thresholds. Although sudden shifts in complex systems will inevitably continue to surprise us, work at the crossroads of these emerging fields offers new approaches for anticipating critical transitions. PMID- 23087242 TI - Self-assembled colloidal superparticles from nanorods. AB - Colloidal superparticles are nanoparticle assemblies in the form of colloidal particles. The assembly of nanoscopic objects into mesoscopic or macroscopic complex architectures allows bottom-up fabrication of functional materials. We report that the self-assembly of cadmium selenide-cadmium sulfide (CdSe-CdS) core shell semiconductor nanorods, mediated by shape and structural anisotropy, produces mesoscopic colloidal superparticles having multiple well-defined supercrystalline domains. Moreover, functionality-based anisotropic interactions between these CdSe-CdS nanorods can be kinetically introduced during the self assembly and, in turn, yield single-domain, needle-like superparticles with parallel alignment of constituent nanorods. Unidirectional patterning of these mesoscopic needle-like superparticles gives rise to the lateral alignment of CdSe CdS nanorods into macroscopic, uniform, freestanding polymer films that exhibit strong photoluminescence with a striking anisotropy, enabling their use as downconversion phosphors to create polarized light-emitting diodes. PMID- 23087243 TI - Integrated compact optical vortex beam emitters. AB - Emerging applications based on optical beams carrying orbital angular momentum (OAM) will probably require photonic integrated devices and circuits for miniaturization, improved performance, and enhanced functionality. We demonstrate silicon-integrated optical vortex emitters, using angular gratings to extract light confined in whispering gallery modes with high OAM into free-space beams with well-controlled amounts of OAM. The smallest device has a radius of 3.9 micrometers. Experimental characterization confirms the theoretical prediction that the emitted beams carry exactly defined and adjustable OAM. Fabrication of integrated arrays and demonstration of simultaneous emission of multiple identical optical vortices provide the potential for large-scale integration of optical vortex emitters on complementary metal-oxide-semiconductor compatible silicon chips for wide-ranging applications. PMID- 23087244 TI - Lethally hot temperatures during the Early Triassic greenhouse. AB - Global warming is widely regarded to have played a contributing role in numerous past biotic crises. Here, we show that the end-Permian mass extinction coincided with a rapid temperature rise to exceptionally high values in the Early Triassic that were inimical to life in equatorial latitudes and suppressed ecosystem recovery. This was manifested in the loss of calcareous algae, the near-absence of fish in equatorial Tethys, and the dominance of small taxa of invertebrates during the thermal maxima. High temperatures drove most Early Triassic plants and animals out of equatorial terrestrial ecosystems and probably were a major cause of the end-Smithian crisis. PMID- 23087245 TI - A complete terrestrial radiocarbon record for 11.2 to 52.8 kyr B.P. AB - Radiocarbon ((14)C) provides a way to date material that contains carbon with an age up to ~50,000 years and is also an important tracer of the global carbon cycle. However, the lack of a comprehensive record reflecting atmospheric (14)C prior to 12.5 thousand years before the present (kyr B.P.) has limited the application of radiocarbon dating of samples from the Last Glacial period. Here, we report (14)C results from Lake Suigetsu, Japan (35 degrees 35'N, 135 degrees 53'E), which provide a comprehensive record of terrestrial radiocarbon to the present limit of the (14)C method. The time scale we present in this work allows direct comparison of Lake Suigetsu paleoclimatic data with other terrestrial climatic records and gives information on the connection between global atmospheric and regional marine radiocarbon levels. PMID- 23087246 TI - Real-time evolution of new genes by innovation, amplification, and divergence. AB - Gene duplications allow evolution of genes with new functions. Here, we describe the innovation-amplification-divergence (IAD) model in which the new function appears before duplication and functionally distinct new genes evolve under continuous selection. One example fitting this model is a preexisting parental gene in Salmonella enterica that has low levels of two distinct activities. This gene is amplified to a high copy number, and the amplified gene copies accumulate mutations that provide enzymatic specialization of different copies and faster growth. Selection maintains the initial amplification and beneficial mutant alleles but is relaxed for other less improved gene copies, allowing their loss. This rapid process, completed in fewer than 3000 generations, shows the efficacy of the IAD model and allows the study of gene evolution in real time. PMID- 23087247 TI - Direct observation of cotranscriptional folding in an adenine riboswitch. AB - Growing RNA chains fold cotranscriptionally as they are synthesized by RNA polymerase. Riboswitches, which regulate gene expression by adopting alternative RNA folds, are sensitive to cotranscriptional events. We developed an optical trapping assay to follow the cotranscriptional folding of a nascent RNA and used it to monitor individual transcripts of the pbuE adenine riboswitch, visualizing distinct folding transitions. We report a particular folding signature for the riboswitch aptamer whose presence directs the gene-regulatory transcription outcome, and we measured the termination frequency as a function of adenine level and tension applied to the RNA. Our results demonstrate that the outcome is kinetically controlled. These experiments furnish a means to observe conformational switching in real time and enable the precise mapping of events during cotranscriptional folding. PMID- 23087248 TI - An evaluation of 2 online advance directive programs. AB - Since 1995, studies have shown mixed results in the efficacy of advance directives. With new technologies, advance care planning is being transformed through video, computer programs, electronic registries, and electronic health records. In Nevada and Texas, Web sites and mobile applications provide education, guided interviews, storage, and retrieval in multiple languages. Drawing on 371 completed evaluations from both states, the authors show that increasingly people are finding advance directive information on the Internet, completing directives to be prepared and to have control, and that the attraction of these Web sites is their ease of use. Users report where they keep their documents, with whom they have end-of-life conversations, and what medical care requests they make. PMID- 23087249 TI - A crossover randomized prospective pilot study evaluating a central venous catheter team in reducing catheter-related bloodstream infections in pediatric oncology patients. AB - BACKGROUND: Treatment for most children with cancer includes the use of a central venous catheter (CVC). CVCs provide reliable venous access for delivery of chemotherapy and supportive care. This advantage is mitigated by an increased risk of bloodstream infections (BSIs). Despite the ubiquitous use of CVCs, few prospective studies have been conducted to address infection prevention strategies in pediatric oncology patients. DESIGN: Prospective, crossover pilot study of a CVC team intervention versus standard care. SETTING: Two inpatient oncology units in a metropolitan children's hospital. PATIENTS: A total of 41 patients/135 admissions for the experimental unit (EU) and 41/129 admissions for the control unit (CU). METHODS: Patients received a CVC blood draw bundle procedure by a CVC registered nurse (RN) team member (experimental intervention: EU) for 6 months and by the assigned bedside RN (standard care: CU) for 6 months. Feasibility of implementing a CVC RN team; a significant difference in CVC related BSIs between the team intervention versus standard care and risk factors associated in the development of CVC-related BSIs were determined. RESULTS: There were 7 CVC-related BSIs/1238 catheter days in the EU group (5.7/1000 catheter days) versus 3 CVC-related BSIs/1419 catheter days in the CU group (2.1/1000 catheter days; P = .97). Selected risk factors were not significantly associated with the development of a CVC-related BSI. CONCLUSIONS: A CVC team in the care of pediatric oncology patients is feasible; however, a larger cohort will be required to adequately determine the effectiveness of the team reducing CVC related BSIs. PMID- 23087250 TI - Nutritional screening and early intervention in children, adolescents, and young adults with cancer. AB - Children and adolescents with cancer who receive chemotherapy and/or radiation treatments are at risk for malnutrition due to side effects such as nausea, vomiting, anorexia, and mouth sores. Malnutrition during treatment for childhood cancer increases the risk of infection, decreases tolerance to treatment, and even affects overall survival. A retrospective analysis of 79 children, adolescents, and young adults was conducted to evaluate nutritional screening at baseline and for the first 6 months of treatment. Interventions were also documented. Forty-nine participants had a positive screen for risk of malnutrition. In the patients with a positive screen, 78% had intervention within 24 hours of the identified risk for malnutrition. Thirty-five patients had a nutritional referral, which resulted in a full nutritional assessment and plan. Key independent variables were analyzed to determine if they were associated with an increased risk of malnutrition. In addition, individual risk factors were analyzed to determine their association with malnutrition. Future studies should find whether early intervention is effective in reversing the risk of malnutrition during treatment for childhood cancer. PMID- 23087251 TI - Stress in pediatric oncology nurses. AB - Although the onset of physiological and emotional stress can greatly affect outcomes for a child with cancer, the focus of this review targets pediatric oncology nurses and their daily occupation-related stress. Literature currently exists that discusses the etiology of stress in the oncology work environment as well as coping strategies and their effects on pediatric oncology nurses' stress levels. To date, however, no literature review has been assembled to comprehensively address practice implications and provide recommendations for pediatric oncology staff nurses. This review of literature seeks to provide a general overview of stress experienced in the pediatric oncology work environment and supportive interventions to decrease negative outcomes such as compassion fatigue and burnout. Recommendations and conclusions are made based on existing interventions, thus creating a framework for future research to be conducted to compare the effectiveness of these measures and optimize patient experiences through caregiver well-being. PMID- 23087252 TI - The dynamics of word retrieval in major depression. AB - OBJECTIVE: Impairment in the retrieval of specific episodes from autobiographical memory is commonly observed in major depression. However, it is unclear whether impairment in retrieval processes is a general characteristic of major depression or is confined to the recollection of personal memories. This study examined the time course of the retrieval of words from semantic memory. METHOD: A letter fluency test was administered to 65 inpatients with major depression and 50 healthy controls. A two-parameter model was fit to the decay curve representing the production of words over a 90-second period. One parameter, N, is an estimate of the total number of words that would be generated if the respondent was given unlimited time. The other, tau, is the average of the difference in time between the first word generated and each subsequent word. RESULTS: There was evidence of a deficit in the retrieval of words from long-term memory in depressed patients. The significant difference between groups suggested that even if given an extended period of time in which to respond to compensate for possible slowness, the depressed group would not retrieve as many words as the controls. The retrieval failure could not be attributed solely to cognitive slowing or the effects of antidepressant medication. CONCLUSIONS: The results extend findings of a deficit in the process of retrieving specific episodes from autobiographical memory and suggest that a generalised impairment in memory retrieval may be characteristic of major depression. PMID- 23087253 TI - On suicide clusters: more than contagion. PMID- 23087254 TI - The novel miR-7515 decreases the proliferation and migration of human lung cancer cells by targeting c-Met. AB - MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression in human diseases, including lung cancer. miRNAs have oncogenic and nononcogenic functions in lung cancer. In this study, we report the identification of a novel miRNA, miR 7515, from lung cancer cells. The novel miR-7515 was characterized using various predictive programs and experimental methods. miR-7515 was able to forming a stem loop structure and its sequence was conserved in mammals. The expression level of miR-7515 in lung cancer cells and tissues was profiled using TaqMan miRNA assays. miR-7515 was downregulated in lung cancer compared with normal human lung cells and tissues. The target of miR-7515 was determined using a dual luciferase reporter assay. Expression of the target gene was determined by quantitative RT PCR and Western blot analysis after transfection with miR-7515. miR-7515 directly suppressed human mesenchymal-epithelial transition factor (c-Met) by binding to the 3' untranslated region (UTR). Overexpression of miR-7515 significantly decreased cell-cycle-related proteins downstream of c-Met through c-Met inhibition. Cell proliferation and migration were examined using the XTT proliferation assay and the Transwell migration assay. miR-7515 led to decreased cell proliferation, migration and invasion in a lung cancer cell line. These results suggest that miR-7515 plays an important role in the proliferation and migration of lung cancer cells through c-Met regulation. PMID- 23087255 TI - Changes in microRNAs associated with podocytic adhesion damage under mechanical stress. AB - INTRODUCTION: Podocytes can respond to various injuries, including mechanical stress secondary to diabetic nephropathy (DN), which may cause deleterious adhesive effects on podocytes. Integrin alpha3beta1 is the major podocyte adhesion molecule. In this study, we aim to investigate alpha3beta1 expression and identify differentially expressed microRNAs in podocytes under mechanical stress compared with normal cells and podocytes under mechanical stress treated with spironolactone, respectively. MATERIALS AND METHODS: Serum and glucocorticoid induced kinase 1 (SGK1), mineralocorticoid receptor (MR) and integrin alpha3beta1 were detected by Western blotting. The miRNA analyses were performed by TaqMan MicroRNA Array v2.0. Genes Itga3 and Itgb1 were analyzed for miRNA binding sites within 3'UTRs using TargetScan and PicTar. RESULTS: Protein SGK1 and MR expression were significantly increased under mechanical stress and decreased after spironolactone treatment. Podocyte alpha3 and beta1 expression were significantly decreased under mechanical stress and increased after spironolactone treatment. MiR-124, miR-190, miR-217 and miR-188 were the overlapped miRNAs that were upregulated under mechanical stress and downregulated after spironolactone treatment. MiR-124 was found to be a predicted miRNA target site in both Itga3 and Itgb1 3'UTRs. CONCLUSION: These results provide a novel idea that miR-124 might play an important role in podocytic adhesion damage under mechanical stress. PMID- 23087256 TI - Neuropathic pain-attenuating potential of aliskiren in chronic constriction injury model in rats. AB - The present study was designed to investigate the potential of aliskiren, a direct renin inhibitor, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. Acetone drop, von Frey hair, pin-prick and hot plate tests were performed to assess cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia, respectively. The levels of Tumor necrosis factor-alpha (TNF alpha) were measured in the sciatic nerve as an inflammatory marker. CCI was associated with the development of cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia along with a rise in the levels of Tumor necrosis factor-alpha (TNF-alpha). Administration of aliskiren (25 or 50 mg/kg intraperitoneal (i.p.)) for 14 days in CCI-subjected rats significantly attenuated CCI-induced pain-related behavior and rise in TNF-alpha level. It may be concluded that aliskiren-mediated anti-inflammatory actions may be responsible for its beneficial effects in neuropathic pain in rats. PMID- 23087257 TI - Development of gene expression-based score to predict sensitivity of multiple myeloma cells to DNA methylation inhibitors. AB - Multiple myeloma is a plasma cell cancer with poor survival, characterized by the clonal expansion of multiple myeloma cells (MMC), primarily in the bone marrow. Novel compounds are currently tested in this disease, but partial or minor patients' responses are observed for most compounds used as a single agent. The design of predictors for drug efficacy could be most useful to better understand basic mechanisms targeted by these drugs and design clinical trials. In the current study, we report the building of a DNA methylation score (DM score) predicting the efficacy of decitabine, an inhibitor of DNA methyltransferase (DNMT), targeting methylation-regulated gene expression. DM score was built by identifying 47 genes regulated by decitabine in human myeloma cell lines and the expression of which in primary MMCs of previously untreated patients is predictive for overall survival. A high DM score predicts patients' poor survival, and, of major interest, high sensitivity of primary MMCs or human myeloma cell lines to decitabine in vitro. Thus, DM score could be useful to design novel treatments with DMNT inhibitor in multiple myeloma and has highlighted 47 genes, the gene products of which could be important for multiple myeloma disease development. PMID- 23087258 TI - Designing an intervention for women with systemic lupus erythematosus from medically underserved areas to improve care: a qualitative study. AB - OBJECTIVE: Systemic lupus erythematosus (lupus) disproportionately affects women, racial/ethnic minorities and low-income populations. We held focus groups for women from medically underserved communities to discuss interventions to improve care. METHODS: From our Lupus Registry, we invited 282 women, >=18 years, residing in urban, medically underserved areas. Hospital-based clinics and support groups also recruited participants. Women were randomly assigned to three focus groups. Seventy-five-minute sessions were recorded, transcribed and coded thematically using interpretative phenomenologic analysis and single counting methods. We categorized interventions by benefits, limitations, target populations and implementation questions. RESULTS: Twenty-nine women with lupus participated in three focus groups, (n = 9, 9, 11). 80% were African American and 83% were from medically underserved zip codes. Themes included the desire for lupus education, isolation at the time of diagnosis, emotional and physical barriers to care, and the need for assistance navigating the healthcare system. Twenty of 29 participants (69%) favored a peer support intervention; 17 (59%) also supported a lupus health passport. Newly diagnosed women were optimal intervention targets. Improvements in quality of life and mental health were proposed outcome measures. CONCLUSION: Women with lupus from medically underserved areas have unique needs best addressed with an intervention designed through collaboration between community members and researchers. PMID- 23087259 TI - Characterization of 5C11-positive activated interferon-producing cells in patients with systemic lupus erythematosus. AB - OBJECTIVE: 5C11 antibody is a novel monoclonal antibody against human BST2 and can be used to detect activation of interferon-producing cells (IPCs). Activated IPCs, which produce large amounts of interferon-alpha (IFNalpha), are considered to play an important role in the pathogenesis of systemic lupus erythematosus (SLE). We investigated the characterization of 5C11-positive cells in patients with SLE. METHODS: The proportions of 5C11-positive cells among blood dendritic cell antigen 2 (BDCA-2)-, CD3-, CD19- and CD14-positive cells in peripheral blood from SLE patients (SLE-PBMCs) and healthy controls (control-PBMCs) were analyzed by flow cytometry. The effect of 5C11 antibody on IFNalpha production from SLE PBMCs under stimulation with cytosine-phosphate-guanosine (CpG2216, bacterial oligonucleotide motif) was also examined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The proportions of 5C11-positive cells among BDCA-2-, CD3- and CD19-, but not CD14-positive cells in SLE-PBMCs were significantly increased compared to those in control-PBMCs (p < 0.0001, all). Especially, the number of 5C11-positive cells among BDCA-2-positive cells was significantly increased in SLE-PBMCs by about six-fold compared to that in control-PBMCs (p < 0.0001). 5C11 antibody inhibited IFNalpha production by SLE-PBMCs induced by CpG and the inhibition rates was 27% (p < 0.001). CONCLUSION: SLE patients had a significantly higher proportion of 5C11-positive cells among CD3 and CD19 cells, and especially BDCA-2 positive cells. The ability of 5C11 antibody to inhibit IFNalpha production from SLE-PBMCs warrants further investigation for its possible clinical application for the treatment of SLE. PMID- 23087260 TI - Extracellular loop II modulates GTP sensitivity of the prostaglandin EP3 receptor. AB - Unlike the majority of G protein-coupled receptors, the prostaglandin E(2) (PGE(2)) E-prostanoid 3 (EP3) receptor binds agonist with high affinity that is insensitive to the presence of guanosine 5[prime]-O-(3-thio)triphosphate (GTPgammaS). We report the identification of mutations that confer GTPgammaS sensitivity to agonist binding. Seven point mutations were introduced into the conserved motif in the second extracellular loop (ECII) of EP3, resulting in acquisition of GTP-sensitive agonist binding. One receptor mutation W203A was studied in detail. Loss of agonist binding was observed on intact human embryonic kidney 293 cells expressing the W203A receptor, conditions where high GTP levels are present; however, high affinity binding [(3)H]PGE(2) was observed in broken cell preparations washed free of GTP. The [(3)H]PGE(2) binding of W203A in broken cell membrane fractions was inhibited by addition of GTPgammaS (IC(50) 21 +/- 1.8 nM). Taken together, these results suggest that the wild-type EP3 receptor displays unusual characteristics of the complex coupled equilibria between agonist-receptor and receptor-G protein interaction. Moreover, mutation of ECII can alter this coupled equilibrium from GTP-insensitive agonist binding to more conventional GTP-sensitive binding. This suggests that for the mutant receptors, ECII plays a critical role in linking the agonist bound receptor conformation to the G protein nucleotide bound state. PMID- 23087261 TI - Lysine 48-linked polyubiquitination of organic anion transporter-1 is essential for its protein kinase C-regulated endocytosis. AB - Organic anion transporter-1 (OAT1) mediates the body's disposition of a diverse array of environmental toxins and clinically important drugs. Therefore, understanding the regulation of this transporter has profound clinical significance. We had previously established that OAT1 undergoes constitutive internalization from and recycling back to the cell surface and that acute activation of protein kinase C (PKC) inhibits OAT1 activity by reducing OAT1 cell surface expression through accelerating its internalization from cell surface to intracellular compartments. However, the underlying mechanisms are poorly understood. In the current study, we provide novel evidence that acute activation of PKC significantly enhances OAT1 ubiquitination both in vitro and ex vivo. We further show that ubiquitination of cell-surface OAT1 increases in cells transfected with dominant negative mutant of dynamin-2, a maneuver blocking OAT1 internalization, which suggests that OAT1 ubiquitination proceeds before OAT1 internalization. Mass spectroscopy has revealed that ubiquitination of OAT1 consists of polyubiquitin chains, primarily through lysine 48 linkage. Transfection of cells with the dominant negative mutant of ubiquitin Ub-K48R, which prevents the formation of Lys48-linked polyubiquitin chains, abolishes PKC stimulated OAT1 ubiquitination and internalization. Together, our findings demonstrate for the first time that Lys48-linked polyubiquitination is essential for PKC-regulated OAT1 trafficking. PMID- 23087262 TI - Effect of rotational therapy on aspiration risk of enteral feeds. AB - BACKGROUND: Enteral nutrition has been demonstrated to reduce ventilator days and the incidence of pneumonia, but the safest route for providing enteral nutrition to mechanically ventilated patients is unclear. Our objective was to determine if there is a difference between the incidences of microaspiration of gastric secretions in patients fed via a nasogastric tube vs a postpyloric tube while undergoing rotational therapy for acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: Institutional review board approval was obtained for this prospective, randomized study. Patients were randomized to gastric or postpyloric enteral feedings. Daily tracheal secretion samples were collected, and we used an immunoassay to detect pepsin. Using the data for aspiration and tube type, a univariate unadjusted odds ratio was calculated to assess the risk of aspiration between the 2 tube types. An independent samples t test was used to analyze the hypothesis that microaspiration significantly affects lung recovery from ARDS. RESULTS: Of the 20 study patients, 9 (45%) received nasogastric feeds and 11 (55%) received postpyloric feeds. Western blot analysis for the presence of pepsin in each tracheal aspirate revealed microaspiration in 2 nasogastric (22%) and 2 (18%) postpyloric patients. The nasogastric tube provided a protective effect for aspirating with an odds ratio of .778 (95% confidence interval, .09 6.98). An independent samples t test was used and showed no significant change in PaO(2):FiO(2) ratio in the aspirating vs nonaspirating group (P = .552). CONCLUSION: The results of this study indicate that enteral nutrition should not be delayed or stopped to position the tube in patients with ARDS on rotational therapy. PMID- 23087263 TI - Review and clinical update on parenteral nutrition-associated liver disease. AB - Parenteral nutrition-associated liver disease (PNALD) is a complex disease that is diagnosed by clinical presentation, biochemical markers of liver injury, concurrent use of parenteral nutrition (PN), and negative workup for other causes of liver disease. Since the first case of PNALD was reported more than 30 years ago, clinicians have had few effective treatments for PNALD, and when disease progressed to liver cirrhosis, it was historically associated with poor outcomes. Within the past 5 years, there has been much excitement about new treatments for PNALD, including use of both parenteral and enteral omega-3 polyunsaturated long chain fatty acids (omega-3 PUFA) as well as restricting dosing of omega-6 PUFA. Scientists are also interested in uncovering the mechanisms associated with liver injury seen in PNALD. This article reviews the recent literature relating to the pathophysiology and treatment of PNALD. PMID- 23087264 TI - Autologous gastrointestinal reconstruction: review of the optimal nontransplant surgical options for adults and children with short bowel syndrome. AB - Short bowel syndrome (SBS) results in loss of absorptive capacity of the development of gut, leading to malabsorption due to protein, energy, fluid, and electrolyte loss and imbalance while on enteral diet alone. Various nonsurgical and surgical therapeutic options that have emerged improve the survival outcome following SBS in both children and adults. An individualized, complex multidisciplinary approach to medical and surgical intestinal rehabilitation is needed to provide an opportunity for enteral autonomy to be possible in a patient with SBS. The remnant bowel plays a very pivotal role in autologous gastrointestinal reconstruction (AGIR) surgery. Intestinal transplantation, although promising and potentially life-saving for SBS, should be reserved for patients with failed AGIR or those who have no prospect for autologous enteral autonomy. This article reviews the evolution of nontransplant surgical management of patients with SBS. PMID- 23087265 TI - Electronic medical records: are nutrition support professionals ready? PMID- 23087266 TI - Management of paediatric head injury in remote Nepal. AB - Soo Jung Hospital in Doti, Far-Western Nepal is a small district hospital founded in 1994 and run as a private hospital with support from charity donations. It is staffed by two doctors, and two health assistants, supported by a team of nurses and nursing students. Approximately 50 people are seen as outpatients each day. There is a four bed emergency department and two inpatient wards which are able to accommodate 16 patients between them. Basic x-ray facilities are available, but for further imagining studies and surgical interventions patients must be referred to a tertiary centre, the nearest being 7-9 h away by road. Cases of major trauma must be managed with these limited facilities for prolonged periods of time. In addition to this, once a decision has been made to attempt an interhospital transfer, this is undertaken in a vehicle ill-equipped, or staffed, to perform medical interventions en route. PMID- 23087267 TI - An unusual adverse effect of sildenafil citrate: acute myocardial infarction in a nitrate-free patient. AB - Myocardial infarction (MI) associated with sildenafil citrate is seen rarely in patients without any history of coronary artery disease. We report a nitrate-free patient with a history of cardiovascular risk factors who developed acute MI after taking sildenafil. A 44-year-old man diagnosed with acute anterior ST segment elevation MI 120 min after self-administration of 150 mg sildenafil was admitted before attempting any sexual intercourse. The coronary angiography revealed 99% occlusion of the left anterior descending artery (LAD) and a bare metal stent was implanted. He was discharged after 5 days without any complication. Sildenafil may cause coronary steal or may lead to vasodilation causing hypotension in patient with pre-existing cardiovascular disease, especially in patients on nitrate therapy. Our patient was nitrate free, with normal blood pressure values. Emotional stimulation associated with anticipated sexual activity may have been a triggering factor for vulnerable coronary plaque rupture. PMID- 23087269 TI - A medical student with symphalangism, would it affect her future career? AB - Absence of the distal crease of the fingers is usually associated with a flexion deformity. A single crease of one or more fingers is found in many syndromes. We present this report as a rare case of absence of interphalangeal crease of the right ring finger with restriction of flexion but without any other anomaly. PMID- 23087268 TI - Uterine adenosarcoma in a patient with history of breast cancer and long-term tamoxifen consumption. AB - Adenosarcoma is a rare tumour which usually originates from endometrium. This paper presents a 69-year-old woman with adenosarcoma of uterus and a history of breast cancer and 10 years tamoxifen therapy. PMID- 23087270 TI - Thigh haematoma following acupuncture treatment in a patient on warfarin. PMID- 23087271 TI - Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis. AB - Thyroid storm is a rare, but critical, illness that can lead to multiorgan failure and carries a high death rate. The following case series describes two adult men with Graves' disease who presented in thyroid storm and either failed or could not tolerate conventional medical management. However, both patients responded well to plasmapheresis, which resulted in clinical and biochemical stabilisation of their disease processes. The treatment option of plasmapheresis should be considered as a stabilising measure, especially when patients have failed or cannot tolerate conventional therapy. Plasmapheresis leads to amelioration of symptoms and a significant decline in thyroid hormone levels, providing a window to treat definitively with thyroidectomy. PMID- 23087272 TI - Unusual presentations of osteoarticular tuberculosis in two paediatric patients. AB - Tuberculosis is a universal mimicker and thus could be a differential diagnosis of any osteolytic lesion. Bone biopsy is crucial in these cases for culture and histological proof of tuberculous infection. This is a case report of two paediatric patients with unusual presentations of tuberculosis. One patient presented with knee pain and had imaged findings of an osteolytic lesion at the epiphysis. Interval scan showed spread of the lesion through the physis to the metaphyseal region. The second patient presented with hip pain and an osteolytic lesion of the acetabulum. He was subsequently found to have involvement of the brain and spine as well. Both patients were diagnosed with tuberculosis by bone biopsy for culture and pathological examination. They were treated successfully with antituberculous medications without chronic sequelae. These two patients showed that early recognition and prompt treatment are critical for management of tuberculosis to avoid chronic sequelae. PMID- 23087274 TI - Miscarriages following caesarean section-induced extra-uterine adhesions. AB - A Caucasian lady in her 30s presented with repeated miscarriages following a previous caesarean section. Following ongoing pain and bleeding, and inconclusive imaging, a scan undertaken after her second miscarriage suggested a possible communication through the uterine wall. Subsequent laparoscopy revealed a dense band of adhesions starting from lower segment of uterus and extending all the way to anterior fundus adherent to the anterior abdominal wall. To our knowledge, this is the first published case of repeated miscarriages following extra-uterine adhesions post caesarean section. Although causality cannot be proven, this is an important and potentially treatable diagnosis to consider. PMID- 23087273 TI - Follow-up bone scintigraphy images of a patient with osteoid osteoma during medical treatment. AB - Osteoid osteoma is a benign bone tumour which is usually seen in long bones. Although the eventual treatment of this tumour is surgery, medical treatment is another option. We present the 3 years follow-up bone scintigraphy images of a patient with osteoid osteoma which show improvement by medical treatment. PMID- 23087275 TI - Dying for a cup of tea. AB - We report the case of a 70-year-old woman who developed life-threatening arrhythmia as a result of acute and severe hypokalaemia, which she developed after consuming large quantities of a liquorice-rich herb tea. She had no previous heart condition. We also discuss the legislative discrepancy in both the USA and in Europe, whereby consumers are warned about the risk of chronic hypertension whenever they buy a product containing liquorice, yet the risk of hypokalaemia may not be mentioned at all. PMID- 23087276 TI - Untreated obstructive sleep apnoea as a therapeutic target in acute aortic dissection. PMID- 23087277 TI - Primary orbital non-Hodgkin's lymphoma. AB - Non-Hodgkin's lymphoma (NHL) can have extra-nodal presentation in approximately 25% of cases unlike Hodgkin's lymphoma which rarely involves extra-nodal sites. Extra-nodal lymphoma in the head and neck region is extremely rare. We report a case of 6-year-old girl who presented with medial canthus mass with proptosis, lagophthalmos and no significant loss of vision. CT findings showed an extra conal homogenous mass lesion in the left orbit along superior and medial orbital wall with extensive destruction of surrounding tissue. Histological sections showed polymorphous population of atypical lymphoid cells accompanied by plasma cells, eosinophils and proliferation of small blood vessels with plump endothelial cells. A diagnosis of NHL was rendered. Further, immunohistochemistry confirmed the lesion as peripheral T-cell lymphoma. The lesion was aggressive in course and the patient succumbed within one-and-half months of diagnosis. PMID- 23087278 TI - Massive pericardial effusion and multiple pericardial masses due to an anterior mediastinal teratoma rupturing in pericardial sac. AB - A 25 -year-old Egyptian man presented to our unit for the evaluation of a large pericardial effusion. At 1 month before presentation he suffered from daily bouts of fever. Chest x-ray revealed cardiomegaly, echocardiography showed large pericardial effusion and multiple pericardial masses. Needle pericardiocentesis revealed a bloody exudate with no malignant cells. Chest CT showed a well circumscribed anterior mediastinal cystic mass with a central fat component and foci of calcification. MRI of the chest similarly showed no intracardiac extension. A cystic mass 7*9 cm was removed via a median sternotomy with uneventful postoperative course. Pathological evaluation revealed a benign cystic teratoma and a thymic cyst. Most cystic teratomas are accidentally discovered, large ones can cause symptoms through the compression of mediastinal structures or rupture in pericardial sac. PMID- 23087279 TI - Hyperdense middle and anterior cerebral arteries: familiar and not so familiar CT signs of acute ischaemic stroke. PMID- 23087280 TI - Heat stroke presented with disseminated intravascular coagulation and bilateral intracerebral bleed. AB - Heat stroke is a life-threatening condition which is characterised by nausea, vomiting, confusion, disorientation and coma. Aggressive treatment in the form of intravenous fluids along with other symptomatic management can be life saving. Here we present an unusual case of heat stroke followed by disseminated intravascular coagulation, multiple organ dysfunction with bilateral intracerebral bleed who survived with judicious management and recovered without any neurological sequeale. PMID- 23087281 TI - Pancreatic extra-gastrointestinal stromal tumour masquerading as a bleeding duodenal mass. AB - We describe a 55-year-old man presenting to our institution with a gastrointestinal bleed. He was found to have a 5 cm pancreatic extra gastrointestinal stromal tumours (EGISTs) eroding into the duodenum and ampulla of Vater. Pancreaticoduodenectomy was performed and the tumour was noted to be positive for CD117 and CD34 with six mitotic figures per 50/high-powered field. At 5 months postoperatively he is receiving treatment with imatinib and doing well. To the best of our knowledge, our patient is only the 18th case reported in the literature to date. PMID- 23087282 TI - Pathological fractures on both lower limbs with Jaffe-Campanacci's syndrome. AB - Jaffe-Campanacci's syndrome is a very rare condition and was first described by Jaffe in 1958. It is presented by non-ossifying fibromas, cafe-au-lait spots and axillar freckling. Non-ossifying fibromas are usually found after minor traumas or stress fractures. Differential diagnosis to neurofibromatosis include the absence of Lisch granules, neurofibromatous skin lesions and schwannomatous soft tissue masses. In this case, we report a 13-year-old white boy with Jaffe Campanacci's syndrome, and bilateral pathological lower limbs fracture. PMID- 23087283 TI - Unilateral facial palsy in Guillain-Barre syndrome (GBS): a rare occurrence. AB - Guillain-Barre syndrome (GBS) is a postinfectious, autoimmune disorder which, apart from limb weakness, is characterised by cranial nerve involvement. Bilateral facial nerve palsy is the most common pattern of cranial nerve involvement in GBS. However, unilateral facial palsy, although uncommon, can be seen in GBS. We report a rare case of unilateral facial palsy in GBS and importance of electrophysiological tests including blink study in such cases has been emphasised. PMID- 23087284 TI - Outcome of mitral valve repair in a patient with systemic lupus erythematosus. AB - We present a 17-year-old woman with a 5-year history of systemic lupus erythematosus (SLE). The patient referred to us with the rheumatic involvement of the mitral valve and was treated with mitral valve repair by ring annuloplasty and anterior leaflet augmentation with autologous pericardium. Follow-up, however, disclosed precocious calcification of the valve, necessitating mitral valve replacement. PMID- 23087286 TI - Piriformis muscle metastasis from a rectal polyp. AB - Rectal cancers constitute over a quarter of all colorectal cancers. Spread of rectal cancer is usually to liver, lung and brain from high risk rectal cancers. Cases have rarely been reported of spread to soft tissue structures. Here we present a case of metastatic spread of a previously excised, early invasive adenocarcinomatous polyp to piriformis. PMID- 23087285 TI - Vasculitides associated with haematological malignancies: a case-based review. AB - Autoimmune phenomena including vasculitis are known to be associated with malignancy, especially those that are haematological in origin. Vasculitis syndromes associated with malignant disease include cutaneous leucocytoclastic vasculitis, polyarteritis nodosa, Churg-Strauss syndrome, microscopic polyangiitis, Wegener's granulomatosis and Henoch-Schonlein purpura. We describe a patient whose initial presentation with vasculitis led to the diagnosis of hairy cell leukaemia. PMID- 23087287 TI - Allopurinol-induced hepatomegaly. AB - Allopurinol has long been recognised as a cause of hepatotoxicity; however, severe side effects remain rare. We report a case of allopurinol-induced hepatomegaly causing abdominal symptoms in an elderly woman after long-term allopurinol use. PMID- 23087288 TI - Toenail onychodystrophy of the diabetic foot. PMID- 23087289 TI - Management of trismus following radiation therapy by cost-effective approach. AB - Radiotherapy when used in head and neck cancer treatment can produce side effects in patients such as the trismus. If allowed to progress trismus can become so severe that the patient becomes debilitated due to lack of nutrition. Furthermore, trismus and limited oral access present a challenge to the clinician for dental treatment. This article describes a simple and cost-effective appliance for management of trismus. PMID- 23087290 TI - Pins and needles and unilateral foot drop: a presentation of sarcoidosis. AB - We describe a case of sarcoidosis in a 57-year-old man who presented with neurological symptoms of pins and needles in both of his hands, left leg weakness and left foot drop. Neurophysiological examination revealed asymmetric motor and sensory polyneuropathy. Common peroneal nerve involvement accounted for the left foot drop. Thoracic CT scan revealed bilateral hilar and mediastinal lymphadenopathy. He had hypercalcaemia and raised serum ACE level. Histological examination of a mediastinal lymph node showed non-caseating epithelioid cell granulomas consistent with the diagnosis of sarcoidosis. There was no evidence of acid-fast bacilli or fungi on special stains. This case highlights the importance of considering sarcoidosis as a potential diagnosis in patients presenting with peripheral neuropathy. Although response to corticosteroids and immunosuppressive therapy may be seen, in our case the patient's neurological deficit remained persistent despite treatment. PMID- 23087291 TI - Assessment and management of mercury poisoning with an unusual abdominal x-ray! AB - This case discusses a gentleman who presented to the medical team after ingesting mercury liquid. We discuss the assessment, management and different types of mercury poisoning. PMID- 23087292 TI - Sjogren's syndrome with distal renal tubular acidosis presenting as hypokalaemic paralysis. AB - A young lady with a history of repeated episodes of generalised weakness and fatigue presented to our hospital with similar symptoms and was found to have severe hypokalaemia. She had been previously diagnosed as hypokalaemic periodic paralysis but during this presentation she had also started complaining of the classic sicca-complex of Sjogren's syndrome, which was not present previously. On subsequent investigations she was found to have normal anion-gap metabolic acidosis with positive urine anion gap consistent with the diagnosis of distal renal tubular acidosis (RTA). It was thus concluded that the distal RTA secondary to Sjogren's syndrome was the cause of severe hypokalaemia in our patient. By presenting this case we aim to not only highlight one of the rare presentations of Sjogren's syndrome but also the favourable response of our patient to potassium replacement alone. PMID- 23087293 TI - Aortic valve replacement with biological substitutes in children. AB - BACKGROUND: this study was performed to assess the results of aortic valve replacement in children with biological substitutes including homografts, pulmonary autografts (Ross procedure), and aortic valve reconstruction with autologous pericardium (Duran technique). METHODS: between March 1992 and July 2009, 73 children with aortic valve disease (mean age, 11.8 +/-2.7 years) underwent aortic valve replacement with biological substitutes including homografts, pulmonary autografts, and aortic valve reconstruction with autologous pericardium. Associated procedures were mitral valve repair in 32 and subaortic membrane resection in 3. RESULTS: early mortality was 1.4% (1 patient). Median follow-up was 94 months. Sixty (83.3%) survivors had insignificant aortic regurgitation. Reoperation was required in 7 (9.6%) patients: for autograft dysfunction alone in 2, autograft failure and failed mitral valve repair in 2, autograft dysfunction with severe pulmonary homograft regurgitation in 1, severe homograft aortic valve regurgitation in 1, and right ventricular outflow tract obstruction in 1. There were 4 (5.4%) late deaths. Actuarial reoperation-free, event-free, and aortic valve dysfunction-free survival were 92.5% +/-4%, 93.4% +/ 3.3 %, 94% +/-2.9%, 86.2% +/-4.3%, respectively, at 94 months. CONCLUSIONS: aortic valve replacement with biological substitutes is associated with acceptable hemodynamics and midterm results. PMID- 23087294 TI - High-sensitive C-reactive protein predicts outcome after coronary artery bypass. AB - BACKGROUND: Elevated high-sensitive C-reactive protein is a powerful independent predictor of cardiovascular events. However, there are scant data on its impact on midterm or long-term outcomes of coronary artery bypass grafting. METHOD: We analyzed data of 2863 patients who underwent coronary artery bypass in 2006-2007. Early endpoints were hospital mortality and major morbidity. Midterm endpoints were overall mortality, major adverse cardiovascular events, and heart failure. RESULTS: During hospital stay, 26 patients died and 288 suffered major morbidity. After 3.6 years of follow-up, 56 patients had died, 105 had major adverse cardiovascular events, and 70 developed heart failure. Multivariate analysis revealed every 1 mg.L(-1) increase of high-sensitive C-reactive protein was associated with increased odds ratio for early mortality (odds ratio = 2.50, p = 0.002), major morbidity (odds ratio = 1.38, p = 0.02), and hazard ratio for midterm mortality (hazard ratio = 1.68, p = 0.03), major adverse cardiovascular events (hazard ratio = 1.48, p = 0.04), and heart failure (hazard ratio = 1.88, p = 0.01). Preoperative high-sensitive C-reactive protein>2.5 mg.L(-1) predicted higher risks of early (hazard ratio = 2.69, p = 0.02) and midterm mortality (hazard ratio = 1.92, p = 0.02), major morbidity (hazard ratio = 1.46, p = 0.004), major adverse cardiovascular events (hazard ratio = 2.06, p<0.001), and heart failure (hazard ratio = 1.71, p = 0.03). CONCLUSIONS: Elevated high sensitive C-reactive protein (>2.5 mg.L(-1)) predicts poor early and midterm outcomes after coronary artery bypass. PMID- 23087295 TI - Mitral stenosis after IMR ETlogix ring annuloplasty for ischemic regurgitation. AB - OBJECTIVES: Ring annuloplasty combined with coronary artery bypass grafting is the standard approach for treatment of patients with ischemic mitral regurgitation. We evaluated mitral valve hemodynamic performance and recurrence of mitral regurgitation after ring annuloplasty. PATIENTS AND METHODS: 40 consecutive patients (mean age, 70+/-8 years) with chronic ischemic mitral regurgitation grade >=2+ received annuloplasty with an IMR ETlogix ring. During follow-up (25.9+/-15.5 months), 84% of surviving patients underwent exercise stress echocardiography to assess recurrence of mitral regurgitation and differences between rest and exercise mitral valve hemodynamic performance. RESULTS: Hospital mortality was 10%. During follow-up, we found no significant differences between left ventricular ejection fraction or end-diastolic and end systolic diameters pre- and postoperatively (41% vs. 45%, 59 vs. 56 mm, and 49 vs. 46 mm, respectively), but there was a significant increase in mitral mean gradient with exercise (3.3+/-1.2 vs. 7.8+/-4 mmHg, p<0.001). Two patients had mitral regurgitation >=grade III-IV. CONCLUSIONS: Mitral annuloplasty with the IMR ETlogix ring provides effective correction of chronic ischemic mitral regurgitation, but this technique may induce functional mitral stenosis. PMID- 23087296 TI - Is a cell saver necessary in off-pump coronary artery bypass surgery? AB - BACKGROUND: Off-pump coronary artery bypass surgery should have a significantly lower risk of postoperated bleeding than on-pump surgery. However, the use of a cell saver has been considered necessary, with significant additional cost incurred. Can we consider performing off-pump coronary artery bypass surgery without a cell saver? PATIENTS AND METHODS: A prospective observational study was performed in 68 consecutive patients operated on for 2- or 3-vessel coronary lesions by the off-pump technique. RESULTS: The mean number of distal anastomoses was 2.7 +/- 0.7. Both internal thoracic arteries were used in 45 patients, and sequential revascularization was performed in 27, with 140 (77.8%) arterial grafts. Cell savers were used in 21 (30.9%) patients. In these 21 patients, the mean volume retransfused after treatment was 315 +/- 177 mL. Postoperatively, 11 (16.2%) patients were transfused with packed red blood cells, with a mean volume of 636 +/- 234 mL per patient. The 2 factors identified as associated with a higher risk of autotransfusion were female sex and a lower preoperative hemoglobin. CONCLUSIONS: The use of a cell saver in off-pump surgery is useless in most cases. Careful surgical hemostasis is essential to limit hypovolemia. PMID- 23087297 TI - Sonoclot analysis in children with congenital heart disease. AB - BACKGROUND: This study aimed to compare preoperative baseline Sonoclot variables between acyanotic and cyanotic congenital heart disease patients. METHODS: 100 patients aged from infancy to 9-years were studied. Fifty patients each from the cyanotic and acyanotic groups were studied for Sonoclot parameters preoperatively. After inhalational anesthetic induction, blood was collected from the arterial line and analyzed in a Sonoclot analyzer to measure Sonoclot activated coagulation time, clot rate, and platelet function. RESULTS: Sonoclot activated coagulation time was normal in both groups, but lower in the cyanotic group (127.95 +/- 51.4 s) than the acyanotic group (147.85 +/- 45.48 s; p = 0.54). Both groups had abnormal clot rates and platelet function. The clot rate was significantly lower in the cyanotic group (19.31 +/- 10.68 U.min(-1)) than acyanotic group (24.88 +/- 9.23 U.min(-1); p = 0.009). Platelet function was deranged in 31% of patients (cyanotic, 59%; acyanotic, 8%; p <0.001). Platelet function was the most severely affected baseline parameter. CONCLUSIONS: Pediatric acyanotic and cyanotic congenital heart disease patients have deranged coagulation parameters as assessed by the Sonoclot analyzer. The abnormality is more marked in cyanotic patients. Platelet function is the most severely affected parameter. These baseline parameters in conjunction with post-bypass parameters for an individual patient will help in the formulation of specific blood component transfusion guidelines. PMID- 23087298 TI - Remote ischemic preconditioning in percutaneous coronary revascularization: a double-blind randomized controlled clinical trial. AB - OBJECTIVE: To assess the impact of pre-procedural remote ischemic preconditioning on the incidence of myocardial complications following percutaneous coronary intervention. BACKGROUND: Ischemic preconditioning of a remote vascular territory improves the subsequent ischemic tolerance of distant organs. METHOD: The Myocardial Event Reduction with Ischemic Preconditioning Therapy (MERIT) trial recruited 80 consecutive patients undergoing elective angioplasty with drug eluting stents to receive two 5-min lower limb tourniquet occlusions or an un inflated tourniquet (controls) 1 h before the procedure. The primary outcome was troponin T level at 24 h. Secondary outcomes were intra-procedural chest pain and ST-segment deviation. RESULTS: 6 patients in the control group and 2 in the ischemic preconditioning group had pre-procedural raised troponin T (p = 0.23). This increased to 16 (40%) in the control group and 5 (12.5%) in the study group at 24 h (p = 0.01). Fewer patients in the study group experienced intra procedural chest pain (1 vs. 7, p = 0.056). Mean ST-segment deviation time was 13 +/- 35 s in the study group and 58 +/- 118 s in the control group (p = 0.02). At a mean follow-up of 11 months, the major adverse cardiac event rate did not differ significantly between the groups. CONCLUSION: These data suggest that ischemic preconditioning reduces the absolute risk of post-procedure cardiomyocyte necrosis by 27.5%, and reduces intra-procedural chest pain and ST segment deviation in patients undergoing percutaneous coronary interventions. We suggest its routine use in percutaneous coronary intervention, although the long term prognostic impact in this patient group warrants further investigation. PMID- 23087299 TI - Cardiac and pulmonary dysfunction in asymptomatic beta-thalassanemia major. AB - This study assessed cardiac and pulmonary dysfunction in 26 asymptomatic patients with beta-thalassemia major. This investigation was a case-controlled study considering 10-20-year-old patients with beta-thalassemia major and no cardiac or pulmonary symptoms. Healthy individuals matched for age and sex were used as controls. At 48-72 h after blood transfusion, the patients underwent echocardiography and spirometry by a cardiologist and a pulmonologist. The results were compared to those of the control group. The right and left myocardial performance index, preejection period/ejection time ratio, ejection fraction, acceleration time, isovolumic contraction time, and bilateral isovolumic relaxation times in the study group demonstrated significant differences from the data of the controls. Right deceleration time was significantly different between the 2 groups. Myocardial performance index, peak early velocity of the right heart, and peak atrial velocity-to-peak early velocity ratio of the right side by Doppler tissue imaging were also significantly different between the 2 groups. Spirometry showed a significant difference in forced expiratory volume in 1 s/forced vital capacity between groups. Based on spirometry, pulmonary involvement in the patients was 77% restrictive. These findings show that systolic and diastolic dysfunction of the heart and pulmonary disturbances are unavoidable in patients with beta thalassemia major. PMID- 23087300 TI - Central vein stenosis in an Asian hemodialysis population. AB - OBJECTIVE AND BACKGROUND: Central vein stenosis occurs commonly after instrumentation of the major thoracic veins. We aimed to investigate factors that contributed to this condition in an Asian hemodialysis population, and the results of intervention. PATIENTS AND METHODS: Hemodialysis patients diagnosed with central vein stenosis between January 2003 and December 2008, were identified from the records of the National University Hospital, Singapore. Eligible controls had a minimum of 2 years of hemodialysis via an arteriovenous fistula and/or central venous catheter, without clinical or radiological evidence of central vein stenosis. RESULTS: Central vein stenosis was diagnosed in 108 patients. The most common presenting features were arm swelling (32%) and failed hemodialysis catheter insertion (28%). The median frequency of permanent hemodialysis catheter insertion in those who subsequently developed venous stenosis (1.44 per patient per year) was 4 times that of controls (0.36 per patient per year; p<0.001). Ischemic heart disease (p = 0.03) and in certain patients, arteriovenous fistula surgery were associated with the development of central vein stenosis; whereas line sepsis, diabetes, and hypertension were not. Central vein angioplasty was attempted in 53 patients; the primary patency was 52% at 1 year. CONCLUSION: Central vein stenosis is associated with a higher frequency of hemodialysis catheter insertion and access surgery. Efforts to decrease permanent hemodialysis catheter use should reduce the incidence of central vein stenosis. PMID- 23087301 TI - Relationship of venous blood gas with cervical esophagogastric anastomotic leak. AB - OBJECTIVE: this study investigated the relationship between various parameters of venous blood gas analysis of gastric fundus veins and cervical esophagogastric anastomotic leaks after transhiatal esophagectomy. BACKGROUND: decreased tissue perfusion is one of the causes of anastomotic leak. There are various methods used to assess gastric conduit perfusion, with different results, and we lack a reliable method. METHOD: this descriptive study, performed from March 2008 to October 2010, consisted of 45 patients with esophageal cancer who underwent transhiatal esophagectomy. After gastrolysis, blood samples were taken from a gastric fundus vein and submitted for venous blood gas analysis. The cervical wounds were examined 5 days postoperatively. The patients were divided into 2 groups based on the presence of leakage, and mean values of the venous blood gas analysis were compared. RESULTS: we observed significant differences in mean pH, PCO(2), and O(2) saturation between the 2 groups (p = 0.04, p = 0.03, and p = 0.04, respectively). CONCLUSION: venous blood gas analysis of gastric fundus veins appears to be a feasible and fast method for intraoperative assessment of microperfusion in the gastric fundus. PMID- 23087302 TI - Eleven-year experience in thoracoscopic excision of bronchogenic cyst. AB - OBJECTIVES: bronchogenic cysts are uncommon congenital cystic lesions. Most are incidentally detected and require surgical excision for histological diagnosis, symptom relief, and to prevent complications. Video-assisted thoracoscopic resection is preferable in suitable patients. In this study, we reviewed the clinical presentation, diagnosis, and thoracoscopic treatment of bronchogenic cysts. METHODS: from January 2001 to December 2011, 14 patients with bronchogenic cyst underwent thoracoscopic surgery for excision of the cyst. Their mean age was 24 years. Twelve patients were symptomatic (85.71%). RESULTS: the average maximum diameter of the cysts was 6.7 cm. The most common location of the cyst was the mediastinum (n = 10, 71.4%). All bronchogenic cysts were completely excised. In 7 cases, the procedure was converted to thoracotomy. The mean hospital stay following thoracoscopic surgery was 4 days. There was no recurrence on follow-up. CONCLUSIONS: thoracoscopic excision of a bronchogenic cyst should be considered the first-line therapeutic option. Proper preoperative case selection can prevent conversion to thoracotomy due to major pleural adhesions. There should be a low threshold for conversion to thoracotomy if complete excision of the cyst is not possible, because this is the main goal of treatment to prevent recurrence. PMID- 23087303 TI - Syphilitic aortic aneurysm presenting with upper airway obstruction. AB - Syphilitic aortic aneurysms are uncommon today. A rare case of syphilitic aortic arch aneurysm with successful surgical treatment is reported. A 42-year-old man presented with upper airway obstruction. Chest radiography showed a superior mediastinal mass, and computed tomography revealed a large saccular aortic arch aneurysm that compressed the trachea. Dacron graft replacement of the aortic arch was successfully performed under circulatory arrest with antegrade cerebral perfusion. PMID- 23087304 TI - Modified Lecompte procedure for repair of double-outlet left ventricle. AB - A modification of the Lecompte procedure was used successfully for total correction in 2 boys aged 3 and 6 months with double-outlet left ventricle. The operative procedure and short-term results are evaluated. PMID- 23087305 TI - Surgical treatment of an interatrial septal paraganglioma. AB - A 39-year-old man presented with chest pain. Chest radiography and echocardiography indicated a possible cardiac tumor. Echocardiography, computed tomography, and magnetic resonance imaging revealed a tumor in the interatrial septum. The patient underwent tumor resection under cardiopulmonary bypass. A paraganglioma was diagnosed on the basis of histopathological findings. PMID- 23087306 TI - Aortic pseudoaneurysm due to graft infection after invasive thymoma resection. AB - A 69-year-old woman with invasive thymoma underwent chemoradiotherapy followed by surgical resection, including extended thymectomy, right upper lobectomy, and innominate vein and superior vena cava reconstruction with a polytetrafluoroethylene graft. Computed tomography on the 27th postoperative day revealed mediastinitis and right hemothorax; open debridement and evacuation were performed. Vacuum-assisted closure was initiated to heal the median incision. The wound gradually cleared, and the vacuum was terminated on the 150th postoperative day. On the 155th postoperative day, the patient suffered a sudden hemorrhage from the anterior thoracic wall. Computed tomography revealed a ruptured ascending aortic pseudoaneurysm surrounding the graft. PMID- 23087307 TI - Endovascular repair of intrathoracic ruptured Kommerell's diverticulum. AB - A right-sided aortic arch associated with an aberrant subclavian artery is a rare anomaly. Regardless, this condition is clinically relevant because mortality is associated with rupture, morbidity results from compression of mediastinal structures, and the surgery is complex. We describe the successful surgical repair of this vascular anomaly by totally debranching the neck vessels and placing an endovascular stent-graft to exclude the ruptured Kommerell's diverticulum. PMID- 23087308 TI - Aorto-left ventricular tunnel: uncommon site of origin and management. AB - Cases of aorto-ventricular tunnel involving the right ventricle and more commonly, the left ventricle have been described. The site of origin is located above the right coronary cusp and occasionally, the left. We describe an aorto left ventricular tunnel in a 16-year-old girl, with aneurysmal expansion into the right ventricular outflow tract. Its aortic origin was above the commissure of the right and noncoronary cusps of the aortic valve. PMID- 23087309 TI - Aortic valve perforation following transcoronary ablation of septal hypertrophy. AB - We report the case of a 47-year-old man with hypertrophic obstructive cardiomyopathy who underwent transcoronary ablation of septal hypertrophy and developed severe aortic regurgitation after the procedure. Intra-operatively, we found a wide perforation of the noncoronary cusp, and performed aortic valve replacement. PMID- 23087310 TI - Intralobar pulmonary sequestration associated with bronchogenic cyst in adult. AB - Pulmonary sequestration and mediastinal bronchogenic cysts are rare but well known to thoracic surgeons. However, their association is exceptional. We report such a case in a young adult. The common origin of these 2 malformations is discussed. PMID- 23087311 TI - Gastric tube reconstruction of esophagus for esophageal and stomach carcinomas. AB - Synchronous carcinomas of the esophagus and other organs are relatively uncommon. A 65-year old man with synchronous carcinomas of the esophagus and stomach underwent esophageal reconstruction using a gastric tube following endoscopic submucosal dissection. PMID- 23087312 TI - Primary pulmonary adenoid cystic carcinoma: report of two cases. AB - A 51-year-old man with adenoid cystic carcinoma in the main stem bronchus was treated by a left lower lobectomy. A 44-year-old man with adenoid cystic carcinoma in the peripheral small bronchi underwent a right sleeve upper lobectomy with tracheobronchoplasty and neo-carina reconstruction; because of positive tumor margins, radiotherapy was administered postoperatively. Both patients were alive without any signs of tumor after 30 and 24 months of follow up, respectively. PMID- 23087313 TI - Unusual cause of chest pain: a "souvenir" from the past. PMID- 23087314 TI - Migration of endovascular stent to the right atrium in dialysis patient. PMID- 23087315 TI - A case of pleomorphic carcinoma of the lung suspected from infectious bulla. PMID- 23087316 TI - Imaging of pulmonary arteriovenous malformation by computed tomography. PMID- 23087317 TI - Cardiothoracic trauma with a mechanical saw. PMID- 23087318 TI - Severe regurgitation in type A aortic dissection due to prolapsed intimal flap. PMID- 23087319 TI - External support in preventing vein graft failure. AB - Saphenous vein remains a widely used conduit in coronary surgery. However, the long-term success of surgical myocardial revascularization is largely limited by the development of neointimal hyperplasia and superimposed atherosclerosis in vein grafts. Although strategies for preventing vein graft failure have been constantly explored, few therapeutic interventions to date have shown sustained benefits in the clinical setting. The application of external support has emerged as a promising strategy for modulating the overall biomechanical responses in venous wall. Nonetheless, clinical translation of this intervention has been formerly challenged, primarily due to several technique limitations. The purpose of the current review is to summarize the possible mechanisms involved in the external support strategy for preventing vein graft failure. Furthermore, several previously tested biomaterials and delivery techniques are also highlighted. PMID- 23087320 TI - Transthoracic intra-aortic balloon pump removal without repeat sternotomy. AB - Transaortic balloon catheter insertion for intra-aortic balloon assistance is a practical alternative to the standard transfemoral cannulation in patients with significant aortoiliac occlusive disease. We describe a technique whereby a transthoracic balloon is removed with the aid of video-assisted thoracoscopy. PMID- 23087321 TI - Ruptured sinus of Valsalva aneurysm: 10-year Indian surgical experience. PMID- 23087322 TI - Effects of site-directed mutagenesis in the N-terminal domain of thermolysin on its stabilization. AB - The thermolysin variant G8C/N60C/S65P in which the triple mutation in the N terminal domain, Gly8->Cys/Asn60->Cys/Ser65->Pro, is undertaken increases stability [Yasukawa, K. and Inouye, K. (2007) Improving the activity and stability of thermolysin by site-directed mutagenesis. Biochim. Biophys. Acta 1774, 1281-1288] and its mechanism is examined in this study. The apparent denaturing temperatures based on ellipticity at 222 nm of the wild-type thermolysin (WT), G8C/N60C, S65P and G8C/N60C/S65P were 85, >95, 88 and >95 degrees C, respectively. The first-order rate constants, k(obs), of the thermal inactivation of WT and variants at 10 mM CaCl2 increased with increasing thermal treatment temperatures (70-95 degrees C), and those at 80 degrees C decreased with increasing CaCl2 concentrations (1-100 mM). The k(obs) values were in the order of WT > S65P > G8C/N60C?G8C/N60C/S65P at all temperatures and CaCl2 concentrations. These results indicate that the mutational combination, Gly8 >Cys/Asn60->Cys and Ser65->Pro, increases stability only as high as Gly8 >Cys/Asn60->Cys does. Assuming that irreversible inactivation of thermolysin occurs only in the absence of calcium ions, the dissociation constants, K(d), to the calcium ions of WT, G8C/N60C, S65P and G8C/N60C/S65P were 47, 8.9, 17 and 7.2 mM, respectively, suggesting that Gly8->Cys/Asn60->Cys and Ser65->Pro stabilize thermolysin by improving its affinity to calcium ions, most probably the one at the Ca2+-binding site III in the N-terminal domain. PMID- 23087323 TI - Analytical performance verification of a molecular diagnostic for cytology indeterminate thyroid nodules. AB - OBJECTIVE: Our objective was to verify the analytical performance of the Afirma gene expression classifier (GEC) in the classification of cytologically indeterminate thyroid nodule fine-needle aspirates (FNAs). DESIGN: Analytical performance studies were designed to characterize the stability of RNA in FNAs during collection and shipment, analytical sensitivity as applied to input RNA concentration and malignant/benign FNA mixtures, analytical specificity (i.e. potentially interfering substances) as tested on blood and genomic DNA, and assay performance studies including intra-nodule, intraassay, inter-assay, and inter laboratory reproducibility. RESULTS: RNA content within FNAs preserved in FNAProtect is stable for up to 6 d at room temperature with no changes in RNA yield (P = 0.58) or quality (P = 0.56). FNA storage and shipping temperatures were found to have no significant effect on GEC scores (P = 0.55) or calls (100% concordance). Analytical sensitivity studies demonstrated tolerance to variation in RNA input (5-25 ng) and to the dilution of malignant FNA material down to 20%. Analytical specificity studies using malignant samples mixed with blood (up to 83%) and genomic DNA (up to 30%) demonstrated negligible assay interference with respect to false-negative calls, although benign FNA samples mixed with relatively high proportions of blood demonstrated a potential for false-positive calls. The test is reproducible from extraction through GEC result, including variation across operators, runs, reagent lots, and laboratories (sd of 0.158 for scores on a >6 unit scale). CONCLUSIONS: Analytical sensitivity, analytical specificity, robustness, and quality control of the GEC were successfully verified, indicating its suitability for clinical use. PMID- 23087324 TI - De novo STX16 deletions: an infrequent cause of pseudohypoparathyroidism type Ib that should be excluded in sporadic cases. AB - CONTEXT: Maternally inherited 3-kb STX16 deletions cause autosomal dominant pseudohypoparathyroidism type Ib (PHP-Ib) characterized by PTH resistance with loss of methylation restricted to the GNAS exon A/B. OBJECTIVE: The objective of the study was to search for the 3-kb STX16 deletion and to establish haplotypes for the GNAS region for two PHP-Ib patients and their families. SETTING: The study was conducted at a research laboratory and tertiary care hospitals. PATIENTS: The index cases presented at the ages 8 and 9.5 yr, respectively, with hypocalcemia, hyperphosphatemia, and elevated PTH. INTERVENTIONS: There were no interventions. RESULTS: DNA analyses of the index cases revealed an isolated loss of the GNAS exon A/B methylation and the 3-kb STX16 deletion. In the first family, the patient's healthy mother and sister showed no genetic or epigenetic abnormality, yet microsatellite analysis of the GNAS region indicated that both siblings share the same maternal allele, with the exception of an allelic loss for marker 261P9-CA1 (located within STX16), leading to the conclusion that a de novo mutation had occurred on the maternal allele. In the second family, three siblings of the index case are also affected, and an analysis of their DNA revealed the 3-kb STX16 deletion, which was also found in the healthy mother and a maternal uncle. Analysis of the siblings of the deceased maternal grandfather and some of their descendants excluded the 3-kb STX16 deletion, but haplotype analysis of the GNAS region suggested that he had acquired the mutation de novo. CONCLUSIONS: De novo 3-kb STX16 deletions, reported only once previously, are infrequent but should be excluded in all cases of PHP-Ib, even when the family history is negative for an inherited form of this disorder. PMID- 23087326 TI - A KH domain-containing putative RNA-binding protein is critical for heat stress responsive gene regulation and thermotolerance in Arabidopsis. AB - Heat stress is a severe environmental factor that significantly reduces plant growth and delays development. Heat stress factors (HSFs) are a class of transcription factors that are synthesized rapidly in response to elevations in temperature and are responsible for the transcription of many heat stress responsive genes including those encoding heat shock proteins (HSPs). There are 21 HSFs in Arabidopsis, and recent studies have established that the HSFA1 family members are master regulators for the remaining HSFs. However, very little is known about upstream molecular factors that control the expression of HSFA1 genes and other HSF genes under heat stress. Through a forward genetic analysis, we identified RCF3, a K homology (KH) domain-containing nuclear-localized putative RNA-binding protein. RCF3 is a negative regulator of most HSFs, including HSFA1a, HSFA1b, and HSFA1d. In contrast, RCF3 positively controls the expression of HSFA1e, HSFA3, HSFA9, HSFB3, and DREB2C. Consistently with the overall increased accumulation of heat-responsive genes, the rcf3 mutant plants are more tolerant than the wild-type to heat stress. Together, our results suggest that a KH domain containing putative RNA-binding protein RCF3 is an important upstream regulator for heat stress-responsive gene expression and thermotolerance in Arabidopsis. PMID- 23087325 TI - AtSYP51/52 functions diverge in the post-Golgi traffic and differently affect vacuolar sorting. AB - Plant sensitive factor attachment protein receptors (SNAREs) encoded by genes of the same sub-family are generally considered as redundant in promoting vesicle associated membrane fusion events. Nonetheless, the application of innovative experimental approaches highlighted that members of the same gene sub-family often have different functional specificities. In this work, two closely related Qc-SNAREs--the AtSYP51 and the AtSYP52--are compared in their ability to influence different secretory pathways. Their role in the vesicle sorting to the central vacuole has been revised and they were found to have a novel inhibitory function. When transiently overexpressed, the SYP51 and the SYP52 distributed between the TGN and the tonoplast. Our data demonstrate that these SYPs (syntaxin of plants) act as t-SNARE when present on the membrane of TGN/PVC, whereas they behave as inhibitory or interfering SNAREs (i-SNAREs) when they accumulate on the tonoplast. Moreover, the performed functional analysis indicated that the AtSYP51 and the AtSYP52 roles differ in the traffic to the vacuole. The findings are a novel contribution to the functional characterization of plant SNAREs that reveals additional non-fusogenic roles. PMID- 23087327 TI - High risk medicolegal autopsies: is a full postmortem examination necessary? AB - AIMS: Aiming to reduce the numbers of high risk autopsies, we use a minimally invasive approach. HIV/hepatitis C virus (HCV)-positive coronial referrals, mainly intravenous drug abusers, have full autopsy only if external examination, toxicology and/or postmortem CT scan do not provide the cause of death. In this study, we review and validate this protocol. METHODS AND RESULTS: 62 HIV/HCV positive subjects were investigated. All had external examination, 59 toxicology and 24 CT. In 42/62, this minimally invasive approach provided a cause of death. Invasive autopsy was required in 20/62, CT/toxicology being inconclusive, giving a potential rather than definite cause of death. Autopsy findings provided the cause of death in 6/20; in the remainder, a negative autopsy allowed more weight to be given to toxicological results previously regarded as inconclusive. In order to validate selection of cases for invasive autopsy using history, external examination and toxicology, a separate group of 57 non-infectious full autopsies were analysed. These were consecutive cases in which there was a history that suggested drug abuse. A review pathologist, provided only with clinical summary, external findings and toxicology, formulated a cause of death. This formulation was compared with the original cause of death, based on full autopsy. The review pathologist correctly identified a drug-related death or requirement for full autopsy in 56/57 cases. In one case, diagnosed as cocaine toxicity by the review pathologist, autopsy additionally revealed subarachnoid haemorrhage and Berry aneurysm. CONCLUSIONS: These findings support the use of minimally invasive techniques in high risk autopsies, which result in a two-thirds reduction in full postmortems. PMID- 23087328 TI - CD24: a potential new marker in differentiating malignant mesothelioma from pulmonary adenocarcinoma. AB - BACKGROUND: The differential diagnosis between malignant mesothelioma (MM) and metastatic lung adenocarcinoma (MLA) often relies on immunohistochemical studies, with no individual immunomarker holding satisfactory discrimination ability. METHODS: We investigated the diagnostic accuracy of CD24 immunoreactivity on 134 patients including 69 cases of MM and 65 MLA. RESULTS: The expression of CD24 favoured MLA, with 57/65 cases showing positive cytoplasmic staining compared with 9/69 MM (p<0.001), whose immunopositivity pattern was prevalently membranous (7/9 cases). CONCLUSIONS: CD24 positivity can accurately discriminate MM from MLA. Prospective studies are warranted to clarify whether CD24 could integrate with other immunomarkers to facilitate the diagnosis of mesothelial malignancies. PMID- 23087329 TI - Her2 amplification distinguishes a subset of non-muscle-invasive bladder cancers with a high risk of progression. AB - BACKGROUND: Several studies have employed immunohistochemistry to detect Her2/neu overexpression in urothelial carcinomas, yielding a tremendous range of positive expression rates. Few studies have examined Her2 status in non-muscle invasive bladder cancer (NMIBC) using fluorescence in situ hybridisation (FISH). AIM: To evaluate Her2 amplification in NMIBC (Ta/T1), to correlate the findings with recurrence and progression, and compare the Her2 status between primary and progressive tumours. METHODS: FISH and immunohistochemistry for Her2/neu were performed on tissue arrays consisting of 36 papillary urothelial neoplasms of low malignant potential (PUNLMPs), 190 low grade urothelial carcinomas (LG-UCs) and 178 high grade urothelial carcinomas (HG-UCs). 32 cases with specimens of both primary and progressive tumours (from Ta/T1 to T2-4) were included for comparative analyses. RESULTS: 16 HG-UCs (9.0%) showed Her2 gene amplification while none of the PUNLMPs and LG-UCs showed this aberration. There was 100% concordance in the status of Her2 amplification between primary and progressive lesions. Immunohistochemistry and FISH results were in closest agreement when overexpression was defined as 50% of tumour cells showing immunoreactivity. The cumulative incidences of recurrence and progression in Her2-amplified HG-UC were significantly higher than in those without amplification. CONCLUSIONS: A subset of high-grade NMIBCs contain Her2 amplification and are associated with markedly aggressive behaviour. Her2 diagnostics are valuable for distinguishing patients who require diligent surveillance and would potentially benefit from anti-Her2 therapies. PMID- 23087330 TI - The manufacture and assessment of tissue microarrays: suggestions and criteria for analysis, with breast cancer as an example. AB - Tissue microarray (TMA) is an established and valuable tool, particularly in translational research and clinical trials, allowing resource-efficient use, and high-throughput profiling, of large numbers of tumours. Despite this, there is little evidence, or guidance, on the optimum manufacture, use and assessment of TMAs. Here we review some of the literature, using breast cancer as an example, to highlight good practice and pitfalls in the design and manufacture of TMAs. Issues, such as the size, number, spacing and layout of cores, as well as the assessment and reporting of studies using TMAs are addressed. We make some suggestions regarding these challenges, and propose a checklist of features that should be considered in order to stimulate debate and improve the quality of data produced by TMA analysis. PMID- 23087331 TI - Better retrieval of lymph nodes in colorectal resection specimens by pathologists' assistants. AB - BACKGROUND: Errors in surgical pathology are partly due to the increasing workload of pathologists. To reduce this workload, 'pathologists' assistants' (PAs) have been trained to take over some of the pathologists' recurrent tasks. One of these tasks is the precise examination of >=10 lymph nodes (LNs), which is of paramount importance to reduce the risk of understaging of colorectal cancer patients. AIMS: To evaluate the role of PAs in harvesting LNs in colorectal resection specimens and, by doing so, in improving patient safety. METHODS: LN harvest was retrospectively reviewed in 557 pathology reports on colorectal resection specimens collected in two Dutch hospitals from 2008 until 2011. RESULTS: PAs sampled >=10 LNs in significantly more cases than pathologists did (83.2% vs 60.9% in hospital A and 79.2% vs 67.6% in hospital B) and recovered on average significantly more LNs than pathologists did (18.5 vs 12.2 in hospital A and 16.6 vs 13.2 in hospital B). PAs harvested a significantly higher percentage of LNs <5 mm than pathologists did (64.2% vs 53.7%). The percentages of colon cancer patients eligible for adjuvant chemotherapy due to inadequate LN sampling alone were significantly higher for cases dissected by pathologists than for those dissected by PAs (17.3% vs 1.1% in hospital A and 13.1% vs 3.4% in hospital B) CONCLUSIONS: PAs contribute to patient safety since they recover more and, in particular, smaller LNs from colorectal resection specimens than pathologists do. Moreover, they help to reduce costs and morbidity by reducing the number of patients eligible for adjuvant chemotherapy due to inadequate LN sampling alone. PMID- 23087332 TI - Honoring Dr. Betty Neuman's contributions to nursing science. PMID- 23087334 TI - A beginner's guide to writing the nursing conceptual model-based theoretical rationale. AB - Writing the theoretical rationale for a study can be a daunting prospect for novice researchers. Nursing's conceptual models provide excellent frameworks for placement of study variables, but moving from the very abstract concepts of the nursing model to the less abstract concepts of the study variables is difficult. Similar to the five-paragraph essay used by writing teachers to assist beginning writers to construct a logical thesis, the authors of this column present guidelines that beginners can follow to construct their theoretical rationale. This guide can be used with any nursing conceptual model but Neuman's model was chosen here as the exemplar. PMID- 23087335 TI - Nursing in a complex world: a case for grand theory. AB - The authors of this column put forth a call for more grand theory to be used as the basis of nursing research. To that end, complexity theory and the Neuman systems model are reviewed followed by a discussion of the links that occur between them. Then evidence of the increased use of middle-range theory as the foundation of current nursing research is put forth. Finally, there is a discussion about the authors' conclusion that the complexity of the phenomena of interest for nursing research requires theories to be used as underpinnings that are more abstract and less reductionistic. PMID- 23087336 TI - Ethical implications and interprofessional education. AB - Policy and position statements from global regulatory agencies in all health disciplines are emphasizing and implementing requirements that interprofessional team education become a mandatory educational component for each of the health disciplines. What is interprofessional and/or interdisciplinary team-based healthcare? What are potential ethical implications specifically for the practice of nursing? In this column the author offers an exploration of potential definitions and meanings for future nursing education, research, and practice from a nursing theoretical perspective. PMID- 23087337 TI - Metaphorically speaking . . . AB - Metaphors are thought to provide a means to better understand phenomena. Metaphors have been found to be helpful in communication, nursing, nursing research, and as a pedagogical tool in the teaching-learning environment. This column briefly discusses metaphors and introduces a column which offers a unique use of metaphors in nursing education. PMID- 23087338 TI - A medieval metaphor to aid use of the Neuman systems model in simulation debriefing. AB - Patient simulation is an effective clinical nursing experience and debriefing is recognized as the most crucial phase for students to internalize learning. The Neuman systems model is an excellent organizing framework for simulation debriefing to maximize learning. However, due to the model's complexity, metaphor may be useful to help students to link simulation events with the model's concepts. A medieval metaphorical adaptation of the Neuman systems model was created as an educational debriefing tool to help students bridge this gap. Neuman's concepts are represented as medieval figures encountering and dealing with stressor dragons, with assistance (nursing intervention) as necessary. The companion questionnaire allows recording of student insights and becomes an evaluation tool for student comprehension. PMID- 23087340 TI - Transparency: a concept analysis. AB - This column is a review of the use of the term transparency as it relates to healthcare with specific emphasis on nursing practice. Concept analysis is guided by Parse's concept inventing approach. The relevance of this concept to nursing has become increasing important in the language of healthcare. There is no standard definition of the term in nursing or healthcare. Transparency or lack thereof shapes the future of disciplines. The author provides a theoretical definition of transparency for nurses to consider. PMID- 23087341 TI - Dialogue with Lois Lowry : development of the Neuman systems model. Interview by Pamela N. Clarke. AB - The column is an interview with one of the Neuman trustees. Dr. Lois Lowry shared her experience with the Neuman systems model in curriculum development and evaluation in this dialogue. She shared insights from the development of the international Neuman conference in Holland in June. PMID- 23087342 TI - New advances in the use of Neuman's Lines of Defense and Resistance in Quantitative Research. AB - In 1997, Gigliotti proposed that certain conceptual and empirical considerations were necessary when using the Neuman systems model lines of defense and resistance in quantitative research. Since that time, a period of theoretical sharpening has resulted both from the iterative process of theory development through research and refinement of proposed relations, and from concept clarification efforts. These new advances prompt new empirical considerations. Specifically, the notion of the flexible line of defense strictly as a moderator has been reconsidered and new relations between the normal line of defense and the lines of resistance, as well as between the core, the lines of resistance and the normal line of defense are proposed. PMID- 23087343 TI - Experience informs: spanning three decades with the Neuman systems model. AB - The efficacy of the Neuman systems model as a guiding framework for curriculum development of a baccalaureate program is examined. Insights from lessons learned provide directions for nursing theory-based curriculum change and program development. Challenges and opportunities during curriculum development are explored. Recommendations and strategies that contribute to consensus building are reported. PMID- 23087344 TI - How well does spirituality predict health status in adults living with HIV Disease: A Neuman systems model study. AB - The purpose of this study was to examine the relationship between spirituality and health status of 39 adult men and women living with HIV-disease. A model building approach was used to explore the associations among the five variables of the Neuman systems model, which was the guiding framework for the study. The model presented includes existential well-being, meaningfulness, age, and income. PMID- 23087346 TI - What's wrong with the concept of self-management? AB - In the following introduction to an update on the use of Betty Neuman Systems Model in Holland, the author raising some questions about the use of the concept of 'self-management' and patient as 'consumer' by nurses. An excessive emphasis on individualism and consumerism in healthcare is seen as too narrow and demoralizing. PMID- 23087345 TI - A qualitative descriptive study of spirituality guided by the Neuman systems model. AB - The purposes of this qualitative descriptive study were to explore the meaning of spirituality as described by aging adults in various states of health, to describe the relationship between spirituality and health, and to explain client expectations for healthcare providers related to spirituality. All identified meanings and themes were compared to the characteristics of spirituality proposed by Betty Neuman in the Neuman systems model to determine the credibility of the model for assessing and guiding holistic nursing practice. Three themes were formulated: a) Spirituality is an individual, conscious, committed connection to God, requiring a human response; b) positive spirituality contributes to personal wholeness and health; and c) spirituality sustains and comforts in times of stress. PMID- 23087347 TI - Neuman systems model in holland: an update. AB - The authors of this column, leading members of the International Neuman Systems Model Association, provide an update on the use of Neuman systems model in Holland and document the various changes in The Netherlands that have influenced the use of the model in that country. The model's link to systems theory and stress theory are discussed, as well as a shift to greater emphasis on patient self-management. The model is also linked to healthcare quality improvement and interprofessional collaboration in Holland. PMID- 23087349 TI - High altitude leadership and the humanbecoming leading-following model: an executive director's perspective. AB - The concept of high altitude leadership and the humanbecoming leading-following model are explored from the perspective of the Executive Director of the South Dakota Board of Nursing. The humanbecoming essentials inherent in leading: commitment to a vision, willingness to risk, and reverence for others, are discussed in relation to high altitude leadership concepts that illuminate the risks, dangers, and patterns for surviving the threats that may surface along the journey of leading. PMID- 23087350 TI - Thoughts about the Neuman systems model: a dialogue. Interview by Jacqueline Fawcett. AB - This is a report of an interview of Betty Neuman, founder of the Neuman systems model, that took place at the 13(th) Neuman Systems Model Symposium in June 2011. The interview, conducted by Jacqueline Fawcett, included questions submitted by Neuman systems model trustees Sarah Beckman, Barbara Cammuso, Marlou de Kuiper, Barbara Freese, Lois Lowry, and Andre Merks. PMID- 23087354 TI - Nursing science quarterly best paper award: 2011. PMID- 23087356 TI - Blood clots are rapidly assembled hemodynamic sensors: flow arrest triggers intraluminal thrombus contraction. AB - OBJECTIVE: Blood clots form under flow during intravascular thrombosis or vessel leakage. Prevailing hemodynamics influence thrombus structure and may regulate contraction processes. A microfluidic device capable of flowing human blood over a side channel plugged with collagen (+/- tissue factor) was used to measure thrombus permeability (kappa) and contraction at controlled transthrombus pressure drops. METHODS AND RESULTS: The collagen (kappa(collagen)=1.98 * 10(-11) cm(2)) supported formation of a 20-um thick platelet layer, which unexpectedly underwent massive platelet retraction on flow arrest. This contraction resulted in a 5.34-fold increase in permeability because of collagen restructuring. Without stopping flow, platelet deposits (no fibrin) had a permeability of kappa(platelet)=5.45 * 10(-14) cm(2) and platelet-fibrin thrombi had kappa(thrombus)=2.71 * 10(-14) cm(2) for DeltaP=20.7 to 23.4 mm Hg, the first ever measurements for clots formed under arterial flow (1130 s(-1) wall shear rate). Platelet sensing of flow cessation triggered a 4.6- to 6.5-fold (n=3, P<0.05) increase in contraction rate, which was also observed in a rigid, impermeable parallel-plate microfluidic device. This triggered contraction was blocked by the myosin IIA inhibitor blebbistatin and by inhibitors of thromboxane A2 (TXA(2)) and ADP signaling. In addition, flow arrest triggered platelet intracellular calcium mobilization, which was blocked by TXA(2)/ADP inhibitors. As clots become occlusive or blood pools following vessel leakage, the flow diminishes, consequently allowing full platelet retraction. CONCLUSIONS: Flow dilution of ADP and thromboxane regulates platelet contractility with prevailing hemodynamics, a newly defined flow-sensing mechanism to regulate clot function. PMID- 23087358 TI - Interference of the CD30-CD30L pathway reduces atherosclerosis development. AB - OBJECTIVE: Costimulatory molecules tightly control immune responses by providing positive signals that promote T-cell activation or by transducing inhibitory signals that limit T-cell responses. CD30 and CD30L are members of the tumor necrosis factor receptor superfamily and are involved in the activation and proliferation of T and B cells, which have been implicated in the initiation and progression of atherosclerosis. In the present study, we thus aimed to determine the role of the CD30-CD30L pathway in the development of atherosclerosis. METHODS AND RESULTS: Western-type diet-fed low-density lipoprotein receptor-deficient mice were treated with an anti-CD30L antibody for 8 weeks, which resulted in a reduction of atherosclerotic lesion formation in the aortic root by 35%. Reduced numbers of adventitial CD3(+) T cells were found in anti-CD30L-treated mice, whereas no differences were observed in collagen and macrophage content of the atherosclerotic lesions. B-cell and mast cell responses were also not affected on anti-CD30L treatment. Interestingly, splenocyte proliferation was reduced by 53%, whereas T-cell numbers were concomitantly reduced in anti-CD30L-treated mice compared with control mice. These data thus indicate that the CD30-CD30L pathway solely exerts its function via inhibition of T-cell responses. CONCLUSIONS: In the present study, we are the first to show that interruption of the CD30-CD30L pathway reduced initial atherosclerosis development by modulating T-cell function. PMID- 23087359 TI - A systematic approach to multifactorial cardiovascular disease: causal analysis. AB - The combination of systems biology and large data sets offers new approaches to the study of cardiovascular diseases. These new approaches are especially important for the common cardiovascular diseases that have long been described as multifactorial. This promise is undermined by biologists' skepticism of the spider web-like network diagrams required to analyze these large data sets. Although these spider webs resemble composites of the familiar biochemical pathway diagrams, the complexity of the webs is overwhelming. As a result, biologists collaborate with data analysts whose mathematical methods seem much like those of experts using Ouija boards. To make matters worse, it is not evident how to design experiments when the network implies that many molecules must be part of the disease process. Our goal is to remove some of this mystery and suggest a simple experimental approach to the design of experiments appropriate for such analysis. We will attempt to explain how combinations of data sets that include all possible variables, graphical diagrams, complementation of different data sets, and Bayesian analyses now make it possible to determine the causes of multifactorial cardiovascular disease. We will describe this approach using the term causal analysis. Finally, we will describe how causal analysis is already being used to decipher the interactions among cytokines as causes of cardiovascular disease. PMID- 23087357 TI - Mitochondrial calcium and reactive oxygen species regulate agonist-initiated platelet phosphatidylserine exposure. AB - OBJECTIVE: To study the interactions of cytoplasmic calcium elevation, mitochondrial permeability transition pore (mPTP) formation, and reactive oxygen species formation in the regulation of phosphatidylserine (PS) exposure in platelets. METHODS AND RESULTS: mPTP formation, but not the degree of cytoplasmic calcium elevation, was associated with PS exposure in wild-type, cyclophilin D null, ionomycin-treated, and reactive oxygen species-treated platelets. In the absence of the mPTP regulator cyclophilin D, agonist-initiated mPTP formation and high-level PS exposure were markedly blunted, but cytoplasmic calcium transients were unchanged. Mitochondrial calcium (Ca(2+)(mit)) transients and reactive oxygen species, key regulators of mPTP formation, were examined in strongly stimulated platelets. Increased reactive oxygen species production occurred in strongly stimulated platelets and was dependent on extracellular calcium entry, but not the presence of cyclophilin D. Ca(2+)(mit) increased significantly in strongly stimulated platelets. Abrogation of Ca(2+)(mit) entry, either by inhibition of the Ca(2+)(mit) uniporter or mitochondrial depolarization, prevented mPTP formation and exposure but not platelet aggregation or granule release. CONCLUSIONS: Sustained cytoplasmic calcium levels are necessary, but not sufficient, for high-level PS exposure in response to agonists. Increased Ca(2+)(mit) levels are a key signal initiating mPTP formation and PS exposure. Blockade of Ca(2+)(mit) entry allows the specific inhibition of platelet procoagulant activity. PMID- 23087360 TI - Retinol-binding protein 4 is an independent factor associated with triglycerides and a determinant of very low-density lipoprotein-apolipoprotein B100 catabolism in type 2 diabetes mellitus. AB - OBJECTIVE: Retinol-binding protein 4 (rbp4) is an adipokine secreted by adipocytes and liver, whose levels are elevated in type 2 diabetes mellitus (T2DM). Plasma levels of rbp4 and triglycerides are strongly correlated in T2DM. However, we do not know whether this association is direct or indirect via liver fat content, and the link between rbp4 and triglyceride metabolism remains unknown. METHODS AND RESULTS: Liver fat measurement by proton spectroscopy was performed in 221 patients with T2DM, and an in vivo kinetic study with stable isotopes was carried out in 14 patients with T2DM. In multivariate analysis, triglycerides were associated positively with rbp4 (beta=0.273, P<0.0001), apolipoprotein (apo) B (beta=0.258, P<0.0001), and liver fat (beta=0.191, P=0.002) and negatively with high-density lipoprotein cholesterol (beta=-0.442, P<0.0001). rbp4 was correlated positively with apoB100 very-low-density lipoprotein (VLDL) pool (r=0.62, P=0.017) and negatively with VLDL-apoB100 total fractional catabolic rate (r=-0.66, P=0.001). In multivariate analysis, rbp4 (P=0.015), plasma triglycerides (P=0.024), and sex (P=0.026) were independently associated with VLDL-apoB100 total fractional catabolic rate. CONCLUSIONS: In T2DM, plasma rbp4 level is associated with plasma triglycerides, independently of liver fat content. There is a strong independent negative correlation between plasma rbp4 and VLDL-apoB100 total fractional catabolic rate. These data suggest that rbp4 may be involved in the pathophysiology of hypertriglyceridemia in T2DM by reducing VLDL catabolism. PMID- 23087361 TI - Induction of anti-anti-idiotype antibodies against sulfated glycosaminoglycans reduces atherosclerosis in apolipoprotein E-deficient mice. AB - OBJECTIVE: The pathogenesis of atherosclerosis is associated with the early retention of low-density lipoproteins that are trapped in the extracellular matrix of the arterial intima by interaction with glycosaminoglycan side chains of proteoglycans. Mutant mouse/human chimeric antibodies of the murine monoclonal antibody P3, which react with N-glycolyl-containing gangliosides and sulfated glycosaminoglycans, were tested for their potentially antiatherogenic properties through the induction of an idiotypic antibody network that may specifically interfere with the binding of low-density lipoproteins to proteoglycan side chains, low-density lipoprotein modification, and foam cell formation. METHODS AND RESULTS: Apolipoprotein E-deficient mice fed a high-fat, high-cholesterol diet received 5 to 6 doses of chP3R99 or chP3S98 mutant antibodies, showing high and low reactivity, respectively, against their respective antigens. Both chimeric antibodies elicited an immunodominant anti-idiotypic response in the absence of adjuvant. A striking (40%-43%) reduction (P<0.01) in total lesion areas was observed in 18-week-old mice immunized with chP3R99, but not chP3S98, compared with PBS-treated mice. The antiatherosclerotic effect was associated with increased mice sera reactivity against heparin and sulfated glycosaminoglycans, including chondroitin and dermatan sulfate. In addition, purified IgG from chP3R99-immunized mice blocked the retention of apolipoprotein B-containing lipoproteins within the arterial wall of apolipoprotein E(-/-) mice. CONCLUSIONS: The present study supports use of active immunization and the mounting of an idiotypic antibody network response against glycosaminoglycans as a novel approach to target atherosclerosis. PMID- 23087363 TI - No shorter telomeres in subjects with a family history of cardiovascular disease in the Asklepios study. AB - OBJECTIVE: Shorter telomere length is associated with the occurrence of cardiovascular events, but the question of causality is complicated by the intertwined effects of inheritance, aging, and lifestyle factors on both telomere length and cardiovascular disease (CVD). Some studies indicated that healthy offspring of coronary artery disease patients exhibited shorter telomeres than subjects without a family history. Importantly, this result would imply that inheritance of shorter telomeres is a primary abnormality associated with an increased risk of CVD, the so-called Telomere Hypothesis of CVD. Therefore, we aimed at further validating the latter results in the large, population representative Asklepios Study. METHODS AND RESULTS: Peripheral blood leukocyte telomere length was measured using telomere restriction fragment analysis in the young to middle-aged (~ 35-55 years old) Asklepios study population, free from overt CVD, and could be successfully combined with data from the Asklepios Family History Database for 2136 subjects. No shorter telomere length could be found in healthy subjects with a family history of CVD compared with those without. CONCLUSIONS: These findings cast serious doubt on the hypothesis that telomere length is shorter in families with an increased risk of CVD and do not support the Telomere Hypothesis of CVD. PMID- 23087362 TI - Thrombospondin-1 regulates blood flow via CD47 receptor-mediated activation of NADPH oxidase 1. AB - OBJECTIVE: Although the matricellular protein thrombospondin-1 (TSP1) is highly expressed in the vessel wall in response to injury, its pathophysiological role in the development of vascular disease is poorly understood. This study was designed to test the hypothesis that TSP1 stimulates reactive oxygen species production in vascular smooth muscle cells and induces vascular dysfunction by promoting oxidative stress. METHODS AND RESULTS: Nanomolar concentrations of TSP1 found in human vascular disease robustly stimulated superoxide (O(2)(*-)) levels in vascular smooth muscle cells at both cellular and tissue level as measured by cytochrome c and electron paramagnetic resonance. A peptide mimicking the C terminus of TSP1 known to specifically bind CD47 recapitulated this response. Transcriptional knockdown of CD47 and a monoclonal inhibitory CD47 antibody abrogated TSP1-triggered O(2)(*-) in vitro and ex vivo. TSP1 treatment of vascular smooth muscle cells activated phospholipase C and protein kinase C, resulting in phosphorylation of the NADPH oxidase organizer subunit p47(phox) and subsequent Nox1 activation, leading to impairment of arterial vasodilatation ex vivo. Further, we observed that blockade of CD47 and NADPH oxidase 1 gene silencing in vivo in rats improves TSP1-induced impairment of tissue blood flow after ischemia reperfusion. CONCLUSIONS: Our data suggest a highly regulated process of reactive oxygen species stimulation and blood flow regulation promoted through a direct TSP1/CD47-mediated activation of Nox1. This is the first report, to our knowledge, of a matricellular protein acting as a ligand for NADPH oxidase activation and through specific engagement of integrin-associated protein CD47. PMID- 23087364 TI - Inhibition of Notch1 signaling reduces abdominal aortic aneurysm in mice by attenuating macrophage-mediated inflammation. AB - OBJECTIVE: Activation of inflammatory pathways plays a critical role in the development of abdominal aortic aneurysms (AAA). Notch1 signaling is a significant regulator of the inflammatory response; however, its role in AAA is unknown. METHODS AND RESULTS: In an angiotensin II-induced mouse model of AAA, activation of Notch1 signaling was observed in the aortic aneurysmal tissue of Apoe(-/-) mice, and a similar activation of Notch1 was observed in aneurysms of humans undergoing AAA repair. Notch1 haploinsufficiency significantly reduced the incidence of AAA in Apoe(-/-) mice in response to angiotensin II. Reconstitution of bone marrow-derived cells from Notch1(+/-);Apoe(-/-) mice (donor) in lethally irradiated Apoe(-/-) mice (recipient) decreased the occurrence of aneurysm. Flow cytometry and immunohistochemistry demonstrated that Notch1 haploinsufficiency prevented the influx of inflammatory macrophages at the aneurysmal site by causing defects in macrophage migration and proliferation. In addition, there was an overall reduction in the inflammatory burden in the aorta of the Notch1(+/ );Apoe(-/-) mice compared with the Apoe(-/-) mice. Last, pharmacological inhibition of Notch1 signaling also prevented AAA formation and progression in Apoe(-/-) mice. CONCLUSIONS: Our data suggest that decreased levels of Notch1 protect against the formation of AAA by preventing macrophage recruitment and attenuating the inflammatory response in the aorta. PMID- 23087365 TI - Expression and significance of hypoxia-inducible factor-1alpha and survivin in laryngeal carcinoma tissue and cells. AB - OBJECTIVE: The aim was to evaluate hypoxia-inducible factor-1alpha (HIF-1alpha) and survivin expression in laryngeal squamous cell carcinoma (LSCC) tissues and cell lines and to investigate whether HIF-1alpha has an effect on the regulation of survivin gene expression in LSCC cells under hypoxia. STUDY DESIGN: Prospective, observational. SETTING: Shanghai Jiaotong University Affiliated First People's Hospital. SUBJECTS AND METHODS: The expression of HIF-1alpha and survivin protein in human LSCC tissues was analyzed by immunohistochemistry. HIF 1alpha and survivin gene expression levels in Hep-2 cells were detected by real time quantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blot under normoxic or hypoxic conditions. In hypoxic cells, HIF-1alpha expression was inhibited by RNA interference. RESULTS: HIF-1alpha and survivin were both highly expressed in LSCC tissues and significantly related to the clinical stage and lymph node metastasis (P < .05). Meanwhile, a positive correlation existed between HIF-1alpha and survivin expression (r = 0.456, P < .01). In LSCC cells, HIF-1alpha and survivin expression were obviously upregulated in response to hypoxia (P < .05). The downregulation of HIF-1alpha expression dramatically decreased survivin gene expression in hypoxic cells (P < .05). CONCLUSION: HIF-1alpha could be considered as an important regulator for the upregulation of survivin gene expression induced by hypoxia in LSCC cells, and both proteins could be regarded as 2 key predictors of malignant progression and metastasis of LSCC. PMID- 23087366 TI - A rare case of a second primary nasopharyngeal angiofibroma. PMID- 23087367 TI - The mortality observed-to-expected ratio in otolaryngology. AB - OBJECTIVE: The mortality observed-to-expected (O:E) ratio is rapidly becoming the most important measured quality metric by allowing quantification and comparison of survival outcomes among different providers and institutions. Although the O:E ratio is monitored by external observers, the ratio is unfamiliar to individuals within most institutions. STUDY DESIGN: Retrospective chart review. SETTING: Vanderbilt University Medical Center. SUBJECTS AND METHODS: Twenty-eight patients cared for by the Department of Otolaryngology died while in the hospital between January 2001 and December 2010. All patient charts were reviewed for indicators related to mortality. From January 2006 to December 2010, a standardized mortality O:E ratio had been available using the All Patient Refined-Diagnosis Related Group (APR-DRG) grouper from the United Healthcare Consortium (UHC). The O:E ratio can be monitored over time to measure and quantify the effect of various interventions. RESULTS: The otolaryngology O:E ratio quarterly results have varied from 1.1 to 0.29, based on a standard of 1.0. Internally, results have been primarily the result of mortalities of patients on the Head and Neck Service. Attention to common postoperative complications, accurate coding of comorbidities, and the compassionate use of palliative care consults have led to a significant decrease in the O:E ratio. Conversely, transfers from other hospitals have increased the ratio. CONCLUSION: The Department of Otolaryngology has reduced the O:E ratio by focusing attention on factors that have been shown to reduce mortality and to enhance compassionate terminal care. PMID- 23087368 TI - Cryptococcus neoformans phosphoinositide-dependent kinase 1 (PDK1) ortholog is required for stress tolerance and survival in murine phagocytes. AB - Cryptococcus neoformans PKH2-01 and PKH2-02 are orthologous to mammalian PDK1 kinase genes. Although orthologs of these kinases have been extensively studied in S. cerevisiae, little is known about their function in pathogenic fungi. In this study, we show that PKH2-02 but not PKH2-01 is required for C. neoformans to tolerate cell wall, oxidative, nitrosative, and antifungal drug stress. Deletion of PKH2-02 leads to decreased basal levels of Pkc1 activity and, consequently, reduced activation of the cell wall integrity mitogen-activated protein kinase (MAPK) pathway in response to cell wall, oxidative, and nitrosative stress. PKH2 02 function also is required for tolerance of fluconazole and amphotericin B, two important drugs for the treatment of cryptococcosis. Furthermore, OSU-03012, an inhibitor of human PDK1, is synergistic and fungicidal in combination with fluconazole. Using a Galleria mellonella model of low-temperature cryptococcosis, we found that PKH2-02 is also required for virulence in a temperature-independent manner. Consistent with the hypersensitivity of the pkh2-02Delta mutant to oxidative and nitrosative stress, this mutant shows decreased survival in murine phagocytes compared to that of wild-type (WT) cells. In addition, we show that deletion of PKH2-02 affects the interaction between C. neoformans and phagocytes by decreasing its ability to suppress production of tumor necrosis factor alpha (TNF-alpha) and reactive oxygen species. Taken together, our studies demonstrate that Pkh2-02-mediated signaling in C. neoformans is crucial for stress tolerance, host-pathogen interactions, and both temperature-dependent and -independent virulence. PMID- 23087369 TI - VeA regulates conidiation, gliotoxin production, and protease activity in the opportunistic human pathogen Aspergillus fumigatus. AB - Invasive aspergillosis by Aspergillus fumigatus is a leading cause of infection related mortality in immunocompromised patients. In this study, we show that veA, a major conserved regulatory gene that is unique to fungi, is necessary for normal morphogenesis in this medically relevant fungus. Although deletion of veA results in a strain with reduced conidiation, overexpression of this gene further reduced conidial production, indicating that veA has a major role as a regulator of development in A. fumigatus and that normal conidiation is only sustained in the presence of wild-type VeA levels. Furthermore, our studies revealed that veA is a positive regulator in the production of gliotoxin, a secondary metabolite known to be a virulent factor in A. fumigatus. Deletion of veA resulted in a reduction of gliotoxin production with respect to that of the wild-type control. This reduction in toxin coincided with a decrease in gliZ and gliP expression, which is necessary for gliotoxin biosynthesis. Interestingly, veA also influences protease activity in this organism. Specifically, deletion of veA resulted in a reduction of protease activity; this is the first report of a veA homolog with a role in controlling fungal hydrolytic activity. Although veA affects several cellular processes in A. fumigatus, pathogenicity studies in a neutropenic mouse infection model indicated that veA is dispensable for virulence. PMID- 23087370 TI - Mutants in the Candida glabrata glycerol channels are sensitized to cell wall stress. AB - Many fungal species use glycerol as a compatible solute with which to maintain osmotic homeostasis in response to changes in external osmolarity. In Saccharomyces cerevisiae, intracellular glycerol concentrations are regulated largely by the high osmolarity glycerol (HOG) response pathway, both through induction of glycerol biosynthesis and control of its flux through the plasma membrane Fps1 glycerol channel. The channel activity of Fps1 is also controlled by a pair of positive regulators, Rgc1 and Rgc2. In this study, we demonstrate that Candida glabrata, a fungal pathogen that possesses two Fps1 orthologs and two Rgc1/-2 orthologs, accumulates glycerol in response to hyperosmotic stress. We present an initial characterization of mutants with deletions in the C. glabrata FPS1 (CAGL0C03267 [www.candidagenome.org]) and FPS2 (CAGL0E03894) genes and find that a double mutant accumulates glycerol, experiences constitutive cell wall stress, and is hypersensitive to treatment by caspofungin, an antifungal agent that targets the cell wall. This mutant is cleared more efficiently in mouse infections than is wild-type C. glabrata by caspofungin treatment. Finally, we demonstrate that one of the C. glabrata RGC orthologs complements an S. cerevisiae rgc1 rgc2 null mutant, supporting the conclusion that this regulatory assembly is conserved between these species. PMID- 23087371 TI - Microsporidian infection in a free-living marine nematode. AB - Microsporidia are unicellular fungi that are obligate endoparasites. Although nematodes are one of the most abundant and diverse animal groups, the only confirmed report of microsporidian infection was that of the "nematode killer" (Nematocida parisii). N. parisii was isolated from a wild Caenorhabditis sp. and causes an acute and lethal intestinal infection in a lab strain of Caenorhabditis elegans. We set out to characterize a microsporidian infection in a wild nematode to determine whether the infection pattern of N. parisii in the lab is typical of microsporidian infections in nematodes. We describe a novel microsporidian species named Sporanauta perivermis (marine spore of roundworms) and characterize its infection in its natural host, the free-living marine nematode Odontophora rectangula. S. perivermis is not closely related to N. parisii and differs strikingly in all aspects of infection. Examination by transmission electron microscopy (TEM) revealed that the infection was localized in the hypodermal and muscle tissues only and did not involve the intestines. Fluorescent in situ hybridization (FISH) confirmed infection in the muscle and hypodermis, and surprisingly, it also revealed that the parasite infects O. rectangula eggs, suggesting a vertical mode of transmission. Our observations highlight the importance of studying parasites in their natural hosts and indicate that not all nematode-infecting microsporidia are "nematode killers"; instead, microsporidiosis can be more versatile and chronic in the wild. PMID- 23087372 TI - A pericentrin-related protein homolog in Aspergillus nidulans plays important roles in nucleus positioning and cell polarity by affecting microtubule organization. AB - Pericentrin is a large coiled-coil protein in mammalian centrosomes that serves as a multifunctional scaffold for anchoring numerous proteins. Recent studies have linked numerous human disorders with mutated or elevated levels of pericentrin, suggesting unrecognized contributions of pericentrin-related proteins to the development of these disorders. In this study, we characterized AnPcpA, a putative homolog of pericentrin-related protein in the model filamentous fungus Aspergillus nidulans, and found that it is essential for conidial germination and hyphal development. Compared to the hyphal apex localization pattern of calmodulin (CaM), which has been identified as an interactive partner of the pericentrin homolog, GFP-AnPcpA fluorescence dots are associated mainly with nuclei, while the accumulation of CaM at the hyphal apex depends on the function of AnPcpA. In addition, the depletion of AnPcpA by an inducible alcA promoter repression results in severe growth defects and abnormal nuclear segregation. Most interestingly, in mature hyphal cells, knockdown of pericentrin was able to significantly induce changes in cell shape and cytoskeletal remodeling; it resulted in some enlarged compartments with condensed nuclei and anucleate small compartments as well. Moreover, defects in AnPcpA significantly disrupted the microtubule organization and nucleation, suggesting that AnPcpA may affect nucleus positioning by influencing microtubule organization. PMID- 23087373 TI - The coactivator role of histone deacetylase 3 in IL-1-signaling involves deacetylation of p65 NF-kappaB. AB - Histone deacetylase (HDAC) 3, as a cofactor in co-repressor complexes containing silencing mediator for retinoid or thyroid-hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR), has been shown to repress gene transcription in a variety of contexts. Here, we reveal a novel role for HDAC3 as a positive regulator of IL-1-induced gene expression. Various experimental approaches involving RNAi-mediated knockdown, conditional gene deletion or small molecule inhibitors indicate a positive role of HDAC3 for transcription of the majority of IL-1-induced human or murine genes. This effect was independent from the gene regulatory effects mediated by the broad-spectrum HDAC inhibitor trichostatin A (TSA) and thus suggests IL-1-specific functions for HDAC3. The stimulatory function of HDAC3 for inflammatory gene expression involves a mechanism that uses binding to NF-kappaB p65 and its deacetylation at various lysines. NF-kappaB p65 deficient cells stably reconstituted to express acetylation mimicking forms of p65 (p65 K/Q) had largely lost their potential to stimulate IL-1-triggered gene expression, implying that the co-activating property of HDAC3 involves the removal of inhibitory NF-kappaB p65 acetylations at K122, 123, 314 and 315. These data describe a novel function for HDAC3 as a co-activator in inflammatory signaling pathways and help to explain the anti-inflammatory effects frequently observed for HDAC inhibitors in (pre)clinical use. PMID- 23087374 TI - The BET bromodomain inhibitor JQ1 activates HIV latency through antagonizing Brd4 inhibition of Tat-transactivation. AB - Latent HIV reservoirs are the primary hurdle to eradication of infection. Identification of agents, pathways and molecular mechanisms that activate latent provirus may, in the presence of highly active antiretroviral therapy, permit clearance of infected cells by the immune system. Promoter-proximal pausing of RNA polymerase (Pol) II is a major rate-limiting step in HIV gene expression. The viral Tat protein recruits human Super Elongation Complex (SEC) to paused Pol II to overcome this limitation. Here, we identify the bromodomain protein Brd4 and its inhibition of Tat-transactivation as a major impediment to latency reactivation. Brd4 competitively blocks the Tat-SEC interaction on HIV promoter. The BET bromodomain inhibitor JQ1 dissociates Brd4 from the HIV promoter to allow Tat recruitment of SEC to stimulate HIV elongation. JQ1 synergizes with another latency activator prostratin, which promotes Pol II loading onto the viral promoter. Because JQ1 activates viral latency without inducing global T cell activation, this and other closely related compounds and their antagonization of Brd4 to promote Tat-SEC interaction merit further investigations as effective agents/strategies for eliminating latent HIV. PMID- 23087375 TI - Mitochondrial targeting of recombinant RNAs modulates the level of a heteroplasmic mutation in human mitochondrial DNA associated with Kearns Sayre Syndrome. AB - Mitochondrial mutations, an important cause of incurable human neuromuscular diseases, are mostly heteroplasmic: mutated mitochondrial DNA is present in cells simultaneously with wild-type genomes, the pathogenic threshold being generally >70% of mutant mtDNA. We studied whether heteroplasmy level could be decreased by specifically designed oligoribonucleotides, targeted into mitochondria by the pathway delivering RNA molecules in vivo. Using mitochondrially imported RNAs as vectors, we demonstrated that oligoribonucleotides complementary to mutant mtDNA region can specifically reduce the proportion of mtDNA bearing a large deletion associated with the Kearns Sayre Syndrome in cultured transmitochondrial cybrid cells. These findings may be relevant to developing of a new tool for therapy of mtDNA associated diseases. PMID- 23087376 TI - IUPHAR-DB: updated database content and new features. AB - The International Union of Basic and Clinical Pharmacology (IUPHAR) database, IUPHAR-DB (http://www.iuphar-db.org) is an open access, online database providing detailed, expert-driven annotation of the primary literature on human and rodent receptors and other drug targets, together with the substances that act on them. The present release includes information on the products of 646 genes from four major protein classes (G protein-coupled receptors, nuclear hormone receptors, voltage- and ligand-gated ion channels) and ~3180 bioactive molecules (endogenous ligands, licensed drugs and key pharmacological tools) that interact with them. We have described previously the classification and curation of data for small molecule ligands in the database; in this update we have annotated 366 endogenous peptide ligands with their amino acid sequences, post-translational modifications, links to precursor genes, species differences and relationships with other molecules in the database (e.g. those derived from the same precursor). We have also matched targets with their endogenous ligands (peptides and small molecules), with particular attention paid to identifying bioactive peptide ligands generated by post-translational modification of precursor proteins. Other improvements to the database include enhanced information on the clinical relevance of targets and ligands in the database, more extensive links to other databases and a pilot project for the curation of enzymes as drug targets. PMID- 23087377 TI - Possible steps of complete disassembly of post-termination complex by yeast eEF3 deduced from inhibition by translocation inhibitors. AB - Ribosomes, after one round of translation, must be recycled so that the next round of translation can occur. Complete disassembly of post-termination ribosomal complex (PoTC) in yeast for the recycling consists of three reactions: release of tRNA, release of mRNA and splitting of ribosomes, catalyzed by eukaryotic elongation factor 3 (eEF3) and ATP. Here, we show that translocation inhibitors cycloheximide and lactimidomycin inhibited all three reactions. Cycloheximide is a non-competitive inhibitor of both eEF3 and ATP. The inhibition was observed regardless of the way PoTC was prepared with either release factors or puromycin. Paromomycin not only inhibited all three reactions but also re associated yeast ribosomal subunits. On the other hand, sordarin or fusidic acid, when applied together with eEF2/GTP, specifically inhibited ribosome splitting without blocking of tRNA/mRNA release. From these inhibitor studies, we propose that, in accordance with eEF3's known function in elongation, the release of tRNA via exit site occurs first, then mRNA is released, followed by the splitting of ribosomes during the disassembly of post-termination complexes catalyzed by eEF3 and ATP. PMID- 23087378 TI - BioLiP: a semi-manually curated database for biologically relevant ligand-protein interactions. AB - BioLiP (http://zhanglab.ccmb.med.umich.edu/BioLiP/) is a semi-manually curated database for biologically relevant ligand-protein interactions. Establishing interactions between protein and biologically relevant ligands is an important step toward understanding the protein functions. Most ligand-binding sites prediction methods use the protein structures from the Protein Data Bank (PDB) as templates. However, not all ligands present in the PDB are biologically relevant, as small molecules are often used as additives for solving the protein structures. To facilitate template-based ligand-protein docking, virtual ligand screening and protein function annotations, we develop a hierarchical procedure for assessing the biological relevance of ligands present in the PDB structures, which involves a four-step biological feature filtering followed by careful manual verifications. This procedure is used for BioLiP construction. Each entry in BioLiP contains annotations on: ligand-binding residues, ligand-binding affinity, catalytic sites, Enzyme Commission numbers, Gene Ontology terms and cross-links to the other databases. In addition, to facilitate the use of BioLiP for function annotation of uncharacterized proteins, a new consensus-based algorithm COACH is developed to predict ligand-binding sites from protein sequence or using 3D structure. The BioLiP database is updated weekly and the current release contains 204 223 entries. PMID- 23087379 TI - Mesoscopic model parametrization of hydrogen bonds and stacking interactions of RNA from melting temperatures. AB - Information about molecular interactions in DNA can be obtained from experimental melting temperature data by using mesoscopic statistical physics models. Here, we extend the technique to RNA and show that the new parameters correctly reproduce known properties such as the stronger hydrogen bonds of AU base pairs. We also were able to calculate a complete set of elastic constants for all 10 irreducible combinations of nearest neighbours (NNs). We believe that this is particularly useful as experimentally derived information about RNA elasticity is relatively scarce. The melting temperature prediction using the present model improves over those from traditional NN model, providing thus an alternative way to calculate these temperatures for RNA. Additionally, we calculated the site-dependent base pair oscillation to explain why RNA shows larger oscillation amplitudes despite having stronger AU hydrogen bonds. PMID- 23087380 TI - RNA polymerase-promoter interactions determining different stability of the Escherichia coli and Thermus aquaticus transcription initiation complexes. AB - Transcription initiation complexes formed by bacterial RNA polymerases (RNAPs) exhibit dramatic species-specific differences in stability, leading to different strategies of transcription regulation. The molecular basis for this diversity is unclear. Promoter complexes formed by RNAP from Thermus aquaticus (Taq) are considerably less stable than Escherichia coli RNAP promoter complexes, particularly at temperatures below 37 degrees C. Here, we used a fluorometric RNAP molecular beacon assay to discern partial RNAP-promoter interactions. We quantitatively compared the strength of E. coli and Taq RNAPs partial interactions with the -10, -35 and UP promoter elements; the TG motif of the extended -10 element; the discriminator and the downstream duplex promoter segments. We found that compared with Taq RNAP, E. coli RNAP has much higher affinity only to the UP element and the downstream promoter duplex. This result indicates that the difference in stability between E. coli and Taq promoter complexes is mainly determined by the differential strength of core RNAP-DNA contacts. We suggest that the relative weakness of Taq RNAP interactions with DNA downstream of the transcription start point is the major reason of low stability and temperature sensitivity of promoter complexes formed by this enzyme. PMID- 23087381 TI - Endovascular treatment of paraclinoid aneurysms: 142 aneurysms in one centre. AB - BACKGROUND: Current endovascular techniques have been widely used to treat paraclinoid aneurysms. METHODS: From January 2009 to December 2011, 126 consecutive patients with 142 saccular paraclinoid aneurysms were treated with endovascular embolization at our institute. A retrospective review of the clinical and imaging data was performed. RESULTS: Of the 142 aneurysms, 121 (86.2%) had small while 21 (14.8%) had large fundus size. 83 aneurysms (58.5%) were narrow necked and 59 (41.5%) were wide necked. The dome-neck ratio was favorable in 26 aneurysms (18.3%) and unfavorable in 116 (81.7%). 24 aneurysms (16.9%) were managed with coil embolization and 118 (83.1%) with a stent assisted coiling technique. Immediate angiography demonstrated complete occlusion in 62 (43.7%), neck remnant occlusion in 47 (33.1%), and residual aneurysm occlusion in 33 (23.2%) aneurysms. The overall recurrence rate in the 112 aneurysms with angiographic follow-up (8.88 +/- 3.40 months, mean +/- SD) was 12.5%. Of the 14 recurrent aneurysms, 10 were managed with endovascular treatment (six by stent assisted coiling, four by coiling) while four are under observation. There were six (4.3%) procedural complications during 137 procedures. Clinical follow-up was available for 119 patients (94%) with a follow-up time of 16.6 +/- 13.6 months, and the majority (98%) had a modified Rankin scale score of 0-1. CONCLUSIONS: The stent assisted coiling technique is effective for the treatment of paraclinoid aneurysms. Small paraclinoid aneurysms (<= 10 mm) are suitable for endovascular treatment, with a low rate of recurrence. In contrast, large paraclinoid aneurysms (>10 mm) treated with current endovascular techniques exhibited a high rate of recurrence. PMID- 23087382 TI - Embolization of the deep cervical collaterals--a unique endovascular approach to prevent repeated posterior fossa strokes refractory to medical therapy. AB - We present a 69-year-old man with advanced vertebral artery atherosclerotic disease and repeated posterior fossa strokes, refractory to aggressive medical treatment. CT angiogram showed heavily calcified long segment occlusion of the dominant right vertebral artery. Beyond the occlusion, the vertebral artery was reconstituted by hypertrophic deep cervical collaterals which had multiple long and short segments of severe stenosis and antegrade flow. The ostium of the right vertebral artery was heavily calcified, and multiple attempts to catheterize the vertebral artery were unsuccessful. Flow reversal was eventually achieved in the right vertebral artery by embolizing the hypertrophied deep cervical artery which reconstituted the right vertebral artery. The patient has remained asymptomatic since the procedure for a follow-up period of 12 months. PMID- 23087383 TI - Do state breastfeeding laws in the USA promote breast feeding? AB - OBJECTIVES: Despite the passage of state laws promoting breast feeding, a formal evaluation has not yet been conducted to test whether and/or what type of laws may increase breast feeding. The enactment of breastfeeding laws in different states in the USA creates a natural experiment. We examined the impact of state breastfeeding laws on breastfeeding initiation and duration as well as on disparities in these infant feeding practices. METHODS: Using data from the Pregnancy Risk Assessment Monitoring System, we conducted differences-in differences models to examine breastfeeding status before and after the institution of laws between 2000 and 2008 among 326 263 mothers from 32 states in the USA. For each mother, we coded the presence of two types of state breastfeeding laws. Mothers reported whether they ever breast fed or pumped breast milk (breastfeeding initiation) and, if so, how long they continued. We defined breastfeeding duration as continuing to breast feed for >=4 weeks. RESULTS: Breastfeeding initiation was 1.7 percentage points higher in states with new laws to provide break time and private space for breastfeeding employees (p=0.01), particularly among Hispanic mothers (adjusted coefficient 0.058). While there was no overall effect of laws permitting mothers to breast feed in any location, among Black mothers we observed increases in breastfeeding initiation (adjusted coefficient 0.056). Effects on breastfeeding duration were in the same direction, but slightly weaker. CONCLUSIONS: State laws that support breast feeding appear to increase breastfeeding rates. Most of these gains were observed among Hispanic and Black women and women of lower educational attainment suggesting that such state laws may help reduce disparities in breast feeding. PMID- 23087384 TI - Pedimap: software for the visualization of genetic and phenotypic data in pedigrees. AB - Pedimap is a user-friendly software tool for visualizing phenotypic and genotypic data for related individuals linked in pedigrees. Genetic data can include marker scores, Identity-by-Descent probabilities, and marker linkage map positions, allowing the visualization of haplotypes through lineages. The pedigrees can accommodate all types of inheritance, including selfing, cloning, and repeated backcrossing, and all ploidy levels are supported. Visual association of the genetic data with phenotypic data simplifies the exploration of large data sets, thereby improving breeding decision making. Data are imported from text files; in addition data exchange with other software packages (FlexQTL(TM) and GenomeStudio(TM)) is possible. Instructions for use and an executable version compatible with the Windows platform are available for free from http://www.plantbreeding.wur.nl/UK/software_pedimap.html. PMID- 23087385 TI - Habitat-linked population genetic differentiation in the blue tit Cyanistes caeruleus. AB - Although the recent emergence of the field of landscape genetics has led to several studies investigating the effects of habitat composition between populations on genetic differentiation, much less is known on the impact of within-habitat ecological characteristics on levels of gene flow and genetic differentiation among populations. Using data on 840 individuals sampled in 8 sites in Corsica and 1 in southern France and analyzed at 10 microsatellite loci, we assessed the spatial and temporal population genetic structure of blue tits (Cyanistes caeruleus) in Corsica and identified the ecological factors, both between- and within-sampling sites, responsible for the observed genetic structure. We found temporally stable fine-scale genetic structure within Corsica, with genetic differentiation values among populations corresponding to ~25% of levels observed between Corsica and the mainland. This structure was not explained by the geographic distance among populations or by the presence of physical barriers but was instead related to local habitat types (deciduous or evergreen oaks). Our results are thus consistent with previously documented phenotypic differences among habitats in morphological and reproductive traits. These findings suggest that although individuals have high dispersal ability, local adaptation might reduce gene flow among populations located in different habitats. PMID- 23087386 TI - The clinical and economic impact of genotype testing at first-line antiretroviral therapy failure for HIV-infected patients in South Africa. AB - BACKGROUND: In resource-limited settings, genotype testing at virologic failure on first-line antiretroviral therapy (ART) may identify patients with wild-type (WT) virus. After adherence counseling, these patients may safely and effectively continue first-line ART, thereby delaying more expensive second-line ART. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications International model of human immunodeficiency virus (HIV) disease to simulate a South African cohort of HIV-infected adults at first-line ART failure. Two strategies were examined: no genotype vs genotype, assuming availability of protease inhibitor-based second-line ART. Model inputs at first-line ART failure were mean age 38 years, mean CD4 173/uL, and WT virus prevalence 20%; genotype cost was $300 per test and delay to results, 3 months. Outcomes included life expectancy, per-person costs (2010 US dollars), and incremental cost effectiveness ratios (dollars per years of life saved [YLS]). RESULTS: No genotype had a projected life expectancy of 106.1 months, which with genotype increased to 108.3 months. Per-person discounted lifetime costs were $16 360 and $16 540, respectively. Compared to no genotype, genotype was very cost-effective, by international guidance, at $900/YLS. The cost-effectiveness of genotype was sensitive to prevalence of WT virus (very cost-effective when prevalence >= 12%), CD4 at first-line ART failure, and ART efficacy. Genotype-associated delays in care >= 5 months decreased survival and made no genotype the preferred strategy. When the test cost was <$100, genotype became cost-saving. CONCLUSIONS: Genotype resistance testing at first-line ART failure is very cost-effective in South Africa. The cost-effectiveness of this strategy will depend on prevalence of WT virus and timely response to genotype results. PMID- 23087387 TI - Editorial commentary: telephone consultation for Staphylococcus aureus bacteremia: opening Pandora's box. PMID- 23087388 TI - Epidemiologic and laboratory features of a large outbreak of pertussis-like illnesses associated with cocirculating Bordetella holmesii and Bordetella pertussis--Ohio, 2010-2011. AB - BACKGROUND: During 9 May 2010-7 May 2011, an outbreak of pertussis-like illness (incidence, 80 cases per 100 000 persons) occurred in Franklin County, Ohio. The majority of cases were identified by IS481-directed polymerase chain reaction (PCR), which does not differentiate among Bordetella species. We sought to determine outbreak etiology and epidemiologic characteristics. METHODS: We obtained demographic, clinical, and vaccination-related data from the Ohio Disease Reporting System and Impact Statewide Immunization Information System. We tested sera from 14 patients for anti-pertussis toxin (PT) antibodies and used species-specific PCR on 298 nasopharyngeal specimens. RESULTS: Reported cases totaled 918. IS481 results were available for 10 serologically tested patients; 5 of 10 had discordant anti-PT antibody and IS481 results, suggestive of Bordetella holmesii, which lacks PT and harbors IS481. We identified specific Bordetella species in 164 of 298 specimens tested with multitarget PCR; B. holmesii and Bordetella pertussis were exclusively detected among 48 (29%) and 112 (68%), respectively; both were detected in 4 (2%). Among 48 patients with B. holmesii infections, 63% were aged 11-18 years, compared with 35% of 112 patients with B. pertussis infections (P = .001). Symptoms were similar among B. holmesii- and B. pertussis-infected patients. Adolescent pertussis ("Tdap") booster vaccinations were more effective against B. pertussis than B. holmesii (effectiveness: 67% and 36%, respectively; 95% confidence intervals, 38%-82% and -33% to 69%, respectively). CONCLUSIONS: We report the first documented mixed outbreak of B. pertussis and B. holmesii infections. Bordetella holmesii particularly affected adolescents. Although laboratory capacity limitations might inhibit routine use of multitarget PCR for clinical diagnosis, focused testing and enhanced surveillance might improve understanding the burden of B. holmesii infection. PMID- 23087389 TI - A prospective comparative study of knowlesi, falciparum, and vivax malaria in Sabah, Malaysia: high proportion with severe disease from Plasmodium knowlesi and Plasmodium vivax but no mortality with early referral and artesunate therapy. AB - BACKGROUND: Plasmodium knowlesi commonly causes severe malaria in Malaysian Borneo, with high case-fatality rates reported. We compared risk, spectrum, and outcome of severe disease from P. knowlesi, Plasmodium falciparum, and Plasmodium vivax and outcomes following introduction of protocols for early referral and intravenous artesunate for all severe malaria. METHODS: From September 2010 to October 2011 we prospectively assessed nonpregnant patients aged >=12 years admitted to Queen Elizabeth Hospital (QEH), Sabah, with polymerase chain reaction confirmed Plasmodium monoinfection. Standardized referral and prereferral intravenous artesunate were instituted at district hospitals. RESULTS: Severe malaria occurred in 38 of 130 (29%) patients with P. knowlesi, 13 of 122 (11%) with P. falciparum, and 7 of 43 (16%) with P. vivax. The commonest severity criteria in knowlesi malaria included parasitemia >100 000/uL (n = 18), jaundice (n = 20), respiratory distress (n = 14), hypotension (n = 13), and acute kidney injury (n = 9). On multivariate analysis, P. knowlesi was associated with a 2.96 fold (95% confidence interval, 1.19-7.38-fold) greater risk of severity than P. falciparum (P = .020); only parasitemia and schizontemia >10% independently predicted knowlesi severity. Risk of severe knowlesi malaria increased 11-fold with parasitemia >20 000/uL, and 28-fold with parasitemia >100 000/uL. Nearly all (92%) knowlesi malaria patients received oral artemisinin therapy; 36 of 38 (95%) and 39 of 92 (42%) with severe and nonsevere disease, respectively, also received >=1 dose of intravenous artesunate. No deaths occurred from any species. CONCLUSIONS: Plasmodium knowlesi is the commonest cause of severe malaria at QEH, with parasitemia the major risk factor for severity. Early referral and treatment with artesunate was highly effective for severe malaria from all species and associated with zero mortality. PMID- 23087390 TI - Escherichia coli bloodstream infection after transrectal ultrasound-guided prostate biopsy: our experience in North West London. PMID- 23087391 TI - Effectiveness of a school district closure for pandemic influenza A (H1N1) on acute respiratory illnesses in the community: a natural experiment. AB - BACKGROUND: Following detection of pandemic influenza A H1N1 (pH1N1) in Dallas/Fort Worth, Texas, a school district (intervention community, [IC]) closed all public schools for 8 days to reduce transmission. Nearby school districts (control community [CC]) mostly remained open. METHODS: We collected household data to measure self-reported acute respiratory illness (ARI), before, during, and after school closures. We also collected influenza-related visits to emergency departments (ED(flu)). RESULTS: In both communities, self-reported ARIs and ED(flu) visits increased from before to during the school closure, but the increase in ARI rates was 45% lower in the IC (0.6% before to 1.2% during) than in the CC (0.4% before to 1.5% during) (RRR(During)(/Before) = 0.55, P < .001; adjusted OR(During/Before) = 0.49, P < .03). For households with school-aged children only (no children 0-5 years), IC had even lower increases in adjusted ARI than in the CC (adjusted OR(During/Before) = 0.28, P < .001). The relative increase of total ED(flu) visits in the IC was 27% lower (2.8% before to 4.4% during) compared with the CC (2.9% before to 6.2% during). Among children aged 6 18 years, the percentage of ED(flu) in IC remained constant (5.1% before vs 5.2% during), whereas in the CC it more than doubled (5.2% before vs 10.9% during). After schools reopened, ARI rates and ED(flu) visits decreased in both communities. CONCLUSIONS: Our study documents a reduction in ARI and ED(flu) visits in the intervention community. Our findings can be used to assess the potential benefit of school closures during pandemics. PMID- 23087392 TI - The endgame for serogroup a meningococcal disease in Africa? PMID- 23087393 TI - Changing epidemiology of herpes simplex virus infections. PMID- 23087394 TI - The "how" of polymerase chain reaction testing for Bordetella pertussis depends on the "why". PMID- 23087395 TI - Epidemiology, clinical presentation, and antibody response to primary infection with herpes simplex virus type 1 and type 2 in young women. AB - BACKGROUND: Herpes simplex virus infections type 1 (HSV-1) and type 2 (HSV-2) are common, but the epidemiology of HSV disease is changing. METHODS: HSV seronegative women, aged 18-30 years, who were in the control arm of the HERPEVAC Trial for Women were followed for 20 months for primary HSV infections. RESULTS: Of the 3438 evaluable participants, 183 became infected with HSV: 127 (3.7%) with HSV-1 and 56 (1.6%) with HSV-2. The rate of infection for HSV-1 (2.5 per 100 person-years) was more than twice that for HSV-2 (1.1 per 100 person-years). Most infections (74% of HSV-1 and 63% of HSV-2) occurred without recognized signs or symptoms of herpes disease. The HSV-2 infection rate was 2.6 times higher in non Hispanic black participants than in Hispanics and 5.5 times higher than in non Hispanic whites (P < .001), while the HSV-1 infection rate was 1.7 times higher in non-Hispanic whites than non-Hispanic blacks. Younger participants (18-22 years) were more likely to acquire HSV-1 infections and less likely to develop recognized disease than older participants. Overall, 84% of recognized disease cases were genital. No differences were noted in the clinical manifestations of genital HSV-1 vs genital HSV-2 disease. The clinicians' assessment that cases were caused by HSV was good when they assessed cases as clinically confirmed or unlikely (validated in 83% and 100% of cases, respectively). CONCLUSIONS: HSV-1 is now more common than HSV-2 as a cause of oral and genital mucosal infections in young women, but there are important age and race differences. PMID- 23087396 TI - Impact of the serogroup A meningococcal conjugate vaccine, MenAfriVac, on carriage and herd immunity. AB - BACKGROUND: The conjugate vaccine against serogroup A Neisseria meningitidis (NmA), MenAfriVac, was first introduced in mass vaccination campaigns of 1-29 year-olds in Burkina Faso in 2010. It is not known whether MenAfriVac has an impact on NmA carriage. METHODS: We conducted a repeated cross-sectional meningococcal carriage study in a representative portion of the 1-29-year-old population in 3 districts in Burkina Faso before and up to 13 months after vaccination. One district was vaccinated in September 2010, and the other 2 were vaccinated in December 2010. We analyzed 25 521 oropharyngeal samples, of which 22 093 were obtained after vaccination. RESULTS: In October-November 2010, NmA carriage prevalence in the unvaccinated districts was comparable to the baseline established in 2009, but absent in the vaccinated district. Serogroup X N. meningitidis (NmX) dominated in both vaccinated and unvaccinated districts. With 4 additional sampling campaigns performed throughout 2011 in the 3 districts, overall postvaccination meningococcal carriage prevalence was 6.95%, with NmX dominating but declining for each campaign (from 8.66% to 1.97%). Compared with a baseline NmA carriage prevalence of 0.39%, no NmA was identified after vaccination. Overall vaccination coverage in the population sampled was 89.7%, declining over time in 1-year-olds (from 87.1% to 26.5%), as unvaccinated infants reached 1 year of age. NmA carriage was eliminated in both the vaccinated and unvaccinated population from 3 weeks up to 13 months after mass vaccination (P = .003). CONCLUSIONS: The disappearance of NmA carriage among both vaccinated and unvaccinated populations is consistent with a vaccine-induced herd immunity effect. PMID- 23087397 TI - Telephone consultation cannot replace bedside infectious disease consultation in the management of Staphylococcus aureus Bacteremia. AB - BACKGROUND: Infectious disease specialist (IDS) consultation improves the outcome of Staphylococcus aureus bacteremia (SAB). Although telephone consultations constitute a substantial part of IDS consultations, their impact on treatment outcome lacks evaluation. METHODS: We retrospectively followed 342 SAB episodes with 90-day follow-up, excluding 5 methicillin-resistant S. aureus SAB cases. Patients were grouped according to bedside, telephone, or no IDS consultation within the first week. Patients with fatal outcome within 3 days after onset of SAB were excluded to allow for the possibility of death occurring before IDS consultation. RESULTS: Seventy-two percent of patients received bedside, 18% telephone, and 10% no IDS consultation. Patients with bedside consultation were less often treated in an intensive care unit during the first 3 days compared to those with telephone consultation (odds ratio [OR], 0.53; 95% confidence interval [CI], .29-.97; P = .037; 21% vs 34%), with no other initial differences between these groups. Patients with bedside consultation more often had deep infection foci localized as compared to patients with telephone consultation (OR, 3.11; 95% CI, 1.74-5.57; P < .0001; 78% vs 53%). Patients with bedside consultation had lower mortality than patients with telephone consultation at 7 days (OR, 0.09; 95% CI, .02-.49; P = .001; 1% vs 8%), at 28 days (OR, 0.27; 95% CI, .11-.65; P = .002; 5% vs 16%) and at 90 days (OR, 0.25; 95% CI, .13-.51; P < .0001; 9% vs 29%). Considering all prognostic markers, 90-day mortality for telephone consultation patients was higher (OR, 2.31; CI, 95% 1.22-4.38; P = .01) as compared to bedside consultation. CONCLUSIONS: Telephone IDS consultation is inferior to bedside IDS consultation. PMID- 23087399 TI - Prospective characterization of catheter-tissue contact force at different anatomic sites during antral pulmonary vein isolation. AB - BACKGROUND: Catheter-tissue contact is critical for effective lesion creation. We characterized the contact force (CF) at different anatomic sites during antral pulmonary vein (PV) isolation for atrial fibrillation. METHODS AND RESULTS: Two experienced operators performed PV isolation in 22 patients facilitated by a novel CF-sensing ablation catheter in a blinded fashion. Average CF and force time integral data from 1602 lesions were analyzed. The left and right PV antra were divided into the following: carina, superior, inferior, anterior, and posterior quadrants for analysis. There was significant variability in CF within and between different PV quadrants (P<0.05). Lowest CF of all left PV sites was at the carina and anterior quadrant, whereas highest CF was at the superior and inferior quadrants (P<0.05). Lowest CF of all right PV sites was at the carina, whereas highest CF was at the anterior and inferior quadrants (P<0.05). When comparing similar PV quadrants on the left versus right (eg, left carina versus right carina), CF was always higher in the right PVs (P<0.05), except at the superior quadrant where CF was similar in the left and right PVs (P=0.19). There was no specific pattern of anatomic distribution of excess CF (P=0.39). CONCLUSIONS: Monitoring of catheter-tissue CF during PV isolation demonstrates significant variability in CF within and between different PV antral sites. Sites of lowest CF were the carina and anterior left PVs and the carina of the right PVs. This information may be important for improving ablation efficacy and clinical outcomes during PV isolation. PMID- 23087400 TI - Ultrasound lung comets: the shape of lung water. PMID- 23087401 TI - Hypertension susceptibility loci and blood pressure response to antihypertensives: results from the pharmacogenomic evaluation of antihypertensive responses study. AB - BACKGROUND: To date, 39 single nucleotide polymorphisms (SNPs) have been associated with blood pressure (BP) or hypertension in genome-wide association studies in whites. Our hypothesis is that the loci/SNPs associated with BP/hypertension are also associated with BP response to antihypertensive drugs. METHODS AND RESULTS: We assessed the association of these loci with BP response to atenolol or hydrochlorothiazide monotherapy in 768 hypertensive participants in the Pharmacogenomics Responses of Antihypertensive Responses study. Linear regression analysis was performed on whites for each SNP in an additive model adjusting for baseline BP, age, sex, and principal components for ancestry. Genetic scores were constructed to include SNPs with nominal associations, and empirical P values were determined by permutation test. Genotypes of 37 loci were obtained from Illumina 50K cardiovascular or Omni1M genome-wide association study chips. In whites, no SNPs reached Bonferroni-corrected alpha of 0.0014, 6 reached nominal significance (P<0.05), and 3 were associated with atenolol BP response at P<0.01. The genetic score of the atenolol BP-lowering alleles was associated with response to atenolol (P=3.3 * 10(-6) for systolic BP; P=1.6 * 10(-6) for diastolic BP). The genetic score of the hydrochlorothiazide BP-lowering alleles was associated with response to hydrochlorothiazide (P=0.0006 for systolic BP; P=0.0003 for diastolic BP). Both risk score P values were <0.01 based on the empirical distribution from the permutation test. CONCLUSIONS: These findings suggest that selected signals from hypertension genome-wide association studies may predict BP response to atenolol and hydrochlorothiazide when assessed through risk scoring. Clinical Trial Registration Information- clinicaltrials.gov; Identifier: NCT00246519. PMID- 23087402 TI - Prognostic role of pulmonary arterial capacitance in advanced heart failure. AB - BACKGROUND: Right ventricular (RV) dysfunction frequently occurs and independently prognosticates in left-sided heart failure. It is not clear which RV afterload measure has the greatest impact on RV function and prognosis. We examined the determinants, prognostic role, and response to treatment of pulmonary arterial capacitance (PAC, ratio of stroke volume over pulmonary pulse pressure), in relation to pulmonary vascular resistance (PVR) in heart failure. METHODS AND RESULTS: We reviewed 724 consecutive patients with heart failure who underwent right heart catheterization between 2000 and 2005. Changes in PAC were explored in an independent cohort of 75 subjects treated for acute decompensated heart failure. PAC showed a strong inverse relation with PVR (r=-0.64) and wedge pressure (r=-0.73), and provides stronger prediction of significant RV failure than PVR (area under the curve ROC 0.74 versus 0.67, respectively, P=0.003). During a mean follow-up of 3.2+/-2.2 years, both lower PAC (P<0.0001) and higher PVR (P<0.0001) portend more adverse clinical events (all-cause mortality and cardiac transplantation). In multivariate analysis, PAC (but not PVR) remains an independent predictor (Hazard ratio=0.92 [95% CI: 0.84-1.0, P=0.037]). Treatment of heart failure resulted in a decrease in PVR (270+/-165 to 211+/-88 dynes.s( 1).cm(-5), P=0.002), a larger increase in PAC (1.65+/-0.64 to 2.61+/-1.42 mL/mm Hg, P<0.0001), leading to an increase in pulmonary arterial time constant (PVR*PAC) (0.29+/-0.12 to 0.37+/-0.15 second, P<0.0001). CONCLUSIONS: PAC bundles the effects of PVR and left-sided filling pressures on RV afterload, explaining its strong relation with RV dysfunction, poor long-term prognosis, and response to therapy. PMID- 23087403 TI - Identification of core DNA elements that target somatic hypermutation. AB - Somatic hypermutation (SHM) diversifies the V region of Ig genes and underlies the process of affinity maturation, in which B lymphocytes producing high affinity Abs are generated and selected. SHM is triggered in activated B cells by deamination of deoxycytosine residues mediated by activation-induced deaminase (AID). Whereas mistargeting of SHM and AID results in mutations and DNA damage in many non-Ig genes, they act preferentially at Ig loci. The mechanisms responsible for preferential targeting of SHM and AID activity to Ig loci are poorly understood. Using an assay involving an SHM reporter cassette inserted into the Ig L chain locus (IgL) of chicken DT40 B cells, we have identified a 1.9-kb DIVAC (diversification activator) element derived from chicken IgL that supports high levels of AID-dependent mutation activity. Systematic deletion analysis reveals that targeting activity is spread throughout much of the sequence and identifies two core regions that are particularly critical for function: a 200-bp region within the IgL enhancer, and a 350-bp 3' element. Chromatin immunoprecipitation experiments demonstrate that whereas DIVAC does not alter levels of several epigenetic marks in the mutation cassette, it does increase levels of serine-5 phosphorylated RNA polymerase II in the mutation target region, consistent with an effect on transcriptional elongation/pausing. We propose that multiple, dispersed DNA elements collaborate to recruit and activate the mutational machinery at Ig gene variable regions during SHM. PMID- 23087404 TI - Ndfip1 negatively regulates RIG-I-dependent immune signaling by enhancing E3 ligase Smurf1-mediated MAVS degradation. AB - Ndfip1 functions as both a recruiter and an activator of multiple HECT domain E3 ubiquitin ligases of the Nedd4 family. In this study, we demonstrate that Ndfip1 is involved in the ubiquitin-mediated degradation of mitochondrial antiviral signaling (MAVS), which is a key adaptor protein in RIG-I-like receptor-mediated immune signaling. We found that overexpression of Ndfip1 severely impaired MAVS and Sendai virus-mediated activation of IFN-stimulated response element, NF kappaB, IFN-beta promoter, and polyinosinic-polycytidylic acid or influenza virus RNA-stimulated IRF-3 phosphorylation, as well as the transcription of IFN-beta. This functional interaction was confirmed by knockdown of Ndfip1, which facilitated MAVS-mediated downstream signaling and elevated MAVS protein levels. Further analysis indicated that Ndfip1 enhances both self-ubiquitination of HECT domain-containing E3 ubiquitin ligase Smurf1 and its interaction with MAVS, and eventually promotes MAVS degradation. In addition, the activation of IFN-beta by MAVS, influenza virus RNA, polyinosinic-polycytidylic acid, and Sendai virus was enhanced in Ndfip1 knockdown cells. These results reveal that Ndfip1 is a potent inhibitor of MAVS-mediated antiviral response. PMID- 23087405 TI - Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. AB - 1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of vitamin D status. However, use of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1alpha hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we show in this study that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact, resulting in the generation and release of 1,25(OH)(2)D(3), which subsequently affects T cell responses. In most tissues, vitamin D binding protein acts as a carrier to enhance the use of vitamin D. However, we show that vitamin D binding protein modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of free 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses. PMID- 23087406 TI - Critical role of B cell lymphoma 10 in BAFF-regulated NF-kappaB activation and survival of anergic B cells. AB - Anergy is a key physiological mechanism for restraining self-reactive B cells. A marked portion of peripheral B cells are anergic B cells that largely depend on BAFF for survival. BAFF activates the canonical and noncanonical NF-kappaB pathways, both of which are required for B cell survival. In this study we report that deficiency of the adaptor protein B cell lymphoma 10 (Bcl10) impaired the ability of BAFF to support B cell survival in vitro, and it specifically increased apoptosis in anergic B cells in vivo, dramatically reducing anergic B cells in mice. Bcl10-dependent survival of self-reactive anergic B cells was confirmed in the Ig hen egg lysozyme/soluble hen egg lysozyme double-transgenic mouse model of B cell anergy. Furthermore, we found that BAFF stimulation induced Bcl10 association with IkappaB kinase beta, a key component of the canonical NF kappaB pathway. Consistently, Bcl10-deficient B cells were impaired in BAFF induced IkappaBalpha phosphorylation and formation of nuclear p50/c-Rel complexes. Bcl10-deficient B cells also displayed reduced expression of NF kappaB2/p100, severely reducing BAFF-induced nuclear accumulation of noncanonical p52/RelB complexes. Consequently, Bcl10-deficient B cells failed to express Bcl x(L), a BAFF-induced NF-kappaB target gene. Taken together, these data demonstrate that Bcl10 controls BAFF-induced canonical NF-kappaB activation directly and noncanonical NF-kappaB activation indirectly. The BAFF-R/Bcl10/NF kappaB signaling axis plays a critical role in peripheral B cell tolerance by regulating the survival of self-reactive anergic B cells. PMID- 23087407 TI - Lifelong persistent viral infection alters the naive T cell pool, impairing CD8 T cell immunity in late life. AB - Persistent CMV infection has been associated with immune senescence. To address the causal impact of lifelong persistent viral infection on immune homeostasis and defense, we infected young mice systemically with HSV-1, murine CMV, or both viruses and studied their T cell homeostasis and function. Herpesvirus(+) mice exhibited increased all-cause mortality compared with controls. Upon Listeria-OVA infection, 23-mo-old animals that had experienced lifelong herpesvirus infections showed impaired bacterial control and CD8 T cell function, along with distinct alterations in the T cell repertoire both before and after Listeria challenge, compared with age-matched, herpesvirus-free controls. Herpesvirus infection was associated with reduced naive CD8 T cell precursors above the loss attributable to aging. Moreover, the OVA-specific CD8 T cell repertoire recruited after Listeria challenge was entirely nonoverlapping between control and herpesvirus(+) mice. To our knowledge, this study for the first time causally links lifelong herpesvirus infection to all-cause mortality in mice and to disturbances in the T cell repertoire, which themselves correspond to impaired immunity to a new infection in aging. PMID- 23087408 TI - Molecular pathways: next-generation immunotherapy--inhibiting programmed death ligand 1 and programmed death-1. AB - The aim of T-cell-based immune therapy for cancer has been to generate durable clinical benefit for patients. Following a generation of therapies that largely showed minimal activity, substantial toxicity, and no biomarkers to identify which patients benefit from treatment, early studies are showing signs that programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) inhibitors are highly active. Preclinical and early data from clinical studies suggest that targeting this pathway can induce durable clinical responses in patients in a variety of tumor types, including lung and colon cancer. Furthermore, correlations with tumor PD-L1 expression may enable selection of patients most likely to benefit from treatment. The emerging data not only offer the hope of better cancer therapy but also provide evidence that changes our understanding of how the host immune system interacts with human cancer. PMID- 23087409 TI - Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma. AB - PURPOSE: To investigate the feasibility of adaptive dosing and the impact of pharmacogenetic variation on 13-cis-retinoic acid (13-cisRA) disposition in high risk patients with neuroblastoma. EXPERIMENTAL DESIGN: 13-cisRA (160 mg/m(2) or 5.33 mg/kg/d) was administered to 103 patients ages 21 years or less and plasma concentrations of 13-cisRA and 4-oxo-13-cisRA quantitated on day 14 of treatment. Seventy-one patients were recruited to a dose adjustment group, targeting a 13 cisRA C(max) of 2 MUmol/L, with dose increases of 25% to 50% implemented for patients with C(max) values less than 2 MUmol/L. A population pharmacokinetic model was applied and polymorphisms in relevant cytochrome P450 genes analyzed. RESULTS: 13-cisRA C(max) values ranged from 0.42 to 11.2 MUmol/L, with 34 of 103 (33%) patients failing to achieve a C(max) more than 2 MUmol/L. Dose increases carried out in 20 patients in the dose adjustment study group led to concentrations more than 2 MUmol/L in 18 patients (90%). Eight of 11 (73%) patients less than 12 kg, receiving a dose of 5.33 mg/kg, failed to achieve a C(max) of 2 MUmol/L or more. Significantly, lower C(max) values were observed for patients treated with 5.33 mg/kg versus 160 mg/m(2) (1.9 +/- 1.2 vs. 3.1 +/- 2.0 MUmol/L; mean +/- SD; P = 0.023). C(max) was higher in patients who swallowed 13 cisRA capsules as compared with receiving the drug extracted from capsules (4.0 +/- 2.2 vs. 2.6 +/- 1.8 MUmol/L; P = 0.0012). The target C(max) was achieved by 93% (25/27) versus 55% (42/76) of patients in these 2 groups, respectively. No clear relationships were found between genetic variants and 13-cisRA pharmacokinetic parameters. CONCLUSIONS: Dosing regimen and method of administration have a marked influence on 13-cisRA plasma concentrations. Body weight-based dosing should not be implemented for children less than 12 kg and pharmacologic data support higher doses for children unable to swallow 13-cisRA capsules. PMID- 23087410 TI - Expression of serotonin receptors in human hepatocellular cancer. AB - PURPOSE: Serotonin is a well-known neurotransmitter and vasoactive substance. Recent research indicates that serotonin contributes to liver regeneration and promotes tumor growth of human hepatocellular cancer. The aim of this study is to investigate the expression of serotonin receptors in hepatocellular cancer and analyze their potential as a cytotoxic target. EXPERIMENTAL DESIGN: Using a tissue microarray and immunohistochemistry, we analyzed the expression of serotonin receptors in the liver from 176 patients with hepatocellular carcinoma, of which nontumor tissue was available in 109 patients. Relevant clinicopathologic parameters were compared with serotonin receptor expression. Two human hepatocellular cancer cell lines, Huh7 and HepG2, were used to test serotonin antagonists as a possible cytotoxic drug. RESULTS: The serotonin receptors 1B and 2B were expressed, respectively, in 32% and 35% of the patients with hepatocellular cancer. Both receptors were associated with an increased proliferation index, and receptor 1B correlated with the size of the tumor. Serotonin antagonists of receptors 1B and 2B consistently decreased viability and proliferation in Huh7 and HepG2 cell lines. CONCLUSION: We identified two serotonin receptors that are often overexpressed in human hepatocellular cancer and may serve as a new cytotoxic target. PMID- 23087411 TI - Incorporating auxiliary information for improved prediction in high-dimensional datasets: an ensemble of shrinkage approaches. AB - With advancement in genomic technologies, it is common that two high-dimensional datasets are available, both measuring the same underlying biological phenomenon with different techniques. We consider predicting a continuous outcome Y using X, a set of p markers which is the best available measure of the underlying biological process. This same biological process may also be measured by W, coming from a prior technology but correlated with X. On a moderately sized sample, we have (Y,X,W), and on a larger sample we have (Y,W). We utilize the data on W to boost the prediction of Y by X. When p is large and the subsample containing X is small, this is a p>n situation. When p is small, this is akin to the classical measurement error problem; however, ours is not the typical goal of calibrating W for use in future studies. We propose to shrink the regression coefficients beta of Y on X toward different targets that use information derived from W in the larger dataset. We compare these proposals with the classical ridge regression of Y on X, which does not use W. We also unify all of these methods as targeted ridge estimators. Finally, we propose a hybrid estimator which is a linear combination of multiple estimators of beta. With an optimal choice of weights, the hybrid estimator balances efficiency and robustness in a data adaptive way to theoretically yield a smaller prediction error than any of its constituents. The methods, including a fully Bayesian alternative, are evaluated via simulation studies. We also apply them to a gene-expression dataset. mRNA expression measured via quantitative real-time polymerase chain reaction is used to predict survival time in lung cancer patients, with auxiliary information from microarray technology available on a larger sample. PMID- 23087412 TI - Extensions of criteria for evaluating risk prediction models for public health applications. AB - We recently proposed two novel criteria to assess the usefulness of risk prediction models for public health applications. The proportion of cases followed, PCF(p), is the proportion of individuals who will develop disease who are included in the proportion p of individuals in the population at highest risk. The proportion needed to follow-up, PNF(q), is the proportion of the general population at highest risk that one needs to follow in order that a proportion q of those destined to become cases will be followed (Pfeiffer, R.M. and Gail, M.H., 2011. Two criteria for evaluating risk prediction models. Biometrics 67, 1057-1065). Here, we extend these criteria in two ways. First, we introduce two new criteria by integrating PCF and PNF over a range of values of q or p to obtain iPCF, the integrated PCF, and iPNF, the integrated PNF. A key assumption in the previous work was that the risk model is well calibrated. This assumption also underlies novel estimates of iPCF and iPNF based on observed risks in a population alone. The second extension is to propose and study estimates of PCF, PNF, iPCF, and iPNF that are consistent even if the risk models are not well calibrated. These new estimates are obtained from case-control data when the outcome prevalence in the population is known, and from cohort data, with baseline covariates and observed health outcomes. We study the efficiency of the various estimates and propose and compare tests for comparing two risk models, both of which were evaluated in the same validation data. PMID- 23087416 TI - An iPad app as a low-vision aid for people with macular disease. PMID- 23087415 TI - Inflammatory response to intravitreal injection of gold nanorods. AB - AIM: To evaluate the utility of gold nanorods (AuNRs) as a contrast agent for ocular optical coherence tomography (OCT). METHODS: Mice were intravitreally injected with sterile AuNRs coated with either poly(strenesulfate) (PSS-AuNRs) or anti-CD90.2 antibodies (Ab-AuNRs), and imaged using OCT. After 24 h, eyes were processed for transmission electron microscopy or rendered into single cell suspensions for flow cytometric analysis to determine absolute numbers of CD45(+) leukocytes and subsets (T cells, myeloid cells, macrophages, neutrophils). Generalised estimation equations were used to compare cell counts between groups. RESULTS: PSS-AuNRs and Ab-AuNRs were visualised in the vitreous 30 min and 24 h post-injection with OCT. At 24 h, a statistically significant increase in leukocytes, comprised primarily of neutrophils, was observed in eyes that received either AuNR in comparison to eyes that received saline. The accumulation of leukocytes was equal in eyes given PSS-AuNR or Ab-AuNR. Endotoxin-resistant C3H/HeJ mice also showed ocular inflammation after injection with AuNRs, indicating that the inflammatory response was not due to lipopolysaccharide contamination of AuNRs. CONCLUSIONS: Although AuNRs can be visualised in the eye using OCT, they can induce ocular inflammation, which limits their use as a contrast agent. PMID- 23087417 TI - Multicentre clinical study of the herpes simplex virus immunochromatographic assay kit for the diagnosis of herpetic epithelial keratitis. AB - BACKGROUND/AIMS: The novel immunochromatographic assay (ICGA) kit was recently developed to diagnose herpes simplex virus (HSV) infection. This multicentre study aimed to evaluate the value of the ICGA kit for the diagnosis of herpetic epithelial keratitis by comparing it with immunofluorescence assay (IFA) and real time PCR. METHODS: Corneal scrapings were collected from 117 patients, including 77 with herpetic keratitis as their final clinical diagnosis as well as 40 others at 21 facilities. These samples were tested by the ICGA kit, IFA and real-time PCR. RESULTS: The positive concordance between final clinical diagnosis and ICGA was 46.7% (35/75 cases) and the negative concordance was 100% (39/39). The positive and negative concordance between real-time PCR and ICGA were 57.4% (35/61 cases) and 100% (53/53), respectively. The positive and negative concordance between IFA and ICGA were 61.1% (22/36 cases) and 83.3% (55/66), respectively. In 92 cases where anti-HSV drugs were not prescribed prior to corneal scraping, the positive and negative concordance between final clinical diagnosis and ICGA were 55.0% (33/60 cases) and 100% (32/32), respectively. CONCLUSIONS: The ICGA kit has moderate sensitivity and high specificity, indicating clinical utility in the diagnosis of herpetic epithelial keratitis. PMID- 23087418 TI - Authors' response to control issues. PMID- 23087419 TI - Subconjunctival bevacizumab induces regression of corneal neovascularisation: a pilot randomised placebo-controlled double-masked trial. AB - OBJECTIVE: To evaluate the off-label use of subconjunctival bevacizumab for corneal neovascularisation (CoNV). METHODS: 30 patients with recent-onset CoNV from various causes were randomly assigned into a double-masked, placebo controlled trial. Each received three 0.1 ml injections containing either 2.5 mg bevacizumab or 0.9% saline at monthly intervals. Dexamethasone 0.1% drops were used four times a day for the first month, when the dose was modified if clinically indicated. The primary outcome was change in area of corneal involvement by CoNV from baseline to 3 months measured using specialised imaging technology. RESULTS: The mean area of CoNV reduced by -36% (range -92% to +40%) in the 15 eyes that received bevacizumab compared with an increase of 90% (range 58% to +1394%) in eyes that received saline placebo (analysis of covariance (ANCOVA); p=0.007). One outlier in the placebo arm developed corneal graft rejection with aggressive neovascularisation (+1384%), but even when this patient was excluded the mean reduction in CoNV in the placebo group (-3%, range -58% to +40%) was still significantly different from the treatment arm (ANCOVA; p=0.016). Changes in best-corrected visual acuity, central corneal thickness, intraocular pressure and endothelial cell counts were similar between groups. The intervention was well tolerated with no major safety concerns. CONCLUSIONS: Three subconjunctival injections of 2.5 mg bevacizumab are more effective than placebo at inducing the regression of recent-onset CoNV. Further studies are needed to confirm this effect and our data suggest that a sample size of 40 patients per treatment group is required. PMID- 23087420 TI - The MANTA 1-year results: the anti-VEGF debate continues. PMID- 23087421 TI - Corneal collagen cross-linkage in keratoconus. PMID- 23087422 TI - Thomas Kuhn's 'Structure of Scientific Revolutions' applied to exercise science paradigm shifts: example including the Central Governor Model. AB - According to Thomas Kuhn, the scientific progress of any discipline could be distinguished by a pre-paradigm phase, a normal science phase and a revolution phase. The science advances when a scientific revolution takes place after silent period of normal science and the scientific community moves ahead to a paradigm shift. I suggest there has been a recent change of course in the direction of the exercise science. According to the 'current paradigm', exercise would be probably limited by alterations in either central command or peripheral skeletal muscles, and fatigue would be developed in a task-dependent manner. Instead, the central governor model (GCM) has proposed that all forms of exercise are centrally regulated, the central nervous system would calculate the metabolic cost required to complete a task in order to avoid catastrophic body failure. Some have criticized the CGM and supported the traditional interpretation, but recently the scientific community appears to have begun an intellectual trajectory to accept this theory. First, the increased number of citations of articles that have supported the CGM could indicate that the community has changed the focus. Second, relevant journals have devoted special editions to promote the debate on subjects challenged by the CGM. Finally, scientists from different fields have recognized mechanisms included in the CGM to understand the exercise limits. Given the importance of the scientific community in demarcating a Kuhnian paradigm shift, I suggest that these three aspects could indicate an increased acceptance of a centrally-regulated effort model, to understand the limits of exercise. PMID- 23087423 TI - Comment on "Expansion of effector memory regulatory T cells represents a novel prognostic factor in lower risk myelodysplastic syndrome". PMID- 23087424 TI - When three negatives made a positive influence in defining four early steps in T cell development. PMID- 23087425 TI - Pillars article: a developmental pathway involving four phenotypically and functionally distinct subsets of CD3-CD4-CD8- triple-negative adult mouse thymocytes defined by CD44 and CD25 expression. J. Immunol. 1993. 150: 4244-4252. PMID- 23087426 TI - IL-4 in the brain: a cytokine to remember. AB - IL-4 has been extensively studied in the context of its role in immunity. Accumulating evidence indicates, however, that it also plays a critical role in higher functions of the normal brain, such as memory and learning. In this review, we summarize current knowledge of the basic immunology of IL-4, describe how and where this cytokine appears to operate in normal brain function, and propose a hypothesis concerning its potential role in neurological pathologies. PMID- 23087427 TI - Response of CFTR-deficient mice to long-term chronic Pseudomonas aeruginosa infection and PTX3 therapy. AB - BACKGROUND: In cystic fibrosis (CF) patients, chronic lung infection and inflammation due to Pseudomonas aeruginosa contribute to the decline of lung function. The increased prevalence of multidrug resistance among bacteria and the adverse effects of antiinflammatory agents highlight the need for alternative therapeutic approaches that should be tested in a relevant animal model. METHODS: Gut-corrected CF and non-CF mice were chronically infected with a multidrug resistant P. aeruginosa strain and treated with the long pentraxin PTX3. Body weight, bacterial count, inflammation, and lung pathology were evaluated after 12 days. PTX3 localization in CF sputum specimens was analyzed by immunofluorescence. RESULTS: Chronic P. aeruginosa infection developed similarly in CF and non-CF mice but differed in terms of the inflammatory response. Leukocyte recruitment in the airways, cytokine levels, and chemokine levels were significantly higher in CF mice, compared with non-CF mice. PTX3 treatment, which facilitates phagocytosis of pathogens, reduced P. aeruginosa colonization and restored airway inflammation in CF mice to levels observed in non-CF mice. The presence of PTX3 in CF sputum, in leukocytes, or bound to P. aeruginosa macrocolonies, as well as previous data on PTX3 polymorphisms in colonized CF patients, confirm the relevance of this molecule. CONCLUSIONS: These findings represent a step forward in demonstrating the therapeutic potential of PTX3 in CF. PMID- 23087428 TI - 1976 and 2009 H1N1 influenza virus vaccines boost anti-hemagglutinin stalk antibodies in humans. AB - BACKGROUND: Infection with pandemic H1N1 influenza A viruses (IAVs) containing hemagglutinin (HA) proteins with globular heads that differ substantially from seasonal strains results in a boost in broadly cross-reactive antibodies that bind to the HA stalk. Boosting these antibodies has become an attractive strategy for creating a universal IAV vaccine. Therefore, it was essential to determine whether vaccines containing H1N1 viruses whose head domains differ substantially compared to seasonal strains could also achieve this boost. METHODS: Prospective samples of subjects who had received the A/New Jersey/1976 (NJ/76) vaccine and healthy, age-matched controls were assessed for the presence of anti-HA stalk antibodies before and after receiving the A/California/04/2009 (Cal/09) vaccine between October 2009 and January 2010. RESULTS: Individuals who received either the NJ/76 vaccine or the Cal/09 vaccine experienced a robust boost in HA stalk reactive, neutralizing antibodies similar to what has been observed in individuals infected with Cal/09. CONCLUSIONS: These results demonstrate that vaccines containing viruses whose HA head domains that differ substantially from seasonal strains are capable of boosting titers of HA stalk antibodies. Furthermore, anti-HA stalk antibodies elicited by vaccination appear to be long lived and therefore could be targeted for the generation of a universal IAV vaccine. PMID- 23087429 TI - Monitoring HPV vaccine impact: early results and ongoing challenges. PMID- 23087430 TI - Fall in human papillomavirus prevalence following a national vaccination program. AB - BACKGROUND: In April 2007, Australia became the first country to introduce a national government-funded human papillomavirus (HPV) vaccination program. We evaluated the program's impact on genotype-specific HPV infection prevalence through a repeat survey of women attending clinical services. METHODS: HPV genoprevalence in women aged 18-24 years attending family planning clinics in the prevaccine period (2005-2007) was compared with prevalence among women of the same age group in the postvaccine period (2010-2011). The same recruitment and testing strategies were utilized for both sets of samples, and comparisons were adjusted for potentially confounding variables. RESULTS: The prevalence of vaccine HPV genotypes (6, 11, 16, and 18) was significantly lower in the postvaccine sample than in the prevaccine sample (6.7% vs 28.7%; P < .001), with lower prevalence observed in both vaccinated and unvaccinated women compared with the prevaccine population (5.0% [adjusted odds ratio, 0.11; 95% confidence interval, 0.06-0.21] and 15.8% [adjusted odds ratio, 0.42; 95% confidence interval, 0.19-0.93], respectively). A slightly lower prevalence of nonvaccine oncogenic HPV genotypes was also found in vaccinated women (30.8% vs 37.6%; adjusted odds ratio, 0.68; 95% confidence interval, 0.46-0.99). CONCLUSIONS: Four years after the commencement of the Australian HPV vaccination program, a substantial decrease in vaccine-targeted genotypes is evident and should, in time, translate into reductions in HPV-related lesions. PMID- 23087431 TI - T-helper 17 cells are associated with pathology in human schistosomiasis. AB - BACKGROUND: Schistosome infections are often clinically silent, but some individuals develop severe pathological reactions. In several disease processes, T-helper 17 (Th17) cells have been linked to tissue injuries, while regulatory T cells (Tregs) are thought to downmodulate inflammatory reactions. We assessed whether bladder pathology in human Schistosoma haematobium infection is related to the balance of Th17 cells and Tregs. We used a murine model of Schistosoma mansoni infection to further investigate whether the peripheral profiles reflected ongoing events in tissues. METHODS: We characterized T-helper cell subsets in the peripheral blood of children residing in a S. haematobium-endemic area and in the peripheral blood, spleen, and hepatic granulomas of S. mansoni infected high-pathology CBA mice and low-pathology C57BL/6 mice. RESULTS: S. haematobium-infected children with bladder pathology had a significantly higher percentage of Th17 cells than those without pathology. Moreover, the Th17/Treg ratios were significantly higher in infected children with pathology, compared with infected children without pathology. Percentages of interleukin 17-producing cells were significantly higher in spleen and granulomas of CBA mice, compared with C57BL/6 mice. This difference was also reflected in the peripheral blood. CONCLUSIONS: This is the first study to indicate that Th17 cells may be involved in the pathogenesis of human schistosomiasis. PMID- 23087432 TI - Presence of memory T cells and naturally acquired antibodies in Plasmodium vivax malaria-exposed individuals against a group of tryptophan-rich antigens with conserved sequences. AB - BACKGROUND: Tryptophan-rich antigens of malarial parasites have been proposed to be the potential vaccine candidate antigens. Plasmodium vivax contains the largest number of such antigens, which need to be evaluated for their immune responses. METHODS: Recombinant proteins of 15 P. vivax tryptophan-rich antigens (PvTRAgs) were expressed, purified, and used for the human humoral and cellular immune responses. Genetic polymorphism of these 15 genes was also determined among clinical P. vivax isolates. RESULTS: The T lymphocytes of P. vivax exposed individuals expressed higher level of CD69 against all 15 PvTRAgs. These antigens also activated the large population of CD4(+) T cells and produced higher level of intracellular IL-2, INF-gamma and IL-4. Although there was a mixed Th1 and Th2 response against these antigens, this response was biased toward Th2. The majority of P. vivax patients (75.7%-100%, n = 33) produced IgG antibodies against these antigens. Most of these antigens showed conserved T- and B-cell epitopes in the parasite population. CONCLUSIONS: These results suggest the presence of memory T cells in humans against these antigens to generate faster and more specific immune responses to minimize the P. vivax infection. Further characterization of these PvTRAgs may lead to the identification of a potential therapeutic target. PMID- 23087433 TI - Localized mucosal response to intranasal live attenuated influenza vaccine in adults. AB - BACKGROUND: Influenza virus infection is a major public health burden worldwide. Available vaccines include the inactivated intramuscular trivalent vaccine and, more recently, an intranasal live attenuated influenza vaccine (LAIV). The measure of successful vaccination with the inactivated vaccine is a systemic rise in immunoglobulin G (IgG) level, but for the LAIV no such correlate has been established. METHODS: Seventy-nine subjects were given the LAIV FluMist. Blood was collected prior to vaccination and 3 days and 30 days after vaccination. Nasal wash was collected 3 days and 30 days after vaccination. Responses were measured systemically and in mucosal secretions for cytokines, cell activation profiles, and antibody responses. RESULTS: Only 9% of subjects who received LAIV seroconverted, while 33% of patients developed at least a 2-fold increase in influenza virus-specific immunoglobulin A (IgA) antibodies in nasal wash. LAIV induced a localized inflammation, as suggested by increased expression of interferon-response genes in mucosal RNA and increased granulocyte colony stimulating factor (G-CSF) and IP-10 in nasal wash. Interestingly, patients who seroconverted had significantly lower serum levels of G-CSF before vaccination. CONCLUSIONS: Protection by LAIV is likely provided through mucosal IgA and not by increases in systemic IgG. LAIV induces local inflammation. Seroconversion is achieved in a small fraction of subjects with a lower serum G-CSF level. PMID- 23087434 TI - Use of oral fluid to examine the molecular epidemiology of varicella zoster virus in the United Kingdom and continental Europe. AB - We investigated oral fluid (OF) as an alternative to sampling of rashes for varicella zoster virus (VZV) genotyping and further characterized VZV clade prevalence in the United Kingdom and Europe. VZV was detected in up to 91% of OF specimens. Paired OF and vesicle fluid samples contained identical VZV clades. While clades 1 and 3 were the most prevalent across the United Kingdom and Europe, in Western Europe, clade 5 viruses were circulating. Viruses from the same outbreak belonged to different clades, but no clade was associated with a severe-disease phenotype. OF is suitable and convenient for large-scale molecular epidemiological studies of VZV. PMID- 23087443 TI - The time of death's badness. AB - Those who endorse the view that death is in some cases bad for the deceased--a view that, as I shall explain, has considerable bearing on many bioethical issues -need to address the following, Epicurean question: When is death bad for the one who dies? The two most popular answers are "before death" (priorism) and "after death" (subsequentism). Part of the support for these two views consists in the idea that a third answer, "at no time" (atemporalism), makes death unsatisfyingly different from other evils. I argue that this objection is mistaken, and that priorism and subsequentism face problems that atemporalism avoids. Moreover, I argue that if it is nonetheless insisted that we must find a time at which my death is bad for me, we can appeal to periods that begin before my death and end after my death. I end with some implications for posthumous harm. PMID- 23087442 TI - Functional rescue of mutant ABCA1 proteins by sodium 4-phenylbutyrate. AB - Mutations in the ATP-binding cassette transporter A1 (ABCA1) are a major cause of decreased HDL cholesterol (HDL-C), which infers an increased risk of cardiovascular disease (CVD). Many ABCA1 mutants show impaired localization to the plasma membrane. The aim of this study was to investigate whether the chemical chaperone, sodium 4-phenylbutyrate (4-PBA) could improve cellular localization and function of ABCA1 mutants. Nine different ABCA1 mutants (p.A594T, p.I659V, p.R1068H, p.T1512M, p.Y1767D, p.N1800H, p.R2004K, p.A2028V, p.Q2239N) expressed in HEK293 cells, displaying different degrees of mislocalization to the plasma membrane and discrete impacts on cholesterol efflux, were subject to treatment with 4-PBA. Treatment restored localization to the plasma membrane and increased cholesterol efflux function for the majority of mutants. Treatment with 4-PBA also increased ABCA1 protein expression in all transfected cell lines. In fibroblast cells obtained from low HDL-C subjects expressing two of the ABCA1 mutants (p.R1068H and p.N1800H), 4-PBA increased cholesterol efflux without any increase in ABCA1 expression. Our study is the first to investigate the effect of the chemical chaperone, 4-PBA on ABCA1 and shows that it is capable of restoring plasma membrane localization and enhancing the cholesterol efflux function of mutant ABCA1s both in vitro and ex vivo. These results suggest 4-PBA may warrant further investigation as a potential therapy for increasing cholesterol efflux and HDL-C levels. PMID- 23087435 TI - Reduced inflammation and lymphoid tissue immunopathology in rhesus macaques receiving anti-tumor necrosis factor treatment during primary simian immunodeficiency virus infection. AB - BACKGROUND: Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infections induce robust, generalized inflammatory responses that begin during acute infection and lead to pathological systemic immune activation, fibrotic damage of lymphoid tissues, and CD4+ T-cell loss, pathogenic processes that contribute to disease progression. METHODS: To better understand the contribution of tumor necrosis factor (TNF), a key regulator of acute inflammation, to lentiviral pathogenesis, rhesus macaques newly infected with SIVmac239 were treated for 12 weeks in a pilot study with adalimumab (Humira), a human anti-TNF monoclonal antibody. RESULTS: Adalimumab did not affect plasma SIV RNA levels or measures of T-cell immune activation (CD38 or Ki67) in peripheral blood or lymph node T cells. However, compared with untreated rhesus macaques, adalimumab-treated rhesus macaques showed attenuated expression of proinflammatory genes, decreased infiltration of polymorphonuclear cells into the T-cell zone of lymphoid tissues, and weaker antiinflammatory regulatory responses to SIV infection (ie, fewer presumed alternatively activated [ie, CD163+] macrophages, interleukin 10-producing cells, and transforming growth factor beta producing cells), along with reduced lymphoid tissue fibrosis and better preservation of CD4+ T cells. CONCLUSIONS: While HIV/SIV replication drives pathogenesis, these data emphasize the contribution of the inflammatory response to lentiviral infection to overall pathogenesis, and they suggest that early modulation of the inflammatory response may help attenuate disease progression. PMID- 23087444 TI - Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust and a cohort mortality study with emphasis on lung cancer. PMID- 23087445 TI - Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust. PMID- 23087446 TI - Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust, a cohort mortality study with emphasis on lung cancer, and the problem with diesel. PMID- 23087447 TI - Re: The problem with diesel. PMID- 23087448 TI - Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust and a cohort mortality study with emphasis on lung cancer. PMID- 23087449 TI - Re: The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust and a cohort mortality study with emphasis on lung cancer. PMID- 23087450 TI - MDMS: Molecular Dynamics Meta-Simulator for evaluating exchange type sampling methods. AB - Replica exchange methods have become popular tools to explore conformational space for small proteins. For larger biological systems, even with enhanced sampling methods, exploring the free energy landscape remains computationally challenging. This problem has led to the development of many improved replica exchange methods. Unfortunately, testing these methods remains expensive. We propose a Molecular Dynamics Meta-Simulator (MDMS) based on transition state theory to simulate a replica exchange simulation, eliminating the need to run explicit dynamics between exchange attempts. MDMS simulations allow for rapid testing of new replica exchange based methods, greatly reducing the amount of time needed for new method development. PMID- 23087451 TI - ICSM: An order N method for calculating electrostatic interactions added to TINKER. AB - We present an order N method for calculating electrostatic interactions that has been integrated into the molecular dynamics portion of the TINKER Molecular Modeling package. This method, introduced in a previous paper [J. Chem. Phys. 131 (2009) 154103] and termed the Image-Charge Solvation Model (ICSM), is a hybrid electrostatic approach that combines the strengths of both explicit and implicit representations of the solvent. A multiple-image method is used to calculate reaction fields due to the implicit part while the Fast Multipole Method (FMM) is used to calculate the Coulomb interactions for all charges, including the explicit part. The integrated package is validated through test simulations of liquid water. The results are compared with those obtained by the Particle Mesh Ewald (PME) method that is built in the TINKER package. Timing performance of TINKER with the integrated ICSM is benchmarked on bulk water as a function of the size of the system. In particular, timing analysis results show that the ICSM outperforms the PME for sufficiently large systems with the break-even point at around 30,000 particles in the simulated system. PMID- 23087452 TI - Perioperative fluid therapy: How much is not too much? PMID- 23087454 TI - Rapid emergence of day-care anaesthesia: A review. AB - The number of day-care surgeries is increasing every day. The boundaries of day care surgeries are being redefined on a continual basis. Multi-dimensional benefits to the patient, hospital and national economy are the driving forces behind the changing scenario on the horizon of day surgery. The literature search included Google, medlinx, pubmed and medline. We have attempted to look at the controversies in patient selection with comorbidities, pre-operative assessment and an acceptable ASA grade of patients. An attempt is also made to look at suitable surgical procedures, a pathway of introducing procedures, which are still complex and specialist procedures in challenging environment. The techniques of general anaesthesia, central neuraxial blocks, regional nerve blocks with indwelling catheters and monitoring techniques are deliberated upon. Finally the most important post-operative issues of discharge criteria, including recovery after spinal anaesthetic, oral fluid intake, voiding and travel after day surgery, are considered. PMID- 23087453 TI - Liver transplantation: Advances and perioperative care. AB - Liver transplantation is one of the treatments for many-life threatening liver diseases. Numerous advances in liver transplant surgery, anaesthesia and perioperative care have allowed for an increasing number of these procedures. The purpose of this review is to consider some of the important advances in perioperative care of liver transplant patients such as pre-operative evaluation, intraoperative monitoring and management and early extubation. A PubMed and EMBASE search of terms "Anaesthesia" and "Liver Transplantation" were performed with filters of articles in "English", "Adult" and relevant recent publications of randomised control trial, editorial, systemic review and non-systemic review were selected and synthesized according to the author's personal and professional perspective in the field of liver transplantation and anaesthesia. The article outlines strategies in organ preservation, training and transplant database for further research. PMID- 23087455 TI - Factors influencing career choice in anaesthesiology. AB - BACKGROUND: There is a shortage of anaesthesiologists in India. The factors that prompt medical students to opt for anaesthesiology as their career are not known; neither do we have any mechanism to know a student's stress-bearing ability before he/she opts for a stressful career like anaesthesiology. We conducted an anonymous, questionnaire-based, cross-sectional survey among 200 post-graduate anaesthesiology students to know various factors that they considered while opting for this speciality, and also evaluated their stress-bearing ability using Antonovsky's 13-point sense of coherence scale. METHODS: Two-hundred anaesthesiology students were asked to complete a questionnaire regarding the factors they considered important while opting for anaesthesiology, also enumerated in order of importance the three most important factors that led to opting this career. Students also answered the questions in Antonovsky's sense of coherence (SOC) scale. RESULTS: Economic security was considered by maximum number of students (67.7%), while intellectual stimulation/challenge offered by anaesthesiology was rated first in order of importance. Influence of doctor patient relationship was not considered by large number of students. The weak SOC score (55) (25(th) percentile) was not greatly different than the mean SOC score (60) in the survey. CONCLUSION: Increasing the exposure of students to anaesthesiology at undergraduate level and building public awareness about the speciality will prompt more students to opt for the speciality, while career counselling with regard to specific needs of a speciality and ability of a student will help in opting the speciality that best suits the student's personality. PMID- 23087456 TI - Randomized crossover comparison of the laryngeal mask airway classic with i-gel laryngeal mask airway in the management of difficult airway in post burn neck contracture patients. AB - PURPOSE: The objective of the study was to compare the performance of i-gel supraglottic airway with cLMA in difficult airway management in post burn neck contracture patients and assess the feasibility of i-gel use for emergency airway management in difficult airway situation with reduced neck movement and limited mouth opening. METHODS: Prospective, crossover, randomized controlled trial was performed amongst forty eight post burn neck contracture patients with limited mouth opening and neck movement. i-gel and cLMA were placed in random order in each patient. Primary outcome was overall success rate. Other measurements were time to successful ventilation, airway leak pressure, fiberoptic glottic view, visualization of square wave pattern. RESULTS: Success rate for the i-gel was 91.7% versus 79.2% for the cLMA. i-gel required shorter insertion time (19.3 seconds vs. 23.5 seconds, P=0.000). Airway leak pressure difference was statistically significant (i-gel 21.2 cm H20; cLMA 16.9 cm H(2)0; P=0.00). Fiberoptic view through the i-gel showed there were less epiglottic downfolding and better fiberoptic view of the glottis than cLMA. Overall agreement in insertion outcome for i-gel was 22/24 (91.7%) successes and 2/24(8.3%) failure and for cLMA, 19/24 (79.16%) successes and 5/24 (16.7%) failure in the first attempt. CONCLUSION: The i-gel is cheap, effective airway device which is easier to insert and has better clinical performance in the difficult airway management of the airway in the post burn contracture of the neck. Our study shows that i gel is feasible for emergency airway management in difficult airway situation with reduced neck movement and limited mouth opening in post burn neck. PMID- 23087457 TI - Comparison of haemodynamic responses to intubation: Flexible fibreoptic bronchoscope versus bonfils rigid intubation endoscope. AB - BACKGROUND: The flexible fibreoptic bronchoscope and bonfils rigid intubation endoscope are being widely used for difficult intubations. METHODS: The haemodynamic response to intubation under general anaesthesia was studied in 60 adult female patients who were intubated using either flexible fibreoptic bronchoscope or bonfils rigid intubation endoscope (30 in each group). Non invasive blood pressure and heart rate (HR) was recorded before induction of anaesthesia, immediately after induction, at the time of intubation and, thereafter, every minute for the next 5 min. The product of HR and systolic blood pressure (rate pressure product) at every point of time was also calculated. STATISTICAL ANALYSES: Graph pad prism, 5.0 statistical software, independent t test and repeated measure ANOVA test were used. RESULTS: Both bonfils rigid intubation endoscope and flexible fibreoptic bronchoscope required a similar time (less than 1 min) for orotracheal intubation. After intubation, there was a significant increase in HR, blood pressure and rate pressure product (P<0.001) in both the groups compared with the baseline and post-induction values. There was no significant difference in HR, blood pressure and rate pressure product at any of the measuring points or in their maximum values during observation between the two groups. The time required for recovery of systolic blood pressure and HR to post-induction value (+/-10%) was not significantly different between the two groups (more than 2 min). CONCLUSION: In female adults under general anaesthesia, bonfils rigid intubation endoscope and flexible fibreoptic bronchoscope require a similar time for successful orotracheal intubation and cause a similar magnitude of haemodynamic response. PMID- 23087458 TI - The effect on post-operative pain of intravenous clonidine given before induction of anaesthesia. AB - BACKGROUND: Treatment of acute post-thoracotomy pain is particularly important not only to keep the patient comfortable but also to minimize pulmonary complications. AIM: This study was designed to test the effect of pre-induction administration of clonidine, given as a single intravenous dose, on post operative pain scores and fentanyl consumption in patients after thoracic surgery. SETTING AND DESIGN: Tertiary referral centre. Prospective, randomised, double-blind, placebo-controlled trial. METHODS: Sixty patients were randomly allocated to receive clonidine (3 mcg/kg) or saline pre-operatively before induction of anaesthesia. The primary endpoint was pain on coughing (visual analogue scale (VAS) 0-100 mm) 120 min after surgery, time to first analgesic injection in the post-anaesthesia care unit (PACU) and 24-h fentanyl consumption. STATISTICAL ANALYSIS: For between-group comparisons, t-test and U-test were used as appropriate after checking normality of distribution. The incidence of complications between the groups was compared by Fisher's exact test. RESULTS: The post-operative VAS for the first 120 min and the fentanyl consumption at 24 h was significantly greater in the placebo group compared with the clonidine group (P<0.05). The sedation score was increased in the clonidine group during study drug infusion, but did not differ significantly on admission to the PACU. CONCLUSIONS: A single intravenous dose of clonidine (3 mcg/kg) given before induction of anaesthesia significantly reduced the post-operative VAS score in the initial period and fentanyl consumption during 24 h after thoracic surgery. PMID- 23087459 TI - Comparision of efficacy of sufentanil and fentanyl with low-concentration bupivacaine for combined spinal epidural labour analgesia. AB - OBJECTIVES: The highly lipid-soluble opioids, sufentanil and fentanyl, are used in combination with low-concentration bupivacaine to provide combined spinal epidural (CSE) analgesia during labour. We designed a prospective, randomized, single-blind study to compare the efficacy of these two opioids with bupivacaine in terms of the quality of analgesia, side-effects and maternal and foetal outcome. METHODS: Sixty parturients requesting labour analgesia were divided into two groups randomly. Group S (n=30) received bupivacaine heavy (2.5 mg) and sufentanil (5 mcg) intrathecally and 10 mL intermittent bolus of sufentanil 0.30 mcg/mL in bupivacaine 0.125% as epidural top-ups. Group F (n=30) received bupivacaine heavy (2.5 mg) and fentanyl (25 mcg) intrathecally and 10 mL intermittent bolus of fentanyl 2.5 mcg/mL in bupivacaine 0.125% as epidural top ups. Duration of intrathecal and epidural analgesia, mean duration between epidural top-ups and total analgesic requirements were noted. Pain and overall satisfaction scores were assessed with a 10-point visual scale. Mode of delivery and neonatal Apgar scores were recorded. RESULTS: Maternal demographic characteristics were comparable between the groups. Although CSE provided satisfactory analgesia in both the groups, parturients of group S had a significant prolongation of analgesia through the intrathecal route compared with parturients of group F. Incidence of caesarean, instrumental delivery did not differ between the groups. No difference in the incidence of motor blockade or cephalad extent of sensory analgesia was observed. Neonatal outcome and incidence of side-effects were similar in both the groups. CONCLUSION: We conclude that combined spinal epidural using sufentanil and fentanyl achieved high patient satisfaction and excellent labour analgesia without serious maternal or neonatal side-effects. Sufentanil provided a significantly longer duration of labour analgesia compared with fentanyl. PMID- 23087460 TI - Randomized double-blind comparison of prophylactic ketamine, clonidine and tramadol for the control of shivering under neuraxial anaesthesia. AB - BACKGROUND: Shivering is a common problem during neuraxial anaesthesia. Neuraxial anaesthesia impairs thermoregulatory control and up to a 56.7% incidence of shivering has been reported. AIM: To evaluate the effectiveness of prophylactic use of intravenous ketamine, clonidine and tramadol in control of shivering and to note any side-effects of the drugs used. SETTING AND DESIGN: Randomised double blind study. METHODS: This study was conducted in 200 ASA grade I and II patients. Neuraxial block was performed with 2.8 mL (14 mg) of 0.5% bupivacaine heavy in all patients. The patients were randomly allocated into four groups of 50 each to receive saline as placebo (group P), ketamine 0.5 mg/kg (group K), Clonidine 75 mcg (group C) and Tramadol 0.5 mg/kg (group T). Temperature and hemodynamic parameters were recorded at every 5-min interval. Shivering was graded from 0 to 4 grades and, if grade 3 shivering occurred, the study drug was considered as ineffective and intravenous pethidine 25 mg was given as rescue drug. STATISTICAL ANALYSIS: Data among groups was compared using one-way ANOVA. The incidence of shivering and side-effects were compared using the chi-square test. RESULTS: The incidence of grade 3 shivering showed a statistically significant difference (P=0.001) in group P (27/50) as compared with the other groups (group K=5/50, group C=2/50, group T=4/50). No drug showed any statistically significant advantage over the other. No major hemodynamic changes were seen with prophylactic use of test drugs; however, sedation score was significantly higher in group K (P<0.05) as compared with the other groups. CONCLUSION: The prophylactic use of ketamine, clonidine and tramadol were effective in preventing shivering during neuraxial anaesthesia without causing any major untoward side-effects. PMID- 23087461 TI - Mechanical and infectious complications of central venous catheterizations in a tertiary-level intensive care unit in northern India. AB - BACKGROUND: Central venous catheters (CVC) are associated with mechanical, infectious and thrombotic complications. AIMS: To study (a) the incidence of mechanical and infectious complications of CVC insertions and to compare, (b) the rates of these complications between the internal jugular venous (IJV) and the subclavian venous (SCV) accesses. SETTINGS AND DESIGN: An adult intensive care unit of a tertiary care hospital. Prospective, observational study. METHODS: All landmark-based CVC insertions performed between 1(st) October 2008 and 30(th) September 2009 were prospectively studied for mechanical and infectious complications. STATISTICAL ANALYSIS: SPSS software for Windows, Version SPSS 16.0, and Epi Info (3.5.1) software. RESULTS: Four hundred and eighty central venous catheterizations were studied (IJV route, 241 and SCV route, 239). Mechanical complications occurred in 86 patients (17.9%, bleeding complications 48, catheter-related complications-27 and pneumothorax-11). The IJV route was associated with a significantly higher incidence of bleeding complications (P=0.009). Forty-seven patients had infectious complications (9.79%), like exit site infections (n=17), catheter tip infections (n=22) and catheter-related bloodstream infections (CRBSIs) (n=8). The risks of infectious complications increased significantly if the CVC was in situ for longer than 7 days (P=0.009), especially with IJV cannulae. The incidence density of CVC tip infections was 7.67 per 1000 catheter days and of CRBSIs was 2.79 per 1000 catheter days. CONCLUSIONS: Bleeding complications occurred more frequently with IJV insertions and infectious complications occurred more commonly in cannulae that were left in situ for longer than 7 days. PMID- 23087462 TI - Echo-guided estimation of formula for paravertebral block in neonates, infants and children till 5 years. AB - AIMS: The aim of the study was to derive a clinically useful formula for paravertebral block for thoracic, lumbar (L1) and cervical level (C6) as per the ultrasound-guided measurements in neonates, infants and children up to 5 years of age. SETTINGS AND DESIGN: Observational study. METHODS: Seventy-five patients from 2 days to 60 months were included. Paravertebral transverse ultrasound scans at cervical (C6), thoracic (T1-12) and lumbar (L1) regions were viewed to determine the optimal insertion point and depth for performing paravertebral blocks. The lateral distance from the spinous process to the insertion point and the depth from the insertion point to the paravertebral space or reference point (point just anterior to the transverse process) were measured. STATISTICAL ANALYSIS: Data was analyzed using the SPSS (V 10.0) package. Preliminary data was collected with the actual values of paravertebral parameters and weight and age. Initially, Pearson Bivariate Correlation Coefficients were calculated between parameters and age and weight so as to predict paravertebral parameters with the help of weight and age. As there were statistically significant associations between parameters and age and weight, an attempt was made to predict parameters with the help of age and weight. Multiple regression method (forward) was applied by taking parameters as dependent variables and age and weight as independent variables. RESULTS: Age and weight correlated very well (statistically significant) with paravertebral parameters; hence, prediction (regression) equations were calculated as: Prediction (regression) equation: C6A=0.005 * wt + 0.005 * age + 1.31 C6B=0.009 * wt + 0.002 * age + 1.78 T1-12 A=0.02 * wt + 0.003 * age + 0.93 T1 to 12 B=0.03 * wt + 0.03 * age + 1.02 L1A=0.03 * wt + 0.02 * age + 0.91 L1B=0.05 * wt + 0.02 * age + 0.94 CONCLUSIONS: We could derive equations to predict the values for paravertebral blocks in centimetres at different levels in the study population. PMID- 23087463 TI - Pulmonary oedema in a patient undergoing vitreo-retinal surgery under peribulbar block. AB - A 42-year-old diabetic and hypertensive male with good effort tolerance was administered peribulbar block for vitreo-retinal surgery. Ten millilitres of an equal mixture of 2% lignocaine and 0.5% bupivacaine was administered for the block after ascertaining negative aspiration for blood. Inadequate akinesia of the eye necessitated further supplementation with 4 mL of local anaesthetic (LA) mixture. Thirty minutes later, the patient complained of uneasiness, respiratory distress and desaturated despite oxygen supplementation. He was found to be in pulmonary oedema. He subsequently developed a weak thready pulse, became unresponsive, apnoeic and had generalized tonic clonic convulsions. Immediately, atropine 0.6 mg, followed by midazolam, intubation, mechanical ventilation, morphine and furosemide, were administered intravenously. Spontaneous respiration returned in 20 minutes and he started responding to verbal commands 90 minutes later. He was weaned off the ventilator the next morning. There was no evidence of an ischemic myocardial event and non-contrast computerized tomography scan of the head was normal. The reversible cardiorespiratory arrest, associated convulsions and loss of consciousness were suggestive of LA toxicity. Pulmonary oedema manifesting as respiratory distress and desaturation can be the initial manifestation of LA toxicity in patients with pre-existing cardiovascular disease undergoing eye surgery under peribulbar block. PMID- 23087464 TI - Anaesthetic consideration in patients with Gorham's syndrome: A case report and review of the literature. AB - Gorham's syndrome (GS) is a rare disorder characterized by proliferation of vascular channels resulting in destruction and resorption of osseous matrix leading to bone loss. Bone loss leads to joint instability and problems during airway management and positioning for surgery. Respiratory involvement further complicates anaesthesia management. We report the anaesthetic care of a 21-year old male patient of known GS for spine decompression and fusion in prone position. Airway management, induction technique, pathophysiology of the disease, drug selection and other concerns of anaesthesia for major spine surgery has been discussed reviewing the sparse literature available. PMID- 23087465 TI - Anaesthetic management in Gorlin-Goltz syndrome. AB - Gorlin-Goltz syndrome is a rare autosomal-dominant syndrome related to mutation in "Patched" tumour suppressor gene on chromosome 9. Basocellular carcinomas, odontogenic keratocysts, palmar and/or plantar pits and ectopic calcifications of the falx cerebri are its major features, along with more than 100 minor features. Odontogenic cysts, notorious for recurrence, can make endotracheal intubation difficult, requiring modification of the standard intubation technique. We report such a case managed successfully by awake fibreoptic intubation. Direct laryngoscopy under anaesthesia later confirmed that it was a good decision. PMID- 23087466 TI - Acute methaemoglobinaemia initially treated as organophosphate poisoning leading to atropine toxicity. AB - A case of unknown compound poisoning is presented. It was initially treated as organophosphate poisoning with lack of response. A timely diagnosis of acute methaemoglobinaemia and iatrogenic atropine toxicity was made based on clinical evaluation. Treatment of methaemoglobinaemia using oral methylene blue and of atropine toxicity with supportive measures could save the patient. PMID- 23087467 TI - Anaesthetic management of a patient with Cushing's syndrome and non-compaction cardiomyopathy for adrenal tumour resection. AB - We describe the anaesthetic management of adrenalectomy in a patient with Cushing's syndrome due to adrenal mass with coexisting non-compaction cardiomyopathy. The problems due to hypersecretion of cortisol in Cushing's syndrome were compounded by the association of a rare form of genetic cardiomyopathy with very few guidelines regarding the perioperative management. The knowledge about the pathophysiological changes, clinical presentation and complications in non-compaction cardiomyopathy is essential for planning the anaesthetic care, and the aim of this presentation is to highlight the issues crucial for management of such challenging patients. PMID- 23087468 TI - Cardiac arrest following ventilator fire: A rare cause. AB - Operating room fires are rare events, but when occur they result in serious and sometimes fatal consequences. Anaesthesia ventilator fire leading to cardiac arrest is a rare incident and has not been reported. We report a near catastrophic ventilator fire leading to cardiac arrest in a patient undergoing subtotal thyroidectomy. In the present case sparks due to friction or electrical short circuit within the ventilator might have acted as source of ignition leading to fire and explosion in the oxygen rich environment. The patient was successfully resuscitated and revived with uneventful recovery and no adverse sequelae. The cardiac arrest was possibly due to severe hypoxia resulting from inhalation of smoke containing high concentrations of carbon monoxide and other noxious gases. PMID- 23087469 TI - The whistling adapter: A device mimicking complication. PMID- 23087470 TI - Perioperative management of term pregnant patient with Guillian Barre syndrome. PMID- 23087471 TI - Trade names that have become generic names in anaesthesia. PMID- 23087472 TI - Use of dexmedetomidine infusion in anaesthesia for awake craniotomy. PMID- 23087473 TI - Central venous catheter rotation malposition: An unusual presentation. PMID- 23087474 TI - Unusual injury sustained by an escort in a radiology suite: Correlation with anaesthesiologists' plight. PMID- 23087475 TI - An innovative use of the flexible fibreoptic scope to identify the tracheo bronchial tree intraoperatively for closure of a bronchopleural fistula. PMID- 23087476 TI - Psoas compartment block for intramedullary supracondylar nailing for fracture shaft femur in an 80-year-old patient with severe ischaemic heart disease, hypertension, COPD and anaemia. PMID- 23087477 TI - Facilitated nasotracheal intubation in patient with restricted mouth opening aided by D-blade of C-Mac videolaryngoscope and Schroeder's directional stylet. PMID- 23087478 TI - Anaesthetic management of an infant with vallecular cyst: A challenging situation. PMID- 23087479 TI - Should ultrasonography check be routinely done following removal of femoral vascular catheter in patients with end-stage renal disease? PMID- 23087480 TI - Catheter malposition in infants: A preventable complication. PMID- 23087481 TI - Rhabdomyolysis complicating non-invasive blood pressure measurement. PMID- 23087482 TI - Management of heparin resistance in an emergency cardiac surgical patient. PMID- 23087483 TI - A simple, feedback-based simulation model for ultrasound-guided regional anaesthesia. PMID- 23087484 TI - A rare potentially hazardous malposition of the nasotracheal tube. PMID- 23087485 TI - A rare, potentially hazardous malposition of the nasotracheal tube. PMID- 23087486 TI - The emergence of complexity in prosody and syntax. AB - The relation between prosody and syntax is investigated here by tracing the emergence of each in a new language, Al-Sayyid Bedouin Sign Language. We analyze the structure of narratives of four signers of this language: two older second generation signers, and two about 15 years younger. We find that younger signers produce prosodic cues to dependency between semantically related constituents, e.g., the two clauses of conditionals, revealing a type and degree of complexity in their language that is not frequent in that of the older pair. In these younger signers, several rhythmic and (facial) intonational cues are aligned at constituent boundaries, indicating the emergence of a grammatical system. There are no overt syntactic markers (such as complementizers) to relate clauses; prosody is the only clue. But this prosodic complexity is matched by syntactic complexity inside propositions in the younger signers, who are more likely to use pronouns as abstract grammatical markers of arguments, and to combine predicates with their arguments within in a constituent. As the prosodic means emerge for identifying constituent types and signaling dependency relations between them, the constituents themselves become increasingly complex. Finally, our study shows that the emergence of grammatical complexity is gradual. PMID- 23087487 TI - Quadratic semiparametric Von Mises calculus. AB - We discuss a new method of estimation of parameters in semiparametric and nonparametric models. The method is based on U-statistics constructed from quadratic influence functions. The latter extend ordinary linear influence functions of the parameter of interest as defined in semiparametric theory, and represent second order derivatives of this parameter. For parameters for which the matching cannot be perfect the method leads to a bias-variance trade-off, and results in estimators that converge at a slower than n(-1/2)-rate. In a number of examples the resulting rate can be shown to be optimal. We are particularly interested in estimating parameters in models with a nuisance parameter of high dimension or low regularity, where the parameter of interest cannot be estimated at n(-1/2)-rate. PMID- 23087488 TI - Estimating the optimal dynamic antipsychotic treatment regime: Evidence from the sequential multiple assignment randomized CATIE Schizophrenia Study. AB - Treatment of schizophrenia is notoriously difficult and typically requires personalized adaption of treatment due to lack of efficacy of treatment, poor adherence, or intolerable side effects. The Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) Schizophrenia Study is a sequential multiple assignment randomized trial comparing the typical antipsychotic medication, perphenazine, to several newer atypical antipsychotics. This paper describes the marginal structural modeling method for estimating optimal dynamic treatment regimes and applies the approach to the CATIE Schizophrenia Study. Missing data and valid estimation of confidence intervals are also addressed. PMID- 23087489 TI - Rhodium catalyzed synthesis of isoindolinones via C-H activation of N benzoylsulfonamides. AB - An efficient approach to a wide range of isoindolinones, including 3 monosubstituted and 3,3-disubstituted isoindolinones, from the annulation of N benzoylsulfonamides with olefins and diazoacetate has been developed. The transformation is broadly compatible with both terminal and internal olefins. Moreover, diazoacetate is for the first time incorporated into an amide-directed C-H functionalization reaction. Specifically, the rhodium complex [{RhCl(2)Cp*}(2)] enables the in situ dimerization of diazoacetate in addition to its role in catalyzing C-H functionalization/cross-coupling. PMID- 23087490 TI - On the Nature and Strategies of Organized Interests in Health Care Policy Making. AB - Relying on a sweeping review of the literature on interest group influence in health care policy making, we propose a basic definition and a typology of interest groups in provincial health care policy making. Then, using Milbrath's communication framework, we analyze organized interests' strategies for influencing policy making. This article is a modest attempt to cross-fertilize the group theory and resource dependency literature. This theoretical framework allows us to explore many of the recurring questions about groups' origins and strategies from an original standpoint. PMID- 23087491 TI - SYNTHESIS AND BIOLOGICAL EVALUATION OF BIARYL ANALOGS OF ANTITUBULIN COMPOUNDS. AB - This paper reports the synthesis of methanones and esters bearing different substitution patterns as spacer groups between aromatic rings. This series of compounds can be considered phenstatin analogs. Two of the newly synthesized compounds, 5a and 5c, strongly inhibited tubulin polymerization and the binding of [(3)H] colchicine to tubulin, suggesting that, akin to phenstatin and combretastatin A-4, they can bind to tubulin at the colchicine site. PMID- 23087492 TI - Attention and Memory Biases in Social Anxiety Disorder: The Role of Comorbid Depression. AB - Cognitive biases play an important role in the onset and maintenance of Social Anxiety Disorder (SAD). Few studies, however, have examined the role of comorbid Major Depressive Disorder (MDD) in the processing of emotional material. In addition, little is known about the relation among different cognitive biases. In the current study, 73 participants (54.79% female) completed an emotion face dot probe task followed by a recognition memory test. Compared to participants with SAD, participants with comorbid SAD and MDD oriented away from supraliminally presented angry faces. Subsequently, SAD participants with and without comorbidity recognized fewer angry faces than non-disordered controls. Furthermore, attention biases for subliminally presented stimuli predicted recognition accuracy only for comorbid participants. These results suggest that the presence of comorbid MDD affects attentional orienting in SAD participants. In addition, it highlights the interconnectedness of attention and memory biases for comorbid participants. PMID- 23087493 TI - Work Values of University Students in Chinese Mainland, Taiwan, and Hong Kong. AB - Leuty and Hansen (Journal of Vocational Behavior 79:379-390, 2011) identified six domains of work values in undergraduate students in the West. The review undertaken in this paper suggests that the factor structure of work values of university students in Mainland China, Taiwan and Hong Kong essentially matches these six domains, except for the omission of 'Family Maintenance' and Wang's (Indigenous Psychological Research in Chinese Societies 2:206-250, 1993) 'Instrumental Values.' This suggests some commonality in the work values construct between the East and West, but there are a few subtle differences. It is argued that such differences heighten the need for measurement scales with context-specific and society-specific items when examining work values in different settings. PMID- 23087494 TI - Dynamical quorum-sensing in oscillators coupled through an external medium. AB - Many biological and physical systems exhibit population-density dependent transitions to synchronized oscillations in a process often termed "dynamical quorum sensing". Synchronization frequently arises through chemical communication via signaling molecules distributed through an external medium. We study a simple theoretical model for dynamical quorum sensing: a heterogenous population of limit-cycle oscillators diffusively coupled through a common medium. We show that this model exhibits a rich phase diagram with four qualitatively distinct physical mechanisms that can lead to a loss of coherent population-level oscillations, including a novel mechanism arising from effective time-delays introduced by the external medium. We derive a single pair of analytic equations that allow us to calculate phase boundaries as a function of population density and show that the model reproduces many of the qualitative features of recent experiments on BZ catalytic particles as well as synthetically engineered bacteria. PMID- 23087495 TI - Estimation of the disease-specific diagnostic marker distribution under verification bias. AB - We consider the estimation of the parameters indexing a parametric model for the conditional distribution of a diagnostic marker given covariates and disease status. Such models are useful for the evaluation of whether and to what extent a marker's ability to accurately detect or discard disease depends on patient characteristics. A frequent problem that complicates the estimation of the model parameters is that estimation must be conducted from observational studies. Often, in such studies not all patients undergo the gold standard assessment of disease. Furthermore, the decision as to whether a patient undergoes verification is not controlled by study design. In such scenarios, maximum likelihood estimators based on subjects with observed disease status are generally biased. In this paper, we propose estimators for the model parameters that adjust for selection to verification that may depend on measured patient characteristics and additonally adjust for an assumed degree of residual association. Such estimators may be used as part of a sensitivity analysis for plausible degrees of residual association. We describe a doubly robust estimator that has the attractive feature of being consistent if either a model for the probability of selection to verification or a model for the probability of disease among the verified subjects (but not necessarily both) is correct. PMID- 23087496 TI - Timing in thick silicon detectors - an update. AB - Thick silicon detectors are becoming widely used with reliable detectors available. They are often considered as a part of coincidence setup, where the timing resolution is of a crucial importance. Since over-biasing of thick detectors is sometimes unpractical, the timing resolution can be compromised in thick detectors. For this article the electric and Ramo fields in a 1.4 by 1.4 mm(2) pad size and 1 mm thick pad detector were calculated. GEANT4 was used to determine the tracks of the interaction electron produced in photon interactions, and the drift of ionized carriers in the detector was simulated. The signals were processed using a virtual preamplifier, a CR-RC shaper with a shaping time of 200 ns and a leading edge discriminator. The distributions of delay of the trigger after the event were compared to the measurements and a good agreement was found, allowing for additional noise in experimental setup. We proposed and evaluated an alternative readout strategy reading signals from 9 nearest pads which greatly reduces the effects of inhomogeneous Ramo field on the timing resolution. PMID- 23087497 TI - Investigation of Crystal Surface Finish and Geometry on Single LYSO Scintillator Detector Performance for Depth-of-Interaction Measurement with Silicon Photomultipliers. AB - Depth of Interaction (DOI) information can improve quality of reconstructed images acquired from Positron Emission Tomography (PET), especially in high resolution and compact scanners dedicated for breast, brain, or small animal imaging applications. Additionally, clinical scanners with time of flight capability can also benefit from DOI information. One of the most promising methods of determining DOI in a crystal involves reading the signal from two ends of a scintillation crystal, and calculating the signal ratio between the two detectors. This method is known to deliver a better DOI resolution with rough crystals compared to highly polished crystals. However, what is still not well studied is how much of a tradeoff is involved between spatial, energy, temporal, and DOI resolutions as a function of the crystal surface treatment and geometry with the use of Silicon Photomultipliers (SiPM) as the photo detectors. This study investigates the effects of different crystal surface finishes and geometries on energy, timing and DOI resolutions at different crystal depths. The results show that for LYSO scintillators of 1.5*1.5*20 mm(3) and 2*2*20 mm(3) with their surfaces finished from 0.5 to 30 micron roughness, almost the same energy and coincidence timing resolutions were maintained, around 15% and 2.4 ns respectively across different crystal depths, while the DOI resolutions were steadily improved from worse than 5 mm to better than 2 mm. They demonstrate that crystal roughness, with proper surface preparing, does not have a significant effect on the energy and coincidence timing resolutions in the crystals examined, and there does not appear to be a tradeoff between improving DOI resolution and degrading other detector performances. These results will be valuable to guide the selection of crystal surface conditions for developing a DOI measurable PET detector with a full array of LYSO scintillators coupled to SiPM arrays. PMID- 23087498 TI - Saying "that" in dialogue: The influence of accessibility and social factors on syntactic production. AB - Previous evidence suggests that when speakers produce sentences from memory or as picture descriptions, their choices of sentence structure are influenced by how easy it is to retrieve sentence material (accessibility). Three experiments assessed whether this pattern holds in naturalistic, interactive dialogue. Pairs of speakers took turns asking each other questions, the responses to which allowed mention of an optional "that" before either repeated (accessible) or unrepeated (inaccessible) material. Speakers' "that" mention was not sensitive to the repetition (accessibility) manipulation. Instead, "that" mention was sensitive to social factors: Speakers said "that" more when adopting another's perspective rather than one's own, and tended to say "that" more when attributing emotions to oneself rather than another. A fourth experiment confirmed that in a memory task, the original pattern is observed. These results suggest that "that" mention is sensitive to the cognitive forces that operate within a production task; in dialogue settings, social factors were especially influential. PMID- 23087499 TI - Alternaria toxins alternariol and alternariol monomethyl ether in grain foods in Canada. AB - Alternaria alternata has been reported to be the most common fungus on Canadian Western wheat. The Alternaria toxins alternariol (AOH) and alternariol monomethyl ether (AME) are mutagenic in vitro and there is also limited evidence for carcinogenic properties. They have been found in wheat from Europe, Argentina, China and Australia, but they have not been looked for in Canadian grains or grain foods. In the present study, 83 samples of grain-based food sold in Canada, including flour, bran, breakfast cereals, infant cereals and bread, were analysed for AOH and AME using extraction with methanol, clean-up on combined aminopropyl/C18 solid phase extraction (SPE) columns, and liquid chromatography (LC) with tandem mass spectrometric (MS/MS) determination. The overall average recoveries of AOH and AME from a variety of spiked cereal foods (n = 13) were 45 +/- 9% and 53 +/- 9%, which could be attributed mainly to MS matrix effects The instrumental limits of detection (LOD) were 0.34 ng/g and 0.13 ng/g for AOH and AME, respectively, and the instrumental limits of quantitation (LOQ) were 1.1 and 0.43 ng/g. Of 83 samples analysed, 70 were positive for AOH (up to 63 ng/g, in a soft wheat bran) and 64 contained AME (up to 12 ng/g in a bran-based breakfast cereal). Of particular interest was the presence of AOH and/or AME in 27 out of 30 infant foods (up to 4.4 ng/g and 9.0 ng/g, respectively, in a sample of multigrain cereal). PMID- 23087501 TI - Basic biostatistics for post-graduate students. AB - Statistical methods are important to draw valid conclusions from the obtained data. This article provides background information related to fundamental methods and techniques in biostatistics for the use of postgraduate students. Main focus is given to types of data, measurement of central variations and basic tests, which are useful for analysis of different types of observations. Few parameters like normal distribution, calculation of sample size, level of significance, null hypothesis, indices of variability, and different test are explained in detail by giving suitable examples. Using these guidelines, we are confident enough that postgraduate students will be able to classify distribution of data along with application of proper test. Information is also given regarding various free software programs and websites useful for calculations of statistics. Thus, postgraduate students will be benefitted in both ways whether they opt for academics or for industry. PMID- 23087502 TI - Nitric oxide in the hippocampal cortical area interacts with naloxone in inducing pain. AB - OBJECTIVE: Role of nitric oxide (NO) in reversing morphine anti-nociception has been shown. However, the interaction between NO and naloxone-induced pain in the hippocampus is unknown. The present study aimed to investigate the involvement of molecule NO in naloxone-induced pain and its possible interaction with naloxone into cortical area 1 (CA1) of hippocampus. MATERIALS AND METHODS: Male Wistar rats (250-350 g), provided by Pasteur Institute of Iran, were housed two per cage with food and water ad libitum. The animals' skulls were cannulated bilaterally at coordinates adjusted for CA1 of hippocampus (AP: -3.8; L: +/-1.8- 2.2: V: 3) by using stereotaxic apparatus. Each experimental group included 6-8 rats. To induce inflammation pain, the rats received subcutaneous (s.c.) injections of formalin (50 MUL at 2.5%) once prior to testing. To evaluate the nociceptive effect of naloxone, the main narcotic antagonist of morphine (0.1-0.4 mg/kg) was injected intraperitoneally (i.p.) 10 min before injection of formalin. Injections of L-arginine, a precursor of NO, and N(G)-Nitro-L-arginine Methyl Ester (L NAME), an inhibitor of NO synthase (NOS), intra-CA1, were conducted orderly prior to the administration of naloxone. The pain induction was analyzed by analysis of variance (ANOVA). RESULTS: Naloxone at the lower doses caused a significant (P<0.01) pain in the naloxone-treated animals. However, pre-administration (1-2 min) of L-arginine (0.04, 0.08, 0.15, 0.3, 1.0, and 3.0 MUg/rat, intra-CA1) reversed the response to naloxone. But, the response to L-arginine was blocked by pre-microinjection (1-2 min) of L-NAME (0.15, 0.3, 1.0, and 3.0 MUg/rat), whilst, L-arginine or L-NAME alone did not induce pain behavior. CONCLUSION: NO in the rat hippocampal CA1 area is involved in naloxone-induced nociception. PMID- 23087503 TI - The in vitro anti-viral potential of Setarud (IMODTM), a commercial herbal medicine with protective activity against acquired immune deficiency syndrome in clinical trials. AB - OBJECTIVES: Setarud (IMODTM) is a herbal medicine with beneficial effect for patients suffering Human immunodeficiency virus (HIV) infection and has been approved for IV (intra venues) injection. The beneficial effect of IMOD administration for acquired immune deficiency syndrome (AIDS) patient has been proved in previous clinical trials. Here the in vitro inhibitory effect of IMOD against HIV-1, Herpes simplex virus (HSV) and murine leukemia viruses (MLV) was evaluated. MATERIALS AND METHODS: HIV single cycle replication and HSV plaque reduction assays were used to evaluate the anti-viral effect. The level of HIV replication was monitored by p24 capture Enzyme-linked immunosorbent assay (ELISA). The single round infection [with green fluorescent protein (GFP) reporter MLV and HIV], virucidal and time-of-additions (HSV) assays were utilized to determine the mode of anti-viral activity. The toxicity of IMOD for cells was monitored by XTT (sodium 3_-[1 (phenylaminocarbonyl)- 3,4-tetrazolium]-bis (4 methoxy-6-nitro)benzene sulfonic acid) cell proliferation assay kit. RESULTS: IMOD inhibited 50% of HIV-1 and HSV replication (IC(50)) at 6.5 * 10(-4) and 4.3 * 10(-3)V/V concentrations, respectively. The IC(50) value against HIV-1 and MLV infection were 6 * 10(-4)V/V and 4.9 * 10(-4)V/V. Virucidal assay showed that IMOD reduces the potency of HIV and HSV particles to 41 and 54% of control, respectively. Time-of-addition study revealed that IMOD inhibits the replication of HSV at a stage after penetration of virions to the target cells. CONCLUSIONS: Data from this study indicate that IMOD has significant anti-viral activity against HIV, HSV and MLV. Setarud could be subjected to further investigation after isolation of the constituents and determination of the toxic components. PMID- 23087504 TI - Antidepressant-like activity of anthocyanidins from Hibiscus rosa-sinensis flowers in tail suspension test and forced swim test. AB - AIM: Flowers of Hibiscus rosa-sinensis Linn (Malvaceae) popularly known as "China rose flowers" contain flavonoids. Flavonoids have been found to have antidepressant activity. The aim of the present study is to evaluate the antidepressant activity of flavonoids in H. rosa-sinensis flowers with possible involvement of monoamines. MATERIALS AND METHODS: Anti-depressant activity of methanol extract containing anthocyanins (MHR) (30 and 100 mg/kg) and anthocyanidins (AHR) (30 and 100 mg/ kg) of H. rosa-sinensis flowers were evaluated in mice using behavioral tests such as tail suspension test (TST) and forced swim test (FST). The mechanism of action involved in antidepressant activity was investigated by observing the effect of extract after pre-treatment with low dose haloperidol, prazosin and para-chlorophenylalanine (p-CPA). RESULTS: Present study exhibited significant decrease in immobility time in TST and FST, similar to that of imipramine (10 mg/kg, i.p.) which served as a positive control. The extract significantly attenuated the duration of immobility induced by Haloperidol (50 MUg/ kg, i.p., a classical D(2)-like dopamine receptor antagonist), Prazosin (62.5 MUg/kg, i.p., an alpha(1)-adrenoceptor antagonist) and p-chlorophenylalanine (100 mg/kg, i.p., * 3 days; an inhibitor of serotonin synthesis) in both TST and FST. CONCLUSION: It can be concluded that MHR and AHR possess potential antidepressant activity (through dopaminergic, noradrenergic and serotonergic mechanisms) and has therapeutic potential in the treatment of CNS disorders and provides evidence at least at preclinical levels. PMID- 23087505 TI - Insulin catalyzes the curcumin-induced wound healing: an in vitro model for gingival repair. AB - OBJECTIVES: Human gingival fibroblasts (hGFs) play a major role in the maintenance and repair of gingival connective tissue. The mitogen insulin with IGFs etc. synergizes in facilitating wound repair. Although curcumin (CUR) and insulin regulate apoptosis, their impact as a combination on hGF in wound repair remains unknown. Our study consists of: 1) analysis of insulin-mediated mitogenesis on CUR-treated hGF cells, and 2) development of an in vitro model of wound healing. MATERIALS AND METHODS: Apoptotic rate in CUR-treated hGF cells with and without insulin was observed by AnnexinV/PI staining, nuclear morphological analysis, FACS and DNA fragmentation studies. Using hGF confluent cultures, wounds were mechanically created in vitro and incubated with the ligands for 48 h in 0.2% fetal bovine serum DMEM. RESULTS: CUR alone showed dose dependent (1-50 MUM) effects on hGF. Insulin (1 MUg/ml) supplementation substantially enhanced cell survival through up-regulation of mitogenesis/anti apoptotic elements. CONCLUSIONS: The in vitro model for gingival wound healing establishes that insulin significantly enhanced wound filling faster than CUR treated hGF cells over 48 h. This reinforces the pivotal role of insulin in supporting CUR-mediated wound repair. The findings have significant bearing in metabolic dysfunctions, e.g. diabetes, atherosclerosis, etc., especially under Indian situations. PMID- 23087506 TI - A quick inexpensive laboratory method in acute paracetamol poisoning could improve risk assessment, management and resource utilization. AB - OBJECTIVES: Acute paracetamol poisoning is an emerging problem in Sri Lanka. Management guidelines recommend ingested dose and serum paracetamol concentrations to assess the risk. Our aim was to determine the usefulness of the patient's history of an ingested dose of >150 mg/kg and paracetamol concentration obtained by a simple colorimetric method to assess risk in patients with acute paracetamol poisoning. MATERIALS AND METHODS: Serum paracetamol concentrations were determined in 100 patients with a history of paracetamol overdose using High Performance Liquid Chromatography (HPLC); (reference method). The results were compared to those obtained with a colorimetric method. The utility of risk assessment by reported dose ingested and colorimetric analysis were compared. RESULTS: The area under the receiver operating characteristic curve for the history of ingested dose was 0.578 and there was no dose cut-off providing useful risk categorization. Both analytical methods had less than 5% intra- and inter batch variation and were accurate on spiked samples. The time from blood collection to result was six times faster and ten times cheaper for colorimetry (30 minutes, US$2) than for HPLC (180 minutes, US$20). The correlation coefficient between the paracetamol levels by the two methods was 0.85. The agreement on clinical risk categorization on the standard nomogram was also good (Kappa = 0.62, sensitivity 81%, specificity 89%). CONCLUSIONS: History of dose ingested alone greatly over-estimated the number of patients who need antidotes and it was a poor predictor of risk. Paracetamol concentrations by colorimetry are rapid and inexpensive. The use of these would greatly improve the assessment of risk and greatly reduce unnecessary expenditure on antidotes. PMID- 23087507 TI - Platycodon grandiflorus alleviates DNCB-induced atopy-like dermatitis in NC/Nga mice. AB - OBJECTIVE: To investigate the therapeutic effect of crude extract from Platycodon grandiflorum (PG) roots on atopic dermatitis (AD)-like skin lesions in NC/Nga mice. MATERIALS AND METHODS: To develop atopic dermatitis-like lesions, 200 MUl of 0.3% 1-chloro-2, 4-dinitro benzene (DNCB) in acetone/olive oil (3:1) was applied 3 times a week for 2 weeks on the shaved skin of their backs. PG extract was dissolved in saline and orally administrated at concentrations of 300 and 500 mg/kg every day for 2 weeks. The therapeutic effect of PG on AD-like skin lesions was assessed by measuring skin severity scores and epithermal thickness, serum total immunoglobulin (Ig) E, histopathological findings for inflammatory cells including mast cells, macrophage and T cells, and mRNA expression of various cytokines related to the inflammatory and allergic response. The significance of inter-group differences was analyzed using the ANOVA test. Data were considered to be significant when P < 0.05 or P < 0.01. RESULTS: Oral treatment of PG suppressed AD-like skin lesions according to the assessment of skin severity and epithermal thickness in the DNCB-treated NC/Nga mice. This alleviation was further correlated with a reduction of elevated serum total IgE or cytokine mRNA in the PG-treated group compared with vehicle-treated positive group. In addition, infiltrated inflammatory cells decreased on the skin lesions compared with vehicle-treated group. CONCLUSION: These results suggest that PG may have a potential therapeutic effect for AD via the inhibition of both inflammatory and allergic reaction. PMID- 23087508 TI - Experimental evaluation of analgesic and anti-inflammatory activity of simvastatin and atorvastatin. AB - AIM: The aim of this study is to evaluate the analgesic and anti-inflammatory activities of atorvastatin and simvastatin in different experimental models in mice and rats. MATERIALS AND METHODS: Analgesic activity of simvastatin and atorvastatin was assessed in tail flick model in rats (n = 6), where it was compared with aspirin and tramadol and in acetic acid induced writhing in mice (n = 6), where it was compared with aspirin. Anti-inflammatory activity of statins was evaluated using carrageenin induced paw edema and formalin induced arthritis in rats. RESULTS: In the tail flick method, analgesic effect of tramadol was significantly more than the other drugs except at two observation times, when it was comparable to simvastatin and atorvastatin. Effect of simvastatin was found to be comparable to aspirin. In acetic acid induced writhing method, analgesic activity of simvastatin was comparable to that of aspirin while that of atorvastatin was significantly less. In carrageenin induced paw edema in rats, both simvastatin and atorvastatin showed anti-inflammatory activity which was comparable to aspirin. Both the statins exhibited significant anti-inflammatory activity (P < 0.01) in formalin induced arthritis model though less than aspirin (P < 0.05). CONCLUSION: The results of this study if substantiated by further experimental and clinical research suggest that simvastatin and atorvastatin may play an adjuvant role, which may be particularly beneficial in the treatment of inflammatory disorders, especially when there is coexisting dyslipidemia. PMID- 23087509 TI - Vasoactive agent buflomedil up-regulated expression of vascular endothelial growth factor in a rat model of sciatic nerve crush injury. AB - OBJECTIVES: To study the effect of Buflomedil on the morphological repair on crush injury of sciatic nerve and also the expression of vascular endothelial growth factor (VEGF). MATERIALS AND METHODS: Rat sciatic nerves were crushed by pincers. All of the 400 Sprague Dawley rats were randomly divided into: Sham operated; saline; saline + VEGF-antibody; Buflomedil; and Buflomedil + VEGF antibody groups. The expression of VEGF in dorsal root ganglia (DRGs), following crush injury to sciatic nerves, was studied by RT-PCR, immunohistochemistry. The effects of Buflomedil on expression of VEGF and repair of neural pathology were also evaluated. RESULTS: VEGF mRNA was significantly increased in Buflomedil and Buflomedil + VEGF-antibody groups, compared with other groups. The number of VEGF positive neurons was significantly increased in the Buflomedil and the saline groups. Besides, Buflomedil also caused less pathological changes in DRGs. CONCLUSIONS: The vasoactive agent Buflomedil may decrease the pathological lesion and improve the functional rehabilitation of peripheral nerves, which may correlate to upregulation of the expression of VEGF, following crush injury to the peripheral nerves. PMID- 23087510 TI - Effect of anti-tuberculosis therapy on polymorphic drug metabolizing enzyme CYP2C9 using phenytoin as a probe drug. AB - OBJECTIVES: Patients on anti-tuberculosis therapy (ATT) are more prone to drug interactions in the presence of coexisting illnesses which warrant drug therapy. Rifampicin is a strong CYP enzyme inducer while isoniazid is a potent CYP inhibitor. The objective of the study was to find the net effect of one month ATT on CYP2C9 enzyme and to correlate it with respect to the CYP2C9 genetic polymorphisms. MATERIALS AND METHODS: Forty eight newly diagnosed tuberculosis patients were included in the study based on the inclusion-exclusion criteria. Before commencing ATT, they were given a single dose of phenytoin 300 mg as a probe drug for CYP2C9. Blood sample was collected after three hours to carry out CYP2C9 genotyping by PCR-RFLP method. Phenotyping for CYP2C9 enzyme was done by measuring the ratio of phenytoin and its metabolite p-HPPH (para hydroxy phenyl hydantoin) by reverse phase HPLC (high performance liquid chromatography) method before and after one month of ATT. RESULTS: In the CYP2C9*1*1 genotype, the mean plasma concentrations of phenytoin before and after one month of ATT were 5.2 +/- 0.3 MUg/ml and 3.5 +/- 0.4 MUg/ml respectively, a reduction by 33% showing significant induction (P < 0.001). There was also significant decrease in the metabolic ratio after one month of ATT from 23.2 +/- 4.8 to 10.1 +/- 1.9 (P < 0.001). The metabolic ratio was also observed to reduce significantly (P < 0.05) when the CYP2C9*1*2, CYP2C9*1*3, and CYP2C9*3*3 data were pooled together. CONCLUSION: The presence of polymorphisms in the CYP2C9 gene does not affect the induction potential of ATT. PMID- 23087511 TI - Evaluation of anxiolytic effect of Erythrina mysorensis Gamb. in mice. AB - AIM AND OBJECTIVES: To evaluate anxiolytic effect of stem bark ethanol and chloroform extracts of Erythrina mysorensis in mice. MATERIALS AND METHODS: The anxiolytic activity was examined by using the elevated plus maze (EPM) and open field test (OFT), and motor coordination by rotarod test (RRT). Twenty four Swiss albino male mice were divided into four groups of six mice each. Group 1 received vehicle (normal saline); group 2 received diazepam (1 mg/kg); groups 3 and 4 received ethanolic and chloroform extract of Erythrina mysorensis, 200 and 400 mg/kg p.o., respectively. RESULTS: Mice treated with diazepam (1 mg/kg, p.o.) showed significant (P < 0.001) increase ini the percentage of open arms entries and time spent whereas, in closed arm the number of entries and time spent were significantly (P < 0.05) decreased. Oral administration of chloroform and ethanol extract of E. mysorensis exhibited significant (P < 0.05) increase in the number of open arm entries and time spent with significant (P < 0.05) reduction in number of entries and time spent in the closed arm as compared to group 1. Chloroform and ethanol extracts treated mice also produced significant increase in the number of rearings (P < 0.05), assisted rearings and number of squares crossed (P < 0.01). Rotarod test showed significant (P < 0.01) reduction in motor activity at 45 min with diazepam and E. mysorensis extracts (400 mg/kg) as compared to groups 3 and 1. CONCLUSION: Erythrina mysorensis possess significant anxiolytic activity in the mice. It can be a promising anxiolytic agent. PMID- 23087512 TI - Analgesic activity of the ethanolic extract of Shorea robusta resin in experimental animals. AB - AIM: Shorea robusta (Sal), an important traditional Indian medicinal plant used in various ailments and rituals and the indigenous use of the resin of this plant as a medicament for treatment of various inflammatory conditions is well documented in literature. In the present study, ethanolic extract of S. robusta resin (SRE) was evaluated for its analgesic activity by making use of different central and peripheral pain models. MATERIALS AND METHODS: The analgesic activity of SRE was assessed by employing different pain models such as, i) hot plate and tail flick tests for central analgesia, ii) acetic acid- induced writhing (peripheral analgesic model), iii) formalin-induced hind paw licking (both central and peripheral model), iv) carrageenan-induced hyperalgesia (peripheral analgesic model) and v) post-surgical pain (peripheral analgesic model). RESULTS: The extract produced significant central and peripheral analgesic effects, as is evident from increase in reaction time in hot plate and tail flick tests, inhibition in writhing counts in acetic acid-induced writhing test, inhibition of licking time in formalin-induced hind paw licking, increased pain threshold in paw withdrawal latency in carrageenan-induced hyperalgesia and increased paw withdrawal threshold in post-surgical pain. CONCLUSION: The results of the present study demonstrate marked antinociceptive effects of SRE. PMID- 23087513 TI - Efficacy of oral miltefosine in visceral leishmaniasis in rural West Bengal, India. AB - CONTEXT: Visceral leishmaniasis (VL), also known as Kala-azar (KA) is a public health problem of tropical and subtropical countries, which infects about 12 million people annually, out of which about 1.5 million are new cases. India contributes a major share of the global burden of VL. For many years leishmaniasis has been treated with pentavalent antimonials. Antimony resistance is a problem in India and in other different geographic areas of the world. Amphotericin B deoxycholate and pentamidine isethionate are effective by parenteral administration and associated with toxicities. The quest for an effective, orally administered, non-toxic and less expensive alternative resulted in the identification of miltefosine (hexadecylphosphocholine). In India, therapeutic efficacy of miltefosine in VL was assessed by many groups of scientists, mainly from Bihar and Uttar Pradesh. No such data is available from West Bengal. AIMS: The present study was designed to observe the efficacy of miltefosine in VL in rural West Bengal. MATERIALS AND METHODS: A total of 71 parasitologically proven VL patients participated in the study who received miltefosine in accordance with the National Vector Born Disease Control Programme (NVBDCP) of India and were followed up for the following one year. RESULTS: The overall efficacy of the drug was 93% and no significant adverse side effects were observed during the study period. CONCLUSIONS: The study concludes that miltefosine is effective, well tolerated, and easily administrable drug in the treatment of visceral leishmaniasis at the field levels. PMID- 23087514 TI - Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement. AB - OBJECTIVES: Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS). MATERIALS AND METHODS: In vivo toxicity studies were performed in male balb 'C' mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation. RESULTS: No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability. CONCLUSION: The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement. PMID- 23087515 TI - Antibacterial activity of the venom of Heterometrus xanthopus. AB - Heterometrus xanthopus (Scorpion) is one of the most venomous and ancient arthropods. Its venom contains anti-microbial peptides like hadrurin, scorpine, Pandinin 1, and Pandinin 2 that are able to effectively kill multidrug-resistant pathogens. The present study was conducted to evaluate the anti-bacterial activity of H. xanthopus venom. Six Gram-positive and Gram-negative bacterial strains were tested against 1/100, 1/10, and 1/1 fractions of distilled water diluted and crude venom. 1/100 and 1/10 dilutions were not successful in any of the six bacterial strains studied while the 1/1 dilution was effective on Bacillus subtilis ATCC 6633, Salmonella typhimurium ATCC 14028, and Pseudomonas aeruginosa ATCC 27853 with highest zone of inhibition were obtained on B. subtilis. Crude venom was effective against Enterococcus faecalis ATCC 14506, B. subtilis, S. typhimurium, and P. aeruginosa. The most effective results were observed on B. subtilis. PMID- 23087516 TI - Endosulfan induced early pathological changes in vital organs of rat: a biochemical approach. AB - AIM: To evaluate the pathogenesis in heart and liver by the early induction of biochemical and antioxidant derangements in rats exposed to endosulfan. MATERIALS AND METHODS: Wistar rats were gavaged with endosulfan (0.5, 1 and 1.5 mg/kg body weight in sunflower oil) for a period of 21 days (single dose at 24 h interval). Control and sunflower oil control groups were also maintained simultaneously. Rats were sacrificed on the 22(nd) day posttreatment. Blood samples, heart and liver were collected and different biochemical parameters such as total protein, cholesterol, triglycerides, amino acids and antioxidant and lipid peroxidation level were measured. Statistical analysis was carried out by one way ANOVA, followed by Bonferroni' post-hoc test. RESULTS: Endosulfan induced a significant increase in the serum levels of total protein, amino acids, triglyceride, total cholesterol, free fatty acid and phospholipid levels in a dose-dependent manner. In the heart and liver, lipid peroxidation was increased significantly in a dose dependent manner and the antioxidant levels such as superoxide dismutase (SOD), glutathione S-transferase, glutathione peroxidase, and catalase were significantly decreased in a dose-dependent pattern. CONCLUSION: Exposure to endosulfan results in a significant derangement in the biochemical parameters with a decrease in antioxidant levels in the heart and liver. This is an early indication of pathogenesis in the vital organs of rats. PMID- 23087517 TI - Calcium antagonistic activity of Bacopa monniera in guinea-pig trachea. AB - OBJECTIVE: To demonstrate the calcium antagonistic property of ethanol extract of Bacopa monniera in guinea-pig trachea. MATERIALS AND METHODS: The dose response curves of CaCl(2) (1 * 10(-5) to 1 * 10(-1) M) were constructed in the absence and presence of ethanol extract of Bacopa monniera (100, 500 and 700 MUg/ml) or nifedipine (1 * 10(-6) M) in guinea-pig trachea in calcium free high K(+)-MOPS PSS (3-(N-morpholino)-propanesulphonic acid physiological salt solution). The data was analyzed by ANOVA followed by least significant difference test or by Student's 't' test for unequal variance when appropriate. A probability of at least P < 0.05 was considered statistically significant. RESULTS: The plant extract (500 and 700 MUg/ml) significantly (P < 0.05) depressed and shifted the calcium concentration-response curves (1 * 10(-3)- 1 * 10(-1) M) to rightward similar to that of nifedipine. CONCLUSIONS: Bacopa monniera extract exhibited calcium channel blocking activity in guinea-pig tracheal smooth muscles that may rationalize its relaxant action on guinea-pig trachea and its traditional use in respiratory disorders. PMID- 23087518 TI - Urine retention in a child treated with oral salbutamol. AB - It is known that voiding difficulties can be caused by some drugs, but little is known about the role about the route of administration, especially in children. We report here a case of a 3-year old Italian boy referred to the Pediatric Emergency Unit complaining of two episodes of acute urinary retention, both after therapy with oral salbutamol. In spite of recommendations to use inhaled salbutamol to treat acute wheezing, oral salbutamol is still sometimes used in some settings. Whereas other side effects of systemic salbutamol are described in children, to our knowledge this is the first description of acute urinary retention as an adverse drug reaction to oral salbutamol. PMID- 23087519 TI - A rare case of unilateral gynecomastia during antituberculous chemotherapy with isoniazid. AB - Gynecomastia refers to enlargement of male breast (s) due to benign proliferation of glandular tissue and is caused by excessive estrogen. The etiology may be pathological, pharmacological, or idiopathic reasons. The present report describes a case of gynecomastia due to isoniazid therapy. PMID- 23087520 TI - Stavudine induced acute necrotizing pancreatitis with tetany in a pediatric patient. AB - A nine year old female patient presented with complaints of severe colicky abdominal pain, vomiting, and tingling with numbness for 3 days. Acute necrotizing pancreatitis associated with tetany due to anti-retroviral therapy was diagnosed. Stavudine was the probable causal agent. Unfortunately, the patient died due to severity of the reaction. High index of suspicion and early withdrawal of the offending drug may prevent further harm in such cases. PMID- 23087521 TI - Clopidogrel-induced spontaneous pectoral hematoma. AB - Clopidogrel is an oral antiplatelet agent used in the treatment of coronary artery disease, peripheral vascular disease and cerebrovascular disease. Gastrointestinal symptoms including nausea, diarrhea and constipation are the common side effects of this drug. Serious side effects like intracranial hemorrhage and severe neutropenia were also reported but spontaneous pectoral hematoma due to the clopidogrel has not been reported previously. We present a case of large spontaneous pectoral hematoma during clopidogrel therapy in an elderly woman. PMID- 23087522 TI - Clonazepam in the treatment of essential palatal tremors. AB - Essential Palatal tremor (EPT) is a rare disorder presenting as unilateral or bilateral rhythmic involuntary movements of the soft palate. There is mention of the utility of benzodiazepines like clonazepam probably because of their gamma amino butyric acid (GABA) agonistic property. But no reports are available for the same. Here we report a 30-year old married female patient who presented with the complaints of pain in the lower part of face, behind the ears, back side of neck and clicking sound in her. General physical examination (GPE) revealed symmetrical rhythmic flapping movements of the soft palate and the uvula. Central nervous system (CNS) examination did not reveal any focal deficits and Magnetic resonance imaging (MRI) of the brain was normal. She was diagnosed as having EPT and treated successfully with clonazepam. PMID- 23087523 TI - Phenobarbital induced Stevens-Johnson syndrome in a child. AB - Phenobarbital, an antiepileptic agent has numerous adverse reactions including Stevens- Johnson syndrome (SJS), a rare medical emergency. A 12-year-old male epileptic child with phenobarbital-induced SJS was referred for the management of severe pain in relation to extensively decayed molar tooth and oral mucosal ulcerations. The patient was managed by withdrawal of phenobarbital and palliative treatment of the lesions. PMID- 23087524 TI - Trimethoprim-sulfamethoxazole-induced Steven Johnson syndrome in an HIV-infected patient. AB - Trimethoprim-sulfamethoxazole (TMP/SMX) is a widely prescribed antimicrobial for the management of several uncomplicated infections. It is commonly used for the treatment and prophylaxis of Pneumocystis jirovecii pneumonia (PCP) in the HIV infected population. The adverse reaction to TMP/SMX is more frequent and severe in HIV-infected patients as compared to the general population. Here, we report a case of Stevens-Johnson syndrome (SJS) secondary to TMP/SMX. The patient had a generalized cutaneous reaction with involvement of the eyes, oral cavity, and genitals. He had elevated hepatic alanine aminotransferase and aspartate aminotransferase enzyme. TMP/SMX therapy was stopped and supportive treatment was started. His condition improved after eight days of stopping TMP/SMX therapy. PMID- 23087525 TI - A preliminary assessment of availability and pricing of children's medicines in government hospitals and private retail pharmacies in a district of Andhra Pradesh. PMID- 23087526 TI - Alloxan: an unpredictable drug for diabetes induction? PMID- 23087527 TI - Investigation of anthelmintic potential of oyster mushroom Pleurotus florida. PMID- 23087528 TI - Phase I clinical trials of anticancer drugs in healthy volunteers: need for critical consideration. PMID- 23087529 TI - Thyroid disruptors and their possible clinical implications. PMID- 23087530 TI - Evaluation of antinociceptive and anti-inflammatory potential of flower extract Tecoma stans. PMID- 23087531 TI - Characterization of candidate reference materials for bone lead via interlaboratory study and double isotope dilution mass spectrometry. AB - Four candidate ground bone reference materials (NYS RMs 05-01 through 04), were produced from lead-dosed bovine and caprine sources, and characterized by interlaboratory study. The consensus value ( X ) and expanded standard uncertainty (U(X) ) were determined from the robust average and standard deviation of the participants' data for each NYS RM 05-01 through 04. The values were 1.08 +/-0.04, 15.3 +/-0.5, 12.4 +/-0.5, and 29.9 +/-1.1 MUg g(-1) Pb, respectively. Youden plots of z-scores showed a statistically significant correlation between the results for pairs of NYS RM 05-02 through 04, indicating common sources of between-laboratory variation affecting reproducibility. NYS RM 05-01 exhibited more random variability affecting repeatability at low concentration. Some participants using electrothermal atomic absorption spectrometry (ETAAS) exhibited a negative bias compared to the all-method consensus value. Other methods used included inductively coupled plasma mass spectrometry (ICP-MS), isotope dilution (ID-) ICP-MS, and ICP atomic (optical) emission spectroscopy (-OES). The NYS RMs 05-01 through 04 were subsequently re analyzed in house using double ID-ICP-MS to assign certified reference values (C ) and expanded uncertainty (U(C) ) of 1.09 +/- 0.03, 16.1 +/- 0.3, 13.2 +/- 0.3 and 31.5 +/- 0.7, respectively, indicating a low bias in the interlaboratory data. SRM 1486 Bone Meal was analyzed for measurement quality assessment obtaining results in agreement with the certified values within the stated uncertainty. Analysis using a primary reference method based on ID-ICP-MS with full quantification of uncertainty calculated according to ISO guidelines provided traceability to SI units. PMID- 23087532 TI - Reliability and Validity of Oral Reading Fluency Median and Mean Scores among Middle Grade Readers When Using Equated Texts. AB - We evaluated the reliability and validity of two oral reading fluency scores for one-minute equated passages: median score and mean score. These scores were calculated from measures of reading fluency administered up to five times over the school year to students in grades 6-8 (n = 1,317). Both scores were highly reliable with strong convergent validity for adequately developing and struggling middle grade readers. These results support the use of either the median or mean score for oral reading fluency assessments for middle grade readers. PMID- 23087533 TI - Phonetic variability in residual speech sound disorders: Exploration of subtypes. AB - PURPOSE: To explore whether subgroups of children with residual speech sound disorders (R-SSDs) can be identified through multiple measures of token-to-token phonetic variability. METHOD: Children with R-SSDs were recorded during a rapid multisyllabic picture naming task and an oral diadochokinetic task. Transcription based and acoustic measures of token-to-token variability were derived. Articulation accuracy and general indices of language skills were also measured. RESULTS: Low correlations were observed between transcription-based and acoustic measures of phonetic variability, and among the acoustic measures themselves. Children who were the most variable on one measure were not necessarily highly variable on other measures. Transcription-based measures of variability were associated with language skills. CONCLUSIONS: Measures of phonetic variability did not identify children in the sample as consistently high or low. Data do not support the notion that clear subgroups based on phonetic variability can be reliably identified in children with R-SSDs. The link between highly variable phonetic output (quantified by transcription-based measures) and lower language skills requires further exploration. PMID- 23087534 TI - Activation of Phosphoinositide Breakdown and Elevation of Intracellular Calcium in a Rat RBL-2H3 Mast Cell Line by Adenosine Analogs: Involvement of A(3) Adenosine Receptors? AB - A variety of adenosine analogs activate phosphoinositide breakdown in a rat RBL 2H3 mast cell line. It is presumed that an A(3)-adenosine receptor is involved, since the phosphoinositide response is insensitive to xanthines. However, the very potent A(3)- receptor agonist 2-chloro-N(6)-iodobenzyl-N methylcarboxamidoadenosine (2-CI-IBMECA) with an EC(50) of 4.1 uM is about twofold less potent (and less efficacious) than N-ethylcarboxamidoadenosine (NECA) with an EC(50) of 2.1 uM. The other agents consisting of N(6)-p aminophenylethyladenosine (APNEA), N(6)-iodobenzylMECA (IB-MECA), N(6)-R- phenylisopropyladenosine (R-PIA), 2-chloroadenosine, N(6)-benzyladenosine, N(6)- cyclohexyladenosine (CHA), N(6)-cyclohexylNECA (CHNECA), 2-(p- carboxyethylphenyl ethylaminoNECA (CGS 21680), 1,3-dibutylxanthine 7-riboside-5'-N-methylcarboxamide (DBXRM), adenosine, and 8-bromoadenosine are all nearly equipotent with EC(50) values of 5.5-13.9 uM. The rank order of potencies of the analogs in causing an elevation of intracellular calcium is quite different. The potent A(3) receptor agonists 2-CI-IBMECA and IB-MECA with EC(50) values of 0.07 and 0.11 uM, respectively, are about fourfold more potent than N(6)-cyclohexylNECA and about 15-fold more potent than NECA. The other analogs are comparable or somewhat less potent than NECA, some are less efficacious, and 8-bromoadenosine is inactive. The results suggest that stimulation of phosphoinositide breakdown by adenosine analogs in RBL-2H3 cells as measured by IP(1) accumulation is not predictive of IP(3)-mediated elevations of intracellular calcium. Rank order of potency for the calcium response is consonant with intermediacy of A(3)-adenosine receptors, while the former, as measured by [(3)H]IP(1)-formation, probably reflects contributions from both an A(3)-mediated response and some other mechanism. Combinations of subthreshold concentrations of 2-CI-IBMECA with either the A(1) selective agonist CHA or the A(2A)-selective agonist CGS 21680 caused a marked stimulation of phosphoinositide breakdown, providing further evidence for dual mechanisms. The selective A(3)-adenosine receptor antagonist 3,6-dichloro-2' (isopropyloxy)-4'-methylflavone (MRS 1067) inhibits 2-CI-IBMECA- and NECA elicited elevation of calcium levels, and had differential effects on phosphoinositide breakdown, blocking [(3)H]IP(3) accumulation and either blocking (NECA) or having no effect (2-CI-IBMECA) on [(3)H]IP(1) accumulation. PMID- 23087535 TI - Trimethylsilyl-Substituted Hydroxycyclopentadienyl Ruthenium Hydrides as Benchmarks to Probe Ligand and Metal Effects on the Reactivity of Shvo Type Complexes. AB - The bis(trimethylsilyl)-substituted hydroxycyclopentadienyl ruthenium hydride [2,5-(SiMe(3))(2)-3,4-(CH(2)OCH(2))(eta(5)-C(4)COH)]Ru(CO)(2)H (10) is an efficient catalyst for hydrogenation of aldehydes and ketones. Because 10 transfers hydrogen rapidly to aldehydes and ketones and because it does not form an inactive bridging hydride during reaction, hydrogenation of aldehydes and ketones can be performed at room temperature under relatively low hydrogen pressure (3 atm); this is a significant improvement compared with previously developed Shvo type catalysts. Kinetic and (2)H NMR spectroscopic studies of the stoichiometric reduction of aldehydes and ketones by 10 established a two-step process for the hydrogen transfer: (1) rapid and reversible hydrogen bond formation between OH of 10 and the oxygen of the aldehyde or ketone, (2) followed by slow transfer of both proton and hydride from 10 to the aldehyde or ketone. The stoichiometric and catalytic activities of complex 10 are compared to those of other Shvo type ruthenium hydrides and related iron hydrides. PMID- 23087536 TI - Early murine immune responses from endotracheal exposures to biotechnology related Bacillus strains. AB - An immunology-based in vivo screening regime was used to assess the potential pathogenicity of biotechnology-related microbes. Strains of Bacillus cereus (Bc), Bacillus subtilis (Bs), Bacillus thuringiensis (Bt), and Bt commercial products (CPs) were tested. Balb/c mice were endotracheally instilled with purified spores, diluted CP, or vegetative cells (VC) (live or dead). Exposed mice were evaluated for changes in behavioral and physical symptoms, bacterial clearance, pulmonary granulocytes, and pulmonary and circulatory pyrogenic cytokines (interleukins (IL)-1beta, IL-6 and tumor necrosis factor (TNF)-alpha), as well as acute phase biomarkers (fibrinogen and serum amyloid A). Except for some differences in clearance rates, no marked effects were observed in mice exposed to any spore at 10(6) or 10(7) colony forming units (cfu). In contrast, live Bc or Bt VCs (10(5) or 10(6) cfu) produced shock-like symptoms (lethargy, hunched appearance, ruffled fur, and respiratory distress), and 11-200-fold elevations in pyrogenic cytokines at 2-h post-exposure. In the study, 4-h effects included increased lethargy, ocular discharge, and 1.5-4-fold rise in circulatory acute phase markers, but no indications of recovery. Bs VC did not produce any changes in symptoms or biomarkers. After 2 or 4 h of exposure to dead VC, increases of only plasma IL-1? and TNF-alpha (4.6- and 12.4-fold, respectively) were observed. These findings demonstrate that purified spores produced no marked effects in mice compared to that of metabolically active bacteria. This early screening regime was successful in distinguishing the pathogenicity of the different Bacillus species, and might be useful for assessing the relative hazard potential of other biotechnology-related candidate strains. PMID- 23087537 TI - High-pressure crystallization of isotactic polypropylene droplets. AB - Dispersions of isotactic polypropylene (PP) particles in polystyrene (PS) were produced by interfacially driven breakup of nanolayers in multilayered systems that were fabricated by means of layer-multiplying coextrusion. The droplet size was controlled by the individual PP layer thickness ranging from 12 to 200 nm. In addition, PP was melt blended with PS to produce PP droplets larger than those formed by breakup of nanolayers. The dispersions of PP particles in the PS matrix were melted and annealed under high pressure of 200 MPa. Only the largest PP droplets, with average sizes of 170 MUm, crystallized predominantly in the gamma form. In the 42-MUm droplets obtained by breakup of 200 nm layers, a minor content of the gamma form was found whereas the smaller droplets obtained by breakup of the thinner nanolayers contained the alpha form and/or the mesophase. The results showed that the gamma phase formed only in the droplets sufficiently large to contain the most active heterogeneities nucleating PP crystallization under atmospheric pressure. It is concluded that the presence of nucleating heterogeneities is necessary for crystallization of PP in the gamma form under high pressure. PMID- 23087538 TI - Estimating the Reliability of Single-Item Life Satisfaction Measures: Results from Four National Panel Studies. AB - Life satisfaction is often assessed using single-item measures. However, estimating the reliability of these measures can be difficult because internal consistency coefficients cannot be calculated. Existing approaches use longitudinal data to isolate occasion-specific variance from variance that is either completely stable or variance that changes systematically over time. In these approaches, reliable occasion-specific variance is typically treated as measurement error, which would negatively bias reliability estimates. In the current studies, panel data and multivariate latent state-trait models are used to isolate reliable occasion-specific variance from random error and to estimate reliability for scores from single-item life satisfaction measures. Across four nationally representative panel studies with a combined sample size of over 68,000, reliability estimates increased by an average of 16% when the multivariate model was used instead of the more standard univariate longitudinal model. PMID- 23087539 TI - A proposed mechanism for nitrogen acquisition by grass seedlings through oxidation of symbiotic bacteria. AB - In this paper we propose and provide evidence for a mechanism, oxidative nitrogen scavenging (ONS), whereby seedlings of some grass species may extract nitrogen from symbiotic diazotrophic bacteria through oxidation by plant-secreted reactive oxygen species (ROS). Experiments on this proposed mechanism employ tall fescue (Festuca arundinaceae) seedlings to elucidate features of the oxidative mechanism. We employed 15N(2) gas assimilation experiments to demonstrate nitrogen fixation, direct microscopic visualization of bacteria on seedling surfaces to visualize the bacterial oxidation process, reactive oxygen probes to test for the presence of H(2)O(2) and cultural experiments to assess conditions under which H(2)O(2) is secreted by seedlings. We also made surveys of the seedlings of several grass species to assess the distribution of the phenomenon of microbial oxidation in the Poaceae. Key elements of the proposed mechanism for nitrogen acquisition in seedlings include: 1) diazotrophic bacteria are vectored on or within seeds; 2) at seed germination bacteria colonize seedling roots and shoots; 3) seedling tissues secrete ROS onto bacteria; 4) bacterial cell walls, membranes, nucleic acids, proteins and other biological molecules are oxidized; 5) nitrates and/or smaller fragments of organic nitrogen-containing molecules resulting from oxidation may be absorbed by seedling tissues and larger peptide fragments may be further processed by secreted or cell wall plant proteases until they are small enough for transport into cells. Hydrogen peroxide secretion from seedling roots and bacterial oxidation was observed in several species in subfamily Pooideae where seeds possessed adherent paleas and lemmas, but was not seen in grasses that lacked this feature or long-cultivated crop species. PMID- 23087540 TI - The effect of meteorological factors on airborne Betula pollen concentrations in Lublin (Poland). AB - The present study investigated the pattern of the birch atmospheric pollen seasons in Lublin in the period 2001-2010. Pollen monitoring was conducted using a Lanzoni VPPS 2000 sampler. The atmospheric pollen seasons were determined with the 98% method. Regression analysis was used to determine correlations between meteorological conditions and the pattern of the birch pollen season. On average, the birch pollen season started on 12 April, ended on 13 May, and lasted 32 days. The peak value and the Seasonal Pollen Index showed the greatest variation in particular years. All the seasons were right-skewed. During the study years, a trend was found towards earlier occurrence of the seasonal peak. Regression equations were developed for the following parameters of the atmospheric pollen season: start, duration, peak value and average pollen concentration during the season. The obtained model fit was at a level of 64-81%. Statistical analysis shows that minimum temperature of February and March and total rainfall in June in the year preceding pollen release have the greatest effect on the birch atmospheric pollen season in Lublin. Low temperatures in February promote the occurrence of high pollen concentrations. PMID- 23087541 TI - Closed-loop minimal sampling method for determining viral-load minima during switching. AB - In previous work, we have developed optimal-control based approaches that seek to minimize the risk of subsequent virological failure by "pre-conditioning" the viral load during therapy switches. These techniques result in the transient susceptibility of the total viral load, and rely on finding the minimum of a dip in viral load and switching before viral load rebound. Model uncertainty necessitates a closed-loop approach to minimum-finding. Blood measurements are costly in terms of money, inconvenience and risk. In this paper, we introduce an iterative parameter estimation approach to find the viral load minimum, and measure the degree of optimality of minimum-seeking under conditions of measurement noise. We evaluate the cost-savings of this approach in terms of number of samples saved from a constant measurement rate. PMID- 23087542 TI - The Role of Romantic Partners, Family and Peer Networks in Dating Couples' Views about Cohabitation. AB - Emerging adults are increasingly cohabiting, but few studies have considered the role of social context in the formation of their views of cohabitation. Drawing on 40 semi-structured interviews with dating couples, we explored the role of romantic partners, family, and peers on evaluations of cohabitation. In couples where each member had a differing view about cohabitation, one romantic partner's desire to not cohabit trumped their partner's more ambivalent feelings about cohabitation. The influence of family in the formation of cohabitation views was evident through a variety of mechanisms, including parental advice, social modeling, religious values, and economic control. Peers also played a key role, with couples using the vicarious trials of their peer networks to judge how cohabitation would affect their own relationship. By using a couple perspective, assessing reports from both members of each couple, this study showcases how beliefs about cohabitation are formed within an intimate dyad. PMID- 23087543 TI - Thermosensitive multilayer hydrogels of poly(N-vinylcaprolactam) as nanothin films and shaped capsules. AB - We report on nanothin multilayer hydrogels of cross-linked poly(N vinylcaprolactam) (PVCL) that exhibit distinctive and reversible thermoresponsive behavior. The single-component PVCL hydrogels were produced by selective cross linking of PVCL in layer-by-layer films of PVCL-NH(2) copolymers assembled with poly(methacrylic acid) (PMAA) via hydrogen bonding. The degree of the PVCL hydrogel film shrinkage, defined as the ratio of wet thicknesses at 25 degrees C to 50 degrees C, was demonstrated to be 1.9+/-0.1 and 1.3+/-0.1 for the films made from PVCL-NH(2)-7 and PVCL-NH(2)-14 copolymers, respectively. No temperature responsive behavior was observed for non-cross-linked two-component films due to the presence of PMAA. We also demonstrated that temperature-sensitive PVCL capsules of cubical and spherical shapes could be fabricated as hollow hydrogel replicas of inorganic templates. The cubical (PVCL)(7) capsules retained their cubical shape when temperature was elevated from 25 degrees C to 50 degrees C exhibiting 21+/-1% decrease in the capsule size. Spherical hydrogel capsules demonstrated similar shrinkage of 23+/-1%. The temperature-triggered capsule size changes were completely reversible. Our work opens new prospects for developing biocompatible and nanothin hydrogel-based coatings and containers for temperate regulating drug delivery, cellular uptake, sensing, and transport behavior in microfluidic devices. PMID- 23087544 TI - Examining the contribution of handwriting and spelling to written expression in kindergarten children. AB - In this study, we examined the development of beginning writing skills in kindergarten children and the contribution of spelling and handwriting to these writing skills after accounting for early language, literacy, cognitive skills, and student characteristics. Two hundred and forty two children were given a battery of cognitive, oral language, reading, and writing measures. They exhibited a range of competency in spelling, handwriting, written expression, and in their ability to express ideas. Handwriting and spelling made statistically significant contributions to written expression, demonstrating the importance of these lower-order transcription skills to higher order text-generation skills from a very early age. The contributions of oral language and reading skills were not significant. Implications of these findings for writing development and instruction are addressed. PMID- 23087545 TI - Amount of Time in Print Reading in General Education Kindergarten Classrooms: What Does It Look Like for Students At-risk for Reading Difficulties? AB - The purpose of this study was to examine the amount of time spent actively engaged in reading sounds, words, and connected text for students at-risk for reading difficulties in the first formal grade of reading instruction, kindergarten. Observational data of 109 kindergarten students at high-risk for later reading difficulties were collected during general education reading instruction across the school year. Findings revealed students read orally for just over 1 minute during their reading instruction with approximately equal time spent reading sounds, words, or connected text. Implications of these results for early reading instruction and intervention for students at-risk for reading difficulties or disabilities are presented. PMID- 23087546 TI - pH-Responsive Hydrogels with Dispersed Hydrophobic Nanoparticles for the Delivery of Hydrophobic Therapeutic Agents. AB - To investigate the delivery of hydrophobic therapeutic agents, a new class of polymer carriers was synthesized. These carriers are composed of two components: (i) a pH-responsive hydrogel composed of methacrylic acid grafted with poly(ethylene glycol) tethers, P(MAA-g-EG), and (ii) hydrophobic poly(methyl methacrylate) (PMMA) nanoparticles. Before the P(MAA-g-EG) hydrogel was crosslinked, PMMA nanoparticles were added to the solution and upon exposure to UV light they were photoencapsulated throughout the P(MAA-g-EG) hydrogel structure. The pH-responsive behavior of P(MAA-g-EG) is capable of triggered release of a loaded therapeutic agent, such as a low molecular weight drug or protein, when it passes from the stomach (low pH) to upper small intestine (neutral pH). The introduction of PMMA nanoparticles into the hydrogel structure affected the swelling behavior, therapeutic agent loading efficiency, and solute release profiles. In equilibrium swelling conditions the swelling ratio of nanoparticle-containing hydrogels decreased with increasing nanoparticle content. Loading efficiencies of the model therapeutic agent fluorescein ranged from 38 - 51 % and increased with increasing hydrophobic content. Release studies from neat P(MAA-g-EG) and the ensuing P(MAA-g-EG) hydrogels containing nanoparticles indicated that the transition from low pH (2.0) to neutral pH (7.0) triggered fluorescein release. Maximum fluorescein release depended on the structure and hydrophobicity of the carriers used in these studies. PMID- 23087547 TI - Fighting fair: Adaptive Marital Conflict Strategies as Predictors of Future Adolescent Peer and Romantic Relationship Quality. AB - This study examined the associations between reasoning during interparental conflict and autonomous adolescent conflict negotiation with peers over time. Participants included 133 adolescents and their parents, peers, and romantic partners in a multi-method, multiple reporter, longitudinal study. Interparental reasoning at adolescent age 13 predicted greater autonomy and relatedness in observed adolescent-peer conflict one year later and lower levels of autonomy undermining during observed romantic partner conflict five years later. Interparental reasoning also predicted greater satisfaction and affection in adolescent romantic relationships seven years later. Findings suggest that autonomy promoting behaviors exhibited in the interparental context may influence adolescents' own more autonomous approaches to subsequent peer and romantic conflict. Possible explanatory models are discussed, including social learning theory and attachment theory. PMID- 23087548 TI - The kidney in pregnancy: A journey of three decades. AB - The spectrum of kidney disease occurring during pregnancy includes preeclampsia, hypertensive disorders of pregnancy, urinary tract infection, acute kidney injury, and renal cortical necrosis (RCN). Preeclampsia affects approximately 3 5% of pregnancies. We observed preeclampsia in 5.8% of pregnancies, and 2.38% of our preeclamptic women developed eclampsia. Severe preeclampsia and the eclampsia or hemolysis, elevated liver enzymes levels, and low platelets count (HELLP) syndrome accounted for about 40% of cases of acute kidney injury (AKI) in pregnancy. Preeclampsia/eclampsia was the cause of acute renal failure (ARF) in 38.3% of the cases. Preeclampsia was the most common (91.7%) cause of hypertension during pregnancy, and chronic hypertension was present in 8.3% of patients. We observed urinary tract infection (UTI) in 9% of pregnancies. Sepsis resulting from pyelonephritis can progress to endotoxic shock, disseminated intravascular coagulation, and AKI. The incidence of premature delivery and low birth weight is higher in women with UTI. The incidence of AKI in pregnancy with respect to total ARF cases has decreased over the last 30 years from 25% in 1980s to 5% in 2000s. Septic abortion-related ARF decreased from 9% to 3%. Prevention of unwanted pregnancy and avoidance of septic abortion are key to eliminate abortion-associated ARF in early pregnancy. The two most common causes of ARF in third trimester and postpartum periods were puerperal sepsis and preeclampsia/HELLP syndrome. Pregnancy-associated thrombotic thrombocytopenic purpura/hemolytic uremic syndrome and acute fatty liver of pregnancy were rare causes of ARF. Despite decreasing incidence, AKI remains a serious complication during pregnancy. PMID- 23087549 TI - Effect of short-term intravenous ascorbic acid on reducing ferritin in hemodialysis patients. AB - Resistance to recombinant erythropoietin (rEPO) in hemodialysis patients may be due to inadequate iron recruitment and defect in iron use. In this cross over randomized clinical trial, 30 hemodialysis patients with serum ferritin levels of >=500 ng/ml, hemoglobin <=11.0 g/dl, and transferrin saturation (TSAT) of 20% or less were administrated intravenous iron (50-100 mg/wk) and rEPO (120-360 U/kg/wk) for 6 months. Patients were excluded if there was a clear explanation for rEPO hyporesponsiveness. Patients were divided into two groups. Group1 received standard care and 500 mg of intravenous ascorbic acid (IVAA) with each dialysis session in the first week of each month for a total of 3 months. Group 2 received standard care only. After 2 month washout period, groups were crossed over. Each month hemoglobin (Hb) was assessed. Iron, TIBC (transferrin iron binding capacity), TSAT, iPTH (intact parathyroid hormone), liver enzymes, albumin and cholesterol levels were measured every 3 months. After 3 months of intervention, Hb significantly increased from 10.11 to 12.19 g/dl (P <0 0.001; 95% confidence interval [CI] 2.7-1.4) and TSAT increased from 18.9 to 28.1% (P = 0.008; 95% CI 0.09-3), while ferritin and serum iron declined significantly from 1391 to 938 ng/ml (P = 0.001; 95% CI 216-689), 97.2 to 64.6 (P = 0.001; 95% CI 14.8-50.4) in the study group. Change of Hb over time in IVAA group was significant (P < 0.0005). There were significant differences between two groups in change of Hb level over time (P < 0.0005) and treatment effect (P = 0.002). Baseline laboratory tests were similar in the two groups and there was no carry over effect at phase 2. We showed that low amount of IVAA could reduce ferritin level and enhance Hb and TSAT, suggesting improved iron utilization. PMID- 23087550 TI - The effect of niacin on serum phosphorus levels in dialysis patients. AB - Hyperphosphatemia is common in patients with end-stage renal disease. Recent studies have shown that niacinamide and niacin achieve clinically significant reductions in serum phosphate in patients undergoing dialysis. The aim of the present study was to evaluate the serum phosphorus lowering effect of niacin in long-term hemodialysis patients. In this 8-week randomized, double-blind clinical trial, 37 patients were assigned to niacin or placebo with titration from 400 to 1000 mg daily. A 2-week washout preceded the switch from niacin to placebo or vice versa. The mean dose of niacin at the end of the 8-week treatment period was 750+/-200 mg/day. Serum phosphorus decreased from 6.66+/-1.40 to 5.96+/-0.87 mg/dL (P = 0.006) in the niacin-treated group after 8-weeks. However, the main reduction occurred at the beginning of study and seems not to be related to the phosphate-lowering effect of drug. In spite of a sharp increase in phosphorus level between w6 and w8 in patients on placebo, phosphorus values in drug-treated group showed nearly steady trend, presumably due to the inhibitory effect of niacin on phosphate absorption from gut. Niacin also increased the high density lipoprotein (HDL) cholesterol (P = 0.018). Our study suggests that niacin should be considered as adjunctive therapy for patients with hyperphosphatemia despite management with phosphate binders. The modest increase in HDL values may be another beneficial effect of this treatment. PMID- 23087551 TI - Risk prediction of acute kidney injury in cardiac surgery and prevention using aminophylline. AB - The incidence of acute kidney injury (AKI) after cardiac surgery remains high. The nonspecific adenosine receptor antagonist aminophylline has been shown to confer benefit in experimental and clinical acute renal failure (ARF) due to ischemia, contrast media, and various nephrotoxic agents. We conducted a prospective open label trial to assess the effectiveness of aminophylline for prevention of renal impairment after cardiac surgery. One hundred and thirty eight patients undergoing cardiac surgery were risk stratified as per Cleveland score to assess for prediction of AKI. Sixty-three patients received a bolus aminophylline of 5 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h for up to 72 h, while 75 patients received usual postoperative care. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery and the glomerular filtration rate estimated using Cockcroft and Gault formula. Hourly urine output was recorded and patients assigned to respective RIFLE stage of AKI. Cleveland score >=6 was associated with higher incidence of AKI: I and F (P<0.005). Number needed to treat, an insight into the clinical relevance of a specific treatment, is 8. These results suggest that the perioperative use of aminophylline infusion is associated with lower incidence of deterioration in renal function following cardiac surgery in high-risk patients. PMID- 23087552 TI - Plasma cell-rich acute rejection of the renal allograft: A distinctive morphologic form of acute rejection? AB - This study was aimed at evaluating the clinicopathologic features of plasma cell rich acute rejection (PCAR) of renal allograft and comparing them with acute cellular rejection (ACR), non-plasma cell-rich type. During a 2-year period, eight renal allograft biopsies were diagnosed as PCAR (plasma cells >10% of interstitial infiltrate). For comparison, 14 biopsies with ACR were included in the study. Detailed pretransplant data, serum creatinine at presentation, and other clinical features of all these cases were noted. Renal biopsy slides were reviewed and relevant immunohistochemistry performed for characterization of plasma cell infiltrate. The age range and duration of transplantation to diagnosis of acute rejection were comparable in both the groups. Histologically, the proportion of interstitial plasma cells, mean interstitial inflammation, and tubulitis score were higher in the PCAR group compared with cases with ACR. A significant difference was found in the outcome at last follow-up, being worse in patients with PCAR. This study shows that PCAR portends a poor outcome compared with ACR, with comparable Banff grade of rejection. Due to its rarity and recent description, nephrologists and renal pathologists need to be aware of this entity. PMID- 23087553 TI - Sevelamer carbonate experience in Indian end stage renal disease patients. AB - This open label, multicentric, comparative clinical trial was done to compare the efficacy and tolerability of two sevelamer formulations, sevelamer carbonate, and sevelamer hydrochloride, in the treatment of hyperphosphatemia in Indian end stage renal disease (ESRD) patients. A total of 97 ESRD patients on hemodialysis, were enrolled. Patients were randomized to receive either sevelamer carbonate or sevelamer hydrochloride. All patients were evaluated every week for 6 weeks for efficacy and safety variables. Total 88 patients completed the study. After 6 weeks of therapy, there were similar reductions (P<0.0001) in mean serum phosphorus and the CaxP product both the groups. The responder rates for test and reference groups were 75%, 68.18% respectively (P=0.3474). The adverse events reported were nausea, abdominal pain/discomfort, heartburn, constipation, diarrhea, increased prothrombin time, and severe arthritis. No serious adverse events were reported. There was no significant difference between the groups for adverse events and the laboratory parameters. From the results of this multicentric, comparative, randomized clinical study on sevelamer carbonate we can recommend that sevelamer carbonate may be used as a phosphate binder in Indian chronic kidney disease patients. PMID- 23087554 TI - Comparison of renal function between normal-weight and overweight children. AB - Obesity in children is associated with hypertension, dyslipidemia, cardiovascular disease, diabetes mellitus, colon cancer, and kidney disease. Most of the studies that evaluate the association between obesity and kidney disease have been done in adults. This study was planned to compare renal function between normal-weight and overweight children. In this case-control study, 92 children (45 boys, 47 girls) aged 7-12 years were included in the analysis. 46 children (23 boys, 23 girls) with BMI 85(th) percentile or greater (mean age, 9.09 years) were compared with 46 controls (22 boys, 24 girls) with BMI 5(th)-84(th) percentile (mean age, 8.63 years). Blood and urine sample were taken from case and control groups. Urine albumin/creatinine ratio and urine calcium/creatinine ratio and glomerular filtration rate (GFR) were determined. Children in the overweight and control groups were matched according to age and sex. Glomerular filtration rate, urine calcium/creatinine ratio, urine albumin/creatinine ratio, blood pressure, and serum creatinine were compared between normal-weight and overweight children. Our finding showed no significant difference regarding GFR, albuminuria, calciuria, blood pressure, and serum creatinine between normal-weight and overweight children. PMID- 23087555 TI - Comparison of serum creatinine and spot urine interleukin-18 levels following radiocontrast administration. AB - Radiocontrast administration is an important cause of acute renal failure. In this study, compared the plasma creatinine levels with spot urine IL-18 levels following radiocontrast administration. Twenty patients (11 males, 9 females) underwent radiocontrast diagnostic and therapeutic-enhanced examinations. The RIN Mehran risk score was low (<=5). The radiocontrast agents used were 623 mg/mL Iopromid (1.5 mL/kg), and 100 mL of 650 mg/mL meglumine diatrizoate as three-way oral and rectal contrast material for abdominal computed tomography (CT) scans. Serum blood urea nitrogen, creatinine, Na, K, Cl, Ca, P, creatinine clearance, and spot urine IL-18 levels were analyzed before and repeated at 24, 48, and 72 h after radiocontrast administration. Six and 24-h urinary IL-18 levels were measured with a human IL-18 ELISA kit following radiocontrast administration. An increase in plasma creatinine 24 and 48 h following radiocontrast administration was observed compared with precontrast values, but it was not statistically significant (P=0.052 and P=0.285, respectively). A statistically significant increase in IL-18 levels was observed at 6 and 24 h, compared with precontrast values (P=0.048 and P=0.028, respectively). A tendency for postcontrast 24-h urinary IL-18 levels to increase was observed compared with 6 h, but the increase was not statistically significant (P=0.808). Our results show that plasma creatinine starts to increase at 24(th) hour; however, spot urine IL-18 levels go up at 6(th) hour following radiocontrast administration implying urine IL-18 to be an earlier parameter for kidney injury. PMID- 23087556 TI - Effect of reuse of polysulfone membrane on oxidative stress during hemodialysis. AB - Patients with chronic renal failure, especially those on long-term hemodialysis (HD), have a high incidence of premature cardiovascular disease. Oxidative stress, which occurs when there is an excessive free radical production or low antioxidant level, has recently been implicated as a causative factor in atherogenesis. Hourly changes in malondialdehyde (MDA) and antioxidant enzymes, vitamins, lipid profile and ferric reducing ability of plasma (FRAP) were studied with the first use and immediate subsequent reuse of polysulfone dialysis membrane in 27 patients on regular HD treatment. Data were corrected for hemoconcentration and standardized to measure the rate of change. Increase in MDA and erythrocyte catalase along with decrease in plasma vitamin E and FRAP levels and no change in glutathione peroxidase levels were observed as a result of both fresh and reuse dialysis. These findings indicate a net oxidative stress in both fresh as well as dialyzer reuse sessions. There was no significant change in oxidative stress in both fresh and reuse sessions. The oxidative stress with reuse dialysis was less when compared to first use dialysis, but the difference was not statistically significant. PMID- 23087557 TI - Non-nephronal hematuria misdiagnosed as C1q nephropathy: Look before you leap. AB - A 19-year-old male presented with persistent macroscopic hematuria for last 3 months. On initial evaluation, he was found to have minimal proteinuria, normal renal function, and normal complement with negative lupus serology. Light microscopy, immunofluorescence and electron microscopy of renal tissue confirmed the presence of C1q nephropathy. Because of poor response to immunosuppressive agent (prednisolone and mycophenolate mofetil), passage of urinary clot once and vexing persistent macroscopic hematuria, alternative diagnosis was considered. Cystourethroscopy showed urethritis of prostatic urethra. Immunosuppressives were stopped and doxycycline started to which hematuria responded dramatically. This case report illustrates that hematuria in this patient was because of undiagnosed urethritis rather than incidental C1q nephropathy. PMID- 23087558 TI - Baclofen-induced encephalopathy in patient with end stage renal disease: Two case reports. AB - We report two end stage renal disease (ESRD) patients, who rapidly developed neurotoxicity after taking baclofen, a centrally acting gamma-aminobutyric acid agonist. They presented to our hospital in a state of confusion. On physical examination, there were no focal neurological deficits and the remainder of the examination was also not diagnostic. Laboratory data were unremarkable. The consciousness improved with supportive treatment and intensive hemodialysis over 3-4 days. In conclusion, physicians should be aware of the possibility of baclofen-induced neurotoxicity in patients with renal disease, especially in ESRD patients and it is necessary to avoid or reduce baclofen dosage in these patients. PMID- 23087559 TI - Diffuse mesangial sclerosis - Report of two cases. AB - Diffuse mesangial sclerosis (DMS) is a rare cause of nephrotic syndrome in the infantile and childhood period. DMS is a phenotypic expression of syndromic entities such as WAGR syndrome (Wilms' tumor, aniridia, genitourinary anomalies and mental retardation), Denys Drash syndrome, Pierson syndrome, Frasier syndrome, or Galloway-Mowat syndrome. We report two cases of DMS, one presenting in first year of life and another in second decade of life. Both of them had fatal outcome. Recognition of the disease is very important in modifying the management of patient and active surveillance of family members. PMID- 23087560 TI - Rapidly progressive renal failure due to chronic lymphocytic leukemia - Response to chlorambucil. AB - Chronic lymphocytic leukemia tends to follow an indolent course and despite infiltration of leukemic cells in numerous organs, resultant target organ damage is uncommon. We present a case of an 83-year-old Caucasian lady who presented with rapidly worsening renal impairment over a several month period with a serum creatinine peak of 2.82 mg/dl. Despite numerous investigations an immediate cause was not apparent. A renal biopsy was therefore conducted which revealed dense infiltration of the interstitium with small lymphocytic lymphoma. Given her age and frailty she was treated with single alkylating agent chemotherapy (chlorambucil). This resulted in a marked decrease in lymphocyte count and resolution of renal impairment close to her previous baseline level. To our knowledge, this is the first case in the literature to demonstrate a marked resolution in renal impairment with chlorambucil alone. We also highlight the value of renal biopsy in identifying a rare cause of renal impairment. PMID- 23087561 TI - Light chain deposition disease in a postrenal transplant patient. AB - The morphological spectrum of light chain deposition disease (LCDD) may range from normal glomerular morphology to mesangio-proliferative to mesangio-capillary to nodular sclerosing patterns. Due to the inconsistencies regarding treatment and the universally poor graft outcome of post-transplant LCDD, it is imperative to maintain a high index of suspicion and perform relevant investigations for clinching this diagnosis. A 40-year-old lady was diagnosed as a case of membrano proliferative glomerulonephritis 3 years back, for which she underwent a live unrelated renal allograft transplant. Postoperative period was complicated by an acute rise in serum creatinine on the 21(st) postoperative day. Biopsy showed patchy acute cortical necrosis, which responded to conservative management. The present admission was for renal failure and subnephrotic proteinuria. A kidney biopsy was performed, and all the 14 glomeruli examined showed a mesangiocapillary pattern of glomerular injury with cellular nodule formation in some. The nodules were PAS and Congo red negative. Immunofluorescence showed glomerular and tubular basement staining for Kappa light chains only. Electron microscopy showed the characteristic granular deposits in subendothelial location in the glomerulus, and in tubular basement membranes, thus confirming the diagnosis of LCDD. Membranoproliferative pattern of glomerular injury in the pre- and posttransplant setting has a wide range of differential diagnoses; LCDD being one of them. PMID- 23087562 TI - Perinephric abscess with extension into mediastinum and epidural space. AB - Perinephric abscess is accumulation of pus in the space between the renal capsule and the Geroto's fascia. The pus that accumulates in the perinephric space, may extend in several directions. Extension into the the mediastinum and spinal epidural space is unusual. Such situation is presented in this report. PMID- 23087563 TI - Complete aortoiliac thrombosis in a patient during pretransplant cardiovascular evaluation. PMID- 23087564 TI - Post-transplant infections. PMID- 23087565 TI - Author's reply. PMID- 23087566 TI - Percutaneous PD catheter insertion after past abdominal surgeries. PMID- 23087567 TI - Authors reply on "Percutaneous nephrostomy under ultrasound guidance". PMID- 23087568 TI - Collapsing glomerulopathy: The Indian scenario. PMID- 23087569 TI - Deceased donor organ transplantation: A good start for a promising future. PMID- 23087570 TI - Renal allograft pathology with C4d immunostaining in patients with graft dysfunction. PMID- 23087571 TI - Authors' reply. PMID- 23087572 TI - Feasibility of screening for urinary abnormalities as a part of school health appraisal. PMID- 23087573 TI - Relevance of forensic odontology in the world today. PMID- 23087574 TI - Usefullness of palatal rugae patterns in establishing identity: Preliminary results from Bengaluru city, India. AB - INTRODUCTION: Palatal rugoscopy is the name given to the study of palatal rugae. Rugae pattern are widely considered to remain unchanged during an individual's lifetime. The rugae pattern has the potential to remain intact by virtue of their internal position in the head when most other anatomical structures are destroyed or burned. Moreover, rugae pattern are considered to be unique similar to fingerprints and are advocated in personal identification. OBJECTIVES: The purpose of the study is to establish, individual identity using palatal rugae patterns. MATERIALS AND METHODS: The study group consisted of 100 study models all of whom were subjects above 14 years old. Martin dos Santos' classification was followed based on form and position to assess the individuality of rugae pattern. RESULTS: Each individual had different rugae patterns including dizygous twins and the rugae patterns were not symmetrical, both in number and in its distribution. CONCLUSION: The preliminary study undertaken here shows no two palates are alike in terms of their rugae pattern. Palatal rugae possess unique characteristics as they are absolutely individualistic and therefore, can be used as a personal soft-tissue 'oral' print for identification in forensic cases. PMID- 23087575 TI - Cheiloscopy: A new role as a marker of sagittal jaw relation. AB - CONTEXT: It has been proved that lip prints are analogous to thumb prints. A correlation between thumb prints and sagittal dental malocclusion has already been established. Soft tissue is gaining more importance in judgement of deformity or identity of a patient. AIM: To find a correlation between sagittal skeletal jaw relation and lip prints. SETTINGS AND DESIGN: Descriptive, cross sectional, comparative, single-blind, hospital-based study. MATERIALS AND METHODS: A total of 90 patients were categorized into skeletal class I, class II, and class III, comprising 30 patients in each group with equal gender distribution. Dolphin imaging (10.5) software was used for analyzing sagittal jaw relation. Lip prints obtained from these 90 patients were analyzed. STATISTICAL ANALYSES USED: Karl Pearson's correlation coefficient, Chi-square test, t-test, Spearman's co-efficient, analysis of variance (ANOVA). RESULTS: It was observed that angle ANB (Angle formed between points nasion[N] to Subnasal[A] and nasion[N] to supramental [B]) and beta angle were statistically significant, revealing a strong negative correlation (-0.9060) with different classes of jaw relation. Significant difference was observed between genders in all the three classes. Significant difference was observed in relation to lip print and the quadrants of upper and lower lips. A statistical significance was noted on the right side of both upper and lower arches. CONCLUSION: This study shows that lip prints can be employed for sagittal jaw relation recognition. A further study on various ethnic backgrounds with a larger sample size in individual group is necessary for comparing lip prints and malocclusion. PMID- 23087576 TI - An evaluation of third molar eruption for assessment of chronologic age: A panoramic study. AB - OBJECTIVES: The identity of a person can be established by assessing one's age, and in order to be entitled to civil rights and social benefits, verification of the chronological age is required and thereby age estimation has gained an increasing significance in recent years. Tooth eruption is one of the criteria of developmental morphology that can be evaluated by either clinical examination or by evaluation of dental radiographs to determine the dental age. The present study was aimed to evaluate the reliability of the third molar eruption stage as a parameter for forensic age estimation in living subjects. MATERIALS AND METHODS: The stage of wisdom tooth eruption in 77 male and 73 female Indian subjects aged between 12-26 years was determined by subjecting them to conventional orthopantomograms and was interpreted to assess the third molar eruption stages to evaluate the dental age. RESULTS: Predicted minimum age and mean age of the study sample were found to be significant predictors (P<0.001) of actual age. Minimum age was able to explain 58.3% of the variation in actual age and the mean age was able to explain 60.3% of variation in actual age. CONCLUSION: Third molar is fairly a reliable indicator to determine the age of alveolar, gingival, and complete emergence of third molar in the occlusal plane in adolescents and young adults. Minimum and most probable ages of examined subjects can also be evaluated using third molar eruption stage. PMID- 23087577 TI - Gender variation in morphological patterns of lip prints among some north Indian populations. AB - BACKGROUND: Personal identification is an integral part of forensic investigations. For the same, DNA profiling and fingerprints are the most commonly used tools. But these evidences are not ubiquitous and may not necessarily be obtained from the crime scene. In such a scenario, other physical and trace evidences play a pivotal role and subsequently the branches employed are forensic osteology, odontology, biometrics, etc. A relatively recent field in the branch of forensic odontology is cheiloscopy or the study of lip prints. A comparison of lip prints from the crime scene and those obtained from the suspects may be useful in the identification or narrowing down the investigation. AIM: The purpose of the present study is to determine the gender and population variability in the morphological patterns of lip prints among brahmins, Jats, and scheduled castes of Delhi and Haryana, India. SETTINGS AND DESIGN: Samples were collected from Jats, brahmins, and scheduled castes of Delhi and Haryana. The total sample size consisted of 1399 individuals including 781 males and 618 females in the age group of 8-60 years. Care was taken not to collect samples from genetically related individuals. The technique was standardized by recording lip prints of 20 persons and analyzing them. MATERIALS AND METHODS: Lip prints were collected by using a corporate's invisible tape and analyzed using a hand lens. The patterns were studied along the entire length and breadth of both the upper and the lower lip. The data were analyzed by SPSS statistical package version 17 to determine the frequencies and percentages of occurrence of the pattern types in each population group and a comparison between males and females among the groups was carried out by using the z test. RESULTS AND CONCLUSIONS: The z-test comparison between patterns of males and females shows significant differences with respect to pattern types I', II, III, and IV among brahmins; I', II, III, IV, and Y among Jats; and I, I', II, III, and V among scheduled castes. Thus, it can be concluded that the variability of the lip print pattern can help sex differentiation among groups and that more studies on the lip print pattern should be carried out to bring new dimensions to forensic anthropology and to aid the law enforcement agencies. PMID- 23087578 TI - Study of lip print pattern in a Punjabi population. AB - BACKGROUND: Lip prints are unique to each individual and can be used for personal identification. The lip prints show differences according to the race and the ethnic origins of a person. AIM: The objective of the study was to determine the predominant lip print type in a Punjabi population. MATERIALS AND METHODS: The study was conducted on 106 students of our institution and comprised 56 males and 50 females in the age group of 18-25 years. The middle part of the lower lip was taken as study area. Analysis of lip print pattern was done according to Tsuchihashi Classification. RESULTS: No two lip prints matched with each other. Type 1 pattern (vertical grooves that run across the entire lip) was found to be predominant in both males (51.02%) and females (43.47%) and there was no statistically observed difference between males and females in individual lip print types. CONCLUSION: In our study, lip prints did not match with each other, hence lip prints are unique and further studies with larger samples are required to obtain statistical significance. PMID- 23087579 TI - Analysis of gonial angle in relation to age, gender, and dentition status by radiological and anthropometric methods. AB - BACKGROUND: With development and function, the mandibular angle has shown changes in size and shape. A variation in mandibular angle with age, gender, and even the dental status has been observed, which is supported by radiographic and anthropometric studies. AIMS: The aim of this study were to evaluate relationship between complete loss of teeth and changes in the gonial angle; the study further intends to evaluate any variation in gonial angle with age and gender. The study intends to assess the reliability and accuracy of age and gender determination using gonial angle as a parameter. MATERIALS AND METHODS: A total of 185 subjects (91 males; 89 females) were included in the study and were divided into five groups on the basis of the chronological age. Physico-forensic anthropometry and lateral cephalometric methods were used to record the gonial angle. RESULTS: The present study shows a definite decrease in the gonial angle with advancing age, but the intergroup analysis does not follow a significant pattern. The study showed no correlation of gonial angle with gender. However, the study observed a 6 degrees increase in gonial angle for edentulous subjects. CONCLUSION: Gonial angle has been used as an adjuvant forensic parameter, but its reliability is questionable, as the mandible does not follow one characteristic pattern. Gonial angle does show changes with dentition status, which may be attributed to physiologic function of the mandible. However, when evidence is scanty, it can be used to direct the investigation. PMID- 23087580 TI - Estimation of stature from maxillo-facial anthropometry in a central Indian population. AB - BACKGROUND: For establishing identity, stature is an important parameter in medico-legal and forensic examination. AIMS: To estimate stature from facial parameters. SETTING AND DESIGN: Prospective study conducted from December 2007 to September 2008 in the Department of Anatomy, Government Medical College, Nagpur. MATERIALS AND METHODS: A total of 470 healthy medical students were taken, comprising 260 males and 210 females in the age group of 18 to 24 years. STATISTICAL ANALYSIS: The data were analyzed using regression analysis and correlation coefficient. RESULTS: The average height of males and females was 170.97 (+/- 6.80) cm and 156.89 (+/- 5.89) cm respectively. It was observed that in males the total facial height had greater correlation with stature (r = 0.19) and had standard error of +/-6.68 cm. In females, nasal height had greater correlation with stature (r = 0.19) and had standard error of +/-5.78 cm CONCLUSION: It can be stated that percutaneous facial dimensions are not good predictors of accurate stature estimation and can be used when other parameters are not available. PMID- 23087581 TI - Forensic odontology: A prosthodontic view. AB - The most common role of the forensic dentist is the identification of deceased individuals. Dental identifications have always played a key role in natural and manmade disaster situations, and in particular, the mass casualties normally associated with aviation disasters. Because of the lack of a comprehensive fingerprint database, dental identification continues to be crucial in the world. An all-acrylic resin appliance such as a full denture or an all-acrylic partial denture (or orthodontic appliance), prior to delivery, could be inscribed with the patient's full name on a substrate (paper, metal) and sealed inconspicuously into the surface of a denture by various processes. It has been noted by several authors that in many cases of air disaster where the limbs are completely burnt off, some denture materials survive, especially the posterior part of acrylic dentures and metal-based dentures. Thus, marked dental prostheses (full and partial dentures, mouthguards and removal orthodontic appliances) would lead to rapid identification in the event of accidents and disaster. PMID- 23087582 TI - Role of deoxyribonucleic acid technology in forensic dentistry. AB - In the last few years, Deoxyribonucleic Acid (DNA) analysis methods have been applied to forensic cases. Forensic dental record comparison has been used for human identification in cases where destruction of bodily tissues or prolonged exposure to the environment has made other means of identification impractical, that is, after fire exposure or mass disaster. Teeth play an important role in identification and criminology, due to their unique characteristics and relatively high degree of physical and chemical resistance. The use of a DNA profile test in forensic dentistry offers a new perspective in human identification. The DNA is responsible for storing all the genetic material and is unique to each individual. The currently available DNA tests have high reliability and are accepted as legal proofs in courts. This article gives an overview of the evolution of DNA technology in the last few years, highlighting its importance in cases of forensic investigation. PMID- 23087584 TI - Comparison of cephalometric norms of caucasians and non-caucasians: A forensic aid in ethnic determination. PMID- 23087583 TI - Cheiloscopy: revisited. AB - Identification plays a very important role in any crime investigation. Cheiloscopy helps in identifying the humans based on the lips' traces. The pattern of wrinkles on the lips has individual characteristics like fingerprints. A review of the literature reveals very little research done on lip prints so far. The present article reviews in detail the history, scope of cheiloscopy, and the use of lip prints in crime detection. It also highlights the current research carried out in the field of cheiloscopy. An effort has been made to help the researchers by reviewing in detail the various methods of classifying and analyzing the lip prints. It concludes by enlightening the readers with the fact that the possibilities to use the red part of lips to identify a human being are wider than it is commonly thought. PMID- 23087585 TI - Development and Assessment of an Integrated Computer-Aided Detection Scheme for Digital Microscopic Images of Metaphase Chromosomes. AB - The authors developed an integrated computer-aided detection (CAD) scheme for detecting and classifying metaphase chromosomes as well as assessing its performance and robustness. This scheme includes an automatic metaphase-finding module and a karyotyping module and it was applied to a testing database with 200 digital microscopic images. The automatic metaphase-finding module detects analyzable metaphase cells using a feature-based artificial neural network (ANN). The ANN-generated outputs are analyzed by a receiver operating characteristics (ROC) method and an area under the ROC curve is 0.966. Then, the automatic karyotyping module classifies individual chromosomes of this cell into 24 types. In this module, a two-layer decision tree-based classifier with eight ANNs established in its connection nodes was optimized by a genetic algorithm. Chromosomes are first classified into seven groups by the ANN in the first layer. The chromosomes in these groups are then separately classified by seven ANNs into 24 types in the second layer. The classification accuracy is 94.5% in the first layer. Six ANNs achieved the accuracy above 95% and only one had lessened performance (80.6%) in the second layer. The overall classification accuracy is 91.5% as compared to 86.7% in the previous study using two independent datasets randomly acquired from our genetic laboratory. The results demonstrate that our automated scheme achieves high and robust performance in identification and classification of metaphase chromosomes. PMID- 23087586 TI - Towards Automatic Quantitative Quality Control for MRI. AB - Quality and consistency of clinical and research data collected from Magnetic Resonance Imaging (MRI) scanners may become suspect due to a wide variety of common factors including, experimental changes, hardware degradation, hardware replacement, software updates, personnel changes, and observed imaging artifacts. Standard practice limits quality analysis to visual assessment by a researcher/clinician or a quantitative quality control based upon phantoms which may not be timely, cannot account for differing experimental protocol (e.g. gradient timings and strengths), and may not be pertinent to the data or experimental question at hand. This paper presents a parallel processing pipeline developed towards experiment specific automatic quantitative quality control of MRI data using diffusion tensor imaging (DTI) as an experimental test case. The pipeline consists of automatic identification of DTI scans run on the MRI scanner, calculation of DTI contrasts from the data, implementation of modern statistical methods (wild bootstrap and SIMEX) to assess variance and bias in DTI contrasts, and quality assessment via power calculations and normative values. For this pipeline, a DTI specific power calculation analysis is developed as well as the first incorporation of bias estimates in DTI data to improve statistical analysis. PMID- 23087587 TI - Brief Trauma and Mental Health Assessments for Female Offenders in Addiction Treatment. AB - Increasing numbers of women in prison raise concerns about gender-specific problems and needs severity. Female offenders report higher trauma as well as mental and medical health complications than males, but large inmate populations and limited resources create challenges in administering proper diagnostic screening and assessments. This study focuses on brief instruments that address specialized trauma and health problems, along with related psychosocial functioning. Women from two prison-based treatment programs for substance abuse were assessed (N = 1,397), including one facility for special needs and one for regular female offenders. Results affirmed that admissions to the special needs facility reported more posttraumatic stress symptoms, higher rates of psychological stress and previous hospitalizations, and more health issues than those in the regular treatment facility. Findings supporting use of these short forms and their applications as tools for monitoring needs, progress, and change over time are discussed. PMID- 23087588 TI - Examining Concurrent Validity and Predictive Utility for the Addiction Severity Index and Texas Christian University (TCU) Short Forms. AB - Treatment providers need tools which are designed to identify risk, treatment needs, and monitor client engagement. These are essential components in substance abuse treatment for offender populations. This study evaluated a flexible set of 1-page modular assessments known as the TCU Short Forms and compared them with the measures of global domains contained in the Addiction Severity Index (ASI). The sample was based on 540 adult males and females in corrections-based substance abuse treatment services located in Arkansas and Missouri. Results suggest the set of TCU forms and ASI both reliably represent core clinical domains, but TCU Short Forms explained more variance in therapeutic engagement criteria measured during treatment. Similarities and differences of the assessment tools are discussed, along with applications. PMID- 23087589 TI - Forward-Projection Architecture for Fast Iterative Image Reconstruction in X-ray CT. AB - Iterative image reconstruction can dramatically improve the image quality in X ray computed tomography (CT), but the computation involves iterative steps of 3D forward- and back-projection, which impedes routine clinical use. To accelerate forward-projection, we analyze the CT geometry to identify the intrinsic parallelism and data access sequence for a highly parallel hardware architecture. To improve the efficiency of this architecture, we propose a water-filling buffer to remove pipeline stalls, and an out-of-order sectored processing to reduce the off-chip memory access by up to three orders of magnitude. We make a floating point to fixed-point conversion based on numerical simulations and demonstrate comparable image quality at a much lower implementation cost. As a proof of concept, a 5-stage fully pipelined, 55-way parallel separable-footprint forward projector is prototyped on a Xilinx Virtex-5 FPGA for a throughput of 925.8 million voxel projections/s at 200 MHz clock frequency, 4.6 times higher than an optimized 16-threaded program running on an 8-core 2.8-GHz CPU. A similar architecture can be applied to back-projection for a complete iterative image reconstruction system. The proposed algorithm and architecture can also be applied to hardware platforms such as graphics processing unit and digital signal processor to achieve significant accelerations. PMID- 23087590 TI - Antiproliferative activity and synthesis of 8-prenylnaringenin derivatives by demethylation of 7-O- and 4'-O-substituted isoxanthohumols. AB - Several analogues of 7-O- and 4'-O-substituted isoxanthohumol and 8 prenylnaringenin, the strongest known phytoestrogen and potential anticancerogenic agent, were synthesized. Acyl, alkyl, and allyl derivatives of isoxanthohumol underwent the demethylation process using MgI(2 )* 2Et(2)O in anhydrous THF with the yields of 61-89%. Some of the compounds approached the international criteria of antiproliferative activity (4 MUg/ml) for synthetic agents against the human cancer cell lines. PMID- 23087591 TI - Family Peer Advocates: A Pilot Study of the Content and Process of Service Provision. AB - Professional family peer advocates are increasingly employed by public mental health systems to deliver family-to-family support that reduces barriers families face in accessing children's mental health care. These services, however, are neither uniformly available nor standardized. This pilot study describes the process, content and context of family-to-family support services. Simulating a parent seeking services, a trained standardized parent participated as a client in meetings with advocates in four programs and collected data through structured observations, a structured survey, and session audiotapes. The "walk-through" process was determined to be feasible and acceptable to family peer advocates as a way of evaluating services. Four family peer advocates provided an average of 25 services during each 2-session simulation with the standardized parent, including the following: information and educational support, instruction and skills development, emotional and affirmational support, instrumental support, and advocacy. Findings also revealed variability in the range of services provided and identified challenges in aspects of service provision, such as boundaries of advocate roles, availability of confidential service environments, and addressing crises and parent concerns about child safety. This paper provides the first in-depth look at services provided by this emerging workforce. PMID- 23087592 TI - Spectral Imaging with Scattered Light: From Early Cancer Detection to Cell Biology. AB - This article reports the evolution of scanning spectral imaging techniques using scattered light for minimally invasive detection of early cancerous changes in tissue and cell biology applications. Optical spectroscopic techniques have shown promising results in the diagnosis of disease on a cellular scale. They do not require tissue removal, can be performed in vivo, and allow for real time diagnoses. Fluorescence and Raman spectroscopy are most effective in revealing molecular properties of tissue. Light scattering spectroscopy (LSS) relates the spectroscopic properties of light elastically scattered by small particles, such as epithelial cell nuclei and organelles, to their size, shape and refractive index. It is capable of characterizing the structural properties of tissue on cellular and sub-cellular scales. However, in order to be useful in the detection of early cancerous changes which are otherwise not visible to the naked eye, it must rapidly survey a comparatively large area while simultaneously detecting these cellular changes. Both goals are achieved by combining LSS with spatial scanning imaging. Two examples are described in this article. The first reviews a clinical system for screening patients with Barrett's esophagus. The second presents a novel advancement in confocal light absorption and scattering spectroscopic (CLASS) microscopy. PMID- 23087593 TI - Modeling Human Exposure to Phthalate Esters: A Comparison of Indirect and Biomonitoring Estimation Methods. AB - Humans are potentially exposed to phthalate esters (PEs) through ingestion, inhalation, and dermal contact. Studies quantifying exposure to PEs include "biomarker studies" and "indirect studies." Biomarker studies use measurements of PE metabolites in urine to back-calculate exposure to the parent diester, while indirect studies use the concentration of the PE in each medium of exposure and the rate of intake of that medium to quantify intake of the PE. In this review, exposure estimates from biomarker and indirect studies are compiled and compared for seven PEs to determine if there are regional differences and if there is a preferred approach. The indirect and biomarker methods generally agree with each other within an order of magnitude and discrepancies are explained by difficulties in accounting for use of consumer products, uncertainty concerning absorption, regional differences, and temporal changes. No single method is preferred for estimating intake of all PEs; it is suggested that biomarker estimates be used for low molecular weight PEs for which it is difficult to quantify all sources of exposure and either indirect or biomarker methods be used for higher molecular weight PEs. The indirect methods are useful in identifying sources of exposure while the biomarker methods quantify exposure. PMID- 23087594 TI - Reading Comprehension Strategies for Adult Literacy Outcomes. AB - Although research on improving child literacy is converging, no such body of research exists for adult literacy. Yet the need is no less significant. This study extends the knowledge garnered with younger populations by determining the reading comprehension strategies most important to adults' success on adult literacy outcome measures and aligning them with previously researched interventions. According to an analysis of key adult literacy outcome measures (i.e., competency-based, standardized tests of literacy commonly accepted as reasonable proxies for the global construct of adult literacy: Comprehensive Adult Student Assessment System [CASAS], General Educational Development [GED], and National Assessment of Educational Progress [NAEP]), adults should benefit from strategies that teach looking for clues in or generating questions about a text. Additionally, adults need to learn how to summarize and draw inferences in order to address higher-level literacy demands. Adult learners also need a metacognitive strategy to self-regulate reading behavior (e.g., choose a strategy to use, evaluate its effectiveness, and abandon and choose another strategy if necessary.) Furthermore, when using a competency-based standardized test, adult learners need to be coincidentally taught test-taking skills to reduce the test related task demands and produce a better index of a learner's reading comprehension skills. PMID- 23087595 TI - Effect of MWCNT surface and chemical modification on in vitro cellular response. AB - The aim of this study was to evaluate the impact of multi-walled carbon nanotubes (MWCNTs with diameter in the range of 10-30 nm) before and after chemical surface functionalisation on macrophages response. The study has shown that the detailed analysis of the physicochemical properties of this particular form of carbon nanomaterial is a crucial issue to interpret properly its impact on the cellular response. Effects of carbon nanotubes (CNTs) characteristics, including purity, dispersity, chemistry and dimension upon the nature of the cell environment material interaction were investigated. Various techniques involving electron microscopy (SEM, TEM), infrared spectroscopy (FTIR), inductively coupled plasma optical emission spectrometry, X-ray photoelectron spectroscopy have been employed to evaluate the physicochemical properties of the materials. The results demonstrate that the way of CNT preparation prior to biological tests has a fundamental impact on their behavior, cell viability and the nature of cell nanotube interaction. Chemical functionalisation of CNTs in an acidic ambient (MWCNT-Fs) facilitates interaction with cells by two possible mechanisms, namely, endocytosis/phagocytosis and by energy-independent passive process. The results indicate that MWCNT-F in macrophages may decrease the cell proliferation process by interfering with the mitotic apparatus without negative consequences on cell viability. On the contrary, the as-prepared MWCNTs, without any surface treatment produce the least reduction in cell proliferation with reference to control, and the viability of cells exposed to this sample was substantially reduced with respect to control. A possible explanation of such a phenomenon is the presence of MWCNT's agglomerates surrounded by numerous cells releasing toxic substances. PMID- 23087596 TI - Magnetic and luminescent hybrid nanomaterial based on Fe(3)O(4) nanocrystals and GdPO(4):Eu(3+) nanoneedles. AB - A bifunctional hybrid nanomaterial, which can show magnetic and luminescent properties, was obtained. A magnetic phase was synthesized as a core/shell type composite. Nanocrystalline magnetite, Fe(3)O(4) was used as the core and was encapsulated in a silica shell. The luminescent phase was GdPO(4) doped with Eu(3+) ions, as the emitter. The investigated materials were synthesized using a coprecipitation method. Encapsulated Fe(3)O(4) was "trapped" in a nano-scaffold composed of GdPO(4) crystalline nanoneedles. When an external magnetic field was applied, this hybrid composite was attracted in one direction. Also, the luminescent phase can move simultaneously with magnetite due to a "trapping" effect. The structure and morphology of the obtained nanocomposites were examined with the use of transmission electron microscopy and X-ray powder diffraction. Spectroscopic properties of the Eu(3+)-doped nanomaterials were studied by measuring their excitation and emission spectra as well as their luminescence decay times. GRAPHICAL ABSTRACT: PMID- 23087597 TI - Transfer Function Compensation in Gyroscope-free Inertial Measurement Units for Accurate Angular Motion Sensing. AB - Gyroscope-free inertial measurement units have been gaining popularity in applications such as motion sensing of hand-held microsurgical instruments. Various accelerometer placement configurations have been proposed in the past. However, the effect of non-identical transfer functions of accelerometers on the accuracy of angular motion sensing has been underestimated and never been taken into consideration. In this paper, significant effect of different phases at different accelerometer outputs due to non-identical transfer functions on the accuracy is highlighted, and a method is proposed to make the transfer functions of all the accelerometers identical. Effectiveness of the method is confirmed with an experiment using ADXL-203 accelerometers. PMID- 23087598 TI - Determination of effective potentials for the stretching of C(alpha) ? C(alpha) virtual bonds in polypeptide chains for coarse-grained simulations of proteins from ab initio energy surfaces of N-methylacetamide and N-acetylpyrrolidine. AB - The potentials of mean force (PMF's) for the deformation of the C(alpha) ? C(alpha) virtual bonds in polypeptide chains were determined from the diabatic energy surfaces of N-methylacetamide (modeling regular peptide groups) and N acetylpyrrolidine (modeling the peptide groups preceding proline), calculated at the Moller-Plesset (MP2) ab initio level of theory with the 6-31G(d,p) basis set. The energy surfaces were expressed in the C(alpha) ? C(alpha) virtual-bond length (d) and the H-N-C(alpha) ? C' improper dihedral angle (alpha) that describes the pyramidicity of the amide nitrogen, or in the C(alpha)-C'(O)-N-C(alpha) dihedral angle (omega) and the angle alpha. For each grid point, the potential energy was minimized with respect to all remaining degrees of freedom. The PMF's obtained from the (d, alpha) energy surfaces produced realistic free-energy barriers to the trans-cis transition (10 kcal/mol and 13 kcal/mol for the regular and proline peptide groups, respectively, compared to 12.6 - 13.9 kcal/mol and 17.3 - 19.6 kcal/mol determined experimentally for glycylglycine and N-acylprolines, respectively), while those obtained from the (omega, alpha) energy maps produced either low-quality PMF curves when direct Boltzmann summation was implemented to compute the PMF's or too-flat curves with too-low free-energy barriers to the trans-cis transition if harmonic extrapolation was used to estimate the contributions to the partition function. An analytical bimodal logarithmic Gaussian expression was fitted to the PMF's, and the potentials were implemented in the UNRES force field. Test Langevin-dynamics simulations were carried out for the Gly-Gly and Gly-Pro dipeptides, which showed a 10(6)-fold increase of the simulated rate of the trans-cis isomerization with respect to that measured experimentally; effectively the same result was obtained with the analytical Kramers theory of reaction rate applied to the UNRES representation of the peptide groups. Application of Kramers' theory to compute the rate constants from the all-atom ab initio energy surfaces of the model compounds studied resulted in isomerization rates close to the experimental values, which demonstrates that the increase of the isomerization rate in UNRES simulations results solely from averaging out the secondary degrees of freedom. PMID- 23087599 TI - Co-occurring Posttraumatic Stress Disorder and Alcohol Use Disorders in Veteran Populations. AB - Co-occurring posttraumatic stress disorder (PTSD) and alcohol use disorders have become increasingly prevalent in military populations. Over the past decade, PTSD has emerged as one of the most common forms of psychopathology among the 1.7 million American military personnel deployed to Iraq and Afghanistan in Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Operation New Dawn (OND). Among veterans from all eras, symptoms of PTSD have been highly correlated with hazardous drinking, leading to greater decreases in overall health and greater difficulties readjusting to civilian life. In fact, a diagnosis of co occurring PTSD and alcohol use disorder has proven more detrimental than a diagnosis of PTSD or alcohol use disorder alone. In order to effectively address co-occurring PTSD and alcohol use disorder, both the clinical and research communities have focused on better understanding this comorbidity, as well as increasing treatment outcomes among the veteran population. The purpose of the present article is threefold: (1) present a case study that highlights the manner in which PTSD and alcohol use disorder co-develop after trauma exposure; (2) present scientific theories on co - occurrence of PTSD and alcohol use disorder; and (3) present current treatment options for addressing this common comorbidity. PMID- 23087600 TI - Diagnosing Alcohol and Cannabis Use Disorders in Adolescents with Bipolar Disorder: A Preliminary Investigation. AB - OBJECTIVE: The aim of this report was to examine the accuracy of diagnosing substance use disorders in manic adolescents with bipolar disorder. METHODS: The substance use disorder modules of the KSADS-PL were administered to a sample of 80 manic adolescents (12-21 years old) with co-occurring bipolar and substance use disorders. Initial substance use disorder diagnoses obtained from the KSADS PL were then compared to a best-estimate diagnosis derived from all available information, including a second diagnostic interview, the Child Semi-Structured Assessment for the Genetics of Alcoholism, Adolescent version (C-SSAGA-A). RESULTS: Relatively low diagnostic agreement was achieved across the initial and the best estimate diagnoses for both alcohol and cannabis use disorders. Age, race, and sex did not predict diagnostic agreement between the two evaluations. CONCLUSIONS: Results of this study call for more research on diagnosing substance use disorders and suggest that a single interview alone may not be accurate for diagnosing substance use disorders in manic adolescents with bipolar disorder. PMID- 23087601 TI - Decomposing differences in utilization of health services between depressed and non-depressed elders in Europe. AB - Utilization rates of non-psychiatric health services are often higher in depressed compared to non-depressed adults. We examine whether these differences can be explained by the increased prevalence or the increased impact of demographic, socioeconomic, geographic, and health-related factors. The sample was taken from The Survey of Health, Ageing and Retirement in Europe (Wave 1 Release 2), a prospective observational study of 31,115 randomly selected people ages 50+ living in Austria, Germany, Sweden, the Netherlands, Spain, Italy, France, Denmark, Greece, Switzerland, Belgium, and Israel. Blinder-Oaxaca decomposition methods for multivariate linear regression models were used to estimate the influence of prevalence and impact of covariates on utilization among depressed and non-depressed participants. We find robust evidence that the gap in utilization between depressed and non-depressed can be accounted for by both prevalence (explained) and impact (unexplained) differences. The prevalence effect accounted for 57.7% whereas differences in the impact of covariates between depressed and non-depressed persons explained 42.3% of differences in utilization rates. Despite cross-national differences in quality and coverage of health services, in all countries, the prevalence effect was explained entirely by health measures, including: chronic diseases, functional mobility, painful symptoms, and self-reported health. The impact effect varied cross-nationally, but was largely explained by socioeconomic status and urbanicity. Hospitalization among depressed adults was twice that of non-depressed adults. Policies aimed at improving adherence and improving disease management among depressed adults should be explored. PMID- 23087603 TI - A systematic comparison of motion artifact correction techniques for functional near-infrared spectroscopy. AB - Near-infrared spectroscopy (NIRS) is susceptible to signal artifacts caused by relative motion between NIRS optical fibers and the scalp. These artifacts can be very damaging to the utility of functional NIRS, particularly in challenging subject groups where motion can be unavoidable. A number of approaches to the removal of motion artifacts from NIRS data have been suggested. In this paper we systematically compare the utility of a variety of published NIRS motion correction techniques using a simulated functional activation signal added to 20 real NIRS datasets which contain motion artifacts. Principle component analysis, spline interpolation, wavelet analysis, and Kalman filtering approaches are compared to one another and to standard approaches using the accuracy of the recovered, simulated hemodynamic response function (HRF). Each of the four motion correction techniques we tested yields a significant reduction in the mean squared error (MSE) and significant increase in the contrast-to-noise ratio (CNR) of the recovered HRF when compared to no correction and compared to a process of rejecting motion-contaminated trials. Spline interpolation produces the largest average reduction in MSE (55%) while wavelet analysis produces the highest average increase in CNR (39%). On the basis of this analysis, we recommend the routine application of motion correction techniques (particularly spline interpolation or wavelet analysis) to minimize the impact of motion artifacts on functional NIRS data. PMID- 23087602 TI - Evidence for transcriptional factor dysregulation in the dorsal raphe nucleus of patients with major depressive disorder. AB - Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits. PMID- 23087605 TI - On the plurality of (methodological) worlds: estimating the analytic flexibility of FMRI experiments. AB - How likely are published findings in the functional neuroimaging literature to be false? According to a recent mathematical model, the potential for false positives increases with the flexibility of analysis methods. Functional MRI (fMRI) experiments can be analyzed using a large number of commonly used tools, with little consensus on how, when, or whether to apply each one. This situation may lead to substantial variability in analysis outcomes. Thus, the present study sought to estimate the flexibility of neuroimaging analysis by submitting a single event-related fMRI experiment to a large number of unique analysis procedures. Ten analysis steps for which multiple strategies appear in the literature were identified, and two to four strategies were enumerated for each step. Considering all possible combinations of these strategies yielded 6,912 unique analysis pipelines. Activation maps from each pipeline were corrected for multiple comparisons using five thresholding approaches, yielding 34,560 significance maps. While some outcomes were relatively consistent across pipelines, others showed substantial methods-related variability in activation strength, location, and extent. Some analysis decisions contributed to this variability more than others, and different decisions were associated with distinct patterns of variability across the brain. Qualitative outcomes also varied with analysis parameters: many contrasts yielded significant activation under some pipelines but not others. Altogether, these results reveal considerable flexibility in the analysis of fMRI experiments. This observation, when combined with mathematical simulations linking analytic flexibility with elevated false positive rates, suggests that false positive results may be more prevalent than expected in the literature. This risk of inflated false positive rates may be mitigated by constraining the flexibility of analytic choices or by abstaining from selective analysis reporting. PMID- 23087606 TI - Do not Bet on the Unknown Versus Try to Find Out More: Estimation Uncertainty and "Unexpected Uncertainty" Both Modulate Exploration. AB - Little is known about how humans solve the exploitation/exploration trade-off. In particular, the evidence for uncertainty-driven exploration is mixed. The current study proposes a novel hypothesis of exploration that helps reconcile prior findings that may seem contradictory at first. According to this hypothesis, uncertainty-driven exploration involves a dilemma between two motives: (i) to speed up learning about the unknown, which may beget novel reward opportunities; (ii) to avoid the unknown because it is potentially dangerous. We provide evidence for our hypothesis using both behavioral and simulated data, and briefly point to recent evidence that the brain differentiates between these two motives. PMID- 23087604 TI - Effects of direct social experience on trust decisions and neural reward circuitry. AB - The human striatum is integral for reward-processing and supports learning by linking experienced outcomes with prior expectations. Recent endeavors implicate the striatum in processing outcomes of social interactions, such as social approval/rejection, as well as in learning reputations of others. Interestingly, social impressions often influence our behavior with others during interactions. Information about an interaction partner's moral character acquired from biographical information hinders updating of expectations after interactions via top down modulation of reward circuitry. An outstanding question is whether initial impressions formed through experience similarly modulate the ability to update social impressions at the behavioral and neural level. We investigated the role of experienced social information on trust behavior and reward-related BOLD activity. Participants played a computerized ball-tossing game with three fictional partners manipulated to be perceived as good, bad, or neutral. Participants then played an iterated trust game as investors with these same partners while undergoing fMRI. Unbeknownst to participants, partner behavior in the trust game was random and unrelated to their ball-tossing behavior. Participants' trust decisions were influenced by their prior experience in the ball-tossing game, investing less often with the bad partner compared to the good and neutral. Reinforcement learning models revealed that participants were more sensitive to updating their beliefs about good and bad partners when experiencing outcomes consistent with initial experience. Increased striatal and anterior cingulate BOLD activity for positive versus negative trust game outcomes emerged, which further correlated with model-derived prediction error learning signals. These results suggest that initial impressions formed from direct social experience can be continually shaped by consistent information through reward learning mechanisms. PMID- 23087607 TI - Multi-class motor imagery EEG decoding for brain-computer interfaces. AB - Recent studies show that scalp electroencephalography (EEG) as a non-invasive interface has great potential for brain-computer interfaces (BCIs). However, one factor that has limited practical applications for EEG-based BCI so far is the difficulty to decode brain signals in a reliable and efficient way. This paper proposes a new robust processing framework for decoding of multi-class motor imagery (MI) that is based on five main processing steps. (i) Raw EEG segmentation without the need of visual artifact inspection. (ii) Considering that EEG recordings are often contaminated not just by electrooculography (EOG) but also other types of artifacts, we propose to first implement an automatic artifact correction method that combines regression analysis with independent component analysis for recovering the original source signals. (iii) The significant difference between frequency components based on event-related (de-) synchronization and sample entropy is then used to find non-contiguous discriminating rhythms. After spectral filtering using the discriminating rhythms, a channel selection algorithm is used to select only relevant channels. (iv) Feature vectors are extracted based on the inter-class diversity and time varying dynamic characteristics of the signals. (v) Finally, a support vector machine is employed for four-class classification. We tested our proposed algorithm on experimental data that was obtained from dataset 2a of BCI competition IV (2008). The overall four-class kappa values (between 0.41 and 0.80) were comparable to other models but without requiring any artifact contaminated trial removal. The performance showed that multi-class MI tasks can be reliably discriminated using artifact-contaminated EEG recordings from a few channels. This may be a promising avenue for online robust EEG-based BCI applications. PMID- 23087609 TI - A Gateway between Recent and Remote Memory. PMID- 23087608 TI - The NKI-Rockland Sample: A Model for Accelerating the Pace of Discovery Science in Psychiatry. AB - The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI RS is an ongoing, institutionally centered endeavor aimed at creating a large scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology. PMID- 23087610 TI - What Silly Postures Tell Us about the Brain. PMID- 23087611 TI - Dancing combines the essence for successful aging. PMID- 23087612 TI - Constitutively expressed Protocadherin-alpha regulates the coalescence and elimination of homotypic olfactory axons through its cytoplasmic region. AB - Olfactory sensory neuron (OSN) axons coalesce into specific glomeruli in the olfactory bulb (OB) according to their odorant receptor (OR) expression. Several guidance molecules enhance the coalescence of homotypic OSN projections, in an OR specific- and neural-activity-dependent manner. However, the mechanism by which homotypic OSN axons are organized into glomeruli is unsolved. We previously reported that the clustered protocadherin-alpha (Pcdh-alpha) family of diverse cadherin-related molecules plays roles in the coalescence and elimination of homotypic OSN axons throughout development. Here we showed that the elimination of small ectopic homotypic glomeruli required the constitutive expression of a Pcdh-alpha isoform and Pcdh-alpha's cytoplasmic region, but not OR specificity or neural activity. These results suggest that Pcdh-alpha proteins provide a cytoplasmic signal to regulate repulsive activity for homotypic OSN axons independently of OR expression and neural activity. The counterbalancing effect of Pcdh-alpha proteins for the axonal coalescence mechanisms mediated by other olfactory guidance molecules indicate a possible mechanism for the organization of homotypic OSN axons into glomeruli during development. PMID- 23087613 TI - Rho-independent stimulation of axon outgrowth and activation of the ERK and Akt signaling pathways by C3 transferase in sensory neurons. AB - Peripheral nerve injury triggers the activation of RhoA in spinal motor and peripheral sensory neurons. RhoA activates a number of effector proteins including the Rho-associated kinase, ROCK, which targets the cytoskeleton and leads to inhibition of neurite outgrowth. Blockade of the Rho/ROCK pathway by pharmacological means improves axon regeneration after experimental injury. C3(bot) transferase, an exoenzyme produced by Clostridium botulinum, inactivates RhoA by ADP-ribosylation. It has been successfully applied in experimental CNS lesions to facilitate axon regeneration. Up to now it was not investigated thoroughly whether C3(bot) exerts positive effects on peripheral axon regeneration as well. In the present study, recombinant membrane permeable C3(bot) produced a small, but significant, axon outgrowth effect on peripheral sensory neurons dissociated from adult dorsal root ganglia (DRG) of the rat. Neuronal overexpression of C3, however, did not enhance axonal growth. Moreover, transfection of plasmids encoding dominant negative RhoA or RhoA specific shRNAs failed to increase axonal growth. Furthermore, we show that the C3(bot) mutant, C3(E174Q), which lacks RhoA inhibitory activity, still stimulates axonal growth. When analyzing possible signaling mechanisms we found that extracellular signal regulated kinase (ERK) and Akt are activated by C3(bot) and ERK is induced by the C3(E174Q) mutant. Upregulation of kinase activities by C3(bot) occurs significantly faster than inactivation of RhoA indicating a RhoA-independent pathway of action by C3(bot). The induction of ERK signaling by C3(bot) was detected in embryonic hippocampal neurons, too. Taken together, although RhoA plays a central role for inhibition of axon outgrowth by myelin-derived inhibitors, it does not interfere with axonal growth of sensory neurons on a permissive substrate in vitro. C3(bot) blocks neuronal RhoA activity, but its positive effects on axon elongation and branching appear to be mediated by Rho independent mechanisms involving activation of axon growth promoting ERK and Akt kinases. PMID- 23087614 TI - Translocating the blood-brain barrier using electrostatics. AB - Mammalian cell membranes regulate homeostasis, protein activity, and cell signaling. The charge at the membrane surface has been correlated with these key events. Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells (EC) are more negatively charged than human umbilical cord cells, using zeta-potential measurements by dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier (BBB) and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components-red blood cells (RBC), platelets, and peripheral blood mononuclear cells (PBMC). To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated. From all the cells tested, brain cell membranes are the most anionic and those having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier. PMID- 23087615 TI - Neuronal representation of visual motion and orientation in the fly medulla. AB - In insects, the first extraction of motion and direction clues from local brightness modulations is thought to take place in the medulla. However, whether and how these computations are represented in the medulla stills remain widely unknown, because electrical recording of the neurons in the medulla is difficult. As an effort to overcome this difficulty, we employed local electroporation in vivo in the medulla of the blowfly (Calliphora vicina) to stain small ensembles of neurons with a calcium-sensitive dye. We studied the responses of these neuronal ensembles to spatial and temporal brightness modulations and found selectivity for grating orientation. In contrast, the responses to the two opposite directions of motion of a grating with the same orientation were similar in magnitude, indicating that strong directional selectivity is either not present in the types of neurons covered by our data set, or that direction selective signals are too closely spaced to be distinguished by our calcium imaging. The calcium responses also showed a bell-shaped dependency on the temporal frequency of drifting gratings, with an optimum higher than that observed in one of the subsequent processing stages, i.e., the lobula plate. Medulla responses were elicited by on- as well as off-stimuli with some spatial heterogeneity in the sensitivity for "on" and "off", and in the polarity of the responses. Medulla neurons thus show similarities to some established principles of motion and edge detection in the vertebrate visual system. PMID- 23087616 TI - Inhibition shapes selectivity to vocalizations in the inferior colliculus of awake mice. AB - The inferior colliculus (IC) is a major center for integration of auditory information as it receives ascending projections from a variety of brainstem nuclei as well as descending projections from the thalamus and auditory cortex. The ascending projections are both excitatory and inhibitory and their convergence at the IC results in a microcircuitry that is important for shaping responses to simple, binaural, and modulated sounds in the IC. Here, we examined the role inhibition plays in shaping selectivity to vocalizations in the IC of awake, normal-hearing adult mice (CBA/CaJ strain). Neurons in the IC of mice show selectivity in their responses to vocalizations, and we hypothesized that this selectivity is created by inhibitory microcircuitry in the IC. We compared single unit responses in the IC to pure tones and a variety of ultrasonic mouse vocalizations before and after iontophoretic application of GABA(A) receptor (GABA(A)R) and glycine receptor (GlyR) antagonists. The most pronounced effects of blocking GABA(A)R and GlyR on IC neurons were to increase spike rates and broaden excitatory frequency tuning curves in response to pure tone stimuli, and to decrease selectivity to vocalizations. Thus, inhibition plays an important role in creating selectivity to vocalizations in the IC. PMID- 23087617 TI - Temporal and spatial adaptation of transient responses to local features. AB - Interpreting visual motion within the natural environment is a challenging task, particularly considering that natural scenes vary enormously in brightness, contrast and spatial structure. The performance of current models for the detection of self-generated optic flow depends critically on these very parameters, but despite this, animals manage to successfully navigate within a broad range of scenes. Within global scenes local areas with more salient features are common. Recent work has highlighted the influence that local, salient features have on the encoding of optic flow, but it has been difficult to quantify how local transient responses affect responses to subsequent features and thus contribute to the global neural response. To investigate this in more detail we used experimenter-designed stimuli and recorded intracellularly from motion-sensitive neurons. We limited the stimulus to a small vertically elongated strip, to investigate local and global neural responses to pairs of local "doublet" features that were designed to interact with each other in the temporal and spatial domain. We show that the passage of a high-contrast doublet feature produces a complex transient response from local motion detectors consistent with predictions of a simple computational model. In the neuron, the passage of a high contrast feature induces a local reduction in responses to subsequent low contrast features. However, this neural contrast gain reduction appears to be recruited only when features stretch vertically (i.e., orthogonal to the direction of motion) across at least several aligned neighboring ommatidia. Horizontal displacement of the components of elongated features abolishes the local adaptation effect. It is thus likely that features in natural scenes with vertically aligned edges, such as tree trunks, recruit the greatest amount of response suppression. This property could emphasize the local responses to such features vs. those in nearby texture within the scene. PMID- 23087618 TI - The brachial plexus branches to the pectoral muscles in adult rats: morphological aspects and morphometric normative data. AB - Animal models provide an important tool to investigate the pathogenesis of neuromuscular disorders. In the present study, we analyze fiber composition of the brachial plexus branches to the pectoral muscles: the medial anterior thoracic nerve (MATN) and the lateral anterior thoracic nerve (LATN). The morphological and morphometric characteristics and the percentage of motor fibers within each nerve are here reported, adding information to microscopic anatomy knowledge of the rat brachial plexus. As control, we employed the quadriceps nerve, commonly used for the evaluation of motor fibers at hindlimbs. We demonstrated that the MATN and the LATN are predominantly composed of large motor fibers and therefore could be employed to evaluate the peripheral nervous system (PNS) involvement at forelimbs in neurological diseases models, predominantly affecting the motor fiber compartment. PMID- 23087620 TI - Striatal signaling: two decades of progress. PMID- 23087621 TI - Keeping their distance? Odor response patterns along the concentration range. AB - We investigate the interplay of odor identity and concentration coding in the antennal lobe (AL) of the honeybee Apis mellifera. In this primary olfactory center of the honeybee brain, odors are encoded by the spatio-temporal response patterns of olfactory glomeruli. With rising odor concentration, further glomerular responses are recruited into the patterns, which affects distances between the patterns. Based on calcium-imaging recordings, we found that such pattern broadening renders distances between glomerular response patterns closer to chemical distances between the corresponding odor molecules. Our results offer an explanation for the honeybee's improved odor discrimination performance at higher odor concentrations. PMID- 23087619 TI - Communication and wiring in the cortical connectome. AB - In cerebral cortex, the huge mass of axonal wiring that carries information between near and distant neurons is thought to provide the neural substrate for cognitive and perceptual function. The goal of mapping the connectivity of cortical axons at different spatial scales, the cortical connectome, is to trace the paths of information flow in cerebral cortex. To appreciate the relationship between the connectome and cortical function, we need to discover the nature and purpose of the wiring principles underlying cortical connectivity. A popular explanation has been that axonal length is strictly minimized both within and between cortical regions. In contrast, we have hypothesized the existence of a multi-scale principle of cortical wiring where to optimize communication there is a trade-off between spatial (construction) and temporal (routing) costs. Here, using recent evidence concerning cortical spatial networks we critically evaluate this hypothesis at neuron, local circuit, and pathway scales. We report three main conclusions. First, the axonal and dendritic arbor morphology of single neocortical neurons may be governed by a similar wiring principle, one that balances the conservation of cellular material and conduction delay. Second, the same principle may be observed for fiber tracts connecting cortical regions. Third, the absence of sufficient local circuit data currently prohibits any meaningful assessment of the hypothesis at this scale of cortical organization. To avoid neglecting neuron and microcircuit levels of cortical organization, the connectome framework should incorporate more morphological description. In addition, structural analyses of temporal cost for cortical circuits should take account of both axonal conduction and neuronal integration delays, which appear mostly of the same order of magnitude. We conclude the hypothesized trade-off between spatial and temporal costs may potentially offer a powerful explanation for cortical wiring patterns. PMID- 23087622 TI - The social-sensory interface: category interactions in person perception. AB - Research is increasingly challenging the claim that distinct sources of social information-such as sex, race, and emotion-are processed in discrete fashion. Instead, there appear to be functionally relevant interactions that occur. In the present article, we describe research examining how cues conveyed by the human face, voice, and body interact to form the unified representations that guide our perceptions of and responses to other people. We explain how these information sources are often thrown into interaction through bottom-up forces (e.g., phenotypic cues) as well as top-down forces (e.g., stereotypes and prior knowledge). Such interactions point to a person perception process that is driven by an intimate interface between bottom-up perceptual and top-down social processes. Incorporating data from neuroimaging, event-related potentials (ERP), computational modeling, computer mouse-tracking, and other behavioral measures, we discuss the structure of this interface, and we consider its implications and adaptive purposes. We argue that an increased understanding of person perception will likely require a synthesis of insights and techniques, from social psychology to the cognitive, neural, and vision sciences. PMID- 23087623 TI - Neural correlates and neural computations in posterior parietal cortex during perceptual decision-making. AB - A recent line of work has found remarkable success in relating perceptual decision-making and the spiking activity in the macaque lateral intraparietal area (LIP). In this review, we focus on questions about the neural computations in LIP that are not answered by demonstrations of neural correlates of psychological processes. We highlight three areas of limitations in our current understanding of the precise neural computations that might underlie neural correlates of decisions: (1) empirical questions not yet answered by existing data; (2) implementation issues related to how neural circuits could actually implement the mechanisms suggested by both extracellular neurophysiology and psychophysics; and (3) ecological constraints related to the use of well controlled laboratory tasks and whether they provide an accurate window on sensorimotor computation. These issues motivate the adoption of a more general "encoding-decoding framework" that will be fruitful for more detailed contemplation of how neural computations in LIP relate to the formation of perceptual decisions. PMID- 23087625 TI - Neural correlates of individual differences in manual imitation fidelity. AB - Imitation is crucial for social learning, and so it is important to identify what determines between-subject variability in imitation fidelity. This might help explain what makes some people, like those with social difficulties such as in autism spectrum disorder (ASD), significantly worse at performance on these tasks than others. A novel paradigm was developed to provide objective measures of imitation fidelity in which participants used a touchscreen to imitate videos of a model drawing different shapes. Comparisons between model and participants' kinematic data provided three measures of imitative fidelity. We hypothesized that imitative ability would predict variation in BOLD signal whilst performing a simple imitation task in the MRI-scanner. In particular, an overall measure of accuracy (correlation between model and imitator) would predict activity in the overarching imitation system, whereas bias would be subject to more general aspects of motor control. Participants lying in the MRI-scanner were instructed to imitate different grips on a handle, or to watch someone or a circle moving the handle. Our hypothesis was partly confirmed as correlation between model and imitator was mediated by somatosensory cortex but also ventromedial prefrontal cortex, and bias was mediated mainly by cerebellum but also by the medial frontal and parietal cortices and insula. We suggest that this variance differentially reflects cognitive functions such as feedback-sensitivity and reward-dependent learning, contributing significantly to variability in individuals' imitative abilities as characterized by objective kinematic measures. PMID- 23087624 TI - Emotion and cognition interactions in PTSD: a review of neurocognitive and neuroimaging studies. AB - Posttraumatic stress disorder (PTSD) is a psychiatric syndrome that develops after exposure to terrifying and life-threatening events including warfare, motor vehicle accidents, and physical and sexual assault. The emotional experience of psychological trauma can have long-term cognitive effects. The hallmark symptoms of PTSD involve alterations to cognitive processes such as memory, attention, planning, and problem solving, underscoring the detrimental impact that negative emotionality has on cognitive functioning. As such, an important challenge for PTSD researchers and treatment providers is to understand the dynamic interplay between emotion and cognition. Contemporary cognitive models of PTSD theorize that a preponderance of information processing resources are allocated toward threat detection and interpretation of innocuous stimuli as threatening, narrowing one's attentional focus at the expense of other cognitive operations. Decades of research have shown support for these cognitive models of PTSD using a variety of tasks and methodological approaches. The primary goal of this review is to summarize the latest neurocognitive and neuroimaging research of emotion cognition interactions in PTSD. To directly assess the influence of emotion on cognition and vice versa, the studies reviewed employed challenge tasks that included both cognitive and emotional components. The findings provide evidence for memory and attention deficits in PTSD that are often associated with changes in functional brain activity. The results are reviewed to provide future directions for research that may direct better and more effective treatments for PTSD. PMID- 23087626 TI - Amygdala's involvement in facilitating associative learning-induced plasticity: a promiscuous role for the amygdala in memory acquisition. AB - It is widely accepted that the amygdala plays a critical role in acquisition and consolidation of fear-related memories. Some of the more widely employed behavioral paradigms that have assisted in solidifying the amygdala's role in fear-related memories are associative learning paradigms. With most associative learning tasks, a neutral conditioned stimulus (CS) is paired with a salient unconditioned stimulus (US) that elicits an unconditioned response (UR). After multiple CS-US pairings, the subject learns that the CS predicts the onset or delivery of the US, and thus elicits a learned conditioned response (CR). Most fear-related associative paradigms have suggested that an aspect of the fear association is stored in the amygdala; however, some fear-motivated associative paradigms suggest that the amygdala is not a site of storage, but rather facilitates consolidation in other brain regions. Based upon various learning theories, one of the most likely sites for storage of long-term memories is the neocortex. In support of these theories, findings from our laboratory, and others, have demonstrated that trace-conditioning, an associative paradigm where there is a separation in time between the CS and US, induces learning-specific neocortical plasticity. The following review will discuss the amygdala's involvement, either as a site of storage or facilitating storage in other brain regions such as the neocortex, in fear- and non-fear-motivated associative paradigms. In this review, we will discuss recent findings suggesting a broader role for the amygdala in increasing the saliency of behaviorally relevant information, thus facilitating acquisition for all forms of memory, both fear- and non-fear-related. This proposed promiscuous role of the amygdala in facilitating acquisition for all memories further suggests a potential role of the amygdala in general learning disabilities. PMID- 23087628 TI - Duration reproduction with sensory feedback delay: differential involvement of perception and action time. AB - Previous research has shown that voluntary action can attract subsequent, delayed feedback events toward the action, and adaptation to the sensorimotor delay can even reverse motor-sensory temporal order judgments. However, whether and how sensorimotor delay affects duration reproduction is still unclear. To investigate this, we injected an onset- or offset-delay to the sensory feedback signal from a duration reproduction task. We compared duration reproductions within (visual, auditory) modality and across audiovisual modalities with feedback signal onset- and offset-delay manipulations. We found that the reproduced duration was lengthened in both visual and auditory feedback signal onset-delay conditions. The lengthening effect was evident immediately, on the first trial with the onset delay. However, when the onset of the feedback signal was prior to the action, the lengthening effect was diminished. In contrast, a shortening effect was found with feedback signal offset-delay, though the effect was weaker and manifested only in the auditory offset-delay condition. These findings indicate that participants tend to mix the onset of action and the feedback signal more when the feedback is delayed, and they heavily rely on motor-stop signals for the duration reproduction. Furthermore, auditory duration was overestimated compared to visual duration in crossmodal feedback conditions, and the overestimation of auditory duration (or the underestimation of visual duration) was independent of the delay manipulation. PMID- 23087627 TI - Modulation of physiological reflexes by pain: role of the locus coeruleus. AB - The locus coeruleus (LC) is activated by noxious stimuli, and this activation leads to inhibition of perceived pain. As two physiological reflexes, the acoustic startle reflex and the pupillary light reflex, are sensitive to noxious stimuli, this review considers evidence that this sensitivity, at least to some extent, is mediated by the LC. The acoustic startle reflex, contraction of a large body of skeletal muscles in response to a sudden loud acoustic stimulus, can be enhanced by both directly ("sensitization") and indirectly ("fear conditioning") applied noxious stimuli. Fear-conditioning involves the association of a noxious (unconditioned) stimulus with a neutral (conditioned) stimulus (e.g., light), leading to the ability of the conditioned stimulus to evoke the "pain response". The enhancement of the startle response by conditioned fear ("fear-potentiated startle") involves the activation of the amygdala. The LC may also be involved in both sensitization and fear potentiation: pain signals activate the LC both directly and indirectly via the amygdala, which results in enhanced motoneurone activity, leading to an enhanced muscular response. Pupil diameter is under dual sympathetic/parasympathetic control, the sympathetic (noradrenergic) output dilating, and the parasympathetic (cholinergic) output constricting the pupil. The light reflex (constriction of the pupil in response to a light stimulus) operates via the parasympathetic output. The LC exerts a dual influence on pupillary control: it contributes to the sympathetic outflow and attenuates the parasympathetic output by inhibiting the Edinger-Westphal nucleus, the preganglionic cholinergic nucleus in the light reflex pathway. Noxious stimulation results in pupil dilation ("reflex dilation"), without any change in the light reflex response, consistent with sympathetic activation via the LC. Conditioned fear, on the other hand, results in the attenuation of the light reflex response ("fear-inhibited light reflex"), consistent with the inhibition of the parasympathetic light reflex via the LC. It is suggested that directly applied pain and fear-conditioning may affect different populations of autonomic neurones in the LC, directly applied pain activating sympathetic and fear-conditioning parasympathetic premotor neurones. PMID- 23087629 TI - Contextual control over expression of fear is affected by cortisol. AB - At the core of anxiety disorders is the inability to use contextual information to modulate behavioral responses to potentially threatening events. Models of the pathogenesis of anxiety disorders incorporate stress and concomitant stress hormones as important vulnerability factors, while others emphasize sex as an important factor. However, translational basic research has not yet investigated the effects of stress hormones and sex on the ability to use contextual information to modulate responses to threat. Therefore, the purpose of the present study was threefold: first, we aimed at developing an experimental paradigm specifically capable of capturing contextual modulation of the expression of fear. Second, we tested whether cortisol would alter the contextualization of fear expression. Third, we aimed at assessing whether alterations in contextualization due to cortisol were different for men and women. Healthy participants (n = 42) received placebo or hydrocortisone (20 mg) prior to undergoing a newly developed differential contextual fear-conditioning paradigm. The results indicated that people rapidly acquire differential contextual modulation of the expression of fear, as measured by fear potentiated startle (FPS) and skin conductance responses (SCR). In addition, cortisol impaired the contextualization of fear expression leading to increased fear generalization on FPS data in women. The opposite pattern was found in men. Finally, as assessed by SCR, cortisol impaired differential conditioning in men. The results are in line with models suggesting heightened vulnerability in women for developing anxiety disorders after stressful events. PMID- 23087630 TI - A zebrafish model of glucocorticoid resistance shows serotonergic modulation of the stress response. AB - One function of glucocorticoids is to restore homeostasis after an acute stress response by providing negative feedback to stress circuits in the brain. Loss of this negative feedback leads to elevated physiological stress and may contribute to depression, anxiety, and post-traumatic stress disorder. We investigated the early, developmental effects of glucocorticoid signaling deficits on stress physiology and related behaviors using a mutant zebrafish, gr(s357), with non functional glucocorticoid receptors (GRs). These mutants are morphologically inconspicuous and adult-viable. A previous study of adult gr(s357) mutants showed loss of glucocorticoid-mediated negative feedback and elevated physiological and behavioral stress markers. Already at 5 days post-fertilization, mutant larvae had elevated whole body cortisol, increased expression of pro-opiomelanocortin (POMC), the precursor of adrenocorticotropic hormone (ACTH), and failed to show normal suppression of stress markers after dexamethasone treatment. Mutant larvae had larger auditory-evoked startle responses compared to wildtype sibling controls (gr(wt)), despite having lower spontaneous activity levels. Fluoxetine (Prozac) treatment in mutants decreased startle responding and increased spontaneous activity, making them behaviorally similar to wildtype. This result mirrors known effects of selective serotonin reuptake inhibitors (SSRIs) in modifying glucocorticoid signaling and alleviating stress disorders in human patients. Our results suggest that larval gr(s357) zebrafish can be used to study behavioral, physiological, and molecular aspects of stress disorders. Most importantly, interactions between glucocorticoid and serotonin signaling appear to be highly conserved among vertebrates, suggesting deep homologies at the neural circuit level and opening up new avenues for research into psychiatric conditions. PMID- 23087631 TI - Toward an integrative account of social cognition: marrying theory of mind and interactionism to study the interplay of Type 1 and Type 2 processes. AB - Traditional theory of mind (ToM) accounts for social cognition have been at the basis of most studies in the social cognitive neurosciences. However, in recent years, the need to go beyond traditional ToM accounts for understanding real life social interactions has become all the more pressing. At the same time it remains unclear whether alternative accounts, such as interactionism, can yield a sufficient description and explanation of social interactions. We argue that instead of considering ToM and interactionism as mutually exclusive opponents, they should be integrated into a more comprehensive account of social cognition. We draw on dual process models of social cognition that contrast two different types of social cognitive processing. The first type (labeled Type 1) refers to processes that are fast, efficient, stimulus-driven, and relatively inflexible. The second type (labeled Type 2) refers to processes that are relatively slow, cognitively laborious, flexible, and may involve conscious control. We argue that while interactionism captures aspects of social cognition mostly related to Type 1 processes, ToM is more focused on those based on Type 2 processes. We suggest that real life social interactions are rarely based on either Type 1 or Type 2 processes alone. On the contrary, we propose that in most cases both types of processes are simultaneously involved and that social behavior may be sustained by the interplay between these two types of processes. Finally, we discuss how the new integrative framework can guide experimental research on social interaction. PMID- 23087632 TI - Combining EEG and eye tracking: identification, characterization, and correction of eye movement artifacts in electroencephalographic data. AB - Eye movements introduce large artifacts to electroencephalographic recordings (EEG) and thus render data analysis difficult or even impossible. Trials contaminated by eye movement and blink artifacts have to be discarded, hence in standard EEG-paradigms subjects are required to fixate on the screen. To overcome this restriction, several correction methods including regression and blind source separation have been proposed. Yet, there is no automated standard procedure established. By simultaneously recording eye movements and 64-channel EEG during a guided eye movement paradigm, we investigate and review the properties of eye movement artifacts, including corneo-retinal dipole changes, saccadic spike potentials and eyelid artifacts, and study their interrelations during different types of eye- and eyelid movements. In concordance with earlier studies our results confirm that these artifacts arise from different independent sources and that depending on electrode site, gaze direction, and choice of reference these sources contribute differently to the measured signal. We assess the respective implications for artifact correction methods and therefore compare the performance of two prominent approaches, namely linear regression and independent component analysis (ICA). We show and discuss that due to the independence of eye artifact sources, regression-based correction methods inevitably over- or under-correct individual artifact components, while ICA is in principle suited to address such mixtures of different types of artifacts. Finally, we propose an algorithm, which uses eye tracker information to objectively identify eye-artifact related ICA-components (ICs) in an automated manner. In the data presented here, the algorithm performed very similar to human experts when those were given both, the topographies of the ICs and their respective activations in a large amount of trials. Moreover it performed more reliable and almost twice as effective than human experts when those had to base their decision on IC topographies only. Furthermore, a receiver operating characteristic (ROC) analysis demonstrated an optimal balance of false positive and false negative at an area under curve (AUC) of more than 0.99. Removing the automatically detected ICs from the data resulted in removal or substantial suppression of ocular artifacts including microsaccadic spike potentials, while the relevant neural signal remained unaffected. In conclusion the present work aims at a better understanding of individual eye movement artifacts, their interrelations and the respective implications for eye artifact correction. Additionally, the proposed ICA-procedure provides a tool for optimized detection and correction of eye movement-related artifact components. PMID- 23087633 TI - Exploring the relationship between math anxiety and gender through implicit measurement. AB - Math anxiety, defined as a negative affective response to mathematics, is suggested as a strong antecedent for the low visibility of women in the science and engineering workforce. However, the assumption of gender differences in math anxiety is still being studied and results are inconclusive, probably due to the use of explicit measures such as direct questionnaires. Thus, our primary objective was to investigate the effects of math anxiety on numerical processing in males and females by using a novel affective priming task as an indirect measure. Specifically, university students (23 males and 30 females) completed a priming task in which an arithmetic equation was preceded by one of four types of priming words (positive, neutral, negative, or related to mathematics). Participants were required to indicate whether the equation (simple math facts based on addition, subtraction, multiplication, or division) was true or false. People are typically found to respond to target stimuli more rapidly after presentation of an affectively related prime than after an affectively unrelated one. In the current study, shorter response latencies for positive as compared to negative affective primes were found in the male group. An affective priming effect was found in the female group as well, but with a reversed pattern. That is, significantly shorter response latencies were observed in the female group for negative as compared to positive targets. That is, for females, negative affective primes act as affectively related to simple arithmetic problems. In contrast, males associated positive affect with simple arithmetic. In addition, only females with lower or insignificant negative affect toward arithmetic study at faculties of mathematics and science. We discuss the advantages of examining pure anxiety factors with implicit measures which are free of response factors. In addition it is suggested that environmental factors may enhance the association between math achievements and math anxiety in females. PMID- 23087634 TI - DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. AB - Oxytocin and its receptor (OXTR) play an important role in a variety of social perceptual and affiliative processes. Individual variability in social information processing likely has a strong heritable component, and as such, many investigations have established an association between common genetic variants of OXTR and variability in the social phenotype. However, to date, these investigations have primarily focused only on changes in the sequence of DNA without considering the role of epigenetic factors. DNA methylation is an epigenetic mechanism by which cells control transcription through modification of chromatin structure. DNA methylation of OXTR decreases expression of the gene and high levels of methylation have been associated with autism spectrum disorders (ASD). This link between epigenetic variability and social phenotype allows for the possibility that social processes are under epigenetic control. We hypothesized that the level of DNA methylation of OXTR would predict individual variability in social perception. Using the brain's sensitivity to displays of animacy as a neural endophenotype of social perception, we found significant associations between the degree of OXTR methylation and brain activity evoked by the perception of animacy. Our results suggest that consideration of DNA methylation may substantially improve our ability to explain individual differences in imaging genetic association studies. PMID- 23087635 TI - Parallel ICA identifies sub-components of resting state networks that covary with behavioral indices. AB - Parallel Independent Component Analysis (para-ICA) is a multivariate method that can identify complex relationships between different data modalities by simultaneously performing Independent Component Analysis on each data set while finding mutual information between the two data sets. We use para-ICA to test the hypothesis that spatial sub-components of common resting state networks (RSNs) covary with specific behavioral measures. Resting state scans and a battery of behavioral indices were collected from 24 younger adults. Group ICA was performed and common RSNs were identified by spatial correlation to publically available templates. Nine RSNs were identified and para-ICA was run on each network with a matrix of behavioral measures serving as the second data type. Five networks had spatial sub-components that significantly correlated with behavioral components. These included a sub-component of the temporo-parietal attention network that differentially covaried with different trial-types of a sustained attention task, sub-components of default mode networks that covaried with attention and working memory tasks, and a sub-component of the bilateral frontal network that split the left inferior frontal gyrus into three clusters according to its cytoarchitecture that differentially covaried with working memory performance. Additionally, we demonstrate the validity of para-ICA in cases with unbalanced dimensions using simulated data. PMID- 23087636 TI - Does the inferior frontal sulcus play a functional role in deception? A neuronavigated theta-burst transcranial magnetic stimulation study. AB - By definition, lying involves withholding the truth. Response inhibition may therefore be the cognitive function at the heart of deception. Neuroimaging research has shown that the same brain region that is activated during response inhibition tasks, namely the inferior frontal region, is also activated during deception paradigms. This led to the hypothesis that the inferior frontal region is the neural substrate critically involved in withholding the truth. In the present study, we critically examine the functional necessity of the inferior frontal region in withholding the truth during deception. We experimentally manipulated the neural activity level in right inferior frontal sulcus (IFS) by means of neuronavigated continuous theta-burst stimulation (cTBS). Individual structural magnetic resonance brain images (MRI) were used to allow precise stimulation in each participant. Twenty-six participants answered autobiographical questions truthfully or deceptively before and after sham and real cTBS. Deception was reliably associated with more errors, longer and more variable response times than truth telling. Despite the potential role of IFS in deception as suggested by neuroimaging data, the cTBS-induced disruption of right IFS did not affect response times or error rates, when compared to sham stimulation. The present findings do not support the hypothesis that the right IFS is critically involved in deception. PMID- 23087637 TI - A meta-analytic review of multisensory imagery identifies the neural correlates of modality-specific and modality-general imagery. AB - The relationship between imagery and mental representations induced through perception has been the subject of philosophical discussion since antiquity and of vigorous scientific debate in the last century. The relatively recent advent of functional neuroimaging has allowed neuroscientists to look for brain-based evidence for or against the argument that perceptual processes underlie mental imagery. Recent investigations of imagery in many new domains and the parallel development of new meta-analytic techniques now afford us a clearer picture of the relationship between the neural processes underlying imagery and perception, and indeed between imagery and other cognitive processes. This meta-analysis surveyed 65 studies investigating modality-specific imagery in auditory, tactile, motor, gustatory, olfactory, and three visual sub-domains: form, color and motion. Activation likelihood estimate (ALE) analyses of activation foci reported within- and across sensorimotor modalities were conducted. The results indicate that modality-specific imagery activations generally overlap with-but are not confined to-corresponding somatosensory processing and motor execution areas, and suggest that there is a core network of brain regions recruited during imagery, regardless of task. These findings have important implications for investigations of imagery and theories of cognitive processes, such as perceptually-based representational systems. PMID- 23087639 TI - Open evaluation: a vision for entirely transparent post-publication peer review and rating for science. AB - The two major functions of a scientific publishing system are to provide access to and evaluation of scientific papers. While open access (OA) is becoming a reality, open evaluation (OE), the other side of the coin, has received less attention. Evaluation steers the attention of the scientific community and thus the very course of science. It also influences the use of scientific findings in public policy. The current system of scientific publishing provides only journal prestige as an indication of the quality of new papers and relies on a non transparent and noisy pre-publication peer-review process, which delays publication by many months on average. Here I propose an OE system, in which papers are evaluated post-publication in an ongoing fashion by means of open peer review and rating. Through signed ratings and reviews, scientists steer the attention of their field and build their reputation. Reviewers are motivated to be objective, because low-quality or self-serving signed evaluations will negatively impact their reputation. A core feature of this proposal is a division of powers between the accumulation of evaluative evidence and the analysis of this evidence by paper evaluation functions (PEFs). PEFs can be freely defined by individuals or groups (e.g., scientific societies) and provide a plurality of perspectives on the scientific literature. Simple PEFs will use averages of ratings, weighting reviewers (e.g., by H-index), and rating scales (e.g., by relevance to a decision process) in different ways. Complex PEFs will use advanced statistical techniques to infer the quality of a paper. Papers with initially promising ratings will be more deeply evaluated. The continual refinement of PEFs in response to attempts by individuals to influence evaluations in their own favor will make the system ungameable. OA and OE together have the power to revolutionize scientific publishing and usher in a new culture of transparency, constructive criticism, and collaboration. PMID- 23087638 TI - Multi-voxel pattern analysis in human hippocampal subfields. AB - A complete understanding of the hippocampus depends on elucidating the representations and computations that exist in its anatomically distinct subfields. High-resolution structural and functional MRI scanning is starting to permit insights into hippocampal subfields in humans. In parallel, such scanning has facilitated the use of multi-voxel pattern analysis (MVPA) to examine information present in the distributed pattern of activity across voxels. The aim of this study was to combine these two relatively new innovations and deploy MVPA in the hippocampal subfields. Delineating subregions of the human hippocampus, a prerequisite for our study, remains a significant challenge, with extant methods often only examining part of the hippocampus, or being unable to differentiate CA3 and dentate gyrus (DG). We therefore devised a new high-resolution anatomical scanning and subfield segmentation protocol that allowed us to overcome these issues, and separately identify CA1, CA3, DG, and subiculum (SUB) across the whole hippocampus using a standard 3T MRI scanner. We then used MVPA to examine fMRI data associated with a decision-making paradigm involving highly similar scenes that had relevance for the computations that occur in hippocampal subfields. Intra- and inter-rater scores for subfield identification using our procedure confirmed its reliability. Moreover, we found that decoding of information within hippocampal subfields was possible using MVPA, with findings that included differential effects for CA3 and DG. We suggest that MVPA in human hippocampal subfields may open up new opportunities to examine how different types of information are represented and processed at this fundamental level. PMID- 23087640 TI - A model of food reward learning with dynamic reward exposure. AB - The process of conditioning via reward learning is highly relevant to the study of food choice and obesity. Learning is itself shaped by environmental exposure, with the potential for such exposures to vary substantially across individuals and across place and time. In this paper, we use computational techniques to extend a well-validated standard model of reward learning, introducing both substantial heterogeneity and dynamic reward exposures. We then apply the extended model to a food choice context. The model produces a variety of individual behaviors and population-level patterns which are not evident from the traditional formulation, but which offer potential insights for understanding food reward learning and obesity. These include a "lock-in" effect, through which early exposure can strongly shape later reward valuation. We discuss potential implications of our results for the study and prevention of obesity, for the reward learning field, and for future experimental and computational work. PMID- 23087641 TI - Spatio-temporal pattern recognizers using spiking neurons and spike-timing dependent plasticity. AB - It has previously been shown that by using spike-timing-dependent plasticity (STDP), neurons can adapt to the beginning of a repeating spatio-temporal firing pattern in their input. In the present work, we demonstrate that this mechanism can be extended to train recognizers for longer spatio-temporal input signals. Using a number of neurons that are mutually connected by plastic synapses and subject to a global winner-takes-all mechanism, chains of neurons can form where each neuron is selective to a different segment of a repeating input pattern, and the neurons are feed-forwardly connected in such a way that both the correct input segment and the firing of the previous neurons are required in order to activate the next neuron in the chain. This is akin to a simple class of finite state automata. We show that nearest-neighbor STDP (where only the pre-synaptic spike most recent to a post-synaptic one is considered) leads to "nearest neighbor" chains where connections only form between subsequent states in a chain (similar to classic "synfire chains"). In contrast, "all-to-all spike-timing dependent plasticity" (where all pre- and post-synaptic spike pairs matter) leads to multiple connections that can span several temporal stages in the chain; these connections respect the temporal order of the neurons. It is also demonstrated that previously learnt individual chains can be "stitched together" by repeatedly presenting them in a fixed order. This way longer sequence recognizers can be formed, and potentially also nested structures. Robustness of recognition with respect to speed variations in the input patterns is shown to depend on rise times of post-synaptic potentials and the membrane noise. It is argued that the memory capacity of the model is high, but could theoretically be increased using sparse codes. PMID- 23087642 TI - Short-term ionic plasticity at GABAergic synapses. AB - Fast synaptic inhibition in the brain is mediated by the pre-synaptic release of the neurotransmitter gamma-Aminobutyric acid (GABA)and the post-synaptic activation of GABA-sensitive ionotropic receptors. As with excitatory synapses, it is being increasinly appreciated that a variety of plastic processes occur at inhibitory synapses, which operate over a range of timescales. Here we examine a form of activity-dependent plasticity that is somewhat unique to GABAergic transmission. This involves short-lasting changes to the ionic driving force for the post-synaptic receptors, a process referred to as short-term ionic plasticity. These changes are directly related to the history of activity at inhibitory synapses and are influenced by a variety of factors including the location of the synapse and the post-synaptic cell's ion regulation mechanisms. We explore the processes underlying this form of plasticity, when and where it can occur, and how it is likely to impact network activity. PMID- 23087643 TI - Cotinine: Beyond that Expected, More than a Biomarker of Tobacco Consumption. AB - A greater incidence of tobacco consumption occurs among individuals with psychiatric conditions including post-traumatic stress disorder (PTSD), bipolar disorder, major depression, and schizophrenia, compared with the general population. Even when still controversial, it has been postulated that smoking is a form of self-medication that reduces psychiatric symptoms among individuals with these disorders. To better understand the component(s) of tobacco-inducing smoking behavior, greater attention has been directed toward nicotine. However, in recent years, new evidence has shown that cotinine, the main metabolite of nicotine, exhibits beneficial effects over psychiatric symptoms and may therefore promote smoking within this population. Some of the behavioral effects of cotinine compared to nicotine are discussed here. Cotinine, which accumulates in the body as a result of tobacco exposure, crosses the blood-brain barrier and has different pharmacological properties compared with nicotine. Cotinine has a longer plasma half-life than nicotine and showed no addictive or cardiovascular effects in humans. In addition, at the preclinical level, cotinine facilitated the extinction of fear memory and anxiety after fear conditioning, improved working memory in a mouse model of Alzheimer's disease (AD) and in a monkey model of schizophrenia. Altogether, the new evidence suggests that the pharmacological and behavioral effects of cotinine may play a key role in promoting tobacco smoking in individuals that suffer from psychiatric conditions and represents a new potential therapeutic agent against psychiatric conditions such as AD and PTSD. PMID- 23087645 TI - Stratified medicine and reimbursement issues. AB - Stratified Medicine (SM) has the potential to target patient populations who will most benefit from a therapy while reducing unnecessary health interventions associated with side effects. The link between clinical biomarkers/diagnostics and therapies provides new opportunities for value creation to strengthen the value proposition to pricing and reimbursement (P&R) authorities. However, the introduction of SM challenges current reimbursement schemes in many EU countries and the US as different P&R policies have been adopted for drugs and diagnostics. Also, there is a lack of a consistent process for value assessment of more complex diagnostics in these markets. New, innovative approaches and more flexible P&R systems are needed to reflect the added value of diagnostic tests and to stimulate investments in new technologies. Yet, the framework for access of diagnostic-based therapies still requires further development while setting the right incentives and appropriate align stakeholders interests when realizing long-term patient benefits. This article addresses the reimbursement challenges of SM approaches in several EU countries and the US outlining some options to overcome existing reimbursement barriers for stratified medicine. PMID- 23087644 TI - Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence. AB - Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of BDNF and COMT on neurocognition in alcohol dependence is unclear. The primary goal of this report was to investigate the associations of single nucleotide polymorphisms (SNPs) in BDNF Val66Met (rs6265) and COMT Val158Met (rs4680) with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC) who completed a comprehensive neuropsychological battery after 33 +/- 9 days of monitored abstinence. After controlling for COMT and BDNF genotypes, smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed, and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains after controlling for genotypes and alcohol consumption. In addition, COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that reported COMT Met carriers demonstrated better performance on measures of executive skills and general intelligence. Results also indicated that the poorer performance of smoking compared to non-smoking ALC across multiple neurocognitive domains was not mediated by COMT or BDNF genotype. Overall, the findings lend support to the expanding clinical movement to make smoking cessation programs available to smokers at the inception of treatment for alcohol/substance use disorders. PMID- 23087646 TI - Regions of KCNQ K(+) channels controlling functional expression. AB - KCNQ1-5 alpha-subunits assemble to form K(+) channels that play critical roles in the function of numerous tissues. The channels are tetramers of subunits containing six transmembrane domains. Each subunit consists of a pore region (S5 pore-S6) and a voltage-sensor domain (S1-S4). Despite similar structures, KCNQ2 and KCNQ3 homomers yield small current amplitudes compared to other KCNQ homomers and KCNQ2/3 heteromers. Two major mechanisms have been suggested as governing functional expression. The first involves control of channel trafficking to the plasma membrane by the distal part of the C-terminus, containing two coiled coiled domains, required for channel trafficking and assembly. The proximal half of the C-terminus is the crucial region for channel modulation by signaling molecules such as calmodulin (CaM), which may mediate C- and N-terminal interactions. The N-terminus of KCNQ channels has also been postulated as critical for channel surface expression. The second mechanism suggests networks of interactions between the pore helix and the selectivity filter (SF), and between the pore helix and the S6 domain that govern KCNQ current amplitudes. Here, we summarize the role of these different regions in expression of functional KCNQ channels. PMID- 23087648 TI - Changes in dive behavior during naval sonar exposure in killer whales, long finned pilot whales, and sperm whales. AB - Anthropogenic underwater sound in the environment might potentially affect the behavior of marine mammals enough to have an impact on their reproduction and survival. Diving behavior of four killer whales (Orcinus orca), seven long-finned pilot whales (Globicephala melas), and four sperm whales (Physeter macrocephalus) was studied during controlled exposures to naval sonar [low frequency active sonar (LFAS): 1-2 kHz and mid frequency active sonar (MFAS): 6-7 kHz] during three field seasons (2006-2009). Diving behavior was monitored before, during and after sonar exposure using an archival tag placed on the animal with suction cups. The tag recorded the animal's vertical movement, and additional data on horizontal movement and vocalizations were used to determine behavioral modes. Killer whales that were conducting deep dives at sonar onset changed abruptly to shallow diving (ShD) during LFAS, while killer whales conducting deep dives at the onset of MFAS did not alter dive mode. When in ShD mode at sonar onset, killer whales did not change their diving behavior. Pilot and sperm whales performed normal deep dives (NDD) during MFAS exposure. During LFAS exposures, long-finned pilot whales mostly performed fewer deep dives and some sperm whales performed shallower and shorter dives. Acoustic recording data presented previously indicates that deep diving (DD) is associated with feeding. Therefore, the observed changes in dive behavior of the three species could potentially reduce the foraging efficiency of the affected animals. PMID- 23087649 TI - Outlook: membrane junctions enable the metabolic trapping of fatty acids by intracellular acyl-CoA synthetases. AB - The mechanism of fatty acid uptake is of high interest for basic research and clinical interventions. Recently, we showed that mammalian long chain fatty acyl CoA synthetases (ACS) are not only essential enzymes for lipid metabolism but are also involved in cellular fatty acid uptake. Overexpression, RNAi depletion or hormonal stimulation of ACS enzymes lead to corresponding changes of fatty acid uptake. Remarkably, ACS are not localized to the plasma membrane where fatty acids are entering the cell, but are found instead at the endoplasmic reticulum (ER) or other intracellular organelles like mitochondria and lipid droplets. This is in contrast to current models suggesting that ACS enzymes function in complex with transporters at the cell surface. Drawing on recent insights into non vesicular lipid transport, we suggest a revised model for the cellular fatty acid uptake of mammalian cells which incorporates trafficking of fatty acids across membrane junctions. Intracellular ACS enzymes are then metabolically trapping fatty acids as acyl-CoA derivatives. These local decreases in fatty acid concentration will unbalance the equilibrium of fatty acids across the plasma membrane, and thus provide a driving force for fatty acid uptake. PMID- 23087647 TI - Maladaptive spinal plasticity opposes spinal learning and recovery in spinal cord injury. AB - Synaptic plasticity within the spinal cord has great potential to facilitate recovery of function after spinal cord injury (SCI). Spinal plasticity can be induced in an activity-dependent manner even without input from the brain after complete SCI. A mechanistic basis for these effects is provided by research demonstrating that spinal synapses have many of the same plasticity mechanisms that are known to underlie learning and memory in the brain. In addition, the lumbar spinal cord can sustain several forms of learning and memory, including limb-position training. However, not all spinal plasticity promotes recovery of function. Central sensitization of nociceptive (pain) pathways in the spinal cord may emerge in response to various noxious inputs, demonstrating that plasticity within the spinal cord may contribute to maladaptive pain states. In this review we discuss interactions between adaptive and maladaptive forms of activity dependent plasticity in the spinal cord below the level of SCI. The literature demonstrates that activity-dependent plasticity within the spinal cord must be carefully tuned to promote adaptive spinal training. Prior work from our group has shown that stimulation that is delivered in a limb position-dependent manner or on a fixed interval can induce adaptive plasticity that promotes future spinal cord learning and reduces nociceptive hyper-reactivity. On the other hand, stimulation that is delivered in an unsynchronized fashion, such as randomized electrical stimulation or peripheral skin injuries, can generate maladaptive spinal plasticity that undermines future spinal cord learning, reduces recovery of locomotor function, and promotes nociceptive hyper-reactivity after SCI. We review these basic phenomena, how these findings relate to the broader spinal plasticity literature, discuss the cellular and molecular mechanisms, and finally discuss implications of these and other findings for improved rehabilitative therapies after SCI. PMID- 23087650 TI - The intestinal microbiome and the leaky gut as therapeutic targets in alcoholic liver disease. AB - Alcoholic liver disease (ALD) encompasses hepatic steatosis, which may progress to alcoholic hepatitis, fibrosis, and cirrhosis. It remains a leading cause of morbidity and mortality in the US and worldwide. The severity of liver disease correlates with plasma levels of bacterial products in patients, and experimental ALD depends on the level of gut derived bacterial products in rodents. Since intestinal decontamination and deficiency of bacterial product receptors or their downstream signaling molecules protect from alcohol-induced liver disease, bacterial translocation (BT), qualitative, and quantitative changes of the enteric microbiome are considered as being of fundamental importance in the pathogenesis of ALD. Recent enhancements in diagnostic technologies provide a better insight into these shifts. This review highlights vital events in ALD such as BT, the importance of Toll-like receptor (TLR) signaling, intestinal bacterial overgrowth (IBO), and changes in the intestinal microbiome. Furthermore, a treatment trial section of patients reviews possible future options of therapy for ALD modifying the enteric microbiome. PMID- 23087651 TI - Modulation of the cough reflex by GABA(A) receptors in the caudal ventral respiratory group of the rabbit. AB - We have previously shown that the caudal ventral respiratory group (cVRG) is a possible site of action of some antitussive drugs and plays a crucial role in determining both the expiratory and inspiratory components of the cough motor pattern. In addition, it has been reported that medullary expiratory neurons of the cVRG are subject to potent GABAergic gain modulation. This study was devoted to investigate the role of cVRG GABA(A) receptors in the control of baseline respiratory activity and cough responses to mechanical and chemical (citric acid) stimulation of the tracheobronchial tree. To this purpose, bilateral microinjections (30-50 nl) of bicuculline or muscimol were performed into the cVRG of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Bicuculline (1 mM) increased peak abdominal activity and respiratory frequency due to decreases in T(E). Cough responses were potentiated mainly owing to increases in the cough number. The recovery was observed within ~2 h. On the contrary, muscimol (0.3 mM) abolished abdominal activity and decreased respiratory frequency due to increases in T(E). In addition, cough responses were progressively reduced and completely suppressed within ~20 min. Partial recovery of cough responses was achieved after ~3 h or within ~5 min following bicuculline microinjections at the same locations. The sneeze reflex induced by mechanical stimulation of the nasal mucosa persisted following bicuculline and muscimol microinjections. However, the number and intensity of expiratory thrusts were enhanced by bicuculline and suppressed by muscimol. The results provide evidence that a potent GABA(A)-mediated inhibitory modulation is exerted at the level of the cVRG not only on respiratory activity, but also on cough and sneeze reflex responses. PMID- 23087652 TI - Ocular convergence deficits in schizophrenia. AB - Individuals with schizophrenia (SZ) have been reported to exhibit a higher prevalence of convergence insufficiency (CI) than the "normal" adult population. The purpose of this study was to determine if individuals with SZ exhibit clinical signs of CI and to determine if the Convergence Insufficiency Symptom Survey (CISS) is an effective instrument for identifying CI in this population. Twenty participants with SZ and 20 healthy controls (HC) completed the study. The prevalence of CI (15%) in the SZ group was slightly higher than reported norms, but the difference was not significant. The SZ group had significantly higher scores on the CISS than the HC group, but the CISS scores did not correlate with clinical measures of CI in individuals with SZ. The only exception was that SZ patients had a significantly reduced fusional reserve as determined by Sheard's criteria. Further study is needed to determine why individuals with SZ reported symptoms associated with CI even though clinical measures did not support this diagnosis. PMID- 23087653 TI - A systematic review of non-invasive brain stimulation therapies and cardiovascular risk: implications for the treatment of major depressive disorder. AB - Major depressive disorder (MDD) and cardiovascular diseases are intimately associated. Depression is an independent risk factor for mortality in cardiovascular samples. Neuroendocrine dysfunctions in MDD are related to an overactive hypothalamus-pituitary-adrenal (HPA) axis and increased sympathetic activity. Novel intervention strategies for MDD include the non-invasive brain stimulation (NIBS) techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). In fact, although these techniques have being increasingly used as a treatment for MDD, their cardiovascular effects were not sufficiently investigated, which would be important considering the dyad MDD/cardiovascular disorders. We investigated this issue through a systematic review for published articles from the first date available to May 2012 in MEDLINE and other databases, looking for main risk factors and surrogate markers for cardiovascular disease such as: cortisol, heart rate variability (HRV), alcohol, smoking, obesity, hypertension, glucose. We identified 37 articles (981 subjects) according to our eligibility criteria. Our main findings were that NIBS techniques might be effective strategies for down regulating HPA activity and regulating food, alcohol, and cigarette consumption. NIBS's effects on HRV and blood pressure presented mixed findings, with studies suggesting that HRV values can decrease or remain unchanged after NIBS, while one study found that rTMS increased blood pressure levels. Also, a single study showed that glucose levels decrease after tDCS. However, most studies tested the acute effects after one single session of rTMS/tDCS; therefore further studies are necessary to investigate whether NIBS modifies cardiovascular risk factors in the long-term. In fact, considering the burden of cardiac disease, further trials in cardiovascular, depressed, and non-depressed samples using NIBS should be performed. PMID- 23087654 TI - Target optimization in transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is an emerging neuromodulation therapy that has been experimentally determined to affect a wide range of behaviors and diseases ranging from motor, cognitive, and memory processes to depression and pain syndromes. The effects of tDCS may be inhibitory or excitatory, depending on the relative polarities of electrodes and their proximity to different brain structures. This distinction is believed to relate to the interaction of current flow with activation thresholds of different neural complexes. tDCS currents are typically applied via a single pair of large electrodes, with one (the active electrode) sited close to brain structures associated with targeted processes. To efficiently direct current toward the areas presumed related to these effects, we devised a method of steering current toward a selected area by reference to a 19-electrode montage applied to a high resolution finite element model of the head. We used a non-linear optimization procedure to maximize mean current densities inside the left inferior frontal gyrus (IFG), while simultaneously restricting overall current, and median current densities within the accumbens. We found that a distributed current pattern could be found that would indeed direct current toward the IFG in this way, and compared it to other candidate 2-electrode configurations. Further, we found a combination of four anterior-posterior electrodes could direct current densities to the accumbens. We conclude that a similar method using multiple electrodes may be a useful means of directing current toward or away from specific brain regions and also of reducing tDCS side effects. PMID- 23087655 TI - Unreliable gut feelings can lead to correct decisions: the somatic marker hypothesis in non-linear decision chains. AB - Dual-process approaches of decision-making examine the interaction between affective/intuitive and deliberative processes underlying value judgment. From this perspective, decisions are supported by a combination of relatively explicit capabilities for abstract reasoning and relatively implicit evolved domain general as well as learned domain-specific affective responses. One such approach, the somatic markers hypothesis (SMH), expresses these implicit processes as a system of evolved primary emotions supplemented by associations between affect and experience that accrue over lifetime, or somatic markers. In this view, somatic markers are useful only if their local capability to predict the value of an action is above a baseline equal to the predictive capability of the combined rational and primary emotional subsystems. We argue that decision making has often been conceived of as a linear process: the effect of decision sequences is additive, local utility is cumulative, and there is no strong environmental feedback. This widespread assumption can have consequences for answering questions regarding the relative weight between the systems and their interaction within a cognitive architecture. We introduce a mathematical formalization of the SMH and study it in situations of dynamic, non-linear decision chains using a discrete-time stochastic model. We find, contrary to expectations, that decision-making events can interact non-additively with the environment in apparently paradoxical ways. We find that in non-lethal situations, primary emotions are represented globally over and above their local weight, showing a tendency for overcautiousness in situated decision chains. We also show that because they tend to counteract this trend, poorly attuned somatic markers that by themselves do not locally enhance decision-making, can still produce an overall positive effect. This result has developmental and evolutionary implications since, by promoting exploratory behavior, somatic markers would seem to be beneficial even at early stages when experiential attunement is poor. Although the model is formulated in terms of the SMH, the implications apply to dual systems theories in general since it makes minimal assumptions about the nature of the processes involved. PMID- 23087656 TI - Imaging when acting: picture but not word cues induce action-related biases of visual attention. AB - In line with the Theory of Event Coding (Hommel et al., 2001a), action planning has been shown to affect perceptual processing - an effect that has been attributed to a so-called intentional weighting mechanism (Wykowska et al., 2009; Memelink and Hommel, 2012), whose functional role is to provide information for open parameters of online action adjustment (Hommel, 2010). The aim of this study was to test whether different types of action representations induce intentional weighting to various degrees. To meet this aim, we introduced a paradigm in which participants performed a visual search task while preparing to grasp or to point. The to-be performed movement was signaled either by a picture of a required action or a word cue. We reasoned that picture cues might trigger a more concrete action representation that would be more likely to activate the intentional weighting of perceptual dimensions that provide information for online action control. In contrast, word cues were expected to trigger a more abstract action representation that would be less likely to induce intentional weighting. In two experiments, preparing for an action facilitated the processing of targets in an unrelated search task if they differed from distractors on a dimension that provided information for online action control. As predicted, however, this effect was observed only if action preparation was signaled by picture cues but not if it was signaled by word cues. We conclude that picture cues are more efficient than word cues in activating the intentional weighting of perceptual dimensions, presumably by specifying not only invariant characteristics of the planned action but also the dimensions of action-specific parameters. PMID- 23087657 TI - Behavioral investigation of the influence of social categorization on empathy for pain: a minimal group paradigm study. AB - Research on empathy for pain has provided evidence of an empathic bias toward racial ingroup members. In this study, we used for the first time the "minimal group paradigm" in which participants were assigned to artificial groups and required to perform pain judgments of pictures of hands and feet in painful or non-painful situations from self, ingroup, and outgroup perspectives. Findings showed that the mere categorization of people into two distinct arbitrary social groups appears to be sufficient to elicit an ingroup bias in empathy for pain. PMID- 23087658 TI - Goal salience affects infants' goal-directed gaze shifts. AB - Around their first year of life, infants are able to anticipate the goal of others' ongoing actions. For instance, 12-month-olds anticipate the goal of everyday feeding actions and manual actions such as reaching and grasping. However, little is known whether the salience of the goal influences infants' online assessment of others' actions. The aim of the current eye-tracking study was to elucidate infants' ability to anticipate reaching actions depending on the visual salience of the goal object. In Experiment 1, 12-month-old infants' goal directed gaze shifts were recorded as they observed a hand reaching for and grasping either a large (high-salience condition) or a small (low-salience condition) goal object. Infants exhibited predictive gaze shifts significantly earlier when the observed hand reached for the large goal object compared to when it reached for the small goal object. In addition, findings revealed rapid learning over the course of trials in the high-salience condition and no learning in the low-salience condition. Experiment 2 demonstrated that the results could not be simply attributed to the different grip aperture of the hand used when reaching for small and large objects. Together, our data indicate that by the end of their first year of life, infants rely on information about the goal salience to make inferences about the action goal. PMID- 23087659 TI - Future morphology? Summary of visual word identification effects draws attention to necessary efforts in understanding morphological processing. PMID- 23087660 TI - Emotion and anticipation in an enactive framework for cognition (response to andy clark). PMID- 23087661 TI - Electrophysiological cross-language neighborhood density effects in late and early english-welsh bilinguals. AB - Behavioral studies with proficient late bilinguals have revealed the existence of orthographic neighborhood density (ND) effects across languages when participants read either in their first (L1) or second (L2) language. Words with many cross language (CL) neighbors have been found to elicit more negative event-related potentials (ERPs) than words with few CL neighbors (Midgley et al., 2008); the effect started earlier, and was larger, for L2 words. Here, 14 late and 14 early English-Welsh bilinguals performed a semantic categorization task on English and Welsh words presented in separate blocks. The pattern of CL activation was different for the two groups of bilinguals. In late bilinguals, words with high CLND elicited more negative ERP amplitudes than words with low CLND starting around 175 ms after word onset and lasting until 500 ms. This effect interacted with language in the 300-500 ms time window. A more complex pattern of early effects was revealed in early bilinguals and there were no effects in the N400 window. These results suggest that CL activation of orthographic neighbors is highly sensitive to the bilinguals' learning experience of the two languages. PMID- 23087662 TI - Whatever after next? Adaptive predictions based on short- and long-term memory in visual search. PMID- 23087663 TI - How Would the World Look if It Looked as if It were Encoded as an Intertwined Set of Probability Density Distributions? PMID- 23087664 TI - Neuromyths in Education: Prevalence and Predictors of Misconceptions among Teachers. AB - The OECD's Brain and Learning project (2002) emphasized that many misconceptions about the brain exist among professionals in the field of education. Though these so-called "neuromyths" are loosely based on scientific facts, they may have adverse effects on educational practice. The present study investigated the prevalence and predictors of neuromyths among teachers in selected regions in the United Kingdom and the Netherlands. A large observational survey design was used to assess general knowledge of the brain and neuromyths. The sample comprised 242 primary and secondary school teachers who were interested in the neuroscience of learning. It would be of concern if neuromyths were found in this sample, as these teachers may want to use these incorrect interpretations of neuroscience findings in their teaching practice. Participants completed an online survey containing 32 statements about the brain and its influence on learning, of which 15 were neuromyths. Additional data was collected regarding background variables (e.g., age, sex, school type). Results showed that on average, teachers believed 49% of the neuromyths, particularly myths related to commercialized educational programs. Around 70% of the general knowledge statements were answered correctly. Teachers who read popular science magazines achieved higher scores on general knowledge questions. More general knowledge also predicted an increased belief in neuromyths. These findings suggest that teachers who are enthusiastic about the possible application of neuroscience findings in the classroom find it difficult to distinguish pseudoscience from scientific facts. Possessing greater general knowledge about the brain does not appear to protect teachers from believing in neuromyths. This demonstrates the need for enhanced interdisciplinary communication to reduce such misunderstandings in the future and establish a successful collaboration between neuroscience and education. PMID- 23087665 TI - Characterization of interictal epileptiform discharges with time-resolved cortical current maps using the helmholtz-hodge decomposition. AB - Source estimates performed using a single equivalent current dipole (ECD) model for interictal epileptiform discharges (IEDs) which appear unifocal have proven highly accurate in neocortical epilepsies, falling within millimeters of that demonstrated by electrocorticography. Despite this success, the single ECD solution is limited, best describing sources which are temporally stable. Adapted from the field of optics, optical flow analysis of distributed source models of MEG or EEG data has been proposed as a means to estimate the current motion field of cortical activity, or "cortical flow." The motion field so defined can be used to identify dynamic features of interest such as patterns of directional flow, current sources, and sinks. The Helmholtz-Hodge Decomposition (HHD) is a technique frequently applied in fluid dynamics to separate a flow pattern into three components: (1) a non-rotational scalar potential U describing sinks and sources, (2) a non-diverging scalar potential A accounting for vortices, and (3) an harmonic vector field H. As IEDs seem likely to represent periods of highly correlated directional flow of cortical currents, the U component of the HHD suggests itself as a way to characterize spikes in terms of current sources and sinks. In a series of patients with refractory epilepsy who were studied with magnetoencephalography as part of their evaluation for possible resective surgery, spike localization with ECD was compared to HHD applied to an optical flow analysis of the same spike. Reasonable anatomic correlation between the two techniques was seen in the majority of patients, suggesting that this method may offer an additional means of characterization of epileptic discharges. PMID- 23087667 TI - The value of glioma extent of resection in the modern neurosurgical era. AB - OBJECTIVE: There remains no general consensus in the neurosurgical oncology literature regarding the role of extent of glioma resection in improving patient outcome. Although the value of resection in establishing a diagnosis and alleviating mass effect is clear, there is less certainty in ascertaining the influence of extent of resection (EOR). Here, we review the recent literature to synthesize a comprehensive review of the value of extent of resection for gliomas in the modern neurosurgical era. METHODS: We reviewed every major peer-reviewed clinical publication since 1990 on the role of EOR in glioma outcome. RESULTS: Thirty-two high-grade glioma articles and 11 low-grade glioma articles were examined in terms of quality of evidence, expected EOR, and survival benefit. CONCLUSION: Despite limitations in the quality of data, mounting evidence suggests that more extensive surgical resection is associated with longer life expectancy for both low- and high-grade newly diagnosed gliomas. PMID- 23087666 TI - Piecing together phenotypes of brain injury and dysfunction in obstructive sleep apnea. AB - Obstructive sleep apnea (OSA) is a highly prevalent condition that is associated with significant neurobehavioral impairments. Cognitive abnormalities identified in individuals with OSA include impaired verbal memory, planning, reasoning, vigilance, and mood. Therapy for OSA improves some but not all neurobehavioral outcomes, supporting a direct role for OSA in brain dysfunction and raising the question of irreversible injury from OSA. Recent clinical studies have refined the neurobehavioral, brain imaging, and electrophysiological characteristics of OSA, highlighting findings shared with aging and some unique to OSA. This review summarizes the cognitive, brain metabolic and structural, and peripheral nerve conduction changes observed in OSA that collectively provide a distinct phenotype of OSA brain injury and dysfunction. Findings in animal models of OSA provide insight into molecular mechanisms underlying OSA neuronal injury that can be related back to human neural injury and dysfunction. A comprehensive phenotype of brain function and injury in OSA is essential for advancing diagnosis, prevention, and treatment of this common disorder. PMID- 23087668 TI - Anesthesia-induced developmental neurodegeneration: the role of neuronal organelles. AB - Exposure to general anesthetics (GAs) and antiepileptics during critical stages of brain development causes significant neurotoxicity to immature neurons. Many animal, and emerging human studies have shown long-term functional sequelae manifested as behavioral deficits and cognitive impairments. Since GAs and antiepileptic drugs are a necessity, current research is focused on deciphering the mechanisms responsible for anesthesia-induced developmental neurotoxicity so that protective strategies can be devised. These agents promote massive and wide spread neuroapoptosis that is caused by the impairment of integrity and function of neuronal organelles. Mitochondria and endoplasmic reticulum are particularly vulnerable. By promoting significant release of intracellular calcium from the endoplasmic reticulum, anesthetics cause an increase in mitochondrial calcium load resulting in the loss of their integrity, release of pro-apoptotic factors, functional impairment of ATP synthesis, and enhanced accumulation of reactive oxygen species. The possibility that GAs may have direct damaging effects on mitochondria, resulting in the impairment of their morphogenesis, also has been proposed. This review will present evidence that neuronal organelles are critical and early targets of anesthesia-induced developmental neurotoxicity. PMID- 23087669 TI - Advanced pre-clinical research approaches and models to studying pediatric anesthetic neurotoxicity. AB - Advances in pediatric and obstetric surgery have resulted in an increase in the duration and complexity of anesthetic procedures. A great deal of concern has recently arisen regarding the safety of anesthesia in infants and children. Because of obvious limitations, it is not possible to thoroughly explore the effects of anesthetic agents on neurons in vivo in human infants or children. However, the availability of some advanced pre-clinical research approaches and models, such as imaging technology both in vitro and in vivo, stem cells, and non human primate experimental models, have provided potentially invaluable tools for examining the developmental effects of anesthetic agents. This review discusses the potential application of some sophisticated research approaches, e.g., calcium imaging, in stem cell-derived in vitro models, especially human embryonic neural stem cells, along with their capacity for proliferation and their potential for differentiation, to dissect relevant mechanisms underlying the etiology of the neurotoxicity associated with developmental exposures to anesthetic agents. Also, this review attempts to discuss several advantages for using the developing rhesus monkey model (in vivo), when combined with dynamic molecular imaging approaches, in addressing critical issues related to the topic of pediatric sedation/anesthesia. These include the relationships between anesthetic-induced neurotoxicity, dose response, time-course, and developmental stage at time of exposure (in vivo studies), serving to provide the most expeditious platform toward decreasing the uncertainty in extrapolating pre clinical data to the human condition. PMID- 23087671 TI - The Close Relationship between Sleep Disorders and Reproductive Dysfunction in Endocrinology. PMID- 23087672 TI - Taltirelin is a superagonist at the human thyrotropin-releasing hormone receptor. AB - Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a superagonist at TRH-R. We suggest the superagonism exhibited by TAL may in part explain its higher activity in mediating central nervous system effects in humans compared to TRH. PMID- 23087673 TI - Gonadotropin-releasing hormone 2 suppresses food intake in the zebrafish, Danio rerio. AB - Gonadotropin-releasing hormone (GnRH) is an evolutionarily conserved neuropeptide with 10 amino acid residues, of which several structural variants exist. A molecular form known as GnRH2 ([His(5) Trp(7) Tyr(8)]GnRH, also known as chicken GnRH II) is widely distributed in vertebrates except for rodents, and has recently been implicated in the regulation of feeding behavior in goldfish. However, the influence of GnRH2 on feeding behavior in other fish has not yet been studied. In the present study, therefore, we investigated the role of GnRH2 in the regulation of feeding behavior in a zebrafish model, and examined its involvement in food intake after intracerebroventricular (ICV) administration. ICV injection of GnRH2 at 0.1 and 1 pmol/g body weight (BW) induced a marked decrease of food consumption in a dose-dependent manner during 30 min after feeding. Cumulative food intake was significantly decreased by ICV injection of GnRH2 at 1 pmol/g BW during the 30-min post-treatment observation period. The anorexigenic action of GnRH2 was completely blocked by treatment with the GnRH type I receptor antagonist Antide at 25 pmol/g BW. We also examined the effect of feeding condition on the expression level of the GnRH2 transcript in the hypothalamus. Levels of GnRH2 mRNA obtained from fish that had been provided excess food for 7 days were higher than those in fish that had been fed normally. These results suggest that, in zebrafish, GnRH2 acts as an anorexigenic factor, as is the case in goldfish. PMID- 23087670 TI - Obstructive sleep apnea and non-alcoholic Fatty liver disease: is the liver another target? AB - Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done. PMID- 23087674 TI - Sensitivity of cholecystokinin receptors to membrane cholesterol content. AB - Cholesterol represents a structurally and functionally important component of the eukaryotic cell membrane, where it increases lipid order, affects permeability, and influences the lateral mobility and conformation of membrane proteins. Several G protein-coupled receptors have been shown to be affected by the cholesterol content of the membrane, with functional impact on their ligand binding and signal transduction characteristics. The effects of cholesterol can be mediated directly by specific molecular interactions with the receptor and/or indirectly by altering the physical properties of the membrane. This review focuses on the importance and differential effects of membrane cholesterol on the activity of cholecystokinin (CCK) receptors. The type 1 CCK receptor is quite sensitive to its cholesterol environment, while the type 2 CCK receptor is not. The possible structural basis for this differential impact is explored and the implications of pathological states, such as metabolic syndrome, in which membrane cholesterol may be increased and CCK1R function may be abnormal are discussed. This is believed to have substantial potential importance for the development of drugs targeting the CCK receptor. PMID- 23087675 TI - Co-occurrence patterns of plants and soil bacteria in the high-alpine subnival zone track environmental harshness. AB - Plants and soil microorganisms interact to play a central role in ecosystem functioning. To determine the potential importance of biotic interactions in shaping the distributions of these organisms in a high-alpine subnival landscape, we examine co-occurrence patterns between plant species and bulk soil bacteria abundances. In this context, a co-occurrence relationship reflects a combination of several assembly processes: that both parties can disperse to the site, that they can survive the abiotic environmental conditions, and that interactions between the biota either facilitate survival or allow for coexistence. Across the entire landscape, 31% of the bacterial sequences in this dataset were significantly correlated to the abundance distribution of one or more plant species. These sequences fell into 14 clades, 6 of which are related to bacteria that are known to form symbioses with plants in other systems. Abundant plant species were more likely to have significant as well as stronger correlations with bacteria and these patterns were more prevalent in lower altitude sites. Conversely, correlations between plant species abundances and bacterial relative abundances were less frequent in sites near the snowline. Thus, plant-bacteria associations became more common as environmental conditions became less harsh and plants became more abundant. This pattern in co-occurrence strength and frequency across the subnival landscape suggests that plant-bacteria interactions are important for the success of life, both below- and above-ground, in an extreme environment. PMID- 23087676 TI - The mercury resistance operon: from an origin in a geothermal environment to an efficient detoxification machine. AB - Mercuric mercury (Hg[II]) is a highly toxic and mobile element that is likely to have had a pronounced and adverse effect on biology since Earth's oxygenation ~2.4 billion years ago due to its high affinity for protein sulfhydryl groups, which upon binding destabilize protein structure and decrease enzyme activity, resulting in a decreased organismal fitness. The central enzyme in the microbial mercury detoxification system is the mercuric reductase (MerA) protein, which catalyzes the reduction of Hg(II) to volatile Hg(0). In addition to MerA, mer operons encode for proteins involved in regulation, Hg binding, and organomercury degradation. Mer-mediated approaches have had broad applications in the bioremediation of mercury-contaminated environments and industrial waste streams. Here, we examine the composition of 272 individual mer operons and quantitatively map the distribution of mer-encoded functions on both taxonomic SSU rRNA gene and MerA phylogenies. The results indicate an origin and early evolution of MerA among thermophilic bacteria and an overall increase in the complexity of mer operons through evolutionary time, suggesting continual gene recruitment and evolution leading to an improved efficiency and functional potential of the Mer detoxification system. Consistent with a positive relationship between the evolutionary history and topology of MerA and SSU rRNA gene phylogenies (Mantel R = 0.81, p < 0.01), the distribution of the majority of mer functions, when mapped on these phylograms, indicates an overall tendency to inherit mer-encoded functions through vertical descent. However, individual mer functions display evidence of a variable degree of vertical inheritance, with several genes exhibiting strong evidence for acquisition via lateral gene transfer and/or gene loss. Collectively, these data suggest that (i) mer has evolved from a simple system in geothermal environments to a widely distributed and more complex and efficient detoxification system, and (ii) merA is a suitable biomarker for examining the functional diversity of Hg detoxification and for predicting the composition of mer operons in natural environments. PMID- 23087678 TI - Microbial Response to the MC-252 Oil and Corexit 9500 in the Gulf of Mexico. AB - The Deepwater Horizon spill released over 4.1 million barrels of crude oil into the Gulf of Mexico. In an effort to mitigate large oil slicks, the dispersant Corexit 9500 was sprayed onto surface slicks and injected directly at the wellhead at water depth of 1,500 m. Several research groups were involved in investigating the fate of the MC-252 oil using newly advanced molecular tools to elucidate microbial interactions with oil, gases, and dispersant. Microbial community analysis by different research groups revealed that hydrocarbon degrading bacteria belonging to Oceanospirillales, Colwellia, Cycloclasticus, Rhodobacterales, Pseudoalteromonas, and methylotrophs were found enriched in the contaminated water column. Presented here is a comprehensive overview of the ecogenomics of microbial degradation of MC-252 oil and gases in the water column and shorelines. We also present some insight into the fate of the dispersant Corexit 9500 that was added to aid in oil dispersion process. Our results show the dispersant was not toxic to the indigenous microbes at concentrations added, and different bacterial species isolated in the aftermath of the spill were able to degrade the various components of Corexit 9500 that included hydrocarbons, glycols, and dioctyl sulfosuccinate. PMID- 23087677 TI - Synechococcus sp. Strain PCC 7002 Transcriptome: Acclimation to Temperature, Salinity, Oxidative Stress, and Mixotrophic Growth Conditions. AB - Synechococcus sp. strain PCC 7002 is a unicellular, euryhaline cyanobacterium. It is a model organism for studies of cyanobacterial metabolism and has great potential for biotechnological applications. It exhibits an exceptional tolerance of high-light irradiation and shows very rapid growth. The habitats from which this and closely related strains were isolated are subject to changes in several environmental factors, including light, nutrient supply, temperature, and salinity. In this study global transcriptome profiling via RNAseq has been used to perform a comparative and integrated study of global changes in cells grown at different temperatures, at different salinities, and under mixotrophic conditions, when a metabolizable organic carbon source was present. Furthermore, the transcriptomes were investigated for cells that were subjected to a heat shock and that were exposed to oxidative stress. Lower growth temperatures caused relatively minor changes of the transcriptome; the most prominent changes affected fatty acid desaturases. A heat shock caused severe changes of the transcriptome pattern; transcripts for genes associated with major metabolic pathways declined and those for different chaperones increased dramatically. Oxidative stress, however, left the transcript pattern almost unaffected. When grown at high salinity, Synechococcus sp. PCC 7002 had increased expression of genes involved in compatible solute biosynthesis and showed increased mRNA levels for several genes involved in electron transport. Transcripts of two adjacent genes dramatically increased upon growth at high salinity; the respective proteins are putatively involved in coping with oxidative stress and in triggering ion channels. Only minor changes were observed when cells were grown at low salinity or when the growth medium was supplemented with glycerol. However, the transcriptome data suggest that cells must acclimate to excess reducing equivalents when a reduced C-source is present. PMID- 23087679 TI - Response of biological soil crust diazotrophs to season, altered summer precipitation, and year-round increased temperature in an arid grassland of the colorado plateau, USA. AB - Biological soil crusts (biocrusts), which supply significant amounts of fixed nitrogen into terrestrial ecosystems worldwide (~33 Tg y(-1)), are likely to respond to changes in temperature and precipitation associated with climate change. Using nifH gene-based surveys, we explored variation in the diazotrophic community of biocrusts of the Colorado Plateau, USA in response to season (autumn vs. spring), as well as field manipulations that increased the frequency of small volume precipitation events and year-round soil temperature. Abundance of nifH genes in biocrusts ranged from 3 * 10(6) to 1 * 10(8) g(-1) soil, and nifH from heterocystous cyanobacteria closely related to Scytonema hyalinum, Spirirestis rafaelensis, and Nostoc commune comprised >98% of the total. Although there was no apparent seasonal effect on total nifH gene abundance in the biocrusts, T-RFLP analysis revealed a strong seasonal pattern in nifH composition. SpirirestisnifH abundance was estimated to oscillate 1 to >2 orders of magnitude between autumn (low) and spring (high). A year-round increase of soil temperature (2-3 degrees C) had little effect on the diazotroph community structure over 2 years. Altered summer precipitation had little impact on diazotroph community structure over the first 1.5 years of the study, when natural background patterns across years and seasons superseded any treatment effects. However, after the second summer of treatments, nifH abundance was 2.6-fold lower in biocrusts receiving altered precipitation. Heterocystous cyanobacteria were apparently more resilient to altered precipitation than other cyanobacteria. The results demonstrate that diazotrophic community composition of biocrusts in this semi-arid grassland undergoes strong seasonal shifts and that the abundance of its dominant members decreased in response to more frequent, small volume precipitation events. PMID- 23087680 TI - Factors influencing the diversity of iron uptake systems in aquatic microorganisms. AB - Iron (Fe) is an essential micronutrient for many processes in all living cells. Dissolved Fe (dFe) concentrations in the ocean are of the order of a few nM, and Fe is often a factor limiting primary production. Bioavailability of Fe in aquatic environments is believed to be primarily controlled through chelation by Fe-binding ligands. Marine microbes have evolved different mechanisms to cope with the scarcity of bioavailable dFe. Gradients in dFe concentrations and diversity of the Fe-ligand pool from coastal to open ocean waters have presumably imposed selection pressures that should be reflected in the genomes of microbial communities inhabiting the pelagic realm. We applied a hidden Markov model (HMM) based search for proteins related to cellular iron metabolism, and in particular those involved in Fe uptake mechanisms in 164 microbial genomes belonging to diverse taxa and occupying different aquatic niches. A multivariate statistical approach demonstrated that in phototrophic organisms, there is a clear influence of the ecological niche on the diversity of Fe uptake systems. Extending the analyses to the metagenome database from the Global Ocean Sampling expedition, we demonstrated that the Fe uptake and homeostasis mechanisms differed significantly across marine niches defined by temperatures and dFe concentrations, and that this difference was linked to the distribution of microbial taxa in these niches. Using the dN/dS ratios (which signify the rate of non-synonymous mutations) of the nucleotide sequences, we identified that genes encoding for TonB, Ferritin, Ferric reductase, IdiA, ZupT, and Fe(2+) transport proteins FeoA and FeoB were evolving at a faster rate (positive selection pressure) while genes encoding ferrisiderophore, heme and Vitamin B12 uptake systems, siderophore biosynthesis, and IsiA and IsiB were under purifying selection pressure (evolving slowly). PMID- 23087681 TI - Trait-based representation of biological nitrification: model development, testing, and predicted community composition. AB - Trait-based microbial models show clear promise as tools to represent the diversity and activity of microorganisms across ecosystem gradients. These models parameterize specific traits that determine the relative fitness of an "organism" in a given environment, and represent the complexity of biological systems across temporal and spatial scales. In this study we introduce a microbial community trait-based modeling framework (MicroTrait) focused on nitrification (MicroTrait N) that represents the ammonia-oxidizing bacteria (AOB) and ammonia-oxidizing archaea (AOA) and nitrite-oxidizing bacteria (NOB) using traits related to enzyme kinetics and physiological properties. We used this model to predict nitrifier diversity, ammonia (NH(3)) oxidation rates, and nitrous oxide (N(2)O) production across pH, temperature, and substrate gradients. Predicted nitrifier diversity was predominantly determined by temperature and substrate availability, the latter was strongly influenced by pH. The model predicted that transient N(2)O production rates are maximized by a decoupling of the AOB and NOB communities, resulting in an accumulation and detoxification of nitrite to N(2)O by AOB. However, cumulative N(2)O production (over 6 month simulations) is maximized in a system where the relationship between AOB and NOB is maintained. When the reactions uncouple, the AOB become unstable and biomass declines rapidly, resulting in decreased NH(3) oxidation and N(2)O production. We evaluated this model against site level chemical datasets from the interior of Alaska and accurately simulated NH(3) oxidation rates and the relative ratio of AOA:AOB biomass. The predicted community structure and activity indicate (a) parameterization of a small number of traits may be sufficient to broadly characterize nitrifying community structure and (b) changing decadal trends in climate and edaphic conditions could impact nitrification rates in ways that are not captured by extant biogeochemical models. PMID- 23087682 TI - Functional constraints on HIV-1 capsid: their impacts on the viral immune escape potency. AB - In mature HIV-1 particles, viral capsid (CA) proteins form the conical core structure that encapsidates two copies of the viral RNA genome. After fusion of the viral envelope and cellular membranes, the CA core enters into the cytoplasm of the target cells. CA proteins then interact with a variety of viral other protein as well as host factors, which may either support or inhibit replication of the virus. Recent studies have revealed that CA proteins are important not only for the uncoating step but also for the later nuclear import step. Identification of proteins that interact with CA to fulfill these functions is, therefore, important for understanding the unknown HIV-1 replication machinery. CA proteins can also be targets of the host immune response. Notably, some HLA restricted cytotoxic T-lymphocyte (CTL) responses that recognize CA functional regions can greatly contribute to delay in AIDS progression. The multi functionality of the CA protein may limit the flexible virus evolution and reduce the possibility of an escape mutant arising. The presence of many functional regions in CA protein may make it a potential target for effective therapies. PMID- 23087683 TI - Metabolic modeling of denitrification in Agrobacterium tumefaciens: a tool to study inhibiting and activating compounds for the denitrification pathway. AB - A metabolic network model for facultative denitrification was developed based on experimental data obtained with Agrobacterium tumefaciens. The model includes kinetic regulation at the enzyme level and transcription regulation at the enzyme synthesis level. The objective of this work was to study the key factors regulating the metabolic response of the denitrification pathway to transition from oxic to anoxic respiration and to find parameter values for the biological processes that were modeled. The metabolic model was used to test hypotheses that were formulated based on the experimental results and offers a structured look on the processes that occur in the cell during transition in respiration. The main phenomena that were modeled are the inhibition of the cytochrome c oxidase by nitric oxide (NO) and the (indirect) inhibition of oxygen on the denitrification enzymes. The activation of transcription of nitrite reductase and NO reductase by their respective substrates were hypothesized. The general assumption that nitrite and NO reduction are controlled interdependently to prevent NO accumulation does not hold for A. tumefaciens. The metabolic network model was demonstrated to be a useful tool for unraveling the different factors involved in the complex response of A. tumefaciens to highly dynamic environmental conditions. PMID- 23087685 TI - The effect of marination on lactic acid bacteria communities in raw broiler fillet strips. AB - Marination with marinade containing salt, sugar, and acetic acid is commonly used in Finland to enhance the value of raw broiler meat. In this study, we investigated the effect of marination, marinade components and storage time on composition of bacterial communities in modified atmosphere-packaged (MAP) broiler fillet strips. The communities were characterized using two culture independent methods: 16S rRNA gene fragment sequencing and terminal restriction fragment length polymorphism. In unmarinated broiler fillet strips, Lactococcus spp. and Carnobacterium spp. predominated at the early storage phase but were partially replaced by Lactobacillus spp. and Leuconostoc spp. when the chilled storage time was extended. In the marinated fillet strips, Lactobacillus spp. and Leuconostoc spp. predominated independent from the storage time. By mixing the different marinade components with broiler meat, we showed that marination changed the community composition and favored Leuconostoc spp. and Lactobacillus spp. by the combined effect of carbohydrates and acetic acid in marinade. Marination increased the maximum level of lactic acid bacteria in broiler meat and enhanced CO(2) production and acidification of meat during the chilled storage. Accumulation of CO(2) in package head-space due to the enhanced growth of Leuconostoc spp. in marinated meat may lead to bulging of packages, which is a spoilage defect frequently associated with marinated and MAP raw broiler preparations in Finland. PMID- 23087684 TI - Redundancy and modularity in membrane-associated dissimilatory nitrate reduction in Bacillus. AB - The genomes of two phenotypically denitrifying type strains of the genus Bacillus were sequenced and the pathways for dissimilatory nitrate reduction were reconstructed. Results suggest that denitrification proceeds in the periplasmic space and in an analogous fashion as in Gram-negative organisms, yet with the participation of proteins that tend to be membrane-bound or membrane-associated. A considerable degree of functional redundancy was observed with marked differences between B. azotoformans LMG 9581(T) and B. bataviensis LMG 21833(T). In addition to the already characterized menaquinol/cyt c-dependent nitric oxide reductase (Suharti et al., 2001, 2004) of which the encoding genes could be identified now, evidence for another novel nitric oxide reductase (NOR) was found. Also, our analyses confirm earlier findings on branched electron transfer with both menaquinol and cytochrome c as reductants. Quite unexpectedly, both bacilli have the disposal of two parallel pathways for nitrite reduction enabling a life style as a denitrifier and as an ammonifying bacterium. PMID- 23087686 TI - Glycosaminoglycan analogs as a novel anti-inflammatory strategy. AB - Heparin, a glycosaminoglycan (GAG), has both anti-inflammatory and anti-coagulant properties. The clinical use of heparin against inflammation, however, has been limited by concerns about increased bleeding. While the anti-coagulant activity of heparin is well understood, its anti-inflammatory properties are less so. Heparin is known to bind to certain cytokines, including chemokines, small proteins which mediate inflammation through their control of leukocyte migration and activation. Molecules which can interrupt the chemokine-GAG interaction without inhibiting coagulation could therefore, represent a new class of anti inflammatory agents. In the present study, two approaches were undertaken, both focusing on the heparin-chemokine relationship. In the first, a structure based strategy was used: after an initial screening of potential small molecule binders using protein NMR on a target chemokine, binding molecules were optimized through structure-based design. In the second approach, commercially available short oligosaccharides were polysulfated. In vitro, these molecules prevented chemokine GAG binding and chemokine receptor activation without disrupting coagulation. However, in vivo, these compounds caused variable results in a murine peritoneal recruitment assay, with a general increase of cell recruitment. In more disease specific models, such as antigen-induced arthritis and delayed-type hypersensitivity, an overall decrease in inflammation was noted, suggesting that the primary anti-inflammatory effect may also involve factors beyond the chemokine system. PMID- 23087687 TI - Advances in human B cell phenotypic profiling. AB - To advance our understanding and treatment of disease, research immunologists have been called-upon to place more centralized emphasis on impactful human studies. Such endeavors will inevitably require large-scale study execution and data management regulation ("Big Biology"), necessitating standardized and reliable metrics of immune status and function. A well-known example setting this large-scale effort in-motion is identifying correlations between eventual disease outcome and T lymphocyte phenotype in large HIV-patient cohorts using multiparameter flow cytometry. However, infection, immunodeficiency, and autoimmunity are also characterized by correlative and functional contributions of B lymphocytes, which to-date have received much less attention in the human Big Biology enterprise. Here, we review progress in human B cell phenotyping, analysis, and bioinformatics tools that constitute valuable resources for the B cell research community to effectively join in this effort. PMID- 23087689 TI - All PI3Kinase signaling is not mTOR: dissecting mTOR-dependent and independent signaling pathways in T cells. AB - The mechanistic target of rapamycin (mTOR) is emerging as playing a central role in regulating T cell activation, differentiation, and function. mTOR integrates diverse signals from the immune microenvironment to shape the outcome of T cell receptor (TCR) antigen recognition. Phosphatidylinositol 3-kinase (PI3K) enzymes are critical mediators of T cell activation through their generation of the second messenger phosphatidylinositol (3,4,5) triphosphate (PIP3). Indeed, PIP3 generation results in the activation of Protein Kinase B (PKB, also known as AKT), a key activator of mTOR. However, recent genetic studies have demonstrated inconsistencies between PI3K disruption and loss of mTOR expression with regard to the regulation of effector and regulatory T cell homeostasis and function. In this review, we focus on how PI3K activation directs mature CD4 T cell activation and effector function by pathways dependent on and independent of mTOR signaling. Importantly, what has become clear is that targeting both mTOR-dependent and mTOR independent PI3K-induced signaling distally affords the opportunity for more selective regulation of T cell differentiation and function. PMID- 23087688 TI - Intestinal antimicrobial peptides during homeostasis, infection, and disease. AB - Antimicrobial peptides (AMPs), including defensins and cathelicidins, constitute an arsenal of innate regulators of paramount importance in the gut. The intestinal epithelium is exposed to myriad of enteric pathogens and these endogenous peptides are essential to fend off microbes and protect against infections. It is becoming increasingly evident that AMPs shape the composition of the commensal microbiota and help maintain intestinal homeostasis. They contribute to innate immunity, hence playing important functions in health and disease. AMP expression is tightly controlled by the engagement of pattern recognition receptors (PRRs) and their impairment is linked to abnormal host responses to infection and inflammatory bowel diseases (IBD). In this review, we provide an overview of the mucosal immune barriers and the intricate crosstalk between the host and the microbiota during homeostasis. We focus on the AMPs and pay particular attention to how PRRs promote their secretion in the intestine. Furthermore, we discuss their production and main functions in three different scenarios, at steady state, throughout infection with enteric pathogens and IBD. PMID- 23087690 TI - IL-1 family cytokines trigger sterile inflammatory disease. AB - Inflammation plays vital roles in protective responses against pathogens and tissue repair, however, improper resolution of inflammatory networks is centrally involved in the pathogenesis of many acute and chronic diseases. Extensive advances have been made in recent years to define the inflammatory processes that are required for pathogen clearance, however, in comparison, less is known about the regulation of inflammation in sterile settings. Over the past decade non communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to global human health. Thus, improved understanding of the sterile inflammatory process has emerged as one of the most important areas of biomedical investigation during our time. In this review we highlight the central role that interleukin-1 family cytokines play in sterile inflammatory diseases. PMID- 23087691 TI - Leptin, CD4(+) T(reg) and the prospects for vaccination against H. pylori infection. AB - Helicobacter pylori infection induces chronic inflammation which is characterized not only by infiltrations of inflammatory cells such as neutrophils and CD4(+) T cells, but also significant populations of regulatory T cells (T(reg)). These cells are important for disease pathogenesis because they are believed to contribute to the persistence of the infection. Despite encouraging results in animal models, the prospects for an effective H. pylori vaccine are currently poor because of generally disappointing results in preclinical and phase 1 trials. As a result, a current major focus of basic research on vaccination is to better understand the mechanisms regulating the inflammatory response with the view it can inform future vaccine design. Our studies in this area have focused on gastric CD4(+) T(reg) in vaccinated mice, and raised the hypothesis that adipokines in particular leptin are involved the establishment of a protective gastric immune response. Here we discuss the hypothesis that vaccination deregulates T(reg) responses in the gastric mucosa, and that this process is mediated by leptin. We propose that reduced suppression permits a protective sub population of H. pylori-specific CD4(+) T cells to exert protective effects, presumably via the gastric epithelium. Evidence from the literature and experimental approaches will be discussed. PMID- 23087693 TI - Transcription factors involved in the regulation of natural killer cell development and function: an update. AB - Natural killer (NK) cells belong to the innate immune system and are key effectors in the immune response against cancer and infection. Recent studies have contributed to the knowledge of events controlling NK cell fate. The use of knockout mice has enabled the discovery of key transcription factors (TFs) essential for NK cell development and function. Yet, unwrapping the downstream targets of these TFs and their influence on NK cells remains a challenge. In this review, we discuss the latest TFs described to be involved in the regulation of NK cell development and maturation. PMID- 23087695 TI - Genetic analysis of the Arabidopsis protein kinases MAP3Kepsilon1 and MAP3Kepsilon2 indicates roles in cell expansion and embryo development. AB - MAP3Kepsilon1 and MAP3Kepsilon2 are a pair of Arabidopsis thaliana genes that encode protein kinases related to cdc7p from Saccharomyces cerevisiae. We have previously shown that the map3kepsilon1;map3kepsilon2 double-mutant combination causes pollen lethality. In this study, we have used an ethanol-inducible promoter construct to rescue this lethal phenotype and create map3kepsilon1(-/ );map3kepsilon2(-/-) double-mutant plants in order to examine the function of these genes in the sporophyte. These rescued double-mutant plants carry a yellow fluorescent protein (YFP)-MAP3Kepsilon1 transgene under the control of the alcohol-inducible AlcA promoter from Aspergillus nidulans. The double-mutant plants were significantly smaller and had shorter roots than wild-type when grown in the absence of ethanol treatment. Microscopic analysis indicated that cell elongation was reduced in the roots of the double-mutant plants and cell expansion was reduced in rosette leaves. Treatment with ethanol to induce expression of YFP-MAP3Kepsilon1 largely rescued the leaf phenotypes. The double mutant combination also caused embryos to arrest in the early stages of development. Through the use of YFP reporter constructs we determined that MAP3Kepsilon1 and MAP3Kepsilon2 are expressed during embryo development, and also in root tissue. Our results indicate that MAP3Kepsilon1 and MAP3Kepsilon2 have roles outside of pollen development and that these genes affect several aspects of sporophyte development. PMID- 23087692 TI - Resolution of inflammation: therapeutic potential of pro-resolving lipids in type 2 diabetes mellitus and associated renal complications. AB - The role of inflammation in the pathogenesis of type 2 diabetes mellitus (T2DM) and its associated complications is increasingly recognized. The resolution of inflammation is actively regulated by endogenously produced lipid mediators such as lipoxins, resolvins, protectins, and maresins. Here we review the potential role of these lipid mediators in diabetes-associated pathologies, specifically focusing on adipose inflammation and diabetic kidney disease, i.e., diabetic nephropathy (DN). DN is one of the major complications of T2DM and we propose that pro-resolving lipid mediators may have therapeutic potential in this context. Adipose inflammation is also an important component of T2DM-associated insulin resistance and altered adipokine secretion. Promoting the resolution of adipose inflammation would therefore likely be a beneficial therapeutic approach in T2DM. PMID- 23087696 TI - Experimental vs. modeled water use in mature Norway spruce (Picea abies) exposed to elevated CO(2). AB - Rising levels of atmospheric CO(2) have often been reported to reduce plant water use. Such behavior is also predicted by standard equations relating photosynthesis, stomatal conductance, and atmospheric CO(2) concentration, which form the core of dynamic global vegetation models (DGVMs). Here, we provide first results from a free air CO(2) enrichment (FACE) experiment with naturally growing, mature (35 m) Picea abies (L.) (Norway spruce) and compare them to simulations by the DGVM LPJ-GUESS. We monitored sap flow, stem water deficit, stomatal conductance, leaf water potential, and soil moisture in five 35-40 m tall CO(2)-treated (550 ppm) trees over two seasons. Using LPJ-GUESS, we simulated this experiment using climate data from a nearby weather station. While the model predicted a stable reduction of transpiration of between 9% and 18% (at concentrations of 550-700 ppm atmospheric CO(2)), the combined evidence from various methods characterizing water use in our experimental trees suggest no changes in response to future CO(2) concentrations. The discrepancy between the modeled and the experimental results may be a scaling issue: while dynamic vegetation models correctly predict leaf-level responses, they may not sufficiently account for the processes involved at the canopy and ecosystem scale, which could offset the first-order stomatal response. PMID- 23087694 TI - AUX/LAX family of auxin influx carriers-an overview. AB - Auxin regulates several aspects of plant growth and development. Auxin is unique among plant hormones for exhibiting polar transport. Indole-3-acetic acid (IAA), the major form of auxin in higher plants, is a weak acid and its intercellular movement is facilitated by auxin influx and efflux carriers. Polarity of auxin movement is provided by asymmetric localization of auxin carriers (mainly PIN efflux carriers). PIN-FORMED (PIN) and P-GLYCOPROTEIN (PGP) family of proteins are major auxin efflux carriers whereas AUXIN1/LIKE-AUX1 (AUX/LAX) are major auxin influx carriers. Genetic and biochemical evidence show that each member of the AUX/LAX family is a functional auxin influx carrier and mediate auxin related developmental programmes in different organs and tissues. Of the four AUX/LAX genes, AUX1 regulates root gravitropism, root hair development and leaf phyllotaxy whereas LAX2 regulates vascular development in cotyledons. Both AUX1 and LAX3 have been implicated in lateral root (LR) development as well as apical hook formation whereas both AUX1 and LAX1 and possibly LAX2 are required for leaf phyllotactic patterning. PMID- 23087697 TI - Phylogenetic analysis of the Kinesin superfamily from physcomitrella. AB - Kinesins are an ancient superfamily of microtubule dependent motors. They participate in an extensive and diverse list of essential cellular functions, including mitosis, cytokinesis, cell polarization, cell elongation, flagellar development, and intracellular transport. Based on phylogenetic relationships, the kinesin superfamily has been subdivided into 14 families, which are represented in most eukaryotic phyla. The functions of these families are sometimes conserved between species, but important variations in function across species have been observed. Plants possess most kinesin families including a few plant specific families. With the availability of an ever increasing number of genome sequences from plants, it is important to document the complete complement of kinesins present in a given organism. This will help develop a molecular framework to explore the function of each family using genetics, biochemistry, and cell biology. The moss Physcomitrella patens has emerged as a powerful model organism to study gene function in plants, which makes it a key candidate to explore complex gene families, such as the kinesin superfamily. Here we report a detailed phylogenetic characterization of the 71 kinesins of the kinesin superfamily in Physcomitrella. We found a remarkable conservation of families and subfamily classes with Arabidopsis, which is important for future comparative analysis of function. Some of the families, such as kinesins 14s are composed of fewer members in moss, while other families, such as the kinesin 12s are greatly expanded. To improve the comparison between species, and to simplify communication between research groups, we propose a classification of subfamilies based on our phylogenetic analysis. PMID- 23087698 TI - Seeds in Chernobyl: the database on proteome response on radioactive environment. AB - Two serious nuclear accidents during the last quarter century (Chernobyl, 1986 and Fukushima, 2011) contaminated large agricultural areas with radioactivity. The database "Seeds in Chernobyl" (http://www.chernobylproteomics.sav.sk) contains the information about the abundances of hundreds of proteins from on going investigation of mature and developing seed harvested from plants grown in radioactive Chernobyl area. This database provides a useful source of information concerning the response of the seed proteome to permanently increased level of ionizing radiation in a user-friendly format. PMID- 23087699 TI - Current challenges in plant cell walls: editorial overview. PMID- 23087700 TI - Arabidopsis thaliana mTERF proteins: evolution and functional classification. AB - Organellar gene expression (OGE) is crucial for plant development, photosynthesis, and respiration, but our understanding of the mechanisms that control it is still relatively poor. Thus, OGE requires various nucleus-encoded proteins that promote transcription, splicing, trimming, and editing of organellar RNAs, and regulate translation. In metazoans, proteins of the mitochondrial Transcription tERmination Factor (mTERF) family interact with the mitochondrial chromosome and regulate transcriptional initiation and termination. Sequencing of the Arabidopsis thaliana genome led to the identification of a diversified MTERF gene family but, in contrast to mammalian mTERFs, knowledge about the function of these proteins in photosynthetic organisms is scarce. In this hypothesis article, I show that tandem duplications and one block duplication contributed to the large number of MTERF genes in A. thaliana, and propose that the expansion of the family is related to the evolution of land plants. The MTERF genes-especially the duplicated genes-display a number of distinct mRNA accumulation patterns, suggesting functional diversification of mTERF proteins to increase adaptability to environmental changes. Indeed, hypothetical functions for the different mTERF proteins can be predicted using co expression analysis and gene ontology (GO) annotations. On this basis, mTERF proteins can be sorted into five groups. Members of the "chloroplast" and "chloroplast-associated" clusters are principally involved in chloroplast gene expression, embryogenesis, and protein catabolism, while representatives of the "mitochondrial" cluster seem to participate in DNA and RNA metabolism in that organelle. Moreover, members of the "mitochondrion-associated" cluster and the "low expression" group may act in the nucleus and/or the cytosol. As proteins involved in OGE and presumably nuclear gene expression (NGE), mTERFs are ideal candidates for the coordination of the expression of organelle and nuclear genomes. PMID- 23087702 TI - Evolutionary conservation and functional roles of ncRNA. AB - Non-coding RNAs (ncRNAs) are a class of transcribed RNA molecules without protein coding potential. They were regarded as transcriptional noise, or the byproduct of genetic information flow from DNA to protein for a long time. However, in recent years, a number of studies have shown that ncRNAs are pervasively transcribed, and most of them show evidence of evolutionary conservation, although less conserved than protein-coding genes. More importantly, many ncRNAs have been confirmed as playing crucial regulatory roles in diverse biological processes and tumorigenesis. Here we summarize the functional significance of this class of "dark matter" in terms its genomic organization, evolutionary conservation, and broad functional classes. PMID- 23087701 TI - PIWI Expression and Function in Cancer. AB - PIWI proteins, a subclade of the Argonaute family proteins, are expressed predominantly in the germline and bind to PIWI-interacting RNAs (piRNAs), which are 25-31 nucleotides in length. The PIWI/piRNA pathway plays critical roles in germline development by regulating transposons and other targets to maintain genome integrity. While the functions of PIWI in the germline have been extensively investigated, recent studies have accumulated evidence that the human PIWI proteins, HIWI and HILI, are aberrantly expressed in a variety of cancers. This review summarizes our knowledge of PIWI expression in cancer and discusses its possible role in tumorigenesis. PMID- 23087703 TI - Molecular mechanisms of genetic variation and transcriptional regulation of CYP2C19. AB - Inherited variation in the function of the drug metabolizing enzyme CYP2C19 was first observed 40 years ago. The SNP variants which underpin loss of CYP2C19 function have been elucidated and extensively studied in healthy populations. However, there has been relatively meagre translation of this information into the clinic. The presence of genotype-phenotype discordance in certain patients suggests that changes in the regulation of this gene, as well as loss of function SNPs, could play a role in deficient activity of this enzyme. Knowledge of the molecular mechanisms which control transcription of this gene, reviewed in this article, may aid the challenge of delivering CYP2C19 pharmacogenetics into clinical use. PMID- 23087704 TI - Genetic Background Specific Hypoxia Resistance in Rat is Correlated with Balanced Activation of a Cross-Chromosomal Genetic Network Centering on Physiological Homeostasis. AB - Genetic background of an individual can drastically influence an organism's response upon environmental stress and pathological stimulus. Previous studies in inbred rats showed that compared to Brown Norway (BN), Dahl salt-sensitive (SS) rat exerts strong hypoxia susceptibility. However, despite extensive narrow-down approaches via the chromosome substitution methodology, this genome-based physiological predisposition could not be traced back to distinct quantitative trait loci. Upon the completion and public data availability of PhysGen SS-BN consomic (CS) rat platform, I employed systems biology approach attempting to further our understanding of the molecular basis of genetic background effect in light of hypoxia response. I analyzed the physiological screening data of 22 CS rat strains under normoxia and 2-weeks of hypoxia, and cross-compared them to the parental strains. The analyses showed that SS-9(BN) and SS-18(BN) represent the most hypoxia-resistant CS strains with phenotype similar to BN, whereas SS-6(BN) and SS-Y(BN) segregated to the direction of SS. A meta-analysis on the transcriptomic profiles of these CS rat strains under hypoxia treatment showed that although polymorphisms on the substituted BN chromosomes could be directly involved in hypoxia resistance, this seems to be embedded in a more complex trans chromosomal genetic regulatory network. Via information theory based modeling approach, this hypoxia relevant core genetic network was reverse engineered. Network analyses showed that the protective effects of BN chromosome 9 and 18 were reflected by a balanced activation of this core network centering on physiological homeostasis. Presumably, it is the system robustness constituted on such differential network activation that acts as hypoxia response modifier. Understanding of the intrinsic link between the individual genetic background and the network robustness will set a basis in the current scientific efforts toward personalized medicine. PMID- 23087705 TI - Computational methods for ab initio detection of microRNAs. AB - MicroRNAs are small RNA sequences of 18-24 nucleotides in length, which serve as templates to drive post-transcriptional gene silencing. The canonical microRNA pathway starts with transcription from DNA and is followed by processing via the microprocessor complex, yielding a hairpin structure. Which is then exported into the cytosol where it is processed by Dicer and then incorporated into the RNA induced silencing complex. All of these biogenesis steps add to the overall specificity of miRNA production and effect. Unfortunately, their modes of action are just beginning to be elucidated and therefore computational prediction algorithms cannot model the process but are usually forced to employ machine learning approaches. This work focuses on ab initio prediction methods throughout; and therefore homology-based miRNA detection methods are not discussed. Current ab initio prediction algorithms, their ties to data mining, and their prediction accuracy are detailed. PMID- 23087706 TI - Clinical applications of gene-based risk prediction for lung cancer and the central role of chronic obstructive pulmonary disease. AB - Lung cancer is the leading cause of cancer death worldwide and nearly 90% of cases are attributable to smoking. Quitting smoking and early diagnosis of lung cancer, through computed tomographic screening, are the only ways to reduce mortality from lung cancer. Recent epidemiological studies show that risk prediction for lung cancer is optimized by using multivariate risk models that include age, smoking exposure, history of chronic obstructive pulmonary disease (COPD), family history of lung cancer, and body mass index. It has also been shown that COPD predates lung cancer in 65-70% of cases, conferring a four- to sixfold greater risk of lung cancer compared to smokers with normal lung function. Genome-wide association studies of smokers have identified a number of genetic variants associated with COPD or lung cancer. In a case-control study, where smokers with normal lungs were compared to smokers who had spirometry defined COPD or histology confirmed lung cancer, several of these variants were shown to overlap, conferring the same susceptibility or protective effects on both COPD and lung cancer (independent of COPD status). In this perspective article, we show how combining clinical data with genetic variants can help identify heavy smokers at the greatest risk of lung cancer. Using this approach, we found that gene-based risk testing helped engage smokers in risk mitigating activities like quitting smoking and undertaking lung cancer screening. We suggest that such an approach could facilitate the targeted selection of smokers for cost-effective life-saving interventions. PMID- 23087707 TI - The developing, aging neocortex: how genetics and epigenetics influence early developmental patterning and age-related change. AB - A hallmark of mammalian development is the generation of functional subdivisions within the nervous system. In humans, this regionalization creates a complex system that regulates behavior, cognition, memory, and emotion. During development, specification of neocortical tissue that leads to functional sensory and motor regions results from an interplay between cortically intrinsic, molecular processes, such as gene expression, and extrinsic processes regulated by sensory input. Cortical specification in mice occurs pre- and perinatally, when gene expression is robust and various anatomical distinctions are observed alongside an emergence of physiological function. After patterning, gene expression continues to shift and axonal connections mature into an adult form. The function of adult cortical gene expression may be to maintain neocortical subdivisions that were established during early patterning. As some changes in neocortical gene expression have been observed past early development into late adulthood, gene expression may also play a role in the altered neocortical function observed in age-related cognitive decline and brain dysfunction. This review provides a discussion of how neocortical gene expression and specific patterns of neocortical sensori-motor axonal connections develop and change throughout the lifespan of the animal. We posit that a role of neocortical gene expression in neocortex is to regulate plasticity mechanisms that impact critical periods for sensory and motor plasticity in aging. We describe results from several studies in aging brain that detail changes in gene expression that may relate to microstructural changes observed in brain anatomy. We discuss the role of altered glucocorticoid signaling in age-related cognitive and functional decline, as well as how aging in the brain may result from immune system activation. We describe how caloric restriction or reduction of oxidative stress may ameliorate effects of aging on the brain. PMID- 23087708 TI - More than insulator: multiple roles of CTCF at the H19-Igf2 imprinted domain. AB - CTCF (CCCTC-binding factor)-mediated insulation at the H19-Insulin-like growth factor 2 (Igf2) imprinted domain is a classic example for imprinted gene regulation. DNA methylation difference in the imprinting control region (ICR) is inherited from the gametes and subsequently determines parental allele-specific enhancer blocking and imprinted expression in the soma. Recent genetic studies showed that proper monoallelic enhancer blocking at the H19-Igf2 ICR is critical for development. Strict biallelic insulation at this locus causes perinatal lethality, whereas leaky biallelic insulation results in smaller size but no lethality. Apart from enhancer blocking, CTCF is also the master organizer of chromatin composition in the maternal allele along this imprinted domain, affecting not only histone tail covalent modifications but also those in the histone core. Additionally, CTCF binding in the soma protects the maternal allele from de novo DNA methylation. CTCF binding is not involved in the establishment of the gametic marks at the ICR, but it slightly delays de novo methylation in the maternally inherited ICR allele in prospermatogonia. This review focuses on the developmental and epigenetic consequences of CTCF binding at the H19-Igf2 ICR. PMID- 23087709 TI - Toxicogenomics in non-mammalian species-Editorial. PMID- 23087712 TI - From the Editor-in-Chief. PMID- 23087711 TI - Regulation of lifespan by chemosensory and thermosensory systems: findings in invertebrates and their implications in mammalian aging. AB - Many environmental factors that dynamically change in nature influence various aspects of animal physiology. Animals are equipped with sensory neuronal systems that help them properly sense and respond to environmental factors. Several studies have shown that chemosensory and thermosensory neurons affect the lifespan of invertebrate model animals, including Caenorhabditis elegans and Drosophila melanogaster. Although the mechanisms by which these sensory systems modulate lifespan are incompletely understood, hormonal signaling pathways have been implicated in sensory system-mediated lifespan regulation. In this review, we describe findings regarding how sensory nervous system components elicit physiological changes to regulate lifespan in invertebrate models, and discuss their implications in mammalian aging. PMID- 23087713 TI - Evaluation of fracture risk and fracture prevention: an Italian picture. AB - Italy has one of the longest life expectancies when compared to other countries in the world, with 20% of the entire population being over 65 years of age and about 6% of these being already 80 years and over. Increased life expectancy is associated with a greater frailty index, typical of the elderly population, with higher prevalence of chronic and degenerative disorders, including fragility fractures. Data have been accumulating about the incidence of fragility fractures in the Italian population, with numbers that are truly alarming for the future decades. In this scenario, the need for the use of antifracture agents becomes strategic in our Country. Therapeutic options currently available for fracture prevention include both antiresorptive and anabolic compounds. Despite the incorporation of this evidence from randomized trials into clinical practice guidelines, these interventions are considerably underutilized. Furthermore, adherence to these therapies is a critical parameter affecting the effectiveness of treatments. Results of institutional databases pose the problem of unsatisfactory outcomes of compliance to antifracture agents prescriptions recorded within regional pharmaceutical databases. These care gaps highlight the finding that additional effort is needed to optimize management of osteoporosis in patients at risk of fragility fractures. Given that there is evidence that appropriate management of osteoporosis decreases fractures, it is felt that the use of appropriate management as the primary outcome is per se relevant. Future efforts should consider treatment appropriateness, treatment sustainability and treatment adherence, as the needed parameters to be applied to programs of osteoporosis care in a community setting. PMID- 23087710 TI - Chromatin loops, gene positioning, and gene expression. AB - Technological developments and intense research over the last years have led to a better understanding of the 3D structure of the genome and its influence on genome function inside the cell nucleus. We will summarize topological studies performed on four model gene loci: the alpha- and beta-globin gene loci, the antigen receptor loci, the imprinted H19-Igf2 locus and the Hox gene clusters. Collectively, these studies show that regulatory DNA sequences physically contact genes to control their transcription. Proteins set up the 3D configuration of the genome and we will discuss the roles of the key structural organizers CTCF and cohesin, the nuclear lamina and the transcription machinery. Finally, genes adopt non-random positions in the nuclear interior. We will review studies on gene positioning and propose that cell-specific genome conformations can juxtapose a regulatory sequence on one chromosome to a responsive gene on another chromosome to cause altered gene expression in subpopulations of cells. PMID- 23087714 TI - Antifracture drugs consumption in Tuscany Region before the Target Project: a valuable model for the analysis of administrative database. AB - OBJECTIVES: As the Target Project of Tuscany Region is aimed to identify significant changes occurring during the time of the project compared to the previous years, we have analyzed antifracture drugs consumption in the years immediately preceding the start-up of the program. METHODS: We have analyzed the regional administrative database to search for antifracture drugs delivered by the regional healthcare system to people living in Tuscany in the year 2009. Both drugs directly distributed by hospitals or local health authorities (direct distribution dataset, FED), and those delivered through pharmacies (pharmaceutical distribution dataset, SPF) were included in the analysis. Private expenditures were indirectly computed because total pharmaceutical expenditures were also known. A specific subgroup analysis has been carried out on elderly patients with femoral fractures (years 2006-2010), which represent the population of Target Project, in order to assess the evolution of all antifracture drug prescriptions before the start up of the project. RESULTS: A total of 690,768 boxes of antifracture drugs (20 million defined daily doses, DDD) have been delivered in year 2009 for total expenditures of 23 million Euros. Public expenditures accounted for 71% of the total (16 million; 6% of regional pharmaceutical expenditures). Alendronate and risedronate were the most used drugs. The number of antifracture medications prescribed within the first 90 days to elderly people with hip fractures increased in the period before the start-up of the Target project but they remained under 14%. CONCLUSIONS: There is the need for an appropriate management of antifracture therapies, as they represent a valuable proportion of pharmaceutical expenditures. This need is pointed out also by the remarkable amount of direct private expenditures and by the few number of hip fractured people starting a treatment. PMID- 23087715 TI - Biochemical markers in the follow-up of the osteoporotic patients. AB - Osteoporosis, a disease characterised by low bone mass and micro-architectural deterioration of bone tissue, is viewed as an emerging medical condition. Bone mineral density (BMD) is considered the gold standard of bone status assessment, however it does not offer the timely response desirable for monitoring. Biochemical markers of bone turnover (BTMs) are claimed to be suitable for that purpose. There is not generalized agreement on which marker could be used in routine. The present paper reviews pros and cons of currently used BTMs and relative analytical methods. Several analytical issues, such as biological variability, molecules stability, lack of reference materials jeopardize the field and, consequently, recommendations are difficult to be drawn. Reference range can't be used to support clinical judgement and, in this view, Least Significant Change (LSC) is regarded as a way to improve the interpretation of analytical results.Bone alkaline phosphatase (bALP) is still a marker of interest and its use is widespread in clinical laboratories; Tartrate Resistant Acid Phosphatase band 5b (TRAP 5b) appears to be a promising marker. N-terminal propeptides of type I collagen (s-PINP) and beta-collagen 1 C-terminal cross linked telopeptides (s-CTX), given low biological variability and assay availability for automatised instruments, should be the marker of choice in future clinical trials, to overcome the paucity of uniform data and should be used in clinical routine, to monitor osteoporosis treatment. Finally, the lack of standardisation of currently available diagnostic methods, could be overcome by harmonisation. PMID- 23087716 TI - The role of the immune system in the physiopathology of osteoporosis. AB - The close anatomical relationship between the immune system, estrogen deficiency and bone loss has been recognized for centuries but the existence of a functional relationship has emerged only recently. The role of the immune system in the development of senile osteoporosis, which arises primarily through the effects of estrogen deficiency and secondary hyperparathyroidism, is slowly being unraveled. This review focuses the evidence that links immune cells, inflammation, cytokine production and osteoclast formation and their activity. The under standing of the interplay of inflammation and osteoclast can lead to the development of new drugs for prevention and treatment of bone loss. PMID- 23087717 TI - Osteoporosis and aromatase inhibitors: experience and future prospects. AB - INTRODUCTION: The aim of this study is to improve the assistance given to patients under treatment with aromatase inhibitors in order to prevent secondary osteoporosis through the planning of an awareness programme for the oncologist and offering a facilitated treatment path. MATERIALS AND METHODS: Thirty-nine postmenopausal women treated with aromatase inhibitors for breast cancer were selected. For each subject, the age at the beginning of the therapy, the type of aromatase inhibitors and the age at the performance of the bone densitometry was registered. In addition, the use of osteoporosis medication and supplementation of calcium and vitamin D were evaluated. Participants were required to answer a questionnaire consisting of closed questions relating to booking procedures of the bone densitometry and about their own knowledge of osteoporosis related to the use of aromatase inhibitors. CONCLUSIONS: Although there is evidence of negative impact of the aromatase inhibitors on bone, our data still show a poor application of the recommendations in order to prevent osteoporosis related to the administration of these drugs. Our suggestion is a more active implementation of the guidelines, also by means of a greater collaboration between the oncologist and the specialist in osteoporosis, and the offer of a diagnostic and therapeutic pathway. PMID- 23087718 TI - Epidemiology and classification of bone tumors. AB - Primary bone tumors are uncommon and this has certainly contributed to the scarcity of data about their relative frequency, and to the limited understanding of the risk factors. Overall, bone sarcomas account for 0.2% of all malignancies, and the adjusted incidence rate for all bone and joint malignancies is 0.9 per 100,000 persons per year, while the 5-year overall survival rate is 67.9%. The age specific incidence rates of bone sarcomas show a bimodal distribution, with a first peak occurring in the second decade, and a second peak occurring in patients older than sixty, in relation with the age distribution of the main histological subtypes. Several bone tumor types occur in the setting of inherited syndromes, while some other develop in association with non-neoplastic precursors or in the setting of previous benign tumors. In recent years, significant advances have occurred in the molecular and cytogenetic characterization of benign and malignant bone tumors. The detection of clonal chromosomal aberrations, specific molecular genetic changes, and the identification of growth related tumor cell signaling pathways have resulted in a better understanding of the pathogenesis of several neoplastic entities, and have provided the basis for an improvement in the diagnostic workup and differential diagnosis of several bone tumors presenting with overlapping clinical, radiological and pathological features, as well as for the identification of new prognostic factors and therapeutic targets. PMID- 23087719 TI - Osteoporosis in haemophilic patient, rehabilitative aspects. AB - The continuous improvement of substitution and antiviral treatments available to date (at least in countries with greater economic and social development) allow better survival of patients with haemophilia, both as regards the duration and quality of life, to the point that the haemophilic arthropathy, that is the co morbidity almost always present and extremely debilitating, come to be treated successfully using prosthetic joint replacement surgery. This has further highlighted other aspects of disease such as osteopenia or osteoporosis, which frequently occurs in these patients, and in recent years has aroused the interest of research.Rehabilitation plays a vital role in helping to tackle the different risk factors in young patients, in containing the consequences of the disease on the skeletal and muscle apparatus such as on the recovery after surgery and prosthetic. PMID- 23087720 TI - Biochemical markers as predictors of bone remodelling in dental disorders: a narrative description of literature. AB - Osteoporosis is a systemic disease in which the skeletal condition is characterized by a decreased mass of normally mineralized bone, due to an augmentation of bone resorption processes. Bone biomarkers serum are used for the diagnosis. On the other hand the main cause of the resorption in the bone jaws are periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms. Periodontal diseases can be localized to a single site of the jaws or can affect all the teeth, with a massive bone resorption. The cysts are classified in developmental and inflammatory. They caused a local bone resorption in the jaws. Keratocystic odontogenic tumor produces a large bone resorption for its local aggressive nature. Their diagnosis is clinical and radiological.The aim of our review is to find a correlation between bone biomarkers serum and periodontitis, inflammatory cists, developmental cysts, odontogenetic neoplasms.The RANK/RANKL/OPG system is the most studied not only in osteoporosis but also in the periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms. In the last years osteoimmunology was used to study the periodontal disease progression, because the immunity cells start the bone resorption processes.A lot of studies analyze the biomarkers present in the biofluids, as saliva and gingival crevicular fluid, but not the correlation with serum biomarkers.Future studies must be organized to deepen the correlation between bone biomarkers and bone jaws resorption and to allow diagnosis and prognosis of periodontitis, inflammatory cysts, developmental cysts, odontogenic neoplasms. PMID- 23087721 TI - Musculoskeletal problems in soccer players: current concepts. AB - Soccer is the most popular sport worldwide, with about 200 million players, both professionals and amateurs. Because of its popularity, it has been often proposed to be able to prevent or cure health problems around the world. Although participation in football leads to significant physical benefits such as improving well-being, extending life expectancy and reducing the likelihood of several major non-communicable diseases, the possibility to incur in soccer injuries must be considered. On average, an elite football player suffers from 1.5-7.6 injuries each 1,000 hours of training and 12-35 injuries each 1000 hours of match. Several risk factors for soccer injuries have been described. The most important of them are the level of play (the risk appears to be higher in professional than amateur players); the exercise load; and the standard of training. The injury prevention program "The 11", developed with the support of the Federation Internationale de Football Association (FIFA), aims to reduce the impact of intrinsic injury risk factors in soccer, and it has been validated in that sport. A successive modified version of "The 11" ("The 11+") has been also shown to be effective in preventing injuries in young female soccer players. The FIFA 11+ provided more than 40% of reduction of the risk of injury. Several factors can be related to the risk of injury during sport. Therefore different exercises or factors might have been responsible for efficacy of the FIFA 11+ to prevent injuries. Several improvements have been surely achieved in the last ten years, but further investigation is needed to improve the benefits of playing soccer on human health. PMID- 23087722 TI - How much vitamin D for children? AB - Recently a number of studies have reported worldwide recrudescence of biochemical and clinical rickets, despite continuous revisions of the experts about the adequate intake of vitamin D for infants and children to maintain an adequate 25 hydroxyvitamin D status and assure the achievement of peak bone mass during the growth. The aim of this review is to illustrate the current opinions and controversies about what should be considered the normal range for serum 25 hydroxyvitamin D concentrations and which doses of vitamin D supplements should be recommended in the various pediatric ages and in different contests as climatic regions, colour of skin and sunlight exposure. PMID- 23087723 TI - "Excess gooD can be Dangerous". A case series of iatrogenic symptomatic hypercalcemia due to hypervitaminosis D. AB - Vitamin D is increasingly recognized to have several beneficial effects. Its toxicity, causing hypercalcemia, is considered as extremely rare. We report case series of 15 patients (most of them being elderly subjects) with iatrogenic symptomatic hypercalcemia in whom toxicity occurred due to empirical excessive administration of vitamin D by oral and parenteral route. PMID- 23087724 TI - Monsters of yesterday and today: from the myth to the hybrids and cybrids. PMID- 23087725 TI - Emergence of cancer stem cells in head and neck squamous cell carcinoma: A therapeutic insight with literature review. AB - Accumulating evidence suggests that self-renewal and differentiation capabilities reside only in a subpopulation of tumor cells, termed cancer stem cells (CSCs), whereas the remaining tumor cell population lacks the ability to initiate tumor development or support continued tumor growth. In head and neck squamous cell carcinoma (HNSCC), as with other malignancies, CSCs have been increasingly shown to have an integral role in tumor initiation, disease progression, metastasis, and treatment resistance. In this article, the author summarizes the current knowledge of the role of CSCs in HNSCC and discusses the therapeutic implications and future directions of this field. PMID- 23087726 TI - Prevalence and pattern of hypodontia in the permanent dentition of 3374 Iranian orthodontic patients. AB - BACKGROUND: Hypodontia is the most common dental anomaly and might cause clinical complications. The aim of this study was to assess the prevalence and pattern of congenital missing in the permanent dentition dentition (excluding third molars), among Iranian orthodontic patients. MATERIALS AND METHODS: In this descriptive cross-sectional study, all approved panoramic radiographs of 3374 orthodontic patients (aged 10 to 20 years old), who had visited the Orthodontic Departments of all Tehran Dentistry Universities and 10 private clinics during the years 1999 to 2009 were investigated, to establish the prevalence of hypodontia in the permanent dentition (excluding third molars). The data were analyzed using a chi square test (alpha = 0.01). RESULTS: Included were 2012 female and 1362 male patients. The prevalence of hypodontia was 5.21% (5.86% in females, 4.25% in males). The difference between the genders in terms of missing teeth was not significant (P = 0.202). A total of 298 teeth were missing (166 in females, 132 in males). The average of missing per individual was found to be 1.69 (1.40 missing for each girl, 2.32 for each boy). There was no significant difference between the number of missing teeth in males and females (P = 0.160). The most common missing teeth were maxillary lateral incisors (37.2%), mandibular second premolars (22.1%), and mandibular central incisors (10.7%). In both unilateral and bilateral hypodontia cases, the maxillary lateral had the highest prevalence of missing, followed by the mandibular second premolar. Missing was significantly more frequent (P = 0.001) in the maxilla (5.3%) compared to the mandible (3.5%). CONCLUSION: Out of every 20 Iranian orthodontic patients, one might have some missing permanent teeth, needing early attention. Hypodontia was more prevalent in females (though not significantly) and in the maxilla. Although more females were affected, the number of missing per individual was greater in males. PMID- 23087727 TI - Reactive lesions of the oral cavity: A retrospective study on 2068 cases. AB - BACKGROUND: Reactive lesions of the oral cavity are non-neoplastic proliferations with very similar clinical appearance to benign neoplastic proliferation. This similarity is troublesome in the differential diagnosis. The aim of this study was to determine the frequency and distribution of oral cavity reactive lesions. MATERIALS AND METHODS: The study was a retrospective archive review. The medical records of 2068 patients with histopathologic diagnosis of oral cavity reactive lesions were studied. The patients' clinical data were registered and evaluated retrospectively. The obtained frequency of patients' age, gender, and anatomic location were analyzed. Descriptive statistics were used for evaluating the registered data. RESULTS: Peripheral giant cell granuloma was the most prevalent lesion (n=623, 30.12%). This was followed by pyogenic granuloma (n=365, 17.65%), epulis fissuratum (n=327, 15.81%), irritation fibroma (n=288, 13.93%), cemento ossifying fibroma (n=277, 13.40%), inflammatory fibrous hyperplasia (n=177, 8.56%), and inflammatory papillary hyperplasia (n=11, 0.53%). The age ranged from 2 to 85 years, with a mean of 39.56 years. The lesions were more common in males (n=1219, 58.95%) than in females (n=849, 41.05%). Attached gingiva with 1331 (64.36%) cases was the most frequent place of reactive lesions. CONCLUSION: Peripheral giant cell granuloma was the most prevalent reactive lesion of the oral cavity. The reactive lesions were more common in males, gingival, and the third decade. Some differences have been found between the findings of the present study and previous reports. PMID- 23087729 TI - Evaluation of serum C-reactive protein levels in subjects with aggressive and chronic periodontitis and comparison with healthy controls. AB - BACKGROUND: Periodontal subgingival pathogens affect local and systemic immune responses and initiate an acute phase systemic inflammatory response characterized by the release of C-reactive proteins (CRPs). This study has been carried out to evaluate the serum concentration of CRPs, which can be used as a marker of periodontal disease as well as a risk indicator for cardiovascular diseases. MATERIALS AND METHODS: In a retrospective study a total number of 45 subjects were selected from the outpatient department of periodontics a mean age of 40 years. Based on the periodontal status, the subjects were divided into 3 groups of 15 subjects each. Group I: Control group [with attachment loss (AL) <= 2 mm and pocket depth (PD) < 3 mm], Group II: Generalized aggressive periodontitis (AL <= 5 mm), Group III: chronic periodontitis (AL >= 2 mm, PD >= 5 mm), which includes moderate and severe periodontitis. The clinical parameters recorded were plaque index,gingival index, bleeding index, probing PD, and clinical attachment levels and scoring was done on 6 surfaces of all teeth. For the CRP assessment, blood samples were collected from subjects at the time of clinical examination. Analysis of covariance was used for comparison of mean values between the groups to adjust the ages (P value < 0.05). RESULTS: Overall, the mean CRP levels were high in subjects with generalized aggressive and chronic periodontitis compared with controls. This was found to be statistically significant. A statistically significant difference (P = 0.012) was found in the CRP level between groups I and II and between groups II and III, and between groups I and III. CONCLUSION: The results of the present study indicated an increase in serum CRP levels in subjects with generalized aggressive periodontitis and chronic periodontitis as compared with the controls. PMID- 23087728 TI - Assessment of antifungal activity of Proroot mineral trioxide aggregate and mineral trioxide aggregate-Angelus. AB - BACKGROUND: Fungi may play a key part in periradicular diseases. The aim of this study was to evaluate and compare the antifungal properties of two root-end filling materials, ProRoot Mineral trioxide aggregate (MTA) and MTA-Angelus, against Candida albicans using tube-dilution test. MATERIALS AND METHODS: The antifungal properties of ProRoot MTA and MTA-Angelus against C. albicans was assessed at 1, 24, and 48 hours following administration of two concentrations of the antifungal agents (50 and 100 mg/ml). A total of 50 culture wells were divided into four experimental groups (Freshly mixed MTA, Freshly mixed MTA Angelus, 24-h set MTA, and 24-h set MTA-Angelus) and two control groups. Each well was prepared for one specific agent with a specific concentration. For the set groups, the mixture was prepared and left for 24 hours. One milliliter of suspension of fungal colonies with concentration of 10(4) CFU/ml was then added to the mixtures in each well. All wells were incubated at 37 degrees C and assessed at 1, 24, and 48 hours. This observation was based on the turbidity of the suspension in the tubes. At each time point, 0.02 ml of each suspension was cultured on a Sabouraud dextrose agar plate to confirm C. albicans growth. The results were analyzed using Kruskal-Wallis test. RESULTS: Although all fresh and set samples were incapable of killing C. albicans at 1 hour, they demonstrated fungicidal ability on agar plates at 24 and 48-hour time points. CONCLUSION: MTA angelus proved to be an effective antifungal agent compared to ProRoot MTA at concentrations of 50 mg/ml and 100 mg/ml. PMID- 23087730 TI - Superoxide dismutase enzyme and thiol antioxidants in gingival crevicular fluid and saliva. AB - BACKGROUND: The possibility of impaired antioxidant status and so increased oxidative damage in periodontal disease is being conjectured. The present randomized controlled study was carried out with the objective of analyzing the activity of superoxide dismutase enzyme and thiol antioxidants in gingival crevicular fluid (GCF) and saliva as indicators of response to periodontal therapy. MATERIALS AND METHODS: SUBJECTS WERE SCREENED AND RANDOMLY DIVIDED INTO THREE GROUPS: 23 periodontally healthy controls, 24 with gingivitis, and 23 with periodontitis. Based on the clinical attachment levels, the periodontitis group was further divided into subgroups, including mild, moderate, and severe periodontitis. GCF and saliva samples were collected for estimation of superoxide dismutase and thiol antioxidant concentrations at baseline and 15 days after nonsurgical treatment. Intragroup comparisons were statistically analyzed using repeated measures analysis of covariance (P value <0.05). RESULTS: Superoxide dismutase was present in greater quantities in the GCF compartment (100.32+/-3.67 U/0.5 mL) than in saliva (39.99+/-3.52 U/0.5 mL), with elevated levels in mild and moderate subgroups as compared with severe periodontitis. Thiol concentrations were comparable in these media, 14.43+/-1.57 micromol /L in GCF and 15.09+/-2.26 micromol/L in saliva. Following treatment, superoxide dismutase and thiol antioxidant concentrations significantly improved in all the patient groups. CONCLUSION: The reduction of the inflammatory response following therapy resulted in improved antioxidant profiles in both the GCF and salivary compartments. PMID- 23087731 TI - The effect of nanoclay filler loading on the flexural strength of fiber reinforced composites. AB - BACKGROUND: Flexural strength of prosthesis made with dental composite resin materials plays an important role in their survival. The aim of this study was investigating the effect of nanoclay fillers and Poly (methyl methacrylate) grafted (PMMA-grafted) nanoclay fillers loading on the flexural strength of fiber reinforced composites (FRCs). MATERIALS AND METHODS: Standard FRC bars (2 * 2 * 25 mm) for flexural strength testing were prepared with E-glass fibers and a synthetic resin loaded with different quantities of unmodified nanoclay and PMMA grafted nanoclay filler particles (0% as control group, 0.2%, 0.5%, 1%, 2%, 5%). Flexural strength and flexural modulus were determined. The data were analyzed using 2-way, 1-way ANOVA and post hoc Tukey's test (alpha = 0.05). The fracture surfaces were evaluated by Scanning Electron Microscopy. RESULTS: For groups with the same concentration of nanoparticles, PMMA-grafted filler-loaded group showed significantly higher flexural strength, except for 0.2% wt. For groups that contain PMMA-grafted nanoclay fillers, the 2% wt had the highest flexural strength value with significant difference to other subgroups. 1% wt and 2% wt showed significantly higher values compared to control (P < 0.05). None of the unmodified nanoclay particles loaded group represented statistically higher values of flexural strength compared to control group (P > 0.05). Flexural modulus of 2%, 5% wt PMMA-grafted and 0.5%, 1%, 2%, 5% wt unmodified nanoclay particles-loaded subgroups decreased significantly compared to control group (P < 0.05). CONCLUSIONS: PMMA-grafted nanoclay filler loading may enhance the flexural strength of FRCs. Addition of unmodified nanoparticles cannot significantly improve the flexural strength of FRCs. Addition of both unmodified and PMMA grafted nanoclay particles in some concentrations decreased the flexural modulus. PMID- 23087732 TI - A novel approach to determine the effect of irrigation on temperature and failure of Ni-Ti endodontic rotary files. AB - BACKGROUND: Nickel-titanium (Ni-Ti) rotary instrument files are important devices in Endodontics in root canal preparation. Ni-Ti file breakage is a critical and problematic issue and irrigation techniques were applied to decrease risk of file failure root. The aim of the present study was to compare the temperature gradient change of different irrigation solutions with Ni-Ti rotary instrument system during root canal preparation and also to define their effects on the file failure. MATERIALS AND METHODS: A novel computerized instrumentation was utilized and thirty standard (ProFile #25/.04) files were divided into three groups and subjected to a filing in the root canal test. Changes in temperature on teeth under constant instrumental conditions with custom-designed computerized experimental apparatus were measured by using a temperature sensor bonded to the apical hole. A rotary instrument for canal preparation in three series of solution was used and the changes in temperature after each solution were compared. Finally, the file failure results were mentored according to each step of test. Comparisons were performed between group status clinically by using ANOVA (t) test, once the sample showed up normal and differences of P<0.01 were considered significant. All data collected were computerized and analyzed for frequency, distribution, and statistical description. RESULTS: There was a decrease in the temperature of the instruments, which were immersed in 5% NaOCl, when compared with the water group (P<0.01). There was also a decrease in the temperature of the instruments immersed in water, when compared with the no solution group (P<0.01). Test results showed that sodium hypochlorite, water, or air of root canals does alter the properties of gradual temperature change and contributes to the failure of the instruments. CONCLUSION: By immersing the file in 5% NaOCl, the temperature gradient decreased and instrument failure was reduced. PMID- 23087733 TI - Evaluation of shear bond strength of orthodontic brackets bonded with Er-YAG laser etching. AB - BACKGROUND: Based on contradictory findings concerning the use of lasers for enamel etching, the purpose of this study was to investigate the shear bond strength of teeth prepared for bonding with Er-YAG laser etching and compare them with phosphoric acid etching. MATERIALS AND METHODS: In this in vitro study forty - eight premolars, extracted for orthodontic purposes were randomly divided in to three groups. Thirty-two teeth were exposed to laser energy for 25 s: 16 teeth at 100 mj setting and 16 teeth at 150 mj setting. Sixteen teeth were etched with 37% phosphoric acid. The shear bond strength of bonded brackets with the Transbond XT adhesive system was measured with the Zwick testing machine. Descriptive statistics, Kolmogorov-Smirnov test, of homogeneity of variances, one- way analysis of variances and Tukey's test and Kruskal Wallis were used to analyze the data. RESULTS: The mean shear bond strength of the teeth lased with 150 mj was 12.26 +/- 4.76 MPa, which was not significantly different from the group with acid etching (15.26 +/- 4.16 MPa). Irradiation with 100 mj resulted in mean bond strengths of 9.05 +/- 3.16 MPa, which was significantly different from that of acid etching (P < 0.001). CONCLUSIONS: laser etching at 150 and 100 mj was adequate for bond strength but the failure pattern of brackets bonded with laser etching is dominantly at adhesive - enamel interface and is not safe for enamel during debonding. PMID- 23087734 TI - Is there an association between early childhood caries and serum iron and serum ferritin levels? AB - BACKGROUND: Early childhood caries (ECC) is a virulent form of dental caries that can destroy the primary dentition of preschool children. The purpose of this study was to investigate a possible association between ECC with serum iron and serum ferritin levels. MATERIALS AND METHODS: Following the ethical approval, 204 children aged 24-71 months were recruited for a double-blind, randomized cross sectional study. Each child was examined clinically for dental caries using the World Health Organization criteria in Rafsanjan, Iran. Decayed, extracted, and filled primary teeth (deft) index was used to measure the dental caries. To determine serum iron and serum ferritin levels 2 mL blood was collected from each child. Data were then analyzed by Pearson's correlation coefficient and t-test using SPSS-16.0 software. RESULTS: The mean values and their standard deviations of the deft index and levels of serum iron and ferritin were 2.4(+/- 3.3), 93.8(+/- 29.0) MUg/dL and 63.1(+/- 32.2) ng/mL, respectively, with the two latter within. There was no significant difference between genders. Pearson's correlation coefficient showed that there was a statistically significant inverse association between ECC and serum iron level (P<0.05); but no association was found with the serum ferritin level. CONCLUSION: The deft index decreased significantly with increasing serum iron levels, but there was no association between ECC experience and serum ferritin levels. PMID- 23087735 TI - Fracture resistance of immature teeth filled with mineral trioxide aggregate or calcium-enriched mixture cement: An ex vivo study. AB - BACKGROUND: The ability of mineral trioxide aggregate (MTA) to strengthen the tooth structure has been studied with contradictory results, and there is a lack of data in the case of Calcium-enriched mixture (CEM) cement as a novel endodontic biomaterial. The aim of the present study was to evaluate the reinforcing effect of MTA and CEM cement on simulated immature teeth. MATERIALS AND METHODS: This ex vivo study was carried out on a total of 46 human maxillary incisors. Access cavities were prepared. Five teeth were randomly selected as negative control. The root length of the remaining teeth was standardized to 9 mm. Rotary files and peeso reamers were used to enlarge the canals. The prepared specimens were randomly assigned into three experimental (n = 12) and a positive control (n = 5) groups. In groups 1 and 2, the canals were filled with MTA or CEM cement, respectively. In group 3, a 5-mm MTA plug was placed, and the remainder of the canal was filled with composite resin. The canals of the positive control were kept unfilled. After 6 months, the teeth were tested for fracture strength in a universal testing machine. The groups were compared using Univariate analysis of variance (ANOVA). RESULTS: There were significant differences between fracture strength of experimental groups with that of both control groups (P<0.05). However, the differences among the three experimental groups were not statistically significant (P>0.05). CONCLUSION: After 6 months, MTA and CEM cement exhibit distinct reinforcing effect on immature teeth. PMID- 23087736 TI - Comparative study of 0.2% and 0.12% digluconate chlorhexidine mouth rinses on the level of dental staining and gingival indices. AB - BACKGROUND: Chlorhexidine (CHX) as a gold standard chemical agent appears to be the most effective antimicrobial agent for reduction of both plaque and gingivitis. The aim of this study was to compare the efficacy of two concentrations of digluconate chlorhexidine (CHX) solutions (0.12% and 0.20%) on gingival indices and the level of dental staining during 14 days. MATERIALS AND METHODS: in this double-blind controlled clinical trial study 60 patients with moderate to severe gingivitis aged 17-56 years were randomly selected and divided to three groups: Group I (placebo) Group II (0.12% CHX), and Group III (0.2% CHX). Patients rinsed their mouthwashes twice a day after brushing. Before the examination and after 14 days plaque index, gingival index, bleeding index, and stain index were evaluated. The data were analyzed by "Mann-Whitney" test and P value was 0.05. RESULTS: the results showed that plaque index and gingival index significantly reduced in Groups II and III in comparison with the placebo group (P < 0.0001). However, the two concentrations did not differ significantly from each other (P = 0.552). Same results were observed in term of gingival bleeding index with this different that 0.2% CHX was significantly more efficient than 0.12% CHX (P < 0.0001). CHX mouthrinse, both concentrations, significantly increased the dental staining level (intensity and area) in comparison with the placebo group. Remarkable difference also was seen between 2 CHX concentrations so that the 0.2% CHX caused much more staining on the teeth than 0.12% CHX. CONCLUSION: based on the results of this study we can conclude that the lower concentrations of CHX should be prescribed, decreasing side effects, since higher concentrations do not seem to be more effective in controlling dental plaque and gingivitis. PMID- 23087737 TI - The effect of sugar-free and sugar chewing gums on plaque deposition. AB - BACKGROUND: Chewing gum is a habit practiced regularly by a relatively high proportion of individuals in many countries including India, and its use has increased within the last decade. The aim of this study was to determine the effects of sugar-free and sugar chewing gums on plaque deposition. MATERIALS AND METHODS: The study is a double blind clinical trial involving 16 healthy volunteers (divided into 2 groups) in a 4-day plaque regrowth model. On day one, subjects received professional prophylaxis, suspended oral hygiene measures, and commenced chewing their allocated product. Gum chewing was one piece chewed for 30 minutes 3 times a day. On day 5, subjects were scored for plaque with the help of Silness and Loe Index. RESULTS: Results show sugar-free group have a lesser mean plaque score of 0.98 as compare to sugar group (1.23), though this difference was not statistically significant. CONCLUSION: The sugar-free gums can be used as an adjunct to mechanical oral hygiene measures. PMID- 23087738 TI - Genotoxicity effects of nano bioactive glass and Novabone bioglass on gingival fibroblasts using single cell gel electrophoresis (comet assay): An in vitro study. AB - BACKGROUND: The greater surface of bioactive glass nanoparticles presents an incomparable and promising feature similar to the biological apatite. Nanoparticles improve cellular adhesion, enhance osteoblast proliferation and differentiation, and increase biomineralization for periodontal regeneration and dental implants. Considering the fact that interaction between periodontal cells and bone graft materials are important for periodontal lesion regeneration, the present study was undertaken to investigate the genotoxicity of a novel synthesized nanoscale bioactive glass and compared it with Novabone bioglass in periodontal fibroblasts cells, in order to approve the biocompatibility of nano bioactive glass. MATERIALS AND METHODS: In this in vitro experimental study, periodontal C165 fibroblasts cells were cultured in their logarithmic phase and the genotoxicity of novel synthesized bioactive glass nanoparticles and Novabone bioglass was studied in different concentrations and a control group using Comet assay test. By using Autocomet software, three parameters (Tail length, %DNA in tail, Tail moment) were analyzed; the genotoxicity of mentioned biomaterials and control group. Obtained data were analyzed by SPSS 11.5 software, Kruskal Wallis H and Mann Whitney tests (P = 0.05). RESULTS: No statistically significant difference was observed between the concentrations of Novabone bioglass (P value = 0.085) with control group and novel nano bioactive glass (P value = 0.437) with control group in the evaluation of %DNA in tail parameter. There was significant difference between genotoxicity of novel nano bioactive glass and control, and between Novabone bioglass and control group in concentrations of 4 and 5 mg/ml. According to significance of the mean difference, novel nano bioactive glass showed higher genotoxicity compared to Novabone bioglass in the concentration of 5 mg/ml (P <= 0.05). CONCLUSION: The findings of this study have demonstrated that novel nano bioactive glass had no genotoxicity in concentrations lower than 4 mg/ml. Nanoparticles have a higher surface area in comparison to microparticles and thus, the amount and rate of ion release for nanoparticles are extremely higher. This difference is the main reason for the different genotoxicity of nano bioactive glass and micro Novabone bioglass in the concentrations higher than 4 mg/ml. PMID- 23087739 TI - Comparison of shear bond strength of orthodontic brackets bonded with halogen and plasma arc light curing. AB - BACKGROUND: Reduced time and appropriate bond strength of brackets is one of the most important aspects of orthodontic treatments. Prolonged halogen light curing for bonding of brackets is undesirable, so the purpose of this study was to compare the shear bond strength of brackets bonded with halogen light and plasma arc system. MATERIALS AND MEHODS: This was an experimental in vitro study. A total of 60 intact premolar teeth were collected and divided into four groups. Stainless steel orthodontic brackets were bonded to them. In groups 1 and 2, curing was done using halogen light given for 20 seconds from two and four angles. In groups 3 and 4, curing was carried out using the plasma arc system for 6 seconds from two and four angles. The shear bond strength was recorded by Instron. The statistics of ANOVA, Tukey's test, and T-test were used in data analysis. RESULTS: There was a statistically significant difference in shear bond strength among the four groups (P = 0.043) and between group 1 with group 2 (P = 0.035). Yet, there was no statistically significant difference between brackets bonded with plasma arc and those bonded with halogen light or between the two groups of plasma arc. CONCLUSION: Using the plasma arc system is superior to other methods due to reduced curing time. Also, since in using the halogen light system, an increase in curing periods from different angles resulted in a significant increase in shear bond strength; it is advisable to apply the halogen light from different angles. PMID- 23087740 TI - Spindle cell variant of ameloblastic carcinoma arising from an unicystic amelobastoma: Report of a rare case. AB - Malignant transformation of ameloblastomas arising from an odontogenic cyst or de novo is well-recognized. Malignancies in ameloblastomas may involve metastasis or a local dysplastic change in the tissue. The latter are classified as ameloblastic carcinomas. A 75-year-old male presented with a mandibular cystic swelling, with no evidence of metastasis. Dysplastic ameloblastic cells with spindle-cell transformation were seen arising from a cystic lining with features of a unicystic ameloblastoma. Immunohistochemically the lesion stained positive with cytokeratin 8,19 and alpha smooth muscle actin, but was negative for vimentin. A diagnosis of spindle-cell ameloblastic carcinoma was made. Spindle cell ameloblastic carcinomas are rare and this is the second case arising from a unicystic ameloblastoma reported in literature. The recognition of this transformation and inclusion of this entity in the classification of ameloblastic carcinomas is stressed. PMID- 23087741 TI - Aggressive osteoblastoma of the mandible: A diagnostic dilemma. AB - The clinical facts and radiologic findings are very important in the diagnostic evaluation of jaw swellings, and must be considered along with histologic findings. Osteoblastoma, an uncommon primary lesion of the bone that occasionally arises in the jaws, is one such lesion causing a localized jaw swelling. Clinically, osteoblastoma can be symptomatic or even remain symptom-free, and may be diagnosed only on routine radiographic examination. Histologically and clinically, differential diagnosis for osteoblastoma ranges from a variety of benign and malignant tumors that poses a diagnostic dilemma. Stressing the importance of the correct diagnosis of such lesions, this report discusses a case of aggressive osteoblastoma of the mandible posing as a diagnostic dilemma. PMID- 23087742 TI - Primary oral malignant melanoma: Clinicopathological series of four cases. AB - Melanoma of the oral cavity is a rare malignant disease. On account of the presence at relatively obscure areas in the oral cavity, most of oral malignant melanomas are diagnosed at a late stage. Early diagnosis is essential for successful treatment and perhaps is the key factor in improving the prognosis of oral malignant melanoma. However, no large clinical series exist, and in fact, clinical cases are the sole key source of information. We hereby present a series of four cases of primary oral malignant melanoma of South-East Asian ethnic origin, with long-term, regular follow-up. The age of the patients ranged between 40 and 70 years, with equal sex predilection, and the gingiva was found to be the most common site of its occurrence. Based on clinical and histological parameters, all the cases were diagnosed as primary malignant melanoma, which were further confirmed by using immunohistochemical markers. PMID- 23087743 TI - Hemangiomatous ameloblastoma in maxilla: A report of a very rare case. AB - Hemangiomatous ameloblastoma (HA), which is a rare ameloblastic variant, is presented in a 15-year-old boy in the maxillary right molar region associated with unerupted canine and premolars. Radiologic and computed tomographic analysis was suggestive of cystic lesion. An histology picture confirmed the diagnosis of HA. There are less than eight cases documented in the literature and mostly are in the middle age with mandibular location. This is first ever reported case of HA in a 15-year-old boy with maxillary location. Due to less number of documented cases and no long-term follow-ups, clinical behavior and prognosis of this lesion are uncertain. In this case report, the clinical, histological, and radiographic features of HA are presented. PMID- 23087744 TI - Large oral lipoma: Case report and literature review in Iran. AB - Lipoma is a benign mesenchymal tumor of fat with uncertain pathogenesis. Although the most common mesenchymal neoplasm in trunk and proximal portions of the extremities, it is rarely seen in the oral cavity. Oral lipomas are clinically soft, smooth-surfaced nodular masses that mostly are less than 3 cm in size. Typically the tumor is asymptomatic unless bitten or become noticeable because of their size. The buccal mucosa and buccal vestibule are the most common intraoral sites and account for 50% of all cases. Reported here is a relatively large lipoma of buccal mucosa that was treated surgically under local anesthesia. In an 18-month postsurgical follow up no complication or recurrence has occurred. This case will also be compared to intraoral lipomas reported in Iranian population. As lipomas are usually smaller than 3 cm in diameter, lipoma with the size reported, is of clinical importance. Since the large lipomas are in differential diagnosis with other, even malignant, mesenchymal, or salivary gland tumors. Thus, this case report recommends clinical awareness in diagnosis of large intraoral soft tissue lesions. PMID- 23087745 TI - Primary melanoma of oral mucosa: A case report and review of literature. AB - Primary oral melanoma is a rare neoplasm of melanocytic origin, accounting for 0.5% of all oral malignancies. The "chameleonic" presentation of a mainly asymptomatic condition, rarity of this lesion, poor prognosis, and the necessity of a highly specialized treatment are factors that should be seriously considered by the involved health provider. Here is a case report presenting a malignant melanoma of oral mucosa in 48-year-old male patient on maxillary gingiva. The lesion was removed by partial maxillectomy and patient is disease free after 11 months of regular followup. This case provides an example of how dental clinicians play a major role in the identification of pigmented lesions of oral cavity and also emphasize on the fact that any pigmented lesion detected in the oral cavity may exhibit potential growth and should be submitted to biopsy to exclude malignancy. PMID- 23087746 TI - Multidisciplinary management of subgingival crown-root fracture of an immature permanent maxillary central incisor. AB - This case report describes the multidisciplinary management of subgingival horizontal crown-root fracture of an immature permanent maxillary central incisor in a 10-year-old boy. After removal of the fractured fragment, pulpotomy was performed within 48 h from the injury to promote apexogenesis. The tooth was orthodontically extruded until the fracture line was located above the alveolar bone level. Frenectomy, supracrestal fiberotomy, and crown lengthening were performed after adequate stabilization of the extruded tooth for 5 months. Finally, the tooth was restored with composite resin by using the acid etch technique. This report highlights that a multidisciplinary treatment approach with strict cooperation among specialists to manage a complicated crown-root fracture can save and restore a traumatized immature permanent tooth. PMID- 23087747 TI - The reduced predictive value of interleukin 28b gene polymorphisms in a cohort of patients with thyroiditis developed during antiviral therapy for chronic hepatitis C: a preliminary study. AB - BACKGROUND: Single nucleotide polymorphism in the interleukin28B (IL28B) gene was recently shown to be associated with a significant increase in response to interferon-alpha and ribavirin treatment in patients with chronic hepatitis C. Similarly, thyroid disease (TD) occurring during treatment confer an improved sustained virologic response (SVR). OBJECTIVES: To determine the role of IL28B genotypes in a cohort of hepatitis C patients who develop TD during treatment and its relationship to SVR. PATIENTS AND METHODS: IL28B gene profiles including rs12979860, rs12980275 and rs 8099917 and their genotypes were determined in a cohort of 23 hepatitis C patients who developed TD during treatment and their relationship to SVR. RESULTS: Out of 23 studies cases, 19 has one or more favorable genotypes, of which 15 (78.9%) achieved SVR. Eleven has all three unfavorable genotypes and yet achieved 72.7 % SVR. The presence of more than one favorable genotype only correctly predicts SVR vs. non- SVR in ~50 % of cases, i.e. by chance. CONCLUSIONS: Despite the small number of subjects, the presence of one or more unfavorable IL28B genotype does not portend a poor SVR prognostic outcome. This suggests that TD in this clinical context may be a critical factor in the achievement of SVR, probably above that of the genetic predisposition. PMID- 23087748 TI - Effects of metformin, pioglitazone, and silymarin treatment on non-alcoholic Fatty liver disease: a randomized controlled pilot study. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common reasons of enzyme increase in liver. In About 10 percent of patients with NAFLD, the disease progresses toward Non Alcoholic Steatohepatitis (NASH) and about one third of them may progress toward cirrhosis, liver dysfunction, and even hepatocellular carcinoma. OBJECTIVES: According to high prevalence of NAFLD and the fact that there is no consensus on treatment of this disease, the aim of this study was to assess the effects of metformin, pioglitazone, and silymarin on treatment of NAFLD. PATIENTS AND METHODS: Sixty six patients with NAFLD who were presented in the Endocrinology and Metabolism clinic of Boo'ali Hospital, Qazvin, Iran, were assigned randomly into three groups (n = 22). First group was treated by pioglitazone 15 mg/d, second group by metformin 500 mg/d, and third group by silymarin 140 mg/d. All patients underwent clinical and biochemical evaluations including weight, fasting blood sugar (FBS), lipid profiles, body mass index (BMI), aspartate aminotransferase (AST ), alanine aminotransferase (ALT), and serum insulin levels in pre- and post-intervention after eight-week follow up. RESULTS: Before the treatment there was no significant difference between three groups with respect to average age, BMI and gender, FBS, lipid profile, AST, ALT, serum insulin level, and Homeostasis Model Assessment (HOMA) index for insulin resistance. After the intervention, a significant reduction was observed in average amount of FBS, lipid profile, ALT, AST, serum insulin level and HOMA index in three groups (P < 0.01). The most reduction in average FBS, TG, serum insulin level, and HOMA index was observed in pioglitazone group, the most reduction in average amount of cholesterol was seen in metformin group, and the most decrease in average amount of AST and ALT occurred in silymarin group. CONCLUSIONS: These results suggest that all drugs are beneficial in improving biochemical indices in patients with NAFLD. Changes in AST and ALT in silymarin group were demonstrated more than that in other groups and the average difference between changes was significant between silymarin and metformin groups. PMID- 23087750 TI - Construction and preparation of three recombinant adenoviruses expressing truncated NS3 and core genes of hepatitis C virus for vaccine purposes. AB - BACKGROUND: In spite of dozens of clinical trials to establish effective therapeutic and/or preventive vaccine to resolve HCV infection, no real vaccine has been proved to date. Genetic vaccines based on replication-defective adenoviruses have proved to elicit strong and long lasting T-cell responses against a number of viral antigens and are even currently being used for vaccine trials in humans. According to the controversy in the immune modulatory effects of both core and NS3 full length genes, it seemed more practical to employ some parts of these HCV proteins for vaccine design. OBJECTIVES: To generate recombinant Adenoviral vectors containing new overlapping-truncated region of NS3 gene or both the N- and C-terminal deleted parts of core gene, as well as a fusion fragment derived from both of them. MATERIALS AND METHODS: The corresponding transfer vectors expressing truncated fragments of core, NS3 or a fusion fragment of both genes were prepared. The integrity and sequence of the transfer vectors were confirmed, and followed by experiments involving homologous recombination between them and the adenovirus backbone plasmid in the bacterial host. Recombinant Ad-pNS3, Ad-pCore and Ad-pNS3pCore viruses were prepared by transfection of these new recombined constructs into 293 packaging cell lines. The virus titer was then calculated by an immunohistochemistry based method. The RT-PCR, Real-Time PCR and western blotting were used to evaluate gene expression by all recombinant constructs. The production of complete virion particles was evaluated by detailed electron microscopy in addition to the appearance of typical cytopathic effects (CPE) and GFP expression patterns in 293 cells. The RT PCR and GFP detection were employed to monitor the integrity as well as infectivity potency of the viral particles in Hep-G2 cells. RESULTS: RT-PCR, Real Time PCR or western blotting confirmed expression of truncated fragment of NS3, core or a fusion fragment of theirs by newly constructed Ad-pNS3, Ad-pCore, Ad- pNS3pCore particles. Electron microscopy, which revealed many adenovirus-like particles and characteristics of CPE in infected cells in addition to GFP detection, confirmed the infectivity, potency and integrity of recombinant adenoviral particles. CONCLUSIONS: These adenoviruses expressing novel fragments of NS3 and core genes may be suitable tools to overcome shortcomings associated with full gene expression in the setting of HCV vaccine therapy. PMID- 23087749 TI - Occult Hepatitis B (OBH) in Clinical Settings. AB - CONTEXT: Occult hepatitis B (OHB), or persistent HBV DNA in patients who are hepatitis B surface antigen (HBsAg) negative, is a recently recognized entity. In an attempt to summarize the issues, this review presents an overview of the current proposed hypothesis on the clinical relevance and also updates the knowledge on the classification of OHB in different clinical settings. EVIDENCE ACQUISITION: OHB COULD BE FOUND IN DIFFERENT POPULATION AND CLINICAL BACKGROUNDS INCLUDING: viral co-infections (with either human immunodeficiency or hepatitis C viruses), HBV chronic carriers, dialysis patients, transplantation settings and certain clinical situations (named in here: special clinical settings) with no apparent distinguishable clinical parameters. RESULTS: The exact magnitude, pathogenesis, and clinical relevance of OHB are unclear. Even the possible role exerted by this cryptic infection on liver disease outcome, and hepatocellular carcinoma development remains unknown. CONCLUSIONS: Monitoring of Individuals with positive anti-HBc, mass immunization programs and improvement in diagnostic tools seem to be important to control the probability of transmission of HBV through cryptic HBV infection. PMID- 23087751 TI - Mitoptosis, a novel mitochondrial death mechanism leading predominantly to activation of autophagy. PMID- 23087752 TI - Organ allocation for liver transplantation according to the public opinion. AB - BACKGROUND: Although liver transplantation is the last resort for treating end stage liver diseases, this medical procedure is not available for all needful patients because of inadequate organ supply. Therefore, guidelines have been developed by medical experts to regulate the process. Some professionals believe that medical criteria are inadequate for organ allocation in all situations and may not secure fairness of organ allocation. OBJECTIVES: The current study has been designed to identify decision criteria about allocation of donated liver to potential recipients from public points of view. PATIENTS AND METHODS: This is a qualitative study that was conducted through individual interviews and Focus Group Discussions. Individual interviews were conducted among patients' companions and nurses in one of the two liver transplant centers in Iran. Group discussions were conducted among groups of ordinary people who had not dealt previously with the subject. Data was analyzed by Thematic Analysis method. RESULTS: Most of the participants in this study believe that in equal medical conditions, some individual and societal criteria could be used to prioritize patients for receiving donated livers. The criteria include psychological acceptance, ability to pay post-operative care costs, being breadwinner of the family, family support, being socially valued, ability to be instructed, lack of mental disorders, young age of the recipient, being on waiting list for a long time, lack of patient's role in causing the illness, first time transplant recipient, critical medical condition, high success rate of transplantation, lack of concurrent medical illnesses, not being an inmate at the time of receiving transplant, and bearing Iranian nationality. CONCLUSIONS: Taking public opinion into consideration may smooth the process of organ allocation to needful patients with equal medical conditions. It seems that considering these viewpoints in drafting organ allocation guidelines may increase confidence of the society to the equity of organ allocation in the country. This strategy may also persuade people to donate organs particularly after death. PMID- 23087753 TI - Solitary Necrotic Nodules of the Liver: Histology and Diagnosis With CT and MRI. AB - BACKGROUND: A solitary necrotic nodule (SNN) of the liver is an uncommon lesion, which is different from primary and metastatic liver cancers. OBJECTIVES: To analyze the classification, CT and MR manifestation, and the pathological basis of solitary necrotic nodule of the liver (SNN) in order to evaluate CT and MRI as a diagnosing tool. PATIENTS AND METHODS: This study included 29 patients with liver SNNs, out of which 14 had no clinical symptoms and were discovered by routine ultrasound examinations, six were found by computed tomography (CT) due to abdominal illness, four had ovarian tumors, and five had gastrointestinal cancer surgeries, previously. Histologically, these SNNs can be divided into three subtypes, i.e., type I, pure coagulation necrosis (14 cases); type II, coagulation necrosis mixed with liquefaction necrosis (five cases); and type III, multi-nodular fusion (10 cases). CT and magnetic resonance imaging (MRI) patterns were shown to be associated with SNN histology. All patients were treated surgically with good prognosis. RESULTS: CT AND MRI APPEARANCE AND CORRELATION WITH PATHOLOGY TYPES: three subtypes of lesions were hypo-density on both pre contrast and post contrast CT, 12 lesions were found the enhanced capsule and 1 lesion of multi- nodular fusion type showed septa enhancement. The lesions were hypo-intensity on T2WI and the lesions of type II showed as mixed hyperintensity on T2WI. The capsule showed delayed enhancement in all cases, and all lesions of multi- nodular fusion type showed delayed septa enhancement on MR images. 15 cases on CT were misdiagnosed and Four cases on MRI were misdiagnosed and the accuracy of CT and MRI were 48.3% and 86.2% respectively. CONCLUSIONS: In conclusion, CT and MRI are useful tools for SNN diagnosis. PMID- 23087755 TI - When Appropriate Statistical Analysis is Dismissed. PMID- 23087754 TI - Hypercalciuria and nephrocalcinosis as early feature of Wilson disease onset: description of a pediatric case and literature review. AB - BACKGROUND: Wilson's disease (WD) is a rare autosomal-recessive disorder characterized by a mutation in the ATP7B gene, located on chromosome 13, which encodes a protein involved in the metabolism of copper. CASE PRESENTATION: We described the case of an Indian male with a history of polydipsia and polyuria, related to hypercalciuria and consequent nephrocalcinosis. The symptoms began at the age of five years old, but he was not diagnosed with WD until he reached an adolescent age. We started therapy with D-Penicillamine, B-vitamin complex and recommended a low copper diet. Renal involvement in Wilson's disease, characterizing by hypercalciuria, was firstly reported by Litin in 1959. CONCLUSION: Our case was different and peculiar from the previously described cases because the patient presented a very long history (10 years) of permanent hypercalciuria without any acute episode of nephrolithiasis. PMID- 23087756 TI - Long-term persistence of seroprotection by hepatitis B vaccination in healthcare workers of southern Italy. AB - BACKGROUND: The impact of hepatitis B virus (HBV) vaccination campaigns on HBV epidemiology needs to be evaluated, in order to assess the long-term immunity offered by vaccines against HBV. OBJECTIVES: To evaluate the current status of anti-HBV vaccine coverage among healthcare workers (HCWs) in Southern Italy, and to determine the long-term persistence of antibodies to hepatitis B surface antigens (anti-HBs) in such a cohort of subjects. PATIENTS AND METHODS: A longitudinal, retrospective seroepidemiological survey was conducted among 451 HCWs, who were working at or visiting, the Occupational Health Department of a city hospital, in Catania, Italy, between January 1976 and December 2010. RESULTS: At the 30-year follow-up (mean follow-up 10.15 +/- 5.96 years, range 0.74-30), 261 HCWs had detectable anti-HBs titers indicating a persistence of seroprotection of 89.4% (out of 292 anti-HBs positive results, three months after vaccination). An inadequate vaccination schedule was the strongest predictor of antibody loss during follow-up (OR = 8.37 95% CI: 5.41-12.95, P < 0.001). A Kaplan-Maier survival curve revealed that the persistence of anti-HBs 30 years after vaccination, was 92.2% for high responders, while it was only 27.3% for low responders (P = 0.001). CONCLUSIONS: A good level of seroprotection persisted in 57.9% of the subjects after 30 years. Factors related to this immunization status confirmed the importance of vaccinating HCWs early in their careers and ensuring an adequate vaccination schedule. However, with particular reference to the low rate of hepatitis B vaccine coverage among HCWs in Southern Italy, the implementation of a new educational intervention as part of an active vaccination program is needed. PMID- 23087757 TI - Development of Global Consensus Sequence and Analysis of Highly Conserved Domains of the HCV NS5B Prote in. AB - BACKGROUND: Hepatitis C virus (HCV) is a plus stranded RNA virus which encodes 10 different genes. The HCV NS5B gene encodes a polymerase, which is responsible for the replication of the virus and is a potential target for the development of antiviral agents. HCV has a high mutation rate and is classified into six major genotypes. OBJECTIVES: The aim of this study was to draw a representing consensus sequence of each HCV genotype, align all six consensus sequences to draw a global consensus sequence and also study the highly conserved residues. MATERIALS AND METHODS: 236 HCV NS5B sequences, belonging to all six genotypes, reported from all over the world were aligned then a representing phylogenetic tree wasdrawn. RESULTS: The active site residues D220, D225, D318 and D319, which bind the divalent cations, are highly conserved among all the HCV genotypes. The other catalytic pocket residues, R158, S367, R386, and T390 and R394, which interact with the triphosphate of NTPs, are also highly conserved while T390 is mutated to valine in the genotype 5. The motif B residues G283, T286, T287 and N291, which take part in sugar selection by RdRp, are also highly conserved except for T286 which is mutated to proline in the genotypes 3 and 6. The residues E18, Y191, C274, Y276 and H502, which take part in primer/template interaction, are also high conserved except for H502 which is mutated to serine in genotype 2. High variation in all the six consensus sequences was observed in a 12 amino acid beta hairpin loop, which interacts with the double stranded RNA. Nine different peptides from the highly conserved regions of HCV NS5B protein were drawn which can be used as a peptide vaccine. The HCV NS5B phylogenetic tree shows the clusters of different genotypes and their evolutionary association. CONCLUSIONS: In spite of a high mutation rate in HCV, the residues which are present in the catalytic pocket, sugar selection and template/primer interaction are highly conserved. These are target sites for the development of antiviral agents or peptide vaccines. The phylogenetic analysis suggests that different HCV genotypes have been evolved from the genotype 1a. PMID- 23087758 TI - Alveolar echinococcosis of the liver: report of three cases from different geographic areas of iran. AB - INTRODUCTION: Alveolar echinococcosis (AE) is a chronic, serious and sometimes lethal parasitic infection, which is caused by Echinococcus multilocularis (EM). AE has been reported to occur in people from the north of Iran; however, until now there have been no cases of AE reportedfrom the southern provinces, such as Khuzestan. CASE PRESENTATION: Herein, we report our experiences with three cases of hepatic AE, who presented with large masses in the liver, from both the northern and southern provinces of Iran. Three patients are described who were presented with hepatic masses from different provinces of the country. CONCLUSIONS: There were three female patients, 21, 47 and 53 year-old. They were presented with liver masses from different centers of the country i.e. Khorasan, Ardabil and Khuzestan. According to our experience, AE is not an uncommon disease in Iran. Moreover, it has a widespread epidemiology, i.e., this disease should be suspected in all provinces of Iran, not only in the northern, but also in the southern regions of the country. PMID- 23087759 TI - Real response to therapy in chronic hepatitis C virus patients: a study from iran. AB - BACKGROUND: Despite significant advances in the treatment of chronic hepatitis C in the past decades, factors which can affect response rates to combination therapy; peginterferon and ribavirin, are still under study and reaching sustained virological response (SVR) is affected by several different factors. OBJECTIVES: To investigate predictor factors contributing to SVR in Iranian patients. PATIENTS AND METHODS: The present non-randomized, clinical trial was conducted on 100 patients referred to the Tehran Hepatitis Center in 2009-2011. The patients were administered combined peginterferon alpha-2a-ribavirin treatment, based on the standard protocol of the Iranian Ministry of Health. At the end of the treatment, the SVR rate and predictors were evaluated. RESULTS: The mean age of the patients was 42 and 78% were male. Genotype 1a was the most common (70%) and 55% of patients were treatment naive. The outcomes showed that 12%, 16% and 22% patients were; non-responders, breakthroughs and relapsers, respectively, while 50% of the patients reached SVR. Patients reaching SVR were aged 40 years or lower, they were less likely to have been a non-responder in prior treatments, more likely to have a non-1a genotype and a higher number had an HCV RNA of less than 600 000 IU/ml. The multivariate analysis showed that an age of 40 or lower (OR = 3.74, CI95% = 1.52-9.22), a non-1a genotype (OR = 3.71, CI 95% = 1.40-9.81) and an HCV RNA less than 600 000 IU/ml (OR = 2.52, CI 95% = 1.03-6.15) may be useful SVR predictors. CONCLUSIONS: The findings of the present study showed that half of the patients reached SVR through combined peginterferon alpha-2a and ribavirin treatment, the majority of whom had genotype 3a and a minority had genotype 1a. In addition, an age of 40 or lower, non-1a genotype and a viral load less than 600 000 IU/ml were strong SVR predictors. PMID- 23087760 TI - Chronic hepatitis C in saudi arabia: three years local experience in a university hospital. AB - BACKGROUND: Chronic hepatitis C (CHC) is a global infection. In Saudi Arabia, the prevalence of CHC is declining due to the implementation of a blood screening program. However, CHC still remains a leading cause of liver cirrhosis and hepatocellular carcinoma. OBJECTIVES: This is a retrospective study of CHC patients at the King Abdul Aziz University Hospital, Jeddah, Saudi Arabia. PATIENTS AND METHODS: Out of a total of 291 CHC patients from the hepatology clinic at King Abdul Aziz University hospital, Jeddah, 279 patients were included in the present study. They were primarily male (152, 54.5%), with a mean age of 50.41 +/- 1.72 years. The majority of patients were either Saudi (108, 38.7%) or Egyptian (60, 21.5%). A total of 61 patients received combination treatment with pegylated interferon and ribavirin, and one patient with sickle-cell anemia received pegylated INF monotherapy. Demographic, clinical and laboratory features of the CHC patients, and their responses to treatment were studied. RESULTS: Decompensated cirrhosis was documented in 60 patients (21.5%), and hepatocellular carcinoma in 14 (5%). The mean level of serum alanine aminotransferase was 83.6 +/- 231 u/L. The predominant genotype among the 70 patients tested, was genotype 4, followed by genotype 1 (39 and 18 patients, respectively). The sustained viral response (SVR) rate was 82.99%. The main predictive factors for SVR were baseline HCV viral load and rapid virologic response (RVR). The mean duration of follow-up was 4.2 +/- .85 years. There were 24 patients who had liver disease-related mortality. CONCLUSIONS: our data showed that 22% of CHC patients progress to cirrhosis and another 22% had treatment. Liver related mortality was more common in patients with advanced cirrhosis. PMID- 23087761 TI - Effects of Oral Levamisole as an Adjuvant to Hepatitis B Vaccine in HIV/ AIDS Patients: A Randomized Controlled Trial. AB - BACKGROUND: Human immunodeficiency virus (HIV) infected patients are also frequently exposed to the hepatitis B virus (HBV), due to the common routes of transmission, therefore, prevention of hepatitis B results in decreased complications of the disease. OBJECTIVES: Since the immune response of HIV patients to hepatitis B vaccination is less robust than that found in healthy individuals, this study aimed to evaluate the effect of a levamisole adjuvant on increasing the immune response. PATIENTS AND METHODS: In this study, 89 HIV infected patients, without a history of HBV infection or vaccination, were randomly allocated into experimental (44 patients) and control (45 patients) groups. HBV vaccination was performed using the Hepavax-Gene TF vaccine, 40 MUg three times at intervals of; zero, one, and three months. Levamisole 50 mg twice a day or a placebo, was administered to the experimental and control groups, respectively, for a period of six days before to six days after the vaccination. Immune response was evaluated by measuring hepatitis B surface antibodies (HBsAb) concurrently with the second and third vaccine administration, and at one and three months at the conclusion of the vaccination program. RESULTS: The immune response following the threevaccinations was higher in those who were receiving levamisole compared with the controls (90% vs. 65.38%) (P = 0.05). Furthermore, the immune response and the mean antibody titer following the repeated vaccination in the experimental group showed a higher increase than in the control group. The immune response and the mean titer of antibody were not associated with; age, sex, body mass index, history of smoking and/or intravenous drug use in either of the groups. However, regarding CD4+ cells more than 200 cell/mm3, mean antibody production significantly increased in both groups. CONCLUSIONS: Using levamisole with the hepatitis B vaccination can increase the immune response and antibody titer mean in HIV infected patients. Since these patients have a more complete response with CD4+ cells more than 200 cell/mm3, vaccination and effective adjuvants seem to be most beneficial when CD4+ cells are greater than 200 cell/mm3, in HIV infected patients. PMID- 23087762 TI - Sustained viral response hematological markers during the treatment of chronic hepatitis C infection in children. PMID- 23087763 TI - Thyroid dysfunction in chinese patients with chronic hepatitis C treated with interferon alpha: incidence, long-term outcome and predictive factors. AB - BACKGROUND: Thyroid dysfunction (TD) represents an extra-hepatic manifestation of chronic hepatitis C (CHC) and it may also be a side effect of interferon-alpha (IFN-alpha) based treatment. However, previous studies have shown a wide variation in the incidence of TD in patients with CHC. Furthermore, the long-term outcomes and the predictive factors of TD in patients who receive IFN-alpha based treatment have still not been fully studied. OBJECTIVES: The purpose of this study was to describe the incidence and long-term outcomes of TD in Chinese patients with CHC receiving IFN-alphabased treatment. We also aimed to identify the predictive factors of TD associated with this type of therapy. PATIENTS AND METHODS: A retrospective case-series study of 592 consecutive CHC patients with normal baseline thyroid functions, who received IFN-alphabased therapy, was performed. Thyroid function was assessed at baseline and every three months during treatment, as well as in the follow-up after cessation of therapy. The incidence and long-term outcomes of TD were observed. The prevalence of pretreatment thyroid peroxidase antibodies (TPOAb) were assayed in a sex- and age matched nested case-control study. Multivariable stepwise regression analysis was used to explore the independent effects of the baseline factors, on the incidence of TD. RESULTS: At the end of the IFN-alphabased therapy, 68 patients (11.5%) in the study had developed TD, 58 patients (85.3%) presented with subclinical TD, and only 10 patients (14.7%) developed overt thyroiditis. The thyroid function of 46 patients (67.8%) spontaneously returned to normal in the six months of follow up and only three patients (4.4%) had persistent overt TD symptoms after the 24 month follow-up period. Multivariate stepwise analysis suggested that gender and pretreatment TPOAb were the independent factors related to the incidence of TD. Both female patients (OR, 4.31; 95%CI, 2.06-7.31; P = 1.26*10-4) and participants with a positive pretreatment TPOAb (OR = 3.9, 95%CI, 1.72-8.54, P = 0.008) had an increased risk for the development of TD. CONCLUSIONS: The incidence of TD in Chinese patients with CHC during IFN-alphabased therapy was 11.5%, the majority of which was subclinical, while only a very small group had long-term overt TD requiring ongoing medical therapy. Female gender and pretreatment TPOAb positivity are risk factors for the development of TD during IFN-alphabased therapy. PMID- 23087764 TI - Seroprevalence of hepatitis B surface antigen and anti hepatitis C antibody in zahedan city, iran: a population-based study. AB - BACKGROUND: There have been studies regarding the prevalence of hepatitis B surface antigen (HBsAg) and anti-hepatitis C antibody (HCVAb) in Iran. However, the majority of these have reported a variety of rates, depending on their study population, which limits the generalizability of their results to the general population. On the other hand, cultural diversity in the different provinces of Iran also necessitates the performing separate population-based studies in the various regions. OBJECTIVES: To evaluate the population-based prevalence of HBsAg and HCVAb and their correlates in Zahedan City, Iran. PATIENTS AND METHODS: Included in this study were 2587 individuals, using a random and cluster sampling approach. The participants were drawn from the Family Registry of the public health centers in Zahedan City, Iran, from 2008 to 2009. Following data collection from the interviews, subjects were assessed for seropositivity of HBsAg and HCVAb. We then calculated the prevalence of HBsAg and HCVAb, and evaluated these viral markers for an association with; age, sex and potential risk factors. RESULTS: Weighted seroprevalence of HBsAg and HCVAb was 2.5% (CI 95% : 1.9 to 3.3 %) and 0.5% (CI 95% : 0.27 to 0.9 %), respectively. Prevalence of HBsAg increased significantly with age (P value < 0.001), but this was not true for HCVAb (P value: 0.67). We observed no sex dominance in the prevalence of HBsAg (3.2% and 2.2% for males and females, respectively, P value: 0.15) or HCVAb (0.4% and 0.7% for males and females, respectively, P value: 0.27). In a multivariate regression analysis, every additional year in age resulted in a 2% increment in the odds of HBsAg seropositivity. HBsAg was also three times more prevalent among married, than single subjects (with a P value reaching toward significance: 0.065) in multivariate analysis. Prevalence of HCVAb did not differ with respect to any of the potential risk factors. CONCLUSIONS: This is the first population-based study on the prevalence of HCVAb and one of the few population based studies on HBsAg in Zahedan City. We detected lower prevalence rates of HBsAg and HCVAb than in previous studies conducted in Zahedan City. In addition to improvements in social awareness and general health elements, we think that the observed low prevalence rates have been achieved due to the efficiency of mass vaccination projects, implemented against HBV infection in Iran. PMID- 23087765 TI - Citation Analysis of Hepatitis Monthly by Journal Citation Report (ISI), Google Scholar, and Scopus. AB - BACKGROUND: Citation analysis as one of the most widely used methods of bibliometrics can be used for computing the various impact measures for scholars based on data from citation databases. Journal Citation Reports (JCR) from Thomson Reuters provides annual report in the form of impact factor (IF) for each journal. OBJECTIVES: We aimed to evaluate the citation parameters of Hepatitis Monthly by JCR in 2010 and compare them with GS and Sc. MATERIALS AND METHODS: All articles of Hepat Mon published in 2009 and 2008 which had been cited in 2010 in three databases including WoS, Sc and GS gathered in a spreadsheet. The IFs were manually calculated. RESULTS: Among the 104 total published articles the accuracy rates of GS and Sc in recording the total number of articles was 96% and 87.5%. There was a difference between IFs among the three databases (0.793 in ISI [Institute for Scientific Information], 0.945 in Sc and 0.85 GS). The missing rate of citations in ISI was 4% totally. Original articles were the main cited types, whereas, guidelines and clinical challenges were the least ones. CONCLUSIONS: None of the three databases succeed to record all articles published in the journal. Despite high sensitivity of GS comparing to Sc, it cannot be a reliable source for indexing since GS has lack of screening in the data collection and low specificity. Using an average of three IFs is suggested to find the correct IF. Editors should be more aware on the role of original articles in increasing IF and the potential efficacy of review articles in long term impact factor. PMID- 23087766 TI - Hepatitis C Prevalence Among Iranian Female prisoners. PMID- 23087768 TI - Natural history of gastric cancer-a case followed up for eight years: early to advanced gastric cancer. AB - We experienced a case of gastric cancer that was prospectively followed up for 8 years. With severe heart disease, the patient did not wish surgery or anticancer drug treatment. After informed consent was obtained, he was followed up for 8 years. He received upper gastrointestinal endoscopy every year, which revealed IIc early gastric cancer, and biopsy showed well differentiated adenocarcinoma. A flat and mildly depressed lesion with redness was observed on endoscopy, exhibiting typical morphology of IIc-type early gastric cancer. The appearance of IIc M cancer was observed macroscopically from 2000 to 2003. Four years later, surface irregularity with ulceration appeared. Then, the whole lesion was elevated, which suggested submucosal invasion, and the tumor exhibited the morphology of IIa + IIc or type 3. The ulcer became deeper and elevated boundaries were formed. Horizontal expansion of the flat lesion was mild, while invasion to deeper layers was predominant. Eventually, he died of heart failure. Estimated M cancer was observed for about 3 years, followed by invasion to deeper layers. Taken together, this is a valuable case that followed up the manner of invasion to deeper layers over time from early to advanced gastric cancer. PMID- 23087767 TI - A cell culture system for the structure and hydrogel properties of basement membranes; Application to capillary walls. AB - In specialized capillary beds such as the kidney glomerulus, the sheet-like structure of the basement membrane in conjunction with opposing monolayers of endothelium and epithelium form the functioning filtration unit of the kidney. Using a novel cross-linking method on a collagen substrate, we have created a novel hydrogel scaffold to substitute for the basement membrane. Using a simple casting method to create thin films of the hydrogel scaffold (1-5MUm), the scaffolds were suitable for long-term static culture, and supported cell attachment and long term cell viability similar to a standard type I collagen substrate. Bulk diffusion and protein permeability of the hydrogel scaffold were evaluated, in addition to its use in a perfusion chamber where it withstood hydraulic pressures typical for glomerular capillaries. This system thus provided a suitable cell substrate for the co-culture of renal epithelial podocytes and endothelial cells in a device that replicates the geometry of the in vivo juxtaposition of the two cell types in relation to their basement membrane. PMID- 23087769 TI - Early Developments in Joint Action. AB - Joint action, critical to human social interaction and communication, has garnered increasing scholarly attention in many areas of inquiry, yet its development remains little explored. This paper reviews research on the growth of joint action over the first 2 years of life to show how children become progressively more able to engage deliberately, autonomously, and flexibly in joint action with adults and peers. It is suggested that a key mechanism underlying the dramatic changes in joint action over the second year of life is the ability to reflect consciously on oneself and one's behavior and volition and correspondingly, on the behavior, goals, and intentions of others. PMID- 23087770 TI - Endovascular repair of abdominal aortic aneurysms in low surgical risk patients: an evidence update. PMID- 23087771 TI - Gastric Electrical Stimulation (GES): An Evidence Update. PMID- 23087772 TI - Safety of laparoscopic adjustable gastric banding: an evidence update. PMID- 23087773 TI - Finding Value in Practice-context Research. PMID- 23087774 TI - The development and validation of the client expectations of massage scale. AB - BACKGROUND: Although there is evidence that client expectations influence client outcomes, a valid and reliable scale for measuring the range of client expectations for both massage therapy and the behaviors of their massage therapists does not exist. Understanding how client expectations influence client outcomes would provide insight into how massage achieves its reported effects. PURPOSE: To develop and validate the Client Expectations of Massage Scale (CEMS), a measure of clients' clinical, educational, interpersonal, and outcome expectations. SETTING: Offices of licensed massage therapists in Iowa. RESEARCH DESIGN: A practice-based research methodology was used to collect data from two samples of massage therapy clients. For Sample 1, 21 volunteer massage therapists collected data from their clients before the massage. Factor analysis was conducted to test construct validity and coefficient alpha was used to assess reliability. Correlational analyses with the CEMS, previous measures of client expectations, and the Life Orientation Test-Revised were examined to test the convergent and discriminant validity of the CEMS. For Sample 2, 24 massage therapists distributed study materials for clients to complete before and after a massage therapy session. Structural equation modeling was used to assess the construct, discriminant, and predictive validity of the CEMS. PARTICIPANTS: Sample 1 involved 320 and Sample 2 involved 321 adult massage clients. INTERVENTION: Standard care provided by licensed massage therapists. MAIN OUTCOMES: Numeric Rating Scale for pain and Positive and Negative Affect Schedule Revised (including the Serenity subscale). RESULTS: The CEMS demonstrated good construct, convergent, discriminant and predictive validity, and adequate reliability. Client expectations were generally positive toward massage and their massage therapists. Positive outcome expectations had a positive effect on clients' changes in pain and serenity. High interpersonal expectations had a negative effect on clients' changes in serenity. CONCLUSIONS: Client expectations contribute to the nonspecific effects of massage therapy. PMID- 23087775 TI - Massage Therapy Produces Short-term Improvements in Balance, Neurological, and Cardiovascular Measures in Older Persons. AB - BACKGROUND: Falls are the primary cause of accidental death in older persons, producing increased morbidity, decreased independence, and billions in medical costs annually. Massage therapy (MT) may produce adaptations that decrease risk of falling. If MT can improve stability in older persons, it may provide a new intervention for this issue. PURPOSE: Determine the acute effects of a 60-minute MT treatment on static and functional balance, neurological measures, heart rate, and blood pressure in healthy, older individuals. SETTING: Laboratory RESEARCH DESIGN: A 2 by 4 (treatment by time) mixed factorial experimental design for the cardiovascular and postural control variables; independent variables were treatment with two levels (control, MT) and time with four levels (pretreatment baseline, immediate post-treatment, 20-minute post-treatment, 60-minute post treatment). Neurological measures utilized a 2 by 2 mixed design, with testing conducted pre- and 60-minutes post-treatment. PARTICIPANTS: Thirty-five healthy, older volunteers (19 male and 16 female; ages 62.9 +/- 4.6). INTERVENTION: A 60 minute full-body therapeutic massage. The control group rested quietly in the treatment room. MAIN OUTCOME MEASURES: Static (double-legged) and functional (single-legged) postural control with eyes-open and eyes-closed; Hoffmann-reflex measures; heart rate, and systolic and diastolic blood pressure. RESULTS: MT significantly decreased rectangular displacement area in both the eyes-open and eyes-closed, double-legged stance conditions (p < 0.05); displacement velocity in both eyes-open conditions (p < .05); and systolic and diastolic blood pressure (p < .05), while increasing heart rate (p < .05). MT also significantly lowered H(max)/M(max) ratios compared to controls (p = .002). Decreased H(max)/M(max) measures were correlated to improved stability. CONCLUSIONS: A single, 60-minute, full-body massage therapy treatment was shown to have a stabilizing effect on measures of static and dynamic balance and physiological factors related to stability in older adults. MT should be investigated as a potential intervention to decrease falls in older individuals. PMID- 23087776 TI - Six weeks of massage therapy produces changes in balance, neurological and cardiovascular measures in older persons. AB - OBJECTIVES: Falls in older adults represent a primary cause of decreased mobility and independence, increased morbidity, and accidental death. Research and clinical reports indicate that therapeutic massage (TM) may positively influence suggested causative factors. The second in a two-part study, this project assessed the effects of six weeks of TM treatment on balance, nervous system, and cardiovascular measures in older adults. DESIGN: A randomized controlled trial assessed the effects of six weekly 60-minute sessions of TM on balance, cardiovascular, and nervous system measures. Thirty-five volunteers (19 male and 16 female; ages 62.9 +/- 4.6) were randomly assigned to relaxation control or TM groups. A 2 * 4 [treatment condition X time (week 1 and 6)] mixed factorial experimental design was utilized for cardiovascular/balance variables assessed at pretreatment baseline, immediate post-treatment, and 20- and 60-minutes post treatment; nervous system measures were assessed only at pretreatment and at 60 minute follow-up (2 * 2 mixed design). Long-term benefits were assessed by comparing the TM and control groups on pretreatment baseline measures at week six and a follow-up assessment at week seven (2 * 3 mixed design). SETTING: Laboratory INTERVENTION: Six weekly 60-minute, full-body TM. OUTCOME MEASURES: Postural control/cardiovascular measures were assessed weeks one, six, and seven; pretreatment and immediate, 20- and 60-minutes post-treatment. Motoneuron pool excitability was assessed pretreatment and 60 minutes post-treatment. RESULTS: The TM group showed significant differences relative to controls in cardiovascular and displacement area/velocity after the week six session, with decreasing blood pressure and increasing stability over time from immediate post TM to 60 minutes post-TM. The TM group revealed lower H-max/M-max ratios 60 minutes post-treatment. Long-term differences between the groups were detected at week seven in displacement area/velocity and systolic blood pressure. CONCLUSIONS: Results suggest six weeks of TM resulted in immediate and long-term improvements in postural stability and blood pressure, compared to a controlled condition. PMID- 23087777 TI - Massage therapy for cervical degenerative disc disease: alleviating a pain in the neck? AB - BACKGROUND: A 66-year-old female client with cervical degenerative disc disease at lateral left facet joint C6/C7 was experiencing symptoms of chronic neck pain accompanied by limited cervical range of motion, as well as radicular left shoulder and arm pain. The objective of this case report was to describe the effect of therapeutic massage on the client's symptoms and impairments of cervical DDD. METHODS: Therapeutic massage interventions included soft-tissue manipulation using petrissage and neuromuscular techniques, fascial work, facilitated stretching, joint play, hydrotherapy, education on self-stretching, and positive guidance about condition management. Assessment included pain-free cervical ROM and a subjective verbal pain scale. RESULTS: After several treatment sessions, client's symptoms had decreased and cervical ROM had improved moderately. There was also a decrease in reported pain and an increase in functional daily activities. Client showed a greater understanding of the physiologic barriers which degenerative changes may present. CONCLUSIONS: This client responded favorably to massage therapy as a treatment intervention for cervical DDD symptoms. PMID- 23087778 TI - Causal inference in longitudinal studies with history-restricted marginal structural models. AB - A new class of Marginal Structural Models (MSMs), History-Restricted MSMs (HRMSMs), was recently introduced for longitudinal data for the purpose of defining causal parameters which may often be better suited for public health research or at least more practicable than MSMs (6, 2). HRMSMs allow investigators to analyze the causal effect of a treatment on an outcome based on a fixed, shorter and user-specified history of exposure compared to MSMs. By default, the latter represent the treatment causal effect of interest based on a treatment history defined by the treatments assigned between the study's start and outcome collection. We lay out in this article the formal statistical framework behind HRMSMs. Beyond allowing a more flexible causal analysis, HRMSMs improve computational tractability and mitigate statistical power concerns when designing longitudinal studies. We also develop three consistent estimators of HRMSM parameters under sufficient model assumptions: the Inverse Probability of Treatment Weighted (IPTW), G-computation and Double Robust (DR) estimators. In addition, we show that the assumptions commonly adopted for identification and consistent estimation of MSM parameters (existence of counterfactuals, consistency, time-ordering and sequential randomization assumptions) also lead to identification and consistent estimation of HRMSM parameters. PMID- 23087780 TI - Kinetic Analysis of Dynamic Positron Emission Tomography Data using Open-Source Image Processing and Statistical Inference Tools. AB - In dynamic mode, positron emission tomography (PET) can be used to track the evolution of injected radio-labelled molecules in living tissue. This is a powerful diagnostic imaging technique that provides a unique opportunity to probe the status of healthy and pathological tissue by examining how it processes substrates. The spatial aspect of PET is well established in the computational statistics literature. This article focuses on its temporal aspect. The interpretation of PET time-course data is complicated because the measured signal is a combination of vascular delivery and tissue retention effects. If the arterial time-course is known, the tissue time-course can typically be expressed in terms of a linear convolution between the arterial time-course and the tissue residue. In statistical terms, the residue function is essentially a survival function - a familiar life-time data construct. Kinetic analysis of PET data is concerned with estimation of the residue and associated functionals such as flow, flux, volume of distribution and transit time summaries. This review emphasises a nonparametric approach to the estimation of the residue based on a piecewise linear form. Rapid implementation of this by quadratic programming is described. The approach provides a reference for statistical assessment of widely used one- and two-compartmental model forms. We illustrate the method with data from two of the most well-established PET radiotracers, (15)O-H(2)O and (18)F fluorodeoxyglucose, used for assessment of blood perfusion and glucose metabolism respectively. The presentation illustrates the use of two open-source tools, AMIDE and R, for PET scan manipulation and model inference. PMID- 23087779 TI - Genetic Susceptibility to Fungal Infections in Humans. AB - Most fungal infections in humans occur in the setting of iatrogenic immunosuppression or HIV infection. In the absence of these factors, fungi cause mild, self-limited infections that typically involve mucocutaneous surfaces. Hence, when persistent or recurrent mucocutaneous infections (chronic mucocutaneous candidiasis [CMC]) or invasive fungal infections (IFIs) develop in a "normal" host, they are indicative of genetic defects causing innate or adaptive immune dysfunction. In this review, recent developments concerning genetic and immunologic factors that affect the risk for IFIs and CMC are critically discussed. PMID- 23087781 TI - Nanoparticles for Uveal Melanoma Treatment. AB - Chemotherapy is a common treatment for uveal melanoma. Rapid clearance of injected drug from the vitreous, necessitates repeated injections in to the eye. We have investigated the use of hydrogel particles to deliver chemotherapeutic drugs to the uveal melanoma site. Fluorescent dye-labeled nano- and micro particles were injected intravenously into the animal. Particle accumulation in the uveal tissue was studied. The nanoparticles showed a much higher accumulation in the uveal tissue than the microparticles. The optimal particle size is between 100 and 300 nm. These particles could be decorated with targeting moieties and loaded with chemotherapeutic drugs to achieve sustained release at the cancerous site. PMID- 23087782 TI - Validation of A Point-of-Care Lactate Device For Screening At-Risk Adults Receiving Combination Antiretroviral Therapy In Botswana. AB - BACKGROUND: Nucleoside reverse-transcriptase inhibitors (NRTIs) are a major component of combination antiretroviral therapy (cART) worldwide but they have been associated with mitochondrial toxicities, with one of the most significant being lactic acidosis. In southern Africa, being female and overweight (BMI > 25) as well as receiving d4T and/or ddI-based cART are risk factors for the development of this potentially life-threatening complication. It is challenging in many resource-limited settings to obtain reliable serum lactate measurements while screening for the presence of lactic acidosis. Point-of-care devices, however, are now available that provide simple, accurate measurements of serum lactate levels at relatively low cost. The objective of this study was to assess the agreement of the portable (AccutrendTM handheld) lactate analyzer to the conventional laboratory system for obtaining serum lactate. METHODS: Eighty two "at-risk" cART-treated adults were evaluated, having their lactate levels tested in parallel using both modalities. RESULTS: The mean (range) lactate level for the portable device was 2.28 (0.9-5.0) compared to 1.96 (0.7-5.4) using the conventional method. There was a strong correlation (p<0.05) between the portable device and the conventional means with a Pearson correlation coefficient of 0.92 [95% CI: 0.88-0.95]. The mean bias was 0.33 [95% CI: -0.39-1.04], with the portable device having slightly higher values. CONCLUSION: The use of a portable lactate device provides an accurate and user-friendly means of screening at-risk patients for the presence of lactic acidosis in resource-limited settings with limited laboratory capacity. PMID- 23087783 TI - Editorial. PMID- 23087784 TI - Caries prevalence in a 7- to 15-year-old Albanian schoolchildren population. AB - The aim of this study was to determine the caries prevalence in urban and suburban Albanian schools. A large sample (n= 2617) of subjects, aged 7-15, was examined by a clinical observation without radiograms. The sample comprised 1257 males and 1360 females. For each subject an anamnestic questionnaire about feeding, fluoride, dentist attendance and familiar informations was obtained. Gender and age differences were compared by Chi-square test. The total dmft index (decayed, missing and filled teeth in deciduous dentition) was 2.082; dmft in males was 2.137, in females was 2.032. The total DMFT index (Decayed, Missing and Filled Teeth in permanent dentition) was 2.327; DMFT in males was 2.253, in females was 2.396. Decayed teeth was principal component of both dmft and the DMFT index. Caries prevalence results higher in girls than boys in deciduous and in permanent teeth. PMID- 23087785 TI - Macroscopic and microscopic evaluation of a new implant design supporting immediately loaded full arch rehabilitation. AB - The purpose of this study is to evaluate macroscopic and microscopic appearance of a new implant design, with particular emphasis given to the type of prosthesis connection. Two dental implants of the same type (Torque Type((r)), WinSix((r)), BioSAFin. S.r.l. - Ancona, Italy), with sandblasted and acid etched surfaces (Micro Rough Surface((r))), but differing from each other for the prosthesis connection system, were examined by scanning electron microscope (SEM) analysis at different magnifications: TTI implant, with a hexagonal internal connection, and TTX implant, with a hexagonal external connection. SEM analysis showed that the Torque Type((r)) implant is characterized by a truncated cone shape with tapered tips. The implant body showed a double loop thread and double pitch with blunt tips. For both types of connection, the implant neck was 0.7 mm in height with a 3% taper. This implant design may be able to guarantee osteotomic properties at the time of insertion in a surgical site suitably prepared, a facilitated screwing, thanks to the thread pitch and to the broad and deep draining grooves, thereby ensuring a good primary stability. The different connection design appears defined and precise, in order to ensure a good interface between the fixture and the prosthetic components. Therefore, this design appears to be particularly suitable in cases where a good primary stability is necessary and a precise coupling between endosseous and prosthetic components, as it allows an easy insertion of the fixture even in conditions of reduced bone availability, and in cases of immediately loaded full-arch rehabilitations. PMID- 23087786 TI - Gnathological postural treatment in a professional basketball player: a case report and an overview of the role of dental occlusion on performance. AB - AIMS: During competitions and training many professional athletes use to wear occlusal splints to improve their sports performance. However, notwithstanding some studies concluded that achieving a balanced cranial-occlusal system could bring to an improvement of sports performances, the results are still contrasting. Probably the gnathological postural treatment of athletes has greater influence on performance when the individual suffers of Temporomandibular Joint Disfunction (TMJ) or physio-postural pathologies owing to the consequent alteration of the "tonic-postural system". This clinical case details a gnathological postural approach to a professional basketball player suffering from muscular problems related to the stomatognathic apparatus and a low back pain unresolved with the only physiotherapy, which limited her performance. METHODS: Force platform and T-Scan III appliances were used in order to check the postural and occlusal condition of the athlete and as an aid to clinical parameters in achieving a correct splint balance. RESULTS: After the treatment involving inserting an occlusal splint and physiotherapy sessions, the patient no longer complained of low back pain problems and the symptoms associated with the stomatognathic apparatus improved considerably. In particular, after the tests carried out on an isokinetic machine, a force increase related to the quadriceps muscles was detected when the patient was wearing the occlusal splint. CONCLUSIONS: All athletes must however be analysed individually and carefully with clinical and instrumental analyses in order to consider the possible real effectiveness of an occlusal splint for improving postural structure and sports performance. PMID- 23087787 TI - Cyclic fatigue resistance of four nickel-titanium rotary instruments: a comparative study. AB - AIMS: The aim of this study is to investigate cyclic fatigue resistance of four nickel - titanium rotary (NTR) instruments produced by a new method or traditional grinding processes. METHODS: FOUR NTR INSTRUMENTS FROM DIFFERENT BRANDS WERE SELECTED: group 1. Twisted File produced by a new thermal treatment of nickel - titanium alloy; group 2. Revo S SU; group 3. Mtwo and group 4. BioRaCe BR3 produced by traditional grinding processes. A total of 80 instruments (20 for each group) were tested for cyclic fatigue resistance inside a curved artificial canal with a 60 degree angle of curvature and 5 mm radius of curvature. Time to fracture (TtF) from the start of the test until the moment of file breakage and the length of the fractured tip was recorded for each instrument. Means and standard deviations (SD) of TtF and fragment length were calculated. Data were subjected to one-way analysis of variance (ANOVA). RESULTS: Group 1 (Twisted File) showed the highest value of TtF means. Cyclic fatigue resistance of Twisted File and Mtwo was significantly higher than group 2 (Revo S SU) and 4 (BioRace BR3), while no significant differences were found between group 1 (Twisted File) and 3 (Mtwo) or group 2 (Revo S SU) and 4 (BioRaCe BR3). CONCLUSIONS: The cyclic fatigue resistance of Twisted File was significantly frigher than instruments produced with traditional grinding process except of Mtwo files. PMID- 23087788 TI - Ultrasonic bone surgery in the treatment of impacted lower third molar associated to a complex odontoma: a case report. AB - The removal of impacted mandibular third molar is a common surgical procedure entailing some risk of complications, especially when the tooth and the inferior alveolar nerve and/or lingual cortical plate are in close proximity. A technique that can reduce the possibility of damage is the Ultra Sonic Bone Surgery. The aim of this report is to present a paradigmatic case of an impacted mandibular third molar closely associated with a complex odontoma, which was treated with the Ultrasonic Bone Surgery (UBS) device. This technique appeared to be a valid alternative to manual or mechanical treatment, strongly minimizing trauma to the inferior alveolar nerve, vascular tissues, or surrounding dental tissues. PMID- 23087789 TI - Knowledge, attitudes and behavior of Italian mothers towards oral health: questionnaire validation and results of a pilot study. AB - AIMS: The study is focused on the analysis of knowledge, attitudes and behaviors of Italian mothers in regards to their oral health, deepening the understanding of how the initiation of habits and behaviors for a healthy lifestyle may influence the empowerment process of their children. METHODS: The questionnaire was composed by 14 sections and has been conducted using an online questionnaire on the mothers association's website. Reliability analysis was tested and content validity was evaluated using Cronbach's alpha to check internal consistency with the intention to obtain no misunderstanding results. Statistical analysis was performed through SPSS 19.0. RESULTS: The total number of the compiled questionnaires was 192. The highest value of the Cronbach's alpha is obtainable in Section 13 (Quality of Life in relation to dental health between 8-17 years old kids) with a value of 0.998 (on 5 items). The total value of the Cronbach's alpha considering the part of questionnaire dedicated only to the mothers that have more than 18 years old children is 0.490 on 116 items. Considering all the sections of the questionnaire on 134 items and 127 questions, we get an alpha value of 0.784. CONCLUSIONS: The questionnaire for the mothers showed a good reliability in the pilot study and it seems it made good results in terms of internal coherence and validity. The online administration allowed the opportunity to optimize the data collection avoiding complications with papers and it offers potentially, a tool able to rapidly gather a vast sample in which to perfect other studies. PMID- 23087790 TI - Effectiveness of adjunctive subgingival administration of amino acids and sodium hyaluronate gel on clinical and immunological parameters in the treatment of chronic periodontitis. AB - AIMS: The aim of this clinical trial was to compare clinical and biochemical healing outcomes following ultrasonic mechanical instrumentation versus ultrasonic mechanical instrumentation associated with topical subgingival application of amino acids and sodium hyaluronate gel. METHODS: Eleven systemically healthy subjects with moderate-severe chronic periodontitis, who had four sites with pocket probing depth and clinical attachment level greater than or equal to 5 mm were randomly assigned to two different types of treatment: two pockets were treated with ultrasonic debridement (Control Group) and two pockets with ultrasonic mechanical instrumentation associated with 0,5 ml of amino acids and sodium hyaluronate gel (Test Group). Probing depth, clinical attachment level, plaque index and bleeding on probing were recorded at baseline, 45 and 90 days. Levels of calprotectin and myeloperoxidase activity in gingival crevicular fluid were assessed at baseline and on day 7 and 45. RESULTS: Statistical significance was found between baseline and day 45 in relation to probing depth reduction and bleeding on probing between groups for both of the tested treatments. Significant reductions in MUg/sample of calprotectin and myeloperoxidase were found after 1-week and an increase at 45 days in both groups. There were no statistically significant differences between other variables evaluated in this study. CONCLUSIONS: These data suggest that subgingival application of hyaluronic acid following ultrasonic mechanical instrumentation is beneficial for improving periodontal parameters. PMID- 23087791 TI - The Rare Cancer Network: achievements from 1993 to 2012. AB - The Rare Cancer Network (RCN), founded in 1993, performs research involving rare tumors that are not common enough to be the focus of prospective study. Over 55 studies have either been completed or are in progress.The aim of the paper is to present an overview of the 30 studies done through the RCN to date, organized by disease site. Five studies focus on breast pathology, including sarcoma, lymphoma, phyllodes tumor, adenoid cystic carcinoma, and ductal carcinoma in situ in young women. Three studies on prostate cancer address prostatic small cell carcinoma and adenocarcinoma of young and elderly patients. Six studies on head and neck cancers include orbital and intraocular lymphoma, mucosal melanoma, pediatric nasopharyngeal carcinoma, olfactory neuroblastoma, and mucosa associated lymphoid tissue lymphoma of the salivary glands. There were 4 central nervous system studies on patients with cerebellar glioblastoma multiforme, atypical and malignant meningioma, spinal epidural lymphoma and myxopapillary ependymoma. Outside of these disease sites, there is a wide variety of other studies on tumors ranging from uterine leiomyosarcoma to giant cell tumors of the bone. The studies done by the RCN represent a wide range of rare pathologies that were previously only studied in small series or case reports. With further growth of the RCN and collaboration between members our ability to analyze rare tumors will increase and result in better understanding of their behavior and ultimately help direct research that may improve patient outcomes. PMID- 23087792 TI - Aleukemic granulocytic sarcoma presenting at multiple sites: ovary, breast and soft tissue. AB - An 18 year old female presented with the history of pain in abdomen, breast engorgement, swelling over both legs and breathlessness for three month. On clinical examination diagnosis of fibroadenoma breast was made. Ultrasonography of abdomen showed bilateral ovarian mass. Bilateral salpingo-ophrectomy was done and specimen was sent for histological examination. Two lobulated solid masses of tissues the larger one measuring 13*8*5 cm and smaller one measuring 10*7*5 cm in size received. Microscopic examination showed monomorphic population of discohesive, hyperchromatic small round cells had high N:C ratio, coarse chromatin, conspicuous nucleoli and scant to moderate amount of basophilic cytoplasm, lying in sheets and separated by fibrous strands and diffusely infiltrating the ovarian stroma. Fine needle aspiration from breast lump and leg swelling showed predominant population of blast cells. Myeloperoxidase was strongly positive and diagnosis of granulocytic sarcoma was confirmed. PMID- 23087793 TI - Large cell neuroendocrine carcinoma originating from the uterine endometrium: a report on magnetic resonance features of 2 cases with very rare and aggressive tumor. AB - Neuroendocrine carcinomas (NEC) of the female genital tract are aggressive and uncommon tumors, which usually involve the uterine cervix and ovary, and are seen very rarely in the endometrium. Only less than 10 cases of large cell NEC (LCNEC) of the endometrium have been reported in the literature and their radiological findings are not well described. We report here two cases of pathologically proven LCNEC of the uterine endometrium. In both cases, the uterine body was enlarged and the tumor occupied part of the uterine cavity. Endometrial mass exhibited heterogeneous high intensity on T2-weighted magnetic resonance (MR) images, and diffusion-weighted MR images revealed high intensity throughout the tumor, consistent with malignancy. LCNEC is a highly malignant neoplasm without particular findings in terms of diagnostic imaging and pathology, so its preoperative definitive diagnosis is very difficult. However, when laboratory test, pathologic diagnosis and MR imaging suggest a poorly differentiated uterine malignancy, positron emission tomography-computed tomography scan should be performed as a general assessment to help with diagnosis. PMID- 23087794 TI - The importance of patient reported functional outcome in paediatric desmoid fibromatosis. PMID- 23087795 TI - Clinical features and outcomes of plasma cell leukemia: a single-institution experience in the era of novel agents. AB - Plasma cell leukemia (PCL) is a rare hematologic malignancy with aggressive clinical and biologic features. Data regarding its prognosis with the use of the novel agents, i.e., the immunomodulatory drugs thalidomide and lenalidomide, and the proteasome inhibitor bortezomib, are limited. We retrospectively reviewed clinical outcomes, response to therapy, and survival of 17 patients seen at the Penn State Hershey Cancer Institute since the availability of novel agents (2006 2011). Twelve patients had primary PCL (pPCL), and 5 secondary PCL (sPCL). PCL was associated with aggressive clinicobiological features, such as high-risk cytogenetics, elevated serum beta-2-microglobulin and lactate dehydrogenase, International Staging System stage III, and rapid relapse after therapy. With the use of thalidomide, lenalidomide, and bortezomib in 53%, 53%, and 88% patients, respectively, median overall survival (OS) was 18 months in the whole group (95% confidence interval, 11-21 months), and 21 and 4 months in pPCL and sPCL, respectively (P=0.015). OS was inferior to that of 313 consecutive patients with multiple myeloma (MM) treated in the same period, even when compared with a subset of 47 MM with high-risk cytogenetics. Although our data are limited by the small sample size, we conclude that novel agents may modestly improve survival in patients with PCL, when compared to historical controls. Novel therapies do not seem to overcome the negative prognosis of PCL as compared with MM. PMID- 23087796 TI - HIV-associated multicentric Castleman's disease. AB - Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder. It is found with higher frequency in patients with HIV infection, with systemic symptoms and poor prognosis. We present the case of a 32-year old man with HIV disease, Kaposi's sarcoma, lymphadenopathy, fever and hemolytic anemia. A diagnosis of Castleman's disease is confirmed through biopsy and treatment is often based only on published case reports. Systemic treatments for MCD have included chemotherapy, anti-herpes virus, highly active antiretroviral therapy and, more recently, monoclonal antibodies against both IL6 and CD20. PMID- 23087797 TI - Lingual metastasis from renal cell carcinoma: a case report and literature review. AB - Renal cell carcinoma (RCC) accounts for the 3% of all solid tumors. Despite continuous improvement in the therapy regimen, less has been achieved in terms of enabling an earlier diagnosis: the neoplasia usually reveals its presence at an advanced stage, obviously affecting prognosis. The most frequent sites of secondary disease are shown to be lungs (50-60%), bone (30-40%), liver (30-40%) and brain (5%); while the head and neck district seems to account for less than 1% of patients with primary kidney lesion. We report here the case of a 70-year old man who presented with acute renal failure due to abdominal recurrence of RCC 18 years post nephrectomy. After a few months of follow up without any systemic therapy due to the renal impairment, the patient presented a vascularized tongue lesion that was demonstrated to be a secondary localization of the RCC. This lesion has, therefore, been treated with microsphere embolization to stop the frequent bleeding and to lessen the unbearable concomitant symptoms it caused, such as dysphagia and pain. A tongue lesion that appears in a RCC patient should always be considered suspect and a multidisciplinary study should be conducted both to assess whether it is a metastasis or a primary new lesion and to understand which method should be selected, if necessary, to treat it (surgery, radiation or embolization). Lingual metastasis should be examined accurately not only because they seem to implicate a poor prognosis, but also because they carry a burden of symptoms that not only threatens patients' lives but also has a strong impact on their quality of life. PMID- 23087798 TI - Stabilization of metastatic myxopapillary ependymoma with sorafenib. AB - We report on a 59-year old woman with three huge intrathoracal masses that were accidentally diagnosed when she consulted a physician for upper abdominal discomfort. A biopsy revealed that they were metastases of a coccygeal myxopapillary ependymoma, resected 20 years before. As neither resection, debulking, nor radiation therapy were considered to be indicated, systemic therapy with temozolomide was started. At the first evaluation after four months, the metastases had progressed. Imatinib delayed the progression, but had to be stopped after six months because of critical increased pleural effusion. Using the multikinase inhibitor sorafenib, the disease was stabilized and an acceptable quality of life could be obtained for one year. PMID- 23087799 TI - Primary testicular lymphoma with cardiac involvement in an immunocompetent patient: case report and a concise review of literature. AB - Primary testicular lymphoma (PTL) is a rare testicular tumor representing less than 9% of all testicular cancers. PTL usually tends to spread to or relapse at nodal structures or extra-nodal sites such as contralateral testes, central nervous system, skin, lung, pleura, waldeyer's ring and soft tissues. We present a case of PTL with huge left atrial mass, an extremely unusual site of involvement. Early disease usually carries a good prognosis, whereas advanced stage carries an extremely poor prognosis. Herein, we report the complete remission to date in a patient with advanced stage PTL with huge left atrial mass, treated with systemic rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone and intrathecal methotrexate. A brief review of literature focusing on various aspects of management of primary testicular lymphoma and lymphomatous involvement of heart is also discussed. PMID- 23087801 TI - A synchronous occurrence of urothelial carcinoma with abundant myxoid stroma and inverted papilloma of the urinary bladder. AB - Abundant myxoid stroma rarely occurs in urothelial carcinomas, and may cause diagnostic challenges when cells with eosinophilic cytoplasm forming nests and cords in a myxoid background are seen, particularly in the absence of typical carcinomatous appearance. Microscopic examination of transurethral resection specimen of a 71-year-old male patient revealed non-cohesive oval or elongated tumor cells with eosinophilic cytoplasm arranged in cord-like filigree pattern in an abundant myxoid stroma. Immunohistochemically the tumor was positive for cytokeratin 7, cytokeratin 20, and 34BE12. About 90 to 100% nuclear staining was observed with p63, p53, and Ki-67. A second neoplasm with a flat overlying urothelial epithelium and a complete inverted cellular growth pattern was also noted. The neoplasm exhibited less than 2% and 10% nuclear staining with Ki-67 and p53, respectively. Considering histological, histochemical, and immunohistochemical findings, a diagnosis of synchronous urothelial carcinoma with abundant myxoid stroma and inverted papilloma was made. PMID- 23087800 TI - Extra-gastrointestinal stromal tumor of the omentum: a rare case report and review of the literature. AB - Gastrointestinal stromal tumors (GIST) are uncommon mesenchymal spindle-cell or epithelioid neoplasms, located mainly with higher frequency in the stomach and small bowel. GISTs represent the majority of primary non-epithelial neoplasms of the digestive tract, most frequently expressing the KIT protein a transmembrane tyrosine kinase receptor for stem cell factor. Extra-gastrointestinal stromal tumors tend to present In fewer than 5% of cases; they originate primarily from the mesentery, omentum or peritoneum. Furthermore, these extra-gastrointestinal tumors (EGIST) tend to be more common in patients over the age of 50 years. EGISTs are neoplasms with overlapping immunohistological features, occurring in the abdomen outside the gastrointestinal tract with no connection to the gastric or intestinal wall. We describe here a rare case of EGIST of the lesser omentum and report the clinical, macroscopic, immunohistological and radiological features of an EGIST arising in the lesser omentum of a 63-year old man. Clinical course and the prognostic factors of such lesions will also be discussed. EGISTs in the lesser omentum can grow slowly and remain silent despite a large tumor size. In most cases, a pre-operative diagnosis is not possible, and the patient undergoes a surgical operation for the generic diagnosis of abdominal mass. During the intervention it is important to achieve a complete removal of the mass and to examine every possible adhesion to the gastrointestinal wall. PMID- 23087802 TI - Giant cell temporal arteritis associated with overlying basal cell carcinoma: co incidence or connection? AB - Giant cell arteritis is a granulomatous vasculitis of large and medium sized arteries manifesting as temporal arteritis and/or polymyalgia rheumatica. The histological assessment of temporal artery biopsies is frequently encountered in anatomical pathology and has important diagnostic consequences in patients clinically suspected of having giant cell arteritis. We present an intriguing case of giant cell arteritis associated with a Basal cell carcinoma and discuss the ongoing controversy pertaining to the association of giant cell arteritis/polymyalgia rheumatica with malignancy. PMID- 23087803 TI - Combination of cyclophosphamide, etoposide, carboplatin and dexamethasone as a salvage regimen for refractory multiple myeloma patients: a comparison with a historical control group. AB - The aim of this study was to design a regimen for refractory multiple myeloma with minimum complications to achieve a reasonable response. Fifteen patients with active multiple myeloma after at least two lines of conventional treatment underwent therapy with our regimen for two cycles. Disease activity was evaluated after the last cycle. Another 15 patients with refractory multiple myelomas that had previously received only supportive therapy and pain management formed a historical control group. The follow-up period was 12 months for each study group. Of the patients receiving therapy, 6.7% achieved a complete response and 26.7% a partial response; overall response rate was 33.3%. Stable disease was achieved in 46.7% and 20% of the patients had progressive disease. There was no treatment related mortality. The hazard rate of death was 0.73 lower in the intervention group than in the historical control group. In the historical control group, 60% had progressive disease and 40% had stable disease; approximately 40% of patients died during the 12-month follow up. Also, the severity of pain was significantly reduced in the intervention group (P=0.033). Our chemotherapy regimen showed a reasonable response in end stage patients with multiple myeloma in terms of disease control, reducing bone pain and improving survival, in addition to reducing toxicity. PMID- 23087804 TI - B-cell acute lymphoblastic leukemia with t(4;11)(q21;q23) in a young woman: evolution into mixed phenotype acute leukemia with additional chromosomal aberrations in the course of therapy. AB - About 5% of adult B-cell acute lymphoblastic leukemias (B-ALL) are characterized by t(4;11)(q21;q23), which confers peculiar features to this B-ALL subtype, including a very immature immunophenotype and poor prognosis. We describe the case of a 21-year-old female who presented with B-ALL carrying the t(4;11)(q21;q23) and blasts positive for CD19, TdT, CD79a, CD38, HLA-DR. Before completing the Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) therapy regimen, the B-cell leukemic clone still was detected, but an additional leukemic clone appeared, with morphology and immunophenotype (CD13, CD33, CD64, CD38, CD56, CD15, CD4(dim)) compatible with derivation from the myeloid/monocytic lineage. Karyotype showed the co-existence of three cell lines, with persistence of t(4;11)(q21;q23) and appearance of +8,+12,+13 and two der(4). The patient died because of disseminated intravascular coagulation. Our report describes a rare, possible evolution of such a subtype of B-ALL, with transformation into mixed phenotype acute leukemia in the course of therapy. This finding suggests a blast cell derivation from a common lymphoid/monocytic precursor leading to a final bilineal acute leukemia. PMID- 23087805 TI - Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2. AB - Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy. PMID- 23087806 TI - Pure red cell aplasia in a simultaneous pancreas-kidney transplantation patient: inside the erythroblast. AB - A case of pure red cell aplasia in a simultaneous kidney-pancreas transplant recipient on immunosuppressive therapy is reported here. The patient presented with anemia unresponsive to erythropoietin treatment. Bone marrow cytomorphology was highly suggestive of parvovirus pure red cell aplasia, which was confirmed with serology and polymerase chain reaction positive for parvovirus B19 DNA in peripheral blood. After the administration of intravenous immunoglobulin the anemia improved with a rising number of the reticulocytes. PMID- 23087807 TI - Overexpression of lung resistance-related protein and P-glycoprotein and response to induction chemotherapy in acute myelogenous leukemia. AB - Lung resistance-related protein (LRP) and P-glycoprotein (P-gp) are associated with multidrug resistance. P-gp overexpression reduces intracellular anticancer drug concentrations and is correlated with low remission rates. However, whether the presence of LRP influences the response to induction chemotherapy remains controversial. Therefore, we investigated the relationship of LRP and P-gp overexpression with the response to induction chemotherapy. Univariate analysis revealed that there was a significant difference between complete remission rates for acute myelogenous leukemia patients depending on their blast cell expressions, between LRP positive versus negative, P-gp positive versus negative, and LRP/P-gp double positive versus other groups. Crude odds ratios (ORs) for complete remission were 0.390, 0.360, and 0.307 for LRP positive, for P-gp positive, and LRP/P-gp double positive patients, respectively. After controlling the confounding variables by stepwise multivariate logistical regression analysis, the presence of LRP/P-gp double positivity and P-gp positivity were found to be independent prognostic factors; adjusted ORs were 0.233 and 0.393, respectively. Furthermore, the monoclonal antibody against LRP significantly increased daunorubicin acumulation (P=0.004) in the nuclei of leukemic blast cells with LRP positivity in more than 10% of the cells. An LRP reversing agent, PAK-104P, was found to increase the daunorubicin content with marginal significance (P=0.060). The present results suggest that not only the presence of P-gp, but also LRP in leukemic blast cells is a risk factor for resistance to induction chemotherapy. Inhibiting LRP function, similar to the inhibition of P gp function, will be necessary to improve the effectiveness of induction chemotherapy. PMID- 23087808 TI - Translocation t(11;14) (q13;q32) and genomic imbalances in multi-ethnic multiple myeloma patients: a Malaysian study. AB - More than 50% of myeloma cases have normal karyotypes under conventional cytogenetic analysis due to low mitotic activity and content of plasma cells in the bone marrow. We used a polymerase chain reaction (PCR)-based translocation detection assay to detect BCL1/JH t(11;14) (q13;q32) in 105 myeloma patients, and randomly selected 8 translocation positive samples for array comparative genomic hybridization (aCGH) analysis. Our findings revealed 14.3% of myeloma samples were positive for BCL1/JH t(11;14) (q13;q32) translocation (n=15 of 105). We found no significant correlation between this translocation with age (P=0.420), gender (P=0.317), ethnicity (P=0.066) or new/relapsed status of multiple myeloma (P=0.412) at 95% confidence interval level by chi(2)test. In addition, aCGH results showed genomic imbalances in all samples analyzed. Frequent chromosomal gains were identified at regions 1q, 2q, 3p, 3q, 4p, 4q, 5q, 7q, 9q, 11q, 13q, 15q, 21q, 22q and Xq, while chromosomal losses were detected at 4q and 14q. Copy number variations at genetic loci that contain NAMPT, IVNS1ABP and STK17B genes are new findings that have not previously been reported in myeloma patients. Besides fluorescence in situ hybridization, PCR is another rapid, sensitive and simple technique that can be used for detecting BCL1/JH t(11;14)(q13;q32) translocation in multiple myeloma patients. Genes located in the chromosomal aberration regions in our study, such as NAMPT, IVNS1ABP, IRF2BP2, PICALM, STAT1, STK17B, FBXL5, ACSL1, LAMP2, SAMSN1 and ATP8B4 might be potential prognostic markers and therapeutic targets in the treatment and management of multiple myeloma patients positive for BCL1/JH t(11;14) (q13;q32) translocation. PMID- 23087809 TI - The Intramolecular Asymmetric Allylation of Aldehydes via Organo-SOMO Catalysis: A Novel Approach to Ring Construction. AB - The intramolecular asymmetric cyclization of aldehydes has been accomplished using singly occupied molecular orbital (SOMO) catalysis. Selective oxidation of chiral enamines (formed by the condensation of an aldehyde and a secondary amine catalyst) leads to the formation of a 3pi-electron radical species. These chiral SOMO-activated radical cations undergo enantioselective cyclization with an array of pendent allylsilanes thus efficiently providing a new approach to the construction of five-, six- and seven-membered carbocycles and heterocycles. PMID- 23087810 TI - C(sp(3))-F reductive elimination from alkylgold(iii) fluoride complexes. AB - Rare examples of C(sp(3))-F reductive elimination were observed from several cis F(2)Au(R)(IPr) intermediates generated by oxidation of (IPr)AuR complexes with XeF(2). For R groups bearing beta-hydrogens, beta-hydride elimination was competitive with C(sp(3))-F reductive elimination. For strained cyclic R groups and most acyclic R groups lacking beta-hydrogens, carbocation-like rearrangements occurred prior to C(sp(3))-F reductive elimination. Kinetics of the decay of one cis-F(2)Au(R)(IPr) species, stereochemical analysis of reductive elimination with a chiral R group, and DFT analysis collectively suggest C(sp(3))-F reductive elimination proceeding through transient cationic [(IPr)Au(F)(R)](+) intermediates with significant ionization of the Au-alkyl bonds. PMID- 23087811 TI - Environmental and genetic controls of soldier caste in a parasitic social wasp. AB - A larval army caste is found in some parasitic wasps with polyembryonic or clonal proliferation, where many clone larvae emerge from a single egg. In contrast to non-parasitic eusocial Hymenoptera, sterile soldier larvae that protect their clonal reproductives are found in both females and males. Recently, the proportion of soldier larvae has been found to vary radically, depending on the internal conditions of the host, such as multiparasitism by other larval parasites. However, the proportion of male soldier larvae is constant, irrespective of the host internal environment. It is unknown if these traits are heritable. Here we show that a high heritability is found in both sexes, while, in the 6th instar hosts, substantially lower heritability is found in females. These results imply that the structure of the larval caste is determined genetically by both female and male embryonic cells, but more likely modified environmentally in females. PMID- 23087812 TI - Visualizing the chemistry and structure dynamics in lithium-ion batteries by in situ neutron diffraction. AB - We report an in-situ neutron diffraction study of a large format pouch battery cell. The succession of Li-Graphite intercalation phases was fully captured under an 1C charge-discharge condition (i.e., charge to full capacity in 1 hour). However, the lithiation and dilithiation pathways are distinctively different and, unlike in slowing charging experiments with which the Li-Graphite phase diagram was established, no LiC24 phase was found during charge at 1C rate. Approximately 75 mol. % of the graphite converts to LiC6 at full charge, and a lattice dilation as large as 4% was observed during a charge-discharge cycle. Our work demonstrates the potential of in-situ, time and spatially resolved neutron diffraction study of the dynamic chemical and structural changes in "real-world" batteries under realistic cycling conditions, which should provide microscopic insights on degradation and the important role of diffusion kinetics in energy storage materials. PMID- 23087813 TI - Breaking the spatial resolution barrier via iterative sound-light interaction in deep tissue microscopy. AB - Optical microscopy has so far been restricted to superficial layers, leaving many important biological questions unanswered. Random scattering causes the ballistic focus, which is conventionally used for image formation, to decay exponentially with depth. Optical imaging beyond the ballistic regime has been demonstrated by hybrid techniques that combine light with the deeper penetration capability of sound waves. Deep inside highly scattering media, the sound focus dimensions restrict the imaging resolutions. Here we show that by iteratively focusing light into an ultrasound focus via phase conjugation, we can fundamentally overcome this resolution barrier in deep tissues and at the same time increase the focus to background ratio. We demonstrate fluorescence microscopy beyond the ballistic regime of light with a threefold improved resolution and a fivefold increase in contrast. This development opens up practical high resolution fluorescence imaging in deep tissues. PMID- 23087814 TI - Disturbances in equilibrium function after major earthquake. AB - Major earthquakes were followed by a large number of aftershocks and significant outbreaks of dizziness occurred over a large area. However it is unclear why major earthquake causes dizziness. We conducted an intergroup trial on equilibrium dysfunction and psychological states associated with equilibrium dysfunction in individuals exposed to repetitive aftershocks versus those who were rarely exposed. Greater equilibrium dysfunction was observed in the aftershock-exposed group under conditions without visual compensation. Equilibrium dysfunction in the aftershock-exposed group appears to have arisen from disturbance of the inner ear, as well as individual vulnerability to state anxiety enhanced by repetitive exposure to aftershocks. We indicate potential effects of autonomic stress on equilibrium function after major earthquake. Our findings may contribute to risk management of psychological and physical health after major earthquakes with aftershocks, and allow development of a new empirical approach to disaster care after such events. PMID- 23087815 TI - Possible magnetic-polaron-switched positive and negative magnetoresistance in the GdSi single crystals. AB - Magnetoresistance (MR) has attracted tremendous attention for possible technological applications. Understanding the role of magnetism in manipulating MR may in turn steer the searching for new applicable MR materials. Here we show that antiferromagnetic (AFM) GdSi metal displays an anisotropic positive MR value (PMRV), up to ~415%, accompanied by a large negative thermal volume expansion (NTVE). Around T(N) the PMRV translates to negative, down to ~-10.5%. Their theory-breaking magnetic-field dependencies [PMRV: dominantly linear; negative MR value (NMRV): quadratic] and the unusual NTVE indicate that PMRV is induced by the formation of magnetic polarons in 5d bands, whereas NMRV is possibly due to abated electron-spin scattering resulting from magnetic-field-aligned local 4f spins. Our results may open up a new avenue of searching for giant MR materials by suppressing the AFM transition temperature, opposite the case in manganites, and provide a promising approach to novel magnetic and electric devices. PMID- 23087816 TI - How to share underground reservoirs. AB - Many resources, such as oil, gas, or water, are extracted from porous soils and their exploration is often shared among different companies or nations. We show that the effective shares can be obtained by invading the porous medium simultaneously with various fluids. Partitioning a volume in two parts requires one division surface while the simultaneous boundary between three parts consists of lines. We identify and characterize these lines, showing that they form a fractal set consisting of a single thread spanning the medium and a surrounding cloud of loops. While the spanning thread has fractal dimension 1.55 +/- 0.03, the set of all lines has dimension 1.69 +/- 0.02. The size distribution of the loops follows a power law and the evolution of the set of lines exhibits a tricritical point described by a crossover with a negative dimension at criticality. PMID- 23087818 TI - Multicentric extramedullary myxopapillary ependymomas: Two case reports and literature review. AB - BACKGROUND: Ependymoma has been described typically as an intramedullary tumor derived from ependymal cells. Intradural extramedullary presentation is rarely described and almost always as a unique lesion. Myxopapillary ependymoma is a histological variant that distinguishes from the ordinary type of ependymoma because of its generally better prognosis. We present two cases of multicentric extramedullary myxopapillary ependymomas. CASE DESCRIPTION: Case 1 was a 30-year old man with progressive paresthesia and paresis in the lower limbs, urinary sphincter disturbances, gait instability, ataxia, and chronic low back pain with multiple intradural extramedullary lesions at C2-C3, D2-D4-D5, and D12-L1. Case 2 was a 32-year-old man, presented with low back pain and mild paresthesia in the right lower limb. Magnetic resonance imaging (MRI) showed multiple intradural extramedullary lesions with homogeneous enhancement after gadolinium injection at C7, D2, D4, D5, D8, D10, D11, L1, L3, L5, S1, and S2. Complete tumor resection of the approached tumors was archived in both cases. Histological studies confirm myxopapillary ependymomas. Patient's neurologic outcome was good and no residual tumor was present at MRI control at 10 years in case 1 and 12 months in case 2. CONCLUSIONS: We report the first two cases of multicentric extramedullary myxopapillary ependymomas, this etiology must be taken into account in the differential diagnosis of intradural extramedullary tumors. PMID- 23087817 TI - In Situ Conversion of Melanoma Lesions into Autologous Vaccine by Intratumoral Injections of alpha-gal Glycolipids. AB - Autologous melanoma associated antigens (MAA) on murine melanoma cells can elicit a protective anti-tumor immune response following a variety of vaccine strategies. Most require effective uptake by antigen presenting cells (APC). APC transport and process internalized MAA for activation of anti-tumor T cells. One potential problem with clinical melanoma vaccines against autologous tumors may be that often tumor cells do not express surface markers that label them for uptake by APC. Effective uptake of melanoma cells by APC might be achieved by exploiting the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. This approach has been developed in a syngeneic mouse model using mice capable of producing anti-Gal. Anti-Gal binds specifically to alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R). Injection of glycolipids carrying alpha-gal epitopes (alpha-gal glycolipids) into melanoma lesions results in glycolipid insertion into melanoma cell membranes, expression of alpha-gal epitopes on the tumor cells and binding of anti-Gal to these epitopes. Interaction between the Fc portions of bound anti-Gal and Fcgamma receptors on APC induces effective uptake of tumor cells by APC. The resulting anti-MAA immune response can be potent enough to destroy distant micrometastases. A clinical trial is now open testing effects of intratumoral alpha-gal glycolipid injections in melanoma patients. PMID- 23087819 TI - A low radiation computed tomography protocol for monitoring shunted hydrocephalus. AB - BACKGROUND: Computed tomography (CT) requires highest radiation doses in radiology. The collective dose from the use of radiation in medicine is rising, partly due to increase in CT use as well as the growing popularity of multislice scanners. There is growing concern from multiple studies that radiation from repeated CT scans could induce malignancies later in life. Patients with hydrocephalus are unique in that they are often subjected to repeated CT imaging throughout their lives to monitor whether their hydrocephalus is under control. We designed a study to see whether a low dose radiation CT protocol could provide effective information for monitoring hydrocephalus. METHODS: A pilot study was done with 10 patients with hydrocephalus who needed CT scanning to monitor their hydrocephalus. The CT protocol was altered for each patient to sequentially bring down the radiation dose to the minimum level, which would provide sufficient diagnostic information. Based on the pilot study, a new low dose CT scanning protocol was devised and tested on 25 shunted patients who needed monitoring of their hydrocephalus. All images were carefully scrutinized by a consultant neuroradiologist and consultant neurosurgeon to ensure that the following diagnostic information could be analyzed: 1. ventricular size, 2. cisterns, 3. sulcii, and 4. cathet er position RESULTS: All low-dose CT images were diagnostically acceptable and provided sufficient information to the requesting clinician. None of the subjects required repeat imaging. The effective radiation dose was reduced from 2.2 mSv using a conventional CT protocol to 0.29 mSv with the new low dose CT protocol. The new CT protocol provides 87% less effective radiation dose compared with conventional scans. CONCLUSIONS: We propose a new low dose CT protocol which can be used for monitoring shunted hydrocephalus. The radiation to the patient with this protocol is comparable to that of a skull X ray. However, this protocol should only be requested by a clinician who is aware of its limitations. PMID- 23087820 TI - Diagnostic performance of the medial hamstring reflex in L5 radiculopathy. AB - BACKGROUND: An avalanche of literature exists on almost every aspect of lumbar disc pathology but very limited studies have quantified the diagnostic performance of elements of clinical examination in predicting disc level, meticulously collated the reflex changes in lumbar disc herniation (LDH) as well as assessed the diagnostic performance of the medial hamstring reflex (MHR). Our study underscores the diagnostic performance of the MHR in L5 radiculopathy comparing its diagnostic power to that of the knee and ankle reflexes. METHODS: One hundred consecutive patients operated for de novo LDH in our department between January and December 2011 were prospectively followed-up. A nested case control study was designed from our cohort to assess the performance of the MHR in L5 sciatica. All patients were examined by two independent examiners pre operatively for the MHR and the results collated and correlated to MRI and intra operative findings. RESULTS: The MHR has a diagnostic performance intermediate to that of knee and ankle reflexes. The percentages correctly classified were respectively: 86%, 79% and 67% for the knee, MHR and ankle reflexes. The MHR is highly precise with an intra-rater reliability of 100% and inter-rater repeatability of above 90% and test-retest reproducibility of 100%. CONCLUSION: The MHR hitherto described as elusive has a high diagnostic performance and is a valid neurologic test that should be included in the routine neurologic examination of patients with suspected L5 radiculopathy. PMID- 23087821 TI - Cranial nerve cavernous malformations causing trigeminal neuralgia and chiasmal apoplexy: Report of 2 cases and review of the literature. AB - BACKGROUND: Cavernous malformations (CMs) confined to the cranial nerves (CN) are extremely rare lesions. CASE DESCRIPTION: The authors report 2 cases of CMs, one involving the trigeminal nerve presenting with a 3 years history of a refractory right trigeminal neuralgia that was microsurgically resected by a retromastoid approach with resolution of the neuralgia; and another CM involving the chiasma with an abrupt onset of vision loss with acute intralesional bleeding that was removed through a right pterional approach with vision improvement. CONCLUSION: Surgical resection is recommended in the context of progressive significant neurological deficit, emergency decompression as a result of recent hemorrhage for symptomatic relief or increase in size on serial magnetic resonance imaging (MRI). PMID- 23087822 TI - Prolonged and regionally progressive symptomatic cerebral hyperperfusion syndrome after superficial temporal artery-middle cerebral artery anastomosis in a patient with moyamoya disease. AB - BACKGROUND: The incidence of symptomatic hyperperfusion syndrome after superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis for patients with moyamoya disease (MMD) approaches 30%. In most cases, hyperperfusion occurs in a localized area and disappears within 1-2 weeks. CASE DESCRIPTION: A 59-year-old female diagnosed with asymptomatic MMD for 4 months became rapidly symptomatic with transient ischemic attacks (TIAs). After left STA MCA anastomosis surgery, she developed symptomatic hyperperfusion, initially (1-2 weeks after surgery) manifesting with severe headache and lesions located in the left basal ganglia. She then developed (2-5 weeks after surgery) aphasia and right hemiparesis caused by new hyperperfusion lesions located in the left frontal area. At discharge (7 weeks after surgery), she recovered fully without any remaining neurologic deficit and no ischemic lesions. CONCLUSION: This report details a rare case of a patient with MMD who presented with regionally progressive hyperperfusion lesions after STA-MCA anastomosis and symptoms that persisted for 5 weeks following surgery. Results from this case suggest that regional differences exist in the functional recovery of cerebrovascular reactivity (CVR) in a patient with rapidly progressive MMD. PMID- 23087823 TI - Anaplastic supratentorial cortical ependymoma presenting as a butterfly lesion. AB - BACKGROUND: Anaplastic cortical ependymomas are rare lesions with few cases reported in the literature. CASE DESCRIPTION: We present a unique case of an anaplastic cortical ependymoma in a 51-year-old female presenting as a butterfly lesion with involvement of both frontal lobes. The patient underwent gross total resection of her tumor with further adjuvant treatment. We present the findings in our case and review the literature surrounding supratentorial ependymomas and their treatment outcomes. CONCLUSION: Rarely, cortical ependymoma can present as a butterfly lesion and should be considered in the differential diagnosis of such lesions in adults. PMID- 23087824 TI - From the bench to the bedside: Brain-machine interfaces in spinal cord injury, the blood-brain barrier, and neurodegeneration, using the hippocampus to improve cognition, metabolism, and epilepsy, and understanding axonal death. PMID- 23087825 TI - NeuroMind 2: Interactive decision support for neurosurgery. PMID- 23087826 TI - Management of intracranial meningiomas in Enugu, Nigeria. AB - BACKGROUND: Meningiomas may range on presentation from incidentally identified small lesions to large symptomatic tumors in eloquent areas of the brain. Management options correspondingly vary and include careful observation, surgical excision, and palliative application of very limited therapeutic maneuvers in select cases. This paper discusses the options and difficulties in the management of meningiomas in a developing country. METHODS: This study is a retrospective analysis of prospectively recorded data of patients managed for intracranial meningioma between January 2006 and September 2011 at Memfys Hospital for Neurosurgery, Enugu. Radiographic diagnosis of meningioma was based on computed tomography (CT) and or magnetic resonance imaging (MRI) criteria in all cases, but only patients who had surgery and a histological diagnosis were analyzed. RESULTS: Seventy-four patients were radiographically diagnosed with intracranial meningioma over the period under review. Fifty-five patients were operated upon and 52 (70.3%) with histological diagnosis of meningioma were further analyzed. Histological diagnosis was complete in 42 (56.8%) patients and in 10 (13.5%) patients the subtype of meningioma was not determined. The male to female ratio was 1:1.08. The peak age range for females was in the 6th decade and for males in the 5th decade. The locations were olfactory groove (26.9%), convexity (21.2%), parasagittal/falx (19.2%), sphenoid ridge (15.4%), tuberculum sellae (7.7%), tentorial (3.8%), and posterior fossa (5.8%). The most common clinical presentation was headaches in 67.3% followed by seizures (40.4%) and visual impairment (38.5%). Histology was benign (World Health Organization [WHO] grade 1) in 39 patients. One patient harbored an atypical and two had anaplastic tumors. Gross total resection of the tumor was achieved in 41 patients. Surgical mortality was 3.9%. CONCLUSION: Effective management of meningioma depends largely on adequate and complete surgical resection and results in good outcomes. Adequate preoperative assessment, including visual assessment, and hormonal assessment in olfactory groove and sphenoid region meningiomas, is necessary. PMID- 23087828 TI - Natural history of hydrocephalus in children with spinal open neural tube defect. AB - BACKGROUND: The long-term prognosis of patients with Spinal Open Neural Tube Defect (SONTD)-associated hydrocephalus is not well known. This study was conducted to ascertain the incidence and natural history of hydrocephalus in patients with SONTD. METHODS: All 82 patients with SONTD referred to Neurosurgery/Spina Bifida Clinics at King Khalid University Hospital, Riyadh, Saudi Arabia (January 1995 - July 2010) were studied and followed for a period of 1-16 years. Patients were divided into three groups: Group "A" with active hydrocephalus treated with ventriculoperitoneal shunt (VPS), or endoscopic third ventriculostomy (ETV); Group "B" with compensated hydrocephalus; and Group "C" with no hydrocephalus. Timing of shunt insertion, complications of treatment and status of hydrocephalus were analyzed. RESULTS: The mean age of the 82 patients was 7.4 years (range 1-16 years). Group "A" included 59 (72%) patients, Group "B" 7 (8.5%) patients, and Group "C" 16 (19.5%) patients. Chiari malformation type II was found in 71 (86.6%) patients, 57 of whom (80%) were in Group "A" with active hydrocephalus. They were treated by VPS (51 patients) and ETV (8 patients). The shunts were revised or replaced in 10 (19.6%) patients due to obstruction or infection. Primary ETV failed in 3/8 patients, and treated by VPS. None of those in Groups "B" or "C" required treatment for hydrocephalus during the follow up. CONCLUSION: Hydrocephalus affects the majority of patients with SONTD who have Myelomeningocele (MMC) and CM II and requires close surveillance and prompt management. Children with SONTD should routinely undergo MRI examination of brain and craniocervical junction to clarify ventricular size, and the presence of CM II. PMID- 23087827 TI - Anatomical features and clinical relevance of a persistent trigeminal artery. AB - BACKGROUND: Although persistent trigeminal artery (PTA) is uncommonly identified, knowledge of this structure is essential for clinicians who interpret cranial imaging, perform invasive studies of the cerebral vasculature, and operate this region. METHODS: A review of the medical literature using standard search engines was performed to locate articles regarding the PTA, with special attention with anatomical descriptions. RESULTS: Although anatomical reports of PTA anatomy are very scarce, those were analyzed to describe in detail the current knowledge about its anatomical relationships and variants. Additionally, the embryology, classification, clinical implications, and imaging modalities of this vessel are extensively discussed. CONCLUSIONS: Through a comprehensive review of isolated reports of the PTA, the clinician can better understand and treat patients with such an anatomical derailment. PMID- 23087830 TI - Are morbidity and mortality conferences DNR (Do Not Resuscitate) or can they be revived? PMID- 23087829 TI - Duration of horizontal decubitus after section of a tight filum terminale as a means to prevent cerebrospinal fluid leakage. AB - OBJECT: The untethering of a tethered spinal cord by transecting a tight filum terminale is a relatively simple surgical procedure that can prevent or ameliorate neurological symptoms. Postoperatively patients are usually kept flat in order to prevent a cerebrospinal fluid (CSF) leak. However, the optimal period of maintaining patients flat has not been determined yet. The authors present their experience, compare with ones of previous reports, and try to determine the optimal period. METHODS: We retrospectively analyzed surgical results of pediatric patients with tethered spinal cord by a tight filum terminale. The patients' charts were reviewed for demographic data, clinical presentation, surgical therapy, and clinical course. RESULTS: One hundred-sixty-one patients underwent sectioning of a tight filum terminale. They all were kept lying flat for 8 days. Magnetic resonance imaging (MRI) was performed 10 to 14 days after the surgery. None of the patients developed a CSF leak. Pseudomeningocele, which was confirmed by MRI, developed in one patient (0.6%). The occurrence rate of a CSF leak was significantly lower in our series than that of previous reports in which patients maintained flat less than 72 hours (P = 0.0069). CONCLUSION: To keep patients flat for a longer time after transection of a tight filum terminale seems to lower the rate of CSF leakage and psuedomeningocele. PMID- 23087831 TI - Overview: Special issue on Drosophila spermatogenesis. PMID- 23087832 TI - Development of sexual dimorphism in the Drosophila testis. AB - The creation of sexual dimorphism in the gonads is essential for producing the male and female gametes required for sexual reproduction. Sexual development of the gonads involves both somatic cells and germ cells, which often undergo sex determination by different mechanisms. While many sex-specific characteristics evolve rapidly and are very different between animal species, gonad function and the formation of sperm and eggs appear more similar and may be more conserved. Consistent with this, the doublesex/mab3 Related Transcription factors (DMRTs) are important for gonad sexual dimorphism in a wide range of animals, including flies, worms and mammals. Here we explore how sexual dimorphism is regulated in the Drosophila gonad, focusing on recent discoveries relating to testis development. We will discuss how sex determination in both the germline and the soma are utilized to create a testis, including the role of the key somatic sex determination factor doublesex. PMID- 23087833 TI - Recent advances in Drosophila male germline stem cell biology. AB - The ability of stem cells to divide asymmetrically to produce both self-renewing and differentiating daughter cells sustains many adult tissues, but germline stem cells (GSCs) are unique among stem cells as they perpetuate the genome of the species. The cellular and molecular mechanisms regulating most mammalian stem cells in their endogenous local microenvironments, or niches, are quite challenging to study. However, studies of stem cell niches such as those found in the Drosophila gonads have proven very useful. In these tissues, GSCs are housed in a readily identifiable niche, and the ability to genetically manipulate these cells and their neighbors has uncovered several fundamental mechanisms that are relevant to stem cells more generally. Here, we summarize recent work on the regulation of GSCs in the Drosophila testis niche by intercellular signals, and on the intracellular mechanisms that cooperate with these signals to ensure the survival of the germline. This review focuses on GSCs within the adult Drosophila testis; somatic stem cells in this tissue are reviewed by Zoller and Schulz in this issue.(1) For a review of the testis niche as a whole, see de Cuevas and Matunis,(2) and for more comprehensive reviews of the Drosophila testis, refer to Fuller(3) and Davies and Fuller.(4). PMID- 23087834 TI - The Drosophila cyst stem cell lineage: Partners behind the scenes? AB - In all animals, germline cells differentiate in intimate contact with somatic cells and interactions between germline and soma are particularly important for germline development and function. In the male gonad of Drosophila melanogaster, the developing germline cells are enclosed by somatic cyst cells. The cyst cells are derived from cyst stem cells (CySCs) of somatic origin and codifferentiate with the germline cells. The fast generation cycle and the genetic tractability of Drosophila has made the Drosophila testis an excellent model for studying both the roles of somatic cells in guiding germline development and the interdependence of two separate stem cell lineages. This review focuses on our current understanding of CySC specification, CySC self-renewing divisions, cyst cell differentiation, and soma-germline interactions. Many of the mechanisms guiding these processes in Drosophila testes are similarly essential for the development and function of tissues in other organisms, most importantly for gametogenesis in mammals. PMID- 23087835 TI - Transcriptional regulation during Drosophila spermatogenesis. AB - Drosophila spermatogenesis has become a paradigmatic system for the study of mechanisms that regulate adult stem cell maintenance, proliferation and differentiation. The dramatic cellular differentiation process from germline stem cell (GSC) to mature sperm is accompanied by dynamic changes in gene expression, which are regulated at transcriptional, post-transcriptional (including translational) and post-translational levels. Post-transcriptional regulation has been proposed as a unique feature of germ cells. However, recent studies have provided new insights into transcriptional regulation during Drosophila spermatogenesis. Both signaling pathways and epigenetic mechanisms act to orchestrate the transcriptional regulation of distinct genes at different germ cell differentiation stages. Many of the regulatory pathways that control male gamete differentiation in Drosophila are conserved in mammals. Therefore, studies using Drosophila spermatogenesis will provide insight into the molecular mechanisms that regulate mammalian germ cell differentiation pathways. PMID- 23087836 TI - Meiosis in male Drosophila. AB - Meiosis entails sorting and separating both homologous and sister chromatids. The mechanisms for connecting sister chromatids and homologs during meiosis are highly conserved and include specialized forms of the cohesin complex and a tightly regulated homolog synapsis/recombination pathway designed to yield regular crossovers between homologous chromatids. Drosophila male meiosis is of special interest because it dispenses with large segments of the standard meiotic script, particularly recombination, synapsis and the associated structures. Instead, Drosophila relies on a unique protein complex composed of at least two novel proteins, SNM and MNM, to provide stable connections between homologs during meiosis I. Sister chromatid cohesion in Drosophila is mediated by cohesins, ring-shaped complexes that entrap sister chromatids. However, unlike other eukaryotes Drosophila does not rely on the highly conserved Rec8 cohesin in meiosis, but instead utilizes two novel cohesion proteins, ORD and SOLO, which interact with the SMC1/3 cohesin components in providing meiotic cohesion. PMID- 23087837 TI - Drosophila spermiogenesis: Big things come from little packages. AB - Drosophila melanogaster spermatids undergo dramatic morphological changes as they differentiate from small round cells approximately 12 MUm in diameter into highly polarized, 1.8 mm long, motile sperm capable of participating in fertilization. During spermiogenesis, syncytial cysts of 64 haploid spermatids undergo synchronous differentiation. Numerous changes occur at a subcellular level, including remodeling of existing organelles (mitochondria, nuclei), formation of new organelles (flagellar axonemes, acrosomes), polarization of elongating cysts and plasma membrane addition. At the end of spermatid morphogenesis, organelles, mitochondrial DNA and cytoplasmic components not needed in mature sperm are stripped away in a caspase-dependent process called individualization that results in formation of individual sperm. Here, we review the stages of Drosophila spermiogenesis and examine our current understanding of the cellular and molecular mechanisms involved in shaping male germ cell-specific organelles and forming mature, fertile sperm. PMID- 23087838 TI - Drosophila sperm proteome evolution: Insights from comparative genomic approaches. AB - Despite their conserved functional role in sexually reproducing organisms, spermatozoa are a diverse and rapidly evolving cell type. This phenomenon is largely attributed to sexual selection in polygamous species where sperm from multiple males compete to fertilize a limited number of oocytes. Drosophila have proven to be a particularly informative model system for the study of spermatogenesis and in this review we discuss how the characterization of the Drosophila melanogaster sperm proteome has advanced our understanding of the evolutionary genomics of sperm form and function. We summarize the molecular evolutionary characteristics of sperm genes and highlight recent evidence demonstrating the importance of novel gene creation in the evolution of sperm function and competitive ability. Comparative proteomic evidence is also provided, supporting an overall functional conservation between the Drosophila and mouse sperm proteomes. This analysis reveals a diverse repertoire of proteins functioning in proteolytic pathways, as well as the presence of proteins of the complement and innate immunity systems. We propose that these pathways may have functional relevance to post-mating female immunological responses as well as coevolved interactions with pathways expressed in the female reproductive tract, including those involved in sperm-oocyte recognition and fertilization. PMID- 23087840 TI - Optimization of Non-Viral Gene Therapeutics Using Bilamellar Invaginated Vesicles. AB - Bilamellar invaginated vesicles (BIVs) are unique liposomal nanoparticles (NPs) that are highly efficient vehicles for intravenous (iv) delivery of encapsulated therapeutics including plasmid DNA. Systemic administration of therapeutics is required to effectively treat or cure metastatic cancer, certain cardiovascular diseases, and other acquired or inherited diseases. In addition to having extended half-life and stability in circulation, BIVs are nontoxic, nonimmunogenic, biodegradable and can be repeatedly administered without losing potency. Furthermore, BIVs encapsulating therapeutic agents can be modified to specifically enter the disease cells using small molecules that mimic beta turns incorporated on the surface of BIV complexes while focusing biodistribution by bypassing uptake in non-target organs and tissues using reversible masking. These modifications do not alter the unique properties of the BIV delivery system that provide for its robust treatment of disease demonstrated in small and large animal models and in Phase I clinical trials. This review will cover the unique properties of BIVs, including its fusogenic entry into cells and its ability to penetrate tight barriers in vivo. Methods to further improve the overall delivery expression system including further purification of plasmid DNA to eliminate colanic acid from all current commercially produced preparations, and enhanced or prolonged expression provided by plasmid design will also be discussed. PMID- 23087839 TI - Oh, the places they'll go: Female sperm storage and sperm precedence in Drosophila melanogaster. AB - Among most animals with internal fertilization, females store sperm in specific regions of their reproductive tract for later use. Sperm storage enables prolonged fertility, physical and temporal separation of mating from fertilization and, when females mate with multiple males, opportunities for differential use of the various males' sperm. Thus, stored sperm move within the female reproductive tract as well as to several potential fates - fertilization, displacement by other sperm or ejection by the female. Drosophila melanogaster is a leading model system for elucidating both the mechanisms and evolutionary consequences of female sperm storage and differential male fertilization success. The prominence of Drosophila is due, in part, to the ability to examine processes influencing sperm movement and fate at several biological levels, from molecules to organ systems. In this review, we describe male and female factors, as well as their interactions, involved in female sperm storage and differential male fertilization success. PMID- 23087841 TI - Rapid Self-Assembly of Tubular Arterial Media Layer from Smooth Muscle Cells in Transient Fibrin Gel. AB - BACKGROUND: Tissue engineered blood vessels could address the large clinical need for small caliber vascular grafts. Self-assembly approaches that employ transient scaffolds to form tissues from only cells and secreted matrix could form completely autologous vascular grafts that rapidly remodel and integrate with host tissue in vivo. The objective of this study was to develop a simple and rapid method to self-assemble vascular cells into vascular grafts. HYPOTHESIS: We hypothesized that entrapment in rapidly degrading fibrin gels could facilitate self-assembly of vascular smooth muscle cells into a tubular tissue comprised mainly of SMCs and secreted matrix. METHODS: Baboon SMCs were entrapped in fibrin around a silicone tube and cultured for 14 days without fibrinolysis inhibitor. Spontaneous delamination from the inner tube allowed for simple isolation of constructs with forceps. RESULTS: Engineered tissues are tubular, handleable, and highly cellular, with substantial collagen deposition. Fibrin is largely degraded within 14 days. Tensile elastic modulus of ring segments is 36.2 kPa and 1.60 MPa for the toe and heel regions of the stress-strain relation, respectively. CONCLUSION: Fibrin entrapment without fibrinolysis inhibitor can facilitate rapid self-assembly of SMCs into tubular tissues. Future work will focus on mechanical conditioning and co-culture with vascular endothelial cells to improve mechanical strength and impart antithrombogenicity. PMID- 23087842 TI - Mobile genetic elements in the bacterial phylum Acidobacteria. AB - Analysis of the genome of Candidatus Solibacter usitatus Ellin6076, a member of the phylum Acidobacteria, revealed a large number of genes associated with mobile genetic elements. These genes encoded transposases, insertion sequence elements and phage integrases. When the amino acid sequences of the mobile element associated genes were compared, many of them had high (90-100%) amino acid sequence identities, suggesting that these genes may have recently duplicated and dispersed throughout the genome. Although phage integrase encoding genes were prevalent in the Can. S. usitatus Ellin6076 genome, no intact prophage regions were found. This suggests that the Can. S. usitatus Ellin6076 large genome arose by horizontal gene transfer via ancient bacteriophage and/or plasmid-mediated transduction, followed by widespread small-scale gene duplications, resulting in an increased number of paralogs encoding traits that could provide selective metabolic, defensive and regulatory advantages in the soil environment. Here we examine the mobile element repertoire of Can. S. usitatus Ellin6076 in comparison to other genomes from the Acidobacteria phylum, reviewing published studies and contributing some new analyses. We also discuss the presence and potential roles of mobile elements in members of this phylum that inhabit a variety of environments. PMID- 23087844 TI - Algal genes in aplastidic eukaryotes are not necessarily derived from historical plastids. AB - In photosynthetic eukaryotes, many genes were transferred from plastids or algal endosymbionts to nuclear genomes of host cells. These transferred genes are often considered genetic footprints of plastids. However, genes of algal origin have also been detected in some plastid-lacking eukaryotes, and these genes are often cited as evidence of historical plastids. In this paper, we discuss two recent publications about algal genes in plastid-lacking eukaryotes. Both studies highlight the point that algal genes are not exclusively derived from historical plastids. Instead, the findings show that gene acquisition through feeding activities is a plausible explanation. PMID- 23087843 TI - OrbId: Origin-based identification of microRNA targets. AB - MicroRNAs coordinate networks of mRNAs, but predicting specific sites of interactions is complicated by the very few bases of complementarity needed for regulation. Although efforts to characterize the specific requirements for microRNA (miR) regulation have made some advances, no general model of target recognition has been widely accepted. In this work, we describe an entirely novel approach to miR target identification. The genomic events responsible for the creation of individual miR loci have now been described with many miRs now known to have been initially formed from transposable element (TE) sequences. In light of this, we propose that limiting miR target searches to transcripts containing a miR's progenitor TE can facilitate accurate target identification. In this report we outline the methodology behind OrbId (Origin-based identification of microRNA targets). In stark contrast to the principal miR target algorithms (which rely heavily on target site conservation across species and are therefore most effective at predicting targets for older miRs), we find OrbId is particularly efficacious at predicting the mRNA targets of miRs formed more recently in evolutionary time. After defining the TE origins of > 200 human miRs, OrbId successfully generated likely target sets for 191 predominately primate-specific human miR loci. While only a handful of the loci examined were well enough conserved to have been previously evaluated by existing algorithms, we find ~80% of the targets for the oldest miR (miR-28) in our analysis contained within the principal Diana and TargetScan prediction sets. More importantly, four of the 15 OrbId miR-28 putative targets have been previously verified experimentally. In light of OrbId proving best-suited for predicting targets for more recently formed miRs, we suggest OrbId makes a logical complement to existing, conservation based, miR target algorithms. PMID- 23087845 TI - Alu elements and human common diseases like obesity. AB - In the past few years the epigenetic impact on human diseases has been studied extensively. However, a controversial debate remains about the influence of environmental factors on the genetic determination of DNA methylation patterns. Although DNA methylation defects have been described in imprinting diseases and linked to cancer development, its impact on common diseases like obesity has yet to be elucidated. In our study we observed a hypermethylation variant of the POMC gene in obese children, which plays a key role in body weight regulation. Phylogenetic analyses reveal a close relationship between the POMC DNA methylation at this site and the presence of primate specific Alu elements. In this commentary we will extensively discuss our observations, including comments on the current debate about the impact of transposable elements on DNA methylation and on the development of human disease in general. PMID- 23087846 TI - Prostaglandin E2: a putative potency indicator of the immunosuppressive activity of human mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are non-hematopoietic, pluripotent cells that give rise to stromal cells in the marrow. MSCs have been shown to be immunosuppressive and have become an attractive therapeutic option for the modulation of undesired immune responses. Currently, ex vivo expanded human (h)MSCs are being utilized in clinical trials both in the USA and in Europe to treat a variety of immune disorders. hMSCs need to be harvested, isolated and expanded in culture. This necessary expansion may also result in decrease or loss of the immunomodulatory potential of hMSCs. Ideally, the intrinsic immunomodulatory activity (potency) of an hMSC preparation should be assessed prior to its administration. The goal of the experiments described here was to develop a simple potency assay for the immunomodulatory properties of hMSCs. The immunosuppressive activity of hMSCs conditioned media was tested in enzyme-linked immunosorbent spot assays (ELISpot) and the immunosuppressive activity of the conditioned media was correlated with the concentration of several cytokines present in these conditioned media. The concentration of prostaglandin E(2) in the media correlated with their immunosuppressive activity. The concentration of the other cytokines measured did not correlate with the immunosuppressive activity of the media. The dose-response effect could be replicated by adding PGE(2) to ELISpot assays. Furthermore, the immunosuppressive activity of the conditioned media was inhibitable by a neutralizing anti-PGE(2) antibody. These data suggest that measurement of PGE(2) in media conditioned by hMSCs exposed to inflammatory stimuli could be used as a surrogate measure of their immunosuppressive capacity. These findings need to be confirmed in vitro using different assays of immune function and validated in vivo to determine the level of correlation of these data with efficacy in pre clinical models of immune disorders. PMID- 23087847 TI - Method and Basis Set Analysis of Oxorhenium(V) Complexes for Theoretical Calculations. AB - A variety of method and basis set combinations has been evaluated for monooxorhenium(V) complexes with N, O, P, S, Cl, and Se donor atoms. The geometries and energies obtained are compared to both high-level computations and literature structures. These calculations show that the PBE0 method outperforms the B3LYP method with respect to both structure and energetics. The combination of 6-31G** basis set on the nonmetal atoms and LANL2TZ effective core potential on the rhenium center gives reliable equilibrium structures with minimal computational resources for both model and literature compounds. Single-point energy calculations at the PBE0/LANL2TZ,6-311+G* level of theory are recommended for energetics. PMID- 23087848 TI - Fibro-calculous pancreatic diabetes: Changing hues with changing times. PMID- 23087849 TI - Patient centred approach in endocrinology: From introspection to action. PMID- 23087850 TI - Imaging of pediatric pituitary endocrinopathies. AB - Accurate investigation of the hypothalamic-pituitary area is required in pediatric patients for diagnosis of endocrine-related disorders. These disorders include hypopituitarism, growth failure, diencephalic syndrome, delayed puberty, precocious puberty, diabetes insipidus, syndrome of inappropriate antidiuretic hormone (SIADH) secretion, and hyperpituitarism. Magnetic resonance imaging (MRI) is the modality of choice to visualize hypothalamic-pituitary axis and associated endocrinopathies. Neuroimaging can be normal or disclose abnormalities related to pituitary-hypothalamic axis like (i) congenital and developmental malformations; (ii) tumors; (iii) cystic lesions; and (iv) infectious and inflammatory conditions. Classical midline anomalies like septo-optic dysplasias or corpus callosum agenesis are commonly associated with pituitary endocrinopathies and also need careful evaluation. In this radiological review, we will discuss neuroendocrine disorders related to hypothalamic pituitary-axis. PMID- 23087851 TI - Imaging in short stature. AB - Short stature can be a sign of disease, disability, and social stigma causing psychological stress. It is important to have an early diagnosis and treatment. Short stature may result from skeletal dysplasias, endocrine disorders, may be familial, or may be the result of malnutrition and chronic illnesses. A team effort of the healthcare professionals like pediatricians, endocrinologists, radiologists, and pathologists is required to diagnose, treat and monitor various pathological conditions associated with growth abnormality. In this review, we have discussed the role of imaging in diagnosing and characterizing various pathological conditions associated with short stature. PMID- 23087852 TI - An approach to constitutional delay of growth and puberty. AB - Constitutional delay of growth and puberty is a transient state of hypogonadotropic hypogonadism associated with prolongation of childhood phase of growth, delayed skeletal maturation, delayed and attenuated pubertal growth spurt, and relatively low insulin-like growth factor-1 secretion. In a considerable number of cases, the final adult height (Ht) does not reach the mid parental or the predicted adult Ht for the individual, with some degree of disproportionately short trunk. In the pre-pubertal male, testosterone (T) replacement therapy can be used to induce pubertal development, accelerate growth and relieve the psychosocial complaints of the adolescents. However, some issues in the management are still unresolved. These include type, optimal timing, dose and duration of sex steroid treatment and the possible use of adjunctive or alternate therapy including: oxandrolone, aromatase inhibitors and human growth hormone. PMID- 23087853 TI - Nuclear medicine imaging in the evaluation of endocrine hypertension. AB - Endocrine hypertension forms a small (< 5%) but curable subset of patients with hypertension. Common endocrine causes of hypertension include pheochromocytoma, Cushing's syndrome, primary hyperaldosteronism, and thyroid disorders. Nuclear medicine imaging plays an important role in evaluation of patients with endocrine hypertension. It has established role in patients of pheochromocytoma/paraganglioma, Cushing's syndrome, aldosteronism, and thyroid disorders. We present a brief overview of role of nuclear medicine imaging in endocrine hypertension. Development of newer radiotracers might further broaden the role of nuclear medicine in these patients. PMID- 23087854 TI - Anatomical and functional imaging in endocrine hypertension. AB - In endocrine hypertension, hormonal excess results in clinically significant hypertension. The functional imaging (such as radionuclide imaging) complements anatomy-based imaging (such as ultrasound, computed tomography, and magnetic resonance imaging) to facilitate diagnostic localization of a lesion causing endocrine hypertension. The aim of this review article is to familiarize general radiologists, endocrinologists, and clinicians with various anatomical and functional imaging techniques used in patients with endocrine hypertension. PMID- 23087855 TI - Endocrine emergencies in critically ill patients: Challenges in diagnosis and management. AB - Endocrine emergencies pose unique challenges for the attending intensivist while managing critically ill patients. Besides taking care of primary disease state, one has to divert an equal attention to the possible associated endocrinopathies also. One of the common reasons for inability to timely diagnose an endocrinal failure in critically ill patients being the dominance of other severe systemic diseases and their clinical presentation. The timely diagnosis and administration of therapeutic interventions for these endocrine disorders can improve the outcome in critically ill patients. The timely diagnosis and administration of timely therapeutics in common endocrine disorders like severe thyroid disease, acute adrenal insufficiency and diabetic ketoacidosis significantly influence the outcome and prognosis. Careful evaluation of clinical history and a high degree of suspicion are the corner stone to diagnose such problems. Aggressive management of the patient is equally important as the complications are devastating and can prove highly fatal. The present article is an attempt to review some of the common endocrine emergencies in intensive care unit and the challenges associated with their diagnosis and management. PMID- 23087856 TI - Low renin hypertension. AB - Low renin hypertension is an important and often underdiagnosed cause of hypertension. It may be associated with high aldosterone levels as in Conn's syndrome or low aldosterone levels as in Liddle syndrome, and syndrome of apparent mineralocorticoid excess, glucocorticoid remediable hypertension etc. Some forms of essential hypertension are also associated with low renin levels. Hypokalemia may be an important finding in low renin hypertension. The aldosterone to renin ratio helps in correct diagnosis. The treatment varies with etiology hence an accurate diagnosis is essential. Aldosterone antagonists play an important role in medical management of some varieties of low renin hypertension. PMID- 23087858 TI - Prevalence of cardiac autonomic neuropathy in Asian Indian patients with fibrocalculous pancreatic diabetes. AB - BACKGROUND: It was formerly believed that since fibrocalculous pancreatic diabetes (FCPD) is a secondary form of diabetes, specific diabetic complications were uncommon. This is no longer considered to be true. Our objective was to study the prevalence and pattern of cardiac autonomic neuropathy (CAN) in patients with FCPD. MATERIALS AND METHODS: A cross-sectional study on consecutive male patients with FCPD was performed. Using an automated CAN System Analyzer, heart rate response to deep breathing, Valsalva maneuver, standing and blood pressure response to standing were measured. The standard Ewing's criteria were used to define normal, borderline, and abnormal values. Prevalence rates were calculated and the patients were defined to have normal autonomic function, parasympathetic, sympathetic, and combined dysfunction. RESULTS: The prevalence of CAN in this study population was 63.3%. Isolated parasympathetic dysfunction (42.3%) was the most common abnormality. Combined sympathetic and parasympathetic dysfunction was noted in 13.3% of patients. Isolated borderline dysfunction was noted among 13.3% of patients. CAN was detected in six patients with a duration of diabetes of less than 1 year after diagnosis. Patients with autonomic dysfunction were found to have a lower body mass index (BMI) and low density lipoprotein (LDL)-cholesterol when compared to those with normal autonomic functions, which was not statistically significant. CONCLUSION: The prevalence of abnormal cardiac autonomic function is as high as 63.3% in the present study population which warrants regular screening of patients with FCPD for autonomic dysfunction. Patients with FCPD and autonomic dysfunction were found to have a lower BMI and lower LDL-cholesterol, which may be indicators of malnutrition in the group with autonomic dysfunction. Whether this malnutrition contributes to autonomic dysfunction needs further exploration. PMID- 23087857 TI - Clinical and critical care concerns in severely ill obese patient. AB - The incidence of obesity has acquired an epidemic proportion throughout the globe. As a result, increasing number of obese patients is being presented to critical care units for various indications. The attending intensivist has to face numerous challenges during management of such patients. Almost all the organ systems are affected by the impact of obesity either directly or indirectly. The degree of obesity and its prolong duration are the main factors which determine the harmful effect of obesity on human body. The present article reviews few of the important clinical and critical care concerns in critically ill obese patients. PMID- 23087859 TI - Effect of maternal anthropometry and metabolic parameters on fetal growth. AB - OBJECTIVE: The aim of this study was to determine the effect of maternal anthropometry and metabolic parameters on neonatal anthropometry. MATERIALS AND METHODS: This observational cross-sectional study was conducted from January 2008 to June 2009 at a single tertiary care center. Maternal anthropometry and metabolic parameters like fasting serum insulin, lipid profile, and random blood glucose were estimated in 50 pregnant women at term. Detailed anthropometry of the neonates was performed. RESULTS: Large for gestational age (LGA) babies had higher maternal body mass index (BMI), fasting serum insulin, and cord blood insulin levels, and lower maternal high density lipoprotein (HDL) compared to appropriate for gestational age (AGA) group (P < 0.001). Among the maternal parameters, BMI, gestational age, fasting serum insulin, and random blood sugar (RBS) had significant positive correlation, while HDL had negative correlation with birth weight (P < 0.05). However, only maternal BMI was the significant predictor of neonatal birth weight on multiple regression analysis (beta = 0.340, P = 0.01). CONCLUSION: The BMI of glucose-tolerant mother is more important than metabolic parameters in determining the birth weight of term babies. PMID- 23087860 TI - Association of depression and its relation with complications in newly diagnosed type 2 diabetes. AB - INTRODUCTION: The prevalence of major depressive disorders is higher among persons with diabetes compared to the general population. These associations may be related to the increased risk of depressive symptoms in individuals with diabetes, increased risk of type 2 diabetes (T2DM) in individuals with depressive symptoms, or both. OBJECTIVES: To study the association of depression with diabetes and its complications in newly diagnosed type 2 diabetes in eastern UP. MATERIAL AND METHODS: Sixty cases and an equal number of age- and sex-matched controls were assessed for depression, diabetes complications, and a demography profile. RESULTS: Depression was found in 26 (43.34%) cases, while it was present in only eight (13.33%) controls (P = 0.002). Depression correlated with the level of hyperglycemia at presentation, as measured by fasting and postprandial blood glucose (FBG and PPBG) values. The presence of diabetic nephropathy was significantly associated with depression, while the prevalence of other complications of diabetes (retinopathy and dyslipidemia), although higher among those with depression, was not statistically significant. The level of HbA1c was 8.56 +/- 1.66 in the depressed versus 8.04 +/- 1.88 in the non-depressed diabetics (P = 0.26). CONCLUSIONS: The association of depression with diabetes and its complications in newly diagnosed type 2 diabetics was highlighted in our subpopulation and emphasized the need for integrated health services. The prevalence of depression was higher among them compared to controls. The chances of becoming depressed increased as the diabetes complications worsened. PMID- 23087861 TI - Prevalence of depression in consecutive patients with type 2 diabetes mellitus of 5-year duration and its impact on glycemic control. AB - CONTEXT: Type 2 diabetes mellitus doubles the odds of suffering from depressive illness. Co-morbid depression is associated with poorer outcomes in diabetes mellitus in terms of glycemic control, medication adherence, quality of life, physical activity, and blood pressure control. AIM: The present study aims to estimate the prevalence of depression among a consecutive group of patients with type 2 diabetes and assess its impact on glycemic and blood pressure control. SETTING: Outpatient department of the endocrinology department of a university affiliated teaching hospital in north India. SUBJECTS: Consecutive adult patients (18-65 years) with type 2 diabetes mellitus of over 5-year duration with no prior history of psychiatric illnesses or intake of anti-depressants. MATERIALS AND METHODS: A semi-structured questionnaire was used for demographic data, HbA1c was obtained to assess glycemic control, and blood pressure was recorded twice during patient interview to assess blood pressure control. Depression was assessed with the Major Depression Inventory and scores obtained were classified as consistent with mild, moderate and severe depression. Data was analyzed with SPSS v16, and multiple logistical regression test was done to compare the effect of depression on glycemic control after adjusting for age and sex. RESULTS: Of the 80 patients interviewed, 31 (38.8%) had depressive symptoms. Among them 20 (25%) had mild depression, 10 (12.5%) had moderate depression, and 1 (1.3%) had severe depression. CONCLUSIONS: Over one third of patients with type 2 diabetes mellitus of over 5-year duration had depressive symptoms. The presence of depressive symptoms was associated with a significant worsening of glycemic control. PMID- 23087862 TI - Plasma adiponectin, IL-6, hsCRP, and TNF-alpha levels in subject with diabetic foot and their correlation with clinical variables in a North Indian tertiary care hospital. AB - AIM: Pro- and anti-inflammatory processes are crucial in different phases of wound healing and their disturbances interfere with tissue homeostasis after the manifestation of ulcers, leading to chronic non-healing wounds. However, data on the association between infl ammation and acute foot syndrome are scarce. MATERIALS AND METHODS: Circulating levels of acute-phase reactants and cytokines were measured in diabetic patients with ulcer (n = 162) and without ulcer (n = 162) in a case control study. RESULTS: Of the patients, 85.1% had type 2 diabetes. Subjects with diabetic foot ulcer showed lower median plasma level of adiponectin [8.4 (7.1-9.2) ng/ml vs. 13.4 (12.1-14.2) ng/ml], and higher median plasma levels of interleukin-6 (IL-6) [32.5 (9.4-44.8) ng/ml vs. 6.7 (4.6-14.6) ng/ml], high-sensitivity C-reactive protein (hsCRP) [12.6 (11.2-13.6) mg/ml vs. 8.4 (7.1-9.2) mg/ml], and tumor necrosis factor-alpha (TNF-alpha) [99.4 (79.9 121.5) ng/ml vs. 4.9 (4.5-5.6) ng/ml]. A positive correlation was found between body mass index (BMI) (r = -0.088, P < 0.264) and retinopathy (r = 0.249, P < 0.001) for adiponectin. For IL-6, it was between grade of ulcer (r = 0.250, P < 0.001), BMI (r = -0.161, P < 0.04), low density lipoprotein-cholesterol (LDL-C) (r = -0.155, P < 0.049), triglycerides (r = -0.165, P < 0.035), retinopathy (r = 0.166, P < 0.035), nephropathy (r = -0.199, P < 0.011), and smoking (r = -0.164, P < 0.036). For hsCRP: grade of ulcer (r = 0.236, P < 0.002), BMI (r = -0.155, P < 0.048), LDL-C (r = -0.174, P < 0.026), triglycerides (r = -0.216, P < 0.005), retinopathy (r = -0.165, P < 0.037), nephropathy (r = -0.028, P < 0.007), and smoking (r = -0.164, P < 0.036), while total cholesterol (r = -0.209, P < 0.007) and neuropathy (r = 0.141, P < 0.072) for TNF-alpha. CONCLUSIONS: This study demonstrates that diabetic subjects with various grades of diabetic foot ulcer showed a higher IL-6, hsCRP, TNF-alpha, and lower adiponectin plasma levels in comparison with diabetes without foot ulcer, independent of the concomitant infections. It would be interesting to fi nd out whether an activation of immune system precedes the development of foot ulcer and whether anti-infl ammatory therapies might be effective in improving the outcome in such patients. PMID- 23087863 TI - Oral manifestations in type-2 diabetes and related complications. AB - BACKGROUND: Knowledge of the wide spectrum of the oral markers of diabetes is imperative as one frequently encounters individuals with undetected, untreated or poorly controlled diabetes. OBJECTIVES: The objective was to study the oral manifestations in type 2 diabetes mellitus (DM) and to establish an association between oral manifestations and associated microvascular and macrovascular complications. MATERIALS AND METHODS: 50 cases of DM were selected who had oral complications. The control group comprised 50 age- and sex-matched diabetic patients without any oral complications. RESULTS: Oral manifestations in DM included periodontal disease in 34%, oral candidiasis in 24%, tooth loss in 24%, oral mucosal ulcers in 22%, taste impairment in 20%, xerostomia and salivary gland hypofunction in 14%, dental caries in 24%, and burning mouth sensation in 10% cases. Fasting [(FBG) (P = 0.003)] and postprandial blood glucose [(PPBG) (P = 0.0003)] levels were significantly higher among cases. The P values for neuropathy, retinopathy, nephropathy, cardiovascular disease, dyslipidemia, and sepsis were 0.0156, 0.0241, 0.68, 0.4047, 0.0278, and 0.3149, respectively, which were significant for neuropathy, retinopathy, and dyslipidemia. CONCLUSIONS: Several oral complications are seen among diabetics. Association of oral markers in DM and microvascular complications suggests that there is a significant association between the two. PMID- 23087864 TI - Celiac disease: A missed cause of metabolic bone disease. AB - INTRODUCTION: Celiac disease (CD) is a highly prevalent autoimmune disease. The symptoms of CD are varied and atypical, with many patients having no gastrointestinal symptoms. Metabolic bone disease (MBD) is a less recognized manifestation of CD associated with spectrum of musculoskeletal signs and symptoms, viz. bone pains, proximal muscle weakness, osteopenia, osteoporosis, and fracture. We here report five patients who presented with severe MBD as the only manifestation of CD. MATERIALS AND METHODS: Records of 825 patients of CD diagnosed during 2002-2010 were retrospectively analyzed for clinical features, risk factors, signs, biochemical, and radiological parameters. RESULTS: We were able to identify five patients (0.6%) of CD who had monosymptomatic presentation with musculoskeletal symptoms and signs in the form of bone pains, proximal myopathy, and fragility fractures without any gastrointestinal manifestation. All the five patients had severe MBD in the form of osteopenia, osteoporosis, and fragility fractures. Four of the five patients had additional risk factors such as antiepileptic drugs, chronic alcohol consumption, malnutrition, and associated vitamin D deficiency which might have contributed to the severity of MBD. CONCLUSION: Severe metabolic disease as the only presentation of CD is rare. Patients show significant improvement in clinical, biochemical, and radiological parameters with gluten-free diet, calcium, and vitamin D supplementation. CD should be looked for routinely in patients presenting with unexplained MBD. PMID- 23087865 TI - Prevalence and cut-off point of vitamin D deficiency among secondary students of Arak, Iran in 2010. AB - INTRODUCTION: Vitamin D has a basic role in bone growth and metabolism and has been noticed for its important role in many diseases, such as diabetes, depression, hypertension, and cardiovascular disease. Regarding some studies, detection of vitamin D deficiency in different places has important implication for health. This study determined prevalence of vitamin D deficiency in Arak, a centrally located city in Iran. MATERIALS AND METHODS: Based upon a cross sectional study in 2010, 420 students 10--16 years old including 220 girls and 200 boys, studied at Arak secondary schools, were selected by a multistage sampling. The level of 25 (OH) D and PTH (parathormone) was measured and also the prevalence of vitamin D deficiency in different intensities was evaluated and compared between girls and boys by the Student t-test. Vitamin D deficiency for the students was categorized into three intensities based on three levels of 25 (OH) D: mild deficiency - 15 <= 25 (OH) D < 20 ng/ml, moderate deficiency -- 8 <= 25 (OH) < 15 ng/ml, severe deficiency - 25 (OH) <8 ng/ml. The relationship between the 25 (OH) D and PTH was assessed by Scatter chart to define cut-off points for vitamin D deficiency. RESULTS: Based on 25 (OH) D < 20 ng/ml, 84% of the students had vitamin D deficiency including 60.7% mild, 22.4% moderate, and 0.7% severe. Three local cut-off points including 13, 21, and 33 ng/ml were defined in the Scatter chart. The results showed that the deficiency of vitamin D in girls is much more than that in boys (P = 0.05). CONCLUSION: The high prevalence of vitamin D deficiency could be probably a result of different etiologies. We recommended that people should be encouraged to take vitamin D and calcium supplements and also they should have more exposure to the sunlight. PMID- 23087866 TI - Linear growth in relation to the circulating concentration of insulin-like growth factor-I in young children with acyanotic congenital heart disease with left to right shunts before versus after surgical intervention. AB - OBJECTIVES: The aim was to determine the degree of linear growth retardation of patients with congenital acyanotic heart disease at presentation and the magnitude of catch-up growth, if any, in relation to their echocardiographic changes and insulin-like growth factor- I (IGF-I) concentration before versus after surgical intervention. MATERIALS AND METHODS: This prospective study recorded the anthropometric data and measured the circulating IGF-I, free thyroxin (FT4), and thyrotropin (TSH) of 27 infants and children with congenital acyanotic heart disease with left to right shunt (10 with VSD, 8 with ASD, 9 PDA) without heart failure, or severe pulmonary hypertension, before and 12 months or more after surgical or catheter intervention. Eighty normal age and sex- matched normal siblings of these patients were included as controls for the auxologic data. RESULTS: At presentation, patients' mean age = 35.6 +/- 26 months, height SDS (HtSDS) = -1.6 +/- 1.1, and body mass index (BMI) = 15.1 +/- 2.5. They were significantly shorter and with lower BMI compared to normal controls (HtSDS = 0.25 +/- 0.3, BMI = 16.4 +/- 1.5). One year or more after catheter or surgical treatment, the HtSDS and BMI increased significantly in patients to -0.55 +/- 0.9 and 15.9 +/- 1.5, respectively). IGF-I levels increased from 46.8 +/- 29 mcg/L before to 77.3 +/- 47.6 mcg/L after intervention. No significant change has been detected in circulating FT4 or TSH concentrations. The HtSDS after treatment was correlated with the IGF-I concentration (r = 0.804, P < 0.001). The change in the HtSDS after intervention was correlated significantly with BMI (r = 0.594, P 0.001) and negatively with age (r = -0.52, P< 0.01). The shunt size was correlated negatively with BMI and HtSDS before intervention (r = -0.35, P < 0.01 and 0.01 and r = -0.461, P < 0.05, respectively). GVSDS after intervention surgery was correlated with BMI after intervention (r = 0.495, P < 0.001) and negatively with the age at operation (r = -0.683, P < 0.001). CONCLUSIONS: In congenital acyanotic heart diseases, early surgical interference and weight gain have beneficial effect on postoperative growth spurt. This catch-up growth appears to be mediated through activation of the GH/IGF-I system and suggests an important role of increasing BMI (an indicator of nutrition) as an imperative factor. PMID- 23087867 TI - Predictors of glycemic control in children with Type 1 diabetes mellitus in Assiut-Egypt. AB - BACKGROUND: Type 1 diabetes mellitus (T1DM) may lead to severe long-term health consequences, such as renal failure, blindness, as well as heart and cerebrovascular disease. Although a direct relationship between blood glucose control and diabetes complications remains to be established beyond doubt, most diabetologists aim to achieve the best possible glucose control in their patients with T1DM. The aim of this study was to detect the predictors of glycemic control among children with T1DM in Assiut Governorate-Egypt. MATERIALS AND METHODS: We enrolled 415 children aged 2 to 18 years with type 1 diabetes of >1-year duration. They were subjected to full history including demographic factors and disease-related factors. Examination was done with determination of the body mass index, and assessment of stage of maturity. Investigations included hemoglobin A1c (HbA1c) and lipid profile. Patients with HbA1c above the recommended values for age by the American Diabetes Association were considered as poor glycemic control group. RESULTS: Of the studied cases, 190 cases (45.8%) were of poor glycemic control. Patients with poor control had significantly higher mean age (16.83 +/- 3.3 vs 9.77 +/- 3.7, P<0.000). Girls aged 15 years or more had significantly higher prevalence of poor glycemic control than males of the same age group. As regard the disease-related factors, patients with poor control had significantly longer duration of disease (7.94 +/- 2.6 vs 2.40 +/- 2.0, P<0.000) and were older in age at onset of disease. Insulin regimen which consists of basal bolus insulin plus three injections of regular insulin was associated with more frequency of good glycemic control than other regimens. Patients with poor control had significantly higher mean of cholesterol, triglyceride (TG), high density lipoprotein cholesterol, and low-density lipoprotein cholesterol than patients with good control. Adjusting for other variables, age of the patients, duration of disease, and serum TG level were significant independent risk factors of poor glycemic control. CONCLUSIONS: This study concluded that children more than 15 years, duration of disease more than 5 years, and high serum TG level are the predictors of poor glycemic control of children with T1DM in Assiut - Egypt. Pediatricians need to be aware of factors associated with poor glycemic control in children with T1DM, so that more effective measures can be implemented to prevent deterioration in diabetes control . PMID- 23087868 TI - Clinical spectrum of hypopituitarism in India: A single center experience. AB - OBJECTIVES: There is paucity of information regarding clinical profile of hypopituitarism from India. We report the clinical profile of hypopituitarism from a tertiary center in North India. MATERIALS AND METHODS: This study was carried out in patients attending our endocrine center between January 2010 and December 2011. All new patients were studied prospectively and those registered before January 2010 retrospectively. Relevant clinical, hormonal, and imaging data were collected. Dynamic testing for pituitary functions was carried out as necessary. Hormonal deficiencies were defined as per prevailing recommendations. RESULTS: This study included 113 subjects. The mean age was 38.6 +/- 17.8 years (range, 4 - 76 years). There were 78 (69%) males and 35 females (31%). There were 22 subjects aged <=18 years (childhood and adolescence) and 91 adults (>18 years). Visual disturbances were the most common presenting complaint (33%), though headache was the most common symptom (81%). Fifteen percent presented with pituitary apoplexy. Tumors comprised of 84% of cases. Hypogonadism (97%) was the most common abnormality seen followed by hypothyroidism (83.2%), hypoadrenalism (79.6%), growth hormone deficiency (88.1% of the 42 patients tested), and diabetes insipidus (13.3%). Panhypopituitarism was seen in 104 (92%) patients. There were no cases of hypopituitarism secondary to traumatic brain injury, subarachnoid hemorrhage, central nervous system infections, or cranial irradiation to extrasellar tumors. CONCLUSION: The most common cause of hypopituitarism at tertiary care center is pituitary tumors and the commonest presenting complaint is visual symptoms. Panhypopituitarism is present in 92% cases. PMID- 23087869 TI - Atherogenic risk factors among preschool children in Crete, Greece. AB - OBJECTIVE: To investigate the presence of atherogenic factors among preschool children of Crete, Greece. MATERIALS AND METHODS: This was a cross-sectional study. The study population included 1189 children, aged four to seven years, examined from January to May 2005, in public kindergartens. Biochemical, anthropometric, and blood pressure measurements were performed. RESULTS: Of the boys 27.4% were classified as overweight or obese (obese 10.8%). The respective percentage for girls was 28.5% (obese 9%); 7.4% percent of the boys and 7.9% of the girls had blood pressure above the ninety-fifth percentile. TC of > 200 mg / dl was found in 14.4% and LDL-C of > 130 mg / dl in 13.8% of the children. Children with serum TG of > 100 mg / dl had a significantly higher mean WC and BMI than those with triglyceride levels of <= 80 mg / dl (59.7 vs. 55.9 cm and 17.9 vs. 16.6 kg / m(2); P < 0.05). Similarly, children with HDL-C < 45 mg / dl had significantly higher WC and BMI than children with HDL-C >= 60 mg / dl (57.7 vs. 53.5 cm and 17.1 vs. 16.5 kg / m(2); P < 0.05). Obese children had an Odds Ratio of 2.87 (95% confidence interval, 1.05 - 7.85, P = 0.041) for hypertriglyceridemia, as compared to non-obese children. CONCLUSION: Levels of obesity and especially central obesity were strongly related to other atherogenic risk factors in Cretan preschool children indicating the presence of this major public health problem in early ages. PMID- 23087870 TI - Too short and too poor: A tale of two siblings. AB - Two short siblings who were brought for evaluation of short stature are described with emphasis on availability of resources in the diagnosis and management of the cause of short stature in them. PMID- 23087871 TI - Growth hormone insensitivity syndrome: A sensitive approach. AB - Patients with Growth Hormone Insensitivity have characteristic phenotypic features and severe short stature. The underlying basis are mutations in the growth hormone receptor gene which gives rise to a characteristic hormonal profile. Although a scoring system has been devised for the diagnosis of this disorder, it has not been indisputably validated. The massive expense incurred in the diagnosis and treatment of this condition with suboptimal therapeutic response necessitates a judicious approach in this regard in our country. PMID- 23087872 TI - Mucocutaneous manifestations of acquired hypoparathyroidism: An observational study. AB - Hypoparathyroidism is a disorder of calcium and phosphorus metabolism due to decreased secretion of parathyroid hormone. Hypoparathyroidism can be hereditary and acquired. Acquired hypoparathyroidism usually occurs following neck surgery (thyroid surgery or parathyroid surgery). Along with systemic manifestations, hypoparathyroidism produces some skin manifestations. Lack of study regarding mucocutaneous manifestations of acquired hypoparathyroidism prompted us to undertake this study. To evaluate the mucocutaneous manifestations of acquired hypoparathyroidism. An observational study done in a tertiary care hospital of Kolkata by comprehensive history taking, through clinical examination and relevant laboratory investigations. Twenty-one patients were included in the study. The commonest form of acquired hypoparathyroidism was neck surgery (thyroidectomy and parathyroidectomy operation). Mucocutaneous manifestations were present in 76.19% of patients. The most frequent mucocutaneous manifestation was found in the hairs like the loss of axillary hair (61.9%), loss of pubic hair (52.38%), coarsening of body hair (47.62%), and alopecia areata (9.52%). The nail changes noted were brittle and ridged nail, followed by onycholysis, onychosezia, and onychomedesis. The most common skin features were xerotic skin in 11 patients (52.38%), followed by pellagra-like skin pigmentation, pustular psoriasis and acne form eruption, bullous impetigo, etc. Mucosa was normal in all the cases excepting the one which showed oral candidiasis. PMID- 23087873 TI - Hepatopathy in an adult, secondary to congenital untreated panhypopituitarism and ectopic posterior pituitary gland. AB - We report a rare case of an adult with advanced liver failure in the setting of an untreated congenital panhypopituitarism. A 32-years-old man presented with a newly onset seizure episode secondary to hypoglycemia. In the initial exploration, we found eunuchoid habitus, absence of secondary sexual characteristics, ascites, and hepatic encephalopathy. Hormonal evaluation confirmed the absence of anterior hypophyseal hormones and the liver function tests showed derangement of liver function. Magnetic Resonance Imaging (MRI) showed hypoplastic adenohypophysis and ectopic posterior pituitary gland. In the approach to liver disease, no cause was identified, besides the untreated panhypopituitarism. PMID- 23087874 TI - An adolescent with 48,XXYY syndrome with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder and renal malformations. AB - 48,XXYY is a rare sex chromosome aneuploidy affecting 1 in 18,000 to 50,000 male births. They present with developmental delay, hypogonadism, gynecomastia, intention tremors, and a spectrum of neurodevelopmental and psychiatric disorders. At one time this condition was considered a variant of Klinefelter syndrome. In clinically suspected cases, 48,XXYY syndrome can be diagnosed by chromosome culture and karyotyping. This patient presented with hypergonadotrophic hypogonadism, attention deficit hyperactive disorder, and renal malformatons. Klinefelter syndrome was clinically suspected. The karyotype confirmed the diagnosis of 48,XXYY syndrome. This is the first reported case of 48,XXYY syndrome from Sri Lanka. PMID- 23087875 TI - Kenny-Caffey syndrome type 1 in an Egyptian girl. AB - Kenny-Caffey syndrome type 1 (KCS1) (OMIM 244460) is a rare syndrome characterized by growth retardation, uniformly small slender long bones with medullary stenosis, thickened cortex of the long bones, hypocalcemia possibly with tetany at an early age and normal intelligence. The primary outcome of KCS1 is short stature. We present here an Egyptian girl aged 32 months with typical feature of KCS1. PMID- 23087876 TI - "Petrified ears" with idiopathic adult-onset pituitary insufficiency. AB - "Petrified ears" or calcification of auricular cartilage is an uncommonly reported condition. The most common causes of this phenomenon are local trauma, frost bite, and inflammation. Adrenal insufficiency is the most frequent systemic disease associated with auricular calcification. We present a case of idiopathic adult-onset pituitary insufficiency with hypocortisolism and bilateral auricular calcification. Recognition of the association between auricular calcification and adrenal insufficiency can be an important step toward the identification of a life-threatening cortisol deficiency. PMID- 23087877 TI - Spontaneous reduction of prolactinoma post cabergoline withdrawal. AB - Prolactinomas are common pituitary tumors usually highly responsive to dopamine agonists. Around 70-90% of the prolactinomas exhibit decrease in tumor size, though variably with these agents. Uncommonly, there may be little or no shrinkage in pituitary tumor. In the absence of medical therapy, pituitary apoplexy may also result in tumor shrinkage, albeit rarely. We report here a case showing only modest reduction in prolactinoma with cabergoline given for a period of one and a half years. Surprisingly, this tumor showed a 40% reduction in the tumor size 3 months after cabergoline withdrawal in the absence of clinical or radiological evidence of apoplexy. PMID- 23087878 TI - Ovarian granulosa cell tumor: An uncommon presentation with primary amenorrhea and virilization in a pubertal girl. AB - A 16-year-old girl presented with primary amenorrhea and excess hair growth on her body and face for the last three years, along with pain and a mass in her lower abdomen for last one year. Examination revealed hirsutism and other virilizing features, with an irregular mass in the lower abdomen corresponding to 16 weeks'gestation. Serum testosterone was 320 ng / dl and ultrasonogram of the pelvis revealed a solid mass of 5 * 4 cm in the left adnexa. Suspecting it to be a virilizing tumor of the left ovary, the patient was subjected to staging laparotomy, which revealed stage 1a ovarian involvement amenable to surgical resection alone. Histopathological examination confirmed the diagnosis of granulosa cell tumor of the ovary. Postoperatively the serum testosterone returned to 40 ng / dl and her menstrual cycle started after two months of surgery. PMID- 23087879 TI - Russell Silver syndrome: a perspective on growth and the influence of growth hormone therapy. AB - A 6 years male child was referred to our Endocrinology clinic with complaints of failure to thrive and he displayed the characteristic features of Russell Silver Syndrome which included short stature, relative macrocephaly, triangular facies and bilateral clinodactyly. He had a birth weight of 2.14 kg and an expected target height of 170 cm. He was subjected to a hormonal analysis which revealed a normal thyroid profile, but low serum markers of growth namely IGF-1=68 ng/ml (52 297 ng/ml) and basal growth hormone (GH) (1.5 MUg/l). No defects were detected on MRI of the sella. Therefore a growth hormone stimulation test with Clonidine was performed which confirmed complete GH deficiency (at 0 min=0.16 MUg/l, 60 min=0.27 MUg/l, 120 min=4.73 MUg/l). He was commenced on rhGH therapy at 8 years of age (height=102 cm, SDS=-4.53), due to financial restraints. Following initiation of GH therapy (1.5 IU/day) for 19 months, a height gain of 15 cm was obtained (Height=117 cm, SDS=-3.05). Bone age at 9 yr. was between 7-8 years. PMID- 23087880 TI - A rare cause for primary amenorrhea: Sporadic perrault syndrome. AB - Gonadal (ovarian) dysgenesis with normal chromosomes (46, XX), XX female gonadal dysgenesis (XX-GD) is a rare genetically heterogeneous disorder. In 1951, Perrault reported the association of gonadal dysgenesis and deafness, now referred to as Perrault syndrome. Perrault syndrome is a rare autosomal recessive condition affecting both females and males, only females have gonadal dysgenesis associated with sensorineural deafness which is present in both sexes. We present a case of Sporadic Perrault syndrome in a 35-year-old female with primary amenorrhea, sensorineural deafness, marfanoid features, and normal karyotype. There are very few case reports describing the condition, even lesser reports of association with marfanoid habitus. We report this case for its rarity and add to the spectrum of the disease that remains undetermined. PMID- 23087881 TI - Combined granulomatous and lymphocytic hypophysitis presenting as pituitary incidentaloma in a middle-aged woman. AB - We report a case of 41-year-old lady who presented with chronic headache of 6 month duration and a sellar mass with a suprasellar extension on imaging, which was interpreted as pituitary macroadenoma. She had normal pituitary function and visual perimetry. On clinical examination and imaging it was provisionally diagnosed as pituitary incidentaloma due to hypophysitis and she was advised steroid therapy, but underwent transnasal resection of the tumor against suggestion. Histopathological examination revealed combined granulomatous and lymphocytic hypophysitis most likely of autoimmune in origin. Definitive diagnosis of hypophysitis can be made only on histopathological examination. As most cases of autoimmune hypophysitis are surgically treated, patients should be assessed on individual basis for requirement of steroids in postoperative period. PMID- 23087882 TI - Positron emission tomography/computed tomography imaging of brown tumors mimicking multiple skeletal metastases in patient with primary hyperparathyroidism. AB - Brown tumors of bone are highly vascular, lytic bone lesions representing a reparative cellular process rather than a neoplastic process usually seen in patients with hyperparathyroidism. These tumors can behave aggressively and be destructive. We report a 49-year-old male patient who was admitted to our hospital with a long-term history of right shoulder and right hip pain. Multiple lytic and destructive bone lesions were found in X-ray graphy and CT images. These bone lesions mimicked multiple skeletal metastatic lesions and seemed to be those of the terminal stage of malignancy. PET scan was requested for the evaluation of FDG uptake of these lesions and to search the unknown primary tumor site. Positron emission tomography/computed tomography (PET/CT) images showed multiple hypermetabolic malignant or metastatic FDG avid bone lesions in skeletal system. However the biopsy results revealed no signs of malignancy and laboratory data showed elevated serum calcium, alkaline phosphatase, parathyroid hormone, low serum phosphate and parathyroid scintigraphy was performed. Adenoma in the left parathyroid gland was seen with Tc-99m MIBI parathyroid scintigraphy. Pathological results confirmed the diagnosis of parathyroid adenoma. Brown tumor is the potential cause of false-positive result in evaluation of a patient for unknown primary tumor or skeletal metastases with PET/CT imaging. PMID- 23087883 TI - Hypokalemic paralysis as a presenting manifestation of primary Sjogren's syndrome: A report of two cases. AB - Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by a progressive lymphocytic infiltration of the exocrine glands with varying degrees of systemic involvement. Overt or latent renal tubular acidosis (RTA), caused by tubulointerstitial nephropathy, is a common extraglandular manifestation of pSS. Hypokalemic paralysis is a well known, albeit rare complication of severe distal RTA from any cause. Cases of pSS manifesting for the first time as hypokalemic paralysis caused by distal RTA have been rarely reported. We herein present our experience of two cases, who presented to us for evaluation of hypokalemic paralysis and on work up found evidence of distal RTA, which on further work up found to be secondary to pSS. A high index of suspicion for pSS should be kept in all patients with hypokalemic paralysis. PMID- 23087884 TI - Milk proteins and human health: A1/A2 milk hypothesis. PMID- 23087885 TI - Relation between anthropometric measurements and serum lipid profile among cardio metabolically healthy subjects: A pilot study. PMID- 23087886 TI - It is short-but so what! PMID- 23087887 TI - Rapid improvement in the bone mineral density with vitamin D supplementation in postmenopausal woman with vitamin D deficiency. PMID- 23087888 TI - What is in a name: Is it Nelson's syndrome? PMID- 23087889 TI - Precocious pubarche in a young boy-unusual etiology. PMID- 23087890 TI - Primary hyperparathyroidism associated with vitamin D toxicity in a patient with severe osteoporosis receiving teriparatide. PMID- 23087891 TI - Non-diabetic use of liraglutide. PMID- 23087892 TI - Localized acromegaly. PMID- 23087893 TI - Vitamin D deficiency in hemodialysis. PMID- 23087894 TI - Charles Bonnet syndrome: An under reported entity in endocrinology. PMID- 23087895 TI - Obesity management: Dancing to the Bhangra beat. PMID- 23087896 TI - Hypofractionated Radiotherapy and Stereotactic Boost with Concurrent and Adjuvant Temozolamide for Glioblastoma in Good Performance Status Elderly Patients - Early Results of a Phase II Trial. AB - Glioblastoma Multiforme (GBM) is an aggressive primary brain neoplasm with dismal prognosis. Based on successful phase III trials, 60 Gy involved-field radiotherapy in 30 fractions over 6 weeks [Standard radiation therapy (RT)] with concurrent and adjuvant temozolomide is currently the standard of care. In this disease, age and Karnofsky Performance Status (KPS) are the most important prognostic factors. For elderly patients, clinical trials comparing standard RT with radiotherapy abbreviated to 40 Gy in 15 fractions over 3 weeks demonstrated similar outcomes, indicating shortened radiotherapy may be an appropriate option for elderly patients. However, these trials did not include temozolomide chemotherapy, and included patients with poor KPS, possibly obscuring benefits of more aggressive treatment for some elderly patients. We conducted a prospective Phase II trial to examine the efficacy of a hypofractionated radiation course followed by a stereotactic boost with concurrent and adjuvant temozolomide chemotherapy in elderly patients with good performance status. In this study, patients 65 years and older with a KPS > 70 and histologically confirmed GBM received 40 Gy in 15 fractions with 3D conformal technique followed by a 1-3 fraction stereotactic boost to the enhancing tumor. All patients also received concurrent and adjuvant temozolomide. Patients were evaluated 1 month post treatment and every 2 months thereafter. Between 2007 and 2010, 20 patients (9 males and 11 females) were enrolled in this study. The median age was 75.4 years (range 65-87 years). At a median follow-up of 11 months (range 7-32 months), 12 patients progressed and 5 are alive. The median progression free survival was 11 months and the median overall survival was 13 months. There was no additional toxicity. These results indicate that elderly patients with good KPS can achieve outcomes comparable to the current standard of care using an abbreviated radiotherapy course, radiosurgery boost, and temozolomide. PMID- 23087897 TI - Isolation and characterization of circulating tumor cells in prostate cancer. AB - Circulating tumor cells (CTCs) are tumor cells found in the peripheral blood that putatively originate from established sites of malignancy and likely have metastatic potential. Analysis of CTCs has demonstrated promise as a prognostic marker as well as a source of identifying potential targets for novel therapeutics. Isolation and characterization of these cells for study, however, remain challenging owing to their rarity in comparison with other cellular components of the peripheral blood. Several techniques that exploit the unique biochemical properties of CTCs have been developed to facilitate their isolation. Positive selection of CTCs has been achieved using microfluidic surfaces coated with antibodies against epithelial cell markers or tumor-specific antigens such as EpCAM or prostate-specific membrane antigen (PSMA). Following isolation, characterization of CTCs may help guide clinical decision making. For instance, molecular and genetic characterization may shed light on the development of chemotherapy resistance and mechanisms of metastasis without the need for a tissue biopsy. This paper will review novel isolation techniques to capture CTCs from patients with advanced prostate cancer, as well as efforts to characterize the CTCs. We will also review how these analyzes can assist in clinical decision making. CONCLUSION: The study of CTCs provides insight into the molecular biology of tumors of prostate origin that will eventually guide the development of tailored therapeutics. These advances are predicated on high yield and accurate isolation techniques that exploit the unique biochemical features of these cells. PMID- 23087899 TI - Skp2 and its emerging role in the pathogenesis of systemic malignancies besides breast carcinomas. PMID- 23087898 TI - Selected anti-tumor vaccines merit a place in multimodal tumor therapies. AB - Multimodal approaches are nowadays successfully applied in cancer therapy. Primary locally acting therapies such as radiotherapy (RT) and surgery are combined with systemic administration of chemotherapeutics. Nevertheless, the therapy of cancer is still a big challenge in medicine. The treatments often fail to induce long-lasting anti-tumor responses. Tumor recurrences and metastases result. Immunotherapies are therefore ideal adjuncts to standard tumor therapies since they aim to activate the patient's immune system against malignant cells even outside the primary treatment areas (abscopal effects). Especially cancer vaccines may have the potential both to train the immune system against cancer cells and to generate an immunological memory, resulting in long-lasting anti tumor effects. However, despite promising results in phase I and II studies, most of the concepts finally failed. There are some critical aspects in development and application of cancer vaccines that may decide on their efficiency. The time point and frequency of medication, usage of an adequate immune adjuvant, the vaccine's immunogenic potential, and the tumor burden of the patient are crucial. Whole tumor cell vaccines have advantages compared to peptide-based ones since a variety of tumor antigens (TAs) are present. The master requirements of cell based, therapeutic tumor vaccines are the complete inactivation of the tumor cells and the increase of their immunogenicity. Since the latter is highly connected with the cell death modality, the inactivation procedure of the tumor cell material may significantly influence the vaccine's efficiency. We therefore also introduce high hydrostatic pressure (HHP) as an innovative inactivation technology for tumor cell-based vaccines and outline that HHP efficiently inactivates tumor cells by enhancing their immunogenicity. Finally studies are presented proving that anti-tumor immune responses can be triggered by combining RT with selected immune therapies. PMID- 23087901 TI - The REDUCE metagram: a comprehensive prediction tool for determining the utility of dutasteride chemoprevention in men at risk for prostate cancer. AB - INTRODUCTION: 5-alpha reductase inhibitors can reduce the risk of prostate cancer (PCa) but can be associated with significant side effects. A library of nomograms which predict the risk of clinical endpoints relevant to dutasteride treatment may help determine if chemoprevention is suited to the individual patient. METHODS: Data from the REDUCE trial was used to identify predictive factors for 9 endpoints relevant to dutasteride treatment. Using the treatment and placebo groups from the biopsy cohort, Cox proportional hazards (PH) and competing risks regression (CRR) models were used to build 18 nomograms, whose predictive ability was measured by concordance index (CI) and calibration plots. RESULTS: A total of 18 nomograms assessing the risks of cancer, high grade cancer, high grade prostatic intraepithelial neoplasia (HGPIN), atypical small acinar proliferation (ASAP), erectile dysfunction (ED), acute urinary retention (AUR), gynecomastia, urinary tract infection (UTI) and BPH-related surgery either on or off dutasteride were created. The nomograms for cancer, high grade cancer, ED, AUR, and BPH-related surgery demonstrated good discrimination and calibration while those for gynecomastia, UTI, HGPIN, and ASAP predicted no better than random chance. CONCLUSIONS: To aid patients in determining whether the benefits of dutasteride use outweigh the risks, we have developed a comprehensive metagram that can generate individualized risks of 9 outcomes relevant to men considering chemoprevention. Better models based on more predictive markers are needed for some of the endpoints but the current metagram demonstrates potential as a tool for patient counseling and decision-making that is accessible, intuitive, and clinically relevant. PMID- 23087900 TI - Nanovectorized radiotherapy: a new strategy to induce anti-tumor immunity. AB - Recent experimental findings show that activation of the host immune system is required for the success of chemo- and radiotherapy. However, clinically apparent tumors have already developed multiple mechanisms to escape anti-tumor immunity. The fact that tumors are able to induce a state of tolerance and immunosuppression is a major obstacle in immunotherapy. Hence, there is an overwhelming need to develop new strategies that overcome this state of immune tolerance and induce an anti-tumor immune response both at primary and metastatic sites. Nanovectorized radiotherapy that combines ionizing radiation and nanodevices, is one strategy that could boost the quality and magnitude of an immune response in a predictable and designable fashion. The potential benefits of this emerging treatment may be based on the unique combination of immunostimulatory properties of nanoparticles with the ability of ionizing radiation to induce immunogenic tumor cell death. In this review, we will discuss available data and propose that the nanovectorized radiotherapy could be a powerful new strategy to induce anti-tumor immunity required for positive patient outcome. PMID- 23087903 TI - Low incidence of fatigue after hypofractionated stereotactic body radiation therapy for localized prostate cancer. AB - BACKGROUND: Fatigue is a common side effect of conventional prostate cancer radiation therapy. The increased delivery precision necessitated by the high dose per fraction of stereotactic body radiation therapy (SBRT) offers the potential of reduce target volumes and hence the exposure of normal tissues to high radiation doses. Herein, we examine the level of fatigue associated with SBRT treatment. METHODS: Forty patients with localized prostate cancer treated with hypofractionated SBRT, and a minimum of 12 months follow-up were included in this analysis. Self-reported fatigue and other quality of life measures were assessed at baseline and at 1, 3, 6, 9, and 12 months post-SBRT. RESULTS: Mean levels of fatigue were elevated at 1 month post-SBRT compared to baseline values (P = 0.02). Fatigue at the 3-month follow-up and later were higher but not statistically significantly different compared to baseline. African-American patients reported higher fatigue post-SBRT than Caucasian patients. Fatigue was correlated with hormonal symptoms as measured by the Expanded Prostate Cancer Index Composite (EPIC) quality of life questionnaire, but not with urinary, bowel, or sexual symptoms. Age, co-morbidities, smoking, prostate specific antigen (PSA) levels, testosterone levels, tumor stage, and treatment variables were not associated with fatigue. CONCLUSION: This is the first study to investigate fatigue as a side effect of SBRT. In contrast to standard radiation therapy, results suggest SBRT-related fatigue is short-term rather than a long term side effect of SBRT. These results also suggest post-SBRT fatigue to be a more frequent complication in African-Americans than Caucasians. PMID- 23087902 TI - Lipid raft involvement in yeast cell growth and death. AB - The notion that cellular membranes contain distinct microdomains, acting as scaffolds for signal transduction processes, has gained considerable momentum. In particular, a class of such domains that is rich in sphingolipids and cholesterol, termed as lipid rafts, is thought to compartmentalize the plasma membrane, and to have important roles in survival and cell death signaling in mammalian cells. Likewise, yeast lipid rafts are membrane domains enriched in sphingolipids and ergosterol, the yeast counterpart of mammalian cholesterol. Sterol-rich membrane domains have been identified in several fungal species, including the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe as well as the pathogens Candida albicans and Cryptococcus neoformans. Yeast rafts have been mainly involved in membrane trafficking, but increasing evidence implicates rafts in a wide range of additional cellular processes. Yeast lipid rafts house biologically important proteins involved in the proper function of yeast, such as proteins that control Na(+), K(+), and pH homeostasis, which influence many cellular processes, including cell growth and death. Membrane raft constituents affect drug susceptibility, and drugs interacting with sterols alter raft composition and membrane integrity, leading to yeast cell death. Because of the genetic tractability of yeast, analysis of yeast rafts could be an excellent model to approach unanswered questions of mammalian raft biology, and to understand the role of lipid rafts in the regulation of cell death and survival in human cells. A better insight in raft biology might lead to envisage new raft-mediated approaches to the treatment of human diseases where regulation of cell death and survival is critical, such as cancer and neurodegenerative diseases. PMID- 23087904 TI - The confluence of radiotherapy and immunotherapy. AB - Radiotherapy (RT) has been considered a local modality and outcomes have emphasized local and regional control of tumors. Recent data suggests that RT may activate the immune system and the combination of radiation therapy and immune therapies may have the potential to improve both local and distant control of tumor deposits. Below we review principals underlying the concepts of combining both modalities. PMID- 23087905 TI - Implications of fidelity difference between the leading and the lagging strand of DNA for the acceleration of evolution. AB - Without exceptions, genomic DNA of living organisms is replicated using the leading and the lagging strand. In a conventional idea of mutagenesis accompanying DNA replication, mutations are thought to be introduced stochastically and evenly into the two daughter DNAs. Here, however, we hypothesized that the fidelity of the lagging strand is lower than that of the leading strand. Our simulations with a simplified model DNA clearly indicated that, even if mutation rates exceeded the so-called threshold values, an original genotype was guaranteed in the pedigree and, at the same time, the enlargement of diversity was attained with repeated generations. According to our lagging-strand biased-mutagenesis model, mutator microorganisms were established in which mutations biased to the lagging strand were introduced by deleting the proofreading activity of DNA polymerase. These mutators ("disparity mutators") grew normally and had a quick and extraordinarily high adaptability against very severe circumstances. From the viewpoint of the fidelity difference between the leading and the lagging strand, the basic conditions for the acceleration of evolution are examined. The plausible molecular mechanism for the faster molecular clocks observed in birds and mammals is discussed, with special reference to the accelerated evolution in the past. Possible applications in different fields are also discussed. PMID- 23087906 TI - Abrogating endocrine resistance by targeting ERalpha and PI3K in breast cancer. AB - Antiestrogen therapies targeting estrogen receptor alpha (ER) signaling are a mainstay for patients with ER+ breast cancer. While many cancers exhibit resistance to antiestrogen therapies, a large body of clinical and experimental evidence indicates that hyperactivation of the phosphatidylinositol 3-kinase (PI3K) pathway promotes antiestrogen resistance. In addition, continued ligand independent ER signaling in the setting of estrogen deprivation may contribute to resistance to endocrine therapy. PI3K activates several proteins which promote cell cycle progression and survival. In ER+ breast cancer cells, PI3K promotes ligand-dependent and -independent ER transcriptional activity. Models of antiestrogen-resistant breast cancer often remain sensitive to estrogen stimulation and PI3K inhibition, suggesting that clinical trials with combinations of drugs targeting both the PI3K and ER pathways are warranted. Herein, we review recent findings on the roles of PI3K and ER in antiestrogen resistance, and clinical trials testing drug combinations which target both pathways. We also discuss the need for clinical investigation of ER downregulators in combination with PI3K inhibitors. PMID- 23087907 TI - FOXM1 coming of age: time for translation into clinical benefits? AB - A decade since the first evidence implicating the cell cycle transcription factor Forkhead Box M1 (FOXM1) in human tumorigenesis, a slew of subsequent studies revealed an oncogenic role of FOXM1 in the majority of human cancers including oral, nasopharynx, oropharynx, esophagus, breast, ovary, prostate, lung, liver, pancreas, kidney, colon, brain, cervix, thyroid, bladder, uterus, testis, stomach, skin, and blood. Its aberrant upregulation in almost all different cancer types suggests a fundamental role for FOXM1 in tumorigenesis. Its dose dependent expression pattern correlated well with tumor progression starting from cancer predisposition and initiation, early premalignancy and progression, to metastatic invasion. In addition, emerging studies have demonstrated a causal link between FOXM1 and chemotherapeutic drug resistance. Despite the well established multifaceted roles for FOXM1 in all stages of oncogenesis, its translation into clinical benefit is yet to materialize. In this contribution, I reviewed and discussed how our current knowledge on the oncogenic mechanisms of FOXM1 could be exploited for clinical use as biomarker for risk prediction, early cancer screening, molecular diagnostics/prognostics, and/or companion diagnostics for personalized cancer therapy. PMID- 23087908 TI - Generation of polycyclic aromatic hydrocarbons (PAHs) during woodworking operations. AB - Occupational exposures to wood dust have been associated with an elevated risk of sinonasal cancer (SNC). Wood dust is recognized as a human carcinogen but the specific cancer causative agent remains unknown. One possible explanation is a co exposure to; wood dust and polycyclic aromatic hydrocarbons (PAHs). PAHs could be generated during incomplete combustion of wood due to heat created by use of power tools. To determine if PAHs are generated from wood during common wood working operations, PAH concentrations in wood dust samples collected in an experimental chamber operated under controlled conditions were analyzed. In addition, personal air samples from workers exposed to wood dust (n = 30) were collected. Wood dust was generated using three different power tools: vibrating sander, belt sander, and saw; and six wood materials: fir, Medium Density Fiberboard (MDF), beech, mahogany, oak and wood melamine. Monitoring of wood workers was carried out by means of personal sampler device during wood working operations. We measured 21 PAH concentrations in wood dust samples by capillary gas chromatography-ion trap mass spectrometry (GC-MS). Total PAH concentrations in wood dust varied greatly (0.24-7.95 ppm) with the lowest being in MDF dust and the highest in wood melamine dust. Personal PAH exposures were between 37.5-119.8 ng m(-3) during wood working operations. Our results suggest that PAH exposures are present during woodworking operations and hence could play a role in the mechanism of cancer induction related to wood dust exposure. PMID- 23087909 TI - Effect of breast and formula feeding on gut microbiota shaping in newborns. PMID- 23087911 TI - Growth conditions and environmental factors impact aerosolization but not virulence of Francisella tularensis infection in mice. AB - In refining methodology to develop a mouse model for inhalation of Francisella tularensis, it was noted that both relative humidity and growth media impacted the aerosol concentration of the live vaccine strain (LVS) of F. tularensis. A relative humidity of less than 55% had a negative impact on the spray factor, the ratio between the concentration of LVS in the aerosol and the nebulizer. The spray factor was significantly higher for LVS grown in brain heart infusion (BHI) broth than LVS grown in Mueller-Hinton broth (MHb) or Chamberlain's chemically defined medium (CCDM). The variability between aerosol exposures was also considerably less with BHI. LVS grown in BHI survived desiccation far longer than MHb-grown or CCDM-grown LVS (~70% at 20 min for BHI compared to <50% for MHb and CCDM). Removal of the capsule by hypertonic treatment impacted the spray factor for CCDM-grown LVS or MHb-grown LVS but not BHI-grown LVS, suggesting the choice of culture media altered the adherence of the capsule to the cell membrane. The choice of growth media did not impact the LD(50) of LVS but the LD(99) of BHI grown LVS was 1 log lower than that for MHb-grown LVS or CCDM-grown LVS. Splenomegaly was prominent in mice that succumbed to MHb- and BHI-grown LVS but not CCDM-grown LVS. Environmental factors and growth conditions should be evaluated when developing new animal models for aerosol infection, particularly for vegetative bacterial pathogens. PMID- 23087910 TI - Links between type III secretion and extracytoplasmic stress responses in Yersinia. AB - The cell envelope of pathogenic bacteria is a barrier against host environmental conditions and immunity molecules, as well as the site where many virulence factors are assembled. Extracytoplasmic stress responses (ESRs) have evolved to help maintain its integrity in conditions where it might be compromised. These ESRs also have important links to the production of envelope-associated virulence systems by the bacteria themselves. One such virulence factor is the type III secretion system (T3SS), the first example of which was provided by the pathogenic Yersinia. This article reviews the reported links between four different ESRs and T3SS function in Yersinia. Components of three of these ESRs affect the function and/or regulation of two different T3SSs. The response regulator of the Rcs ESR is involved in positive regulation of the Ysa-Ysp T3SS found in the highly pathogenic 1B biogroup of Y. enterocolitica. Conversely, the response regulator of the Y. pseudotuberculosis Cpx ESR can down-regulate production of the Ysc-Yop T3SS, and at least one other envelope virulence factor (invasin), by direct repression. Also in Y. pseudotuberculosis, there is some evidence suggesting that an intact RpoE ESR might be important for normal Yersinia outer proteins (Yop) production and secretion. Besides these regulatory links between ESRs and T3SSs, perhaps the most striking connection between T3SS function and an ESR is that between the phage shock protein (Psp) and Ysc-Yop systems of Y. enterocolitica. The Psp response does not affect the regulation or function of the Ysc-Yop system. Instead, Ysc-Yop T3SS production induces the Psp system, which then mitigates T3SS-induced envelope stress. Consequently, the Y. enterocolitica Psp system is essential when the Ysc-Yop T3SS is produced. PMID- 23087914 TI - A study of adulteration in gasoline samples using flame emission spectroscopy and chemometrics tools. AB - This work presents a low cost system based on Flame Emission Spectroscopy (FES) that enables the prediction of fuel adulteration. The spectral data acquired using FES were associated with chemometric tools--Partial Least Squares Discriminant Analysis (PLS-DA) and Partial Least Squares (PLS), aiming to predict gasoline adulterations with different solvents. The classification of the Brazilian adulterated gasoline samples with turpentine, thinner, kerosene, rubber solvent and ethanol was carried out through a PLS-DA model built using five latent variables (LV) with an accumulated variance of 100% on X and 76.78% on Y. The combination of these techniques provided the discrimination of distinct groups for each one of the studied adulterants. Subsequent to the classification, samples of adulterated gasoline with the same solvents with contents varying from 1 to 50% (v/v) were analyzed through FES and multivariate calibration curves were employed in order to predict the contents of the respective solvents. The results obtained by the combination of FES and PLS provided the determination of gasoline adulterants with small calibration and validation errors and also lower values than the ones reported in the literature using other spectroscopic techniques. PMID- 23087912 TI - Diverse phosphorylation patterns of B cell receptor-associated signaling in naive and memory human B cells revealed by phosphoflow, a powerful technique to study signaling at the single cell level. AB - Following interaction with cognate antigens, B cells undergo cell activation, proliferation, and differentiation. Ligation of the B cell receptor (BCR) leads to the phosphorylation of BCR-associated signaling proteins within minutes of antigen binding, a process with profound consequences for the fate of the cells and development of effector immunity. Phosphoflow allows a rapid evaluation of various signaling pathways in complex heterogenous cell subsets. This novel technique was used in combination with multi-chromatic flow cytometry (FC) and fluorescent-cell barcoding (FCB) to study phosphorylation of BCR-associated signaling pathways in naive and memory human B cell subsets. Proteins of the initiation (Syk), propagation (Btk, Akt), and integration (p38MAPK and Erk1/2) signaling units were studied. Switched memory (Sm) CD27+ and Sm CD27- phosphorylation patterns were similar when stimulated with anti-IgA or -IgG. In contrast, naive and unswitched memory (Um) cells showed significant differences following IgM stimulation. Enhanced phosphorylation of Syk was observed in Um cells, suggesting a lower activation threshold. This is likely the result of higher amounts of IgM on the cell surface, higher pan-Syk levels, and enhanced susceptibility to phosphatase inhibition. All other signaling proteins evaluated also showed some degree of enhanced phosphorylation in Um cells. Furthermore, both the phospholipase C-gamma2 (PLC-gamma2) and phosphatidylinositol 3-kinase (PI3K) pathways were activated in Um cells, while only the PI3K pathway was activated on naive cells. Um cells were the only ones that activated signaling pathways when stimulated with fluorescently labeled S. Typhi and S. pneumoniae. Finally, simultaneous evaluation of signaling proteins at the single cell level (multiphosphorylated cells) revealed that interaction with gram positive and negative bacteria resulted in complex and diverse signaling patterns. Phosphoflow holds great potential to accelerate vaccine development by identifying signaling profiles in good/poor responders. PMID- 23087913 TI - Population-based study of high plasma C-reactive protein concentrations among the Inuit of Nunavik. AB - BACKGROUND: The shift away from traditional lifestyle in the Inuit population over the past few decades has been associated with an increased prevalence of coronary heart disease (CHD) risk factors such as obesity, high blood pressure (BP) and diabetes. However, the impact of this transition on the pro-inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has not been documented. OBJECTIVES: To examine the prevalence of elevated plasma hs-CRP concentrations in Inuit from Nunavik in the province of Quebec (Canada) and identify anthropometric, biochemical and lifestyle risk factors associated with elevated hs-CRP. DESIGN: A population-representative sample of 801 Inuit residents from 14 villages of Nunavik, aged between 18 and 74 years, was included in the analyses. Subjects participated in a clinical session and completed questionnaires on lifestyle. Multivariate logistic regression was used to determine risk factors for elevated hs-CRP. RESULTS: Elevated plasma hs-CRP concentrations (>= 2 mg/L) were present in 32.7% (95% confidence interval (CI) 29.5-35.8) of the Inuit adult population and were more prevalent among women than among men (36.7% vs. 29.0%, p=0.007). Multivariate logistic regression analysis indicated that every 1 mmHg increase in systolic BP was associated with a 3% increase in the odds of having hs-CRP concentrations >= 2 mg/L in the Inuit population (95% CI 1.01-1.04). The combination of older age (>= 50 vs. <30 years) and elevated waist circumference (gender-specific cut-off values) in a multivariate logistic model was also associated with a 13.3-fold increase in the odds of having plasma hs-CRP concentrations >= 2 mg/L (95% CI 5.8-30.9). CONCLUSIONS: These data indicate that elevated hs-CRP is relatively prevalent among Inuit with values that are similar to those seen in Canadian Caucasian populations. Sex, age, waist circumference and systolic BP are major factors that increase the risk of this inflammatory phenotype among Inuit from Nunavik, despite their different lifestyle background compared with Caucasians. PMID- 23087915 TI - A new combination MALDI matrix for small molecule analysis: application to imaging mass spectrometry for drugs and metabolites. AB - Since the development of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, this procedure has been specifically used for analyzing proteins or high molecular weight compounds because of the interference of matrix signals in the regions of the low mass range. Recently, scientists have been using a wide range of chemical compounds as matrices that ionize small molecules in a mass spectrometer and overcome the limitations of MALDI mass spectrometry. In this study, we developed a new combination matrix of 3-hydroxycoumarin (3-HC) and 6 aza-2-thiothymine (ATT), which is capable of ionizing small molecules, including drugs and single amino acids. In addition to ionization of small molecules, the combination matrix by itself gives less signals in the low mass region and can be used for performing imaging mass spectrometry (IMS) experiments on tissues, which confirms the vacuum stability of the matrix inside a MALDI chamber. The drug donepezil was mapped in the intact tissue slices of mice simultaneously with a spatial resolution of 150 MUm during IMS. IMS analysis clearly showed that intact donepezil was concentrated in the cortical region of the brain at 60 min after oral administration. Our observations and results indicate that the new combination matrix can be used for analyzing small molecules in complex samples using MALDI mass spectrometry. PMID- 23087916 TI - Interaction of C70 fullerene with the Kv1.2 potassium channel. AB - Fullerene C(70) is known to partition into lipid membranes and change their physical properties. Together with gallic acid (GA), C(70) induces cell contraction and cell death. How C(70) and GA-induced perturbations of lipid membranes affect cellular function and membrane protein activity is not understood, though. Meanwhile, fullerene is also known to interfere with the activity of potassium channel proteins, but the mechanisms of protein inhibition are not known. Here we consider the possibility that membrane protein function would be inhibited by C(70) and/or GA through direct contact or through lipid mediated interactions. To this end, we use microsecond time scale atomistic simulations to explore (a) modifications of membrane properties in the presence of C(70) and/or GA, and (b) the possible conformational changes in Kv1.2, a voltage-gated potassium channel, upon exposure to C(70), or GA, or both. C(70) is found to have an observable effect on structural and elastic properties of protein-free membranes, while the effects of GA on the membrane are less evident. Fullerene-GA interaction is strong and affects significantly the partitioning of C(70) in the membrane, stabilizing C(70) in the aqueous phase. When Kv1.2 is exposed to the solutes, only small conformational changes are observed on the microsecond time scale - comparable to the fluctuations observed in the absence of any solute. Blocking of the channel entrance is not observed, as fullerene binds mainly to hydrophobic residues, both in the water-exposed loops and in the transmembrane helices. The tilt angle of transmembrane helices in the voltage sensing domain appears to be affected by direct contact with fullerene, but a generic effect due to the small increase in membrane thickness might also play a role. A small rotation of the S3 and S4 helices in the voltage-sensing domain is noticed when C(70) is embedded in the membrane. The interpretation of the observed conformational changes is not straightforward due to the associated time scales, which are difficult to sample with state-of-the-art computing resources. We cannot exclude that both membrane-mediated interactions and specific protein solute interactions affect the conformation of the protein. PMID- 23087917 TI - Walter Monroe Fitch (May 21, 1929 - March 10, 2011): a memorial tribute. PMID- 23087919 TI - The importance of gene-gene interactions in statin efficacy. PMID- 23087918 TI - Update on emerging infections: news from the Centers for Disease Control and Prevention. Pseudomonas aeruginosa respiratory tract infections associated with contaminated ultrasound gel used for transesophageal echocardiography-Michigan, December 2011-January 2012. PMID- 23087920 TI - The role of genome-wide association studies in confirming the importance of potential therapeutic targets. PMID- 23087921 TI - Valve-in-vale implants delivered without open-heart surgery. Research shows the catheter procedure is effective in replacing failing bioprosthetic valves. PMID- 23087922 TI - Biofeedback may have a role in cardiac treatment. Cleveland Clinic researchers are studying the effects of self-regulation therapy on heart patients. PMID- 23087923 TI - Coronary artery calcium levels help predict heart risk. By looking at calcium buildup and other factors, such as blood pressure, doctors can better classify a patient's odds of a coronary heart disease event. PMID- 23087924 TI - Gout raises heart-attack risk in older women. Take steps to prevent this unexpected consequence. PMID- 23087925 TI - Trans fats: the enemies of a healthy heart. Here's why you need to eliminate them from your diet. PMID- 23087926 TI - Additional role for APJ in cardiac hypertrophy. PMID- 23087927 TI - Discovery of activator for cryptochrome may shape development of metabolic drugs. PMID- 23087928 TI - Diagnosis, removal of obstructions in endodontic therapy. PMID- 23087929 TI - Management of sensitive dentin. AB - No panacea presently exists for dentinal sensitivity. Careful, systematic diagnosis and selection of treatment based on diagnostic findings provide a solution to most cases. Often in fact, cases require no treatment because spontaneous closure of dentinal tubules usually provides relief within several weeks. Simple dentinal sensitivity responds immediately to tubule closure induced by application of oxalates, creation of a smear layer, application of adhesives, and other local methods. Patients with sensitivity who do not respond may have pulpitis, a cracked tooth, or defective restorations involving the tooth that is believed to be sensitive or an unsuspected tooth that may be responding to stimuli. Pain referred from the source to another area is not uncommon. Long-term or chronic simple dentinal sensitivity may result from repeated acidic erosion, especially from dietary acids. PMID- 23087930 TI - Retentive characteristics of dental cementation materials. AB - Glass ionomer, polycarboxylate, zinc phosphate, and two resin cements were tested in vitro to cement base and noble metal crowns to prepared extracted teeth. The cements had different retentive characteristics. Among cements, statistically significant tensile resistance to dislodgment in order of decreasing strength was: (1) C & B Metabond (resin); (2) Panavia (resin); (3) Fuji I (glass ionomer); (4) Durelon (polycarboxylate); and (5) Fleck's (zinc phosphate). Tensile resistance to dislodgment did not differ statistically among base and noble metal crowns cemented with glass ionomer, polycarboxylate, or zinc phosphate cements. Tensile resistance to dislodgment differed statistically among base and noble crowns cemented with the resin cements (C & B Metabond and Panavia); the base metal crowns had the highest rate of retention. PMID- 23087931 TI - Cosmetic dentistry: patients' perspectives. AB - More dentists now are offering cosmetic dentistry to their patients. In this study, patients' perspectives on a variety of cosmetic procedures were surveyed. Women and older respondents seemed most willing to have cosmetic treatment. Perception of fees and discomfort level of these procedures also were examined. Many practitioners report an increase in office productivity with cosmetic dentistry, and an increase in personal satisfaction from performing esthetic procedures that their patients appreciate. PMID- 23087932 TI - Apicoectomy and retrofilling preparation of Thermafil obturations. PMID- 23087933 TI - Safety of ultrasonics in endodontics. PMID- 23087934 TI - Debris forced through apical foramina by ultrasonic and hand instrumentation. PMID- 23087935 TI - C-shaped canals: diagnosis and treatment. AB - C-shaped canal configurations present special clinical problems including relief of pain, copious bleeding, and difficulty in cleaning, shaping, and filling. A review of the literature, radiographic characteristics that make diagnosis possible before the canal is accessed, and suggestions for instrumentation and filling are provided here. PMID- 23087936 TI - Rapid removal of sealer following root canal treatment. AB - A case of acute exacerbation following nonsurgical root canal treatment is presented. Clinical symptoms of acute inflammation superimposed on chronic inflammation were initiated, presumably from root canal treatment and overfilling of AH-26. Unusually rapid removal of the root canal sealer overfilling was observed. Possible mechanisms of resolution, including inflammation and immune response, were discussed. PMID- 23087937 TI - Restoration of a severely eroded dentition. AB - A method is presented to restore severely eroded dentition. Due to the complexity of the case, many facets of restorative dentistry and orthodontics were used in the treatment plan. By following the basic principles described, general dentists can perform this type of restorative therapy. PMID- 23087938 TI - Who speaks for you? PMID- 23087939 TI - Sticky terms. PMID- 23087940 TI - Choose the best answer. PMID- 23087941 TI - Pregnant pause. PMID- 23087942 TI - 1993 Albert Knab Memorial Lectures: AIDS update. PMID- 23087943 TI - What a dentist should know about dental technology certification. PMID- 23087944 TI - Nonprescription pain relievers, Part II. PMID- 23087945 TI - Cross-cultural issues in family violence. PMID- 23087946 TI - Diffuse abnormalities of posterior dentition. Radiation effects. PMID- 23087947 TI - Numerous missing teeth. Hypodontia. PMID- 23087948 TI - Vitamin C and dental healing: testing and placebo effect. AB - The present study augments a growing body of evidence that indicates supplemental vitamin C may be beneficial in speeding healing following tooth extraction and in reducing the likelihood of alveolalgia and other complications. No adverse side effects were encountered from administration of vitamin C in our studies or in a recent investigation involving intake of 10 g/day; thus, carefully tested higher dosages ("megadose therapy") might be applied successfully to patients with alveolalgia or orthognathic conditions. Hanck comments on the relative safety of ascorbic acid in medicine: "The few literature references suggesting adverse effects of ascorbic acid are outnumbered by a large number of clinical studies in which no adverse effects have been observed. Up to 5 g of ascorbic acid daily may be administered safely even over a long-term". Further research is recommended to determine whether vitamin C is of similar value in hastening proper recovery from other oral surgical procedures. Vitamin C is a relatively safe, inexpensive, over the-counter product that may be more effective in dental healing than previously known. PMID- 23087949 TI - Hepatitis B vaccination and exposure protocol: update. PMID- 23087950 TI - Skill assessment of the HIV+ practitioner: the role of invasive procedures. PMID- 23087951 TI - Retrospective analysis of alveolar osteitis (dry socket) over four years. PMID- 23087952 TI - Idiopathic leukoplakia lingualis. AB - A 67-year-old man had a nonspecific leukoplakia of the tongue. It was of recent onset and had no readily apparent etiology. From the differential diagnosis of seven conditions, biopsy was consistent with a benign hyperkeratotic process. Although several atypical cells were noted in the epithelium, no foci of dysplasia or frank squamous cell carcinoma were observed. The characteristic histologic features of lichen planus, hairy leukoplakia, and hyperplastic candidiasis were similarly not present in the biopsy specimen. No evidence of coexisting systemic disturbances or risk factors associated with lupus erythematosus or human immunodeficiency virus infection were evident from the workup. The lesion's recent onset was inconsistent with white sponge nevus. This oral lesion can be best described clinically as an idiopathic leukoplakia. Histologically, it displayed hyperkeratosis of the epithelium. When oral leukoplakia of unknown etiology is encountered, careful consideration of contributing history, oral habits, systemic diseases, and histologic findings is necessary to achieve an accurate diagnosis. Developing a differential diagnosis can aid in systemically ruling out various entities as clinical and laboratory data are obtained. PMID- 23087953 TI - The Class IV resin composite restoration: results of a national survey. AB - Various aspects and principles of the Class IV acid-etched direct resin composite restoration are reviewed through an examination of the literature and a national survey. The purpose of the survey was to determine what is being taught and relate it to literature on the subject. The general conclusion is that responding dental schools in the United States teach the most currently accepted concepts of material selection, tooth preparation, and clinical technique associated with this treatment service. Among respondents: (1) 73 percent report that they teach use of a liner before placement of the resin composite; (2) two include instruction for a total-etch technique; (3) 15 percent regularly teach use of DBAs; (4) 21 percent teach placement of a microfilled resin composite veneer, while 69 percent teach placement of a single resin composite restoration; (5) all use visible light-cured resin composite systems exclusively; (6) all indicate that some type of preparation is required, and circumferental preparation was preferred most (95 percent); types of margins taught most frequently are the long bevel (33 percent), chamfer (26 percent), and either the long bevel or chamfer (14 percent); one school prefers porcelain laminate veneers as the restoration for larger Class IV lesions; and. 74 percent prefer incremental addition of resin composite layers as their placement technique. In most cases, the literature and survey findings agree, but there are a number of areas (liners, DBAs, and occlusion) for which further research is indicated to determine an optimal direction for dental school instruction. This article will be useful if it improves clinical performance or spurs answers to those items for which consensus is lacking. PMID- 23087955 TI - Is adequate good enough? Part II. PMID- 23087954 TI - Effects of prophylactic agents on shear bond strength of resin composite bonding to enamel. AB - In this study, the effect of different tooth cleansing methods on shear bond strength of resin composite bonding to enamel was evaluated. The buccal enamel surface of 45 noncarious permanent molars was ground flat to provide a uniform surface to which composite was applied. Care was taken to avoid dentin exposure in this procedure. The teeth were divided randomly into 3 groups of 15 teeth. Group 1 was treated with prophylaxis with a rubber cup and pumice, Group 2 with prophylaxis with a rubber cup and nonfluoridated paste, and Group 3 with prophylaxis with a rubber cup and fluoridated paste. After thermocycling, the samples were sheared in the Instron. Results, in MPa, were: Group 1: 14.70 +/- 4.44, Group 2:15.82 +/- 2.70, and Group 3: 16.41 +/- 5.93. Analysis of variance showed no difference among the three groups. PMID- 23087956 TI - Diagnosis of an odontogenic keratocyst with computed tomography. AB - The CT scan aided diagnosis here of two odontogenic keratocysts in the maxillary sinus. The CT scan defines borders and provides insight into the contents of lesions and a three-dimensional view of an area of specific interest. In terms of diagnostic value, the CT scan has a definite advantage over other radiographic techniques. The treatment of maxillary odontogenic keratocysts was discussed, and the importance of postoperative observation was emphasized. PMID- 23087957 TI - Treatment of ectopic eruption of maxillary permanent first molars. AB - A review of treatment of the ectopic maxillary permanent first molar is presented; prevalence and possible etiologies of the condition are explained. A step-by-step procedure for correctly diagnosing and treating the problem is suggested. A case is described in which diagnosis and treatment followed the principles outlined. PMID- 23087958 TI - Quiz no. 71: Periodontics. PMID- 23087959 TI - Pedunculated retromolar mass. Mucoepidermoid carcinoma. PMID- 23087960 TI - Interradicular radiolucency. Lateral radicular cyst. PMID- 23087961 TI - Sialolithiasis: literature review and case report. AB - Sialolithiasis is a common disorder of the salivary ducts and glands. If a patient has pain and swelling in these regions, and (especially) a history of occurrence near mealtimes, this diagnosis should be considered. For accessible stones, conservative therapy of milking the duct, together with palliative therapy, should be attempted. If these therapies are unsuccessful, excision can be attempted if the sialolith is far enough anterior in the duct. Excision of the gland may be necessary if the sialolith is too far posterior in the duct or gland. This treatment may be indicated if recurrence is frequent. A fibrosed gland may not need to be excised. Lithotripsy shows promise as a nonsurgical treatment, but is relegated to larger medical centers and is not readily available. Occasionally, sialoliths exfoliate, as in the case presented. PMID- 23087962 TI - Giant submandibular sialoliths: literature review and case reports. AB - In this report, two giant sialoliths are described that had recurred 25 years after removal of small stones from the same ducts. This is a longer interval between occurrences than has been reported elsewhere. The sialoliths did not cause distress, so the patients declined further investigations or treatment. PMID- 23087964 TI - Don't open the wrong tooth. PMID- 23087963 TI - Health promotion in the dental office: a comprehensive perspective. PMID- 23087965 TI - Analysis of panoramic and full-mouth radiographs for redundancy and missed diagnoses. PMID- 23087966 TI - Vitamin C and dental healing. III: The nutrition factor. PMID- 23087967 TI - Temporomandibular disorders: a practical screening process. AB - The one-page screening process presented is efficient and easy to complete (Fig. 12). Other TMD screening forms and processes provide equally valid classification and prediction. Screening systems like the TMJ Scale have been validated by extensive epidemiological application and can be used if greater reliability is desired. Regardless of the screening process used, additional history review and clinical examination are indicated for all potential TMD patients before diagnosis. For therapy to be efficacious, the number and variety of disorders require various treatment modalities. A screening process can be incorporated easily into dental practice and is a safeguard against overlooking these dysfunctional problems while other oral health needs are met. PMID- 23087968 TI - Denture cleaner chemical burn. PMID- 23087969 TI - Evaluation of various methods of removing gutta-percha and endodontic sealer. AB - Extracted human teeth were studied to evaluate three methods of removing gutta percha and endodontic sealer from previously obturated canals. The results showed that: (1) Each method of removal left debris in the canals. (2) Significantly more debris remained in the apical third than in the middle or coronal thirds. Likewise, significantly more debris remained in the middle than in the coronal third. (3) Use of the GPX instruments enabled gutta-percha to be removed as effectively as the other methods. (4) Use of the GPX instruments required significantly less time for gutta-percha removal, compared to removal by the other methods. PMID- 23087970 TI - Emergency direct fabrication of a resin fixed partial denture by using a ceramometal crown with reinforcing woven polyethylene ribbon as a pontic. AB - In this emergency case of a fractured tooth, immediate short-term treatment was necessary to relieve pain and replace a missing coronal portion of the maxillary central incisor. The need to remove additional fractured root fragments subgingivally precluded accessibility to the remaining root for conventional restorative procedures. The patient could not decide which course of treatment to accept, so a fixed partial denture was fabricated, with the ceramometal crown restoration as a provisional pontic splinted to the adjacent teeth. Restoring and reinforcing the posterior composite splint with a gas plasma-treated woven polyethylene ribbon has been detailed and illustrated. This ribbon material reputed to be 10 times stronger than steel by volume, is a true reinforcing material because it is woven. Mechanically, it becomes an integral part of the splint. Because it is gas plasma-treated, the superficial layer, when placed in BIS-GMA or polymethyl methacrylate, reacts chemically with the resin. The pliable, memory-free fiber--together with the open, woven, lacelike, lock stitch leno--allows the ribbon to follow the contours of the teeth and dental arch easily. The ribbon design reduces and dissipates forces exerted onto the splinting resin. The neutral color of the material permits it to have a chameleonlike effect on the color of the resin into which it is positioned. This ribbon product has been used in other dental applications: periodontal splinting, orthodontic retention, indirect composite fixed partial dentures, long-term temporary restorations with applicability in implant treatments, repair and conversion of prostheses, and reinforcing endodontically treated teeth, and complete dentures and orthodontic retainers when weaknesses are anticipated, such as shallow palatal vaults of complete dentures against a full complement of mandibular natural teeth, and the horseshoe mandibular removable modified Hawley retainer. PMID- 23087971 TI - The injection procedure as a source of stress for dentists. AB - A questionnaire was mailed to 3,000 practicing dentists to inquire about their physical and psychological responses to injecting local anesthesia; 711 dentists completed questionnaires (a 24 percent response rate). Six percent of respondents considered their thoughts and feelings associated with injection to be a serious problem; two percent reported no negative reactions to this aspect of clinical practice. Reported reactions to various anesthetic procedures were compared, and the various responses are discussed. Injection of local anesthesia, rarely discussed in the literature, contributes significantly to overall stress of dentists, but not all dentists. PMID- 23087972 TI - An intrapulpal foreign object. PMID- 23087974 TI - Quiz no. 83: Operative/restorative dentistry. PMID- 23087973 TI - Dentists' attitudes toward the peer-review process. PMID- 23087975 TI - Two-tiered allowances by third party carriers. PMID- 23087976 TI - New fluoride dosage schedule. PMID- 23087977 TI - Antibiotics and their use in the treatment of orofacial infections, part II. PMID- 23087978 TI - Therapeutic privilege and truth telling. PMID- 23087979 TI - Radicular radiolucency. Internal root resorption. PMID- 23087980 TI - Pericoronal radiolucency. Squamous cell carcinoma. PMID- 23087981 TI - Microbial contamination of dental unit waterlines: short- and long-term effects of flushing. AB - The extensive microbial contamination of DUW in this study is consistent with that described in previous reports. Comparisons with other common public potable water sources emphasize the relatively high concentrations of microorganisms in DUW, and the low numbers of bacteria in most domestic water samples. Microscopic evidence of amebas and worms in DUW reinforces the need for further qualitative and quantitative studies of these contaminants of dental tubing biofilm. In most cases, flushing for two minutes reduced microbial concentrations in DUW. However, in a few cases, concentrations rose; in others, the reductions were negligible. Moreover, after 30 minutes of stasis, or use of the waterline in a routine dental procedure, microbial counts were frequently restored to preflush levels or higher. The longer-term ineffectiveness 30 minutes after flushing is understandable when the hydrodynamics of laminar flow of water in narrow-bore tubing are considered. Biofilm on the tubing wall remains intact during flushes and quickly generates more bacteria during stasis. Increased bacterial concentrations after flushing probably result from sloughing of biofilm from the tubing wall because of stretching and movement of the line during routine use. These two phenomena undermine the benefits of routine water flushes. It is a common belief that bacterial levels build to extremes during overnight or weekend stasis; we observed more variation in contamination levels during the workday than between overnight stasis and typical workday samples. The presence of hemolytic staphylococci and streptococci in water samples from lines that were supplied only from sterile water reservoirs adds to the growing evidence that part of the microbial flora in DUWLs may be derived from patients' mouths. Additional prophylactic measures to limit bacterial contamination in DUW should be implemented according to standard principles used in other medical fluid delivery devices. PMID- 23087982 TI - Delivering coolant through the bur: a preliminary report. PMID- 23087983 TI - Practical infection control in dental laboratories. AB - Regardless of the dental laboratory infection control methods that are used, excellent communication and cooperation between laboratory staff members and clients must be maintained. The safety of patients is assured only through confidence that dentists and dental technicians use the proper procedures correctly. Whenever a question exists about possible contamination of an item that is brought into the laboratory, the item should be treated as contaminated until processed by prescribed methods. PMID- 23087984 TI - Porcelain veneer restorations: an option in removable partial denture design. PMID- 23087985 TI - Pain and paresthesia secondary to loose Kirschner wires. AB - A clinical case is reported in which pain, swelling, and paresthesia of the left submandibular area and tongue was variously diagnosed as a sublingual infection, a submandibular gland infection or tumor, nonunion of the mandible from previous orthognathic surgery seven years earlier, and finally as a sequela to loose Kirschner wires used as fixation in the previously mentioned surgery. Proper diagnosis by history, examination, and radiology, followed by surgical removal of two loose Kirschner wires resulted in complete remission of all symptoms. PMID- 23087986 TI - Dental rehabilitation through a mandibular removable partial denture with labial plate major connector. PMID- 23087987 TI - Sterilizer monitoring: option or responsibility? PMID- 23087988 TI - Effect of internal disinfectants on selective microbe recovery from irreversible hydrocolloid. PMID- 23087989 TI - Tooth erosion: an unusual case. AB - A case of tooth erosion due to prolonged exposure to acidic pool water has been presented. Dentists and swimmers must be aware of the detrimental dental effects associated with prolonged exposure to improperly maintained pool water, and what measures can be taken to prevent such effects. PMID- 23087990 TI - Quiz no. 77: Ceramics. PMID- 23087991 TI - Interview with Donald P. Fesko, OD, FACHE, Chief Executive Officer of community hospital. Interview by Stephen J. O'Connor. PMID- 23087992 TI - Using technology to enhance patient-centered care. PMID- 23087993 TI - Managing to customer specifications. PMID- 23087994 TI - Environmental market factors associated with physician career satisfaction. AB - Previous research has found that physician career satisfaction is declining, but no study has examined the relationship between market factors and physician career satisfaction. Using a theoretical framework, we examined how various aspects of the market environment (e.g., munificence, dynamism, complexity) are related to overall career satisfaction. Nationally representative data from the 2008 Health Tracking Physician Survey were combined with environmental market variables from the 2008 Area Resource File. After controlling for physician and practice characteristics, at least one variable each representing munificence, dynamism, and complexity was associated with satisfaction. An increase in the market number of primary care physicians per capita was positively associated with physician career satisfaction (OR = 2.11, 95% CI: 1.13 to 3.9) whereas an increase in the number of specialists per capita was negatively associated with physician satisfaction (OR = 0.68, 95% CI: 0.48 to 0.97). Moreover, an increase in poverty rates was negatively associated with physician career satisfaction (OR = 0.95, 95% CI: 0.91 to 1.01). Lastly, physicians practicing in states with a malpractice crisis (OR = 0.81, 95% CI: 0.68 to 0.96) and/or those who perceived high competition in their markets (OR = 0.76, 95% CI: 0.61 to 0.95) had lower odds of being satisfied. A better understanding of an organization's environment could assist healthcare managers in shaping their policies and strategies to increase physician satisfaction. PMID- 23087995 TI - Hospital financial management: what is the link between revenue cycle management, profitability, and not-for-profit hospitals' ability to grow equity? AB - Effective revenue cycle management--from appointment scheduling and patient registration at the front end of the revenue cycle to billing and cash collections at the back end--plays a crucial role in hospitals' efforts to improve their financial performance. Using data for 1,397 bond-issuing, not-for profit US hospitals for 2000 to 2007, this study analyzed the relationship between hospitals' performance at managing the revenue cycle and their profitability and ability to build equity capital. Hospital-level fixed effects regression analysis was used to model four different measures of profitability and equity capital as functions of two key financial indicators of revenue cycle management--amount of patient revenue and speed of revenue collection. The results indicated that higher amounts of patient revenue in relation to a hospital's assets were associated with statistically significant increases in operating and total profit margins, free cash flow, and equity capital (p < 0.01 for all four models); that is, hospitals that generated more patient revenue per dollar of assets invested reported improved financial performance. Likewise, a statistically significant link existed between lower revenue collection periods and all four indicators of hospital financial performance (p < 0.01 for three models; p < 0.05 for one model). Hospitals that collected faster on their patient revenue reported higher profit margins and larger equity values. For revenue cycle managers, these findings represent good news: Streamlining a hospital's management of the patient revenue cycle can advance the organization's financial viability by improving profitability and enabling equity growth. PMID- 23087996 TI - The impact of HCA's 2006 leveraged buyout on hospital performance. AB - Leveraged buyout (LBO) arrangements are a reorganization strategy whereby a firm assumes a substantial amount of debt to buy back its publicly held stock to become privately held. LBOs offer a firm several advantages and have the potential to increase efficiency. In the past 20 years, several healthcare firms have engaged in LBOs, but the literature on performance changes in healthcare organizations as a result of an LBO is limited. In this article, we report on a study that examined the performance of Hospital Corporation of America (HCA) hospitals before and after the LBO that was initiated in 2006. We used data from the Medicare Hospital Cost Report Information System and analyzed data from 130 HCA hospitals and 490 comparison hospitals. Findings show that HCA hospitals reduced expenses and their number of full-time equivalents (FTEs) relative to local competitor hospitals. HCA hospitals' cash-flow-margin ratio was substantially higher when adjusted for its local competing hospitals at the beginning of the LBO as well as at end of the LBO. When compared to local hospitals, HCA hospitals had a significant decrease in their capital investment in fixed assets from 2006 to 2009. These findings underscore the effectiveness of HCA's management strategies to repay debt and increase the value of the company, and they are informative for healthcare firms and their managers who are considering LBOs. PMID- 23087997 TI - Predictors of hospital CEO affiliation with a professional association. AB - Based on a 2008 cross-sectional survey of 582 hospital CEOs in the United States, this study reports the findings of two logistic regression models designed to identify CEO and hospital characteristics associated with Member and Fellow status in the American College of Healthcare Executives (ACHE). The purpose of the study was to understand the personal and organizational characteristics of those CEOs who choose to be Members and Fellows of a professional association such as ACHE. The results showed that most (74 percent) of the respondents considered ACHE to be their primary professional association. The results also revealed that a master's degree in health administration [beta = .88, t(427) = 5.35, p < .0001], male gender [beta = .59, t(427) = 3.01, p = .002], and financial incentives provided by the parent hospital [beta = .25, t(427) = 2.73, p = .006] were statistically positively linked with Member status in ACHE. A master's degree in health administration [beta = .81, t(424) = 5.79, p < .0001], male gender [beta = .39, t(424) = 2.25, p = .02], and age [beta = .02, t(424) 2.32, p = .02] were also statistically positively associated with Fellow status in ACHE. Notably, organizational factors such as size, geographic location, for profit status, and financial strength of the hospital do not seem to play an important role in the CEOs' decision to become a Member or Fellow of ACHE. The implication of these findings is that membership and fellowship at a professional association are influenced by characteristics of the individual, and incentives provided by employers can encourage employees to get involved with their professional associations. PMID- 23087998 TI - [Pancreatic adenocarcinoma--a therapeutic challenge]. AB - In Finland, the 5-year survival rate of pancreatic adenocarcinoma is 3%. Surgery is the only treatment that may be curative. Adjuvant chemotherapy after radical surgery is beneficial and patients with locally advanced disease may also benefit from chemoradiotherapy. The treatment of metastatic pancreatic cancer, expert symptomatic and palliative care is essential. New therapeutic approaches, e.g. combined cytostatics and/or targeted biologic drugs are being investigated to improve patient outcome. PMID- 23087999 TI - [Assessment of working capacity of a patient with cardiovascular disease for health insurance purposes]. AB - Assessment of the working and functional capacity of a patient with cardiovascular disease is based on the application by the person applying for health insurance or pension benefit, and on the data of the medical records and other documents. In addition to the description of the restrictions in everyday life, careful clinical examination, interpretation of electrocardiogram and, if necessary, a chest radiograph, remain essential in the assessment of working and functional capacity. Today, echocardiography is becoming increasingly important. A correctly conducted exercise test and its interpretation form the basis for an objective assessment of working capacity. PMID- 23088000 TI - [Treatment of severe constipation]. AB - Commonly used therapeutic products in constipation, i.e. fiber supplements and laxatives, are not sufficiently effective for intractable constipation. Biofeedback therapy is utilized in functional obstructed defecation syndrome. Botulin injections into the levator muscle have been described to be beneficial. For some patients, retrograde rectal lavage is sufficient. Slow-transit constipation can also be treated by applying sacral nerve stimulation as well as antegrade lavage through a colonic stoma made into the proximal part of the large intestine. Surgical treatment can be offered for selected patients having a mechanical defecation block. Resection of the bowel is the most common surgical treatment. PMID- 23088001 TI - [Psychoactive drugs and accident risk in road traffic]. AB - In the DRUID (Driving under the influence of drugs, alcohol and medicines) study, the risk of injury and death was calculated for different psychoactive substances on the basis of samples collected from drivers in road traffic and in various accident situations. The number of persons having used alcohol or drugs with negative effects on the ability to drive was lower in Finland than in Europe on the average. Aggravated drunk drivers and mixed substance abusers pose an accident risk that can be several hundredfold higher compared with sober drivers. More attention should be focused on traffic risks due to mixed use of drugs and alcohol. PMID- 23088002 TI - [Endemic cryptosporidiosis--underdiagnosed disease in Finland]. AB - Acute diarrhea caused by Cryptosporidium-protozoan is rarely diagnosed in Finland. The infection is usually self-limited and does not require antimicrobial treatment. Cryptosporidiosis, like other intestinal parasite infections, is mostly associated with travelling, but may also cause large waterborne epidemics. Contact with infected calves may be a source of cryptosporidiosis also in Finland. Cryptosporidiosis should be considered in patients suffering from severe or long-lasting watery diarrhea. We describe three cases of cryptosporidiosis, originating from infected calves. These cases show that verification of the etiology of human cryptosporidiosis associated with calves may be difficult and demands collaboration of clinicians, laboratories and veterinarians. PMID- 23088003 TI - [Treatment of hepatitis C infection: towards eradication of chronic virus]. AB - Hepatitis C virus multiplies efficiently in the body and causes a chronic infection. The current treatment with pegylated interferon and ribavirin is effective only in some patients. The viral genome codes for no more than ten proteins, several of which are, however, proving to be suitable targets for small molecular inhibitors. Two protease inhibitors have been approved for therapeutic use. Preliminary results anticipate good efficiency for the new drugs either combined with previous therapy or by using combinations of the new inhibitors. PMID- 23088004 TI - [Influenza viruses--a challenge for vaccinations]. AB - The clinical picture of influenza may vary from mild respiratory infection to pneumonia requiring intensive care. Annual epidemics are most commonly caused by H3N2 or H1N1 type influenza A or influenza B viruses. The population's immune protection against a new virus type is low, whereupon morbidity and mortality may be high. Vaccinations are the most important means to decrease influenza morbidity. Annual variation and quick intercontinental migration of influenza viruses, combined with the possibility of the creation of reassortant viruses, are significant challenges for the development of influenza vaccines. PMID- 23088005 TI - [Control of arthropods]. AB - In Ralf Pettersson, we have lost an influential and internationally recognized investigator with a significant impact in the field of animal virology. The Bunyaviridae constitute the viral family that he studied the most. These are relatively simple enveloped viruses with a tri-segmented negative-sense single stranded RNA genome. With few exceptions, bunyaviruses are transmitted by arthropod vectors and are introduced into the skin of hosts via bites of infected arthropods. Dermal dendritic cells (DCs) are among the first cells to encounter incoming viruses. In this short review, we will discuss how arthropod-borne viruses exploit DCs to spread throughout the body of the human host. The mechanism depends on interactions with DC-SIGN, a C-type lectin abundantly expressed on DCs. PMID- 23088006 TI - Delay in ordering blood resulted in death & $9 million verdict. University Medical Center, Inc. v. Beglin, 2009SC-000289-DG S.W. 3d (10/27/2011) -KY. PMID- 23088007 TI - Postop nurse told pt. an 'incident' occurred during procedure. Case on point: Smith v. Hines, 2011 OK 51, 107198 P.3d (6/8/2011)-OK. PMID- 23088008 TI - NY: suicidal pt. lept to death during transport: court affirmed nurse & doctor not liable. Dumas v. Adirondack Medical Center, 2011-07769 (11/3/2011)-NY. PMID- 23088009 TI - NY: failure to identify stages of decubitus ulcer: court denied hospital's motion to dismiss suit. Batista v. Residence, 211-32891 NYMISC (10/28/2011)-NY. PMID- 23088010 TI - Nurse awarded over $500,000 in defamation suit. Case on point: Alterra Healthcare Corp. v. Campbell, 2D10-4444 (11/9/2011)-FL. PMID- 23088011 TI - Securing care for women living with HIV: challenges and solutions for HIV positive women. PMID- 23088012 TI - Black women, society, and HIV. PMID- 23088013 TI - Everyone needs a support system. PMID- 23088015 TI - AIDS 2012, Washington, D.C. PMID- 23088014 TI - Nine months to birth day. PMID- 23088016 TI - The mirror has two faces: a personal account of using facial filler for lipoatrophy. PMID- 23088017 TI - [Health at work: harmonization of terminology, laws and practice with international standards]. AB - The terminology, laws and practice of workers' health protection in Russian Federation are considered in the light of harmonization with documents of WHO, ILO, EU as well as good foreign practice. The proposals are put forward as to functions, structure and staff of workers' health protection units taking into account the new problems and risk factors. Instead of notion "labour protection" the term "health and safety at work" is proposed. PMID- 23088018 TI - [The main directions of improving the system of state accounting and control of radioactive substances and radioactive waste products]. AB - This paper describes a modification of the basic directions of state accounting and control of radioactive substances and radioactive waste products, whose implementation will significantly improve the efficiency of its operation at the regional level. Selected areas are designed to improve accounting and control system for the submission of the enterprises established by the reporting forms, the quality of the information contained in them, as well as structures of information and process for collecting, analyzing and data processing concerning radioactive substances and waste products. PMID- 23088019 TI - [Distribution of equivalent equilibrium volume activity of radon in buildings of Moscow and calculating individual exposure doses for population if heterogenic on territory]. AB - Results of survey in living and public buildings on Moscow territory over 2002 2010 demonstrated that equivalent equilibrium volume activity of radon on the city territory matches normal distribution law, thus individual effective doses of internal irradiation by radon, when calculated according to conventional method, are overrated. PMID- 23088020 TI - [Physical and mental development of preschool children in South Municipal County of Moscow, residing near objects with potential radiation jeopardy]. AB - Moscow State Unitary Enterprise--united ecological, scientific and research centre of decontamination of radioactive waste (RAW) and environmental protection SUE SIA "Radon"; Territorial department of the Moscow Administration of the Federal service on customers' rights protection and human well-being surveillance in the South Administrative district of Moscow Study covered physical and mental development of 2733 children aged 4-7 years, residing in South Moscow Municipal County with objects of potential radiation jeopardy. Findings are that residence near that objects causes no negative influences on physical and mental development of the preschoolers. Share of children with lower functional parameters and arrested development was smaller and that of children with weight deficit was higher in the area with objects of potential radiation jeopardy. The differences revealed result from socio-economic conditions in the families and from general educational and physical training programs level at the preschool institutions. PMID- 23088021 TI - [The functional status of respiratory organs assessment in the Mayak PA nuclear workers and quantitative analysis on the basis of the multivariate model]. AB - Effects of ionizing radiation and smoking on the respiratory function (RF) were assessed in nuclear workers of the Mayak Production Association (Mayak PA) using a multivariate threshold model. An insignificant decline in RF was noted with total absorbed lung dose from internal alpha-radiation (D(alpha)) due to incorporated 239Pu, which amounted to 0.15-0.39 Gy, and the smoking index (SI) over 3-9 packs x year. No effect of the prolonged whole-body exposure from external gamma-rays in total dose (D(gamma)) from 0 to 3.8 Gy on RF was found. PMID- 23088022 TI - [Incidence and mortality from acute myocardial infarction in the cohort of Mayak workers]. AB - Incidence and mortality from acute myocardial infarction in the cohort of Mayak workers Southern Urals Biophysics Institute (SUBI), Ozyorsk, Chelyabinsk Region Incidence and mortality from acute myocardial infarction (AMI) was analyzed for nuclear workers at the Mayak PA with regard to non-radiation (gender, age, smoking, hypertension, alcohol consumption, and body mass index) and radiation (total dose from external gamma-rays, 239Pu body burden) factors. The study indicated that incidence and mortality from AMI in the study cohort significantly depended on gender, age, smoking and hypertension, which was consistent with the literature data. Rates of incidence and mortality from AMI were significantly higher for males chronically exposed to external gamma-rays in total dose over 1.0 Gy as shown by the univariate analysis without adjustment for non-radiation factors. PMID- 23088023 TI - [Scrining workers employed at the weapons and military technology recycling and disposal facilitie]. AB - A screening study was performed to identify factors of the raised risk of cardiovascular and bronchopulmonary diseases among workers involved in weapons and military technology recycling and disposal. A high prevalence of risk factors such as smoking, excess body mass, adiposis, disorders of the carbohydrate, lipid and purine metabolism was found for workers aged 35 years and older. Circulatory, musculoskeletal, and eye diseases prevailed in the structure of first diagnosed diseases. Taking into account an unfavorable profile of risk factors, groups with the raised risk of cardiovascular and bronchopulmonary diseases were identified. An expansion of the standard scope of examination in the framework of regular medical monitoring in compliance with the applicable regulatory documents by inclusion of screening studies would provide additional opportunities for the early diagnosing and prevention of the above diseases. PMID- 23088025 TI - [General practice newcomer: should I be insured against redress penalty?]. PMID- 23088024 TI - [A young man with lower left abdominal pain: diverticulitis? Appendicitis? Epiploic appendicitis]. PMID- 23088026 TI - [Family physicians: "Specialists for the entire person" ]. PMID- 23088027 TI - [Maintaining lung function and stress tolerance: reaching these goals in COPD therapy]. PMID- 23088028 TI - [Dangerous sports trends: accidental injuries in children frequently mistreated (interview by Dr. Christine Starostzik)]. PMID- 23088030 TI - [Minor nonspecific symptoms: and still fatally ill]. PMID- 23088029 TI - [From muscle cramp to rhabdomyolysis: what is causing muscle pain?]. PMID- 23088031 TI - [Naturopathy consultation. Gastritis]. PMID- 23088032 TI - [Expensive drugs for private patients: we reconcile these directly with the pharmacy for a long time already]. PMID- 23088033 TI - [Alternative causes of angina pectoris: in dyspnea symptoms consider the lungs first]. PMID- 23088034 TI - [Patients in the family doctor's office are getting older]. PMID- 23088035 TI - [Geriatric assessment in general practice: diagnostic impact and therapeutic consequences]. PMID- 23088036 TI - [Visits in the nursing home--cumbersome or challenging?]. PMID- 23088037 TI - [Decubitus ulcer of the elderly]. PMID- 23088038 TI - [Injuries of the upper ankle joint]. PMID- 23088039 TI - [Clostridium-difficile-colitis: more frequent and more severe]. PMID- 23088041 TI - [Antidiabetic drugs and drug interactions]. PMID- 23088040 TI - [Influence of headers on blood coagulation]. PMID- 23088042 TI - [Therapy of bronchial asthma: MART concept: maintenance and acute therapy with extra fine particles]. PMID- 23088043 TI - [Common colds: early intervention - plant combinations already at the first sign of a respiratory tract infection]. PMID- 23088044 TI - Two epidemics: incarceration and HIV. How the criminal justice system has played a role in the HIV epidemic. PMID- 23088045 TI - Money well spent. Opt-out testing in prisons can catch STD cases--and save taxpayers money in the long run. PMID- 23088046 TI - Positive progress. Improvements in HIV testing, treatment, and continuity of care. PMID- 23088047 TI - Female trouble. Studies look at the factors that lead women to HIV and incarceration. PMID- 23088048 TI - Disconnected. Incarceration cuts you off from your social network--and HIV thrives on that. PMID- 23088049 TI - Prosecuting HIV: take the test--and risk arrest? PMID- 23088050 TI - Charles Weis negotiating a unique partnership to improve care. PMID- 23088051 TI - Standards, please. PMID- 23088052 TI - 5 ways to prevent medication errors. PMID- 23088053 TI - Computer-assisted coding and clinical documentation: first things first. AB - Computer-assisted coding tools have the potential to drive improvements in seven areas: Transparency of coding. Productivity (generally by 20 to 25 percent for inpatient claims). Accuracy (by improving specificity of documentation). Cost containment (by reducing overtime expenses, audit fees, and denials). Compliance. Efficiency. Consistency. PMID- 23088054 TI - The cost of quality: how VBP scores correlate with hospital costs. AB - A study sought to correlate projected total performance scores (TPSs) for hospitals under the Medicare value-based purchasing (VBP) program with routine costs as reported by each hospital for the corresponding measurement periods. The study focused on routine service costs and common departmental costs because they are generally shared among all hospitals. The study's findings suggest that these costs tend to be higher among hospitals that achieve higher levels of quality as measured by VBP scores. PMID- 23088055 TI - New partnership opportunities for payers and providers. AB - Healthcare finance executives should consider several key factors when forming partnerships with physicians and insurers: Market expansion opportunities. Resources. Risk sharing. Capturing created value. Market response. PMID- 23088056 TI - Implementing clinical and financial collaboration between payers and providers. AB - An IPA learned three important lessons while implementing a clinical and financial collaboration with its payers: Eliminate mixed messages. Focus on delivery and operational changes, not just payment change. Set realistic expectations and deliver on them. PMID- 23088058 TI - Pharmacy revenue cycle audits can bring unexpected returns. AB - An end-to-end pharmacy revenue cycle analysis, led by a multidisciplinary team with broad expertise, can enable a hospital to identify unsuspected errors and oversights that could be causing the organization to lose millions of dollars in revenue annually that it is entitled to receive. If the analysis finds that considerable revenue is being lost, the next step for the team should be to develop a remediation plan to identify the exact cause of each issue and correct it. Following completion of the initial analysis, the hospital should assign permanent accountability and ownership to the team to ensuring the ongoing integrity and accuracy of the pharmacy revenue cycle. PMID- 23088057 TI - Changing the game: what CFOs should know about physician compensation. AB - Healthcare CFOs should ask three critical questions in determining the right approach to physician compensation: How will market characteristics influence physician compensation? To what extent should base salaries and incentives be used to compensate physicians? How should the organization's physician compensation package be structured? PMID- 23088059 TI - People and change management in an uncertain environment. AB - Change management for healthcare organizations should be rooted in the following practices: Articulating a business case and vision for change. Assessing organizational risk and readiness. Mobilizing and aligning leaders. Building awareness of and commitment to the change effort. Aligning the organization. Tracking performance improvement and benefit realization. PMID- 23088060 TI - Commercially reasonable--whose responsibility is it? AB - According to federal regulations, any business arrangement between a hospital and a physician or physicians must comply with a set standard establishing that the arrangement is commercially reasonable. The commercially reasonable standard can be briefly defined as the requirement that the arrangement make business sense without being contingent on physician referrals. Before engaging outside expertise to assist in making the determination that an arrangement is commercially reasonable, hospital executives can address many key questions with respect to this determination themselves using a checklist of key operational, clinical, and financial considerations. PMID- 23088061 TI - Is your clinical documentation improvement program compliant? AB - Hospitals and health systems should consider four strategies for improving documentation: Develop a short list of the most commonly underdocumented or incorrectly documented clinical conditions at the facility. Develop definitions for each of the conditions on this list. Ask the medical director of each specialty area to educate the clinicians in their group on these definitions. Measure and manage documentation performance. PMID- 23088062 TI - Creating a stand-alone fundraising foundation. AB - When considering a stand-alone fundraising foundation, healthcare organizations should: Review the costs and benefits of starting a separate stand-alone foundation. Perform a competitive analysis to see which hospitals use them. Work with a team of legal, development, and investment advisory experts who can help map out a plan. Review governance requirements. Develop an investment policy statement. PMID- 23088063 TI - How business intelligence can improve value. AB - Case studies of three healthcare organizations reinforce the premise that business intelligence--the ability to convert data into actionable information for decision making--is critical to demonstrating improved value. PMID- 23088064 TI - Driving value: solving the issue of data overload with an executive dashboard. AB - Many health systems suffer from having too little data to identify significant quality improvement opportunities, while others suffer from the confusion of having too much. PMID- 23088065 TI - What would you do? Is independence the right strategy? PMID- 23088066 TI - Considering the risks and rewards of payment reform. PMID- 23088067 TI - Nonresponse in the National Survey of Children's Health, 2007. AB - OBJECTIVES: For random-digit-dial telephone surveys, the increasing difficulty in contacting eligible households and obtaining their cooperation raises concerns about the potential for nonresponse bias. This report presents an analysis of nonresponse bias in the 2007 National Survey of Children's Health, a module of the State and Local Area Integrated Telephone Survey conducted by the Centers for Disease Control and Prevention's National Center for Health Statistics. METHODS: An attempt was made to measure bias in six key survey estimates using four different approaches: comparison of response rates for subgroups, use of sampling frame data, study of variation within the existing survey, and comparison of survey estimates with similar estimates from another source. RESULTS: Even when nonresponse-adjusted survey weights were used, the interviewed population was more likely to live in areas associated with higher levels of home ownership, lower home values, and greater proportions of non-Hispanic white persons when compared with the nonresponding population. Bias was found (although none greater than 3%) in national estimates of the proportion of children in excellent or very good health, those with consistent health insurance coverage, and those with a medical home. However, the level and direction of the bias depended on the approach used to measure it. There was no evidence of significant bias in the proportion of children with preventive medical care visits, those with families who ate daily meals together, or those living in safe neighborhoods. PMID- 23088068 TI - [Modified Misgav-Labach at a tertiary hospital]. AB - BACKGROUND: According to several studies from around the globe, the modified Misgav Ladach technique simplifies the surgical procedure for cesarean section, reduces operation time, costs, and complications, and optimizes obstetric and perinatal outcomes. OBJECTIVE: Compare obstetric outcomes between patients operated on using traditional cesarean section technique and those operated on using modified Misgav Ladach technique. PATIENTS AND METHODS: The study included 49 patients operated on using traditional cesarean section technique and 47 patients operated on using modified Misgav Ladach technique to compare the outcomes in both surgical techniques. RESULTS: The modified Misgav Ladach technique was associated with more benefits than those of the traditional technique: less surgical bleeding, less operation time, less analgesic total doses, less rescue analgesic doses and less need of more than one analgesic drug. CONCLUSION: The modified Misgav Ladach surgical technique was associated with better obstetric results than those of the traditional surgical technique; this concurs with the results reported by other national and international studies. PMID- 23088069 TI - [Assisted hatching following embryo implantation failure]. AB - BACKGROUND: Assisted hatching in reproduction techniques has improved the successful implantation rates in certain groups of patients with poor prognosis. This study focuses on its effect in groups of patients with previous implantation failure and according to age groups. OBJECTIVE: Compare the pregnancy rates of patients who turned to this technique following an implantation failure using in vitro fertilization with those of patients who did not use assisted hatching before another attempt of in vitro fertilization and according to specific age groups. MATERIAL AND METHOD: Cases of patients using assisted hatching in our Center between January 2008 and December 2009 were studied. The results were compared in terms of age in three groups: group I, >35 years; group II, 35-39 years, and group III, > 40 years. RESULTS: Patients in group II had better pregnancy rate (30%) than those in groups I and III (16.98 and 20.83%, respectively). When comparing the results of the group of patients using assisted hatching with those of the group that did not, the first reported a 20% pregnancy rate versus no pregnancy in the other group. PMID- 23088070 TI - [Conservative management of cervical ectopic pregnancy]. AB - BACKGROUND: Cervical ectopic pregnancy is a rare type of ectopic pregnancy (less than one percent of all ectopic pregnancies). OBJECTIVE: Assess the efficacy of the treatment options available. MATERIAL AND METHODS: Retrospective study of the cervical ectopic pregnancies treated in our hospital from January 2005 to December 2011. RESULTS: Three patients were diagnosed cervical ectopic pregnancy in our hospital during that period, that is, an incidence of 1.7 per 10,000 gestations. The main symptom was a moderate-to-severe genital hemorrhage. In two of the cases a single dose of 50 mg/cm2 methotrexate was administered, and in the third one, curettage and uterine arterial embolization were performed. Histerectomy was not necessary in either of the cases. CONCLUSION: Conservative management of cervical ectopic pregnancy is an effective and safe option. PMID- 23088071 TI - [Clinical implications for fertility and pregnancy in Turner syndrome]. AB - Turner syndrome patients have high risk of severe obstetrical complications and even of death during pregnancy. A medical team including cardiologists, genetists and maternal-fetal medicine specialists should perform a preconception and prenatal assessment in case pregnancy is contemplated. The main clinical implications for fertility and pregnancy in Turner Syndrome are reviewed and recommendations for management and follow-up of these patients are given. PMID- 23088072 TI - [Cotyledonoid dissecting leiomyoma of the uterus. A malignant-looking benign tumor]. AB - The cotyledonoid dissecting leiomyoma of the uterus, or Stenberg tumor, is a rare variant of a smooth muscle benign tumor, classified in the group presenting an unusual growth pattern; clinically, it affects women in reproductive age. We report the case of a 43 year-old woman, who turned up at the Centro Estatal de Atencion Oncologica (State Cancer Care Center) in Morelia, Michoacan, presenting abnormal uterine bleeding and uterine fibroid of major elements. When performing a palpatory bimanual exam, a loose uterus of approximately 7 by 6 inches was identified; it ached when moving. The laboratory tests reported normal parametriums; the ultrasound showed, however, uterine fibroids of major elements. The uterus was enlarged due to a tumor of exophytic growth, which resembles placental cotyledons extended over the uterine surface, composed by smooth muscle nodules that dissected the uterine wall, and with infiltrative appearance in parametriums and the myometrial wall. Despite this microscopic aggressive appearance, a number of ultrastructuctural studies and immunohistochemical techniques proved its benign nature. This can help patients who want to preserve fertility avoid radical surgery. PMID- 23088073 TI - [Differential diagnosis of Dandy-Walker syndrome different presentations]. AB - OBJECTIVE: Dandy-Walker syndrome is a set of abnormalities of the posterior fossa including three modalities: classic Dandy-Walker malformation, Dandy-Walker variant and mega-cisterna magna. Our objective is clarify the differential diagnosis among these entities. MATERIAL AND METHOD: Descriptive and retrospective study of Dandy-Walker cases diagnosed at our Department during the last five years plus a review of the related Medical literature. RESULTS: Three cases of Dandy-Walker modalities are reported: one case of classic Dandy-Walker malformation, one case of Dandy-Walker variant, and one case of false Dandy Walker. In the first two cases the patients underwent legal abortion, whereas in the last one a healthy male newborn was delivered in the week 38 of gestation. CONCLUSIONS: Malformations in the posterior fossa, including Dandy-Walker syndrome, are still a challenge in prenatal diagnosis. Technical developments in imaging, such as in three-dimensional sonography and magnetic resonance, allow higher resolution and multiplanar images for an easier diagnose. There is a high rate of false positive, particularly before the 18th week of gestation. It is advisable not to establish a final diagnose before that week. PMID- 23088074 TI - [Diagnosis of molar pregnancy by hysteroscopy]. AB - BACKGROUND: Gestational trophoblastic disease has a high incidence worldwide. Proper pre-evacuation diagnosis must be performed due to the risk of malignant complications associated with hydatidiform moles. Diagnosis of early molar pregnancies might be elusive due to atypical clinical manifestations and inconclusive ultrasonographic findings. OBJECTIVE: Report on the efficiency and precision by hysteroscopy for the diagnosis of molar pregnancy in one particular case. CLINICAL CASE: Thirty-year old woman, 5.6-week pregnant, suffering from pelvic pain, uterine bleeding and high concentrations of human chorionic gonadotropin beta fraction (beta-hCG). Ultrasonography suggested inconclusively either a hematoma or a gestational sac so that further evaluation by hysteroscopy had to be performed in order to reach a proper diagnosis. RESULTS: Hysteroscopic evaluation provided conclusive diagnostic images of hydropic degeneration of the chorionic villi. Histopathological evaluation confirmed a molar pregnancy. The mole was removed by uterine curettage and beta-hCG tests followed. CONCLUSIONS: Hysteroscopy is a useful tool for diagnostic protocol in case of early atypical molar pregnancy. PMID- 23088075 TI - [Urinary ascites following open myomectomy]. AB - OBJECTIVE: A case of urinary ascites following a bladder injury during laparoscopic myomectomy, and its resolution. CLINICAL CASE: 42-year-old woman referred for urologic consultation for acute urinary retention 11 days after myomectomy. RESULTS: Ultrasound showed abdominal ascites. Cystoscopy gave evidence of one-centimeter bladder dome injury. During retrograde cystography contrast material leaked out through the bladder. CONCLUSION: Early treatment with drainage of urinary ascites and bladder injury surgical repair had excellent results. PMID- 23088076 TI - [Handling of climateric syndrome. 1957]. PMID- 23088077 TI - [Estimating the incidence of induced abortion. Response to the criticism to the methodology used by the Guttmacher Institute]. PMID- 23088078 TI - [Altered mental status in intensive care unit patients]. AB - Altered mental status is one of the most common disorders encountered by doctors in intensive care units and one of the most recognizable signs of serious illness. It can be caused by an organic, functional (psychiatric), or mixed disorder. There are two components of altered mental status, i.e. the level of consciousness and the contents of consciousness. The level of consciousness can be easily assessed by simple observation of the patient during routine history and physical examination, while the contents of consciousness can be measured by multiple assessment tools usable by non-psychiatrists. Because it is a complex condition with multiple symptoms, the main task of intensive care unit physicians is to identify patients at risk and to introduce appropriate treatments immediately. Early recognition and timely treatment can result in recovery, while late treatment may be associated with irreversible disorder. In this article, we give a brief overview of the issues related to altered mental status of intensive care unit patients. PMID- 23088079 TI - [Word recognition test after general anesthesia: the influence of previous anesthesia]. AB - Among other higher brain functions such as consciousness and learning, general anesthesia also affects memory. A number of information retrieval tests are performed to determine the effects of drugs on explicit memory. In this study, we investigated the recognition of words before and after general anesthesia in subjects having and not having received anesthesia on one or more occasions before the present one. The study included 51 patients, ASA physical status I or II, median age 50, at least high-school graduates, without head trauma, known psychiatric or memory disorder, and taking no psychoactive medication. A standardized anesthesia technique, a single surgical procedure and a defined study-test interval were used. We designed our own test as a combination of story recall test and brief word learning test, both widely used in psychological and psychiatric examination. There was no significant difference in word recognition before and after general anesthesia in either patient group. Many studies indicate that anesthesia and surgery are associated with cognitive impairment lasting for 33 months in 10%-14% of elderly patients. We hypothesized that general anesthetics can cause prolonged cognitive alterations. Study results showed that previous anesthesia in addition to the current one had no significant influence on the word recognition test. PMID- 23088080 TI - [Medicolegal dilemmas on restraint use in delirious patients in intensive care unit]. AB - The use of physical or chemical restraint in delirious patients in the intensive care unit (ICU) is related to an array of ethical and medicolegal dilemmas. In most cases, they arise from insufficient knowledge of the regulations in force or due to their vague wording. The aim of this review article is to outline the basic views of the medical profession regarding restraint use as a method in the treatment of delirium and to give an insight into the existing legislation at the national and international level. According to the contemporary research, restraint of patients in delirium, whether it is physical restraint or application of psychoactive drugs, has a number of potentially harmful side effects and must be used with clear indications, under strict supervision, and with meticulously kept medical records. A delirious patient must be treated in accordance with medical ethics, international conventions and the laws and regulations related to patient rights. This includes the general principles of respecting the patient's autonomy and dignity, giving him or her timely information, notification of informed consent, as well as abiding by the rules of the profession integrated in every hospital written instructions on the treatment of a patient in delirium. A detailed medicolegal frame of restraint use in delirious patients is given by the Croatian Hospital Accreditation Rules, which is currently the highest existing standard for restraint use in delirious patients in ICU, as well as in the other hospital departments. PMID- 23088081 TI - [Wernicke's encephalopathy as a complication of bariatric surgery]. AB - Wernicke's encephalopathy is an acute, serious brain disorder resulting from thiamine deficiency, which is important as a cofactor in several enzymes associated with carbohydrate metabolism. The encephalopathy is most often associated with severe alcohol abuse, but thiamine deficiency can be caused by many other medical conditions. Bariatric surgery is listed among the causes of Wernicke's encephalopathy. This review provides a brief overview of the risk factors that cause thiamine deficiency, along with clinical features, diagnostic and therapeutic procedures important for timely recognition, therapy and prophylaxis of Wernicke's encephalopathy that occurs as a complication of bariatric surgery. PMID- 23088082 TI - [Postoperative delirium after regional anesthesia]. AB - Postoperative delirium or acute confusional state is common after major surgery. The objective of this article is to provide an overview of the current knowledge of the risk factors and the importance of anesthetic technique in postoperative delirium. The risk factors for postoperative delirium include patient characteristics such as advanced age, poor preoperative functional state, depression, and abnormal serum levels of sodium, potassium, glucose and albumin. The type of surgery is also important, so delirium is common after high operative stress procedures. Perioperative risk factors also include blood loss, postoperative hematocrit, hypotension and hypoxemia, pain and polypharmacy. Anesthetic technique is a potentially modifiable risk factor. Although administration of many drugs can be avoided or limited with regional anesthetic techniques and reduction in the prevalence of postoperative delirium has been analyzed in many studies, the results are inconsistent. Literature data were analyzed to determine whether type of anesthesia determines the incidence of postoperative delirium. According to PubMed, there are several studies comparing postoperative delirium after regional or general anesthesia. Many of these studies showed a trend toward increased postoperative delirium with general anesthesia, but the difference was not significant. On interpreting these results, it should be taken in consideration that many of these studies were retrospective and nonrandomized with a small number of participants, so further large, multicenter, randomized trials are needed to make any firm conclusion on the influence of anesthetic technique on postoperative delirium. Although the pathophysiology of delirium is not fully understood, it appears that multiple metabolic and neurochemical insults disrupt neuronal functioning in susceptible patients. Prevention and optimal treatment consist of minimizing or correcting these metabolic and other insults. Early detection of coexisting postoperative medical problems, pain, infections, or other complications is crucial. Regional anesthetic techniques have many potential advantages such as reduced stress response and good postoperative analgesia, but further investigations are needed to confirm these observations. PMID- 23088083 TI - [Paraneoplastic limbic encephalitis]. AB - Paraneoplastic limbic encephalitis (PLE) is a condition characterized by nervous system damage or dysfunction without indication that the nervous system is directly affected by tumor cells. Since it is clinically presented with an array of neuropsychiatric symptoms that usually precede the occurrence of malignant disease, and because of mimicking a psychiatric disease, it can sometimes make the diagnosis difficult and can be overlooked. Typical presentations consist of progressive confusion and deficits in short-term memory, which worsen over days to weeks. The current hypothesis on the pathogenesis of PLE implicates an autoimmune process involving antigens shared by tumor cells and neuronal cells in limbic structures. It has been considered that the autoantibodies cross-react with antigens on normal cells such as the neurons, resulting in cytotoxicity, or they can form complexes with a circulating antigen to induce organ damage through immune complex deposition. The treatment of PLE involves underlying cancer removal by surgery, chemotherapy, radiotherapy or hormonal treatment, and immunosuppressive therapy. Unfortunately, this therapy combination is still generally unsatisfactory. Although PLE is a relatively rare neurologic disorder, because of its association with malignancies and difficulty in diagnosing, this article gives a brief review of the literature and summarizes current knowledge of this syndrome. PMID- 23088084 TI - [Delirium assessment scoring scales]. AB - Delirium is a significant psychiatric disorder in intensive care units that has negative impact on morbidity and mortality of intensive care patients. Subjective clinical assessment of patients by non-psychiatric health professionals in intensive care units is not sufficient for detection and measurement of delirium. Therefore, different scoring scales for delirium assessment have been developed. This paper reviews the characteristics of commonly used scoring scales for assessment of delirium in intensive care units: the Confusion Assessment Method Intensive Care Unit (CAM-ICU), the Intensive Care Delirium Screening Checklist (ICD-SC), the Nursing Delirium Screening Scale (Nu-DESC) and the Detecting Delirium Scale (DDS). Routine implementation of objective scoring scales is not widespread. Evidence suggests that objective assessment of delirium contributes to its early detection in intensive care and initiation of appropriate treatment. It is therefore advisable to make additional educational effort to provide an objective scoring scale for the assessment of delirium, such as CAM-ICU, to be routinely used in intensive care units. PMID- 23088085 TI - [Pain, delirium and sedation in intensive unit care]. AB - Delirium is a complication of intensive care treatment associated with permanent cognitive decline and increased mortality after hospital discharge. In several studies, postoperative pain was found as a possible precipitating factor. Aggressive pain treatment is part of current multicompartment protocols for delirium prevention after hip fracture. Protocol based sedation, pain and delirium management in intensive care units have been shown to have clinical and economic advantages. PMID- 23088086 TI - [Delirium incidence in pediatric intensive care unit]. AB - Delirium is a serious neuropsychiatric disorder and pediatric delirium (PD) is a similarly serious condition. PD is understudied and very often misdiagnosed, especially in pediatric intensive care units (PICU). It is important to early diagnose PD, so that early psychosocial interventions and therapy can be introduced. Valid diagnostic instruments are needed at PICU to assess PD. There are many scales and tests to diagnose delirium but none of them is specific enough to diagnose PD. Although PD is a serious complication at PICU, clinical guidelines for PD are still lacking, therefore additional investigations are needed to bring them out. PMID- 23088087 TI - [Prevention and treatment of intensive care unit delirium]. AB - Delirium is a common problem in intensive care patients, frequently underdiagnosed and resulting in prolonged hospital stay and a high risk of morbidity and mortality. On the other hand, reversibility of the condition points to the importance of prevention, early diagnosis and immediate therapy. Management strategy is directed to nonpharmacological interventions as preventive measures and pharmacological treatment, which includes typical and atypical neuroleptics. Delirium management includes haloperidol as the first line medication, but also olanzapine and risperidone as atypical neuroleptics. Benzodiazepines are used in delirium caused by alcohol withdrawal. PMID- 23088088 TI - [Does the anesthesiologist sleep soundly?]. AB - Working in night shifts influences human health, mood, and cognitive functions. Anesthesia residents and consultants work in long shifts that include the night. Changes of cognitive functions may diminish the quality of anesthesiologist's work, increase the number of errors, and endanger the patient. Changes of biological rhythms can influence health of the anesthesiologist himself. The alterations in circulation, metabolism, memory, fine motor control, mood and attention have been recorded. After night work, the possibility of car accident for an anesthesiologist is higher. Attempts have been made to reduce negative influences of night work by shortening the number of working hours during the week. The debate about this step is vivid and still present. From this viewpoint, the most interesting aspects are the quality of educational process, the number of errors in practical work, and the quality of health care. After shortening of working hours, there are no clear indicators of the positive effects in any of these fields. Shortening of the working week is part of 'the culture of safety' in anesthesiology. PMID- 23088089 TI - [Pathophysiology of delirium]. AB - Today's understanding of the pathophysiological mechanisms of delirium is still limited, but there are several promising hypotheses. It is believed that biomarkers sensitive to death of neurons or glial cells indicate delirium. Several neurotransmitters are considered to be involved in the state of delirium, with greatest emphasis on acetylcholine and dopamine acting in opposite ways; acetylcholine reduces, while dopamine increases neuron excitability. Other neurotransmitters that probably play a role in the pathogenesis of delirium are GABA, glutamate and monoamines. Sepsis leading to systemic inflammatory response syndrome often presents with delirium and perhaps is the most common causal factor for delirium in intensive care unit; sedatives and analgesics are also common iatrogenic risk factors. Patients receiving benzodiazepines are more likely to have postoperative delirium than those who do not. Postoperative cognitive changes are more common in older than in younger patients, and they can be categorized as postoperative delirium, postoperative cognitive dysfunction and dementia. The mechanisms responsible for postoperative cognitive changes are not fully understood, but it is certain that they are multifactorial. Risk factors may be associated with patient characteristics, type of surgery and type of anesthesia. PMID- 23088090 TI - [Postoperative mental disorders in cardiovascular surgery]. AB - Postoperative mental disorders are a common complication of cardiovascular surgery, with serious consequences. The main types of postoperative mental disorders include postoperative delirium and postoperative cognitive dysfunction. Their incidence ranges up to 15%-80%. Postoperative mental disorders may be reversible and irreversible. Although reversible in most cases, postoperative mental disorders are associated with increased mortality, morbidity and increasing costs of treatment. The treatment is usually symptomatic and may be associated with dangerous side effects. Safer and more effective is preventive action. Preoperative preventive action need to recognize, avoid and optimize risk factors. Intraoperative prevention involves maintaining optimal oxygenation of the brain during cardiovascular surgery. For postoperative prevention, multimodal approach is applied. It includes early extubation, early enteral nutrition, early mobilization, regular evaluation of cognitive function, activation of cognitive function and optimal analgesia, which requires teamwork of medical staff who care for patients. Combining all these methods can show promising results in reducing the incidence of postoperative mental disorders as a complication in cardiovascular surgery. PMID- 23088091 TI - [Perioperative disorders of mental functions]. AB - Mental disorders are characterized by disturbances of thought, perception, affect and behavior, which occur as a result of brain damage. Recognizing and treating these conditions is necessary not only for psychiatrists but for all physicians. Disorder of mental function is one of the most common associated conditions in intensive care unit (ICU) patients. However, disturbances of mental function often remain unrecognized. In ICU patients, different types of mental function disorders may develop. They range from sleep disorders, severe depression, anxiety, posttraumatic stress disorder (PTSD) to cognitive disorders including delirium. The causes of mental dysfunction in ICU patients can be divided into environmental and medical. Cognitive disorders are related to mental processes such as learning ability, memory, perception and problem solving. Cognitive disorders are usually not prominent in the early postoperative period and in many cases are discovered after hospital discharge because of difficulties in performing everyday activities at home or at work. The etiology of postoperative cognitive impairment is unclear. Older age, previous presence of cognitive dysfunction, severity of disease, and polypharmacy with more than four drugs are some of the risk factors identified. Delirium is a multifactorial disorder. It is an acute confusional state characterized by alteration of consciousness with reduced ability to focus, sustain, or shift attention. It is considered as the most common form of mental distress in ICU patients. Nearly 30% of all hospitalized patients pass through deliriant phase during their hospital stay. Delirium can last for several days to several weeks. Almost always it ends with complete withdrawal of psychopathological symptoms. Sometimes it can evolve into a chronic brain syndrome (dementia). The causes are often multifactorial and require a number of measures to ease the symptoms. Delirious patient is at risk of complications of immobility and confusion, leading to a high prevalence of irreversible functional decline. An interdisciplinary approach to delirium should also include family or other caregivers. In the diagnosis of delirium, several tests are used to complement clinical assessment. Among the most commonly used are the Confusion Assessment Method (CAM-ICU) and Clinical Dementia Rating (CDR) test. Depression is a common disorder among patients treated at ICU and occurs due to the impact of the disease on the body and the quality of life, independence, employment and other aspects of life. Depression can interfere with the speed of recovery, affects the postoperative quality of life, and in a certain number of patients may lead to suicidal thoughts and intentions. Phobias and generalized anxiety are the most common anxiety disorders. Generalized anxiety disorder is characterized by strong, excessive anxiety and worry about everyday life events. PTSD is delayed and/or protracted response to a stressful event or situation, extremely threatening or catastrophic nature, which is outside the common experience of people and would hit or traumatize almost all people. Treatment of delirium and other disorders is causal. The causes of psychosis are often multifactorial and require a number of measures to ease symptoms. The primary objective of prevention is appropriate therapy and correction of potential imbalances possibly underlying disturbances, stabilization of vital functions as well as early return to daily activities. Doctors and other medical staff must be aware of the importance and consequences of behavioral and emotional disorders in critically ill patients. Additional research is needed to discover the ways to prevent and/ or reduce the frequency and severity of the consequences and treatment of cognitive and emotional disorders. PMID- 23088092 TI - [Neurological disorders in pregnancy]. AB - Preeclampsia is characterized by hypertension, peripheral edema and proteinuria, but very often also includes neurologic complications. Neurologic complications of severe preeclampsia are indentical to those of hypertensive encephalopathy. The most common neurologic symptoms are headache, vomiting, mental disorders, visual disturbances, sensorimotor deficits and seizures. Endothelial cell dysfunction is the main cause of multiorgan failure. It is of utmost importance to recognize these symptoms and initiate apropriate therapy. Systemic blood presure must not exceed the cerebrovascular autoregulatory capacity. Serum magnesium level is significantly decreased in pregnant women with severe preeclampsia and cerebral edema. Magnesium has been shown to be effective in reducing the occurrence of seizures in preeclampsia by decreasing neuronal excitability, protecting the endothelium against free radicals and reducing cerebral perfusion. PMID- 23088093 TI - [Septic encephalopathy]. AB - Septic encephalopathy is the most common form of encephalopathy in intensive care units (ICU) and its severity correlates with mortality. Septic encephalopathy is induced by the systemic inflammatory response regardless of its cause. This inflammation damages blood brain barrier and allows circulating neurotoxic substances to extravasate into the brain parenchyma and provoke an inflammatory response. The severity of septic encephalopathy can be assessed with electroencephalography and Glasgow Coma Scale score. Treatment should be focused on early and appropriate antibiotic administration. Supportive treatment measures commonly used in other ICU patients are of limited value in this indication. PMID- 23088094 TI - Elaboration of natural polyfunctional preparations with antiparasitic and biostimulating properties for plant growing. AB - Producer of macrolide antibiotic avermectin Streptomyces avermitilis UCM Ac-2179 has been isolated from Ukrainian chernozem soil, its biosynthetic activity has been increased by the traditional selection and chemical mutagenesis methods. Streptomyces avermitilis UCM Ac-2179 synthesizes avermectin with the content of anti-parasitic B-components more than 40%. Addition of exogenous Na-pyruvate (1.5 mg/L) in cultural medium promotes a 2.5-fold augmentation of the avermectin synthesis. The preparation Avercom has been obtained by the method of ethanol extraction from the producer biomass. This preparation includes antibiotic avermectin and other biologically active substances: free amino acids, lipids, phytohormones. Avercom has high nematicidic activity and raises plant resistance to fungal and viral diseases. On the base of Avercom and plant growth regulators the complex preparations Actinolan and Ascoldia have been elaborated. The effectiveness of the biopreparations as nematicidic and plantstimulating means under experimental and industrial conditions was confirmed. PMID- 23088095 TI - [Temperature range for growth of the Antarctic microorganisms]. AB - The assessment of a temperature range for growth of microorganisms isolated at various temperatures (1-5 degrees C or 30 degrees C) from biotopes of the Antarctic region (soil, grass Deschampcia antarctica, grass Colobanthus, a green moss, crustose black lichens and encrustation biofilm on vertical rocks) is made. From 40 to 70% of the investigated Antarctic microorganisms, irrespective of temperature conditions of their isolation, were capable of growing in a wide temperature range (from 1 degrees C to 30 degrees C), i.e. they are psychrotolerant. In selective conditions (1 degrees C or 5 degrees C) the psychrophilic Antarctic bacteria and yeast are isolated which grew in the range from 1 degrees C to 20 degrees C and did not grow at 30 degrees C. At the same time, among the Antarctic microorganisms isolated in nonselective conditions (at 30 degrees C), almost 50% are capable of growing at the lowest temperature (5 degrees C), and a smaller number of strains--at 1 degrees C. However with a decrease of cultivation temperature the growth lag-phase of the Antarctic bacteria increased. Thus the level of the final biomass of the investigated strains did not depend on cultivation temperature. When comparing the temperature range of growth of the mesophilic Antarctic bacteria and collection strains of the same species isolated more than 10 years ago from the region with a temperate climate, the psychrotolerant forms were also revealed among the latter. So, it is shown that the investigated Antarctic bacteria can exist in the temperature range characteristic of terrestrial biotopes of the Antarctic Region (from 1 degrees C to 10 degrees C). PMID- 23088096 TI - [Investigation of functional groups of Cryptococcus albidus alpha-L rhamnosidase]. AB - The effect of cations, anions and specific chemical reagents: 1-[3 (dimethylamino)propyl]-3-ethylcarbodimide methiodide, EDTA, o-phenantroline, dithiotreitol, L-cysteine, beta-mercaptoethanol, p-chlormercurybenzoate (p-ChMB), N-ethylmaleimide on the alpha-L-rhamnosidase activity of Cryptococcus albidus has been investigated. The essential role of Ag+ which inhibits the alpha-L rhamnosidase activity by 72.5% was shown. Rhamnose at 1-5 mM protect the enzyme from the negative effect of Ag(+). It was expected that carboxyl group of C terminal aminoacid and imidazole group of histidine would participate in the catalytic action of alpha-L-rhamnosidase on the basis of inhibition and kinetic analysis. PMID- 23088097 TI - [Glycerol metabolism in surfactants producers Acinetobacter calcaaceticus IMV B 7241 and Rhodococcus erythropolis IMV Ac-5017]. AB - Key enzymes of glycerol metabolism were detected in the cells of surfactants producers Rhodococcus erythropolis IMV Ac-5017 and Acinetobacter calcaaceticus IMV B-7241 grown on glycerol. It has been established that in the both strains glycerol catabolism to dihydroxyacetonephosphate (the intermediate of glycolysis) may be performed in two ways: through glycerol-3-phosphate (glycerol kinase activity 740-840 nmol min(-1) mg(-1) of protein) and through dihydroxyacetone. Glycerol oxidation to dihydroxyacetone in the strains IMV B-7241 and Ac-5017 is catalised by pyrrholo-quinolinquinone-dependent glycerol dehydrogenases and nitroso-N,N-dimethylaniline-dependent alcohol dehydrogenases. Both glyoxylate cycle and phosphoenol pyruvate(PEP)-carboxylase function as anaplerotic paths in R. erythropolis IMV Ac-5017, and only PEP-carboxylase reaction (1045 +/- 52 nmol min(-1) mg(-1) of proteins) functions in A. calcoaceticus IMV B-7241. The data obtained serve as the basis for theoretical calculations of optimal molar ratio of concentrations of energetically nonequivalent substrates for intensifying the surfactants synthesis on their mixture. PMID- 23088099 TI - [Bacteriocidal activity of Streptomyces cultures]. AB - Bacteriocidal activity of metabolites synthesized by 17 plasmid-containing cultures of Streptomyces has been studied. These cultures were isolated from soils of Ukraine with different anthropogenic contamination. The cultures, in their majority (85.3%), synthesized bioactive metabolites, which suppressed growth of microorganisms of different taxonomical groups, pathogenic for people, animals or plants. None of 17 Streptomyces cultures was able to suppress growth of yeasts or Escherichia coli. All 17 investigated cultures of Streptomyces were polyresistant to antibiotics, which were used in medicine and veterinary: makrolide, aminoglycoside, beta-lactam and other groups. Resistance of 8 cultures to the antibiotic thiostrepton, which was widely used in some branches of science, was found. PMID- 23088098 TI - [Basal bacteriosis of wheat and influence of agrotechnical methods on its spread]. AB - Monitoring of bacterial diseases of wheat was conducted allowing for different doses of mineral fertilizers and crops predecessors. It is shown that symptoms of development of the basic disease of wheat, which is caused by Pseudomonas syringae pv. atrofaciens, varied depending on agrotechnical methods, stages of plant growth and environmental factors. Introduction of different doses of nitrogen, phosphate and potassium fertilizers, especially high ones, increases the damage of wheat by the agent of basal bacteriosis P. syringae pv. atrofaciens. Strains of this pathogen, isolated from the infected wheat plants, affect in the experiment such weeds as sow thistle, field horsetail, and couch grass. PMID- 23088100 TI - [Biological activity of Penicillium sp. 10-51 exometabolites]. AB - Silica gel column chromatography (silica gel "L" II kind of activity 100/160 mkm) of the chloroform extract from the cultural filtrate of Penicillium sp. 10-51 gave two fractions (chloroform and chloroform-acetone, 5:1) having biological activity. Recrystallization yielded two compounds. On the basis of physico chemical and spectral data these compounds were identified as curvularin and hydroxycurvularin, which have a large spectrum of biological action as to bacteria, yeast, blue-green algae and phytopathogenic micromycetes. PMID- 23088101 TI - [Microbiocenosis of intestine and nutrition of healthy and osteoporotic aged women]. AB - The composition of microflora of the distal part of intestine of 25 healthy and osteoporotic women-patients aged 50-79 years, depending on their diet, has been studied. The quantitative composition of intestinal microflora of women with osteoporosis, indicates the presence of dysbiosis caused by the decrease in the content of bifidobacteria and lactobacilli and a high level of undesirable microorganisms. The content of 78 nutrients in the diet of the examined women was analyzed. It was shown that the diet of patients with osteoporosis was more calorie rich and included a higher amount of essential nutrients than the diet of healthy women. The indicators of bone mineral density, depending on the number of representatives of nine groups of microorganisms isolated from the contents of the distal part of intestine, were analyzed. It has been well established that with an increase in the number of enterococci in the contents of the distal part of intestine the deterioration of the structural-functional state of the bone tissue can be observed. PMID- 23088102 TI - Identification of the major proteins of the virions of bacteriophage ZF40 Pectobacterium carotovorum. AB - The vast variety of bacteriophages and the uniqueness of their individual representatives dictate to perform the detailed study of the actual phage-cell interactions, the virion morphogenesis and morphopoiesis in particular. An analysis of the complete genome sequence of the temperate phage ZF40 Pectobacterium carotovorum has shown that it is a representative of a unique group of phages of the Myoviridae family [Comeau A. M, Tremblay D., Moineau S., Rattei T., Kushkina A. I, Tovkach F I., H.M. Krisch, H.W. Ackermann Phage Morphology Recapitulates Phylogeny: The Comparative Genomics of a New Group of Myoviruses // PLoS ONE.--July 2012. - 7. - N 7. - e40102]. Characteristic features of these viruses are a small length of the tail compared with the diameter of the capsid and a complicated pattern of the tail sheath, leading to its criss-cross striation. In the presented article the major proteins were identified by means of the SDS-PAGE method: the head proteins (mp2: 33.9 kDa), the sheath (mp1: 39.2 kDa) and the tail tube ones (mp3: 19.9 kDa). It was proved that the mp2 molecular weight is the same with the gp46, the putative major capsid protein derived from the results of the genome sequencing. Therefore, it is still not determined whether the gp46 (mp2) of the virulent mutant 421 of the phage ZF40 is exposed to post-translational modification in the course of the phage particle maturation during its development in the cells of the strain M2 4/50RI P. carotovorum. To study the morphogenetic development pathways it was proposed to use the phage variants that form an excess of individual components of the virion: capsids, procapsids and separate tails propagated on different hosts. PMID- 23088103 TI - [Modelling of the adeno-herpetic infection in lymphoblastoid cell cultures]. AB - Viral infections take the key place in medical practice. A large group of diseases are caused by adenoviral and herpes infection. As a rule, the investigations carried out in scientific laboratories are directed to the study of certain aspects of the interaction between the virus and the cell on the model of single infection. At the same time different viral infections at the level of macroorganism are constantly interacting with each other. The paper presents the studies on the selection of optimal models of lymphoblastoid cell lines for analysis of peculiarities of the mixed adeno-herpetic infection. The reproduction of human adenovirus type 5 and Epstein-Barr virus in the mono- and mixed infection in lymphoblastoid cell cultures of B-phenotype: B95-8, Raji, Namalwa have been studied. Both interfering and inhibiting action of viruses are shown. So EBV, which has a short 48-hour cycle of reproduction, inhibits the adenovirus at the given time. The obtained cell models of adeno-herpes infection will allow to study peculiarities of the antiviral action of etiotropic antiviral preparations in conditions of coinfection. PMID- 23088104 TI - Dose-dependent IFN-stimulating and immunomodulating properties of 6H-indolo[2,3 B] quinoxaline derivatives. AB - Two 6H-indoloquinoxaline derivatives were studied in different doses and schemes of application for their INFgamma-inducing potential and ability to effect functional activity of phagocytic cells. Tested compounds were shown to possess comparable or higher activity than reference drug Amixin in analogous doses. One indoloquinoxaline significantly elevated metabolic activity of macrophages and increased their potential for phagocytosis. Application of multiple treatments and higher doses allowed us to reveal differences between studied derivatives that were not obvious in previous in vivo experiment. Capacity of 6H indoloquinoxalines to induce vast IFN amounts on in vivo level was demonstrated for the first time. PMID- 23088105 TI - [Teichoic acids from lactic acid bacteria]. AB - The current view of the structural diversity of teichoic acids and their involvement in the biological activity of lactobacilli has been reviewed. The mechanisms of effects of probiotic lactic acid bacteria, in particular adhesive and immunostimulating functions have been described. The prospects of the use of structure data of teichoic acid in the assessment of intraspecific diversity of lactic acid bacteria have been also reflected. PMID- 23088106 TI - [Joining forces in the fight against epidemics--priority task in cooperation between Russia and Kazakhstan]. AB - This problem has historically existed for Russia and Kazakhstan. Traditionally plague, Crimean-Congo hemorrhagic fever anthrax, cholera, and other diseases have been a matter of greater public health concern in the above countries. Under Russia's chairmanship in the Group of Eight in 2006 and in the Shanghai Cooperation Organization in 2008-2009, these countries were first to join their effects to control epidemics. As for Kazakhstan, its cooperation with Russia has been reinforced only by a solid contractual base. The creation of the Customs Union is also an important event in the development of relations between Russia and Kazakhstan as this increases the responsibility of each country for the transmission of infectious diseases and the delivery of dangerous goods and cargoes. It is these well-organized and step-by-step infectious disease controlling actions of the countries that will be able to reduce risks and threats to both our countries and other regions in this area. PMID- 23088107 TI - [Influence of environmental factors on the body's immunological resistance]. AB - Due to the presence of metals having immunotropic activity in the environmental objects, the authors analyzed the level and structure of morbidity due to immunodeficiency states in the context of micro-regions. It may be stated with sufficient assurance that the combined influence of environmental chemical factors leads to immunodeficiency states, in the presence of which the risk of allergic diseases and other immunodeficiencies increases. PMID- 23088108 TI - [Interleukin-6 in endemic goiter patients in the south Ural region]. AB - The cytokine and thyroid status was studied in patients with endemic goiter (EG) depending on thyroid function. IL-6 correlated with free T3 levels (a negative relationship) in hyperthyroidism, with IL-2 and IFN-gamma levels in EG patients with euthyroidism, and with IL-1beta, IL-2, IL-8, IL-10, and IFN-gamma in hypothyroidism. The EG patients with high IL-6 levels showed positive relationships to IL-2 and thyroid peroxidase antibodies and a negative relationship to free T3. In these patients, IL-6 acted to stimulate the secretion of antithyroid antibodies, which is a risk of autoimmune thyroiditis. PMID- 23088109 TI - [Mercury in the streams and reservoirs in the territory of the Orenburg Region]. AB - The State Education Institution of Higher professional education "The Orenburg State Medical Academy of Federal Agency in Public Health and Social Development". The state of some freshwater streams and reservoirs in the Orenburg Region was estimated from the level of mercury in the water extract of their bed silt. The concentration of this pollutant is shown to exceed the set standards. PMID- 23088110 TI - [Monitoring the quality of drinking water and air in the industrial center]. AB - The quality of potable water at the exit point for distribution networks and a network for three zones (central, east and northern) where the Orenburg population lived compactly were studied which showed its difference. The complex anthropogenic and total oxidative loads created by aqueous and air environments were calculated; the maximum values for inhabitants of the east part of the city were established, which correspond to the higher levels of nitrates, chlorides, and sulfates in the water and its general mineralization and general rigidity. PMID- 23088111 TI - [Features of apoptosis in conditions of the exposure to organochlorine compounds and vanadium]. AB - The cell structures involved into the apoptotic mechanism is an ideal object for the study of toxic effects produced by low-molecular-weight compounds on the immune system. Organic chlorine compounds and heavy metals were tested for their effects in the in vitro system. The experiments show that organic chlorine compounds inhibit apoptotic cell death. An assessment of their results has demonstrated that vanadium promotes activation-induced lymphocyte death. Thus, there are multidirectional immune responses upon exposure to organic chlorine compounds and heavy metals. PMID- 23088112 TI - [Features of the immune status in the population of urban areas with a high content of heavy metals]. AB - The immune status was studied in of 4000 Aktobe citizens. The findings indicate that cell immunity indicators as the maximally informative parameter are of criteria significance in evaluating the influence of environmental factors on the body. A direct correlation was found between the sensitization to chromium and CD3, CD4, CD8 and the functional response of T lymphocytes to phytohemagglutinin. PMID- 23088113 TI - [Features of formation of postvaccinal immunity in the population of one-company towns and rural settlements 1]. AB - When assessing the risk of developing non carcinogenic effects, the authors calculated the summary danger indices for the Orenburg Region's population living in the urbanized and rural areas. The risk of developing harmful effects for children from monotowns and rural settlements was also determined. The findings lead to the conclusion that monotowns are the most unfavorable in terms of their risk of non carcinogenic effects. The next stage of the investigation was to study the strength of postvaccinal measles immunity, which revealed a close relation between the ecological state of a dwelling area and the formation of postvaccinal immunity. PMID- 23088114 TI - [The inflammatory response as a manifestation of the influence of environmental chemical factors]. AB - The paper shows that a chronic slowly developing inflammation manifesting itself as adipokine imbalance and lipid metabolism abnormalities in the body under the influence of unfavorable environmental factors. PMID- 23088115 TI - [Rare-earth metals as a factor in mutagenicity]. AB - Both the regions of the Orenburg Region area and individual examined streams and reservoirs were shown to be characterized by a varying load index for rare earth elements. The total level of rare earth elements was directly correlated with different types of mutations. PMID- 23088116 TI - [The role of anthropotechnogenic impact in shaping the allergic morbidity]. AB - The paper gives information on the prevalence of allergic diseases in Aktobe depending on the level of an anthropotechnogenic load area. The findings indicate that children that the degree of immunodeficiency in persons living in different micro-areas of the city depends on the magnitude of environmental pollution. Among allergic diseases, pollinoses (58.6%) rank first, asthma (19.9%) and allergic rhinitis (15.6%) occupy the second and third places, respectively. At the same time, the incidence of allergic diseases is 21.2-30.3% of all cases in the areas near an industrial area and 9.1-12.1% in those maximally remote from it. The impact of environmental quality on the incidence of allergic diseases depends on gender and age. PMID- 23088117 TI - [Resistance of the fungi Candida to human innate immunity factors]. AB - The paper presents the results of studying the anti-lactoferrin and sIgA-protease activities of Candida strains isolated in varying human intestinal dysbiosis. Thirty-eight Candida strains were isolated from patients with dysbiosis. The isolated strains were found to have anti-lactoferrin and sIgA-protease activities. The wide spread of the examined properties of Candida and their dependence on its species and the degree of dysbiotic disorders were established. The findings gain more insight into the range of biological properties in the fungi Candida, which contribute to the long-term survival of their host with microenvironmental abnormalities. PMID- 23088118 TI - [Risk factors for violations of the fertility in men living in urban areas]. AB - The immunocytokine status of the reproductive tract was evaluated in men with different forms of gonorrhea, who lived in the urbanized areas of the Orenburg Region. The typical form of gonorrhea, which is a risk for infertility, is accompanied by the reduced levels of lysozyme and IL-10 and the increase content of lactoferrin and proinflammatory cytokines, such as IL-1, Ibeta-6, and IL-8 in the ejaculate. PMID- 23088119 TI - [Characteristics of clinical and laboratory parameters in women under the conditions of a large industrial center]. AB - The paper characterizes clinical, hormonal, and immunological parameters in 443 female patients residing under anthropogenic loading. The high prevalence of thyroid diseases was ascertained in infertile women living in an industrial center. Non-pregnant patients were found to have more pronounced hormonal changes than pregnant ones. The immunity status data may be suggestive of cell-mediated and humoral immunity derangements that are typical of secondary immunodeficiency. PMID- 23088120 TI - [Efficacy of immunomodulators in children with respiratory diseases in environmentally poor areas]. AB - The authors evaluated the clinical efficacy and safety of the antiviral and immunomodulatory drug Isoprinosine (inosine pranobex, Teva Pharmaceutical Industries, Ltd) in the treatment of bronchopulmonary diseases in children. One hundred and fifty-two children with acute respiratory diseases and an exacerbation of recurrent respiratory diseases were followed up. The use of Isoprinosine in their combined treatment showed both positive clinical changes and a better immunogram. PMID- 23088121 TI - [Sonographic parameters of spleen in children depending on the level of anthropogenic pollution of areas of residence]. AB - Sonographic parameters of spleen in children living in the Orenburg region taking into account the level and character of anthropogenous pollution of territory of residing are studied. The analysis of indicators of pollution of factors of inhabitancy (atmospheric air, potable water soil) is carried out. One-stage population research of 7000 children aged from 1 to 18 years living in urbanized and rural territories is conducted. Research has established that the linear sizes of a spleen according to ultrasonic research in children living in urbanized territories appear to be more than the linear sizes of a spleen in children residing in rural areas. These data are related to the raised level of anthropogenous pollution of the urbanized territories. PMID- 23088122 TI - [Mitotoxic and genotoxic effect of sediment on the example of the small rivers of the Orenburg region]. AB - The Purpose--an estimation mitotoxic and genotoxic activities of sediments from small Blyava and Kuraganka rivers (Orenburg region) with the use of ana- telophase method. The results have shown the reduction in mitotoxic and genotoxic activities of the sediments over the 2007-2010 period. PMID- 23088123 TI - [Physiological and hygienic characteristics of working conditions of workers in petrochemical enterprise]. AB - The paper presents results of a study of the functional state of major workers of the refinery "Gazprom Neftekhim Salavat" when exposed to hazardous working conditions. The results have shown adverse effects of chemical factors of working environment and the intensity of the labor process on the functional state of the body of workers that shows a violation of efficiency and adaptability of the their organism to the working conditions. PMID- 23088124 TI - [Environmental influences on cellular and humoral immunity in athletes]. AB - The study of seasonal changes in the state of cellular and humoral immunity in trained athletes with predominantly aerobic energy supply of muscle activity, but different different dynamics of the level of physical activity in the annual cycle has been performed. The immune status of athletes, the level of several hormones and interleukins have been established to undergo significant, regular fluctuations training--competitive load throughout the annual cycle that may affect the level of morbidity of athletes. PMID- 23088125 TI - [Effect of occupational factors on the immunological system condition of medical practitioners of clinical and laboratorial services]. AB - Labor conditions, health and immune status of employees of clinicodiagnostic (biochemical and bacteriological) laboratories of medicoprophylactic institutions are studied. Syndromes of immunodeficiency are revealed, labor conditions and general and chronic morbidity rate among laboratories employees are interrelated. PMID- 23088127 TI - [Hygienic substantiation of rational nutrition for grammar schoolchildren]. AB - The article presents the results of a study of factual nutrition and nutritional status of schoolchildren and grammar schoolchildren. The data obtained indicate that the nutrition of pupils is irrational and inadequate and does not satisfy the needs of the body of the grammar-schoolchildren in nutrients, which leads to a decrease in the level of efficiency, adaptive reserve capacity of the body and the low supply of vitamin B2, A, E, compared with schoolchildren. PMID- 23088126 TI - [Hygienic characteristics of nutrition of pupils at general educational establishments]. AB - In article results of studying of structure of a food, the food allowances, organized on the basis of educational institutions, diets of an actual daily food, and also the data of the laboratory analysis of qualitative structure of school breakfasts of pupils of educational institutions of the Orenburg area and the Seamarks district are presented. The obtained data testifies that a food of city and rural schoolchildren proves to be both age and gender irrational and inappropriate. PMID- 23088128 TI - [Role of the nutrients supply in the functioning of major organs and systems of the body of students]. AB - The article presents the results of a study of factual nutrition of first-year students of Orenburg Medical Academy and the assessment of its impact on nutritional status. These data suggest that nutrition students is irrational and inadequate due to low nutritional value of diets, inadequate intake of macro-and micronutrients, which lead to a breach of nutritional status of students, as evidenced by the increase in the percentage of students with significant and sharply reduced functional capabilities of the body and deviations in physical development. PMID- 23088129 TI - [Organization of medical and psycho-educational services for first-grader's under condition of gymnasium education secondary education]. AB - In this paper a model of organization of medical-psychological-pedagogical service for first graders not ready for systematic teaching in secondary education has been suggested. The results of study of the effectiveness of the introduction of medical, psychological and educational services in school are presented. Based on the dynamics of the autonomic balance, and functional reserve of biological adaptation in children at risk--not ready for medical and psycho physiological criteria for the systematic training the need for such services on the basis of modern educational institutions has been proven in order to prevent deterioration of the health of students. PMID- 23088130 TI - [Peculiarities of food status of children in different ecological conditions]. AB - Features of the nutritional status of children living in different environmental conditions, are determined by such factors as the physical development of children, level of hemoglobin, serum iron and ferritin. More pronounced adverse effect on the nutritional status of children observed in the oil and gas processing regions and the Aral Sea region. PMID- 23088131 TI - [Features of immunity in tobacco smoking among adolescents]. AB - The work is devoted to the study of indicators of systemic and local immunity in the respiratory tract in healthy adolescent tobacco use. The aim of the work is to characterize indices of general and local immunity of the respiratory tract during smoking in healthy adolescents. The study of local immunity was performed in induced sputum with the use of 0.1% solution of dithiothreitol. The study used tests assessing immune status I and II level. Active smoking in healthy adolescents induces a local and general immunological signs of inflammation: in sputum--elevation of IL-1alpha level and number of cells with activation markers (SD45 and HLA-DR); in the peripheral blood--the rise of levels of IL-6, IL-8, TNF CD19 (+) - cells, IgE and IL-4 in combination with a reduction in the number of CCD3(+)-, CD4(+)-, CD8(-)-lymphocytes and depression of the phagocytic activity of neutrophils. PMID- 23088132 TI - [The content of metals in hair and blood in the child population of cities of Aktobe region]. AB - The content of metal carcinogens in hair and blood in children's population in thee cities of Aktobe area has been studied. These data indicate that levels of carcinogens in children living in the Khromtau and Aktobe cities are 2 times higher than levels of carcinogens in children living in the Alga city. PMID- 23088133 TI - [Effect of benzene and chromium on the trace element composition in biosubstrates in Wistar rats]. AB - The chronic effects of benzene and chromium on the level of trace elements in the biospheres of Wistar rats were studied for 45, 90, and 135 days. As compared to the controls, the experimental groups of patients were found to have lower concentrations of copper (in blood) and iron (in blood and spleen) and higher levels of zinc (in blood, spleen) and chromium (in blood, spleen). PMID- 23088134 TI - [Effect of domestic gas on morphological and functional state of parenchymatous organs in rats]. AB - The work is devoted to a study of morphological and functional changes in liver and kidneys in the simulation of subacute toxic exposure of rats to domestic gas in the experiment. In the course of studies found that the subacute intoxication by domestic gas and its metabolites were shown to causes profound structural and metabolic lesions of the liver and kidneys that can progress to develop the chronic liver and kidney insufficiency. PMID- 23088135 TI - [The study of corrective role of plant--based drugs with antioxidant action in experimental intoxication with potassium dichromate]. AB - The disturbance of the structure and function of pulmonary surfactant system (pSS) is an essential component of almost all pulmonary diseases. Chromium compounds have a damaging effect on the PSS, which contributes to the formation of nonspecific pulmonary diseases and a burden of chrome disease. The results showed that the oil of licorice (Glycyrrhiza glabra L) protects PSS in chronic chrome intoxication. PMID- 23088136 TI - [Morphological features of the organs of the immune system in conditions of exposure to chromium and benzene]. AB - Morphological features of the thymus, spleen and lymph nodes on the 45th--and 90th day of oral exposure to benzene, potassium dichromate and their mixtures were studied in 40 Wistar rats. A strong trend to a decrease in the activity of T lymphocytes has been established. Apoptotic thymocytes and lymphocytes in the T dependent areas of spleen and lymph nodes have been revealed. PMID- 23088137 TI - [The comparative characteristics of antibacterial properties of the peptides of the active site of GM-CSF, and substances delivered from supernatants of hematopoietic progenitor CD34+45- cells]. AB - The antibacterial activity of synthetic peptides of the active site of GM-CSF and supernatants of CD34+45- hematopoietic progenitor cells has been investigated GM CSF peptides and cell supernatants were found to possess pronounced antibacterial activity, at that a combination of these substances has a more pronounced activity in comparison with the single substances. Possible mechanisms of the identified effects of synthetic peptides and substances from the supernatants of CD34+5- cells are discussed. PMID- 23088138 TI - [The development of secondary immunodeficiency in body when exposed to the effect of xenobiotics with immunosuppressive activity]. AB - The State Education Institution of Higher professional education "The Orenburg State Medical Academy of Federal Agency in Public Health and Social Development". In the experiment on mice (CBA x C57Bl6) F1 and Wistar rats is shown the protective effect of triterpenoid plant--miliatsina (3-beta-methoxy-delta18 oleanena) in relation to the humoral immune response and clearance macrophage function hepatic xenobiotic conditions of use--methotrexate. The results define the term as used miliatsina immunoprotector with adverse effects on the body of environmental and industrial chemical factors that form the secondary immunodeficiency. PMID- 23088139 TI - [Toxicological and sanitary characterization of bentonite nanoclay]. AB - Intragastric administration of nanoclay to rats during 28 days led to reductions in the relative weight of the liver, the activity of its conjugating enzymes, the antagonistic activity of bifidoflora, and the hyperproduction of colonic yeast microflora. The findings lead to the conclusion that nanoclays that may be present in foods must be the object of sanitary regulation. PMID- 23088140 TI - [The tasks to maintain the achieved results of malaria elimination in the post elimination period]. AB - The experience of the countries who have achieved malaria elimination on their territories suggests that the main tasks of a malaria program in the post elimination period are as follows: to maintain healthcare workers' alertness for possible malaria importation from outside and for a risk of its renewed transmission in the malaria-free area; to preserve the medical staff and to improve its professional skills in malaria diagnosis, treatment, and prevention in both the public and private sectors; to maintain malaria alertness among the population, among higher-risk population groups in particular; to elaborate and implement an effective program for collaboration with neighboring malaria-endemic countries, in the boundary regions in particular. The national governments' determination to continue long-term financial support of the prevention program of malaria in its elimination period is the guarantee of successful solution of the tasks set. PMID- 23088141 TI - [The problem of human helminthiasis in the Republic of Bashkortostan]. AB - This investigation was undertaken to study trends in helminthiasis morbidity in the Republic of Bashkortostan in 2009-2011. A total of 1497 subjects who came to the Laboratory of the Department of Microbiology, Virology, and Immunology, Bashkir State Medical University, in 2009-2011, have been randomly selected for this investigation. IgG antibodies were identified in their blood. Enzyme immunoassay has revealed anti-helminth antibodies in 4.7, 4.9, and 4.6% of the examinees in 2009, 2010, and 2011, respectively. Antibodies against Ascaris, Ecchinococcus, Opisthorchis, and Toxocara were most common in the examinees. According to the official statistics, the Republic of Bashkiria showed a 26.4% decrease in helminthiasis morbidity, alterations in the structure of morbidity, and a reduction in the proportion of helminths habiting the intestine, and an increase in the proportion of tissue helminthiases in the period 2006 to 2011. PMID- 23088142 TI - [Efficiency of standard versus instrumental studies in detecting helminth eggs]. AB - Testing confirmed that the applied brush washing methods developed in the 1970s could provide the adequate representativeness of a sample and full information on the actual presence of helminth eggs in the objects under study. An instrumental study was found to increase the probability of helminth egg detection by up to 3.1 times due to the representativeness of a sample, to reduce the labor- and time-consumption to have analysis results, as well as to unify a procedure for sanitary parasitological studies of washouts, and to enhance the efficiency of the equipment already used in parasitology laboratories. PMID- 23088143 TI - [Analysis of the diagnostic efficiency of excretory-secretory antigens of Trichinella spiralis and Trichinella nativa with sera from rats experimentally infected with arctic Trichinella, by using ELISA]. AB - The diagnostic efficiency of excretory-secretory antigens of Trichinella spiralis and Trichinella nativa with sera from Wistar rats experimentally infected with arctic Trichinella was comparatively tested. Trichinella derived from the muscles of wild carnivorous mammals inhabiting the biocenoses of Chukotka were used to infest animals and to obtain the antigen. There was a considerable excess of the effectiveness of enzyme immunoassay when the antigen derived from T. native larvae was used to analyze the titers of sera from the rats experimentally infected with arctic Trichinella. PMID- 23088144 TI - [Seroepidemiological study of native inhabitants of the Chukotka Autonomous District for trichinosis]. AB - The 2010 seroepidemiological study of sera from 259 inhabitants of two settlements located on the shore of the Chukchi Sea revealed 63 (24.32%) seropositive respondents, which suggests the intensity of an epidemic process in these populated areas. The detection of specific antibodies in the population to the pathogen of trichinosis is of great importance for the objective assessment of the epidemic situation in the foci of invasion and the prediction of sporadically occurring epidemics of this anthropozoonosis. PMID- 23088145 TI - [The epizootology and epidemiology of echinococcosis and paecilomycosis]. AB - Fungi of the genus Paecilomyces, a causative agent of the fungal disease paecilomycosis, have been found in the blood of productive animals (sheep, cattle, pigs, goats) that are carriers of Echinococcus larvocysts. In the Republic of Uzbekistan, the echinococcosis affection of sheep, cattle, pigs, and goats continues to remain high. Domestic fowls (chickens, turkeys, and gooses) have been established to be blood carriers of Paecilomyces fungi, which is also true for wild birds, such as my-lady's-belts, quails, chukars, and crows. The degree of fungal affection has been also established for birds. PMID- 23088146 TI - [Study of the pathogenesis of paecilomycosis-complicated echinococcosis]. AB - Experiments were carried out on 35 lambs infected with echinococcus eggs taken from canine donors, 5 lambs with echinococcosis, 5 lambs with echinococcosis + paecilomycosis, 5 lambs with coenurosis, 5 with cysticercosis ovis, 5 with alveococcosis, 5 with paecilomycosis, inoculated by the material taken from patients; and 5 healthy lambs formed a control group. Cystic hydatidosis was found to induce substantial cardiovascular changes. PMID- 23088148 TI - [The species composition and epidemiological significance of mosquitoes (Diptera, Psychodidae, Phlebotominae) in the foci of visceral leishmaniasis in the Papsky District, Namangan Region, Uzbekistan]. AB - In 2008, mosquito observations were made in 4 populated areas of the Papsky District, Namangan Region, Uzbekistan (Fergana Valley), where visceral leishmaniasis cases had been registered. The mosquitoes were caught in Oltinkan, Gulistan, Chodak, and Chorkesar in July and in Oltinkan in September. A total of 7245 mosquitoes were caught in the living and utility premises during the observation period. The mosquito fauna of this focus was found to represent 10 species: P. papatasi, P. sergenti, P. alexandri, P. caucasicus, P. nuri, P. keshishiani, P. angustus, P. longiductus, S. grecovi, and S. sumbarica. It also contained P. papatasi, a vehicle for transmission of zoonotic cutaneous leishmaniasis, P. sergenti, an anthroponotic cutaneous leishmaniasis vehicle, and P. longiductus, a visceral leishmaniasis one. The major site of hatching and habitat for mosquitoes were utility premises for large and small cattle. A polymerase chain reaction was used to determine mosquito infestation with L. infantum. A total of 38 female pools of 5 species: P. papatasi, P. sergenti, P. keshishiani, P. angustus, and P. longiductus were tested. Testing of female mosquitoes for L. infantum yielded a negative result. PMID- 23088147 TI - [Malaria mosquitoes (Diptera, Culicidae, Anopheles) of North Tajikistan, their ecology, and role in the transmission of malaria pathogens]. AB - Five species of malaria mosquitoes: An. artemievi, An. claviger, An. hyrcanus, An. superpictus, and An. pulcherrimus were found in North Tajikistan in 2006 - 2007. Species affiliation was identified according to the morphological signs of their larvae and imagoes, and by using the polymerase chain reaction-restriction fragment length polymorphism analysis. There was a larger number of An. hyrcanus (34%), An. artemievi (29%), and An. pulcherrimus (24%) and a smaller number of An. superpictus (11%); and An. claviger was few (2%). The hatching sites of the above species and the preferred types of their day refuges were found. The intensity of attack of different Anopheles species on humans and animals was studied. Among the North Tajikistan malaria mosquitoes, An. pulcherrimus and An. superpictus are of the greatest epidemiological importance as vehicles for transmission of malaria pathogens. An. artemievi and An. hyrcanus are minor vehicles. At present, An. claviger is of no epidemiological significance in transmitting malaria in North Tajikistan. PMID- 23088150 TI - [Enteric microbiocenosis in humans with parasitic diseases]. PMID- 23088149 TI - [Ratio of the numbers of Ixodes persulcatus imagoes in the near-Baikal area with the use of different recording methods]. AB - The data of estimating the number of Ixodes perculcatus by two methods (the number of ticks per flag-hour and that per flag-kilometer) in the near-Baikal area were analyzed. According to these values, the abundance of taiga ticks in individual calculations ranged from 0 to 394. The association between the time of passage and the number of collected ticks was positive and high significant. The correction factors were calculated to obtain the abundance values expressed in per flag-kilometer units from the abundance values per flag-hour and conversely. The value of these factors depended on the number of ticks. PMID- 23088151 TI - [The specific features of the clinical picture of blastocystosis and laboratory methods for its diagnosis]. PMID- 23088152 TI - [The vivax malaria causative agent Plasmodium ovale: the present global area, intraspecies polymorphism, importation to the Russian Federation (1992-2011)]. AB - The global area for Plasmodium ovale is small as compared with that for other species of human malaria pathogens. It has expanded in Asian areas and remained as before in the African ones. In the past 20 years, there have been 2129 malaria cases imported from far abroad to Russia, including 84 (4%) cases of vivax malaria (P. ovale). The patients were most foreign citizens: 70 from 20 African countries and 7 from two countries of Oceania, such as Papua New Guinea and Indonesia. The other 7 patients were Russia's people who had returned from different countries of Africa. For this period there have been a total of 5 cases of mixed infection: tropical P. falciparum malaria + vivax P. ovale malaria. The mission of detected new sympatric subspecies (P. ovale curtisi and P. ovale wallikeri) inhabiting the tropical countries with continuous local transmission remains unclear. Only a thorough study of these subspecies will be able to effectively apply preventive measures and to carry out their elimination in future. PMID- 23088153 TI - [Aedes aegypti L. and Aedes albopictus Skuse mosquitoes are a new biological threat to the south of Russia]. PMID- 23088154 TI - [Cryptosporidiosis: prevalence and water-related outbreaks of infection]. AB - The data available in the literature show that 1.5-3% of Russia's population is carriers of cryptosporidium oocysts. Cryptosporidia are ascertained to be able to cause diarrhea of varying severity in preschool children. However, cryptosporidiosis in the latter is not frequently diagnosed. The urgency of the problem of cryptosporidiosis is also due to the practically ubiquitous prevalence of the causative agent in nature and to the role of this infection in the development of perinatal diseases, as well as complications in immunocompetent patients (infected and uninfected with AIDS virus). Cryptosporidiasis is an HIV associated infection and of great importance for the diagnosis of AIDS. PMID- 23088155 TI - Studies toward the unique pederin family member psymberin: structure-activity relationships, biochemical studies, and genetics identify the mode-of-action of psymberin. AB - Psymberin is the only member of the pederin natural product family that contains a dihydroisocoumarin side chain. Structural modifications of psymberin uncoupled inhibition of protein translation from cytotoxicity, suggesting that psymberin has more than one bioactivity. A forward genetic screen in Caenorhabditis elegans was conducted to identify the molecular target(s) of psymberin. Multiple independent psymberin-resistant mutants were isolated, each containing the same point mutation in a gene encoding a ribosomal protein. However, a psymberin resistant mutant strain bearing this mutation was not cross-resistant to the pederin family member mycalamide A, which binds to the archaeal form of the same protein. Thus, two pederin family members likely differ in how they bind the same molecular target. The accumulation of psymberin in cells was sensitive to the stereochemistry of the amide side chain at C4 or C8 and the presence of the dihydroisocoumarin side chain. The observation that psymberin diastereomers or dihydroisocoumarin-truncated analogs lose all cytotoxic activity while retaining the ability to inhibit protein translation in a cell-free in vitro assay can be explained in the context of these differential cell uptake issues. Finally, we also demonstrate that the blistering activity associated with pederin and other members of the family is not due to their protein synthesis inhibiting activity. Unlike pederin and mycalamide, psymberin does not display irritant or blistering activity. PMID- 23088157 TI - Ca10Pt7Tt3 (Tt = Si, Ge): new platinide phases featuring electron-rich 4c-6e bonded [Pt7Tt3]20- intermetalloid clusters. AB - Two new phases Ca(10)Pt(7)Tt(3) (with Tt = Si, Ge) were obtained by reacting stoichiometric mixtures of the elements at high temperature. Their structures were refined from single crystal X-ray diffraction data. They are isostructural and crystallize in the Ba(10)Al(3)Ge(7) type structure, space group P6(3)/mcm (No. 193) with a = b = 8.7735(3) A, c = 13.8260(5) A, V = 921.66(6) A(3), Z = 2 for Tt = Si, and a = b = 8.7995(6) A, c = 13.9217(14) A, V = 933.56(16) A(3) for Tt = Ge phase. The most interesting structural features in these phases are the propeller shape {Pt(7)Tt(3)} (Tt = Si, Ge) intermetalloid clusters in a D(3h) local symmetry. LMTO electronic structure calculations and COHP analyses reveal that both Ca(10)Pt(7)Tt(3) (Tt = Si, Ge) phases are charge optimized, which is not predicted by the classical Zintl concept and the octet or Wade-Mingo's rules, but rather by a more complex bonding model based on the unprecedented electron rich 4c-6e multicenter bonding. The clusters are best described as three condensed trigonal planar [TtPt(3)](8-) units, resulting in a central Pt atom also with a trigonal planar coordination of three symmetrical equivalent Si/Ge atoms that are further connected to two terminal Pt atoms each. The "trefoil" electron-rich multicenter bonding is proposed here for the first time, and may be viewed as a unique bonding feature with potential relevance for the catalytic properties of the noble metal platinum. PMID- 23088156 TI - Drimane sesquiterpenoids from Marasmius sp. inhibiting the conidial germination of plant-pathogenic fungi. AB - From the basidiomycete Marasmius sp., strain IBWF 96046, three new sesquiterpenoids based on the drimane skeleton were isolated and named marasmene B and marasmals B and C. In this study, their isolation, structure elucidation, and biological evaluation are described. The compounds have a pronounced inhibitory effect on the conidial germination of several plant-pathogenic fungi. PMID- 23088158 TI - Platinum-catalyzed oxoarylations of ynamides with nitrones. AB - A new platinum-catalyzed oxoarylation of ynamides with nitrones is reported. Cascade sequences for the synthesis of indolin-2-ones via NaBH(3)CN reduction in situ of the initially formed oxoarylation products are also developed. PMID- 23088159 TI - Apocynin improves erectile function in diabetic rats through regulation of NADPH oxidase expression. AB - INTRODUCTION: Diabetes is a risk factor for erectile dysfunction (ED). The proposed mechanisms responsible for diabetic ED are associated with an increase in reactive oxygen species (ROS) production, overactivity of RhoA/ROCK signaling pathway and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, as seen in experimental models of diabetic rats. AIM: The aim of this study was to investigate whether NADPH oxidase inhibitor apocynin can ameliorate Streptozotocin (STZ)-induced diabetes-related ED by reducing the ROS production and inhibiting the activity of RhoA/ROCK signaling pathway. METHODS: The diabetic rats were treated with and without the NADPH oxidase inhibitor apocynin. MAIN OUTCOME MEASURES: Erectile responses were evaluated by determining mean arterial blood pressure (MAP) and intracavernosal pressure (ICP) with electrical stimulation of the cavernous nerve. Levels of mRNA expression were measured by real-time polymerase chain reaction (RT-PCR). Levels of protein expression were examined by Western Blot. ROS production was measured by dihydroethidium (DHE) staining and thiobarbituric acid reactive substances assay. RESULTS: The ratio of Maximum ICP-to-MAP (MaxICP/MAP) was significantly decreased in diabetic ED rats, compared to that of age-matched control rats (P < 0.05). Apocynin improved erectile function of diabetic rats (P < 0.05). Expression levels of RhoA (cytosol), nNOS and eNOS were reduced, compared to those of control rats (P < 0.05). Apocynin significantly elevated their expression levels in diabetic rats (P < 0.05). Expression levels of ROCK1, RhoA (membrane fraction), p-MYPT1 and NADPH oxidase subunits p47(phox) and p67(phox) were increased in diabetic rats when compared to those of control rats (P < 0.05), and it was observed that apocynin significantly reduced their expression levels in diabetic rats (P < 0.05). ROS production was increased in diabetic rats when compared to that of control rats (P < 0.05), the effect of apocynin was a reduction in the ROS production in diabetic rats (P < 0.05). CONCLUSION: NADPH oxidase inhibitor apocynin can ameliorate diabetes-related ED by reducing the ROS production and inhibiting the activity of RhoA/ROCK signaling pathway. PMID- 23088160 TI - Spectrally resolved chemiluminescent probes for sensitive multiplex molecular quantification. AB - Luminophores are frequently utilized probe labels for detecting biological analytes. Multiple fluorescent luminophores, or fluorophores, can be readily distinguished from one another based on different energy excitation and emission wavelengths and lifetimes. However, suitable methods and reagents for distinguishing multiples of the much more sensitive chemically initiated luminophores have been limited. Herein we describe a new class of hybrid luminophore probes that emit light of distinct wavelength ranges and intensities upon energy transfer (ET) from an in-common, acridinium ester chemiluminophore to a covalently conjugated fluorophore. This format supports rapid, rational design of spectrally resolvable, chemically initiated probes. Time-resolved spectrographic and luminescence characterizations indicate that ET is not dependent on overlap in the emission spectrum of the luminophore and the absorption spectra of acceptors, suggesting a non-Forster resonance ET mechanism. Analysis of a combination of the chemiluminophore and new chemiluminophore acceptor conjugate probes demonstrates the benefits of their use in sensitive, multiplex quantification of nucleic acid sequences indicative of environmentally relevant microbes without prior enzymatic amplification. PMID- 23088161 TI - Development of a monoclonal antibody-based competitive indirect enzyme-linked immunosorbent assay for furaltadone metabolite AMOZ in fish and shrimp samples. AB - A monoclonal antibody-based competitive indirect enzyme-linked immunosorbent assay (ELISA) with improved sensitivity and specificity for the determination of furaltadone metabolite 5-methylamorpholino-3-amino-2-oxazolidone (AMOZ) was described. AMOZ was derivatized with 2-(3-formylphenoxy)acetic acid and coupled with bovine serum albumin to form a novel immunogen. BABL/c mice were immunized and monoclonal antibody specific to the nitrophenyl derivative of AMOZ (NP-AMOZ) was produced and characterized. Four other haptens with different heterology to the immunizing hapten were synthesized and coupled to ovalbumin as coating antigens to study the effect of heterologous coating on assay sensitivity. Under the optimized heterologous coating format, the competitive indirect ELISA showed very high sensitivity to NP-AMOZ, with an IC(50) of 0.14 MUg/L and limit of detection of 0.01 MUg/L. The assay showed high specificity toward NP-AMOZ, and negligible cross-reactivity with analogous compounds was observed. The average recoveries of AMOZ from spiked fish and shrimp samples were estimated to range from 81.0 to 104.0%, with coefficients of variation below 20%. Good correlation was obtained between the results of ELISA analysis and of standard liquid chromatography-tandem mass spectrometry analysis. These results indicated that the proposed ELISA is ideally suited as a monitoring method for AMOZ residues at trace level. PMID- 23088162 TI - Laparoscopic resection of colorectal cancer facilitates simultaneous surgery of synchronous liver metastases. AB - AIM: Combined resection of colorectal cancer with surgery for synchronous liver metastases (LM) still remains controversial because of the possible higher morbidity rate, the necessity of an adequate abdominal approach for both resections and the impact on oncological results. However, laparoscopy may be beneficial in terms of operative results and could facilitate this combined procedure. The aim was to assess the benefit of the laparoscopic approach for colorectal cancer resection in patients undergoing simultaneous liver resection for synchronous LM. METHOD: From 2006 to 2011, all patients with colorectal cancer and resectable synchronous LM, for which the total length of the procedure was suspected to be less than 8 h, underwent colorectal laparoscopic resection combined with open and/or laparoscopic liver surgery. In order to identify selection criteria, a comparative analysis was performed between patients with and without major postoperative morbidity. RESULTS: Fifty-one patients underwent combined surgery with laparoscopic colectomy (n = 31) and proctectomy (n = 20). The conversion rate was 8%. Liver resections included major surgery (n = 10) and minor surgery (n = 41). Extraction of the colorectal specimen was performed through an incision used for open liver resection, except in seven patients who underwent a total laparoscopic procedure. Overall and major morbidity rates were 55% and 25%, respectively. Median (range) hospital stay was 16 (6-40) days. Regarding patient and tumour characteristics, no independent criteria of major morbidity risk were identified. CONCLUSION: This study showed that laparoscopic colorectal resection combined with liver resection for synchronous LM was feasible and safe. Moreover, laparoscopy facilitates the surgical abdominal approach for combined colorectal and liver resection. PMID- 23088163 TI - A suggested model for decision-making regarding hearing conservation: towards a systems theory approach. AB - OBJECTIVE: The aim of the study was to investigate potential health promotion variables associated with adolescents' hearing protection use at concerts. STUDY SAMPLE: The sample consisted of 242 upper secondary school students aged 15-19 years. DESIGN: Variables defined by the theory of planned behaviour (TBP) and health belief model were tested in this quantitative study. RESULTS: Fifty-three percent of the adolescents reported that they used hearing protection at concerts to some degree, and 33 individuals (14%) reported that they used hearing protection in 50% of cases or more. The average degree of hearing protection use was reported to be 17% of the visits at concerts. Norms, perceived control, barriers, and noise sensitivity were associated with attitudes towards loud music. In addition, norms, barriers, permanent tinnitus, and noise sensitivity were significantly correlated with hearing protection use. However, intention was not significantly correlated with hearing protection use. CONCLUSIONS: From a systems theoretical approach it can be suggested that preventive strategies must consider more levels than just the individual, in order to achieve long lasting behavioural changes in adolescents' listening habits. To be able to get useful knowledge about preventive strategies, it is necessary to add context-specific variables into generic models such as TPB. PMID- 23088164 TI - Does cognitive function predict frequency compressed speech recognition in listeners with normal hearing and normal cognition? AB - OBJECTIVE: The aim was to investigate the relationship between cognitive ability and frequency compressed speech recognition in listeners with normal hearing and normal cognition. DESIGN: Speech-in-noise recognition was measured using Institute of Electrical and Electronic Engineers sentences presented over earphones at 65 dB SPL and a range of signal-to-noise ratios. There were three conditions: unprocessed, and at frequency compression ratios of 2:1 and 3:1 (cut off frequency, 1.6 kHz). Working memory and cognitive ability were measured using the reading span test and the trail making test, respectively. STUDY SAMPLE: Participants were 15 young normally-hearing adults with normal cognition. RESULTS: There was a statistically significant reduction in mean speech recognition from around 80% when unprocessed to 40% for 2:1 compression and 30% for 3:1 compression. There was a statistically significant relationship between speech recognition and cognition for the unprocessed condition but not for the frequency-compressed conditions. CONCLUSIONS: The relationship between cognitive functioning and recognition of frequency compressed speech-in-noise was not statistically significant. The findings may have been different if the participants had been provided with training and/or time to 'acclimatize' to the frequency-compressed conditions. PMID- 23088165 TI - Applications of graphene electrophoretic deposition. A review. AB - This Review summarizes research progress employing electrophoretic deposition (EPD) to fabricate graphene and graphene-based nanostructures for a wide range of applications, including energy storage materials, field emission devices, supports for fuel cells, dye-sensitized solar cells, supercapacitors and sensors, among others. These carbonaceous nanomaterials can be dispersed in organic solvents, or more commonly in water, using a variety of techniques compatible with EPD. Most deposits are produced under constant voltage conditions with deposition time also playing an important role in determining the morphology of the resulting graphene structures. In addition to simple planar substrates, it has been shown that uniform graphene-based layers can be deposited on three dimensional, porous, and even flexible substrates. In general, electrophoretically deposited graphene layers show excellent properties, e.g., high electrical conductivity, large surface area, good thermal stability, high optical transparency, and robust mechanical strength. EPD also enables the fabrication of functional composite materials, e.g., graphene combined with metallic nanoparticles, with other carbonaceous materials (e.g., carbon nanotubes) or polymers, leading to novel nanomaterials with enhanced optical and electrical properties. In summary, the analysis of the available literature reveals that EPD is a simple and convenient processing method for graphene and graphene-based materials, which is easy to apply and versatile. EPD has, therefore, a promising future for applications in the field of advanced nanomaterials, which depend on the reliable manipulation of graphene and graphene containing systems. PMID- 23088166 TI - Quinine localizes to a non-acidic compartment within the food vacuole of the malaria parasite Plasmodium falciparum. AB - BACKGROUND: The naturally fluorescent compound quinine has long been used to treat malaria infections. Although some evidence suggests that quinine acts in the parasite food vacuole, the mechanism of action of quinine has not yet been resolved. The Plasmodium falciparum multidrug resistance (pfmdr1) gene encodes a food vacuolar membrane transporter and has been linked with parasite resistance to quinine. The effect of multiple pfmdr1 copies on the subcellular localization of quinine was explored. METHODS: Fluorescence microscopy was used to evaluate the subcellular localization of quinine in parasites containing different pfmdr1 copy numbers to determine if copy number of the gene affects drug localization. The acidotropic dye LysoTracker Red was used to label the parasite food vacuole. Time-lapse images were taken to determine quinine localization over time following quinine exposure. RESULTS: Regardless of pfmdr1 copy number, quinine overlapped with haemozoin but did not colocalize with LysoTracker Red, which labeled the acidic parasite food vacuole. CONCLUSIONS: Quinine localizes to a non acidic compartment within the food vacuole possibly haemozoin. Pfmdr1 copy number does not affect quinine subcellular localization. PMID- 23088167 TI - Frequent intratype neutralization by plasma immunoglobulin a identified in HIV type 2 infection. AB - Human immunodeficiency virus type 2 (HIV-2) is less transmissible and less pathogenic compared to HIV-1 and, when matched for CD4(+) T cell count, the plasma viral load in HIV-2-infected individuals is approximately one log lower than in HIV-1-infected individuals. The explanation for these observations is elusive, but differences in virus controlling immunity generated in the two infections may be contributing factors. In the present study, we investigated neutralization by immunoglobulin A (IgA), in parallel with IgG, purified from plasma of HIV-1, HIV-2, and HIV-1/HIV-2 dually (HIV-D) infected individuals. Neutralization was analyzed against HIV-1 and HIV-2 isolates using a plaque reduction assay. In HIV-2 infection, intratype-specific neutralization by IgA was frequently detected, although at a lesser magnitude then the corresponding IgG neutralizing titers. In contrast, neutralization by IgA could rarely be demonstrated in HIV-1 infection despite similar plasma IgA levels in both infections. In addition, IgA and IgG of HIV-D plasma neutralized the HIV-2 isolate more potently than the HIV-1 isolate, suggesting that the difference between neutralizing activity of plasma IgA and IgG depends on the virus itself. Taken together, these findings suggest that both IgA and IgG add to the potent intratype neutralizing activity detected in HIV-2 plasma, which may contribute to virus control in HIV-2 infection. PMID- 23088168 TI - Design of a trial to evaluate the impact of clinical pharmacists and community health promoters working with African-Americans and Latinos with diabetes. AB - BACKGROUND: Given the increasing prevalence of diabetes and the lack of patients reaching recommended therapeutic goals, novel models of team-based care are emerging. These teams typically include a combination of physicians, nurses, case managers, pharmacists, and community-based peer health promoters (HPs). Recent evidence supports the role of pharmacists in diabetes management to improve glycemic control, as they offer expertise in medication management with the ability to collaboratively intensify therapy. However, few studies of pharmacy based models of care have focused on low income, minority populations that are most in need of intervention. Alternatively, HP interventions have focused largely upon low income minority groups, addressing their unique psychosocial and environmental challenges in diabetes self-care. This study will evaluate the impact of HPs as a complement to pharmacist management in a randomized controlled trial. METHODS/DESIGN: The primary aim of this randomized trial is to evaluate the effectiveness of clinical pharmacists and HPs on diabetes behaviors (including healthy eating, physical activity, and medication adherence), hemoglobin A1c, blood pressure, and LDL-cholesterol levels. A total of 300 minority patients with uncontrolled diabetes from the University of Illinois Medical Center ambulatory network in Chicago will be randomized to either pharmacist management alone, or pharmacist management plus HP support. After one year, the pharmacist-only group will be intensified by the addition of HP support and maintenance will be assessed by phasing out HP support from the pharmacist plus HP group (crossover design). Outcomes will be evaluated at baseline, 6, 12, and 24 months. In addition, program and healthcare utilization data will be incorporated into cost and cost-effectiveness evaluations of pharmacist management with and without HP support. DISCUSSION: The study will evaluate an innovative, integrated approach to chronic disease management in minorities with poorly controlled diabetes. The approach is comprised of clinic-based pharmacists and community-based health promoters collaborating together. They will target patient-level factors (e.g., lack of adherence to lifestyle modification and medications) and provider-level factors (e.g., clinical inertia) that contribute to poor clinical outcomes in diabetes. Importantly, the study design and analytic approach will help determine the differential and combined impact of adherence to lifestyle changes, medication, and intensification on clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01498159. PMID- 23088170 TI - Endobronchial tuberculosis: histopathological subsets and microbiological results. AB - BACKGROUND: Endobronchial tuberculosis (EBTB) is defined as a tuberculous infection of the tracheobronchial tree with microbial and histopathological evidence, with or without parenchymal involvement. Bronchoscopic appearances of EBTB have been divided into seven subtypes: actively caseating, edematous hyperemic, fibrostenotic, tumorous, granular, ulcerative, and nonspecific bronchitic. However, information for establishing a definite microbiological diagnosis in each of these categories is lacking.We aimed to present bronchoscopic appearances and percentages for the EBTB subtypes and to compare bronchoscopic appearances with microbiological positivity in bronchial lavage fluid. METHODS: From 2003 to 2009, 23 biopsy-proven EBTB patients were enrolled in the study. Diagnosis of EBTB was histopathologically confirmed in all patients. RESULTS: The commonest subtype was the edematous-hyperemic type (34.7%); other subtypes in order of occurrence were: tumorous (21.7%), granular (17.3%), actively caseating (17.3%), fibrostenotic (4.3%), and nonspecific bronchitic (4.3%). Although all patients were sputum-smear-negative for acid-fast bacilli (AFB), 26% of patients were smear-positive for AFB in the bronchial lavage fluid. The bronchial lavage fluid grew Mycobacterium tuberculosis in 39.1% of all patients.The bronchial lavage smear positivity for AFB in the bronchial lavage fluid was 75%, 25%, 20%, 12.5%, 0%, and 0% for the granular, actively caseating, tumorous, edematous-hyperemic, fibrostenotic, and nonspecific bronchitic subtypes of EBTB, respectively. Culture positivity for Mycobacterium tuberculosis in bronchial lavage fluid was 75%, 50%, 40%, 25%, 0%, and 0%, respectively. CONCLUSION: The commonest subtype of EBTB was the edematous hyperemic subtype. The granular type had the highest smear positivity and culture positivity for Mycobacterium tuberculosis in bronchial lavage fluid. Bronchoscopy should be performed in all patients suspected to have EBTB. PMID- 23088169 TI - Tolerance of fungal infection in European water frogs exposed to Batrachochytrium dendrobatidis after experimental reduction of innate immune defenses. AB - BACKGROUND: While emerging diseases are affecting many populations of amphibians, some populations are resistant. Determining the relative contributions of factors influencing disease resistance is critical for effective conservation management. Innate immune defenses in amphibian skin are vital host factors against a number of emerging pathogens such as ranaviruses and the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). Adult water frogs from Switzerland (Pelophylax esculentus and P. lessonae) collected in the field with their natural microbiota intact were exposed to Bd after experimental reduction of microbiota, skin peptides, both, or neither to determine the relative contributions of these defenses. RESULTS: Naturally-acquired Bd infections were detected in 10/51 P. lessonae and 4/19 P. esculentus, but no disease outbreaks or population declines have been detected at this site. Thus, this population was immunologically primed, and disease resistant. No mortality occurred during the 64 day experiment. Forty percent of initially uninfected frogs became sub-clinically infected upon experimental exposure to Bd. Reduction of both skin peptide and microbiota immune defenses caused frogs to gain less mass when exposed to Bd than frogs in other treatments. Microbiota-reduced frogs increased peptide production upon Bd infection. Ranavirus was undetectable in all but two frogs that appeared healthy in the field, but died within a week under laboratory conditions. Virus was detectable in both toe-clips and internal organs. CONCLUSION: Intact skin microbiota reduced immune activation and can minimize subclinical costs of infection. Tolerance of Bd or ranavirus infection may differ with ecological conditions. PMID- 23088171 TI - A daily analysis of physical activity and satisfaction with life in emerging adults. AB - OBJECTIVE: Subjective well-being has well-established positive health consequences. During emerging adulthood, from ages 18 to 25 years, people's global evaluations of their well-being (i.e., satisfaction with life [SWL]) appear to worsen more than any other time in the adult life span, indicating that this population would benefit from strategies to enhance SWL. In these studies, we investigated top-down (i.e., time-invariant, trait-like) and bottom-up (i.e., time-varying, state-like) influences of physical activity (PA) on daily SWL. METHODS: Two daily diary studies lasting 8 days (N = 190) and 14 days (N = 63) were conducted with samples of emerging adults enrolled in college to evaluate relations between daily PA and SWL while controlling for established and plausible top-down and bottom-up influences on SWL. RESULTS: In both studies, multilevel models indicated that people reported greater SWL on days when they were more active (a within-person, bottom-up effect). Top-down effects of PA were not significant in either study. These findings were robust when we controlled for competing top-down influences (e.g., sex, personality traits, self-esteem, body mass index, mental health symptoms, fatigue) and bottom-up influences (e.g., daily self-esteem, daily mental health symptoms, daily fatigue). CONCLUSIONS: We concluded that SWL was impacted by people's daily PA rather than their trait level of PA over time. These findings extend evidence that PA is a health behavior with important consequences for daily well-being and should be considered when developing national policies to enhance SWL. PMID- 23088172 TI - Testing two principles of the Health Action Process Approach in individuals with type 2 diabetes. AB - OBJECTIVE: The Health Action Process Approach (HAPA) proposes principles that can be translated into testable hypotheses. This is one of the first studies to have explicitly tested HAPA's first 2 principles, which are (1) health behavior change process can be subdivided into motivation and volition, and (2) volition can be grouped into intentional and action stages. The 3 stage groups are labeled preintenders, intenders, and actors. METHOD: The hypotheses of the HAPA model were investigated in a sample of 1,193 individuals with Type 2 diabetes. Study participants completed a questionnaire assessing the HAPA variables. The hypotheses were evaluated by examining mean differences of test variables and by the use of multigroup structural equation modeling (MSEM). RESULTS: Findings support the HAPA's 2 principles and 3 distinct stages. The 3 HAPA stages were significantly different in several stage-specific variables, and discontinuity patterns were found in terms of nonlinear trends across means. In terms of predicting goals, action planning, and behavior, differences transpired between the 2 motivational stages (preintenders and intenders), and between the 2 volitional stages (intenders and actors). CONCLUSIONS: Results indicate implications for supporting behavior change processes, depending on in which stage a person is at: All individuals should be helped to increase self-efficacy. Preintenders and intenders require interventions targeting outcome expectancies. Actors benefit from an improvement in action planning to maintain and increase their previous behavior. Overall, the first 2 principles of the HAPA were supported and some evidence for the other principles was found. Future research should experimentally test these conclusions. PMID- 23088173 TI - Pain acceptance, psychological functioning, and self-regulatory fatigue in temporomandibular disorder. AB - OBJECTIVE: A growing body of evidence suggests that chronic pain patients suffer from chronic self-regulatory fatigue: difficulty controlling thoughts, emotions, and behavior. Pain acceptance, which involves responding to pain and related experiences without attempts to control or avoid them (pain willingness), and pursuit of valued life activities regardless of pain (activity engagement) has been associated with various favorable outcomes in chronic pain patients, including better psychological functioning. The study presented here tested the hypotheses that pain acceptance is associated with less psychological distress, higher psychological well-being, and reduced self-regulatory fatigue in temporomandibular disorder (TMD) patients, particularly for those with longer pain duration. METHODS: Cross-sectional data were provided by 135 TMD patients during an initial evaluation at a university-based tertiary orofacial pain clinic. RESULTS: Results of hierarchical linear regression models indicated that, controlling for pain severity, pain willingness is associated with less psychological distress and lower self-regulatory fatigue, and activity engagement is associated with greater psychological well-being. Furthermore, the effect of pain willingness on psychological distress was moderated by pain duration such that pain willingness was more strongly associated with less psychological distress in patients with longer pain duration; this moderating effect was fully mediated by self-regulatory fatigue. CONCLUSION: These findings suggest pain willingness may buffer against self-regulatory fatigue in those with longer pain duration, and such conservation of self-regulatory resources may protect against psychological symptoms. PMID- 23088175 TI - Do you want the good news or the bad news? Gain- versus loss-framed messages following health risk information: The effects on leisure time physical activity beliefs and cognitions. AB - OBJECTIVE: The primary purpose was to examine the relative effectiveness of chronic disease and psychological health risk information combined with gain- versus loss-framed leisure time physical activity (LTPA) messages for changing perceived personal risk, LTPA response efficacy (i.e., the belief that LTPA can effectively reduce risk), and LTPA intentions. A secondary purpose was to explore the relationship between message framing and cognitive processing. METHOD: Baseline assessments of perceived risk for inactivity-related disease and psychological health problems, LTPA response efficacy, and intentions were measured among 96 individuals with spinal cord injury (SCI). Participants read population-specific information about the risk for inactivity-related disease and psychological health problems following SCI, and perceived risk was reassessed. Participants were then randomized to read LTPA response efficacy messages emphasizing the benefits of LTPA (gain framed) or the risks of inactivity (loss framed). Immediately following message exposure, cognitive processing (i.e., thought listing and message recall), LTPA response efficacy, and LTPA intentions were assessed. RESULTS: Changes in perceived risk were observed following exposure to health risk information. Changes in LTPA response efficacy and intentions were greater following loss-framed messages targeting psychological health compared with gain-framed messages. Greater cognitive processing was observed following loss-framed messages compared with gain-framed messages. CONCLUSION: Following exposure to psychological health risk information, loss framed messages may be more effective than gain-framed messages for eliciting cognitive processing and changing LTPA beliefs and intentions. PMID- 23088174 TI - Chronic exposure to everyday discrimination and sleep in a multiethnic sample of middle-aged women. AB - OBJECTIVE: Researchers have suggested that poor sleep may play a role in the association between discrimination and health, but studies linking experiences of discrimination to sleep are limited. The authors examined associations between reports of everyday discrimination over 4 years (chronic everyday discrimination) and subjective and objective indicators of poor sleep. METHOD: Participants were 368 African American, Caucasian, and Chinese women from the Study of Women's Health Across the Nation Sleep Study. Everyday discrimination was assessed each year from baseline through the third follow-up exam via questionnaire with the Everyday Discrimination Scale (intraclass correlation coefficient over 4 years = .90). Subjective sleep complaints were measured beginning in Year 5 with the Pittsburgh Sleep Quality Index. Objective indices of sleep continuity, duration, and architecture were assessed via in-home polysomnography, beginning in Year 5. RESULTS: In linear regression analyses adjusted for age, race/ethnicity, and financial strain, chronic everyday discrimination was associated with more subjective sleep complaints (Estimate = 1.52, p < .001) and polysomnography assessed wakefulness after sleep onset (Estimate = .19, p < .02), a marker of sleep continuity. Findings did not differ by race/ethnicity and remained significant after adjusting for menopausal status, body mass index, medication use, and depressive symptoms. CONCLUSION: Experiences of chronic everyday discrimination are independently associated with both subjective and objective indices of poor sleep. Findings add to the growing literature linking discrimination to key markers of biobehavioral health. PMID- 23088176 TI - Young and worried: Age and fear of recurrence in breast cancer survivors. AB - OBJECTIVE: Fear of cancer recurrence (FCR) is a frequently cited and unmet need of cancer survivors. While the relation between age and FCR is well documented, the mechanisms that may explain this phenomenon remain to be investigated. This study examined four possible mechanisms of the relation between age and FCR: motherhood, severity of the cancer (defined as cancer stage and chemotherapy), anxiety, and illness intrusiveness. METHODS: 3,239 women with breast cancer (mean time since diagnosis: 6.6 years) completed the Concerns About Recurrence Scale (CARS), the State Trait Anxiety Inventory (STAI), and the Illness Intrusiveness Ratings Scale (IIRS) within a larger web-based study. Women were divided into four groups based on their current age: < 34, 35-49, 50-64, and >65. Multivariate analyses were performed with age category and motherhood as the independent variables and the CARS subscales as the dependent variables, controlling for age of children and relevant covariates. Severity of the cancer, anxiety, and illness intrusiveness were simultaneously tested as mediators of the relation between age and FCR. RESULTS: Results indicated that age category was related to FCR, F = 10.37, p < .001. Follow-up tests revealed that women under 34 or 35-49 expressed the highest levels of FCR. Mothers, regardless of their ages or the ages of their children, expressed greater FCR. Illness intrusiveness and to a lesser extent anxiety were mediators of the relation between age and FCR, while severity of the cancer was not. CONCLUSIONS: Younger age was associated with more FCR among breast cancer patients, regardless of motherhood status. Our findings suggest new, potentially valuable ways of managing FCR by helping affected people to reduce anxiety and illness intrusiveness. PMID- 23088177 TI - Racial identification, racial composition, and substance use vulnerability among African American adolescents and young adults. AB - OBJECTIVE: Two studies examined racial identity (RI) as a protective factor against substance-related cognitions and substance use among Black adolescents and young adults living in high versus low percentage Black social environments. METHOD: Using structural equation modeling techniques, Study 1 examined longer term effects of RI on substance use cognitions and behaviors among 720 Black adolescents. Study 2 examined the impact of RI and percentage Black peer environment on alcohol use among 203 Black young adults. RESULTS: Study 1 revealed that RI was prospectively associated with lower levels of perceived friends' use and lower favorability of the substance user prototype and, in turn, lower substance willingness and use, but only among Black adolescents in predominantly White neighborhoods. These adolescents also reported greater access to substances. In Study 2, low RI Black young adults who reported predominantly White peer environments reported the highest levels of alcohol use. CONCLUSIONS: These findings highlight the importance of RI among Black youth and the impact of the social context on the health risk behaviors of adolescents and young adults. This research also demonstrates the utility of social psychological models, such as the prototype-willingness model, to examine mediating and moderating effects of individual differences and contextual factors on health risk cognitions and behavior. Theoretical and applied implications of the results are discussed. PMID- 23088178 TI - Psychosocial moderators of presurgical stress management for men undergoing radical prostatectomy. AB - OBJECTIVE: It is important to identify factors that predict who will benefit the most from psychosocial interventions in cancer populations. METHODS: This study examines the moderating effect of baseline social support (social support, SS; dyadic adjustment DA), distress (Brief Symptom Inventory, BSI; Impact of Event Scale, IES), and coping style (Brief COPE) on quality of life outcomes (SF-36 Physical Component Summary scores, PCS) 1 year postsurgery derived from a presurgical cognitive-behavioral stress management (SM; n = 23) program, supportive attention (SA; n = 37), or standard care (SC; n = 29). RESULTS: Moderation analyses indicated that men who reported low SS and were in the SM group had increased PCS 1 year after surgery as compared with men with low SS in the SC group (beta = -0.39, p < .01), with SA having a nonsignificant intermediate effect. Men who reported high distress (BSI) at baseline and were in the SA group had increased PCS 1 year after surgery, as compared with those in the SC group (beta = 24.80, p = .01), with SM having a nonsignificant intermediate effect. Mediation analyses suggested that neither SM nor SA improved quality of life simply by increasing social support or decreasing general distress. CONCLUSIONS: Distressed individuals may benefit more from unstructured discussion of distress, whereas those low in social support may benefit more from a structured approach to learning coping skills. PMID- 23088179 TI - Plasticity genes do not modify associations between physical activity and depressive symptoms. AB - OBJECTIVE: Physical activity is inversely associated with depression in adolescents, but the overall associations are fairly weak, suggesting individual differences in the strength of the associations. The aim of this study was to investigate whether plasticity genes modify the reciprocal prospective associations between physical activity and depressive symptoms found previously. METHODS: In a prospective population-based study (N = 1,196), physical activity and depressive symptoms were assessed three times, around the ages of 11, 13.5, and 16. Structural Equation Modeling was used to examine reciprocal effects of physical activity and depressive symptoms over time. The plasticity genes examined were 5-HTTLPR, DRD2, DRD4, MAOA, TPH1, 5-HTR2A, COMT, and BDNF. A cumulative gene plasticity index consisting of three groups (low, intermediate, and high) according to the number of plasticity alleles carried by the adolescents was created. Using a multigroup approach, we examined whether the associations between physical activity and depressive symptoms differed between the three cumulative plasticity groups, as well as between the individual polymorphisms. RESULTS: We found significant cross-sectional and cross-lagged paths from physical activity to depressive symptoms and vice versa. Neither the cumulative plasticity index nor the individual polymorphisms modified the strengths of these associations. CONCLUSION: Associations between adolescents' physical activity and depressive symptoms are not modified by plasticity genes. PMID- 23088180 TI - Real-time assessment of encapsulated neonatal porcine islets prior to clinical xenotransplantation. AB - BACKGROUND: Porcine islet transplantation is emerging as an attractive option for the treatment of patients with type 1 diabetes, with the possibility of providing islets of higher and more consistent quality and in larger volumes than available from human pancreata. The use of encapsulated neonatal porcine islets (ENPI) is appealing because it can address islet supply limitations while reducing the need for anti-rejection therapy. Pre-transplant characterization of ENPI viability and potency is an essential component of the production process. We applied the validated assay for oxygen consumption rate normalized for DNA content (OCR/DNA) to characterize ENPI viability. METHODS: ENPI of low viscosity and high m alginate were prepared according to standard methods and characterized at various culture time points up to 5 weeks. RESULTS: The OCR/DNA (nmol/min.mgDNA +/- SEM) of ENPI (235 +/- 10, n = 9) was comparable to that of free NPI (255 +/- 14, n = 13). After encapsulation, NPI OCR/DNA was sustained over a culture period of up to 5 weeks. The average OCR/DNA of ENPI cultured longer than 9 days was higher than that of freshly encapsulated NPI. CONCLUSION: This is the first characterization of ENPI by a validated and more sensitive method for product viability. The NPI encapsulation process does not compromise viability as measured by OCR/DNA, and ENPI can be cultured for up to 5 weeks with maintenance of viability. ENPI meet or exceed current adult porcine islet product release criteria (established at the University of Minnesota) for preclinical xenotransplantation in terms of OCR/DNA. PMID- 23088181 TI - Perioperative outcomes of esophagectomy preceded by the laparoscopic transhiatal approach for esophageal cancer. AB - This study was designed to determine the efficacy of esophagectomy preceded by the laparoscopic transhiatal approach (LTHA) with regard to the perioperative outcomes of esophageal cancer. The esophageal hiatus was opened by hand-assisted laparoscopic surgery, and carbon dioxide was introduced into the mediastinum. Dissection of the distal esophagus was performed up to the level of the tracheal bifurcation. En bloc dissection of the posterior mediastinal lymph nodes was performed using LTHA. Next, cervical lymphadenectomy, reconstruction via a retrosternal route with a gastric tube and anastomosis from a cervical approach were performed. Finally, a small thoracotomy (around 10 cm in size) was made to extract the thoracic esophagus and allow upper mediastinal lymphadenectomy to be performed. The treatment outcomes of 27 esophageal cancer patients who underwent LTHA-preceding esophagectomy were compared with those of 33 patients who underwent the transthoracic approach preceding esophagectomy without LTHA (thoracotomy; around 20 cm in size). The intrathoracic operative time and operative bleeding were significantly decreased by LTHA. The total operative time did not differ between the two groups, suggesting that the abdominal procedure was longer in the LTHA group. The number of resected lymph nodes did not differ between the two groups. Postoperative respiratory complications occurred in 18.5% of patients treated with LTHA and 30.3% of those treated without it. The increase in the number of peripheral white blood cells and the duration of thoracic drainage were significantly decreased by this method. Our surgical procedure provides a good surgical view of the posterior mediastinum, markedly shortens the intrathoracic operative time, and decreases the operative bleeding without increasing major postoperative complications. PMID- 23088182 TI - On the dissociation of the naphthalene radical cation: new iPEPICO and tandem mass spectrometry results. AB - The dissociation of the naphthalene radical cation has been reinvestigated here by a combination of tandem mass spectrometry and imaging photoelectron photoion coincidence spectroscopy (iPEPICO). Six reactions were explored: (R1) C(10)H(8)(*+) -> C(10)H(7)(+) + H (m/z = 127); (R2) C(10)H(8)(*+) -> C(8)H(6)(*+) + C(2)H(2) (m/z = 102); (R3) C(10)H(8)(*+) -> C(6)H(6)(*+) + C(4)H(2) (m/z = 78); (R4) C(10)H(8)(*+) -> C(10)H(6)(*+) + H(2) (m/z = 126); (R5) C(10)H(7)(+) -> C(6)H(5)(+) + C(4)H(2) (m/z = 77); (R6) C(10)H(7)(+) -> C(10)H(6)(*+) + H (m/z = 126). The E(0) activation energies for the reactions deduced from the present measurements are (in eV) 4.20 +/- 0.04 (R1), 4.12 +/- 0.05 (R2), 4.27 +/- 0.07 (R3), 4.72 +/- 0.06 (R4), 3.69 +/- 0.26 (R5), and 3.20 +/- 0.13 (R6). The corresponding entropies of activation, DeltaS(?)(1000K), derived in the present study are (in J K(-1) mol(-1)) 2 +/- 2 (R1), 0 +/- 2 (R2), 4 +/- 4 (R3), 11 +/- 4 (R4), 5 +/- 15 (R5), and -19 +/- 11 (R6). The derived E(0) value, combined with the previously reported IE of naphthalene (8.1442 eV) results in an enthalpy of formation for the naphthyl cation, Delta(f)H degrees (0K) = 1148 +/- 14 kJ mol( 1)/Delta(f)H degrees (298K) = 1123 +/- 14 kJ mol(-1) (site of dehydrogenation unspecified), slightly lower than the previous estimate by Gotkis and co-workers. The derived E(0) for the second H-loss leads to a Delta(f)H degrees for ion 7, the cycloprop[a]indene radical cation, of Delta(f)H degrees (0K) =1457 +/- 27 kJ mol(-1)/Delta(f)H degrees (298K)(C(10)H(6)(+)) = 1432 +/- 27 kJ mol(-1). Detailed comparisons are provided with values (experimental and theoretical) available in the literature. PMID- 23088183 TI - Improvement in stroke risk prediction: role of C-reactive protein and lipoprotein associated phospholipase A2 in the women's health initiative. AB - BACKGROUND: Classification of risk of ischemic stroke is important for medical care and public health reasons. Whether addition of biomarkers adds to predictive power of the Framingham Stroke Risk or other traditional risk factors has not been studied in older women. METHODS: The Hormones and Biomarkers Predicting Stroke Study is a case-control study of blood biomarkers assayed in 972 ischemic stroke cases and 972 controls, nested in the Women's Health Initiative Observational Study of 93, 676 postmenopausal women followed for an average of eight-years. We evaluated additive predictive value of two commercially available biomarkers: C-reactive protein and lipoprotein-associated phospholipase A2 to determine if they added to risk prediction by the Framingham Stroke Risk Score or by traditional risk factors, which included lipids and other variables not included in the Framingham Stroke Risk Score. As measures of additive predictive value, we used the C-statistic, net reclassification improvement, category-less net reclassification improvement, and integrated discrimination improvement index. RESULTS: Addition of C-reactive protein to Framingham risk models or additional traditional risk factors overall modestly improved prediction of ischemic stroke and resulted in overall net reclassification improvement of 6.3%, (case net reclassification improvement=3.9%, control net reclassification improvement=2.4%). In particular, high-sensitivity C-reactive protein was useful in prediction of cardioembolic strokes (net reclassification improvement=12.0%; 95% confidence interval 4.3-19.6%) and in strokes occurring in less than three years (net reclassification improvement=7.9%, 95% confidence interval 0.8-14.9%). Lipoprotein-associated phospholipase A2 was useful in risk prediction of large artery strokes (net reclassification improvement=19.8%, 95% confidence interval 7.4-32.1%) and in early strokes (net reclassification improvement=5.8%, 95% confidence interval 0.4-11.2%). CONCLUSIONS: C-reactive protein and lipoprotein associated phospholipase A2 can improve prediction of certain subtypes of ischemic stroke in older women, over the Framingham stroke risk model and traditional risk factors, and may help to guide surveillance and treatment of women at risk. PMID- 23088184 TI - In situ precipitation of amorphous calcium phosphate and ciprofloxacin crystals during the formation of chitosan hydrogels and its application for drug delivery purposes. AB - The immobilization of more than one single substance within the structure of a biocompatible polymer provides multifunctional biomaterials with attractive and enhanced properties. In the context of bone tissue engineering, it could be of great interest to synthesize a biomaterial that simultaneously contains amorphous calcium phosphate (ACP), to favor calcium and phosphate precipitation and promote osteogenesis, and an antibiotic such as ciprofloxacin (CFX) that can, eventually, avoid infections resulting after surgical scaffold implantation. However, the co immobilization of multiple substances is by no means a trivial issue because of the enhanced number of interactions that can take place. One of the main issues is controlling not only the diverse solid forms that individual substances can eventually adopt, but also the forces responsible for the self-organization of the individual components. The latter determines whether phase-separated structures or conjugated architectures are obtained and, consequently, may dramatically affect their functionality. Herein, we have observed-by SEM, TEM, and solid-state NMR-that enzymatically-assisted coprecipitation of ACP and CFX resulted in phase-separated structures. Thus, CFX crystals showed identical morphology to that obtained in the absence of ACP, but the size was smaller. Neither the size nor the morphology of ACP exhibited significant differences whether precipitated with or without CFX, but, in the former case, ACP was stabilized over a wider range of pH and temperature. Finally, by using this methodology and the ice segregation induced self-assembly process (ISISA), we have successfully co-immobilized ACP and CFX in chitosan-based scaffolds. Interestingly, the presence of ACP exerted significant control on the CFX release from these materials. PMID- 23088185 TI - Effect of propofol on hypoxia re-oxygenation induced neuronal cell damage in vitro*. AB - Propofol may protect neuronal cells from hypoxia re-oxygenation injury, possibly via an antioxidant actions under hypoxic conditions. This study investigated the molecular effects of propofol on hypoxia-induced cell damage using a neuronal cell line. Cultured human IMR-32 cells were exposed to propofol (30 MUm) and biochemical and molecular approaches were used to assess cellular effects. Propofol significantly reduced hypoxia-mediated increases in lactate dehydrogenase, a marker of cell damage (mean (SD) for normoxia: 0.39 (0.07) a.u.; hypoxia: 0.78 (0.21) a.u.; hypoxia+propofol: 0.44 (0.17) a.u.; normoxia vs hypoxia, p<0.05; hypoxia vs hypoxia+propofol, p<0.05), reactive oxygen species and hydrogen peroxide. Propofol also diminished the morphological signs of cell damage. Increased amounts of catalase, which degrades hydrogen peroxide, were detected under hypoxic conditions. Propofol decreased the amount of catalase produced, but increased its enzymatic activity. Propofol protects neuronal cells from hypoxia re-oxygenation injury, possibly via a combined direct antioxidant effect along with induced cellular antioxidant mechanisms. PMID- 23088186 TI - The use of bur and laser for root caries treatment: a comparative study. AB - This research analyzed the influence of bur and erbium, chromium:yttrium-scandium gallium-garnet (Er,Cr:YSGG) laser caries removal on cavity characteristics and marginal seal of composite resin restorations. One hundred and forty human dental root samples were used. After in vitro root caries induction using Streptococcus mutans, the carious lesions were removed either by a conventional technique using burs (G1=control) or by using an Er,Cr:YSGG laser (lambda=2.78 MUm, 20 Hz, pulse duration is approximately equal to 140 MUs, noncontact mode using a 600-MUm tip) with the following power outputs: G2: 1.0 W; G3: 1.25 W; G4: 1.5 W; G5: 1.75 W; G6: 2.0 W; G7: 2.25 W; G8: 2.5 W; G9: 2.75 W; G10: 3.0 W; G11: 3.25 W; G12: 3.5 W; G13: 3.75 W; and G14: 4.0 W. Samples in the 14 groups (n=10) were conditioned with Clearfil SE Bond and restored with a flowable composite. They were then thermocycled (1000 cycles) and immersed into a 2% methylene blue solution for microleakage analysis. The data were statistically compared (analysis of variance or Spearman correlation tests; p<=0.05). The lased groups showed significantly greater microleakage indexes, cavity depths, and presence of residual caries than did those of the control group. There was a strong positive correlation between residual caries and microleakage. The results indicate that Er,Cr:YSGG laser irradiation is not a good alternative to the use of burs for root caries removal since it may cause a significant loss of marginal sealing in composite resin restorations. PMID- 23088187 TI - Effect of using silorane-based resin composite for restoring conservative cavities on the changes in cuspal deflection. AB - OBJECTIVE: To investigate the effect of using two resin-composite materials for restoring conservative mesio-occluso-distal (MOD) cavities on the changes (incremental and cumulative) in cuspal deflection. METHODS: Forty extracted sound human maxillary second premolars were subjected to standardized MOD cavity preparation and then divided into two groups (n=20). The first group of teeth was restored with Filtek Z250 (3M ESPE, St Paul, MN, USA), and Filtek P90 (3M ESPE, St Paul, MN, USA) was used in the second group. Incremental cuspal deflection was calculated by measuring the intercuspal distance between the indexed cusp tips before the restoration and at five-minute intervals up to 30 minutes using a stereomicroscope connected to a digital camera. Cumulative cuspal deflection for both materials was also calculated. RESULTS: Comparing the incremental cuspal deflection of the tested groups at each time interval, it was found that there was no significant difference immediately after curing and at five, 15, 20, and 25 minutes. However, a significant difference was recorded at 10 and 30 minutes. For the cumulative cuspal deflection, Filtek P90 showed significantly lower deflection values than Filtek Z250 only after five minutes. CONCLUSIONS: Incremental cuspal deflections of both materials over the tested intervals were almost comparable. However, after five minutes of curing, silorane-based resin composite surpassed the methacrylate-based resin composite in controlling the cumulative cuspal deflection. PMID- 23088188 TI - Evaluating dentin surface treatments for resin-modified glass ionomer restorative materials. AB - This in vitro study evaluated the effect of six surface treatments on the shear bond strength of three resin-modified glass ionomers (RMGIs) to dentin. Occlusal surfaces of caries-free third molars were reduced to expose only dentin. Surface treatments were smear layer intact (negative control), Cavity Conditioner, EDTA, Ketac Primer, Self Conditioner, and etching with 35% phosphoric acid followed by the application of Optibond Solo Plus. Filtek Z250 composite resin bonded with Optibond Solo Plus served as a positive control. Conditioning agents were used according to the manufacturers' instructions. After surface treatments, Fuji II LC, Riva LC, Ketac Nano, and Filtek Z250 were placed in copper-band matrices 5 mm in diameter and 2 mm in height and were light-cured for 20 seconds. Specimens were stored in 100% humidity for 24 hours, after which they were placed in deionized water for 24 hours at 37 degrees C. They were then tested under shear forces in an Instron Universal Testing Machine at a crosshead speed of 0.5 mm/min. A two-way analysis of variance and Tukey honestly significant difference statistical analyses (p<0.05) indicated significant interaction between RMGIs and conditioning agents. Acid etching followed by Optibond Solo Plus provided highest bond strengths for all three RMGIs, which were not statistically different from the positive control. PMID- 23088189 TI - Effects of preheating and precooling on the hardness and shrinkage of a composite resin cured with QTH and LED. AB - The aim of this study was to evaluate in vitro the hardness and shrinkage of a pre-cooled or preheated hybrid composite resin cured by a quartz-tungsten-halogen light (QTH) and light-emitting diode (LED) curing units. The temperature on the tip of the devices was also investigated. Specimens of Charisma resin composite were produced with a metal mold kept under 37 degrees C. The syringes were submitted to 4 degrees C, 23 degrees C, and 60 degrees C (n=20) before light curing, which was carried out with the Optilux 501 VCL and Elipar FreeLight 2 units for 20 seconds. The specimens were kept under 37 degrees C in a high humidity condition and darkness for 48 hours. The Knoop hardness test was carried out with a 50 gram-force (gf) load for 10 seconds, and the measurement of the shrinkage gap was carried out using an optical microscope. The data were subjected to analysis of variance and the Games-Howell test (alpha=0.05). The mean hardness of the groups were similar, irrespective of the temperatures (p>0.05). For 4 degrees C and 60 degrees C, the top surface light-cured by LED presented significantly reduced shrinkage when compared with the bottom and to both surfaces cured by QTH (p<0.05). It was concluded that the hardness was not affected by pre-cooling or preheating. However, polymerization shrinkage was slightly affected by different pre-polymerization temperatures. The QTH-curing generated greater shrinkage than LED-curing only when the composite was preheated. Different temperatures did not affect the composite hardness and shrinkage when cured by a LED curing unit. PMID- 23088191 TI - Public health nursing and interprofessional collaboration in Norwegian municipalities: a questionnaire study. AB - The purpose of this study was to examine collaboration relating to public health nursing in different sized Norwegian municipalities. It sought to gain insight into factors that are important for successful collaboration, frequency of meeting points for collaborating activities and missing professionals in different sized municipalities. A cross-sectional e-post questionnaire study was carried out on a national sample of public health nurses and their collaborators. A total of 849 public health nurses (43.64%), 113 doctors at clinics and school health services (54.8%), 519 child protection workers (16.34%) and 115 midwives (41.3%) returned the questionnaire. The data were analysed using descriptive and inferential statistics. Analysis of variance (anova), Kruskal-Wallis H and chi square tests were used to tests differences between groups. Trust, respect and collaborative competence were ranked highest by all the respondents and formalised structures, economy and leadership ranked least important in collaborative activity. The majority of the respondents stated that they do not have fewer meeting points compared with 5 years ago. Collaboration with mental health services was missed most by all respondents. There were associations between frequency of meeting points and statements on collaboration related to municipality size. Norway is in the throes of a major coordination reform. The fact that relational factors were deemed most important for successful collaboration is an important finding at a time when focus is on structural change. The findings indicate the need for further in depth qualitative studies on reasons for 'missing collaborators,' on professional cultures in different sized municipalities and on interpersonal relationships. Qualitative enquiry is necessary to gain a greater understanding of how relational concepts of respect, trust and conflict are understood by municipal public health professionals. PMID- 23088190 TI - Divergence of the SigB regulon and pathogenesis of the Bacillus cereus sensu lato group. AB - BACKGROUND: The Bacillus cereus sensu lato group currently includes seven species (B. cereus, B. anthracis, B. mycoides, B. pseudomycoides, B. thuringiensis, B. weihenstephanensis and B. cytotoxicus) that recent phylogenetic and phylogenomic analyses suggest are likely a single species, despite their varied phenotypes. Although horizontal gene transfer and insertion-deletion events are clearly important for promoting divergence among these genomes, recent studies have demonstrated that a major basis for phenotypic diversity in these organisms may be differential regulation of the highly similar gene content shared by these organisms. To explore this hypothesis, we used an in silico approach to evaluate the relationship of pathogenic potential and the divergence of the SigB-dependent general stress response within the B. cereus sensu lato group, since SigB has been demonstrated to support pathogenesis in Bacillus, Listeria and Staphylococcus species. RESULTS: During the divergence of these organisms from a common "SigB-less" ancestor, the placement of SigB promoters at varied locations in the B. cereus sensu lato genomes predict alternative structures for the SigB regulon in different organisms. Predicted promoter changes suggesting differential transcriptional control of a common gene pool predominate over evidence of indels or horizontal gene transfer for explaining SigB regulon divergence. CONCLUSIONS: Four lineages of the SigB regulon have arisen that encompass different gene contents and suggest different strategies for supporting pathogenesis. This is consistent with the hypothesis that divergence within the B. cereus sensu lato group rests in part on alternative strategies for regulation of a common gene pool. PMID- 23088192 TI - Chronic lymphocytic leukemia presenting as an intracranial epidural mass in a patient with myeloproliferative neoplasm associated with JAK2 V617F mutation. PMID- 23088193 TI - Framing and global health governance: key findings. AB - Despite widespread agreement that collective action to address shared health challenges across countries is desirable and necessary, the realm of global health governance has remained highly problematic. A key reason for this is the manner in which health issues are presented ('framed'). Because multiple frames are operating simultaneously, confusion and a range of competing policy recommendations and priorities result. Drawing on the previous articles published in this Special Supplement, these key findings explore how health issues are framed, what makes a framing successful, what frames are used for and what effects framing has. PMID- 23088194 TI - Can tapentadol cause a false-positive urine drug screen result for amphetamine? PMID- 23088195 TI - Age differences in strategy shift: retrieval avoidance or general shift reluctance? AB - Previous studies of metacognitive age differences in skill acquisition strategies have relied exclusively on tasks with a processing shift from an algorithm to retrieval strategy. Older adults' demonstrated reluctance to shift strategies in such tasks could reflect either a specific aversion to a memory retrieval strategy or a general, inertial resistance to strategy change. Haider and Frensch's (1999) alphabet verification task (AVT) affords a non-retrieval-based strategy shift. Participants verify the continuation of alphabet strings such as D E F G [4] L, with the bracketed digit indicating a number of letters to be skipped. When all deviations are restricted to the letter-digit-letter portion, participants can speed their responses by selectively attending to only that part of the stimulus. We adapted the AVT to include conditions that promoted shift to a retrieval strategy, a selective attention strategy, or both strategies. Item level strategy reports were validated by eye movement data. Older adults shifted more slowly to the retrieval strategy but more quickly to the selective attention strategy than young adults, indicating a retrieval-strategy avoidance. Strategy confidence and perceived strategy difficulty correlated with shift to the two strategies in both age groups. Perceived speed of responses with each strategy specifically correlated with older adults' strategy choices, suggesting that some older adults avoid retrieval because they do not appreciate its efficiency benefits. PMID- 23088196 TI - Age and the association between negative affective states and diurnal cortisol. AB - The current study examined age differences in the association between daily negative affect, average negative affect, and diurnal cortisol among participants from the National Study of Daily Experiences (N = 1,423; age range: 33-84 years). Across four consecutive days, participants reported the negative emotions they experienced and provided four saliva samples per day, from which cortisol was assayed. Results revealed that higher levels of average negative affect were associated with greater daily cortisol output (area-under-the-curve, with respect to ground), but only among the older participants in our sample. Higher levels of daily negative affect were also associated with elevated levels of bedtime cortisol, but only among older adults who, on average, reported lower levels of average negative affect. Findings support the theory of strength and vulnerability integration, and underscore the importance of age when examining associations between negative affective states and diurnal cortisol. PMID- 23088197 TI - The choices we make: an examination of situation selection in younger and older adults. AB - The current study examined the effects of age and control beliefs on the use of situation selection. Younger and older adults spent 15 min in a room containing multiple affective streams that varied in emotional valence, and were given free choice to engage with whatever they wanted. No significant main effect of age emerged on the number of choices of, or time spent with, material of each valence. However, age and beliefs interacted such that older adults with strong emotion regulation self-efficacy and general control beliefs chose fewer negative stimuli, whereas younger adults with strong beliefs chose more negative stimuli. Results are discussed from aging and individual differences perspectives. PMID- 23088199 TI - Parental bereavement during mid-to-later life: pre- to postbereavement functioning and intrapersonal resources for coping. AB - The death of a child when parents are in mid-to-late life is a traumatic event for aging parents. In order to evaluate adjustment, the impact of unanticipated versus anticipated deaths, and the effects of internal resources for coping with bereavement, we examined pre- and postbereavement functioning, using the 1992/94 and 2004/06 waves of the Wisconsin Longitudinal Study, for parents (M age = 54 and 65 years, respectively) whose adult child died between these dates (n = 175). The results revealed a general pattern of adaptation in which most bereaved parents were functioning as well as a matched comparison group (n = 175), though more depression symptoms were present both before and after the death of the child for the mothers of children who died from long-term illnesses and the fathers of children who committed suicide, suggesting that conditions predating the death were chronic strains for these parents. Intrapersonal resources, including a sense of purpose in life and high levels of agreeableness, were associated with better functioning, particularly for bereaved parents whose children's deaths were not anticipated. The study places parental bereavement in the context of normative aging and the framework of chronic life strain. PMID- 23088200 TI - Confirmatory factor analysis of the Beck Depression Inventory-II in bariatric surgery candidates. AB - Screening for depression is an integral part of psychological evaluations conducted prior to bariatric surgery. The Beck Depression Inventory-II (BDI-II) is the most commonly used measure of depression in these treatment evaluations. The reliability and validity of the BDI-II has not yet been evaluated within bariatric surgery-seeking samples, evidencing a significant gap in the present literature. The purpose of the present study is to evaluate the structural validity of the BDI-II and to examine the reliability and convergent and criterion validity of this instrument within a bariatric surgery-seeking sample. The study population consisted of 505 ethnically diverse bariatric surgery candidates presenting for presurgical psychological evaluations in a midwestern urban academic medical center. Confirmatory factor analytic results indicated that a 3-factor model consisting of affective, cognitive, and somatic factors was the best fitting model of depression within this sample. Internal consistency reliability was satisfactory for each subscale, ranging from .72 to .82. Moderate to large correlations were observed between each BDI-II subscale and a measure of depression previously validated with bariatric surgery candidates indicating adequate convergent validity. On the basis of clinical interview, 14% of the sample was diagnosed with current major depression. Significant mean differences were observed between depressed and nondepressed patients with respect to each BDI-II subscale score, demonstrating criterion-related validity. The BDI-II is a reliable and valid measure of depression for bariatric surgery candidates. Understanding the factor structure of the BDI-II can be useful for planning potential presurgical psychological interventions. PMID- 23088201 TI - Concurrent and predictive associations between early adolescent perceptions of peer affiliates and mood states collected in real time via ecological momentary assessment methodology. AB - This study uses ecological momentary assessment (EMA) to simultaneously capture youths' perceptions of peer affiliates and social contexts to determine their association with youths' current and future mood states. A sample of 82 seventh grade students (36 at risk for developing or escalating rule breaking and substance use and 46 randomly selected) from 4 schools participated. Using EMA methodology, we had students report their peer affiliations, perceptions of peer affiliates, moods, activities, location, and behaviors during their free time. Data from 3 assessment waves were collected; each wave consisted of 27 randomly prompted assessments during a week. Youths spent a large portion of their free time watching television, on the computer, or playing video games. Being "out and about" increased over the school year, whereas adult supervision decreased, showing an increase in potentially risky situations. Happiness was associated with affiliating with peers who were perceived to be popular. Negative moods were associated with affiliating with peers by whom they were teased or treated meanly. Multilevel models found that both levels and lability of negative moods (i.e., sadness, anxiety) were predicted by risk status and affiliation with peers who tease them. Compared with boys, girls who affiliated more with peers who teased them and were classified as at risk had more extreme negative moods and negative mood lability. EMA methodology has demonstrated the ways in which salient intrapersonal and peer processes are associated over time, which can inform efforts to prevent the development and escalation of behavior problems, substance use, and mood disorders in adolescence. PMID- 23088202 TI - Factorial invariance of the Brief Symptom Inventory-18 (BSI-18) for adults of Mexican descent across nativity status, language format, and gender. AB - The cultural equivalence of psychological outcome measures remains a major area of investigation. The current study sought to test the factor structure and factorial invariance of the Brief Symptom Inventory-18 (BSI-18) with a sample of adult individuals of Mexican descent (N=923) across nativity status (U.S.- vs. foreign-born), language format (English vs. Spanish), and gender. The results show that 1-factor and 3-factor measurement models provided a good fit to the data; however, a single-factor model was deemed more appropriate and parsimonious. Tests of measurement invariance and invariance of factor variances (i.e., structural invariance) indicated at least partial measurement invariance across gender, nativity status, and language format. These findings suggest that the BSI-18 operates in a similar fashion among adults of Mexican descent regardless of nativity status, language format of the survey, and gender. Clinical and practical implications for use of the BSI-18 with Latino populations are discussed. PMID- 23088203 TI - Assessment of global psychiatric categories: the PSI/PSI-2 and the MMPI-2-RF. AB - The 3 Higher Order (HO) scales of the Minnesota Multiphasic Personality Inventory 2 Restructured Form and the 3 core clinical scales of the Psychological Screening Inventory/Psychological Screening Inventory-2 were developed to broadly represent the 3 traditional psychiatric categories of mental disorder: major psychiatric disorder ("psychotic"), general psychological distress ("neurotic"), and significant antisocial characteristics ("character disorder"). The present article reports 2 studies that assessed the validity of test scores from each scale for their intended purpose. Participants included 2 groups of forensic clients (n=138 and 78), college undergraduates (n=100), and previously reported data on larger groups of participants. Validity was supported in 2 ways: high loadings in confirmatory factor models based on the 3 psychiatric categories and medium to large effect sizes in discriminating between relevant disordered groups and normative groups. The tests showed comparable results. Limitations included co-morbidity in some participant groups and the relatively narrow range of psychopathology in undergraduate participants. PMID- 23088204 TI - Psychopathy and the combination of psychopathy and sexual deviance as predictors of sexual recidivism: meta-analytic findings using the Psychopathy Checklist- Revised. AB - Clinicians routinely administer Hare's (2003) Psychopathy Checklist-Revised (PCL R) to sex offenders and report PCL-R scores as meaningful predictors of recidivism risk. Although a 2005 meta-analysis reported a small (d=0.29) association between PCL-R scores and sexual recidivism (Hanson & Morton-Bourgon, 2005), no meta-analysis has examined effects for PCL-R factors and facets, the widely cited combination of high PCL-R and high sexual deviance scores, or potential moderators of the PCL-R/recidivism relation. We conducted a meta analysis of effects from all available studies examining the relation between PCL R scores and sexual recidivism (k=20, N=5,239). The effect for PCL-R Total scores predicting sexual recidivism was d=0.40, which falls beyond the upper end of the 2005 confidence interval [.20, .38]. Effects were stronger for Factor 2 (d=0.44) and Facet 4 (d=0.40) scores than other factor or facet scores (ds=0.01 to 0.17). Effects tended to be stronger for scores calculated for research (d=0.44) compared to those calculated for clinical use (d=0.28). Offenders who scored high on both the PCL-R and a measure of sexual deviance were more likely to reoffend sexually than other offenders (odds ratio=2.80 to 3.21, k=6). Results indicate that PCL-R scores, particularly combined with a measure of sexual deviance, are potentially relevant to sex offender risk. But results also underscore several practical challenges to implementing these findings in routine clinical practice. PMID- 23088206 TI - Psychopathy and depression as predictors of psychosocial difficulties in a sample of court evaluated adolescents. AB - Psychopathy and depression have rarely been studied together despite relatively high rates of both in court-referred adolescent samples. To determine if youth high in psychopathy and depression experience more psychosocial difficulties, the current study examined psychopathy and depression in 103 adolescent offenders using two well-validated assessments: The Psychopathy Checklist-Youth Version (PCL-YV; Forth, Kosson, & Hare, 1996/2003) and the depression scale of the Adolescent Psychopathology Scale (APS; Reynolds, 1998). Findings showed that psychopathy and depression interact to statistically predict much higher levels of anger, aggression, interpersonal problems, and substance use. Implications for these findings include that youth who are high in psychopathy and come in contact with the law are also at high risk for numerous problems. Clinical implications driven from the current findings are that assessment and treatment programs in juvenile justice settings should be tailored and systematized to address externalizing and internalizing symptoms in youth and also to consider the co occurrence of the two. Juvenile justice systems might also benefit from developing clinical practices that require assessment and treatment units to undergo program training to ensure that they (a) account for possible co occurring effects of commonly assessed disorders and (b) adequately treat complex youth mental health problems with customized treatment programs. Such training would allow for more effective treatment affording youth greater opportunities to succeed in society. PMID- 23088205 TI - Psychometric properties of the Therapeutic Alliance Scale for Caregivers and Parents. AB - This study examined the psychometric properties of the Therapeutic Alliance Scale for Caregivers and Parents (TASCP) in a sample of 209 caregivers whose children (4-13 years of age) presented with disruptive behavior problems to a publicly funded outpatient mental health clinic in San Diego County. Information about therapeutic alliance was collected from caregivers, children, and their therapists across the course of therapy (up to 16 months). Results support the reliability, temporal stability, convergent validity, and discriminant validity of scores on the TASCP. The multilevel factor structure of this new measure was consistent with the parallel child-report version, with 2 within-level factors and 1 between-level factor. Furthermore, predictive validity was strong, with stronger caregiver-reported alliance associated with less treatment dropout, more sessions attended, and greater satisfaction with perceived improvement. PMID- 23088207 TI - Psychophysiological assessment of emotional processing in patients with borderline personality disorder with and without comorbid substance use. AB - This study assessed physiological measures for the study of emotional dysregulation associated with borderline personality disorder (BPD). Two patient groups, the first comprised of individuals with BPD only (n = 16) and the second, individuals with BPD and co-occurring substance-use disorder (SUD; n = 35), and a group of healthy controls (n = 45) were shown standardized pictures of varying valance and arousal levels. Affective modification of startle eye-blink responses, heart rate, facial electromyography (EMG, including corrugator and zygomatic activity), and skin-conductance responses were collected during picture presentation and during a brief recovery period. Startle data during picture presentation indicated a trend toward the expected increase in startle response magnitude to negative stimuli, to be moderated by group status, with patients with BPD-SUD showing a lack of affective modification and the BPD-only group showing similar affective modification to that of controls. Heart-rate data suggested lower reactivity to negative pictures for both patient groups. Differences in facial EMG responses did not provide a clear pattern, and skin conductance responses were not significantly different between groups. The data did not suggest differences between groups in recovery from exposure to the emotional stimuli. The startle and heart-rate data suggest a possible hyporeactivity to emotional stimuli in BPD. PMID- 23088208 TI - A review of preliminary observations on agomelatine in the treatment of anxiety disorders. AB - Agomelatine is an antidepressant with a novel mechanism of being a selective melatonergic MT1/MT2 receptor agonist with serotonin 5-HT(2c) receptor antagonist activities. Although the vast majority of the clinical data concerning the effectiveness of agomelatine concern its antidepressant properties, there is also preliminary evidence of anxiolytic effects. The purpose of the study was to perform a review of studies that investigated the efficacy of agomelatine in the treatment of anxiety disorders (ADs) and a discussion of the clinical utility of agomelatine in this clinical population. Previous clinical data indicated that agomelatine was more efficacious than both placebo and comparator drugs in reducing anxiety symptoms in depressed patients. Moreover, agomelatine effectiveness in the treatment of AD patients was observed in 2 double-blind, randomized trials, in a case series and in 3 case reports. Greater clinical evidence was observed with generalized AD patients. Agomelatine was efficacious both in reducing anxiety symptoms and in preventing relapses after a 6-month follow-up. However, concerning other ADs, evidence of agomelatine's effects on anxiety was found only in isolated case descriptions. Nevertheless, those case reports emphasized the drug's favorable side effect profile (in comparison to serotonin reuptake inhibitors) and its effectiveness in treatment-refractory patients. Considering the high incidence of poor efficacy and tolerability of the first-line agents in the treatment of ADs, agomelatine seems to be a promising option in cases of treatment failure, and it could be used as a second or third option, as monotherapy or as augmentation treatment. PMID- 23088209 TI - How to achieve universal coverage of cataract surgical services in developing countries: lessons from systematic reviews of other services. AB - PURPOSE: Since the Declaration of Alma Ata, universal coverage has been at the heart of international health. The purpose of this study was to review the evidence on factors and interventions which are effective in promoting coverage and access to cataract and other health services, focusing on developing countries. METHODS: A thorough literature search for systematic reviews was conducted. Information resources searched were Medline, The Cochrane Library and the Health System Evidence database. Medline was searched from January 1950 to June 2010. The Cochrane Library search consisted of identifying all systematic reviews produced by the Cochrane Eyes and Vision Group and the Cochrane Effective Practice and Organisation of Care. These reviews were assessed for potential inclusion in the review. The Health Systems Evidence database hosted by MacMaster University was searched to identify overviews of systematic reviews. RESULTS: No reviews met the inclusion criteria for cataract surgery. The literature search on other health sectors identified 23 systematic reviews providing robust evidence on the main factors facilitating universal coverage. The main enabling factors influencing access to services in developing countries were peer education, the deployment of staff to rural areas, task shifting, integration of services, supervision of health staff, eliminating user fees and scaling up of health insurance schemes. CONCLUSION: There are significant research gaps in eye care. There is a pressing need for further high quality primary research on health systems-related factors to understand how the delivery of eye care services and health systems' capacities are interrelated. PMID- 23088211 TI - Pharmacological modulation of the bradykinin-induced differentiation of human lung fibroblasts: effects of budesonide and formoterol. AB - OBJECTIVE: Bradykinin (BK) induces differentiation of lung fibroblasts into myofibroblasts, which play an important role in extracellular matrix remodeling in the airways of asthmatic patients. It is unclear whether this process is affected by antiasthma therapies. Here, we evaluated whether a glucocorticoid, budesonide (BUD), and a long-acting beta2-agonist, formoterol (FM), either alone or in combination, modified BK-induced lung fibroblast differentiation, and affected the BK-activated intracellular signaling pathways. METHODS: Human fetal lung fibroblasts were incubated with BUD (0.001-0.1 MUM) and/or FM (0.0001-0.1 MUM) before exposure to BK (0.1 or 1 MUM). Fibroblast differentiation into alpha smooth-muscle-actin-positive (alpha-SMA+) myofibroblasts, BK2 receptor (B2R) expression, extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation (p-ERK1/2), intracellular Ca2+ concentration ([Ca2+]i), and p65 nuclear factor kappa B translocation were evaluated. RESULTS: BUD (0.1 MUM) and FM (0.1 MUM), either alone or in combination, completely inhibited BK-induced alpha-SMA protein expression and decreased the numbers of alpha-SMA+ fibroblasts, with a clear reduction in alpha-SMA stress fibers organization. BUD also completely inhibited the increase of B2R, whereas FM with or without BUD had no effect. BK-induced increases of [Ca2+]i and p-ERK1/2 were significantly reduced to similar levels by BUD and FM, either alone or in combination, whereas p65 translocation was completely inhibited by all treatments. CONCLUSION: Both BUD and FM, either alone or in combination, effectively inhibited the BK-induced differentiation of fibroblasts into alpha-SMA+ myofibroblasts and the intracellular signaling pathways involved in fibroblast activation. These results suggest that BUD and FM combination therapy has potential to inhibit fibroblast-dependent matrix remodeling in the airways of asthmatic patients. PMID- 23088210 TI - NADPH oxidase-mediated triggering of inflammasome activation in mouse podocytes and glomeruli during hyperhomocysteinemia. AB - AIM: Our previous studies have shown that NOD-like receptor protein (NALP3) inflammasome activation is importantly involved in podocyte dysfunction and glomerular sclerosis induced by hyperhomocysteinemia (hHcys). The present study was designed to test whether nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated redox signaling contributes to homocysteine (Hcys)-induced activation of NALP3 inflammasomes, an intracellular inflammatory machinery in podocytes in vitro and in vivo. RESULTS: In vitro confocal microscopy and size exclusion chromatography revealed that upon NADPH oxidase inhibition by gp91(phox) siRNA, gp91ds-tat peptide, diphenyleneiodonium, or apocynin, aggregation of inflammasome proteins NALP3, apoptosis-associated speck-like protein (ASC), and caspase-1 was significantly attenuated in mouse podocytes. This NADPH oxidase inhibition also resulted in diminished Hcys-induced inflammasome activation, evidenced by reduced caspase-1 activity and interleukin 1beta production. Similar findings were observed in vivo where gp91(phox-/-) mice and mice receiving a gp91ds-tat treatment exhibited markedly reduced inflammasome formation and activation. Further, in vivo NADPH oxidase inhibition protected the glomeruli and podocytes from hHcys-induced injury as shown by attenuated proteinuria, albuminuria, and glomerular sclerotic changes. This might be attributed to the fact that gp91(phox-/-) and gp91ds-tat-treated mice had abolished infiltration of macrophages and T-cells into the glomeruli during hHcys. INNOVATION: Our study for the first time links NADPH oxidase to the formation and activation of NALP3 inflammasomes in podocytes. CONCLUSION: Hcys induced NADPH oxidase activation is importantly involved in the switching on of NALP3 inflammasomes within podocytes, which leads to the downstream recruitment of immune cells, ultimately resulting in glomerular injury and sclerosis. PMID- 23088212 TI - Comparison of salvage chemoradiation versus salvage surgery for recurrent esophageal squamous cell carcinoma after definitive radiochemotherapy or radiotherapy alone. AB - A consensus treatment strategy for esophageal squamous cell carcinoma (ESCC) patients who recur after definitive radiochemotherapy/radiotherapy has not been established. This study compared the outcomes in ESCC patients who underwent salvage surgery, salvage chemoradiation (CRT) or best supportive care (BSC) for local recurrence. Ninety-five patients with clinical stage I to III ESCC who had completely responded to the initial definitive radiochemotherapy or radiotherapy alone and developed local recurrence were enrolled in this study. Fifty-one of them received salvage esophagectomy, and R0 resection was performed in 41 patients, 36 underwent salvage CRT, and the remaining eight patients received BSC only. The 5-year overall survival was 4.6% for the 87 patients receiving salvage surgery or CRT, while all patients in the BSC group died within 12.0 months, the difference was statistically significant (P = 0.018). The 1-, 3-, 5-year survival rates in the salvage surgery and salvage CRT groups were 45.1%, 20.0%, 6.9% and 51.7%, 12.2%, 3.1%, respectively, there was no difference of overall survival between the two groups (P = 0.697). Patients also presented with lymph node relapse had inferior survival compared to those with isolated local tumor recurrence after salvage therapy. In the salvage surgery group, infections occurred in eight patients, and three developed anastomotic leakage. In the salvage CRT group, grade 2-4 esophagitis and radiation pneumonitis was observed in 19 and 3 patients, respectively. Seven patients (19.4%) developed esophagotracheal fistula or esophageal perforation. This study of salvage CRT versus salvage surgery for recurrent ESCC after definitive radiochemotherapy or radiotherapy alone did not demonstrate a statistically significant survival difference, but the frequency of complications including esophagotracheal fistula and esophageal perforation following salvage CRT was high. PMID- 23088213 TI - Caregivers in older peoples' care: perception of quality of care, working conditions, competence and personal health. AB - The aim was to describe and compare nursing assistants', enrolled nurses' and registered nurses' perceptions of quality of care, working conditions, competence and personal health in older peoples' care. Altogether 70 nursing assistants, 163 enrolled nurses and 198 registered nurses completed a questionnaire comprising Quality from the Patient's Perspective modified for caregivers, Creative Climate Questionnaire, Stress of Conscience Questionnaire, items on education and competence and Health Index. The caregivers reported higher perceived reality of quality of care in medical-technical competence and physical-technical conditions than in identity-oriented approach and socio-cultural atmosphere. In subjective importance, the highest rating was assessed in one of the physical-technical items. The organisational climate was for three of the dimensions rather close/reached the value for a creative climate, for seven dimensions close to a stagnant climate. In perceived stress of conscience, there were low values. Nursing assistants had lower values than enrolled nurses and registered nurses. The caregivers reported highest values regarding previous education making them feel safe at work and lowest value on the item about education increasing the ability for a scientific attitude. Registered nurses could use knowledge in practice and to a higher degree than nursing assistants/enrolled nurses reported a need to gain knowledge, but the latter more often received education during working hours. The health index among caregivers was high, but registered nurses scored lower on emotional well-being than nursing assistants/enrolled nurses. The caregivers' different perceptions of quality of care and work climate need further attention. Although stress of conscience was low, it is important to acknowledge what affected the caregivers work in a negative way. Attention should be paid to the greater need for competence development among registered nurses during working hours. PMID- 23088214 TI - Making a human right to tobacco control: expert and advocacy networks, framing and the right to health. AB - This article addresses the proliferation of human rights in international public health over the last 20 years by examining recent attempts at framing the global smoking epidemic as a human rights problem. Rather than advocating in favour or against human rights-based approaches, the article purports to understand how and why such approaches are being articulated and disseminated. First, it argues that the representation of the global smoking epidemic as a human rights issue has been the product of a small, international network of public health experts and lawyers: the human rights and tobacco control collective or community (HTC). The article describes in particular the HTC's membership, its style of thinking and its efforts to articulate and disseminate human rights-based approaches to tobacco control. Second, the article argues that the aim of the HTC when framing tobacco control as a human rights issue was not to generate public attention for and the political will to tackle the global smoking epidemic, as the literature on framing and human rights presupposes. Instead, as the article shows, the HTC framed tobacco control as a human rights problem to tap into the powerful, judicial monitoring and enforceability mechanisms that make up international human rights. PMID- 23088215 TI - Knotless "three-U-stitches" technique for urethrovesical anastomosis during laparoscopic radical prostatectomy. AB - We describe a new technique for urethrovesical anastomosis that consists of placing three "U" stitches of Monocryl 2-0 to connect the bladder neck and urethral stump together. The margins are united by a double passage of the suture, without tying any knots. The sutures are tied on the bladder's surface using Lapra-Ty clips fixed at a certain distance from where to two mucosal margins have been joined. We carried out this technique on 90 patients who underwent laparoscopic extraperitoneal radical prostatectomy. The good joining of the margins, the absence of knots and the minimum trauma to the urethral wall together enable to create an anastomosis that is both "sealed" and "tension free", allowing a quick "welding" of the margins and an early catheter removal. Regarding urinary continence, 56.6% (51) of patients were continent at catheter removal, 87.6% (78) were continent 3 months later and 98.9% (89) were continent after 6 months. In nine patients (10%), an episode of acute urinary retention occurred within 24 h after the removal of the catheter. We did not encounter any cases of vesicourethral anastomosis stenosis. PMID- 23088216 TI - The value of inflammation markers and body temperature in acute diverticulitis. AB - AIM: To determine the diagnostic value of serological infection markers and body temperature in discriminating complicated from uncomplicated diverticulitis. METHODS: Patients in whom diverticulitis was pathologically or radiologically proven at presentation were included. Patients were classified as either complicated (Hinchey Ib, II, III and IV) or uncomplicated (Hinchey Ia) diverticulitis. The discriminative value of C-reactive protein (CRP), white blood cell (WBC) count and body temperature at presentation was tested. RESULTS: A total of 426 patients were included in this study of which 364 (85%) presented with uncomplicated and 62 (15%) with complicated diverticulitis. Only CRP was of sufficient diagnostic value (area under the curve 0.715). The median CRP in patients with complicated diverticulitis was significantly higher than in patients with uncomplicated disease (224 mg/l, range 99-284 vs 87 mg/l, range 48 151). Patients with a CRP of 25 mg/l had a 15% chance of having complicated diverticulitis. This increased from 23% at a CRP value of 100 mg/l to 47% for 250 mg/l or higher. The optimal threshold was reached at 175 mg/l with a positive predictive value of 36%, negative predictive value of 92%, sensitivity of 61% and a specificity of 82%. CONCLUSION: WBC count and body temperature are of no value in discriminating complicated from uncomplicated diverticulitis. Only CRP can be used as an indicator for the presence of complications, but a low CRP does not mean that complicated disease can safely be excluded. Therefore, radiological examination remains central in the diagnostic work-up of patients presenting with diverticulitis. PMID- 23088217 TI - Use of nonsteroidal anti-inflammatory drugs among healthy people and specific cerebrovascular safety. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs can increase bleeding and thrombosis, but little is known about the cerebrovascular safety of these drugs, especially among healthy people. AIMS: The aim of this study was to examine the risk of ischemic and hemorrhagic stroke associated with the use of nonsteroidal anti-inflammatory drugs in healthy people. METHODS: By individual-level linkage of nationwide administrative registers in Denmark, information on hospital admissions, prescription claims, vital status, and cause of death were obtained. A cohort of healthy people without hospital admissions for five-years and no important prescription claims for two-years was selected. Case crossover and Cox proportional hazard models were used to analyze the relationship between nonsteroidal anti-inflammatory drug utilization and specific cerebrovascular risk (fatal or non-fatal ischemic or hemorrhagic stroke). RESULTS: We selected 1,028,437 healthy individuals (median age 39 years). At least one nonsteroidal anti-inflammatory drug was claimed by 44.7% of the study population, and the drugs were generally used for a short period of time and in low doses. High-dose ibuprofen and diclofenac were associated with increased risk of ischemic stroke [hazard ratio 2.15 (95% confidence interval 1.66-2.79) and 2.37 (confidence interval 1.99-2.81), respectively]. Diclofenac was also associated with increased risk of hemorrhagic stroke and so was naproxen [hazard ratio 2.15 (confidence interval 1.35-3.42)]. CONCLUSIONS: In healthy individuals, use of commonly available nonsteroidal anti-inflammatory drugs such as ibuprofen, diclofenac, and naproxen was associated with increased risk of stroke. PMID- 23088218 TI - Association of a tgf-b1-509c/t polymorphism with gastric cancer risk: a meta analysis. AB - Published data on the association between the transforming growth factor B1 (TGF B1) gene 509C/T polymorphism and gastric cancer risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis of the TGFB1 509C/T polymorphism (with 2130 cases and 2374 controls) from seven published case control studies was performed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association in the codominant model, the dominant model, and the recessive model. In the overall analysis, the T allele was significantly associated with susceptibility to gastric cancer in the recessive model (TT vs. CC+CT) (TT vs. CC+CT: OR = 1.35, 95% CI: 1.10-1.66, P = 0.10 for heterogeneity) when all the included studies were pooled into the meta analysis. In the stratified analysis by country, the T allele was also found to be significantly associated with increased gastric cancer risk in the recessive model (TT vs. CC+CT) in Chinese studies and in T versus C in the Indian study. In conclusion, this meta-analysis supports the TGFB1-509T polymorphism as a susceptibility factor for gastric cancer. PMID- 23088219 TI - Specific aquaporins increase the ammonia tolerance of a Saccharomyces cerevisiae mep1-3 fps1 deletion strain. AB - Abstract Aquaporins (AQPs) are channel proteins which facilitate the bidirectional membrane permeation of small neutral molecules such as water and glycerol. A convenient way to characterize their permeability is by growth of transformed Saccharomyces cerevisiae deletion strains on nutrient-limited substrates. We selected a yeast strain deficient in its endogenous ammonium transporters Mep1-3 and aquaglyceroporin Fps1 in order to study the ammonia permeability of heterologously expressed AQPs. Surprisingly, AQP-expression improved yeast growth at high, not low, concentrations of unprotonated ammonia. At neutral or mildly alkaline pH, ammonia concentrations above 10 MUM decreased the growth rate and especially the number of yeast cell duplications, but did not affect the lag phase. AQP-expression raised the threshold to about 100 MUM. The exchange of ammonium ions for amino acids or urea did not completely abolish this effect. AQPs capable of rescuing growth had a selectivity filter wide enough to permit passage of molecules larger than water but smaller than glycerol. It appears that the endogenous aquaglyceroporin Fps1 may, under alkaline conditions, be beneficial to yeast by facilitating the membrane permeation of an as yet unidentified molecule other than glycerol. PMID- 23088221 TI - The female prostate: correcting the G-spot. PMID- 23088220 TI - CARD8 rs2043211 (p.C10X) polymorphism is not associated with disease susceptibility or cardiovascular events in Spanish rheumatoid arthritis patients. AB - Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis, which is the main cause of increased cardiovascular (CV) morbidity and mortality in RA patients. CARD8 is a constituent of inflammasome, which regulates interleukin 1-beta production, and has been associated with a worse disease course in early RA. One thousand six hundred twenty-one patients fulfilling the 1987 ACR classification criteria for RA and 1300 matched controls, were genotyped for the CARD8 rs2043211 (30T>A, p.C10X) single-nucleotide polymorphism (SNP) using predesigned TaqMan SNP genotyping assay. The genotyping success rate in our study was greater than 94%. We assessed CARD8 rs2043211 gene polymorphism results in 1530 Spanish RA patients in whom information on CV disease and CV risk factors was available at the time of the study. Also, a subgroup of patients with no history of CV events (n=276) was assessed for the potential influence of the rs2043211 variant in the development of subclinical atherosclerosis, by measurement of carotid intima media thickness (IMT) and presence of carotid plaques. No statistically significant differences in allele or genotype frequencies for the rs2043211 CARD8 gene variant between patients with RA and controls were seen. Similarly, CARD8 rs2043211 (30T>A, p.C10X) SNP did not influence the development of CV events or the risk of CV events throughout the time. Likewise, no significant association between this gene variant and carotid IMT or the presence of plaques was found. In summary, our results do not support a role of the CARD8 rs2043211 gene variant in susceptibility to RA or in the development of CV disease in patients with RA. PMID- 23088222 TI - The ASTUTE Health study protocol: deliberative stakeholder engagements to inform implementation approaches to healthcare disinvestment. AB - BACKGROUND: Governments and other payers are yet to determine optimal processes by which to review the safety, effectiveness, and cost-effectiveness of technologies and procedures that are in active use within health systems, and rescind funding (partially or fully) from those that display poor profiles against these parameters. To further progress a disinvestment agenda, a model is required to support payers in implementing disinvestment in a transparent manner that may withstand challenge from vested interests and concerned citizens. Combining approaches from health technology assessment and deliberative democratic theory, this project seeks to determine if and how wide stakeholder engagement can contribute to improved decision-making processes, wherein the views of both vested and non-vested stakeholders are seen to contribute to informing policy implementation within a disinvestment context. METHODS/DESIGN: Systematic reviews pertaining to illustrative case studies were developed and formed the evidence base for discussion. Review findings were presented at a series of deliberative, evidence-informed stakeholder engagements, including partisan (clinicians and consumers) and non-partisan (representative community members) stakeholders. Participants were actively facilitated towards identifying shared and dissenting perspectives regarding public funding policy for each of the case studies and developing their own funding models in response to the evidence presented. Policy advisors will subsequently be invited to evaluate disinvestment options based on the scientific and colloquial evidence presented to them, and to explore the value of this information to their decision-making processes with reference to disinvestment. DISCUSSION: Analysis of the varied outputs of the deliberative engagements will contribute to the methodological development around how to best integrate scientific and colloquial evidence for consideration by policy advisors. It may contribute to the legitimization of broad and transparent stakeholder engagement in this context. It is anticipated that decision making will benefit from the knowledge delivered through informed deliberation with engaged stakeholders, and this will be explored through interviews with key decision makers. PMID- 23088223 TI - FRAX(r) tool, the WHO algorithm to predict osteoporotic fractures: the first analysis of its discriminative and predictive ability in the Spanish FRIDEX cohort. AB - BACKGROUND: The WHO has recently published the FRAX(r) tool to determine the absolute risk of osteoporotic fracture at 10 years. This tool has not yet been validated in Spain. METHODS/DESIGN: A prospective observational study was undertaken in women in the FRIDEX cohort (Barcelona) not receiving bone active drugs at baseline. Baseline measurements: known risk factors including those of FRAX(r) and a DXA. Follow up data on self-reported incident major fractures (hip, spine, humerus and wrist) and verified against patient records. The calculation of absolute risk of major fracture and hip fracture was by FRAX(r) website. This work follows the guidelines of the STROBE initiative for cohort studies. The discriminative capacity of FRAX(r) was analyzed by the Area Under Curve (AUC), Receiver Operating Characteristics (ROC) and the Hosmer-Lemeshow goodness-of-fit test. The predictive capacity was determined using the ratio of observed fractures/expected fractures by FRAX(r) (ObsFx/ExpFx). RESULTS: The study subjects were 770 women from 40 to 90 years of age in the FRIDEX cohort. The mean age was 56.8 +/- 8 years. The fractures were determined by structured telephone questionnaire and subsequent testing in medical records at 10 years. Sixty-five (8.4%) women presented major fractures (17 hip fractures). Women with fractures were older, had more previous fractures, more cases of rheumatoid arthritis and also more osteoporosis on the baseline DXA. The AUC ROC of FRAX(r) for major fracture without bone mineral density (BMD) was 0.693 (CI 95%; 0.622-0.763), with T-score of femoral neck (FN) 0.716 (CI 95%; 0.646-0.786), being 0.888 (CI 95%; 0.824-0.952) and 0.849 (CI 95%; 0.737-0.962), respectively for hip fracture. In the model with BMD alone was 0.661 (CI 95%; 0.583-0.739) and 0.779 (CI 95%; 0.631 0.929). In the model with age alone was 0.668 (CI 95%; 0.603-0.733) and 0.882 (CI 95%; 0.832-0.936). In both cases there are not significant differences against FRAX(r) model. The overall predictive value for major fracture by ObsFx/ExpFx ratio was 2.4 and 2.8 for hip fracture without BMD. With BMD was 2.2 and 2.3 respectively. Sensitivity of the four was always less than 50%. The Hosmer Lemeshow test showed a good correlation only after calibration with ObsFx/ExpFx ratio. CONCLUSIONS: The current version of FRAX(r) for Spanish women without BMD analysed by the AUC ROC demonstrate a poor discriminative capacity to predict major fractures but a good discriminative capacity for hip fractures. Its predictive capacity does not adjust well because leading to underdiagnosis for both predictions major and hip fractures. Simple models based only on age or BMD alone similarly predicted that more complex FRAX(r) models. PMID- 23088224 TI - Integrated vector management targeting Anopheles darlingi populations decreases malaria incidence in an unstable transmission area, in the rural Brazilian Amazon. AB - BACKGROUND: Studies on vector behaviour should be conducted in order to evaluate the effectiveness of vector control measures on malaria protection in endemic areas of Latin America, where P. vivax predominates. This work aims to investigate the fauna of anopheline mosquitoes and verify the impact of integrated vector management in two colonization projects in the Careiro Municipality, Western Brazilian Amazon. METHODS: Four mosquitoes' captures were carried out from August 2008 to March 2010, with an interval of six months between each collection. Since September 2009 a large programme to reduce the burden of malaria has started in the two communities by distribution of insecticide-treated bed nets (ITN) and intensification of indoor residual spraying (IRS). Human biting rates (HBRs), entomological inoculation rates (EIRs), malaria incidence rate (MIR) and Plasmodium carrier's prevalence were used as outcomes to estimate the impact of the control measures. RESULTS: A total of 3,189 anophelines were collected, belonging to 13 species. Anopheles darlingi was the predominant species in the period (42.6%), followed by Anopheles albitarsis (38.4%). An. darlingi HBRs showed a notable decreasing trend from the start to the end of the study. Conversely, An. albitarsis increased its contribution to overall HBRs throughout the study. For An. darlingi there was a significant positive correlation between HBRs and MIR (p = 0.002). Anopheles albitarsis HBRs showed a significant negative correlation with the corresponding MIR (p = 0.045). EIR from total anophelines and from An. darlingi and An. albitarsis presented decreasing patterns in the successive collections. Four species of anophelines (An. darlingi, An. albitarsis, Anopheles braziliensis and Anopheles nuneztovari) were naturally infected with Plasmodium, albeit at very low infection rates. There were a decrease in the MIR for both vivax and falciparum malaria and in the prevalence of Plasmodium vivax and Plasmodium falciparum carriers during the period of study. CONCLUSIONS: There is strong evidence of association between the density of An. darlingi and the incidence of malaria in the studies sites, further highlighting the importance of this vector in malaria transmission in this region. An. darlingi susceptibility to control using ITN and IRS is likely to be high in the rural settlements studied. PMID- 23088225 TI - Multiple-locus variable-number tandem-repeat analysis of Streptococcus pneumoniae and comparison with multiple loci sequence typing. AB - BACKGROUND: Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. The diversity of pneumococci was first evidenced by serotyping of their capsular polysaccharides, responsible of virulence, resolving into more than 93 serotypes. Molecular tools have been developed to track the emergence and the spread of resistant, hyper virulent or non-vaccine type clones, particularly DNA-based methods using genetic polymorphism. Pulsed-Field Gel Electrophoresis analysis (PFGE) and Multiple Loci Sequence Typing (MLST) are the most frequently used genotyping techniques for S. pneumoniae. MLST is based on sequence comparison of housekeeping genes clustering isolates within sequence types. The availability of genome sequence data from different S. pneumoniae strains facilitated the search for other class of genetic markers as polymorphic DNA sequences for a Multiple-Locus Variable-Number Tandem-Repeat Analysis (MLVA). This study aims at confirming the relevance of MLVA of S. pneumoniae, comparing MLST and MLVA performances when discriminating subgroups of strains belonging to the same Sequence Type (ST), and defining a restricted but universal set of MLVA markers that has at least the same discriminatory power as MLST for S. pneumoniae by applying marker sets used by different authors on 331 isolates selected in UK. RESULTS: A minimum spanning tree was built including the serotypes distribution and comparing MLVA and MLST results. 220 MLVA types were determined grouped in 10 Sequence Types (ST). MLVA differentiated ST162 in two clonal complexes. A minimal set was defined: ms 25 and ms37, ms17, ms19, ms33, ms39, and ms40 including two universal markers. The selection was based on MLVA markers with a Diversity Index >0.8 and a selection of others depending of the population tested and the aim of the study. This set of 7 MLVA markers yields strain clusters similar to those obtained by MLST. CONCLUSIONS: MLVA can discriminate relevant subgroups among strains belonging to the same ST. MLVA offers the possibility to deduce the ST from the MLVA Type. It permits to investigate local outbreaks or to track the worldwide spread of clones and the emergence of variants. PMID- 23088226 TI - Endobronchial Tubercolosis: a peculiar feature of TB often underdiagnosed. PMID- 23088228 TI - The wishful memory of interpersonal responsiveness. AB - Perceived partner responsiveness, or trust in partners' care, positive regard, and commitment, is widely believed to be an important determinant of relationship quality. This trust may be based, in part, on memory of partners' prior behaviors, which may be biased. The current research provided support for the prediction that memories of partners' prior responsiveness are biased by perceivers' desires to bond with partners. A dyadic daily report study (Study 1) and a dyadic longitudinal study with a behavioral observation component (Study 2) suggested that perceivers' valuing of partners biased their memories of partners' behavior independently of perceivers' initial encoding, partners' sentiments, and partners' behavior. This bias was not explained by other potential sources of bias, including relationship satisfaction, attachment dimensions, trait self esteem, and consistency effects. Results also suggested that responsiveness memories reduce emotional reactivity in response to current perceptions of partners' lack of responsiveness (Study 1) and contribute to global feelings of trust (Study 2). These results indicate that perceivers' memories of partners' prior responsiveness are shaped by their own desires to bond with partners and that biased responsiveness memories contribute to current trust and therefore have interpersonal significance. PMID- 23088229 TI - The burden of disclosure: increased compliance with distrusted advice. AB - Professionals often face conflicts of interest that give them an incentive to provide biased advice, and disclosure (informing advisees about the conflict) is frequently proposed as a solution to the problem. We present 6 experiments that reveal a previously unrecognized perverse effect of disclosure: Although disclosure can decrease advisees' trust in the advice, it can also increase pressure to comply with that advice if advisees feel obliged to satisfy their advisors' personal interests. Hence, disclosure can burden those it is ostensibly intended to protect. Beyond demonstrating the effect, we show that this increased pressure to comply with advice is reduced if (a) the disclosure is provided by an external source rather than from the advisor, (b) the disclosure is not common knowledge between the advisor and advisee, (c) the advisee has an opportunity to change his/her mind later, or (d) the advisee is able to make the decision in private. PMID- 23088227 TI - Stereotypes of age differences in personality traits: universal and accurate? AB - Age trajectories for personality traits are known to be similar across cultures. To address whether stereotypes of age groups reflect these age-related changes in personality, we asked participants in 26 countries (N = 3,323) to rate typical adolescents, adults, and old persons in their own country. Raters across nations tended to share similar beliefs about different age groups; adolescents were seen as impulsive, rebellious, undisciplined, preferring excitement and novelty, whereas old people were consistently considered lower on impulsivity, activity, antagonism, and Openness. These consensual age group stereotypes correlated strongly with published age differences on the five major dimensions of personality and most of 30 specific traits, using as criteria of accuracy both self-reports and observer ratings, different survey methodologies, and data from up to 50 nations. However, personal stereotypes were considerably less accurate, and consensual stereotypes tended to exaggerate differences across age groups. PMID- 23088230 TI - Men and women are from Earth: examining the latent structure of gender. AB - Taxometric methods enable determination of whether the latent structure of a construct is dimensional or taxonic (nonarbitrary categories). Although sex as a biological category is taxonic, psychological gender differences have not been examined in this way. The taxometric methods of mean above minus below a cut, maximum eigenvalue, and latent mode were used to investigate whether gender is taxonic or dimensional. Behavioral measures of stereotyped hobbies and physiological characteristics (physical strength, anthropometric measurements) were examined for validation purposes, and were taxonic by sex. Psychological indicators included sexuality and mating (sexual attitudes and behaviors, mate selectivity, sociosexual orientation), interpersonal orientation (empathy, relational-interdependent self-construal), gender-related dispositions (masculinity, femininity, care orientation, unmitigated communion, fear of success, science inclination, Big Five personality), and intimacy (intimacy prototypes and stages, social provisions, intimacy with best friend). Constructs were with few exceptions dimensional, speaking to Spence's (1993) gender identity theory. Average differences between men and women are not under dispute, but the dimensionality of gender indicates that these differences are inappropriate for diagnosing gender-typical psychological variables on the basis of sex. PMID- 23088231 TI - On the directive function of episodic memories in people's lives: a look at romantic relationships. AB - We argue that episodic memories have an active and directive function with respect to a number of relational outcomes. In line with self-determination theory, it is expected that the satisfaction of 3 needs (autonomy, competence, relatedness) in couple-related memories facilitates the quality of romantic relationships and their development. Results of 4 studies support this contention. Study 1 showed that need satisfaction in couple-related memories was associated with relationship quality, even after controlling for other important relational constructs. Study 2 underscored the context-dependent aspect of the directive function of episodic memories. Need satisfaction in couple-related memories was found to be associated with partner relationship quality but not with friendship quality, whereas need satisfaction in friend-related memories was associated with friendship quality but not with partner relationship quality. Study 3 showed that couple-related memories contributed independently to each partner's perceptions of relationship quality, that is, both the rememberer and the partner. Study 4 showed the long-term directive function of episodic memories. Need satisfaction in couple-related memories positively and negatively predicted increases in relationship quality and the likelihood of a breakup over a 1-year period, respectively. This directive function of memories was examined along with the self function of memories (self-enhancement, self-protection) and shown to be complementary. We also examined the stability of need satisfaction in couple-related memories over time and investigated this stability as a function of whether the partners had broken up or not over the year. Overall, the findings suggest that episodic memories play an important role in romantic relationships. PMID- 23088236 TI - The Wellcome Trust Image Awards 2012. PMID- 23088232 TI - Are all interventions created equal? A multi-threat approach to tailoring stereotype threat interventions. AB - To date, stereotype threat interventions have been considered interchangeable. Across 4 experiments, the present research demonstrates that stereotype threat interventions need to be tailored to the specific form of experienced stereotype threat to be effective. The Multi-Threat Framework (Shapiro & Neuberg, 2007) distinguishes between group-as-target stereotype threats-concerns that a stereotype-relevant performance will reflect poorly on the abilities of one's group-and self-as-target stereotype threats-concerns that a stereotype-relevant performance will reflect poorly on one's own abilities. The present experiments explored Black college students' performance on diagnostic intelligence tests (Experiments 1 and 3) and women's interest (Experiment 2) and performance (Experiment 4) in science, technology, engineering, and math (STEM). Across the 4 experiments, participants were randomly assigned to experience either a group-as target or self-as-target stereotype threat. Experiments 1 and 2 revealed that role model interventions were successful at protecting only against group-as target stereotype threats, and Experiments 3 and 4 revealed that self-affirmation interventions were successful at protecting only against self-as-target stereotype threats. The present research provides an experimental test of the Multi-Threat Framework across different negatively stereotyped groups (Black students, female students), different negatively stereotyped domains (general intelligence, STEM), and different outcomes (test performance, career interest). This research suggests that interventions should address the range of possible stereotype threats to effectively protect individuals against these threats. Through an appreciation of the distinct forms of stereotype threats and the ways in which interventions work to reduce them, this research aims to facilitate a more complete understanding of stereotype threat. PMID- 23088237 TI - Creation of abdominal palpation model prototype for training of medical students in detection and diagnosis of liver disease. PMID- 23088239 TI - Creating a novel mock clinical examination for the Membership of the Royal College of Paediatrics and Child Health in Malta. AB - Clinical medical examinations are difficult. Courses that attempt to instil such clinical examination skills are expensive, and this is even more so for Maltese graduates who must perforce travel by air from the island of Malta to such venues. This year (2012) was a landmark year with a record seven Maltese candidates planning to take the MRCPCH examination, and it was therefore decided to set up a mock clinical exam under true examination conditions in Malta. This was done successfully and this paper describes the modus operandi and the requirements for such a process. PMID- 23088238 TI - Electronic requesting of clinical photography... would you like ICE with that? PMID- 23088241 TI - Mothers of Africa. PMID- 23088242 TI - Developing and sharing your CPD portfolio. PMID- 23088243 TI - Institute of Medical Illustrators Scottish Regional Meeting--Colour Management Masterclass, Glasgow, 1 March 2012. PMID- 23088245 TI - Photographic measuring scales. AB - Mark Bartley is a senior photographer at Addenbrooke's. Following an interesting discussion on the Institute of Medical Illustrators discussion forum he decided to write a short viewpoint article on the subject of the use of scales in clinical photography. It was fascinating to read all the arguments both for and against the digital rule. Clinical Photographers have been using digital rulers at Addenbrooke's since 2008 after comparing this type of measuring scale with our old adhesive rulers in consultation with our Dermatology department. The digital rulers are dragged onto our image from a layer in a ready-made psd file, of which a number of sizes are available in the magnification ratios that we commonly use for close-ups photography of lesions. The author prefers this digital method as it provides a neater more efficient way of placing a ruler within the image. PMID- 23088246 TI - The uncanny body: blood, flesh and the anatomical illustration. PMID- 23088247 TI - Perimetry in children: survey of current practices in the United Kingdom and Ireland. AB - PURPOSE: Visual fields are key functional outcome measures in children with a variety of ophthalmologic disorders. However, reliably assessing fields in children is challenging. We report the findings of a survey of current practices of perimetry in children in the United Kingdom and Ireland. METHODS: An electronic questionnaire was sent to Orthoptic Service Heads in July 2008. Respondents were asked for comments regarding visual field testing in children as well as details of the volume and type of perimetry performed in their units, over a 1-year period. RESULTS: Of the 98 (62%) completed questionnaires, 16 departments reported not testing visual fields in children. In total 3675 subjects under 16 years of age were reported to have undergone perimetry in 1 year, most in units with a >= 50% pediatric caseload for orthoptics. A total of 42% of units used static perimetry alone, 11% kinetic, and 47% used a combination of both. CONCLUSION: High numbers of visual field tests are carried out in children in the UK and Ireland annually. Automated perimetry is used predominantly, despite the underlying algorithms having been developed for adult populations. Thus there is a clear need for more research, to ensure that evolving management practices are informed by understanding of the diagnostic accuracy and value of perimetry in children. PMID- 23088248 TI - Perceptions of patient education during hospital visit--described by school-age children with a chronic illness and their parents. AB - BACKGROUND: Families having a child with a chronic disease face changes in their everyday lives, and the whole family is involved in patient education. Nurses bear a great responsibility for patient education, but their school-age patients' and their parents' perceptions of patient education have only been studied to a limited extent. AIM: The current study aimed to explore the elements of significant patient education events during a hospital visit described by school age children with a chronic illness and their parents. METHOD: The design was qualitative and descriptive. A total of nineteen Finnish parents and their 12 children aged 5-12, suffering from chronic diseases, were interviewed using a critical incident technique. The data were analysed by deductive content analysis. FINDINGS: The descriptions of patient education comprised cases with parents' shock at the outset of the patient education sessions and cases with the outcome of these sessions, including an experience of empowerment or lack of it. The patient education practices were examined by determining nursing, didactic and interpersonal competences. Nursing competence involved illustrations of knowledge and the ability to care for children and families as well as knowledge of the disease and its management. Didactic competence comprised practical examples of knowledge of teaching and the ability to implement the education process. Interpersonal competence manifested itself in the ability to have a dialogue. CONCLUSION: The findings show the importance of comprehensive patient education competence required of nurses giving education to families having children with chronic illnesses. This knowledge can be applied to promote nurses' professional training and to develop patient education. PMID- 23088249 TI - Non-separative headspace solid phase microextraction-mass spectrometry profile as a marker to monitor coffee roasting degree. AB - This study describes a non-separative headspace solid phase microextraction-mass spectrometry (HS-SPME-MS) approach, in view of its application to online monitoring of a roasting process. The system can quickly provide representative and diagnostic fingerprints of the volatile fraction of samples and, in combination with appropriate chemometric pattern recognition and regression techniques, can successfully be applied to characterize, discriminate, and/or correlate patterns with the roasting process. Eighty coffee samples of different varieties, geographical origins, and blends were analyzed. The experimental HS SPME-MS results show that the TIC fingerprint can be used to discriminate the degree of roasting; diagnostic ion abundance(s) or ratios were closely correlated with the roasting process; both could successfully be used as markers or analytical decision makers, to monitor roasting processes online, and to define quality and safety of roasted coffee. PMID- 23088251 TI - Direct observation of giant Pickering emulsion and colloidosome droplet interaction and stability. AB - The interactions of two 2-mm pendant oil droplets grown in the presence of an aqueous solution of poly(glycerol monomethacrylate)-stabilized polystyrene latex particles was observed using a high-speed video camera. The coalescence behavior was monitored as a function of oil type (n-dodecane versus sunflower oil) and particle size (135 versus 902 nm), as well as in the presence and absence of an oil-soluble cross-linker [tolylene 2,4-diisocyanate-terminated poly(propylene glycol)]. The damping coefficient of the coalescing n-dodecane droplets was found to increase in the presence of the latex, demonstrating particle adsorption. Coalescence times increased when the oil phase was changed from n-dodecane to sunflower oil, because of the much higher viscosity of the latter oil. In addition, increasing the adsorbed particle size from 135 to 902 nm led to longer coalescence times because of the greater distance separating the oil droplets. Coalescence times observed in the presence of the larger 902-nm particles indicated that two different modes of contact can occur prior to a coalescence event (bilayer or bridging monolayer of particles in the film). Addition of an oil-soluble surface-active cross-linker to the sunflower oil phase to react with the hydroxy groups of the particle stabilizer reduced the interfacial elasticity and ultimately prevented coalescence after cross-linking for 20 min at 25 degrees C. Such giant colloidosomes can remain in contact for several hours without undergoing coalescence, which demonstrates their high stability. Furthermore, coalescence is prevented even if the cross-linker is present in only one of the pendant droplets. Finally, evidence for cross-linker diffusion from one pendant droplet to another was indicated by a visible filament connecting the two droplets upon retraction. PMID- 23088250 TI - Binding efficiency of protein-protein complexes. AB - We examine the relationship between binding affinity and interface size for reversible protein-protein interactions (PPIs), using cytokines from the tumor necrosis factor (TNF) superfamily and their receptors as a test case. Using surface plasmon resonance, we measured single-site binding affinities for binding of the large receptor TNFR1 to its ligands TNFalpha (K(D) = 1.4 +/- 0.4 nM) and lymphotoxin-alpha (K(D) = 50 +/- 10 nM), and also for binding of the small receptor Fn14 to TWEAK (K(D) = 70 +/- 10 nM). We additionally assembled data for all other TNF-TNFR family complexes for which reliable single-site binding affinities have been reported. We used these values to calculate the binding efficiencies, defined as binding energy per square angstrom of surface area buried at the contact interface, for nine of these complexes for which cocrystal structures are available, and compared the results to those for a set of 144 protein-protein complexes with published affinities. The results show that the most efficient PPI complexes generate ~20 cal mol(-1) A(-2) of binding energy. A minimal contact area of ~500 A(2) is required for a stable complex, required to generate sufficient interaction energy to pay the entropic cost of colocalizing two proteins from 1 M solution. The most compact and efficient TNF-TNFR complex was the BAFF-BR3 complex, which achieved ~80% of the maximal achievable binding efficiency. Other small receptors also gave high binding efficiencies, while the larger receptors generated only 44-49% of this limit despite interacting primarily through just a single small domain. The results provide new insight into how much binding energy can be generated by a PPI interface of a given size, and establish a quantitative method for predicting how large a natural or engineered contact interface must be to achieve a given level of binding affinity. PMID- 23088252 TI - Thulium laser vaporesection versus standard transurethral resection of the prostate: a randomized trial with transpulmonary thermodilution hemodynamic monitoring. AB - OBJECTIVES: To characterize the hemodynamics comparing thulium laser vaporesection of the prostate with traditional transurethral resection of the prostate. METHODS: A total of 80 consecutive patients with benign prostatic hyperplasia were randomly assigned into the thulium laser vaporesection of the prostate group or transurethral resection of the prostate group. Transpulmonary thermodilution hemodynamic monitoring was used before and 1 h after surgery to assess patient hemodynamics. Acute complications and treatment efficiency were evaluated after surgery. RESULTS: There were no statistical differences in age, prostate volume, anticoagulants and International Prostate Symptom Score between the two groups. The postoperative Stroke Volume Index was significantly higher in the thulium laser vaporesection of the prostate group (P = 0.007). The extravascular lung water and intrathoracic blood volume indices differed significantly pre- and postoperatively, and were similar in both groups. Decreases in serum sodium and hemoglobin concentrations after surgery were lower in the thulium laser vaporesection of the prostate group (P < 0.01). Acute complications, and improvements in International Prostate Symptom Score and maximum urinary flow rates, were similar in both groups. CONCLUSIONS: Transpulmonary thermodilution hemodynamic monitoring provides additional safety measures during surgical procedures. Thulium laser vaporesection of the prostate is associated with fewer hemodynamic changes and provides similar efficacy to transurethral resection of the prostate. Thus, it can be considered a safe and effective procedure. PMID- 23088253 TI - Renal impairment among acute hospital admissions in a rural Ethiopian hospital. AB - AIM: Acute renal injury (AKI) is a relatively common clinical condition, reported to be associated with high rates of in-hospital mortality. Although here is an extensive literature on the nature and consequence of AKI in the developed World, much less is known in the developing World and more specifically in sub-Saharan Africa, which is addressed directly in this study. METHODS: We describe the prevalence, clinical characteristics and impact of AKI in patients admitted to a single centre in Ethiopia with no dedicated renal services. RESULTS: Renal function tests are not preformed routinely in many Ethiopian hospitals. This occurred in 32% of all patients in this study, falling to 23% on surgical wards. As a consequence no cases of AKI were identified in the context of surgical admissions. AKI was only identified in a cohort of patients on medical wards, with a prevalence of roughly 20% of medical patients in which renal function was measured. The patients with AKI were younger than those at risk of AKI in studies from the developed World but were older than those who did not develop AKI in this study. In the majority of cases AKI could be considered to be pre-renal in its origin. In contrast to studies in the developed World, AKI did not adversely impact on either duration of hospital stay or on patient mortality. Residual renal impairment was, however, common at the point of discharge. CONCLUSION: The data suggest subtle differences in the nature and impact of AKI between those published and mainly derived from the developed world and patients in sub-Saharan Africa. PMID- 23088255 TI - Navigating changing food environments - Transnational perspectives on dietary behaviours and implications for nutrition counselling. AB - United States (US) migrants are often characterised as experiencing unhealthy nutrition transitions. 'Looking-back' into dietary behaviours and the processes that affect dietary changes before migration may improve counselling interventions. We conducted a qualitative study of an indigenous Zapotecan transnational community based in Monterey, California, and Oaxaca, Mexico. Four focus groups and 29 interviews were conducted with transnational participants concerning health beliefs around and dietary differences between the US and Oaxaca. Analysis focused on nutrition-related themes. The four major themes were: (1) the paradox between participants' experience growing up with food insecurity and fond memories of a healthier diet; (2) mothers' current kitchen struggles as they contend with changes in food preferences and time demands, and the role 'care packages' play in alleviating these challenges; (3) positive views about home-grown versus store-bought vegetables; and (4) the role of commercial nutritional supplements and the support they provide. Counselling implications include (1) taking a detailed medical/social history to explore experiences with food insecurity and views on the role of nutrition in maintaining health and (2) exploring patients' struggles with different dietary preferences within their families. Transnational experiences may provide new insights for dietary counselling and patient-centred health communication. PMID- 23088254 TI - H2O2 accumulation mediates differentiation capacity alteration, but not proliferative decline, in senescent human fetal mesenchymal stem cells. AB - AIMS: Mesenchymal stem cells (MSCs) with multilineage differentiation capacity and immunomodulatory properties are novel sources for cell therapy. However, in vitro expansion of these rare somatic stem cells leads to senescence, resulting in declines of differentiation and proliferative capacities. We therefore investigated the mechanisms mediating senescence in human fetal MSCs termed placenta-derived multipotent cells (PDMCs). RESULTS: Long-term cultured PDMCs underwent senescence, with increased levels of hydrogen peroxide (H2O2; a reactive oxygen species), positive beta-galactosidase staining, decreased sirtuin 1 expression, increased p21 expression, and cell cycle arrest at the G0/G1 phase. Senescent PDMCs also showed decreased osteogenic capacity. Mechanistically, increased p21 expression and proliferative decline were not due to elevated H2O2 levels nor mediated by p53. Instead, inhibition of protein kinase C (PKC)-alpha and -beta in senescent PDMCs decreased p21 expression and reversed cell cycle arrest. H2O2 was involved in the alteration of differentiation potential, since scavenging of H2O2 restored expression of c-MAF, an osteogenic and age-sensitive transcription factor, and osteogenic capacity in senescent PDMCs. INNOVATION: Our findings not only show the effects of senescence on MSCs, but also reveal mechanisms involved in mediating decreased proliferation and differentiation capacity. Moreover, targeting increased levels of H2O2 associated with senescence may reverse the decreased osteogenic capacity of senescent MSCs. CONCLUSION: Our study suggests that the two biological consequences of senescence, differentiation alteration, and proliferative decline, in fetal MSCs are distinctly regulated by the H2O2-c-MAF and PKC-p21 pathways, respectively. PMID- 23088256 TI - Copper-assisted palladium(II)-catalyzed direct arylation of cyclic enaminones with arylboronic acids. AB - Described herein is a palladium(II)-catalyzed direct arylation of cyclic enaminones with arylboronic acids. The versatility of this method is that both electron-rich and electron-poor boronic acids can be coupled in high yields. A mixture of two Cu(II) additives was crucial for efficient cross-coupling. The role of each Cu(II) reagent appears to be distinct and complementary serving to assist catalyst reoxidation and transmetalation through a putative arylcopper intermediate. PMID- 23088257 TI - Genetic differentiation of Ompok bimaculatus (Teleostei: Siluridae) population based on mtDNA cytochrome b gene. AB - Ompok bimaculatus commonly called as Indian butter catfish is a commercially important food fish and distributed throughout India and Southeast Asia. Genetic differentiation of O. bimaculatus was investigated using cytochrome b (cyt b) gene of three different riverine populations. A total of 37 sequences of cyt b gene (1118 bp) were generated from O. bimaculatus. The mitochondrial DNA analysis revealed that O. bimaculatus has relatively high genetic diversity. The estimated haplotype and nucleotide diversity were 0.063 and 0.005, respectively. The analysis of molecular variance indicated 73.53% genetic variability between the populations and 26.47% genetic variation within population. The understanding of genetic differentiation of O. bimaculatus populations will play a key role in conservation and management of the important endangered fish species. PMID- 23088258 TI - Intracavernous delivery of freshly isolated stromal vascular fraction rescues erectile function by enhancing endothelial regeneration in the streptozotocin induced diabetic mouse. AB - INTRODUCTION: Men with diabetic erectile dysfunction (ED) often have severe endothelial dysfunction and respond poorly to oral phosphodiesterase-5 inhibitors. AIM: To examine whether and how freshly isolated stromal vascular fraction (SVF) promotes cavernous endothelial regeneration and restores erectile function in diabetic animals. METHODS: Eight-week-old C57BL/6J mice were used. Diabetes was induced by intraperitoneal injection of streptozotocin. SVF was isolated from epididymal adipose tissues of green fluorescence protein transgenic mice. At 8 weeks after the induction of diabetes, the animals were divided into six groups: controls, diabetic mice, and diabetic mice treated with a single intracavernous injection of phosphate-buffered saline (PBS) or SVF (1 * 10(4) cells, 1 * 10(5) cells, or 2 * 10(5) cells/20 uL, respectively). MAIN OUTCOME MEASURES: Two weeks later, erectile function was measured by cavernous nerve stimulation. The penis was stained with antibodies to CD31, CD34, phosphohistone H3, phospho-endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor-A (VEGF-A). We also performed Western blot for phospho-eNOS and eNOS, and determined cyclic guanosine monophosphate (cGMP) concentration in the corpus cavernosum tissue. RESULTS: Significant improvement in erectile function was noted in diabetic mice treated with SVF at concentrations of 1 * 10(5) and 2 * 10(5) cells, which reached up to 82% of the control values. Local delivery of SVF significantly increased cavernous endothelial cell proliferation, eNOS phosphorylation, and cGMP expression compared with that in the untreated group and the PBS-treated diabetic group. Intracavernous injection of SVF increased cavernous VEGF-A expression and induced recruitment of CD34(+)CD31(-) progenitor cells. Some SVF underwent differentiation into cavernous endothelial cells. SVF induced promotion of cavernous angiogenesis and erectile function was abolished in the presence of VEGF-Trap, a soluble VEGF-A neutralizing antibody. CONCLUSION: The results support the concept of cavernous endothelial regeneration by use of SVF as a curative therapy for diabetic ED. PMID- 23088261 TI - Analytical gradients for density functional calculations with approximate spin projection. AB - We have derived and implemented analytical gradients for broken-symmetry unrestricted density functional calculations (BS-UDFT) with removal of spin contamination by Yamaguchi's approximate spin projection method. Geometry optimizations with these analytical gradients (AGAP-opt) yield results consistent with those obtained with the previously available numerical gradients (NAP-opt). The AGAP-opt approach is found to be more precise, efficient, and robust than NAP opt. It allows full geometry optimizations for large open-shell systems. We report results for three types of organic diradicals and for a binuclear vanadium(II) complex to demonstrate the merits of removing the spin contamination effects during geometry optimization (AGAP-opt vs BS-UDFT) and to illustrate the superior performance of the analytical gradients (AGAP-opt vs NAP-opt). The results for the vanadium(II) complex indicate that the AGAP-opt method is capable of handling pronounced spin contamination effects in large binuclear transition metal complexes with two magnetic centers. PMID- 23088260 TI - A facile and green approach for the controlled synthesis of porous SnO2 nanospheres: application as an efficient photocatalyst and an excellent gas sensing material. AB - A facile and elegant methodology invoking the principles of Green Chemistry for the synthesis of porous tin dioxide nanospheres has been described. The low temperature (~50 degrees C) synthesis of SnO2 nanoparticles and their self assembly into organized, uniform, and monodispersed porous nanospheres with high surface area is facilitated by controlling the concentration of glucose, which acts as a stabilizing as well as structure-directing agent. A systematic control on the stannate to glucose molar concentration ratio determines the exact conditions to obtain monodispersed nanospheres, preferentially over random aggregation. Detailed characterization of the structure, morphology, and chemical composition reveals that the synthesized material, 50 nm SnO2 porous nanospheres possess BET surface area of about 160 m2/g. Each porous nanosphere consists of a few hundred nanoparticles ~2-3 nm in diameter with tetragonal cassiterite crystal structure. The SnO2 nanospheres exhibit elevated photocatalytic activity toward methyl orange with good recyclability. Because of the high activity and stability of this photocatalyst, the material is ideal for applications in environmental remediation. Moreover, SnO2 nanospheres display excellent gas sensing capabilities toward hydrogen. Surface modification of the nanospheres with Pd transforms this sensing material into a highly sensitive and selective room temperature hydrogen sensor. PMID- 23088259 TI - N-Acyl amines of docosahexaenoic acid and other n-3 polyunsatured fatty acids - from fishy endocannabinoids to potential leads. AB - N-3 Long-chain polyunsaturated fatty acids (n-3 LC-PUFAs), in particular alpha linolenic acid (18:3n-3), eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) are receiving much attention because of their presumed beneficial health effects. To explain these, a variety of mechanisms have been proposed, but their interactions with the endocannabinoid system have received relatively little attention so far. However, it has already been shown some time ago that consumption of n-3 LC-PUFAs not only affects the synthesis of prototypic endocannabinoids like anandamide but also stimulates the formation of specific n-3 LC-PUFA-derived conjugates with ethanolamine, dopamine, serotonin or other amines. Some of these fatty amides show overlapping biological activities with those of typical endocannabinoids, whereas others possess distinct and sometimes largely unknown receptor affinities and other properties. The ethanolamine and dopamine conjugates of DHA have been the most investigated thus far. These mediators may provide promising new leads to the field of inflammatory and neurological disorders and for other pharmacological applications, including their use as carrier molecules for neurotransmitters to target the brain. Furthermore, combinations of n-3 LC-PUFA-derived fatty acid amides, their precursors and FAAH inhibitors offer possibilities to optimise their effects in health and disease. PMID- 23088262 TI - Dynamics of formamide ionic solutions investigated by ultrafast optical Kerr effect. AB - Molecular dynamics of formamide solutions of alkali metal halide salts were investigated using the time-resolved ultrafast optical Kerr effect (OKE) to observe the effects of ion solvation on the dynamics of a nonaqueous high permittivity H-bonding solvent. The picosecond orientational and ultrafast intermolecular dynamics of liquid formamide as a function of concentration of NaI and KI are compared with the temperature effect on the pure solvent. The effect of a range of other salts at fixed concentration is also recorded. Transient OKE and corresponding low-frequency (THz) Raman spectra of the solutions revealed differences in the solvent dynamics caused by ion solvation. Increasing concentrations of NaI and KI have the effect of slowing down the diffusive reorientation and reducing the librational frequencies of formamide, with cation related effects observed on the THz Raman spectrum. These effects are discussed in terms of an ion perturbation of the H-bonding structure in the solution. This approach provides a valuable means of investigating the dynamics, structure, and interactions in complex, interacting systems. PMID- 23088264 TI - Open data for drug discovery: learning from the biological community. PMID- 23088263 TI - The Alberta Stroke Prevention in TIAs and mild strokes (ASPIRE) intervention: rationale and design for evaluating the implementation of a province-wide TIA triaging system. AB - RATIONALE: Stroke risk after transient ischaemic attack is high and, it is a challenge worldwide to provide urgent assessment and preventive services to entire populations. AIMS: To determine whether a province-wide transient ischaemic attack Triaging algorithm and transient ischaemic attack hotline (the Alberta Stroke Prevention in transient ischaemic attacks and mild strokes intervention) can reduce the rate of stroke recurrence following transient ischaemic attack across the population of Alberta, Canada (population 3.7 million, 90-day rate of post-stroke transient ischaemic attack currently 9.5%). It also seeks to improve upon current transient ischaemic attack triaging rules by incorporating time from symptom onset as a predictive variable. DESIGN: The transient ischaemic attack algorithm and hotline were developed with a broad consensus of clinicians, patients, policy-makers, and researchers and based on local adaptation of the work of others and research and insights developed within the province. Because neither patient-level nor region-level randomization was possible, we conducted a quasi-experimental design examining changes in the post transient ischaemic attack rate of stroke recurrence before and after the 15 month implementation period using an interrupted time-series regression analysis. The design controls for changes in case-mix, co-interventions, and secular trends. A prospective transient ischaemic attack cohort will also be concurrently created with telephone follow-up at seven-days and 90 days as well as passive follow-up over the longer term using linkages to provincial healthcare administrative databases. STUDY OUTCOMES: The primary outcome measure is the change in recurrence rate of stroke following transient ischaemic attack at seven days and 90 days, comparing a period of two-years before vs. two-years after the intervention is implemented. All cases of recurrent stroke will be validated. Secondary outcomes include functional status, hospitalizations, morbidity, and mortality. CONCLUSIONS: We are undertaking a rigorous evaluation of a population based approach to improving quality of transient ischaemic attack care. Whether positive or negative, our work should provide important insights for all potential stakeholders. PMID- 23088265 TI - Noticing the unnoticed: bridging structural data and drug design. PMID- 23088266 TI - Local intense cellular electric fields and their relevance in the computational modeling of biochemical reactions. PMID- 23088268 TI - Interview: interview with Gisbert Schneider. AB - Gisbert Schneider studied biochemistry and computer science at the Free University of Berlin, Germany, where he received his doctoral degree in 1994. After several international post-doctoral research activities he joined F.Hoffmann-La Roche Pharmaceuticals in Basel, Switzerland, where he headed the cheminformatics group until 2001. He received his habilitation and venia legendi in biochemistry and bioinformatics from the University of Freiburg, Germany. From 2002 to 2009 he was Full Professor of Chem- and Bioinformatics (Beilstein Endowed Chair) at Goethe-University Frankfurt, Germany. In 2010 he joined ETH Zurich, Switzerland, as a Full Professor of Computer-Assisted Drug Design. Professor Schneider spoke to Future Medicinal Chemistry about how he became involved in the field, the effects advances in software have had on research and how computational chemistry is becoming more important in the role of a traditional medicinal chemist. Interview conducted by Isaac Bruce, Commissioning Editor. PMID- 23088269 TI - Is that a scientific publication or an advertisement? Reproducibility, source code and data in the computational chemistry literature. PMID- 23088270 TI - Why don't we see a greater uptake of computational chemistry approaches by the medicinal chemistry community? PMID- 23088271 TI - Computational chemistry and drug discovery: a call to action. PMID- 23088272 TI - Significance estimation for sequence-based chemical similarity searching (PhAST) and application to AuroraA kinase inhibitors. AB - BACKGROUND: Chemical similarity searching allows the retrieval of preferred screening molecules from a compound database. Candidates are ranked according to their similarity to a reference compound (query). Assessing the statistical significance of chemical similarity scores helps prioritizing significant hits, and identifying cases where the database does not contain any promising compounds. METHOD: Our text-based similarity measure, Pharmacophore Alignment Search Tool (PhAST), employs pair-wise sequence alignment. We adapted the concept of E-values as significance estimates and employed a sampling technique that incorporates the principle of importance sampling in a Markov chain Monte Carlo simulation to generate distributions of random alignment scores. These distributions were used to compute significance estimates for similarity scores in a preliminary prospective virtual screen for inhibitors of Aurora A kinase. CONCLUSION: Assessing the significance of compound similarity computed with PhAST allows for a statistically motivated identification of candidate screening compounds. Inhibitors of Aurora A kinase were retrieved from a large compound library. PMID- 23088274 TI - Computational tools and resources for metabolism-related property predictions. 2. Application to prediction of half-life time in human liver microsomes. AB - BACKGROUND: The most important factor affecting metabolic excretion of compounds from the body is their half-life time. This provides an indication of compound stability of, for example, drug molecules. We report on our efforts to develop QSAR models for metabolic stability of compounds, based on in vitro half-life assay data measured in human liver microsomes. METHOD: A variety of QSAR models generated using different statistical methods and descriptor sets implemented in both open-source and commercial programs (KNIME, GUSAR and StarDrop) were analyzed. The models obtained were compared using four different external validation sets from public and commercial data sources, including two smaller sets of in vivo half-life data in humans. CONCLUSION: In many cases, the accuracy of prediction achieved on one external test set did not correspond to the results achieved with another test set. The most predictive models were used for predicting the metabolic stability of compounds from the open NCI database, the results of which are publicly available on the NCI/CADD Group web server ( http://cactus.nci.nih.gov ). PMID- 23088275 TI - Fingerprint design and engineering strategies: rationalizing and improving similarity search performance. AB - Fingerprints (FPs) are bit or integer string representations of molecular structure and properties, and are popular descriptors for chemical similarity searching. A major goal of similarity searching is the identification of novel active compounds on the basis of known reference molecules. In this review recent FP design and engineering strategies are discussed. New types of FPs continue to be replaced, often applying different design principles. FP engineering techniques have recently been introduced to further improve search performance and computational efficiency and elucidate mechanisms by which FPs recognize active compounds. In addition, through feature selection and hybridization techniques, standard FPs have been transformed into compound class-specific versions with further increased search performance. Moreover, scaffold hopping mechanisms have been explored. FPs will continue to play an important role in the search for novel active compounds. PMID- 23088273 TI - Computational tools and resources for metabolism-related property predictions. 1. Overview of publicly available (free and commercial) databases and software. AB - Metabolism has been identified as a defining factor in drug development success or failure because of its impact on many aspects of drug pharmacology, including bioavailability, half-life and toxicity. In this article, we provide an outline and descriptions of the resources for metabolism-related property predictions that are currently either freely or commercially available to the public. These resources include databases with data on, and software for prediction of, several end points: metabolite formation, sites of metabolic transformation, binding to metabolizing enzymes and metabolic stability. We attempt to place each tool in historical context and describe, wherever possible, the data it was based on. For predictions of interactions with metabolizing enzymes, we show a typical set of results for a small test set of compounds. Our aim is to give a clear overview of the areas and aspects of metabolism prediction in which the currently available resources are useful and accurate, and the areas in which they are inadequate or missing entirely. PMID- 23088276 TI - Molecular simulations of drug-receptor complexes in anticancer research. AB - Molecular modeling and computer simulation techniques have matured significantly in recent years and proved their value in the study of drug-DNA, drug-DNA protein, drug-protein and protein-protein interactions. Evolution in this area has gone hand-in-hand with an increased availability of structural data on biological macromolecules, major advances in molecular mechanics force fields and considerable improvements in computer technologies, most significantly processing speeds, multiprocessor programming and data-storage capacity. The information derived from molecular simulations of drug-receptor complexes can be used to extract structural and energetic information that is usually beyond current experimental possibilities, provide independent accounts of experimentally observed behavior, help in the interpretation of biochemical or pharmacological results, and open new avenues for research by posing novel relevant questions that can guide the design of new experiments. As drug-screening tools, ligand- and fragment-docking platforms stand out as powerful techniques that can provide candidate molecules for hit and lead development. This review provides an overall perspective of the main methods and focuses on some selected applications to both classical and novel anticancer targets. PMID- 23088277 TI - Chemogenomics in drug discovery: computational methods based on the comparison of binding sites. AB - Novel computational methods for understanding relationships between ligands and all possible biological targets have emerged in recent years. Proteins are connected to each other based on the similarity of their ligands or based on the similarity of their binding sites. The assumption is that compounds sharing chemical similarity should share targets and that targets with a similar binding site should also share ligands. A large number of computational techniques have been developed to assess ligand and binding site similarity, which can be used to make quantitative predictions of the most probable biological target of a given compound. This review covers the recent advances in new computational methods for relating biological targets based on the similarity of their binding sites. Binding site comparisons are used for the prediction of their most likely ligands, their possible cross reactivity and selectivity. These comparisons can also be used to infer the function of novel uncharacterized proteins. PMID- 23088278 TI - C8-linked bulky guanosine DNA adducts: experimental and computational insights into adduct conformational preferences and resulting mutagenicity. AB - Bulky DNA adducts are formed through the covalent attachment of aryl groups to the DNA nucleobases. Many of these adducts are known to possess conformational heterogeneity, which is responsible for the variety of mutagenic outcomes associated with these lesions. The present contribution reviews several conformational and mutagenic themes that are prevalent among the DNA adducts formed at the C8-site of the guanine nucleobase. The most important conclusions obtained (to date) from experiments are summarized including the anti/syn conformational preference of the adducts, their potential to inflict DNA mutations and mismatch stabilization, and their interactions with DNA polymerases and repair enzymes. Additionally, the unique role that computer calculations can play in understanding the structural properties of these adducts are highlighted. PMID- 23088280 TI - Predicted lithium-boron compounds under high pressure. AB - High pressure can fundamentally alter the bonding patterns of light elements and their compounds, leading to the unexpected formation of materials with unusual chemical and physical properties. Using an unbiased structure search method based on particle-swarm optimization algorithms in combination with density functional theory calculations, we investigate the phase stabilities and structural changes of various Li-B systems on the Li-rich regime under high pressures. We identify the formation of four stoichiometric lithium borides (Li(3)B(2), Li(2)B, Li(4)B, and Li(6)B) having unforeseen structural features that might be experimentally synthesizable over a wide range of pressures. Strikingly, it is found that the B B bonding patterns of these lithium borides evolve from graphite-like sheets in turn to zigzag chains, dimers, and eventually isolated B ions with increasing Li content. These intriguing B-B bonding features are chemically rationalized by the elevated B anionic charges as a result of Li->B charge transfer. PMID- 23088281 TI - Bilateral pulmonary sequestration in the elderly adult. AB - Pulmonary sequestration (PS) is a rare malformation consisting of aberrant lung tissue which is not affiliated with the normal bronchial system and is fed by an aberrant artery that derives from systemic arteries. However, PS is usually seen unilaterally but, only rarely, it is bilateral. Most patients with PS are diagnosed because of symptoms due to pulmonary infection or cardiac disease, while a small portion of patients are asymptomatic and diagnosed incidentally. In this report, we present an extremely rare case of asymptomatic bilateral PS which was diagnosed at advanced age. To our knowledge, this case represents the oldest patient in the literature, and the second case that was diagnosed in a patient over the age of 50. PMID- 23088282 TI - Ag(I)-catalyzed aminofluorination of alkynes: efficient synthesis of 4 fluoroisoquinolines and 4-fluoropyrrolo[alpha]isoquinolines. AB - A silver-catalyzed intramolecular oxidative aminofluorination of alkynes has been developed by using NFSI as a fluorinating reagent. This reaction represents an efficient method for the synthesis of various 4-fluoroisoquinolines and 4 fluoropyrrolo[alpha]isoquinolines. PMID- 23088283 TI - Outcome and patterns of failure after postoperative intensity modulated radiotherapy for locally advanced or high-risk oral cavity squamous cell carcinoma. AB - BACKGROUND: To determine the outcome and patterns of failure in oral cavity cancer (OCC) patients after postoperative intensity modulated radiotherapy (IMRT) with concomitant systemic therapy. METHODS: All patients with locally advanced (AJCC stage III/IV) or high-risk OCC (AJCC stage II) who underwent postoperative IMRT at our institution between December 2006 and July 2010 were retrospectively analyzed. The primary endpoint was locoregional recurrence-free survival (LRRFS). Secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), acute and late toxicities. RESULTS: Overall 53 patients were analyzed. Twenty-three patients (43%) underwent concomitant chemotherapy with cisplatin, two patients with carboplatin (4%) and four patients were treated with the monoclonal antibody cetuximab (8%).At a median follow-up of 2.3 (range, 1.1 4.6) years the 3-year LRRFS, DMFS and OS estimates were 79%, 90%, and 73% respectively. Twelve patients experienced a locoregional recurrence. Eight patients, 5 of which had both a flap reconstruction and extracapsular extension (ECE), showed an unusual multifocal pattern of recurrence. Ten locoregional recurrences occurred marginally or outside of the high-risk target volumes. Acute toxicity grades of 2 (27%) and 3 (66%) and late toxicity grades of 2 (34%) and 3 (11%) were observed. CONCLUSION: LRRFS after postoperative IMRT is satisfying and toxicity is acceptable. The majority of locoregional recurrences occurred marginally or outside of the high-risk target volumes. Improvement of high-risk target volume definition especially in patients with flap reconstruction and ECE might transfer into better locoregional control. PMID- 23088284 TI - Awareness and use of nonoccupational HIV post-exposure prophylaxis among people receiving rapid HIV testing in Spain. AB - OBJECTIVES: This paper examines the awareness and use of nonoccupational HIV post exposure prophylaxis (nPEP) in Spain, and the factors that influence this awareness. METHODS: Between June 2009 and July 2010, a mobile unit offered free, rapid HIV tests in a number of Spanish cities. A total of 2545 people were passively recruited and tested, and answered a self-administered questionnaire containing sociodemographic, behavioural and nPEP-related questions. Bivariate and multivariate analyses were performed, stratifying by gender/sexual behaviour. RESULTS: Some 34% of the responders were men who have sex with men (MSM), 30% were men who have sex exclusively with women (MSW), and 35% were women. Approximately 26% were foreigners, 46% had a university degree, and 51% had previously taken an HIV test. Overall, 22% were aware of nPEP. Only 2% had ever used it; 70% of these after high-risk sexual intercourse. Awareness was higher among MSM (34%) than women (16%) and MSW (15%). Multivariate analysis showed a lack of nPEP awareness to be associated with being born in Latin America, while awareness increased with the number of previous HIV tests among women and MSW. In MSM, awareness was also associated with having a university degree, the degree of interaction with gay culture, number of partners, and use of the internet as the main way of meeting partners. CONCLUSIONS: nPEP awareness in the studied population was unacceptably low. The promotion of its availability should be made a major objective of prevention programmes, as a complementary measure to condom use. PMID- 23088285 TI - Changes in perioperative management of radical prostatectomy using clinical pathways according to a standardized care plan: a multi-institutional study. AB - OBJECTIVES: To improve the perioperative care for radical prostatectomy patients at a multi-institutional level and practice. METHODS: A prospective multi institutional study involving 50 hospitals was carried out in cooperation with the Japanese Society of Endourology. As the first step, a consensus meeting was held to establish a standardized perioperative care plan. Second, the clinical pathways were individually developed and revised according to the standardized care plan in each of the participating hospitals. Patterns of perioperative care, including preoperative hospital stay, resuming meals and ambulation, removal of pelvic drain and urethral catheter, antimicrobial administration, and postoperative hospital stay, were compared before (2007) and after developing/revising pathways (2009). Furthermore, actual practice and complications before and after implementing the pathways were investigated. RESULTS: Except for resuming ambulation, all perioperative pathways were significantly shortened with the adoption of the newly defined clinical pathway (P < 0.001). Furthermore, all settings except for postoperative hospital stay significantly decreased in terms of variance (P < 0.002). In 2009, the overall complication rate significantly decreased (P < 0.001), and all of the outcomes except urethral catheter removal were also significantly shortened (P <= 0.008) and decreased in variance after implementation of the new pathways (P <= 0.006). In multivariate analyses, implementation of the refined clinical pathways was an important factor to improve perioperative care. CONCLUSIONS: When standardized goals in perioperative care are recommended to hospitals and care plans are developed/revised in individual hospitals, both settings and practice are significantly improved. It is to be investigated whether a similar intervention could be useful to achieve a standardization of surgical pathway for other diseases. PMID- 23088286 TI - Characterization of the major odor-active compounds in Thai durian ( Durio zibethinus L. 'Monthong') by aroma extract dilution analysis and headspace gas chromatography-olfactometry. AB - An aroma extract dilution analysis applied on the volatile fraction isolated from Thai durian by solvent extraction and solvent-assisted flavor evaporation resulted in 44 odor-active compounds in the flavor dilution (FD) factor range of 1-16384, 41 of which could be identified and 24 that had not been reported in durian before. High FD factors were found for ethyl (2S)-2-methylbutanoate (fruity; FD 16384), ethyl cinnamate (honey; FD 4096), and 1 (ethylsulfanyl)ethanethiol (roasted onion; FD 1024), followed by 1 (ethyldisulfanyl)-1-(ethylsulfanyl)ethane (sulfury, onion), 2(5)-ethyl-4-hydroxy 5(2)-methylfuran-3(2H)-one (caramel), 3-hydroxy-4,5-dimethylfuran-2(5H)-one (soup seasoning), ethyl 2-methylpropanoate (fruity), ethyl butanoate (fruity), 3 methylbut-2-ene-1-thiol (skunky), ethane-1,1-dithiol (sulfury, durian), 1 (methylsulfanyl)ethanethiol (roasted onion), 1-(ethylsulfanyl)propane-1-thiol (roasted onion), and 4-hydroxy-2,5-dimethylfuran-3(2H)-one (caramel). Among the highly volatile compounds screened by static headspace gas chromatography olfactometry, hydrogen sulfide (rotten egg), acetaldehyde (fresh, fruity), methanethiol (rotten, cabbage), ethanethiol (rotten, onion), and propane-1-thiol (rotten, durian) were found as additional potent odor-active compounds. Fourteen of the 41 characterized durian odorants showed an alkane-1,1-dithiol, 1 (alkylsulfanyl)alkane-1-thiol, or 1,1-bis(alkylsulfanyl)alkane structure derived from acetaldehyde, propanal, hydrogen sulfide, and alkane-1-thiols. Among these, 1-(propylsulfanyl)ethanethiol, 1-{[1-(methylsulfanyl)ethyl]sulfanyl}ethanethiol, and 1-{[1-(ethylsulfanyl)ethyl]sulfanyl}ethanethiol were reported for the first time in a natural product. PMID- 23088287 TI - Should researchers use single indicators, best indicators, or multiple indicators in structural equation models? AB - BACKGROUND: Structural equation modeling developed as a statistical melding of path analysis and factor analysis that obscured a fundamental tension between a factor preference for multiple indicators and path modeling's openness to fewer indicators. DISCUSSION: Multiple indicators hamper theory by unnecessarily restricting the number of modeled latents. Using the few best indicators - possibly even the single best indicator of each latent - encourages development of theoretically sophisticated models. Additional latent variables permit stronger statistical control of potential confounders, and encourage detailed investigation of mediating causal mechanisms. SUMMARY: We recommend the use of the few best indicators. One or two indicators are often sufficient, but three indicators may occasionally be helpful. More than three indicators are rarely warranted because additional redundant indicators provide less research benefit than single indicators of additional latent variables. Scales created from multiple indicators can introduce additional problems, and are prone to being less desirable than either single or multiple indicators. PMID- 23088291 TI - Impact of geographic density of eye care professionals on eye care among adults with diabetes. AB - OBJECTIVE: To examine the impact of the geographic density of eye care professionals (ECPs) on the receipt of annual dilated eye examinations among adults in the United States with diabetes. METHOD: Data from the 2006 Behavioral Risk Factor Surveillance System were linked to the 2007 Area Resource File to examine the association between the density of ECPs (ophthalmologists and optometrists) per 100,000 people and self-reports of having had a dilated eye examination in the last year. The sample included adults aged 18+ years with diabetes (N = 29,495). Multivariate logistic regression was conducted to estimate adjusted odds ratios of annual dilated eye examinations, while controlling for age, sex, marital status and education, and stratifying by health insurance. RESULTS: Approximately 10% of respondents with diabetes lived in counties with no ECPs. Prevalence of being uninsured was 7.4% and 15.5% in those with and without dilated eye exams, respectively. After controlling for covariates and stratifying by health insurance, diabetic adults with health insurance cover residing in areas with no ECPs were less likely to report having had a dilated eye examination in the past year than those with 20 or more ECPs/100,000 people (odds ratio 0.72, 95% confidence interval 0.58-0.91). CONCLUSION: Residence in a county with a low density of ECPs reduced the likelihood of receiving annual dilated eye examinations among insured adults with diabetes. Enhancing the ability of ECPs to reach and care for those in need might better protect vision in people with diabetes. More research is needed to determine the mix of services that produces the best patient outcome. PMID- 23088292 TI - Effects of pressure and osmolytes on the allosteric equilibria of Salmonella typhimurium tryptophan synthase. AB - Osmolytes are common constituents of bacteria that may be produced or accumulate at high concentrations, up to 1 M, when cells are subjected to stresses like ionic strength and temperature. However, the effects of osmolytes on the allosteric properties of bacterial enzymes have rarely been examined. We have studied the effects of osmolytes and hydrostatic pressure on the allosteric equilibria of Salmonella typhimurium tryptophan (Trp) synthase. Trp synthase is a well-studied multienzyme complex with activity tightly regulated by allosteric interactions between the alpha- and beta-subunits. Trp synthase activity is affected by a wide range of physical parameters, including monovalent cations, pH, ligands, solvents, and hydrostatic pressure. Osmolytes, including betaine, taurine, sucrose, and polyethylene glycol, activate Trp synthase 2-3-fold in the absence of monovalent cations, indicating that osmolytes can stabilize the active closed conformation. However, in the presence of monovalent cations, osmolytes have only minor effects on activity and allosteric equilibria, but 1 M betaine stabilizes the Trp synthase-Ser-indoline complex against apparent pressure induced subunit dissociation. Na(+) and K(+) are more effective at shifting the alpha-aminoacrylate-indoline quinonoid equilibrium toward the quinonoid side, with a K(Q) of 8-10, than NH(4)(+)(K(Q) ~ 2). Furthermore, pressure-jump experiments show that the mechanism of indoline reaction to form a quinonoid complex may be different for the NH(4)(+) enzyme than the Na(+) and K(+) forms. These results show that osmolytes have subtle but significant effects on the allosteric properties of Trp synthase, and these effects may be important in vivo. PMID- 23088294 TI - Complexity reduction of chromatin architecture in macula densa cells during mouse postnatal development. AB - AIM: To determine whether complexity of chromatin structure in kidney macula densa cells (MDC) decreases during postnatal development in mice. METHODS: The levels of chromatin structural complexity were measured by determining fractal dimension of MDC nuclei. Kidney tissue was obtained from the total of 32 male Swiss albino mice divided into four age groups (n = 8): newborn (0 days), 10 days old, 20 days old and 30 days old. For a total of 640 MDC chromatin structures, fractal dimension, lacunarity, as well as parameters of Grey level co-occurrence matrix (GLCM) texture were determined. RESULTS: Chromatin fractal dimension in animals aged 10 days, 20 days and 30 days was significantly lower (P < 0.05, P < 0.01 and P < 0.001, respectively), compared with newborn mice. This complexity reduction of chromatin architecture is in accordance with previously published studies, which detected generalized and sustained loss of both tissue and cell complexity during aging. The loss of complexity was texture-independent, since there was no statistically significant difference (P > 0.05) in both chromatin angular second moment and inverse difference moment between the age groups. CONCLUSION: Our results indicate that age-related nuclear intrinsic factors which do not influence chromatin texture may have an important role in MDC postnatal development. PMID- 23088295 TI - A single nucleotide polymorphism of interleukin-6 gene is related to plasma adrenomedullin levels. AB - OBJECTIVE: Elevated plasma adrenomedullin (ADM) levels are associated with cardiovascular diseases. Single nucleotide polymorphisms (SNPs) in the gene encoding ADM (ADM) are associated with plasma ADM levels. The presence of a nuclear factor for interleukin-6 (IL-6) expression binding site in the promoter region of the ADM gene suggests a possible relationship between the expression of the ADM and IL-6. Therefore, we investigated whether plasma ADM levels are related to SNPs in the gene encoding IL-6 (IL6). METHODS: Plasma ADM levels were measured in 476 subjects in the Hong Kong Cardiovascular Risk Factor Prevalence Study-2 (CRISPS2). The subjects were genotyped for three tagging SNPs in the IL6 gene. RESULTS: The minor allele frequencies of the IL6 SNPs rs17147230, rs1800796 and rs2069837 were 41.8%, 20.0% and 15.4%, respectively. The tagging SNP, rs17147230, was associated with plasma ADM levels after adjusting for age and sex (beta=-0.096, P = 0.034). The association was significant in women (beta=-0.115, P = 0.021) but not in men. Among all subjects, plasma ADM levels decreased with an increasing number of minor alleles of rs17147230 in multivariate analysis (P = 0.034). Compared to subjects with the AA genotype, subjects with the TT genotype had plasma ADM levels 12.8% lower (95% CI: 0.6-23.5%, P = 0.041). Haplotype analysis demonstrated a significant association of the haplotype ACA with plasma ADM levels in women (P < 0.05). CONCLUSION: Plasma ADM levels are related to the SNP rs17147230 in IL6 gene. The effect of the polymorphism on inflammation and cardiovascular disease remains to be determined. PMID- 23088296 TI - Lanthanide metal-organic frameworks: searching for efficient solvent-free catalysts. AB - Three Ln-based 2D metal-organic frameworks with the formula [Ln(3,5-DSB)(Phen)] (Ln = La, Pr, Nd; 3,5-DSB = 3,5-disulfobenzoate; Phen = 1,10-phenathroline) were hydrothermally synthesized. They belong to two 2D structural types, and their nets own different topologies. The isostructural La and Pr compounds possess a uninodal 5-connected SP 2-periodic net (6,3). The Nd compound has a binodal 3- and 6-connected kgd net. The novel compounds exhibit excellent catalytic activities toward the cyanosilylation reaction under solvent-free conditions. PMID- 23088293 TI - Endothelial peroxisomal dysfunction and impaired pexophagy promotes oxidative damage in lipopolysaccharide-induced acute kidney injury. AB - AIMS: We examined that (a) how the endotoxic stress affects peroxisomal function and autophagic degradation of peroxisomes-pexophagy, (b) how a superimposed dysfunction of lysosomes and pexophagy modifies responses to lipopolysaccharide (LPS), and (c) the mechanisms of peroxisomal contribution to renal injury. To accomplish this, we used lysosome-defective Lyst-mice in vivo and primary endothelial cells in vitro, and compared the responses with wild-type (WT) littermates. RESULTS: LPS induced pexophagic degradation, followed by proliferation of peroxisomes in WT mice, which was abolished in Lyst-mice. Lyst mice exhibited impaired activation of catalase, which together with preserved hydrogen peroxide-generating beta-oxidation resulted in redox disequilibrium. LPS treatment induced a heightened inflammatory response, increased oxidative damage, and aggravated renal injury in Lyst-mice. Similarly, as in vivo, LPS-activated lysosomal (LYS) pexophagy and transiently repressed peroxisomes in vitro, supported by reduced peroxisomal density in the vicinity of lysosomes. Peroxisomal dynamics was also abolished in lysosome-defective cells, which accumulated peroxisomes with compromised functions and intraorganellar redox imbalance. INNOVATION: We demonstrated that pexophagy is a default response to endotoxic injury. However, when LYS dysfunction (a frequent companion of chronic diseases) is superimposed, recycling and functioning of peroxisomes are impaired, and an imbalance between hydrogen peroxide-generating beta-oxidation and hydrogen peroxide-detoxifying catalase ensues, which ultimately results in peroxisomal burnout. CONCLUSION: Our data strongly suggest that pexophagy, a cellular mechanism per se, is essential in functional maintenance of peroxisomes during LPS exposure. Inhibition of pexophagy results in accumulation of impaired peroxisomes, redox disequilibrium, and aggravated renal damage. PMID- 23088297 TI - Metabolomics reveals the metabolic shifts following an intervention with rye bread in postmenopausal women--a randomized control trial. AB - BACKGROUND: Epidemiological studies have consistently shown that whole grain (WG) cereals can protect against the development of chronic diseases, but the underlying mechanism is not fully understood. Among WG products, WG rye is considered even more potent because of its unique discrepancy in postprandial insulin and glucose responses known as the rye factor. In this study, an NMR based metabolomics approach was applied to study the metabolic effects of WG rye as a tool to determine the beneficial effects of WG rye on human health. METHODS: Thirty-three postmenopausal Finnish women with elevated serum total cholesterol (5.0-8.5 mmol/L) and BMI of 20-33 kg/m2 consumed a minimum of 20% of their daily energy intake as high fiber WG rye bread (RB) or refined wheat bread (WB) in a randomized, controlled, crossover design with two 8-wk intervention periods separated by an 8-wk washout period. At the end of each intervention period, fasting serum was collected for NMR-based metabolomics and the analysis of cholesterol fractions. Multilevel partial least squares discriminant analysis was used for paired comparisons of multivariate data. RESULTS: The metabolomics analysis of serum showed lower leucine and isoleucine and higher betaine and N,N dimethylglycine levels after RB than WB intake. To further investigate the metabolic effects of RB, the serum cholesterol fractions were measured. Total- and LDL-cholesterol levels were higher after RB intake than after WB (p<0.05). CONCLUSIONS: This study revealed favorable shifts in branched amino acid and single carbon metabolism and an unfavorable shift in serum cholesterol levels after RB intake in postmenopausal women, which should be considered for evaluating health beneficial effects of rye products. PMID- 23088298 TI - Mechanism of activity and toxicity of Nystatin-Intralipid. AB - A novel lipid formulation of Nystatin (NYT), Nystatin-Intralipid (NYT-IL), which was found to be more active and less toxic in vitro and in vivo, was developed in our laboratory. The aim of the present study was to explore the possible mechanisms underlying its biological activity. To assess mechanisms affecting fungal cells we conducted the following experiments: killing kinetics, scanning and transmission electron microscopy (EM), measurements of potassium ion leakage and susceptibility in the presence of ergosterol. To study mechanisms affecting mammalian cells, we evaluated the effect of NYT-IL on a kidney cell line, with respect to viability, metabolic activity, potassium leakage and internalization of FITC-labeled human transferrin. NYT-IL exhibited killing kinetics patterns against Candida albicans similar to those of NYT and caused disruption of fungal cells and potassium ion leakage. Susceptibility tests showed that NYT-IL had lower antifungal activity in the presence of ergosterol. Thus, NYT-IL acts apparently by damaging fungal membrane, possibly through interaction with ergosterol, and maybe by additional modes of action. NYT-IL did not cause potassium leakage from mammalian kidney cells at any tested concentration and was not cytotoxic, whereas NYT, at high concentrations, led to K(+) leakage and was cytotoxic. Furthermore, the high NYT concentration interfered in the internalization process of human transferrin receptor (hTfnR) while NYT-IL did not. In summary, the Intralipid formulation of NYT diminishes the mechanisms responsible for toxicity to mammalian cells but preserves mechanisms of action against fungi, thereby suggesting superiority of NYT-IL as compared to NYT as an antifungal agent. PMID- 23088299 TI - In vivo molecular microimaging of pulmonary aspergillosis. AB - The early diagnosis of invasive pulmonary aspergillosis (IPA) is challenging. Fibered confocal fluorescence microscopy (FCFM) is a new technique that allows in vivo imaging of the lung microstructure during bronchoscopy. In this study, we investigated the ability of FCFM to detect a fluorescent peptide-tracer bound to Aspergillus fumigatus in experimental IPA in 13 immunosuppressed, non-neutropenic rats. Subpleural IPA microabscesses were imaged through a transthoracic window using FCFM in vivo after i.v. injection of the c(CGGRLGPFC)-NH2([FITC]) peptide (n = 7) or saline. Results were compared to 10 immunosuppressed, non-infected rats and to six immunosuppressed Geosmithia argillacea-infected rats with and without i.v. injection of the peptide. The peptide in vitro specifically labeled A. fumigatus grown under biofilm growth conditions but not G. argillacea. In vivo, FCFM showed a local infiltration of fluorescent host cells in both Aspergillus and Geosmithia infections. Lung/inner thoracic wall fluorescence intensity ratio (FI) did not differ before and after peptide administration on healthy lung areas, on non-specific inflammatory areas, or on Geosmithia micro abscesses. In contrast, FI increased from 1.05 without peptide to 1.83 after peptide injection on Aspergillus micro-abscesses (p < 0.0001). In peptide injected rats, FI from IPA foci was higher than from non-specific inflammation or from Geosmithia abscesses (p <= 0.002). Using c(CGGRLFPC)-NH2([FITC]) peptide, FCFM allows the in vivo specific imaging of pulmonary aspergillosis. These data provide the basis for the in vivo diagnosis of human pulmonary aspergillosis using alveolar confocal endomicroscopy. PMID- 23088300 TI - Autonomic modulation of heart rate in paraplegic wheelchair basketball players: Linear and nonlinear analysis. AB - This study aimed to evaluate the autonomic modulation of heart rate in sedentary paraplegics and paraplegic wheelchair basketball players with thoracic spinal cord injury below T6. Seven paraplegic wheelchair basketball players (active paraplegic group), five paraplegics who were not involved in regular exercise (sedentary paraplegic group) and 10 able-bodied participants (control group) took part in the study. The heart rate variability was evaluated by linear (low frequency and high frequency band in normalised units and low frequency/high frequency ratio) and nonlinear methods (Shannon entropy, corrected conditional entropy, and symbolic analysis). The sedentary group presented significantly higher values for low frequency, low frequency/high frequency ratio and symbolic index with no significant variations (0V%), and also lower values for the high frequency and symbolic index with two significant unlike variation (2ULV%) compared to active paraplegic group. Shannon entropy and corrected conditional entropy analyses revealed significantly lower values in the sedentary group than in the control or active paraplegic groups. Paraplegic individuals who regularly undertake physical exercise have higher complexity of R-R interval time series, lower sympathetic modulation, and higher parasympathetic modulation than sedentary paraplegic participants. PMID- 23088301 TI - Efficient fluorescence quenching in carbon dots by surface-doped metals- disruption of excited state redox processes and mechanistic implications. AB - The carbon dots in this study were small carbon nanoparticles with the particle surface functionalized by oligomeric poly(ethylene glycol) diamine molecules. Upon photoexcitation, the brightly fluorescent carbon dots in aqueous solution served the function of excellent electron donors to reduce platinum(IV) and gold(III) compounds into their corresponding metals to be deposited on the dot surface. The deposited metals even in very small amounts were found to have dramatic quenching effects on the fluorescence emission intensities, but essentially no effects on the observed fluorescence decays. The obviously exclusive near-neighbor static quenching could be attributed to the disruption of electron-hole radiative recombinations (otherwise responsible for the fluorescence emissions in carbon dots). The results provide important evidence for the availability of photogenerated electrons that could be harvested for productive purposes, which in turn supports the current mechanistic framework on fluorescence emission and photoinduced redox properties of carbon dots. PMID- 23088302 TI - Testicular augmentation using chin implants. AB - INTRODUCTION: Disturbances in testicular integrity have the potential to cause severe concerns about masculinity, body image, and sexual function. Testicular volume replacement surgery with prosthesis has been known about since 1941, although esthetic procedures for testicular augmentation have not been satisfactory. AIM: To describe an unprecedented testicular augmentation surgical technique that is specially focused on preserving testicular function and providing a favorable esthetic outcome. METHODS: We present a case of a 45-year old man with body dysmorphic disorder. Surgical treatment using a new technique by placing a chin implant on the testicle was offered and accepted. RESULTS: Good symmetry between both testicles was achieved. No complications were reported. One month after the procedure, the patient started a satisfactory sex life. Functional monitoring was normal during the year after the procedure. CONCLUSIONS: This technique is unprecedented in literature, it represents a safe and effective therapeutic alternative; nevertheless, more experience in performing this procedure is needed. PMID- 23088303 TI - Polymer-inorganic core-shell nanofibers by electrospinning and atomic layer deposition: flexible nylon-ZnO core-shell nanofiber mats and their photocatalytic activity. AB - Polymer-inorganic core-shell nanofibers were produced by two-step approach; electrospinning and atomic layer deposition (ALD). First, nylon 6,6 (polymeric core) nanofibers were obtained by electrospinning, and then zinc oxide (ZnO) (inorganic shell) with precise thickness control was deposited onto electrospun nylon 6,6 nanofibers using ALD technique. The bead-free and uniform nylon 6,6 nanofibers having different average fiber diameters (~80, ~240 and ~650 nm) were achieved by using two different solvent systems and polymer concentrations. ZnO layer about 90 nm, having uniform thickness around the fiber structure, was successfully deposited onto the nylon 6,6 nanofibers. Because of the low deposition temperature utilized (200 degrees C), ALD process did not deform the polymeric fiber structure, and highly conformal ZnO layer with precise thickness and composition over a large scale were accomplished regardless of the differences in fiber diameters. ZnO shell layer was found to have a polycrystalline nature with hexagonal wurtzite structure. The core-shell nylon 6,6-ZnO nanofiber mats were flexible because of the polymeric core component. Photocatalytic activity of the core-shell nylon 6,6-ZnO nanofiber mats were tested by following the photocatalytic decomposition of rhodamine-B dye. The nylon 6,6-ZnO nanofiber mat, having thinner fiber diameter, has shown better photocatalytic efficiency due to higher surface area of this sample. These nylon 6,6-ZnO nanofiber mats have also shown structural stability and kept their photocatalytic activity for the second cycle test. Our findings suggest that core shell nylon 6,6-ZnO nanofiber mat can be a very good candidate as a filter material for water purification and organic waste treatment because of their photocatalytic properties along with structural flexibility and stability. PMID- 23088304 TI - Illustrating problems faced by stroke researchers: a review of cluster-randomized controlled trials. AB - The cluster-randomized controlled trial is a design increasingly used in prevention and health care evaluation studies and is highly relevant to stroke research. However, there are methodological issues that make it complex to implement. These are not always fully appreciated, with reviews continuing to reveal deficiencies. We searched PUBMED and CENTRAL databases to March 31, 2011 for cluster-randomized controlled trials in stroke. Two investigators independently reviewed citations for eligibility and extracted data on key aspects of each trial. Fifteen trials met the eligibility criteria. No trial fully met CONSORT cluster-randomized controlled trial guidelines, although good design and reporting practice were usually present. Twelve trials included the term 'cluster-randomized' (or 'group-randomized') in the title, and 12 trials stated the intraclass correlation coefficient used to plan the number of clusters and cluster size. However, few provided a clear, evidence-based justification for the choice of intraclass correlation coefficient, and only two-thirds reported the intraclass correlation coefficient for primary outcomes. Several trials appeared underpowered because of problems in determining an appropriate sample size, defining appropriate clusters, and recruiting and retaining clusters and patients. Cluster-randomized controlled trials are difficult to design and perform due to the combination of methodological and practical difficulties. It is important that further improvements are made to reporting cluster-randomized trials and intraclass correlation coefficients should be estimated using a standardized approach and reported consistently; this would be beneficial for stroke researchers when designing future cluster-randomized trials. PMID- 23088305 TI - Ground and excited state properties of new porphyrin based dyads: a combined theoretical and experimental study. AB - The properties of the ground and excited states of several porphyrins appended with external chelates coordinated to ruthenium-bisbipyridine units are reported. The important modification of the absorption spectrum upon coordination with the ruthenium complex showed that a significant electronic communication between the two subunits was present in the ground state. Experimental results were compared with quantum chemistry calculations performed at density functional theory and time-dependent density functional theory level. The influence of the exchange correlation functional on the quality of the computed absorption spectrum is shown, and the better behavior of hybrid functionals over long-range corrected ones was rationalized. The excited states topology analysis, performed using natural transition orbitals, gave a more evident confirmation of the communication between the subunits and showed that these new compounds can be promising as dyes in dye-sensitized solar cells. PMID- 23088306 TI - Electrostatic origin of the catalytic effect of a supramolecular host catalyst. AB - The development of enzyme mimetic catalysts as well as the analysis of the catalytic effects of such catalysts has been a major challenge for synthetic chemists. One of the impressive examples of artificial catalysts has been the development of a highly charged host compound that provides a significant acceleration to the hydrolysis of orthoformates and other systems. However, the origin of the catalytic effect has not been quantified, and its origin remains somewhat unclear. The understanding of the corresponding supramolecular catalysis has thus become a major challenge, both in terms of computational modeling and in terms of the analysis of the corresponding acid-catalyzed reaction. Here we present a computer simulation study and kinetic analyses that reproduce the experimentally observed catalytic effect, establishing that this effect is due to electrostatic stabilization of the positively charged transition state (relative to the uncharged bound complex). Our study illustrates the crucial need for careful analysis of the complex kinetics of the catalytic effect and the host system, as well as the need for computational modeling in analyzing the catalytic effect and in the potential design of better catalysts. Finally, our finding of the large stabilization of the bound H(3)O(+) points out the very low "local pH" inside the host system even when the solvent is kept at a high pH. PMID- 23088307 TI - Differences between HIV-infected and uninfected adults in the contributions of smoking, diabetes and hypertension to acute coronary syndrome: two parallel case control studies. AB - OBJECTIVES: The aim of the study was to assess the separate contributions of smoking, diabetes and hypertension to acute coronary syndrome (ACS) in HIV infected adults relative to uninfected adults. METHODS: Two parallel case-control studies were carried out. In the first study, HIV-positive adults diagnosed with ACS between 1997 and 2009 (HIV+/ACS) were matched for age, gender and known duration of HIV infection with HIV-positive adults without ACS (HIV+/noACS), each individual in the HIV+/ACS group being matched with three individuals in the HIV+/noACS group. In the second study, each individual in the HIV+/ACS group in the first study was matched for age, gender and calendar date of ACS diagnosis with three HIV-negative individuals diagnosed with ACS between 1997 and 2009 (HIV /ACS). Each individual in the HIV-/ACS group was then matched for age and gender with an HIV-negative adult without ACS (HIV-/noACS). After matching, the ratio of numbers of individuals in the HIV+/ACS, HIV+/noACS, HIV-/ACS and HIV-/noACS groups was therefore 1 : 3 : 3 : 3, respectively. We performed logistic regression analyses to identify risk factors for ACS in each case-control study and calculated population attributable risks (PARs) for smoking, diabetes and hypertension in HIV-positive and HIV-negative individuals. RESULTS: There were 57 subjects in the HIV+/ACS group, 173 in the HIV+/noACS group, 168 in the HIV-/ACS group, and 171 in the HIV-/noACS group. Independent risk factors for ACS were smoking [odds ratio (OR) 4.091; 95% confidence interval (CI) 2.086-8.438; P < 0.0001] and a family history of cardiovascular disease (OR 7.676; 95% CI 1.976 32.168; P = 0.0003) in HIV-positive subjects, and smoking (OR 4.310; 95% CI 2.425 7.853; P < 0.0001), diabetes (OR 5.778; 95% CI 2.393-15.422; P = 0.0002) and hypertension (OR 6.589; 95% CI 3.554-12.700; P < 0.0001) in HIV-negative subjects. PARs for smoking, diabetes and hypertension were 54.35 and 30.58, 6.57 and 17.24, and 9.07 and 38.81% in HIV-positive and HIV-negative individuals, respectively. CONCLUSIONS: The contribution of smoking to ACS in HIV-positive adults was generally greater than the contributions of diabetes and hypertension, and was almost twice as high as that in HIV-negative adults. Development of effective smoking cessation strategies should be prioritized to prevent cardiovascular disease in HIV-positive adults. PMID- 23088308 TI - Protective effect of puerarin against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: involvement of the GSK-3beta/Nrf2 signaling pathway. AB - Current evidence suggests that amyloid beta (Abeta) peptides may play a major role in the pathogenesis of Alzheimer's disease in part by eliciting oxidative stress. Puerarin, a major isoflavone glycoside from Kudzu root (Pueraria lobata), has been reported to exert estrogen-like and antioxidant activities. The central hypothesis guiding this study is that puerarin will prevent or at least markedly attenuate Abeta(25-35)-induced excess production of reactive oxygen species (ROS) by interrupting glycogen synthase kinase-3beta (GSK-3beta) signaling. In this study, we demonstrate that pretreatment of primary hippocampal neurons with puerarin significantly reduced Abeta(25-35)-induced oxidative stress characterized by scavenging of ROS and inhibiting lipid peroxidation. Puerarin induced expression of nuclear Nrf2 protein, but not in the Nrf2 mRNA level, and increased heme oxygenase-1 (HO-1) levels at levels of transcription and translation. Puerarin-induced Serine 9 phosphorylation of GSK-3beta was blocked by lithium chloride treatment in primary hippocampal neurons, indicating the participation of the GSK-3beta inactivation. This protective effect was partially reversed when GSK-3beta were blocked by the chemical inhibitors such as lithium chloride. These results suggest puerarin as a phytoestrogen with potential of a possible therapeutic agent in neurodegenerative diseases involving oxidative stress. PMID- 23088310 TI - R- and S-equol have equivalent cytoprotective effects in Friedreich's ataxia. AB - BACKGROUND: Estradiol (E2) is a very potent cytoprotectant against a wide variety of cellular insults in numerous different cell models, including a Friedreich's ataxia (FRDA) model. Previously, we demonstrated that estrogen-like compounds are able to prevent cell death in an FRDA model independent of any known estrogen receptor (ER) by reducing reactive oxygen species (ROS) and the detrimental downstream effects of ROS buildup including oxidative damage to proteins and lipids and impaired mitochondrial function. RESULTS: We have previously demonstrated by western blot that our cell model lacks ERalpha and expresses only very low levels of ERbeta. Using L-buthionine (S,R)-sulfoximine (BSO) to induce oxidative stress in human FRDA fibroblasts, we determine the potency and efficacy of the soy-derived ERbeta agonist S-equol and its ERalpha-preferring enantiomer, R-equol in vitro on cell viability and ROS accumulation. Here we demonstrate that these equol biphenolic compounds, while significantly less potent and efficacious than E2, provide statistically similar attenuation of ROS and cytoprotection against a BSO-induced oxidative insult. CONCLUSIONS: These preliminary data demonstrate that estrogen and soy-derived equols could have a beneficial effect in delaying the onset and decreasing the severity of symptoms in FRDA patients by an antioxidant mechanism. In addition, these data confirm that the protection seen previously with E2 was indeed unrelated to ER binding. PMID- 23088309 TI - (S)-1-alpha-naphthylmethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (CKD712), promotes wound closure by producing VEGF through HO-1 induction in human dermal fibroblasts and mouse skin. AB - BACKGROUND AND PURPOSE: Given the importance of VEGF and haem oxygenase (HO)-1 in wound healing, the present study tested the hypothesis that CKD712, a synthetic tetrahydroisoquinoline alkaloid, activated VEGF production through the induction of HO-1 in human dermal fibroblasts (HDFs) and in mouse skin to stimulate wound healing. EXPERIMENTAL APPROACH: Using HDFs, the effects of CKD712 on the production of VEGF and migration were evaluated. The mechanisms responsible were investigated using various signal inhibitors and small interfering RNA techniques. The ability of CKD712 to promote wound healing was also investigated in full-thickness skin-wounded mice. KEY RESULTS: CKD712 treatment of HDFs increased VEGF production and accelerated migration, which was antagonized by anti-VEGF antibodies. Both an AMPK inhibitor (compound C) and a HO-1 activity inhibitor (SnPPIX) but not inhibitors of MAPKs, PI3K and PKC reduced the production of VEGF by CKD712. Interestingly, SnPPIX inhibited HO-1 expression but not p-AMPK, whereas compound C inhibited both p-AMPK and HO-1 induction by CKD712. Moreover, CKD712 decreased HO-1 expression without affecting the expression of p-AMPK by siHO-1 transfection, but it failed to induce HO-1 in siAMPKalpha1-transfected cells, suggesting that AMPK is involved in HO-1 induction by CKD712 in HDFs. Also, CKD712 shortened the time of wound closure in an SnPPIX-sensitive manner in a full-thickness skin-wounded mouse model. CONCLUSION AND IMPLICATIONS: CKD712 accelerated cutaneous wound healing, at least in part, by the production of VEGF through HO-1 induction in HDFs and mouse skin. PMID- 23088311 TI - Multiplexed quantitation of protein expression and phosphorylation based on functionalized soluble nanopolymers. AB - We report here for the first time the multiplexed quantitation of phosphorylation and protein expression based on a functionalized soluble nanopolymer. The soluble nanopolymer, pIMAGO, is functionalized with Ti (IV) ions for chelating phosphoproteins in high specificity and with infrared fluorescent tags for direct, multiplexed assays. The nanopolymer allows for direct competition for epitopes on proteins of interest, thus facilitating simultaneous detection of phosphorylation by pIMAGO and total protein amount by protein antibody in the same well of microplates. The new strategy has a great potential to measure cell signaling events by clearly distinguishing actual phosphorylation signals from protein expression changes, thus providing a powerful tool to accurately profile cellular signal transduction in healthy and disease cells. We anticipate broad applications of this new strategy in monitoring cellular signaling pathways and discovering new signaling events. PMID- 23088312 TI - Patients with depression, somatoform disorders, and eating disorders on the stages of change: validation of a short version of the URICA. AB - The study aimed at constructing a time-efficient short version of the University of Rhode Island Change Assessment (URICA), and at exploring differences in the stages of change between patients with depression, somatoform disorders, and eating disorders across the course of therapy. The URICA and diverse outcome measures were administered to 253 patients in early-, middle-, and late stages of inpatient therapy. The factor structure of the short form of the URICA (URICA-S) was excellent as shown by (1) an exploratory factor analysis on a randomized one half of the sample, (2) a confirmatory factor analysis on the other half of the sample, and (3) a stable factor structure over a 6-week interval. The resulting factors of the URICA-S were called precontemplation, contemplation, action, and maintenance. The internal consistencies of the URICA-S factors were sufficient to excellent. Supporting the criterion-related validity, the URICA-S predicted relevant outcome measures. Analyses of variance showed that the ratings on the action and the maintenance factors were differentially associated with outcome in patients with depression, somatoform disorders, and eating disorders. These findings implicate that a disorder-specific combination of action and relapse prevention-oriented interventions might optimize outcome in inpatients with different psychiatric disorders. PMID- 23088313 TI - The relationship between cognitive errors and interpersonal patterns in depressed women. AB - Individuals with depression process information in an overly negative or biased way (e.g., Henriques & Leitenberg, 2002) and demonstrate significant interpersonal dysfunction (e.g., Zlotnick, Kohn, Keitner, & Della Grotta, 2000). This study examined the relationship between cognitive errors (CEs) and interpersonal interactions in early psychotherapy sessions of 25 female patients with major depression. Transcripts were rated for CEs using the Cognitive Error Rating Scale (Drapeau, Perry, & Dunkley, 2008). Interpersonal patterns were assessed using the Structural Analysis of Social Behavior (Benjamin, 1974). Significant associations were found between CEs and markers of interpersonal functioning in selected contexts. The implications of these findings in bridging the gap between research and practice, enhancing treatment outcome, and improving therapist training are discussed. PMID- 23088314 TI - Coordinated aqua vs methanol substitution kinetics in fac-Re(I) tricarbonyl tropolonato complexes. AB - Water-soluble fac-[Re(CO)(3)(L,L'-Bid)(X)] (L,L'-Bid = tropolonato, X = H(2)O, methanol) complexes have been synthesized, and the aqua and methanol substitution reactions were investigated in water (pH range 6.3-10.0) and methanol, respectively, and compared. Thiocyanate ions were used as monodentate entering ligand. The complexes were characterized by UV-vis, IR, and NMR spectroscopy. The crystal structures of the complexes [NEt(4)] fac [Re(Trop)(CO)(3)(H(2)O)].NO(3).H(2)O (reactant) and fac-[Re(CO)(3)(Trop)(Py)], a substitution product, are reported. Overall it was found that the aqua substitution of fac-[Re(CO)(3)(Trop)(H(2)O)] is about 10 times faster than the methanol substitution reaction for fac-[Re(CO)(3)(Trop)(MeOH)], with forward and reverse rate and stability constants [k(1) (M(-1) s(-1)), k(-1) (s(-1)), K(1), (M(-1))] for thiocyanate as monodentate entering ligand as follows: fac [Re(CO)(3)(Trop)(H(2)O)] = 2.54 +/- 0.03, 0.0077 +/- 0.0005, 330 +/- 22/207 +/- 14 and fac-[Re(CO)(3)(Trop)(MeOH)] = 0.268 +/- 0.002, 0.0044 +/- 0.0002, (61 +/- 3)/(52 +/- 4). The activation parameters [DeltaH(?)(k1) (kJ mol(-1)), DeltaS(?)(k1) (J K(-1) mol(-1))] for the aqua and methanol complex respectively are 56.1 +/- 0.7, -49 +/- 2 and 64 +/- 1, -43 +/- 5. PMID- 23088315 TI - Synthesis of the C20-C32 tetrahydropyran core of the phorboxazoles and the C22 epimer via a stereodivergent Michael reaction. AB - A stereoselective synthesis of the C20-C32 tetrahydropyran core of the phorboxazoles has been achieved in only seven steps and in a 31% overall yield. The C22 epimer was also synthesized. The key step was a silyl ether deprotection/oxy-Michael cyclization. When this step was conducted under Bronsted acid conditions, the C20-C32 core was formed with the desired 2,6-cis stereochemistry. However, when the silyl ether deprotection/oxy-Michael cyclization was conducted under fluoride conditions buffered with acetic acid, the C22 epimer of the core was the sole product. PMID- 23088316 TI - Prebiopsy magnetic resonance studies for prostate cancer diagnosis. PMID- 23088317 TI - Relationship between the microsatellite D2S388-5 and D2S2232 polymorphisms and chronic obstructive pulmonary disease in the Chinese Kazakh population. AB - BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is influenced by multiple genetic and environmental factors. The role of genetic susceptibility in the pathogenesis of COPD has recently gained more attention. The surface lung surfactant protein B plays an important role in COPD pathogenesis. Microsatellite DNA has been characterized in the surfactant protein B alleles D2S388-5 and D2S2232. The aim of this research was to investigate the distribution of the D2S388-5 and D2S2232 microsatellite polymorphisms in smokers of the Kazakh ethnic group in Xinjiang, China, with and without COPD to assess whether such polymorphisms are associated with COPD susceptibility. METHODS: DNA was extracted from the blood of 197 smokers with COPD and 236 control smokers of Kazakh ethnicity. The smokers diagnosed with COPD were registered at the Department of Respiratory Medicine from four different hospitals. The control group was recruited at the medical examination centre from the same area. The polymorphisms of the D2S388-5 and D2S2232 microsatellite loci were measured by multiple short tandem repeat amplification using fluorescence-labelled polymerase chain reaction and capillary electrophoresis. RESULTS: Nine alleles and 32 genotypes were identified in D2S388-5, while 9 alleles and 31 genotypes were identified in D2S2232. Both genotype distributions in control smokers were in accordance with Hardy-Weinberg equilibrium. The frequency of the 254 bp allele from the D2S388-5 locus was significantly higher in the COPD group versus the control (P < 0.001, odds ratio = 5.942). CONCLUSIONS: D2S388-5 microsatellite polymorphism may be associated with susceptibility to COPD in Xinjiang Kazakhs. PMID- 23088318 TI - Improved therapeutic performance of dithranol against psoriasis employing systematically optimized nanoemulsomes. AB - Despite marked antipsoriatic activity of dithranol (anthralin), the drug is quite infrequently employed in therapeutic practice owing to its strong propensity to cause skin problems like irritation, erythema and peeling, and potential formulation problems like photolability and high lipophilicity. Accordingly, it was planned to systematically formulate optimized dithranol-loaded emulsomes with enhanced biocompatibility, efficacy and stability. Emulsomes were prepared by a thin film hydration technique and optimized for composition using formulation by design (FbD). The optimized dithranol-loaded emulsomes were found to substantially enhance the antipsoriatic activity on a mouse-tail model vis-a-vis marketed product. Also, the selected composition offered enhanced drug permeation and marked skin retention. The formulation was found to be quite non-irritant, stable and biocompatible in comparison to the marketed product. The present findings establish the usefulness of lipid-based colloidal carriers to increase the stability, and enhance the efficacy and patient compliance of an age-old irritant dithranol. PMID- 23088319 TI - Characterization of the spray drying behaviour of emulsions containing oil droplets with a structured interface. AB - The aim of this study was to characterize the process of atomization and drying of layer-by-layer emulsions containing lecithin (single layer emulsion) and lecithin/chitosan (bilayer emulsion) and the oxidative stability of the microcapsules during storage. For this purpose, the analysis of the emulsion spray droplet size during two-fluid nozzle and rotary atomization was carried out to identify suitable process parameters. The drying behaviour of single and bilayer emulsions was investigated by calculation of the volume flow density during single-droplet drying during acoustic levitation. In spray-dried solid particles, the oxidative stability in the single layer microcapsules was higher than in the bilayer microcapsules. This was partly attributed to lower microencapsulation efficiency in the bilayer microcapsules compared to the single layer microcapsules. Furthermore, it could be shown, that excess chitosan in the bulk carrier matrix affects the free volume elements and thus oxygen diffusion. PMID- 23088320 TI - Intracellular delivery of docetaxel using freeze-dried polysaccharide nanocapsules. AB - This article describes the development of a freeze-dried formulation of chitosan (CS) nanocapsules containing docetaxel (DCX) and the evaluation of its efficacy in the NCI-H460 cancer cell line. More specifically, two prototypes of nanocapsules differing in their coating, CS alone or in combination with poloxamer 188 were developed using the solvent displacement technique. These prototypes (150 nm and +45 mV) exhibited high encapsulation efficiencies of DCX (78%) and very similar release profiles. The nanocapsules made of solely CS could be freeze-dried and reconstituted without altering their particle size distribution. CS nanocapsules were tested for their ability to deliver intracellularly the anticancer drug DCX. The results showed that CS nanocapsules maintained the antiproliferative effect of the drug and that it was not affected by the freeze-drying process. Moreover, it was found that this cytostatic effect of DCX was related to its intracellular delivery in the cancer cells. PMID- 23088321 TI - Permanent hair dye-incorporated hyaluronic acid nanoparticles. AB - We prepared p-phenylenediamine (PDA)-incorporated nanoparticles using hyaluronic acid (HA). PDA-incorporated HA nanoparticles have spherical shapes and sizes were less than 300 nm. The results of FT-IR spectra indicated that PDA-incorporated HA nanoparticles were formed by ion-complex formation between amine group of PDA and carboxyl group of HA. Furthermore, powder-X-ray diffractogram (XRD) measurement showed that intrinsic crystalline peak of PDA disappeared by formation of nanoparticle with HA at XRD measurement. These results indicated that PDA incorporated HA nanoparticles were formed by ion-complex formation. At drug release study, the higher PDA contents induced faster release rate from nanoparticles. PDA-incorporated nanoparticles showed reduced intrinsic toxicity against HaCaT human keratinocyte cells at MTT assay and apoptosis assay. We suggest that PDA-incorporated HA nanoparticles are promising candidates for novel permanent hair dye. PMID- 23088322 TI - Mitochondrial protein synthesis: efficiency and accuracy. AB - SIGNIFICANCE: The mitochondrial genetic system is responsible for the production of a few core-subunits of the respiratory chain and ATP synthase, the membrane protein complexes driving oxidative phosphorylation (OXPHOS). Efficiency and accuracy of mitochondrial protein synthesis determines how efficiently new OXPHOS complexes can be made. RECENT ADVANCES: The system responsible for expression of the mitochondrial-encoded subunits developed from that of the bacterial ancestor of mitochondria. Importantly, many aspects of genome organization, transcription, and translation have diverged during evolution. Recent research has provided new insights into the architecture, regulation, and organelle-specific features of mitochondrial translation. Mitochondrial ribosomes contain a number of proteins absent from prokaryotic ribosomes, implying that in mitochondria, ribosomes were tailored to fit the requirements of the organelle. In addition, mitochondrial gene expression is regulated post-transcriptionally by a number of mRNA-specific translational activators. At least in yeast, these factors can regulate translation in respect to OXPHOS complex assembly to adjust the level of newly synthesized proteins to amounts that can be successfully assembled into respiratory chain complexes. CRITICAL ISSUES: Mitochondrial gene expression is determining aging in eukaryotes, and a number of recent reports indicate that efficiency of translation directly influences this process. FUTURE DIRECTIONS: Here we will summarize recent advances in our understanding of mitochondrial protein synthesis by comparing the knowledge acquired in the systems most commonly used to study mitochondrial biogenesis. However, many steps have not been understood mechanistically. Innovative biochemical and genetic approaches have to be elaborated to shed light on these important processes. PMID- 23088324 TI - Correction to "Structural evidence of a productive active site architecture for an evolved quorum-quenching GKL lactonase". PMID- 23088323 TI - Effects of nanoparticle charge and shape anisotropy on translocation through cell membranes. AB - Nanotoxicity is becoming a major concern as the use of nanoparticles in imaging, therapeutics, diagnostics, catalysis, sensing, and energy harvesting continues to grow dramatically. The tunable functionalities of the nanoparticles offer unique chemical interactions in the translocation process through cell membranes. The overall translocation rate of the nanoparticle can vary immensely on the basis of the charge of the surface functionalization along with shape and size. Using advanced molecular dynamics simulation techniques, we compute translocation rate constants of functionalized cone-, cube-, rod-, rice-, pyramid-, and sphere shaped nanoparticles through lipid membranes. The computed results indicate that depending on the nanoparticle shape and surface functionalization charge, the translocation rates can span 60 orders of magnitude. Unlike isotropic nanoparticles, positively charged, faceted, rice-shaped nanoparticles undergo electrostatics-driven reorientation in the vicinity of the membrane to maximize their contact area and translocate instantaneously, disrupting lipid self assembly and thereby causing significant membrane damage. In contrast, negatively charged nanoparticles are electrostatically repelled from the cell membrane and are less likely to translocate. Differences in translocation rates among various shapes may have implications on the structural evolution of pathogens from spherical to rodlike morphologies for enhanced efficacy. PMID- 23088325 TI - Coordination and solvation of the Au+ cation: infrared photodissociation spectroscopy of mass-selected Au(H2O)n+ (n = 1-8) complexes. AB - Gold cation-water complexes with attached argon atoms are produced via a laser vaporization supersonic cluster source. The [Au(H(2)O)(n)Ar(x)](+) (n = 1-8; x = 1 or 2) complexes are each mass selected and studied by infrared photodissociation spectroscopy in the OH stretching frequency region to explore the coordination and solvation structures of the Au(+) cation. Density functional calculations have been performed, and the calculated vibrational spectra are compared to the experimental spectra to identify the gas-phase structures of the Au(H(2)O)(n)(+) complexes. Confirming previous theoretical predications, the first coordination shell of the Au(+) cation contains two water molecules forming a linear O-Au(+)-O arrangement; subsequent water molecules bind to the two H(2)O ligands of the Au(H(2)O)(2)(+) core ion via hydrogen bond forming of the second hydration shell, which is complete at n = 6. For the complexes with n <= 7, the experimental spectrum can in general be assigned to the predicted global minimum structure. However, the spectrum suggests that two or more conformers coexist for the n = 8 complex, indicating that the identification of a single global minimum becomes less important upon increasing the number of solvating water molecules. PMID- 23088326 TI - Talent development: linking the stakeholders to the process. AB - The three stakeholders (coaches, parents and the National Governing Body) in Talent Identification and Development (TID) are important factors in athlete development. How each of them perceive the key constructs of Talent Identification and Development (i.e. sport specialisation and selection, practice, athlete development, junior and adult success, and the role of the stakeholders), and the coherence of that understanding is not well understood. This study focuses on junior performance tennis and investigates the perceptions of coaches, parents and sports organisations (a National Governing Body) of the five key constructs of Talent Identification and Development. We were interested in examining (a) the extent to which stakeholder perceptions relate to research, (b) the coherence of each stakeholder's perceptions and (c) the extent to which there is coherence between what stakeholders understand each other thinks. Seventy-five coaches, parents, and National Governing Body staff completed a questionnaire that asked participants to rate their degree of agreement/disagreement with researched 'principles' of Talent Identification and Development. The results suggest that stakeholders do not strongly agree with the research supporting principles of Talent Identification and Development. Furthermore, a significant lack of coherence of stakeholder perceptions was evident. This lack of coherence was also evident in each group's understanding of what the other stakeholders believed. The impact of these results on the Talent Identification and Development process is discussed. PMID- 23088327 TI - Atomistic simulations of a multicomponent asymmetric lipid bilayer. AB - The cell membrane is inherently asymmetric and heterogeneous in its composition, a feature that is crucial for its function. Using atomistic molecular dynamics simulations, the physical properties of a 3-component asymmetric mixed lipid bilayer system comprising an unsaturated POPC (palmitoyloleoylphosphatidylcholine), a saturated PSM (palmitoylsphingomyelin), and cholesterol are investigated. Our simulations explore both the dynamics of coarsening following a quench from the mixed phase and the final phase-segregated regime obtained by equilibrating a fully segregated configuration. Following a quench, the membrane quickly enters a coarsening regime, where the initial stages of liquid ordered, l(o), domain formation are observed. These growing domains are found to be highly enriched in cholesterol and PSM. Consistent with this, the final phase-segregated regime contains large l(o) domains at equilibrium, enriched in cholesterol and PSM. Our simulations suggest that the cholesterol molecules may partition into these PSM-dominated regions in the ratio of 3:1 when compared to POPC-dominated regions. PSM molecules exhibit a measurable tilt and long-range tilt correlations within the l(o) domain as a consequence of the asymmetry of the bilayer, with implications to local membrane deformation and budding. Tagged particle diffusion for PSM and cholesterol molecules, which reflects spatial variations in the physical environment encountered by the tagged particle, is computed and compared with recent experimental results obtained from high-resolution microscopy. PMID- 23088329 TI - The Tie retraction syndrome. AB - Tissue retraction is implicated in the pathogenesis of various ophthalmic disorders. Here we describe the clinical characteristics, epidemiology and pathophysiology of a form of retraction syndrome which - to the best of our knowledge - has not been reported in the ophthalmic literature so far. We have termed this condition - consisting of a slowly progressive pseudovertical shortening of tie length due to a horizontal extension of girth length - the "Tie retraction syndrome" (TRS). Other pathognomonic features include an increased tie tip to belt buckle distance and a prolapse of the subumbilical fat pad (SUFP). The syndrome has a clear male to female preponderance and shows an increasing incidence with age and income before tax. Based on a newly proposed grading scheme we discuss and illustrate the diagnosis as well as the medical and surgical management options of this abundant, but often undiagnosed condition. The authors have no explanation for the apparent lack of awareness for this widely preponderant syndrome and its severe cosmetically disfiguring potential. We thus would like to invite all fellow colleagues with expertise in the field to comment or present their views. PMID- 23088328 TI - Injectable and implantable sustained release naltrexone in the treatment of opioid addiction. AB - Sustained release technologies for administering the opioid antagonist naltrexone (SRX) have the potential to assist opioid-addicted patients in their efforts to maintain abstinence from heroin and other opioid agonists. Recently, reliable SRX formulations in intramuscular or implantable polymers that release naltrexone for 1-7 months have become available for clinical use and research. This qualitative review of the literature provides an overview of the technologies currently available for SRX and their effectiveness in reducing opioid use and other relevant outcomes. The majority of studies indicate that SRX is effective in reducing heroin use, and the most frequently studied SRX formulations have acceptable adverse events profiles. Registry data indicate a protective effect of SRX on mortality and morbidity. In some studies, SRX also seems to affect other outcomes, such as concomitant substance use, vocational training attendance, needle use, and risk behaviour for blood-borne diseases such as hepatitis or human immunodeficiency virus. There is a general need for more controlled studies, in particular to compare SRX with agonist maintenance treatment, to study combinations of SRX with behavioural interventions, and to study at-risk groups such as prison inmates or opioid-addicted pregnant patients. The literature suggests that sustained release naltrexone is a feasible, safe and effective option for assisting abstinence efforts in opioid addiction. PMID- 23088331 TI - Sulphur levels in saliva as an estimation of sulphur status in cattle: a validation study. AB - Effective assessment of sulphur (S) status in cattle is important for optimal health, yet remains difficult. Rumen fluid S concentrations are preferred, but difficult to sample under practical conditions. This study aimed to evaluate salivary S concentration as estimator of S status in cattle. Saliva and rumen fluid samples were collected from dairy cows (n = 16) as well as samples of different feedstuffs offered to the animals. The N and S concentrations were determined using the Dumas technique. The average dietary N and S content were calculated as well as N:S ratio of saliva, rumen fluid and diet. Salivary S concentrations could not predict rumen fluid or dietary S concentrations (p > 0.05). The log transformed salivary N:S ratio (x) could predict the rumen fluid N:S ratio (y) with a linear equation of y = 9.83 (+/-4.59) x + 0.39 (+/-4.56) (r = 0.497, p = 0.05), but left too much residual variation to serve as reliable predictor. Further research should investigate this relationship in the search for an S status estimator. PMID- 23088332 TI - Circulating soluble lectin-like oxidized low-density lipoprotein receptor-1 levels are associated with erectile dysfunction in patients without known coronary artery disease. AB - AIM: Endothelial dysfunction and microvascular damage are involved in the pathogenesis of erectile dysfunction (ED). Soluble lectin-like oxidized low density lipoprotein receptor-1 (sLOX-1) is identified endothelial receptor for oxidized low-density lipoprotein (ox-LDL) that plays a pivotal role in ox-LDL induced endothelial dysfunction. The purpose of the current study was to determine the association between sLOX-1 and ED in patients without known coronary artery disease (CAD). MAIN OUTCOME MEASURES: Diagnosis of ED was based on the International Index of Erectile Function Score-5. Levels of sLOX-1 were measured in serum by enzyme-linked immunosorbent assay. METHODS: One hundred thirty-eight subjects with ED patients without known CAD (ED group) and 75 age matched subjects without ED and known CAD (Non-ED Group) were included in this study. RESULTS: Plasma levels of sLOX-1 were significantly higher in ED than in Non-ED group (95+/-87 and 49+/-30 pg/mL, respectively, P<0.001). The levels of sLOX-1 highly negative correlated with score of ED (r=-0.618, P<0.001). The sLOX 1 levels>75 pg/mL predicts ED with 26.8% sensitivity and 96.0% specificity on receiver operator characteristic analysis. CONCLUSIONS: Our study demonstrated that serum sLOX-1 levels were associated with endothelial dysfunction that predicts ED. Moreover, the current study revealed that there was strong negative correlation between the levels of circulating sLOX-1 and score of ED. This study suggested sLOX-1 may be involved in the pathogenesis of ED in patients without known CAD. PMID- 23088330 TI - Validity of information on atopic disease and other illness in young children reported by parents in a prospective birth cohort study. AB - BACKGROUND: The longitudinal birth cohort study is the preferred design for studies of childhood health, particularly atopic disease. Still, prospective data collection depends on recollection of the medical history since the previous visit representing a potential recall-bias. We aimed to ascertain the quality of information on atopic disease and other health symptoms reported by parental interview in a closely monitored birth cohort study. Possible bias from symptom severity and socioeconomics were sought. METHODS: Copenhagen study on Asthma in Childhood (COPSAC) is a clinical birth cohort study of 411 children born of asthmatic mothers from 1999 to 2001. Child health is monitored at six-monthly visits with particular emphasis on atopic symptoms and infections. Data from the first three study years on 260 children was compared with records from their family practitioner as an external reference. RESULTS: A total of 6134 medical events were reported at the COPSAC interviews. Additional 586 medical events were recorded by family practitioners but not reported at the interview. There were no missed events related to asthma, eczema or allergy. Respiratory, infectious and skin related symptoms showed completeness above 90%, other diseases showed lower completeness around 77%. There was no meaningful influence from concurrent asthma or socioeconomics. CONCLUSIONS: The COPSAC study exhibited full sensitivity to the main study objectives, atopic disease, and high sensitivity to respiratory, infectious and skin related illness. Our findings support the validity of parental interviews in longitudinal cohort studies investigating atopic disease and illness in childhood. PMID- 23088333 TI - Development of abstract grammatical categorization in infants. AB - This study examined abstract syntactic categorization in infants, using the case of grammatical gender. Ninety-six French-learning 14-, 17-, 20-, and 30-month olds completed the study. In a preferential looking procedure infants were tested on their generalized knowledge of grammatical gender involving pseudonouns and gender-marking determiners. The pseudonouns were controlled to contain no phonological or acoustical cues to gender. The determiner gender feature was the only information available. During familiarization, some pseudonouns followed a masculine determiner and others a feminine determiner. Test trials presented the same pseudonouns with different determiners in correct (consistent with familiarization gender pairing) versus incorrect gender agreement. Twenty-month olds showed emerging knowledge of gender categorization and agreement. This knowledge was robust in 30-month-olds. These findings demonstrate that abstract, productive grammatical representations are present early in acquisition. PMID- 23088334 TI - Coordination chemistry of N,N,N',N'-tetrakis(3,5-substituted benzyl-2-oxide)-2,2' (ethylenedioxy)diethanamine modified Group 4 metal alkoxides. AB - The coordination behavior of a set of (ethylenedioxy)diethanamine-based tetraphenol ligands with a series of Group 4 metal alkoxides ([M(OR)(4)]) was determined. The ligands were synthesized from a modified Mannich reaction and fully characterized as N,N,N',N'-tetrakis(3,5-tert-butyl-benzyl-2-hydroxy)-2,2' (ethylenedioxy)diethanamine, termed H(4)-OEA-DBP(4) (1), and N,N,N',N' tetrakis(3,5-chloro-benzyl-2-hydroxy)-2,2'-(ethylenedioxy)diethanamine, termed H(4)-OEA-DCP(4) (2). The reaction of 1 with a set of [M(OR)(4)] [M = Ti, Zr, or Hf; OR = iso-propoxide (OPr(i)), neo-pentoxide (ONep), or tert-butoxide (OBu(t))] precursors led to the isolation of [(OPr(i))(2)Ti](2)(MU-OEA-DBP(4)) (3), [(ONep)(2)Ti](2)(MU-OEA-DBP(4)) (4), and [(OBu(t))(2)M](2)(MU-OEA-DBP(4)) where M = Ti (5), Zr (6), or Hf (7). In addition, the [(ONep)(2)Ti](2)(MU-OEA-DCP(4)) (4a) derivative was isolated from the reaction of 2 and [Ti(ONep)(4)], demonstrating the similarity of coordination behavior between the two OEA-R(4) ligands. For 3-7, the metal center adopts a slightly distorted octahedral geometry by binding the two O atoms of the phenoxide moiety, as well as one N and one O atom from the OEA moieties, while retaining two of the original OR ligands. Solution NMR demonstrates inequivalent protons for the majority of the bound OEA ligands, which argues for retention of structure in solution. The synthesis and characterization of these compounds are presented in detail. PMID- 23088335 TI - Enumeration of 166 billion organic small molecules in the chemical universe database GDB-17. AB - Drug molecules consist of a few tens of atoms connected by covalent bonds. How many such molecules are possible in total and what is their structure? This question is of pressing interest in medicinal chemistry to help solve the problems of drug potency, selectivity, and toxicity and reduce attrition rates by pointing to new molecular series. To better define the unknown chemical space, we have enumerated 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens forming the chemical universe database GDB-17, covering a size range containing many drugs and typical for lead compounds. GDB-17 contains millions of isomers of known drugs, including analogs with high shape similarity to the parent drug. Compared to known molecules in PubChem, GDB-17 molecules are much richer in nonaromatic heterocycles, quaternary centers, and stereoisomers, densely populate the third dimension in shape space, and represent many more scaffold types. PMID- 23088336 TI - Final 192-week efficacy and safety of once-daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive patients in the ARTEMIS trial. AB - OBJECTIVE: This paper presents the final analysis of once-daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment-naive HIV-1-infected adults. METHODS: ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects; NCT00258557) was a randomized, open-label, phase-III, 192-week trial. Patients were stratified by baseline HIV-1 RNA and CD4 count, and randomized to once-daily DRV/r 800/100 mg or LPV/r 800/200 mg total daily dose (either once or twice daily) plus tenofovir/emtricitabine. RESULTS: Of 689 randomized patients receiving treatment (DRV/r: 343; LPV/r: 346), 85 and 114 patients in the DRV/r and LPV/r arms, respectively, had discontinued by week 192. Noninferiority was shown in the primary endpoint of virological response (HIV-1 RNA < 50 copies/mL) [DRV/r: 68.8%; LPV/r: 57.2%; P < 0.001; intent to treat (ITT)/time to loss of virological response; estimated difference in response 11.6% (95% confidence interval 4.4-18.8%)]. Statistical superiority in virological response of DRV/r over LPV/r was demonstrated for the primary endpoint (P = 0.002) and for the ITT non-virological-failure-censored analysis (87.4% vs. 80.8%, respectively; P = 0.040). No protease inhibitor (PI) primary mutations developed and only low levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance developed in virological failures in both groups. Significantly fewer discontinuations because of adverse events were observed with DRV/r (4.7%) than with LPV/r (12.7%; P = 0.005). Grade 2-4 treatment-related diarrhoea was significantly less frequent with DRV/r than with LPV/r (5.0% vs. 11.3%, respectively; P = 0.003). DRV/r was associated with smaller median increases in total cholesterol and triglyceride levels than LPV/r. Changes in low and high-density lipoprotein cholesterol were similar between groups. Similar increases in aspartate aminotransferase and alanine aminotransferase for DRV/r and LPV/r were observed. CONCLUSION: Over 192 weeks, once-daily DRV/r was noninferior and statistically superior in virological response to LPV/r, with a more favourable gastrointestinal profile, demonstrating its suitability for long term use in treatment-naive patients. PMID- 23088337 TI - Circulating tumor cells, disease recurrence and survival in newly diagnosed breast cancer. AB - INTRODUCTION: The presence of circulating tumor cells (CTC) is an independent prognostic factor for progression-free survival and breast cancer-related death (BRD) for patients with metastatic breast cancer beginning a new line of systemic therapy. The current study was undertaken to explore whether the presence of CTC at the time of diagnosis was associated with recurrence-free survival (RFS) and BRD. METHODS: In a prospective single center study, CTC were enumerated with the CellSearch system in 30 ml of peripheral blood of 602 patients before undergoing surgery for breast cancer. There were 97 patients with a benign tumor, 101 did not meet the inclusion criteria of which there were 48 patients with DCIS, leaving 404 stage I to III patients. Patients were stratified into unfavorable (CTC >=1) and favorable (CTC = 0) prognostic groups. RESULTS: >=1 CTC in 30 ml blood was detected in 15 (15%) benign tumors, in 9 DCIS (19%), in 28 (16%) stage I, 32 (18%) stage II and in 16 (31%) patients with stage III. In stage I to III patients 76 (19%) had >=1 CTC of whom 16 (21.1%) developed a recurrence. In 328 patients with 0 CTC 38 (11.6%) developed a recurrence. Four-year RFS was 88.4% for favorable CTC and 78.9% for unfavorable CTC (P = 0.038). A total of 25 patients died of breast cancer-related causes and 11 (44%) had >=1 CTC. BRD was 4.3% for favorable and 14.5% for unfavorable CTC (P = 0.001). In multivariate analysis >=1 CTC was associated with distant disease-free survival, but not for overall recurrence-free survival. CTC, progesterone receptor and N-stage were independent predictors of BRD in multivariate analysis. CONCLUSIONS: Presence of CTC in breast cancer patients before undergoing surgery with curative intent is associated with an increased risk for breast cancer-related death. PMID- 23088338 TI - Structural study of octacalcium phosphate bone cement conversion in vitro. AB - The nature of precursor phase during the biomineralization process of bone tissue formation is still controversial. Several phases were hypothesized, among them octacalcium phosphate. In this study, an in situ monitoring of structural changes, taking place upon the octacalcium phosphate bone cement hardening, was carried out in the presence of biopolymer chitosan and simulated body fluid (SBF). Several systems with different combinations of components were studied. The energy dispersive X-ray diffraction was applied to study the structural changes in real time, while morphological properties of the systems were investigated by the scanning electron microscopy. The obtained results evidence that final hydroxyapatite phase is formed only in the presence of chitosan and/or SBF, providing new insights into the in vivo biomineralization mechanism and, consequently, favoring the development of new approaches in biomaterials technology. PMID- 23088339 TI - Social class disparities in health and education: reducing inequality by applying a sociocultural self model of behavior. AB - The literature on social class disparities in health and education contains 2 underlying, yet often opposed, models of behavior: the individual model and the structural model. These models refer to largely unacknowledged assumptions about the sources of human behavior that are foundational to research and interventions. Our review and theoretical integration proposes that, in contrast to how the 2 models are typically represented, they are not opposed, but instead they are complementary sets of understandings that inform and extend each other. Further, we elaborate the theoretical rationale and predictions for a third model: the sociocultural self model of behavior. This model incorporates and extends key tenets of the individual and structural models. First, the sociocultural self model conceptualizes individual characteristics (e.g., skills) and structural conditions (e.g., access to resources) as interdependent forces that mutually constitute each other and that are best understood together. Second, the sociocultural self model recognizes that both individual characteristics and structural conditions indirectly influence behavior through the selves that emerge in the situation. These selves are malleable psychological states that are a product of the ongoing mutual constitution of individuals and structures and serve to guide people's behavior by systematically shaping how people construe situations. The theoretical foundation of the sociocultural self model lays the groundwork for a more complete understanding of behavior and provides new tools for developing interventions that will reduce social class disparities in health and education. The model predicts that intervention efforts will be more effective at producing sustained behavior change when (a) current selves are congruent, rather than incongruent, with the desired behavior and (b) individual characteristics and structural conditions provide ongoing support for the selves that are necessary to support the desired behavior. PMID- 23088342 TI - Two distinct exploratory behaviors in decisions from experience: comment on Gonzalez and Dutt (2011). AB - Gonzalez and Dutt (2011) recently reported that trends during sampling, prior to a consequential risky decision, reveal a gradual movement from exploration to exploitation. That is, even when search imposes no immediate costs, people adopt the same pattern manifest in costly search: early exploration followed by later exploitation. From this isomorphism in costless and costly search, the authors concluded that the same cognitive mechanisms underlay the control of sampling in 2 experimental paradigms employed to investigate decisions from experience: the sampling paradigm implementing costless search and the repeated-choice paradigm implementing costly search. We show that this is a misinterpretation of the human data resulting from drawing inferences about cognitive processes from data aggregated across individuals. Because of an inverse relationship between sample size and the propensity to explore, aggregating across individuals produces a pattern where exploration is gradually replaced by exploitation. On an individual level, however, there is no general reduction in exploration in the sampling paradigm. We list ensuing problems for the instance-based learning model Gonzalez and Dutt presented to explain the similarities between sampling and repeated decisions from experience. PMID- 23088345 TI - Opening ZIF-8: a catalytically active zeolitic imidazolate framework of sodalite topology with unsubstituted linkers. AB - A zeolitic imidazolate framework material of SOD topology possessing primarily unsubstituted imidazolate (im) linkers has been synthesized via solvent-assisted linker exchange (SALE) of ZIF-8. The structure of the new material, SALEM-2, has been confirmed through (1)H NMR and powder and single-crystal X-ray diffraction. SALEM-2 is the first example of a porous Zn(im)(2) ZIF possessing a truly zeolitic topology that can be obtained in bulk quantities. Upon treatment with n butyllithium, the open analogue exhibits Bronsted base catalysis that cannot be accomplished by the parent material ZIF-8. Additionally, it displays a different size cutoff for uptake and release of molecular guests than does ZIF-8. PMID- 23088341 TI - Word learning emerges from the interaction of online referent selection and slow associative learning. AB - Classic approaches to word learning emphasize referential ambiguity: In naming situations, a novel word could refer to many possible objects, properties, actions, and so forth. To solve this, researchers have posited constraints, and inference strategies, but assume that determining the referent of a novel word is isomorphic to learning. We present an alternative in which referent selection is an online process and independent of long-term learning. We illustrate this theoretical approach with a dynamic associative model in which referent selection emerges from real-time competition between referents and learning is associative (Hebbian). This model accounts for a range of findings including the differences in expressive and receptive vocabulary, cross-situational learning under high degrees of ambiguity, accelerating (vocabulary explosion) and decelerating (power law) learning, fast mapping by mutual exclusivity (and differences in bilinguals), improvements in familiar word recognition with development, and correlations between speed of processing and learning. Together it suggests that (a) association learning buttressed by dynamic competition can account for much of the literature; (b) familiar word recognition is subserved by the same processes that identify the referents of novel words (fast mapping); (c) online competition may allow the children to leverage information available in the task to augment performance despite slow learning; (d) in complex systems, associative learning is highly multifaceted; and (e) learning and referent selection, though logically distinct, can be subtly related. It suggests more sophisticated ways of describing the interaction between situation- and developmental-time processes and points to the need for considering such interactions as a primary determinant of development. PMID- 23088346 TI - Impact of 18F-FDG PET/CT on target volume delineation in recurrent or residual gynaecologic carcinoma. AB - BACKGROUND: To evaluate the impact of 18F-FDG PET/CT on target volume delineation in gynaecological cancer. METHODS: F-FDG PET/CT based RT treatment planning was performed in 10 patients with locally recurrent (n = 5) or post-surgical residual gynaecological cancer (n = 5). The gross tumor volume (GTV) was defined by 4 experienced radiation oncologists first using contrast enhanced CT (GTVCT) and secondly using the fused 18F-FDG PET/CT datasets (GTVPET/CT). In addition, the GTV was delineated using the signal-to-background (SBR) ratio-based adaptive thresholding technique (GTVSBR). Overlap analysis were conducted to assess geographic mismatches between the GTVs delineated using the different techniques. Inter- and intra-observer variability were also assessed. RESULTS: The mean GTVCT (43.65 cm3) was larger than the mean GTVPET/CT (33.06 cm3), p = 0.02. In 6 patients, GTVPET/CT added substantial tumor extension outside the GTVCT even though 90.4% of the GTVPET/CT was included in the GTVCT and 30.2% of the GTVCT was found outside the GTVPET/CT. The inter- and intra-observer variability was not significantly reduced with the inclusion of 18F-FDG PET imaging (p = 0.23 and p = 0.18, respectively). The GTVSBR was smaller than GTVCT p <= 0.005 and GTVPET/CT p <= 0.005. CONCLUSIONS: The use of 18F-FDG PET/CT images for target volume delineation of recurrent or post-surgical residual gynaecological cancer alters the GTV in the majority of patients compared to standard CT-definition. The use of SBR-based auto-delineation showed significantly smaller GTVs. The use of PET/CT based target volume delineation may improve the accuracy of RT treatment planning in gynaecologic cancer. PMID- 23088347 TI - Hair follicle stem cells can be driven into a urothelial-like phenotype: an experimental study. AB - The aim of this study was to show that conditioned medium might induce transdifferentiation of hair follicle stem cells into urothelial-like cells. Several conditioned media and culture conditions (skeletal muscle cell conditioned medium, smooth muscle cell conditioned medium, fibroblast conditioned medium, transforming growth factor-conditioned medium, urothelial cell conditioned medium, and co-culture of hair follicle stem cells and urothelial cells) were used. The hair follicle stem cells phenotype from rat whisker hair follicles was checked by using flow cytometry and immunofluorescence. Cytokeratins 7, 8, 15 and 18 were used as markers. Urothelial cell conditioned medium increased the expression of urothelial markers (cytokeratin 7, cytokeratin 8, cytokeratin 18), whereas it decreased a hair follicle stem cells marker (cytokeratin 15) after 2 weeks of culture. This process depended on the time of cultivation. This medium was able to sustain the epithelial phenotype of the culture. Other media including a co-culture system failed to induce similar changes. Smooth muscle conditioned medium resulted in a loss of cells in culture. Hair follicle stem cells are capable of differentiating into urothelial-like cells in vitro when exposed to a bladder-specific microenvironment. PMID- 23088348 TI - Human serum albumin stabilized gold nanoclusters as selective luminescent probes for Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. AB - In this work, human serum albumin (HSA) stabilized gold nanoclusters (HSA-AuNCs) with reddish photoluminescence were used as sensing probes for pathogenic bacteria including Enterobacter cloacae, Escherichia coli J96, Pseudomonas aeruginosa, pandrug-resistant Acinetobacter baumannii (PDRAB), Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), Streptococcus pyogenes, and vancomycin-resistant Enterococcus faecalis (VRE). We discovered that HSA-AuNCs have unique affinity with S. aureus and MRSA. In addition to demonstrating the selective sensing ability of HSA-AuNCs toward S. aureus and MRSA, the binding peptide motifs identified from HSA-AuNCs were characterized by mass spectrometry. The identified binding peptides were further used as the reducing and stabilizing agents for generation of peptide-bound AuNCs (Pep-AuNCs). The generated Pep-AuNCs were demonstrated to have the binding affinities with S. aureus and MRSA. PMID- 23088349 TI - Stereoselective synthesis of conjugated trienols from allylic alcohols and 1-iodo 1,3-dienes. AB - The stereoselective synthesis of conjugated trienes has been achieved from allylic alcohols and 1-iodo-1,3-dienes using Pd(OAc)(2)/AgOAc. PMID- 23088351 TI - XPS, EXAFS, and FTIR as tools to probe the unexpected adsorption-coupled reduction of U(VI) to U(V) and U(IV) on Borassus flabellifer-based adsorbents. AB - Palm shell-based adsorbents prepared under five different thermochemical conditions and palm shell powder have been shown to be quite effective for removal of uranium from aqueous solutions. X-ray photoelectron spectroscopy (XPS), extended X-ray absorption fine structure (EXAFS), and Fourier transform infrared spectroscopy (FTIR) have been used to determine information about the speciation and binding of uranium on the adsorbents under study. Studies indicate that the uranium which is present as uranyl ion in aqueous solution is present in mixed valence states (U(IV), U(V), and U(VI)) when it is bound to the adsorbents. The mechanism of adsorption is likely to be adsorption-coupled reduction as well as complexation. Adsorption of uranium, cesium, and iron was found to be quantitative in binary as well as ternary mixtures. PMID- 23088350 TI - A prospective test of the late effects of potentially antineuroplastic drugs in a stroke rehabilitation study. AB - BACKGROUND: Extensive data, primarily from animal studies, suggest that several classes of drugs may have antineuroplastic effects that could impede recovery from brain injury or reduce the efficacy of rehabilitation. AIMS: The Locomotor Experience Applied Post-Stroke trial, a randomized controlled study of 408 subjects that tested the relative efficacy of two rehabilitation techniques on functional walking level at one-year poststroke, provided us the opportunity to prospectively assess the potential antineuroplastic effects of several classes of drug. METHODS: Subjects were randomized to receive one of the two rehabilitation therapies at two-months poststroke. Drugs taken were recorded at time of randomization. Outcome was assessed at one-year poststroke. Regression models were used to determine the amount of variance in success in improving functional walking level, gains in walking speed, and declines in lower extremity, upper extremity, and cognitive impairment accounted for by alpha1 noradrenergic blockers + alpha2 noradrenergic agonists, benzodiazepines, voltage-sensitive sodium channel anticonvulsants, and alpha2delta voltage-sensitive calcium channel blockers. RESULTS: The maximum variance accounted for by any drug class was 1.66%. Drug effects were not statistically significant when using even our most lenient standard for correction for multiple comparisons. CONCLUSIONS: Drugs in the classes we were able to assess do not appear to exert a clinically important effect on outcome over the period between two- and 12 months poststroke. However, the potential antineuroplastic effects of certain drugs remain an incompletely settled scientific question. PMID- 23088352 TI - Analysis of F8 mRNA in haemophilia A patients with silent mutations or presumptive splice site mutations. AB - Mutation screenings in haemophilia A (HA) patients identified a great variety of mutations in the factor VIII gene (F8): intron 22 or intron 1 inversions, missense mutations, nonsense mutations, small or large deletions, insertions, duplications and splice site mutations. Mutations which do not result in amino acid substitutions (silent mutations) and intronic variants located outside the splice site consensus sequences cannot be easily classified as causative for HA. In these cases, special prediction software algorithms are applied to estimate their impact on splicing. Here, we present mRNA analysis of novel F8 mutations with possible impact on splicing in four HA patients with silent mutations and seven patients with intronic variants close to or within splice site consensus sequences. Seven of eleven mutations examined in vitro could be shown to have an effect on F8 mRNA splicing and the results were compared to in silico predictions. In addition, to validate the splice site prediction software Alamut v2.0 (Interactive Biosoftware), we compared published F8 mRNA analyses with the results of the in silico prediction. In general, the results of the splice site prediction tools of Alamut were in good accordance with the experimental F8 mRNA analyses, but a fundamental discrepancy between in silico and in vitro analyses was obtained in some cases. In conclusion, this study shows that the functional classification of potential splicing mutations should not only rely on prediction software, but be rather based on mRNA analysis experiments. PMID- 23088353 TI - Ultrafast evolution of imidazole after electronic excitation. AB - The ultrafast dynamics of the imidazole chromophore has been tracked after electronic excitation in the 250-217 nm energy region, by time delayed ionization with 800 nm laser pulses. The time-dependent signals collected at the imidazole(+) mass channel show the signature of femtosecond dynamics, originating on the pisigma*- and pipi*-type states located in the explored energy region. The fitting of the transients, which due to the appearance of nonresonant coherent adiabatic excitation requires a quantum treatment based in the Bloch equations, yields two lifetimes of 18 +/- 4 and 19 +/- 4 fs. The first is associated with the pisigma* <- pipi* internal conversion, while the second reflects the loss of ionization cross-section as the system evolves along the dissociative pisigma* surface. This study provides a comprehensive picture of the photophysics of the molecule that agrees with previous experimental and theoretical findings. PMID- 23088354 TI - Educational intervention in CKD retards disease progression and reduces medical costs for patients with stage 5 CKD. AB - BACKGROUND: Nephrologist-based multidisciplinary care (MDC) has a positive impact on slowing chronic kidney disease (CKD) progression. However, the benefits of MDC in patients with stage 5 CKD remain unclear. METHODS: Stage 5 CKD patients who visited the Chang Gung Memorial Hospital, Chiayi, Taiwan during the period of 2002-2008 were enrolled. The incident dialysis and medical cost were compared between MDC recipients and nonrecipients. The MDC recipients were divided into two groups by educational duration to observe the clinical renal outcome and medical care expenses. The effect of MDC on renal disease progression was also compared in MDC recipients with and without diabetes. RESULTS: Out of 307 patients, 171 received MDC. For MDC recipients, the temporary usage of catheter was reduced (54.7% vs. 79.4%, p < 0.001), the hospital stay was shorter (18.64 +/ 1.20 vs. 24.63 +/- 1.22 months, p = 0.001), and the total medical cost was lower [New Taiwan dollars (NTD) 105,948.54 +/- 9,967.22 vs. NTD 160,388.61 +/- 16,373.97, p = 0.005] than for nonrecipients. Out of the 171 MDC recipients, those with MDC for more than 1 year had slower renal disease progression (0.76 +/ 0.27 mL/min per 1.73 m(2) per year) and had an estimated per- capita annual cost savings of about NTD 336,500.66. MDC recipients with diabetes had a higher risk of requiring dialysis than those without diabetes. CONCLUSIONS: MDC could significantly reduce temporary use of the catheter, hospital stay, and total medical costs in patients with stage 5 CKD. Furthermore, longer (>1 year) MDC could preserve renal function and deliver annual medical cost savings. PMID- 23088355 TI - eMedical Teacher. PMID- 23088357 TI - Mapping a curriculum database to the USMLE Step 1 content outline. AB - Assessing the completeness of topic coverage in medical curricula is difficult to establish as no universal standard for completeness has been agreed upon. However, the United States Medical Licensing Examination (USMLE) Step 1 Exam Content Outline may provide a beginning framework. This project developed a computer-based tool that matched ArizonaMed curriculum content (Tucson track) against a modified USMLE content outline. The project involved three phases: (1) the USMLE Step 1 content outline was deconstructed and translated using equivalent Medical Subject Heading (MeSH) terms; (2) a report was made of all MeSH terms used to identify the content in the ArizonaMed curriculum database, compared to the MeSH-modified USMLE outline, and the resulting matches are graphically expressed. The frequency with which each MeSH term appeared across the years also was reported; and (3) a retreat was held with faculty and others to ensure the MeSH-translated outline was accurate and complete. Faculty were able to visualize how content was being expressed among instructional blocks across the first two years. Results also assured faculty and students that all subjects contained in the USMLE content outline were covered in the curriculum. The success of this effort is leading to improvements in content-tracking capability for the ArizonaMed database. PMID- 23088358 TI - Virtually present: the perceived impact of remote facilitation on small group learning. AB - BACKGROUND: The engagement of facilitators located remotely for small group learning has received little research attention. However, this approach could increase the pool of experts for small group learning, thus addressing challenges to sustainability faced by in-person models of small group facilitation. AIM: The objective of this study was to describe the experiences and perceptions of students regarding the use of remote facilitation for small group learning in a health education setting. METHODS: This qualitative study involved three focus groups (n = 16) composed of students in the advanced neuromusculoskeletal teaching unit in the University of Toronto, Department of Physical Therapy. Focus groups were audio-taped and transcribed verbatim, and data were analyzed thematically. RESULTS: Three main influences emerged related to the experiences of students regarding the use of remote facilitation for small group learning in a health education setting: technology (including audio and visual), facilitator (including quality of facilitation and facilitator expertise), and group dynamics (including ground rules, roles and responsibilities, and learning style). Each of these influences acted independently and interdependently to shape participants' perceptions. CONCLUSION: This study prompts a widening of the concept of distance learning to also include distance teaching, which may have wide applicability to health profession programs. PMID- 23088359 TI - Globalization and the modernization of medical education. AB - BACKGROUND: Worldwide, there are essential differences underpinning what educators and students perceive to be effective medical education. Yet, the world looks on for a recipe or easy formula for the globalization of medical education. AIMS: This article examines the assumptions, main beliefs, and impact of globalization on medical education as a carrier of modernity. METHODS: The article explores the cultural and social structures for the successful utilization of learning approaches within medical education. Empirical examples are problem-based learning (PBL) at two medical schools in Jamaica and the Netherlands, respectively. RESULTS: Our analysis shows that people do not just naturally work well together. Deliberate efforts to build group culture for effective and efficient collaborative practice are required. Successful PBL is predicated on effective communication skills, which are culturally defined in that they require common points of understanding of reality. Commonality in cultural practices and expectations do not exist beforehand but must be clearly and deliberately created. CONCLUSIONS: The globalization of medical education is more than the import of instructional designs. It includes Western models of social organization requiring deep reflection and adaptation to ensure its success in different environments and among different groups. PMID- 23088360 TI - Designing simulator-based training: an approach integrating cognitive task analysis and four-component instructional design. AB - Most studies of simulator-based surgical skills training have focused on the acquisition of psychomotor skills, but surgical procedures are complex tasks requiring both psychomotor and cognitive skills. As skills training is modelled on expert performance consisting partly of unconscious automatic processes that experts are not always able to explicate, simulator developers should collaborate with educational experts and physicians in developing efficient and effective training programmes. This article presents an approach to designing simulator based skill training comprising cognitive task analysis integrated with instructional design according to the four-component/instructional design model. This theory-driven approach is illustrated by a description of how it was used in the development of simulator-based training for the nephrostomy procedure. PMID- 23088361 TI - Adult orbital myeloid sarcoma (granulocytic sarcoma): two cases and review of the literature. AB - BACKGROUND/AIMS: [corrected] To report two rare cases of orbital myeloid sarcoma in adults and discuss special features relevant to this entity. METHODS: Complete ophthalmologic and systemic examinations followed by incisional biopsy and pathological examination. RESULTS: Two cases of myeloid sarcoma with orbital involvement were identified. Both cases presented with a clinical picture and imaging which demonstrated infiltrative orbital masses. When combined with 8 previous reported cases, 8/10 demonstrated systemic AML involvement. CONCLUSIONS: Orbital myeloid sarcoma is a rare entity in adults and highly associated with myelodysplastic syndromes, especially acute myelogenous leukemia (AML). It may present at any stage of AML and requires appropriate workup and treatment, though generally carries a poor prognosis. PMID- 23088362 TI - A new triterpenoid saponin from Gymnema sylvestre. AB - Besides four known compounds, a new triterpenoid saponin was isolated from the stems of Gymnema sylvestre. The structure of the new triterpenoid saponin was established as 3beta,16beta,22alpha-trihydroxy-olean-12-ene 3-O-beta-D xylopyranosyl-(1 -> 6)-beta-D-glucopyranosyl-(1 -> 6)-beta-D-glucopyranoside (1) on the basis of 1D and 2D NMR techniques, including COSY, HMBC, HMQC, and NOESY correlations. Four known compounds 2, 3, 4, and 5 were identified on the basis of spectroscopic data. PMID- 23088363 TI - Energetics and ion permeation characteristics in a glutamate-gated chloride (GluCl) receptor channel. AB - An invertebrate glutamate-gated chloride channel (GluCl) has recently been crystallized in an open-pore state. This channel is homologous to the human Cys loop receptor family of pentameric ligand-gated ion channels, including anion selective GlyR and GABAR and cation-selective nAChR and 5HT(3). We implemented molecular dynamics (MD) in conjunction with an elastic network model to perturb the X-ray structure of GluCl and investigated the open channel stability and its ion permeation characteristics. Our study suggests that TM2 helical tilting may close GluCl near the hydrophobic constriction L254 (L9'), similar to its cation selective homologues. Ion permeation characteristics were determined by Brownian dynamics simulations using a hybrid MD/continuum electrostatics approach to evaluate the free energy profiles for ion transport. Near the selectivity filter region (P243 or P-2'), the free energy barrier for Na(+) transport is over 4 k(B)T higher than that for Cl(-), indicating anion selectivity of the channel. Furthermore, three layers of positivity charged rings in the extracellular domain also contribute to charge selectivity and facilitate Cl(-) permeability over Na(+). Collectively, the charge selectivity of GluCl may be determined by overall electrostatic and ion dehydration effects, perhaps not deriving from a single region of the channel (the selectivity filter region near the intracellular entrance). PMID- 23088364 TI - Denaturation of RNA secondary and tertiary structure by urea: simple unfolded state models and free energy parameters account for measured m-values. AB - To investigate the mechanism by which urea destabilizes RNA structure, urea induced unfolding of four different RNA secondary and tertiary structures was quantified in terms of an m-value, the rate at which the free energy of unfolding changes with urea molality. From literature data and our osmometric study of a backbone analogue, we derived average interaction potentials (per square angstrom of solvent accessible surface) between urea and three kinds of RNA surfaces: phosphate, ribose, and base. Estimates of the increases in solvent accessible surface areas upon RNA denaturation were based on a simple model of unfolded RNA as a combination of helical and single-strand segments. These estimates, combined with the three interaction potentials and a term to account for interactions of urea with released ions, yield calculated m-values that are in good agreement with experimental values (200 mm monovalent salt). Agreement was obtained only if single-stranded RNAs were modeled in a highly stacked, A-form conformation. The primary driving force for urea-induced denaturation is the strong interaction of urea with the large surface areas of bases that become exposed upon denaturation of either RNA secondary or tertiary structure, though interactions of urea with backbone and released ions may account for up to a third of the m-value. Urea m values for all four RNAs are salt-dependent, which we attribute to an increased extension (or decreased charge density) of unfolded RNAs with an increased urea concentration. The sensitivity of the urea m-value to base surface exposure makes it a potentially useful probe of the conformations of RNA unfolded states. PMID- 23088366 TI - Efficacy of psychosocial interventions in men and women with sexual dysfunctions- a systematic review of controlled clinical trials: part 2--the efficacy of psychosocial interventions for female sexual dysfunction. AB - INTRODUCTION: As yet, a summary of the research evidence concerning the efficacy of psychological treatment in female sexual dysfunction is lacking. Previous reviews were often nonsystematic or explored one specific sexual dysfunction. AIM: Our systematic review provides an overview of the efficacy of psychosocial interventions in all female sexual dysfunction. MAIN OUTCOME MEASURES: Main outcome measures included for example psychometrically validated scales, diary notes, interviews, and vulvar algesiometer. The efficacy of psychosocial interventions was measured for example by the frequency of and satisfaction with sexual activity and sexual functioning. Safety and acceptance were evaluated on the basis of adverse events and dropout rates. METHODS: The systematic literature search included electronic database search, handsearch, contact with experts, and an ancestry approach. Studies were included if the woman was given a formal diagnosis of a sexual dysfunction (International Statistical Classification of Diseases and Related Health Problems-ICD10/-9; Diagnostic and Statistical Manual of Mental Disorders-IV/-III-R) and when the intervention was psychosocial or psychotherapeutic. The control group included either another treatment or a waiting-list control group. The report of relevant outcomes was necessary for inclusion as well as the design of the study (randomized, controlled trials [RCTs] and controlled clinical trials). The assessment of methodological quality comprised aspects of randomization, blinding, incomplete outcome data, selective reporting, and allegiance. RESULTS: We identified 15 RCTs that investigated efficacy in female sexual dysfunction and two further studies that examined male and female sexual dysfunction together. Most trials explored sexual pain disorders. About half of all studies in women used either a concept derived from Masters and Johnson or a cognitive-behavioral treatment program. Both approaches showed significant improvements compared with a control group. Benefit was not always maintained over the (variable) follow-up period. CONCLUSIONS: Traditional sexual therapeutic concepts proved to be efficacious in the treatment of female sexual dysfunction. A shortcoming was the rather low methodological quality of included studies. PMID- 23088365 TI - Mitochondrial phosphorylation in apoptosis: flipping the death switch. AB - SIGNIFICANCE: Apoptosis is a complex cellular process subject to multiple layers of regulation. One such layer of regulation includes post-translational modifications, including acetylation and phosphorylation. In particular, phosphorylation of proteins directly implicated in the apoptotic process has been extensively documented. Importantly, these phosphorylation events often have functional consequences, affecting the onset of apoptotic cell death. RECENT ADVANCES: Large-scale proteomics studies have identified multiple novel phosphorylation sites on proteins involved in the apoptotic process. The delineation of the regulation and functional consequences of these phosphorylation events will be important in understanding the regulatory complexity of apoptosis. CRITICAL ISSUES: Multiple mitochondrial-localized proteins involved in apoptosis are functionally affected by phosphorylation, which can ultimately dictate whether a cell lives or dies. The dynamic interplay between these phosphorylated proteins and their regulatory enzymes is critical for understanding the complex cellular decision to undergo apoptosis. FUTURE DIRECTIONS: Detailed analysis of the kinetic and spatial regulation of phosphorylation events on apoptotic proteins, as well as how these dynamics influence the cell death process, will illuminate the complex interplay between the network of proteins that control the decision to undergo cell death. PMID- 23088367 TI - Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis. AB - AIMS: Aldosterone antagonists (AldoAs) have been used to treat severe chronic heart failure (CHF). There is uncertainty regarding the efficacy of using AldoAs in mild to moderate CHF with New York Heart Association (NYHA) classifications of I to II. This study summarizes the evidence for the efficacy of spironolactone (SP), eplerenone (EP) and canrenone in mild to moderate CHF patients. METHODS: PubMed, MEDLINE, EMBASE and OVID databases were searched before June 2012 for randomized and quasi-randomized controlled trials assessing AldoA treatment in CHF patients with NYHA classes I to II. Data concerning the study's design, patients' characteristics and outcomes were extracted. Risk ratio (RR) and weighted mean differences (WMD) or standardized mean difference were calculated using either fixed or random effects models. RESULTS: Eight trials involving 3929 CHF patients were included. AldoAs were superior to the control in all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and in re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74), the left ventricular ejection fraction was improved by AldoA treatment (WMD 2.94%, P = 0.52). Moreover, AldoA therapy decreased the left ventricular end-diastolic volume (WMD -14.04 ml, P < 0.00001), the left ventricular end-systolic volume (WMD -14.09 ml, P < 0.00001). A stratified analysis showed a statistical superiority in the benefits of SP over EP in reducing LVEDV and LVESV. AldoAs reduced B-type natriuretic peptide concentrations (WMD -37.76 pg ml(-1), P < 0.00001), increased serum creatinine (WMD 8.69 MUmol l(-1), P = 0.0003) and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23). CONCLUSIONS: Additional use of AldoAs in CHF patients may decrease mortality and re-hospitalization for cardiac reasons, improve cardiac function and simultaneously ameliorate LV reverse remodelling. PMID- 23088368 TI - Novel NMNAT1 mutations causing Leber congenital amaurosis identified. PMID- 23088369 TI - High-grade renal injury: non-operative management of urinary extravasation and prediction of long-term outcomes. AB - OBJECTIVE: To predict the outcomes of a non-operative approach to managing urinary extravasation after blunt renal trauma. PATIENTS AND METHODS: A prospective observational study was conducted between January 2004 and October 2011. First-line non-operative management was proposed for 99 patients presenting with a grade IV blunt renal injury according to the revised American Association for the Surgery of Trauma (AAST) classification. Among them, 72 patients presented with a urinary extravasation. Management and outcomes were recorded and compared between patients presenting and those who did not present with urinary leakage. Relative postoperative renal function was assessed 6 months after the trauma using dimercapto-succinic acid renal scintigraphy. Predictors of the need for endoscopic or surgical management and long-term renal function were evaluated on multivariate analysis. RESULTS: Among patients with urinary leakage, endoscopic ureteric stent placement and open surgery were required in 37% and 15%, respectively. On multivariate analysis, fever of >38.5 degrees C and ureteric clot obstruction were independent predictors of the need for ureteric stent placement. The only predictor of open surgery was the percentage of devitalised parenchyma. Long-term renal function loss was correlated to the percentage of devitalised parenchyma and associated visceral lesions. Urinary extravasation did not predict surgical intervention or long-term renal function loss. CONCLUSIONS: Urinary extravasation after blunt renal trauma can be successfully managed conservatively and does not predict long-term decreased renal function or surgery requirement. A devascularised parenchyma volume of >25% predicts a higher rate of surgery and poorer renal function. PMID- 23088370 TI - Profiles of physical, emotional and psychosocial wellbeing in the Lothian birth cohort 1936. AB - BACKGROUND: Physical, emotional, and psychosocial wellbeing are important domains of function. The aims of this study were to explore the existence of separable groups among 70-year olds with scores representing physical function, perceived quality of life, and emotional wellbeing, and to characterise any resulting groups using demographic, personality, cognition, health and lifestyle variables. METHODS: We used latent class analysis (LCA) to identify possible groups. RESULTS: Results suggested there were 5 groups. These included High (n = 515, 47.2% of the sample), Average (n = 417, 38.3%), and Poor Wellbeing (n = 37, 3.4%) groups. The two other groups had contrasting patterns of wellbeing: one group scored relatively well on physical function, but low on emotional wellbeing (Good Fitness/ Low Spirits,n = 60, 5.5%), whereas the other group showed low physical function but relatively well emotional wellbeing (Low Fitness/Good Spirits, n = 62, 5.7%). Salient characteristics that distinguished all the groups included smoking and drinking behaviours, personality, and illness. CONCLUSIONS: Despite there being some evidence of these groups, the results also support a largely one dimensional construct of wellbeing in old age--for the domains assessed here- though with some evidence that some individuals have uneven profiles. PMID- 23088372 TI - On the combinatorics of sparsification. AB - BACKGROUND: We study the sparsification of dynamic programming based on folding algorithms of RNA structures. Sparsification is a method that improves significantly the computation of minimum free energy (mfe) RNA structures. RESULTS: We provide a quantitative analysis of the sparsification of a particular decomposition rule, Lambda*. This rule splits an interval of RNA secondary and pseudoknot structures of fixed topological genus. Key for quantifying sparsifications is the size of the so called candidate sets. Here we assume mfe structures to be specifically distributed (see Assumption 1) within arbitrary and irreducible RNA secondary and pseudoknot structures of fixed topological genus. We then present a combinatorial framework which allows by means of probabilities of irreducible sub-structures to obtain the expectation of the Lambda*-candidate set w.r.t. a uniformly random input sequence. We compute these expectations for arc-based energy models via energy-filtered generating functions (GF) in case of RNA secondary structures as well as RNA pseudoknot structures. Furthermore, for RNA secondary structures we also analyze a simplified loop-based energy model. Our combinatorial analysis is then compared to the expected number of Lambda* candidates obtained from the folding mfe-structures. In case of the mfe-folding of RNA secondary structures with a simplified loop-based energy model our results imply that sparsification provides a significant, constant improvement of 91% (theory) to be compared to an 96% (experimental, simplified arc-based model) reduction. However, we do not observe a linear factor improvement. Finally, in case of the "full" loop-energy model we can report a reduction of 98% (experiment). CONCLUSIONS: Sparsification was initially attributed a linear factor improvement. This conclusion was based on the so called polymer-zeta property, which stems from interpreting polymer chains as self-avoiding walks. Subsequent findings however reveal that the O(n) improvement is not correct. The combinatorial analysis presented here shows that, assuming a specific distribution (see Assumption 1), of mfe-structures within irreducible and arbitrary structures, the expected number of Lambda*-candidates is Theta(n2). However, the constant reduction is quite significant, being in the range of 96%. We furthermore show an analogous result for the sparsification of the Lambda* decomposition rule for RNA pseudoknotted structures of genus one. Finally we observe that the effect of sparsification is sensitive to the employed energy model. PMID- 23088371 TI - Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland. AB - INTRODUCTION: The organisation of the mammary epithelial hierarchy is poorly understood. Our hypothesis is that the luminal cell compartment is more complex than initially described, and that an understanding of the developmental relationships within this lineage will help in understanding the cellular context in which breast tumours occur. METHODS: We used fluorescence-activated cell sorting along with in vitro and in vivo functional assays to examine the growth and differentiation properties of distinct subsets of human and mouse mammary epithelial cells. We also examined how loss of steroid hormones influenced these populations in vivo. Gene expression profiles were also obtained for all the purified cell populations and correlated to those obtained from breast tumours. RESULTS: The luminal cell compartment of the mouse mammary gland can be resolved into nonclonogenic oestrogen receptor-positive (ER+) luminal cells, ER+ luminal progenitors and oestrogen receptor-negative (ER-) luminal progenitors. The ER+ luminal progenitors are unique in regard to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared with the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation composed of nonclonogenic luminal cells, and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one-quarter of human breast samples examined contained an additional population that had a distinct luminal progenitor phenotype, characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. The ER- luminal progenitors in the mouse and the ALDH+ luminal progenitors in the human appear to be analogous populations since they both have gene signatures that are associated with alveolar differentiation and resemble those obtained from basal-like breast tumours. CONCLUSION: The luminal cell compartment in the mammary epithelium is more heterogeneous than initially perceived since progenitors of varying levels of luminal cell differentiation and proliferative capacities can be identified. An understanding of these cells will be essential for understanding the origins and the cellular context of human breast tumours. PMID- 23088373 TI - Selective gene delivery to cancer cells using an integrated cationic amphiphilic peptide. AB - Gene therapy provides a number of potential treatments that could be applied in clinic to prevent deaths from cancer. However, the transfer of gene therapy to the clinical application has proven difficult because many problems remain to be solved concerning the transfection efficiency, target specificity, and safety issues. To overcome these barriers, a peptide-based vector, K(12)H(6)V(8)SSQHWSYKLRP (KHV-LHRH) that comprises four functional blocks, is studied in this work for the targeted delivery of a model gene drug to cancer cells. KHV-LHRH peptide, which contains a luteinizing hormone-releasing hormone (LHRH) sequence, can specifically target cancer cells expressing LHRH receptors. The gene expression, cytotoxicity, and cellular uptake mediated by this vector were evaluated against MCF-7 human breast cancer cells (LHRH-receptor-positive) and SKOV-3 human ovarian carcinoma cells (LHRH-receptor-negative) and compared to a peptide vector (K(12)H(6)V(8)) (KHV) without the LHRH ligand and poly(ethylenimine) (PEI). The results showed that KHV-LHRH enhanced the DNA internalization and induced significantly higher gene expression than KHV in LHRH receptor-positive MCF-7 cells. Also, the peptide-based vectors had low cytotoxicity compared to that of PEI. The high specificity and transfection efficiency of the integrated peptide-based vector make it a very promising material for targeted gene delivery in cancer therapy. PMID- 23088374 TI - Quantifying the impact of recent negative life events on suicide attempts. AB - The extent to which a specific negative life event (NLE) is a triggering factor for a suicide attempt is unknown. The current study used a case-crossover design, an innovative within-subjects design, to quantify the unique effects of recent NLEs on suicide attempts. In an adult sample of 110 recent suicide attempters, a timeline follow-back methodology was used to assess NLEs within the 48 hours prior to the suicide attempt. Results indicated that individuals were at increased odds of attempting suicide soon after experiencing a NLE and that this effect was driven by the presence of an interpersonal NLE, particularly those involving a romantic partner. Moreover, the relation between interpersonal NLEs and suicide attempts was moderated by current suicide planning. Interpersonal NLEs served as triggers for suicide attempts only among patients who were not currently planning their attempt. Findings suggest the importance of considering potential interpersonal NLEs when evaluating imminent risk for suicide attempts. PMID- 23088375 TI - The level and nature of autistic intelligence III: Inspection time. AB - Across the autism spectrum, level of intelligence is highly dependent on the psychometric instrument used for assessment, and there are conflicting views concerning which measures best estimate autistic cognitive abilities. Inspection time is a processing speed measure associated with general intelligence in typical individuals. We therefore investigated autism spectrum performance on inspection time in relation to two different general intelligence tests. Autism spectrum individuals were divided into autistic and Asperger subgroups according to speech development history. Compared to a typical control group, mean inspection time for the autistic subgroup but not the Asperger subgroup was significantly shorter (by 31%). However, the shorter mean autistic inspection time was evident only when groups were matched on Wechsler IQ and disappeared when they were matched using Raven's Progressive Matrices. When autism spectrum abilities are compared to typical abilities, results may be influenced by speech development history as well as by the instrument used for intelligence matching. PMID- 23088376 TI - Mental disorder comorbidity and suicide among 2.96 million men receiving care in the Veterans Health Administration health system. AB - Comorbid mental disorders are common among suicide decedents. It is unclear if mental disorders in combination confer additive risk for suicide, in other words, if risk associated with two disorders is approximately the sum of the risk conferred by each disorder considered separately, or if there are departures from additivity such that the combined risk is less (i.e., subadditive) or more than additive (i.e., synergistic). Using a retrospective cohort design, all male Department of Veterans Affairs, Veterans Health Administration (VHA) service users who utilized VHA services in fiscal year (FY) 1999 and were alive at the start or FY 2000 (N = 2,962,810) were analyzed. Individuals were followed until death or the end of FY 2006. Using the VHA National Patient Care Database, diagnoses of mental disorders in FY 1999 were grouped into six categories (e.g., posttraumatic stress disorder). In proportional hazards models, 2-way interactions between disorders were used to examine departures from additive risk. There were 7,426 suicide deaths in the study period. Two-way interaction tests were nearly all statistically significant, indicating departures from additivity, and the results of these tests were consistent with subadditive risk. Sensitivity analyses examining the first year of follow-up showed similar results. Subadditive risk may be explained by factors that serve to lower the increased risk associated with a comorbid diagnosis, which may include common underlying causes of mental disorders, difficulties of differential diagnosis, the nature of etiological relationships between mental disorders, and intensive clinical care and monitoring of patients with comorbidity. PMID- 23088377 TI - Elucidation of tetraboric acid with a new borate fundamental building block in a chiral uranyl fluoroborate. AB - A new neutral borate species, H(2)B(4)O(7) (also known as tetraboric acid), with a one-dimensional chain structure, is found in the interlayer spacing in Rb(2)[(UO(2))(2)B(8)O(12)F(6)].H(2)B(4)O(7) (RbUBOF-2) derived from boric acid flux reaction of uranyl(VI) nitrate with RbBF(4). This new form of tetraboric acid possesses a novel borate fundamental building block with the symbol 4Delta:<3Delta>Delta. PMID- 23088379 TI - Children and the test of memory malingering: is one trial enough? AB - There is a growing body of research suggesting that the first trial of the TOMM may provide an accurate screener of effort in children. During neuropsychological assessments, some circumstances result in only one completed trial of the TOMM. Research on adults reflects that passing scores on Trial 1 (based on Trial 2 cutoff) are highly predictive of passing scores on Trial 2 and the TOMM overall. Pediatric research found that 100% of children and adolescents who passed Trial 1 of the TOMM also passed Trial 2. Our research hypothesis is that children who pass Trial 1 will also pass Trial 2. Data from 75 clinically diagnosed children (ages 6-18 years) found that 64% performed above the published adult TOMM cutoff on Trial 1. All children who passed Trial 1 also passed Trial 2 suggesting support for the research hypothesis. Sensitivity was 1.0, specificity was 0.72, positive predictive value was .33, and negative predictive value was 1.0. These findings suggest that in this sample, the children who performed above the Trial 2 cutoff on Trial 1 also all passed Trial 2 (so there were no false negatives, thus a perfect sensitivity and negative predictive value). Of the 36% of children who did not pass the Trial 1 cutoff, 67% passed on Trial 2. Data clearly support that children passing Trial 1 have a high likelihood of passing Trial 2, thus drawing conclusions about performance validity after passing Trial 1. Conclusions after failing Trial 1 require further investigation. PMID- 23088378 TI - Nervous network for lower urinary tract function. AB - Traditionally, sensory signaling in the urinary bladder has been largely attributed to direct activation of bladder afferents. There is substantive evidence that sensory systems can be influenced by non-neuronal cells, such as the urothelium, which are able to respond to various types of stimuli that can include physiological, psychological and disease-related factors. The corresponding release of chemical mediators (through activation of a number of receptors/ion channels) can initiate signaling mechanisms between and within urothelial cells, as well as other cell types within the bladder wall including bladder nerves. However, the mechanisms underlying how various cell types in the bladder wall respond to normal filling and emptying, and are challenged by a variety of stressors (physical and chemical) are still not well understood. Alterations or defects in signaling mechanisms are likely to contribute to the pathophysiology of bladder disease with symptoms including urinary urgency, increased voiding frequency and pain. This review will discuss some of the components involved in control of lower urinary tract function, with an emphasis on the sensor and transducer roles of the urothelium. PMID- 23088380 TI - Trends and variations in intravenous vitamin D use among hemodialysis patients in the United States. AB - Injectable vitamin D agents are commonly used to manage secondary hyperparathyroidism in dialysis patients. Yet, there are few data documenting the trends and geographic variations in the use of these agents in large, representative samples. We sought to describe patterns and variations in the use of vitamin D formulations (calcitriol, paricalcitol, and doxercalciferol) in hemodialysis patients. We studied patients in the United States Renal Data System between January1999 and December 2008 with Medicare as a primary payer. Annual percentages of patients treated with each type of formulation were tabulated by race, sex, and age at dialysis initiation. The geographical distribution of vitamin D dose per patient was mapped at the state level. Intravenous vitamin D use has increased sharply from 1999 to 2008 with 83.9% of patients treated with any vitamin D formulation in 2008. The use of calcitriol has declined since 1999, going from being administered in 58.6% of patients in 1999 to 1.8% in 2008. Paricalcitol was found to be the overwhelmingly preferred formulation during the study years. In 2008, the average dose among black patients was 84% greater than among white patients (136 mcg vs. 73.6 mcg). Higher doses of vitamin D were administered to patients in the southern region of the country. Vitamin D use has increased and parallels the rise in use of paricalcitol and doxercalciferol. Given the variations in use and known pharmacologic differences in vitamin D formulations, future research should focus on whether the formulations differentially affect patient outcomes. PMID- 23088381 TI - Impact of collateral circulation on early outcome and risk of hemorrhagic complications after systemic thrombolysis. AB - BACKGROUND: In stroke patients, collateral flow can rapidly be assessed on computed tomography angiography (CTA). AIMS: In this study, the impact of baseline collaterals on early outcome and risk of symptomatic intracerebral hemorrhages after systemic thrombolysis in patients with proximal arterial occlusions within the anterior circulation were analyzed. METHODS: Collateralization scores were determined on the CT angiography source images (0 = absent; 1 <= 50%, 2 > 50% but <100%, and 3 = 100% collateral filling) of patients with distal intracranial carotid artery and/or M1 segment occlusions treated from 2008 to December 2011. A collateral score of 0 to 1 was designated as poor and 2 to 3 as good collateral vessel status. Outcome variables included in hospital mortality, favorable outcome at discharge (modified Rankin score <= 2), and rates of symptomatic intracerebral hemorrhage based on the European-Australasian Acute Stroke Study II definition. RESULTS: Among 246 subjects (mean age of 74 years; median National Institutes of Health Stroke Scale N at admission 14), 205 patients (83%) had good collaterals, whereas 41 patients (17%) had poor collaterals, respectively. Patients with poor collaterals had significantly higher rates of in-hospital mortality (41% vs. 12%, P < 0.001), of symptomatic intracerebral hemorrhage (15% vs. 4.9%, P < 0.05) and had significantly lower rates of favorable early clinical outcome (0% vs. 28%, P < 0.001) compared with those with good collaterals. The grade of collateralization was independently associated with in-hospital mortality (P < 0.001), early clinical outcome (P < 0.01), and rates of symptomatic intracerebral hemorrhage (P < 0.01). CONCLUSION: Patients with proximal arterial occlusions within the anterior circulation and poor baseline collaterals have a poor early functional outcome and high rates of symptomatic intracerebral hemorrhage after systemic thrombolysis. Since similar findings have also been reported after endovascular therapy, strategies to improve collateral blood flow should be assessed in this patient population. PMID- 23088383 TI - Site-selective doping effect in AMn3V4O12 (A = Na+, Ca2+, and La3+). AB - A-site-ordered perovskite-structure oxides with Mn and V at A' and B sites, respectively, were synthesized by using a high-pressure method. Valence-state analyses revealed that the A-site substitution modulated the valence states of the Mn ions at the A' site and V ions at the B site sequentially. By changing the A-site ions from Na(+) to Ca(2+) and from Ca(2+) to La(3+), the valence distribution changed site-selectively from Na(+)Mn(2.33+)3V(4+)4O12 to Ca(2+)Mn(2+)3V(4+)4O12 and to La(3+)Mn(2+)3V(3.75+)4O12. The electrons of the A' site Mn were localized and contributed to the magnetic properties, that is, spin glass-like behavior in NaMn3V4O12 and antiferromagnetic behavior in CaMn3V4O12 and LaMn3V4O12. The valence electrons of the B-site V, in contrast, were delocalized, as could be seen from the low resistivity of the samples. The delocalized electrons at the B-site V did not correlate with the localized spins at the A'-site Mn. PMID- 23088382 TI - Orbital cavernous haemangiomas: immunohistochemical study of proliferative capacity, vascular differentiation and hormonal receptor status. AB - BACKGROUND/AIMS: Immunohistochemical characterisation of orbital cavernous haemangiomas (CHs) with respect to proliferative capacity, hormone receptor status and vascular differentiation. METHODS: Eleven cases of orbital CHs were reviewed. Immunohistochemical stains for Mib-1, proliferating cell nuclear antigen (PCNA), Bcl-2, estrogen and progesterone receptors (ER & PR), CD31, D2 40, and VEGF were investigated in 11 specimens. RESULTS: Immunohistochemical staining revealed positivity for PCNA in ten of the 11 cases (91%). Bcl-2 was positive in 8 cases (73%). VEGF and PR were each weakly positive in 3 cases. All cases were negative for Mib-1, ER and D2-40. The staining was localized around the endothelium. CONCLUSION: This is the first study to characterise in detail the immunohistochemical features of orbital CHs. The proliferative markers PCNA and Mib-1 show discordant expression in these lesions and the expression of PCNA and Bcl-2 in the absence of Mib-1 is indicative of low proliferative potential. Small subsets of these tumors express PR and VEGF, which may partly explain the proliferative capacity of some orbital CHs. PMID- 23088384 TI - Shaeer's glans augmentation technique: a pilot study. AB - INTRODUCTION: Augmentation of the glans penis may be indicated for cosmetic reasons, lack of glans tumescence following implantation of a penile prosthesis, or asymmetry following girth augmentation of the shaft. Many augmentation techniques have been offered to increase the length and girth of penile shaft, but not the glans penis, with the exception of hyaluronic acid gel injection that is known to decrease sensitivity of the glans and is restricted for cases with premature ejaculation. AIM: This work is the first report on glans augmentation by grafting. MAIN OUTCOME MEASURES: Maximum circumference of the glans, self reported impression of the augmented volume and glans sensitivity. METHODS: Ten males requesting augmentation of the glans were selected for the study after failing counseling, with normal erectile function and ejaculatory control. Two ventral incisions were cut along the ventral aspects of the coronal sulcus, one on either side of the frenulum. Lateral glans flaps were dissected on either side. The urethra was circumvented, creating a plane all around it. A dermal fat graft was inserted into the space created. The flaps were closed by simple absorbable sutures. RESULTS: Maximum circumference of the glans increased by 16.6%, declining to 14.2% by the last follow-up visit (10-12 months), a 2.3% decline. Self-reported impression of the augmented volume was high and well maintained over the follow-up period. Glans sensation, engorgement, erectile function, and ejaculatory control were preserved. CONCLUSION: This pilot study on glans augmentation by grafting reports promising results with retention of the added volume at 1-year follow-up, preservation sensitivity and engorgement, and no adverse effects on erectile function or ejaculatory control. PMID- 23088385 TI - In vitro evaluation of schistosomicidal potential of curcumin against Schistosoma japonicum. AB - Curcumin is a polyphenol derived from the dietary spice turmeric. The aim of this study was to investigate the in vitro effect of curcumin against eggs, cercariae, pre-adults, and adults of Schistosoma japonicum compared to praziquantel. After incubated by different concentration of curcumin or praziquantel in different time, the percent hatching rates of eggs, the percent dead rates of cercariae, and the number of dead worms were observed. Curcumin showed time- and dose dependent schistosomicidal effects on every life stages of S. japonicum. In addition, curcumin exhibited an optimal activity against the adult stage with no differential sensitivity between male and female worms and decreased motor activity of these worms without tegumental alterations. The promising in vitro effects on all stages of S. japonicum warrants further evaluation for the prophylactic and therapeutic values in the early and late schistosomiasis in field trials. PMID- 23088386 TI - SIMPATIQCO: a server-based software suite which facilitates monitoring the time course of LC-MS performance metrics on Orbitrap instruments. AB - While the performance of liquid chromatography (LC) and mass spectrometry (MS) instrumentation continues to increase, applications such as analyses of complete or near-complete proteomes and quantitative studies require constant and optimal system performance. For this reason, research laboratories and core facilities alike are recommended to implement quality control (QC) measures as part of their routine workflows. Many laboratories perform sporadic quality control checks. However, successive and systematic longitudinal monitoring of system performance would be facilitated by dedicated automatic or semiautomatic software solutions that aid an effortless analysis and display of QC metrics over time. We present the software package SIMPATIQCO (SIMPle AuTomatIc Quality COntrol) designed for evaluation of data from LTQ Orbitrap, Q-Exactive, LTQ FT, and LTQ instruments. A centralized SIMPATIQCO server can process QC data from multiple instruments. The software calculates QC metrics supervising every step of data acquisition from LC and electrospray to MS. For each QC metric the software learns the range indicating adequate system performance from the uploaded data using robust statistics. Results are stored in a database and can be displayed in a comfortable manner from any computer in the laboratory via a web browser. QC data can be monitored for individual LC runs as well as plotted over time. SIMPATIQCO thus assists the longitudinal monitoring of important QC metrics such as peptide elution times, peak widths, intensities, total ion current (TIC) as well as sensitivity, and overall LC-MS system performance; in this way the software also helps identify potential problems. The SIMPATIQCO software package is available free of charge. PMID- 23088387 TI - Templating effect of mesostructured surfactant-silica monolithic films on the surface structural and mechanical properties. AB - Mesostructured surfactant-silica monolithic films were prepared using a supramolecular templating method. The effect of the templating in the monolithic films on the interfacial interactions was evaluated and elucidated using the atomic force microscope techniques combined with other surface analyses to produce different surface structures and force curves depending on the surfactants. The transparent and flexible surfactant-silica monolithic films were prepared to exhibit the ordered nanostructures. The monolithic films templated by nonionic triblock copolymers (poly(ethylene oxide (EO))--poly(propylene oxide (PO))--poly(ethylene oxide (EO))) of EO20PO70EO20 (P123) and EO106PO70EO106 (F127) significantly exhibited flat surfaces and the higher viscoelastic properties which were supported by surface stiffness and adhesive force, whereas the monolithic film by cationic alkylammonium surfactant indicated a rough surface and the plastic deformation property by application of force. This indicated that the higher molecular weight of the EO and PO phases enhanced the phase segregation in the silica surfaces due to the higher solubility differences between both blocks to consolidate the surfactant-silica interfacial interactions. Therefore, the different surface structural and mechanical properties attributed to the interfacial organic-inorganic interaction patterns were successfully clarified. PMID- 23088388 TI - Whole blood impedance aggregometry as a biomarker for the diagnosis and prognosis of severe sepsis. AB - INTRODUCTION: Sepsis leads to an activation of the immune system and hemostatis. However, studies on platelet aggregation in severe sepsis using impedance aggregometry have not been performed and the diagnostic and prognostic capabilities are unknown. In the present study we hypothesized that impedance aggregometry findings might serve as a biomarker for the diagnosis and prognosis of severe sepsis. METHODS: Eighty patients with severe sepsis and 50 postoperative patients were included in the prospective observational study. Platelet function was determined at the first day of severe sepsis and surgery, respectively, using impedance aggregometry (Multiplate(r)). Moreover, platelet count, procalcitonin, interleukin 6, C-reactive protein and 30-day mortality were determined. RESULTS: Compared to postoperative patients, platelet aggregation was significantly reduced in patients with severe sepsis (collagen-test: 70.8 (44.4, 83.2) arbitrary units (A.U.) vs. 26.8 (12.7, 45.8) A.U.; P <0.001; median and quartiles). Furthermore, marked differences in platelet function were observed in survivors and non-survivors of severe sepsis (collagen-test: 33.4 (10.9, 48.8) A.U. vs. 12.4 (6.5, 25.0) A.U.; P = 0.001). Kaplan-Meier analysis demonstrated that higher platelet function was associated with a mortality of 10%, while mortality was 40% when platelet function was low (collagen-test; P = 0.002). The odds ratio was 6.0. In both univariate and multivariate analyses (including procalcitonin, IL6, C-reactive protein and platelet count) impedance aggregometry using collagen as the activator proved to be the best and an independent predictor for the diagnosis and prognosis of severe sepsis in critical illness. CONCLUSIONS: In severe sepsis, impedance aggregometry allows better prediction of diagnosis and survival than conventional biomarkers and platelet count. PMID- 23088389 TI - Evolution of the European guidelines for the clinical development of factor VIII products: little progress towards improved patient management. AB - In the process of clinical development and licensing of factor VIII (FVIII) products for treatment of haemophilia A, the safety concerns generated in the 1980s by the risk of pathogen transmission were tremendously reduced by the implementation of an array of methods for inactivation/removal of blood borne pathogens. The current focus on the risk of FVIII inhibitors does not stem from a new awareness, because this multifactorial complication has long been recognized. With this background, I believe that the current European regulatory guidelines for the clinical development and licensing of FVIII products fail to reflect the tremendous progress made in terms of clinical efficacy and safety, because they are witnessing a continuous increase in the demands from health agencies to the point that clinical studies have become more and more difficult to carry out. This article reviews the evolution of the European regulations on new FVIII products, lists a number of regulatory requirements whose scientific and/or clinical rationale is perhaps questionable and recommends keeping such requirements in reasonable limits of feasibility, without jeopardizing current high standards of efficacy and safety. PMID- 23088390 TI - Hydrolytic enzymes of the interfollicular epidermis differ in expression and correlate with the phenotypic difference observed between light and dark skin. AB - Degradation of melanosomes in light skin (LS, i.e. phototype I/II) appears to occur more rapidly than dark skin (DS, i.e. phototype IV/V). Hydrolytic enzymes known to reside and be expressed in a differential pattern within the interfollicular epidermis are implicated in playing a role in epidermal differentiation and potentially melanosome degradation. The aim of this present study was to evaluate the differential expression of hydrolytic enzymes that may correlate with physiological and phenotypic differences seen between DS and LS. Expression of six hydrolytic enzymes was confirmed by microarray analysis of the suprabasal epidermis from LS and DS. Specific lysosomal hydrolases identified by microarray analysis were analyzed by indirect immunofluorescence (IIF) and immunoblot analysis. Immunogold electron microscopy (IEM) was completed to visualize cellular expression of the hydrolytic enzyme cathepsin L2 (Cath L2) and biochemical assay was performed to ascertain Cath L2 activity. Immunoblotting of light and dark epidermal lysates demonstrated that of the six enzymes initially analyzed, both prostatic acid phosphatase (ACPP) and Cath L2 were reproducibly upregulated in DS and LS, respectively. IIF and IEM analyses of Cath L2 in tissue confirmed this differential expression. Biochemical analysis of Cath L2 in light and dark epidermal lysates displays increased activity of Cath L2 in LS. The results of this study confirm differential expression of ACPP and Cath L2 in DS and LS at gene and protein level. Additionally, Cath L2 displays increased activity in LS-derived epidermal lysates. This study indentified two acid hydrolases that may play a role in melanosome degradation and pigment processing. PMID- 23088391 TI - The impact of hospital pay-for-performance on hospital and Medicare costs. AB - OBJECTIVE: To evaluate the effects of Medicare's hospital pay-for-performance demonstration project on hospital revenues, costs, and margins and on Medicare costs. DATA SOURCES/STUDY SETTING: All health care utilization for Medicare beneficiaries hospitalized for acute myocardial infarction (AMI; ICD-9-CM code 410.x1) in fiscal years 2002-2005 from Medicare claims, containing 420,211 admissions with AMI. STUDY DESIGN: We test for changes in hospital costs and revenues and Medicare payments among 260 hospitals participating in the Medicare hospital pay-for-performance demonstration project and a group of 780 propensity score-matched comparison hospitals. Effects were estimated using a difference-in difference model with hospital fixed effects, testing for changes in costs among pay-for-performance hospitals above and beyond changes in comparison hospitals. PRINCIPAL FINDINGS: We found no significant effect of pay-for-performance on hospital financials (revenues, costs, and margins) or Medicare payments (index hospitalization and 1 year after admission) for AMI patients. CONCLUSIONS: Pay for-performance in the CMS hospital demonstration project had minimal impact on hospital financials and Medicare payments to providers. As P4P extends to all hospitals under the Affordable Care Act, these results provide some estimates of the impact of P4P and emphasize our need for a better understanding of the financial implications of P4P on providers and payers if we want to create sustainable and effective programs to improve health care value. PMID- 23088392 TI - Spectroscopic evidence of the role of an axial ligand histidinate in the mechanism of adrenal cytochrome b561. AB - Adrenal cytochrome b(561) (AdCytb) is the prototype of a widespread protein family that specializes in delivering electrons donated by ascorbic acid for different processes in eukaryotic cells. AdCytb transports redox equivalents from cytoplasmic ascorbate across the membranes of chromaffin granules to support norepinephrine synthesis within their matrix. The interaction of AdCytb with ascorbate is central to a proposed mechanism of AdCytb's function, and a histidine in the active site of AdCytb was suggested to bind cytoplasmic ascorbate and serve as the acceptor of the proton released during ascorbate oxidation. AdCytb contains high- and low-potential hemes but their orientation relative to the matrix and cytoplasmic interfaces of chromaffin granule membrane is disputed. Using a combination of three spectroscopic methods (UV-vis absorption, near-infrared magnetic circular dichroism, and electron paramagnetic resonance), we find that a histidine residue that serves as an axial ligand to the high-potential heme undergoes deprotonation with a pK of ~8.0 and is thus a good candidate for interaction with cytoplasmic ascorbate. The low-potential heme of AdCytb is found to have a pK of ~10.5, making it an unlikely candidate for accepting a proton at physiological pH. UV-vis spectroscopy reveals an additional proton acceptor group in AdCytb with a pK of ~6.5 that is not observed by the other two techniques; whether it plays a role in the mechanism of AdCytb is unknown. We incorporate these results into an updated mechanism of AdCytb reduction predicated on the high-potential heme's localization on the cytoplasmic interface of the chromaffin granule membrane. PMID- 23088393 TI - Temporary epicardial left ventricular and biventricular pacing improves cardiac output after cardiopulmonary bypass. AB - BACKGROUND: To evaluate, with different pacing modes, acute changes in left ventricular systolic function, obtained by continuous cardiac output thermodilution in various subsets of patients undergoing cardiopulmonary bypass surgery. Increments of mean arterial pressure and cardiac output were considered the end point. METHODS: Fifty cases electively submitted to cardiac surgery were analyzed. Isolated valve surgery 62%, coronary revascularization 30% and 8% mixed disease. Left ventricular ejection fraction was preserved in 50%,36% had moderate depression,(EF 36%-50%) whereas 14% had severe depression (EF < 35%). Left bundle branch block occurred in 18%. Preoperatively 84% were in sinus rhythm and 16% in atrial fibrillation. The different subgroups were analyzed for comparisons. Right atrial-right ventricular and right atrial-left ventricular pacing were employed in sinus rhytm. Biventricular pacing was also used in atrial fibrillation. RESULTS: Right atrium-right ventricular pacing, decreased significantly mean arterial pressure and cardiac output (2.3%) in the overall population and in the subgroups studied. Right atrium-left ventricle, increased mean arterial pressure and cardiac output in 79% of patients and yielded cardiac output increments of 7.5% (0.40 l/m) in the low ejection fraction subgroup and 7.3% (0.43 l/m) in the left bundle branch block subset. In atrial fibrillation patients, left ventricular and biventricular pacing produced a significant increase in cardiac output 8.5% (0.39 l/min) and 11.6% (0.53 l/min) respectively. The dP/dt max increased significantly with both modes (p = 0.021,p = 0.028). CONCLUSION: Right atrial-right ventricular pacing generated adverse hemodynamic effects. Right atrium-left ventricular pacing produced significant CO improvement particularly in cases with depressed ventricular function and left bundle branch block. The greatest increments were observed with left ventricular or biventricular pacing in atrial fibrillation with depressed ejection fraction. PMID- 23088394 TI - High-grade renal injury: non-operative management of urinary extravasation and prediction of long-term outcomes. PMID- 23088395 TI - Theoretical study on the structure and stabilities of molecular clusters of oxalic acid with water. AB - The importance of aerosols to humankind is well-known, playing an integral role in determining Earth's climate and influencing human health. Despite this fact, much remains unknown about the initial events of nucleation. In this work, the molecular properties of common organic atmospheric pollutant oxalic acid and its gas phase interactions with water have been thoroughly examined. Local minima single-point energies for the monomer conformations were calculated at the B3LYP and MP2 level of theory with both 6-311++G(d,p) and aug-cc-pVDZ basis sets and are compared with previous works. Optimized geometries, relative energies, and free energy changes for the stable clusters of oxalic acid conformers with up to six waters were then obtained from B3LYP calculations with 6-31+G(d) and 6 311++G(d,p) basis sets. Initially, cooperative binding is predicted to be the most important factor in nucleation, but as the clusters grow, dipole cancellations are found to play a pivotal role. The clusters of oxalic acid hydrated purely with water tend to produce extremely stable and neutral core systems. Free energies of formation and atmospheric implications are discussed. PMID- 23088396 TI - Inversion of membrane surface charge by trivalent cations probed with a cation selective channel. AB - We demonstrate that the cation-selective channel formed by gramicidin A can be used as a reliable sensor for studying the multivalent ion accumulation at the surfaces of charged lipid membranes and the "charge inversion" phenomenon. In asymmetrically charged membranes with the individual leaflets formed from pure negative and positive lipids bathed by 0.1 M CsCl solutions the channel exhibits current rectification, which is comparable to that of a typical n/p semiconductor diode. We show that even at these highly asymmetrical conditions the channel conductance can be satisfactorily described by the electrodiffusion equation in the constant field approximation but, due to predictable limitations, only when the applied voltages do not exceed 50 mV. Analysis of the changes in the voltage dependent channel conductance upon addition of trivalent cations allows us to gauge their interactions with the membrane surface. The inversion of the sign of the effective surface charge takes place at the concentrations, which correlate with the cation size. Specifically, these concentrations are close to 0.05 mM for lanthanum, 0.25 mM for hexaamminecobalt, and 4 mM for spermidine. PMID- 23088397 TI - Long term follow-up of drug resistant and drug susceptible tuberculosis contacts in a Low incidence setting. AB - BACKGROUND: Studies examining the transmission of multidrug-resistant tuberculosis (MDR-TB) strains have yielded conflicting results. METHODS: We examined transmission of MDR-TB strains using contact tracing data from a low incidence setting. Contacts of MDR-TB cases diagnosed in British Columbia, Canada, from 1990-2008 were identified through a provincial tuberculosis (TB) registry. Tuberculin skin test (TST) results and TB disease incident rates were determined for contacts. For comparison, TB disease incident rates and TST results were measured in close contacts of isoniazid mono-resistant (HMR-TB) and drug susceptible TB (DS-TB) cases. RESULTS: Of 89 identified close contacts of MDR-TB patients, 5 patients (6%) developed TB disease and 42 (47%) were TST positive. The incidence rate of TB disease (3%, p = 0.31) and TST positivity (49%, p = 0.82) were similar in contacts of HMR-TB cases. Compared with MDR-TB contacts, DS-TB contacts had lower incidence rate of TB disease (2%, p = 0.04) and TST positivity (32%, p < 0.01). All MDR-TB contacts with culture positive TB diagnosed in follow-up were drug-susceptible; three of six HMR-TB contacts with culture positive TB were HMR-TB. Multivariate analysis demonstrated that contact with MDR-TB (adjusted OR 1.72; 95%CI 1.05-2.81) and HMR-TB (adjusted OR 1.99; 95%CI 1.48-2.67) was associated with TST positivity. In addition, adult age, male gender, BCG positivity, source case sputum smear positivity, foreign birth and fewer contacts per source case were significantly associated with TST positivity in the multivariate model. CONCLUSION: Contacts of MDR-TB and HMR-TB patients in a low incidence setting show high rates of TST positivity and TB disease but low rates of drug resistance. PMID- 23088398 TI - Topological versatility of oxalate-based bimetallic one-dimensional (1D) compounds associated with ammonium cations. AB - A new family of oxalate-bridged chains of formula (C(1))[Mn(H(2)O)(3)Cr(ox)(3)].H(2)O (1), (C(2))(4)[Mn(2)(H(2)O)(3)ClCr(2)(ox)(6)]Cl.H(2)O.2C(2)H(6)O (2a), (C(2))(4)[Co(2)(H(2)O)(3)ClCr(2)(ox)(6)]Cl.2H(2)O.2C(2)H(6)O (2b), [Mn(C(3))(H(2)O)(2)Cr(ox)(3)].H(2)O (3), and (C(4))(4)[Mn(H(2)O){Cr(ox)(3)}(2)].H(2)O (4) [C(1)(+) = tetramethylammonium, C(2)(+) = 4-N,N-dimethylaminopyridinium, C(3)(+) = 1-hydroxyethyl-4-N,N dimethylamino-pyridinium, C(4)(+) = 1-hydroxyethyl-4-(4'-dimethylamino-alpha styryl)-pyridinium, ox(2-) = oxalate] have been synthesized by self-assembly of the (C(n))(3)[Cr(ox)(3)] (n = 1-4) mononuclear compound and the chloride salts of the corresponding metal(II) ions. The crystal structures of the five chain compounds have been determined by single-crystal X-ray diffraction. Compounds 1 and 2 crystallize in the Pc and P2(1)/c centrosymmetrical space groups, respectively, whereas 3 and 4 crystallize in the C2cb and P1 noncentrosymmetrical space groups, respectively. Compounds 1, 2, and 3 adopt a zigzag chain structure while 4 exhibits a comb-like chain structure consisting of the repetition of the [Mn(H(2)O){Cr(MU-ox)(ox)(2)}{Cr(MU-ox)(2)(ox)}](4-) entities. Compound 3 displays large second-order optical nonlinearity. The magnetic properties of 1-4 have been investigated in the temperature range 2-300 K. Monte Carlo simulations on 1, 2a, 2b, and 3 provide a quantitative description of the magnetic properties indicating ferromagnetic interactions through the bis(bidentate) oxalate bridges [J = +0.55 cm(-1) (1), J = +1.02 cm(-1) (2a), J = +3.83 cm(-1) (2b), and J = +0.75 cm(-1) (3) using Hamiltonian H = -J(S(i).S(j))]. On the other side, the fit of the magnetic susceptibility data of 4 by full-matrix diagonalization agrees with a ferromagnetic exchange interaction within the [Mn(H(2)O){Cr(MU ox)(ox)(2)}{Cr(MU-ox)(2)(ox)}](4-) trinuclear units (J = +2.07 cm(-1)) antiferromagnetically coupled along the chain. Compound 2b exhibits a metamagnetic behavior, the value of the critical field being H(C) = 1000 G, due to the occurrence of weak interchain antiferromagnetic interactions. PMID- 23088399 TI - C-MYC controlled TIP110 protein expression regulates OCT4 mRNA splicing in human embryonic stem cells. AB - We reported previously that HIV-1 the Tat-interacting protein of 110 kDa (TIP110; P110(NRB)/SART3/p110) is important in regulation of hematopoiesis, and in maintaining pluripotent factor (NANOG, OCT4, and SOX2) expression in and pluripotency of human embryonic stem cells (hESCs). Here we show that TIP110 expression in hESCs line H9 and embryonal carcinoma cell line NT-2 is regulated by C-MYC expression in ESCs through an E box present in the TIP110 promoter region. Through up- and down- modulation of expression, TIP110 induces OCT4 exon 1a inclusion and exon 1b skipping in our OCT4 minigene model. Thus, TIP110 expression in ESCs regulates alternative splicing of OCT4, an event required for pluripotency of ESCs. PMID- 23088400 TI - Important aspects of oral paracoccidioidomycosis--a literature review. AB - Paracoccidioidomycosis is a deep mycosis endemic to Latin America, with considerable morbidity and mortality. It is caused by the dimorphic fungus Paracoccidioides brasiliensis, which affects, among other organs in the human body, the oral cavity. Fungus virulence and immunocompetence of the host determine the establishment of infection or active disease, whose severity and clinical behaviour depend mostly on the cellular immune response of the host. Often, oral lesions constitute the first sign and site of confirmation of diagnosis, which in most cases is delayed. The success of the treatment depends on early and correct diagnosis, as well as on the patient's adherence to the drug therapy. PMID- 23088401 TI - Enhancing services response to crisis incidents involving veterans: a role for law enforcement and mental health collaboration. AB - When crisis situations involving veterans occur, responding police officers find themselves playing an important role in the spectrum of health and mental health services for those veterans. Crisis response training can help officers respond in a manner that increases safety and optimizes outcomes for all people involved. Yet, current crisis response police training models are only accessible to select officers. Nor do they emphasize the unique challenges and strengths that impact veterans who experience acute symptoms of mental illness. In the current study, we report the results from the first generation of training, collaboratively designed to enhance officers' (a) knowledge of relevant topics, including posttraumatic stress disorder and traumatic brain injury, (b) attitudes about veterans, and (c) and skills helpful in identifying and deescalating veterans and referring them to treatment. Officers completed in-class evaluations (N = 314), and a subsample (n = 53) completed 3-month follow-up evaluations. Pre- versus posttest comparisons indicated significant improvements in total score, and individually in knowledge, attitudes, and skills. Consistent with previous literature, the specific in-class gains were not retained on follow-up. However, responding officers widely endorsed use of de-escalation techniques during, and a positive impact of the training on, their interactions with veterans in the 3 months following the training. Implications for future training and policy are discussed. PMID- 23088402 TI - Kids at the VA? A call for evidence-based parenting interventions for returning veterans. AB - Veterans of the current and recent U.S. military conflicts are at risk for negative physical, psychological, and family functioning outcomes. Children of veterans are also at risk for developing mental and behavioral difficulties. Furthermore, the parent-child relationship can be negatively affected by deployment-related problems. These child and family functioning difficulties can result in less positive outcomes for the veteran. Therefore, treatments targeting family and parent-child functioning have the potential to promote veterans' recovery. This article reviews literature related to child mental health, parenting, and veteran outcomes and calls for research regarding the implementation of parenting interventions at facilities which provide mental health care to veterans, such as VA medical centers. Using an example treatment, Parent-Child Interaction Therapy (PCIT), the authors outline the components needed to make a parenting intervention most useful to veterans. Challenges to implementation are outlined, including policy, resource, and population-specific factors. Research directions related to each challenge are also discussed, emphasizing the ability of interventions such as PCIT to adapt to serve new populations, and the ability of the VA to adapt to provide ideal services to veterans. PMID- 23088403 TI - Alcohol expectancies, perceived norms, and drinking behavior among college students: examining the reciprocal determinism hypothesis. AB - Social learning mechanisms, such as descriptive norms for drinking behavior (norms) and positive alcohol expectancies (PAEs), play a major role in college student alcohol use. According to the principle of reciprocal determinism (Bandura, 1977), norms and PAEs should be reciprocally associated with alcohol use, each influencing one another over time. However, the nature of these prospective relationships for college students is in need of further investigation. This study provided the first examination of the unique reciprocal associations among norms, PAEs, and drinking together in a single model. PAEs become more stable with age, whereas norms are likely to be more dynamic upon college entry. Thus, we hypothesized that alcohol use would show stronger reciprocal associations with norms than with PAEs for college students. Students (N = 557; 67% women) completed online measures of PAEs, norms, and quantity and frequency of alcohol use in September of their first (T1), second (T2), and third (T3) years of college. Reciprocal associations were analyzed using a cross-lagged panel design. PAEs had unidirectional influences on frequency and quantity of alcohol use, with no prospective effects from alcohol use to PAEs. Reciprocal associations were observed between norms and alcohol use, but only for quantity and not for frequency. Specifically, drinking quantity prospectively predicted quantity norms and quantity norms prospectively predicted drinking quantity. This effect was observed across both years in the model. These findings support the reciprocal determinism hypothesis for norms but not for PAEs in college students and may help to inform norm-based interventions. PMID- 23088404 TI - Consistency of daily cigarette smoking amount in dependent adults. AB - Self-reported cigarettes per day (CPD) is a very common screening as well as dependent or independent measure in clinical and nonclinical research on smoking, but the consistency of CPD across days in dependent smokers is uncertain. Adult dependent smokers (N = 357; 170 men, 187 women) retrospectively reported "usual" CPD at screening and then prospectively self-monitored CPD on 3 consecutive days of 1 week during an ad libitum baseline period. Participants were those recruited for later tests of brief medication effects in those with high (n = 170) versus low (n = 187) interest in quitting smoking soon (within 3 months). Consistency was determined by intraclass correlation (ICC). Prospective daily CPD was generally consistent (ICC = 0.78, 95% CI of 0.74-0.81), but CPD changed (increased or decreased) by 5 cigarettes/day or more in 40% of participants and by at least 10/day in 10%. Consistency in CPD was greater in higher dependent smokers and in women with low (vs. high) quit interest, but consistency tended to be greater in men with high (vs. low) quit interest. Although retrospectively reported CPD at screening was consistent with the overall mean for prospectively monitored daily CPD, 15% of participants differed by at least 5/day between methods, and digit bias was twice as likely with retrospective versus prospective CPD, which was at chance levels. Understanding variability in CPD may improve knowledge of dependence and factors that foster or discourage daily smoking amount, but precise assessment of daily CPD likely requires prospective monitoring. PMID- 23088405 TI - Outcome expectancy liking: a self-generated, self-coded measure predicts adolescent substance use trajectories. AB - This study tested the predictive validity of a novel, brief, and easy-to-use self report measure of expectancies and their subjective values for alcohol and marijuana use. Canadian students in Grades 7 to 11 were administered paper-and pencil questionnaires once per year for 3 consecutive years (Krank et al., 2011). As part of the questionnaire, participants completed an outcome expectancy measure where they were asked to list 3 or 4 things they expected would happen if they used a particular substance (i.e., alcohol, marijuana) and to indicate for each whether they would or would not like this outcome. "Liking" outcomes were coded as +1, "not like" as -1, and summed to obtain an outcome expectancy liking (OEL) sum for each participant and each substance. Participants also completed substance use behavior questions for alcohol and marijuana. Multilevel modeling demonstrated that OEL sum significantly predicted the intercept and slope of substance use trajectories by participants, even when demographic variables were controlled. For both alcohol and marijuana, multilevel modeling analyses indicated that a more positive OEL sum for a substance in the first year of the study were more likely to have tried that substance earlier (intercept) and were more likely to escalate their use at a greater rate over time (slope). The results complement the predictive validity found with other direct and indirect measures of substance use associations. The outcome expectancy liking task is a simple and unobtrusive method for identifying adolescents who are at risk for early substance abuse. PMID- 23088407 TI - The interaction of approach-alcohol action tendencies, working memory capacity, and current task goals predicts the inability to regulate drinking behavior. AB - The inability to regulate alcohol consumption has been attributed to an imbalance between stimulus-driven behavioral biases, or action tendencies, and the ability to exert goal-directed control, or working memory capacity (WMC). Previous research assessing the interaction between these variables has not considered the effect of whether individuals' current goals or task demands require goal directed control. Our aim was to examine the potential interaction of appetitive action tendencies and the ability to exert control over these action tendencies as a function of whether task demands require applying control for successful task completion. Two groups of social drinkers (n = 40 per group) who differed in their ability to regulate their alcohol consumption completed a novel variant of the Approach-Avoidance Task (AAT), which separately assessed approach and avoid trials. The approach and avoidance responses differentially require goal-directed control, depending on whether the task-relevant response is incongruent with the stimulus-driven action tendency. Results indicated that (a) group differences in AAT indices were only observed on trials that required an avoidance movement, which are trials where the task-relevant response would be incongruent with an approach action tendency, and (b) the extent of the group differences for these avoidance trials was moderated by individual differences in WMC, such that problem drinkers with lower WMC showed greater behavioral bias toward alcohol than those with higher WMC. These findings suggest that difficulties in regulating alcohol consumption arise from a complex interaction of action tendencies, WMC, and current goals or task demands. PMID- 23088406 TI - Drinking less and drinking smarter: direct and indirect protective strategies in young adults. AB - Efforts to increase the use of protective behavioral strategies are a common component in interventions for young adult drinking. Some strategies, including those utilized while drinking, are directly correlated with lower drinking levels (cf. Martens et al., 2005). Other strategies, however, may be indirectly related to drinking and instead be more closely associated with alcohol-related consequences. Two studies assessed the Protective Strategies Questionnaire (PSQ; Palmer, 2004), which may be well suited to the assessment of direct and indirect strategies. In Study 1, data from a sample of undergraduate drinkers (N = 370) [corrected] was used to examine the structure of the PSQ with principle components analysis (PCA) and confirmatory factor analysis (CFA). In Study 2, data from a clinical sample of young adult drinkers (N = 168) [corrected] was used to replicate the CFA model. In both studies, relationships among the factors, alcohol use, and consequences were examined. PCA and CFA in split halves of the undergraduate sample and CFA in the clinical sample confirmed two factors: a Direct Strategies (e.g., "space drinks out over time") factor and an Indirect Strategies (e.g., "have a designated driver") factor. Direct strategies were associated with lower alcohol consumption. Indirect strategies were less strongly associated with drinking but were associated with fewer alcohol-related consequences. Interventions for young adult drinking may be tailored to patient goals to decrease consumption and/or consequences. PMID- 23088408 TI - Acceptance of non-abstinence goals by addiction professionals in the United States. AB - Previous research has found relatively limited acceptance of nonabstinence goals in addiction treatment settings in the United States. Because such attitudes may have changed over time, this study was designed to assess the current acceptance of nonabstinence goals by addiction professionals as a function of type of substance (alcohol vs. drug), severity of the disorder (DSM-IV abuse vs. DSM-IV dependence), and finality of the outcome goal (intermediate vs. final). The sample comprised 913 members of a national association of addiction professionals who completed a web-based survey. Over one half of respondents rated nonabstinence as somewhat or completely acceptable as both an intermediate and final outcome goal for clients with alcohol abuse, but considerably smaller proportions rated nonabstinence an acceptable intermediate or final outcome goal for clients with alcohol dependence. Regarding drug-taking clients, one half and one third of respondents rated nonabstinence at least somewhat acceptable as an intermediate goal and final outcome goal, respectively, for clients with drug abuse, but fewer rated nonabstinence an acceptable outcome goal for clients with drug dependence. One implication of the findings is that individuals with alcohol and drug problems who avoid treatment because they are ambivalent about abstinence should know that--depending on the severity of their condition, the finality of their nonabstinence goal, and their drug of choice--their interest in moderating their consumption will be acceptable to many clinicians, especially those working in outpatient and independent practice settings. PMID- 23088409 TI - Pre-college pregaming: practices, risk factors, and relationship to other indices of problematic drinking during the transition from high school to college. AB - This study examined alcohol use and pregaming (i.e., drinking before going out) in the transition from high school to college and had 3 objectives: (1) evaluating pregaming prevalence and characteristics during this time, (2) determining whether it represents a unique risk for problematic drinking above and-beyond traditional measures of consumption (i.e., quantity/frequency: QFI, and heavy episodic drinking: HED), and (3) identifying characteristics of individuals who pregame. Alcohol use and beliefs (i.e., self-reported quantity/frequency, pregaming practices, drinking game participation, alcohol related problems, and expectancies) were assessed in entering freshmen (N = 1171) with prior alcohol use for the 3 months between high school and starting college. Results revealed that 65% of drinkers pregamed in the past, and most did so on fewer than 50% of their overall drinking occasions, consuming an average of 3 drinks in 27 min and most (87%) drank afterward. Hierarchical regression analyses indicated that pregaming frequency explained an additional 7.0% of variance in problematic alcohol use above-and-beyond overall drinking and demographic risk factors (e.g., gender, ethnicity, and Greek affiliation: R2 = .43 for overall model). Separate analyses indicated that demographics did not moderate the relationship between pregaming and problems. Regression analyses predicting pregaming frequency identified 7 characteristics associated with this outcome including demographics (gender, ethnicity, Greek affiliation), heavy drinking, drinking game frequency, and 2 scales of the Alcohol Expectancy Inventory (AEI: Attractive and Woozy). Findings implicate pregaming as a common practice during the transition to college, and highlight the need for additional studies examining pregaming changes across the freshman year. PMID- 23088410 TI - Identifying indicators of reactivity for chemical reductants in sediments. AB - To conduct site-specific exposure assessments for contaminants containing reducible functional groups, it is imperative to know the identity and reactivity of chemical reductants in natural sediments and to associate their reactivity with easily measurable sediment properties. For this purpose the reactivity, as defined by pseudofirst order reduction rate constants for p-cyanonitrobenzene (pCNB), was measured in twenty-one natural sediments of different origins that were incubated to attain both anoxic (less reducing) and anaerobic (microbially reducing) conditions. The reactivity of the anoxic sediments increased with pH and an increasing amount of Fe(II) added. A good electron balance between pCNB reduction and Fe(II) consumption was observed for anaerobic sediments of high solids loading (50 g/L), but not when solids loading was 5 g/L. Based on cluster and regression analysis, pCNB reactivity in the anaerobic sediments correlates strongly with aqueous Fe(II) concentrations for sediments with low organic carbon (OC) content (<4.2%), but with dissolved OC concentrations (DOC) for the sediments with high OC content (>6.4%). These observations indicate surface associated Fe(II) and reduced DOC are the predominant reductants in the anaerobic sediments, and that aqueous Fe(II) and DOC will serve as readily measurable indicators of pCNB reactivity in these systems. PMID- 23088411 TI - The origin of life: look up and look down. PMID- 23088413 TI - Inhibition of charge disproportionation of MnO2 electrocatalysts for efficient water oxidation under neutral conditions. AB - The development of Mn-oxide electrocatalysts for the oxidation of H(2)O to O(2) has been the subject of intensive researches not only for their importance as components of artificial photosynthetic systems, but also as O(2)-evolving centers in photosystem II. However, limited knowledge of the mechanisms underlying this oxidation reaction hampers the ability to rationally design effective catalysts. Herein, using in situ spectroelectrochemical techniques, we demonstrate that the stabilization of surface-associated intermediate Mn(3+) species relative to charge disproportionation is an effective strategy to lower the overpotential for water oxidation by MnO(2). The formation of N-Mn bonds via the coordination of amine groups of poly(allylamine hydrochloride) to the surface Mn sites of MnO(2) electrodes effectively stabilized the Mn(3+) species, resulting in an ~500-mV negative shift of the onset potential for the O(2) evolution reaction at neutral pH. PMID- 23088412 TI - Multifactorial resistance of Bacillus subtilis spores to high-energy proton radiation: role of spore structural components and the homologous recombination and non-homologous end joining DNA repair pathways. AB - The space environment contains high-energy charged particles (e.g., protons, neutrons, electrons, alpha-particles, heavy ions) emitted by the Sun and galactic sources or trapped in the radiation belts. Protons constitute the majority (87%) of high-energy charged particles. Spores of Bacillus species are one of the model systems used for astro- and radiobiological studies. In this study, spores of different Bacillus subtilis strains were used to study the effects of high energetic proton irradiation on spore survival. Spores of the wild-type B. subtilis strain [mutants deficient in the homologous recombination (HR) and non homologous end joining (NHEJ) DNA repair pathways and mutants deficient in various spore structural components such as dipicolinic acid (DPA), alpha/beta type small, acid-soluble spore protein (SASP) formation, spore coats, pigmentation, or spore core water content] were irradiated as air-dried multilayers on spacecraft-qualified aluminum coupons with 218 MeV protons [with a linear energy transfer (LET) of 0.4 keV/MUm] to various final doses up to 2500 Gy. Spores deficient in NHEJ- and HR-mediated DNA repair were significantly more sensitive to proton radiation than wild-type spores, indicating that both HR and NHEJ DNA repair pathways are needed for spore survival. Spores lacking DPA, alpha/beta-type SASP, or with increased core water content were also significantly more sensitive to proton radiation, whereas the resistance of spores lacking pigmentation or spore coats was essentially identical to that of the wild-type spores. Our results indicate that alpha/beta-type SASP, core water content, and DPA play an important role in spore resistance to high-energy proton irradiation, suggesting their essential function as radioprotectants of the spore interior. PMID- 23088414 TI - Secondary prevention of stroke in Saskatchewan, Canada: hypertension control. AB - BACKGROUND: In the province of Saskatchewan, Canada, stroke is the third leading cause of death as well as the major cause of adult disability. Once a person suffers a stroke or transient ischemic attack (TIA), they are at high risk for having a secondary stroke. Hypertension (elevated blood pressure) is the single most important modifiable risk factor for both first and recurrent stroke, and is thus an important risk factor to be controlled. According to the Canadian Stroke Strategy (CSS) Best Practice Recommendations, blood pressure lowering treatment should be initiated before discharge from hospital for all stroke/TIA patients. The purpose of this study was to examine the quality of medically driven secondary stroke prevention care in Saskatchewan as applied to hypertension control. AIMS: The objectives of the study were to: (1) develop methodology and calculate a secondary stroke process of care measure using available data in Saskatchewan, based on an appropriate hypertension therapy indicator recommendation from the CSS Performance Measurement Manual; (2) examine variation in secondary stroke prevention hypertensive care among the Saskatchewan Regional Health Authorities; and (3) investigate factors associated with receiving evidence-based hypertensive secondary stroke prevention. METHODS: This multi-year cross-sectional study was an analysis of deidentified health data derived from linkage of administrative health data. A select indicator from the CSS Performance Measurement Manual that measures adherence to a CSS Best Practice Guidelines concerning use of antihypertensive medications for secondary stroke prevention was calculated. Logistic regression was used to quantify the association of patient demographic and socioeconomic characteristics and geographic location of care with receipt of guideline-recommended hypertensive secondary stroke prevention. The target population was all Saskatchewan residents who were hospitalized in Saskatchewan for a stroke or TIA between April 1, 2001 and March 31, 2008. RESULTS: The results of this study indicate that the management of hypertension for secondary stroke prevention is sub-optimal in Saskatchewan. Although there was some improvement over the time period, approximately 40% of patients were not taking antihypertensives at 90 days after discharge from acute care. The correlates, urban/non-urban, previous use of antihypertensive drugs and effect of age modified by sex, were found to be significantly associated with receiving hypertensive secondary stroke prevention, suggesting there are modifiable factors that contribute to variations in this form of secondary stroke care quality in Saskatchewan. CONCLUSIONS: The results of this study suggest that there is a need for province-wide improvement to secondary stroke prevention in Saskatchewan, Canada. PMID- 23088415 TI - Bis(amidinato)germylenerhodium complexes: synthesis, structure, and density functional theory calculations. AB - The first monogermylenerhodium complexes stabilized by bulky amidinato ligands on the divalent germanium center have been synthesized and characterized by NMR spectroscopy and X-ray crystallography. Their stability strongly depends on the steric hindrance of the amidinato ligand. With trimethysilyl groups on the nitrogen atoms of the amidinato ligand, only the germylene oxide rhodium complex could be obtained; by contrast, with t-Bu groups, the germylenerhodium complex was isolated. In both cases, the formation of amidinatorhodium complexes was observed. The donating ability of the germylene ligand has been assessed from the CO stretching frequency of the corresponding dicarbonylrhodium complex and was confirmed by density functional theory calculations. PMID- 23088416 TI - Tenotomy versus tenodesis in the treatment of the long head of biceps brachii tendon lesions. AB - BACKGROUND: The superiority of tenotomy vs. tenodesis for surgery on lesions of the long head of the biceps brachii tendon is still under debate. Indeed, high quality evidence is lacking, mainly because of methodological problems, such as retrospective design, population sample size or lack of patient randomization. METHODS/DESIGN: The study will be a two-center, double-blind, randomized, controlled trial to compare patients treated with biceps tenotomy or tenodesis for lesions of the long head of the biceps brachii tendon over a 2-year follow-up period. The study participants will be 128 adults with biceps brachii tendinopathy and supraspinatus tendon tears. The primary end point will be the postoperative difference in the Constant-Murley score (CMS) between the 2 groups at the two-year follow-up. A comparison of the mean improvement with standard age and gender-related CMS will be performed. The secondary end point will be evaluation of the postoperative general health of patients, as evaluated with Short Form 36 (SF-36) scores. The number and severity of complications associated with use of the different surgical techniques will be assessed. DISCUSSION: This study will be the first randomized and appropriately powered clinical trial to directly compare tenotomy and biceps tenodesis. The results of this study will help to establish clinical practice guidelines for patients suffering from lesions of the long head of the biceps brachii tendon, providing important information to patients and health care providers about the possible complications, outcome predictors and effectiveness of the targeted interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN38839558. PMID- 23088417 TI - Two approaches for repeat cardiac surgery. AB - BACKGROUND: With recent advances in post-operative care and surgical methods, the number of cardiovascular re-operations is increasing. We analyzed our institutional experience to evaluate the safety and efficacy of the approach methods for cardiac re-operations. METHODS: Between September 2007 and December 2010, we performed 208 cardiac re-operations, defined as surgery which was not performed within a month from the previous operation or during the same hospitalization for the same disease and reviewed retrospectively. According to the surgical approach, we divided patients into two groups: median sternotomy group (S-group, n = 146), and thoracotomy group (T-group, n = 62). RESULTS: There were no differences in sex or mean interval from the first surgery to re operation between the two groups. Mean cardiopulmonary bypass, adhesion dissection time, bleeding control time, and operation time were significantly shorter in the T-group. The need for transfusion (p = 0.001) during adhesion dissection and the chest tube drainage (p < 0.001) were significantly lower in the T-group. There were 10 operative deaths in the S-group (6.8%) and 5 in the T group (8.1%) (p = 0.757). Pneumonia was the most common cause of death in both groups. Post-operative bleeding did not result in death and there were no cases of wound infection in the T-group. CONCLUSIONS: Two approaches for repeated cardiac surgery were safe and effective in terms of mortality, wound infection, bleeding, operation time, adhesion dissecting time, and bleeding control time. We were able to obtain a good visual field and perform safe surgery by applying the thoracotomy method in selective patients for cardiovascular re-operation. PMID- 23088418 TI - Two new lignans from the stems of Schisandra bicolor. AB - Two new lignans, named zuihonins E (1) and F (2), were isolated from the stems of Schisandra bicolor Cheng var. tuberculata Law. The structures of the new lignans were elucidated on the basis of extensive spectroscopic analysis, including 1D, 2D NMR, and MS experiments, and their absolute stereochemistry was determined by circular dichroism spectrum. Compounds 1 and 2 did not inhibit the growth of hepatoma carcinoma cell (HepG2), lung carcinoma cell (A549), and human breast carcinoma (MCF-7) cell lines. PMID- 23088419 TI - Simple and accurate bedside diagnostic kit for determining haemophilia A and B: a revised version. PMID- 23088420 TI - Prevalence, molecular characteristics and risk factors for cryptosporidiosis among Iranian immunocompromised patients. AB - Cryptosporidium spp. is a major cause of diarrhea in developing countries, mainly affecting people with compromised immune systems in general and HIV-infected individuals with low CD4 + T-cell counts in particular. This infection is self limiting in healthy persons; however, it can be severe, progressive and persistent in those who are immunocompromised. There are few published studies concerning cryptosporidiosis and Cryptosporidium genotypes in Iranian immunocompromised patients and none of them describe risk factors. This study was undertaken to identify prevalence, genotypes and risk factors for cryptosporidiosis in immunocompromised patients. Three fecal samples were obtained at two day intervals from each of the 183 patients and processed with modified Ziehl-Neelsen staining methods and 18S rRNA gene amplification and sequencing. The overall infection prevalence was 6%. Cryptosporidium parvum was identified in isolates from five HIV-infected patients, one patient who had undergone bone marrow transplantation and one with chronic lymphocytic leukemia. Cryptosporidium hominis was identified in isolates from two HIV-infected patients and two patients with acute lymphocytic leukemia. According to univariate analysis, the statistically significant factors were diarrhea (OR = 21.7, CI = 2.83-78.4, P= 0.003), CD4 + lymphocytes less than 100 cells/mm(3) (OR = 41.3, CI = 13.45-114.8, P < 0.0001), other microbial infections (OR = 7.1321.7, CI = 1.97 25.73, P = 0.006), weight loss (OR = 73.78, CI = 15.5-350, P < 0.0001), abdominal pain (OR = 10.29, CI = 2.81-37.74.4, P= 0.001), dehydration (OR = 72.1, CI = 17.6 341.5, P < 0.0001), vomiting (OR = 4.87, CI = 1.4-16.9, P= 0.015), nausea (OR = 9.4, CI = 2.38-37.2, P < 0.001), highly active antiretroviral therapy (OR = 0.089, CI = 0.01-0.8, P= 0.015) and diarrhea in household members (OR = 7.37, CI = 2.04-26.66, P= 0.001). After multivariate analysis and a backward deletion process, only < 100 CD4 + T-lymphocytes/mm(3) maintained a significant association with infection. The authors recommend that this infection should be suspected in patients with diarrhea, weight loss and dehydration in general and in diarrheal individuals with < 100 CD4 + T-lymphocytes/mm(3). PMID- 23088421 TI - Does a medical management program for CKD patients postpone renal replacement therapy and mortality? A 5-year-cohort study. AB - BACKGROUND: Many countries have started screening and prevention programs for chronic kidney disease (CKD). However, one of the main concerns of health authorities is whether management strategies for diagnosed CKD patients can decrease mortality or morbidity. This study aimed to investigate the effect of two competing clinical strategies of treatments under nephrologists' supervision compared with no treatment on the frequency of the need to start renal replacement therapy (RRT) and mortality in CKD patients. METHODS: Our cohort comprised consecutive newly diagnosed patients with CKD in an outpatient clinic in Tehran between October 2002 and October 2011. CKD Patient enrollment occurred if two criteria of high plasma creatinine level and chronicity of renal disease by at least 3 months of clinical history or small sized kidneys in ultrasound findings were met. Demographic data and time of RRT or mortality in patients who had been followed up regularly were compared with those in the control group. The control group included those patients who did not attend a nephrology clinic to receive CKD management package for at least 1 year during the study period. RESULTS: The cohort included 76 patients in the control group and 389 patients in the supervised group. The mean age of the patients was 61.33+/-14.9 years (16-95 years). The ratio of males/females was 1.47 (277/188). The mean follow-up in the control and supervised groups was 33.29+/-20.50 (7-111) and 36.03+/-25.24 (6-124) months , respectively, and the total patient years of follow-up was 1382.3. A substantial number of patients survived without RRT until the first year of follow up (96%) in both groups, but afterward, those in the control group had more deaths or need to start RRT in comparison with those who received medical advice (20 vs. 67 months; p= 0.029). This cohort also showed a higher survival and a longer time to show a GFR of less than 15 cc/min (84 vs 34 months, p<0.0001) in patients who had been under physician supervision compared with the control group. CONCLUSIONS: Active follow-up of CKD patients appears to significantly decrease the risk of death or progression to end-stage renal disease and the requirement to start renal replacement therapy. PMID- 23088422 TI - Determination of pre-steady-state rate constants on the Escherichia coli pyruvate dehydrogenase complex reveals that loop movement controls the rate-limiting step. AB - Spectroscopic identification and characterization of covalent and noncovalent intermediates on large enzyme complexes is an exciting and challenging area of modern enzymology. The Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc), consisting of multiple copies of enzymic components and coenzymes, performs the oxidative decarboxylation of pyruvate to acetyl-CoA and is central to carbon metabolism linking glycolysis to the Krebs cycle. On the basis of earlier studies, we hypothesized that the dynamic regions of the E1p component, which undergo a disorder-order transition upon substrate binding to thiamin diphosphate (ThDP), play a critical role in modulation of the catalytic cycle of PDHc. To test our hypothesis, we kinetically characterized ThDP-bound covalent intermediates on the E1p component, and the lipoamide-bound covalent intermediate on the E2p component in PDHc and in its variants with disrupted active-site loops. Our results suggest that formation of the first covalent predecarboxylation intermediate, C2alpha-lactylthiamin diphosphate (LThDP), is rate limiting for the series of steps culminating in acetyl-CoA formation. Substitutions in the active center loops produced variants with up to 900-fold lower rates of formation of the LThDP, demonstrating that these perturbations directly affected covalent catalysis. This rate was rescued by up to 5-fold upon assembly to PDHc of the E401K variant. The E1p loop dynamics control covalent catalysis with ThDP and are modulated by PDHc assembly, presumably by selection of catalytically competent loop conformations. This mechanism could be a general feature of 2-oxoacid dehydrogenase complexes because such interfacial dynamic regions are highly conserved. PMID- 23088423 TI - Surveying the epigenomic landscape, one base at a time. AB - Epigenomics, the determination of epigenetic landscapes on a genome-wide scale, has progressed at an astounding rate over the past decade. Recent technological developments have enabled base-pair resolution of various epigenomic features, leading to new insights into epigenetic regulation. PMID- 23088425 TI - SPLINTED ZIRCONIA FIXED PARTIAL DENTURE SUPPORTED BY MINI IMPLANTS IN THE POSTERIOR MANDIBLE: A CASE REPORT. AB - Abstract One of the most frequently extracted tooth is the mandibular molar. A highly accepted and elegant solution is to replace the missing molar with an endossous implant and a fixed crown. A biologically, anatomically and physiologically appropriate solution could be to replace the two roots of the missing molar with two implants. One way to incorporate the use of two implants to support a molar sized crown is to use implants of smaller diameter. Mini implants may successfully support fixed partial dentures in the posterior mandible in highly selected patients with an appropriate prosthetic design and occlusal scheme. Jaw forces, bone quality and volume are edentulous site conditions that may affect treatment decisions. The implant dentist should consider many diverse implant and prosthetic designs to appropriately treat the atrophic mandible. Zirconia splinted crowns supported by mini dental implants may be an effective treatment for selected posterior sites. PMID- 23088424 TI - Composites with macroporous poly(vinyl alcohol) cryogels with attached activated carbon microparticles with controlled accessibility of a surface. AB - A set of glutaraldehyde (GA) cross-linked poly(vinyl alcohol)/activated carbon (PVA/GA/AC) composites prepared in the form of monolithic rods using a cryogelation technique and studied using adsorption, mercury porosimetry, scanning electron microscopy (SEM), and quantum chemistry methods display porosity similar to that of PVA/GA cryogel at a high GA content (content ratio GA/AC = 1 and GA/PVA = 0.2). GA cross-linked PVA multilayer coverage is an effective barrier for adsorption on AC particles. Variations in surface chemistry (AC initial and oxidized in air at 300 degrees C for 12 h) and content (14 62.5%w/w) of ACs in PVA/GA/AC composites relatively weakly affect their textural characteristics at a high GA content (specific surface area S(BET) < 120 m2/g, pore volume V(p) < 0.35 cm3/g). However, PVA/GA/AC composite rods formed with a lower concentration of GA (content ratio GA/AC = 1/6 and GA/PVA = 1/10) have significantly greater S(BET) (~500 m2/g) and V(p) (>0.55 cm3/g) values because of improved accessibility of the AC surface. This provides better adsorption of methylene blue as a probe compound. PMID- 23088427 TI - Mild acute stress reactivates memory of a discriminative avoidance task in mice. AB - Previous studies have demonstrated that stress or glucocorticoids impair the retrieval of spatial memory in rodents and declarative memory in humans. However, the effects on memory retrieval of stress introduced a long time after learning have not been well studied. We investigated whether a mild, extrinsic stressor (1 s 0.1 or 0.3 mA foot shock) would reactivate low baseline retrieval of an aversive memory [the plus-maze discriminative avoidance task (PM-DAT)] and if it would be modulated by glucocorticoids. In Experiment 1, male Swiss mice received pre-test foot shock (n = 10 mice/group) 7 days after training and just before testing. A time-retrieval curve for low baseline retrieval for the subsequent experiments was also determined (Experiment 2, n = 10 mice/group). We investigated if pre-test foot shock could modify corticosterone release (Experiment 3, n = 8-9 mice/group) and reinstate retrieval in the PM-DAT (Experiment 4, n = 15 mice/group). The effects of metyrapone (100 mg/kg) on retrieval reinstatement (Experiment 5, n = 15 mice/group) and serum corticosterone enhancement (Experiments 6, n = 7-9 mice/group) induced by foot shock were analyzed. Finally, the effects of foot shock itself on PM-DAT exploration were verified (Experiment 7, n = 10 mice/group). We demonstrated here that foot shock reinstated the retrieval of a low baseline, discriminative avoidance task 30 (but not 7) days after training. This facilitative effect was not dependent on corticosterone secretion because metyrapone abolished the enhancement of corticosterone concentration but did not reverse the stress induced reinstatement of retrieval. PMID- 23088426 TI - Lower mortality for abdominal aortic aneurysm repair in high-volume hospitals is contingent upon nurse staffing. AB - OBJECTIVE: To determine whether and to what extent the lower mortality rates for patients undergoing abdominal aortic aneurysm (AAA) repair in high-volume hospitals is explained by better nursing. DATA SOURCES: State hospital discharge data, Multi-State Nursing Care and Patient Safety Survey, and hospital characteristics from the AHA Annual Survey. STUDY DESIGN: Cross-sectional analysis of linked patient outcomes for individuals undergoing AAA repair in four states. DATA COLLECTION: Secondary data sources. PRINCIPAL FINDINGS: Favorable nursing practice environments and higher hospital volumes of AAA repair are associated with lower mortality and fewer failures-to-rescue in main-effects models. Furthermore, nurse staffing interacts with volume such that there is no mortality advantage observed in high-volume hospitals with poor nurse staffing. When hospitals have good nurse staffing, patients in low-volume hospitals are 3.4 times as likely to die and 2.6 times as likely to die from complications as patients in high-volume hospitals (p < .001). CONCLUSIONS: Nursing is part of the explanation for lower mortality after AAA repair in high-volume hospitals. Importantly, lower mortality is not found in high-volume hospitals if nurse staffing is poor. PMID- 23088428 TI - A buried ionizable residue destabilizes the native state and the transition state in the folding of monellin. AB - A buried ionizable residue can have a drastic effect on the stability of a native protein, but there has been only limited investigation of how burial of an ionizable residue affects the kinetics of protein folding. In this study, the effect of burial of ionizable residues on the thermodynamics and kinetics of folding and unfolding of monellin has been investigated. The stability of wild type (wt) monellin is known to decrease with an increase in pH from 4 to 10. The Glu24 -> Ala mutation makes the stability of the resultant E24A mutant protein independent of pH in the range from 4 to 8. An additional mutation, Cys42 -> Ala, results in the stability becoming independent of pH in the range from 4 to 10. Like the wt protein, E24A folds via very fast, fast, and slow folding pathways. Compared to that of the wt protein, the rate of slow folding pathway of E24A is ~7-fold faster, the rate of fast folding pathway is ~1.5-fold faster, while the rate of very fast folding pathway is similar. E24A unfolds ~7-fold slower than the wt. The extent of stabilization of the transition state (TS) observed for the slow pathway of refolding and for unfolding is the same, indicating that unfolding occurs via the TS populated on the slow pathway of refolding. The stabilization of the TS of folding (1.1 kcal mol(-1)) is less than that of the native state (2.3 kcal mol(-1)) of E24A, indicating that structure has only partially formed in the vicinity of Glu24 in the TS of folding. PMID- 23088429 TI - Which controls wetting? Contact line versus interfacial area: simple experiments on capillary rise. AB - Working equations that describe wetting phenomena can be derived in a variety of ways starting from capillary forces, Laplace pressure, or solid surface energies. We examined the relative importance of the contact line and interfacial areas in the capillary rise inside small diameter glass tubes. A series of simple experiments demonstrate that this wetting phenomenon is controlled by interactions in the vicinity of the contact line. PMID- 23088430 TI - Spray water reactivation/pelletization of spent CaO-based sorbent from calcium looping cycles. AB - This paper presents a novel method for reactivation of spent CaO-based sorbents from calcium looping (CaL) cycles for CO(2) capture. A spent Cadomin limestone derived sorbent sample from a pilot-scale fluidized bed (FBC) CaL reactor is used for reactivation. The calcined sorbent is sprayed by water in a pelletization vessel. This reactivation method produces pellets ready to be used in FBC reactors. Moreover, this procedure enables the addition of calcium aluminate cement to further enhance sorbent strength. The characterization of reactivated material by nitrogen physisorption (BET, BJH) and scanning electron microscopy (SEM) confirmed the enhanced morphology of sorbent particles for reaction with CO(2). This improved CO(2) carrying capacity was demonstrated in calcination/carbonation tests performed in a thermogravimetric analyzer (TGA). Finally, the resulting pellets displayed a high resistance to attrition during fluidization in a bubbling bed. PMID- 23088431 TI - An economical and practical method for whole-mount in situ hybridization for mouse embryos and organs. AB - Whole-mount in situ hybridization (WISH) is a useful method for detecting specific gene expression patterns at their site of action during embryonic development. Traditional WISH methods are costly and suitable only for mouse embryos younger than 11.5 days. We present here an economical and practical in situ hybridization method using DIG-labeled RNA probes. We changed the conditions in several steps to make the WISH method suitable for whole mouse embryos from embryonic days 9.5 to 12.5 and for older stage mouse embryonic organs. We performed all steps in one microcentrifuge tube up to the staining steps to avoid losing or damaging the mouse embryos. We re-used the solutions and materials to make the method more economical and suitable for less sophisticated laboratories. We also performed beta-galactosidase staining on Tb * 18 Cre/Rosa26/LacZ mouse embryos; the results agreed with the in situ hybridization results. Finally, we sectioned the specimens after hybridization and beta-galactosidase staining; the results agreed with the literature. PMID- 23088432 TI - Cytodiagnosis of malignant transformation in a solitary osteochondroma: report of a rare case with a literature review. PMID- 23088433 TI - Psychotherapies provided for eating disorders by community clinicians: infrequent use of evidence-based treatment. AB - This study describes the psychological interventions used for eating disorders (EDs) by community practitioners. Of 573 clinicians we screened across Alberta, 130 (22.7%) had treated EDs; 118 (90.8%) were interviewed. Clinicians reported varied reasons for psychotherapy choice and diverse training experiences; the primary approaches used varied by education and field. The most common primary approach was eclectic (43.2%), followed by cognitive-behavior therapy (CBT; 22.9%). However, self-reported CBT clinicians used specific CBT techniques infrequently. Half of clinicians incorporated addictions-based techniques. These results indicate that ED treatment provided by community clinicians is varied and generally does not align with evidence-based practice guidelines. PMID- 23088434 TI - Job-related strain and sexual health difficulties among heterosexual men from three European countries: the role of culture and emotional support. AB - INTRODUCTION: Epidemiological evidence for the association between job-related stress and sexual difficulties in men is largely lacking. Little is known about the factors that may mediate or moderate this relationship. AIM: This study analyzes the association between job-related difficulties and men's sexual difficulties. MAIN OUTCOME MEASURES: Job-related difficulties were measured by 10 yes/no questions that addressed a range of adverse workplace situations. The experience of sexual difficulties in the past 12 months was assessed by using seven dichotomous indicators developed in the National Study of Sexual Attitudes and Lifestyles (NATSAL) 2000. METHOD: Analyses were carried out using data from a 2011 online study of Portuguese, Croatian, and Norwegian men (N = 2,112). Multivariate logistic regression and mediation analysis were used to test the hypothesized association. RESULTS: Men with job-related concerns reported lower sexual satisfaction than men without such concerns did (F = 7.53, P < 0.001). Multivariate analysis confirmed the association between job-related and sexual health concerns. The odds of experiencing one or more sexual health difficulties in the past 12 months were about 1.8 times higher among men who reported the highest levels of workplace difficulties than among men who experienced no such difficulties. The odds of reporting sexual health difficulties were significantly reduced by a higher income (adjusted odds ratio [AOR] = 0.87, P < 0.01), emotional intimacy with one's partner (AOR = 0.93, P < 0.001), having children (AOR = 0.62-0.66, P < 0.01), and country-specific effects (AOR = 1.98-2.22, P < 0.001). In all three countries, the relationship between job-related and sexual health difficulties was mediated by anxiety and depression. CONCLUSIONS: The findings suggest that negative mood is the mechanism behind the association between workplace strain and sexual difficulties. Emotional support, such as couple intimacy and fatherhood, can reduce--independently from sociocultural and socioeconomic factors--the risk of sexual health concerns. PMID- 23088436 TI - Lower urinary tract function in childhood; normal development and common functional disturbances. AB - This review aims to provide researchers and clinicians involved with the adult lower urinary tract with background knowledge regarding the early development of bladder function and its most common disturbances in childhood. Bladder development begins in weeks 4-6 and the detrusor muscle is formed during weeks 9 12 of gestation. Higher CNS centres are involved in micturition at birth, and the infant usually wakes up, at least briefly, to void. Voiding during the first years of life is often incomplete, owing to detrusor-sphincter dyscoordination, but this disappears when bladder control is attained. Approximately 5-10% of 7 year-old children suffer from daytime incontinence and/or nocturnal enuresis, and a few per cent of them will not outgrow it. Daytime incontinence in childhood is usually attributable to detrusor overactivity, although it is unclear to what extent it is the detrusor or the micturition reflex per se that is overactive. Enuresis - nocturnal incontinence - is caused by either nocturnal polyuria and/or nocturnal detrusor overactivity, in both cases combined with high arousal thresholds. Bladder problems in childhood constitute a risk factor for the development or persistence of bladder problems in adulthood. PMID- 23088435 TI - Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells. AB - Exogenous and endogenous damage to DNA is constantly challenging the stability of our genome. This DNA damage increase the frequency of errors in DNA replication, thus causing point mutations or chromosomal rearrangements and has been implicated in aging, cancer, and neurodegenerative diseases. Therefore, efficient DNA repair is vital for the maintenance of genome stability. The general notion has been that DNA repair capacity decreases with age although there are conflicting results. Here, we focused on potential age-associated changes in DNA damage response and the capacities of repairing DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) in human peripheral blood mononuclear cells (PBMCs). Of these lesions, DSBs are the least frequent but the most dangerous for cells. We have measured the level of endogenous SSBs, SSB repair capacity, gamma H2AX response, and DSB repair capacity in a study population consisting of 216 individuals from a population-based sample of twins aged 40-77 years. Age in this range did not seem to have any effect on the SSB parameters. However, gamma-H2AX response and DSB repair capacity decreased with increasing age, although the associations did not reach statistical significance after adjustment for batch effect across multiple experiments. No gender differences were observed for any of the parameters analyzed. Our findings suggest that in PBMCs, the repair of SSBs is maintained until old age, whereas the response to and the repair of DSBs decrease. PMID- 23088437 TI - Extracting the truth from conflicting eyewitness reports: a formal modeling approach. AB - Eyewitnesses often report details of the witnessed crime incorrectly. However, there is usually more than 1 eyewitness observing a crime scene. If this is the case, one approach to reconstruct the details of a crime more accurately is aggregating across individual reports. Although aggregation likely improves accuracy, the degree of improvement largely depends on the method of aggregation. The most straightforward method is the majority rule. This method ignores individual differences between eyewitnesses and selects the answer shared by most eyewitnesses as being correct. We employ an alternative method based on cultural consensus theory (CCT) that accounts for differences in the eyewitnesses' knowledge. To test the validity of this approach, we showed 30 students 1 of 2 versions of a video depicting a heated quarrel between 2 people. The videos differed in the amount of information pertaining to the critical event. Participants then answered questions about the critical event. Analyses based on CCT rendered highly accurate eyewitness competence estimates that mirrored the amount of information available in the video. Moreover, CCT estimates resulted in a more precise reconstruction of the video content than the majority rule did. This was true for group sizes ranging from 4 to 15 eyewitnesses, with the difference being more pronounced for larger groups. Thus, through simultaneous consideration of multiple witness statements, CCT provides a new approach to the assessment of eyewitness accuracy that outperforms standard methods of information aggregation. PMID- 23088438 TI - B-cell maturation antigen, a proliferation-inducing ligand, and B-cell activating factor are candidate mediators of spinal cord injury-induced autoimmunity. AB - Autoimmunity is thought to contribute to poor neurological outcomes after spinal cord injury (SCI). There are few mechanism-based therapies, however, designed to reduce tissue damage and neurotoxicity after SCI because the molecular and cellular bases for SCI-induced autoimmunity are not completely understood. Recent groundbreaking studies in rodents indicate that B cells are responsible for SCI induced autoimmunity. This novel paradigm, if confirmed in humans, could aid in the design of neuroprotective immunotherapies. The aim of this study was to investigate the molecular signaling pathways and mechanisms by which autoimmunity is induced after SCI, with the goal of identifying potential targets in therapies designed to reduce tissue damage and inflammation in the chronic phase of SCI. To that end, we performed an exploratory microarray analysis of peripheral blood mononuclear cells to identify differentially expressed genes in chronic SCI. We identified a gene network associated with lymphoid tissue structure and development that was composed of 29 distinct molecules and five protein complexes, including two cytokines, a proliferation-inducing ligand (APRIL) and B cell-activating factor (BAFF), and one receptor, B-cell maturation antigen (BMCA) involved in B cell development, proliferation, activation, and survival. Real time polymerase chain reaction analysis from ribonucleic acid samples confirmed upregulation of these three genes in SCI. To our knowledge, this is the first report that peripheral blood mononuclear cells produce increased levels of BAFF and APRIL in chronic SCI. This finding provides evidence of systemic regulation of SCI-autoimmunity via APRIL and BAFF mediated activation of B cells through BMCA and points toward these molecules as potential targets of therapies designed to reduce neuroinflammation after SCI. PMID- 23088439 TI - In search of vigilance: the problem of iatrogenically created psychological phenomena. AB - To what extent are identified psychological processes created in laboratories? The present work addresses this issue with reference to one particular realm of behavior: vigilance. Specifically, I argue that the classic vigilance decrement function can be viewed more realistically and advantageously as an "invigilant" increment function. Rather than characterizing the transient decrease in detection capability that is evident on exposure to enforced monitoring as a diminishment in capacity, it may be more usefully seen as an appropriate scaling by the designated observer to adapt to the nonoptimal circumstances that he or she is forced to endure. This proposition emphasizes the dynamic response characteristics of the observer and locates the origin of the phenomenon and the onus for practical improvements in the design of operational displays with designers rather than apportioning blame for performance decrements to the operator. This perspective reinforces the recognition of a crucial presence of the necessary but often unrecognized external arbiter in the vigilance paradigm and the extrinsically imposed imperative to sustain attention. Explicit recognition of this fact also helps explain the stress involved with extended vigils. In identifying the traditional vigilance decrement as a form of iatrogenic disease, I argue that modern design of work systems should alleviate the need for either the acute or the chronic expressions of such enforced human monitoring activity. It is possible that the case of vigilance is itself representative of a modern propensity to create new psychological phenomena in the face of human exposure to modern, evolving technical environments. PMID- 23088441 TI - Synthesis of silenyllithiums Li(R'3Si)Si?C(SiR3)(1-Ad) via transient silyne silylidene intermediates. AB - The first two lithium silenides, Li(tBu(2)MeSi)Si?C(SiMetBu(2))(1-Ad) (1) and Li(tBuMe(2)Si)Si?C(SiMetBu(2))(1-Ad) (2) were prepared by THF addition to the corresponding lithium-silenolates, [(tBu(2)MeSi)(2)Si?C(OLi)(1-Ad)].(R(3)SiLi) (3a: R(3)Si?tBu(2)MeSi, 3b: R(3)Si?tBuMe(2)Si). 1 and 2 were crystallized, and their structures were determined by X-ray crystallography. This process requires the presence of both coaggregated silyllithium (R(3)SiLi) (3a and 3b) and THF. Based on reaction products and DFT calculations, it is suggested that elimination of tBu(2)MeSiOLi from 3a (or 3b) produces first the corresponding silyne intermediate which rearranges to the corresponding silylidene, which is then trapped by R(3)SiLi giving 1 (or 2). PMID- 23088440 TI - The trisomy 18 syndrome. AB - The trisomy 18 syndrome, also known as Edwards syndrome, is a common chromosomal disorder due to the presence of an extra chromosome 18, either full, mosaic trisomy, or partial trisomy 18q. The condition is the second most common autosomal trisomy syndrome after trisomy 21. The live born prevalence is estimated as 1/6,000-1/8,000, but the overall prevalence is higher (1/2500 1/2600) due to the high frequency of fetal loss and pregnancy termination after prenatal diagnosis. The prevalence of trisomy 18 rises with the increasing maternal age. The recurrence risk for a family with a child with full trisomy 18 is about 1%. Currently most cases of trisomy 18 are prenatally diagnosed, based on screening by maternal age, maternal serum marker screening, or detection of sonographic abnormalities (e.g., increased nuchal translucency thickness, growth retardation, choroid plexus cyst, overlapping of fingers, and congenital heart defects ). The recognizable syndrome pattern consists of major and minor anomalies, prenatal and postnatal growth deficiency, an increased risk of neonatal and infant mortality, and marked psychomotor and cognitive disability. Typical minor anomalies include characteristic craniofacial features, clenched fist with overriding fingers, small fingernails, underdeveloped thumbs, and short sternum. The presence of major malformations is common, and the most frequent are heart and kidney anomalies. Feeding problems occur consistently and may require enteral nutrition. Despite the well known infant mortality, approximately 50% of babies with trisomy 18 live longer than 1 week and about 5-10% of children beyond the first year. The major causes of death include central apnea, cardiac failure due to cardiac malformations, respiratory insufficiency due to hypoventilation, aspiration, or upper airway obstruction and, likely, the combination of these and other factors (including decisions regarding aggressive care). Upper airway obstruction is likely more common than previously realized and should be investigated when full care is opted by the family and medical team. The complexity and the severity of the clinical presentation at birth and the high neonatal and infant mortality make the perinatal and neonatal management of babies with trisomy 18 particularly challenging, controversial, and unique among multiple congenital anomaly syndromes. Health supervision should be diligent, especially in the first 12 months of life, and can require multiple pediatric and specialist evaluations. PMID- 23088442 TI - Three new flavonoids from the seeds of Hippophae rhamnoides subsp. sinensis. AB - To study the chemical constituents of the seeds of Hippophae rhamnoides subsp. sinensis, three new flavonoids acylated with one monoterpenic acid, named 3-O beta-D-glucosyl-kaempferol-7-O-{2-O-[2(E)-2,6-dimethyl-6-hydroxy-2,7 octadienoyl]}-alpha-L-rhamnoside (3), 3-O-beta-D-sophorosyl-kaempferol-7-O-{3-O [2(E)-2,6-dimethyl-6-hydroxy-2,7-octadienoyl]}-alpha-L-rhamnoside (4), and 3-O beta-D-sophorosyl-kaempferol-7-O-{2-O-[2(E)-2,6-dimethyl-6-hydroxy-2,7 octadienoyl]}-alpha-L-rhamnoside (5), together with four known compounds, were isolated from the seeds of H. rhamnoides subsp. sinensis. Compounds 1 and 2 are reported for the first time from this genus. Their structures were elucidated on the basis of chemical and spectral analysis, including 1D and 2D NMR and HR-MS, and by comparison with literature data. PMID- 23088443 TI - Evaluation of stain removal and inhibition properties of eight denture cleansers: an in vitro study. AB - OBJECTIVES: To determine the ability of eight denture cleansers to remove and inhibit tea-stain build-up on acrylic resin. MATERIALS AND METHODS: In the stain removal study, Perspex((r)) (cast heat polymerised resin) specimens previously soaked in saliva were stained using multiple exposures of chlorhexidine and tea solutions. Specimens were exposed for 1 min to one of the eight denture cleansers for five cycles, washed and dried and their optical density read on a uv/vis spectrophotometer at 295 nm. In the stain inhibition study, clear specimens were exposed to saliva followed by cleansers then tea solution, for five cycles. The build-up of stain at each cycle was measured, and differences in optical densities from baseline were calculated. RESULTS: All denture cleansers were significantly more effective than water in removing stain (p < 0.05). There were significant differences in cleaning ability between cleansers (p < 0.001), Dentural((r)) and Kleenite((r)) were particularly effective. The stain inhibition experiment showed that most cleansers were significantly more effective than water in inhibiting stain (p < 0.05). There were significant differences in inhibition ability between cleansers (p < 0.01). Kleenite((r)) and Equate were particularly effective. CONCLUSIONS: All denture cleansers had a capacity to remove stain and most had an inhibitory effect on staining. Kleenite((r)) was particularly effective in controlling stain formation. PMID- 23088444 TI - Determination of chain flip rates in poly(ethylene) crystallites by solid-state low-field 1H NMR for two different sample morphologies. AB - Using simple and cheap low-field (1)H NMR methods such as the magic sandwich echo technique and FID component analysis, we determine jump rates for 180 degrees chain flips in poly(ethylene) (PE) crystallites, which are comparable to literature data obtained from advanced, complex, and time-consuming (13)C-based NMR methods. In the investigated temperature range, we find similar jump rates for the local chain flip process in a melt-crystallized sample containing lamellar crystals with disordered fold surface and in reactor powder samples having a rather adjacent-reentry-like structure. Previous NMR studies of Yao et al. revealed different chain diffusion coefficients for the resulting long-range chain diffusion between amorphous and crystalline regions in melt- vs solution crystallized (adjacent reentry) samples. From our results, we conclude that, in the investigated temperature range, the fold surface, which presumably influences the effective chain transport, does not have a strong effect on the time scale of the local chain flip process. We confirm an Arrhenius temperature dependence of the jump rate for the local flip process and calculate activation energies which show a slight trend toward smaller values for the reactor powders (~76 kJ/mol) in comparison to the melt-crystallized sample (~103 kJ/mol). PMID- 23088446 TI - Physician styles of patient management as a potential source of disparities: cluster analysis from a factorial experiment. AB - OBJECTIVE: To identify styles of physician decision making (as opposed to singular clinical actions) and to analyze their association with variations in the management of a vignette presentation of coronary heart disease (CHD). DATA SOURCE: Primary data were collected from primary care physicians in North and South Carolina. STUDY DESIGN: In a balanced factorial experimental design, primary care physicians viewed one of 16 (2(4)) video vignette presentations of CHD and provided detailed information about how they would manage the case. DATA COLLECTION METHOD: 256 MD primary care physicians were interviewed face-to-face in North and South Carolina. PRINCIPAL FINDINGS: We identify three clusters depicting unique styles of CHD management that are robust to controls for physician (gender and level of experience) and patient characteristics (age, gender, socioeconomic status, and race) as well as key organizational features of physicians' work settings. Physicians in Cluster 1 "Cardiac" (N = 92) were more likely to focus on cardiac issues compared with their counterparts; physicians in Cluster 2 "Talkers" (N = 93) were more likely to give advice and take additional medical history; whereas physicians in Cluster 3 "Minimalists" (N = 71) were less likely than their counterparts to take action on any of the types of management behavior. CONCLUSIONS: Variations in styles of decision making, which encompass multiple outcome variables and extend beyond individual-level demographic predictors, may add to our understanding of disparities in health quality and outcomes. PMID- 23088445 TI - The roles of the reprogramming factors Oct4, Sox2 and Klf4 in resetting the somatic cell epigenome during induced pluripotent stem cell generation. AB - Somatic cell reprogramming to induced pluripotent stem (iPS) cells by defined factors is a form of engineered reverse development carried out in vitro. Recent investigation has begun to elucidate the molecular mechanisms whereby these factors function to reset the epigenome. PMID- 23088448 TI - Significant hydration shell formation instead of hydrogen bonds in nanoconfined aqueous electrolyte solutions. AB - Nanoscale confined electrolyte solutions are frequently observed, specifically in electrochemistry and biochemistry. However, the mechanism and structure of such electrolyte solutions are not well understood. We investigated the structure of aqueous electrolyte solutions in the internal nanospaces of single-walled carbon nanotubes, using synchrotron X-ray diffraction. The intermolecular distance between the water molecules in the electrolyte solution was increased because of anomalously strong hydration shell formation. Water correlation was further weakened at second-neighbor or longer distances. The anomalous hydrogen-bonding structure improves our understanding of electrolyte solutions in nanoenvironments. PMID- 23088447 TI - Pregnancy and fetal outcomes after Glatiramer Acetate exposure in patients with multiple sclerosis: a prospective observational multicentric study. AB - BACKGROUND: Only few studies have assessed safety of in utero exposure to glatiramer acetate (GA). Following a previous study assessing the safety of interferon beta (IFNB) pregnancy exposure in multiple sclerosis (MS), we aimed to assess pregnancy and fetal outcomes after in utero exposure to GA, using the same dataset, with a specific focus on the risk of spontaneous abortion. MATERIALS AND METHODS: We recruited MS patients, prospectively followed-up in 21 Italian MS Centres, for whom a pregnancy was recorded in the period 2002-2008. Patients were divided into 2 groups: drug-exposed pregnancies (EP: suspension of the drug less than 4 weeks from conception); non-exposed pregnancies (NEP: suspension of the drug at least 4 weeks from conception or never treated pregnancies). All the patients were administered a structured interview which gathered detailed information on pregnancy course and outcomes, as well as on possible confounders. Multivariate logistic and linear models were used for treatment comparisons. RESULTS: Data on 423 pregnancies were collected, 17 were classified as EP to GA, 88 as EP to IFNB, 318 as NEP. Pregnancies resulted in 16 live births in the GA EP, 75 live births in the IFNB EP, 295 live births in the NEP. GA exposure was not significantly associated with an increased risk of spontaneous abortion (OR = 0.44;95% CI 0.044-4.51;p = 0.49). Mean birth weight and length were not significantly different in pregnancies exposed to GA than in non exposed pregnancies (p = 0.751). The frequency of preterm delivery, observed in 4 subjects exposed to GA (25% of full term deliveries), was not significantly higher in pregnancies exposed to GA than in those non exposed (p > 0.735). These findings were confirmed in the multivariate analysis. There were neither major complications nor malformations after GA exposure. CONCLUSIONS: Data in our cohort show that mother's GA exposure is not associated with a higher frequency of spontaneous abortion, neither other negative pregnancy and fetal outcomes. Our findings point to the safety of in utero GA exposure and can support neurologists in the therapeutic counselling of MS women planning a pregnancy. PMID- 23088449 TI - A new gyrodactylid (Monogenea) parasitizing bay pipefish (Syngnathus leptorhynchus) from the Pacific Coast of North America. AB - Gyrodactylus leptorhynchi n. sp. (Monogenea) is described from bay pipefish ( Syngnathus leptorhynchus ) (Syngnathidae) in coastal waters of southern California and British Columbia, and from an outbreak of gyrodactylosis at the Cabrillo Marine Aquarium in California. Gyrodactylus leptorhynchi is morphologically similar (stout hamuli, superficial bar with no anterolateral processes, and a small, triangular membrane, similarly shaped marginal hook sickles, and a male copulatory organ [MCO] with numerous small spines) to the other 6 species of Gyrodactylus known from pipefish in north and south regions of the Atlantic Ocean. It resembles most closely Gyrodactylus corleonis Paladini, Cable, Fioravanti, Faria, and Shinn, 2010 , parasitizing Syngnathus typhle L. from the French Mediterranean in having relatively large hamuli (58 MUm). However, in G. leptorhynchi, the marginal hook sickle has a reduced heel and a ledged toe, while in G. corleonis, it has a noticeable heel and a toe with no distinct ledge. DNA sequence data of a partial ITS1 (700+ bp), complete 5.8S (157 bp), complete ITS2 (392 bp), and a partial 18S (441 bp) are included in the description; the data are distinct from those available for other species of Gyrodactylus. The molecular data reveal that G. leptorhynchi is a member of a basal lineage of marine species within Gyrodactylus sensu lato that is known to have radiated among coastal syngnathid, anguillid, and gobiid fishes throughout the Atlantic Ocean and some adjacent waters. Occurrence of G. leptorhynchi in the eastern Pacific supports the idea that such lineages may have global distributions. Sixty-three percent (15 of 24) of bay pipefish caught at Inner Cabrillo Beach, California, were infected with 1-3 worms, predominately located on the dorsal fin, but also on the anterior body surfaces. Intensely infected pipefish at the marine aquarium had parasites distributed all over the body surface, including the open edge of the brood pouch and, on 2 occasions, inside the brood pouch. A quarantine protocol, involving the treatment of wild pipefish with serial repeats of topical anthelmintic chemicals (formalin, Trichlorfon, and Praziquantel), that helps to diminish outbreaks of G. leptorhynchi in aquarium exhibits is described. PMID- 23088450 TI - Synthesis and characterization of ionic polymer networks in a room-temperature ionic liquid. AB - Ionic liquid gels (ILGs) for potential use in ion transport and separation applications were generated via a free radical copolymerization of 2-acrylamido-2 methyl-1-propanesulfonic acid (AMPS) and N,N'-methylene(bis)acrylamide (MBA) using 1-ethyl-3-methylimidazolium ethylsulfate (IL) as a room temperature ionic liquid solvent medium. The AMPS and MBA monomer solubility window in the IL in the temperature range of 25 to 65 degrees C was determined. In situ ATR-FTIR showed near complete conversion of monomers to a cross-linked polymer network. ILGs with glass transition temperatures (T(g)s) near -50 degrees C were generated with T(g) decreasing with increasing IL content. The elastic moduli in compression (200 to 6600 kPa) decreased with increasing IL content and increasing AMPS content while the conductivities (0.35 to 2.14 mS cm-1) increased with increasing IL content and decreasing MBA content. The polymer-IL interaction parameter (chi) (0.48 to 0.55) was determined via a modified version of the Bray and Merrill equation. PMID- 23088452 TI - Disease recurrence plays a minor role as a cause for retransplantation after living-donor liver transplantation for primary biliary cirrhosis: A multicenter study in Japan. AB - AIM: To clarify the role of disease recurrence as a cause of graft loss after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC), we investigated explant grafts, as well as the native liver and liver biopsy specimens, of patients who underwent retransplantation. METHODS: Of 516 patients who underwent LDLT for PBC and were registered in the Japanese Liver Transplant Registry, nine patients (1.7%) underwent retransplantation. RESULTS: Seven patients undergoing retransplantation later than 6 months after primary liver transplantation (LT) were enrolled. All seven patients were female, with ages ranging from 34-57 years, and Model for End-Stage Liver Disease scores ranging 10 28. The right lobe was used as graft in one and the left lobe in six. The initial immunosuppression regimen was tacrolimus in six and cyclosporin in one. The period between the primary LT and retransplantation ranged 11-120 months, with a median of 36 months. Three patients survived and four patients died due to poor graft functions or complications after retransplantation. The primary causes of primary graft loss revealed by histological examination of the explant livers were chronic rejection in three, portal thrombus and/or steatohepatitis in three and outflow block in one. PBC recurrence was observed in 3 and the stage was mild in all. CONCLUSION: PBC recurrence has a small impact as a cause of graft loss after LDLT. PMID- 23088451 TI - Prosthesis alignment affects axial rotation motion after total knee replacement: a prospective in vivo study combining computed tomography and fluoroscopic evaluations. AB - BACKGROUND: Clinical consequences of alignment errors in total knee replacement (TKR) have led to the rigorous evaluation of surgical alignment techniques. Rotational alignment in the transverse plane has proven particularly problematic, with errors due to component malalignment relative to bone anatomic landmarks and an overall mismatch between the femoral and tibial components' relative positions. Ranges of nominal rotational alignment are not well defined, especially for the tibial component and for relative rotational mismatch, and some studies advocate the use of mobile-bearing TKR to accommodate the resulting small rotation errors. However, the relationships between prosthesis rotational alignment and mobile-bearing polyethylene insert motion are poorly understood. This prospective, in vivo study evaluates whether component malalignment and mismatch affect axial rotation motions during passive knee flexion after TKR. METHODS: Eighty patients were implanted with mobile-bearing TKR. Rotational alignment of the femoral and tibial components was measured from postoperative CT scans. All TKR were categorized into nominal or outlier groups based on defined norms for surgical rotational alignment relative to bone anatomic landmarks and relative rotational mismatch between the femoral and tibial components. Axial rotation motion of the femoral, tibial and polyethylene bearing components was measured from fluoroscopic images acquired during passive knee flexion. RESULTS: Axial rotation motion was generally accomplished in two phases, dominated by polyethylene bearing rotation on the tibial component in early to mid-flexion and then femoral component rotation on the polyethylene articular surface in later flexion. Opposite rotations of the femur-bearing and bearing-baseplate articulations were evident at flexion greater than 80 degrees . Knees with outlier alignment had lower magnitudes of axial rotation and distinct transitions from external to internal rotation during mid-flexion. Knees with femoral-tibial rotational mismatch had significantly lower total axial rotation compared to knees with nominal alignment. CONCLUSIONS: Maintaining relative rotational mismatch within +/-5 degrees during TKR provided for controlled knee axial rotation during flexion. TKR with rotational alignment outside of defined surgical norms, with either positive or negative mismatch, experienced measurable kinematic differences and presented different patterns of axial rotation motions during passive knee flexion compared to TKR with nominal mismatch. These findings support previous studies linking prosthesis rotational alignment with inferior clinical and functional outcomes. TRIAL REGISTRATION: Clinical Trials NCT01022099. PMID- 23088453 TI - A pilot study evaluating liquid-based endometrial cytology and transvaginal ultrasonography in women with postmenopausal bleeding. PMID- 23088454 TI - Effects of B-cell lymphoma 2 gene transfer to myoblast cells on skeletal muscle tissue formation using magnetic force-based tissue engineering. AB - Tissue-engineered skeletal muscle should possess a high cell-dense structure with unidirectional cell alignment. However, limited nutrient and/or oxygen supply within the artificial tissue constructs might restrict cell viability and muscular functions. In this study, we genetically modified myoblast cells with the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene and evaluated their function in artificial skeletal muscle tissue constructs. Magnetite cationic liposomes were used to magnetically label C2C12 myoblast cells for the construction of skeletal muscle bundles by applying a magnetic force. Bcl-2-overexpressing muscle bundles formed highly cell-dense and viable tissue constructs, while muscle bundles without Bcl-2 overexpression exhibited substantial necrosis/apoptosis at the central region of the bundle. Bcl-2-overexpressing muscle bundles contracted in response to electrical pulses and generated a significantly higher physical force. These findings indicate that the incorporation of anti-apoptotic gene transduced myoblast cells into tissue constructs significantly enhances skeletal muscle formation and function. PMID- 23088456 TI - Measuring productivity in bioanalysis. PMID- 23088455 TI - Protective effects of astaxanthin on capillary regression in atrophied soleus muscle of rats. AB - AIM: The capillary regression in skeletal muscles associated with a chronic decrease in activity is related to a dysfunction of endocapillary cells induced by over-expression of oxidative stress. We hypothesized that treatment with astaxanthin, an antioxidant, would attenuate the oxidative stress induced by decreased skeletal muscle use, and that this attenuation would prevent the associated capillary regression. The purpose of the present study was to investigate the antioxidant and preventive effects of astaxanthin on capillary regression in the soleus muscle during hindlimb unloading. METHODS: Twenty-four adult male Wistar rats were assigned randomly either to a control, control plus astaxanthin treatment, hindlimb unloaded or hindlimb unloaded plus astaxanthin treatment group for 7 days. RESULTS: Hindlimb unloading resulted in a decrease in mean soleus absolute weight, capillary number, volume and luminal diameter. The accumulation of reactive oxygen species and the over-expression of superoxide dismutase (SOD-1), a decrease in the levels of vascular endothelial growth factor (VEGF) and its receptors, an inhibition of the angiopoietin pathway and an increase of thrombospondin-1 (TSP-1), as an anti-angiogenic factor were showed. Administration of astaxanthin attenuated the changes in SOD-1 and VEGF, up regulated the angiogenic factors and reduced the capillary regression in the soleus of hindlimb unloaded rats. In addition, the VEGF-to-TSP1 ratio was higher in the astaxanthin treated groups than in the control and HU groups. CONCLUSION: These results suggest that astaxanthin may be an effective treatment to counter the detrimental effects of a chronic decrease in skeletal muscle use on the capillary network and associated angiogenic pathways. PMID- 23088457 TI - Extraction and microextraction in bioanalysis. PMID- 23088459 TI - Interview: challenges faced by the modern bioanalytical laboratory. AB - Timothy Sangster (Charles River Laboratories) and Mike Oliver (Thermo Fisher Scientific) speak to Thomas Payne at Bioanalysis in September 2012 about the challenges faced by the modern bioanalytical laboratory. Timothy Sangster has been with Charles River Laboratories since September 2009. Having worked for Quintiles, Pharmacia, Astrazeneca and Huntingdon Life Sciences, he has gained experience over 17 years in both CRO and pharmaceutical environments, and also in both Europe and the USA. Specific areas of interest over the past years have been microchromatography, sample preparation and matrix effects, to name a few. Mike Oliver has held the position of Global Product Manager for sample preparation at Thermo Fisher Scientific since 2010, being responsible for the development and introduction of new innovative technologies such as SOLATM to the market place. Prior to this role, Mike has worked for two leading MS vendors over a 9-year period, being responsible for biotechnology sales within the UK and providing application solutions for proteomic and metabolic workflows based on high resolution LC-MS platforms, respectively. Mike holds a PhD in MS and Biochemistry from the MS Research Unit, University of Wales, Swansea, UK. PMID- 23088460 TI - Conference report: 6th GCC focus on LBA: critical reagents, positive controls and reference standards; specificity for endogenous compounds; biomarkers; biosimilars. PMID- 23088461 TI - Surrogate matrix and surrogate analyte approaches for definitive quantitation of endogenous biomolecules. AB - BACKGROUND: Quantitation of biomarkers by LC-MS/MS is complicated by the presence of endogenous analytes. This challenge is most commonly overcome by calibration using an authentic standard spiked into a surrogate matrix devoid of the target analyte. A second approach involves use of a stable-isotope-labeled standard as a surrogate analyte to allow calibration in the actual biological matrix. For both methods, parallelism between calibration standards and the target analyte in biological matrix must be demonstrated in order to ensure accurate quantitation. RESULTS: In this communication, the surrogate matrix and surrogate analyte approaches are compared for the analysis of five amino acids in human plasma: alanine, valine, methionine, leucine and isoleucine. In addition, methodology based on standard addition is introduced, which enables a robust examination of parallelism in both surrogate analyte and surrogate matrix methods prior to formal validation. Results from additional assays are presented to introduce the standard-addition methodology and to highlight the strengths and weaknesses of each approach. CONCLUSION: For the analysis of amino acids in human plasma, comparable precision and accuracy were obtained by the surrogate matrix and surrogate analyte methods. Both assays were well within tolerances prescribed by regulatory guidance for validation of xenobiotic assays. When stable-isotope labeled standards are readily available, the surrogate analyte approach allows for facile method development. By comparison, the surrogate matrix method requires greater up-front method development; however, this deficit is offset by the long-term advantage of simplified sample analysis. PMID- 23088462 TI - Implementation of a universal analytical method in early-stage development of human antibody therapeutics: application to pharmacokinetic assessment for candidate selection. AB - BACKGROUND: Effective bioanalytical support for pharmacokinetic assessment of therapeutics in early development remains challenging. Concurrent evaluation of multiple candidates per program is typical, requiring efficient characterization in various preclinical species; an ambitious effort often complicated by assay reagent unavailability and limited sample volume. Accordingly, a universal anti human Fc assay for human monoclonal antibody and derived therapeutics was developed using a microfluidics platform to address these bioanalytical challenges. RESULTS: The universal assay with standardized format was qualified for quantitation of human IgG Fc-containing biotherapeutics in matrices from commonly used preclinical species. Results from this assay compared well with those from traditional colorimetric immunoassays. Furthermore, result comparison between the universal and target-specific assays provided additional information on the effect of antidrug antibodies and in vivo drug catabolism. CONCLUSION: This assay has wide applicability as a default bioanalytical approach in therapeutic candidate selection and preliminary pharmacokinetics evaluation during early-stage therapeutic development. PMID- 23088463 TI - Clinical significance of CYFRA21-1, Scc-Ag and telomerase activity in serum and pleural effusion of patients with squamous-cell lung cancer. AB - BACKGROUND: The aim was to evaluate the diagnostic value of CYFRA21-1, Scc-Ag and telomerase activity in serum and pleural effusion in patients with squamous-cell lung cancer. CYFRA21-1, Scc-Ag and telomerase activity were measured using electrochemiluminescent, microparticle enzyme immunoassay and telomeric-repeat amplification protocol. RESULTS: We evaluated 302 patients diagnosed with squamous-cell lung cancer and 153 patients diagnosed with benign lung diseases. All examined tumor markers were higher in pleural effusion than serum (p < 0.05). The areas under receiver operating characteristic curve of CYFRA21-1 and Scc-Ag were higher in pleural effusion than serum. Optimizations for sensitivity, specificity and specificity in pleural effusion for CYFRA21-1 + Scc-Ag: 88.24, 97.17 and 92.79%; telomerase activity + Scc-Ag: 90.2, 95.28 and 92.8%; CYFRA21-1, Scc-Ag + telomerase activity: 91.18, 96.86 and 94.64%; respectively. Optimizations for sensitivity, specificity and specificity in serum for CYFRA21-1 + telomerase activity: 81.37, 94.34 and 87.98%; CYFRA21-1 + Scc-Ag and telomerase activity: 87.25, 93.08 and 90.8%; respectively. CONCLUSION: The combined detection of tumor markers in pleural effusion showed higher sensitivity, better accuracy and higher clinical value than serum and single detection. However, the cost-effectiveness of these methods should be considered in clinical practice. PMID- 23088464 TI - Split calibration curve: an approach to avoid repeat analysis of the samples exceeding ULOQ. AB - BACKGROUND: The current practice of using calibration curves with narrow concentration ranges during bioanalysis of new chemical entities has some limitations and is time consuming. In the present study we describe a split calibration curve approach, where sample dilution and repeat analysis can be avoided without compromising the quality and integrity of the data obtained. RESULTS: A split calibration curve approach is employed to determine the drug concentration in plasma samples with accuracy and precision over a wide dynamic range of approximately 0.6 to 15,000 ng/ml for dapsone and approximately 1 to 25,000 ng/ml for cyclophosphamide and glipizide. A wide dynamic range of concentrations for these three compounds was used in the current study to construct split calibration curves and was successfully validated for sample analysis in a single run. CONCLUSION: Using this method, repeat analysis of samples can be avoided. This is useful for the bioanalysis of toxicokinetic studies with wide dose ranges and studies where the sample volume is limited. PMID- 23088465 TI - LC-MS systems for quantitative bioanalysis. AB - LC-MS has become the method-of-choice in small-molecule drug bioanalysis (molecular mass <800 Da) and is also increasingly being applied as an alternative to ligand-binding assays for the bioanalytical determination of biopharmaceuticals. Triple quadrupole MS is the established bioanalytical technique due to its unpreceded selectivity and sensitivity, but high-resolution accurate-mass MS is recently gaining ground due to its ability to provide simultaneous quantitative and qualitative analysis of drugs and their metabolites. This article discusses current trends in the field of bioanalytical LC-MS (until September 2012), and provides an overview of currently available commercial triple quadrupole MS and high-resolution LC-MS instruments as applied for the bioanalysis of small-molecule and biopharmaceutical drugs. PMID- 23088466 TI - Free and total biotherapeutic evaluation in chromatographic assays: interference from targets and immunogenicity. AB - Measurement of drug concentrations is critical during drug development, supporting evaluation of safety and efficacy in the context of pharmacokinetics. Protein-based therapeutics have been historically measured by immunoassay methods. Technological advances provide new opportunities to measure these biotherapeutics using previously incompatible chromatographic techniques, such as MS. These advances are breaking down the barriers between 'large-molecule' and 'small-molecule' bioanalysis, and pushing scientists outside their comfort zones. One challenge in measuring biotherapeutic concentration is potential impact from other matrix components, such as therapeutic target or antidrug antibodies. Depending on the specific assay development objective, target interference could be either desired (favoring free measurement) or undesired (favoring total measurement). Orthogonal techniques provide additional tools to meet this challenge. The goal of this review is to introduce both small- and large-molecule bioanalytical scientists to the opportunities and challenges to consider while evaluating orthogonal methods for biotherapeutic bioanalysis. PMID- 23088467 TI - Application of supercritical fluid carbon dioxide to the extraction and analysis of lipids. AB - Supercritical carbon dioxide (SCCO(2)) is an ecofriendly supercritical fluid that is chemically inert, nontoxic, noninflammable and nonpolluting. As a green material, SCCO(2) has desirable properties such as high density, low viscosity and high diffusivity that make it suitable for use as a solvent in supercritical fluid extraction, an effective and environment-friendly analytical method, and as a mobile phase for supercritical fluid chromatography, which facilitates high throughput, high-resolution analysis. Furthermore, the low polarity of SCCO(2) is suitable for the extraction and analysis of hydrophobic compounds. The growing concern surrounding environmental pollution has triggered the development of green analysis methods based on the use of SCCO(2) in various laboratories and industries. SCCO(2) is becoming an effective alternative to conventional organic solvents. In this review, the usefulness of SCCO(2) in supercritical fluid extraction and supercritical fluid chromatography for the extraction and analysis of lipids is described. PMID- 23088469 TI - Twelve month impact of the Just Walk It program on physical activity levels. AB - ISSUE ADDRESSED: There is limited evaluation on the impact of community-based walking groups on physical activity (PA). This study examined the amount of walking and total PA minutes when adults joined the Just Walk It (JWI) program in Queensland, and changes over time. METHODS: All adult participants (n=1258) were sent a survey on registration with the JWI program between April 2002 and December 2003, and after 6 and 12 months. Outcomes included self-reported minutes of walking and total PA in the past week and the proportion meeting PA recommendations. RESULTS: Of the 1,258 registrants, 601 returned the 12-month survey; 423 of these confirmed they still participated. At baseline, 36 (8.5%) of these were inactive, 280 (66.2%) were insufficiently active to meet PA recommendations and 107 (25.3%) met PA recommendations. Among these groups, the largest 12-month increases in walking and total PA were in participants who were inactive (177 minutes, 95% CI 144-210, p<0.001 and 233 minutes, 95% CI 169-297, p<0.001, respectively) and in participants who were insufficiently active (63 minutes, 95% CI 39-86, p<0.001 and 122 minutes, 95% CI 81-162, p<0.001, respectively). Walking minutes increased more for men (n=92) [100 minutes, 95% CI 51-150] than for women (n=331) [52 minutes, 95% CI 32-72, p=0.044], as did total PA minutes (158 minutes, 95% CI 61-247 compared to 67 minutes, 95% CI 31-103, p=0.038). Furthermore, compared with participants aged 18-44 years (n=41) [-12 minutes, 95% CI -75-50] and 65 and older (n=183) [57 minutes, 95% CI 27-87], walking increased more in those aged 45-64 years (n=199) [83 minutes, 95% CI 56 110, p=0.018). CONCLUSIONS: Participation in a community-based walking group for 12 months increased both walking and total PA, especially in men, mid-aged participants and those who were inactive or insufficiently active at registration. PMID- 23088470 TI - Punching loan sharks on the nose: effective interventions to reduce financial hardship in New Zealand. AB - ISSUES ADDRESSED: Growth in the high-cost, unregulated fringe lender market (with these lenders commonly referred to as loan sharks) has occurred both internationally and in New Zealand in recent years. The credit practices of loan sharks create financial hardship for many people including Maori, Pacific and low income New Zealanders. This paper reports on research that explored strategies for reducing the impact of the fringe lender market on Maori, Pacific and low income New Zealanders. METHODS: A narrative literature review and 10 key informant interviews were conducted to provide information on how best to intervene to reduce the impact of the fringe lender market for these people. RESULTS: The main interventions identified were: two regulatory approaches, one for capping interest rates and another to create codes of responsible lending; access to safe affordable micro-finance options; financial literacy education; and Pacific cultural change around fa'alavelave, which are the 'obligations' of giving. CONCLUSIONS: Protecting consumers from the unsafe practices of fringe lenders requires a combined approach of discouraging the undesirable practices of fringe lenders through regulation and encouraging the growth of safe, affordable micro-finance options. Financial literacy education is a valuable activity for directing consumer attention to the safest options, but in isolation will have limited effect if options are limited. Health promoters have a valuable role to play in implementing these interventions. PMID- 23088471 TI - A qualitative evaluation of the views of Child and Family Health Nurses on the early childhood oral health education materials in New South Wales, Australia. AB - ISSUE ADDRESSED: Health literacy is an important determinant of oral health. We explored the Child and Family Health Nurses' reflections on the usefulness of leaflets giving dental advice for parents of preschool children in New South Wales, Australia. METHODS: Child and Family Health Nurses (n=19) who recruited new mothers to an ongoing birth cohort study in South Western Sydney, Australia, were invited to take part in a qualitative study. A semi-structured, in-depth interview technique was used to explore their views on two leaflets designed by New South Wales Health, which gave dental advice to parents of preschool children. Interviews were audio-recorded, transcribed verbatim, and analysed using interview debriefing and a thematic coding. RESULTS: The nurses reported that the leaflets did not have clear consistent messages and had medical/dental jargon which could be confusing for parents from disadvantaged backgrounds. The advice on using a "pea-sized amount of toothpaste" was considered to be culturally irrelevant. Some early childhood oral health issues were inadequately addressed and the use of pictures was strongly recommended. CONCLUSIONS: Producers of paediatric oral health education materials in New South Wales, should reach a consensus on the key health promotion messages. Health authorities should consider re-designing dental leaflets and tailor them to the needs of the parents from disadvantaged backgrounds. PMID- 23088472 TI - Assessing the capacity of New Zealand health promoters to develop programs that meet the health literacy needs of both consumers and government. AB - ISSUES ADDRESSED: Since 2008 a conservative government in New Zealand has emphasised the importance of individual responsibility for health, with the implication that health promotion, including health literacy, would be of low priority. This paper discusses this in the context of research that aims to assess (i) the views of disadvantaged consumers on nutrition information and (ii) health promoter competence in health literacy practice, and argues that aspects of health literacy principles may indeed be of interest to conservative governments. METHODS: First, four focus groups of consumers drawn from disadvantaged neighbourhoods discussed nutrition information. Second, a self completed questionnaire to health promoters in six non-government agencies assessed health promotion competencies and understanding of health literacy. RESULTS: Consumers confirmed the need for personal responsibility for food choices, were critical of confusing information and sought simple messages on which they could act. They also acknowledged environmental constraints on their actions. Survey respondents (n=56; 53% response rate) reported technical competence in health promotion but less competence in strategic and leadership areas. More than one-third of respondents were assessed as having a good understanding of health literacy. CONCLUSION: Consumer acceptance of individual responsibility and workforce capability in technical aspects of health literacy suggest that health promotion organisations can align themselves with government goals and seek to improve personal health literacy. PMID- 23088473 TI - Using the Transtheoretical Model of Behaviour Change to describe readiness to rescreen for colorectal cancer with faecal occult blood testing. AB - ISSUE ADDRESSED: This study used the Transtheoretical Model of Behaviour Change (TTM) to describe reparticipation in colorectal cancer (CRC) screening according to social cognitive and background variables. METHODS: A random sample of men and women aged 50-74 years living in South Australia completed a questionnaire measuring TTM stage and attitudes toward screening using a faecal occult blood test (FOBT). Participants were categorised according to four stages of readiness to rescreen: action, maintenance, relapse and inconsistent. Multivariate techniques were used to determine predictors of lower readiness stages compared with maintenance. RESULTS: Of the 849 study participants, 29.9% were either non adherent or had no intentions to maintain adherence (inconsistent and relapse). Compared with maintenance rescreeners, relapse participants reported less: social influences to screen (RR=0.86, p<0.001); satisfaction with prior screening (RR=0.87, p=0.03), self-efficacy (RR=0.96, p=0.01); and screening benefits (RR=0.84, p<0.001). Relapse participants were also more likely to not have private health insurance (RR=1.33, p=0.04) and be unaware of the need to repeat screening (RR=1.41, p=0.02). Inconsistent screeners were less likely to have planned when they will next rescreen (RR= 0.84, p=0.04) and reported greater barriers to rescreening (RR=1.05, p=0.05). Action participants were younger (RR= 0.98, p=<0.001), reported less social influences to screen (RR=0.94, p<0.001) and were less likely to have known someone who has had CRC (RR=0.82, p=0.01). CONCLUSIONS: Social cognitive, demographic and background variables significantly differentiated screening maintenance from lower readiness stages. PMID- 23088474 TI - Measuring the food environment in three rural towns in New South Wales, Australia. AB - ISSUE ADDRESSED: Food availability affects eating habits, and in the Australian context, refers to the numbers and locations of food retail and food service outlets and the types and range of foods in those outlets. The aim of this study was to assess the community and consumer food environment in three small rural towns in New South Wales, Australia. METHODS: Geographical analyses were used to measure the diversity, variety and locations of food outlets (community food environment); and checklists were used to assess the availability of selected indicator foods within food outlets (consumer food environment). RESULTS: Supermarkets provided access to the full range of healthy indicator foods, with convenience stores selling a more limited set of healthy food items. There were high numbers of take-away food outlets in each town that had no, or a limited number of, healthy food items. Energy-dense, nutrient-poor foods such as soft drinks and potato crisps were readily available across all food retail outlets in all towns. CONCLUSION: This study illustrates a valid, reliable and practical way of systematically describing food availability at a local level. The findings emphasise the ubiquity of energy-dense, nutrient-poor foods, and suggest that interventions to promote the availability of healthier food items in take-away food outlets are required. Further research is required to assess other factors which may affect residents' food access, such as cost and transport. PMID- 23088475 TI - Implementing workplace health promotion initiatives: who should we target? AB - BACKGROUND: With recent increase in focus on population-based interventions in workplaces, targeting lifestyle risk factors for chronic disease, there is a need to ensure that interventions maximise total reach while still reaching more disadvantaged groups within the workforce. This requires assembling information on NSW workforce and health risks data in a way that is useful to guide planning in health promotion. This paper aims to describe the NSW workforce by employer size, industry divisions, occupation classification, geographic location and risk factor prevalence. METHODS: Data from a unique combination of public and non publicly available data sets was used to describe the NSW workforce by demographic, setting-specific variables and risk factor prevalence. RESULTS: NSW represents 31% of Australia's workforce. Large employers represent 1% of businesses but employ 33% of the NSW workforce. Reaching large numbers of NSW workers can be achieved by targeting large employers in metropolitan regions; however, a high proportion of workers with multiple health risks are located in non-metropolitan areas and industries that have a high proportion of small employers. CONCLUSIONS: The workplace as a setting for population based health promotion interventions provides a number of challenges due to the fragmented nature and dispersed distribution of the workforce. PMID- 23088476 TI - Exploring the feasibility of implementing a pedometer-based physical activity program in primary school settings: a case study of 10,000 steps. AB - ISSUES ADDRESSED: The school environment provides an ideal setting for physical activity programs. The aim of the current research was to explore the feasibility and appropriateness of implementing program resources from an adult pedometer based physical activity program (10,000 Steps) into the primary school environment. METHODS: 10,000 Steps resources were implemented in three primary schools as a pilot study. Qualitative evaluation of the pilot study included semi structured interviews with teachers and focus groups with students. RESULTS: Four major themes were identified regarding implementation enablers: pedometers; curriculum inclusion; 10,000 Steps challenges and resources; and motivation and enthusiasm. CONCLUSIONS: To achieve a suitable and successful implementation, the 10,000 Steps program and resources need to be adapted for school settings so as to optimise teacher load and curriculum inclusion, and enhance adaptability or flexibility of programs and resources. PMID- 23088477 TI - Riding the wave or paddling in the shallows? Understanding older Australians' use of the internet. AB - ISSUES ADDRESSED: Australia's ageing population is set to become an increasing burden on an already over-stretched primary health care system. Potential strategies to alleviate this pressure need to be investigated. Increased knowledge of older Australians' use of the internet would allow the appropriateness of online health intervention to be assessed. This initial, exploratory study examined the proportion of people aged 55 years and older who accessed the internet. It investigated their duration of use, level of comfort, use of the internet to seek health information and perceived reliability of information found on the internet. METHODS: A paper based survey was distributed to a purposive sample of adults in metropolitan New South Wales. Complete data was received from 115 respondents. RESULTS: Sixty-two per cent of respondents reported internet use, with use decreasing with age. The majority of respondents who used the internet reported high confidence levels and long-term use. The majority had used the internet to search for health information which was generally perceived to be reliable. Logistic regression showed tertiary education and household income greater than $40,000 per year predicted use of a computer to access the internet. CONCLUSIONS: The majority of older Australians surveyed were successfully riding the internet wave. They have both the skills and equipment to access health information online and many were already doing so. PMID- 23088478 TI - Healthy food and beverages in senior community football club canteens in New South Wales, Australia. AB - ISSUE ADDRESSED: Little is known of the extent to which senior sports clubs support the consumption of healthy food and beverages. This study of senior community football clubs aimed to describe: i) the food and beverages available in club canteens; ii) the perceived acceptability of club representatives (e.g. club president or secretary) to selling healthy food and beverages in club canteens; iii) the perceived barriers of club representatives to providing healthy food and beverage options in their club canteen; iv) the associations between the availability of healthy options in canteens, perceived barriers to healthy food and drink availability, and club characteristics; and (v) the food and beverages usually purchased from canteens by club members. METHODS: The study involved 70 senior community football clubs (Australian Rules Football, Soccer, Rugby League and Rugby Union) across New South Wales, Australia. Club representatives and club members took part in cross-sectional telephone surveys. RESULTS: The most frequently available items at club canteens were regular soft drinks and potato chips or other salty snacks (available at 99% of clubs). Approximately two-thirds (66%) of club representatives agreed or strongly agreed that clubs should provide a greater variety of healthy food options. Perishability and lack of demand were the most frequently cited barriers to healthy food provision. Healthy food options were more available at AFL clubs compared with other football codes. Overall, 6% of club members reported purchasing a healthy food option. CONCLUSIONS: Senior community football clubs primarily stock and sell unhealthy food and beverage items. There is support within clubs for providing more healthy options; however, clubs face a number of barriers to the inclusion of healthy foods in club canteens. PMID- 23088479 TI - Do food and physical activity environments vary between disadvantaged urban and rural areas? Findings from the READI Study. AB - ISSUES ADDRESSED: The presence or absence of amenities in local neighbourhood environments can either promote or restrict access to opportunities to engage in healthy and/or less healthy behaviours. Rurality is thought to constrain access to facilities and services. This study investigated whether the presence and density of environmental amenities related to physical activity and eating behaviours differs between socioeconomically disadvantaged urban and rural areas in Victoria, Australia. METHODS: We undertook cross-sectional analysis of environmental data collected in 2007-08 as part of the Resilience for Eating and Activity Despite Inequality (READI) study. These data were sourced and analysed for 40 urban and 40 rural socioeconomically disadvantaged areas. The variables examined were the presence, raw count, count/km2, and count/'000 population of a range of environmental amenities (fast-food restaurants, all supermarkets (also separated by major chain and other supermarkets), greengrocers, playgrounds, gyms/leisure centres, public swimming pools and public open spaces). RESULTS: A greater proportion of urban areas had a fast-food restaurant and gym/leisure centre present while more rural areas contained a supermarket and public swimming pool. All amenities examined (with the exception of swimming pools) were more numerous per km2 in urban areas, however rural areas had a greater number of all supermarkets, other supermarkets, playgrounds, swimming pools and public open space per '000 population. CONCLUSION: Although opportunities to engage in healthy eating and physical activity exist in many rural areas, a lower density per km2 suggests a greater travel distance may be required to reach these. PMID- 23088480 TI - School canteens--places for increasing social connectedness? PMID- 23088481 TI - In reply to article 'Sales of healthy choices at fast food restaurants in Australia' by Wellard, Glasson and Chapman. PMID- 23088482 TI - Left out, left off, left over: Why migrants from non-English speaking backgrounds are not adequately recognised in health promotion policy and programs. PMID- 23088483 TI - Public opinion on food-related obesity prevention policy initiatives. AB - ISSUE ADDRESSED: The study was designed to determine public acceptability of various forms of regulation to support a healthy eating environment. METHODS: Telephone interviews were undertaken in June-July 2010 with a random sample of adults in Australia who were the main grocery buyer for their household. RESULTS: Data were analysed for 1,511 adults. A clear majority of participants (80% or more) were in favour of traffic light and kilojoule menu labelling, reformulation to reduce the fat, salt and sugar content of processed foods, and regulation of broadcast and non-broadcast avenues used to market unhealthy food and drinks to children. Relatively less support (two-thirds or more), particularly among lower socioeconomic status participants, was shown for taxation policies and controls on food company sponsorship of sports and education programs. Despite the survey's focus on food marketing avenues and methods directed at children, for the most part non-parents were just as likely as parents to support restrictions. CONCLUSIONS: Overall, these findings indicate that there is strong public support for the introduction of policy initiatives aimed at creating a healthier food environment. PMID- 23088484 TI - Generating news media interest in tobacco control; challenges in an advanced policy environment. AB - OBJECTIVE: To determine the efficacy of using media releases for tobacco control advocacy in Australia's advanced policy environment. METHODS: Between February and August 2010, news releases that summarised either newly published but unpublicized research findings, or local developments in tobacco control, were sent to NSW media outlets. Reports arising from the releases were tracked using commercial services Media Monitors and Factiva, as well as Google and Google News. Other tobacco control related news items during the same period were also tracked and recorded. RESULTS: Twenty-one news releases generated 93 news items across all news media, with a quarter of these related to a story of porcine haemoglobin in cigarette filters. By comparison, 'live' policy issues (especially plain packaging and a significant tobacco tax increase) covered in this period attracted 1,033 news stories in the Australian media. Press releases describing recently published, but underpublicized research were issued in weeks where no major competing tobacco control news occurred. Results of this project indicate that in environments with advanced tobacco policy, media opportunities related to tobacco control advocacy are limited, as many objectives have been achieved. CONCLUSION: The media can still play a key advocacy role in such environments, and advocates need to be particularly vigilant for opportunities that do arise. The paper also highlights the increasingly important role of internet-based media, including opportunities presented by social media for tobacco control. PMID- 23088485 TI - Alcohol management in community sports clubs: impact on viability and participation. AB - ISSUE ADDRESSED: Whether improved alcohol management delivers additional benefits to clubs in the form of financial viability, expanded membership, increased spectators and greater capacity for competition. METHODS: Measures were derived from 657 Australian community sporting clubs enrolled in the Good Sports program. The program assists clubs to manage alcohol through an accreditation process that sets minimum standards for regulatory compliance, club practices and policies. Measures were taken from survey information collected prior to Level 1 accreditation and at the third and final level of club accreditation. RESULTS: Income was found to increase and reliance on alcohol as a funding source was found to diminish over time. Membership increased and was accelerated among females, young people and non-players. No changes in the number of junior and senior teams or players were found. CONCLUSIONS: Improved alcohol management can produce a range of benefits beyond responsible drinking patterns that add to club sustainability. PMID- 23088486 TI - Fulfilling our mission to facilitate communication between researchers, practitioners and policy makers. PMID- 23088487 TI - Long-term changes of sexual function in men with obstructive sleep apnea after initiation of continuous positive airway pressure. AB - INTRODUCTION: Obstructive sleep apnea (OSA), particularly intermittent nocturnal hypoxemia, is associated with erectile dysfunction (ED). AIM: We investigated in patients with OSA whether continuous positive airway pressure (CPAP) therapy has a long-term effect on sexual function, including ED, in the presence of other risk factors for ED. METHODS: Within a long-term observational design, we reassessed 401 male patients who had been referred for polysomnography, with respect to erectile and overall sexual function. Mean +/- standard deviation follow-up time was 36.5 +/- 3.7 months. Patients with moderate to severe ED were stratified according to the regular use of CPAP. MAIN OUTCOME MEASURE: Changes of sexual function were assessed by the 15-item International Index of Erectile Function (IIEF-15) questionnaire, including the domains erectile function (EF), intercourse satisfaction, orgasmic function (OF), sexual desire (SD), and overall satisfaction (OS). RESULTS: Of the 401 patients, 91 returned a valid IIEF-15 questionnaire at follow-up. Their baseline characteristics were not different from those of the total study group. OSA (apnea-hypopnea index >5/hour) had been diagnosed in 91.2% of patients. In patients with moderate to severe ED (EF domain <17), CPAP users (N = 21) experienced an improvement in overall sexual function (IIEF-15 summary score; P = 0.014) compared with CPAP non-users (N = 18), as well as in the subdomains OF (P = 0.012), SD (P = 0.007), and OS (P = 0.033). Similar results were obtained in patients with poor overall sexual dysfunction (IIEF-15 summary score <44). In patients with moderate to severe ED and low mean nocturnal oxygen saturation (<=93%, median), also the EF subdomain improved in CPAP users vs. non-users (P = 0.047). CONCLUSIONS: These data indicate that long-term CPAP treatment of OSA and the related intermittent hypoxia can improve or preserve sexual function in men with OSA and moderate to severe erectile or sexual dysfunction, suggesting a certain reversibility of OSA-induced sexual dysfunctions. PMID- 23088488 TI - Relearning attenuates the benefits and costs of spacing. AB - The literature on spacing effects is vast, but no prior research has examined the effects of initial spacing when students learn to criterion and then subsequently relearn items. In addition, minimal research has evaluated the costs associated with spaced practice as well as the benefits. Accordingly, in the current research, we examined the benefits and costs of initial spacing using Bahrick's (1979) method of successive relearning. Across 3 experiments, 567 students practiced key term definitions via test-restudy practice until items were correctly recalled 1 or 3 times during initial learning. Practice trials during initial learning were either massed or spaced (including relatively longer lags in all experiments as well as intermediate lags in Experiment 1). All students then relearned items in 2-3 subsequent relearning sessions (across experiments, almost 40,000 short-answer recall responses were collected and hand scored). The benefits of initial spacing were measured by interim cued recall tests and a final test administered days or weeks after relearning, and costs were measured by total practice time across sessions. A consistent qualitative pattern emerged: The benefits of initial spacing were substantial prior to relearning but were significantly attenuated after relearning. Moreover, the costs associated with achieving criterion via spaced practice during initial learning were also substantially attenuated by faster relearning in subsequent sessions. PMID- 23088489 TI - Process benchmarking appraisal of surgical decompression of spinal cord following traumatic cervical spinal cord injury: opportunities to reduce delays in surgical management. AB - Prior pre-clinical and clinical studies indicate that early decompression of the spinal cord (<= 24 h post-trauma) may have benefits regarding clinical outcomes and neurological recovery after spinal cord injury (SCI). This study examines the benchmarking of management of patients with acute traumatic cervical SCI in order to determine the potential barriers and ideal timelines for each step to early surgical decompression. We reviewed patient charts and the Surgical Trial in Acute Spinal Cord Injury Study (STASCIS) forms regarding the time and reasons for delay of each step in the management of patients with SCI. The reasons for delays were classified into: 1) health care-related ("extrinsic") factors and 2) patient related ("intrinsic") factors. The cases were grouped into patients who underwent early surgical decompression of spinal cord (early-surgery group) and individuals who underwent later decompression (later-surgery group). Whereas both groups showed comparable time periods related to intrinsic factors, patients in the early surgery group had a significantly shorter time period associated with extrinsic factors when compared with the later surgery group. Both groups were comparable regarding pre-hospital time, time in a second general hospital prior to transfer to a spine center, and time in the trauma emergency department. Patients in the early surgery group had a significantly shorter waiting time, shorter waiting time for assessment by a spine surgeon, and a shorter waiting time for a surgical decision than did the later surgery group. Our benchmarking analysis suggests that health-related factors are key determinants of the timing from SCI to spinal cord decompression. Time in the general hospital and time of waiting for a surgical decision were the most important causes of delay of surgical spinal cord decompression. Early surgery is possible in the vast majority of the cases. PMID- 23088490 TI - Effect of peptide and guest charge on the structural, mechanical and release properties of beta-sheet forming peptides. AB - The effect of peptide charge on the self-assembly, gelation behavior, and model drug release profiles has been explored here for three octa-peptides, VEVKVEVK (VEK2), VKVKVEVK (VEK3), and VEVEVKVE (VEK1), that carry a net charge of 0, +2, and -2 at neutral pH, respectively. Transparent, self-supporting hydrogels were found to form above a critical concentration when the peptide charge modulus was >1 and this was independent of the sign of the charge. TEM, SAXS, and shear rheology revealed that there were no differences in hydrogel structure or mechanical properties when the peptides were at the same concentration and carried the same charge modulus. All peptides were found to form dense fibrillar networks formed by beta-sheet rich single fibers where lateral aggregation of the fibers occurred and increased with decreasing charge modulus. Such behavior was found to correlate with an increase in hydrogel mechanical properties, demonstrating that fiber lateral aggregation is inextricably linked with the mechanical properties of these hydrogels. Two hydrophilic model drug molecules, namely napthol yellow (NY) and martius yellow (MY), were subsequently incorporated within the VEK1 and VEK3 hydrogels at pH 7 and although they did not effect the self-assembly of the peptide at a molecular level, they did effect the level of lateral fiber aggregation observed and, therefore, the mechanical properties of the hydrogels. The release of each molecule from the hydrogels was monitored over time and shown to be controlled by Fickian diffusion where the diffusion rate, D, was dependent on the ratio between the overall effective charges carried by the peptide, i.e., the fibrillar network, and the overall charges carried by the guest molecules, but independent from the hydrogel concentration and mechanical properties within the ranges investigated. This work highlights the possibility of controlling the rate of release of small drug molecules by manipulating the charges on the guest molecules as well as the charged state of the self-assembling peptide. PMID- 23088491 TI - Stepwise adsorption of phenanthrene at the fly ash-water interface as affected by solution chemistry: experimental and modeling studies. AB - Fly ash (FA) is predominantly generated from coal-fired power plants. Contamination during disposal of FA can cause significant environmental problems. Knowledge about the interaction of FA and hydrophobic organic pollutants in the environment is very limited. This study investigated the adsorption of phenanthrene at the interface of FA and water. The performance of phenanthrene adsorption on FA and the effects of various aqueous chemistry conditions were evaluated. The adsorption isotherms exhibited an increasing trend in the adsorbed amounts of phenanthrene, while a stepwise pattern was apparent. A stepwise multisite Langmuir model was developed to simulate the stepwise adsorption process. The adsorption of phenanthrene onto FA was noted to be spontaneous at all temperatures. The thermodynamic results indicated that the adsorption was an exothermic process. The adsorption capacity gradually decreased as pH increased from 4 to 8; however, this trend became less significant when pH was changed from 8 to 10. The binding affinity of phenanthrene to FA increased after the addition of humic acid (HA). The pH variation was also responsible for the changes of phenanthrene adsorption on FA in the presence of HA. High ionic strength corresponded to low mobility of phenanthrene in the FA-water system. Results of this study can help reveal the migration patterns of organic contaminants in the FA-water system and facilitate environmental risk assessment at FA disposal sites. PMID- 23088493 TI - Single-crystalline octahedral Au-Ag nanoframes. AB - We report the formation of single-crystalline octahedral Au-Ag nanoframes by a modified galvanic replacement reaction. Upon sequential addition of AgNO(3), CuCl, and HAuCl(4) to octadecylamine solution, truncated polyhedral silver nanoparticles formed first and then changed into octahedral Au-Ag nanoframes, without requiring a conventional Ag removal step with additional oxidation etchant. The nanoframes have 12 sides, and all of the eight {111} faces are empty. The side grows along the [110] direction, and the diameter is less than 10 nm. The selective gold deposition on the high-energy (110) surface, the diffusion, and the selective redeposition of Au and Ag atoms are the key reasons for the formation of octahedral nanoframes. PMID- 23088492 TI - Ca(2+) modulation of ANF-RGC: new signaling paradigm interlocked with blood pressure regulation. AB - ANF-RGC is the prototype receptor membrane guanylate cyclase that is both the receptor and the signal transducer of the most hypotensive hormones, ANF and BNP. It is a single-transmembrane protein. After binding these hormones at the extracellular domain, ANF-RGC at its intracellular domain signals the activation of the C-terminal catalytic module and accelerates the production of the second messenger, cyclic GMP, which controls blood pressure, cardiac vasculature, and fluid secretion. At present, this is the sole transduction mechanism and the physiological function of ANF-RGC. Through comprehensive studies involving biochemistry, immunohistochemistry, and blood pressure measurements in mice with targeted gene deletions, this study demonstrates a new signaling model of ANF-RGC that also controls blood pressure. In this model, (1) ANF-RGC is not the transducer of ANF and BNP, (2) its extracellular domain is not used for signaling, and (3) the signal flow is not downstream from the extracellular domain to the core catalytic domain. Instead, the signal is the intracellular Ca(2+), which is translated at the site of its reception, at the core catalytic domain of ANF-RGC. A model for this Ca(2+) signal transduction is diagrammed. It captures Ca(2+) through its Ca(2+) sensor myristoylated neurocalcin delta and upregulates ANF-RGC activity with a K(1/2) of 0.5 MUM. The neurocalcin delta modulated domain resides in the (849)DIVGFTALSAESTPMQVV(866) segment of ANF-RGC, which is a part of the core catalytic domain. Thereby, ANF-RGC is primed to receive, transmit, and translate the Ca(2+) signals into the generation of cyclic GMP at a rapid rate. The study defines a new paradigm of membrane guanylate cyclase signaling, which is linked to the physiology of cardiac vasculature regulation and possibly also to fluid secretion. PMID- 23088495 TI - Bootstrap confidence intervals for the mean correlation corrected for Case IV range restriction: a more adequate procedure for meta-analysis. AB - In this study, we proposed to use the nonparametric bootstrap procedure to construct the confidence interval for the mean correlation r corrected for Case IV range restriction in meta-analysis (i.e., ; Hunter, Schmidt, & Le, 2006). A comprehensive Monte Carlo study was conducted to evaluate the accuracy of the parametric confidence interval and 3 nonparametric bootstrap confidence intervals for r(c4). Of the 4 intervals, our results showed that the bootstrap bias corrected and accelerated percentile interval (BCaI) yielded the most accurate results across different data situations. In addition, the mean-corrected correlation r(c4) was found to be more accurate than the uncorrected estimate. Implications of the mean-corrected correlation r(c4) and BCaI in organizational studies are also discussed. PMID- 23088494 TI - Alterations of the SWI/SNF chromatin remodelling subunit-BRG1 and BRM in hepatocellular carcinoma. AB - BACKGROUND: The SWI/SNF chromatin remodelling complex, which contains either brahma-related gene-1 (BRG1) or brahma (BRM) as the catalytic ATPase, functions as a master regulator of gene expression. AIMS: To examine alterations of BRG1 and BRM in hepatocellular carcinoma (HCC). METHODS: We investigated DNA copy number aberrations in human HCC cell lines using a high-density oligonucleotide microarray. We determined DNA copy numbers and expression levels of BRG1 and BRM genes in primary HCC tumours, and conducted further searches for mutations in BRG1 and BRM genes. RESULTS: Homozygous deletion of the BRG1 gene was found in HCC cell line SNU398. Copy number losses of BRG1 and BRM genes were observed in 14 (26%) and 7 (13%) of 54 primary HCC tumours respectively. We found four somatic missense mutations in the BRG1 gene in two of 36 primary HCC tumours, but no mutations in BRM gene. Expression of BRM mRNA, but not BRG1 mRNA, was significantly reduced in primary HCC tumours, compared to non-tumour tissue counterparts. Immunohistochemical analyses of non-tumour liver tissues showed that BRM protein was expressed in hepatocytes and bile-duct epithelial cells, whereas BRG1 protein was expressed in bile-duct epithelial cells, but not in hepatocytes. BRM protein expression was lost in nine (22.5%) of 40 HCC tumours. Loss of BRM protein expression was significantly associated with poor overall survival. CONCLUSION: Reduced expression of BRM may contribute to the carcinogenesis of HCC. Although deletions and mutations in BRG1 gene were identified, the role of BRG1 in HCC tumourigenesis remains unclear. PMID- 23088496 TI - Higher heart rate increases risk of diabetes among men: The Australian Diabetes Obesity and Lifestyle (AusDiab) Study. AB - AIMS: A very limited number of prospective studies have reported conflicting data on the relation between heart rate and diabetes risk. Our aim therefore was to determine in a large, national, population-based cohort if heart rate predicts the development of diabetes. METHODS: The Australian Diabetes Obesity and Lifestyle study followed up 6537 people over 5 years. Baseline measurements included questionnaires, anthropometrics and blood and urine collection. Heart rate was recorded in beats per min (Dinamap). An oral glucose tolerance test was performed at baseline and follow-up, and diabetes was defined using World Health Organization criteria. RESULTS: A total of 5817 participants were eligible for analysis, 221 of whom developed diabetes. Compared with participants with a heart rate < 60 b min(-1), those with a heart rate >= 80 b min(-1) were more likely to develop diabetes (odds ratio 1.89, 95% CI 1.07-3.35) over 5 years, independent of traditional risk factors. This relationship was highly significant, particularly in non-obese men (odds ratio 5.61, 95% CI 1.75-17.98), but not in their obese counterparts or in women. CONCLUSIONS: Resting heart rate is associated with an increased risk of diabetes over a 5-year period, particularly among non-obese men. This suggests that sympathetic overactivity may be a contributing factor to the development of diabetes, and that resting heart rate may be useful in predicting risk of Type 2 diabetes in non-obese men. PMID- 23088498 TI - Bicyclization and tethering to albumin yields long-acting peptide antagonists. AB - Proteolytically stable peptide architectures are required for the development of long-acting peptide therapeutics. In this work, we found that a phage-selected bicyclic peptide antagonist exhibits an unusually high stability in vivo and subsequently deciphered the underlying mechanisms of peptide stabilization. We found that the bicyclic peptide was significantly more stable than its constituent rings synthesized as two individual macrocycles. The two rings protect each other from proteolysis when linked together, conceivably by constraining the conformation and/or by mutually shielding regions prone to proteolysis. A second stabilization mechanism was found when the bicyclic peptide was linked to an albumin-binding peptide to prevent its rapid renal clearance. The bicyclic peptide conjugate not only circulated 50-fold longer (t(1/2) = 24 h) but also became entirely resistant to proteolysis when tethered to the long-lived serum protein. The bicyclic peptide format overcomes a limitation faced by many peptide leads and appears to be suitable for the generation of long-acting peptide therapeutics. PMID- 23088497 TI - Defining regulatory and phosphoinositide-binding sites in the human WIPI-1 beta propeller responsible for autophagosomal membrane localization downstream of mTORC1 inhibition. AB - BACKGROUND: Autophagy is a cytoprotective, lysosomal degradation system regulated upon induced phosphatidylinositol 3-phosphate (PtdIns(3)P) generation by phosphatidylinositol 3-kinase class III (PtdIns3KC3) downstream of mTORC1 inhibition. The human PtdIns(3)P-binding beta-propeller protein WIPI-1 accumulates at the initiation site for autophagosome formation (phagophore), functions upstream of the Atg12 and LC3 conjugation systems, and localizes at both the inner and outer membrane of generated autophagosomes. In addition, to a minor degree WIPI-1 also binds PtdIns(3,5)P2. By homology modelling we earlier identified 24 evolutionarily highly conserved amino acids that cluster at two opposite sites of the open Velcro arranged WIPI-1 beta-propeller. RESULTS: By alanine scanning mutagenesis of 24 conserved residues in human WIPI-1 we define the PtdIns-binding site of human WIPI-1 to critically include S203, S205, G208, T209, R212, R226, R227, G228, S251, T255, H257. These amino acids confer PtdIns(3)P or PtdIns(3,5)P2 binding. In general, WIPI-1 mutants unable to bind PtdIns(3)P/PtdIns(3,5)P2 lost their potential to localize at autophagosomal membranes, but WIPI-1 mutants that retained PtdIns(3)P/PtdIns(3,5)P2 binding localized at Atg12-positive phagophores upon mTORC1 inhibition. Both, downregulation of mTOR by siRNA or cellular PtdIns(3)P elevation upon PIKfyve inhibition by YM201636 significantly increased the localization of WIPI-1 at autophagosomal membranes. Further, we identified regulatory amino acids that influence the membrane recruitment of WIPI-1. Exceptional, WIPI-1 R110A localization at Atg12-positive membranes was independent of autophagy stimulation and insensitive to wortmannin. R112A and H185A mutants were unable to bind PtdIns(3)P/PtdIns(3,5)P2 but localized at autophagosomal membranes, although in a significant reduced number of cells when compared to wild-type WIPI-1. CONCLUSIONS: We identified amino acids of the WIPI-1 beta-propeller that confer PtdIns(3)P or PtdIns(3,5)P2 binding (S203, S205, G208, T209, R212, R226, R227, G228, S251, T255, H257), and that regulate the localization at autophagosomal membranes (R110, R112, H185) downstream of mTORC1 inhibition. PMID- 23088499 TI - Two new alkaloids from a marine-derived fungus Neosartorya sp.HN-M-3. AB - Two new indole alkaloids, tryptoquivalines P and Q, have been isolated from a marine-derived fungus Neosartorya sp.HN-M-3. Their structures were determined on the basis of spectroscopic methods. PMID- 23088500 TI - Favorable selection, risk adjustment, and the Medicare Advantage program. AB - OBJECTIVES: To examine the effects of changes in payment and risk adjustment on (1) the annual enrollment and switching behavior of Medicare Advantage (MA) beneficiaries, and (2) the relative costliness of MA enrollees and disenrollees. DATA: From 1999 through 2008 national Medicare claims data from the 5 percent longitudinal sample of Parts A and B expenditures. STUDY DESIGN: Retrospective, fixed effects regression analysis of July enrollment and year-long switching into and out of MA. Similar regression analysis of the costliness of those switching into (out of) MA in the 6 months prior to enrollment (after disenrollment) relative to nonswitchers in the same county over the same period. FINDINGS: Payment generosity and more sophisticated risk adjustment were associated with substantial increases in MA enrollment and decreases in disenrollment. Claims experience of those newly switching into MA was not affected by any of the policy reforms, but disenrollment became increasingly concentrated among high-cost beneficiaries. CONCLUSIONS: Enrollment is very sensitive to payment levels. The use of more sophisticated risk adjustment did not alter favorable selection into MA, but it did affect the costliness of disenrollees. PMID- 23088502 TI - Characteristics of colored passive layers on zirconium: morphology, optical properties, and corrosion resistance. AB - Brightly colored and uniform passive layers on Zr can be formed by applying alternating current (ac) voltage (V(ac)) for 10 s in 10 wt % aqueous Na(2)SO(4) solution at T = 298 K. The coloration originating from iridescence can be fine tuned by adjusting V(ac) in the 10-80 V range. Visible light microscopy analysis shows that different grains reveal two or three different colors due to the polycrystalline nature of Zr, and the resultant coloration is the sum of these contributions. Reflectance spectroscopy spectra show maxima that can be related to the coloration displayed by various grains. Surface morphology and roughness in the micrometer and nanometer ranges are examined using stylus surface profilometry and atomic force microscopy. The formation of colored passive layers on polished Zr makes them smoother but their formation on etched Zr decreases the roughness in the case of low V(ac) and increases in the case of high V(ac). Focused ion beam and scanning electron microscopy are used to determine the thickness (d) of the colored passive layer on etched Zr. It is found that d is in the 51-264 nm range and increases linearly with V(ac). Scanning transmission electron microscopy and electron back scattered diffraction measurements demonstrate that the colored passive layers are uniform and crystalline in nature. Corrosion behavior of the colored passive layers in 1 wt % aqueous NaCl solution is examined using inductively coupled plasma-mass spectrometry. The results indicate that the polished samples hardly undergo any corrosion and the amount of dissolved Zr does not exceed 12 ppb even after exposure for 56 days. On the other hand, the corrosion of the etched samples is ~3 orders of magnitude greater than that of the polished ones, and the amount of dissolved Zr approaches 970 ppb after exposure for 56 days. Corrosion behavior of etched and colored passive layers on Zr in 1 wt % aqueous NaCl solution is also analyzed by recording potentiodynamic polarization curves in the -1.0 to 3.0 V vs RHE range at a scan rate of s = 1 mV s(-1) and at T = 298 K. They have similar shapes but the formation of colored passive layers decreases the current density (j) at any given potential (E), and the thicker the passive layer the greater the reduction in j. The development of colored passive layers on etched Zr increases the corrosion potential (E(corr)) and decreases the corrosion current density (j(corr)). PMID- 23088501 TI - Individual and institutional determinants of caesarean section in referral hospitals in Senegal and Mali: a cross-sectional epidemiological survey. AB - BACKGROUND: Two years after implementing the free-CS policy, we assessed the non financial factors associated with caesarean section (CS) in women managed by referral hospitals in Senegal and Mali. METHODS: We conducted a cross-sectional survey nested in a cluster trial (QUARITE trial) in 41 referral hospitals in Senegal and Mali (10/01/2007-10/01/2008). Data were collected regarding women's characteristics and on available institutional resources. Individual and institutional factors independently associated with emergency (before labour), intrapartum and elective CS were determined using a hierarchical logistic mixed model. RESULTS: Among 86 505 women, 14% delivered by intrapartum CS, 3% by emergency CS and 2% by elective CS. For intrapartum, emergency and elective CS, the main maternal risk factors were, respectively: previous CS, referral from another facility and suspected cephalopelvic-disproportion (adjusted Odds Ratios from 2.8 to 8.9); vaginal bleeding near full term, hypertensive disorders, previous CS and premature rupture of membranes (adjusted ORs from 3.9 to 10.2); previous CS (adjusted OR=19.2 [17.2-21.6]). Access to adult and neonatal intensive care, a 24-h/day anaesthetist and number of annual deliveries per hospital were independent factors that affected CS rates according to degree of urgency. The presence of obstetricians and/or medical-anaesthetists was associated with an increased risk of elective CS (adjusted ORs [95%CI] = 4.8 [2.6 8.8] to 9.4 [5.1-17.1]). CONCLUSIONS: We confirm the significant effect of well known maternal risk factors affecting the mode of delivery. Available resources at the institutional level and the degree of urgency of CS should be taken into account in analysing CS rates in this context. PMID- 23088503 TI - The impact of parental bonding on sexual distress in women with type 1 diabetes mellitus. AB - INTRODUCTION: Psychosomatic and social issues have been found to be determinants of sexual distress in diabetic and non-diabetic populations. However, the role of parental bonding as a determinant for sexual distress has not been studied in women with type 1 diabetes mellitus (DM-1). AIM: To study the role of parental care and overprotection, in the pathogenesis of sexual distress in women with DM 1. METHODS: Seventy-seven women with uncomplicated DM-1 and 77 healthy controls were enrolled in the study. The Female Sexual Distress Scale (FSDS), the General Health Questionnaire-28, and the Parental Bonding Instrument were used to evaluate sexual distress, general health and bonding with parents, respectively. MAIN OUTCOME MEASURES: To assess the role of parental bonding as risk factor for sexual distress, in women with DM-1. RESULTS: Women with DM-1 had significantly higher FSDS scores compared with controls. Furthermore, women with DM-1 had significantly higher maternal and paternal care, and lower maternal overprotection in comparison with the healthy ones. Paternal overprotection and general health were similar in both groups (P > 0.05). Sexual distress was more frequent in women with DM-1 (31.43% vs. 8.57% of controls, P < 0.05). Diabetic women with sexual distress had lower maternal care, higher maternal overprotection and lower paternal overprotection compared to diabetics without sexual distress (P < 0.05). No difference was found in the paternal care between the two groups (P > 0.05). Moreover, sexually distressed DM-1 women had worse general health parameters in comparison with the non-sexually distressed diabetics (P < 0.05). In the DM-1 group, low maternal care and low paternal overprotection were significant risk factors for sexual distress (P < 0.05). CONCLUSIONS: Parental care and overprotection can lead to sexual distress and, therefore, to Female Sexual Dysfunction in DM-1 women. Evaluation of parental bonding is necessary in DM-1 women with distressing sexual problems. PMID- 23088505 TI - Cloud CPFP: a shotgun proteomics data analysis pipeline using cloud and high performance computing. AB - We have extended the functionality of the Central Proteomics Facilities Pipeline (CPFP) to allow use of remote cloud and high performance computing (HPC) resources for shotgun proteomics data processing. CPFP has been modified to include modular local and remote scheduling for data processing jobs. The pipeline can now be run on a single PC or server, a local cluster, a remote HPC cluster, and/or the Amazon Web Services (AWS) cloud. We provide public images that allow easy deployment of CPFP in its entirety in the AWS cloud. This significantly reduces the effort necessary to use the software, and allows proteomics laboratories to pay for compute time ad hoc, rather than obtaining and maintaining expensive local server clusters. Alternatively the Amazon cloud can be used to increase the throughput of a local installation of CPFP as necessary. We demonstrate that cloud CPFP allows users to process data at higher speed than local installations but with similar cost and lower staff requirements. In addition to the computational improvements, the web interface to CPFP is simplified, and other functionalities are enhanced. The software is under active development at two leading institutions and continues to be released under an open-source license at http://cpfp.sourceforge.net. PMID- 23088504 TI - Modulation of BMP-2-induced chondrogenic versus osteogenic differentiation of human mesenchymal stem cells by cell-specific extracellular matrices. AB - Bone morphogenetic protein-2 (BMP-2) is known to induce both osteogenic and chondrogenic commitment of human mesenchymal stem cells (hMSCs). However, factors influencing BMP-2-dependent chondrogenic and osteogenic differentiation have not been investigated. In this study, we demonstrated that extracellular microenvironments, in the form of cell-derived matrices, play important roles in determining the specific lineage commitment of hMSCs in the presence of BMP-2. Extracellular matrices (ECMs) derived from osteoblasts and chondrocytes were utilized to regulate cell differentiation. Osteogenic and chondrogenic differentiation of hMSCs cultured on the two different cell-derived ECMs were assessed by quantitative real-time-polymerase chain reaction, immunocytochemistry, and western blot analysis. To minimize the effects of the cell-adhesion proteins contained in serum on the ECMs, hMSCs were cultured in serum-free osteogenic or chondrogenic differentiation medium. Fibronectin-, collagen type I-, or collagen type II-coated substrates were utilized as ECM controls. The ECM specific to each cell type promoted lineage-specific commitment of hMSCs in the presence of BMP-2, that is, osteoblast- and chondrocyte-derived ECM promoted osteogenic and chondrogenic commitment, respectively. Therefore, cell-specific ECMs are capable of modulating the BMP-2-induced osteogenic and chondrogenic differentiation of hMSCs. PMID- 23088506 TI - A binational comparison of HIV provider attitudes towards the use of complementary and alternative medicine among HIV-positive Latino patients receiving care in the US-Mexico border region. AB - Use of complementary and alternative medicine (CAM) is common among Latinos living with HIV in the United States (US)-Mexico border region. Health providers may vary in their approach to communicating acceptance or non acceptance of CAM use, which can undermine patient confidence in disclosing CAM use. Patient provider communication about CAM is important because certain types of CAM can affect antiretroviral therapy (ART) adherence. We undertook the present binational study to understand US and Mexican provider beliefs, and perceptions surrounding CAM use among Latino patients, and to learn if and how CAM communication occurs. Between July and December 2010, we conducted in-depth, qualitative interviews in Tijuana and San Diego. Analysis procedures drew upon principles of Grounded Theory. The sample was comprised of 19 HIV-health care providers, including 7 women and 12 men. Emerging CAM-related themes were: Provider's perceptions, attitudes and knowledge about CAM; CAM types and modalities; and patient-provider CAM communication. Many clinicians were uncomfortable supporting CAM use with their patients. San Diego providers reported more frequent instances of CAM use among Latino patients than Tijuana providers. Providers from both cities reported that patients infrequently disclose CAM use and almost half do not routinely ask patients about CAM practices. Most of the providers acknowledged that they lack information about CAM, and are concerned about the drug interaction as well as the effects of CAM on adherence. Our findings have important implications for understanding provider communication surrounding CAM use in a highly transnational population and context. Because CAM use may undermine ART adherence and is highly prevalent among Latinos, provider communication about CAM is critical to improved health outcomes among HIV-positive Latinos. Considering the significant growth of US Latinos, especially in the US-Mexico border region, assessment of Mexican and US provider training and communication needs surrounding Latino patient CAM use is warranted. PMID- 23088507 TI - Auditory discrimination of frequency ratios: the octave singularity. AB - Sensitivity to frequency ratios is essential for the perceptual processing of complex sounds and the appreciation of music. This study assessed the effect of ratio simplicity on ratio discrimination for pure tones presented either simultaneously or sequentially. Each stimulus consisted of four 100-ms pure tones, equally spaced in terms of frequency ratio and presented at a low intensity to limit interactions in the auditory periphery. Listeners had to discriminate between a reference frequency ratio of 0.97 octave (about 1.96:1) and target frequency ratios, which were larger than the reference. In the simultaneous condition, the obtained psychometric functions were nonmonotonic: as the target frequency ratio increased from 0.98 octave to 1.04 octaves, discrimination performance initially increased, then decreased, and then increased again; performance was better when the target was exactly one octave (2:1) than when the target was slightly larger. In the sequential condition, by contrast, the psychometric functions were monotonic and there was no effect of frequency ratio simplicity. A control experiment verified that the non monotonicity observed in the simultaneous condition did not originate from peripheral interactions between the tones. Our results indicate that simultaneous octaves are recognized as "special" frequency intervals by a mechanism that is insensitive to the sign (positive or negative) of deviations from the octave, whereas this is apparently not the case for sequential octaves. PMID- 23088508 TI - Extraction of linguistic information from successive words during reading: evidence for spatially distributed lexical processing. AB - Two experiments examined whether word recognition progressed from one word to the next during reading, as maintained by sequential attention shift models such as the E-Z Reader model. The boundary technique was used to control the visibility of to-be-identified short target words, so that they were either previewed in the parafovea or masked. The eyes skipped a masked target on more than a quarter of the trials, and the following fixation must have been mislocated, if word recognition and saccade targeting progressed from one word to the next. Readers responded to the skipping parafoveally masked target words with relatively long viewing duration for the following posttarget word or with corrective saccades that returned the eyes from the posttarget word to the target. Experiment 2 manipulated the time-line of posttarget onset after target skipping, so that the posttarget word was either visible immediately upon fixation or after a short delay. The delay influenced posttarget viewing even when attention should have been focused at the target location according to E-Z Reader 10 simulations. These findings favor theoretical conceptions according to which lexical processing can encompass more than one word at a time. PMID- 23088509 TI - Impact of age and sex on carotid and peripheral arterial wall thickness in humans. AB - BACKGROUND: Although previous studies have reported age-related wall thickening in carotid arteries, it is not clear whether this is a systemic phenomenon which is also apparent in peripheral conduit arteries or whether conduit wall thickness (WT) changes occur to a similar degree in men and women. AIM: To determine whether sex modifies the impact of ageing on WT or wall-to-lumen ratio (W:L) in atherosclerosis-prone (i.e. carotid artery, femoral, superficial femoral, popliteal artery) and atherosclerosis-resistant (i.e. brachial artery) conduit arteries. METHODS: We included 30 young (23 +/- 2 year; 15M : 15F) and 31 older (70 +/- 5 year; 18M : 13F) healthy subjects. High-resolution ultrasound was used to measure diameter, WT and wall-to-lumen ratio (W/L) in all arteries. RESULTS: Older subjects had increased WT and W/L in the carotid, femoral, superficial femoral, popliteal and brachial arteries (all P < 0.05). Compared with women, men demonstrated larger diameter and WT (both P < 0.01) across all arteries. Sex did not impact upon age-related changes in WT or W/L (P = 0.39 and 0.43 respectively). CONCLUSION: Our data suggest that age-related wall thickening, evident in the carotid artery, is also apparent in the arteries of the upper and lower limbs. The impact of age on wall thickening did not differ between men and women. These data support the presence of systemic increases in WT and W/L with age in apparently healthy humans, independent of sex. PMID- 23088510 TI - A unifying stereochemical analysis for the formation of halogenated C15 acetogenin medium-ring ethers from Laurencia species via intramolecular bromonium ion assisted epoxide ring-opening and experimental corroboration with a model epoxide. AB - A unifying stereochemical analysis for the formation of the constitutional isomeric halogenated C(15)-acetogenin medium-ring ether natural products from Laurencia species is presented, where an intramolecular bromonium ion assisted epoxide ring-opening reaction of enantiomerically pure epoxides can account for ring-size, the position of the halogen substituents, and relative and absolute configurations of the known natural products. Experimentally, a model epoxide corroborates the feasibility of this process for concurrent formation of 7-, 8- and 9-ring ethers corresponding to the halogenated medium-ring ethers of known metabolites from Laurencia species. PMID- 23088511 TI - pH-controllable water permeation through a nanostructured copper mesh film. AB - Water permeation is an important issue in both fundamental research and industrial applications. In this work, we report a novel strategy to realize the controllable water permeation on the mixed thiol (containing both alkyl and carboxylic acid groups) modified nanostructured copper mesh films. For acidic and neutral water, the film is superhydrophobic, and the water cannot permeate the film because of the large negative capillary effect resulting from the nanostructures. For basic water, the film shows superhydrophilic property, and thus the water can permeate the film easily. The permeation process of water can be controlled just by simply altering the water pH. A detailed investigation indicates that nanostructures on the substrate and the appropriate size of the microscale mesh pores can enhance not only the static wettability but also the dynamic properties. The excellent controllability of water permeation is ascribed to the combined effect of the chemical variation of the carboxylic acid group and the microstructures on the substrate. This work may provide interesting insight into the new applications that are relevant to the surface wettability, such as filtration, microfluidic device, and some separation systems. PMID- 23088512 TI - Effect of the use of a ready-made plastic stent on the peri-implant soft tissue. AB - OBJECTIVE: This study compared the effect of the use of a ready-made plastic stent on the width of peri-implant keratinized mucosa with that of conventional methods and examined the effects of a plastic stent on peri-implant soft tissue. MATERIALS AND METHODS: Five young-adult beagle dogs were used. Forty titanium implants were placed in the mandibular alveolar ridge. Stage 2 surgery was performed 8 weeks after implant installation. Each dog received a full-thickness, apically positioned flap (fAPF) with a lingual crestal incision using a suture material in the control group (n = 20) and a ready-made plastic stent in the test group (n = 20). The keratinized mucosa width after stage 2 surgery was measured in each group. The pocket depth, length of connective-tissue contact and biological width were measured in the tissue samples. A student's t-test was used to test the differences between the groups (95% confidence level). RESULTS: The width of the keratinized mucosa was significantly higher and the distance from the top of the implant platform to the mucogingival junction was significantly longer in the test group than the control group. Histometric observations revealed the pocket depth and biological width to be significantly lower in the test group than the control group. CONCLUSION: The use of a fAPF with a lingual crestal incision using a ready-made plastic stent can effectively preserve or enhance the width of the keratinized mucosa and might restore a more optimal biological environment at the early soft-tissue healing stage. PMID- 23088513 TI - Flexibility is not always adaptive: affective flexibility and inflexibility predict rumination use in everyday life. AB - The present study examined whether cognitive flexibility in the processing of emotional material (i.e., affective flexibility) predicts the use of rumination in response to negative events in daily life. One hundred fifty-seven undergraduate participants completed daily diaries for six consecutive days. Affective flexibility was measured with a novel task-switching paradigm using emotional pictures. Results show that affective inflexibility when switching away from processing the emotional meaning of negative material was associated with increased use of rumination in daily life. In contrast, affective inflexibility when switching away from processing the emotional meaning of positive material was related to decreased use of rumination. Importantly, affective flexibility predicted use of rumination beyond non-affective measures of executive functioning. This is the first study to show that inflexibility is not uniformly associated with increased rumination but that inflexibility in the processing of positive material can predict lower levels of rumination. PMID- 23088515 TI - Prognosis of autoimmune hepatitis showing acute presentation. AB - AIM: The number of patients with autoimmune hepatitis (AIH) showing acute presentation has increased. This study aimed to assess their prognosis. METHODS: A survey of AIH patients by sending questionnaires was performed, and 96 patients showing acute presentation were investigated. RESULTS: The median age was 58 years and 78 patients (81%) were female. Eighty-four patients (88%) were positive for antinuclear antibody and/or anti-smooth muscle antibody. The median serum immunoglobulin G level was 2252 mg/dL. Twenty-five patients (26%) showed histological acute hepatitis. As initial treatment, 88 patients (92%) were treated with corticosteroid, and 28 of them received pulse steroid treatment. Overall, 11 patients (11%) reached fatal outcomes (nine death and two liver transplantation). Patients with histological acute hepatitis showed higher serum bilirubin levels, lower prothrombin activities and higher prothrombin time international normalized ratios (PT-INR) and reached fatal outcomes more frequently. With a multivariate logistic regression analysis, prothrombin activity and PT-INR at presentation was associated with fatal outcomes. Nine of 13 patients (69%) showing prothrombin activity of 40% or lower at presentation and nine of 19 patients (47%) showing PT-INR of 1.5 or higher reached fatal outcomes. Furthermore, of 13 patients showing prothrombin activity of 40% or lower and/or PT-INR of 1.5 or higher at presentation who were treated with pulse steroid treatment, four (31%) died from infectious disease. CONCLUSION: Prothrombin activity and PT-INR are prognostic factors for AIH showing acute presentation. Physicians should pay attention to the development of infectious disease when pulse steroid treatment is performed. PMID- 23088514 TI - Effect of the yellow passion fruit peel flour (Passiflora edulis f. flavicarpa deg.) in insulin sensitivity in type 2 diabetes mellitus patients. AB - BACKGROUND: A study with the yellow passion fruit peel flour showed positive action in blood glucose control as therapies' adjuvant in patients with type 2 diabetes mellitus. Therefore, we evaluated its effect on insulin sensitivity since there is a quest for studies that focus at better understanding of insulin resistance aspects in diabetic patients. Furthermore its relationship with chronic complications can also give good prospects for alternative treatments. METHODS: A total of 43 type 2 diabetes volunteers (28 females and 15 males) ingested 30 g/day of the yellow passion fruit peel flour for two months. The levels of blood glucose and fasting insulin, HOMA index and glycated hemoglobin were measured for each patient before and after dietary supplementation. RESULTS: There was a significant difference in the fasting blood glucose values (P = 0.000) and glycated hemoglobin (P = 0.032) after supplementation. It was also seen a reduction in HOMA IR (P = 0.005) in the supplemented group, however it was not observed changes in insulin values for females. HOMA beta (P = 0.000) showed significant increase in its values for the studied group. CONCLUSIONS: The supplementation used decreased insulin resistance in type 2 diabetic patients, suggesting a positive action in blood glucose control as adjuvant therapy in conventional treatments. PMID- 23088516 TI - Control of the orientation of symmetric poly(styrene)-block-poly(D,L-lactide) block copolymers using statistical copolymers of dissimilar composition. AB - The interactions of block copolymers with surfaces can be controlled by coating those surfaces with appropriate statistical copolymers. Usually, a statistical copolymer comprised of monomer units identical to those of the block copolymer is used; that is, typically a poly(styrene)-stat-poly(methyl methacrylate) (PS-stat PMMA) is used to direct the alignment of poly(styrene)-block-poly(methyl methacrylate) (PS-block-PMMA), and poly(styrene)-stat-poly(2-vinylpyridine) (PS stat-P2VP) has been used for poly(styrene)-block-poly(2-vinylpyridine) (PS-block P2VP). Reports of controlling the orientation of block copolymers with statistical copolymers with a dissimilar composition are limited. Here, we demonstrate that this method can be further extended to show that PS-stat-PMMA can be used to control the wetting properties of poly(styrene)-block-poly(D,L lactide) (PS-block-PDLA). Surfaces were modified with a series of cross-linked PS stat-PMMA-stat-glycidyl methacrylate terpolymers, and the surface chemistries and energies were assessed using angle-dependent X-ray photoelectron spectroscopy and the two-liquid harmonic method, respectively. From these experiments, an expected neutral compositional window was identified for symmetrical PS-block-PDLA. Moreover, high-resolution SEM, AD-XPS, and grazing-incidence SAXS measurements were used to evaluate the morphology of PS-block-PDLA as a function of the surface composition of the underlying cross-linked copolymer films, and the neutral composition was found to range from 32 to 38 mol % of PS, in the bulk polymer. Ultimately, we demonstrated the determination of nonpreferential surface compositions that allow the self-assembly of lamellae with sizes in the sub-10 nm regime that are oriented perpendicular to the substrate. These findings have important implications for the use of PS-block-PDLA block copolymers in directed self-assembly, most specifically in advanced lithographic processes. PMID- 23088517 TI - Sorafenib modulates the radio sensitivity of hepatocellular carcinoma cells in vitro in a schedule-dependent manner. AB - BACKGROUND: Hepatocellular carcinoma (HCC) has a high incidence and mortality. Radiotherapy and sorafenib have proven effective for HCC. Here, we investigated whether sorafenib modulated the response of HCC cells to irradiation in vitro, effect of timing of sorafenib, and the underlying mechanisms. METHODS: Cell viability of the HCC cell lines, SMMC-7721 and Bel-7402, was examined by the 3 (4,5-dimethylthiazol-2-yl)-5(3-carboxymethoxyphenyl)-2(4-sulfophenyl)-2 H terazolium (MTT) assays. Clonogenic growth assays of SMMC-7721 and Bel-7402 were determined by colony formation assays. DNA damage was assessed by monitoring gamma-HAX foci in irradiated cells with immunofluorescence microscopy, and cell cycle distribution changes were examined by flow cytometry. Effects of sorafenib (15 MUM) added 30 min prior to radiation (pre-irradiation sorafenib) of SMMC-7721 and BEL-7402 or 24 h post-irradiation (post-irradiation sorafenib) on irradiated SMMC-7721 and BEL-7402 cells were compared to those of radiation alone or no treatment. RESULTS: The effect of sorafenib was dependent on its time of addition in relationship to irradiation of cells. Pre-irradiation sorafenib did not significantly affect the viability of SMMC-7221 and BEL-7402 cells compared with irradiation treatment alone. In contrast, post-irradiation sorafenib increased the sensitivity of irradiated SMMC-7221 and BEL-7402 cells significantly in a time-dependent manner. Pre-irradiation sorafenib significantly increased the surviving fraction of SMMC-7221 and BEL-7402 cells in clonogenic assays whereas post-irradiation sorafenib significantly reduced the surviving fractions of SMMC 7221 and BEL-7402 cells. SMMC-7721 cells treated with sorafenib 30 min before irradiation had significantly fewer cells with gamma-H2AX foci (23.8 +/- 2.9%) than SMMC-7721 cells receiving radiation alone (59.9 +/- 2.4; P < 0.001). Similarly, BEL-7402 cells receiving sorafenib prior to irradiation had significantly fewer cells with gamma-H2AX foci (46.4 +/- 3.8%) than those receiving radiation alone (25.0 +/- 3.0%; P < 0.001). In addition, irradiation (6 Gy) caused a significant increase in the percentage of both SMMC-7721 and BEL 7402 cells in G2/M at 12 to 16 h post irradiation, which was markedly delayed by pre-irradiation sorafenib. CONCLUSIONS: Sorafenib combined with irradiation exerted a schedule-dependent effect in HCC cells in vitro, which has significant implications for the combined use of sorafenib and radiotherapy for HCC patients. PMID- 23088518 TI - The activity of gammadelta T cells against paediatric liver tumour cells and spheroids in cell culture. AB - BACKGROUND: Chemoresistance and advanced tumour stage at time of diagnosis are the major reasons for poor treatment results in hepatoblastoma (HB) and paediatric hepatocellular carcinoma (HCC). Positive results with transplantation of liver and bone marrow revealed the impact of the immune system on the treatment of liver malignancies. AIM: Cytotoxic-immune-cells-like natural killer (NK) and T cells are major player in the defence against developing tumours. This study aimed to specifically analyse the ability of ex-vivo expanded gammadelta T cells to recognise and lyse HB and HCC cell lines in coculture assays. METHODS: Cell viability after treatment with gammadelta T cells was evaluated with two HB (HUH6 and HepT1) and one HCC cell line (HC-AFW1) using a MTT-based cytotoxicity assay. The binding of T cells to target cells was monitored using immunofluorescence microscopy. RESULTS: Incubation of hepatic tumour cell lines with gammadelta T cells led to a significant decrease in tumour cell viability. This was enhanced by zoledronic acid and histone deacetylase inhibitors. MT110, an EpCAM/CD3-bispecific BiTE antibody could bluntly enhance tumour cell lysis close to completion. gammadelta T cells efficiently interacted with HB and HCC cells in a spheroid culture model. CONCLUSION: Bispecific antibodies such as MT110 might be used to intensify the antitumoural effect of gammadelta T cells in context of adoptive immune cell transfer. Optimised immunotherapeutic strategies might therefore improve the outcome of high risk hepatoblastoma and hepatocellular carcinoma. PMID- 23088520 TI - Organic aerosol yields from alpha-pinene oxidation: bridging the gap between first-generation yields and aging chemistry. AB - Secondary organic aerosol formation from volatile precursors can be thought of as a succession of generations of reaction products. Here, we constrain first generation SOA formation from the alpha-pinene + OH reaction and also study SOA formation from alpha-pinene ozonolysis carried out without an OH scavenger. SOA yields from OH oxidation of alpha-pinene are significantly higher than SOA yields from ozonolysis including an OH scavenger, and the SOA mass yields for unscavenged ozonolysis generally fall within the range of mass yields for alpha pinene ozonolysis under various conditions. Taken together, first-generation product yields parametrized with a volatility basis set fit provide a starting point for atmospheric models designed to simulate both the production and subsequent aging of SOA from this important terpene. PMID- 23088519 TI - Affinity-based probes based on type II kinase inhibitors. AB - Protein kinases are key components of most mammalian signal transduction networks and are therapeutically relevant drug targets. Efforts to study protein kinase function would benefit from new technologies that are able to profile kinases in complex proteomes. Here, we describe active site-directed probes for profiling kinases in whole cell extracts and live cells. These probes contain general ligands that stabilize a specific inactive conformation of the ATP-binding sites of protein kinases, as well as trifluoromethylphenyl diazirine and alkyne moieties that allow covalent modification and enrichment of kinases, respectively. A diverse group of serine/threonine and tyrosine kinases were identified as specific targets of these probes in whole cell extracts. In addition, a number of kinase targets were selectively labeled in live cells. Our chemical proteomics approach should be valuable for interrogating protein kinase active sites in physiologically relevant environments. PMID- 23088521 TI - Novel 3-Azaindolyl-4-arylmaleimides exhibiting potent antiangiogenic efficacy, protein kinase inhibition, and antiproliferative activity. AB - Tumor growth and metastasis are highly associated with the overexpression of protein kinases (PKs) regulating cell growth, apoptosis resistance, and prolonged cell survival. This study describes novel azaindolyl-maleimides with significant inhibition of PKs, such as VEGFR, FLT-3, and GSK-3beta which are related to carcinogenesis. Furthermore, these compounds exhibit high kinase selectivity and potent inhibition of angiogenesis and cell proliferation, offering versatile options in cancer treatment strategies. PMID- 23088522 TI - The robustness of the Escherichia coli signal-transducing UTase/UR-PII covalent modification cycle to variation in the PII concentration requires very strong inhibition of the UTase activity of UTase/UR by glutamine. AB - Uridylyltransferase/uridylyl-removing enzyme (UTase/UR) catalyzes uridylylation of PII and deuridylylation of PII-UMP, with both activities regulated by glutamine. In a reconstituted UTase/UR-PII cycle containing wild-type UTase/UR, the steady-state modification of PII varied from nearly complete modification to nearly complete demodification as glutamine was varied, whether the level of PII was saturating or unsaturating, but when a His-tagged version of UTase/UR was used, the robustness to variations in PII concentration was lost and the range of PII modification states in response to glutamine became smaller as the PII concentration increased. The presence of the His tag on UTase/UR did not alter PII substrate inhibition of the UT activity and had little effect on the level of the UT activity but resulted in a slight defect in UR activity. Importantly, at high PII concentrations, glutamine inhibition of the UT activity was incomplete. We hypothesized that binding of PII to the UR active site in the HD domain was responsible for PII substrate inhibition of the UT activity and, in the His tagged enzyme, also weakened glutamine inhibition of the UT activity. Consistent with this, three different UTase/UR proteins with HD domain alterations lacked substrate inhibition of UT activity by PII; in one case, the HD alteration eliminated glutamine regulation of UT activity, while for the other two proteins, alterations of the HD domain partially compensated for the effect of the His tag in restoring glutamine regulation of UT activity. We conclude that very strong inhibition of UT activity was required for the UTase/UR-PII cycle to display robustness to the PII concentration, that in the wild-type enzyme PII brings about substrate inhibition of the UT activity by binding to the HD domain of the enzyme, and that addition of an N-terminal His tag resulted in an altered enzyme with subtle changes in the interactions between domains such that binding of PII to the HD domain interfered with glutamine regulation of the UT domain. PMID- 23088523 TI - Out-of-network physicians: how prevalent are involuntary use and cost transparency? AB - OBJECTIVE: To determine the proportion of privately insured adults using an out of-network physician, the prevalence of involuntary out-of-network use, and whether patients experienced problems with cost transparency using out-of-network physicians. DATA SOURCES: Nationally representative internet panel survey conducted in February 2011. STUDY DESIGN: Screener questions identified a sample of 7,812 individuals in private health insurance plans with provider networks who utilized health services within the prior 12 months. Participants reported details of their inpatient and outpatient contacts with out-of-network physicians. An inpatient out-of-network contact was defined as involuntary if: (1) it was due to a medical emergency; (2) the physician's out-of-network status was unknown at the time of the contact; or (3) an attempt was made to find an in network physician in the hospital but none was available. Outpatient contacts were only defined as involuntary if the physician's out-of-network status was unknown at the time of the contact. PRINCIPAL FINDINGS: Eight percent of respondents used an out-of-network physician. Approximately 40 percent of individuals using out-of-network physicians experienced involuntary out-of network care. Among out-of-network physician contacts, 58 percent of inpatient contacts and 15 percent of outpatient contacts were involuntary. The majority of inpatient involuntary contacts were due to medical emergencies (68 percent). In an additional 31 percent, the physician's out-of-network status was unknown at the time of the contact. Half (52 percent) of individuals using out-of-network services experienced at least one contact with an out-of-network physician where cost was not transparent at the time of care. CONCLUSIONS: The frequency of involuntary out-of-network care is not inconsequential. Policy interventions can increase receipt of cost information prior to using out-of-network physician services, but they may be less helpful when patients have constrained physician choice due to emergent problems or limited in-hospital physician networks. PMID- 23088524 TI - Hyaluronic Acid as an adjunct after scaling and root planing: a prospective randomized clinical trial. AB - BACKGROUND: The study is designed to determine the effect on clinical variables, subgingival bacteria, and local immune response brought about by application of hyaluronan-containing gels in early wound healing after scaling and root planing (SRP). METHODS: In this randomized clinical study, data from 34 individuals with chronic periodontitis were evaluated after full-mouth SRP. In the test group (n = 17), hyaluronan gels in two molecular weights were additionally applied during the first 2 weeks after SRP. The control group (n = 17) was treated with SRP only. Probing depth (PD) and clinical attachment level (CAL) were recorded at baseline and after 3 and 6 months, and subgingival plaque and sulcus fluid samples were taken for microbiologic and biochemical analysis. RESULTS: In both groups, PD and CAL were significantly reduced (P <0.001). The changes in PD and the reduction of the number of pockets with PD >=5 mm were significantly higher in the test group after 3 (P = 0.014 and 0.021) and 6 (P = 0.046 and 0.045) months. Six months after SRP, the counts of Treponema denticola were significantly reduced in both groups (both P = 0.043), as were those of Campylobacter rectus in the test group only (P = 0.028). Prevotella intermedia and Porphyromonas gingivalis increased in the control group. CONCLUSION: The adjunctive application of hyaluronan may have positive effects on PD reduction and may prevent recolonization by periodontopathogens. PMID- 23088525 TI - Periodontal inflammatory conditions among gutka chewers and non-chewers with and without prediabetes. AB - BACKGROUND: It is known that gutka chewing jeopardizes periodontal health; however, severity of periodontal inflammation in gutka chewers with and without prediabetes remains unknown. The aim of this study is to investigate the association of periodontal inflammatory conditions with gutka chewing and prediabetes. METHODS: In this cross-sectional study, the effect of gutka use on periodontal health is investigated among 44 individuals with prediabetes and 44 without prediabetes. Demographic information regarding age, sex, duration of prediabetes, and gutka-chewing habits was collected using a questionnaire. Periodontal inflammatory conditions (plaque index [PI], bleeding on probing [BOP], probing depth [PD], marginal bone loss [MBL]) and fasting blood glucose levels (FBGLs) were recorded. Group differences in periodontal inflammatory parameters were tested using univariate and multivariable analyses (alpha <=5%). RESULTS: Periodontal inflammatory parameters (PI, BOP, and PD) were significantly higher in individuals with prediabetes irrespective of gutka-chewing habit (P <0.05). Odds of periodontal inflammation in individuals with prediabetes were nine times higher than in healthy controls (95% confidence interval [CI] = 3.4 to 23.6). Gutka chewing alone, chewing among individuals with prediabetes, and chewing among healthy controls did not significantly increase the odds of periodontal inflammatory conditions. Individuals with prediabetes were significantly more likely to have periodontal inflammation than individuals without prediabetes even after controlling for sex and gutka chewing (odds ratio = 13.2; 95% CI = 4.3 to 40.7). CONCLUSION: In medically healthy individuals, periodontal inflammatory conditions are worse in gutka chewers compared to non chewers; in patients with prediabetes, the severity of periodontal inflammation is governed by hyperglycemia when compared to habitual gutka usage. PMID- 23088526 TI - Inhibition of transforming growth factor beta1/Smad3 signaling decreases hypoxia inducible factor-1alpha protein stability by inducing prolyl hydroxylase 2 expression in human periodontal ligament cells. AB - BACKGROUND: Hypoxia-inducible factor-1alpha (HIF-1alpha), the alpha subunit of the heterodimeric transcription factor HIF-1, maintains oxygen homeostasis by regulating gene expression. Under normoxic conditions, HIF-1alpha expression is maintained at low steady-state levels by the critical oxygen sensor prolyl hydroxylase 2 (PHD2). Transforming growth factor beta1 (TGF-beta1) activates Smad3 signaling and contributes to HIF-1alpha stabilization under normoxic conditions. In chronic periodontitis, HIF-1alpha is expressed highly in gingival fibroblasts and upregulates inflammatory factor transcription, which promotes periodontal inflammation. Here, the authors investigated the effect of TGF beta1/Smad3 signaling and its blockade by the specific inhibitor of Smad3 (SIS3) on HIF-1alpha expression and stability in human periodontal ligament cells. METHODS: The authors investigated the effect of TGF-beta1 on HIF-1alpha protein stability using cycloheximide. Furthermore, they analyzed HIF-1alpha expression, PHD2 expression, and Smad3 phosphorylation following TGF-beta1 stimulation in the presence or absence of SIS3. RESULTS: The half-life of HIF-1alpha was prolonged in TGF-beta1-treated cells. TGF-beta1 treatment induced HIF-1alpha gene expression and enhanced HIF-1alpha protein stability while decreasing PHD2 expression and activating Smad3 phosphorylation. Notably, HIF-1alpha protein expression was not detectable prior to TGF-beta1 stimulation. Furthermore, SIS3 treatment abrogated Smad3 phosphorylation, impaired TGF-beta1-induced HIF-1alpha gene expression and protein stability, and stimulated TGF-beta1-mediated PHD2 inhibition. CONCLUSION: These results demonstrate that HIF-1alpha transcription and protein synthesis are controlled by TGF-beta1/Smad3 signaling, whereas HIF 1alpha protein stability is controlled by PHD2, which is regulated by TGF beta1/Smad3 signaling. PMID- 23088528 TI - Evaluation of supracrestal gingival tissue after surgical crown lengthening: a 6 month clinical study. AB - BACKGROUND: Previous studies on crown lengthening (CL) report contradictory results regarding stability of crown length gained at the time of surgery. The "3 mm rule" has dictated the amount of alveolar bone to be removed during CL surgery for decades. With the current understanding of wide variations in supracrestal gingival tissue (SGT) dimensions, bone removal can be customized to the situation. The purpose of this study is to assess alterations in periodontal tissue levels 6 months after CL surgery and to evaluate factors that may influence stability of CL achieved over time. METHODS: Sixty-four patients requiring CL surgery on 64 teeth are included in this study. Clinical parameters were recorded along six surfaces of treated tooth and neighboring teeth. Sites were labeled as treated sites, adjacent sites, and non-adjacent sites. Bone was reduced based on the minimal amount of tooth structure required for restorative purpose and SGT dimensions at each site. Patients were re-evaluated at 3 and 6 months. RESULTS: Significant soft-tissue rebound (0.77 +/- 0.58 mm) was observed 6 months after CL surgery. This rebound was found to be significantly correlated with periodontal biotype (r = 0.325, P = 0.000) and post-suturing flap position (r = -0.601, P = 0.000). SGT was not reestablished to its preoperative dimensions by the end of 6 months (P = 0.001). CONCLUSIONS: Crown length gained during surgery significantly decreased 6 months post-surgery. Suturing the flap <=3 mm from the osseous crest and thick-flat biotype were associated with greater tissue rebound. PMID- 23088527 TI - Progression of osteogenic cell cultures grown on microtopographic titanium coated with calcium phosphate and functionalized with a type I collagen-derived peptide. AB - BACKGROUND: The functionalization of metallic surfaces aims at promoting the cellular response at the biomaterial-tissue interface. This study investigates the effects of the functionalization of titanium (Ti) microtopography with a calcium phosphate (CaP) coating with and without peptide 15 (P-15), a synthetic peptide analog of the cell-binding domain of collagen I, on the in vitro progression of osteogenic cells. METHODS: Sandblasting and acid etching (SBAE; control) Ti microtopography was coated with CaP, enabling the loading of two concentrations of P-15: 20 or 200 MUg/mL. A machined Ti was also examined. Rat calvarial osteogenic cells were cultured on Ti disks with the surfaces mentioned above for periods up to 21 days (n = 180 per group). RESULTS: CaP coating exhibited a submicron-scale needle-shaped structure. Although all surfaces were hydrophobic at time zero, functionalization increased hydrophilicity at equilibrium. Microtopographies exhibited a lower proportion of well-spread cells at 4 hours of culture and cells with long cytoplasmic extensions at day 3; modified SBAE supported higher cell viability and larger extracellular osteopontin (OPN) accumulation. For SBAE and modified SBAE, real-time polymerase chain reaction showed the following results: 1) lower levels for runt-related transcription factor 2 at 7 days and for bone sialoprotein at days 7 and 10 as well as higher OPN levels at days 7 and 10 compared to machined Ti; and 2) higher alkaline phosphatase levels at day 10 compared to day 7. At 14 and 21 days, modified SBAE supported higher proportions of red-dye-stained areas (calcium content). CONCLUSION: Addition of a CaP coating to SBAE Ti by itself may affect key events of in vitro osteogenesis, ultimately resulting in enhanced matrix mineralization; additional P-15 functionalization has only limited synergistic effects. PMID- 23088529 TI - Use of a collagen membrane loaded with recombinant human bone morphogenetic protein-2 with collagen-binding domain for vertical guided bone regeneration. AB - BACKGROUND: Vertical bone regeneration of severe atrophic alveolar ridges remains a challenging procedure in implant dentistry. METHODS: The aim of this study, accordingly, is to use a rabbit vertical guided bone regeneration model to evaluate whether using a collagen membrane (CM) loaded with small doses of recombinant human bone morphogenetic protein-2 with collagen-binding domain (rhBMP-2/CBD) would enhance two-way vertical bone regeneration. In each of eight rabbits, four titanium cylinders were screwed in perforated slits made into the external cortical bones of the calvaria. The following four treatment modalities were randomly allocated: 1) cylinders filled with mineralized bone matrix and covered with CM/rhBMP-2/CBD; 2) cylinders filled with mineralized bone matrix and covered with CM/rhBMP-2; 3) cylinders filled with mineralized bone matrix and covered with CM alone; or 4) cylinders filled with mineralized bone matrix without a membrane cover. RESULTS: After 6 weeks, the new bones were examined by histologic analysis. Slender new bone trabeculae were observed in the superficial layer of the titanium cylinders covered with CM/rhBMP-2/CBD, and higher degrees of bone were observed in this group compared with the other three groups. The average area fraction of newly formed bone was significantly more in the CM/rhBMP 2/CBD group compared with the CM/rhBMP-2, CM, or the no membrane control groups (all P <0.01). CONCLUSIONS: The present study demonstrates that CMs loaded with small doses of rhBMP-2/CBD induce new bone formation not only from the surface of the native bone, but also from the superficial structures. The augmented new bone, therefore, is improved in both quantity and quality. PMID- 23088530 TI - Efficacy of acellular dermal matrix and coronally advanced flaps for the treatment of induced gingival recession defects: a histomorphometric study in dogs. AB - BACKGROUND: Gingival recession (GR) defects can be treated by various methods, including acellular dermal matrix (ADM) or coronally advanced flaps (CAFs). The aim of this histomorphometric experiment is to compare the efficacy of ADM and CAF for treating GR defects in dogs. METHODS: In eight beagle dogs, a critical size labial GR defect was surgically induced on bilateral maxillary cuspids under general anesthesia. Test sites received ADM and CAF, and control sites underwent CAF treatment alone. Plaque index (PI), bleeding index (BI), and gingival index (GI) were measured at 4 weeks (baseline), 8 weeks, and 16 weeks. Width of keratinized gingiva (KG) was determined at baseline and at 16 weeks. Depth of recession and width of GR below the cemento-enamel junction (CEJ) was also determined. After 4 months, animals were sacrificed, and jaw blocks were histomorphometrically assessed for tissue thickness and distance from the stent to the gingival margin (GM) and to the CEJ. RESULTS: At 4-, 8-, and 16-week intervals, there was no significant difference in the BI, GI, and PI at the test and control sites. At 16 weeks, thickness of KG was significantly higher at the control sites than test sites (P <0.01). There was no difference in the midfacial recession depth and recession width at the test and control sites at baseline and before euthanasia (16 weeks). Histomorphometrically, there was no significant difference in tissue thicknesses and distances from the stent to the GM and CEJ in the test and control sites. CONCLUSION: ADM might yield similar results to a CAF alone and could decrease the amount of KG. PMID- 23088531 TI - Plasma rich in growth factors promotes bone tissue regeneration by stimulating proliferation, migration, and autocrine secretion in primary human osteoblasts. AB - BACKGROUND: Alveolar bone loss can be a major clinical concern affecting both functionality and esthetics. Osteoblasts are the main cells charged with the repair and regeneration of missing bone tissue. Plasma rich in growth factors (PRGF) allows delivery of a cocktail of proteins and growth factors that promote wound healing and tissue regeneration to the site of injury. This study tests the effect of this endogenous regenerative technology to stimulate alveolar osteoblast bone-forming potential. METHODS: Primary human osteoblasts were retrieved from alveolar bone of patients undergoing oral surgery. Cell proliferation was evaluated, and culture inserts and permeable transwell supports were used to assess cell migration and chemotaxis. The expression of differentiation markers was quantified by enzyme-linked immunosorbent assay. RESULTS: PRGF succeeded in increasing proliferation, migration, and chemotaxis of osteoblasts. Also, PRGF significantly enhanced the autocrine expression of two relevant proangiogenic factors, vascular endothelial growth factor and hepatocyte growth factor, and three markers of osteoblastic activity, procollagen I, osteocalcin, and alkaline phosphatase. CONCLUSION: The results indicate that PRGF can stimulate some of the biologic processes of the main cells responsible for bone regeneration and help support the positive clinical outcomes that have been reported with this technology. PMID- 23088532 TI - Tooth loss and periodontitis in older individuals: results from the Swedish National Study on Aging and Care. AB - BACKGROUND: Due to the increasing number of older people, there is a need for studies focused on this population. The aims of the present study are to assess oral and systemic conditions in individuals aged 60 to 95 years with access to dental insurance. METHODS: Probing depths (PDs), tooth loss, alveolar bone levels, and systemic health were studied among a representative cohort of older individuals. RESULTS: A total of 1,147 individuals in young-old (aged 60 or 67 years), old (aged 72 or 78 years), and old-old (aged >=81 years) age groups were enrolled, including 200 individuals who were edentulous, in this study. Annual dental care was received by 82% of dentate individuals. Systemic diseases were common (diabetes: 5.8%; cardiovascular diseases: 20.7%; obesity: 71.2%; elevated C-reactive protein [CRP]: 98.4%). Serum CRP values were unrelated to periodontal conditions. Rates of periodontitis, defined as >=30% of sites with a distance from cemento-enamel junction to bone of >=5 mm, were 11.2% in women in the young old age group and 44.9% in men in the old-old age group. Individuals in older age groups had a higher likelihood of periodontitis defined by bone loss and cutoff levels of PD >=5 mm (odds ratio: 1.8; 95% confidence interval: 1.2 to 2.5; P <0.01). A total of 7% of individuals in the old-old age group had >=20 teeth and no periodontitis. Systemic diseases, dental use, or smoking were not explanatory, whereas age and sex were explanatory for periodontitis. CONCLUSIONS: The prevalence of periodontitis increased with age. Sex seems to be the dominant explanatory factor for periodontitis in older individuals. Despite frequent dental visits, overall oral health in the oldest age cohort was poor. PMID- 23088533 TI - Efficacy of psychosocial interventions in men and women with sexual dysfunctions- a systematic review of controlled clinical trials: part 1-the efficacy of psychosocial interventions for male sexual dysfunction. AB - INTRODUCTION: As yet, a summary of research evidence concerning the efficacy of psychological treatment in male sexual dysfunction is lacking. AIM: Our systematic review gives an overview of the efficacy of psychosocial interventions in all male sexual dysfunctions. MAIN OUTCOME MEASURES: Main outcome measures included, for example, psychometrically validated scales, interviews, and clinical assessment by an independent rater. The efficacy of psychosocial interventions was measured, for example, by the frequency of and satisfaction with sexual activity and sexual functioning. METHODS: The systematic literature search included electronic database search, handsearch, contact with experts, and an ancestry approach. Studies were included if the man was given a formal diagnosis of a sexual dysfunction (International Statistical Classification of Diseases and Related Health Problems [ICD10/-9]; Diagnostic and Statistical Manual of Mental Disorders [DSM-IV/-III-R]) and when the intervention was psychosocial or psychotherapeutic. The control group included either another treatment or a waiting-list control group. The report of relevant outcomes was necessary for inclusion as well as the design of the study (randomized controlled trials [RCTs] and controlled clinical trials [CCTs]). The assessment of methodological quality comprised aspects of randomization, blinding, incomplete outcome data, selective reporting, and allegiance. RESULTS: We identified 19 RCTs and one CCT that investigated the efficacy in male sexual dysfunction and two further studies that examined male and female sexual dysfunction together. Twelve out of 20 trials in men used either a concept derived from Masters and Johnson or a cognitive-behavioral treatment program. Overall, psychosocial interventions improved sexual functioning. While one study found that psychotherapy is superior to sildenafil, another study found the opposite. In men with premature ejaculation, behavioral techniques proved to be effective. A shortcoming was the rather low methodological quality of included studies. CONCLUSIONS: Most of the compared interventions proved to be similarly effective. Possibly, there are underlying constructs throughout all therapies that have an effect on the outcome. PMID- 23088535 TI - Two novel secoiridoid glucosides from Tripterospermum chinense. AB - Two novel secoiridoid glucosides, tripterospermumcins C (1) and D (2), were isolated from the aerial parts of Tripterospermum chinense, along with four known compounds, tripterospermumcin B (3), sweroside (4), loganic acid (5), and 8-epi kingiside (6). Their structures were determined by analysis of 1D and 2D NMR data, as well as by comparison with model compounds. Compound 1 was a rare iridoid tetramer with four glucosides. PMID- 23088534 TI - Gene delivery to pancreatic exocrine cells in vivo and in vitro. AB - BACKGROUND: Effective gene transfer to the pancreas or to pancreatic cells has remained elusive although it is essential for studies of genetic lineage tracing and modulation of gene expression. Different transduction methods and viral vectors were tested in vitro and in vivo, in rat and mouse pancreas. RESULTS: For in vitro transfection/transduction of rat exocrine cells lipofection reagents, adenoviral vectors, and Mokola- and VSV-G pseudotyped lentiviral vectors were used. For in vivo transduction of mouse and rat pancreas adenoviral vectors and VSV-G lentiviral vectors were injected into the parenchymal tissue. Both lipofection of rat exocrine cell cultures and transduction with Mokola pseudotyped lentiviral vectors were inefficient and resulted in less than 4% EGFP expressing cells. Adenoviral transduction was highly efficient but its usefulness for gene delivery to rat exocrine cells in vitro was hampered by a drastic increase in cell death. In vitro transduction of rat exocrine cells was most optimal with VSV-G pseudotyped lentiviral vectors, with stable transgene expression, no significant effect on cell survival and about 40% transduced cells. In vivo, pancreatic cells could not be transduced by intra-parenchymal administration of lentiviral vectors in mouse and rat pancreas. However, a high efficiency could be obtained by adenoviral vectors, resulting in transient transduction of mainly exocrine acinar cells. Injection in immune-deficient animals diminished leukocyte infiltration and prolonged transgene expression. CONCLUSIONS: In summary, our study remarkably demonstrates that transduction of pancreatic exocrine cells requires lentiviral vectors in vitro but adenoviral vectors in vivo. PMID- 23088536 TI - Molecular mechanisms underlying the interaction of protein phosphatase-1c with ASPP proteins. AB - The serine/threonine PP-1c (protein phosphatase-1 catalytic subunit) is regulated by association with multiple regulatory subunits. Human ASPPs (apoptosis stimulating proteins of p53) comprise three family members: ASPP1, ASPP2 and iASPP (inhibitory ASPP), which is uniquely overexpressed in many cancers. While ASPP2 and iASPP are known to bind PP-1c, we now identify novel and distinct molecular interactions that allow all three ASPPs to bind differentially to PP-1c isoforms and p53. iASPP lacks a PP-1c-binding RVXF motif; however, we show it interacts with PP-1c via a RARL sequence with a Kd value of 26 nM. Molecular modelling and mutagenesis of PP-1c-ASPP protein complexes identified two additional modes of interaction. First, two positively charged residues, Lys260 and Arg261 on PP-1c, interact with all ASPP family members. Secondly, the C terminus of the PP-1c alpha, beta and gamma isoforms contain a type-2 SH3 (Src homology 3) poly-proline motif (PxxPxR), which binds directly to the SH3 domains of ASPP1, ASPP2 and iASPP. In PP-1cgamma this comprises residues 309-314 (PVTPPR). When the Px(T)PxR motif is deleted or mutated via insertion of a phosphorylation site mimic (T311D), PP-1c fails to bind to all three ASPP proteins. Overall, we provide the first direct evidence for PP-1c binding via its C-terminus to an SH3 protein domain. PMID- 23088538 TI - Reply to Rees et al. Acute tubulointerstitial nephritis following treatment with exenatide. PMID- 23088537 TI - Genipin-crosslinked cartilage-derived matrix as a scaffold for human adipose derived stem cell chondrogenesis. AB - Autologous cell-based tissue engineering using three-dimensional scaffolds holds much promise for the repair of cartilage defects. Previously, we reported on the development of a porous scaffold derived solely from native articular cartilage, which can induce human adipose-derived stem cells (ASCs) to differentiate into a chondrogenic phenotype without exogenous growth factors. However, this ASC-seeded cartilage-derived matrix (CDM) contracts over time in culture, which may limit certain clinical applications. The present study aimed to investigate the ability of chemical crosslinking using a natural biologic crosslinker, genipin, to prevent scaffold contraction while preserving the chondrogenic potential of CDM. CDM scaffolds were crosslinked in various genipin concentrations, seeded with ASCs, and then cultured for 4 weeks to evaluate the influence of chemical crosslinking on scaffold contraction and ASC chondrogenesis. At the highest crosslinking degree of 89%, most cells failed to attach to the scaffolds and resulted in poor formation of a new extracellular matrix. Scaffolds with a low crosslinking density of 4% experienced cell-mediated contraction similar to our original report on noncrosslinked CDM. Using a 0.05% genipin solution, a crosslinking degree of 50% was achieved, and the ASC-seeded constructs exhibited no significant contraction during the culture period. Moreover, expression of cartilage-specific genes, synthesis, and accumulation of cartilage-related macromolecules and the development of mechanical properties were comparable to the original CDM. These findings support the potential use of a moderately (i.e., approximately one-half of the available lysine or hydroxylysine residues being crosslinked) crosslinked CDM as a contraction-free biomaterial for cartilage tissue engineering. PMID- 23088540 TI - Retraction: Luciferase-transfected colon adenocarcinoma cell line (DLD-1) for use in Orthotopic Xenotransplantation studies. PMID- 23088539 TI - Impairment in delayed nonmatching to sample following lesions of dorsal prefrontal cortex. AB - The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Nonmatching to Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore, Schettler, Killiany, Rosene, & Moss, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought. PMID- 23088541 TI - How do static and dynamic risk factors work together to predict violent behaviour among offenders with an intellectual disability? AB - BACKGROUND: Research on risk assessment with offenders with an intellectual disability (ID) has largely focused on estimating the predictive accuracy of static or dynamic risk assessments, or a comparison of the two approaches. The aim of this study was to explore how static and dynamic risk variables may 'work together' to predict violent behaviour. METHODS: Data from 212 offenders with an ID were analysed. Risk assessment tools included one static measure (Violence Risk Appraisal Guide), and two dynamic measures (Emotional Problems Scale and the Short Dynamic Risk Scale). Six-month concurrent prediction data on violent behaviour were collected. A structured methodology was employed to explore putative relationships between static and dynamic factors. RESULTS: Static risk factors temporally preceded dynamic ones, and were shown to dominate both dynamic measures, while there was a non-zero relationship between the static and the two dynamic measures. According to Kraemer et al., these findings suggest that dynamic risk factors function as proxy risk factors for static risk. CONCLUSIONS: Dynamic and static risk factors appear to capture elements of the same underlying risk associated with violent behaviour in individuals with an ID. This is the first study to empirically explore risk interrelationships in the forensic ID field. We discuss the importance of the contribution of dynamic variables in the prediction and management of risk. PMID- 23088542 TI - The advantage of word-based processing in Chinese reading: evidence from eye movements. AB - In 2 experiments, we tested the prediction that reading is more efficient when characters belonging to a word are presented simultaneously than when they are not in Chinese reading using a novel variation of the moving window paradigm (McConkie & Rayner, 1975). In Experiment 1, we found that reading was slowed down when Chinese readers could not see characters belonging to a word simultaneously compared to when they could do so. In Experiment 2, when Chinese readers could choose whether the 2 characters in the moving window contained a word or 2 characters that did not constitute a word, they had a clear tendency to look at 2 characters belonging to a word simultaneously. The results of the current study provide strong evidence that character processing is affected by word knowledge and the processing of other characters belonging to the same word in Chinese reading, and add to a growing body of evidence demonstrating that words do have psychological reality for Chinese readers. The results also suggest that the eye movement control strategy of Chinese readers is rather flexible in that it can be adjusted online to modify the characteristics of the window. PMID- 23088543 TI - More attention to attention? An eye-tracking investigation of selection of perceptual attributes during a task switch. AB - Switching tasks prolongs response times, an effect reduced but not eliminated by active preparation. To explore the role of attentional selection of the relevant stimulus attribute in these task-switch costs, we measured eye fixations in participants cued to identify either a face or a letter displayed on its forehead. With only 200 ms between cue and stimulus onsets, the eyes fixated the currently relevant region of the stimulus less and the irrelevant region more on switch than on repeat trials, at stimulus onset and for 500 ms thereafter, in a pattern suggestive of delayed orientation of attention to the relevant region on switch trials. With 800 ms to prepare, both switch costs and inappropriate fixations were reduced, but on switch trials participants still tended (relative to repeat trials) to fixate the now-irrelevant region more at stimulus onset and to maintain fixation on, or refixate, the irrelevant region more during the next 500 ms. The size of this attentional persistence was associated with differences in performance costs between and within participants. We suggest that reorientation of attention is an important, albeit somewhat neglected and controversial, component of advance task-set reconfiguration and that the task set inertia (or reactivation) to which many attribute the residual task-switch cost seen after preparation includes inertia in (or reactivation of) attentional parameters. PMID- 23088544 TI - Defining a boundary in goal localization: Infinite number of points or extended surfaces. AB - Four experiments examined the roles of extended surfaces and the number of points in the boundary superiority effect in goal localization. Participants learned the locations of 4 objects in the presence of a boundary, landmarks, or both in an immersive virtual environment by reproducing the locations with feedback. Participants then localized the objects in the presence of either the boundary or the landmarks during testing without feedback. The results showed that when both 1 landmark and a circular boundary were presented during learning, localization error during testing increased significantly when only the landmark was presented during testing, whereas localization error did not increase when only the boundary was presented during testing, thus demonstrating a boundary superiority effect. This boundary superiority effect was not observed when 36 landmarks forming a circle and a circular boundary were presented during learning. The landmark superiority effect was observed when 36 landmarks, forming a circular shape, and 1/36th part of the circular boundary were presented during learning. Furthermore, when a varied number of landmarks were presented with a circular boundary during learning, the localization error when the boundary was removed during testing was negatively correlated with the number of the landmarks. These results indicate that the superiority of a circular boundary to a landmark might be due to the larger number of points in the circular boundary but not due to the extended surface of the circular boundary. PMID- 23088545 TI - Sleep can eliminate list-method directed forgetting. AB - Recent work suggests a link between sleep and memory consolidation, indicating that sleep in comparison to wakefulness stabilizes memories. However, relatively little is known about how sleep affects forgetting. Here we examined whether sleep influences directed forgetting, the finding that people can intentionally forget obsolete memories when cued to do so. We applied the list-method directed forgetting task and assessed memory performance after 3 delay intervals. Directed forgetting was present after a short 20-min delay and after a 12-hr delay filled with diurnal wakefulness; in contrast, the forgetting was absent after a 12-hr delay that included regular nocturnal sleep. Successful directed forgetting after a delay thus can depend on whether sleep or wakefulness follows upon encoding: When wakefulness follows upon encoding, the forgetting can be successful; when sleep follows upon encoding, no forgetting may arise. Connections of the results to recent studies on the interplay between forgetting and sleep are discussed. PMID- 23088546 TI - Resolving interference between body movements: retrieval-induced forgetting of motor sequences. AB - When body movements are stored in memory in an organized manner, linked to a common retrieval cue like the effector with which to execute the movement, interference may arise as soon as one initiates the execution of a specific body movement in the presence of the retrieval cue because related motor programs also are activated. We investigated the resolution of such interference between motor programs. Participants learned several sequential finger movements, each consisting of the movement of 2 fingers of either the left or the right hand. Subsequently, they performed retrieval practice on half of the items of 1 hand. A final recall test then assessed memory for all initially learned items. In 3 experiments, retrieval-induced forgetting occurred; that is, retrieval practice impaired the recall of unpracticed movements belonging to the practiced hand. The results suggest that retrieval-based inhibition resolved interference between motor programs pertaining to the same hand, thereby pointing to a common principle pertaining to different domains of human information processing, concerning verbal, perceptual, or motor information. PMID- 23088547 TI - Processing (non)compositional expressions: mistakes and recovery. AB - Current models of idiom representation and processing differ with respect to the role of literal processing during the interpretation of idiomatic expressions. Word-like models (Bobrow & Bell, 1973; Swinney & Cutler, 1979) propose that idiomatic meaning can be accessed directly, whereas structural models (Cacciari & Tabossi, 1988; Cutting & Bock, 1997; Sprenger, Levelt, & Kempen, 2006) propose that literal processing is crucial in the access of idiomatic meaning. We used a self-paced reading task to examine how contextual expectations influence real time processing of phrasal verbs that are ambiguous between a literal and idiomatic sense (e.g., look up, turn in) and how comprehenders recover from expectations that are revealed to be incorrect. Our results suggest that when comprehenders expect a literal interpretation in a situation where the sentence turns out to be idiomatic, real-time processing is disrupted more than if comprehenders are expecting an idiomatic interpretation and the sentence turns out to be literal. We interpret our results in favor of models of idiom processing that propose obligatory literal processing (e.g., Cacciari & Tabossi, 1988; Cutting & Bock, 1997; Sprenger et al., 2006). (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23088548 TI - Novel word lexicalization and the prime lexicality effect. AB - This study investigates how newly learned words are integrated into the first language lexicon using masked priming. Two lexical decision experiments are reported, with the aim of establishing whether newly learned words behave like real words in a masked form priming experiment. If they do, they should show a prime lexicality effect (PLE), in which less priming is obtained due to form similarity when the prime is a word. In the first experiment, subjects were taught the meanings of novel words that were neighbors of real words, but no PLE was observed; that is, equally strong form priming was obtained for both trained and untrained novel primes. In the second experiment, 4 training sessions were spread over 4 weeks, and under these conditions, a clear PLE was obtained in the final session. It is concluded that lexicalization requires multiple training sessions. Possible explanations of the PLE are discussed. PMID- 23088549 TI - Contextual match and cue-independence of retrieval-induced forgetting: Testing the prediction of the model by Norman, Newman, and Detre (2007). AB - Retrieval-induced forgetting (RIF) is the finding of impaired memory performance for information stored in long-term memory due to retrieval of a related set of information. This phenomenon is often assigned to operations of a specialized mechanism recruited to resolve interference during retrieval by deactivating competing memory representations. This inhibitory account is supported by, among others, findings showing that RIF occurs with independent cues not used during retrieval practice. However, these findings are not always consistent. Recently, Norman, Newman, and Detre (2007) have proposed a model that aims at resolving discrepancies concerning cue-independence of RIF. The model predicts that RIF should be present with independent cues when episodic associations are created between independent cues and their targets in the same episodic context that is later used to cue memory during retrieval practice. In the present study we aimed to test this prediction. We associated studied items with semantically unrelated words during the main study phase of the retrieval practice paradigm, and we tested memory with both cues used during retrieval practice (Experiment 2) and episodic associates serving as independent cues (Experiments 3a and 3b). Although RIF was present when the same cues were used during retrieval practice and a final test, contrary to the prediction formulated by Norman et al., RIF failed to emerge when episodic associates were employed as independent cues. PMID- 23088550 TI - Does logic feel good? Testing for intuitive detection of logicality in syllogistic reasoning. AB - Recent research on syllogistic reasoning suggests that the logical status (valid vs. invalid) of even difficult syllogisms can be intuitively detected via small changes in affective state (Morsanyi & Handley, 2012). In a series of 6 experiments, we replicated effects of logical status on liking ratings of difficult syllogisms (although their shape differs from that reported by Morsanyi and Handley), and we tested 2 alternative accounts of our and Morsanyi and Handley's findings in terms of surface features accidentally confounded with logical status: the partial-repetition hypothesis and the content-effects hypothesis. The results support the content-effects hypothesis, according to which the effects of logical status reflect differences in mean liking for the presented conclusions rather than effects of logical status itself. PMID- 23088553 TI - Tuning the quinoid versus biradicaloid character of thiophene-based heteroquaterphenoquinones by means of functional groups. AB - A series of quinoidal bithiophenes (QBTs) with controlled variations in steric hindrance and electron activity of the substituents has been synthesized. Evidence of their quinoidal versus biradicaloid ground-state electronic character has been experimentally detected and coherently identified as fingerprints by spectroscopic methods such as NMR, UV-vis, multiwavelength Raman. From this analysis, alkoxy groups have been shown to strongly affect the electronic structure and the ground-state energy and stability of QBTs. Quantum-chemical calculations correctly predict the experimental spectroscopic response, even while changing the alkyl on phenone from a tertiary carbon atom to secondary to primary toward an unsubstituted phenone, further confirming the validity of the approach proposed. A control of the electronic structure accompanied by negligible variations of the optical gap of the molecules has thus been demonstrated, extending the potential use of quinoidal species in fields ranging from photon harvesting to magnetic applications. PMID- 23088551 TI - A review of reproductive health research, guidelines and related gaps for women living with HIV. AB - The study of pregnancy and motherhood in women living with HIV (WLWH) has concentrated on the health of the unborn baby and the prevention of mother-to child transmission, whereas consideration of the broader aspects of women's reproductive health has been largely overlooked. The rights of WLWH with respect to their reproductive health should be exactly the same as non-HIV-positive women, however, inequalities exist due to discrimination and also because the treatment guidelines used in the care of women are often based on insufficient evidence. The purpose of this article is to review the available literature on reproductive health issues for WLWH and to identify gaps requiring further investigation. Our review indicates that further research is warranted into a number of aspects of reproductive health among WLWH. Currently, access to the relevant reproductive health resources and services, such as advice on contraception and fertility services, for WLWH is far from optimal in many developed countries and most developing countries. More data are needed on the most appropriate family planning options with the consideration of drug interactions between contraceptives and antiretroviral therapy and the risk of HIV transmission. Also, more research is needed to improve understanding of the maternal health challenges facing WLWH. Similarly, our understanding of the impact of HIV on the physical and emotional health of pregnant women and new mothers is far from complete. Answering these questions and countering these inequalities will help to ensure the reproductive health and child-bearing intentions of WLWH become an integral part of HIV medicine. PMID- 23088552 TI - Effect of essential oils containing and alcohol-free chlorhexidine mouthrinses on cariogenic micro-organisms in human saliva. AB - OBJECTIVE: The aim of this study was to evaluate the effect on mutans streptococci and lactobacilli in saliva of mouthrinsing with essential oils and an alcohol-free chlorhexidine. MATERIALS AND METHOD: Twenty healthy volunteers (mean age 59 years) participated in the double-blind randomized cross-over study. Three mouthrinses were used in 16 days rinsing periods in addition to their regular mechanical oral hygiene: a solution with essential oils (EO; Listerine), a solution with alcohol-free chlorhexidine (CHX; Paroex) and water (negative control). The mouthrinse periods were separated by 3-month washout periods. At days 0 (baseline) and 17 (end) of each mouthrinse period, paraffin stimulated whole saliva was collected in order to analyse CFU/ml saliva of mutans streptococci and lactobacilli. RESULTS: Only the CHX rinse showed a significant difference for CFU mutans streptococci between baseline and end (p = 0.004). The CFU mutans streptococci at the end of the rinse periods showed statistically significant differences between CHX vs EO (p = 0.039) and CHX vs water (p = 0.022). The difference in CFU lactobacilli between baseline and end was significant for CHX (p = 0.031), but not for the other rinses. No statistically significant differences for lactobacilli were found at the end of the rinse periods between the mouthrinses. CONCLUSION: A significant reduction in amount of cariogenic bacteria in saliva was observed after 16 days of alcohol-free chlorhexidine mouthrinse but not after the essential oils rinse. The high number of participant's not changing to a bacterial class with a reduced number of micro organisms showed that both rinses had little clinical significance as a caries preventing treatment method, which can decrease the number of CFU cariogenic micro-organisms. PMID- 23088554 TI - Cognitive and affective Theory of Mind in mild to moderate Alzheimer's disease. AB - Theory of Mind (ToM) allows one's own and others' cognitive and emotional mental states to be inferred. Although many patients with Alzheimer's disease (AD) display impaired social functioning as their disease progresses, very few studies have investigated ToM in AD. Those that have done so suggest that patients' ToM deficits are the consequence of other cognitive impairments. The aim of this study was thus to investigate changes in both the cognitive and the affective dimensions of ToM in AD, using tasks designed to circumvent the patients' comprehension difficulties. Sixteen mild to moderate AD patients and 15 healthy controls matched on age, sex and education level underwent cognitive (preference judgment and first- and second-order false belief) and affective (Reading the Mind in the Eyes) ToM assessments. Comprehension of false belief stories was verified and an additional neuropsychological examination was undergone. We observed impaired performances by AD patients on all the ToM tasks. While working memory and executive functioning impairments contributed to the deterioration in the more complex aspects of cognitive ToM abilities as highlighted by a correlation analysis, we failed to observe any comprehension difficulties in patients who performed poorly on simple cognitive ToM tasks, which suggests that AD truly affects cognitive ToM. PMID- 23088555 TI - Avoiding back wound dehiscence in extended latissimus dorsi flap reconstruction. AB - BACKGROUND: The latissimus dorsi breast reconstruction flap has a number of advantages, but despite the advances in surgical techniques, it has remained vulnerable to skin dehiscence or necrosis at the donor site. We describe a novel surgical technique to prevent this. METHODS: Patients treated with extended latissimus dorsi flap reconstruction between January 2005 and January 2010 were studied prospectively. RESULTS: Eighteen patients were reviewed (12 immediate and 6 delayed). Two patients were smokers. The mean age was 54.4 (range: 42-64) years and the mean body mass index was 31.6 (range: 22.3-38). The mean weight of the mastectomy specimen was 551 g (range: 280-980 g). Six patients developed back seroma which required aspiration, and one patient developed a haematoma of the reconstructed breast. All wounds healed primarily. CONCLUSION: The new technique is safe, simple and effective in avoiding wound dehiscence at the donor site after extended latissimus dorsi flap reconstruction. PMID- 23088556 TI - Solution-processed inorganic-organic hybrid electron injection layer for polymer light-emitting devices. AB - A lithium quinolate complex (Liq) has high solubility in polar solvents such as alcohols and can be spin-coated onto emitting polymers, resulting in a smooth surface morphology. A polymer light-emitting device fabricated with spin-coated Liq as an electron injection layer (EIL) exhibited a lower turn-on voltage and a higher efficiency than a device with spin-coated Cs2CO3 and a device with thermally evaporated Ca. The mixture of ZnO nanoparticles and Liq served as an efficient EIL, resulting in a lower driving voltage even in thick films (~10 nm), and it did not require a high-temperature annealing process. PMID- 23088557 TI - Spatial and temporal attention deficits following brain injury: a neuroanatomical decomposition of the temporal order judgement task. AB - We investigated spatial and temporal deficits following brain injury using the temporal order judgement (TOJ) task. Patients judged the order in which two letters appeared to the left and right of fixation. We measured the extent of any spatial bias and the temporal resolution of the decision. Temporal and spatial deficits on the TOJ task were significantly correlated. The spatial bias on the TOJ task was also correlated with the spatial bias on a neglect task and with unilateral deficits on an extinction task, but not with extinction itself. These spatial deficits were all associated with damage to contralateral temporoparietal cortex. In contrast, the temporal resolution of TOJs was linked specifically to deficits in processing multiple stimuli on the neglect and extinction tasks and to damage to the right parietal lobe and the cerebellum. These data suggest that spatial and temporal deficits on the TOJ task reflect different underlying processes. PMID- 23088558 TI - Novel acidic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2 adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329). AB - Inhibition of 11beta-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability. PMID- 23088559 TI - Biocompatibility of crystalline opal nanoparticles. AB - BACKGROUND: Silica nanoparticles are being developed as a host of biomedical and biotechnological applications. For this reason, there are more studies about biocompatibility of silica with amorphous and crystalline structure. Except hydrated silica (opal), despite is presents directly and indirectly in humans. Two sizes of crystalline opal nanoparticles were investigated in this work under criteria of toxicology. METHODS: In particular, cytotoxic and genotoxic effects caused by opal nanoparticles (80 and 120 nm) were evaluated in cultured mouse cells via a set of bioassays, methylthiazolyldiphenyl-tetrazolium-bromide (MTT) and 5-bromo-2'-deoxyuridine (BrdU). RESULTS: 3T3-NIH cells were incubated for 24 and 72 h in contact with nanocrystalline opal particles, not presented significant statistically difference in the results of cytotoxicity. Genotoxicity tests of crystalline opal nanoparticles were performed by the BrdU assay on the same cultured cells for 24 h incubation. The reduction of BrdU-incorporated cells indicates that nanocrystalline opal exposure did not caused unrepairable damage DNA. CONCLUSIONS: There is no relationship between that particles size and MTT reduction, as well as BrdU incorporation, such that the opal particles did not induce cytotoxic effect and genotoxicity in cultured mouse cells. PMID- 23088560 TI - A closed-tube methylation-sensitive high resolution melting assay (MS-HRMA) for the semi-quantitative determination of CST6 promoter methylation in clinical samples. AB - BACKGROUND: CST6 promoter is highly methylated in cancer, and its detection can provide important prognostic information in breast cancer patients. The aim of our study was to develop a Methylation-Sensitive High Resolution Melting Analysis (MS-HRMA) assay for the investigation of CST6 promoter methylation. METHODS: We designed primers that amplify both methylated and unmethylated CST6 sequences after sodium bisulfate (SB) treatment and used spiked control samples of fully methylated to unmethylated SB converted genomic DNA to optimize the assay. We first evaluated the assay by analyzing 36 samples (pilot training group) and further analyzed 80 FFPES from operable breast cancer patients (independent group). MS-HRMA assay results for all 116 samples were compared with Methylation Specific PCR (MSP) and the results were comparable. RESULTS: The developed assay is highly specific and sensitive since it can detect the presence of 1% methylated CST6 sequence and provides additionally a semi-quantitative estimation of CST6 promoter methylation. CST6 promoter was methylated in 39/80 (48.75%) of FFPEs with methylation levels being very different among samples. MS-HRMA and MSP gave comparable results when all samples were analyzed by both assays. CONCLUSIONS: The developed MS-HRMA assay for CST6 promoter methylation is closed tube, highly sensitive, cost-effective, rapid and easy-to-perform. It gives comparable results to MSP in less time, while it offers the advantage of additionally providing an estimation of the level of methylation. PMID- 23088561 TI - Staphylococcus aureus nasal carriage in a Moroccan dialysis center and isolates characterization. AB - Staphylococcus aureus, which has its ecological niche in the anterior nares, has been shown to cause a variety of infectious diseases mainly for patients in hemodialysis units. We performed this study to evaluate the prevalence of nasal S. aureus carriage among hemodialysis outpatients, to determine the antimicrobial susceptibility of isolates, to characterize the virulence genes, and to identify associated risk factors. Nares swab specimens were obtained from 70 outpatients on hemodialysis between March and June 2010. Samples were plated immediately onto S. aureus specific media and pattern of antibacterial sensitivity was determined using disk diffusion method. Polymerase chain reaction was used to detect nuc, mecA, and genes encoding staphylococcal toxins. Medical record of patients was explored to determine S.aureus carriage risk factors. Nasal screening identified 42.9% S. aureus carriers with only one (3.3%) methicillin-resistant S. aureus isolate. Among the methicillin-susceptible S. aureus isolates, high rate of penicillin resistance (81.8%) has been detected. The identified risk factors were male gender and age <= 30 years. Research of virulence factors showed a high genetic diversity among the 30 S. aureus isolates. Twenty-one (70%) of them had at least one virulence gene, of which 3.3% were Panton-Valentine leukocidin (lukS/F-PV) genes. S. aureus carriage must be screened for at regular intervals in hemodialysis patients. Setting up a bacterial surveillance system is one of the strategies to understand the epidemiology of methicillin-resistant S. aureus, to guide local antibiotic policy and prevent spread of antibiotic-resistant S. aureus. PMID- 23088563 TI - The complex interaction between marine debris and toxic chemicals in the ocean. AB - Marine debris, especially plastic debris, is widely recognized as a global environmental problem. There has been substantial research on the impacts of plastic marine debris, such as entanglement and ingestion. These impacts are largely due to the physical presence of plastic debris. In recent years there has been an increasing focus on the impacts of toxic chemicals as they relate to plastic debris. Some plastic debris acts as a source of toxic chemicals: substances that were added to the plastic during manufacturing leach from plastic debris. Plastic debris also acts as a sink for toxic chemicals. Plastic sorbs persistent, bioaccumulative, and toxic substances (PBTs), such as polychlorinated biphenyls (PCBs) and dioxins, from the water or sediment. These PBTs may desorb when the plastic is ingested by any of a variety of marine species. This broad look at the current research suggests that while there is significant uncertainty and complexity in the kinetics and thermodynamics of the interaction, plastic debris appears to act as a vector transferring PBTs from the water to the food web, increasing risk throughout the marine food web, including humans. Because of the extremely long lifetime of plastic and PBTs in the ocean, prevention strategies are vital to minimizing these risks. PMID- 23088562 TI - Medical care price indexes for patients with employer-provided insurance: nationally representative estimates from MarketScan Data. AB - OBJECTIVE: Commonly observed shifts in the utilization of medical care services to treat diseases may pose problems for official price indexes at the Bureau of Labor Statistics (BLS) that do not account for service shifts. We examine how these shifts may lead to different price estimates than those observed in official price statistics at the BLS. DATA SOURCES: We use a convenience sample of enrollees with employer-provided insurance from the MarketScan database for the years 2003 to 2007. Population weights that consider the age, sex, and geographic distribution of enrollees are assigned to construct representative estimates. STUDY DESIGN: We compare two types of price indexes: (1) a Service Price Index (SPI) that is similar to the BLS index, which holds services fixed and measures the prices of the underlying treatments; (2) a Medical Care Expenditure Index (MCE) that measures the cost of treating diseases and allows for utilization shifts. PRINCIPAL FINDINGS: Over the entire period of study the CAGR of the SPI grows 0.7 percentage points faster than the preferred MCE index. CONCLUSIONS: Our findings suggest that the health component of inflation may be overstated by 0.7 percentage points per year, and real GDP growth may be understated by a similar amount. However, more work may be necessary to precisely replicate the indexes of the BLS to obtain a more accurate measure of these price differences. PMID- 23088564 TI - Distress, sexual dysfunctions, and DSM: dialogue at cross purposes? AB - INTRODUCTION: A distress criterion was added to the diagnostic criteria of sexual dysfunctions in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV; 1994). This decision was neither based on empirical evidence, nor on an open, academic, or public debate about its necessity. As a result, this decision has been disputed ever since the publication of DSM-IV. AIM: In this article, the necessity to include or exclude the distress criterion from the diagnostic criteria of sexual dysfunctions is critically evaluated, illustrating its consequences for both sex research and clinical practice. METHODS: Apart from careful reading of relevant sections in DSM-II, DSM-III, DSM-IV, DSM-IV Text Revision, and articles about and online proposals for DSM-5, an extensive PubMed literature search was performed including words as "sexual dysfunction"/"sexual difficulty"/"sexual disorder,""distress"/"clinical significance,""diagnostic criteria," and "DSM"/"Diagnostic and statistical manual of mental disorders." Based on analysis of the references of the retrieved works, more relevant articles were also found. MAIN OUTCOME MEASURES: ARGUMENTS for or against removal of distress from the diagnostic criteria of sexual dysfunctions by former and current members of the DSM Task Force and Work Group on Sexual Disorders, as well as by other authors in the field of sex research, are reviewed and critically assessed. RESULTS: Proponents and opponents of including the distress criterion in the diagnostic criteria of sexual dysfunctions appear to be unresponsive to each others' arguments. To prevent the debate from becoming an endlessly repetitive discussion, it is first necessary to acknowledge that this is a philosophical debate about the nature, function, and goals of the diagnosis of a sexual dysfunction. CONCLUSIONS: Given the current lack of data supporting either the retention or removal of the distress criterion, distress should always be taken into account in future research on sexual dysfunctions. Such forthcoming data should increase our understanding of the association between distress and sexual difficulties. PMID- 23088566 TI - Characterization of the reconstituted UTase/UR-PII-NRII-NRI bicyclic signal transduction system that controls the transcription of nitrogen-regulated (Ntr) genes in Escherichia coli. AB - A reconstituted UTase/UR-PII-NRII-NRI bicyclic cascade regulated PII uridylylation and NRI phosphorylation in response to glutamine. We examined the sensitivity and robustness of the responses of the individual cycles and of the bicyclic system. The sensitivity of the glutamine response of the upstream UTase/UR-PII monocycle depended upon the PII concentration, and we show that PII exerted substrate inhibition of the UTase activity of UTase/UR, potentially contributing to this dependence of sensitivity on PII. In the downstream NRII-NRI monocycle, PII controlled NRI phosphorylation state, and the response to PII was hyperbolic at both saturating and unsaturating NRI concentration. As expected from theory, the level of NRI~P produced by the NRII-NRI monocycle was robust to changes in the NRII or NRI concentrations when NRI was in excess over NRII, as long as the NRII concentration was above a threshold value, an example of absolute concentration robustness (ACR). Because of the parameters of the system, at physiological protein levels and ratios of NRI to NRII, the level of NRI~P depended upon both protein concentrations. In bicyclic UTase/UR-PII-NRII-NRI systems, the NRI phosphorylation state response to glutamine was always hyperbolic, regardless of the PII concentration or sensitivity of the upstream UTase/UR-PII cycle. In these bicyclic systems, NRI phosphorylation state was only robust to variation in the PII/NRII ratio within a narrow range; when PII was in excess NRI~P was low, and when NRII was in excess NRI phosphorylation was elevated, throughout the physiological range of glutamine concentrations. Our results show that the bicyclic system produced a graded response of NRI phosphorylation to glutamine under a range of conditions, and that under most conditions the response of NRI phosphorylation state to glutamine levels depended on the concentrations of NRI, NRII, and PII. PMID- 23088565 TI - Screening and detection of human papillomavirus (HPV) high-risk strains HPV16 and HPV18 in saliva samples from subjects under 18 years old in Nevada: a pilot study. AB - BACKGROUND: Human papillomaviruses (HPV) are oncogenic and mainly associated with cervical cancers. Recent evidence has demonstrated HPV infection in other tissues, including oral epithelia and mucosa. Although a recent pilot study provided new information about oral HPV status in healthy adults from Nevada, no information was obtained about oral HPV prevalence among children or teenagers, therefore, the goal of this study is to provide more detailed information about oral prevalence of high-risk HPV among children and teenagers in Nevada. METHODS: This retrospective study utilized previously collected saliva samples, obtained from pediatric dental clinic patients (aged 2 - 11) and local school district teenagers (aged 12-17) for high-risk HPV screening (n=118) using qPCR for quantification and confirmation of analytical sensitivity and specificity. RESULTS: A small subset of saliva samples were found to harbor high-risk HPV16 (n=2) and HPV18 (n=1), representing a 2.5% of the total. All three were obtained from teenage males, and two of these three samples were from White participants. CONCLUSIONS: Although this retrospective study could not provide correlations with behavioral or socioeconomic data, this project successfully screened more than one hundred saliva samples for high-risk HPV, confirming both HPV16 and HPV18 strains were present in a small subset. With increasing evidence of oral HPV infection in children, this study provides critical information of significant value to other dental, medical, oral and public health professionals who seek to further an understanding of oral health and disease risk in pediatric populations. PMID- 23088567 TI - Factors associated with maternal visitation and participation in skin-to-skin care in an all referral level IIIc NICU. AB - AIM: To identify variables associated with maternal visitation and participation in skin-to-skin care (SSC) with their extremely premature (<27 weeks) neonate. METHODS: In an all referral level IIIc, 32 extremely premature neonates and their mothers were studied. Standardized instruments were the Parental Stressor Scale: NICU and the Parent-Staff Communication Rating Scale. Unstandardized Tools included a self-report demographics sheet and a self-report parent SSC log. RESULTS: Using regression analysis, two factors were identified that were significantly associated with the amount of time that mothers visit and participate in SSC: the amount and type of stress that mothers experience and their perceived level of communication with medical staff. CONCLUSION: Future interventions for increasing SSC should involve education about the NICU environment and neonatal behaviour along with methods for enhancing communication between mothers and healthcare providers. PMID- 23088568 TI - Doped polycyclic aromatic hydrocarbons as building blocks for nanoelectronics: a theoretical study. AB - Density functional theory (DFT) and semiempirical UHF natural orbital configuration interaction (UNO-CI) calculations are used to investigate the effect of heteroatom substitution at the central position of a model polycyclic aromatic hydrocarbon. The effects of the substitution on structure, strain, electronic and spectral properties, and aromaticity of the compounds are discussed. PMID- 23088569 TI - Four new sesquiterpenoids from Ligularia cymbulifera. AB - Four new highly oxygenated bisabolane sesquiterpenoids were obtained from the EtOH extract from Ligularia cymbulifera, and their structures were elucidated by interpretation of spectroscopic data. Their relative configurations were clarified by a detailed analysis of 1H NMR coupling constants, nuclear overhauser effect (NOE) experiments and two-dimensional NMR spectra. These four new compounds were assayed for their antimicrobial activities against four Gram positive and Gram-negative bacteria, as well as against one human pathogenic fungus. PMID- 23088570 TI - The competition-performance relation: a meta-analytic review and test of the opposing processes model of competition and performance. AB - What is the relation between competition and performance? The present research addresses this important multidisciplinary question by conducting a meta-analysis of existing empirical work and by proposing a new conceptual model--the opposing processes model of competition and performance. This model was tested by conducting an additional meta-analysis and 3 new empirical studies. The first meta-analysis revealed that there is no noteworthy relation between competition and performance. The second meta-analysis showed, in accord with the opposing processes model, that the absence of a direct effect is the result of inconsistent mediation via achievement goals: Competition prompts performance approach goals which, in turn, facilitate performance; and competition also prompts performance-avoidance goals which, in turn, undermine performance. These same direct and mediational findings were also observed in the 3 new empirical studies (using 3 different conceptualizations of competition and attending to numerous control variables). Our findings provide both interpretational clarity regarding past research and conceptual guidance regarding future research on the competition-performance relation. PMID- 23088571 TI - Competition and performance: more facts, more understanding? Comment on Murayama and Elliot (2012). AB - Murayama and Elliot (2012) made a significant contribution to the literature on competition by presenting the results of 2 meta-analyses and 3 primary studies on the relation between competition and performance. Murayama and Elliot established that in general, there is no relationship between competition and performance. They then made the case that the lack of relationship is due to 2 opposing processes (performance-approach and performance-avoidance goals) that cancel each other out. The meta-analyses made a significant contribution to the literature on competition but had problems with the way in which the types of competition were defined and the clarity of the control condition. Their opposing processes model suffers from the relatively high relationship between performance-approach and performance-avoidance goals, their failure to include likelihood of success or failure in their model, and the lack of specification of the process through which competition prompts one type of goal or the other. Their results do highlight the need for further research on competition focusing on the combination of personality traits and situational variables. PMID- 23088573 TI - The Bayesian evaluation of categorization models: comment on Wills and Pothos (2012). AB - Wills and Pothos (2012) reviewed approaches to evaluating formal models of categorization, raising a series of worthwhile issues, challenges, and goals. Unfortunately, in discussing these issues and proposing solutions, Wills and Pothos (2012) did not consider Bayesian methods in any detail. This means not only that their review excludes a major body of current work in the field, but also that it does not consider the body of work that provides the best current answers to the issues raised. In this comment, we argue that Bayesian methods can be--and, in most cases, already have been--applied to all the major model evaluation issues raised by Wills and Pothos (2012). In particular, Bayesian methods can address the challenges of avoiding overfitting, considering qualitative properties of data, reducing dependence on free parameters, and testing empirical breadth. PMID- 23088575 TI - An update on noise and performance: comment on Szalma and Hancock (2011). AB - Reviews of the effects of noise on performance carried out in the 1980s suggested that results depended on the type of noise, nature of the task, and characteristics of the person performing in noise. This general view has been confirmed in the recent meta-analysis and synthesis by Szalma and Hancock (2011). There are, however, some notable omissions from this review. For example, beneficial effects of noise in low alertness states receive no coverage, and yet these provide the strongest support for arousal theories. The importance of predictability and perceived control was also overlooked, yet relevant studies, especially those looking at aftereffects of noise, are crucial for explanations based on compensatory effort. Also neglected was research emphasizing the importance of examining the microstructure of responding and strategies of performance. Recent accounts emphasize the importance of considering the specific processes involved in carrying out a task and show that analyses based on gross characteristics present an inappropriate profile of effects. Laboratory studies of auditory distraction are now largely restricted to investigation of the effects of irrelevant speech. Noise and performance research has also moved toward field studies, including effects of chronic noise exposure on children. Future noise research is likely to focus on different noise parameters and performance outcomes, potentially leading to the investigation of different underlying mechanisms. This type of research will have clear implications for policy and practice. PMID- 23088578 TI - Relationship between interleukin-10 polymorphism and maternal serum leptin level in preeclampsia. AB - The objective of this study is to show that pregnancy is a unique immune phenomenon because the feto-placental unit can develop without being attacked by the maternal immune system despite the admixing of maternal and fetal cells. There is a growing body of evidence that regulatory T cells (Tregs) act as modulators of vascular homeostasis. The aim of this study was to evaluate the role of interleukin-10 polymorphism along with leptin in the pathogenesis of preeclampsia. The study was carried out on 20 primigravida pregnant women with preeclampsia and 20 normal primigravida pregnant women. Blood samples sent for laboratory tests showed the presence of serum leptin, which was determined by DRGLeptin sandwich (Enzyme-linked immunosorbent assay (ELISA) technique) (EIA 2395; DRG International, Inc., Mountainside, NJ, USA) and serum IL-10 was determined by ELISA (Genzyme, Cambridge, MA, USA). The detection of IL-10 polymorphism was done by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques. The results of this study show that there was a significant difference between the frequency of genotype in patients and control group with regard to GG genotype, AA genotype, A allele, and G allele (P < .05) However, it was not significant with regard to the frequency of AG genotype (P > .05). The serum leptin was found to be significantly higher in preeclampsia group and with a more significant increase in AA genotype. PMID- 23088577 TI - Decellularized tissue-engineered heart valve leaflets with recellularization potential. AB - Tissue-engineered heart valves (TEHV) have been proposed as a promising solution for the clinical needs of pediatric patients. In vivo studies have shown TEHV leaflet contraction and regurgitation after several months of implantation. This has been attributed to contractile cells utilized to produce the extracellular matrix (ECM) during TEHV culture. Here, we utilized such cells to develop a mature ECM in a fibrin-based scaffold that generates commissural alignment in TEHV leaflets and then removed these cells using detergents. Further, we evaluated recellularization with potentially noncontractile cells. A tissue engineered leaflet model was developed with mechanical anisotropy and tensile properties comparable to an ovine pulmonary valve leaflet. No change in tensile properties occurred after decellularization using 1% sodium dodecyl sulfate and 1% Triton detergent treatment. Cell removal was verified by DNA quantitation and western blot analysis for cellular proteins. Histological and scanning electron microscope imaging showed no significant change in the ECM organization and microstructure. We further tested the recellularization potential of decellularized leaflets by seeding human mesenchymal stem cells (hMSC) on the surface of the leaflets and evaluated them at 1 and 3 weeks in two culture conditions. One medium (M1) was chosen to maintain the MSC phenotype while a second medium (M2) was used to potentially differentiate cells to an interstitial cell phenotype. Cellular quantitation showed that the engineered leaflets were recellularized to the highest concentration with M2 followed by M1, with minimum cell invasion of decellularized native leaflets. Histology showed cellular invasion throughout the thickness of the leaflets in M2 and partial invasion in M1. hMSC stained positive for MSC markers, but also for alpha-smooth muscle actin in both media at 1 week, with no presence of MSC markers at 3 weeks with the exception of CD90. These results show that engineered leaflets, while having similar tensile properties and collagen content compared to native leaflets, have better recellularization potential. PMID- 23088579 TI - A novel transcriptional regulator, Sll1130, negatively regulates heat-responsive genes in Synechocystis sp. PCC6803. AB - A conserved hypothetical protein, Sll1130, is a novel transcription factor that regulates the expression of major heat-responsive genes in Synechocystis sp. PCC6803. Synechocystis exhibited an increased thermotolerance due to disruption of sll1130. Deltasll1130 cells recovered much faster than wild-type cells after they were subjected to heat shock (50 degrees C) for 30 min followed by recovery at 34 degrees C for 48 h. In Deltasll1130 cultures, 70% of the cells were viable compared with the wild-type culture in which only 30% of the cells were viable. DNA microarray analysis revealed that in Deltasll1130, expression of the heat responsive genes such as htpG, hspA, isiA, isiB and several hypothetical genes were up-regulated. Sll1130 binds to a conserved inverted-repeat (GGCGATCGCC) located in the upstream region of the above genes. In addition, both the transcript and protein levels of sll1130 were immediately down-regulated upon shift of wild-type cells from 34 to 42 degrees C. Collectively the results of the present study suggest that Sll1130 is a heat-responsive transcriptional regulator that represses the expression of certain heat-inducible genes at optimum growth temperatures. Upon heat shock, a quick drop in the Sll1130 levels leads to de repression of the heat-shock genes and subsequent thermal acclimation. On the basis of the findings of the present study, we present a model which describes the heat-shock response involving Sll1130. PMID- 23088580 TI - Nutritive quality of romanian hemp varieties (Cannabis sativa L.) with special focus on oil and metal contents of seeds. AB - BACKGROUND: The study aims to determine the nutritional value of hemp seed expressed by the oil content and by the concentration of metals (Ca, Mg, K, Fe, Mn, Zn and Cd), for five varieties of monoecious and dioecious hemp seeds approved in Romania, comparative with the concentration of these metals in the soil. RESULTS: The content of oil in hempseed registers a slight decrease in the production records of 2011, losses due to drought and low levels of precipitation during the growth period. The greatest loss is found in Diana monoecious variety (26.54-20.82%) followed by Zenit varieties (27.37-22.97%), Armanca (29.27 25.32%), Silvana (28.89-25.04%) and Denise (26.96-25.30%). Siccative hemp oil has a yellowish green color and an iodine index of 140-156 g I2/100 g oil. Hemp seed are rich in mineral based Ca (144-955 mg/100 g seed), Mg (237-694 mg/100 g seed), K (463-2821 mg/100 g seed), Fe (1133-2400 mg.kg-1), Mn (63-110 mg.kg-1) and Zn (42-94 mg.kg-1). For the soil the following macroelements concentrations were determined: Ca (2100-2520 mg.kg-1), Mg (320-376 mg.kg-1) and K (232-257 mg.kg-1). Mn (156-197 mg.kg-1) and Zn (54-67 mg.kg-1) remain within normal limits for Romania. The soils in the experience area contain large amounts of Fe (19000 20430 mg.kg-1). The presence of K in large quantities determines the accumulation of large quantities of Fe in the soil. CONCLUSION: Hempseed belonging to the five Romanian varieties are rich source of nutrients (Ca, Mg, K) and unsaturated oil easily digestible by the body, but the presence of Cd concentrations above the upper limit puts a question mark over the use of seeds in various food products. Hemp extracts easily certain metals from the soil. Significant amounts of Fe (1133-2400 mg.kg-1), Mn (63-110 mg.kg-1), Zn (42-94 mg.kg-1) and Cd (1.3-4.0 mg.kg-1) are found in hemp seeds. Hemp (Cannabis sativa L.) is included among plants suitable for phytoremediation of soil contaminated with cadmium, zinc and iron. PMID- 23088581 TI - Caries risk profiles of Korean dental patients using simplified Cariogram models. AB - OBJECTIVES: The objective of this study was to compare the caries risk profiles obtained from the simplified Cariogram models and the conventional Cariogram model of Korean dental patients. MATERIALS AND METHODS: Data required for a caries risk assessment with the Cariogram were collected from 80 young adult patients (mean: 23 years old). Three different simplified Cariogram models were produced with exclusion of either or both salivary secretion rate and lactobacilli count: group 1, conventional model; group 2, both salivary secretion rate and lactobacilli count excluded; group 3, salivary secretion rate excluded; group 4, lactobacilli count excluded. RESULTS: The mean chance of avoiding caries in group 1 (55.5%) was not significantly different from those in groups 2 and 3. Also four caries-related sectors of the Cariogram (diet, bacteria, susceptibility and circumstance) in group 1 were not significantly different than in groups 2 and 3. Group 4 showed significant differences from group 1 in the mean chance of avoiding caries and the diet, susceptibility and circumstance sectors (p < 0.05). Significant correlations were detected between all risk factors and their corresponding risk sectors (p < 0.05). Also there were significant correlations between each risk factor and the chance of avoiding caries, except for the amount of plaque, in groups 1, 2 and 3 (p < 0.05). CONCLUSIONS: The simplified Cariogram model without salivary secretion rate and lactobacilli count did not significantly change the outcome produced from the conventional model. However, single exclusion of lactobacilli count noticeably changed the caries risk profile. PMID- 23088582 TI - Genetic and neurocognitive foundations of emotion abnormalities in bipolar disorder. AB - INTRODUCTION: Bipolar Disorder (BD) is a serious mood disorder, the aetiology of which is still unclear. The disorder is characterised by extreme mood variability in which patients fluctuate between markedly euphoric, irritable, and elevated states to periods of severe depression. The current research literature shows that BD patients demonstrate compromised neurocognitive ability in addition to these mood symptoms. Viable candidate genes implicated in neurocognitive and socioemotional processes may explain the development of these core emotion abnormalities. Additionally, links between faulty neurocognition and impaired socioemotional ability complement genetic explanations of BD pathogenesis. This review examines associations between cognition indexing prefrontal neural regions and socioemotional impairments including emotion processing and regulation. A review of the effect of COMT and TPH2 on these functions is also explored. METHODS: Major computer databases including PsycINFO, Google Scholar, and Medline were consulted in order to conduct a comprehensive review of the genetic and cognitive literature in BD. RESULTS: This review determines that COMT and TPH2 genetic variants contribute susceptibility to abnormal prefrontal neurocognitive function which oversees the processing and regulation of emotion. This provides for greater understanding of some of the emotional and cognitive symptoms in BD. CONCLUSIONS: Current findings in this direction show promise, although the literature is still in its infancy and further empirical research is required to investigate these links explicitly. PMID- 23088583 TI - Medically unexplained illness and the diagnosis of hysterical conversion reaction (HCR) in women's medicine wards of Bangladeshi hospitals: a record review and qualitative study. AB - BACKGROUND: Frequent reporting of cases of hysterical conversion reaction (HCR) among hospitalized female medical patients in Bangladesh's public hospital system led us to explore the prevalence of "HCR" diagnoses within hospitals and the manner in which physicians identify, manage, and perceive patients whom they diagnose with HCR. METHODS: We reviewed admission records from women's general medicine wards in two public hospitals to determine how often and at what point during hospitalization patients received diagnoses of HCR. We also interviewed 13 physicians about their practices and perceptions related to HCR. RESULTS: Of 2520 women admitted to the selected wards in 2008, 6% received diagnoses of HCR. HCR patients had wide-ranging symptoms including respiratory distress, headaches, chest pain, convulsions, and abdominal complaints. Most doctors diagnosed HCR in patients who had any medically-unexplained physical symptom. According to physician reports, women admitted to medical wards for HCR received brief diagnostic evaluations and initial treatment with short-acting tranquilizers or placebo agents. Some were referred to outpatient psychiatric treatment. Physicians reported that repeated admissions for HCR were common. Physicians noted various social factors associated with HCR, and they described failures of the current system to meet psychosocial needs of HCR patients. CONCLUSIONS: In these hospital settings, physicians assign HCR diagnoses frequently and based on vague criteria. We recommend providing education to increase general physicians' awareness, skill, and comfort level when encountering somatization and other common psychiatric issues. Given limited diagnostic capacity for all patients, we raise concern that when HCR is used as a "wastebasket" diagnosis for unexplained symptoms, patients with treatable medical conditions may go unrecognized. We also advocate introducing non-physician hospital personnel to address psychosocial needs of HCR patients, assist with triage in a system where both medical inpatient beds and psychiatric services are scarce commodities, and help ensure appropriate follow up. PMID- 23088584 TI - Intraoperative imprint cytology for breast cancer sentinel nodes: is it worth it? AB - BACKGROUND: Re-operative surgery is stressful for patients and is an additional burden to an already stretched public health system. Intraoperative confirmation of breast cancer metastases in sentinel lymph nodes (SLNs) provides the necessary information for the surgeon to proceed with immediate axillary dissection, avoiding the need for a second operation, its associated cost, morbidity and adjuvant treatment delays. Our challenge was to implement a technique that was rapid, inexpensive and had a negligible false positive rate. The aim of this study was to determine whether touch imprint cytology (TIC) could reduce returns to theatre without compromising patient safety and pathology department and operating theatre efficiency. METHODS: Intraoperative TIC was performed on bisected SLNs from 134 patients. Post-operatively, specimens were examined as haematoxylin and eosin-stained, paraffin-embedded 2-mm sections. Further sectioning and immunohistochemisty was performed on negative SLNs. RESULTS: The sensitivity of TIC for metastases was 23.8%, the specificity was 100% and the accuracy was 76.1%. Ten patients with macrometastases and none with micrometastastes were detected intraoperatively. The sensitivity of TIC for detecting macrometastases was 34.5%, the accuracy was 78.4% and the specificity was 100%. CONCLUSION: Ten patients avoided a subsequent surgery. The technique caused no theatre delays and the minimal cost was compensated for by the avoidance of a second procedure for a third of patients who definitively required axillary clearance. No patients had an unnecessary axillary clearance and no patients with micrometastases or isolated tumour cells were subjected to an immediate axillary clearance. It would be justifiable to continue this simple, low-cost and non-disruptive approach. PMID- 23088585 TI - Haloarene derivatives of carbamazepine with reduced bioactivation liabilities: 2 monohalo and 2,8-dihalo derivatives. AB - The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2 monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation. PMID- 23088586 TI - The Global Online Sexuality Survey (GOSS): the United States of America in 2011 chapter II: phosphodiesterase inhibitors utilization among English speakers. AB - INTRODUCTION: Utility of phosphodiesterase inhibitors (PDEi's) for the treatment of erectile dysfunction (ED) has been the focus of experimental and clinical studies. However, public preferences, attitudes, and experiences with PDEi's are rarely addressed from a population/epidemiology viewpoint. The Global Online Sexuality Survey (GOSS) is a worldwide epidemiologic study of sexuality and sexual disorders, first launched in the Middle East in 2010, followed by the United States in 2011. AIM: To describe the utilization rates, trends, and attitudes toward PDEi's in the United States in the year 2011. METHODS: GOSS was randomly deployed to English-speaking male Web surfers in the United States via paid advertising on Facebook(r), comprising 146 questions. MAIN OUTCOME MEASURES: Utilization rates and preferences for PDEi's by brand. RESULTS: Six hundred three subjects participated; mean age 53.43 years +/- 13.9. Twenty-three point seven percent used PDEi's on more consistent basis, 37.5% of those with ED vs. 15.6% of those without ED (recreational users). Unrealistic safety concerns including habituation were pronounced. Seventy-nine point six percent of utilization was on prescription basis. PDEi's were purchased through pharmacies (5.3% without prescription) and in 16.5% over the Internet (68% without prescription). Nine point six percent nonprescription users suffered coronary heart disease. Prescription use was inclined toward sildenafil, generally, and particularly in severe cases, and shifted toward tadalafil in moderate ED and for recreational use, followed by vardenafil. Nonprescription utilization trends were similar, except in recreational use where sildenafil came first. CONCLUSION: In the United States unrealistic safety concerns over PDEi's utility exist and should be addressed. Preference for particular PDEi's over the others is primarily dictated by health-care providers, despite lack of guidelines that govern physician choice. Online and over-the-counter sales of PDEi's are common, and can expose a subset of users to health risks. Recreational use of PDEi's is common, and could be driven by undiagnosed premature ejaculation. PMID- 23088587 TI - Measuring aqueous solubility in the presence of small cosolvent volume fractions by passive dosing. AB - A new passive dosing method was developed to determine aqueous solubility of hydrophobic chemicals. In the passive dosing method, chemical crystals were loaded to a polydimethylsiloxane (PDMS) phase to maintain the maximum chemical activity and to prevent direct contact of chemical crystals with the aqueous solution. Eight polycyclic aromatic hydrocarbons (PAHs) were chosen covering their literature aqueous solubility from 0.001 to 30 mg L(-1). Values of the aqueous solubility for less hydrophobic PAHs (naphthalene, 2-methylnaphthalene, and fluorene) were measured by an Organization for Economic Co-ordination and Development (OECD)-recommended generator column method and those for more hydrophobic PAHs (anthracene, chrysene, and benzo(a)pyrene) were measured by the passive dosing method. For phenanthrene and pyrene, both methods were used for comparison. The results obtained by the passive dosing method were very close to those obtained by the generator column method. Aqueous solubilities in deionized water for more hydrophobic PAHs obtained using the passive dosing method agreed very well with values reported in the literature, suggesting the utility of the passive dosing method for the determination of aqueous solubility for highly hydrophobic chemicals. Because hydrophobic chemicals are often introduced in aqueous solutions by using a cosolvent, the solubility enhancement for PAHs at low cosolvent volume fractions was also evaluated. Three cosolvents (dimethyl sulfoxide, ethanol, and acetone) were chosen and their volume fractions in water were between 0.2% and 2%. The enhancement of the aqueous solubility could be well explained quantitatively by using a log-linear cosolvency model. The measured values of cosolvency power at the range of volume fraction investigated (sigma(0.02)) correlated very well with log K(ow) of the PAHs. The combination of the log-linear model and semiempirical relationships between sigma(0.02) and log K(ow) would be useful for the prediction of the solubility enhancement of hydrophobic chemicals. PMID- 23088588 TI - Flexible free-standing graphene/SnO2 nanocomposites paper for Li-ion battery. AB - A flexible free-standing graphene/SnO2 nanocomposites paper (GSP) was prepared by coupling a simple filtration method and a thermal reduction together for the first time. Compared with the pure SnO2 nanoparticles, the GSP exhibited a better cycling stability, because the graphene with high mechanical strength and elasticity can work as a buffer to prevent the volume expansion and contraction of SnO2 nanoparticles during the Li+ insertion/extraction process. Meanwhile, compared with single graphene paper, the GSP showed a higher capacity because of the hybridizing with higher capacity SnO2 nanoparticles. The excellent electrochemical performance of the GSP as an anode material in Li-ion battery was obtained. The as-prepared GSP shows a great potential for flexible Li-ion batteries. PMID- 23088589 TI - Interconnected roles of scaffold hydrophobicity, drug loading, and encapsulation stability in polymeric nanocarriers. AB - Polymer-based nanoassemblies have emerged as viable platforms for the encapsulation and delivery of lipophilic molecules. Among the criteria that such carriers must meet, if they are to be effective, are the abilities to efficiently solubilize lipophilic guests within an assembled scaffold and to stably encapsulate the molecular cargo until desired release is achieved through the actions of appropriately chosen stimuli. The former feature, dictated by the inherent loading capacity of a nanocarrier, is well studied, and it has been established that slight variations in assembly structure, such as introducing hydrophobic content, can improve miscibility with the lipophilic guests and increase the driving force for encapsulation. However, such clear correlations between assembly properties and the latter feature, nanocarrier encapsulation stability, are not yet established. For this purpose, we have investigated the effects of varying hydrophobic content on the loading parameters and encapsulation stabilities of self-cross-linked polymer nanogels. Through investigating this nanogel series, we have observed a fundamental relationship between nanoassembly structure, loading capacity, and encapsulation stability. Furthermore, a combined analysis of data from different loading amounts suggests a model of loading-dependent encapsulation stability that underscores an important correlation between the principal features of noncovalent encapsulation in supramolecular hosts. PMID- 23088590 TI - Statin use and association with colorectal cancer survival and risk: case control study with prescription data linkage. AB - BACKGROUND: In Scotland colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer death. Epidemiological studies have reported conflicting associations between statins and CRC risk and there is one published report of the association between statins and CRC survival. METHODS: Analysis was carried out on 309 cases and 294 controls from the Scottish Study of Colorectal Cancer (SOCCS). Cox's hazard and logistic regression models were applied to investigate the association between statin use and CRC risk and survival. RESULTS: In an adjusted logistic regression model, statins were found to show a statistically significant association for three of the four statin variables and were found to not show a statistically significant association with either all cause or CRC-specific mortality (OR 0.49; 95%CI 0.49-1.36; p-value = 0.17 and OR 0.33; 95%CI 0.08-1.35; P-value = 0.12, respectively). CONCLUSION: We did find a statistically significant association between statin intake and CRC risk but not statin intake and CRC-specific mortality. However, the study was insufficiently powered and larger scale studies may be advisable. PMID- 23088591 TI - Physicians' management approach to an incidental pulmonary embolism: an international survey. PMID- 23088592 TI - Susceptibility of important Gram-negative pathogens to tigecycline and other antibiotics in Latin America between 2004 and 2010. AB - BACKGROUND: The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance study of antimicrobial susceptibility. This study reports data from Gram-negative isolates collected from centers in Latin America between 2004 and 2010. METHODS: Consecutive bacterial isolates were tested at each center using broth microdilution methodology as described by the Clinical Laboratory Standards Institute (CLSI). Susceptibility was determined using the CLSI interpretive criteria. For tigecycline the US Federal Drug Administration (FDA) criteria were used. RESULTS: A total of 16 232 isolates were analyzed. Susceptibility to imipenem, meropenem, and tigecycline was >95% against both non extended-spectrum beta-lactamase (ESBL) and ESBL producing Escherichia coli. Susceptibility to amikacin was also >95% for non-ESBL E. coli. 24.3% of E. coli were ESBL producers, ranging from 11.2% (58/519) in Colombia to 40.3% (31/77) in Honduras. Greater than 90% of non-ESBL Klebsiella pneumoniae were susceptible to tigecycline, carbapenems and amikacin. 35.3% of K. pneumoniae were ESBL producers, ranging from 17.2% (36/209) in Venezuela to 73.3% (55/75) in Honduras, with only imipenem and tigecycline maintaining >90% susceptibility. Greater than 90% of Klebsiella oxytoca, Enterobacter spp., and Serratia marcescens were susceptible to amikacin, carbapenems and tigecycline. The highest rates of susceptibility against Acinetobacter baumannii were seen for minocycline (89.4%) and imipenem (62.5%), while 95.8% of the A. baumannii isolates displayed an MIC<=2 MUg/mL for tigecycline. CONCLUSIONS: In this study carbapenems and tigecycline remain active against Enterobacteriaceae and A. baumannii; however, there is cause for concern with carbapenem non-susceptible isolates reported in all countries included in this study. PMID- 23088593 TI - Decision making is affected in obstructive sleep apnoea syndrome. AB - We assessed decision making in 20 patients newly diagnosed with obstructive sleep apnoea (OSA) and 20 healthy controls with the Iowa Gambling Task (IGT), which evaluates the ability to learn to sacrifice immediate rewards in favour of long term gains. A standard neuropsychological battery was administered. Switching scores tended to be lower in patients. Patients persisted in selecting risky decks throughout the IGT, whereas controls behaved normally. Performance was correlated with hypoxaemia. Brain regions underlying decision making may be affected by OSA-related hypoxaemia. PMID- 23088594 TI - Land development in and around protected areas at the wilderness frontier. AB - Protected areas' chief conservation objectives are to include species within their boundaries and protect them from negative external pressures. Many protected areas are not achieving these goals, perhaps in part due to land development inside and outside protected areas. We conducted spatial analyses to evaluate the ability of Canadian protected areas to mitigate the effects of nearby land development. We investigated correlations of national patterns of land development in and around protected areas and then examined national patterns of roads, urban area, and croplands in protected areas. We calculated the amount of developed land in protected areas and within 25-100 km of protected area borders, the density of roads, and extent of urban and cropland area in protected areas. We constructed logistic-regression models to test whether development in a protected area was associated with landscape and protected-area characteristics. Land development was far less extensive inside than outside protected areas. However, several protected areas, particularly small southern areas near small urban centers had substantial development inside their boundaries, and nearly half of protected areas had roads. The cumulative extent of development within 50 km of protected areas was the best predictor of the probability of land development in protected areas. Canadian First Nations, industries, government, and nongovernmental organizations are currently planning an unprecedented number of new protected areas. Careful management of areas beyond protected-area boundaries may prove critical to meeting their long-term conservation objectives. PMID- 23088595 TI - Spine function: a concert of many different players. PMID- 23088597 TI - Bone regeneration associated with nontherapeutic and therapeutic surface coatings for dental implants in osteoporosis. AB - Oral implantology is considered as the treatment of choice for replacing missing teeth in elderly people. However, implant complications may occur in patients with osteoporosis. The pathogenesis underlying osteoporosis is due to an alteration in bone cell response to hormonal, nutritional, and aging factors. For such challenging situations, improved bone regeneration has been shown around dental implants for certain surface modifications. These modifications include coatings of titanium implants with calcium phosphate (CaP) ceramics. Surface coating developments also allow for the addition of organic biomolecules, like growth factors, into the inorganic coatings that increase the bone formation process at the bone-implant interface. The application of therapeutic-based coatings is becoming a rapidly growing research field of interest. CaP-coated implants have the ability to incorporate anti-osteoporotic drugs, which then can be locally released over time from an implant surface in a controlled manner. Thus, it can be anticipated that nontherapeutic and/or therapeutic coated implants can significantly increase low bone density as well as improve impaired bone regeneration in osteoporosis. This review aims to provide a thorough understanding of the underlying mechanisms for impaired bone regeneration around dental implants in osteoporosis. Secondly, the review will focus on biological interactions and beneficial role of the surface-coated (i.e., nontherapeutics and therapeutics) bone implants in osteoporotic bone tissue. PMID- 23088596 TI - Sharing and re-use of phylogenetic trees (and associated data) to facilitate synthesis. AB - BACKGROUND: Recently, various evolution-related journals adopted policies to encourage or require archiving of phylogenetic trees and associated data. Such attention to practices that promote sharing of data reflects rapidly improving information technology, and rapidly expanding potential to use this technology to aggregate and link data from previously published research. Nevertheless, little is known about current practices, or best practices, for publishing trees and associated data so as to promote re-use. FINDINGS: Here we summarize results of an ongoing analysis of current practices for archiving phylogenetic trees and associated data, current practices of re-use, and current barriers to re-use. We find that the technical infrastructure is available to support rudimentary archiving, but the frequency of archiving is low. Currently, most phylogenetic knowledge is not easily re-used due to a lack of archiving, lack of awareness of best practices, and lack of community-wide standards for formatting data, naming entities, and annotating data. Most attempts at data re-use seem to end in disappointment. Nevertheless, we find many positive examples of data re-use, particularly those that involve customized species trees generated by grafting to, and pruning from, a much larger tree. CONCLUSIONS: The technologies and practices that facilitate data re-use can catalyze synthetic and integrative research. However, success will require engagement from various stakeholders including individual scientists who produce or consume shareable data, publishers, policy-makers, technology developers and resource-providers. The critical challenges for facilitating re-use of phylogenetic trees and associated data, we suggest, include: a broader commitment to public archiving; more extensive use of globally meaningful identifiers; development of user-friendly technology for annotating, submitting, searching, and retrieving data and their metadata; and development of a minimum reporting standard (MIAPA) indicating which kinds of data and metadata are most important for a re-useable phylogenetic record. PMID- 23088598 TI - Root lengths in the permanent teeth of 45,X females. AB - OBJECTIVE: Studies in permanent and deciduous tooth crowns and permanent tooth roots in individuals with sex chromosome anomalies and in their relatives have given proof that the X chromosome affects enamel formation, root length and crown and root morphology. The present research studies the effects of sex chromosome deficiency on the development of permanent tooth root. MATERIALS AND METHODS: This research investigated tooth root lengths in a group of 97 45,X females. As controls there were 32 sisters and 28 mothers of the 45,X females, 45 female and 42 male population controls and 15 45,X/46,XX females from the KVANTTI research project. Tooth root lengths on both sides of the jaws were measured from panoramic radiographs in each acceptable instance. RESULTS: The results showed significantly shorter tooth root lengths in the 45,X females than in the female and male controls in all teeth measured, whereas in the female relatives tooth root lengths were shifted towards the aneuploids in relation to that in the general population. The tooth root lengths in the 45,X females differed more from those found in their sisters than in their mothers. CONCLUSIONS: These results with the large pure sample size of the whole dentitions in patients with monosomy X confirm the earlier findings of short tooth roots in 45,X females. The fact that in most instances there were no significant differences in tooth root lengths between 45,X and 45,X/46,XX females comes close to the earlier findings regarding mesio-distal tooth crown sizes. PMID- 23088599 TI - Part-time general surgical training in South Australia: its success and future implications (or: pinnacles, pitfalls and lessons for the future). AB - BACKGROUND: Flexible training options are sought by an increasing number of Australasian surgical trainees. Reasons include increased participation of women in the surgical workforce, postgraduate training and changing attitudes to family responsibilities. Despite endorsement of flexible training by the Royal Australasian College of Surgeons and Board in General Surgery, part-time (PT) training in General Surgery in Australia and New Zealand is not well established. A permanent 'stand-alone' PT training position was established at the Royal Adelaide Hospital in 2007 under the Surgical Education and Training Program. This position offered 12 months of General Surgical training on a 0.5 full-time (FT) equivalent basis with pro rata emergency and on-call commitments and was accredited for 6 months of General Surgical training. This paper reviews the PT training experience in South Australia. METHODS: De-identified logbook data were obtained from the South Australian Regional Subcommittee of the Board in General Surgery with consent of each of the trainees. Totals of operative cases were compared against matched FT trainees working on the same unit. RESULTS: Overall, PT trainees achieved comparable operative caseloads compared with their FT colleagues. All trainees included in this review have subsequently passed the Royal Australasian College of Surgeons Fellowship Examination in General Surgery and returned to FT workforce positions. CONCLUSION: This paper presents two validated models of PT training. Training, resource and regulatory requirements and individual and institutional barriers to flexible training are substantial. Successful PT models offer positive and beneficial training alternatives for General Surgical trainees and contribute to workforce flexibility. PMID- 23088600 TI - Phase transformations in lipid A-diphosphate initiated by sodium hydroxide. AB - The nature of the fluid phase transitions of charged-stabilized spherical lipid A diphosphate clusters in aqueous dispersions was explored using a combination of small-angle X-ray scattering (SAXS) and electron microscopy. In contrast to previous studies, rather than removing NaCl, NaOH was added to the dispersions to promote crystallization. The fluid phase experiments were carried out employing titrations with mM.L(-1) NaOH (c(S)), along with variations in the particle number density, n. When c(S) was increased, a new fluid disordered phase of self assembled lipid A-diphosphate was encountered, followed by a crystalline bcc phase and then a new fluid phase containing 70 nm lipid A-diphosphate particles. The bcc crystal structure found in this regime had a lattice constant of 35.6 nm. By varying c(S) (mM L(-1)), it was possible to determine the effective charge, z(eff), for various n values and the screening parameter, k, for the excess electrolyte. For sufficiently large values of n, lipid A-diphosphate crystallized because of an increase in z(eff) at a constant c(S). When the c(S) was increased, the crystals melted with little change in z(eff). The existence of a bcc-fluid phase transition for different values of c(S) was supported by applying the Debye correlation function to the obtained data. An increase in c(S) enhanced interparticle interaction and attraction. The effective charge and k accounted for counterion condensation and many-body effects. If the effective charge determined from scattering measurements was used in the simulations, the equilibrium phase boundaries were consistent with predicted universal melting line simulations. At any particle-number densities, n, when the melting line was reached, 70 nm clusters were formed. PMID- 23088601 TI - Role of the repressor Oaf3p in the recruitment of transcription factors and chromatin dynamics during the oleate response. AB - Cellular responses to environmental stimuli are mediated by the co-ordinated activity of multiple control mechanisms, which result in the dynamics of cell function. Communication between different levels of regulation is central for this adaptability. The present study focuses on the interplay between transcriptional regulators and chromatin modifiers to co-operatively regulate transcription in response to a fatty acid stimulus. The genes involved in the beta-oxidation of fatty acids are highly induced in response to fatty acid exposure by four gene-specific transcriptional regulators, Oaf (oleate-activated transcription factor) 1p, Pip2p (peroxisome induction pathway 2), Oaf3p and Adr1p (alcohol dehydrogenase regulator 1). In the present study, we examine the interplay of these factors with Htz1p (histone variant H2A.Z) in regulating POT1 (peroxisomal oxoacyl thiolase 1) encoding peroxisomal thiolase and PIP2 encoding the autoregulatory oleate-specific transcriptional activator. Temporal resolution of ChIP (chromatin immunoprecipitation) data indicates that Htz1p is required for the timely removal of the transcriptional repressor Oaf3p during oleate induction. Adr1p plays an important role in the assembly of Htz1p-containing nucleosomes on the POT1 and PIP2 promoters. We also investigated the function of the uncharacterized transcriptional inhibitor Oaf3p. Deletion of OAF3 led to faster POT1 mRNA accumulation than in the wild-type. Most impressively, a highly protected nucleosome structure on the POT1 promoter during activation was observed in the OAF3 mutant cells in response to oleate induction. PMID- 23088602 TI - Nitro-substituted 4-[(phenylmethylene)imino]phenolates: solvatochromism and their use as solvatochromic switches and as probes for the investigation of preferential solvation in solvent mixtures. AB - Four 4-[[(4-nitrophenyl)methylene]imino]phenols (2a-d) were synthesized. After deprotonation in solution, they formed the solvatochromic phenolates 3a-d, which revealed a reversal in solvatochromism. Their UV-vis spectroscopic behavior was explained on the basis of the interaction of the dyes with the medium through combined effects, such as nonspecific solute-solvent interactions and hydrogen bonding between the solvents and the nitro and phenolate groups. Dyes 3a-c were used as probes to investigate binary solvent mixtures, and the synergistic behavior observed was attributed to solvent-solvent and solute-solvent interactions. A very unusual UV-vis spectroscopic behavior occurred with dye 3d, which has in its molecular structure two nitro substituents as acceptor groups and two phenyl groups on the phenolate moiety. In alcohol/water mixtures, the E(T)(3d) values increase from pure alcohol (methanol, ethanol, and propan-2-ol) until the addition of up to 80-96% water. Subsequently, the addition of a small amount of water causes a very sharp reduction in the E(T)(3d) value (for methanol, this corresponds to a bathochromic shift from 543 to 732 nm). This represents the first example of a solvatochromic switch triggered by a subtle change in the polarity of the medium, the color of the solutions being easily reversed by adding small amounts of the required cosolvent. PMID- 23088603 TI - Frequency of pericardial effusion in childhood acute lymphoblastic leukemia and clinical features of these patients. AB - In this study, we aimed to determine the frequency of pericardial effusion (PE) in children diagnosed with acute lymphoblastic leukemia (ALL). Clinical features of patients with effusion were evaluated. For this purpose, we reviewed the medical records of ALL patients who had pretherapy echocardiograms. A total of 90 patients aged between 1.8 and 16.3 years were analyzed retrospectively. In 23 of 90 (25.6%) patients, PE was detected at initial diagnosis. The age of patients with PE ranged between 1.8 and 14.8 years (mean 5.05 +/- 3.77 years). The female/male ratio was 9/14. Six (26.1%) patients were T-lineage and 17 (73.9%) were B-lineage ALL. Nine (39%) patients were in standard risk group, 13 (57%) were in median risk group, 1 (4%) patient was in high-risk group. Mean initial white blood cell count was 40.756 +/- 38.653/mm(3) (range 23.000-130.000/mm(3)). Mean initial hemoglobin count was 7.3 +/- 1.39 gr/dL (range 5.5-10.1 gr/dL), mean initial platelet count was 35.200 +/- 26.300/mm(3) (range 4.000-118.000 mm(3)). Size of effusions was between 2 and 6 mm (mean size 3.3 +/- 1.8 mm). All patients had normal left ventricular systolic function. In 87% of patients, effusions disappeared in the first 7 days and, in 13%, disappeared between 8th and 15th days of chemotherapy. None of the patients required pericardiocentesis. Cardiac dysfunction did not occur among any of these patients during chemotherapy. In conclusion, PE is not frequent in childhood ALL. It usually does not cause cardiac impairment. It responds to treatment of leukemia. PMID- 23088604 TI - Comment on "Feather meal: a previously unrecognized route for reentry into the food supply of multiple pharmaceuticals and personal care products (PPCPs)". PMID- 23088605 TI - Seasonal evaluation of fine and coarse culturable bacterial aerosols from residences within a rural and an urban city in Egypt. AB - Non-complaint Egyptian homes were examined to determine the residential culturable airborne bacterial concentrations so that these could be used as comparisons in indoor air quality investigations. Concentrations of airborne bacteria were investigated in 26 urban flats across Cairo and 17 rural flats in the Dakahlia governorate. Air samples were collected using a two-stage viable cascade impactor sampler, dividing particles into coarse (>8 MUm) and fine (<8 MUm) sizes. For urban flats, the year's median indoor and comparison site concentrations were 9133 CFU/m(3) and 9423 CFU/m(3), respectively. For rural flats, the year's median indoor and comparison site concentrations were 15,915 CFU/m(3) and 10,859 CFU/m(3), respectively. The median indoor bacterial concentrations increased in winter and spring compared to autumn and summer. Winter months had the greatest median concentration for coarse indoor organisms, whereas spring had the largest for the fine indoor organisms. Fine bacterial concentration composed more than 60% of the indoor bacterial fraction. PMID- 23088606 TI - Salvage management of prolonged ischemic priapism: Al-Ghorab shunt plus cavernous tunneling with blunt cavernosotomy. AB - INTRODUCTION: The management of ischemic priapism (IP), especially in cases of prolonged IP (PIP), is enigmatic. The T-shaped shunt and intracavernous tunneling and the corporal "snake" maneuver have been reported as effective surgical procedures for PIP; however, management of the PIP that is refractory to these procedures is controversial. AIM: The present study is a report of two PIP cases that were successfully treated by a novel technique. METHODS: Two cases with 5- and 7-day histories of IP that were refractory to T-shaped shunt and intracavernous tunneling or the corporal "snake" maneuver, respectively, were included in this study. After creating the Al-Ghorab distal shunts, part of the cavernous tissue was bluntly excised with Pean forceps through the shunts to create a large drainage route. The effectiveness, safety and effect on erectile function after this procedure were assessed. RESULTS: In both cases, the erection and penile pain were immediately diminished, and corporal blood flow measured by color Doppler ultrasonography was restored after the surgery. There was no urethral injury or perforation of the tunica albuginea. Pathological findings showed that the excised tissues were fibrotic and necrotic. There was no recurrence of IP after the salvage surgery. One patient noticed partial erection, and the administration of sildenafil was effective for completing sexual intercourse. CONCLUSION: Al-Ghorab distal shunt plus cavernous tunneling with blunt cavernosotomy creates a large blood drainage route by removing the necrotic or fibrous cavernous tissues. Further investigation regarding to erectile function is needed; however, this procedure is safe and effective even in repeat cases after T-shaped shunt and intracavernous tunneling or the corporal "snake" maneuver. PMID- 23088608 TI - Target Selectivity of FimH Antagonists. AB - Mannose-based FimH antagonists are considered new therapeutics for the treatment of urinary tract infections (UTIs). They prevent the adhesion of uropathogenic Escherichia coli (UPEC) to urothelial cell surfaces triggered by the lectin FimH, which is located at the tip of bacterial type 1 pili. Because all reported FimH antagonists are alpha-d-mannosides, they are also potential ligands of mannose receptors of the human host system. We therefore investigated the selectivity range of five FimH antagonists belonging to different compound families by comparing their affinities for FimH and eight human mannose receptors. On the basis of the detected selectivity range of approximately 5 orders of magnitude, no adverse side effects resulting from nonselective binding to the human receptors have to be expected. FimH antagonists can therefore be further considered as potential therapeutics for the treatment of UTI. PMID- 23088607 TI - Hypoxia and estrogen are functionally equivalent in breast cancer-endothelial cell interdependence. AB - BACKGROUND: Rapid breast tumor development relies on formation of new vasculature to supply the growing malignancy with oxygenated blood. Previously we found that estrogen aided in this neovasculogenesis via recruitment of bone marrow derived endothelial progenitor cells (BM-EPCs), leading to increased vessel formation and vascular endothelial growth factor (VEGF) production in vivo. However, the cellular mechanism of this induction and the signaling pathways involved need elucidation. RESULTS: Using the murine mammary cell line TG1-1 we observed estrogen (E2) lead to an up regulation of hypoxia inducible factor-1 (HIF-1), an effect abrogated by the anti-estrogen Fulvestrant and the HIF-1 inhibitor YC-1 (3 (5'-hydroxymethyl-2'-furyl)-1-benzylindazole) suggesting the interchangeability of hypoxia and estrogen mediated effects. Estrogen modulation of HIF-1 and subsequent effects on endothelial cells is dependent on the Akt/PI3K pathway and protein synthesis as validated by the use of the inhibitors wortmannin and cycloheximide which abrogated estrogen's effects respectively. Estrogen treated TG1-1 cells secreted higher levels of VEGF which were comparable to secreted levels from cells grown under hypoxic conditions. Soluble factors in conditioned media from E2 treated breast cancer cells also lead to migration and tube formation of human umbilical vein endothelial cells (HUVEC) in vitro. CONCLUSIONS: Our data provide evidence that estrogen signaling mediates the tumor vasculogenic process required for breast cancer progression and involves a key regulator of the hypoxia signaling pathway. Further, hypoxia and estrogen are interchangeable as both similarly modulate epithelial-endothelial cell interaction. PMID- 23088609 TI - Rural mental health workforce needs assessment - a national survey. AB - INTRODUCTION: A variety of studies have indicated that rural communities have fewer mental health services and professionals than their urban counterparts. This study will examine the shortages of mental health professionals in rural communities as well as the impact of inadequate mental health services access on rural hospitals. METHODS: A sample frame of 1162 rural hospitals was compiled, and a two-page survey was mailed to each hospital Chief Executive Officer (CEO). RESULTS: Of the 1162 surveys mailed, 228 were returned. The majority of CEOs agreed that there was a shortage of mental health professionals, that referral centers were too distant, and that there were many barriers to care including infrastructure, poverty, and substance abuse. Solutions offered by CEOs included telemedicine and residency training programs. CONCLUSIONS: This study shows that many rural areas have great need for more mental health professional recruitment and retention. PMID- 23088610 TI - Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats. AB - BACKGROUND: Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. METHODS: Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000 mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. RESULTS: In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. CONCLUSION: Acute study reveals that the LD50 of NK is greater than 2000 mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions. PMID- 23088611 TI - Evaluation and application of the diffusive gradients in thin films technique using a mixed-binding gel layer for measuring inorganic arsenic and metals in mining impacted water and soil. AB - The diffusive gradients in thin films (DGT) equipped with a Chelex or ferrihydrite binding gel has been designed to enable the measurement of either labile metal species or inorganic arsenic, respectively. In the mine impacted environment, metals and metalloids commonly coexist in a variety of species. This study, for the first time reports the performance of the DGT with a mixed-binding layer (MBL), consisting of Chelex and ferrihydrite for measurements of both metals and arsenic in a single assay. The MBL that consists of a combination of Chelex and ferrihydrite at a ratio of 1:2 has the greatest binding capacity for arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn). The elemental concentrations measured by using MBL-DGT (C(DGT)) were comparable (92-104%) with the original test solution concentrations (C(SOL)). The measurement of As by using MBL-DGT was consistent across a wide pH range (3-8) and ionic strength (0.001-0.1 M). At high pH (9), As measurement was slightly affected (~80%). The measurements of Cd, Pb, and Zn were affected at low pH (<3) and high pH (9). Measurements of Cd, Cu, and Pb were affected at low ionic strength (0.001 M). At high ionic strength (0.1 M), measurements of Cd; Cu and Pb were slightly affected. The capacity of MBL-DGT for quantitative measurement in a multielements solution is effectively limited to 15 MUg for As and 70 MUg for metals per MBL DGT device. Good correlations (p < 0.01) between MBL-DGT measurements and ferrihydrite or Chelex DGT were obtained for As, Cd, Cu, Pb, and Zn in water and soil with exception for Cd and Cu (p < 0.05) when deployed in soil. PMID- 23088612 TI - European innovation partnership on active and healthy ageing: triggers of setting the headline target of 2 additional healthy life years at birth at EU average by 2020. AB - BACKGROUND: The objective of this paper is to provide analytical research that supported the European Commission in setting the global target of additional two healthy life years (HLY) at birth by 2020 in the EU on average, within the European Innovation Partnership on Active and Healthy Ageing (the EIP on AHA). It produces a straightforward analysis of HLY projections that helped the European Commission set a firm, politically sound, target. In order to reach that goal, policy makers need to commit to redefining health priorities and goals and developing and implementing relevant strategies and programmes. METHODS: The study computes a simple simulation of the HLY at birth based on three demographic scenarios: compression of morbidity, expansion of morbidity and an intermediary scenario, the dynamic equilibrium, given the expected 2.1 year gain in male and 1.6 in female life expectancy (LE) by 2020. Data on HLY and projections of life expectancy were obtained from Eurostat and 2008 was taken as a baseline. For consistency and given data gaps, EU27 average values of HLY were calculated. RESULTS: In the EU27 as a whole, the difference between LE and HLY in 2008 was nearly 15 years for men and 20 years for women. The developments of healthy life expectancies across the EU Member States (MSs) are even more diverse that makes it difficult to model any robust EU level trends.Under compression of morbidity, life expectancy and HLY would increase by 2020 on average by 2.1 and 2.0 years for men and by 1.6 and 1.4 years for women respectively. The expected years with disability would remain unchanged while the HLY/LE ratio would improve leading to a 0.5% gain for both genders. Under expansion of morbidity, life expectancy would increase by 2.1 years for men and 1.4 years for women by 2020, while HLY would remain unchanged and the expected years with disability would increase by 2.1 years and 1.6 years in women. This would imply the deterioration of the HLY/LE ratio for both men and women generating a 2.2% and 1.4% loss of health for men and women accordingly. Under dynamic equilibrium, the HLY would increase but to a lesser extent as the rise in life expectancy. The HLY would increase by 1.6 and 1.2 years for men and women respectively. HLY/LE ratio would remain unchanged for both men (+0.1%) and women. The study shows that the first scenario would reduce the HLY gap between the EU MSs by 1.4 years in men and 1.2 years in women, the second would generate no change, while the third one would reduce the gap by 0.9 years in men and increase it by 0.7 years in women. CONCLUSIONS: The results of the study triggered the political decision of setting the global target of 2 additional HLY for the European Innovation Partnership on Active and Healthy Ageing to be achieved by 2020. It is a 'grand' goal but can be achieved. Statistics clearly show that EU countries characterise very different levels of health progress, with a gap of 2 decades and diverging trends. With this in mind, the EU HLY target should be complemented by national HLY targets for men and women, set by MSs. PMID- 23088613 TI - 2-Arylbenzofuran and tyrosinase inhibitory constituents of Morus notabilis. AB - Phytochemical investigation of the stem of Morus notabilis led to the isolation and characterization of 10 compounds of 2-arylbenzofurans (1-10), including two new compounds, (2'R)-2',3'-dihydro-2'-(1-hydroxy-1-methylethyl)-2,6'-bibenzofuran 6,4'-diol (1) and 5,6-dimethoxy-2-(3-hydroxy-5-methoxyphenyl)benzofuran (2). Moracins O (6) and P (10) showed inhibitory effects on mushroom tyrosinase with IC50 values being lower than that of kojic acid. PMID- 23088614 TI - BMP and TGFbeta pathways in human central chondrosarcoma: enhanced endoglin and Smad 1 signaling in high grade tumors. AB - BACKGROUND: As major regulators of normal chondrogenesis, the bone morphogenic protein (BMP) and transforming growth factor beta (TGFB) signaling pathways may be involved in the development and progression of central chondrosarcoma. In order to uncover their possible implication, the aim of this study was to perform a systematic quantitative study of the expression of BMPs, TGFBs and their receptors and to assess activity of the corresponding pathways in central chondrosarcoma. METHODS: Gene expression analysis was performed by quantitative RT-PCR in 26 central chondrosarcoma and 6 healthy articular cartilage samples. Expression of endoglin and nuclear localization of phosphorylated Smad1/5/8 and Smad2 was assessed by immunohistochemical analysis. RESULTS: The expression of TGFB3 and of the activin receptor-like kinase ALK2 was found to be significantly higher in grade III compared to grade I chondrosarcoma. Nuclear phosphorylated Smad1/5/8 and Smad2 were found in all tumors analyzed and the activity of both signaling pathways was confirmed by functional reporter assays in 2 chondrosarcoma cell lines. Immunohistochemical analysis furthermore revealed that phosphorylated Smad1/5/8 and endoglin expression were significantly higher in high-grade compared to low-grade chondrosarcoma and correlated to each other. CONCLUSIONS: The BMP and TGFbeta signaling pathways were found to be active in central chondrosarcoma cells. The correlation of Smad1/5/8 activity to endoglin expression suggests that, as described in other cell types, endoglin could enhance Smad1/5/8 signaling in high-grade chondrosarcoma cells. Endoglin expression coupled to Smad1/5/8 activation could thus represent a functionally important signaling axis for the progression of chondrosarcoma and a regulator of the undifferentiated phenotype of high-grade tumor cells. PMID- 23088615 TI - Sulfonated poly(ether ether ketone)/polypyrrole core-shell nanofibers: a novel polymeric adsorbent/conducting polymer nanostructures for ultrasensitive gas sensors. AB - Conducting polymers-based gas sensors have attracted increasing research attention these years. The introduction of inorganic sensitizers (noble metals or inorganic semiconductors) within the conducting polymers-based gas sensors has been regarded as the generally effective route for further enhanced sensors. Here we demonstrate a novel route for highly-efficient conducting polymers-based gas sensors by introduction of polymeric sensitizers (polymeric adsorbent) within the conducting polymeric nanostructures to form one-dimensional polymeric adsorbent/conducting polymer core-shell nanocomposites, via electrospinning and solution-phase polymerization. The adsorption effect of the SPEEK toward NH3 can facilitate the mass diffusion of NH3 through the PPy layers, resulting in the enhanced sensing signals. On the basis of the SPEEK/PPy nanofibers, the sensors exhibit large gas responses, even when exposed to very low concentration of NH3 (20 ppb) at room temperature. PMID- 23088616 TI - Axial displacements in external and internal implant-abutment connection. AB - OBJECTIVES: The purpose of this study was to evaluate the axial displacement of the abutments during clinical procedures by the tightening torque and cyclic loading. MATERIALS AND METHODS: Two different implant-abutment connection systems were used (external butt joint connection [EXT]; internal tapered conical connection [INT]). The master casts with two implant replicas, angulated 10 degrees from each other, were fabricated for each implant connection system. Four types of impression copings were assembled and tightened with the corresponding implants (hex transfer impression coping, non-hex transfer impression coping, hex pick-up impression coping, non-hex pick-up impression coping). Resin splinted abutments and final prosthesis were assembled. The axial displacement was measured from the length of each assembly, which was evaluated repeatedly, after 30 Ncm torque tightening. After 250 N cyclic loading of final prosthesis for 1,000,000 cycles, additional axial displacement was recorded. The mean axial displacement was statistically analyzed (repeated measured ANOVA). RESULTS: There was more axial displacement in the INT group than that of the EXT group in impression copings, resin splinted abutments, and final prosthesis. Less axial displacement was found at 1-piece non-hex transfer type impression coping than other type of impression copings in the INT group. There was more axial displacement at the final prosthesis than resin splinted abutments in the INT and the EXT groups. After 250 N cyclic loading of final prosthesis, the INT group showed more axial displacement than that of the EXT group. CONCLUSION: Internal tapered conical connection demonstrated a varying amount of axial displacement with tightening torque and cyclic loading. PMID- 23088617 TI - The patterns of anticoagulation control and the risk of stroke, bleeding and mortality in patients with non-valvular atrial fibrillation. AB - BACKGROUND: Anticoagulation control is often summarized using the percentage of time spent in a therapeutic range (TTR). This method does not describe the timing and severity of fluctuations in the International Normalised Ratio (INR). OBJECTIVE: To evaluate whether the TTR method can be improved by considering the patterns of INR over time. METHODS: The cohort included adults aged 40+ years with atrial fibrillation (AF) and laboratory records of INR as recorded in the UK Clinical Practice Research Datalink. Statistical clustering techniques based on simple INR measures were used to describe the patterns of INR. Nested case control studies calculated the odds ratios (ORs) for the risk of stroke, bleeding and mortality with TTR and different INR patterns. It was also evaluated whether cluster analyses improved the prediction of outcomes over TTR. RESULTS: A number of 27 381 patients were studied with a mean age of 73 years. The OR for mortality was 3.76 (95% confidence interval [CI] 3.03-4.68) in patients with < 30% TTR compared with patients with 100% TTR. INR patterns were found to be best described by six different clusters. The cluster with the most unstable pattern was associated with the largest risk of mortality (OR 10.7, 95% CI 8.27-13.85) and stroke (OR 3.42, 95% CI 2.08-5.63). INR measures that predicted death independent of the TTR-included absolute difference between two subsequent INR measurements and change relative to the mean over time. CONCLUSION: Cluster analysis of INR patterns improved the prediction of clinical outcomes over TTR and may help to identify warfarin users who need additional anticoagulation monitoring. PMID- 23088618 TI - Identification of novel virulence genes and metabolic pathways required for full fitness of Pseudomonas savastanoi pv. savastanoi in olive (Olea europaea) knots. AB - Comparative genomics and functional analysis of Pseudomonas syringae and related pathogens have mainly focused on diseases of herbaceous plants; however, there is a general lack of knowledge about the virulence and pathogenicity determinants required for infection of woody plants. Here, we applied signature-tagged mutagenesis (STM) to Pseudomonas savastanoi pv. savastanoi during colonization of olive (Olea europaea) knots, with the goal of identifying the range of genes linked to growth and symptom production in its plant host. A total of 58 different genes were identified, and most mutations resulted in hypovirulence in woody olive plants. Sequence analysis of STM mutations allowed us to identify metabolic pathways required for full fitness of P. savastanoi in olive and revealed novel mechanisms involved in the virulence of this pathogen, some of which are essential for full colonization of olive knots by the pathogen and for the lysis of host cells. This first application of STM to a P. syringae-like pathogen provides confirmation of functional capabilities long believed to play a role in the survival and virulence of this group of pathogens but not adequately tested before, and unravels novel factors not correlated previously with the virulence of other plant or animal bacterial pathogens. PMID- 23088619 TI - AO type-C distal radius fractures: the influence of computed tomography on surgeon's decision-making. AB - BACKGROUND: Computed tomography (CT) has become a widely accepted adjunct imaging tool in the preoperative evaluation of complex intra-articular distal radius fractures. The aim of this study was to evaluate the impact of CT scanning compared with plain X-rays on the choice of intervention in complex distal radius fractures. METHODS: Five orthopaedic surgeons were given the de-identified plain films (AP, lateral and oblique) of 20 closed complex intra-articular distal radius fractures (AO23-C), randomly selected from our institution's prospectively maintained fracture database. Each surgeon individually selected a management option for each patient from a series of five interventions, ranked in increasing level of invasiveness. The same patients' CT scans (in randomized order) were blindly reviewed after a 1-week interval by the same clinicians with the same management options again offered. Kappa statistic was used to measure the intra observer agreement between X-ray and CT decisions, and inter-observer agreement within each modality. RESULTS: The intra-observer agreement on management between X-rays alone versus CT scan was poor, with an average kappa score of 0.038. Inter observer agreement based on X-ray alone was higher than that based on CT alone. Regression analysis indicated a trend towards a slightly higher level of invasiveness when the management decision was based on the CT compared with plain X-rays. CONCLUSION: There is a very poor intra- and inter-rater agreement between decision-making based on X-ray and on CT. Decision-making based on CT could increase the level of invasiveness in the surgical management of complex distal radius fractures. PMID- 23088620 TI - Comparative effectiveness of medication versus cognitive-behavioral therapy in a randomized controlled trial of low-income young minority women with depression. AB - OBJECTIVE: To examine whether there are latent trajectory classes in response to treatment and whether they moderate the effects of medication versus psychotherapy. METHOD: Data come from a 1-year randomized controlled trial of 267 low-income, young (M = 29 years), minority (44% Black, 50% Latina, 6% White) women with current major depression randomized to antidepressants, cognitive behavioral therapy (CBT), or referral to community mental health services. Growth mixture modeling was used to determine whether there were differential effects of medication versus CBT. Depression was measured via the Hamilton Depression Rating Scale (Hamilton, 1960). RESULTS: We identified 2 latent trajectory classes. The first was characterized by severe depression at baseline. At 6 months, mean depression scores for the medication and CBT groups in this class were 13.9 and 14.9, respectively (difference not significant). At 12 months, mean depression scores were 16.4 and 11.0, respectively (p for difference = .04). The second class was characterized by moderate depression and anxiety at baseline. At 6 months, mean depression scores for the medication and CBT groups were 4.4 and 6.8, respectively (p for difference = .03). At 12 months, the mean depression scores were 7.1 and 7.8, respectively, and the difference was no longer significant. CONCLUSIONS: Among depressed women with moderate baseline depression and anxiety, medication was superior to CBT at 6 months, but the difference was not sustained at 1 year. Among women with severe depression, there was no significant treatment group difference at 6 months, but CBT was superior to medication at 1 year. PMID- 23088621 TI - Insecticide susceptibility of Aedes aegypti populations from Senegal and Cape Verde Archipelago. AB - BACKGROUND: Two concomitant dengue 3 (DEN-3) epidemics occurred in Cape Verde Archipelago and Senegal between September and October 2009. Aedes aegypti was identified as the vector of these epidemics as several DEN-3 virus strains were isolated from this species in both countries. The susceptibility to pyrethroids, organochlorine, organophosphates and carbamate was investigated in two field strains of Aedes aegypti from both countries using WHO diagnostic bioassay kits in order to monitor their the current status of insecticide susceptibility. FINDINGS: The two tested strains were highly resistant to DDT. The Cape Verde strain was found to be susceptible to all others tested insecticides except for propoxur 0.1%, which needs further investigation. The Dakar strain was susceptible to fenitrothion 1% and permethrin 0.75%, but displayed reduced susceptibility to deltamethrin, lambda-cyhalothrin and propoxur. CONCLUSIONS: As base-line results, our observations stress a careful management of insecticide use for the control of Ae. aegypti. Indeed, they indicate that DDT is no longer efficient for the control of Ae. aegypti populations in Cape Verde and Dakar and further suggest a thorough follow-up of propoxur susceptibility status in both sites and that of deltamethrin and lambda-cyhalothrin in Ae. aegypti populations in Dakar. Thus, regular monitoring of susceptibility is greatly needed as well as the knowing if this observed resistance/susceptibility is focal or not and for observed resistance, the use of biochemical methods is needed with detailed comparison of resistance levels over a large geographic area. KEYWORDS: Aedes aegypti, Insecticides, Susceptibility, Cape Verde, Senegal. PMID- 23088622 TI - Factors influencing distress toward erectile dysfunction and attitude toward erectile dysfunction drugs among middle-aged and elderly Chinese women and men in Hong Kong. AB - AIM: This study aims to explain distress toward erectile dysfunction (ED), attitude toward ED drugs, and experiences with ED drug use in terms of sexual attitudes, relationship satisfaction, and sociodemographic factors among the middle-aged and elderly Chinese population. Studies show that a significant number of middle-aged and elderly men in Asia suffer from ED. However, people's attitudes toward ED drugs are not positive. Few studies have sought to reveal the influencing factors of this negative attitude. METHODS: Nine hundred forty-six Hong Kong women and men aged 36-80 with stable partners were administered a structured questionnaire through face-to-face street-intercept survey. Self reporting on single-item questions using a five-point Likert scale was adopted for most of the variables, including attitude toward sex, relationship satisfaction, distress toward ED, and attitude toward ED drugs. Perceived importance of sex in an intimate relationship and attitude toward sex were assessed through three items. Respondents were asked to report whether they had taken ED drugs or bought ED drugs for their partners. RESULTS: While perceived importance of sex in an intimate relationship and distress toward ED both contributed to the estimation of attitudes toward ED drugs for both genders, relationship satisfaction was only associated with men's attitude, while women's attitude was related to two other factors: relationship status and income level. Both age and attitude toward ED drugs influenced experiences with ED drug use for women and men. Men's experience with ED drug use was further related to the perceived importance of sex and to men's self-esteem and relationship status. CONCLUSION: Results of this study could help identify people who are disturbed by ED but reluctant to seek treatment. Clinicians and public health policy makers could make use of the findings to encourage proper understanding of ED. PMID- 23088623 TI - In vivo gene transfer targeting in pancreatic adenocarcinoma with cell surface antigens. AB - BACKGROUND: Pancreatic ductal adenocarcinoma is a deadly malignancy resistant to current therapies. It is critical to test new strategies, including tumor targeted delivery of therapeutic agents. This study tested the possibility to target the transfer of a suicide gene in tumor cells using an oncotropic lentiviral vector. RESULTS: Three cell surface markers were evaluated to target the transduction of cells by lentiviruses pseudotyped with a modified glycoprotein from Sindbis virus. Only Mucin-4 and the Claudin-18 proteins were found efficient for targeted lentivirus transductions in vitro. In subcutaneous xenografts of human pancreatic cancer cells models, Claudin-18 failed to achieve efficient gene transfer but Mucin-4 was found very potent. Human pancreatic tumor cells were modified to express a fluorescent protein detectable in live animals by bioimaging, to perform a direct non invasive and costless follow up of the tumor growth. Targeted gene transfer of a bicistronic transgene bearing a luciferase gene and the herpes simplex virus thymidine kinase gene into orthotopic grafts was carried out with Mucin-4 oncotropic lentiviruses. By contrast to the broad tropism VSV-G carrying lentivirus, this oncotropic lentivirus was found to transduce specifically tumor cells, sparing normal pancreatic cells in vivo. Transduced cells disappeared after ganciclovir treatment while the orthotopic tumor growth was slowed down. CONCLUSION: This work considered for the first time three aspect of pancreatic adenocarcinoma targeted therapy. First, lentiviral transduction of human pancreatic tumor cells was possible when cells were grafted orthotopically. Second, we used a system targeting the tumor cells with cell surface antigens and sparing the normal cells. Finally, the TK/GCV anticancer system showed promising results in vivo. Importantly, the approach presented here appeared to be a safer, much more specific and an as efficient way to perform gene delivery in pancreatic tumors, in comparison with a broad tropism lentivirus. This study will be useful in future designing of targeted therapies for pancreatic cancer. PMID- 23088624 TI - N-Myristoylation is essential for protein phosphatases PPM1A and PPM1B to dephosphorylate their physiological substrates in cells. AB - PPM [metal-dependent protein phosphatase, formerly called PP2C (protein phosphatase 2C)] family members play essential roles in regulating a variety of signalling pathways. While searching for protein phosphatase(s) that act on AMPK (AMP-activated protein kinase), we found that PPM1A and PPM1B are N-myristoylated and that this modification is essential for their ability to dephosphorylate the alpha subunit of AMPK (AMPKalpha) in cells. N-Myristoylation was also required for two other functions of PPM1A and PPM1B in cells. Although a non-myristoylated mutation (G2A) of PPM1A and PPM1B prevented membrane association, this relocalization did not likely cause the decreased activity towards AMPKalpha. In in vitro experiments, the G2A mutants exhibited reduced activities towards AMPKalpha, but much higher specific activity against an artificial substrate, PNPP (p-nitrophenyl phosphate), compared with the wild-type counterparts. Taken together, the results of the present study suggest that N-myristoylation of PPM1A and PPM1B plays a key role in recognition of their physiological substrates in cells. PMID- 23088625 TI - Characterization of methionine oxidation and methionine sulfoxide reduction using methionine-rich cysteine-free proteins. AB - BACKGROUND: Methionine (Met) residues in proteins can be readily oxidized by reactive oxygen species to Met sulfoxide (MetO). MetO is a promising physiological marker of oxidative stress and its inefficient repair by MetO reductases (Msrs) has been linked to neurodegeneration and aging. Conventional methods of assaying MetO formation and reduction rely on chromatographic or mass spectrometry procedures, but the use of Met-rich proteins (MRPs) may offer a more streamlined alternative. RESULTS: We carried out a computational search of completely sequenced genomes for MRPs deficient in cysteine (Cys) residues and identified several proteins containing 20% or more Met residues. We used these MRPs to examine Met oxidation and MetO reduction by in-gel shift assays and immunoblot assays with antibodies generated against various oxidized MRPs. The oxidation of Cys-free MRPs by hydrogen peroxide could be conveniently monitored by SDS-PAGE and was specific for Met, as evidenced by quantitative reduction of these proteins with Msrs in DTT- and thioredoxin-dependent assays. We found that hypochlorite was especially efficient in oxidizing MRPs. Finally, we further developed a procedure wherein antibodies made against oxidized MRPs were isolated on affinity resins containing same or other oxidized or reduced MRPs. This procedure yielded reagents specific for MetO in these proteins, but proved to be ineffective in developing antibodies with broad MetO specificity. CONCLUSION: Our data show that MRPs provide a convenient tool for characterization of Met oxidation, MetO reduction and Msr activities, and could be used for various aspects of redox biology involving reversible Met oxidation. PMID- 23088626 TI - Attenuated stress-evoked anxiety, increased sucrose preference and delayed spatial learning in glucocorticoid-induced receptor-deficient mice. AB - The glucocorticoid-induced receptor (GIR) is a stress-responsive gene that is abundantly expressed in forebrain limbic regions. Glucocorticoid-induced receptor has been classified as a Neuropeptide Y-like receptor, however, physiological attributes have not been investigated. In this study, mice lacking GIR (-/-) were screened in various paradigms related to stress, anxiety, activity, memory, fear and reward. GIR -/- mice elicited behavioral insensitivity to the anxiogenic effects of restraint stress. However, hypothalamic pituitary adrenal axis response to stress was not impacted by GIR deficiency. Increased preference for sucrose was observed in GIR -/- mice suggestive of modulation of reward associated behaviors by the receptor. A delayed acquisition of spatial learning was also observed in GIR -/- mice. There were no effects of genotype on the modulation of anxiety-like behavior, activity, fear-conditioning and extinction. Our data extend previous studies on GIR regulation by glucocorticoids and provide novel evidence for a role of GIR in reward, learning and the behavioral outcomes of stress. PMID- 23088627 TI - Solubility and apical sealing characteristics of a new calcium silicate-based root canal sealer in comparison to calcium hydroxide-, methacrylate resin- and epoxy resin-based sealers. AB - AIM: To assess and compare the water sorption, solubility and apical sealing ability of iRoot SP and three other widely used root canal sealers. MATERIALS AND METHODS: Solubility was assessed by immersing standardized samples of calcium silicate- (iRoot SP), calcium hydroxide- (Sealapex), methacrylate resin- (EndoREZ) and epoxy resin- (AH Plus) based sealers in distilled water and measuring weight gain and weight loss at 6 h, 24 h and daily for 14 days. Roots of extracted mandibular premolars (n = 80) were prepared with 0.04-taper nickel titanium rotary files to a final size 40. Roots were then randomly divided into four experimental groups (n = 18) and two control groups (n = 4), root canal sealers were applied and apical leakage was assessed using the fluid filtration method. Data was analyzed using Kruskal Wallis analysis of variance and Mann Whitney U-tests, with the level of significance set at p <= 0.05. RESULTS: EndoREZ exhibited the highest water sorption, followed by iRoot SP, Sealapex and AH Plus. Sealapex exhibited significantly higher solubility than the other sealers, whereas no significant differences in solubility levels were observed between the other three sealers tested. AH Plus exhibited significantly lower microleakage than Sealapex and EndoREZ, whereas no difference in microleakage was found between AH Plus and iRoot SP. CONCLUSIONS: In view of the study findings, all tested sealers except Sealapex met the ANSI/ADA's requirements for solubility and no difference was found between AH Plus and iRoot SP in terms of apical sealing ability. PMID- 23088630 TI - Enhanced osteogenesis of human alveolar bone-derived mesenchymal stem cells for tooth tissue engineering using fluid shear stress in a rocking culture method. AB - This study instituted a simple approach to stimulate alveolar bone regeneration for tooth tissue engineering by controlling effects of low fluid dynamic shear stress (LFDSS) on growth and differentiation in vitro. Human alveolar bone derived mesenchymal stem cells (hABMSCs) harvested from human mandibular alveolar bone were cultured with LFDSS to generate cultures containing bone-like formations. To distinguish between osteodifferentiation and bone-like formation, cells were cultured either with or without fluid shear stress. The calcium content and alkaline phosphatase (ALP) activity of hABMSCs were used as indicators of osteogenesis. Cell viability and proliferation after stimulating with LFDSS for 10-60 min/day were higher than with longer stimulations. Mineralized nodules formed when osteoblasts were cultured with an induction medium, a marker of osteogenic differentiation. ALP activity tended to increase after 10 and 60 min/day of stimulation. In addition, LFDSS conditions also increased gene expression of IBSP, RUNX2, COL-I, ALP, OCN, and OPN, as shown by reverse transcriptase-polymerase chain reaction. From the results of a proteomics array, LFDSS groups were intensely expressed with several factors (EGF, HGF, IGF, TGF, and PDGF). Furthermore, CD146 and Stro-1 expression increased in cells treated with 30 min/day and decreased in cells treated with 120 min/day, as determined by cell surface antigen analysis by fluorescence-activated cell sorting analysis. These results strongly showed that LFDSS at the proper intensity and time enhanced the differentiation and maturation of hABMSCs. In conclusion, an appropriate level of LFDSS can potently and positively modulate proliferation and differentiation in hABMSCs. PMID- 23088631 TI - Precise determination of the absolute isotopic abundance ratio and the atomic weight of chlorine in three international reference materials by the positive thermal ionization mass spectrometer-Cs2Cl+-graphite method. AB - Because the variation in chlorine isotopic abundances of naturally occurring chlorine bearing substances is significant, the IUPAC Inorganic Chemistry Division, Commission on Isotopic Abundances and Atomic Weights (CIAAW-IUPAC) decided that the uncertainty of atomic weight of chlorine (A(r)(Cl)) should be increased so that the implied range was related to terrestrial variability in 1999 (Coplen, T. B. Atomic weights of the elements 1999 (IUPAC Technical Report), Pure Appl. Chem.2001, 73(4), 667-683; and then, it emphasized that the standard atomic weights of ten elements including chlorine were not constants of nature but depend upon the physical, chemical, and nuclear history of the materials in 2009 (Wieser, M. E.; Coplen, T. B. Pure Appl. Chem.2011, 83(2), 359-396). According to the agreement by CIAAW that an atomic weight could be defined for one specified sample of terrestrial origin (Wieser, M. E.; Coplen, T. B. Pure Appl. Chem.2011, 83(2), 359-396), the absolute isotope ratios and atomic weight of chlorine in standard reference materials (NIST 975, NIST 975a, ISL 354) were accurately determined using the high-precision positive thermal ionization mass spectrometer (PTIMS)-Cs(2)Cl(+)-graphite method. After eliminating the weighing error caused from evaporation by designing a special weighing container and accurately determining the chlorine contents in two highly enriched Na(37)Cl and Na(35)Cl salts by the current constant coulometric titration, one series of gravimetric synthetic mixtures prepared from two highly enriched Na(37)Cl and Na(35)Cl salts was used to calibrate two thermal ionization mass spectrometers in two individual laboratories. The correction factors (i.e., K(37/35) = R(37/35meas)/R(37/35calc)) were obtained from five cycles of iterative calculations on the basis of calculated and determined R((37)Cl/(35)Cl) values in gravimetric synthetic mixtures. The absolute R((37)Cl/(35)Cl) ratios for NIST SRM 975, NIST 975a, and ISL 354 by the precise calibrated isotopic composition measurements are 0.319876 +/- 0.000067, 0.319768 +/- 0.000187, and 0.319549 +/- 0.000044, respectively. As a result, the atomic weights of chlorine in NIST 975, NIST 975a, and ISL 354 are derived as 35.45284(8), 35.45272(21), and 35.45252(2) individually, which are consistent with the issued values of 35.453(2) by IUPAC in 1999. PMID- 23088633 TI - Synthesis and stability of phosphate modified ATP analogues. AB - Nucleotides modified at the phosphate have numerous applications. Nevertheless, the number of attachment modes is limited and little is known about their stability. Here, we present results on the elaboration of the synthesis of five classes of ATP analogues and studies concerning their stability. We show that the nitrogen-linked ATP analogue is less stable, whereas the oxygen- and novel carbon linked adenosine tri- and tetraphosphate analogues are stable from pH 3 to 12 rendering them interesting for further applications and designs. PMID- 23088632 TI - A tunable and reversible platform for the intracellular formation of genetically engineered protein microdomains. AB - From mitochondria to the nuclear envelope, the controlled assembly of micro- and nanostructures is essential for life; however, the level at which we can deliberately engineer the assembly of microstructures within intracellular environments remains primitive. To overcome this obstacle, we present a platform to reversibly assemble genetically engineered protein microdomains (GEPMs) on the time scale of minutes within living cells. Biologically inspired from the human protein tropoelastin, these protein polymers form a secondary aqueous phase above a tunable transition temperature. This assembly process is easily manipulated to occur at or near physiological temperature by adjusting molecular weight and hydrophobicity. We fused protein polymers to green fluorescent protein (GFP) to visualize their behavior within the cytoplasm. While soluble, these polymers have a similar intracellular diffusion constant as cytosolic proteins at 7.4 MUm(2)/s; however, above their phase transition temperature, the proteins form distinct microdomains (0.1-2 MUm) with a reduced diffusion coefficient of 1.1 MUm(2)/s. Microdomain assembly and disassembly are both rapid processes with half-lives of 3.8 and 1.0 min, respectively. Via selection of the protein polymer, the assembly temperature is tunable between 20 and 40 degrees C. This approach may be useful to control intracellular formation of genetically engineered proteins and protein complexes into concentrated microdomains. PMID- 23088629 TI - A model for homeopathic remedy effects: low dose nanoparticles, allostatic cross adaptation, and time-dependent sensitization in a complex adaptive system. AB - BACKGROUND: This paper proposes a novel model for homeopathic remedy action on living systems. Research indicates that homeopathic remedies (a) contain measurable source and silica nanoparticles heterogeneously dispersed in colloidal solution; (b) act by modulating biological function of the allostatic stress response network (c) evoke biphasic actions on living systems via organism dependent adaptive and endogenously amplified effects; (d) improve systemic resilience. DISCUSSION: The proposed active components of homeopathic remedies are nanoparticles of source substance in water-based colloidal solution, not bulk form drugs. Nanoparticles have unique biological and physico-chemical properties, including increased catalytic reactivity, protein and DNA adsorption, bioavailability, dose-sparing, electromagnetic, and quantum effects different from bulk-form materials. Trituration and/or liquid succussions during classical remedy preparation create "top-down" nanostructures. Plants can biosynthesize remedy-templated silica nanostructures. Nanoparticles stimulate hormesis, a beneficial low-dose adaptive response. Homeopathic remedies prescribed in low doses spaced intermittently over time act as biological signals that stimulate the organism's allostatic biological stress response network, evoking nonlinear modulatory, self-organizing change. Potential mechanisms include time-dependent sensitization (TDS), a type of adaptive plasticity/metaplasticity involving progressive amplification of host responses, which reverse direction and oscillate at physiological limits. To mobilize hormesis and TDS, the remedy must be appraised as a salient, but low level, novel threat, stressor, or homeostatic disruption for the whole organism. Silica nanoparticles adsorb remedy source and amplify effects. Properly-timed remedy dosing elicits disease-primed compensatory reversal in direction of maladaptive dynamics of the allostatic network, thus promoting resilience and recovery from disease. SUMMARY: Homeopathic remedies are proposed as source nanoparticles that mobilize hormesis and time-dependent sensitization via non-pharmacological effects on specific biological adaptive and amplification mechanisms. The nanoparticle nature of remedies would distinguish them from conventional bulk drugs in structure, morphology, and functional properties. Outcomes would depend upon the ability of the organism to respond to the remedy as a novel stressor or heterotypic biological threat, initiating reversals of cumulative, cross-adapted biological maladaptations underlying disease in the allostatic stress response network. Systemic resilience would improve. This model provides a foundation for theory-driven research on the role of nanomaterials in living systems, mechanisms of homeopathic remedy actions and translational uses in nanomedicine. PMID- 23088634 TI - Reversible posterior leukoencephalopathy syndrome induced by pazopanib. AB - BACKGROUND: The reversible posterior leukoencephalopathy syndrome is a clinical/radiological syndrome characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging findings. There are several reports in the literature that depict its occurrence in cancer patients. The list of common anticancer and supportive care drugs that predispose to reversible posterior leukoencephalopathy syndrome is expanding and includes not only a large number of chemotherapeutic agents but also an increased number of new targeted drugs, particularly angiogenesis inhibitors such as bevacizumab,sorefenib and sunitinib. Pazopanib is an oral tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit which after a positive phase III randomized clinical trial in patients with advanced renal cell cancer received FDA approval for the treatment of advanced renal cell carcinoma. Until now no cases of reversible posterior leukoencephalopathy syndrome induced by pazopanib have been reported. CASE REPORT: We present the case of a 40 years old female patient with heavily pre-treated metastatic renal cell carcinoma who received pazopanib as salvage treatment. After 21 days of pazopanib therapy the patient referred to the emergency department with epileptic seizure, impaired vision at both eyes and headache. MRI of the brain revealed subcortical oedema at the occipital and parietal lobes bilaterally. She was treated with anticonvulsants, i.v. administration of mannitol and antihypertensives and she recovered completely from her symptoms and was discharged on the tenth hospital day. A brain MRI performed 3 weeks after showed that the subcortical oedema had been subsided. CONCLUSION: In conclusion this is the first case of pazopanib induced reversible posterior leukoencephalopathy syndrome. Although usually reversible, this syndrome is a serious and potentially life threatening adverse effect, if untreated, that should be considered by physicians treating metastatic renal cell carcinoma patients with pazopanib. PMID- 23088635 TI - Microsurgical replantation and postoperative leech treatment of a large severed nasal segment. AB - The survival of a microsurgically replanted segment of nose in a 41-year-old woman was facilitated by the assistance of the medicinal leech Hirudo medicinalis. An arterial microanastomosis was made to a severed partial segment of nose with no possibility of recreating a venous anastomosis. The resulting venous congestion was treated with nine days of treatment with a medical leech until venous neovascularisation had been achieved. At follow-up six months after discharge there was a well-heeled nasal segment and a satisfying functional - as well as cosmetic - result. PMID- 23088636 TI - Evaluation of measurement of fat mass reduction after liposuction in obese patients. AB - Body composition measurements are used to evaluate surgical treatment, such as bariatric surgery in overweight patients. Nowadays, there are many different methods to measure body composition available. However, none of them has been validated for use in patients after operation. The aim of the present study was to compare the amount of surgically removed fat with two different methods, bioelectrical impedance analysis (BIA) and total body potassium (TBK). Amount of removed fat during liposuction was measured 1, 2, 3, 4, 14 days, and 1 year postoperatively in 27 obese patients after liposuction. The results were compared with actual removed fat during the operation. The median fat mass removed was 4020 grams (range 1954-9655). Postoperatively there was a varying reduction in fat mass, as measured with BIA and with TBK. There was a clear difference between the range of amounts removed measured with BIA and the range of amount removed measured with TBK. This study indicates that BIA, but not TBK, is an appropriate method to measure fat mass in obese subjects in a surgical setting. BIA seems to underestimate the amount of fat removed, whereas TBK seems to overestimate it. PMID- 23088637 TI - Complications of abdominoplasty after weight loss as a result of bariatric surgery or dieting/postpregnancy. AB - It is well known that the risk of complications after abdominal contouring surgery is high. Sparse data in published reports exist, suggesting that complication rates are higher in postbariatric patients compared with patients who have lost weight by dieting. The aim of this study was to analyse the incidence of complications after abdominoplasty in postbariatric patients compared with in patients who have not had weight loss surgery. The aim was also to identify predictive factors associated with the development of postoperative complications. This study retrospectively analysed 190 consecutive patients operated on with abdominoplasty due to abdominal tissue excess from January 2006 to December 2008 at Sahlgrenska University Hospital. Variables analysed were sex, age, max body mass index (BMI), delta BMI (max BMI minus preoperative BMI), preoperative BMI, method of weight reduction, resection weight, and complications. The early complication rates were significantly higher in postbariatric patients (48%) than in patients who had not had weight loss surgery (29%). Resection weight was significantly higher for patients with early local complications compared with patients without early local complications. Max BMI, delta BMI, or preoperative BMI had no influence on the incidence of complications. In conclusion, this study confirms in a fairly large sample that the complication rate after abdominoplasty seems to be higher in postbariatric patients compared with patients who have not had weight loss surgery. However, no predictive factors could be identified explaining these differences. Further studies need to be conducted to identify predictive factors for the occurrence of complications after abdominal contouring surgery. PMID- 23088638 TI - Epidermoid cyst of the phalanx of the finger caused by nail biting. AB - Intraosseous epidermoid inclusion cysts of the phalanx of the finger are rare, and are regarded as reactive or post-traumatic pseudotumours. We describe a case of an epidermoid cyst in the distal phalanx of the fifth finger caused by chronic nail biting, which was successfully excised. PMID- 23088639 TI - Bilateral carpal tunnel syndrome with anomalous palmaris profundus tendons. AB - This report presents the case of a 44-year-old man who presented with elective bilateral carpal tunnel decompression. At the operation, he was found to have bilateral palmaris profundus tendons within the carpal tunnel, impinging on the median nerve. In releasing both carpal tunnels, the patient's symptoms were alleviated and there was regain of full function. There have been very few documented cases of these anomalous tendons implicated in carpal tunnel syndrome and this case highlights how such anatomical variations are important in the surgical approach to carpal tunnel decompression. PMID- 23088640 TI - BRAF mutations in chronic lymphocytic leukemia. AB - BRAF mutations have been shown to occur at a high frequency in melanoma and thyroid cancer, but also at lower frequencies in hematological malignancies. To assess the potential role of BRAF, we have sequenced exons 11 and 15 of BRAF in 138 cases with chronic lymphocytic leukemia (CLL) and 32 cases of B-cell prolymphocytic leukemia (B-PLL). We found an incidence of BRAF mutations of 2.8% in CLL (4/138), while no cases with B-PLL showed BRAF mutations. The analysis of a cohort of patients with fludarabine-refractory disease (n = 87) showed no increase in the mutation incidence, suggesting that this mutation is not selected for during the disease progression. A limited analysis of the effect of BRAF inhibition in primary CLL cells showed no cell death induction in CLL samples with and without BRAF mutations. Our analysis suggests that BRAF mutations occur at a low frequency in CLL. The pharmacological inhibition of MEK/ERK signaling using the mutant BRAF inhibitor PLX4720 showed no effect on viability in vitro in CLL cases. PMID- 23088641 TI - Application of a catalytic asymmetric Povarov reaction using chiral ureas to the synthesis of a tetrahydroquinoline library. AB - A 2328-membered library of 2,3,4-trisubstituted tetrahydroquinolines was produced using a combination of solution- and solid-phase synthesis techniques. A tetrahydroquinoline (THQ) scaffold was prepared via an asymmetric Povarov reaction using cooperative catalysis to generate three contiguous stereogenic centers. A matrix of 4 stereoisomers of the THQ scaffold was prepared to enable the development of stereo/structure-activity relationships (SSAR) upon biological testing. A sparse matrix design strategy was employed to select library members to be synthesized with the goal of generating a diverse collection of tetrahydroquinolines with physicochemical properties suitable for downstream discovery. PMID- 23088643 TI - Tau-tubulin kinase 1 expression, phosphorylation and co-localization with phospho Ser422 tau in the Alzheimer's disease brain. AB - Recent reports have implicated tau-tubulin kinase 1 (TTBK1) in the pathological phosphorylation of tau that occurs in Alzheimer's disease (AD). The present study was undertaken to provide an extensive characterization of TTBK1 mRNA and protein expression in human brain from AD cases and non-demented controls so as to better understand the disease relevance of this novel kinase. In situ hybridization and immunohistochemistry revealed abundant expression of TTBK1 in the somatodendritic compartment of cortical and hippocampal neurons of both AD cases and controls. TTBK1 immunoreactivity appeared to vary with the level of phospho-tau staining, and was strong in the somatodendritic compartment of apparently healthy hippocampal neurons as well as in pre-tangle neurons where it co-localized with diffuse phospho-Ser422 tau staining. Ser422 was confirmed as a TTBK1 substrate in vitro, and an antibody towards the site, in addition to labeling AT8-positive neurofibrillary tangles (NFTs), neuritic plaques and neuropil threads, also labeled a small population of neurons that were unlabeled with AT8. These data suggest a role for TTBK1 in pre-tangle formation prior to the formation of fibrillar tau and strengthen the idea that tau is phosphorylated at Ser422 at an early/intermediate stage in NFT formation. PMID- 23088642 TI - The complexity of elastic fibre biogenesis in the skin--a perspective to the clinical heterogeneity of cutis laxa. AB - Elastic fibres are critical connective tissue components providing elasticity and resilience to skin and other tissues. These fibres are composed of elastin and a number of elastin-associated microfibrillar proteins that assemble in a complex fibre network in a multi-step process. Multiple cellular processes, including mitochondrial function, specific molecules in the secretory pathways and temporally and spatially ordered production of elastic fibre components, are required for the biogenesis of functional elastic fibres. Abnormalities in these processes can lead to loss of functional elastic fibres manifesting phenotypically as a skin disease. The paradigm of elastic fibre diseases affecting the skin is cutis laxa, a clinically and genetically heterogeneous group of disorders characterized by loose and sagging skin, frequently associated with extracutaneous manifestations in the lungs and the arterial blood vessels. The complexity of cutis laxa is emphasized by the fact that as many as 10 distinct genes can harbour mutations in this and related disorders. Understanding of the pathomechanistic pathways involved in perturbed elastic fibre assembly in cutis laxa provides information potentially helpful for the development of molecular strategies towards treatment of these, currently intractable, diseases. PMID- 23088645 TI - Expression profiles of aquaporin homologues and petal movement during petal development in Tulipa gesneriana. AB - Previously, we have characterized two tonoplast intrinsic proteins (TIPs) and four plasma membrane intrinsic proteins (PIPs) from the 2-day-old petals of tulip (Tulipa gesneriana). In this study, we analyzed the development of tulip petals and stems, temperature-dependent petal movement, the amount of 3H2O transported into petals and stems during petal movement, and the transcript levels of two TIP (TgTIP1;1 and TgTIP1;2) and four TgPIP genes in petals and stems, from the first day of petal opening to day 12. The development of the petals and stems was completed by days 6 and 9, respectively, after the first day of petal opening. Temperature-dependent petal movement and the amount of 3H2O that was transported into petals could be detected at significant levels up to day 6 with petal movement reaching a peak at day 3. Real-time reverse transcription-polymerase chain reaction analysis revealed that TgTIP1;1 and TgTIP1;2 were expressed ubiquitously in petals, stems, leaves, bulbs and roots. However, the expression level of TgTIP1;2 was very low in bulbs. The expression of both TgTIP1 genes was upregulated in close association with the development of petals but not with that of the stem. The four TgPIP genes were expressed at almost the same level during the development of the petals and the stem. However, the levels of the TgTIP1 and TgPIP transcripts in petals decreased during the course of petal wilting from day 9 onwards. These results suggest that TgTIP1;1 and TgTIP1;2 may contribute to petal development. PMID- 23088644 TI - Design, synthesis, and biological evaluation of 3-(1H-1,2,3-triazol-1 yl)benzamide derivatives as Potent Pan Bcr-Abl inhibitors including the threonine(315)->isoleucine(315) mutant. AB - A series of 3-(1H-1,2,3-triazol-1-yl)benzamide derivatives were designed and synthesized as new Bcr-Abl inhibitors by using combinational strategies of bioisosteric replacement, scaffold hopping, and conformational constraint. The compounds displayed significant inhibition against a broad spectrum of Bcr-Abl mutants including the gatekeeper T315I and p-loop mutations, which are associated with disease progression in CML. The most potent compounds 6q and 6qo strongly inhibited the kinase activities of Bcr-Abl(WT) and Bcr-Abl(T315I) with IC(50) values of 0.60, 0.36 and 1.12, 0.98 nM, respectively. They also potently suppressed the proliferation of K562, KU812 human CML cells, and a panel of murine Ba/F3 cells ectopically expressing either Bcr-Abl(WT) or any of a panel of other Bcr-Abl mutants that have been shown to contribute to clinical acquired resistance, including Bcr-Abl(T315I), with IC(50) values in low nanomolar ranges. These compounds may serve as lead compounds for further development of new Bcr Abl inhibitors capable of overcoming clinical acquired resistance against imatinib. PMID- 23088646 TI - Simulation-based surgical education. AB - The reduction in time for training at the workplace has created a challenge for the traditional apprenticeship model of training. Simulation offers the opportunity for repeated practice in a safe and controlled environment, focusing on trainees and tailored to their needs. Recent technological advances have led to the development of various simulators, which have already been introduced in surgical training. The complexity and fidelity of the available simulators vary, therefore depending on our recourses we should select the appropriate simulator for the task or skill we want to teach. Educational theory informs us about the importance of context in professional learning. Simulation should therefore recreate the clinical environment and its complexity. Contemporary approaches to simulation have introduced novel ideas for teaching teamwork, communication skills and professionalism. In order for simulation-based training to be successful, simulators have to be validated appropriately and integrated in a training curriculum. Within a surgical curriculum, trainees should have protected time for simulation-based training, under appropriate supervision. Simulation based surgical education should allow the appropriate practice of technical skills without ignoring the clinical context and must strike an adequate balance between the simulation environment and simulators. PMID- 23088647 TI - Salmon fishing by bears and the dawn of cooperative predation. AB - Although bears are an epitome of solitary predation, black (Ursus americanus) and brown bears (U. arctos) occasionally act in pairs to capture salmon (Onchorynchous spp.). I sought to identify conditions that promote pairing and how this relates to optimal foraging. This study on Alaskan black bears assessed whether each mode of fishing (solo vs. paired) occurs mainly where it is most efficient at harvesting salmon--that is, whether modal group size (1 vs. 2) is also optimal size. Not in this case. Pairing increased captures per attempt (benefit/cost ratio = profitability) by up to 47% and captures per minute by up to 5.2-fold. Yet, the ratio of paired versus solo fishing was significantly lower than either profitability or chance explains. Modal group size was 1, optimal size was 2. This discrepancy did not result from intervention by other current benefits and costs, but from unnecessary defensiveness toward any rapidly approaching conspecific, even though it was chasing salmon, not threatening. For bears to regularly hunt cooperatively, they would have to more readily habituate to agonistic-like predatory actions, communicate intentions from > 10 m apart, and assess situational variations in benefit/cost ratios for solo versus paired hunting. It would be revealing to discover how social carnivores overcame these challenges. PMID- 23088648 TI - Analysis of movement kinematics on analogous spatial learning tasks demonstrates conservation of direction and distance estimation across humans (Homo sapiens) and rats (Rattus norvegicus). AB - This series of experiments evaluates the nature of the representation that mediates human (Homo sapiens) and rat (Rattus norvegicus) movement characteristics on analogous spatial learning tasks. The results of Experiment 1 demonstrated that self-movement cues were sufficient to guide the performance of human participants during place training and matching-to-place testing tasks adapted to tabletop or manipulatory scale. Experiment 2 investigated the effect of manipulating access to environmental cues during place training on the nature of the representation used to guide performance. Blindfolded human participants appeared to encode the absolute location of the goal, whereas participants with access to environmental cues appeared to encode the relative location of the goal. The results of Experiment 3 demonstrated that human participants with access to environmental cues exhibited a similar response tendency (as observed in Experiment 2) after half as many trials of place training. During Experiment 4, rats exhibited movement characteristics in the water maze that were similar to movement characteristics observed in human participants who were provided access to environmental cues. These observations provide evidence that direction and distance estimation processes mediate performance on spatial tasks that are conserved across humans and rats. PMID- 23088649 TI - Turtle vocalizations as the first evidence of posthatching parental care in chelonians. AB - Until recently, freshwater turtles were thought to be silent reptiles, neither vocalizing nor hearing very well. We recorded individuals in nature, captivity, and during interactions between adults and hatchlings and show that hatchlings and adult turtles, Podocnemis expansa, produce sounds in and out of the water. Sounds were emitted by hatchlings inside the egg, in open nests, in the river, and in captive conditions. Adult females were recorded producing sounds in the river, while basking, while nesting, and in captivity. Females were recorded in the river approaching and responding to hatchling sounds. We detected 2,122 sounds, classified in 11 different types. These data suggest that there is sound communication between adults and hatchings and that these sounds may be used to congregate hatchlings with adults for mass migration. Hatchlings and females with transmitters were found migrating together. We consider these findings as the first evidence of acoustic communication mediating posthatching parental care in chelonians. We anticipate that our findings will influence the way turtle behavior is studied and interpreted, and add communication and sound pollution to turtle conservation concerns. PMID- 23088651 TI - The Global Online Sexuality Survey (GOSS): the United States of America in 2011. Chapter I: erectile dysfunction among English-speakers. AB - INTRODUCTION: The Global Online Sexuality Survey (GOSS) is a worldwide epidemiologic study of sexuality and sexual disorders, based on validated questionnaires and applying age adjustment to the World Standard Population (WSP) by the World Health Organization. In 2010, the first report of GOSS came from the Middle East, describing an erectile dysfunction (ED) prevalence rate of 47%. AIM: This report studies the prevalence rate of ED in the United States as of 2011 2012 and evaluates risk factors for ED. MAIN OUTCOME MEASURES: Prevalence of ED. METHODS: GOSS was randomly deployed to English-speaking male web surfers in the United States via paid advertising on Facebook, comprising 146 questions including the abbreviated 5-item International Index of Erectile Function. RESULTS: Two thousand twenty-two males participated; with a mean age was 52.38 years +/- 14.5. Prevalence of ED was 37.7%, adjusted to 33.7% according to WSP, comparable across ethnic groups. The following risk factors were associated with higher risk for ED: diabetes mellitus, hypertension with and without antihypertensive treatment, coronary heart disease, obesity (defined by body mass index), difficult micturition, subjectively reported depression, interpersonal distress, subjectively reported impotence, in addition to novel factors such as subjectively reported premature ejaculation (PE) and concerns over genital size (not a smaller penis per se), low libido, and irregular coitus. Frequency of smoking and alcohol were not associated with higher prevalence of ED, although duration of smoking was. CONCLUSION: Adjusted to WSP, prevalence rate of ED in the United States of America is 33.7% in the year 2011, in contrast to the adjusted prevalence in the Middle East (47%). Most of the classical risk factors for ED play the same role in the United States and the World, including diabetes, hypertension, and aging. Concerns over genital size and PE are emerging risk factors for ED. PMID- 23088650 TI - Bortezomib plus rituximab versus rituximab in patients with high-risk, relapsed, rituximab-naive or rituximab-sensitive follicular lymphoma: subgroup analysis of a randomized phase 3 trial. AB - BACKGROUND: The randomized phase 3 LYM3001 trial in relapsed follicular lymphoma (FL) demonstrated higher overall (ORR) and complete response (CR) rates and prolonged progression-free survival (PFS) with bortezomib-rituximab versus rituximab. We report findings in high-risk patients (FL International Prognostic Index [FLIPI] score >=3, and high tumor burden by modified Groupe d'Etude des Lymphomas Folliculaires [GELF] criteria). METHODS: Patients aged >=18 years with grade 1/2 FL, >=1 measurable lesion, and documented relapse or progression following prior therapy, rituximab-naive or rituximab-sensitive, were enrolled at 164 centers in 29 countries across Europe, the Americas, and Asia-Pacific. Patients were randomized (1:1) to five 5-week cycles of bortezomib-rituximab (bortezomib 1.6 mg/m2, days 1, 8, 15, and 22, all cycles; rituximab 375 mg/m2, days 1, 8, 15, and 22, cycle 1, and day 1, cycles 2-5; N=336) or rituximab alone (N=340). Randomization was stratified by FLIPI score, prior rituximab, time since last dose of anti-lymphoma therapy, and geographical region. The primary endpoint of the study was PFS. RESULTS: 103 bortezomib-rituximab and 98 rituximab patients had high-risk FL. The ORR was 59% versus 37% (p=0.002), the CR/CRu rate was 13% versus 6% (p=0.145), and the durable response rate was 45% versus 26% (p=0.008) with bortezomib-rituximab versus rituximab. Median PFS was 9.5 versus 6.7 months (hazard ratio [HR] 0.667, p=0.012) with bortezomib-rituximab versus rituximab; median time to progression was 10.9 versus 6.8 months (HR 0.656, p=0.009); median time to next anti-lymphoma treatment was 14.8 versus 9.1 months (HR 0.762, p=0.103); and the 1-year Overall Survival rate was 83.1% versus 76.6%. Overall, 51% of bortezomib-rituximab and 32% of rituximab patients reported grade >=3 adverse events, including neutropenia (18%, 6%), anemia (4%, 5%), diarrhea (8%, 0%), thrombocytopenia (5%, 2%), and sensory neuropathy (1%, 0%). CONCLUSIONS: High-risk FL patients treated with bortezomib-rituximab had significantly higher ORR and longer PFS than patients receiving rituximab alone, with greater clinical benefit than in the overall study population; additional toxicity was acceptable and did not affect treatment feasibility. TRIAL REGISTRATION: The phase 3 LYM3001 trial is registered with ClinicalTrials.gov, with the identifier NCT00312845. PMID- 23088652 TI - Myeloperoxidase-derived oxidants modify apolipoprotein A-I and generate dysfunctional high-density lipoproteins: comparison of hypothiocyanous acid (HOSCN) with hypochlorous acid (HOCl). AB - Oxidative modification of HDLs (high-density lipoproteins) by MPO (myeloperoxidase) compromises its anti-atherogenic properties, which may contribute to the development of atherosclerosis. Although it has been established that HOCl (hypochlorous acid) produced by MPO targets apoA-I (apolipoprotein A-I), the major apolipoprotein of HDLs, the role of the other major oxidant generated by MPO, HOSCN (hypothiocyanous acid), in the generation of dysfunctional HDLs has not been examined. In the present study, we characterize the structural and functional modifications of lipid-free apoA-I and rHDL (reconstituted discoidal HDL) containing apoA-I complexed with phospholipid, induced by HOSCN and its decomposition product, OCN- (cyanate). Treatment of apoA I with HOSCN resulted in the oxidation of tryptophan residues, whereas OCN- induced carbamylation of lysine residues to yield homocitrulline. Tryptophan residues were more readily oxidized on apoA-I contained in rHDLs. Exposure of lipid-free apoA-I to HOSCN and OCN- significantly reduced the extent of cholesterol efflux from cholesterol-loaded macrophages when compared with unmodified apoA-I. In contrast, HOSCN did not affect the anti-inflammatory properties of rHDL. The ability of HOSCN to impair apoA-I-mediated cholesterol efflux may contribute to the development of atherosclerosis, particularly in smokers who have high plasma levels of SCN- (thiocyanate). PMID- 23088653 TI - Dose-dependent LDL-cholesterol lowering effect by plant stanol ester consumption: clinical evidence. AB - Elevated serum lipids are linked to cardiovascular diseases calling for effective therapeutic means to reduce particularly LDL-cholesterol (LDL-C) levels. Plant stanols reduce levels of LDL-C by partly blocking cholesterol absorption. Accordingly the consumption of foods with added plant stanols, typically esterified with vegetable oil fatty acids in commercial food products, are recommended for lowering serum cholesterol levels. A daily intake of 1.5 to 2.4 g of plant stanols has been scientifically evaluated to lower LDL-C by 7 to 10% in different populations, ages and with different diseases. Based on earlier studies, a general understanding is that no further reduction may be achieved in intakes in excess of approximately 2.5 g/day. Recent studies however suggest that plant stanols show a continuous dose-response effect in serum LDL-C lowering. This review discusses the evidence for a dose-effect relationship between plant stanol ester consumption and reduction of LDL-C concentrations with daily intakes of plant stanols of 4 g/day or more. We identified five such studies and the overall data demonstrate a linear dose-effect relationship with the most pertinent LDL-Cholesterol lowering outcome, 18%, achieved by a daily intake of 9 to 10 g of plant stanols. Along with reduction in LDL-C, the studies demonstrated a decrease in cholesterol absorption markers, the serum plant sterol to cholesterol ratios, by increasing the dose of plant stanol intake. None of the studies with daily intakes up to 10 g of plant stanols reported adverse clinical or biochemical effects from plant stanols. In a like manner, the magnitude of decrease in serum antioxidant vitamins was not related to the dose of plant stanols consumed and the differences between plant stanol ester consumers and controls were minor and insignificant or nonexisting. Consumption of plant stanols in high doses is feasible as a range of food products are commercially available for consumption including spreads and yoghurt type drinks. In conclusion, a dose-effect relationship of plant stanols in higher doses than currently recommended has been demonstrated by recent clinical studies and a meta analysis. Further studies are called for to provide confirmatory evidence amenable for new health claim applications and dietary recommendations. PMID- 23088654 TI - Thyroid volume and severity of Graves' orbitopathy. AB - BACKGROUND: Graves' orbitopathy (GO) is thought to be related to one or more autoantigens present in the thyroid and in orbital tissues. Although this may not imply a quantitative relation between thyroid antigens and degree of GO, which in turn is a risk factor for a more pronounced GO, we postulated that the severity of GO may parallel the amount of thyroid tissue, namely, the size of the thyroid gland. This hypothesis is also based on the observation that patients with Graves' disease presenting with large goiters tend to have more severe hyperthyroidism. Thus, we evaluated retrospectively whether there is a correlation between the degree of GO at its first observation and, among other parameters, the thyroid volume. METHODS: Eighty-six consecutive patients with untreated GO lasting for no longer than 24 months underwent an endocrinological and an ophthalmological evaluation, the latter including: exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity. The overall degree of GO was ranked using the NOSPECS score as well as a modification of the NOSPECS score. The following parameters were considered for correlations: time since GO appearance, time since detection of hyperthyroidism, FT3, anti thyrotropin receptor antibodies, thyroid volume, and cigarette-years. RESULTS: Thyroid volume, but not the other parameters, correlated significantly by simple regression with exophthalmometry (p=0.02) and CAS (p=0.02). The standard NOSPECS score correlated with FT3 (p=0.05), thyroid volume (p=0.02), and cigarette-years (p=0.03), by simple, but not by multiple regression analysis. The modified NOSPECS score correlated with thyroid volume (p=0.007) and cigarette-years (p=0.04) by simple regression, and with thyroid volume also by multiple regression analysis (p=0.05). CONCLUSIONS: Thyroid volume correlates with the severity of GO at its first observation, especially with exophthalmometry and CAS. The finding is in line with a possible pathogenetic role of antigens shared by the thyroid and orbital tissues. Nevertheless, other mechanisms may explain this observation, including an overall more reactive immune system in patients with a large goiter, resulting in more severe thyroid and eye disease, regardless of the nature of the autoantigen, or whether it is shared by the thyroid and the orbit. PMID- 23088655 TI - Natural organic UV-absorbent coatings based on cellulose and lignin: designed effects on spectroscopic properties. AB - Novel nanocomposite coatings composed of cellulose nanocrystals (CNCs) and lignin (either synthetic or fractionated from spruce and corn stalks) were prepared without chemical modification or functionalization (via covalent attachment) of one of the two biopolymers. The spectroscopic properties of these coatings were investigated by UV-visible spectrophotometry and spectroscopic ellipsometry. When using the appropriate weight ratio of CNC/lignin (R), these nanocomposite systems exhibited high-performance optical properties, high transmittance in the visible spectrum, and high blocking in the UV spectrum. Atomic force microscopy analysis demonstrated that these coatings were smooth and homogeneous, with visible dispersed lignin nodules in a cellulosic matrix. It was also demonstrated that the introduction of nanoparticles into the medium increases the weight ratio and the CNC-specific surface area, which allows better dispersion of the lignin molecules throughout the solid film. Consequently, the larger molecular expansion of these aromatic polymers on the surface of the cellulosic nanoparticles dislocates the pi-pi aromatic aggregates, which increases the extinction coefficient and decreases the transmittance in the UV region. These nanocomposite coatings were optically transparent at visible wavelengths. PMID- 23088656 TI - Gene expression anti-profiles as a basis for accurate universal cancer signatures. AB - BACKGROUND: Early screening for cancer is arguably one of the greatest public health advances over the last fifty years. However, many cancer screening tests are invasive (digital rectal exams), expensive (mammograms, imaging) or both (colonoscopies). This has spurred growing interest in developing genomic signatures that can be used for cancer diagnosis and prognosis. However, progress has been slowed by heterogeneity in cancer profiles and the lack of effective computational prediction tools for this type of data. RESULTS: We developed anti profiles as a first step towards translating experimental findings suggesting that stochastic across-sample hyper-variability in the expression of specific genes is a stable and general property of cancer into predictive and diagnostic signatures. Using single-chip microarray normalization and quality assessment methods, we developed an anti-profile for colon cancer in tissue biopsy samples. To demonstrate the translational potential of our findings, we applied the signature developed in the tissue samples, without any further retraining or normalization, to screen patients for colon cancer based on genomic measurements from peripheral blood in an independent study (AUC of 0.89). This method achieved higher accuracy than the signature underlying commercially available peripheral blood screening tests for colon cancer (AUC of 0.81). We also confirmed the existence of hyper-variable genes across a range of cancer types and found that a significant proportion of tissue-specific genes are hyper-variable in cancer. Based on these observations, we developed a universal cancer anti-profile that accurately distinguishes cancer from normal regardless of tissue type (ten-fold cross-validation AUC > 0.92). CONCLUSIONS: We have introduced anti-profiles as a new approach for developing cancer genomic signatures that specifically takes advantage of gene expression heterogeneity. We have demonstrated that anti profiles can be successfully applied to develop peripheral-blood based diagnostics for cancer and used anti-profiles to develop a highly accurate universal cancer signature. By using single-chip normalization and quality assessment methods, no further retraining of signatures developed by the anti profile approach would be required before their application in clinical settings. Our results suggest that anti-profiles may be used to develop inexpensive and non invasive universal cancer screening tests. PMID- 23088657 TI - Ion pair recognition receptor based on an unsymmetrically 1,1'-disubstituted ferrocene-triazole derivative. AB - The ferrocene-triazole derivative 4, available from 1,1'-bis(diazido)ferrocene by sequential functionalization through click-type chemistry and the Staudinger reaction, is elaborated as a lab-on-a-molecule for the selective sensing of HP(2)O(7)(3-) and Hg(2+). Receptor 4 behaves as a ratiometric fluorescent probe for HP(2)O(7)(3-) with a good selectivity over other anions, whereas in the presence of Hg(2+) it modifies the fluorescent emission of the pyrene unit, acting as a selective on-off fluorescent sensor for Hg(2+) with a low detection limit. The most salient feature of compound 4 is its behavior as an excellent electrooptical ion pair recognition receptor able to simultaneously recognize Pb(2+) cations in the presence of HP(2)O(7)(3-) anion through multichannel perturbations of the redox potential of the ferrocene unit, the emission spectrum, and a noticeable color change from yellow to green. PMID- 23088658 TI - The association of DNA Repair with breast cancer risk in women. A comparative observational study. AB - BACKGROUND: Previous studies have found a link between a low DNA repair capacity (DRC) level and increased cancer risk. Our aim was to assess the statistical association of DRC level and breast cancer (BC) using a case-control epidemiological study in a Hispanic community. METHODS: We conducted a comparative observational study to assess the validity of DRC in detecting BC in 824 women throughout Puerto Rico. Over a 6-year period, we compared 285 women newly diagnosed with BC to 539 without BC. DRC levels were measured in lymphocytes by means of a host-cell reactivation assay. We assessed the sensitivity, specificity, and association using the receiver operating characteristic curve analysis. Multiple logistic regression-adjusted odds ratios were estimated with 95% confidence level to measure the strength of the association of DRC and BC after adjusting for all confounders simultaneously. RESULTS: Compared to women without cancer, women with BC showed an average decrease of 60% in their DRC levels (p < 0.001). Validity of the association of DRC as a measure of BC risk showed a sensitivity of 83.2% and specificity of 77.6% (p < 0.0001). CONCLUSIONS: Our results support the usefulness of DRC level as a measure of BC risk. Additional studies in other populations are needed to further verify its usefulness. PMID- 23088659 TI - Psychometric properties of the Dental Hygienist Anxiety Scale in a group of general dental patients. AB - OBJECTIVE: The aim of the present study was to evaluate the psychometric properties of the Dental Hygienist Anxiety Scale (DHAS) in a sample of adult general dental patients. MATERIALS AND METHODS: The DHAS is a questionnaire adapted to assess fear and anxiety of dental hygienist (DH) treatment. The DHAS contains four items and the sum of scores range from 4 (no anxiety) to 20 (extreme fear). A convenient sample of 80 patients in treatment at two DH programs in Sweden were consecutively included in the study. The DHAS was distributed together with questions regarding self-perceived oral health and experience of dental care at the first visit after a clinical examination performed by a DH. Re-test assessments of DHAS were conducted ~ 2 weeks later in conjunction with the next visit to the DH before treatment (scaling session). RESULTS: The results verified a significant positive correlation between the average DHAS sum of scores and global fear of DH and dentist treatment, perceived pain during the last DH treatment and female gender. The DHAS sum of scores had a high internal consistency, Cronbach's coefficient of 0.89 and 0.87 at the first and at the second assessment, respectively. The test-re-test reliability of the DHAS sum of scores was acceptable, with an intra-class coefficient of 0.82 and Kappa coefficients between 0.49-0.78 for the four single items in the DHAS. CONCLUSIONS: These results suggest that the DHAS has acceptable psychometric proprieties and is a valid and reliable scale to assess anxiety in DH treatment. PMID- 23088660 TI - Downregulation of the expression of mitochondrial electron transport complex genes in autism brains. AB - Mitochondrial dysfunction (MtD) and abnormal brain bioenergetics have been implicated in autism, suggesting possible candidate genes in the electron transport chain (ETC). We compared the expression of 84 ETC genes in the post mortem brains of autism patients and controls. Brain tissues from the anterior cingulate gyrus, motor cortex, and thalamus of autism patients (n = 8) and controls (n = 10) were obtained from Autism Tissue Program, USA. Quantitative real-time PCR arrays were used to quantify gene expression. We observed reduced expression of several ETC genes in autism brains compared to controls. Eleven genes of Complex I, five genes each of Complex III and Complex IV, and seven genes of Complex V showed brain region-specific reduced expression in autism. ATP5A1 (Complex V), ATP5G3 (Complex V) and NDUFA5 (Complex I) showed consistently reduced expression in all the brain regions of autism patients. Upon silencing ATP5A1, the expression of mitogen-activated protein kinase 13 (MAPK13), a p38 MAPK responsive to stress stimuli, was upregulated in HEK 293 cells. This could have been induced by oxidative stress due to impaired ATP synthesis. We report new candidate genes involved in abnormal brain bioenergetics in autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in autism. PMID- 23088662 TI - Herpes zoster duplex bilateralis in an immunocompetent woman--is gender a risk factor? AB - Herpes zoster duplex is a rare presentation of herpes zoster in which noncontiguous dermatomes are involved. If both sides of the body are affected, it is called herpes zoster duplex bilateralis; if only 1 side is involved, it is called herpes zoster unilateralis. Usually, this presentation of herpes zoster is associated with some level of immunosuppression. We present a case concerning herpes zoster duplex bilateralis occurring in a healthy, immunocompetent woman and discuss if female sex may be a risk factor for this presentation of herpes zoster. PMID- 23088661 TI - Single-beam optical biosensing based on enzyme-linked laser nanopolymerization of o-phenylenediamine. AB - We report an innovative biosensing technique using a focused laser beam for the fabrication of a polymer nanostructure and the detection of its nanoscale growth. A nanoaggregate structure is formed by focusing a single beam of a continuous wave (cw) green laser beam on an o-phenylenediamine (o-pD) solution dropped on a glass substrate. The backreflection intensity of the focused laser beam shows a temporal oscillation, whereas the size of the aggregate monotonously increases. Simple calculations based on the Fresnel equation qualitatively reproduce the experimental results, indicating that the backreflected laser oscillation occurs because of the interference between two beams reflected at the front and the back surfaces of the aggregate. Because the growth speed of the aggregate depends on light absorption by the oxidized o-PD, the backreflection oscillation curve can be used to monitor the oxidative reaction in the solution. We apply this phenomena to optical biosensing based on the oxidation of o-PD by the peroxidase enzyme reaction. A reliable quantification of glucose can be achieved by simply focusing a single laser beam and detecting its reflection intensity in a manner similar to the optical pickup unit of optical storage drives. PMID- 23088663 TI - It is an exciting time in the study and management of shingles and postherpetic neuralgia (PHN). Introduction. PMID- 23088664 TI - Discussing the zoster vaccine: an interview with Julie Gerberding, president of Merck Vaccines. PMID- 23088665 TI - Roundtable on postherpetic neuralgia--what, why, how long, and what's next? PMID- 23088666 TI - Nutritional factors in herpes zoster, postherpetic neuralgia, and zoster vaccination. AB - Herpes zoster (HZ) results from a reactivation of latent varicella-zoster virus (VZV). HZ and its most common complication, termed postherpetic neuralgia (PHN), often cause long-term psychological distress and physical disabilities leading to profoundly negative impacts on the quality of patients' lives. The incidence and severity of HZ and PHN increase with advanced age as a consequence of declining cell-mediated immunity. Aging has been linked to progressive senescence of the immune system and also is associated with a greater susceptibility to nutritional deficiencies. Suppressing VZV reactivation depends on intact cell-mediated immunity, which requires adequate nutrients to maintain its efficient function. Contrarily, nutritional deficiencies may lead to dysfunction of the host immune responses. Recently, micronutrient deficiencies have been shown to increase the risk of HZ and PHN and to affect the immune response to vaccinations, whereas nutritional supplements effectively reduce herpetic pain and pain in patients with PHN. As the elderly population grows, the incidence and severity of HZ and PHN are expected to increase and cause a substantial financial burden on the health care system. Thus, enhancing knowledge of the risk factors of HZ and PHN and developing better interventions to treat and prevent HZ and PHN are important to public health. This article provides an overview of the present understanding of the association among nutritional deficiencies, diminished cell-mediated immunity, and the risk of HZ and PHN, and then illustrates the potential of nutritional intervention in the prevention, vaccination, and management of HZ and PHN. PMID- 23088667 TI - Effect of tunnel excavation on source and mixing of groundwater in a coastal granitoidic fracture network. AB - The aim of this study was to assess how the excavation of the Aspo Hard Rock Laboratory tunnel has impacted on sources and mixing of groundwater in fractured crystalline (granitoidic) bedrock. The tunnel is 3600 m long and extends to a depth of 460 m at a coastal site in Boreal Europe. The study builds on a unique data set consisting of 1117 observations on chloride and delta(18)O of groundwater collected from a total of 356 packed-off fractures between 1987 and 2011. On the basis of the values of these two variables in selected source waters, a classification system was developed to relate the groundwater observations to source and postinfiltration mixing phenomena. The results show that the groundwater has multiple sources and a complex history of transport and mixing, and is composed of at least glacial water, marine water, recent meteoric water, and an old saline water. The tunnel excavation has had a large impact on flow, sources, and mixing of the groundwater. Important phenomena include upflow of deep-lying saline water, extensive intrusion of current Baltic Sea water, and substantial temporal variability of chloride and delta(18)O in many fractures. PMID- 23088668 TI - Trans-Golgi network: an intersection of trafficking cell wall components. AB - The cell wall, a crucial cell compartment, is composed of a network of polysaccharides and proteins, providing structural support and protection from external stimuli. While the cell wall structure and biosynthesis have been extensively studied, very little is known about the transport of polysaccharides and other components into the developing cell wall. This review focuses on endomembrane trafficking pathways involved in cell wall deposition. Cellulose synthase complexes are assembled in the Golgi, and are transported in vesicles to the plasma membrane. Non-cellulosic polysaccharides are synthesized in the Golgi apparatus, whereas cellulose is produced by enzyme complexes at the plasma membrane. Polysaccharides and enzymes that are involved in cell wall modification and assembly are transported by distinct vesicle types to their destinations; however, the precise mechanisms involved in selection, sorting and delivery remain to be identified. The endomembrane system orchestrates the delivery of Golgi-derived and possibly endocytic vesicles carrying cell wall and cell membrane components to the newly-formed cell plate. However, the nature of these vesicles, their membrane compositions, and the timing of their delivery are largely unknown. Emerging technologies such as chemical genomics and proteomics are promising avenues to gain insight into the trafficking of cell wall components. PMID- 23088669 TI - Enhancing pigmentation via activation of A3 adenosine receptors in B16 melanoma cells and in human skin explants. AB - A3 adenosine receptor, A3AR, belongs to the Gi proteins coupled receptors. Activation of A3AR by its agonist, IB-MECA, decreases cAMP and was expected to reduce melanin level. Unexpectedly, B16 melanoma cells exposed to IB-MECA increased melanin levels in a dose-dependent manner. Human skin explants exposed to IB-MECA showed an increase in DOPA positive cells and in melanin deposition in keratinocytes. The agonist induced AKT phosphorylation, leading to a rapid translocation of the transcription factor MiTF towards the nucleus. DOPA oxidase activity and melanin levels induced by IB-MECA were further enhanced by PD98509, an inhibitor ERK signalling pathway. Our study shows that IB-MECA decreases cAMP while inducing melanogenesis. The proposed mechanism involves activation of PI3K/AKT signalling pathway by beta/gamma subunits of the G protein coupled to A3AR. The increase in melanin level in human skin explants suggests that IB-MECA may be a potential candidate to the treatment of hypopigmentation of skin. PMID- 23088670 TI - Comparison of complication rates of Hickman((r)) catheters versus peripherally inserted central catheters in patients with acute myeloid leukemia undergoing induction chemotherapy. AB - Central venous access devices (CVADs) are used for intravenous therapy in patients with hematological malignancies. There are limited data comparing catheter outcomes in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy. A retrospective review comparing the incidence of early and late CVAD-associated complications and their effect on CVAD removal was performed in patients with AML undergoing induction chemotherapy between 2007 and 2011. Overall, 64 Hickman((r)) catheters and 84 peripherally inserted central catheters (PICCs) were inserted. There was a trend toward increasing use of PICCs. The rate of CVAD occlusion was higher in PICCs compared to Hickman catheters (48.2% vs. 3.2%), for a rate of 20.43 vs. 1.25 per 1000 CVAD-days (p = 0.0001). There was no significant difference in the rates of CVAD-associated thrombosis, premature removal, blood stream infection (BSI) and CVAD-related BSI. Importantly, there was no significant difference in the rate of CVAD removal between Hickman catheters and PICCs for the duration that the CVADs were in place. The choice of type of CVAD inserted into patients with newly diagnosed AML will depend on ease of catheter placement, cost, perception of frequency and severity of complications, and clinician preference. PMID- 23088671 TI - Pancreatic insufficiency in HIV: is it possible? AB - Pancreatic involvement in AIDS is very important and common, but there are few studies in the literature concerning the pancreas in AIDS. Therefore, our research involves an important issue in the pancreatic field. The objective of the study was to evaluate the profile of HIV-infected patients with probable exocrine pancreatic insufficiency and its relation to the degree of human immunodeficiency virus (HIV) infection. This is a cross-sectional study carried out at Faculdade de Medicina do ABC in partnership with the basic health care unit Vila Guiomar in Santo Andre. We selected 118 individuals divided into four groups (a control group and three other groups composed of AIDS patients, separated according to CD4 levels); participants had an interview, completed a questionnaire, and had laboratory and imaging tests. The only clinical variables with significant differences among the studied groups were the use of highly active antiretroviral therapy (HAART), the incidence of opportunistic infections, the administration of chemoprophylaxis, and weight loss. There were no differences in the amylase, lipase, and steatocrit dosages among the groups. Levels of fecal elastase 1 were lower in the HIV patient groups (2, 3, and 4) when compared with the control group, although all of them showed average levels that were much higher than the cutoff point (200 MUg/g). Only nonalcoholic individuals showed a relationship between diarrhea and alterations in elastase levels. A relationship between the use of HAART and exocrine pancreatic insufficiency in different phases of HIV infection could not be verified. PMID- 23088672 TI - Laxative effects and mechanism of action of Brazilian green propolis. AB - BACKGROUND: Brazilian green propolis is reported to have wide range of biological properties including antibacterial, anti-inflammatory, anti-influenza, and antioxidant activities. In the digestive system, a protective effect of propolis on gastric ulcer has been reported, but a laxative effect has not yet been reported. We investigated the effect and the mechanism of action of water and ethanol extracts of Brazilian green propolis. METHODS: We examined the laxative effect of propolis on stool frequency by administering orally an ethanol extract of propolis (EEP) or a water extract of propolis (WEP) at 10, 50, 100, or 500 mg/kg to normal mice. We then investigated the effects of propolis using constipation model mice induced by two types of drugs, loperamide (a MU opioid receptor agonist) and clonidine (an alpha-2 adrenergic receptor agonist). We also investigated the effects of WEP on gastrointestinal transit and contractional tension of the ileum to uncover the mechanism of action of WEP. RESULTS: Treatment with WEP, but not with EEP, significantly increased the weight of stools (p<0.01 at 500 mg/kg). WEP treatment significantly restored stool frequency and stool weight in clonidine-induced constipation model mice, but not in loperamide-induced constipation model mice. WEP treatment did not affect gastro-intestinal transit, but significantly increased the contractional tension of the isolated ileum of guinea pigs. This increase was inhibited by an acetylcholine receptor antagonist (atropine), but not by a 5-HT receptor antagonist (GR113808). CONCLUSION: These findings indicate that WEP has laxative effects both in normal mice and in clonidine-induced constipation model mice. The laxative effects of WEP might be mediated by increased contractional tension of the ileum exerted at least in part via activation of an acetylcholine receptor. PMID- 23088673 TI - Strynuxlines A and B, alkaloids with an unprecedented carbon skeleton from Strychnos nux-vomica. AB - The investigation of the seeds of Strychnos nux-vomica led to the isolation of two novel indole alkaloids, strynuxlines A (1) and B (2), with an unprecedented 6/5/9/6/7/6 hexacyclic ring system. Their structures and absolute configurations were elucidated on the basis of their MS, NMR, and ECD data. A plausible biosynthesis pathway of 1 and 2 is also proposed. PMID- 23088675 TI - Sexual dysfunction among male veterans returning from Iraq and Afghanistan: prevalence and correlates. AB - INTRODUCTION: Sexual dysfunction (SD) is not well described in the Iraq/Afghanistan veteran population despite high prevalence of multiple risk factors for this issue. AIM: To estimate the prevalence and examine the association of various sociodemographic, mental health, comorbid conditions and life style factors with sexual dysfunction in Iraq/Afghanistan veterans. METHODS: This exploratory cross-sectional study was conducted using data from the VA administrative database. A total of 4,755 Iraq/Afghanistan veterans were identified who sought treatment from the Michael E. DeBakey Veterans Affairs Medical Center inpatient and outpatient clinic between September 2007 and August 2009. MAIN OUTCOME MEASURES: Sexual dysfunction was determined by ICD9-CM codes related to sexual health issues and/or by specific medications, primarily phosphodiesterase-5 inhibitors (PDE5i), prescribed for erectile dysfunction. RESULTS: The overall prevalence of sexual dysfunction was 5.5% (N = 265). By age category, it was 3.6% (N = 145) for Iraq/Afghanistan veterans aged 18-40 years and 15.7% (N = 120) for Iraq/Afghanistan veterans aged > 40 years, respectively. A multivariate logistic-regression model revealed that annual income, marital status, post-traumatic stress disorder, and hypertension were significant risk factors of SD (all P < 0.05) among younger Iraq/Afghanistan veterans, whereas among the older Iraq/Afghanistan veterans, being African American and having PTSD and hypertension were significant risk factors of SD (all P < 0.05). There was marked discrepancy between documented erectile dysfunction and prescription of a PDE5i. CONCLUSIONS: These data demonstrate that a significant proportion of Iraq/Afghanistan veterans have SD and that the risk factors differ between younger and older veterans. Our findings also suggest that SD is likely under coded. To better identify the scope of the problem, systematic screening for sexual dysfunction may be appropriate perhaps as part of an initial post deployment health evaluation. PMID- 23088676 TI - Bone tissue engineering with periosteal-free graft and pedicle omentum. AB - BACKGROUND: The histological characteristics of periosteum make it a specific tissue with a unique capacity to be engineered. Higher flexibility of the greater omentum is useful for reconstructive surgery as it facilitates not only filling of the site of infections such as myelitis, but also is effective in filling complicated defects of the soft and hard tissues, and these criteria make it suitable for tissue engineering. The present study was designed to evaluate bone tissue engineering with periosteal-free graft concurrent with pedicle omentum and compare it with subcuticular periosteal grafting in a dog model. This is the first report in which periosteum-free graft has been used as bone tissue engineering. METHODS: Eight young female indigenous dogs were used in this experiment. In omental group (n = 4), end of omentum was wrapped by periosteum of the radial bone in the abdomen of each dog, while in the subcutaneous group (n = 4), the harvested periosteum was sutured on the subcutaneous layer. Lateral view radiographs were taken from the abdominal cavity post-operatively at 2, 4, 6 and 8 weeks post surgery. Eight weeks after operation, the dogs were re-anaesthetized and the omental or subcutical grafted periosteom was found and removed for histopathological evaluation. RESULTS AND DISCUSSION: Radiological, gross and histopathological evaluations revealed a superior bone formation in the wrapped omentum with periosteum compared with that of the subcuticular periosteal grafting. This is a novel and efficient technique in producing mature trabecular bone and could be used as a potential source of bone tissue engineering for autotransplantation. PMID- 23088680 TI - Bacillus coagulans GBI-30, 6086 limits the recurrence of Clostridium difficile Induced colitis following vancomycin withdrawal in mice. AB - BACKGROUND: Recently, we found that the probiotic strain Bacillus coagulans GBI 30, 6086 (GanedenBC30) improved indices of Clostridium difficile (C. difficile) induced colitis in mice (Fitzpatrick et al., Gut Pathogens, 2011). Our goal was to determine if BC30 could also prevent the recurrence of C. difficile-induced colitis in mice, following initial treatment with vancomycin. During study days 0 through 5, mice were treated with antibiotics. On day 6, the C. difficile strain VPI 10463 was given by oro-gastric gavage at ~ 5x104 CFU to induce colitis. Mice were treated on study days 6 to 10 with vancomycin (50 mg/kg) (vanco) or vehicle (saline) by gavage. On days 10 to16, mice were dosed by gavage with saline vehicle or BC30 (2 x 109 CFU per day). Mice were monitored for mortality, weight loss and diarrhea. On study days 14, 16 and 17, stools and colons were collected for analyzing other parameters of colitis. RESULTS: The mean stool consistency score in Vehicle/C.difficile/Vanco mice increased from 0.4 (day 10) to a range of 1.1 to 1.4 (days 14 to 17), indicating the recurrence of colitis. On days 13 through 17, the stool consistency scores for the vancomycin/BC30 mice were significantly lower (p< 0.05) than for the vancomycin/vehicle cohort of animals. On day 17, 88.9% of mice treated with BC30 had normal stools, while this value was 0% with vehicle treatment (p value = 0.0004). Colonic myeloperoxidase (Units/2 cm colon) was significantly (p < 0.05) reduced from 4.3 +/- 0.7 (Vehicle/C.difficile/Vanco) to 2.6 +/- 0.2 (BC30/C. Difficle/Vanco). The colonic histology score and Keratinocyte derived-chemokine level in the colon were also lower in BC30 treated mice. SUMMARY: In BC30-treated mice, there was evidence of better stool consistency, as well as improved biochemical and histological indices of colitis, following initial treatment of animals with vancomycin. CONCLUSION: BC30 limited the recurrence of CD-induced colitis following vancomycin withdrawal in mice. PMID- 23088681 TI - Differentiating the role of three self-compassion components in buffering cognitive-personality vulnerability to depression among Chinese in Hong Kong. AB - Research shows that sociotropy, autonomy, and self-criticism are cognitive personality vulnerability styles contributing significantly to the development of depression symptoms, but little is known about the factors that may protect sociotropic, autonomous, and self-critical individuals against mental health problems. The present study examined self-compassion components (i.e., self kindness, common humanity, and mindfulness) as potential moderators to protect these individuals from developing depression. On the basis of survey data from 345 Chinese adults in Hong Kong, the relationships between cognitive-personality vulnerability styles, self-compassion components, and depression were examined. The results of the present study show that when the effect of gender and the 2 other self-compassion components were controlled, self-kindness and mindfulness could moderate the association between autonomy and depression, and the association between self-criticism and depression, while common humanity could moderate the association between self-criticism and depression. Unexpectedly, interaction between sociotropy and mindfulness was found, with the association between sociotropy and depression being stronger among individuals with high mindfulness than it was with individuals with low mindfulness. These results suggest the differentiating role of the 3 self-compassion components in buffering autonomous and self-critical individuals from depression. Applications of self compassion and the hypothesized moderation model in future psychological interventions are discussed. PMID- 23088677 TI - Systematic evaluation of the dependence of deoxyribozyme catalysis on random region length. AB - Functional nucleic acids are DNA and RNA aptamers that bind targets, or they are deoxyribozymes and ribozymes that have catalytic activity. These functional DNA and RNA sequences can be identified from random-sequence pools by in vitro selection, which requires choosing the length of the random region. Shorter random regions allow more complete coverage of sequence space but may not permit the structural complexity necessary for binding or catalysis. In contrast, longer random regions are sampled incompletely but may allow adoption of more complicated structures that enable function. In this study, we systematically examined random region length (N(20) through N(60)) for two particular deoxyribozyme catalytic activities, DNA cleavage and tyrosine-RNA nucleopeptide linkage formation. For both activities, we previously identified deoxyribozymes using only N(40) regions. In the case of DNA cleavage, here we found that shorter N(20) and N(30) regions allowed robust catalytic function, either by DNA hydrolysis or by DNA deglycosylation and strand scission via beta-elimination, whereas longer N(50) and N(60) regions did not lead to catalytically active DNA sequences. Follow-up selections with N(20), N(30), and N(40) regions revealed an interesting interplay of metal ion cofactors and random region length. Separately, for Tyr-RNA linkage formation, N(30) and N(60) regions provided catalytically active sequences, whereas N(20) was unsuccessful, and the N(40) deoxyribozymes were functionally superior (in terms of rate and yield) to N(30) and N(60). Collectively, the results indicate that with future in vitro selection experiments for DNA and RNA catalysts, and by extension for aptamers, random region length should be an important experimental variable. PMID- 23088682 TI - College men's intimate partner violence attitudes: contributions of adult attachment and gender role stress. AB - Primary prevention of men's intimate partner violence (IPV) toward women in dating relationships is an important area of psychological inquiry and a significant concern for counselors working with college student populations. Previous research has identified that certain beliefs condoning or accepting physical, sexual, and psychological violence in relationships are key risk factors for IPV perpetration; however, comparatively few studies have examined the social and relational variables related to IPV acceptance attitudes. In the present study, we proposed and tested a structural model examining the combined contributions of adult attachment dimensions (i.e., attachment anxiety and attachment avoidance) and masculine gender role stress in the prediction of IPV acceptance attitudes in a large sample of college men (N = 419). We hypothesized that the relationship between attachment insecurity and IPV acceptance attitudes would be partially mediated by men's gender role stress. A partially mediated model produced the best indices of model fit, accounting for 31% of the variance in an IPV acceptance attitudes latent variable. A bootstrapping procedure confirmed the significance of mediation effects. These results suggest that aspects of adult attachment insecurity are associated with tendencies to experience stress from violations of rigidly internalized traditional male role norms, which, in turn, are associated with acceptance of IPV. Findings are further discussed in relation to adult attachment theory (Mikulincer & Shaver, 2007), gender role strain theory (Pleck, 1995), and their implications for IPV prevention in college student populations. PMID- 23088683 TI - Attachment anxiety and avoidance and perceptions of group climate: an actor partner interdependence analysis. AB - There is a lack of research examining group members' attachment styles and group climate perceptions in the context of the attachment styles and group climate perceptions of the other group members. In the current study, the actor-partner interdependence model (APIM) was used to examine the relationships among (a) a group member's attachment pattern, (b) the aggregated attachment patterns of the other group members, (c) a group member's perceptions of the group's climate, and (d) the aggregated group climate perceptions of the other group members. One hundred ten Italian graduate students in six 10-session interpersonal growth groups were studied. Group members filled out the Attachment Style Questionnaire prior to group participation and the Group Climate Questionnaire after the 3rd group session. Contrary to the hypotheses, a group member's attachment pattern (anxiety and avoidance) was unrelated to her or his perceptions of group climate, and only group member attachment anxiety was positively related to the other group members' perceptions of conflict in the group's climate. There was, however, strong support for the hypotheses involving the aggregate attachment of the other group members and group climate perceptions. As hypothesized, aggregated perceptions of attachment anxiety and avoidance were positively related to a member's perception of group conflict and aggregated perceptions of attachment anxiety and avoidance were negatively related to a member's perception of group engagement. Both aggregated attachment anxiety and avoidance were related in the expected directions to aggregated perception of group climate. Finally, as hypothesized, a group member's perception of group climate was positively related to the aggregated climate perceptions of the other group members. The findings suggest that the APIM is a useful approach for examining group process variables in the group counseling context. PMID- 23088684 TI - Managing difficulties in supervision: supervisors' perspectives. AB - Few studies have examined the practice wisdom of expert supervisors. This study addresses this gap by exploring how experienced supervisors manage difficulties in supervision in the context of the supervisory relationship. The supervisors were a purposive sample of 16 senior members of the profession with considerable expertise in supervision. In-depth interviews were first conducted with the supervisors. An interpersonal process recall method was then used to explore their reflections on one of their DVD-recorded supervision sessions. Analysis of transcripts was completed using a modified consensual qualitative research method. Major difficulties included the broad domains of supervisee competence and ethical behavior, supervisee characteristics, supervisor countertransference, and problems in the supervisory relationship. Supervisors managed these difficulties using 4 key approaches: relational (naming, validating, attuning, supporting, anticipating, exploring parallel process, acknowledging mistakes, and modeling); reflective (facilitating reflectivity, remaining mindful and monitoring, remaining patient and transparent, processing countertransference, seeking supervision, and case conceptualizing); confrontative (confronting tentatively, confronting directly, refusing/terminating supervision, taking formal action, referring to personal therapy, and becoming directive); and avoidant interventions (struggling on, withholding, and withdrawing). Two brief case studies illustrate the process of applying these strategies sequentially in managing difficulties. The study highlights the importance of relational strategies to maintain an effective supervisory alliance, reflective strategies particularly when difficulties pertain to clinical material and the supervisory relationship-and confrontative strategies with unhelpful supervisee characteristics and behaviors that impede supervision. PMID- 23088685 TI - Developing a taxonomy of helpful and harmful practices for clinical work with boys and men. AB - This study drew upon the knowledge base of member practitioners of the American Psychological Association (APA) to develop a taxonomy of helpful and harmful practices for treatment with boys and men. Four hundred seventy-five APA-member practitioners solicited from practice-related divisions provided responses to 4 open-ended questions about helpful and harmful practices in working with boys and men. Ten themes emerged from qualitative analyses. Beneficial and sensitive practices included addressing gender socialization and gender-sensitive issues as they apply to boys and men in psychological practice. Harmful practices included biased practices, stereotypes, and a lack of awareness and training around gender and diversity issues as they apply to boys and men. We discuss the specific themes that emerged from analysis of the responses, how these findings are situated within previous work examining helpful and harmful practices, limitations to the study, suggestions for research, and implications for training psychologists. PMID- 23088686 TI - Can two psychotherapy process measures be dependably rated simultaneously? A generalizability study. AB - Observer ratings in psychotherapy are a common way of collecting information in psychotherapy research. However, human observers are imperfect instruments, and their ratings may be subject to variability from several sources. One source of variability can be raters' assessing more than 1 instrument at a time. The purpose of this research is to investigate whether it is possible to have raters assess 2 different psychotherapy process measures simultaneously and still produce dependable scores. Two studies were designed. The first compared scores assessed by raters who rated either 1 instrument or 2 instruments simultaneously. The second compared scores of raters who assessed 2 instruments simultaneously and scores of expert raters who assessed 1 instrument. The results show that variability in scores is largely due to differences across the object of measurement (e.g., patients). Small variability was reported for raters, raters' interaction with patients, and whether the rater assessed 1 instrument or 2 instruments simultaneously. The results are promising for the quality of observer ratings of psychotherapy process and for the feasibility of future psychotherapy process research. (PsycINFO Database Record (c) 2012 APA, all rights reserved). PMID- 23088688 TI - Theoretical study on cyclopropanation of endo-dicyclopentadiene with zinc carbenoids: effects of solvent and (ICH2)2Zn. AB - A computational study using a hybrid DFT method (M06) on the cyclopropanation of endo-dicyclopentadiene with Simmons-Smith zinc carbenoids is reported. Each channel proceeds via the methylene-transfer mechanism with a reactant complex (RC) and subsquently a asynchronous transition state (TS). The channels with monomeric IZnCH(2)I attacking the double bonds from the exo-face have a much lower barrier (about 16.17-18.43 kcal/mol) in the gas phase, compared with the channels from the endo-face (21.80-31.13 kcal/mol). Thus, P1 and P3 are the primary cyclopropanated compounds, and P5 is the sole final product, representing remarkable stereospecificity. When considering the bulk solvent effect of diethyl ether, the barriers are decreased about 0.50-7.77 kcal/mol due to more "destabilization" of RC than TS. The solvated (ICH(2))(2)Zn can further reduce the barriers about 0.18-2.30 kcal/mol. In addition, the solvated IZnCH(2)I and (ICH(2))(2)Zn do not change the reaction pathways and retain the stereospecificity. Our computational results agree with the experimental observations quite well and suggest that both IZnCH(2)I and (ICH(2))(2)Zn might be the active species in the real reaction system. Regarding the solvent effect, the polar continuum model is more realistic than the direct involvement of diethyl ether molecules. PMID- 23088687 TI - Prevalence of overweight in children with bone fractures: a case control study. AB - BACKGROUND: Children's fractures have been enlisted among orthopaedics complaints of childhood obesity. Unhealthy lifestyle behaviours may contribute to increased risk. This study described the prevalence of overweight/obesity in children and adolescents reporting a recent fracture in relation to gender, dynamic of trauma, and site of fracture. METHODS: Four-hundred-forty-nine children and adolescents with fracture and 130 fracture-free controls were recruited from a large children's hospital. The interaction between overweight and gender, dynamic of trauma, site of fracture was explored. Sports participation, television viewing, and calcium intake were also investigated. RESULTS: Overweight/obesity rate was increased in girls with fracture either at the upper or the lower limb (p= 0.004), while it was increased only in boys with fracture at the lower limb (p <0.02). Overweight/obesity rate did not differ between groups with low or moderate trauma. TV viewing >= 2 hrs was more frequent in children with fractures than controls (61.5% vs 34.5%, p =0.015) in the overweight/obese group. CONCLUSIONS: The increased prevalence of overweight/obesity in children with fractures is related to gender and site of fracture. Higher levels of sedentary behaviours characterize overweight children reporting fractures. PMID- 23088689 TI - Identification of the kinetic mechanism of succinyl-CoA synthetase. AB - The kinetic mechanism of SCS [succinyl-CoA (coenzyme A) synthetase], which participates in the TCA (tricarboxylic acid) cycle, ketone body metabolism and haem biosynthesis, has not been fully characterized. Namely, a representative catalytic mechanism and associated kinetic parameters that can explain data on the enzyme-catalysed reaction kinetics have not been established. To determine an accurate model, a set of putative mechanisms of SCS, proposed by previous researchers, were tested against experimental data (from previous publication) on SCS derived from porcine myocardium. Based on comparisons between model simulation and the experimental data, an ordered ter-ter mechanism with dead-end product inhibition of succinate against succinyl-CoA is determined to be the best candidate mechanism. A thermodynamically constrained set of parameter values is identified for this candidate mechanism. PMID- 23088690 TI - Putting on the breaks: regulating organelle movements in plant cells(f). AB - A striking characteristic of plant cells is that their organelles can move rapidly through the cell. This movement, commonly referred to as cytoplasmic streaming, has been observed for over 200 years, but we are only now beginning to decipher the mechanisms responsible for it. The identification of the myosin motor proteins responsible for these movements allows us to probe the regulatory events that coordinate organelle displacement with normal cell physiology. This review will highlight several recent developments that have provided new insight into the regulation of organelle movement, both at the cellular level and at the molecular level. [ PMID- 23088691 TI - Titanium dioxide photocatalysis in atmospheric chemistry. PMID- 23088692 TI - Platinum availability for future automotive technologies. AB - Platinum is an excellent catalyst, can be used at high temperatures, and is stable in many aggressive chemical environments. Consequently, platinum is used in many current industrial applications, notably automotive catalytic converters, and prospective vehicle fuel cells are expected to rely upon it. Between 2005 and 2010, the automotive industry used approximately 40% of mined platinum. Future automotive industry growth and automotive sales shifts toward new technologies could significantly alter platinum demand. The potential risks for decreased platinum availability are evaluated, using an analysis of platinum market characteristics that describes platinum's geophysical constraints, institutional efficiency, and dynamic responsiveness. Results show that platinum demand for an automotive fleet that meets 450 ppm greenhouse gas stabilization goals would require within 10% of historical growth rates of platinum supply before 2025. However, such a fleet, due largely to sales growth in fuel cell vehicles, will more strongly constrain platinum supply in the 2050 time period. While current platinum reserves are sufficient to satisfy this increased demand, decreasing platinum ore grade and continued concentration of platinum supply in a single geographic area are availability risk factors to platinum end-users. PMID- 23088693 TI - Cystic fibrosis: a clinician's tool for management of care advancing into the adult population. AB - PURPOSE: To discuss the role of the nurse practitioner in medical management of adult patients with cystic fibrosis (CF). DATA SOURCES: A systematic literature review was done by searching online databases: CINAHYL, OVID, and Medline. The Cystic Fibrosis Foundation (CFF) guidelines were reviewed. Tables were compiled for recommended screening and treatment for adult CF patients. CONCLUSIONS: Comorbidities occur among adult CF patients and include: CF-related diabetes (CFRD), fertility issues, CF liver disease (CFLD), and CF bone disease. Diabetes management is reviewed. Current fertility surgical treatments for males and recommendations for females are discussed. Ursodiol is the main treatment regimen for those affected. Bone disease and CF has multiple etiologies and the focus of treatment is based on appropriate vitamin D replacement and bisphosphonates. New standards for vitamin D replacement are discussed. IMPLICATIONS FOR PRACTICE: Clinicians must be familiar with the current treatments and regimens of adults with CF including comorbidities. The CF adult population is expanding and care is extending beyond the CF clinic. More healthcare providers must be educated on the best practices of adult CF care. The importance of early identification and treatment of CF comorbidities cannot be overestimated. PMID- 23088694 TI - Timing is everything: when to consult palliative care. AB - PURPOSE: Consults promote additional perspectives and help with complex patient management. As the population ages and healthcare demands increase, providers are consulting palliative care (PC). Nurse practitioners (NPs) should understand when to consult PC. DATA SOURCES: Information was obtained from an extensive search of the scientific literature to include Pallimed (http://www.pallimed.org/) and the author's clinical experience. CONCLUSIONS: Based on the 2009 Clinical Practice Guidelines for Quality PC developed from the Hospice and PC Coalition, PC should be consulted at diagnosis. These findings have also been validated in a landmark randomized controlled trial by Temel et al. (2010). The goals of PC are to alleviate suffering and promote quality of life for people with illnesses. PC accepts and incorporates hospice philosophies, but is distinct. IMPLICATIONS FOR PRACTICE: Many professional organizations are incorporating PC into their specialties and guidelines. In addition to incorporating PC at diagnosis, PC access needs to be improved. New and experienced NPs may appreciate collaborating with PC specialists. Such conversations and relationships will likely offer practical and supportive guidance to both patients and NPs. Overall, the future for PC is promising. PMID- 23088695 TI - Evidence-based practice for the busy nurse practitioner: part two: searching for the best evidence to clinical inquiries. AB - PURPOSE: The purpose of this four-part evidence-based practice (EBP) series is to enhance the nurse practitioner's (NP's) EBP skills by reviewing the process of developing a clinical question, searching for the best evidence, and critically appraising and applying the findings. Part two of the series focuses on how to search the published scientific literature for the most relevant studies that will answer a specific clinical question of importance to the NP. DATA SOURCES: Scientific literature review, gray searching, PubMed and other online literature databases and resources, and online EBP websites. CONCLUSIONS: Technology has allowed multiple healthcare resources to be available at one's fingertips enabling both NPs and their patients to find answers to clinical questions. EBP databases can be categorized as synthesized/filtered, unfiltered, and background information/expert opinion resources. Learning which database can best answer the clinical inquiry can streamline the search process. IMPLICATIONS FOR PRACTICE: For the busy NP, EBP has emerged as an important strategy to maintain valid, accurate, and relevant clinical knowledge. It is expected that this part of the series will enable NPs to identify appropriate databases to answer clinical inquires while refining their search strategy skills, which takes both time and practice. PMID- 23088696 TI - Advanced nursing practice hours as part of endorsement requirements for nurse practitioners in Australia: a definitional conundrum. AB - PURPOSE: To define what can be considered to be nursing practice, time that can be calculated as the practice of nursing as well as what is considered to be advanced nursing practice and how all this can be related to the current endorsement process for nurse practitioner (NP) in Australia. DATA SOURCES: Current codes and guidelines cited by the Nurse and Midwifery Board of Australia related to nursing practice and NPs, cited competency standards from the Australian Midwifery Accreditation Council, as well as published material of peak nursing bodies from within Australia as well as internationally were used. Information was also obtained through government health and professional organization websites. All information in the literature regarding current and past status and nomenclature of advanced practice nursing was considered relevant. CONCLUSIONS: The definitional entanglement of what is considered to be nursing practice, the calculation of specific hours and what is advanced nursing practice interferes with endorsement of NPs in Australia, and a clear understanding of what is meant by advanced practice is required to move forward. IMPLICATIONS FOR PRACTICE: Dependent on how practice is interpreted by the Nurse and Midwifery Board of Australia directly affects the outcome of the endorsement proceedings for individual NP candidates. PMID- 23088697 TI - Coping behaviors used by Army wives during deployment separation and their perceived effectiveness. AB - PURPOSE: The purpose of this descriptive correlational study was to describe the coping behaviors used by Army wives during deployment separation, the perceived effectiveness of the coping behaviors used, and the correlation between the two variables. DATA SOURCES: A secondary analysis was conducted to examine coping use and perceived effectiveness, measured by the Jalowiec Coping Scale (JCS), in a sample of 102 Army wives surveyed during deployment separation. CONCLUSIONS: The most used coping subscales from the JCS were the optimistic and supportant and the most effective were the supportant and confrontive. The strongest correlations between coping use and effectiveness were found in the supportant subscale, which measures use of support systems (r = 0.77, p < .00), and the confrontive subscale, which includes behaviors of constructive problem solving (r = 0.62, p < .00). The use and effectiveness of individual behaviors are also identified. IMPLICATIONS FOR PRACTICE: Identifying effective and ineffective coping behaviors of spouses of deployed troops can potentially reduce stress and improve well-being. Primary care providers should encourage military spouses to engage in optimistic thinking, seek out spiritual support, talk to others in a similar situation, and participate in physical activity. PMID- 23088698 TI - Factors predicting older adults' use of exercise and acetaminophen for osteoarthritis pain. AB - PURPOSE: To identify predictors of older adults' use of exercise and/or acetaminophen, and avoidance of nonsteroidal anti-inflammatory drugs (NSAIDs) to treat their osteoarthritis pain. DATA SOURCES: Data were analyzed from 457 adults aged 60 and older with moderate or greater osteoarthritis pain intensity who responded to the Brief Pain Inventory between 2006 and 2007. The following predictors were entered into a logistic regression to predict use of exercise and/or acetaminophen and nonuse of NSAIDs: age, gender, ethnicity, race, education, arthritis treatment by a practitioner, pain treatment by a practitioner, pain intensity, functional interference from the pain, and percent of pain relief from current treatments. CONCLUSIONS: A total of 213 (46.6%) reported using exercise and/or acetaminophen and did not report using NSAIDs. Older adults reporting arthritis treatment by a practitioner were 2.2 (confidence interval 1.08-4.59) more likely to use recommended arthritis pain treatment, p < .03. Only 3-4% of the variance for use of recommended pain management treatment was explained by the predictors. IMPLICATIONS FOR PRACTICE: Results underscore the importance of guidance by practitioners who are knowledgeable about safe osteoarthritis pain management for older adults. PMID- 23088699 TI - Medication adherence among homeless patients: a pilot study of cell phone effectiveness. AB - PURPOSE: We examined the feasibility of using cell phones to monitor medication adherence among homeless participants and collected data for research purposes. DATA SOURCES: Ten homeless individuals with a co-occurring substance use and psychiatric disorders who were receiving psychopharmacologic treatment participated in the study. All psychopharmacologic treatment was provided by a psychiatric mental health nurse practitioner. Cell phones were provided to participants with unlimited phone service for 45 days. An automated telephone system was programmed to call participants daily for 30 days. All participant responses were reported to a computer and reviewed by study staff on a daily basis. CONCLUSIONS: The automated calls reached study participants 93% of days and, when reached, participants reported 100% adherence with the prescribed medication regimen. Exit interviews indicated strong support for the usefulness of the phone and the value of the call and survey as reminders to take their medication. No patients dropped out of this study. IMPLICATIONS FOR PRACTICE: This pilot study establishes the feasibility of using cell phones to monitor and manage medication regimens for hard-to-reach populations, such as the homeless with co-occurring disorders. It also establishes that this technology would work for research data collection. PMID- 23088700 TI - Genotoxic biomonitoring of flowable and non-flowable composite resins in peripheral blood leukocytes. AB - OBJECTIVE: Composite restorative materials represent one of the most important groups of materials in contemporary dental practice. However, their incomplete polymerization may lead to monomer-induced genotoxicity. The objective of this study was to evaluate the genotoxicity of three flowable (Filtek Supreme XT Flow, Tetric EvoFlow, Gradia Direct Flo) and three non-flowable dental composite materials (Filtek Z250, Tetric EvoCeram, Gradia Direct Posterior). MATERIALS AND METHODS: Genotoxicity assessment of composite materials was carried out in vitro in human peripheral blood leukocytes using the alkaline single-cell gel electrophoresis technique (comet assay). Prepared materials were eluted in saline solution for 1 h, 1 day and 5 days. Thereafter leukocyte cultures were treated with different concentrations of eluates obtained from each of the tested dental composite materials. Kruskall-Wallis non-parametric test was used for statistical analysis (p < 0.05). RESULTS: The tested materials did not show genotoxic effects after exposure of leucocytes to 1 h eluates. Culture treated with 1 day eluates of all tested materials, only at a highest concentration (10(-2)), affected the measured cytogenetic parameters. Of all tested materials, only Filtek Z250 and Filtek Supreme XT Flow did not exhibit a genotoxic effect in cultures that were under the influence of 5 day eluates. CONCLUSION: Tested materials exhibited limited genotoxic activity in peripheral blood leukocytes. Since the effect was observed only in leukocyte cultures treated by 1-day eluates at the highest concentration (10(-2)) and it decreases in cultures exposed to 5 day eluates, it should not pose a significant risk to the human genome. PMID- 23088701 TI - Management of skin-related adverse events during locomotor training with robotic assisted body weight supported treadmill: A case report. AB - The purpose of this case report is to describe attempts to prevent skin-related adverse events from occurring and protect the skin once breakdown occurred in a person with chronic stroke during locomotor training. There is scant literature in how to address skin during locomotor training with the Lokomat((r)), particularly when a patient presents with sensory deficits and frail skin. The patient was a 75-year-old male survivor of stroke who participated in the Lokomat((r)) group of a randomized clinical pilot study comparing locomotor training with the Lokomat((r)) and conventional means. He had diminished sensation to light touch and proprioception on his left leg with skin on both lower legs presenting as thin, flaky, and virtually hairless. Although much effort was put towards prevention of skin breakdown, he developed numerous skin related adverse events during his training. However, his skin healed completely with reduced training intensity and initiation of "pre-wrapping" his lower legs with Akton((r)) viscoelastic polymer sheets and elastic bandages. Significant improvements were noted in his Functional Improvement Measure(TM) locomotion score and Stroke Impact Scale domains of strength, participation/role function, and total recovery, though not in his 10-m walk test velocity or 6-min walk test. The Akton((r)) sheets and team approach between study team, patient, and his wife allowed simultaneous safe continuation of locomotor training with the Lokomat((r)) and healing of his skin breakdown. PMID- 23088702 TI - The clinical effects of Kinesio(r) Tex taping: A systematic review. AB - Kinesio((r)) Tex tape (KTT) is used in a variety of clinical settings. The purpose of this study was to investigate the effect of KTT from randomized controlled trials (RCTs) in the management of clinical conditions. A systematic literature search of CINAHL; MEDLINE; OVID; AMED; SCIENCE DIRECT; PEDRO; www.internurse.com; SPORT DISCUS; BRITISH NURSING INDEX; www.kinesiotaping.co.uk; www.kinesiotaping.com; COCHRANE CENTRAL REGISTER OF CLINICAL TRIALS; and PROQUEST was performed up to April 2012. The risk of bias and quality of evidence grading was performed using the Cochrane collaboration methodology. Eight RCTs met the full inclusion/exclusion criteria. Six of these included patients with musculoskeletal conditions; one included patients with breast-cancer-related lymphedema; and one included stroke patients with muscle spasticity. Six studies included a sham or usual care tape/bandage group. There was limited to moderate evidence that KTT is no more clinically effective than sham or usual care tape/bandage. There was limited evidence from one moderate quality RCT that KTT in conjunction with physiotherapy was clinically beneficial for plantar fasciitis related pain in the short term; however, there are serious questions around the internal validity of this RCT. There currently exists insufficient evidence to support the use of KTT over other modalities in clinical practice. PMID- 23088703 TI - Effect of diaphragmatic breathing exercise on quality of life in subjects with asthma: A systematic review. AB - The aim of this systematic review was to determine if diaphragmatic breathing exercise improves quality of life (QoL) in asthma. Electronic databases were searched for randomized controlled trials (RCTs). Data were extracted and risk of bias was assessed by two independent reviewers. Three RCTs were eligible for inclusion (254 subjects). Two studies compared diaphragmatic breathing exercise to asthma education, and one compared with asthma medication. Meta-analysis was not possible due to clinical heterogeneity of the studies. All three studies had a low risk of bias. All studies reported short-term effects, and long-term effects of breathing exercise on asthma quality life. There is a moderate evidence of improvement in QoL following diaphragmatic breathing both in short term and long-term basis. PMID- 23088704 TI - Using digital photography to document rectus femoris flexibility: A reliability study of the modified Thomas test. AB - BACKGROUND: Research indicates that rectus femoris muscle flexibility assessment techniques suffer from multiple sources of measurement error. OBJECTIVE: To examine whether scoring of rectus femoris muscle flexibility from digital photographs of clinical examination using the modified Thomas test would be highly reliable. METHODS: Twenty-eight individuals were digitally photographed while having their rectus femoris muscle flexibility evaluated using the modified Thomas test. Therapists were then asked to view these digital photographs and score participant's flexibility using modified Thomas test scoring criteria. A retest session was completed approximately 1-week later. RESULTS: Kappa values for positive/negative scoring (intra-rater experienced X- = 0.86, in experienced X- = 0.98; interrater experienced X- = 0.95, in-experienced X- = 0.99) and ICC values for goniometer scoring (intra-rater experienced X- = 0.98, in-experienced X- = 0.98; interrater experienced X- = 0.97, in experienced X- = 0.98) indicated very high levels of reliability. Measurement error values (SEM = 1.0 degrees , ME = 1.53 degrees , and CV = 3%) and Bland and Altman plots (with 95% limits of agreement) further illustrated the very small degree of scoring variance. CONCLUSIONS: Results indicate that goniometer and positive/negative scoring of rectus femoris muscle flexibility from digital photographs of clinical examination using the modified Thomas test were highly reliable. This finding suggests that using digital photography as a means to document patient function during clinical examination may serve as a method to help standardize physical assessment, minimize error measurement, and assist the clinician/researcher in establishing whether an observed change between testing sessions is clinically significant. PMID- 23088706 TI - Understanding the solvent polarity effects on surfactant-capped nanoparticles. AB - Understanding the molecular interactions between suspended nanoparticles (NPs) and the suspending solvent fluid may provide a useful avenue to create and to study exotic NP ensembles. This study focused on using a coarse-grained computational model to investigate the molecular interactions between oleate capped NPs in various solvents, and to relate the results to experimental features of solvent-suspended, oleate-capped CdSe quantum dots (QDs). The QDs were modeled as a closed-shell fullerene molecule with an oleate-like ligand attached to each vertex. Solvent polarity was found to correlate to the simulation and experimental results more strongly than either dielectric constant or dipole moment. Computational results showed that the nonpolar solvents of hexane, toluene, and benzene (polarity index E(T)(N) < 0.120) kept NPs in suspension and solvated the oleate chains such that the oleate layer swelled to full extension. In contrast, as the most polar solvent tested (E(T)(N) = 1.000), water caused NPs to aggregate and precipitate. It partially solvated the oleate chains and compressed the layer to 86% of full extension. For solvents of intermediate polarity like ethanol, acetone, and chloroform, the oleate layer swelled with decreasing polarity index values, with rapid swelling occurring close to E(T)(N) = 0.307 (~50:50 vol % chloroform/acetone) below which QDs were colloidally stable. This study represents the first attempt to delineate the solvent effect on surfactant-coated NP hydrodynamic size, colloidal stability, and aggregation behavior. PMID- 23088705 TI - Disease severity is associated with the use of complementary medicine to treat or manage type-2 diabetes: data from the 2002 and 2007 National Health Interview Survey. AB - BACKGROUND: The overall prevalence of complementary medicine (CM) use among adults in the United States with diabetes has been examined both in representative national samples and in more restricted populations. However, none of these earlier studies attempted to identify predictors of CM use to treat diabetes among the populations sampled, nor looked for a relationship between CM use and diabetes severity. METHODS: Combining data from the 2002 and 2007 National Health Interview Survey (NHIS), we constructed a nationally representative sample of 3,978 U.S. adults aged >=18 years with self-reported diabetes. Both the 2002 and 2007 NHIS contained extensive questions on the use of CM. We used logistic regression to examine the association between diabetes severity and overall CM use, as well as the use of specific categories of CM. RESULTS: In adults with type-2 diabetes, 30.9% used CM for any reason, but only 3.4% used CM to treat or manage their type-2 diabetes versus 7.1% of those with type-1 diabetes. Among those using CM to treat/manage their type-2 diabetes, 77% used both CM and conventional prescription medicine for their diabetes. The most prevalent types of CM therapies used were diet-based interventions (35.19%, S.E. 5.11) and non-vitamin/non-mineral dietary supplements (33.74%, S.E. 5.07). After controlling for sociodemographic factors, we found that, based on a count of measures of diabetes severity, persons with the most severe diabetes had nearly twice the odds of using CM as those with less severe disease (OR=1.9, 95%CI 1.2 3.01). Persons who had diabetes 10 years or more (OR=1.66, 95%CI 1.04-3.66) and those that had a functional limitation resulting from their diabetes (OR=1.74, 95%CI 1.09-2.8) had greater odds of using CM than those not reporting these measures. No significant associations were observed between overall CM use and other individual measures of diabetes severity: use of diabetic medications, weak or failing kidneys, coronary heart disease, or severe vision problems. CONCLUSIONS: Our results demonstrate that individuals with more severe diabetes are more likely to use CM independent of sociodemographic factors. Further studies are essential to determine if CM therapies actually improve clinical outcomes when used to treat/manage diabetes. PMID- 23088707 TI - Three year follow-up of an early childhood intervention: is movement skill sustained? AB - BACKGROUND: Movement skill competence (e.g. the ability to throw, run and kick) is a potentially important physical activity determinant. However, little is known about the long-term impact of interventions to improve movement skills in early childhood. This study aimed to determine whether intervention preschool children were still more skill proficient than controls three years after a 10 month movement skill focused intervention: 'Tooty Fruity Vegie in Preschools'. METHODS: Children from 18 intervention and 13 control preschools in NSW, Australia were assessed at ages four (Time1), five (T2) and eight years (T3) for locomotor (run, gallop, hop, leap, horizontal jump, slide) and object control proficiency (strike, bounce, catch, kick, overhand throw, underhand roll) using the Test of Gross Motor Development-2. Multi-level object control and locomotor regression models were fitted with variables time, intervention (yes/no) and a time*intervention interaction. Both models added sex of child and retained if significant, in which case interactions of sex of child with other variables were modelled and retained. SPSS (Version 17.0) was used. RESULTS: Overall follow-up rate was 29% (163/560). Of the 137 students used in the regression models, 53% were female (n = 73). Intervention girls maintained their object control skill advantage in comparison to controls at T3 (p = .002), but intervention boys did not (p = .591). At T3, there were no longer intervention/control differences in locomotor skill (p = .801). CONCLUSION: Early childhood settings should implement movement skill interventions and more intensively target girls and object control skills. PMID- 23088708 TI - Development of a biochemical oxygen demand sensor using gold-modified boron doped diamond electrodes. AB - Gold-modified boron doped diamond (BDD) electrodes were examined for the amperometric detection of oxygen as well as a detector for measuring biochemical oxygen demand (BOD) using Rhodotorula mucilaginosa UICC Y-181. An optimum potential of -0.5 V (vs Ag/AgCl) was applied, and the optimum waiting time was observed to be 20 min. A linear calibration curve for oxygen reduction was achieved with a sensitivity of 1.4 MUA mg(-1) L oxygen. Furthermore, a linear calibration curve in the glucose concentration range of 0.1-0.5 mM (equivalent to 10-50 mg L(-1) BOD) was obtained with an estimated detection limit of 4 mg L(-1) BOD. Excellent reproducibility of the BOD sensor was shown with an RSD of 0.9%. Moreover, the BOD sensor showed good tolerance against the presence of copper ions up to a maximum concentration of 0.80 MUM (equivalent to 50 ppb). The sensor was applied to BOD measurements of the water from a lake at the University of Indonesia in Jakarta, Indonesia, with results comparable to those made using a standard method for BOD measurement. PMID- 23088709 TI - Anatomic single-bundle anterior cruciate ligament reconstruction in Asian population. AB - BACKGROUND: Non-anatomic tunnel placement, which leads to failure in double bundle anterior cruciate ligament (ACL), has focused greater attention on single bundle ACL reconstruction. However, single-bundle ACL with 2- to 4-strand autogenous hamstring tendon graft always showed weak graft strength. METHODS: To solve this problem, single-bundle ACL with 6-strand autogenous hamstring tendon graft was performed on 32 Asian patients in this study. At 24 months post operatively, all patients were evaluated with Lysholm knee scores, Tegner activity level and KT-1000 examinations. RESULTS: The results demonstrated that no patients showed knee extension limitation. Of the 32 patients, there were 26 negative and 6 positive 1 degrees in Lachman test; 31 negative and 1 positive 1 degrees in pivot-shift test. There were four patients with a 5 degrees flexion limitation. The median Lysholm score increased from 45 preoperatively to 92 post operatively (P < 0.001). The median Tegner sport level score increased from 1 preoperatively to 4 post-operatively (P < 0.001). KT-1000 examination revealed that the median anterior laxity at 25 degrees of flexion was 6.3 mm preoperatively and 1.7 mm post-operatively (P < 0.001). CONCLUSIONS: The data showed that arthroscopic central anatomic single-bundle ACL reconstruction with 6 strand autogenous hamstring tendon graft is a reliable method to restore stabilization and function of the knee. PMID- 23088710 TI - Individualized tumor response testing profile has a prognostic value in childhood acute leukemias: multicenter non-interventional long-term follow-up study. AB - A total number of 817 children with acute lymphoblastic leukemia (ALL) and 181 with acute myeloblastic leukemia (AML) were assessed for individualized tumor response testing (ITRT) profile as a prognostic factor in long-term follow-up. For each patient, ITRT, initial response to therapy and long-term outcome were assessed. In initial ALL, an impact on long-term response was shown in ITRT for 13 drugs, while in initial AML only for cytarabine. For patients with ALL, a combined five-drug ITRT profile for prednisolone, l-asparaginase, vincristine, cytarabine and daunorubicin or doxorubicin had predictive value for probability of disease-free survival (pDFS) in univariate analysis, whereas in multivariate analysis, bone marrow response by day 33 was the only prognostic factor. For patients with AML, no factor had prognostic value for pDFS in univariate analysis, while ITRT to cytarabine almost reached significance. In conclusion, ITRT can possibly be regarded as a risk factor in childhood acute leukemias. PMID- 23088712 TI - Effects of current physical activity on affective response to exercise: physical and social-cognitive mechanisms. AB - Affective responses during exercise are often important determinants of exercise initiation and maintenance. Current physical activity may be one individual difference that is associated with the degree to which individuals have positive (or negative) affective experiences during exercise. The objective of this study was to explore physical and cognitive explanations of the relationship between current activity status (more versus less active) and affective response during a 30-minute bout of moderate-intensity exercise. Participants reported their current level of physical activity, exercise self-efficacy and affect during a 30 minute bout of moderate-intensity exercise. More active individuals experienced higher levels of positive affect and tranquillity and lower levels of negative affect and fatigue during exercise. Multivariate models for each affective state indicated separate processes through which physical activity may be associated with changes in affect during exercise. These models indicate that affect experienced during physical activity is related to the current activity level and these relationships can be partially explained by the physical and cognitive factors explored in this study. Recommendations for future research to elucidate whether positive affective response to physical activity improves as a function of becoming more active over time are discussed. PMID- 23088714 TI - A specific combination of zeaxanthin, spermidine and rutin prevents apoptosis in human dermal papilla cells. AB - Hair follicle (HF) regression is characterized by the activation of apoptosis in HF cells. Dermal papilla cells play a leading role in the regulation of HF development and cycling. Human follicular dermal papilla cells (HFDPC) were used to investigate the protective activities of rutin, sperimidine and zeaxanthine. HFDP cell incubation with staurosporine caused apoptosis, which was completely inhibited by exposure to rutin (2.2 MUM), spermidine (1 MUM) and zeaxanthin (80 MUM). These agents were much less effective when applied as single compounds. Moreover, treatment preserved the expression of anti-apoptotic molecules such as Bcl-2, MAP-kinases and their phosphorylated forms. In conclusion, the investigated agents may represent an effective treatment for the prevention of apoptosis, one of the leading events involved in hair bulb regression. PMID- 23088713 TI - Protein interactions of the transcription factor Hoxa1. AB - BACKGROUND: Hox proteins are transcription factors involved in crucial processes during animal development. Their mode of action remains scantily documented. While other families of transcription factors, like Smad or Stat, are known cell signaling transducers, such a function has never been squarely addressed for Hox proteins. RESULTS: To investigate the mode of action of mammalian Hoxa1, we characterized its interactome by a systematic yeast two-hybrid screening against ~12,200 ORF-derived polypeptides. Fifty nine interactors were identified of which 45 could be confirmed by affinity co-purification in animal cell lines. Many Hoxa1 interactors are proteins involved in cell-signaling transduction, cell adhesion and vesicular trafficking. Forty-one interactions were detectable in live cells by Bimolecular Fluorescence Complementation which revealed distinctive intracellular patterns for these interactions consistent with the selective recruitment of Hoxa1 by subgroups of partner proteins at vesicular, cytoplasmic or nuclear compartments. CONCLUSIONS: The characterization of the Hoxa1 interactome presented here suggests unexplored roles for Hox proteins in cell-to cell communication and cell physiology. PMID- 23088715 TI - The Sexual Disgust Questionnaire; a psychometric study and a first exploration in patients with sexual dysfunctions. AB - INTRODUCTION: Disgust may be involved in sexual problems by disrupting sexual arousal and motivating avoidance of sexual intercourse. To test whether heightened disgust for sexual contaminants is related to sexual dysfunctions, the Sexual Disgust Questionnaire (SDQ) has recently been developed. Previous research showed that particularly women with vaginismus display a generally heightened dispositional disgust propensity and heightened disgust toward stimuli depicting sexual intercourse. AIM: To determine the psychometric properties of the SDQ and test whether heightened disgust toward sexual stimuli is specific to vaginismus or can be observed in other sexual dysfunctions as well. METHODS: First, a large sample of undergraduates and university employees completed the SDQ (N = 762) and several trait disgust indices. Next, women with vaginismus (N = 39), dyspareunia (N = 45), and men with erectile disorder (N = 28) completed the SDQ and were compared to participants without sexual problems (N = 70). MAIN OUTCOME MEASURE: SDQ to index sexual disgust. RESULTS: The SDQ proved a valid and reliable index to establish disgust propensity for sexual stimuli. Supporting construct validity of the SDQ, sexual disgust correlated with established trait indices. Furthermore, sexual disgust and willingness to handle sexually contaminated stimuli were associated with sexual functioning in women, but not in men. Specifically women with vaginismus displayed heightened sexual disgust compared to women without sexual problems, while men with erectile disorders demonstrated a lower willingness to handle sexually contaminated stimuli compared to men without sexual problems. CONCLUSIONS: The SDQ appears a valid and reliable measure of sexual disgust. The pattern of SDQ-scores across males and females with and without sexual dysfunctions corroborates earlier research suggesting that disgust appraisals are involved especially in vaginismus and supports the view that the difficulty with vaginal penetration experienced by women in vaginismus may partly be due to disgust-induced defensive reflexes that could disrupt sexual arousal. PMID- 23088716 TI - Iodocyclization of o-alkynylbenzamides revisited: formation of isobenzofuran 1(3H)-imines and 1H-isochromen-1-imines instead of lactams. AB - The iodocyclization of o-alkynylbenzamides with various electrophiles has been reported to yield five- or six-membered lactams by nucleophilic attack of the amide nitrogen onto the triple bond. While the formation of an isobenzofuran 1(3H)-imine with two bulky substituents under Larock conditions was initially attributed to steric hindrance, we found out that cyclization via the amide oxygen is the rule rather than the exception. Thus, the structures of the products reported in the literature need to be revised. PMID- 23088717 TI - Synthesis and bioactivity study of 2-acylamino-substituted N' benzylbenzohydrazide derivatives. AB - The discovery of new safe and effective pesticides is one of the main means of providing eco-friendly agricultural agents for modern crop protection. To identify new biological molecules based of the anthranilic diamide skeleton of the novel pesticide chlorantraniliprole, which acts on the ryanodine receptor and functional groups in acyl hydrazine insect growth regulators, more than 40 new compounds of 2-acylamino-substituted N'-benzylbenzohydrazide derivatives were designed and synthesized. The structures of the new compounds were characterized using (1)H nuclear magnetic resonance (NMR), high-resolution mass spectrometry (HRMS), or electron impact mass spectrometry (EI-MS), and their biological activities at a concentration of 600 mg L(-1) were determined against cotton aphid (Aphis gossypii Glover), carmine spider mite (Tetranychus cinnabarinus), and diamondback moth (Plutella xylostella). The results of a preliminary assay showed that compounds 6a-I-2 and 6d-III-4 maintained the lethal activity of anthranilic diamide against P. xylostella; compounds 6c-II-4, 6d-I-7, 6d-II-1, and 6d-III-5 exhibited good lethal activity against A. gossypii; and compounds 6a II-1, 6a-III-1, 6b-I-7, 6c-I-1, and 6c-III-5 retained promising larvicidal activities against T. cinnabarinus. In subsequent further tests against T. cinnabarinus, compounds 6a-II-1, 6a-III-1, 6c-I-1, and 6c-III-5 showed an LC(50) value of <90 mg L(-1); especially, the LC(50) of compound 6a-III-1 was only 27.9 mg L(-1). In conclusion, the introduction of the functional fragment-substituted acyl hydrazine improved the acaricidal activity of the anthranilic diamide skeleton, and the halogen atom at X position and the methyl group at R(1) play crucial roles in the biological activities of the compounds. PMID- 23088718 TI - Bone health in children with long-term idiopathic subclinical hypothyroidism. AB - BACKGROUND: Subclinical hypothyroidism (SH) is a relatively common condition characterized by a mild persistent thyroid failure. The management of children with SH is still a controversial issue and the decision to treat with L-thyroxine represents a clinical dilemma. Thyroid hormone and TSH play an important role in skeletal growth and bone mineral homeostasis. AIM: To evaluate whether untreated idiopathic SH may affect bone health in childhood and to compare two different diagnostic tools such as dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS). PATIENTS AND METHODS: Twenty-five children and adolescents (11 males) aged 9.8 +/- 3.5 years (range 4.2-18.7) with untreated idiopathic SH were enrolled in the study. SH was diagnosed on the basis of normal FT4 levels with TSH concentrations between 4.2 and 10 mU/l. Children have been followed for 3.3 +/- 0.3 years from the time of SH diagnosis. Twenty-five healthy children, age- and sex-matched, were enrolled as controls. Patients and controls underwent DXA to evaluate lumbar spine bone mineral density (BMD) and QUS at proximal phalanges of the non-dominant hand to assess bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) and bone transmission time (BTT). RESULTS: Mean BMD Z score was -0.4 +/- 1.36 in patients and -0.2 +/- 1.2 in controls. Mean Ad-SoS Z score was 0.01 +/- 1.0 in patients and 0.1 +/- 1.2 in controls and mean BTT Z score was -0.03 +/- 0.8 and 0.04 +/- 1.1 respectively. All values were within the normal range, both in patients and in controls. There were no statistically significant differences between the two groups. CONCLUSION: Bone health, evaluated by lumbar spine DXA and phalangeal QUS, is not impaired in our children, despite long-term duration of idiopathic SH. Data about bone status provided by QUS are comparable to those provided by DXA. Therefore, QUS may represent a good, cheaper and safe screening test for bone evaluation in children with SH. PMID- 23088719 TI - Computer use and stress, sleep disturbances, and symptoms of depression among young adults--a prospective cohort study. AB - BACKGROUND: We have previously studied prospective associations between computer use and mental health symptoms in a selected young adult population. The purpose of this study was to investigate if high computer use is a prospective risk factor for developing mental health symptoms in a population-based sample of young adults. METHODS: The study group was a cohort of young adults (n = 4163), 20-24 years old, who responded to a questionnaire at baseline and 1-year follow up. Exposure variables included time spent on computer use (CU) in general, email/chat use, computer gaming, CU without breaks, and CU at night causing lost sleep. Mental health outcomes included perceived stress, sleep disturbances, symptoms of depression, and reduced performance due to stress, depressed mood, or tiredness. Prevalence ratios (PRs) were calculated for prospective associations between exposure variables at baseline and mental health outcomes (new cases) at 1-year follow-up for the men and women separately. RESULTS: Both high and medium computer use compared to low computer use at baseline were associated with sleep disturbances in the men at follow-up. High email/chat use was negatively associated with perceived stress, but positively associated with reported sleep disturbances for the men. For the women, high email/chat use was (positively) associated with several mental health outcomes, while medium computer gaming was associated with symptoms of depression, and CU without breaks with most mental health outcomes. CU causing lost sleep was associated with mental health outcomes for both men and women. CONCLUSIONS: Time spent on general computer use was prospectively associated with sleep disturbances and reduced performance for the men. For the women, using the computer without breaks was a risk factor for several mental health outcomes. Some associations were enhanced in interaction with mobile phone use. Using the computer at night and consequently losing sleep was associated with most mental health outcomes for both men and women. Further studies should focus on mechanisms relating information and communication technology (ICT) use to sleep disturbances. PMID- 23088720 TI - Switching orientation of two axial imidazole ligands between parallel and perpendicular in low-spin Fe(III) and Fe(II) nonplanar porphyrinates. AB - We have reported here the synthesis, structure, and properties of low-spin bis imidazole-coordinated Fe(III) and Fe(II) complexes of 5,10,15,20 tetrakis(pentafluorophenyl)-2,3,7,8,12,13,17,18-octachloroporphyrin, [Fe(III)(TFPPCl(8))(L)(2)]ClO(4) and Fe(II)(TFPPCl(8))(L)(2) (L = 1 methylimidazole, 4-methylimidazole, imidazole). The X-ray structure of Fe(II)(TFPPCl(8))(1-MeIm)(2) is reported here, which demonstrated the near perpendicular axial ligand orientation (dihedral angle between two 1 methylimidazoles is 80.7 degrees ) for Fe(II) porphyrins in a highly saddle distorted macrocyclic environment. Oxidation of Fe(II)(TFPPCl(8))(L)(2) using thianthrenium perchlorate produces [Fe(III)(TFPPCl(8))(L)(2)]ClO(4), which was also isolated in the solid state and characterized spectroscopically. The complex gives rhombic EPR spectra in both solid and solution phases at 77 K and thus represents a rare example of nearly parallel axial ligand orientations for the unhindered imidazoles in a saddle-distorted porphyrin macrocycle. Geometry optimization using DFT also converged to the parallel axial alignment when 1 methylimidazole was used as the axial ligand (the dihedral angle between two axial ligands is 8.6 degrees ). The potential energy surface (PES) scan results also show that the relatively parallel axial orientations are energetically preferred for Fe(III), while perpendicular orientations are preferred for the Fe(II) complexes reported here. Bulk oxidation of Fe(II)(TFPPCl(8))(L)(2) in dichloromethane at a constant potential under nitrogen converts it to [Fe(III)(TFPPCl(8))(L)(2)]ClO(4), which gives identical EPR spectra at 77 K and which upon reduction regenerates Fe(II)(TFPPCl(8))(L)(2) again. Thus, we have demonstrated here very rare examples of Fe porphyrins in which the relative axial imidazole orientations switch between parallel and perpendicular just upon changing the oxidation states of iron from +3 to +2, respectively, in a nonplanar porphyrinic environment. These observations could be immensely important for understanding the possible effects of axial histidine orientations on similar macrocyclic deformations observed in various heme proteins. PMID- 23088721 TI - The comparison of the relationship between sociocultural-economic features and sexual dysfunction frequency in sexually active premenopausal female patients on renal replacement therapy. AB - INTRODUCTION: Many studies determine different risk factors for sexual dysfunction (SD) in women, but little is known about the influence of socioeconomic and cultural factors, medical and psychological features on female SD frequency in patients under renal replacement therapy (RRT). AIM: This study aimed to compare the relationship between medical, psychological, sociocultural economic factors, and SD frequency in patients on RRT with the diagnosis of end stage renal disease. METHOD: The 115 RRT patients (hemodialysis [HD] 39, peritoneal dialysis [PD] 43, kidney transplant [KT] 33) and 103 healthy premenopausal female volunteers (control) without any known health problems were included in the study. MAIN OUTCOME MEASURES: The questionnaire forms containing sociodemographic data, the hospital anxiety depression scale, and Arizona Sexual Experiences Scale were completely filled by subjects who were included in the study. RESULTS: There was no significant difference about mean age, dialysis duration, and body mass index between the groups. While there were significant differences among participants training period and employment conditions, socioeconomic status scores were similar. Significant differences were found in marriage type, marital duration, husband's age, training period and working time per week, spending time with each other, weekly sexual intercourse frequency, the number of children, mothers' and fathers' education. RRT groups were more depressed than control, but no significant differences were observed among the RRT groups. PD and HD groups were more anxious than the KT and control groups. It was identified that SD rates were higher in KT and dialysis patients compared with the control. SD rates were significantly high in the HD group. Multivariate analysis showed that marital duration and being an HD patient are independent SD risk factors for RRT population. CONCLUSIONS: Successful KT may improve SD. Differences in sociocultural, economic, medical, and psychological factors among individuals with SD should be taken into consideration in their treatment management. PMID- 23088722 TI - Mortality rates after surgery in New South Wales. AB - BACKGROUND: Studies have been conducted to determine 30-day and 365-day mortality rates after surgical procedures in different regions; however, there is a lack of data for mortality rates in New South Wales (NSW), Australia. The aim of this study was to determine 30-day and 365-day post-operative mortality rates after selected common operations performed in NSW. METHODS: Using the Centre for Health Record Linkage, we linked the NSW Admitted Patient Data Collection with the NSW Registry of Births, Deaths and Marriages and Australian Bureau of Statistics to retrospectively calculate 30-day and 365-day post-operative mortality rates for 21 selected surgical procedures between 2000 and 2009. One year (365 days) standardized mortality ratios, and proportion of public and private hospital admissions and mortality, were calculated for each procedure. RESULTS: Thirty-day mortality was lower than in previous studies for femur fracture fixation (3.7%), cervical spine fusion (0.8%), prostatectomy (0.2%), coronary valve replacement (4.2%), pulmonary resection (2.5%), bariatric surgery (0.07%) and pancreaticoduodenectomy (6.2%). Thirty-day mortality was higher than previously reported for abdominal aortic aneurysm (12.6%) and tonsillectomy (0.02%). One year mortality rates ranged from 0.2% for tonsillectomy and bariatric surgery, to 24.6% for hip fracture fixation. CONCLUSIONS: Thirty-day mortality rates in NSW are similar, if not lower for most procedures when compared with rates reported in other studies. The reported mortality rates for each procedure allow clinicians and patients to be more informed of surgical risks. PMID- 23088723 TI - Professor Christopher S. Potten (1940-2012). PMID- 23088724 TI - Guillain-Barre syndrome after human herpesvirus-6 reactivation in unrelated hematopoietic stem cell transplantation. PMID- 23088725 TI - Anatomy teaching with portable ultrasound to medical students. AB - BACKGROUND: Medical students as future clinicians will apply their anatomy knowledge in medical imaging. There are various radiological resources available for the medical students to learn anatomy and contextualise it to the clinical setting. Ultrasound is a safe and non- invasive imaging procedure commonly used in clinical practice. This study aimed to use portable ultrasound and evaluate its impact as an adjunct to cadaveric anatomy teaching together with cross sectional anatomy images and line diagrams. METHODS: Ultrasound teaching was incorporated into upper limb and lower limb anatomy practical dissecting room sessions. The number of medical students who participated was 121 students from the year 2008 - 2009 and 94 students from the year 2009- 2010. The students were divided into groups of 15-20. Initially ultrasound demonstration was carried out on a volunteer and then the students were given the opportunity to use the ultrasound and identify normal anatomical structures visualized on images. For the students in the year 2009- 2010, ultrasound teaching was supplemented with cross sectional anatomy images and line diagrams. Questionnaires were distributed with seven questions rated using four point Likert scale and free text. Qualitative data was analysed using 2- proportion Z test and Fischer's exact test. RESULTS: The number of students in the 2009-2010 year group who were confident in interpreting ultrasound images increased significantly when compared to the 2008-2009 year group of students. The majority of students were able to identify structures like bone, muscles and blood vessels on ultrasound images. There was a significant increase in the number of students who found the ultrasound teaching useful and also those who regarded ultrasound to have improved understanding of anatomy considerably. CONCLUSIONS: Ultrasound acts as a useful adjunct to teach anatomy in a clinical context to medical students. The use of cross sectional anatomy images and line diagrams together can aid ultrasound image orientation of structures during these sessions. Early exposure to this imaging technology may prime students for later encounters with ultrasound during clinical practice. PMID- 23088726 TI - Relative recovery over time - an in vivo microdialysis study of human skeletal muscle. AB - BACKGROUND: The microdialysis technique is a method for sampling endogenous molecules from the interstitial compartments of varying tissues and relies on diffusion of molecules between the tissue and a perfusate via a membrane. Such samples do not allow determination of the true interstitial concentration but only a certain percentage. This gives rise to one of the most crucial parameter that needs to be considered for a dependable microdialysis; the relative recovery. Relative recovery states the efficiency of which an analyte is extracted from its external medium. Aim. To investigate the relative recovery of small molecules (< 20 kDa) such as lactate, fluid recovery and the reproducibility of the relative recovery at group and individual level of the microdialysis technique applied in muscle. MATERIALS AND METHODS: Using in vivo microdialysis of the trapezius muscle of 65 women from two separate occasions 4-6 months apart. Relative recovery of small molecules was measured from samples collected every 20 min during a period of 220 min. RESULTS: Good reproducibility at group level of catheters with cut-offs 100 and 20kDa were found. Furthermore, there was a high and steady relative recovery with an overall good fluid recovery. Poor reproducibility was found at the individual level for both catheters. CONCLUSIONS: This study demonstrates that when using microdialysis in skeletal muscle relative recovery is stable over time and is not affected by low force exercise. Although there is a good reproducibility at group level this is not the case at the individual level. Thus in vivo, the relative recovery should be determined for each test subject and at each test occasion. PMID- 23088727 TI - A model to test how ticks and louping ill virus can be controlled by treating red grouse with acaricide. AB - Ticks are the most important vectors of disease-causing pathogens in Europe. In the U.K., Ixodes ricinus L. (Ixodida: Ixodidae) transmits louping ill virus (LIV; Flaviviridae), which kills livestock and red grouse, Lagopus lagopus scoticus Lath. (Galliformes: Phasianidae), a valuable game bird. Tick burdens on grouse have been increasing. One novel method to reduce ticks and LIV in grouse may be acaricide treatment. Here, we use a mathematical model parameterized with empirical data to investigate how the acaricide treatment of grouse might theoretically control ticks and LIV in grouse. Assuming a situation in which ticks and LIV impact on the grouse population, the model predicts that grouse density will depend on deer density because deer maintain the tick population. In low deer densities, no acaricide treatment is predicted to be necessary because abundances of grouse will be high. However, at higher deer densities, the model predicts that grouse densities will increase only if high numbers of grouse are treated, and the efficacy of acaricide is high and lasts 20 weeks. The qualitative model predictions may help to guide decisions on whether to treat grouse or cull deer depending on deer densities and how many grouse can be treated. The model is discussed in terms of practical management implications. PMID- 23088729 TI - Uncertainty estimates for electron probe X-ray microanalysis measurements. AB - It has been over 60 years since Castaing (Castaing, R. Application of Electron Probes to Local Chemical and Crystallographic Analysis. Ph.D. Thesis, University of Paris, Paris, France, 1951; translated by P. Duwez and D. Wittry, California Institute of Technology, 1955) introduced the technique of electron probe X-ray microanalysis (EPMA), yet the community remains unable to quantify some of the largest terms in the technique's uncertainty budget. Historically, the EPMA community has assigned uncertainties to its measurements which reflect the measurement precision portion of the uncertainty budget and omitted terms related to the measurement accuracy. Yet, in many cases, the precision represents only a small fraction of the total budget. This paper addresses this shortcoming by considering two significant sources of uncertainty in the quantitative matrix correction models--the mass absorption coefficient, [MU/rho], and the backscatter coefficient, eta. Understanding the influence of these sources provides insight into the utility of EPMA measurements, and equally important, it allows practitioners to develop strategies to optimize measurement accuracy by minimizing the influence of poorly known model parameters. PMID- 23088728 TI - Exploring the dominant role of Cav1 channels in signalling to the nucleus. AB - Calcium is important in controlling nuclear gene expression through the activation of multiple signal-transduction pathways in neurons. Compared with other voltage-gated calcium channels, Ca(V)1 channels demonstrate a considerable advantage in signalling to the nucleus. In this review, we summarize the recent progress in elucidating the mechanisms involved. Ca(V)1 channels, already advantaged in their responsiveness to depolarization, trigger communication with the nucleus by attracting colocalized clusters of activated CaMKII (Ca(2+)/calmodulin-dependent protein kinase II). Ca(V)2 channels lack this ability, but must work at a distance of >1 MUm from the Ca(V)1-CaMKII co clusters, which hampers their relative efficiency for a given rise in bulk [Ca(2+)](i) (intracellular [Ca(2+)]). Moreover, Ca(2+) influx from Ca(V)2 channels is preferentially buffered by the ER (endoplasmic reticulum) and mitochondria, further attenuating their effectiveness in signalling to the nucleus. PMID- 23088730 TI - Histrionicotoxin alkaloids finally detected in an ant. AB - Workers of the ant Carebarella bicolor collected in Panama were found to have two major poison-frog alkaloids, cis- and trans-fused decahydroquinolines (DHQs) of the 269AB type, four minor 269AB isomers, two minor 269B isomers, and three isomers of DHQ 271D. For the first time in an ant, however, the DHQs were accompanied by six histrionicotoxins (HTXs), viz., 283A, 285A, 285B, 285C, 287A, and 287D. This co-occurrence of the HTX and DHQ alkaloids is the usual pattern seen in dendrobatid frogs. This finding contrasts with our earlier study, where workers of a Brazilian ant, Solenopsis (Diplorhoptrum) sp., were found to have a very similar DHQ complex but failed to show HTXs. Several new DHQ alkaloids of MW 271 (named in the frog as 271G) are reported from the above ants that have both m/z 202 and 204 as major fragment ions, unlike the spectrum seen for the poison frog alkaloid 271D, which has only an m/z 204 base peak. Found also for the first time in skin extracts from the comparison frog Oophaga granulifera of Costa Rica is a trace DHQ of MW 273. It is coded as 273F in the frog; a different isomer is found in the ant. PMID- 23088731 TI - Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis. AB - Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08 2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other environmental factors, like carcinogen consumption, in the screening analysis. PMID- 23088732 TI - Tobacco and dental caries: a systematic review. AB - OBJECTIVE: Despite the abundance of evidence linking tobacco consumption to many oral conditions, no systematic review of the relationship with dental caries is available. The main aim of this systematic review was, therefore, to evaluate the effect of tobacco smoking on dental caries in adult smokers. MATERIALS AND METHODS: According to the PRISMA checklist, observational studies published from January 1991 to June 2011 were reviewed. The quality of evidence for each finding was rated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: Five studies, four related to dental caries and one on oral bacteria activity, were finally included in a qualitative analysis; they were all cross-sectional studies. As a result, the overall quality of evidence was poor, with two articles given a score of very low and three a score of low according to GRADE. CONCLUSIONS: Tobacco smoking was found to be associated with an increased risk of dental caries. However, the overall poor quality of studies produced no validation for such an association. Further, more extensive research on this topic and prospective studies are needed. PMID- 23088733 TI - Study of serum hepcidin in hereditary hemolytic anemias. AB - The aim of this study was to assess the level of hepcidin in hereditary chronic hemolytic anemias and to correlate the serum hepcidin levels to the need for blood transfusions (frequency of blood transfusions and the serum ferritin level). Seventy pediatric patients with hereditary chronic hemolytic anemias, attending to hematology clinics of Cairo University and Misr University for Science and Technology (MUST) hospitals were the subjects of this study [53 patients with beta-thalassemia major (beta-TM), 10 patients with beta-thalassemia intermedia (beta-TI), four patients with congenital spherocytosis and three patients with sickle cell disease) (38 males and 32 females)]; their ages ranged from 1-14 years. Seventy normal children, age- and sex-matched, served as the control group. The results of this study revealed decreased hepcidin levels in patients (all types of congenital chronic hemolytic anemias) [mean +/- SD (standard deviation) = 22.9 +/- 6.0] compared to controls (mean +/- SD = 132.4 +/ 16.7) with highly significant statistical difference in between. Hepcidin levels were higher in beta-TM patients (mean +/- SD = 23.7 +/- 6.2) than in beta-TI patients (mean +/- SD = 21.8 +/- 4.0), the hepcidin to ferritin ratio was significantly less than one. In beta-TM patients, the mean +/- SD was 0.03 +/- 0.004, and in beta-TI patients the mean +/- SD = 0.025 +/- 0.002, with highly significant statistical difference with hepcidin-to-ferritin ratios in controls being mean +/- SD = 2.3 +/- 0.7. Hepcidin and hepcidin/ferritin ratios can be used as good markers of hemolytic anemia and iron overload as they have very high sensitivity (99.0 and 99.0%, respectively) and very high specificity (98.0 and 97.0%, respectively). Our findings highlight the potential usefulness of hepcidin measurement as a diagnostic tool. The use of hepcidin as an adjuvant therapy with iron chelators is important as it has a vital role in combating hemosidrosis. PMID- 23088734 TI - Anisotropic, hierarchical surface patterns via surface wrinkling of nanopatterned polymer films. AB - By combining surface wrinkling and nanopatterned polymer films, we create anisotropic, hierarchical surfaces whose larger length-scale (wrinkling wavelength) depends intimately on the geometry and orientation of the smaller length-scale (nanopattern). We systematically vary the pattern pitch, pattern height, and residual layer thickness to ascertain the dependence of the wrinkling wavelength on the nanopattern geometry. We apply a composite mechanics model to gain a quantitative understanding of the relationship between the geometric parameters and the anisotropy in wrinkling wavelength. Additionally, these results shed light on the effect of surface roughness, as represented by the nanopattern, on the metrology of thin films via surface wrinkling. PMID- 23088736 TI - Insight into newly discovered innate immune modulation in atopic dermatitis. AB - Atopic dermatitis (AD) is a highly pruritic, chronic relapsing inflammatory skin disease characterized by innate and adaptive immune reactions. In AD, innate immune mechanisms such as pattern recognition receptors and antimicrobial peptides have been investigated in detail, but recently, epidermis-derived cytokines, namely thymic stromal lymphopoietin (TSLP), IL-25 and IL-33, were shown to participate in innate immune reactions independently of adaptive immunity. In addition to conventional innate cells, such as mast cells, basophils and eosinophils, Th2 cytokine-producing invariant natural killer T (iNKT) cells, innate lymphoid cells (ILCs) and Th17/Th22 cytokine-producing innate cells - iNKT cells and natural killer (NK)-like cells - can participate in innate immune modulation in AD. Accordingly, early control of innate immune responses in AD before activation of adaptive immune responses by conventional T and B cells that perpetuate chronic skin inflammation may adequately alleviate acute exacerbations of AD. Therefore, we hypothesized that select immune modulators targeting the innate immune response could potentially be used for individualized treatment of AD. PMID- 23088735 TI - Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling. AB - BACKGROUND: Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA) characterized by nightly intermittent hypoxia (IH). This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. METHODS: Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH) using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. RESULTS: Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated the IH-induced Mcl-1 increase. In SH, only p38MAPK inhibition decreased Mcl-1 expression. Similar to neutrophils of healthy subjects exposed to IH (0.97+/- 0.2), in OSA neutrophils, Bax/Mcl-1 ratio was significantly lower compared to normoxic controls (1.0+/-0.5 vs.1.99+/-0.3, p=0.015), and Bax did not co-localize with mitochondria. CONCLUSIONS: These findings suggest that decreased Bax/Mcl-1 balance promotes neutrophil survival in IH in-vitro as well as in OSA patients. Moreover, Bax/Mcl-1 protein function in IH and SH might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH. PMID- 23088737 TI - Analysis of DNA variations in GSTA and GSTM gene clusters based on the results of genome-wide data from three Russian populations taken as an example. AB - BACKGROUND: Extensive genome-wide analyses of many human populations, using microarrays containing hundreds of thousands of single-nucleotide polymorphisms, have provided us with abundant information about global genomic diversity. However, these data can also be used to analyze local variability in individual genomic regions. In this study, we analyzed the variability in two genomic regions carrying the genes of the GSTA and GSTM subfamilies, located on different chromosomes. RESULTS: Analysis of the polymorphisms in GSTA and GSTM gene clusters showed similarities in their allelic and haplotype diversities. These patterns were similar in three Russian populations and the CEU population of European origin. There were statistically significant differences in all the haploblocks of both the GSTM and GSTA regions when the Russian populations were compared with populations from China and Japan. Most haploblocks also differed between the Russians and Nigerians from Yoruba, but, some of them had similar allelic frequencies. Special attention was paid to SNP rs4986947 from the intron of the GSTA4 gene, which is represented in apes by an A nucleotide. In the Asian and African samples, it was represented only by a G allele, and both allelic variants (G/A) occurred in the Russian and European populations. CONCLUSIONS: The results obtained suggest the presence of common features in the evolutionary histories of the GSTA and GSTM gene regions, and that African subpopulations were involved differently in the formation of the European and Asian human lineages. PMID- 23088738 TI - Effect of germination on phytochemical profiles and antioxidant activity of mung bean sprouts (Vigna radiata). AB - Epidemiological studies have shown that regular consumption of fruits and vegetables is associated with reduced risk of chronic diseases. It is recommended to increase consumption of fruits and vegetables to prevent chronic diseases related to free radical-induced oxidative stress. Different varieties of fruits and vegetables provide different vitamins, phenolics, flavonoids, minerals, and dietary fibers for optimal health benefits. Mung bean sprouts are one of the major vegetables in human diet. However, the profiles of phytochemicals and effect of germination on phytochemical content and antioxidant activity of mung bean sprouts have not been studied. The objective of this study was to determine the effect of germination on phytochemical profiles and antioxidant activity of mung bean sprouts. Germination of mung beans dramatically increased vitamin C content in mung bean sprouts in a time-dependent manner and reached the peak on day 8 of germination up to 285 mg/100 g DW, almost 24 times higher than the initial concentration in mung bean seeds (p < 0.05). On fresh weight basis, one serving of mung bean sprouts (about 104 g) provides 21.6 mg of vitamin C, which could meet 36% of Daily Value (DV). In addition, the germination dramatically increased total phenolic compounds and total flavonoids in mung bean sprouts in a time-dependent manner, up to 4.5 and 6.8 times higher than the original concentration of mung bean seeds, respectively. Quercetin-3-O-glucoside content was significantly increased in mung bean sprouts after germination. The total antioxidant activity of mung bean sprouts was increased by 6 times higher than that of mung bean seeds. Therefore, the germination of mung bean sprouts significantly increased phytochemical content, vitamin C content, and antioxidant activity. PMID- 23088739 TI - Prescription of testosterone-lowering medications for sex offender treatment in German forensic-psychiatric institutions. AB - INTRODUCTION: Different clinical guidelines suggest using testosterone-lowering medications (TLM) in sex offender treatment in addition to psychotherapy. Within Germany, there are two officially approved agents. So far, no current data exist about the routine use of TLM in a clinical context. AIM: The present observational study evaluates the frequency of the prescription of TLM and other medications in sex offender treatment in German forensic-psychiatric institutions. Experts are asked about the observed effects and side effects of TLM. METHOD: The heads of all 69 German forensic-psychiatric hospitals and outpatient clinics were asked to fill out a questionnaire assessing offender characteristics and treatment methods in use. MAIN OUTCOME MEASURES: Main outcome measures were the number of patients being treated with TLM and other pharmacological agents for reducing sexual drive. Further effects and side effects of the agents were evaluated. RESULTS: Thirty-two participating institutions reported on 3,963 patients, 611 of them being sex offenders (15.4%). Most sex offenders had been convicted for child sexual abuse (39.8%) or a sexual assault/rape (37.6%). Almost all sex offenders were treated psychotherapeutically and 37% were receiving an additional pharmacological treatment. Of all the sex offenders, 15.7% were treated with TLM; 10.6% were treated with a gonadotropin releasing hormone agonist; and 5.1% were treated with cyproterone acetate. Of these, 26.0-75.4% showed improvements in such outcomes as reduction of frequency and/or intensity of sexual thoughts. The remaining 21.3% of sex offenders who received a pharmacological agent were treated with selective serotonin reuptake inhibitors (11.5%) or antipsychotic medications (9.8%). CONCLUSIONS: TLM are a frequently used addition to psychotherapy in sex offenders. In light of the lack of controlled clinical trials and the many side effects, benefits and risks should always be thoroughly assessed. PMID- 23088740 TI - Syntheses, structures, and properties of new manganese carbonyls as photoactive CO-releasing molecules: design strategies that lead to CO photolability in the visible region. AB - The unusual role of CO as a signaling molecule in several physiological pathways has spurred research in the area of synthesizing new CO-releasing molecules (CORMs) as exogenous CO donors. Auxiliary control on CO delivery can be achieved if CO can be released under the control of light. To synthesize such photoactive CORMs (photoCORMs) with the aid of smart design, a series of manganese carbonyls have been synthesized with ligands that contain extended conjugation and electron rich donors on their frames. Five such photoCORMs, namely, [Mn(pimq)(CO)(3)(MeCN)]ClO(4) (1, where pimq = (2-phenyliminomethyl)quinoline), [Mn(qmtpm)(CO)(3)(MeCN)]ClO(4) (2, where qmtpm = 2-quinoline-N-(2' methylthiophenyl) methyleneimine), [Mn(qmtpm)(CO)(3)Br] (3) [Mn(pmtpm)(CO)(3)(MeCN)]ClO(4) (4, where pmtpm = 2-pyridyl-N-(2' methylthiophenyl)methyleneimine), and [Mn(pmtpm)(CO)(3)Br] (5), have been synthesized and structurally characterized. These designed carbonyls readily release CO upon exposure to light (400-550 nm). The apparent CO release rates and quantum yield values at 509 nm (phi(509)) of the photoCORMs increase steadily with rise in conjugation in the ligand frame and inclusion of a -SMe group. Addition of Br(-) as an ancillary ligand also improves the CO-donating capacity. Results of density functional theory (DFT) and time dependent DFT (TDDFT) studies indicate that low energy metal-to-ligand charge transfer (MLCT) transitions from Mn-CO bonding into ligand-pi orbitals lead to reduction of M-CO(pi*) back-bonding and loss of CO from these photoCORMs. Inclusion of -SMe and Br(-) in the coordination sphere attenuates the energies of the HOMO and LUMO levels and causes further enhancement of CO photorelease. Collectively, the results of this work demonstrate that new photoCORMs with excellent sensitivity to visible light can be synthesized on the basis of smart design principles. PMID- 23088741 TI - Complete genome, catabolic sub-proteomes and key-metabolites of Desulfobacula toluolica Tol2, a marine, aromatic compound-degrading, sulfate-reducing bacterium. AB - Among the dominant deltaproteobacterial sulfate-reducing bacteria (SRB), members of the genus Desulfobacula are not only present in (hydrocarbon-rich) marine sediments, but occur also frequently in the anoxic water bodies encountered in marine upwelling areas. Here, we present the 5.2 Mbp genome of Desulfobacula toluolica Tol2, which is the first of an aromatic compound-degrading, marine SRB. The genome has apparently been shaped by viral attacks (e.g. CRISPRs) and its high plasticity is reflected by 163 detected genes related to transposases and integrases, a total of 494 paralogous genes and 24 group II introns. Prediction of the catabolic network of strain Tol2 was refined by differential proteome and metabolite analysis of substrate-adapted cells. Toluene and p-cresol are degraded by separate suites of specific enzymes for initial arylsuccinate formation via addition to fumarate (p-cresol-specific enzyme HbsA represents a new phylogenetic branch) as well as for subsequent modified beta-oxidation of arylsuccinates to the central intermediate benzoyl-CoA. Proteogenomic evidence suggests specific electron transfer (EtfAB) and membrane proteins to channel electrons from dehydrogenation of both arylsuccinates directly to the membrane redox pool. In contrast to the known anaerobic degradation pathways in other bacteria, strain Tol2 deaminates phenylalanine non-oxidatively to cinnamate by phenylalanine ammonia-lyase and subsequently forms phenylacetate (both metabolites identified in (13) C-labelling experiments). Benzoate degradation involves CoA activation, reductive dearomatization by a class II benzoyl-CoA reductase and hydrolytic ring cleavage as found in the obligate anaerobe Geobacter metallireducens GS-15. The catabolic sub-proteomes displayed high substrate specificity, reflecting the genomically predicted complex and fine-tuned regulatory network of strain Tol2. Despite the genetic equipment for a TCA cycle, proteomic evidence supports complete oxidation of acetyl-CoA to CO2 via the Wood-Ljungdahl pathway. Strain Tol2 possesses transmembrane redox complexes similar to that of other Desulfobacteraceae members. The multiple heterodisulfide reductase-like proteins (more than described for Desulfobacterium autotrophicum HRM2) may constitute a multifaceted cytoplasmic electron transfer network. PMID- 23088742 TI - Change in healthcare utilization and costs following initiation of benzodiazepine therapy for long-term treatment of generalized anxiety disorder: a retrospective cohort study. AB - BACKGROUND: Selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and benzodiazepine anxiolytics are used in the US to treat generalized anxiety disorder (GAD). While benzodiazepines typically provide rapid symptomatic relief, long-term use is not recommended due to risks of dependency, sedation, falls, and accidents. METHODS: Using a US health insurance database, we identified all persons with GAD (ICD-9-CM diagnosis code 300.02) who began a long term course of treatment (>= 90 days) with a benzodiazepine anxiolytic between 1/1/2003 and 12/31/2007, We compared healthcare utilization and costs over the six-month periods preceding and following the date of treatment initiation ("pretreatment" and "post-treatment", respectively), and focused attention on accident-related encounters (e.g., for treatment of fractures) and care received for other reasons possibly related benzodiazepine use (e.g., sedation, dizziness). RESULTS: A total of 866 patients met all study entry criteria; 25% of patients began treatment on an add-on basis (i.e., adjunctive to escitalopram, paroxetine, sertraline, or venlafaxine), while 75% of patients did not receive concomitant therapy. Mean total healthcare costs increased by $2334 between the pretreatment and post-treatment periods (from $4637 [SD=$9840] to $6971 [$17,002]; p<0.01); costs of accident-related encounters and other care that was possibly related to use of benzodiazepines increased by an average of $1099 ($1757 [$7656] vs $2856 [$14,836]; p=0.03). CONCLUSIONS: Healthcare costs increase in patients with GAD beginning long-term (>= 90 days) treatment with a benzodiazepine anxiolytic; a substantial proportion of this increase is attributable to care associated with accidents and other known sequelae of long term benzodiazepine use. PMID- 23088743 TI - Evidence-based pain management: is the concept of integrative medicine applicable? AB - This article is dedicated to the concept of predictive, preventive, and personalized (integrative) medicine beneficial and applicable to advance pain management, overviews recent insights, and discusses novel minimally invasive tools, performed under ultrasound guidance, enhanced by model-guided approach in the field of musculoskeletal pain and neuromuscular diseases. The complexity of pain emergence and regression demands intellectual-, image-guided techniques personally specified to the patient. For personalized approach, the combination of the modalities of ultrasound, EMG, MRI, PET, and SPECT gives new opportunities to experimental and clinical studies. Neuromuscular imaging should be crucial for emergence of studies concerning advanced neuroimaging technologies to predict movement disorders, postural imbalance with integrated application of imaging, and functional modalities for rehabilitation and pain management. Scientific results should initiate evidence-based preventive movement programs in sport medicine rehabilitation. Traditional medicine and mathematical analytical approaches and education challenges are discussed in this review. The physiological management of exactly assessed pathological condition, particularly in movement disorders, requires participative medical approach to gain harmonized and sustainable effect. PMID- 23088744 TI - Immune reconstitution after combined haploidentical and umbilical cord blood transplant. AB - Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplant, but delayed myeloid and lymphoid immune reconstitution leads to increased risk of infections. We recently reported the clinical results of 45 patients enrolled on a pilot study combining UCB with a human leukocyte antigen (HLA)-haploidentical donor with reduced-intensity conditioning who showed rapid neutrophil and platelet recovery. We report here preliminary immune reconstitution data of these patients. Patients were assessed for lymphocyte subsets, T-cell diversity, Cylex ImmuKnow assay and serological response to pneumococcal vaccination. Natural killer (NK)-cell and B-cell reconstitution were rapid at 1 month and 3 months, respectively. T-cell recovery was delayed, with a gradual increase in the number of T-cells starting around 6 months post transplant, and was characterized by a diverse polyclonal T-cell repertoire. Overall, immune reconstitution after haplo-cord transplant is similar to that seen after cord blood transplant, despite infusion of much lower cord blood cell dose. PMID- 23088745 TI - Comparing hospital mortality--how to count does matter for patients hospitalized for acute myocardial infarction (AMI), stroke and hip fracture. AB - BACKGROUND: Mortality is a widely used, but often criticised, quality indicator for hospitals. In many countries, mortality is calculated from in-hospital deaths, due to limited access to follow-up data on patients transferred between hospitals and on discharged patients. The objectives were to: i) summarize time, place and cause of death for first time acute myocardial infarction (AMI), stroke and hip fracture, ii) compare case-mix adjusted 30-day mortality measures based on in-hospital deaths and in-and-out-of hospital deaths, with and without patients transferred to other hospitals. METHODS: Norwegian hospital data within a 5-year period were merged with information from official registers. Mortality based on in-and-out-of-hospital deaths, weighted according to length of stay at each hospital for transferred patients (W30D), was compared to a) mortality based on in-and-out-of-hospital deaths excluding patients treated at two or more hospitals (S30D), and b) mortality based on in-hospital deaths (IH30D). Adjusted mortalities were estimated by logistic regression which, in addition to hospital, included age, sex and stage of disease. The hospitals were assigned outlier status according to the Z-values for hospitals in the models; low mortality: Z values below the 5-percentile, high mortality: Z-values above the 95-percentile, medium mortality: remaining hospitals. RESULTS: The data included 48 048 AMI patients, 47 854 stroke patients and 40 142 hip fracture patients from 55, 59 and 58 hospitals, respectively. The overall relative frequencies of deaths within 30 days were 19.1% (AMI), 17.6% (stroke) and 7.8% (hip fracture). The cause of death diagnoses included the referral diagnosis for 73.8-89.6% of the deaths within 30 days. When comparing S30D versus W30D outlier status changed for 14.6% (AMI), 15.3% (stroke) and 36.2% (hip fracture) of the hospitals. For IH30D compared to W30D outlier status changed for 18.2% (AMI), 25.4% (stroke) and 27.6% (hip fracture) of the hospitals. CONCLUSIONS: Mortality measures based on in-hospital deaths alone, or measures excluding admissions for transferred patients, can be misleading as indicators of hospital performance. We propose to attribute the outcome to all hospitals by fraction of time spent in each hospital for patients transferred between hospitals to reduce bias due to double counting or exclusion of hospital stays. PMID- 23088746 TI - Comparison of peri-operative core temperature in obese and non-obese patients. AB - Our aim was to compare peri-operative core temperatures and the incidence of hypothermia in obese and non-obese women with active forced-air warming. Twenty female patients scheduled for abdominal surgery were allocated to two groups according to body mass index. Ten obese (30.0-34.9 kg.m(-2) ) and 10 non-obese (18.5-24.9 kg.m(-2) ) women received forced-air warming on their lower limbs. At the end of surgery, the mean (SD) core temperatures were 36.7 (0.5) degrees C in the obese group and 36.0 (0.6) degrees C in the non-obese group (p < 0.001). Only in the non-obese group was there a significant decrease in the intra operative core temperature values (p < 0.001). The incidences of intra-operative hypothermia were lower in the obese group (10%) compared with non-obese group (60%; p = 0.019). In the postoperative recovery phase, the mean (SD) core temperature data were higher in the obese group than in the non-obese group (36.2 (0.4) vs 35.6 (0.5) degrees C, respectively (p < 0.001)). In conclusion, obese female patients have higher peri-operative core temperature and a lower incidence of hypothermia compared with non-obese female patients during abdominal surgery with active forced-air warming. PMID- 23088747 TI - A new life-span approach to conscientiousness and health: combining the pieces of the causal puzzle. AB - Conscientiousness has been shown to predict healthy behaviors, healthy social relationships, and physical health and longevity. The causal links, however, are complex and not well elaborated. Many extant studies have used comparable measures for conscientiousness, and a systematic endeavor to build cross-study analyses for conscientiousness and health now seems feasible. Of particular interest are efforts to construct new, more comprehensive causal models by linking findings and combining data from existing studies of different cohorts. Although methodological perils can threaten such integration, such efforts offer an early opportunity to enliven a life course perspective on conscientiousness, to see whether component facets of conscientiousness remain related to each other and to relevant mediators across broad spans of time, and to bolster the findings of the few long-term longitudinal studies of the dynamics of personality and health. A promising approach to testing new models involves pooling data from extant studies as an efficient and heuristic prelude to large-scale testing of interventions. PMID- 23088748 TI - Subcutaneous versus intravenous insulin therapy for glucose control in non diabetic trauma patients. A randomized controlled trial. AB - WHAT IS KNOWN AND OBJECTIVE: Hyperglycaemia in trauma patients admitted to the intensive care unit (ICU) is associated with increased morbidity and mortality. Our pilot study is a prospective randomized controlled trial comparing the impact of two glucose control regimens on outcomes in non-diabetic trauma patients admitted with hyperglycaemia to the ICU. METHODS: Trauma patients with blood glucose levels (BGLs) >=7.8 mm within the first 48 h of the hospital admission were randomized to receive intermittent SQ or continuous IV insulin to maintain BGLs between 4.4 and 6.1 mm. We excluded diabetics on the basis of history, or a glycosylated haemoglobin >=6% on admission. We compared the effect of SQ vs. IV insulin therapy on the ICU length of stay (ILOS). RESULTS AND DISCUSSION: A total of 58 patients were included in the study. The SQ and IV groups were comparable in terms of age, gender, injury severity, revised trauma, Glasgow coma scores and type of trauma (blunt vs. penetrating). There was no significant difference between the two treatment groups in the ILOS (3 vs. 2 days, P = 0.084), hospital length of stay (8 vs. 6, P = 0.09), ventilator support days (6 vs. 3, P = 0.98), requirement for blood transfusion (P = 0.66), rates of infections (P = 0.70), acute kidney injury (P = 0.99) and mortality (P = 0.61). WHAT IS NEW AND CONCLUSION: There was no difference between SQ and IV insulin therapy in the ILOS in non-diabetic trauma patients. PMID- 23088749 TI - A chiron approach to the total synthesis of (-)-juglomycin A, (+)-kalafungin, (+) frenolicin B, and (+)-deoxyfrenolicin. AB - A general, efficient, and common strategy for the synthesis of (-)-juglomycin A, (+)-kalafungin, (+)-frenolicin B, and (+)-deoxyfrenolicin is reported here. The strategy involves the synthesis of a key building block alkyne from a cheap chiral pool material, D-glucono-delta-lactone, Dotz benzannulation, oxa-Pictet Spengler reaction, and H(2)SO(4)-mediated epimerization. PMID- 23088751 TI - Chrolactomycins from the actinomycete actinospica. AB - Examination of the metabolites produced by an Actinospica strain led to the identification of 6-hydroxychrolactomycin (compound 1), which is produced along with minor amounts of chrolactomycin (compound 2). The structure of 1 was established on the basis of extensive spectroscopic analysis, including one- and two-dimensional NMR. Compound 1 showed antimicrobial activity against Gram positive bacteria, although it was generally less active than 2. PMID- 23088750 TI - Covalent intermediate in the catalytic mechanism of the radical S-adenosyl-L methionine methyl synthase RlmN trapped by mutagenesis. AB - The posttranscriptional modification of ribosomal RNA (rRNA) modulates ribosomal function and confers resistance to antibiotics targeted to the ribosome. The radical S-adenosyl-L-methionine (SAM) methyl synthases, RlmN and Cfr, both methylate A2503 within the peptidyl transferase center of prokaryotic ribosomes, yielding 2-methyl- and 8-methyl-adenosine, respectively. The C2 and C8 positions of adenosine are unusual methylation substrates due to their electrophilicity. To accomplish this reaction, RlmN and Cfr use a shared radical-mediated mechanism. In addition to the radical SAM CX(3)CX(2)C motif, both RlmN and Cfr contain two conserved cysteine residues required for in vivo function, putatively to form (cysteine 355 in RlmN) and resolve (cysteine 118 in RlmN) a covalent intermediate needed to achieve this challenging transformation. Currently, there is no direct evidence for this proposed covalent intermediate. We have further investigated the roles of these conserved cysteines in the mechanism of RlmN. Cysteine 118 mutants of RlmN are unable to resolve the covalent intermediate, either in vivo or in vitro, enabling us to isolate and characterize this intermediate. Additionally, tandem mass spectrometric analyses of mutant RlmN reveal a methylene-linked adenosine modification at cysteine 355. Employing deuterium labeled SAM and RNA substrates in vitro has allowed us to further clarify the mechanism of formation of this intermediate. Together, these experiments provide compelling evidence for the formation of a covalent intermediate species between RlmN and its rRNA substrate and well as the roles of the conserved cysteine residues in catalysis. PMID- 23088753 TI - Periodontal ligament cell behavior on different titanium surfaces. AB - AIM: The purpose of this study was to investigate proliferation, morphology, mineralization and mRNA expressions of mineralized tissue associated proteins of PDL cells on smooth (S), sandblasted small-grit (SSG), sandblasted large-grit (SLG) and sodium titanate (NaTi) coated titanium alloys, in vitro. METHODS AND MATERIALS: PDL cells were cultured with DMEM media containing 10% FBS on the S, SSG, SLG and NaTi titanium surfaces. PDL cell proliferation, mineralization and immunohistochemistry experiments for Bone Sialoprotein (BSP) were performed. The morphology of the PDL cells was examined using confocal and scanning electron microscopy (SEM). Gene expression profiles of cells were evaluated using a quantitative-polymerase chain reaction (Q-PCR) for type I collagen (COL I), Osteocalcin (OCN), osteopontin (OPN) and Runt-related transcription factor-2 (Runx2) on days 7 and 14. RESULTS: Proliferation results on days 6 and 10 were similar in groups, while those of day 13 revealed a decrease in the NaTi group when compared to the S group. NaTi surface induced BSP mRNA expression which was correlated with mineralization tests and BSP immunostaining results. Increased Runx2 mRNA expression was also noted in the NaTi surface when compared to other surfaces. CONCLUSIONS: This study considers the NaTi surface as a potential alternative to SSG and SLG surfaces. This surface might provide a promising environment for PDL ligament-anchored implants. PMID- 23088754 TI - Quantitative SERS using the sequestration of small molecules inside precise plasmonic nanoconstructs. AB - We show how the macrocyclic host, cucurbit[8]uril (CB[8]), creates precise subnanometer junctions between gold nanoparticles while its cavity simultaneously traps small molecules; this enables their reproducible surface-enhanced Raman spectroscopy (SERS) detection. Explicit shifts in the SERS frequencies of CB[8] on complexation with guest molecules provides a direct strategy for absolute quantification of a range of molecules down to 10(-11) M levels. This provides a new analytical paradigm for quantitative SERS of small molecules. PMID- 23088752 TI - Reactive intermediates produced from the metabolism of the vanilloid ring of capsaicinoids by p450 enzymes. AB - This study characterized electrophilic and radical products derived from the metabolism of capsaicin by cytochrome P450 and peroxidase enzymes. Multiple glutathione and beta-mercaptoethanol conjugates (a.k.a., adducts), derived from the trapping of quinone methide and quinone intermediates of capsaicin, its analogue nonivamide, and O-demethylated and aromatic hydroxylated metabolites thereof, were produced by human liver microsomes and individual recombinant human P450 enzymes. Conjugates derived from concomitant dehydrogenation of the alkyl terminus of capsaicin were also characterized. Modifications to the 4-OH substituent of the vanilloid ring of capsaicinoids largely prevented the formation of electrophilic intermediates, consistent with the proposed structures and mechanisms of formation for the various conjugates. 5,5'-Dicapsaicin, presumably arising from the bimolecular coupling of free radical intermediates was also characterized. Finally, the analysis of hepatic glutathione conjugates and urinary N-acetylcysteine conjugates from mice dosed with capsaicin confirmed the formation of glutathione conjugates of O-demethylated quinone methide and 5 OH-capsaicin in vivo. These data demonstrated that capsaicin and structurally similar analogues are converted to reactive intermediates by certain P450 enzymes, which may partially explain conflicting reports related to the cytotoxic, pro-carcinogenic, and chemoprotective effects of capsaicinoids in different cells and/or organ systems. PMID- 23088755 TI - Thermodynamic determination of the metal/semiconductor separation of carbon nanotubes using hydrogels. AB - The metal/semiconductor separation of single-wall carbon nanotubes (SWCNTs) using hydrogels, such as agarose gel and Sephacryl, together with sodium dodecyl sulfate is one of the most successful techniques necessary for industrial applications. Despite recent improvements in the technique, little is known about the separation mechanism. Here, we show that SWCNTs are reversibly adsorbed onto hydrogels in the presence of sodium dodecyl sulfate. The results enabled us to examine the thermodynamics of the adsorption reaction and thereby elucidate the separation mechanism. The adsorbability of SWCNTs onto the hydrogels was described by the standard Gibbs free energy for the adsorption, as well as the area of the hydrogels allowing the adsorption. We demonstrated, for the first time, that the free energy of adsorption for semiconducting SWCNTs was 0-12 kJ/mol lower than that for metallic SWCNTs in the temperature range of 290-320 K (e.g., ca. -4 kJ/mol for the agarose gel and ca. -9 kJ/mol for Sephacryl at 300 K), which permits metal/semiconductor separation. Importantly, the difference in the free energy was attributed to the difference in the enthalpy of adsorption: the enthalpy of adsorption of metallic SWCNTs was ca. 70 kJ/mol higher than that of semiconducting SWCNTs. Thus, the enthalpy of adsorption was found to be an important parameter in the metal/semiconductor separation of SWCNTs using hydrogels. In addition, the thermodynamic parameters depended on the hydrogel type and the surfactant concentration, which is most likely why under certain conditions hydrogels and surfactants produce different separations, e.g., chirality-selective or diameter-selective separation. PMID- 23088756 TI - Synthesis and characterization of polysaccharide-maghemite composite nanoparticles and their antibacterial properties. AB - The aim of this study was to obtain saccharide (dextran and sucrose)-coated maghemite nanoparticles with antibacterial activity. The polysaccharide-coated maghemite nanoparticles were synthesized by an adapted coprecipitation method. X ray diffraction (XRD) studies demonstrate that the obtained polysaccharide-coated maghemite nanoparticles can be indexed into the spinel cubic lattice with a lattice parameter of 8.35 A. The refinement of XRD spectra indicated that no other phases except the maghemite are detectable. The characterization of the polysaccharide-coated maghemite nanoparticles by various techniques is described. The antibacterial activity of these polysaccharide-coated maghemite nanoparticles (NPs) was tested against Pseudomonas aeruginosa 1397, Enterococcus faecalis ATCC 29212, Candida krusei 963, and Escherichia coli ATCC 25922 and was found to be dependent on the polysaccharide type. The antibacterial activity of dextran coated maghemite was significantly higher than that of sucrose-coated maghemite. The antibacterial studies showed the potential of dextran-coated iron oxide NPs to be used in a wide range of medical infections. PMID- 23088757 TI - The skin surface as antimicrobial barrier: present concepts and future outlooks. AB - Human skin protects the body as an outer barrier from various environmental threats and has to deal with an immense quantity of microbes comprising members of the own microbiota as well as potential pathogenic microbes. In this viewpoint, we highlight important cutaneous first-line defense barriers from the perspective of a microbe that tries to colonize and invade human skin. We place special emphasis on the role of antimicrobial peptides and the microbiota. In addition, we discuss and try to provide answers to some emerging issues concerning the various defense strategies of the epidermis. PMID- 23088758 TI - Esophageal motor disorders in subjects with incidentally discovered Chagas disease: a study using high-resolution manometry and the Chicago classification. AB - In patients with chronic indeterminate Chagas disease, conventional manometry has shown that 25-48% had esophageal motor disorders. Recently, esophageal high resolution manometry (HRM) has revolutionized the assessment of esophageal motor function. In this study, we performed esophageal HRM in a group of subjects with incidentally positive serological findings for Trypanosoma cruzi. In this prospective observational study, we evaluated subjects who had positive serological tests for Chagas disease detected during a screening evaluation for blood donation. All subjects underwent symptomatic evaluation and esophageal HRM with a 36 solid-state catheter. Esophageal abnormalities were classified using the Chicago classification. Forty-two healthy subjects (38 males) aged 18-61 years (mean age, 40.7 years) were included. When specific symptoms questionnaire was applied, 14 (33%) subjects had esophageal symptoms. Esophageal high resolution manometry revealed that 28 (66%) of the subjects had an esophageal motility disorder according to the Chicago classification. Most common findings were hypocontractile disorders in 18 subjects (43%) and esophagogastric junction (EGJ) outflow obstruction in 6 (15%). Esophageal high-resolution manometry reveals that up to two thirds of the subjects with an incidental diagnosis of Chagas disease have esophageal abnormalities. This technology increases the detection and allows a more complete assessment of esophageal motor function in subjects infected with T. cruzi even in the early stages of the disease. PMID- 23088759 TI - Radical cystectomy in patients with preexisting three-piece inflatable penile prosthesis. AB - INTRODUCTION: Radical cystectomy with urinary diversion is the treatment of choice for muscle-invasive, and certain populations with non-invasive, urothelial carcinoma of the bladder. There have not been any reports to date on patients undergoing this surgery who have had previous placement of an inflatable penile prosthesis. AIM: To present the outcomes of four patients with pre-existing inflatable penile prostheses (IPP) with reservoirs within the space of Retzius who were subsequently treated with radical cystectomy for bladder cancer management. METHODS: After obtaining institutional review board approval, the demographic, clinical, and pathologic data were reviewed in the Johns Hopkins Cystectomy Database for patients who underwent radical cystectomy for bladder cancer from 1994 to 2012. A case series of four patients is presented who had a preexisting IPP and their post-operative course and long-term outcomes are reviewed. RESULTS: All four patients had radical cystectomy and ileal conduit urinary diversion with no intra-operative or post-operative complications. One patient was not sexually active and therefore had the reservoir explanted and not replaced. The other three patients had the reservoir removed prior to bladder extirpation and the tubing capped, with reservoir replacement in the pseudocapsule at the termination of the procedure. In one patient an omental flap was used to ensure separation between the reservoir and ileal conduit. The devices were all functional intra-operatively and on follow-up. CONCLUSIONS: As erectile dysfunction is more commonly being diagnosed and treated with IPP insertion at younger ages, surgeons will increasingly encounter pre-placed abdominal reservoirs when performing pelvic surgery. This case series of four patients undergoing radical cystectomy with prior-placed IPPs reveals that the functionality of the IPP can be preserved while still performing oncologically sound extirpative procedures. PMID- 23088762 TI - Elucidating the mechanism of the halide-induced ligand rearrangement reaction. AB - The formation of heteroligated Rh(I) complexes containing two different hemilabile phosphinoalkyl ligands, (kappa(2)-Ph(2)PCH(2)CH(2)S-Aryl)(kappa(1) Ph(2)PCH(2)CH(2)O-C(6)H(5))RhCl, through a halide-induced ligand rearrangement (HILR) reaction has been studied mechanistically. The half-life of this rearrangement reaction depends heavily on the Rh(I) precursor used and the chelating ability of the phosphinoalkyl thioether (PS) ligand, while the chelating ability of the phosphinoalkyl ether (PO) ligand has less of an effect. An intermediate complex which contains two PO ligands, (nbd)(kappa(1) Ph(2)PCH(2)CH(2)O-C(6)H(5))(2)RhCl (nbd = norbornadiene), converts to (nbd)(kappa(1)-Ph(2)PCH(2)CH(2)O-C(6)H(5))RhCl resulting in a free PO ligand. The free PO ligand can then react with a homoligated PS complex [(kappa(2) Ph(2)PCH(2)CH(2)S-Aryl)(2)Rh](+)Cl(-) producing the heteroligated product. The PS ligand generated during the reaction pathway can be trapped by the monoligated PO complex (nbd)(kappa(1)-Ph(2)PCH(2)CH(2)O-C(6)H(5))RhCl, leading to the formation of the same heteroligated product. In this study, some of the key intermediates and reaction steps underlying the HILR reaction have been identified by variable temperature (31)P{(1)H} NMR spectroscopy and in two cases by single-crystal X-ray diffraction studies. Significantly, this work provides mechanistic insight into the HILR process, which is a key reaction used to prepare a large class of highly sophisticated three-dimensional metallosupramolecular architectures and allosteric catalysts. PMID- 23088761 TI - Monitoring the prevalence of chronic conditions: which data should we use? AB - BACKGROUND: Chronic diseases are an increasing threat to people's health and to the sustainability of health organisations. Despite the need for routine monitoring systems to assess the impact of chronicity in the population and its evolution over time, currently no single source of information has been identified as suitable for this purpose. Our objective was to describe the prevalence of various chronic conditions estimated using routine data recorded by health professionals: diagnoses on hospital discharge abstracts, and primary care prescriptions and diagnoses. METHODS: The ICD-9-CM codes for diagnoses and Anatomical Therapeutic Chemical (ATC) codes for prescriptions were collected for all patients in the Basque Country over 14 years of age (n=1,964,337) for a 12 month period. We employed a range of different inputs: hospital diagnoses, primary care diagnoses, primary care prescriptions and combinations thereof. Data were collapsed into the morbidity groups specified by the Johns Hopkins Adjusted Clinical Groups (ACGs) Case-Mix System. We estimated the prevalence of 12 chronic conditions, comparing the results obtained using the different data sources with each other and also with those of the Basque Health Interview Survey (ESCAV). Using the different combinations of inputs, Standardized Morbidity Ratios (SMRs) for the considered diseases were calculated for the list of patients of each general practitioner. The variances of the SMRs were used as a measure of the dispersion of the data and were compared using the Brown-Forsythe test. RESULTS: The prevalences calculated using prescription data were higher than those obtained from diagnoses and those from the ESCAV, with two exceptions: malignant neoplasm and migraine. The variances of the SMRs obtained from the combination of all the data sources (hospital diagnoses, and primary care prescriptions and diagnoses) were significantly lower than those using only diagnoses. CONCLUSIONS: The estimated prevalence of chronic diseases varies considerably depending of the source(s) of information used. Given that administrative databases compile data registered for other purposes, the estimations obtained must be considered with caution. In a context of increasingly widespread computerisation of patient medical records, the complementary use of a range of sources may be a feasible option for the routine monitoring of the prevalence of chronic diseases. PMID- 23088760 TI - The efficiencies of damage recognition and excision correlate with duplex destabilization induced by acetylaminofluorene adducts in human nucleotide excision repair. AB - Nucleotide excision repair (NER) removes lesions caused by environmental mutagens or UV light from DNA. A hallmark of NER is the extraordinarily wide substrate specificity, raising the question of how one set of proteins is able to recognize structurally diverse lesions. Two key features of good NER substrates are that they are bulky and thermodynamically destabilize DNA duplexes. To understand what the limiting step in damage recognition in NER is, we set out to test the hypothesis that there is a correlation of the degree of thermodynamic destabilization induced by a lesion, binding affinity to the damage recognition protein XPC-RAD23B, and overall NER efficiency. We chose to use acetylaminofluorene (AAF) and aminofluorene (AF) adducts at the C8 position of guanine in different positions within the NarI (GGCGCC) sequence, as it is known that the structures of the duplexes depend on the position of the lesion in this context. We found that the efficiency of NER and the binding affinity of the damage recognition factor XPC-RAD23B correlated with the thermodynamic destabilization induced by the lesion. Our study is the first systematic analysis correlating these three parameters and supports the idea that initial damage recognition by XPC-RAD23B is a key rate-limiting step in NER. PMID- 23088763 TI - MDR1 polymorphisms associated with risk and survival in diffuse large B-cell lymphoma. AB - MDR1 encodes an adenosine triphosphate (ATP)-dependent efflux transporter that protects the body from environmental xenobiotics to maintain optimal health. Five single nucleotide polymorphisms (SNPs) of MDR1, T-2410C, T-129C, C1236T, G2677T/A and C3435T, were identified in our previous study. To investigate further the biological significance of these SNPs, we genotyped the SNPs in 135 patients with diffuse large B-cell lymphoma (DLBCL) and 376 age- and sex-matched controls. Statistical analysis indicated that the MDR1-129TC genotype was associated with an increased risk of DLBCL (p = 0.040) compared with the TT genotype, and the increased risk was more pronounced in older patients (> 50 years, p = 0.011). Patients with MDR1 2677TT displayed worse survival rates compared with those carrying MDR1 2677G/A alleles (p = 0.036). Multivariate Cox analysis revealed that the G2677T/A polymorphism was an independent prognostic factor for overall survival (OS). Further, we found a combined effect of MDR1 G2677T/A and C3435T on OS of patients with DLBCL. These results suggest that the MDR1 T-129C, G2677T/A and C3435T polymorphisms are associated with risk of and survival in DLBCL, although the p-values are not as strong after Bonferroni correction. Further investigations with a relatively larger number of patients and longer follow-up periods should be undertaken to confirm our results. PMID- 23088764 TI - Auramine-O as a fluorescence marker for the detection of amyloid fibrils. AB - There is an indispensable need for a fluorescence marker for the detection of amyloid fibrils, where, at present, the most used marker is thioflavin-T (ThT). Here, we present the use of auramine-O (AuO) as a possible alternative to ThT. As with ThT, the increase in the emission of AuO upon binding to amyloid fibrils is the result of inhibition of the free rotation of the two dimethylamino arms of the molecule. This inhibition prevents the excited-state electronic wave function from moving from the emissive locally excited state to the dark charge-transfer state. We further show that not only AuO is comparable to ThT as a fluorescent marker for amyloid fibrils but also it has a unique spectroscopic signature. AuO has distinct two modes that are characterized by a large shift in the absorption and emission peak positions between its unbound and bound states (before and after the fibrils formation, respectively). In this context, we show that, whereas the emission band position is red-shifting, the absorption peak shifts to the blue and the spectrum exhibits an isosbestic point. The large shifts in emission and absorption peak positions can be explained by the photoacid activity of AuO exhibiting an excited-state proton-transfer process. PMID- 23088765 TI - Penile abscess and urethrocutaneous fistula following intracavernous injection: a case report. AB - INTRODUCTION: Intracavernous injection with pharmacological agents is described as a safe and efficient method for erectile dysfunction treatment. Among other adverse events, penile abscess is a potentially difficult-to-treat complication. AIM: We present a rare case of penile abscess presenting 6 months after intracavernous papaverine injection. The etiology, diagnosis, and management of this condition are discussed briefly. METHODS: A 49-year-old afebrile man presented with the development of distal penile shaft swelling. A 6 * 4-cm tender lump was palpable on the left ventrolateral side, with mobile overlying skin but fixed to underlying tissue, without any local or general signs of infection. The swelling gradually increased in volume over a period of 2 weeks following intracavernous papaverine injection. However, the patient did not seek medical advice for 6 months because of the minimal symptoms associated with his condition. RESULTS: The abscess was revealed through sub-coronal circumferential skin degloving incision. The thick abscess sheath was incised and pus drained, followed by blunt excision down to the intact cavernosal tunica albuginea. On the 12th postoperative day, the case was further complicated by development of an urethrocutaneous fistula, 6 mm in diameter, on the ventral side of the spongy urethra. The patient was initially managed by suprapubic cystostomy and an Orandi urethroplasty was performed after 3 months. On day 14, post-urethroplasty, the fistula was completely closed and no complaints concerning micturition were reported. At follow-up, the patient showed good functional results in terms of maintained normal sexual function and absent penile curvature. CONCLUSIONS: Penile abscess after intracavernous injection is a rare condition. This unusual case speaks to the importance of a thoughtful surgical management with the need of operating team collaboration in order to resolve the abscess and manage potential complications. PMID- 23088766 TI - Effect of table tilt on ligamentum flavum length measured using ultrasonography in pregnant women*. AB - The purpose of this study was to assess whether applying dorsal table tilt to a seated parturient positioned for neuraxial anaesthesia (i.e. facing laterally with her legs over the side of the table) increased the size of the target area for the neuraxial needle. We performed lumbar ultrasonography on 20 pregnant women with the table level (0 degrees ) and tilted 8 degrees and 15 degrees dorsally. For each position, the size of the 'target area', defined as the visible length of the ligamentum flavum in the longitudinal paramedian view, and the interlaminar distance, were measured at the L3-4 interspace. There were significant increases in the mean (SD) size of the target area with increasing table tilt (10.7 (1.3) mm at 0 degrees , 11.5 (1.3) mm at 8 degrees and 12.2 (1.7) mm at 15 degrees ; p < 0.0001). Interlaminar distances were not significantly increased. These data show that using dorsal table tilt in obstetric patients increases the target area for neuraxial needles. Additional research is required to assess whether this eases the placement of neuraxial needles in clinical practice. PMID- 23088767 TI - Reduced contribution of thermally-labile sugar lesions to DNA double-strand break formation after exposure to neutrons. AB - In cells exposed to ionizing radiation, double-strand breaks (DSBs) form within clustered damage sites from lesions disrupting the DNA sugar-phosphate backbone. It is commonly assumed that DSBs form promptly and are immediately detected and processed by the cellular DNA damage response apparatus. However, DSBs also form by delayed chemical conversion of thermally-labile sugar lesions (TLSL) to breaks. We recently reported that conversion of thermally-labile sugar lesions to breaks occurs in cells maintained at physiological temperatures. Here, we investigate the influence of radiation quality on the formation of thermally labile sugar lesions dependent DSBs. We show that, although the yields of total DSBs are very similar after exposure to neutrons and X rays, the yields of thermally-labile sugar lesions dependent DSBs from neutrons are decreased in comparison to that from X rays. Thus, the yields of prompt DSBs for neutrons are greater than for X rays. Notably, after neutron irradiation the decreased yield of thermally-labile sugar lesion dependent DSBs is strongly cell line dependent, likely reflecting subtle differences in DNA organization. We propose that the higher ionization density of neutrons generates with higher probability prompt DSBs within ionization clusters and renders the ensuing chemical evolution of thermally-labile sugar lesions inconsequential to DNA integrity. Modification of thermally-labile sugar lesion evolution may define novel radiation protection strategies aiming at decreasing DSB formation by chemically preserving thermally labile sugar lesions until other DSB contributing lesions within the clustered damage site are removed by non-DSB repair pathways. PMID- 23088768 TI - Mast cells and ionizing radiation induce a synergistic expression of inflammatory genes in endothelial cells by a mechanism involving p38alpha MAP kinase and (p65) NF-kappaB activation. AB - Vascular endothelium is a key compartment involved in the development of normal tissue toxicity associated with cancer radiation therapy, i.e., acute inflammation and late fibrosis. Radiation-induced endothelial cell activation has been extensively studied, and activated endothelial cells are characterized by increased expression of inflammatory mediators and adhesion molecules, and activation of the coagulation and thrombosis pathways. However, little is known about the role of vascular endothelium interaction with resident immune cells, such as mast cells on its response to irradiation. Here, we report that endothelial exposure to mast cell conditioned medium and irradiation induces a synergistic expression of many inflammatory genes including interleukin-6 and interleukin-8, CXCL2 and E-selectin. This synergy is blocked by the histamine H1 receptor antagonist mepyramine and partially mimicked by exogenous histamine addition before irradiation. Using pharmacological and molecular inhibition approaches, we show the p38alpha MAP kinase and p65 (NF-kappaB) dependence of the synergy. Moreover, our data show a link between both pathways, with p65 (NF kappaB) being downstream of p38. These data highlight the possible exacerbation of the radiation-induced endothelial inflammatory response by its interactions with immune cells. It also suggest that p38alpha MAP kinase and p65 (NF-kappaB) inhibition in vascular endothelium may limit excessive tissue inflammation induced by radiation therapy, and thereby limit the associated acute and late tissue damage. PMID- 23088769 TI - The experience of providing end-of-life care to a relative with advanced dementia: an integrative literature review. AB - The number of people with dementia is growing at an alarming rate. An abundance of research over the past two decades has examined the complex aspects of caring for a relative with dementia. However, far less research has been conducted specific to the experiences of family caregivers providing end-of-life care, which is perplexing, as dementia is a terminal illness. This article presents what is known and highlights the gaps in the literature relevant to the experiences of family caregivers of persons with dementia at the end of life. A thorough search of the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and PubMed databases from 1960 to 2011 was conducted. Ten studies were identified that specifically addressed the experience of family caregivers providing end-of-life care to a relative with advanced dementia. Common themes of these studies included: 1) the experience of grief, 2) guilt and burden with decision making, 3) how symptoms of depression may or may not be resolved with death of the care receiver, 4) how caregivers respond to the end-stage of dementia, and 5) expressed needs of family caregivers. It is evident from this literature review that much remains to be done to conceptualize the experience of end-of-life caregiving in dementia. PMID- 23088770 TI - Ectopically expressed IBP promotes cell proliferation in oral squamous cell carcinoma. AB - IFN regulatory factor 4 binding protein (IBP) has been shown to play an important role in the progression of malignant tumors such as breast cancer cells, but its function in oral squamous cell carcinoma (OSCC) remains unclear. We found that IBP ectopically expressed in some OSCC specimens but not in normal oral mucosa epithelium tissues. IBP expression was significantly correlated with tumor size, differentiation, clinical stage, and distant metastasis. Furthermore, IBP markedly promoted OSCC cell proliferation, shortened the G1 interval in the cell cycle, and increased cyclin D1 expression. These findings suggest that IBP may be a potential therapeutic target for OSCC. PMID- 23088772 TI - Effects of essential oils from herbal plants and citrus fruits on DNA polymerase inhibitory, cancer cell growth inhibitory, antiallergic, and antioxidant activities. AB - In this study, the biological activity of 20 essential oils (EOs) from herbal plants and citrus fruits were investigated in terms of mammalian DNA polymerase (pol) inhibitory activity, cancer cell (human colon carcinoma, HCT116) growth inhibitory activity, antiallergic activity, as anti-beta-hexosaminidase release activity in rat basophilic leukemia RBL-2H3 cells treated with calcium ionophore A23187, and antioxidant activity by a lipophilic-oxygen radical absorbance capacity method. These EOs showed patterns of inhibition of pol alpha, a DNA replicative pol, similar to their cancer cell growth inhibitory activity, and their inhibitory activity on pol lambda, a DNA repair/recombination pol, by the EOs showed correlation with anti-beta-hexosaminidase release activity. Among these EOs, chamomile (Matricaria chamomilla L.) was the strongest inhibitor of pols alpha and lambda and showed significant effects on both cancer cell growth and mast cell degranulation. On the basis of these results, chamomile EO can be recommended as a potentially useful, bioactive candidate for therapeutic applications. PMID- 23088771 TI - Atopic dermatitis and indoor use of energy sources in cooking and heating appliances. AB - BACKGROUND: Atopic dermatitis (AD) prevalence has considerably increased worldwide in recent years. Studying indoor environments is particularly relevant, especially in industrialised countries where many people spend 80% of their time at home, particularly children. This study is aimed to identify the potential association between AD and the energy source (biomass, gas and electricity) used for cooking and domestic heating in a Spanish schoolchildren population. METHODS: As part of the ISAAC (International Study of Asthma and Allergies in Childhood) phase III study, a cross-sectional population-based survey was conducted with 21,355 6-to-7-year-old children from 8 Spanish ISAAC centres. AD prevalence, environmental risk factors and the use of domestic heating/cooking devices were assessed using the validated ISAAC questionnaire. Crude and adjusted odds ratios (cOR, aOR) and 95% confidence intervals (CIs) were obtained. A logistic regression analysis was performed (Chi-square test, p-value < 0.05). RESULTS: It was found that the use of biomass systems gave the highest cORs, but only electric cookers showed a significant cOR of 1.14 (95% CI: 1.01-1.27). When the geographical area and the mother's educational level were included in the logistic model, the obtained aOR values differed moderately from the initial cORs. Electric heating was the only type which obtained a significant aOR (1.13; 95% CI: 1.00-1.27). Finally, the model with all selected confounding variables (sex, BMI, number of siblings, mother's educational level, smoking habits of parents, truck traffic and geographical area), showed aOR values which were very similar to those obtained in the previous adjusted logistic analysis. None of the results was statistically significant, but the use of electric heating showed an aOR close to significance (1.14; 95% CI: 0.99-1.31). CONCLUSION: In our study population, no statistically significant associations were found between the type of indoor energy sources used and the presence of AD. PMID- 23088773 TI - Synthesis of two unnatural oxygenated aaptaminoids. AB - Two unprecedented oxygenated aaptaminoids have been synthesized starting from cheap and easily available 2,3-dihydroxybenzoic acid with the satisfactory overall yields of 31% and 34%. The key step of the procedure is the divergent thermic 5-exodig vs base-promoted 6-endodig cyclization of a 5-alkynylquinolinone derivative. PMID- 23088775 TI - Regio- and diastereoselective synthesis and X-ray structure determination of (+) 2-deoxyoryzalexin S from (+)-podocarpic acid. Structural nonidentity with its nominal natural isolated enantiomer. AB - (+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+) 1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures. PMID- 23088776 TI - Absence of the RET+3:T allele in the MTC patients. AB - The mutations of the RET proto-oncogene contributes to the development of MTC by increasing the activity of the receptor encoded by this gene. Variant T of polymorphism rs2435357 located in the enhancer of the RET gene reduces the enhancer's activity. The opposite effects of rs2435357 and the mutations causing medullary thyroid carcinoma resulted in the investigation of the status of this polymorphism in patients with MTC. In our study, we compared the frequency of polymorphism rs2435357 in the group of 48 MTC patients with its frequency in Polish population. The frequency of heterozygotes C/T at rs2435357 reached almost 12% (18/152) for the Polish population, in contrast to the group of MTC patients where not even a single T allele was found. The frequency difference is statistically significant. This observation might indicate that the presence of the heterozygous T allele at rs2435357 may be associated with the inhibition of medullary thyroid carcinoma development. PMID- 23088777 TI - It felt fluent, and I liked it: subjective feeling of fluency rather than objective fluency determines liking. AB - According to the processing-fluency explanation of aesthetics, more fluently processed stimuli are preferred (R. Reber, N. Schwarz, & P. Winkielman, 2004, Processing fluency and aesthetic pleasure: Is beauty in the perceiver's processing experience? Personality and Social Psychology Review, Vol. 8, pp. 364 382.). In this view, the subjective feeling of ease of processing is considered important, but this has not been directly tested in perceptual processing. In two experiments, we therefore objectively manipulated fluency (ease of processing) with subliminal perceptual priming (Study 1) and variations in presentation durations (Study 2). We assessed the impact of objective fluency on feelings of fluency and liking, as well as their interdependence. In line with the processing fluency account, we found that objectively more fluent images were indeed judged as more fluent and were also liked more. Moreover, differences in liking were even stronger when data were analyzed according to felt fluency. These findings demonstrate that perceptual fluency is not only explicitly felt, it can also be reported and is an important determinant of liking. PMID- 23088778 TI - The Easterlin paradox revisited. AB - The traditional view that well-being depends on both absolute and relative income was challenged in a 1974 paper by Richard Easterlin (Does economic growth improve the human lot? In P. David and M. Reder (Eds.), Nations and households in economic growth: Essays in honor of Moses Abramovitz (pp. 89-125), New York: Academic Press). He noted that although individual well-being is strongly positively associated with income within any country at a given point in time, the average level of measured well-being for a country changes little over time, even in the face of substantial growth in average incomes. For decades, social scientists have struggled to explain this "Easterlin Paradox." In a 2008 paper, Betsey Stephenson and Justin Wolfers (Economic growth and subjective well-being: Reassessing the Easterlin Paradox, Brookings Papers on Economic Activity, Vol. 39, pp. 1-87) argued that the Easterlin Paradox was a statistical illusion. Using richer data sets that facilitate more precise estimates of the various links between income and well-being, they assert that average well-being in a country does, in fact, rise as average income rises over time, and that rich countries are happier than slightly poorer ones. They also suggest that the link between income and well-being may run through absolute income alone-that is, that individual well-being may be completely independent of relative income. In this article, I argue that there have always been good reasons to believe that well being is positively linked to absolute income. I also argue, however, that there is no reason to believe that individual well-being is independent of relative income. PMID- 23088779 TI - Analysis of a slow-growing line reveals wide genetic variability of carcass and meat quality-related traits. AB - BACKGROUND: Slow-growing lines are widely used in France for the production of high quality free-range chickens. While such production is mainly dedicated to the whole carcass market, new prospects are opening up for the development of cuts and processed products. Whether the body composition and meat quality of slow-growing birds can be improved by selection has thus become an important issue. The genetic parameters of growth, body composition and breast meat quality traits were evaluated in relation to behaviour at slaughter in a large pedigree population including 1022 male and female slow-growing birds. RESULTS: The heritability coefficients (h2) of body weight and body composition traits varied from 0.3 to 0.5. Abdominal fat percentage was genetically positively correlated with body weight but negatively correlated with breast muscle yield. The characteristics of the breast meat (i.e., post-mortem fall in pH, colour, drip loss, shear-force and lipid content) were all heritable, with h2 estimates ranging from 0.18 to 0.48. The rate and extent of the fall in pH were under different genetic control. Strong negative genetic correlations were found between the ultimate pH and the lightness, yellowness and drip loss of the meat. Wing flapping on the shackle line was significantly heritable and exhibited marked genetic correlations with the pH at 15 min post-slaughter and the redness of the meat. The genetic relationships between meat quality traits, body weight and body composition appeared slightly different between males and females. CONCLUSION: This study suggested that there are a number of important criteria for selection on carcass and breast meat quality in slow-growing birds. Selection for reduced abdominal fatness and increased breast muscle yield should be effective as both traits were found to be highly heritable and favourably correlated. Substantial improvement in meat quality could be achieved by selection on ultimate pH which was highly heritable and strongly correlated with the colour and water-holding capacity of the meat. Moreover, this study revealed for the first time that the behaviour at slaughter is partly genetically determined in the chicken. PMID- 23088780 TI - Gene therapy briefs. PMID- 23088782 TI - Magnetic anisotropy in isotropic and nanopatterned strongly exchange-coupled nanolayers. AB - In this study, the fabrication of magnetic multilayers with a controlled value of the in-plane uniaxial magnetic anisotropy field in the range of 12 to 72 kA/m was achieved. This fabrication was accomplished by the deposition of bilayers consisting of an obliquely deposited (54 degrees ) 8-nm-thick anisotropic Co layer and a second isotropic Co layer that was deposited at a normal incidence over the first layer. By changing the thickness value of this second Co layer (X) by modifying the deposition time, the value of the anisotropy field of the sample could be controlled. For each sample, the thickness of each bilayer did not exceed the value of the exchange correlation length calculated for these Co bilayers. To increase the volume of the magnetic films without further modification of their magnetic properties, a Ta spacer layer was deposited between successive Co bilayers at 54 degrees to prevent direct exchange coupling between consecutive Co bilayers. This step was accomplished through the deposition of multilayered films consisting of several (Co8 nm-54 degrees /CoX nm 0 degrees /Ta6 nm-54 degrees ) trilayers. PMID- 23088783 TI - Nano in the brain: nano-neuroscience. PMID- 23088785 TI - Rationally designed tumor-penetrating nanocomplexes. AB - Small interfering RNA (siRNA) therapeutics have broad potential uses in medicine but require safe and effective delivery vehicles to function. An ideal delivery system should encapsulate and protect the siRNA cargo from serum proteins, exhibit target tissue and cell specificity, penetrate the cell surface, and release its cargo in the desired intracellular compartment. One approach to the design of delivery vehicles that meets all of these requirements utilizes the systematic assembly of multiple components that can address each barrier. This rational approach was adopted by Ren et al., who designed novel myristoylated tandem peptides that consist of a tumor-targeting module and a cell-penetrating module, as described in this issue of ACS Nano. These tandem peptides were formulated with siRNAs into nanocomplexes for cell-specific delivery to a variety of tumor cell lines. The correlation of the structural properties of the nanocomplex to cell-type-specific activity via a computational approach identified the valence of the tumor-targeting ligand and overall nanocomplex charge as important parameters for the activity of the formulations. The in vivo gene silencing potency of these peptide-based nanocomplex formulations was demonstrated by Ren et al. in an ovarian cancer model. Tumor-penetrating nanocomplexes carrying a siRNA sequence against a novel oncogene (ID4) led to a significant reduction in tumor burden and an 80% increase in mouse survival. As such, the combination of a systematic approach with computational modeling can be advantageous for improving the delivery and potency of siRNA therapeutics. PMID- 23088786 TI - A cysteine-reactive alkyl hydroquinone modifies topoisomerase IIalpha, enhances DNA breakage, and induces apoptosis in cancer cells. AB - We previously reported that the anticancer activity of a botanical compound 10'(Z),13'(E),15'(E)-heptadecatrienylhydroquinone [HQ17(3)] was attributed to topoisomerase (Topo) IIalpha poisoning and the induction of oxidative damage. HQ17(3) irreversibly inhibits Topo IIalpha activity in vitro and is more cytotoxic in leukemia HL-60 cells than in Topo IIalpha-deficient variant HL 60/MX2 cells, which suggests that Topo IIalpha is a cellular target of HQ17(3). This study further characterizes the molecular mechanisms of the anticancer activity of HQ17(3). Proteomic analyses indicated that HQ17(3) reacted with Cys 427, Cys-733, and Cys-997 of recombinant Topo IIalpha in vitro, whereas it reacted with Cys-427 of cellular Topo IIalpha in Huh7 hepatoma cells. The modification of HQ17(3) inhibited Topo IIalpha catalytic activity, increased the Topo IIalpha-DNA cleavage complex, and caused the accumulation of DNA breakage. In Huh7 cells, HQ17(3) treatment caused prompt inhibition of DNA synthesis and consequently induced the expression of DNA damage-related genes DDIT3, GADD45A, and GADD45G. Topo IIalpha inhibition, apoptosis, and oxidative stress were found to account for cytotoxicity caused by HQ17(3). Pretreatment of Huh7 cells with N acetylcysteine (NAC) partially attenuated mitochondrial membrane damage, DNA breakage, and caspase activation. However, NAC pretreatment did not diminish HQ17(3)-induced cell death. These results suggest that the anticancer activity of HQ17(3) is attributed significantly to Topo IIalpha poisoning. The structural feature of HQ17(3) can be used as a model for the design of Topo IIalpha inhibitors and anticancer drugs. PMID- 23088787 TI - Hepatitis B viral core protein disrupts human host gene expression by binding to promoter regions. AB - BACKGROUND: The core protein (HBc) of hepatitis B virus (HBV) has been implicated in the malignant transformation of chronically-infected hepatocytes and displays pleiotropic functions, including RNA- and DNA-binding activities. However, the mechanism by which HBc interacts with the human genome to exert effects on hepatocyte function remains unknown. This study investigated the distribution of HBc binding to promoters in the human genome and evaluated its effects on the related genes' expression. RESULTS: Whole-genome chromatin immunoprecipitation microarray (ChIP-on-chip) analysis was used to identify HBc-bound human gene promoters. Gene Ontology and pathway analyses were performed on related genes. The quantitative polymerase chain reaction assay was used to verify ChIP-on-chip results. Five novel genes were selected for luciferase reporter assay evaluation to assess the influence of HBc promoter binding. The HBc antibody immunoprecipitated approximately 3100 human gene promoters. Among these, 1993 are associated with known biological processes, and 2208 regulate genes with defined molecular functions. In total, 1286 of the related genes mediate primary metabolic processes, and 1398 encode proteins with binding activity. Sixty-four of the promoters regulate genes related to the mitogen-activated protein kinase (MAPK) pathways, and 41 regulate Wnt/beta-catenin pathway genes. The reporter gene assay indicated that HBc binding up-regulates proto-oncogene tyrosine protein kinase (SRC), type 1 insulin-like growth factor receptor (IGF1R), and neurotrophic tyrosine kinase receptor 2 (NTRK2), and down-regulates v-Ha-ras Harvey rat sarcoma viral oncogene (HRAS). CONCLUSION: HBc has the ability to bind a large number of human gene promoters, and can disrupt normal host gene expression. Manipulation of the transcriptional profile in HBV-infected hepatocytes may represent a key pathogenic mechanism of HBV infection. PMID- 23088788 TI - Lung ultrasound-guided management of acute breathlessness during pregnancy. AB - Lung ultrasonography is a standard tool in the intensive care unit and in emergency medicine, but has not been described in the particular setting of the labour ward. During pregnancy, acute respiratory failure and pulmonary oedema are not uncommon life-threatening events. We present two case reports outlining the potential of lung ultrasonography in parturients. In case 1, lung ultrasonography allowed early diagnosis and treatment of acute dyspnoea in a parturient admitted for suspected asthma exacerbation. Lung ultrasonography revealed a 'B-pattern' of vertical lines radiating into the lung tissue, indicating severe pulmonary oedema complicating previously undiagnosed pre-eclampsia. In case 2, a pre-eclamptic patient was managed with combined transthoracic echocardiography and lung ultrasonography. The accuracy of lung ultrasonography in detecting interstitial oedema at a pre-clinical stage allowed adequate fluid resuscitation in this patient who had a high risk of alveolar pulmonary oedema. We believe that these cases strongly support the prospective validation of lung ultrasound for management of lung disorders in pregnant women. PMID- 23088789 TI - Assessment of IL-1beta and VEGF concentration in a rat model during orthodontic tooth movement and extracorporeal shock wave therapy. AB - OBJECTIVE: This study aimed to investigate PDL's cytokine concentration fluctuations after induction of orthodontic force with and without extracorporeal shock wave therapy in a rat model. MATERIALS AND METHODS: An orthodontic appliance was fabricated and applied between the molars and the incisors of rats. The rats were treated by a single episode of 1000 shock waves and gingival crevicular fluid was collected for 3 days. The expression and concentration of IL 1beta and VEGF were evaluated by ELISA assay. On day 3 all rats were sacrificed and histologic and immunohistochemical assays were applied. RESULTS: IL-1beta concentration rose in both the treated and non treated shockwave groups on the first day, however it was statistically significantly higher in the treated group on day 2. No statistically significant difference was detected between the groups on day 3. The number/area of TRAP positive cells was higher in the non shockwave group than in the treated group. The percentage of cells expressing VEGF displayed the opposite trend. The findings regarding the immunohistochemical assay for IL-1beta corresponded with those of the ELISA assay on day 3. CONCLUSION: The application of shockwaves during orthodontic tooth movement influences the expression of IL-1beta and VEGF and may alternate the periodontal remodelling expected rate. PMID- 23088790 TI - Characterization of volatile sulfur compound production by Solobacterium moorei. AB - OBJECTIVE: Solobacterium moorei is a Gram positive bacterium that has been specifically associated with halitosis. The aim of this study was to characterize volatile sulfur compound (VSC) production by S. moorei. METHODS: S. moorei was either grown or incubated in the presence of various supplements prior to determining VSC production with a Halimeter sulfide monitor. The effect of exogenous proteases or glycosidase inhibitors on VSC production by S. moorei was examined. RESULTS: We first showed that S. moorei can convert cysteine into hydrogen sulfide. The capacity of S. moorei to produce VSCs from serum, saliva, and mucin was dependent on the presence of an exogenous source of proteases such as pancreatic trypsin or Porphyromonas gingivalis gingipains. VSC production from mucin was inhibited by the presence of a beta-galactosidase inhibitor, thus suggesting that deglycosylation of mucin by S. moorei is critical for VSC production. CONCLUSION: Our study suggests that S. moorei can be a major source of malodorous compounds in halitosis by producing VSCs through a process involving the beta-galactosidase activity of the bacterium and an exogenous source of proteases. PMID- 23088791 TI - Series of inorganic-organic hybrid materials constructed from octamolybdates and metal-organic frameworks: syntheses, structures, and physical properties. AB - Series of inorganic-organic hybrid materials based on octamolybdates, silver ions, and multidentate N-donor ligands, namely, [Ag(2)(2,3'-tmbpt)(beta Mo(8)O(26))(0.5)] (1), [Ag(2)(2,4'-tmbpt)(2)(alpha Mo(8)O(26))(0.5)(H(2)O)(0.5)].2H(2)O (2), [Ag(3)(3,3'-tmbpt)(2)(alpha H(2)Mo(8)O(26))(0.5)(beta-Mo(8)O(26))(0.5)].3.5H(2)O (3), [Ag(2)(3,3' tmbpt)(epsilon-Mo(8)O(26))(0.5)].1.75H(2)O (4), [Ag(2)(3,4'-tmbpt)(2)(beta Mo(8)O(26))(0.5)].0.5H(2)O (5), and [Ag(3,4'-Htmbpt)(beta-Mo(8)O(26))(0.5)] (6), where 2,3'-tmbpt = 1-((1H-1,2,4-triazol-1-yl)methyl)-3-(3-pyridyl)-5-(2-pyridyl) 1,2,4-triazole), 2,4'-tmbpt = 1-((1H-1,2,4-triazol-1-yl)methyl)-3-(4-pyridyl)-5 (2-pyridyl)-1,2,4-triazole), 3,3'-tmbpt = 1-((1H-1,2,4-triazol-1-yl)methyl)-3,5 bis(3-pyridyl)-1,2,4-triazole, and 3,4'-tmbpt = 1-((1H-1,2,4-triazol-1-yl)methyl) 3-(4-pyridyl)-5-(3-pyridyl)-1,2,4-triazole) have been synthesized under hydrothermal conditions. Compound 1 displays a rare 3D (3,4,8)-connected net with (4.8(2))(4(2).8(4))(4(3).8(20).10(5)) topology. Compound 2 shows a rare 3D (4,6) connected self-catenated framework with (6(4).8(2))(4(2).6(3).8(2))(4(2).6(8).8(4).10) topology. Compound 3 is a scarce 3D framework based on two different kinds of [Mo(8)O(26)](4-) isomers. Compound 4 exhibits a 3D framework constructed by silver-organic sheets and the rare [epsilon-Mo(8)O(26)](4-) anions. Compound 5 shows an interesting 1D -> 2D polythreaded structure. Compound 6 displays a 2D layer structure, which is further linked by the N-H...O hydrogen bonds to form a 3D supramolecular architecture. Their structures have been further characterized by infrared spectra (IR), elemental analyses, powder X-ray diffraction (PXRD), electrochemistry and photoluminesce. Moreover, the photocatalytic activities for degradation of organic pollutant have been investigated for compounds 3-6. PMID- 23088793 TI - "Large eaters" meet blood vessels: a new thematic series on macrophages and angiogenesis. AB - Vascular Cell has launched a new series on macrophages and angiogenesis, a quickly evolving field critical to blood and lymphatic vessels during development, inflammation and tumorigenesis. PMID- 23088792 TI - Integrated complex care coordination for children with medical complexity: a mixed-methods evaluation of tertiary care-community collaboration. AB - BACKGROUND: Primary care medical homes may improve health outcomes for children with special healthcare needs (CSHCN), by improving care coordination. However, community-based primary care practices may be challenged to deliver comprehensive care coordination to complex subsets of CSHCN such as children with medical complexity (CMC). Linking a tertiary care center with the community may achieve cost effective and high quality care for CMC. The objective of this study was to evaluate the outcomes of community-based complex care clinics integrated with a tertiary care center. METHODS: A before- and after-intervention study design with mixed (quantitative/qualitative) methods was utilized. Clinics at two community hospitals distant from tertiary care were staffed by local community pediatricians with the tertiary care center nurse practitioner and linked with primary care providers. Eighty-one children with underlying chronic conditions, fragility, requirement for high intensity care and/or technology assistance, and involvement of multiple providers participated. Main outcome measures included health care utilization and expenditures, parent reports of parent- and child quality of life [QOL (SF-36(r), CPCHILD(c), PedsQLTM)], and family-centered care (MPOC-20(r)). Comparisons were made in equal (up to 1 year) pre- and post-periods supplemented by qualitative perspectives of families and pediatricians. RESULTS: Total health care system costs decreased from median (IQR) $244 (981) per patient per month (PPPM) pre-enrolment to $131 (355) PPPM post-enrolment (p=.007), driven primarily by fewer inpatient days in the tertiary care center (p=.006). Parents reported decreased out of pocket expenses (p<.0001). Parental QOL did not significantly change over the course of the study. Child QOL improved between baseline and 6 months in two PedsQLTM domains [Social (p=.01); Emotional (p=.003)], and between baseline and 1 year in two CPCHILD(c) domains [Health Standardization Section (p=.04); Comfort and Emotions (p=.03)], while total CPCHILD(c) score decreased between baseline and 1 year (p=.003). Parents and providers reported the ability to receive care close to home as a key benefit. CONCLUSIONS: Complex care can be provided in community-based settings with less direct tertiary care involvement through an integrated clinic. Improvements in health care utilization and family-centeredness of care can be achieved despite minimal changes in parental perceptions of child health. PMID- 23088794 TI - Micafungin as empirical antifungal therapy in hematological patients: a retrospective, multicenter study in the Czech and Slovak Republics. AB - The objective of this retrospective, multicenter study was to evaluate the efficacy and safety of micafungin as empirical antifungal therapy during febrile neutropenia (FN) in 73 hematological patients from six centers in two countries. All patients received 100 mg of micafungin/day. The overall favorable response rate (RR) was 64.8% when the resolution of fever during neutropenia was included in the response criteria and 84.5% when excluded. A significantly lower favorable RR in patients with persistent fever and non-specific pulmonary infiltrates compared to patients with persistent fever only (82.8 vs. 52.4%, respectively; p = 0.011) was not found when resolution of fever was not included in the composite endpoint criteria (93.1 vs. 78.6%, respectively; p = 0.180). Breakthrough fungal disease developed in 2.7% of patients. Treatment was discontinued in 16.4% of cases. Only one patient (1.4%) discontinued therapy due to an adverse event. Posaconazole prophylaxis improved favorable RR when defervescence was included as composite endpoint criterion (p = 0.047), but not when it was excluded (p = 0.485). However, neutrophil recovery did not influence favorable RR (p = 0.803 and p = 0.112, respectively). These data suggest that micafungin is safe and effective as an empirical therapy in patients with FN. PMID- 23088796 TI - Validating the Concord Index as a measure of family relationships in China. AB - Interest in family functioning across cultures has become more widespread, but our instruments have not kept pace by measuring constructs that are especially relevant outside the West. We present the psychometric properties of the Concord Index (CI) in the family context. The CI examines (qihe), translated most closely into English as concord. The term includes concepts of harmony and mutuality, and is a characteristic of dyadic relationships valued in Chinese cultural groups that form about a fifth of the world's population. The scale was adapted to measure 2 types of family relationships: specific dyadic relationships within the family between any individual family member and another (the A-P perspective), as well as an individual's composite assessment of all his/her family relationships (the A-FAM perspective). The 10-item measure was internally consistent, stable over 2 weeks, and showed factor invariance across gender, age, relationship, and household size for A-P and A-FAM perspectives. The A-P correlated negatively with disagreement with the partner. The A-FAM correlated with measures of family functioning, well-being, leisure time spent with family members, and with measures of emotional but not physical symptoms. Furthermore, the A-FAM measure added predictive power to individual measures of emotional functioning in assessing subjective happiness. The CI adds to other "imported" instruments designed to measure family function in Chinese populations because of its brevity, its adaptability for measuring dyadic and global family relationships across family roles, its easily understood items, and its incremental validity in predicting well-being beyond individually focused measures. PMID- 23088795 TI - Accounting for the physical and mental health benefits of entry into marriage: a genetically informed study of selection and causation. AB - Married adults show better psychological adjustment and physical health than their separated/divorced or never-married counterparts. However, this apparent "marriage benefit" may be due to social selection, social causation, or both processes. Genetically informed research designs offer critical advantages for helping to disentangle selection from causation by controlling for measured and unmeasured genetic and shared environmental selection. Using young-adult twin and sibling pairs from the National Longitudinal Study of Adolescent Health (Harris, 2009), we conducted genetically informed analyses of the association between entry into marriage, cohabitation, or singlehood and multiple indices of psychological and physical health. The relation between physical health and marriage was completely explained by nonrandom selection. For internalizing behaviors, selection did not fully explain the benefits of marriage or cohabitation relative to being single, whereas for externalizing symptoms, marriage predicted benefits over cohabitation. The genetically informed approach provides perhaps the strongest nonexperimental evidence that these observed effects are causal. PMID- 23088797 TI - Acculturation-based and everyday parent-adolescent conflict among Chinese American adolescents: longitudinal trajectories and implications for mental health. AB - The purpose of the study was to examine 2 types of conflict for Chinese American families that have not been integrated in previous literature: everyday conflict and acculturation-based conflict. We explored the relation between the 2 types of conflict over time and their associations with adolescent adjustment (i.e., anxiety/somatization, loneliness, depressive symptoms, and self-esteem). The sample consisted of 316 Chinese American adolescents (M = 14.8 years, SD = .73 at Wave 1) who participated in a 3-wave longitudinal study. The results showed that everyday and acculturation-based conflict are related and change in parallel over time. However, the 2 types of conflict are unique predictors of the 4 different indicators of psychological functioning. Results also suggested that psychological functioning is a better predictor of trajectories of conflict than vice versa. Taken together, the results highlight the importance of considering how the acculturation process contributes to parent-adolescent conflict regarding everyday issues and deeper cultural values. PMID- 23088798 TI - Tryptophan rotamer distribution revealed for the alpha-helix in tear lipocalin by site-directed tryptophan fluorescence. AB - Rotamer libraries are a valuable tool for protein structure determination, modeling, and design. Site-directed tryptophan fluorescence (SDTF) was used in combination with the rotamer model for the fluorescence intensity decays to solve alpha-helical conformations of proteins in solution. Single Trp mutations located in an alpha-helical segment of human tear lipocalin were explored for structure assignment. Along with fluorescence lambda(max) values, the rotamer model assignment of fluorescence lifetimes fits the backbone conformation. Typically, Trp fluorescence in proteins shows three lifetimes. However, for the alpha-helix, two lifetimes assigned to t and g(-) rotamers were satisfactory to describe Trp fluorescence intensity decays. The g(+) rotamer is not feasible in the alpha helix due to steric restriction. Trp rotamer distributions obtained by fluorescence were compared with the rotamer library derived from X-ray crystallography data of proteins. The Trp rotamer distributions vary for solvent exposed and buried (tertiary interaction) sites. A new strategy using the rotamer distribution with SDTF (RD-SDTF) removes the limitation of regular SDTF and other labeling techniques, in which site-specific differences, e.g., accessibility, are presumed. The RD-SDTF technique does not rely on environmental differences of side chains and is able to detect alpha-helical structure where all side chains are exposed to solvent. Potentially, this technique is applicable to various proteins including membrane proteins, which are rich in alpha-helix motif. PMID- 23088799 TI - End of life in residential care from the perspective of care aides. AB - We explored contextual features shaping end-of-life (EOL) care in residential care facilities by drawing on the perspectives of 11 resident care aides (RCAs) in one Western Canadian urban centre. RCAs characterized EOL care as "providing comfort", including physical and emotional comfort. Concerns with time and workload challenges dominated accounts and generated guilt, sadness, and frustration. RCAs tried to "find the time" by taking it from themselves or other residents, and by relying on the commitment of co-workers and on families. Findings emphasize the importance of the RCA role (particularly in emotional comfort), yet call for attention to interpretations of what is involved in this work, and to definitions of scopes of practice and training requirements. Findings reiterate the importance, among Canadian RCAs, of appropriate workloads to facilitate quality EOL care, and raise concerns about how time constraints shape EOL care practice and the meanings infusing this practice. PMID- 23088800 TI - The effects of and interactions between the maturity of grass silage and concentrate starch source when offered as total mixed rations on the performance of dairy cows. AB - A 2 * 2 factorial feeding experiment was conducted to examine the effects of varying the maturity level of the grass used to prepare silage and the nature of concentrate starch source and their interactions on dry matter intake (DMI), diet digestibility, energy corrected milk (ECM) production and milk composition in dairy cows. Twenty-eight multiparous Swedish Red dairy cows, 133 +/- 45 days in milk (DIM), with an average milk yield of 30 +/- 4 kg/day and a live weight of 624 +/- 69 kg were blocked by DIM and randomly assigned to seven replicated balanced 4 * 4 Latin squares with four 21-day experimental periods. The experimental diets consisted of four total mixed rations (TMR) consisting of early-cut grass silage (EGS) supplemented with either barley- or maize-based concentrate and late-cut grass silage (LGS) supplemented with either barley- or maize-based concentrate. All TMR contained identical proportions of forage (51%) and concentrate (49%). Total tract digestibility was estimated by determining indigestible NDF (iNDF) concentrations in feeds and faeces and using iNDF as an internal marker. The feeds' ruminal degradation parameters were determined using both in situ (nylon bag) and in vitro (gas production (GP)) techniques. Cows offered diets containing EGS had greater (P < 0.001) daily dry matter (DM) intakes, ECM yields and total tract digestibilities for DM and organic matter (OM), but these were not affected by the nature of the concentrate starch source. No interaction between the maturity of the silage and the nature of the concentrate starch source was observed for DMI, diet digestibility or ECM yield. Both grass silages and concentrates had similar rates of ruminal degradation of NDF when measured in situ. The in situ DM (P < 0.001) and starch (P = 0.001) degradation rates of barley-based concentrate were greater than those for maize based concentrate. In vitro OM GP rates and extents were similar for both concentrate feeds. The results showed that diets containing EGS offered better animal performance and diet digestibility than diets containing LGS. The concentrate starch source did not affect animal performance, but total NDF digestibility was better with diet containing barley- than maize-based concentrate. PMID- 23088801 TI - High cost patients for cardiac surgery and hospital quality in Turkey. AB - OBJECTIVE: Encourage quality improvements and assess high expenditures for patients with coronary artery bypass graft (CABG) surgery and hospital quality in Turkey. METHODS: Using the Turkish National Health Insurance Database (2009 2011), CABG surgery patients were identified using International Classification of Diseases Tenth Revision Clinical Modification codes. High-cost cardiac surgery patients had annual healthcare costs in the top 20% post-surgery. The empirical Bayes approach was used to combine mortality rates with hospital volume for quality index, weighing observed mortality according to estimation reliability, with the remaining weight placed on hospital volume. The relationship between hospital quality and high-cost payments was assessed using chi-square tests. RESULTS: Total annual healthcare payments for 20,126 identified CABG patients were approximately ?70 million. High-cost patients incurred 31% of the total expenditures. Although disease severity did not differ for patients across hospitals, those in the lowest quartile, in terms of quality, cared for 25% of high-costs surgery patients, compared with only 18% in the highest quality hospitals (p<0.0001). ?4M in associated cost savings was calculated for patients shifting from low- to high-quality hospitals. CONCLUSIONS: Results imply that hospital quality improvements can reduce costs and improve morbidity and mortality rates in Turkey. PMID- 23088802 TI - Commonalities and differences in HTA outcomes: a comparative analysis of five countries and implications for coverage decisions. AB - OBJECTIVE: To identify diverging HTA recommendations across five countries, understand the rationale for decision-making in specific therapeutic categories, and suggest ways forward to minimize these inter-country differences. METHODS: A comparative analysis of HTA recommendations for 287 drug-indication pairs appraised by five countries (England, Scotland, Sweden, Canada, and Australia) between 2007 and 2009, including an in-depth analysis of two case studies. Agreement levels were measured using kappa scores. Associations were explored through correspondence analysis. RESULTS: Significant inter-country variability in the HTA recommendations exists: 46% of the drug-indication pairs studied received diverging recommendations across countries. The level of agreement between agencies was poor to moderate. Associations between HTA recommendations issued by each HTA body per therapy area (cancer, orphan, CNS) differed from the general pattern observed across the complete sample. Expectations from HTA bodies in terms of relative effectiveness differ depending on the drug and disease's characteristics, although agency-specific guidelines are homogeneous for all treatments. POLICY IMPLICATIONS: Distinguishing and accounting for the specifics underpinning individual conditions and their characteristics in HTA processes may constitute a way forward to improved HTA methods, while increasing transparency in the expectations that HTA bodies have in terms of relative effectiveness of the drug depending on these characteristics. PMID- 23088803 TI - Endovascular rescue of a thoracoabdominal fenestrated endograft presenting with combined type 1 and type 3 endoleaks from aortic graft migration and visceral stent separation. AB - BACKGROUND: To describe successful endovascular rescue of a prior fenestrated endograft repair of a thoracoabdominal aneurysm that presented with combined type I and type III endoleaks due to aortic stent migration and subsequent visceral stent dislodgement. METHOD: A 67 year old male with significant cardiac dysfunction and chronic renal insufficiency underwent fenestrated endograft repair of a 7 cm type IV thoracoabdominal aneurysm with 4 fenestrations in 2008. He presented with acute onset abdominal pain. CT scan revealed type I and III endoleaks with aneurysm enlargement to 10 cm. Angiography revealed the superior mesenteric and renal artery stents within their target vessels, but separation from their respective fenestrations in the aortic graft with significant gaps (>15 mm) and resultant type 3 endoleaks. The celiac artery stent was fractured; part of it remained within the celiac artery and part within the celiac fenestration and a 30 mm craniocaudal gap between the two pieces. All 4 visceral stents were patent with intact distal flow. A large proximal type 1 endoleak was also seen. All fenestrations were successfully catheterized via percutaneous approach and gaps were successfully bridged with covered stents eliminating the type III endoleaks. A thoracic endograft was placed proximally to repair the type I endoleak. RESULTS: Completion angiography demonstrated successful resolution of the type I and type III endoleaks with flow through all 4 branches and tertiary vessels. CONCLUSION: Endovascular rescue of prior branched endografts is a feasible solution in patients at prohibitive risk for open surgery. PMID- 23088804 TI - Splenic artery rupture during pregnancy concealed by a pancreatic lymphangioma: a rare co-occurrence. AB - A pregnant woman presented to a local hospital with abdominal pain and hemorrhagic shock. Emergency caesarean section ruled out an obstetric cause and revealed a large mass, interpreted as a hematoma, with active bleeding of unknown origin. Because of her poor clinical condition, the patient was admitted to our hospital. Computed tomographic findings were suspicious for bleeding originating from the splenic artery. Laparotomy confirmed the presence of a ruptured splenic artery. A splenic artery aneurysm-a relatively well known entity during pregnancy was absent. Hemostasis was achieved by clipping the artery. A large pancreatic cystic mass, which was misinterpreted earlier as a hematoma, was surgically removed. The pathologic examination revealed a pancreatic lymphangioma, an uncommon benign tumor. The ruptured splenic artery was presumably related to the pancreatic lymphangioma and vascular changes caused by pregnancy. A splenic artery rupture in co-occurrence of a pancreatic lymphangioma is a unique presentation which has not been reported previously. PMID- 23088805 TI - Risk factors and impact of proximal fixation on acute and chronic renal dysfunction after endovascular aortic aneurysm repair using glomerular filtration rate criteria. AB - BACKGROUND: The incidence of renal impairment relevant to proximal fixation of aortic endograft devices remains unclear. METHODS: Retrospective cohort of 208 consecutive patients that underwent EVAR from 2006 to 2011. Estimated glomerular filtration rate (eGFR) was based on MDRD study equation. Acute kidney injury (AKI) and chronic kidney disease (CKD) were classified with ADIQ/RIFLE criteria and National Kidney Foundation criteria, respectively. Kaplan-Meier curve was applied to evaluate progression to CKD. Multivariate regression model was fit to identify predictors for developing AKI and CKD. RESULTS: Suprarenal fixation group (SF) included 110 patients and infrarenal fixation group (IF) included 98 patients. Both groups had similar demographics, baseline eGFR, and renal protection protocols. There was a trend for decreased use of contrast in IF group (median: 93.5 vs. 103 cc, P = 0.07). AKI occurred in 15% of patients in SF group and 19% of patients in IF group (RR: 1.24, P = 0.47). The freedom from progression to stage 3 or 4 CKD in the SF group was 0.76, 0.72, and 0.49 at 6, 12, and 18 months, respectively, while for IF group was 0.8, 0.73, and 0.68, respectively (P = 0.4). Increasing age (P = 0.07), lengthy procedures (P < 0.001), and baseline renal dysfunction (P < 0.001) were significant predictors for developing CKD. Contrast volume (P < 0.001) and ace-inhibitors (P = 0.07) were predictors for AKI. CONCLUSION: Proximal fixation type has no significant effect on both acute and chronic renal function. Identification of modifiable perioperative risk factors may be used to improve renal function outcomes. PMID- 23088806 TI - The effect of statin use on embolic potential during carotid angioplasty and stenting. AB - BACKGROUND: Statin use results in atherosclerotic plaque stabilization. We sought to determine the effects of statins on the size and number of embolic particles generated during carotid artery stenting (CAS). METHODS: Embolic debris from carotid filters following CAS was analyzed using photomicroscopy and imaging software. Patient comorbidities, pre-operative cerebrovascular symptoms, statin use, and outcomes (peri-operative major adverse events, MAE) were reviewed. RESULTS: Carotid filters from 62 consecutive CAS procedures were examined. The mean age is 68.7 +/- 9.8 years, 64% were men, 41 (66%) were on statins at the time of CAS, and 27 (43.5%) had neurological symptoms pre-procedurally. The mean intra-procedural stenosis was similar between groups (statin: 89.4 +/- 7.4% vs. no statin: 88.4 +/- 5.9%, P = NS). There was no significant difference in overall pre-operative symptoms between the two groups. Statin users were more likely to have coronary artery disease (CAD, P = 0.02), hyperlipidemia (HL, P = 0.047), or have undergone coronary artery bypass (CABG, P = 0.01). Statin use was associated with significantly less embolic particles (statin: 16.4 +/- 2.1 vs. no statin: 42.4 +/- 9.5, P = 0.001) during CAS. Further, multivariate analysis controlling for CAD, HL, and CABG confirmed that statin use was independently associated with less captured debris (P = 0.005). There was no significant difference in the mean particle size (statin: 326.2 MUm +/- 31.1 vs. no statin 310.5 MUm +/- 41.8), peri procedural stroke, and MAE between the two groups (P = NS). CONCLUSIONS: Statin use is associated with less embolic debris during CAS. Further investigation utilizing a larger study group is necessary to assess the impact of statin use on peri-procedural outcomes. PMID- 23088807 TI - Assessment of the level of difficulty of four techniques of endovenous thermal ablation of the great saphenous vein and the echogenicity of the tip of the working device in vivo. AB - BACKGROUND: To compare the level of difficulty of four techniques of endovenous thermal ablation (EVTA) of the great saphenous vein and the echogenicity of the tip of the working device in vivo. METHODS: Sixty patients qualified to the EVTA of the great saphenous vein were randomly assigned to treatment with an 810-nm axial diode laser [endovenous laser ablation (EVLA) 810] with two different delivery systems: 4-F introducer, 0.018" guidewire, 22-G needle (EVLA810-1) and 4 F introducer, 0.035" guidewire, 19-G needle (EVLA810-2); a 1470-nm radial diode laser (EVLA1470); or radiofrequency ablation (RFA; ClosureFAST). The level of difficulty of four stages of the procedure-cannulation of a vein, advancement of the working part to the saphenofemoral junction (SFJ), visualization of a tip of the working part at SFJ, and difficulty of performing the ablation and delivering the planned linear energy density-was subjectively assessed. An objective comparison of visibility of working parts in ultrasonography was performed with analysis of grayscale median. RESULTS: The cannulation of a distal segment of the obliterated vein was the most difficult in EVLA810-1, P = 0.015. The delivery of a working part to the SFJ was the least problematic in RFA and EVLA1470, P = 0.024. The visualization of the working tip at the SFJ was the most difficult in RFA, P = 0.028. The application of desired amount of energy was the easiest in RFA, P = 0.038. The EVLA1470 presented the best echogenicity. CONCLUSIONS: Although all the examined techniques have advantages and disadvantages, EVTA with the 1470-nm diode laser with radial optic fiber seems to be the easiest. PMID- 23088808 TI - Cysts and swellings: a systematic review of the association between polycystic kidney disease and abdominal aortic aneurysm. AB - BACKGROUND: Whether abdominal aortic aneurysm (AAA) forms part of the extrarenal manifestations of autosomal-dominant polycystic kidney disease (ADPKD) is unclear. We set out to review the evidence for an association. MATERIALS AND METHODS: PubMed, Medline, Embase, and Web of Science databases 1960-2011 were searched [abdominal aortic aneurysm OR AAA OR triple A] AND [polycystic kidney disease OR PKD OR ADPKD OR Renal Cysts]. No limitations were placed on article type or language. Reference lists were recursively searched as were pertinent journal contents. RESULTS: Eighteen papers were included. Since the first documented case of ADPKD and AAA in 1980, there have been 23 case reports. The voluminous kidneys make AAA diagnosis challenging and surgical exposure difficult. Two studies have assessed aortic diameter in patients with ADPKD and controls, one finding increased aortic diameter in ADPKD (2.7 cm vs. 2.3 cm, P < 0.02) and the other finding no difference. A further study identified a higher incidence of renal cysts in patients with AAA compared to controls (54% vs. 30%, P = 0.0006). CONCLUSION: There is not enough clinical evidence to determine if ADPKD and AAA share a common pathology. Larger multicenter trials are required to determine if a link exists. PMID- 23088809 TI - Chronic mesenteric ischemia: critical review and guidelines for management. AB - BACKGROUND: CMI is caused by chronic occlusive disease of mesenteric arteries. In such an uncommon disease, clear recommendations are strongly needed. Unfortunately, treatment options for symptomatic CMI are still controversial and no guidelines exist. METHODS: A systematic literature review of the last 25-years was conducted through MEDLINE, Embase, and Cochrane Review/Trials register to identify studies reporting on CMI treatment with more than 10 patients. Primary outcomes were perioperative mortality and morbidity rates. Secondary outcomes were survival rates, primary and secondary patency rates, vessels treated, CMI recurrence, follow-up (FU), technical success (TS), and in-hospital length of stay (InH-LOS). Patients were divided into endovascular treatment (ET) or open treatment (OT) groups. Subsequently, primary and secondary outcomes were analyzed by study publication year for the interval periods 1986-2000 ("A") and 2001-2010 ("B"). Differences were assessed using the t-test and the chi(2) test. RESULTS: Forty-three articles with 1,795 patients were included. Perioperative mortality and morbidity rates were lower in the ET group. No difference in survival rate was observed. Primary and secondary patencies were superior in the OT group. A greater number of vessels were revascularized in the OT group. CMI recurrence was more frequent in the ET group. FU was longer in the OT group. TS was superior in the OT group and InH-LOS was shorter in the ET group. A higher number of patients were treated by ET in the period "A." No differences in mortality and morbidity were observed between period "A" and "B" in ET and OT groups. CONCLUSIONS: Considering the lower periprocedural mortality and morbidity after ET, this approach should be considered as the first treatment option in most CMI patients, especially in those with severe malnutrition. Primary OT should be restricted to cases that do not qualify for ET or good surgical risk patients with long life expectancy. Considering better long-term results of OT, ET treatment should be considered as a bridge therapy to OT in some patients requiring retreatment if ET does not preclude subsequent OT. PMID- 23088810 TI - Effect of hormone replacement therapy in matrix metalloproteinase expression and intimal hyperplasia development after vascular injury. AB - BACKGROUND: Postmenopausal women taking hormone replacement therapy (HRT) require secondary intervention after vascular reconstruction more frequently than women not taking HRT, often due to increased development of intimal hyperplasia (IH). Matrix metalloproteinases (MMPs) play a role in IH by degradation and remodeling of components of the vascular basement membrane. The MMP pathway is regulated by a balance between MMPs, membrane-type MMPs (MT-MMPs), and tissue inhibitor of MMPs (TIMPs). We have recently provided evidence for unbalanced regulation of the MT1-MMP/MMP-2 pathway in vascular smooth muscle cells (VSMCs) exposed to hormones in vitro. Herein we study the role of HRT in the development of IH in a postmenopausal rodent model of vascular injury and in the modulation of this MMP regulatory pathway in vivo. METHODS: Female rats were aged to 12 months. Animals were ovariectomized (OVX) and 4 weeks later hormones or placebo was delivered via a 90-day slow-release pellet. After 6 weeks of HRT each rat underwent balloon angioplasty of the left common carotid artery. At 14 days postinjury tissue samples were collected and stained with trichrome elastin and for isoform specific MMPs. RESULTS: After vascular injury, the intima:media (I:M) ratio was decreased in OVX rats receiving placebos as compared with non-OVX controls (P < 0.05). In OVX animals receiving HRT, estrogen with and without progesterone and progesterone alone slightly increased I:M ratio compared with placebo, although no significant difference was found in any HRT group. Injury-induced intimal expression of MMP-2 and -9 was decreased in OVX placebo animals compared with non OVX controls (P < 0.05). MMP-2 and -9 levels were subsequently increased by each type of hormone therapy compared with placebo, with a significant increase in MMP 9 in response to estrogen with and without progesterone (P < 0.05). Conversely, TIMP-2 was decreased by estrogen compared with placebo (P < 0.05). There was no effect on intimal MT1-MMP in any group. CONCLUSIONS: In this study we detected a statistically significant decrease in IH as a result of OVX. Subsequent HRT exposure resulted in increased I:M ratios compared with OVX animals given placebo, although significance was not reached with the doses given. Long-term exogenous exposure may have a more deleterious effect compared with acute exposure and should be examined further. We also demonstrated a significant reduction in MMP-2 and -9 and TIMP-2 in response to OVX. Subsequent hormone exposure resulted in the upregulation of MMP-2 and -9 without a counterregulatory increase in TIMP, indicating that HRT modulates the MMP regulatory pathway in vivo. The data suggest that the lack of hormones after OVX protects against pathologic remodeling in our aged model of disease and that exposure to both natural and exogenous hormones could be a negative risk factor resulting in an exaggerated vascular response to injury. Future studies should focus on in vivo manipulation of unbalanced MMP regulation for prevention of IH in response to HRT and in general. Furthermore, the age-associated difference in response to the presence of natural hormones in young vs aged models should be investigated. PMID- 23088812 TI - The sleep patterns and well-being of Australian adolescents. AB - AIM: Adolescent sleep patterns vary between countries, and these differences influence adolescent functioning and well-being. The present study provides data on the sleep and well-being of Australian adolescents. METHODS: 385 adolescents aged 13-18 years were recruited from 8 South Australian schools spanning the socio-economic spectrum. Adolescents completed survey battery during class time at school, followed by a 7-day sleep diary. RESULTS: Australian adolescents, on average, obtained inadequate sleep across the school week. Adolescents commonly reported difficulty initiating sleep, unrefreshing sleep, and the subjective feeling of restless legs. Problematic levels of sleepiness, fatigue, depressed mood and anxiety were highly prevalent. Later bedtimes, longer sleep onset latencies, and shorter sleep duration were significantly associated with aspects of poor daytime functioning. CONCLUSION: These results add to our knowledge of adolescent sleep and well-being worldwide. They also highlight the need for greater attention to sleep during this phase of development, when future behaviors and outcomes are being shaped. PMID- 23088811 TI - Why do smokers diagnosed with COPD not quit smoking? - a qualitative study. AB - BACKGROUND: Chronic Obstructive Pulmonary Disease (COPD) is currently one of the most widespread chronic lung diseases and a growing cause of suffering and mortality worldwide. It is predicted to become the third leading cause of death in the near future. Smoking is the most important risk factor, and about 50% of smokers develop COPD. Smoking cessation is the most important way to improve prognosis. The aim of the study was to describe difficulties of smoking cessation experienced by individuals with COPD who are unable to stop smoking. METHODS: Ten smokers (five women) with COPD, GOLD stage II, participated in semi-structured interviews in 2010. The data were analyzed using qualitative content analysis. The participants were recruited from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. RESULTS: The participants lives were governed by a lifelong smoking habit that was difficult to break although they had knowledge about the harmful effects and the consequences of COPD. The participants described incidents in their lives as reasons for never finding the time to quit smoking. Demands to quit smoking from other people could lead to continued smoking or get them started again after cessation as they did not want to be patronized. They wanted to receive support from relatives and care providers but they wanted to make the decision to quit on their own. CONCLUSION: For successful smoking cessation, it is important to understand the difficulties smokers are experiencing that influence their efforts to quit smoking. To achieve a successful lasting smoking cessation it might be more effective to first ensure that the smoker has the right internal motivation to make the decision to quit, then assist with smoking cessation. PMID- 23088813 TI - Improved method for the extraction and determination of bromophenols in seafoods by high-performance liquid chromatography with fluorescence detection. AB - A sensitive precolumn derivatization method using 10-methylacridone-2-sulfonyl chloride (MASC) as derivatizing reagent followed by high-performance liquid chromatography (HPLC) with fluorescence detection has been developed for the determination of naturally occurring bromophenols in seafoods. Instead of using a traditional complex steam distillation solvent extraction method, the extraction method was modified by using sulfuric acid hydrolysis followed by hexane extraction and subsequent alkaline back extraction to obtain good recoveries and fewer interferences. Batch analysis of bromophenols thus became more performable because the sample amount and analysis time were greatly reduced. The recoveries of the five bromophenols were >80% with a noticeable improvement for 4-BP, the recoveries of which were usually <40% when analyzed by traditional methods. The HPLC sensitivity for the determination of bromophenols was greatly enhanced through derivatization. Under optimal conditions, the quantification limits obtained by using 4.0 g of sample were in the range of 0.60-1.0 ng/g. This is the first time that derivatization was applied to enhance the HPLC sensitivity of bromophenols. The proposed method was successfully applied to the determination of the target compounds in seafoods with a much higher sensitivity than traditional HPLC method. PMID- 23088814 TI - Sensory reweighting in controls and stroke patients. AB - OBJECTIVE: To test sensitivity to proprioceptive, vestibular and visual stimulations of stroke patients with regard to balance. METHOD: The postural control of 20 hemiparetic patients after a single hemispheric stroke that had occurred at least 6 months before the study along with 20 controls was probed with vibration, optokinetic, and vestibular galvanic stimulations. Balance was assessed using a force platform (PF) with two miniature inertial sensors placed on the head (C1) and the trunk (C2) under each sensory condition and measured by three composite scores as the mean displacement of the body (PF, C1, C2) during the stimulation. A subject with a composite score greater than the 75th percentile of the composite scores found in the control subjects was arbitrarily considered to be sensitive to that stimulation. RESULTS: Both control and stroke patients showed large inter-individual variations in response to the three types of sensory stimulation. Among the hemiparetic patients, nearly 65% were sensitive to the optokinetic stimulation, 60% to the galvanic stimulation and 65% to the vibration stimulation. In contrast to the control group, all the hemiparetic subjects were sensitive to at least one type of stimulation. CONCLUSION: Stroke patients are highly dependent on visual, proprioceptive and vestibular information in order to control their standing posture and individually differ in their relative sensitivity to each type of sensory stimulation. SIGNIFICANCE: Contrarily to what one might suppose, the increased visual dependence manifested by stroke patients does not necessarily entail any neglect of proprioceptive and vestibular information. PMID- 23088815 TI - Evaluation of point-of-care haemoglobin measuring devices: a comparison of Radical-7TM pulse co-oximetry, HemoCue((r)) and laboratory haemoglobin measurements in obstetric patients*. AB - We prospectively compared two point-of-care haemoglobin concentration measuring devices with laboratory measurements to determine their accuracy in women undergoing caesarean section delivery. The two devices were the Masimo Rainbow SET((r)) Radical -7TM pulse co-oximeter and the HemoCue((r)) HB 201+, which is a cuvette-type system that uses photometry. Co-oximeter readings and HemoCue measurements were taken before and after surgery, and compared with laboratory measurements of haemoglobin concentration taken at the same time. We analysed data from 137 patients using Bland-Altman plots. Limits of agreement for co oximeter readings were -2.19 to 3.41 g.dl(-1) and for the HemoCue were -1.52 to 1.79 g.dl(-1) . The bias (mean difference) for the co-oximeter was -0.61 g.dl(-1) (95% CI 0.36 to -0.86) and for the HemoCue was 0.13 g.dl(-1) (95% CI -0.015 to 0.28). [corrected] Overall, 110/274 (40%) co-oximeter readings were within 1 g.dl(-1) of laboratory values compared with 247/274 (90%) HemoCue measurements (p < 0.001 for difference). The co-oximeter gave lower readings and was less accurate than the HemoCue system when compared with laboratory measurements. PMID- 23088816 TI - Does the persistence of development delay predict receipt of early intervention services? AB - OBJECTIVE: To examine how the persistence of infants' and toddlers' developmental delays affects their access to early intervention services (EI). METHODS: Using the Early Childhood Longitudinal Study, Birth cohort (ECLS-B), we examined receipt of EI at 24 months for each category of developmental change. Development delay was measured at 9 and 24 months and categorized as none (ie, within 1 SD below the mean), mild (ie, between 1 and 1.5 SD below the mean), and moderate/severe (more than 1.5 SD below the mean). Changes in the subjects' developmental skills between 9 and 24 months were calculated. For children with a delay at either time point, adjusted logistic regression models estimated the likelihood of receiving EI at 24 months. RESULTS: Use of EI varied across severity, type, and timing of developmental delay. Among the children with a cognitive delay, those with delays at 9 and 24 months were significantly more likely to receive EI at 24 months than peers whose delays improved, emerged, or worsened. Among the children with a motor delay, those with regression from normal to moderate/severe were significantly more likely to receive services than children with persistent delays (adjusted odds ratio 2.7, 95% confidence interval 1.1-6.6). CONCLUSIONS: Except for children whose motor skills regress substantially, children with dynamic developmental delays are less likely than their peers with persistent delays to receive EI. This finding suggests the need for improved understanding of developmental surveillance, referral, and use of EI services. PMID- 23088818 TI - Theory of mind development can withstand compromised episodic memory development. AB - As humans, we are consciously aware of unobservable mental states, including our own during episodic memory and other people's by having a "theory of mind" (ToM). Episodic memory and ToM are closely related: they share a neural substrate and emerge close in time in ontogenetic development. This relationship is central to prominent child development and cognitive neuroscience theories of ToM, but its causal nature has not been tested empirically. The current study examined whether normal episodic memory development is necessary for normal ToM development. To investigate this, we tested H.C., a young woman with impaired episodic memory development due to early hippocampal damage, on a wide range of ToM measures. H.C.'s performance was indistinguishable from that of controls on all tests of ToM suggesting that, contrary to theoretical claims in the literature, normal episodic memory development and hippocampal function are not essential for the development of ToM. PMID- 23088819 TI - Impaired visual expertise for print in French adults with dyslexia as shown by N170 tuning. AB - Efficient reading relies on expertise in the visual word form area, with abnormalities in the functional specialization of this area observed in individuals with developmental dyslexia. We have investigated event related potentials in print tuning in adults with dyslexia, based on their N170 response at 135-255 ms. Control and dyslexic adults performed a lexical decision task with symbol strings and four sets of word-like stimuli (consonant strings, pseudowords, low frequency words and high frequency words). N170 tuning was observed in the control group, with larger left occipito-temporal negativities for word-like stimuli than for symbol strings. In contrast, N170 specialization was lacking in dyslexics, suggesting no visual expertise for print. Moreover, behavioral data indicated that adults with dyslexia had longer latencies and more errors for pseudowords than for other stimuli, suggesting a persistent phonological deficit in these individuals. These findings suggest that altered decoding abilities may disrupt perceptual expertise for print. The results are discussed in the context of the phonological mapping deficit theory. PMID- 23088817 TI - Language and reading skills in school-aged children and adolescents born preterm are associated with white matter properties on diffusion tensor imaging. AB - Children born preterm are at risk for deficits in language and reading. They are also at risk for injury to the white matter of the brain. The goal of this study was to determine whether performance in language and reading skills would be associated with white matter properties in children born preterm and full-term. Children born before 36 weeks gestation (n=23, mean+/-SD age 12.5+/-2.0 years, gestational age 28.7+/-2.5 weeks, birth weight 1184+/-431 g) and controls born after 37 weeks gestation (n=19, 13.1+/-2.1 years, 39.3+/-1.0 weeks, 3178+/-413 g) underwent a battery of language and reading tests. Diffusion tensor imaging (DTI) scans were processed using tract-based spatial statistics to generate a core white matter skeleton that was anatomically comparable across participants. Fractional anisotropy (FA) was the diffusion property used in analyses. In the full-term group, no regions of the whole FA-skeleton were associated with language and reading. In the preterm group, regions of the FA-skeleton were significantly associated with verbal IQ, linguistic processing speed, syntactic comprehension, and decoding. Combined, the regions formed a composite map of 22 clusters on 15 tracts in both hemispheres and in the ventral and dorsal streams. ROI analyses in the preterm group found that several of these regions also showed positive associations with receptive vocabulary, verbal memory, and reading comprehension. Some of the same regions showed weak negative correlations within the full-term group. Exploratory multiple regression in the preterm group found that specific white matter pathways were related to different aspects of language processing and reading, accounting for 27-44% of the variance. The findings suggest that higher performance in language and reading in a group of preterm but not full-term children is associated with higher fractional anisotropy of a bilateral and distributed white matter network. PMID- 23088820 TI - Combating healthcare corruption and fraud with improved global health governance. AB - Corruption is a serious threat to global health outcomes, leading to financial waste and adverse health consequences. Yet, forms of corruption impacting global health are endemic worldwide in public and private sectors, and in developed and resource-poor settings alike. Allegations of misuse of funds and fraud in global health initiatives also threaten future investment. Current domestic and sectorial-level responses are fragmented and have been criticized as ineffective. In order to address this issue, we propose a global health governance framework calling for international recognition of "global health corruption" and development of a treaty protocol to combat this crucial issue. PMID- 23088821 TI - Rural experiences with mental illness: through the eyes of patients and their families. AB - People living in rural areas are often faced with multiple, complex, and seemingly insurmountable barriers to receiving appropriate treatment for mental health problems. Some of the barriers identified in the research literature include inaccessibility to mental health providers, stigma, and limited resources in the community. Despite existing data regarding rural patients and their families, little is known about their lived, personal experiences. For this reason, the purpose of this study was to determine the experience of patients and family members who are dealing with mental illness in rural communities. Based on this qualitative analysis of patient and family members' experiences in rural areas, issues surrounding mental health and treatment are accompanied by significant stigma, often left unresolved, and exacerbated by practical challenges which hinder access to proper mental health resources, frequently leaving rural residents to cope with inadequate solutions or seek their own, alternative solutions. PMID- 23088822 TI - Teaching the value of continuity of care: a case conference on long-term healing relationships. AB - The Continuity Case Conference provides a model for teaching family medicine residents the value, importance, and impact of developing long-term doctor patient relationships. A resident's presentation of challenging patient cases and the ensuing group interaction with resident peers, faculty, and medical staff are designed to offer residents alternate perspectives on complex, multiproblem cases while validating the often emotional process of patient care. This learning model is designed to demonstrate how a physician, in the context of the cumulative progression of contacts with a patient, can better manage myriad health issues, chronic and acute, and improve patient outcomes. The description of the 1-hr, once-a-month conference format contained herein includes details on preconference preparation, examples. PMID- 23088823 TI - Anatomy of open access publishing: a study of longitudinal development and internal structure. AB - BACKGROUND: Open access (OA) is a revolutionary way of providing access to the scholarly journal literature made possible by the Internet. The primary aim of this study was to measure the volume of scientific articles published in full immediate OA journals from 2000 to 2011, while observing longitudinal internal shifts in the structure of OA publishing concerning revenue models, publisher types and relative distribution among scientific disciplines. The secondary aim was to measure the share of OA articles of all journal articles, including articles made OA by publishers with a delay and individual author-paid OA articles in subscription journals (hybrid OA), as these subsets of OA publishing have mostly been ignored in previous studies. METHODS: Stratified random sampling of journals in the Directory of Open Access Journals (n = 787) was performed. The annual publication volumes spanning 2000 to 2011 were retrieved from major publication indexes and through manual data collection. RESULTS: An estimated 340,000 articles were published by 6,713 full immediate OA journals during 2011. OA journals requiring article-processing charges have become increasingly common, publishing 166,700 articles in 2011 (49% of all OA articles). This growth is related to the growth of commercial publishers, who, despite only a marginal presence a decade ago, have grown to become key actors on the OA scene, responsible for 120,000 of the articles published in 2011. Publication volume has grown within all major scientific disciplines, however, biomedicine has seen a particularly rapid 16-fold growth between 2000 (7,400 articles) and 2011 (120,900 articles). Over the past decade, OA journal publishing has steadily increased its relative share of all scholarly journal articles by about 1% annually. Approximately 17% of the 1.66 million articles published during 2011 and indexed in the most comprehensive article-level index of scholarly articles (Scopus) are available OA through journal publishers, most articles immediately (12%) but some within 12 months of publication (5%). CONCLUSIONS: OA journal publishing is disrupting the dominant subscription-based model of scientific publishing, having rapidly grown in relative annual share of published journal articles during the last decade. PMID- 23088824 TI - Hyperspectral imaging for non-contact analysis of forensic traces. AB - Hyperspectral imaging (HSI) integrates conventional imaging and spectroscopy, to obtain both spatial and spectral information from a specimen. This technique enables investigators to analyze the chemical composition of traces and simultaneously visualize their spatial distribution. HSI offers significant potential for the detection, visualization, identification and age estimation of forensic traces. The rapid, non-destructive and non-contact features of HSI mark its suitability as an analytical tool for forensic science. This paper provides an overview of the principles, instrumentation and analytical techniques involved in hyperspectral imaging. We describe recent advances in HSI technology motivating forensic science applications, e.g. the development of portable and fast image acquisition systems. Reported forensic science applications are reviewed. Challenges are addressed, such as the analysis of traces on backgrounds encountered in casework, concluded by a summary of possible future applications. PMID- 23088825 TI - Investigation of quartz grain surface textures by atomic force microscopy for forensic analysis. AB - This paper presents a study of quartz sand grain surface textures using atomic force microscopy (AFM) to image the surface. Until now scanning electron microscopy (SEM) has provided the primary technique used in the forensic surface texture analysis of quartz sand grains as a means of establishing the provenance of the grains for forensic reconstructions. The ability to independently corroborate the grain type classifications is desirable and provides additional weight to the findings of SEM analysis of the textures of quartz grains identified in forensic soil/sediment samples. AFM offers a quantitative means of analysis that complements SEM examination, and is a non-destructive technique that requires no sample preparation prior to scanning. It therefore has great potential to be used for forensic analysis where sample preservation is highly valuable. By taking quantitative topography scans, it is possible to produce 3D representations of microscopic surface textures and diagnostic features for examination. Furthermore, various empirical measures can be obtained from analysing the topography scans, including arithmetic average roughness, root-mean square surface roughness, skewness, kurtosis, and multiple gaussian fits to height distributions. These empirical measures, combined with qualitative examination of the surfaces can help to discriminate between grain types and provide independent analysis that can corroborate the morphological grain typing based on the surface textures assigned using SEM. Furthermore, the findings from this study also demonstrate that quartz sand grain surfaces exhibit a statistically self-similar fractal nature that remains unchanged across scales. This indicates the potential for a further quantitative measure that could be utilised in the discrimination of quartz grains based on their provenance for forensic investigations. PMID- 23088827 TI - Why do families still not receive the child support grant in South Africa? A longitudinal analysis of a cohort of families across South Africa. AB - BACKGROUND: Child cash transfers are increasingly recognised for their potential to reduce poverty and improve health outcomes. South Africa's child support grant (CSG) constitutes the largest cash transfer in the continent. No studies have been conducted to look at factors associated with successful receipt of the CSG. This paper reports findings on factors associated with CSG receipt in three settings in South Africa (Paarl in the Western Cape Province, and Umlazi and Rietvlei in KwaZulu-Natal). METHODS: This study used longitudinal data from a community-based cluster-randomized trial (PROMISE EBF) promoting exclusive breastfeeding by peer-counsellors in South Africa (ClinicalTrials.gov: NCT00397150). 1148 mother-infant pairs were enrolled in the study and data on the CSG were collected at infant age 6, 12, 24 weeks and 18-24 months. A stratified cox proportional hazards regression model was fitted to the data to investigate factors associated with CSG receipt. RESULTS: Uptake of the CSG amongst eligible children at a median age of 22 months was 62% in Paarl, 64% in Rietvlei and 60% in Umlazi. Possessing a birth certificate was found to be the strongest predictor of CSG receipt (HR 3.1, 95% CI: 2.4 -4.1). Other factors also found to be independently associated with CSG receipt were an HIV-positive mother (HR 1.2, 95% CI: 1.0-1.4) and a household income below R1100 (HR1.7, 95% CI: 1.1 -2.6). CONCLUSION: Receipt of the CSG was sub optimal amongst eligible children showing administrative requirements such as possessing a birth certificate to be a serious barrier to access. In the spirit of promoting and protecting children's rights, more efforts are needed to improve and ease access to this cash transfer program. PMID- 23088826 TI - New "lethal highs": a case of a deadly cocktail of GHB and Mephedrone. AB - Drug scenes within several countries have changed in recent years to incorporate a range of licit psychoactive products collectively known as "legal highs": these in combination with substances already in use can cause major health problems and even death. Consumption of Gamma-hydroxybutyric acid (GHB) spread from 1980s to 2000s, when several nations have enacted laws that have made it illegal. Cases of GHB-caused or related deaths are often described in association with alcohol or traditional drugs (heroin, cocaine, amphetamine); few cases of acute lethal toxicity due to Mephedrone have been recently reported; we describe the first case of fatality due to concomitant consumption of GHB and Mephedrone. A 43 years old man died during a drugs-based party: the two substances were not detected at toxicological screening, but were identified by further analysis on the basis of circumstantial data reported by a survivor. Through our work we aim to bring to the attention in the emerging role of new drugs of abuse, and highlight problems in identifying these drugs with immunoassay screening test commonly used. PMID- 23088828 TI - Unusual roles of host metabolic enzymes and housekeeping proteins in plant virus replication. AB - Viruses have developed the ability to improvise their own replication machineries with host proteins, adapt to different environments, and overcome difficulties encountered during various stages of their infection cycles. The modular nature of protein functional motifs allows for the novel use of ordinary host factors. Recent studies have revealed that positive-sense RNA [(+)RNA] viruses may adapt regular metabolic enzymes and housekeeping proteins of host plants by exploiting unusual functions to accommodate their need for replication, mainly for recruitment and subcellular localization of RNA templates or components of replicase complexes and for controlling switches in different stages of replication. This review compares the newly discovered roles of selected metabolic enzymes and housekeeping proteins in plant (+)RNA virus replication with their original cellular functions and the different consequences when utilized by different viruses. PMID- 23088829 TI - A registry of adult African American twins: the Carolina African American Twin Study of Aging. AB - Twin studies have seldom addressed ethnicity as one of the possible factors that create unique combinations of genetic and environmental influences. The major objective of the Carolina African American Twin Study of Aging is to identify the proportion of the genetic and environmental sources of individual variation in measures of health and behavioral factors in a sample of adult African Americans. Drawn from birth records from the State of North Carolina, this in-person study used public records to identify a cohort of twins between 22 and 92 years of age (X = 49.82 yrs, SD = 14.62), 39.7% of which were men. Members of non-intact twin pairs and siblings were also recruited to explore alternative models to the classic twin design. To date, the project has contributed to knowledge about blood pressure, forced expiratory volume, chronic illness, body mass index, and waist-hip ratio memory, personality, social, and demographic factors, mortality, and mental health. PMID- 23088830 TI - Relationship between cortisol level and prevalent/incident cognitive impairment and its moderating factors in older adults. AB - BACKGROUND: The objectives of this study were to examine the factors modifying the relationship between cortisol level and prevalent/incident cognitive impairment in older adults and to verify whether these relationships were non linear. METHODS: Data were collected from 1,226 individuals aged 65 and older by two in-home interviews separated by 12 months. Cortisol level was measured using saliva samples taken at the beginning of the baseline interview before cognitive, mental, and physical health evaluations. Prevalent and incident cognitive impairment were defined using the Mini-Mental State Examination scores according to normative data for age, education level, and sex. RESULTS: High morning cortisol level increased the risk of incident cognitive impairment in participants with anxiety or depressive episode while low cortisol level increased the risk in participants without anxiety or depressive episode. In high educated participants, but not in low educated participants, high morning cortisol level was associated with prevalent cognitive impairment and high afternoon cortisol level increased the risk of incident cognitive impairment. The results also suggested that lower morning cortisol values could increase the risk of incident cognitive impairment in individuals with few chronic diseases. A curvilinear relationship was observed between morning cortisol and the probability of incident cognitive impairment, but further analyses suggested that it was likely explained by anxiety and depressive episode. CONCLUSIONS: These results suggest that cognitive impairment in older adults is linked to higher or lower cortisol level depending on characteristics such as anxiety, depressive episode, education level, and physical health. PMID- 23088831 TI - Corticosterone treatment impairs auditory fear learning and the dendritic morphology of the rat inferior colliculus. AB - Stress leads to secretion of the adrenal steroid hormone corticosterone (CORT). The aim of this study was to determine the effects of chronic CORT administration on auditory and visual fear conditioning. Male Sprague-Dawley rats received CORT (400 mg/ml) in their drinking water for 10 consecutive days; this treatment induces stress levels of serum CORT. CORT impaired fear conditioning (F((1,28)) = 11.52, p < 0.01) and extinction (F((1,28)) = 4.86, p < 0.05) of auditory fear learning, but did not affect visual fear conditioning. In addition, we analyzed the CORT effects on the neuronal morphology of the inferior colliculus (flat neurons, auditory mesencephalon, a key brain area for auditory processing) and superior colliculus (wide-field neurons, related to visual processing) by Golgi stain. CORT decreased dendritic arborization of inferior colliculus neurons by approximately 50%, but did not affect superior colliculus neurons. Thus, CORT had more deleterious effects on the auditory fear processing than the visual system in the brain. PMID- 23088832 TI - Tinnitus-related neural activity: theories of generation, propagation, and centralization. AB - The neuroscience of tinnitus represents an ideal model to explore central issues in brain functioning such as the formation of auditory percepts, in addition to opening up new treatment avenues for the condition in the long-term. The present review discusses the origin and nature of tinnitus-related neural activity. First, we review evidence for the hypothesis that tinnitus is caused by the central nervous system changes induced by sensory deprivation, even when hearing loss is not visible in the audiogram. Second, we suggest that changes in neural activity in individual central structures may not be sufficient to underlie the tinnitus percept. Instead, we propose that tinnitus may arise from functional alterations at multiple levels which promote abnormal propagation of neural activity throughout the network involved in auditory perception. In this context, functional coupling within and between central auditory structures may be especially important to consider. Investigating how sensory deprivation affects functional coupling between areas, which might be reflected in changes in temporal coherence of intrinsic ongoing activity patterns, may give critical insights into the mechanisms of tinnitus. PMID- 23088833 TI - The detection of Cryptosporidium and the resolution of mixtures of species and genotypes from water. AB - Environmental concentrations of Cryptosporidium require molecular assays with ultra-sensitive detection limits and which provide critical information on genetic diversity within the genus, a feat particularly challenging from a diagnostics point of view. In this study, the performance of repetitive nested PCR-RFLP and limiting template dilution repetitive nested PCR-RFLP were assessed for their ability to detect Cryptosporidium and resolve mixtures of species and genotypes on microscope slides prepared by USEPA Method 1623 from raw water samples. Seventy percent of water samples positive for Cryptosporidium oocysts by immunofluorescent microscopy tested positive by molecular assays and resulted in species/genotype identification. Multiple species/genotypes were detected in 41% of the samples, including 30 samples from which 3 species/genotypes were detected and 11 samples where 4 species/genotypes were detected. In all, 29 species or genotypes were detected which were represented by the 102 different sequences identified. Of these, 64 were considered novel as no matches were available in GenBank. These results support the use of repetitive and limiting template approaches for the detection and resolution of Cryptosporidium from the environment as well as further supporting the use of DNA sequencing as the most appropriate tool for identifying Cryptosporidium species and genotypes from water. PMID- 23088834 TI - Plasmodium knowlesi: the emerging zoonotic malaria parasite. AB - Plasmodium knowlesi was initially identified in the 30s as a natural Plasmodium of Macaca fascicularis monkey also capable of experimentally infecting humans. It gained a relative notoriety in the mid-30s as an alternative to Plasmodium vivax in the treatment of the general paralysis of the insane (neurosyphilis). In 1965 the first natural human infection was described in a US military surveyor coming back from the Pahang jungle of the Malaysian peninsula. P. knowlesi was again brought to the attention of the medical community when in 2004, Balbir Singh and his co-workers reported that about 58% of malaria cases observed in the Kapit district of the Malaysian Borneo were actually caused by P. knowlesi. In the following years several reports showed that P. knowlesi is much more widespread than initially thought with cases reported across Southeast Asia. This infection should also be considered in the differential diagnosis of any febrile travellers coming back from a recent travel to forested areas of Southeast Asia. P. knowlesi can cause severe malaria with a rate of 6-9% and with a case fatality rate of 3%. Respiratory distress, acute renal failure, shock and hyperbilirubinemia are the most frequently observed complications of severe P. knowlesi malaria. Chloroquine is considered the treatment of choice of uncomplicated malaria caused by P. knowlesi. PMID- 23088835 TI - Detection of Toxoplasma gondii oocysts in different water resources by Loop Mediated Isothermal Amplification (LAMP). AB - Human toxoplasmosis is potentially contracted due to consumption of contaminated drinking water and represents an increasing public health risk worldwide. Toxoplasma gondii oocysts can be resistant to standard disinfection processes, including UV radiation. Increased awareness of the risk of waterborne toxoplasmosis outbreaks has led to an increase in research interest in the detection of oocysts in environmental water systems. Ninety-five environmental water samples from the Lower Rhine area in Germany have been included in the study and examined for the presence of Toxoplasma. Water samples were filtered or flocculated by aluminum sulfate and purified by sucrose density gradient. DNA was then extracted, and the DNA samples were then examined by LAMP analysis. T. gondii DNA was detected in eight out of 83 (9.6%) influent and effluent samples obtained from wastewater treatment plants. All samples (n=12) from the surface, ground, raw and tap waters tested negative. The purpose of this work was to investigate the occurrence and distribution of Toxoplasma oocysts on the Lower Rhine in Germany. Our study provides evidence that the assay is a sensitive, specific, rapid and cost effective method for the detection of T. gondii and is useful for both the investigations of cases of waterborne outbreaks and for identifying the source of contamination. PMID- 23088836 TI - Conditions for patchiness in plankton models. AB - Plankton patchiness in homogeneous physical environments is studied in this paper assuming that all involved populations disperse diffusively. A recent but powerful sufficient condition for the emergence of spatial patterns in models with any number of species is systematically applied to all food chain and food web plankton models and the result is rather sharp: all models explicitly containing phytoplankton, zooplankton and planktivorous fish suggest zooplankton patchiness, while models not containing phytoplankton or fish populations do not. The results are in agreement with many previous but particular theoretical studies on plankton patchiness and Turing instability, and a testable prediction of the models satisfying the sufficient predictions is that zooplankton should be more patchy than phytoplankton, a property that is often seen in natural settings. An application to a complex model with five compartments (nutrient, phytoplankton, zooplankton, planktivorous fish, carnivorous fish) highlights the predictive power of the method. PMID- 23088837 TI - Comparison of the single-use Ambu((r)) aScopeTM 2 vs the conventional fibrescope for tracheal intubation in patients with cervical spine immobilisation by a semirigid collar*. AB - Fibreoptic intubation remains a key technique for the management of difficult intubation. We randomly compared the second generation single-use Ambu((r)) aScopeTM 2 videoscope with a standard re-usable flexible intubating fibrescope in 50 tracheal intubations in patients with a difficult airway simulated by a semirigid collar. All patients' tracheas were intubated successfully with the aScope 2 or the re-usable fibrescope. The median (IQR [range]) time to intubate was significantly longer with the aScope 2 70 (55-97 [41?-226]) s vs 50 (40-59 [27-175]) s, p = 0.0003) due to an increased time to see the carina. Quality of vision was significantly lower with the aScope 2 (excellent 24 (48%) vs 49 (98%), p = 0.0001; good 22 (44%) vs 1 (2%), p = 0.0001; poor 4 (8%) vs 0, p = 0.12) but with no difference in the subjective ease to intubate (easy score of 31 (62%) vs 38 (76%), p = 0.19; intermediate 12 (24%) vs 7 (14%), p = 0.31; difficult 7 (14%) vs 5 (5%), p = 0.76). The longer times to intubate and the poorer scores for quality of vision do not support the use of the single-use aScope 2 videoscope as an alternative to the re-usable fibrescope. PMID- 23088838 TI - The use of native chemical functional groups presented by wound beds for the covalent attachment of polymeric microcarriers of bioactive factors. AB - The development of versatile methods that provide spatial and temporal control over the presentation of physical and biochemical cues on wound beds can lead to new therapeutic approaches that expedite wound healing by favorably influencing cellular behaviors. Toward that goal, we report that native chemical functional groups presented by wound beds can be utilized for direct covalent attachment of polymeric microbeads. Specifically, we demonstrated the covalent attachment of maleimide-functionalized and catechol-functionalized microbeads, made of either polystyrene (non-degradable) or poly(lactic-co-glycolic acid) ((PLGA), degradable), to sulfhydryl and amine groups present on porcine dermis used here as an ex vivo model wound bed. A pronounced increase (10-70 fold) in the density and persistence of the covalently reactive microbeads was observed relative to microbeads that adsorb via non-covalent interactions. Complementary characterization of the surface chemistry of the ex vivo wound beds using Raman microspectroscopy provides support for our conclusion that the increased adherence of the maleimide-functionalized beads results from their covalent bond formation with sulfhydryl groups on the wound bed. The attachment of maleimide functionalized microbeads to wounds created in live wild-type and diabetic mice led to observations of differential immobilization of microbeads on them and were consistent with anticipated differences in the presentation of sulfhydryl groups on the two different wound types. Finally, the incorporation of maleimide functionalized microbeads in wounds created in wild-type mice did not impair the rate of wound closure relative to an untreated wound. Overall, the results presented in this paper enable a general and facile approach to the engineering of wound beds in which microbeads are covalently immobilized to wound beds. Such immobilized microbeads could be used in future studies to release bioactive factors (e.g., antimicrobial agents or growth factors) and/or introduce topographical cues that promote cell behaviors underlying healing and wound closure. PMID- 23088840 TI - AG73-modified Bubble liposomes for targeted ultrasound imaging of tumor neovasculature. AB - Ultrasound imaging is a widely used imaging technique. The use of contrast agents has become an indispensible part of clinical ultrasound imaging, and molecular imaging via ultrasound has recently attracted significant attention. We recently reported that "Bubble liposomes" (BLs) encapsulating US imaging gas liposomes were suitable for ultrasound imaging and gene delivery. The 12 amino acid AG73 peptide derived from the laminin alpha1 chain is a ligand for syndecans, and syndecan-2 is highly expressed in blood vessels. In this study, we prepared AG73 peptide-modified BLs (AG73-BLs) and assessed their specific attachment and ultrasound imaging ability for blood vessels in vitro and in vivo. First, we assessed the specific attachment of AG73-BLs in vitro, using flow cytometry and microscopy. AG73-BLs showed specific attachment compared with non-labeled or control peptide-modified BLs. Next, we examined ultrasound imaging in tumor bearing mice. When BLs were administered, contrast imaging of AG73-BLs was sustainable for up to 4 min, while contrast imaging of non-labeled BLs was not observed. Thus, it is suggested that AG73-BLs may become useful ultrasound contrast agents in the clinic for diagnosis based on ultrasound imaging. PMID- 23088839 TI - The influence of specific binding of collagen-silk chimeras to silk biomaterials on hMSC behavior. AB - Collagen-like proteins in the bacteria Streptococcus pyogenes adopt a triple helix structure with a thermal stability similar to that of animal collagens, can be expressed in high yield in Escherichia coli and can be easily modified through molecular biology techniques. However, potential applications for such recombinant collagens are limited by their lack of higher order structure to achieve the physical properties needed for most biomaterials. To overcome this problem, the S. pyogenes collagen domain was fused to a repetitive Bombyx mori silk consensus sequence, as a strategy to direct specific non-covalent binding onto solid silk materials whose superior stability, mechanical and material properties have been previously established. This approach resulted in the successful binding of these new collagen-silk chimeric proteins to silk films and porous scaffolds, and the binding affinity could be controlled by varying the number of repeats in the silk sequence. To explore the potential of collagen-silk chimera for regulating biological activity, integrin (Int) and fibronectin (Fn) binding sequences from mammalian collagens were introduced into the bacterial collagen domain. The attachment of bioactive collagen-silk chimeras to solid silk biomaterials promoted hMSC spreading and proliferation substantially in comparison to the controls. The ability to combine the biomaterial features of silk with the biological activities of collagen allowed more rapid cell interactions with silk-based biomaterials, improved regulation of stem cell growth and differentiation, as well as the formation of artificial extracellular matrices useful for tissue engineering applications. PMID- 23088841 TI - Folic acid-modified dendrimer-entrapped gold nanoparticles as nanoprobes for targeted CT imaging of human lung adencarcinoma. AB - We report a new usage of folic acid-modified dendrimer-entrapped gold nanoparticles (Au DENPs-FA) as nanoprobes for in vitro and in vivo targeted computed tomography (CT) imaging of human lung adencarcinoma. In this study, Au DENPs prepared using amine-terminated generation 5 poly(amidoamine) dendrimers as templates were covalently linked with FA, followed by an acetylation reaction to neutralize the remaining dendrimer surface amines. The formed Au DENPs-FA was used for both in vitro and in vivo targeted CT imaging of human lung adencarcinoma cells (SPC-A1 cells) and the xenograft tumor model, which express folic acid receptors (FAR) verified by immunohistochemical staining. Micro-CT images show that SPC-A1 cells can be detected under X-ray after incubation with the Au DENPs-FA in vitro and the xenograft tumor model can be imaged after intravenous, intratumoral, and intraperitoneal administration of the particles. Transmission electron microscopy data confirm that the Au DENPs-FA is able to be uptaken dominantly in the lysosomes of the cells. Combined morphological observation of cells after Hematoxylin and Eosin staining, MTT (3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay of cell viability, and flow cytometric analysis of cell cycle and apoptosis show that the Au DENPs FA does not affect cell morphology, viability, and cell cycle and apoptosis, indicating their good biocompatibility at the given concentration range. These findings suggest that the developed Au DENPs-FA have a great potential to be used as imaging probes for targeted CT imaging of human lung adencarcinoma. PMID- 23088842 TI - May you live in interesting times. PMID- 23088843 TI - VGKC complex antibodies in pediatric severe acute encephalitis: a study and literature review. AB - BACKGROUND: Antibodies to surface proteins like voltage-gated potassium channel (VGKC) complexes are increasingly found in different neurologic diseases and encephalitis in adults and recently, in children. Detecting such antibodies can help identify forms of encephalitis that may respond to immuno-therapies. However, there are few reports on VGKC complex antibodies in pediatric severe acute encephalitis. METHODS: This study retrospectively reviewed antibodies to VGKC, leucine-rich glioma-inactivated 1 (Lgi1), and contactin-associated protein like 2 (Caspr2) in 46 children with severe acute encephalitis. Published cases of VGKC complex antibodies in pediatric encephalitis in the period of 2000-2012 were also reviewed. RESULTS: Elevated VGKC complex antibodies (>100pM) were detected in one of the 46 children with severe acute encephalitis. The 4-year and 6-month old girl presented with seizure and disturbed consciousness. Viral PCR/culture and serologic evidence of influenza A infection was noted. She also had complications of epilepsy, impaired cognition, and altered behavior and psychology. Antibodies to Lgi1 and Caspr2 were not detected. Ten previously published reports revealed that VGKC complex antibodies can occur in children with limbic encephalitis and acute or sub-acute encephalitis. CONCLUSION: The incidence of VGKC complex antibodies in pediatric severe acute encephalitis is not high with only one (2.2%) of 46 children in this study. And, this is the first report on the association of VGKC complex antibodies and patients with influenza A-related severe acute encephalitis. The mechanism of VGKC complex antibodies in pediatric severe acute encephalitis warrants further study. PMID- 23088844 TI - Malaria and gravidity interact to modify maternal haemoglobin concentrations during pregnancy. AB - BACKGROUND: Primigravidity is one of the main risk factors for both malaria and anaemia. Since the implementation of intermittent preventive treatment (IPTp) in sub-Saharan Africa, the relationship between anaemia and gravidity and its evolution during pregnancy has been little explored. This study aimed to evaluate the impact of gravidity on the variation of haemoglobin during pregnancy according to the timing of gestation. METHODS: Data from three studies carried out in nearby areas in south Benin (Ouidah, Come, Allada) between 2005 and 2012 were analysed. At inclusion (first antenatal visit, ANV1) women's age, area of residence, schooling, gravidity, gestational age, weight and height were recorded. Thick blood smears were performed on ANV1, second visit (ANV2) and at delivery. In Allada, women's serum ferritin and CRP concentrations were also assessed. The impact of gravidity on maternal haemoglobin (Hb) was analysed using a logistic or linear regression depending on the outcome. The statistical significance was set to P < 0.05. RESULTS: In total, data from 3,591 pregnant women were analysed. Both univariate and multivariate analyses showed a constant association between Hb concentrations and gravidity in the three periods of Hb assessment (ANV1, ANV2 and delivery). Mean Hb concentration was significantly lower in primigravidae than in multigravidae at ANV1 (mean difference = -2.4 g/L, CI 95%: [-3.4, -1.4], P < 0.001). Afterwards, there was a significant increase in primigravidae only, with a tendency to reversal between primigravidae and multigravidae, which was confirmed at delivery (mean difference = 2.8 g/L, CI 95%: [1.3, 4.2], P < 0.001). The prevalence of malaria infection was halved between ANV1 and delivery in primigravidae while it decreased by only 38% among multigravidae, who were less prone to malaria infection (prevalence at ANV1, 20% and 10% respectively). Iron deficiency was more common in multigravidae, and it decreased slightly in this group between ANV1 and delivery. CONCLUSION: In a context of IPTp, Hb levels improved progressively throughout pregnancy in primigravidae, likely as a result of reduction in malaria infection. In multigravidae, the improvement was less perceptible and anaemia was mainly due to iron deficiency. PMID- 23088845 TI - Molecular characterization of hepatitis c virus in multi-transfused Colombian patients. AB - BACKGROUND: Hepatitis C virus (HCV) infects 170 million persons worldwide and is a public health problem. Considering that HCV is principally transmitted by exposure to infected blood, multi-transfused patients constitute one of the most important risk groups in developing countries. To explore the dynamics of this infection in Colombia, we performed a study to determine the genotypes of HCV in a cohort of multi-transfused patients. RESULTS: The serum samples from patients positive for anti-HCV were evaluated for HCV RNA by nested-PCR of the 5'untranslated region (5'UTR). Viral genotype was determined by RFLP and/or automated sequencing. HCV subtype 1b was found in eight cases (66.7%) and subtype 1a in two cases (16.7%); seven isolates of subtype 1b were obtained from patients who had received the first transfusion before 1986. Either genotypes 2b (8.3%) or 3a (8.3%) were found in the remaining positive specimens. CONCLUSIONS: This is the first HCV genotyping study developed in multi-transfused patients in Colombia where HCV subtype 1b was the most prevalent. The mutation G235A in the 5'UTR of three isolates generated an additional restriction site and an RFLP pattern different from those previously described for genotype 1. PMID- 23088846 TI - Dimensions of positive symptoms in late versus early onset psychosis. AB - BACKGROUND: Casenote studies have characterized late onset schizophrenia (LOS) and related psychoses as somewhat different symptomatically from patients with an early onset schizophrenia (EOS). This study examined a range of phenomenological aspects of delusions and hallucinations as well as traditional symptom measures in both groups. METHODS: 34 LOS and 235 EOS completed the Positive and Negative Syndrome Scale, the Psychotic Symptom Rating Scales, and the Beck Depression and Anxiety inventories. Subgroups experiencing delusions were compared matching for chronological age and gender, and also when matched for chronicity and gender. RESULTS: Delusions were very common at over 80% in both groups. LOS participants with delusions exhibited greater suspiciousness/paranoia, greater belief conviction, and reduced insight when compared with the EOS group. These findings remained when matching for chronicity of illness, but disappeared when matching for chronological age. Hallucinations were surprisingly rarer in LOS (35%) than EOS (57%), with half the LOS group reporting whispers rather than clearly audible sounds. In general, anxiety, depression, and distress were as marked in LOS and EOS. CONCLUSIONS: Similarities between EOS and LOS far outweighed the differences across a range of symptoms and measures. Greater delusional conviction, paranoia, and poorer insight in LOS were associated with the later age of onset rather than relating to chronicity of illness. As belief-conviction in LOS was not associated with increased grandiosity, disorientation, or unusualness of thought content, as it was in EOS, delusional conviction may be determined somewhat differently later in life. PMID- 23088847 TI - An update on the Italian Twin Register: advances in cohort recruitment, project building and network development. AB - The Italian Twin Register has been in place for more than 10 years. Since its establishment, it has been focusing, on the one hand, on a continuous update of the existing information, and on the other hand, on new phenotypes and sample collection. Demographic data on about 140,000 twins have been updated using the municipality registries. The Italian Twin Register has been carrying out several new studies during the last few years. A birth cohort of twins, Multiple Births Cohort Study, has been started and the enrollment is ongoing. For this cohort, data on pregnancy and birth are collected, and periodical follow-ups are made. DNA is being collected for the twins and their parents. In the area of behavioral genetics, most efforts have been directed to psychological well being assessed with self-reported tools. Research on age-related traits continues with studies on arteriosclerosis development, early biomarkers in mild cognitive impairment, and the relation between lifestyle habits and mutagen sensitivity. The Italian Twin Register biobanking has grown in its size and in its know-how in terms of both technical issues and ethical procedures implementation. Furthermore, attitudes toward biobank-based research, together with willingness and motivation for donation, are being investigated. A valuable key resource for the Italian Twin Register is the possibility of linking twin data with disease registries. This approach has been yielding several important results, such as the recent study on the heritability of type 1 diabetes. PMID- 23088848 TI - Anti-inflammatory effects and acute toxicity of hydroethanolic extract of Jacaranda decurrens roots in adult male rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Jacaranda decurrens subsp. symmetrifoliolata Farias and Proenca (Bignoniaceae) is a species traditionally used for the treatment of inflammatory diseases. However, until this moment, there is no scientific evidence of these effects. AIM OF STUDY: To evaluate the anti inflammatory effects of hydroethanolic root extract of Jacaranda decurrens in rats and to determine the safe of this plant after acute exposure. MATERIALS AND METHODS: The acute toxicity of Jacaranda decurrens root extract (EJD) was evaluated by oral administration to male rats as single doses of 0; 500; 1000 or 2000 mg/kg body weight. General behavior and toxic symptoms were observed for 14 days. The anti-inflammatory activity was evaluated in carrageenan-induced inflammatory paw edema and myeloperoxidase activity in male rats. RESULTS: No signs of acute toxicity were observed, indicating that the LD(50) is greater than 2000 mg/kg. EJD (100 and 300 mg/kg) significantly reduced edema formation and at higher dose, the reduction was similar to dexamethasone. A significant decrease in myeloperoxidase activity was also observed. CONCLUSIONS: The present study shows that Jacaranda decurrens extract has anti-inflammatory properties in rats without causing acute toxicity. These properties observed may be due to the presence of bioactive constituents such as ursolic acid. PMID- 23088849 TI - The activity of mate saponins (Ilex paraguariensis) in intra-abdominal and epididymal fat, and glucose oxidation in male Wistar rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ilex paraguariensis A. St. Hilaire (mate) has traditionally been used in several South American countries to prepare tea-like beverages having stimulant effects on the CNS and appetite. In recent years, however, mate preparations have been recommended putatively as an appetite suppressant and slimming remedy. Moreover, studies carried out on either normal or diet-induced obese rats treated with mate extracts revealed anti-obesity and satiety effects, thus refuting ethnopharmacological data. In this work, the effect of mate on the intra-abdominal and epididymal fat, and glucose oxidation levels after oral administration in male Wistar rats, was studied using crude extract from leaves, unripe fruits, and a chemically well-defined purified saponin fraction (MSF). MATERIAL AND METHODS: Saponin, polyphenol and methylxanthine contents in MSF were analyzed by HPLC-PDA and UPLC/Q-TOF-MS. Crude extracts from mate leaves (LAE) and unripe fruits (FHE) were assayed for comparison purposes. Male Wistar rats fed with standard diet and water ad libitum were used as the control group. RESULTS: The fat weight and both liver and adipose glucose oxidation were reduced significantly by MSF (35, 90 and 60%, respectively), while LAE and FHE were less active. Also, a significant lowering of the blood triglycerides level was observed in rats treated with MSF and LAE. All creatinine, urea, and transaminase plasma levels remained unaffected no matter what mate preparation was considered. It is also worth pointing out that the glucose blood level was increased after treatment with FHE. This finding did not correlate either with the content of methylxanthines, polyphenols or saponins. CONCLUSION: A reduction in both visceral fat weight and glucose oxidation of hepatic and adipose tissue in healthy rats fed with a standard diet could be ascribed to a purified mate saponin fraction from unripe fruits. These findings agree with former studies carried out with crude mate extracts and also suggest their potential use as an anti-obesity preparation. Nonetheless, further in vivo experiments are still required to corroborate its effect on human beings. PMID- 23088850 TI - Resveratrol depletes mitochondrial DNA and inhibition of autophagy enhances resveratrol-induced caspase activation. AB - We recently demonstrated that resveratrol induces caspase-dependent apoptosis in multiple cancer cell types. Whether apoptosis is also regulated by other cell death mechanisms such as autophagy is not clearly defined. Here we show that inhibition of autophagy enhanced resveratrol-induced caspase activation and apoptosis. Resveratrol inhibited colony formation and cell proliferation in multiple cancer cell types. Resveratrol treatment induced accumulation of LC3-II, which is a key marker for autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, increased resveratrol-mediated caspase activation and cell death in breast and colon cancer cells. Inhibition of autophagy by silencing key autophagy regulators such as ATG5 and Beclin-1 enhanced resveratrol-induced caspase activation. Mechanistic analysis revealed that Beclin-1 did not interact with proapoptotic proteins Bax and Bak; however, Beclin-1 was found to interact with p53 in the cytosol and mitochondria upon resveratrol treatment. Importantly, resveratrol depleted ATPase 8 gene, and thus, reduced mitochondrial DNA (mtDNA) content, suggesting that resveratrol induces damage to mtDNA causing accumulation of dysfunctional mitochondria triggering autophagy induction. Together, our findings indicate that induction of autophagy during resveratrol-induced apoptosis is an adaptive response. PMID- 23088851 TI - The influence of deep brain stimulation intensity and duration on symptoms evolution in an OFF stimulation dystonia study. AB - BACKGROUND: Deep brain stimulation (DBS) of the internal globus pallidus (GPi) is an established therapy for primary generalized dystonia. However, the evolution of dystonia symptoms after DBS discontinuation after years of therapy has only rarely been reported. We therefore longitudinally studied the main physiological measurements known to be impaired in dystonia, with DBS ON and then again after termination of DBS, after at least five years of continuous DBS. OBJECTIVE: We studied whether dystonia evolution after DBS discontinuation in patients benefiting from long-term GPi DBS is different from that observed in earlier stages of the therapy. METHODS: In eleven DYT1 patients treated with bilateral GPi DBS for at least 5 years, dystonia was assessed ON-DBS, immediately after switch-off (OFF-DBS1) and 48 h after DBS termination (OFF-DBS2). We studied the influence of DBS intensity on dystonia when DBS was discontinued. RESULTS: On average a significant difference in symptoms was measured only between ON-DBS and OFF-DBS1 conditions. Importantly, none of the patients returned to their preoperative dystonia severity, even 48 h after discontinuation. The amount of clinical deterioration in the OFF conditions positively correlated with higher stimulation current in the chronic ON-DBS condition. CONCLUSIONS: The duration of DBS application influences symptom evolution after DBS termination. DBS intensity seems to have a prominent role on evolution of dystonic symptoms when DBS is discontinued. In conclusion, DBS induces changing modulation of the motor network with less worsening of symptoms after long term stimulation, when DBS is stopped. PMID- 23088852 TI - Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation. AB - BACKGROUND: Vagus nerve stimulation (VNS) is a palliative treatment for drug resistant epilepsy for which the efficacy and safety are well established. Accumulating evidence suggests that ascending vagal signals modulate abnormal cortical excitability via various pathways. However, there is no direct evidence for an ascending conduction of neural impulses in a clinical case of VNS. OBJECTIVE: We recorded and analyzed the short-latency components of the vagus nerve (VN) evoked potential (EP) from the viewpoint of determining whether or not it is a marker for the ascending neural conduction. METHODS: EPs within 20 ms were prospectively recorded simultaneously from a surgical wound in the neck and at multiple scalp sites during implantation surgery in 25 patients with drug resistant epilepsy. Electrical stimulation was delivered using the clinical VNS Therapy system. A recording was made before and after a muscle relaxant was administered, when changing the rostrocaudal position of stimulation, or when stimulating the ansa cervicalis instead of the VN. RESULTS: The short-latency components consisted of four peaks. The early component around 3 ms, which was most prominent in A1-Cz, remained unchanged after muscle relaxation while the later peaks disappeared. Rostral transition of the stimulation resulted in an earlier shift of the early component. The estimated conduction velocity was 27.4 +/- 10.2 m/s. Stimulation of the ansa cervicalis induced no EP. CONCLUSIONS: The early component was regarded as directly resulting from ascending neural conduction of A fibers of the VN, probably originating around the jugular foramen. Recording of VN-EP might document the cause of treatment failure in some patients. PMID- 23088853 TI - Effects of repeated deep brain stimulation on depressive- and anxiety-like behavior in rats: comparing entopeduncular and subthalamic nuclei. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or internal globus pallidus (GPi) has been routinely used for the treatment of some movement disorders. However, DBS may be associated with adverse psychiatric effects, such as depression, anxiety and impulsivity. OBJECTIVE: To compare DBS applied to the entopeduncular nucleus (EPN; the rodent homolog of the GPi) and STN in terms of their effects on depressive- and anxiety-like behavior in rats. METHODS: DBS was applied for 21 days (4 h a day) to either the STN or EPN. Rats then underwent behavioral testing on learned helplessness and elevated plus maze tasks before being sacrificed for brain analyses of zif268, BDNF and trkB mRNA as well as BDNF protein levels. RESULTS: Repeated DBS of the STN, but not of the EPN, led to impaired performance in the learned helplessness task, suggesting that STN-DBS induces or potentiates depressive-like behavior. There was no effect of DBS on elevated plus maze or on open field behavior. Repeated STN-DBS, but not EPN-DBS, led to decreased levels of BDNF and trkB mRNA in hippocampus. Acute stimulation of the STN or EPN resulted in similar changes in zif268 levels in several brain areas, except for the raphe where decreases were seen only after STB-DBS. CONCLUSIONS: Together these results indicate that the effects of STN- and EPN-DBS differ in behavioral and neurochemical respects. Results further suggest that the EPN may be a preferable target for clinical DBS when psychiatric side effects are considered insofar as it may be associated with a lower incidence of depressive-like behavior than the STN. PMID- 23088854 TI - Interaction between simultaneously applied neuromodulatory interventions in humans. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) is a neuromodulatory technique with the potential to enhance the efficacy of traditional therapies such as neuromuscular electrical stimulation (NMES). Yet, concurrent application of tDCS/NMES may also activate homeostatic mechanisms that block or reverse effects on corticomotor excitability. It is unknown how tDCS and NMES interact in the human primary motor cortex (M1) and whether effects are summative (increase corticomotor excitability beyond that of tDCS or NMES applied alone) or competitive (block or reduce corticomotor excitability effects of tDCS or NMES applied alone). OBJECTIVE: To investigate corticomotor excitability in response to NMES after concurrent application of tDCS protocols that enhance (anodal tDCS) or suppress (cathodal tDCS) excitability of M1. METHODS: We used transcranial magnetic stimulation (TMS) to examine corticomotor excitability before and after the concurrent application of: i) NMES with anodal tDCS; and ii) NMES with cathodal tDCS. Effects were contrasted to four control conditions: i) NMES alone, ii) anodal tDCS alone, iii) cathodal tDCS alone, and iv) sham stimulation. RESULTS: Concurrent application of two protocols that enhance excitability when applied alone (NMES and anodal tDCS) failed to induce summative effects on corticomotor excitability, as predicted by homeostatic plasticity mechanisms. Combined cathodal tDCS and NMES suppressed the enhanced excitation induced by NMES, an effect that might be explained by calcium dependent anti-gating models. CONCLUSIONS: These novel findings highlight the complex mechanisms involved when two neuromodulatory techniques are combined and suggest that careful testing of combined interventions is necessary before application in clinical contexts. PMID- 23088855 TI - Airborne benzene exposures from cleaning metal surfaces with small volumes of petroleum solvents. AB - Airborne benzene concentrations were measured in a room with controlled air exchange during surface cleaning with two petroleum-based solvents (a paint thinner and an engine degreaser). The solvents were spiked with benzene to obtain target concentrations of 0.001, 0.01, and 0.1% by volume in the liquid. Personal samples on the worker and area samples up to 1.8m away were collected over 12 events (n=84 samples) designed to examine variation in exposure with solvent type, cleaning method (rag wipe or spatula scrape), surface area cleaned, air exchange rate, solvent volume applied, and distance from the cleaned surface. Average task breathing zone concentrations of benzene represented by 18-32 min time-weighted averages were 0.01 ppm, 0.05 ppm, and 0.27 ppm, when the solvents contained approximately 0.003, 0.008, and 0.07% benzene. Solvent benzene concentration, volume applied, and distance from the handling activities had the greatest effect on airborne concentrations. The studied solvent products containing 0.07% benzene (spiked) did not exceed the current OSHA permissible exposure limit of 1 ppm (averaged over 8h) or the ACGIH Threshold Limit Value of 0.5 ppm, in any of the tested short-term exposure scenarios. These data suggest that, under these solvent use scenarios, petroleum-based solvent products produced in the United States after 1978 likely did not produce airborne benzene concentrations above those measured if the concentration was less than 0.1% benzene. PMID- 23088856 TI - Analysis of the canine genome and canine health: a commentary. PMID- 23088858 TI - Protective effects and mechanisms of curcumin on podophyllotoxin toxicity in vitro and in vivo. AB - Podophyllotoxin (POD) is a naturally occurring lignan with pronounced antineoplastic and antiviral properties. POD binds to tubulin and prevents the formation of mitotic spindle. Although cases of overdose or accidental ingestion are quite often, no specific therapy is currently available to treat the POD intoxication. In the current investigation, the protective effects and mechanisms of curcumin (CUR) on podophyllotoxin toxicity were evaluated in vitro and in vivo. The results showed that CUR could protect POD-induced cytotoxicity by recovering the G2/M arrest and decrease the changes of membrane potential and microtubule structure in Vero cells. A significant decrease of mortality rates was observed in Swiss mice treated by intragastrical administration of POD+CUR as compared with POD alone. The POD+CUR group also exhibited decreases in plasma transaminases, alkaline phosphatase, lactate dehydrogenase, plasma urea, creatinine and malondialdehyde level but elevated superoxide dismutase and glutathione levels as compared to the POD group. Histological examination of the liver and kidney demonstrated less morphological changes in the treatment of POD+CUR as compared with POD alone. The mechanism of the protective effects might be due to the competitive binding of CUR with POD in the same colchicines binding site as revealed by the tubulin polymerization assay and the molecular docking analysis, and the antioxidant activity against the oxidative stress induced by POD. In summary, both in vitro and in vivo data indicated the promising role of CUR as a protective agent against the POD poisoning. PMID- 23088857 TI - Prenatal cadmium exposure produces persistent changes to thymus and spleen cell phenotypic repertoire as well as the acquired immune response. AB - Cadmium (Cd) is a common environmental contaminant. Adult exposure to Cd alters the immune system, however, there are limited studies on the effects of prenatal exposure to Cd. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose of CdCl(2) (10 ppm) and the effects on the immune system of the offspring were assessed at 20 weeks of age. Prenatal Cd exposure caused an increase in the percent of CD4(-)CD8(-)CD44(+)CD25(-) (DN1) thymocytes in both sexes and a decrease in the percent of CD4(-)CD8(-)CD44(-)CD25(+) (DN3) thymocytes in females. Females had an increase in the percent of splenic CD4(+) T cells, CD8(+) T cells, and CD45R/B220(+) B cells and a decrease in the percent of NK cells and granulocytes (Gr-1(+)). Males had an increase in the percent of splenic CD4(+) T cells and CD45R/B220(+) B cells and a decrease in the percent of CD8(+) T cells, NK cells, and granulocytes. The percentage of neutrophils and myeloid-derived suppressor cells were reduced in both sexes. The percent of splenic nTreg cells was decreased in all Cd-exposed offspring. Cd-exposed offspring were immunized with a streptococcal vaccine and the antibody response was determined. PC specific serum antibody titers were decreased in Cd exposed female offspring but increased in the males. PspA-specific serum IgG titers were increased in both females and males compared to control animals. Females had a decrease in PspA specific serum IgM antibody titers. Females and males had a decrease in the number of splenic anti-PspA antibody-secreting cells when standardized to the number of B cells. These findings demonstrate that very low levels of Cd exposure during gestation can result in long term sex-specific alterations on the immune system of the offspring. PMID- 23088859 TI - Localisation and characterisation of uncoupling protein-2 (UCP2) in the human preterm placenta. AB - The increase in oxidative stress during pregnancy is associated with increased placental antioxidant enzyme activity and may additionally be limited by the uncoupling proteins (UCPs). There is little data on the expression and localisation of UCP2 in the human preterm placenta or on its role in the regulation of placental oxidative stress. Placentae were collected from women with singleton pregnancies who delivered between 24 and 36 weeks gestation (n = 54) and from a term reference group who delivered following uncomplicated pregnancy (n = 11). UCP2 expression and localisation was determined by quantitative real-time RTPCR using Taqman gene expression assays and immunohistochemistry. Placental lipid hydroperoxide and nitrotyrosine content was determined by ELISA. UCP2 mRNA expression increased from 24 to 41 weeks gestation (p < 0.001) and was positively correlated with placental weight (p = 0.004). While UCP2 expression was lower in small for gestational age infants (p = 0.045) it did not differ with respect to timing of antenatal betamethasone exposure nor with placental lipid hydroperoxide or nitrotyrosine content. UCP2 staining was identified in the cytotrophoblast in 34% of samples and in the syncytiotrophoblast in 63% of samples. Cytotrophoblast staining was more frequent in later gestations (p = 0.03) with syncytiotrophoblast UCP2 staining was not altered by gestation. In the preterm group, no association was observed with time since antenatal betamethasone exposure or placental lipid hydroperoxide or nitrotyrosine content. The current data supports gestation dependant alterations in UCP2 mRNA expression and immunohistochemical localisation in the human placenta but no evidence for an important role for UCP2 in protection against placental oxidative damage. PMID- 23088860 TI - Acute intracerebral haemorrhage: grounds for optimism in management. AB - Spontaneous intracerebral haemorrhage (ICH) is one of the most devastating types of stroke, which has considerable disease burden in "non-white" ethnic groups where the population-attributable risks of elevated blood pressure are very high. Since the treatment of ICH remains largely supportive and expectant, nihilism and the early withdrawal of active therapy influence management decisions in clinical practice. However, approaches to management are now better defined on the basis of evidence that both survival and speed (and degree) of recovery are critically dependent on the location, size, and degree of expansion and extension into the intraventricular system of the haematoma of the ICH. Although no medical treatment has been shown to improve outcome in ICH, several promising avenues have emerged that include haemostatic therapy and intensive control of elevated blood pressure. Conversely, there is continued controversy over the role of evacuation of the haematoma of ICH via open craniotomy. Despite being an established practice for several decades, and having undergone evaluation in multiple randomised trials, there is uncertainty over which patients have the most to gain from an intervention with clear procedural risk. Minimally invasive surgery via local anaesthetic applied drill-puncture of the cranium and infusion of a thrombolytic agent is an attractive option for patients requiring critical management of the haematoma, not just in low resource settings but arguably also in specialist centres of western countries. With several ongoing clinical trials nearing completion, these treatments could enter routine practice within the next few years, further justifying the urgency of "time is brain" and that active management within well-organized, comprehensive acute stroke care units includes patients with ICH. PMID- 23088861 TI - Ensuring a sustainable supply of drugs for anaesthesia and peri-operative care. PMID- 23088862 TI - The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. AB - The EPR effect results from the extravasation of macromolecules or nanoparticles through tumor blood vessels. We here provide a historical review of the EPR effect, including its features, vascular mediators found in both cancer and inflamed tissue. In addition, architectural and physiological differences of tumor blood vessels vs that of normal tissue are commented. Furthermore, methods of augmentation of the EPR effect are described, that result in better tumor delivery and improved therapeutic effect, where nitroglycerin, angiotensin I converting enzyme (ACE) inhibitor, or angiotensin II-induced hypertension are employed. Consequently, better therapeutic effect and reduced systemic toxicity are generally observed. Obviously, the EPR effect based delivery of nanoprobes are also useful for tumor-selective imaging agents with using fluorescent or radio nuclei in nanoprobes. We also commented a key difference between passive tumor targeting and the EPR effect in tumors, particularly as related to drug retention in tumors: passive targeting of low-molecular-weight X-ray contrast agents involves a retention period of less than a few minutes, whereas the EPR effect of nanoparticles involves a prolonged retention time-days to weeks. PMID- 23088864 TI - N-Acetyl-cysteine causes analgesia by reinforcing the endogenous activation of type-2 metabotropic glutamate receptors. AB - BACKGROUND: Pharmacological activation of type-2 metabotropic glutamate receptors (mGlu2 receptors) causes analgesia in experimental models of inflammatory and neuropathic pain. Presynaptic mGlu2 receptors are activated by the glutamate released from astrocytes by means of the cystine/glutamate antiporter (System x(c)(-) or Sx(c)(-)). We examined the analgesic activity of the Sx(c)(-) activator, N-acetyl-cysteine (NAC), in mice developing inflammatory or neuropathic pain. RESULTS: A single injection of NAC (100 mg/kg, i.p.) reduced nocifensive behavior in the second phase of the formalin test. NAC-induced analgesia was abrogated by the Sxc- inhibitor, sulphasalazine (8 mg/kg, i.p.) or by the mGlu2/3 receptor antagonist, LY341495 (1 mg/kg, i.p.). NAC still caused analgesia in mGlu3(-/-) mice, but was inactive in mGlu2(-/-) mice. In wild-type mice, NAC retained the analgesic activity in the formalin test when injected daily for 7 days, indicating the lack of tolerance. Both single and repeated injections of NAC also caused analgesia in the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, and, again, analgesia was abolished by LY341495. Data obtained in mice developing neuropathic pain in response to chronic constriction injury (CCI) of the sciatic nerve were divergent. In this model, a single injection of NAC caused analgesia that was reversed by LY341495, whereas repeated injections of NAC were ineffective. Thus, tolerance to NAC induced analgesia developed in the CCI model, but not in models of inflammatory pain. The CFA and CCI models differed with respect to the expression levels of xCT (the catalytic subunit of Sx(c)(-)) and activator of G-protein signaling type 3 (AGS3) in the dorsal portion of the lumbar spinal cord. CFA-treated mice showed no change in either protein, whereas CCI mice showed an ipislateral reduction in xCT levels and a bilateral increase in AGS3 levels in the spinal cord. CONCLUSIONS: These data demonstrate that pharmacological activation of Sxc- causes analgesia by reinforcing the endogenous activation of mGlu2 receptors. NAC has an excellent profile of safety and tolerability when clinically used as a mucolytic agent or in the management of acetaminophen overdose. Thus, our data encourage the use of NAC for the experimental treatment of inflammatory pain in humans. PMID- 23088865 TI - Methylphenidate effects on blood serotonin and melatonin levels may help to synchronise biological rhythms in children with ADHD. AB - The neuroendocrine mediators that may contribute to ADHD (Attention deficit and hyperactivity disorder), serotonin and melatonin, are both thought to regulate circadian rhythms, neurological function and stress response. The objective of this study was to determine the effect of the chronic administration of prolonged release methylphenidate (PRMPH) on daily variations in blood serotonin and melatonin and on the excretion of 6-sulphatoxy-melatonin. A total of 179 children (136 males, 42 females) between the ages of 5 and 14 (9.70 +/- 2.55) years were enrolled in a controlled quasi-experimental open clinical study. Of the sample, there were 136 Children with ADHD (based on DSM-IV-TR criteria), who were further grouped into subtypes, and the 42 siblings of the participants who did not ADHD patients. Blood samples were taken at 20:00 and 09:00; urine was collected between 21:00 and 09:00. In the ADHD group, the study protocol was repeated after 4.61 +/- 2.3 months of treatment. Measurements included melatonin and serotonin by RIA and urine 6-S-aMT by ELISA. Factorial analyses were conducted by STATA 12.0. RESULTS: ADHD patients showed reduced morning serotonin with a daily profile that was different than the control group due to the predominance of nocturnal concentrations. PRMPH did not result in any significant changes. Melatonin and its daily profile did not differ between controls and the ADHD group with a diurnal rhythm showing higher morning levels that disappear after PRMPH administration. Melatonin was higher in children with predominantly hyperactive-impulsive/conduct disorder subtype. PRMPH resulted in a decrease in 6 S-aMT excretion for both ADHD subtypes. CONCLUSION: Chronic treatment with prolonged release methylphenidate induces subtle changes in the daily fluctuations and concentrations of both serotonin and melatonin. Improvement in Children's Depression Inventory (CDI) scores was not related to a morning increase in serotonin. PMID- 23088866 TI - Resistance to malaria in humans: the impact of strong, recent selection. AB - Malaria is one of the leading causes of death worldwide and has been suggested as the most potent type of selection in humans in recent millennia. As a result, genes involved in malaria resistance are excellent examples of recent, strong selection. In 1949, Haldane initially suggested that infectious disease could be a strong selective force in human populations. Evidence for the strong selective effect of malaria resistance includes the high frequency of a number of detrimental genetic diseases caused by the pleiotropic effects of these malaria resistance variants, many of which are "loss of function" mutants. Evidence that this selection is recent comes from the genetic dating of the age of a number of these malaria resistant alleles to less than 5,000 years before the present, generally much more recent than other human genetic variants. An approach to estimate selection coefficients from contemporary case-control data is presented. In the situations described here, selection is much greater than 1%, significantly higher than generally observed for other human genetic variation. With these selection coefficients, predictions are generated about the joint change of alleles S and C at the beta-globin locus, and for alpha-thalassaemia haplotypes and S, variants that are unlinked but exhibit epistasis. Population genetics can be used to determine the amount and pattern of selection in the past and predict selection in the future for other malaria resistance variants as they are discovered. PMID- 23088863 TI - Advanced materials and processing for drug delivery: the past and the future. AB - Design and synthesis of efficient drug delivery systems are of vital importance for medicine and healthcare. Materials innovation and nanotechnology have synergistically fueled the advancement of drug delivery. Innovation in material chemistry allows the generation of biodegradable, biocompatible, environment responsive, and targeted delivery systems. Nanotechnology enables control over size, shape and multi-functionality of particulate drug delivery systems. In this review, we focus on the materials innovation and processing of drug delivery systems and how these advances have shaped the past and may influence the future of drug delivery. PMID- 23088867 TI - Histone deacetylase inhibitors disrupt the mitotic spindle assembly checkpoint by targeting histone and nonhistone proteins. AB - Histone deacetylase inhibitors exhibit pleiotropic effects on cell functions, both in vivo and in vitro. One of the more dramatic effects of these drugs is their ability to disrupt normal mitotic division, which is a significant contributor to the anticancer properties of these drugs. The most important feature of the disrupted mitosis is that drug treatment overcomes the mitotic spindle assembly checkpoint and drives mitotic slippage, but in a manner that triggers apoptosis. The mechanism by which histone deacetylase inhibitors affect mitosis is now becoming clearer through the identification of a number of chromatin and nonchromatin protein targets that are critical to the regulation of normal mitotic progression and cell division. These proteins are directly regulated by acetylation and deacetylation, or in some cases indirectly through the acetylation of essential partner proteins. There appears to be little contribution from deacetylase inhibitor-induced transcriptional changes to the mitotic effects of these drugs. The overall mitotic phenotype of drug treatment appears to be the sum of these disrupted mechanisms. PMID- 23088868 TI - Mechanisms of resistance to histone deacetylase inhibitors. AB - Histone deacetylase (HDAC) inhibitors are a new class of anticancer agents. HDAC inhibitors induce acetylation of histones and nonhistone proteins which are involved in regulation of gene expression and in various cellular pathways including cell growth arrest, differentiation, DNA damage and repair, redox signaling, and apoptosis (Marks, 2010). The U.S. Food and Drug Administration has approved two HDAC inhibitors, vorinostat and romidepsin, for the treatment of cutaneous T-cell lymphoma (Duvic & Vu, 2007; Grant et al., 2010; Marks & Breslow, 2007). Over 20 chemically different HDAC inhibitors are in clinical trials for hematological malignancies and solid tumors. This review considers the mechanisms of resistance to HDAC inhibitors that have been identified which account for the selective effects of these agents in inducing cancer but not normal cell death. These mechanisms, such as functioning Chk1, high levels of thioredoxin, or the prosurvival BCL-2, may also contribute to resistance of cancer cells to HDAC inhibitors. PMID- 23088869 TI - HDAC inhibitors: roles of DNA damage and repair. AB - Histone deacetylase inhibitors (HDACis) increase gene expression through induction of histone acetylation. However, it remains unclear whether specific gene expression changes determine the apoptotic response following HDACis administration. Herein, we discuss evidence that HDACis trigger in cancer and leukemia cells not only widespread histone acetylation but also actual increases in reactive oxygen species (ROS) and DNA damage that are further increased following treatment with DNA-damaging chemotherapies. While the origins of ROS production are not completely understood, mechanisms, including inflammation and altered antioxidant signaling, have been reported. While the generation of ROS is an explanation, at least in part, for the source of DNA damage observed with HDACi treatment, DNA damage can also be independently induced by changes in the DNA repair activity and chromatin remodeling factors. Recent development of sirtuin inhibitors (SIRTis) has shown that, similar to HDACis, these drugs induce increases in ROS and DNA damage used singly, or in combination with HDACis and other drugs. Thus, induction of apoptosis by HDACis/SIRTis may result through oxidative stress and DNA damage mechanisms in addition to direct activation of apoptosis-inducing genes. Nevertheless, while DNA damage and stress responses could be of interest as markers for clinical responses, they have yet to be validated as markers for responses to HDACi treatment in clinical trials, alone, and in combination. PMID- 23088870 TI - HDAC inhibitor modulation of proteotoxicity as a therapeutic approach in cancer. AB - The strong clinical activity of the proteasome inhibitor bortezomib (Velcade) in multiple myeloma and other hematological malignancies has focused considerable attention on its mechanisms of action. Although NFkappaB inhibition was initially the mechanism in focus, accumulating evidence indicates that misfolded protein accumulation leading to proteotoxicity plays an even more important role in cell killing. Proteotoxicity that occurs as a consequence of protein aggregate accumulation has long been associated with the development of neurodegenerative diseases, and a large and growing body of literature has documented how protein aggregates are handled and disposed of via evolutionarily conserved mechanisms involving cross talk between the proteasome and autophagy in normal cells. The type II histone deacetylase HDAC6 plays important roles in these processes and HDAC6 inhibition enhances proteotoxicity. These observations served as the basis for the development of HDAC6-specific chemical inhibitors that are now being evaluated in combination with proteasome inhibitors in preclinical models. Nonetheless, there is also strong evidence that the more classical, chromatin associated (type I) HDACs are also involved in the regulation of proteotoxicity, although the biochemical mechanisms underlying their effects are not well defined. Importantly, emerging evidence indicates that subsets of tumor cells contain defects in these protein quality control pathways, which may underlie their vulnerability to proteasome inhibitor-induced death. In addition, our clearer understanding of cytoprotective protein quality control responses is identifying novel candidate targets for therapeutic intervention. In this chapter, we present an overview of protein quality control mechanisms in normal tissues and describe how this information is informing our development of proteasome inhibitors and other agents that impact upon these pathways for cancer therapy. PMID- 23088871 TI - Intrinsic and extrinsic apoptotic pathway signaling as determinants of histone deacetylase inhibitor antitumor activity. AB - Histone deacetylase inhibitors (HDACi) can elicit a range of biological responses that impede the growth and/or survival of tumor cells. Depending on the physiological context, HDACi can induce apoptosis via two well-defined apoptotic pathways; the intrinsic/mitochondrial pathway and the death receptor (DR)/extrinsic pathway. A number of groups have demonstrated that overexpression of prosurvival Bcl-2 family members significantly reduces HDACi-mediated tumor cell death and therapeutic efficacy in preclinical models. In many cases, HDACi activate the intrinsic pathway via upregulation of a number of proapoptotic BH3 only Bcl-2 family genes including Bim, Bid, and Bmf. Additionally, HDACi can engage the extrinsic pathway through upregulation of DR expression, reductions in c-FLIP, and upregulation of ligands such as TRAIL. Overall, it appears that activation of the intrinsic apoptotic pathway is the predominant mechanism of HDACi-induced tumor cell death; however, the DR pathway may also be engaged, either to amplify the apoptotic signal through the intrinsic pathway or to directly induce cell death. PMID- 23088872 TI - Histone deacetylase inhibitors and rational combination therapies. AB - Histone deacetylase inhibitors (HDACIs) are epigenetically acting agents that modify chromatin structure and by extension, gene expression. However, they may influence the behavior and survival of transformed cells by diverse mechanisms, including promoting expression of death- or differentiation-inducing genes while downregulating the expression of prosurvival genes; acting directly to increase oxidative injury and DNA damage; acetylating and disrupting the function of multiple proteins, including DNA repair and chaperone proteins; and interfering with the function of corepressor complexes. Notably, HDACIs have been shown in preclinical studies to target transformed cells selectively, and these agents have been approved in the treatment of certain hematologic malignancies, for example, cutaneous T-cell lymphoma and peripheral T-cell lymphoma. However, attempts to extend the spectrum of HDACI activity to other malignancies, for example, solid tumors, have been challenging. This has led to the perception that HDACIs may have limited activity as single agents. Because of the pleiotropic actions of HDACIs, combinations with other antineoplastic drugs, particularly other targeted agents, represent a particularly promising avenue of investigation. It is likely that emerging insights into mechanism(s) of HDACI activity will allow optimization of this approach, and hopefully, will expand HDACI approvals to additional malignancies in the future. PMID- 23088873 TI - HDAC inhibitors and chaperone function. AB - Cellular chaperones promote the folding and maturation of newly synthesized proteins and partially folded proteins in the cytosol and endoplasmic reticulum (ER) as well as prevent the aggregation of misfolded proteins. Histone deacetylases (HDACs) and histone acetyl transferases catalyze the reversible acetylation of histones and nonhistone substrates to control the epigenetic and transcriptomic landscape of normal and tumor cells. Treatment with HDAC inhibitors results in the hyperacetylation of chaperones including heat shock protein (hsp)90, hsp70, hsp40, and the ER-resident hsp70 homolog, glucose regulated protein 78 (GRP78), which affects their function. HDAC inhibitor mediated deregulation of chaperone function, in turn, deregulates protein homeostasis and induces protein misfolding and proteotoxic stress. In the context of tumors which are particularly dependent on functional chaperones for maintaining protein homeostasis, HDAC inhibitors tip the balance toward lethal proteotoxic and ER stress. In this chapter, we describe HDAC inhibitor-induced hyperacetylation of major chaperones and its implication for the use of HDAC inhibitors in the treatment of solid and hematologic tumors. PMID- 23088874 TI - Preface. PMID- 23088875 TI - Endo-beta-N-acetylglucosaminidase H de-N-glycosylation in a domestic microwave oven: application to biomarker discovery. AB - Sample preparation is the rate-limiting step in glycan analysis workflows. Among all of the steps, enzymatic digestions, which are usually performed overnight, are the most time-consuming. In the current study, we report an economical and fast preparation of N-glycans from serum, including microwave-assisted enzymatic digestion in the absence of denaturing chemicals and solvents during the release. To this end, we used a household microwave oven to accelerate both pronase and endo-beta-N-acetylglucosaminidase H (Endo H) digestions. Purification was then performed using self-made SP20SS and carbon tips. We were able to prepare samples in 55 min instead of 21 h. Finally, the method was applied in the context of oncological biomarker discovery exemplarily to ovarian and colon cancer. We observed a significant downregulation of sialylated hybrid structures in ovarian cancer samples using capillary electrophoresis-laser-induced fluorescence (CE LIF). Furthermore, sepsis, a systemic inflammatory response syndrome, was also included in the study to understand whether the changes observed in ovarian cancer patients were due to the cancer itself or to the inflammation that usually accompanies its development. Because sialylated hybrid structures were upregulated in sepsis samples, the downregulation of these structures in ovarian cancer is specific to the cancer itself and, therefore, could be used as a biomarker. PMID- 23088876 TI - Examining supervised meals in patients with restrictive eating disorders. AB - OBJECTIVES: Anorexia nervosa is a chronic, life-threatening illness affecting adolescents with increasing incidence. Previous research has demonstrated that, although weight gain is a key to medical stabilization, there is wide and significant variability in treatment practices. Meal supervision in hospitalized patients involves the use of clinical staff as active and supportive observers during meal time. No studies to date have examined the effects of meal supervision in medically hospitalized patients with anorexia nervosa. The primary aim of this study was to examine the effect of meal supervision on outcomes during inpatient medical hospitalization. METHODS: A retrospective record review of 52 patients with restrictive eating disorders admitted to a tertiary pediatric hospital from July 2008 to July 2009 was conducted. RESULTS: The data revealed higher average weights and improved overnight heart rate trends for patients who received at least 1 supervised meal during hospitalization compared with those who received no supervised meals. CONCLUSIONS: The findings warrant further investigation of meal supervision as a possible treatment modality. PMID- 23088877 TI - How to read and report CTC. AB - Owing to encouraging results achieved in the clinical practice, CT colonography (CTC) is being increasingly employed for the examination of the whole colon and rectum and is quickly becoming a widely accepted diagnostic technique that is replacing double contrast barium enema and appears a promising tool for colorectal cancer screening as well. The increasing number of symptomatic and asymptomatic patients undergoing CTC for both evaluation of symptoms and colorectal cancer screening, along with the growing availability of CTC facilities in most healthcare departments and imaging centres, requires that a sufficient number of radiologists be adequately trained in performing and interpreting CTC studies. Indeed, optimal performance of CTC depends on a number of factors, including the quality of colonic preparation (e.g. laxative bowel cleansing and optimised colonic distension), the CTC image acquisition protocol used, and reading approach and specific skills of radiologists for correct detection and interpretation of colonic findings. Consequently, dedicated training and expertise is key to obtain high sensitivity in lesion detection and reduce the number of false positives, thus ensuring an optimal clinical management of patients. To this purpose, dedicated training programmes are essential to teach and standardise not only the approach to CTC reading, but also reporting of colonic findings. PMID- 23088878 TI - Biomechanics of the spine. Part II: spinal instability. AB - Spine stability is the basic requirement to protect nervous structures and prevent the early deterioration of spinal components. All bony and soft spinal components contribute to stability, so any degenerative, traumatic or destructive lesion to any spinal structure gives rise to some degree of instability. Degenerative instability is considered a major cause of axial and radicular pain and is a frequent indication for surgery. Nevertheless the assessment of instability remains difficult in both clinical and imaging settings. All static imaging modalities, even conventional MR, the most accurate technique, are unreliable in assessing instability and chronic pain due to degenerative spine. Dynamic-positional MR is considered the most sophisticated imaging modality to evaluate abnormal spinal motion and instability. In spinal traumas, as multi detector CT yields high-resolution reconstructions in every spatial plane, it will detect even the tiniest fractures revealing potentially unstable lesions, often avoid the routine use of MR. Nevertheless, MR remains the only modality that will directly and routinely assess soft tissue changes. Unfortunately the objectivity of MR in assessing the integrity of ligaments is not rigorously defined and its use in routine protocols to clear blunt spinal injuries remains controversial. There are no evidence-based guidelines currently available to assess the risk of spinal instability in the setting of neoplastic spinal disease, so predicting the risk of a pathological fracture or the timing of a collapse remains challenging even when the lesions are well-characterized by neuroimaging. Diagnostic difficulties lead to controversy in the choice of the best treatment in all forms of spinal instability. PMID- 23088879 TI - Biomechanics of the spine. Part I: spinal stability. AB - Biomechanics, the application of mechanical principles to living organisms, helps us to understand how all the bony and soft spinal components contribute individually and together to ensure spinal stability, and how traumas, tumours and degenerative disorders exert destabilizing effects. Spine stability is the basic requirement to protect nervous structures and prevent the early mechanical deterioration of spinal components. The literature reports a number of biomechanical and clinical definitions of spinal stability, but a consensus definition is lacking. Any vertebra in each spinal motion segment, the smallest functional unit of the spine, can perform various combinations of the main and coupled movements during which a number of bony and soft restraints maintain spine stability. Bones, disks and ligaments contribute by playing a structural role and by acting as transducers through their mechanoreceptors. Mechanoreceptors send proprioceptive impulses to the central nervous system which coordinates muscle tone, movement and reflexes. Damage to any spinal structure gives rise to some degree of instability. Instability is classically considered as a global increase in the movements associated with the occurrence of back and/or nerve root pain. The assessment of spinal instability remains a major challenge for diagnostic imaging experts. Knowledge of biomechanics is essential in view of the increasing involvement of radiologists and neuroradiologists in spinal interventional procedures and the ongoing development of new techniques and devices. Bioengineers and surgeons are currently focusing on mobile stabilization systems. These systems represent a new frontier in the treatment of painful degenerative spine and aim to neutralize noxious forces, restore the normal function of spinal segments and protect the adjacent segments. This review discusses the current concepts of spine stability. PMID- 23088880 TI - Goblet cell carcinoid neoplasm of the appendix: clinical and CT features. AB - PURPOSE: To describe the clinical and CT imaging features of goblet cell carcinoid (GCC) neoplasm of the appendix. METHODS AND MATERIALS: A computer search of pathology and radiology records over a 19-year period at our two institutions was performed using the search string "goblet". In the patients with appendiceal GCC neoplasms who had abdominopelvic CT, imaging findings were categorized, blinded to gross and surgical description, as: "Appendicitis", "Prominent appendix without peri-appendiceal infiltration", "Mass" or "Normal appendix". The CT appearance was correlated with an accepted pathological classification of: low grade GCC, signet ring cell adenocarcinoma ex, and poorly differentiated adenocarcinoma ex GCC group. RESULTS: Twenty-seven patients (age range, 28-80 years; mean age, 52 years; 15 female, 12 male) with pathology-proven appendiceal GCC neoplasm had CT scans that were reviewed. Patients presented with acute appendicitis (n=12), abdominal pain not typical for appendicitis (n=14) and incidental finding (n=1). CT imaging showed 9 Appendicitis, 9 Prominent appendices without peri-appendiceal infiltration, 7 Masses and 2 Normal appendices. Appendicitis (8/9) usually correlated with typical low grade GCC on pathology. In contrast, the majority of Masses and Prominent Appendices without peri-appendiceal infiltration were pathologically confirmed to be signet ring cell adenocarcinoma ex GCC. Poorly differentiated adenocarcinoma ex GCC was seen in only a small minority of patients. Hyperattenuation of the appendiceal neoplasm was seen in a majority of cases. CONCLUSIONS: GCC neoplasm of the appendix should be considered in the differential diagnosis in patients with primary appendiceal malignancy. Our cases demonstrated close correlation between our predefined CT pattern and the pathological classification. PMID- 23088881 TI - A reduced contrast volume acquisition regimen based on cardiovascular dynamics improves visualisation of head and neck vasculature with carotid MDCT angiography. AB - PURPOSE: To investigate enhancement of head and neck arteries during carotid computed tomography angiography using a reduced volume contrast regimen and craniocaudal scan acquisition. MATERIALS AND METHODS: Two hundred and two patients underwent carotid angiography using a 64 channel computed tomography scanner. Patients were allocated to one of two acquisition/contrast regimens: regimen A, the department's standard protocol, consisting of a caudocranial scan direction with 100mL of contrast intravenously; regimen B, involving a craniocaudal scan direction and approximately 50 mL of contrast using a timing dictated by patient hemodynamics. Attenuation profiles of cranial arteries and veins in 6 anatomical segments were assessed and arteriovenous contrast ratios (AVCR) calculated. Receiver operating characteristic (ROC) analysis was performed using DBM methodology. RESULTS: Arterial attenuation was up to 54% (p<0.01) higher following regimen B compared with A. Attenuation in the veins were significantly lower in regimen B than in regimen A with a maximum reduction of up to 93% (p<0.0001). With regimen B, there were significant (p<0.0001) improvements in AVCR at a variety of anatomical sites. The ROC analysis demonstrated a significantly higher Az score for the novel regimen compared with regimen A (p<0.002) with inter-neuroradiologist agreement increasing from poor to moderate. CONCLUSION: Significant improvements in visualisation of head and neck arterial vasculature can be achieved with a CT acquisition regimen using low contrast volume and injection timing based on patient specific contrast formula and craniocaudal scan direction. PMID- 23088882 TI - Stimulation of proangiogenesis by calcium silicate bioactive ceramic. AB - Angiogenesis is critical for bone tissue engineering. Stimulating proangiogenesis in an engineered bone construct using bioglass or bioceramic is now attracting much attention. However, the specific ion that plays important roles in the stimulation of proangiogenesis has not yet been elucidated. In this study, calcium silicate (CS), an osteogenic bioceramic containing only Ca and Si ions, significantly stimulated proangiogenesis of human umbilical vein endothelial cells (HUVECs). The determination of the ionic dissolution product indicates that Si ion concentrations of the CS extracts were significantly higher than that of the calcium phosphate ceramic extracts and control medium. However, the concentrations of Ca and P ions of both ceramic extracts and normal medium were at the same level. With the specific Si ion and its effective concentrations, CS extracts stimulated the proliferation of HUVECs, up-regulated the expression of vascular endothelial growth factor, basic fibroblast growth factor and their receptors, and finally stimulated the proangiogenesis. As the Si ion played an important role in osteogenesis stimulated by Si-containing bioceramics, confirmation of the Si ion's specific role and its effective ion concentrations in CS-induced angiogenesis may be extremely useful in designing osteogenic and angiogenic bioactive materials for bone tissue engineering. PMID- 23088883 TI - Adsorption state of fibronectin on poly(dimethylsiloxane) surfaces with varied stiffness can dominate adhesion density of fibroblasts. AB - The state of adsorbed fibronectin and the subsequent cell adhesion behavior on polydimethylsiloxane (PDMS) substrates with varied stiffness were investigated. The bulk elastic modulus as well as the macroscale and nanoscale surface repulsion forces on PDMS substrates with five different cross-linker concentrations (2.5, 5, 10, 20 and 40wt.%) were evaluated by using tensile and compression tests as well as atomic force microscopy (AFM) indentation. The PDMS substrate with 10wt.% cross-linker showed the maximum stiffness in the bulk elastic modulus and macroscale compression test. In contrast, PDMS substrates with 2.5 and 5wt.% cross-linker concentration showed the maximum stiffness in the nanoscale compression test, which indicates that the physical properties of the nanoscale outermost surface are different from the bulk and macroscale surface properties. The fibronectin-treated PDMS substrates showed almost the same amount of fibronectin adsorption. However, the outermost surface density of fibronectin was related to the macroscale surface stiffness, and the exposure of the cell binding motif was related to the nanoscale surface stiffness. Moreover, the different adsorption state of fibronectin was further confirmed by quartz crystal microbalance-dissipation (QCM-D) monitoring. The adhesion behavior of NIH3T3 mouse fibroblasts was in turn related to the exposure of the cell-binding motif. These results suggest that the well-known differences in cell adhesion behavior on PDMS substrates with varied stiffness are primarily induced by different responses of fibronectin to the PDMS substrates. PMID- 23088884 TI - Orientia tsutsugamushi, the causative agent of scrub typhus, induces an inflammatory program in human macrophages. AB - Scrub typhus is a life-threatening disease caused by Orientia tsutsugamushi, a bacterium that primarily infects endothelial cells both in vitro and in vivo. Evidence suggests that the interaction of O. tsutsugamushi with myeloid cells may play a pivotal role in O. tsutsugamushi infection. We demonstrated that O. tsutsugamushi replicated within human monocyte-derived macrophages. Bacteria stimulated the expression of a large number of genes, including type I interferon genes, interferon-stimulated genes, inflammation-associated genes and apoptosis related genes, and the release of inflammatory cytokines such as Tumor Necrosis Factor and interleukin-1beta. In addition, O. tsutsugamushi induced an M1-type genetic program in macrophages. O. tsutsugamushi viability was required for the type I interferon response and, to a lesser degree, for the inflammatory response. As interferon-gamma is known to elicit M1 polarization, we assessed the effect of interferon-gamma on the fate of O. tsutsugamushi in macrophages. Exogenous interferon-gamma partially inhibited O. tsutsugamushi replication within macrophages. Our results suggest that the inflammatory response induced by O. tsutsugamushi may account for the local and systemic inflammation observed in scrub typhus. PMID- 23088885 TI - No association between influenza A(H1N1)pdm09 vaccination and narcolepsy in South Korea: an ecological study. AB - BACKGROUND: There is concern about a possible association between influenza A(H1N1)pdm09 vaccination and narcolepsy. In this study, we assessed the incidence and incidence rate of narcolepsy in the South Korean population before and after the implementation of an A(H1N1)pdm09 vaccination campaign to see if vaccination led to a change in the occurrence of narcolepsy. METHODS: We conducted an ecological study, comparing incident cases and incidence rates for newly diagnosed narcolepsy case-patients in South Korea, between July 2006 and June 2011. We used data from the Health Insurance Review Agency and Korea Centers for Disease Control and Prevention, which have limited information on case ascertainment. During vaccination campaign period, South Korea used non adjuvanted and MF59-adjuvanted A(H1N1)pdm09 vaccines. RESULTS: Generally, incidence rate was highest in prepandemic period. No trend toward increase in the incidence of narcolepsy after pandemic period was found. Observation of incidence by season did not suggest any time pattern for occurrence of narcolepsy. CONCLUSION: No increase in cases or incidence rate for narcolepsy during the A(H1N1)pdm09 vaccination campaign was found in South Korea. Our data do not support the use of MF59-adjuvanted or non-adjuvanted A(H1N1)pdm09 vaccine as a trigger for narcolepsy on a population level. PMID- 23088886 TI - The recombinant tuberculosis vaccine rBCG DeltaureC::hly(+) induces apoptotic vesicles for improved priming of CD4(+) and CD8(+) T cells. AB - BACKGROUND: The recombinant BCG DeltaureC::hly(+) (rBCG) vaccine candidate is more efficient than parental BCG (pBCG) against tuberculosis (TB) in preclinical models. Evidence exists for superior CD4 and CD8 T cell stimulation. Although the responsible immune mechanisms are incompletely understood, crosspriming of CD8 T cells has been proposed as a major mechanism underlying better protection of rBCG over pBCG. The present study investigates the role of apoptotic vesicles from pBCG- and rBCG-infected macrophages in crosspriming. METHODS: Apoptotic vesicles were isolated from pBCG- and rBCG-infected mouse macrophages. The priming potential of the isolated vesicles was evaluated in terms of dendritic cell activation and specific T cell stimulation. RESULTS: Apoptotic vesicles from both pBCG- and rBCG-infected macrophages activated dendritic cells but to a different degree. Overall, rBCG-infected apoptotic vesicles induced more profound CD4 and CD8 T cell responses as compared to pBCG. CONCLUSIONS: These data support the notion that the improved vaccine efficacy of rBCG rests on enhanced crosspriming as a consequence of stronger apoptosis. PMID- 23088887 TI - Antigenic analysis of divergent genotypes human Enterovirus 71 viruses by a panel of neutralizing monoclonal antibodies: current genotyping of EV71 does not reflect their antigenicity. AB - In recent year, Enterovirus 71 (EV71)-associated hand, foot and mouth disease (HFMD) has become an important public health issue in China. EV71 has been classified into genotypes A, B1-B5 and C1-C5. With such genetic diversity, whether the convalescent or recovery antibody responses can cross-protect infections from other genotypes remains a question. Understanding of the antigenicity of such diverse genetic EV71 isolates is crucial for the EV71 vaccine development. Here, a total of 186 clones anti-EV71 MAbs was generated and characterized with Western blot and cell-based neutralization assay. Forty neutralizing anti-EV71 MAbs were further used to analyze the antigenic properties of 18 recent EV71 isolates representing seven genotypes in neutralization assay. We found that most neutralizing anti-EV71 MAbs are specific to conformational epitopes. We also classified the 40 neutralizing anti-EV71 MAbs into two classes according to their reactivity patterns with 18 EV71 isolates. Class I MAb can neutralize all isolates, suggesting conserved epitopes are present among EV71. Class II MAb includes four subclasses (IIa-IId) and neutralizes only subgroups of EV71 strains. Conversely, 18 EV71 strains were grouped into antigenic types 1 and four antigenic subtypes (2.1-2.4). These results suggest that the current genotyping of EV71 does not reflect their antigenicity which may be important in the selection of EV71 vaccine strains. This panel of neutralizing anti-EV71 MAbs may be useful for the recognition of emerging antigenic variants of EV71 and vaccine development. PMID- 23088888 TI - Equine IgE responses to non-viral vaccine components. AB - Vaccination of horses is performed annually or semi-annually with multiple viral antigens, either in a combination vaccine or as separate injections. While this practice undoubtedly prevents infection from such diseases as rabies, equine influenza, West Nile virus, and equine herpes virus, the procedure is not without repercussions. Hypersensitivity reactions, including fatal anaphylactic shock, after vaccination, although uncommon, have increased in incidence in recent years. Studies reported herein document the development of IgE antibodies against non-target antigen components of equine viral vaccines. We hypothesize that viral vaccines can induce an IgE response to non-target antigens, which could elicit an adverse response after vaccination with another viral vaccine containing the same component. In one study IgE responses to components of West Nile virus vaccine were evaluated by ELISA before and after vaccination in 30 horses. In a second five-year study 77 horses were similarly tested for IgE antibodies against bovine serum albumin (BSA), a component of most viral vaccines. Mast cell sensitization was evaluated in horses with high, moderate, and negative serum BSA specific IgE using an intradermal skin test with BSA. Over the five-year period high IgE responder horses showed gradually increasing BSA specific serum IgE levels and positive skin test reactivity, yet none had an adverse event. Sera from horses that had developed adverse vaccine reactions were also tested for IgE antibodies. Several of these horses had extremely high levels of BSA-specific IgE. These data suggest that non-essential protein components of vaccines may sensitize horses for future adverse responses to vaccination. PMID- 23088889 TI - The UK Adult Twin Registry (TwinsUK Resource). AB - TwinsUK is a nation-wide registry of volunteer twins in the United Kingdom, with about 12,000 registered twins (83% female, equal number of monozygotic and dizygotic twins, predominantly middle-aged and older). Over the last 20 years, questionnaire and blood/urine/tissue samples have been collected on over 7,000 subjects, as well as three comprehensive phenotyping assessments in the clinical facilities of the Department of Twin Research and Genetic Epidemiology, King's College London. The primary focus of study has been the genetic basis of healthy aging process and complex diseases, including cardiovascular, metabolic, musculoskeletal, and ophthalmologic disorders. Alongside the detailed clinical, biochemical, behavioral, and socio-economic characterization of the study population, the major strength of TwinsUK is availability of several 'omics' technologies for the participants. These include genome-wide scans of single nucleotide variants, next-generation sequencing, exome sequencing, epigenetic markers (MeDIP sequencing), gene expression arrays and RNA sequencing, telomere length measures, metabolomic profiles, and gut flora microbiomics. The scientific community now can freely access parts of the phenotype data from the 'TwinsUK', and interested researchers are encouraged to contact us via our Web site (www.twinsuk.ac.uk) for future collaborations. PMID- 23088890 TI - 180 degrees rotatory dislocation of the rotating platform of a posterior stabilized mobile-bearing knee prosthesis; possible complication after closed reduction of a posterior dislocation--a case report. AB - Dislocation of the rotating platform is a significant early complication of mobile-bearing total knee arthroplasty. The authors report an unusual case of acute 180 degrees rotatory dislocation of the rotating platform after closed reduction of a posterior dislocation of a posterior-stabilized mobile-bearing total knee prosthesis. A 71-year-old male with knee osteoarthritis underwent TKRA using a posterior-stabilized mobile-bearing prosthesis. Posterior dislocation of the prosthesis occurred at 5 weeks postoperatively, and closed reduction of the posterior dislocation resulted in complete 180 degrees rotatory dislocation of the rotating platform. The patient was treated by open exploration and polyethylene exchange for a larger component. This case illustrates that dislocation of a posterior-stabilized mobile-bearing total knee prosthesis can occur given valgus laxity and causes a 90 degrees spin-out of the polyethylene insert, and that closed reduction attempts may contribute to complete 180 degrees rotatory dislocation of the rotating platform. Special attention should be given to both AP and lateral views to ensure that the platform is truly reduced and not rotated by 180 degrees . Plain digital radiography, which enhances the density of polyethylene, or arthrography is helpful for diagnosing this complication. PMID- 23088891 TI - Estimating contribution of anthocyanin pigments to osmotic adjustment during winter leaf reddening. AB - The association between plant water stress and synthesis of red, anthocyanin pigments in leaves has led some plant biologists to propose an osmotic function of leaf reddening. According to this hypothesis, anthocyanins function as a solute in osmotic adjustment (OA), contributing to depression of osmotic potential (Psi(pi)) and maintenance of turgor pressure during drought-stressed conditions. Here we calculate the percent contribution of anthocyanin to leaf Psi(pi) during OA in two angiosperm evergreen species, Galax urceolata and Gaultheria procumbens. Both species exhibit dramatic leaf reddening under high light during winter, concomitant with declines in leaf water potential and accumulation of solutes. Data previously published by the authors on osmotic potential at full turgor (Psi(pi,100)) of G. urceolata and G. procumbens leaves before and after leaf reddening were used to estimate OA. In vivo molar concentrations of anthocyanin, glucose, fructose, and sucrose measured from the same individuals were converted to pressure equivalents using the Ideal Gas Law, and percent contribution to OA was estimated. Estimated mean OA during winter was -0.7MPa for G. urceolata and -0.8MPa for G. procumbens. In vivo concentrations of anthocyanin (3-10mM) were estimated to account for ~2% of OA during winter, and comprised <0.7% of Psi(pi,100) in both species. Glucose, fructose, and sucrose combined accounted for roughly 50 and 80% of OA for G. urceolata and G. procumbens, respectively, and comprised ~20% of Psi(pi,100). We observed that a co-occurring, acyanic species (Vinca minor) achieved similar OA without synthesizing anthocyanin. We conclude that anthocyanins represent a measurable, albeit meager, component of OA in red-leafed evergreen species during winter. However, due to their low concentrations, metabolic costliness relative to other osmolytes, and striking red color (unnecessary for an osmotic function), it is unlikely that they are synthesized solely for an osmoprotectant role. PMID- 23088893 TI - Advanced (>second) line chemotherapy in the treatment of patients with recurrent epithelial ovarian cancer. AB - OBJECTIVE: To explore the pattern of chemotherapy (beyond the second-line) used to treat patients with recurrent epithelial ovarian cancer (including primary peritoneal carcinoma). STUDY DESIGN: This retrospective study included 156 patients with recurrent epithelial ovarian cancer and primary peritoneal carcinoma who were treated in the Gynecologic Oncologic Department at Meir Medical Center between November 1995 and December 2003. Clinical characteristics and data regarding the surgery, chemotherapy, and response to treatment were abstracted from the patients' medical records to determine patient response to advanced lines of chemotherapy for recurrent epithelial ovarian cancer. RESULTS: Of the 156 patients, 63 (40%) were treated beyond second-line chemotherapy. Clinical response to third-line chemotherapy was 11.9% (6.8% had complete clinical response and 5.1% partial clinical response) and 3.4% had stable disease. A total of 17% did not show immediate progression, with a median progression free-interval of 1.5 months. A drastic decline in clinical response rates was shown beyond third-line chemotherapy. Any response to treatment in more advanced lines was consistently under 5%. CONCLUSION: These results imply that advanced lines of chemotherapy are associated with low response rates, although a small percentage of patients showed some clinical response or remained with stable disease at the end of treatment. Along with patient preferences, the advantages and disadvantages of continued therapy should be considered, for the side effects of each treatment cannot be overlooked. PMID- 23088894 TI - Interobserver agreement in the sonographic diagnosis of fetal malformations: a pilot study comparing general and specialized services in Rio de Janeiro, Brazil. PMID- 23088895 TI - How many motion signals can be simultaneously perceived? AB - Previous research indicates that the maximum number of motion signals that can be simultaneously perceived is 2, if they are defined only by direction differences, or 3 if they also differ in speed or depth (Greenwood & Edwards, 2006b). Those previous studies used transparent, spatially-sparse stimuli. Here we investigate this motion-number perception limit using spatially-localised stimuli that drive either the standard or form-specific motion systems (Edwards, 2009). Each motion signal was defined by four signal-dots that were arranged in either a square pattern (Square Condition), to drive the form-specific system, or a random pattern (Random Condition), to drive the standard motion-system. A temporal 2AFC procedure was used with each interval (150 ms duration) containing n or n+1 signals. The observer had to identify the interval containing the highest number of signals. The total number of dots in each interval was kept constant by varying the number of noise dots (dots that started off in the same spatial arrangement as the signal dots but then each of those dots moved in different directions). A mask was used at the end of each motion sequence to prohibit the use of iconic memory. In the Square Condition, up to five directions could be simultaneously perceived, and only 1 in the Variable condition. Decreasing the number of noise dots improved performance for the Variable condition, and increasing it decreased performance in the Square Condition. These results show that the previously observed limit of 3 is not a universal limit for motion perception and further, that signal-to-noise limits are a fundamental factor in determining the number of directions that can be simultaneously perceived. Hence the greater sensitivity to motion of the form-specific system makes it well suited to extracting the motion of multiple moving objects. PMID- 23088896 TI - Do changes in coping style explain the effectiveness of interventions for psychological morbidity in family carers of people with dementia? A systematic review and meta-analysis. AB - BACKGROUND: Observational studies find that family carers of people with dementia who use more emotional support and acceptance-based coping, and less dysfunctional coping, are less depressed and anxious. We hypothesized that interventions effective in reducing psychological symptoms would increase emotional support and acceptance-based coping, or decrease dysfunctional coping. METHODS: We systematically reviewed randomized controlled trials published up to July 2011, of interventions for carers of people with dementia measuring coping and psychological morbidity. We rated study validity and reported findings. We conducted fixed-effect meta-analyses for interventions where possible. RESULTS: Eight of 433 papers identified by the search met inclusion criteria. All measured coping immediately after intervention. Two interventions significantly decreased depressive or anxiety symptoms: the smaller study found no change in dysfunctional coping. Neither measured emotional support and acceptance-based coping. Meta-analysis found that both group coping skills interventions alone (SMD = -0.39, 95% CI = -0.75 to -0.03, p = 0.04) and with behavioral activation (SMD = -0.26, 95% CI = -0.48 to -0.04, p = 0.02) significantly increased dysfunctional coping, while significantly reducing depressive symptoms. Positive coping (a mix of emotional and solution-focused strategies) increased (SMD = 0.28, 95% CI = 0.05-0.51, p = 0.02) with group coping skills interventions and behavioral activation. CONCLUSIONS: Contrary to our hypothesis, dysfunctional coping increased when carer depressive symptoms improved. There was preliminary evidence that emotional support and acceptance-based coping increased, as positive coping increased although solution-focused coping alone did not. More research is needed to elucidate whether successful interventions work through changing coping strategies immediately and in the longer term. PMID- 23088897 TI - Shoulder internal and external rotations torque steadiness in overhead athletes with and without impingement symptoms. AB - OBJECTIVES: This study aimed to investigate torque steadiness of shoulder internal and external rotations in regularly training overhead athletes with and without impingement symptoms. DESIGN: Cross-sectional laboratory study. METHODS: Three groups were evaluated: athletes with impingement symptoms (n=21), asymptomatic athletes (n=25) and non-athletes (n=21). To assess torque steadiness, the participants performed 3 submaximal contractions (35% of peak torque) for 10s each, with the arm at 90 degrees of shoulder abduction and 90 degrees of external rotation. The standard deviation, coefficient of variation, mean exerted torque and time to stability were measured from the steadiness trials. RESULTS: The standard deviation of internal rotation was higher in asymptomatic athletes than in non-athletes (p<0.01); however, there was no difference between the athletes with impingement symptoms and the other groups. The other variables presented no differences among the groups. CONCLUSIONS: Higher torque fluctuation of shoulder internal rotation in asymptomatic athletes may point to neuromuscular adaptations related to throwing training. However, the steadiness patterns of athletes with impingement symptoms did not differ from those of asymptomatic athletes or non-athletes. PMID- 23088898 TI - Kinanthropometric differences between 1997 World championship junior elite and 2011 national junior elite triathletes. AB - OBJECTIVES: In 1997, anthropometry measures were made to determine the body size and shapes of both senior and junior elite triathletes. Since then, the junior event distance has changed and the optimal morphology of participants may have evolved. Thus the objective of this study was to compare the morphology of 1997 World championship junior elite triathlon competitors with junior elite competitors in 2011. DESIGN: Comparative study of junior elite triathlete kinanthropometry. METHODS: Twenty-nine males and 20 females junior elite competitors in the 1997 Triathlon World Championships underwent 26 anthropometric measurements. Results were compared with 28 male and 14 female junior elite triathletes who competed in the 2011 Australian National Junior Series, as qualifying for 2011 Triathlon World Championships. Comparisons were made on the raw scores, as well as somatotype, and body proportional scores. RESULTS: Both male and female junior elite triathletes in the 2011 group were significantly more ectomorphic than their 1997 counterparts. The 2011 triathletes were also proportionally lighter, with significantly smaller flexed arm and thigh girths, and femur breadths. The 2011 males recorded significantly longer segmental lengths and lower endomorphy values than the 1997 junior males. CONCLUSIONS: Junior elite triathlete morphology has evolved during the past 14 years possibly as a result of changing race distance and race tactics, highlighting the importance of continually monitoring and updating such anthropometric data. PMID- 23088899 TI - Impact on plate waste of switching from a tray to a trayless delivery system in a university dining hall and employee response to the switch. AB - A potential strategy for decreasing food waste in foodservice operations is trayless dining. The objective of this 2010 study was to compare the impact of using a tray vs a trayless system on plate waste and on employees' attitudes. To test the hypothesis that going trayless would reduce waste, liquid and solid plate waste were measured for 1 week with the then-existing tray system and again after a new trayless system was implemented in a buffet-style university dining hall serving roughly1,000 meals a day. Foodservice staff were invited to participate in a focus group about the impact on their jobs. The investigators calculated plate waste per patron under the two systems and used an independent samples t test to examine the significance of the difference. Comments from the focus group were analyzed for themes. A significant decrease in solid waste per patron (0.81 oz; P=0.001) was observed in switching from the tray to the trayless system (4.39 +/- 0.24 oz vs 3.58 +/- 0.08 oz per patron). A nonsignificant reduction was observed with liquid waste (49.77 +/- 2.62 mL vs 46.36 +/- 4.51 mL; P=0.18). Most of the employees preferred the trayless system as long as it did reduce waste, but felt that increased breakage of dishware and increased need to wipe down tables were possible concerns resulting from the switch. This study demonstrates that trayless dining can reduce plate waste, and that employees can be supportive of the change. PMID- 23088900 TI - Spontaneous regression of hypertrophic cardiomyopathy in an infant with Pompe's disease. PMID- 23088901 TI - Saccharin and aspartame, compared with sucrose, induce greater weight gain in adult Wistar rats, at similar total caloric intake levels. AB - It has been suggested that the use of nonnutritive sweeteners (NNSs) can lead to weight gain, but evidence regarding their real effect in body weight and satiety is still inconclusive. Using a rat model, the present study compares the effect of saccharin and aspartame to sucrose in body weight gain and in caloric intake. Twenty-nine male Wistar rats received plain yogurt sweetened with 20% sucrose, 0.3% sodium saccharin or 0.4% aspartame, in addition to chow and water ad libitum, while physical activity was restrained. Measurements of cumulative body weight gain, total caloric intake, caloric intake of chow and caloric intake of sweetened yogurt were performed weekly for 12 weeks. Results showed that addition of either saccharin or aspartame to yogurt resulted in increased weight gain compared to addition of sucrose, however total caloric intake was similar among groups. In conclusion, greater weight gain was promoted by the use of saccharin or aspartame, compared with sucrose, and this weight gain was unrelated to caloric intake. We speculate that a decrease in energy expenditure or increase in fluid retention might be involved. PMID- 23088902 TI - Single incision laparoscopic approach for esophageal achalasia: A case report. AB - INTRODUCTION: Esophageal achalasia is an uncommon, benign, neurodegenerative disease that induces a transit disorder characterized by incomplete lower esophageal sphincter relaxation. PRESENTATION OF CASE: A 56-year-old woman with dysphagia was admitted to our hospital. An esophagography revealed flask-type achalasia. Endoscopy revealed a dilated esophagus and some resistance at the esophagogastric junction. We used a capped wound protector, common straight forceps, and hook-type electrocautery to perform transumbilical single incision laparoscopic Heller myotomy with Dor fundoplication (SILHD). The left liver lobe and cardia were pulled by a thread. A 6-cm Heller myotomy of the esophagus was performed with an additional 2-cm myotomy of the gastric wall. Dor fundoplication was performed to cover the exposed submucosa. Intraoperative endoscopy confirmed the adequacy of the myotomy and Dor fundoplication. There were no postoperative complications. An esophagography and an endoscopic examination did not reveal stenosis or reflux at 1-year follow-up, and the patient has been satisfactorily symptom free. DISCUSSION: LHD is the most accepted surgical treatment for achalasia and has low invasiveness and long-term efficacy. SILHD for achalasia is a new approach and may provide improved cosmetics and less invasiveness compared with those by conventional LHD. The 1-year follow-up results in the present case are the longest reported to date. The evaluation of long-term results in a large scale study is necessary in future. CONCLUSION: SILHD can be safe, widely accepted, mid-term minimal invasive and cosmetically superior surgical procedure for achalasia. PMID- 23088903 TI - Off pump repair of left ventricular rupture following mitral valve replacement: The crucial assistance of the IntraAortic Balloon Pump. AB - INTRODUCTION: Left ventricular (LV) rupture is a not as frequent, but potentially lethal complication of mitral valve replacement or repair. PRESENTATION OF CASE: We report a case of a 67-year-old man who underwent mitral valve replacement and Cox Maze IV procedure. A massive bleed from the LV rupture was noted postoperatively while the patient was extubated. The control of bleeding was impossible until an IntraAortic Balloon Pump (IABP) was inserted. A bovine pericardial patch was applied, overlapping an extensive epicardial area, perimetrically of the hematoma. Between the epicardium and the pericardial patch we applied an autologous fibrin sealant. DISCUSSION: The off-pump technique used to repair the LV rupture after a MVR, is more feasible when the patient is supported by an IABP that subsequently decreases the tension of the myocardial suture site. CONCLUSION: The IABP, is a necessary device, that decreases the tension along the suture site post a left ventricular rupture following a MVR. PMID- 23088904 TI - Surgical second-look in high risk gastrointestinal stromal tumor of small intestine: A case report. AB - INTRODUCTION: The peritoneum is one of the most common sites of distant gastrointestinal stromal tumor (GIST) metastases. In particular, GIST arising from the small intestine with resected minimal synchronous macroscopic peritoneal carcinomatosis or with primary tumor rupture has a higher risk of developing peritoneal recurrence. Current clinical practice does not envisage second-look surgery in GIST patients at high risk of developing peritoneal recurrence, and no literature data are available. PRESENTATION OF CASE: We describe a 45-year-old woman who underwent emergency surgical resection of jejunal GIST presenting with spontaneous tumor rupture, synchronous ovarian and minimal macroscopic peritoneal involvement, and subsequent second-look surgery after 13 months of imatinib treatment. DISCUSSION: Second-look surgery confirmed a 2.6cm lesion close to the mesenteric border of the fourth jejunal loop, and 11 peritoneal lesions with a macroscopic necrotic aspect related to treatment response. After conversion to an open procedure, a segmental jejunal resection was performed with removal of all peritoneal lesions and macroscopic radical cytoreduction. CONCLUSION: Second-look surgery in selected GIST patients may be performed after at least 12 months of medical treatment with tyrosine-kinase inhibitors to identify those patients with limited peritoneal disease not disclosed by instrumental imaging who could undergo radical cytoreduction of peritoneal lesions. PMID- 23088905 TI - Gouty arthritis at interphalangeal joint of foot after sildenafil use: A case report. AB - INTRODUCTION: Interphalangeal joint of foot is a very unusual location for gouty arthritis and sildenafil use may cause this phenomenon. PRESENTATION OF CASE: A 58-year-old hypertensive man was admitted to hospital with pain and swelling over interphalengeal joint of his right great toe. His health history included the use of diuretics for a long time and his last gout attack was two years ago at first metatarsophalengeal joint of right foot. Sildenafil, a selective inhibitor of phosphodiesterase type 5 (PDE5), was administered in case of erectile dysfunction for two months. Subsequently, he had several episodes of pain and swelling at first interphalangeal joint of right great toe. Both the onset and recurrence of symptoms were just seen the day after sildenafil use. The patient was free of symptoms after discontinuation of the drug. After an initial evaluation, gout was diagnosed on the basis of synovial fluid analysis. DISCUSSION: This case demonstrates a rare location of gouty arthritis with an uncommon etiology: sildenafil. Regarding the clinical data, the discussion was made to expand the horizon for diagnosis of patients with similar symptoms, to identify risk factors for gout relevant to elderliness, and to review the management of gout. CONCLUSION: Sildenafil use may cause gouty arthritis, and surgical decompression may be helpful for definitive diagnosis and symptom relief in atypical presentation of gout. PMID- 23088906 TI - Continuous controllable balloon dilation: a novel approach for cervix dilation. AB - BACKGROUND: Cervical dilation using mechanical dilators is associated with various complications, such as uterine perforation, cervical laceration, infections and intraperitoneal hemorrhage. To achieve safe and painless cervical dilation, we constructed a new medical device to achieve confident mechanical cervical dilation: a continuous controllable balloon dilator (CCBD). METHODS: Controlled pumping of incompressible fluid into the CCBD increases the pressure and outer diameter of the CCBD, continuously dilating the cervical canal. The reliability of the CCBD was confirmed in vitro (testing for consistency and endurance, with no detected risk for breakage) and in vivo. A multi-center clinical study was conducted,with 120 pregnant women randomly assigned to one of three groups: Group I,control group, no dilation;Group II,mechanical dilation, Hegar dilator (HeD); and Group III,CCBD. The tissue material for histological evaluation was obtained from the endocervical mucosa before and after dilation using the HeD or CCBD. RESULTS: The CCBD dilations were successful and had no complications in all 40 patients of Group III. The cervical tissue was markedly less damaged after CCBD dilation compared with HeD dilation (epithelium damage: 95% (HeD) vs. 45% (CCBD), P <0.001; basal membrane damage: 82.5% (HeD) vs. 27.5% (CCBD), P <0.001; stromal damage: 62.5% (HeD) vs. 37.5% (CCBD), P <0.01). Cervical hemorrhagia was observed in 90% of the patients after HeD dilation versus in 32.5% of the patients after CCBD dilation. CONCLUSIONS: The CCBD should be used as a replacement for mechanical dilators to prevent uterine and cervical injury during cervical dilation. TRIAL REGISTRATION: ISRCTN54007498. PMID- 23088907 TI - Arthroscopic cauterization of retrodiscal tissue as a successful minimal invasive therapy in habitual temporomandibular joint luxation. AB - Habitual temporomandibular joint (TMJ) luxation is a serious condition for the patient, and is often managed by extensive open joint surgery. Arthroscopic eminoplasty is an alternative, but this technique could also cause concomitant damage to the articular surface. The aim of this study was to evaluate the therapeutic effects and side effects of arthroscopic electrocautery of retrodiscal tissues in habitual TMJ luxation. All patients with habitual TMJ luxations who needed surgical management from 1 January 2000 to 31 December 2009 in the authors' institution in The Netherlands, were included in this study. All patients were primarily treated with arthroscopic electrocautery. Pre- and postoperative evaluation parameters were: TMJ luxations, maximum mouth opening, translatory capacity, pain and joint noises. Sixteen patients with habitual luxation were treated with arthroscopic electrocautery. Patient reluxation occurred in one. None of the patients had joint pain or mobility restrictions. The overall success rate was 95%. After 86 months there was a high success rate for this therapy. No other morbidity was seen, in contrast with open joint surgery or using sclerosing agents. The authors conclude that arthroscopic eletrocautery of retrodiscal tissues is a highly successful minimal invasive therapy in habitual TMJ luxation without side effects. PMID- 23088908 TI - Tracheal responsiveness to methacholine and ovalbumin; and lung inflammation in guinea pigs exposed to inhaled lead after sensitization. AB - The association between lead exposure and asthma is controversial. The effect of inhaled lead acetate on lung inflammation, tracheal responsiveness and immune components in guinea pigs after sensitization was examined in this study. Five groups of guinea pigs were randomly allocated to control (group C), sensitized (group S), and three test groups exposed to inhaled lead concentrations 0.1, 0.2 and 0.4M Pb after sensitization (n=6 for each group). The measured variables included tracheal responsiveness to methacholine and ovalbumin (OA); total and differential white blood cells (WBC) counts of lung lavage; serum cytokine levels (IFN-gamma and IL-4); and lead concentration in lung tissue. Tracheal responsiveness to methacholine and OA; total and differential WBC counts; IL-4 and IFN-gamma were significantly increased in sensitized animals compared to control group (p<0.05 to p<0.001). However, the ratio of IFN-gamma/IL-4 were significantly decreased in group S (p<0.05). In addition, all measured parameters in animals exposed to highest lead concentration and most of them in animals exposed to medium lead concentration were significantly higher than group S, except for the IFN-gamma and IFN-gamma/IL-4 ratio, which were significantly decreased (p<0.05 to p<0.001). The lead concentration in lung tissues of all test animals was significantly higher than that of group C (p<0.001 for all groups). These results showed that lead acetate exposure can cause further increase in tracheal responsiveness to methacholine and OA, total and differential WBC count and IL-4, IFN-gamma and IFN-gamma/IL-4 ratio. Therefore, environmental exposure to lead may aggravate the severity of asthma. PMID- 23088909 TI - Synthesis of retinoid enhancers based on 2-aminobenzothiazoles for anti-cancer therapy. AB - Indole-3-amides and dipeptides were produced from 2-aminobenzothiazoles using the PyBop peptide coupling reagent. These analogues were tested in anti-cancer cell viability assays against SH-SY5Y neuroblastoma and MDA-MB-231 breast adenocarcinoma cell lines, and were found to exhibit cytotoxic activities at concentrations ranging from 0.1 to 20MUM. These compounds were also found to act additively with a low dosage of 13-cis-retinoic acid in neuroblastoma cells. Then, using neuroblastoma cells transfected to stably overexpress the RARbeta(2) gene, a SAR was developed for the indole-3-amides. Real-time PCR was also used to demonstrate their RARbeta(2) agonistic activity. PMID- 23088910 TI - Synthesis and structure based optimization of 2-(4-phenoxybenzoyl)-5 hydroxyindole as a novel CaMKII inhibitor. AB - Based on 2-(4-phenoxybenzoyl)-5-hydroxyindole (2), a novel structural class of CaMKII inhibitors were synthesized and further optimized. The strong acidity of the hydroxyl group and the lipophilic group at the 4 and 6-positions were found to be necessary for strong CaMKII inhibition. Compound 25 was identified as a promising compound with 50-fold more potent inhibitory activity for CaMKII than 2. Compound 25 also showed high selectivity for CaMKII over off-target kinases. PMID- 23088911 TI - Control of leakage activities of alamethicin analogs by metals: side chain dependent adverse gating response to Zn(2+). AB - Alamethicin (Alm), an antimicrobial peptide rich in alpha-aminoisobutyric acid (Aib), is known to self-assemble to form channels in the membranes. Previously, we reported that HG-Alm, an Alm analog with a single His residue at the N terminus, forms channel assemblies with extremely long lifetimes in the presence of Zn(2+). In this study, HG-Alm analogs, in the sequences of which all Aib residues were substituted by Leu, norvaline (Nva), or norleucine (Nle), were synthesized and their leakage activities were measured using fluorescent dye loaded liposomes. We found that these peptides could be categorized into two classes with different gating responses to Zn(2+). PMID- 23088912 TI - Cysteine-rich toxins from Lachesana tarabaevi spider venom with amphiphilic C terminal segments. AB - Venom of Lachesana tarabaevi (Zodariidae, "ant spiders") exhibits high insect toxicity and serves a rich source of potential insecticides. Five new peptide toxins active against insects were isolated from the venom by means of liquid chromatography and named latartoxins (LtTx). Complete amino acid sequences of LtTx (60-71 residues) were established by a combination of Edman degradation, mass spectrometry and selective proteolysis. Three toxins have eight cysteine residues that form four intramolecular disulfide bridges, and two other molecules contain an additional cystine; three LtTx are C-terminally amidated. Latartoxins can be allocated to two groups with members similar to CSTX and LSTX toxins from Cupiennius salei (Ctenidae) and Lycosa singoriensis (Lycosidae). The interesting feature of the new toxins is their modular organization: they contain an N terminal cysteine-rich (knottin or ICK) region as in many neurotoxins from spider venoms and a C-terminal linear part alike some cytolytic peptides. The C-terminal fragment of one of the most abundant toxins LtTx-1a was synthesized and shown to possess membrane-binding activity. It was found to assume amphipathic alpha helical conformation in membrane-mimicking environment and exert antimicrobial activity at micromolar concentrations. The tails endow latartoxins with the ability to bind and damage membranes; LtTx show cytolytic activity in fly larvae neuromuscular preparations. We suggest a membrane-dependent mode of action for latartoxins with their C-terminal linear modules acting as anchoring devices. PMID- 23088913 TI - Membrane docking mode of the C2 domain of PKCepsilon: an infrared spectroscopy and FRET study. AB - The C2 domain of PKCepsilon binds to negatively charged phospholipids but little is known so far about the docking orientation of this domain when it is bound. By using a FRET assay we have studied the binding of this domain to model membranes. We have also used ATR-Fourier transform infrared spectroscopy with polarized light (ATR-FTIR) to determine the docking mode by calculating the beta-sandwich orientation when the domain is bound to different types of model membranes. The vesicle lipid compositions were: POPC/POPE/POPA (22:36:42) imitating the inner leaflet of a plasma membrane, POPC/POPA (50:50) in which POPE has been eliminated with respect to the former composition and POPC/POPE/CL (43:36:21) imitating the inner mitochondrial membrane. Results show that the beta-sandwich of the PKCalpha C2 domain is inclined at an angle alpha close to 45 degrees to the membrane normal. Some differences were found with respect to the extent of binding as a function of phospholipid composition and small changes on secondary structure were only evident when the domain was bound to model membranes of POPC/POPA: in this case, the percentage of beta-sheet of the C2 domain increases if compared with the secondary structure of the domain in the absence of vesicles. With respect to the beta-sandwich orientation, when the domain is bound to POPC/POPE/CL membranes it forms an angle with the normal to the surface of the lipid bilayer (39 degrees ) smaller than that one observed when the domain interacts with vesicles of POPC/POPA (49 degrees ). PMID- 23088914 TI - Porter domain opening and closing motions in the multi-drug efflux transporter AcrB. AB - Acriflavine resistance protein B acts as the active transporter in the multi-drug efflux pump Acriflavine resistance proteins A / B - Tolerance to colicins protein in Escherichia coli. Within the same reaction cycle intermediate all Acriflavine resistance protein B X-ray structures display highly similar conformations of the substrate-recruiting and transporting porter domain. To assess if this structural homogeneity is an intrinsic feature of Acriflavine resistance protein B or stems from other causes we performed a series of six independent, unbiased 100 ns molecular dynamics simulations of membrane-embedded, asymmetric, substrate-free wild type Acriflavine resistance protein B in a 150 mM NaCl solution. We find the porter domain more flexible than previously assumed displaying clear opening and closing motions of the proximal binding pocket (L and T-state) and the exit of the drug transport channels (O-intermediate). Concurrently the hydrophobic binding pocket favors a closed conformation in all three protomers. Our findings suggest that the conformational homogeneity seen in the crystal structures is likely an effect of bound but structurally unresolved substrate. Our simulations further imply that each of the known three reaction cycle intermediates occurs in at least two variants, the Thr676 loop independently regulates porter domain access and likely plays a key role in substrate transport. On a 100 ns time scale we find no evidence supporting the proposed LLL resting state in the absence of substrate. If the proximal binding pocket dynamics have an inhibiting effect on Acriflavine resistance protein B pump activity lowering the life time of substrate-accessible conformations, the observed dynamics could provide a structural explanation for the Acriflavine resistance protein B activity enhancing effect of the adaptor protein Acriflavine resistance protein A stabilizing PC1 and PC2 subdomain orientations. PMID- 23088915 TI - The melanocortin 4 receptor: oligomer formation, interaction sites and functional significance. AB - This study involves the structural and functional properties of the recombinant melanocortin 4 receptor (MC(4)R) expressed in the HEK-293 cell line. Using co immuno-purification approaches, the receptor appears to be an oligomer, which can be crosslinked through disulphide bonds involving a native cysteine residue (84) to give a dimeric species. This position is located near the cytosolic region of transmembrane segment 2 and it is suggested that this is an interacting interface between MC(4)R monomers. Using co-expression of the native protein and a C84A mutant, it appears that the receptor also forms higher order oligomers via alternative interfaces. Interestingly, disulphide crosslink formation does not occur if the receptor is uncoupled from its G-protein, even though the oligomeric state is preserved. This suggests that the conformational changes, which occur on activation, affect the TM2 interface. The pharmacology of the agonist, NDP-MSH, indicates that the MC(4)R retains high affinity for the ligand in the absence of the G-protein but occupancy for the ligand is increased. The data can be interpreted to suggest that the G-protein exerts a negative allosteric effect on the receptor. Co-expression of one receptor lacking the ability to signal with another, which cannot bind the agonist, restored ligand-dependent activation of the G-protein to situations in which neither receptor on its own could activate the G-protein. Such transactivation suggests meaningful cross talk between the receptor subunits in the oligomeric complex. These studies demonstrate further unique features of the MC(4)R. PMID- 23088917 TI - The communicating junctions, roles and dysfunctions. PMID- 23088916 TI - FTIR, (1)H NMR and EPR spectroscopy studies on the interaction of flavone apigenin with dipalmitoylphosphatidylcholine liposomes. AB - Apigenin (5,7,4'-trihydroxyflavone) is a cancer chemopreventive agent and a member of the family of plant flavonoids. Apigenin interaction with liposomes formed with dipalmitoylphosphatidylcholine (DPPC) was investigated by means of FTIR spectroscopy, (1)H NMR and EPR techniques. Fluorescent microscopy and electron microscopy were applied to study the apigenin effects on colon myofibroblasts and human skin fibroblasts. The strong rigidifying effect of apigenin with respect to polar head groups was concluded on the basis of the action of the flavone on partition coefficient of Tempo spin label between the water and lipid phases. The ordering effect was also found in hydrophobic region at the depth monitored by 5-SASL and 16-SASL spin labels. The inclusion of apigenin to the membrane restricted the motional freedom of polar head groups lowering penetration of Pr(3+) ions to the membranes. The (1)H NMR technique supported also the restriction of motional freedom of the membrane in the hydrophobic region, especially in the zone of CH(2) groups of alkyl chains. FTIR analysis showed that apigenin incorporates into DPPC liposomes via hydrogen bonding between its own hydroxyl groups and lipid polar head groups in the C-O-P O-C segment. It is also very likely that hydroxyl groups of apigenin link with polar groups of DPPC by water bridges. Electron and fluorescence microscopic observations revealed changes in the internal membrane organization of the examined cells. In conclusion, the changes of the structural and dynamic properties of membranes can be crucial for processes involving tumor suppression signal transduction pathways and cell cycle regulation. PMID- 23088918 TI - Hyperoncotic albumin attenuates lung and intestine injuries caused by peritonitis induced sepsis in rats. AB - BACKGROUND: Hyperoncotic albumin may be a therapeutic option to improve tissue perfusion and organ injury in sepsis. To clarify the hypothesis and its mechanism, hyperoncotic albumin was administered to the rats in a polymicrobial sepsis-peritonitis model. MATERIALS AND METHODS: Peritonitis was induced by a surgery of cecal ligation and puncture (CLP) in 27 male Wistar rats. For control purposes, sham operations without ligating and puncturing the cecum were performed in 20 rats. Three hours later, rats were randomized to receive intravenously 3 mL/kg of 5% albumin, 25% albumin, or normal saline. All the hemodynamic and biochemical parameters were measured during the 18-h observation. RESULTS: In septic rats, 25% albumin attenuated hypotension, vascular hyporeactivity to norepinephrine, and the elevated serum levels of lactate dehydrogenase and blood urea nitrogen. However, these improvements were not noted in CLP rats after 5% albumin treatment. In addition, 25% albumin decreased metabolic acidosis and improved the CLP-induced hypoperfusion in the intestine and kidney. Superoxide levels in the aorta and lung and the protein expression of inducible nitric oxide synthase in the lung were also attenuated by 25% albumin in CLP rats. Microscopic findings confirmed that 25% albumin attenuated the substantial swelling and cell infiltration in the intestine and lung caused by CLP. CONCLUSIONS: In this sepsis rat model, 25% albumin reduced macro- and microhemodynamic changes and attenuated intestine and lung injuries in peritonitis-induced sepsis. PMID- 23088919 TI - Experimental study on the effect of controlled hypotension levels on rabbit CA1 neurons. AB - OBJECTIVE: The present study investigated the effect of controlled hypotension (CH) levels regulated by nitroprusside on hippocampal CA1 neurons. MATERIALS AND METHODS: All experimental rabbits were randomly divided into five groups to perform CH for recording their vital signs and survived for a certain time. The arterial blood was collected to measure the serum levels of interleukin 6 and tumor necrosis factor alpha and then the brain tissues were perfused and sectioned to carry out hematoxylin-eosin staining, TdT-mediated dUTP nick end labeling fluorescence, c-fos immunohistochemistry, and ultrastructural observation of hippocampal neuronal mitochondria. All data were analyzed with SPSS13.0 software, and P < 0.05 was indicated as statistically significant. RESULTS: Heart rate, mean arterial pressure, and the dosage of sodium nitroprusside were not statistically significant between groups, but at T2, heart rate levels in groups II-IV were lower than those in groups I and V. Simultaneously, interleukin 6 was remarkably overexpressed in group II than in other groups at T2, whereas tumor necrosis factor alpha was higher in groups I III than in groups IV and V. At the light and electronic microscopic levels, the CA1 regional neurons of group IV were more seriously damaged and deranged compared with other groups so was the expression of c-fos. However, fluorescence from TdT-mediated dUTP nick end labeling assay was more intensive in groups II-IV than that in other groups. Results further showed that Flameng scores of mitochondria were the highest in group IV, but they were not statistically significant among the other groups. CONCLUSIONS: The different levels of CH remarkably affected the functional activities of hippocampal CA1 neurons; with the decrease of mean arterial pressure, neuronal apoptosis, and c-fos expression was gradually increased and reached the peak in 45% of basic values of blood pressure. PMID- 23088920 TI - Establishing a twin registry in Guinea-Bissau. AB - Twins traditionally retain a special status in many African societies. In Guinea Bissau, twins are often well regarded yet still suffer from a very high mortality, especially in the perinatal and infant period. At the Bandim Health Project, a health and demographic surveillance site, we have recently established one of the first twin registries in Sub-Saharan Africa. Our short-term aim is to describe twin mortality and morbidity in order to design appropriate health interventions. Our long-term goal is a large-scale database to explore the pathogenesis of prevalent diseases; for example, diabetes mellitus, metabolic syndrome, and infectious diseases such as HIV, tuberculosis, and malaria. A major focus area is also the etiology of low birth weight and how epigenetic processes might modulate the consequences of low birth weight in Sub-Saharan Africa. For this, monozygotic twin studies represent a powerful tool. Though twin studies have been carried out by the Bandim Health Project for more than 30 years, the renewed registry described here was officially established in 2009 and includes both a cohort of newborn twins and a cohort of young and adult twins. Currently more than 1,500 twins are being followed in the two cohorts combined. We believe that the registry holds exciting possibilities and will encourage the establishment of further twin registries across the region. PMID- 23088921 TI - Patient narratives of surgical site infection: implications for practice. AB - BACKGROUND: Exploring patients' experiences has been used widely within healthcare to improve clinical service delivery. To date there has been minimal patient input of this kind into aspects of surgical site infection (SSI), such as surveillance or prevention interventions. AIM: To obtain information from patients' experiences of SSIs to improve clinical practice. METHODS: Narrative interviews with 17 patients with SSIs (four deep, 12 organ space and one superficial) from three hospitals in England were conducted followed by thematic content analysis. RESULTS: Patients lacked overall awareness, concern and understanding of SSIs. Seven patients did not know that they had SSIs and, judging from patients' accounts, staff may have contributed to the lack of awareness by not informing patients of SSIs or downplaying their existence. The use of primary care resources was considerable and six of the patients were absent from work for two to four months. CONCLUSIONS: SSIs have a low profile among patients which, if it were raised, could increase compliance with preventive interventions. This study confirms the appropriateness of using patient self-assessment post-discharge surveillance questionnaires to identify SSI symptoms, and highlights the need to identify total costings including to primary care, patients and the economy. PMID- 23088922 TI - The antimicrobial peptide, shrimp anti-lipopolysaccharide factor (SALF), inhibits proinflammatory cytokine expressions through the MAPK and NF-kappaB pathways in Trichomonas vaginalis adherent to HeLa cells. AB - Trichomonas vaginalis is a parasitic protozoan that causes sexually transmitted infections (STIs) worldwide. The infection is dangerous and easily spreads within a community. Also, some cases of drug resistance were reported. Previously, we reported that the shrimp anti-lipopolysaccharide factor (SALF), an antimicrobial peptide of 24 amino acids, modulates inflammatory responses and inhibits T. vaginalis growth. To date, there is no report on the mechanism of SALF's actions in T. vaginalis' adherence to HeLa cells. In this research using an ELISA, we found that the SALF downregulated the release of proinflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1alpha, IL-6, IL-8, and monocyte chemoattractant protein (MCP)-1) secreted by T. vaginalis which was adhering to HeLa cells. We also performed real-time PCR experiments to determine the roles of the SALF in the expressions of several proinflammatory genes. Through a Western blot analysis, we determined that SALF treatment inhibited T. vaginalis-treated HeLa cells through the p38 and NF-kappaB pathways. Furthermore, we used different inhibitors to confirm the pathway by ELISA and Western blotting. Taken together, it is apparent that the SALF suppresses T. vaginalis-induced secretion of proinflammatory cytokines by HeLa cells by acting through the p38 and NF-kappaB pathways. PMID- 23088923 TI - Simultaneous estimation and validation of some binary mixtures of antihypertensive drugs by RP-LC methods using two new generation silica columns. AB - Two reversed phase liquid chromatographic (RP-LC) techniques are presented for the rapid, accurate, precise, simultaneous determination of olmesartan hydrochlorothiazide and zofenopril-hydrochlorothiazide binary mixtures in their dosage forms. The separation of these binary mixtures was carried out by using two new stationary phases that have different surface chemistries which were used for the first time in the determination of these binary mixtures. The analyte peaks were detected at 216 nm. Linearity was obtained in different concentration ranges between 0.5 and 20 MUg mL(-1) for all compounds. The proposed methods have been extensively validated and sample preparation, flow rate, run time of the analytical systems were at low levels. The proposed methods would decrease the consumption of organic solvents and reagents further safeguarding to our environment. PMID- 23088924 TI - Kinematics during lower extremity functional screening tests in young athletes - are they reliable and valid? AB - OBJECTIVE: To determine if lower extremity functional tests are reliable and valid screening tests of lower extremity dynamic alignment in healthy young athletes. DESIGN: Quantitative experimental test-re-test. METHODS: Peak three dimensional pelvis and lower extremity kinematics were quantified in 23 uninjured young athletes (11 +/- 1 years) during three lower extremity functional tests (Small Knee Bend [SKB], Single Leg SKB and Drop Jump) and Running. A nine camera motion analysis system captured three trials of all tests. All functional tests were repeated by 10 young athletes eight to ten weeks later. Visual 3D and Labview were used to process all data. Intraclass correlation coefficients (ICC) and typical errors (TE) were used to assess within- and between-day reliability of all variables. Pearson correlation coefficients were used to evaluate associations between peak kinematics during the SKB and Drop Jump and between the Single Leg SKB and Running. RESULTS: Within-day reliability was excellent (ICC >= 0.85) and between-day reliability was excellent to good (ICC range 0.60-0.92) for the majority of kinematic variables. Correlations for peak lower extremity kinematics between SKB and Drop Jump were moderate to very large (r = 0.39-0.87) as were correlations between Single Leg SKB and Running (r = 0.45-0.84). CONCLUSIONS: Kinematics during the SKB and single leg SKB have moderate to high reliability and are similar to those during a drop jump or running. PMID- 23088926 TI - Accuracy of colposcopy management to detect CIN3 and invasive cancer in women with abnormal screening tests: results from a primary HPV screening project from 2006 to 2011 in Wolfsburg, Germany. AB - OBJECTIVE: Combining HPV and Pap screening achieves very good risk stratification and sensitive detection of CIN3 and cancer (CIN3 +), but poorer specificity, and may result in an increased risk of glandular and new lesions during follow-up. We examined if this phenomenon may compromise the accuracy of colposcopy. METHODS: As part of a primary HPV screening pilot project comprising 19,624 participants aged over 30 years, the failure rate to detect CIN3 at first visit was measured over a five-year period to assess the quality of colposcopy as an overall management concept. Management relied on excisional biopsies in all HSIL cytology or major findings on colposcopy, endocervical assessment in type 3 transformation zones (TZ) and guided biopsies in type 1 or 2 TZ. RESULTS: Of 667 women referred for colposcopy because of atypical Pap smears and/or HPV persistency, 171 were diagnosed with CIN3+. All 18 cancers and 140/153 CIN3 cases were diagnosed at the first visit. Of 13 CIN3 observed during follow-up, five were classified as new cases, five as definite and three as probably colposcopy failures, giving a failure rate of 4.7% (8/171). Only three failures were related to false-negative punch biopsies while five occurred because of false-negative endocervical assessment in type 3 TZ. CONCLUSIONS: Colposcopy management following defined pathways was safe in this HPV screening program with an acceptable failure rate. Further improvements may depend on developing better methods for endocervical assessment rather than for ectocervical biopsies. PMID- 23088925 TI - Social-cognitive processes associated with fear of recurrence among women newly diagnosed with gynecological cancers. AB - OBJECTIVE: This cross sectional study aimed to characterize fears of recurrence among women newly diagnosed with gynecologic cancer. The study also evaluated models predicting the impact of recurrence fears on psychological distress through social and cognitive variables. METHODS: Women (N=150) who participated in a randomized clinical trial comparing a coping and communication intervention to a supportive counseling intervention to usual care completed baseline surveys that were utilized for the study. The survey included the Concerns about Recurrence Scale (CARS), Beck Depression Inventory (BDI), Impact of Event Scale (IES), and measures of social (holding back from sharing concerns and negative responses from family and friends) and cognitive (positive reappraisal, efficacy appraisal, and self-esteem appraisal) variables. Medical data was obtained via medical chart review. RESULTS: Moderate-to-high levels of recurrence fears were reported by 47% of the women. Younger age (p<.01) and functional impairment (p<.01) correlated with greater recurrence fears. A social-cognitive model of fear of recurrence and psychological distress was supported. Mediation analyses indicated, that as a set, the social and cognitive variables mediated the association between fear of recurrence and both depression and cancer-specific distress. Holding back and self-esteem showed the strongest mediating effects. CONCLUSION: Fears of recurrence are prevalent among women newly diagnosed with gynecologic cancer. Social and cognitive factors play a role in women's adaptation to fears and impact overall psychological adjustment. These factors may be appropriate targets for intervention. PMID- 23088927 TI - Changes of proteome and phosphoproteome trigger embryo-larva transition of honeybee worker (Apis mellifera ligustica). AB - The development of the last day embryo to the first instar larva is an essential process in the honeybee life cycle. However, the molecular mechanism of this life transition is still unknown. The proteome and phosphoproteome of last day embryos (72 h) and first instar larvae (24h, post hatching) were analyzed using 2-DE, multiplex fluorescent staining, mass spectrometry, bioinformatics, and qRT-PCR. Sixty-five proteins and 34 phosphoproteins changed their expression across the shift of embryos to larvae. The embryo stronger expression of proteins related to energy metabolism, development and amino acid metabolism suggests its high metabolic energy demand during active embryogenesis. While, the newly hatched larvae escalated the expression of proteins related to cytoskeleton, biosynthesis, protein folding, fatty acid and oxidative metabolism, particularly the higher phosphorylation of cytoskeleton and biosynthesis indicates their roles to ensure the fast growing larvae. These differences in protein expression level illustrate that specific protein functions are restricted to particular developmental stage. Our data suggest the essential changes of proteome and phosphoproteome to trigger the transition of embryo to larvae. This unravels the molecular event behind the first life cycle transition of honeybees and is potentially helpful for future reverse genetic studies in this model insect. PMID- 23088928 TI - A combined de novo protein sequencing and cDNA library approach to the venomic analysis of Chinese spider Araneus ventricosus. AB - In past years, spider venoms have attracted increasing attention due to their extraordinary chemical and pharmacological diversity. The recently popularized proteomic method highly improved our ability to analyze the proteins in the venom. However, the lack of information about isolated venom proteins sequences dramatically limits the ability to confidently identify venom proteins. In the present paper, the venom from Araneus ventricosus was analyzed using two complementary approaches: 2-DE/Shotgun-LC-MS/MS coupled to MASCOT search and 2 DE/Shotgun-LC-MS/MS coupled to manual de novo sequencing followed by local venom protein database (LVPD) search. The LVPD was constructed with toxin-like protein sequences obtained from the analysis of cDNA library from A. ventricosus venom glands. Our results indicate that a total of 130 toxin-like protein sequences were unambiguously identified by manual de novo sequencing coupled to LVPD search, accounting for 86.67% of all toxin-like proteins in LVPD. Thus manual de novo sequencing coupled to LVPD search was proved an extremely effective approach for the analysis of venom proteins. In addition, the approach displays impeccable advantage in validating mutant positions of isoforms from the same toxin-like family. Intriguingly, methyl esterifcation of glutamic acid was discovered for the first time in animal venom proteins by manual de novo sequencing. PMID- 23088929 TI - An iTRAQ-based mitoproteomics approach for profiling the nephrotoxicity mechanisms of ochratoxin A in HEK 293 cells. AB - Nephrotoxicity is the most prominent of ochratoxin A (OTA) among the diverse range of toxicological effects. Previous work indicated that reactive oxygen species (ROS) play an important role in the pathogenesis of a variety of renal diseases, and its major endogenous source is mitochondria. No research has used global protein expression profiling to investigate potential toxicity mechanisms of OTA at the mitochondria level. An iTRAQ-based mitoproteomics approach was used to explore possible toxicity mechanisms of OTA and potential protective mechanisms of N-acetyl-L-cysteine (NAC) using the mitochondria of Human Embryonic Kidney 293 (HEK 293) cells. Our results showed that OTA induced a decrease in DeltaPsim, and an increase in ROS and cell death. We identified a total of 1973 nonredundant proteins, among which 1398 proteins (70.86%) were overlapped. There were 66 significantly different proteins expressed in response to OTA, which were mainly involved in the perturbation of the mitochondrial electron transport chain (mETC), inhibition of protein synthesis, and induction of stress response and cell death. In addition, NAC could almost completely reverse the adverse effects of OTA at the protein level. Finally, a hypothetical model of OTA-induced mitochondria damage is proposed to provide a framework for the toxicity mechanism of OTA. PMID- 23088930 TI - Molecular modeling and description of a newly characterized activating mutation of the EGFR gene in non-small cell lung cancer. AB - Lung cancer is the leading cause of death among malignant diseases in humans worldwide. In the last decade development of new targeted drugs for the treatment of non-small cell lung cancer proved to be a promising approach to prolong the otherwise very poor prognosis of patients with advanced UICC stages. Epidermal growth factor receptor (EGFR) has been in the focus of this lung cancer science and specific activating mutations are eligible for the treatment with specific tyrosine kinase inhibitors like gefitinib or erlotinib. Beside typical deletions in exon 19 and point mutations in exons 18 and 21 several insertions in exon 19 have been described and attributed activating properties as well. This is the first European and overall the 5th description in English literature of one of these specific insertions. To elucidate its structural changes leading to the activating properties we performed molecular modeling studies. These revealed conformational and electrostatic force field changes in the kinase domain of EGFR. To not miss uncommon mutations thorough and precise characterization of EGFR hotspots, i. e. at least exons 18, 19 and 21, should therefore be conducted to provide best medical care and to offer lung cancer patients appropriate cancer treatment. VIRTUAL SLIDES: The vistual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2209889658102062. PMID- 23088931 TI - Cardiac findings and long-term thromboembolic outcomes following pulmonary embolism in children: a combined retrospective-prospective inception cohort study. AB - In paediatric pulmonary embolism, cardiac findings and thromboembolic outcomes are poorly defined. We conducted a mixed retrospective-prospective cohort study of paediatric pulmonary embolism at the Children's Hospital Colorado between March, 2006 and January, 2011. A total of 58 consecutive children - age less than or equal to 21 years - with acute pulmonary embolism were enrolled. Data collection included clinical and laboratory characteristics, treatments, serial echocardiographic and electrocardiographic findings, and outcomes of pulmonary embolism non-resolution and recurrence. The median age was 16.5 years ranging from 0 to 21 years. The most prevalent clinical risk factors were oral contraceptive pill use (52% of female patients), presence of a non-infectious inflammatory condition (21%), and trauma (21%). Thrombophilias included heterozygous factor V Leiden in 21%; antiphospholipid antibody syndrome was established in 31% overall. Proximal pulmonary artery involvement was present in 34%. At presentation, nearly half of the patients had hypoxaemia and 37% had tachycardia. The classic electrocardiographic finding of S1Q3T3 was present in 12% acutely; tricuspid regurgitation greater than 3 metres per second, septal flattening, and right ventricular dilation were each present on acute echocardiogram in 25%. Nearly all patients received therapeutic anticoagulation, with initial systemic tissue plasminogen activator administered in 16% for occlusive iliofemoral deep venous thrombosis and/or massive pulmonary embolism. Pulmonary embolism resolution was observed in 82% by 6 months. Recurrent pulmonary embolism occurred in 9%. There were no pulmonary embolism-related deaths. Right ventricular dysfunction was rare in follow-up. These data indicate that acute heart strain is common, but chronic cardiac dysfunction is rare, following aggressive management of acute pulmonary embolism in children. PMID- 23088932 TI - 99mTc/Re complexes bearing bisnitroimidazole or mononitroimidazole as potential bioreductive markers for tumor: synthesis, physicochemical characterization and biological evaluation. AB - Four monoamine-monoamide dithiol (MAMA) ligands containing two or one nitroimidazole moieties were synthesized and labeled with (99m)Tc (labeling yield > 95%). The proposed structures of (99m)Tc-complexes are identified by comparison with analogous Re-MAMA complexes. (99m)Tc-MAMA complexes show better physicochemical characters than (99m)TcO-(PnAO-1-(2-nitroimidazole)). Reduction potentials of nitro groups of the rhenium complexes are within the range for bioreductive compounds. As expected, biodistribution studies demonstrate that the 2-nitroimidazole complex shows better tumor-to-tissue ratios than 4 nitroimidazole analog for mononitroimidazole complexes, but not for MAMA bisnitroimidazoles due to higher lipophilicity. Both the bisnitroimidazole compounds show rapider excretion, lower background activity in liver and higher tumor-to-tissue ratios than the mononitroimidazoles. Better biodistribution characteristic makes both the MAMA-bisnitroimidazole complexes, especially (99m)Tc-15, be potential tumor hypoxia marker. PMID- 23088933 TI - Synthesis and anti-staphylococcal activity of new 4-diazopyrazole derivatives. AB - Several new 4-diazopyrazole derivatives 6a-g and 9a-c were obtained by the reaction of 1-(R-substituted-phenyl)-3-(1,3-dimethyl-1H-pyrazol-5-yl)ureas 5a-g and N-(1,3-dimethyl-1H-pyrazol-5-yl)-2-(R-substituted-phenyl)acetamides 8a-c respectively with a sevenfold excess of nitrous acid in acetic acid solution. The compounds were assayed for their activity against the Staphylococcus aureus reference strains ATCC 25923, ATCC 29213 and ATCC 6538, as well as six veterinary strains. The best anti-staphylococcal profile was showed by [(R-substituted phenyl)acetyl](4-diazonio-1,3-dimethyl-1H-pyrazol-5-yl)azanides 9a,c. Compound 9c was also able at 3.1 MUg mL(-1) to inhibit of 45.7% the biofilm formation of the strains S. aureus ATCC 29213. PMID- 23088934 TI - Effects of considering greenhouse gas consequences on fertilizer use in loblolly pine plantations. AB - Fertilizer use, widely practiced in forest plantation management to stimulate tree growth, contributes to greenhouse gas (GHG) emissions. We explore how accounting for GHG consequences affects optimal fertilizer application rates of commercial forest plantations. A generic model that maximizes the equivalent annual net benefit of timber production and GHG balance is developed and applied to loblolly pine (Pinus taeda L.) plantations in the southern United States. We find that fertilizer use still is a viable practice for managing loblolly pine plantations in the region although fertilizer application rate should be reduced when GHG consequences are valued. A greater reduction in fertilizer application rate is recommended where wood is used for paper production because life cycle GHG emissions of paper products are much higher than those of solid wood or bioenergy products. A higher fertilizer rate should be applied when forest residues are used for the production of bioenergy that offsets GHG emissions from consuming fossil fuels. PMID- 23088935 TI - Serum uric acid as an independent predictor of mortality in high-risk patients with obstructive coronary artery disease: a prospective observational cohort study from the ET-CHD registry, 1997-2003. AB - BACKGROUND: Serum uric acid (SUA) has been observed to be highly associated with the development of cardiovascular disease for more than 50 years. Several studies have reported elevated SUA as an independent predictor of mortality in patients with coronary artery disease (CAD) after adjustment for classic risk factors but some studies did not find similar results. METHODS: Between January 1997 and December 2003, a prospective cohort study was performed in 1054 patients with angiographically defined CAD, and their classic risk factors and SUA levels were determined at enrollment. The study cohort was followed for an average of 3.2 years, with a median of 3.1 years. The main outcome measure was death from cardiac disease and any cause. RESULTS: Of all study patients, 789 (74.9%) were men and 265 (25.1%) were women. The mean age of the male and female patients was 64.8 and 66.9 years, respectively. The mean SUA level of all patients was 410.4 MUmol/L. There were grading effects of SUA quartiles on cardiac and all-cause mortality in univariate and multivariate Cox regression analyses. After adjustment, the multivariate analyses revealed that patients in the highest SUA quartile (>487 MUmol/L) had 2.08 (95% CI=1.19-3.62, p=0.01) fold increased risk of cardiac death, and 1.68 (95% CI=1.10-2.57, p=0.017) fold increase risk of overall mortality compared with the lowest quartile (<315 MUmol/L). CONCLUSIONS: SUA may be a significant predictor of cardiac and overall mortality, independent of classic risk factors in high-risk patients with obstructive CAD. PMID- 23088936 TI - Usefulness of ablation of complex fractionated atrial electrograms using nifekalant in persistent atrial fibrillation. AB - BACKGROUND: Additional ablation of complex fractionated atrial electrograms (CFAE) after pulmonary vein isolation (PVI) has been shown to improve the success of ablation of persistent atrial fibrillation (AF). However, extensive ablation is often necessary to eliminate all CFAE or to terminate AF. We assessed the usefulness of the administration of an antiarrhythmic drug (AAD) before CFAE ablation. METHODS AND RESULTS: One-hundred and ten patients with persistent AF first underwent PVI, roof and floor linear ablation (box isolation). One hundred patients who remained in AF after box isolation were then randomized to either receive (AAD group, n=50) or not receive (no-AAD group, n=50) intravenous nifekalant (0.3mg/kg) followed by a CFAE ablation. In the AAD group, nifekalant terminated AF in 19 (38%) patients and ablation of localized CFAE was performed in 31 patients who remained in AF after nifekalant, and terminated AF in 11 (35%) patients. In the no-AAD group, ablation of CFAE terminated AF in 13 (26%) patients. The AAD group had a significantly lesser number of radio frequency applications at CFAE sites (18 +/- 12 versus 36 +/- 10, p<0.0001) and shorter procedure time (162 +/- 34 versus 197 +/- 29 min, p<0.0001) compared with the no AAD group. However, there was no significant difference in success rate at 12 months after a single ablation procedure between the two groups (AAD group, 74% versus no-AAD group, 76%). CONCLUSIONS: An approach to ablation using nifekalant may be useful in localizing areas of CFAE, reducing the number of applications at CFAE sites and procedure time. Ablation of only CFAE localized with nifekalant may be sufficient for clinical outcome. PMID- 23088937 TI - Analysis of the C9orf72 hexanucleotide repeat expansion in Korean patients with familial and sporadic amyotrophic lateral sclerosis. AB - The expansion of a noncoding hexanucleotide repeat (GGGGCC) in the chromosome 9 open reading frame (C9orf72) gene has been identified as the most common cause of familial and sporadic amyotrophic lateral sclerosis (ALS) in Caucasian populations. The role of the C9orf72 repeat expansion in Korean ALS patients, however, has not been reported. We therefore investigated the frequency of the C9orf72 repeat expansion in 254 Korean patients with familial (n = 8) and sporadic (n = 246) ALS and found that none of the patients had the expansion. The number of hexanucleotide repeats ranged from 2 to 11 in the 254 ALS patients without the expansion. Our results suggest that the C9orf72 repeat expansion is not the main cause of ALS in the Korean population. PMID- 23088939 TI - Acute right ventricular infarction: insights for the interventional era. AB - Acute right ventricular infarction is associated with higher in-hospital morbidity and mortality related to life-threatening hemodynamic compromise and arrhythmias during acute occlusion and abruptly with reperfusion, complications which have implications for interventional management. Acute right coronary artery occlusion proximal to the right ventricular (RV) branches results in depressed RV systolic function, leading to diminished transpulmonary delivery of left ventricular preload and resulting in low-output hypotension. Under these conditions, RV pressure generation and output are dependent on left ventricular septal contraction via paradoxical septal motion. With culprit lesions distal to the right atrial (RA) branches, augmented RA contractility enhances RV performance and cardiac output, whereas proximal occlusions induce RA ischemia, which exacerbates hemodynamic compromise. Hypotension may respond to volume resuscitation and restoration of a physiologic rhythm. Refractory cases usually respond to parenteral inotropes, though in some cases mechanical support is required. The right ventricle is relatively resistant to infarction and usually recovers even after prolonged occlusion. Acute percutaneous mechanical reperfusion enhances recovery of RV performance and improves the clinical course and survival of patients with right ventricular infarction. PMID- 23088941 TI - Mechanisms of immune dysfunction and bacterial persistence in non-cystic fibrosis bronchiectasis. AB - Bronchiectasis is a chronic inflammatory lung disease. The underlying cause is not identified in the majority of patients, but bronchiectasis is associated with a number of severe infections, immunodeficiencies and autoimmune disorders. Regardless of the underlying cause, the disease is characterised by a vicious cycle of bacterial colonisation, airway inflammation and airway structural damage. Inflammation in bronchiectasis is predominantly neutrophil driven. Neutrophils migrate to the airway under the action of pro-inflammatory cytokines such as interleukin-8, tumour necrosis factor-alpha and interleukin-1beta, all of which are increased in the airway of patients with bronchiectasis. Bacterial infection persists in the airway despite large numbers of neutrophils that would be expected to phagocytose and kill pathogens under normal circumstances. Evidence suggests that neutrophils are disabled by multiple mechanisms including cleavage of phagocytic receptors by neutrophil elastase and inhibition of phagocytosis by neutrophil peptides. Complement activation is impaired and neutrophil elastase may cleave activated complement from pathogens preventing effective opsonisation. Organisms also evade clearance by adapting to chronic infection. The formation of biofilms, reduced motility and the down-regulation of virulence factors are among the strategies used to subvert innate immune mechanisms. Greater understanding of the mechanisms underlying chronic colonisation in bronchiectasis will assist in the development of new treatments for this important disease. PMID- 23088942 TI - Gadolinium-based magnetic resonance contrast agents for neuroradiology: an overview. AB - There has been much progress in contrast enhanced neuroradiologic magnetic resonance imaging in the almost 25 years since the first gadolinium-based contrast agent was approved in the United States. Much of this now focuses on the introduction of significantly higher relaxivity agents into our clinical armamentarium and the addition of T2*-weighted imaging sequences to hyperacute stroke or neoplastic evaluations. All 4 magnetic resonance contrast agents approved in the United States during the past decade have been higher relaxivity agents, suggesting a strong trend in our industry to continue to find more efficient, more powerful, more diagnostic means of increasing contrast on imaging studies. PMID- 23088940 TI - Prolonged alendronate treatment prevents the decline in serum TGF-beta1 levels and reduces cortical bone strength in long-term estrogen deficiency rat model. AB - INTRODUCTION: While the anti-resorptive effects of the bisphosphonates (BPs) are well documented, many questions remain about their mechanisms of action, particularly following long-term use. This study evaluated the effects of alendronate (Ale) treatment on TGF-beta1 signaling in mesenchymal stem cells (MSCs) and osteocytes, and the relationship between prolonged alendronate treatment on systemic TGF-beta1 levels and bone strength. METHODS: TGF-beta1 expression and signaling were evaluated in MSCs and osteocytic MLO-Y4 cells following Ale treatment. Serum total TGF-beta1 levels, a bone resorption marker (DPD/Cr), three-dimensional microCT scans and biomechanical tests from both the trabecular and cortical bone were measured in ovariectomized rats that either received continuous Ale treatment for 360 days or Ale treatment for 120 days followed by 240 days of vehicle. Linear regression tests were performed to determine the association of serum total TGF-beta1 levels and both the trabecular (vertebrae) and cortical (tibiae) bone strength. RESULTS: Ale increased TGF-beta1 signaling in the MSCs but not in the MLO-Y4 cells. Ale treatment increased serum TGF-beta1 levels and the numbers of TGF-beta1-positive osteocytes and periosteal cells in cortical bone. Serum TGF-beta1 levels were not associated with vertebral maximum load and strength but was negatively associated with cortical bone maximum load and ultimate strength. CONCLUSIONS: The increase of serum TGF-beta1 levels during acute phase of estrogen deficiency is likely due to increased osteoclast-mediated release of matrix-derived latent TGF-beta1. Long-term estrogen-deficiency generally results in a decline in serum TGF-beta1 levels that are maintained by Ale treatment. Measuring serum total TGF-beta1 levels may help to determine cortical bone quality following alendronate treatment. PMID- 23088943 TI - Use of contrast media in neuroimaging. AB - Since their introduction, gadolinium-based contrast media are routinely used in most CNS MR imaging indications. Due to their paramagnetic effect, they significantly shorten the T1 relaxation times of the tissue and are therefore applied to improve the sensitivity and specificity of CNS diseases and to allow a better treatment decision, planning, and follow-up. More recently, contrast media have also been used to allow the measurement of tissue perfusion and to follow the time course of enhancement in dynamic contrast-enhanced imaging studies or dynamic MRA studies. With the presence of the BBB, contrast media does not leak into the tissue. Only vascular structures and areas of the brain that have no BBB(choroid plexus, pineal and anterior lobe of pituitary gland) physiologically enhance after contrast injection. The mechanisms of tissue enhancement in the brain are related to a higher vascularity of the pathology or a disruption of the BBB.Tissue enhancement is, besides the degree of BBB disruption, further dependent on the applied magnetic field strength, with higher field providing a better enhancement and the applied dose of contrast media. PMID- 23088944 TI - Contrast-enhanced MR imaging in neuroimaging. AB - MR imaging without and with gadolinium-based contrast agents (GBCAs) is an important imaging tool for defining normal anatomy and characteristics of lesions. GBCAs have been used in contrast-enhanced MR imaging in defining and characterizing lesions of the central nervous system for more than 20 years. The combination of unenhanced and GBCA-enhanced MR imaging is the clinical gold standard for the noninvasive detection and delineation of most intracranial and spinal lesions. MR imaging has a high predictive value that rules out neoplasm and most inflammatory and demyelinating processes of the central nervous system. PMID- 23088945 TI - Contrast-enhanced magnetic resonance angiography. AB - Magnetic resonance (MR) angiography is a powerful tool for the evaluation of cervical and intracranial vasculature. Both noncontrast and contrast-enhanced MR angiography can provide exquisite vascular contrast and detail without the use of ionizing radiation. More advanced techniques such as time-resolved MR angiography and parallel imaging provide dynamic information in rapid fashion. This article describes the basic principles and techniques of MR angiography image acquisition. PMID- 23088947 TI - Use of magnetic resonance imaging contrast agents in the liver and biliary tract. AB - This article presents an overview of liver and biliary contrast agents including their mechanisms of action, dosage and elimination, current clinical indications, and potential future uses. PMID- 23088948 TI - Contrast-enhanced cardiac magnetic resonance imaging. AB - Cardiac magnetic resonance (CMR) imaging has significantly evolved in the past decade and is well established in the evaluation of coronary artery disease (CAD). The evaluation of cardiac anatomy and contractility by high-resolution CMR can be improved by using intravenous administration of gadolinium-based contrast agents. Delayed enhancement CMR imaging has become the gold standard for quantification of myocardial viability in CAD. Contrast-enhanced CMR imaging may circumvent the need for endomyocardial biopsy or localize the involved regions, thereby improving the diagnostic yield of this invasive procedure. The application of contrast-enhanced CMR as an advanced imaging technique for ischemic and nonischemic diseases is reviewed. PMID- 23088946 TI - Advanced techniques using contrast media in neuroimaging. AB - This article presents an overview of advanced magnetic resonance (MR) imaging techniques using contrast media in neuroimaging, focusing on T2*-weighted dynamic susceptibility contrast MR imaging and T1-weighted dynamic contrast-enhanced MR imaging. Image acquisition and data processing methods and their clinical application in brain tumors, stroke, dementia, and multiple sclerosis are discussed. PMID- 23088949 TI - Peripheral MR Angiography. AB - Since the introduction of contrast-enhanced MR angiography (MRA), several different techniques for imaging the peripheral arteries have evolved. All of them provide good diagnostic image quality, whereas some older techniques suffer from drawbacks, such as long acquisition time, impaired image quality from venous enhancement, and limited spatial resolution. MRA provides the most comprehensive modality offering the ability to tailor the examination to the patient and the specific question to be answered. The drawbacks experienced at the introduction of MRA to clinical routine have largely been overcome or at least diminished, so that the benefits of MRA outbalance the limitations. PMID- 23088950 TI - Contrast media in breast imaging. AB - Although mammography is the standard imaging modality for detection of breast cancer, magnetic resonance (MR) imaging is a valuable adjunct and, in certain cases, is the imaging of choice. Contrast-enhanced breast MR imaging provides a noninvasive means of staging disease, assessing posttreatment response, and screening of high-risk patients with genetic predispositions. Additional indications for MR mammography include lesion characterization, contralateral breast evaluation in patients with proved malignancy, and identifying primary malignancy in patients with axillary nodal disease. There are several competing factors that influence the quality of the study. Finding the right balance is the key to providing high-quality images that can be accurately interpreted. PMID- 23088951 TI - MR Imaging of the brachial plexus. AB - MR imaging of the brachial plexus assesses the continuity of the elements, relationship, and orientation of lesions, evaluates morphology, and reveals secondary features of plexopathies. The selection of sequences and imaging planes is guided by the history, clinical examination, and suspected type and location of the abnormality. Increased magnet strength and isotropic imaging with multiplanar reconstructions may allow for standardized imaging protocols and shorter examination time. This article discusses MR imaging evaluation of the brachial plexus, relevant anatomy, and common pathology with clinical and imaging details, indications for use of intravenous contrast, differential considerations, and diagnostic pitfalls. PMID- 23088954 TI - Human safety risk assessment of lymph node angiomas observed in 2-year carcinogenicity studies in rats. AB - The occurrence of mesenteric lymph node angiomas (benign vascular neoplasms including lymphangioma and hemangioma) in untreated control rats in 2-year carcinogenicity studies can range from rare to common depending on the strain used. This lesion is most common in male rats. Factors and conditions that may contribute to the etiopathogenesis of lymph node angiomas in rats include: (1) genetic drift, (2) congenital/developmental malformation, (3) sinus vascular transformation/venous obstruction of outflow, (4) "inflammatory" pseudo-tumors, and/or (5) defects of endothelial lymphatic vascular secretion/permeability. Lymph node angiomas in humans are extremely rare, not reported in mesenteric lymph nodes, and more common in females than males. The evaluation of increased mesenteric lymph node angiomas in rats for overall human safety risk assessment of novel pharmaceutical therapeutics should consider: genotoxicity of the test article, occurrence of vascular neoplasms in other locations in rats and in mice, occurrence of proliferative vascular lesions in nonclinical toxicology studies in non-rodent species, dose/exposure response, and pathophysiologic/morphologic differences and similarities of lymph node angiomas between rats and humans. Angiomas are independent lesions from angiosarcomas and are not precursors for angiosarcomas in either humans or animals. Mesenteric lymph node angiomas in rats are unlikely to be relevant for human risk assessment of pharmaceutical agents. PMID- 23088955 TI - Adjuvant radiotherapy in the management of axillary node negative invasive breast cancer: a qualitative systematic review. AB - PURPOSE: To actualize and to detail guidelines used in technical radiotherapy and indications for innovative radiation technologies in early axillary node negative breast cancer (BC). METHODS: Dosimetric and treatment planning studies, phase II and III trials, systematic reviews and retrospective studies were all searched (Medline((r)) database). Their quality and clinical relevance were also checked against validated checklists. A level of evidence was associated for each result. RESULTS: A total of 75 references were included. Adjuvant BC radiotherapy (50Gy/25 fractions/5 weeks followed by a tumor boost of 16Gy/8 fractions) is still the standard of care. Overall treatment time could be shortened for patients who present with low local relapse risk BC by using either hypofractionated whole breast irradiation; or accelerated partial breast irradiation. BC IMRT is not used in current practice. CONCLUSION: Our group aimed to provide guidelines for technical and clinical applications of innovative BC radiation technologies. PMID- 23088956 TI - Indications of external beam radiation therapy in non-anaplastic thyroid cancer and impact of innovative radiation techniques. AB - BACKGROUND: The mainstay of treatment for differentiated thyroid carcinomas is surgery. There is hardly any room for radiation therapy in differentiated thyroid carcinomas. We aimed to update recommendations for RT in the context of histological variants, increased use of radioiodine and new irradiations techniques. MATERIALS AND METHODS: A search of the French and English literature was performed using thyroid carcinoma, radiation therapy, surgery, variants and radioiodine. RESULTS: Papillary, follicular, Hurthle and medullary carcinomas represent about 80%, 11%, 3% and 4% of all thyroid carcinomas, respectively. Ten year survival rates for patients with papillary, follicular and Hurthle cell carcinomas are 93%, 85%, and 76%, respectively. The occurrence of criteria such as older age (45 or 60 years-old), massive primary disease, extensive extracapsular spread and macroscopic iodine-negative components inconsistently indicate external beam irradiation (EBRT). The impact of EBRT on poorer-prognosis histological variants is an emerging issue. Noteworthy, the incidence of laryngeal and wound healing complications has been an important limitation to EBRT. However, intensity modulated radiation therapy (IMRT) offers clear dosimetric advantages on tumor coverage and organ sparing such as the larynx, thus reducing late toxicities to less than 5%. Iodine contrast agents should be avoided during 4-6 weeks before radioiodine. PET CT is increasingly used in iodine-negative tumors. CONCLUSION: There are elective indications for EBRT and IMRT has the potential to improve local control. PMID- 23088957 TI - Trimodality treatment in the conservative management of infiltrating bladder cancer: a critical review of the literature. AB - Although radical cystectomy is still the treatment of choice for patients with infiltrating bladder cancer, there is growing evidence of the effectiveness of a conservative approach. Developed as a treatment of need for elderly or unfit patients unable to undergo radical cystectomy, conservative therapy is becoming a true alternative to surgery for highly selected patients. Although transurethral bladder resection, external radiotherapy and systemic chemotherapy can control the disease as single treatments, the best results have been observed when they are combined. Moreover, new irradiation techniques and new-generation drugs are now being tested in an attempt to improve disease control further. Conservative management requires the multidisciplinary involvement of different specialties in order to give patients a real alternative to surgical treatment. PMID- 23088958 TI - Scratching the itch: new tools to advance understanding of scabies. AB - Scabies remains a significant public health problem worldwide. Research into aspects of Sarcoptes scabiei biology and host-parasite interactions has been impeded by an inability to maintain mites in vitro and by limited access to parasite material and infected subjects. The generation of comprehensive expressed sequence tag libraries has enabled the initial characterisation of molecules of interest to diagnostics, vaccines, and drug resistance. The recent development and utilisation of animal models, combined with next-generation technologies, is anticipated to lead to new strategies to prevent, diagnose, and treat scabies, ultimately improving skin health in both human and veterinary settings. This article will summarise recent molecular and immunologic advances on scabies, and will address priorities for the exciting 'next chapter' of scabies research. PMID- 23088960 TI - Sialic acid cyclization of human Th homing receptor glycan associated with recurrent exacerbations of atopic dermatitis. AB - BACKGROUND: The molecular pathogenesis underlying recurrent exacerbations of atopic dermatitis (AD) is unclear. Some peripheral CCR4(+) and CCR7(+) helper memory T cells express the specific homing receptor, sialyl 6-sulfo Lewis X (G152 glycan). This glycan loses receptor activity via cyclization of its sialic acid moiety, thus becoming cyclic sialyl 6-sulfo Lewis X (G159 glycan). These findings suggest that the disordered expression of G152 and G159 glycans may be associated with recurrent exacerbations of AD. OBJECTIVE: To assess the possible association of G152 and G159 glycans, which are expressed on peripheral helper T (Th) cells, with frequency of exacerbations. METHODS: The percentage of glycan-expressing cells among peripheral blood CD4(+)CD45RO(+) lymphocytes was determined by flow cytometry. The association of glycans with the frequency of exacerbations determined by recurrence scores as well as with current disease activity was statistically tested. RESULTS: Current disease activity was significantly associated with CCR4(+)CCR7(-) memory Th cells expressing CSLEX-1 glycan, the conventional skin-trafficking receptor without sialic-acid-cyclization activity. In contrast, the frequency of exacerbations was positively and negatively associated with CCR4(+)CCR7(+) memory Th cells expressing G152 and G159 glycans, respectively. Receiver operating characteristics analyses indicated that the ratio of the G152(+)/G159(+) cell percentages discriminated patients with highly recurrent AD with the best accuracy. CONCLUSION: Flow cytometric determination of G159 and G152 glycans on peripheral helper memory T cells may be clinically useful for identifying patients with highly recurrent AD. Disordered sialic acid cyclization of G152 glycan may underlie highly recurrent AD, which may provide a novel therapeutic approach. PMID- 23088959 TI - Suppression of melanogenesis by a newly synthesized compound, MHY966 via the nitric oxide/protein kinase G signaling pathway in murine skin. AB - BACKGROUND: Ultraviolet B (UVB) radiation is the main physiological stimulus for skin pigmentation. Nitric oxide (NO) and the NO/PKG signaling pathway play an important role in UVB-induced melanogenesis, which is related to the induction of expression of tyrosinase. In an attempt to find a novel anti-melanogenic agent, we synthesized a new compound, 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY966). OBJECTIVE: The purpose of this study was to investigate the action of MHY966 on NO and the NO-mediated signaling pathway using in vitro and in vivo models of melanogenesis. METHODS: NO generation, melanin synthesis, and the expression of tyrosinase and PKG were measured in B16F10 melanoma cells to verify the anti-melanogenic effect of MHY966 in vitro. Next, melanin-possessing hairless mice were pre-treated with MHY966 and then irradiated with UVB repeatedly. Morphological, histological, and biochemical analyses including the expressions of PKG, tryosinase and nuclear MITF, and productions of nitric oxide, peroxynitrite and ROS were conducted. RESULTS: MHY966 effectively inhibited NO generation and subsequent melanin synthesis induced by sodium nitroprusside, an NO donor, and suppressed the expression of tyrosinase and PKG. Topical application of MHY966 dose-dependently attenuated UVB-induced pigmentation in a mouse model. This hypopigmentation effect induced by MHY966 treatment was mediated by the down-regulation of tyrosinase, PKG, and nuclear MITF, which was accompanied by decreased NO and NO-related oxidative stress. CONCLUSION: The novel compound, MHY966 had an inhibitory effect on NO generation and the NO mediated signaling pathway leading to the down-regulation of tyrosinase. The significance of the present study is the finding of a promising anti-melanogenic agent targeting the NO/PKG signaling pathway. PMID- 23088961 TI - Assessment of the AAV-mediated expression of channelrhodopsin-2 and halorhodopsin in brainstem neurons mediating auditory signaling. AB - The physiology and circuitry associated with dorsal cochlear nucleus neurons (DCN) have been well described. The ability to remotely manipulate neuronal activity in these neurons would represent a step forward in the ability to understand the specific function of DCN neurons in hearing. Although, optogenetics has been used to study the function of pathways in other systems for several years, in the auditory system only neurons in the auditory cortex have been studied using this technique. Adeno-associated viral vectors with either channelrhodopsin-2 fused with GFP (ChR2-GFP) or halorhodopsin fused with mCherry (HaloR-mCherry), capable of expressing light sensitive cation channels or chloride pumps, respectively, were delivered into the dorsal cochlear nucleus (DCN). One to 18 months later, expression of ChR2 and HaloR was observed throughout the DCN. Rhodopsin distribution within the DCN was determined to be within several cell types identified based on morphology and location within the DCN. Expression of ChR2-GFP and HaloR-mCherry was found at both the injection site as well as in regions receiving projections from the site. Wavelength appropriate optical stimulation in vivo resulted in neuronal activity that was significantly increased over pre-stimulation levels with no return to baseline levels during the time of the light exposure. We also examined the effects of optically driven neuronal activity on subsequent tone driven responses in the DCN. In the DCN 75% of the 16 electrode sites showed decreased neuronal activity in response to a tone immediately following light stimulation while six percent were decreased following tone stimulation and 19% of the electrode sites showed no change. This is in contrast to tone driven neuronal activity prior to the light exposure in which the majority of electrode sites showed increased neuronal activity. Our results indicate that expression and activation of rhodopsin within neurons involved in auditory processing does not appear to have deleterious effects on hearing even 18 months following expression. In addition, virally targeted rhodopsins may be useful as tract tracers to delineate as well as modulate the activity of pathways and specific neurons. In the future rhodopsins can be targeted to specific subpopulations of auditory neurons. Ultimately, photostimulation may provide a physiologically relevant method for modulating the function of auditory neurons and affecting hearing outcomes. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID- 23088962 TI - Different effects of low frequency stimulation to infralimbic prefrontal cortex on extinction of aversive memories. AB - Experimental extinction is a behavioral technique in which animals learn to extinguish previously learned fear responses. The infralimbic cortex (IL) of the medial prefrontal cortex has an important role in extinction of aversive memories. We have recently shown that electrical stimulation of the IL in a form of high-frequency stimulation (HFS), which induces potentiation in the IL, was associated with enhanced ability to extinguish aversive memory in two aversive paradigms, the fear conditioning and the conditioned taste aversion paradigms. These results suggest that the induction of potentiation in the IL is associated with better ability to extinguish. In the present study we examined the opposite hypothesis that inducing depression in the IL by the application of low-frequency stimulation (LFS) will result in impairments in extinction. Our results show that the application of LFS to the IL retards extinction of fear conditioning only, suggesting that the application of LFS to the IL results in impairments in extinction of conditioned fear. In the conditioned taste aversion paradigm (CTA), LFS to the IL was associated with delayed enhancement of extinction of CTA that was apparent 48 h following stimulation. These results suggest that localized electrical stimulation to the IL may be an effective method for manipulating learned fear and affecting the ability to extinguish aversive associations. PMID- 23088963 TI - The respiratory chemoreception conundrum: light at the end of the tunnel? AB - Arterial PCO2 is tightly regulated via changes in breathing. A rise in PCO2 activates the carotid bodies and exerts additional effects on neurons located within the CNS, causing an increase in lung ventilation. Central respiratory chemoreception refers to the component of this homeostatic reflex that is triggered by activation of receptors located within the brain (central chemoreceptors). Throughout the body, CO2 generally operates via the proxy of pH. Since countless proteins, ion channels and neurons display some degree of pH sensitivity, the notion that central respiratory chemoreception could rely on a few specialized neurons seems a priori counter-intuitive. Yet, two types of neurons currently stand out as critically important for breathing regulation by CO2: the retrotrapezoid nucleus (RTN) and the raphe. RTN neurons are glutamatergic, strongly activated by hypercapnia in vivo and by CO2 or protons in slices. These neurons target selectively the pontomedullary regions implicated in generating the respiratory rhythm and pattern. Their response to CO2 seems to involve both cell-autonomous and paracrine effects of CO2, the latter presumably mediated by the surrounding glia. The specific connections that these excitatory neurons establish with the rest of the breathing network are likely to be the main explanation of their importance to respiratory chemoreception. Serotonergic neurons have a powerful stimulatory effect on breathing, they facilitate the chemoreflexes and a subset of them likely function as CO2 sensors. Opto- and pharmacogenetic methods have played an important role in assessing the contribution of RTN and serotonergic neurons as well as glial cells to respiration. These particular experiments are emphasized here for thematic reasons although the current perception of the importance of the RTN and serotonergic cells to respiratory chemoreception also relies on many other types of evidence. A small portion of this evidence is presented as background. This article is part of a Special Issue entitled Optogenetics (7th BRES). PMID- 23088964 TI - Vorinostat and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells. AB - PURPOSE: Protein ubiquitination is a novel strategy used to treat malignancies. We investigated whether the histone deacetylase inhibitor vorinostat (Cayman Chemical, Ann Arbor, Michigan) and the proteasome inhibitor bortezomib (LC Laboratories, Woburn, Massachusetts) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells. MATERIALS AND METHODS: LNCaP, PC-3 and DU 145 cells (ATCCTM) were treated with vorinostat and/or bortezomib. Cell viability and induction of apoptosis were assessed. In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC-3 cells. The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference. Changes in the expression of ubiquitinated proteins, cell cycle associated proteins and acetylated histone were evaluated. RESULTS: Androgen receptor expression seemed to decrease bortezomib activity. PC-3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity. Vorinostat and bortezomib synergistically induced apoptosis, inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model. The combination decreased cyclin D1 and cyclin-dependent kinase 4 expression, and increased p21 expression. The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation. This histone acetylation was a consequence of the accumulation of ubiquitinated proteins. CONCLUSIONS: Vorinostat and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells. The current study provides a framework for testing the combination in patients with advanced prostate cancer. PMID- 23088965 TI - Re: Cost-effectiveness of percutaneous tibial nerve stimulation versus extended release tolterodine for overactive bladder: H. W. Chen, R. S. Bercik, E. F. Werner And S. F. Thung; J Urol 2012; 187: 178-184. PMID- 23088966 TI - Unilateral hypercalciuria: a stealth culprit in recurrent ipsilateral urolithiasis in children. AB - PURPOSE: Hypercalciuria is a risk factor for nephrolithiasis. We hypothesized that children with recurrent stones in 1 but not both kidneys and a normal 24 hour bladder urine calcium-to-creatinine ratio might exhibit isolated hypercalciuria of the affected kidney. MATERIALS AND METHODS: Patients 18 years or younger with symptomatic urolithiasis who had undergone ureteroscopic stone removal were included. All subjects underwent 24-hour bladder urinalysis. Subjects with an increased urine calcium-to-creatinine ratio from the 24-hour urine collection were excluded. The 4 subject cohorts defined were 1) single stone episode in 1 kidney, 2) single stone episode in both kidneys, 3) recurrent stone episodes on 1 side and 4) recurrent stone episodes on both sides. All urine collections were obtained at ureteroscopy. Urine was obtained from the bladder and from the renal pelvis of the kidney forming the stone. Spot urine calcium-to creatinine ratio was determined from these samples. RESULTS: A total of 329 patients were included. Nine of 74 subjects (12%) with recurrent stone episodes on 1 side had increased spot urine calcium-to-creatinine ratio from the affected kidney. No patients in the other cohorts had increased spot urine calcium-to creatinine ratio. Patients who formed recurrent stones in 1 kidney had increased spot urine calcium-to-creatinine ratio in the affected kidney vs other stone formers (ANOVA p <0.001). CONCLUSIONS: Unilateral hypercalciuria can occur in children with normal calcium levels in bladder urine. Unilateral hypercalciuria should be considered as a risk factor for nephrolithiasis in children with recurrent stone episodes in 1 kidney only. PMID- 23088967 TI - Is pelvic osteotomy associated with lower risk of pelvic organ prolapse in postpubertal females with classic bladder exstrophy? AB - PURPOSE: Bladder exstrophy is a major congenital anomaly involving defects in the genitourinary tract and pelvic musculoskeletal system. It appears intuitive that closure of the pelvic ring using osteotomy would be associated with a decreased risk of pelvic organ prolapse. We investigated whether osteotomy is associated with a decreased risk of pelvic organ prolapse in females with classic bladder exstrophy. MATERIALS AND METHODS: We searched our institutional review board approved exstrophy database of 1,078 patients and identified 335 females. We excluded patients who were younger than 13 years, had cloacal exstrophy or epispadias and did not have postpubertal imaging for measurement of pubic diastasis available. Our final study population consisted of 67 females. Univariate analysis was performed using t test or rank sum test for continuous variables and chi-square test for categorical variables. Logistic regression was used for multivariate analysis. RESULTS: Median patient age was 23 years (range 13 to 60). A total of 20 patients (29.9%) had pelvic organ prolapse at a median age of 20 years (range 11 to 43). Of the 67 patients 25 (37.3%) had undergone osteotomy at a median age of 6 months (range birth to 10 years). Seven patients had at least 1 pregnancy (range 1 to 3), and 24 patients had undergone vaginoplasty. On univariate analysis only diastasis was associated with pelvic organ prolapse, with smaller diastasis associated with a decreased risk of prolapse. On multivariate analysis including diastasis and osteotomy only diastasis was statistically significant. CONCLUSIONS: Osteotomy does not decrease the risk of pelvic organ prolapse in patients with classic bladder exstrophy. Rather, degree of diastasis is significantly associated with pelvic organ prolapse. PMID- 23088968 TI - Epidemiological assessment of hypospadias by degree of severity. AB - PURPOSE: Hypospadias is one of the most common congenital malformations, with reportedly increasing rates of prevalence but poorly defined etiological factors for the disease and the varying degrees of manifestation. We characterize the prevalence of hypospadias in Arkansas with consideration of the degree of hypospadias. MATERIALS AND METHODS: Data from the Arkansas State Birth Defects Surveillance Program of the Arkansas Reproductive Health Monitoring System were used to identify hypospadias cases and all male births by women residing in Arkansas between 1998 and 2007. Categorization of hypospadias severity into first, second or third degree was determined by a common 6-digit birth defect coding system used by surveillance programs across the country. Prevalence rates were computed for maternal and infant characteristics, birth year and birth residence. RESULTS: The prevalence of hypospadias in Arkansas for births between 1998 and 2007 was 74.2 cases per 10,000 live births. Degrees of hypospadias were graded as first (coronal/distal) in 60.7% of cases, second (mid penile/subcoronal) in 18.8%, third (perineal/proximal penile) in 4.6% and hypospadias not otherwise specified in 16%. The prevalence of hypospadias increased during the surveillance period, with 66.9 per 10,000 live births between 1998 and 2002, and 81.0 per 10,000 live births between 2003 and 2007 (p = 0.0003). While the prevalence rates for every degree of hypospadias also increased, the prevalence of hypospadias not otherwise specified decreased from 14.8 to 9.0 during these periods. CONCLUSIONS: Hypospadias prevalence in Arkansas is increasing. Improvement in recognition and categorization of degrees of hypospadias may have an impact on the reported prevalence rates. PMID- 23088970 TI - Editorial comment. PMID- 23088972 TI - Nitric oxide synthase (eNOS4a/b) gene polymorphism is associated with tumor recurrence and progression in superficial bladder cancer cases. AB - PURPOSE: We investigated the relationship between the distribution of the eNOS4a/b polymorphism and the clinical features of superficial bladder cancer. MATERIALS AND METHODS: This study included 201 healthy controls with a mean +/- SD age of 62.35 +/- 7.96 years and 123 patients with a mean age of 64.03 +/- 11.00 years diagnosed with histopathologically confirmed superficial bladder cancer. The eNOS4a/b polymorphism genotype (aa, bb or ab) was identified by polymerase chain reaction. Blood glutathione and plasma malondialdehyde levels were measured by spectrophotometry as an indicator of oxidative stress. We estimated total plasma levels of nitric oxide metabolites using a colorimetric assay kit. RESULTS: There were no significant differences in age or body mass index between patients and controls. Malondialdehyde and nitric oxide metabolite levels were statistically significantly increased (p = 0.000 and 0.024, respectively) and glutathione levels were decreased (p = 0.000) in patients with superficial bladder cancer. The bb genotype of the eNOS4a/b polymorphism is the most frequent one in the Turkish population and the aa genotype was significantly more common in patients with superficial bladder cancer (p = 0.000). Also, the aa plus ab genotype was significantly more common in patients with high grade tumors (p = 0.013) and in those with more progression to muscle invasive disease (p = 0.000). This genotype was also a significant independent risk factor for recurrence after adjusting for smoking status, stage, grade and the presence of carcinoma in situ on logistic regression analyses (OR 3.095, 95% CI 1.21-7.86, p = 0.018). CONCLUSIONS: The current study suggests that a genotype containing the a allele of the eNOS4a/b polymorphism may be a risk factor for bladder cancer. Additionally, patients harboring the aa plus ab genotype are more likely to experience tumor recurrence and progression. PMID- 23088973 TI - Transcript levels of androgen receptor variant AR-V1 or AR-V7 do not predict recurrence in patients with prostate cancer at indeterminate risk for progression. AB - PURPOSE: AR-V7, a ligand independent splice variant of androgen receptor, may support the growth of castration resistant prostate cancer and have prognostic value. Another variant, AR-V1, interferes with AR-V7 activity. We investigated whether AR-V7 or V1 expression would predict biochemical recurrence in men at indeterminate (about 50%) risk for progression following radical prostatectomy. MATERIALS AND METHODS: AR-V7 and V1 transcripts in a mixed grade cohort of 53 men in whom cancer contained 30% to 70% Gleason grade 4/5 and in a grade 3 only cohort of 52 were measured using a branched chain DNA assay. Spearman rank correlations of the transcripts, and histomorphological and clinical variables were determined. AR-V7 and V1 levels were assessed as determinants of recurrence in the mixed grade cohort by logistic regression and survival analysis. The impact of TMPRSS2-ERG gene fusion on prognosis was also evaluated. RESULTS: Neither AR-V7 nor V1 levels in grade 3 or 4/5 cancer in the mixed grade cohort were associated with recurrence or time to recurrence. However, AR-V7 and V1 inversely correlated with serum prostate specific antigen and positively correlated with age. The AR-V1 level in grade 3 cancer in the grade 3 only cohort was higher than in grade 3 or grade 4/5 components of mixed grade cancer. TMPRSS2 ERG fusion was not associated with AR-V7, AR-V1 or recurrence but it was associated with the percent of grade 4/5 cancer. CONCLUSIONS: The AR-V1 or V7 transcript level does not predict recurrence in patients with high grade prostate cancer at indeterminate risk for progression. Grade 3 cancer in mixed grade tumors may differ from 100% grade 3 cancer, at least in AR-V1 expression. PMID- 23088976 TI - Re: Repeat transurethral manipulation of bulbar urethral strictures is associated with increased stricture complexity and prolonged disease duration: S. J. Hudak, T. H. Atkinson and A. F. Morey; J Urol 2012; 187: 1691-1695. PMID- 23088974 TI - Geometric evaluation of systematic transrectal ultrasound guided prostate biopsy. AB - PURPOSE: Transrectal ultrasound guided prostate biopsy results rely on physician ability to target the gland according to the biopsy schema. However, to our knowledge it is unknown how accurately the freehand, transrectal ultrasound guided biopsy cores are placed in the prostate and how the geometric distribution of biopsy cores may affect the prostate cancer detection rate. MATERIALS AND METHODS: To determine the geometric distribution of cores, we developed a biopsy simulation system with pelvic mock-ups and an optical tracking system. Mock-ups were biopsied in a freehand manner by 5 urologists and by our transrectal ultrasound robot, which can support and move the transrectal ultrasound probe. We compared 1) targeting errors, 2) the accuracy and precision of repeat biopsies, and 3) the estimated significant prostate cancer (0.5 cm(3) or greater) detection rate using a probability based model. RESULTS: Urologists biopsied cores in clustered patterns and under sampled a significant portion of the prostate. The robot closely followed the predefined biopsy schema. The mean targeting error of the urologists and the robot was 9.0 and 1.0 mm, respectively. Robotic assistance significantly decreased repeat biopsy errors with improved accuracy and precision. The mean significant prostate cancer detection rate of the urologists and the robot was 36% and 43%, respectively (p <0.0001). CONCLUSIONS: Systematic biopsy with freehand transrectal ultrasound guidance does not closely follow the sextant schema and may result in suboptimal sampling and cancer detection. Repeat freehand biopsy of the same target is challenging. Robotic assistance with optimized biopsy schemas can potentially improve targeting, precision and accuracy. A clinical trial is needed to confirm the additional benefits of robotic assistance. PMID- 23088977 TI - Delayed primary repair of bladder exstrophy: ultimate effect on growth. AB - PURPOSE: Late referrals or unsuitable bladder templates often require delayed primary repair of bladder exstrophy. We investigated longitudinal bladder growth rates and eventual outcomes following this approach. MATERIALS AND METHODS: After institutional review board approval, we reviewed the medical records of patients with classic bladder exstrophy who underwent neonatal or delayed (more than 30 days) primary closure at our institution between 1970 and 2006. Clinical characteristics and annual cystographic bladder capacity before the continence procedure were compared. Failed primary exstrophy repairs were excluded. RESULTS: A total of 33 patients with available bladder capacity measurements underwent delayed exstrophy closure due to small bladder template in 18 (88% male) and late referral in 15 (80% male) at respective median ages of 305 days (range 86 to 981) and 172 days (31 to 676). They were compared to 82 patients (71% male) undergoing neonatal closure at a median of 2 days of life (range 0 to 27). Pelvic osteotomy was performed in 32 of 33 delayed closures. Longitudinal analysis of the bladder capacities demonstrated that, compared to neonatally closed cases, bladder capacities were on average 36 ml smaller in those with delayed repair due to small templates (p = 0.01) and 29 ml smaller in those with late referrals (p = 0.13). However, the rate of bladder growth did not differ significantly among the 3 groups. CONCLUSIONS: Delayed primary repair of exstrophy does not compromise the rate of bladder growth. However, children born with smaller templates will have overall smaller capacities and are less likely to undergo bladder neck reconstruction. PMID- 23088979 TI - Re: B7-H3 over expression in prostate cancer promotes tumor cell progression: H. Yuan, X. Wei, G. Zhang, C. Li, X. Zhang And J. Hou; J Urol 2011; 186: 1093-1099. PMID- 23088980 TI - Role of peroxisome proliferator activated receptor-gamma in bacillus Calmette Guerin bladder cancer therapy. AB - PURPOSE: We evaluated the effects of combined PPARg agonist with bacillus Calmette-Guerin in bladder cancer growth in vitro and in vivo, focusing on the tissue remodeling mechanisms induced by bacillus Calmette-Guerin. MATERIALS AND METHODS: PPARs are a superfamily of nuclear receptors that are transcription factors activated by ligands. Activation of PPARg, the gamma subtype, causes proliferation inhibition or differentiation of tumor cells. Previously, we reported that the inhibition of murine bladder tumor growth induced by bacillus Calmette-Guerin, which is the standard treatment for patients with nonmuscle invasive, high grade bladder cancer, increased PPARg expression in vitro and in vivo. In vitro the cell growth inhibition induced by bacillus Calmette-Guerin was enhanced by the PPARg agonist 15-d-PGJ2, raising the possibility that PPARg activation may be a therapeutic modality for this disease. RESULTS: In MB49 cells bacillus Calmette-Guerin and 15-d-PGJ2 induced PPARg expression, nuclear translocation and transcriptional activity. In vivo bacillus Calmette-Guerin reduced tumor size, an effect that was partially reversed when bacillus Calmette Guerin was combined with the PPARg agonist rosiglitazone. The same result was found when we analyzed the effect of the PPARg antagonist BADGE (Fluka Chemical, Buchs, Switzerland) combined with bacillus Calmette-Guerin. Analysis of the activation of macrophages and fibroblasts demonstrated that rosiglitazone inhibited the tissue remodeling mechanisms induced by bacillus Calmette-Guerin. CONCLUSIONS: Results suggest that PPARg is involved in the antitumor action of bacillus Calmette-Guerin. However, exogenous PPARg agonists would not be a favorable therapeutic modality because they can inhibit the tissue remodeling needed for an overall satisfactory bacillus Calmette-Guerin response. PMID- 23088981 TI - Early postoperative ultrasound after open pyeloplasty in children with prenatal hydronephrosis helps identify low risk of recurrent obstruction. AB - PURPOSE: Prediction of successful pyeloplasty can be challenging, particularly in asymptomatic children treated for worsening prenatally diagnosed hydronephrosis. We evaluated early noninvasive objective predictors of success in this population. MATERIALS AND METHODS: We reviewed patients who underwent pyeloplasty for asymptomatic, prenatally detected, worsening hydronephrosis treated between 2000 and 2010 with followup greater than 1 year. For all patients renal pelvis anteroposterior diameter in a mid transverse view and Society for Fetal Urology hydronephrosis grade were evaluated preoperatively and 3 to 4 months postoperatively. Aside from subjective evaluation based on change in hydronephrosis grade, we estimated the percentage of improvement in anteroposterior diameter (preoperative diameter--postoperative diameter/preoperative diameter). Repeat intervention after pyeloplasty arbitrarily defined failure. Patients were categorized into 3 groups, ie no failure on followup ultrasound (group 1), no failure with postoperative nuclear scan to document success (group 2) and failed pyeloplasty (group 3). ROC curves were plotted to correlate 4 variables with failure, namely preoperative anteroposterior diameter, postoperative anteroposterior diameter, percent improvement in anteroposterior diameter and subjective change in grade. RESULTS: Of 229 patients 192 (84%) who met inclusion criteria had ultrasound at 3 to 4 months postoperatively available. Mean age at surgery was 19 months and mean +/- SD followup was 49.9 +/- 27.7 months. Percent improvement in anteroposterior diameter and postoperative anteroposterior diameter measure were the most reliable variables to predict failure (AUC 0.88 and 0.86, respectively, p <0.0001), whereas preoperative anteroposterior diameter and subjective changes in grade were not good predictors (AUC 0.52, p >0.05). A percent improvement in anteroposterior diameter of 38% or greater or postoperative anteroposterior diameter of 11.5 mm or less was associated with success, with sensitivity of 100% and specificity of 61% and 55%, respectively. CONCLUSIONS: Percent improvement in anteroposterior diameter and postoperative pelvic anteroposterior diameter measure can provide objective guidance as to which patients need closer monitoring during followup, and can help select children at low risk for repeat intervention after pyeloplasty. PMID- 23088982 TI - Re: The CROES percutaneous nephrolithotomy global study: the influence of body mass index on outcome: A. Fuller, H. Razvi, J. D. Denstedt, L. Nott, M. Pearle, F. Cauda, D. Bolton, A. Celia and J. de la Rosette on behalf of the CROES PCNL Study Group; J Urol 2012; 188: 138-144. PMID- 23088984 TI - Re: Survival among men with clinically localized prostate cancer treated with radical prostatectomy or radiation therapy in the prostate specific antigen era: A. S. Kibel, J. P. Ciezki, E. A. Klein, C. A. Reddy, J. D. Lubahn, J. Haslag minoff, J. O. Deasy, J. M. Michalski, D. Kallogjeri, J. F. Piccirillo, D. M. Rabah, C. Yu, M. W. Kattan And A. J. Stephenson; J Urol 2012; 187: 1259-1265. PMID- 23088985 TI - A first in human phase 1 study of CG0070, a GM-CSF expressing oncolytic adenovirus, for the treatment of nonmuscle invasive bladder cancer. AB - PURPOSE: We assessed the safety, pharmacokinetics and anticancer activity of intravesical CG0070, a cancer selective, replication competent adenovirus, for the treatment of nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 35 patients received single or multiple (every 28 days * 3 or weekly * 6) intravesical infusions of CG0070 at 1 of 4 dose levels (1 * 10(12), 3 * 10(12), 1 * 10(13) or 3 * 10(13) viral particles). Response to treatment was based on cystoscopic assessment and biopsy or urine cytology. Urine and plasma CG0070, and granulocyte-monocyte colony-stimulating factor were measured in all patients. A subset of 18 patients was assessed for retinoblastoma phosphorylation status. RESULTS: Grade 1-2 bladder toxicities were the most common adverse events observed. A maximum tolerated dose was not reached. High levels of granulocyte monocyte colony-stimulating factor were detected in urine after administration in all patients. Virus replication was suggested based on an increase in urine CG0070 genomes between days 2 and 5 in 58.3% of tested patients (7 of 12). The complete response rate and median duration of the complete response across cohorts was 48.6% and 10.4 months, respectively. In the multidose cohorts the complete response rate for the combined groups (every 28 days and weekly * 6) was 63.6% (14 of 22 patients). In an exploratory, retrospective assessment patients with borderline or high retinoblastoma phosphorylation who received the multidose schedules had an 81.8% complete response rate (9 of 11). CONCLUSIONS: Intravesical CG0070 was associated with a tolerable safety profile and antibladder cancer activity. Granulocyte-monocyte colony-stimulating factor transgene expression and CG0070 replication were also suggested. PMID- 23088986 TI - Diagnostic potential of urinary alpha1-antitrypsin and apolipoprotein E in the detection of bladder cancer. AB - PURPOSE: The ability to reliably diagnose bladder cancer in voided urine samples would be a major advance. Using high throughput technologies, we identified a panel of bladder cancer associated biomarkers with potential clinical usefulness. In this study we tested 4 potential biomarkers for the noninvasive detection of bladder cancer. MATERIALS AND METHODS: We examined voided urine specimens from 124 patients, including 63 newly diagnosed with bladder cancer and 61 controls. Concentrations of proteins were assessed by enzyme-linked immunosorbent assay, including alpha1-antitrypsin, apolipoprotein E, osteopontin and pentraxin 3. Data were compared to the results of urinary cytology and the BTA Trak(r) enzyme linked immunosorbent assay based bladder cancer detection assay. We used the AUC of ROC curves to compare the usefulness of each biomarker to detect bladder cancer. RESULTS: Urinary levels of alpha1-antitrypsin, apolipoprotein E and bladder tumor antigen were significantly increased in subjects with bladder cancer. alpha1-Antitrypsin (AUC 0.9087, 95% CI 0.8555-0.9619) and apolipoprotein E (AUC 0.8987, 95% CI 0.8449-0.9525) were the most accurate biomarkers. The combination of alpha1-antitrypsin and apolipoprotein E (AUC 0.9399) achieved 91% sensitivity, 89% specificity, and a positive and negative predictive value of 89% and 90%, respectively. Multivariate regression analysis highlighted only apolipoprotein E as an independent predictor of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004). CONCLUSIONS: Alone or in combination, alpha1-antitrypsin and apolipoprotein E show promise for the noninvasive detection of bladder cancer (OR 24.9, 95% CI 4.22-146.7, p = 0.0004). Larger, prospective studies including more low grade, low stage tumors are needed to confirm these results. PMID- 23088987 TI - Adenosine triphosphate induced P2Y2 receptor activation induces proinflammatory cytokine release in uroepithelial cells. AB - PURPOSE: We characterized and identified the uroepithelial P2 receptor responsible for adenosine triphosphate mediated release of the cytokines interleukin-8 and 6. MATERIALS AND METHODS: The human renal epithelial cell line A498 (ATCCTM) was cultured and stimulated with different purinergic agonists with or without prior inhibition with different antagonists or signaling pathway inhibitors. Supernatant was analyzed for interleukin-8 and 6 by enzyme-linked immunosorbent assay. P2 receptor mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction. The candidate receptor was knocked down with siRNA technology. Interleukin-8 and 6 responses were measured after purinergic stimulation of knocked down cells. RESULTS: ATP and ATP-gamma-S (Roche Diagnostics, Mannheim, Germany) were equipotent as inducers of interleukin 8 and 6 release. Agonist profile experiments using different P2 receptor agonists indicated that P2Y(2) was the main contributor to this release, although P2Y(11) and P2X(7) activation could not be excluded. Signaling pathway experiments showed that interleukin-8 release involved phospholipase C and inositol trisphosphate mediated signaling, indicating a P2Y receptor subtype. Antagonist experiments indicated P2Y(2) as the responsible receptor. Gene expression analysis of P2 receptors showed that strong expression of P2Y(2) receptor and subsequent knockdown of P2Y(2) receptor mRNA for 72 and 96 hours abrogated interleukin-8 and 6 release after purinergic stimulation with adenosine triphosphate-gamma-S. CONCLUSIONS: Interleukin-8 and 6 release after purinergic stimulation in uroepithelial A498 cells is mediated through P2Y(2) receptor activation. PMID- 23088988 TI - Editorial comment. PMID- 23088990 TI - High level of circulating endothelial progenitor cells positively correlates with serum vascular endothelial growth factor in patients with renal cell carcinoma. AB - PURPOSE: Although accumulated evidence indicates that circulating endothelial progenitor cells contribute to tumor neovascularization, to our knowledge the level of these cells and its correlation with serum vascular endothelial growth factor in patients with renal cell carcinoma have not been studied. We measured this level and investigated its clinical significance in patients with renal cell carcinoma. MATERIALS AND METHODS: The level of circulating endothelial progenitor cells (percent of total peripheral blood mononuclear cells) was quantified by assaying the CD45(-)CD34(+)vascular endothelial growth factor receptor 2(+) cell phenotype in 53 patients with renal cell carcinoma, 33 with benign renal tumors and 40 healthy controls. Serum vascular endothelial growth factor was quantified. RESULTS: The mean circulating endothelial progenitor cell level in patients with renal cell carcinoma was 0.281%, significantly higher than in patients with benign renal tumors and healthy controls (0.073% and 0.076%, respectively, each p <0.001). Patients with stage III-IV renal cell carcinoma had a statistically higher level of these cells than those with stage I-II (0.339% vs 0.243%, p <0.001). The mean level in patients with renal cell carcinoma greater than 7 cm was 0.331%, significantly higher than in those with tumors 4 or less and 4 to 7 cm (0.225% and 0.231%, respectively, each p <0.001). Mean serum vascular endothelial growth factor in patients with renal cell carcinoma was higher than in patients with benign renal tumors and healthy controls (315.5 vs 34.6 and 26.9 pg/ml, respectively, each p <0.001). The preoperative circulating endothelial progenitor cell level positively correlated with serum vascular endothelial growth factor in patients with renal cell carcinoma (r = 0.710, p <0.001). Levels of these cells and of vascular endothelial growth factor significantly decreased postoperatively compared to preoperatively (0.081% vs 0.297% and 31.69 vs 310.70 pg/ml, respectively, each p <0.001). CONCLUSIONS: A high circulating endothelial progenitor cell level was found in patients with renal cell carcinoma, which positively correlated with serum vascular endothelial growth factor. Results support the potential use of circulating endothelial progenitor cells as a novel biomarker for renal cell carcinoma. PMID- 23088991 TI - Combination of foot stimulation and tramadol treatment reverses irritation induced bladder overactivity in cats. AB - PURPOSE: We determined whether transcutaneous electrical foot stimulation combined with a low dose of tramadol (Sigma-Aldrich(r)) could completely suppress bladder overactivity. MATERIALS AND METHODS: Repeat cystometrograms were performed in 18 alpha-chloralose anesthetized cats by infusing the bladder with saline or 0.25% acetic acid. Transcutaneous electrical stimulation (5 Hz) of the cat hind foot at 2 to 4 times the threshold intensity needed to induce observable toe movement was applied to suppress acetic acid induced bladder overactivity. Tramadol (1 to 3 mg/kg intravenously) was administered to enhance foot inhibition. RESULTS: Acetic acid irritated the bladder, induced bladder overactivity and significantly decreased bladder capacity to a mean +/- SE of 26% +/- 5% of saline control capacity (p <0.01). Without tramadol, foot stimulation at 2 and 4 threshold intensity applied during acetic acid cystometrograms significantly increased bladder capacity to a mean of 47% +/- 5% and 62% +/- 6% of saline control capacity, respectively (p <0.05). Without foot stimulation, tramadol (1 mg/kg) only slightly changed bladder capacity to a mean of 39% +/- 2% of saline control capacity (p >0.05), while 3 mg/kg significantly increased capacity to 85% +/- 14% that of control (p <0.05). However, 1 mg/kg tramadol combined with foot stimulation increased bladder capacity to a mean of 71% +/- 18% (2 threshold intensity) and 84% +/- 14% (4 threshold intensity), respectively, which did not significantly differ from saline control capacity. In addition, long lasting (greater than 1.5 to 2 hours) post-stimulation inhibition was induced by foot stimulation combined with 3 mg/kg tramadol treatment. CONCLUSIONS: This study suggests a new treatment strategy for overactive bladder by combining foot stimulation with a low dose of tramadol, which is noninvasive and has potentially high efficacy and fewer adverse effects. PMID- 23088992 TI - Exploration of gene-environment interactions, maternal effects and parent of origin effects in the etiology of hypospadias. AB - PURPOSE: Hypospadias is a common congenital malformation of the male external genitalia. Association studies for single nucleotide polymorphisms in genes encoding steroid 5alpha-reductase, estrogen receptors 1 and 2, and activating transcription factor 3 have been equivocal. We examined whether nonreplication of findings for 4 single nucleotide polymorphisms in these genes could be due to interaction with environmental exposures. MATERIALS AND METHODS: We genotyped 712 Dutch hypospadias case-parent triads for the 4 single nucleotide polymorphisms, used questionnaire information to determine exposures and performed association tests using the log-linear approach. We studied gene-environment interactions for the 4 single nucleotide polymorphisms with exposure to estrogens, cytokines or cigarette smoke, multiple birth, being born small for gestational age, maternal hypertension or preeclampsia, high body mass index or primiparity. In addition, the presence of maternal genetic and parent of origin effects was tested. RESULTS: Gene-environment interactions were identified for rs523349 in SRD5A2 with estrogen exposure and maternal hypertension or preeclampsia, as well as for rs11119982 in ATF3 with exposure to cytokines. Both single nucleotide polymorphisms seemed to influence hypospadias risk only in exposed cases. For rs6932902 in ESR1 only maternally derived alleles appeared to increase hypospadias risk in offspring. CONCLUSIONS: Interactions between genetic and environmental factors may help to explain nonreplication in genetic studies of hypospadias. PMID- 23088994 TI - Ketorolac-associated renal morbidity: risk factors in cardiac surgical infants. AB - We aimed to identify the risk factors for acute kidney injury in infants who have received ketorolac after a cardiac surgical procedure by identifying patients with a > or = 50% increase in serum creatinine from baseline and matching them by age with three controls that had < 50% increase in serum creatinine. Significant differences in primary surgical procedure, baseline serum creatinine, and concomitant aspirin use were noted. We conclude that the concomitant use of aspirin with ketorolac is associated with increased renal morbidity in young post cardiac surgical infants. PMID- 23088995 TI - The vertebrate diencephalic MCH system: a versatile neuronal population in an evolving brain. AB - Neurons synthesizing melanin-concentrating hormone (MCH) are described in the posterior hypothalamus of all vertebrates investigated so far. However, their anatomy is very different according to species: they are small and periventricular in lampreys, cartilaginous fishes or anurans, large and neuroendocrine in bony fishes, or distributed over large regions of the lateral hypothalamus in many mammals. An analysis of their comparative anatomy alongside recent data about the development of the forebrain, suggests that although very different, MCH neurons of the caudal hypothalamus are homologous. We further hypothesize that their divergent anatomy is linked to divergence in the forebrain - in particular telencephalic evolution. PMID- 23088997 TI - Citizen, interrupted: the 2011 English riots from a psychosocial perspective. AB - Aims. This is a contribution to the debate over the 2011 English riots from a psychosocial perspective. Methods. We compare the impulsive and 'mindless' behaviour of rioters with the impulsive, violent and contradictory behaviour of people affected by severe personality disorders. Results. We propose that the lack of a sense of social identity and of mentalization skills is a common feature of the two conditions - the lack of social identity, leading to frustration and anger, coupled with a lack of mentalization, leading to the impulsive and violent expression. Furthermore, we highlight the confusing impact that the social marginalization and consumerism can have on young generations from lower classes in cities from the Western world. Conclusions. By building a parallel with the therapeutic intervention offered to severe personality disorders, we speculate on how the community, by modifying its communication's style and actively intervene in deprived socio-economic contexts, could inspire more confidence, trust and sense of belonging in its marginalized members. PMID- 23088998 TI - Independent but not isolated. PMID- 23088996 TI - A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. AB - CONTEXT: Pathology standards for the diagnosis of bladder cancer (BCa) have recently evolved to better reflect patient diagnosis and clinical outcomes. OBJECTIVE: To update pathology reporting standards for BCa. EVIDENCE ACQUISITION: We searched the international medical literature and reviewed all articles that addressed BCa gross dissection, pathologic diagnosis, staging, and reporting as of June 6, 2012. We also reviewed the proceedings from the recent Second International Consultation on Bladder Cancer (Vienna, Austria). The literature selected for review focuses on evidence-based studies that address histopathologic factors in BCa, with emphasis placed on factors that influence patient diagnosis and clinical outcomes. EVIDENCE SYNTHESIS: We separated data into three main components for analysis based on the type of specimen obtained: (1) transurethral resection specimens, with an emphasis on pathologic staging, variants of urothelial carcinoma, angiolymphatic invasion, and relevant ancillary techniques such as immunohistochemistry in assessing these features; (2) cystectomy specimens, with an emphasis on pT0 disease, prostatic involvement by urothelial carcinoma and lymph node dissection and analysis; and (3) cytology correlates, with recommendations for the use of cytology paired with tissue-based sampling. Areas of controversy are described and recommendations based on existing guidelines are provided. The value of a multidisciplinary team is highlighted. CONCLUSIONS: Ongoing international collaborations amongst pathologists have led to emerging standards in the reporting and microscopic diagnosis of BCa specimens. Although some areas remain controversial, we present the most up-to-date data and guidelines relevant to neoplastic pathology of the urinary bladder. PMID- 23088999 TI - Radiation effects. AB - International Commission on Radiological Protection (ICRP) Committee 1 (C1) considers the risk of induction of cancer and heritable disease; the underlying mechanisms of radiation action; and the risks, severity, and mechanisms of induction of tissue reactions (formerly 'deterministic effects'). C1 relies upon the interpretation of current knowledge of radio-epidemiological studies; current information on the underlying mechanisms of diseases and radiation-induced disease; and current radiobiological studies at the whole animal, tissue, cell, and molecular levels. This overview will describe the activities of C1 in the context of the 2007 Recommendations of ICRP. In particular, the conclusions from the most recent C1 Task Group deliberations on radon and lung cancer, and tissue reactions will be discussed. Other activities are described in summary fashion to illustrate those areas that C1 judge to be likely to influence the development of the risk estimates and nominal risk coefficients used for radiation protection purposes. PMID- 23089000 TI - Doses from radiation exposure. AB - Practical implementation of the International Commission on Radiological Protection's (ICRP) system of protection requires the availability of appropriate methods and data. The work of Committee 2 is concerned with the development of reference data and methods for the assessment of internal and external radiation exposure of workers and members of the public. This involves the development of reference biokinetic and dosimetric models, reference anatomical models of the human body, and reference anatomical and physiological data. Following ICRP's 2007 Recommendations, Committee 2 has focused on the provision of new reference dose coefficients for external and internal exposure. As well as specifying changes to the radiation and tissue weighting factors used in the calculation of protection quantities, the 2007 Recommendations introduced the use of reference anatomical phantoms based on medical imaging data, requiring explicit sex averaging of male and female organ-equivalent doses in the calculation of effective dose. In preparation for the calculation of new dose coefficients, Committee 2 and its task groups have provided updated nuclear decay data (ICRP Publication 107) and adult reference computational phantoms (ICRP Publication 110). New dose coefficients for external exposures of workers are complete (ICRP Publication 116), and work is in progress on a series of reports on internal dose coefficients to workers from inhaled and ingested radionuclides. Reference phantoms for children will also be provided and used in the calculation of dose coefficients for public exposures. Committee 2 also has task groups on exposures to radiation in space and on the use of effective dose. PMID- 23089001 TI - Radiological protection in medicine: work of ICRP Committee 3. AB - Committee 3 of the International Commission on Radiological Protection (ICRP) is concerned with protection in medicine, and develops recommendations and guidance on the protection of patients, staff, and the public against radiation exposure in medicine. This paper presents an overview of the work of Committee 3 over recent years, and the work in progress agreed at the last annual meeting in Bethesda, MD in October 2011. The reports published by ICRP dealing with radiological protection in medicine in the last 10 years cover topics on: education and training in radiological protection; preventing accidental exposures in radiation therapy; dose to patients from radiopharmaceuticals; radiation safety aspects of brachytherapy; release of patients after therapy with unsealed radionuclides; managing patient dose in digital radiology and computed tomography; avoidance of radiation injuries from medical interventional procedures; pregnancy and medical radiation; and diagnostic reference levels in medical imaging. Three new reports will be published in the coming months dealing with aspects of radiological protection in fluoroscopically guided procedures outside imaging departments; cardiology; and paediatric radiology. The work in progress agreed by Committee 3 is also described. PMID- 23089002 TI - Application of the Commission's recommendations: the activities of ICRP Committee 4. AB - Committee 4 of the International Commission on Radiological Protection (ICRP) is responsible for developing principles, recommendations, and guidance on the protection of man against radiation exposure; and considering their practical application in all exposure situations. The Committee also acts as a major point of contact between ICRP and other international organisations and professional bodies concerned with protection against ionising radiation. The current work of the Committee involves the development of a series of reports on implementation of the 2007 Recommendations, and a reflection on the ethical foundations of the radiological protection system. Following the accident in Fukushima, Committee 4 also initiated an analysis of management of the consequences of the accident, with the objective of revising, if necessary, the Commission's publications on emergency and post-accident situations. PMID- 23089003 TI - Radiation and protection of the environment: the work of Committee 5. AB - The development of a systematic approach to protection of the environment has required a number of basic steps to be taken, including a discussion of what objectives could reasonably be set, together with an examination of how existing knowledge could best be used in order to achieve them. It has required bold decisions to be made, new modelling to be undertaken, and new data sets to be compiled. Equally challenging, however, has been the need to fold the entire subject area into an expanded system originally developed for the protection of human beings. There are, inevitably, a number of data gaps, and further decisions need to be made. However, the priority now is to examine how this approach to protection of the environment can be used in practice. With an intensifying worldwide debate about the environmental merits of different forms of energy production, it would seem imperative that the various practices involved in the nuclear fuel cycle are able to demonstrate, clearly and independently, their own actual or potential impact on the environment. The International Commission on Radiological Protection now has the basic means for such evaluations to be made, and further developments in this system will reflect the experience of its practical application. PMID- 23089004 TI - A regulatory perspective on whether the system of radiation protection is fit for purpose. AB - The system of radiation protection has its origins in the early efforts to protect people from x rays and radium. It was at the Second International Congress of Radiology in Stockholm in 1928 where the first radiation protection recommendations were adopted. The system of protection steadily evolved as new sources of exposure arose and understanding of radiation-related health risks improved. Safeguarding against these risks has required regulators to set enforceable (i.e. measurable) standards. From erythema dose to tolerance dose, critical organ dose to effective dose equivalent, and now effective dose, the units used to set these limits have evolved along with the science underpinning them. Similarly, the definition of the person or group being protected has changed - from Standard Man to Reference Man to Reference Person, with age and gender differences now considered explicitly. As regulators look towards implementing the changes in the 2007 Recommendations of the International Commission on Radiological Protection (ICRP), there remain questions about how to translate an optimisation-based system of constraints and reference levels into the more familiar regime of enforceable limits. Nevertheless, as the new ICRP Recommendations are refinements of a system that did the job it was designed to do more than adequately, so too will the new system of radiation protection be fit for purpose. PMID- 23089005 TI - Radiation biology and radiation protection. AB - For protection purposes, the biological effects of radiation are separated into stochastic effects (cancer, hereditary effects) presumed to be unicellular in origin, and tissue reactions due to injury in populations of cells. The latter are deterministic effects, renamed 'tissue reactions' in the 2007 Recommendations of the International Commission on Radiological Protection because of the increasing evidence of the ability to modify responses after irradiation. Tissue reactions become manifest either early or late after doses above a threshold dose, which is the basis for recommended dose limits for avoiding such effects. Latency time before manifestation is related to cell turnover rates, and tissue proliferative and structural organisation. Threshold doses have been defined for practical purposes at 1% incidence of an effect. In general, threshold doses are lower for longer follow-up times because of the slow progression of injury before manifestation. Radiosensitive individuals in the population may contribute to low threshold doses, and in the future, threshold doses may be increased by the use of various biological response modifiers post irradiation for reducing injury. Threshold doses would be expected to be higher for fractionated or protracted doses, unless doses below the threshold dose only cause single-hit-type events that are not modified by repair/recovery phenomena, or if different mechanisms of injury are involved at low and high doses. PMID- 23089006 TI - Mechanisms and dose-response relationships for radiation-induced cardiovascular disease. AB - Epidemiological studies have shown a clear association between therapeutic doses of thoracic irradiation and increased risk of cardiovascular disease in long-term cancer survivors. Survivors of Hodgkin's lymphoma and childhood cancers, for example, show 2- to >7-fold increases in risk of cardiac death after total tumour doses of 30-40 Gy, given in 2-Gy fractions. The risk of cardiac mortality increases linearly with dose, although there are large uncertainties for mean cardiac doses <5 Gy. Experimental studies show that doses of >= 2 Gy induce the expression of inflammatory and thrombotic molecules in endothelial cells. In the heart, this causes progressive loss of capillaries and eventually leads to reduced perfusion, myocardial cell death, and fibrosis. In large arteries, doses of >= 8 Gy, combined with elevated cholesterol, initiates atherosclerosis and predisposes to the formation of inflammatory, unstable lesions, which are prone to rupture and may cause a fatal heart attack or stroke. In contrast, doses <1 Gy inhibit inflammatory cell adhesion to endothelial cells and inhibit the development of atherosclerosis in mice. It seems likely that mechanisms other than accelerated atherosclerosis are responsible for cardiovascular effects after low total-body exposures of radiation (e.g. impaired T-cell immunity or persistent increase in systemic cytokines). PMID- 23089007 TI - Radiation cataract. AB - Until very recently, ocular exposure guidelines were based on the assumption that radiation cataract is a deterministic event requiring threshold doses generally greater than 2 Gy. This view was, in part, based on older studies which generally had short follow-up periods, failed to take into account increasing latency as dose decreased, had relatively few subjects with doses below a few Gy, and were not designed to detect early lens changes. Newer findings, including those in populations exposed to much lower radiation doses and in subjects as diverse as astronauts, medical workers, atomic bomb survivors, accidentally exposed individuals, and those undergoing diagnostic or radiotherapeutic procedures, strongly suggest dose-related lens opacification at significantly lower doses. These observations resulted in a recent re-evaluation of current lens occupational exposure guidelines, and a proposed lowering of the presumptive radiation cataract threshold to 0.5 Gy/year and the occupational lens exposure limit to 20 mSv/year, regardless of whether received as an acute, protracted, or chronic exposure. Experimental animal studies support these conclusions and suggest a role for genotoxicity in the development of radiation cataract. Recent findings of a low or even zero threshold for radiation-induced lens opacification are likely to influence current research efforts and directions concerning the cellular and molecular mechanisms underlying this pathology. Furthermore, new guidelines are likely to have significant implications for occupational and/or accidental exposure, and the need for occupational eye protection (e.g. in fields such as interventional medicine). PMID- 23089008 TI - Radiation effects: Modulating factors and risk assessment -- an overview. AB - Following low dose or low dose-rate exposures to ionising radiation, the principal resulting radiation-related risk is cancer. Site-specific cancer risk models have been developed that describe how the radiation-induced risk of a particular cancer type varies with the relevant tissue-specific absorbed dose of radiation. The degree of risk will also be determined by the radiation quality and the dose-rate, factors that will vary between types of radiation and cancer. Risk models also include a number of intrinsic factors that modify the radiation related excess risk - sex, age at exposure, time since exposure, and attained age - although not all these factors enter into each site-specific model. Of some importance is how the radiation-related excess risk is transferred between populations when background incidence rates differ. For most cancer types, expert groups consider that the radiation-related excess risk in a population depends, to some extent, upon the background incidence rate, and therefore that radiation interacts with at least some of the major risk factors that determine the background risk for a person. For example, the radiation-induced risk of lung cancer depends on the degree of individual exposure to tobacco smoke, but the implicit assumption of the currently accepted risk transfer models is that interactions are a general feature of radiation-related cancer risk. PMID- 23089009 TI - Genetic predisposition to radiation-related cancer and potential implications for risk assessment. AB - Several lines of evidence suggest that risk estimates for cancer associated with radiation exposure incorporate individuals who are more and less inherently susceptible to the carcinogenic effects of radiation, and the technology to further evaluate this issue is now available. For example, genome-wide association scan studies could be undertaken to address, at least in part, the direction of causality in the observations of differential sensitivity to radiomimetic agents in cancer cases compared with normal individuals, thereby building on previous observations that sensitivity to these agents is higher in apparently normal individuals carrying gene mutations in NBS and ATM. Direct studies of risk of second cancers in relation to radiation are underway, and some results have been reported (e.g. for the PRDM1 gene as related to sensitivity to radiation-related cancers after treatment for Hodgkin's lymphoma). It is important to understand the risk synergies between variants affecting associations with various cancers defining susceptibility in unexposed populations and the excess risk in populations therapeutically or occupationally exposed to radiation for the purpose of risk protection, especially as additional baseline risk variants are discovered in increasingly large-scale analyses. While there are studies that are beginning to address these questions, there have been no compelling new discoveries, to date, to indicate that predisposition information should be included in risk assessment. The conclusions in ICRP Publications 79 and 103 appear relevant today. PMID- 23089010 TI - Effective dose: a radiation protection quantity. AB - Modern radiation protection is based on the principles of justification, limitation, and optimisation. Assessment of radiation risks for individuals or groups of individuals is, however, not a primary objective of radiological protection. The implementation of the principles of limitation and optimisation requires an appropriate quantification of radiation exposure. The International Commission on Radiological Protection (ICRP) has introduced effective dose as the principal radiological protection quantity to be used for setting and controlling dose limits for stochastic effects in the regulatory context, and for the practical implementation of the optimisation principle. Effective dose is the tissue weighted sum of radiation weighted organ and tissue doses of a reference person from exposure to external irradiations and internal emitters. The specific normalised values of tissue weighting factors are defined by ICRP for individual tissues, and used as an approximate age- and sex-averaged representation of the relative contribution of each tissue to the radiation detriment of stochastic effects from whole-body low-linear energy transfer irradiations. The rounded values of tissue and radiation weighting factors are chosen by ICRP on the basis of available scientific data from radiation epidemiology and radiation biology, and they are therefore subject to adjustment as new scientific information becomes available. Effective dose is a single, risk-related dosimetric quantity, used prospectively for planning and optimisation purposes, and retrospectively for demonstrating compliance with dose limits and constraints. In practical radiation protection, it has proven to be extremely useful. PMID- 23089011 TI - We can do better than effective dose for estimating or comparing low-dose radiation risks. AB - The effective dose concept was designed to compare the generic risks of exposure to different radiation fields. More commonly these days, it is used to estimate or compare radiation-induced cancer risks. For various reasons, effective dose represents flawed science: for instance, the tissue-specific weighting factors used to calculate effective dose are a subjective mix of different endpoints; and the marked and differing age and gender dependencies for different health detriment endpoints are not taken into account. This paper suggests that effective dose could be replaced with a new quantity, 'effective risk', which, like effective dose, is a weighted sum of equivalent doses to different tissues. Unlike effective dose, where the tissue-dependent weighting factors are a set of generic, subjective committee-defined numbers, the weighting factors for effective risk are simply evaluated tissue-specific lifetime cancer risks per unit equivalent dose. Effective risk, which has the potential to be age and gender specific if desired, would perform the same comparative role as effective dose, be just as easy to estimate, be less prone to misuse, be more directly understandable, and would be based on solid science. An added major advantage is that it gives the users some feel for the actual numerical values of the radiation risks they are trying to control. PMID- 23089012 TI - Effective dose and risks from medical X-ray procedures. AB - The radiation risks from a range of medical x-ray examinations (radiography, fluoroscopy, and computed tomography) were assessed as a function of the age and sex of the patient using risk models described in Publication 103 (ICRP, 2007) and UNSCEAR (2006, Annex A). Such estimates of risk based on typical organ doses were compared with those derived from effective doses using the International Commission on Radiological Protection's nominal risk coefficients. Methodologically similar but not identical dose and risk calculations were performed independently at the Institute of Radiation Hygiene (Russia) and the Health Protection Agency (UK), and led to similar conclusions. The radiogenic risk of stochastic health effects following various x-ray procedures varied significantly with the patient's age and sex, but to differing degrees depending on which body organs were irradiated. In general, the risks of radiation-induced stochastic health effects in children are estimated to be higher (by a factor of <= 4) than in adults, and risks in senior patients are lower by a factor of >= 10 relative to younger people. If risks are assessed on the basis of effective dose, they are underestimated for children of both sexes by a factor of <= 4. This approach overestimates risks by a factor of <= 3 for adults and about an order of magnitude for senior patients. The significant sex and age dependence of radiogenic risk for different cancer types is an important consideration for radiologists when planning x-ray examinations. Whereas effective dose was not intended to provide a measure of risk associated with such examinations, it may be sufficient to make simple adjustments to the nominal risk per unit effective dose to account for age and sex differences. PMID- 23089013 TI - Radiation transport calculations for cosmic radiation. AB - The radiation environment inside and near spacecraft consists of various components of primary radiation in space and secondary radiation produced by the interaction of the primary radiation with the walls and equipment of the spacecraft. Radiation fields inside astronauts are different from those outside them, because of the body's self-shielding as well as the nuclear fragmentation reactions occurring in the human body. Several computer codes have been developed to simulate the physical processes of the coupled transport of protons, high charge and high-energy nuclei, and the secondary radiation produced in atomic and nuclear collision processes in matter. These computer codes have been used in various space radiation protection applications: shielding design for spacecraft and planetary habitats, simulation of instrument and detector responses, analysis of absorbed doses and quality factors in organs and tissues, and study of biological effects. This paper focuses on the methods and computer codes used for radiation transport calculations on cosmic radiation, and their application to the analysis of radiation fields inside spacecraft, evaluation of organ doses in the human body, and calculation of dose conversion coefficients using the reference phantoms defined in ICRP Publication 110. PMID- 23089014 TI - ICRP and IAEA actions on radiation protection in computed tomography. AB - In 1998, the International Commission on Radiological Protection (ICRP) warned that computed tomography (CT) doses were high, and the frequency of usage was likely to increase in view of spiral CT technology that enhances patient convenience and provides high-quality diagnostic information. Two ICRP publications (Publications 87 and 102) have provided patient dose management recommendations while reviewing the technology and results of optimisations to date, and stimulated interest in patient dose management. The International Atomic Energy Agency, on the other hand, has been instrumental in assessing the state of practice at grassroots level, identifying lacunae in justification and optimisation, providing guidance to counterparts in various countries, and improving practice. The results from approximately 50 less-resourced countries for adult and paediatric CT studies have become available, and some have been published. The concerted efforts and actions by these two international organisations have contributed to better awareness and improvement of patient protection in CT in adults and children in many countries. PMID- 23089015 TI - Minimising medically unwarranted computed tomography scans. AB - As computed tomography (CT) is such a superb diagnostic tool and individual CT risks are small, whenever a CT scan is clinically warranted, the CT benefit/risk balance is by far in the patient's favour. However, if a CT scan is not clinically warranted, this balance shifts dramatically. It is likely that at least 25% of CT scans fall into this latter category, in that they could either be replaced with alternative imaging modalities or could be avoided entirely. Use of clinical decision rules for CT usage represents a powerful approach for slowing down the increase in CT usage, because they have the potential to overcome some of the major factors that result in some CT scans being undertaken when they may not be clinically helpful. PMID- 23089016 TI - Radiological protection in paediatric computed tomography. AB - It is well known that paediatric patients are generally at greater risk for the development of cancer per unit of radiation dose compared with adults, due both to the longer life expectancy for any harmful effects of radiation to manifest, and the fact that developing organs and tissues are more sensitive to the effects of radiation. Multiple computed tomography (CT) examinations may cumulatively involve absorbed doses to organs and tissues that can sometimes approach or exceed the levels known from epidemiological studies to significantly increase the probability of cancer development. Radiation protection strategies include rigorous justification of CT examinations and the use of imaging techniques that are non-ionising, followed by optimisation of radiation dose exposure (according to the 'as low as reasonably achievable' principle). Special consideration should be given to the availability of dose reduction technology when acquiring CT scanners. Dose reduction should be optimised by adjustment of scan parameters (such as mAs, kVp, and pitch) according to patient weight or age, region scanned, and study indication (e.g. images with greater noise should be accepted if they are of sufficient diagnostic quality). Other strategies include restricting multiphase examination protocols, avoiding overlapping of scan regions, and only scanning the area in question. Newer technologies such as tube current modulation, organ-based dose modulation, and iterative reconstruction should be used when appropriate. Attention should also be paid to optimising study quality (e.g. by image post-processing to facilitate radiological diagnoses and interpretation). Finally, improving awareness through education and advocacy, and further research in paediatric radiological protection are important to help reduce patient dose. PMID- 23089017 TI - Accident prevention in day-to-day clinical radiation therapy practice. AB - Nearly 50-60% of cancer patients will undergo radiotherapy at some point in their treatment. Around 85% of the world's population live in developing countries served by approximately 30% of the world's radiotherapy facilities. It has been suggested that 1 megavoltage unit is required for every 500 new treatment courses per year, while others estimate that 1 megavoltage unit is needed for every 300 new treatments. However, these numbers do not necessarily take into account the development of new technologies and treatment modalities, which are more time- and resource-intensive. The International Commission on Radiological Protection has emphasised that 'purchasing new equipment without a concomitant effort on education and training and on a programme of quality assurance is dangerous', and 'the decision to implement a new technology for radiation therapy should be based on a thorough evaluation of the expected benefits, rather than being driven by the technology itself'. It is estimated that the rate of serious mistakes could be as high as 0.2%, which is several orders of magnitude higher than the rate reported for commercial aviation. So, how safe is safe? It can be stated that the development of a culture of safety is critical and requires efforts in education and training, which could prove difficult in overloaded departments. PMID- 23089018 TI - Impact of complexity and computer control on errors in radiation therapy. AB - A number of recent publications in both the lay and scientific press have described major errors in patient radiation treatments, and this publicity has galvanised much work to address and mitigate potential safety issues throughout the radiation therapy planning and delivery process. The complexity of modern radiotherapy techniques and equipment, including computer-controlled treatment machines and treatment management systems, as well as sophisticated treatment techniques that involve intensity-modulated radiation therapy, image-guided radiation therapy, stereotactic body radiation therapy, volumetric modulated arc therapy, respiratory gating, and others, leads to concern about safety issues related to that complexity. This article illustrates the relationship between complexity and computer control, and various safety problems and errors that have been reported, and describes studies that address the issue of these modern techniques and whether their complexity does, in fact, result in more errors or safety-related problems. Clinical implications of these results are discussed, as are some of the ways in which the field should respond to the ongoing concerns about errors and complexity in radiation therapy. PMID- 23089019 TI - Tools for risk assessment in radiation therapy. AB - Radiotherapy has unquestionable benefits, but it is also associated with unique and specific safety issues. It is the only application of radiation in which humans are intentionally delivered very high doses. Safety in radiotherapy remains heavily dependent on human actions. A step-by-step approach is suggested for the prevention of accidental exposures in radiation therapy: (1) allocation of responsibilities to qualified professionals, and design of a quality and safety programme - no radiotherapy practice should be operated without these key elements; (2) use of the lessons from accidental exposures to test whether the quality and safety programme is sufficiently robust against these types of events -publications by the International Commission on Radiological Protection (ICRP) and the International Atomic Energy Agency provide a collection of lessons to facilitate this step; and (3) find other latent risks by posing the questions 'What else could go wrong?' or 'What other potential hazards might be present?' in a systematic, anticipative manner - methods to do so are described briefly in ICRP Publication 112. PMID- 23089020 TI - Biological basis for protection of the environment. AB - The approach to protection of the environment may vary considerably depending on ethical basis, methodological approach, and identification of endpoints and protective targets. The International Commission on Radiological Protection (ICRP) reviewed these issues in Publication 91, 'A framework for assessing the impact of ionising radiation on non-human species', published in 2003. At the same time, ICRP proposed that a possible future ICRP system addressing environmental assessment and protection would focus on biota, that the system should be effect-based so that any reasoning about adequate protection would be derived from firm understanding of harm at different exposure levels, and that the system should be based on data sets for Reference Animals and Plants. ICRP has thus chosen to approach environmental protection on the basis of biology, and further developed the approach in Publications 103, 108 and 114. This paper explores the biological basis for the ICRP system of environmental protection from the viewpoints of: the effects endpoints of concern; the hierarchy of biological organisation; adequate and appropriate protective targets; and the derivation of benchmark dose (rates) to guide protective efforts. PMID- 23089021 TI - Dosimetry for Reference Animals and Plants: current state and prospects. AB - The enormous diversity of non-human biota is a specific challenge when developing and applying dosimetric models for assessing exposures to flora and fauna from environmental radioactivity. Dosimetric models, adopted by the International Commission on Radiological Protection (ICRP), provide dose conversion coefficients for a large variety of biota, including the Reference Animals and Plants. The models use a number of simplified approaches, often ignoring presumably insignificant details. Simple body shapes with uniform composition and density, homogeneous internal contamination, a limited set of external radiation sources for terrestrial animals and plants, and truncation of radioactive decay chains are a few examples of simplifying assumptions underlying the dose conversion coefficients included in ICRP Publication 108. However, many specific assessment tasks require dosimetric data for non-standard species or irradiation scenarios. The further development of dosimetric models aims at the implementation of flexible choices of animals and plants, as well as of their irradiation conditions (e.g. trees); more systematic consideration of internal exposures from radionuclides concentrated in specific organs; and task-oriented choice of decay chains based on ICRP Publication 107. An extensive set of non human dosimetric data might require specific software to facilitate fast, accurate, and flexible selection of pertinent dose conversion coefficients for specific assessment tasks. PMID- 23089022 TI - Relative biological effectiveness and radiation weighting factors in the context of animals and plants. AB - Radiation weighting factors have long been employed to modify absorbed dose as part of the process of evaluating radiological impact to humans. Their use represents an acknowledgement of the fundamental difference in energy deposition patterns of charged and uncharged particles, and how this can translate into varying degrees of biological impact. Weighting factors used in human radiation protection are derived from a variety of endpoints taken from in-vitro experiments that include human and animal cell lines, as well as in-vivo experiments with animals. Nonetheless, the application of radiation weighting factors in the context of dose assessment of animals and plants is not without some controversy. Specifically, radiation protection of biota has largely focused on limiting deterministic effects, such as reduced reproductive fitness. Consequently, the application of conventional stochastic-based radiation weighting factors (when used for human protection) appears inappropriate. While based on research, radiation weighting factors represent the parsing of extensive laboratory studies on relative biological effectiveness. These studies demonstrate that the magnitude of a biological effect depends not just on dose, but also on other factors including the rate at which the dose is delivered, the type and energy of the radiation delivering the dose, and, most importantly, the endpoint under consideration. This article discusses the efforts taken to develop a logical, transparent, and defensible approach to establishing radiation weighting factors for use in assessing impact to non-human biota, and the challenges found in differentiating stochastic from deterministic impacts. PMID- 23089023 TI - Clarifying and simplifying the management of environmental exposures under different exposure situations. AB - The International Commission on Radiological Protection recognises three different exposure situations: planned, existing, and emergency. In all three situations, the release of radionuclides into the natural environment leads to exposures of non-human species, as well as having the potential for exposures of the general public. Each release may therefore need separate evaluations of these two consequences in order to clarify the relevant objectives of protection, their compliance with various legal requirements, and how these objectives can be achieved. However, the need to meet more than one objective should not necessarily lead to a more complicated regulatory system. Indeed, with regard to low-level routine discharges from most nuclear plants, there would appear to be scope for simplifying the entire system, to protect both humans and biota, by using discharge consent and specified radionuclide environmental quality standards for water, soil, and air in a manner similar to that used to regulate other major, non-nuclear industries. In contrast, different objectives for humans and the environment need to be set and evaluated independently for existing exposure situations. For emergency situations, the separate consequences of different management options for humans and the environment should be made clear. Should an emergency occur, it is important to have meaningful environmental criteria in order to communicate clearly with the public at large as events unfold. PMID- 23089024 TI - Regulatory experience in applying a radiological environmental protection framework for existing and planned nuclear facilities. AB - Frameworks and methods for the radiological protection of non-human biota have been evolving rapidly at the International Commission on Radiological Protection and through various European initiatives. The International Atomic Energy Agency has incorporated a requirement for environmental protection in the latest revision of its Basic Safety Standards. In Canada, the Canadian Nuclear Safety Commission has been legally obligated to prevent unreasonable risk to the environment since 2000. Licensees have therefore been meeting generic legal requirements to demonstrate adequate control of releases of radioactive substances for the protection of both people and biota for many years. In the USA, in addition to the generic requirements of the Environmental Protection Agency and the Nuclear Regulatory Commission, Department of Energy facilities have also had to comply with specific dose limits after a standard assessment methodology was finalised in 2002. Canadian regulators developed a similar framework for biota dose assessment through a regulatory assessment under the Canadian Environmental Protection Act in the late 1990s. Since then, this framework has been applied extensively to satisfy legal requirements under the Canadian Environmental Assessment Act and the Nuclear Safety and Control Act. After approximately a decade of experience in applying these methods, it is clear that simple methods are fit for purpose, and can be used for making regulatory decisions for existing and planned nuclear facilities. PMID- 23089025 TI - Application of radiological protection measures to meet different environmental protection criteria. AB - The International Commission on Radiological Protection (ICRP) recognises that there is no simple or single universal definition of 'environmental protection', and that the concept differs from country to country and from one circumstance to another. However, there is an increasing need to be able to demonstrate that the environment is protected from radioactive substances released under authorisation for various reasons, such as for wildlife conservation requirements, or wildlife management for commercial reasons, or simply as part of pollution control. The Commission is developing the concept of Representative Organisms, which may be identified from any specific legal requirements or from more general requirements to protect local habitats or ecosystems. Such organisms may be the actual objects of protection or they may be hypothetical, depending on the objectives of the assessment. They may be similar to, or even congruent with, one or more of the Reference Animals and Plants (RAPs). Where this is not the case, attempts can be made to consider the extent to which the Representative Organisms differ from the nearest RAP in terms of known radiation effects upon it, basic biology, radiation dosimetry, and pathways of exposure. This paper discusses the practical implications of such an approach. PMID- 23089026 TI - Global nuclear industry views: challenges arising from the evolution of the optimisation principle in radiological protection. AB - Over the last few decades, the steady progress achieved in reducing planned exposures of both workers and the public has been admirable in the nuclear sector. However, the disproportionate focus on tiny public exposures and radioactive discharges associated with normal operations came at a high price, and the quasi-denial of a risk of major accident and related weaknesses in emergency preparedness and response came at an even higher price. Fukushima has unfortunately taught us that radiological protection (RP) for emergency and post emergency situations can be much more than a simple evacuation that lasts 24-48 h, with people returning safely to their homes soon afterwards. On optimisation of emergency and post-emergency exposures, the only 'show in town' in terms of international RP policy improvements has been the issuance of the 2007 Recommendations of the International Commission on Radiological Protection (ICRP). However, no matter how genuine these improvements are, they have not been 'road tested' on the practical reality of severe accidents. Post-Fukushima, there is a compelling case to review the practical adequacy of key RP notions such as optimisation, evacuation, sheltering, and reference levels for workers and the public, and to amend these notions with a view to making the international RP system more useful in the event of a severe accident. On optimisation of planned exposures, the reality is that, nowadays, margins for further reductions of public doses in the nuclear sector are very small, and the smaller the dose, the greater the extra effort needed to reduce the dose further. If sufficient caution is not exercised in the use of RP notions such as dose constraints, there is a real risk of challenging nuclear power technologies beyond safety reasons. For nuclear new build, it is the optimisation of key operational parameters of nuclear power technologies (not RP) that is of paramount importance to improve their overall efficiency. In pursuing further improvements in the international RP system, it should be clearly borne in mind that the system is generally based on protection against the risk of cancer and hereditary diseases. The system also protects against deterministic non-cancer effects on tissues and organs. In seeking refinements of such protective notions, ICRP is invited to pay increased attention to the fact that a continued balance must be struck between beneficial activities that cause exposures and protection. The global nuclear industry is committed to help overcome these key RP issues as part of the RP community's upcoming international deliberations towards a more efficient international RP system. PMID- 23089027 TI - Reference levels in the context of Fukushima - lessons learned and a challenge for the radiation protection system. AB - A number of dose criteria were set after the accident in Fukushima, including a criterion regarding the use of school playgrounds in Fukushima. Considering the band of 1-20 mSv/year recommended by the International Commission on Radiological Protection (ICRP) for public exposure under existing exposure situations, Japanese authorities set 20 mSv/year as a 'start line' for reducing the dose to school children. However, this led to considerable confusion among the general public and some experts. They thought that the dose limit was increased to 20 mSv/year (20 times as high as before), and that school children could be exposed to 20 mSv in 1 year. This is just an example of confusion caused by inadequate comprehension of radiation effects, misunderstanding of radiation protection concepts, or both. Another issue was raised regarding the higher radiosensitivity of children compared with adults. In the 2007 ICRP Recommendations, a higher risk coefficient is given to the whole population than the adult population, because the whole population includes children; a subpopulation with higher radiosensitivity and a longer life span. The point of argument was whether a lower reference level should be set for children alone. Radiation protection experts should continue to collect scientific information to improve the radiation protection system. In addition, it is the role of these experts to explain the framework of radiation protection to the general public in plain language. PMID- 23089028 TI - Radioactive waste management in France: safety demonstration fundamentals. AB - The main challenge in development of the safety case for deep geological disposal is associated with the long periods of time over which high- and intermediate level long-lived wastes remain hazardous. A wide range of events and processes may occur over hundreds of thousands of years. These events and processes are characterised by specific timescales. For example, the timescale for heat generation is much shorter than any geological timescale. Therefore, to reach a high level of reliability in the safety case, it is essential to have a thorough understanding of the sequence of events and processes likely to occur over the lifetime of the repository. It then becomes possible to assess the capability of the repository to fulfil its safety functions. However, due to the long periods of time and the complexity of the events and processes likely to occur, uncertainties related to all processes, data, and models need to be understood and addressed. Assessment is required over the lifetime of the radionuclides contained in the radioactive waste. PMID- 23089029 TI - Report of ICRP Task Group 80: 'radiological protection in geological disposal of long-lived solid radioactive waste'. AB - The report of International Commission on Radiological Protection (ICRP) Task Group 80 entitled 'Radiological protection in geological disposal of long-lived solid radioactive waste' updates and consolidates previous ICRP recommendations related to solid waste disposal (ICRP Publications 46, 77, and 81). The recommendations given in this report apply specifically to geological disposal of long-lived solid radioactive waste. The report explains how the 2007 system of radiological protection, described in ICRP Publication 103, can be applied in the context of the geological disposal of long-lived solid radioactive waste. The report is written as a self-standing document. It describes the different stages in the lifetime of a geological disposal facility, and addresses the application of relevant radiological protection principles for each stage depending on the various exposure situations that can be encountered. In particular, the crucial factor that influences application of the protection system over the different phases in the lifetime of a disposal facility is the level of oversight that is present. The level of oversight affects the capability to reduce or avoid exposures. Three main time frames have to be considered for the purpose of radiological protection: time of direct oversight when the disposal facility is being implemented and active oversight is taking place; time of indirect oversight when the disposal facility is sealed and indirect oversight is being exercised to provide additional assurance on behalf of the population; and time of no oversight when oversight is no longer exercised because memory is lost. PMID- 23089030 TI - Experience in implementing ICRP recommendations: IRPA's perspective on the role of the radiation protection professional. AB - The International Radiation Protection Association (IRPA) has a membership of approximately 17,000 individuals who are members of 48 national societies in 60 countries worldwide. As such, IRPA's vision is to be recognised as the international voice of the radiation protection professional. This article will discuss elements of the outcome of the 12th International Congress of IRPA ('Focus on the future'), objectives and current activities of IRPA, criteria and priorities for the engagement of IRPA with international organisations, current IRPA initiatives in the areas of radiation protection culture and certification/qualification of radiation protection experts, planning for the 13th International Congress of IRPA, comments on the implementation of recent recommendations of the International Commission on Radiological Protection (ICRP), and suggestions about IRPA and ICRP collaboration in their implementation. IRPA recognises that ICRP is the international body to determine policy and to make recommendations for protection against ionising radiation, and IRPA is in a position to participate in and facilitate the implementation of those recommendations. PMID- 23089031 TI - US NRC discussion of options to revise radiation protection recommendations. AB - The Nuclear Regulatory Commission (NRC) is continuing the process of engaging stakeholders on issues associated with possible changes to the radiation protection regulations contained in 10 CFR Part 20, and other parts of the NRC regulations, to increase alignment with international recommendations. The Commission is particularly seeking to explore implications, as appropriate and where scientifically justified, of greater alignment with the 2007 Recommendations of the International Commission for Radiological Protection. Other information from national and international sources is also being considered. Given that the NRC regulations provide adequate protection, the discussion has been focusing on discerning the benefits and burdens associated with revising the radiation protection regulatory framework. NRC, through three Federal Register Notices, has officially solicited comments on a series of key issues, and has conducted a series of facilitated workshops to encourage feedback from a wide range of stakeholders. The issues include the use of updated scientific methodologies and terminology, the occupational dose limits, and the use of the concepts of constraints in optimisation. NRC staff provided a policy paper with recommendations to the Commission on April 25, 2012 (NRC, 2012). PMID- 23089032 TI - NORM management in the oil and gas industry. AB - It has been established that naturally occurring radioactive material (NORM) may accumulate at various locations along the oil and gas production process. Components such as wellheads, separation vessels, pumps, and other processing equipment can become contaminated with NORM, and NORM can accumulate in the form of sludge, scale, scrapings, and other waste media. This can create a potential radiation hazard to workers, the general public, and the environment if certain controls are not established. Saudi Aramco has developed NORM management guidelines, and is implementing a comprehensive strategy to address all aspects of NORM management that aim to enhance NORM monitoring; control of NORM contaminated equipment; control of NORM waste handling and disposal; and protection, awareness, and training of workers. The benefits of shared knowledge, best practice, and experience across the oil and gas industry are seen as key to the establishment of common guidance. This paper outlines Saudi Aramco's experience in the development of a NORM management strategy, and its goals of establishing common guidance throughout the oil and gas industry. PMID- 23089034 TI - NORM situation in non-uranium mining in China. AB - The Ministry of Environmental Protection in China is responsible for regulatory control on radiation protection from naturally occurring radioactive material (NORM). The natural radiation caused by human activities is a major contributor to public and occupational exposure in China. This paper introduces the first national census on pollution sources (target year 2007) in China, and describes NORM sites in Baotou, Inner Mongolia, one of the largest rare earth deposits in China. The ores are rich in radioactive elements, with a concentration of ThO(2) of 0.01-0.05% and concentration of U(3)O(8) of 0.0005-0.002%. The large amount of NORM residues is regulated and controlled. After treatment of the waste water, it is discharged into tailing ponds and then pumped directly to milling plants for re-use. The waste gas after off-dust cleaning is discharged into the environment. A substantial amount of blast furnace iron slag from the waste treatment is transformed into cement, concrete, and bricks, or used directly for highway construction. This raises a serious environmental concern. As a result, environmental radiation monitoring and assessment have been introduced recently. Regulatory control of NORM is very important in order to take effective measures to lower the dose. PMID- 23089033 TI - Advances in NORM management in Norway and the application of ICRP's 2007 recommendations. AB - In Norway, the largest reported quantities of radioactive discharges and radioactive waste containing naturally occurring radioactive material (NORM) come from the oil and gas sector, and smaller quantities of other NORM waste are also produced by industrial or mining processes. The Gulen final repository for radioactive waste from the oil and gas industry from the Norwegian continental shelf was opened in 2008 and has a capacity of 6000 tonnes. As of 1 January 2011, a new regulation was enforced whereby radioactive waste and radioactive pollution was integrated in the Pollution Control Act from 1981. This means that radioactive waste and radioactive pollution are now regulated under the same legal framework as all other pollutants and hazardous wastes. The regulation establishes two sets of criteria defining radioactive waste: a lower value for when waste is considered to be radioactive waste, and a higher value, in most cases, for when this waste must be disposed of in a final waste repository. For example, waste containing >= 1 Bq/g of Ra-226 is defined as radioactive waste, while radioactive waste containing >= 10 Bq/g of Ra-226 must be disposed of in a final repository. Radioactive waste between 1 and 10B q/g can be handled and disposed of by waste companies who have a licence for handling hazardous waste according to the Pollution Control Act. Alternatively, they will need a separate licence for handling radioactive waste from the Norwegian Radiation Protection Authority. The goal of the new regulation is that all radioactive waste should be handled and stored in a safe manner, and discharges should be controlled through a licensing regime in order to avoid/not pose unnecessary risk to humans or the environment. This paper will elaborate on the new regulation of radioactive waste and the principles of NORM management in Norway in view of the International Commission on Radiological Protection's 2007 Recommendations. PMID- 23089035 TI - NORM survey in Argentina. AB - A survey programme was initiated several years ago with the aim of estimating the incidence of naturally occurring radioactive material (NORM) exposure for workers in the oil and gas industry, gold mining, spas, and a tourist cavern in Argentina. This work presents the procedures, methods employed, and results to date from the survey, including protection and remedial actions recommended when deemed necessary. Radium isotope concentrations measured in some samples were well above the exemption values established by IAEA Standards. Elevated radon levels (above the action level established for workplaces) were detected in the gas facilities, the gold mine, and the tourist cavern. The pertinent authorities and the facilities were informed of the detected values in order to take actions to reduce concentrations. In terms of the spas, almost all values for geothermal waters were below the corresponding guidance levels. Some regulatory aspects for the management of NORM are suggested. PMID- 23089036 TI - Risk of lung cancer from radon exposure: contribution of recently published studies of uranium miners. AB - The International Commission on Radiological Protection (ICRP) recently estimated the risk of lung cancer associated with radon exposure, and a statement was issued in ICRP Publication 115. This was based on recent epidemiological studies and the results from a joint analysis of cohorts of Czech, French, and German uranium miners, and indicated that the excess relative risk of lung cancer per unit of exposure should be expressed with consideration of chronic exposure over more than 10 years, by modelling time since median exposure, age attained or age at exposure, and taking in account, if possible, interaction between radon and tobacco. The lifetime excess absolute risk (LEAR) calculated from occupational exposure studies is close to 5 * 10(-4) per working level month (WLM) (14 * 10( 5) per hmJ/m(3)). LEAR values estimated using risk models derived from both miners and domestic exposure studies are in good agreement after accounting for factors such as sex, attained age, and exposure scenario. A sensitivity analysis highlighted the high dependence of background mortality rates on LEAR estimates. Using lung cancer rates among Euro-American males instead of the ICRP reference rates (males and females, and Euro-American and Asian populations), the estimated LEAR is close to 7 * 10(-4) per WLM (20 * 10(-5) per hm J/m(3)). PMID- 23089037 TI - Effective dose from inhaled radon and its progeny. AB - Currently, the International Commission on Radiological Protection (ICRP) uses the dose conversion convention to calculate effective dose per unit exposure to radon and its progeny. In a recent statement, ICRP indicated the intention that, in future, the same approach will be applied to intakes of radon and its progeny as is applied to all other radionuclides, calculating effective dose using reference biokinetic and dosimetric models, and radiation and tissue weighting factors. Effective dose coefficients will be given for reference conditions of exposure. In this paper, preliminary results of dose calculations for Rn-222 progeny are presented and compared with values obtained using the dose conversion convention. Implications for the setting of reference levels are also discussed. PMID- 23089038 TI - Radon and the system of radiological protection. AB - At its meeting in Porto, Portugal, in November 2009, the Main Commission of the International Commission on Radiological Protection (ICRP) approved the formation of a new Task Group, reporting to Committee 4, to develop guidance on radiological protection against radon exposure. This article describes the Task Group's draft report entitled "Radiological Protection against Radon Exposure" which has been posted on the ICRP website for public consultation between January and June 2012. In this report, the Commission provides updated guidance on radiological protection against radon exposure. The report was developed considering the recently consolidated ICRP general recommendations, the new scientific knowledge about radon risk, and the experience gained by many organisations and countries in the control of radon exposure. The report describes the characteristics of radon exposure, covering sources and transfer mechanisms, nature of the risk, exposure conditions, similarities with other existing exposure situations, and challenges to manage radon exposure. In order to control radon exposure, the Commission recommends an integrated approach that is focused as much as possible on the management of the building or location in which radon exposure occurs, regardless of the purpose of the building and the category of the occupants. This approach is based on the optimisation principle, and a graded approach according to the degree of responsibilities at stake, notably in workplaces, and the level of ambition of the national authorities. The report emphasises the importance of preventive actions, and provides recommendations on how to control radon exposure in workplaces when workers' exposure can reasonably be regarded as being the responsibility of the operating management. In such a case, workers' exposures are considered to be occupational, and are controlled using the corresponding requirements on the basis of the optimisation principle, and application, as appropriate, of the dose limit. PMID- 23089039 TI - Uranium mining industry views on ICRP statement on radon. AB - In 2009, the International Commission on Radiological Protection issued a statement on radon which stated that the dose conversion factor for radon progeny would likely double, and the calculation of risk from radon should move to a dosimetric approach, rather than the longstanding epidemiological approach. Through the World Nuclear Association, whose members represent over 90% of the world's uranium production, industry has been examining this issue with a goal of offering expertise and knowledge to assist with the practical implementation of these evolutionary changes to evaluating the risk from radon progeny. Industry supports the continuing use of the most current epidemiological data as a basis for risk calculation, but believes that further examination of these results is needed to better understand the level of conservatism in the potential epidemiological-based risk models. With regard to adoption of the dosimetric approach, industry believes that further work is needed before this is a practical option. In particular, this work should include a clear demonstration of the validation of the dosimetric model which includes how smoking is handled, the establishment of a practical measurement protocol, and the collection of relevant data for modern workplaces. Industry is actively working to address the latter two items. PMID- 23089041 TI - Prepared or not prepared: top-down modulation on memory of features and feature bindings. AB - Orienting attention to the to-be-tested representations can enhance representations and protect them from interference. Previous studies have found that this effect on feature and bound representations was comparable despite their difference in stability. This may have occurred because participants were tested in a block design, which is susceptible to participants' effective top down control on the cued representations based on the predictability of the design. In this study, we investigated how the foreknowledge of when and what to expect would affect visual representations in a change-detection task. Cue onset time was either early or late; changes included either features or feature bindings. When predictability was maximized via a block design (Experiments 1, 5, and 6), early cues equally facilitated both representations while late cues did not affect either representation. When either cue onset time (Experiment 2) or change type (Experiment 3) was unpredictable, early cues consistently facilitated feature representations, while bound representations were enhanced only when cue onset time was predictable. Additionally, late cuing only cost bound representations. Finally, when both factors were no longer predictable via an intermixed design (Experiment 4), early-cuing benefit was eliminated, with a late cuing cost for the bound representations. These results highlight the critical role of effective top-down control in memory maintenance for visual representations. PMID- 23089040 TI - High vancomycin minimum inhibitory concentration and clinical outcomes in adults with methicillin-resistant Staphylococcus aureus infections: a meta-analysis. AB - BACKGROUND: Patients with methicillin-resistant Staphylococcus aureus (MRSA) infections caused by isolates with a high but 'susceptible' minimum inhibitory concentration (MIC) to vancomycin may suffer poor outcomes. The aim of this study was to determine the association of high compared to low vancomycin MICs and clinical outcomes (treatment failure and mortality) in patients with MRSA infections. METHODS: PubMed, the Cochrane Library, and electronic abstracts from meetings were queried from January 2000 to July 2010. Two reviewers independently screened titles and abstracts of studies evaluating outcomes of patients with MRSA infections, using broth microdilution (BMD) or the Etest to determine MIC, for full-text review. Patients participating in included studies were classified into two mutually exclusive groups: high MIC or low MIC. High MIC was defined as MIC >=1mg/l by BMD or >=1.5mg/l by Etest. Study-defined failure and mortality were assessed in each group. RESULTS: Fourteen publications and six electronic abstracts met the inclusion criteria, with 2439 patients (1492 high MIC and 947 low MIC). There was no evidence of publication bias or heterogeneity. An increased risk of failure was observed in the high MIC group compared to the low MIC group (summary risk ratio (RR) 1.40, 95% confidence interval (CI) 1.15-1.71). The overall mortality risk was greater in the high MIC group than in the low MIC group (summary RR 1.42, 95% CI 1.08-1.87). Sensitivity analyses showed similar findings for failure (summary RR 1.37, 95% CI 1.09-1.73) and mortality (summary RR 1.46, 95% CI 1.06-2.01) for patients with bacteremia. The study quality was poor-to-moderate, and study-defined endpoints were variable. CONCLUSIONS: A susceptible but high MIC to vancomycin is associated with increased mortality and treatment failure among patients with MRSA infections. PMID- 23089042 TI - The importance of the first and last letter in words during sentence reading. AB - Previous research suggests that the first and last letters of words are more important than the interior letters during reading. A question that has yet to be fully studied is why this is so. The current study reports four experiments in which participants read sentences containing words with transposed letters occurring at the beginning of the word, near the middle of the word, or at the end of the word. Experiments 1 and 2 also included some sentences where the spaces were removed and replaced with hash marks (#) to equate all letters on their degree of lateral interference from adjacent letter positions. In Experiment 3, equating was done by adding an additional space between all of the letters, so that no letter position received lateral interference from any letter. In Experiment 4, readers read sentences from right to left so that word initial letters were presented furthest into the parafovea. The results indicate that although the first letter of a word has a privileged role over interior letters regardless of the degree of lateral interference it receives or its location in the parafovea (suggesting that it is intrinsically related to how we process, store, or access lexical information), the last letter of a word is more important than interior letters only when it receives less lateral interference or when its parafoveal location was close to the fovea (suggesting that it is privileged only due to low-level visual factors). These findings have important implications for current theories and computational models regarding the roles of various letter positions in reading. PMID- 23089043 TI - Estimating time savings: the use of the proportion and percentage heuristics and the role of need for cognition. AB - People generally overestimate the time they can save when increasing from a relatively high driving speed. Previous research suggested that people follow a Proportion Heuristic, calculating the time saved as the proportion of speed increase from the new higher speed. The present study suggests that drivers use another heuristic - the Percentage Heuristic - to calculate how much time they save by increasing speed. In the percentage heuristic, the initial (rather than higher) speed is used as the denominator. Using a discriminating set of questions, we classified participants' responses as normative (correct answer), as following the proportion or percentage heuristic, or some other strategy. We found that participants used the percentage heuristic more often, perhaps because it predicts linearly increasing values of time saved when increasing speed. In addition, we found that participants high in need for cognition (NFC) gave correct answers more often than low NFC participants who relied more on heuristics. PMID- 23089044 TI - Testing boundary conditions of the ideomotor hypothesis using a delayed response task. AB - Ideomotor theory accounts for how an action's consequence is incorporated into an action concept in the form of a perceptual image that, when retrieved, serves to initiate the action. The ideomotor idea is compelling, because the ultimate purpose of an action is to bring about a certain change in the environment. This study investigated the time-course of response-effect compatibility (REC), which produces a shorter reaction-time when response effects are compatible with the responses than when they are not. We used a delayed choice-reaction task that required the response to be withheld until a Go signal occurred. In Experiment 1 an effect was delivered by the location of a square in either a spatially compatible or incompatible relation to the keypress action. A significant REC effect for reaction time was found only when an effect-achieving instruction was used, for which evidence indicated a locus in an early action phase. In Experiment 2 a cursor effect occurred causally, continuously and simultaneously with the movement of a computer mouse. No matter whether instructions in terms of cursor or mouse movement were used, a strong REC effect was found that preserved its power from the early to later parts of motor planning until execution ended. The results provide evidence that an action concept incorporates the action's consequent changes more strongly when they are goal-satisfying or highly causal events. PMID- 23089045 TI - Developmental consequences of the ColQ/MuSK interactions. AB - CollagenQ (ColQ) is a specific collagen that anchors acetylcholinesterase (AChE) in the synaptic basal lamina of the neuromuscular junction (NMJ). Over 30 mutations in the COLQ gene have been identified that are responsible for a congenital myasthenic syndrome with AChE deficiency, highlighting the importance of this collagen in the physiology of the NMJ. The anchoring of AChE at the synapse requires the interaction of ColQ with MuSK (Muscle-Specific Kinase), a tyrosine kinase expressed on the muscle membrane that is necessary for the formation and the maintenance of the NMJ. MuSK forms with its co-receptor LRP4, a member of the Low-density Related Protein family, a receptor complex for agrin and Wnts, representing the core system from which the postsynaptic domain is built, the growth cone attracted and the presynaptic element instructed for some aspects of its differentiation. Therefore, the discovery that ColQ binds to MuSK prompted us to study a possible regulatory function of ColQ during NMJ development. In this review, after a brief survey on ColQ, we summarize our recent data demonstrating that ColQ, in addition to its anchoring role, exerts signaling functions and controls some aspects of postsynaptic differentiation such as the clustering of acetylcholine receptors. Our results also strengthen the hypothesis that the defects observed in synaptic congenital myasthenic syndromes might be linked, at least in part, to alterations of ColQ signaling functions and not only to AChE deficiency. Finally, we discuss future research directions to understand how ColQ may modulate the action of the other ligands of the MuSK/LRP4 complex and cooperate with them to coordinate the different steps of NMJ formation and maintenance. PMID- 23089046 TI - Controversies in family planning: contraceptive counseling in the solid organ transplant recipient. PMID- 23089048 TI - Can early ultrasound reduce the gestational age at abortion for fetal anomalies? AB - BACKGROUND: A significant proportion of second-trimester abortions are done for fetal anomalies. Our objective was to evaluate the impact of ultrasound at <14 weeks on the gestational age at abortion for structural fetal abnormalities. STUDY DESIGN: Retrospective review identified all patients undergoing abortion following sonographic diagnosis of structural fetal anomalies at a single institution from 2004-2011. First-trimester ultrasound findings were reviewed, and abnormalities were categorized as "diagnostic" or "nondiagnostic." Chi-square analysis and Mann-Whitney U test were used for statistical comparison. RESULTS: One hundred thirty-two patients who underwent abortion due to structural fetal abnormalities were included, 109 of whom underwent ultrasound at 11-13 weeks. In those scanned at <14 weeks, there were diagnostic findings in 36 cases (33.0%) and abnormal nuchal translucency or other nondiagnostic finding leading to early second-trimester ultrasound in 16 cases (14.7%). In those scanned at <14 weeks, median gestational age at abortion was earlier compared to those who underwent initial anatomic evaluation in the second trimester, 19 weeks (13.5-21) versus 21 weeks (19-22), p=.001. CONCLUSION: Ultrasound at <14 weeks was associated with an earlier gestational age at abortion in pregnancies with structural fetal abnormalities. PMID- 23089047 TI - Effectiveness of an optimized benzalkonium chloride gel as vaginal contraceptive: a randomized controlled trial among Chinese women. AB - BACKGROUND: This study was conducted to evaluate the efficacy, safety and acceptability of a newly developed benzalkonium chloride (BZK) contraceptive gel which was compared to nonoxynol-9 (N-9) gel. STUDY DESIGN: A Phase II, multicenter, randomized, controlled study at three Chinese centers was conducted to compare 120 women who used BZK gel with 120 women who used N-9 gel for 6 months. Contraceptive efficacy was assessed by pregnancy rate, and safety was evaluated by adverse events report, gynecologic examination, Papanicolaou smears, leukorrhea test, and blood and urine tests. The acceptability was assessed through follow-up visit forms and a questionnaire at the 6-month visit. RESULTS: Net cumulative rates in the BZK group at 6 months were as follows: follow-up 100%, terminations 5.1%, pregnancy 1.7%, medical reasons 0% and fear of failure 3.4%. At 6 months, the rates in the N-9 group were as follows: follow-up 99.2%, terminations 9.4%, pregnancy 0.9%, medical reasons 2.5%, fear of failure 3.4% and other personal reasons 2.6%. No significant difference in pregnancy rate and termination rate between the two groups was found (p>.05). Seven cases in the BZK group (5.8%) complained about leukorrhagia and vaginal irritation symptoms (itching and burning) at 6 months, while 16 cases in the N-9 group (13.3%) had similar complaints (p<.05). This significant difference continued to exist until the 6-month visit. The general satisfaction rate for BZK gel use (72.8%) is significantly higher than that for N-9 gel (42.5%). CONCLUSION: The optimized BZK gel is comparable to N-9 gel in terms of contraceptive efficacy and safety, and may be more acceptable to Chinese users. PMID- 23089049 TI - Spread of the bla(IMP-13) gene in French Pseudomonas aeruginosa through sequence types ST621, ST308 and ST111. PMID- 23089050 TI - Normal HDL-apo AI turnover and cholesterol enrichment of HDL subclasses in New Zealand rabbits with partial nephrectomy. AB - OBJECTIVE: The kidney has been proposed to play a central role in apo AI catabolism, suggesting that HDL structure is determined, at least in part, by this organ. Here, we aimed at determining the effects of a renal mass reduction on HDL size distribution, lipid content, and apo AI turnover. METHODS: We characterized HDL subclasses in rabbits with a 75% reduction of functional renal mass (Nptx group), using enzymatic staining of samples separated on polyacrylamide electrophoresis gels, and also performed kinetic studies using radiolabeled HDL-apo AI in this animal model. RESULTS: Creatinine clearance was reduced to 35% after nephrectomy as compared to the basal values, but without increased proteinuria. A slight, but significant modification of the relative HDL size distribution was observed after nephrectomy, whereas cholesterol plasma concentrations gradually augmented from large HDL2b (+54%) to small HDL3b particles (+150%, P<0.05). Cholesteryl esters were the increased fraction; in contrast, free cholesterol phospholipids and triglycerides of HDL subclasses were not affected by nephrectomy. HDL-apo AI fractional catabolic rates were similar to controls. CONCLUSION: Reduction of functional renal mass is associated to enrichment of HDL subclasses with cholesteryl esters. Structural abnormalities were not related to a low apo AI turnover, suggesting renal contribution to HDL remodeling beyond being just a catabolic site for these lipoproteins. PMID- 23089051 TI - Myocardial infarction marker levels are influenced by prothrombin and tumor necrosis factor-alpha gene polymorphisms in young patients. AB - Polymorphisms of genes encoding key factors for the control and activation of inflammatory response and coagulation cascade regulation may play a role in genetic susceptibility to acute myocardial infarction (AMI). This study sought to analyze the effect of TNF -308G/A and pro-thrombin (FII) 20210G/A polymorphisms on the laboratory parameters of young patients affected by AMI. Results indicated that TNF -308A positive genotype frequencies were increased in these patients and that a genetically determined higher production of TNF-alpha is associated in young subjects to a more severe cardiac damage as depicted by higher levels of troponin, Creatine kinase-MB Isoenzyme (mCK-MB) and a significant increased plasma fibrinogen levels. Similar and probably additive effects on might have a genetically determined increased production of pro-thrombin even if no significant differences in genotype frequencies of pro-thrombin (FII) 20210G/A polymorphisms were observed in this study. All together these results, indicating the relationship among genetically determined TNFalpha and FII production and increased levels of tissue damage markers of AMI, suggest that a complex genetic background, might be involved in susceptibility to AMI in young men influencing the extension and severity of the disease. PMID- 23089052 TI - Late onset neonatal anaemia due to maternal anti-Kp(b) induced haemolytic disease of the newborn. AB - BACKGROUND: Alloanti-Kp(b) is a rare, clinically significant antibody against high frequency red cell antigen Kp(b) of Kell blood group system. We report here a case of Haemolytic disease of newborn (HDN) due to anti-Kp(b), which manifested as severe anaemia at the age of 1 month. AIM: To diagnose and successfully manage anti-Kp(b) induced HDN. METHODOLOGY: Direct antiglobulin test (DAT), antigen typing, irregular antibody screening and identification were done by polyspecific LISS Coombs Gel card and standard methods. RESULTS: At presentation the neonate had severe anemia with reticulocytopenia. Blood group was B, Rh D positive and DAT was 2+. Anti-Kp(b) was detected in mother's serum. Due to unavailability of Kp(b) negative red cells and incompatible blood group of mother (A(1)B Rh D positive) infant was transfused group B Rh D, Kp(b) positive PRBCs under steroid cover. He was symptom free at 4 months of age and DAT became negative at 6 months. CONCLUSION: Anti-Kp(b) is capable of causing severe late HDN. Infants born to irregular antibody positive mothers should be investigated and closely monitored for several weeks after birth for immune HDN even if asymptomatic at birth. PMID- 23089053 TI - Is mental illness complex? From behavior to brain. AB - A defining but elusive feature of the human brain is its astonishing complexity. This complexity arises from the interaction of numerous neuronal circuits that operate over a wide range of temporal and spatial scales, enabling the brain to adapt to the constantly changing environment and to perform various amazing mental functions. In mentally ill patients, such adaptability is often impaired, leading to either ordered or random patterns of behavior. Quantification and classification of these abnormal human behaviors exhibited during mental illness is one of the major challenges of contemporary psychiatric medicine. In the past few decades, attempts have been made to apply concepts adopted from complexity science to better understand complex human behavior. Although considerable effort has been devoted to studying the abnormal dynamic processes involved in mental illness, unfortunately, the primary features of complexity science are typically presented in a form suitable for mathematicians, physicists, and engineers; thus, they are difficult for practicing psychiatrists or neuroscientists to comprehend. Therefore, this paper introduces recent applications of methods derived from complexity science for examining mental illness. We propose that mental illness is loss of brain complexity and the complexity of mental illness can be studied under a general framework by quantifying the order and randomness of dynamic macroscopic human behavior and microscopic neuronal activity. Additionally, substantial effort is required to identify the link between macroscopic behaviors and microscopic changes in the neuronal dynamics within the brain. PMID- 23089054 TI - Advances in the surgical treatment of morbid obesity. AB - Due to the rapidly expanding prevalence of obesity, bariatric surgery is becoming an increasingly popular treatment option. Bariatric surgeries including Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) produce long-term weight loss and metabolic improvement, reducing mortality. This review discusses the important benefits and risks of RYGB and VSG, highlighting hypothesized mechanisms for these effects. We present data suggesting that VSG, albeit a newer procedure, may be as effective as RYGB with fewer adverse effects including less surgical risk, reduced nutritional deficiency, and less incidence of dumping syndrome. This may position VSG as an increasingly important procedure, particularly for the treatment of pediatric obesity. PMID- 23089056 TI - Ossification centres in a radiograph of a child's elbow. PMID- 23089055 TI - Atrial septal defect closure with an Amplatzer septal occluder fenestrated with a coronary stent in a child with pulmonary arterial hypertension. AB - The presence of an atrial septal defect in pulmonary hypertension has benefits and detractions. Even in idiopathic pulmonary arterial hypertension, a significant left-to-right shunt at atrial level may increase the pulmonary arterial pressure and exacerbate the disease. However, it is well recognised that the presence of an atrial communication may be protective in subgroups with severe disease, allowing maintenance of cardiac output during times of increased pulmonary resistance. In the present paper, we present the case of a young boy with significant idiopathic pulmonary arterial hypertension and an atrial septal defect. We report our technique of septal occlusion using a device to decrease left-to-right shunting with concomitant stent insertion in that device to maintain the potential for right-to-left shunting during times of high pulmonary arterial pressure. PMID- 23089057 TI - Fatigue in primary biliary cirrhosis. PMID- 23089058 TI - Obama and Romney disagree on contraception in second presidential debate. PMID- 23089059 TI - UK government's contract with Atos is "unacceptably loose," MPs say. PMID- 23089060 TI - Coverage of mental health and substance misuse topics in the Cochrane review system. AB - Aims. To assess the breadth of mental and substance coverage in the Cochrane review system. Methods. All mental health and substance entries were identified from the 2005 to April 2012 Cochrane Database of Systematic Reviews. Results. A total of 1019 entries focused on mental health or substance misuse, with 698 (68.5%) being completed reviews. One out of every five entries focused on serious mental illness/psychosis. Systematic reviews addressing unipolar depression, dementia and certain substance disorders also appeared well-represented. In contrast, a number of impairing disorders frequently seen in practice received less attention, with bipolar disorder, obsessive compulsive disorder (OCD), post traumatic stress disorder (PTSD) and autism spectrum disorders each accounting for less than 2% of the entries. The majority of interventions reviewed involved medication (57.1%), although this was not the case for a number of childhood onset disorders. Some diagnostic areas (sleep, anxiety, mood and substance) were addressed by multiple Cochrane review groups (CRGs). Conclusions. The Cochrane Collaboration is well poised to be a strong guiding influence to those seeking to employ evidence-based mental health care. Broadening its diagnostic coverage and diversifying types of intervention reviewed would probably further maximize its impact. A more centralized and directed approach of prioritizing topics could help ensure more comprehensive coverage. PMID- 23089061 TI - Using slow-release permanganate candles to remediate PAH-contaminated water. AB - Surface waters impacted by urban runoff in metropolitan areas are becoming increasingly contaminated with polycyclic aromatic hydrocarbons (PAHs). Slow release oxidant candles (paraffin-KMnO(4)) are a relatively new technology being used to treat contaminated groundwater and could potentially be used to treat urban runoff. Given that these candles only release permanganate when submerged, the ephemeral nature of runoff events would influence when the permanganate is released for treating PAHs. Our objective was to determine if slow-release permanganate candles could be used to degrade and mineralize PAHs. Batch experiments quantified PAH degradation rates in the presence of the oxidant candles. Results showed most of the 16 PAHs tested were degraded within 2-4 h. Using (14)C-labled phenanthrene and benzo(a)pyrene, we demonstrated that the wax matrix of the candle initially adsorbs the PAH, but then releases the PAH back into solution as transformed, more water soluble products. While permanganate was unable to mineralize the PAHs (i.e., convert to CO(2)), we found that the permanganate-treated PAHs were much more biodegradable in soil microcosms. To test the concept of using candles to treat PAHs in multiple runoff events, we used a flow-through system where urban runoff water was pumped over a miniature candle in repetitive wet-dry, 24-h cycles. Results showed that the candle was robust in removing PAHs by repeatedly releasing permanganate and degrading the PAHs. These results provide proof-of-concept that permanganate candles could potentially provide a low-cost, low-maintenance approach to remediating PAH contaminated water. PMID- 23089062 TI - Evaluation of joint toxicity of nitroaromatic compounds and copper to Photobacterium phosphoreum and QSAR analysis. AB - The individual toxicities of Cu and 11 nitroaromatic compounds to Photobacterium phosphoreum were determined. The toxicity was expressed as the concentrations causing a 50% inhibition of bioluminescence after 15 min exposure (IC(50)). To evaluate the joint effect between the metal ion and the 11 nitroaromatic compounds, the joint toxicity of Cu and 11 nitroaromatic compounds were measured at different Cu concentrations (0.2IC(50), 0.5IC(50) and 0.8IC(50)), respectively. The result shows that the binary joint effect between Cu and nitroaromatic compounds is mainly simple addition at the low Cu concentration (0.2IC(50)). However, an antagonism effect, 55% and 64%, was observed between Cu and 11 nitroaromatic compounds for Cu at medium and high concentrations (0.5IC(50) and 0.8IC(50)). Quantitative structure-activity relationship (QSAR) analysis was performed to study the joint toxicity for the 11 nitroaromatic compounds. The result shows that the toxicity of nitroaromatic compounds is related to descriptors of Connolly solvent-excluded volume (CSEV) and dipolarity/polarizability (S) at low Cu concentration. On the other hand, the toxicity is related to Connolly accessible area (CAA) at medium and high Cu concentrations. The result indicates that different QSAR models on complex mixtures need to be developed to assess the ecological risk in real environments. Using single toxic data to evaluate the toxic effect of mixtures may result in wrong conclusions. PMID- 23089063 TI - Uranium extraction from TRISO-coated fuel particles using supercritical CO2 containing tri-n-butyl phosphate. AB - High-temperature gas-cooled reactors (HTGRs) are advanced nuclear systems that will receive heavy use in the future. It is important to develop spent nuclear fuel reprocessing technologies for HTGR. A new method for recovering uranium from tristructural-isotropic (TRISO-) coated fuel particles with supercritical CO(2) containing tri-n-butyl phosphate (TBP) as a complexing agent was investigated. TRISO-coated fuel particles from HTGR fuel elements were first crushed to expose UO(2) pellet fuel kernels. The crushed TRISO-coated fuel particles were then treated under O(2) stream at 750 degrees C, resulting in a mixture of U(3)O(8) powder and SiC shells. The conversion of U(3)O(8) into solid uranyl nitrate by its reaction with liquid N(2)O(4) in the presence of a small amount of water was carried out. Complete conversion was achieved after 60 min of reaction at 80 degrees C, whereas the SiC shells were not converted by N(2)O(4). Uranyl nitrate in the converted mixture was extracted with supercritical CO(2) containing TBP. The cumulative extraction efficiency was above 98% after 20 min of online extraction at 50 degrees C and 25 MPa, whereas the SiC shells were not extracted by TBP. The results suggest an attractive strategy for reprocessing spent nuclear fuel from HTGR to minimize the generation of secondary radioactive waste. PMID- 23089064 TI - Synthesis of heavy metal chelating agent with four chelating groups of N1,N2,N4,N5-tetrakis(2-mercaptoethyl)benzene-1,2,4,5-tetracarboxamide (TMBTCA) and its application for Cu-containing wastewater. AB - A novel heavy metal chelating agent, N(1),N(2),N(4),N(5)-tetrakis(2 mercaptoethyl) benzene-1,2,4,5-tetracarboxamide (TMBTCA), was designed with four chelating groups, and a facile one-step synthetic procedure was developed with pyromellitic dianhydride (PMDA) and cysteamine hydrochloride (CHC) as raw materials by aqueous acylation. The effects of mole ratio of reactants (CHC/PMDA), reaction temperature, and reaction time on the yield of TMBTCA were studied. Its application for Cu-containing wastewater was investigated. The experimental results showed that the maximum yield of TMBTCA was 75.92%, as the mole ratio of CHC/PMDA reached 4.8, reaction temperature was 5 degrees C, and reaction time was 6h. It was observed that TMBTCA could effectively remove Cu(2+) and CuEDTA to much lower than 0.5 mg/L (the discharge limit of copper ions in China). Furthermore, TMBTCA showed more affinity for cadmium and copper than some traditional commercial precipitants, such as DTC, TBA and TMT, via comparison of their ability for heavy metal removal, and the precipitates of Cu-TMBTCA and Cd TMBTCA presented good stability in leaching tests. The results can provide a reference for design and further research on new kind of heavy metal chelating agent with more bonding sites, especially for heavy metal precipitation in PCB wastewater treatment. PMID- 23089066 TI - Total oxidative stress and antioxidant status in patients with carpal tunnel syndrome. AB - OBJECTIVES: Studies in the carpal tunnel syndrome (CTS) are supported ischemia induced changes rather than inflammation of the flexor tenosynovium. In this study, total antioxidant status (TAS), total oxidative stress (TOS) and oxidative stress index (OSI) in patients with CTS has been investigated. METHODS: Forty three patients (38 female and 5 male, 81 hands in total) diagnosed as CTS after the physical examination and electrophysiological findings included in study. The mean age of patients was 43.30 +/- 10.49 years. RESULTS: Bilateral CTS in 38 (88%) patients and unilateral CTS in five patients were detected. Dominant hand was involved in all patients. The mean symptoms duration was 30.9 months (range, 5-67 months). TAS in patients with CTS was significantly lower compared with control (1.01 +/- 0.14 versus 1.11 +/- 0.20 mmol Trolox equiv./l), (P = 0.008). TOS and OSI in patients with CTS were significant higher compared with control (15.60 +/- 7.03 versus 11.86 +/- 2.18 umol H2O2 equiv./l and 1.57 +/- 0.72 versus 1.09 +/- 0.28), (respectively P = 0.002 and <0.001). CONCLUSION: This study shows that there is a change in the oxidative stress and antioxidant defences in patients with CTS. Increased TOS and OSI and decreased TAS might be stimulate fibrosis through disturbed signaling pattern in the tenosynovium and median nerve. These processes might play a role in occurrence and progression of CTS. PMID- 23089065 TI - Association of treatment modality for depression and burden of comorbid chronic illness in a nationally representative sample in the United States. AB - OBJECTIVE: We examined associations between treatment modality for depression and morbidity burden. We hypothesized that patients with higher numbers of co occurring chronic illness would be more likely to receive recommended treatment for depression with both antidepressant medication and psychotherapy. METHODS: Using a retrospective cross-sectional design, we analyzed data on 165,826 people over 16 years from 2004 to 2008. Using a single multinomial logistic regression model, we examined the likelihood of treatment modality for depression: no treatment, psychotherapy alone, medication alone, and psychotherapy and medication. We examined the following predictors of therapy: (a) morbidity burden; (b) five specific chronic conditions individually: diabetes mellitus II, coronary artery disease, congestive heart failure, hypertension, and chronic obstructive pulmonary disease or asthma; and (c) sociodemographic factors. RESULTS: The likelihood of any treatment for depression, specifically psychotherapy with medication, increased with the number of co-occurring illnesses. We did not find a clear pattern of association between the five specific conditions and treatment modality, although we identified treatment patterns associated with multiple sociodemographic factors. CONCLUSIONS: This study provides insight into the relationship between multimorbidity and treatment modalities which could prove helpful in developing implementation strategies for the dissemination of evidence-based approaches to depression care. PMID- 23089067 TI - [Location of radiotherapy centers: an exploratory geographic analysis for Belgium]. AB - PURPOSE: The distance between the patient's home and a radiotherapy department may represent a hurdle for the patient and influence treatment choice. Therefore, it is necessary to check whether the geographical distribution of radiotherapy centers is in accordance with cancer incidence, taking also into account the cost of travelling to the radiotherapy department. The objective of this study is double; first, to map the current locations of radiotherapy centers across the country and second, to evaluate the observed spatial disparities with appropriate tools. MATERIALS AND METHODS: A model of operational research (P-median) is used to suggest the optimal locations and allocations and to compare them with the current situation. This is an exploratory study with simple inputs. It helps to better understand the current geographical distribution of radiotherapy centers in Belgium as well as its possible limitations. RESULTS-CONCLUSION: It appears that the current situation is on the average acceptable in terms of accessibility to the service and that the method presents huge potentialities for decision making so as to yield a spatial system that is both efficient and equitable. PMID- 23089068 TI - [Fingerprints identification of radiotherapy patients]. AB - The identification of patient plays a key role in the quality and safety of radiotherapy. It does impact on all professional staff and on patients. After the regulatory authority approval (Cnil), a pilot study has been performed on 1901 patients. Acceptance has been very high (>93%) with a low risk of misidentification (<0.1%). The next step will be to implement and test a bimodal system in order to improve registration capacity and sensitivity. PMID- 23089069 TI - [Are there any dosimetric advantages in using VMAT for treatment of locally advanced non-small cell lung cancer?]. AB - PURPOSE: To analyse the dosimetric differences between the conventional conformal radiation therapy (CR) and the volumetric modulated arc therapy (VMAT) for non small-cell locally advanced lung cancer (NSCLC). PATIENTS AND METHODS: Two plans (CR and VMAT) were calculated for ten NSCLC patients. Dose to PTV, organs at risk and external contours (body), conformity index (PTV volume/volume of the 95% reference isodose) and homogeneity index ([maximal dose-minimal dose]/dose prescription) were compared. RESULTS: Doses delivered to PTV (homogeneity index, maximal, minimal and mean dose) are similar with both techniques but conformity index is improved by 60% with VMAT: from 0.55+/-0.07 with CR to 0.89+/-0.07 with VMAT (P=0.002). Pulmonary protection is improved with VMAT: with CR and VMAT, respectively, the mean lung dose is 14.1+/-5.2Gy and 12.2+/-4.5Gy, the lung volume which receives at least 30Gy (V30) is 20+/-8% and 14+/-5%, and the V20 is 24+/-11% and 20+/-10% (P=0.002). The mean dose received by the body is also 9% lower (P=0.004) and V5 is 13% higher (P=0.004) with VMAT. V10 and V15 were similar with both modalities. From 20Gy and higher, irradiated body volume is larger with CR than with VMAT. The relative difference increases with the dose: from 10% for 20Gy (P=0.014) up to 39% for 62.7Gy (P=0.002). CONCLUSION: Compared to CR, VMAT greatly improves conformity and reduces mean dose and dose delivered from 20Gy and higher to the lungs and the body. PMID- 23089070 TI - Radiotherapy combined with cetuximab for locally advanced head and neck cancer: results and toxicity. AB - PURPOSE: To describe the clinical results and tolerance of the combined treatment with radiotherapy and cetuximab for locally advanced head and neck cancer. PATIENTS AND METHODS: From August 2006 and October 2010, 36 patients with advanced squamous cell head and neck carcinoma were treated with radiotherapy (70Gy/35 fractions) and cetuximab (400mg/m(2) one week before radiotherapy, following by 250mg/m(2) once weekly, until week 7 of radiotherapy). Tolerance was evaluated every week. All patients were examined every 3months the first 3years after therapy, and then every year. RESULTS: The median follow-up was 14months. The majority of patients were male (31 out of 36). Mean age was 59years. The tumours sites were: oral cavity (n=8); oropharynx (n=15); hypopharynx (n=5); larynx (n=8). Ninety percent of tumors were T3 or T4, and 45% were N2 or N3. Complete response was seen in 74% of patients, partial response in 17% and no response in 9% of patients. The overall survival was 44.4%. Relapse occurred in six patients. Anaphylactic reaction during the first infusion of cetuximab was observed in one patient. One patient developed severe aplasia after 48Gy and 5weeks of cetuximab, and died of sepsis. Eighty percent of patients presented acne, 16 patients developed a mucositis grade 2-3 and 23 patients a grade 2 skin reaction. CONCLUSION: The concomitant use of cetuximab and radiotherapy in locally advanced head and neck carcinoma is well tolerated in this group of patients. The results seem comparable to those in the literature. PMID- 23089071 TI - Can melamine levels in 1-spot overnight urine specimens predict the total previous 24-hour melamine excretion level in school children? AB - BACKGROUND: We investigated whether melamine concentrations in 1-spot overnight urine sample can represent the previous 8- and 24-h total urinary melamine excretions in school children. The relationship between urinary melamine levels and several clinical biomarkers of early renal injury such as microalbumin and N acetyl-beta-D-glucosaminidase (NAG) in urine was also examined. METHODS: School children, aged 6-10 y, and their parents who were healthy and lived closely to Kaohsiung Medical University-affiliated hospitals were recruited. All study children had the first 1-spot overnight urine sample collected on the Sunday morning (the first day) immediately when they woke up, and then all the subsequent urine samples continued to be collected until the first 1-spot overnight urine sample on the morning of the next day (Monday, the second day). Two first 1-spot overnight urine samples from their parents on the same Sunday and Monday mornings were also collected. This protocol was completed in the July and August of 2011. All urine samples were measured for melamine, biomarkers of early renal injury, and creatinine. RESULTS: There were 7 girls and 16 boys in this study. Except for one missing urine sample from 1-spot overnight urine sample on the morning of the second day, melamine levels in the rest of urine samples among the study children were all detectable. The median melamine levels of 1-spot overnight urine samples on the first and second day mornings were 0.93 and 1.73 MUg/mmol of creatinine respectively. We found that melamine concentrations of 1-spot overnight urine samples on the second day morning were highly correlated with the previous 8- and 24-h total melamine excretions in urine (r=0.936, p<0.001, n=21 and r=0.616, p<0.001, n=21 respectively). Good correlation of 1-spot overnight urine sample on the first and second day mornings was also found (r=0.619, p=0.003, n=21). In contrast, there were no significant correlations of 24-h total urinary melamine and 24-h total urinary microalbumin and NAG excretions (r=-0.221, p=0.319, n=22 and r=0.084, p=0.710, n=22). CONCLUSION: Melamine levels in 1-spot overnight urine sample can predict the previous 8- and 24-h total melamine excretions in urine. Since melamine exposure levels in these school children were relatively low, its association with clinical biomarkers of early renal injury was not found. A future study is necessary to increase the sample size and to find the more sensitive preclinical biomarkers of renal injury to link with low melamine exposure in children in the community. PMID- 23089072 TI - Matrix-assisted laser desorption ionization/time-of-flight mass spectrometry for clinical diagnosis. AB - BACKGROUND: Matrix-assisted laser desorption ionization/time-of-flight (MALDI TOF) mass spectrometry is known as an extremely sensitive analytical tool for characterizing different types of biological compounds including proteins, peptides and lipids. Since MALDI-TOF analysis requires very simple sample pretreatment, the technique can be used for rapidly detecting biochemical compounds serving as disease biomarkers. RESULTS: This mini-review focuses on the applications of MALDI-TOF in the detection of potential disease biomarkers in various biological samples. CONCLUSIONS: The potential disease biomarkers are mostly abundant proteins, peptides, or lipids including: albumin; hemoglobin; alpha-defensins; trimethylamine; phospholipids; and glycated alpha- and beta globin, which are indicators of albuminuria; fecal occult blood and ischemic stroke; dry eye disease and/or aging; trimethylaniuria; breast cancer; and diabetes, respectively. PMID- 23089073 TI - Hydroxy-itraconazole pharmacokinetics is similar to that of itraconazole in immunocompromised patients receiving oral solution of itraconazole. AB - BACKGROUND: The pharmacokinetic variability of hydroxy-itraconazole (OH-ITZ), an active metabolite of itraconazole (ITZ), is not fully known. METHODS: Oral solution of ITZ was administered in 46 immunocompromised patients as a single 200 mg dose for at least 12 days. The plasma concentrations of ITZ, active OH-ITZ, and keto-itraconazole (keto-ITZ), an inactive metabolite, 12 h after administration were determined by LC-UV or LC-MS/MS. RESULTS: The mean+/-SD of plasma concentrations of ITZ, OH-ITZ, and keto-ITZ were 833+/-468, 798+/-454, and 3.94+/-2.68 MUg/l, respectively. A greater correlation coefficient was observed between plasma concentrations of ITZ and OH-ITZ (r=0.90, P<0.01) than between OH ITZ and keto-ITZ (r=0.44, P<0.01). Plasma concentration of OH-ITZ was inversely correlated with concentration ratio of keto-ITZ to OH-ITZ (r=-0.52, P<0.01). Plasma concentrations of ITZ and OH-ITZ were correlated with serum concentration of albumin (r=0.36, P=0.01 and r=0.37, P=0.01) and estimated glomerular filtration rate (r=-0.27, P=0.08 and r=-0.35, P=0.02). CONCLUSIONS: The pharmacokinetic variability of OH-ITZ was associated with saturated metabolism to keto-ITZ, serum concentration of albumin, and renal function in immunocompromised patients. The plasma concentration of OH-ITZ was strongly correlated with that of ITZ. Prevention of fungal infections can be improved by determining the plasma concentration of ITZ or OH-ITZ. PMID- 23089074 TI - Is there a link between endothelial dysfunction, coagulation activation and nitric oxide synthesis in preeclampsia? AB - BACKGROUND: There may be a relationship between endothelial dysfunction, coagulation activation and nitric oxide (NO) synthesis in women with mild and severe preeclampsia (PE). METHODS: Plasma thrombomodulin (TM), D-Dimer (D-Di), cyclic guanosine monophosphate (cGMP) and placental nitric oxide synthase activity (NOS) were investigated in 21 normotensive pregnant women (G1), 22 pregnant women with mild PE (G2) and 20 pregnant women with severe PE (G3). RESULTS: TM and D-Di were significantly increased in G3 compared to G1 (P=0.001 and P=0.006, respectively) and G2 (P=0.001, in both cases). However, there was no significant difference when G1 was compared to G2. For total NOS, calcium independent NOS, calcium dependent NOS no significant difference was observed among the groups studied. CONCLUSIONS: TM and D-Di levels are raised in women with severe PE compared to normotensive pregnant women and women with mild PE. While increased TM levels may reflect endothelial dysfunction, raised D-Di levels indicate a hypercoagulable state. NO assessed by 2 indirect methods did not show any significant difference among the groups studied. Due to current limitations with in vitro NO measurements and interferences associated with NO bioavailability, particularly in PE, such findings should not be over interpreted. PMID- 23089075 TI - Calibration of glucose oxidase-based test strips for capillary blood measurement with oxygen saturated venous blood samples. AB - BACKGROUND: Glucose oxidase biosensors are used in self-monitoring blood glucose concentrations. The capillary blood glucose quantitation requires a calibration curve. Due to the limitation in obtaining calibration curve from capillary blood, an alternate approach by using venous blood for neonatal measurement was investigated. METHODS: A signal correlation between oxygen saturated venous blood and capillary blood was derived. The hematocrit effect was studied for different glucose concentrations. The calibrated glucose strips were validated by neonatal intensive care unit (NICU) samples. RESULTS: A simple equation, finger blood signal=1.39*(oxygen saturated venous blood signal)-31.2 was derived. The rate of change in glucose concentration due to hematocrit effect was low in lower glucose concentration samples. The BeneCheck Glucose Strips were compared with Beckman Coulter analyzer by using 52 NICU samples. More than 95% of test results were within the variation of +/-10 mg/dl of bias and +/-15% of bias% when glucose concentration is <75 mg/dl and >=75 mg/dl respectively. CONCLUSIONS: The BeneCheck Glucose Strips can be accurately calibrated with venous blood. The hematocrit effect can also be predicted. Based on this study, BeneCheck Blood Glucose Monitoring System can be suitable for neonatal glucose measurement. PMID- 23089077 TI - Performance of music elevates pain threshold and positive affect: implications for the evolutionary function of music. AB - It is well known that music arouses emotional responses. In addition, it has long been thought to play an important role in creating a sense of community, especially in small scale societies. One mechanism by which it might do this is through the endorphin system, and there is evidence to support this claim. Using pain threshold as an assay for CNS endorphin release, we ask whether it is the auditory perception of music that triggers this effect or the active performance of music. We show that singing, dancing and drumming all trigger endorphin release (indexed by an increase in post-activity pain tolerance) in contexts where merely listening to music and low energy musical activities do not. We also confirm that music performance results in elevated positive (but not negative) affect. We conclude that it is the active performance of music that generates the endorphin high, not the music itself. We discuss the implications of this in the context of community bonding mechanisms that commonly involve dance and music making. PMID- 23089078 TI - Men smelling women: null effects of exposure to ovulatory sweat on men's testosterone. AB - Males of many species, humans included, exhibit rapid testosterone increases after exposure to conspecific females. Female chemical stimuli are sufficient to trigger these responses in many nonhuman species, which raises the possibility of similar effects in humans. Recently, Miller and Maner (2010) reported that smelling T-shirts worn by women near ovulation can trigger testosterone responses in men; however, men were aware that they were smelling women's scents, and thus mental imagery associated with that knowledge may have contributed to the hormone responses. Here, we collected axillary sweat samples from women on days near ovulation. In a crossover design, men who were not explicitly aware of the specific stimuli smelled the sweat samples in one session and water samples in a second session. There were no differences in testosterone responses across the experimental conditions. Our null findings suggest that the relevant chemical signal is not found in axillary sweat, and/or that knowledge of the stimulus source is necessary for hormone responses. These results thus suggest boundary conditions for the effects reported in Miller and Maner (2010), and recommend further research to define the precise circumstances under which men's testosterone may respond to chemosensory cues from women. PMID- 23089076 TI - Glycine treatment of the risk syndrome for psychosis: report of two pilot studies. AB - Patients meeting criteria for the risk syndrome for psychosis have treatment needs including positive and negative symptoms and cognitive impairment. These features could potentially respond to NMDA glycine-site agonists. The present objective was to determine which symptoms or domains of cognition promise to show the greatest response to glycine in risk syndrome patients. We conducted two short-term pilot studies of glycine used without adjunctive antipsychotic medication. In the first trial, 10 risk syndrome subjects received open-label glycine at doses titrated to 0.8 g/kg/d for 8 weeks, followed by discontinuation and 16 weeks of evaluation for durability of effects. In the second, 8 subjects were randomized to double-blind glycine vs. placebo for 12 weeks, followed by open-label glycine for another 12 weeks. Patients were evaluated every 1-2 weeks with the Scale Of Psychosis-risk Symptoms (SOPS) and before and after treatment with a neurocognitive battery. Within-group and between-group effect sizes were calculated. Effect sizes were large for positive (open-label within-group -1.10, double-blind between-group -1.11) and total (-1.39 and -1.15) symptoms and medium to-large (-0.74 and -0.79) for negative symptoms. Medium or large effect sizes were also observed for several neurocognitive measures in the open-label study, although data were sparse. No safety concerns were identified. We conclude that glycine was associated with reduced symptoms with promising effect sizes in two pilot studies and a possibility of improvement in cognitive function. Further studies of agents that facilitate NMDA receptor function in risk syndrome patients are supported by these preliminary findings. PMID- 23089079 TI - Vaccine-related mumps infections in Thailand and the identification of a novel mutation in the mumps fusion protein. AB - An outbreak of nine cases of mumps was reported from a total of 97 vaccinated nursing students at two medical colleges in Thailand in 2010, 16-26 days after administration of MMR vaccine containing the L-Zagreb mumps strain. Symptoms ranged in severity from fever and parotid swelling to orchitis. Clinical samples were obtained from seven patients and three were suitable for further study. Sequencing confirmed that the SH gene of the mumps virus in the unpassaged clinical specimens was identical to the L-Zagreb SH gene in the vaccine. Further analysis of the viral genome identified nucleotide position 5170 as a novel mutation which corresponds to an amino acid change in the fusion protein. This study provides another virologically confirmed example of mumps resulting from the L-Zagreb vaccine strain. PMID- 23089080 TI - Respiratory protection during simulated emergency pediatric life support: a randomized, controlled, crossover study. AB - INTRODUCTION: Emergency pediatric life support (EPLS) of children infected with transmissible respiratory diseases requires adequate respiratory protection for medical first responders. Conventional air-purifying respirators (APR) and modern loose-fitting powered air-purifying respirator-hoods (PAPR-hood) may have a different impact during pediatric resuscitation and therefore require evaluation. OBJECTIVE: This study investigated the influence of APRs and PAPR-hoods during simulated pediatric cardiopulmonary resuscitation. METHODS: Study design was a randomized, controlled, crossover study. Sixteen paramedics carried out a standardized EPLS scenario inside an ambulance, either unprotected (control) or wearing a conventional APR or a PAPR-hood. Treatment times and wearer comfort were determined and compared. RESULTS: All paramedics completed the treatment objectives of the study arms without adverse events. Study subjects reported that communication, dexterity and mobility were significantly better in the APR group, whereas the heat-build-up was significantly less in the PAPR-hood group. Treatment times compared to the control group did not significantly differ for the APR group but did with the PAPR-hood group (261+/-12 seconds for the controls, 275+/-9 seconds for the conventional APR and 286+/-13 seconds for the PAPR-hood group, P < .05. CONCLUSIONS: APRs showed a trend to better treatment times compared to PAPR-hoods during simulated pediatric cardiopulmonary resuscitation. Study participants rated mobility, ease of communication and dexterity with the tight-fitting APR system significantly better compared to the loose-fitting PAPR-hood. PMID- 23089082 TI - [Floating elbow: retrospective study and review of literature]. AB - The floating elbow represents an uncommon combination of lesions in traumatology. Few studies have described this lesion especially in adults. Over a period of 6 years, 12 floating elbows were reviewed retrospectively. One osteoporotic elderly patient was treated conservatively. Reduction and internal fixation using different implants was performed in the other patients. Consolidation was obtained at the humerus at 3 months (2.5-3.5 months) on average, and 2.6 months (2-3 months) at forearm bones. According to the classification of Lange and Foster, our functional results were good in 67% of cases, fair in 17% and poor in 16% cases. Good functional prognosis of the upper limb requires rapid and adequate management of floating elbows. Internal fixation followed by early rehabilitation is recommended. The choice of surgical acts depends on the location of fractures. This strategy gave satisfactory results. PMID- 23089081 TI - Color stability of experimental composites containing different photoinitiators. AB - OBJECTIVES: To evaluate the color stability (DeltaE) of experimental composites containing different photoinitiators when submitted to accelerated artificial ageing (AAA). MATERIAL AND METHODS: Thirty test specimens were made in a Teflon matrix (8mm*2mm), using an experimental composite (n=10) with the same monomer composition and particle size, but varying photoinitiator used: Group CQ (0.4% Camphorquinone), Group PPD (0.4% 1-Phenyl-1,2 Propanodione) and Group CQ+PPD (0.2% CQ+0.2% PPD). The samples were light activated (QTH - Ultralux - Dabi Atlante - 40s) and polished before performing the initial color readouts (EasyShade - Vita). Next, they were submitted to AAA for 300h, after which final color readouts were made. RESULTS: The results (1-way ANOVA - Tukey - p<0.05) demonstrated that all the groups presented color alteration above the clinically acceptable level (DeltaE>=3.3), however, with no statistically significant difference among them (p>0.05). Analysis of Deltab demonstrated increase in the values of this coordinate, indicating yellowing in all groups. CONCLUSIONS: It was concluded that the type of photoinitiator, which presented a tendency towards yellowing, did not interfere in the color stability of composites submitted to AAA. CLINICAL SIGNIFICANCE: Alternative photoinitiators have been extensively studied since Camphorquinone presents a yellowish color, which compromises the aesthetic performance of composites, especially the lighter-shade ones. PMID- 23089083 TI - Lesions of the scapholunate ligament associated with minimally displaced or non displaced fractures of the scaphoid waist. Which incidence? AB - INTRODUCTION: It was commonly considered that a non-displaced or minimally displaced isolated scaphoid fracture was mechanically incompatible with a lesion of the scapholunate ligament (SL). However, some authors who described such an association have recently challenged this statement. The aim of this prospective study was to determine, after screw fixation and using arthroscopy, the existence and incidence of lesions of the SL as associated with acute non-displaced or minimally displaced isolated fractures of the scaphoid. METHODS: Between December 2009 and January 2011, the study included all patients presenting with an acute non-displaced or minimally displaced isolated fracture of the scaphoid waist, eligible for percutaneous screw fixation and accepting the procedure after informed consent. The surgical protocol included a first retrograde arthroscopically controlled percutaneous screwing of the scaphoid, followed by a second arthroscopy seeking only lesions of the SL. Geissler's classification was used for the classification of SL lesions. RESULTS: Eighteen patients were included in the study. The mean was 29 years. In 17 cases, the scaphoid fracture was due to a low-energy fall, and in 1 case, to a road accident. No SL lesion was evidenced by the diagnostic arthroscopy. CONCLUSION: Unlike some published reports, we did not observe any SL lesion associated with non-displaced or minimally displaced isolated fractures of the scaphoid. Nevertheless, despite such results and based on the literature, we recommend arthroscopy with percutaneous scaphoid screw fixation, with the triple advantage of providing reduction control, adequate screw fixation verification, and diagnosis of potential associated ligament lesions. PMID- 23089084 TI - Therapy for couples after an affair: a randomized-controlled trial. AB - To examine the efficacy of a couples treatment approach for promoting recovery from a recently disclosed affair, 89 couples that disclosed an affair by one of the partners in the past 6 months were randomly assigned to treatment (n = 46) or to a control group that waited about 3 months for treatment (n = 43). The couples completed self-report measures (Beck Depression Inventory, Impact of Event Scale Revised, Partnership Questionnaire) at pre- and post-treatment. Since about half of the couples dropped out for various reasons (e.g., ongoing affair, separation), we used multiple imputations to handle the missing data problem. We analyzed the dyadic data with hierarchical linear modeling in a two-level model. Significant improvements on scores of anxiety corresponded with large effect sizes for both partners. Yet significant improvements on depression scores were only found for the unfaithful partner with moderate effect size. Results suggest that the treatment can improve individual complaints, but not relationship satisfaction in a sufficient amount for both partners. Hence, future research should address how this intervention could encourage couples to maintain therapy, and how they might achieve more and sustained improvement in relationship satisfaction. PMID- 23089085 TI - Adjunctive mirror exposure for eating disorders: a randomized controlled pilot study. AB - Mirror exposure therapy has proven efficacious in improving body image among individuals with shape/weight concerns and eating disorders. No randomized controlled trials have examined the effect of mirror exposure in a healthy-weight clinical sample of eating disordered individuals. The purpose of the current study was to test the efficacy of a five-session acceptance based mirror exposure therapy (A-MET) versus a non directive body image therapy (ND) control as an adjunctive treatment to outpatient eating disorder treatment. Thirty-three males and females aged 14-65 with a body mass index of 18.5-29.9 were randomized to five sessions of A-MET or ND with a 1-month follow-up. Results indicated large to moderate effect size differences for efficacy of A-MET across measures of body checking, body image dissatisfaction, and eating disorder symptoms (d = -0.38 to 1.61) at end of treatment and follow-up. Baseline measures of social comparison and history of appearance-related teasing were predictive of treatment response. There were also differential effects of treatment on participants' perceived homework quality, but no differences in therapeutic alliance. Results suggest that A-MET is a promising adjunctive treatment for residual body image disturbance among normal and overweight individuals undergoing treatment for an eating disorder. Future research and clinical implications are discussed. PMID- 23089086 TI - Potential of quaternization-functionalized chitosan fiber for wound dressing. AB - Quaternization-functionalized chitosan fibers were successfully prepared by using 2,3-epoxypropyl trimethyl ammonium chloride as a quaternized reagent reacted with chitosan fiber. FTIR and (1)H NMR were used to characterize the structure of quaternized chitosan fibers (QCFs). The swelling behavior and mechanical property of QCFs were studied. The results showed that, QCFs had higher liquid absorption capacity than chitosan fiber, while the tensile strength and elongation at break of QCFs were lower than those of chitosan fiber. The antibacterial activity of the QCF had been evaluated by Gram-positive bacteria Staphylococcus aureus (S. aureus). The results indicated that, the antibacterial activity of QCF against S. aureus was stronger than that of chitosan fiber. Indirect cytotoxicity assessment of the fibers indicated that QCF was nontoxic to the L929 cell with relatively low extraction concentration. This novel fiber would be used as potential wound dressing for skin regeneration. PMID- 23089087 TI - A simple technique of ureteric spatulation & handling during laparoscopic pyeloplasty in infants & children. AB - Laparoscopic pyeloplasty is being performed successfully in children with results comparable to open pyeloplasty. Pediatric laparoscopic pyeloplasty, however, remains a technically demanding procedure. Some of the most difficult, time consuming, and at the same time critical steps of the procedure are ureteral spatulation and intracorporeal suturing of the anastomosis. It is also preferable to avoid grasping the ureter with any instrument. The difficulty of ureteral spatulation has led to the development of some technical modifications, including an ex-vivo spatulation technique. In our own practice, we tried some modifications to overcome this challenging part of the procedure. We have finally developed a technique that simplifies this surgical step. This technique can be performed with simple conventional laparoscopic instruments and is easily reproducible. PMID- 23089088 TI - Images in emergency medicine. Young boy with eye pain. Herpes zoster ophthalmicus, varicella zoster stromal keratitis, episcleritis and iritis. PMID- 23089089 TI - Safety climate and medical errors in 62 US emergency departments. AB - STUDY OBJECTIVE: We describe the incidence and types of medical errors in emergency departments (EDs) and assess the validity of a survey instrument that identifies systems factors contributing to errors in EDs. METHODS: We conducted the National Emergency Department Safety Study in 62 urban EDs across 20 US states. We reviewed 9,821 medical records of ED patients with one of 3 conditions (myocardial infarction, asthma exacerbation, and joint dislocation) to evaluate medical errors. We also obtained surveys from 3,562 staff randomly selected from each ED; survey data were used to calculate average safety climate scores for each ED. RESULTS: We identified 402 adverse events (incidence rate 4.1 per 100 patient visits; 95% confidence interval [CI] 3.7 to 4.5) and 532 near misses (incidence rate 5.4 per 100 patient visits; 95% CI 5.0 to 5.9). We judged 37% of the adverse events, and all of the near misses, to be preventable (errors); 33% of the near misses were intercepted. In multivariable models, better ED safety climate was not associated with fewer preventable adverse events (incidence rate ratio per 0.2-point increase in ED safety score 0.82; 95% CI 0.57 to 1.16) but was associated with more intercepted near misses (incidence rate ratio 1.79; 95% CI 1.06 to 3.03). We found no association between safety climate and violations of national treatment guidelines. CONCLUSION: Among the 3 ED conditions studied, medical errors are relatively common, and one third of adverse events are preventable. Improved ED safety climate may increase the likelihood that near misses are intercepted. PMID- 23089090 TI - Stepping back: why patient safety is in need of a broader view than the safety climate survey provides. PMID- 23089091 TI - Commentary. Update on emerging infections : news from the Centers for Disease Control and Prevention. PMID- 23089092 TI - Change of shift. Another day, another code, another thank you. PMID- 23089093 TI - Annals of Emergency Medicine Journal Club. rt-PA and Stroke: does IST-3 make it all clear or muddy the waters? PMID- 23089094 TI - Images in emergency medicine. 10-year-old female with a subglottic mass. Ranula. PMID- 23089095 TI - Understanding the role for crisis standards of care. PMID- 23089097 TI - Prophylaxis for acute mountain sickness. PMID- 23089100 TI - The RACE to Where? For What? PMID- 23089101 TI - Medical direction of emergency medical services. Policy statement. PMID- 23089102 TI - Medical direction for staffing of ambulances. Policy statement. PMID- 23089103 TI - Interfacility transportation of the critical care patient and its medical direction. Policy statement. PMID- 23089104 TI - Proteomics advancements in fetomaternal medicine. AB - The study of interactions between genes and their environment, thus of molecules that form the "functional genome", has been greatly enhanced throughout the course of post-genomic era by the expansion of the omic technologies. Proteomic technologies and mass spectrometry in particular, form a well-armored strategy towards high-throughput simultaneous analysis of thousands of proteins and protein-related molecules. Proteomics as in the past, are still currently offering novel perspectives in the understanding over the pathophysiology of malicious conditions as well as in the development of molecular-targeted therapeutics against them. This review examines the offerings of proteomics research over the unique physiological phenomenon of pregnancy and its related complications, which affect both maternal and perinatal health. PMID- 23089105 TI - Translational proteomics in Alzheimer's disease and related disorders. AB - Alzheimer's disease (AD) and its related syndromes--especially frontotemporal dementia (FTD), Lewy body dementia (LBD) and dementias associated with cerebrovascular disease--are the principal causes of dementia. Until a recent period, the diagnosis of AD and its related disorders relied almost exclusively on the combination of a neurological examination and the use neuropsychological tests. Cerebrospinal fluid (CSF) dosage of neuropathologically AD-associated proteins has already been incorporated into the neurochemical diagnosis of AD, attesting the relevance of translational research. The analysis of the human proteome has made considerable advances in the last years and is prepared to overcome several obstacles for its routine application. In this review we discuss i) how biomarkers are modernizing the diagnosis of AD and related disorders, ii) the different sources of samples used for clinically oriented analysis highlighting the different challenges and approaches associated with these iii) studies investigating changes in circulating proteome in subjects at risk for dementia. There is urgent need for more large-scale longitudinal studies to establish the analytical and global proteome intraindividual variability for contemporary proteomics platforms. In addition, combing proteomics and endophenotypes such as imaging or other biomarkers is of paramount importance. PMID- 23089106 TI - Acylcarnitine profile in thyroid disease. AB - OBJECTIVES: To examine acylcarnitine profiles in individuals with hypo- or hyperthyroidism, and determine whether any atypical acylcarnitine species identified would normalize with correction of thyroid status. DESIGN AND METHODS: Serum acylcarnitine levels were measured in hypo- and hyperthyroid subjects before and after treatment with thyroxine or thionamide therapy respectively. RESULTS: No discernible differences were observed in the serum acylcarnitine profiles between hypo-, hyper- and euthyroid states. CONCLUSIONS: Acylcarnitine profiles are relatively unremarkable in thyroid disease. PMID- 23089107 TI - Biomarker discovery in transplantation--proteomic adventure or mission impossible? AB - Optimal management of transplanted organs requires specific and sensitive biomarkers for immunologic graft monitoring and subsequently patient tailored treatment. Proteomic science has emerged as an attractive tool in clinical biomarker research generating massive amounts of proteomic-driven data. However, critical interpretation of these data requires basic knowledge of proteomic principles and technology. This review provides an overview of proteomic approaches along with their advantages and limitations. Furthermore, this article summarizes the current status of biomarker achievements in the different areas of solid organ transplantation and discusses the hurdles that have precluded routine clinical application of these promising markers so far. PMID- 23089108 TI - Idiopathic pulmonary fibrosis and polymorphisms of the folate pathway genes. AB - OBJECTIVES: This study aims to determine the possible association between folate pathway gene polymorphisms and idiopathic pulmonary fibrosis. This represents the first study carried out on folate pathway gene polymorphisms as possible risk factors in this kind of pathology. The premise is that several polymorphisms mapping on genes responsible for folate uptake are associated with the risk of numerous diseases occurring between pregnancy and old age, and that too little is currently known about idiopathic pulmonary fibrosis. DESIGN AND METHODS: We genotyped 9 single nucleotide polymorphisms and 1 polymorphic insertion in 7 essential genes belonging to the folate pathway in 32 Italian idiopathic pulmonary fibrosis patients and 81 control subjects. This was done by PCR and restriction analysis. RESULTS: Allelic and genotypic association tests indicated that for all the analysed polymorphisms there were no significant differences between patients and controls. Nevertheless, the haplotype association analysis revealed a significant association between idiopathic pulmonary fibrosis and transcobalamin II gene polymorphisms: specifically the haplotype 776G (rs1801198) c.1026-394G (rs7286680)-444C (rs10418) (OR=2.84; 95% C.I. 1.36-5.93, P value=0.004). CONCLUSIONS: This small-scale preliminary study would suggest the importance of further research focusing on the role of folate in the onset of idiopathic pulmonary fibrosis. PMID- 23089109 TI - Fish consumption, omega-3 fatty acids, and environmental contaminants in relation to low-grade inflammation and early atherosclerosis. AB - BACKGROUND: Fish consumption and omega-3 polyunsaturated fatty acid (PUFA) intake are shown to protect from cardiovascular diseases (CVD). However, most fish contain environmental contaminants such as dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and methylmercury (MeHg) that may have adverse effects on cardiovascular health. OBJECTIVE: Our aim was to elucidate the associations of fish consumption, omega-3 PUFAs, environmental contaminants with low-grade inflammation, early atherosclerosis, and traditional CVD risk factors. METHODS: The Health 2000 survey participants (n=1173) represented the general Finnish population and the Fishermen study participants (n=255) represented a population with high fish consumption and high exposure to environmental contaminants. Model-adjusted geometric means and tests for linear trend were calculated for CVD risk factors by tertiles of fish consumption and serum omega-3 PUFAs, and additionally in the Fishermen study only, by tertiles of serum PCDD/F+PCB, and blood MeHg. RESULTS: Serum triglyceride decreased across omega-3 PUFA tertiles in both sexes and studies. Insulin resistance, C-reactive protein, tumour necrosis factor alpha, and interleukin 6 decreased across omega-3 PUFA tertiles among the Health 2000 survey participants. Among the Fishermen study men, insulin resistance and arterial stiffness indicated by beta-stiffness index tended to increase and the RR estimate for carotid artery plaque tended to decrease across tertiles of PCDD/F+PCB and MeHg. CONCLUSION: Previously established hypotriglyceridemic and anti-inflammatory effects of omega-3 PUFAs were seen also in this study. The hypothesised favourable effect on insulin sensitivity and arterial elasticity was suggested to be counteracted by high exposure to environmental contaminants but the effect on plaque prevalence appeared not to be harmful. PMID- 23089110 TI - [Venous thromboembolism prevention in non-surgical adult patients admitted in a general hospital]. AB - Adult patients hospitalized for a non-surgical condition, usually have a high risk of venous thromboembolism and may develop some form of this disease when they do not receive appropriate preventive treatment. The objectives of this prospective, analytical, observational and cross-sectional study were: 1) to determine what percentage of adult patients hospitalized for a non-surgical acute condition at the Hospital de Clinicas Jose de San Martin, Universidad de Buenos Aires, had indication for preventive thromboprophylaxis, 2) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism, 3) to establish how many of them had been prescribed a preventive treatment of venous thromboembolism without having reasons to justify the treatment. The study was performed on 93 patients for 72 consecutive hours. It resulted in 90.3% in need of preventive treatment for venous thromboembolism and 76.2% of these patients had received pharmacological thromboprophylaxis. A 33.3% of the studied patients had received preventive pharmacological treatment without having a proper indication. In this study, the percentage of patients treated is higher than in those reported in other published observational studies. PMID- 23089111 TI - [Factors associated to late clinical stage at the initiation of antiretroviral therapy]. AB - In order to evaluate the frequency of a late clinical stage in HIV infected patients at onset of antiretroviral therapy (LART) and to identify possible associated factors, we performed a retrospective analysis of data reported in two prospective cohorts of HIV infected patients who started antiretroviral therapy for the first time between 2005 and 2009. Medical records of 265 patients -123 women (46.6%) and 141 men, median age 37.7 years old- were analyzed. LART was observed in 132 cases (50%), out of them 102 (77.2%) were associated to late diagnosis of HIV infection and 30 (22.8%) to patients that had not been retained in HIV care. The median of CD4 was 120 cells/ml and that of viral load 58 038 copies/ml. CD4 cells count was below 200 cells/ml in 174 patients (71.3%). There was a higher incidence of LART in men than in women (59.8% and 42.2% respectively). Diagnosis in women took place during pregnancy control in 25:2% of the cases. High alcohol consumption (p 0.006), single hood (p 0.04) and level of education lower than secondary (p 0.008) were associated to LART at bivariate analysis. Male sex (p 0.003) was the only associated factor both in bivariate and multivariate analysis. Our data reinforce the need of expanding HIV testing and should assist programs to define actions promoting early entry in HIV care. PMID- 23089112 TI - [Directly observed treatment for tuberculosis in a Buenos Aires City hospital]. AB - The outcomes of directly observed therapy of tuberculosis (DOT) between 1/1/1979 and 12/31/2009 were analyzed. Results obtained in the 1979-1999 period were compared with those achieved in the 2000-2009 period. In a Buenos Aires City hospital, 582 HIV negative TB patients received rifampin, isoniazid, pyrazinamide and ethambutol or streptomycin in the initial stage, followed by a second stage where patients were included in two groups: G1 composed by 424 patients (period 1/1/1979-12/31/1999) who received either rifampin and isoniazid or rifampin and streptomicin twice a week, and G2, with 158 patients (period 1/1/2000-12/31/2009) who received either rifampin and isoniazid twice or three times a week. National and Buenos Aires City TB Control Programs recommendations were followed. Patients who underwent DOT had higher completeness rates than those included in self administered therapy (82.8% vs. 48.7%), (p <0.0001). Mean age: 36.3 +/- 15.3 years, males: 63.1% and 69.4% were Argentine citizens. A 8.9% had been previously treated, 6.1% had co-morbidities. A 70.6% of pulmonary cases was bacteriologically confirmed, 82.8% of them completed the treatment, while 11.5% defaulted. Adverse effects to antituberculosis drugs were observed in 9.5% of cases; male patients showed higher rates of non adherence. G2 had a lower proportion of native people (48.7% vs. 77.1%), (p = 0.0001), higher frequency of co-morbidities (10.7% vs. 4.4%), (p = 0.005), of bacteriologically confirmed pulmonary cases (95% vs. 87%), (p = 0.02) and more adverse effects than G1 (17% vs. 6.6%), (p = 0.0001). In coincidence with other experiences, this work shows high treatment success rates in patients treated under DOT strategy. PMID- 23089113 TI - [Olindias sambaquiensis jellyfish sting. Analysis of 49 cases]. AB - Olindias sambaquiensis jellyfish sting occurs frequently in Buenos Aires province coast beaches. Among five hundred and one thousand stings by jellyfish are reported each season at Monte Hermoso, a beach village in the South of Buenos Aires province. The skin damage provoked because of its highly irritant effect poses a serious issue related to tourism development. A total number of 49 cases that were examined during the first hour after the sting were enrolled in Monte Hermoso during January 1998. Twenty eight were males (57.1%). The average age was 16 +/- 4.1 (range 5-80). Of them, 54% showed linear erythema-edematous lesions, 28% showed predominantly erythematous lesions, and in 18% the injuries were erythema-edematous plaques. In 73% of the cases the lesions were located in lower limbs. We had hereby redefined cutaneous lesions produced by O. sambaquiensis, its evolution, its dimensions and most frequent localizations. Besides, it has been typified and quantified the pain it provokes and other signs and symptoms that go with the sting during the posterior hour, during the first 24 hours, and after 30 days. We described the therapeutic conducts used in our coasts and we assessed the effectiveness of some of them in pain control, and finally we propose a therapeutic scheme for this sting. PMID- 23089114 TI - [The role of prenatal hyperandrogenism on lipid metabolism during adult life in a rat model]. AB - Polycystic ovary syndrome (PCOS) is one of the commonest endocrine diseases that affect women in their reproductive ages; however, the etiology of the syndrome remains unknown. A hypothesis proposes that during gestation increased exposure of androgen would induce fetal programming that may increase the risk of PCOS development during the adult life. By means of a prenatally hyperandrogenized (HA) rat model we demonstrated the importance of determining the lipid profile at early ages. HA induced two different phenotypes: ovulatory and anovulatory PCOS. HA did not modify total cholesterol but decreased HDL cholesterol and increased both LDL and tryglicerides (TG) when compared with controls. Both, the ratio total cholesterol: HDL (marker of cardiovascular risk) and TG:HDL (marker of metabolic syndrome) were increased in the HA group with respect to controls. In addition, these abnormalities were stronger in the anovulatory than ovulatory phenotype. Our results point out the need to find early markers of PCOS in girls or adolescents with increased risk to develop PCOS (as in daughters of women with PCOS). PMID- 23089115 TI - [Patients' preferences for information in health care decision-making]. AB - A survey was carried out among patients who concurred to cardiologic services to know how patients preferred to be informed about their health status, and the demographic characteristics associated to these preferences, considering the following items: knowledge about the disease, information about different therapeutic options and decision-making. From 770 people surveyed, 738 (95.8%) answered the form completely. A trend to trust only in the doctor's knowledge to obtain information (81.7%), in wanting to know the options of treatment and express one's point of view (85.9%), and to involve the family in the decisions (63.2%) was observed. 9.6% preferred to receive the minimum necessary information or "to know nothing" about an alleged serious disease. Males tended less to request options and give opinion on the subject (or: 0.64), giving less freedom to family involvement (or: 1.31). people with a lower social and economical level claim fewer options (or: 0.48) and gave less family participation (or = 1.79). Natives from other South American countries had a minor tendency to demand for options and express their thoughts (or: 0.60); and the ones with lower education level trusted less in the doctor's knowledge (or: 1.81), demanded fewer options (or: 0.45) and chose not to know the severity of the disease (or: 0.56). the analysis of the demographical variables allowed to define preferences associated to age, sex, origin, education, religion and health status. In conclusion, although it is imperative to promote the patient's autonomy, individual preferences must be taken into account before informing and compromising the patient in decision-making about his disease. PMID- 23089116 TI - [Staghorn calculi in DXA of lumbar spine]. PMID- 23089118 TI - [The Argentine Health System: organization and financial features]. AB - The Argentine health system is defined by the following features: a) federal country organization; b) coexistence of public and private services with either outpatients or inpatients; c) fragmented entities of social security, most of these originated outside of the state organization. Components of the system are described and weighed; making decisions strength between national and provincial health authorities is analyzed and the Argentine system is compared with that of other countries. Statistical data on distribution of health expenditures and coverage of health services are presented as well as financial flow among diverse funding sources, insurers, providers and users of each sector. PMID- 23089117 TI - [Poorly controlled asthma: diagnosis and therapeutics in children and adolescents]. AB - Asthma is one of the most common chronic diseases in children. While most children with asthma respond to low doses of inhaled corticosteroids and /or leukotriene receptor antagonists, some of them remain symptomatic regardless of any therapeutic effort, showing a high morbidity and even mortality. While most of the patients control symptoms adequately, there is a large group with severe symptoms of the disease and difficult to control. The aim of this review is to discuss the clinical aspects, diagnosis and treatment of poorly controlled asthma in children and adolescents and its implications in daily clinical practice. PMID- 23089119 TI - [Bleeding during anti-vitamin K treatment. Incidence, risk factors and comparison with the new oral anticoagulants]. AB - Bleeding is the main complication of oral anticoagulants, anti-vitamin K or new drugs such as anti-factor Xa or anti-thrombin agents. Risk factors associated with bleeding during warfarin therapy are discussed. For the new drugs no published data is available yet. Comparative frequencies of major bleeding during anticoagulation in atrial fibrillation and venous thromboembolism are shown. Beyond the intrinsic properties of the classic and new agents, patients characteristics and co-morbidities and an appropriate management of the antithrombotic therapy will be the factors associated with bleeding incidence in real life. PMID- 23089120 TI - [Hyperammonemic encephalopathy and fibrolamellar hepatocellular carcinoma]. AB - We present the case of a young woman, 22 years old, with an aggressive form of fibrolamellar hepatocellular carcinoma. She began with the signs and symptoms of a hyperammonemic encephalopathy, an uncommon form of presentation. Fibrolamellar carcinoma is a rare liver tumor, which affects young patients without previous liver disease. Its etiology is unknown, and it has been considered as a tumor with a better prognosis than the classic hepatocellular carcinoma. PMID- 23089121 TI - [Primary bone lymphoma with multicentric involvement]. AB - Primary bone lymphoma is a rare disease, which usually has a different presentation and evolution than lymphomas of other locations. We are presenting a case of primary bone lymphoma of rapid growth, in cranial and sternal locations. In its evolution, once the excision of the primary lesion of the skull was performed, the patient presented new lesions of rapid growth at the skull and femur level, and progression of pre-sternal lesion. With large B-cell diffuse non Hodgkin lymphoma pathology, the patient initiated R-CHOPP (cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab) with rapid reduction of all lesions without evidence of progression after the six cycles. PMID- 23089122 TI - [Percutaneous closure of a mitral paraprosthetic leak with an Amplatzer(r) device]. AB - Mitral paraprosthetic leaks are present in 5 to 17% of patients who receive valve replacement surgery. Overall, the defects are single, most of them are located in the postero-medial region of the annulus, and only one third produce a severe reflux. Percutaneous closure by endovascular surgery is a valid therapeutic alternative in patients at high risk for re-operation. The approach depends on the location, size, morphology and relationships or neighboring defects. The procedure must be performed by professionals with experience in the treatment of structural heart disease and in the management of these closure devices. Guidance with three dimensional transesophageal echocardiography is considered essential. A case of a mitral paraprosthetic leak that was closed with an Amplatzer(r) device introduced percutaneously from the femoral vein is here presented. PMID- 23089123 TI - [Disseminated histoplasmosis, lymphopenia and Sjogren's syndrome]. AB - Sjogren's syndrome is an autoimmune disease characterized by decreased exocrine gland secretions; patients may also present several hematological abnormalities, like lymphopenia. We describe the case of a 28 year old man who complained of headache a month of duration, with fever and vomiting in the last 48 hours. He also presented skin lesions on trunk and face, without neck stiffness. The diagnosis of duration infection was confirmed by culture from the skin biopsy and spinal fluid specimens; in addition, the presence of lymphopenia, positive anti Ro-SSA antibodies, poor concentration of the tracer in scintigraphy and lymphocytic infiltration in salivary glands confirmed the diagnosis of Sjogren's syndrome. the patient was successfully treated with liposomal amphotericin and itraconazole. We report this case to emphasize that opportunistic infections, such as disseminated histoplasmosis, may be an uncommon clinical presentation of Sjogren's syndrome. PMID- 23089124 TI - [Serendipity in investigation]. PMID- 23089125 TI - [Stem cells. Life beyond death]. PMID- 23089126 TI - [Shared care-demand management in primary care: an opportunity for nursing staff?]. PMID- 23089127 TI - [New methods of calculating staffing needs adjusted to individual departments: a possible alternative?]. PMID- 23089128 TI - [Measles in France]. AB - Measles is one of the most contagious diseases implicated in an outbreak in Western Europe for a few years. In France, the outbreak began in 2008, especially in the southern regions. Most of the cases are mild but deleterious effects can occur in infants, during the pregnancy, or in immunosuppressive patients. Pneumonia and encephalitis are the major complications in these patients. Measles illness during pregnancy results in a higher risk of premature labor, spontaneous abortion, and low-birthweight infants. Death from measles was reported in approximately 0.3% of cases. The National Reference Center for measles and paramyxoviridae is implicated in biological confirmation of cases and epidemiologic surveillance. Virologic diagnosis consists in a direct detection of viral RNA (real time PCR), or indirect detection of the immune response (IgM and IgG) in saliva samples. The measles genotype is determined by sequencing a 450 nucleotids fragment of the N gene, as the World Health Organization (WHO) recommendation. This molecular analysis helps determine the geographic origin of the virus and the viral strains circulating in the country. In 2011, 3105 specimens were received. PCR was positive for 1990 patients (64%), with a large majority of children younger than 2 years of age and young adults. The most important cause of measles resurgence is low vaccination coverage. The role of pediatricians is important in order to achieve the goal of 95% of vaccination coverage established by the WHO. PMID- 23089129 TI - Lower rate of depressive switch following antimanic treatment with second generation antipsychotics versus haloperidol. AB - BACKGROUND: Treatment of acute mania with second-generation antipsychotics has been claimed to involve a lower risk of switch to depression than haloperidol. However, clinical guidelines clearly state that this is not a proven fact. METHODS: Meta-analysis of double-blind randomized controlled trials in acute mania, comparing rates of switch to depression with atypical antipsychotics and with haloperidol. Search was conducted in MEDLINE and CENTRAL databases (last search: September 2011). RESULTS: 8 randomized clinical trials fulfilled inclusion criteria. 2 of them were excluded because of low methodological quality or lack of data. 5 second-generation antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone) were compared to haloperidol. In the mixed effects model the Risk Ratio for depressive switch was 0.71 (0.52, 0.96) favouring atypical antipsychotics. In the random effects model the difference did not reach statistical significance. In the heterogeneity analysis, exclusion of an outlying aripiprazole trial yielded a Risk Ratio of 0.58 (0.42, 0.82) with a non-significant heterogeneity test. Although no atypical antipsychotic was individually significantly superior to haloperidol, a trend could be seen favouring olanzapine (RR=0.56 [0.29, 1.08]), quetiapine (RR=0.36 [0.10, 1.33]), and ziprasidone (RR=0.51 [0.22, 1.18]). LIMITATIONS: All trials were industry supported, with some variability in dosage of haloperidol. Switch to depression was not the primary outcome of the trials. Heterogeneity could be explained as a lack of class-effect for atypicals. CONCLUSIONS: Treating acute mania with atypicals is associated to 42% less risk of switch to depression than with haloperidol. Nevertheless, caution should be taken when considering this a class effect, as only olanzapine, quetiapine, and ziprasidone may show a better profile. PMID- 23089130 TI - Mixed states with predominant manic or depressive symptoms: baseline characteristics and 24-month outcomes of the EMBLEM cohort. AB - BACKGROUND: While factors associated with mixed states have been extensively studied, data are scant regarding the clinical heterogeneity of mixed states. The EMBLEM study was a prospective, observational study on patients with manic and mixed states. We describe and compare baseline characteristics and 24-month clinical course of mixed states with predominant depressive symptoms (MSDS) and mixed states with predominant manic symptoms (MSMS). METHODS: Adult inpatients/outpatients with bipolar disorder were enrolled within the standard course of care if they initiated or changed oral medication for acute mania or mixed states. A logistic regression was used to identify the baseline factors associated with each polarity. Comparisons with mixed episode without symptom predominance (OMS) were performed for informational purpose only. RESULTS: About 573 mixed patients were analyzed (23.7% of the cohort): 59.5% (n=341) had MSMS, 11.9% (n=68) had MSDS, and 28.6% (n=164) had OMS. At baseline, hallucinations/delusions during the index episode, inpatient status, high CGI-BP overall score, and low education level were more often associated with MSMS versus MSDS. Alcohol abuse or dependence and selective serotonin reuptake inhibitor (SSRI) or benzodiazepine use at inclusion were significantly more frequent with MSDS. MSDS had a significantly lower 24-month recurrence rate than MSMS; MSMS experienced more switches to mania whereas MSDS switched more to depression. LIMITATIONS: The post hoc dimensional definitions in the study require caution in the interpretation of the results. CONCLUSION: These results present evidence of clinical heterogeneity within mixed states. Predominant manic or depressive symptoms within mixed episode could influence clinicians' decisions in term of hospitalization, treatment, and perception of bipolar severity. PMID- 23089131 TI - Modulation of trichloroethylene in vitro metabolism by different drugs in rats. AB - Trichloroethylene (TCE) is a widely used chemical to which humans are frequently exposed. Toxicological interactions with drugs are among factors having the potential to modulate the toxicity of TCE. The aim of this study was to identify metabolic interactions between TCE and 14 widely used drugs in rat suspended hepatocytes and characterize the strongest using microsomal assays (oxidation and/or glucuronidation). The concentrations of TCE and its metabolites, trichloroethanol (TCOH) and trichloroacetate (TCA), were measured by gas chromatography with injection headspace coupled to mass spectrometry (GC-MS). Results in hepatocyte incubations show that selected drugs can be segregated into four groups: group 1: drugs causing no significant interactions (five drugs: amoxicillin, carbamazepine, ibuprofen, mefenamic acid and ranitidine); group 2: increasing both TCE metabolites (two drugs: naproxen and salicylic acid); group 3: decreasing both TCE metabolites (five drugs: acetaminophen, gliclazide, valproic acid, cimetidine and diclofenac) and group 4: affecting only one (two drugs: erythromycin and sulphasalazine). Naproxen and salicylic acid (group 2) and acetaminophen, gliclazide and valproic acid (from group 3) presented the strongest interactions (i.e. drugs changing metabolite levels by 50% or more). For group 2 drugs, characterization in rat microsomes confirmed interaction with naproxen only, which was found to partially competitively inhibit TCOH glucuronidation (K(i) = 211.6 MUM). For group 3 selected drugs, confirmation was positive only for gliclazide (K(i) = 58 MUM for TCOH formation) and valproic acid (K(i) = 1215.8 MUM for TCA formation and K(i) = 932.8 MUM for TCOH formation). The inhibition was found to be partial non competitive for both drugs. Our results confirm the existence of interactions between TCE and a variety of widely used drugs. Further efforts are undertaken to determine if these interactions are plausible in humans and if they can impact the risk of toxicity of TCE in medicated population. PMID- 23089132 TI - Potential of in vitro reconstituted 3D human airway epithelia (MucilAirTM) to assess respiratory sensitizers. AB - Respiratory sensitizers are considered as substances of higher risk, at the same level as carcinogens, mutagens and toxic chemicals for reproduction. Presently, there is no validated assay for identifying the respiratory sensitizers. Based on a fully differentiated and functional in vitro cell model of the human airway epithelium, MucilAirTM, we attempt to develop such assay. To this end, we invented a novel method, using Dextran as carrier, for applying the water insoluble chemicals to the apical surface of the airway epithelia. Using the Dextran carrier method, we successfully tested some reference chemical compounds known to cause respiratory sensitisation in human beings, including MDI, TMA and HCPt. Interestingly, these chemical sensitizers differentially up-regulated the releases of certain cytokines and chemokines involved in allergic responses. We believe that based on MucilAirTM an in vitro assay could be developed for identification and characterization of the respiratory sensitizers. PMID- 23089133 TI - Glycosylceramides from marine green microalga Tetraselmis sp. AB - Glycosylceramides are ubiquitous and important components of the plasma membrane in most eukaryotic cells and a few bacteria. They play significant roles in a variety of cellular functions. Their molecular structures are well recognized in animals, higher plants, and fungi, but are poorly characterized in lower plants. In this study, a high glycosylceramide-producing microalgal strain Tetraselmis sp. NKG 400013 was found. TLC and MS analyses established the presence of glycosylceramides, GT1 and GT2, in this strain. Their chemical structures were determined by NMR spectroscopy and GC/MS, and were identified as glycosylceramides consisting of the typical botanical sphingoid base ([4E, 8E] sphinga-4, 8-dienine) and 2-hydroxy-Delta3-unsaturated fatty acyl chains, respectively. To our knowledge, the occurrence of glycosylceramides in microalga of the class Prasinophyceae was previously unknown. PMID- 23089134 TI - The biosynthesis of hydroxycinnamoyl quinate esters and their role in the storage of cocaine in Erythroxylum coca. AB - Complexation of alkaloids is an important strategy plants utilize to facilitate storage in vacuoles and avoid autotoxicity. Previous studies have implicated hydroxycinnamoyl quinate esters in the complexation of purine alkaloids in Coffea arabica. The goal of this study was to determine if Erythroxylum coca uses similar complexation agents to store abundant tropane alkaloids, such as cocaine and cinnamoyl cocaine. Metabolite analysis of various E. coca organs established a close correlation between levels of coca alkaloids and those of two hydroxycinnamoyl esters of quinic acid, chlorogenic acid and 4-coumaroyl quinate. The BAHD acyltransferase catalyzing the final step in hydroxycinnamoyl quinate biosynthesis was isolated and characterized, and its gene expression found to correlate with tropane alkaloid accumulation. A physical interaction between chlorogenic acid and cocaine was observed and quantified in vitro using UV and NMR spectroscopic methods yielding similar values to those reported for a caffeine chlorogenate complex in C. arabica. These results suggest that storage of cocaine and other coca alkaloids in large quantities in E. coca involves hydroxycinnamoyl quinate esters as complexation partners. PMID- 23089135 TI - Validation of the Italian version of the Functioning Assessment Short Test (FAST) for bipolar disorder. AB - Aim. The Functioning Assessment Short Test (FAST) is a useful instrument for the assessment of overall functioning of people with bipolar disorder, showing good psychometric properties. The aim of this study is to validate the Italian version of FAST. Methods. Translation and back-translation of the original FAST Spanish version were performed. Participants with bipolar disorder (n = 132) and healthy controls (n = 132) completed the FAST as a part of an assessment package including the Montgomery-Asberg Depression Rating Scale and the Young Mania Rating Scale. Internal consistency, inter-rater reliability, construct and discriminant validity were assessed. Results. The FAST Italian version showed good internal consistency, inter-rater reliability and discriminant validity. The cut-off discriminating patients from controls was 15, with a sensitivity of 0.79 and a specificity of 0.80. Principal component analysis with oblique rotation showed factor loadings consistent with the a priori structure of the instrument. Conclusions. This study confirmed the psychometric properties of FAST and extended its generalization and validity to the Italian population. PMID- 23089136 TI - Novel bioactive glycerol-based lysophospholipids: new data -- new insight into their function. AB - Based on the results of research conducted over last two decades, lysophospholipids (LPLs) were observed to be not only structural components of cellular membranes but also biologically active molecules influencing a broad variety of processes such as carcinogenesis, neurogenesis, immunity, vascular development or regulation of metabolic diseases. With a growing interest in the involvement of extracellular lysophospholipids in both normal physiology and pathology, it has become evident that those small molecules may have therapeutic potential. While lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) have been studied in detail, other LPLs such as lysophosphatidylglycerol (LPG), lysophosphatidylserine (LPS), lysophosphatidylinositol (LPI), lysophosphatidylethanolamine (LPE) or even lysophosphatidylcholine (LPC) have not been elucidated to such a high degree. Although information concerning the latter LPLs is sparse as compared to LPA and S1P, within the last couple of years much progress has been made. Recently published data suggest that these compounds may regulate fundamental cellular activities by modulating multiple molecular targets, e.g. by binding to specific receptors and/or altering the structure and fluidity of lipid rafts. Therefore, the present review is devoted to novel bioactive glycerol-based lysophospholipids and recent findings concerning their functions and possible signaling pathways regulating physiological and pathological processes. PMID- 23089137 TI - Maintenance and thermal stabilization of NADH dehydrogenase-2 conformation upon elimination of its C-terminal region. AB - Development of an artificial enzyme with activity and structure comparable to that of natural enzymes is an important goal in biological chemistry. Respiratory NADH dehydrogenase-2 (NDH-2) of Escherichia coli is a peripheral membrane-bound flavoprotein, belonging to a group of enzymes with scarce structural information. By eliminating the C-terminal region of NDH-2, a water soluble version with significant enzymatic activity was previously obtained. Here, NDH-2 structural features were established, in comparison to those of the truncated version. Far UV circular dichroism, Fourier transform infrared spectroscopy and limited proteolysis analysis showed that the overall structure of both proteins was similar at 30 degrees C. Experimental data agree with the predicted NDH-2 structure (PDB: 1OZK). The absence of C-terminal region stabilized in ~5-10 degrees C the truncated protein conformation. However, truncation impaired enzymatic activity at low temperatures, probably due to the weak interaction of the mutant protein with FAD cofactor. PMID- 23089138 TI - CD4 and CD8 homologues in Japanese flounder, Paralichthys olivaceus: Differences in the expressions and localizations of CD4-1, CD4-2, CD8alpha and CD8beta. AB - CD4 and CD8 molecules are co-receptors of T cell receptors which interact specifically with MHC class II and I, respectively, during antigen presentation. Here we investigated CD4 and CD8 expression patterns in a fish, Japanese flounder, Paralichthys olivaceus in response to infection and tuberculin injection. The CD4-1 mRNA level was gradually and weakly increased in trunk kidney after infection with Streptococcus iniae, Edwardsiella tarda and viral hemorrhagic septicemia virus (VHSV), while the CD4-2 mRNA level was dramatically increased after E. tarda and VHSV infection, but not increased after S. iniae infection. CD4-2 mRNA but not CD4-1mRNA increased in the kidney during tuberculin response which is mediated by memory Th1 cells. The patterns for the change of mRNA level in CD8alpha and CD8beta were similar to those of the CD4-2 during the infections and tuberculin response. Fluorescent in situ hybridization detected CD4-1 mRNAs on melano-macrophage centers and CD4-2 mRNAs at some cell clusters located near the melano-macrophage centers. CD8alpha and CD8beta mRNAs were detected at the same cell clusters in the spleen and head kidney. These results suggest that CD4-1 and CD4-2 are expressed in different cells and that CD4-2 positive cells, rather than CD4-1-positive cells, have a main role in Th1-related immune responses collaborating with CD8alpha- and CD8beta-positive cells in Japanese flounder. PMID- 23089139 TI - Bone mineral density in children and young adults with neurofibromatosis type 1. AB - Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2-24.8; mean 13.7 +/- 4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2-4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score <=-2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (-1.60 +/- 1.26) were more impaired compared with both the FN (-0.54 +/- 1.58; P=0.0003) and the whole-body BMC/height Z-scores (-1.16 +/- 0.90; P=0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (r(s)=-0.36, P=0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height. PMID- 23089140 TI - Siglec-6 is expressed in gestational trophoblastic disease and affects proliferation, apoptosis and invasion. AB - Sialic acid immunoglobulin-like lectin (Siglec)-6 is a transmembrane receptor that binds leptin. Leptin is an obesity-associated peptide hormone overexpressed in gestational trophoblastic disease (GTD). GTD encompasses several placental abnormalities that range from benign to malignant. Among GTD, molar placentas are characterized by excess proliferation, whereas gestational trophoblastic neoplasias (GTN) have characteristically aggressive invasion. We hypothesized that in GTD, Siglec-6 expression would increase with disease severity and that Siglec-6 and leptin would promote proliferation, inhibit apoptosis and/or promote invasion. Siglec-6 expression patterns were evaluated with particular attention to the diagnostic utility of Siglec-6 in GTD (controls: normal placentas (n=32), hydropic abortus placentas (n=7), non-GTD reproductive tract cancers (n=2); GTD: partial moles (PM; n=11), complete moles (n=24), GTN (n=6)). In normal placentas, Siglec-6 expression dramatically decreased after 8 weeks gestation. Complete molar placentas had significantly higher Siglec-6 expression than controls, but expression was not significantly different from PM. In GTN, Siglec-6 expression was low. These data suggest that Siglec-6 may have diagnostic utility for distinguishing complete moles from normal and hydropic abortus placentas. Functional studies in choriocarcinoma-derived BeWO cells demonstrated a complex interplay between Siglec-6 expression and leptin exposure. In cells lacking Siglec-6, leptin treatment promoted invasion, likely through interaction with LepR leptin receptor, without affecting proliferation or apoptosis. Siglec-6 expression promoted proliferation in a leptin-dependent manner, but protected cells from apoptosis and promoted invasion in a leptin-independent manner. We propose that Siglec-6 and leptin play a role in the aberrant properties characteristic of GTD, namely excess proliferation and invasion. PMID- 23089141 TI - Measuring postmortem glycated hemoglobin - A comparison of three methods. AB - Glycated hemoglobin (HbA1c) is a glycoprotein formed as a result of the non enzymatic addition of d-glucose to the hemoglobin beta-chain. The amount of HbA1c in the blood is dependent on mean glucose levels present during the 1-2 months preceding measurement, and it is an indicator of long-term glycemic levels. HbA1c is a useful marker in postmortem biochemistry in determining cause of death in acetonemic cases by allowing to distinguish diabetic ketoacidosis (DKA) from starvation or alcoholic ketoacidosis (AKA) and intoxication by acetone or isopropanol. We evaluated three methods for postmortem HbA1c measurement: Mono S cation exchange HPLC, affinity chromatography using point-of-care analyzer and a direct enzymatic method by. Additionally, optimization of sample storage and preservatives was performed and interpretation of the results in autopsy cases is discussed. Our results indicate that the HbA1c levels of postmortem samples can be reliably measured with Mono S HPLC. EDTA is the preferable preservative, as samples can be measured after as long as 4 weeks storage at +4 degrees C. Our study shows that HbA1c analysis is a valuable tool alongside glucose and ketone body analysis in determining the metabolic state of deceased persons in medicolegal autopsies. PMID- 23089142 TI - Mixture interpretation: Experimental and simulated reevaluation of qualitative analysis. AB - We present here analytical data using the 15 STR typing (Identifiler) kit regarding heterozygote balance in experimental DNA samples including one or two persons. Surprisingly, the allelic imbalance was observed even in samples consisting of only one person but adequate DNA for the standard protocol. The variance of heterozygote balance was more expanded in two-person mixtures than in one-person samples. Therefore, it is not suitable to use allelic peak heights/areas for estimating the genotypes of the contributors such as the quantitative analysis. We also reevaluated the effectiveness of qualitative analysis by simulation, i.e. consideration of the probability of all possible genotype combinations from the typing results of a mixed DNA sample. As demonstrated, the qualitative analysis using 15 STR loci is still extremely effective even in a mixture from two or three individuals. PMID- 23089143 TI - Relationship between time from ambulance call to arrival at emergency center and level of consciousness at admission in severe stroke patients. AB - INTRODUCTION: Timely access to acute medical treatment can be critical for patients suffering from severe stroke. Little information is available about the impact of prehospital delays on the clinical conditions of stroke patients, but it is possible that prehospital delays lead to neurological deterioration. The aim of this study was to examine the impact of prehospital delays related to emergency medical services on the level of consciousness at admission in patients with severe stroke. METHODS: This retrospective study assessed 712 consecutive patients diagnosed with cerebrovascular diseases who were admitted to an intensive care unit in Tokyo, Japan, from April 1998 through March 2008. Data, including the time from the call to the ambulance service to the arrival of the ambulance at the patient location (on-scene), and the time from the arrival of the ambulance on-scene to its arrival at the emergency center were obtained. The following demographic and clinical information also were obtained from medical records: sex, age, and Glasgow Coma Scale (GCS) score at admission. RESULTS: The mean time from ambulance call to arrival on-scene was 7 (SD=3) minutes, and the mean time from ambulance call to arrival at the center was 37 (SD=8) minutes. A logistic regression model for predicting GCS scores of 3 and 4 at admission was produced. After adjusting for sex, age, and time from arrival on-scene to arrival at the center, a longer call-to-on-scene time was significantly associated with poor GCS scores (OR = 1.056/min; 95% confidence interval, [CI] = 1.008-1.107). After adjusting for sex and age, a longer call-to-arrival at the center time also was significantly associated with poor GCS scores (OR = 1.020; 95% CI = 1.002 1.038). CONCLUSIONS: Prehospital delays were significantly associated with decreased levels of consciousness at admission in patients suffering from a stroke. As level of consciousness is the strongest predictor of outcome, reducing prehospital delays may be necessary to improve the outcomes in patients with severe stroke. PMID- 23089144 TI - An association of transferrin gene polymorphism and serum transferrin levels with age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a degenerative disease of the eye, triggered by the damage of the macular cells. In the Western world it is the most frequent cause of blindness in the elderly. Oxidative stress is proved to play a key role in AMD pathogenesis and since iron accumulation has been found in AMD maculas, it may accelerate the oxidative processes in this tissue. In the present work we investigated the association between four polymorphisms of the transferrin gene (rs8177178; rs8177179; rs4481157; rs1130459) and AMD in dependence on the transferrin protein and iron serum levels. We employed PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) for genotype determination, ELISA assay for serum transferrin evaluation and colorimetric assay for measurement of iron concentration in the serum. We found that advanced age and AMD family history may be independent risk factors for AMD (1.02, p < 0.05 and 8.88, p < 0.001, respectively). At the rs4481157 site The GG genotype of the rs4481157 polymorphism decreased the risk of dry AMD (OR 0.50; p < 0.05), while the GA increased this risk (OR 1.07; p < 0.05). Moreover, the GA genotype of this polymorphism decreased the risk of progression to the wet form (OR 0.63; p < 0.05). The analysis of the gene-environment interactions showed that the rs4481157 polymorphism modulates the AMD risk among obese (BMI above 30) individuals. In the former smokers group we observed a moderate association between rs4481157 polymorphism and AMD risk while this association in current smokers was stronger. We found also that the serum level of transferrin was higher in the AMD group (p < 0.001) than in the control, but the total serum iron levels did not differ between both groups. We found that the serum transferrin was associated with the rs8177178 (p < 0.001) and rs4481157 (p < 0.01) polymorphisms, and the common variant (GG) of both sites was related to a lower level of transferrin. Presented data may contribute to the involvement of iron homeostasis in AMD risk. PMID- 23089145 TI - Synthesis of S- and C-galactofuranosides via a galactofuranosyl iodide. Isolable 1-galactofuranosylthiol derivative as a new glycosyl donor. AB - The use of the easily available persilylated derivative 1 for the synthesis of C- and S-Galf derivatives has been investigated. By anomeric iodination of 1 with TMSI, followed by in situ coupling with C- and S-nucleophiles under very mild conditions and in the absence of promoters, derivatives with value as glycomimetics or as precursors of glycobiological tools were synthesized. Among them, the synthesis of the isolable 1-galactofuranosylthiol 15 is remarkable, as it paves the way for alternative approaches for S-galactofuranosyl derivatives. PMID- 23089147 TI - First report of Dirofilaria immitis in the Republic of Cape Verde. AB - In Maio Island, Republic of Cape Verde, a seven-year old mongrel female dog exhibiting severe generalized adenomegaly and a poor body condition was examined during an animal welfare campaign. A blood smear was drawn from peripheral blood collection and several organisms consistent with Dirofilaria immitis microfilariae were identified. Both the antigen test conducted from plasma and the RT-PCR test performed from the blood smear sample were positive for D. immitis. This is, to the best of our knowledge, the first report of D. immitis in Cape Verde. The fact that the dog was autochthonous and had never left the island strongly suggests there might be other animals infected with the parasite. Our finding confirms the existence of the parasite in the canine population and necessarily implies the presence of a competent vector. As a serious cardiopulmonary disease and with the risk of the pathogen spreading rapidly, broader epidemiological studies need to be conducted to determine D. immitis prevalence in the canine population of Maio Island. PMID- 23089148 TI - Cloning and characterization of a plasminogen-binding enolase from the saliva of the argasid tick Ornithodoros moubata. AB - Significant amounts of enolase have recently been found in the saliva of the argasid tick Ornithodoros moubata, raising the question as to what the function of enolase in the tick-host interface is. Enolase is a multifunctional glycolytic enzyme known to act as a plasminogen receptor on cellular surfaces, promoting fibrinolysis and extracellular matrix degradation. Fibrinolysis could be important for ticks to dissolve clots that might be formed during feeding as well as to prevent clotting of the ingested blood meal in the tick midgut. Additionally, enolase-mediated extracellular matrix degradation could contribute to the tick feeding lesion. Moreover, previous observations suggested an additional antihaemostatic role for O. moubata enolase as a P-selectin antagonist ligand. Accordingly, the aim of the present study was to investigate the potential role of the O. moubata salivary enolase as a plasminogen receptor and P selectin ligand, and to evaluate its potential as an antigen target for anti-O. moubata vaccines. The study included the cloning, sequencing and recombinant production of the O. moubata enolase, plasminogen binding and activation assays, P-selectin binding assays, animal immunization trials, and RNAi knockdown of the enolase gene. Here we confirmed that enolase is secreted to the saliva of the tick and provide convincing evidence for a role of this salivary enolase as a plasminogen receptor, most likely stimulating host fibrinolysis and maintaining blood fluidity during tick feeding. The RNAi experiments and immunization trials indicated that enolase could be also involved in the regulation of tick reproduction, suggesting new potential control strategies. Finally, the P selectin binding experiments demonstrated that this enolase is not a P-selectin ligand. PMID- 23089150 TI - One in four cases of bowel cancer in England are diagnosed only after emergency admission. PMID- 23089151 TI - Ethics committee chairwoman is not obliged to reveal source of concerns about surgeon's work, judge rules. PMID- 23089152 TI - Resting state networks in paroxysmal disorders of consciousness. AB - Functional MRI (fMRI) has transformed academic neuroscience in the last decade and is now the most widely used non-invasive functional brain imaging technique. However, it has had much less of an impact in clinical neuroscience. While a majority of fMRI applications examine brain function in response to an externally driven task, an alternative approach characterizes the brain's intrinsic functional architecture. This involves fMRI scanning in the absence of an explicit task (i.e., in the resting state) and is, therefore, much more easily performed and tolerated by neurological and neuropsychiatric patient groups. The data are easily acquired, and the functional networks extracted are reproducible and reliable. However, quantifying networks of distributed brain activity and identifying the most informative features in a particular disorder remain a challenge. Progress has been made in this direction in recent years, with the adoption of mathematical tools from communications engineering. Specific alterations to the brain's functional connectivity at rest have been observed in generalized and focal epilepsies, as well as in non-epileptic attack disorder. The challenge for the future is to exploit knowledge of how the brain works as a complex system in order to develop more accurate and sensitive diagnostic tests for neurological and neuropsychiatric disorders. PMID- 23089149 TI - Neglected tropical diseases: survey and geometry of randomised evidence. AB - OBJECTIVE: To assess the quantity and distribution of evidence from randomised controlled trials for the treatment of the major neglected tropical diseases and to identify gaps in the evidence with network analysis. DESIGN: Systematic review and network analysis. DATA SOURCES: Cochrane Central Register of Controlled Trials and PubMed from inception to 31 August 2011. STUDY SELECTION: Randomised controlled trials that examined treatment of 16 neglected tropical diseases or complications thereof published in English, French, Spanish, Portuguese, German, or Dutch. RESULTS: We identified 971 eligible randomised trials. Leishmaniasis (184 trials, 23,039 participants) and geohelminth infections; 160 trials, 46,887 participants) were the most studied, while dracunculiasis (nine trials, 798 participants) and Buruli ulcer (five trials, 337 participants) were least studied. Relative to its global burden of disease, lymphatic filariasis had the fewest trials and participants. Only 11% of trials were industry funded. Either a single trial or trials with fewer than 100 participants comprised the randomised evidence for first or second line treatments for Buruli ulcer, human African trypanosomiasis, American trypanosomiasis, cysticercosis, rabies, echinococcosis, New World cutaneous leishmaniasis, and each of the foodborne trematode infections. Among the 10 disease categories with more than 40 trials, five lacked sufficient head to head comparisons between first or second line treatments. CONCLUSIONS: There is considerable variation in the amount of evidence from randomised controlled trials for each of the 16 major neglected tropical diseases. Even in diseases with substantial evidence, such as leishmaniasis and geohelminth infections, some recommended treatments have limited supporting data and lack head to head comparisons. PMID- 23089153 TI - Redox control of teratogenesis. AB - A number of human teratogens elicit their deleterious effects through mechanisms involving the generation of reactive oxygen species (ROS) and oxidative stress. However, classic definitions of oxidative stress do not fully coincide with basic fundamental principles of teratology. Newer definitions of oxidative stress focus on the targeted redox modification of cysteine/thiol functional groups found in the regulatory domains of critical signaling pathway proteins, suggesting that the targeted disruption of signaling through specific redox couples may account for the specificity of teratogen-induced malformations which previously could not be rationalized. Here, we review examples of teratogens that induce ROS and oxidative injury, describe oxidative stress-related teratogenic mechanisms, and provide rationale for developmental periods of sensitivity and species susceptibility. Understanding how chemicals disrupt redox status, induce oxidative stress leading to dysmorphogenesis becomes important to identify potential teratogens and develop therapeutic interventions for attenuation of harmful chemical effects in utero following exposure. PMID- 23089154 TI - Behavioural treatment of tics: habit reversal and exposure with response prevention. AB - Behaviour therapy has been shown to be an effective strategy in treating tics; both habit reversal (HR) and exposure and response prevention (ER) are recommended as first-line interventions. This review provides an overview of the history, theoretical concepts and evidence at present for HR and ER. In addition, treatment manuals for HR and ER are described. Despite the evidence and availability of treatment manuals, many patients do not receive a first-line psychological intervention for tics. Barriers to the acceptance and dissemination of behaviour therapy are discussed as are ways to overcome these barriers, such as the use of E-health and E-learning. PMID- 23089155 TI - Pharmacological animal models of Tourette syndrome. AB - Pharmacological animal models of Tourette syndrome (TS) are an important tool for studying the neural mechanisms underlying this disorder. Dysfunction of the cortico-basal ganglia (CBG) system has been widely implicated in TS but the exact nature of this dysfunction is unknown. Pharmacological treatments of TS have prompted multiple hypotheses regarding the involvement of different neuromodulators in the disorder. Pharmacological manipulations in animal models were used to investigate the relationships between these neuromodulators and different symptoms of TS, including motor (tics) and non-motor (sensorimotor gating deficits) phenomena. Models initially focused on the direct effects of pharmacology on behavior, and only recently have begun providing neurophysiological data reflecting the neuronal mechanism linking the two. Animal models support the notion of CBG dysfunction as the neural mechanism underlying TS, and suggest that it may be derived from either direct deficits of local striatal GABAergic networks or a dysfunction of the neuromodulator systems controlling them. These findings can provide the much- needed conceptual construct for the TS etiology and point to new therapeutic targets. PMID- 23089156 TI - Risk factors associated with seropositivity to small ruminant lentiviruses in goat herds. AB - Cross-sectional studies based on serological testing and questionnaires were conducted at 5-yr intervals (1996, 2002 and 2007) in goat breeding herds from Poland to determine true herd-level seroprevalence of caprine arthritis encephalitis and the herd-level risk factors for seropositivity. Multivariable logistic regression models were developed for data from 1996 and the combined data from 2002 and 2007, separately. True herd-level seroprevalences in 1996, 2002 and 2007 were 30.8% (CI 95%: 20.5-41.0%), 65.7% and 71.9%, respectively. The import of goats from abroad was a risk factor only in 1996 (OR 13.6, CI 95%: 1.14 162). The presence of seropositive bucks in a herd was a risk factor in 1996 (OR 21, CI 95%: 1.89-233) and in 2002-2007 (OR 2.9, CI 95%: 1.04-8.4). Moreover, large herds (>30 does in 1996 or >100 does in 2002-2007) were more likely to be seropositive than smaller herds (OR=10.1, CI 95%: 2.17-46 in 1996 and OR 5.4, CI 95%: 1.11-26 in 2002-2007). PMID- 23089157 TI - Improvement of intestinal absorption of forsythoside A in weeping forsythia extract by various absorption enhancers based on tight junctions. AB - Forsythoside A (FTA), one of the main active ingredients in weeping forsythia extract, possesses strong antibacterial, antioxidant and antiviral effects, and its content was about 8% of totally, higher largely than that of other ingredients, but the absolute bioavailability orally was approximately 0.5%, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of absorption enhancers based on tight junctions: sodium caprate and water-soluble chitosan on the intestinal absorption of FTA, and the eventual mucosal epithelial damage resulted from absorption enhancers was evaluated by MTT test, measurement of total amount of protein and the activity of LDH and morphology observation, respectively. The pharmacological effects such as antioxidant activity improvement by absorption enhancers were verified by PC12 cell damage inhibition rate after H2O2 insults. The observations from in vitro Caco-2 cell showed that the absorption of FTA in weeping forsythia extract could be improved by absorption enhancers. Meanwhile, the absorption enhancing effect of water-soluble chitosan may be almost saturable up to 0.0032% (w/v), and sodium caprate at concentrations up to 0.64 mg/ml was safe for the Caco-2 cells, but water-soluble chitosan at different concentrations was all safe for these cells. The observations from single-pass intestinal perfusion in situ model showed that duodenum, jejunum, ileum and colon showed significantly concentration-dependent increase in P(eff)-value, and that P(eff)-value in the ileum and colon groups, where sodium caprate was added, was higher than that of duodenum and jejunum groups, but P(eff)-value in the jejunum group was higher than that of duodenum, ileum and colon groups where water-soluble chitosan was added. Intestinal mucosal toxicity studies showed no significant toxicity below 800 MUg/ml sodium caprate and water-soluble chitosan at different concentrations. In pharmacokinetics study, water-soluble chitosan at dosage of 50mg/kg improved the bioavailability of FTA in weeping forsythia extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with weeping forsythia extract with water-soluble chitosan at dosage of 50 mg/kg prevented PC12 cell damage upon H2O2 stimulation better than that of control. All findings above suggested that water-soluble chitosan at dosage of 50 mg/kg might be safe and effective absorption enhancer for improving the bioavailability of FTA and the antioxidant activity in vivo in weeping forsythia extract. PMID- 23089158 TI - The effect of percutaneous coronary intervention in patients suffering from ST segment elevation myocardial infarction complicated by out-of-hospital cardiac arrest on 30 days survival. AB - AIM OF THE STUDY: To question the beneficial effects of the recommended early percutaneous coronary intervention (PCI) after out-of-hospital cardiac arrest on 30-day survival with favourable neurological outcome. METHODS: Prospectively collected data of 1277 out of hospital cardiac arrest patients between 2005 and 2010 from a registry at a tertiary care university hospital were used for a cohort study. RESULTS: In 494 (39%) arrest patients ST-segment elevation was identified in 249 (19%). Within 12h after restoration of spontaneous circulation catheter laboratory investigations were initiated in 197 (79%) and PCI in 183 (93%) (78% got PCI in less than 180 min). Adjustment for a cumulative time without chest compressions <2 min, initial shockable rhythm, cardiac arrest witnessed by healthcare professionals, and a higher core temperature at time of hospitalization reduced the effect of PCI on favourable neurological outcome at 30 days (OR 1.40; 95% CI, 0.53-3.7) compared to the univariate analysis (OR 2.52; 95% CI, 1.42-4.48). CONCLUSION: This cohort study failed to demonstrate the beneficial effects of PCI as part of post-resuscitation care on 30-day survival with a favourable neurological outcome. PMID- 23089159 TI - Quality control in CPR: the next step forward? PMID- 23089160 TI - The nature and correlates of paid and unpaid work among service users of London Community Mental Health Teams. AB - Aims. Little is known about how the rates and characteristics of mental health service users in unpaid work, training and study compare with those in paid employment. Methods. From staff report and patient records, 1353 mental health service users of seven Community Mental Health Teams in two London boroughs were categorized as in paid work, unpaid vocational activity or no vocational activity. Types of work were described using Standard Occupational Classifications. The characteristics of each group were reported and associations with vocational status were explored. Results. Of the sample, 5.5% were in paid work and 12.7% were in unpaid vocational activity, (including 5.3% in voluntary work and 8.1% in study or training). People in paid work were engaged in a broader range of occupations than those in voluntary work and most in paid work (58.5%) worked part-time. Younger age and high educational attainment characterized both groups. Having sustained previous employment was most strongly associated with being in paid work. Conclusions. Rates of vocational activity were very low. Results did not suggest a clear clinical distinction between those in paid and unpaid activity. The motivations for and functions of unpaid work need further research. PMID- 23089161 TI - Why must we attribute our own action to ourselves? Auditory hallucination like experiences as the results both from the explicit self-other attribution and implicit regulation in speech. AB - The sense of agency, which is the awareness that "I am the one who causes action," is important in understanding passive schizophrenic symptoms and bodily self-consciousness. However, this potential linkage between subjective self-other attribution (explicit agency) and automatic self-monitoring of an action (implicit agency) has not been examined fully. The present study included two experiments conducted with the same group of healthy participants (N=48) in order to examine explicit (Exp. 1) and implicit (Exp. 2) measures of the sense of agency in speech. Exp. 1 suggested that participants who tend not to attribute a fed-back voice to themselves (the other-attribution group) might have a stronger tendency toward auditory hallucinations, as measured by the Auditory Hallucination Experience Scale 17 (AHES-17). Furthermore, the results of Exp. 2 suggested that this other-attribution group might not utilize auditory feedback during speech production, indicating the expected link between explicit and implicit agency. These results are discussed in relation to the sense-of-agency model, wherein people are understood to construct the online "self" monitoring of action. PMID- 23089162 TI - Olfactory perception in schizophrenia: the rating range for hedonic judgements is increased during acute episodes. AB - Deficits in olfactory performance have been reported in schizophrenia but results on subjective odour ratings remain unclear. Compared to controls (N=34), schizophrenia inpatients (N=34) expressed deficits concerning odour threshold, discrimination and identification but intact intensity ratings. Most interestingly, patients showed an increased rating range concerning olfactory hedonic judgements. PMID- 23089163 TI - A preliminary investigation into the influence of therapist experience on the outcome of individual anger interventions for people with intellectual disabilities. AB - BACKGROUND: There is a developing literature into Anger Management interventions for people with intellectual disability. While initial reports suggest that these interventions are effective there are few evaluations examining what aspects of the therapeutic process contribute to effectiveness. METHOD: Individuals with an intellectual disability and anger control difficulties who were referred to community psychology services were allocated to either experienced clinical psychologists or a less experienced assistant psychologist who followed the same intervention framework. RESULTS: Significant reductions in self-reported anger intensity were reported; however, the group who were treated by more experienced therapists reported more change and more individuals reported clinically significant change. CONCLUSIONS: While effective change was reported by both groups, these results suggest that clinical experience and training may be an important variable in determining the magnitude of change. This has implications for the design of intellectual disability mental health services. PMID- 23089165 TI - Ultrasonic assisted synthesis of imidazo[1,2-a]azine catalyzed by ZnO nanorods. AB - ZnO nanorods have been successfully used as an efficient, economic, and reusable catalyst for the synthesis of imidazo[1,2-a]azine under ultrasonic irradiation. This procedure offers advantages in terms of higher yields, short reaction times and mild reaction conditions. PMID- 23089166 TI - Graphene nanosheets: Ultrasound assisted synthesis and characterization. AB - A facile sonochemical route for the synthesis of graphene nanosheets via reduction of graphene oxide (GO) has been reported. The synthesized graphene sheets are characterized using UV-vis spectra, Fourier transform infra-red (FT IR) spectra, transmission electron microscope, X-ray photoelectron spectra (XPS) and Raman spectroscopic techniques. The UV-vis spectroscopy results showed that the absorption peak was red shifted due to the reduction of GO into graphene. FT IR and XPS spectra revealed the removal of oxygenated functional groups in graphene after the reduction process. Raman spectra confirmed the restoration of new sp(2) carbon domains in graphene sheets after the reduction. The sonochemical approach for the synthesis of graphene nanosheets is relatively fast, cost effective and efficient as compared to other methods. PMID- 23089164 TI - Association of intrauterine and early life factors with uterine leiomyomata in black women. AB - PURPOSE: Uterine leiomyomata (UL) are the primary indication for hysterectomy and are 2-3 times more common in black than white women. Previous studies indicate that early life may be a critical time window of susceptibility to UL. We assessed the association of UL with selected intrauterine and early life factors, expanding on previous research by using a prospective design and validated data on exposure and disease. METHODS: During 1997-2009, we followed 23,505 premenopausal women aged 23-50 years for new diagnoses of UL in the Black Women's Health Study. We used Cox regression models to compute incidence rate ratios (IRR) and 95% confidence intervals, adjusting for potential confounders. RESULTS: During 12 years of follow-up, there were 7268 incident UL cases diagnosed by ultrasound (n = 5727) or surgery (n = 1541). There was little evidence of an association between UL and birth weight, gestational age, or exposure to soy formula in infancy. Significant associations were found for being first born, foreign born, or exposed to passive smoke in childhood, but the associations were weak, with IRRs ranging from 1.06 to 1.12. CONCLUSIONS: These findings do not support the hypothesis that intrauterine and early life factors are strongly related to UL risk. PMID- 23089167 TI - [Cell-free nucleic acid-based non-invasive prenatal diagnosis of fetal aneuploidies]. AB - Prenatal detection of fetal aneuploidies is one of the main goals of the prenatal diagnostic approach. As a benefit of the development of advanced ultrasound equipment and advances in molecular biology in the last decade, there is a significant progress in screening methods for fetal aneuploidies, although invasive methods remain the gold standard for aneuploidy detection. Non-invasive prenatal diagnosis has substantial medical impact as it targets the development of safer and more effective methods to avoid the risk of fetal loss associated with currently used invasive methods. Identification of fetal-specific messenger ribonucleic acids, digital polymerase chain reaction and next-generation sequencing give the real chance for non-invasive prenatal diagnosis of fetal aneuploidies. Although all these methods have both advantages and limitations, some of them are moving closer to clinical implementation. In this review the authors highlight the most recent advances in methods for non-invasive prenatal diagnosis of aneuploidies. PMID- 23089168 TI - [The past, present and future of food consumption databases]. AB - Results of the food consumption surveys are utilized in many areas, such as for example risk assessment, cognition of consumer trends, health education and planning of prevention projects. Standardization of national consumption data for international comparison is an important task. The intention work began in the 1970s. Because of the widespread utilization of food consumption data, many international projects have been done with the aim of their harmonization. The present study shows data collection methods for groups of the food consumption data, their utilization, furthermore, the stations of the international harmonization works in details. The authors underline that for the application of the food consumption data on the international level, it is crucial to harmonize the surveys' parameters (e.g. time of data collection, method, number of participants, number of the analysed days and the age groups). For this purpose the efforts of the EU menu project, started in 2012, are promising. PMID- 23089169 TI - [Clinical evaluation of the renin-aldosterone system: comparison of two methods in different clinical conditions]. AB - INTRODUCTION: Measurement of plasma aldosterone/renin ratio is the key step in the diagnosis of primary aldosteronism. AIM: The aim of the authors was to analyze and compare the diagnostic utility of plasma aldosterone/renin activity and plasma aldosterone/renin concentration ratios. METHODS: Plasma aldosterone and plasma renin activity were determined by radioimmunoassays and plasma renin concentration was measured by immunoradiometric assay in 134 subjects (80 women and 54 men, aged 46+/-15.5 years) including 49 healthy blood donors (control group), 59 patients with hypertension (25 treated and 34 untreated) and 26 patients with incidentally discovered adrenal adenomas. RESULTS: There was a weak correlation (r = 0.59) between plasma renin activity and plasma renin concentration in the lower range (plasma renin activity, 0.63+/-0.41 ng/ml/h; plasma renin concentration, 8.1+/-4.9 ng/l). Considering the cut-off value of plasma aldosterone/renin ratios determined in controls (plasma aldosterone/renin activity ratio, 30 ng/dl/ng/ml/h; plasma aldosterone/renin concentration ratio, 3.0 ng/dl/ng/l), high proportion of falsely positive results were found among patients on beta-receptor blocker therapy (plasma aldosterone/renin activity ratio, 22.2%; plasma aldosterone/renin concentration ratio, 44.4%) CONCLUSION: The widely used plasma aldosterone/renin activity ratio can only be replaced with plasma aldosterone/renin concentration ratio with precaution on different clinical conditions. PMID- 23089170 TI - [Assessment of multicultural sensitivity in patient care, based on a survey]. AB - INTRODUCTION: The internationalization of societies and the processes of globalization raise new challenges towards health provision systems, including professional, ethical, social, cultural and communicational references of nursing and nursing education. AIMS: In this study the authors wanted to answer the following question: To what extent are health care professionals aware of and able to respond to the new challenges? METHODS: As an investigation method, the authors used a questionnaire and made a comparative analysis of answers related to the knowledge, skills and attitude of BSc nurses and other health professionals who possess a secondary qualification. The questionnaire was compiled based on the internationally accepted and validated Transcultural Self Efficacy Test. With the permission of the authors of the test, some questions were adapted to the national conditions. The responses were evaluated by statistical methods. RESULTS: There were better results in the components of skills and attitude of BSc nurses but there was a very high number of professionals in both groups who either failed to have or could not meet the requirements and phenomena related to intercultural skills. CONCLUSIONS: The survey performed among nurses proved that there is a real demand for intercultural skills and knowledge related to expectations of the society. In order to improve the quality of health care, the development of these skills is necessary. PMID- 23089171 TI - [Treatment of pretibial myxoedema with pentoxifylline]. AB - Pretibial myxoedema is a rare symptom of Graves' disease. Histological studies detected mucopolysaccharide and glycosaminoglycan accumulation, and the role of anti-TSH receptor antibodies has been suggested. In this paper the authors present the case of a 34-year-old male patient with pretibial myxoedema treated successfully with pentoxifylline. In his case history multiple autoimmune diseases (type 1 diabetes mellitus, Graves' disease with severe ophthalmopathy) concomitantly occurred. His severe pretibial myxoedema was undiagnosed and untreated at the time of admission. Because of his diabetes, steroid was contraindicated, which made the choice of the treatment more difficult. He received first intradermal, then intravenous and, finally, oral pentoxifylline, which resulted in a regression of the dermatological symptoms. The beneficial effect of pentoxifylline might be explained by its inhibitory effect of proinflammatory cytokines and proliferation of fibroblasts, and the production of glycosaminoglycan. It was concluded that pentoxifylline can be an effective and safe treatment of pretibial myxoedema. PMID- 23089173 TI - Synthetic carbohydrate research based on organic electrochemistry. AB - Development of a novel method for generating glycosyl cations or their equivalents is highly desired, because such intermediates are crucial for developing stereoselective glycosylations in oligosaccharide syntheses. In this review we focus on electrochemical methods that we have recently developed. The anodic oxidation of thioglycosides is effective for generating glycosyl triflate pools, which react with glycosyl acceptors. The reaction of glycosyl triflate pools with diorganosulfides gives glycosyl sulfonium ions, which also serve as effective glycosylation intermediates. The indirect electrochemical method is effective for the generation of glycosyl cations or their equivalents and the use of a flow-microreactor system enables glycosylation using such intermediates. PMID- 23089174 TI - Delayed diagnosis of white phosphorus burn. PMID- 23089175 TI - The effects of botulinum toxin A on mast cell activity: preliminary results. PMID- 23089176 TI - A four arm, double blind, randomized and placebo controlled study of pregabalin in the management of post-burn pruritus. AB - Post-burn itch is a distressing symptom in burns rehabilitation and its treatment often proves frustrating for the patient and the multidisciplinary burns team. Traditionally, the mainstay of antipruritic therapy for decades has been antihistamines and massage with emollients. With a better understanding of the neurophysiology of itch emerged a new dimension in the treatment of post-burn pruritus. Gabapentin, a centrally modulating anti-epileptic agent and alpha2delta ligand, proved in clinical trials to be immensely better in the treatment of post burn pruritus. Pregabalin is a newer structural analog of gabapentin. It has a much better anxiolytic effect and pharmacokinetic profile as compared to gabapentin. The current study was initiated to specifically study the role of pregabalin in relieving post-burn itch as this has never been investigated before. This double blind, randomized and placebo controlled study had four arms and was carried out on 80 adult patients (20 each). The four arms were: pregabalin, cetirizine with pheniramine maleate, combination of pregabalin, cetirizine and pheniramine maleate, and placebo (vit. B comp.). Massage with coconut oil was integral to all groups. Drug dosage was determined by initial VAS (visual analog scale) scores. All groups matched in demographic data and initial VAS scores. VAS scores were evaluated over next 28 days (days 3, 7, 14, 21 and 28). In patients with mild itch (VAS scores 2-5) or moderate itch (VAS scores 6 8) near complete remission of itch was seen in combination group and pregabalin group where the response was comparable and close to 95%. This was significantly better response than antihistaminic combination or massage alone. However, massage alone was sufficient in decreasing mean scores in mild itch, in a large percentage of patients. Amongst the patients with severe itch (VAS scores 9-10), 3/6 and 6/7 patients dropped out of trial in the antihistaminic and placebo groups, respectively. Combination therapy and pregabalin alone had exactly similar decrease in itch scores by day 28 (78.9%). This far exceeded the response in the antihistaminic and placebo groups (23.9% and 9.2% respectively). We conclude that moderate to severe pruritus (VAS 6-10) should be treated with a systemic, centrally acting agent like pregabalin or gabapentin to eliminate itch or bring it down to tolerable limits. Patients with mild itch having VAS scores between 4 and 5 may be better served with addition of pregabalin even if massage and antihistaminics can control post-burn itch to a reasonable extent because of quicker, predictable and complete response, along with anxiolysis. PMID- 23089177 TI - UDP-N-acetylglucosamine transporter and UDP-galactose transporter form heterologous complexes in the Golgi membrane. AB - UDP-galactose transporter (UGT; SLC35A2) and UDP-N-acetylglucosamine transporter (NGT; SLC35A3) are evolutionarily related. We hypothesize that their role in glycosylation may be coupled through heterologous complex formation. Coimmunoprecipitation analysis and FLIM-FRET measurements performed on living cells showed that NGT and UGT form complexes when overexpressed in MDCK-RCA(r) cells. We also postulate that the interaction of NGT and UGT may explain the dual localization of UGT2. For the first time we demonstrated in vivo homodimerization of the NGT nucleotide sugar transporter. In conclusion, we suggest that NGT and UGT function in glycosylation is combined via their mutual interaction. PMID- 23089178 TI - Sim3 shares some common roles with the histone chaperone Asf1 in fission yeast. AB - An H3/H4 histone chaperone, Asf1, plays an essential role in maintaining genomic stability in many species, including fission yeast. Here, we showed that overexpression of a CENP-A chaperone Sim3 suppressed the temperature sensitive phenotype of asf1-33 and asf1-30 mutants and the defect in chromatin structure, and prevented the accumulation of DNA damage in asf1-33 mutants at high temperatures. Furthermore, asf1-33 and Deltasim3 were synthetic lethal. Consistent with this, shutdown of sim3 expression in asf1-33 Deltasim3 double mutants that contained extragenic sim3 resulted in growth retardation. In addition, the Deltasim3 mutant displayed sensitivity to thiabendazol and hydroxyurea, which suggests that Sim3 plays a general role in maintaining chromatin structure. Our results suggest a possibility that Sim3 functions as a histone chaperone. PMID- 23089179 TI - "eta6"-Type anion-pi in biomolecular recognition. AB - Theoretical and compelling experimental evidence indicates that the interaction between an anion and an aromatic pi system when the anion is directly above the ring face ("eta(6)"-type anion-pi), can be attractive. This may play an important role in the formation and recognition of biomolecular structures. We examined high-resolution structures of proteins and nucleic acids for the presence of "eta(6)"-type anion-pi. Though less frequent than its counterpart cation-pi, "eta(6)"-type anion-pi is observed unambiguously, occurring in protein/nucleic acid loops and often involving conserved/coevolving sites in proteins, suggesting it plays an important role in macromolecular folding and function. PMID- 23089180 TI - Heme incorporation into the cytochrome bo3 occurs at a late stage of assembly. AB - Respiratory complexes in both prokaryotes and eukaryotes contain multiple co factors, which are coordinated in defined positions so that they can function as electron wires. Intriguingly, co-factors are usually buried deep within hetero oligomeric protein complexes and it is not clear when or how they are incorporated. In this study we show that heme is incorporated into the cytochrome bo(3) complex of Escherichia coli at a late stage of assembly. Specifically the apo-form of subunit I (the catalytic subunit) interacts with subunits III and IV before accepting heme. Assembly of subunit II is stalled until heme is incorporated. PMID- 23089181 TI - Ligand binding and conformational states of the photoprotein obelin. AB - Many proteins require a non-covalently bound ligand to be functional. How ligand binding affects protein conformation is often unknown. Here we address thermal unfolding of the free and ligand-bound forms of photoprotein obelin. Fluorescence and far-UV circular dichroism (CD) data show that the various ligand-dependent conformational states of obelin differ significantly in stability against thermal unfolding. Binding of coelenterazine and calcium considerably stabilizes obelin. In solution, all obelin structures are similar, except for apo-obelin without calcium. This latter protein is an ensemble of conformational states, the populations of which alter upon increasing temperature. PMID- 23089182 TI - Comparison of methods for the microbiological identification and profiling of Cronobacter species from ingredients used in the preparation of infant formula. AB - Cronobacter spp. (formerly Enterobacter sakazakii) can be isolated from a wide range of foods and environments, and its association with neonatal infections has drawn considerable attention from regulatory authorities. The principle route of neonatal infection has been identified as the ingestion of contaminated infant formula. A number of methods have been developed to identify Cronobacter spp., however these were before the most recent (2012) taxonomic revision of the genus into seven species. In this study, phenotyping, protein profiling and molecular methods were used to identify Cronobacter strains which had been recently isolated from ingredients used in the preparation of infant formula. Pulsed field gel electrophoresis revealed that different Cronobacter strains had been recovered from the same food products. All isolates were identified as Cronobacter sakazakii according to four genus specific PCR-probes and protein profiling using MALDI-TOF analysis. However, 16S rDNA sequence analyses and fusA allele sequencing gave more accurate identification: four strains were C. sakazakii, one strain was Cronobacter malonaticus and the remaining strain was Cronobacter universalis. Multilocus sequence typing showed the strains were different sequence types. These results demonstrate the presence of different Cronobacter species in food ingredients used in the preparation of infant formula, and also the need for molecular identification and profiling methods to be revised according to taxonomic revisions. PMID- 23089183 TI - Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study. AB - To evaluate the efficacy and toxicity of reduced-intensity conditioning (RIC) combining fludarabine, low-dose total body irradiation (TBI) and rituximab before allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leucocyte antigen (HLA) identical siblings, we conducted a prospective study in patients <=65 years old with advanced chronic lymphocytic leukemia (CLL) stage B or C in response after a salvage treatment. Conditioning included rituximab (375 mg/m2 on day 5), fludarabine (30 mg/m2 from day 4 to day 2), TBI (2 Gy on day 0), and rituximab (500 mg/m2 on days 1 and 8). Forty patients were included, 34 (85%) were male with a median age of 54 years (range, 35-65 years), 38 (95%) were in B stage, and 2 were in stage C; only 7 patients (17%) were in complete response. Seven (17%) patients did not receive rituximab. Thirty-nine (98%) patients engrafted, 17 patients developed acute graft-versus-host disease (GVHD) grade >=II with a cumulative incidence at 3 months of 44% (36-52) with a significant protective effect of rituximab (p = 0.02). The cumulative incidence of chronic GVHD was 29% (21-36) at 12 months for both limited and extensive forms. The median overall survival was not reached with 5-years probability of 55% (41-74). The multivariate analysis showed a positive effect of rituximab on overall survival and event-free survival (hazard ratio [HR] = 0.1 [0-0.6], p = 0.02; and HR = 0.1 [0-0.4], p = 0.035, respectively). The association of fludarabine, TBI, and rituximab is feasible, well tolerated, and allows better outcomes in advanced CLL. PMID- 23089184 TI - [Amniotic fluid embolism: a case history over the last 10 years]. PMID- 23089185 TI - [Impact on the implementation of patient controlled epidural analgesia for pain management during labor. A survey in a university hospital in Chile]. AB - OBJECTIVE: Analgesia for labor is a legal obligation in Chile. In our institution we implemented patient controlled analgesia for pain relief during labor. We describe the perception of the several professionals involved in the medical care of patients in labor in terms of effectiveness, usefulness, satisfaction, and safety. MATERIAL AND METHODS: A self-reported questionnaire was given to the professionals involved, and the obstetrical and neonatal outcomes were recorded along with the workload indices. Twenty-five structured questions were presented with a Likert type score to evaluate analgesia quality, workload of professionals involved, adverse effects, patient satisfaction, and healthcare workers satisfaction. Finally, a question was asked about the overall perception. RESULTS: We found that the overall perception of the analgesic technique was (mean) 6.0 (SD) (0.88). A decrease in the anesthesiologist workload was observed, without affecting obstetric outcomes. CONCLUSION: Considering the study design limitations, absence of knowledge of economical impact, and the satisfaction level of patients under standard epidural analgesia, we recommend the patient controlled analgesia technique due to its good obstetric outcomes, general satisfaction and workload decrease. PMID- 23089188 TI - Prolonged burst as a new method for cardioverter-defibrillator testing. AB - AIM: To find out whether it is possible to anaesthetize patients safely without analgesia and sedation, using burst pacing prolonged until the patient becomes unconscious. METHODS: One hundred and four patients undergoing implantation or reimplantation of a cardioverter-defibrillator were included. Patients randomized into Group B underwent prolonged burst pacing without analgesia and sedation. Patients in Group T underwent a T-wave shock under analgesia and sedation. Blood samples for measurement of serum neuron-specific enolase were taken before surgery and 6, 24, and 48 h after the procedure. RESULTS: From the 104 patients, 51 were randomly assigned to Group B and 53 to Group T. Four patients from Group B were switched to Group T (ventricular fibrillation not induced by burst pacing). The clinical characteristics of both groups were similar. The mean total time of cardiac arrest was significantly longer in Group B (23.0 +/- 4.4 s, median 22.7) vs. Group T (10.3 +/- 3.0 s, median 10.0), P < 0.0001 (Mann-Whitney U-test). The effectiveness of both induction methods was similar (92.1% in Group B and 100% in Group T). The mean neuron-specific enolase levels after 6, 24, and 48 h were similar in Groups B and T (13.1 +/- 6.3 and 11.6 +/- 5.8 mg/L, 14.5 +/- 7.5 and 13.4 +/- 6.0 mg/L, and 14.9 +/- 5.9 and 12.2 +/- 6.0 mg/L, respectively) as were these levels compared with baseline neuron-specificenolase levels (14.0 +/- 5.9 and 13.4 +/- 4.0 mg/L, respectively), P = NS for all. CONCLUSION: Despite a longer time of total cardiac arrest, prolonged burst pacing appears to be a safe and effective method for induction of ventricular fibrillation during cardioverter-defibrillator testing, which enables omission of analgesia and sedation or general anaesthesia. PMID- 23089186 TI - Age dependent increase in prostaglandin pathway coincides with onset of ovarian cancer in laying hens. AB - Chronic inflammation has been linked to cancer. Prostaglandin E2 (PGE2) is the most pro-inflammatory lipid and one of the downstream products of 2 isoforms of cyclooxygenase (COX) enzymes: COX-1 and COX-2. Ovarian cancer is the most lethal gynecological malignancy and mainly occurs in older women. The factors that contribute to the correlation of age and ovarian cancer are unknown. The purpose of this study was to examine the expression of COX enzymes and PGE2 levels in ovaries and correlate them to ovarian cancer and aging. White Leghorn hens aged 1, 1.5, 2, 2.5, 3 and 3.5 years were used. The incidence of ovarian cancer was determined by gross pathology and histology. COX-1 and COX-2 protein and mRNA expression and PGE2 concentrations in ovaries were measured using Western blot, quantitative real-time PCR and ELISA, respectively. Our results indicated an increase in ovarian cancer incidence and expression of both COX enzymes in ovaries of older hens. In correlation with ovarian cancer incidence and COX enzymes expression, PGE2 concentrations were elevated with age. Ovaries with tumor had elevated COX-1 expression and PGE2 concentration compared to normal ovaries. Our findings suggest that the up-regulation of COX enzymes with age is the main contributing factor in the age associated increase in PGE2. Furthermore, elevated PGE2 in ovaries of hens concomitant with age suggests its important role in early stages of ovarian carcinogenesis. These finding may provide the basis for clinical trials utilizing COX specific inhibitors or dietary intervention targeting prostaglandin biosynthesis for the prevention and treatment of ovarian cancer. PMID- 23089189 TI - National Institute for Clinical Excellence guidelines on the surgical management of otitis media with effusion: are they being followed and have they changed practice? AB - OBJECTIVE: UK National Institute of Clinical Excellence (NICE) guidelines on surgical management of otitis media with effusion (OME) in children call for an initial 3 month period of observation, with ventilation tube (VT) insertion considered for children with persistent bilateral OME with a hearing level in better ear of 25-30 dB HL or worse ("core criteria"), or for children not meeting those audiologic criteria but when OME has significant impact on developmental, social or educational status (exceptional circumstances). We aimed to establish whether guidelines are followed and whether they have changed clinical practice. METHODS: Retrospective case-notes review in five different centres, analysing practice in accordance with guidelines in all children having first VT insertion before (July-December 06) and after (July-December 08) guidelines introduction. RESULTS: Records of 319 children were studied, 173 before and 146 after guidelines introduction. There were no significant differences in practice according to guidelines before and after their introduction with respect to having 2 audiograms 3 months apart (57.8 vs. 54.8%), OME persisting at least 3 months (94.8 vs. 92.5%), or fulfilment of the 25 dB audiometric criteria (68.2 vs. 61.0%). Practice in accordance with the core criteria fell significantly from 43.9 to 32.2% (Chi squared p=0.032). However, if the exceptional cases were included there was no significant difference (85.5 vs. 87.0%), as the proportion of exceptional cases rose from 48.3 to 62.2% (Chi squared p=0.021). CONCLUSION: This study shows that 87.0% of children have VTs inserted in accordance with NICE guidelines providing exceptional cases are included, but only 32.2% comply with the core criteria. A significant number have surgery due to the invoking of exceptional criteria, suggesting that clinicians are personalising the treatment to each individual child. PMID- 23089190 TI - To drain or not to drain - management of pediatric deep neck abscesses: a case control study. AB - Optimal management of deep neck abscesses has been the subject of debate for more than a century: surgical drainage has been the mainstay of treatment, but recently many centres have reported successful non-operative management in selected cases. OBJECTIVES: Our objective was to review the management of deep neck abscesses in our institution and to identify characteristics that would predict successful non-operative management. METHODS: A retrospective chart review from January 2001 to August 2010 was performed. Children up to age fifteen years with a CT-confirmed diagnosis of retropharyngeal or parapharyngeal abscess were included. A case-control study of small deep space neck abscesses (<= 25 mm maximal diameter) was performed, comparing antibiotic treatment alone with antibiotics plus abscess drainage. RESULTS: 54 children met the inclusion criteria, of whom half had abscesses <= 25 mm diameter. Younger children within the group with smaller abscesses were more likely to need surgical drainage (p<0.05). Of 13 children requiring operative management, ten underwent a period of antibiotic treatment and observation prior to surgery, eight (80%) had fever beyond 48 h compared with three (23%) in the non-surgical group (p<0.01). 27 children had an abscess > 25 mm diameter on CT scan, four (15%) of whom responded quickly to antibiotics and were managed non-operatively, while the rest underwent surgery. There were no significant differences between the surgical and non surgical group characteristics with larger abscesses. CONCLUSION: High dose intravenous antibiotics are an effective treatment for deep space neck abscesses and may obviate the need for surgical drainage, particularly in smaller abscesses. Children who do not respond quickly to antibiotics are more likely to require surgery to achieve resolution. Children with larger abscesses may respond to antibiotic therapy alone but should be closely observed. A trial of high dose intravenous antibiotics in stable children with close observation is warranted as first line treatment, especially for small deep space neck abscesses. PMID- 23089191 TI - Emergency department staff views and experiences on diagnostic overshadowing related to people with mental illness. AB - Aims. To investigate recognition of diagnostic overshadowing, i.e., misattribution of physical symptoms to mental illness, among emergency medicine professionals; further, to identify contributory and mitigating factors to diagnostic overshadowing. Methods. In-depth individual interviews of 25 emergency department clinicians and qualitative analysis using thematic analysis. Results. Diagnostic overshadowing was described as a significant issue. Contributing factors included: (1) problems of knowledge and information gathering; (2) clinicians' attitudes toward people with mental illness, substance misuse and frequent attenders; and (3) difficulties in working with mental health services in the context of a 4-h target for discharge from the emergency department. Avoidance of patients with a psychiatric diagnosis was also described, due to fear of violence. Conclusion. The physical health care of people with mental illness in emergency departments may be adversely affected by diagnostic overshadowing and avoidance by clinical staff, along with difficulties created by the illness, medication and the emergency department environment. Greater joint working between psychiatric and emergency department staff is suggested as one way to reduce diagnostic overshadowing. PMID- 23089192 TI - Impaired decision-making as a young adult outcome of girls diagnosed with attention-deficit/hyperactivity disorder in childhood. AB - We examined decision-making in young adulthood in a follow-up study of females diagnosed with attention-deficit/hyperactivity disorder (ADHD) between 6 and 12 years. Participants with childhood ADHD (n = 114) and matched comparison females (n = 77), followed prospectively for 10 years, performed the Iowa Gambling Task (IGT) at ages 17-25 years. This task assesses preference for high-reward/high risk chances that result in lower overall gains (disadvantageous decks of cards) compared to low-reward/low-risk chances that result in higher overall gains (advantageous decks of cards). Relative to comparison participants, young adult females with a history of ADHD did not increase their preference for advantageous decks across time blocks, suggesting difficulties in learning to change behavior over the course of the IGT. Overall, childhood diagnoses of ADHD were associated with disadvantageous decision-making in young adulthood. These results extend findings on decision-making in males with ADHD by demonstrating comparable levels of impairment in an all-female sample. PMID- 23089193 TI - A panel analysis of the strategic association between information and communication technology and public health delivery. AB - BACKGROUND: In this exploratory research, we use panel data analysis to examine the correlation between Information and Communication Technology (ICTs) and public health delivery at the country level. OBJECTIVE: The goal of this exploratory research is to examine the strategic association over time between ICTs and country-level public health. METHODS: Using data from the World Development Indicators, we construct a panel data set of countries of five different income levels and look closely at the period from 2000 to 2008. The panel data analysis allows us to explore this dynamic relationship under the control for unobserved country-specific effects by using a fixed-effects estimation method. In particular,, we examine the association of five ICT factors with five public health indicators: adolescent fertility rate, child immunization coverage, tuberculosis case detected, life expectancy, and adult mortality rate. RESULTS: First, overall ICTs' factors substantially improve a country's public health delivery on the top of wealth effect. Second, among all the ICTs' factors, accessibility is the only one that is associated with improvements in all aspects of public health delivery, while the contributions from the usage, quality, and applications are negligible. ICTs' accessibility factor is associated with a considerable extension to life expectancy and reduced adult mortality rate. Third, all entity-specific factors are significant in each model, indicating that countries' economic development level does influence their public health delivery. CONCLUSIONS: Our results indicate that ICT accessibility has a strong association with effective delivery of public health. There are others, but the key strategic applications are eHealth and mHealth. The findings of this study will help government officials and public health policy makers to formulate strategic decisions regarding the best ICT investments and deployment. For example, the study shows that providing accessibility should be a critical focus. PMID- 23089194 TI - Thymic alterations induced by Plasmodium berghei: expression of matrix metalloproteinases and their tissue inhibitors. AB - The thymus plays a crucial role in the generation of T-cells, and so our laboratory has been interested in the study of the intrathymic events that occur during infection diseases and may cause disruption in its functions. Previously, we showed that thymus from experimentally Plasmodium berghei-infected mice present histological alterations with high levels of apoptosis, changes in cell migration-related molecules, and premature egress of immature thymocytes to periphery. In addition, parasites were found inside the thymus. In this work we investigated alterations in the expression pattern and activity of matrix metalloproteinases MMP-2 and -9, and their tissue inhibitors, TIMP-1 and TIMP-2. Our results show enhanced expression and widespread distribution of these molecules in thymus from infected animals. Also, the presence of active MMP-2 was detected. These data are suggestive of MMPs and TIMPs importance in the earlier observed changes in the extracellular matrix during thymic alterations after plasmodium infection. PMID- 23089196 TI - Impact of beta 2-microglobulin on tapasin expression and covalent association. AB - Cellular immunity is dependent on major histocompatibility complex (MHC) class I molecules enabling cytotoxic T cell recognition of malignant and infected cells. Loading of antigenic peptides onto MHC class I is assisted by a peptide-loading protein complex including tapasin. We found that tapasin expression is enhanced by beta 2-microglobulin via both transcriptional and post-transcriptional mechanisms. In addition, using conditions which preserve the tapasin-ERp57 disulfide-bonded conjugate, we demonstrated that beta 2-microglobulin increases tapasin-containing protein complexes, and reduces the level of MHC class I/ERp57 complexes lacking tapasin. Overall, our results provide a new perspective on the regulation of tapasin expression and association. PMID- 23089197 TI - A novel placebo-controlled clinical study design without ethical concerns - the free choice paradigm. AB - All doubled-blinded and placebo-controlled randomized drug trials carry the ethical limitation that up to 50% of patients are treated by an inert placebo pill for a prolonged period of time, and that treatment effects of the drug have to be separated from unspecific (placebo) effects that also occur in the drug arm of the treatment. We propose the "free choice paradigm" (FCP) as an alternative. It allows patients to choose between two pills identical in shape and colour of which one is the drug and the other is the placebo (in a double-blinded fashion), and drug efficacy is assessed as the difference in the number of events (days) one pill is chosen over the other. Advantages as well as disadvantages and limitations of the FCP still need to be assessed, as need the computational statistics to demonstrate superiority of drug over placebo. Ethical limitations are, however, minimized. PMID- 23089195 TI - Context and location dependence of adaptive Foxp3(+) regulatory T cell formation during immunopathological conditions. AB - Circulating Foxp3(+) regulatory T cells (Treg) may arise in the thymus (natural Treg, nTreg) or through the adaptive upregulation of Foxp3 after T cell activation (induced Treg, iTreg). In this brief review, we explore evidence for the formation and function of iTreg during pathologic conditions. Determining the ontogeny and function of Treg populations has relied on the use of manipulated systems in which either iTreg or nTreg are absent, or lineage tracing of T cell clones through repertoire analyses. iTreg appear particularly important at mucosal interfaces. iTreg can also ameliorate tissue-specific autoimmunity and are a prominent source of tumor-infiltrating Treg in some models. However, under many conditions, including in CNS autoimmunity, diabetes, and some tumor systems, iTreg formation appears limited. The immunological contribution of iTreg is thus highly context dependent. Deciphering immune parameters responsible for iTreg formation and their role in modulating pathologic immune responses will be important. PMID- 23089198 TI - Early relapse in alcohol dependence may result from late withdrawal symptoms. AB - Alcohol dependence has two distinct clinical features: (1) Physiological Dependence (PD), which characterizes the pharmacological tolerance that alcohol progressively induces in the brain and (2) Alcohol Addiction (AA), which is the behavioral conditioning of alcohol drinking resulting from the chronic activation of the reward system. PD results from a progressive imbalance between excitatory and inhibitory neurotransmission systems and leads to the occurrence of Alcohol Withdrawal Syndrome (AWS), which is prevented by benzodiazepines in cases of alcohol cessation. AA is considered to persist much longer and results from a disruption of the dopaminergic mesolimbic pathway, which is treated by anticraving drugs. Relapse in alcohol dependence is usually considered to be the result of AA. However, 50% of the relapses in alcohol occur within the first month after alcohol cessation. During this period, it has been shown that many patients experience anxious symptoms that have been neurobiologically related to withdrawal symptoms and PD. Thus, we hypothesize that early relapses are more the consequence of late symptoms of PD than AA. From this standpoint, we propose that prolonged treatment with benzodiazepines may reduce the first-month relapse rate. PMID- 23089199 TI - Warfarin-antibiotic interactions in older adults of an outpatient anticoagulation clinic. AB - BACKGROUND: Several classes of drugs, such as antibiotics, may interact with warfarin to cause an increase in warfarins anticoagulant activity and the clinical relevance of warfarin-antibiotic interactions in older adults is not clear. OBJECTIVE: The aim of this study was to determine the effect of oral antibiotics, such as amoxicillin, azithromycin, cephalexin, ciprofloxacin, levofloxacin, and moxifloxacin, on the international normalized ratio (INR) in patients >=65 years on stable warfarin therapy. The secondary objective was to compare the effect of warfarin-antibiotic interactions on outcomes of overanticoagulation. METHODS: Data for this retrospective cohort study were collected through a medical record review of patients in an outpatient anticoagulation clinic of a Veterans Affairs medical center. Patients aged >=65 years on stable warfarin therapy and with at least 1 prescription of an oral antibiotic of interest during the period from January 1, 2003 to March 1, 2011 were included. A mixed-effects repeated-measures ANOVA model was used to determine the effect of antibiotics on the mean change in patients' INR. The Fisher exact test was used to determine the association between the antibiotics and secondary outcomes of overanticoagulation, using cephalexin as the control. Statistical significance was defined as a P value <0.05. RESULTS: A total of 205 patients had 364 prescriptions for warfarin and antibiotics concomitantly, and there was a significant interaction between antibiotic and time (F(15, 358) = 1.9; P = 0.0221). Antibiotics with a significant increase in INR were amoxicillin (P = 0.0019), azithromycin (P < 0.0001), ciprofloxacin (P = 0.002), levofloxacin (P < 0.0001) and moxifloxacin (P < 0.0001). There was a significant association between type of antibiotic and secondary outcomes of overanticoagulation. CONCLUSIONS: In older patients on stable warfarin therapy, antibiotics may lead to an increase in INR. However, this may not result in clinically significant outcomes of bleeding or hospitalization, suggesting that antibiotics may be prescribed for older adults taking warfarin as long as their INR is being routinely monitored. PMID- 23089200 TI - Cu(II) removal from aqueous solution by ureolytic mixed culture (UMC). AB - The study describes the sorption of living ureolytic mixed culture (UMC) to remove Cu(II) from aqueous solution under various conditions. The effects of various parameters such as optimum biomass, contact time, and Cu(II) concentrations on Cu(II) removal efficiency were investigated. The process was investigated using concentrations of Cu(II) ions ranging from 1 to 200 mg/L in equilibrium batch tests for Langmiur, D-R, and Freundlich isotherm models. The maximum removal efficiency of 99% was obtained a 1 g/L solid-to-liquid ratio with 1-min contact time for 100 mg/L initial concentration of Cu(II). PMID- 23089201 TI - Human type 2 myeloid dendritic cells produce interferon-lambda and amplify interferon-alpha in response to hepatitis C virus infection. AB - BACKGROUND & AIMS: The type III interferons (IFN-lambdas: interleukin [IL]-28a, IL-28b, and IL-29) have important roles in hepatitis C virus (HCV) infection, but little is understood about what cells produce these cytokines or how production is activated. We investigated whether human immune cells recognize HCV-infected cells and respond by producing IFN-lambda. METHODS: We cultured healthy human peripheral blood mononuclear cells (PBMCs) with different populations of immune cells and Japanese fulminant hepatitis-1 (JFH-1) HCV-infected Huh7.5 (cell culture-derived HCV particles [HCVcc]/Huh7.5) cells. RESULTS: Human PBMCs recognized HCVcc/Huh7.5 cells and responded by producing IFN-alpha, IFN-gamma, and IFN-lambda. A rare subset of myeloid dendritic cells (mDCs), which are blood DC antigen (BDCA)+ (also called mDC2 cells), were the major source of IL-28 and IL-29 production in response to HCVcc/Huh7.5 cells. Plasmacytoid DCs produced IFN alpha, whereas natural killer and natural killer T cells were the main source of IFN-gamma production in co-culture experiments. Of the endosomal Toll-like receptors (TLRs)3, 7, 8, and 9, only TLR3 or double-stranded HCV RNA induced production of IL-28 and IL-29 by mDC2s; endosomal maturation was required. Production of IFN-alpha and IFN-lambda were linked-IFN-lambda increased production of IFN-alpha by plasmacytoid DCs and IFN-alpha significantly increased production of IFN-lambda. CONCLUSIONS: mDC2s are a major source of IFN-lambda production by PBMCs in response to HCVcc/Huh7.5 cells. mDC2s are activated through the TLR3 pathway, indicating that human DCs efficiently can initiate an immune response against HCV infection. IFN-lambda therefore has an important role in HCV infection. PMID- 23089202 TI - Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. AB - BACKGROUND & AIMS: The intestinal symport system moves nutrients across membranes via transporters, and is required for absorption of major nutrients such as glucose, amino acids, and bile acids (which are required for fat absorption). Most of these transporters are regulated by Na(+), but the standard diet does not provide sufficient levels of this ion to the intestinal lumen to support this system. Claudins form paracellular barriers between epithelial cells, and claudin 2 and -15 regulate paracellular ion flow in the intestine. We investigated how cell adherence, tight junction barriers, and claudins regulate the supply of Na(+) to the intestinal lumen in mice. METHODS: We created Cldn2(-/-)Cldn15(-/-) (double-knockout) mice and analyzed intestinal tissues by reverse-transcription polymerase chain reaction, immunoblot, immunofluorescence, electron microscopy, and H&E analyses. We also measured paracellular Na(+) flow, luminal Na(+) concentration, and absorption of glucose, amino acids, and fats, which were administered orally to the mice. RESULTS: Paracellular flow of Na(+) from the intestinal submucosa to the lumen, and therefore the concentration of Na(+) in the lumen, was greatly reduced in intestines of Cldn2(-/-)Cldn15(-/-) mice. Absorption of glucose, amino acids, and fats also decreased in the mice, which died by postnatal day 25 from malnutrition. CONCLUSIONS: The paracellular flow of Na(+) from the intestinal submucosa is regulated by tight junctions that contain claudin-2 and -15. This system is required for the absorption of glucose, amino acids, and fats; disruption of this system in mice leads to infant death as a result of malabsorption. PMID- 23089204 TI - The impact of post-discharge patient call back on patient satisfaction in two academic emergency departments. AB - BACKGROUND: Patients' satisfaction is a common parameter tracked by health care systems and Emergency Departments (EDs). OBJECTIVES: To determine whether telephone calls by health care providers to patients after discharge from the ED was associated with improved patient satisfaction. METHODS: Retrospective analysis of Press Ganey (PG; Press Ganey Associates, South Bend, IN) surveys from two EDs operated by the University of California San Diego Health System. Responses to the YES/NO question, "After discharge, did you receive a phone call from an ED staff member?" was compared to the responses to the question "likelihood of recommending this ED to others" (LR). This variable could be ranked with a score of 1 (very poor) to 5 (very good). Responses were dichotomized into two groups, 1-4 and 5. Chi-squared was performed to assess LR between those answering YES vs. NO to the call back question. Differences in proportion, 95% confidence interval (CI), and p-value are reported. Rankings for percentage of 5s across all EDs in the PG database were compared based upon YES/NO responses. RESULTS: In the 12-month study period, about 30,000 surveys were mailed and 2250 (7.5%) were returned. Three hundred forty-seven (15.4%) checked off YES for the call back question. Percentage of 5s for LR for NO call back was 51.1% and for YES call back was 70.6% (difference = 19.5; 95% CI 14.0 24.6; p < 0.001).These values correlated with an ED ranking of 14(th) and 85(th) percentile, respectively. CONCLUSION: This retrospective study demonstrated a strong association between post-visit patient call back and LR. Further prospective study with control for co-variables is warranted. PMID- 23089203 TI - Selective inhibitors of nuclear export block pancreatic cancer cell proliferation and reduce tumor growth in mice. AB - BACKGROUND & AIMS: Tumor-suppressor proteins are inactivated by many different mechanisms, including nuclear exclusion by chromosome region maintenance (CRM)-1. Increased tumor levels of CRM-1 have been correlated with poor prognosis of patients with pancreatic cancer, making it a therapeutic target. Selective inhibitors of nuclear export (SINEs) bind to CRM-1 to irreversibly inhibit its ability to export proteins; we investigated a new class of SINEs in pancreatic cancer cells. METHODS: We studied the effects of SINE analogs in a panel of pancreatic cancer cell lines and nontransformed human pancreatic ductal epithelial cells using proliferation, apoptosis, immunoblot, co immunoprecipitation, small inhibitor RNA, and fluorescence microscopy analyses. The effects of the SINEs also were investigated in mice with subcutaneous and orthotopic tumors. RESULTS: SINEs (KPT-185, KPT-127, KPT-205, and KPT-227) inhibited proliferation and promoted apoptosis of pancreatic cancer cells, but did not affect human pancreatic ductal epithelial cells. The nuclei of cells incubated with KPT-185 accumulated tumor-suppressor proteins (p27, FOXO, p73, and prostate apoptosis response-4 [PAR-4]) and inhibited interactions between CRM-1 and these proteins. Mutations in the region of CRM-1 that bind to SINEs (Cys 528), or small inhibitor RNA knockdown of PAR-4, prevented the ability of KPT-185 to block proliferation and induce apoptosis of pancreatic cancer cells. Oral administration of KPT-330 to mice reduced growth of subcutaneous and orthotopic xenograft tumors without major toxicity. Analysis of tumor remnants showed that KPT-330 disrupted the interaction between CRM-1 and PAR-4, activated PAR-4 signaling, and reduced proliferation of tumor cells. CONCLUSIONS: We identified SINEs that inhibit CRM-1 and promote nuclear accumulation of tumor-suppressor proteins in pancreatic cancer cells. Oral administration of the drug to mice reduces growth of xenograft tumors. PMID- 23089205 TI - Respiratory distress. PMID- 23089206 TI - How well do emergency medical dispatch codes predict prehospital medication administration in a diverse urban community? AB - BACKGROUND: The Medical Priority Dispatch System (MPDS) is an emergency medical dispatch (EMD) system that is widely used to prioritize 9-1-1 calls and optimize resource allocation. MPDS is a computer-based EMD system that uses callers' responses to scripted questions to categorize cases into groups and subgroups, based on complaint and perceived acuity. OBJECTIVE: This study evaluates the ability of MPDS codes to predict prehospital use of medications. METHODS: All transported prehospital patients assigned a subgroup by MPDS from January 1, 2009 to December 31, 2009 in a diverse urban community were matched with their prehospital electronic patient care records. The records of transported patients dispatched through EMD were queried for prehospital interventions and matched to their MPDS classifications. Only MPDS subgroups with 10 or more calls were included in the analysis. RESULTS: A total of 38,005 patients met inclusion criteria. Patients with chest pain, breathing problems, heart problems, and diabetic problems received the most medications. Medications were administered in 19% of all calls. The individual MPDS subgroup with the highest rate of medication administration was 6E1A (breathing problems, 76%). Higher rates of Advanced Life Support (ALS) interventions in higher-acuity categories (e.g., Alpha, Bravo, Charlie) were seen in several EMD categories, including unconscious/fainting, breathing problems, and abdominal pain; but this was not observed in many other categories, including seizure, sick person, traumatic injury, and hemorrhage/lacerations. CONCLUSIONS: Medications were administered in 19% of all calls. There were higher rates of ALS interventions in higher-acuity categories that were not observed in many other categories. PMID- 23089207 TI - Childhood mortality in sub-Saharan Africa: cross-sectional insight into small scale geographical inequalities from Census data. AB - OBJECTIVES: To estimate and quantify childhood mortality, its spatial correlates and the impact of potential correlates using recent census data from three sub Saharan African countries (Rwanda, Senegal and Uganda), where evidence is lacking. DESIGN: Cross-sectional. SETTING: Nation-wide census samples from three African countries participating in the 2010 African Census round. All three countries have conducted recent censuses and have information on mortality of children under 5 years. PARTICIPANTS: 111 288 children under the age of 5 years in three countries. PRIMARY AND SECONDARY OUTCOME MEASURES: Under-five mortality was assessed alongside potential correlates including geographical location (where children live), and environmental, bio-demographic and socioeconomic variables. RESULTS: Multivariate analysis indicates that in all three countries the overall risk of child death in the first 5 years of life has decreased in recent years (Rwanda: HR=0.04, 95% CI 0.02 to 0.09; Senegal: HR=0.02 (95% CI 0.02 to 0.05); Uganda: HR=0.011 (95% CI 0.006 to 0.018). In Rwanda, lower deaths were associated with living in urban areas (0.79, 0.73, 0.83), children with living mother (HR=0.16, 95% CI 0.15 to 0.17) or living father (HR=0.38, 95% CI 0.36 to 0.39). Higher death was associated with male children (HR=1.06, 95% CI 1.02 to 1.08) and Christian children (HR=1.14, 95% CI 1.05 to 1.27). Children less than 1 year were associated with higher risk of death compared to older children in the three countries. Also, there were significant spatial variations showing inequalities in children mortality by geographic location. In Uganda, for example, areas of high risk are in the south-west and north-west and Kampala district showed a significantly reduced risk. CONCLUSIONS: We provide clear evidence of considerable geographical variation of under-five mortality which is unexplained by factors considered in the data. The resulting under-five mortality maps can be used as a practical tool for monitoring progress within countries for the Millennium Development Goal 4 to reduce under-five mortality in half by 2015. PMID- 23089208 TI - Antiviral therapy for prevention of hepatocellular carcinoma in chronic hepatitis C: systematic review and meta-analysis of randomised controlled trials. AB - OBJECTIVES: To determine whether antiviral therapy reduces the risk of developing hepatocellular carcinoma (HCC) in chronic hepatitis C. DESIGN: Systematic review and meta-analyses of randomised controlled trials. Prospective cohort studies were included in sensitivity analyses. DATA SOURCES: Eligible trials were identified through electronic and manual searches. STUDY SELECTION: Eight randomised controlled trials comparing antiviral therapy (interferon or pegylated interferon alone or with ribavirin) versus placebo or no intervention were included. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers assessed the methodological quality of studies and extracted data. Random effects meta analyses were performed. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate sources of intertrial heterogeneity, the risk of bias and the robustness of the results after adjusting for multiple testing. RESULTS: Random effects meta-analysis showed that antiviral therapy reduced the risk of HCC (81/1156 vs 129/1174; risk ratio 0.53, 95% CI 0.34 to 0.81). In subgroup analyses, antiviral therapy was more beneficial (test for subgroup differences p=0.03) in virological responders (0.15, 0.05 to 0.45) than in non responders (0.57; 0.37 to 0.85). No evidence of bias was seen in regression analyses. Sequential analysis confirmed the overall result. The sensitivity analyses showed that the cohort studies found that antiviral therapy reduced the risk of HCC. There was clear statistical evidence of bias in the cohort studies (p=0.02). CONCLUSIONS: Antiviral therapy may reduce the risk of HCC in hepatitis C-related fibrosis and cirrhosis. The effect may be seen irrespective of the virological response, but is more pronounced among virological responders compared with non-responders. PMID- 23089209 TI - An application of reconfigurable technologies for non-invasive fetal heart rate extraction. AB - This paper illustrates the use of a reconfigurable system for fetal electrocardiogram (FECG) estimation from mother's abdomen ECG measurements. The system is based on two different reconfigurable devices. Initially, a field programmable analog array (FPAA) device implements the analog reconfigurable preprocessing for ECG signal acquisition. The signal processing chain continues onto a field-programmable gate array (FPGA) device, which contains all the communication and interfacing protocols along with specific digital signal processing blocks required for fundamental period extraction from FECG waveforms. The synergy between these devices provides the system the ability to change any necessary parameter during the acquisition process for enhancing the result. The use of a FPGA allows implementing different algorithms for FECG signal extraction, such as adaptive signal filtering. Preliminary works employ commercially available development platforms for test experiments, which suffice for the processing of real FECG signals from biomedical databases, as the presented results illustrate. PMID- 23089210 TI - [Wilson's disease: clinical spectrum of liver disease]. AB - Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism,characterized by copper accumulation in the liver and brain. This rare entity, which has a broad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson's disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment. PMID- 23089211 TI - Cholesterol ester droplets and steroidogenesis. AB - Intracellular lipid droplets (LDs) are dynamic organelles that contain a number of associated proteins including perilipin (Plin) and vimentin. Cholesteryl ester (CE)-rich LDs normally accumulate in steroidogenic cells and their mobilization is the preferred initial source of cholesterol for steroidogenesis. Plin1a, 1b and 5 were found to preferentially associate with triacylglycerol-rich LDs and Plin1c and Plin4 to associate with CE-rich LDs, but the biological significance of this remains unanswered. Vimentin null mice were found to have decreased ACTH stimulated corticosterone levels, and decreased progesterone levels in females, but normal hCG-stimulated testosterone levels in males. Smaller LDs were seen in null cells. Lipoprotein cholesterol delivery to adrenals and ovary was normal, as was the expression of steroidogenic genes; however, the movement of cholesterol to mitochondria was reduced in vimentin null mice. These results suggest that vimentin is important in the maintenance of CE-rich LDs and in the movement of cholesterol for steroidogenesis. PMID- 23089212 TI - Inhibition and stimulation of activity of purified recombinant CYP11A1 by therapeutic agents. AB - In vertebrates, the biosynthesis of steroid hormones is initiated by cytochrome P450 CYP11A1 which converts cholesterol to pregnenolone. We investigated whether some of the experimental and FDA-approved therapeutic agents alter the activity of CYP11A1 in the reconstituted system in vitro. We found that under the experimental conditions used and when phospholipids are included, ketoconazole, posaconazole, carbenoxolone, and selegiline inhibit CYP11A1-mediated production of pregnenolone by at least 67%. Conversely, pemirolast, clobenpropit, desogestrel, dexmedetomidine, and tizanidine stimulate the enzyme activity by up to 70%. We then evaluated the identified inhibitors and activators for spectral binding to CYP11A1 and their effect on enzyme activity in the absence of phospholipids. The data obtained provide insight into how different drugs interact with CYP11A1 and demonstrate that P450 association with the lipid bilayer determines, in many cases, a drug's effect on enzyme activity. PMID- 23089213 TI - Dentistry, veterinary medicine and outcomes. PMID- 23089214 TI - Randomised controlled trials of veterinary homeopathy: characterising the peer reviewed research literature for systematic review. AB - INTRODUCTION: Systematic review of the research evidence in veterinary homeopathy has never previously been carried out. This paper presents the search methods, together with categorised lists of retrieved records, that enable us to identify the literature that is acceptable for future systematic review of randomised controlled trials (RCTs) in veterinary homeopathy. METHODS: All randomised and controlled trials of homeopathic intervention (prophylaxis and/or treatment of disease, in any species except man) were appraised according to pre-specified criteria. The following databases were systematically searched from their inception up to and including March 2011: AMED; Carstens-Stiftung Homeopathic Veterinary Clinical Research (HomVetCR) database; CINAHL; Cochrane Central Register of Controlled Trials; Embase; Hom-Inform; LILACS; PubMed; Science Citation Index; Scopus. RESULTS: One hundred and fifty records were retrieved; 38 satisfied the acceptance criteria (substantive report of a clinical treatment or prophylaxis trial in veterinary homeopathic medicine randomised and controlled and published in a peer-reviewed journal), and were thus eligible for future planned systematic review. Approximately half of the rejected records were theses. Seven species and 27 different species-specific medical conditions were represented in the 38 papers. Similar numbers of papers reported trials of treatment and prophylaxis (n=21 and n=17 respectively) and were controlled against placebo or other than placebo (n=18, n=20 respectively). Most research focused on non-individualised homeopathy (n=35 papers) compared with individualised homeopathy (n=3). CONCLUSION: The results provide a complete and clarified view of the RCT literature in veterinary homeopathy. We will systematically review the 38 substantive peer-reviewed journal articles under the main headings: treatment trials; prophylaxis trials. PMID- 23089215 TI - A systematic review and meta-analysis on the use of Hypericum perforatum (St. John's Wort) for pain conditions in dental practice. AB - BACKGROUND: Hypericum perforatum (St. John's Wort) has been used for a variety of medicinal indications. Most recent research has focussed on its use in herbal form for depression, but its claimed analgesic and anti-inflammatory properties in homeopathic form have also led to a number of studies in patients with acute pain conditions. This systematic review overviews the literature on the use of St. John's Wort for pain conditions in homeopathic dental practice. MATERIAL AND METHODS: PubMed, EMBASE, AMED, CAMbase and the electronic archives of Thieme Publishers were searched with the search terms "(Hypericum OR St. Johns Wort) AND pain". We reviewed and meta-analysed the evidence on Hypericum in pain after tooth extraction was carried out. RESULTS: Twenty one relevant articles were found: four described general recommendations, three basic research, six reported studies in dental care and eight were expert opinions or case reports. Four studies were eligible for the meta-analysis. There was marked high heterogeneity in the effects pain (Chi-Squared = 26.46; I(2) = 0.89). The overall effect of 0.24 (95% CI: [0.06; 1.03]) favours Hypericum but is not statistically significant. CONCLUSION: Although case reports suggest therapeutic potential of Hypericum for pain conditions in dental care, this effect is not currently supported by clinical studies. All studies included in this meta-analysis used Arnica montana as well as Hypericum the results are more influenced by Arnica than Hypericum. Further clinical controlled trials of Hypericum alone in dental practice should be performed. PMID- 23089216 TI - Observational study of the use of Symphytum 5CH in the management of pain and swelling after dental implant surgery. AB - OBJECTIVE: To assess the effect of Symphytum 5CH on the postoperative pain and swelling after placement of a titanium dental implant. MATERIAL AND METHODS: Data on pain and swelling following pure titanium implants were reviewed. Patients were treated postoperatively with ketoprofen only or ketoprofen and Symphytum 5CH, according to the treating dentist's usual practice. Demographics and baseline characteristics were recorded and compared. Pain and swelling were compared between the two treatment groups using the Wilcoxon rank sum test and ordinal logistic regression, estimating odds ratios and confidence intervals. RESULTS: 100 implants in 57 patients (28 males, 29 females) were treated with ketoprofen alone; 100 implants in 60 patients (14 males, 46 females) with ketoprofen and Symphytum. The group treated with ketoprofen and Symphytum appeared to have a better response in terms of both pain and swelling. Ordinal logistic regression: pain 0.23, 95% CI 0.13-0.41; swelling 0.24, 95% CI 0.13 0.44. Correction for demographics and implant characteristics greatly widened the confidence intervals so that the results were no longer statistically significant (pain: OR = 0.15, 95% CI 0.07-34.56; swelling OR = 0.18, 95% CI 0.07-46.78). CONCLUSIONS: Adding Symphytum 5CH to conventional analgesia may reduce pain and swelling after minor dental implant surgery. No firm conclusion can be drawn since the results are confounded by baseline differences, principally gender. Further, randomized, studies should be conducted. PMID- 23089217 TI - Constitutional, organopathic and combined homeopathic treatment of benign prostatic hypertrophy: a clinical trial. AB - BACKGROUND: Benign Prostatic Hypertrophy (BPH) is common in older men. This study compared homeopathic treatment strategies using constitutional medicines (CM) or organopathic medicines (OM) alone or in combination (BCOM) in patients suffering from BPH. METHODS: 220 men aged 30-90 years were recruited in Odisha, India. Patients presenting symptoms of prostatism, with or without evidence of bladder outflow obstruction were included in the study. Patients with serum prostate specific antigen (PSA)> 4 nmol/mL, malignancy, complete urine retention, stone formation and gross bilateral hydronephrosis were excluded. Patients were sequentially allocated to OM, CM or BCOM. The main outcome measure was the International Prostate Symptom Score (IPSS). RESULTS: 73, 70 and 77 patients respectively were sequentially allocated to OM, CM or BCOM. 180 patients (60 per group) completed treatment and were included in the final analysis. Overall 85% of patients showed improvement of subjective symptoms such as frequency, urgency, hesitancy, intermittent flow, unsatisfactory urination, feeble stream, diminution of residual urine volume but there was no reduction in prostate size. Treatment response was highest with BCOM (38.24%) compared to OM (31.62%) and CM (30.15%). Effect sizes were highest for the decrease in IPSS, residual urine volume and urinary flow rate. PMID- 23089218 TI - Individualized homeopathy in a group of Egyptian asthmatic children. AB - OBJECTIVES: To evaluate homeopathy as an adjunctive treatment for bronchial asthma in children. METHODS: In a prospective observational longitudinal study the effects of individualised homeopathic medicines were assessed in 30 children with asthma as an adjunct to conventional treatment. The main outcome measures were frequency of attacks, use of medication, night awakening and spirometry at baseline and at follow-up till 6 months. RESULTS: There were clinically relevant and statistically significant changes in those measuring severity, indicating relative improvements after 3 months and absolute improvements after 6 months of treatment by homeopathic medicines. CONCLUSIONS: This study provides evidence that homeopathic medicines, as prescribed by experienced homeopathic practitioners, improve severity of asthma in children. Controlled studies should be conducted. PMID- 23089219 TI - Antiresorptive drugs (bisphosphonates), atypical fractures and rebound effect: new evidence of similitude. AB - BACKGROUND: Homeopathy is based on treatment by similitude ('like cures like') administering to sick individuals substances that cause similar symptoms in healthy individuals, employing the secondary and paradoxical action of the organism as therapeutic response. This vital or homeostatic reaction of the organism can be scientifically explained by the rebound effect of drugs, resulting in worsening of symptoms after suspension of treatment. Bisphosphonates (BPs) reduce 'typical' fractures in patients with osteoporosis, but recent studies report 'atypical' fractures of the femur after stopping the BPs, a rebound effect may be the causal mechanism. METHOD: Review of the literature concerning the relationship between atypical femoral fractures and antiresorptive drugs (bisphosphonates), identifying the pathogenesis of this adverse event. RESULTS: Several studies have described multiple cases of 'atypical' low-impact subtrochanteric stress fractures or complete fractures of the femur. These fractures are often bilateral, preceded by pain in the affected thigh, may have a typical X-ray appearance, and may delayed healing. Rebound of osteoclastic activity after suspension of antiresorptive drugs is a plausible mechanism to explain this phenomenon. CONCLUSION: As for other classes of drugs, the rebound effect of antiresorptive drugs supports Hahnemann's similitude principle (primary action of the drugs followed by secondary and opposite action of the organism), and clarifies this 'unresolved' issue. Unfortunately, the rebound effect is little discussed among health professionals, depriving them of important knowledge ensure safe management of drugs. PMID- 23089220 TI - The effect of individualized homeopathic treatment on the semen quality of bulls with reproductive disorders: a case series. AB - BACKGROUND: Poor semen quality of pedigree bulls has major economic implications in cattle breeding. AIMS: To evaluate the effect of homeopathy on the semen of bulls with reproductive disorders. METHODS: The behavioral, clinical and spermatic characteristics of four Nelore bulls were evaluated. The bulls received individualized homeopathic treatment mixed into the feed and administered once per day. Semen was collected using an artificial vagina. Successful collection, freezing, effective doses, and the number of doses of semen per collection were compared before and after homeopathic treatment. RESULTS: The bulls were treated with Sulphur, Phosphorus, Lycopodium and Argentum nitricum all in 30CH dilution. The rates of successful collection were 97.14%, 100%, 96.67% and 30.77% pretreatment and 95.45%, 100%, 94.67% and 96.77% at post-treatment for bulls A, B, C and D, respectively. The average number of doses per ejaculate pre and post treatment were 102.67 (SD 74.41) vs. 300.08 (SD 180.58), 0 vs. 234.78 (SD 96.12), 0 vs. 105.12 (SD 54.98), 0 +/- vs. 107.37 (SD 52.12) respectively. Many of these differences were statistically significant. CONCLUSION: The use of homeopathy apparently improved the production of viable doses of semen from bulls with previous freezing problems and poor semen quality. Controlled studies should be conducted. PMID- 23089221 TI - Targeting the kallikrein-related peptidases for drug development. AB - Kallikrein-related peptidases (KLKs) constitute a family of 15 serine proteases. Recent studies have shed light on key physiological functions of KLK enzymes and implicate their deregulation in major human pathologies such as neurodegenerative and inflammatory diseases, skin conditions, asthma, and cancer. Consequently, KLKs have emerged as novel targets for pharmacological intervention. Given the pleiotropic roles of KLKs, both activators and inhibitors of KLK activities are of therapeutic interest. For example, inhibitors of hyperactive KLKs in the epidermis would be effective against excess skin desquamation and inflammation, whereas KLK activators could benefit hyperkeratosis caused by diminished KLK proteolysis. Expression of active KLKs by cancer cells and tissues can be exploited to target prodrugs that are proteolytically cleaved to release a cytotoxic compound or a cytolytic toxin at the site of KLK protease activity. Here, we review current approaches for the design and testing of KLK-based therapeutics. PMID- 23089222 TI - Pre-beamformed RF signal reconstruction in medical ultrasound using compressive sensing. AB - Compressive sensing (CS) theory makes it possible - under certain assumptions - to recover a signal or an image sampled below the Nyquist sampling limit. In medical ultrasound imaging, CS could allow lowering the amount of acquired data needed to reconstruct the echographic image. CS thus offers the perspective of speeding up echographic acquisitions and could have many applications, e.g. triplex acquisitions for CFM/B-mode/Doppler imaging, high-frame-rate echocardiography, 3D imaging using matrix probes, etc. The objective of this paper is to study the feasibility of CS for the reconstruction of channel RF data, i.e. the 2D set of raw RF lines gathered at the receive elements. Successful application of CS implies selecting a representation basis where the data to be reconstructed have a sparse expansion. Because they consist mainly in warped oscillatory patterns, channel RF data do not easily lend themselves to a sparse representation and thus represent a specific challenge. Within this perspective, we propose to perform and assess CS reconstruction of channel RF data using the recently introduced wave atoms [1] representation, which exhibit advantageous properties for sparsely representing such oscillatory patterns. Reconstructions obtained using wave atoms are compared with the reconstruction performed with two conventional representation bases, namely Fourier and Daubechies wavelets. The first experiment was conducted on simulated channel RF data acquired from a numerical cyst phantom. The quality of the reconstructions was quantified through the mean absolute error at varying subsampling rates by removing 50-90% of the original samples. The results obtained for channel RF data reconstruction yield error ranges of [0.6-3.0]*10(-2), [0.2-2.6]*10(-2), [0.1 1.5]*10(-2), for wavelets, Fourier and wave atoms respectively. The error ranges observed for the associated beamformed log-envelope images are [2.4-20.6]dB, [1.1 12.2]dB, and [0.5-8.8dB] using wavelets, Fourier, and wave atoms, respectively. These results thus show the superiority of the wave atom representation and the feasibility of CS for the reconstruction of US RF data. The second experiment aimed at showing the experimental feasibility of the method proposed using a data set acquired by imaging a general-purpose phantom (CIRS Model 054GS) using an Ultrasonix MDP scanner. The reconstruction was performed by removing 80% of the initial samples and using wave atoms. The reconstructed image was found to reliably preserve the speckle structure and was associated with an error of 5.5dB. PMID- 23089223 TI - Band gap structures in two-dimensional super porous phononic crystals. AB - As one kind of new linear cellular alloys (LCAs), Kagome honeycombs, which are constituted by triangular and hexagonal cells, attract great attention due to the excellent performance compared to the ordinary ones. Instead of mechanical investigation, the in-plane elastic wave dispersion in Kagome structures are analyzed in this paper aiming to the multi-functional application of the materials. Firstly, the band structures in the common two-dimensional (2D) porous phononic structures (triangular or hexagonal honeycombs) are discussed. Then, based on these results, the wave dispersion in Kagome honeycombs is given. Through the component cell porosity controlling, the effects of component cells on the whole responses of the structures are investigated. The intrinsic relation between the component cell porosity and the critical porosity of Kagome honeycombs is established. These results will provide an important guidance in the band structure design of super porous phononic crystals. PMID- 23089225 TI - Does nitric oxide signaling differ in pre- and post-conditioning? Importance of S nitrosylation vs. protein kinase G activation. PMID- 23089224 TI - Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptor function. AB - Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA(-/-)) are prone to the development of high-fat-diet-induced insulin resistance and a reduced physiological insulin response compared to high-fat-fed wild-type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high-fat-fed mice show similar reduction in insulin receptor function and increase in insulin receptor oxidation, which are further exacerbated by the lack of MsrA. Together, these data demonstrate for the first time that MsrA and protein oxidation play a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation. PMID- 23089226 TI - Nox4- and Nox2-dependent oxidant production is required for VEGF-induced SERCA cysteine-674 S-glutathiolation and endothelial cell migration. AB - Endothelial cell (EC) migration in response to vascular endothelial growth factor (VEGF) is a critical step in both physiological and pathological angiogenesis. Although VEGF signaling has been extensively studied, the mechanisms by which VEGF-dependent reactive oxygen species (ROS) production affects EC signaling are not well understood. The aim of this study was to elucidate the involvement of Nox2- and Nox4-dependent ROS in VEGF-mediated EC Ca(2+) regulation and migration. VEGF induced migration of human aortic ECs into a scratch wound over 6 h, which was inhibited by overexpression of either catalase or superoxide dismutase (SOD). EC stimulation by micromolar concentrations of H2O2 was inhibited by catalase, but also unexpectedly by SOD. Both VEGF and H2O2 increased S-glutathiolation of SERCA2b and increased Ca(2+) influx into EC, and these events could be blocked by overexpression of catalase or overexpression of SERCA2b in which the reactive cysteine-674 was mutated to a serine. In determining the source of VEGF-mediated ROS production, our studies show that specific knockdown of either Nox2 or Nox4 inhibited VEGF-induced S-glutathiolation of SERCA, Ca(2+) influx, and EC migration. Treatment with H2O2 induced S-glutathiolation of SERCA and EC Ca(2+) influx, overcoming the knockdown of Nox4, but not Nox2, and Amplex red measurements indicated that Nox4 is the source of H2O2. These results demonstrate that VEGF stimulates EC migration through increased S-glutathiolation of SERCA and Ca(2+) influx in a Nox4- and H2O2-dependent manner, requiring Nox2 downstream. PMID- 23089227 TI - Chloride transport in functionally active phagosomes isolated from Human neutrophils. AB - Chloride anion is critical for hypochlorous acid (HOCl) production and microbial killing in neutrophil phagosomes. However, the molecular mechanism by which this anion is transported to the organelle is poorly understood. In this report, membrane-enclosed and functionally active phagosomes were isolated from human neutrophils by using opsonized paramagnetic latex microspheres and a rapid magnetic separation method. The phagosomes recovered were highly enriched for specific protein markers associated with this organelle such as lysosomal associated membrane protein-1, myeloperoxidase (MPO), lactoferrin, and NADPH oxidase. When FITC-dextran was included in the phagocytosis medium, the majority of the isolated phagosomes retained the fluorescent label after isolation, indicative of intact membrane structure. Flow cytometric measurement of acridine orange, a fluorescent pH indicator, in the purified phagosomes demonstrated that the organelle in its isolated state was capable of transporting protons to the phagosomal lumen via the vacuolar-type ATPase proton pump (V-ATPase). When NADPH was supplied, the isolated phagosomes constitutively oxidized dihydrorhodamine 123, indicating their ability to produce hydrogen peroxide. The preparations also showed a robust production of HOCl within the phagosomal lumen when assayed with the HOCl-specific fluorescent probe R19-S by flow cytometry. MPO-mediated iodination of the proteins covalently conjugated to the phagocytosed beads was quantitatively measured. Phagosomal uptake of iodide and protein iodination were significantly blocked by chloride channel inhibitors, including CFTRinh-172 and NPPB. Further experiments determined that the V-ATPase-driving proton flux into the isolated phagosomes required chloride cotransport, and the cAMP-activated CFTR chloride channel was a major contributor to the chloride transport. Taken together, the data suggest that the phagosomal preparation described herein retains ion transport properties, and multiple chloride channels including CFTR are responsible for chloride supply to neutrophil phagosomes. PMID- 23089229 TI - Mitochondrial-associated nitric oxide synthase activity inhibits cytochrome c oxidase: implications for breast cancer. AB - Nitric oxide (NO) is produced and nitric oxide synthase (NOS) activity is expressed in many types of tumor cells, but their precise role in tumor proliferation has not been clearly elucidated. Recently, it has been observed that patients with triple-negative breast tumors expressing NOS have a significantly worse prognosis compared to those that do not express any NOS. We observed that NOS activity was associated with the mitochondria in two breast cancer cell lines, ZR-75-30 and BT-474, compared with another NO-producing benign breast epithelial cell line, MCF-12F, in which no significant mitochondrial associated NOS activity was detected. The rate of proliferation of the malignant cells expressing mitochondrial-associated NOS was decreased in the presence of an inhibitor of NO synthesis, but it had no effect on the normal breast epithelial cells, MCF-12F, which also expressed NOS, but not associated with mitochondria. The basal rate of proliferation was not affected by ODQ, an inhibitor of soluble guanylate cyclase, indicating that the effects of the endogenous NO produced by the malignant cell lines on proliferation are cGMP independent. Our results indicate that mitochondrial-associated NOS activity exhibited by the cancer cell lines ZR-75-30 and BT-474 inhibited cytochrome c oxidase, resulting in increased production of hydrogen peroxide (H2O2), which inhibited protein phosphatase 2A activity. This resulted in the maintenance of Akt and ERK1/2 in a phosphorylated state, leading to cell proliferation. PMID- 23089228 TI - Treatment with heme arginate alleviates adipose tissue inflammation and improves insulin sensitivity and glucose metabolism in a rat model of Human primary aldosteronism. AB - Visceral adiposity and insulin resistance are common pathophysiological denominators in patients with primary aldosteronism. Although we recently reported the antidiabetic effects of heme oxygenase (HO), no study has examined the effects of upregulating HO on visceral adiposity in uninephrectomized (UnX) deoxycorticosterone acetate (DOCA-salt) hypertensive rats, a model of human primary aldosteronism characterized by elevated endothelin (ET-1) and oxidative/inflammatory events. Here, we report the effects of the HO inducer heme arginate and the HO blocker chromium mesoporphyrin (CrMP) on visceral adipose tissue obtained from retroperitoneal fat pads of UnX DOCA-salt rats. UnX DOCA salt rats were hypertensive but normoglycemic. Heme arginate reduced visceral adiposity and enhanced HO activity and cGMP in the adipose tissue, but suppressed ET-1, nuclear-factor kappaB (NF-kappaB), activating-protein (AP-1), c-Jun-NH2 terminal kinase (JNK), macrophage chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and 8-isoprostane. These were associated with reduced glycemia, increased insulin, and the insulin-sensitizing protein adiponectin, with corresponding reduction in insulin resistance. In contrast, the HO inhibitor, CrMP, abolished the effects of heme arginate, aggravating insulin resistance, suggesting a role for the HO system in insulin signaling. Importantly, the effects of the HO system on ET-1, NF-kappaB, AP-1, JNK, MCP-1, and ICAM-1 in visceral or retroperitoneal adiposity in UnX-DOCA-salt rats have not been reported. Because 8-isoprostane stimulates ET-1 to enhance oxidative insults, and increased oxidative events deplete adiponectin and insulin levels, the suppression of oxidative/inflammatory mediators such as 8 isoprostane, NF-kappaB, AP-1, MCP-1, ICAM-1, and JNK, an inhibitor of insulin biosynthesis, may account for the potentiation of insulin signaling/glucose metabolism by heme arginate. These data indicate that although UnX DOCA-salt rats were normoglycemic, insulin signaling was impaired, suggesting that dysfunctional insulin signaling may be a forerunner to overt diabetes in primary aldosteronism. PMID- 23089230 TI - Peptidases trimming MHC class I ligands. AB - Peptides presented by MHC class I molecules are typically produced through antigen degradation by the proteasome followed by trimming by exopeptidases. According to recent results, these include both aminopeptidases and carboxypeptidases in the cytosol and the endoplasmic reticulum. While cytosolic peptidases have a net neutral or destructive effect on MHC ligands, endoplasmic reticulum aminopeptidases are required for efficient class I loading and have a strong effect on the repertoire of peptide/MHC complexes. Cells lacking these enzymes can be eliminated both by NK cells and by CD8+ T cells recognizing complexes formed between an MHC class Ib molecule and a conserved peptide. Cross presented peptides derived from internalized antigens can be processed by insulin regulated aminopeptidase, the only endosomal trimming peptidase. PMID- 23089231 TI - Human airway epithelial cell innate immunity: relevance to asthma. AB - The innate immunity function of the human airway epithelium is responsible for orchestrating defence against inhaled viruses, bacteria, fungi, allergens, pollution, and other environmental insults. Epithelial cells present a mechanically tight, pseudostratified, multi-cell barrier that secretes mucus, surfactants, and anti-microbial peptides to manage minor insults. Secondary to the mechanical impedances, cell surface and cytoplasmic pattern recognition receptors await detection of more aggressive insults. The differentiation state of the airway epithelium contributes to innate immunity by compartmentalizing receptors and mediator production. Activation of innate immune receptors triggers production of interferons, cytokines, and chemokines, which influence adaptive immune responses. Mounting evidence suggests that these responses are aberrant in asthma and may contribute to disease progression and exacerbations. In this review, we discuss the recent evidence supporting these statements, focusing primarily on data generated from using human samples. PMID- 23089232 TI - Dichotomizing rating scale scores in psychiatry: a bad idea? AB - In psychiatry, the use of rating scales as measures of outcome in clinical trials allows us to generate continuous outcome data, where each individual's outcome is measured in numbers. Continuous outcomes can be divided into two categories, such as improved and not improved, or may be kept continuous. This article briefly presents the main advantages and disadvantages of these two approaches, which are commonly employed in the analyses of rating scale scores in clinical trials and systematic reviews. PMID- 23089233 TI - Initiating palliative care conversations: lessons from Jewish bioethics. AB - What are the ethical responsibilities of the medical staff (doctors, nurses, social workers, and chaplains) regarding the preservation of meaningful life for their patients who are approaching the end of life (EOL)? In particular, what is the staff's ethical responsibility to initiate a conversation with their patient regarding palliative care? By subjecting traditional Jewish teachings to an ethical analysis and then exploring the underlying universal principles, we will suggest a general ethical duty to inform patients of the different care options, especially in a manner that preserves hope. The principle that we can derive from Jewish bioethics teaches that the medical staff has a responsibility to help our patients live in a way that is consistent with how they understand their task or responsibility in life. For some patients, the best way to preserve a meaningful life in which they can fulfill their sense of purpose in the time that remains is to focus on palliation. For this reason, although palliative and supportive care are provided from the time of diagnosis, it is critical we make sure our patients realize that they have the opportunity to make a decision between either pursuing additional active treatments or choosing to focus primarily on palliative therapies to maximize quality of life. The Jewish tradition and our experience in spiritual care suggest the importance of helping patients preserve hope while, simultaneously, honestly acknowledging their situation. Staff members can play a vital role in helping patients make the most of this new period of their lives. PMID- 23089234 TI - Proton pump inhibitor induced hypomagnesemia: a case report. PMID- 23089235 TI - Measuring priority symptoms in advanced bladder cancer: development and initial validation of a brief symptom index. AB - BACKGROUND: Improved measurement of clinically meaningful symptoms is needed in advanced bladder cancer. OBJECTIVE: This study developed and examined the initial reliability and validity of a new measure of advanced bladder cancer-specific symptoms, the NCCN-FACT Bladder Symptom Index-18 (NFBISI-18), which assesses the symptoms perceived as most important by patients and oncology clinical experts. METHODS: A total of 31 individuals with advanced bladder cancer rated the importance of 28 symptoms. In addition, 10 oncology clinical experts rated symptoms as treatment- or disease-related. Patient-rated symptoms were reconciled with published clinicians' symptom priorities, producing the NFBISI-18. Participants completed measures of quality of life (QOL) and performance status to examine initial validity. RESULTS: An 18-item symptom index for advanced bladder cancer included 3 subscales: disease-related symptoms, treatment side effects, and general function/well-being. Lower scores indicate greater symptom burden. Preliminary reliability reveals good internal consistency for the full NFBISI-18 (alpha = 0.83). The NFBISI-18 was significantly associated with QOL criteria and performance status, in the expected direction. LIMITATIONS: Limitations include the cross-sectional design and the relatively low reliability of the disease-related symptoms subscale. CONCLUSION: The NFBISI-18 demonstrates preliminary evidence as a valid brief measure of the most important symptoms of advanced bladder cancer, as rated by both patients and oncology clinical experts. The NFBISI-18 should have greater acceptability to regulatory authorities than previously developed questionnaires. PMID- 23089236 TI - Differences in neuromuscular control between impact and no impact roundhouse kick in athletes of different skill levels. AB - This study aimed at investigating two aspects of neuromuscular control around the hip and knee joint while executing the roundhouse kick (RK) using two techniques: Impact RK (IRK) at trunk level and No-Impact RK at face level (NIRK). The influence of technical skill level was also investigated by comparing two groups: elite Karateka and Amateurs. Surface electromyographic (sEMG) signals have been recorded from the Vastus Lateralis (VL), Biceps Femoris (BF), Rectus Femoris (RF), Gluteus Maximum (GM) and Gastrocnemious (GA) muscles of the kicking leg in six Karateka and six Amateurs performing the RKs. Hip and knee kinematics were also assessed. EMG data were rectified, filtered and normalized to the maximal value obtained for each muscle over all trials; co-activation (CI) indexes of antagonist vs. overall (agonist and antagonist) activity were computed for hip and knee flexion and extension. Muscle Fiber Conduction Velocity (CV) obtained from VL and BF muscles was assessed as well. The effect of group and kick on angular velocity, CIs, and CVs was tested through a two-way ANOVA (p < 0.05). An effect of group was showed in both kicks. Karateka presented higher knee and hip angular velocity; higher BF-CV (IRK: 5.1 +/- 1.0 vs. 3.5 +/- 0.5 m/s; NIRK: 5.7 +/- 1.3 vs. 4.1 +/- 0.5 m/s), higher CIs for hip movements and knee flexion and lower CI for knee extension. The results obtained suggest the presence of a skill dependent activation strategy in the execution of the two kicks. CV results are suggestive of an improved ability of elite Karateka to recruit fast MUs as a part of training induced neuromuscular adaptation. PMID- 23089237 TI - Changes of human decidual natural killer cells cocultured with YFP-Toxoplasma gondii: implications for abnormal pregnancy. AB - OBJECTIVE: To investigate the changes of human decidual natural killer (dNK) cells cocultured with Toxoplasma gondii in vitro and to infer implications on pregnancy. DESIGN: Case-control study. SETTING: College and hospital. PATIENT(S): Decidual tissue was obtained from 85 patients undergoing voluntary abortion during the first trimester of gestation (6-12 weeks). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The dNK cells were isolated and infected with YFP-Toxoplasma gondii. Cells were observed by fluorescence and confocal microscopy. The CD56(bright)CD16(-)/CD56(dim)CD16(+) dNK ratio, expression of KIR2DL4, ILT-2, and NKG2D on dNK cells were analyzed by flow cytometry and the cytotoxic activity of infected dNK cells were evaluated. RESULT(S): The CD56(dim)CD16(+)/CD56(bright)CD16(-) dNK ratio was significantly elevated at 12, 24, and 48 hours after YFP-T. gondii infection. Expression of KIR2DL4, ILT-2, and NKG2D were increased after infection, but NKG2D were significantly higher than those of KIR2DL4 and ILT-2. Both the CD56(dim)CD16(+)/CD56(bright)CD16(-) dNK ratio and NKG2D expression were correlated with dNK cytotoxic activity. CONCLUSION(S): Enhanced dNK cytotoxicity due to increased CD16 and NKG2D expression may contribute to abnormal pregnancy outcomes observed with maternal infection with T. gondii. PMID- 23089238 TI - Clinical value of sperm DNA damage should be assessed in motile sperm fraction rather than whole ejaculated sperm. AB - OBJECTIVE: To determine differences and frequency of excessive (>=50%) sperm DNA damage between ejaculated and motile sperm. DESIGN: Sperm DNA damage was assessed by acridine orange fluorescence and the results of ejaculated and motile sperm were compared. SETTING: Public and private clinical assisted reproduction centers. PATIENT(S): A total of 272 subfertile men were studied. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Semen analysis and sperm DNA damage. RESULT(S): Sperm DNA damage was negatively correlated with sperm motility and normal morphology. Overall, 39.7% (108 of 272) of semen samples had excessive sperm DNA damage. In contrast, only 15% (41 of 272) of motile sperm fractions had excessive DNA damage. Based on DNA results of motile sperm and semen characteristics, the proportion of men with excessive sperm DNA damage was 26% in severe teratozoospermia, 17.5% in oligozoospermia, 12.5% in moderate teratozoospermia, and 4.6% in normozoospermia. Severe teratozoospermia had five times more frequent excessive DNA damage than normozoospermia. CONCLUSION(S): Abnormal sperm morphology is highly associated with sperm DNA damage. Results of DNA damage of ejaculated sperm do not accurately reflect DNA status of motile sperm. Therefore, sperm DNA damage should be assessed in motile sperm fraction rather than whole ejaculated sperm. PMID- 23089239 TI - Dietary composition and nutrient content of the New Nordic Diet. AB - OBJECTIVE: To describe the dietary composition of the New Nordic Diet (NND) and to compare it with the Nordic Nutrition Recommendations (NNR)/Danish Food-based Dietary Guidelines (DFDG) and with the average Danish diet. DESIGN: Dietary components with clear health-promoting properties included in the DFDG were included in the NND in amounts at least equivalent to those prescribed by the DFDG. The quantities of the other dietary components in the NND were based on scientific arguments for their potential health-promoting properties together with considerations of acceptability, toxicological concerns, availability and the environment. Calculations were conducted for quantifying the dietary and nutrient composition of the NND. SETTING: Denmark. SUBJECTS: None. RESULTS: The NND is characterized by a high content of fruits and vegetables (especially berries, cabbages, root vegetables and legumes), fresh herbs, potatoes, plants and mushrooms from the wild countryside, whole grains, nuts, fish and shellfish, seaweed, free-range livestock (including pigs and poultry) and game. Overall, the average daily intakes of macro- and micronutrients in the NND meet the NNR with small adjustments based on evidence of their health-promoting properties. CONCLUSIONS: The NND is a prototype regional diet that takes palatability, health, food culture and the environment into consideration. Regionally appropriate healthy diets could be created on similar principles anywhere in the world. PMID- 23089240 TI - Functional health literacy in Switzerland--validation of a German, Italian, and French health literacy test. AB - OBJECTIVE: This study aimed to translate and validate German, Italian, and French versions of the Short-Test of Functional Health Literacy (S-TOFHLA), to be used in Switzerland and its neighboring countries. METHODS: The original English version of the S-TOFHLA was translated by applying standardized translation methods and cultural adaptations. 659 interviews were conducted with Swiss residents in their preferred language (249 German, 273 Italian, and 137 French). To assess the validity of the measures, known predictors for health literacy (age, education, and presence of a chronic condition) were tested. RESULTS: For all three language versions, results show that younger participants, participants with a higher education and participants with chronic medical conditions had significantly higher levels of health literacy. Furthermore, the three health literacy scales categorized participants into three health literacy levels with most people possessing either inadequate or adequate levels. The highest levels of health literacy were found in the Swiss-German sample (93%), followed by the Swiss-French (83%) and Swiss-Italian (67%) samples. CONCLUSION: The German, Italian, and French versions of the S-TOFHLA provide valid measures of functional health literacy. PRACTICE IMPLICATIONS: The translated versions can be used in the three different language regions of Switzerland as well as in neighboring countries following 'country specific' adjustments and validations. PMID- 23089242 TI - Pre-death grief in Parkinson's caregivers: a pilot survey-based study. AB - OBJECTIVE: To evaluate the evidence for pre-death grief in caregivers (CGs) of persons with Parkinson's disease (PD) and to compare non-motor PD symptoms (cognitive decline, depression, hallucinations) versus motor symptoms (fluctuations of mobility) for associations with CG grief reactions. BACKGROUND: Prolonged grief in response to loss has been associated with negative outcomes and decreased well-being in caregivers (i.e. spouse or adult child) of relatives with dementia. In Parkinson's disease (PD) the negative impact of providing care has been referred to as caregiver strain. Grief has not been explored in PD caregivers, and understanding grief may offer new insights for future intervention. METHODS: Volunteer caregivers (n = 74) filled out the Marwit and Meuser Caregiver Grief Inventory (MM-CGI-SF) which measures 3 types (i.e. subscales) of grief: Personal Sacrifice and Burden, Heartfelt Sadness and Longing, Worry and Felt Isolation. This scale also provided a total grief score. Volunteer caregivers also responded to self-reported UPDRS questions about the motor and non-motor symptoms of their PD relative (i.e. spouse or parent). T tests were used to correlate CG subscales of grief with patient variables. A hierarchical regression analysis was used to determine the predictive contribution of motor and nonmotor symptoms to grief. RESULTS: Grief based on the total score was found in 17% of CGs. Grief was significantly higher in CG's whose relative had more severe symptoms. The type of grief experienced was similar across all three subscales. Hierarchical regression analysis revealed that nonmotor symptoms explained slightly more of the variance (14-23%) than motor symptoms (11-17%). CONCLUSIONS: This study revealed that pre-death grief is a significant finding in PD caregivers. The severity of symptoms and the presence of nonmotor symptoms, especially cognitive decline, predict caregivers who are at greatest risk of prolonged grief; however it should be kept in mind that motor symptoms also contribute. PMID- 23089241 TI - Effect of canola oil emulsion injection on processing characteristics and consumer acceptability of three muscles from mature beef. AB - The study was undertaken to investigate the impact of the combined effect of blade tenderization and canola oil emulsion injection on processing yield and eating quality-related parameters of selected loin and hip muscles (longissimus lumborum, LL, biceps femoris, BF and semimembranosus, SM) from over thirty month (OTM) cattle. Canola oil emulsion injection significantly reduced shear force, increased sensory scores for juiciness and tenderness, and made connective tissue less perceptible. Targeted levels of omega-3 fatty acids can be achieved by the inclusion of canola oil containing marinades/emulsions at levels sufficient to retain omega-3 fatty acids in cooked product. All consumer acceptability attributes of OTM muscles were improved with the use of canola oil emulsion injection treatments without compromising colour although slightly decreasing oxidative stability of BF muscle. Injection of omega-3 oil emulsions in combination with blade tenderization can be effectively utilized to enrich injected products in essential fatty acids and enhance eating quality of OTM beef. PMID- 23089243 TI - Prevalence and features of unreported dystonia in a family study of "pure" essential tremor. AB - BACKGROUND: Essential tremor (ET) is considered to be a highly heritable disorder, yet no susceptibility genes have been identified. The search for ET genes is severely hampered by clinical and genetic heterogeneity; the existence of this heterogeneity complicates the genetic analyses. We sought to determine the prevalence and clinical features of unreported dystonia in a family study of "pure" ET. METHODS: ET probands and their reportedly affected first-and second degree relatives were enrolled in a genetics study, the Family Study of Essential Tremor (FASET) at Columbia University Medical Center. The goal was to enroll cases with "pure" ET (i.e., ET without dystonia or other neurological problems). Each enrollee underwent a detailed neurological evaluation. RESULTS: There were 100 enrollees (28 probands, 72 relatives). Dystonia (primarily torticollis) occurred in 9 (32.1%) of 28 families, with 5 cases in one family, 2 cases in two families, and 1 case in six families. Those affected with dystonia included 3 (10.7%) probands and 12 (16.7%) relatives. There was a gender predilection: 14/15 (93.3%) with dystonia vs. 41/85 (48.2%) without dystonia were women (p = 0.001). Dystonia was previously undiagnosed in 14/15 (93.3%) cases. CONCLUSIONS: Dystonia (esp. torticollis in women) was present in nearly one-third of the ET families in a genetics study, including 10.7% of ET probands. Dystonia was unreported and previously undiagnosed in nearly all of these individuals. The overarching biological issue is whether ET and dystonia should be regarded as one disease or two; this has obvious implications for the structuring of analyses in genetic studies. PMID- 23089244 TI - [Managing of the patient with dyspepsia. Clinical Practice Guideline. Update 2012]. AB - The "Preparation of Clinical Practice Guidelines in Digestive Diseases, from Primary Care to Specialist Care" Program, is a joint project by the Spanish Gastroenterology Association (AEG), the Spanish Society of Family and Community Medicine (SEMFyC), and the IberoAmerican Cochrane Center (CCI). We present the update of the Guidelines on the Management of Dyspepsia, which was published in 2003. The essential criteria provided in the AGREE (Appraisal of Guidelines, Research and Evaluation for Europe) Instrument were taken into account in the preparation of this document. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to classify the scientific evidence and strengthen the recommendations. PMID- 23089245 TI - Cancer stem cell dynamics in tumor progression and metastasis: is the microenvironment to blame? AB - Stem cells are defined by their self-renewal capacity and the ability to give rise to all differentiated progeny necessary for one specific organ. These two characteristics are also inherent in cancer stem cells (CSCs), which are thought to be the only subpopulation within a tumor endowed with tumorigenic potential. CSCs combine many features that render cancer one of the leading causes of death in the Western world: metastasis, tumor recurrence, and therapy refractoriness. Strikingly, CSCs are not a fixed entity, but differentiated tumor cells are able to revert to a stem-like state. Thus, CSCs are not only intrinsically programmed to fulfill their detrimental roles, but are orchestrated by stromal cells residing in their vicinity and forming the CSC niche. Yet, this relationship is not a one-way road: CSCs are able to manipulate stromal cells to their needs, not only in the primary tumor, but also in distant organs and thus prime the foreign soil for their arrival by inducing a premetastatic niche. The suggested plasticity between the differentiation states of cancer cells and the regulation by microenvironmental cues provides new starting-points for novel cancer therapies. PMID- 23089246 TI - Comparative aspects of kisspeptin gene regulation. AB - Kisspeptin plays an important role in the onset of puberty through stimulation of gonadotropin-releasing hormone (GnRH), a master molecule of reproduction. Furthermore, the existence of multiple kisspeptins is evident in most vertebrate species. Therefore, elucidating the regulatory mechanisms of the kisspeptin genes is important to understand the functions of multiple kisspeptin forms in the brain. This review focuses on the comparative aspects of kisspeptin gene regulation with an emphasis on the role of environmental signals including gonadal steroids, photoperiods and metabolic signals. These environmental signals differently regulate the kisspeptin genes distinctively in each species. In addition, photoperiodic regulation of the kisspeptin genes alters during sexual maturational, suggesting interactions between the gonadal hormone pathway and the photoperiod pathway. Further studies of the regulatory mechanisms of kisspeptin genes especially in teleosts which possess multiple kisspeptin/kisspeptin receptor systems will help to understand the precise role of multiple kisspeptin forms in different species. PMID- 23089247 TI - Estrogenic regulation of Kiss1 mRNA variants in Hatano rats. AB - Differences in reproductive endocrinology distinguish Hatano high-avoidance animals (HAA) from low-avoidance animals (LAA). Compared to HAA rats, female LAA rats secrete low levels of basal luteinizing hormone (LH) and a reduced LH surge. To investigate the underlying cause of the differences between the two strains, levels of the following mRNAs were measured in the hypothalamus of intact and ovariectomized (OVX) females treated with vehicle control or estradiol-17beta (E2): gonadotropin-releasing hormone (Gnrh), newly isolated rat kisspeptin (Kiss)1 mRNA variant-1 (Kiss1V1) and variant-2 (Kiss1V2) and estrogen receptor (Er) alpha. In OVX-HAA rats, the levels of Gnrh mRNA in the preoptic area (POA) 30 h after E2 treatment were significantly higher than in OVX-LAA rats. For HAA rats, the levels of Kiss1V1 and Kiss1V2 mRNA in the anteroventral periventricular nucleus (AVPV) were significantly higher in the E2-treated group than in the vehicle-treated group. In the arcuate nucleus (Arc) of HAA rats, Kiss1V1 and Kiss1V2 expression was significantly lower in E2-treated females compared to vehicle-treated females. Kiss1V2 expression was significantly higher than Kiss1V1 expression in intact HAA rats. In E2-treated OVX-LAA rats, there were no changes in the expression levels of Gnrh, Kiss1V1 or Kiss1V2. In intact LAA rats, no differences were observed in the expression levels of Kiss1V1 or Kiss1V2 in the AVPV, but the expression levels of these mRNAs in the Arc were significantly lower in E2-treated OVX-LAA rats. Additionally, no strain differences were observed for Eralpha mRNA expression in either the AVPV or Arc. These results indicate that the failure of estrogenic regulation of GnRH neurons in the POA and of kisspeptin neurons in the AVPV of LAA rats causes low LH secretion and reduced reproductive function. PMID- 23089249 TI - Carbaryl exposure and recovery modify the interrenal and thyroidal activities and the mitochondria-rich cell function in the climbing perch Anabas testudineus Bloch. AB - We examined the effects of carbaryl (1-naphthyl methylcarbamate; sevin), a carbamate pesticide, on interrenal and thyroid activities and mitochondrial rich (MR) cell function in climbing perch to understand the physiological basis of toxicity acclimation in this fish to the chemical stressor. Carbaryl exposure (5 20 mg L(-1)) for 48 h increased cortisol and glucose, but decreased the T(3) level without affecting T(4) concentration in the plasma. These responses of the carbaryl-exposed fish were nullified and a rise in plasma T(4) occurred in these fish when they were kept for 96 h recovery in clean water. A tight plasma mineral control was indicated in the carbaryl-exposed fish as reflected by the unchanged plasma Na, K, Ca and inorganic phosphate levels. The ouabain-sensitive Na(+), K(+)-ATPase activity showed an increase in the gills but the intestinal and renal tissues showed little response to carbaryl treatment. However, substantial increases in the intestinal and renal Na(+), K(+)-ATPase activities occurred in the recovery fish. The MR cells in the branchial epithelia showed a strong Na(+), K(+)-ATPase immunoreactivity to carbaryl treatment indicating an activated MR cell function. The numerical MR cell density remained unchanged, but stretching of secondary gill lamellae as part of gill remodeling occurred during carbaryl exposure. The increased surface of these lamellae with abundant MR cells as a result of its migration into the lamellar surface points to marked structural and functional modifications of these cells in the carbaryl-treated fish which is likely to a target for carbaryl action. The rise in plasma T(4) and the restoration of normal branchial epithelia in the recovery fish indicate a thyroidal involvement in the recovery response and survival. Our data thus provide evidence that carbaryl exposure and its recovery evoke interrenal and thyroid disruption in this fish leading to a modified osmotic response including an altered MR cell function. PMID- 23089250 TI - The interactive effects of selenomethionine and methylmercury on their absorption, disposition, and elimination in juvenile white sturgeon. AB - Selenium (Se) and mercury (Hg) are prevalent pollutants of industrialized watersheds. However, when co-administered, Se has protective effects on organisms from Hg. The mechanism is not fully understood, but it is thought that Se reduces Hg availability, either by forming biologically inert complexes and/or associating with selenoproteins. Despite concerns with aquatic contaminations, relatively little information is available on the interaction in aquatic organisms. In the present study, the interactive effects of Se and Hg on their absorption, disposition, and elimination were examined in juvenile white sturgeon, a benthic fish species at high risk to exposures of both contaminants. Selenium and Hg were provided as L-selenomethionine (SeMet) and methylmercury (MeHg), respectively. Groups of 10 sturgeon were orally intubated with a single dose of either 0 (control), SeMet (500 MUg Se/kg body weight; BW), MeHg (850 MUg Hg/kg BW), or their combination (Se/Hg; 500 MUg Se/kg and 850 MUg Hg/kg BW). The blood was repeatedly sampled and urine collected from the fish, over a 48 h post intubation period. At 48 h, the fish were sacrificed for Se and Hg tissue concentration and distribution. The co-administration of SeMet and MeHg significantly (p<0.05) lowered blood concentrations of both Se and Hg and tissue Se concentrations. Similarly, assimilation of Se and Hg was also reduced significantly. The interaction has a more quantitative effect on Se metabolism because the reduction in the overall tissue Se is a consequence of reduced Se absorption at the gut and not from the metabolic effects after absorption. In contrast, given the pulse increase in blood Hg concentration, tissue redistribution, and increased urinary elimination, the interactive effect on tissue Hg concentration is likely to be post-absorption. Even in the absence of exogenous SeMet, Se and Hg co-accumulated in tissue at a Se:Hg molar ratio greater than 1. Thus, similar to mammals, maintaining at least a 1:1 molar ratio of Se and Hg is of great physiological importance in the white sturgeon. Interestingly, SeMet did not divert Hg from the brain. Allocation of Se from the kidneys may have occurred in order to maintain the high Se:Hg molar ratios in the brain of white sturgeon. In the current study, the combined use of kinetic analysis and that of the conventional approach of measuring tissue concentration changes provided a comprehensive understanding of the interactive effect of SeMet and MeHg on their respective metabolic processes in juvenile white sturgeon. PMID- 23089251 TI - The effectiveness and cost-effectiveness of enzyme and substrate replacement therapies: a longitudinal cohort study of people with lysosomal storage disorders. AB - OBJECTIVES: To determine natural history and estimate effectiveness and cost of enzyme replacement therapy (ERT) and substrate replacement therapy (SRT) for patients with Gaucher disease, Fabry disease, mucopolysaccharidosis type I (MPS I), mucopolysaccharidosis type II (MPS II), Pompe disease and Niemann-Pick type C (NPC) disease. DESIGN: Cohort study including prospective and retrospective clinical- and patient-reported data. Age- and gender-adjusted treatment effects were estimated using generalised linear mixed models. Treated patients contributed data before and during treatment. Untreated patients contributed natural history data. SETTING: National Specialised Commissioning Group designated lysosomal storage disorder (LSD) treatment centres in England. PARTICIPANTS: Consenting adults and children with a diagnosis of Gaucher disease (n = 272), Fabry disease (n = 499), MPS I (n = 126), MPS II (n = 58), NPC (n = 58) or Pompe disease (n = 93) who had attended a treatment centre in England. INTERVENTIONS: ERT and SRT. MAIN OUTCOME MEASURES: Clinical outcomes chosen by clinicians to reflect disease progression for each disorder; patient-reported quality-of-life (QoL) data; cost of treatment and patient-reported service-use data; numbers of hospitalisations, outpatient and general practitioner appointments; medication use; data pertaining to associated family/carer costs and QoL impacts. RESULTS: Seven hundred and eleven adults and children were recruited. In those with Gaucher disease (n = 175) ERT was associated with improved platelet count, haemoglobin, liver function and reduced risk of enlarged liver or spleen. No association was found between ERT and QoL. In patients with Fabry disease (n = 311) increased time on ERT was associated with small decreases in left ventricular mass and improved glomerular filtration rate, but not with changes in risk of stroke/transient ischaemic attacks or the need for a hearing aid. There was a statistically significant association between duration of ERT use and worsening QoL and fatigue scores. We found no statistical difference in estimates of treatment effectiveness between the two preparations, agalsidase beta (Fabrazyme((r)), Genzyme) (n = 127) and agalsidase alpha (Replagal((r)), Shire HGT) (n = 91), licensed for this condition. In Pompe disease (n = 77) our data provide some evidence of a beneficial effect on muscle strength and mobility as measured by a 6-minute walk test in adult-onset patients; there were insufficient data from infantile-onset Pompe patients to estimate associations between ERT and outcome. Among subjects with MPS I (n = 68), 42 of the 43 patients with MPS I subtype Hurler's disease had undergone a bone marrow transplant. No significant associations were found between ERT and any outcome measure for the MPS I subtype Scheie disease and heparan sulphate patients. An association between duration of ERT and growth in children was the only statistically significant finding among patients with MPS II (n = 39). There were insufficient data for patients with NPC disease to draw any conclusions regarding the effectiveness of SRT. The current annual cost to the NHS of the different ERTs means that between 3.6 and 17.9 discounted quality-adjusted life-years (QALYs) for adult patients and between 2.6 and 10.5 discounted QALYs for child patients would need to be generated for each year of being on treatment for ERTs to be considered cost-effective by conventional criteria. CONCLUSIONS: These data provide further evidence on the effectiveness of ERT in people with LSDs. However, the results need to be interpreted in light of the fact that the data are observational and the relative lack of power due to the small numbers of patients with MPS I, MPS II, Pompe disease and NPC disease. Future work should aim to effectively address the unanswered questions and this will require agreement on a common set of outcome measures and their consistent collection across all treatment centres. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 39. See the HTA programme website for further project information. PMID- 23089252 TI - Phages of lactic acid bacteria: the role of genetics in understanding phage-host interactions and their co-evolutionary processes. AB - Dairy fermentations are among the oldest food processing applications, aimed at preservation and shelf-life extension through the use of lactic acid bacteria (LAB) starter cultures, in particular strains of Lactococcus lactis, Streptococcus thermophilus, Lactobacillus spp. and Leuconostoc spp. Traditionally this was performed by continuous passaging of undefined cultures from a finished fermentation to initiate the next fermentation. More recently, consumer demands on consistent and desired flavours and textures of dairy products have led to a more defined approach to such processes. Dairy (starter) companies have responded to the need to define the nature and complexity of the starter culture mixes, and dairy fermentations are now frequently based on defined starter cultures of low complexity, where each starter component imparts specific technological properties that are desirable to the product. Both mixed and defined starter culture approaches create the perfect environment for the proliferation of (bacterio)phages capable of infecting these LAB. The repeated use of the same starter cultures in a single plant, coupled to the drive towards higher and consistent production levels, increases the risk and negative impact of phage infection. In this review we will discuss recent advances in tracking the adaptation of phages to the dairy industry, the advances in understanding LAB phage-host interactions, including evolutionary and genomic aspects. PMID- 23089253 TI - Essential role of RIG-I in the activation of endothelial cells by dengue virus. AB - Dengue virus (DENV) infection is associated to exacerbated inflammatory response and structural and functional alterations in the vascular endothelium. However, the mechanisms underlying DENV-induced endothelial cell activation and their role in the inflammatory response were not investigated so far. We demonstrated that human brain microvascular endothelial cells (HBMECs) are susceptible to DENV infection, which induces the expression of the cytoplasmic pattern recognition receptor (PRR) RIG-I. Infection of HBMECs promoted an increase in the production of type I IFN and proinflammatory cytokines, which were abolished after RIG-I silencing. DENV-infected HBMECs also presented a higher ICAM-1 expression dependent on RIG-I activation as well. On the other hand, ablation of RIG-I did not interfere with virus replication. Our data suggest that RIG-I activation by DENV may participate in the disease pathogenesis through the modulation of cytokine release and expression of adhesion molecules, probably contributing to leukocyte recruitment and amplification of the inflammatory response. PMID- 23089255 TI - Monolithic ion exchange chromatographic methods for virus purification. AB - We report an ion exchange chromatographic purification method powerful for preparation of virus particles with ultrapure quality. The technology is based on large pore size monolithic anion exchangers, quaternary amine (QA) and diethyl aminoethyl (DEAE). These were applied to membrane-containing icosahedral bacteriophage PRD1, which bound specifically to both matrices. Virus particles eluted from the columns retained their infectivity, and were homogenous with high specific infectivity. The yields of infectious particles were up to 80%. Purified particles were recovered at high concentrations, approximately 5mg/ml, sufficient for virological, biochemical and structural analyses. We also tested the applicability of the monolithic anion exchange purification on a filamentous bacteriophage phi05_2302. Monolithic ion exchange chromatography is easily scalable and can be combined with other preparative virus purification methods. PMID- 23089254 TI - HCMV gB shares structural and functional properties with gB proteins from other herpesviruses. AB - Glycoprotein B (gB) facilitates HCMV entry into cells by binding receptors and mediating membrane fusion. The crystal structures of gB ectodomains from HSV-1 and EBV are available, but little is known about the HCMV gB structure. Using multiangle light scattering and electron microscopy, we show here that HCMV gB ectodomain is a trimer with the overall shape similar to HSV-1 and EBV gB ectodomains. HCMV gB ectodomain forms rosettes similar to rosettes formed by EBV gB and the postfusion forms of other viral fusogens. Substitution of several bulky hydrophobic residues within the putative fusion loops with more hydrophilic residues reduced rosette formation and abolished cell fusion. We propose that like gB proteins from HSV-1 and EBV, HCMV gB has two internal hydrophobic fusion loops that likely interact with target membranes. Our work establishes structural and functional similarities between gB proteins from three subfamilies of herpesviruses. PMID- 23089256 TI - Thioridazine potentiates the effect of a beta-lactam antibiotic against Staphylococcus aureus independently of mecA expression. AB - The neuroleptic antipsychotic derivate thioridazine has been shown to increase the susceptibility of a methicillin-resistant Staphylococcus aureus (MRSA) isolate towards dicloxacillin. The aim of this study was to investigate the combinatorial effect of the two drugs on a broad selection of staphylococcal strains by analyzing a large collection of MRSA strains carrying different types of SCCmec, as well as MSSA strains. Transcription and translation of the resistance marker PBP2a encoded by mecA within the SCCmec cassette were analyzed by primer extension and western blotting. We observed increased susceptibility to dicloxacillin in the presence of thioridazine in all tested MRSA isolates. In contrast to previously published results, the synergistic effect was also applicable to methicillin-susceptible S. aureus (MSSA). We conclude that the combination of dicloxacillin and thioridazine potentiates the killing effect against S. aureus in a broad selection of clinical isolates. Additionally, the study indicates that the killing effect by the combinatorial treatment is independent of PBP2a-mediated resistance mechanisms. PMID- 23089257 TI - Effects of intracellular poly(3-hydroxybutyrate) reserves on physiological biochemical properties and growth of Ralstonia eutropha. AB - Microbial polyhydroxyalkanoates (PHAs), because of their well studied complex physiology and commercial potential, are vehicles for carbon and potential storage reduction for many microbial species. Even with the wealth of studies about microbial PHAs in the scientific literature, polymer accumulation and degradation are still not comprehensively understood. Poly(3-hydroxybutyrate) (P3HB) granule formation and polymer mobility were studied here in the bacterium Ralstonia eutropha strain B5786 in autotrophic cultures. Electron microscopy studies revealed decreasing cell size concomitant with enlargement of size and number of intracellular granules, and inhibition of cell division during intracellular polymer production. Activities of key P3HB biosynthetic enzymes demonstrated correlations with each other during polymer accumulation, suggesting an intricately regulated P3HB cycle in autotrophically grown R. eutropha cells. PMID- 23089258 TI - Perinatal maternal and neonatal outcomes in women with gestational diabetes mellitus according to fetal sex. AB - BACKGROUND: Male sex is a well-known risk factor for unfavorable perinatal outcomes. Fetal sex has been considered only occasionally in diabetic pregnancy. OBJECTIVE: Our aim was to evaluate perinatal outcomes in women with gestational diabetes mellitus (GDM) according to fetal sex. METHODS: We conducted a retrospective review of all singleton pregnancies of women with GDM progressing to >22 weeks and delivering in our center between 1981 and 2007. Evaluated maternal characteristics included anthropometrics, obstetric history, GDM diagnosis characteristics (ie, gestational age, blood glucose values), HbA(1c) (after diagnosis and in the third trimester). Outcomes variables were cesarean section (CS), gestational hypertension, preterm birth, abnormal Apgar, large and small for gestational age newborns, obstetric trauma, major and minor malformations, neonatal hypoglycemia, jaundice, respiratory distress, polycythemia, hypocalcemia, perinatal mortality, and a composite outcome. We used a descriptive and multiple logistic regression analysis (backwards method). RESULTS: A total of 2299 pregnancies were included (1125 female and 1174 male infants). Maternal characteristics were essentially similar in male and female newborns. For outcomes, unadjusted figures were higher in pregnancies of male newborns in 14 of 16 perinatal outcomes, but significance was only reached for CS. The logistic regression analyses revealed male sex as an independent predictor of CS (odds ratio = 1.48; 95% CI, 1.15-1.90) and neonatal hypoglycemia (odds ratio = 2.13; 95% CI, 1.02-4.43). CONCLUSIONS: In this group of women with GDM, perinatal outcomes in pregnancies of male newborns differ in only 2 of 16 evaluated variables: an increased frequency of CS and neonatal hypoglycemia. Male newborns of mothers with GDM could benefit from increased awareness of neonatal hypoglycemia. PMID- 23089259 TI - Determining brain death after therapeutic hypothermia on nonpulsatile continuous flow mechanical circulatory support devices. PMID- 23089260 TI - Limitations of cerebral oxygenation monitoring by near-infrared spectroscopy in children with cyanotic congenital heart disease and profound polycythemia. PMID- 23089261 TI - 3-dimensional right ventricular volume assessment. AB - PURPOSE: The purpose of this review was to evaluate new computer software available for 3-dimensional right ventricular (RV) volume estimation. DESCRIPTION: Based on 2-dimensional echocardiography, various algorithms have been used for RV volume estimation. These are complex, time-consuming techniques and are prone to significant error. The current clinical paradigm of RV volume assessment is based on the visual quantitative assessment of chamber size and the use of tricuspid annular and RV internal diameters as a surrogate measure of RV volume. Hence, there is a need for a practical method for the intraoperative assessment of RV volume. EVALUATION: The evaluation consists of an objective review of the capabilities of this software and its potential application in the operating room. The authors also performed a detailed review of the potential limitations and possible improvements. CONCLUSIONS: This new software has the potential to be incorporated into the existing workflow environment of the ultrasound systems in the future, making it clinically feasible to perform perioperative RV volume analysis. PMID- 23089263 TI - Reply to Drs Rady and Verheijde. PMID- 23089262 TI - Extracorporeal membrane oxygenation as a bridge therapy for massive pulmonary embolism after esophagectomy. PMID- 23089265 TI - Fatty acid profile of the milk of cows reared in the mountain region of Poland. AB - An appropriate composition of milk fatty acids (FA) improves the nutritional value of milk and milk products, and improves milk processing. Polish dairy farms in the mountainous region are rather small, animal nutrition there is based on locally produced forages and this, together with the transitional climate zone brings about seasonal changes in FA composition of milk. The aim of the study was to evaluate the composition of FA in bovine milk fat in relation to fat intake in forages and their FA profiles. The study involved 5 herds reared in low-input mountain farms located at an altitude of 670-780 m above sea level (Beskid Mountains). The cows were fed forages produced locally. FAs in forages and milk samples were subjected to gas chromatography. Highest fat intake observed in grazing season (4.2-4.7%) and high amounts of polyunsaturated FA in forages from that period (51.8-64.1 g/100 g FA) resulted in a markedly high content of valuable FAs: t-11 C18:1 (3.22 g/100 g FA), c-9, t-11 C18:2 (CLA; 1.20 g/100 g FA) in milk. Lower fat intake of forages containing high amount of SFA (32.42 38.83 g/100 g FA) in the indoor period resulted in changes in milk composition. The content of total short-chain saturated FA (SCFA) was highest in winter and early spring samples (14.10 and 13.44 g/100 g FA, respectively), like the amounts of myristic C14:0 and palmitic C16:0 acids (11.80 and 37.92 g/100 g FA). Total odd- and branched-chain fatty acids (OBCFA; 6.58 g/100 g FA) content was highest at the beginning of the grazing period. Fresh grass consumed by cows promoted the activity of Delta(9)-desaturase in mammary gland as evidenced by higher C14:1 : C14:0 (0.054) and C16:1 : C16:0 (0.026) ratios in grazing than in the indoor periods. PMID- 23089266 TI - Direct estimation of sialic acid in milk and milk products by fluorimetry and its application in detection of sweet whey adulteration in milk. AB - Sialic acid, being a biologically active compound, is recognised as an important component of milk and milk products. Almost all the sialic acid estimation protocols in milk require prior hydrolysis step to release the bound sialic acid followed by its estimation. The objective of this work was to estimate sialic acid in milk and milk products by fluorimetric assay which does not require a prior hydrolysis step thus decreasing the estimation time. The recovery of added sialic acid in milk was 91.6 to 95.8%. Sialic acid in milk was found to be dependent on cattle breed and was in the range of 1.68-3.93 g/kg (dry matter basis). The assay was further extended to detect adulteration of milk with sweet whey which is based on the detection of glycomacropeptide (GMP) bound sialic acid in adulterated milk. GMP is the C-terminal part of kappa-casein which is released into the whey during cheese making. For detection of adulteration, selective precipitation of GMP was done using trichloroacetic acid (TCA). TCA concentration in milk was first raised to 5% to precipitate milk proteins, especially kappa casein, followed by raising the TCA concentration to 14% to precipitate out GMP. In the precipitates GMP bound sialic acid was estimated using fluorimetric method and the fluorescence intensity was found to be directly proportional to the level of sweet whey in adulterated milk samples. The method was found to detect the presence of 5% sweet whey in milk. PMID- 23089268 TI - Uric Acid: a clearer focus. PMID- 23089267 TI - Reframing family-centred obesity prevention using the Family Ecological Model. AB - OBJECTIVE: According to the Family Ecological Model (FEM), parenting behaviours are shaped by the contexts in which families are embedded. In the present study, we utilize the FEM to guide a mixed-methods community assessment and summarize the results. Additionally, we discuss the utility of the FEM and outline possible improvements. DESIGN: Using a cross-sectional design, qualitative and quantitative methods were used to examine the ecologies of parents' cognitions and behaviours specific to children's diet, physical activity and screen-based behaviours. Results were mapped onto constructs outlined in the FEM. SETTING: The study took place in five Head Start centres in a small north-eastern city. The community assessment was part of a larger study to develop and evaluate a family centred obesity prevention programme for low-income families. SUBJECTS: Participants included eighty-nine low-income parents/caregivers of children enrolled in Head Start. RESULTS: Parents reported a broad range of factors affecting their parenting cognitions and behaviours. Intrafamilial factors included educational and cultural backgrounds, family size and a lack of social support from partners. Organizational factors included staff stability at key organizations, a lack of service integration and differing school routines. Community factors included social connectedness to neighbours/friends, shared norms around parenting and the availability of safe public housing and play spaces. Policy- and media-related factors included requirements of public assistance programmes, back-to-work policies and children's exposure to food advertisements. CONCLUSIONS: Based on these findings, the FEM was refined to create an evidence-based,temporally structured logic model to support and guide family-centred research in childhood obesity prevention. PMID- 23089269 TI - Gout: a step forward. PMID- 23089271 TI - Changes in serum urate and urate excretion with age. AB - A cross-sectional study was performed evaluating serum urate levels and fractional excretion of urate in a group of patients referred for screening for inherited metabolic disorders. From 2003 through 2010, serum urate, serum creatinine, urinary urate, and urinary creatinine levels were obtained as part of a research protocol to identify individuals with inherited metabolic disorders. These values were compared with individuals with uromodulin-associated kidney disease (UAKD). Laboratory studies were evaluated on 1274 individuals. The fractional excretion of urate was very high in infancy (27 +/- 21% in males and 29 +/- 25% in females). The high fractional excretion declined rapidly over the first several months of life, together with a decline in serum urate levels. The mean fractional excretion was approximately 8% during childhood. It then remained stable in females but decreased in males to 5.9 +/- 5.6% in adolescence and 5.3 +/- 3.8% in adulthood. Serum urate levels in childhood were influenced by age and kidney function but not gender. In adulthood, serum urate was influenced by age, gender, and estimated glomerular filtration rate. Although patients with UAKD had lower fractional excretions of urate than individuals with normal kidney function, there was considerable overlap. PMID- 23089272 TI - Hyperuricemia and hypertension. AB - Over the past century, uric acid has been considered a possible risk factor for hypertension and cardiovascular disease. However, only in the past decade, animal models and clinical trials have supported a more mechanistic link. Results from animal models suggest a 2-phase mechanism for the development of hyperuricemic hypertension in which uric acid induces acute vasoconstriction by activation of renin-angiotensin system, followed by uric acid uptake into vascular smooth muscle cells leading to cellular proliferation and secondary arteriolosclerosis that impairs pressure natriuresis. This acute hypertension remains uric acid dependent and sodium independent, whereas the chronic hypertension becomes uric acid independent and sodium dependent. Small clinical trials, performed in adolescents with newly diagnosed essential hypertension, demonstrate that reduction of serum uric acid can reduce blood pressure. Although more research is clearly necessary, the available data suggest that uric acid is likely causative in some cases of early onset hypertension. PMID- 23089273 TI - Hyperuricemia and the progression of chronic kidney disease: is uric acid a marker or an independent risk factor? AB - Hyperuricemia is seen when kidney function declines. Whether elevated uric acid (UA) levels play a role in the initiation and progression of kidney disease is a subject of a great debate. Animal studies demonstrate that elevated UA level is a risk factor for kidney disease. In humans, the relationship between UA and kidney disease is more complicated. Cross-sectional studies show an association of hyperuricemia with the presence of CKD; however, from cross-sectional studies, one cannot determine which came first-the elevated UA level or the kidney disease. UA levels are also associated with other risk factors for kidney disease, including hypertension, metabolic syndrome, and microalbuminuria, but it is not clear whether these are mediators or confounders of a relationship. Observational studies suggest a relationship of UA level with incident CKD, but studies evaluating the relationship with decline in kidney function in established CKD are conflicting. Finally, small clinical trials using allopurinol to lower UA levels provide weak, but potentially promising, evidence that lowering UA levels may retard the progression of CKD. In this article, we will review the evidence of the association of hyperuricemia and CKD. PMID- 23089274 TI - A perspective on diet and gout. AB - The epidemiology of gout has changed dramatically over the past century. Once thought of as a disease of the nobility, it is now an egalitarian disease that affects patients across the socioeconomic spectrum. The incidence of gout has also risen in recent years, to the point that we are now seeing what is regarded by some as a "second epidemic" of gout. This change coincides with a significant dietary shift for many Americans - in particular, the advent of high-fructose corn syrup as the most prominent sweetener in the modern American diet and what may be a related rise in obesity. Fructose is a powerful driver of ATP catabolism that, in turn, leads to the production of uric acid. The new epidemic of gout is likely secondary in significant part to the rise in fructose consumption, as well as to the increase in obesity, the endurance of other dietary and non-dietary gout risk factors such as consumption of meat and alcohol, the continued use of culprit medications and potentially to the under-recognition of the benefits of certain foods and drinks (such as dairy products and coffee). Though the exact reasons for the rise in gout are yet unproven, this reopens the opportunity for dietary control of hyperuricemia through restraints that curtail not only exogenous but also endogenous pathways of purine production. PMID- 23089270 TI - Renal transport of uric acid: evolving concepts and uncertainties. AB - In addition to its role as a metabolic waste product, uric acid has been proposed to be an important molecule with multiple functions in human physiologic and pathophysiologic processes and may be linked to human diseases beyond nephrolithiasis and gout. Uric acid homeostasis is determined by the balance between production, intestinal secretion, and renal excretion. The kidney is an important regulator of circulating uric acid levels by reabsorbing about 90% of filtered urate and being responsible for 60% to 70% of total body uric acid excretion. Defective renal handling of urate is a frequent pathophysiologic factor underpinning hyperuricemia and gout. Despite tremendous advances over the past decade, the molecular mechanisms of renal urate transport are still incompletely understood. Many transport proteins are candidate participants in urate handling, with URAT1 and GLUT9 being the best characterized to date. Understanding these transporters is increasingly important for the practicing clinician as new research unveils their physiologic characteristics, importance in drug action, and genetic association with uric acid levels in human populations. The future may see the introduction of new drugs that act specifically on individual renal urate transporters for the treatment of hyperuricemia and gout. PMID- 23089275 TI - Genetic disorders resulting in hyper- or hypouricemia. AB - Serum uric acid concentrations are governed by the balance of urate production and excretion. Besides well-known secondary causes of hyperuricemia, such as myeloproliferative diseases, decreased renal function, and excessive dietary purine intake, there are a number of genetic disorders that result in hyper- or hypouricemia. Renal impairment in these disorders may be associated with the development of chronic kidney disease, acute kidney injury, or urate nephrolithiasis. These conditions are frequently misdiagnosed, not because the diagnosis is complicated and difficult to ascertain, but rather because of a lack of awareness of the particular condition. The first important step in the diagnosis is obtaining a detailed family history, with evaluation of serum and urinary urate concentrations. This review will aid physicians in identifying these inherited kidney disorders associated with hyperuricemia and hypouricemia. Identification of these conditions will help to explain the pathogenesis of different types of gout, and may extend insights into the urate transport and chronic kidney disease. PMID- 23089276 TI - The rheumatology of gout. AB - Gout is a metabolic disorder of purine metabolism with primary manifestations of acute and chronic arthritis and tophus formation. The prevalence of gout appears to be increasing and may affect up to 8 million people in the United States. The development of novel therapies for gout after a 40-year hiatus has opened new understanding of this disease. In addition to causing severe musculoskeletal pain, gout is associated with impaired quality of life, reduced functional status, and injury to joints. The quality of care for many patients with gout is unfortunately not in keeping with current guidelines. The approval of new therapies to treat hyperuricemia, such as febuxostat and pegloticase, has increased our knowledge of the challenges of adequately controlling the disease. Rather than providing a comprehensive overview of gout, this review focuses on new developments in the clinical aspects of gout and highlights advances in the drug therapy of gout. PMID- 23089277 TI - Uric acid stones and hyperuricosuria. AB - Recent work has highlighted the strong relationships among obesity, diabetes, and the metabolic syndrome as causes of low urinary pH. Low urinary pH in turn is the major urinary risk factor for uric acid stones. Unlike calcium stones, uric acid stones can be dissolved and easily prevented with adequate urinary alkalinization. Recognizing the relevant risk factors should lead to increased identification of these radiolucent stones. The cornerstone of therapy is raising urinary pH; xanthine dehydrogenase inhibitors should be used only when urinary alkalinization cannot be achieved. PMID- 23089278 TI - Advanced kidney failure and hyperuricemia. AB - Metabolic end products accumulate in kidney failure, including uric acid (UA), a terminal product of purine catabolism. Hyperuricemia (HUA) can cause gout and has been increasingly linked with cardiovascular (CV) morbidity and mortality, outcomes that are highly prevalent in patients with kidney disease. Serum UA levels rise as glomerular filtration declines, whereas the frequency of gouty attacks declines and the incidence of CV death rises precipitously. Herein, we review the kinetics of UA metabolism in CKD and dialysis and discuss the possible mechanisms of gout mitigation in kidney failure and the potential contribution of hyperuricemic milieu to CV outcomes in patients with kidney disease. PMID- 23089279 TI - Prostaglandin F2alpha regulation of mRNA for activating protein 1 transcriptional factors in porcine corpora lutea (CL): lack of induction of JUN and JUND in CL without luteolytic capacity. AB - Porcine corpora lutea (CL) develop sensitivity to regression by prostaglandin F2alpha (PGF2alpha), termed luteolytic capacity, about 13 d after estrus. We postulated that PGF2alpha regulation of activating protein 1 (AP-1) transcriptional factor expression underlies acquisition of luteolytic capacity. CL were collected from gilts on day 9 (estrous cycle) or day 17 (pseudopregnancy) before or after PGF2alpha treatment with mRNA measured for FOS, FOSB, FOSL1, FOSL2, JUN, JUNB, and JUND and the AP-1 target genes CCL2 and SERPINE1. At 0.5 h after PGF2alpha, both day-9 and day-17 CL had increased (P < 0.01) mRNA for FOS (2,225% and 1,817%), JUNB (237% and 358%), and FOSB (1,060% and 925%). Intriguingly, at 0.5 h after PGF2alpha there was increased (P < 0.01) mRNA encoding JUN (1,099%) and JUND (300%) in day-17 but not day-9 CL. At 10 h after PGF2alpha there was elevated FOSB mRNA in day-17 (771%) but not day-9 CL and no PGF2alpha-induced change in FOS, JUN, JUND, and JUNB mRNA in day-9 or day-17 CL. Treatment with PGF2alpha increased mRNA for AP-1-responsive genes, CCL2 at 0.5 h (202%) and CCL2 and SERPINE1 at 10 h (719% and 1,515%), only in day-17 CL. Thus, many of the fos family of transcription factors are dramatically induced by PGF2alpha in CL with or without luteolytic capacity. However, PGF only induced JUN and JUND expression in CL with luteolytic capacity, a finding that may be key for understanding the acquisition of luteolytic capacity, given that JUN is the only AP-1 family member with strong N-terminal trans-activation activity. PMID- 23089280 TI - Malnutrition and associated factors in nursing home residents: a cross-sectional, multi-centre study. AB - BACKGROUND & AIMS: Malnutrition is a common problem in the elderly living in nursing homes. A clear understanding of associated factors is missing. The aim of this study was to evaluate prevalence of malnutrition and to determine factors independently associated with malnutrition in this setting. METHODS: A cross sectional, multi-centre study was conducted in 23 nursing homes in Flanders, Belgium. The nutritional status was assessed using the Mini Nutritional Assessment (MNA). Data on possible associated factors were collected using validated scales. RESULTS: The study included 1188 elderly residents; 38.7% were at risk for malnutrition and 19.4% were malnourished. The presence of a wound/pressure ulcer, a recent hospitalization (<3 months ago), being involved in a tailored nutritional intervention, and suffering from a lower cognitive state were significantly associated with malnutrition. Receiving additional meals provided by family members was negatively associated with malnutrition. CONCLUSION: Malnutrition is a prevalent problem in nursing homes in Flanders. Systematic screening and well-defined tailored interventions should be further developed and evaluated in this population at risk. PMID- 23089281 TI - Changes in retinal neurons in the guinea pig retina stimulated by strobe lights during development. AB - The modern-day population is overexposed to visual stimuli accompanied by contrast and strength changes, such as the television or videogames, beginning early in life. These light stimuli may have an influence on the development of the visual system. The purpose of this study was to examine the effects of light stimuli on retinal development. We reared guinea pigs under a daily 12-h strobe light (2Hz)/dark cycle from birth, while control animals were reared under a 12-h light/dark cycle. The animals were sacrificed 1, 2, and 4 weeks after birth. The thickness of the outer nuclear layer (ONL) thickness decreased by 14.8% in the strobe-reared animals compared to the control group at 4 weeks, but not at 1 and 2 weeks. The Muller cells of the strobe-reared animals showed a stouter branch compared to that of the control animals at 2 and 4 weeks. In the strobe-reared model, axon-like processes emerging from the rod bipolar cell bodies were observed in the outer plexiform layer (OPL). These findings show that strobe light stimuli induce morphological changes in retinal neurons, which may lead to the disturbance of normal visual processing during development. PMID- 23089282 TI - Insulin-like growth factor 1 (IGF1) polymorphism is associated with Alzheimer's disease in Han Chinese. AB - A review of pathogenic findings in Alzheimer's brains and the functional consequences of altered insulin-like growth factor 1 (IGF1) input to the brain suggest the association between Alzheimer's disease (AD) and the disrupted IGF1 signaling. Recently, the identification of polymorphism rs972936 that was associated with both an increased risk of AD and high circulating levels of IGF1 was reported in Southern European population. In order to evaluate the involvement of the IGF1 polymorphism in the risk of developing late-onset Alzheimer's disease (LOAD) in Chinese, we performed an independent case-control association study in a Han Chinese population (794 LOAD cases and 796 controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P = 0.006, allele P = 0.047). The T allele of rs972936 demonstrated a 1.16-fold risk for developing LOAD when compared with the C allele, which diverges to the report in the Caucasian population. After stratification by apolipoprotein E (APOE) E4-carrying status, rs972936 polymorphism was only significantly associated with LOAD in non-ApoE E4 allele carriers (genotype P = 0.002, allele P = 0.039). Multivariate logistic regression analysis also conferred this positive association between the SNP rs972936 and LOAD in the recessive and additive model after adjustment for age, gender, and the ApoE E4 carrier status. These results suggest that IGF1 polymorphism has a possible role in changing the genetic susceptibility to LOAD in a Han Chinese population. PMID- 23089283 TI - What type of action understanding is subserved by mirror neurons? AB - The role of the mirror mechanism in cognition remains an intriguing and hotly debated topic in cognitive neuroscience. Since its discovery in the monkey and human brain, many have claimed that the mirror mechanism is critically involved in understanding action. But what does understand mean here? What kind of action understanding, if any, can be ascribed to the mirror mechanism? The aim of the paper is to face these questions by providing a refined notion of both action and action understanding. PMID- 23089284 TI - Thomas Young (1773-1829) and the first description of the volume-rate regulation of cardiac output. PMID- 23089285 TI - Diagnostic value of nonenhanced multidetector computed tomography for ruling out acute aortic dissection in patients presenting with chest or back pain. AB - BACKGROUND: Multidetector computed tomography (MDCT) is widely used for diagnosing acute aortic dissection (AAD). However, the diagnostic value of nonenhanced MDCT for AAD remains unknown. We evaluated the usefulness of nonenhanced 64-slice MDCT for ruling out AAD in patients presenting with chest or back pain. METHODS: Of 107 patients with clinical suspicion of AAD who underwent MDCT, AAD was confirmed in 47 and ruled out in 60. Nonenhanced MDCT data of all patients were retrospectively assessed by 2 independent observers unaware of clinical information and contrast-enhanced MDCT data. The diagnostic performance of nonenhanced MDCT parameters to detect AAD was calculated. RESULTS AND CONCLUSION: Among the parameters, positive intimal flap, defined as the clear presence of a high-density membrane-like structure in the aorta on serial axial images, had a sensitivity of 87%, a specificity of 100%, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 91%, respectively. The addition of equivocal intimal flap, defined as the ambiguous presence of a high-density membrane-like structure in the aorta on at least one axial image, increased both the sensitivity and NPV to 96%. Furthermore, the combination of intimal flap (positive+equivocal or positive alone) and high-density area in the aorta showed the highest sensitivity (98%) and NPV (98%). Combination of the nonenhanced MDCT parameters intimal flap and high-density area in the aorta provides excellent sensitivity and NPV, suggesting that nonenhanced MDCT is an effective modality for ruling out AAD in patients with chest or back pain. PMID- 23089286 TI - Improvement of survival of the house fly (Musca domestica L.) larvae under mass rearing conditions. AB - Two new approaches were examined, aimed at increasing survival of the house fly (Musca domestica L.) larvae under mass-rearing conditions of a biodegradation facility: modification of the larval substrate and dispersal of the eggs during inoculation. The two types of pig manure used in this study (manure with sawdust and manure without sawdust) differed in terms of larval survival and nutritional value for the house fly larvae. Larval survival in manure without sawdust in the control treatment was low (46.8 +/- 2.1%) and its nutritional value for the larvae were high. Addition of 5.7% of previously biodegraded manure did not significantly affect larval survival (52.3 +/- 1.9%), but larval development was faster and the pupae were significantly smaller (14.28 +/- 0.4 mg) compared to the control (16.29 +/- 0.5 mg). Using alternative substrate for incubation of eggs and first-instar larvae significantly increased larval survival (63.3 +/- 3.3%) and decreased the mean weight of produced pupae (14.39 +/- 0.71 mg). Overall, the weight of recovered biomass in the alternative substrate treatment increased by 14.3 kg ton-1 of manure compared to the control. Larval survival in manure with sawdust was generally higher than 70%, but its nutritional value for the larvae was lower than in manure without sawdust. Dispersal of eggs over the surface of manure with sawdust significantly affected larval survival and mean weight of pupae. Larval survival was significantly lower (59.2 +/- 4.0%) and pupae were significantly heavier (18.45 +/- 0.8 mg) when eggs were applied to a small area on the manure surface (spot treatment), as compared to diagonal, Z line and multiple zig-zag dispersal (72.5 +/- 2.4 to 74.6 +/- 3.0% and 14.76 +/- 0.6 to 15.97 +/- 0.6 mg, respectively). No significant differences were observed in larval survival or mean weight of pupae when comparing the diagonal, Z-line and multiple zig-zag dispersal patterns. Implementation of the techniques which improve larval survival and increase the weight of produced fly biomass may decrease demand for production of house fly eggs and, therefore, reduce the maintenance costs of adult colony, as well as increase the revenue earned by selling the products. PMID- 23089287 TI - Expression of autophagy and ER stress-related proteins in primary salivary adenoid cystic carcinoma. AB - Autophagy is the endogenous cellular pathway that facilitates cellular survival by maintaining energy homeostasis and macromolecular synthesis during cellular stress and nutrient deprivation. Endoplasmic reticulum (ER) stress is the process in which disruption of these physiological functions leads to an accumulation of unfolded proteins and induces the unfolded protein response (UPR). ER stress and autophagy are involved in human cancer. We investigated the expression of autophagic proteins (LC3 and beclin 1) and ER stress-related protein (GRP78) in head and neck adenoid cystic carcinoma tissue. Tissue samples from 79 cases of head and neck adenoid cystic carcinoma tissue were utilized for immunohistochemistry. LC3 expression was significantly correlated with lymph node involvement (P=.016) and TNM (P=.021). Beclin 1 expression was significantly correlated with the histological growth pattern (P=.002), the histological grade (P=.000), and longer survival (P=.000). GRP78 expression was significantly correlated with the histological growth pattern (P=.019), the histological grade (P=.019), and longer survival (P=.001). LC3 expression was positively correlated with beclin 1 expression (P=.000); LC3 and beclin 1 expressions were positively correlated with GRP78 expression respectively (P=.035) (P=.008). Our study describes the expression of LC3, beclin 1, and GRP78 in adenoid cystic carcinoma and its relationship with clinicopathologic factors and overall survival. These results suggest that LC3, beclin 1, and GRP78 may play an important role in the tumorigenesis of adenoid cystic carcinoma, and that beclin 1 and GRP78 may serve as new prognostic indicators for the outcome of patients with adenoid cystic carcinoma. PMID- 23089288 TI - Adenocarcinoma with sarcomatous dedifferentiation arising from mature cystic teratoma of the anterior mediastinum. AB - Mediastinal teratoma with malignant transformation (TMT) is a very rare condition. A 44-year-old man presented with a large cystic mass of the anterior mediastinum. The tumor was surgically removed. The cystic mass was well demarcated, with an irregularly thickened wall. Histologically, the cystic wall was mainly lined by non-ciliated columnar epithelium and focally by squamous epithelium. A nodular part of the cystic wall revealed well-differentiated adenocarcinoma composed of tubulopapillary structures. Deep in the nodular tissue, neoplastic glands merged into undifferentiated sarcomatous cells. Immunohistochemically, CK7, CK19, and smad-4 were strongly and diffusely positive in adenocarcinoma. CD10 was focally positive on the luminal surface of the glands, and MUC5AC was also focally positive. TTF-1, cdx-2, and CK20 were negative in the adenocarinoma. Sarcomatous area showed diffuse strong positivity for vimentin, but was negative for the aforementioned epithelial markers. About 10 months postoperatively, a left pleural effusion had developed with multiple pleural nodules on computed tomography scan of the chest. The cytologic diagnosis from pleural fluid was metastatic adenocarcinoma. To our knowledge, in the English literature, this is the first case of adenocarcinoma with sarcomatous transformation that has developed in a mature cystic teratoma of the mediastinum and shows pleural metastasis. PMID- 23089289 TI - Benign anal and perianal polypoid neoplasms and tumor-like lesions. AB - Mesenchymal anal and perianal tumors are relatively uncommon. The majority are malignant. Benign mesenchymal anal tumors are rare. Some are common stromal neoplasms, but with the rare presentation as anal polyps. Other lesions are rare, but unique to the anal/perianal region. Common keratinous cysts might uncommonly present as anal polyps, while other rare cysts are unique to the anogenital region. A retrospective review study of 493 anal and perianal specimens conducted over seven years showed twenty cases (4.0%) of benign anal polypoid lesions. We excluded the usual fibroepithelial polyps, anal tags, papilla, hemorrhoids and warts. We found six cysts, three lipomas, two papillary hidradenomas, two melanocytic nevi, one hamartoma, one xanthogranuloma, one seborrheic keratosis, one hematoma, one fibrous histiocytoma, one granular cell tumor and one lymphangioma. The male to female ratio was 1.5:1. They were found in adults (mean age 37.8 years) and in infants (mean age 2.4 years). In general, they were smaller than 2 cm. They were either asymptomatic or presented with anal pain, bleeding or lumps. Some were clinically confused with the more common non neoplastic anal tags, hemorrhoids and fibroepithelial polyps/papilla. A variety of common and rare benign lesions might present as anal polyps with important surgical and pathologic challenges and implications. PMID- 23089290 TI - From shared contexts to syntactic categories: the role of distributional information in learning linguistic form-classes. AB - A fundamental component of language acquisition involves organizing words into grammatical categories. Previous literature has suggested a number of ways in which this categorization task might be accomplished. Here we ask whether the patterning of the words in a corpus of linguistic input (distributional information) is sufficient, along with a small set of learning biases, to extract these underlying structural categories. In a series of experiments, we show that learners can acquire linguistic form-classes, generalizing from instances of the distributional contexts of individual words in the exposure set to the full range of contexts for all the words in the set. Crucially, we explore how several specific distributional variables enable learners to form a category of lexical items and generalize to novel words, yet also allow for exceptions that maintain lexical specificity. We suggest that learners are sensitive to the contexts of individual words, the overlaps among contexts across words, the non-overlap of contexts (or systematic gaps in information), and the size of the exposure set. We also ask how learners determine the category membership of a new word for which there is very sparse contextual information. We find that, when there are strong category cues and robust category learning of other words, adults readily generalize the distributional properties of the learned category to a new word that shares just one context with the other category members. However, as the distributional cues regarding the category become sparser and contain more consistent gaps, learners show more conservatism in generalizing distributional properties to the novel word. Taken together, these results show that learners are highly systematic in their use of the distributional properties of the input corpus, using them in a principled way to determine when to generalize and when to preserve lexical specificity. PMID- 23089291 TI - Amelioration of the periparturient relaxation of immunity to parasites through a reduction in mammalian reproductive effort. AB - The degree of periparturient relaxation of immunity to gastrointestinal parasites has a nutritional basis, as overcoming protein scarcity through increased protein supply improves lactational performance, enhances local immune responses and reduces worm burdens. Herein lactating rats, re-infected with Nippostrongylus brasiliensis, are used to test the hypothesis that a similar and rapid improvement of immunity can be achieved through reducing nutrient demand at times of dietary protein scarcity. Reducing litter size from 12 to three pups during lactation resulted, as expected, in cessation of maternal body weight loss and increased pup body weight gain compared with dams which continued to nurse 12 pups. This increase in performance concurred with a rapid decrease in parasitism; within 3 days post nutrient reduction, a 87% reduction in the number of worm eggs found in the colon and 83% reduction in worm burdens was observed, which concurred with increased local immune responses, i.e. 70% more mast cells and 44% more eosinophils in the small intestinal mucosa, to levels similar to those in dams nursing three pups throughout. However, there were no concurrent changes in goblet cell hyperplasia, serum anti-N. brasiliensis-specific antibody levels or mRNA expression of IL-4, IL-10 or IL-13 in the mesenteric lymph nodes. To our knowledge the current study is the first to employ a litter reduction strategy to assess the rate of immune improvement upon overcoming nutrient scarcity in a non ruminant host. These data support the hypothesis that periparturient relaxation of immunity to gastrointestinal nematodes can be reduced by restoring nutrient adequacy and, importantly, that this improvement can occur very rapidly. PMID- 23089292 TI - Construction and characterization of a reporter gene cell line for assessment of human glucocorticoid receptor activation. AB - Glucocorticoids are widely used drugs in human pharmacotherapy. There is an increasing demand for tools allowing detection of the ligands for glucocorticoid receptor (GR), with regard to pre-clinical drug testing and environmental applications. We constructed human luciferase reporter gene cell line AZ-GR derived from HeLa human cervix carcinoma cells, which were stably transfected with reporter plasmid containing three copies of glucorticoid response element (GRE) upstream of luciferase reporter gene. We isolated five dexamethasone responsive clones, and we further characterized two most responsive ones (AZ-GR). Dose-response analyses were performed with 22 different natural and synthetic steroids and the values of EC(50) were calculated. AZ-GR cells displayed high specificity and sensitivity to glucocorticoids, very low responsiveness to mineralocorticoids, but no responsiveness to estrogens, gestagens or androgens. Time-course analyses revealed that AZ-GR cells allow detection of GR activators soon after 14 h of the treatment (6-10-fold induction by 100 nM dexamethasone). Functionality of AZ-GR cells was not affected with cryopreservation. Generated reporter gene cell lines fully maintained responsiveness to glucocorticoids for 32 days in the culture and over 16 passages without significant alterations. The sensitivity of the assay allows high throughput format using 96-well plates. Collectively, we present here glucocorticoid-responsive stable reporter gene cell line that allows high throughput, rapid, sensitive and selective detection of GR activators, with possible use in pre-clinical research and environmental applications. PMID- 23089293 TI - How to enhance public health service utilization in community pharmacy?: general public and health providers' perspectives. AB - BACKGROUND: Community pharmacists (PHs) in England are increasingly providing a range of public health services. However, the general public view pharmacists as drug experts and not experts in health, and therefore, services may be underutilized. OBJECTIVES: To explore experiences and views of 4 groups of participants, the general public, PHs, general practitioners (GPs), and other stakeholders (STs) on pharmacy-based public health services, and identify potential factors affecting service use. METHODS: The study was undertaken in a locality of North West England. Three focus groups were conducted with the general public (n=16), grouped by socioeconomic status. Fourteen semistructured interviews were undertaken with PHs (n=9), GPs (n=2), and STs (n=3). Discussions/interviews were audio recorded, transcribed verbatim, and analyzed thematically. RESULTS: All 4 groups of participants agreed that community pharmacies are a good source of advice on medicines and minor ailments but were less supportive of public health services. Six factors were identified affecting utilization of pharmacy services: community pharmacy environment, pharmacist and support staff, service publicity, general public, GP services, and health care system and policies. Crucial obstacles that could inhibit service utilization are perceptions of both the general public and other health providers toward pharmacists' competencies, privacy and confidentiality in pharmacies, high dispensing workload, and inadequate financial support. Networking between local health professionals could enhance confidence in service delivery, general awareness, and thus utilization. CONCLUSIONS: Community pharmacy has the potential to deliver public health services, although the impact on public health may be limited. Addressing the factors identified could help to increase utilization and impact of pharmacy public health services. PMID- 23089294 TI - A review of the information-gathering process for the provision of medicines for self-medication via community pharmacies in developing countries. AB - BACKGROUND: Currently, no review has been completed regarding the information gathering process for the provision of medicines for self-medication in community pharmacies in developing countries. OBJECTIVE: To review the rate of information gathering and the types of information gathered when patients present for self medication requests. METHODS: Six databases were searched for studies that described the rate of information gathering and/or the types of information gathered in the provision of medicines for self-medication in community pharmacies in developing countries. The types of information reported were classified as: signs and symptoms, patient identity, action taken, medications, medical history, and others. RESULTS: Twenty-two studies met the inclusion criteria. Variations in the study populations, types of scenarios, research methods, and data reporting were observed. The reported rate of information gathering varied from 18% to 97%, depending on the research methods used. Information on signs and symptoms and patient identity was more frequently reported to be gathered compared with information on action taken, medications, and medical history. CONCLUSION: Evidence showed that the information-gathering process for the provision of medicines for self-medication via community pharmacies in developing countries is inconsistent. There is a need to determine the barriers to appropriate information-gathering practice as well as to develop strategies to implement effective information-gathering processes. It is also recommended that international and national pharmacy organizations, including pharmacy academics and pharmacy researchers, develop a consensus on the types of information that should be reported in the original studies. This will facilitate comparison across studies so that areas that need improvement can be identified. PMID- 23089295 TI - Medication reconciliation: A qualitative analysis of clinicians' perceptions. AB - BACKGROUND: Medication reconciliation has been at the forefront of national patient safety efforts for nearly a decade, yet health care institutions remain challenged with implementation. OBJECTIVES: The objective of this article was to report an analysis of a qualitative study of the experiences of physicians, nurses, and pharmacists with medication management practices, specifically focusing on the practice of medication reconciliation. METHODS: This study used focus groups in a qualitative approach to explore participant perceptions about interprofessional communication and adverse drug events. Three focus groups were conducted at each of 3 Veterans Administration hospitals, 1 each for physicians (13), nurses (19), and pharmacists (16). The analysis for this article focused on specific discussions about medication reconciliation. RESULTS: Two primary thematic questions emerged from the discussion about medication reconciliation: What does medication reconciliation really mean? Who is actually responsible for the process? Participants from each profession had differing perspectives about the purpose and processes of medication reconciliation. Perceived responsibilities appeared to be influenced by their distinct views regarding the meaning and purpose of medication reconciliation. The pharmacist role emerged as a critical role to assure medication safety. CONCLUSIONS: Translating the intent of medication reconciliation into effective practice requires acknowledgment of the involved professionals' diverse perspectives on the independent, joint, and overlapping functions of medication management as well as recognizing the limitations of technology. PMID- 23089296 TI - Relative importance of attributes of drug benefit plans: Thai civil servants' perspective. AB - BACKGROUND: The drug benefit plan of Thailand's Civil Servant Medical Benefit Scheme (CSMBS) must be amended to control increasing costs; to that end, it is important to gather the views of beneficiaries before making changes to the benefit plan. OBJECTIVES: To examine the relative importance of attributes of drug benefit plans from the perspective of CSMBS beneficiaries. METHODS: Attributes and levels adopted from focus group discussions and a preliminary survey were used to develop a questionnaire concerning hypothetical drug benefit plans. A convenience sample of 650 CSMBS beneficiaries in Songkhla province was asked to rate the drug benefit plans. To determine the beneficiaries' decision models, judgment analysis was used. Policy-capturing analysis was used to examine the beneficiaries' preferences, and cluster analysis was conducted to explore the variability among judgment plans. Judgment policy insight was also examined. RESULTS: The results of the study showed that the beneficiaries weighed on cost sharing as their most important attribute. The results remained unchanged, although only data from the beneficiaries who used the compensatory model were analyzed. The results of the cluster analysis showed that the largest cluster of beneficiaries weighed mostly on the cost-sharing attribute. The judgment policy insight results not only supported the finding that most beneficiaries focused on the cost-sharing attribute but also revealed that they might have the least understanding of how the formulary attribute affected beneficiaries' decision making. CONCLUSIONS: Cost-sharing was the most important attribute for the CSMBS beneficiaries. This study indicated that a possible preferred drug benefit plan should have no cost-sharing, permit access only to drugs listed in a closed formulary, allow beneficiaries to obtain 3 months of drugs, and allow them to obtain drugs from either a community pharmacy or a government hospital. PMID- 23089297 TI - A qualitative investigation of protege expectations and proposition of an evaluation model for formal mentoring in pharmacy education. AB - BACKGROUND: Student pharmacist mentoring programs have gained attention from colleges of pharmacy as a way to enhance the student experience. However, no evaluative models have been proposed or theoretical explanations described for use in improving formal mentoring programs in pharmacy or for guiding the construction of a literature base. OBJECTIVES: The objectives of this study were to investigate student expectations and preferences for formal mentoring programs and propose a model for evaluating formal mentoring programs in pharmacy education. METHODS: Five, 60-minute focus groups were conducted in September 2009. Participants were PharmD candidates in their first 3 years of professional education. Discussion was facilitated using a question guide. Following transcription, an initial iteration of the model was used to code the data. A consensus-forming process was used to derive themes and identify representative quotes. Elaboration and specification of the final proposed model is presented. RESULTS: In all, 28 students participated. Emergent constructs were identified from the data. Structures or inputs of the formal mentoring program included mentor and protege characteristics and program structure. Mentoring processes included mentor functions, mentoring activities, and relationship development. Outcomes included both proximal outcomes in the form of mentor and protege change, program satisfaction, and organizational learning; and distal outcomes comprised mentor, protege, and organizational outcomes. CONCLUSIONS: This formal mentoring evaluation model was useful in guiding analysis of protege experiences and preferences for a college-sponsored program. The model can be used to guide college administrators and researchers on future theory-based inquiry into protege; mentor; and organizational structures, processes, and outcomes for formal mentoring programs. PMID- 23089298 TI - Time domain reflectometry measured moisture content of sewage sludge compost across temperatures. AB - Time domain reflectometry (TDR) is a prospective measurement technology for moisture content of sewage sludge composting material; however, a significant dependence upon temperature has been observed. The objective of this study was to assess the impacts of temperature upon moisture content measurement and determine if TDR could be used to monitor moisture content in sewage sludge compost across a range of temperatures. We also investigated the combined effects of temperature and conductivity on moisture content measurement. The results revealed that the moisture content of composting material could be determined by TDR using coated probes, even when the measured material had a moisture content of 0.581 cm(3)cm( 3), temperature of 70 degrees C and conductivity of 4.32 mS cm(-1). TDR probes were calibrated as a function of dielectric properties that included temperature effects. When the bulk temperature varied from 20 degrees C to 70 degrees C, composting material with 0.10-0.70 cm(3)cm(-3) moisture content could be measured by TDR using coated probes, and calibrations based on different temperatures minimized the errors. PMID- 23089299 TI - Case study of landfill reclamation at a Florida landfill site. AB - A landfill reclamation project was considered to recover landfill airspace and soil, reduce future groundwater impacts by removing the waste buried in the unlined area, and optimize airspace use at the site. A phased approach was utilized to evaluate the technical and economic feasibility of the reclamation project; based on the results of these evaluations, approximately 6.8 ha of the unlined cells were reclaimed. Approximately 371,000 in-place cubic meters of waste was mined from 6.8 ha in this project. Approximately 230,600 cubic meters of net airspace was recovered due to beneficial use of the recovered final cover soil and reclaimed soil as intermediate and daily cover soil, respectively, for the current landfill operations. This paper presents the researchers' landfill reclamation project experience, including a summary of activities pertaining to reclamation operations, an estimation of reclamation rates achieved during the project, project costs and benefits, and estimated composition of the reclaimed materials. PMID- 23089300 TI - Long-term follow-up of lung and heart transplant recipients with pre-transplant malignancies. AB - BACKGROUND: Concern regarding recurrence of pre-transplant (Tx) malignancy has disqualified patients from Tx. Because this has been poorly studied in lung and heart Tx recipients our aim was to investigate the influence of pre-Tx malignancy on post-Tx recurrence and long-term survival, focusing on pre-operative cancer free intervals. METHODS: From our lung and heart Tx programs (1983 to 2011) we retrospectively identified 111 (lung, 37; heart, 74) of 3,830 recipients with 113 pre-Tx malignancies. The patients were divided into 3 groups by pre-Tx cancer free interval: Group I, <12 months (n = 24); Group II, >=12 to<60 months (n = 18); and Group III, >=60 months (n = 71). RESULTS: Mean age at pre-Tx malignancy was 35+/-18 years. Mean post-Tx follow-up time was 70+/-63 months (range, 0-278 months), and malignancy recurrence was 63% in Group I, 26% in Group II, and 6% in Group III. Kaplan-Meier analysis of freedom from post-Tx recurrence revealed the following differences among the groups: Group I vs II, p = 0.08; II vs III, p = 0.002; and I vs III, p<0.001. Overall survival (51 deaths) was significantly poorer in Group I than in Groups II and III (p = 0.044). Survival between Groups II and III did not differ significantly (p = 0.93). CONCLUSIONS: Cancer-free survival of >=5 years pre-Tx is associated with the lowest recurrence. However, recurrence is related to the time the patients were cancer-free, as seen in Groups I and II. PMID- 23089301 TI - Plant-wide control: eco-efficiency and control loop configuration. AB - Since the eco-efficiency of all industrial processes/plants has become increasingly important, engineers need to find a way to integrate the control loop configuration and the measurements of eco-efficiency. A new measure of eco efficiency, the exergy eco-efficiency factor, for control loop configuration, is proposed in this paper. The exergy eco-efficiency factor is based on the thermodynamic concept of exergy which can be used to analyse a process in terms of its efficiency associated with the control configuration. The combination of control pairing configuration techniques (such as the relative gain array, RGA and Niederlinski index, NI) and the proposed exergy eco-efficiency factor will guide the process designer to reach the optimal control design with low operational cost (i.e., energy consumption). The exergy eco-efficiency factor is implemented in the process simulation case study and the reliability of the proposed method is demonstrated by dynamic simulation results. PMID- 23089302 TI - Determinants of middle-school students asking parents for fruits and vegetables: a theory-based salient belief elicitation. AB - OBJECTIVE: Despite the benefits of fruit and vegetable intake, many young Americans do not consume them at adequate levels. The present study sought to determine the beliefs that children have about asking their parents to have fruits and vegetables available at home in order to better understand the role children may play in influencing their own fruit and vegetable consumption. DESIGN: An instrument utilizing the Reasoned Action Approach, with closed-ended questions on demographic and behavioural variables and open-ended questions eliciting the belief structure underlying asking parents to make fruits and vegetables available, was distributed. Thematic and frequency analyses were performed for open-ended questions. Statistical analyses were conducted to assess differences between children who had v. had not asked for fruits and vegetables. SETTING: Three middle schools in rural Indiana, U.S.A. SUBJECTS: A sub-sample of sixty students aged 12-15 years from a larger study of 344 students. RESULTS: Qualitative analysis identified benefits (i.e., make me healthier; make parents happy), disadvantages (i.e., will upset my parents) and strategies (i.e., asking when you are at the store) that could be used to improve fruit and vegetable intake. Findings also revealed that students who asked their parents for fruits and vegetables were significantly more likely to perform several healthy eating and physical activity behaviours. CONCLUSIONS: Data suggest that young people's view of parental reactions is critical. While additional research is necessary, the findings support a role for children in shaping their own environment and suggest multilevel interventions that simultaneously address parents and children. PMID- 23089303 TI - Salvage antegrade visceral revascularization and antegrade aortic stenting for type I and III endoleaks after fenestrated juxtarenal aneurysm repair. AB - A 73-year-old man developed type I and III endoleaks from a fractured right renal stent with downward migration of a fenestrated endograft, 6 years after endovascular repair of a juxtarenal aneurysm. Endovascular treatment attempts were unsuccessful. He underwent aortic debranching and antegrade visceral artery revascularization via a left thoracolaparotomy incision and an extraperitoneal approach to the visceral aorta. An antegrade aortic stent covered the endoleak, with technical and clinical success at 9 months. Failure of complex endografts presents particular problems, potentially not amenable to totally endovascular repair. Continued surveillance is mandated as late, asymptomatic sac expansion can occur. PMID- 23089304 TI - Glutathione and infection. AB - BACKGROUND: The tripeptide gamma-glutamylcysteinylglycine or glutathione (GSH) has demonstrated protective abilities against the detrimental effects of oxidative stress within the human body, as well as protection against infection by exogenous microbial organisms. SCOPE OF REVIEW: In this review we describe how GSH works to modulate the behavior of many cells including the cells of the immune system, augmenting the innate and the adaptive immunity as well as conferring protection against microbial, viral and parasitic infections. This article unveils the direct antimicrobial effects of GSH in controlling Mycobacterium tuberculosis (M. tb) infection within macrophages. In addition, we summarize the effects of GSH in enhancing the functional activity of various immune cells such as natural killer (NK) cells and T cells resulting in inhibition in the growth of M. tb inside monocytes and macrophages. Most importantly we correlate the decreased GSH levels previously observed in individuals with pulmonary tuberculosis (TB) with an increase in the levels of pro-inflammatory cytokines which aid in the growth of M. tb. MAJOR CONCLUSIONS: In conclusion, this review provides detailed information on the protective integral effects of GSH along with its therapeutic effects as they relate to the human immune system and health. GENERAL SIGNIFICANCE: It is important to note that the increases in the levels of pro-inflammatory cytokines are not only detrimental to the host due to the sequel that follow such as fever and cachexia, but also due to the alteration in the functions of immune cells. The additional protective effects of GSH are evident after sequel that follows the depletion of this antioxidant. This is evident in a condition such as Cystic Fibrosis (CF) where an increased oxidant burden inhibits the clearance of the affecting organism and results in oxidant-induced anti-protease inhibition. GSH has a similar protective effect in protozoans as it does in human cells. Thus GSH is integral to the survival of some of the protozoans because some protozoans utilize the compound trypanothione [T(SH)2] as their main antioxidant. T(SH)2 in turn requires GSH for its production. Hence a decrease in the levels of GSH (by a known inhibitor such as buthionine sulfoximine [BSO] can have adverse effects of the protozoan parasites. This article is part of a Special Issue entitled Cellular functions of glutathione. PMID- 23089305 TI - Mediastinal lymph node position variability in non-small cell lung cancer patients treated with radical irradiation. AB - BACKGROUND AND PURPOSE: Detailed knowledge on mediastinal lymph nodes position variability is lacking. In this study we quantified the variability over the irradiation course in non-small cell lung cancer (NSCLC) patients. METHODS: A 0.35*5 mm gold fiducial marker was inserted in mediastinal lymph nodes of 14 stage III NSCLC patients. A respiration correlated 4D-planning-CT (pCT) and daily 4D-Cone Beam (CB)CT-scans were acquired. To calculate the systematic and random baseline variations, and respiratory motion variability of the lymph nodes, all CBCT scans were registered to both the bony anatomy and marker in the pCT. Patient population statistics of the peak-to-peak amplitude and time averaged mean position relative to the bony anatomy were calculated. RESULTS: The average peak-to-peak amplitude was 0.21 cm, 0.52 cm and 0.20 cm in the Left-Right, Cranial-Caudal and Anterior-Posterior direction respectively, while the amplitude variability was <=0.1 cm in each direction. Inter-fraction lymph node baseline variation was 0.21/0.2 cm, 0.34/0.23 cm, and 0.17/0.15 cm systematic/random. PTV margins for these variations were 0.92 cm, 1.24 cm, 0.82 cm for an online bone match and could be reduced to 0.77 cm, 0.82 cm and 0.86 cm for an online carina match. CONCLUSIONS: Substantial and anisotropic, systematic and random mediastinal lymph node baseline variations were found in NSCLC patients indicating that non-uniform margins could be beneficial. PMID- 23089307 TI - A novel widespread interkingdom signaling circuit. AB - Extensive communication is believed to occur between eukaryotes and prokaryotes via signaling molecules; this field of research is now called interkingdom signaling. Recently, it has been discovered that many different plant-associated bacteria possess a protein closely related to the quorum-sensing (QS) LuxR-family protein that binds and responds to plant compounds. This LuxR protein does not have a cognate N-acyl homoserine lactone (AHL) signal synthase and therefore is regarded as a 'solo' or 'orphan'. The protein is involved in interkingdom signaling in rhizobia, xanthomonads, and pseudomonads, regulating processes important for plant-bacteria interaction. In this review, we focus on this new interkingdom signaling circuit, which is widespread among pathogenic and beneficial plant-associated bacteria. PMID- 23089306 TI - Changes in functional imaging parameters following induction chemotherapy have important implications for individualised patient-based treatment regimens for advanced head and neck cancer. AB - BACKGROUND: When induction chemotherapy (IC) is used prior to chemoradiotherapy (CRT) in head and neck cancer (HNC), functional imaging (FI) may inform adaptation of treatment plans with the aim of optimising outcomes. Understanding the impact of IC on FI parameters is, therefore, essential. PURPOSE: To prospectively evaluate the feasibility of acquiring serial FI ((18)F-FDG-PET, diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) MRI) and its role in defining individualised treatment regimens following IC in HNC. METHODS AND MATERIALS: Ten patients with stage III and IV HNC underwent conventional (CT and MRI) and functional (DW, DCE-MRI and (18)F-FDG-PET/CT) imaging at baseline and following two cycles of IC prior to definitive CRT. RESULTS: One patient withdrew due to claustrophobia. Seven out of nine patients had a complete metabolic response to IC on (18)F-FDG-PET imaging. DCE-MRI showed a significant fall in transfer constant (K(trans)) (0.209 vs 0.129 min(-1)P<0.01) and integrated area under gadolinium curve at 60s (IAUGC6O) (18.4 vs 11.9 mmol/min, P<0.01) and DW MRI a rise in ADC (0.89 vs 1.06 * 10(-3) mm(2)/s, P<0.01) following IC. CONCLUSIONS: Acquiring FI sequences is feasible in HNC. There are marked changes in FI parameters following IC which may guide adaptation of individualised treatment regimens. PMID- 23089308 TI - Reduced glutathione and procaine hydrochloride protect the nucleoprotein structure of boar spermatozoa during freeze-thawing by stabilising disulfide bonds. AB - One important change the head of boar spermatozoa during freeze-thawing is the destabilisation of its nucleoprotein structure due to a disruption of disulfide bonds. With the aim of better understanding these changes in frozen-thawed spermatozoa, two agents, namely reduced glutathione (GSH) and procaine hydrochloride (ProHCl), were added at different concentrations to the freezing media at different concentrations and combinations over the range 1-2mM. Then, 30 and 240 min after thawing, cysteine-free residue levels of boar sperm nucleoproteins, DNA fragmentation and other sperm functional parameters were evaluated. Both GSH and ProHCl, at final concentrations of 2mM, induced a significant (P<0.05) increase in the number of non-disrupted sperm head disulfide bonds 30 and 240 min after thawing compared with the frozen-thawed control. This effect was accompanied by a significant (P<0.05) decrease in DNA fragmentation 240 min after thawing. Concomitantly, 1 and 2mM GSH, but not ProHCl at any of the concentrations tested, partially counteracted the detrimental effects caused by freeze-thawing on sperm peroxide levels, motility patterns and plasma membrane integrity. In conclusion, the results show that both GSH and ProHCl have a stabilising effect on the nucleoprotein structure of frozen-thawed spermatozoa, although only GSH exerts an appreciable effect on sperm viability. PMID- 23089309 TI - Low cost, disposable biosensors allow detection of antibodies with results equivalent to ELISA in 15 min. AB - An assay for detection of antibodies to bovine herpesvirus-1 (BoHV-1) was developed by combining a commercial low cost, disposable biosensor system (VantixTM) and reagents from an established Enzyme-Linked Immunosorbent Assay (ELISA). The biosensor assay produced equivalent results to ELISA within 15 min when testing 194 bovine serum and 50 bulk milk samples submitted for routine testing. The biosensor assay can provide quantitative analysis demonstrated by measuring the level of antibody in milk samples. The results of this study suggest that VantixTM is a promising platform for routine immunological testing. The technology may be particularly useful for low to medium throughput tests where rapid results are required. The biosensors could also form the basis of a future point-of-care test platform. PMID- 23089310 TI - Mechanism of inhibition of P-glycoprotein mediated efflux by Pluronic P123/F127 block copolymers: relationship between copolymer concentration and inhibitory activity. AB - The aim of this study was to clarify the relationship between the concentration of Pluronic P123/F127 block copolymers and P-glycoprotein (P-gp) inhibitory potency. Modulation of multidrug resistance (MDR) by Pluronic P123/F127 was evaluated in P-gp over-expressing human breast cancer cell line MCF-7/ADR and its non-P-gp over-expressing counterpart MCF-7 cells. Four different probes (known as P-gp substrates) including rhodamine 123 (R-123), rhodamine 6G (R-6G), doxorubicin (DOX), and paclitaxel (PTX) were applied to investigate the impact of Pluronic P123/F127 copolymers with different concentrations on the intracellular accumulation of these probes. Additionally, the intracellular ATP and mitochondrial transmembrane potential in MCF-7/ADR cells were determined over a wide concentration range of Pluronic P123/F127. Furthermore, the endocytic mechanisms of Pluronic micelles were performed. It was suggested that P-gp substrate hydrophobicity and the concentration of P123/F127 copolymers had little impact on P-gp inhibitory activity of Pluronic P123/F127 itself. Intracellular ATP depletion was the main mechanism of Pluronic P123/F127 for P-gp inhibition. In vitro cytotoxicity study was also conducted in order to compare cytotoxic effect among different PTX formulations. It indicated that the IC50 of PTX-loaded Pluronic P123/F127 mixed micelles was 6.3-fold lower than free PTX and 2.3-fold lower than Taxol, respectively. Therefore, Pluronic P123/F127 polymeric micelles could be considered a promising drug delivery system to overcome MDR in cancer therapy. PMID- 23089311 TI - Plasma distribution of tetraphenylporphyrin derivatives relevant for Photodynamic Therapy: importance and limits of hydrophobicity. AB - In the course of a Photodynamic Therapy (PDT) protocol, disaggregation of the sensitizer upon binding to plasma proteins and lipoproteins is one of the first steps following intravenous administration. This step governs its subsequent biodistribution and has even been evoked as possibly orientating mechanism of tumor destruction. It is currently admitted as being mainly dependent on sensitizer's hydrophobicity. In this context, as far as glycoconjugation of meso tetraphenylporphyrin (TPP) macrocycle, a promising strategy to improve targeting of retinoblastoma cells confers to the sensitizer an amphiphilic character, we have studied the effect of this strategy on binding to plasma proteins and lipoproteins. With the exception of the majoritary protein binding (more than 80%) of more hydrophilic para-tetraglycoconjugated derivatives, high density lipoproteins (HDL) appear as main plasma carriers of the other amphiphilic glycoconjugated photosensitizers. This HDL-binding is a combined result of binding affinities (logKa ranging from 4.90 to 8.77 depending on the carrier and the TPP derivative considered) and relative plasma concentrations of the different carriers. Evaluation of binding affinities shows that if hydrophobicity can account for LDL- and HDL-affinities, it is not the case for albumin-affinity. Molecular docking simulations show that, if interactions are mainly of hydrophobic nature, polar interactions such as hydrogen bonds are also involved. This combination of interaction modalities should account for the absence of clear relationship between albumin-affinity and hydrophobicity. Taken together, our findings clarify the importance, but also the limits, of hydrophobicity's role in structure-plasma distribution relationship. PMID- 23089312 TI - TIS21(/BTG2/PC3) accelerates the repair of DNA double strand breaks by enhancing Mre11 methylation and blocking damage signal transfer to the Chk2(T68)-p53(S20) pathway. AB - DNA double strand breaks (DSBs) occur more frequently in TIS21(-/-) mouse embryo fibroblasts than that in wild type MEFs (wt-MEFs). Therefore, the role TIS21 plays in the DNA damage response was investigated. Adenoviral transduction of Huh7 tumor cells with the TIS21 gene accelerated the repair of DSBs induced by etoposide treatment as evaluated by clearance of gammaH2AX foci and the Comet assay. TIS21 increased methylation of Mre11 and protein arginine methyltransferase 1 (PRMT1) activity, leading to Mre11 activation in vitro and in vivo, as determined by immunoprecipitation and radiolabeling analyses. When downstream DNA damage response mediators were evaluated in various human cancer cells lines, TIS21 was found to strongly inhibit Chk2(T68) and p53(S20) phosphorylation by p-ATM(S1981) but not p53(S15). The loss of Chk2 activation after etoposide treatment reduced apoptosis in the cells by downregulating the expression of E2F1 and Bax. These data suggest that TIS21 regulates DSB repair and apoptosis. Expression of TIS21 promoted the repair of DSBs and reduced apoptosis by blocking the damage signal from p-ATM(S1981) to Chk2(T68) p53(S20)via the activation of Mre11 and PRMT1. PMID- 23089313 TI - Inducing local DNA damage by visible light to study chromatin repair. AB - Dynamics of DNA repair and recruitment of repair factors to damaged DNA can be studied by live cell microscopy. DNA damage is usually inflicted by a laser beam illuminating a DNA-interacting photosensitizer in a small area of the nucleus. We demonstrate that a focused beam of visible low intensity light alone can inflict local DNA damage and permit studies of DNA repair, thus avoiding potential artifacts caused by exogenous photosensitizers. PMID- 23089314 TI - Skull base osteomyelitis: current microbiology and management. AB - INTRODUCTION: Skull base osteomyelitis typically presents in an immunocompromised patient with severe otalgia and otorrhoea. Pseudomonas aeruginosa is the commonest pathogenic micro-organism, and reports of resistance to fluoroquinolones are now emerging, complicating management. We reviewed our experience of this condition, and of the local pathogenic organisms. METHODS: A retrospective review from 2004 to 2011 was performed. Patients were identified by their admission diagnostic code, and computerised records examined. RESULTS: Twenty patients were identified. A facial palsy was present in 12 patients (60 per cent). Blood cultures were uniformly negative, and culture of ear canal granulations was non-diagnostic in 71 per cent of cases. Pseudomonas aeruginosa was isolated in only 10 (50 per cent) cases; one strain was resistant to ciprofloxacin but all were sensitive to ceftazidime. Two cases of fungal skull base osteomyelitis were identified. The mortality rate was 15 per cent. The patients' treatment algorithm is presented. CONCLUSION: Our treatment algorithm reflects the need for multidisciplinary input, early microbial culture of specimens, appropriate imaging, and prolonged and systemic antimicrobial treatment. Resolution of infection must be confirmed by close follow up and imaging. PMID- 23089315 TI - Predictors of prognosis in IgA nephropathy. AB - IgA nephropathy (nephropathy with mesangial IgA and IgG deposits, so-called Berger's disease) is the most common primary chronic glomerulonephritis worldwide, and was first described in 1968. Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. This disease, therefore, is considered to be an immune-complex-mediated glomerulonephritis although the antigenic agents are still obscure. Clinically, patients with IgA nephropathy show microscopic and macroscopic hematuria and/or proteinuria. Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia, and end-stage kidney disease is not as rare as originally thought. Since pathogenesis and radical treatment for IgA nephropathy are still not established, it is necessary to study them using various clinical findings. PMID- 23089316 TI - Decreased leptin concentration in neonates is associated with enhanced postnatal growth during the first year. AB - Leptin regulates maternal metabolism and fetal growth by reducing food intake and increasing energy expenditure, particularly during the third trimester. In this study, we investigated the relationships between leptin and growth, and explored the longitudinal change of leptin in early postnatal life. A total of 58 infants were categorized according to gestational length and birth weight. Arterial blood samples were taken within 24 hours (Day 1), and on Days 4 and 7 of life. Plasma leptin levels were measured by commercial human leptin enzyme immunometric assay. The average serum leptin level declined in the first week of life. There was a positive correlation between leptin level and body weight on Day 4. Neonates with leptin decrease between Day 1 and Day 4 had better weight gain at one year old, and the hospital stay day was shorter. Furthermore, the full feeding days and the duration of feeding priming and full feeding days in the leptin decrease group were less than in the leptin increase group. Serum leptin was significantly decreased and positively correlated with neonates' body weight gain in the first week of life. A rapid decline in serum leptin after birth is associated with greater future weight gain and physiological advantage for infants' life. PMID- 23089317 TI - The value of plasma osteopontin levels as a predictive factor of disease stage and recurrence in patients with bladder urothelial carcinoma: a prospective study. AB - This study was performed in order to determine the value of plasma osteopontin (OPN) levels as a predictive factor of disease stage and recurrence in patients with bladder urothelial carcinoma (UC). Data from 50 patients diagnosed to have bladder UC after transurethral resection of bladder tumor (TURBT) from 2009 to 2010 were evaluated prospectively. Blood tests were performed before and after TURBT, and plasma OPN levels were measured using enzyme-linked immunosorbent assay. Differences in OPN levels according to clinicopathologic variables were analyzed statistically. Significant differences in plasma OPN levels were observed between groups with and without muscle invasion (89.16 vs. 67.08 ng/mL, p=0.041). Comparison according to tumor grade found no significant difference between high and low grade groups (p=0.115). Mean plasma OPN levels decreased after TURBT without statistical significance (p=0.571). Between groups with recurrence and those without recurrence, OPN levels of the group with recurrence were higher without statistical significance (p=0.161). Comparison of plasma OPN levels according to performance of radical cystectomy (RC) showed significant differences; patients who underwent RC showed higher levels of plasma OPN (95.58 vs. 70.37 ng/mL, p=0.030). Comparison according to T stage after RC showed significant differences in OPN levels (T1: 67.45, T2: 86.60 and T3: 95.23 ng/mL, respectively, p=0.006). The group with lymph node invasion showed significantly higher levels of OPN, compared to the group without invasion (153.24 vs. 68.03 ng/mL, p=0.017). Preoperative plasma OPN levels correlated to muscle invasion of bladder UC and pathological stage after RC. PMID- 23089318 TI - Clinical characteristics, pathogens implicated and therapeutic outcomes of mixed infection in adult bacterial meningitis. AB - We reviewed retrospectively the data for adult patients with bacterial meningitis over a period of 10.5 years in our hospital. The clinical characteristics and laboratory data of the 21 cases (52 strains) of mixed infection were analyzed. Two hundred and fifteen cases of single pathogen adult bacterial meningitis (ABM) were also included for comparison. Post-neurosurgical type of ABM was presented in 86% of the mixed infection group. Brain abscess was found in three patients. Fourteen patients survived and seven cases died. The analysis showed a statistical significance for the mixed infection group having a higher rate of nosocomially-acquired, post-neurosurgical condition, hydrocephalus, and lower level of cerebrospinal fluid white cell count, protein and lactate than the single pathogen group. Logistic regression analysis showed the independent factor of "hydrocephalus" (p = 0.002). Presence of hydrocephalus is a significant neuroimaging feature when compared with the single pathogen group. As compared with the previous study results of mixed infection in ABM, the present study showed a change of pathogens implicated of increasing Pseudomonas spp. and Acinetobacter spp. infections, and an emergence of anaerobic pathogens. All these changes deserve special attention because of the need for an appropriate choice of empirical antibiotics and choice of culture method. PMID- 23089319 TI - Correlation between the ossification of nuchal ligament and clinical cervical disorders. AB - This is a correlation analysis between severity of the ossification of the nuchal ligament (ONL) and clinical cervical disorders including neck dysfunction, cervical malalignment, and morphologic changes of the cervical neural foramen (CNF). The clinical effects of ONL on active range of motion (AROM) of neck, cervical radiculopathy, abnormal cervical curvature, and the degree of CNF stenosis in patients with painful neck stiffness are investigated. Studies have investigated the predisposing factors to cervical dysfunction and degenerative disorders; however, few studies have examined the influence of the ONL on neck function and cervical spine. A total of 31 participants with painful neck stiffness were recruited. They accepted measurement of cervical AROM and serial cervical radiographs at anterior-posterior view, lateral view, and bilateral oblique views. Parameters of radiographs measurement included cervical lordotic curve, and cross-sectional areas (CSA) of the ONL and CNF (C2-C3, C4-C5, C5-C6, and C6-C7 levels). The ratio of CSA of the lower CNF (C4-C5, C5-C6, C6-C7) to CSA of the upper CNF (C2-C3) was used as a CNF stenosis ratio. The correlations of ONL size, neck symptoms, cervical AROM, lordotic curve, and CNF stenosis ratio were analyzed. More than half of all patients were positive in cervical root signs and prone to have larger ONL. Neck AROM of all participants was significantly below normal average in all directions, and a moderate negative association was found between the ONL CSA and AROM in flexion-extension. Most patients had moderate loss of cervical lordotic curve despite there being no significant correlation between ONL CSA and cervical curvature. Moreover, CNF stenosis ratio significantly negatively correlated with ONL CSA. Patients with larger ONL had more severe cervical radiculopathy, more stiffness in flexion extension direction, more complex degenerative change of spine, and worse CNF stenosis. PMID- 23089320 TI - Expression of MMP-2, MMP-9 and MMP-11 in dermatofibroma and dermatofibrosarcoma protuberans. AB - Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) are the spindle cell mesenchymal neoplasms of the dermis and subcutis. Their histogenesis still remains uncertain and controversial. Traditionally, CD34 and factor XIIIa or other markers have been widely used to distinguish these two diseases. However, the results of these markers reveal overlapping and they lack specificity. Formalin-fixed, paraffin-embedded blocks were collected from the biopsied cases in Kaohsiung Medical University Hospital in Taiwan between 2004 and 2006. This study included 19 cases of DF and 17 cases of DFSP. Immunohistochemical analysis using antibodies CD34, matrix metalloproteinases (MMP)-2, MMP-9, and MMP-11 was performed. We found that the expression of CD34, MMP-2 and MMP-11 shows significant statistical differences in Immunohistochemistry (IHC) study positive or negative reactivity (positive of CD34 in DFSP and positive of MMP-2 and MMP-11 in DF; p=0.03, p<0.001, and p<0.001, respectively) between DF and DFSP. The result for expression of MMP-9 reveals no differences. The results indicate that the pathogenesis of DF and DFSP are affected by different expressions of extracellular matrix proteins. Metalloproteinases may play a direct role in these two diseases. Since no single marker can completely distinguish DF from DFSP, a combination of more than two or three stains may elevate the accuracy of diagnosis. PMID- 23089321 TI - Complications of laparoscopic radical prostatectomy--a single institute experience. AB - Laparoscopic radical prostatectomy (LRP) is a demanding procedure that requires surgical skill, a long learning curve and significant laparoscopic expertise. We report herein our initial experience with 41 laparoscopic radical prostatectomies to assess all perioperative complications in our initial 5-year experience. We reviewed retrospectively the case records of 41 patients who underwent laparoscopic radical prostatectomy for clinically localized prostate cancer from 2005 to 2010 at our institution. All abnormal symptoms were developed during the 30 days after the operation. Complications were noted as well as their severity according to the Clavien grading system. No conversion to open surgery was necessary in all cases. The median postoperative hospital stay was 10 days (range 9-16). The median duration of bladder catheterization was 8 days (range 7-35). There was no case of multiple-organ dysfunction or death. Minor complications constituted 82.6% of all complications. The incidence of severe complications was 17.4%. LRP displayed some advantages over open surgery in the perioperative period. Our complication rates were significantly higher than those indicated in the series previously reported. We found that most complications occurred in the first 30 patients who underwent LRP. We suggest that the surgeons should pay more attention to the difficulties of the procedure. PMID- 23089322 TI - Atypical femoral fracture after long-term alendronate treatment: report of a case evidenced with magnetic resonance imaging. AB - Postmenopausal osteoporosis is commonly treated with alendronate, one of the bisphosphonates used for the prevention and treatment of osteoporotic fractures. However, the correlation between atypical femoral fractures and long-term bisphosphonate therapy has not been clearly identified. We report here the case of a 69-year-old woman with postmenopausal osteoporosis who presented with an atypical femoral subtrochanteric fracture on magnetic resonance imaging (MRI) confirmation after having received alendronate therapy for about 3 years. The fracture united after refixation and after administration of alendronate was stopped. Several published reports were reviewed, and some clinical characteristics of this atraumatic fracture were revealed, including the clinical symptoms of thigh pain, stress reaction or stress fracture, and transverse fracture with unicortical beak in an area of cortical hypertrophy. In addition to a regular radiographic survey, MRI, which may provide early information, and bone biopsy for pathologic analysis may be used as tools for early detection and final diagnosis. Once an insufficiency fracture is suspected or proved to be related to bisphosphonate, the withholding of bisphosphonate should be highly recommended to enhance fracture healing. Prophylactic fixation should be considered if fracture healing is not good or if the patient cannot tolerate protection of weight bearing. PMID- 23089323 TI - Optimizing anterior esthetics of a single-tooth implant through socket augmentation and immediate provisionalization: a case report with 7-year follow up. AB - Tooth extraction inevitably accompanies alveolar ridge resorption with loss of pre-existing tissue morphology. Replacing missing teeth with dental implants has become popular, but restoring anterior teeth with implant-supported restorations is a technique-sensitive task and poses challenges for dentists. With the progress of implant dentistry, the demand for optimal esthetics has become linked with the desire for faster, easier techniques that shorten treatment time and also satisfy patients. Immediate provisionalization of a single-tooth implant provides significant benefits compared with traditional delayed protocols, such as aiding the contouring of peri-implant soft tissue and enhancing patient comfort and satisfaction. This article describes a meticulous approach to a hopeless maxillary central incisor with root fracture. The defect in the extraction socket was reconstructed using autogenous bone harvested from the chin. Four months later, an implant was installed and immediately restored. After another healing period of 6 months, the peri-implant soft tissue had been shaped and matured according to the contours of the provisional restoration. The emergence profile was used to duplicate the definitive restoration. Peri-implant esthetics was achieved through socket augmentation and immediate provisionalization of the implant. This treatment modality attained predictable and maintainable outcomes, both functionally and esthetically. PMID- 23089324 TI - Composite hemangioendothelioma on the neck. PMID- 23089325 TI - A simple "clickable" biosensor for colorimetric detection of copper(II) ions based on unmodified gold nanoparticles. AB - A novel colorimetric copper(II) biosensor has been developed based on the high specificity of alkyne-azide click reaction to the catalysis of copper ions and unmodified gold nanoparticles (AuNPs) as the signal reporter. The clickable DNA probe consists of two parts: an azide group-modified double-stranded DNA (dsDNA) hybrid with an elongated tail and a short alkyne-modified single-stranded DNA (ssDNA). Because of low melting temperature of the short ssDNA, these two parts are separated in the absence of Cu(2+). Copper ion-induced azide-alkyne click ligation caused a structural change of probe from the separated form to entire dsDNA form. This structural change of probe can be monitored by the unmodified AuNPs via mediating their aggregation with a red-to-blue colorimetric read-out because of the differential ability of ssDNA and dsDNA to protect AuNPs against salt-induced aggregation. Under the optimum conditions, this biosensor can sensitively and specifically detect Cu(2+) with a low detection limit of 250 nM and a linear range of 0.5-10 MUM. The method is simple and economic without dual labeling DNA and AuNPs modification. It is also highly selective for Cu(2+) in the presence of high concentrations of other environmentally relevant metal ions because of the great specificity of the copper-caused alkyne-azide click reaction, which potentially meets the requirement of the detection in real samples. PMID- 23089326 TI - Size-tunable Pt nanoparticles assembled on functionalized ordered mesoporous carbon for the simultaneous and on-line detection of glucose and L-lactate in brain microdialysate. AB - This study presents a facile electrochemical method for simultaneous and selective on-line detection of glucose and L-lactate in the striatum of anesthetic rats through the integration of selective electrochemical detection with in vivo microdialysis system. A positively-charged polyelectrolyte, (diallyldimethylammonium chloride) (PDDA), was attached onto carbon mesoporous material (CMM) through non-covalent interaction, which provided an ideal environment for the assembling and dispersion of nanoparticle electrocatalysts. Platinum nanoparticles with wide loadings from 5 to 50 wt% were successfully self assembled on PDDA-functionalized CMM via electrostatic interaction. TEM results showed that with the increase in the Pt loadings, both the size and interconnectivity between particles increased, with particle sizes ranging from 3.2+/-0.4 to 6.8+/-1.4 nm. Moreover, the electrocatalytic activities of the as prepared six Pt/PDDA-CMM hybrid nanocomposites were also observed to show an inverted-V-shaped profile as a function of loading amount of Pt NPs. Integrated with glucose oxidase (GOx), L-lactate oxidase (LOD) and the in vivo microdialysis system, the constructed dual oxidase/Pt/PDDA-CMM/Nafion biosensors were successfully applied for the simultaneous and on-line detection of glucose and L lactate. After post-calibration, the basal level of glucose and L-lactate in the striatum of anesthetic rats was calculated to be 0.27+/-0.03 and 0.71+/-0.05 mM (mean +/-s.d., n=3), respectively. What is more important, the dual oxidase biosensors almost suffered from little cross-talk, which is characteristic of an excellent sensor with high performance. This property, along with the good linearity and a high stability substantially enables this method promising application in physiology and pathology. PMID- 23089327 TI - On-line blood viscosity monitoring in vivo with a central venous catheter, using electrical impedance technique. AB - Blood viscosity is an important determinant of microvascular hemodynamics and also reflects systemic inflammation. Viscosity of blood strongly depends on the shear rate and can be characterized by a two parameter power-law model. Other major determinants of blood viscosity are hematocrit, level of inflammatory proteins and temperature. In-vitro studies have shown that these major parameters are related to the electrical impedance of blood. A special central venous catheter was developed to measure electrical impedance of blood in-vivo in the right atrium. Considering that blood viscosity plays an important role in cerebral blood flow, we investigated the feasibility to monitor blood viscosity by electrical bioimpedance in 10 patients during the first 3 days after successful resuscitation from a cardiac arrest. The blood viscosity-shear rate relationship was obtained from arterial blood samples analyzed using a standard viscosity meter. Non-linear regression analysis resulted in the following equation to estimate in-vivo blood viscosity (Viscosity(imp)) from plasma resistance (R(p)), intracellular resistance (R(i)) and blood temperature (T) as obtained from right atrium impedance measurements: Viscosity(imp)=( 15.574+15.576R(p)T)SR ((-.138RpT-.290Ri)). This model explains 89.2% (R(2)=.892) of the blood viscosity-shear rate relationship. The explained variance was similar for the non-linear regression model estimating blood viscosity from its major determinants hematocrit and the level of fibrinogen and C-reactive protein (R(2)=.884). Bland-Altman analysis showed a bias between the in-vitro viscosity measurement and the in-vivo impedance model of .04 mPa s at a shear rate of 5.5s( 1) with limits of agreement between -1.69 mPa s and 1.78 mPa s. In conclusion, this study demonstrates the proof of principle to monitor blood viscosity continuously in the human right atrium by a dedicated central venous catheter equipped with an impedance measuring device. No safety problems occurred and there was good agreement with in-vitro measurements of blood viscosity. PMID- 23089328 TI - A signal-on fluorescent aptasensor based on Tb3+ and structure-switching aptamer for label-free detection of Ochratoxin A in wheat. AB - On the basis of Tb(3+), structure-switching aptamer and magnetic beads (MBs), a signal-on fluorescent aptasensor was developed for the label-free determination of OTA in wheat. Initially, the specific sequence of the anti-OTA aptamer labeled with a biotin group, was attached to streptavidin-modified MBs. Two single stranded signal probes were added and naturally hybridized with anti-OTA aptamer to form the duplex structure in the solution. Due to the fact that single stranded oligonucleotides can greatly enhance the emission of Tb(3+) in solution but duplexes do not, through magnetic separation, the supernatant liquid of the above solution contained no single-stranded DNA and cannot increase the emission of Tb(3+). While upon OTA addition, it will bind with aptamer to form OTA-aptamer G-quadruplex while releasing two single-stranded signal probes. Through magnetic separation, the released single-stranded signal probes left in the supernatant liquid can dramatically increase the fluorescent intensity of Tb(3+). By employing the above strategy, this aptasensor can detect as low as 20 pg/mL OTA with high specificity. To the best of our knowledge, the proposed aptasensor is the first attempt to use the fluorescent characteristics of Tb(3+) for OTA detection, which may represent a promising path toward routine quality control of food safety. PMID- 23089329 TI - [Chronotherapy with 5-fluorouracil folinic acid and oxaliplatin delivered over 48 hours every second week in colorectal cancer. The CHC-Liege experience (Belgium)]. AB - One hundred and ten consecutive patients suffering from a colorectal cancer received chronotherapy infused over two days every two weeks. Each course comported 5 FU 3g/m(2), folinic acid (600 mg/m(2) - l. form or 1200 mg/m(2)- racemic form) and oxaliplatin (85/mg/m(2)--adjuvant indication or 100mg/m(2)- palliative indication). According to chronobiological concepts, 5 FU and folinic acid were infused from 10 pm to 10 am with a peak at 4 am while oxaliplatin was delivered from 10 am to 10 pm with a peak at 4 pm. The overall tolerance was excellent with a maximum of 17% patients experiencing a grade 3 toxicity. The toxicity was higher in women, in older patients (>=70) or in case of flat infusion. In adjuvant situation (60 cases), progression free and overall survivals established respectively at 76% (42+months) and 88% (45+months). Fifty two percent response rate were recorded within the palliative group (50 cases) with an overall 68% disease control. Median progression free survival was seven months but median survival was not attained at 31+ months. Thirty percent patients could benefit from a curative surgery after chemotherapy. Older patients (>=70) experienced worsened survival. In conclusion, we think that our chrono FOLFOX 2-12 should be proposed as standard treatment for colorectal cancer patients. PMID- 23089330 TI - Ankle variability is amplified in older adults due to lower EMG power from 30-60 Hz. AB - The purpose of this study was to determine the neuromuscular mechanisms of the involved muscles that contribute to the greater positional variability at the ankle joint in older adults compared with young adults. Eleven young adults (25.6+/-4.9 years) and nine older adults (76.9+/-5.9 years) were asked to accurately match and maintain a horizontal target line with 5 degrees dorsiflexion of their ankle for 20 s. The loads were 5 and 15% of the one repetition maximum load (1 RM). The visual gain was kept constant at 1 degrees for all trials. Positional variability was quantified as the standard deviation (SD) of the detrended position signal. The neural activation of the tibialis anterior and soleus muscles was quantified as the normalized EMG amplitude, power spectrum density (PSD; EMG oscillations) and coactivation of the two muscles. As expected, positional variability was greater in older adults (older: 0.11+/-0.06 degrees vs. young: 0.04+/-0.02 degrees ; p=.003). The only significant neural difference occurred for the PSD of the tibialis anterior muscle, where young adults exhibited significantly greater power than older adults from 30-60 Hz. The amplified positional variability of ankle joint in older adults was associated with lower power from 30-60 Hz oscillations in the tibialis anterior muscle (r(2)=.3, p=.01). These results provide novel evidence that older adults exhibit greater positional variability with the ankle joint relative to young adults likely due to their inability to activate the tibialis anterior muscle from 30-60 Hz. PMID- 23089331 TI - Patterns of local recurrence after primary resection of cancers that arise in the sinonasal region and the maxillary alveolus. AB - Local recurrence remains the most important sign of relapse of disease after treatment of advanced cancer of the maxilla and sinonasal region. In this retrospective study we describe patterns of recurrence in a group of patients who had had open resection for cancer of the sinonasal region and posterior maxillary alveolus with curative intent. Casenotes and imaging studies were reviewed to find out the pattern of any relapse, with particular reference to local recurrence. The minimum follow-up period was 12 months. Of 50 patients a total of 16 developed recurrences, 11 of which were local. Of those 11, a total of 8 were in posterior and superior locations (the orbit, the infratemporal and pterygopalatine fossas, the traversing neurovascular canals of the body of the sphenoid to the cavernous sinus, the Gasserian ganglion, and the dura of the middle cranial fossa). Advanced cancer of the midface often equates with disease at the skull base. Treatment, including surgical tactics, should reflect that. PMID- 23089332 TI - Location of the dsRNA-dependent polymerase, VP1, in rotavirus particles. AB - Double-stranded RNA (dsRNA) viruses transcribe and replicate RNA within an assembled, inner capsid particle; only plus-sense mRNA emerges into the intracellular milieu. During infectious entry of a rotavirus particle, the outer layer of its three-layer structure dissociates, delivering the inner double layered particle (DLP) into the cytosol. DLP structures determined by X-ray crystallography and electron cryomicroscopy (cryoEM) show that the RNA coils uniformly into the particle interior, avoiding a "fivefold hub" of more structured density projecting inward from the VP2 shell of the DLP along each of the twelve 5-fold axes. Analysis of the X-ray crystallographic electron density map suggested that principal contributors to the hub are the N-terminal arms of VP2, but reexamination of the cryoEM map has shown that many features come from a molecule of VP1, randomly occupying five equivalent and partly overlapping positions. We confirm here that the electron density in the X-ray map leads to the same conclusion, and we describe the functional implications of the orientation and position of the polymerase. The exit channel for the nascent transcript directs the nascent transcript toward an opening along the 5-fold axis. The template strand enters from within the particle, and the dsRNA product of the initial replication step exits in a direction tangential to the inner surface of the VP2 shell, allowing it to coil optimally within the DLP. The polymerases of reoviruses appear to have similar positions and functional orientations. PMID- 23089334 TI - Diabetes mellitus in an aging population: the challenge ahead. PMID- 23089333 TI - Skeletal muscle autophagy and protein breakdown following resistance exercise are similar in younger and older adults. AB - BACKGROUND: The loss of skeletal muscle mass and strength during aging, sarcopenia, increases the risk for falls and dependency. Resistance exercise (RE) training is effective at improving muscle mass and strength in older adults; however, aging is associated with reduced training-induced hypertrophy. Recent research has illustrated an impaired muscle protein synthetic response following an acute bout of RE in older adults but much less is known regarding the effect of acute RE on muscle protein breakdown (MPB). We hypothesize that the ubiquitin proteasome system and the autophagosomal-lysosomal system may regulate the overall rate of MPB during postexercise recovery. METHODS: Muscle biopsies of the vastus lateralis were sampled from 16 older (age = 70+/-2 years) and 16 younger (age = 27+/-2 years) participants at baseline and at 3, 6, and 24 hours following an acute bout of RE. In conjunction with stable isotopic techniques to measure MPB, we utilized immunoblotting and RT-PCR to examine protein and mRNA expression for key signaling molecules in both the ubiquitin proteasome system and the autophagosomal-lysosomal system. RESULTS: MuRF1 mRNA expression increased, whereas GABARAP mRNA decreased after RE in both younger and older adults (p < .05). The LC3B-II/LC3B-I protein ratio decreased in both groups after RE (p < .05), but MPB was not different 24 hour post-RE in either group (p > .05). CONCLUSIONS: Aging does not influence skeletal MPB, autophagy, or the ubiquitin proteasome system following an acute bout of RE. Therefore, targeting the muscle protein synthesis response to exercise may hold more promise in the prevention of sarcopenia. PMID- 23089336 TI - Probing the relationship between insulin sensitivity and longevity using genetically modified mice. AB - Interference in insulin and/or insulin-like growth factor 1 (IGF-1) signaling can extend invertebrate life span, and interference in IGF-1 signaling can extend murine life span. Whether interference with murine insulin signaling, which can be diabetogenic and pathological, is also life-extending is controversial. We therefore measured life span in 3 murine strains genetically modified to reduce or increase insulin sensitivity. Mice with reduced insulin sensitivity were hemizygous for a null mutation in the insulin receptor (insulin receptor knockout mice; IRKO(+/-)). Mice with increased insulin sensitivity either had a null mutation of protein tyrosine phosphatase 1B (PTP-1B(-/-)) or overexpressed Peroxisome proliferator-activated receptor-alpha coactivator (PGC)-1alpha (PGC 1alpha(TG)). Life span of insulin insensitive IRKO(+/) mice was increased (males) or unaffected (females). Life spans of mice with increased insulin sensitivity were shortened overall (PTP-1B(-/-) mice) or partially (PGC-1alpha(TG): survival at the 25th percentile was reduced). These results show that insulin sensitivity in some murine genotypes is inversely related to longevity and provide further evidence for evolutionary conservation of this pathway as a modulator of longevity. PMID- 23089337 TI - Beneficial effects of tibolone on blood pressure and liver redox status in ovariectomized rats with renovascular hypertension. AB - Estrogen deficiency is associated with aging and increases the incidence of metabolic syndrome and hypertension. In this study, the effects of tibolone, a synthetic steroid, on the cardiovascular system, liver lipid metabolism, and redox status were evaluated, in ovariectomized (OVX) rats with renovascular hypertension (two-kidneys, one-clip, OVX + 2K1C). This study encompassed direct measurements of mean arterial pressure , plasma biochemical analysis, liver lipid contents, and assessments of the mitochondrial and peroxisomal beta-oxidation capacities. Additionally, the liver redox status was assayed. Tibolone significantly reduced the mean arterial pressure of OVX + 2K1C rats, albeit reducing total and high-density lipoprotein (HDL) cholesterol levels. In the liver, although exerting an undesirable inhibition of mitochondrial and peroxisomal beta-oxidation, tibolone reversed steatosis. Tibolone also improved the liver redox status: the reduced glutathione contents and the activity of glucose-6-phosphate dehydrogenase were restored by this compound, which also reduced the levels of thiobarbituric acid-reactive substances and the generation of mitochondrial reactive oxygen species. So, tibolone reversed the main alterations caused by hypertension and estrogen deficiency. PMID- 23089335 TI - Trajectory classes of body mass index in a representative elderly community sample. AB - BACKGROUND: It is unclear whether distinct weight-related trajectory classes, differing in course, demographics, and health characteristics, exist in the elderly population. METHODS: Data came from the 10-year (1986-1996) Duke Established Populations for Epidemiologic Studies of the Elderly study of 3,861 black (54%) and white (46%) participants aged 65-105 years. Latent-class trajectories of body mass index (BMI: kg/m(2)) based on self-reported weight and height at baseline, 3, 6, and 10 years later were determined using generalized mixture models. Polytomous logistic regression was used to identify baseline demographic and health characteristics that distinguished the trajectories, and 10-year postbaseline data to confirm the findings. RESULTS: We identified three trajectories: normal weight (BMI ~24, 27.6% of the sample), overweight (BMI ~26, 65.1%), and obese (BMI ~31, 7.3%). Demographic characteristics distinguished the three trajectories: highest odds of blacks, women, and less education in the obese trajectory, lowest in the normal-weight trajectory. Obese and overweight differed adversely from normal-weight trajectories, but not significantly from each other on cognitive impairment, hypertension, and diabetes. Depressive symptomatology was more prevalent in the obese; they were also younger. There was no association with cancer or heart disease. CONCLUSION: Distinct trajectories and course of BMI were present in this older population. Weight loss increased with increase in BMI class. Although demographic characteristics distinguished all trajectory classes, adverse health characteristics distinguished the overweight and obese classes from the normal-weight class, but not from each other. Problems associated with education and health are present at study entry and should be addressed earlier in life. PMID- 23089338 TI - Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants. AB - BACKGROUND: Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs). METHODS: Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers. RESULTS: We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants. CONCLUSIONS: These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases. PMID- 23089340 TI - Associations between parenting styles and nutrition knowledge and 2-5-year-old children's fruit, vegetable and non-core food consumption. AB - OBJECTIVE: During the early years, parents have a major influence on children's diets and developing food choices. We investigated parenting styles as predictors of 2-5-year-old children's diets and whether general nutrition knowledge (GNK) mediated these influences. DESIGN: Cross-sectional research. Questionnaires measured demographic and lifestyle variables, family environment, parenting styles and feeding practices, child diet and GNK. Regression models tested GNK as a mediator of relationships between parenting variables and child diet (fruit/vegetable and non-core food consumption), controlling for confounders and family environment. SETTING: Questionnaires were completed by main caregivers at home. SUBJECTS: Parents of children aged 2-5 years (n 269). RESULTS: Higher child fruit/vegetable consumption was associated with lower overreactive parenting and restriction, higher authoritative parenting and dining together as a family; with lax parenting approaching statistical significance (P50?083) and 19% of variance explained by the model. GNK was not a significant predictor. Conversely, non-core food consumption was associated with higher over-reactive and lax parenting as well as child age, increased takeaway food consumption and higher television viewing; GNK had a small effect (P = 0.043) and 28% of variance was explained by the model. GNK was a significant mediator only for authoritative parenting on non core food (effect = -0.005). CONCLUSIONS: These findings highlight that young children's diets may be improved by interventions targeting a range of positive and supportive parenting practices in conjunction with nutrition knowledge education for parents of young children. Further insights will come from closer attention to the nature and role of restrictive feeding practices v. laxness and longitudinal research. PMID- 23089341 TI - Re-claim the condition: the shifting roles of PCPs and urologists. PMID- 23089339 TI - Strength training induces muscle hypertrophy and functional gains in black prostate cancer patients despite androgen deprivation therapy. AB - BACKGROUND: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with weakness, fatigue, sarcopenia, and reduced quality of life (QoL). Black men have a higher incidence and mortality from PCa than Caucasians. We hypothesized that despite ADT, strength training (ST) would increase muscle power and size, thereby improving body composition, physical function, fatigue levels, and QoL in older black men with PCa. METHODS: Muscle mass, power, strength, endurance, physical function, fatigue perception, and QoL were measured in 17 black men with PCa on ADT before and after 12 weeks of ST. Within-group differences were determined using t tests and regression models. RESULTS: ST significantly increased total body muscle mass (2.7%), thigh muscle volume (6.4%), power (17%), and strength (28%). There were significant increases in functional performance (20%), muscle endurance (110%), and QoL scores (7%) and decreases in fatigue perception (38%). Improved muscle function was associated with higher functional performance (R (2) = 0.54) and lower fatigue perception (R (2) = 0.37), and both were associated with improved QoL (R (2) = 0.45), whereas fatigue perception tended to be associated with muscle endurance (R (2) = 0.37). CONCLUSIONS: ST elicits muscle hypertrophy even in the absence of testosterone and is effective in counteracting the adverse functional consequences of ADT in older black men with PCa. These improvements are associated with reduced fatigue perception, enhanced physical performance, and improved QoL. Thus, ST may be a safe and well-tolerated therapy to prevent the loss of muscle mass, strength, and power commonly observed during ADT. PMID- 23089342 TI - Medical management of overactive bladder. AB - Overactive bladder (OAB) with or without urinary incontinence is a common condition in both men and women. OAB has a significant impact on quality of life for most patients. In most cases, sophisticated testing is not required for a primary care physician to diagnose OAB and start treating a patient. Management of OAB requires behavioral modification and, if necessary, pharmacotherapy may be added. If a patient does not respond to treatment initiated by a primary care physician, then he or she should be referred to a specialist in OAB to undergo further investigations and treatments. PMID- 23089343 TI - Benign prostatic hyperplasia (BPH) management in the primary care setting. AB - Benign prostate hyperplasia (BPH) occurs in up to 50% of men by age 50, and the incidence increases with age. This common clinical problem is diagnosed by history, including the International Prostate Symptom Score (IPSS) questionnaire, and physical examination by digital rectal examination (DRE). Initial management for BPH includes lifestyle modification, and smooth muscle relaxant alpha blocker therapy. Alpha blockers usually take effect quickly within 3-5 days, and have minimal side effects. Current commonly used alpha blockers include the selective alpha blockers tamsulosin (Flomax), alfusosin (Xatral), and silodosin (Rapaflo). For patients with larger prostates, the 5-alpha reductase inhibitor class (finasteride (Proscar) and dutasteride (Avodart)) work effectively to shrink prostate stroma resulting in improved voiding. The 5-ARI class of drugs, in addition to reducing prostate size, also reduce the need for future BPH-related surgery, and reduce the risk of future urinary retention. Drugs from the phosphodiesterase-5 (PDE-5) inhibitor class may now be considered for treating BPH. Once daily 5 mg tadalafil has been shown to improve BPH-related symptoms and is currently approved to treat patients with BPH. Referral to a urologist can be considered for patients with a rising prostate-specific antigen (PSA), especially while on 5-ARI, failure of urinary symptom control despite maximal medical therapy, suspicion of prostate cancer, hematuria, recurrent urinary infections, urinary retention, or renal failure. Currently the primary care physician is armed with multiple treatment options to effectively treat men with symptomatic BPH. PMID- 23089344 TI - Erectile dysfunction and testosterone deficiency syndrome: the "portal to men's health". AB - Erectile dysfunction (ED) and testosterone deficiency syndrome (TDS) are closely related. In addition to affecting men's sexual health, both conditions also affect other male health issues. Screening for ED, especially in younger men, should become standard clinical practice for the primary care physician. Possible systemic effects and associated effects of TDS are now well documented. Testosterone replacement therapy (TRT) is very safe and effective in the right man. PMID- 23089345 TI - PSA implications and medical management of prostate cancer for the primary care physician. AB - Prostate cancer remains a common cancer diagnosis and cause of cancer-related death in men. Despite its high prevalence, screening for prostate cancer for early detection remains controversial. This article outlines evidence from contemporary prostate cancer screening clinical trials and presents an overview of therapeutic options across the spectrum of prostate-cancer states. PMID- 23089346 TI - What is significant hematuria for the primary care physician? AB - Hematuria is a common finding in primary care practice. Causes of significant hematuria include urinary tract infection, urolithiasis, malignancies, benign prostatic hyperplasia, and nephropathies. Hematuria is identified by taking a patient history and by performing a routine urine dipstick test. If a patient has a history of gross hematuria and/or a positive urine dipstick test, he or she should then have a microscopic urinalysis. The primary care physician can order ancillary tests such as laboratory tests to assess renal function, and possible imaging tests such as ultrasound, computed tomography urography, or magnetic resonance urography. The patient may be referred to a nephrologist or urologist for further assessment if required. Cystoscopy may be considered. Even if the patient has a negative work up, guidelines recommend that primary care physicians follow the patient semi-annually for 3 years. PMID- 23089347 TI - Diagnosis and management of simple and complicated urinary tract infections (UTIs). AB - Urinary tract infections (UTIs) remain a common clinical problem in both the community and healthcare-associated settings. Each patient should be carefully assessed to ensure that a correct diagnosis is made and that antimicrobial therapy is appropriately prescribed--defined as using a clinically indicated agent in the correct dose and route of administration, for the correct duration- for symptomatic patients, and avoided for most asymptomatic patients. This should help stem the growing tide of antimicrobial resistance and allow for the continued use of simpler, less expensive agents. Continued surveillance and monitoring of antimicrobial resistance rates will be critical to help formulate and update future treatment recommendations for all categories of patients with UTIs. PMID- 23089348 TI - Emerging therapies: what's new is old and what's old is new. AB - Researchers are constantly seeking ways to improve existing drugs, drug mechanisms of activity, find new indications for old drugs or to develop new drugs to treat urological diseases and conditions. In Canada, tadalafil in a 5 mg daily dosage (old drug), and a new drug, silodosin, have recently become available to treat patients who have benign prostatic hyperplasia (BPH) with lower urinary tract symptoms (LUTS). In clinical studies, silodosin has shown promise as a treatment for ureteral stones, whereas it has shown conflicting results as a potential treatment for prostatitis. Two new therapies have emerged for treating overactive bladder (OAB): Mirabegron (not yet available in Canada) and fesoterodine (newly introduced in the marketplace). New therapies--denosumab (to prevent skeletal events) and abiraterone acetate and enzalutamide--were recently approved to treat certain patients with advanced prostate cancer. With the advent of new therapies to treat urological diseases, in many cases, primary management of the patient is often shifted from the urologist to the family physician, and sometimes moved from the oncologist to the urologist. PMID- 23089349 TI - Tourniquet use does not affect rehabilitation, return to activities, and muscle damage after arthroscopic meniscectomy: a prospective randomized clinical study. AB - PURPOSE: The purpose of this prospective randomized trial was to examine the effect of tourniquet use on rehabilitation rate, return to work and sport activities, and muscle damage after arthroscopic meniscectomy. METHODS: Eighty patients who underwent arthroscopic partial meniscectomy were randomly allocated to the use of an inflated (group A, n = 40) or deflated (group B, n = 40) pneumatic tourniquet. Patients with concomitant ligamentous deficiency or grade III and IV chondral lesions were excluded. The primary outcome measures were pain, measured with a visual analog scale (VAS), and knee range of motion (ROM) on days 8 and 15 postoperatively; time required for patients to discontinue the use of crutches; time to return to light activities and moderate sporting activities such as jogging; and serum creatine phosphokinase (CPK) levels monitored preoperatively and on days 1, 8, and 15 postoperatively. RESULTS: The 2 groups did not differ in terms of age; male-female ratio; body mass index; and preoperative International Knee Documentation Committee, Tegner, and Lysholm scores. Operative time was not significantly different between groups (mean, 27.5 for group A and 31.2 for group B; P = .83). VAS pain scores and knee ROM were not significant between groups (minimum P = .22). The patients progressed to weight bearing without crutches within 13.4 and 12.9 days for groups A and B, respectively (P = .9). Return to work and jogging did not differ significantly between groups (minimum P = .34). Serum CPK values were also not significantly different between or within groups during consecutive measurements (P = .3). Tourniquet time did not significantly affect postoperative ROM, VAS pain scores, or serum CPK levels (minimum P = .14). CONCLUSIONS: Tourniquet use for less than 30 minutes during arthroscopic meniscectomy does not affect postoperative pain or return to light work and jogging. In addition, tourniquet-induced muscle damage after arthroscopic meniscectomy, though potentially present locally, is not detectable in the systemic circulation. LEVEL OF EVIDENCE: Level I, prospective randomized trial. PMID- 23089350 TI - The effect of screw position and number on the time to union of arthroscopic ankle arthrodesis. AB - PURPOSE: This study aimed to investigate the factors that influence the time to union after arthroscopic ankle arthrodesis. METHODS: From June 2005 to October 2010, 46 patients (50 ankles) underwent arthroscopic ankle arthrodesis with 6.0 mm cannulated cancellous screws. There were 22 men and 24 women (mean age, 63 years). Medical records and radiographs were retrospectively reviewed. Screw configurations used were as follows: 3 transmedial and translateral malleolar screws (ML3) in 12 ankles (24%), 2 transmedial and translateral malleolar screws (ML2) in 4 ankles (8%), 3 transmedial malleolar screws (M3) in 23 ankles (46%), and 2 transmedial malleolar screws (M2) in 11 ankles (22%). RESULTS: Radiographic fusion was achieved in 46 (92%) of the 50 ankles. The mean time to fusion was 11.0 +/- 4.5 weeks for ML3, 13.1 +/- 3.3 weeks for ML2, 9.7 +/- 2.7 weeks for M3, and 12.5 +/- 3.5 weeks for M2 (P < .05). The mean American Orthopaedic Foot & Ankle Society scores were 81.3 +/- 2.2 for ML3, 83.5 +/- 4.4 for ML2, 88.3 +/- 1.5 for M3, and 85.3 +/- 2.2 for M2. The mean time until radiographic fusion was 10.2 +/- 3.4 weeks for correction angles of less than 10 degrees and 13.2 +/- 3.4 weeks for angles of 10 degrees or greater (P < .01). In obese patients a significant difference in ankle fusion time was observed (12.6 +/- 3.5 weeks for patients with body mass index >=25 v 9.4 +/- 2.9 weeks for patients with body mass index <25, P < .01). CONCLUSIONS: Overall, this study showed that arthroscopic ankle arthrodesis achieves a high rate of union, with fastest union achieved with 3 parallel screws placed medially from the distal tibia into the talus. Care should be taken when one is designing treatment strategies for obese patients and/or patients with large correction angles. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 23089351 TI - Aloe-emodin inhibits proliferation of adult human keratinocytes in vitro. AB - Aloe-emodin (AE) is a plant-derived hydroxyanthraquinone with several biological activities. It is present in a variety of skin-conditioning agents containing aloe extracts, but its influence on keratinocyte growth was not examined so far. We investigated the influence of AE on human keratinocyte proliferation and apoptosis in vitro. AE significantly inhibited proliferation of cultivated human keratinocytes at 5 MUM concentration, as revealed by incorporation of radioactive thymidine. The antiproliferative effect of AE was accompanied with induction of apoptosis, but not necrosis, as demonstrated by flow cytometric analysis and lactate dehydrogenase release assay. Based on the half maximal inhibitory concentration values, we demonstrated that AE may impair proliferation of keratinocytes at concentrations far below the industry standards for commercial products containing aloe extracts. Therefore, further research of AE effects on the human skin and proper labeling of products are necessary for maximizing benefits from aloe extracts and to avoid undesired responses. PMID- 23089352 TI - Relationships among skin conditions, mood, and polyunsaturated fatty acids of RBCs in healthy women. AB - Little is known about nonpathological facial skin problems at present. The aim of the present study was to investigate the relationships among facial skin conditions, mood, and the fatty acid composition of red blood cells (RBCs) in women. One hundred and thirty-two apparently healthy Japanese women aged between 20 and 60 years were recruited. Facial skin conditions were analyzed using a Robo Skin Analyzer, and the RBC fatty acid composition was also determined. Questionnaires concerning mood were administered. Forehead pigmentation was more mood-dependent (in 20s group) and less arachidonic acid (AA)-dependent (in all participants) than that in other areas of the face. Actually there was no correlation in pigmentation between the forehead and other areas of the face when adjusted for age, smoking, and drinking. Skin conditions were adversely correlated with a negative mood. alpha-Linolenic acid concentrations were negatively correlated with negative mood scores. Pigmentation characteristics in the forehead were independent from other areas of the face. Negative mood and AA were adversely correlated with skin conditions. PMID- 23089353 TI - Skin-whitening effects of Mediterranean herbal extracts by in vitro and in vivo models. AB - Several plant extracts are able to protect skin against ultraviolet-light-induced damage and hyperpigmentation in a safe way. The anti-melanogenic effect of herbal extracts seems to be related to their antioxidant activity and their polyphenolic content. In this study, the skin-whitening effect of some Mediterranean species, already known for their strong antioxidant and radical scavenger activity, has been evaluated by in vitro and in vivo models. The results obtained showed that herbal extracts possessed an inhibitory effect on tyrosinase enzyme. Each extract showed a similar inhibiting activity even though it was less intensive than kojic acid and hydroquinone. Otherwise, a significant higher activity than kojic acid and hydroquinone was observed when the herbal extracts were combined. Furthermore, the anti-melanogenic activity and an evaluation of skin tolerance were affected by in vivo methods. PMID- 23089354 TI - Simultaneous determination of 13 components in oxidative hair dyes by high performance chromatography using an ion-pair reagent. AB - A reliable high-performance liquid chromatography (HPLC) method was developed for the simultaneous determination of 13 dye intermediates, including benzenediamines, aminophenols, benzenediols, naphthalenediol, and diaminopyridine, in oxidative hair dyes. Samples were extracted with 50% ethanol by adding sodium dithionite to prevent oxidation. The influences of buffer type, buffer pH, ion-pair reagent, and elution gradient were studied. A C18 column with aqueous compatibility and acetonitrile-citric acid mobile phase system (pH 2.6) with sodium 1-octanesulfonate as ion-pair reagent were selected for the separation of target compounds. Detection was performed by a diode array detector, (DAD) and two different wavelengths (280 and 331 nm) were used for quantification. Results showed that 13 dye intermediates got good separation within 25 min. The detection limits of these compounds were in the range of 0.2-2 mg/l. The calibration curves were linear within 2-500 mg/l with 0.999 as a typical correlation coefficient. The recoveries of target compounds in hair dyes ranged from 81.7% to 102.0% with four addition levels. The method described was validated by five different laboratories and successfully applied to the analysis of commercial oxidative hair dyes. PMID- 23089355 TI - Preparation of emulsions by rotor-stator homogenizer and ultrasonic cavitation for the cosmeceutical industry. AB - Oil-in-water (O/W) nanoemulsions play an important key role in transporting bioactive compounds into a range of cosmeceutical products to the skin. Small droplet sizes have an inherent stability against creaming, sedimentation, flocculation, and coalescence. O/W emulsions varying in manufacturing process were prepared. The preparation and characterization of O/W nanoemulsions with average diameters of as low as 62.99 nm from palm oil esters were carried out. This was achieved using rotor-stator homogenizer and ultrasonic cavitation. Ultrasonic cell was utilized for the emulsification of palm oil esters and water in the presence of mixed surfactants, Tween 80 and Span 80 emulsions with a mean droplet size of 62.99 nm and zeta potential value at -37.8 mV. Results were comparable with emulsions prepared with rotor-stator homogenizer operated at 6000 rpm for 5 min. The stability of the emulsions was evaluated through rheology measurement properties. This included non-Newtonian viscosity, elastic modulus G', and loss modulus G". A highly stable emulsion was prepared using ultrasonic cavitation comprising a very small particle size with higher zeta potential value and G' > G" demonstrating gel-like behavior. PMID- 23089356 TI - Lack of huntingtin promotes neural stem cells differentiation into glial cells while neurons expressing huntingtin with expanded polyglutamine tracts undergo cell death. AB - Huntington's disease (HD) is a neurodegenerative disorder that affects muscle coordination and diminishes cognitive abilities. The genetic basis of the disease is an expansion of CAG repeats in the Huntingtin (Htt) gene. Here we aimed to generate a series of mouse neural stem (NS) cell lines that carried varying numbers of CAG repeats in the mouse Htt gene (Hdh CAG knock-in NS cells) or that had Hdh null alleles (Hdh knock-out NS cells). Towards this end, Hdh CAG knock-in mouse ES cell lines that carried an Htt gene with 20, 50, 111, or 140 CAG repeats or that were Htt null were neuralized and converted into self-renewing NS cells. The resulting NS cell lines were immunopositive for the neural stem cell markers NESTIN, SOX2, and BLBP and had similar proliferative rates and cell cycle distributions. After 14 days in vitro, wild-type NS cells gave rise to cultures composed of 70% MAP2(+) neurons and 30% GFAP(+) astrocytes. In contrast, NS cells with expanded CAG repeats underwent neuronal cell death, with only 38%+/-15% of the MAP2(+) cells remaining at the end of the differentiation period. Cell death was verified by increased caspase 3/7 activity on day 14 of the neuronal differentiation protocol. Interestingly, Hdh knock-out NS cells treated using the same neuronal differentiation protocol showed a dramatic increase in the number of GFAP(+) cells on day 14 (61%+/-20% versus 24%+/-10% in controls), and a massive decrease of MAP2(+) neurons (30%+/-11% versus 64%+/-17% in controls). Both Hdh CAG knock-in NS cells and Hdh knock-out NS cells showed reduced levels of Bdnf mRNA during neuronal differentiation, in agreement with data obtained previously in HD mouse models and in post-mortem brain samples from HD patients. We concluded that Hdh CAG knock-in and Hdh knock-out NS cells have potential as tools for investigating the roles of normal and mutant HTT in differentiated neurons and glial cells of the brain. PMID- 23089357 TI - Hexachlorobenzene dechlorination in constructed wetland mesocosms. AB - We studied the dechlorination of hexachlorobenzene (HCB) in wetland mesocosm (MC) trials filled with sediment (well mineralized homogenized peat mixed with mud) from a wastewater treatment wetland located in a floodplain: three MCs were planted with common reed (Phragmites australis) and another three with broad leaved cattail (Typha latifolia). According to the rootzone development we distinguished between the upper (0-10 cm from the soil surface) and lower layers (20-30 cm). Over 36 days, the initial measured concentration of HCB was reduced to 61%, 51%, 42% and 40% in the lower layer without roots of Phragmites, in the lower layer with roots of Typha, in the upper layer with roots of Typha, and in the upper layer with roots of Phragmites respectively. The 90% degradation time (DT(90)) of the initial measured HCB can be calculated as 192, 121, 110 and 92 days (d) respectively. PeCB, 1, 2, 3, 4-, 1, 2, 3, 5- and 1, 2, 4, 5-TeCB, and 1, 2, 3-, 1, 2, 4- and 1, 3, 5-TCB were the main dechlorination products detected in MC sediment samples. The dechlorination rates of HCB were higher in sediment layers with well-developed root zones. According to the DT(50) of 28-58 days and DT(90) of 92-192 days, HCB can be considered to be a less persistent organic pollutant in constructed wetlands. PMID- 23089358 TI - Linking hydrolytic activities to variables influencing a submerged membrane bioreactor (MBR) treating urban wastewater under real operating conditions. AB - The seasonal variation of the hydrolytic activities acid and alkaline phosphatase, alpha-glucosidase and protease, was studied in both the aerated and anoxic phases of a full-scale membrane bioreactor (MBR) (total operational volume = 28.2 m(3)), operated in pre-denitrification mode and fed real urban wastewater. Non-metric multidimensional scaling (MDS) and BIO-ENV analysis were used to study the distribution of enzyme activities in different seasons of the year (spring, summer and autumn) and unveil their relationships with changes in variables influencing the system (composition of influent wastewater, activated sludge temperature and biomass concentration in the bioreactors). The activities of all the tested hydrolases were remarkably dynamic, and each enzyme showed complex and diverse patterns of variation. Except in the summer season, the variables included in this study gave a good explanation of those patterns and displayed high and consistent correlations with them; however, markedly different correlation trends were found in each season, indicating dissimilar adaptation responses of the community to the influence of changing conditions. A consistent and highly negative correlation between protease and alpha-glucosidase was revealed in all the experiments. The variables included in this study showed contrary influences on these activities, suggesting an alternation of the major groups of carbon-degrading hydrolases in connection to changes in temperature and the availability and composition of nutrients in the different seasons. Sampling over a long period of time was required to adequately lay down the links between hydrolytic activities and the variables influencing the MBR system. These results highlight the complexity of the regulation of substrate degradation by the mixed microbial sludge communities under real operating conditions. PMID- 23089359 TI - Effect of wastewater colloids on membrane removal of antibiotic resistance genes. AB - Recent studies have demonstrated that wastewater treatment plants (WWTPs) significantly alter the magnitude and distribution of antibiotic resistance genes (ARGs) in receiving environments, indicating that wastewater treatment represents an important node for limiting ARG dissemination. This study examined the potential for membrane treatment of microconstituent ARGs and the effect of native wastewater colloids on the extent of their removal. Plasmids containing vanA (vancomycin) and bla(TEM) (beta-lactam) ARGs were spiked into three representative WWTP effluents versus a control buffer and tracked by quantitative polymerase chain reaction through a cascade of microfiltration and ultrafiltration steps ranging from 0.45 MUm to 1 kDa. Significant removal of ARGs was achieved by membranes of 100 kDa and smaller, and presence of wastewater colloids resulted in enhanced removal by 10 kDa and 1 kDa membranes. ARG removal was observed to correlate significantly with the corresponding protein, polysaccharide, and total organic carbon colloidal fractions. Alumina membranes removed ARGs to a greater extent than polyvinylidene fluoride membranes of the same pore size (0.1 MUm), but only in the presence of wastewater material. Control studies confirmed that membrane treatment was the primary mechanism of ARG removal, versus other potential sources of loss. This study suggests that advanced membrane treatment technology is promising for managing public health risks of ARGs in wastewater effluents and that removal may even be enhanced by colloids in real-world wastewaters. PMID- 23089360 TI - The viscoelastic behaviour of raw and anaerobic digested sludge: strong similarities with soft-glassy materials. AB - Over the last few decades, municipal and industrial wastewater treatment activities have been confronted with a dramatically increasing flow of sewage sludge. To improve treatment efficiency, process and material parameters are needed but engineers are dealing with vast quantities of fundamentally poorly understood and unpredictable material Thus, accurate prediction of critically important, but analytically elusive process parameters is unattainable and is a matter of grave concern. Because engineers need reliable flow properties to simulate the process, this work is an attempt to approach sludge rheological behaviour with well-known materials which have similar characteristics. Sludge liquid-like behaviour is already well documented so, we have focused mainly on the solid-like behaviour of both raw and digested sludge by performing oscillatory measurements in the linear and non-linear regimes. We have shown that the viscoelastic behaviour of sludge presents strong similarities with soft glassy materials but differences can be observed between raw and digested sludge. Finally, we confirm that colloidal glasses and emulsions may be used to model the rheological behaviour of raw and anaerobic digested sludge. PMID- 23089361 TI - Conventional working memory training may not improve intelligence. AB - A recent study by Redick and colleagues found no improvements in cognition or intelligence after working memory training using a randomized, placebo-controlled design. Here, I argue that, although conventional training protocols may be ineffective, positive effects might be obtained when future research takes into account factors known to promote more general learning. PMID- 23089362 TI - Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects. AB - In acute ischaemic brain injury and chronic neurodegeneration, the primary step leading to excitotoxicity and cell death is the excessive and/or prolonged activation of glutamate (Glu) receptors, followed by intracellular calcium (Ca(2+)) overload. These steps lead to several effects: a persistent depolarisation of neurons, mitochondrial dysfunction resulting in energy failure, an increased production of reactive oxygen species (ROS), an increase in the concentration of cytosolic Ca(2+) [Ca(2+)]i, increased mitochondrial Ca(2+) uptake, and the activation of self-destructing enzymatic mechanisms. Antagonists for NMDA receptors (NMDARs) are expected to display neuroprotective effects, but no evidence to support this hypothesis has yet been reported. A number of clinical trials using NMDAR antagonists have failed to demonstrate neuroprotective effects, either by reducing brain injury or by preventing neurodegeneration. Recent advances in NMDAR research have provided an explanation for this phenomenon. Synaptic and extrasynaptic NMDARs are composed of different subunits (GluN2A and GluN2B) that demonstrate opposing effects. Synaptic GluN2A containing and extrasynaptic GluN2B-containing NMDARs have different co-agonists: d-serine for synaptic NMDARs and glycine for extrasynaptic NMDARs. Both co agonists are of glial origin. The mechanisms of cell destruction or cell survival in response to the activation of NMDAR receptors depend in part on [Ca(2+)]i and the route of entry of this ion and more significantly on the subunit composition and localisation of the NMDARs. While synaptic NMDAR activation is involved in neuroprotection, the stimulation of extrasynaptic NMDARs, which are composed of GluN2B subunits, triggers cell destruction pathways and may play a key role in the neurodegeneration associated with Glu-induced excitotoxicity. In addition, it has been found that synaptic and extrasynaptic NMDA receptors have opposing effects in determining the fate of neurons. This result has led to the targeting of nonsynaptic GluN2B-containing NMDARs as promising candidates for drug research. Under hypoxic conditions, it is likely that the failure of synaptic glutamatergic transmission, the impairment of the GluN2A-activated neuroprotective cascade, and the persistent over-activation of extrasynaptic GluN2B-containing NMDARs lead to excitotoxicity. Fluoxetine, a drug widely used in clinical practice as an antidepressant, has been found to selectively block GluNR2B-containing NMDARs. Therefore, it seems to be a potential candidate for neuroprotection. PMID- 23089363 TI - The role of RNA structure in posttranscriptional regulation of gene expression. AB - As more information is gathered on the mechanisms of transcription and translation, it is becoming apparent that these processes are highly regulated. The formation of mRNA secondary and tertiary structures is one such regulatory process that until recently it has not been analysed in depth. Formation of these mRNA structures has the potential to enhance and inhibit alternative splicing of transcripts, and regulate rates and amount of translation. As this regulatory mechanism potentially impacts at both the transcriptional and translational level, while also potentially utilising the vast array of non-coding RNAs, it warrants further investigation. Currently, a variety of high-throughput sequencing techniques including parallel analysis of RNA structure (PARS), fragmentation sequencing (FragSeq) and selective 2-hydroxyl acylation analysed by primer extension (SHAPE) lead the way in the genome-wide identification and analysis of mRNA structure formation. These new sequencing techniques highlight the diversity and complexity of the transcriptome, and demonstrate another regulatory mechanism that could become a target for new therapeutic approaches. PMID- 23089364 TI - Effect of genome-wide genotyping and reference panels on rare variants imputation. AB - Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genome-wide genotypic arrays offers a cost-efficient strategy to achieve necessary sample sizes required for adequate statistical power. To estimate the performance of imputation of rare variants, we imputed 153 individuals, each of whom was genotyped on 3 different genotype arrays including 317k, 610k and 1 million single nucleotide polymorphisms (SNPs), to two different reference panels: HapMap2 and 1000 Genomes pilot March 2010 release (1KGpilot) by using IMPUTE version 2. We found that more than 94% and 84% of all SNPs yield acceptable accuracy (info > 0.4) in HapMap2 and 1KGpilot-based imputation, respectively. For rare variants (minor allele frequency (MAF) <=5%), the proportion of well-imputed SNPs increased as the MAF increased from 0.3% to 5% across all 3 genome-wide association study (GWAS) datasets. The proportion of well-imputed SNPs was 69%, 60% and 49% for SNPs with a MAF from 0.3% to 5% for 1M, 610k and 317k, respectively. None of the very rare variants (MAF <= 0.3%) were well imputed. We conclude that the imputation accuracy of rare variants increases with higher density of genome-wide genotyping arrays when the size of the reference panel is small. Variants with lower MAF are more difficult to impute. These findings have important implications in the design and replication of large-scale sequencing studies. PMID- 23089365 TI - Molecular evolution of the TAC1 gene from rice (Oryza sativa L.). AB - Tiller angle is a key feature of the architecture of cultivated rice (Oryza sativa), since it determines planting density and influences rice yield. Our previous work identified Tiller Angle Control 1 (TAC1) as a major quantitative trait locus that controls rice tiller angle. To further clarify the evolutionary characterization of the TAC1 gene, we compared a TAC1-containing 3164-bp genomic region among 113 cultivated varieties and 48 accessions of wild rice, including 43 accessions of O. rufipogon and five accessions of O. nivara. Only one single nucleotide polymorphism (SNP), a synonymous substitution, was detected in TAC1 coding regions of the cultivated rice varieties, whereas one synonymous and one nonsynonymous SNP were detected among the TAC1 coding regions of wild rice accessions. These data indicate that little natural mutation and modification in the TAC1 coding region occurred within the cultivated rice and its progenitor during evolution. Nucleotide diversities in the TAC1 gene regions of O. sativa and O. rufipogon of 0.00116 and 0.00112, respectively, further indicate that TAC1 has been highly conserved during the course of rice domestication. A functional nucleotide polymorphism (FNP) of TAC1 was only found in the japonica rice group. A neutrality test revealed strong selection, especially in the 3'-flanking region of the TAC1 coding region containing the FNP in the japonica rice group. However, no selection occurred in the indica and wild-rice groups. A phylogenetic tree derived from TAC1 sequence analysis suggests that the indica and japonica subspecies arose independently during the domestication of wild rice. PMID- 23089366 TI - Establishment of a genetic transformation system and its application in Thermoanaerobacter tengcongensis. AB - The whole-genome sequence of Thermoanaerobacter tengcongensis, an anaerobic thermophilic bacterium isolated from the Tengchong hot spring in China, was completed in 2002. However, in vivo studies on the genes of this strain have been hindered in the absence of genetic manipulation system. In order to establish such a system, the plasmid pBOL01 containing the replication origin of the T. tengcongensis chromosome and a kanamycin resistance cassette, in which kanamycin resistance gene expression was controlled by the tte1482 promoter from T. tengcongensis, was constructed and introduced into T. tengcongensis via electroporation. Subsequently, the high transformation efficiency occurred when using freshly cultured T. tengcongensis cells without electroporation treatment, suggesting that T. tengcongensis is naturally competent under appropriate growth stage. A genetic transformation system for this strain was then established based on these important components, and this system was proved to be available for studying physiological characters of T. tengcongensis in vivo by means of hisG gene disruption and complementation. PMID- 23089367 TI - Atypical deletion in Williams-Beuren syndrome critical region detected by MLPA in a patient with supravalvular aortic stenosis and learning difficulty. PMID- 23089368 TI - Reduced systemic arterial compliance measured by routine Doppler echocardiography: a new and independent predictor of mortality in patients with type 2 diabetes mellitus. AB - OBJECTIVES: This study was designed to examine the prognostic value of systemic arterial compliance (SAC) by Doppler-echocardiography in patients with type 2 diabetes mellitus (T2D). BACKGROUND: Reduced SAC has been shown to predict outcomes in patients with hypertension. T2D is associated with accelerated arterial stiffening and increased cardiovascular events. We hypothesized that SAC measured by Doppler-echocardiography would independently predict mortality in patients with T2D. METHODS: Since 2001, SAC calculated as the ratio of stroke volume index to arterial pulse pressure by sphygmomanometer is routinely performed in our laboratory. Data from 505 consecutive patients with T2D were retrospectively analyzed. Based on a previously validated cut-off value of SAC < 0.6 ml/m(2)/mmHg, patients were divided into Group 1, reduced SAC, 255 patients (50%) and Group 2, preserved SAC, 250 patients (50%). The primary endpoint was overall mortality. RESULTS: Patients with reduced SAC had significantly lower 5 year survival than those with preserved SAC (66 +/- 5 vs. 82 +/- 5%, p = 0.02) and a 1.57-fold (95% CI: 1.04-2.43; p = 0.03) increased risk of mortality after adjusting for other risk factors. Blood pressure did not predict mortality and pseudo-normalized blood pressures related to LV dysfunction and low cardiac output were found in 75 patients (15%). CONCLUSION: Reduced SAC is encountered frequently in T2D, is an independent predictor of mortality and allows identification of patients who, despite a normal blood pressure, are at increased risk. Future studies are necessary to further evaluate the clinical utility of this simple echocardiographic parameter and therapies are needed to alter vascular stiffness to improve clinical outcomes in these high-risk patients. PMID- 23089370 TI - Hyperuricemia and metabolic syndrome in children with overweight and obesity. AB - OBJECTIVE: To study the prevalence of hyperuricemia in children with overweight or obesity and analyze the relation with metabolic syndrome and the diseases that define it. MATERIALS AND METHODS: This is a cross-sectional prevalence study in 148 children recruited from pediatric endocrinology consultation, with overweight or obesity (12+/-3 years, 48% boys, BMI 31.8+/-6.1). We measured BMI, waist height, waist circumference, blood pressure with standard instrumentation and glucose (fasting and after overload with 75 g), insulin resistance, cholesterol HDL, triglycerides and uric acid. RESULTS: The prevalence of hyperuricemia was 53%. Patients with hyperuricemia had greater BMI (33.9 vs 30.6, p=0.003), plus waist circumference (101.4 vs 91.1cm, p<0.001), higher blood pressure: systolic (123.4 vs 111.9 mm Hg, p<0.001), diastolic (78.2 vs 68.7 mm Hg, p<0.001). They presented greater blood glucose after overload oral glucose (107.5 vs 100.7 mg/dl, p=0.03), insulin was higher (29.2 vs 20.7 mg/dl, p=0.001) as well as HOMA IR (6.5 vs 4.4, p<0.001) and HDL levels were lower (49.5 vs 54.4 mg/dl, p=0.02). Uric acid's level which most is the likely diagnosis of metabolic syndrome corresponds to 5.4 mg/dl in our sample (sensitivity: 64% and specificity 62%). CONCLUSION: The prevalence of hyperuricemia in children with overweight and obesity is high. In the group of patients with obesity and hyperuricemia, we found out that the parameters measured to diagnose with metabolic syndrome were less favorable. Uric acid's level from where there is a higher possibility to see metabolic syndrome is 5.4 mg/dl. PMID- 23089371 TI - Distinct PKA and Epac compartmentalization in airway function and plasticity. AB - Asthma and chronic obstructive pulmonary disease (COPD) are obstructive lung diseases characterized by airway obstruction, airway inflammation and airway remodelling. Next to inflammatory cells and airway epithelial cells, airway mesenchymal cells, including airway smooth muscle cells and (myo)fibroblasts, substantially contribute to disease features by the release of inflammatory mediators, smooth muscle contraction, extracellular matrix deposition and structural changes in the airways. Current pharmacological treatment of both diseases intends to target the dynamic features of the endogenous intracellular suppressor cyclic AMP (cAMP). This review will summarize our current knowledge on cAMP and will emphasize on key discoveries and paradigm shifts reflecting the complex spatio-temporal nature of compartmentalized cAMP signalling networks in health and disease. As airway fibroblasts and airway smooth muscle cells are recognized as central players in the development and progression of asthma and COPD, we will focus on the role of cAMP signalling in their function in relation to airway function and plasticity. We will recapture on the recent identification of cAMP-sensing multi-protein complexes maintained by cAMP effectors, including A kinase anchoring proteins (AKAPs), proteins kinase A (PKA), exchange protein directly activated by cAMP (Epac), cAMP-elevating seven-transmembrane (7TM) receptors and phosphodiesterases (PDEs) and we will report on findings indicating that the pertubation of compartmentalized cAMP signalling correlates with the pathopysiology of obstructive lung diseases. Future challenges include studies on cAMP dynamics and compartmentalization in the lung and the development of novel drugs targeting these systems for therapeutic interventions in chronic obstructive inflammatory diseases. PMID- 23089369 TI - Association of subclinical atherosclerosis with lipid levels amongst antiretroviral-treated and untreated HIV-infected women in the Women's Interagency HIV study. AB - OBJECTIVE: We examined serum lipids in association with carotid artery intima media thickness (CIMT) in HIV-infected and HIV-uninfected women. METHODS: In 2003 4, among 1827 Women's Interagency HIV Study participants, we measured CIMT and lipids (high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), non-HDL-c). A subset of 520 treated HIV-infected women had pre-1997 lipid measures. We used multivariable linear regression to examine associations between lipids and CIMT. RESULTS: In HIV uninfected women, higher TC, LDL-c and non-HDL-c were associated with increased CIMT. Among HIV-infected women, associations of lipids with CIMT were observed in treated but not untreated women. Among the HIV-infected women treated in 2003-4, CIMT was associated both with lipids measured a decade earlier in infection, and with late lipid measurements. CONCLUSION: Among HIV-infected women, hyperlipidemia is most strongly associated with subclinical atherosclerosis in treated women. Among treated women, the association appeared strongest early in the disease course. PMID- 23089372 TI - Hybrid niche-neutral models outperform an otherwise equivalent neutral model for fitting coral reef data. AB - Niche theory and neutral theory are two major developments aiming at explaining patterns of biodiversity observed in nature. Both theories have been found relevant either separately or simultaneously in some real communities, and it has been theoretically demonstrated that they can produce similar species abundance distributions. However, it remains controversial whether the two theories can produce similar patterns via different mechanisms, or can interact to jointly produce the observed diversity patterns, or whether the patterns generated by the neutral model are robust to niche structure. Here we show that, although the neutral model proposed for spatially discrete communities remains robust to strong niche structure for high-diversity communities, the inclusion of more realistic niche differentiation modes greatly improves the goodness of fit to Indo-Pacific coral reefs. Actually, the multiple discrete communities' neutral model, due to its underestimation of the number or abundance of common species, fails to capture the combination of many rare species and a few highly abundant species that characterize the Indo-Pacific coral reef communities. By incorporating niche structure into the multiple discrete communities' model, the hybrid niche-neutral models can successfully reproduce both the species-based and individual-based abundance distribution patterns observed in the coral reefs. We proposed that both niche theory and neutral theory may be involved in explaining the structure of such communities. Our results also suggest a negative relationship between per capita birth to death ratio and immigration among different guilds of coral species, which clearly deserves further investigation. PMID- 23089373 TI - The metabolic fate of ivermectin in host (Ovis aries) and parasite (Haemonchus contortus). AB - Ivermectin (IVE), one of the most important anthelmintics, is often used in the treatment of haemonchosis in ruminants. The objective of our work was (1) to find and identify phase I and II metabolites of IVE formed by the Barber's pole worm (Haemonchus contortus), and (2) to compare IVE metabolites in helminths with IVE biotransformation in sheep (Ovis aries) as host species. Ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS) was used for this purpose. During in vitro incubations, microsomes (from adult worms or from ovine liver) and a primary culture of ovine hepatocytes were incubated with IVE. In the ex vivo study, living H. contortus adults were incubated in the presence of 1 MUM IVE for 24 h. The results showed that the H. contortus enzymatic system is not able to metabolize IVE. On the other hand, 7 different phase I as well as 9 phase II IVE metabolites were detected in ovine samples using UHPLC/MS/MS analyses. Most of these metabolites have not been described before. Haemonchus contortus is not able to deactivate IVE through biotransformation; therefore, biotransformation does not contribute to the development of IVE-resistance in the Barber's pole worm. PMID- 23089374 TI - The rapid recovery of 5-HT cell firing induced by the antidepressant vortioxetine involves 5-HT(3) receptor antagonism. AB - The therapeutic effect of current antidepressant drugs appears after several weeks of treatment and a significant number of patients do not respond to treatment. Here, we report the effects of the multi-modal antidepressant vortioxetine (Lu AA21004), a 5-HT(3) and 5-HT(7) receptor antagonist, 5-HT(1B) receptor partial agonist, 5-HT(1A) receptor agonist and 5-HT transporter (SERT) inhibitor, on rat 5-HT neurotransmission. Using in vivo electrophysiological recordings in the dorsal raphe nucleus of anaesthetized rats, we assessed the acute and subchronic effects of vortioxetine and/or the selective 5-HT(3) receptor agonist, SR57227 or the selective 5-HT(1A) receptor agonist flesinoxan, on 5-HT neuronal firing activity. Using ex-vivo autoradiography, we correlated SERT occupancy and presumed 5-HT firing activity. The selective serotonin reuptake inhibitor, fluoxetine, was used as comparator. Importantly, the recovery of 5-HT neuronal firing was achieved after 1 d with vortioxetine and 14 d with fluoxetine. SR57227 delayed this recovery. In contrast, vortioxetine failed to alter the reducing action of 3 d treatment of flesinoxan. Acute dosing of vortioxetine inhibited neuronal firing activity more potently than fluoxetine. SR57227 prevented the suppressant effect of vortioxetine, but not of fluoxetine. In contrast, flesinoxan failed to modify the suppressant effect of vortioxetine acutely administered. Differently to fluoxetine, vortioxetine suppressed neuronal firing without saturating occupancy at the SERT. Vortioxetine produced a markedly faster recovery of 5-HT neuronal firing than fluoxetine. This is at least partly due to 5-HT(3) receptor antagonism of vortioxetine in association with its reduced SERT occupancy. PMID- 23089375 TI - [Dexmedetomidine and clonidine: a review of their pharmacodynamy to define their role for sedation in intensive care patients]. AB - Alpha-2 adrenergic agonists ("alpha-2 agonists") present multiple pharmacodynamic effects: rousable sedation, decreased incidence of delirium in the setting of critical care, preservation of respiratory drive, decreased whole body oxygen consumption, decreased systemic and pulmonary arterial impedance, improved left ventricular systolic and diastolic function, preserved vascular reactivity to exogenous catecholamines, preserved vasomotor baroreflex with lowered set point, preserved kidney function, decreased protein catabolism. These pharmacodynamic effects explain the interest for these drugs in the critical care setting. However, their exact role for sedation in critically ill-patients remains open for further studies. Given the few double-blind randomized multicentric trials available, the present non exhaustive analysis of the literature aims at presenting the utilization of alpha-2 agonists as potential first-line sedative agents, in the critical care setting. Suggestions regarding the use of alpha-2 agonists as sedatives are detailed. PMID- 23089376 TI - [Themes of current Endocrinology Congresses]. PMID- 23089377 TI - [Hypophysitis: increasingly complex clinicopathological spectrum!]. AB - Hypophysitis is a chronic inflammation of the pituitary gland that comprises an increasingly complex clinicopathological spectrum. Lymphocytic and granulomatous hypophysitis are the most common forms, but new variants have recently been reported such as IgG4-related hypophysitis that is identified by well-defined criteria. For the first time, hypophysitis in ANCA-associated vasculitides has been reported. Monoclonal antibodies directed against the cytotoxic T-lymphocyte antigen-4 (CTLA-4), investigated in metastatic melanoma, can induce hypophysitis. Hypophysitis's pathogenesis remains obscure but several candidate pituitary autoantigens have been described in the last decade, although none has proven useful as a diagnostic tool. PMID- 23089378 TI - [Brown, white, beige: the color of fat and new therapeutic perspectives for obesity...]. AB - Three articles published in the NEJM in 2009 have renewed the interest for brown adipose tissue (BAT) in humans. This review reports interesting new findings on adipocyte cell types that have been presented at the last meeting of the Endocrine Society in Houston, TX, in June 2012. Many studies have focused on identifying factors involved in brown adipocyte lineage, the site of adaptive thermogenesis. Indeed, the role of the transcription factors, such as PRDM16, in brown adipocyte differentiation has been unambiguously established. Very recently, the concept of "beigeing", defined as the occurrence of thermogenic brown adipocytes in white adipose tissue, has emerged, leading to the identification, by Bruce Spiegelman's group, of a new muscular hormone, called irisin, which is able to stimulate the "beigeing". This finding should convey toward the discovery of new mutations involved in the pathogenesis of obesity and lipodystrophies, and should be translated into innovative therapeutic perspectives. Finally, the nature of BAT innervation has been clarified and the presence of an autoregulatory loop between BAT and notably hypothalamic paraventricular nuclei via the sensory and sympathetic nervous systems has been delineated. These feedback circuits appear to be crucial to control BAT thermogenic activity. PMID- 23089379 TI - [Update on endocrine hypertension]. AB - Endocrine hypertension is the most common cause of secondary hypertension affecting ~3 % of the population, with primary hyperaldosteronism and pheochromocytoma being the principal conditions. Both diseases share an increased cardiovascular risk in comparison with essential hypertension patients (at the same blood pressure level). This augmented cardiovascular risk as well as the availability of specific treatment emphasize the importance of timely and correct diagnosis. Primary hyperaldosteronism, representing one tenth of hypertensive patients, is an under-diagnosed disease partly because of difficult diagnostic steps and absence of standard criteria. Recently, the description of somatic mutations in KCNJ5 gene in Conn adenomas had precipitated a resurgence of research activity to understand the pathophysiology of this common disease. Research had confirmed the role of these mutations in aldosterone hypersecretion; however, its role in adenoma formation is still to be elucidated. Elsewhere, much remains to be done in order to understand the pathogenesis of bilateral idiopathic hyperaldosteronism, the other common subtype of primary hyperaldosteronism. In pheochromocytoma, the revolution of genetics has led to major advances in the characterization of this rare disease. It is now clear that up to 50 % of patients with pheochromocytoma have a genetic abnormality and that different pheochromocytomas segregate into two clusters with distinct genotypes, signal transduction pathways and expression of biomarkers (phenotype). This continuing progress has huge effects on patient's management and follow-up. In this article we will shed light on the recent developments in both diseases with emphasis on their role in patient care. PMID- 23089380 TI - [Endocrine disruptors: echoes of congress of Endocrinology in 2012]. AB - The increased prevalence of certain diseases, along with the development of new technologies and industrialization raised the possibility of the involvement of environmental factors, industrial products, nutritional factors, infections, drugs... and endocrine disruptors. These factors may interfere via signaling pathways specific to the organism. Endocrine Disrupting Chemicals (EDCs) have been redefined by the Endocrine Society in 2012 as "exogenous chemical, or mixture of chemicals, that can interfere with any aspect of hormone action". They have therefore potentially deleterious effects on development, growth, metabolism, reproduction, the nervous, immune and cardiovascular systems. Therefore, they constitute a real public health issue. Their long half-life may explain delayed effects and their often lipophilic character may promote maternofetal transmission. Except diethylstilbestrol (DES), few formal proofs have been made on the direct role of EDCs ; arguments are based on cross sectional studies, in vitro models and animal models. Basic research puts insight into mechanisms of action of EDCs but many questions remain unanswered. Epidemiological data are difficult to interpret because of interindividual differences in susceptibility to EDCs and of nonlinear/nonmonotonique action (as opposed to toxic dose effect), multiple interactions between environmental agents (additive effects and/or synergistic and/or antagonists), the role of the window of exposure, latency, and the possibility of transgenerational effects. PMID- 23089381 TI - [Subclinical adrenal diseases: silent pheochromocytoma and subclinical Addison's disease]. AB - The silent pheochromocytoma, a hidden form of pheochromocytoma, exposes the patient to an increased risk of mortality if the diagnosis is not established on time. Biological diagnosis of pheochromocytoma can be difficult. Catecholamine secretion is dependent on tumor size and a large number of physiological, pharmacological, lifestyle modifications and sampling conditions influence the measurement of urinary and plasma metanephrines. The prevalence of pheochromocytoma is 2% among adrenal incidentaloma smaller than 3 cm (2/3 of tumors). Recent studies suggest the almost zero risk of pheochromocytoma among these tumors if they are hypodense (<10 housefield units) on adrenal tomography. Addison's disease is a pathology affecting about 1 in 8000. Immunopathology is still unknown, but some elements advocated the hypothesis of a predominant cell mediated immunity in particular Interferon-gamma production by CD4 T lymphocytes in the presence of an epitope from the 21-hydroxylase, as well as IgG1 subtype produced by activated B lymphocytes, autoantibodies do appear to be a simple marker of the disease. Subclinical Addison's disease is defined by the presence of anti-21-hydroxylase autoantibodies, without clinical symptoms. It evolves faster to the clinical phase in young subjects, male, having high levels of autoantibodies and with an initially impaired adrenal function. Dosage of ACTH, plasma renin active, and basal cortisol and after Synacthen allow to discriminate the subjects with low or high risk of evolution and establish an appropriate monitoring. PMID- 23089382 TI - [New pathophysiological mechanisms of metabolic syndrome: implication of orphan nuclear receptors?]. AB - This review focuses on a number of new data on biology and pathophysiology of the metabolic syndrome (MetS) and the involvement of nuclear receptors that have been presented during the last Endocrine Society meeting, held in Houston in June 2012. Several studies have reported beneficial effects of various orphan nuclear receptors, including SHP (Small Heterodimeric Partner, NR0B2) and LXR (Liver X Receptor, NR1H3 and NR1H2), on various components of MetS. By using an inactivation model of SHP, David Moore has shown that SHP exerts "antidiabetic" effects but associated with hepatic steatosis development. He also showed that DLPC (dilauroyl phosphatidylcholine), an unconventional phospholipid, exhibited anti-diabetic properties through its binding to LRH-1 (Liver Receptor Homolog-1, NR5A2), a molecular partner of SHP. Interestingly, Carolyn Cummins investigated LXR alpha and beta isoforms knock-out mice and provided experimental evidence for the detailed mechanisms involved in the deleterious metabolic effects of glucocorticoids, pointing out to the functional interaction between LXRbeta, and the glucocorticoid receptor. These new and original studies open new therapeutic opportunities for the management of metabolic disorders in humans by selective modulators of these receptors. PMID- 23089384 TI - Abstract concepts: data from a Grey parrot. AB - Do humans and nonhumans share the ability to form abstract concepts? Until the 1960s, many researchers questioned whether avian subjects could form categorical constructs, much less more abstract formulations, including concepts such as same different or exact understanding of number. Although ethologists argued that nonhumans, including birds, had to have some understanding of divisions such as prey versus predator, mate versus nonmate, food versus nonfood, or basic relational concepts such as more versus less, simply in order to survive, no claims were made that these abilities reflected cognitive processes, and little formal data from psychology laboratories could initially support such claims. Researchers like Anthony Wright, however, succeeded in obtaining such data and inspired many others to pursue these topics, with the eventual result that several avian species are now considered "feathered primates" in terms of cognitive processes. Here I review research on numerical concepts in the Gray parrot (Psittacus erithacus), demonstrating that at least one subject, Alex, understood number symbols as abstract representations of real-world collections, in ways comparing favorably to those of apes and young human children. He not only understood such concepts, but also appeared to learn them in ways more similar to humans than to apes. PMID- 23089383 TI - Conditioned place preference and aversion for music in a virtual reality environment. AB - The use of a virtual reality environment (VRE) enables behavioral scientists to create different spatial contexts in which human participants behave freely, while still confined to the laboratory. In this article, VRE was used to study conditioned place preference (CPP) and aversion (CPA). In Experiment 1, half of the participants were asked to visit a house for 2 min with consonant music and then they were asked to visit an alternate house with static noise for 2 min, whereas the remaining participants did the visits in reverse order. In Experiment 2, we used the same design as Experiment 1, except for replacing consonant music with dissonant music. After conditioning in both experiments, the participants were given a choice between spending time in the two houses. In Experiment 1, participants spent more time in the house associated with the consonant music, thus showing a CPP toward that house. In Experiment 2, participants spent less time in the house associated with the dissonant music, thus showing a CPA for that house. These results support VRE as a tool to extend research on CPP/CPA in humans. PMID- 23089385 TI - Beacons and surface features differentially influence human reliance on global and local geometric cues when reorienting in a virtual environment. AB - In the reorientation literature, non-geometric cues include discrete objects (e.g., beacons) and surface-based features (e.g., colors, textures, and odors). To date, these types of non-geometric cues have been considered functionally similar, and it remains unknown whether beacons and surface features differentially influence the extent to which organisms reorient via global and local geometric cues. In the present experiment, we trained human participants to approach a location in a trapezoid-shaped enclosure uniquely specified by global and local geometric cues. We explored the role of beacons on the use of geometric cues by training participants in the presence or absence of uniquely-colored beacons. We explored the role of surface features on the use of geometric cues by recoloring two adjacent walls at the correct location and/or adding a line on the floor which corresponded to the major principal axis of the enclosure. All groups were then tested in novel-shaped enclosures in the absence of unique beacons and surface features to assess the relative use of global and local geometric cues. Results suggested that beacons facilitated the use of global geometric cues, whereas surface features either facilitated or hindered the use of geometric cues, depending on the feature. PMID- 23089386 TI - The effect of zinc on aquatic microbial ecosystems and the degradation of dissolved organic matter. AB - We developed a simple aquatic microbial ecosystem model in order to examine potential effects of zinc on microorganisms and the related degradation of dissolved organic matter (DOM). The model is a combination of both a traditional food chain and a microbial loop. The traditional food chain is mainly composed of phytoplankton and zooplankton, whilst the microbial loop is composed of DOM, bacteria and bacterivorous protozoa. We incorporated the suppressive effect of zinc on the bacterial uptake of DOM and assessed the steady state responses of the model for various zinc concentrations. The analytical and numerical results of the model implied that either zooplankton or bacterivorous protozoa might be the most vulnerable group to excessive zinc load than bacteria, depending on the grazing preference of zooplankton between phytoplankton and bacterivorous protozoa. The sensitivity analyses supported that the microbial loop solely is more sensitive to zinc than the coupled system combining both the traditional food chain and the microbial loop. PMID- 23089387 TI - Adsorption-desorption behavior of 2,4-D on NCP-modified bentonite and zeolite: implications for slow-release herbicide formulations. AB - Clay minerals have obtained considerable attention for slow-release formulation of herbicides to increase weed control efficacy and reduce leaching potential and environmental pollution. This study deals with preparing, characterizing and examining the potentials of modified bentonite and zeoilite in adsorption and release of 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide. 2,4-D sorption of the N-cetylpyridinium (NCP)-modified bentonites and zeolites were much higher than those of unmodified substrates. The 2,4-D adsorption capacity of the organo minerals increased with increasing surfactant loading. Desorption isotherms of 2,4-D did not coincide their corresponding sorption isotherms showing hysteresis. The proportion of 2,4-D released from the organo-minerals after seven desorption cycles varied between 29% and 50% of the total retained herbicide. The sorbed 2,4 D on the adsorbents showed gradual release pattern with time. The release pattern of 2,4-D from NCP-modified bentonite and zeolite, make these synthetic organo minerals suitable candidate for slow release formulation of 2,4-D. PMID- 23089388 TI - Origin of heat-induced structural changes in dissolved organic matter. AB - Humic substances play an important role in many environmental processes such as sequestration and transport of hydrophobic compounds. The supramolecular character of humic substances imparts high flexibility of the aggregates associated with their variable reactivity under different conditions. In this study, heat-induced transitions and character of the hydration shell of sodium salts of humic and fulvic acids originating from various sources were investigated using ultrasonic velocimetry in the temperature interval from 5 to 90 degrees C. Results clearly showed differences in stability and characteristics of the hydrated states at concentrations above and below 1 g L( 1) with the exception of Pahokee peat fulvic acids. It has been concluded that predominantly the relaxation part of the adiabatic compressibility plays an important role below 1 g L(-1) in contrast to both relaxation and intrinsic parts of the compressibility being important at higher concentrations. Dilution brought several temperature induced transitions which were investigated with respect to composition of all investigated humic substances. Correlation analysis revealed that the transition around 17 degrees C is associated with disruption of H interactions whereas the transition around 42 degrees C depends on the aromaticity. Comparison of cooling and heating records revealed hysteresis in the structural relaxation resembling the behavior of physically stabilized hydrogels. Results indicated a difference in the conformation and therefore reactivity of dissolved humic substances in the dependence on temperature and thermal history. It has been hypothesized that this may play an important role in the transport and sequestration of hydrophobic pollutants by dissolved organic matter. PMID- 23089389 TI - The sorption of organic contaminants on biochars derived from sediments with high organic carbon content. AB - Biochars were produced using a Dianchi Lake sediment at different temperatures and their sorption characteristics with five organic contaminants (with solubilities varied three orders of magnitude) were compared. Freundlich model showed satisfying fitting results of the sorption isotherms. Distinct decrease of nonlinear factors was observed for all five contaminants with pyrolysis suggesting wider energy distribution of the sorption sites after pyrolysis. No clear trend was observed between K(d) and the chemical properties of the five chemicals. Phenanthrene and sulfamethoxazole (SMX) showed increased sorption with increased pyrolysis temperature, while the sorption of bisphenol A (BPA), ofloxacin (OFL) and norfloxacin (NOR) in the original sediment was comparable to those in the thermally treated samples. Electrostatic repulsion played an important role in SMX sorption as suggested by its lowest hydrophobicity normalized sorption coefficients among the five chemicals. Possible sorption mechanisms were discussed and the sorption of SMX and PHE on the produced biochars were compared with natural adsorbents (including soils, sediments, and inorganic mineral particles). PMID- 23089390 TI - Polyfluorinated telomers in indoor air of Japanese houses. AB - The fluorotelomer alcohols (FTOHs) have been detected in various environmental compartments, including indoor and outdoor air, in North America and Europe. In our previous studies, FTOHs were detected at a relative higher concentration in outdoor air in the Keihan (Kyoto-Osaka, one of the major industrial zones) area, Japan compared to reported data. The exposure level of FTOHs in indoor air in the Keihan area remains unclear. In the present study, indoor air FTOH concentrations were investigated using a passive air sampler containing activated carbon felts. The indoor air sampling was conducted in 49 households of the Keihan area, during winter and summer 2008. Most samples contained 6:2 FTOH, 8:2 FTOH, 10:2 FTOH and 8:2 FTOAc. The median concentration of 8:2 FTOH (5.84 ng m(-3)) was highest among fluorotelomers, followed by those of 10:2 FTOH (1.12 ng m(-3)), 6:2 FTOH (0.29 ng m(-3)), and others. Significant correlations among fluorotelomers were observed in collected samples. The association between housing conditions and 8:2 FTOH concentrations showed that samples collected from bed rooms have higher 8:2 FTOH concentrations than those collected from other locations. In addition, samples collected in winter showed lower levels of 8:2 FTOH than those collected in summer. These findings suggest that 8:2 FTOH is the predominant component among fluorotelomers in indoor air, and that there are emission sources of fluorotelomers in indoor environments of the Keihan area. Further investigations into the origins of fluorotelomers are needed to evaluate indoor contamination with fluorotelomers. PMID- 23089391 TI - Pyrene photochemical species in commercial clays. AB - The photochemistry of pyrene, a polycyclic aromatic hydrocarbon, adsorbed on kaolinite, sodium montmorillonite and acid bentonite K10(r) was investigated to determine how the concentration and structure of the clay minerals affect the formation of different species of pyrene. Fluorescence emission spectra were obtained using reflection geometry for pyrene at the concentrations ranging from 0.5 to 100.0 MUmol g(-1) (pyrene:clay). Two pyrene photochemical species were observed, the monomer, which fluoresces at 396 nm, and its excimer which fluoresces at 470 nm. The formation of excimers occurred first on the kaolinite, due to the smaller surface area. In the acid montmorillonite, the fixed interlamellar space provided greater specific area, leading to lower formation of excimers. Emission from pyrene crystals was also detected for samples with high loadings. PMID- 23089392 TI - Screening analysis of hundreds of sediment pollutants and evaluation of their effects on benthic organisms in Dokai Bay, Japan. AB - Dokai Bay in Kitakyushu, Japan, is polluted with complex mixtures of micro pollutants originating from the extensive industry and urbanization. In order to evaluate effects of these micro-pollutants on benthic organisms in this almost completely enclosed bay, we screened for the occurrence of approximately 900 organic chemicals and heavy metals, and in addition quantified the density and biomass of benthic animals. For the chemical analysis, we used a newly developed comprehensive analytical method using an automated identification and quantification system with a GC-MS database. We detected 184 organic chemicals in the sediments. Since their concentrations, as well as those of metals, increased with proximity to the innermost part of the bay, their source seem to be factories and a sewage treatment plant located in this area. Confirming this, the identified pollutants in this area are characteristic of industrial chemicals and residues, as well as household chemicals, fecal matter and sewage effluent. Several polycyclic aromatic hydrocarbons (PAHs) and metals had concentrations higher than the effects range-median of the sediment quality guidelines of National Oceanic and Atmospheric Administration. The species richness and abundance of benthic animals were lowest in areas where concentrations of metals, PAHs and other organic pollutants were high, suggesting that these contaminants are having an adverse effect on benthic animals in the bay. PMID- 23089393 TI - Treatment of high-ammonium anaerobic digester supernatant by aerobic granular sludge and ultrafiltration processes. AB - Anaerobic sludge digester supernatant characterized by 569 mg TKN L(-1), high color and a COD/N ratio of 1.4 was treated in granular sequencing batch reactors (GSBRs) followed by post-denitrification (P-D) and ultrafiltration (UF) steps. The use of granular sludge allowed for the oxidation of ammonium in anaerobic digester supernatant at all investigated GSBR cycle lengths of 6, 8 and 12 h. The highest ammonium removal rate (15 mg N g(-1) VSS h(-1)) with removal efficiency of 99% was noted at 8 h. Since the GSBR effluent was characterized by a high concentration of nitrites, slowly-degradable substances and biomass, additional purification steps were applied. In P-D stage, the microbial activity of granular biomass in the GSBR effluent was implemented. The P-D was supported by external carbon source addition and the most advantageous variant comprised dosing of half of the theoretical acetate dose for nitrite reduction in the 3-h intervals. The use of the system consisting of the GSBR with 8 h, an optimal P-D variant and a UF for the treatment of anaerobic digester supernatant allowed for the 99%, 71% and 97% reductions of TKN, COD and color, respectively. PMID- 23089395 TI - Lipopolysaccharide and sphingosine-1-phosphate cooperate to induce inflammatory molecules and leukocyte adhesion in endothelial cells. AB - Given that TLRs and sphingosine-1-phosphate (S1P) are key players in inflammation, we explored the potential interplay between TLRs and S1P in the adhesion/inflammatory pathways in primary human endothelial cells. As determined by Western blot and flow cytometry, cells treated with LPS (a TLR4 ligand) and S1P showed significantly enhanced expression of adhesion molecules such as ICAM-1 and E-selectin compared with the effect of either ligand alone. Cell-type differences on E-selectin upregulation were observed. In contrast, no cooperation effect on ICAM-1 or E-selectin was observed with a TLR2/TLR1 ligand. Consistent with an increase in adhesion molecule expression, endothelial cell treatment with LPS plus S1P significantly enhanced adhesion of PBMCs under shear stress conditions compared with the effect of either ligand alone and exhibited comparable levels of cell adhesion strength as those after TNF-alpha treatment. Moreover, LPS and S1P cooperated to increase the expression of proinflammatory molecules such as IL-6, cyclooxygenase-2, and prostacyclin, as determined by ELISA and Western blot. The analysis of signaling pathways revealed the synergistic phosphorylation of ERK upon LPS plus S1P treatment of HUVEC and human aortic endothelial cells and cell-type differences on p38 and NF-kappaB activation. Moreover, pharmacological and small interfering RNA experiments disclosed the involvement of S1P(1/3) and NF-kappaB in the cooperation effect and that cell origin determines the S1P receptors and signaling routes involved. Sphingosine kinase activity induction upon LPS plus S1P treatment suggests S1P- Sphingosine kinase axis involvement. In summary, LPS and S1P cooperate to increase proinflammatory molecules in endothelial cells and, in turn, to augment leukocyte adhesion, thus exacerbating S1P-mediated proadhesive/proinflammatory properties. PMID- 23089394 TI - Local complement-targeted intervention in periodontitis: proof-of-concept using a C5a receptor (CD88) antagonist. AB - When excessively activated or deregulated, complement becomes a major link between infection and inflammatory pathology including periodontitis. This oral inflammatory disease is associated with a dysbiotic microbiota, leads to the destruction of bone and other tooth-supporting structures, and exerts an adverse impact on systemic health. We have previously shown that mice deficient either in complement C5a receptor (C5aR; CD88) or TLR2 are highly and similarly resistant to periodontitis, suggesting that a cross-talk between the two receptors may be involved in the disease process. In this paper, we show that C5aR and TLR2 indeed synergize for maximal inflammatory responses in the periodontal tissue and uncover a novel pharmacological target to abrogate periodontitis. Using two different mouse models of periodontitis, we show that local treatments with a C5aR antagonist inhibited periodontal inflammation through downregulation of TNF, IL-1beta, IL-6, and IL-17 and further protected against bone loss, regardless of the presence of TLR2. These findings not only reveal a crucial cooperation between C5aR and TLR2 in periodontal inflammation but also provide proof-of concept for local targeting of C5aR as a powerful candidate for the treatment of human periodontitis. PMID- 23089397 TI - Contribution of pulmonary KLRG1(high) and KLRG1(low) CD8 T cells to effector and memory responses during influenza virus infection. AB - In response to pathogen insult, CD8 T cells undergo expansion and a dynamic differentiation process into functionally different subpopulations. In this study, we show that during the effector response to influenza virus infection lung CD8 T cell subsets expressing killer cell lectin-like receptor G1 (KLRG1)(high) or KLRG1(low) had similar effector functions and immediate recall efficacy. The KLRG1 expression profile of lung CD8 T cells was not permanent after adoptive transfer and recall. Airway CD8 T cells exhibited a unique phenotype expressing low levels of KLRG1 together with high levels of markers of cellular activation. We investigated the functional characteristics of these cells by analyzing their capacity to survive and to respond to a secondary challenge outside of the airway environment. KLRG1(high) CD8 T cells isolated from the lung during the peak of the effector T cell response could survive for more than a month in the absence of cognate viral Ags after systemic adoptive transfer, and these "rested" CD8 T cells proliferated and participated in a recall response to influenza virus infection. These data highlight the unique phenotype and plasticity of effector CD8 T cell responses in the lung. PMID- 23089396 TI - Antibodies to a superantigenic glycoprotein 120 epitope as the basis for developing an HIV vaccine. AB - Failure to induce synthesis of neutralizing Abs to the CD4 binding determinant (CD4BD) of gp120, a central objective in HIV vaccine research, has been alternately ascribed to insufficient immunogen binding to Abs in their germline V region configuration expressed as BCRs, insufficient adaptive mutations in Ab V regions, and conformational instability of gp120. We employed peptide analogs of gp120 residues 421-433 within the CD4BD (CD4BD(core)) to identify Abs produced without prior exposure to HIV (constitutive Abs). The CD4BD(core) peptide was recognized by single-chain Fv fragments from noninfected humans with lupus that neutralized genetically diverse strains belonging to various HIV subtypes. Replacing the framework region (FR) of a V(H)4-family single-chain Fv with the corresponding V(H)3-family FRs from single-chain Fv JL427 improved the CD4BD(core) peptide-binding activity, suggesting a CD4BD(core) binding site outside the pocket formed by the CDRs. Replacement mutations in the FR site vicinity suggested the potential for adaptive improvement. A very small subset of serum CD4BD(core)-specific serum IgAs from noninfected humans without autoimmune disease isolated by epitope-specific chromatography neutralized the virus potently. A CD4BD(core)-specific, HIV neutralizing murine IgM with H and L chain V regions (V(H) and V(L) regions) free of immunogen-driven somatic mutations was induced by immunization with a CD4BD(core) peptide analog containing an electrophilic group that binds B cells covalently. The studies indicate broad and potent HIV neutralization by constitutive Abs as an innate, germline-encoded activity directed to the superantigenic CD4BD(core) epitope that is available for amplification for vaccination against HIV. PMID- 23089398 TI - GM-CSF and IL-4 stimulate antibody responses in humanized mice by promoting T, B, and dendritic cell maturation. AB - Engraftment of human hematopoietic stem cells into immunodeficient mice that lack T cells, B cells, and NK cells results in reconstitution of human blood lineage cells, especially B cells, in the recipient mice. However, these humanized mice do not make any significant level of IgG Ab in response to Ag stimulation. In this study, we show that in humanized mice, B cells are immature, and there is a complete deficiency of CD209(+) (DC-SIGN) human dendritic cells. These defects can be corrected by expression of human GM-CSF and IL-4 in humanized mice. As a result, these cytokine-treated humanized mice produced significant levels of Ag specific IgG after immunization, including the production of neutralizing Abs specific for H5N1 avian influenza virus. A significant level of Ag-specific CD4 T cell response was also induced. Thus, we have identified defects in humanized mice and devised approaches to correct these defects such that the platform can be used for studying Ab responses and to generate novel human Abs against virulent pathogens and other clinically relevant targets. PMID- 23089399 TI - Typical and atypical clinical presentation of uterine myomas. AB - Myoma is the most common benign neoplasm that can occur in the female reproductive system, most frequently seen in women in their 50s. Although the majority of myomas are asymptomatic, some patients have symptoms and/or signs of varying degrees. Typical myoma-related symptoms or signs include: (1) menstrual disturbances like menorrhagia, dysmenorrhea and intermenstrual bleeding, (2) pelvic pain unrelated to menstruation, (3) compression symptoms, similar to a sensation of bloatedness, urinary frequency and constipation, (4) subfertility status such as recurrent abortion, preterm labor, dystocia with an increased incidence of Cesarean section, and postpartum hemorrhage, and (5) cosmetic problems due to increased abdominal girth However, there are undoubtedly some clinical presentations secondary to uterine myomas are not so specific, such as: (1) uncommon compression-related symptoms, (2) cardiac symptom and atypical symptoms secondary to vascular involvement or dissemination, (3) abdominal symptoms mimicking pelvic carcinomatosis, (4) dyspnea, (5) pruritus, (6) hiccup or internal bleeding, and (7) vaginal protruding mass or uterine inversion. Familiarization with these symptoms and awareness of other unusual or atypical presentations of uterine myomas will remind clinical practitioners of their significance, and of the necessity of follow-up examinations and individualized management to fit the needs and childbirth desires of the patients. PMID- 23089400 TI - Lengthening of mouse hind limbs with local administration of insulin-like growth factor 2. AB - BACKGROUND: For devising potential clinical approaches for limb length discrepancies, we examined local administration of insulin-like growth factor 2 (IGF2). METHODS: C57/BL/6 mice (~ 8 weeks old) were used in this study, and the mice were separated into two groups: an IGF2-treated group and a placebo group. In the IGF2-treated group, IGF2 was locally administered into the distal epiphysis of the left femur, and the right femur was used as a contralateral control. In the placebo group, saline was administered to the left femur as a vehicle control. The left and right tibiae, without any direct intervention, were employed as negative controls. The dosage of IGF2 was 100 MUg/kg/day for 5 consecutive days, and bone samples were harvested on Day 14. Microcomputed tomography images did not show any anomaly at the IGF2 or saline injection sites. RESULTS: In comparison with the vehicle control as well as the contralateral control, the results revealed that IGF2 significantly lengthened the treated femur, with an elevation of bone mineral density (BMD) as well as bone mineral content (BMC). The increase in the femoral length of the IGF2-treated left limb was 1.6% (p < 0.05) to the vehicle control, and 1.7% (p < 0.05) to the contralateral control. However, the length, BMD, and BMC of the tibiae were not affected by administration of IGF2 or saline. Western blotting analysis demonstrated that this administration of IGF2 upregulated phosphorylation of an extracellular signal-regulated kinase in the treated femur. CONCLUSION: The current study supports for the first time the potential effectiveness of administration of IGF2 in adjusting limb length discrepancy. PMID- 23089401 TI - Aliskiren reduces portal pressure and intrahepatic resistance in biliary cirrhotic rats. AB - BACKGROUND: It is a well-accepted fact that angiotensin II (Ang II) contributes to increased vascular tone in cirrhotic livers. However, aliskiren attenuates the effect of Ang II through direct renin inhibition. Our study aimed to evaluate the effects of aliskiren on portal pressure and intrahepatic resistance in bile duct ligated (BDL) rats. METHODS: The effects of acute intravenous infusion (1 mg or 3 mg) or a course of 2-day oral administration of aliskiren (20 mg/kg/day) on blood pressure and portal pressure were evaluated in BDL and sham rats. Intrahepatic resistance was evaluated by a liver perfusion study isolated in situ. Ang II efflux was measured by Enzyme-linked immunosorbent assay (ELISA). The hepatic gene expression of angiotensinogen, renin, angiotensin-converting enzyme (ACE), Ang II type 1 receptor (AT(1)R) was analyzed with quantitative reverse transcription polymerase chain reaction. RESULTS: Aliskiren infusion intravenously reduced portal pressure with a minimal effect on blood pressure in BDL rats. Direct infusion of aliskiren in an isolated cirrhotic liver caused greater vasorelaxation and decreased hepatic production of Ang II. Two days of aliskiren treatment reduced portal pressure and hepatic ACE mRNA; in addition, it improved the vasodilator response to acetylcholine in the cirrhotic livers and decreased Ang II efflux. CONCLUSION: Aliskiren reduced portal pressure in cirrhotic rats. The portal hypotensive effect of aliskiren was related to the amelioration of the Ang II induced intrahepatic vasoconstriction. PMID- 23089402 TI - Hyponatremia in patients with symptomatic pericardial effusion. AB - BACKGROUND: Hyponatremia is related to cardiac tamponade in isolated case reports. However, the incidence of hyponatremia in patients with cardiac tamponade is still undetermined. METHODS: In a tertiary referral medical center, patients who presented with cardiac tamponade necessitating evacuation of pericardial effusion were included. Medical records were reviewed for the diagnosis of effusion and the underlying disease in each patient. Serum sodium concentrations before and after evacuation of effusion were analyzed. RESULTS: A total of 48 patients were identified during a 3-year period and 26 patients (54.2%) were found to have hyponatremia. The condition was mild (130-134 mEq/L) in eight; moderate (120-129 mEq/L) in 16; and severe (<120 mEq/L) in two patients. The frequency of hyponatremia was significantly higher in patients with malignancy-related rather than nonmalignancy-related cardiac tamponade (62.2% vs. 27.3%, p = 0.041). Nineteen patients had hyponatremia at presentation and had paired serum sodium concentrations measured after evacuation of pericardial effusion. The postevacuation serum sodium concentrations were significantly higher than the pre-evacuation levels in all patients (p < 0.001). CONCLUSION: Hyponatremia is common in patients with cardiac tamponade. However, prompt management of pericardial effusion will result in spontaneous and rapid recovery from hyponatremia. PMID- 23089403 TI - Relationship between acute stroke outcome, aspirin resistance, and humoral factors. AB - BACKGROUND: The relationship between biochemical aspirin resistance (AR) and functional outcome of acute ischemic stroke is uncertain. METHODS: Prospectively, 269 patients with acute ischemic stroke were recruited. Their responsiveness to aspirin was evaluated by platelet function analyzer (PFA-100). All patients received blood tests for fibrinogen, high-sensitivity C-reactive protein (hs CRP), CD40-ligand, P-selectin, intercellular adhesion molecule -1, von Willebrand factor (vWF), and D-dimer. The patients' National Institutes of Health Stroke Scale and modified Rankin Scale scores were recorded on admission, at 30 days, and at 90 days after stroke. RESULTS: Closure-time measured by PFA-100 equipped with epinephrine/collagen cartridge (Epi-CT) was <193 seconds (defined as AR) in 83 patients (30.9%). Patients with AR were less likely to have favorable outcome at 30 days (47.0%, p = 0.047; odds ratio: 0.69, 0.48-0.99) and 90 days (57.8%, p = 0.037; odds ratio: 0.69, 0.47-0.97) after stroke compared with those of patients without AR (60.2% and 71.0%, respectively). The Epi-CT correlated with closure-time measured by adenosine diphosphate/collagen cartridge (r = 0.241, p < 0.001), blood white cell count (r = -0.125, p = 0.041), low density lipoprotein cholesterol (r = 0.120, p = 0.050), hs-CRP (r = -0.150, p = 0.015), vWF (r = 0.134, p = 0.028), and body mass index (r = 0.143, p = 0.019). Multivariate logistic regression analysis showed that higher National Institutes of Health Stroke Scale at admission, atrial fibrillation, increased plasma levels of hs CRP, and D-dimer were independent predictors for unfavorable stroke outcome at 90 days. CONCLUSION: Aspirin resistance evaluated by PFA-100 test was associated with unfavorable 90-day outcome. However, AR determined by PFA-100 dose not predict 90-day functional outcome. The results of PFA-100 testing represented a complex interaction between drug effect, inflammatory reaction, and prothrombotic activity. PMID- 23089404 TI - Evaluation of the harmonic scalpel in breast conserving and axillary staging surgery. AB - BACKGROUND: The ultrasonically activated scalpel has been introduced as an alternative to conventional methods of hemostasis in surgical procedures. The present study investigated the benefits of using the Harmonic FOCUS (HF) scalpel in breast-conserving surgery (BCS) and in axillary staging surgery. METHODS: All early-stage breast cancer patients who underwent BCS and axillary staging surgery between January 2009 and December 2010 were retrospectively identified. Those patients treated with the HF scalpel were defined as the HF group, while patients whose surgery involved the electrocautery and the clamp-and-tie technique were designated as the conventional method (CM) group. Both groups were subsequently divided into the axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) subgroups, respectively. RESULTS: A total of 89 patients were included in the study, with 41 patients in the HF group and 48 in the CM group. There were 13 patients in the SLNB subgroup and 28 were in the ALND subgroup of the HF group, and 21 patients were in the SLNB subgroup and 27 in the ALND subgroup of the CM group. Multiple linear regression analysis revealed that the length of surgery was significantly reduced in the ALND subgroup of the HF group (beta = -16.70, p < 0.001). The incidence of axillary numbness was significantly decreased in the ALND subgroup of the HF group, with the results measured by multiple logistic regression analysis (OR = 0.27, p = 0.044). No statistically significant differences were identified concerning intraoperative blood loss, postoperative drainage, and seroma between the HF and CM groups. CONCLUSION: Using the Harmonic FOCUS scalpel in breast conserving surgery and axillary lymph mode dissection significantly reduced the length of surgery and decreased the axillary numbness rate as compared to conventional methods. PMID- 23089405 TI - Effect of Tong Qiao drops on the expression of eotaxin, IL-13 in the nasal mucosa of rats with allergic rhinitis. AB - BACKGROUND: In recent years, particularly in China, many Chinese medicines and prescriptions for treating allergic rhinitis have been evaluated for their clinical relevance. Studies have found that numerous herbs and their constituent compounds can significantly alleviate allergic symptoms and are effective treatments for allergic rhinitis. The purpose of this study was to examine the modulatory effect of Tong Qiao nose drops on allergy symptoms and the expression of cytokines in the nasal mucosa of rats with ovalbumin-induced allergic rhinitis. METHODS: Sixty healthy male Sprague Dawley rats were randomly divided into three groups (n = 20): negative, control, and experimental. Rats in the control or experimental groups were sensitized with ovalbumin to induce allergic rhinitis. The sensitized rats in the experimental group were subsequently exposed to Tong Qiao nose drops, whereas the sensitized control rats were given saline nose drops. Negative control rats were only treated with saline. Allergic symptoms and the pathologic features of the nasal mucosa were observed. The expression of eotaxin in the mucous membrane of rat nasal septums was detected by immunohistochemical staining, and the expression levels of interleukin (IL)-5 and IL-13 were measured by enzyme-linked immunosorbent assay. RESULTS: The symptom scores for the experimental group were significantly lower than those of control rats (p < 0.01). Histopathologic examination revealed pathologic changes of nasal mucosa edema in the experimental group was mild and the infiltration of eosinophils was insubstantial. The expression levels of eotaxin, IL-5, and IL-13 in the nasal mucosa from experimental rats were significantly lower than that of control rats (p < 0.01). CONCLUSION: Tong Qiao nose drops alleviated the symptoms of allergic rhinitis in a rat model and lowered the expression levels of eotaxin, IL-5, and IL-13. PMID- 23089406 TI - Application of the balanced scorecard to an academic medical center in Taiwan: the effect of warning systems on improvement of hospital performance. AB - BACKGROUND: The balanced scorecard (BSC) is considered to be a useful tool for management in a variety of business environments. The purpose of this article is to utilize the experimental data produced by the incorporation and implementation of the BSC in hospitals and to investigate the effects of the BSC red light tracking warning system on performance improvement. METHODS: This research was designed to be a retrospective follow-up study. The linear mixed model was applied for correcting the correlated errors. The data used in this study were secondary data collected by repeated measurements taken between 2004 and 2010 by 67 first-line medical departments of a public academic medical center in Taipei, Taiwan. The linear mixed model of analysis was applied for multilevel analysis. RESULTS: Improvements were observed with various time lags, from the subsequent month to three months after red light warning. During follow-up, the red light warning system more effectively improved controllable costs, infection rates, and the medical records completion rate. This further suggests that follow-up management promotes an enhancing and supportive effect to the red light warning. CONCLUSION: The red light follow-up management of BSC is an effective and efficient tool where improvement depends on ongoing and consistent attention in a continuing effort to better administer medical care and control costs. PMID- 23089407 TI - Acute necrotizing eosinophilic myocarditis in a young woman. AB - Eosinophilic myocarditis is recognized by severe heart failure and marked eosinophilia infiltration resulting from different etiologies. Acute necrotizing eosinophilic myocarditis, the initial presentation of the disease, is rare and often fatal, with unique echocardiographic pictures, and followed by endocardial thrombosis and chronic endomyocardial fibrosis. We report a young female with acute lymphoblastic leukemia who presented fever and acute heart failure syndrome. The echocardiography showed severe left ventricle diastolic dysfunction with preserved ejection fraction. Systemic eosinophilia and the unique echocardiographic images made the diagnosis of acute necrotizing eosinophilic myocarditis. The patient survived after intensive cytotoxic chemotherapy including high-dose steroid. PMID- 23089408 TI - Combination effect of ribavirin and erythropoietin treatment on hemoglobin A1c in a diabetic patient with chronic hepatitis C. AB - Any condition that shortens erythrocyte lifespan or decreases mean erythrocyte age may falsely lower hemoglobin A1c (A1C) test results. Ribavirin (RBV) used for chronic hepatitis C virus (HCV) infection can cause reversible hemolytic anemia; erythropoietin (EPO) used for treatment-related anemia can stimulate the production of red blood cells. We reported a 55-year-old woman with diabetes who received peginterferon alfa plus RBV for HCV infection. Four weeks following HCV therapy, her Hb level declined from 13.3 g/dL to 11.3 g/dL with elevated lactate dehydrogenase and reduced haptoglobin, which confirmed hemolysis. As her Hb fell to a nadir of 8.5 g/dL at the eighth week, darbepoetin alfa was administered to treat anemia consecutively for 10 weeks. Two months later, the patient's A1C declined from 7.5% to an extremely low value of 4.0%, accompanied by a fasting glucose level of 116 mg/dL. During the preceding 3 months, there was no self reported hypoglycemia or documented low blood glucose. About 3 months after HCV therapy was terminated, the A1C returned to 6.1% without medication adjustment. The concurrent use of RBV and EPO treatments can synergistically cause falsely low A1C values and may lead to inappropriate relaxation of glycemic control. During HCV treatment with RBV, A1C should not be used alone to guide diabetes therapy. PMID- 23089409 TI - Successful removal of a potentially lethal left atrial thrombus detected by transesophageal echocardiography following the removal of a left ventricular assist device inflow cannula. AB - The left ventricular assist device (LVAD) is a battery-operated, mechanical pump type device that helps in maintaining the pumping ability of a failing heart. Thromboembolism poses a significant risk during and after LVAD implantation. It occurs in up to 35% of patients with adverse sequelae. We present the case of a 75-year-old man who underwent coronary artery bypass graft surgery and LVAD implantation for acute myocardial ischemia and severe left ventricular dysfunction. However, subsequent transthoracic echocardiographic examination revealed an LVAD thrombus, and LVAD removal was suggested following the failure of thrombolytic therapy. After the LVAD cannula was removed, transesophageal echocardiography (TEE) revealed a residual thrombus in the left atrium. Thrombectomy was successfully performed by opening the left atrium with cardiopulmonary bypass. We believe that TEE monitoring aided the implantation and removal of the LVAD device. In this case, we found that TEE not only helped in monitoring the ventricular function but also in detecting other problems such as the residual thrombus. We strongly recommend TEE monitoring during the entire LVAD-removal procedure, particularly for patients who need to undergo LVAD removal because of thrombosis formation. PMID- 23089410 TI - Modulation of intestinal barrier by intestinal microbiota: pathological and therapeutic implications. AB - Mammals and their intestinal microbiota peacefully coexist in a mutualistic relationship. Commensal bacteria play an active role in shaping and modulating physiological processes in the host, which include, but are not restricted to, the immune system and the intestinal barrier. Both play a crucial role in containing intestinal bacteria and other potentially noxious luminal antigens within the lumen and mucosal compartment. Although mutualism defines the relationship between the host and the intestinal microbiota, disruptions in this equilibrium may promote disease. Thus, alterations in gut microbiota (dysbiosis) have been linked to the recent increased expression of obesity, allergy, autoimmunity, functional and inflammatory disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). In this article, we review the evidence supporting a role of gut microbiota in regulating intestinal barrier function. We discuss the hypothesis that microbial factors can modulate the barrier in ways that can prevent or promote gastrointestinal disease. A better understanding of the role of the intestinal microbiota in maintaining a functional intestinal barrier may help develop targeted strategies to prevent and treat disease. PMID- 23089411 TI - Capillary leak syndrome and abdominal compartment syndrome from occult rectal malignancy. PMID- 23089412 TI - Neurofibromatosis 1 and breast cancer: be alert. PMID- 23089413 TI - Catheter-directed thrombolysis in a patient with purpura fulminans. PMID- 23089414 TI - Left lobe hemiagenesis of the thyroid gland. PMID- 23089415 TI - "Whirl sign": small bowel volvulus in patients after gastrectomy. PMID- 23089416 TI - Facial cutaneous metastasis of colon adenocarcinoma. PMID- 23089417 TI - Dual carcinoma of the breast with neuroendocrine differentiation. PMID- 23089418 TI - A reoperation of a local recurrent nonfunctioning pancreatic neuroendocrine tumor after pancreaticoduodenectomy. PMID- 23089419 TI - Nonoperative management of adrenal myelolipoma hemorrhage resulting from trauma. PMID- 23089420 TI - The role of drain in laparoscopic sleeve gastrectomy. PMID- 23089421 TI - Recurrent splenic cyst. PMID- 23089422 TI - Management of exophytic gastrointestinal stromal tumors arising in the duodenopancreatic region. PMID- 23089423 TI - Novel use of a magnet to help remove metallic foreign bodies from the gastrointestinal tract. PMID- 23089424 TI - Peritonitis resulting from ruptured splenic abscess after splenic infarction in a patient with polycythemia vera. PMID- 23089425 TI - Pancreatic lymphangioma. PMID- 23089426 TI - Pancreatoduodenectomy in patients with a history of a Billroth-II gastrojejunostomy. PMID- 23089427 TI - Paralytic ileus secondary to intestinal ascariasis. PMID- 23089428 TI - Unusual presentation of the retrorectal neoplasm masquerading as a subcutaneous hip tumor. PMID- 23089429 TI - Extrapleural solitary fibrous tumor of the bile duct arisen on a choledochal cyst. PMID- 23089430 TI - Laparoscopic repair of acute penetrating diaphragm injury. PMID- 23089431 TI - Giant appendicolith, a rare cause of chronic right iliac fossa pain. PMID- 23089432 TI - Incisionless laparoscopic stoma construction using a 12-mm Hassan trocar. PMID- 23089433 TI - Management of Barrett's Esophagus. AB - Barrett's esophagus is a pathologic change of the normal squamous epithelium of the esophagus to specialized columnar metaplasia. Barrett's esophagus is a result of prolonged exposure of the esophagus to gastroduodenal refluxate. Although Barrett's itself is not symptomatic, and, in fact, patients with Barrett's esophagus may be completely asymptomatic, it does identify patients at higher risk of developing esophageal adenocarcinoma. Traditionally, antireflux surgery was reserved for patients with symptoms, because it was believed that antireflux surgery did not eliminate Barrett's esophagus and reduce cancer risk. Rationale for the treatment of Barrett's esophagus beyond treating symptoms of gastroesophageal reflux disease stems from the hope to decrease, if not eliminate, the risk of adenocarcinoma. Treatment options ranged from medical acid suppression without surveillance to resection. Ablation, particularly endoscopic radiofrequency ablation, has become the standard of care for Barrett's esophagus with high-grade dysplasia. It role in nondysplastic or low-grade dysplastic Barrett's is less clear. Combined endoscopic mucosal resection with ablation is effective in nodular high-grade Barrett's esophagus. Resection should be reserved for patients with persistent high-grade dysplasia despite multiple attempts at endoscopic ablation or resection or for patients with evidence of carcinoma. PMID- 23089434 TI - John Y. Templeton III: Pioneer of modern cardiothoracic surgery. AB - John Young Templeton III was born in 1917 in Portsmouth, Virginia, and graduated from Jefferson Medical College in 1941. He completed his residency training under Dr. John H. Gibbon, Jr., and was the first resident who worked on Gibbon's heart lung machine. After his training, he remained at Jefferson as an American Cancer Society fellow and Damon Runyon fellow and went on to become the fourth Samuel D. Gross Professor and Chair of the Department of Surgery in 1967. Dr. Templeton was the recipient of numerous grants and published over 80 papers in the field of cardiothoracic surgery. As a teacher and mentor, he was a beloved figure who placed great faith in his residents. He participated in over 60 professional societies, serving as president to many such as the Philadelphia Academy of Surgery and the Pennsylvania Association of Thoracic Surgery. He was also recognized through his many awards, in particular the John Y. Templeton III lectureship established in 1980 at Jefferson of whom Denton Cooley was the first lecturer. Dr. Templeton retired from practice in 1987. He is forever remembered as an important model of a modern surgeon evident in numerous academic achievements, the admiration and affection of his trainees, and the lives of patients that he had touched. PMID- 23089435 TI - Pediatric pancreatic trauma: trending toward nonoperative management? AB - Pancreatic trauma is rare in children and optimal care has not been defined. We undertook this study to review the cumulative experience from three centers. After obtaining Institutional Review Board approval at each site, the trauma registries of three institutions were searched for pancreatic injuries. The charts were reviewed and data pertaining to demographics, hospital course, and outcome were obtained and analyzed. During the study period, a total of 79 pancreatic injuries were noted. The most common mechanism of injury was motor vehicle crash (44%) followed by child abuse (11%) and bicycle crashes (11%). Computed tomographic (CT) scans were obtained in 95 per cent with peripancreatic fluid the most common finding. Median Injury Severity Score (ISS) was 9, whereas median organ injury score was 2, and a higher grade correlated with need for operation (P = 0.001). Pancreatic operations were performed in 32 patients, whereas nonoperative management was noted in 47 cases. We noted no differences in length of stay, age, ISS, or initial blood pressure in operative versus nonoperatively managed cases. Pancreatic injuries were rare in children with trauma. CT scans were the most common method of diagnosis. Nonoperative management appeared to be safe and was more common, especially for the lower grade injuries. PMID- 23089436 TI - Multifocal micropapillary thyroid cancer: a new indication for total thyroidectomy? AB - American Thyroid Association guidelines recommend total thyroidectomy (TT) for thyroid cancers 1 cm or greater. Liberal use of neck sonography has resulted in an increased incidence of papillary cancers detected at earlier stages with approximately half at the micropapillary level and occasionally multifocal. Concerns regarding the safety of routine TT, especially in young patients with favorable cancers, and the clinical significance of detected multifocal micropapillary cancers have been raised. Records of 516 consecutively treated patients with thyroid cancer were reviewed. A subset of 269 cases with well differentiated papillary thyroid cancer (WDPTC) confined within the capsule of the involved lobe undergoing TT was analyzed. Patients were stratified according to age, tumor size, evidence of ipsilateral multifocality, and presence or absence of contralateral nonpalpable malignancy. Overall contralateral histologic malignancy was demonstrated in 46.4 per cent (125 of 269). The incidence was 34 per cent (30 of 88) of subcentimeter (less than 1 cm) tumors and significantly increased to 52 per cent (95 of 181) in tumors 1 cm or greater (P = 0.006). This incidence significantly approached 76 per cent (13 of 17) in subcentimeter but multifocal tumors when 45 years or older (P = 0002). One patient developed permanent hypocalcemia (0.4%). There were no recurrent nerve injuries. The incidence of bilateral cancer was significant in 1-cm or greater WDPTC. Patients with subcentimeter multifocal tumors, when older than 45 years, were even at higher risk for bilateral cancer. Because TT is advocated for patients with WDPTC 1 cm or greater, it should also be considered in those older than 45 years with ipsilateral multifocal micropapillary cancers, because it can be performed safely. PMID- 23089437 TI - The surgical management of papillary thyroid microcarcinoma: a 162-month single center experience of 273 cases. AB - The aim of this study was to evaluate outcomes for patients with papillary thyroid microcarcinoma (PTMC) treated at a single institution during a 162-month period and to determine which patients need aggressive treatment. Two hundred seventy-three patients with PTMC had subtotal or total thyroidectomy + prophylactic or therapeutic lymph node dissection. Clinical and histopathological characteristics of 273 patients were identified and statistically analyzed. The tumors were multifocal in 36.3 per cent of the patients with PTMCs. Fifty-six per cent had neck lymph node metastases at diagnosis. Large-sized tumor (over 5 mm), age older than 45 years, multifocality, bilaterality, and extrathyroidal extension were associated with subclinical central lymph node metastases. Ninety six patients older than 45 years of age were upgraded from Stage I to III or IVA. Ten patients with lateral node recurrence or local recurrence in the residual thyroid had one or more risk factors. The high rates of multifocality and Level VI area subclinical lymph node metastasis were two important clinical and histopathological characteristics of PTMC. Patients who had one or more risk factors should receive more aggressive surgical management. PMID- 23089438 TI - Negative laparotomy in trauma: are we getting better? AB - One of the trauma surgeons' daily challenges is the balancing act between negative laparotomy and missed abdominal injury. We opted to characterize the indications that prompted a negative trauma exploratory laparotomy and the rate of missed abdominal injuries in an effort to optimize patient selection for laparotomy. At the Los Angeles County + University of Southern California Medical Center, negative laparotomies and missed injuries are consecutively captured and reviewed at the weekly mortality + morbidity (MM) conferences. All written reports of the MM meetings from January 2003 to December 2008 were reviewed to identify all patients who underwent a negative laparotomy or a laparotomy as a result of an initially missed abdominal injury. Over the 6-year study period, a total of 1871 laparotomies were performed, of which 73 (3.9%) were negative. The rate of missed injuries requiring subsequent laparotomy was 1.3 per cent (25 of 1871). The negative laparotomy rate and the rate of missed injuries did not vary significantly during the study period (2.8 to 4.7%, P = 0.875, and 0.7 to 2.9%, P = 0.689). Penetrating mechanisms accounted for the majority of negative laparotomies (58.9%). The primary indication for negative laparotomy was peritonitis (54.8%) followed by hypotension (28.8%) and suspicious computed tomographic scan findings (27.4%). The complication rate after negative laparotomy was 14.5 per cent, and of these, 10.1 per cent were directly related to the procedure. A low but steady rate of negative laparotomies and missed abdominal injuries after trauma remains. Negative laparotomies and missed abdominal injuries when they occur are still associated with significant complication rates and a prolonged length of stay. PMID- 23089439 TI - Comparison of incision and drainage against needle aspiration for the treatment of breast abscess. AB - We aim to compare the incision and drainage against ultrasound-guided aspiration for the treatment of breast abscesses. Sixty-four patients were randomly allocated to Group A (incision and drainage) and Group B (needle aspiration). Incision and drainage was done under general, whereas aspiration was done under local anesthesia with antibiotic coverage after the pus sample was taken for cultures. Time taken to resolve symptoms including point tenderness, erythema and hyperthermia, recurrence of breast abscess, and healing time was recorded. Patients were followed until 8 weeks. Culture and sensitivity of the pus were done. Data were analyzed in SPSS 16.0. The mean difference of healing time was significant (P = 0.001). A total of 93.3 per cent were healed in Group B and 76.6 per cent in Group A (P = 0.033). Twenty-two samples (34.37%) had no bacterial yield and the remaining 42 samples (65.6%) yielded 11 anaerobic cultures (17.18%) and 31 aerobic cultures (48.4%). Ultrasound-guided aspiration of breast abscesses with the judicious use of antibiotics is a better treatment modality than incision and drainage. PMID- 23089440 TI - Absence of cystic duct leakage using locking clips in 1017 cases of laparoscopic cholecystectomy. AB - Cystic duct leakage with metal clips persists after laparoscopic cholecystectomy (LC). The aim of the study is to evaluate the preventive effect of locking clips on leaks from the cystic duct stump after LC as an alternative to metal clips. Locking clips were routinely used to close the cystic duct in LC. A total of 1101 patients who underwent LC were retrospectively assessed from a database of the surgical department at our university hospital. A main outcome measurement is bile leakage after LC. From January 2006 to April 2011, 1053 LCs were performed. Of these, the cystic duct was closed with locking clips in 1017 cases, and no bile leaks from the cystic duct were observed in any of these 1017 cases. Locking clips should be routinely used to close the cystic duct in preference to metallic clips to reduce postoperative bile leaks after LC. PMID- 23089441 TI - Size of Stage IIIA primary lung cancers and survival: a surveillance, epidemiology and end results database analysis. AB - Size of early-stage lung cancer is important in the prognosis of patients. We examined the large population-based Surveillance, Epidemiology and End Results database to determine if tumor size was an independent risk factor of survival in patients undergoing lobectomy for N2 positive Stage IIIA nonsmall cell lung cancer (NSCLC). This study identified 1971 patients diagnosed with N2 positive Stage IIIA NSCLC, from 1998 to 2007, and who underwent lobectomy. Five tumor groups based on the seventh edition TNM lung cancer staging system (pathologic T1a 2 cm or less; T1b greater than 2 cm and 3 cm or less; T2a greater than 3 cm and 5 cm or less; T2b greater than 5 cm and 7 cm or less; T3 greater than 7 cm) were analyzed. Survival was reduced in patients with T3, T2a, and T2b tumors compared with patients with T1a and T1b (P < 0.001). Survival estimates correlated with tumor size with poorer survival in T3 followed by T2b, T2a, and then T1b and T1a. Cohorts with T1a (hazard ratio [HR], 0.53; P = 0.01) and T1b (HR, 0.54; P = 0.01) were both found to have decreased hazard of death. Negative predictors of survival, in addition to increasing tumor size, included age and male gender, whereas positive predictors included tumor Grade I and upper lobe location. Increasing size of tumor is an independent negative risk factor for survival in patients undergoing lobectomy for N2 positive Stage IIIA NSCLC. PMID- 23089442 TI - Lymphatic and capillary invasion patterns in triple negative breast cancer. AB - Triple negative breast cancer (TNBC) comprises approximately 15 to 20 per cent of all breast cancer cases. Many studies have detected less lymph node metastasis in TNBC than sporadic breast cancers. In this study, we studied capillary and lymphatic invasion in tumors of patients with TNBC. To differentiate the capillary invasion and lymphovascular invasion. We used the Antihuman CD34 and antihuman D2-40 antibodies. Antihuman CD34 antibodies stain the blood vessels and lymphatics. However, antihuman D2-40 antibodies stain lymphatics specifically. Two experienced pathologists blinded to clinical data evaluated capillary and lymphatic invasion existence in 39 TNBC patients' tumor samples. Tumor samples were immunohistochemically stained with CD34 (endothelial cell marker) and D2-40 (podoplanin, a membrane protein, specific for lymphatic endothelium). The CD34 positive samples were categorized into two groups depending on their reaction with D2-40: lymphatic (D2-40-positive) and capillary (D2-40-negative) invasion. We have detected vascular invasion in 15 of 39 samples (38.5%) with CD34. Among those, capillary invasion was found in 14 (35.9%) and lymphatic invasion in three (7.7%) and both in two (5.1%) tumors. We did not find any significant correlation among capillary invasion, lymphatic invasion, vascular invasion, tumor grade, menopause status, history of cancer, and TNM. Capillary invasion is more commonly observed than lymphatic invasion in patients with TNBC. This finding supports the fact that more hematogenous metastasis (spreading) and less lymph node metastasis are seen in patients with TNBC. PMID- 23089444 TI - An objective study of the impact of the electronic medical record on outcomes in trauma patients. AB - It is commonly believed that the electronic medical record (EMR) will improve patient outcomes. However, there is scant published literature to support this claim and no studies in any surgical population. Our hypothesis was that the EMR would not improve objective outcome measures in patients with traumatic injury. Prospectively collected data from our university-based Level I trauma center was retrospectively reviewed. Demographic, injury severity as well as outcomes and complications data were compared for all patients admitted over a 20-month period before introduction of the EMR and a 20-month period after full, hospital-wide use of the EMR. Implementation of the EMR was associated with a decreased hospital length of stay, P = 0.02; intensive care unit length of stay, P = 0.001; ventilator days, P = 0.002; acute respiratory distress syndrome, P = 0.006, pneumonia, P = 0.008; myocardial infarction, P = 0.001; line infection, P = 0.03; septicemia, P = 0.000; renal failure, P = 0.000; drug complication, P = 0.001; and delay in diagnosis, P = 0.04. There was no difference in mortality, unexpected cardiac arrest, missed injury, pulmonary embolism/deep vein thrombosis, or late urinary tract infection. This is the first study to investigate the impact of the EMR in surgical patients. Although there was an improvement in some complications, the overall impact was inconsistent. PMID- 23089443 TI - Combined hepatic arterial embolization and hepatic ablation for unresectable colorectal metastases to the liver. AB - Liver-directed therapy for hepatic metastases includes: intra-arterial techniques such as transarterial chemoembolization (TACE) and yttrium-90 resin ((90)Y) microsphere radioembolization and ablative technologies: cryoablation, radiofrequency ablation, and microwave ablation. Combining embolization techniques with liver ablation may enhance the therapeutic benefit of each and result in improved patient survival. We retrospectively reviewed our experience with combined intra-arterial therapies and ablation for unresectable hepatic colorectal metastases from 1996 to 2011. Patient demographics, tumor characteristics, specific liver-directed treatments, procedure-related morbidity and mortality, and overall survival were recorded. There were 17 (53%) males and 15 (47%) females. Average age for the group was 74.1 years (median, 75.5 years). Fifteen patients (46.9%) had a single hepatic metastasis. Eleven (34%) patients had bilobar tumor distribution and seven (22%) patients had vascular invasion of the portal vein or hepatic/caval venous structures. Seven (21%) tumors were greater than 5 cm in diameter. Twenty-seven (84.4%) patients received TACE and five (15.6%) received (90)Y. Fourteen (43%) were embolized before any ablation. Fifty-three per cent of patients required multiple hepatic ablation sessions. Median length of hospital stay was 1 day. There were no procedure-related mortalities and complications occurred in six (18.8%) patients. Mean follow-up for the group was 33 months. Kaplan-Meier 1-, 3-, and 5-year estimated survival was 93.8, 50.0, and 10.1 per cent, respectively. Median survival for the group was 46 months. Hepatic ablation and embolization techniques can be combined safely with minimal morbidity. In our series, we observed 5-year survival in 10 per cent of patients. PMID- 23089445 TI - The use of bioabsorbable staple-line reinforcement performing stapled hemorrhoidopexy to decrease the risk of postoperative bleeding. AB - Postoperative staple-line bleeding after stapled hemorrhoidopexy represents a major issue of this procedure, especially in the day surgery setting. In this study we assess the possible benefit of using circular bioabsorbable staple-line reinforcement to reduce the risk of hemorrhage when performing stapled hemorrhoidopexy in a day surgery setting. Patients with symptomatic II to III grade hemorrhoidal disease were randomly assigned into two groups. In Group A we performed a stapled hemorrhoidopexy using PPH33-03((r)) with Seamguard((r)), a bioabsorbable staple-line reinforcement; in Group B, we used only a PPH33 03((r)) stapler. We evaluated the intraoperative and postoperative staple-line bleeding and, secondarily, the duration of surgery, need for additional hemostatic stitches, and presence of postoperative complications. One hundred patients were enrolled in the study. Group A patients showed a statistically significant decrease of intraoperative bleeding (4 vs 42% in Group B) and hemostatic stitch placement (5.7 vs 42%) with the consequent reduction in mean operative time, postoperative pain, and tenesmus. There were no differences between the two groups in hemorrhoidal disease control or postoperative late complications. The use of bioabsorbable staple-line reinforcement while performing stapled hemorrhoidopexy may allow improvement of the safety of this procedure, especially in a day surgery setting. PMID- 23089446 TI - Does Acute Physiology and Chronic Health Evaluation II provide a valid metric to directly compare disease severity in trauma versus surgical intensive care unit patients? AB - The Acute Physiology and Chronic Health Evaluation II (APACHE II) score has never been validated to risk-adjust between critically ill trauma (TICU) and general surgical (SICU) intensive care unit patients, yet it is commonly used for such a purpose. To study this, we evaluated risk of death in TICU and SICU patients with pneumonia. We hypothesized that mortality for a given APACHE II would be significantly different and that using APACHE II to directly compare TICU and SICU patients would not be appropriate. We conducted a retrospective review of patients admitted to the TICU or SICU at a tertiary medical center over an 18 month period with pneumonia. Admission APACHE II scores, in-hospital mortality, demographics, and illness characteristics were recorded. One hundred eighty patients met inclusion criteria, 116 in the TICU and 64 in the SICU. Average APACHE II scores were not significantly different in the TICU versus SICU (25 vs 24; P = 0.4607), indicating similar disease severity; overall mortality rates, however, were significantly different (24 vs 50%; P = 0.0004). Components of APACHE II, which contributed to this mortality differential, were Glasgow Coma Score, age, presence of chronic health problems, and operative intervention. APACHE II fails to provide a valid metric to directly compare the severity of disease between TICU and SICU patients with pneumonia. These groups represent distinct populations and should be separated when benchmarking outcomes or creating performance metrics in ICU patients. Improved severity scoring systems are needed to conduct clinically relevant and methodologically valid comparisons between these unique groups. PMID- 23089447 TI - Early repair of pelvic and abdominal nonurological surgery-induced iatrogenic ureteral injuries in three distinct waiting-for-repair time periods. AB - The purpose of this study was to explore whether the time from pelvic and abdominal nonurological surgery-induced iatrogenic ureteral injuries to repair associates with outcomes. We retrospectively reviewed 81 cases of pelvic and abdominal nonurological surgery-induced iatrogenic ureteral injuries occurring in 78 patients treated at our hospital from January 2000 to December 2009. Time between injury and surgical repair, operative times, and incidence of complications were compared. Lower ureteral segment injuries occurred in 66 cases, middle segment injuries in 13, and upper segment injuries in two. Surgical repair methods included 36 ureteroneocystostomies, 17 ureteroneocystostomy with psoas hitch, 14 ureteroureterostomies/ureteral end-to end anastomosis, and 10 ureteroneocystostomies with a Boari flap. Immediate intraoperative repair was carried out in 23 cases. In 42 cases, repair was delayed as a result of late identification and performed within 1 month after surgery. In 10 cases, repair was performed 3 months after surgery. No significant differences were observed in operative times of repair surgeries or incidence of postoperative complications. Delayed discovery of iatrogenic ureteral injury can still result in good therapeutic effects if the surgical repair is done within 1 month after injury under the premise that no serious urinary tract infection is present and the patient can tolerate surgery. PMID- 23089448 TI - Sharing lessons learned to prevent incorrect surgery. AB - The purpose of this report is to discuss surgical adverse event lessons learned and to recommend action. Examples of incorrect surgical adverse events managed in the Veterans Health Administration (VHA) patient safety system and results of a survey regarding the impact of the surgery lessons learned process are provided. The VHA implemented a process for sharing deidentified stories of surgical lessons learned. The cases are in-operating room selected examples from lessons learned from October 1, 2009, to June 30, 2011. Examples selected illustrate helpful human factors principles. To learn more about the awareness and impact of the lessons learned, we conducted a survey with Chiefs of Surgery in the VHA. The types of examples of adverse events include wrong eye implants, incorrect nerve blocks, and wrong site excisions of lesions. These are accompanied by human factors recommendations and change concepts such as designing the system to prevent mistakes, using differentiation, minimizing handoffs, and standardizing how information is communicated. The survey response rate was 76 per cent (88 of 132). Of those who had seen the surgical lessons learned (76% [67 of 88]), the majority (87%) reported they were valuable and 85% that they changed or reinforced patient safety behaviors in their facility as a result of surgical lessons learned. Simply having a policy will not ensure patient safety. When reviewing adverse events, human factors must be considered as a cause for error and for the failure to follow policy without assigning blame. VHA surgeons reported that the surgery lessons learned were valuable and impacted practice. PMID- 23089449 TI - Breast reconstruction after mastectomy at an urban community-based program. AB - Reconstruction after mastectomy is an elective procedure. To date many factors have been associated with the choice of operation in these patients including socioeconomic status, insurance, age, comorbidities, and community factors. In an effort to understand the characteristics of patients who undergo reconstruction at our hospital, we performed a retrospective review of patients who received mastectomy at our institution. A total of 354 patients underwent mastectomy from 2006 to 2010 at our hospital. Data from 332 patients undergoing reconstruction within 1 year of mastectomy were then analyzed and chi(2) analysis was performed to identify factors significant in the choice of reconstruction. Age younger than 50 years (odds ratio [OR], 3.87), age older than 70 years (OR, 0.09), presence of insurance (OR, 2.89), diabetes (OR, 0.401), hypertension (OR, 0.379), and Medicare (0.182) were found to be significant factors associated with a choice of reconstruction among our patients. When age was corrected for, insurance status was no longer a significant factor in choice of reconstruction. Over 90 per cent of patients underwent implant or tissue expanders for reconstruction. This study reflects the reconstruction choices of patients in our community, city-based hospital. PMID- 23089450 TI - Surgical outcomes for cancer at the gastroesophageal junction. AB - The aim of this study was to evaluate the clinicopathological characteristics and prognostic factors of cancer at the gastroesophageal junction (GEJ) whose center is situated at a site within 2 cm above and below the junction. This retrospective study included 90 patients with cancer at the GEJ, including 58 with adenocarcinoma (ADC) and 32 with squamous cell carcinoma (SCC). ADC tumors were larger in size than SCC tumors. ADC and SCC at the GEJ showed a similar distribution of the pattern of lymphatic spread. The rate of lower mediastinal lymph node metastasis was approximately 20 per cent, which is similar to the nodes along the celiac artery and the nodes along the common hepatic artery. The overall survival rates were similar between the groups. The presence of five or more lymph node metastases was an independent prognostic factor according to a multivariate analysis. When two or more lymph nodes larger than 10 mm were detected preoperatively, five or more lymph node metastases were proven by histology in most cases. The most frequent sites of recurrence of ADC and SCC were the peritoneum and lymph nodes, respectively. Aggressive additional treatment may be needed if two or more lymph nodes are seen on preoperative imaging. PMID- 23089451 TI - Measuring pain in outpatient surgical patients: variation resulting from instrument choice. AB - Our hypothesis is that the type of instrument will affect variation in pain assessment. A sample of 269 patients administered the visual analog pain scale (VAS) and the generic quality-of-life instrument, and the SF-36 were evaluated for gender, age, the VAS score and the bodily pain domain of the SF-36 (BP-SF 36) score, primary surgical diagnosis, preoperative or postoperative status, and type of operation. Patients were grouped into preoperative (Preop) and postoperative (postop) status and those with chronic pain (CP) conditions and acute/no pain (AP) conditions. Linear regression analysis showed statistically significant (all P value <= 0.0006) correlations between the VAS and BP-SF-36 scores all patients, preoperative patients, postoperative patients, acute pain patients, and chronic pain patients. However, the strength of these correlations were moderate (r values between 0.51 and 0.61). Preoperative had more pain compared with postoperative patients as measured by both the VAS and BP-SF-36 (P = 0.05). Similarly, chronic pain patients had more pain compared with acute pain patients as measured by both scales (P < 0.0001). Although there are statistically significant associations between the BP-SF-36 and VAS, the correlations are moderate. Different instruments may measure different aspects of pain and the precision with which pain is measured in surgical patients. PMID- 23089452 TI - Rising self-inflicted injuries in the United States: a call for a comprehensive prevention plan and insurance coverage. PMID- 23089453 TI - Radiation exposure in trauma patients. PMID- 23089454 TI - Postcolonoscopy appendicitis: laparoscopy a viable option. PMID- 23089455 TI - Congenital intrathoracic accessory spleen. PMID- 23089456 TI - Low-density lipoprotein transport within a multi-layered arterial wall--effect of the atherosclerotic plaque/stenosis. AB - Low-density lipoprotein (LDL) transport while incorporating the thickening of the arterial wall and cholesterol lipid accumulation is analyzed. A multi-layered model is adopted to represent the heterogeneity using the Darcy-Brinkman and Staverman filtration equations to describe transport within the porous layers of the wall. The fiber matrix model is utilized to represent the cholesterol lipid accumulation and the resulting variable properties. The impact of atherosclerotic wall thickening is shown to be negligible in the axial direction, but is found to be considerable in the radial direction within intima. The reference values of intima's porosity and effective fiber radius are obtained through the fiber matrix model, which characterizes the microstructure within the intima. Transport through dysfunctional endothelium and fibrous cap, and the impact on hydraulic and molecular transport properties by LDL accumulation in a thickened arterial wall is analyzed. The effect of variable properties on plasma and LDL molecular transport is also discussed. PMID- 23089457 TI - Clustering and classification of regional peak plantar pressures of diabetic feet. AB - High plantar pressures have been associated with foot ulceration in people with diabetes, who can experience loss of protective sensation due to peripheral neuropathy. Therefore, characterization of elevated plantar pressure distributions can provide a means of identifying diabetic patients at potential risk of foot ulceration. Plantar pressure distribution classification can also be used to determine suitable preventive interventions, such as the provision of an appropriately designed insole. In the past, emphasis has primarily been placed on the identification of individual focal areas of elevated pressure. The goal of this study was to utilize k-means clustering analysis to identify typical regional peak plantar pressure distributions in a group of 819 diabetic feet. The number of clusters was varied from 2 to 10 to examine the effect on the differentiation and classification of regional peak plantar pressure distributions. As the number of groups increased, so too did the specificity of their pressure distributions: starting with overall low or overall high peak pressure groups and extending to clusters exhibiting several focal peak pressures in different regions of the foot. However, as the number of clusters increased, the ability to accurately classify a given regional peak plantar pressure distribution decreased. The balance between these opposing constraints can be adjusted when assessing patients with feet that are potentially "at risk" or while prescribing footwear to reduce high regional pressures. This analysis provides an understanding of the variability of the regional peak plantar pressure distributions seen within the diabetic population and serves as a guide for the preemptive assessment and prevention of diabetic foot ulcers. PMID- 23089458 TI - Chondrocyte deformation under extreme tissue strain in two regions of the rabbit knee joint. AB - Articular cartilage and its native cells-chondrocytes-are exposed to a wide range of mechanical loading. Chondrocytes are responsible for maintaining the cartilage matrix, yet relatively little is known regarding their behavior under a complete range of mechanical loads or how cell mechanics are affected by region within the joint. The purpose of this study was to investigate chondrocyte deformations in situ under tissue loads ranging from physiological to extreme (0-80% nominal strain) in two regions of the rabbit knee joint (femoral condyles and patellae). Local matrix strains and cell compressive strains increased with increasing loads. At low loads the extracellular matrix (ECM) strains in the superficial zone were greater than the applied tissue strains, while at extreme loads, the local ECM strains were smaller than the applied strains. Cell compressive strains were always smaller than the applied tissue strains and, in our intact, in situ preparation, were substantially smaller than those previously found in hemi cylindrical explants. This resulted in markedly different steady-state cell volume changes in the current study compared to those working with cartilage explants. Additionally, cells from different regions in the knee exhibited striking differences in deformation behavior under load. The current results suggest: (i) that the local extracellular and pericellular matrix environment is intimately linked to chondrocyte mechanobiology, protecting chondrocytes from potentially damaging strains at high tissue loads; and (ii) that cell mechanics are a function of applied load and local cartilage tissue structure. PMID- 23089459 TI - Lower mortality from nasopharyngeal cancer in The Netherlands since 1970 with differential incidence trends in histopathology. AB - OBJECTIVE: Nasopharyngeal carcinoma (NPC) is rare in western countries albeit affected by common and unrelated phenomena: smoking less in men, more in women and immigration from China and North Africa. We studied trends in NPC incidence, tumour morphology, survival and mortality in order to assess progress against this cancer. MATERIALS AND METHODS: A trend analysis was performed with nationwide incidence and survival data (from The Netherlands Cancer registry in 1989-2009), followed by analysis of mortality (data from Statistics Netherlands) covering the period 1970-2009, and calculating estimated percentages of change (EAPC) in both. According to the WHO classification we distinguished keratinizing SCC (WHO-I), differentiated (WHO-IIA) and undifferentiated (WHO-IIB) non keratinizing carcinoma. RESULTS: NPC incidence significantly decreased since 1989, especially in males (EAPC 1989-2009: -1.3; 95% CI: -2.5, -0.2) and in patients with keratinizing SCC (WHO-I) (EAPC: -3.6; 95% CI: -5.3, -1.8). By contrast, the incidence of differentiated non-keratinizing tumours (WHO-IIA) significantly increased in the same period (EAPC: 9.6; 95% CI: 5.6, 13.5). One- and three-year relative survival, as an indicator of disease-specific survival increased slightly from 79% to 81% and from 57% to 65% since 1989. NPC mortality significantly decreased since 1970 (EAPC: -1.2; 95% CI: -1.8, -0.5) and more pronounced since 1989 (EAPC: -3.0; 95% CI: -4.3, -1.6). CONCLUSION: During the past two decades, the incidence of NPC in The Netherlands decreased mainly by less keratinizing, supposedly smoking-related NPC (WHO-I). However, the incidence of non-keratinizing NPC (WHO-IIA, B) increased, most likely due to EBV infection and thus related to higher immigration levels of people from high-incidence areas. PMID- 23089460 TI - Volumetric staging in oropharyngeal cancer patients treated with definitive IMRT. AB - BACKGROUND: The superiority of volumetric staging (VS) over TNM/TNM-grouping system was previously prospectively tested in our head neck cancer population treated with intensity-modulated radiotherapy (IMRT); gross tumor volume (GTV) was the strongest predictor for disease control. Aim of this work was to specifically assess the prognostic value of VS in oropharyngeal cancer (OC). PATIENTS: Between 04/2002 and 12/2011, 277 consecutive OC patients underwent definitive IMRT. Mean/median follow-up was 33/27 months (3-113). Three volumetric cut-offs were used (resulting in 4 GTV subgroups: 1-15 cc (14%), 16-70 cc (62%), 71-130 cc (20%), >130 cc (4%)). METHODS: Outcome in the OC subgroup was prospectively assessed with VS and compared with that resulting from TNM and AJCC staging. RESULTS: Primary GTV was most reliably predicting local control (p<0.0001), all other outcome parameters were predicted best by the total GTV (p<0.0001). CONCLUSION: This is -to our knowledge- the first volumetric staging system for OC, and was found to be most reliable in predicting outcome in OC patients treated with IMRT. PMID- 23089461 TI - Tumor-associated macrophages and the profile of inflammatory cytokines in oral squamous cell carcinoma. AB - OBJECTIVE: To evaluate and characterize macrophage populations (M1/M2) in the tumor microenvironment of oral cavity squamous cell carcinoma (OCSCC). The relationship between macrophages and clinicopathological factors, such as survival data, lymph node metastasis, tumoral proliferation, and WHO histological grading are also analyzed. MATERIALS AND METHODS: The samples consisted of surgically excised specimens from patients with non-metastatic and metastatic OCSCC and normal oral mucosa (control). Immunohistochemistry, flow cytometry, and qRT-PCR were used to evaluate macrophage populations and the expression of pro- (IL-12, IL-23, and INF-gamma) and anti-inflammatory (IL-10 and TGF-beta) cytokines. The level required for statistical significance was defined as p<0.05. RESULTS: The data showed a predominance of M2 phenotype (high percentage of IL 10(+)TGF-beta(+)) macrophages in the tumor microenvironment of OCSCC. A higher percentage of macrophages expressing TGF-beta was seen in the OCSCC group when compared with healthy individuals. The assessment of mRNA expression also presented a greater expression of anti-inflammatory cytokines TGFbeta and IL10 in OCSCC when compared with the control group. The percentage of macrophages, demonstrated by immunohistochemistry, was significantly higher in the metastatic OCSCC group than in the non-metastatic and control groups. The log-rank test also showed that the mean survival time for patients with high levels of macrophages was less (44 months) when compared with patients with a low percentage of such cells (93 months). CONCLUSION: A predominance of the M2 phenotype in the tumor microenvironment of OCSCC could contribute to local immunosuppression, via TGF beta production, and consequently greater lymph node involvement and reduced patient survival time. PMID- 23089462 TI - A study on the use of near-infrared spectroscopy for the rapid quantification of major compounds in Tanreqing injection. AB - In this paper we describe the strategy used in the development and validation of a near infrared spectroscopy method for the rapid determination of baicalin, chlorogenic acid, ursodeoxycholic acid (UDCA), chenodeoxycholic acid (CDCA), and the total solid contents (TSCs) in the Tanreqing injection. To increase the representativeness of calibration sample set, a concentrating-diluting method was adopted to artificially prepare samples. Partial least square regression (PLSR) was used to establish calibration models, with which the five quality indicators can be determined with satisfied accuracy and repeatability. In addition, the slope/bias (S/B) method was used for the models transfer between two different types of NIR instruments from the same manufacturer, which is contributing to enlarge the application range of the established models. With the presented method, a great deal of time, effort and money can be saved when large amounts of Tanreqing injection samples need to be analyzed in a relatively short period of time, which is of great significance to the traditional Chinese medicine (TCM) industries. PMID- 23089463 TI - Synthesis and conformational studies of newly synthesized cis-2r,6c distyryltetrahydro thiopyran-4-one and its oxime: comparison of experimental and theoretical NMR spectral data. AB - The cis-2r,6c-distyryltetrahydro thiopyran-4-one (4) was synthesized by the reaction of dicinnamylacetone with hydrogen sulphide. cis-2r,6c distyryltetrahydro thiopyran-4-one oxime (5) was synthesized via oximination of 4. The synthesized compounds were characterized by IR, NMR spectral studies and elemental analysis. The proton and carbon chemical shift values were unambiguously assigned using two dimensional NMR (1H1H COSY, HSQC, HMBC, NOESY) spectra. 1H NMR and 13C NMR chemical shifts of 4 were also obtained by the density functional theory (DFT) using 6-311++G(d,p) basis sets and the theoretical values were compared with experimental values. PMID- 23089464 TI - Transitioning from active treatment: colorectal cancer survivors' health promotion goals. AB - OBJECTIVE: The purpose of this study is to describe the post-treatment goals of colorectal cancer (CRC) survivors. We sought to determine whether goals were a salient concept during the period immediately following treatment, and whether a goal-setting intervention might be feasible and acceptable to these patients. METHOD: Semi-structured qualitative interviews were administered to a convenience sample of 41 CRC patients who were 0-24 months post-treatment. Topics discussed included expectations and goals for future health, cancer prevention awareness, health-promoting behavior-change goals, and post-treatment cancer issues. Content analysis was used to explore emergent themes. RESULTS: Overall, participants' health-related goals were: being healthy, getting back to normal, and not having a cancer recurrence. Most of the CRC survivors reported being proactive with their health by maintaining healthy behaviors or making healthy behavior changes, or had goals to change their behavior. All respondents had plans to maintain follow-up care and regular screening appointments. Some patients were managing treatment side effects or non-cancer issues that limited their functional abilities. Many respondents were satisfied with the care they received, and felt it was now their responsibility to do their part in taking care of themselves. SIGNIFICANCE OF RESULTS: CRC survivors talk about goals, and many of them are either making or have an interest in making health behavior changes. Self management support could be an appropriate strategy to assist patients with achieving their health goals post-treatment. Patients may need help addressing lingering treatment side effects or non-cancer issues. Healthcare providers should consider assessing patients' goals to help patients resolve post-treatment issues and promote healthy behaviors. PMID- 23089465 TI - Klf4 transcription factor is expressed in the cytoplasm of prostate cancer cells. AB - BACKGROUND: Cancer initiation and progression might be driven by small populations of cells endowed with stem cell-like properties. Here we comparatively addressed the expression of genes encoding putative stemness regulators including c-Myc, Klf4, Nanog, Oct4A and Sox2 genes in benign prostatic hyperplasia (BPH) and prostate cancer (PCA). METHODS: Fifty-eight PCA and thirty nine BPH tissues samples were used for gene expression analysis, as evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of specific Klf4 isoforms was tested by conventional PCR. Klf4 specific antibodies were used for protein detection in a tissue microarray including 404 prostate samples. RESULTS: Nanog, Oct4A and Sox2 genes were comparably expressed in BPH and PCA samples, whereas c-Myc and Klf4 genes were expressed to significantly higher extents in PCA than in BPH specimens. Immunohistochemical studies revealed that Klf4 protein is detectable in a large majority of epithelial prostatic cells, irrespective of malignant transformation. However, in PCA, a predominantly cytoplasmic location was observed, consistent with the expression of a differentially spliced Klf4alpha isoform. CONCLUSION: Klf4 is highly expressed at gene and protein level in BPH and PCA tissues but a cytoplasmic location of the specific gene product is predominantly detectable in malignant cells. Klf4 location might be of critical relevance to steer its functions during oncogenesis. PMID- 23089466 TI - Preoperative accuracy of diagnostic evaluation of the urachal mass. AB - PURPOSE: Urachal carcinoma is a rare urological neoplasm that arises along the urachal remnant from umbilicus to bladder dome. To our knowledge no published study has examined the diagnostic accuracy of modern preoperative testing to differentiate urachal carcinoma from a benign urachal cyst and spare the resection of potentially benign urachal tissue. We determined whether a urachal mass could be safely diagnosed preoperatively. MATERIALS AND METHODS: We reviewed the records of 104 patients with a urachal mass treated between 1979 and 2011. Study exclusion criteria were unresectable metastatic disease at presentation, no surgery and management by transurethral resection alone. Of the patients who remained only 65 had preoperative diagnostic testing as well as definitive pathological results available for analysis. Mean age was 51 years. Of the patients 86% were white and 65% were male. The accuracy of diagnosis based on preoperative tests was compared to that of final pathology (cancer or benign). RESULTS: A total of 57 tumors (87%) were malignant and 83% of the masses were adenocarcinoma. Compared to computerized tomography, cytology and exploration under anesthesia, transurethral resection of bladder tumor had the highest sensitivity (0.93), specificity (1) and positive predictive value (1) but low negative predictive value (0.5). Study limitations included small cohort size and few benign urachal masses for comparison. CONCLUSIONS: No test has a high enough negative predictive value to prevent urachal mass excision. With few treatment options for localized, advanced and metastatic urachal cancer, these data suggest that early excision remains the best treatment for a suspicious urachal mass. PMID- 23089467 TI - The impotent certificate of need. PMID- 23089468 TI - The plant non-specific phospholipase C gene family. Novel competitors in lipid signalling. AB - Non-specific phospholipases C (NPCs) were discovered as a novel type of plant phospholipid-cleaving enzyme homologous to bacterial phosphatidylcholine-specific phospholipases C and responsible for lipid conversion during phosphate-limiting conditions. The six-gene family was established in Arabidopsis, and growing evidence suggests the involvement of two articles NPCs in biotic and abiotic stress responses as well as phytohormone actions. In addition, the diacylglycerol produced via NPCs is postulated to participate in membrane remodelling, general lipid metabolism and cross-talk with other phospholipid signalling systems in plants. This review summarises information concerning this new plant protein family and focusses on its sequence analysis, biochemical properties, cellular and tissue distribution and physiological functions. Possible modes of action are also discussed. PMID- 23089469 TI - High therapeutic concentration of prazosin up-regulates angiogenic IL6 and CCL2 genes in hepatocellular carcinoma cells. AB - Alteration of the oxidative stress of hepatocellular carcinoma (HCC) cells can influence the expressions of genes favored angiogenesis. Quinone reductase 2 which can activate quinones leading to reactive oxygen species production is a melatonin receptor known as MT3. Prazosin prescribed for benign prostate hyperplasia and hypertension is a potent antagonist for MT3. This study was to investigate the influence of therapeutic concentrations of prazosin (0.01 and 0.1MUM) on cell proliferation and differential expressions of CCL2, CCL20, CXCL6, CXCL10, IL8 and IL6 genes related to inflammation and/or oxidative stress in human HCC cell lines. Two HCC cell lines including one without susceptible to amphotericin B-induced oxidative stress (cell line A; HCC24/KMUH) and one with this effect (cell line B; HCC38/KMUH) were investigated by 0.01 and 0.1MUM prazosin. The premixed WST-1 cell proliferation reagent was applied for proliferation assay. Differential expressions of genes were examined by quantitative reverse transcriptase-polymerase chain reaction. Our results showed that both 0.01 and 0.1MUM prazosin did not influence cell proliferation in both cell lines. Both 0.01 and 0.1MUM prazosin in cell line A and 0.01MUM prazosin in cell line B did not cause differential expressions of tested genes. However, 0.1MUM prazosin caused remarkable up-regulation of IL6 gene and slightly up regulation of CCL2 gene in cell line B. In conclusion, high therapeutic concentration of prazosin can up-regulate angiogenic IL6 and CCL2 genes in human HCC cells susceptible to amphotericin B-induced oxidative stress. Clinical application of prazosin in patients with HCC should consider this possibility. PMID- 23089470 TI - Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. AB - Melanoma is the most common malignant skin cancer, appears indestructible and is notoriously resistant to all current modalities of cancer treatment strategies. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, has shown to have radiosensitizing properties for a variety of cancers. Recently, we have shown that PTX exhibits antimetastatic and anti-angiogenic activities in B16F10 melanoma cells in vitro as well as in vivo. In the present study, we have demonstrated the anticancer and antimetastatic potential of PTX against A375 human melanoma cell line at sub-toxic doses. The results implicate that PTX at sub-toxic doses exhibited an inhibitory effect on the ability of cellular proliferation as shown by MTT and colony formation assay. It impedes migration and also induces apoptosis. A375 cells pretreated with PTX showed decrease in adhesion to both Matrigel and Collagen type IV. Further, Gelatin zymography result reveals that PTX treatment decreases the secretion of MMP2 and MMP9. Finally, PTX significantly inhibited A375 subcutaneous tumour xenograft growth without having any toxicity. Thus PTX at sub-toxic doses affected melanoma metastasis at multiple steps in vitro as well as tumour growth in vivo. These data demonstrate its antimetastatic potential and provide preclinical evidence for the development of PTX as a potential agent against metastatic melanoma. PMID- 23089471 TI - Autophagy induction of reversine on human follicular thyroid cancer cells. AB - The incurable differentiated thyroid cancer (DTC), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are the most aggressive in all of the thyroid cancers. Unfortunately, there are almost no effective therapies. A novel and effective treatment is urgently needed to develop. Recently, reversine, a small synthetic purine analogue, has been reported to be effective in human thyroid cancer suppression through cell cycle arrest and apoptosis induction. In this study, we performed an in vitro evaluation of reversine on autophagy activation, one of the programmed cell death, and the related mechanisms in human follicular thyroid cancer cell line WRO. Incubation of WRO cells with reversine induced autophagosome formation in a short time treatment. LC3-II overexpression in a dosage-dependent manner with reversine treatment was demonstrated in the autophagy activation. Moreover, reversine suppressed Akt/mTOR related signaling pathway activation, a major pathway for autophagy activation, was also revealed in WRO cells. Our data demonstrated that reversine is effective to induce autophagy. Moreover, the LC3-II overexpression and the p62 protein were degraded in a time-dependent manner, indicating that the autophagic flux has happened in the reversine treated WRO cells. In addition, the activation of Akt/mTOR/p70S6K related pathways were shown to be reduced, suggesting these pathways may involve in the reversine mediated autophagy induction. Reversine is therefore worthy of further investigation in clinical therapeutics. PMID- 23089472 TI - Histopathological and immunohistochemical alterations in rat heart after thyroidectomy and the role of hemin and ketoconazole in treatment. AB - The heart is a major target organ for thyroid hormone action and marked changes occur in cardiac function in the case of hypo- or hyperthyroidism. Also, thyroid hormone has a significant regulatory effect on the rate of heme oxidation in the liver. Heme oxygenase (HO) is a heme-catabolizing enzyme that converts heme into biliverdin, iron and carbon monoxide. HO(-1) and its reaction products protect the heart and vasculature in pathological conditions. We studied the changes in the heart structure of thyroidectomized rat at the post-pubertal stage, in addition to the role of hemin as HO inducer and ketoconazole (KTZ) as HO inhibitor in treatment. 35 male Wistar rats were equally divided into seven groups; the first and second groups were the control and Sham-operated groups respectively while the 3rd and 4th groups were subjected to sham operation then treated with hemin (G(3)) and KTZ (G(4)). The 5th group (G(5)) was thyroidectomized group. The 6th and 7th groups were subjected to thyroidectomy then treated with hemin (G(5)) and KTZ (G(6)) respectively. Serum T(3) & TSH levels in thyroidectomized rats were significantly decreased and increased respectively when compared with the control group. Left ventricle section in the heart of thyroidectomized rats showed many of abnormalities as hydrophobic changes of myofibrillar structure with striations, myocardial atrophy and edema, focal haemorrhage when compared with that in control and sham groups. The iNOS label index was significantly decreased in thyroidectomized rat heart (grade 1) and their levels were significantly increased in treated thyroidectomized rats with hemin and KTZ (grades 3 & 2 respectively) when compared with control and sham rat groups (grade 4). Treatment of thyroidectomized rat with hemin improves the histopathological alternation and the intensity of iNOS immunoreactive cells demonstrating the recovery of some injury. PMID- 23089473 TI - STAT3 & Cytochrome P450 2C9: a novel signaling pathway in liver cancer stem cells. AB - Although cancer stem cells (CSCs) are believed to be the key drivers in tumor growth and resistance to therapy, the specific signaling of CSCs is largely unknown. In this study, we evaluated the roles of hypoxia and STAT3 signaling on the treatment resistance of CSCs. Side population (SP) cell analysis and sorting were used to detect subpopulations that function as CSCs. Huh-7 cells, doxorubicin, sulfaphenazole (a CYP2C9 inhibitor), and AG490 (a STAT3 inhibitor) were used in this study. Cell growth and apoptosis were assessed using MTS assays, and apoptotic and kinase signaling pathways were explored by immunoblotting. Treatment with IL-6 induced STAT3 activation more significantly in SP than non-SP cells. Hypoxia induced SP cell proliferation, and microarray analysis showed that the expression of CYP2C9 was significantly increased in hypoxic than normoxic SP cells. Although hypoxic SP cells were less sensitive to doxorubicin-induced apoptosis, pretreatment with sulfaphenazole sensitized hypoxic SP cells to doxorubicin cytotoxicity. These results indicate that STAT3 is critical for CSC survival and hypoxia-inducible CYP2C9 expression is responsible the doxorubicin resistance of CSCs under hypoxic conditions. Thus, the selective inhibition of CYP2C9 and STAT3 may be implicated in the sensitization of CSCs to anti-cancer treatment, particularly in advanced cases. PMID- 23089474 TI - Evaluation of the effects of thalidomide-loaded biodegradable devices in solid Ehrlich tumor. AB - Regarding thalidomide's effects in cancer and the problems related to its physicochemical characteristics and toxic effects, we proposed a new biodegradable polymeric implant to this drug. In this paper, we evaluate the antiangiogenic activity and antitumor effect of thalidomide when incorporated in poly-lactide-co-glycolide (PLGA) implants in an animal model for Ehrlich tumor. This dosage form permits the prolonged drug release. The biodegradable implants could reduce the blood vessel in a chorioallantoic membrane (CAM) model. When applied to the Ehrlich tumor model, implant also showed to reduce the number of vessels. It was also observed to reduce areas of inflammation and increases the area of necrosis in the group of thalidomide implant. A 47% reduction in tumor volume was observed in the thalidomide implant group, which is discussed in relation to literature reported results of thalidomide conventional administration ways. PMID- 23089475 TI - Overexpression of pro-inflammatory genes and down-regulation of SOCS-1 in human PTC and in hypoxic BCPAP cells. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is frequently overexpressed and activated in many cancer types. However, its regulation and function in thyroid carcinomas are only partially known. Aim of our study was to demonstrate that adaptation to the hypoxic micro-environment by human papillary thyroid carcinoma (PTC) cells, in the absence of leukocyte infiltrate, induces a "molecular inflammation" process characterized by the expression of a large set of genes normally involved in inflammation. To address this, tumor, peritumor or normal host tissue from eleven human PTC surgical samples, were separated by laser capture microdissection (LCMD) and studied by real-time quantitative PCR and Western blot. In such condition, we observed an increased expression and activation of HIF-1alpha, NF-kB and pro-inflammatory genes only in tumor tissues. Importantly, an anti-inflammatory gene such as SOCS-1 was markedly down-regulated in tumor tissue compared to surrounding normal host tissue. Similar results were found in fine-needle aspiration biopsy (FNAB)-derived specimens from PTC and in hypoxic human papillary thyroid tumor cell line, BCPAP. Moreover, we also detected an elevated expression of metalloproteinase-9 (MMP9) both in solid tumor and in hypoxic-treated BCPAP cells. Our findings reveal that, in human PTC tumor, hypoxic conditions are accompanied by up-regulation of pro-inflammatory genes, down-regulation of anti-inflammatory genes and increased expression of MMP9. We propose that a better understanding of the pro- and anti-inflammatory pathways involved in the "molecular inflammation" process even in the absence of leukocyte, may help to clarify progression toward malignancy and may prove useful for new anti-tumor strategy. PMID- 23089476 TI - Feeder-free culture of human embryonic stem cell line BG01V/hOG using magnetic field-magnetic nanoparticles system. AB - PURPOSE: Human embryonic stem (hES) cells are useful tools for regenerative medicine. Maintaining hES cells for research and clinical purposes remains a challenge. The hES cells have typically been grown on a mouse or human cell feeder layer, but these methods harbor potential health problems for the recipient. A culture system using magnetic field and iron oxide nanoparticles were previously demonstrated to sustain mouse embryonic stem cells in vitro. Now, by using the BG01v/hOG cell line, we could assess the effect of this culture system on the stemness of an embryonic stem cell of human origin. METHODS: Using a variant hES cell line, BG01V/hOG, expressing an emerald green fluorescent protein (EmGFP), we grown these cells in the presence of serum-free medium supplemented with magnetic nanoparticles functionalized with citrate. The cells were positioned over a circular magnet (4000 Gauss) and monitored daily by fluorescence microscopy. RESULTS: We discovered that hES cells can proliferate when labeled with magnetic nanoparticles and in the presence of a magnetic field without losing pluripotency. CONCLUSION: These results establish an alternative method for maintaining hES cells which would minimize health concerns as well as label cells for subsequent clinical tracking. PMID- 23089477 TI - Morphogenetic events in the perinodal connective tissue in a metastatic cancer model. AB - BACKGROUND: The modifications of connective tissue surrounding metastatic lymph nodes in a murine model of rectal cancer are described. METHODS: Athymic nude mice (n=36) were inoculated with 10*10(5) ht-29 cancer cells into the submucosal layer of the rectum. Control mice (n=5) were treated with a sterile buffer. Tumor and the involved lymph nodes were visualized in vivo by magnetic resonance imaging at 1 to 4 weeks after cell injection. After the sacrifice, the excised samples were processed for histology. RESULTS: After one week from cell injection all treated animals developed rectal cancer. Since the first week, neoplastic cells were visible in the nodes. In the surrounding connective tissue, the diameter of the adipocytes was reduced and a mesenchymal-like pattern with stellate cells embedded in an oedematous environment was visible. Since the second week, in the perinodal connective an enlargement of the stroma was present. The tissue was organized in cords and areas with extracellular accumulation of lipids were found. At the fourth week, we observed an enlargement of multilocular areas and lobules of elongated elements almost devoid of lipid droplets. In control animals, in absence of neoplastic masses, pelvic nodes were surrounded by a typical connective tissue characterized by unilocular adipocytes with groups of multilocular adipocytes. CONCLUSIONS: We have developed a model of rectal cancer with nodal metastases. Using this model, the work demonstrates that around secondary lesions, the morphogenetic events follow a standard evolution characterized by an early phase with lipolysis and mesenchymalization and later phases with a brown-like phenotype acquisition. PMID- 23089478 TI - Biophysical and molecular docking studies of naphthoquinone derivatives on the ATPase domain of human topoisomerase II. AB - Numerous naphthoquinone derivatives, such as rhinacanthins function as anticancer drugs, which target hTopoII. The structure of hTopoII contains both an ATPase domain and a DNA binding domain. Several drugs bind to either one or both of these domains, thus modifying the activity of hTopoII. The naphthoquinone esters and amides used in this study showed that their hTopoIIalpha inhibitory activity was inversely proportional to ATP concentration. In order to better characterize the inhibitory action of these compounds, sufficient quantities of soluble functional hTopoII-ATPase domain were required. Therefore, both the alpha and beta isoforms of the hTopoII-ATPase domain were over-expressed in Escherichia coli. The hTopoIIalpha-ATPase activity was reduced in the presence of naphthoquinone derivatives. Additionally, a molecular docking study revealed that the selected naphthoquinone ester and amide bind to the ATP-binding domain of hTopoIIalpha. Collectively, the results here provide for the first time a novel insight into the interaction between naphthoquinone esters and amides, and the ATP-binding domain of hTopoIIalpha. The further elucidation of the mechanism of action of the naphthoquinone esters and amides inhibitory activity is essential. PMID- 23089479 TI - Proliferation and differentiation of osteoblastic cells on silicon-doped TiO(2) film deposited by cathodic arc. AB - This study aimed at the proliferation and differentiation of osteoblastic cells on silicon-doped TiO(2) and pure TiO(2) films prepared by cathodic arc deposition. The films were examined by X-ray photo-electron spectroscopy, which showed that silicon was successfully doped into the Si-TiO(2) film. Meanwhile, no significant difference was found between the surface morphology of silicon-doped TiO(2) and pure TiO(2) films. When osteoblastic cells were cultured on silicon doped TiO(2) film, accelerated cell proliferation was observed. Furthermore, cell differentiation was evaluated using alkaline phosphatase (ALP), type I collagen (COL I) and osteocalcin (OC) as differentiation markers. It was found that ALP activity, the expression levels of OC gene, COL I gene and protein were up regulated on silicon-doped TiO(2) film at 3 and 5 days of culture. Moreover, no significant difference was found in apoptosis between the cells cultured on silicon-doped TiO(2) and pure TiO(2) films. Therefore, findings from this study indicate that silicon-doped film favors osteoblastic proliferation and differentiation, and has the potential for surface modification of implants in the future. PMID- 23089480 TI - Proteasome inhibitor bortezomi-induced the apoptosis of laryngeal squamous cell carcinoma Hep-2 cell line via disrupting redox equilibrium. AB - Bortezomib, a proteasome inhibitor, has been therapeutic effects in some solid tumors. In the present work, the effects of bortezomib on laryngeal squamous cell carcinoma Hep-2 cell line was investigated and the role of redox equilibrium was explored. The results showed that bortezomib decreased the cell viability and increased the apoptosis in Hep-2 cells. In addition, bortezomib overproduced reactive oxygen species (ROS) and induced the loss of mitochondrial membrane potential (DeltaPsi(m)). And the activity of caspase-3 increased. N-acetyl-L cysteine (L-NAC), a ROS scavenger, alleviated oxidative stress and inhibited the apoptosis induced by bortezomib. However, buthionine sulfoximine (BSO), an inhibitor of GSH synthetase, aggravated bortezomib-induced oxidative stress and apoptosis. So bortezomi-induced the apoptosis of Hep-2 cells via disrupting redox equilibrium. PMID- 23089481 TI - Characterization of activin A in the culture of primitive human umbilical cord blood hematopoietic cells. AB - Transforming growth factor-beta (TGF-beta) superfamily controls many physiological processes such as cell proliferation and differentiation, immune responses, wound repair and various endocrine activities. As a member of TGF beta, activin A can maintain the pluripotency of embryonic stem cells. We report here that activin A exhibited cell type-dependent function of expanding the human primitive hematopoietic cells isolated from umbilical cord blood (UCB). However, the multipotency of the cells pretreated with activin A was exhausted in the sequential dilution culture. In conclusion, activin A may not be a key factor, but a regulator, in the multipotency maintenance of primitive hematopoietic cells and the application of activin A in the hematopoietic stem/progenitor cells (HS/PCs) culture expansion remains a significant challenge. PMID- 23089482 TI - Letter to the editor: smoking and mental health in young women - challenges in interpretation. PMID- 23089483 TI - Protection of piglets against enteric colibacillosis by intranasal immunization with K88ac (F4ac) fimbriae and heat labile enterotoxin of Escherichia coli. AB - Enterotoxigenic Escherichia coli (ETEC) is an important diarrheal agent of young domestic animals. Currently, there are no commercially available non-living vaccines to protect weaned pigs from the disease and no major veterinary biologics company markets a postweaning ETEC vaccine of any kind. While efforts have been made to develop a non-living postweaning ETEC vaccine for pigs, studies have been limited to the assessment of immune responses to experimental immunogens. In the present study, we describe a reproducible gnotobiotic piglet model of post-weaning ETEC diarrhea and efficacy tests in that model of subunit vaccines consisting of K88 (F4) fimbriae and/or heat labile enterotoxin (LT) delivered by the intranasal route. We also report antibody responses to the vaccine antigens. Piglets vaccinated with both antigens mounted a substantial immune response with serum and cecal antibody titers to K88 antigen significantly greater than those of controls. Serum anti-LT antibody titers were also significantly greater than those of controls. Piglets vaccinated with both antigens remained healthy following challenge with ETEC. At least some pigs vaccinated with either antigen alone, and most of the control piglets developed dehydrating diarrhea and suffered significant weight loss. The results of this study suggest that an intranasal vaccine consisting of both antigens is highly protective against a vigorous experimental challenge of pigs with K88+ ETEC, while that against either antigen alone is not. The current study provides a system whereby various ETEC antigens and/or combinations of antigens can be tested in exploring strategies for the development of vaccines for ETEC. PMID- 23089484 TI - The role of research on the development and implementation of policy. PMID- 23089485 TI - A systematic review of contextual factors relating to smokeless tobacco use among South Asian users in England. AB - INTRODUCTION: Certain types of smokeless tobacco (ST) are popular among some people of South Asian origin in England; however, little is known about the contextual factors surrounding use in this population. This systematic review explores the factors associated with ST use among people of South Asian origin in England. METHODS: An iterative search strategy in targeted databases and grey literature sources was conducted in the summer of 2011. Data extractions and quality assessments were completed and verified by two reviewers, and results were presented as a narrative. RESULTS: A total of 2,968 references were screened by two reviewers who agreed on the inclusion of 14 studies. ST use is more prevalent among older participants who may have started chewing in India; however, the evidence suggests that some younger English-born South Asians are using ST as well. Reasons for chewing included the use of these products in times of stress, boredom or simply to relax. Traditional health messages and prior held beliefs may lead them to chew these products because of misconceptions about their health benefits, since very few people were aware of the health risks. Many expressed a desire to quit, however found it difficult to go without ST. CONCLUSION: This review examines the complex factors that underpin and influence ST use among South Asians in England with the potential of informing targeted interventions and health policy. PMID- 23089487 TI - NNAL exposure by race and menthol cigarette use among U.S. smokers. AB - INTRODUCTION: Researchers have recently suggested that nicotine and carcinogen exposure as measured by biomarkers such as cotinine and NNAL (4 (methylnitrosamino)-1-(3-pyridyl)-1-butanol) does not vary with cigarettes smoked per day (CPD) among Black smokers. Researchers have also suggested that nicotine exposure does not differ between menthol and nonmenthol smokers. In this study, we examine NNAL exposure for U.S. smokers by race, CPD, and menthol cigarette use. METHODS: We analyzed urinary NNAL concentrations for more than 1500 everyday smokers participating in the National Health and Nutrition Examination Survey from 2007-2010. For purposes of comparison, we also analyzed serum cotinine concentrations for these smokers. We used linear regression analysis to estimate mean biomarker concentrations by CPD and race/ethnicity group and to examine the association between biomarker concentrations and menthol cigarette use by race/ethnicity group, controlling for other demographic and smoking characteristics. RESULTS: Biomarker concentrations increased with CPD for White, Black, and Hispanic smokers although NNAL concentrations leveled off for Black smokers at lower CPD levels compared with other smokers. Mean NNAL concentrations were lower among menthol smokers compared with nonmenthol smokers among smokers overall (beta = -0.165, p = .032) and White smokers (beta = -0.207, p = .048). CONCLUSIONS: We find evidence in national health survey data that nicotine and carcinogen exposure generally increases with CPD across race/ethnicity groups although the pattern of NNAL exposure differs by race/ethnicity group at high CPD levels. We also find evidence of differences in NNAL exposure for menthol smokers compared with nonmenthol smokers among smokers overall and White smokers. PMID- 23089486 TI - Readiness to quit smoking and quit attempts among Australian mental health inpatients. AB - INTRODUCTION: Mental health inpatients smoke at higher rates than general population smokers. However, provision of nicotine-dependence treatment in inpatient settings is low, with barriers to the provision of such care including staff views that patients do not want to quit. This paper reports the findings of a survey of mental health inpatients at a psychiatric hospital in New South Wales, Australia, assessing smoking and quitting motivations and behaviors. METHODS: Smokers (n = 97) were surveyed within the inpatient setting using a structured survey tool, incorporating the Fagerstrom Test for Nicotine Dependence, Reasons for Quitting Scale, Readiness and Motivation to Quit Smoking Questionnaire, and other measures of smoking and quitting behavior. RESULTS: Approximately 47% of smokers reported having made at least one quit attempt within the past 12 months, despite nearly three quarters (71.2%) being classified as in a "precontemplative" stage of change. Multinomial logistic regressions revealed that self-reporting "not enjoying being a smoker" and having made a quit attempt in the last 12 months predicted having advanced beyond a precontemplative stage of change. A high self-reported desire to quit predicted a quit attempt having been made in the last 12 months. CONCLUSIONS: The majority of smokers had made several quit attempts, with a large percentage occurring recently, suggesting that the actual quitting behavior should be considered as an important indication of the "desire to quit." This paper provides further data supporting the assertion that multimodal smoking cessation interventions combining psychosocial and pharmacological support should be provided to psychiatric inpatients who smoke. PMID- 23089488 TI - Diagnosis, treatment, and long-term outcomes of fetal hydrocephalus. AB - This study analyzed 156 cases of fetal hydrocephalus treated at Osaka National Hospital from 1992 to 2011 to review current methods for diagnosing and treating fetal hydrocephalus, and for estimating its clinical outcome. This was a retrospective study of a single institute (Osaka National Hospital). Of 156 cases in total, 37% were diagnosed as isolated ventriculomegaly, 50% as another type of malformation (36 cases of myelomeningocele, six of holoprosencephaly, three of Dandy-Walker syndrome, one case of Joubert syndrome, 12 of arachnoid cyst, nine of encephalocele, three of atresia of Monro and eight of corpus callosum agenesis, and 13% as secondary hydrocephalus. Diagnoses were made between 13 and 40 weeks of gestation (average 27 weeks). Diagnosis was made before 21 weeks of gestation in 24% of cases, from the first day of 22 weeks to the sixth day of 27 weeks in 27%, and after the first day of 28 weeks in 49%. With the exclusion of 17 aborted cases and 40 cases in which the patients were too young to evaluate or lost during follow-up, the final outcome was analyzed for 90 cases. Of these, 17% of the patients died, 21% showed severe retardation, 13% moderate retardation, 26% mild retardation, and 23% showed a good outcome. The long-term outcome was mostly influenced by the basic disease and accompanying anomaly. The time of diagnosis showed no correlation with outcome. Hydrocephalus associated with arachnoid cyst, atresia of Monro, and corpus callosum agenesis, and hydrocephalus due to fetal intracranial hemorrhage, resulted in good outcomes. By contrast, holoprosencephaly, hydrocephalus associated with encephalocele, syndromic hydrocephalus, and hydrocephalus due to fetal virus infection led to poor outcomes. For accurate diagnosis and proper counseling, established protocols are important for the diagnosis and treatment of fetal hydrocephalus, including not only fetal sonography, fetal magnetic resonance imaging, and TORCH (toxoplasma, rubella, cytomegalovirus, herpes simplex) screening test, but also chromosomal and gene testing. PMID- 23089489 TI - Detection of the BRAF V600E mutation in serous ovarian tumors: a comparative analysis of immunohistochemistry with a mutation-specific monoclonal antibody and allele-specific PCR. AB - Mutations of components of the mitogen-activated protein kinase pathway, mainly BRAF, are common in serous ovarian borderline tumors, whereas high-grade serous ovarian carcinomas rarely show this feature. With the advent of specific kinase inhibitors active against BRAF-mutated cancers, rapid and sensitive detection of the BRAF V600E, by far the most common mutation of this gene, is of great practical relevance. Currently, BRAF mutations are detected by DNA-based techniques. Recently, a monoclonal antibody (VE1) specific for the BRAF V600E protein suitable for archival tissues has been described. In this study, we compared detection of the V600E mutation in serous ovarian tumors by VE1 immunostaining and by allele-specific polymerase chain reaction. All 141 cases of high-grade serous ovarian cancer showed negative or rarely weak, diffuse background VE1 immunostaining, and BRAF wild type was confirmed by molecular analysis in all tested cases. In contrast, 1 (14%) of 7 low-grade serous carcinomas and 22 (71%) of 31 serous borderline tumors revealed moderate to strong VE1 positivity. Immunostaining was clearly evaluable in all cases with sufficient tumor cells, and only rare cases with narrow cytoplasm were difficult to interpret. The V600E mutation was confirmed by allele-specific polymerase chain reaction and sequencing in all VE1-positive cases. Two VE1-positive cases with low epithelial cell content required repeat microdissection to confirm the presence of the mutation. Immunohistochemistry with the VE1 antibody is a specific and sensitive tool for detection of the BRAF V600E mutation in serous ovarian tumors and may provide a practical screening test, especially in tumor samples with low epithelial content. PMID- 23089490 TI - Synchronous ductal carcinoma in situ of the breast and within epithelial inclusions in an ipsilateral sentinel lymph node. AB - Epithelial inclusions in the axillary lymph nodes are very rare and have even less commonly been reported with either benign or malignant changes. We present a case of synchronous high-grade micropapillary ductal carcinoma in situ arising in the breast and in an epithelial inclusion in an ipsilateral sentinel lymph node. Despite extensive sampling, no focus of invasive carcinoma was identified. This unique case highlights the difficulty in diagnosis of metastatic disease when there is a malignant change in an epithelial inclusion in a sentinel lymph node and highlights the need for very careful histologic assessment of such lesions. PMID- 23089491 TI - Deceptively benign low-grade fibromyxoid sarcoma: array-comparative genomic hybridization decodes the diagnosis. AB - Low-grade fibromyxoid sarcoma (previously known as Evans tumor) is a rare soft tissue neoplasm characterized by a deceptively bland appearance despite the potential for late metastasis or recurrence. We describe a 13-year-old patient with a popliteal fossa mass initially thought to be benign that, because of array comparative genomic hybridization findings and subsequent immunohistochemistry, was diagnosed as low-grade fibromyxoid sarcoma. The array-comparative genomic hybridization demonstrated a loss of 11p11.2p15.5 and a gain of 16p11.2p13.3 with breakpoints involving the CREB3L1 (cAMP responsive element-binding protein 3-like 1) and FUS (fused in sarcoma) genes, respectively. Subsequent fluorescence in situ hybridization analysis of a dual-labeled break-apart FUS probe on interphase cells was positive. Our case highlights the importance of using genetic information obtained via array-comparative genomic hybridization to classify accurately pediatric soft tissue tumors. PMID- 23089492 TI - Preferential up-regulation of osteopontin in primary central nervous system lymphoma does not correlate with putative receptor CD44v6 or CD44H expression. AB - Osteopontin (SPP1) is reportedly the most up-regulated gene in primary central nervous system lymphoma (PCNSL). Our objective was to confirm immunoexpression of osteopontin and determine if CD44v6 and CD44H played a significant role as receptors for osteopontin in PCNSL. Twenty PCNSL, 12 nodal diffuse large B-cell lymphoma (N-DLBCL), and 17 extra-nodal DLBCL (EN-DLBCL) archival pathology cases were examined. Osteopontin nuclear positivity was observed in 20 (100%) of 20 PCNSL cases, 16 (95 %) of 17 EN-DLBCL, and 3 of 12 (25%) N-DLBCL. The immunohistochemical score of osteopontin in PCNSL (7.0 +/- 3.5) and EN-DLBCL (4.4 +/- 4.1) was significantly higher than N-DLBCL (0.3 +/- 0.6). Sixteen cases were positive for CD44v6 (33%), including 6 PCNSL, and 5 each EN-DLBCL and N-DLBCL; no statistical difference was observed. CD44H was positive in all cases except one PCNSL but without any significant differences across the 3 groups. CD44H expression was significantly higher in non-germinal center B-cell (GCB) (score 12 +/- 1.5) as compared to the GCB group (9.5 +/- 3.1), and in non-GCB PCNSL (7.9 +/ 4.2) as compared to non-GCB non-CNS lymphoma (2.8 +/- 4.0) (P = .009); the differences were insignificant for osteopontin and CD44v6. Neither CD44H nor CD44v6 scores correlated with the osteopontin expression score or Ki-67 index. Osteopontin immunoexpression was highest in PCNSL, suggesting its probable role in its pathogenesis. However, its lack of correlation with CD44v6 excludes the latter as the likely osteopontin receptor in PCNSL. The significantly higher CD44H expression in the non-GCB than GCB group may contribute to the aggressiveness of the non-GCB DLBCL. Further studies are needed to elucidate the pathway and the prognostic/predictive role of osteopontin in PCNSL. PMID- 23089493 TI - Microsatellite pathologic score does not efficiently identify high microsatellite instability in colorectal serrated adenocarcinoma. AB - The microsatellite pathologic score has been proposed as a valuable tool to estimate the probability of a colorectal cancer having high microsatellite instability; however, this score has not been tested in serrated adenocarcinoma. Our aim was to evaluate microsatellite pathologic score in serrated adenocarcinoma, conventional carcinoma, and colorectal cancer with high microsatellite instability histologic features. Eighty-nine serrated adenocarcinoma and 81 matched conventional carcinomas were tested with microsatellite pathologic score, and the results were compared with those of 24 high microsatellite instability histologic features. Validation was performed by microsatellite instability analysis. Although all colorectal cancers with high microsatellite instability histologic features rendered a more than 5.5 score, the microsatellite pathologic score performance was of lower rank in high microsatellite instability serrated adenocarcinoma because none of the cases scored above 5.5 (>77% probability of being high microsatellite instability). High microsatellite instability serrated adenocarcinoma shows pathologic features different from those observed in high microsatellite instability histologic features such as adverse prognostic histologic features at the invasive front. We describe a serrated adenocarcinoma subtype showing high microsatellite instability and some, but not all, high microsatellite instability histologic features that would not be detected if the microsatellite pathologic score cutoff is set at the highest rank. To increase microsatellite pathologic score sensitivity in serrated adenocarcinoma, we propose to set up a 2.1 cutoff score when faced by a right-sided colorectal cancer with serrated features. PMID- 23089494 TI - Establishment of a rapid and scalable gene expression system in livestock by site specific integration. AB - Somatic cell-mediated transgenesis is routinely used to transfer exogenous genes to livestock genomes. However, transgene insertion events are essentially random which may lead to transgene silencing or alter animal phenotype because of insertional mutagenesis. To overcome these problems, we established a gene manipulation system in goat somatic cells based on homologous recombination and flp recombinase-mediated site-specific integration. First, we performed gene targeting to introduce an frt-docking site into the alpha1 (I) procollagen (ColA1) locus in goat somatic cells. Second, the targeted cell clones were rejuvenated by embryo cloning, and the vigorous cells with targeted frt were reestablished. Third, a gene-replacement system was used to introduce an EGFP reporter gene into the targeted ColA1 locus via flp mediated recombination. As a result, the transgenic somatic cell exhibited faithful expression of EGFP gene under control of the CMV promoter. Similarly, other expression vectors can be introduced into the defined site to evaluate gene functions or express valuable proteins. The gene manipulation system described here will be applicable in other livestock somatic cells, and would allow for the rapid generation of livestock with transgene targeted to the defined site. PMID- 23089495 TI - Characterization of TsMRP-L28, a mitochondrial ribosomal protein L28 from the parasitic nematode Trichinella spiralis. AB - A cDNA encoding mitochondrial ribosomal protein (MRP)-L28 was isolated and cloned from Trichinella spiralis, an economically important parasitic nematode. The predicted TsMRP-L28 protein consists of 276 amino acids. Phylogenetic analysis revealed that TsMRP-L28 was closely related to Caenorhabditis elegans mitochondrial ribosomal protein L28. The TsMRP-L28 transcript was expressed in newborn larvae, muscle larvae and male and female adult worms. Western blot showed that TsMRP-L28 was expressed in muscle larvae and adult worms. Immuno localization revealed that TsMRP-L28 was ubiquitously distributed in newborn larvae, muscle larvae and adult worms, and that TsMRP-L28 was enriched in cells with higher protein synthesis activity, such as in newborn larvae and the cytoplasm of different developmental stages of embryos. These data suggest that TsMRP-L28 is required for the early development of T. spiralis. PMID- 23089496 TI - The pathophysiology of perioperative lung injury. AB - The degree of perioperative lung injury that patients sustain results from a complex interaction between their current physiologic state, comorbidities, lifestyle choices, underlying surgical diagnosis, operative, and ultimately their cardiopulmonary interaction with a mechanical ventilator. This review addresses primarily the pathophysiology of perioperative lung injury with reference to ventilator-induced lung injury and acute respiratory distress syndrome. PMID- 23089497 TI - Perioperative oxygen toxicity. AB - This article challenges the use of hyperoxia in the perioperative period. It describes the biochemical and physiologic basis for both the direct and indirect adverse effects of oxygen. The reasons for using hyperoxia in the perioperative period are critically evaluated, and the evidence and guidelines for oxygen use in common acute medical conditions are reviewed. PMID- 23089498 TI - Perioperative lung protection strategies in cardiothoracic anesthesia: are they useful? AB - Patients are at risk for several types of lung injury in the perioperative period. These injuries include atelectasis, pneumonia, pneumothorax, bronchopleural fistula, acute lung injury, and acute respiratory distress syndrome. Anesthetic management can cause, exacerbate, or ameliorate most of these injuries. Lung-protective ventilation strategies using more physiologic tidal volumes and appropriate levels of positive end-expiratory pressure can decrease the extent of this injury. This review discusses the effects of mechanical ventilation and its role in ventilator-induced lung injury with specific reference to cardiothoracic anesthesia. PMID- 23089499 TI - Advances in therapy for acute lung injury. AB - Despite advances in the therapy for acute lung injury and adult respiratory distress syndrome, mortality remains high. The iatrogenic risk of ventilator induced lung injury might contribute to this high mortality because the lungs are hyperinflated. Low tidal volume and inspiratory pressure are surrogates for the stress and strain concept; but lung compliance, transpulmonary pressure, and chest wall elastance might differ in individual patients. In previous published studies, an increasing number of patients were treated successfully with extracorporeal support. Extracorporeal membrane oxygenation and interventional lung assist allow ultraprotective ventilation strategies. However, these assists have different technical aspects and different indications. PMID- 23089500 TI - Fluid management in thoracic surgery. AB - Better understanding of the pathophysiology of acute lung injury (ALI) and the hazards inherent to extremes in volume status has led efforts toward goal directed, individualized therapies designed to achieve optimal hemodynamic status. The role for colloids both as a volume expander and potential protective agent against ALI is receiving revived interest. The evidence for the impact of fluid therapy is encouraging and supports the undertaking of properly designed perioperative fluid trials in thoracic surgeries. Such work offers hope that optimal fluid strategies can be defined and reduce the adverse events that have affected patients having lung resection. PMID- 23089501 TI - Transesophageal echocardiography in noncardiac thoracic surgery. AB - In high-risk surgeries with medically complicated patients, transesophageal echocardiography (TEE) adds an additional level of monitoring with which few can disagree. This article presents multiple applications of TEE that can assist both the anesthesiologist and the surgeon through major noncardiac thoracic surgery. It highlights how TEE can be used as an adjuvant to lung resection surgery; TEE as a monitor during lung transplantation; TEE to assess patients for extracorporeal membrane oxygenation; TEE for thoracic aortic surgery; and TEE in the assessment of patients with acute pulmonary hypertension undergoing noncardiac thoracic surgery. PMID- 23089502 TI - How to choose the double-lumen tube size and side: the eternal debate. AB - Although disposable double-lumen tubes have been used for many years, there is still controversy regarding what size and which side to use for thoracic procedures requiring lung isolation. Thoracic and nonthoracic anesthesiologists often debate performance, efficiency, and outcome of small and large double-lumen tubes, and left- and right-sided tubes. This article focuses on current data in the literature and expert opinion on the topic. PMID- 23089503 TI - Managing hypoxemia during minimally invasive thoracic surgery. AB - An ever-increasing number of thoracic procedures are being performed through minimally invasive techniques. Although the incidence of hypoxemia during one lung ventilation (OLV) has decreased over the years, it remains an issue in roughly 10% of cases. Algorithms for the management of OLV hypoxemia have to be adapted to the thoracoscopic approach, in particular the need for optimal surgical exposure. With appropriate planning and caution, most of the treatment modalities for OLV hypoxemia can be applied to the thoracoscopy setting, with some modifications. PMID- 23089504 TI - Advancements in robotic-assisted thoracic surgery. AB - Advancements in robotic-assisted thoracic surgery present potential advantages for patients as well as new challenges for the anesthesia and surgery teams. This article describes the major aspects of the surgical approach for the most commonly performed robotic-assisted thoracic surgical procedures as well as the pertinent preoperative, intraoperative, and postoperative anesthetic concerns. PMID- 23089505 TI - Anesthesia for tracheal resection and reconstruction. AB - Tracheal resection and reconstruction (TRR) is the treatment of choice for most patients with tracheal stenosis or tracheal tumors. Anesthesia for TRR offers distinct challenges, especially for the less experienced practitioner. This article explores the preoperative assessment, strategies for induction and emergence from anesthesia, the essential coordination between the surgical and anesthesia teams during airway excision and anastomosis, and postoperative care. The most common complications are reviewed. Targeted readership is practitioners with less extensive experience in managing airway surgery cases. As such, the article focuses first on the most common proximal tracheal resection. Final sections discuss specific considerations for more complicated cases. PMID- 23089506 TI - Anesthetic management for esophageal resection. AB - Surgical resection remains a standard treatment option for localized esophageal cancer. Surgical approaches to esophagectomy include transhiatal and transthoracic techniques as well as minimally invasive techniques that have been developed to reduce the morbidities associated with laparotomy and thoracotomy incisions. The perioperative mortality for esophagectomy remains high with cardiopulmonary and anastomotic complications as the most frequent and serious morbidities. This article reviews the management of patients presenting for esophagectomy, with a focus on evidence-based anesthetic and perioperative approaches for improving outcomes. PMID- 23089507 TI - Perioperative management of the pregnant patient with an anterior mediastinal mass. AB - This article describes the perioperative risks of pregnant patients with anterior mediastinal masses, and demonstrates the importance of a multidisciplinary approach for the management of high-risk patients. Mediastinal mass syndrome is defined as immediate right heart failure secondary to vascular compression when positive pressure ventilation is initiated. Greater emphasis on the potential for cardiovascular collapse (versus respiratory collapse) challenges the conventional teaching of risks associated with mediastinal masses in the adult population. PMID- 23089509 TI - Thoracic Anesthesia. Foreword. PMID- 23089510 TI - Thoracic anesthesia. Preface. PMID- 23089508 TI - Pulmonary pathophysiology and lung mechanics in anesthesiology: a case-based overview. AB - Anesthesia, surgical requirements, and patients' unique pathophysiology all combine to make the accumulated knowledge of respiratory physiology and lung mechanics vital in patient management. This article take a case-based approach to discuss how the complex interactions between anesthesia, surgery, and patient disease affect patient care with respect to pulmonary pathophysiology and clinical decision making. Two disparate scenarios are examined: a patient with chronic obstructive pulmonary disease undergoing a lung resection, and a patient with coronary artery disease undergoing cardiopulmonary bypass. The impacts of important concepts in pulmonary physiology and respiratory mechanics on clinical management decisions are discussed. PMID- 23089511 TI - Relationship of copeptin, a surrogate marker for arginine vasopressin, with change in total kidney volume and GFR decline in autosomal dominant polycystic kidney disease: results from the CRISP cohort. AB - BACKGROUND: Experimental studies indicate that arginine vasopressin (AVP) may have deleterious effects in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). However, the significance of AVP in human ADPKD is unclear. STUDY DESIGN: Longitudinal observational study with 8.5 (IQR, 7.7-9.0) years' follow-up (CRISP [Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease]). SETTING & PARTICIPANTS: 241 patients with ADPKD with creatinine clearance >70 mL/min. PREDICTOR: Plasma copeptin concentration, a surrogate marker for AVP. OUTCOMES: Change in measured glomerular filtration rate (mGFR, assessed by iothalamate clearance) and total kidney volume (measured by magnetic resonance imaging). MEASUREMENTS: Baseline copeptin level, plasma and urinary osmolality, and measurements of total kidney volume and mGFR during follow-up. RESULTS: In these patients (median age, 34 [IQR, 25-40] years; 38% men; median mGFR, 94 [IQR, 79-145] mL/min/1.73 m(2); median total kidney volume, 859 [IQR, 577-1,299] mL), median copeptin level was 2.9 (IQR, 1.8-5.1) pmol/L. Copeptin was not associated with plasma osmolality (P = 0.3), the physiologic stimulus for AVP release, but was associated significantly with change in total kidney volume during follow-up (P < 0.001). This association remained significant after adjusting for sex, age, cardiovascular risk factors, and diuretic use (P = 0.03). Copeptin level was associated borderline significantly with change in mGFR after adjusting for these variables (P = 0.09). LIMITATIONS: No standardization of hydration status at time of copeptin measurement. CONCLUSIONS: These data show that in ADPKD, copeptin level, as a marker for AVP, is not correlated with plasma osmolality. Most importantly, high copeptin levels are associated independently with disease progression in early ADPKD. This is in line with experimental studies that indicate a disease-promoting role for AVP. PMID- 23089513 TI - Headspace-multicapillary column-ion mobility spectrometry for the direct analysis of 2,4,6-trichloroanisole in wine and cork samples. AB - Headspace-multicapillary column-ion mobility spectrometry coupling has been evaluated for the direct analysis of wine and cork stopper samples for the determination of 2,4,6-trichloroanisole (2,4,6-TCA). The instrumental configuration permits the sample to be introduced in headspace vials which are placed into the autosampler oven in order to facilitate the transference of the volatile compounds from the sample to its headspace. Further, an aliquot of 200 MUL of the homogenized gaseous phase is injected into the multicapillary column in order to separate the target compounds from potential interferents. The detection of 2,4,6-TCA was carried out in an ion mobility spectrometer with a radioactive source and working under negative mode. All the system was computer controlled, including data acquisition and treatment. The limits of detection achieved were 0.012 ng L(-1) for wine and 0.28 ng g(-1) for the cork stopper. The procedure was applied to the analysis of commercial wine samples in different packages and 2,4,6-TCA was found in all of those closed with a cork stopper. The excellent recovery values obtained testify for the goodness of the method as no interference from the sample matrix exits. PMID- 23089512 TI - Effectiveness of educational and social worker interventions to activate patients' discussion and pursuit of preemptive living donor kidney transplantation: a randomized controlled trial. AB - BACKGROUND: Many patients with chronic kidney disease (CKD) have difficulty becoming actively engaged in the pursuit of preemptive living donor kidney transplantation. STUDY DESIGN: The Talking About Live Kidney Donation (TALK) Study was a randomized controlled trial of the effectiveness of educational and social worker interventions designed to encourage early discussions and active pursuit of preemptive living donor kidney transplantation in patients with progressive CKD. SETTING & PARTICIPANTS: We recruited participants with progressive CKD from academically affiliated nephrology practices in Baltimore, MD. INTERVENTION: Participants randomly received: (1) usual care (routine care with their nephrologists), the (2) TALK education intervention (video and booklet), or the (3) TALK social worker intervention (video and booklet plus patient and family social worker visits). OUTCOMES: We followed participants for 6 months to assess their self-reported achievement of behaviors reflecting their discussions about and/or pursuit of living donor kidney transplantation (discussions with family, discussions with physicians, initiating recipient evaluation, completing recipient evaluation, and identifying a potential living donor). MEASUREMENTS: We assessed outcomes through a questionnaire at 1-, 3-, and 6-months follow-up. RESULTS: Participants receiving usual care with their nephrologists (n = 44), TALK education (n = 43), and the TALK social worker (n = 43) were similar at baseline. TALK Study interventions improved participants' living donor kidney transplantation discussion and pursuit behaviors, with the social worker leading to greater patient activation (participants' predicted probability of achieving living donor kidney transplantation discussions, evaluations, or donor identification over 6 months): probabilities were 30% (95% CI, 20%-46%), 42% (95% CI, 33%-54%), and 58% (95% CI, 41%-83%), respectively, in the usual care, TALK education, and TALK social worker groups (P = 0.03). LIMITATIONS: Our population was well educated and mostly insured, potentially limiting generalizability of our findings. CONCLUSIONS: TALK interventions improved discussion and active pursuit of living donor kidney transplantation in patients with progressive CKD and may improve their use of preemptive living donor kidney transplantation. PMID- 23089514 TI - Gut and microbial resveratrol metabolite profiling after moderate long-term consumption of red wine versus dealcoholized red wine in humans by an optimized ultra-high-pressure liquid chromatography tandem mass spectrometry method. AB - Resveratrol exerts a variety of biological and pharmacological activities, which are observed despite its extremely low bioavailability and rapid clearance from the circulation due to extensive sulfation and glucuronidation in the intestine and liver. In order to more accurately quantify all known resveratrol metabolites, a sensitive and optimized analytical assay was developed and validated by pure standards. Methodology improvements aimed to the chromatographic detection of disulfates and sulfoglucuronides, improving resolution of sulfates, by using a buffered solution, with recovery values of resveratrol and its metabolites, even of sulfates, of 99%. The adapted methodology was then applied to a clinical study with high cardiovascular risk subjects, after the moderate consumption of red wine (RW) or dealcoholized red wine (DRW) for 28 days. Up to 21 resveratrol metabolites, including those formed by gut and microbial metabolism, were identified in 24-h urine samples. Interestingly, after long-term consumption of RW and DRW, resveratrol metabolite concentration significantly increased in urine with no differences between the two interventions, indicating that bioavailability and biotransformation of resveratrol is not affected by the alcoholic matrix of wine. In summary, we established a sensitive analytical assay for the quantification of a wide resveratrol metabolic profile in human urine, also regarding gut microbial derived metabolites, which may also be applied to blood and tissue samples. The resveratrol metabolic pattern might therefore act as an excellent marker for the efficacy of resveratrol in clinical and epidemiological studies for the study of the beneficial effects of grape product consumption. In this sense, having a more precise concentration value of all the resveratrol metabolites in target tissues would finally lead to a better interpretation of the obtained results. PMID- 23089515 TI - Compounds for expanding the descriptor space for characterizing separation systems. AB - A combination of gas chromatography and liquid-liquid partitions in totally organic biphasic systems is used to determine descriptor values for compounds of low volatility suitable for characterizing open tubular columns at high temperatures. The descriptor database of varied compounds includes several difficult to determine by conventional techniques due to their low water solubility or stability. The descriptor database facilitates an expansion of the descriptor space and compound variation for characterizing separation systems. As an application the descriptor database is used to determine the system constants for SPB-Octyl, HP-5, Rxi-5Sil MS, Rtx-440, and Rtx-OPP for the temperature range 200-300 degrees C. As an example of the broader affect of temperature on column selectivity the variation of the system constants for Rtx-440 over the temperature range 60-300 degrees C is described in detail. These studies demonstrate the persistence of polar interactions to the highest temperature studied and that at high temperatures selectivity differences persist for moderately polar stationary phases. PMID- 23089516 TI - Chiral analysis of metoprolol and two of its metabolites, alpha-hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry. AB - A LC-MS/MS method for the chiral separation of metoprolol and two of its main metabolites, alpha-hydroxymetoprolol (alpha-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and alpha-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were >= 73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of alpha-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of alpha-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of alpha-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors' knowledge, the first time the stereoisomers of alpha OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC-MS/MS methods were validated in wastewater samples. PMID- 23089517 TI - Hollow fiber-based liquid-liquid-liquid micro-extraction with osmosis: II. Application to quantification of endogenous gibberellins in rice plant. AB - The phenomenon and benefits of osmosis in hollow fiber-based liquid-liquid-liquid micro-extraction (HF-LLLME) were theoretically discussed in part I of this study. In this work, HF-LLLME with osmosis was coupled with high performance liquid chromatography-triple quadrupole mass spectrometry (HPLC-triple quadrupole MS/MS) to analyze eight gibberellins (gibberellin A(1), gibberellin A(3), gibberellin A(4), gibberellin A(7), gibberellin A(8), gibberellin A(9), gibberellin A(19) and gibberellin A(20)) in rice plant samples. According to the theory of HF-LLLME with osmosis, single factor experiments, orthogonal design experiments and mass transfer simulation of extraction process were carried out to select the optimal conditions. Cyclohexanol - n-octanol (1:3, v/v) was selected as organic membrane. Donor phase of 12 mL was adjusted to pH 2 and 20% NaCl (w/v) was added. Acceptor phase with an initial volume of 20 MUL was the solution of 0.12 mol L(-1) Na(2)CO(3)-NaHCO(3) buffer (pH 9). Temperature was chosen to be 30 degrees C and extraction time was selected to be 90 min. Under optimized conditions, this method provided good linearity (r, 0.99552-0.99991) and low limits of detection (0.0016-0.061 ng mL(-1)). Finally, this method was applied to the analysis of endogenous gibberellins from plant extract which was obtained with traditional solvent extraction of rice plant tissues, and the relative recoveries were from 62% to 166%. PMID- 23089518 TI - Purge-assisted headspace solid-phase microextraction combined with gas chromatography/mass spectrometry for the determination of trace nitrated polycyclic aromatic hydrocarbons in aqueous samples. AB - This study describes a new procedure, namely, purge-assisted headspace solid phase microextraction combined with gas chromatography/negative ion chemical ionization mass spectrometry (PA/HS-SPME-GC/NICI-MS), which is used to determine seven nitrated polycyclic aromatic hydrocarbons (NPAHs) in aqueous samples. High extraction efficiency was obtained with PA/HS-SPME with polydimethylsiloxane (PDMS) fiber coating. A programmable temperature vaporizing (PTV) inlet was used in the desorption process. Selected ion monitoring (SIM) was used for quantitative and qualitative purposes. The linear range of detection of the proposed method was 5-5000 pg/mL with coefficients of determination between 0.995 and 0.999. Limits of detection (LODs) for seven NPAHs were 0.01-0.06 pg/mL. The relative standard deviation was below 12.7% at a concentration of 50 pg/mL. Compared with headspace-solid phase microextraction (HS-SPME), the purge procedure enhanced the extraction efficiency for high boiling point analytes, such as 7-nitrobenz[a]anthracene (7-NBA) and 6-nitrochrysene (6-NC). The proposed method provides a sensitive method for NPAH analysis at the pg/mL level. The application of the proposed method for the determination of trace NPAHs in real samples was investigated by analyzing aqueous samples from rivers. The concentrations of NPAHs detected from the samples ranged from 5.2 to 7.5 pg/mL. This method was applied successfully in the analysis of trace NPAHs in river samples. PMID- 23089519 TI - Determination of partition coefficients of refrigerants by gas liquid chromatographic headspace analysis. AB - Gas-water partition coefficients, K(w), and gas-solvent partition coefficients, K(s), have been determined for chlorodifluoromethane and for 1,1,1,3,3,3 hexafluoropropane by headspace analysis, using a very simple experimental procedure. These partition coefficients then yield water-solvent partition coefficients, P(s). Where comparisons can be made there is excellent agreement with literature values for K(w) and P(s). The obtained values of K(s) and P(s) can be used to obtain physicochemical properties, or descriptors, for the refrigerants. Combination of these descriptors with previous equations we have developed enables partition coefficients to be obtained for a host of systems. PMID- 23089520 TI - Separation of epigallocatechin gallate from tea polyphenol by simulated moving bed chromatography. AB - (-)-Epigallocatechin gallate (EGCG) was purified from tea polyphenol by a two step simulated moving bed (SMB) chromatographic process with C18-bonded silica gel as stationary phase and a mixture of methanol and water as mobile phase, removing the more retained components firstly and the less retained components secondly. An open-loop 3-zone SMB approach was used, a gradient of solvent strength in zones I and II was formed by different methanol dosage in purge and desorbent solutions and pre-equilibration was reached by the elution at the end of zone III. Under the approximation including linear adsorption and ideal chromatographic model, the operating parameters of the simulated moving bed were selected according to the "triangle theory". In the first SMB separation, a solution of tea polyphenol with 55.5% purity of EGCG was used for feeding and a raffinate solution with 92.2% purity and 99.7% recovery of EGCG was obtained. The raffinate solution was concentrated for feeding in the second SMB separation and an extract solution with 97.8% purity and 99.8% recovery of EGCG was obtained. PMID- 23089521 TI - Quality metrics for detailed clinical models. AB - OBJECTIVE: To develop quality metrics for detailed clinical models (DCMs) and test their validity. METHODS: Based on existing quality criteria which did not include formal metrics, we developed quality metrics by applying the ISO/IEC 9126 software quality evaluation model. The face and content validity of the initial quality metrics were assessed by 9 international experts. Content validity was defined as agreement by over 70% of the panelists. For eliciting opinions and achieving consensus of the panelists, a two round Delphi survey was conducted. Valid quality metrics were considered reliable if agreement between two evaluators' assessments of two example DCMs was over 0.60 in terms of the kappa coefficient. After reliability and validity were tested, the final DCM quality metrics were selected. RESULTS: According to the results of the reliability test, the degree of agreement was high (a kappa coefficient of 0.73). Based on the results of the reliability test, 8 quality evaluation domains and 29 quality metrics were finalized as DCM quality metrics. CONCLUSION: Quality metrics were validated by a panel of international DCM experts. Therefore, we expect that the metrics, which constitute essential qualitative and quantitative quality requirements for DCMs, can be used to support rational decision-making by DCM developers and clinical users. PMID- 23089522 TI - Work culture among healthcare personnel in a palliative medicine unit. AB - OBJECTIVE: Understanding and assessing health care personnel's work culture in palliative care is important, as a conflict between "high tech" and "high touch" is present. Implementing necessary changes in behavior and procedures may imply a profound challenge, because of this conflict. The aim of this study was to explore the work culture at a palliative medicine unit (PMU). METHOD: Healthcare personnel (N = 26) at a PMU in Norway comprising physicians, nurses, physiotherapists, and others filled in a questionnaire about their perception of the work culture at the unit. The Systematizing Person-Group Relations (SPGR) method was used for gathering data and for the analyses. This method applies six different dimensions representing different aspects of a work culture (Synergy, Withdrawal, Opposition, Dependence, Control, and Nurture) and each dimension has two vectors applied. The method seeks to explore which aspects dominate the particular work culture, identifying challenges, limitations, and opportunities. The findings were compared with a reference group of 347 ratings of well functioning Norwegian organizations, named the "Norwegian Norm." RESULTS: The healthcare personnel working at the PMU had significantly higher scores than the "Norwegian Norm" in both vectors in the "Withdrawal" dimension and significant lower scores in both vectors in the "Synergy," "Control," and "Dependence" dimensions. SIGNIFICANCE OF RESULTS: Healthcare personnel at the PMU have a significantly different perception of their work culture than do staff in "well functioning organizations" in several dimensions. The low score in the "Synergy" and "Control" dimensions indicate lack of engagement and constructive goal orientation behavior, and not being in a position to change their behavior. The conflict between "high tech" and "high touch" at a PMU seems to be an obstacle when implementing new procedures and alternative courses of action. PMID- 23089523 TI - Response to vaccination of Atlantic cod (Gadus morhua L.) progenies from families with different estimated family breeding values for vibriosis resistance. AB - The purpose of the study was to elucidate whether responses to vibriosis vaccination and gene expressions in parts of the innate immune system were different in families of Atlantic cod (Gadus morhua). The fish were progenies of families with differences in estimated breeding values (EBV) for vibriosis resistance. Families of coastal cod (CC) and northeast Arctic cod (AC) responded well to vaccination with a relative percent survival of 72-95. No correlation between response to vaccination and vibriosis resistance were found (p = 0.146). The AC family with medium low (M) resistance had significant (p <= 0.019) lowest mortality among all the unvaccinated fish but the CC-M family. Further, when comparing the vaccinated fish the AC family with very high (VH) resistance had significant (p <= 0.004) higher mortality than all except the CC-VL and CC-H families. Parts of the innate immune response were studied by measuring the gene expression of innate immune genes 2 and 4 days post dip vaccination. Vaccinated fish from two families had a weak but significant higher innate immune response compared to control fish of the same family. In vaccinated fish, the gene expression of interleukin (IL) 1b, IL-10, IL-12p40 and hepcidin were significant up-regulated. While, no measureable activations of interferon gamma (IFNgamma), IL-8, cathelicidin, LBP/BPI and G-type lysozyme were found. PMID- 23089524 TI - Direct antibacterial activity of CD8+/CD4+ T-cells in ginbuna crucian carp, Carassius auratus langsdorfii. AB - Cytotoxic T cells (CTLs) constitute an important component of the specific effector mechanism in killing against microbial-infected or transformed cells. In addition to these activities, recent studies in mammals have suggested that CTLs can exhibit direct antimicrobial activity. Therefore, the present investigation was conducted to find out the microbicidal activity of CD8alpha(+) T cells of ginbuna crucian carp, Carassius auratus langsdorfii. The CD8alpha(+) T cells from immunised ginbuna exhibited the antibacterial activity against both facultative intracellular bacteria and extracellular bacteria. The maximum reduction of viable count of pathogens was recorded with effector (sensitized) cells and target (bacteria) ratio of 10:1 co-incubated for a period of 1-2 h at 26 degrees C when effector cells were derived from ginbuna 7 days after one booster dose at 15th day of primary sensitization/immunisation. Sensitized CD8alpha(+) T cells are found to kill 92.1 and 98.9% of Lactococcus garvieae and Edwardsiella tarda, respectively. No significant difference in the bacterial killing activity could be recorded against facultative intracellular bacteria and extracellular bacteria. The specificity study indicated the non-specific killing of bacteria. CD8alpha(+) T cells from E. tarda immunised ginbuna exhibited 40% of non-specific killing activity against L. garvieae and those from L. garvieae immunised ginbuna showed 42.7% of non-specific killing activity against E. tarda. Furthermore, CD4(+) T cells also killed 88% and 95.7% of L. garvieae and E. tarda, respectively. In addition to T cell subsets, surface IgM(+) cells also killed both types of pathogens. Therefore, the present study demonstrated the direct antibacterial activity of CD8alpha(+), CD4(+) T-cells and surface IgM(+) cells in fish. PMID- 23089525 TI - Characterisation of immune-related gene expression in clam (Venerupis philippinarum) under exposure to di(2-ethylhexyl) phthalate. AB - Di(2-ethylhexyl) phthalate (DEHP) mediates the immune system mainly by triggering the production of reactive oxygen species (ROS) and nitric oxide (NO) in higher animals. In the present study, spatial variation in the expression of immune related genes in clam (Venerupis philippinarum) under acute short-term DEHP treatment was assessed by qPCR. The expression of six genes including glutamine synthetase (GS), IkB (IK), transcription factor activator protein-1 (AP-1), cyclophilin A-1 (CypA-1), heat shock protein 90 (HSP90) and superoxide dismutase (SOD) was dose-dependent. A negative correlation between expression and DEHP treatment was observed for big defensin (BD), glutathione S-transferase (GST), and thioredoxin peroxidase (TP). Surprisingly, lysozyme (LYZ) exhibited two distinct expression patterns at two DEHP doses. Significant differences between the experimental and control groups were observed for all tested genes at the various time points. Overall, our results revealed that DEHP mediates immune responses in clams by various means, and certain genes are promising candidate for biomarkers in DEHP monitoring. PMID- 23089526 TI - The design and synthesis of indazole and pyrazolopyridine based glucokinase activators for the treatment of type 2 diabetes mellitus. AB - Glucokinase activators represent a promising potential treatment for patients with Type 2 diabetes. Herein, we report the identification and optimization of a series of novel indazole and pyrazolopyridine based activators leading to the identification of 4-(6-(azetidine-1-carbonyl)-5-fluoropyridin-3-yloxy)-2-ethyl-N (5-methylpyrazin-2-yl)-2H-indazole-6-carboxamide (42) as a potent activator with favorable preclinical pharmacokinetic properties and in vivo efficacy. PMID- 23089527 TI - The structural requirements of histone deacetylase inhibitors: suberoylanilide hydroxamic acid analogs modified at the C6 position. AB - Suberoylanilide hydroxamic acid (SAHA, Vorinostat), the first FDA-approved histone deacetylase (HDAC) inhibitor drug, was modified at the C6 position to study the structural requirements for high potency and selectivity. Substituents on the C6 position only modestly influenced inhibitor potency, with poorer activity observed as substituent size increased. Interestingly, C6 substituents also modestly influenced selectivity compared to the parent compound, SAHA. This systematic study documenting the influence of substituents on the SAHA linker region will aid development of anti-cancer drugs targeting HDAC proteins. PMID- 23089528 TI - Antithrombotic therapy after coronary stenting in patients with nonvalvular atrial fibrillation. AB - BACKGROUND: The safety and efficacy of triple therapy (TT; warfarin with dual antiplatelet therapy [DAPT]) in post-percutaneous coronary intervention (PCI) patients with atrial fibrillation (AF) are unclear. We aimed to determine whether TT is associated with a decreased stroke rate and an acceptable bleeding rate in this population. METHODS: This was a single-centre, retrospective study. Primary composite outcome was death, ischemic stroke, or transient ischemic attack. Secondary outcomes included components of primary outcome, bleeding, and blood transfusion rates. RESULTS: Of 602 post-PCI patients with AF between 2000 and 2009, 382 received TT, 220 DAPT. Mean follow-up post PCI was 5.9 +/- 5.0 months. The TT group had a higher CHADS(2) score (2.6 vs 2.1, P < 0.001), older age (72.9 vs 70.5 years, P = 0.039), more heart failure (72.3% vs 36.9%, P = 0.010), and more strokes (14.4% vs 6.4%, P = 0.010). Neither primary outcome, major bleeding, nor blood transfusion rates differed between treatment groups, but more gastrointestinal bleeding occurred with TT use (2.6% vs 0.5%, P = 0.045). Net clinical benefit was -5.2 (CHADS(2) <= 2), 0.9 (CHADS(2) > 2), and -3.2 (overall) per 100 patient-years. CONCLUSIONS: Although we found no association with TT usage and a reduction in cerebrovascular ischemic or major bleeding events in post-PCI patients with AF regardless of CHADS(2) score vs DAPT, the study was likely underpowered to demonstrate a clinically relevant reduction. TT was associated with a 5-fold increase in gastrointestinal bleeding vs DAPT. Net clinical benefit calculations suggest benefits of TT in patients with CHADS(2) > 2. Stratification with CHADS(2) might be useful to determine the optimal antithrombotic therapy post PCI. PMID- 23089529 TI - Trifecta or triple threat? The challenge of post-PCI management in patients receiving chronic oral anticoagulant therapy. PMID- 23089530 TI - How to develop a business case to establish a neonatal pulse oximetry programme for screening of congenital heart defects. AB - Pulse oximetry screening for critical congenital heart defects (CCHDs) is a highly specific, moderately sensitive test which is cost effective, acceptable to both clinical staff and parents and meets the criteria for universal screening. Pulse oximetry screening is gaining considerable worldwide support and last year was added to the recommended uniform screening panel in the USA following endorsement by the Health and Human Services Secretary. There is significant heterogeneity in published screening protocols and it is important to consider all available evidence and also take local factors into account when developing a screening programme, whether it is within an individual hospital, neonatal network or even at a national level. This paper presents available options based both on the published evidence and personal practice experience which will aid those considering the introduction of screening to make the right decisions both from a clinical and financial perspective. PMID- 23089531 TI - Pharmacokinetics of tacrolimus in adult renal transplant recipients. AB - BACKGROUND: The success of an immunosuppressive drug therapy depends on the extent of exposure to the drugs (the blood levels and duration), which is measured as the area under the curve (AUC). Tacrolimus shows considerable variability in its pharmacokinetics, with poor correlation between the tacrolimus trough level and systemic exposure, as measured by the AUC of concentration time. Monitoring trough levels helps not only in reducing nephrotoxiicity but also in reducing the chances of acute rejection; although there is no international consensus, the trough concentration is used to determine dosing and the AUC for calculating the exposure of the patient to the drug. The major objective of this study was to find the best sampling time for an abbreviated AUC0-6 (area under the concentration time curve) to predict the total body exposure to tacrolimus in adult renal transplantation recipients. METHODS: The study involved retrospective analysis of 14 renal transplant patients (2 female and 12 male) that were on triple immunosuppressive therapy, methyl prednisolone, mycophenolate mofetil and tacrolimus. To determine trough concentrations, blood samples were collected before administration of tacrolimus (0 h) and at fixed time points of 2 h, 4 h and 6 h after administration of oral tacrolimus and analyzed in duplicate by microparticle enzyme immunoassay. AUC0-6 was determined using the linear trapezoidal rule. The association between the blood concentration and AUC6 were evaluated by the Pearson correlation coefficient. All statistical analyses were performed using the SPSS software (IBM Corp., NY, USA) program. RESULTS: Trough levels were fairly consistent at 7.9-18 ng.h/mL in all the patients included in this study, and this did not show variation with age or sex. The AUC0-6 was higher [202-290 ng/mL at 3-8 mg bis-daily (b.d.) dosage] in patients who received kidneys from cadavers compared to recipients from live donors (60.5-171 ng/mL at 3-8 mg b.d. dosage), but the clinical significance of this is not known. The highest AUC0-6 was 246 ng/mL, observed at 4.5 mg b.d. dosage. Dosages higher than 2 mg b.d. did not result in a noticeable increase in AUC0-6. Peak blood levels of tacrolimus were obtained 4 h after administration. CONCLUSIONS: Trough level determination and a C2, C4 two-point limited sampling strategy may be useful to plan the dosing strategy and estimate the exposure of renal transplant patients to tacrolimus. PMID- 23089532 TI - The effect of gabapentin on oxidative stress in a model of toxic demyelination in rat brain. AB - BACKGROUND: Gabapentin, a structural analog of gamma-aminobutyric acid (GABA), is used in the treatment of neuropathic pain in multiple sclerosis. METHODS: This study investigated the effect of gabapentin on oxidative stress in a model of brain demyelination evoked by intracerebral injection (i.c.i) of ethidium bromide (10 MUL of 0.1%). Rats received saline (control) or gabapentin at 100 or 300 mg/kg orally daily for 10 days prior to injection of ethidium bromide. Rats were euthanized 1 day later, and then the levels of reduced glutathione (GSH), glutathione peroxidase (GPx) activity, lipid peroxidation (malondialdehyde; MDA), nitrite, acetyl cholinesterase (AChE) and paraoxonase activities were assessed in the brain cortex in different treatment groups. RESULTS: Ethidium bromide resulted in increased oxidative stress in the cortex 1 day after its injection. Malondialdehyde increased by 30.2%, whereas GSH decreased by 17.6%. GPx activity was inhibited by 78.6%. Brain nitrite increased by 55.4%, AChE activity decreased by 33.4% and paraoxonase activity decreased by 27.5%. In ethidium bromide treated rats, gabapentin administered at 300 mg/kg increased cortical MDA by 66%. GSH was unaltered by gabapentin, but GPx activity decreased by 54.3% by the higher dose of gabapentin. Nitrite decreased by 21.4% and 29.2% after 100 and 300 mg/kg of gabapentin, respectively. AChE activity increased by 28.6% and 69.3% by 100 and 300 mg/kg of gabapentin, respectively. Paraoxonase activity showed 83.3% and 73% decreases by 100 and 300 mg/kg of gabapentin, respectively. CONCLUSIONS: These results suggest that gabapentin increases brain lipid peroxidation and decreases brain antioxidant enzymes in this model of chemical demyelination. PMID- 23089533 TI - Auditory sensation via moist contact of the bone vibrator with skin at soft tissue sites. AB - BACKGROUND: Auditory sensation can be elicited not only by air conduction (AC) with an earphone and by bone conduction by applying a bone vibrator to bony sites on the head, but also by a newly described mode based on applying the bone vibrator to soft tissue sites on the head, neck, and thorax (soft tissue conduction - STC). This study was designed to assess whether it is necessary to compress the skin at the STC sites, which could induce vibrations of the underlying bone. METHODS: In 15 normal-hearing subjects, thresholds were assessed with the bone vibrator in air (control for possible AC), direct contact of the bone vibrator with the mastoid and regions around the lip, and indirect contact (via a cotton wool wick, dry or wet) of the bone vibrator with sites around the lip. RESULTS: Even though the best (lowest) thresholds were obtained with direct contact, the subjects clearly heard the sound stimulation when presented only by the gentle contact of the wick with the skin, especially when the contact site was moist. CONCLUSIONS: STC stimulation does not require vibrations of the skull bone and seems to involve the transmission of auditory frequency vibrations, through a series of soft tissues, to the inner ear. PMID- 23089534 TI - beta-trefoil inhibitors--from the work of Kunitz onward. AB - Protein protease inhibitors are the tools of nature in controlling proteolytic enzymes. They come in different shapes and sizes. The beta-trefoil protease inhibitors that come from plants, first discovered by Kunitz, were later complemented with representatives from higher fungi. They inhibit serine (families S1 and S8) and cysteine proteases (families C1 and C13) as well as other hydrolases. Their versatility is the result of the plasticity of the loops coming out of the stable beta-trefoil scaffold. For this reason, they display several different mechanisms of inhibition involving different positions of the loops and their combinations. Natural diversity, as well as the initial successes in de novo protein engineering, makes the beta-trefoil proteins a promising starting point for the generation of strong, specific, multitarget inhibitors capable of inhibiting multiple types of hydrolytic enzymes and simultaneously interacting with different protein, carbohydrate, or DNA molecules. This pool of knowledge opens up new possibilities for the exploration of their naturally occurring as well as modified properties for applications in many fields of medicine, biotechnology, and agriculture. PMID- 23089535 TI - Structural basis of the TAL effector-DNA interaction. AB - Phytopathogen transcription activator-like effectors (TALEs) bind DNA in a sequence specific manner in order to manipulate host transcription. TALE specificity correlates with repeat variable diresidues in otherwise highly stereotypical 34-35mer repeats. Recently, the crystal structures of two TALE DNA binding domains have illustrated the molecular basis of the TALE cipher. The structures show that the TALE repeats form a right-handed superhelix that is wound around largely undistorted B-DNA to match its helical parameters. Surprisingly, repeat variable residue 1 is not in contact with the bases. Instead, it is involved in hydrogen bonding interactions that stabilize the overall structure of the protein. Repeat variable residue 2 contacts the top strand base and forms sequence-specific hydrogen bonds and/or van der Waals contacts. Very unexpectedly, bottom strand bases are exposed to solvent and do not make any direct contacts with the protein. This review contains a summary of TALE biology and applications and a detailed description of the recent breakthroughs that have provided insights into the molecular basis of the TALE code. PMID- 23089536 TI - Dual-specificity phosphatases are targets of the Wnt/beta-catenin pathway and candidate mediators of beta-catenin/Ras signaling interactions. AB - The Wnt/beta-catenin and the Ras/mitogen-activated protein kinase (MAPK) pathways play important roles in cancer development. Both pathways have been studied discretely, but the mechanisms of possible crosstalk are still not fully understood. We have previously shown that beta-catenin and MAPK signaling interfere with each other in murine liver in vivo and in vitro. Here, we show that dual specificity phosphatases (Dusps) 6 and 14, known to play an essential role in regulating MAPK pathway activity via feedback mechanisms, are up regulated by activation of beta-catenin in murine liver cells, whereas the epidermal growth factor receptor, an upstream effector in the Ras/MAPK cascade, is down-regulated by beta-catenin. In addition, we identified a beta-catenin binding site within the Dusp6 promoter, which is responsible for the activation of the promoter by beta-catenin signaling, and demonstrated reduced inducibility of MAPK signaling in cultured mouse hepatoma cells following beta-catenin activation. Thus, beta-catenin is able to inhibit activation of the Egfr/Ras/MAPK signaling cascade, both at the receptor level and by interfering with MAPK activity via Dusps. PMID- 23089537 TI - The combined use of neutrophil gelatinase-associated lipocalin and brain natriuretic peptide improves risk stratification in pediatric cardiac surgery. AB - BACKGROUND: The aim of this study is to test the hypothesis whether the combined use of a cardio-specific biomarker, the brain natriuretic peptide (BNP) and a marker of early renal damage, the assay of urinary neutrophil gelatinase associated lipocalin (uNGAL), may improve risk stratification in pediatric cardiac surgery. METHODS: We prospectively enrolled 135 children [median age 7 (interquartile range 1-49) months] undergoing to cardiac surgery for congenital heart disease. All biomarkers were evaluated pre- and post-operatively at different times after cardiopulmonary-bypass (CPB): uNGAL at 2, 6 and 12 h; BNP at 12 and 36 h; serum creatinine at 2, 6, 12, and 36 h. Primary endpoints were development of acute kidney injury (AKI) (defined as 1.5 serum creatinine increase) and intubation time. RESULTS: AKI occurred in 39% of patients (65% neonates and 32% older children, p=0.004). The peak of uNGAL values occurred more frequently at 2 h. uNGAL values at 2 h [median 28.2 (interquartile range 7.0 124.6) ng/L] had a good diagnostic accuracy for early diagnosis of AKI with an AUC (area under the curve) ROC (receiver operating characteristic) curve of 0.85 (SE 0.034). Using multivariable logistic regression analysis, development of AKI was significantly associated with uNGAL values at 2 h after CPB [OR=1.88 (1.30 2.72, p=0.001)], together with the CPB time and Aristotle score, as an index of complexity of the surgical procedure, while pre-operative BNP values were not. Furthermore, uNGAL and pre-operative BNP values (together with Aristotle score) were significantly associated with adverse outcome (longer intubation time and mortality). CONCLUSIONS: Pre-operative BNP and uNGAL values after surgery (together with the Aristotle score) were independently associated with a more severe course and worse outcome in children undergoing cardiac surgery for congenital heart disease. PMID- 23089538 TI - The CCLM contribution to improvements in quality and patient safety. AB - Clinical laboratories play an important role in improving patient care. The past decades have seen unbelievable, often unpredictable improvements in analytical performance. Although the seminal concept of the brain-to-brain laboratory loop has been described more than four decades ago, there is now a growing awareness about the importance of extra-analytical aspects in laboratory quality. According to this concept, all phases and activities of the testing cycle should be assessed, monitored and improved in order to decrease the total error rates thereby improving patients' safety. Clinical Chemistry and Laboratory Medicine (CCLM) not only has followed the shift in perception of quality in the discipline, but has been the catalyst for promoting a large debate on this topic, underlining the value of papers dealing with errors in clinical laboratories and possible remedies, as well as new approaches to the definition of quality in pre , intra-, and post-analytical steps. The celebration of the 50th anniversary of the CCLM journal offers the opportunity to recall and mention some milestones in the approach to quality and patient safety and to inform our readers, as well as laboratory professionals, clinicians and all the stakeholders of the willingness of the journal to maintain quality issues as central to its interest even in the future. PMID- 23089539 TI - Improvement in the performance of external quality assessment in Korean HIV clinical laboratories using unrecalcified human plasma. AB - BACKGROUND: The external quality assessment schemes (EQAS) organizer provides a suitable program to monitor and improve the quality of human immunodeficiency virus (HIV) testing laboratories with EQAS panels prepared under various conditions. The aim of the current study was to investigate the effects of human plasma samples on the EQAS results of HIV obtained from hospital-based clinical laboratories. METHODS: From 2007 to 2009, HIV EQAS panels consisted of four to six samples that consisted of undiluted positive and negative samples and were provided to laboratories twice per year. Up until the first half EQAS in 2008, EQAS panel materials were obtained by converting acid citrate dextrose treated plasma to serum via chemical treatment with CaCl2. Beginning with the second EQAS in 2008, all materials were prepared without the defibrination process. RESULTS: Approximately 300 HIV clinical laboratories participated in this program. The overall performance of clinical laboratories was shown to be improved when using unrecalcified plasma panels compared with recalcified panels. Significant differences were observed in EIA analyses of plasma for both positive (p<0.001) and negative (p<0.001) samples between the recalcified and unrecalcified groups. CONCLUSIONS: Our finding suggested that defibrination status of EQAS panels might affect the results of anti-HIV EQAS of Korean HIV testing laboratories. PMID- 23089540 TI - Prognostic impact of SUMO-specific protease 1 (SENP1) in prostate cancer patients undergoing radical prostatectomy. AB - OBJECTIVES: To investigate small ubiquitin-like modifier (SUMO)-specific protease 1 (SENP1) expression in human prostate cancer (CaP) cells and its prognostic value for CaP patients after radical prostatectomy (RP). MATERIALS AND METHODS: SENP1 expression in CaP cells was detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. By using immunohistochemistry coupled with the tissue microarray (TMA) technique, we examined SENP1 protein expression in 115 specimens of CaP, 19 prostatic intra epithelial neoplasia (PIN) tissues, and 24 normal prostate tissues. Moreover, correlations between SENP1 protein expression, clinicopathologic features, and prognosis were statistically analyzed. RESULTS: Three CaP cells, DU145, PC-3, and LNCaP had overexpression of SENP1 mRNA and protein, while the nontransformed immortalized prostate cell RWPE-1 had relatively weak SENP1 expression. Especially, DU145, a hormone-independent CaP cell line, showed higher transcriptional and translational level of SENP1 than the others. SENP1 protein expression correlated with some clinicopathologic parameters, such as pathologic stage, Gleason score, and biochemical recurrence (BCR). Positive SENP1 immunostaining in the CaP, PIN, and normal prostate tissue samples were 76.5%, 57.9%, and 4.2%, respectively. CaP patients undergoing RP with positive SENP1 expression were significantly associated with poor biochemical-free survival. Multivariate analysis indicated that SENP1 protein expression was an independent prognostic factor for BCR-free survival after RP. CONCLUSIONS: This study confirmed the up-regulation of SENP1 mRNA and protein level in CaP cells. We suggested that SENP1 expression might contribute to the malignant progression of CaP. Importantly, SENP1 presented as a potential prognostic factor for BCR after RP. PMID- 23089541 TI - Single parenchymal brain cysticercus: relationship between age of patients and evolutive stage of parasites. AB - BACKGROUND: A recent hypothesis suggested that in many cases cysticercal granulomas represent recently established Taenia solium metacestodes rapidly destroyed by the host's immune system. Here, we attempted to determine whether patients with cysticercal granulomas are younger than those with other forms of parenchymal brain cysticercosis. METHODS: Series of 185 patients with single parenchymal brain cysticercus, classified according to the stage of the parasite at the moment of diagnosis in cysts without inflammation, cysts with inflammation, granular lesions, and calcifications. We correlated the age of the patients with the parasite evolutive stage. RESULTS: Patients with cysticercus granulomas were significantly younger than those with vesicular cysts (17.7 +/- 12.9 versus 36.8 +/- 15.1 years, P<0.005) or calcifications (17.7 +/- 12.9 versus 40.8 +/- 19.7 years, P<0.0001). There was also a non-significant trend for patients with granulomas to be younger than those with coloidal cysts (17.7 +/- 12.9 versus 26.7 +/- 15.6 years, P = 0.367). CONCLUSIONS: Results from this study argued against the classical hypothesis that granulomas are the end result from long-established vesicular cysts destroyed by the host's immune system. Vesicular (viable) cysticerci must be treated with cysticidal drugs as it is unlikely that they will be spontaneously destroyed. PMID- 23089542 TI - Teduglutide and short bowel syndrome: every night without parenteral fluids is a good night. PMID- 23089543 TI - An unusual cause of sepsis after laparoscopic cholecystectomy. PMID- 23089546 TI - Endoscopic therapy for sphincter of Oddi dysfunction in idiopathic pancreatitis: from empiric to scientific. PMID- 23089547 TI - A rare cause of abdominal pain and ascites. PMID- 23089548 TI - IL-17 promoted metastasis of non-small-cell lung cancer cells. AB - Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Recent data suggested that IL-17 might be a pivotal cytokine involved in tumor progression of NSCLC. However, the direct effect of IL-17 on metastasis of NSCLC cells still remains intractable. In this study, we found that the metastasis of NSCLC was significantly impaired in IL-17-/- mice. Further, we revealed that IL-17 could directly promote the invasion of NSCLC cells both in vitro and in vivo. Furthermore, we found that IL-6-Stat3 pathway was crucial for IL-17 to enhance the invasive potential of NSCLC cells. Finally, we found that elevated expression of IL-17 in peripheral blood was associated with the TNM stage, and elevated expression of IL-17R in NSCLC cells was associated with their invasive potential in NSCLC patients. These findings could facilitate our understanding of the potential role of IL-17 in tumor biology, and provide clues for developing promising strategies against NSCLC. PMID- 23089549 TI - In vitro assessment of mesenchymal stem cells immunosuppressive potential in multiple sclerosis patients. AB - Mesenchymal stem cells (MSC) are promising for multiple sclerosis (MS) treatment. However, clinical results remain controversial, and no criteria are available for predicting the efficiency of MSC therapy. Using an in vitro model of lymphocytes and MSC cocultivation we revealed that the Index of MSC Suppression of myelin induced memory T cells proliferation was stronger than that of PHA-stimulated proliferation and inversely correlated with patients'EDSS score. In vitro expression of CD119 (IFNGR1) in mitogen/myelin-stimulated T cells increased in the presence of MSC being inversely correlated with T-lymphocytes proliferation. The Index of MSC Suppression and CD119 expression in T-lymphocytes may be useful when assessing MSC immunosuppressive potential in MS patients. PMID- 23089551 TI - The impact of 1,25-dihydroxy vitamin D3 on the expressions of vascular endothelial growth factor and transforming growth factor-beta1 in the retinas of rats with diabetes. AB - AIMS: To define whether 1,25-dihydroxy vitamin D3 (1,25-(OH)2 D3) can protect diabetic retinopathy and to investigate its impact on the expressions of vascular endothelial growth factor (VEGF) and transforming growth factor-beta1 (TGF-beta1) in the retinas of rats with diabetes. METHODS: Male Sprague-Dawley (SD) rats were divided into normal control group, 1,25-(OH)2 D3 group and diabetes group. The rats in 1,25-(OH)2 D3 group and diabetes group were established to type 2 diabetes model with high-fat and high-sugar diet and streptozotocin (STZ). Meanwhile, the rats of 1,25-(OH)2 D3 group were treated with 1,25-(OH)2 D3. After 13 weeks, morphological changes of retinal tissues were observed under microscopes after hematoxylin-eosin staining. VEGF and TGF-beta1 expressions in the retinal tissues were detected with immunohistochemistry staining. RESULTS: Pathological examination showed an appearance of edema and disordered arrangement of retinal tissues in diabetes group, but milder pathological changes in 1,25 (OH)2 D3 group. VEGF and TGF-beta1 expressions of both diabetes group and 1,25 (OH)2 D3 group significantly increased (P<0.05), but those of 1,25-(OH)2 D3 group were significantly lower than diabetes group (P<0.05). CONCLUSION: 1,25-(OH)2 D3 had partially protective effect on diabetic retinopathy of diabetic rats, the mechanism of which might inhibit VEGF and TGF-beta1 expressions in the retinal tissues. PMID- 23089550 TI - MHC class-I-restricted CD8 T cells play a protective role during primary Salmonella infection. AB - Protective immunity against Salmonella infection is known to require CD4 Th1 cells and B cells, but the role of MHC class-I-restricted CD8 T cells is less clear. Previous studies have suggested that CD8 T cells participate in secondary, but not primary, bacterial clearance. However, these studies have used experimental models that are difficult to interpret and do not clearly isolate the role of MHC class-I-restricted CD8 T cells from other cell populations. Here, we examined the role of class-I-restricted T cells in protection against Salmonella infection using mice lacking all classical MHC class-Ia molecules, perforin, or granzyme B. Immunized K(b)D(b)-, perforin-, granzyme B-, or perforin/granzyme B-deficient mice were able to resolve secondary infection with virulent Salmonella, demonstrating that class-I-restricted CTLs are not required for acquired immunity. However, during primary infection with attenuated bacteria, bacterial clearance was delayed in each of these mouse strains when compared to wild-type mice. Taken together, these data demonstrate that CD8 T cells are not required for acquired immunity to Salmonella, but can play a protective role in resolving primary infection with attenuated bacteria. PMID- 23089552 TI - Validation of an enzyme-linked immunosorbent assay for C-peptide analysis in Cameroon. AB - AIMS: To validate an ELISA method for C-peptide analysis in Cameroon. METHODS: We evaluated the linearity, detection limit, functional sensitivity, precision and accuracy, and further investigated for cross-reactivity by proinsulin, and interferences by lipids, bilirubin and hemoglobin. This method was compared with the Roche electrochemiluminescence immunoassay. C-peptide stability was assessed following a series of freeze-thaw cycles, and after storage at room temperature. The C-peptide reference range was determined by analyzing fifty plasma samples of Cameroonians without diabetes. RESULTS: The ELISA was linear at least up to 7.09 MUg/L, and had a detection limit of 0.09 MUg/L, and a functional sensitivity of 0.32 MUg/L. The inter- and intraassay %CV were 2.9-9.9%, and 5.2-9.4%, respectively. Recoveries were 81-94% in serum, and 93-98% in buffer. Comparison with the ECLIA yielded a good correlation coefficient (R(2)=0.98). There was no cross-reactivity with proinsulin, and no interference with lipids, bilirubin and hemoglobin. C-peptide was stable at room temperature for 24 h and up to 7 freeze thaw cycles for medium (1-6 MUg/L) and high (>6 MUg/L) levels (<-15 degrees C and <-70 degrees C). The reference range for C-peptide was 0.38-3.63 MUg/L. CONCLUSIONS: This method is suitable for C-peptide analysis in low-income countries like Cameroon. PMID- 23089553 TI - Aegle marmelos (L.) Correa (Bael) and its phytochemicals in the treatment and prevention of cancer. AB - Aegle marmelos, commonly known as Bael and belonging to the family Rutaceae is an important medicinal plant in the traditional Indian system of medicine, the Ayurveda. The extract prepared by boiling the bark, leaves or roots in water is useful as laxative, febrifuge, and expectorant. The extract is also useful in ophthalmia, deafness, inflammations, catarrh, diabetes, and asthmatic complaints. The fruits are used in treating diarrhea, dysentery, stomach ache, and cardiac ailments. Scientific studies have validated many of Bael's ethnomedicinal properties and its potential antimicrobial effects, hypoglycemic, astringent, antidiarrheal, antidysenteric, demulcent, analgesic, anti-inflammatory, antipyretic, wound-healing, insecticidal, and gastroprotective properties. In addition, studies have also shown that Bael and some of the Bael phytochemicals possess antineoplastic, radioprotective, chemoprotective, and chemopreventive effects, properties efficacious in the treatment and prevention of cancer. For the first time, the current review summarizes the results related to these properties and emphasizes aspects that require further investigation for Bael's safe and effective use in the near future. PMID- 23089554 TI - Thymoquinone efficiently inhibits the survival of EBV-infected B cells and alters EBV gene expression. AB - Epstein--Barr virus (EBV) is a human virus with oncogenic potentials that is implicated in various human diseases and malignancies. In this study, the modulator activity of the potent herbal extract drug thymoquinone on EBV was assessed in vitro. Thymoquinone was tested for cytotoxicity on human cells of lymphoblastoid cells, Raji Burkitt's lymphoma, DG-75 Burkitt's lymphoma, peripheral blood mononuclear cells, and periodontal ligament fibroblast. Apoptosis induction was analyzed via TUNEL assay and activity studies of caspase 3. The effect of thymoquinone on EBV gene expression was determined using real time polymerase chain reaction. We report here, for the first time, a promising selective inhibitory affect of thymoquinone on EBV-infected B cell lines in vitro, compared with lower activity on EBV negative B cell line and very low toxicity on human peripheral blood mononuclear cells and periodontal ligament fibroblasts. Moreover, the drug was found to efficiently suppress the RNA expression of EBNA2, LMP1, and EBNA1 genes. Specifically, EBNA2 expression levels were the most affected indicating that this gene might have a major contribution to thymoquinone potency against EBV infected cells. Overall, our results suggest that thymoquinone has the potential to suppress the growth of EBV-infected B cells efficiently. PMID- 23089555 TI - Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. AB - We aimed to investigate the cytotoxic effects of nimbolide, a limonoid present in leaves and flowers of the neem tree (Azadirachta indica) on human breast cancer cells. The molecular mechanisms involved in the apoptotic activity exerted by nimbolide were studied on the estrogen dependent (MCF-7) and estrogen independent (MDA-MB-231) human breast cancer cell lines. The growth inhibitory effect of nimbolide was assessed by MTT assay. Apoptosis induction by nimbolide treatment was determined by JC-1 mitochondrial membrane potential staining, cytochrome c release, caspase activation, cleavage of PARP and AO/EtBr dual staining. The modulation of apoptotic proteins (intrinsic pathway: Bax, bad, Bcl-2, Bcl-xL, Mcl 1, XIAP-1 and caspase-3, 9; extrinsic pathway: TRAIL, FasL, FADDR and Caspase-8) were studied by western blot and real time PCR analysis. Treatment with nimbolide resulted in dose and time-dependent inhibition of growth of MCF-7 and MDA-MB-231 cells. The occurrence of apoptosis in these cells was indicated by JC-1 staining, modulation of both intrinsic and extrinsic apoptotic signaling molecules expression and further apoptosis was confirmed by AO/EtBr dual staining. These events were associated with: increased levels of proapoptotic proteins Bax, Bad, Fas-L, TRAIL, FADDR, cytochrome c and reduced levels of the anti-apoptotic proteins Bcl-2, Bcl-xL, Mcl-1 and XIAP-1. Nimbolide induces the cleavage of pro caspase-8, pro-caspase-3 and PARP. The above data suggest that nimbolide induces apoptosis by both the intrinsic and extrinsic pathways. With evidence of above data it is suggested that nimbolide exhibit anticancer effect through its apoptosis-inducing property. Thus, nimbolide raises new hope for its use in anticancer therapy. PMID- 23089556 TI - Innovations in papermaking: an LCA of printing and writing paper from conventional and high yield pulp. AB - Pulp and paper industry is facing challenges such as resource scarcity and greenhouse gas (GHG) emissions. The objective of this research is to investigate whether the use of new coatings (micro or nano TiO(2)) and different pulp types could bring savings in wood, energy, GHG emissions and other environmental impacts in comparison with conventional printing and writing paper. We studied three types of pulp, namely i) unbleached virgin kraft pulp, ii) recovered fiber, and iii) high yield virgin chemithermo-mechanical pulp (CTMP). A life cycle assessment (LCA) was conducted from cradle to grave. Applying attributional modeling, we found that wood savings amount to 60% for the nanoparticle coated recovered fiber paper and 35% for the micro TiO(2) coated CTMP paper. According to the ReCiPe single score impact assessment method, the new product configurations allow the reduction of the environmental impacts by 10-35% compared to conventional kraft paper. Applying consequential modeling, we found larger energy and GHG emission savings compared to attributional modeling because the saved wood is used for producing energy, thereby replacing fossil fuels. The nanoparticle coated recovered fiber paper offered savings of non-renewable energy use (NREU) by 100% (13GJ/ton paper) and GHG emission reduction by 75% (0.6 tonCO(2)eq./ton paper). Micro TiO(2) coated CTMP paper offered NREU savings by 25% (3GJ/ton paper) and savings of GHG emissions by 10% (0.1 tonCO(2)eq./ton paper). The taking into account of all environmental impacts with the ReCiPe single score method leads to comparable results as that of attributional modeling. We conclude that the nanoparticle coated recovered fiber paper offered the highest savings and lowest environmental impacts. However, human toxicity and ecotoxicity impacts of the nanoparticles were not included in this analysis and need further research. If this leads to the conclusion that the toxicity impacts of the nanoparticles are serious, then the CTMP paper with micro TiO(2) coating is the preferred option. PMID- 23089557 TI - Adhesion and size dependent friction anisotropy in boron nitride nanotubes. AB - The frictional properties of individual multiwalled boron nitride nanotubes (BN NTs) synthesized by chemical vapour deposition (CVD) and deposited on a silicon substrate are investigated using an atomic force microscope tip sliding along (longitudinal sliding) and across (transverse sliding) the tube's principal axis. Because of the tube's transverse deformations during the tip sliding, a larger friction coefficient is found for the transverse sliding as compared to the longitudinal sliding. Here, we show that the friction anisotropy in BN-NTs, defined as the ratio between transverse and longitudinal friction forces per unit area, increases with the nanotube-substrate contact area, estimated to be proportional to (L(NT)R(NT))(1/2), where L(NT) and R(NT) are the length and the radius of the nanotube, respectively. Larger contact area denotes stronger surface adhesion, resulting in a longitudinal friction coefficient closer to the value expected in the absence of transverse deformations. Compared to carbon nanotubes (C-NTs), BN-NTs display a friction coefficient in each sliding direction with intermediate values between CVD and arc discharge C-NTs. CVD BN NTs with improved tribological properties and higher oxidation temperature might be a better candidate than CVD C-NTs for applications in extreme environments. PMID- 23089558 TI - An analysis of a stochastic model for bacteriophage systems. AB - In this article, we analyze a system modeling bacteriophage treatments for infections in a noisy context. In the small noise regime, we show that after a reasonable amount of time the system is close to a bacteria free equilibrium (which is a relevant biologic information) with high probability. Mathematically speaking, our study hinges on concentration techniques for delayed stochastic differential equations. PMID- 23089559 TI - Fat mass influence on bone mass is mediated by the independent association between lean mass and bone mass among elderly women: a cross-sectional study. AB - OBJECTIVES: To study the independent association of fat mass (FM) and lean mass (LM) with bone mass and to study the differences in bone mass by weight and fat status in 223 seniors (aged 65-89 years) from the city of Zaragoza (Spain), after controlling for age, height, physical activity (PA) and LM. STUDY DESIGN: Cross sectional study. MAIN OUTCOME MEASURES: LM, FM, bone mineral content (BMC) and density (BMD) were measured with dual energy X-ray absortiometry. The relationships of FM and LM with bone-related variables (subtotal body, hip, femoral neck and lumbar spine) were analyzed by linear regression and differences between weight and fat status were analyzed by one-way analysis of covariance. RESULTS: In men, there were no significant associations between FM and BMC or BMD. In women FM was positively associated with bone-related variables after adjustment for age, height and PA, whereas adjustment for LM removed all these significant associations. Overweight/obese elderly women had higher BMC and BMD than their non-overweight peers in all regions studied. Additional adjustment for PA did not change the differences between weight status groups, while adjusting for LM removed some of the associations. Overfat/obese men and women did not show higher levels of bone mass than their non-overfat peers. LM was positively associated with bone variables in both sexes. Additional adjustment for PA and FM did not alter the results. CONCLUSION: The association between fat mass and bone mass of elderly women is mediated by the independent association between lean mass and bone mass. PMID- 23089560 TI - Evaluation of screening tests for predicting older driver performance and safety assessed by an on-road test. AB - A number of tests and test batteries are available for the prediction of older driver safety, but many of these have not been validated against standardized driving outcome measures. The aim of this study was to evaluate a series of previously described screening tests in terms of their ability to predict the potential for safe and unsafe driving. Participants included 79 community dwelling older drivers (M=72.16 years, SD=5.46; range 65-88 years; 57 males and 22 females) who completed a previously validated multi-disciplinary driving assessment, a hazard perception test, a hazard change detection test and a battery of vision and cognitive tests. Participants also completed a standardized on-road driving assessment. The multi-disciplinary test battery had the highest predictive ability with a sensitivity of 80% and a specificity of 73%, followed by the hazard perception test which demonstrated a sensitivity of 75% and a specificity of 61%. These findings suggest that a relatively simple and practical battery of tests from a range of domains has the capacity to predict safe and unsafe driving in older adults. PMID- 23089561 TI - Ethics committees and research: an unintentional barrier? PMID- 23089562 TI - Case of the month #179: nasal mucosal melanotic melanoma. PMID- 23089563 TI - Many days at home during neutropenia after allogeneic hematopoietic stem cell transplantation correlates with low incidence of acute graft-versus-host disease. AB - Patients are isolated in the hospital during the neutropenic phase after allogeneic hematopoietic stem cell transplantation. We challenged this by allowing patients to be treated at home. A nurse from the unit visited and checked the patient. One hundred forty-six patients treated at home were compared with matched hospital control subjects. Oral intake was intensified from September 2006 and improved (P = .002). We compared 4 groups: home care and control subjects before and after September 2006. The cumulative incidence of acute graft-versus-host disease (GVHD) of grades II to IV was 15% in the "old" home care group, which was significantly lower than that of 32% to 44% in the other groups (P < .03). Transplantation-related mortality, chronic GVHD, and relapse were similar in the groups. The "new" home care patients spent fewer days at home (P = .002). In multivariate analysis, GVHD of grades 0 to I was associated with home care (hazard ratio [HR], 2.46; P = .02) and with days spent at home (HR, .92; P = .005) but not with oral nutrition (HR, .98; P = .13). Five year survival was 61% in the home care group as compared with 49% in the control subjects (P = .07). Home care is safe. Home care and many days spent at home were correlated with a low risk of acute GVHD. PMID- 23089564 TI - Hematopoietic cell transplantation with cord blood for cure of HIV infections. AB - Hematopoietic cell transplantation (HCT) using CCR5-Delta32/Delta32 stem cells from an adult donor has resulted in the only known cure of human immunodeficiency virus (HIV) infection. However, it is not feasible to repeat this procedure except rarely because of the low incidence of the CCR5-Delta32 allele, the availability of only a small number of potential donors for most patients, and the need for a very close human leukocyte antigen (HLA) match between adult donors and recipients. In contrast, cord blood (CB) transplantations require significantly less stringent HLA matching. Therefore, our hypothesis is that cure of HIV infections by HCT can be accomplished much more readily using umbilical CB stem cells obtained from a modestly sized inventory of cryopreserved CCR5 Delta32/Delta32 CB units. To test this hypothesis, we developed a screening program for CB units and are developing an inventory of CCR5-Delta32/Delta32 cryopreserved units available for HCT. Three hundred such units are projected to provide for white pediatric patients a 73.6% probability of finding an adequately HLA matched unit with a cell dose of >=2.5 * 10(7) total nucleated cells (TNCs)/kg and a 27.9% probability for white adults. With a cell dose of >=1 * 10(7) TNCs/kg, the corresponding projected probabilities are 85.6% and 82.1%. The projected probabilities are lower for ethnic minorities. Impetus for using CB HCT was provided by a transplantation of an adult with acute myelogenous leukemia who was not HIV infected. The HCT was performed with a CCR5-Delta32/Delta32 CB unit, and posttransplantation in vitro studies indicated that the patient's peripheral blood mononuclear cells were resistant to HIV infection. PMID- 23089565 TI - Increased plasma indoleamine 2,3-dioxygenase activity and interferon-gamma levels correlate with the severity of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. AB - Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme for the tryptophan catabolism that plays an important role in the induction of immune tolerance. To evaluate the expression levels of IDO and interferon (IFN)-gamma in patients receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT) and to identify the correlation between IDO activity, IFN-gamma, and acute graft-versus host disease (aGVHD), we measured IDO mRNA expression in peripheral blood mononuclear cells in 89 allo-HSCT patients by reverse transcription-polymerase chain reaction. The IDO activity in plasma was also performed by reverse-phase high-performance liquid chromatography; plasma IFN-gamma was detected by a standard enzyme-linked immunosorbent assay. IDO mRNA was detected in 55 of 74 patients (74.32%) with aGVHD. Of patients without aGVHD, only 2 of 26 expressed IDO mRNA (7.69%); none of 8 healthy volunteers was positive for IDO expression. Plasma IDO activity was much higher in aGVHD patients than in those without aGVHD (4.74 +/- 3.35 vs 1.79 +/- 1.02, respectively; P < .0001) or in healthy control subjects (4.74 +/- 3.35 vs 1.77 +/- .22; P < .0001). Patients with severe (grade III/IV) aGVHD had much higher IDO activity than those with mild (grade I/II) aGVHD (6.57 +/- 3.34 vs 2.46 +/- 1.41; P < .0001). Meanwhile, there was a significant increase in plasma IFN-gamma level in aGVHD patients (P = .0043). IDO activity decreased after alleviation of aGVHD, whereas fluctuation of plasma IDO was also observed upon the recurrence of aGVHD. Plasma IDO activity was correlated with the level of plasma IFN-gamma (r = .8288; P < .0001). Using receiver-operating characteristic curves analysis, the sensitivity and specificity for evaluation of aGVHD were determined. The area under the curve of IDO activity was higher than that of IFN-gamma (.852 vs .694) with a sensitivity and specificity for IDO of 81% and 78%, respectively, whereas the sensitivity and specificity for IFN-gamma were 41% and 93%, respectively. IDO mRNA was expressed in blood mononuclear cells of patients with aGVHD. Plasma IDO activity was elevated in aGVHD patients and was correlated with the severity of aGVHD. In combination with plasma IFN-gamma, IDO activity may represent a potential biomarker for the diagnosis and evaluation of aGVHD after allo-HSCT. Intervention of the IDO pathway may also represent an alternative way to overcome steroid resistant aGVHD. PMID- 23089566 TI - Prognostic impact of posttransplantation iron overload after allogeneic stem cell transplantation. AB - In patients referred for allogeneic hematopoietic stem cell transplantation (HSCT), iron overload is frequent and associated with increased morbidity and mortality. Both the evolution of iron overload after transplantation and its correlation with late posttransplantation events are unknown. We studied 290 patients undergoing myeloablative allogeneic HSCT between 2000 and 2009. Serum ferritin, transferrin saturation, transferrin, iron, and soluble transferrin receptor were determined regularly between 1 and 60 months after HSCT, and values were correlated with transplantation outcome. Ferritin levels peaked in the first 3 months posttransplantation and then decreased to normal values at 5 years. Transferrin saturation and iron behaved analogously, whereas transferrin and soluble transferrin receptor increased after an early nadir. Landmark survival analysis showed that hyperferritinemia had a detrimental effect on survival in all periods analyzed (0 to 6 months P < .001; 6 to 12 months P < .001; 1 to 2 years P = .02; 2 to 5 years P = .002). This effect was independent of red blood cell transfusion dependency and graft-versus-host disease. Similar trends were seen for other iron parameters. These data show the natural dynamics of iron parameters in the setting of allogeneic HSCT and provide evidence for a prognostic role of iron overload extending beyond the immediate posttransplantation period. Interventions to reduce excessive body iron might therefore be beneficial both before and after HSCT. PMID- 23089567 TI - Hepatic veno-occlusive disease after hematopoietic stem cell transplantation: novel insights to pathogenesis, current status of treatment, and future directions. PMID- 23089568 TI - Controversies in BMT for lymphoma. AB - In this supplement the authors have outlined some of the important recent advances and areas for future investigation that will shape our current and future treatments of DLBCL.With a better understanding of the biology of this distinct yet heterogeneous group of diseases, we will more precisely classify the disease that each patient has and develop specific treatments to improve the results of both initial and salvage therapy. Improved classification schemas and therapeutic interventions based on specific disease biology should then lead to more effective application of both autologous and allogeneic HSCTs for these patients. It is hoped that these approaches, coupled with maintenance therapies such as those that have prolonged survival after autologous HSCT for multiple myeloma, will enhance the curability of DLBCL as well. PMID- 23089569 TI - Discrepancy between anti-hepatitis E virus immunoglobulin G prevalence assessed by two assays in kidney and liver transplant recipients. AB - BACKGROUND: Hepatitis E virus (HEV) is an emerging clinical threat in Europe among kidney and liver-transplant recipients. The incidence and prevalence of HEV infection in this special population are poorly known. False-negative results have been observed for anti-HEV IgG detection in severely immunocompromized persons. Moreover, large discrepancies have been reported between rates of anti HEV IgG detection in blood donors and hepatitis E cases. OBJECTIVES: To compare anti-HEV IgG and IgM prevalence using two different commercial microplate enzyme immuno assays (MEIAs) (Adaltis and Wantai) in 64 kidney-/liver-transplant recipients. STUDY DESIGN: Serum samples tested in our routine clinical practice over the 12/2009-12/2011 period with Adaltis MEIAs were retrospectively tested using Wantai MEIAs. IgG-positive sera were further tested by an immunoblot while those found IgM-positive were further tested with an immunochromatography rapid test and for the presence of HEV RNA. RESULTS: Positive results on anti-HEV IgG testing were obtained for seven (10.9%) compared to 20 (31.3%) serum samples with Adaltis and Wantai assays, respectively (p=0.005). Then, 6/7 (86%) of the serum samples positive with Adaltis and 16/20 (80%) of those positive with Wantai were positive with the immunoblot. One patient with chronic HEV infection was IgG negative with both MEIAs. Regarding anti-HEV IgM, Adaltis and Wantai assays were concordant for 97% of the serum samples, prevalence being 8% with both MEIAs. CONCLUSIONS: The accuracy of currently available commercial or in-house anti-HEV IgG MEIAs should be tested comparatively on a panel of serum samples collected from solid organ-transplant recipients, including some who experienced PCR documented HEV infection. PMID- 23089570 TI - Physicians' intentions to change pap smear frequency following human papillomavirus vaccination. AB - STUDY OBJECTIVE: We evaluated factors associated with physicians' intentions to perform Pap smears in human papillomavirus-vaccinated women. DESIGN: Physicians were mailed a survey asking about intentions to change cervical cancer screening based on patients' human papillomavirus vaccination status. PARTICIPANTS: A national sample of 1,738 Family Physicians, Internal Medicine Physicians, Pediatricians, and Obstetricians and Gynecologists was selected from the American Medical Association Physician Masterfile. Completed surveys were received from 1,118 physicians, of which 791 were included in the analyses. MAIN OUTCOME MEASURES: Bivariate analyses compared physician, practice, and patient characteristics by intention change screening frequency. Significant variables were included in a multivariable logistic regression model. RESULTS: Overall, 81.8% (n = 647) of physicians reported not planning to change Pap smear frequency for vaccinated women. Internal Medicine physicians were significantly more likely than Obstetrician/Gynecologists to report intentions to change frequency for vaccinated patients. Other factors significantly associated with the intention to change frequency were self-identification as a late adopter of new vaccines, a solo practice, and practicing primarily in a clinic or hospital-based setting. CONCLUSIONS: Although it appears most clinicians understand that human papillomavirus vaccination should not alter current screening practices, there is a need to develop and evaluate interventions for physicians who are likely to change their screening pattern based on human papillomavirus vaccination receipt. PMID- 23089571 TI - Factors contributing to initial weight loss among adolescents with polycystic ovary syndrome. AB - STUDY OBJECTIVE: To evaluate the impact of a multidisciplinary clinic on weight management among adolescents with PCOS. DESIGN: 140 adolescent females were evaluated in a multidisciplinary PCOS clinic from March 2005 to December 2008. The team included a pediatric endocrinologist, health psychologist, dietitian, and pediatric gynecologist. 110 were diagnosed with PCOS based on the Rotterdam Criteria. Height, weight, BMI, number of subspecialists seen, use of metformin, and compliance with return visits were obtained from medical records. SETTING: American Family Children's Hospital in Madison, Wisconsin. PARTICIPANTS: 110 adolescent females with polycystic ovary syndrome. INTERVENTIONS: Consultation with a dietitian and health psychologist. MAIN OUTCOME MEASURE: Change in weight. RESULTS: The average age at first visit was 15.9 years. The average BMI was 34.7 kg/m(2) (range 18.1-55.5). Seventy-six percent had an initial BMI above the 95(th) percentile. Interactions with providers at the initial visit included a pediatric endocrinologist (100%), health psychologist (60.9%), dietitian (75.5%) and gynecologist (70.9%). Seventy one percent returned for a follow-up visit, (average time of 4.5 months between visits) with 57% achieving weight loss (average 3.5 kg) and an additional 12.6% demonstrating no significant weight gain (< 1.5 kg). Thus, 69.6% demonstrated weight loss/stabilization. CONCLUSIONS: In this multidisciplinary clinic for adolescents with PCOS, nearly 70% of patients succeeded in short-term weight stabilization, with 57% demonstrating weight loss. Interactions with the health psychologist and dietitian appeared to play a key role in successful weight control, supporting the importance of psychology and nutrition expertise in the management of this disorder. PMID- 23089572 TI - Bilateral ovariectomy in young rats: what happens in their livers during cecal ligation and puncture induced sepsis? AB - STUDY OBJECTIVE: Pediatric ovarian masses comprise a heterogeneous group of benign and malignant lesions. Surgical methods consist of emergency or programmed surgery with tumoral resection and uni/bilateral oophorectomy or salpingo oophorectomy. We examined whether bilateral ovariectomy (OVX) worsens liver injury during the onset of cecal ligation and puncture (CLP)-induced sepsis in rats. DESIGN: The rat groups were: sham, bilateral-OVX, sepsis, and OVX-sepsis. SETTINGS: After OVX operation, rats were allowed to recover for 12 weeks. At the end of recovery, CLP was applied 16 hours after sepsis induction. MAIN OUTCOME: There was a significant difference in the numerical density of hepatocytes only between the sepsis and the OVX-sepsis groups. Serum ALT and AST were increased significantly in the OVX-sepsis group. NF-kappaB activation after OVX increased after induction of sepsis. OVX-sepsis group showed marked thrombosis in portal vein branches and the central vein, degeneration in the bile ducts, and widespread ischemic areas in liver sections. Intra-inflammatory cell invasion was observed in both the portal and intrasinusoidal areas. DISCUSSION: This study indicates that increases in liver NF-kappaB activity in ovariectomized rats following CLP-induced sepsis correlates with elevated levels of serum ALT and AST and with histopathologic changes in rat liver. Bilateral OVX therefore appears to play a role in the activation of NF-kappaB or in production of cytokines in liver cells. Thus, we provided novel insight into the effects of OVX on liver injury following CLP-induced sepsis. PMID- 23089573 TI - Clinical and metabolic features of polycystic ovary syndrome among Chinese adolescents. AB - OBJECTIVES: To explore the clinical and metabolic features exhibited by Chinese adolescents with polycystic ovary syndrome (PCOS) and to determine the differences between nonobese and obese adolescent patients with PCOS. DESIGN: Clinical cross-sectional study. SETTING: Department of Gynecology and Reproductive Center. PARTICIPANTS: 25 obese and 66 nonobese adolescents with PCOS and 26 age-matched controls. INTERVENTIONS: Fasting venous blood samples and an oral glucose tolerance test using 75 g of glucose were obtained from PCOS patients and controls. MAIN OUTCOME MEASURES: Clinical features were summarized. Serum levels of FSH, LH, E(2), TT, SHBG, fasting insulin, and fasting glucose were measured. RESULTS: The prevalence of obesity in adolescents with PCOS was 27% (25/91). 99% of these patients presented with menstrual disorders, 84% presented with clinical and/or biochemical hyperandrogenism, and 90% exhibited an ultrasonographic appearance of polycystic ovaries. The prevalence of hirsutism and acanthosis nigricans were higher in the obese PCOS group than in the nonobese PCOS group (72% vs 41% and 44% vs 5%, respectively). A total of 5 of 20 obese (25%) and 5 of 36 nonobese patients (14%) demonstrated impaired glucose tolerance levels. CONCLUSIONS: Chinese adolescents with PCOS manifest clinical and metabolic features similar to those of adult Chinese women with PCOS except for the increased prevalence of hyperandrogenism and insulin resistance. Adolescents with high risk factors, especially those with menstrual disorders and hyperandrogenism, may need careful clinical screening. PMID- 23089574 TI - Partner roles in contraceptive use: what do adolescent mothers say? AB - STUDY OBJECTIVE: To examine the role of sexual partners in adolescent mothers' use of non-coital dependent contraceptive methods in the postpartum period. DESIGN/SETTING/PARTICIPANTS: 40 African American adolescent mothers completed surveys and qualitative interviews during the first postpartum year as part of a larger longitudinal study in Chicago, Illinois. Themes related to contraception and sexual partners were analyzed. MAIN OUTCOME MEASURES: Adolescent mothers' reports of partners' roles in the use of non-coital dependent contraceptive methods (i.e., oral contraceptives, intrauterine contraception, and depot medroxyprogesterone acetate). RESULTS: Partners largely supported the use of non coital dependent contraceptive methods, yet mechanisms of support varied greatly, from advocating for specific methods to facilitating participants' continuation of their chosen method. Unsupportive partners either expressed concerns about the safety and side effects of specific methods or desired another child in the near future. Participants valued these preferences to different degrees when making their contraceptive decisions. CONCLUSIONS: Partners of adolescent mothers play varying roles in postpartum contraceptive decisions. They thus have the potential both to inhibit and to facilitate the use of non-coital dependent contraception. Quantitative research is needed to further evaluate how partner attitudes and support behaviors, among other factors, affect contraceptive initiation and continuation among adolescent mothers. PMID- 23089575 TI - Genotype-specific Taqman(r) assays for the detection and rapid characterisation of European strains of viral haemorrhagic septicaemia virus. AB - Viral haemorrhagic septicaemia virus (VHSV) is the agent of a disease that causes mortality events in marine and freshwater fish. It is one of the most important pathogens in European rainbow trout (Oncorhynchus mykiss) aquaculture. Four major genotypes of the virus are recognised reflecting different geographic and host ranges. Genotyping of VHS isolates is important for disease management enabling monitoring of disease spread into new geographical regions or susceptible species. This study sought to develop molecular tools for rapid and efficient classification of European VHSV genotypes. Specificity of genotype-specific real time reverse transcription polymerase chain reaction (RT-qPCR) assays targeting the viral nucleoprotein (N) gene was tested using 66 viral isolates. All designed Taqman((r)) RT-qPCR assays were genotype specific, displayed a high sensitivity and together constituted a diagnostic method for the rapid discrimination of European VHSV genotypes. Practical diagnostic applications of such assays demonstrated in this study include: (1) rapid genotype determination of isolates; and (2) identification of mixed-genotype isolates originating from pooled samples in areas where genotype distribution is known to overlap. However, the most important application will be supporting international VHSV surveillance programmes through the provision of a rapid specific and sensitive isolate characterisation method. PMID- 23089576 TI - Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier. AB - The aim of this study was to investigate the ability of a third-generation (G3) polyamidoamine (PAMAM) dendrimer-based carrier to enhance the permeability of paclitaxel (pac) and to overcome cellular barriers. G3 dendrimers were surface modified with lauryl chains (L) and conjugated with paclitaxel (pac) via a glutaric anhydride (glu) linker, followed by labeling with FITC. Biological evaluation of the dendrimer and conjugates was conducted using the human colon adenocarcinoma cell line (Caco-2) and primary cultured porcine brain endothelial cells (PBECs). LDH assay was used to evaluate the cytotoxicity of the dendrimer and conjugates. Cytotoxicity studies showed that the conjugation of lauryl chains and paclitaxel on G3 dendrimer significantly (p<0.05) increased the cytotoxicity against both cell types. Permeability studies of dendrimer-drug conjugates demonstrated an increase in the apparent permeability coefficient (P(app)) in both apical to basolateral A->B and basolateral to apical B->A directions across both cell monolayers compared to unmodified G3 and free drug. The B->A P(app) of paclitaxel was significantly (p<0.05) higher than the A->B P(app), indicating active function of P-gp efflux transporter system in both cell models. L6-G3-glu pac conjugate had approximately 12-fold greater permeability across both cell monolayers than that of paclitaxel alone. PMID- 23089578 TI - Hot-melt coating with lipid excipients. AB - Polymer coatings are widely used to provide drug protection, taste masking, coloration and modified drug release. Typically, coating polymers must be diluted or dispersed in solvents (water or organic) prior to coating and gliding agents are commonly added to prevent particle sticking throughout processing. Lipid excipients present an attractive alternative to standard polymer coatings as they only require melting before application directly onto the substrate. Solvent evaporation is not required; consequently powders with very high specific surface areas can be coated rapidly. A number of different lipid excipients can be used in coating and choosing the appropriate excipient for the application requires an understanding of their physico-chemical properties and its associated effect on drug release. PMID- 23089577 TI - Preparation and evaluation of lidocaine hydrochloride-loaded TAT-conjugated polymeric liposomes for transdermal delivery. AB - Transactivation transcriptional activator (TAT) peptides were conjugated on the octadecyl-quaternized, lysine-modified chitosan to form polymeric liposomes (TAT PLs) with cholesterol for improving transdermal delivery of local anesthetic lidocaine hydrochloride (LID). In this study, the LID loaded TAT-conjugated polymeric liposomes (LID-TAT-PLs) have been successfully prepared. LID-TAT-PLs were characterized by determination of their particle size, polydispersity, morphology, drug encapsulation efficiency, drug release behavior in vitro, and storage-stability. The skin permeation of LID-TAT-PLs was examined using a Franz diffusion cell mounted with depilated mouse skin in vitro, and penetration of TAT PLs was visualized by confocal laser scanning microscopy (CLSM). The results showed that LID-TAT-PLs were spherical in solution, with substantially smaller mean diameter (154.7+/-10.7 nm), higher encapsulation efficiency (80.05+/-2.64%) and better stability in contrast to conventional liposomes (CLs). From the in vitro skin permeation results, transdermal flux of LID-TAT-PLs was approximately 4.17 and 1.75 times higher than that of LID solution and LID CLs (P<0.05). CLSM studies also confirmed that TAT-PLs reached viable layers of the skin. Hence, the results indicate that LID-TAT-PLs are effective and potential alternative for the LID transdermal formulation. PMID- 23089579 TI - Nanogels fabricated by lysozyme and sodium carboxymethyl cellulose for 5 fluorouracil controlled release. AB - Lysozyme (Ly) and sodium carboxymethyl cellulose (CMC) were used to fabricate nanogels by a convenient method without using any chemical treatment except simple heating to achieve the denaturation temperature of Ly. The prepared nanogels were characterized by dynamic laser scattering (DLS), rheological analysis, transmission electron microscopy (TEM), field emission scanning electron microscope (FE-SEM) and X-ray photoelectron spectroscopy (XPS). The nanogels are of spherical shape with average hydrodynamic diameter of 241 nm and the swelling ratio of nanogels is about 5. Then 5-fluorouracil was used as a model drug to investigate the entrapment efficiency and release ability in nanogels. It turned out to be that the release in simulated gastric fluid (SGF) was more slowly compared with that in simulated intestinal fluid (SIF), which could protect the 5-Fu in stomach and ensure it released in intestines. PMID- 23089580 TI - Integrity and stability of oral liposomes containing bile salts studied in simulated and ex vivo gastrointestinal media. AB - The objective of this study was to investigate the integrtity and stability of oral liposomes containing glycocholate (SGC-Lip) in simulated gastrointestinal (GI) media and ex vivo GI media from rats in comparison with conventional liposomes (CH-Lip) composed of soybean phosphatidylcholine and cholesterol. Membrane integrity of liposomes was evaluated by monitoring calcein release, particle size and distribution in different simulated GI media. The stability of liposomes encapsulating insulin was investigated in simulated GI fluids containing pepsin or pancreatin and ex vivo GI enzyme fluids. Simulated GI media with low pH or physiological bile salts resulted in significant increase in calcein release, but dynamic laser scattering data showed that the size and distribution were generally stable. SGC-Lip retained the major amount of the initially encapsulated insulin as compared with CH-Lip in simulated GI fluids (SGF, FaSSGF, SIF and FeSSIF-V2). SGC-Lip retained respectively 17.1% and 20.5% of the initially encapsulated insulin in ex vivo GI fluid, which were also significantly more than CH-Lip. These results suggested that SGC-Lip could protect insulin from degradation to some degree during their transit through the gastrointestinal tract and contributed to enhanced oral absorption. PMID- 23089581 TI - Polymeric nanocapsules with SEDDS oil-core for the controlled and enhanced oral absorption of cyclosporine. AB - Self-microemulsifying drug delivery system (SEDDS) cored-polymeric nanocapsules (NC) were fabricated using emulsion diffusion method for the controlled oral absorption of the poorly water soluble drug, cyclosporine. Poly-dl-lactide (PDLLA) was used as the shell-forming polymer. The NCs in different polymer/oil ratios (from 25/125 to 125/125) were prepared following a solvent-diffusion method. Especially, the SEDDS oil-core compositions, which can form microemulsions on dispersion, were selected based on a pseudo-phase diagram study and further optimized based on the solubility and permeability studies. The prepared NCs were with a mean diameter of 150-220 nm and 9.4-4.5% w/w drug loading. In vivo study in rats showed that the optimized NC(50/125) and NC(100/125) released the drug in controlled way as well as enhanced the bioavailability significantly with AUC(0-24h) values of 14880.3+/-1470.6 and 12657.8+/-754.5 ng h/ml, respectively, compared to that of SEDDS-core solution (9878.9+/-409.6 ng h/ml). Moreover it was observed that the NCs maintained blood concentration of cyclosporine (>500 ng/ml) for 14-20 h but in the case of control formulation it was only 7.33 h. Our results suggest that the prepared NCs could be a potential carrier for the oral controlled release formulation of cyclosporine. PMID- 23089582 TI - Characterization of reducible peptide oligomers as carriers for gene delivery. AB - The stability of DNA-polyplexes and intracellular DNA release are important features of gene delivery systems. To study these features, we have evaluated reducible cysteine-flanked linear lysine and arginine-rich peptides, modified with histidine residues. The reducible disulfide bonds in cysteine flanked peptides and histidine residues should augment DNA release from the peptide-DNA complexes upon disintegration of the reducible bonds. Template polymerization and oxidative polycondensation were applied to obtain peptide oligomers used for DNA polyplex preparation. The peptides and DNA-peptide complexes were investigated with physical, chemical and transfection measurements. Physicochemical and transfection properties of DNA-polyplexes depended on the amino acid sequence of the peptidic polymers and type of the polymerization. MALDI-TOF analysis of oxidatively polycondensed products revealed several forms of peptide oligomers corresponding to 5-8 amino acid monomers. DNA-peptide particles based on template polymerized complexes were more resistant to relaxation by negatively charged heparan sulfate than polyplexes formed with oxidatively condensed peptides. Complexes of DNA with the polycations prepared by oxidative polycondensation exhibited a 100-1000-fold higher level of gene expression compared to DNA/template-polymerized peptide complexes. The most efficient transgene expression was shown with arginine-rich polyplexes. Transfection efficacy of the arginine-rich polyplexes was even 10-fold better than that of DNA/PEI complexes. On average, polyplexes based on cysteine-flanked peptide oligomers showed lower cytotoxicity than non-reducible high molecular weight polylysine/DNA particles. We conclude that reducible peptide oligomers provide efficient DNA transfection and have the potential as vehicles for gene delivery. PMID- 23089583 TI - In vitro and in vivo anticancer activity of a novel puerarin nanosuspension against colon cancer, with high efficacy and low toxicity. AB - The present study aims to evaluate the anticancer activity of puerarin nanosuspensions in human colon cancer HT-29 cell line in vitro and in vivo. Puerarin nanosuspensions were prepared by the high-pressure homogenization (HPH) technique. The HT-29 cells were incubated with increasing concentrations of puerarin solution and nanosuspensions for indicated times. MTT evaluated cellular viability and investigated the effect of puerarin on cell proliferation of HT-29. Annexin V-FITC/PI staining method was conducted to determine the influences of the puerarin nanosuspensions on cell cycle and apoptosis. The in vivo anticancer activity of the puerarin nanosuspensions was observed in HT-29 cancer bearing mice. The puerarin nanosuspensions were well re-dispersed in aqueous media a mean diameter about 400-500 nm. Cytotoxicity assay, observation of morphological changes and early apoptosis revealed that the puerarin nanosuspensions could significantly enhance the in vitro anti-proliferation against HT-29 cells compared to the puerarin free solution. The prepared puerarin nanosuspensions in vivo evaluation showed higher anticancer efficacy and lower toxicity compared to the free solution, as shown by changes in tumor volumes, body weights, and survival rates. Based on these data, the potential of the puerarin nanosuspensions to serve as a cancer chemotherapeutic agent for colon cancer could be suggested. PMID- 23089584 TI - Characterization of clinical course and usual care patterns in female metastatic breast cancer patients treated with zoledronic acid. AB - PURPOSE: To describe usual care received by women with bony metastatic breast cancer (ICD-9: 174.xx and 198.5) treated in a United States specialty cancer hospital, an Electronic Medical Record (EMR)-based retrospective review identified 111 deceased female breast cancer patients >=18 years of age treated with zoledronic acid (ZOL). RESULTS: Baseline symptoms included bone pain/fracture (58.6%), breathing difficulties (24.3%), or mental status changes (11.7%). ZOL was started at/after metastatic diagnosis for 75.7% of women (N = 84), with average administration of 15.9 months (median 11.3). Nearly 20% required reduced ZOL doses, most (54.5%) due to impaired renal function; 61.3% discontinued ZOL due to patient death/disease progression. Adverse events were reported in 10.8%, while 0.9% (N = 1) had a documented osteonecrosis of the jaw. CONCLUSIONS: Initiation of palliative care should be considered early in patients with a history of metastatic breast cancer who report bone pain or other skeletal related events. PMID- 23089585 TI - Mortality in the 2011 tsunami in Japan. AB - INTRODUCTION: On 11 March 2011, a magnitude 9.0 earthquake caused a huge tsunami that struck Northeast Japan, resulting in nearly 20 000 deaths. We investigated mortality patterns by age, sex, and region in the 3 most severely affected prefectures. METHODS: Using police data on earthquake victims in Iwate, Miyagi, and Fukushima prefectures, mortality rates by sex, age group, and region were calculated, and regional variability in mortality rates across age groups was compared using rate ratios (RRs), with the rates in Iwate as the reference. RESULTS: In all regions, age-specific mortality showed a tendency to increase with age; there were no sex differences. Among residents of Iwate, mortality was markedly lower among school-aged children as compared with other age groups. In northern Miyagi and the southern part of the study area, RRs were higher among school-aged children than among other age groups. CONCLUSIONS: The present study could not address the reasons for the observed mortality patterns and regional differences. To improve preparedness policies, future research should investigate the reasons for regional differences. PMID- 23089586 TI - Hemispheric differences in the organization of memory for text ideas. AB - The goal of this study was to examine hemispheric asymmetries in episodic memory for discourse. Access to previously comprehended information is essential for mapping incoming information to representations of "who did what to whom" in memory. An item-priming-in-recognition paradigm was used to examine differences in how the hemispheres represent discourse. Both hemispheres retained accurate information about concepts from short passages, but the information was organized differently. The left hemisphere was sensitive to the structural relations among concepts in a text, whereas the right hemisphere differentiated information that appeared in one passage from information that appeared in another. Moreover, the right hemisphere, but not the left hemisphere, retained information about the spatial/temporal proximity among concepts in a passage. Implications of these results for the roles of the right and left hemispheres in comprehending connected discourse are discussed. PMID- 23089587 TI - Copeptin: a marker for stress reaction in fetuses with intrauterine growth restriction. AB - OBJECTIVE: To compare venous cord plasma concentrations of 4 vasoactive peptide precursors: carboxy-terminal proarginine vasopressin, CT-prondothelin (ET)-1, midregional proadrenomedullin, and MR-proatrial natriuretic peptide, between fetuses with intrauterine growth restriction and appropriate for gestational age controls. STUDY DESIGN: Matched-pair analysis of 12 fetuses with significant intrauterine growth restriction and 42 healthy appropriate for gestational age control fetuses. All infants were singletons, delivered by elective section after 34 weeks and without chromosomal abnormalities. RESULTS: Umbilical cord plasma copeptin levels (median [range]) were 4-fold higher in intrauterine growth restriction infants than in matched appropriate for gestational age controls: 23.2 (6.7-449) vs 5.1 (2.5-53) pmol/L (P < .001). Multivariate regression analysis revealed an association between copeptin and umbilical artery resistance index z-score (P = .034). The 3 other precursor peptides showed no changes. CONCLUSION: High copeptin concentrations in the cord blood of intrauterine growth restriction newborns reflect a fetal stress response and support the fetal programming hypothesis. PMID- 23089588 TI - Reply to Chan-Tack et al. PMID- 23089589 TI - Type I interferon signaling protects mice from lethal henipavirus infection. AB - Hendra virus (HeV) and Nipah virus (NiV) are closely related, recently emerged paramyxoviruses that form Henipavirus genus and are capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. However, in contrast to many other species and despite expression of functional virus entry receptors, mice are resistant to henipavirus infection. We report here the susceptibility of mice deleted for the type I interferon receptor (IFNAR-KO) to both HeV and NiV. Intraperitoneally infected mice developed fatal encephalitis, with pathology and immunohistochemical features similar to what was found in humans. Viral RNA was found in the majority of analyzed organs, and sublethally infected animals developed virus-specific neutralizing antibodies. Altogether, these results reveal IFNAR-KO mice as a new small animal model to study HeV and NiV pathogenesis, prophylaxis, and treatment and suggest the critical role of type I interferon signaling in the control of henipavirus infection. PMID- 23089591 TI - Clinical experience with intravenous zanamivir under an emergency investigational new drug program in the United States. PMID- 23089592 TI - Well-defined novel fluorene-containing polymers: synthesis, fluorescent properties, and micellar nanoparticles. AB - We report the synthesis of a new monomer, 9,9-diethylfluoren-2-yl methyl methacrylate (FMMA) and its controlled reversible addition-fragmentation chain transfer (RAFT) homopolymerization to give PFMMA with narrow polydispersity indices (PDIs). The corresponding copolymerization with 2-(N,N dimethylamino)ethyl methacrylate (DMAEMA) also gave well-defined block and random copolymers with controlled molecular weights and narrow PDIs. Their thermal behavior, UV-Vis absorption, and photoluminescent properties were studied. The PDMAEMA-b-PFMMA amphiphilic block copolymers showed self-assembly into aqueous spherical micellar nanoparticles with uniform size. The PFMMA core showed photoluminescence when carrying dichloromethane "guest" molecules and its emission was shown to be quenched after the release of the guest. PMID- 23089590 TI - Cell-based measures of viral persistence are associated with immune activation and programmed cell death protein 1 (PD-1)-expressing CD4+ T cells. AB - BACKGROUND: Studies aimed at defining the association between host immune responses and human immunodeficiency virus (HIV) persistence during therapy are necessary to develop new strategies for cure. METHODS: We performed a comprehensive assessment of ultrasensitive plasma HIV RNA levels, cell-associated HIV RNA levels, proviral HIV DNA levels, and T cell immunophenotyping in a cohort of 190 subjects in whom HIV levels were suppressed by highly active antiretroviral therapy. RESULTS: The median CD4(+) T cell count was 523 cells/mm(3), and the median duration of viral suppression was 31 months. Cell associated RNA and proviral DNA levels (but not ultrasensitive plasma HIV RNA levels) were positively correlated with frequencies of CD4(+) and CD8(+) T cells expressing markers of T-cell activation/dysfunction (CD38, HLA-DR, CCR5, and/or programmed cell death protein 1 [PD-1]) (P < .05). Having a low CD4(+) T-cell count despite receipt of virologically suppressive therapy was associated with high cell-associated RNA and proviral DNA levels (P < .01) and higher frequencies of CD4(+) T cells expressing CD38, HLA-DR, CCR5, and/or PD-1 (P < .0001). CONCLUSIONS: Cell-based measurements of viral persistence were consistently associated with markers of immune activation and the frequency of PD-1-expressing CD4(+) T cells. Treated patients with a low CD4(+) T-cell count had higher frequencies of PD-1-expressing CD4(+) T cells and cell-based measures of viral persistence, suggesting that HIV infection in these individuals may be more difficult to cure and may require unique interventions. PMID- 23089593 TI - One-pot preparation of highly fluorescent cadmium telluride/cadmium sulfide quantum dots under neutral-pH condition for biological applications. AB - Water-soluble CdTe/CdS quantum dots (QDs) with tuneable emissions were prepared in aqueous solution at pH=6-7 via refluxing and hydrothermal treatment. The resultant CdTe/CdS QDs are stabilized with mercaptosuccinic acid (MSA) and show high fluorescence quantum yields (maximum QY is 84%). Characterization with UV Vis, PL, XPS, XRD and TEM demonstrates a core (CdTe)-shell (CdS) structure, which leads to high fluorescence quantum yields. The effective protection from CdS shell and MSA enables CdTe QDs to be chemically stable in a pH range of 6-9 and less toxic. These merits make our CdTe/CdS QDs very promising for bio-imaging applications, as exemplified by labelling HEK 293 cells. PMID- 23089594 TI - Surface-active copolymer formation stabilizes PEG droplets and bubbles in silicone foams. AB - Large increases in viscosity are not normally observed when insoluble liquid polymers are mixed in the absence of a compatibilizing agent: the liquids separate into bulk phases. Mixing propyl- or allyl-modified oligo(ethylene glycol)(PEG), but not the parent hydroxy-terminated oligo(ethylene glycol), with silicone pre-elastomers led a sharp increase in viscosity that preceded the onset of cure. Only in the case of allyl-modified PEG, however, did a low density, closed cell silicone foam form that, in addition to trapped bubbles, contained dispersed PEG droplets. Rheological studies demonstrate that the origins of the viscosity build lie in the formation, shortly after mixing, of organo-PEG stabilized droplets that act as fillers within the silicone pre-elastomers. Similar viscosity builds were not observed with hydroxy-terminated oligo(ethylene glycol). Although the propyl-modified PEG led initially to large viscosity increases, its ability to stabilize bubbles was comparably limited. The surface activity of the propyl- and allyl-PEG compounds themselves facilitates the formation of a colloidal dispersion within the silicone. However, the key to the observed foamed product is the in situ platinum-catalyzed hydrosilylation of the allyl group, prior to or concomitant with silicone cure, leading to PEG-silicone copolymers that are able to stabilize both dispersed PEG droplets and bubbles. PMID- 23089595 TI - Electroosmotic shear flow in microchannels. AB - We generate and study electroosmotic shear flow in microchannels. By chemically or electrically modifying the surface potential of the channel walls a shear flow component with controllable velocity gradient can be added to the electroosmotic flow caused by double layer effects at the channel walls. Chemical modification is obtained by treating the channel wall with a cationic polymer. In case of electric modification, we used gate electrodes embedded in the channel wall. By applying a voltage to the gate electrode, the zeta potential can be varied and a controllable, uniform shear stress can be applied to the liquid in the channel. The strength of the shear stress depends on both the gate voltage and the applied field which drives the electroosmotic shear flow. Although the stress range is still limited, such a microchannel device can be used in principle as an in situ micro-rheometer for lab on a chip purposes. PMID- 23089596 TI - Combined HPLC/HPSEC study of Suwannee River Fulvic Acid adsorptive fractionation on alpha-aluminum oxide. AB - A novel liquid chromatographic (LC) method with repeated injections of Suwannee River Fulvic Acid (SRFA) was used to investigate its adsorptive fractionation by synthetic alpha-Al(2)O(3). Eluent (i.e., non-retained) SRFA for each injection was monitored by two ultraviolet (UV) absorbance detection channels (300 and 365 nm) and one fluorescence detection channel (lambda(ex)=350 nm, lambda(em)=450 nm). Preferential adsorption of SRFA constituents was revealed by the different responses of the three LC detection channels. Samples of non-retained SRFA from injections of three independent replicate experiments were collected and aggregated for subsequent analysis by steady state ultraviolet-visible (UV/vis) absorption spectrometry and size exclusion chromatography (SEC). The ratio of absorbance at 254 and 204 nm, a surrogate for specific UV absorbance at 254 nm, increased with increasing injection number for the non-retained SRFA, indicating the preferential adsorption of SRFA constituents containing aromatic moieties. SEC analysis confirmed the preferential adsorption of higher molecular weight (MW) SRFA constituents as the non-adsorbed SRFA fractions increased in MW across the series of injections. The SEC results also suggested that certain SRFA constituents in the ca. 2-5 kDa MW range adsorbed in early injections were displaced by higher MW species (ca. 5-10 kDa) in later injections. PMID- 23089597 TI - N-stearoyl amino acid derivatives: potent biomimetic hydro/organogelators as templates for preparation of gold nanoparticles. AB - New potent N-(2-aminoethyl)-alpha-[(1-oxoheptadecyl)amino]acetamide derivative gelators were synthesized and their self-assembly in various common solvents was examined. These compounds exhibit high gelation ability in many organic solvents, such as toluene or acetonitrile, with a lower critical gelation concentration of 0.15 wt.% in some cases. The organogels were analyzed by (1)H nuclear magnetic resonance (NMR) and Fourier transform-infrared (FT-IR) spectroscopies, and their phase transition temperatures (T(gel)) were determined using differential scanning calorimetry (DSC). The homogeneity of the gel networks was observed using field emission scanning electron microscopy (FE-SEM) and transmission electron microscopy (TEM) and a lamellar structure was confirmed by X-ray diffraction (XRD) analysis. A correlation between the more stable conformations of N-acyl glutamine derivative determined by molecular modeling and the gelation behavior afforded evidence for the influence of the dimethylene side chain on the gelation ability. The organogels were employed as templates for the in situ preparation of stable gold nanoparticles (GNPs) using different reduction methods of HAuCl(4) dispersed in the gel matrix, and the resulting GNPs solutions were studied using UV-Visible absorption and TEM. PMID- 23089598 TI - Investigation of surface synergetic oxygen vacancy in CuO-CoO binary metal oxides supported on gamma-Al2O3 for NO removal by CO. AB - The influence of CO pretreatment on the properties of CuO-CoO/gamma-Al(2)O(3) catalysts was investigated by SEM, TEM, XRD, LRS, XPS, TPR, and in situ FT-IR techniques. And the activities were measured by NO removal by CO. It was shown that the CuO-CoO/gamma-Al(2)O(3) catalysts following CO pretreatment exhibited extremely high activity and selectivity. The interaction between copper oxide and cobalt oxide upon the gamma-Al(2)O(3) support before and after CO pretreatment was tentatively discussed in the view of incorporation model. According to this model, the dispersed Cu-O-Co species could be reduced to Cu-?-Co species by CO pretreatment, which was considered to be the primary active component for this reaction. FT-IR results suggested that CO was apt to adsorb on Cu(+) sites rather than Co(2+) while the NO adsorbates could convert to much more stable species with the temperature increasing. Undoubtedly, it was the surface synergetic oxygen vacancy coupled with the adjacent Cu and Co ions that guaranteed the reaction well processing over the CO pretreated samples. As a result, a possible mechanism was tentatively proposed. PMID- 23089599 TI - Properties of surface-cross-linked micelles probed by fluorescence spectroscopy and their catalysis of phosphate ester hydrolysis. AB - Cross-linking of a tripropargylated ammonium surfactant by a diazide cross-linker in the presence of Cu(I) catalysts yielded surface-cross-linked micelles (SCMs) as water-soluble nanoparticles. Cross-linking had a profound impact on the properties of the micelles. The binding of 1-anilinonaphthalene-8-sulfonic acid (ANS) indicated that the SCMs contained two types of binding sites, favoring the polar and nonpolar excited states of the probe, respectively. The SCMs also shielded the excited states of ANS from solvent exposure better than the micelles of cetyltrimethylammonium bromide (CTAB). The SCMs inhibited the excited state proton transfer (ESPT) of a polyanionic probe, pyranine, more strongly than CTAB micelles. The ESPT of a more hydrophobic probe, 2-naphthol, was found to be influenced by the stronger surface basicity of the SCMs, as well as their better shielding of the probe from the aqueous phase than the CTAB micelles. The stronger surface basicity of the SCMs also enabled them to catalyze the hydrolysis of an activated phosphate ester at neutral pH better than CTAB micelles. PMID- 23089600 TI - Comparative solution equilibrium studies of anticancer gallium(III) complexes of 8-hydroxyquinoline and hydroxy(thio)pyrone ligands. AB - The stoichiometry and stability constants of the Ga(III) complexes of 8 hydroxyquinoline (HQ), 8-hydroxyquinoline-5-sulfonate (HQS), maltol, thiomaltol, allomaltol and thioallomaltol were determined by means of pH-potentiometry, UV vis spectrophotometry, spectrofluorometry and (1)H NMR spectroscopy in aqueous solution. Spectrofluorometry was used to determine the stability constants of the Ga(III)-HQ species in water. Formation of [GaL](2+), [GaL(2)](+) and [GaL(3)] complexes was found and the Ga(III) binding ability of the ligands followed the order: thioallomaltol4 min. RESULTS: At least one signal loss >4 min was present for, respectively, 4% (95% confidence interval [CI] 0-9.43) of patients in Period A and 28% (95% CI 15.5 40.5) of patients in Period B (P<0.05). A significant difference was detected for all variables analyzed between the two periods (P<0.05). CONCLUSION: STAN quality signal deteriorates in the second stage of labor compared to that in the first stage. As guidelines clearly indicate that signal quality influences the decision process, it should be carefully and systematically checked before including STAN analysis in the decision-making. PMID- 23089604 TI - Multisensory emotions: perception, combination and underlying neural processes. AB - In our everyday lives, we perceive emotional information via multiple sensory channels. This is particularly evident for emotional faces and voices in a social context. Over the past years, a multitude of studies have addressed the question of how affective cues conveyed by auditory and visual channels are integrated. Behavioral studies show that hearing and seeing emotional expressions can support and influence each other, a notion which is supported by investigations on the underlying neurobiology. Numerous electrophysiological and neuroimaging studies have identified brain regions subserving the integration of multimodal emotions and have provided new insights into the neural processing steps underlying the synergistic confluence of affective information from voice and face. In this paper we provide a comprehensive review covering current behavioral, electrophysiological and functional neuroimaging findings on the combination of emotions from the auditory and visual domains. Behavioral advantages arising from multimodal redundancy are paralleled by specific integration patterns on the neural level, from encoding in early sensory cortices to late cognitive evaluation in higher association areas. In summary, these findings indicate that bimodal emotions interact at multiple stages of the audiovisual integration process. PMID- 23089605 TI - Inducible pluripotent stem cells for the treatment of ischemic stroke: current status and problems. AB - Despite dramatic advancements in medical and surgical care, effective clinical therapies for ischemic stroke are limited. Stem-cell transplantation has emerged as a potential therapeutic approach for cell replacement in ischemic brain injuries. Inducible pluripotent stem cells (iPSCs) have become an alternative cell source for transplantation. They possess efficient capacities for neural differentiation without ethical and immune-rejection concerns. Substantial function of iPSCs in pre-clinical models of ischemic brain injury has been observed. However, several problems remain regarding the treatment of ischemic stroke with iPSCs: tumorigenicity, poor iPSC derivation methods, and undefined delivery variables. With the development of iPSC research, safer and more effective strategies will be achieved for highly effective and tumor-free cell treatment of ischemic stroke. PMID- 23089606 TI - Breaking away from dopamine deficiency: an essential new direction for Parkinson's disease. AB - For the past 40 years Parkinson's disease (PD) has been intrinsically associated with dopamine (DA) deficiency of the nigrostriatal DA system. One of the fundamental strengths of this theoretical approach is based on a presumed relationship between the degree of DA deficiency and the severity of motor impairment in the disease and its models. However, detailed examination of a substantial number of exemplary preclinical and clinical studies reveals that any such interpretation is overoptimistic and suggests that DA deficiency may be merely an epiphenomenon of a larger process underlying this disorder. Such a conclusion is based on numerous examples of miscarriage of basic principles of good scientific practice including (i) failure to thoroughly examine the adverse effects of DA replacement, (ii) drawing of statistical inference without recognising excessive spread of measure thereby lessening the importance of outliers, (iii) confounding independent and dependent variables within the scientific paradigm, (iv) overlooking fundamental principles of modern pharmacology, (v) confusing correlation with causation in linking cause and effect and (vi) disinclination to incorporate conflicting findings thereby infringing the quintessential scientific principle of tertium quid. This review demonstrates the inherent risks and dangers in the incontrovertible defence of DA deficiency theory and serves to address the ethical problems that emerge from the clinical application of scientific findings. There is increasing interest in new directions for PD research by dimming down the current emphasis on the importance of DA deficiency and its replacement. This would provide genuine hope and a new direction for the sufferers of a most debilitating disease. PMID- 23089607 TI - High-performance liquid chromatography method using ultraviolet detection for the quantification of aripiprazole and dehydroaripiprazole in psychiatric patients. AB - BACKGROUND: Aripiprazole (ARI) is an antipsychotic drug that is metabolized to dehydroaripiprazole (DARI) by CYP2D6. Because of the large interindividual variability in ARI and DARI plasma concentrations, therapeutic drug monitoring may be of use in psychiatric patients during treatment with ARI. The aim of the present study was to develop a simple and reliable method for the quantitative determination of ARI and DARI in plasma using liquid-liquid extraction and reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. The method was tested in psychiatric patients during regular treatment with ARI. METHODS: Separation was by the liquid-liquid method, and UV detection at 254 nm. Linear responses for ARI and DARI were obtained between 2 and 1000 ng/mL, and precision assays were lower than 10.4 for both analytes. RESULTS: Lower limit of quantification and detection were 1 and 0.38 ng/mL for ARI and 0.78 and 0.44 ng/mL for DARI, respectively. The method was successfully applied to plasma samples drawn from 22 patients with concentrations ranging between 2 and 189 ng/mL for ARI and between 11 and 359 ng/mL for DARI. CONCLUSIONS: The chromatographic method developed has been demonstrated to be sensitive and reliable for the measurement of ARI and DARI simultaneously in human plasma, and the present method represents an alternative procedure to evaluate plasma concentration in patients during treatment with ARI. PMID- 23089603 TI - Neurologic and motor dysfunctions in APP transgenic mice. AB - The discovery of gene mutations underlying autosomal dominant Alzheimer's disease has enabled researchers to reproduce several hallmarks of this disorder in transgenic mice, notably the formation of Abeta plaques in brain and cognitive deficits. APP transgenic mutants have also been investigated with respect to survival rates, neurologic functions, and motor coordination, which are all susceptible to alteration in Alzheimer dementia. Several transgenic lines expressing human mutated or wild-type APP had higher mortality rates than non transgenic controls with or without the presence of Abeta plaques. Mortality rates were also elevated in APP transgenic mice with vascular amyloid accumulation, thereby implicating cerebrovascular factors in the precocious death observed in all APP transgenic models. In addition, myoclonic jumping has been described in APP mutants, together with seizure activity, abnormal limb-flexion and paw-clasping reflexes, and motor coordination deficits. The neurologic signs resemble the myoclonic movements, epileptic seizures, pathological reflexes, and gait problems observed in late-stage Alzheimer's disease. PMID- 23089608 TI - No end in sight: the development of protein crystallography in Martinsried. PMID- 23089609 TI - Inhibition of Aeromonas sobria serine protease (ASP) by alpha2-macroglobulin. AB - ASP is a serine protease secreted by Aeromonas sobria. ASP cleaves various plasma proteins, which is associated with onset of sepsis complications, such as shock and blood coagulation disorder. To investigate a host defense mechanism against this virulence factor, we examined the plasma for ASP inhibitor(s). Human plasma inhibited ASP activity for azocasein, which was almost completely abolished by treating plasma with methylamine, which inactivates alpha2-macroglobulin (alpha2 MG). The ASP-inhibitor complex in ASP-added plasma was not detected by immunoblotting using anti-ASP antibody; however, using gel filtration of the plasma ASP activity for an oligopeptide, the ASP substrate was eluted in the void fraction (Mw>200 000), suggesting ASP trapping by alpha2-MG. Indeed, human alpha2 MG inhibited ASP azocaseinolytic activity in a dose-dependent manner, rapidly forming a complex with the ASP. Fibrinogen degradation by ASP was completely inhibited in the presence of alpha2-MG. alpha1-Protease inhibitor, antithrombin, and alpha2-plasmin inhibitor neither inhibited ASP activity nor formed a complex with ASP. Surprisingly, ASP degraded these plasma serine protease inhibitors. Thus, alpha2-MG is the major ASP inhibitor in the human plasma and can limit ASP virulence activities in A. sobria infection sites. However, as shown by fluorescence correlation spectroscopy, slow ASP inhibition by alpha2-MG in plasma may indicate insufficient ASP control in vivo. PMID- 23089610 TI - Bone mass density selectively correlates with serum markers of oxidative damage in post-menopausal women. AB - BACKGROUND: Post-menopausal osteoporosis (PO) affecting a large fraction of elderly women, is triggered by the decline in 17beta-estradiol (E2) level. Experimental studies in animal models and cell cultures have suggested that the fall in E2 might contribute to developing oxidative stress (OS) which in turn is believed to play an important role in PO pathogenesis. The scarcity of human studies focusing on this issue prompted us to investigate the effects of the reproductive and post-reproductive phase of women's life on OS and bone health. METHODS: Serum parameters of oxidative challenge (lipid hydroperoxides and protein advanced oxidation products) and antioxidant defence (total serum antioxidants levels) along with bone mineral density (BMD) at femoral neck and lumbar spine were assessed in a sample of 191 women (98 pre- and 93 post menopausal, of whom 30 osteoporotic). RESULTS: Pearson's correlation analysis unveiled that spinal BMD was negatively correlated with lipid hydroperoxides in overall postmenopausal subsample (r=-0.251, p=0.012), while no significant link between these two variables was detected in women in reproductive age (r=-0.022, p=0.833). Noteworthy, stepwise multiple regression analysis showed that the association found in post-menopausal women retained significance after adjusting for potential confounding factors (p=0.001). CONCLUSIONS: Our data showed that markers of oxidative challenge are associated with bone loss in women in post menopausal status. We suggest that menopause-related estrogen withdrawal might contribute to make bone more vulnerable to oxidative injury thereby increasing the risk of PO development. PMID- 23089612 TI - Detection of differential protein expression in cerebrospinal fluid of patients with multiple sclerosis through two-dimensional differential in gel electrophoresis. PMID- 23089611 TI - Neutrophil gelatinase-associated lipocalin as a biomarker of cardiovascular disease: a systematic review. AB - BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury (AKI). Recently, elevated NGAL levels have also been reported in heart failure, coronary heart disease, and stroke. Other studies demonstrate that NGAL is upregulated in failing myocardium and in atherosclerotic plaque. Our aim was to synthesize the current evidence on NGAL and cardiovascular disease (CVD), and to clarify the prognostic significance of systemic NGAL levels in CVD. METHODS: We performed a systematic review to identify experimental and human studies on NGAL and CVD. We excluded articles which specifically dealt with AKI or renal endpoints. RESULTS: We identified 22 studies, including both animal and human data. NGAL is highly expressed in the heart, both in failing myocardium and myocarditis, and is also expressed in atherosclerotic plaques. Areas of co localization of NGAL and matrix metalloproteinase (MMP)-9 exhibited increased MMP 9 proteolytic activity. Systemic NGAL levels correlated with renal function and severity of CVD in several, but not all, studies. An association between elevated systemic NGAL levels and clinical outcomes (e.g., death, hospital readmissions) were reported in six CVD studies, but these had limited adjustment for potential confounders. CONCLUSIONS: There is ample literature to support a putative role of NGAL in the pathophysiology of CVD, but at present there is insufficient data regarding the clinical utility of systemic NGAL levels in the management of CVD. Available evidence regarding NGAL as a predictor of outcomes in CVD is very limited. PMID- 23089613 TI - Marginalized identities, discrimination burden, and mental health: empirical exploration of an interpersonal-level approach to modeling intersectionality. AB - Intersectionality is a term used to describe the intersecting effects of race, class, gender, and other marginalizing characteristics that contribute to social identity and affect health. Adverse health effects are thought to occur via social processes including discrimination and structural inequalities (i.e., reduced opportunities for education and income). Although intersectionality has been well-described conceptually, approaches to modeling it in quantitative studies of health outcomes are still emerging. Strategies to date have focused on modeling demographic characteristics as proxies for structural inequality. Our objective was to extend these methodological efforts by modeling intersectionality across three levels: structural, contextual, and interpersonal, consistent with a social-ecological framework. We conducted a secondary analysis of a database that included two components of a widely used survey instrument, the Everyday Discrimination Scale. We operationalized a meso- or interpersonal level of intersectionality using two variables, the frequency score of discrimination experiences and the sum of characteristics listed as reasons for these (i.e., the person's race, ethnicity, gender, sexual orientation, nationality, religion, disability or pregnancy status, or physical appearance). We controlled for two structural inequality factors (low education, poverty) and three contextual factors (high crime neighborhood, racial minority status, and trauma exposures). The outcome variables we modeled were posttraumatic stress disorder symptoms and a quality of life index score. We used data from 619 women who completed the Everyday Discrimination Scale for a perinatal study in the U.S. state of Michigan. Statistical results indicated that the two interpersonal-level variables (i.e., number of marginalized identities, frequency of discrimination) explained 15% of variance in posttraumatic stress symptoms and 13% of variance in quality of life scores, improving the predictive value of the models over those using structural inequality and contextual factors alone. This study's results point to instrument development ideas to improve the statistical modeling of intersectionality in health and social science research. PMID- 23089614 TI - Neighborhood context and racial/ethnic differences in young children's obesity: structural barriers to interventions. AB - Numerous studies in the last ten years have investigated racial/ethnic disparities in obesity for young children. Increasing attention is paid to the influence of neighborhood environments - social and physical-on a variety of young children's health outcomes. This work identifies resource-based and community-based mechanisms that impede on the maintenance of healthy weights for young children in socioeconomically depressed areas, and shows consistently higher rates of obesity in more deprived areas. None of this work, however, has explored whether area deprivation or the race/nativity composition of neighborhoods contributes to racial/ethnic disparities in young children's obesity. Utilizing restricted geo-coded data from the Early Childhood Longitudinal Study (Kindergarten) (N = 17,540), we utilize multilevel logistic regression models to show that neighborhood level measures do little to explain racial and ethnic differences in childhood obesity. However, living in neighborhoods with higher levels of poverty, lower levels of education, and a higher proportion of black residents is associated with increased child obesity risk after considering a host of relevant individual level factors. In addition, living in neighborhoods with a higher proportion of foreign-born residents is associated with reduced child obesity risk. Although well-intentioned childhood obesity intervention programs aimed at changing individual-level behaviors are important, our results highlight the importance of considering neighborhood structural factors for child obesity prevention. PMID- 23089615 TI - The duty to care in an influenza pandemic: a qualitative study of Canadian public perspectives. AB - Ever since the emergence of SARS, when we were reminded that the nature of health care practitioners' duty to care is greatly contested, it has remained a polarizing issue. Discussions on the nature and limits of health care practitioners' duty to care during disasters and public health emergencies abounds the literature, ripe with arguments seeking to ground its foundations. However, to date there has been little public engagement on this issue. This study involved three Townhall meetings held between February 2008 and May 2010 in three urban settings in Canada in order to probe lay citizens' views about ethical issues related to pandemic influenza, including issues surrounding the duty to care. Participants included Canadian residents aged 18 and over who were fluent in English. Data were collected through day-long facilitated group discussions using case scenarios and focus group guides. Participant's views were organized according to several themes, including the following main themes (and respective sub-themes): 1. Legitimate limits; a) competing obligations; and b) appeal to personal choice; and 2. Legitimate expectations; a) reciprocity; and b) enforcement and planning. Our findings show that participants moved away from categorical notions of the duty to care towards more equivocal and often normative views throughout deliberations. Our analysis contributes a better understanding of the constitutive nature of the duty to care, defined in part by taking account of public views. This broadened understanding can further inform the articulation of acceptable norms of duty to care and policy development efforts. What is more, it illustrates the urgent need for policy-makers and regulators to get clarity on obligations, responsibilities, and accountability in the execution of HCPs' duty to care during times of universal vulnerability. PMID- 23089616 TI - Solvent structure improves docking prediction in lectin-carbohydrate complexes. AB - Recognition and complex formation between proteins and carbohydrates is a key issue in many important biological processes. Determination of the three dimensional structure of such complexes is thus most relevant, but particularly challenging because of their usually low binding affinity. In silico docking methods have a long-standing tradition in predicting protein-ligand complexes, and allow a potentially fast exploration of a number of possible protein carbohydrate complex structures. However, determining which of these predicted complexes represents the correct structure is not always straightforward. In this work, we present a modification of the scoring function provided by AutoDock4, a widely used docking software, on the basis of analysis of the solvent structure adjacent to the protein surface, as derived from molecular dynamics simulations, that allows the definition and characterization of regions with higher water occupancy than the bulk solvent, called water sites. They mimic the interaction held between the carbohydrate -OH groups and the protein. We used this information for an improved docking method in relation to its capacity to correctly predict the protein-carbohydrate complexes for a number of tested proteins, whose ligands range in size from mono- to tetrasaccharide. Our results show that the presented method significantly improves the docking predictions. The resulting solvent-structure-biased docking protocol, therefore, appears as a powerful tool for the design and optimization of development of glycomimetic drugs, while providing new insights into protein-carbohydrate interactions. Moreover, the achieved improvement also underscores the relevance of the solvent structure to the protein carbohydrate recognition process. PMID- 23089617 TI - Xanthan chain length is modulated by increasing the availability of the polysaccharide copolymerase protein GumC and the outer membrane polysaccharide export protein GumB. AB - Xanthan is a polysaccharide secreted by Xanthomonas campestris that contains pentameric repeat units. The biosynthesis of xanthan involves an operon composed of 12 genes (gumB to gumM). In this study, we analyzed the proteins encoded by gumB and gumC. Membrane fractionation showed that GumB was mainly associated with the outer membrane, whereas GumC was an inner membrane protein. By in silico analysis and specific globomycin inhibition, GumB was characterized as a lipoprotein. By reporter enzyme assays, GumC was shown to contain two transmembrane segments flanking a large periplasmic domain. We confirmed that gumB and gumC mutant strains uncoupled the synthesis of the lipid-linked repeat unit from the polymerization process. We studied the effects of gumB and gumC gene amplification on the production, composition and viscosity of xanthan. Overexpression of GumB, GumC or GumB and GumC simultaneously did not affect the total amount or the chemical composition of the polymer. GumB overexpression did not affect xanthan viscosity; however, a moderate increase in xanthan viscosity was achieved when GumC protein levels were increased 5-fold. Partial degradation of GumC was observed when only that protein was overexpressed; but co-expression of GumB and GumC diminished GumC degradation and resulted in higher xanthan viscosity than individual GumB or GumC overexpression. Compared with xanthan from the wild-type strain, longer polymer chains from the strain that simultaneously overexpressed GumB and GumC were observed by atomic force microscopy. Our results suggest that GumB-GumC protein levels modulate xanthan chain length, which results in altered polymer viscosity. PMID- 23089618 TI - Bifidobacterial alpha-galactosidase with unique carbohydrate-binding module specifically acts on blood group B antigen. AB - Bifidobacterium bifidum is one of the most frequently found bifidobacteria in the intestines of newborn infants. We previously reported that B. bifidum possesses unique metabolic pathways for O-linked glycans on gastrointestinal mucin (Yoshida E, Sakurama H, Kiyohara M, Nakajima M, Kitaoka M, Ashida H, Hirose J, Katayama T, Yamamoto K, Kumagai H. 2012. Bifidobacterium longum subsp. infantis uses two different beta-galactosidases for selectively degrading type-1 and type-2 human milk oligosaccharides. Glycobiology. 22:361-368). The nonreducing termini of O linked glycans on mucin are frequently covered with histo-blood group antigens. Here, we identified a gene agabb from B. bifidum JCM 1254, which encodes glycoside hydrolase (GH) family 110 alpha-galactosidase. AgaBb is a 1289-amino acid polypeptide containing an N-terminal signal sequence, a GH110 domain, a carbohydrate-binding module (CBM) 51 domain, a bacterial Ig-like (Big) 2 domain and a C-terminal transmembrane region, in this order. The recombinant enzyme expressed in Escherichia coli hydrolyzed alpha1,3-linked Gal in branched blood group B antigen [Galalpha1-3(Fucalpha1-2)Galbeta1-R], but not in a linear xenotransplantation antigen (Galalpha1-3Galbeta1-R). The enzyme also acted on group B human salivary mucin and erythrocytes. We also revealed that CBM51 specifically bound blood group B antigen using both isothermal titration calorimetry and a solid-phase binding assay, and it enhanced the affinity of the enzyme toward substrates with multivalent B antigens. We suggest that this enzyme plays an important role in degrading B antigens to acquire nutrients from mucin oligosaccharides in the gastrointestinal tracts. PMID- 23089619 TI - Nanometer-scale, quantitative composition mappings of InGaN layers from a combination of scanning transmission electron microscopy and energy dispersive x ray spectroscopy. AB - Using elastic scattering theory we show that a small set of energy dispersive x ray spectroscopy (EDX) measurements is sufficient to experimentally evaluate the scattering function of electrons in high-angle annular dark field scanning transmission microscopy (HAADF-STEM). We then demonstrate how to use this function to transform qualitative HAADF-STEM images of InGaN layers into precise, quantitative chemical maps of the indium composition. The maps obtained in this way combine the resolution of HAADF-STEM and the chemical precision of EDX. We illustrate the potential of such chemical maps by using them to investigate nanometer-scale fluctuations in the indium composition and their impact on the growth of epitaxial InGaN layers. PMID- 23089620 TI - Appropriate use criteria: past, present, future. PMID- 23089621 TI - Will standardization make strain a standard measurement? PMID- 23089622 TI - Positioning echocardiography as the most valuable imaging technique in a changing healthcare environment. PMID- 23089623 TI - Value of ASE guidelines, training underscored by educational outreach in India. PMID- 23089624 TI - Travel grants provide opportunities for growth and renewal. PMID- 23089625 TI - The inducers 1,3-diaminopropane and spermidine produce a drastic increase in the expression of the penicillin biosynthetic genes for prolonged time, mediated by the laeA regulator. AB - We described previously that an autoinducer molecule, identified as 1,3 diaminopropane (1,3-DAP), is secreted by Penicillium chrysogenum and Acremonium chrysogenum. Using pH-controlled fermentor cultures we have observed in this work that 1,3-DAP and spermidine clearly stimulate the biosynthesis of benzylpenicillin in P. chrysogenum, both in defined and in complex penicillin production media. Both 1,3-DAP and spermidine, but not putrescine (1,4 diaminobutane), produce a drastic increase in the transcript levels of the penicillin biosynthetic genes pcbAB, pcbC and penDE. These polyamines do not affect the expression of the global pH-stress regulator pacC gene, thus excluding that the effect of 1,3-DAP and spermidine is due to a modification of the pH control mechanism. Expression of the three penicillin biosynthetic genes is drastically reduced in a laeA-knock-down mutant of P. chrysogenum, which produces very low levels of benzylpenicillin. Interestingly, 1,3-DAP and spermidine revert the effect of the laeA knock-down mutation, completely restoring the levels of penicillin production. Furthermore, 1,3-DAP and spermidine enhanced the expression of laeA in the parental strain and restored the levels of laeA transcripts in the laeA knock-down mutant. Taken together these results indicate that the stimulatory effect of the inducer molecules 1,3-DAP and spermidine is exerted, at least in part, through the stimulation of the expression of laeA, a global regulator that acts epigenetically on the expression of secondary metabolite genes by heterochromatin reorganization. PMID- 23089626 TI - BDNF profoundly and specifically increases KCNQ4 expression in neurons derived from embryonic stem cells. AB - Neurons resembling the spiral ganglion neurons (SGNs) of the auditory nerve can be generated from embryonic stem cells through induced overexpression of the transcription factor Neurogenin-1 (Neurog1). While recapitulating this developmental pathway produces glutamatergic, bipolar neurons reminiscent of SGNs, these neurons are functionally immature, being characterized by a depolarized resting potential and limited excitability. We explored the effects of two neurotrophins known to be present in the inner ear, brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), on the electrophysiology of neurons following Neurog1 induction. Our data reveal a significant reduction in resting membrane potential (RMP) following neurotrophin exposure, with BDNF producing a more robust effect than NT-3. This effect was accompanied by a profound and specific upregulation of the KCNQ4 subtype, where a 9-fold increase was observed with quantitative PCR. The other neuronally expressed KCNQ subtypes (2, 3, and 5) exhibited upregulation which was 3-fold or less in magnitude. Quantitative immunohistochemistry confirmed the increase in KCNQ4 expression at the protein level. The present data show a novel link between BDNF and KCNQ4 expression, yielding insight into the restricted expression pattern of a channel known to play special roles in setting the resting potential of auditory cells and in the etiology of progressive high-frequency hearing loss. PMID- 23089628 TI - Repolarization reserve determines drug responses in human pluripotent stem cell derived cardiomyocytes. AB - Unexpected induction of arrhythmias in the heart is still one of the major risks of new drugs despite recent improvements in cardiac safety assays. Here we address this in a novel emerging assay system. Eleven reference compounds were administrated to spontaneously beating clusters of cardiomyocytes from human pluripotent stem cells (hPSC-CM) and the responses determined using multi electrode arrays. Nine showed clear dose-dependence effects on field potential (FP) duration. Of these, the Ca(2+) channel blockers caused profound shortening of action potentials, whereas the classical hERG blockers, like dofetilide and d,l-sotalol, induced prolongation, as expected. Unexpectedly, two potent blockers of the slow component of the delayed rectifier potassium current (I(Ks)), HMR1556 and JNJ303, had only minor effects on the extracellular FP of wild-type hPSC-CM despite evidence of functional I(Ks) channels. These compounds were therefore re evaluated under conditions that mimicked reduced "repolarization reserve," a parameter reflecting the capacity of cardiomyocytes to repolarize and a strong risk factor for the development of ventricular arrhythmias. Strikingly, in both pharmacological and genetic models of diminished repolarization reserve, HMR1556 and JNJ03 strongly increased the FP duration. These profound effects indicate that I(Ks) plays an important role in limiting action potential prolongation when repolarization reserve is attenuated. The findings have important clinical implications and indicate that enhanced sensitization to repolarization prolonging compounds through pharmacotherapy or genetic predisposition should be taken into account when assessing drug safety. PMID- 23089627 TI - Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis. AB - Ascorbic acid (Vitamin C) has a critical role in bone formation and osteoblast differentiation, but very little is known about the molecular mechanisms of ascorbic acid entry into bone marrow stromal cells (BMSCs). To address this gap in knowledge, we investigated the identity of the transport system that is responsible for the uptake of ascorbic acid into bone marrow stromal cells (BMSCs). First, we examined the expression of the two known isoforms of the sodium-coupled ascorbic acid transporter, namely SVCT1 and SVCT2, in BMSCs (Lin ve Sca1+ve) and bone at the mRNA level. Only SVCT2 mRNA was detected in BMSCs and bone. Uptake of ascorbic acid in BMSCs was Na(+)-dependent and saturable. In order to define the role of SVCT2 in BMSC differentiation into osteoblasts, BMSCs were stimulated with osteogenic media for different time intervals, and the activity of SVCT2 was monitored by ascorbic acid uptake. SVCT2 expression was up regulated during the osteogenic differentiation of BMSCs; the expression was maximal at the earliest phase of differentiation. Subsequently, osteogenesis was inhibited in BMSCs upon knock-down of SVCT2 by lentivirus shRNA. We also found that the expression of the SVCT2 could be negatively or positively modulated by the presence of oxidant (Sin-1) or antioxidant (Ascorbic acid) compounds, respectively, in BMSCs. Furthermore, we found that this transporter is also regulated with age in mouse bone. These data show that SVCT2 plays a vital role in the osteogenic differentiation of BMSCs and that its expression is altered under conditions associated with redox reaction. Our findings could be relevant to bone tissue engineering and bone related diseases such as osteoporosis in which oxidative stress and aging plays important role. PMID- 23089630 TI - Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. AB - The hypothalamic-pituitary-adrenal (HPA) axis and the inflammatory response system have been suggested as pathophysiological mechanisms implicated in the etiology of major depressive disorder (MDD). Although meta-analyses do confirm associations between depression and these biological systems, effect sizes vary greatly among individual studies. A potentially important factor explaining variability is heterogeneity of MDD. Aim of this study was to evaluate the association between depressive subtypes (based on latent class analysis) and biological measures. Data from 776 persons from the Netherlands Study of Depression and Anxiety, including 111 chronic depressed persons with melancholic depression, 122 with atypical depression and 543 controls were analyzed. Inflammatory markers (C-reactive protein, interleukin-6, tumor necrosis factor alpha), metabolic syndrome components, body mass index (BMI), saliva cortisol awakening curves (area under the curve with respect to the ground (AUCg) and with respect to the increase (AUCi)), and diurnal cortisol slope were compared among groups. Persons with melancholic depression had a higher AUCg and higher diurnal slope compared with persons with atypical depression and with controls. Persons with atypical depression had significantly higher levels of inflammatory markers, BMI, waist circumference and triglycerides, and lower high-density lipid cholesterol than persons with melancholic depression and controls. This study confirms that chronic forms of the two major subtypes of depression are associated with different biological correlates with inflammatory and metabolic dysregulation in atypical depression and HPA-axis hyperactivity in melancholic depression. The data provide further evidence that chronic forms of depressive subtypes differ not only in their symptom presentation, but also in their biological correlates. These findings have important implications for future research on pathophysiological pathways of depression and treatment. PMID- 23089631 TI - GLP-1 analog attenuates cocaine reward. PMID- 23089633 TI - Associations between gonadotropins, testosterone and beta amyloid in men at risk of Alzheimer's disease. AB - Testosterone and gonadotropins have been associated with cognitive decline in men and the modulation of beta amyloid (Abeta) metabolism. The relatively few studies that have investigated whether changes in one or a combination of these hormones influence Abeta levels have focused primarily on plasma Abeta(1-40) and not on the more pathogenic Abeta(1-42). Currently, no study has investigated whether these hormones are associated with an increase in brain amyloid deposition, ante mortem. Through the highly characterised Australian imaging, biomarkers and lifestyle study, we have determined the impact of these hormones on plasma Abeta levels and brain amyloid burden (Pittsburgh compound B (PiB) retention). Spearman's rank correlation and linear regression analysis was carried out across the cohort and within subclassifications. Luteinizing hormone (LH) was the only variable shown, in the total cohort, to have a significant impact on plasma Abeta(1-40) and Abeta(1-42) levels (beta=0.163, P<0.001; beta=0.446, P<0.001). This held in subjective memory complainers (SMC) (Abeta(1-40); beta=0.208, P=0.017; Abeta(1-42); beta=0.215, P=0.017) but was absent in mild cognitive impairment (MCI) and Alzheimer's disease (AD) groups. In SMC, increased frequency of the APOE-E4 allele (beta=0.536, P<0.001) and increasing serum LH levels (beta=0.421, P=0.004) had a significant impact on PiB retention. Whereas in MCI, PiB retention was associated with increased APOE-E4 allele copy number (beta=0.674, P<0.001) and decreasing calculated free testosterone (beta=-0.303, P=0.043). These findings suggest a potential progressive involvement of LH and testosterone in the early preclinical stages of AD. Furthermore, these hormones should be considered while attempting to predict AD at these earliest stages of the disease. PMID- 23089635 TI - Alternative methods to central venous pressure for assessing volume status in critically ill patients. AB - INTRODUCTION: Early goal-directed therapy increases survival in persons with sepsis but requires placement of a central line. We evaluate alternative methods to measuring central venous pressure (CVP) to assess volume status, including peripheral venous pressure (PVP) and stroke volume variation (SVV), which may facilitate nurse-driven resuscitation protocols. METHODS: Patients were enrolled in the emergency department or ICU of an academic medical center. Measurements of CVP, PVP, SVV, shoulder and elbow position, and dichotomous variables Awake, Movement, and Vented were measured and recorded 7 times during a 1-hour period. Regression analysis was used to predict CVP from PVP and/or SVV, shoulder/elbow position, and dichotomous variables. RESULTS: Twenty patients were enrolled, of which 20 had PVP measurements and 11 also had SVV measurements. Multiple regression analysis demonstrated significant predictive relationships for CVP using PVP (CVP = 6.7701 + 0.2312 * PVP - 0.1288 * Shoulder + 12.127 * Movement - 4.4805 * Neck line), SVV (CVP = 14.578 - 0.3951 * SVV + 18.113 * Movement), and SVV and PVP (CVP = 4.2997 - 1.1675 * SVV + 0.3866 * PVP + 18.246 * Awake + 0.1467 * Shoulder = 0.4525 * Elbow + 15.472 * Foot line + 10.202 * Arm line). DISCUSSION: PVP and SVV are moderately good predictors of CVP. Combining PVP and SVV and adding variables related to body position, movement, ventilation, and sleep/wake state further improves the predictive value of the model. The models illustrate the importance of standardizing patient position, minimizing movement, and placing intravenous lines proximally in the upper extremity or neck. PMID- 23089632 TI - A genome-wide association study of alcohol-dependence symptom counts in extended pedigrees identifies C15orf53. AB - Several studies have identified genes associated with alcohol-use disorders (AUDs), but the variation in each of these genes explains only a small portion of the genetic vulnerability. The goal of the present study was to perform a genome wide association study (GWAS) in extended families from the Collaborative Study on the Genetics of Alcoholism to identify novel genes affecting risk for alcohol dependence (AD). To maximize the power of the extended family design, we used a quantitative endophenotype, measured in all individuals: number of alcohol dependence symptoms endorsed (symptom count (SC)). Secondary analyses were performed to determine if the single nucleotide polymorphisms (SNPs) associated with SC were also associated with the dichotomous phenotype, DSM-IV AD. This family-based GWAS identified SNPs in C15orf53 that are strongly associated with DSM-IV alcohol-dependence symptom counts (P=4.5 * 10(-8), inflation-corrected P=9.4 * 10(-7)). Results with DSM-IV AD in the regions of interest support our findings with SC, although the associations were less significant. Attempted replications of the most promising association results were conducted in two independent samples: nonoverlapping subjects from the Study of Addiction: Genes and Environment (SAGE) and the Australian Twin Family Study of AUDs (OZALC). Nominal association of C15orf53 with SC was observed in SAGE. The variant that showed strongest association with SC, rs12912251 and its highly correlated variants (D'=1, r(2)? 0.95), have previously been associated with risk for bipolar disorder. PMID- 23089634 TI - Glucocorticoid receptor dimerization is required for proper recovery of LPS induced inflammation, sickness behavior and metabolism in mice. AB - Endogenous glucocorticoids are essential for mobilizing energy resources, restraining inflammatory responses and coordinating behavior to an immune challenge. Impaired glucocorticoid receptor (GR) function has been associated with impaired metabolic processes, enhanced inflammation and exaggerated sickness and depressive-like behaviors. To discern the molecular mechanisms underlying GR regulation of physiologic and behavioral responses to a systemic immune challenge, GR(dim) mice, in which absent GR dimerization leads to impaired GR-DNA binding-dependent mechanisms but intact GR protein-protein interactions, were administered low-dose lipopolysaccharide (LPS). GR(dim)-LPS mice exhibited elevated and prolonged levels of plasma corticosterone (CORT), interleukin (IL)-6 and IL-10 (but not plasma tumor necrosis factor-alpha (TNFalpha)), enhanced early expression of brain TNFalpha, IL-1beta and IL-6 mRNA levels, and impaired later central TNFalpha mRNA expression. Exaggerated sickness behavior (lethargy, piloerection, ptosis) in the GR(dim)-LPS mice was associated with increased early brain proinflammatory cytokine expression and late plasma CORT levels, but decreased late brain TNFalpha expression. GR(dim)-LPS mice also exhibited sustained locomotor impairment in the open field, body weight loss and metabolic alterations measured by indirect calorimetry, as well as impaired thermoregulation. Taken together, these data indicate that GR dimerization dependent DNA-binding mechanisms differentially regulate systemic and central cytokine expression in a cytokine- and time-specific manner, and are essential for the proper regulation and recovery of multiple physiologic responses to low dose endotoxin. Moreover, these results support the concept that GR protein protein interactions are not sufficient for glucocorticoids to exert their full anti-inflammatory effects and suggest that glucocorticoid responses limited to GR monomer-mediated transcriptional effects could predispose individuals to prolonged behavioral and metabolic sequelae of an enhanced inflammatory state. PMID- 23089636 TI - Production of nitric oxide is lower in Shiga toxin-stimulated neutrophils of infants compared to those of children or adults. AB - Hemolytic uremic syndrome (HUS) in infants is mainly caused by the Shiga toxin (Stx), which is produced by pathogenic Escherichia coli O157:H7. Infants are prone to develop HUS in comparison to older children and adults, but its underlying mechanism remains unknown. Recent observations suggest that reactive oxygen species (ROS) and reactive nitrogen species (RNS) including nitric oxide (NO) may be involved in the pathogenesis of HUS. We therefore measured NO production by neutrophils prepared from infants (6-27 months old), children (5.3 11 years old) or adults (25-47 years old). The NO production was measured by a flow cytometric analysis with a fluorescent indicator (expressed as mean fluorescence intensity), and mRNA expression of inducible NO synthase (iNOS) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The amount of NO produced was significantly lower in Stx-stimulated neutrophils prepared from infants (45.8 +/- 23.3) than that in those from children (120.5 +/- 81.5) or adults (127.7 +/- 45.8) (n = 10 each group, P < 0.05). The expression level of iNOS mRNA was lower in Stx-stimulated neutrophils of the infants than the level in those of children or adults. In conclusion, Stx increased NO production in neutrophils probably via iNOS. Importantly, the degree of the Stx-mediated increase in NO production was lower in neutrophils of infants compared to those of children or adults, which may explain the higher incidence of HUS in infants. These results suggest that NO may contribute to the cellular defense mechanisms against Stx. PMID- 23089637 TI - Infantile immunoglobulin A nephropathy showing features of membranoproliferative glomerulonephritis. AB - Immunoglobulin A nephropathy (IgAN) showing predominant IgA and complement 3 (C3) deposition on the mesangium is an immune complex-mediated glomerulonephritis. This renal disease is the most common primary glomerular disease worldwide. However, infantile onset of IgAN is rare. In the present patient, urinary protein and occult blood were detected in a girl aged 1 year and 8 months on urinalysis at a nursery school. Despite being young, a kidney biopsy was performed for diagnosis and the correct choice of therapy. Glomerular mesangial cell proliferation and a double contour of the glomerular basement membrane (GBM) resembling a railroad track were noted on light microscopy. Therefore, the patient was diagnosed morphologically with membranoproliferative glomerulonephritis (MPGN), because mesangial hypercellularity and thickening of the GBM were identified. However, on immunofluorescent staining, the deposition of immune complexes mainly consisting of IgA, IgG, and C3 was noted in the mesangial region and glomerular capillary loops. On electron microscopy, electron-dense deposits were recognized in the subendothelial and paramesangial regions associated with mesangial cell interposition into the subendothelial space. Autoimmune diseases and infection-associated secondary glomerulonephritis were clinically excluded, because there were no relevant signs or symptoms. Steroid treatment was initiated and findings of urinalysis were normalized within 8 months. This patient was finally diagnosed with IgA nephropathy showing the features of MPGN. The present patient was the youngest among reported cases of IgA nephropathy, suggesting that early onset of IgAN is associated with an MPGN like lesion. The present report provides information for pathogenesis of IgA nephropathy. PMID- 23089638 TI - Possible involvement of endocannabinoids in the increase of morphine consumption in maternally deprived rat. AB - Whether adolescent exposure to chronic delta-9-tetrahydrocannabinol (THC) facilitates progression to opioid consumption is still controversial. In a maternal deprivation model (3 h daily from postnatal day 1-14), we previously reported that adolescent exposure to chronic THC blocks morphine dependence in maternally deprived (D) rats. Owing to the existence of a functional cross interaction between the opioid and cannabinoid systems in reward, we evaluated if the vulnerability to opiate reward in D rats, may involve an alteration of the endocannabinoid system. Anandamide and 2-arachidonoylglycerol (2-AG), were quantified in the striatum and mesencephalon of adolescent and adult D and non deprived (animal facility rearing, AFR) rats by isotope dilution liquid chromatography-mass spectrometry. Oral morphine self-administration behavior was analyzed for 14 weeks, 24 days after chronic injection of the cannabinoid CB1 receptor antagonist/inverse agonist, SR141716A (3 mg/kg) for 2 weeks during adolescence (PND 35-48). Adolescent D rats exhibited higher basal levels of anandamide than adolescent AFR rats in the nucleus accumbens (38%), the caudate putamen nucleus (62%) and the mesencephalon (320%), whereas adult D rats showed an increase of anandamide and 2-AG levels in the nucleus accumbens (50% and 24%, respectively) and of 2-AG in the caudate-putamen nucleus (48%), compared to adult AFR rats. Chronic administration of SR141716A to adolescent D rats blocked the escalation behavior in the morphine consumption test. Our data suggest that altered brain endocannabinoid levels may contribute to the escalation behavior in the morphine consumption test in a maternal deprivation model. PMID- 23089639 TI - Retrievable, tooth-implant-supported, complete-arch fixed restorations in the maxilla: a 6-year retrospective study. AB - The aim of this retrospective study was to evaluate the survival rate of implants, abutment teeth, and suprastructures along with the management of the complications for complete-arch, semipermanent cemented tooth-implant-supported restorations in 44 maxillae. Permanent cemented copings protect the prepared teeth from caries. The metal-ceramic fixed dental prostheses (FDPs) were cemented onto copings and implant abutments using acryl-urethane cement. Data were assessed via patient records and a final clinical examination. Six years after cementation, no implant or restoration had failed. After the extraction of two teeth and placement of an additional implant, three restorations had to be subsequently changed (89% of restorations were unchanged after 6 years). The loss of retention without tooth intrusion occurred in two restorations. All 23 restoration removals for prosthetic aftercare were non-destructive. The results of this study indicate that complete-arch, semipermanently cemented FDP rigidly connecting the maxillary teeth and implants are a reliable treatment option. PMID- 23089640 TI - Characterization of serotonin neurotransmission in knockout mice: implications for major depression. AB - The interaction between genes and environment plays a significant role in the pathogenesis of major depression and mood disorders. Preclinical and clinical studies have established that a dysfunction of serotonin (5-HT) neurotransmission is a common hallmark in major depression and drugs acting on the 5-HT system have antidepressant properties. In the past 15 years, the development of knockout mice showing a depressive-like or resilience-like phenotype have allowed us to better understand the complex relationship between genes, behaviour and the 5-HT system in mood disorders. The present review revises several knockout mice genotypes with 'mood' alteration and analyses how 5-HT firing activity, measured with electrophysiological techniques, is impaired after a gene manipulation. The behavior and electrophysiology data from 5-HT transporter (5HTT), 5-HT1(A), 5 HT4, the neurokinin 1 (NK1) receptor, fatty acid amide hydrolase (FAAH) and the TWIK-1 related K+ (TREK-1) channel knockout mice are here analysed. Interestingly, a correlation between 5-HT firing rate and depressive/resilience phenotypes can be established in these different knockouts. Furthermore, findings in knockout mice have been successfully translated to humans, and findings from human studies have helped to design and generate knockout mice to explore new hypotheses of the etiology of human depression. The correlation of 5-HT activity and behavior could be a predictor factor for understanding the role of receptors, channels and enzymes in depression, and could be used also to assess the potential antidepressive effects of novel drugs. PMID- 23089643 TI - Comments on a performance evaluation of cartridge-type blood gas analyzers. Reply. PMID- 23089641 TI - Biochemical and functional characterization of human phospholipid scramblase 4 (hPLSCR4). AB - Human phospholipid scramblase 4 (hPLSCR4), an isoform of the scramblase family, is a type II single-pass transmembrane protein whose function remains unknown. To understand its role, recombinant hPLSCR4 was obtained by cloning the ORF into a pET28 a(+) vector and overexpressed in Escherichia coli. Functional assay showed that Ca2+, Mg2+, and Zn2+ activate hPLSCR4 and mediate scrambling activity independent of the phospholipid head group. Far-UV-CD and fluorescence spectroscopy revealed that Ca2+ and Mg2+ binding induces conformation change in hPLSCR4, exposing hydrophobic patches of the protein, and Ca2+ has more affinity than Mg2+ and Zn2+. Stains-all studies further confirm that hPLSCR4 is a Ca2+ binding protein. Point mutation (Asp290->Ala) in hPLSCR4 decreased the Ca2+ binding affinity as well as Tb3+ luminescence, suggesting residues of the predicted Ca2+-binding motif are involved in Ca2+ binding. Functional reconstitution with (Asp290->Ala) mutant led to ~50% and ~40% decrease in scramblase activity in the presence of Ca2+ and Mg2+, respectively. PMID- 23089644 TI - Inhibition of NF-kappaB activation by Pyrrolidine dithiocarbamate partially attenuates hippocampal MMP-9 activation and improves cognitive deficits in streptozotocin-induced diabetic rats. AB - Matrix metalloproteinase-9 (MMP-9) has been found at significantly increased activity and also contributes to blood-brain barrier degradation in diabetes. Activation of NF-kappaB pathway is associated with diabetes-induced cognitive impairment, and MMP-9 gene promoter contains a highly conserved motif that matches the NF-kappaB p65 binding element. No data have been yet provided to show that diabetes-induced cognitive decline is actually associated with increased activity of MMP-9, however, so we sought to understand the potential role of NF kappaB-MMP-9 pathway in diabetic rats' brain. Streptozocin (STZ) was used to induce diabetes in Wistar rats. Pyrrolidine dithiocarbamate (PDTC), an effective NF-kappaB inhibitor, was administrated to diabetic rats for 6 weeks from the end of diabetes induction. Six weeks later, separate cohorts of rats were tested for cognitive function with Morris water maze task, or euthanized to assess MMP-9 and NF-kappaB levels in hippocampus. The diabetic rats developed cognitive deficit which was associated with enhanced hippocampal MMP-9 and NF-kappaB expression. PDTC treatment returned the levels of NF-kappaB toward their control values and significantly improved diabetes-induced behavioral dysfunction. However, the hippocampal MMP-9 expression triggered by diabetes was only slightly (though significantly) attenuated because MMP-9 protein level in PDTC treated diabetic rats was still higher than that in control rats. Moreover, chronic PDTC treatment did not affect the body weight and plasma glucose levels as compared to the diabetic group, which suggested that PDTC could not ameliorate the diabetic metabolic disorder. In conclusion, these data reveal that diabetes-associated cognitive deficit stems partially from up-regulation of hippocampal MMP-9 via activation of NF-kappaB signaling pathway. PMID- 23089645 TI - Comparison between low doses of TMT and cat odor exposure in anxiety- and fear related behaviors in mice. AB - Few comparisons were made between cat odor and synthetic fox odor (TMT) to study fear and anxiety in rodents. TMT is frequently used are at high concentration while the stimulus should be as possible closer to natural conditions. The aim of this work was to compare behavioral responses of mice exposed to cat odor and low doses of TMT (i.e. 10 MUl of a solution containing 1%, 0.1% or 0.01% TMT). Behavioral parameters were recorded in elevated plus-maze and in open field. Results showed that 1% TMT and 0.1% TMT induced similar responses to cat odor, contrary to water and 0.01% TMT which failed to elicit fear or anxiety-related behaviors. Additionally, behavioral changes were more marked in EPM - e.g. time spent in open arms - than in open field - e.g. freezing. These findings are discussed in terms of a possible continuum of mild anxiety-like behaviors to strong fear-like behaviors linked to predator odor intensity. PMID- 23089646 TI - LRRTM1-deficient mice show a rare phenotype of avoiding small enclosures--a tentative mouse model for claustrophobia-like behaviour. AB - The LRRTM family proteins have been shown to act as synaptogenic cell adhesion molecules via interaction with presynaptic neurexins and are associated with neuropsychiatric disorders. LRRTM1-knockout mice have subtle morphological deficits in excitatory hippocampal synapses and were suggested to have impaired cognitive function. Here we report that LRRTM1-knockout mice exhibit an extraordinary phenotype of avoiding small enclosures. In the light-dark box, the knockout mice escape to dark through a standard opening as quickly as wild-type littermates but avoid escaping through a small doorway. While all wild-type mice spontaneously enter a small tube, most knockout mice do not. This apparent aversion to enter narrow space may explain other abnormalities such as increased time in open arms in the elevated plus maze and less visits through a tunnel in the IntelliCage. Moreover, LRRTM1-knockout mice show increased social interaction, reduced nest building and MK801-induced locomotion, and slower swim speed but normal water maze learning. Since LRRTM1 is predominantly expressed in thalamus, hippocampus and limbic cortex, specific synaptic defects in those areas presumably cause these behavioural abnormalities. PMID- 23089647 TI - Effects of L-histidine and histamine H3 receptor modulators on ethanol-induced sedation in mice. AB - Recent studies suggest that the brain histaminergic system and especially the H3 receptors are involved in the regulation of alcohol consumption and alcohol induced behaviors. Part of this effect might be due to a modulation of ethanol induced sedation by central histamine. The aim of the present study was to investigate the effects of several histaminergic drugs on ethanol-induced sedation using the loss of righting reflex experimental protocol in female Swiss mice. A pretreatment with L-histidine, the histamine precursor, significantly reduced ethanol-induced sedation, suggesting that brain histamine protects against the sedative effects of ethanol. In a second set of experiments, several H3 receptor agonists (immepip or imetit) and inverse agonists/antagonists (thioperamide, A331440, or BF2.649) were tested. Surprisingly, both H3 receptor agonists and antagonists potentiated the sedative effects of ethanol. This paradoxical effect might be due to the subtle regulatory actions related to the H3 heteroreceptor function. PMID- 23089648 TI - The role of the GPR39 receptor in zinc deficient-animal model of depression. AB - During the last decade it has been shown that zinc may activate neural transmissions via the GPR39 Zn(2+)-sensing receptor, which can be involved in the regulation of neuronal plasticity. According to the neurotrophic hypothesis of depression, decreased brain derived neurotrophic factor (BDNF) levels in depressed patients play a key role in the pathogenesis of this disorder. BDNF, similarly as zinc, is known to be involved in the process of neuron survival and the regulation of neuronal plasticity. The aim of the present study was to determine whether the administration of a 6-week diet deficient in zinc would cause depressive-like behaviour and if such behavioural alterations would correlate with changes in the expression of the BDNF protein and GPR39 receptor. In the first part of the present study the animal behaviour after a 6-week zinc deficient diet, in the forced swim test (FST) was investigated. In the second part expression of the GPR39 and BDNF protein level in the frontal cortex was measured using the Western Blot method. Administration of a zinc-deficient diet for 6 weeks increased immobility time in the FST by 24%, so exerted depression like behaviour. A biochemical study showed a significant reduction in GPR39 (by 53%) and BDNF (by 49%) protein expression in the frontal cortex in mice receiving the zinc deficient diet for 6 weeks. Our study provides evidence that the GPR39 Zn(2+)-sensing receptor may be responsible for lowering the BDNF protein level and in consequence may be involved in the pathogenesis of depression. PMID- 23089649 TI - Decreased acetylcholine release delays the consolidation of object recognition memory. AB - Acetylcholine (ACh) is important for different cognitive functions such as learning, memory and attention. The release of ACh depends on its vesicular loading by the vesicular acetylcholine transporter (VAChT). It has been demonstrated that VAChT expression can modulate object recognition memory. However, the role of VAChT expression on object recognition memory persistence still remains to be understood. To address this question we used distinct mouse lines with reduced expression of VAChT, as well as pharmacological manipulations of the cholinergic system. We showed that reduction of cholinergic tone impairs object recognition memory measured at 24h. Surprisingly, object recognition memory, measured at 4 days after training, was impaired by substantial, but not moderate, reduction in VAChT expression. Our results suggest that levels of acetylcholine release strongly modulate object recognition memory consolidation and appear to be of particular importance for memory persistence 4 days after training. PMID- 23089650 TI - Nature of the attractive interaction between proton acceptors and organic ring systems. AB - Systematic ab initio calculations are combined with a deconvolution of electrostatic contributions to analyze the interplay between potential hydrogen bond acceptors and organic rings with C(sp(2))-H groups (benzene, pyridine and cyclopentadiene). A distinct anisotropic interaction between the ring systems and the electron lone pairs of cyanide, water and other acceptor species is revealed that favors the in-plane orientation of the proton acceptor group. In the attractive regime this interaction carries a pronounced electrostatic signature. By decomposing the electrostatic contribution into parts attributed to different subunits of the ring systems we demonstrate that a major proportion of the interaction energy gain is originating from the non-adjacent moieties, that are not in close contact with. This behavior holds equally for homocyclic, heterocyclic and non-aromatic rings but contrasts that of the ethyne molecule, taken as reference for a weak hydrogen bond donor clearly exhibiting the expected localized character. The ring interaction requires the presence of pi-electron clouds and typically results in an interaction energy gain of 40 to 80 meV. Our findings suggest the proton acceptor-ring interaction as a new category of intermolecular non-covalent interactions. PMID- 23089651 TI - Optical and thermal response of single-walled carbon nanotube-copper sulfide nanoparticle hybrid nanomaterials. AB - This paper reports the optical and thermal response of a single-walled carbon nanotube-copper sulfide nanoparticle (SWNT-CuS NP) hybrid nanomaterial and its application as a thermoelectric generator. The hybrid nanomaterial was synthesized using oleylamine molecules as the linker molecules between SWNTs and CuS NPs. Measurements found that the hybrid nanomaterial has significantly increased light absorption (up to 80%) compared to the pure SWNT. Measurements also found that the hybrid nanomaterial thin-film devices exhibit a clear optical and thermal switching effect, which can be further enhanced up to 10 * by asymmetric illumination of light and thermal radiation on the thin-film devices instead of symmetric illumination. A simple prototype thermoelectric generator enabled by the hybrid nanomaterials is demonstrated, indicating a new route for achieving thermoelectricity. PMID- 23089652 TI - Self-assembly and electrical properties of a novel heptameric thiophene benzothiadiazole based architectures. AB - A novel semiconducting benzothiadiazole (BTZ)-thiophene (T) co-oligomer having an unprecedented BTZ-T alternated motif has been synthesized and self-assembled into micrometer sized fibers by simple solution processing. The electrical properties of these low-dimensional architectures have been characterized by integrating them in an organic field-effect transistor. PMID- 23089653 TI - Clinical anesthetic effectiveness of intraoral mucoadhesive tablets of amitriptyline in healthy volunteers. AB - PURPOSE: Topical anesthetics are widely used in dentistry. One of their indications is to diminish the pain of the injection of anesthetics. Amitriptyline is a tricyclic antidepressant that provides local anesthetic effects by blocking the sodium channels. The present study was performed in an attempt to assess the anesthetic efficacy of an intraoral mucoadhesive tablet of amitriptyline. MATERIALS AND METHODS: The present study was performed as a randomized, double-blind, placebo-controlled, clinical trial of 25 healthy female volunteers. The mucoadhesive tablet was randomly placed for 15 minutes on the buccal mucogingival tissue adjacent to the root of the upper lateral incisor, and a placebo was placed on the other side. A 27-gauge needle was inserted to touch the alveolar periosteum of the designated site. The pain intensity associated with the stimulation was evaluated every 5 minutes after removing the mucoadhesive tablet using a visual analog pain scale and pain rating scoring methods. RESULTS: The difference between the amitriptyline and placebo groups was statistically significant 20, 25, 30, 35, and 40 minutes after placing the mucoadhesive tablet. Its mean onset and duration of action was 25 and 20 minutes, respectively (P<.05). CONCLUSIONS: To our knowledge, the present study represents an initial step toward achieving an efficient and safe anesthetic method. The intraoral mucoadhesive amitriptyline tablet proved to be a promising anesthetic device for manipulating pain in dental procedures. However, it should also be mentioned that to achieve high efficiency, it will be necessary to optimize the release profile. PMID- 23089654 TI - Healing of intraoral wounds closed using silk sutures and isoamyl 2-cyanoacrylate glue: a comparative clinical and histologic study. AB - PURPOSE: To compare the clinical and histologic healing of intraoral wounds closed using No. 3-0 silk suture with that obtained with isoamyl 2-cyanoacrylate glue. MATERIALS AND METHODS: We performed alveoloplasty in 30 cases in the mandibular anterior region of edentulous arches; the length of incision in all cases was the same distance from the midline. The closure was performed on 1 side with No. 3-0 silk suture, and the other side was closed with isoamyl 2 cyanoacrylate. The surgical sites were evaluated on the first, seventh, fourteenth, and twenty-first postoperative days for tenderness and erythema. In 15 cases (group A), incisional biopsies on both sutured and glued sides were performed on the seventh postoperative day. In the other 15 patients, similar biopsies were executed on the fourteenth postoperative day (group B). All specimens were examined under a microscope for inflammatory cell infiltration, vascularity, and fibroblastic activity. RESULTS: The incidence of tenderness and erythema was increased on the sutured side on the first, seventh, and fourteenth postoperative days but was similar to that on the glued side on the twenty-first postoperative day. In the patients biopsied on the seventh postoperative day, values of inflammatory cell infiltration and vascularity were higher on the sutured side, whereas in patients biopsied on the fourteenth postoperative day, only vascularity was higher on the sutured side. CONCLUSION: On the seventh postoperative day, both clinical and histologic indicators of inflammation were higher on the sutured side, but these indicators had reached similar values on the fourteenth postoperative day on both the sutured and glued sides. This suggests that isoamyl 2-cyanoacrylate may aid initial healing. PMID- 23089656 TI - Winter depression and diabetes. AB - Depression is a common and often harmful disorder, which is frequently associated with the winter season. Research has shown a link between type 2 diabetes mellitus and depression. Furthermore, diabetics with depression have a higher rate of adverse outcomes. Little has been published regarding the seasonality of depression in diabetics. The case report described in this article concerns a 65 year-old woman with type 2 diabetes and a history of winter depression. Current evidence-based management options are reviewed. PMID- 23089655 TI - Does cold tolerance plasticity correlate with the thermal environment and metabolic profiles of a parasitoid wasp? AB - Tolerance of ectotherm species to cold stress is highly plastic according to thermal conditions experienced prior to cold stress. In this study, we investigated how cold tolerance varies with developmental temperature (at 17, 25 and 30 degrees C) and whether developmental temperature induces different metabolic profiles. Experiments were conducted on the two populations of the parasitoid wasp, Venturia canescens, undergoing contrasting thermal regimes in their respective preferential habitat (thermally variable vs. buffered). We predicted the following: i) development at low temperatures improves the cold tolerance of parasitoid wasps, ii) the shape of the cold tolerance reaction norm differs between the two populations, and iii) these phenotypic variations are correlated with their metabolic profiles. Our results showed that habitat origin and developmental acclimation interact to determine cold tolerance and metabolic profiles of the parasitoid wasps. Cold tolerance was promoted when developmental temperatures declined and population originating from variable habitat presented a higher cold tolerance. Cold tolerance increases through the accumulation of metabolites with an assumed cryoprotective function and the depression of metabolites involved in energy metabolism. Our data provide an original example of how intraspecific cold acclimation variations correlate with metabolic response to developmental temperature. PMID- 23089657 TI - Holiday season for a healthy heart. AB - The term "holiday heart" is defined as an acute cardiac arrhythmia or conduction disturbance associated with heavy alcohol intake in individuals with no known heart disease, but in whom heart rhythm is restored to normal with abstinence of alcohol. This article provides a brief overview of the literature on this topic, discusses causes of increased cardiac events during the holiday season, describes a patient profile and the effect on patients' health as well as on their families, and provides suggestions to decrease the risk of holiday heart during the festive season. PMID- 23089658 TI - The role of vitamin D in critical illness. AB - The role of vitamin D in critical illness is under investigation. Recent data indicate declining levels of serum vitamin D in multiple adult populations. Deficiencies have been strongly linked to infectious processes and certain chronic disorders. Vitamin D deficiency that is present at the onset of critical illness may impact the severity of illness and contribute to less-than-optimal outcomes. This article describes the function of vitamin D, the effects that deficiencies have on body systems, and the emerging role of vitamin D deficiency for critically ill patients. PMID- 23089659 TI - Viral gastroenteritis in the adult population: the GI peril. AB - Viral gastroenteritis is extremely common, causing millions of cases of diarrhea in all age groups worldwide. Norovirus has been identified as the leading cause of viral gastroenteritis in the adult population. The combination of a low infectious dose, viral shedding before and for weeks after illness, and resistance to temperatures from freezing to 60 degrees C and to many common household cleaners makes norovirus a winter peril. Mild disease requires symptomatic treatment alone. Complicated cases develop severe dehydration and hypovolemia, requiring the skills of critical care nurses to meet the challenges of care. This article addresses diagnosis and prevention strategies. PMID- 23089660 TI - Respiratory syncytial virus bronchiolitis in children. AB - Respiratory syncytial virus is a highly infectious virus that commonly causes bronchiolitis and leads to high morbidity and a low, but important, incidence of mortality. Supportive therapy is the foundation of management. Hydration/nutrition and respiratory support are important evidence-based interventions. For children with severe disease, continuous positive airway pressure or mechanical ventilation may be necessary. Ribavirin may be used for treatment of patients with severe disease. Palivizumab provides important ongoing immunoprophylaxis during epidemic months for high-risk infants. Caregiver education and incorporating an explanation of all therapies and anticipatory guidance, including strategies for reducing the risk of infection, are vital. PMID- 23089661 TI - A review of influenza: implications for the geriatric population. AB - The influenza virus is a significant cause of morbidity and mortality each year in the United States, and is a major public health problem. Individuals aged 65 years and older comprise a sizeable population subgroup at high risk of infection and subsequent complications. Although influenza may cause substantial morbidity and mortality across the age spectrum, it becomes particularly problematic for those older than 65. This article presents an overview of influenza, with a focus on how the influenza virus has particular implications for the geriatric population. PMID- 23089662 TI - Critical care for frostbite. AB - Frostbite, a preventable cold-weather injury, occurs when the skin temperature cools to below 0 degrees C with the formation of extracellular ice crystals. On rewarming, an inflammatory response develops, contributing to ischemia and tissue loss. The severity of injury depends on the temperature, duration of exposure, and amount and depth of frozen tissue. Environmental, individual, behavioral, and physiologic factors increase susceptibility to cold. Rapid rewarming and watchful waiting remains the mainstay of treatment. Prevention can be accomplished through increasing public awareness of the adverse effects of cold exposure, and recognizing and mitigating the risks associated with the development of frostbite. PMID- 23089663 TI - Rural trauma challenges in Alaska. AB - Rural trauma during winter months in Alaska requires a coordinated highly skilled approach for rescue, recovery, resuscitation, and transport to distant tertiary care centers. Clinicians in this state face travel delays, extreme weather conditions, and unique transport scenarios. Early assessment and resuscitation may focus more on minimizing delays than on the traditional ABCs of emergency medicine. Clinical evaluation and treatment is also impacted by subzero temperatures, hypothermia, and prolonged exposure. Mechanical and equipment malfunctions can complicate decisions and further add to the challenges faced by medical teams who respond and deliver care in the vast wilderness of this state. PMID- 23089664 TI - Journey of a survivor of near drowning, polymicrobial pneumonia, and acute respiratory distress syndrome. AB - This article discusses a woman who collapsed and landed in a puddle of water in a park near a horse trail. Her rescue and resuscitation started an extraordinary effort by her body to heal from multiple insults. This case study highlights the diagnosis and support of polymicrobial pneumonia secondary to near drowning and the multisystem complications throughout the 3-month hospitalization. It highlights the evidence for treatment of the polymicrobial nature of submersion injury, acute lung injury, and benefits of progressive mobility. Social media as a tool for the family's communication and coping are also discussed. PMID- 23089665 TI - Winter trauma. Preface. PMID- 23089666 TI - Effect of axonal micro-tubules on the morphology of retinal nerve fibers studied by second-harmonic generation. AB - Many studies suggest that the degradation of microtubules in the retinal ganglion cells may be an early event in the progression of glaucoma. Because reflectance and birefringence of the retinal nerve fibers arise primarily from microtubules, the optical properties have been intensively studied for early detection of the disease. We previously reported a novel nonlinear optical signal from axonal microtubules for visualizing the retinal nerve fibers, namely second-harmonic generation (SHG). We demonstrate the use of axonal SHG to investigate the effect of microtubules on the morphology of the retinal nerve fiber bundles. Time-lapse SHG imaging of ex vivo rat retinal flat mounts was performed during pharmacological treatment of nocodazole, and the intensity of axonal SHG and the changes in nerve fiber bundle morphology were monitored. We found that the microtubule disruption does not lead to immediate modification in the morphology of the nerve fibers. Our results indicate that microtubular SHG may provide a useful means for sensitive detection of axonal injuries. Since the intrinsic radiation depends on the regular architecture of the cytoskeleton element as maintained by active cellular regulations, the intensity of signal reflects the health of the retinal ganglion cell axons. PMID- 23089667 TI - Photoacoustic detection of functional responses in the motor cortex of awake behaving monkey during forelimb movement. AB - Photoacoustic (PA) imaging was applied to detect the neuronal activity in the motor cortex of an awake, behaving monkey during forelimb movement. An adult macaque monkey was trained to perform a reach-to-grasp task while PA images were acquired through a 30-mm diameter implanted cranial chamber. Increased PA signal amplitude results from an increase in regional blood volume and is interpreted as increased neuronal activity. Additionally, depth-resolved PA signals enabled the study of functional responses in deep cortical areas. The results demonstrate the feasibility of utilizing PA imaging for studies of functional activation of cerebral cortex in awake monkeys performing behavioral tasks. PMID- 23089668 TI - Low NRF2 mRNA expression in spermatozoa from men with low sperm motility. AB - Antioxidant genes and enzymes play important roles in human spermatogenesis. Although low levels of antioxidant enzyme expression are associated with poor sperm quality, it is not clear whether mRNA expression of antioxidant genes is lower in these men than in normozoospermic men. In this study, 55 asthenozoospermic and oligoasthenozoospermic patients and 65 controls were recruited. Quantitative real-time reverse transcription PCR was performed and the abundance of mRNA of four antioxidant genes known to be important to spermatogenesis were evaluated. These genes were nuclear factor erythroid 2 related factor 2 (NRF2), catalase (CAT), glutathione S-transferase Mu 1 (GSTM1), and superoxide dismutase isoenzyme 2 (SOD2). Results showed the level of NRF2 mRNA expression to be significantly lower in patients than in controls (P < 0.001), but no statistically significant difference in the level of SOD2, CAT, or GSTM1 gene expression was observed between the two groups. A significant correlation was observed between the level of NRF2 mRNA expression and specific sperm function parameters, including concentration, progressive motility, immotility, vitality, and morphology (all P < 0.01). NRF2 expression was also found to be associated with seminal SOD activity and mRNA levels of the CAT and SOD2 genes (all P < 0.05). Therefore, our data demonstrated that the level of NRF2 mRNA expression is significantly lower in human males with low sperm motility and correlated with specific sperm function parameters. This suggests that NRF2 is important to spermatogenesis and may serve as a useful biomarker in the prediction of male infertility. PMID- 23089669 TI - Regioselective azidotrimethylsilylation of carbohydrates and applications thereof. AB - Azidotrimethylsilylation of carbohydrates (monosaccharides and disaccharides) has been achieved in high yields under Mitsunobu conditions. The azidation of carbohydrates is effected at 0 degrees C essentially only at the primary alcoholic position in mono, di- and triols in protected/unprotected glycosides, whereas the remaining secondary hydroxyl groups got silylated. Surprisingly, no azidation of the secondary hydroxyls was observed in all the carbohydrate substrates. Applications of the methodology for the synthesis of amino sugars, triazoles and azasugars are reported. PMID- 23089670 TI - A novel 96-well gel-based assay for determining antifungal activity against filamentous fungi. AB - In recent years the global rise in antibiotic resistance and environmental consciousness lead to a renewed fervour to find and develop novel antibiotics, including antifungals. However, the influence of the environment on antifungal activity is often disregarded and many in vitro assays may cause the activity of certain antifungals to be overestimated or underestimated. The general antifungal test assays that are economically accessible to the majority of scientists primarily rely on visual examination or on spectrophotometric analysis. The effect of certain morphogenic antifungals, which may lead to hyperbranching of filamentous fungi, unfortunately renders these methods unreliable. To minimise the difficulties experienced as a result of hyperbranching, we developed a straightforward, economical 96-well gel-based method, independent of spectrophotometric analysis, for highly repeatable determination of antifungal activity. For the calculation of inhibition parameters, this method relies on the visualisation of assay results by digitisation. The antifungal activity results from our novel micro-gel dilution assay are comparable to that of the micro-broth dilution assay used as standard reference test of The Clinical and Laboratory Standard Institute. Furthermore, our economical assay is multifunctional as it permits microscopic analysis of the preserved assay results, as well as rendering highly reliable data. PMID- 23089671 TI - A systematic review and meta-analysis of MTHFR polymorphisms in methotrexate toxicity prediction in pediatric acute lymphoblastic leukemia. AB - Methotrexate (MTX) is an important component of therapy used to treat childhood acute lymphoblastic leukemia (ALL). Two single-nucleotide polymorphisms (SNPs) in the methylenetetrahydrofolate reductase (MTHFR) gene, C677T and A1298C, affect MTHFR activity. A large body of studies has investigated the potential role of MTHFR SNPs in MTX toxicity in pediatric ALL. However, the results are controversial. In this review and meta-analysis, we critically evaluate the relationship between the C677T and A1298C polymorphisms of MTHFR and MTX toxicity in pediatric ALL. The majority of published reports do not find associations between MTHFR polymorphisms and toxicity in pediatric ALL. When associations are reported, often the results are contradictory to each other. The meta-analysis confirms a lack of association. In conclusion, MTHFR, C677T and A1298C polymorphisms do not seem to be good markers of MTX-related toxicity in pediatric ALL. PMID- 23089672 TI - Pharmacogenomics of drug-metabolizing enzymes: a recent update on clinical implications and endogenous effects. AB - Interindividual differences in drug disposition are important causes for adverse drug reactions and lack of drug response. The majority of phase I and phase II drug-metabolizing enzymes (DMEs) are polymorphic and constitute essential factors for the outcome of drug therapy. Recently, both genome-wide association (GWA) studies with a focus on drug response, as well as more targeted studies of genes encoding DMEs have revealed in-depth information and provided additional information for variation in drug metabolism and drug response, resulting in increased knowledge that aids drug development and clinical practice. In addition, an increasing number of meta-analyses have been published based on several original and often conflicting pharmacogenetic studies. Here, we review data regarding the pharmacogenomics of DMEs, with particular emphasis on novelties. We conclude that recent studies have emphasized the importance of CYP2C19 polymorphism for the effects of clopidogrel, whereas the CYP2C9 polymorphism appears to have a role in anticoagulant treatment, although inferior to VKORC1. Furthermore, the analgesic and side effects of codeine in relation to CYP2D6 polymorphism are supported and the influence of CYP2D6 genotype on breast cancer recurrence during tamoxifen treatment appears relevant as based on three large studies. The influence of CYP2D6 polymorphism on the effect of antidepressants in a clinical setting is yet without any firm evidence, and the relation between CYP2D6 ultrarapid metabolizers and suicide behavior warrants further studies. There is evidence for the influence of CYP3A5 polymorphism on tacrolimus dose, although the influence on response is less studied. Recent large GWA studies support a link between CYP1A2 polymorphism and blood pressure as well as coffee consumption, and between CYP2A6 polymorphism and cigarette consumption, which in turn appears to influence the lung cancer incidence. Regarding phase II enzyme polymorphism, the anticancer treatment with mercaptopurines and irinotecan is still considered important in relation to the polymorphism of TPMT and UGT1A1, respectively. There is a need for further clarification of the clinical importance and use of all these findings, but the recent research in the field that encompasses larger studies and a whole genome perspective, improves the possibilities be able to make firm and cost-effective recommendations for drug treatment in the future. PMID- 23089673 TI - Pharmacogenetic and pharmacokinetic aspects of CYP3A induction by efavirenz in HIV patients. AB - We investigated the effects of pharmacogenetic variations and efavirenz pharmacokinetics on inter-individual differences in the extent of CYP3A induction by efavirenz using 4beta-hydroxycholesterol/cholesterol (4beta-OHC/Chol) as a marker for CYP3A induction. Plasma 4beta-hydroxycholesterol and cholesterol concentrations were determined at baseline, and at the 4th, 16th and 48th week of efavirenz-based highly active antiretroviral therapy in antiretroviral therapy naive HIV patients (n=77). Efavirenz plasma concentrations were quantified at weeks 4 and 16. CYP2B6, CYP3A5, ABCB1, UGT2B7 genotyping were done. Compared with baseline, the median plasma 4beta-OHC/Chol ratio increased at the 4th (257%), 16th (291%) and 48th (165%) week (P<0.0001). CYP2B6*6 genotype significantly influenced 4beta-OHC/Chol ratio at weeks 16 (P=0.02) and 48 (P=0.04) being highest in CYP2B6*6/*6>*1/*6>*1/*1. There were positive correlations between plasma efavirenz and 4beta-OHC/Chol ratios (week 4: P=0.02, week 16: P=0.001). CYP3A enzyme induction by efavirenz is pronounced in CYP2B6 slow metabolizers who have high efavirenz plasma exposure. PMID- 23089674 TI - The reliability of a two-item scale: Pearson, Cronbach, or Spearman-Brown? PMID- 23089675 TI - A quasi-randomized group trial of a brief alcohol intervention on risky single occasion drinking among secondary school students. AB - OBJECTIVES: To show the effectiveness of a brief group alcohol intervention. Aims of the intervention were to reduce the frequency of heavy drinking occasions, maximum number of drinks on an occasion and overall weekly consumption. METHODS: A cluster quasi-randomized control trial (intervention n = 338; control n = 330) among 16- to 18-year-old secondary school students in the Swiss Canton of Zurich. Groups homogeneous for heavy drinking occasions (5+/4+ drinks for men/women) consisted of those having medium risk (3-4) or high risk (5+) occasions in the past 30 days. Groups of 8-10 individuals received two 45-min sessions based on motivational interviewing techniques. RESULTS: Borderline significant beneficial effects (p < 0.10) on heavy drinking occasions and alcohol volume were found 6 months later for the medium-risk group only, but not for the high-risk group. None of the effects remained significant after Bonferroni corrections. CONCLUSIONS: Group intervention was ineffective for all at-risk users. The heaviest drinkers may need more intensive treatment. Alternative explanations were iatrogenic effects among the heaviest drinkers, assessment reactivity, or reduction of social desirability bias at follow-up through peer feedback. PMID- 23089676 TI - Beneficial role of endogenous immunoglobulin subclasses and isotypes in septic shock. AB - PURPOSE: There is increasing evidence on the relationship between endogenously produced immunoglobulins and the clinical outcome in septic shock (SS). MATERIALS AND METHODS: Levels of immunoglobulin G (IgG) subclasses, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin E were measured in plasma from 42 patients with SS and in 36 patients with systemic inflammatory response syndrome at diagnosis. Association of immunoglobulins levels with disease severity and outcome was evaluated. RESULTS: Eighteen patients with SS finally died. Both patients with systemic inflammatory response syndrome and SS showed subnormal levels of total IgG, IgG2, and IgM. Patients with SS who died showed the lowest levels of total IgG and IgG1. Total IgG, IgG1, IgG2, IgG3, IgG4, and IgA correlated inversely with Acute Physiology and Chronic Health Evaluation II score in SS. Univariate Cox regression analysis showed that levels of IgG1, IgG2, IgG3, IgM, IgA, and total IgG were inversely associated to the probability of death at 28 days. Multivariate analysis showed that IgG1, total IgG, IgM, and IgA behaved as independent protective factors against mortality (hazard ratio, P): 0.23, 0.026; 0.16, 0.028; 0.11, 0.042; 0.05, 0.010, respectively, whereas IgG3 showed a protective trend also. CONCLUSIONS: Our study evidenced that, in addition to IgG1, other major endogenous immunoglobulins isotypes and subclasses seem to play a beneficial role in SS. PMID- 23089677 TI - Prognostic factors and outcomes of patients with pulmonary hypertension admitted to the intensive care unit. AB - PURPOSE: Patients with pulmonary hypertension (PH) can decompensate to the point where they require care in the intensive care unit (ICU). Our objective is to examine the outcomes and characteristics of patients with PH admitted to the ICU. METHODS: This is a retrospective study of 99 patients with PH who were admitted to the medical ICU of a single tertiary care center. Baseline characteristics, interventions during ICU admission, and ICU and 6-month outcome were documented. Univariate and multivariate logistic regressions were used to evaluate association of patient characteristics with mortality. RESULTS: Intensive care unit mortality was 30%, and 6-month mortality was 40%. Acute Physiology and Chronic Health Evaluation II score, World Health Organization Group 3 PH, and preexisting treatment with a prostacyclin at time of ICU admission were associated with worse outcome. Patients who received cardiopulmonary resuscitation had 100% mortality. The requirement for mechanical ventilation and dialysis was also associated with increased mortality. Pulmonary artery catheter placement was associated with reduced mortality, specifically if it was placed early during ICU admission and if associated with a change in the present management. CONCLUSIONS: Mortality is high in critically ill patients with PH. The identification of prognostic baseline characteristics and interventions in the ICU is important and warrants further investigation. PMID- 23089678 TI - Interrelationship between blood and tissue lactate in a general intensive care unit: a subcutaneous adipose tissue microdialysis study on 162 critically ill patients. AB - PURPOSE: The aim of the study was to study the interrelationship between blood and tissue lactate in critically ill patients with or without shock admitted in a general intensive care unit. MATERIALS AND METHODS: We studied 162 mechanically ventilated patients: 106 with shock (septic shock, 97; cardiogenic shock, 9) and 56 without shock (severe sepsis, 38; systemic inflammatory response syndrome, 18). A microdialysis catheter was inserted in the subcutaneous adipose tissue of the upper thigh, and interstitial fluid was collected every 4 hours for a maximum of 6 days. We assessed the relationship between tissue and blood lactate using cross-approximate entropy and cross-correlation analysis. RESULTS: Patients with shock had higher area under the curve for blood (261 vs 175 mmol/L*hours, P < .0001) and tissue lactate (386 vs 281 mmol/L*hours, P < .0001) compared with patients without shock. The interrelationship of tissue-blood lactate, as assessed with cross-approximate entropy, was more regular in patients with shock compared with patients without shock. Cross-correlation of tissue vs blood lactate yielded higher correlation coefficients in patients with shock compared with those without shock, being higher when tissue lactate preceded blood lactate by 4 hours compared with tissue vs blood lactate with no lag time. CONCLUSIONS: In critical illness, the detailed dynamics between blood and tissue lactate are affected by the presence of shock. In patients with shock, microdialysis-assessed tissue lactate is higher compared with those without shock and may detect metabolic disturbances before these become evident in the systemic circulation. PMID- 23089681 TI - Localized surface plasmon resonances in gold nano-patches on a gallium nitride substrate. AB - In this paper we describe the design, fabrication and characterization of gold nano-patches, deposited on gallium nitride substrate, acting as optical nanoantennas able to efficiently localize the electric field at the metal dielectric interface. We analyse the performance of the proposed device, evaluating the transmission and the electric field localization by means of a three-dimensional finite difference time domain (FDTD) method. We detail the fabrication protocol and show the morphological characterization. We also investigate the near-field optical transmission by means of scanning near-field optical microscope measurements, which reveal the excitation of a localized surface plasmon resonance at a wavelength of 633 nm, as expected by the FDTD calculations. Such results highlight how the final device can pave the way for the realization of a single optical platform where the active material and the metal nanostructures are integrated together on the same chip. PMID- 23089680 TI - Prediction of pulmonary edema by plasma protein levels in patients with sepsis. AB - PURPOSE: The difficulties of fluid therapy in patients with septic shock are to maintain sufficient vascular volume while preventing pulmonary edema formation. Thus, it is important to find a biomarker that can reliably predict pulmonary edema formation after fluid loading. We evaluated the association of plasma protein levels with the increase in extravascular lung water index (DeltaEVLWI) after fluid loading. METHODS: This was an observational study in which we retrospectively reviewed medical records of septic patients in whom hemodynamic variables were measured by transpulmonary thermodilution technique before and after fluid loading. Plasma protein levels were measured before fluid loading. Patients were divided into 2 groups according to the changes in EVLWI (DeltaEVLWI >= 10%) after fluid loading. Diagnostic performance of plasma proteins in predicting pulmonary edema formation was assessed. RESULTS: A total of 62 patients were included, and 27 of them showed a DeltaEVLWI 10% or higher after fluid loading. Plasma albumin and transferrin were significantly lower in this group than in the group with DeltaEVLWI less than 10% (21.7 +/- 5.8 vs 25.3 +/- 5.0 g/L for albumin, P < .05; 107.9 +/- 50.1 vs 136.8 +/- 44.2 mg/dL for transferrin, P < .05). Areas under the curve of albumin and transferrin were 0.68 (cardiac index, 0.54-0.83) and 0.72 (cardiac index, 0.59-0.86), respectively. At a cutoff value of 87.9 mg/dL, transferrin had a sensitivity of 0.91 in predicting DeltaEVLWI 10% or higher. CONCLUSIONS: Plasma transferrin and albumin levels were associated with DeltaEVLWI 10% or higher after fluid loading. The high sensitivity of both biomarkers indicated that patients with normal values were less likely to develop pulmonary edema after fluid loading. PMID- 23089683 TI - Sequestration-based bistability enables tuning of the switching boundaries and design of a latch. AB - Natural biological systems have evolved a diverse array of switches to realize their strategies for environmental response and development. Emerging applications of synthetic biology have begun to exploit such switches to achieve increasingly sophisticated designed behaviors. However, not all switch architectures allow facile design of the switching and memory properties. Furthermore, not all designs are built from components for which large families of variants exist, a requirement for building many orthogonal switch variants. Therefore, there is a critical need from genetic engineers for scalable strategies that yield custom bistable switches. Here, we use a sigma factor and its cognate anti-sigma factor to experimentally verify that ultrasensitivity from sequestration combined with positive feedback is sufficient to build a bistable switch. We show that sequestration allows us to predictably tune the switching boundaries, and we can easily tune our switch to function as a set-reset latch that can be toggled between two states by a pulse of inducer input. PMID- 23089682 TI - A functional selection model explains evolutionary robustness despite plasticity in regulatory networks. AB - Evolutionary rewiring of regulatory networks is an important source of diversity among species. Previous evidence suggested substantial divergence of regulatory networks across species. However, systematically assessing the extent of this plasticity and its functional implications has been challenging due to limited experimental data and the noisy nature of computational predictions. Here, we introduce a novel approach to study cis-regulatory evolution, and use it to trace the regulatory history of 88 DNA motifs of transcription factors across 23 Ascomycota fungi. While motifs are conserved, we find a pervasive gain and loss in the regulation of their target genes. Despite this turnover, the biological processes associated with a motif are generally conserved. We explain these trends using a model with a strong selection to conserve the overall function of a transcription factor, and a much weaker selection over the specific genes it targets. The model also accounts for the turnover of bound targets measured experimentally across species in yeasts and mammals. Thus, selective pressures on regulatory networks mostly tolerate local rewiring, and may allow for subtle fine tuning of gene regulation during evolution. PMID- 23089684 TI - Similarity in recombination rate and linkage disequilibrium at CYP2C and CYP2D cytochrome P450 gene regions among Europeans indicates signs of selection and no advantage of using tagSNPs in population isolates. AB - OBJECTIVE: Linkage disequilibrium (LD) and recombination rate variations are known to vary considerably between human genome regions and populations mostly because of the combined effects of mutation, recombination, and demographic history. Thus, the pattern of LD is a key issue to disentangle variants associated with complex traits. Here, we aim to describe the haplotype structure and LD variation at the pharmacogenetically relevant cytochrome P450 CYP2C and CYP2D gene regions among European populations. METHODS: To assess the haplotype structure, LD pattern, and recombination rate variations in the clinically significant CYP2C and CYP2D regions, we genotyped 143 single-nucleotide polymorphisms (SNPs) across these two genome regions in a diverse set of 11 European population samples and one sub-Saharan African sample. RESULTS: Our results showed extended patterns of LD and in general a low rate of recombination at these loci, and a low degree of allele differentiation for the two cytochrome P450 regions among Europeans, with the exception of the Sami and the Finns as European outliers. The Sami sample showed reduced haplotype diversity and higher LD for the two cytochrome P450 regions than the other Europeans, a feature that is proposed to enhance the LD mapping of underlying common complex traits. However, recombination hotspots and LD blocks at these two regions showed highly consistent structures across Europeans including Finns and Sami. Moreover, we showed that the CEPH sample has significantly higher tag transferability among Europeans and a more efficient tagging of both the rare CYP2C9 and the common CYP2C19 functional variants than the Sami. Our data set included CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) enzyme activity-altering variants associated in a recent genome-wide study with acenocoumarol-induced and warfarin induced anticoagulation or to the antiplatelet effect of clopidogrel, respectively. Including these known activity-altering variants, we showed the haplotype variation and high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci in a comprehensive set of 11 European populations. Furthermore, a significant frequency difference of a CYP2C19*2 gene mutation causing variable drug reactions was observed among Europeans. CONCLUSION: The CEPH sample representing the general European population as such in the HapMap project seems to be the optimal population sample for the LD mapping of common complex traits among Europeans. Nevertheless, it is still argued that the unique pattern of LD in the Sami may offer an advantage for further association mapping, especially if multiple rare variants play a role in disease etiology. However, besides the activity-altering CYP2C9*3 (rs1057910) and CYP2C19*2 (rs4244285) variants, the high derived allele frequencies of novel recently identified acenocoumarol genome-wide associated SNPs at CYP2C9 (rs4086116) and CYP2C18 (rs12772169, rs1998591, rs2104543, rs1042194) loci variants indicated that the CYP2C region may have been influenced by selection. Thus, this fine-scale haplotype map of the CYP2C and CYP2D regions may help to choose markers for further association mapping of complex pharmacogenetic traits at these loci. PMID- 23089685 TI - Home intervention and predictor variables for rehospitalization in chronic obstructive pulmonary disease exacerbations. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) exacerbation increases mortality and resources used associated with hospitalization. We studied whether early home monitoring reduces the rate of readmission and if there are any predictor variables. PATIENTS AND METHODS: We performed a prospective, controlled, parallel-group study in patients who were hospitalized for COPD. Patients whose residence was within less than 15km from the hospital were assigned to an interventional group (home visits by nurses about 48-72hours after discharge), the remainder were assigned to a conventional care group. The rate of rehospitalization within the first month was compared between the two groups, as well as those variables that showed a predictive capability. RESULTS: Seventy one patients were included: 35 in the conventional care group and 36 in the interventional group. In the latter, the treatment was modified in 13 patients (36%). The hospital readmission rate was 17%, which was similar in both groups (P=.50). For every 5-year increase in age, the risk for readmission was 2.54 (95%CI, 1.06-5.07) and for each increase of 10mmHg in PaCO(2), the risk of readmission was 8.34 (95%CI, 2.43-18.55). CONCLUSIONS: Early home monitoring did not decrease the readmission rate during the first month. Older age and high PaCO(2) are factors that identify the group with a high risk for rehospitalization. PMID- 23089686 TI - Latent infection treatment to prevent TB transmission in school settings. PMID- 23089687 TI - Non-alcoholic fatty liver disease: an emerging liver disease in Taiwan. AB - Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in Western countries, and has become increasingly recognized as a public health problem in Taiwan. Patients with non-alcoholic steatohepatitis, a more severe form of NAFLD, may progress to cirrhosis and its related complications, including hepatocellular carcinoma. Since NAFLD is highly linked to metabolic syndrome, such patients may have increased risks of complications related to both liver disease and metabolic syndrome. Therefore, if we fail to cope with this growing health problem, NAFLD may gradually replace viral hepatitis as the major etiology of liver disease in Taiwan. PMID- 23089688 TI - Epidemiological and microbiological characteristics of culture-proven acute otitis media in Taiwanese children. AB - BACKGROUND/PURPOSE: Acute otitis media (AOM) is one of the most common diseases in children. Here, we describe the epidemiological and microbiological characteristics of AOM in Taiwanese children over a 10-year period. METHODS: We retrospectively enrolled pediatric patients with culture-proven AOM who were treated at Mackay Memorial Hospital, Taipei between 1999-2008. The data include demographic characteristics, clinical history, and microbiological characteristics. RESULTS: Six hundred and fourteen patients were included. The male:female ratio was 1.4 (p<0.001). Greater than three-fourths of the patients (476 [77.5%]) were < 5 years of age, and most patients were 1-2 years of age. The most common isolated pathogen was Streptococcus pneumoniae (419 patients [68.2%]), followed by nontypeable Haemophilus influenzae (NTHi; 118 patients [19.2%]). The distributions of age, gender, use of tympanocentesis, history of previous AOM, and use of antibiotic between patients infected with the two pathogens were not significantly different. However, the number of patients with AOM caused by S. pneumoniae, but not NTHi, decreased during the study period (p=0.004). Three hundred and eighty-seven children (63.0%) with AOM developed spontaneous otorrhea. Compared with patients who underwent tympanocentesis, those with spontaneous otorrhea were younger (27.0+/-16.4 vs. 31.1+/-15.2 months of age, p=0.004), more likely to have a previous history of AOM (p=0.019), and more likely to receive more antibiotics (p=0.012). The third most common pathogen was S. pyogenes (25 patients [4.1%]). S. pyogenes occurred more often in children > 5 years of age and was associated with spontaneous otorrhea (p<0.001). CONCLUSION: S. pneumoniae and NTHi are common causes of culture-confirmed AOM in Taiwanese children. Although S. pyogenes is not as common, it usually causes AOM in children > 5 years of age and is associated with spontaneous otorrhea. PMID- 23089689 TI - Initial manifestations and clinical course of systemic onset juvenile idiopathic arthritis: a ten-year retrospective study. AB - BACKGROUND/PURPOSE: The diagnosis of systemic onset juvenile idiopathic arthritis (SoJIA) on disease onset is challenging and made mainly by exclusion. This study aimed to investigate the initial clinical and laboratory features of children with SoJIA in Taiwan. METHODS: Patients diagnosed with SoJIA at the National Taiwan University Hospital between 1997 and 2007 were evaluated and data were collected by retrospective chart review. Inferential statistics were used to compare features of patients with steroid use for <6 months or >6 months. RESULTS: Twenty-eight (28) patients (13 boys and 15 girls) were included in this study. The mean age of onset was 8.7 years old. The most common presentations were fever (100%), arthritis (89.3%), and skin rash (67.9%). The patterns of arthritis in affected patients were 50% oligoarticular type and 39% polyarticular type. The most common joints involved were the knee (76% of patients with arthritis), ankle (56%), and elbow and proximal interphalangeal joints (28%). The most common pattern of fever during first week was intermittent (53%). Prolonged use of steroid was associated with leukocytosis (17.63+/-7.71 vs. 11.93+/ 4.43*10(9) leukocytes/L, p<0.05) and higher aspartate aminotransferase (89.4 vs. 31.2 U/L, p<0.05) on initial presentation. CONCLUSION: In SoJIA, extra-articular features such as fever, rash, and lymphadenopathy are most prominent. Leukocytosis and polyarticular pattern on presentation may indicate a refractory clinical course. PMID- 23089690 TI - Green tea extract supplementation ameliorates CCl4-induced hepatic oxidative stress, fibrosis, and acute-phase protein expression in rat. AB - BACKGROUND/PURPOSE: We evaluated the long-term effects of green tea extract (GTE) supplementation on oxidative stress, biliary acute phase protein expression, and liver function in CCl(4)-induced chronic liver injury. METHODS: We evaluated the antioxidant activity of GTE in comparison with those of vitamin C, vitamin E, and beta-carotene in vitro by using an ultrasensitive chemiluminescence analyzer. Chronic liver injury was induced by intraperitoneally administering carbon tetrachloride (CCl(4)) (1 mL/kg body weight, twice weekly) to female Wistar rats for 8 weeks. The effects of low (4 mg/kg body weight per day) and high (20 mg/kg body weight per day) doses of intragastric GTE on CCl(4)-induced liver dysfunction and fibrosis were examined by measuring the bile and blood reactive oxygen species levels and biochemical parameters by using Western blot and two dimensional polyacrylamide gel electrophoresis techniques. RESULTS: GTE has greater scavenging activity against O(2)(-), H(2)O(2), and Hypochlorous acid (HOCl) in vitro than vitamin C, vitamin E, and beta-carotene do. In vivo, CCl(4) markedly increased bile and blood reactive oxygen species production, lipid accumulation, number of infiltrated leukocytes, fibrosis, hepatic hydroxyproline content, and plasma alanine aminotransferase and aspartate aminotransferase activities, and reduced plasma albumin levels. Two-dimensional polyacrylamide gel electrophoresis revealed that CCl(4) increased the acute-phase expression of six biliary proteins and decreased hepatic B-cell lymphoma 2 (Bcl-2), catalase, and CuZn superoxide dismutase protein expression. GTE supplementation attenuated CCl(4)-enhanced oxidative stress, levels of biochemical parameters, pathology, and acute-phase protein secretion, and preserved antioxidant/antiapoptotic protein expression. CONCLUSION: GTE supplementation attenuates CCl(4)-induced hepatic oxidative stress, fibrosis, acute phase protein excretion, and hepatic dysfunction via the antioxidant and antiapoptotic defense mechanisms. PMID- 23089691 TI - Effect of simulated debracketing on enamel damage. AB - BACKGROUND/PURPOSE: A smooth enamel surface after the removal of a bracket from a tooth is essential for both esthetic demands and the prevention of plaque accumulation. The purpose of this study was to evaluate enamel damage caused by three standardized debracketing techniques. METHODS: We established three standardized test devices based on the principles of the squeezing, shearing, and tensile testing methods, which were simulated using a How Plier (TASK 60-306), a Direct Bond Bracket Remover (TASK 60-335 T), and a Lift-Off Debracketing Instrument (3 M-Unitek 444-761), respectively. Thirty teeth in each group were evaluated after debracketing. An optical stereomicroscope and a CCD camera with a computerized image analysis system were used to ascertain the proportion of remnant adhesive area (RAE) on the enamel surface. Fractography was analyzed using a scanning electron microscope. RESULTS: The squeezing debracketing method exhibited the highest debonding force (54.3 +/- 7.0 N) and the least damage to the enamel surface (RAE = 99.5% +/- 2.4%). The tensile debracketing method preserved most of the adhesive on the enamel surface (RAE = 98.7% +/- 3.3%) and required the least debonding force (6.8 +/- 1.2 N). However, the shearing debracketing method exhibited a significantly higher debonding force (32.0 +/- 8.2 N) and smaller RAE (77.3% +/- 33.5%) compared to the tensile debracketing method (p < 0.05). Three specimens appeared to have vertical fractures on their enamel prisms when using the shearing method. CONCLUSION: With the proposed method, we conclude that the squeezing and tensile methods are acceptable for clinical use when debracketing, whereas the Direct Bond Bracket Remover may cause shearing failure, leading to a risk for enamel damage. PMID- 23089679 TI - Rates and determinants of informed consent: a case study of an international thromboprophylaxis trial. AB - BACKGROUND: Successful completion of randomized trials depends upon efficiently and ethically screening patients and obtaining informed consent. Awareness of modifiable barriers to obtaining consent may inform ongoing and future trials. OBJECTIVE: The objective of this study is to describe and examine determinants of consent rates in an international heparin thromboprophylaxis trial (Prophylaxis for ThromboEmbolism in Critical Care Trial, clinicaltrials.gov NCT00182143). DESIGN: Throughout the 4-year trial, research personnel approached eligible critically ill patients or their substitute decision makers for informed consent. Whether consent was obtained or declined was documented daily. SETTING: The trial was conducted in 67 centers in 6 countries. MEASUREMENTS AND MAIN RESULTS: A total of 3764 patients were randomized. The overall consent rate was 82.2% (range, 50%-100%) across participating centers. Consent was obtained from substitute decision makers and patients in 90.1% and 9.9% of cases, respectively. Five factors were independently associated with consent rates. Research coordinators with more experience achieved higher consent rates (odds ratio [OR], 3.43; 95% confidence interval, 2.42-4.86; P < .001 for those with >10 years of experience). Consent rates were higher in smaller intensive care units with less than 15 beds compared with intensive care units with 15 to 20 beds, 21 to 25 beds, and greater than 25 beds (all ORs, <0.5; P < .001) and were higher in centers with more than 1 full-time research staff (OR, 1.95; 95% confidence interval, 1.28-2.99; P < .001). Consent rates were lower in centers affiliated with the Canadian Critical Care Trials Group or the Australian and New Zealand Intensive Care Society Clinical Trials Group compared with other centers (OR, 0.57; 95% confidence interval, 0.42-0.77; P < .001). Finally, consent rates were highest during the pilot trial, lowest during the initiation of the full trial, and increased over years of recruitment (P < .001). CONCLUSIONS: Characteristics of study centers, research infrastructure, and experience were important factors associated with successfully procuring informed consent to participate in this thromboprophylaxis trial. PMID- 23089692 TI - Mortality among dentists in Taiwan, 1985-2009. AB - BACKGROUND/PURPOSE: Controversy exists in the literature regarding whether dentists with multiple occupational exposures suffer from premature mortality. A cohort mortality study was conducted to evaluate the survival outcome and determine if potential exposure to harmful agents leads to premature mortality among dentists. METHODS: Using the Life Table Analysis System, we calculated standardized mortality ratios (SMRs) for a cohort of 11,700 dentists affiliated with the Taiwan Dental Association. These dentists were followed from 1985-2009. Reference rates were derived from cause-, gender-, and age-specific mortality rates of the general population of Taiwan and 18,664 Taiwanese internists, who were considered to be more socioeconomically proximal to dentists. A Cox proportional hazard model was also constructed to determine multiple risk factors associated with mortality. RESULTS: Compared with the general population, dentists in Taiwan consistently demonstrated reduced from all-cause mortality. However, compared with internists, significant and excess mortality were observed in dentists for overall mortality (SMR=1.13; 95% confidence interval [CI]=1.00 1.26), drowning (SMR=6.62; 95% CI=2.15-15.45), and heart diseases (SMR=1.66; 95% CI=1.22-2.21). After adjusting for other risk factors, the Cox model showed an increased hazard ratio of 1.17 (95% CI=1.01-1.37) for dentists. CONCLUSION: Taiwanese dentists demonstrated significant elevated SMRs for overall causes, drowning, and heart diseases. Careful precaution should be taken to reduce these trends. Future studies are also needed for in-depth exploration of the mechanisms regarding how professional stress and exposure contribute to the increased risk of mortality in Taiwanese dentists. PMID- 23089693 TI - Assessment of quality of life among Taiwanese patients with visual impairment. AB - BACKGROUND/PURPOSE: This study aims at evaluating the relationship between visual impairment and health-related quality of life (QoL) by identifying factors that affect the EQ-5D index score and Visual Functioning Questionnaire (VFQ) global score, and determining whether the VFQ-25 scores and the European Quality of Life 5 Dimensions (EQ-5D) scores are correlated. METHODS: This cross-sectional study comprised 318 patients aged 40 years or more presenting with best corrected visual acuity (BCVA) of 20/40 or worse in the better eye.Patients received comprehensive ophthalmologic examinations, and were administered the National Eye Institute VFQ-25 and the EQ-5D instruments. A higher VFQ-25 score indicates a better QoL and, after conversion of the EQ-5D scores to an index score, a higher EQ-5D index score indicates a better QoL. RESULTS: On multivariate analysis of the EQ-5D index scores, women and those with arthritis were found to have significantly worse QoL, and the EQ-5D index score was increased by every unit increase in BCVA or mean deviation. Multivariate analysis of the VFQ-25 scores revealed that a history of heart disease, arthritis, and eye diseases, such as age-related macular degeneration or diabetic retinopathy, had significant negative effects on patients' QoL, and VFQ-25 global score was decreased by every unit increase in logMAR. According to this analysis, patients' QoL was improved by each unit increase in BCVA or mean deviation. The correlation between the two questionnaires was only weak to moderate. CONCLUSION: Visual impairment was associated with lower QoL, as assessed by either questionnaire in Taiwanese patients. PMID- 23089695 TI - Aortobronchial fistula: secondary to patent ductus arteriosus. PMID- 23089694 TI - Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis. AB - Cystic fibrosis (CF) is an inherited disease of the secretory glands caused by mutations of the cystic fibrosis transmembrane regulator (CFTR) gene. The clinical manifestations of CF are repetitive lung infections, biliary cirrhosis, pancreatic abnormalities, and gastrointestinal disorders. We report a 21-year-old Taiwanese man with CF who had abdominal pain for 2 days. The diagnosis of CF had been confirmed by peripheral blood analysis of the CFTR gene 5 years before admission. He presented to the emergency department with nausea, vomiting, abdominal distension, and crampy abdominal pain, which is atypical for acute appendicitis. The physical examination and a series of studies revealed intestinal obstruction, but acute appendicitis could not be ruled out. After conservative treatment, together with empiric antibiotics, the refractory abdominal pain and leukocytosis with a left-shift warranted surgical intervention. A diagnostic laparoscopy revealed a swollen, hyperemic appendix, a severely distended small intestine, and serous ascites. The laparoscopic procedure was converted to a laparotomy for open disimpaction and appendectomy. He was discharged on the eighth postoperative day. The histologic examination of the appendix was consistent with early appendicitis. In conclusion, acute abdominal pain in adult CF patients is often associated with intestinal obstruction syndrome. The presentation of concurrent appendicitis may be indolent and lead not only to diagnostic difficulties, but also a number of therapeutic choices. PMID- 23089696 TI - Shell tension forces propel Dictyostelium slugs forward. AB - The Dictyostelium slug is an excellent model system for studying collective movements, as it is comprised of about 10(5) cells all moving together in the same direction. It still remains unclear how this movement occurs and what the physical mechanisms behind it are. By applying our recently developed 3D traction force microscopy, we propose a simple explanation for slug propulsion. Most of the forces are exerted by the sheath surrounding the slug. This secreted shell is under a rather uniform tension (around 50 mN m(-1)) and will give rise to a tissue under pressure. Finally, we propose that this pressure will naturally push the slug tip forwards if a gradient of shell mechanical properties takes place in the very anterior part of the raised tip. PMID- 23089697 TI - Cancer epigenomics: moving slowly, but at a steady pace from laboratory bench to clinical practice. PMID- 23089698 TI - Laboratory networking and sample quality: a still relevant issue for patient safety. PMID- 23089699 TI - DNA methylation biomarkers and their utility for solid cancer diagnostics. AB - Cellular DNA undergoes profound changes in methylation during cancer development, with hypermethylation occurring in specific gene promoters, amidst a backdrop of generalized hypomethylation. DNA methylation in cancer often causes the silencing of tumor suppressors and other genes important for cellular growth, regulation and differentiation. Over the past two decades, there have been thousands of publications describing the methylation status of hundreds of genes in cancer, with numerous associations with clinical states, disease outcomes and therapeutic responses being reported. New methods for DNA methylation fingerprinting have emerged, allowing for the exponential growth of "epigenomic" information. Despite this wealth of data, only a handful of methylated genes are utilized as cancer biomarkers in the clinical laboratory. A literature review centered on DNA methylation in six solid cancers was performed, including colorectal, pancreatic, prostate, bladder, breast and ovarian. Commonly methylated genes in the six cancer types were identified and catalogued, and could serve in the future as tissue-based biomarkers or as part of cancer-specific panels. Perhaps more importantly, this endeavor has also focused on methylated genes that appear to be unique to particular cancers. These genes may be more versatile for clinical use, with blood or urine-based cancer screening becoming a reality. PMID- 23089700 TI - DNA methylation biomarkers in biological fluids for early detection of respiratory tract cancer. AB - Cancers of the respiratory tract (lung and head and neck) share common aetiologies, risk factors and molecular characteristics. Epigenetic reprogramming is one of the hallmarks of cancer and DNA methylation is currently the best studied form. There are a number of characteristics of DNA methylation, which seem advantageous in biomarker development. Early detection is still an unmet clinical care need, which guarantees to significantly reduce the mortality of patients with respiratory cancers. The application of such biomarkers in biological fluids being sampled in everyday clinical practice is a long-term demand. In this review we summarise the current literature on DNA methylation detection in bronchial washings, sputum, saliva, plasma and serum and discuss the potential of their clinical implementation. We also discuss important aspects of biomarker development and validation pointing to the appropriate route for a biomarker to reach clinical standards. PMID- 23089701 TI - Global DNA hypomethylation in cancer: review of validated methods and clinical significance. AB - Abstract DNA methylation is one of the best-known epigenetic modifications in mammals. The alteration of DNA methylation patterns has been found to be related to many diseases, including cancer. It is well-known that during carcinogenesis, a site-specific DNA hypermethylation and a global DNA hypomethylation take place. This overall loss of DNA methylation has been proposed as a valid biomarker for cancer. Given its medical utility, in recent years it has become apparent that there is a need to develop methods for the analysis of DNA methylation using different approaches: global, locus-specific, or genome-wide. Here we review some of these techniques and discuss their potential clinical utility. PMID- 23089702 TI - delta0-Thalassemia in cis of betaKnossos globin gene: first homozygous description in thalassemia intermedia Libyans and first combination with codon 39 (C->T) in thalassemia intermedia Tunisian patients. AB - BACKGROUND: beta-Thalassemia is the most common disease among hemoglobinopathies in North African and Arab populations. In the present study we report the first description of the beta-Knossos codon27 (G->T) (betaKnossos) allele in cis with the delta059 (-A) mutation in thalassemia intermedia patients in Tunisia and Libya. METHODS: This identification was carried out by sequencing analysis of the whole coding regions of the delta- and beta-globin genes. RESULTS: We noted that heterozygous inheritance of the betaKnossos mutation results in a mild beta thalassemia phenotype with a low level of HbA2 while homozygous leads to intermediate beta-thalassemia with an atypical high performance liquid chromatogram showing a complete absence of HbA2 and HbF. Compound heterozygosity of the betaKnossos with beta0 codon39 (C->T) is identified in a Tunisian proband for the first time and gives rise to a mild phenotype. In both families, the delta0 codon59 (-A) and the betaKnossos alleles were found to be associated with a single Mediterranean beta-haplotype I similar to that observed in previous reports from Algeria, Egypt, Cyprus, and Turkey. CONCLUSIONS: The chromosome supporting the betaKnossos and the delta0 codon59 (-A) alleles seems to be of a single Mediterranean origin. Premarital screening studies in families in which only one of the parents has typical aspects of beta-thalassemia trait and the other has a normal HbA2 level associated with abnormal red cell indices becomes a necessity to avoid missing thalassemia carriers. PMID- 23089703 TI - Genetic-based reference values for angiotensin-converting enzyme (ACE) according to I/D polymorphism in a Spanish population sample. AB - BACKGROUND: Serum angiotensin-converting enzyme (ACE) activity has been related to sarcoidosis and other granulomatous diseases. It has been demonstrated that serum ACE activity is influenced by ACE gene I/D polymorphism. The aim of this study was to establish ACE activity reference values according to genotype in a Spanish population to improve diagnostic sensitivity and treatment monitoring in sarcoidosis patients. METHODS: A sample population of 150 blood donors was included in the study. Serum ACE activity and genotype were determined and the reference intervals, defined as the 95% central range of the population (2.5th 97.5th percentiles) were obtained for all three genotypes (DD, DI, II) and for the entire sample. RESULTS: Genotype frequencies were 37% DD (n=54), 43% DI (n=63), and 20% II (n=30). Individuals with DD genotype showed the highest ACE activity (mean 39.0 U/L, SD 13.6), ID genotype showed intermediate levels (mean 29.5 U/L, SD 10.2) and II genotype lowest levels (mean 19.1 U/L, SD 4.9). ACE activity differed significantly between these groups: F (2144)=33.15, p<0.05. The corresponding reference intervals for ACE activity were 13.3-63.9 U/L in the overall sample, 12.3-65.6 U/L in genotype DD, 9.5-49.5 U/L in DI and 9.6-28.7 in II. CONCLUSIONS: The preliminary reference values for ACE activity in healthy Spanish individuals according to I/D polymorphism are presented. Significant differences in these values were found between the genotype groups. PMID- 23089704 TI - Effects of sample transportation on commonly requested laboratory tests. AB - BACKGROUND: Little evidence is available in literature on the effects of sample transportation. The aim of the present study was to evaluate the effects of an integrated system for sample transportation on the quality of six laboratory parameters considered representative of the quality of all tests requested and performed. METHODS: The values of alanine aminotransferase (ALT), calcium (Ca), potassium (K), activated prothrombin time (APTT), prostate specific antigen (PSA), and hemoglobin (Hb) obtained in samples collected in peripheral centers in 2007 were compared with those obtained in 2011, following the introduction of the integrated transportation system entailing a tertiary and a secondary container, a data-logger for registering time and temperature, a mission starter and a system manager. RESULTS: In 2007, for ALT, APTT and K, there were significant variations between findings for samples transported from long-term and those from short-term peripheral centers; following the introduction of the transportation system, no such variations were found. CONCLUSIONS: Improvement in the quality of sample transportation has been achieved, particularly for three of the six parameters evaluated, following the introduction of the integrated system described in the present study. PMID- 23089705 TI - Long-term (in)stability of folate and vitamin B12 in human serum. AB - BACKGROUND: In epidemiological research it is very important to test the stability of biomarkers as a function of both storage time and temperature. In this study the stability of both folate and vitamin B12 in human serum samples have been tested after storage at three different temperatures up to 1 year. METHODS: Serum samples of 16 individuals were used in this study. The concentration of folate and vitamin B12 has been determined at T=0 and at several time points up to 1 year after storage at -20 degrees C, -70 degrees C and -196 degrees C. The statistical difference from the initial value at T=0 were determined with a t-test. RESULTS: Folate in serum samples remained stable at -70 degrees C but was not stable during storage at -20 degrees C. A fast decrease was observed after Day 4 which resulted in a stable level of about 60% of the original value measured at T=0 (p<0.001). The rank order of folate concentration in the samples, however, was not affected. The stability of vitamin B12 was good at all temperatures tested. CONCLUSIONS: Measurements of folate concentrations in serum stored at -20 degrees C are not reliable. The rank order, however, was not changed. Vitamin B12 was stable at all temperatures tested. For both folate and vitamin B12 storage at -70 degrees C is sufficient to maintain the original concentration for 1 year. Storage at -196 degrees C in liquid nitrogen is not necessary for these nutrients. PMID- 23089706 TI - Information comparison of the effects of drugs on laboratory tests in drug labels and Young's book. AB - BACKGROUND: The effects of drugs on laboratory tests may lead to misinterpretation of laboratory data, unnecessary tests, higher costs and missed diagnoses. This study compared the information on drug-laboratory effects (DLE) described in 200 drug labels with that in Young's book. METHODS: Information on DLE was searched in the drug labels of 200 frequently prescribed drugs using the keywords 'interfer*', 'influence', and 'laborator*'. This information was compared with the information in Young's book. Each item of information scored 1 point if it was specific and exactly the same. Primary outcome was the percentage of DLE with completely the same information. RESULTS: In 23 (11.5%) of the 200 drug labels 83 DLE were described. Most DLE were described in drug labels of contraceptives (71%) and antibacterials (15%). The most frequently affected laboratory tests were adrenal gland (17%), urine tests (15%), liver tests (10%) and renal function tests (10%). Comparison of six DLE with Young's book was not possible because the information was not described in the book. Twelve (14.5%) DLE of the information in the drug label was identical to that in Young's book. Detailed information about nature of the effect, strength of the effect and body fluid was not described in the drug labels. CONCLUSIONS: In a limited number of DLE in the drug labels the information was the same as in Young's book. Overall, the information on DLE provided in drug labels is unclear, inconsistent and incomplete and does not support healthcare professionals in making evidence-based monitoring decisions. PMID- 23089707 TI - First evaluation of Capillarys 2 Flex Piercing(r) (Sebia) as a new analyzer for HbA1c assay by capillary electrophoresis. AB - BACKGROUND: HbA1c is a key biomarker for the monitoring of glycemic balance in diabetic patients. It may be measured by various methods, including HPLC and immunoassays. Here we report the results of the first evaluation of Capillarys 2 Flex Piercing(r), a new analyzer using capillary electrophoresis for the separation and the quantification of HbA1c. METHODS: We have evaluated the analytical performances of the method as well as the influence of the most frequent analytical interferences regarding HbA1c assays (i.e., labile HbA1c, carbamylated hemoglobin, high HbF and hemoglobin variants). RESULTS: Intra-assay and between-assays CVs were respectively lower than 1.98% and 2.68% on the pre market version of the instrument, and lower than 1.62% and 1.45% on the commercial version. The linearity was excellent for HbA1c values ranging from 19 mmol/mol (3.9%) to 161 mmol/mol (16.9%) (r=0.999). The results were well correlated with those obtained by the HPLC method routinely used in the laboratory (Variant II(r) NU Kit - Bio-Rad): HbA1c[Capillarys 2]=0.9452*HbA1c[Variant II]+1.7279 (r=0.994, n=500). The use of titrated quality control samples indicated a good accuracy of the method. Neither the presence of HbF (until 15%), labile HbA1c or carbamylated hemoglobin, nor that of some typical hemoglobin variants, such as hemoglobin S, D, C and E, affected HbA1c measurement. CONCLUSIONS: This evaluation showed that the analytical performances of Capillarys 2 Flex Piercing(r) analyzer for HbA1c assay fulfilled quality criteria requested for clinical use, and allowed to recommend its implementation in clinical chemistry laboratories for routine practice. PMID- 23089708 TI - Antioxidant and oligonutrient status, distribution of amino acids, muscle damage, inflammation, and evaluation of renal function in elite rugby players. AB - BACKGROUND: Our study investigated the biochemical and anthropometric characteristics in elite athletes of rugby union based in the south of France during the different periods of the competition to identify metabolic and biochemical adaptations to particular lifestyle conditions. METHODS: Participants included 35 players in 2008 and 43 players in 2009. Biochemical variables [creatinine, uric acid, creatine kinase (CK), alanine aminotransferase, aspartate aminotransferase, C-reactive protein] were evaluated. Specific protein levels (albumin, acid alpha-glycoprotein, prealbumin), vitamins (A, E, C), antioxidant enzymes [glutathione peroxidase (GPx), superoxide dismutase (SOD)], oligoelements (Zn, Se, Cu, erythrocyte magnesium), homocysteine (Hcy), carnitine and the distribution of amino acids were specifically determined for our study during a pre-competition period (September 2008 and 2009). RESULTS: Globally, no deficit was observed for vitamins, oligonutrients and amino acids levels. The high SOD and GPx activities in rugby players suggest a presence of oxidative stress of exercise. The evaluation of renal function should be used with caution because of the interaction between creatinine and lean body mass. In addition, a profound effect of intense exercise on the CK values was reported to establish specific reference values for athletes. The analysis of the biological variation allows optimization of the interpretation of the changes from an increased or decreased baseline value from a season to the other one. CONCLUSIONS: The conclusions of present study were: 1) the necessity of rugby-specific reference intervals for CK and creatinine parameters; 2) the use of enzymatic creatinine for Modification of Diet in Renal Disease (MDRD) and CKD-EPI, or cystatin C to improve glomerular filtration rate estimation; 3) to take into account the oxidative stress testifying of a bad recovery; and 4) better to take care the nutritional status of the players by adapting needs and amino acids supplementations but also to consider a follow-up of oxidative stress and antioxidants according our results. PMID- 23089709 TI - Validation of the body fluid module on the new Sysmex XN-1000 for counting blood cells in cerebrospinal fluid and other body fluids. AB - BACKGROUND: We evaluated the body fluid (BF) module on the new Sysmex XN-1000 for counting blood cells. METHODS: One hundred and eighty-seven BF samples [73 cerebrospinal fluid (CSF), 48 continuous ambulatory peritoneal dialysis (CAPD), 46 ascites, and 20 pleural fluid] were used for method comparison between the XN 1000 and manual microscopy (Fuchs-Rosenthal chamber and stained cytospin slides) for counting red blood cells (RBCs) and white blood cells (WBCs) (differential). RESULTS: Good agreement was found for counting WBCs (y=1.06x+0.09, n=67, R2=0.96) and mononuclear cells (MNs) (y=1.04x-0.01, n=40, R2=0.93) in CSF. However, the XN 1000 systematically counted more polymorphonuclear cells (PMNs) (y=1.48x+0.18, n=40, R2=0.99) compared to manual microscopy. Excellent correlation for RBCs >1*109/L (y=0.99x+116.56, n=26, R2=0.99) in CSF was found. For other fluids (CAPD, ascites and pleural fluid) excellent agreement was found for counting WBCs (y=1.06x+0.26, n=109, R2=0.98), MNs (y=1.06x-0.41, n=93, R2=0.96), PMNs (y=1.06x+0.81, n=93, R2=0.98) and RBCs (y=1.04x+110.04, n=43, R2=0.98). By using BF XN-check, the lower limit of quantitation (LLoQ) for WBC was defined at 5*106/L. Linearity was excellent for both the WBCs (R2=0.99) and RBCs (R2=0.99) and carry-over never exceeded 0.05%. CONCLUSIONS: The BF module on the XN-1000 is a suitable tool for fast and accurate quantification of WBC (differential) and RBC counts in CSF and other BFs in a diagnostic setting. PMID- 23089710 TI - Measuring Rivaroxaban in a clinical laboratory setting, using common coagulation assays, Xa inhibition and thrombin generation. AB - BACKGROUND: Rivaroxaban, a direct Xa inhibitor, is one of the new oral antithrombotic agents for which laboratory monitoring is thought to be unnecessary in most cases due to predictable pharmacokinetics. Circumstances are conceivable, however, in which reliable laboratory testing of Rivaroxaban is desirable. The aim of the present in vitro study was to investigate and compare the analytical and practical use of Rivaroxaban monitoring with routine screening assays, thrombin generation and anti-Xa activity, in a clinical laboratory setting. METHODS: Rivaroxaban was added to nine normal donor plasmas and to a normal pooled plasma in concentrations up to 1000 MUg/L. Prothrombin time (PT), activated partial thromboplastin time (APTT), endogenous thrombin potential (ETP) and anti-Xa activity were measured in all donor samples. Responsiveness to Rivaroxaban and imprecision of Rivaroxaban recovery were assessed. RESULTS: Low intra-, but high inter-individual imprecision was found for PT displaying a linear dose-response relationship. Imprecision was much lower when directly measuring anti-Xa activity. Responsiveness of ETP lag-time was high, but of total thrombin generation was low, illustrating that the main effect of Rivaroxaban Xa inhibition lies in delaying thrombin formation rather than in preventing it. CONCLUSIONS: Despite a high inter-individual imprecision of the PT, this relatively fast and cost-friendly assay is sensitive to Rivaroxaban and integrates its effects on the global coagulant state of patients. Anti-Xa activity assays can be run to assess the actual Rivaroxaban concentration and in the future ETP could serve as a fine-tuned hemostatic balance indicator for patients using Rivaroxaban. PMID- 23089711 TI - Increased concentrations of growth factors and activation of the EGFR system in breast cancer. AB - BACKGROUND: In this study the total and phosphorylated amount of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) were measured together with EGFR ligands in tissue samples of breast cancer patients in order to investigate interrelations and possible prognostic values. METHODS: Samples of malignant and non-cancer autologous reference tissue were collected from 415 breast cancer patients. The tissue samples were cut and either paraffin-embedded or homogenized in a lysis buffer to extract the proteins. HER2 was measured using both immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) and ADVIA Centaur. Phosphorylated HER2 and EGFR (pHER2, pEGFR), total EGFR and the ligands: epidermal growth factor (EGF), transforming growth factor-alpha (TGFalpha), amphiregulin (AREG), heparin binding EGF-like growth factor (HB-EGF), betacellulin (BTC) and epiregulin (EREG) were measured using the Luminex. RESULTS: The HER2 positivity rate was determined to be 25.2% by the Centaur method vs. 15.8% by IHC and FISH. HER2, HB-EGF, TGFalpha and AREG were upregulated in cancer tissue as compared with autologous reference tissue while EGFR, pEGFR and EGF were downregulated (p<10-6). pEGFR in autologous reference tissue was negatively correlated to the number of positive lymph nodes and to the tumor size (p=0.0007 and p=0.001, respectively) and furthermore, decreased in the group of mastectomy operated patients as compared with the lumpectomy group (p<10-6). HB-EGF in cancer tissue was positively associated with high grade tumors (p<10-6) and pHER2, HB-EGF and BTC were associated with poor disease free survival (p=0.017, p=0.012 and p=0.0026, respectively). CONCLUSIONS: Our study demonstrated a profound activation of the EGFR system. HB-EGF was increased by factor 10 in cancer tissue and related to the biological aggressiveness of the tumors, and pHER2, HB-EGF and BTC were associated with poor clinical outcome. PMID- 23089712 TI - Incidence and significance of elevated lactate in the identification of critically ill patients. AB - BACKGROUND: The frequency and characteristics of patients with critical lactate values (>4.0 mmol/L) is unknown. METHODS: The laboratory database was reviewed for adult patients with non-point of care lactate values over a 6-month period. RESULTS: There were 6914 lactate values, including 625 (9.0%) critical values. Medical records were reviewed in 100 patients with critical and non-critical lactate values. Patients with critical vs. non-critical values had more metabolic acidosis (n=70/100 vs. 22/100, p<0.01), hypotension or tachycardia (n=62/100 vs. 29/100, p<0.01), and a higher 1-month mortality (n=42/100 vs. 7/100, p<0.01). Few patients (n=10/100) with a critical value were not in the emergency department or intensive care unit. CONCLUSIONS: Critical lactate values are associated with a longer duration of hospitalization and increased mortality. However, the incremental value of critical lactate values was low, as most patients had abnormal vital signs and laboratory parameters. Requiring notification of lactate values >4.0 mmol/L would be unlikely to augment clinical care. PMID- 23089713 TI - Lipoprotein-associated phospholipase A2 is elevated in patients with severe aortic valve stenosis without clinically overt atherosclerosis. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory mediator involved in atherosclerosis. Since aortic valve stenosis (AVS) is regarded as an atherosclerosis-like inflammatory disease, we sought to investigate whether AVS is associated with elevated Lp-PLA2. METHODS: Plasma Lp PLA2 levels were determined in 48 consecutive patients with severe AVS without atherosclerotic vascular disease and compared with the values obtained in 48 controls matched for age, sex and cardiovascular risk factors. RESULTS: Lp-PLA2 was higher in AVS than in controls (242.3+/-50.4 vs. 151.9+/-28.1 ng/mL, p<0.0001). Lp-PLA2 correlated inversely with aortic valve area (AVA) (r=-0.53; p=0.0001) and positively with mean pressure gradient (PG) (r=0.32; p=0.029). In multivariable analysis C-reactive protein (CRP) (OR=1.42; 95% CI 0.95-2.1; p=0.09) and AVA (OR=0.003; 95% CI 0.00004-0.23; p<0.01) were independently associated with Lp-PLA2 above a mean of 242 ng/mL. After adjustment for CRP, AVA was the only independent predictor of Lp-PLA2 in AVS patients (p<0.001). CONCLUSIONS: This study is the first to show that AVS is characterized by increased plasma Lp-PLA2 levels associated with the severity of AVS, which suggests active involvement of Lp-PLA2 in the pathogenesis of AVS. PMID- 23089714 TI - Serum cystatin C as a marker for early detection of chronic kidney disease and grade 2 nephropathy in Japanese patients with type 2 diabetes. AB - BACKGROUND: Diabetic nephropathy (DN) is a significant cause of hemodialysis, and its early detection is extremely important to prevent or delay end-stage renal disease. The significance of the renal function marker serum cystatin C (sCysC) and its relationship with glomerular filtration rate in chronic kidney disease (CKD) and DN in Japanese patients with type 2 diabetes remains uncertain. In this study, we examined the effectiveness of sCysC as a marker of early DN and CKD in Japanese subjects. METHODS: A total of 325 Japanese patients with type 2 diabetes and 88 healthy subjects were studied retrospectively. sCysC concentration (mg/L) was determined by a latex turbidmetric immunoassay using a BioMajesty 8040 analyzer. The renal function of the diabetic patients was evaluated using the albumin-creatinine ratio (ACR) and Kidney Disease Outcome Quality Initiative Kidney Disease Improving Global Outcomes (K/DOQI-KDIGO) classification. RESULTS: There was a significant increase in sCysC but not in serum creatinine (sCr) or serum beta2-microglobulin (sbeta2M) in patients with grade 2 DN (ACR 30-300 mg/g) compared to grade 1 patients. Receiver operating characteristic analysis in grade 2 and 3 DN patients showed that sCysC had superior sensitivity and specificity than sCr and sbeta2M for early detection of DN. In addition, sCysC showed particularly high sensitivity and specificity in DN patients with stage 2 CKD. CONCLUSIONS: sCysC was effective for detection of grade 2 DN and would be especially useful for screening stage 2 CKD patients (K/DOQI-KDIGO). PMID- 23089715 TI - Establishing professional phlebotomist group for quality control of the preanalytic variables of clinical laboratory. PMID- 23089716 TI - Application of quality specification based on biological variation in planning quality control strategy. PMID- 23089717 TI - Analytical and clinical evaluation of a new immunoassay for therapeutic drug monitoring of infliximab and adalimumab. PMID- 23089718 TI - Comparison of relationships between FT4 and log TSH in Access DXI 800 Unicel, Modular E170 and ADVIA Centaur XP Analyzer. PMID- 23089719 TI - Assay-specific pitfalls of catecholamine HPLC assays. PMID- 23089720 TI - Evaluation of automated nucleated red blood cells counting on Sysmex XE5000 and Siemens ADVIA 2120. PMID- 23089721 TI - Evaluation of the immature myeloid information (IMI) by Sysmex XE 2100(r) hematology analyzer in the identification of blasts of myeloid lineage. AB - The immature myeloid information (IMI) provided by the Sysmex XE 2100 hematology analyzer has demonstrated that it is possible to differentiate granulocytes of immature cells in daily practice. A specific reagent lyses mature white blood cells, allowing that immature myeloid cells remain intact and consequently detectable. It is known that lymphoblasts cannot be detected in this channel. This channel does not entail additional costs, since it is provided by the traditional hematology analyzers used in blood tests and is widely useful in differentiating cell lines. This study has aimed to assess the consonance between IMI results and subtypes of acute leukemias and other hematologic malignancies in order to use it as screening test in the definition of cell lineage. A total of 141 cases of hematologic malignancies have been evaluated. Results of the IMI channel were compared using the Sudan Black cytochemical and flow cytometry. The Cohen's Kappa coefficient of agreement between IMI and flow cytometry results was 0.8%. IMI had sensibility and specificity levels of 90.7% and 90.8%, respectively; VP: 68 (91.9%); FP: 6 (8.1%); VN: 59 (89.4%) and FN: 7 (10.6%); PPV 91.9% and NPV 89.4%. The Sysmex XE 2100 analyzer showed a good analytical performance for the detection of immature myeloid cells. These results indicate that the IMI channel has sensitivity and specificity levels, consistent with previous studies. Given this situation, one may conclude that IMI was able to be used as a screening test to complement cytochemistry for identify blasts of myeloid lineage. PMID- 23089722 TI - Cellular alarms and whispers contribute to the polyphonic melody of danger signals required for immunity. PMID- 23089723 TI - BMC public health. PMID- 23089724 TI - The association of metabolic syndrome with alcohol consumption among urban Chinese. AB - BACKGROUND: Along with economic improvement, China is experiencing increasing rates of non-communicable disease and a rise in alcohol consumption. While a modest intake of red wine has been shown to be health enhancing, the pathophysiology associated with excessive alcohol consumption is being increasingly recognized. The purpose of this study is to demonstrate the health consequences of alcohol consumption among middle-aged urban Chinese people. METHODS: This cross-sectional study included 793 subjects aged 44, 48 or 52 years, from urban community health centres and a local hospital, who participated in a survey, anthropometrics and blood chemistry. Multiple logistic regression analysis was used to obtain adjusted odds ratios (OR) between alcohol intake and medical history of diabetes and hypertension, metabolic syndrome and its five component variables. RESULTS: Metabolic syndrome (MetS) was detected in 53.5% and 42.8% of men and women, respectively, (p < .05), and regular alcohol consumption was found among 72.5% and 12.4% of men and women (p < .00). A weak association was found between consuming alcohol >= 2 times a week (or having quit) and MetS (OR = 1.7, 1.0, 2.9) and elevated blood pressure (OR = 1.8, 1.0, 3.1). CONCLUSION: Alcohol consumption is an under-appreciated risk factor found in association with increased rates of metabolic syndrome and associated non communicable diseases among urban residents in China. PMID- 23089725 TI - Pro-alcohol-use social environment and alcohol use among female sex workers in China: beyond the effects of serving alcohol. AB - The current study was designed to fill the literature gap by examining the roles of the pro-alcohol social environment in alcohol use among female sex workers (FSWs) in China. In this study, a total of 1,022 FSWs were recruited through community outreach from both alcohol-serving and nonalcohol-serving commercial sex venues in Guangxi, China. The pro-alcohol social environment was measured in four areas: institutional norms, institutional practices, risk perceptions and peer norms. The measures of the pro-alcohol social environment were significantly associated with the venues' alcohol-serving practices, with FSWs from those venues reporting a more positive pro-alcohol social environment than their counterparts from nonalcohol-serving venues. However, these pro-alcohol social environment measures were independently predictive of alcohol use after controlling for venues' alcoholserving practices and other demographic characteristics. Public health interventions need to target environmental structural factors through altering pro-alcohol-use social norms and practices at both institutional and individual levels among FSWs in China. PMID- 23089726 TI - Preparing for national implementation of an evidence-based, effective HIV prevention program among bahamian sixth-grade students. AB - Using data from the preparatory phase prior to national implementation of an effective HIV prevention program (Focus on Youth in the Caribbean; FOYC) in all Bahamian government sixth-grade classes, we describe (1) actual FOYC implementation, (2) factors that influenced implementation, and (3) the relationship of implementation with intervention outcome. Six elementary schools (with 17 grade six classrooms) were selected to participate in the preparatory phase. The 17 teachers were invited to attend a training workshop, coordinate administration of questionnaires to the students, teach the 10 sessions of FOYC and complete self-assessment checklists. A total of 395 students submitted baseline and 311 students submitted year-end questionnaires. Thirteen teachers initiated FOYC; five completed all 10 sessions. Implementation of FOYC was not related to teacher FOYC workshop experience but did cluster by school. There were significant positive correlations between improved student knowledge of HIV/AIDS, protective health skills, perceived parental monitoring and reduced risk behaviours with the number of FOYC sessions delivered. Implementation was impeded by logistics issues, structural issues with the measures, and comfort-level issues, most of which can be addressed for national implementation. Degree of FOYC implementation is correlated with positive student outcomes. PMID- 23089727 TI - HIV prevalence among high school learners - opportunities for school-based HIV testing programmes and sexual reproductive health services. AB - BACKGROUND: Young girls in sub Saharan Africa are reported to have higher rates of human immunodeficiency virus (HIV) infection compared to boys in the same age group. Knowledge of HIV status amongst high schools learners provides an important gateway to prevention and treatment services. This study aimed at determining the HIV prevalence and explored the feasibility of HIV testing among high school learners. METHODS: Between September 2010 and February 2011, a linked, anonymous cross-sectional survey was conducted in two public sector high schools in the rural KwaZulu-Natal midlands. Following written informed consent, dried blood spot samples (DBS) were collected and tested for HIV. The overall and age-specific HIV prevalence were compared with select demographic variables. RESULTS: The HIV prevalence in learners aged 12 to 25 in school A was 4.7% (95% CI 2.8-6.5) compared to 2.5% (95% CI 1.6-3.5) in school B, (p=0.04). Whilst the HIV prevalence was similar for boys at 1.3% (95% CI 0-2.8) in school A and 1.7% (95% CI 0.5-2.8) in school B, the prevalence in girls was consistently higher and was 7.7% (95% CI 4.5-10.9) in school A and 3.2% (95% CI 1.8-4.6) in school B. The age-specific HIV prevalence in girls increased 1.5 to 2 fold for each two year age category, while for boys the prevalence was stable across all age groups. CONCLUSIONS: The high HIV prevalence in female learners underscores the importance of sexual reproductive health and schools-based HIV testing programs as an important gateway to prevention and treatment services. PMID- 23089728 TI - Formation of ethyl acetate from whey by Kluyveromyces marxianus on a pilot scale. AB - Whey arising in huge amounts during milk processing is a valuable renewable resource in the field of White Biotechnology. Kluyveromyces marxianus is able to convert whey-borne lactose into ethyl acetate, an environmentally friendly solvent. Formation of ethyl acetate as a bulk product is triggered by iron (Fe). K. marxianus DSM 5422 was cultivated aerobically in whey-borne medium originally containing 40 MUg/L Fe, supplemented with 1, 3 or 10 mg/L Fe in the pre-culture, using an 1 L or 70 L stirred reactor. The highest Fe content in the pre-culture promoted yeast growth in the main culture causing a high sugar consumption for growth and dissatisfactory formation of ethyl acetate, while the lowest Fe content limited yeast growth and promoted ester synthesis but slowed down the process. An intermediate Fe dose (ca. 0.5 MUg Fe/g sugar) lastly represented a compromise between some yeast growth, a quite high yield of ethyl acetate and an acceptable duration of the process. The mass of ethyl acetate related to the sugar consumed amounted to 0.113, 0.265 and 0.239 g/g in the three processes corresponding to 21.9%, 51.4% and 46.3% of the theoretically maximum yield. The performance on a pilot scale was somewhat higher than on lab scale. PMID- 23089729 TI - The first promoter for conditional gene expression in Acremonium chrysogenum: iron starvation-inducible mir1(P). AB - The filamentous fungus Acremonium chrysogenum is of enormous biotechnological importance as it represents the natural producer of the beta-lactam antibiotic cephalosporin C. However, a limitation in genetic tools, e.g. promoters for conditional gene expression, impedes genetic engineering of this fungus. Here we demonstrate that in A. chrysogenum iron starvation induces the production of the extracellular siderophores dimerumic acid, coprogen B, 2-N-methylcoprogen B and dimethylcoprogen as well as expression of the putative siderophore transporter gene, mir1. Moreover, we show that the promoter of mir1, mir1(P), is suitable for conditional expression of target genes in A. chrysogenum as shown by mir1(P) driven and iron starvation-induced expression of genes encoding green fluorescence protein and phleomycin resistance. The obtained iron-starvation dependent phleomycin resistance indicates the potential use of this promoter for selection marker recycling. Together with easy scorable siderophore production, the co-regulation of mir1 expression and siderophore production facilitates the optimization of the inducing conditions of this expression system. PMID- 23089730 TI - ELP-z and ELP-zz capturing scaffolds for the purification of immunoglobulins by affinity precipitation. AB - The increasing demand of monoclonal antibodies for therapeutic applications along with the high manufacturing cost have made it necessary to evaluate better process options and technologies for their purification. Affinity precipitation is an attractive alternative to traditional chromatographic methods by affording effective purification using a simple environmental trigger. The feature of elastin-like-protein (ELP) fused with antibody binding domains has already been explored for the purification of antibodies. However, ELP when fused with the bulkier domains such as Protein A, resulted in lower protein production. In this study, ELP was fused to smaller synthetic IgG binding domains such as the z or zz domain, resulting in up to 10-fold higher level of production. Both ELP-z and ELP zz bind tightly to human immunoglobulin (HIgG) with a dissociation constant of 768+/-142 nM and 68+/-23 nM, respectively. Owing to the higher binding affinity, the use of ELP-zz resulted in more than 99% recovery of HIgG in four repeated binding and elution cycles with no observable decrease in the purification performance. The same binding and elution cycle was successfully implemented for the purification of monoclonal antibodies from hybridoma culture supernatant with close to 100% recovery. PMID- 23089731 TI - AAV9-mediated VEGF-B gene transfer improves systolic function in progressive left ventricular hypertrophy. AB - Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3) were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno associated virus serotype 9 (AAV9)-VEGF-B(186) gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B(186)-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF B(186) gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure. PMID- 23089732 TI - Intra-amniotic transient transduction of the periderm with a viral vector encoding TGFbeta3 prevents cleft palate in Tgfbeta3(-/-) mouse embryos. AB - Cleft palate is a developmental defect resulting from the failure of embryonic palatal shelves to fuse with each other at a critical time. Immediately before and during palatal fusion (E13-E15 in mice), transforming growth factor beta3 (TGFbeta3) is expressed in the palatal shelf medial edge epithelium (MEE) and plays a pivotal role in palatal fusion. Using Tgfbeta3(-/-) mice, which display complete penetrance of the cleft palate phenotype, we tested the hypothesis that intra-amniotic gene transfer could be used to prevent cleft palate formation by restoring palatal midline epithelial function. An adenoviral vector encoding Tgfbeta3 was microinjected into the amniotic sacs of mouse embryos at successive developmental stages. Transduced Tgfbeta3(-/-) fetuses showed efficient recovery of palatal fusion with mesenchymal confluence following injection at E12.5 (100%), E13.5 (100%), E14.5 (82%), and E15.5 (75%). Viral vectors injected into the amniotic sac transduced the most superficial and transient peridermal cell layer but not underlying basal epithelial cells. TGFbeta3 transduction of the peridermdal cell layer was sufficient to induce adhesion, fusion, and disappearance of the palatal shelf MEE in a cell nonautonomous manner. We propose that intra-amniotic gene transfer approaches have therapeutic potential to prevent cleft palate in utero, especially those resulting from palatal midline epithelial dysfunction. PMID- 23089733 TI - Transient removal of CD46 is safe and increases B-cell depletion by rituximab in CD46 transgenic mice and macaques. AB - We have developed a technology that depletes the complement regulatory protein (CRP) CD46 from the cell surface, and thereby sensitizes tumor cells to complement-dependent cytotoxicity triggered by therapeutic monoclonal antibodies (mAbs). This technology is based on a small recombinant protein, Ad35K++, which induces the internalization and subsequent degradation of CD46. In preliminary studies, we had demonstrated the utility of the combination of Ad35K++ and several commercially available mAbs such as rituximab, alemtuzumab, and trastuzumab in enhancing cell killing in vitro as well as in vivo in murine xenograft and syngeneic tumor models. We have completed scaled manufacturing of Ad35K++ protein in Escherichia coli for studies in nonhuman primates (NHPs). In macaques, we first defined a dose of the CD20-targeting mAb rituximab that did not deplete CD20-positive peripheral blood cells. Using this dose of rituximab, we then demonstrated that pretreatment with Ad35K++ reconstituted near complete elimination of B cells. Further studies demonstrated that the treatment was well tolerated and safe. These findings in a relevant large animal model provide the rationale for moving this therapy forward into clinical trials in patients with CD20-positive B-cell malignancies. PMID- 23089734 TI - Embedding siRNA sequences targeting apolipoprotein B100 in shRNA and miRNA scaffolds results in differential processing and in vivo efficacy. AB - Overexpression of short hairpin RNA (shRNA) often causes cytotoxicity and using microRNA (miRNA) scaffolds can circumvent this problem. In this study, identically predicted small interfering RNA (siRNA) sequences targeting apolipoprotein B100 (siApoB) were embedded in shRNA (shApoB) or miRNA (miApoB) scaffolds and a direct comparison of the processing and long-term in vivo efficacy was performed. Next generation sequencing of small RNAs originating from shApoB- or miApoB-transfected cells revealed substantial differences in processing, resulting in different siApoB length, 5' and 3' cleavage sites and abundance of the guide or passenger strands. Murine liver transduction with adeno associated virus (AAV) vectors expressing shApoB or miApoB resulted in high levels of siApoB expression associated with strong decrease of plasma ApoB protein and cholesterol. Expression of miApoB from the liver-specific LP1 promoter was restricted to the liver, while the H1 promoter-expressed shApoB was ectopically present. Delivery of 1 * 10(11) genome copies AAV-shApoB or AAV miApoB led to a gradual loss of ApoB and plasma cholesterol inhibition, which was circumvented by delivering a 20-fold lower vector dose. In conclusion, incorporating identical siRNA sequences in shRNA or miRNA scaffolds results in differential processing patterns and in vivo efficacy that may have serious consequences for future RNAi-based therapeutics. PMID- 23089737 TI - Clinical utility of ADAMTS-13 testing in suspected thrombotic microangiopathy: an audit of ADAMTS-13 activity assay requests in routine practice from a tertiary hospital. AB - AIMS: Differentiation between thrombotic thrombocytopenic purpura (TTP) and other microangiopathic haemolytic anaemia (MAHA) processes can be difficult. Since the documentation of ADAMTS-13 deficiency in TTP, several ADAMTS-13 activity assays have been developed for use in the diagnosis of TTP and/or other microangiopathic disorders. We reviewed the clinical utility of ADAMTS-13 activity testing in suspected TTP, as used in routine clinical practice in a tertiary referral hospital. METHODS: All requests for ADAMTS-13 activity levels performed at our institution after introduction of the assay were retrospectively audited with respect to clinical diagnosis and results. RESULTS: In total 57 individual patients were tested, of whom only 46% had a MAHA process. Severe ADAMTS-13 deficiency was present in five TTP patients and in one patient with fulminant hepatic failure. CONCLUSIONS: Our experience suggests that severely reduced levels are relatively specific for TTP, but may also occur in fulminant hepatic failure. Patients without MAHA may have reduced ADAMTS-13 activity and there is significant overlap in the range of ADAMTS-13 activity seen in non-TTP MAHA diagnoses. This supports the observation that outside the diagnosis and (possible) follow-up of suspected idiopathic TTP, the ADAMTS-13 activity assay has limited clinical utility. Further education about the role of ADAMTS-13 activity testing is needed. PMID- 23089735 TI - Hematopoietic stem cell gene therapy for the multisystemic lysosomal storage disorder cystinosis. AB - Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders (LSDs). The defective gene is CTNS encoding the lysosomal cystine transporter, cystinosin. Cystine accumulates in all tissues and leads to organ damage including end-stage renal disease. Using the Ctns(-/-) murine model for cystinosis, we tested the use of hematopoietic stem and progenitor cells (HSPC) genetically modified to express a functional CTNS transgene using a self-inactivating-lentiviral vector (SIN-LV). We showed that transduced cells were capable of decreasing cystine content in all tissues and improved kidney function. Transduced HSPC retained their differentiative capabilities, populating all tissue compartments examined and allowing long-term expression of the transgene. Direct correlation between the levels of lentiviral DNA present in the peripheral blood and the levels present in tissues were demonstrated, which could be useful to follow future patients. Using a new model of cystinosis, the DsRed Ctns(-/-) mice, and a LV driving the expression of the fusion protein cystinosin-enhanced green fluorescent protein (eGFP), we showed that cystinosin was transferred from CTNS-expressing cells to Ctns-deficient adjacent cells in vitro and in vivo. This transfer led to cystine decreases in Ctns-deficient cells in vitro. These data suggest that the mechanism of cross correction is possible in cystinosis. PMID- 23089738 TI - Expression of oxytocin and its receptor in healthy and varicose great saphenous veins. PMID- 23089736 TI - ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans. AB - The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets. PMID- 23089740 TI - Positive and negative interference in immunoassays following biotin ingestion: a pharmacokinetic study. PMID- 23089739 TI - Arrhythmogenic right ventricular cardiomyopathy: reassessing the link with the desmosome. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an uncommon heart disease characterised by arrhythmias, right ventricular scarring, and fibrofatty change. Although mutations in the desmosome have been frequently observed in patients clinically diagnosed with ARVC, recent data have put a direct causal relationship in question. Many patients with ARVC and mutations have not had histological confirmation, and many family members with mutations are not affected. Desmosomal mutations have been found in other cardiac diseases, and the specificity of histopathological features is even in question. We aim to review the purported link between ARVC and the desmosome by a critical analysis of reported data. PMID- 23089741 TI - Sulcus construction in microtia repair: a retrospective comparison of different techniques. AB - OBJECTIVE: To compare the auricular projection results across 3 different techniques of sulcus construction in microtia repair (using a temporoparietal fascial flap, a retroauricular fascial flap from the mastoid region, or a superficial muscular aponeurotic system advancement flap). METHODS: All the patients had been photographed at least 3 months after the second stage (construction of the retroauricular sulcus) in auricular reconstruction for microtia. The auricular projection of each patient was measured, and the results of 3 different techniques were compared. RESULTS: No statistically significant differences in the auricular projection results were observed among patients operated on using the 3 techniques. CONCLUSIONS: The superficial muscular aponeurotic system advancement flap is suitable for patients requiring middle ear and auricle reconstruction. The performance of this flap is easier, quicker, less expensive, and associated with fewer perioperative complications compared with the other 2 techniques described herein. PMID- 23089742 TI - Electrophoresis of a charged porous sphere normal to an air-water interface. AB - Electrophoretic behavior of a charged porous sphere normal to an air-water interface is investigated theoretically. The charged porous sphere is a very popular model of DNA and proteins, among other polyelectrolytes, based on the experimental observation of the DNA and protein conformations in a free solution. Two major motion-deterring effects are thoroughly investigated in particular: the boundary effect due to the presence of an air-water interface and the double layer polarization effect due to the convection-induced ion flux redistribution. The presence of the air-water interface is found to reduce the particle mobility in general, especially when the double layer is very thick or the particle is close to the interface. This boundary effect diminishes as the double layer gets very thin. However, an interesting phenomenon is observed that a particle closer to the interface may actually move faster than a farther one under some circumstances. The reason behind this phenomenon is attributed to the interaction between the boundary and polarization effects. This is demonstrated with evidence of corresponding contour plots. Convenient charts of correction factors are provided to facilitate the usage by interested experimental researchers. PMID- 23089743 TI - Ca2+ activation of cytosolic calpain induces the transition from apoptosis to necrosis in neutrophils with externalized phosphatidylserine. AB - Physiologically, apoptotic neutrophils are ingested before they undergo necrosis. However, failure of ingestion will lead to necrosis of neutrophils and the unregulated release of neutrophil-derived pathogenic molecules, such as protease and hydrolases. Understanding the mechanism of postapoptotic necrosis is thus clearly important. Here, we monitored the apoptotic-to-necrotic transition in individual-aged human neutrophils in vitro by imaging fluorescent probes for externalized PS, cytosolic Ca(2+), and membrane integrity. This showed that prenecrotic-aged neutrophils with externalized PS had a significantly elevated cytosolic-free Ca(2+) level. A further unregulated Ca(2+) influx into PS externalized neutrophils always preceded the necrotic transition. Ca(2+) elevation was not simply a consequence of aging, as PS externalization was not uniform in similarly aged neutrophil populations. PS-externalized neutrophils could be induced to undergo necrosis experimentally by simply elevating cytosolic Ca(2+) further with ionomycin. This effect was observed only in neutrophils that had externalized PS, and was independent of the time after their isolation from blood (i.e., in vitro age). As pharmacological inhibition of calpain-1 inhibition significantly reduced this CAIN, it was concluded that the apoptotic-to-necrotic transition was a consequence of uncontrolled calpain activation that resulted from Ca(2+) overload in PS-externalized neutrophils. PMID- 23089744 TI - P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis. AB - P2RX7, a mediator of IL-1beta and IL-18 processing and release, is a ligand-gated cation channel that is expressed by macrophages. In experimental Crgn, P2RX7 deficiency attenuates renal injury, but the underlying mechanism is unknown. Here, we show that P2RX7 levels and the expression of several genes belonging to the Nlrp3-inflammasome pathway are up-regulated in the macrophages of the WKY rat, a strain uniquely susceptible to macrophage-dependent NTN. Importantly, following P2RX7 activation, WKY BMDMs produce markedly increased levels of active caspase-1, IL-1beta, and IL-18 when compared with the NTN-resistant LEW rat BMDMs. P2RX7 and active IL-1beta, IL-18, and caspase-1 protein levels were markedly increased in the WKY nephritic glomeruli 4 days following induction of NTN, and the use of a P2RX7 antagonist reduced the levels of secreted active IL 1beta. Interestingly, the post-translational control of P2RX7-mediated inflammasome activation is under the genetic regulation of two previously identified Crgn quantitative trait loci in the BMDMs and nephritic glomeruli of the WKY rat. In conclusion, we propose a novel mechanism, whereby genetically determined P2RX7 levels in macrophages regulate Nlrp3-inflammasome activation and susceptibility to Crgn. PMID- 23089746 TI - Evaluation of caspofungin susceptibility testing by the new Vitek 2 AST-YS06 yeast card using a unique collection of FKS wild-type and hot spot mutant isolates, including the five most common candida species. AB - FKS mutant isolates associated with breakthrough or failure cases are emerging in clinical settings. Discrimination of these from wild-type (wt) isolates in a routine laboratory setting is complicated. We evaluated the ability of caspofungin MIC determination using the new Vitek 2 AST-Y06 yeast susceptibility card to correctly identify the fks mutants from wt isolates and compared the performance to those of the CLSI and EUCAST reference methods. A collection of 98 Candida isolates, including 31 fks hot spot mutants, were included. Performance was evaluated using the FKS genotype as the "gold standard" and compared to those of the CLSI and EUCAST methodologies. The categorical agreement for Vitek 2 was 93.9%, compared to 88.4% for the CLSI method and 98.7% for the EUCAST method. Vitek 2 misclassified 19.4% (6/31) of the fks mutant isolates as susceptible, in contrast to <4% for each of the reference methods. The overall essential agreement between the CLSI method and Vitek 2 MICs was 92.6% (88/95) but was substantially lower for fks mutant isolates (78.6% [22/28]). Correct discrimination between susceptible and intermediate Candida glabrata isolates was not possible, as the revised species-specific susceptibility breakpoint was not included in the Vitek 2 detection range (MIC of <=0.250 to >=4 mg/liter). In conclusion, the Vitek 2 allowed correct categorization of all wt isolates as susceptible. However, despite an acceptable categorical agreement, it failed to reliably classify isolates harboring fks hot spot mutations as intermediate or resistant, which was in part due to the fact that the detection range did not span the susceptibility breakpoint for C. glabrata. PMID- 23089745 TI - Insights into the role of progranulin in immunity, infection, and inflammation. AB - PGRN, a pleiotrophic growth factor, is known to play an important role in the maintenance and regulation of the homeostatic dynamics of normal tissue development, proliferation, regeneration, and the host-defense response and therefore, has been widely studied in the fields of infectious diseases, wound healing, tumorigenesis, and neuroproliferative and degenerative diseases. PGRN has also emerged as a multifaceted immune-regulatory molecule through regulating the signaling pathways known to be critical for immunology, especially TNF/TNFR signaling. In this review, we start with updates about the interplays of PGRN with ECM proteins, proteolytic enzymes, inflammatory cytokines, and cell-surface receptors, as well as various pathophysiological processes involved. We then review the data supporting an emerging role of PGRN in the fields of the "Cubic of I", namely, immunity, infection, and inflammation, with special focus on its regulation of autoimmune syndromes. We conclude with insights into the immunomodulating, anti-inflammatory, therapeutic potential of PGRN in treating diseases with an inflammatory etiology in a vast range of medical specialties. PMID- 23089747 TI - Increased survival of antibiotic-resistant Escherichia coli inside macrophages. AB - Mutations causing antibiotic resistance usually incur a fitness cost in the absence of antibiotics. The magnitude of such costs is known to vary with the environment. Little is known about the fitness effects of antibiotic resistance mutations when bacteria confront the host's immune system. Here, we study the fitness effects of mutations in the rpoB, rpsL, and gyrA genes, which confer resistance to rifampin, streptomycin, and nalidixic acid, respectively. These antibiotics are frequently used in the treatment of bacterial infections. We measured two important fitness traits-growth rate and survival ability-of 12 Escherichia coli K-12 strains, each carrying a single resistance mutation, in the presence of macrophages. Strikingly, we found that 67% of the mutants survived better than the susceptible bacteria in the intracellular niche of the phagocytic cells. In particular, all E. coli streptomycin-resistant mutants exhibited an intracellular advantage. On the other hand, 42% of the mutants incurred a high fitness cost when the bacteria were allowed to divide outside of macrophages. This study shows that single nonsynonymous changes affecting fundamental processes in the cell can contribute to prolonged survival of E. coli in the context of an infection. PMID- 23089748 TI - Elevated chitin content reduces the susceptibility of Candida species to caspofungin. AB - The echinocandin antifungal drugs inhibit synthesis of the major fungal cell wall polysaccharide beta(1,3)-glucan. Echinocandins have good efficacy against Candida albicans but reduced activity against other Candida species, in particular Candida parapsilosis and Candida guilliermondii. Treatment of Candida albicans with a sub-MIC level of caspofungin has been reported to cause a compensatory increase in chitin content and to select for sporadic echinocandin-resistant FKS1 point mutants that also have elevated cell wall chitin. Here we show that elevated chitin in response to caspofungin is a common response in various Candida species. Activation of chitin synthesis was observed in isolates of C. albicans, Candida tropicalis, C. parapsilosis, and C. guilliermondii and in some isolates of Candida krusei in response to caspofungin treatment. However, Candida glabrata isolates demonstrated no exposure-induced change in chitin content. Furthermore, isolates of C. albicans, C. krusei, C. parapsilosis, and C. guilliermondii which were stimulated to have higher chitin levels via activation of the calcineurin and protein kinase C (PKC) signaling pathways had reduced susceptibility to caspofungin. Isolates containing point mutations in the FKS1 gene generally had higher chitin levels and did not demonstrate a further compensatory increase in chitin content in response to caspofungin treatment. These results highlight the potential of increased chitin synthesis as a potential mechanism of tolerance to caspofungin for the major pathogenic Candida species. PMID- 23089749 TI - Pharmacodynamics of a simulated single 1,200-milligram dose of oritavancin in an in vitro pharmacokinetic/pharmacodynamic model of methicillin-resistant staphylococcus aureus infection. AB - The safety and efficacy of a single 1,200-mg dose of the lipoglycopeptide oritavancin are currently being investigated in two global phase 3 studies of acute bacterial skin and skin structure infections. In this study, an in vitro pharmacokinetic/pharmacodynamic model was established to compare the free-drug pharmacodynamics associated with a single 1,200-mg dose of oritavancin to once daily dosing with daptomycin at 6 mg/kg of body weight and twice-daily dosing with vancomycin at 1,000 mg against three methicillin-resistant Staphylococcus aureus (MRSA) strains over 72 h. The area under the bacterial-kill curve (AUBKC) was used to assess the antibacterial effect of each dosing regimen at 24 h (AUBKC(0-24)), 48 h (AUBKC(0-48)), and 72 h (AUBKC(0-72)). The rapid bactericidal activities of oritavancin and daptomycin contributed to lower AUBKC(0-24)s for the three MRSA strains than with vancomycin (P < 0.05, as determined by analysis of variance [ANOVA]). Oritavancin exposure also resulted in a lower AUBKC(0-48) and AUBKC(0-72) against one MRSA strain and a lower AUBKC(0-48) for another strain than did vancomycin exposure (P < 0.05). Furthermore, daptomycin exposure resulted in a lower AUBKC(0-48) and AUBKC(0-72) for one of the MRSA isolates than did vancomycin exposure (P < 0.05). Lower AUBKC(0-24)s for two of the MRSA strains (P < 0.05) were obtained with oritavancin exposure than with daptomycin. Thus, the antibacterial effect from the single-dose regimen of oritavancin is as effective as that from either once-daily dosing with daptomycin or twice-daily dosing with vancomycin against the MRSA isolates tested in an in vitro pharmacokinetic/pharmacodynamic model over 72 h. These results provide further justification to assess the single 1,200-mg dose of oritavancin for treatment of acute bacterial skin and skin structure infections. PMID- 23089750 TI - High beta-lactamase levels change the pharmacodynamics of beta-lactam antibiotics in Pseudomonas aeruginosa biofilms. AB - Resistance to beta-lactam antibiotics is a frequent problem in Pseudomonas aeruginosa lung infection of cystic fibrosis (CF) patients. This resistance is mainly due to the hyperproduction of chromosomally encoded beta-lactamase and biofilm formation. The purpose of this study was to investigate the role of beta lactamase in the pharmacokinetics (PK) and pharmacodynamics (PD) of ceftazidime and imipenem on P. aeruginosa biofilms. P. aeruginosa PAO1 and its corresponding beta-lactamase-overproducing mutant, PADeltaDDh2Dh3, were used in this study. Biofilms of these two strains in flow chambers, microtiter plates, and on alginate beads were treated with different concentrations of ceftazidime and imipenem. The kinetics of antibiotics on the biofilms was investigated in vitro by time-kill methods. Time-dependent killing of ceftazidime was observed in PAO1 biofilms, but concentration-dependent killing activity of ceftazidime was observed for beta-lactamase-overproducing biofilms of P. aeruginosa in all three models. Ceftazidime showed time-dependent killing on planktonic PAO1 and PADeltaDDh2Dh3. This difference is probably due to the special distribution and accumulation in the biofilm matrix of beta-lactamase, which can hydrolyze the beta-lactam antibiotics. The PK/PD indices of the AUC/MBIC and C(max)/MBIC (AUC is the area under concentration-time curve, MBIC is the minimal biofilm inhibitory concentration, and C(max) is the maximum concentration of drug in serum) are probably the best parameters to describe the effect of ceftazidime in beta-lactamase-overproducing P. aeruginosa biofilms. Meanwhile, imipenem showed time-dependent killing on both PAO1 and PADeltaDDh2Dh3 biofilms. An inoculum effect of beta-lactams was found for both planktonic and biofilm P. aeruginosa cells. The inoculum effect of ceftazidime for the beta-lactamase-overproducing mutant PADeltaDDh2Dh3 biofilms was more obvious than for PAO1 biofilms, with a requirement of higher antibiotic concentration and a longer period of treatment. PMID- 23089751 TI - Wide dissemination of GES-type carbapenemases in Acinetobacter baumannii isolates in Kuwait. AB - Acinetobacter baumannii is an opportunistic pathogen that is an important source of nosocomial infections. Production of extended-spectrum beta-lactamases (ESBLs) of the GES type in A. baumannii has been increasingly reported, and some of these GES-type enzymes possess some carbapenemase activity. Our aim was to analyze the resistance determinants and the clonal relationships of carbapenem-nonsusceptible A. baumannii clinical isolates recovered from hospitals in Kuwait. A total of 63 isolates were analyzed, and all were found to be positive for bla(GES)-type genes. One isolate harbored the bla(GES-14) gene encoding an ESBL with significant carbapenemase activity, whereas the other isolates harbored the bla(GES-11) ESBL gene. Thirty-three isolates coharbored the bla(OXA-23) and bla(GES-11) genes. Analyses of the genetic locations indicated that the bla(GES 11/-14) genes were plasmid located. It is noteworthy that the bla(OXA-23) and bla(GES-11) genes were colocated onto a single plasmid. Nine different pulsotypes were observed among the 63 isolates. This study showed the emergence of GES-type ESBLs in A. baumannii in Kuwait, further suggesting that the Middle East region might be a reservoir for carbapenemase-producing A. baumannii. PMID- 23089752 TI - Variations of subunit {varepsilon} of the Mycobacterium tuberculosis F1Fo ATP synthase and a novel model for mechanism of action of the tuberculosis drug TMC207. AB - The subunit epsilon of bacterial F(1)F(O) ATP synthases plays an important regulatory role in coupling and catalysis via conformational transitions of its C terminal domain. Here we present the first low-resolution solution structure of epsilon of Mycobacterium tuberculosis (Mtepsilon) F(1)F(O) ATP synthase and the nuclear magnetic resonance (NMR) structure of its C-terminal segment (Mtepsilon(103-120)). Mtepsilon is significantly shorter (61.6 A) than forms of the subunit in other bacteria, reflecting a shorter C-terminal sequence, proposed to be important in coupling processes via the catalytic beta subunit. The C terminal segment displays an alpha-helical structure and a highly positive surface charge due to the presence of arginine residues. Using NMR spectroscopy, fluorescence spectroscopy, and mutagenesis, we demonstrate that the new tuberculosis (TB) drug candidate TMC207, proposed to bind to the proton translocating c-ring, also binds to Mtepsilon. A model for the interaction of TMC207 with both epsilon and the c-ring is presented, suggesting that TMC207 forms a wedge between the two rotating subunits by interacting with the residues W15 and F50 of epsilon and the c-ring, respectively. T19 and R37 of epsilon provide the necessary polar interactions with the drug molecule. This new model of the mechanism of TMC207 provides the basis for the design of new drugs targeting the F(1)F(O) ATP synthase in M. tuberculosis. PMID- 23089753 TI - Daptomycin concentrations in valve tissue and vegetation in patients with bacterial endocarditis. AB - In a patient with mitral-aortic native-valve Streptococcus oralis endocarditis, daptomycin concentrations in aortic and mitral valves were 8.6 and 30.8 MUg/g, respectively, and 26 MUg/g in the mitral vegetation. In the case of porcine aortic-valve Staphylococcus epidermidis endocarditis, the daptomycin concentrations were 53.1 MUg/g in the valve and 18.1 MUg/g in perivalvular tissues. Daptomycin achieved apparently adequate tissue concentrations. S. epidermidis was eradicated, whereas Streptococcus oralis persisted, and its daptomycin MIC displayed a 4-fold increase. PMID- 23089754 TI - pSK41-like plasmid is necessary for Inc18-like vanA plasmid transfer from Enterococcus faecalis to Staphylococcus aureus in vitro. AB - Vancomycin-resistant Staphylococcus aureus (VRSA) is thought to result from the in vivo conjugative transfer of a vanA plasmid from an Enterococcus sp. to S. aureus. We studied bacterial isolates from VRSA cases that occurred in the United States to identify microbiological factors which may contribute to this plasmid transfer. First, vancomycin-susceptible, methicillin-resistant S. aureus (MRSA) isolates from five VRSA cases were tested for their ability to accept foreign DNA by conjugation in mating experiments with Enterococcus faecalis JH2-2 containing pAM378, a pheromone-response conjugative plasmid. All of the MRSA isolates accepted the plasmid DNA with similar transfer efficiencies (~10(-7)/donor CFU) except for one isolate, MRSA8, for which conjugation was not successful. The MRSA isolates were also tested as recipients in mating experiments between an E. faecalis isolate with an Inc18-like vanA plasmid that was isolated from a VRSA case patient. Conjugative transfer was successful for 3/5 MRSA isolates. Successful MRSA recipients carried a pSK41-like plasmid, a staphylococcal conjugative plasmid, whereas the two unsuccessful MRSA recipients did not carry pSK41. The transfer of a pSK41-like plasmid from a successful MRSA recipient to the two unsuccessful recipients resulted in conjugal transfer of the Inc18-like vanA plasmid from E. faecalis at a frequency of 10(-7)/recipient CFU. In addition, conjugal transfer could be achieved for pSK41-negative MRSA in the presence of a cell-free culture filtrate from S. aureus carrying a pSK41-like plasmid at a frequency of 10(-8)/recipient CFU. These results indicated that a pSK41-like plasmid can facilitate the transfer of an Inc18-like vanA plasmid from E. faecalis to S. aureus, possibly via an extracellular factor produced by pSK41 carrying isolates. PMID- 23089755 TI - Two hits are better than one: membrane-active and DNA binding-related double action mechanism of NK-18, a novel antimicrobial peptide derived from mammalian NK-lysin. AB - The extensive use and misuse of antibiotics in medicine result in the emergence of multidrug-resistant bacteria, creating an urgent need for the development of new chemotherapeutic agents. Nowadays, antimicrobial peptides are widely recognized as a class of promising candidates with activity against multidrug resistant bacteria. NK-18 is a truncated peptide derived from NK-Lysin, an effector of cytotoxic T cells and natural killer cells. In this study, we studied the antibacterial mechanism of action of NK-18. The results revealed that NK-18 has potent antibacterial activity against Escherichia coli and Staphylococcus aureus. According to our findings, NK-18 is membrane active and its target of action is not only the bacterial membrane but also the DNA in the cytoplasm. The double targets of NK-18 make it difficult for bacteria to generate resistance, which may present a new strategy to defend against multidrug-resistant bacteria and provide a new lead in the design of potent antimicrobial peptides with therapeutic application in the presence of increasing resistance to conventional antibiotics. PMID- 23089756 TI - Fosfomycin-daptomycin and other fosfomycin combinations as alternative therapies in experimental foreign-body infection by methicillin-resistant Staphylococcus aureus. AB - The efficacy of daptomycin, imipenem, or rifampin with fosfomycin was evaluated and compared with that of daptomycin-rifampin in a tissue cage model infection caused by methicillin-resistant Staphylococcus aureus (MRSA). Strain HUSA 304 was used. The study yielded the following results for MICs (in MUg/ml): fosfomycin, 4; daptomycin, 1; imipenem, 0.25; and rifampin, 0.03. The study yielded the following results for minimum bactericidal concentration (MBC) (in MUg/ml): fosfomycin, 8; daptomycin, 4; imipenem, 32; and rifampin, 0.5. Daptomycin rifampin was confirmed as the most effective therapy against MRSA foreign-body infections. Fosfomycin combinations with high doses of daptomycin and rifampin were efficacious alternative therapies in this setting. Fosfomycin-imipenem was relatively ineffective and did not protect against resistance. PMID- 23089757 TI - Innate aminoglycoside resistance of Achromobacter xylosoxidans is due to AxyXY OprZ, an RND-type multidrug efflux pump. AB - Achromobacter xylosoxidans is an innately multidrug-resistant pathogen which is emerging in cystic fibrosis (CF) patients. We characterized a new resistance nodulation-cell division (RND)-type multidrug efflux pump, AxyXY-OprZ. This system is responsible for the intrinsic high-level resistance of A. xylosoxidans to aminoglycosides (tobramycin, amikacin, and gentamicin). Furthermore, it can extrude cefepime, carbapenems, some fluoroquinolones, tetracyclines, and erythromycin. Some of the AxyXY-OprZ substrates are major components widely used to treat pulmonary infections in CF patients. PMID- 23089758 TI - In vitro activity of daclatasvir on hepatitis C virus genotype 3 NS5A. AB - The NS5A replication complex inhibitor daclatasvir (DCV; BMS-790052) inhibits hybrid replicons containing hepatitis C virus (HCV) genotype 3a (HCV3a) NS5A genes with 50% effective concentrations (EC(50)s) ranging from 120 to 870 pM. Selection studies with a hybrid HCV3a replicon identified NS5A residues 31 and 93 as sites for DCV-selected resistance. Our results support the potential use of DCV as a component in combination therapies for HCV3a chronic infection. PMID- 23089759 TI - Complete nucleotide sequence of the first KPC-2- and SHV-12-encoding IncX plasmid, pKpS90, from Klebsiella pneumoniae. AB - We report the complete nucleotide sequence of the pKpS90 plasmid, carrying the bla(KPC-2) and bla(SHV-12) genes. This plasmid was isolated from a sequence type 258 (ST258) Klebsiella pneumoniae strain responsible for an outbreak in a French university hospital in 2009. pKpS90 is a 53,286-bp plasmid that belongs to the IncX incompatibility group. pKpS90 consists of a backbone from IncX plasmids, in which the KPC-2-encoding Tn4401 transposon and a bla(SHV-12)-encoding region have been inserted. PMID- 23089760 TI - Complete deletion of the ramR gene in an in vitro-selected mutant of Klebsiella pneumoniae overexpressing the AcrAB efflux pump. PMID- 23089761 TI - Stepwise development of a homozygous S80P substitution in Fks1p, conferring echinocandin resistance in Candida tropicalis. AB - Three Candida tropicalis isolates were obtained from a patient with acute lymphoblastic leukemia. The first isolate was susceptible to all drug classes, while isolates 2 and 3, obtained after 8 and 8.5 weeks of caspofungin treatment, respectively, were resistant to the three echinocandins. Multilocus sequence genotyping suggested a clonal relation among all isolates. FKS1 sequencing revealed a stepwise development of a heterozygous and finally a homozygous mutation, leading to S80S/P and S80P amino acid substitutions. PMID- 23089763 TI - Optical performance of coherent and incoherent imaging systems in the presence of ghost images. AB - Ghost image analysis is of interest for optical designers as ghost images may degrade image quality in imaging systems. In a previous paper by Abd El-Maksoud and Sasian [Appl. Opt. 50, 2305 (2011)10.1364/AO.50.002305], ghost image analysis for incoherent systems was evaluated using geometrical optics. Some criteria were presented to identify focused ghost images at the nominal image plane. The main goal of this paper is to provide a conceptual understanding of ghost image formation and its impact on the performance of imaging systems using wave theory and Fourier optics. To achieve this goal, a methodology is developed to model ghost images after considering diffraction effects. Expressions for the ghost diffraction point spread function and the ghost transfer function are presented. These functions are used to construct effective point spread and effective transfer functions. To provide insights on the developed theory, some simulation examples are provided and discussed. PMID- 23089762 TI - Screen for agents that induce autolysis in Bacillus subtilis. AB - The growing prevalence of antibiotic-resistant infections underscores the need to discover new antibiotics and to use them with maximum effectiveness. In response to these needs, we describe a screening protocol for the discovery of autolysis inducing agents that uses two Bacillus subtilis reporter strains, SH-536 and BAU 102. To screen chemical libraries, autolysis-inducing agents were first identified with a BAU-102-based screen and then subdivided with SH-536 into two major groups: those that induce autolysis by their direct action on the cell membrane and those that induce autolysis secondary to inhibition of cell wall synthesis. SH-536 distinguishes between the two groups of autolysis-inducing agents by synthesizing and then releasing beta-galactosidase (beta-Gal) in late stationary phase at a time that cells have nearly stopped growing and are therefore tolerant of cell wall synthesis inhibitors. Four hits, named compound 2, compound 3, compound 5, and compound 24, obtained previously as inducers of autolysis by screening a 10,080-compound discovery library with BAU-102, were probed with SH-536 and found to release beta-Gal, indicating that their mode of action was to permeabilize the B. subtilis cell membrane. The four primary hits inhibited growth in Staphylococcus aureus, Enterococcus faecium, Bacillus subtilis, and Bacillus anthracis, with MICs in the 12.5- to 25-MUg/ml (20 to 60 MUM) range. The four primary hits were further used to probe B. subtilis, and their action was partially characterized with respect to the dependence of induced autolysis on specific autolysins. PMID- 23089764 TI - Polarized spectral properties and laser demonstration of Nd-doped Sr3Y2(BO3)4 crystal. AB - Detailed polarized spectral properties of a 0.685 at. % Nd(3+):Sr(3)Y(2)(BO(3))(4) crystal grown by the Czochralski method have been investigated, including the absorption cross section, the emission cross section, and the fluorescence lifetime. The anisotropy of the spectral properties in different polarized directions was discussed thoroughly. The absorption and emission spectra of Nd(3+) are found to be inhomogeneously broadened due to its internal disordered lattice. Additionally, the CW laser operation at 1.06 MUm was also demonstrated for the first time. The maximum output power of 905 mW was achieved, with corresponding optical conversion efficiency of 10.8% and slope efficiency of 12.8%. PMID- 23089765 TI - Analytical solutions for anisotropic time-dependent heat equations with Robin boundary condition for cubic-shaped solid-state laser crystals. AB - The problem of finding analytical solutions for time-dependent or time independent heat equations, especially for solid-state laser media, has required a lot of work in the field of thermal effects. However, to calculate the temperature distributions analytically, researchers often have to make some approximations or employ complex methods. In this work, we present full analytical solutions for anisotropic time-dependent heat equations in the Cartesian coordinates with various source terms corresponding to various pumping schemes. Moreover, the most general boundary condition of Robin (or impedance boundary condition), corresponding to the convection cooling mechanism, was applied. This general condition can be easily switched to constant temperature and thermal insulation as special cases. To this end, we first proposed a general approach to solving time-dependent heat equations with an arbitrary heat source. We then applied our approach to explore the temperature distribution for three cases: steady-state pumping or long transient, single-shot pumping or short transient, and repetitively pulsed pumping. Our results show the possibility of an easier and more accurate approach to analytical calculations of the thermal dispersion, thermal stresses (strains), thermal bending, thermal phase shift, and other thermal effects. PMID- 23089766 TI - High-peak-power pulse generation from a monolithic master oscillator power amplifier at 1.5 MUm. AB - We present an experimental study on the generation of high-peak-power short optical pulses from a fully integrated master-oscillator power-amplifier emitting at 1.5 MUm. High-peak-power (2.7 W) optical pulses with short duration (100 ps) have been generated by gain switching the master oscillator under optimized driving conditions. The static and dynamic characteristics of the device have been studied as a function of the driving conditions. The ripples appearing in the power-current characteristics under cw conditions have been attributed to mode hopping between the master oscillator resonant mode and the Fabry-Perot modes of the entire device cavity. Although compound cavity effects have been evidenced to affect the static and dynamic performance of the device, we have demonstrated that trains of single-mode short optical pulses at gigahertz frequencies can be conveniently generated in these devices. PMID- 23089767 TI - Bulk regeneration of optical fiber Bragg gratings. AB - The reliability and reproducibility of regenerated gratings for mass production is assessed through simultaneous bulk regeneration of 10 gratings. The gratings are characterized and variations are compared after each stage of fabrication, including seed (room-temperature UV fabrication), regeneration (annealing at 850 degrees C), and postannealing (annealing at 1100 degrees C). In terms of Bragg wavelength (lambda(B)), the seed grating variation lies within Deltalambda(B)=0.16 nm, the regenerated grating within Deltalambda(B)=0.41 nm, and the postannealed grating within Deltalambda(B)=1.42 nm. All the results are within reasonable error, indicating that mass production is feasible. The observable spread in parameters from seed to regenerated grating is clearly systematic. The postannealed spread arises from the small tension on the fiber during postannealing and can be explained by the softening of the glass when the strain temperature of silica is reached. PMID- 23089768 TI - Applications of Fresnel diffraction from the edge of a transparent plate in transmission. AB - When a transparent plane-parallel plate is illuminated at the edge region by a quasi-monochromatic parallel beam of light, diffraction fringes appear on a plane perpendicular to the transmitted beam direction. The sharp change in the refractive index at the plate boundary imposes an abrupt change on the phase of the illuminating beam that leads to the Fresnel diffraction. The visibility of the diffraction fringes depends on the plate thickness, refractive index, light wavelength, and angle of incidence. In this report we show that, by recording the visibility repetition versus incident angle, one can measure the plate refractive index, its thickness, and light wavelength very accurately. It is also shown that the technique is indispensable for specifying color dispersion in plate shape samples. The technique is applied to the measurement of dispersion in a fused silica plate and the refractive indices of soda lime slides. PMID- 23089769 TI - Fat emulsions as diffusive reference standards for tissue simulating phantoms? AB - Intralipid 20% was recently suggested as a diffusive reference standard for tissue simulating phantoms. In this work, we extend previously obtained results to other fat emulsions, specifically Intralipid 10%, Intralipid 30%, Lipovenoes 10%, Lipovenoes 10% PhosphoLipid Reduced, Lipovenoes 20%, Lipofundin S 10%, and Lipofundin S 20%. Of particular importance for practical applications, our measurements carried out at a wavelength of 751 nm show the following features. First, these products show high stability and small batch-to-batch variations in their diffusive optical properties, similar to Intralipid 20%. Second, the absorption coefficient of Intralipid, Lipovenoes, and Lipofundin S are very similar and their measured values are within the experimental errors; moreover the reduced scattering coefficient of Intralipid 20%, Lipovenoes 20%, and Lipofundin S 20% are similar and their measured values are within 5%. Third, the reduced scattering coefficient of Intralipid 10% and Intralipid 30% can be scaled from that of Intralipid 20% with an error of 9% and 2%, respectively. A similar scaling property is valid for Lipovenoes and Lipofundin S. We have verified that this scaling property depends on the composition of the fat emulsions: If the ingredients exactly scale with the concentration then the reduced scattering coefficient almost exactly scale as well. PMID- 23089770 TI - Incoherent pump assisted atomic filter based on laser-induced optical anisotropy. AB - We describe the effects of incoherent pump on an atomic filter based on laser induced optical anisotropy in a three-level ladder system interacting with a strong pump polarized circularly and a weak probe polarized linearly. According to the analysis of the numerical simulation results with some comparison, at the same time of eliminating noise, the filter can enhance the probe's transmission or even the probe gain can be achieved without population inversion. Moreover, the incoherent pumping rate and the cell temperature performance are evaluated and measures are taken to improve the filter's transmission and tunability by selecting proper parameters. PMID- 23089771 TI - Analytical treatment of the polychromatic spatially multiplexed volume holographic grating. AB - An alternative model to N-coupled wave theory of the spatially multiplexed finite thickness volume holographic reflection grating is developed from the parallel stacked mirrors (PSM) model in terms of N infinite arrays of parallel stacked mirrors each characterized by a different grating vector. A plane reference wave interacts with each of the N sets of stacked mirrors, producing N signal waves. First-order coupled partial differential equations describing the detailed process of Fresnel reflection within the grating are derived for the reference and N signal waves. These equations can be solved analytically at Bragg resonance where agreement with conventional N-coupled wave theory is exact. The new model is compared for the case of some simple multiplexed volume phase reflection gratings at and away from Bragg resonance with a rigorous coupled-wave solution of the Helmholtz equation. Good agreement is attained for even rather high values of index modulation. For lower modulations more characteristic of modern holographic materials, agreement appears extremely good at and around Bragg resonance, although differences inevitably appear in the higher-order diffractive sideband structure. The analytic model is extended to cover polychromatic spatially multiplexed volume phase gratings at Bragg resonance, where once again agreement with rigorous coupled-wave calculations is very good for index modulations typical for modern holographic gratings. Finally, the model is extended to cover the case of the lossless multicolor phase-reflection hologram, where analytic and graphical results are presented concerning diffractive efficiency. PMID- 23089772 TI - Thin LED collimator with free-form lens array for illumination applications. AB - We propose a compact optical system made up of a thin collimator and a free-form lens array to provide the uniform illumination of various-shape regions. Analytical formulas to design the lens array are derived. The simulation results for the designed optical elements demonstrate the high-level illumination uniformity of various regions in the form of a rectangle, a cross, a flag-shaped region, a line segment, and a set of line segments. PMID- 23089773 TI - Signal-to-noise ratio calculation in a moving-optical-wedge spectrometer. AB - In this paper we study the signal-to-noise ratio degradation in a moving-optical wedge interferometer when used as an optical spectrometer. Both the mechanical vibration and temperature fluctuation effects are studied, and the effects are compared to their counterparts in a conventional Michelson interferometer. While the wedge interferometer is found to be more immune to linear translational vibration, it shows much higher sensitivity to rotational vibration. PMID- 23089775 TI - Active optics for dynamical correction of fluctuations of atmospheric refraction on a differential optical absorption spectroscopy device. AB - We have designed and developed a feedback mechanism for continuous monitoring in a long-pass differential optical absorption spectroscopy (LP-DOAS) setup. This allows one to correct photo-thermal deflection due to the local fluctuations refraction index of the air. For this purpose, using an unbalanced beam splitter, a small fraction of the collected DOAS signal is imaged onto a low-cost CCD camera using a biconvex lens, while the other portion of the signal is coupled into a fiber optic for trace gas detection. By monitoring the registered signal at the CCD camera, a feedback mechanism acting on the transversal position of the lens is able to compensate an arbitrary transversal displacement of the collected signal at the focal plane of the receiver telescope, allowing an optimal coupling into the optical fiber. PMID- 23089774 TI - Diffraction of digital micromirror device gratings and its effect on properties of tunable fiber lasers. AB - A digital micromirror device (DMD) is a kind of widely used spatial light modulator. We apply DMD as wavelength selector in tunable fiber lasers. Based on the two-dimensional diffraction theory, the diffraction of DMD and its effect on properties of fiber laser parameters are analyzed in detail. The theoretical results show that the diffraction efficiency is strongly dependent upon the angle of incident light and the pixel spacing of DMD. Compared with the other models of DMDs, the 0.55 in. DMD grating is an approximate blazed state in our configuration, which makes most of the diffracted radiation concentrated into one order. It is therefore a better choice to improve the stability and reliability of tunable fiber laser systems. PMID- 23089776 TI - Thermal expansion coefficient and thermomechanical properties of SiN(x) thin films prepared by plasma-enhanced chemical vapor deposition. AB - We present a new method based on fast Fourier transform (FFT) for evaluating the thermal expansion coefficient and thermomechanical properties of thin films. The silicon nitride thin films deposited on Corning glass and Si wafers were prepared by plasma-enhanced chemical vapor deposition in this study. The anisotropic residual stress and thermomechanical properties of silicon nitride thin films were studied. Residual stresses in thin films were measured by a modified Michelson interferometer associated with the FFT method under different heating temperatures. We found that the average residual-stress value increases when the temperature increases from room temperature to 100 degrees C. Increased substrate temperature causes the residual stress in SiN(x) film deposited on Si wafers to be more compressive, but the residual stress in SiN(x) film on Corning glass becomes more tensile. The residual-stress versus substrate-temperature relation is a linear correlation after heating. A double substrate technique is used to determine the thermal expansion coefficients of the thin films. The experimental results show that the thermal expansion coefficient of the silicon nitride thin films is 3.27*10(-6) degrees C(-1). The biaxial modulus is 1125 GPa for SiN(x) film. PMID- 23089777 TI - Fluorescence volume imaging with an axicon: simulation study based on scalar diffraction method. AB - In a two-photon excitation fluorescence volume imaging (TPFVI) system, an axicon is used to generate a Bessel beam and at the same time to collect the generated fluorescence to achieve large depth of field. A slice-by-slice diffraction propagation model in the frame of the angular spectrum method is proposed to simulate the whole imaging process of TPFVI. The simulation reveals that the Bessel beam can penetrate deep in scattering media due to its self-reconstruction ability. The simulation also demonstrates that TPFVI can image a volume of interest in a single raster scan. Two-photon excitation is crucial to eliminate the signals that are generated by the side lobes of Bessel beams; the unwanted signals may be further suppressed by placing a spatial filter in the front of the detector. The simulation method will guide the system design in improving the performance of a TPFVI system. PMID- 23089778 TI - Heterodyne efficiency of a coherent free-space optical communication model through atmospheric turbulence. AB - The heterodyne efficiency of a coherent free-space optical (FSO) communication model under the effects of atmospheric turbulence and misalignment is studied in this paper. To be more general, both the transmitted beam and local oscillator beam are assumed to be partially coherent based on the Gaussian Schell model (GSM). By using the derived analytical form of the cross-spectral function of a GSM beam propagating through atmospheric turbulence, a closed-form expression of heterodyne efficiency is derived, assuming that the propagation directions for the transmitted and local oscillator beams are slightly different. Then the impacts of atmospheric turbulence, configuration of the two beams (namely, beam radius and spatial coherence width), detector radius, and misalignment angle over heterodyne efficiency are examined. Numerical results suggest that the beam radius of the two overlapping beams can be optimized to achieve a maximum heterodyne efficiency according to the turbulence conditions and the detector radius. It is also found that atmospheric turbulence conditions will significantly degrade the efficiency of heterodyne detection, and compared to fully coherent beams, partially coherent beams are less sensitive to the changes in turbulence conditions and more robust against misalignment at the receiver. PMID- 23089779 TI - Colorimetric characterization models based on colorimetric characteristics evaluation for active matrix organic light emitting diode panels. AB - The colorimetric characterization of active matrix organic light emitting diode (AMOLED) panels suffers from their poor channel independence. Based on the colorimetric characteristics evaluation of channel independence and chromaticity constancy, an accurate colorimetric characterization method, namely, the polynomial compensation model (PC model) considering channel interactions was proposed for AMOLED panels. In this model, polynomial expressions are employed to calculate the relationship between the prediction errors of XYZ tristimulus values and the digital inputs to compensate the XYZ prediction errors of the conventional piecewise linear interpolation assuming the variable chromaticity coordinates (PLVC) model. The experimental results indicated that the proposed PC model outperformed other typical characterization models for the two tested AMOLED smart-phone displays and for the professional liquid crystal display monitor as well. PMID- 23089780 TI - Increase in laser beam resistance to random inhomogeneities of atmospheric permittivity with an optical vortex included in the beam structure. AB - The role of the vortical phase in the initial structure of the wave field of a laser beam propagating in the turbulent atmosphere in statistical regularities of beam wandering is studied. It is found that in the near diffraction zone the variances of wandering of the vortical beam and the fundamental Gaussian beam turns out to be identical, if the initial radius of the Gaussian beam is equal to the radius of the ring intensity distribution of the vortical beam. In the far diffraction zone, the vortical beam wanders more slightly than the Gaussian beam with the same effective radius of the initial intensity distribution does. It is also shown that laser beams with the initial ring intensity distribution similar to the intensity distribution of a vortical beam, but not having the vortical phase distribution, are less resistant to the atmospheric turbulence than the vortical beam. PMID- 23089781 TI - Integrated hybrid Raman/fiber Bragg grating interrogation scheme for distributed temperature and point dynamic strain measurements. AB - We propose and experimentally demonstrate the feasibility of an integrated hybrid optical fiber sensing interrogation technique that efficiently combines distributed Raman-based temperature sensing with fiber Bragg grating (FBG)-based dynamic strain measurements. The proposed sensing system is highly integrated, making use of a common optical source/receiver block and exploiting the advantages of both (distributed and point) sensing technologies simultaneously. A multimode fiber is used for distributed temperature sensing, and a pair of FBGs in each discrete sensing point, partially overlapped in the spectral domain, allows for temperature-independent discrete strain measurements. Experimental results report a dynamic strain resolution of 7.8 nepsilon/?Hz within a full range of 1700 MUepsilon and a distributed temperature resolution of 1 degrees C at 20 km distance with 2.7 m spatial resolution. PMID- 23089782 TI - Characterization of cylindrical terahertz metallic hollow waveguide with multiple dielectric layers. AB - Dielectric-coated metallic hollow waveguides (DMHW) are drawing considerable attention for their application in terahertz (THz) waveguiding. This paper theoretically analyzes the multilayer structure to reduce the transmission and bending loss of DMHW. The efficiency of THz multilayer DMHW depends on a proper selection of dielectric materials and geometrical parameters. The low-loss properties are demonstrated by studying the multilayer gold waveguides with a stack of polypropylene (PP) and Si-doped polypropylene (PP(Si)). Comparisons are made with single-layer Au/PP and Au-only waveguides. The effect of dielectric absorption is discussed in detail. It is found that low index dielectric causes more additional loss than that of high index dielectric layers. Several design considerations for the THz multilayer DMHW are pointed out by studying the effects of multilayer structure parameters with a stack of polyethylene (PE) and TiO(2)-doped polyethylene (PE(TiO2)). We conclude that the inner radius of the waveguide and the refractive indices of the dielectrics tend to be larger in order to reduce the influence of material absorption. An optimal value exists for the total number of layers when the dielectrics are absorptive. The absorption tolerances are pointed out to guarantee a smaller loss for multilayer DMHW than that of metal-only waveguide. Finally, a fabrication method for THz multilayer DMHW Ag/PE/PE(TiO2) is proposed based on co-rolling technique. PMID- 23089783 TI - Theoretical and experimental analysis of basic parameters of two-element optical systems. AB - Our work presents detailed theoretical analysis of two-element optical systems of telephoto lenses and objectives of anallactic telescopes with internal focusing. The first element of such systems has positive optical power and the second element has negative optical power. This type of optical system is widespread in practice mainly in the field of photographic lenses and in surveying instruments (theodolites, leveling instruments, etc.) where the anallactic telescope with internal focusing is being used. In our work we propose methods to determine the basic parameters of such objectives, i.e., the focal lengths of both the elements of the objective lens and their mutual axial separation. Furthermore, the detailed analysis of aberration properties of such optical systems is performed and methods for measuring the focal lengths of individual elements and their mutual distance without the need for disassembling the investigated optical system are presented. PMID- 23089784 TI - Generation of multiple vortex-cones by direct-phase modulation of annular aperture array. AB - The generation of multiple vortex cones using an annular aperture array and a spatial light modulator (SLM) is studied. The direct downscale imaging of an SLM on the surface of an annular aperture enables the direct-phase modulation of the annular aperture. It is experimentally demonstrated that the direct-phase modulation of an annular aperture array can control both the topological charge and the horizontal positions of multiple vortex cones simultaneously. PMID- 23089785 TI - Fast high-resolution computer-generated hologram computation using multiple graphics processing unit cluster system. AB - To overcome the computational complexity of a computer-generated hologram (CGH), we implement an optimized CGH computation in our multi-graphics processing unit cluster system. Our system can calculate a CGH of 6,400*3,072 pixels from a three dimensional (3D) object composed of 2,048 points in 55 ms. Furthermore, in the case of a 3D object composed of 4096 points, our system is 553 times faster than a conventional central processing unit (using eight threads). PMID- 23089786 TI - Self-referenced technique for the determination of meridional figure errors of a toroidal mirror with a Sagnac interferometer. AB - A simple, self-referenced technique for the determination of meridional surface slope errors of toroidal mirrors (TMs) used in synchrotron radiation is presented. An expanded, collimated, linearly polarized laser beam is allowed to fall on a TM, and the reflected toric wavefront from the TM is allowed to enter a Sagnac interferometer based lateral shearing interferometer setup, which duplicates the beam into identical wavefront components having orthogonal linear polarizations, i.e., p and s polarizations, and introduces appropriate lateral shear between the identical pair of wavefronts along the meridional direction. The laterally sheared identical wavefronts interfere when brought to the same state of polarization. The optical path difference (OPD) variation along the direction of the lateral shear in the interference field is a map of the slope variation. Polarization phase shifting interferometery has been applied to find the OPD variation and thus the slope distribution and errors. Results obtained for a TM of moderately long average radius of curvature along the central meridional section and a relatively shorter radius of curvature along the sagittal section are presented and compared with that obtained with a long trace profiler. PMID- 23089787 TI - Research on FBG-based longitudinal-acousto-optic modulator with Fourier mode coupling method. AB - Fourier mode coupling model was first applied to achieve the spectra property of a fiber Bragg grating (FBG)-based longitudinal-acousto-optic modulator. Compared with traditional analysis algorithms, such as the transfer matrix method, the Fourier mode coupling model could improve the computing efficiency up to 100 times with a guarantee of accuracy. In this paper, based on the theoretical analysis of this model, the spectra characteristics of the modulator in different frequencies and acoustically induced strains were numerically simulated. In the experiment, a uniform FBG was modulated by acoustic wave (AW) at 12 different frequencies. In particular, the modulator responses at 563 and 885.5 KHz with three different lead zirconate titanate (PZT) loads applied were plotted for illustration, and the linear fitting of experimental data demonstrated a good match with the simulation result. The acoustic excitation of the longitudinal wave is obtained using a conic silica horn attached to the surface of a shear mode PZT plate paralleled to the fiber axis. This way of generating longitudinal AW with a transversal PZT may shed light on the optimal structural design for the FBG-based longitudinal-acousto-optic modulator. PMID- 23089788 TI - Modern design tools and a new paradigm in optical coating design. AB - Several modern optical coating designs tools are discussed in the frame of a new design paradigm proposing the search not for a formally optimal solution with the lowest possible merit function value but for the most practical solution that takes into account additional feasibility demands. Considered design tools include a stochastic optimization procedure that takes into account upper and lower constraints for layer optical thicknesses. This procedure allows one to obtain multiple solutions to a design problem, which presents additional opportunities for choosing a practically optimal design. Two special design techniques involving integer optimization also take into account additional demands. The first one is aimed at designing multicavity narrow bandpass filters with quarter wave or multiple quarter wave layer optical thicknesses. It enables obtaining bandpass filters with extremely steep transmittance slopes, bandwidths of several tens of nanometers, and very small ripples in transmission zones. The second technique is aimed at covering design problems that have been traditionally solved using the theory of equivalent layers. One more technique considered in this paper is aimed at reducing the influence of noncorrelated thickness errors on design spectral characteristics. PMID- 23089789 TI - Dynamics of photoinduced refractive index changes in As2S3 fibers. AB - We investigate the dynamics of photoinduced index changes in chalcogenide As(2)S(3) fibers. Using a novel phase sensitive technique for measuring the photoinduced index change, we find that the index evolution is a two-stage process: it consists of a fast reduction and a subsequent slow increase in the refractive index. We show that the index change depends strongly on the beam intensity with both positive and negative changes possible. These findings can have application in design and fabrication of photoinduced devices such as Bragg gratings and photonic cavities. PMID- 23089790 TI - Generation of pulsed Bessel-Gauss beams using passive axicon-theoretical and experimental studies. AB - We studied the conditions for generating passive Bessel-Gauss beams by using an axicon. We designed an appropriate Gaussian resonator and extracted a quasi fundamental Gaussian mode from a pulsed Nd:YAG laser pumped by a Xenon flash lamp and measured its parameters, such as propagation factor, divergence angle, and Rayleigh range. Then we generated passive Bessel-Gauss beams using an axicon and investigated their propagation properties, theoretically and experimentally. For example, for the axicon of 1 degrees , the output energy and the Rayleigh range of the generated Bessel-Gauss beams were measured to be 58 mJ and 229.3 mm, respectively. We compared these properties with our results of the Gaussian mode. Finally, by using axicons with different apex angles, and also by changing the beam spot size on the axicon, we generated Bessel-Gauss beams and studied their properties theoretically and experimentally. PMID- 23089791 TI - Polarimetric imaging beyond the speckle grain scale. AB - We address an experimental Stokes imaging setup allowing one to explore the polarimetric properties of a speckle light field with spatial resolution well beyond the speckle grain scale. We detail how the various experimental difficulties inherent to such measurements can be overcome with a dedicated measurement protocol involving a careful speckle registration step. The setup and protocol are then validated on a metallic reference sample, and used to measure the state of polarization (SOP) of light in each pixel of highly resolved speckle patterns (>2000 pixels per speckle grain) resulting from the scattering of an incident coherent beam on samples exhibiting different polarimetric properties. Evolution of the SOP with spatial averaging and across adjacent speckle grains is eventually addressed. PMID- 23089792 TI - Investigation of active filter using injection-locked slotted Fabry-Perot semiconductor laser. AB - We investigate the selective amplification and filtering of injection-locked slotted Fabry-Perot semiconductor lasers. Current and temperature tuning are used to selectively filter and amplify subcarriers of coherent optical combs with a selectivity of at least 10 GHz with an optical gain of up to 18 dB for filtered lines. A side mode suppression ratio in excess of 20 dB is also achieved. PMID- 23089793 TI - Shack-Hartmann centroid detection using the spiral phase transform. AB - We present a Shack-Hartmann (SH) centroid detection algorithm capable to measure in presence of strong noise, background illumination and spot modulating signals, which are typical limiting factors of traditional centroid detection algorithms. The proposed method is based on performing a normalization of the SH pattern using the spiral phase transform method and Fourier filtering. The spot centroids are then obtained using global thresholding and weighted average methods. We have tested the algorithm with simulations and experimental data obtaining satisfactory results. A complete MATLAB package that can reproduce all the results can be downloaded from [http://goo.gl/o2JhD]. PMID- 23089794 TI - Tapered-fiber-based refractive index sensor at an air/solution interface. AB - An approach to achieve refractive index sensing at an air and aqueous glycerol solution interface is proposed using a tapered-fiber-based microfiber Mach Zehnder interferometer (MFMZI). Compared to a surrounding uniform medium of air or solutions, the spectral interference visibility of the MFMZI at the air/solution interface is significantly reduced due to a weak coupling between the fundamental cladding mode and high-order asymmetric cladding modes, which are extremely sensitive to the external refractive index. The MFMZI is experimentally demonstrated as an evanescent wave refractive index sensor to measure concentrations of glycerol solutions by monitoring average power attenuation of the tapered fiber. PMID- 23089795 TI - Spatiotemporal structure of a laser beam over 144 km in a Canary Islands experiment. AB - We analyzed the observations of scintillations in a laser beam (532 nm, ~200 mW power) traveling along a 144 km path at an altitude of 2.2-2.4 km above sea level, just above the atmospheric boundary layer, between the islands of La Palma and Tenerife. The observations were performed during nighttime on 18 July 2011, by means of a telescope with an aperture diameter of 1 m. Strong scintillations were observed. The estimates of spatial spectra and correlation functions indicated that the observed intensity fields possess, statistically, a locally isotropic structure, which agrees with the idea of a locally isotropic turbulence. The estimates of spatial autospectra and autocorrelation functions of the intensity field indicated that the characteristic scale of the internal structure of the observed clusters is 6.5-8 mm, while the characteristic size of the clusters is 4-5 cm. The major contribution to the observed scintillations comes from the inhomogeneities of the intensity field with scales from 1-2 cm up to 10-12 cm. The analysis of the cross-spectra indicated that the hypothesis of frozen turbulence introduced by Taylor can be used for the description of spatiotemporal structure of intensity fluctuations of laser beams traveling through long paths in the atmosphere. PMID- 23089796 TI - Modeling of line roughness and its impact on the diffraction intensities and the reconstructed critical dimensions in scatterometry. AB - We investigate the impact of line-edge and line-width roughness (LER, LWR) on the measured diffraction intensities in angular resolved extreme ultraviolet (EUV) scatterometry for a periodic line-space structure designed for EUV lithography. LER and LWR with typical amplitudes of a few nanometers were previously neglected in the course of the profile reconstruction. The two-dimensional (2D) rigorous numerical simulations of the diffraction process for periodic structures are carried out with the finite element method providing a numerical solution of the 2D Helmholtz equation. To model roughness, multiple calculations are performed for domains with large periods, containing many pairs of line and space with stochastically chosen line and space widths. A systematic decrease of the mean efficiencies for higher diffraction orders along with increasing variances is observed and established for different degrees of roughness. In particular, we obtain simple analytical expressions for the bias in the mean efficiencies and the additional uncertainty contribution stemming from the presence of LER and/or LWR. As a consequence this bias can easily be included into the reconstruction model to provide accurate values for the evaluated profile parameters. We resolve the sensitivity of the reconstruction from this bias by using simulated data with LER/LWR perturbed efficiencies for multiple reconstructions. If the scattering efficiencies are bias-corrected, significant improvements are found in the reconstructed bottom and top widths toward the nominal values. PMID- 23089797 TI - Detection of toxic metals (lead and chromium) in talcum powder using laser induced breakdown spectroscopy. AB - A laser induced breakdown spectroscopic (LIBS) system was developed using a 266 nm laser and a high-resolution spectrograph (Andor SR 500 i-A) to detect the trace levels of the highly toxic metals such as lead and chromium present in different brands of talcum powder available in the local market. The strongest atomic transition lines of lead (Pb) (405.7 nm) and chromium (Cr) (425.4 nm) were used as spectral markers to simultaneously detect lead and chromium. The LIBS system was calibrated for these two heavy metals, and the system was able to detect 15-20 parts per million (ppm) of lead and 20-30 ppm of chromium in the talcum powder sample. The limits of detection of the LIBS system were also estimated, and they are 1.96 and 1.72 ppm per million respectively for lead and chromium. This study is highly significant due to the use of cosmetic products that could affect the health of millions of people around the globe. PMID- 23089798 TI - Fine structures in refractive index of sapphire at the L(II,III) absorption edge of aluminum determined by soft x-ray resonant reflectivity. AB - The optical constants of sapphire crystal (alpha-Al(2)O(3)) and amorphous Al(2)O(3) in the soft x-ray region (67-85 eV) around the aluminum LII,III absorption edge (73.1 eV) are determined by angle-dependent x ray reflectivity. The differences between the optical constant values of both the samples are discussed. The fine structures obtained in the absorption of crystalline sapphire are explained. An absorption feature at 70.2 eV is observed for the first time for crystalline alumina. Both datasets are compared to the tabulated values of Henke et al. [At. Data Nucl. Data Tables 54, 181 (1993)], Weaver et al. [Physik Daten, Physics Data: Optical Properties of Metals (Fach information zentrum, 1981), Vols. 18-1 and 18-2], and [Handbook of Optical Constants of Solids II (Academic, 1991)]. PMID- 23089799 TI - Vortex metrology using Fourier analysis techniques: vortex networks correlation fringes. AB - In this work, we introduce an alternative method of analysis in vortex metrology based on the application of the Fourier optics techniques. The first part of the procedure is conducted as is usual in vortex metrology for uniform in-plane displacement determination. On the basis of two recorded intensity speckled distributions, corresponding to two states of a diffuser coherently illuminated, we numerically generate an analytical signal from each recorded intensity pattern by using a version of the Riesz integral transform. Then, from each analytical signal, a two-dimensional pseudophase map is generated in which the vortices are located and characterized in terms of their topological charges and their core's structural properties. The second part of the procedure allows obtaining Young's interference fringes when Fourier transforming the light passing through a diffracting mask with multiple apertures at the locations of the homologous vortices. In fact, we use the Fourier transform as a mathematical operation to compute the far-field diffraction intensity pattern corresponding to the multiaperture set. Each aperture from the set is associated with a rectangular hole that coincides both in shape and size with a pixel from recorded images. We show that the fringe analysis can be conducted as in speckle photography in an extended range of displacement measurements. Effects related with speckled decorrelation are also considered. Our experimental results agree with those of speckle photography in the range in which both techniques are applicable. PMID- 23089800 TI - Detecting mode hopping in single-longitudinal-mode fiber ring lasers based on an unbalanced fiber Michelson interferometer. AB - A method of detecting mode hopping for single-longitudinal-mode (SLM) fiber ring lasers has been proposed and experimentally demonstrated. The method that is based on an unbalanced Michelson interferometer (MI) utilizing phase generated carrier modulation instantly transforms mode-hopping dynamics into steep phase changes of the interferometer. Multiform mode hops in an SLM erbium-doped fiber ring laser with an 18.6 MHz mode spacing have been detected exactly in real-time domain and discussed in detail. Numerical results show that the MI-based method has a high testing sensitivity for identifying mode hopping, which will play a significant role in evaluating the output stability of SLM fiber lasers. PMID- 23089801 TI - Population pharmacokinetics and exposure-response relationship of a muscarinic receptor antagonist, imidafenacin. AB - This study was designed to update the population pharmacokinetic model and investigate the exposure-response (efficacy and safety) and concentration-QT relationships for imidafenacin, a synthetic orally active muscarinic receptor antagonist. The population pharmacokinetic model was updated using data from 90 healthy subjects and 852 patients with an overactive bladder. Plasma concentration data from nine clinical studies were used, including new data from a long-term dose escalation study. The updated population pharmacokinetic model for imidafenacin adequately described the plasma concentration profile. The results were generally consistent with those obtained from the previous population pharmacokinetic analysis, indicating that no new covariates were found to influence the pharmacokinetics of imidafenacin. Exposure-response relationships in the long-term dose escalation study were investigated using a regression analysis with efficacy and safety endpoints as dependent variables. There was no clear relationship between exposure and any endpoint. The concentration-QT relationship was also evaluated to assess whether imidafenacin prolonged the concentration-dependent QT interval. There was no clear relationship between the plasma concentration of imidafenacin and QTc, indicating that concentration-dependent QTc interval prolongation was not observed. PMID- 23089802 TI - Function, genetic polymorphism, and transcriptional regulation of human UDP glucuronosyltransferase (UGT) 1A1. AB - Human UDP-glucuronosyltransferase (UGT) 1A1 is the enzyme that detoxifies neurotoxic bilirubin by conjugating it with glucuronic acid. UGT1A1 also plays a critical role in the detoxification and excretion of endogenous and exogenous lipophilic compounds mainly in the liver and gastrointestinal tract. Impaired or reduced UGT1A1 activity causes unconjugated hyperbilirubinemia (Gilbert's syndrome and Crigler-Najjar syndrome) and side effects of drug treatment such as SN-38 (active metabolite of the anticancer drug irinotecan)-induced toxicity. Understanding the regulatory mechanism of human UGT1A1 expression is critical in treating patients with unconjugated hyperbilirubinemia and for effective drug treatment. We identified the distal enhancer module of the UGT1A1 gene and a single nucleotide polymorphism in it that significantly reduces the transcriptional activity associated with the manifestation of Gilbert's syndrome. This review describes the transcriptional regulation of the human UGT1A1 gene by transcription factors and their co-factors, the genetic polymorphism associated with reduced transcriptional activity, and the induction of UGT1A1 expression by non-genetic factors including environmental factors and its pharmacological and toxicological meaning. PMID- 23089803 TI - Comparison of serotonin glucuronidation activity of UDP-glucuronosyltransferase 1a6a (Ugt1a6a) and Ugt1a6b: evidence for the preferential expression of Ugt1a6a in the mouse brain. AB - Mouse UDP-glucuronosyltransferase (Ugt) 1a6a and Ugt1a6b share 98% sequence homology, but there have been no reports to date that compare their expression levels or enzymatic activities in serotonin glucuronidation. Thus, we designed specific primers for Ugt1a6a and Ugt1a6b to compare their expression in mouse brain regions and livers. Ugt1a6a was dominantly expressed in mouse brains, especially the hippocampus, while both Ugt1a6a and Ugt1a6b were highly expressed in mouse livers, indicating that there are significant differences in the expression patterns of Ugt1a6a and Ugt1a6b among mouse tissues. Glucuronidation of endogenous neurotransmitter serotonin was catalyzed by Ugt1a6b with k(cat)/K(m) (4.5 M(-1).s(-1)) slightly higher than that of Ugt1a6a (2.4 M(-1).s( 1)). However, the difference in expression levels between Ugt1a6a and Ugt1a6b in the hippocampus led us to speculate that Ugt1a6a is likely the predominant catalyst of serotonin glucuronidation in the mouse brain. In conclusion, we successfully elucidated the differences between Ugt1a6a and Ugt1a6b expression in the mouse brain. Our new findings indicate that Ugt1a6a and Ugt1a6b play different roles in mice, driven by differences in expression and kinetic properties for serotonin glucuronidation. PMID- 23089804 TI - Oxygen-sulfur rearrangement in the reaction of thiocarbamate imidazolium ylide with arylaldehyde. AB - The nucleophilic addition of thiocarbamate imidazolium ylide to aldehyde triggered sequential intramolecular N to O migration of thiocarbonyl amide group and reversible oxygen-sulfur rearrangement to afford 2-imidazolium alkylcarbamothioate. The ortho group on phenyl of aldehyde strongly affects the balance of the O- to S-rearrangement. PMID- 23089805 TI - Is S-ketamine with or without magnesium sulphate an alternative for postoperative pain treatment? Randomised study. PMID- 23089806 TI - The impact on costs and efficiency of reducing the number of collected tubes. PMID- 23089807 TI - A reproducing kernel-based spatial model in poisson regressions. AB - A semi-parametric spatial model for spatial dependence is proposed in Poisson regressions to study the effects of risk factors on incidence outcomes. The spatial model is constructed through an application of reproducing kernels. A Bayesian framework is proposed to infer the unknown parameters. Simulations are performed to compare the reproducing kernel-based method with several commonly used approaches in spatial modeling, including independent Gaussian and CAR models. Compared with these models, the reproducing kernel-based method is easy to implement and more flexible in terms of the ability to model various spatial dependence patterns. To further demonstrate the proposed method, two real data applications are discussed: Scottish lip cancer data and Florida smoke-related cancer data. PMID- 23089808 TI - Breast tumour as the first manifestation of extramedullary relapse of Philadelphia positive (Ph+) acute lymphoblastic leukemia. AB - Extramedullary relapses of acute lymphoblastic leukemia (ALL) are rare and usually localized in the central nervous system. We describe such an uncommon case of extramedullary relapse of ALL in the breast of a 44 year old female. The patient, who had been diagnosed with precursor B cell, Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) 5 years before and had been in complete molecular remission for the last 19 months, was admitted to the hospital for investigation of a hard, non-tender lump in her right breast. Mammography detected a dense, ill-defined mass, whereas on grey-scale and power Doppler sonography, the appearance of the lesion was consistent with malignancy. Histopathologic and immunohistochemical examination of the specimen demonstrated a similar immunophenotype (CD20+, CD10+, Tdt+, CD3-) as this of the onset ALL cell population in the bone marrow. PMID- 23089809 TI - Breast tuberculosis: rare but still present in Italy--a case of mycobacterium breast infection. AB - Breast tuberculosis is a rare disease in highly endemic countries, and it is even rarer in Western countries, where only occasionally the local population is affected. The rarity of the disease and particularly the lack of a typical clinical-radiological presentation may cause tuberculosis to be mistaken for breast cancer or a pyogenic abscess. The authors present a case of breast tuberculosis in a 27-year-old nulliparous woman, an Italian citizen of the Caucasian race, who has never resided in a tuberculosis endemic area. She presented with painful retroareolar and para-areolar swelling in the right breast associated with cutaneous hyperemia (without fistulization), resistant to antibiotic therapy. Histopathological examination revealed features of mastitis with epithelioid histiocytes and Langhans giant cells and was characterized by the presence of caseous necrosis which suggested tuberculous inflammation. Ziehl Neelsen staining showed the presence of acid fast bacilli. In countries where tuberculosis is non-endemic, breast tuberculosis should always be included in the differential diagnosis in cases of inflammatory breast lesions resistant to the usual antibiotic therapies. Early recognition may prevent both clinical progression and surgical excision, as breast tuberculosis usually regresses as a response to appropriate anti-tuberculosis therapy. PMID- 23089810 TI - Review of the current techniques in use for the treatment of mammary duct associated inflammatory disease sequence (MDAIDS) in males taking into account two new cases. AB - Mammary duct-associated inflammatory disease sequence (MDAIDS) is a common pathology in the female breast that stands out because of its high therapeutic failure rate with both medical and surgical treatments. However, in males, the incidence is extremely low, although the treatment is similar. In this article, we present two new cases of MDAIDS in men, taking advantage of this extraordinary event to review the few cases reported in medical literature regarding the origin, diagnosis and treatment of this pathology. PMID- 23089811 TI - Entropy based genetic association tests and gene-gene interaction tests. AB - In the past few years, several entropy-based tests have been proposed for testing either single SNP association or gene-gene interaction. These tests are mainly based on Shannon entropy and have higher statistical power when compared to standard chi2 tests. In this paper, we extend some of these tests using a more generalized entropy definition, Renyi entropy, where Shannon entropy is a special case of order 1. The order lambda (>0) of Renyi entropy weights the events (genotype/haplotype) according to their probabilities (frequencies). Higher lambda places more emphasis on higher probability events while smaller lambda (close to 0) tends to assign weights more equally. Thus, by properly choosing the lambda, one can potentially increase the power of the tests or the p-value level of significance. We conducted simulation as well as real data analyses to assess the impact of the order lambda and the performance of these generalized tests. The results showed that for dominant model the order 2 test was more powerful and for multiplicative model the order 1 or 2 had similar power. The analyses indicate that the choice of lambda depends on the underlying genetic model and Shannon entropy is not necessarily the most powerful entropy measure for constructing genetic association or interaction tests. PMID- 23089812 TI - Bayesian learning from marginal data in bionetwork models. AB - In studies of dynamic molecular networks in systems biology, experiments are increasingly exploiting technologies such as flow cytometry to generate data on marginal distributions of a few network nodes at snapshots in time. For example, levels of intracellular expression of a few genes, or cell surface protein markers, can be assayed at a series of interim time points and assumed steady states under experimentally stimulated growth conditions in small cellular systems. Such marginal data on a small number of cellular markers will typically carry very limited information on the parameters and structure of dynamic network models, though experiments will typically be designed to expose variation in cellular phenotypes that are inherently related to some aspects of model parametrization and structure. Our work addresses statistical questions of how to integrate such data with dynamic stochastic models in order to properly quantify the information-or lack of information-it carries relative to models assumed. We present a Bayesian computational strategy coupled with a novel approach to summarizing and numerically characterizing biological phenotypes that are represented in terms of the resulting sample distributions of cellular markers. We build on Bayesian simulation methods and mixture modeling to define the approach to linking mechanistic mathematical models of network dynamics to snapshot data, using a toggle switch example integrating simulated and real data as context. PMID- 23089813 TI - Fully moderated T-statistic for small sample size gene expression arrays. AB - Gene expression microarray experiments with few replications lead to great variability in estimates of gene variances. Several Bayesian methods have been developed to reduce this variability and to increase power. Thus far, moderated t methods assumed a constant coefficient of variation (CV) for the gene variances. We provide evidence against this assumption, and extend the method by allowing the CV to vary with gene expression. Our CV varying method, which we refer to as the fully moderated t-statistic, was compared to three other methods (ordinary t, and two moderated t predecessors). A simulation study and a familiar spike-in data set were used to assess the performance of the testing methods. The results showed that our CV varying method had higher power than the other three methods, identified a greater number of true positives in spike-in data, fit simulated data under varying assumptions very well, and in a real data set better identified higher expressing genes that were consistent with functional pathways associated with the experiments. PMID- 23089814 TI - Determining coding CpG islands by identifying regions significant for pattern statistics on Markov chains. AB - Recent experimental and computational work confirms that CpGs can be unmethylated inside coding exons, thereby showing that codons may be subjected to both genomic and epigenomic constraint. It is therefore of interest to identify coding CpG islands (CCGIs) that are regions inside exons enriched for CpGs. The difficulty in identifying such islands is that coding exons exhibit sequence biases determined by codon usage and constraints that must be taken into account. We present a method for finding CCGIs that showcases a novel approach we have developed for identifying regions of interest that are significant (with respect to a Markov chain) for the counts of any pattern. Our method begins with the exact computation of tail probabilities for the number of CpGs in all regions contained in coding exons, and then applies a greedy algorithm for selecting islands from among the regions. We show that the greedy algorithm provably optimizes a biologically motivated criterion for selecting islands while controlling the false discovery rate. We applied this approach to the human genome (hg18) and annotated CpG islands in coding exons. The statistical criterion we apply to evaluating islands reduces the number of false positives in existing annotations, while our approach to defining islands reveals significant numbers of undiscovered CCGIs in coding exons. Many of these appear to be examples of functional epigenetic specialization in coding exons. PMID- 23089815 TI - Unsupervised classification for tiling arrays: ChIP-chip and transcriptome. AB - Tiling arrays make possible a large-scale exploration of the genome thanks to probes which cover the whole genome with very high density, up to 2,000,000 probes. Biological questions usually addressed are either the expression difference between two conditions or the detection of transcribed regions. In this work, we propose to consider both questions simultaneously as an unsupervised classification problem by modeling the joint distribution of the two conditions. In contrast to previous methods, we account for all available information on the probes as well as biological knowledge such as annotation and spatial dependence between probes. Since probes are not biologically relevant units, we propose a classification rule for non-connected regions covered by several probes. Applications to transcriptomic and ChIP-chip data of Arabidopsis thaliana obtained with a NimbleGen tiling array highlight the importance of a precise modeling and of the region classification. The "TAHMMAnnot" package is implemented in R and C and is freely available from CRAN. PMID- 23089816 TI - False discovery rate estimation for stability selection: application to genome wide association studies. AB - Stability Selection, which combines penalized regression with subsampling, is a promising algorithm to perform variable selection in ultra high dimension. This work is motivated by its evaluation in the context of genome-wide association studies (GWAS). One critical aspect for its use lies in the choice of a decision rule that accounts for the massive number of comparisons realised. The current decision rule relies on the control of the Family Wise Error Rate (FWER) by means of an upper bound derived theoretically. Alternatively, we propose to set the detection threshold according to the more liberal false discovery rate (FDR) criterion. The procedure we propose for its estimation relies on permutations. This procedure is evaluated by simulations according to several scenarios mimicking various correlation structures of genetic data and is compared to the original FWER upper bound. The proposed procedure is shown to be less conservative, and able to pick up more true signals than the FWER upper bound. Finally, the proposed methodology is illustrated on a GWAS analysis of a lipid phenotype (high-density lipoproteins, HDL) in the Northern Finland Birth Cohort. PMID- 23089817 TI - Fitting Boolean networks from steady state perturbation data. AB - Gene perturbation experiments are commonly used for the reconstruction of gene regulatory networks. Typical experimental methodology imposes persistent changes on the network. The resulting data must therefore be interpreted as a steady state from an altered gene regulatory network, rather than a direct observation of the original network. In this article an implicit modeling methodology is proposed in which the unperturbed network of interest is scored by first modeling the persistent perturbation, then predicting the steady state, which may then be compared to the observed data. This results in a many-to-one inverse problem, so a computational Bayesian approach is used to assess model uncertainty. The methodology is first demonstrated on a number of synthetic networks. It is shown that the Bayesian approach correctly assigns high posterior probability to the network structure and steady state behavior. Further, it is demonstrated that where uncertainty of model features is indicated, the uncertainty may be accurately resolved with further perturbation experiments. The methodology is then applied to the modeling of a gene regulatory network using perturbation data from nine genes which have been shown to respond synergistically to known oncogenic mutations. A hypothetical model emerges which conforms to reported regulatory properties of these genes. Furthermore, the Bayesian methodology is shown to be consistent in the sense that multiple randomized applications of the fitting algorithm converge to an approximately common posterior density on the space of models. Such consistency is generally not feasible for algorithms which report only single models. We conclude that fully Bayesian methods, coupled with models which accurately account for experimental constraints, are a suitable tool for the inference of gene regulatory networks, in terms of accuracy, estimation of model uncertainty, and experimental design. PMID- 23089818 TI - Assessing modularity using a random matrix theory approach. AB - Random matrix theory (RMT) is well suited to describing the emergent properties of systems with complex interactions amongst their constituents through their eigenvalue spectrums. Some RMT results are applied to the problem of clustering high dimensional biological data with complex dependence structure amongst the variables. It will be shown that a gene relevance or correlation network can be constructed by choosing a correlation threshold in a principled way, such that it corresponds to a block diagonal structure in the correlation matrix, if such a structure exists. The structure is then found using community detection algorithms, but with parameter choice guided by RMT predictions. The resulting clustering is compared to a variety of hierarchical clustering outputs and is found to the most generalised result, in that it captures all the features found by the other considered methods. PMID- 23089819 TI - A calibrated multiclass extension of AdaBoost. AB - AdaBoost is a popular and successful data mining technique for binary classification. However, there is no universally agreed upon extension of the method for problems with more than two classes. Most multiclass generalizations simply reduce the problem to a series of binary classification problems. The statistical interpretation of AdaBoost is that it operates through loss-based estimation: by using an exponential loss function as a surrogate for misclassification loss, it sequentially minimizes empirical risk through fitting a base classifier to iteratively reweighted training data. While there are several extensions using loss-based estimation with multiclass base classifiers, these use multiclass versions of the exponential loss that are not classification calibrated: unless restrictions are placed on conditional class probabilities, it becomes possible to have optimal surrogate risk but poor misclassification risk. In this work, we introduce a new AdaBoost extension called AdaBoost. SL that does not reduce the problem into binary subproblems and that uses a classification calibrated multiclass exponential loss function. Numerical experiments show the algorithm performs well on benchmark datasets. PMID- 23089820 TI - Genetic linkage analysis in the presence of germline mosaicism. AB - Germline mosaicism is a genetic condition in which some germ cells of an individual contain a mutation. This condition violates the assumptions underlying classic genetic analysis and may lead to failure of such analysis. In this work we extend the statistical model used for genetic linkage analysis in order to incorporate germline mosaicism. We develop a likelihood ratio test for detecting whether a genetic trait has been introduced into a pedigree by germline mosaicism. We analyze the statistical properties of this test and evaluate its performance via computer simulations. We demonstrate that genetic linkage analysis has high power to identify linkage in the presence of germline mosaicism when our extended model is used. We further use this extended model to provide solid statistical evidence that the MDN syndrome studied by Genzer-Nir et al. has been introduced by germline mosaicism. PMID- 23089821 TI - Weighted lasso with data integration. AB - The lasso is one of the most commonly used methods for high-dimensional regression, but can be unstable and lacks satisfactory asymptotic properties for variable selection. We propose to use weighted lasso with integrated relevant external information on the covariates to guide the selection towards more stable results. Weighting the penalties with external information gives each regression coefficient a covariate specific amount of penalization and can improve upon standard methods that do not use such information by borrowing knowledge from the external material. The method is applied to two cancer data sets, with gene expressions as covariates. We find interesting gene signatures, which we are able to validate. We discuss various ideas on how the weights should be defined and illustrate how different types of investigations can utilize our method exploiting different sources of external data. Through simulations, we show that our method outperforms the lasso and the adaptive lasso when the external information is from relevant to partly relevant, in terms of both variable selection and prediction. PMID- 23089822 TI - Choice of summary statistic weights in approximate Bayesian computation. AB - In this paper, we develop a Genetic Algorithm that can address the fundamental problem of how one should weight the summary statistics included in an approximate Bayesian computation analysis built around an accept/reject algorithm, and how one might choose the tolerance for that analysis. We then demonstrate that using weighted statistics, and a well-chosen tolerance, in such an approximate Bayesian computation approach can result in improved performance, when compared to unweighted analyses, using one example drawn purely from statistics and two drawn from the estimation of population genetics parameters. PMID- 23089823 TI - Multiscale characterization of signaling network dynamics through features. AB - Inference methods applied to biological networks suffer from a main criticism: as the latter reflect associations measured under static conditions, an evaluation of the underlying modular organization can be biologically meaningful only if the dynamics can also be taken into consideration. The same limitation is present in protein interactome networks. Given the substantial uncertainty characterizing protein interactions, we identify at least three aspects that must be considered for inference purposes: 1. Coverage, which for most organisms is only partial; 2. Stochasticity, affecting both the high-throughput experimental and the computational settings from which the interactions are determined, and leading to suboptimal measurement accuracy; 3. Information variety, due to the heterogeneity of technological and biological sources generating the data. Consequently, advances in inference methods require adequate treatment of both system uncertainty and dynamical aspects. Feasible solutions are often made possible by data (omic) integration procedures that complement the experimental design and the computational approaches for network modeling. We present a multiscale stochastic approach to deal with protein interactions involved in a well-known signaling network, and show that based on some topological network features, it is possible to identify timescales (or resolutions) that characterize complex pathways. PMID- 23089824 TI - A modified maximum contrast method for unequal sample sizes in pharmacogenomic studies. AB - In pharmacogenomic studies, biomedical researchers commonly analyze the association between genotype and biological response by using the Kruskal-Wallis test or one-way analysis of variance (ANOVA) after logarithmic transformation of the obtained data. However, because these methods detect unexpected biological response patterns, the power for detecting the expected pattern is reduced. Previously, we proposed a combination of the maximum contrast method and the permuted modified maximum contrast method for unequal sample size in pharmacogenomic studies. However, we noted that the distribution of the permuted modified maximum contrast statistic depends on nuisance parameter sigma2, which is the population variance. In this paper, we propose a modified maximum contrast method with a statistic that does not depend on the nuisance parameter. Furthermore, we compare the performance of these methods via simulation studies. The simulation results showed that the modified maximum contrast method gave the lowest false-positive rate; therefore, this method is powerful for detecting the true response patterns in some conditions. Further, it is faster and more accurate than the permuted modified maximum contrast method. On the basis of these results, we suggest a rule of thumb to select the appropriate method in a given situation. PMID- 23089825 TI - Adaptive elastic-net sparse principal component analysis for pathway association testing. AB - Pathway or gene set analysis has become an increasingly popular approach for analyzing high-throughput biological experiments such as microarray gene expression studies. The purpose of pathway analysis is to identify differentially expressed pathways associated with outcomes. Important challenges in pathway analysis are selecting a subset of genes contributing most to association with clinical phenotypes and conducting statistical tests of association for the pathways efficiently. We propose a two-stage analysis strategy: (1) extract latent variables representing activities within each pathway using a dimension reduction approach based on adaptive elastic-net sparse principal component analysis; (2) integrate the latent variables with the regression modeling framework to analyze studies with different types of outcomes such as binary, continuous or survival outcomes. Our proposed approach is computationally efficient. For each pathway, because the latent variables are estimated in an unsupervised fashion without using disease outcome information, in the sample label permutation testing procedure, the latent variables only need to be calculated once rather than for each permutation resample. Using both simulated and real datasets, we show our approach performed favorably when compared with five other currently available pathway testing methods. PMID- 23089827 TI - MA-SNP--A new genotype calling method for oligonucleotide SNP arrays modeling the batch effect with a normal mixture model. AB - Genome-wide association studies hold great promise in identifying disease susceptibility variants and understanding the genetic etiology of complex diseases. Microarray technology enables the genotyping of millions of single nucleotide polymorphisms. Many factors in microarray studies, such as probe selection, sample quality, and experimental process and batch, have substantial effect on the genotype calling accuracy, which is crucial for downstream analyses. Failure to account for the variability of these sources may lead to inaccurate genotype calls and false positive and false negative findings. In this study, we develop a SNP-specific genotype calling algorithm based on the probe intensity composite representation (PICR) model, while using a normal mixture model to account for the variability of batch effect on the genotype calls. We demonstrate our method with SNP array data in a few studies, including the HapMap project, the coronary heart disease and the UK Blood Service Control studies by the Wellcome Trust Case-Control Consortium, and a methylation profiling study. Our single array based approach outperforms PICR and is comparable to the best multi-array genotype calling methods. PMID- 23089826 TI - Modeling read counts for CNV detection in exome sequencing data. AB - Varying depth of high-throughput sequencing reads along a chromosome makes it possible to observe copy number variants (CNVs) in a sample relative to a reference. In exome and other targeted sequencing projects, technical factors increase variation in read depth while reducing the number of observed locations, adding difficulty to the problem of identifying CNVs. We present a hidden Markov model for detecting CNVs from raw read count data, using background read depth from a control set as well as other positional covariates such as GC-content. The model, exomeCopy, is applied to a large chromosome X exome sequencing project identifying a list of large unique CNVs. CNVs predicted by the model and experimentally validated are then recovered using a cross-platform control set from publicly available exome sequencing data. Simulations show high sensitivity for detecting heterozygous and homozygous CNVs, outperforming normalization and state-of-the-art segmentation methods. PMID- 23089828 TI - Smoothing gene expression data with network information improves consistency of regulated genes. AB - Gene set analysis methods have become a widely used tool for including prior biological knowledge in the statistical analysis of gene expression data. Advantages of these methods include increased sensitivity, easier interpretation and more conformity in the results. However, gene set methods do not employ all the available information about gene relations. Genes are arranged in complex networks where the network distances contain detailed information about inter gene dependencies. We propose a method that uses gene networks to smooth gene expression data with the aim of reducing the number of false positives and identify important subnetworks. Gene dependencies are extracted from the network topology and are used to smooth genewise test statistics. To find the optimal degree of smoothing, we propose using a criterion that considers the correlation between the network and the data. The network smoothing is shown to improve the ability to identify important genes in simulated data. Applied to a real data set, the smoothing accentuates parts of the network with a high density of differentially expressed genes. PMID- 23089829 TI - [Non-pharmacological and pharmacological treatment of arterial hypertension: current situation]. AB - A permanent and successful treatment of high blood pressure is based on a combination of non-pharmacological treatment measures and pharmacological therapy. The most proven non-pharmacological measures are physical and sports activities, weight reduction, dietary adaption and reduction of salt intake as well as nicotine abstinence and moderate alcohol consumption. A blood pressure reducing effect of evidence grade A was demonstrated for these 4 pillars of non pharmacological therapy in studies. For pharmacological treatment five main substance groups are available: thiazide diuretics, ACE inhibitors, AT1 blockers, calcium channel blockers and beta blockers. A very good blood pressure reducing effect with an advantageous side effect profile has been proven for all substances. The initial high blood pressure therapy can be carried out with monotherapy but therapy with several antihypertensives is often necessary for the very varied combination of compounds which are available in a meaningful combination and dosage of effective ingredients. For the treatment of comorbid hypertensive patients recommendations are available for an individualized pharmacological treatment corresponding to the specific cardiovascular risk and comorbidity. High blood pressure therapy must be continuously carried out over many years. For permanent success of the therapy good compliance is indispensible which can be encouraged by integration in the therapy and should be regularly controlled. PMID- 23089831 TI - [Measurement of slice thickness in magnetic resonance image by the impulse response]. AB - The purpose of this study was to verify the applicability of measurement of slice thickness of magnetic resonance imaging (MRI) by the delta method, and to discuss the measurement precision by the disk diameter and baseline setup of the slice profile of the delta method. The delta method used the phantom which put in the disk made of acrylic plastic. The delta method measured the full width at half maximum (FWHM) and the full width at tenth maximum (FWTM) from the slice profile of the disk signal. Evaluation of the measurement precision of the delta method by the disk diameter and baseline setup were verified by comparison of the FWHM and FWTM. In addition, evaluation of the applicability of the delta method was verified by comparison of the FWHM and FWTM using the wedge method. The baseline setup had the proper signal intensity of an average of 10 slices in the disk images. There were statistically significant difference in the FWHM between disk diameter of 10 mm and disk diameter of 30 mm and 5 mm. The FWHM of the disk diameter of 10 mm was smaller than the disk diameter of 30 mm and 5 mm. There was no statistically significant difference in the FWHM between the delta method and the wedge method. There is no difference in the effective slice thickness of the delta method and the wedge method. The delta method has an advantage in measurement of thin slice thickness. PMID- 23089830 TI - Image-based measurement of post-swallow residue: the normalized residue ratio scale. AB - Post-swallow residue is considered a sign of swallowing impairment. Existing methods for capturing post-swallow residue (perceptual and quantitative) have inherent limitations. We employed several different perceptual and quantitative (ratio) methods for measuring post-swallow residue on the same 40 swallows and addressed the following questions: (1) Do perceptual and quantitative methods demonstrate good agreement? (2) What differences in precision are apparent by measurement method (one-dimensional, two-dimensional, and circumscribed area ratios)? (3) Do residue ratios agree strongly with residue area measures that are anatomically normalized? Based on the findings of this series of questions, a new method for capturing residue is proposed: the Normalized Residue Ratio Scale (NRRS). The NRRS is a continuous measurement that incorporates both the ratio of residue relative to the available pharyngeal space and the residue proportionate to the size of the individual. A demonstration of this method is presented to illustrate the added precision of the NRRS measurement in comparison to other approaches for measuring residue severity. PMID- 23089832 TI - [An experiment to estimate locations of radioisotopes producing black spots on medical images]. AB - Caused by the accident of nuclear power plants in the Fukushima at 2011, many radioisotopes (RI) were diffused to the environment. As a result, X-ray detectors were stained with RIs and black spots appeared on the medical images. Using the RI of (134)Cs and (137)Cs, black spots which appeared on the photostimulable phosphor plate (X-ray detector) were reproduced experimentally. The aim of this study is the following two points; firstly, to clarify the relationship between long-time irradiations of RI and fading effect, and secondly, to clarify the positional relationship between the RI sources and the X-ray detector based on irradiation times of RI. For the latter experiment, the samples were made by spraying water (containing the RI) in order to reproduce small point sources. Then, the sources were placed on the photostimulable phosphor plate or on the cassette, and corresponding images with different irradiation times were taken. The black spots could be reproduced with the condition, in which sources were directly adhered to the photostimulable phosphor plate. We observed the black spots when sources were placed on the cassette for one week. Based on the result, we summarized that the RI which are directly adhered on the photostimulable phosphor plate may produce the black spots. PMID- 23089833 TI - [The trial of business data analysis at the Department of Radiology by constructing the auto-regressive integrated moving-average (ARIMA) model]. AB - This study aimed to contribute to the management of a healthcare organization by providing management information using time-series analysis of business data accumulated in the hospital information system, which has not been utilized thus far. In this study, we examined the performance of the prediction method using the auto-regressive integrated moving-average (ARIMA) model, using the business data obtained at the Radiology Department. We made the model using the data used for analysis, which was the number of radiological examinations in the past 9 years, and we predicted the number of radiological examinations in the last 1 year. Then, we compared the actual value with the forecast value. We were able to establish that the performance prediction method was simple and cost-effective by using free software. In addition, we were able to build the simple model by pre processing the removal of trend components using the data. The difference between predicted values and actual values was 10%; however, it was more important to understand the chronological change rather than the individual time-series values. Furthermore, our method was highly versatile and adaptable compared to the general time-series data. Therefore, different healthcare organizations can use our method for the analysis and forecasting of their business data. PMID- 23089834 TI - [Comparison of various image guided radiation therapy systems; image-guided localization accuracy and patient throughput]. AB - In this study, we evaluated various image guided radiation therapy (IGRT) systems regarding accuracy and patient throughput for conventional radiation therapy. We compared between 2D-2D match (the collation by 2 X-rays directions), cone beam computed tomography (CBCT), and ExacTrac X-Ray system using phantom for CLINAC iX and Synergy. All systems were able to correct within almost 1 mm. ExacTrac X-Ray system showed in particular a high accuracy. As for patient throughput, ExacTrac X-Ray system was the fastest system and 2D-2D match for Synergy was the slowest. All systems have enough ability with regard to accuracy and patient throughput on clinical use. ExacTrac X-Ray system showed superiority with accuracy and throughput, but it is important to note that we have to choose the IGRT technique depending on the treatment site, the purpose, and the patient's state. PMID- 23089835 TI - [Quality assurance procedure for assessing mechanical accuracy of a radiation field center in stereotactic radiotherapy]. AB - Stereotactic radiotherapy requires a quality assurance (QA) program that ensures the mechanical accuracy of a radiation field center. We have proposed a QA method for achieving the above requirement by conducting the Winston Lutz test using an electronic portal image device (EPID). An action limit was defined as three times the standard deviation. Then, the action limits for mean deviations of the radiation field center during collimator rotation, gantry rotation, and couch rotation in clockwise and counterclockwise resulted in 0.11 mm, 0.52 mm, 0.37 mm, and 0.41 mm respectively. Two years after the QA program was launched, the mean deviation of the radiation field center during gantry rotation exceeded the above action limit. Consequently, a mechanical adjustment for the gantry was performed, thereby restoring the accuracy of the radiation field center. A field center shift of 0.5 mm was also observed after a micro multi-leaf collimator was unmounted. PMID- 23089836 TI - [Development of software for the verification of patient flow through a daily clinical environment by use of the radiology information system (RIS)]. AB - In order to manage relationship between patients' movements and operating efficiency, we developed a special software which can make patient flow visible on a display monitor by use of actual data obtained from the radiology information system (RIS). In this software, a simple floor map of the radiology department in our hospital was drawn on the monitor and each patient was indicated with a small figure. This software was developed with commercialized computer software [Excel 2007 visual basic applications (VBA) Microsoft]. Movements of the patient figures were simulated by use of actual time data such as registration of radiology department, and start and ending time of examinations. The patient figures were moved along with predetermined flow lines every second. The movements of the patient figures were controlled by several buttons (i.e., play and stop) and setting switches for determining reproduction date and time. In conclusion, by use of this software, the patient flows could be analyzed systematically by checking efficient operation such as average waiting time of the patients and/or standby time of radiological technologists. PMID- 23089837 TI - [Expansion of sensitivity area for magnetic resonance imaging of the hand using parallel-array coil]. AB - It is difficult for Rheumatoid Arthritis (RA) patients to remain in a strenuous position for a long time during examinations. The field of view (FOV): 250 mm is needed for hand examinations from the wrist to the finger. Two channel phased array coils are effective to use when examinations of the 'off center' are taken for the upper and lower extremities. The area of the array coils' sensitivity can be expanded by shifting both coil elements 40-60% in the opposite direction of the element's diameter. This method is given credibility due to the increased signal-to-noise ratio (SNR) in the peripheral regions (shifted directions), but loses value in the central area, as indicated by the decrease in SNR. This was confirmed in the image of the hand using visual assessment including the fat suppression technique. It was verified that the sensitivity area was expanded using Scheffe's method of paired comparison (Ura's modified method). An application at the other regions of the body can be expected to be used in the case of using parallel positioned coils during clinical situation. PMID- 23089838 TI - [Setup accuracy of stereotactic body radiation therapy (SBRT) using virtual isocenter in image-guided radiation therapy (IGRT)]. AB - We use Novalis Body system for stereotactic body radiation therapy (SBRT) in lung and liver tumors. Novalis system is dedicated to SBRT with image-guided patient setup system ExacTrac. The spinal bone is the main landmark in patient setup during SBRT using ExacTrac kV X-ray system. When the target tumor is located laterally distant from the spinal bone at the midline, it is difficult to ensure the accuracy of the setup, especially if there are rotational gaps (yaw, pitch and roll) in the setup. For this, we resolve the problem by using a virtual isocenter (VIC) different from isocenter (IC) .We evaluated the setup accuracy in a rand phantom by using VIC and checked the setup errors using rand phantom and patient cases by our original method during the setup for IC. The accuracy of setup using VIC was less than 1.0 mm. Our original method was useful for checking patient setup when VIC used. PMID- 23089839 TI - [Modified DIXON: examination of the different flip angles and echo times for water-fat separation and contrast]. AB - The method known as DIXON is imaging from two different echo times (TE), using the opposite phase of water and fat. Modified DIXON (mDIXON) is the method that is calculated from changing the opposing phases 'in' and 'opposed' phases of the actual measurement, to fit the theoretical value. We reviewed that the effect of the water-fat separation and contrast depended on the different flip angles (FA) and echo times (TE). The diluted gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) (from 0 to 5 mmol/l) and liver model was stabilized by lard. In order to measure the SNR and %CV of the lard, the various combinations of TE and FA (from 5 to 20 degrees) were changed. The suitable range for the measurement of the SNR and %CV of the lard, and the contrast of gadolinium Gd-EOB-DTPA and the liver model, in the axial view (including 50% fat), was around the 'opposed' phase in the first TE (TE1) and around the 'in' phase in the second TE (TE2) and FA: 15degrees (TE1: 2.0-2.9 ms, TE2: 4.1-5.0 ms). In order to avoid phase dispersion, shorter TE range is more desirable (TE1: 2.0-2.25 ms, TE2: 4.1-4.5 ms). It is our understanding that the water-fat separation is better in these ranges and under these circumstances, good contrast was obtained. PMID- 23089840 TI - [Importance of radiation education for nurses]. AB - Radiation safety education/training is essential and is associated with a reduction in the radiation dose to both patients and staff. We used a questionnaire to assess the level of radiation safety knowledge among nurses working at Tohoku Kosei-Nenkin Hospital. Some nurses were also interviewed. The results of our study indicate that the nurses had insufficient radiation safety knowledge and that a high percentage of nurses were concerned about the health hazards of radiation. Moreover, more than 80% of the nurses expressed an interest in attending periodic radiation safety seminars. Appropriate radiation safety training is required to reduce nurse radiation doses, and an understanding of radiation safety can help to optimize the patient dose. PMID- 23089841 TI - [The potential of dual-energy virtual monochromatic imaging in reducing renal cyst pseudoenhancement: a phantom study]. AB - Renal cyst pseudoenhancement, an artifactual increase of computed tomography (CT) attenuation for cysts with increased iodine concentrations in the renal parenchyma, complicates the classification of cysts and may thus lead to the mischaracterization of a benign non-enhancing lesion as an enhancing mass. The purpose of this study was to use a phantom model to assess the ability of dual energy virtual monochromatic imaging to reduce renal pseudoenhancement. A water filled cylindrical cyst model suspended in varying concentrations of iodine solution, to simulate varying levels of parenchymal enhancement, was scanned with a dual-energy CT scanner using the following three scanning protocols with different combinations of tube voltage: 80 and 140 kV; 80 and 140 kV with tin filter; and 100 and 140 kV with tin filter. Virtual monochromatic images were then synthesized for each dual-energy scan. Single-energy scan with a tube voltage of 120 kV was also performed to obtain polychromatic images as controls. Mean attenuation values (in Hounsfield units) of cyst proxies were measured on both polychromatic and virtual monochromatic images. Pseudoenhancement was considered to be present when the cyst attenuation level increased by more than 10 HU as the background iodine concentration increased from 0.0% to 0.4%, 1.5%, or 2.5%. Our results revealed that pseudoenhancement was not observed on any of the monochromatic images, but appeared on polychromatic images at a background iodine concentration of 2.5%. We thus conclude that dual-energy virtual monochromatic images have a potential to reduce renal pseudoenhancement. PMID- 23089842 TI - [Traps in the soft-copy interpretation of the digital mammography]. PMID- 23089843 TI - [Statistical methods for radiologic research. 2. Research design for the radiologic technology]. PMID- 23089844 TI - [From diagnosis to therapy of breast cancer. 8. Sentinel lymph node biopsy]. PMID- 23089846 TI - [Three-dimensional computer graphics. 1. Hardware topics]. PMID- 23089847 TI - [The essential knowledge for exposition of radiation protection]. PMID- 23089848 TI - [Domestic market trend for medical imaging and radiological system]. PMID- 23089849 TI - The fusion loops and membrane proximal region of Epstein-Barr virus glycoprotein B (gB) can function in the context of herpes simplex virus 1 gB when substituted individually but not in combination. AB - Among the herpesvirus glycoprotein B (gB) fusion proteins, the hydrophobic content of fusion loops and membrane proximal regions (MPRs) are inversely correlated with each other. We examined the functional importance of the hydrophobicity of these regions by replacing them in herpes simplex virus type 1 gB with corresponding regions from Epstein-Barr virus gB. We show that fusion activity is dependent on the structural context in which the specific loops and MPR sequences exist, rather than a simple hydrophobic relationship. PMID- 23089850 TI - Exotic and indigenous viruses infect wild populations and captive collections of temperate terrestrial orchids (Diuris species) in Australia. AB - Four species of Diuris temperate terrestrial orchids from wild and captive populations were tested for the presence of polyadenylated RNA viruses. The genomes of three exotic viruses were determined: two potyviruses, Bean yellow mosaic virus and Ornithogalum mosaic virus, and the polerovirus Turnip yellows virus. The genomes of five indigenous viruses were detected, including four novel species. They were the potyvirus Blue squill virus A, another potyvirus, two proposed capilloviruses, and a partitivirus. Partitivirus infection is of interest as this group of viruses is also associated with endophytic fungi (mycorrhizae) that are necessary for the germination, growth, development of many terrestrial orchids. Sequence divergence data indicate post-European, pre European, and endemic origins for these viruses via inoculum from introduced and native plants. The implications of the findings of this study for orchid conservation, and particularly reintroduction programs where viruses may be spread inadvertently to wild populations from infected propagation sources, are discussed. PMID- 23089851 TI - In guidelines we cannot trust. PMID- 23089852 TI - 100 years of the hydrogen bond. PMID- 23089858 TI - Protein design: Engineering di-iron enzymes. PMID- 23089859 TI - Heterogeneous catalysis: Teaching an old material new tricks. PMID- 23089860 TI - Molecular magnetism: A three-headed Janus material. PMID- 23089862 TI - Selectivity and direct visualization of carbon dioxide and sulfur dioxide in a decorated porous host. AB - Understanding the mechanism by which porous solids trap harmful gases such as CO(2) and SO(2) is essential for the design of new materials for their selective removal. Materials functionalized with amine groups dominate this field, largely because of their potential to form carbamates through H(2)N(delta( ))...C(delta(+))O(2) interactions, thereby trapping CO(2) covalently. However, the use of these materials is energy-intensive, with significant environmental impact. Here, we report a non-amine-containing porous solid (NOTT-300) in which hydroxyl groups within pores bind CO(2) and SO(2) selectively. In situ powder X ray diffraction and inelastic neutron scattering studies, combined with modelling, reveal that hydroxyl groups bind CO(2) and SO(2) through the formation of O=C(S)=O(delta(-))...H(delta(+))-O hydrogen bonds, which are reinforced by weak supramolecular interactions with C-H atoms on the aromatic rings of the framework. This offers the potential for the application of new 'easy-on/easy off' capture systems for CO(2) and SO(2) that carry fewer economic and environmental penalties. PMID- 23089861 TI - Heterogeneities of individual catalyst particles in space and time as monitored by spectroscopy. AB - Recent years have witnessed the introduction of spatiotemporal spectroscopy for the characterization of catalysts at work at previously unattainable resolution and sensitivity. They have revealed that heterogeneous catalysts are more heterogeneous than often expected. Dynamic changes in the nature of active sites, such as their distribution and accessibility, occur both between and within particles. Scientists now have micro- and nanospectroscopic methods at hand to improve the understanding of catalyst heterogeneities and exploit them in catalyst design. Here we review the latest developments within this lively field. The trends include detection of single particles or molecules, super-resolution imaging, the transition from two- to three-dimensional imaging, selective staining, integration of spectroscopy with electron microscopy or scanning probe methods, and measuring under realistic reaction conditions. Such experimental approaches change the hitherto somewhat static picture of heterogeneous catalysis into one that acknowledges that catalysts behave almost like living objects- explaining why many characterization methods from the life sciences are being incorporated into catalysis research. PMID- 23089863 TI - Prebiotic synthesis of simple sugars by photoredox systems chemistry. AB - A recent synthesis of activated pyrimidine ribonucleotides under prebiotically plausible conditions relied on mixed oxygenous and nitrogenous systems chemistry. As it stands, this synthesis provides support for the involvement of RNA in the origin of life, but such support would be considerably strengthened if the sugar building blocks for the synthesis--glycolaldehyde and glyceraldehyde--could be shown to derive from one carbon feedstock molecules using similarly mixed oxygenous and nitrogenous systems chemistry. Here, we show that these sugars can be formed from hydrogen cyanide by ultraviolet irradiation in the presence of cyanometallates in a remarkable systems chemistry process. Using copper cyanide complexes, the process operates catalytically to disproportionate hydrogen cyanide, first generating the sugars and then sequestering them as simple derivatives. PMID- 23089864 TI - Alteration of the oxygen-dependent reactivity of de novo Due Ferri proteins. AB - De novo proteins provide a unique opportunity to investigate the structure function relationships of metalloproteins in a minimal, well-defined and controlled scaffold. Here, we describe the rational programming of function in a de novo designed di-iron carboxylate protein from the Due Ferri family. Originally created to catalyse the O(2)-dependent, two-electron oxidation of hydroquinones, the protein was reprogrammed to catalyse the selective N hydroxylation of arylamines by remodelling the substrate access cavity and introducing a critical third His ligand to the metal-binding cavity. Additional second- and third-shell modifications were required to stabilize the His ligand in the core of the protein. These structural changes resulted in at least a 10(6) fold increase in the relative rate between the arylamine N-hydroxylation and hydroquinone oxidation reactions. This result highlights the potential for using de novo proteins as scaffolds for future investigations of the geometric and electronic factors that influence the catalytic tuning of di-iron active sites. PMID- 23089865 TI - Hidden complexity in the isomerization dynamics of Holliday junctions. AB - A plausible consequence of the rugged folding energy landscapes inherent to biomolecules is that there may be more than one functionally competent folded state. Indeed, molecule-to-molecule variations in the folding dynamics of enzymes and ribozymes have recently been identified in single-molecule experiments, but without systematic quantification or an understanding of their structural origin. Here, using concepts from glass physics and complementary clustering analysis, we provide a quantitative method to analyse single-molecule fluorescence resonance energy transfer (smFRET) data, thereby probing the isomerization dynamics of Holliday junctions, which display such heterogeneous dynamics over a long observation time (T(obs) ~ 40 s). We show that the ergodicity of Holliday junction dynamics is effectively broken and that their conformational space is partitioned into a folding network of kinetically disconnected clusters. Theory suggests that the persistent heterogeneity of Holliday junction dynamics is a consequence of internal multiloops with varying sizes and flexibilities frozen by Mg(2+) ions. An annealing experiment using Mg(2+) pulses lends support to this idea by explicitly showing that interconversions between trajectories with different patterns can be induced. PMID- 23089866 TI - Synthesis of highly strained terpenes by non-stop tail-to-head polycyclization. AB - Non-stop carbocationic polycyclizations of isoprenoids have been called the most complex chemical reactions occurring in nature. We describe a strategy for the initiation of tail-to-head polycyclization that relies on the sequestration of the counteranion away from the carbocation, which allows full propagation of the cationic charge. If the anion is mobile, Coulombic forces hold this species in close proximity to the carbocation and cause preemptive termination through elimination. Anion sequestration is crucial for effecting the biomimetic synthesis of complex and unstable terpenes, including the highly strained funebrenes. This study illustrates the deleterious role of the counterion in tail to-head carbocationic polycyclization reactions, which to the best of our knowledge has not been rigorously explored. These observations are also expected to find use in the design and control of cationic polycyclization along biosynthetic pathways that have previously been inaccessible in bulk solvent. PMID- 23089867 TI - Three-way switching in a cyanide-bridged [CoFe] chain. AB - Bistable compounds that exist in two interchangeable phases under identical conditions can act as switches under external stimuli. Among such switchable materials, coordination complexes have energy levels (or phases) that are determined by the electronic states of their constituent metal ions and ligands. They can exhibit multiple bistabilities and hold promise in the search for multifaceted materials that display different properties in different phases, accessible through the application of contrasting external stimuli. Molecular systems that exhibit both thermo- and photoinduced magnetic bistabilities are excellent candidates for such systems. Here we describe a cyanide-bridged [CoFe] one-dimensional chiral coordination polymer that displays both magnetic and electric bistabilities in the same temperature range. Both the electric and magnetic switching probably arise from the same electron-transfer coupled spin transition phenomenon, which enables the reversible conversion between an insulating diamagnetic phase and either a semiconducting paramagnetic (thermoinduced) or a type of ferromagnetic single-chain magnet (photoinduced) state. PMID- 23089868 TI - Amyloid beta-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity. AB - The amyloid protein aggregation associated with diseases such as Alzheimer's, Parkinson's and type II diabetes (among many others) features a bewildering variety of beta-sheet-rich structures in transition from native proteins to ordered oligomers and fibres. The variation in the amino-acid sequences of the beta-structures presents a challenge to developing a model system of beta-sheets for the study of various amyloid aggregates. Here, we introduce a family of robust beta-sheet macrocycles that can serve as a platform to display a variety of heptapeptide sequences from different amyloid proteins. We have tailored these amyloid beta-sheet mimics (ABSMs) to antagonize the aggregation of various amyloid proteins, thereby reducing the toxicity of amyloid aggregates. We describe the structures and inhibitory properties of ABSMs containing amyloidogenic peptides from the amyloid-beta peptide associated with Alzheimer's disease, beta(2)-microglobulin associated with dialysis-related amyloidosis, alpha-synuclein associated with Parkinson's disease, islet amyloid polypeptide associated with type II diabetes, human and yeast prion proteins, and Tau, which forms neurofibrillary tangles. PMID- 23089869 TI - Ammonia synthesis using a stable electride as an electron donor and reversible hydrogen store. AB - Industrially, the artificial fixation of atmospheric nitrogen to ammonia is carried out using the Haber-Bosch process, but this process requires high temperatures and pressures, and consumes more than 1% of the world's power production. Therefore the search is on for a more environmentally benign process that occurs under milder conditions. Here, we report that a Ru-loaded electride [Ca(24)Al(28)O(64)](4+)(e(-))(4) (Ru/C12A7:e(-)), which has high electron donating power and chemical stability, works as an efficient catalyst for ammonia synthesis. Highly efficient ammonia synthesis is achieved with a catalytic activity that is an order of magnitude greater than those of other previously reported Ru-loaded catalysts and with almost half the reaction activation energy. Kinetic analysis with infrared spectroscopy reveals that C12A7:e(-) markedly enhances N(2) dissociation on Ru by the back donation of electrons and that the poisoning of ruthenium surfaces by hydrogen adatoms can be suppressed effectively because of the ability of C12A7:e(-) to store hydrogen reversibly. PMID- 23089870 TI - RNA catalysis through compartmentalization. AB - RNA performs important cellular functions in contemporary life forms. Its ability to act both as a catalyst and a storage mechanism for genetic information is also an important part of the RNA world hypothesis. Compartmentalization within modern cells allows the local concentration of RNA to be controlled and it has been suggested that this was also important in early life forms. Here, we mimic intracellular compartmentalization and macromolecular crowding by partitioning RNA in an aqueous two-phase system (ATPS). We show that the concentration of RNA is enriched by up to 3,000-fold in the dextran-rich phase of a polyethylene glycol/dextran ATPS and demonstrate that this can lead to approximately 70-fold increase in the rate of ribozyme cleavage. This rate enhancement can be tuned by the relative volumes of the two phases in the ATPS. Our observations support the importance of compartmentalization in the attainment of function in an RNA World as well as in modern biology. PMID- 23089871 TI - Control of selectivity in heterogeneous catalysis by tuning nanoparticle properties and reactor residence time. AB - A combination of the advantages of homogeneous and heterogeneous catalysis could enable the development of sustainable catalysts with novel reactivity and selectivity. Although heterogeneous catalysts are often recycled more easily than their homogeneous counterparts, they can be difficult to apply in traditional organic reactions and modification of their properties towards a desired reactivity is, at best, complex. In contrast, tuning the properties of homogeneous catalysts by, for example, modifying the ligands that coordinate a metal centre is better understood. Here, using olefin cyclopropanation reactions catalysed by dendrimer-encapsulated Au nanoclusters as examples, we demonstrate that changing the dendrimer properties allows the catalytic reactivity to be tuned in a similar fashion to ligand modification in a homogeneous catalyst. Furthermore, we show that these heterogeneous catalysts employed in a fixed-bed flow reactor allow fine control over the residence time of the reactants and thus enables the control over product distribution in a way that is not easily available for homogeneous catalysts. PMID- 23089872 TI - Osmium weighs in. PMID- 23089873 TI - Heme binding site in apomyoglobin may be effectively targeted with small molecules to control aggregation. AB - A number of ligands with affinities for the heme binding site of apomyoglobin were tested to control amorphous and fibrillar aggregation in the protein. Several techniques, including fluorescence, dynamic light scattering, transmission electron microscopy, dot blot analysis combined with viability studies were employed for structural characterization and cytotoxicity assessment of the intermediate and final protein structures formed during the aggregation process. Of the small molecules investigated, chrysin and Nile red with high structural similarities to heme were chosen for further studies. Only fibril formation was found to be prevented by Nile red, while chrysin, with a greater structural flexibility, was able to prevent both types of aggregate formation. The two ligands were found to influence aggregation at different stages of intermediate structure formation, an ability determined by their degrees of similarities with heme. Based on structural characterization and toxicity studies, it is concluded that ligands similar in structure to heme may be effective in influencing various stages of aggregate formation and toxicity potencies of the protein structures. Since metalloproteins constitute more than thirty percent of all known proteins, it is concluded that the present strategy may be of general significance. PMID- 23089875 TI - Synthesis of C-linked carbo-beta2-amino acids and beta2-peptides: design of new motifs for left-handed 12/10- and 10/12-mixed helices. AB - C-linked carbo-beta(2)-amino acids (beta(2)-Caa), a new class of beta-amino acid with a carbohydrate side chain having d-xylo configuration, were prepared from d glucose. The main idea behind the design of the new beta-amino acids was to move the steric strain of the bulky carbohydrate side chain from the Cbeta- to the Calpha-carbon atom and to explore its influence on the folding propensities in peptides with alternating (R)- and (S)-beta(2)-Caas. The tetra- and hexapeptides derived were studied employing NMR (in CDCl(3)), CD, and molecular dynamics simulations. The beta(2)-peptides of the present study form left-handed 12/10- and 10/12-mixed helices independent of the order of the alternating chiral amino acids in the sequence and result in a new motif. These results differ from earlier findings on beta(3)-peptides of the same design, containing a carbohydrate side chain with d-xylo configuration, which form exclusively right handed 12/10-mixed helices. Quantum chemical calculations employing ab initio MO theory suggest the side chain chirality as an important factor for the observed definite left- or right-handedness of the helices in the beta(2)- and beta(3) peptides. PMID- 23089876 TI - Spectroscopic assessment of the role of hydrogen in surface defects, in the electronic structure and transport properties of TiO2, ZnO and SnO2 nanoparticles. AB - The interaction of metal oxides with gases is very important for the operation of energy devices such as fuel cells and gas sensors, and also relevant for materials synthesis and processing. The electronic transport properties of metal oxides for the aforementioned devices strongly depend on the chemistry of these gases and on the presence or absence of defects on the surface and in the bulk. The Debye screening length is in this respect a material specific property which becomes particularly significant when the material is comprised of nanoparticles. In the present study, poly-crystalline TiO(2), ZnO and SnO(2) nanoparticles were synthesized by a high temperature flame spray combustion process and investigated for their interaction with hydrogen. The chemistry of the reduced and oxidized surfaces of these metal oxides, where the interaction with gases takes place, was investigated in detail with X-ray photoelectron spectroscopy (XPS). The transitions found near E(F) with XPS are consistent with those found by diffuse reflectance spectroscopy (DRS) and were assigned to surface states originating from non-equilibrium oxygen vacancies. We show how the non-stoichiometric character of the metal oxide surface constitutes electronic surface defects, in particular oxygen vacancies which allow for additional transitions near the Fermi energy (E(F)). The concentration of these surface defects can be strongly reduced by thermal after-treatment under air or increased by Ar(+)-sputtering, after which significant spectral features appear near E(F). Such prominent changes are particularly observed for TiO(2) and SnO(2), whereas the stoichiometry of the ZnO surface seems to be less responsive to such reducing and oxidizing conditions. Pronounced changes of the electrical conductivity upon changing from reducing to oxidizing conditions at elevated temperatures were monitored by electrochemical impedance spectroscopy (EIS). The lowering of the potential barrier for the charge transport particularly at lower temperatures already at reducing conditions is confirmed. The impedance response indicates that charge transfer is governed predominantly by one single process, i.e. by interaction of surface-like states localized within depletion layer with gas molecules. This implies that the free charge carriers in the material are determined by the intrinsic property like non-stoichiometry. Gas sensors made from such FSS nanoparticulate metal oxides showed well developed sensing characteristics of the hydrogen sensing at moderate temperatures. PMID- 23089877 TI - Osteoid osteomas: a pain in the night diagnosis. AB - Osteoid osteoma is a common benign bone-forming lesion that is composed of a nidus of vascular osteoid tissue and woven bone lined by osteoblasts. It is frequently associated with considerable surrounding inflammation. The diagnosis is usually straightforward when imaging reveals a radiolucent nidus surrounded by variable degrees of reactive sclerosis. However, the diagnosis can be elusive when osteoid osteomas occur in atypical locations, as they may have a nonspecific and misleading appearance on different imaging modalities, particularly on MRI. The purpose of this pictorial essay is to review the typical and atypical features of osteoid osteomas on different imaging modalities, and the appearance of osteoid osteomas in different locations. We also review growth disturbances caused by osteoid osteomas and potential mimickers, with imaging characteristics that can aid in diagnosis. PMID- 23089878 TI - Expanding the molecular recognition repertoire of antifreeze polypeptides: effects on nucleoside crystal growth. AB - Despite differences in the crystal structures of ice and nucleosides, antifreeze polypeptides (AFPs) have been demonstrated to inhibit nucleation of 5 methyluridine, cytidine, and inosine and modify the crystal growth of the nucleosides efficiently. The molecular recognition repertoire of AFPs has been expanded to non-ice-like crystalline solids. PMID- 23089879 TI - Economic modelling of early transjugular intrahepatic portosystemic shunt insertion for acute variceal haemorrhage. AB - INTRODUCTION: Early insertion of transjugular intrahepatic portosystemic shunt (TIPS) in high-risk patients with acute variceal haemorrhage reduces rebleeding and mortality. However, the economic benefit of utilizing this approach remains unclear. We evaluated the economic implications of introducing early TIPS into routine algorithms for the management of variceal bleeding. METHODS: Consecutive patients admitted in 2009 with variceal haemorrhage to two liver units and eligible for early TIPS insertion were identified retrospectively. The costs of a 12-month follow-up from index bleeding admission were calculated--the actual cost of follow-up and rebleeding in this cohort was compared with the theoretical 12 month follow-up costs of instead inserting an early TIPS at index admission. Our findings were subjected to a sensitivity analysis to assess the cost effectiveness of early TIPS insertion compared with standard care. RESULTS: In 2009, 78 patients were admitted to our units with variceal haemorrhage; 27 patients (35%) were eligible for early TIPS insertion. The actual cost of a 12 month follow-up was L138 473.50. Early TIPS insertion, assuming a 3.2% rebleeding rate, would save L534.70 per patient per year (P<0.0001). On sensitivity analysis, early TIPS dominated standard care up to an early TIPS rebleeding rate of 6% and remained cost-effective up to a rebleeding rate of 12%. CONCLUSION: Early TIPS insertion for high-risk patients with acute variceal bleeding is a cost-efficient intervention. This has important implications for the introduction of early TIPS as standard care and the organization of interventional radiology services. PMID- 23089880 TI - Effects of radiation on the expression of adhesion molecules and cytokines in a static model of human dermal microvascular endothelial cells. AB - BACKGROUND: Radiation-induced wound healing complications represent an important clinical problem. Microvascular compromise is an important component of its pathogenesis and the microvascular endothelial cell is the key representative affected at the cellular level. MATERIAL AND METHODS: Human dermal microvascular endothelial cells (HDMEC) were cultured and irradiated with doses of 2 to 12 Gy. Cell density was determined 48 h after radiation using a semi-automated cell counting system. Levels of interleukin-6 (IL-6), basic fibroblast growth factor (FGF), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the supernatants of HDMEC were determined by polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Non irradiated HDMEC were used as controls. RESULTS: Cell density was significantly impaired in irradiated cells compared to non irradiated controls. Radiation resulted in significant elevation of levels of IL-6, FGF, ICAM-1 and VCAM-1 in the supernatants of HDMEC in a dose dependent manner. CONCLUSION: The inflammatory response observed clinically after radiation seems to correlate with elevated expression of cytokines and adhesion molecules by microvascula endothelial cells. The model of HDMEC documents the impairment of microcirculation. These in vitro changes may enhance our understanding of the pathomechanisms leading to radiation-induced vasculitis and associated wound healing problems. PMID- 23089881 TI - Disaggregating shear stress: the roles of cell deformability and fibrinogen concentration. AB - Red blood cell (RBC) aggregation is greatly affected by cell deformability and reduced deformability and increased RBC aggregation are frequently observed in hypertension, diabetes mellitus, and sepsis, thus measurement of both these parameters is essential. In this study, we investigated the effects of cell deformability and fibrinogen concentration on disaggregating shear stress (DSS). The DSS was measured with varying cell deformability and geometry. The deformability of cells was gradually decreased with increasing concentration of glutaraldehyde (0.001~0.005%) or heat treatment at 49.0 degrees C for increasing time intervals (0~7 min), which resulted in a progressive increase in the DSS. However, RBC rigidification by either glutaraldehyde or heat treatment did not cause the same effect on RBC aggregation as deformability did. The effect of cell deformability on DSS was significantly increased with an increase in fibrinogen concentration (2~6 g/L). These results imply that reduced cell deformability and increased fibrinogen levels play a synergistic role in increasing DSS, which could be used as a novel independent hemorheological index to characterize microcirculatory diseases, such as diabetic complications with high sensitivity. PMID- 23089882 TI - Rheologic results and their correlation to hemostatic changes in patients with moderate and severe preeclampsia: an observational cross-sectional study. AB - Previous study have shown an association between failure of physiological hemodilution during 2nd trimester and an increased risk for the development of subsequent pregnancy complications such as early birth, birth of a growth retarded newborn (IUGR), low fetal birth weight and preeclampsia. The latter complication in particular goes along with dramatic changes in the placental perfusion as well as systemic maternal blood flow. Severity of preeclampsia may be preceded by distinct impaired hemodilution and reflected by the results of rheological parameters. A subgroup analysis was performed in a community based retrospective study of 4,985 consecutively recorded singleton pregnant women of whom 423 had preeclampsia. Mean 2nd trimester hemoglobin levels and blood rheological results at the time of delivery were assessed and compared in women with moderate and severe preeclampsia. Mean 2nd trimester hemoglobin levels were calculated from the maternal records. Rheological variables included plasma viscosity (KSPV 1 Fresenius) and Red blood cell aggregation in stasis and under low shear conditions (MA1-Aggregometer; Myrenne). According to the definition of the German Society of Gynecology and Obstetrics (DGGG) 314 women had moderate preeclampsia (74.2%), while 109 had severe preeclampsia due to the presence of a blood pressure>170/110 mmHg (n=41; 9.7%), and/or IUGR<5th percentile (n=28; 6.6%), and/or HELLP-Syndrome (n=10; 2.4%), and/or proteinuria>=5 g/24 h (n=30; 7.1%). Age, BMI, smoking, and maternal weight were comparable in the groups, while gestational age at delivery as well as fetal outcome parameter were statistically significant unfavourable in patients with severe preeclampsia. Mean 2nd trimester hemoglobin level were statistically significantly higher in women who developed severe vs. moderate preeclampsia (m=12.75+/-0.99 g/dL vs. m=12.50+/ 1.05 g/dL; p=0.033). However, in the ROC calculations a hemoglobin value of 12.05 g/dL revealed best sensitivity (78%) and specificity (33.8%) in women with subsequent diagnosis of severe preeclampsia, whereas sensitivity was 100% for a value>10.95 g/dL. There were no statistically significant differences for none of the rheological parameters at the time of delivery between groups of patient with moderate v.s severe preeclampsia. Severe preeclampsia and IUGR, however, was associated with statistically significantly higher RBC aggregation as compared to patients with moderate preeclampsia. Plasma viscosity was statistically significantly (p<0.05) correlated with Fibrinogen values (r=0.16), leukocyte (r=0.11) and platelets-count (r=0.127), and hemoglobin/hematocrit values in particular (r=0.23/0.26). Although mean 2nd trimester hemoglobin concentration are higher in patients with subsequent development of severe preeclampsia, due to the low sensitivity and specificity of this parameter clinical use for identifying women at risk is of limited value. On the other hand, a hemoglobin value below 11.0 g/dL excluded the risk for severe preeclampsia to 100%. Blood rheological parameters at the time of delivery in the absence of IUGR are not markedly influenced by severity of preeclampsia. PMID- 23089883 TI - Alterations of haemorheological parameters in patients with peripheral arterial disease. AB - Peripheral arterial disease (PAD), is a common manifestation of systemic atherosclerosis. Advances on the development of such vascular disease have described with a number of novel risk factors. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role on the pathogenesis of the disease. Aim of this study was to evaluate the possible association between hemorheological variables and PAD. The hemorheological variables [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV)] were analyzed in 90 patients and in 180 healthy subjects. WBV and PLV were measured by a Rotational Viscosimeter and DI by a filtrometer. DI and PLV were significantly different in patients as compared to controls. To investigate the possible association between these parameters and the disease we divided the study population into tertiles. At the univariate analysis, we found a significant association between the highest tertiles of PLV, of DI and the disease. A model adjusted for traditional risk factors showed an association between highest tertiles of PLV and PAD. After adjustment for confounding parameters highest tertiles of PLV remained to be significantly associated with the disease. Our data indicate that an alteration of plasma viscosity may modulate the predisposition to PAD. PMID- 23089884 TI - Peripheral microvascular dysfunction as an independent predictor of atherosclerotic damage in type 1 diabetes patients: a preliminary study. AB - It has been recently hypothesized that peripheral microvascular dysfunction may contribute to atherosclerotic damage (AD) in diabetic patients. In order to test this hypothesis, we assessed forearm skin post-occlusive reactive hyperaemia (skin-PORH), an index of peripheral microvascular function, using laser-Doppler flowmetry, in 40 type 1 diabetes patients (T1D-pts), aged 49 +/- 11 years, with no known cardiovascular complications, and in 50 age and sex-matched healthy control subjects (CS). T1D-pts also underwent carotid arteries ultrasound scanning (Ca-US) and ankle-brachial index (ABI) measurement. An arbitrary index of AD (AD-index), ranging from "0" (normal ABI, normal Ca-US) to "3" (abnormal ABI, one or more plaques at the Ca-US), was determined in T1D-pts. Linear and multiple regression analyses were performed to identify independent predictors of AD in T1D-pts. T1D-pts had a lower skin-PORH compared with CS (p = 0.015). In T1D pts AD-index resulted to be negatively related with skin-PORH (R = 0.44; p < 0.005) or deep-breathing test (DBT) (R = 0.53; p < 0.0005), and positively related with systolic arterial pressure (R = 0.31; p < 0.05), microalbuminuria (R = 0.46; p < 0.005), patients' age (R = 0.51; p < 0.001) and diabetes duration (R = 0.39; p < 0.05). At the multiple regression analysis skin-PORH (R = 0.36; p < 0.005), patients' age R = 0.24; p < 0.05) and DBT (R = 0.4 - p < 0.005) resulted to be independent predictors of AD-index in T1D-pts. These preliminary findings support the hypothesis that peripheral microvascular dysfunction may contribute to AD in T1D-pts. PMID- 23089885 TI - Psoriasis and hemorheology. Influence of the metabolic syndrome. AB - Psoriasis is a systemic inflammatory disorder with increased cardiovascular risk which has been partly attributed to the increased prevalence of the metabolic syndrome (MS). However, the contribution of rheological alterations to cardiovascular risk has been scarcely investigated. In 91 psoriasis patients and in 101 healthy volunteers, we determined the rheological profile (fibrinogen, blood viscosity and erythrocyte aggregation), along with lipidic and inflammatory parameters. Patients showed statistically higher BMI, waist, triglycerides, insulin, c-reactive protein (CRP), neutrophils, lower HDL-cholesterol and a higher MS prevalence (p<0.05). When subjects with MS were excluded from the study, patients with psoriasis still showed a worse inflammatory, lipidic and rheological profile in the above-mentioned variables compared with controls without MS (p<0.05). The logistic regression analysis revealed that abdominal obesity and fibrinogen>384 mg/dL were independent predictors of psoriasis (OR 3.75 95% CI 1.77-7.94, p<0.001; OR 2.95 95% CI 1.14-7.64, p=0.025), respectively. Patients on biologics, showed less inflammation and a better rheological profile than those not on biological treatment. In conclusion, patients with psoriasis show an altered rheological profile, which may contribute to increased cardiovascular risk. Although the presence of MS worsens this profile, psoriasis per se shows rheological alterations due to both inflammation and altered metabolic parameters. Anti TNF-alpha treatment markedly improves the rheological profile by mostly decreasing inflammation. PMID- 23089887 TI - Searching for markers to identify angiogenic endothelial cells: a proteomic approach. AB - In the field of angiogenesis research considerable effort is put in the development of in vitro assays of angiogenesis to replace animal experiments. Unfortunately, reproducibility of these assays frequently fails depending on the particular batch of endothelial cells delivered by the distributor. This is due to the lack of reliable markers for the identification and isolation of angiogenic microvascular endothelial cells that have the capacity to perform all stages of the angiogenic cascade. This study was carried out to identify potential markers for angiogenic versus non-angiogenic endothelial cells. The protein expression profile of four capillary-derived human microvascular primary endothelial cell cultures of which only two batches could be stimulated to angiogenesis was investigated and compared by two-dimensional gel electrophoresis. Seven proteins were found to be expressed in the angiogenic batches only. One protein was detected exclusively in the non-angiogenic batches. These proteins might be verified as markers for angiogenic endothelial cells. PMID- 23089886 TI - Effects of ethanol on red blood cell rheological behavior. AB - Consumption of red wine is associated with a decreased risk of several cardiovascular diseases (e.g., coronary artery disease, stroke), but unfortunately literature reports regarding ethanol's effects on hemorheological parameters are not concordant. In the present study, red blood cell (RBC) deformability was tested via laser ektacytometry (LORCA, 0.3-30 Pa) using two approaches: 1) addition of ethanol to whole blood at 0.25%-2% followed by incubation and testing in ethanol-free LORCA medium; 2) addition of ethanol to the LORCA medium at 0.25%-6% then testing untreated native RBC in these media. The effects of ethanol on deformability for oxidatively stressed RBC were investigated as were changes of RBC aggregation (Myrenne Aggregometer) for cells in autologous plasma or 3% 70 kDa dextran. Significant dose-related increases of RBC deformability were observed at 0.25% (p < 0.05) and higher concentrations only if ethanol was in the LORCA medium; no changes occurred for cells previously incubated with ethanol then tested in ethanol-free medium. The impaired deformability of cells pre-exposed to oxidative stress was improved only if ethanol was in the LORCA medium. RBC aggregation decreased with concentration at 0.25% and higher for cells in both autologous plasma and dextran 70. Our results indicate that ethanol reversibly improves erythrocyte deformability and irreversibly decreases erythrocyte aggregation; the relevance of these results to the health benefits of moderate wine consumption require further investigation. PMID- 23089888 TI - Moderate red wine consumption improves hemorheological parameters in healthy volunteers. AB - Pieces of epidemiological evidence have supported that moderate red wine consumption reduces the risk of cardiovascular diseases (French-paradox). Our previous in vitro experiment has demonstrated favourable hemorheological effects of red wine, alcohol-free red wine extract and ethanol. Thirty-nine healthy, non smoking male volunteers between 18-40 years were assigned into two groups: control group had drunk water, while red wine group had consumed 2 dl of red wine each day at dinner for 3 weeks. No alcohol had been drunk for one week prior to the study. Blood was obtained in the morning of the first and last day. Hematocrit (Hct), plasma (PV) and whole blood viscosity (WBV) (Hevimet 40 capillary viscometer), red blood cell (RBC) aggregation (Myrenne and LORCA aggregometer) and deformability (LORCA ektacytometer) were measured and Hct/WBV ratio was calculated to determine oxygen carrying capacity. Hct was adjusted to 40%. Hct and PV were not affected. WBV remained unchanged in controls, but it considerably decreased in the red wine group compared to the 3-week control group, while Hct/WBV ratio became significantly higher in the red wine group compared to the control (p < 0.05). RBC aggregation significantly decreased in the red wine group and became significantly lower compared to the 3-week controls (p < 0.05). Red wine significantly increased RBC deformability (p < 0.05) at high shear stress. Our results show that moderate red wine consumption has beneficial effects on hemorheological parameters which may contribute to the French-paradox. PMID- 23089889 TI - 1,5-Migration of rhodium via C-H bond activation in catalytic decyanative silylation of nitriles. AB - Unprecedented aryl-to-aryl 1,5-rhodium migration is involved in decyanative silylation of aryl cyanides bearing a tethered arene. The 1,5-migration proceeds through remote C-H bond activation. 1,5-Migration also occurs in other rhodium catalyzed reactions, including borylation and oxidative Mizoroki-Heck reactions. PMID- 23089890 TI - Analysis of 10-year nationwide population-based data on sex differences in hospitalization for heart failure. AB - Sex-related factors play an important role in the pathophysiology of heart failure (HF). However, trends in sex-related differences in hospital management for HF are not clear. We identified patients hospitalized for HF through a nationwide database (National Health Insurance in Taiwan), containing 722,272 subjects from 1999 to 2008. Higher incidences of diabetes mellitus (37 vs. 25 %, p < 0.001), thyroid dysfunction (2 vs. 0 %, p < 0.001), and transient cerebral ischemia (2 vs. 1 %, p < 0.05), as well as a lower incidence of chronic lung disease (14 vs. 22 %, p < 0.001) differentiated female HF patients from male HF patients. During this 10-year period, both percentage of HF hospitalization and age-adjusted HF rates significantly increased for total HF sample (1.92 vs. 2.49 0/00, p < 0.05, and 20.44 vs. 27.38/100,000, p < 0.05) and for female (1.76 vs. 2.86 0/00, p < 0.05, and 20.94 vs. 32.12/100,000, p < 0.05), but such changes did not occur among male patients (2.12 vs. 2.09 0/00, p > 0.05, and 19.93 vs. 22.51/100,000, p > 0.05). The age at the time of hospitalization and the length of the hospital stay increased significantly for all HF patients during the 10 year study period. However, the daily cost of hospitalization increased in males, but not in females. Compared to the survivors, patients who died were older and had a longer hospitalization and higher daily cost both in males and females. Through our analysis of the NHI database, we observed trends in factors related to hospitalization of HF patients in Taiwan that may be attributable to sex related differences in the pathophysiology and treatment strategies for HF. PMID- 23089891 TI - Left ventricular apical aneurysm following primary percutaneous coronary intervention. AB - Left ventricular apical aneurysm (LVAA) is a serious complication of acute anterior myocardial infarction (MI). The purpose of our study was to investigate the clinical features of LVAA in the primary PCI era. A total of 161 acute anterior MI patients who had primary PCI and had an echocardiogram on chronic phase were included. The development of LVAA was reviewed on chronic phase. Univariate and multivariate logistic regression analyses were performed to identify the predictors of LVAA. Primary stenting was performed in 160 patients (99.4 %). Procedural success was obtained in all patients with a final TIMI flow grade 3 obtained in 142 patients (88.2 %). LVAA developed in the chronic phase in 29 patients (18.0 %). Multivariate logistic regression analysis revealed that peak CK (500 mU/ml increase; OR 1.24, 95 % CI 1.09-1.41, p = 0.001), heart rate at discharge (5/min increase; OR 1.39, 95 % CI 1.03-1.87, p = 0.03), final TIMI flow grade <=2 (vs. TIMI 3; OR 6.95, 95 % CI 1.70-28.36, p = 0.01) and final myocardial brush grade (MBG) <=2 (vs. MBG 3; OR 4.33, 95 % CI 1.06-17.66, p = 0.04) were significantly associated with the development of LVAA. The initial TIMI flow grade or the grade of collateral flow was not associated with LVAA. In conclusion, peak CK, heart rate, and final TIMI flow grade or final MBG <=2 were significantly associated with the development of LVAA. Achieving a TIMI flow grade 3 by primary PCI may be important for preventing LVAA. PMID- 23089892 TI - Identification of very high risk octogenarians undergoing coronary artery bypass surgery: results of a multicenter study. AB - Excellent late survival is expected after coronary artery bypass (CABG) in patients aged >=80 years, but immediate postoperative mortality can be rather high. This study was planned to identify variables associated with very high operative risk in these fragile patients. This is a multicenter study including 2,246 patients aged >=80 years who underwent isolated CABG at 68 Italian hospitals. The proportion of patients aged >=80 years varied from 1.7 to 13.6 % (overall 5.6 %, p < 0.0001) in different institutions. The median logistic EuroSCORE varied from 6.2 to 31.7 % (overall median 11.3 %, p = <0.0001) in different institutions. Thirty-day mortality in patients aged >=80 years correlated with that of patients aged <80 years (rho: 0.310, p = 0.027). The overall 30-day mortality rate was 6.5 %. Both logistic regression and CART showed that emergency procedure, low left ventricular ejection fraction, unstable hemodynamics, and use of nitrates infusion at arrival in the operating room were independent predictors of 30-day mortality. CART analysis showed that 30-day mortality among patients undergoing emergency CABG with unstable hemodynamic conditions was 32.60 % and it was 20.0 % in patients undergoing non-emergency operation with nitrates infusion at arrival in the operating room and left ventricular ejection fraction <30 %. The proportion and operative risk of patients aged >=80 years and undergoing CABG significantly varied among institutions. Patients requiring emergency surgery, with unstable hemodynamic conditions, requiring nitrates infusion, and low ejection fraction have a prohibitive operative risk. This small proportion of patients may benefit from percutaneous coronary intervention in order to stabilize their preoperative conditions. PMID- 23089893 TI - Choroidal thickness in relation to hypercholesterolemia on enhanced depth imaging optical coherence tomography. AB - PURPOSE: To investigate the relationship of hypercholesterolemia and choroidal thickness in normal healthy volunteers. METHOD: This was a cross-sectional observational study. Volunteers with no ocular abnormalities were examined using enhanced depth imaging optical coherence tomography. Choroidal and retinal thicknesses were measured at the fovea, and at 4 different locations 1 mm superior, inferior, temporal, and nasal to the fovea. Subjects were further divided into those with hypercholesterolemia (Group 1) and normal control subjects (Group 2) for subgroup analysis regarding the effect of hypercholesterolemia on choroidal thickness. Subjects with hypertension and diabetes were excluded. RESULTS: A total of 322 eyes of 161 subjects were studied. Mean age was 59.9 years (range, 24-84 years). The mean subfoveal choroidal thickness was 261 +/- 98.7 MUm. Mean subfoveal choroidal thickness negatively correlated with age (r = -0.326; P = 0.001). The mean serum total cholesterol was 5.02 +/- 0.98 mmol/L. In Group 1, it was 5.65 +/- 1.15 mmol/L, while in Group 2, it was 4.72 +/- 0.73 mmol/L. The difference was statistically significant (P = 0.003). Subjects in Group 1 tended to be older and have worse vision, although the difference did not reach statistical significance. The mean subfoveal choroidal thickness in Group 1 was 306 +/- 111 MUm, while that in Group 2 was 258 +/- 97 MUm. The difference was statistically significant (P = 0.041). The same difference was also found at the 1 mm nasal (P = 0.041) and 1 mm superior (P = 0.040). CONCLUSION: The subfoveal choroidal thickness was found to be significantly higher in subjects with hypercholesterolemia. This has to be taken into account when analyzing choroidal thickness. PMID- 23089894 TI - A national survey on myocarditis associated with influenza H1N1pdm2009 in the pandemic and postpandemic season in Japan. AB - An influenza pandemic occurred in 2009. We performed a retrospective national questionnaire survey about H1N1pdm2009 myocarditis to compare influenza A H1N1pdm2009 myocarditis in the pandemic (2009/2010) and postpandemic seasons (2010/2011) by collecting data from 360 hospitals. The diagnosis of myocarditis was performed using the guidelines for Diagnosis and Treatment of Myocarditis published by the Japanese Circulation Society (JCS 2009). Twenty-nine patients with influenza A H1N1pdm2009 myocarditis were reported, with 25 from the 2009/2010 season and only 4 patients from the 2010/2011 season. Morbidity and mortality was 28 % (8/29) among all the myocarditis patients. Six patients with myocarditis were complicated by pneumonia. Myocarditis was proved by endomyocardial biopsy or autopsy in 9 patients, although histological findings showed mild myocarditis even in clinically defined fulminant myocarditis cases. Seventeen patients were diagnosed with fulminant H1N1pdm2009 myocarditis with fatal arrhythmias or varying degrees of cardiogenic shock. Fifteen fulminant myocarditis patients were seen in the 2009/2010 season and only 2 in the 2010/2011 season. Ventilators were used in 16 patients. Mechanical circulatory support with intraaortic balloon pumping or percutaneous cardiopulmonary support (IABP/PCPS) was emergently inserted in 13 patients. Of these, 9 patients were rescued with mechanical circulatory support, and 4 patients died. Four fulminant myocarditis patients treated without IABP/PCPS died. We described the clinical features of patients with myocarditis associated with influenza H1N1pdm2009 in the pandemic and postpandemic seasons and demonstrated the high prevalence of fulminant myocarditis (17/29, 59 %). The number of patients with myocarditis associated with influenza A virus seemed to increase in the pandemic season. PMID- 23089895 TI - Bactericidal activity of garenoxacin against in vitro biofilm formed by nontypeable Haemophilus influenzae. AB - Using beta-lactamase-negative ampicillin (ABPC)-susceptible (BLNAS) and beta lactamase-negative ABPC-resistant (BLNAR) nontypeable Haemophilus influenzae (NTHi) strains isolated from otological patients, colony biofilm was prepared on membrane filter substrates. Bactericidal activities of garenoxacin (GRNX), levofloxacin (LVFX), cefditoren (CDTR), and clavulanic acid/amoxicillin (CVA/AMPC) were examined by counting viable cells after drug exposure to biofilm cells for 6 and 24 h and by observation under a scanning electron microscope (SEM). After exposure of biofilm to the 100-fold MIC of GRNX or LVFX for 24 h, GRNX and LVFX showed potent bactericidal activity (?log10 CFU/ml, >=5.1). In this case, the drug-exposure AUC, exposure concentration * 24 MUg h/ml, was 64-128 % for GRNX and 121 % for LVFX of free AUC at the clinical dosage in humans, respectively. CDTR and CVA/AMPC at 100-fold MIC exhibited little bactericidal activity against biofilm cells. Under an SEM, after exposure of BLNAS and BLNAR biofilms to GRNX or LVFX, most of the biofilm matrices were transformed. Quinolones such as GRNX show potent bactericidal activity against biofilm-forming NTHi at the usual clinical dosage. PMID- 23089896 TI - ATP binding cassette transporters in two distinct compartments of the skin contribute to transdermal absorption of a typical substrate. AB - The role of two ATP binding cassette transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in transdermal absorption of a typical common substrate was examined in vivo. Skin and plasma concentrations of rhodamine123 (Rho123) after dermal application were reduced in P-gp knockout (mdr1a/1b-/-) mice and were below the detection limit in P-gp and BCRP triple knockout (mdr1a/1b/bcrp-/-) mice. Lower epidermal-to-hypodermal permeation of Rho123 in mdr1a/1b/bcrp-/- mouse skin compared to the wild-type mouse skin was confirmed in an Ussing-type chamber experiment. The reduction in skin concentration after dermal application in mdr1a/1b/bcrp-/- mice was greater in the dermis than in the epidermis, suggesting functional expressions of these transporters in two distinct skin compartments. Coadministration of the inhibitor itraconazole reduced the skin and plasma concentrations of Rho123 in the wild type mice, but not in mdr1a/1b/bcrp-/- mice, and a marked decrease of Rho123 concentration was seen in the dermis, demonstrating that the functional activities of these transporters can be modulated in vivo. On the other hand, the distribution of Rho123 after intravenous infusion was higher in mdr1a/1b/bcrp-/- mice than in the wild-type mice. This supports the occurrence of vectorial transport from the skin into systemic circulation, and is consistent with the immunohistochemical localization of P-gp and BCRP in mouse dermal endothelial cells. BCRP was immunohistochemically identified in human epidermis and dermal endothelial cells. Thus, our findings show that ABC transporters in different compartments of the skin contribute to transdermal absorption of a typical substrate in vivo and can be modulated by a specific inhibitor. These findings have implications for transdermal drug delivery. PMID- 23089897 TI - [Everything has its place: ideal location for cerebral oximetry]. PMID- 23089898 TI - Characterization of early repolarization during ajmaline provocation and exercise tolerance testing. AB - BACKGROUND: Early repolarization (ER) in the inferior electrocardiogram leads is associated with idiopathic ventricular fibrillation, but the majority of subjects with ER have a benign prognosis. At present, there are no risk stratifiers for asymptomatic ER. OBJECTIVE: To examine the response to ajmaline provocation and exercise in potentially high-risk subjects with ER and without a definitive cardiac diagnosis. METHODS: Electrocardiographic data were reviewed for ER at baseline and during ajmaline and exercise testing in 229 potentially high-risk patients (mean age 37.7+/-14.9 years; 55.9% men). ER was defined as J-point elevation in >=2 consecutive leads and stratified by type, territory, J-point height, and ST-segment morphology. RESULTS: Baseline ER was present in 26 (11.4%; 19 men) patients. During ajmaline provocation and exercise, there were no new ER changes. ER with rapidly ascending ST-segment and lateral ER consistently diminished. There were 7 patients with persistent ER during ajmaline and/or exercise. They were all men with inferior or inferolateral ER and horizontal/descending ST segment. Those with persistent ER during exercise were more likely to have a history of unexplained syncope than those in whom ER changes diminished (P<.01). Subtle nondiagnostic structural abnormalities were demonstrated in 3 of these patients. CONCLUSIONS: ER with horizontal/descending ST-segment morphology in the inferior or inferolateral leads that persists during exercise is more common in patients with prior unexplained syncope and may identify patients at higher risk of arrhythmic events. ER that persists during ajmaline provocation and/or exercise may reflect underlying subtle structural abnormalities and should prompt further investigation. PMID- 23089899 TI - Catheter ablation of ventricular tachycardia using intracoronary wire mapping and coil embolization: description of a new technique. PMID- 23089901 TI - Knowledge about and use of pharmacological and non-pharmacological headache therapies. AB - OBJECTIVE: To analyse knowledge and use of pharmacological and non pharmacological therapies in headache patients referred to a tertiary headache centre. METHODS: We included 114 consecutive patients referred by a neurologist and asked them to fill out a comprehensive questionnaire immediately before their first appointment at our outpatient headache clinic. The questionnaire covered 23 compounds for acute treatment, 21 prophylactic drugs, and 30 complementary and alternative treatments. RESULTS: The proportion of patients who knew at least one acute therapy stood at 92 %; 62 % knew at least one pharmaco-prophylaxis and 80 % knew at least one non-pharmacological treatment. Even though 87 % of the patients with migraine had 3 4 disabling headache days per month, only 41 % had used triptans and not more than 19 % had taken drugs of first choice for migraine prophylaxis for at least 3 months. In contrast, 75 % had used complementary or alternative treatments. Univariate analyses showed several predictors for the use of pharmaco-prophylaxis and non-pharmacological treatment, of which only knowledge about pharmaco-prophylaxis predicted use of alternative treatments in multivariate analysis. CONCLUSION: In Austria, a significant proportion of patients suffering from frequent recurrent headaches or migraines who are referred to a tertiary headache centre do not know and do not use triptans and pharmacological prophylaxis, while there is obviously broad acceptance and frequent use of mostly questionable alternative treatments. Improvement of primary and secondary care as well as patient education is desirable. PMID- 23089902 TI - Failure of clinical practice guidelines to meet institute of medicine standards: Two more decades of little, if any, progress. AB - BACKGROUND: In March 2011, the Institute of Medicine (IOM) issued a new set of standards for clinical practice guidelines intended to enhance the quality of guidelines being produced. To our knowledge, no systematic review of adherence to such standards has been undertaken since one published over a decade ago. METHODS: Two reviewers independently screened 130 guidelines selected at random from the National Guideline Clearinghouse (NGC) website for compliance with 18 of 25 IOM standards. RESULTS: The overall median number (percentage) of IOM standards satisfied (out of 18) was 8 (44.4%), with an interquartile range of 6.5 (36.1%) to 9.5 (52.8%). Fewer than half of the guidelines surveyed met more than 50% of the IOM standards. Barely a third of the guidelines produced by subspecialty societies satisfied more than 50% of the IOM standards surveyed. Information on conflicts of interest (COIs) was given in fewer than half of the guidelines surveyed. Of those guidelines including such information, COIs were present in over two-thirds of committee chairpersons (71.4%) and 90.5% of co chairpersons. Except for US government agency-produced guidelines, criteria used to select committee members and the selection process were rarely described. Committees developing guidelines rarely included an information scientist or a patient or patient representative. Non-English literature, unpublished data, and/or abstracts were rarely considered in developing guidelines; differences of opinion among committee members generally were not aired in guidelines; and benefits of recommendations were enumerated more often than potential harms. Guidelines published from 2006 through 2011 varied little with regard to average number of IOM standards satisfied. CONCLUSION: Analysis of a random sample of clinical practice guidelines archived on the NGC website as of June 2011 demonstrated poor compliance with IOM standards, with little if any improvement over the past 2 decades. PMID- 23089903 TI - Faculty perceptions and practices regarding carrying concealed handguns on university campuses. AB - The presence of firearms in an environment significantly increases firearm trauma. So far, four states have passed legislation permitting the carrying of concealed handguns on university campuses and several other states are considering such legislation. The purpose of this study to assess the perceptions and practices of college faculty regarding support for carrying concealed handguns on their campuses. A valid and reliable questionnaire was sent to a random sample of 1,125 faculty at 15 randomly selected state universities in five Great Lakes states. A two wave postal mailing in the Spring of 2012 was conducted to help ensure an adequate response rate. A total of 791 (70 %) of the faculty responded. The vast majority felt safe on their campuses (98 %) and were not supportive of people carrying concealed handguns on their campuses (94 %). Seven of the eight potential disadvantages of carrying concealed handguns on campus were supported by the majority of faculty members. Those who were significantly more likely to perceive there to be disadvantages to carrying concealed handguns on campus were: those who did not own a firearm (OR = 4.89), Democrats (OR = 4.52) or Independents (OR = 2.25), Asians (OR = 2.49), and females (OR = 1.51). The vast majority of faculty felt safe on their campuses and perceived that carrying concealed handguns on campuses create more risks than benefits to the campus environment. Aggressive efforts are needed to help maintain the uniquely safe environment of college campuses. PMID- 23089905 TI - ATP cleavage by cone tetraguanidinocalix[4]arene. AB - The upper rim cone tetraguanidinocalix[4]arene 1 is a highly effective catalyst of ATP hydrolysis. The catalytically most active species is the triprotonated form of the catalyst. The three protonated guanidinium groups provide the electrostatic driving force for substrate binding and activation, while the neutral guanidine most likely acts as a nucleophilic catalyst. PMID- 23089906 TI - [Updated guidelines 2012 for gastroesophageal reflux disease]. AB - In 2010, a Korean guideline for the management of gastroesophageal reflux disease (GERD) was made by the Korean Society of Neurogastroenterology and Motility, in which the definition and diagnosis of GERD were not included. The aim of this guideline was to update the clinical approach to the diagnosis and management of GERD in adult patients. This guideline was developed by the adaptation process of the ADAPTE framework. Twelve guidelines were retrieved from initial queries through the Appraisal of Guidelines for Research & Evaluation II process. Twenty seven statements were made as a draft and revised by modified Delphi method. Finally, 24 consensus statements for the definition (n=4), diagnosis (n=7) and management (n=13) of GERD were developed. Multidisciplinary experts participated in the development of the guideline, and the external review of the guideline was conducted at the finalization phase. PMID- 23089907 TI - [The prevalence of Barrett's esophagus and the comparison of Barrett's esophagus with cardiac intestinal metaplasia in the health screening at a secondary care hospital]. AB - BACKGROUND/AIMS: The purpose of this study was to estimate the prevalence of Barrett's esophagus (BE) and its association with reflux esophagitis (RE) and peptic ulcer disease detected by free charge endoscopy which was covered by the National Health Insurance at a secondary care hospital, and to compare the results of the biopsy of BE with that of cardiac intestinal metaplasia (CIM). METHODS: A total of 4,002 patients underwent endoscopy from March 2010 to December 2012. BE was diagnosed if there was histologically proven specialized intestinal metaplasia, and CIM was diagnosed if intestinal metaplasia was accompanied with chronic gastritis. RESULTS: Four hundred twenty four patients underwent endoscopic biopsy, and the prevalence of BE was 1.0% (42/4,002). The mean age and the proportion of males in BE were significantly higher than those of the rest of study population, and BE had slight tendency related to RE than the rest of study population. CIM was observed in 34 patients and BE and CIM showed similar results, regarding age, sex and association with RE. The mean length of endoscopic Barrett's mucosa of BE group was 9.2+/-5.1 mm, and it was similar to that of CIM. CONCLUSIONS: The prevalence of BE in the secondary care hospital was not low, and old age and male sex were significantly associated with BE. Because BE was observed in about 10% of biopsied patients and CIM was observed in a similar percentage with BE, the precise targeted biopsy is warranted and the biopsy method should be reestablished through the large prospective study of multiple secondary care hospitals. PMID- 23089908 TI - [The natural course of early gastric cancer]. AB - BACKGROUND/AIMS: Early gastric cancer (EGC) has a relatively long natural course compared to advanced gastric cancer (AGC). But, few studies about the natural course of EGC are currently available in the literature. In this study we investigated the natural course of EGC in patients who did not receive any treatment. METHODS: All patients diagnosed with gastric cancer on endoscopy at Kosin University Gospel Hospital between January 2001 and December 2010 were reviewed. Those among them who had EGC and did not receive any treatment were enrolled, and an analysis was performed. RESULTS: Twenty seven patients were enrolled. Nine of the enrolled patients were women and the median age was 73 years (range, 38-95). Initial endoscopic findings revealed 11 cases of protruded type, 16 cases of flat and depressed type. Histopathologic analysis indicated that there were 14 cases of well and moderately differentiated adenocarcinoma, 6 cases of poorly differentiated adenocarcinoma and signet ring cell carcinoma. Twelve patients underwent follow-up endoscopy and three of them developed AGC within a mean of 9.6 months (range, 5-12 months). Overall median survival time was 40 months and the 5-year survival rate was 45%. CONCLUSIONS: Although there were some differences in EGC progression, patients who did not receive any treatment progressed eventually. We were unable to identify specific factors predictive of median survival time in these patients. PMID- 23089909 TI - Significance of preoperative tissue levels of vascular-endothelial cadherin, liver-intestine cadherin and vascular endothelial growth factor in gastric cancer. AB - BACKGROUND/AIMS: The aims of this study were to examine the expressions of endothelium specific VE-cadherin, intestine specific LI-cadherin, and vascular endothelial growth factor (VEGF), and to determine their relationships with the clinicopathological parameters of gastric cancer. METHODS: A total 47 patients with gastric cancer who underwent surgery were enrolled. Endoscopic biopsies were obtained from the cancer and normal mucosa, respectively. Using semiquantitative RT-PCR, the mRNA expression levels of VE-cadherin, LI-cadherin and VEGF were measured by tumor/normal (T/N) ratios. The protein expressions of VE-cadherin, LI cadherin and VEGF were examined by Western blot and immunohistochemical stain in surgically resected tissues. The clinicopathological variables were reviewed and analyzed, retrospectively. RESULTS: Twenty two cases (46.8%) of VE-cadherin, 25 cases (53.2%) of LI-cadherin and 27 cases (51.1%) of VEGF mRNA expressions were overexpressed in gastric cancer compared to normal tissue. There was a tendency for T/N ratio of VE-cadherin mRNA to correlate with the lymphatic invasion (p=0.07) and the lymph node metastasis (p=0.099) in advanced gastric cancer. The T/N ratio of LI-cadherin mRNA showed significant association with distant metastasis (p=0.031) and lymphatic invasion especially in advanced gastric cancer (p=0.023). There was a tendency for the T/N ratio of VEGF mRNA to correlate with the distant metastasis (p=0.073) in advanced gastric cancer. CONCLUSIONS: As increased mRNA expression of LI-cadherin was associated with distant metastasis and lymphatic invasion especially in the biopsy specimen of advanced gastric cancer before surgery, it may provide useful preoperative information on tumor aggressiveness. PMID- 23089910 TI - [Hepatic angiomyolipoma with variable histologic features: 8 cases resembling hepatocellular carcinoma or inflammatory pseudotumor]. AB - BACKGROUND/AIMS: Hepatic angiomyolipoma (AML) is a rare mesenchymal tumor of the liver and demonstrates a marked histologic diversity. HMB-45 is a promising immunomarker for this tumor and especially helpful to diagnosis of some AMLs with unusual morphology. The purpose of this study was to better define the variable histologic feature of hepatic AML. METHODS: Eight hepatic AMLs were examined, and all of that were resection specimens. The diagnosis was confirmed by the presence of HMB-45 positive cells. Median age was 41.5 years old, and mean size of tumor was 8.94 cm. RESULTS: Conventional mixed type was 5 cases which showed myomatous, angiomatous and lipomatous component, and 3 cases were myomatous predominant. Variable patterns including spider web cell morphology, solid sheet-like and trabecular pattern were identified on myomatous component and variable amount and patterns of inflammatory cell infiltration was identified. CONCLUSIONS: With only histologic features, it is difficult to distinguish hepatic AML from other hepatic tumor including hepatocellular carcinoma or inflammatory pseudotumor. A correct diagnosis of hepatic AML is possible by a close histologic examination with immunohistochemical stainings such as HMB-45 which is important to patient's prognosis. PMID- 23089911 TI - [A case of conservatively resolved intramural esophageal dissection combined with pneumomediastinum]. AB - Intramural esophageal dissection (IED) is a rare form of esophageal injury. We report a rare case of spontaneous IED complicated with pneumomediastinum and successfully improved by conservative management. A 46-year-old man presented to the emergency department with chest pain and hematemesis. The endoscopic diagnosis was suspicious of IED. Chest CT scan performed to rule out complication noted IED combined with pneumomediastinum. He was managed conservatively with nil per oral, intravenous antibiotics and parenteral nutrition. Follow up study after 2 weeks later showed near complete resolution of IED. IED should be included in the differential diagnosis for unexplained acute chest pain, especially, associated with dysphagia and hematemesis. IED with pneumomediastinum or mediastinitis require prompt surgery. So far, there is no case report of IED combined with pneumomediastinum which resolved without surgical treatment. In this case, IED combined with pneumomediastinum has improved by conservative management, so we present a case report. PMID- 23089912 TI - Massive life-threatening lower gastrointestinal hemorrhage caused by an internal hemorrhoid in a patient receiving antiplatelet therapy: a case report. AB - A Dieulafoy lesion in the rectum is a very rare and it can cause massive lower gastrointestinal bleeding. An 83-year-old man visited our hospital. He had chronic constipation and had taken aspirin for about 10 years because of a previous brain infarction. He was admitted because of a recent brain stroke. On the third hospital day, he had massive hematochezia and suddenly developed hypovolemic shock. Abdominal computed tomography showed active arterial bleeding on the left side of the mid-rectum. Emergency sigmoidoscopy showed an exposed vessel with blood spurting from the rectal wall. The active bleeding was controlled successfully by an injection of epinephrine and two hemoclippings. On the fourth day after the procedure, he had massive recurrent hematochezia, and his vital signs were unstable. Doppler-guided hemorrhoidal artery band ligation was performed urgently at two sites. However, he rebled on the third postoperative day. Selective inferior mesenteric angiography revealed an arterial pseudoaneurysm in a branch of the superior rectal artery, as the cause of rectal bleeding, and this was embolized successfully. We report a rare case of life threatening rectal bleeding caused by a Dieulafoy lesion combined with pseudoaneurysm of the superior rectal artery which was treated successfully with embolization. PMID- 23089913 TI - A case of intraperitoneal immunoglobulin G4-related inflammatory pseudotumor. AB - The term inflammatory pseudotumor (IPT) has been used to describe inflammatory and fibrosing tumoral processes of an undetermined cause that may involve a variety of organ system. IgG4-related disease is a newly recognized fibroinflammatory condition characterized by IgG4-producing plasma cell expansion in affected organs and, often but not always, elevated serum IgG4 concentrations. IgG4-related IPTs, a subtype of IPT, are characterized by dense infiltration of IgG4-positive plasma cells and stromal fibrosis. The association between inflammatory pseudotumor and IgG4 was first reported with a regard to sclerosing pancreatitis. Despite there are many reports on intraperitoneal IPTs including both cellular and lymphoplasmacytic type, only a few cases have been confirmed to be IgG4-related. We experienced a case of intraperitoneal IgG4-related inflammatory pseudotumor in an 83-year-old woman presenting with epigastric pain and malaise. Surgical specimens revealed an IgG4-related inflammatory pseudotumor. PMID- 23089914 TI - [A case of hepatic metastasis of gastric hepatoid adenocarcinoma mistaken for primary hepatocellular carcinoma]. AB - Gastric hepatoid adenocarcinoma is a special type of gastric carcinoma, which produces AFP. We report a case of an metastatic gastric hepatoid adenocarcinoma mistaken for primary hepatocellular carcinoma (HCC). A 72 year-old woman was transferred to our hospital for treatment of the hepatic mass. She underwent subtotal gastrectomy for gastric cancer 2 years ago. A year ago, she was diagnosed with hepatic mass and treated with transhepatic chemoembolization under the suspicion of primary HCC in other hospital. The hepatic mass looked like primary HCC on CT, and serum AFP was elevated to 18,735 IU/mL. We did the transhepatic mass biopsy and compared it to the histology of the previous gastric cancer. The results of immunohistochemical staining between them was coincident, and so it was diagnosed as a hepatic metastasis of gastric hepatoid adenocarcinoma. PMID- 23089915 TI - Fas activates lipolysis in a Ca2+-CaMKII-dependent manner in 3T3-L1 adipocytes. AB - Fas (CD95) is a member of the tumor necrosis factor (TNF) receptor superfamily and plays a crucial role in the induction of apoptosis. However, like TNF, Fas can induce nonapoptotic signaling pathways. We previously demonstrated that mice lacking Fas specifically in adipocytes are partly protected from diet-induced insulin resistance, potentially via decreased delivery of FAs to the liver, as manifested by lower total liver ceramide content. In the present study, we aimed to delineate the signaling pathway involved in Fas-mediated adipocyte lipid mobilization. Treatment of differentiated 3T3-L1 adipocytes with membrane-bound Fas ligand (FasL) significantly increased lipolysis after 12 h without inducing apoptosis. In parallel, Fas activation increased phosphorylation of ERK1/2, and FasL-induced lipolysis was blunted in the presence of the ERK-inhibitor U0126 or in ERK1/2-depleted adipocytes. Furthermore, Fas activation increased phosphorylation of the Ca(2+)/calmodulin-dependent protein kinases II (CaMKII), and blocking of the CaMKII-pathway (either by the Ca(2+) chelator BAPTA or by the CaMKII inhibitor KN62) blunted FasL-induced ERK1/2 phosphorylation and glycerol release. In conclusion, we propose a novel role for CaMKII in promoting lipolysis in adipocytes. PMID- 23089916 TI - Structural basis of specific interactions of Lp-PLA2 with HDL revealed by hydrogen deuterium exchange mass spectrometry. AB - Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), specifically Group VIIA PLA(2), is a member of the phospholipase A(2) superfamily and is found mainly associated with LDL and HDL in human plasma. Lp-PLA(2) is considered as a risk factor, a potential biomarker, a target for therapy in the treatment of cardiovascular disease, and evidence suggests that the level of Lp-PLA(2) in plasma is associated with the risk of future cardiovascular and stroke events. The differential location of the enzyme in LDL/HDL lipoproteins has been suggested to affect Lp-PLA(2) function and/or its physiological role and an abnormal distribution of the enzyme may correlate with diseases. Although a mutagenesis study suggested that a surface helix (residues 362-369) mediates the association between Lp-PLA(2) and HDL, the molecular details and mechanism of association has remained unknown. We have now employed hydrogen deuterium exchange mass spectrometry to characterize the interaction between recombinant human Lp-PLA(2) and human HDL. We have found that specific residues 113-120, 192 204, and 360-368 likely mediate HDL binding. In a previous study, we showed that residues 113-120 are important for Lp-PLA(2)-liposome interactions. We now find that residues 192-204 show a decreased deuteration level when Lp-PLA(2) is exposed to apoA-I, but not apoA-II, the most abundant apoproteins in HDL, and additionally, residues 360-368 are only affected by HDL.The results suggest that apoA-I and phospholipid membranes play crucial roles in Lp-PLA(2) localization to HDL. PMID- 23089917 TI - Inverse design of molecules with optimal reactivity properties: acidity of 2 naphthol derivatives. AB - The design of molecules with optimal properties is an important challenge in chemistry because of the astronomically large number of possible stable structures that is accessible in chemical space. This obstacle can be overcome through inverse molecular design. In inverse design, one uses the computation of certain indices to design molecules with an optimal target property. In this study, for the first time, inverse design was used to optimize reactivity properties of molecules. Specifically, we optimized the acidity of substituted 2 naphthols, both in the ground and the excited state. Substituted 2-naphthols belong to the class of photoacids, showing enhanced acidity when excited from the singlet ground state to the first singlet excited state. The focus of this work is the ground state. As a measure of acidity, three different properties are optimized: the charge on the hydroxyl hydrogen atom of the acid, the charge on the negatively charged oxygen atom of the conjugate base and the energy difference between acid and conjugate base. Both the practical use of the methodology and the results for ground and excited states are discussed. PMID- 23089918 TI - Fabrication and characterization of nanostructured ZnO thin film microdevices by scanning electrochemical cell microscopy. AB - Scanning electrochemical cell microscopy (SECCM) was proven to be a prospective microfabrication method for the in situ synthesis and multiscale assembly of functional nanomaterials into microdevices. Nanostructured ZnO thin film was synthesized and assembled by SECCM, which has excellent electrochemical capacitance and electronic I-V properties. PMID- 23089919 TI - Depolarization-induced automaticity in rat ventricular cardiomyocytes is based on the gating properties of L-type calcium and slow Kv channels. AB - Depolarization-induced automaticity (DIA) of cardiomyocytes is the property of those cells to generate pacemaker cell-like spontaneous electrical activity when subjected to a depolarizing current. This property provides a candidate mechanism for generation of pathogenic ectopy in cardiac tissue. The purpose of this study was to determine the biophysical mechanism of DIA in terms of the ion conductance properties of the cardiomyocyte membrane. First, we determined, by use of the conventional whole-cell patch-clamp technique, the membrane conductance and DIA properties of ventricular cardiomyocytes isolated from adult rat heart. Second, we reproduced and analysed DIA properties by using an adapted version of the experimentally based mathematical cardiomyocyte model of Pandit et al. (Biophys J 81:3029-3051 2001, Biophys J 84:832-841 2003) and Padmala and Demir (J Cardiovasc Electrophysiol 14:990-995 2003). DIA in 23 rat cardiomyocytes was a damped membrane potential oscillation with a variable number of action potentials and/or waves, depending on the strength of the depolarizing current and the particular cell. The adapted model was used to reconstruct the DIA properties of a particular cardiomyocyte from its whole-cell voltage-clamp currents. The main currents involved in DIA were an L-type calcium current (I CaL) and a slowly activating and inactivating Kv current (I ss), with linear (I B) and inward rectifier (I K1) currents acting as background currents and I Na and I t as modulators. Essential for DIA is a sufficiently large window current of a slowly inactivating I CaL combined with a critically sized repolarizing current I ss. Slow inactivation of I ss makes DIA transient. In conclusion, we established a membrane mechanism of DIA primarily based on I CaL, I ss and inward rectifier properties; this may be helpful in understanding cardiac ectopy and its treatment. PMID- 23089920 TI - Susceptibility to toxoplasmic retinochoroiditis is associated with HLA alleles reported to be implicated with rapid progression to AIDS. AB - BACKGROUND/AIMS: The frequency of HLA markers associated with rapid progression to AIDS was evaluated in Brazilian patients with AIDS exhibiting or not toxoplasmic retinochoroiditis (TRC). METHODS: 98 AIDS patients (25 with TRC, 43 with anti-T. gondii antibodies but without TCR, and 30 without anti-T. gondii antibodies and without TCR) were studied. RESULTS: The HLA-B35 was significantly increased in TRC group (p=0.0038). CONCLUSION: The presence of HLA-B35 may simultaneously predispose to progression to AIDS and TRC. PMID- 23089921 TI - Common oxytocin receptor gene polymorphisms and the risk for preterm birth. AB - Oxytocin is crucially involved in the onset and maintenance of labor. We investigated the association between oxytocin receptor gene polymorphisms and preterm birth. The presence of four common oxytocin receptor gene polymorphisms (rs2254298, rs53576, rs2228485 and rs237911) was evaluated in one hundred women with preterm birth and one hundred healthy women using restriction fragment length polymorphism genotyping. No association was found between the presence of any individual oxytocin receptor gene polymorphism and preterm birth. In haplotype analysis, the haplotype combination of rs2254298 A allele, rs2228485 C allele and rs237911 G allele was found to be significantly associated with an increased risk of preterm birth (OR=3.2 [CI 1.04-9.8], p=0.043). In conclusion our findings suggest that a combination of three oxytocin receptor gene polymorphisms is associated with an increased risk for preterm birth. We propose further studies investigating the role of oxytocin receptor gene polymorphisms and preterm birth. PMID- 23089922 TI - Decrease in antioxidant status of plasma and erythrocytes from geriatric population. AB - BACKGROUND: Ageing is associated with an accumulation of free radical damage, which leads to physiological and clinical modifications. The study aims to find out the status of lipid profile, antioxidant enzymes, malondialdehyde in geriatric population. PATIENTS/METHODS: The study was conducted on 150 subjects (75 healthy control between the ages of 20-30 years and 75 elderly subjects between ages of 50-70 years as cases). The following parameters were analyzed using the standard reference methods: lipid profile, reduced glutathione, glutathione peroxidase, glutathione reductase, catalase, superoxide dismutase and malondialdehyde. RESULTS: The present study was conducted to estimate the oxidative stress parameters in geriatric population. Highly significant increase in total cholesterol (TC), triglyceride (TG), LDL-cholesterol (LDL-C), VLDL cholesterol (VLDL-C), malondialdehyde, catalase and decrease in high density lipoprotein cholesterol (HDL-C), reduced glutathione, glutathione peroxidase, glutathione reductase, superoxide dismutase was observed in geriatrics when compared with their younger counterparts. CONCLUSION: This study concluded that there is enhanced oxidative stress and decreased antioxidant defence in geriatrics as compared to younger subjects which could play an important role in ageing. Dyslipidemia has become one of the important risk factors for the increasing prevalence of cardiovascular diseases. There is lack of awareness on the relationship between blood lipids and the risk of cardiovascular diseases in geriatric population. The strategy of early prevention should be adopted against dyslipidemia. PMID- 23089923 TI - Maternal SNPs in the p53 pathway: risk factors for trisomy 21? AB - The p53 family and its regulatory pathway play an important role as regulators of developmental processes, limiting the propagation of aneuploid cells. Its dysfunction or imbalance can lead to pathological abnormalities in humans. The aim of this study was to evaluate the effect of maternal polymorphisms TP53 c.215G>C (P72R), TP73 4 c.-30G>A and 14 c.-20C>T, MDM2 c.14+309T>G (SNP309), MDM4 c.753+572C>T and USP7 c.2719-234G>A as risk factors for Down Syndrome (DS) birth. A case-control study was conducted with 263 mothers of DS children and 196 control mothers. The distribution of these genotypic variants was similar between case and control mothers. However, the combined alleles TP53 C and MDM2 G, and P53 C and USP7 A increased the risk of having offspring with DS (OR=1.84 and 1.77; 95% CI; P < 0.007 and 0.018, respectively). These results suggest that, although the individual polymorphisms were not associated with DS birth, the effect of the combined genotypes among TP53, MDM2 and USP7 genes indicates a possible role of TP53 and its regulatory pathway as a risk factor for aneuploidy. PMID- 23089924 TI - MTHFR gene C677T mutation and ACE gene I/D polymorphism in Turkish patients with osteoarthritis. AB - Osteoarthritis is a degenerative joint disorder resulting in destruction of articular cartilage, osteophyte formation, and subchondral bone sclerosis. In recent years, numerous genetic factors have been identified and implicated in osteoarthritis. The aim of the current study was to examine the influence of methylenetetrahydrofolate reductase (MTHFR) gene C677T mutation and angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) variations on the risk of osteoarthritis. Genomic DNA is obtained from 421 persons (221 patients with osteoarthritis and 200 healthy controls). ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction using I and D allele-specific primers. The MTHFR C677T mutation was analyzed by polymerase chain reaction (PCR) based restriction fragment length polymorphism (RFLP) methods. We found significant difference between the groups with respect to both ACE and MTHFR genotype distributions (p< 0.001, p< 0.001 respectively). Our study suggests that ACE gene DD genotype and MTHFR gene CC genotype could be used as genetic markers in osteoarthritis in Turkish study populations. PMID- 23089925 TI - Oxidized low-density lipoprotein cholesterol and the ratio in the diagnosis and evaluation of therapeutic effect in patients with coronary artery disease. AB - OBJECTIVE: The purpose of the present study was to investigate the value of ox LDL and oxidation ratio of LDL (ox-LDL/TC, ox-LDL/HDL-C and ox-LDL/LDL-C) in diagnosis and prognosis evaluation in CAD patients. Also, we aimed to observe the effect of statins on reducing level of ox-LDL and oxidation ratio of LDL, and explore whether statins still have similar effect on ox-LDL in a short period of therapy (within 2 weeks). METHODS: Blood ox-LDL, TC, HDL-C, LDL-C, and TG were measured in cases with acute myocardial infarction (AMI, n=177), unstable angina pectoris (UAP, n=195), stable angina pectoris (SAP, n=228), normal control (n=120), and high risk control (n=140). RESULTS: Mean value of ox-LDL and oxidation ratio of LDL was significantly higher in the CAD group than in the two control groups. The AUC of ROC curve of ox-LDL, ox-LDL/TC, ox-LDL/HDL-C, ox LDL/LDL-C and apoA1/apoB were more than 0.50 (P < 0.001). Multivariate logistic regression analysis showed that age and ox-LDL/LDL-C related with short-term, while ox-LDL/LDL-C and ox-LDL/TC related with long-term prognosis (p < 0.05). Furthermore, after treatment with statins for 2 weeks, TC, LDL-C, ox-LDL, ox LDL/TC, ox-LDL/HDL-C and ox-LDL/LDL-C decreased by 22%, 28%, 38%, 29%, 23% and 25% respectively. And the reduction of ox-LDL by statins is independent of lowering of LDL-C and TC. CONCLUSIONS: Ox-LDL and oxidation ratio of LDL are closely related with AS, and they are better biomarkers for discriminating between patients with coronary artery disease and healthy subjects. In addition, statins can decrease level of ox-LDL significantly, which is independent of lowering of LDL-C and TC. PMID- 23089926 TI - Association of the HindIII and S447X polymorphisms in LPL gene with hypertension and type 2 diabetes in Mexican families. AB - Lipoprotein lipase (LPL) is a key enzyme in lipid metabolism and is associated with obesity, dyslipidemias, hypertension (HTN) and type 2 diabetes mellitus (T2DM). LPL gene polymorphisms can be related with the development of cardiovascular risk factors. The present study was conducted to analyze the relationship of the HindIII and S447X polymorphisms in LPL gene with cardiovascular risk factors in Mexican families. The study population comprised ninety members of 30 Mexican families, in which an index case had obesity, were included in the study. We evaluated the body composition by bioelectrical impedance. Peripheral blood samples were collected to determine biochemical parameters. Screening for both polymorphisms was made by PCR-RFLPs. In the parents, both polymorphisms were in Hardy-Weinberg's equilibrium. We found that the genotype T/T of HindIII was associated with diastolic blood pressure >= 85 mmHg (OR=1.1; p=0.011), whereas the genotype C/C of S447X was associated with systolic blood pressure >= 130 mmHg (OR=1.2; p<0.001), diastolic blood pressure >= 85 mmHg (OR = 1.3; p< 0.001), T2DM (OR=1.3; p< 0.001) and with increase of total cholesterol (beta =23.6 mg/mL; p=0.03). These data suggest that the HindIII and S447X LPL gene polymorphisms can confer susceptibility for the development of hypertension and T2DM in Mexican families. PMID- 23089927 TI - Measuring protein synthesis with SUnSET: a valid alternative to traditional techniques? AB - Protein synthesis rates commonly are measured using isotopic tracers to quantify the incorporation of a labeled amino acid into muscle proteins. Here we provide evidence supporting our hypothesis that the nonisotopic SUnSET technique is a valid and accurate method for the measurement of in vivo changes in protein synthesis at the whole-muscle and single-muscle fiber levels. PMID- 23089928 TI - Lenke 1C and 5C spinal deformities fused selectively: 5-year outcomes of the uninstrumented compensatory curves. AB - STUDY DESIGN: Multicenter review of prospectively collected data. OBJECTIVE: To analyze the natural history of uninstrumented compensatory curves prospectively during a 5-year postoperative period in patients with selectively fused Lenke type 1C and 5C adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: After a selective fusion for 1C and 5C adolescent idiopathic scoliosis curve types, there is concern that uninstrumented compensatory curves will continue to progress over time. However, to date, there have been no studies using prospectively collected data beyond 2 years to determine the natural history of these uninstrumented compensatory curves. METHODS: Lenke 1C and 5C adolescent idiopathic scoliosis cases, prospectively collected from a multicenter study were analyzed. All patients underwent a selective fusion (1C only thoracic curve fused; 5C only thoracolumbar/lumbar curve fused). Preoperative, first-erect, 1 year, 2-year, and 5-year postoperative coronal, sagittal, and axial (Perdriolle) radiographical outcomes were compared using repeated measures analysis of variance with Bonferroni post hoc comparisons (P < 0.05). RESULTS: Twenty-four selectively fused Lenke 1C curves and 21 selectively fused Lenke 5C curves were reviewed. Preoperative compensatory curve Cobb angles were 40 degrees +/- 6 degrees and 25 degrees +/- 9 degrees , respectively. In Lenke 1C curves, the uninstrumented compensatory lumbar curves were corrected by 32% +/- 16% at first erect, 44% +/- 17% correction at 1 year, 38% +/- 15% correction at 2 years, and 39% +/- 19% at 5 years. In Lenke 5C curves, the uninstrumented compensatory thoracic curves were corrected by a mean of 37% +/- 29% at first erect, 42% +/- 29% at 1 year, 37% +/- 29% at 2 years, and 30% +/- 23% at 5 years. The sagittal and axial measures of the compensatory curves remained stable during the postoperative period. CONCLUSION: In Lenke 1C and 5C adolescent idiopathic scoliosis deformity patterns fused selectively, the uninstrumented compensatory curves adjust to match the instrumented primary curve and do not seem to progress between 1 and 5 years postoperatively. PMID- 23089929 TI - Prospective analysis of magnetic resonance imaging accuracy in diagnosing traumatic injuries of the posterior ligamentous complex of the thoracolumbar spine. AB - STUDY DESIGN: Prospective cohort study. OBJECTIVE: To study magnetic resonance imaging (MRI) accuracy in diagnosing posterior ligamentous complex (PLC) damage, when applying the new dichotomic instability criteria in a prospective cohort of patients with vertebral fracture. SUMMARY OF BACKGROUND DATA: Recent studies dispute MRI accuracy to diagnose PLC injuries. They analyze the complex based on 3 categories (intact/indeterminate/rupture), including the indeterminate in the ruptured group (measurement bias) in the accuracy analysis. Moreover, fractures with conservative treatment (selection bias) are not included. Both facts reduce the specificity. A recent study has proposed new criteria where posterior instability is determined with supraspinous ligament (SSL) rupture. METHODS: Prospective study of patients with acute thoracolumbar fracture, using radiography and MRI (FS-T2-w/short-tau inversion-recovery sequences). 1. The integrity (ruptured/unruptured) of each isolated component of the PLC (facet capsules, interspinous ligament, SSL, and ligamentum flavum) was assessed via MRI and surgical findings. 2. PLC integrity as a whole was assessed, adopting the new dichotomic stability criteria from previous studies. In the MR images, PLC is considered ruptured when the SSL is found discontinued, and intact when not (this excludes the "indeterminate" category). In surgically treated fractures, PLC stability as a whole was assessed dynamically (ruptured/unruptured). In conservative fractures, PLC stability was assessed according to change in vertebral kyphosis measured with the local kyphotic angle at 2-year follow-up (ruptured if difference is > 5 degrees /unruptured if difference is < 5 degrees ).3. Comparative analysis among findings provided MRI accuracy in diagnosing PLC damage. RESULTS: Fifty-eight vertebral fractures were studied (38 surgical, 20 conservative), of which 50% were in males; average age, 40.4 years. MRI sensitivity for injury diagnosis of each isolated PLC component varied between 92.3% (interspinous ligament) and 100% (ligamentum flavum). Specificity varied between 52% (facet capsules) and 100% (SSL). PLC integrity sensitivity and specificity as a whole were 91% and 100%, respectively. CONCLUSION: Adopting the new stability criteria, MRI accuracy in PLC injury diagnosis increases. Specificity is increased (true positives) both in isolated component analysis and PLC as a whole. PMID- 23089930 TI - Aseptic loosening of pedicle screw as a result of metal wear debris in a pediatric patient. AB - STUDY DESIGN: This is a case report. OBJECTIVE: To report a case of soft-tissue reaction to wear debris and osteolysis around a pedicle screw after posterior spine fusion in a pediatric patient. SUMMARY OF BACKGROUND DATA: Posterior spine fusion with instrumentation is a standard procedure for stabilization and curve correction in patients with scoliosis. Late operative site pain accounts for the highest frequency of reoperation. Debris accumulation for steel and titanium constructs occurs at the pedicle screw-rod junction. Cellular reaction to metal wear may be responsible for osteolysis and aseptic loosening around spinal implants. METHODS: A 14-year-old male patient with neurofibromatosis and right thoracic scoliosis of 50 degrees underwent posterior spine fusion from T2 to T10. The postoperative course was complicated by continuous pain, and imaging studies demonstrated hardware failure, requiring a revision and subsequent development of a perihilar opacity of unknown origin. Further studies demonstrated hypermobility with adjacent soft-tissue reactivity and inflammation surrounding the right T5 transpedicle screw. RESULTS: After hardware removal, the patient's recovery was uneventful. Six months later, a repeated computed tomographic scan demonstrated resolution of the previously described soft-tissue mass and a satisfactory fusion of the thoracic spine. CONCLUSION: Metal wear debris can form in pediatric patients during the healing process after spinal fusions or when pseudarthrosis is present. Clinically, this manifests as back pain with a possible aseptic inflammatory abscess. Hardware removal can achieve resolution of symptoms and regression of inflammation. PMID- 23089931 TI - Combined pre- and subtemporal transtentorial approach for epidermoid cysts of the cerebellopontine angle. AB - OBJECTIVE: Epidermoid cysts of the cerebellopontine angle (CPA) can be a surgical challenge for the pediatric neurosurgeon. Ideally, total removal must be achieved; however, occasional adhesions of these tumors to vital neurovascular structures and extension far beyond the midline may preclude their total removal. The aims of this article are to present an alternative surgical approach to these lesions and to provide the rationale for this technique. MATERIAL AND METHODS: A 16-year-old boy was admitted to our pediatric neurosurgery department with a 1 year history of nonspecific headaches. His neurological examination showed right sided dysmetria and gait ataxia. Magnetic resonance scans showed a space occupying lesion on the right CPA with low intensity on T(1)-weighted images and high intensity on T(2)-weighted images. RESULTS: Craniotomy for tumor excision via pre- and subtemporal transtentorial approach was performed disclosing a 3.5 * 3 * 2.8-cm(3) well-encapsulated tumor, which was confirmed to be an epidermoid cyst. The postoperative course was uneventful. CONCLUSIONS: A combined pre- and subtemporal approach utilizes a wide opening of the tentorium and the option of supratentorial retraction of the cerebellum to provide an excellent angle of approach to CPA lesions involving the anterolateral aspect of the brain stem in children. PMID- 23089932 TI - Neurophysiologic intraoperative monitoring in children with Down syndrome. AB - OBJECTIVE: Neurophysiological monitoring during complex spine procedures may reduce risk of injury by providing feedback to the operating surgeon. This tool is a well-established and important surgical adjunct in adults, but clinical data in children are not well described. Moreover, to the best of our knowledge, neurophysiologic intraoperative monitoring data have not been reported in children with neurodevelopmental disorders, such as Down syndrome, who commonly present with craniocervical instability requiring internal fixation. The purpose of this study is to determine the reliability and safety of neurophysiologic intraoperative monitoring in a group of children with Down syndrome undergoing neurosurgical spine procedures. METHODS: A total of six consecutive spinal procedures in six children with Down syndrome (three boys and three girls; mean age 10 years, range 4-16 years) were analyzed between January 1, 2008 and June 31, 2011. Somatosensory evoked potentials were stimulated at the ulnar nerve and tibial nerve for upper and lower extremities, respectively, and recorded at Erb's point and the scalp. Motor evoked potentials were elicited by transcranial electrical stimulation and recorded at the extensor carpi ulnaris muscle and tibialis anterior muscle for upper and lower extremities, respectively. A standardized anesthesia protocol for monitoring consisted of a titrated propofol drip combined with bolus dosing of fentanyl or sufentanil. RESULTS: Somatosensory and motor evoked potentials were documented at the beginning and end of the procedure in all six patients. Changes during the surgery were recorded. Five patients maintained somatosensory potentials throughout surgery. One patient demonstrated a >10% increase in latency or >50% decrease in amplitude suggesting spinal cord dysfunction. A mean baseline stimulation threshold for motor evoked potentials of 485 + 85 V (range 387-600 V) was used. Four patients maintained motor evoked potentials throughout surgery. One patient had loss of left lower somatosensory evoked potentials (SSEPs) and motor evoked potentials (MEPs) after rod placement; upon removal of the rod, SSEPs returned but not MEPs. Another patient did not have consistent MEPs on one side and had absent MEPs on the contralateral side throughout the case. Loss of MEPs in these two patients did not correlate with postoperative neurological status. There were no complications directly related to neurophysiologic intraoperative monitoring technique. CONCLUSIONS: Neurophysiologic intraoperative monitoring during neurosurgical procedures in children with Down syndrome may be reliably and safely implemented. Changes in neurophysiologic parameters during surgery must be carefully interpreted, and discussed with the neurosurgeon, neurophysiologist, and neuroanesthesiologist, and may not correlate with postoperative clinical changes. These changes may be related to abnormal physiology rather than an insult at the time of surgery. Nonetheless, the authors advocate routine neurophysiologic intraoperative monitoring in this special group of children undergoing neurosurgical spine procedures. PMID- 23089933 TI - A systematic review of the results of surgery and radiotherapy on tumor control for pediatric craniopharyngioma. AB - OBJECTIVE: Craniopharyngiomas are rare tumors with bimodal incidence in the pediatric and adult age groups. Treatment strategies range from aggressive resection to planned limited resection combined with adjuvant therapies. Currently there is no consensus for standard of care for pediatric craniopharyngioma. MATERIALS AND METHODS: We performed a systematic review of the published literature on pediatric craniopharyngioma. Patients were grouped based on extent of resection into gross total resection (GTR), subtotal resection (STR), and biopsy procedures. These groups were compared with respect to tumor control. Chi square was used to compare rates of recurrence. Kaplan-Meier was used to generate progression-free survival (PFS) estimates. Cox proportional hazard modeling was used to evaluate risk of progression. Each extent of resection group was also subdivided based on adjuvant therapy and compared. RESULTS: A total of 109 studies described extent of resection resulting in a cohort of 531 patients. Recurrence data were available for 377 patients. There was no difference in 1- or 5-year PFS between the groups who underwent GTR and STR combined with radiation (XRT; log-rank; p = 0.76; 1-year PFS 89 vs 84%; 5 year PFS 77 vs 73%, respectively). One-year PFS was 84% for STR+XRT compared to 76% for STR alone while 5-year PFS was 73% for STR+XRT compared to 43% for STR alone (log-rank; p = 0.003). CONCLUSION: Although there are limitations of a systematic review of retrospective data, our results suggest that STR+XRT of pediatric craniopharyngioma is associated with similar rates of tumor control as GTR. PMID- 23089934 TI - Morris water maze function and histologic characterization of two age-at-injury experimental models of controlled cortical impact in the immature rat. AB - PURPOSE: Controlled cortical impact (CCI) is commonly used in adult animals to study focal traumatic brain injury (TBI). Our study aims to further study injury mechanisms in children and variable models of pathology in the developing brain. METHODS: Develop a focal injury model of experimental TBI in the immature, postnatal days (PND) 7 and 17 rats that underwent a CCI at varying depths of deflection, 1.5-2.5 mm compared with sham and then tested using the Morris water maze (MWM) beginning on post-injury day (PID) 11. Histopathologic analysis was performed at PID 1 and 28. RESULTS: In PND 7, the 1.75- and 2.0-mm deflections (diameter (d) = 3 mm; velocity = 4 m/s; and duration = 500 ms) resulted in significant MWM deficits while the 1.5-mm injury did not produce MWM deficits vs. sham controls. In PND 17, all injury levels resulted in significant MWM deficits vs. sham controls with a graded response; the 1.5-mm deflection (d = 6 mm; velocity = 4 m/s; and duration = 500 ms) produced significantly less deficits as compared WITH the 2.0- and 2.5-mm injuries. Histologically, a graded injury response was also seen in both ages at injury with cortical and more severe injuries, hippocampal damage. Cortical contusion volume increased in most injury severities from PID 1 to 28 in both ages at injury while hippocampal volumes subsequently decreased. CONCLUSIONS: CCI in PND 7 and 17 rat results in significant MWM deficits and cortical histopathology providing two different and unique experimental models of TBI in immature rats that may be useful in further investigations into the mechanisms and treatments of pediatric TBI. PMID- 23089936 TI - Smartphone-assisted guide for the placement of ventricular catheters. AB - OBJECTIVE: Freehand placement of ventricular catheters (VC) is reported to be inaccurate in 10-40 %. Endoscopy, ultrasound, or neuronavigation are used in selected cases with significant technical and time-consuming efforts. We suggest a smartphone-assisted guiding tool for the placement of VC. METHODS: Measurements of relevant parameters in 3D-MRI datasets in a patient cohort with narrow ventricles for a frontal precoronal VC placement were performed. In this context, a guiding tool was developed to apply the respective measures for VC placement. The guiding tool was tested in a phantom followed by CT imaging to quantify placement precision. A smartphone application was designed to assist the relevant measurements. The guide was applied in 35 patients for VC placement. RESULTS: MRI measurements revealed the rectangular approach in the sagittal plane and the individual angle towards the tangent in the coronal section as relevant parameter for a frontal approach. The latter angle ranged from medial (91.96 degrees +/- 2.75 degrees ) to lateral margins (99.56 degrees +/- 4.14 degrees ) of the ventricle, which was similar in laterally shifted (+/-5 mm) entry points. The subsequently developed guiding tool revealed precision measurements in an agarose model with 1.1 degrees +/- 0.7 degrees angle deviation. Using the smartphone assisted guide in patients with narrow ventricles (frontal occipital horn ratio, 0.38 +/- 0.05), a primary puncture of the ventricles was possible in all cases. No VC failure was observed during follow-up (9.1 +/- 5.3 months). CONCLUSIONS: VC placement in narrow ventricles requires accurate placement with simple means in an every-case routine. The suggested smartphone-assisted guide meets these criteria. Further data are planned to be collected in a prospective randomized study. PMID- 23089937 TI - Low-temperature elastic anomalies in CaTiO3: dynamical characterization. AB - Pulse-echo ultrasonic measurements of elastic coefficients of CaTiO(3) show anomalous behavior around 200 K, with a notable rise in the attenuation coefficient. Molecular dynamics simulation is used to simulate the elastic response of a mono-domain (MDm) and a poly-domain (PDm) configuration of CaTiO(3) using the Vashishta-Raman interatomic potential. The PDm is obtained by cooling the melt from 3600 to 300 K at a rate of 0.5 K ps(-1), so that it recrystallizes to the PDm orthorhombic configuration. The elastic behavior is simulated in the temperature range from 300 to 20 K. In the MDm, it is observed that the bulk modulus varies linearly with temperature, while in the PDm an anomalous hardening is seen around 210 K. The bulk modulus of the PDm fluctuates strongly and is lower than that of the MDm. Neither the pair correlation function nor the Ti-Ti-O bonding angle indicate a true structural phase transition in this range of temperatures. Given the absence of any apparent change in the structure, a possible explanation for this phenomenon is the emergence of a certain class of dynamical instability associated with domain wall motion. Curiously, the pressure fluctuations in both the MDm and PDm configurations follow a power law distribution f ~ P(-alpha), with the exponent independent of applied strain and temperature. Time series for pressure are used to analyze the dynamics by time delay reconstruction techniques. The calculus of embedding and correlation dimension indicates that in the polycrystalline configuration, low-dimension dynamics (<26) appears, which tend to disappear at higher temperatures. PMID- 23089935 TI - L5 spondylolysis/spondylolisthesis: a comprehensive review with an anatomic focus. AB - INTRODUCTION: Spondylolysis is most commonly observed in the lumbar spine, particularly L5, and is associated with spondylolisthesis, or anterior "slippage" of a vertebra in relation to an adjacent vertebra. Isthmic spondylolisthesis is the result of a pars interarticularis defect and will be the only type of spondylolisthesis addressed in this review. CONCLUSIONS: Spondylolysis and spondylolisthesis represent a relatively common cause of low back pain, especially in young athletes, and a less common cause of neurologic compromise. When discovered in a symptomatic patient with corroborating imaging findings, early intervention provides an excellent prognosis. Herein, we review the anatomy and pathology of spondylosis and spondylolisthesis of the L5 vertebra. PMID- 23089938 TI - Will newer anticoagulants improve therapy persistence? PMID- 23089939 TI - A single daily dose enhances the adherence to immunosuppressive treatment in kidney transplant recipients: a cross-sectional study. AB - BACKGROUND: Nonadherence to treatment regimens for immunosuppressive agents is one of the major risk factors for allograft failure in kidney transplant recipients. The aim of this study was to estimate the relative effect of daily dosing on treatment adherence, not to identify how patients are non-adherent, in long-term kidney transplant recipients. METHODS: In January 2009, a cross sectional, anonymous, and voluntary questionnaire survey was given to kidney transplant recipients who regularly visited Inoue Hospital. A self-reporting questionnaire underestimates nonadherence, but we reasoned that the effect of the dosing regimen should be estimated with relative accuracy by using the generalized ordered logit/partial proportional hazard odds model given that the distribution patterns in the degree of nonadherence have been shown to be similar with other measures. RESULTS: Of 336 eligible patients, 312 (92.9 %) participated in this study. Two hundred seventy-four patients (87.8 %) were more than 3 years post-transplant. Univariate analysis revealed that a single daily dose was significantly associated with better adherence. After controlling for age, sex, time since transplantation, and the number of prescribed drugs, the effect of a single daily dose still remained significant [odds ratio, 0.40 (95 % confidence interval, 0.19-0.81); p = 0.011]. Several sensitivity analyses yielded similar results. CONCLUSIONS: To our knowledge, this is the first report that, in long term kidney transplant recipients, a single daily regimen-one of few modifiable factors-might improve treatment adherence and allograft survival. PMID- 23089940 TI - Darbepoetin alfa for the treatment of anemia in children undergoing peritoneal dialysis: a multicenter prospective study in Japan. AB - BACKGROUND: Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD). METHODS: Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 MUg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to <=13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks. RESULTS: In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 +/- 1.0 to 11.1 +/ 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events. CONCLUSIONS: The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD. PMID- 23089941 TI - Perirenal hemorrhage: rare complication of warfarin coagulopathy. PMID- 23089942 TI - Four consecutive cases of Achilles tendon disorders associated with levofloxacin treatment in hemodialysis patients. PMID- 23089943 TI - Psychological distress in cancer patients undergoing radiation therapy treatment. AB - PURPOSE: The objective of this study was to examine the likely presence of, and factors associated with, anxiety, depression and overall psychological distress in cancer outpatients undergoing radiation therapy treatment in Sydney, Australia. METHODS: A touchscreen computer survey was conducted in four radiation therapy treatment centre waiting rooms. Patients waiting to receive treatment completed the survey which included questions about demographic and disease characteristics, survey acceptability and the Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 454 patients (70 %) completed the touchscreen computer survey. The likely presence of anxiety (HADS-A >=11), depression (HADS-D >=11) and overall psychological distress (HADS-T >=15) was 15, 5.7 and 22 %, respectively. Cancer type was found to be associated with each HADS screening category. The majority of patients reported high survey acceptability and willingness to complete similar touchscreen computer surveys in the treatment centre waiting room on additional occasions. CONCLUSIONS: As radiotherapy patients frequently attend the radiation oncology department, routine screening and intervention for elevated levels of psychological distress in this setting appears to be feasible. High survey completion rates and high patient-rated acceptability support this approach to screening. The likely presence of psychological distress is reported for this sample; however, the selection of HADS threshold scores is likely to have influenced the reported rates. Further research is needed to identify how cancer type impacts on likely caseness across the different HADS classifications examined. PMID- 23089944 TI - Linguistic validation of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog): methodological concerns. PMID- 23089946 TI - [Necrotizing soft tissue infections: the timing of therapy is decisive!]. PMID- 23089947 TI - [Incidental finding of an anomalous pulmonary vein after thoracic trauma]. PMID- 23089948 TI - [Neuromonitoring can reduce the frequency of aerodigestive tract complaints after thyroid gland operations]. PMID- 23089945 TI - Biological and biomedical applications of engineered nucleases. AB - The development of engineered nucleases is the fruit of a new technological approach developed in the last two decades which has led to significant benefits on genome engineering, particularly on gene therapy. These applications enable efficient and specific genetic modifications via the induction of a double-strand break (DSB) in a specific genomic target sequence, followed by the homology directed repair (HDR) or non-homologous end joining (NHEJ) pathways. In addition to the application on gene modification in cells and intact organisms, a number of recent papers have reported that this gene editing technology can be applied effectively to human diseases. With the promising data obtained using engineered endonucleases in gene therapy, it appears reasonable to expect that more diseases could be treated and even be cured in this new era of individualized medicine. This paper first brief introduces the development of engineered nucleases with a special emphasis on zinc-finger nucleases (ZFNs) and transcription activator-like effector (TALE) nucleases (TALENs), and then takes CCR5-based gene therapy as an example to discuss the therapeutic applications of engineered nucleases. PMID- 23089949 TI - [Preoperative chemoradiotherapy and postoperative chemotherapy with 5 fluorouracil and oxaliplatin in rectal cancer: initial results of the CAO/ARO/AIO 04 study]. PMID- 23089951 TI - Photochemical and photophysical behavior of indolyl anions in photostimulated intramolecular arylation reactions. AB - O-Arylation reaction is obtained when N-(2-halophenyl) indolo carboxamides are irradiated in a basic medium. On the basis of photochemical and photophysical experiments, we propose that 2-indolylbenzoxazole is formed by intramolecular electron transfer followed by fast dehalogenation of the halophenyl radical anion pendant moiety, finally a radical-radical collapse renders the observed product. PMID- 23089952 TI - Metallodynameric membranes--are metallic ions facilitating the transport of CO2? AB - The concomitant operation of dynamic covalent frameworks and metallodynamers results in the formation of selective Zn(2+)-based dynameric membranes for restrictive facilitated and selective transport of CO(2). PMID- 23089953 TI - Characterization of an efficient catalytic and organic solvent-tolerant azoreductase toward methyl red from Shewanella oneidensis MR-1. AB - The acyl carrier protein (ACP) phosphodiesterase gene (SO 4396) of Shewanella oneidensis MR-1 which was analyzed to have azoreductase activity was heterologously expressed in Escherichia coli. The ACP phosphodiesterase was found to reach maximum enzyme velocity 220.59 U/mg, named azoreductase in this study. The azoreductase had highest specific activity (153.16 U/mg) at pH 6.5, which showed a preference for nicotinamide adenine dinucleotide (NADH) as electron donor. The phylogenetic tree analysis indicated that the azoreductase had preference for NADH and dependence for flavin mononucleotide (FMN). However, the azoreductase from S. oneidensis MR-1 still had high enzyme activity in the absence of FMN. The Mg(2+) had a positive influence on the enzyme activity with 25 mM concentration, whereas Cr(3+), Cd(2+) usually had significantly negative effect on enzyme activity. The purified azoreductase retained nearly 100 % activity after incubating in 30 % dimethyl sulfoxide (DMSO), 30 % acetone, 30 % methanol, 20 % ethanol, 20 % isopropanol, and 10 % propanol. PMID- 23089954 TI - One-year measurements of chloroethenes in tree cores and groundwater at the SAP Mimon Site, Northern Bohemia. AB - Chlorinated ethenes (CE) are among the most frequent contaminants of soil and groundwater in the Czech Republic. Because conventional methods of subsurface contamination investigation are costly and technically complicated, attention is directed on alternative and innovative field sampling methods. One promising method is sampling of tree cores (plugs of woody tissue extracted from a host tree). Volatile organic compounds can enter into the trunks and other tissues of trees through their root systems. An analysis of the tree core can thus serve as an indicator of the subsurface contamination. Four areas of interest were chosen at the experimental site with CE groundwater contamination and observed fluctuations in groundwater concentrations. CE concentrations in groundwater and tree cores were observed for a 1-year period. The aim was to determine how the CE concentrations in obtained tree core samples correlate with the level of contamination of groundwater. Other factors which can affect the transfer of contaminants from groundwater to wood were also monitored and evaluated (e.g., tree species and age, level of groundwater table, river flow in the nearby Ploucnice River, seasonal effects, and the effect of the remediation technology operation). Factors that may affect the concentration of CE in wood were identified. The groundwater table level, tree species, and the intensity of transpiration appeared to be the main factors within the framework of the experiment. Obtained values documented that the results of tree core analyses can be used to indicate the presence of CE in the subsurface. The results may also be helpful to identify the best sampling period for tree coring and to learn about the time it takes until tree core concentrations react to changes in groundwater conditions. Interval sampling of tree cores revealed possible preservation of the contaminant in the wood of trees. PMID- 23089955 TI - Influence of organic and inorganic markers in the source apportionment of airborne PM10 in Zaragoza (Spain) by two receptor models. AB - Improving knowledge on the apportionment of airborne particulate matter will be useful to handle and fulfill the legislation regarding this pollutant. The main aim of this work was to assess the influence of markers in the source apportionment of airborne PM10, in particular, whether the use of particle polycyclic aromatic hydrocarbon (PAH) and ions provided similar results to the ones obtained using not only the mentioned markers but also gas phase PAH and trace elements. In order to reach this aim, two receptor models: UNMIX and positive matrix factorization were applied to two sets of data in Zaragoza city from airborne PM10, a previously reported campaign (2003-2004) (Callen et al. Chemosphere 76:1120-1129, 2009), where PAH associated to the gas and particle phases, ions and trace elements were used as markers and a long sampling campaign (2001-2009), where only PAH in the particle phase and ions were analyzed. For both campaigns, positive matrix factorization was able to explain a higher number of sources than the UNMIX model. Independently of the sampling campaign and the receptor model used, soil resuspension was the main PM10 source, especially in the warm period (21st March-21st September), where most of the PM10 exceedances were produced. Despite some of the markers of anthropogenic sources were different for both campaigns, common sources associated to different combustion sources (coal, light-oil, heavier-oil, biomass, and traffic) were found and PAH in particle phase and ions seemed to be good markers for the airborne PM10 apportionment. PMID- 23089956 TI - Combined effect of cadmium, lead, and UV rays on Bacillus cereus using comet assay and oxidative stress parameters. AB - Exposure to environmental chemicals and oxidative stress particularly at low dose levels may produce additive or synergistic interactions not seen in single component exposure. Exposure to cadmium, lead, and ultraviolet rays occurs in many occupational settings, such as pigment and battery production, galvanization, and recycling of electric tools. However, little is known about interactions between heavy metals and ultraviolet rays. This study aimed to evaluate the interactions of ultraviolet rays of 254 nm (UV-B) with cadmium or lead on Bacillus cereus. B. cereus was treated with different concentrations of cadmium or lead followed by exposure to UV-B radiation as combined effect. Photoirradiation of B. cereus with UV-B with exposure to cadmium or lead results in DNA damage, cytotoxicity, depletion of glutathione, and formation of lipid peroxidation. UV-B rays alone enhanced glutathione production which was depleted with lead and high doses of cadmium. Lead alone does not increase DNA breaking. The mechanism behind these interactions might be repair inhibition of oxidative DNA damage, since a decrease in repair capacity will increase susceptibility to reactive oxygen species generated by cadmium or lead. Lipid peroxidation was increased with exposure to UV-B and cadmium or lead. DNA, glutathione, and lipid peroxidation can be used as biomarkers to identify possible environmental contamination in bacteria. One conclusion from this model is the existence of more than multiplicative effects for co-exposures of cadmium or lead and UV rays. PMID- 23089957 TI - Biofilm comprising phototrophic, diazotrophic, and hydrocarbon-utilizing bacteria: a promising consortium in the bioremediation of aquatic hydrocarbon pollutants. AB - Biofilms harboring simultaneously anoxygenic and oxygenic phototrophic bacteria, diazotrophic bacteria, and hydrocarbon-utilizing bacteria were established on glass slides suspended in pristine and oily seawater. Via denaturing gradient gel electrophoresis analysis on PCR-amplified rRNA gene sequence fragments from the extracted DNA from biofilms, followed by band amplification, biofilm composition was determined. The biofilms contained anoxygenic phototrophs belonging to alphaproteobacteria; pico- and filamentous cyanobacteria (oxygenic phototrophs); two species of the diazotroph Azospirillum; and two hydrocarbon-utilizing gammaproteobacterial genera, Cycloclasticus and Oleibacter. The coexistence of all these microbial taxa with different physiologies in the biofilm makes the whole community nutritionally self-sufficient and adequately aerated, a condition quite suitable for the microbial biodegradation of aquatic pollutant hydrocarbons. PMID- 23089958 TI - Sublethal detergent concentrations increase metabolization of recalcitrant polyphosphonates by the cyanobacterium Spirulina platensis. AB - As a consequence of increasing industrial applications, thousand tons of polyphosphonates are introduced every year into the environment. The inherent stability of the C-P bond results in a prolonged half-life. Moreover, low uptake rates limit further their microbial metabolization. To assess whether low detergent concentrations were able to increase polyphosphonate utilization by the cyanobacterium Spirulina platensis, tolerance limits to the exposure to various detergents were determined by measuring the growth rate in the presence of graded levels below the critical micellar concentration. Then, the amount of hexamethylenediamine-N,N,N',N'-tetrakis(methylphosphonic acid) that is metabolized in the absence or in the presence of sublethal detergent concentrations was quantified by (31)P NMR analysis on either P-starved or P-fed cyanobacterial cultures. The strain tolerated the presence of detergents in the order: nonionic > anionic > cationic. When added to the culture medium at the highest concentrations showing no detrimental effects upon cell viability, detergents either improved or decreased polyphosphonate utilization, the anionic sodium dodecyl sulfate being the most beneficial. Metabolization was not lower in P-fed cells--a result that strengthens the possibility of using, in the future, this strain for bioremediation purposes. PMID- 23089959 TI - Characterisation of four major histocompatibility complex class II genes of the koala (Phascolarctos cinereus). AB - Major histocompatibility complex (MHC) class II molecules have an integral role in the adaptive immune response, as they bind and present antigenic peptides to T helper lymphocytes. In this study of koalas, species-specific primers were designed to amplify exon 2 of the MHC class II DA and DB genes, which contain much of the peptide-binding regions of the alpha and beta chains. A total of two DA alpha1 domain variants and eight DA beta1 (DAB), three DB alpha1 and five DB beta1 variants were amplified from 20 koalas from two free-living populations from South East Queensland and the Port Macquarie region in northern New South Wales. We detected greater variation in the beta1 than in the alpha1 domains as well as evidence of positive selection in DAB. The present study provides a springboard to future investigation of the role of MHC in disease susceptibility in koalas. PMID- 23089960 TI - Knowledge acquisition for medical diagnosis using collective intelligence. AB - The wisdom of the crowds (WOC) is the process of taking into account the collective opinion of a group of individuals rather than a single expert to answer a question. Based on this assumption, the use of processes based on WOC techniques to collect new biomedical knowledge represents a challenging and cutting-edge trend on biomedical knowledge acquisition. The work presented in this paper shows a new schema to collect diagnosis information in Diagnosis Decision Support Systems (DDSS) based on collective intelligence and consensus methods. PMID- 23089961 TI - A severely infected diabetic foot treated successfully without using systemic antibiotics. AB - About 50% to 70% of all lower extremity amputations are related to diabetes infection. And antibiotic therapy is routinely used for all infected wounds to reduce the mortality of diabetic foot. Here, we report a case of diabetic foot with acute and deep severe infection. During hospital therapy, we used negative pressure therapy and extensive debridement without systemic antibiotic application, and we successfully rescued a foot from amputation. Negative pressure therapy and extensive debridement are very important and effective methods to control infection and promote wound healing in diabetes foot. PMID- 23089962 TI - Reconstruction of traumatic lower extremity soft tissue defects with the combination of ipsilateral and contralateral perforator flaps. AB - Many flaps have been used to repair complex soft tissue defects of the leg. When the affected areas are relatively small and the local flaps are not suitable, microsurgical operation seems to be an excessive treatment and thus perforator flaps can be used. The authors present the combination of ipsilateral and contralateral perforator flaps for coverage of the traumatic lower extremity. PMID- 23089963 TI - Establishing an education program for chronic wound care in China. AB - Chronic wounds in China are an important issue. However, wound care knowledge and the skill of health care professionals varies among hospitals and cities. The Chinese Tissue Repair Society (CTRS) has developed a 3-year training program in wound care in China that is sponsored by the World Diabetes Foundation and the Coloplast Access to Healthcare foundation. The project focuses on training physicians and nurses in wound care for patients with diabetic mellitus and other chronic skin wounds. In the past 2 years, 1618 health care professionals, including 915 physicians and 703 nurses, have been trained. Participants are from more than 200 hospitals in 21 provinces. About 1200 patients per month, on average, have benefited from this project. In total, 13 hospitals have become training bases to continue the education program. The aim of the program is to help Chinese medical professionals efficiently manage chronic wounds, thereby shortening the wound healing time, reducing the amputation rate and treatment costs, and improving quality of life. PMID- 23089964 TI - Endostar injection inhibits rabbit ear hypertrophic scar formation. AB - This study aims to investigate the effect of Endostar injection on the rabbit ear hypertrophic scar formation and expand the use of Endostar. The rabbit ear hypertrophic scar models were established 4 weeks postoperation and were treated with Endostar injection; the control group was injected with saline, once a week, 3 times totally. At the seventh week, the scar tissue was harvested and processed with hematoxylin and eosin (HE) staining and CD34 immunohistochemistry and cell apoptosis assay. In addition, the endothelial cell was cultured and seeded on Martrigel with different concentrations of Endostar to observe the vessel tube formation. The results showed that the volume of the hypertrophic scar with Endostar injection was greatly reduced compared with what was seen in the control group; meanwhile, HE staining showed that the cell number decreased and collagen density became looser. In addition, the CD34 staining indicated that microvessel formation in the study group also decreased and cell apoptosis increased. In vitro, the addition of Endostar could reduce vessel tube formation in a dose dependent manner. In conclusion, the Endostar is effective for hypertrophic scar inhibition and could be a potential tool to treat scars. PMID- 23089965 TI - Revascularization by angioplasty of type D femoropopliteal and long infrapopliteal lesion in diabetic patients with critical limb ischemia: are TASC II recommendations suitable? A population-based cohort study. AB - Feasibility of revascularization of type D femoropopliteal and long infrapopliteal lesions by angioplasty (peripheral translumenal angioplasty [PTA]) in diabetic patients with critical limb ischemia (CLI) according to the TransAtlantic Inter-Society Consensus (TASC) II recommendations was studied. A total of 292 diabetic patients were admitted for CLI; 308 limbs underwent a PTA. Out of 211 femoropopliteal lesions treated with PTA, 44 were TASC II type A, 45 type B, 48 type C, and 76 type D lesions. In 44 of the 76 patients with type D lesions revascularized by PTA, no artery was patent down to the foot before the PTA. In 172 limbs with all infrapopliteal arteries occluded, revascularization was carried out down to the foot in 167 limbs. Follow-up was 3.1 +/- 0.3 years. A first episode of restenosis occurred in 66/308 limbs with an incidence/year of 7.9. PTA procedures were successfully repeated in 57/66 restenosis episodes: secondary patency was 97.1%. The incidence/year of type D femoropopliteal lesions was 5.4, the incidence/year in others was 5.0, without statistically significant differences: P = .417. The only variable found significantly associated with restenosis occurrence on logistic analysis was the presence of lesions in both femoropopliteal and infrapopliteal axes. A total of 26/308 above-the-ankle amputations were performed, with an incidence/year of 2.5. Multivariate analysis showed the independent role of only crural artery occlusion after PTA. These data show that the choice to refer to angioplasty diabetic patients with type D and/or long infrapopliteal lesions without good run-off at the foot and/or high surgical risk allowed high revascularization feasibility, with an optimal amputation outcome. PMID- 23089966 TI - Repair and regeneration of skin injury by transplanting microparticles mixed with Wharton's jelly and MSCs from the human umbilical cord. AB - The prognosis for extensive and deep skin injury is not satisfactory because of scar formation and the loss of normal function and skin appendages. Several novel therapies for skin repair and regeneration have emerged. Currently, stem cell based therapies are attractive candidates in regenerative medicine to treat skin injuries. Human umbilical cord Wharton's jelly-derived mesenchymal stem cells (hUC-MSCs) have become a unique, accessible, and noncontroversial source of regeneration in medicine. The aim of this study was to explore a new strategy for treating skin wounds. A mixture of hUC-MSCs, Wharton's jelly, and skin microparticles were transplanted to 10-mm diameter, full-thickness, middorsal, excisional skin wounds of mice. After 7 days, the tissue sections were sampled for reconstruction analysis and histological examination. After transplantation, there was a remarkable development of newborn skin and its appendages. We could see newly generated layers of epidermis, sebaceous glands, hair follicle, and sweat glands clearly. This innovative strategy could be very promising and may significantly increase the quality of repair and regeneration of skin in injuries. PMID- 23089968 TI - [Establishment of the oral food challenge network]. PMID- 23089967 TI - Apotemnophilia or body integrity identity disorder: a case report review. AB - Apotemnophilia or body integrity identity disorder (BIID) denotes a syndrome in which a person is preoccupied with the desire to amputate a healthy limb. In this report, we review the available case reports in the literature in order to enhance psychiatrists' and physicians' comprehension of this disorder. A search for the case reports available via MEDLINE was done since the first case report published by Money et al in 1977 till May 2011, using the following terms: apotemnophilia, self-demand amputation, body integrity identity disorder, and BIID. In all, 14 case reports were found relevant to our search. The desire to amputate one's healthy limb seems to be related to a major disturbance in the person's perception of one's own identity, where limb amputation can relieve temporarily the patient's feeling of distress without necessarily and uniformly adjusting the patient's own identity misperception. More investigations are needed in this domain in order to develop noninvasive treatment strategies that approach this aspect of the patient's distress within a globalist perspective. In addition, the health professionals' awareness regarding this disorder is required to ensure professional management of patients' suffering. PMID- 23089969 TI - [The role of allergy educator]. PMID- 23089970 TI - [Diagnostic criteria for cutaneous adverse drug reactions]. PMID- 23089971 TI - [Latex allergy safety-measures guideline 2009 -the latex allergy which should be understood at least-]. PMID- 23089972 TI - [On the road of 25 years research around the IgE-FcepsilonRI-mast cell axis in allergy]. PMID- 23089973 TI - [Findings of blood examinations before posttransfusion urticaria]. AB - BACKGROUND: Although the occurrence of posttransfusion urticaria in the immunosuppressive period is believed to be rare, from our experiences, this disease develops regardless of the immune status of the patients. Therefore, we performed a retrospective study to determine whether posttransfusion urticaria develops during the period of bone marrow suppression. METHODS: This study included 20 patients who developed urticaria as a complication of blood transfusion from January 2010 to January 2011 at the Department of Pediatrics, Hiroshima University Hospital. We retrospectively analyzed the patients' the blood examination data obtained before blood transfusion to elucidate the mechanism underlying posttransfusion urticaria. RESULTS: White blood cell counts were low before the patients developed urticaria; particularly, neutrophil counts were significantly low. Furthermore, the monocyte, eosinophil, and basophil counts were significantly lower before the development of urticaria. DISCUSSION: Urticaria tends to develop in a condition of neutropenia. Thus, care must be taken to prevent the development of this disease during the neutropenia period. PMID- 23089974 TI - [Analysis of cytology in nasal smear of Japanese ceder pollinosis before and in season]. AB - BACKGROUND: In Japanese cedar pollinosis (JCP), some patients attacked nasal symptoms similar to pollinosis before season. Nobody knows the reason. We analyzed the nasal cytology from patients before and in season in 2010. METHODS: Cytology of nasal smear by taking with nasal swab and Hansel's staining was performed. Degree of infiltrating cells are graded, and five types are divided; neutrophil only (N), neutrophil predominant (N> Eo/Mc), Eo/Mc outnumber or equal neutrophil (Eo/Mc>= N), either Eosinophil or mast cell (Eo/Mc), and no infiltrating cells Cell-). Bacterial culture was enforced symptomatic patients of JCP with neutrophil predominant before season. Chi-square test was used for statistic analysis between before and in season, and among symptomatic JCP (SyJP), combined JCP with HD or other allergy (SyCJP), and asymptomatic JCP and CJCP (AsJP/CJP). RESULTS: Before season, 58% of SyJP (n=83) was N with significantly higher (p< 0.005) compared to 21% of SyCJP (n=42) and 10% of AsJP/CJP (n=19). And before season, 45% of SyCJP was Eo/Mc with significantly higher (p< 0.005) than 9.6% of SyJP (n=83) and 10% of AsJP/CJP (n=19). In season (March), percentage of Eo/Mc in SyJP (n=42) and SyCJP (n=64) was of 58%, 56% respectively with statistically higher than before season in both groups. Fifty seven percentage of AsJP/CJP (n=19) was Cell- with much higher (p< 0.005) than SyJP and SyCJP (0~7%) before and in season. Staphylococcus aureus in 25 and Staphylococcus epidermis in 12 patients were detected from 39 patients. CONCLUSION: These results mean Staphylococcus species might involve symptom appearance of SyJP before season. PMID- 23089975 TI - [A case of an allergic reaction due to Anisakis simplex possibly after the ingestion of squid--successful detection of four A. simplex allergens, Ani s 1, Ani s 2, Ani s 12 and troponin C-like protein]. AB - A 62-year-old man ingested dressed salmon and its roe (ikura) and grilled mackerel and one hour later further ingested raw tuna and squid as an evening meal at a bar. Soon after the ingestion of raw seafood, he showed wheals, loss of consciousness and low blood pressure. Specific serum IgE to the nematode Anisakis simplex was positive but those to some seafoods were negative. Moreover, a skin prick test using the crude extract was positive for A. simplex but negative for the seafoods, which he ingested on the day of the above episode. When the A. simplex extract was analyzed by IgE-binding immunoblot analysis using the patient serum, two highly intense protein bands were recognized at 18 and 17 kDa, one intense band at 35 kDa and two weak bands at 28 and 26 kDa. ELISA with 11 natural or recombinant A. simplex allergens (Ani s 1-6, 8, 9, 11 and 12 and troponin C like protein) showed that the patient serum strongly reacted to Ani s 1 and Ani s 12 and weakly to Ani s 2 and troponin C-like protein. Based on these results, he was diagnosed as IgE-mediated A. simplex allergy due to four allergens (Ani s 1, Ani s 2, Ani s 12 and troponin C-like protein), possibly infested in the raw squid which he had ingested just before manifestation of allergic reactions. PMID- 23089976 TI - Aneurysm of Vieussens' arterial ring in a patient studied with coronary computed tomography. AB - We present the case of Vieussens' arterial ring aneurysm in a patient who underwent coronary computed tomography. Vieussens' arterial ring is a remnant of the embryonic conotruncal circle. Only four cases of aneurysm are described in literature. This is the first reported case in which a dilated Vieussens' arterial ring is observed without coronary stenosis. PMID- 23089977 TI - The reciprocal relationship of neurocognitive and neuropsychiatric function in late life. PMID- 23089978 TI - Perioperative morbidity and mortality of total hip replacement in liver transplant recipients: a 7-year single-center experience. AB - OBJECTIVE: This study aims to evaluate perioperative mortality and morbidity after total hip replacement in liver transplant recipients and suggesting safety guidelines. BACKGROUND: Hip replacement surgery is one of the most common elective surgeries even for organ transplant recipients. However, there is a paucity of literature addressing the morbidity and complications of hip replacement surgery for liver transplant recipients. MATERIALS AND METHODS: We analyzed retrospectively 33 arthroplasty cases in 20 liver transplant recipients carried out in a single center from 2005 to 2011. All perioperative clinical and laboratory data were evaluated together with early and late morbidity and mortality. RESULT: Of 2253 liver transplant recipients, 20 (0.9%) patients underwent 33 total hip arthroplasties. Thirty-two arthroplasties were performed for avascular necrosis of the femoral head, whereas only one was performed for osteoarthritis. There was no death, liver failure, or infection within 30 days after surgery. Three patients showed elevated liver enzyme more than 5 times the normal value, but it eventually decreased to normal within 1 week. Of 33 cases of arthroplasty, postoperative blood transfusion was needed in 14 cases with 1 case receiving more than 4 U. On long-term follow-up, no patients have developed periprosthetic fracture, implant loosening, or liver failure. All patients showed good to excellent postoperative Harris hip score. CONCLUSION: In this series, we can infer that hip replacement surgery in liver transplantation patients is safe and gives a reliably good result. Some preoperative conditions should be obtained to reduce postoperative morbidity. PMID- 23089979 TI - Angiotensin II type I receptor agonistic autoantibody-induced apoptosis in neonatal rat cardiomyocytes is dependent on the generation of tumor necrosis factor-alpha. AB - Angiotensin II type I receptor agonistic autoantibodies (AT1-AA) are related to pre-eclampsia and hypertension and have a direct effect of stimulating the production of tumor necrosis factor-alpha (TNF-alpha) in the placenta. TNF-alpha is a known mediator of apoptosis. However, few studies have reported the role of TNF-alpha and its relationship within AT1-AA-induced apoptosis of cardiomyocytes. In this study, neonatal rat cardiomyocytes were treated with various concentrations of AT1-AA. The apoptosis of neonatal rat cardiomyocytes was determined using TUNEL assay and flow cytometry. The level of secreted TNF-alpha was measured by enzyme-linked immunosorbent assay, and caspase-3 activity was measured by a fluorogenic protease assay kit. AT1 receptor blockade and TNF inhibitor were added to determine whether they could inhibit the apoptotic effect of AT1-AA. Results showed that AT1-AA induced the apoptosis of neonatal rat cardiomyocytes in a dose-dependent and time-dependent manner. AT1-AA increased TNF secretion and caspase-3 activities. AT1 receptor blockade completely abrogated AT1-AA-induced TNF-alpha secretion, caspase-3 activation, and cardiomyocyte apoptosis. TNF-alpha receptor inhibitor significantly attenuated AT1-AA-induced neonatal rat cardiomyocyte apoptosis. AT1-AA in the plasma of pre eclamptic patients promoted neonatal rat cardiomyocyte apoptosis through a TNF caspase signaling pathway. PMID- 23089980 TI - Copolymer-templated nitrogen-enriched porous nanocarbons for CO2 capture. AB - Nitrogen-enriched porous carbon materials made via the carbonization of polyacrylonitrile containing block copolymer act as efficient and highly selective CO(2) sorbents. Nitrogen content and surface area, which are both influenced by pyrolysis temperature and atmosphere, are crucial for CO(2) adsorption performance. PMID- 23089981 TI - Trends in the treatment and outcome of congenital diaphragmatic hernia over the last decade. AB - PURPOSE: Congenital diaphragmatic hernia (CDH) remains a challenging and life threatening congenital anomaly. The aim was to evaluate whether treatment and survival has changed during the last decade. METHODS: We retrospectively analysed all consecutive infants with CDH referred to two European tertiary paediatric surgical centres over 11 years (January 1999 to December 2009). Minimum follow-up was 1 year. chi(2) test for trend was used to evaluate significance. RESULTS: There were 234 infants. There was no significant variation over time in the proportion of infants receiving high frequency oscillatory ventilation (HFOV) (p = 0.89), inhaled nitric oxide (iNO) (p = 0.90) or extracorporeal membrane oxygenation (ECMO) (p = 0.22). 205 infants (88 %) were stabilised and underwent surgical repair; of these, 186 (79 %) survived after surgery. Over time there was a significant increase in the proportion of infants undergoing surgical repair (p = 0.018) without a concomitant significant improvement in survival (p = 0.099). CONCLUSION: This multicentre analysis indicates that the survival rate of infants with CDH referred to two European paediatric surgical centres is high (79 %). The use of HFOV, iNO and ECMO has not changed in recent years. We observed a significant increase in the proportion of infants who undergo surgery but this has not resulted in a significant increase in the overall survival rate. PMID- 23089982 TI - PI3K independent activation of mTORC1 as a target in lapatinib-resistant ERBB2+ breast cancer cells. AB - Therapies targeting the ERBB2 receptor, including the kinase inhibitor lapatinib (Tykerb, GlaxoSmithKline), have improved clinical outcome for women with ERBB2 amplified breast cancer. However, acquired resistance to lapatinib remains a significant clinical problem, and the mechanisms governing resistance remain poorly understood. We sought to define molecular alterations that confer an acquired lapatinib resistance phenotype in ER-/ERBB2+ human breast cancer cells. ERBB2-amplified SKBR3 breast cancer cells were rendered resistant to lapatinib via culture in increasing concentrations of the drug, and molecular changes associated with a resistant phenotype were interrogated using a collaborative enzyme-enhanced immunoassay platform and immunoblotting techniques for detection of phosphorylated signaling cascade proteins. Interestingly, despite apparent inactivation of the PI3K/AKT signaling pathway, resistant cells exhibited constitutive activation of mammalian target of rapamycin complex 1 (mTORC1) and were highly sensitive to mTOR inhibition with rapamycin and the dual PI3K/mTOR inhibitor NVP-BEZ235. These data demonstrate a role for downstream activation of mTORC1 in the absence of molecular alterations leading to PI3K/AKT hyperactivation as a potential mechanism of lapatinib resistance in this model of ERBB2+ breast cancer and support the rationale of combination or sequential therapy using ERBB2 and mTOR-targeting molecules to prevent or target resistance to lapatinib. Moreover, our data suggest that assessment of mTOR substrate phosphorylation (i.e., S6) may serve as a more robust biomarker to predict sensitivity to mTOR inhibitors in the context of lapatinib resistance than PI3K mutations, loss of PTEN and p-AKT levels. PMID- 23089983 TI - Lipid concentrations in postmenopausal women on letrozole after 5 years of tamoxifen: an NCIC CTG MA.17 sub-study. AB - To evaluate changes in serum lipid parameters (cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, and lipoprotein(a) [Lp(a)]), in postmenopausal women receiving letrozole after tamoxifen therapy. MA.17L is a sub-study of MA.17, a double-blind, placebo-controlled trial of extended adjuvant letrozole. Eligible postmenopausal women were non-hyperlipidemic and not on lipid-lowering drugs. This analysis considers the 183 patients on the letrozole arm. Lipid parameters evaluated at baseline, 6 months, 12 months, and yearly thereafter until completion of 5 years of letrozole. The median duration of letrozole treatment was 5.0 years with a range from 0.03 to 6.05 years. After 5 year tamoxifen, patients on letrozole experienced significant increases from baseline in total cholesterol, LDL cholesterol, and Lp(a) at all study time points but no statistically significant changes in triglycerides. Specifically, a statistically significant increase was found at 60 months in total cholesterol [mean percentage change from baseline (PC) 5.27; p = 0.003], HDL cholesterol (mean PC 6.75; p = 0.003), LDL cholesterol (mean PC 10.02; p = 0.001), Lp(a) (mean PC 105.95; p < 0.0001). 103 (56 %) women in the study had clinically significantly elevated levels of Lp(a) (106 % above baseline) after 5 years of therapy. The results were similar after excluding the 21 % of patients who had ever received anti-lipid treatment. Significant increases in total cholesterol, HDL cholesterol, LDL cholesterol, and, most notably, Lp(a) in postmenopausal women were observed following 5 years of adjuvant letrozole treatment and after 5 years of tamoxifen therapy and such patients should have monitoring of their lipid levels in clinical practice. PMID- 23089984 TI - Single aerosol trapping with an annular beam: improved particle localisation. AB - In this paper we explore the trapping of aerosol droplets using an annular beam, formed by blocking the central portion of a Gaussian beam, and quantify the improvements over conventional Gaussian beam traps. Recent work on the modelling of single aerosol dynamics within an optical tweezer trap [Burnham et al., Journal of the Optical Society of America B, 2011, 28, 2856-2864] has indicated that the use of annular beams can allow smaller droplets to be trapped, which we experimentally verify. We also demonstrate that annular beams allow droplets to be trapped at higher powers, and with reduced axial displacement with increasing power, than Gaussian beams. We confirm these results, due to a reduction in the axial scattering forces, using this theoretical model. Finally back focal plane interferometry is used to determine the axial and lateral trap stiffnesses for a series of droplets, showing a significant increase in the axial : lateral trap stiffness ratio from 0.79 +/- 0.04 to 1.15 +/- 0.04 when an annular beam is used. PMID- 23089985 TI - Alternative metrics. PMID- 23089986 TI - Progress towards an all-renewable electricity supply. PMID- 23089992 TI - Electron tomography: seeing atoms in three dimensions. PMID- 23089993 TI - Defect dynamics: breaking up in a curved plane. PMID- 23089994 TI - Nanoparticle-based sensors: striped cation-trappers. PMID- 23089995 TI - Material witness: cell physics. PMID- 23089996 TI - Superhydrophobic surfaces: Leidenfrost becomes a fakir. PMID- 23089997 TI - From metamaterials to metadevices. AB - Metamaterials, artificial electromagnetic media that are structured on the subwavelength scale, were initially suggested for the negative-index 'superlens'. Later metamaterials became a paradigm for engineering electromagnetic space and controlling propagation of waves: the field of transformation optics was born. The research agenda is now shifting towards achieving tunable, switchable, nonlinear and sensing functionalities. It is therefore timely to discuss the emerging field of metadevices where we define the devices as having unique and useful functionalities that are realized by structuring of functional matter on the subwavelength scale. In this Review we summarize research on photonic, terahertz and microwave electromagnetic metamaterials and metadevices with functionalities attained through the exploitation of phase-change media, semiconductors, graphene, carbon nanotubes and liquid crystals. The Review also encompasses microelectromechanical metadevices, metadevices engaging the nonlinear and quantum response of superconductors, electrostatic and optomechanical forces and nonlinear metadevices incorporating lumped nonlinear components. PMID- 23089998 TI - p-Phosphonic acid calix[8]arene assisted exfoliation and stabilization of 2D materials in water. AB - Exfoliated 2D materials including graphene, BN, MoS(2) and WS(2) are accessible in water over a wide range of pH for a synergistic process involving sonication in the presence of p-phosphonic acid calix[8]arene. PMID- 23089999 TI - Effect of legumes as part of a low glycemic index diet on glycemic control and cardiovascular risk factors in type 2 diabetes mellitus: a randomized controlled trial. AB - BACKGROUND: Legumes, including beans, chickpeas, and lentils, are among the lowest glycemic index (GI) foods and have been recommended in national diabetes mellitus (DM) guidelines. Yet, to our knowledge, they have never been used specifically to lower the GI of the diet. We have therefore undertaken a study of low-GI foods in type 2 DM with a focus on legumes in the intervention. METHODS: A total of 121 participants with type 2 DM were randomized to either a low-GI legume diet that encouraged participants to increase legume intake by at least 1 cup per day, or to increase insoluble fiber by consumption of whole wheat products, for 3 months. The primary outcome was change in hemoglobin A1c (HbA1c) values with calculated coronary heart disease (CHD) risk score as a secondary outcome. RESULTS: The low-GI legume diet reduced HbA1c values by -0.5% (95% CI, 0.6% to -0.4%) and the high wheat fiber diet reduced HbA1c values by -0.3% (95% CI, -0.4% to -0.2%). The relative reduction in HbA1c values after the low-GI legume diet was greater than after the high wheat fiber diet by -0.2% (95% CI, 0.3% to -0.1%; P < .001). The respective CHD risk reduction on the low-GI legume diet was -0.8% (95% CI, -1.4% to -0.3%; P = .003), largely owing to a greater relative reduction in systolic blood pressure on the low-GI legume diet compared with the high wheat fiber diet (-4.5 mm Hg; 95% CI, -7.0 to -2.1 mm Hg; P < .001). CONCLUSION: Incorporation of legumes as part of a low-GI diet improved both glycemic control and reduced calculated CHD risk score in type 2 DM. PMID- 23090000 TI - Clinical utility of quantitative HBsAg in natural history and nucleos(t)ide analogue treatment of chronic hepatitis B: new trick of old dog. AB - Using commercial quantitative assays, quantitative hepatitis B surface antigen (qHBsAg) has improved our understanding and management of chronic hepatitis B (CHB). The HBsAg level is highest in the immune tolerance phase, starts to decline during the immune clearance phase, and decreases slowly but progressively after hepatitis B e antigen (HBeAg) seroconversion. The HBsAg level is lowest in individuals with an inactive carrier state but higher in those who develop HBeAg negative hepatitis. It has been shown that a reduction of HBsAg by 1 log IU/mL or more reflects improved host immune control of HBV infection. A combination of HBsAg <1000 IU/mL and HBV-DNA <2000 IU/mL can identify a 3-year inactive state in a genotype D HBeAg-negative carrier population. In the Asian-Pacific region, where HBV genotypes B and C are dominant, HBsAg levels of <=10-100 IU/mL predict HBsAg loss over time. As to the prediction of disease progression, low-viremic carriers with HBsAg >1000 IU/mL have been shown to be at higher risks of HBeAg negative hepatitis, cirrhosis, and hepatocellular carcinoma than those with HBsAg <1000 IU/mL. Although qHBsAg has been widely used in CHB patients receiving pegylated interferon therapy, the HBsAg decline is slow and does not correlate with HBV-DNA levels during nucleos(t)ide analogue (NUC) therapy. However, a rapid HBsAg decline during NUC therapy may identify patients who will finally clear HBsAg. A 6- to 12-monthly assessment of HBsAg level could be considered during NUC therapy. Taking these lines of evidence together, qHBsAg can complement HBV DNA levels to optimize the management of CHB patients in our daily clinical practice. PMID- 23090002 TI - Diagnostic ability and factors affecting accuracy of endoscopic ultrasound-guided fine needle aspiration for pancreatic solid lesions: Japanese large single center experience. AB - BACKGROUND: Several studies have investigated the diagnostic accuracy of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) for pancreatic lesions, but they have included only limited patient populations. This study aimed to clarify the diagnostic accuracy of EUS-FNA in a large number of pancreatic lesions, and to describe the factors that influence it. METHODS: From March 1997 to May 2010, 944 consecutive patients who had undergone EUS-FNA for pancreatic solid lesions were evaluated retrospectively. Factors affecting EUS FNA accuracy were then analyzed. RESULTS: A total of 996 solid pancreatic lesions were sampled by EUS-FNA. The overall sampling adequacy and diagnostic accuracy of these lesions were 99.3 % (989/996) and 91.8 % (918/996), respectively. The sensitivity and specificity for differentiating malignant from benign lesions were 91.5 % (793/867) and 97.7 % (126/129), respectively. The diagnostic performance was significantly higher when both cytological and cell-block examinations were carried out than with only cytological examination. In multivariate analysis, final diagnosis, location of lesion, lesion size, availability of on-site cytopathological evaluation, and experience of EUS-FNA procedure were independent factors affecting the accuracy of EUS-FNA. On-site cytopathological evaluation and lesion size were found to be the most weighted factors affecting diagnostic accuracy. CONCLUSIONS: EUS-FNA for pancreatic solid lesions yielded a high accuracy and low complication rate. Both cytological and cell-block preparations and on-site cytopathological evaluation contributed to improve the accuracy. The diagnostic ability of EUS-FNA was less for smaller lesions, and repeated procedures may be needed if malignancy is suspected. PMID- 23090001 TI - Evidence-based clinical practice guidelines for Crohn's disease, integrated with formal consensus of experts in Japan. AB - Crohn's disease is a disorder of unknown etiology and complicated pathogenesis. A substantial amount of evidence has accumulated recently and has been applied to clinical practice. The present guidelines were developed based on recent evidence and the formal consensus of experts relevant to this disease. Here we provide an overview of these guidelines, as follows. Target disease: Crohn's disease Users: Clinical practitioners in internal medicine, surgery, gastroenterology, and general practice Purpose: To provide appropriate clinical indicators to practitioners Scope of clinical indicators: Concept of Crohn's disease, epidemiology, classifications, diagnosis, treatment, follow up, and special situations Intervention: Diagnosis (interview, physical examination, clinical laboratory tests, imaging, and pathology) and treatment (lifestyle guidance, drug therapy, nutritional therapy, surgery, etc.) Outcome assessment: Attenuation of symptoms, induction and maintenance of remission, imaging findings, quality of life (QOL), prevention of complications and harm of therapy Methods for developing these guidelines: Described in the text Basis of recommendations: Integration of evidence level and consensus of experts Cost-benefit analysis: Not implemented Evaluation of effectiveness: Yet to be confirmed Status of guidelines: Updated version of the first Guidelines published in 2010 Publication sources: Printed publication available and electronic information in preparation Patient information: Not available Date of publication: October 2011 These guidelines were intended primarily to be used by practitioners in Japan, and the goal of these guidelines is to improve the outcomes of patients with Crohn's disease. PMID- 23090003 TI - Risk factors for lymphatic and venous involvement in endoscopically resected gastric cancer. AB - BACKGROUND: Lymphatic and venous involvement is a critical factor in the curability assessment of endoscopically resected gastric cancers; however, the risk factors for lymphatic and venous involvement in endoscopically resected gastric cancers remain unknown. METHODS: To identify risk factors for lymphatic and venous involvement in endoscopically resected gastric cancers, we retrospectively reviewed a consecutive series of 1229 endoscopically resected gastric cancers in 1083 patients treated between January 2009 and December 2011. RESULTS: Lymphatic and venous involvement was detected in 57 (4.6%) and 32 (2.6%) lesions, respectively. A multivariate analysis identified a larger tumor size, deeper invasion (submucosal invasion or deeper), and the presence of a papillary or an undifferentiated-type adenocarcinoma component as independent risk factors for lymphatic involvement. As for venous involvement, deeper invasion (>=500 MUm submucosal invasion), a macroscopically elevated type, and the presence of an undifferentiated-type adenocarcinoma component were identified as independent risk factors. CONCLUSIONS: The present study identified the independent risk factors for lymphatic and venous involvement in endoscopically resected gastric cancers. The recognition of these risk factors would help in the selection of lesions that may require a particularly careful histological evaluation. PMID- 23090004 TI - The results of the Tokyo trial of prevention of post-ERCP pancreatitis with risperidone (Tokyo P3R): a multicenter, randomized, phase II, non-placebo controlled trial. AB - BACKGROUND: A previous study suggested that ulinastatin effectively prevented post-ERCP pancreatitis (PEP) and hyperenzymemia (PEH) in patients at average risk. In experimental models, risperidone, a selective serotonin 2A antagonist, ameliorated acute pancreatitis. We assessed the effect of risperidone combined with ulinastatin for the prevention of PEP in high-risk patients. METHODS: In a multicenter, randomized, controlled, phase II trial, patients undergoing therapeutic ERCP were randomly assigned to receive ulinastatin (150000 U) with or without risperidone (1 mg). A risperidone tablet was taken orally 30-60 min before ERCP and ulinastatin was administered intravenously for 10 min immediately prior to ERCP. The primary end point was the incidence of PEP; secondary end points were PEH severity and enzyme levels (amylase, pancreatic amylase, lipase). RESULTS: A total of 226 patients (113 per group) were included in the study. Six patients in the risperidone + ulinastatin group and ten patients in the ulinastatin group developed pancreatitis (5.3 vs. 8.8 %, p = 0.438). The incidence of moderate/severe PEP was lower in the risperidone + ulinastatin group (1.8 %) than in the ulinastatin group (4.4 %), but this difference was not significant. Although the incidence of PEH did not differ significantly, post ERCP levels of all pancreatic enzymes were significantly lower in the risperidone + ulinastatin group. CONCLUSIONS: Prophylactic oral risperidone administration in combination with ulinastatin did not reduce the incidence and severity of PEP in high-risk patients as compared with ulinastatin alone. However, risperidone showed an additive effect with ulinastatin, reducing serum pancreatic enzyme levels. PMID- 23090006 TI - Retrogenesis: a model of dementia progression in Alzheimer's disease related to neuroplasticity. PMID- 23090005 TI - Fucoidan prevents depression-like behavior in rats exposed to repeated restraint stress. AB - Previous studies have demonstrated that repeated restraint stress in rodents increased depression-like behavior and altered the expression of corticotrophin releasing factor in the hypothalamus. The current study focused on verifying the impact of fucoidan (FCN) administration on repeated restraint stress-induced behavioral responses using the forced swimming test (FST). Additionally, we examined the effect of FCN on the central noradrenergic system by observing changes in neuronal tyrosine hydroxylase (TH) immunoreactivity and brain-derived neurotrophic factor (BDNF) mRNA expression in the rat brains. Male rats received 10, 20, or 50 mg/kg FCN (i.p.) 30 min before daily exposures to repeated restraint stress (2 h/day) for 14 days. Repeated restraint stress increased immobility in the FST. Daily administration of FCN during the repeated restraint stress period significantly inhibited the stress-induced behavioral deficits in this behavioral test. Administration of FCN also significantly blocked the increase in TH expression in the locus coeruleus and the basolateral nucleus of the amygdala, and the decrease in BDNF mRNA expression in the hippocampus. Taken together, these findings indicate that administration of FCN prior to restraint stress significantly improved helpless behavior in rats, possibly through modulating the central noradrenergic system. Therefore, FCN may be a useful agent for treating complex symptoms of depression disorder. PMID- 23090007 TI - Enhancing the salience of fluency improves recognition memory performance in mild Alzheimer's disease. AB - Recognition memory can rely on recollection (recall of the details from the encoding episode) and familiarity (feeling that some information is old without any recollection). In Alzheimer's disease (AD), where there is a clear deficit of recollection, the evidence regarding familiarity is mixed, with some studies showing preserved familiarity and others reporting impairment. The current study examined whether recognition memory performance can be improved in AD when the use of familiarity is facilitated by the salience of processing fluency due to an earlier encounter with the information. Fifteen AD patients and 16 healthy controls performed a verbal recognition memory task where the salience of fluency was manipulated by means of letters overlap. Studied and unstudied words were constituted of either two separate sets of letters (no-overlap condition, high fluency salience) or the same set of letters (overlap condition, low fluency salience). The results showed that, although performance was globally poorer in AD patients than in the controls, both groups performed significantly better in the no-overlap condition than in the overlap condition. This suggests that AD patients benefited as much as the controls from the salience of fluency. PMID- 23090010 TI - Radiation-induced galectin-1 by endothelial cells: a promising molecular target for preferential drug delivery to the tumor vasculature. AB - The present study reports on a new strategy for selective, radiation therapy amplified drug delivery using an antiangiogenic 33-a.a., tumor vasculature targeting ligand, anginex, to improve the therapeutic ratio for strategies developed against solid tumors. Our findings indicate that galectin-1 is (a) one of the major receptors for anginex (b) overexpressed by tumor neovasculature and (c) further specifically upregulated in endothelial cells in response to radiation exposure as low as 0.5 Gy. An investigation of [18]-F-labeled anginex biodistribution in SCK tumors indicates that anginex is an effective targeting molecule for image and radiation-guided therapy of solid tumors. An anginex conjugated liposome capable of being loaded with drug was shown to selectively target endothelial cells post-radiation. The presence of endothelial cells in a three-dimensional co-culture system with tumor cells developed to study tumor/endothelial cell interactions in vitro led to higher levels of galectin-1 and showed a further increase in expression upon radiation exposure when compared to tumor cell spheroids alone. Similar increase in galectin-1 was observed in tumor tissue originating from the tumor-endothelial cell spheroids in vivo and radiation exposure further induced galectin-1 in these tumors. The overall results suggest feasibility of using a clinical or subclinical radiation dose to increase expression of the galectin-1 receptor on the tumor microvasculature to promote delivery of therapeutics via the anginex peptide. This approach may reduce systemic toxicity, overcome drug resistance, and improve the therapeutic efficacy of conventional chemo/radiation strategies. PMID- 23090013 TI - Formation of mesostructured thin films at the air-liquid interface. AB - The growth of free-standing surfactant-templated films of inorganic oxides at the air-solution interface is an attractive route to manufacture unsupported mesostructured membranes for a range of potential applications. So far this synthesis method has been relatively neglected due to the fragility of the initial films. More recent work to understand the mechanism of formation has led to development of thicker, more robust films, as well as providing new information on the general formation mechanisms of mesoporous materials whether in film or particulate form. This review describes the properties of silica and other inorganic oxide films templated by surfactants and grown at the air solution interface, their formation mechanisms and implications for further development of these materials. PMID- 23090009 TI - NADPH oxidases as a source of oxidative stress and molecular target in ischemia/reperfusion injury. AB - Ischemia/reperfusion injury (IRI) is crucial in the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. Paradoxically, both the lack of oxygen during ischemia and the replenishment of oxygen during reperfusion can cause tissue injury. Clinical outcome is also determined by a third, post-reperfusion phase characterized by tissue remodeling and adaptation. Increased levels of reactive oxygen species (ROS) have been suggested to be key players in all three phases. As a second paradox, ROS seem to play a double-edged role in IRI, with both detrimental and beneficial effects. These Janus-faced effects of ROS may be linked to the different sources of ROS or to the different types of ROS that exist and may also depend on the phase of IRI. With respect to therapeutic implications, an untargeted application of antioxidants may not differentiate between detrimental and beneficial ROS, which might explain why this approach is clinically ineffective in lowering cardiovascular mortality. Under some conditions, antioxidants even appear to be harmful. In this review, we discuss recent breakthroughs regarding a more targeted and promising approach to therapeutically modulate ROS in IRI. We will focus on NADPH oxidases and their catalytic subunits, NOX, as they represent the only known enzyme family with the sole function to produce ROS. Similar to ROS, NADPH oxidases may play a dual role as different NOX isoforms may mediate detrimental or protective processes. Unraveling the precise sequence of events, i.e., determining which role the individual NOX isoforms play in the various phases of IRI, may provide the crucial molecular and mechanistic understanding to finally effectively target oxidative stress. PMID- 23090011 TI - A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma. AB - Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development. PMID- 23090014 TI - Diastereoselective, multicomponent access to trans-2-aryl-4-arylamino-1,2,3,4 tetrahydroquinolines via an AA'BC sequential four-component reaction and their application to 2-arylquinoline synthesis. AB - The CAN-catalyzed reaction between 3,5-disubstituted anilines, vinyl ethers and aromatic aldehydes leads to trans-2-aryl-4-arylaminotetrahydroquinolines, in an AA'BC sequential multicomponent transformation related to the Povarov reaction that was also extended to the use of a second aniline as the C-4 substituent. The unusual trans stereochemistry was explained by stabilization of the corresponding intermediate by intramolecular hydrogen bonding. The presence of the 4-anilino substituent allowed adapting the method to the synthesis of 4-unsubstituted 2 arylquinolines, by treatment of the crude product from the MCR with FeCl(3) in methanol. PMID- 23090008 TI - Potential therapeutic approaches for modulating expression and accumulation of defective lamin A in laminopathies and age-related diseases. AB - Scientific understanding of the genetic components of aging has increased in recent years, with several genes being identified as playing roles in the aging process and, potentially, longevity. In particular, genes encoding components of the nuclear lamina in eukaryotes have been increasingly well characterized, owing in part to their clinical significance in age-related diseases. This review focuses on one such gene, which encodes lamin A, a key component of the nuclear lamina. Genetic variation in this gene can give rise to lethal, early-onset diseases known as laminopathies. Here, we analyze the literature and conduct computational analyses of lamin A signaling and intracellular interactions in order to examine potential mechanisms for altering or slowing down aberrant Lamin A expression and/or for restoring the ratio of normal to aberrant lamin A. The ultimate goal of such studies is to ameliorate or combat laminopathies and related diseases of aging, and we provide a discussion of current approaches in this review. PMID- 23090016 TI - Experiences in sub-Saharan Africa with GM crop risk communication: outcome of a workshop. AB - In tackling agricultural challenges, policy-makers in sub-Saharan Africa (SSA) have increasingly considered genetically modified (GM) crops as a potential tool to increase productivity and to improve product quality. Yet, as elsewhere in the world, the adoption of GM crops in SSA has been marked by controversy, encompassing not only the potential risks to animal and human health, and to the environment, but also other concerns such as ethical issues, public participation in decision-making, socio-economic factors and intellectual property rights. With these non-scientific factors complicating an already controversial situation, disseminating credible information to the public as well as facilitating stakeholder input into decision-making is essential. In SSA, there are various and innovative risk communication approaches and strategies being developed, yet a comprehensive analysis of such data is missing. This gap is addressed by giving an overview of current strategies, identifying similarities and differences between various country and institutional approaches and promoting a way forward, building on a recent workshop with risk communicators working in SSA. PMID- 23090015 TI - Identification and characterization of a 66-68-kDa protein as a methotrexate binding protein in murine leukemia L1210 cells. AB - We previously observed an unidentified, tyrosine-phosphorylated, membrane associated, 66-68-kDa protein which was present in the L1210 murine leukemia cells but not present, at least in the tyrosine-phosphorylated form, in cisplatin methotrexate (CDDP-MTX) cross-resistant L1210/DDP cells. We purified and characterized this 66-68-kDa protein by affinity chromatography purification using its two identified properties, tyrosine phosphorylation and MTX-binding, and yielded a single band of 66-68 kDa. The purified protein was subjected to trypsin digestion and the isolated peptide fragments were sequenced and yielded two partial peptide sequences: VEIIANDQ and VTNAVVTVPAYFNDSQRQA. The two peptide sequences were used to search for the mouse genome at the national center for biotechnology information (NCBI) database for Open Reading Frame Sequence (ORFs) containing these peptides using the TBLASTN function. A single gene was identified containing both sequences, the HSPa8 gene, which codes for the heat shock family protein, HSC70. We further demonstrated that HSC70 is a MTX-binding protein using a binding assay with MTX-agarose beads followed by Western blotting. The HSC70 also existed in various cancer cell lines and showed binding to MTX. Additionally, the HSC70 protein, cloned from the L1210 murine leukemia cells, was expressed and purified from E. coli cells using a polyhistidine-tag purification system and it also showed the binding properties with MTX. DnaK, the HSC70 homologue in E. coli, also binds to MTX. By using the purified truncated HSC70 domains, we identified the adenosine triphosphatase (ATPase) domain of HSC70 that can bind to MTX. Thus, we have tentatively characterized a new, novel property of HSC70 as a MTX-binding protein. PMID- 23090017 TI - Two new cholic acid derivatives from the marine ascidian-associated bacterium Hasllibacter halocynthiae. AB - The investigation of secondary metabolites in liquid cultures of a recently discovered marine bacterium, Hasllibacter halocynthiae strain KME 002T, led to the isolation of two new cholic acid derivatives. The structures of these compounds were determined to be 3,3,12-trihydroxy-7-ketocholanic acid (1) and 3,3,12-trihydroxy-7-deoxycholanic acid (2) through HRFABMS and NMR data analyses. PMID- 23090018 TI - Phenylmethimazole blocks dsRNA-induced IRF3 nuclear translocation and homodimerization. AB - Previous studies revealed that phenylmethimazole (C10) inhibits IRF3 signaling, preventing dsRNA-induction of type 1 interferon gene expression, production, and downstream signaling. In the present study, we investigated the molecular basis for C10 inhibition of dsRNA-stimulated IRF3 signaling. IRF-3 Trans-AM assays were used to measure C10 effects on dsRNA induction of IRF3 DNA binding. Green fluorescent protein-labeled IRF3 was used to measure C10 effects on dsRNA-induced IRF3 nuclear translocation. Native PAGE, SDS PAGE, and western blotting were used to identify effects of C10 on IRF3 homodimer formation and phosphorylation, respectively. There was a significant impairment of dsRNA-induced IRF3 DNA binding activity in human embryonic kidney and pancreatic cancer cells with C10 treatment. C10 also blocked dsRNA-induced IRF3 nuclear translocation and homodimer formation without blocking serine 396 phosphorylation of IRF3. Together, these results indicate that C10 interferes with IRF3 signaling by blocking dsRNA-induced IRF3 homodimer formation, a prerequisite for nuclear translocation and DNA binding activities. PMID- 23090019 TI - Synthesis of a cholesteryl-HEG phosphoramidite derivative and its application to lipid-conjugates of the anti-HIV 5'TGGGAG3' Hotoda's sequence. AB - A novel phosphoramidite derivative of cholesterol, with an ether-linked hexaethylene glycol (HEG) spacer arm, has been obtained through simple and reproducible solid phase modified oligonucleotide synthesis manipulations. This building block and the known phosphoramidite derivative of 3b-(2 hydroxyethoxy)cholesterol have been exploited in standard oligonucleotide synthesis protocols for the preparation of 5'- conjugates of the G-quadruplex forming 5'TGGGAG3' oligomer, known as the Hotoda's sequence, to produce new potential anti-HIV agents. PMID- 23090020 TI - trans-Resveratrol in nutraceuticals: issues in retail quality and effectiveness. AB - Fourteen brands of resveratrol-containing nutraceuticals were evaluated in order to verify their actual resveratrol content and to control if their health promoting properties are related to manufacturing quality. Products included pure resveratrol capsules or multi-ingredient formulations with standardized amounts of resveratrol and other phytochemicals. Samples were analyzed for total trans resveratrol, flavonoids, procyanidin, polyphenol content and the results were compared with the content declared on-label. Only five out of 14 brands had near label values, compliant with Good Manufacturing Practices (GMP) requirements (95 105% content of active constituent), four products were slightly out of this range (83-111%) and three were in the 8-64% range. Two samples were below the limit of detection. The greater the difference between actual and labeled resveratrol content, the lower was the antioxidant and antiproliferative activity strength. Dietary supplements containing pure trans-resveratrol exhibited a greater induction of differentiation towards human leukemic K562 cells when compared to multicomponent products. Great differences currently exist among resveratrol food supplements commercially available and GMP-grade quality should not be taken for granted. On the other side, dosages suggested by most "pure", "high-dosage" supplements may allow a supplementation level adequate to obtain some of the purported health benefits. PMID- 23090021 TI - The effect of curcumin on human bronchial epithelial cells exposed to fine particulate matter: a predictive analysis. AB - Fine particulate matter (PM2.5) has been associated in humans with inflammation, oxidative stress and cancer. Studies had shown that curcumin could potentially inhibit these effects; however, there had been no in vivo or in vitro reports about the effects of curcumin on organisms exposed to PM2.5. This predictive study explored the possible biological functions and pathways involved in the mechanism of curcumin inhibition of the hazardous effects of PM2.5. For predictive analysis, microarray data were used to investigate the effect of PM2.5 on human bronchial epithelial cells (HBEC), and human target proteins of curcumin were retrieved from PubChem. Two protein-protein interaction (PPI) networks were established based upon differential genes and target proteins, respectively, and the common network of these two networks was found. Functional and pathway analysis of the common network was performed using the Ingenuity Pathways Analysis (IPA) software. The results suggested that the predictive effects of curcumin on HBEC exposed to PM2.5 were involved in bio-functions, including inflammatory response of airway, cancerogenesis, and apoptosis, and in pathways such as cancer, glucocorticoid receptor signaling, and NF-kappaB signaling. This study predicted for the first time that curcumin could be a potential therapeutic agent for protecting the human airway from the hazardous effects of PM2.5. PMID- 23090022 TI - Synthesis, FTIR, 13C-NMR and temperature-dependent 1H-NMR characteristics of bis naphthalimide derivatives. AB - Chemotherapy is still the most important method of cancer treatment. To make this method more effective and safe, new drugs to destroy cancer cells are needed. Some bis-naphthalimide derivatives show potential anticancer activity via an intercalation mechanism. A higher degree of DNA intercalation corresponds to better therapeutic effects. The degree of intercalation of naphthalimides depends on their structure, molecular dynamics and intermolecular interactions with DNA. In order to apply any active substance as a drug, its molecular dynamics as well as possible interactions with target molecules have to be examined in exhaustive details. This paper describes a practical preparation of some novel bis naphthalimide derivatives with different functional groups and their FTIR and 1H- and 13C-NMR spectral characteristics. To determine the molecular dynamics of the obtained compounds the temperature, their 1H-NMR spectra were measured. It has been clearly proven in this paper that the unusual temperature-dependent 1H-NMR behavior of the aromatic protons of phthalimide derivatives, previously described in the literature as "hypersensitivity" and explained by n-pi interactions and molecular motions of aromatic amide rings, is a result of temperature driven changes of the geometry of carbonyl groups. PMID- 23090023 TI - Acute toxicity and gastroprotective effect of the Schiff base ligand 1H-indole-3 ethylene-5-nitrosalicylaldimine and its nickel (II) complex on ethanol induced gastric lesions in rats. AB - The present study was performed to evaluate the gastroprotective activity of Schiff base ligand derived from the condensation reaction of tryptamine (an indole derivative) and 5-nitrosalicylaldehyde (TNS) and its nickel (II) complex against ethanol-induced gastric ulcer in rats. The compounds were orally administered with low (30 mg/kg) and high (60 mg/kg) doses to ulcer-induced Sprague-Dawley rats. Macroscopically, the ulcer control group exhibited severe mucosal injury, whereas pre-treatment with either cimetidine or TNS and its nickel (II) complex each resulted in significant protection against gastric mucosal injury. Flattening of gastric mucosal folds was also observed in rats pretreated with TNS and its nickel complex. Histological studies of the gastric wall of ulcer control group revealed severe damage of gastric mucosa, along with edema and leucocytes infiltration of the submucosal layer compared to rats pre treated with either cimetidine or TNS and its nickel (II) compound, where there was marked gastric protection along with reduction of edema and leucocytes infiltration of the submucosal layer. Acute toxicity study done on mice with a higher dose of 5 g/kg of TNS and its nickel (II) complex did not manifest any toxicological signs. Research finding suggest that TNS and its nickel (II) complex could be considered as effective gastroprotective compounds. PMID- 23090024 TI - A sub-pathway based method to identify candidate agents for Ankylosing Spondylitis. AB - The need for new therapeutics for Ankylosing Spondylitis (AS) is highlighted by the general lack of efficacy for most agents currently available for this disease. Many recent studies have detailed molecular pathways in AS, and several molecule-targeting agents are undergoing evaluation. We aimed to explore the mechanism of AS and identify biologically active small molecules capable of targeting the sub-pathways which were disregulated in the development of AS. By using the GSE25101 microarray data accessible from the Gene Expression Omnibus database, we first identified the differentially expressed genes (DEGs) between AS samples and healthy controls, followed by the sub-pathway enrichment analysis of the DEGs. In addition, we propose the use of an approach based on targeting sub-pathways to identify potential agents for AS. A total of 3,280 genes were identified as being significantly different between patients and controls with p values < 0.1. Our study showed that neurotrophic signaling pathway and some immune-associated pathways may be involved in the development of AS. Besides, our bioinformatics analysis revealed a total of 15 small molecules which may play a role in perturbing the development of AS. Our study proposes the use of an approach based on targeting sub-pathways to identify potential agents for AS. Candidate agents identified by our approach may provide the groundwork for a combination therapy approach for AS. PMID- 23090026 TI - Angiogenesis: A deeper understanding of VEGFR inhibitors. PMID- 23090025 TI - Conformational transitions provoked by organic solvents in chicken egg ovalbumin: mimicking the local environment. AB - Glycoprotein ovalbumin is an important protein to study helix/sheet transitions as it possess almost equal amount of alpha-helix and beta-sheet. Conformational changes on ovalbumin at various concentrations of glyoxal, ethylene glycol (EG) and polyethylene glycol-400 (PEG-400) were investigated by fluorescence spectroscopy, circular dichroism, attenuated total reflection Fourier transform infra red spectroscopy, 8-anilino-1-naphthalenesulfonic acid and thioflavin T assay. A partially folded state of ovalbumin at 50 % v/v glyoxal was detected that preceded the onset of the aggregation process at the maximum concentration (90 % v/v) of this aldehyde. Aggregates of ovalbumin in the presence EG and PEG 400 were deduced at 70 and 80 % v/v respectively. Maximum aggregation of ovalbumin was observed at 80 % v/v PEG-400, followed by 70 % v/v EG and 90 % v/v glyoxal. Our study confirms that protein aggregation is influenced by the chemistry of organic solvent used thus follows an order of solvent effectiveness (PEG > EG > glyoxal) in inducing the transition. These results provide valuable information on the mechanisms involved in the pathogenesis of some conformational diseases. The alpha-helix to beta-sheet conversion is a diagnostic feature of protein aggregation and has been considered as a general characteristic of amyloid fibrillogenesis in vitro. PMID- 23090033 TI - Titanium sulphene: two-dimensional confinement of electrons and phonons giving rise to improved thermoelectric performance. AB - We investigated the thermoelectric properties of titanium sulphene, namely, few layered TiS(2) nanosheets, by using density functional theory and the Boltzmann transport equations. The Seebeck coefficient of titanium sulphene was found to increase if the thickness fell below 14 triple layers (~8 nm) and for the monolayer becomes 40% larger than that of the bulk TiS(2). This behavior is attributed to an enhancement in the density of states near the conduction band minimum in the monolayer. Moreover, the acoustic phonon band of the monolayer is more flat than that of the bulk, which results in a 37% reduction of the acoustic phonon group velocity and was beneficial for a low lattice thermal conductivity. Therefore, the combined effects from quantum confinement of both electrons and phonons could lead to a significant enhancement in thermoelectric performance in the two-dimensional titanium sulphene. PMID- 23090034 TI - Menstrual and reproductive factors, exogenous hormone use, and risk of thyroid carcinoma in postmenopausal women. AB - PURPOSE: To investigate the association of reproductive factors and hormone therapy, including type of hormone therapy, with risk of thyroid cancer in postmenopausal women. METHODS: We assessed these associations with risk of incident thyroid cancer in a cohort of 145,007 postmenopausal women enrolled in the Women's Health Initiative. Over 12.7 years of follow-up, 296 cases of thyroid cancer were identified, including 243 with papillary thyroid cancer. Cox proportional hazards models were used to estimate hazard ratios and 95 % confidence intervals for exposures of interest. RESULTS: In both age-adjusted and multivariable-adjusted analyses, menstrual and reproductive factors including age at menarche, age at menopause, age at first birth, age at last live birth, parity, duration of breastfeeding, miscarriages, stillbirths, hysterectomy, bilateral oophorectomy, and use of oral contraceptives were not associated with risk of all thyroid cancer or papillary thyroid cancer. In addition, ever use of menopausal hormone therapy, current or former use, duration of use, and type were not associated with risk. CONCLUSION: We found little support for associations of reproductive or hormonal factors with risk of developing thyroid cancer. Importantly, our study showed no association of type of hormone therapy used with thyroid cancer risk. PMID- 23090035 TI - The association between cancer and amyotrophic lateral sclerosis. AB - OBJECTIVE: Increasing evidence suggests that some neurodegenerative disorders, such as Parkinson's disease, are inversely related to cancer. Few epidemiologic studies have examined the relationship between cancer and amyotrophic lateral sclerosis (ALS), another major neurodegenerative disease. This study addresses that gap. METHODS: Using data from 16 population-based cancer registries of the Surveillance, Epidemiology, and End Results (SEER) Program of the U.S. National Cancer Institute and death certificates, we followed 2.7 million cancer survivors who were diagnosed between 1973 and 2007, and who survived at least 1 year following cancer diagnosis. The standardized mortality ratio (SMR) of observed to expected ALS deaths in cancer survivors was calculated. RESULTS: A total of 1,216 ALS deaths were reported among 1 year survivors of cancer over 16.6 million person-years of follow-up. ALS mortality was not significantly associated with the incidence of total cancers [SMR = 1.00 (95 % confidence interval (CI), 0.95 1.06)]. There was, however, a significantly elevated risk of ALS death among survivors of melanoma [SMR = 1.49 (95 % (CI), 1.17-1.85)] and of tongue cancer [SMR = 2.57 (95 % CI, 1.41-4.32)], and a significantly reduced ALS death risk among prostate cancer survivors [SMR = 0.86 (95 % CI, 0.76-0.96)]. CONCLUSIONS: Cancer at certain sites may be related to risk of ALS death. Possible biologic factors linking ALS to these cancers are discussed. Future studies should attempt to confirm these associations using incident ALS outcomes. Establishing relationships between cancer and neurodegenerative diseases, such as ALS, opens new opportunities for understanding related pathophysiologic and therapeutic possibilities for these diseases. PMID- 23090036 TI - Development of microscopic colitis secondary to duloxetine. PMID- 23090037 TI - The incidence of primary antibiotic resistance of Helicobacter pylori in Vietnam. AB - GOALS: To determine the susceptibility of Helicobacter pylori strains isolated from a Vietnamese population to 5 antibiotics. BACKGROUND: The incidence of antibiotic resistance in H. pylori infection is increasing worldwide and has become a leading cause for failure of treatment. Antibiotic susceptibility testing is very important to provide optimal regimens in a clinical setting. STUDY: We isolated 103 H. pylori strains from the gastric mucosa of H. pylori infected patients from 2 areas in Vietnam (Ho Chi Minh and Hanoi) in 2008. Epsilometer test was used to determine the minimum inhibitory concentrations of amoxicillin, clarithromycin (CLR), metronidazole (MNZ), levofloxacin, and tetracycline. RESULTS: Among the 103 strains, the resistance rates were 0% (amoxicillin), 33% (CLR), 69.9% (MNZ), 18.4% (levofloxacin), and 5.8% (tetracycline). The resistant strains showed a high-level of resistance (>= 256 ug/mL) to CLR, 23.5% (8/34), and MNZ, 29.1% (21/72). The resistance rate for CLR was significantly higher in Ho Chi Minh than in Hanoi (49% vs. 18.5%, P=0.001). Resistance to both CLR and MNZ was most commonly observed (24.3%). Two strains (1.9%) were resistant to 4 of the 5 antibiotics. No significant association was observed between antibiotic resistance rates and age, sex, or clinical outcomes of the patients. CONCLUSIONS: High incidence of resistance to CLR and MNZ suggests that standard triple therapies may not be useful as first-line treatment in Vietnam. Alternative strategies such as bismuth-based quadruple therapies or sequential therapy may be more effective in Vietnam. PMID- 23090038 TI - Colonic methane production modifies gastrointestinal toxicity associated with adjuvant 5-fluorouracil chemotherapy for colorectal cancer. AB - GOALS: To investigate the association of colonic methane, formed by methanogenic achaea, and pH with gastrointestinal symptoms during colorectal cancer chemotherapy. BACKGROUND: Adjuvant 5-fluorouracil chemotherapy reduces recurrences in colorectal cancer, but causes severe gastrointestinal toxicity, partly related to disturbed intestinal microbiota. STUDY: Resected colorectal cancer patients (n=143) were analyzed for colonic methanogenesis and pH before and during the 24 weeks of 5-fluorouracil chemotherapy and for gastrointestinal symptoms during chemotherapy. This study was performed within the setting of an intervention study on the effects of Lactobacillus on chemotherapy-related gastrointestinal toxicity. The site of resected cancer, resection type, stoma, chemotherapy regimen, hypolactasia, and Lactobacillus intervention were considered as possible confounding factors, and multivariate models were constructed. RESULTS: Baseline methane producers had less frequent diarrhea (more than or equal to moderate) during chemotherapy than nonproducers [odds ratio (OR), 0.42; 95% confidence interval (CI), 0.20 to 0.88; P=0.022] and more frequent constipation (OR, 4.56; 95% CI, 2.01 to 10.32; P<0.001). Baseline fecal pH was also associated with symptoms during chemotherapy; higher the pH, the lower the risk of diarrhea (OR, 0.56; 95% CI, 0.31 to 1.02; P=0.058) and higher the risk of constipation (OR, 2.23; 95% CI, 1.35 to 3.68; P=0.002). In multivariate stepwise models, methanogenesis was a significant explaining factor with inverse association with diarrhea and positive association with constipation. Fecal pH, which was significantly associated with methane production, was no longer a significant explaining factor when methanogensis was included in the model. CONCLUSIONS: Methane producer status has a role in determining whether patient experiences diarrhea or constipation during 5 fluorouracil therapy. This underscores the importance of intestinal microbiota in the development of intestinal toxicity during 5-fluorouracil therapy. PMID- 23090039 TI - High proportion of hepatitis C virus in community Asian American patients with non-liver-related complaints. AB - GOALS AND BACKGROUND: Besides United States population born between 1945 and 1965, screening for hepatitis C virus (HCV) is not recommended for the general US population. However, HCV may be more prevalent in certain subgroups and screening may be warranted. The goal of this study was to examine the proportion of HCV in a large sample of community Asian American patients presenting for non-liver related complaints. STUDY: We conducted a cross-sectional study of 1246 patients tested for hepatitis C virus antibodies (anti-HCV) referred to 2 gastroenterology clinics for non-liver-related gastrointestinal reasons between January 2001 and February 2011. We determined HCV status and patient history via electronic medical record review. RESULTS: Of the 1246 study patients tested for anti-HCV, the majority were Asian (81.4%) and 29 Asian patients (2.9%) had positive anti HCV. HCV proportion in the remaining 232 non-Asians (non-Hispanic whites and Hispanics) was 1.7%. Asians with positive anti-HCV were more likely to have had blood transfusions (31.0% vs. 6.6%, P<0.0001) or acupuncture (10.3% vs. 1.5%, P<0.0001). Of the 976 Asian patients with hepatitis B surface antigen testing, 38 (3.9%) also had detectable hepatitis B surface antigen. CONCLUSIONS: Among patients seen at community gastroenterology clinics for non-liver-related reasons, HCV proportion was 1.7% for non-Asians and 2.9% for Asians. Screening for HCV should be offered to high-risk patients presenting to gastroenterology clinics with unrelated gastrointestinal complaints. PMID- 23090041 TI - Use of administrative claims data for identifying patients with cirrhosis. AB - BACKGROUND: Administrative data are used in clinical research, but the validity of ICD-9 codes to identify cirrhotic patients has not been well established. GOALS: To determine the diagnostic accuracy of ICD-9 codes for cirrhosis in clinical practice. STUDY: We conducted a retrospective cohort study of patients from a safety-net hospital between 2008 and 2011. Patients were initially identified using ICD-9 codes for cirrhosis or a resultant complication. The gold standard for diagnosis of cirrhosis was histology and/or imaging based on medical record review. Sensitivity, specificity, positive predictive values, and negative predictive values for each ICD-9 code were calculated. Diagnostic accuracy was assessed by the c-statistic using receiver operator characteristic curve analysis. RESULTS: We identified 2893 patients with an ICD-9 code for cirrhosis, of whom 50.2% had 1 ICD-9 code, 20.3% had 2 different codes, and 29.5% had 3 or more codes. Cirrhosis was confirmed in 44.0% of patients with 1 ICD-9 code, 82.6% with 2 codes, and 95.7% of those with at least 3 codes. Ascites had a significantly lower positive predictive values for cirrhosis than other ICD-9 codes (P<0.001). The optimal combination of ICD-9 codes to identify cirrhotic patients included all codes except that of ascites, with a c-statistic of 0.71 in our derivation cohort. The sensitivity of this combination was confirmed to be 98% in a validation cohort of 285 patients with known cirrhosis. CONCLUSIONS: Administrative data can identify patients with cirrhosis with high accuracy, although ascites has a significantly lower positive predictive value than other ICD-9 codes. PMID- 23090040 TI - The association between metabolic syndrome and colorectal neoplasm: systemic review and meta-analysis. AB - BACKGROUND: There has been constant speculation about the association between metabolic syndrome (MetS) and colorectal neoplasia (CN); however, the published results are conflicting. The aims of this study are to conduct a systematic search, and assess the literature to determine the available evidence on the association between these two conditions. METHODS: Meta-analysis was conducted based on relevant studies identified through a systematic literature review from PubMed, OvidSP, and Cochrane database during January 1980 to July 2011. A combined analysis was performed, followed by a subgroup analyses stratified by the study design, type of colorectal lesions, and sex. Publication bias was assessed using the Begg and Egger tests and visual inspection of funnel plot. RESULTS: Eighteen studies were included in the final analysis. Overall, MetS was associated with 34% increase in the risk of CN [summary relative risk (RR), 1.34; 95% confidence interval (CI), 1.24-1.44]. The association between MetS and CN was found to be statistically significant in separate analysis for both case-control studies (summary RR, 1.58; 95% CI, 1.44-1.73) and cohort studies (summary RR, 1.21; 95% CI, 1.13-1.29). The association remained significant when analyses were restricted by type of colorectal lesions (colorectal cancer: RR, 1.30; 95% CI, 1.18-1.43; colorectal adenoma: RR, 1.37; 95% CI, 1.26-1.49). Further subgroup analysis by sex showed significant association between MetS and CN in both male and female population. CONCLUSIONS: Our meta-analysis showed significant association between presence of MetS and CN. These results may help in identifying high-risk individuals at early stage, who might benefit from targeted colorectal cancer screening intervention. PMID- 23090042 TI - KRAS mutations are associated with specific morphologic features in colon cancer. AB - BACKGROUND: Mutations in the KRAS gene occur at an early stage in the development of colorectal carcinoma. Importantly, KRAS mutation predicts resistance to anti epidermal growth factor receptor therapy in stage IV disease. GOALS: The aim of the current study is to correlate histologic features of colon cancer with the presence of KRAS mutations. STUDY: Tumor tissue from 145 colon cancer resections was tested for KRAS mutations. KRAS mutation status was correlated with demographic and histologic characteristics. Statistical analysis was performed using the Pearson chi2 test and multivariate analysis. RESULTS: KRAS mutations were present in 55/145 cases (37.9%), consistent with reported rates. KRAS mutations were significantly associated with usual adenocarcinoma morphology (multivariate P=0.014), peritumoral lymphocytic response (chi2, P=0.028; multivariate P=0.017), T3-T4 status (chi2, P=0.012; multivariate P=0.015), right sided location (multivariate P=0.027), absence of lymphovascular invasion (multivariate P=0.008), and metastases at the time of resection (multivariate P=0.034). No association was found between KRAS mutation status and other factors. CONCLUSIONS: Specific morphologic features in colon cancer suggest a higher likelihood of the presence of KRAS mutations. These morphologic features overlap partially with those associated with DNA mismatch repair gene mutations. If confirmed, these results may suggest a paradigm for directed KRAS testing. PMID- 23090043 TI - Clinical response to steroid treatment is an important consideration when deciding whether to administer antiviral therapy to patients with active ulcerative colitis. PMID- 23090044 TI - Coupled plasma filtration adsorption combined with continuous veno-venous hemofiltration treatment in patients with severe acute pancreatitis. AB - BACKGROUND: Severe acute pancreatitis (SAP) still has a high mortality rate. Coupled plasma filtration adsorption (CPFA) and continuous veno-venous hemofiltration (CVVH) are 2 extracorporeal blood purification techniques. We hypothesized that CPFA combined with CVVH could preferentially improve prognosis and suppress clinical manifestations of SAP. METHODS: In this observational cohort study, 25 patients with SAP were enrolled, in which 12 received CPFA plus CVVH treatment (group 1), and 13 received CVVH therapy (group 2). All the patients underwent a successive 10-day intervention. Clinical indicators were detected before or after the intervention and the results were compared between the 2 groups. The feasibility and the survival rate were evaluated on day 28. RESULTS: Compared with group 2, oxygenation index (PaO(2)/FiO(2)), mean arterial pressure, serum amylase, and blood urine nitrogen showed significant differences (all P<0.01) and serum TNF-alpha, IL-1beta, IL-6 were reduced and IL-10 was elevated with time in group 1 (all P<0.01). Liver functions, electrolyte, and acid-base balance did not show significant difference before and after the 10-day treatment with CPFA plus CVVH compared with CVVH (P>0.05). No therapy-related adverse reactions were noted in both groups. Twenty-eight-day survival rate of group 1 was higher than that in group 2 [91.7% (11/12) vs. 53.8% (7/13), P<0.05]. CONCLUSIONS: CPFA combined with CVVH was an effective and safe method for treatment of SAP patients, the mechanism being related to its effect on regulating the level of cytokines and serum amylase. PMID- 23090045 TI - Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation in Helicobacter pylori eradication therapy. AB - GOALS: To meta-analyze whether Lactobacillus-containing and Bifidobacterium containing probiotic compound preparation could improve Helicobacter pylori (H. pylori) eradication rates and reduce side effects. BACKGROUND: There have been several studies demonstrating that Lactobacillus and Bifidobacterium species have an inhibitory effect on H. pylori. The application of probiotics in clinical practice is more often in the form of Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation. STUDY: We included all parallel controlled trials comparing Lactobacillus-containing and Bifidobacterium containing probiotic compound preparation supplementation or not during H. pylori eradication therapy in meta-analysis. Statistical analysis was performed with the Stata version 11.0 software. Subgroup analysis and sensitivity analysis were also performed. RESULTS: Ten clinical trials were included in our meta-analysis. Eradication odds ratio (OR) was available for 1469 patients (708 in the probiotics supplementation group and 761 in the control group). The pooled OR by intention-to-treat analysis and by per-protocol analysis in the probiotics supplementation versus without probiotics was 2.066 [95% confidence interval (CI), 1.398-3.055] and 2.321 (95% CI, 1.715-3.142), respectively. The pooled OR of incidence of total side effects was significantly decreased in the probiotics supplementation group (OR=0.305; 95% CI, 0.117-0.793) by the random model without significant publication bias. CONCLUSIONS: Lactobacillus-containing and Bifidobacterium-containing probiotic compound preparation during initial H. pylori eradication therapy in the adult may have beneficial effects on eradication rate and incidence of total side effects. PMID- 23090046 TI - Response to higher dose of entecavir 1.0 mg daily in patients with partial response to entecavir 0.5 mg daily. AB - BACKGROUND: Despite its high potency against hepatitis B virus (HBV), entecavir (ETV) 0.5 mg daily may not be sufficient to induce complete viral suppression in some patients with very high pretreatment viremia. It is not clear whether ETV 1.0 mg daily would have additive effect in such patients. GOALS: Our goal was to examine virologic outcome of ETV 1.0 mg daily in patients with partial response to ETV 0.5 mg daily. METHODS: We retrospectively studied 31 consecutive treatment naive patients who were switched to ETV 1.0 mg daily after partial response [reduction of HBV DNA >=2 log10 IU/mL but with detectable HBV DNA levels (>100 IU/mL) after 24 weeks of therapy or longer] with ETV 0.5 mg daily from January 2005 to January 2010 at 2 clinics. RESULTS: All patients were Asians and 90% had positive hepatitis B e antigen. Mean HBV DNA was 8.04+/-0.65 log10 IU/mL before therapy and 3.64+/-0.91 log10 IU/mL at the time of switch. Overall rate of complete viral suppression were 29% (n=9/31) after 24 weeks of ETV 1.0 mg daily and 22% (n=5/23) after 48 weeks. Complete viral suppression after 24 weeks with ETV 1.0 mg daily was significantly higher in patients with lower HBV DNA (<3 log10 IU/mL) at time of switch: 75% versus 5%, P<0.0001. CONCLUSIONS: The majority of patients with partial response to ETV 0.5 mg daily did not achieve complete viral suppression with the higher dose of ETV 1.0 mg daily except those with minimal residual viremia (HBV DNA <3 log10 IU/mL). PMID- 23090047 TI - Predictive factors of impaired quality of life in Korean patients with inactive inflammatory bowel disease: association with functional gastrointestinal disorders and mood disorders. AB - BACKGROUND AND AIM: Inflammatory bowel disease is a chronic and relapsing inflammatory disorder of the intestine and has a great effect on patients' health related quality of life (HRQOL). Some patients in remission are known to show functional gastrointestinal disorders (FGIDs) and mood disorders (MDs), which may also negatively impact HRQOL. The aim of this study was to evaluate predictors of impaired HRQOL in inactive inflammatory bowel disease (IBD) patients. METHODS: Patients presenting a long-standing remission during the previous year completed questionnaires of EuroQol, Rome III criteria for FGID, and Hospital Anxiety and Depression Survey. Demographic data including age, sex, employment status, education, smoking, and location of residence were also collected. RESULTS: Among the 513 patients with IBD, 226 (Crohn's disease 107 and ulcerative colitis 119, age 39.01+/-15.63, male 141) defined in remission were enrolled. Overall, 147 (65.0%) had at least 1 FGID with irritable bowel syndrome being the most common disorder (36.3%). Anxiety and depression were identified in 27.4% and 33.6%, respectively. Participants with FGID or MD had a significantly lower HRQOL status than those without disorders (P<0.01). Among various demographic and clinical variables, aged 40 or older [odds ratio (OR), 2.342; 95% confidence interval (CI), 1.195-4.590; P=0.01], irritable bowel syndrome (OR, 3.932; 95% CI, 1.937 7.982; P<0.01), and anxiety (OR, 2.423; 95% CI, 1.067-5.502; P=0.03) were significant independent predictors of impaired HRQOL in inactive IBD patients. CONCLUSIONS: FGID and MD are common in Korean quiescent IBD patients. Appropriate management should be administered according to age of patients and presence of concomitant FGID and MD to improve patients' HRQOL. PMID- 23090048 TI - Immunosuppressive therapy does not increase operative morbidity in patients with Crohn's disease. AB - GOALS: The aim of this study was to examine the impact of immunosuppressive therapy on the morbidity of intestinal surgery in patients with Crohn's disease. BACKGROUND: An increasing number of immunomodulating agents are being used in the treatment of Crohn's disease. The effect of these medications on surgical morbidity is controversial. STUDY: We performed a retrospective review of our prospectively maintained database of patients with Crohn's disease who underwent intestinal surgery between June 1999 and May 2010. The effect of perioperative immunomodulation on postoperative outcomes, specifically anastomotic complications, was evaluated. Predictors of postoperative morbidity among demographic and surgical variables were identified. Length of hospitalization and rate of hospital readmission were compared between groups. Comparisons were made using Student t test and Fisher exact test. RESULTS: One hundred ninety-six intestinal procedures were performed. One hundred twenty-seven (64.8%) of these were performed among patients who received perioperative immunomodulation. Forty six (23.5%) procedures were in patients who received >1 immunomodulating medication perioperatively. Complications occurred in 45 (23.0%) cases. There were 20 (10.2%) anastomotic complications, including 8 (4.1%) intra-abdominal abscesses, 8 (4.1%) anastomotic leaks, and 4 (2%) enterocutaneous fistulas. Preoperative treatment with steroids (P=0.21), 6-MP (P=0.10), and anti-tumor necrosis factor biologics (P=1.0) was not associated with increased postoperative anastomotic complications. Combination immunosuppressive therapy also did not increase morbidity (P=0.39). CONCLUSIONS: In our series, single agent and combination immunosuppressive therapy given around the time of intestinal surgery did not increase the incidence of surgical complications in patients with Crohn's disease. PMID- 23090050 TI - Organocatalytic asymmetric cyanation of isatin derived N-Boc ketoimines. AB - We report the first catalytic asymmetric cyanation of N-Boc ketoimines, which enables highly enantioselective synthesis of oxindole based alpha-amino nitriles. An unprecedented tandem aza-Wittig/Strecker reaction is also developed, emerging as a promising strategy for the catalytic asymmetric cyanation of ketoimines formed in situ from achiral ketones. PMID- 23090049 TI - The effect of long-term supplementation with branched-chain amino acid granules in patients with hepatitis C virus-related hepatocellular carcinoma after radiofrequency thermal ablation. AB - GOALS: To elucidate whether long-term supplementation with branched-chain amino acid (BCAA) granules improves overall survival (OS) and recurrence-free survival (RFS) after radiofrequency thermal ablation (RFA) in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC)<=3 cm in diameter with up to 3 nodules and a serum albumin level before RFA of <=3.5 g/dL. BACKGROUND: Whether BCAA treatment after curative RFA for patients with HCV-related HCC improves OS and RFS remains unclear. STUDY: We compared the OS rate and the RFS rate between the BCAA group (n=115) and the control group (n=141). We also examined factors contributing to OS and RFS. RESULTS: The 1 and 3 years OS rates after RFA were 94.0% and 70.0%, respectively, in the BCAA group, and 94.0% and 49.8%, respectively, in the control group (P=0.001). The corresponding RFS rates 1 and 3 years after RFA were 61.8% and 28.0%, respectively, in the BCAA group, and 52.0% and 12.0%, respectively, in the control group (P=0.013). In the multivariate analysis, in terms of OS, BCAA treatment, and serum albumin level of >=3.4 g/dL, and in terms of RFS, age 70 years or older, BCAA treatment, and a serum albumin level of >=3.4 g/dL were significant independent factors, respectively. CONCLUSIONS: BCAA treatment may improve OS and RFS after RFA in patients with HCV related HCC<=3 cm in diameter with up to 3 nodules and a serum albumin level before RFA of 3.5 g/dL. PMID- 23090051 TI - First-principles molecular dynamics study for average structure and oxygen diffusivity at high temperature in cubic Bi2O3. AB - Bismuth oxide, Bi(2)O(3), has a cubic structure (delta-phase) at high temperature. High oxygen conductivity of delta-Bi(2)O(3) should be closely related to disordering of the oxygen sublattice. In order to reconstruct the disordered structure in the crystal using first-principles molecular dynamics (FPMD), a sufficiently long simulation time is essentially required. In this study, the FPMD simulation up to 1 ns is performed with special interest given to the convergence of the average structure and the oxygen diffusivity with respect to the simulation time. The obtained average structure and the oxygen diffusivity are in good agreement with those obtained by experimental analysis. PMID- 23090052 TI - Toluene biodegradation rates in unsaturated soil systems versus liquid batches and their relevance to field conditions. AB - Contaminant biodegradation in unsaturated soils may reduce the risks of vapor intrusion. However, the reported rates show large variability and are often derived from slurry experiments that are not representative of unsaturated conditions. Here, different laboratory setups are used to derive the biodegradation capacity of an unsaturated soil layer through which gaseous toluene migrates from the water table upwards. Experiments in static unsaturated soil microcosms at 6-30 % water-filled porosity (WFP) and unsaturated soil columns at 9, 14, and 27 % WFP were compared with liquid batches containing the same culture of Alicycliphilus denitrificans. The biodegradation rates for the liquid batches were orders of magnitude lower than for the other setups. Hence, liquid batches do not necessarily reflect optimal conditions for bacteria; either oxygen or toluene mass transfer at the cell scale or the absence of soil-water air interfaces seemed to be limiting bacterial activity. For the column setup, the rates were limited by mass supply. The microcosm results could be described by apparent first-order biodegradation constants that increased with WFP or through a numerical model that included biodegradation as a first-order process taking place in the liquid phase only. The model liquid phase first-order rates varied between 6.25 and 20 h(-1) and were not related to the water content. Substrate availability was the primary factor limiting bioactivity, with evidence for physiological stress at the lowest water-filled porosity. The presented approach is useful to derive liquid phase biodegradation rates from experimental data and to include biodegradation in vapor intrusion models. PMID- 23090053 TI - The effect of managing nutrients in the performance of anaerobic digesters of municipal wastewater treatment plants. AB - Is it possible to create conditions in the anaerobic digesters to control nutrients without changing the performance of a reactor? This study investigates an answer for this question. To this purpose, anaerobic reactors are operated at high concentrations of Mg(2+) ion to harvest the nutrient ions (NH4 (+) and PO4 (3-)) in the form of struvite, that is, magnesium ammonium phosphate. The effects of this modification on the anaerobic digestion of sewage sludge were investigated in terms of chemical oxygen demand (COD) removal and cumulative CH4 production as well as the changes in the biological diversity. The results showed that approximately 50 % of the nutrients (NH4 (+) and PO4 (3-)) were removed regardless of the method adopted for the addition of Mg(2+) ion, slug or daily dosing. The numbers of Methanosaeta and Methanosarcina in the samples withdrawn prior to and after the addition of Mg(2+) did not show significant difference according to the results obtained from qPCR analyses. The research results showed that the addition of Mg(2+) into the anaerobic digesters in municipal wastewater treatment facilities may help to remove the nutrients from the effluent while recovering in their solid forms. PMID- 23090054 TI - Activity, distribution, and abundance of methane-oxidizing bacteria in the near surface soils of onshore oil and gas fields. AB - Methane-oxidizing bacteria (MOB) have long been used as an important biological indicator for oil and gas prospecting, but the ecological characteristics of MOB in hydrocarbon microseep systems are still poorly understood. In this study, the activity, distribution, and abundance of aerobic methanotrophic communities in the surface soils underlying an oil and gas field were investigated using biogeochemical and molecular ecological techniques. Measurements of potential methane oxidation rates and pmoA gene copy numbers showed that soils inside an oil and gas field are hot spots of methane oxidation and MOB abundance. Correspondingly, terminal restriction fragment length polymorphism analyses in combination with cloning and sequencing of pmoA genes also revealed considerable differences in the methanotrophic community composition between oil and gas fields and the surrounding soils. Principal component analysis ordination furthermore indicated a coincidence between elevated CH4 oxidation activity and the methanotrophic community structure with type I methanotrophic Methylococcus and Methylobacter, in particular, as indicator species of oil and gas fields. Collectively, our results show that trace methane migrated from oil and gas reservoirs can considerably influence not only the quantity but also the structure of the methanotrophic community. PMID- 23090055 TI - Development of a novel recombinant strain Zygosacharomyces rouxii JL2011 for 1,3 propanediol production from glucose. AB - 1,3-propanediol (1,3-PDO) is one of the most important industrial chemicals due to its highly desired properties and its wide applications as a key component of the emerging polymer industry. Biotechnology route has been one of the most interesting methods for 1,3-PDO production, whereas, the dha genes were essential to 1,3-PDO biosynthesis. In this study, we cloned and placed the dha cassettes under the control of a glyceraldehyde 3-phosphate dehydrogenase gene promoter pGAP and homologous ZrFPS1 gene promoter pZrfps1; these two promoters were further integrated into the chromosome of Z. rouxii JL2011 to generate recombinant strain JL2011-GZ and JL2011-ZZ, respectively. The results showed that the two strains could produce 1,3-PDO from glucose with a final yield of 6.9 and 10.3 g/l, respectively. The engineered strain JL2011-ZZ showed a 2.3- and 1.5 fold increase in the specific activities and final concentration of 1,3-PDO, respectively, with respect to JL2011-GZ. Batch fermentation with aerobic/micro aerobic combined strategy of JL2011-ZZ resulted a titer of 17.1 g/l and a yield from glucose of 8.6 %. These results demonstrated that JL2011-ZZ would be a potential strain for 1,3-PDO production from glucose. PMID- 23090056 TI - A new polysialic acid production process based on dual-stage pH control and fed batch fermentation for higher yield and resulting high molecular weight product. AB - To determine the factors influencing the resulting molecular weight of polysialic acid (PSA), batch fermentations by using Escherichia coli were conducted. It was found that temperature and pH were significant factors affecting the PSA production and its resulting molecular weight. When pH was set at 6.4, temperature of 37 degrees C was suitable for cell growth and PSA production while 33 degrees C facilitated production of higher molecular weight of PSA. pH 6.4 was favorable for PSA production while pH 7.4 was good for higher molecular weight of PSA at 37 degrees C. Intramolecular self-cleavage of PSA might lead to relatively low molecular weight under mild acidic condition. Our data suggest that the PSA molecular weight is significantly affected by the pH condition rather than the temperature. It is concluded that the resulting PSA molecular weight not only depends on fermentation conditions but also relates to cell growth rate and PSA production rate. Higher PSA molecular weight was made when its production rate was faster than degradation rate. A novel two-stage pH control fermentation process for production of high molecular weight PSA was developed. At the first stage, pH was set at 6.4 to encourage cell growth and PSA production, whereas pH was set at 7.4 at the second stage to promote the formation of higher molecular weight PSA. PSA yield up to 5.65 g/L and its resulting molecular weight of 260 kDa was attained, the highest level ever reported. PMID- 23090057 TI - Evidence for opponent process analysis of sound source location in humans. AB - Research with barn owls suggested that sound source location is represented topographically in the brain by an array of neurons each tuned to a narrow range of locations. However, research with small-headed mammals has offered an alternative view in which location is represented by the balance of activity in two opponent channels broadly tuned to the left and right auditory space. Both channels may be present in each auditory cortex, although the channel representing contralateral space may be dominant. Recent studies have suggested that opponent channel coding of space may also apply in humans, although these studies have used a restricted set of spatial cues or probed a restricted set of spatial locations, and there have been contradictory reports as to the relative dominance of the ipsilateral and contralateral channels in each cortex. The current study used electroencephalography (EEG) in conjunction with sound field stimulus presentation to address these issues and to inform the development of an explicit computational model of human sound source localization. Neural responses were compatible with the opponent channel account of sound source localization and with contralateral channel dominance in the left, but not the right, auditory cortex. A computational opponent channel model reproduced every important aspect of the EEG data and allowed inferences about the width of tuning in the spatial channels. Moreover, the model predicted the oft-reported decrease in spatial acuity measured psychophysically with increasing reference azimuth. Predictions of spatial acuity closely matched those measured psychophysically by previous authors. PMID- 23090060 TI - Tuning the magnetic anisotropy in coordination nanoparticles: random distribution versus core-shell architecture. AB - Core-shell magnetic coordination nanoparticles made of a soft core and a hard magnetic shell, containing anisotropic Co(II) ions, display a dramatic increase in their average blocking temperature with a coercive field value 25 times larger than that of the soft core, due to a large enhancement of the magnetic anisotropy. PMID- 23090059 TI - Population pharmacokinetics of olprinone in patients undergoing cardiac surgery with cardiopulmonary bypass. AB - PURPOSE: Olprinone, a phosphodiesterase type III inhibitor, is a strong inotrope and vasodilator that does not increase oxygen consumption and is often used during weaning from cardiopulmonary bypass (CPB). To control the pharmacological effects of olprinone, pharmacokinetic information is essential; however, there is little published information on the pharmacokinetics of olprinone in a large population. Therefore, the purpose of this study was to determine olprinone pharmacokinetic parameters in a large population undergoing cardiac surgery with CPB. METHODS: Olprinone was infused at a rate of 0.2 MUg/kg/min when weaning from CPB was started. Whole blood samples were periodically obtained to determine the olprinone concentrations using high-performance liquid chromatography. Measured olprinone concentrations were analyzed with a one-compartment model via a population approach. RESULTS: A total of 86 blood samples from 26 patients were used for pharmacokinetic analysis. The calculated clearance, volume of distribution (V(d)), and elimination half-life were 378 ml/min, 40.7 l, and 97.1 min, respectively. Olprinone clearance depended on weight and creatinine clearance, whereas V(d) depended only on weight. CONCLUSION: We investigated the pharmacokinetic parameters of olprinone in patients undergoing cardiac surgery with CPB. Olprinone clearance depended on weight and creatinine clearance, whereas V(d) depended only on weight. When olprinone is infused according to the recommended dosing regimen, it takes more than 60 min to reach the target concentration (20 ng/ml). However, there is a possibility that a lower concentration is sufficient for weaning from CPB in combination with a continuous infusion of dopamine. PMID- 23090061 TI - Diabetes mellitus nutrition therapy: beyond the glycemic index. PMID- 23090062 TI - A selective co-sensitization approach to increase photon conversion efficiency and electron lifetime in dye-sensitized solar cells. AB - Ruthenium-based C106 and organic D131 sensitizers have been judicially chosen for co-sensitization due to their complementary absorption properties and different molecular sizes. Co-sensitization yields a higher light-harvesting efficiency as well as better dye coverage to passivate the surface of TiO(2). The co-sensitized devices C106 + D131 showed significant enhancement in the performance (eta = 11.1%), which is a marked improvement over baseline devices sensitized with either D131 (eta = 5.6%) or C106 (eta = 9.5%). The improved performance of the co sensitized cell is attributed to the combined enhancement in the short circuit current, open circuit voltage, and the fill-factor of the solar cells. J(sc) is improved because of the complementary absorption spectra and favorable energy level alignments of both dyes; whereas, V(oc) is improved because of the better surface coverage helping to reduce the recombination and increase the electron life time. The origins of these enhancements have been systematically studied through dye desorption, absorption spectroscopy, and intensity modulated photovoltage spectroscopy investigations. PMID- 23090063 TI - Cross-reactivity of anti-programmed death ligand 2 polyclonal antibody in mouse tissues. AB - The inhibitory co-receptor programmed death 1 (PD-1, encoded by pdcd1) and its two ligands PD-L1 and PD-L2 comprise an important immune inhibitory signaling pathway for defense against microbes and for self-tolerance. Unlike other members of the B7-CD28 family, expression of PD-L1 and PD-L2 is not limited to the immune system. In this study, we determined that a polyclonal antibody (pAb) (R&D Systems) against extracellular domains of mouse PD-L2 (mPD-L2) could recognize antigen(s) in diverse mouse tissues, including the anterior and intermediate pituitary gland, olfactory bulbs and olfactory epithelium, tongue epithelium, keratinized epithelial cells and skin and whisker hair follicles. These findings differed from previous reports of mPD-L2 localization. Reverse transcription PCR and Western blot analyses, however, were unable to detect any mPD-L2 transcripts or proteins of the 25-kD predicted molecular weight in RNA and protein extracts, respectively, from the above tissues, suggesting that the anti-mPD-L2 pAb cross reacts with certain novel antigen(s). Developmental studies revealed that the earliest expression of mPD-L2-like antigen was in the olfactory epithelium at embryonic day 12.5 (E12.5). At E14.5, mPD-L2-like antigen was present in the skin, tongue and follicles of the skin and whiskers. The distribution patterns of mPD-L2-like antigen remained similar from E18.5 to adulthood. The results of bioinformatic analysis and other experiments suggested neural cell adhesion molecule and hemicentin-1 as candidate proteins with cross-reactivity to the anti mPD-L2 pAb. These results demonstrate that care is required in interpreting staining patterns generated when anti-PD-L2 pAb is used to locate PD-L2 expressing cells in the central nervous system and epithelial tissues, such as the olfactory epithelium. In addition, this anti-PD-L2 pAb may be used as an alternative antibody for labeling the olfactory epithelium during embryonic development in mice. PMID- 23090064 TI - Sphingosine-1-phosphate (S1P) mediates darkness-induced stomatal closure through raising cytosol pH and hydrogen peroxide (H2O2) levels in guard cells in Vicia faba. AB - The role and signaling of sphingosine-1-phosphate (S1P) during darkness-induced stomatal closure were examined in Vicia faba. Darkness substantially raised S1P and hydrogen peroxide (H(2)O(2)) levels and closed stomata. These darkness effects were significantly suppressed by DL-threo-dihydrosphingosine (DL-threo DHS) and N,N-dimethylsphingosine (DMS), two inhibitors of long-chain base kinases. Exogenous S1P led to stomatal closure and H(2)O(2) production, and the effects of S1P were largely prevented by the H(2)O(2) modulators ascorbic acid, catalase, and diphenyleneiodonium. These results indicated that S1P mediated darkness-induced stomatal closure by triggering H(2)O(2) production. In addition, DL-threo-DHS and DMS significantly suppressed both darkness-induced cytosolic alkalization in guard cells and stomatal closure. Exogenous S1P caused cytosolic alkalization and stomatal closure, which could be largely abolished by butyric acid. These results demonstrated that S1P synthesis was necessary for cytosolic alkalization during stomatal closure caused by darkness. Furthermore, together with the data described above, inhibition of darkness-induced H(2)O(2) production by butyric acid revealed that S1P synthesis-induced cytosolic alkalization was a prerequisite for H(2)O(2) production during stomatal closure caused by darkness, a conclusion supported by the facts that the pH increase caused by exogenous S1P had a shorter lag and peaked faster than H(2)O(2) levels and that butyric acid prevented exogenous S1P-induced H(2)O(2) production. Altogether, our data suggested that darkness induced S1P synthesis, causing cytosolic alkalization and subsequent H(2)O(2) production, finally leading to stomatal closure. PMID- 23090065 TI - Sustained local delivery of insulin for potential improvement of peri-implant bone formation in diabetes. AB - Dental implantation is an effective standard treatment modality to restore missing teeth and maxillofacial defects. However, in diabetics there is an increased risk for implant failure due to impaired peri-implant osseous healing. Early topical insulin treatment was recently shown to normalize diabetic bone healing by rectifying impairments in osteoblastic activities. In this study, insulin/poly(lactic-co-glycolic acid) (PLGA) microspheres were prepared by a double-emulsion solvent evaporation method. Microspheres were then incorporated in fibrin gel to develop a local drug delivery system for diabetic patients requiring implant treatment. In vitro release of insulin from fibrin gel loaded with these microspheres was assessed, and sustained prolonged insulin release over 21 days ascertained. To assess the bioactivity of released insulin and determine whether slow release might improve impaired diabetic bone formation, 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), alkaline phosphatase (ALP) activity, mineralized nodule formation, and ELISA (enzyme linked immunosorbent assay) assays were performed. The insulin released from the drug delivery system stimulated cell growth in previously inhibited cells, and ameliorated the impaired bone-forming ability of human MG-63 cells under high glucose conditions. Fibrin gel loaded with insulin/PLGA microspheres shows potential for improving peri-implant bone formation in diabetic patients. PMID- 23090066 TI - Q fever endocarditis: an unusual presentation. AB - Coxiella burnetii, the agent of Q fever, is an obligate intracellular pathogen typically associated with exposure to livestock. This organism may present with acute or chronic manifestations, the most typical chronic manifestation being endocarditis. We report a highly unusual case of Q fever endocarditis acquired in the United States marked by atypical cardiac manifestations. PMID- 23090067 TI - Evaluation of excess statistical significance in meta-analyses of 98 biomarker associations with cancer risk. AB - BACKGROUND: Numerous biomarkers have been associated with cancer risk. We assessed whether there is evidence for excess statistical significance in results of cancer biomarker studies, suggesting biases. METHODS: We systematically searched PubMed for meta-analyses of nongenetic biomarkers and cancer risk. The number of observed studies with statistically significant results was compared with the expected number, based on the statistical power of each study under different assumptions for the plausible effect size. We also evaluated small study effects using asymmetry tests. All statistical tests were two-sided. RESULTS: We included 98 meta-analyses with 847 studies. Forty-three meta-analyses (44%) found nominally statistically significant summary effects (random effects). The proportion of meta-analyses with statistically significant effects was highest for infectious agents (86%), inflammatory (67%), and insulin-like growth factor (IGF)/insulin system (52%) biomarkers. Overall, 269 (32%) individual studies observed nominally statistically significant results. A statistically significant excess of the observed over the expected number of studies with statistically significant results was seen in 20 meta-analyses. An excess of observed vs expected was observed in studies of IGF/insulin (P <= .04) and inflammation systems (P <= .02). Only 12 meta-analyses (12%) had a statistically significant summary effect size, more than 1000 case patients, and no hints of small-study effects or excess statistical significance; only four of them had large effect sizes, three of which pertained to infectious agents (Helicobacter pylori, hepatitis and human papilloma viruses). CONCLUSIONS: Most well-documented biomarkers of cancer risk without evidence of bias pertain to infectious agents. Conversely, an excess of statistically significant findings was observed in studies of IGF/insulin and inflammation systems, suggesting reporting biases. PMID- 23090069 TI - Synthesis of nucleosides and dNTPs bearing oligopyridine ligands linked through an octadiyne tether, their incorporation into DNA and complexation with transition metal cations. AB - Modified nucleosides (dA(R)s and dC(R)s) bearing bipyridine or terpyridine ligands attached through an octadiyne linker were prepared by single-step aqueous phase Sonogashira cross-coupling of 7-iodo-7-deaza-2'-deoxyadenosine and 5-iodo 2'-deoxycytidine with the corresponding bipyridine- or terpyridine-octadiynes and were triphosphorylated to the corresponding nucleoside triphosphates (dA(R)TPs and dC(R)TPs). The modified dN(R)TPs were successfully incorporated into the oligonucleotides by primer extension experiment (PEX) using different DNA polymerases and the PEX products were used for post-synthetic complexation with divalent metal cations. The complexation of these DNAs containing flexibly tethered ligands was compared with the previously reported ones bearing rigid acetylene-linked ligands suggesting the possible formation of both inter- and intra-strand complexes with Ni(2+) or Fe(2+). PMID- 23090071 TI - "Clicked" plasmonic core-satellites: covalently assembled gold nanoparticles. AB - In this communication, we describe the covalent assembly of gold nanoparticles into core-satellite clusters using the "cream of the crop" Click reaction, namely, azide-alkyne Huisgen 1,3-dipolar cycloaddition. Surface enhanced Raman scattering (SERS), localized surface plasmon resonance (LSPR) spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) confirm the successful "Click" between the plasmonic cores and satellites. PMID- 23090068 TI - Quantitative assessment of effect of preanalytic cold ischemic time on protein expression in breast cancer tissues. AB - BACKGROUND: Companion diagnostic tests can depend on accurate measurement of protein expression in tissues. Preanalytic variables, especially cold ischemic time (time from tissue removal to fixation in formalin) can affect the measurement and may cause false-negative results. We examined 23 proteins, including four commonly used breast cancer biomarker proteins, to quantify their sensitivity to cold ischemia in breast cancer tissues. METHODS: A series of 93 breast cancer specimens with known time-to-fixation represented in a tissue microarray and a second series of 25 matched pairs of core needle biopsies and breast cancer resections were used to evaluate changes in antigenicity as a function of cold ischemic time. Estrogen receptor (ER), progesterone receptor (PgR), HER2 or Ki67, and 19 other antigens were tested. Each antigen was measured using the AQUA method of quantitative immunofluorescence on at least one series. All statistical tests were two-sided. RESULTS: We found no evidence for loss of antigenicity with time-to-fixation for ER, PgR, HER2, or Ki67 in a 4-hour time window. However, with a bootstrapping analysis, we observed a trend toward loss for ER and PgR, a statistically significant loss of antigenicity for phosphorylated tyrosine (P = .0048), and trends toward loss for other proteins. There was evidence of increased antigenicity in acetylated lysine, AKAP13 (P = .009), and HIF1A (P = .046), which are proteins known to be expressed in conditions of hypoxia. The loss of antigenicity for phosphorylated tyrosine and increase in expression of AKAP13, and HIF1A were confirmed in the biopsy/resection series. CONCLUSIONS: Key breast cancer biomarkers show no evidence of loss of antigenicity, although this dataset assesses the relatively short time beyond the 1-hour limit in recent guidelines. Other proteins show changes in antigenicity in both directions. Future studies that extend the time range and normalize for heterogeneity will provide more comprehensive information on preanalytic variation due to cold ischemic time. PMID- 23090072 TI - Role of low-cost thyroid follow-up in children treated with radiotherapy for primary tumors at high risk of developing a second thyroid tumor. AB - AIM: Differentiated thyroid cancer (DTC) is uncommon in childhood and data on its prevalence as a second malignant neoplasm (SNM) after radiotherapy (RT) for malignancies are limited. We evaluated: 1) the incidence DTC in pediatric oncologic patients treated with RT; 2) the relationship between DTC, RT and the features of the first malignancy; 3) the usefulness of thyroid follow-up in irradiated oncological patients. METHODS: We have followed up 252 patients treated with RT out of 966 oncologic pediatric patients. Thyroid follow-up included TSH level evaluation and neck ultrasonography. In the presence of thyroid nodule/s >=1 cm and/or with ultrasonography suspicious for malignancy, fine needle aspiration biopsy (FNAB) was performed. When papillary/follicular lesions were detected by cytology, thyroidectomy was performed. If DTC was confirmed, patients underwent radioactive iodine (RAI) treatment. RESULTS: At least one thyroid nodule was detected in 106 irradiated patients (42%): 45 patients underwent FNAB and 27 underwent thyroidectomy. Seventeen DTC (6.7%) were found on histology. A higher incidence of DTC was seen in patients with neuroblastoma (38%) or Wilms' tumor (18%). One third of DTC showed capsule invasion, and one fourth node involvement. Eleven patients, treated with a single RAI treatment, showed undetectable thyroglobulin levels after rh-TSH-stimulation. Five patients underwent at least two RAI treatments: four patients showed complete remission and one patient partial remission. CONCLUSION: A high rate of DTC, often with invasive features, was observed in children treated with RT for primary tumors. This finding underlines the usefulness of thorough low-cost thyroid follow-up in this high-risk population. PMID- 23090073 TI - Amorphous graphene: a realization of Zachariasen's glass. AB - Amorphous graphene is a realization of a two-dimensional Zachariasen glass as first proposed 80 years ago. Planar continuous random networks of this archetypal two-dimensional network are generated by two complementary simulation methods. In the first, a Monte Carlo bond switching algorithm is employed to systematically amorphize a crystalline graphene sheet. In the second, molecular dynamics simulations are utilized to quench from the high temperature liquid state. The two approaches lead to similar results as detailed here, through the pair distribution function and the associated diffraction pattern. Details of the structure, including ring statistics and angular distortions, are shown to be sensitive to preparation conditions, and await experimental confirmation. PMID- 23090075 TI - Induction of Thelper1-driven antiviral T-cell lines for adoptive immunotherapy is determined by differential expression of IFN-gamma and T-cell activation markers. AB - Viral infections with cytomegalovirus (CMV) or human adenovirus (HAdV) after stem cell transplantation are still associated with a high morbidity and mortality. Transfer of T-cell immunity from a healthy individual to a stem cell transplant recipient, known as adoptive T-cell transfer, has been shown to be effective to prevent viral complications. Treatment efficacy will depend on the availability of functional T-cell lines with a strong T(helper)1 response. Ex vivo isolation of antigen-specific T cells could be performed on the basis of the cytokine capture technique or antigen-induced expression of activation markers. In this study, we compare the specificity, expansion/differentiation potential, and T(helper)1 response against CMV and HAdV after different isolation strategies. Antigen-specific T cells from healthy donors were isolated by antigen-induced expression of IFN-gamma and/or CD137 after stimulation with the viral antigens hexon (HAdV) or pp65 (CMV). Isolation of antigen-specific T cells based on the expression of activation markers is feasible and less time consuming, but in contrast to isolation based on IFN-gamma secretion, it leads to a reduction of T(helper)1 cells. Both isolated CD137(+) and isolated IFN-gamma(+) T cells mainly consist of CD4(+) T(CentralMemory) and T(EffectorMemory) cells with high expansion potential and effective cytokine production. CD154(+) is mainly expressed on CD4(+)T cells and shows coexpression with IFN-gamma on activated T cells, which cannot be found for CD137(+) cells. In conclusion, T-cell lines could be easily generated on the basis of IFN-gamma(+) and/or expression of the activation marker CD137 but both approaches result in different T-cell populations, which may lead to divergent T-cell responses in vivo. PMID- 23090076 TI - Combined TLR stimulation with Pam3Cys and Poly I: C enhances Flt3-ligand dendritic cell activation for tumor immunotherapy. AB - The cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 are frequently used for generating dendritic cells (DCs) for therapeutic vaccination against cancer. These in vitro DCs share several characteristics with inflammatory monocyte-derived DCs in vivo. In contrast, culture of bone marrow cells in Flt3-ligand (Flt3L) generates a heterogeneous population of DCs, which comprise conventional DCs (cDCs) and plasmacytoid DCs similar to the steady-state populations found in vivo. Although previous studies have identified combinations of toll-like receptor ligands (TLR-Ls) that induce optimal activation of GM-CSF/IL-4 DCs in vitro, the conditions for optimal activation of Flt3L-DCs have not been established. In this study, we show that various combinations of the TLR-Ls Pam3Cys, Poly I:C, lipopolysaccharide, and CpG all increased Flt3L-DC maturation, but only the combination of Pam3Cys/Poly I:C showed a trend to enhanced production of IL-12p70 and tumor necrosis factor-alpha by cDCs. Pam3Cys/Poly I:C-treated cDCs also displayed enhanced capacity to present antigen to CD4(+) T cells, and cross-present to CD8(+) T cells, increasing T-cell proliferation in vitro. Within a prophylactic vaccination setting, cDCs activated with Pam3Cys/Poly I:C conferred tumor protection in mice. However, the numbers of cDCs required for protection were higher than the numbers of optimally activated GM-CSF/IL-4 DCs required for a similar effect. Our results show that combined TLR stimulation can enhance both the phenotypic and functional properties of Flt3L-DCs, but even under conditions of optimal activation these cells are not superior in activity to GM-CSF/IL-4 DCs in vivo. PMID- 23090074 TI - Sorting through subsets: which T-cell populations mediate highly effective adoptive immunotherapy? AB - CD8(+) T cells have been described as being naive or one of 4 antigen (Ag) experienced subtypes representing a continuum of differentiation and maturation: T memory stem cell, central memory T cell, effector memory T cell, and terminally differentiated effector T cells. In mice, adoptive cell transfer of less differentiated naive T cells, T memory stem cell, and central memory T cell subsets have consistently demonstrated superior in vivo expansion, persistence, and antitumor capacities relative to the more differentiated effector memory T cell and effector T cell subsets. Retrospective analyses from human adoptive cell transfer trials have confirmed that transfer of less-differentiated T-cell subsets is highly correlated with objective clinical responses. These findings, combined with the recent ability to convey de novo Ag reactivity with high efficiency through genetic engineering of exogenous T-cell or chimeric Ag receptors, now challenge the field with 3 important questions: (1) how should less-differentiated T-cell subsets be isolated for human clinical trials?; (2) what is the best means of expanding T cells ex vivo in such a way as to not corrupt the beneficial traits of the younger subsets?; and (3) is it necessary to physically separate younger subsets from their more differentiated counterparts? Answering these questions will allow for the rational development of the next generation of highly effective and potentially curative T-cell therapies for the treatment of cancer. PMID- 23090077 TI - Characterization of T-cell receptors directed against HLA-A*01-restricted and C*07-restricted epitopes of MAGE-A3 and MAGE-A12. AB - The ability of T cells that have been genetically engineered to express T-cell receptors (TCRs) directed against tumor antigens to mediate tumor regression has been demonstrated in several clinical trials. These TCRs have primarily targeted HLA-A*0201-restricted TCRs, as approximately 50% of whites, who represent the predominant population of patients who develop melanomas, expresses this HLA class I allele. These therapies could be extended to additional patients through the use of TCRs that target epitopes that are presented by additional class I alleles that are prevalent in this population such as HLA-C*07 and HLA-A*01, which are expressed by approximately 50% and 30% of the patient population respectively. Therefore, 2 TCRs that recognize an epitope of MAGE-A12 in the context of HLA-C*07 and 2 TCRs that recognize an epitope of MAGE-A3 in the context of HLA-A*01 were isolated from tumor-reactive T-cell clones and cloned in a recombinant retroviral expression vector. Comparative studies indicated that one of the 2 MAGE-A3-reactive TCRs and one of the 2 MAGE-A12-reactive TCRs were superior to the additional TCRs in conferring transduced peripheral blood mononuclear cells with the capacity to recognize a broad array of antigen and MHC positive target cells. These results provide support for the use of these TCRs in cancer adoptive immunotherapy trials. PMID- 23090078 TI - Phenotypic and functional attributes of lentivirus-modified CD19-specific human CD8+ central memory T cells manufactured at clinical scale. AB - A key determinant of the therapeutic potency of adoptive T-cell transfer is the extent to which infused cells can persist and expand in vivo. Ex vivo propagated virus-specific and chimeric antigen receptor (CAR)-redirected antitumor CD8 effector T cells derived from CD45RA(-) CD62L(+) central memory (TCM) precursors engraft long-term and reconstitute functional memory after adoptive transfer. Here, we describe a clinical scale, closed system, immunomagnetic selection method to isolate CD8(+) T(CM) from peripheral blood mononuclear cells (PBMC). This method uses the CliniMACS device to first deplete CD14(+), CD45RA(+), and CD4(+) cells from PBMC, and then to positively select CD62L(+) cells. The average purity and yield of CD8(+) CD45RA(-) CD62L TCM obtained in full-scale qualification runs were 70% and 0.4% (of input PBMC), respectively. These CD8(+) T(CM) are responsive to anti-CD3/CD28 bead stimulation, and can be efficiently transduced with CAR encoding lentiviral vectors, and undergo sustained expansion in interleukin (IL)-2/IL-15 over 3-6 weeks. The resulting CD8(+) T(CM)-derived effectors are polyclonal, retain expression of CD62L and CD28, exhibit CAR redirected antitumor effector function, and are capable of huIL-15-dependent in vivo homeostatic engraftment after transfer to immunodeficient NOD/Scid IL 2RgCnull mice. Adoptive therapy using purified T(CM) cells is now the subject of a Food and Drug Administration-authorized clinical trial for the treatment of CD19(+) B-cell malignancies, and 3 clinical cell products expressing a CD19 specific CAR for IND #14645 have already been successfully generated from lymphoma patients using this manufacturing platform. PMID- 23090079 TI - Differing patterns of circulating regulatory T cells and myeloid-derived suppressor cells in metastatic melanoma patients receiving anti-CTLA4 antibody and interferon-alpha or TLR-9 agonist and GM-CSF with peptide vaccination. AB - Changes in the biomarkers of host suppressor immune response were evaluated in patients with melanoma enrolled in 2 trials. Two similar cohorts of patients participating in the 2 studies were evaluated. The first (IFN/treme) tested interferon (IFN)-alpha2b and tremelimumab in metastatic melanoma and reported a response rate of 24%, 6.4 months median progression-free survival, and 21 months median overall survival. The second [toll-like receptor 9 (TLR)/GM] tested vaccination with MART-1, gp100, tyrosinase given with TLR-9 agonist and granulocyte-macrophage colony-stimulating factor and reported 9% response rate, median progression-free survival of 1.9 months, and median overall survival of 13.4 months. We monitored circulating T regulatory cells (T-reg) and myeloid derived suppressor cells (MDSC) utilizing multicolor flow cytometry. In "IFN/treme," changes in circulating T-reg and MDSC were compared between baseline, day 29 (end of IFN-alpha induction) and day 85 (1 course). The CD4(+)CD25hi(+)CD39(+) T-reg percentage was increased most at day 85 (P = 0.018) and less significantly at day 29 (P = 0.09). There was a decrease in the percentage of MDSC populations taken in aggregate, which was most significant for monocytic MDSC (HLA-DR(+) low/CD14(+)) at day 29 (P < 0.0001) and day 85 (P = 0.001). In "TLR-9/GM," changes in T-reg and MDSC were compared between baseline and day 50 (4 vaccinations) and day 90 (8 vaccinations). There were no significant changes in T-reg or MDSC, except for a trend towards decreased (HLA DR(+) low/CD14(+)) MDSC at day 50 (P = 0.07). Therefore, IFN/treme significantly downregulated MDSC suggesting a role on the significant clinical activity observed in this trial. T-reg findings suggest that IFN/treme induced clinically significant antitumor responses by inhibiting CTLA4 suppressive effects on T effectors, and less so by affecting T-reg. PMID- 23090080 TI - Characterizing the clinical benefit of ipilimumab in patients who progressed on high-dose IL-2. AB - Ipilimumab improves overall survival (OS) in patients with metastatic melanoma including those previously treated with high-dose interleukin-2 (HD IL-2). The primary objective of this study was to determine if clinical response or progression-free survival (PFS) to HD IL-2 could predict benefit to subsequent ipilimumab. The secondary objective was to further characterize the clinical benefit of ipilimumab in patients who have progressed on HD IL-2. We reviewed the records of all patients with metastatic melanoma who received HD IL-2 at MD Anderson Cancer Center or Beth Israel Deaconess Medical Center from 2003 to 2009 and further identified patients who also received ipilimumab after progressing on HD IL-2. OS to ipilimumab was calculated from the first dose of ipilimumab, determined by Kaplan-Meier analysis, and was compared in patients based on their prior clinical response and PFS to HD IL-2 using the log-rank test. Patients were grouped based on their prior response to HD IL-2 as follows: complete response and partial response, stable disease, and progressive disease. Patients were also grouped and compared by prior PFS to HD IL-2 in >60 days versus <=60 days. A total of 208 patients with melanoma were treated with HD IL-2, 130 (63%) received additional systemic therapy after confirmed disease progression, and 48 (23%) received ipilimumab. The clinical benefit of ipilimumab was similar to previously published results (OS, 12.0 mo; PFS, 2.5 mo; response rate, 16.7%). Prior clinical response or PFS to HD IL-2 did not predict benefit to subsequent ipilimumab. Prospective trials of HD IL-2 followed by ipilimumab could potentially identify patients most likely to benefit from a sequential approach of HD IL-2 followed by ipilimumab. PMID- 23090081 TI - Combined intralesional Bacille Calmette-Guerin (BCG) and topical imiquimod for in transit melanoma. AB - The introduction of numerous immunotherapeutic agents into the clinical arena has allowed the long-time promise of immunotherapy to begin to become reality. Intralesional immunotherapy has demonstrated activity in multiple tumor types, and as the number of locally applicable agents has increased, so has the opportunity for therapeutic combinations. Both intralesional Bacille Calmette Guerin (ILBCG) and topical 5% imiquimod cream have been used as single agents for the treatment of dermal/subcutaneous lymphatic metastases or in-transit melanoma, but the combination has not previously been reported. We used this combination regimen in 9 patients during the period from 2004 to 2011 and report their outcomes here. All patients were initially treated with ILBCG, followed by topical imiquimod after development of an inflammatory response to BCG. In this retrospective study, we examined their demographics, tumor characteristics, clinical and pathologic response to treatment, associated morbidities, local and distant recurrence, and overall survival. The 9 patients (8 male) had a mean age of 72 years (range, 56-95 y). Mild, primarily local toxicities were noted. Five patients (56%) had complete regression of their in-transit disease and 1 had a partial response. The 3 others had "surgical" complete responses with resection of solitary resistant lesions. The mean interval between the first treatment and complete resolution of in-transit disease was of 6.5 months (range, 2-12 mo). With a mean follow-up of 35 months (range 12-58 mo), 7 patients (78%) had not developed recurrent in-transit disease. Two patients (22%) have died of nonmelanoma causes, and none have died due to melanoma. PMID- 23090084 TI - Prevention of demoralization in prolonged bicultural conflict and interaction: the role of cultural receptors II - genesis of hybridization. AB - BACKGROUND: The objective of this article is to show that bicultural hybridization for the prevention of demoralization is anchored on the discovery of certain thematic areas (cultural receptors) in which social roles or cultural mandates are missing, unclear, ambiguous or congruent. MATERIAL: The specific setting is the history of Goa, a former Portuguese territory on the western coast of India. Both published and unpublished sources of information were studied. DISCUSSION: Education, occupation and income, the three dimensions of social class, were less dominant than other aspects of the Hindu caste system, such as birth into a group viewed as a caste, observance of marriage circles, regulations of kinship and inheritance, and identification with a location. These other aspects were preserved as much as possible. The result was the conversion of the caste system into a system more akin to social class. Other examples of cultural receptors were found. CONCLUSIONS: A key step in the adaptation to acculturative stress is the discovery of cultural receptors in both cultures and the development of meaningful interconnections among those receptors. Psychotherapy attempts the restoration of morale. To be effective, therapists should consider the hierarchical organization of symbols and sentiments in the patient's culture. PMID- 23090085 TI - How promiscuous are pharmaceutically relevant compounds? A data-driven assessment. AB - Given the increasing notion of target promiscuity of bioactive compounds and polypharmacological drug behavior, a detailed analysis of publicly available compound activity data from medicinal chemistry sources was carried out to determine and quantify the degree of promiscuity of active compounds across all known human target families. The results are surprising. Approximately 62% of currently available compounds with high-confidence activity data are only annotated with a single biological target, whereas 36% are known to act against multiple targets within the same family (i.e., closely related targets). However, only ~2% of bioactive compounds are promiscuous across different target families. Thus, despite general data sparseness, these findings indicate that highly promiscuous bioactive compounds only rarely occur. Because pharmaceutically relevant active compounds represent the pool from which drug candidates emerge, one might extrapolate from these results and conclude that there is a low statistical probability to obtain drugs that act against multiple targets belonging to distinct families. PMID- 23090086 TI - Heart failure: Registry data reveal disparities in care. PMID- 23090089 TI - [Intracerebral lesions after TNF-alpha inhibitor therapy with pre-existing sarcoidosis and sacroiliitis]. AB - This article reports the case of a 55-year-old man who presented with aphasia caused by intracerebral lesions and had a history of pulmonary sarcoidosis. Due to nonsteroidal anti-inflammatory drug-resistant spondyloarthritis TNF-alpha inhibitor treatment was started after a negative tuberculosis screening. Subsequently the patient developed pulmonary tuberculosis and cerebral tuberculoma reactivated by the TNF-alpha inhibitor therapy accompanied by pulmonary sarcoidosis with sacroiliitis and oligoarthritis. This case report emphasises the risk of atypical tuberculosis infections under TNF-alpha inhibitors despite negative results of tuberculosis screening. PMID- 23090090 TI - [New classification criteria for polymyalgia rheumatica]. PMID- 23090091 TI - Pelvic fixation for adult scoliosis. AB - INTRODUCTION: Obtaining a fusion, especially to the sacrum for adult deformity correction remains a challenge. Prior to modern fixation techniques, the reported fusion rates for adult scoliotic deformities were low. However sacropelvic fixation techniques for adult deformity continue to evolve. As a result, modern day pelvic fixation techniques have improved fusion rates at the base of long constructs. The purpose of this article is to discuss the history, indications, and modern fixation techniques for pelvic fixation in the surgical management of adult scoliosis patients. METHODS: We searched PUBMED using the search terms pelvic fixation, deformity, lumbopelvic, sacropelvic, and iliac fixation. Linkage or association studies published in English and available full-text were analyzed specifically regarding techniques and innovations in pelvic fixation. RESULTS: Sacropelvic fixation should be considered in any patient with a long construct ending in the sacrum, those patients with associated risk factors for loss of distal fixation or high risk for pseudarthrosis at L5-S1, and those undergoing three column osteotomies or vertebral body resections in the low lumbar spine. Current pelvic fixation techniques with iliac screws, multiple screw/rod constructs, and S2-alar-iliac screws are all viable techniques for achieving pelvic fixation. CONCLUSIONS: There is growing evidence that pelvic fixation may become the standard for obtaining long fusions in adult scoliosis. Although technically challenging, in selected cases the use of four pelvic screws and/or four rods across the lumbosacral pelvis can help address pseudarthroses, implant breakage, and screw pullout secondary to osteoporosis. Ultimately, indications and techniques should be individualized to the patient and based on surgeon preference and experience. PMID- 23090092 TI - Reviewer's comment concerning "aneurysmal bone cysts of the spine" (doi:10.1007/s00586-012-2510-x by M. Zileli et al.). PMID- 23090087 TI - Altered sarcoplasmic reticulum calcium cycling--targets for heart failure therapy. AB - Cardiac myocyte function is dependent on the synchronized movements of Ca(2+) into and out of the cell, as well as between the cytosol and sarcoplasmic reticulum. These movements determine cardiac rhythm and regulate excitation contraction coupling. Ca(2+) cycling is mediated by a number of critical Ca(2+) handling proteins and transporters, such as L-type Ca(2+) channels (LTCCs) and sodium/calcium exchangers in the sarcolemma, and sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA2a), ryanodine receptors, and cardiac phospholamban in the sarcoplasmic reticulum. The entry of Ca(2+) into the cytosol through LTCCs activates the release of Ca(2+) from the sarcoplasmic reticulum through ryanodine receptor channels and initiates myocyte contraction, whereas SERCA2a and cardiac phospholamban have a key role in sarcoplasmic reticulum Ca(2+) sequesteration and myocyte relaxation. Excitation-contraction coupling is regulated by phosphorylation of Ca(2+)-handling proteins. Abnormalities in sarcoplasmic reticulum Ca(2+) cycling are hallmarks of heart failure and contribute to the pathophysiology and progression of this disease. Correcting impaired intracellular Ca(2+) cycling is a promising new approach for the treatment of heart failure. Novel therapeutic strategies that enhance myocyte Ca(2+) homeostasis could prevent and reverse adverse cardiac remodeling and improve clinical outcomes in patients with heart failure. PMID- 23090093 TI - Limaprost alfadex and nonsteroidal anti-inflammatory drugs for sciatica due to lumbar spinal stenosis. AB - PURPOSE: Limaprost, a prostaglandin E1 analog, has vasodilatory properties and increases blood flow of the nerve root. However, it has not been clarified whether limaprost affects pain sensation associated with radiculopathy due to lumbar spinal stenosis (LSS). The aim of this study was to compare the efficacy of oral limaprost with nonsteroidal anti-inflammatory drugs (NSAIDs) for radiculopathy. METHODS: We performed a multicenter prospective randomized trial. Patients with LSS who had radicular-type neurologic intermittent claudication assessed based on a self-reported diagnostic support tool were randomized into three treatment groups. Limaprost, NSAIDs, or limaprost plus NSAIDs were administered orally for 6 weeks. Leg pain, low back pain (LBP) and the associated symptoms were assessed by a numerical rating scale (NRS) both at rest and on movement as well as the Roland-Morris Disability Questionnaire (RDQ) and Short Form (SF)-36. RESULTS: Sixty-one patients were enrolled in the study. Each treatment finally reduced radicular pain, and the improvement was prominent in a combination treatment. There were no significant differences in radicular pain among three groups at final follow-up. LBP was not influenced by limaprost, and a significant reduction of LBP and RDQ was confirmed in a combination treatment compared with limaprost. Physical function of the SF-36 subscales after a combination treatment showed a marked alleviation compared with NSAIDs. CONCLUSIONS: These obtained findings suggest that the effects of limaprost seem to be limited to radicular pain, not for LBP. Overall, a combination treatment might be more effective in the management of radiculopathy induced by LSS than monotherapy with either agent. PMID- 23090094 TI - Effects of orthoses on three-dimensional load-displacement properties of the cervical spine. AB - PURPOSE: Our objectives were to develop a skull-neck-thorax model capable of quantifying spinal motions in an intact human cadaver neck with and without cervical orthoses, determine the effect of orthoses on three-dimensional load displacement properties of all cervical spinal levels, and compare and contrast our results with previously reported in vivo data. METHODS: Load input flexibility tests were performed to evaluate two cervical collars (Vista((r)) collar and Vista((r)) Multipost collar) and two cervicothoracic orthoses (CTOs: Vista((r)) TS and Vista((r)) TS4) using the skull-neck-thorax model with 10 intact whole cervical spine specimens. The physiologic range of motion (RoM) limit was the peak obtained from flexibility tests with no orthosis. Pair-wise repeated measures, analysis of variance (p < 0.05), and Bonferroni post hoc tests determined significant differences in average peak RoM at each spinal level among the experimental conditions. RESULTS: Significant reductions below physiologic limits were observed due to all orthoses in: three-dimensional head/T1 RoMs, all sagittal intervertebral RoMs, and lateral bending at C4/5 through C7/T1. Both CTOs significantly reduced C6/7 sagittal RoM as compared to both collars. Intervertebral RoMs with the orthoses could not be differentiated from physiologic limits at the upper cervical spine in lateral bending and throughout the entire cervical spine in axial rotation, with the exception of C1/2. CONCLUSIONS: Our results indicate that cervical orthoses effectively immobilized the entire cervical spine in flexion/extension and the lower cervical spine in lateral bending. The CTOs improved immobilization of the lower cervical spine in flexion/extension as compared to the collars. The orthoses were least effective at restricting lateral bending of the upper spinal levels and axial rotation of all spinal levels, except C1/2. Understanding immobilization provided by orthoses will assist clinicians in selecting the most appropriate brace based upon patient specific immobilization requirements. PMID- 23090096 TI - Sulfur dioxide oxidation induced mechanistic branching and particle formation during the ozonolysis of beta-pinene and 2-butene. AB - Recent studies have suggested that the reaction of stabilised Criegee Intermediates (CIs) with sulfur dioxide (SO(2)), leading to the formation of a carbonyl compound and sulfur trioxide, is a relevant atmospheric source of sulfuric acid. Here, the significance of this pathway has been examined by studying the formation of gas phase products and aerosol during the ozonolysis of beta-pinene and 2-butene in the presence of SO(2) in the pressure range of 10 to 1000 mbar. For beta-pinene at atmospheric pressure, the addition of SO(2) suppresses the formation of the secondary ozonide and leads to highly increased nopinone yields. A complete consumption of SO(2) is observed at initial SO(2) concentrations below the yield of stabilised CIs. In experiments using 2-butene a significant consumption of SO(2) and additional formation of acetaldehyde are observed at 1 bar. A consistent kinetic simulation of the experimental findings is possible when a fast CI + SO(2) reaction rate in the range of recent direct measurements [Welz et al., Science, 2012, 335, 204] is used. For 2-butene the addition of SO(2) drastically increases the observed aerosol yields at higher pressures. Below 60 mbar the SO(2) oxidation induced particle formation becomes inefficient pointing to the critical role of collisional stabilisation for sulfuric acid controlled nucleation at low pressures. PMID- 23090098 TI - Persistence with therapy among patients treated with warfarin for atrial fibrillation. PMID- 23090099 TI - Effect of arm position on the prediction of kinematics from EMG in amputees. AB - Myoelectric control has been extensively applied in multi-function hand/wrist prostheses. The performance of this type of control is however, influenced by several practical factors that still limit its clinical applicability. One of these factors is the change in arm posture during the daily use of prostheses. In this study, we investigate the effect of arm position on the performance of a simultaneous and proportional myoelectric control algorithm, both on trans-radial amputees and able-bodied subjects. The results showed that changing arm position adversely influences the performance of the algorithm for both subject groups, but that this influence is less pronounced in amputee subjects with respect to able-bodied subjects. Thus, the impact of arm posture on myoelectric control cannot be inferred from results on able-bodied subjects and should be directly investigated in amputee subjects. PMID- 23090100 TI - [Intracranial aneurysms - a heterogeneous disorder]. PMID- 23090101 TI - Efficient asymmetric synthesis of trifluoromethylated beta-aminophosphonates and their incorporation into dipeptides. AB - Addition of anions derived from dialkyl methylphosphonates to (Ss)-N-tert butanesulfinyl (3,3,3)-trifluoroacetaldimine afforded (Ss,R) addition adducts in moderate to good yield (53-75%) with excellent diastereoselectivity (94-95% de). After selective removal of the N-sulfinyl group, dipeptides containing enantiomerically pure diethyl 2-amino-3,3,3-trifluoropropylphosphonate were synthesized to investigate the influence of the trifluoromethyl substituent on N terminal coupling. PMID- 23090102 TI - Desflurane versus sevoflurane: a comparison on stress response. AB - BACKGROUND: Neurohumoral, immunologic and metabolic alteration characterize surgical procedures in relation with the intensity of injury, the total operating time and the anesthetic technique. We, therefore, compared the effects of desflurane versus sevoflurane anesthesia on intra and postoperative release of the stress hormones and inflammatory cytokines. METHODS: Fifty Caucasian women undergoing laparoscopic surgery for benign ovarian cysts were randomized to receive inhaled anesthesia with desflurane (DES group; N.=25) or sevoflurane (SEVO group; N.=25), with fentanyl bolus and remifentanil infusion. Plasma levels of noradrenaline, adrenaline, ACTH and cortisol were measured preoperatively (T1), 30 minutes after the beginning of surgery (T2), and 30 minutes, 2 and 4 hours after the end of surgery (T3, T4, T5 respectively). Interleukin 6 (IL-6), glucose and C-reactive protein (CRP) were measured at T1, T2,T3, T4, T5 and 12 hours after the end of surgery (T6). RESULTS: An increase of catecholamines during (T2) and immediately after surgery (T3) was observed in both groups. However, adrenaline and noradrenaline levels were significantly higher in the DES group compared to the SEVO group. Despite a drop of cortisol concentration was observed in both groups, only in the DES group there was a significant difference intraoperatively as compared to the baseline levels and to the SEVO group. While, the consequent increase of ACTH was significantly higher in the SEVO group at T2 T4. The preoperatory levels were restored at T5. Glucose, IL-6, CRP levels and postoperative pain did not show significant differences in timing within the same group and comparing DES vs SEVO group. CONCLUSION: In the present study we demonstrated that desflurane and sevoflurane produced a different stress response in the setting of laparoscopic surgery. The greater release of catecholamines during desflurane anesthesia could have adverse effects in patients with pre existing cardiovascular disease. In low stress surgery desflurane, as compared to sevoflurane, was associated with a better control of intraoperative cortisol and ACTH response (T2). Moreover, the ACTH secretion resulted attenuated also postoperatively (T3-T4). Both gases did not influence the plasmatic levels of Il 6, CRP and glucose. PMID- 23090103 TI - Hyperdynamic circulation in cirrhosis: predictive factors and outcome following liver transplantation. AB - BACKGROUND: Liver cirrhosis is associated with a hyperdynamic circulation (HC). In this observational study, we aimed to investigate the predictive factors of HC, its impact on intraoperative hemodynamic and postoperative outcome, early ICU and in-hospital mortality, in cirrhotic patients undergoing orthotopic liver transplantation (OLT). METHODS: Two hundred and forty-two patients with cirrhosis undergoing cadaveric OLT were included. Before starting the transplant procedure and under general anesthesia, a pulmonary artery catheter was introduced to assess hemodynamic parameters. The baseline assessment was carried out approximately 30 minutes after the catheter placement and repeated during the anhepatic phase, 10 minutes after the reperfusion and at the end of surgery. The patients were divided into two groups: in group 1 the patients had SVR>900dynes s 1 m-2 cm-5, in group 2 SVR <=900 dynes s-1 m-2 cm-5. RESULTS: Eighty-two patients (33%) presented severe HC. In multivariate analysis 2 factors were associated with the occurrence of HC: beta-blockers use (Exp [B]=4.42 (95% CI 1.18-17); P=0.001, [34% and 12% in groups 1 and 2, P<0.001, respectively]) and model for end-stage liver disease (MELD) score (Exp [B]=1.066; 95% CI=1.025-1.109; P=0.001). CONCLUSION: MELD score was an independent predictor of HC, and beta blockers resulted associated with lower incidence of HC in cirrhotic patients undergoing cadaveric OLT. Intraoperative HC correlates with hemodynamic alterations, requiring more blood products and vasopressor use, this may increase the risk of renal failure, early ICU death and in-hospital mortality. PMID- 23090104 TI - The best timing for defibrillation in shockable cardiac arrest. AB - High quality cardiopulmonary resuscitation (CPR, i.e. chest compressions and ventilations) and prompt defibrillation when appropriate (i.e. in ventricular fibrillation and pulseless ventricular tachycardia, VF/VT) are currently the best early treatment for cardiac arrest (CA). In cases of prolonged CA due to shockable rhythms, it is reasonable to presume that a period of CPR before defibrillation could partially revert the metabolic and hemodynamic deteriorations imposed to the heart by the no flow state, thus increasing the chances of successful defibrillation. Despite supporting early evidences in CA cases in which Emergency Medical System response time was longer than 5 minutes, recent studies have failed to confirm a survival benefit of routine CPR before defibrillation. These data have imposed a change in guidelines from 2005 to 2010. To take in account all the variables encountered when treating CA (heart condition before CA, time elapsed, metabolic and hemodynamic changes, efficacy of CPR, responsiveness to defibrillation attempt), it would be very helpful to have a real-time and non invasive tool able to predict the chances of defibrillation success. Recent evidences have suggested that ECG waveform analysis of VF, such as the derived Amplitude Spectrum Area, can fit the purpose of monitoring the CPR effectiveness and predicting the responsiveness to defibrillation. While awaiting clinical studies confirming this promising approach, CPR performed according to high quality standard and with minimal interruptions together with early defibrillation are the best immediate way to achieve resuscitation in CA due to shochable rhythms.. PMID- 23090105 TI - High molecular weight hydroxyethyl starch solutions are not more effective than a low wmolecular weight hydroxyethyl starch solution in a porcine model of septic shock. AB - BACKGROUND: There is evidence that suggests that early fluid resuscitation is beneficial in the treatment of sepsis. We previously demonstrated that hydroxyethyl starch (HES) 130/0.42 attenuated capillary leakage better than HES 200/0.5. Using a similar porcine fecal sepsis model, we tested the effects of two new synthetic high molecular weight (700 kDa) hydroxyethyl starches with the same molar substitution of 0.42 but with a different C2/C6 ratio compared to 6% HES 130/0.42 on plasma volume (PV), systemic and tissue oxygenation. METHODS: This was a prospective, randomized, controlled animal study. Twenty-five anesthetized and mechanically ventilated pigs (28.4+/-2.3 kg) were observed over 8 h. Septic shock was induced with fecal peritonitis. Animals were randomized for volume replacement therapy with HES 700/0.42 C2/C6/2.5:1 (N.=5), HES 700/0.42 C2/C6/6:1 (N.=5), HES 130/0.42 C2/C6/5:1 (N.=5) or Ringer's Solution (RS, N.=5), and compared to non-septic controls receiving RS (N.=5). The albumin escape rate (AER) was calculated and plasma volume was determined at the end of the study. Tissue Oxygen Saturation was measured with the InSpectraTM Device (InSpectra Tissue Spectrometer, Hutchinson Technology Inc., Hutchinson, MN, USA). RESULTS: The AER increased in all groups compared to control. All colloids (HES 700/6:1 68+/-15; HES 130 67+/-4; HES 700/2.5:1 71+/-12; P<0.05) but not RS (44+/-7) stabilized PV (mL/kg BW) after eight hours of sepsis. Systemic oxygenation was significantly lower in the RS group (44+/-17%; P<0.05) compared to all other groups at study end (P<0.05). CONCLUSION: In this porcine fecal peritonitis model, the high molecular weight artificial colloids HES 700/2.5:1 and HES 700/6:1 were not more effective in maintaining plasma volume and systemic and tissue oxygenation than HES 130. In comparison to crystalloid RS, all HES solutions were more effective at maintaining plasma volume, mean arterial pressure (MAP), and systemic and tissue oxygenation. PMID- 23090106 TI - When the end is really the end? The extubation in the difficult airway patient. AB - Difficult airway management remains one of the most important sources of anesthesia related accidents; recent reviews and dedicated guidelines suggest that not only intubation, but extubation too is a critical phase in terms of potential accidents and serious complications. This paper will highlight some fundamental concepts regarding extubation related problems, focusing particularly on epidemiology, risk factors and time course of difficult extubation, suggesting some conceptual points to plan and manage patients in which a difficult extubation might be expected, including parameters and test to be performed to assess and predict such a situation. PMID- 23090107 TI - General anesthesia in an adult female with propionic acidemia: anesthetic considerations. PMID- 23090108 TI - Automated intermittent aspiration of subglottic secretions and tracheal mucosa damage. PMID- 23090109 TI - Chlorhexidine salt-loaded polyurethane orthodontic chains: in vitro release and antibacterial activity studies. AB - The widespread use of indwelling medical devices has enormously increased the interest in materials incorporating antibiotics and antimicrobial agents as a means to prevent dangerous device-related infections. Recently, chlorhexidine loaded polyurethane has been proposed as a material suitable for the production of devices which are able to resist microbial contamination. The aim of the present study was to characterize the in vitro release of chlorhexidine from new polymeric orthodontic chains realized with polyurethane loaded with two different chlorhexidine salts: chlorhexidine diacetate or chlorhexidine digluconate. The orthodontic chains constituted of three layers: a middle polyurethane layer loaded with chlorhexidine salt inserted between two layers of unloaded polymer. In vitro release of chlorhexidine diacetate and digluconate from orthodontic chains loaded with 10% or 20% (w/w) chlorhexidine salt was sustained for 42 days and followed Fickian diffusion. The drug diffusion through the polyurethane was found to be dependent not only on chlorhexidine loading, but also on the type of chlorhexidine salt. The antibacterial activity of 0.2% (w/w) chlorhexidine diacetate-loaded orthodontic chain was successfully tested towards clinically isolated biofilm forming ica-positive Staphylococcus epidermidis via agar diffusion test. In conclusion, the chlorhexidine salt-loaded chains could provide an innovative approach in the prevention of oral infections related to the use of orthodontic devices. PMID- 23090111 TI - Accelerated polymer biodegradation of risperidone poly(D, L-lactide-co-glycolide) microspheres. AB - The influence of a tertiary amine, namely risperidone (pKa = 7.9) on the degradation of poly(D, L lactide-co-glycolide) (PLGA) microspheres was elucidated. Risperidone and blank microspheres were fabricated at two lactide/glycolide ratios, 65:35 and 85:15. The microspheres were characterized for drug loading by high-performance liquid chromatography, particle size by laser diffractometry, and surface morphology by scanning electron microscopy. Polymer degradation studies were carried out with drug-loaded microspheres and blank microspheres in presence of free risperidone in 0.02 M PBS containing 0.02% Tween(r)80 at 37 degrees C. Molecular weight was monitored by gel permeation chromatography. Risperidone and blank microspheres had similar size distribution and were spherical with a relatively nonporous smooth surface. The presence of risperidone within the microspheres enhanced the hydrolytic degradation in both polymeric matrices with faster degradation occurring in 65:35 PLGA. The molecular weight decreased according to pseudo-first-order kinetics for all the formulations. During the degradation study, the surface morphology of drug-loaded microspheres was affected by the presence of risperidone and resulted in shriveled microspheres in which there appeared to be an intrabatch variation with the larger microspheres being less shriveled than the smaller ones. When blank microspheres were incubated in free risperidone solutions, a concentration dependent effect on the development of surface porosity could be observed. Risperidone accelerates the hydrolytic degradation of PLGA, presumably within the microenvironment of the drug-loaded particles, and this phenomenon must be taken into consideration in designing PLGA dosage forms of tertiary amine drugs. PMID- 23090110 TI - Characterization and in vitro drug release studies of a natural polysaccharide Terminalia catappa gum (Badam gum). AB - The main objective of the present study is the physicochemical characterization of naturally available Terminalia catappa gum (Badam gum [BG]) as a novel pharmaceutical excipient and its suitability in the development of gastroretentive floating drug delivery systems (GRFDDS) to retard the drug for 12 h when the dosage form is exposed to gastrointestinal fluids in the gastric environment. As BG was being explored for the first time for its pharmaceutical application, physicochemical, microbiological, rheological, and stability studies were carried out on this gum. In the present investigation, the physicochemical properties, such as micromeritic, rheological, melting point, moisture content, pH, swelling index, water absorption, and volatile acidity, were evaluated. The gum was characterized by scanning electron microscopy, differential scanning calorimetry (DSC), powder X-ray diffraction studies (PXRD), and Fourier transform infrared spectroscopy (FTIR). Gastroretentive floating tablets of BG were prepared with the model drug propranolol HCl by direct compression methods. The prepared tablets were evaluated for all their physicochemical properties, in vitro buoyancy, in vitro drug release, and rate order kinetics. PBG 04 was selected as an optimized formulation based on its 12-h drug release and good buoyancy characteristics. The optimized formulation was characterized with FTIR, DSC, and PXRD studies, and no interaction between the drug and BG was found. Thus, the study confirmed that BG might be used in the gastroretentive drug delivery system as a release-retarding polymer. PMID- 23090112 TI - Using USP I and USP IV for discriminating dissolution rates of nano- and microparticle-loaded pharmaceutical strip-films. AB - Recent interest in the development of drug particle-laden strip-films suggests the need for establishing standard regulatory tests for their dissolution. In this work, we consider the dissolution testing of griseofulvin (GF) particles, a poorly water-soluble compound, incorporated into a strip-film dosage form. The basket apparatus (USP I) and the flow-through cell dissolution apparatus (USP IV) were employed using 0.54% sodium dodecyl sulfate as the dissolution medium as per USP standard. Different rotational speeds and dissolution volumes were tested for the basket method while different cell patterns/strip-film position and dissolution media flow rate were tested using the flow-through cell dissolution method. The USP I was not able to discriminate dissolution of GF particles with respect to particle size. On the other hand, in the USP IV, GF nanoparticles incorporated in strip-films exhibited enhancement in dissolution rates and dissolution extent compared with GF microparticles incorporated in strip-films. Within the range of patterns and flow rates used, the optimal discrimination behavior was obtained when the strip-film was layered between glass beads and a flow rate of 16 ml/min was used. These results demonstrate the superior discriminatory power of the USP IV and suggest that it could be employed as a testing device in the development of strip-films containing drug nanoparticles. PMID- 23090113 TI - Development of amphotericin B-loaded cubosomes through the SolEmuls technology for enhancing the oral bioavailability. AB - The oral administration of amphotericin B (AmB) has the major drawback of poor bioavailability. The aim of this work was to evaluate the potential of AmB-loaded cubosomes as an oral formulation with improved bioavailability. This manuscript firstly developed AmB-loaded cubosomes by using the SolEmuls technology. The encapsulation efficiency, the in vitro release, and stability studies in simulated gastrointestinal fluid were used to evaluate AmB-loaded cubosomes. The acute nephrotoxicity, bioavailability, and tissue distribution study of AmB loaded cubosomes were assayed upon oral administration to rats. SAXS and cryo-TEM exhibited AmB-loaded cubosomes as a bicontinuous cubic liquid crystalline phase with Pn3m geometry. The encapsulation efficiency and the results of in vitro release and stability studies in simulated gastrointestinal fluid further demonstrated that AmB was successfully encapsulated in cubosomes. AmB-loaded cubosomal formulation orally administrated in rats did not show nephrotoxicity and its relative bioavailability was approximately 285% as compared to Fungizone(r). The AmB-loaded cubosomal formulation presented an effective potential approach for enhancing the oral bioavailability of AmB. PMID- 23090114 TI - Single-molecule genomic data delineate patient-specific tumor profiles and cancer stem cell organization. AB - Substantial evidence supports the concept that cancers are organized in a cellular hierarchy with cancer stem cells (CSC) at the apex. To date, the primary evidence for CSCs derives from transplantation assays, which have known limitations. In particular, they are unable to report on the fate of cells within the original human tumor. Because of the difficulty in measuring tumor characteristics in patients, cellular organization and other aspects of cancer dynamics have not been quantified directly, although they likely play a fundamental role in tumor progression and therapy response. As such, new approaches to study CSCs in patient-derived tumor specimens are needed. In this study, we exploited ultradeep single-molecule genomic data derived from multiple microdissected colorectal cancer glands per tumor, along with a novel quantitative approach to measure tumor characteristics, define patient-specific tumor profiles, and infer tumor ancestral trees. We show that each cancer is unique in terms of its cellular organization, molecular heterogeneity, time from malignant transformation, and rate of mutation and apoptosis. Importantly, we estimate CSC fractions between 0.5% and 4%, indicative of a hierarchical organization responsible for long-lived CSC lineages, with variable rates of symmetric cell division. We also observed extensive molecular heterogeneity, both between and within individual cancer glands, suggesting a complex hierarchy of mitotic clones. Our framework enables the measurement of clinically relevant patient-specific characteristics in vivo, providing insight into the cellular organization and dynamics of tumor growth, with implications for personalized patient care. PMID- 23090115 TI - Targeting the transposase domain of the DNA repair component Metnase to enhance chemotherapy. AB - Previous studies have shown that the DNA repair component Metnase (SETMAR) mediates resistance to DNA damaging cancer chemotherapy. Metnase has a nuclease domain that shares homology with the Transposase family. We therefore virtually screened the tertiary Metnase structure against the 550,000 compound ChemDiv library to identify small molecules that might dock in the active site of the transposase nuclease domain of Metnase. We identified eight compounds as possible Metnase inhibitors. Interestingly, among these candidate inhibitors were quinolone antibiotics and HIV integrase inhibitors, which share common structural features. Previous reports have described possible activity of quinolones as antineoplastic agents. Therefore, we chose the quinolone ciprofloxacin for further study, based on its wide clinical availability and low toxicity. We found that ciprofloxacin inhibits the ability of Metnase to cleave DNA and inhibits Metnase-dependent DNA repair. Ciprofloxacin on its own did not induce DNA damage, but it did reduce repair of chemotherapy-induced DNA damage. Ciprofloxacin increased the sensitivity of cancer cell lines and a xenograft tumor model to clinically relevant chemotherapy. These studies provide a mechanism for the previously postulated antineoplastic activity of quinolones, and suggest that ciprofloxacin might be a simple yet effective adjunct to cancer chemotherapy. PMID- 23090117 TI - Preventing postoperative metastatic disease by inhibiting surgery-induced dysfunction in natural killer cells. AB - Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients. PMID- 23090116 TI - Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. AB - Generating antitumor responses through the inhibition of tumor-derived immune suppression represents a promising strategy in the development of cancer immunotherapeutics. Here, we present a strategy incorporating delivery of the bacterium Salmonella typhimurium (ST), naturally tropic for the hypoxic tumor environment, transformed with a small hairpin RNA (shRNA) plasmid against the immunosuppressive molecule indoleamine 2,3-dioxygenase 1 (shIDO). When systemically delivered into mice, shIDO silences host IDO expression and leads to massive intratumoral cell death that is associated with significant tumor infiltration by polymorphonuclear neutrophils (PMN). shIDO-ST treatment causes tumor cell death independently of host IDO and adaptive immunity, which may have important implications for use in immunosuppressed patients with cancer. Furthermore, shIDO-ST treatment increases reactive oxygen species (ROS) produced by infiltrating PMNs and, conversely, PMN immunodepletion abrogates tumor control. Silencing of host IDO significantly enhances S. typhimurium colonization, suggesting that IDO expression within the tumor controls the immune response to S. typhimurium. In summary, we present a novel approach to cancer treatment that involves the specific silencing of tumor-derived IDO that allows for the recruitment of ROS-producing PMNs, which may act primarily to clear S. typhimurium infection, but in the process also induces apoptosis of surrounding tumor tissue resulting in a vigorous antitumor effect. PMID- 23090118 TI - Tryptophan catabolism in cancer: beyond IDO and tryptophan depletion. AB - Tryptophan catabolism in cancer is increasingly being recognized as an important microenvironmental factor that suppresses antitumor immune responses. It has been proposed that the essential amino acid tryptophan is catabolized in the tumor tissue by the rate-limiting enzyme indoleamine-2,3-dioxygenase (IDO) expressed in tumor cells or antigen-presenting cells. This metabolic pathway creates an immunosuppressive milieu in tumors and in tumor-draining lymph nodes by inducing T-cell anergy and apoptosis through depletion of tryptophan and accumulation of immunosuppressive tryptophan catabolites. Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid cancer, with the aim of enhancing the efficacy of conventional chemotherapy. There are, however, certain tumor types that are capable of catabolizing tryptophan but are largely IDO-negative. Recent evidence from studies in malignant gliomas and other types of cancers points to alternative enzymatic pathways of tryptophan catabolism involving tryptophan-2,3-dioxygenase (TDO). TDO, which is considered responsible for regulating systemic tryptophan levels in the liver, is constitutively expressed in some cancers and is equally capable of suppressing antitumor immune responses. Depletion of tryptophan induces signaling events in T cells, leading to anergy and apoptosis; however, active immunomodulation by accumulating tryptophan catabolites, most notably kynurenine, appears to play an equally important role. These immunomodulatory effects of kynurenine are mediated by the aryl hydrocarbon receptor. This intracellular transcription factor has classically been viewed as a receptor for environmental toxins, such as dioxin, and its important role in influencing immune responses, especially in epithelial barriers, is only beginning to emerge. This review summarizes the exciting developments in our understanding of tryptophan catabolism as a key factor in the immunobiology of cancer. PMID- 23090119 TI - Control of breast cancer growth and initiation by the stem cell-associated transcription factor TCF3. AB - Regulatory factors controlling stem cell identity and self-renewal are often active in aggressive cancers and are thought to promote their growth and progression. TCF3 (also known as TCF7L1) is a member of the TCF/LEF transcription factor family that is central in regulating epidermal and embryonic stem cell identity. We found that TCF3 is highly expressed in poorly differentiated human breast cancers, preferentially of the basal-like subtype. This suggested that TCF3 is involved in the regulation of breast cancer cell differentiation state and tumorigenicity. Silencing of TCF3 dramatically decreased the ability of breast cancer cells to initiate tumor formation, and led to decreased tumor growth rates. In culture, TCF3 promotes the sphere formation capacity of breast cancer cells and their self-renewal. We found that in contrast to ES cells, where it represses Wnt-pathway target genes, TCF3 promotes the expression of a subset of Wnt-responsive genes in breast cancer cells while repressing another distinct target subset. In the normal mouse mammary gland, Tcf3 is highly expressed in terminal end buds, structures that lead duct development. Primary mammary cells are dependent on Tcf3 for mammosphere formation, and its overexpression in the developing gland disrupts ductal growth. Our results identify TCF3 as a central regulator of tumor growth and initiation, and a novel link between stem cells and cancer. PMID- 23090120 TI - Purines, purinergic receptors, and cancer. AB - Purines were long thought to be restricted to the intracellular compartment, where they are used for energy transactions, nucleic acid synthesis, and a multiplicity of biochemical reactions. However, it is now clear that both adenosine and adenosine triphosphate are (i) abundant biochemical components of the tumor microenvironment, (ii) potent modulators of immune cell responses and cytokine release, and (iii) key players in host-tumor interaction. Moreover, both ATP and adenosine directly affect tumor cell growth. Adenosine is a powerful immunosuppressant (mainly acting at A2A receptors) and a modulator of cell growth (mainly acting at A3 receptors). ATP is a proinflammatory (acting at P2Y1, P2Y2, P2Y4, P2Y6, and P2Y12, and at P2X4 and P2X7 receptors), an immunosuppressant (acting at P2Y11), and a growth-promoting agent (acting at P2Y1, P2Y2, and P2X7 receptors). This complex signaling network generates an array of inhibitory and stimulatory responses that affect immune cell function, tumor growth, and metastatic dissemination. Investigation of purinergic signaling has increased our understanding of the tumor microenvironment and opened new and exciting avenues for the development of novel therapeutics. PMID- 23090121 TI - Structural and optical characterization of the local environment of Er3+ ions in PbO-ZnO tellurite glasses. AB - Erbium activated PbO-ZnO tellurite glasses ((70TeO(2)-(30-x)ZnO-xPbO)(0.99) (Er(2)O(3))(0.01) (TZPE), (x = 5, 10, 15, 20)) were prepared by a melt quenching process and studied by optical absorption, luminescence, Raman and x-ray absorption spectroscopy measurements as a function of the PbO/ZnO ratio. The glass structure, as monitored by Raman scattering, shows important changes with the PbO/ZnO ratio, attributed to a glass former action of PbO. The local environment of Er(3+) ions, as measured by extended x-ray absorption spectroscopy, does not appreciably change as regards the first oxygen shell. However, the intensity of the optical transitions is quite sensitive to the PbO/ZnO ratio, indicating a progressive increase of the site symmetry with the PbO content. The emission probability and radiative lifetime of several excited states of Er(3+) ions were calculated using Judd-Ofelt analysis. PMID- 23090122 TI - Acute effects of resistance exercise and intermittent intense aerobic exercise on blood cell count and oxidative stress in trained middle-aged women. AB - The aim of this study was to compare the effect of an intermittent intense aerobic exercise session and a resistance exercise session on blood cell counts and oxidative stress parameters in middle-aged women. Thirty-four women were selected and divided into three groups: RE group (performing 60 min of resistance exercises, N = 12), spinning group (performing 60 min of spinning, N = 12), and control group (not exercising regularly, N = 10). In both exercise groups, lymphocytes and monocytes decreased after 1-h recuperation (post-exercise) compared to immediately after exercise (P < 0.05). Immediately after exercise, in both exercised groups, a significant increase in TBARS (from 16.5 +/- 2 to 25 +/- 2 for the spinning group and from 18.6 +/- 1 to 28.2 +/- 3 nmol MDA/mL serum for the RE group) and protein carbonyl (from 1.0 +/- 0.3 to 1.6 +/- 0.2 for the spinning group and from 0.9 +/- 0.2 to 1.5 +/- 0.2 nmol/mg protein for the RE group) was observed (P < 0.05). A decrease in antioxidant activities (non-protein sulfhydryl, superoxide dismutase, catalase) was also demonstrated with a negative correlation between damage markers and antioxidant body defenses (P < 0.05). These results indicate that an acute bout of intermittent or anaerobic exercise induces immune suppression and increases the production of reactive oxygen species, causing oxidative stress in middle-aged and trained women. Furthermore, we demonstrated that trained women show improved antioxidant capacity and lower oxidative damage than sedentary ones, demonstrating the benefits of chronic regular physical activity. PMID- 23090123 TI - In vitro and in vivo antitumor activity of crude extracts obtained from Brazilian Chromobacterium sp isolates. AB - Natural products produced by microorganisms have been an important source of new substances and lead compounds for the pharmaceutical industry. Chromobacterium violaceum is a Gram-negative beta-proteobacterium, abundant in water and soil in tropical and subtropical regions and it produces violacein, a pigment that has shown great pharmaceutical potential. Crude extracts of five Brazilian isolates of Chromobacterium sp (0.25, 2.5, 25, and 250 ug/mL) were evaluated in an in vitro antitumor activity assay with nine human tumor cells. Secondary metabolic profiles were analyzed by liquid chromatography and electrospray ionization mass spectrometry resulting in the identification of violacein in all extracts, whereas FK228 was detected only in EtCE 308 and EtCE 592 extracts. AcCE and EtCE 310 extracts showed selectivity for NCI/ADR-RES cells in the in vitro assay and were evaluated in vivo in the solid Ehrlich tumor model, resulting in 50.3 and 54.6% growth inhibition, respectively. The crude extracts of Chromobacterium sp isolates showed potential and selective antitumor activities for certain human tumor cells, making them a potential source of lead compounds. Furthermore, the results suggest that other compounds, in addition to violacein, deoxyviolacein and FK228, may be involved in the antitumor effect observed. PMID- 23090125 TI - President's perspective: health care reform and neurologic physical therapy. PMID- 23090124 TI - The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto's thyroiditis but not in Graves' disease. AB - Hashimoto's thyroiditis (HT) is considered to be mediated mainly by Th1 cells, but it is not known whether Graves' disease (GD) is associated with Th1 or Th2 predominance. Th17 cells, a novel subset of Th cells, play a crucial role in the pathogenesis of various autoimmune disorders. In the present study, the expression of IL-17A and IFN-gamma was investigated in patients with HT or GD. mRNA expression of IL-17A and IFN-gamma in peripheral blood mononuclear cells (PBMC) from 43 patients with autoimmune thyroid disease (AITD) and in thyroid tissues from 40 AITD patients were measured by real-time qRT-PCR. The protein expression of IL-17A and IL-23p19 was examined by immunohistochemistry in thyroid tissues from 28 AITD patients. The mRNA levels of IL-17A and IFN-gamma were higher in both PBMC and thyroid tissues of HT patients than in controls (mRNA levels are reported as the cytokine/beta-actin ratio: IL-17 = 13.58- and 2.88 fold change and IFN-gamma = 16.54- and 2.74-fold change, respectively, P < 0.05). Also, the mRNA levels of IL-17A and IFN-gamma did not differ significantly in GD patients (P > 0.05). The high protein expression of IL-17A (IOD = 15.17 +/- 4.8) and IL-23p19 (IOD = 16.84 +/- 7.87) in HT was confirmed by immunohistochemistry (P < 0.05). The similar high levels of IL-17A and IFN-gamma suggest a mixed response of Th17 and Th1 in HT, where both cells may play important roles in the destruction procedure by cell-mediated cytotoxicity. PMID- 23090130 TI - Genetics. Identifying CUP tumours with PCR. PMID- 23090133 TI - Immunotherapy. Relapse-tuning the microenvironment. PMID- 23090134 TI - Management of substance use disorders in ambulatory care in the United States, 2001-2009. PMID- 23090135 TI - Modulation of CYP19 expression by cabbage juices and their active components: indole-3-carbinol and 3,3'-diindolylmethene in human breast epithelial cell lines. AB - PURPOSE: The aim of this study was to evaluate the effect of white cabbage and sauerkraut juices of different origin and indole-3-carbinol (I3C) and diindolylmethane (DIM) on expression of CYP19 gene encoding aromatase, the key enzyme of estrogen synthesis. METHODS: Human breast cell lines (MCF7, MDA-MB-231 and MCF10A) were examined to compare the action of cabbage juices versus their active components (I3C, DIM). Real-time PCR and Western blot were used in order to analyse CYP19 mRNA and protein, respectively. RESULTS: Remarkable differences in the effect on CYP19 transcript and protein level were found between the cabbage juices (in 2.5-25 mL/L concentrations) and indoles (in 2.5-50 MUM doses) in the three cell lines. While cabbage juices at the lower doses diminished the aromatase expression in nontumorigenic/immortalized MCF10A breast cells (0.25 0.86-fold change, P < 0.05), I3C and DIM were more efficient in decreasing the aromatase expression in estrogen-dependant MCF7 breast cancer cells (0.24-0.82 fold change, P < 0.05). Inhibition of aromatase by juice obtained from cabbage grown on industrial farm was correlated with the induction of apoptosis (1.7-1.8 fold change, P < 0.01) in MCF10A cells. In estrogen-independent MDA-MB-231 cells, up-regulation of CYP19 expression by I3C and DIM (1.5-2.0-fold change, P < 0.05) was observed. Similarly, in MCF7 cells juices increased aromatase expression (1.1 2.2-fold change, P < 0.05). CONCLUSION: These results, particularly that obtained in nontumorigenic/immortalized MCF10A cells, suggest that chemopreventive activity of cabbage against breast cancer observed in epidemiological studies may be partly explained by inhibition of the aromatase expression. PMID- 23090136 TI - SOI nanowire for the high-sensitive detection of HBsAg and alpha-fetoprotein. AB - Silicon-on-isolator-nanowires (SOI-NWs) were used for the label-free, real-time biospecific detection of the hepatitis B marker HBsAg and cancer marker alpha fetoprotein (AFP). Specific protein-protein recognition was carried out using individual NWs that were functionalized with antibodies. To solve the problem of non-specific binding of target protein molecules to the sensor element the use of a reference NW with immobilized antibodies against non-target proteins was proposed. Using individual SOI-NW surface functionalization allowed the fabrication of a NW array, containing working NWs and reference NWs within one chip. It was shown that this approach allows us to reach a detection limit up to 10(-14) and 10(-15) M for HBsAg and AFP, respectively. Our investigations also allowed us to reveal the influence of the charged state of the target protein molecules and antibodies in solutions with various pH values on the target protein detection limit. A high sensitivity NW-detector is of interest for the creation of diagnosticums for hepatitis B and for the early stages of cancer diseases. PMID- 23090138 TI - Highly efficient SO2 absorption/activation and subsequent utilization by polyethylene glycol-functionalized Lewis basic ionic liquids. AB - Up to now, flue-gas desulfurization (FGD) is one of the most effective techniques to control SO(2) emission from the combustion of fossil fuels. The conventional technology for FGD poses serious inherent drawbacks such as formation of byproducts and volatilization of solvents. In this work, polyethylene glycol (PEG)-functionalized Lewis basic ionic liquids (ILs) derived from DABCO were proved to be highly efficient absorbents for FGD due to its specific features such as high thermal stability, negligible vapor pressure, high loading capacity. Notably, PEG(150)MeDABCONTf(2) gave an extremely high SO(2) capacity (4.38 mol mol(-1) IL), even under 0.1 bar SO(2) partial pressure (1.01 mol mol(-1) IL), presumably owing to the strong SO(2)-philic characterization of the PEG chain. Furthermore, the absorbed SO(2) could be easy to release by just bubbling N(2) at room temperature, greatly reducing energy requirement for SO(2) desorption. In addition, SO(2)/CO(2) selectivity (110) of PEG(150)MeDABCONTf(2) is two times larger than the non-functionalized imidazolium IL (45). On the other hand, through activation of SO(2) with the tertiary nitrogen in the cation, Lewis basic ILs such as PEG(150)MeDABCOBr proved to be efficient catalysts for the conversion of SO(2) to some value-added chemicals such as cyclic sulfites without utilization of any organic solvent or additive. Thus, this protocol would pave the way for the development of technological innovation towards efficient and low energy demanded practical process for SO(2) absorption and subsequent transformation. PMID- 23090139 TI - Clinicopathological significance of decreased galectin-3 expression and the long term prognosis in patients with breast cancer. AB - PURPOSE: Galectin-3 expression is modulated in cancer cells, and that finding has led to the recognition of galectin-3 as a diagnostic or prognostic marker for various cancers, including breast cancer. This study investigated the correlation between galectin-3 expression and the clinicopathological features in patients with breast cancer, in order to determine the relevance and role of galectin-3 in breast cancer progression. METHODS: Galectin-3 expression was investigated immunohistochemically in 116 patients with breast cancer, and a statistical analysis was performed. RESULTS: Galectin-3 expression in breast cancer was significantly associated with tumor vascular invasion. However, galectin-3 expression was not associated with Ki-67 expression, which reflects tumor proliferation. Disease-free survival and long-term overall survival were significantly shorter for patients with reduced galectin-3 expression. CONCLUSIONS: This study demonstrated that the galectin-3 expression was associated with tumor vascular invasion and metastasis, suggesting that galectin 3 plays a critical role in tumor progression via an invasive mechanism but not via proliferation in breast cancer. Furthermore, reduced expression of galectin-3 is useful for predicting a long-term poor prognosis in patients with breast cancer. PMID- 23090140 TI - Intrahepatic cholangiocarcinoma arising 28 years after excision of a type IV-A congenital choledochal cyst: report of a case. AB - This report presents a rare case of intrahepatic cholangiocarcinoma (IHCC) arising 28 years after excision of a type IV-A congenital choledochal cyst. The patient underwent excision of a congenital choledochal cyst (Todani's type IV-A) at 12 years of age, with Roux-en-Y hepaticojejunostomy reconstruction. She received a pancreaticoduodenectomy (PD) using the modified Child method for an infection of a residual congenital choledochal cyst in the pancreatic head at the age of 18. She was referred to this department with a liver tumor 22 years later. Left hemihepatectomy with left-side caudate lobectomy was performed and the tumor was pathologically diagnosed to be IHCC. The cause of the current carcinogenesis was presumed to be reflux of pancreatic juice into the residual intrahepatic bile duct during surgery. This case suggests that a careful long-term follow-up is important for patients with congenital choledochal cysts, even if a separation operation was performed at a young age, and especially after PD. PMID- 23090142 TI - Hybrid rye performance under natural drought stress in Europe. AB - Several rye growing regions of Central Europe suffered from severe drought stress in the last decade. Rye is typically grown on sandy soils with low water-holding capacity in areas with low rainfall, thus drought-tolerant varieties are urgently needed. The main objective of our study was to evaluate the drought stress tolerance of rye hybrids using large-scaled field experiments. Two biparental populations (Pop-A, Pop-B) each consisting of 220 F(2:4) lines from the Petkus gene pool and their parents were evaluated for grain yield testcross performance under irrigated (I) and rainfed (R) regime in six environments. We observed for most environments severe drought stress leading to an average grain yield reduction of 23.8 % for rainfed compared to irrigated regime in drought stress environments. A decomposition of the variance revealed significant (P < 0.01) genotypic and genotype * environment interaction variances but only a minor effect of drought stress on the ranking of the genotypes with regard to grain yield. In conclusion, separate breeding programs for drought-tolerant genotypes are not superior to the currently practiced selection under rainfed conditions without irrigation in hybrid rye breeding in Central Europe. PMID- 23090141 TI - Multilevel regulation of autophagosome content by ethanol oxidation in HepG2 cells. AB - Acute and chronic ethanol administration increase autophagic vacuole (i.e., autophagosome; AV) content in liver cells. This enhancement depends on ethanol oxidation. Here, we used parental (nonmetabolizing) and recombinant (ethanol metabolizing) Hep G2 cells to identify the ethanol metabolite that causes AV enhancement by quantifying AVs or their marker protein, microtubule-associated protein 1 light chain 3-II (LC3-II). The ethanol-elicited rise in LC3-II was dependent on ethanol dose, was seen only in cells that expressed alcohol dehydrogenase (ADH) and was augmented in cells that coexpressed cytochrome CYP2E1 (P450 2E1). Furthermore, the rise in LC3-II was inversely related to a decline in proteasome activity. AV flux measurements and colocalization of AVs with lysosomes or their marker protein Lysosomal-Associated Membrane Protein 1 (LAMP1) in ethanol-metabolizing VL-17A cells (ADH (+) /CYP2E1 (+) ) revealed that ethanol exposure not only enhanced LC3-II synthesis but also decreased its degradation. Ethanol-induced accumulation of LC3-II in these cells was similar to that induced by the microtubule inhibitor, nocodazole. After we treated cells with either 4 methylpyrazole to block ethanol oxidation or GSH-EE to scavenge reactive species, there was no enhancement of LC3-II by ethanol. Furthermore, regardless of their ethanol-metabolizing capacity, direct exposure of cells to acetaldehyde enhanced LC3-II content. We conclude that both ADH-generated acetaldehyde and CYP2E1 generated primary and secondary oxidants caused LC3-II accumulation, which rose not only from enhanced AV biogenesis, but also from decreased LC3 degradation by the proteasome and by lysosomes. PMID- 23090143 TI - Molecular mapping of Yr53, a new gene for stripe rust resistance in durum wheat accession PI 480148 and its transfer to common wheat. AB - Stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most damaging diseases of wheat worldwide. It is essential to identify new genes for effective resistance against the disease. Durum wheat PI 480148, originally from Ethiopia, was resistant in all seedling tests with several predominant Pst races in the US under controlled greenhouse conditions and at multiple locations subject to natural infection for several years. To map the resistance gene(s) and to transfer it to common wheat, a cross was made between PI 480148 and susceptible common wheat genotype Avocet S (AvS). Resistant F(3) plants with 42 chromosomes were selected cytologically and by testing with Pst race PST-100. A total of 157 F(4) plants from a single F(3) plant with 2n = 42 tested with PST 100 segregated in a 3 resistant: 1 susceptible ratio, indicating that a single dominant gene from PI 480148 conferred resistance. Using the F(3:4) population and the resistance gene-analog polymorphism (RGAP) and simple sequence repeat (SSR) markers, the gene was mapped to the long arm of chromosome 2B. SSR marker Xwmc441 and RGAP marker XLRRrev/NLRRrev ( 350 ) flanked the resistance gene by 5.6 and 2.7 cM, respectively. The effective resistance of the gene to an Australian Pst isolate virulent to Yr5, which is also located on 2BL and confers resistance to all US Pst races, together with an allelism test of the two genes, indicated that the gene from PI 480148 is different from Yr5 and should be a new and useful gene for resistance to stripe rust. Resistant common wheat lines with plant types similar to AvS were selected for use in breeding programs. PMID- 23090144 TI - Roles of the Hd5 gene controlling heading date for adaptation to the northern limits of rice cultivation. AB - During the diversification of cultivated rice after domestication, rice was grown in diverse geographic regions using genetic variations attributed to the combination of alleles in loci for adaptability to various environmental conditions. To elucidate the key gene for adaptation in rice cultivars to the northern limit of rice cultivation, we conducted genetic analyses of heading date using extremely early-heading cultivars. The Hd5 gene controlling heading date (flowering time) generated variations in heading date among cultivars adapted to Hokkaido, where is the northernmost region of Japan and one of the northern limits of rice cultivation in the world. The association of the Hd5 genotype with heading date and genetical analysis clearly showed that the loss-of-function Hd5 has an important role in exhibiting earlier heading among a local population in Hokkaido. Distinct distribution of the loss-of-function Hd5 revealed that this mutation event of the 19-bp deletion occurred in a local landrace Bouzu and that this mutation may have been selected as an early-heading variety in rice breeding programs in Hokkaido in the early 1900s. The loss-of-function Hd5 was then introduced into the rice variety Fanny from France and contributed to its extremely early heading under the presence of functional Ghd7. These results demonstrated that Hd5 plays roles not only in generating early heading in variations of heading date among a local population in Hokkaido, but also in extremely early heading for adaptation to northern limits of rice cultivation. PMID- 23090145 TI - Residual neuromuscular blockade affects postoperative pulmonary function. AB - BACKGROUND: Residual neuromuscular blockade (RNMB) is known to be associated with respiratory complications in the postoperative period after muscle relaxant usage. The authors hypothesized that RNMB causes reductions in pulmonary function test (PFT) parameters in the immediate postoperative period. METHODS: An open label prospective randomized cohort study was conducted comparing reductions in PFT parameters due to RNMB among different neuromuscular blocking agents. One hundred and fifty patients were randomized to receive vecuronium, atracurium, or rocuronium. After reversal of neuromuscular blockade and extubation, train-of four ratio was measured every 5 min until the train-of-four ratio of 0.9 or greater was attained. PFTs were performed preoperatively and postoperatively when the patients were willing and fit. The train-of-four ratio, measured at PFT, was used to classify patients into "RNMB absent" and "RNMB present." RNMB was defined as a train-of-four ratio less than 0.9. RESULTS: Thirty-nine patients had RNMB at the time of performing PFT. There was no statistically significant difference in the postoperative reductions in PFT parameters in patients with RNMB among different neuromuscular blocking agents. Patients were regrouped as RNMB absent and RNMB present, irrespective of neuromuscular blocking agents. Postoperative PFT values for the RNMB-absent and RNMB-present groups were 62% and 49% of baseline forced vital capacity and 47% and 38% of baseline peak expiratory flow of the baseline, respectively. Postoperative forced vital capacity and peak expiratory flow values of RNMB-present patients were lower by 13% and 9% in absolute terms (P<0.008) and 21% and 19% in relative terms, respectively, compared with RNMB-absent patients. CONCLUSION: RNMB results in reductions in forced vital capacity and peak expiratory flow in the immediate postoperative period indicating impaired respiratory muscle function. PMID- 23090146 TI - Relationship of erythrocyte transfusion with short- and long-term mortality in a population-based surgical cohort. AB - BACKGROUND: When comparing transfused versus nontransfused patients, erythrocyte transfusion is consistently associated with increased mortality. Nonetheless, unmeasured confounding may unduly influence this comparison. This unmeasured risk may have less influence on comparisons of patients undergoing surgery at hospitals with differing transfusion rates. METHODS: Administrative databases were used to conduct a population-based cohort study of patients who underwent elective hip- or knee-replacement surgery from 1999 to 2008 in Ontario, Canada. The authors used Cox proportional-hazards models to determine the adjusted association of hospital-specific erythrocyte transfusion rates (i.e., comparing hospitals with differing transfusion rates) with postoperative mortality. For comparison, they also determined the adjusted association of patient receipt of transfusion (i.e., comparing transfused vs. nontransfused patients) with mortality. RESULTS: Of 162,190 patients, 23% (n=37,015) were transfused. Hospital specific transfusion rates at the 66 included hospitals ranged from 10.3 to 57.9%. Compared with nontransfused patients, transfused patients experienced increased adjusted 30-day (hazard ratio 2.32; 95% CI, 1.91-2.83) and 1-yr mortality (hazard ratio 1.75; 95% CI, 1.60-1.91). However, when hospitals were categorized into quartiles based on hospital-specific transfusion rates, mortality rates were similar (highest transfusion quartile vs. lowest transfusion quartile: 30-day mortality, hazard ratio 1.11, 95% CI 0.82-1.50; 1-yr mortality, hazard ratio 1.02, 95% CI 0.82-1.26). CONCLUSIONS: The association of transfusion with postoperative mortality differed significantly when comparing transfused versus nontransfused patients, as opposed to comparing hospitals with differing transfusion rates. This discrepancy raises questions about the true relationship between transfusion and mortality. PMID- 23090147 TI - Erythrocyte transfusion: remedy or poison? PMID- 23090148 TI - Fumbling at your soul: from celestial to chemical ether, the hypothesis of anesthesia in Emily Dickinson's poem 315 ("He fumbles at your soul"). PMID- 23090149 TI - Images in anesthesiology: liver contusion after spine fusion surgery in prone position. PMID- 23090150 TI - Differences in microRNA changes of healthy rat liver between sevoflurane and propofol anesthesia. AB - BACKGROUND: In previous studies, the authors showed that anesthetics affect the expression ratios of many genes in rat liver. microRNAs (miRNA) negatively regulate more than 30% of genes in cells, and control cell proliferation, inflammation, and metabolism. The authors hypothesized that anesthetics influence miRNA expression in the liver, and performed miRNA screening tests using TaqMan low-density arrays. METHODS: Rats were randomly assigned to the 2.4% sevoflurane group, the 600 ug.kg-1.min-1 propofol group, and the control group without anesthetics. Rats were allowed to breathe spontaneously under anesthesia for 6 h. The miRNA expression profile of the liver was analyzed, and 15 representative miRNAs were validated by quantitative real-time reverse transcriptase polymerase chain reaction. RESULTS: TaqMan low-density arrays analysis showed 46 miRNAs that were differentially expressed by anesthetics. After sevoflurane treatment, 16 miRNAs were significantly increased and 11 were significantly decreased compared with controls, whereas after propofol treatment, 31 miRNAs were increased and 8 were decreased. Twenty expressed miRNAs were common to both anesthetics, whereas three miRNAs were differentially expressed. Bland-Altman analysis was performed across the validations to compare the fold changes measured by both methods, and they were equivalent (mean difference=0.01, 95% CI=-0.26 to 0.27). This showed that the TaqMan low-density arrays results are accurate and can be confirmed using an independent experimental approach. CONCLUSION: The results showed that anesthetics cause many miRNA expression changes, and the miRNA expression pattern was particular for each anesthetic. Further studies are needed to determine the functional consequence of miRNA modulation by anesthetics. PMID- 23090151 TI - Cu nanoparticles enable plasmonic-improved silicon photovoltaic devices. AB - This work examines the effect of copper nanoparticles (Cu NPs) on the photocurrent efficiency of silicon photovoltaic (Si PV) devices. An optimized synthesis of stable Cu NPs is reported together with a procedure for their immobilization on the Si PV surface. A comprehensive analysis of the photocurrent and power dependence of the Cu NPs surface coverage and size is presented. A decrease in photoconversion was observed for wavelengths shorter than ~500 nm, due to the Cu interband absorption. In the low surface coverage limit, where the level of aggregation was found to be low, the surface plasmon resonance absorption dominates leading to a modest effect on the photocurrent response. As the number of aggregates increased with the surface coverage, the photocurrent efficiency also increased, and a maximum enhancement power conversion of 16% was found for a 54 +/- 6 NPs per MUm(2) PV cell. This enhancement was attributed to SPR light scattering and trapping into the Si PV device. Higher surface coverage yielded numerous aggregates which acted as a bulk coating and caused a decrease in both photocurrent and power measurements. PMID- 23090153 TI - Characterization of sensitivity and specificity in leaky droplet-based assays. AB - This paper uses numerical methods to characterize the crosstalk of small fluorescent molecules and molecular probes among aqueous droplets immersed in a continuous phase of hydrocarbons or fluorocarbons in microfluidic systems. Droplet-based biochemical assays rely on the reagents to remain isolated in individual droplets. It has been observed, however, that small and hydrophobic fluorescent molecules can diffuse across the droplet boundary into other drops. The contents among droplets become mixed and homogenized over time. Such cross contamination can have detrimental effects on the accuracy of droplet-based assays, especially those using fluorescent molecules and the corresponding number of fluorescent droplets for a quantitative readout. This work examines the competing dynamics of the generation of fluorescent molecules in "positive" drops (in response to the presence of molecules or cells of interest), against its leakage into "negative" drops, where such molecules or cells of interest are absent. In ideal droplet assays, the signal-to-noise ratio (SNR)--defined as the fluorescence signal from a positive drop to that from a negative drop--would increase and saturate with time. In a leaky droplet assay, the SNR tends to decay with time. Under certain conditions, however, the SNR from a leaky droplet assay could increase and reach a maximum value before it starts to diminish. This maximum value can be estimated from a dimensionless number relating the rate of leakage relative to the rate of generation of fluorescence signal in the drops. Beyond the time when the SNR peaks, the SNR value, as well as the accuracy of the leaky droplet assay continues to degrade. In the absence of immediate experimental remedies to completely eliminate the crosstalk of molecules among drops, performing detection at the optimal time point becomes critical to minimize errors in leaky droplet assays. PMID- 23090155 TI - Convenient tautomeric forms in an amino-anthraquinone diimine for the generation of a mixed-valent push-pull conjugated polymer. AB - The use of NH(2) on the (Pt(C=C)(2)(PBu(3))(2))(n)/anthraquinone diimine)(n) polymer induces a tautomeric species which leads to a mixed-valent form reminiscent of emaraldine in polyaniline. PMID- 23090154 TI - Transcription factor networks in invasion-promoting breast carcinoma-associated fibroblasts. AB - Carcinoma-associated fibroblasts (CAFs) contribute to both tumor growth and cancer progression. In this report, we applied an emerging transcription factor (TF) activity array to fibroblasts to capture the activity of the intracellular signaling network and to define a signature that distinguishes mammary CAFs from normal mammary fibroblasts. Normal fibroblasts that restrained cancer cell invasion developed into an invasion-promoting CAF phenotype through exposure to conditioned medium from MDA-MB-231 breast cancer cells. A myofibroblast-like CAF cell line expressing high levels of smooth muscle actin was compared to normal mammary fibroblasts before and after induction. Comparison of TF activity profiles for all three fibroblast types identified a TF activity signature common to CAFs which included activation of reporters for TFs ELK1, GATA1, retinoic acid receptor (RAR), serum response factor (SRF), and vitamin D receptor (VDR). Additionally, CAFs resembling myofibroblasts, relative to normal fibroblasts, had elevated activation corresponding to NF-kappaB, RUNX2, and YY1, and distinct activity patterns for several differentiation-related TF reporters. Induction of CAFs by exposure of normal fibroblasts to conditioned medium from MDA-MB-231 cells resulted in increased activation of reporters for HIF1, several STAT TFs, and proliferation-related TFs such as AP1. Myofibroblast-like CAFs and induced normal mammary fibroblasts promoted invasion of breast cancer cells by distinct mechanisms, consistent with their distinct patterns of TF activation. The TF activity profiles of CAF subtypes provide an overview of intracellular signaling associated with the induction of a pro-invasive stroma, and provide a mechanistic link between the microenvironmental stimuli and phenotypic response. PMID- 23090156 TI - Anagenetic speciation in Ullung Island, Korea: genetic diversity and structure in the island endemic species, Acer takesimense (Sapindaceae). AB - Anagenetic speciation is an important mode of speciation in oceanic islands; one fourth of the endemic plants are estimated to have been derived via this process. Few studies, however, have critically examined the genetic consequences of anagenesis in comparison with cladogenesis (involved with adaptive radiation). We hypothesize that endemic species originating via anagenetic speciation in a relatively uniform environment should accumulate genetic variation with limited populational differentiation. We undertook a population genetic analysis using nine nuclear microsatellite loci of Acer takesimense, an anagenetically derived species endemic to Ullung Island, Korea, and its continental progenitor A. pseudosieboldianum on the Korean Peninsula. Microsatellite data reveal a clear genetic distinction between the two species. A high F value in the cluster of A. takesimense was found by Bayesian clustering analysis, suggesting a strong episode of genetic drift during colonization and speciation. In comparison with A. pseudosieboldianum, A. takesimense has slightly lower genetic diversity and possesses less than half the number of private and rare alleles. Consistent with predictions, weak geographical genetic structure within the island was found in A. takesimense. These results imply that anagenetic speciation leads to a different pattern of specific and genetic diversity than often seen with cladogenesis. PMID- 23090157 TI - Identification of chromosome regions controlling seed storage proteins of narrow leafed lupin (Lupinus angustifolius). AB - Narrow-leafed lupin (Lupinus angustifolius L.) is a valuable legume crop for animal feed and human health food because of its high proteins content. However, the genetics of seed storage proteins is unclear, limiting further improvement of protein quantity and quality. In this study, matrix-assisted laser desorption/ionization time of flight mass spectrometry was used for the first time to analyze lupin seed storage proteins and the spectra generated was treated as markers to investigate the chromosome locations controlling seed storage proteins in the narrow-leafed lupin. In a recombinant inbred line population of 89 individuals, 48 polymorphic protein peaks were identified and seven of which were successfully mapped onto four existing linkage groups: two on NLL-04, three on NLL-05, one on NLL-07 and one on NLL-14, with LOD values ranging from 2.6 to 7.7 confirming a significant linkage. Most protein-based markers showed distorted segregation and were failed to be integrated into the reference map. Among them, 31 were grouped into six clusters and the other ten were totally unlinked. This study provides a significant clue to study the comparative genomics/proteomics among legumes as well as for protein marker-assisted breeding. The distribution pattern of genes controlling seed storage protein revealed in this study probably exists universally among legumes or even all plants and animals. Whether genes controlling seed storage protein share the same gene expression pattern controlling other enzymes and what is the mechanism behind it are the questions which remain to be answered in the future. PMID- 23090158 TI - Full range physiological mass transport control in 3D tissue cultures. AB - We report the first demonstration of a microfluidic platform that captures the full physiological range of mass transport in 3-D tissue culture. The basis of our method used long microfluidic channels connected to both sides of a central microtissue chamber at different downstream positions to control the mass transport distribution within the chamber. Precise control of the Peclet number (Pe), defined as the ratio of convective to diffusive transport, over nearly five orders of magnitude (0.0056 to 160) was achieved. The platform was used to systematically investigate the role of physiological mass transport on vasculogenesis. We demonstrate, for the first time, that vasculogenesis can be independently stimulated by interstitial flow (Pe > 10) or hypoxic conditions (Pe < 0.1), and not by the intermediate state (normal living tissue). This simple platform can be applied to physiological and biological studies of 3D living tissue followed by pathological disease studies, such as cancer research and drug screening. PMID- 23090159 TI - Effects of work and lifestyle on risk for future disability pension due to low back diagnoses: a 30-year prospective study of Finnish twins. AB - OBJECTIVE: To investigate work and lifestyle factors as predictors for disability pension (DP) due to low back diagnoses (LBDs) during a 30-year follow-up. METHODS: Baseline survey data were obtained in 1975 for 16,028 working-age twins followed with register data on DP, emigration, old-age pension, and death until end of 2004; analyzed by Cox proportional hazards regression. RESULTS: Among those at work at baseline, 470 DPs due to LBDs were granted during the follow-up. Monotonous work, lifting and carrying at work or physically heavy work, and unemployment at least once before baseline were significant predictors for DP. A healthy lifestyle was a protective factor for DP. Family background played a role in all these associations. CONCLUSION: The factors shared by family members seemed to influence both work and lifestyle factors, which then influenced the incidence of DP due to LBDs. PMID- 23090160 TI - Workplace health promotion implementation, readiness, and capacity among midsize employers in low-wage industries: a national survey. AB - OBJECTIVE: To describe workplace health promotion (WHP) implementation, readiness, and capacity among midsize employers in low-wage industries in the United States. METHODS: A cross-sectional survey of a national sample of midsize employers (100 to 4999 employees) representing five low-wage industries. RESULTS: Employers' WHP implementation for both employees and employees' spouses and partners was low. Readiness scales showed that employers believe WHP would benefit their employees and their companies, but they were less likely to believe that WHP was feasible for their companies. Employers' capacity to implement WHP was very low; nearly half the sample reported no capacity. CONCLUSION: Midsize employers in low-wage industries implement few WHP programs; their responses to readiness and capacity measures indicate that low capacity may be one of the principal barriers to WHP implementation. PMID- 23090162 TI - Twenty years of editorship. PMID- 23090163 TI - Periodontal disease treatment and risk of preterm birth: a systematic review and meta-analysis. AB - The events leading to preterm birth are still not completely understood. A quantitative systematic review was performed to estimate the effects of periodontal care during pregnancy on preventing preterm birth and low birth weight. The meta-analysis included randomized trials with pregnant women with a diagnosis of periodontal disease before 20 weeks of gestation. Relative risk (RR) with 95% confidence intervals (95%CI) was calculated. We evaluated the reduction in preterm and low birth weight. Thirteen trials were included, comparing 3,576 women in intervention groups with 3,412 women receiving usual care. The meta analysis of the effects of periodontal disease treatment during pregnancy indicated a non-significant reduction in preterm births (RR = 0.90; 95%CI: 0.68 1.19) and low birth weights (RR = 0.92; 95%CI: 0.71-1.20). The creation and examination of a funnel plot revealed clear evidence of publication bias. In summary, primary periodontal care during pregnancy cannot be considered an efficient way of reducing the incidence of preterm birth. PMID- 23090161 TI - Acute cardiovascular effects of firefighting and active cooling during rehabilitation. AB - OBJECTIVES: To determine the cardiovascular and hemostatic effects of fire suppression and postexposure active cooling. METHODS: Forty-four firefighters were evaluated before and after a 12-minute live-fire drill. Next, 50 firefighters performing the same drill were randomized to undergo postfire forearm immersion in 10 degrees C water or standard rehabilitation. RESULTS: In the first study, heart rate and core body temperature increased and serum C reactive protein decreased but there were no significant changes in fibrinogen, sE-selectin, or sL-selectin. The second study demonstrated an increase in blood coagulability, leukocyte count, factors VIII and X, cortisol, and glucose, and a decrease in plasminogen and sP-selectin. Active cooling reduced mean core temperature, heart rate, and leukocyte count. CONCLUSIONS: Live-fire exposure increased core temperature, heart rate, coagulability, and leukocyte count; all except coagulability were reduced by active cooling. PMID- 23090164 TI - [Disease prevention in the elderly: misconceptions in current models]. AB - The Brazilian population is aging significantly within a context of gradual improvement in the country's social and economic indicators. Increased longevity leads to increased use of health services, pressuring the public and social welfare health services, generating higher costs, and jeopardizing the system's sustainability. The alternative to avoid overburdening the system is to invest in policies for disease prevention, stabilization of chronic diseases, and maintenance of functional capacity. The current article aims to analyze the difficulties in implementing preventive programs and the reasons for the failure of various programs in health promotion, prevention, and management of chronic diseases in the elderly. There can be no solution to the crisis in financing and restructuring the health sector without implementing a preventive logic. Scientific research has already correctly identified the risk factors for the elderly population, but this is not enough. We must use such knowledge to promote the necessary transition from a healthcare-centered model to a preventive one. PMID- 23090165 TI - [Previous history of Pap smears and cervical cancer: a case-control study in the Baixada Fluminense, Rio de Janeiro State, Brazil]. AB - This hospital-based case-control study (2007-2010) aimed to estimate the association between previous Pap smear and cervical cancer diagnosis in the Baixada Fluminense, Rio de Janeiro State, Brazil. The sample consisted of 152 histologically confirmed cases and 169 controls from the same hospital as the cases. The analysis was conducted according to a model in three hierarchical levels considering sociodemographic characteristics (distal), sexual/reproductive and lifestyle factors (intermediate), and previous Pap smear (proximal). Odds ratios (OR) and respective 95% confidence intervals (95%CI) were calculated using unconditional logistic regression. History of three or more Pap smears was associated with an 84% reduction in cervical cancer risk (OR = 0.16; 95%CI: 0.074; 0.384) after adjusting for selected variables. The results highlight the importance of preventive gynecological examination for reducing the risk of cervical cancer and emphasize the need to increase adherence to the guidelines of the Brazilian program, besides identifying and scheduling women that have proven reluctant to submit to cervical cancer screening. PMID- 23090166 TI - Sickness benefit claims due to mental disorders in Brazil: associations in a population-based study. AB - This study aims to determine the prevalence and duration of sickness benefit claims due to mental disorders and their association with economic activity, sex, age, work-relatedness and income replacement using a population-based study of sickness benefit claims (> 15 days) due to mental disorders in Brazil carried out in 2008. The prevalence of mental disorders was 45.1 claims per 10,000 workers. Prevalence and duration of sickness benefit claims due to mental disorder were higher and longer in workers aged over 40 years. Prevalence of claims was 73% higher in women but duration of sickness benefit claims was longer in men. Prevalence rates for claims differed widely according to economic activity, with sewage, residential care and programming and broadcasting activities showing the highest rates. Claims were deemed to be work-related in 8.5% of cases with mental disorder showing low work-relatedness in Brazil. A wide variation of prevalence and duration between age, economic activity and work-relatedness was observed, suggesting that working conditions are a more important factor in mental disorder work disability than previously assumed. PMID- 23090167 TI - [Urban sporotrichosis: a neglected epidemic in Rio de Janeiro, Brazil]. AB - In the scientific literature, sporotrichosis has traditionally been associated with agricultural work, since the causative agent is found naturally in the soil. However, cases have been reported recently in an urban area, related to zoonotic transmission. The current study aimed to contribute to knowledge on sporotrichosis in an urban area through an exploratory analysis of its socio spatial distribution in Rio de Janeiro, Brazil, from 1997 to 2007, identifying the areas with the heaviest transmission. The database from the Health Surveillance Service at the Evandro Chagas Institute for Clinical Research, Oswaldo Cruz Foundation, was used to estimate incidence rates and spatial distribution. During the study period, 1,848 cases of sporotrichosis were reported, predominantly in adult women not currently in the labor market. The leading source of infection was wounds caused by domestic cats, which contributed to the spread of sporotrichosis in this urban area. Georeferencing of 1,681 cases showed a transmission belt along the border between the city of Rio de Janeiro and the adjacent municipalities in the Greater Metropolitan Area. PMID- 23090168 TI - Setting oral health goals that include oral health-related quality of life measures: a study carried out among adolescents in Thailand. AB - The aim of this study was to assess the association between oral diseases and condition-specific oral health-related quality of life (CS-OHRQoL) as a basis for proposing OHRQoL-based goals for the population of 15-year-olds in Thailand. Oral examinations and OHRQoL interviews were conducted with 871 15-year-olds as part of the Sixth Thailand National Oral Health Survey. The severity of oral impacts was categorized using "intensity". Associations between oral diseases and CS OHRQoL were analyzed using chi-square and logistic regression. Thirty-nine percent of 15-year-olds experienced moderate/higher levels oral impacts on quality of life. Compared to those individuals with no tooth decay, adolescents with one or four or more decaying teeth were three and seven times more likely to experience moderate/higher impacts, respectively. Adolescents with extensive gingivitis in 3 or more mouth sextants were twice as likely to experience moderate/higher CS-impacts. Based on these findings, it is proposed that goals should focus on untreated decaying teeth and extensive gingivitis. Oral health goals for 15-year-olds should include specific OHRQoL measures. PMID- 23090169 TI - [Patterns of physical activity during a typical day for adults in Niteroi, Rio de Janeiro State, Brazil: the Nutrition, Physical Activity, and Health Survey (PNAFS)]. AB - The current study aimed to assess patterns of typical daily physical activity in a probability sample (N = 1,689) of adults in Niteroi, Rio de Janeiro State, Brazil, using 24-hour recall. The sample was designed in three stages (census enumeration area - CEA, household within the CEA, and an adult selected with equal probability among all eligible adults in the household). Physical activities were classified as light, moderate, or vigorous and grouped in household chores, occupational, leisure-time, and commuting. Men performed more moderate and vigorous activities during significantly more time (91.2 +/- 5.6 and 8.2 +/- 1.4 minutes, respectively; mean +/- SD) as compared to women (68.5 +/- 2.7 and 2.9 +/- 0.4 minutes, respectively). The proportions of adults that reached the recommended 30 minutes of moderate/vigorous physical activity per day were 63.8% (men) and 55.9% (women). Household chores for women and leisure-time activity for men contributed the most to total moderate/vigorous physical activity. In conclusion, most adults in Niteroi are physically active. PMID- 23090170 TI - Social inequality in health among women in Campinas, Sao Paulo State, Brazil. AB - The aim of this study was to assess social inequalities in health status and use of health services according to level of schooling in women. This was a cross sectional population-based study with a sample of 508 women from 20 to 59 years of age living in Campinas, Sao Paulo State, Brazil (ISA-Camp 2008). Women with less schooling showed higher prevalence of hypertension, circulatory problems, headache, dizziness, obesity, common mental disorders, worse self-rated health, use of dental prosthesis, and visual impairment, but lower prevalence for use of eyeglasses. There were no differences between the two schooling strata in prevalence of medical visits in the previous two weeks, use of medicines in the three previous days, Pap smear, breast self-examination, clinical breast examination, hospitalizations and surgeries in the previous year, and rubella vaccination any time in life. The only significant differences were in use of dental services and mammograms. The results show social inequalities in various health indicators and equity in access to various components of the health services. PMID- 23090171 TI - Risk factors for infant mortality in a municipality in southern Brazil: a comparison of two cohorts using hierarchical analysis. AB - This study compared risk factors for infant mortality in 2000-2001 and 2007-2008 in Londrina, Parana State, Brazil. Data on live births and infant deaths were linked in a single database, and a hierarchical regression model was used. Distal risk factors for infant mortality in 2000-2001 were maternal age < 20 or >= 35 years and lower maternal schooling. In 2007-2008, maternal age >= 35 or < 20 years were risk factors, while low schooling appeared as a protective factor. The following intermediate factors were associated with increased infant mortality in 2000-2001: multiple pregnancy, history of stillbirth, and insufficient number of prenatal visits, while cesarean delivery was a protective factor. Multiple pregnancy was the only intermediate risk factor in 2007-2008. All of the proximal factors were associated with higher infant mortality in 2000-2001, but only gestational age and 5-minute Apgar in 2007-2008. The risk factors for infant mortality changed from the first to the second cohort, which may be related to the expansion of social policies and primary care and changes in the reproductive and social patterns of Brazilian women. PMID- 23090172 TI - [Self-rated oral health: results of the World Health Survey-Primary Care in four municipalities in Rio de Janeiro State, Brazil, 2005]. AB - Self-rated health is a subjective indicator that combines physical and emotional components and individual well-being. It has gained an important role in Public Health, with increasing use in the evaluation of the general population's health status. This study focuses on dental care and oral health status, including self rated oral health, using data from 1,871 individuals 18 years or older, interviewed in World Health Survey-Primary Care, conducted in four municipalities in the State of Rio de Janeiro, Brazil. Bivariate logistic regression models were used to identify the determinants of 'excellent' or 'good' self-rated oral health. For both men and women, variables significantly associated with self rated oral health were: per capita family income, frequency of dental visits, tooth loss, and use of dental prostheses. The results showed a socioeconomic gradient in self-rated oral health, precarious oral health among the elderly, and the importance of regular dental visits for maintaining oral health. PMID- 23090173 TI - [The impact of low birth weight related to gestational depression on federal funding of public health: a study in Pelotas, Rio Grande do Sul State, Brazil]. AB - Low birth weight is related to morbidity and mortality and sequelae during infant development, thereby impacting health system costs. It is thus important to evaluate factors that influence low birth weight and to estimate their impact on the Brazilian Unified National Health System (SUS). This was a nested prospective study in a cohort of pregnant women who received prenatal care and gave birth in the National Health System in hospitals with ICUs in the city of Pelotas, Rio Grande do Sul State, Brazil. Gestational depression was associated with a fourfold risk of low birth weight (PR = 3.94; CI: 1.49-10.36). Based on the population-attributable fraction, in the overall population an estimated 36.17% of low birth weight infants are born to mothers with an episode of depression during pregnancy, with an estimated cost of more than R$76 million (U$38 million) in Brazil. The study recommends the expansion of preventive and therapeutic mental health care measures for pregnant women and the adequate use of resources in the Unified National Health System to improve neonatal outcomes. PMID- 23090174 TI - Space-time cluster analysis of American visceral leishmaniasis in Bauru, Sao Paulo State, Brazil. AB - A space-time analysis of American visceral leishmaniasis (AVL) in humans in the city of Bauru, Sao Paulo State, Brazil was carried out based on 239 cases diagnosed between June 2003 and October 2008. Spatial analysis of the disease showed that cases occurred especially in the city's urban areas. AVL annual incidence rates were calculated, demonstrating that the highest rate occurred in 2006 (19.55/100,000 inhabitants). This finding was confirmed by the time series analysis, which also showed a positive tendency over the period analyzed. The present study allows us to conclude that the disease was clustered in the Southwest side of the city in 2006, suggesting that this area may require special attention with regard to control and prevention measures. PMID- 23090175 TI - Factors related to poor self-perceived oral health among community-dwelling elderly individuals in Sao Paulo, Brazil. AB - The present study investigated the prevalence of poor self-perceived oral health and its association with oral health, general health and socioeconomic factors among elderly individuals from Sao Paulo, Brazil. The sample consisted of 871 elderly individuals enrolled in the Health, Wellbeing and Aging cohort study. Self-perceived oral health was measured by the question: "How would you rate your oral health?". Most subjects self-rated their oral health as good. Among dentate individuals, poor oral health was related to depression, poor self-rated health, dental treatment, dental checkups and the psychosocial subscale scores of the Geriatric Oral Health Assessment Index. Edentulous individuals were more likely to report poor oral health, whereas those with higher psychosocial scores were less likely to report poor self-rated oral health. Poor self-rated oral health is associated with general health factors and the psychosocial impact of oral health on quality of life, regardless of socioeconomic and clinical health measures. PMID- 23090176 TI - [Factors associated with lack of Pap smear screening in a group of postmenopausal Brazilian women]. AB - This study aimed to analyze risk factors for lack of Pap smear screening among menopausal women. This population-based study evaluated 456 women 45-69 years of age (mean 58.7; SD 5.7), with age at menopause 48.0 years (SD 5.0) living in the urban area of Maringa, Parana State, Brazil. Most reported having 7 years of schooling or less, were married or living with a partner, had paid work, were sedentary, and were not on hormone replacement therapy. Coverage of Pap smear screening was 84.5%. After adjustment by multivariate analysis, the 45-69-year age bracket, paid work, no visit to the gynecologist in the previous year, and no mammogram in the two previous years were statistically associated with lack of Pap smear screening. Efforts to improve cervical cancer screening should focus on women's knowledge and reduce the factors that hinder women from performing Pap smear tests. PMID- 23090177 TI - [Brazilian version of the Non-communicative Patient's Pain Assessment Instrument (NOPPAIN): conceptual, item, and semantic equivalence]. AB - The evaluation and measurement of pain in individuals with dementia and unable to communicate verbally has been a challenging experience. The Non-communicative Patient's Pain Assessment Instrument (NOPPAIN) is an instrument that evaluates this phenomenon by observing behaviors that express pain. Considering the lack of instruments for this purpose in Brazil, the current study was designed to translate the NOPPAIN instrument into Brazilian Portuguese and culturally adapt it to the Brazilian reality. This was a methodological study, with Guillemin et al. as the theoretical reference. The study included four steps: translation; obtaining a consensus version; back-translation; and evaluation of the translation and back-translation by an expert panel. In this initial approach, the NOPPAIN-Br showed semantic equivalence to the original instrument and is now available in Brazilian Portuguese for further validation. PMID- 23090178 TI - [Semantic and item equivalences of the Brazilian Portuguese version of the Vecu et Sante Percue de l'Adolescent: an adolescent quality-of-life questionnaire]. AB - In Brazil, no instruments evaluating adolescents' health-related quality of life (HRQoL) have been developed from the adolescents' point of view. The use of an instrument developed in another socio-cultural context requires prior cultural adaptation, including conceptual, item, and semantic equivalence in the process. Vecu et Sante Percue de l'Adolescent (VSP-A) is a French generic instrument developed to evaluate adolescents' HRQoL. The objective of the study was to evaluate the semantic, item, and conceptual equivalence of a Brazilian Portuguese version of the VSP-A. VSP-A was translated into Portuguese, back-translated (with steps evaluated by experts), and pre-tested in a group of 14 adolescents. Discussion with experts resulted in a final version of the questionnaire, considered semantically and conceptually equivalent to the original, despite the need to modify some items to facilitate use. Pretest results showed that the instrument is easy for adolescents to understand and answer. For use in Brazil, its psychometric properties need to be evaluated. PMID- 23090179 TI - HRWeb Americas: a tool to facilitate better research governance in Latin America and the Caribbean. PMID- 23090180 TI - Pesticide exposure and poor pregnancy outcomes: weaknesses of the evidence. PMID- 23090181 TI - Dengue infection and maternal mortality. PMID- 23090183 TI - The 4,5,6-triphospha[3]radialene dianion: a phosphorus analogue of the deltate dianion. A NICS(0)(pizz) examination of their aromaticity. AB - Reduction of a 4,5,6-triphospha[3]radialene gave the corresponding isolable dianionic species. Despite having two deltate dianion-like pi-electrons delocalized over the central framework, its small NICS(0)(pizz) value (only -2.2 ppm) indicates only limited aromaticity. PMID- 23090185 TI - A retrospective investigation of women's experience with breast reconstruction after mastectomy. AB - PURPOSE: A diagnosis of breast cancer is often accompanied by the fear of loss of previous body image and attractiveness. Hence, many patients opt for reconstructive surgery. This study evaluated the effects of different types of reconstructive surgery after mastectomy on the functional and psychological adjustment of patients. METHODS: In a cohort study, patients, who had breast reconstruction after mastectomy by means of four different allogenic or autologues techniques between 1999-2006 were retrospectively interviewed in person or by telephone. The questions addressed complication rates, physical complaints, functional impairments, body image outcomes, sexuality and patient satisfaction. RESULTS: Of 139 patients, 89 (64.7 %) completed the survey. 32 (35.9 %) patients experienced one or more postoperative complications like seroma, hematoma, infections or necrosis. 16 (20 %) and 13 (16 %) patients reported strong and moderate adverse effects on sexuality, respectively. 62 (70 %) patients indicated that they were actively included in the decision making process. Patient ratings of good or bad medical advice were associated with complication rates (p = 0.008). Patients, who evaluated their first preoperative counseling positively, reported higher consent rates when a re-reconstruction became necessary (p <= 0.001). Satisfaction with the functional outcome after reconstruction and satisfaction with the cosmetic result was highly correlated (p < 0.001). CONCLUSIONS: A significant association of patient satisfaction with postoperative complications and the decision for a re-reconstruction was demonstrated. Furthermore, our results emphasize the importance of detailed preoperative counseling for women's adjustment to reconstructive surgery. PMID- 23090186 TI - Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db/db mice. AB - AIMS/HYPOTHESIS: Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)gamma co activator 1alpha (PGC-1alpha), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. METHODS: Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. RESULTS: The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1alpha signalling and of the key downstream effectors, the PPARalpha-oestrogen-related receptor (ERR) 1alpha-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1alpha signalling and the downstream effectors, PPARalpha-ERR-1alpha-SREBP1. CONCLUSIONS/INTERPRETATION: The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1alpha signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney. PMID- 23090187 TI - Human blood outgrowth endothelial cells improve islet survival and function when co-transplanted in a mouse model of diabetes. AB - AIMS/HYPOTHESIS: As current islet-transplantation protocols suffer from significant graft loss and dysfunction, strategies to sustain the long-term benefits of this therapy are required. Rapid and adequate oxygen and nutrient delivery by blood vessels improves islet engraftment and function. The present report evaluated a potentially beneficial effect of adult human blood outgrowth endothelial cells (BOEC) on islet graft vascularisation and function. METHODS: Human BOEC, 5 * 10(5), were co-transplanted with a rat marginal-islet graft under the kidney capsule of hyperglycaemic NOD severe combined immunodeficiency (SCID) mice, and the effect on metabolic outcome was evaluated. RESULTS: Although vessel density remained unaffected, co-transplantation of islets with BOEC resulted in a significant and specific improvement of glycaemia and increased plasma C-peptide. Moreover, in contrast to control mice, BOEC recipients displayed reduced beta cell death and increases in body weight, beta cell proliferation and graft-vessel and beta cell volume. In vivo cell tracing demonstrated that BOEC remain at the site of transplantation and do not expand. The potential clinical applicability was underscored by the observed metabolic benefit of co-transplanting islets with BOEC derived from a type 1 diabetes patient. CONCLUSIONS/INTERPRETATION: The present data support the use of autologous BOEC in translational studies that aim to improve current islet-transplantation protocols for the treatment of brittle type 1 diabetes. PMID- 23090194 TI - What is more valuable: fenofibrate patents or fenofibrate clinical outcomes? PMID- 23090188 TI - Complex evolution and epidemiology of Dobrava-Belgrade hantavirus: definition of genotypes and their characteristics. AB - Dobrava-Belgrade virus (DOBV) is a human pathogen that has evolved in, and is hosted by, mice of several species of the genus Apodemus. We propose a subdivision of the species Dobrava-Belgrade virus into four related genotypes - Dobrava, Kurkino, Saaremaa, and Sochi - that show characteristic differences in their phylogeny, specific host reservoirs, geographical distribution, and pathogenicity for humans. PMID- 23090195 TI - Generic competition in a flawed system: pill them, bill them. PMID- 23090197 TI - Subclinical hypothyroidism and cardiovascular disease. PMID- 23090199 TI - Charge variability for acute appendicitis: is the problem overstated? PMID- 23090200 TI - Of appendectomies, markets, and fictional charges. PMID- 23090201 TI - Appendicitis: the great masquerader. PMID- 23090202 TI - Basic health care is not a "market good". PMID- 23090204 TI - GRP78-targeted nanotherapy against castrate-resistant prostate cancer cells expressing membrane GRP78. AB - Glucose-regulated protein 78, GRP78, is a chaperone protein mainly located in the endoplasmic reticulum (ER) of normal cells. In stress conditions, GRP78 is overexpressed and in different cancer cell types, it is expressed at the cell surface, whereas it stays intracellular in non-cancerous cells. Therefore, it appears as a strategic target to recognize malignant cells. Prostate cancer is one of the most diagnosed cancers in men. The development of castrate resistant tumors and the resistance to chemotherapy frequently occur. The carboxy-terminal ER retention domain is defined by the KDEL amino acid sequence. We developed anti KDEL functionalized polymeric nanoparticles (NPs) loaded with paclitaxel (Tx) to specifically target prostate cancer cells expressing GRP78. The sensitivity to Tx in different formulations was compared in three prostate cell lines: PNT1B, a normal cell line, PC3, a cancer cell line faintly expressing GRP78 at its surface, and DU145, a cancer cell line expressing GRP78 at its cell surface. Our results show that the targeted formulation significantly increases Tx sensitivity of cell line expressing GRP78 at its surface compared to other treatments suggesting the added value of GRP78 targeted therapy for castrate resistant tumor which expresses GRP78 at its cell surface. PMID- 23090206 TI - Functional disorders of the ano-rectal compartment of the pelvic floor: clinical and diagnostic value of dynamic MRI. AB - The obstructed defecation syndrome is the main functional disorder of the posterior or ano-rectal pelvic floor compartment. Different mechanical and functional rectal disorders may cause this syndrome, including rectocele, rectal invagination, rectal prolapse, and pubo-rectalis muscle dyskinesia. Since pelvic floor muscles and fasciae act as a unique functional entity, dysfunctions of the posterior compartment are usually associated to variable dysfunctions of the anterior and middle urogenital compartments as well. Over 50% of postmenopause women are affected by severe symptoms due to pelvic floor disorders, with frequent need of surgical invasive treatments. Both diagnosis of the specific ano rectal dysfunction and identification of all possible associated disorders are mandatory for an effective surgical or conservative treatment. Currently, dynamic MRI provides an excellent morphological and functional display of the pelvic floor like no other imaging modality. Pros and cons of posterior pelvic floor MRI, different evaluation techniques, reference lines and grading systems together with the main imaging findings will be discussed and illustrated. PMID- 23090207 TI - Diabetes: screening for T2DM does not reduce mortality. PMID- 23090205 TI - Long lasting efficacy of sorafenib in a heavily pretreated patient with thymic carcinoma. AB - Thymoma and thymic carcinoma are rare neoplasms of the mediastinum, arising from the epithelial cells of the thymus. While surgical resection is the treatment of choice in early stages, platin-based chemotherapy is mainly used in patients with advanced or metastatic disease; however, the prognosis is poor. Here we present the case of a 54 year old female patient suffering from a CD117-negative thymic carcinoma with widespread metastases. After several courses of different kinds of chemotherapy, finally these approaches failed to be effective. Thus we initiated a treatment with sorafenib, an inhibitor of several receptor tyrosine kinases. The treatment was tolerated very well, and within a few weeks the general condition of the patient improved significantly. A CT-scan, performed 3 months after therapy with sorafenib started, showed a 50 % reduction of tumor size, and this effect lasted for 15 months. When the carcinoma relapsed again, we administered another course of chemotherapy and, because of lacking success, we even tried to use sunitinib. However, the patient died in a septic shock, based on progressive disease. In summary, we present a patient with metastastic thymic carcinoma, in which sorafenib led to a tumor-control for 18 months. PMID- 23090208 TI - Rhodium-catalyzed regio- and enantioselective amination of racemic secondary allylic trichloroacetimidates with N-methyl anilines. AB - We report the chiral diene ligated rhodium-catalyzed dynamic kinetic asymmetric transformation (DYKAT) of racemic secondary allylic trichloroacetimidates with a variety of N-methyl anilines, providing allylic N-methyl arylamines in high yields, regioselectivity, and enantiomeric excess. The rhodium-catalyzed DYKAT method addresses limitations previously associated with this particular class of aromatic nitrogen nucleophiles. PMID- 23090209 TI - Automated, foot-bone registration using subdivision-embedded atlases for spatial mapping of bone mineral density. AB - We present an atlas-based registration method for bones segmented from quantitative computed tomography (QCT) scans, with the goal of mapping their interior bone mineral densities (BMDs) volumetrically. We introduce a new type of deformable atlas, called subdivision-embedded atlas, which consists of a control grid represented as a tetrahedral subdivision mesh and a template bone surface embedded within the grid. Compared to a typical lattice-based deformation grid, the subdivision control grid possesses a relatively small degree of freedom tailored to the shape of the bone, which allows efficient fitting onto subjects. Compared with previous subdivision atlases, the novelty of our atlas lies in the addition of the embedded template surface, which further increases the accuracy of the fitting. Using this new atlas representation, we developed an efficient and fully automated pipeline for registering atlases of 12 tarsal and metatarsal bones to a segmented QCT scan of a human foot. Our evaluation shows that the mapping of BMD enabled by the registration is consistent for bones in repeated scans, and the regional BMD automatically computed from the mapping is not significantly different from expert annotations. The results suggest that our improved subdivision-based registration method is a reliable, efficient way to replace manual labor for measuring regional BMD in foot bones in QCT scans. PMID- 23090210 TI - Liquid crystal pump. AB - We report a dielectrically actuated liquid crystal (LC) pump. A small volume of LC forms a pillar-like droplet in a cylindrical hole which partially touches the bottom substrate with embedded interdigitated electrodes. By applying a voltage, the LC droplet can be largely stretched along the electrode direction by the generated dielectric force, which in turn exerts a pressure to displace a small volume of fluid on the opposite side of the chamber. Once the voltage is removed, the LC droplet returns to its initial state. The LC droplet with such a reciprocating movement behaves like a pump. In this work, the actuation mechanism of the LC pump is presented and the performance evaluated experimentally. Our LC pump has the following advantages: simple structure, easy fabrication, compact size, high precision, low power consumption, and relatively fast response time. It is promising for applications in lens actuators, biotechnology, drug delivery, and other lab-on-a-chip devices. PMID- 23090211 TI - Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument. AB - Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter rater reliability and another trial of 28 SCA patients to assess short-term intra rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials. PMID- 23090212 TI - Neuroanatomical correlates of depression in Friedreich's ataxia: a voxel-based morphometry study. AB - Affective disorders have been increasingly recognized in neurodegenerative diseases and often result in poor quality of life. However, the frequency, clinical relevance, and anatomical substrate of depression in Friedreich's ataxia were not yet evaluated. We assessed 22 patients with Friedreich's ataxia for major depression using Beck Depression Inventory and cerebral 3 T MRI scans. We then employed whole-brain voxel-based morphometry analyses on volumetric T1 datasets to compare tissue loss between patients with and without major depression. Patients (36.3 %) fulfilled criteria for major depression (8/22). Mean Beck Depression Inventory (BDI) score was 9.63 +/- 8.95 and the depressive group had significantly higher score compared to non-depressive group (18.5 +/- 8.6 vs 4.4 +/- 2.9, p < 0.001). There was no correlation between Beck Depression Inventory score and age of patients, ataxia severity, age at onset, or duration of the disease. The comparison between patient groups found no significant differences of white matter volumes. In contrast, we found reduction of gray matter volumes in the depressive group in medial and orbital region of frontal lobe and anterior cingulate gyri (p < 0.001). Regression analyses have shown that BDI scores were inversely correlated with gray matter volume at right superior frontal gyrus. Major depression is frequent in Friedreich's ataxia and possibly under recognized. Our results strongly suggest that this may not be a simply reactive phenomenon, but rather associated to structural abnormalities. PMID- 23090213 TI - Cardiac PET/CT misregistration causes significant changes in estimated myocardial blood flow. AB - Misregistration of cardiac PET/CT data can lead to misinterpretation of regional myocardial perfusion. However, the effect of misregistration on the quantification of myocardial blood flow (MBF) has not been studied. METHODS: Cardiac (82)Rb-PET/CT scans of 10 patients with normal regional myocardial perfusion were analyzed. Realignment was done for the baseline and stress PET/CT images as necessary, and MBF was obtained from dynamic data. Then, the stress images were misregistered by 5 mm along the x-axis (left) and z-axis (cranial) and again by 10 mm. A 10-mm misregistration in the opposite direction (-10 mm along the x-axis [right] and z-axis [caudal]) was also tested. Stress MBF was recalculated for 5-, 10-, and -10-mm misregistrations. RESULTS: Stress MBF of the left ventricle decreased by 10% +/- 6% (P = 0.005) after 5-mm misregistration and by 24% +/- 15% (P = 0.001) after 10-mm misregistration. In descending order, the most important stress MBF changes occurred in the anterior (39% +/- 9%), lateral (34% +/- 9%), apical (20% +/- 16%), inferior (12% +/- 10%), and septal (10% +/- 12%) walls after 10-mm misregistration. Lesser changes were observed after 5-mm misregistration, with the same wall distribution. In contrast, -10-mm misregistration increased global MBF by 9% +/- 6% (P = 0.004). In descending order, the overestimation of estimated MBF after -10-mm misregistration occurred in the lateral (15% +/- 8%), apical (15% +/- 18%), anterior (9% +/- 5%), and inferior (9% +/- 11%) walls. CONCLUSION: Misregistration of the stress PET/CT dataset leads to significant global and regional artifactual alterations in the estimated MBF. Quantitative error was observed throughout the myocardium and was not confined to those heart regions that extended into the lung on misregistered CT. PMID- 23090214 TI - The influence of morphine on cerebral 5-HT2A availability in dogs: a SPECT study. AB - The opioid and serotonergic systems are closely involved in pain processing and mood disorders. The aim of this study was to assess the influence of systemic morphine on cerebral serotonin 2A receptor (5-HT(2A)) binding in dogs using SPECT with the 5-HT(2A) radioligand (123)I-5I-R91150. METHODS: 5-HT(2A) binding was estimated with and without morphine pretreatment in 8 dogs. The 5-HT(2A) binding indices in the frontal, parietal, temporal, and occipital cortex and in the subcortical region were obtained by semiquantification. RESULTS: A significantly decreased 5-HT(2A) binding index was found in the morphine group for the right (morphine, 1.41 +/- 0.06; control, 1.52 +/- 0.10) and left (morphine, 1.44 +/- 0.08; control, 1.55 +/- 0.11) frontal cortices, with P = 0.012 and P = 0.040, respectively. No significant differences were noted for the other regions. CONCLUSION: Morphine decreased the frontocortical 5-HT(2A) availability, confirming an interaction between the 5-HTergic and the opioid systems. Whether this interaction is caused by decreased receptor density due to direct internalization or is the result of indirect actions, such as increased endogenous serotonin release, remains to be elucidated. PMID- 23090215 TI - Motivational differences for participation among championship and non championship caliber NCAA division III football teams. AB - Reasons for participation in National Collegiate Athletic Association (NCAA) Division III athletics vary greatly. The purpose of this study was to investigate if differences in motivational climate existed between championship and non championship-level NCAA Division III football teams, and differences in player status (starter vs. nonstarter). Players (N = 224) from 3 NCAA Division III football programs (1 championship level and 2 non-championship level) were recruited as participants. All players completed the Sport Motivation Scale, and the results were analyzed using a 2 * 2 multivariate analysis of variance (MANOVA) to examine differences among the motivation variables for starter vs. nonstarter and championship vs. non-championship teams. A 1-way MANOVA was used to examine differences across year in school. Dependent variables included internal motivation to experience stimulation, internal motivation for accomplishment, internal motivation for knowledge, external motivation for identification regulation, external motivation for introjection regulation, external motivation for external regulation, and amotivation. The interaction between starter status and team was not significant (Lambda = 0.996, p > 0.40). Additionally, there were no significant differences in the mean vector scores for starter vs. nonstarter (Lambda = 0.965, p = 0.378). For team type, however, differences did exist across dependent variables (Lambda = 0.898, p = 0.002). For all variables except amotivation, the championship-level team had significantly higher scores than the non-championship-level teams. Members of NCAA Division III championship-level football teams have higher motivation to participate in their sport compared with members of non-championship teams. These results could have an impact on player morale, coaching strategies, and future success in athletic related activities. PMID- 23090216 TI - Discussion. PMID- 23090217 TI - Unexpected finding in computed tomographic pulmonary angiography. PMID- 23090218 TI - Phantom tumor of the lung. PMID- 23090219 TI - Sensorineural hearing loss: radiologic diagnosis. PMID- 23090221 TI - Molecular analysis of rubella virus in travelers suspected of measles infection in Sao Paulo, Brazil. AB - OBJECTIVE: To identify measles virus genotypes in three cases of travelers suspected of measles infection. METHODS: Samples (blood and urine) were collected for serology, virus isolation, and genotyping. Sera were analyzed for IgM antibodies against measles virus and rubella virus by enzyme-linked immunosorbent assay (ELISA) (Siemens - Marburg, Germany). Clinical samples (lymphocytes and urine) were inoculated into Statens Serum Institute rabbit corneal epithelial cell line- ATCC CL 60 (SIRC) and Vero Slam cells. RNA was extracted from clinical samples and cell culture was inoculated and processed by polymerase chain reaction (PCR) with oligonucleotides specific for measles virus (MV) and rubella virus (RV). RESULTS: All patients showed IgM negative serology for MV and positive IgM for RV. RV belonging to genotypes 1B, 1C, and 1E were isolated from patients who came from Finland, Peru, and Germany, respectively. Genotype 1B has been found in Europe and on the East Coast of South America; 1C has been found in Peru and the West Coast of South America, and 1E, first identified in 1997, now appears to have worldwide distribution. CONCLUSION: Information about RV and MV genotypes circulating in Sao Paulo is essential for the control of measles, rubella, and congenital rubella syndrome (CRS) in Brazil. PMID- 23090222 TI - Analysis of the concordance rates between core needle biopsy and surgical excision in patients with breast cancer. AB - OBJECTIVE: To evaluate whether immunohistochemical marker studies performed on core needle biopsy (CNB) specimens accurately reflect the marker status of the tumor obtained from final surgical specimen. METHODS: This was a retrospective study that used the database of the Division of Mastology of the Hospital das Clinicas, Sao Paulo, Brazil. Sixty-nine patients submitted to ultrasound-guided CNB diagnosed with breast cancer were retrospectively analyzed. Immunohistochemistry (IHC) on core biopsy specimens was compared to that of excisional biopsy regarding estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 gene (HER2), p53, and Ki67. The analysis of the concordance between CNB and surgical biopsy was performed using the kappa (k) coefficient (95% CI). RESULTS: A perfect concordance between the labeling in the surgical specimens and the preoperative biopsies in p53 (k = 1.0; 95% CI: 0.76-1.0) was identified. There was an almost perfect concordance for ER (k = 0.89; 95% CI: 0.65-1.0) and a substantial concordance for PR (k = 0.70; 95% CI: 0.46-0.93). HER2 (k = 0.61; 95% CI: 0.38-0.84) and Ki-67 (k = 0.74; 95% CI: 0.58 0.98) obtained a substantial concordance this analysis. CONCLUSION: The results of this study indicate that the immunohistochemical analysis of ER, PR, Ki-67, and p53 from core biopsy specimens provided results that accurately reflect the marker status of the tumor. The concordance rate of HER2 was less consistent; although it produced substantial concordance, values were very close to moderate concordance. PMID- 23090223 TI - Association between HLA-DRB1* polymorphisms and hepatitis B infection in a brazilian population. AB - OBJECTIVE: The aim of the present study was to determine the genotype association for alleles of class II human leukocyte antigens (HLA) in the DRB1* locus among blood donors at the Fundacao Hemope (Brazil) infected by or immunized for the hepatitis B virus (HBV). METHODS: A case-control study was performed, comprising a group of individuals infected by HBV and a control group of immunized individuals at a proportion of 1:4. Blood samples were taken for the HLA typing of the DRB1* locus. Univariate and multivariate analyses were performed for the assessment of associations between the categorical variables using the chi squared test and Fisher's exact test. RESULTS: A total of 320 blood donors were analyzed (241 males [75%] and 79 females [25%] with a mean age of 39 years). The case group consisted of 64 HBV-infected donors and the control group was composed of 256 HBV-immunized donors. The multivariate analysis stratified by gender revealed that the DRB1*09 allele was associated with infected male donors (p = 0.016) and the DRB1*08 allele was associated with infected donors aged 39 years or younger (p = 0.031). CONCLUSION: The results of the present study reveal that younger blood donors and male blood donors who respectively exhibit the DRB1*08 and DRB1*09 alleles are more susceptible to intensification of HBV infection. PMID- 23090224 TI - Side effects of the hepatitis C treatment at the ABC application center. AB - OBJECTIVE: To review and compare side effects of hepatitis C treatment with pegylated interferon and ribavirin at the CRIE of the Hospital Mario Covas (Santo Andre), Sao Paulo, Brazil, from February 23 to May 5, 2011. METHODS: Cross sectional study through questionnaire, with a non-probability sample comprised of 340 patients that had received at least one dose of the medication. RESULTS: Side effects presented were fatigue (82.9%), arthralgia and/or myalgia (76.8%), weight loss (71.8%), headache (67.6%), listlessness (65.9%), depression and/or irritability (64.4%), itching (60.6%), fever (59.1%), alopecia (51.5%), dry cough (34.1%), nausea (11.7%), inappetence (11.7%), and dizziness (7.9%). Up to 19 symptoms were reported during treatment. Only four patients (1.2%) did not present side effects. When comparing the types of interferon, it was observed that alpha-2b caused an average of 8.01 symptoms per patient, while alpha-2a was responsible for an average of 7.50 symptoms. Patients using interferon alpha-2b showed more fever, weight loss, headache, arthralgia and/or myalgia, fatigue, listlessness, depression and/or irritability, and dry cough than patients using alpha-2a, who had more alopecia and itching. CONCLUSION: The study shows a high morbidity related to the treatment, as only 1.2% of the patients showed no side effects. In the sample, the pegylated interferon alpha-2b was responsible for higher prevalence of fever and weight loss when compared to alpha-2a, and this was a statistically significant relation (p < 0.05). PMID- 23090225 TI - Improving cardiovascular prevention through patient awareness. AB - OBJECTIVE: Patients with peripheral artery disease (PAD) or coronary artery disease (CAD) must have their risk factors rigorously controlled, but there is a gap between practice and ideal. This study aimed to demonstrate how cardiovascular prevention is performed for these patients in a Brazilian university hospital, and to identify predictors of good practice. METHODS: 192 patients with CAD or PAD were included in this transversal study. Six prevention goals were analyzed: 1) systolic blood pressure < 140 mmHg; 2) diastolic blood pressure < 90 mmHg; 3) LDL < 100 mg/dL; 4) HDL > 40 mg/dL for men/ > 50 mg/dL for women; 5) not smoking; 6) regular practice of aerobic exercise. RESULTS: The mean age of the patients was 65.7 years, and 60% were men. The percentage of patients that achieved goals 1 to 6 was 57.3%, 67.2%, 40.1%, 27.6%, 88.5%, and 25%, respectively. The average number of goals achieved by patients was 3.06 +/- 1.31. When asked about the reason for being treated, 182(94.8%) patients claimed to know about their disease, but when the diagnosis reported by the patients with the physician's diagnosis were compared, it was discordant in 12% of cases. The average number of goals achieved by patients was 2.67 and 3.46 for the PAD and the CAD group, respectively. The independent predictors of a higher number of goals/patient were: male gender (p = 0.011), hospitalization (p < 0.0001), CAD diagnosis (p = 0.011), knowing the reason for treatment (p = 0.028), and receiving prescription of beta -blocker (p = 0.011). CONCLUSION: Even in an university hospital, prevention is far from ideal. Efforts to increase patients' awareness should be stimulated, and can possibly improve the effectiveness of preventive measures. PMID- 23090226 TI - Prevalence of anti-HCV in an inmate population. AB - OBJECTIVE: To estimate the prevalence of hepatitis C using a rapid hepatitis C virus (HCV) test in an inmate population from the countryside of Rio Grande do Sul, Brazil. METHODS: Through a descriptive study, 195 inmates were evaluated by random sampling. RESULTS: A total of 9.7% of the inmates were positive. In this analysis, the variable injectable drug use was predictive of HCV infection. CONCLUSION: The high prevalence of positive serology for HCV observed among the inmates is of particular concern, as it is much higher than in the general population. Therefore, it is necessary to conduct specific approach campaigns to gather more information on infectious diseases in prison settings, as well as to provide appropriate treatment to prevent viral dissemination. PMID- 23090227 TI - A comparative analysis of outpatient costs in HIV treatment programs. AB - OBJECTIVE: To analyze the costs of human immunodeficiency virus (HIV) outpatient treatment for individuals with different CD4 cell counts in the Brazilian public health system, and to compare to costs in other national health systems. METHODS: A retrospective survey was conducted in five public outpatient clinics of the Brazilian national HIV program in the city of Sao Paulo. Data on healthcare services provided for a period of one year of HIV outpatient treatment were gathered from randomly selected medical records. Prices of inputs used were obtained through market research and public sector databases. Information on costs of HIV outpatient treatment in other national health systems were gathered from the literature. Annual costs of HIV outpatient treatment from each country were converted into 2010 U.S. dollars. RESULTS: Annual cost of HIV outpatient treatment for the Brazilian national public program was US$ 2,572.92 in 2006 in Sao Paulo, ranging from US$ 1,726.19 for patients with CD4 cell count > 500 to US$ 3,693.28 for patients with 51 < CD4 cell count < 200. Antiretrovirals (ARVs) represented approximately 62.0% of annual HIV outpatient costs. Comparing among different health systems during the same period, HIV outpatient treatment presented higher costs in countries where HIV treatment is provided by the private sector. CONCLUSION: The main cost drivers of HIV outpatient treatment in different health systems were: ARVs, other medications, health professional services, and diagnostic exams. Nevertheless, the magnitude of cost drivers varied among HIV outpatient treatment programs due to health system efficiency. The data presented may be a valuable tool for public policy evaluation of HIV treatment programs worldwide. PMID- 23090228 TI - Hypertriglyceridemic waist and cardiometabolic risk in hypertensive women. AB - OBJECTIVE: To evaluate the association between hypertriglyceridemic waist (HW) and cardiometabolic risk factors in women with hypertension. METHODS: A cross sectional study was performed in 218 patients monitored by HiperDia (Enrollment and Monitoring Program for Hypertensive and Diabetic Individuals) in two health units in Sao Luis, MA, Brazil. The dependent variable was HW and the independent variables were sociodemographics, lifestyle, anthropometrics, and health problems. RESULTS: HW was present in 33% of the sample and was predominant in women aged > 60 years (56.4%), non-whites (81.7%), those with eight or fewer years of schooling (57.3%), and those belonging to socioeconomic class C (49%). Excess weight (68.8%) and hypercholesterolemia (68.8%) were observed. HW was associated with: smoking (PR: 2.08; p = 0.017), overweight (PR: 2.46; p = 0.010), obesity (PR: 4.13; p < 0.001), hypercholesterolemia (PR: 1.87; p = 0.015), high levels of high-density lipoproteins (HDL) cholesterol (PR: 3.41; p < 0.001), and fasting glycemia > 100 mg/dL or being diabetic (PR: 1.86; p = 0.006). After adjustment, total cholesterol (PR = 1.78; p = 0.012), HDL-cholesterol (PR: 3.03; p < 0.001), body mass index (BMI) > 25 to < 30 kg/m2 (PR = 2.60; p = 0.005), and BMI > 30 kg/m2 (PR = 3.61; p < 0.001) remained associated. CONCLUSION: A high prevalence of HW and its association with altered lipid profile and excess body weight was observed. HW showed to be an important diagnostic tool for the monitoring of hypertensive women with metabolic risk, which is low cost, easily accessible, and useful in clinical practice, especially in primary health care in the Brazilian Unified Health System (Sistema Unico de Saude - SUS). PMID- 23090229 TI - Muscular static strength test performance: comparison between normotensive and hypertensive workers. AB - OBJECTIVE: The aim of the study was to compare static muscular strength test performance between hypertensive and normotensive workers, considering the hypothesis that hypertensive individuals have lower strength than normotensive individuals. METHODS: The participants consisted of 354 workers (246 men and 108 women) who underwent height, body mass, waist circumference, systolic and diastolic blood pressure (BP) measurements, as well as right and left handgrip, and scapular and lumbar strength tests. Assessments were performed during three days in all three shifts, with workers from a candy and sweets factory located in Rio Claro, SP, Brazil. BP measurements were performed with a 10-minute interval, with the subject in the sitting position. Before the strength tests were performed, the workers were familiarized with the equipment; the highest value was recorded after two attempts at each test. RESULTS: The results showed significant differences between hypertensive and normotensive individuals for age, body mass, body mass index, and waist circumference greater for hypertensive individuals. Regarding static muscle strength tests performance, the hypertensive individuals did not differ significantly from normotensive individuals; however, this difference was observed when groups divided by body mass index (BMI) were compared. The obesity group had strength values above those of the normal weight/overweight group among normotensive individuals, but this was not observed among the hypertensive individuals. As for the intragender comparison, there were no significant differences for the strength tests. CONCLUSION: Normotensive and hypertensive workers showed no significant differences in the performance of static muscular strength tests; however, body mass and gender seem to affect the association between muscle strength and blood pressure. PMID- 23090231 TI - Low Apgar scores at 5 minutes in a low risk population: maternal and obstetrical factors and postnatal outcome. AB - OBJECTIVE: To evaluate the association between Apgar scores of less than seven at five minutes (AS5min < 7) and antenatal factors and postnatal outcomes. METHODS: A retrospective cohort and case-control study of 27,252 consecutive term newborns in a low risk obstetrical population between January 2003 and December 2010. Maternal and infant databases were reviewed from all cases with AS5min < 7 (n = 121; 0.4%) and 363 cases with AS5min > 7 at 5 minutes who were randomly selected by a computer program. The main outcomes were neonatal death, newborn respiratory distress, need for orotracheal intubation and neonatal intensive care unit (NICU), and hypoxic-ischemic-encephalopathy. RESULTS: After multiple regression analysis, repeated late decelerations on cardiotocography (OR: 2.4; 95% CI: 1.4 4.1) and prolonged second stage of labor (OR: 3.3; 95% CI: 1.3-8.3) were associated with AS5min < 7, as well as neonatal respiratory distress (OR: 3.0; 95% CI: 1.3-6.9), orotracheal intubation (OR: 2.5; 95% CI: 1.2-4.8), need for NICU (OR: 9.5; 95% CI: 6.7-16.8), and hypoxic-ischemic-encephalopathy (OR: 14.1; 95% CI: 3.6-54.7). No other antenatal factors were associated with AS5min < 7 (p > 0.05). CONCLUSION: Repeated late decelerations and prolonged second stage of labor in the low-risk population are predictors of AS5min < 7, a situation associated with increased risk of neonatal respiratory distress, need for mechanical ventilatory support and NICU, and hypoxic-ischemic-encephalopathy. PMID- 23090230 TI - Protein-calorie adequacy of enteral nutrition therapy in surgical patients. AB - OBJECTIVE: To evaluate the protein-calorie adequacy of enteral nutrition therapy (ENT) in surgical patients. METHODS: A prospective study was performed in surgical patients who received ENT from March to October 2011. Patients were evaluated anthropometrically and by subjective global assessment (SGA). The amount of calories and protein prescribed and administered were recorded daily, as well as the causes of discontinuation of the diet. A 90% value was used as the adequacy reference. The difference between the prescribed and administered amount was verified by Student's t-test. RESULTS: A sample of 32 patients, aged 55.8 +/- 14.9 years, showed a malnutrition rate of 40.6% to 71.9%, depending on the assessment tool used. Gastric cancer and gastrectomy were the most common diagnosis and surgery, respectively. Of the patients, 50% were able to meet their caloric and protein needs. The adequacy of the received diet in relation to the prescribed one was 88.9 +/- 12.1% and 87.9 +/- 12.2% for calories and proteins, respectively, with a significant difference (p < 0.0001) of 105.9 kcal/day and 5.5 g protein/day. 59.4% of the patients had adequate caloric intake and 56.2% had adequate protein intake. Causes of diet suspension occurred in 81.3%, with fasting for procedures (84.6%) and nausea/vomiting (38.5%) being the most frequently observed causes in pre- and postoperative periods, respectively. CONCLUSION: Inadequate caloric and protein intake was common, which can be attributed to complications and diet suspensions during ENT, which may have hampered the sample reached their nutritional needs. This may contribute to the decline in the nutritional status of surgical patients, who often have impaired nutrition, as observed in this study. PMID- 23090232 TI - Traditional learning and problem-based learning: self-perception of preparedness for internship. AB - OBJECTIVE: This study aims to evaluate Pontificia Universidade Catolica de Sao Paulo (PUC-SP) medical students' perception of their preparedness to attend the internship course by comparing students who entered the internship in 2009, who were taught according to the traditional learning method, and those who entered the internship in 2010, who were taught according to the new method, i.e. problem based learning (PBL). METHODS: 50 traditional learning method students answered a standard Lickert scale questionnaire upon entering internship in 2009. In 2010, the process was repeated with PBL students. The questionnaire was based upon the Preparation for Hospital Practice Questionnaire. This questionnaire was evaluated by professors from three medical schools in Brazil regarding its applicability. The original questions were classified according to the importance these professors attributed to them, and less important questions were removed. Scores obtained from the Student's t-test were considered significant with p < 0.05. RESULTS: A significant statistical difference was observed in 16 questions, and the traditional learning method students reported higher average scores. When questions were divided into dimensions, a significant statistical difference appeared in the dimensions " social aspects of health", "medical skills", and "ethical concepts"; traditional learning method students again reported higher scores (p < 0.001 for all dimensions). Higher scores were also reported when the average of the answers to the whole questionnaire was calculated. CONCLUSION: Traditional learning method students consider themselves to be better prepared for internship activities than PBL students, according to the following three comparative means: by analyzing the answers to each question, by grouping these answers into dimensions, and by calculating the means of answers to the whole questionnaire. PMID- 23090233 TI - Does bench model fidelity interfere in the acquisition of suture skills by novice medical students? AB - OBJECTIVE: Although several inanimate bench models have been described for training of suture skills, so far, there is no ideal method for teaching and learning this skill during medical education. The aim was to evaluate whether bench model fidelity interferes in the acquisition of suture skills by novice medical students. METHODS: 36 medical students with no surgical skills' background (novices) were randomized to three groups (n = 12): theoretical suture training alone (control); low-fidelity suture training model (synthetic ethylene vinyl acetate bench model); or high-fidelity suture training model (pig feet skin bench model). Pre- and post-tests were applied (performance of simple interrupted sutures and subdermal interrupted sutures on ox tongue). Three tools (Global Rating Scale with blinded assessment, effect size, and self-perceived confidence based on Likert scale) were used to measure all suture performances. RESULTS: The post-training analysis showed that the students that practiced on bench models (hands-on training) presented better (all p < 0.0000) performance in the Global Rating Scale evaluation, compared with the control, regardless of the model fidelity. The magnitude of the effect (training) was considered large (> 0.80) in all measurements. Students felt more confident (all p < 0.0000) to perform both types of sutures after training. CONCLUSION: The acquisition of suture skills on the low-fidelity bench model was similar to that of the high-fidelity bench model, and the increase in the performance of participants that received bench model training was superior to those who received training based on theoretical teaching materials. PMID- 23090234 TI - Minimal and mild endometriosis negatively impact on pregnancy outcome. AB - Endometriosis, a highly prevalent gynecological disease, can lead to infertility in moderate to severe cases. Whether minimal stages are associated with infertility is still unclear. The purpose of this systematic review is to present studies regarding the association between pregnancy rates and the presence of early stages of endometriosis. Studies regarding infertility, minimal (stage I, American Society of Reproductive Medicine [ASRM]) and mild (stage II, ASRM) endometriosis were identified by searching on the MEDLINE database from 1985 to September 2011 using the following MESH terms: endometriosis; infertility; minimal; mild endometriosis; pregnancy rate. 1188 articles published between January of 1985 and November of 2011 were retrieved; based on their titles, 1038 citations were excluded. Finally, after inclusion and exclusion criteria, 16 articles were selected to be part of this systematic review. Several reasons have been discussed in the literature to explain the impact of minimal endometriosis on fertility outcome, such as: ovulatory dysfunction, impaired folliculogenesis, defective implantation, decrease embryo quality, abnormal immunological peritoneal environment, and luteal phase problems. Despite the controversy involving the topic, the largest randomized control trial, published by Marcoux et al. in 1997 found a statistically different pregnancy rate after resection of superficial endometrial lesions. Earlier stages of endometriosis play a critical role in infertility, and most likely negatively impact pregnancy outcomes. Further studies into stage I endometriosis, especially randomized controlled trials, still need to be conducted. PMID- 23090235 TI - Use of cell-free fetal nucleic acids in maternal blood for prenatal diagnosis: the reality of this scenario in Brazil. AB - The discovery of cell-free fetal nucleic acids in the plasma of pregnant women has allowed the development of new, noninvasive prenatal diagnostic tests for the determination of fetal gender and Rh. These tests have been implemented in the public health system in several countries of Europe for over five years. The new possibilities for diagnostic use of these technologies are the detection of fetal chromosomal aneuploidies, monogenic fetal disorders, and placental-related disorders, subjects that have been intensively studied by several groups around the world. The aim of this review was to assess the Brazilian research and clinical scenarios regarding the utilization of commercially available tests that use these plasma markers, stressing the advantages, both economic and safety related, that non-invasive tests have when compared to those currently used in the Brazilian public health system. PMID- 23090236 TI - Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling. AB - Endometriosis is a benign gynecological disease characterized by the presence and growth of endometrial cells outside the uterus. Genetic, endocrine, immunological, and environmental factors have been suggested in its pathogenesis. A great number of studies have related genetic polymorphisms as a factor that contributes to the development of endometriosis. This review presents a detailed description of the contribution of genetic polymorphisms in genes that regulate vascular function and tissue remodeling in endometriosis (alpha 2-HS glycoprotein [AHSG], epidermal growth factor receptor [EGFR], vascular endothelial growth factor [VEGF], endostatin, plasminogen activator inhibitor 1 [PAI-1], angiotensin I-converting enzyme [ACE], and matrix metalloproteinases [MMPs]). Some polymorphisms of the VEGF (-460 C/T, +405 G/C, +936 C/T), PAI, MMP-1, 2, and 3 genes were widely studied, while polymorphisms of the AHSG, EGF, endostatin, and VEGF (-1154 G/A, -2578 A/C) genes were not. In this latter case, additional studies are required to confirm the findings of the few studies that have analyzed these single nucleotide polymorphisms (SNPs). Additionally, studies that found a positive or negative association of SNP with endometriosis emphasize the relevance of studies with a large number of control cases to confirm their findings. The haplotype analysis was performed only for the VEGF (-460, +405, 1154 and -2578), ACE (-240/2350) and MMP-1, 2, 3, and 9 genes, and in most of them, there was no association with endometriosis. Of the eight works that analyzed haplotypes of the VEGF gene, five did not associate them with endometriosis. Haplotypes of ACE and MMP-2 genes were not associated with endometriosis, while those of MMP-1, 3, and 9 genes were related to a high risk for the disease. PMID- 23090237 TI - Redox- and expression-proteomic analysis of plasma biomarkers in bladder transitional cell carcinoma. AB - Recent progress in quantitative proteomics has offered opportunities in discovering plasma proteins as biomarkers to track the progression and understand the molecular mechanisms of bladder transitional cell carcinoma (TCC). In this study, differential plasma protein levels and redox regulation were analyzed by lysine- and cysteine-labeling two-dimensional differential gel electrophoresis (2D-DIGE), and combined with matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS/MS). This study shows 50 and 34 plasma protein features that were significantly changed in protein expression and thiol reactivity, respectively, and shows that plasma proteins involved in inflammatory responses are up-regulated in bladder TCC. In contrast, plasma proteins responsible for cytoskeleton and cytoskeleton regulation are down-regulated. In addition, plasma proteins involving cell adhesion, inflammatory responses, protease inhibitors, and plasma protein transport are shown to be altered in their thiol reactivity. In summary, we perform a comprehensive patient-based plasma proteomic approach for the identification of potential plasma biomarkers in bladder TCC screening and detection. PMID- 23090238 TI - Molecular phylogeny, population genetics, and evolution of heterocystous cyanobacteria using nifH gene sequences. AB - In order to assess phylogeny, population genetics, and approximation of future course of cyanobacterial evolution based on nifH gene sequences, 41 heterocystous cyanobacterial strains collected from all over India have been used in the present study. NifH gene sequence analysis data confirm that the heterocystous cyanobacteria are monophyletic while the stigonematales show polyphyletic origin with grave intermixing. Further, analysis of nifH gene sequence data using intricate mathematical extrapolations revealed that the nucleotide diversity and recombination frequency is much greater in Nostocales than the Stigonematales. Similarly, DNA divergence studies showed significant values of divergence with greater gene conversion tracts in the unbranched (Nostocales) than the branched (Stigonematales) strains. Our data strongly support the origin of true branching cyanobacterial strains from the unbranched strains. PMID- 23090239 TI - Characterization of novel gene expression related to glyoxal oxidase by agro infiltration of the leaves of accession Baihe-35-1 of Vitis pseudoreticulata involved in production of H2O2 for resistance to Erysiphe necator. AB - Glyoxal oxidase (GLOX), an extracellular H(2)O(2)-producing enzyme, has been reported in Phanerochaete chrysosporium and Ustilago maydis. We previously isolated a grapevine GLOX gene from the highly resistant to Erysiphe necator Chinese wild Vitis pseudoreticulata accession Baihe-35-1 and designated it as VpGLOX (GenBank accession no. DQ201181). Transient expression of VpGLOX can suppress Powdery Mildew in susceptible genotype were studied. To further investigate the function of the VpGLOX gene, real-time PCR and Western blot analysis were performed to examine expression patterns at transcriptional and translational levels, respectively. The results showed that VpGLOX expression at the transcriptional level increased significantly in the disease-resistant accession Baihe-35-1 after Erysiphe necator inoculation, but no significant changes in the susceptible accession, V. pseudoreticulata accession Guangxi-2 could be observed. As evident from a Western blot analysis, VpGLOX protein increased slightly in Baihe-35-1 after E. necator inoculation, but not statistical significant difference changes in Guangxi-2. The immunolocalization via immunogold electron microscopy showed that VpGLOX was mainly located in the adaxial epidermal cell wall of E. necator-inoculated leaves of both Baihe-35-1 and Guangxi-2. Agrobacterium-mediated transient expression assays revealed that VpGLOX expression could produce H(2)O(2), which may directly play a role in defense mechanism during plant-pathogen interactions. Our results could provide further insight into the biological role of VpGLOX in the defense response against E. necator in V. pseudoreticulata. PMID- 23090241 TI - Highly enantioselective organocatalytic Strecker reaction of cyclic N-acyl trifluoromethylketimines: synthesis of anti-HIV drug DPC 083. AB - A highly efficient, organocatalytic, enantioselective Strecker reaction of cyclic N-acyl ketimines was developed for the preparation of enantioenriched cyclic alpha-amino nitriles with a quaternary carbon stereocentre and anti-HIV drug DPC 083. PMID- 23090240 TI - The oxidative protein folding machinery in plant cells. AB - Formation of intra-molecular disulfides and concomitant oxidative protein folding is essential for stability and catalytic function of many soluble and membrane bound proteins in the endomembrane system, the mitochondrial inter-membrane space and the thylakoid lumen. Disulfide generation from free cysteines in nascent polypeptide chains is generally a catalysed process for which distinct pathways exist in all compartments. A high degree of similarities between highly diverse eukaryotic and bacterial systems for generation of protein disulfides indicates functional conservation of key processes throughout evolution. However, while many aspects about molecular function of enzymatic systems promoting disulfide formation have been demonstrated for bacterial and non-plant eukaryotic organisms, it is now clear that the plant machinery for oxidative protein folding displays distinct details, suggesting that the different pathways have been adapted to plant-specific requirements in terms of compartmentation, molecular function and regulation. Here, we aim to evaluate biological diversity by comparing the plant systems for oxidative protein folding to the respective systems from non-plant eukaryotes. PMID- 23090242 TI - Quality assurance of imaging techniques used in the clinical management of osteoporosis. AB - Recent advances in the densitometric and imaging techniques involved in the management of osteoporosis are associated with increasing accuracy and precision as well as with higher exposure to ionising radiation. Therefore, special attention to quality assurance (QA) procedures is needed in this field. The development of effective and efficient QA programmes is mandatory to guarantee optimal image quality while reducing radiation exposure levels to the ALARA principle (as low as reasonably achievable). In this review article, the basic QA procedures are discussed for the techniques applied to everyday clinical practice. PMID- 23090243 TI - Parathyroid-gland ultrasonography in clinical and therapeutic evaluation of renal secondary hyperparathyroidism. AB - PURPOSE: This study evaluated the relationship between ultrasonographic (US) parameters of parathyroid glands (PTGs) in haemodialysis patients (HDP) and degree of secondary hyperparathyroidism (SHPT), therapeutic responsiveness and type of PTG hyperplasia (diffuse or nodular). MATERIALS AND METHODS: In 85 HDP, we evaluated the following US parameters of all and of the largest PTGs: number, maximum longitudinal diameter (MLD), structural (hypoechoic, heterogeneous, nodular) and vascular (nonhypovascular, intermediate, hypervascular) echo-pattern scores. Sixty-nine HDP underwent medical therapy (vitamin D, 39; vitamin D/cinacalcet, 30) and 16 underwent parathyroidectomy. The 69 HDP were classified as responders [median intact parathyroid hormone (iPTH) <=300 pg/ml during follow up) or nonresponders (iPTH >300 pg/ml). RESULTS: Number, MLD and structural and vascular echo patterns of PTGs were significantly correlated with iPTH and calcium concentrations. In the 41 (59%) responders, number (0-1), MLD (<10 mm) and structural and vascular scores (1-2) of the largest PTG were significantly lower than in nonresponders. Receiver operating curve (ROC) curve analysis showed high sensitivity and specificity (90% and 73%, respectively) of the MLD (<10mm) of the largest PTG in the predicting therapeutic outcome. US and histological MLD are significantly correlated and predict the type of hyperplasia. CONCLUSIONS: US parameters of PTGs are correlated to the degree of SHPT and type of hyperplasia and predict responsiveness to medical therapy. PMID- 23090244 TI - Setup margins and geometric uncertainties in intensity-modulated radiation therapy in treating pituitary adenomas: the experience of Lyon Sud Hospital. AB - PURPOSE: The authors retrospectively evaluated the setup uncertainties in Intensity-Modulated Radiation Therapy (IMRT) for pituitary adenomas and verified the margins used in daily practice (3 mm). MATERIALS AND METHODS: Craniocaudal (CC), anteroposterior (AP) and laterolateral (LL) displacements were measured during the first 3 days of treatment and then weekly by comparing two orthogonal images obtained by an electronic system of portal imaging with Digitally Reconstructed Radiographs (DRRs). Setup Margins (SM) were defined according to the International Commission on Radiation Units (ICRU)-62 formula, the Stroom equation and the van Herk equation. The systematic (Sigma) and random (sigma) errors of the population were calculated as standard deviation (SD) of the population mean and the mean of SDs for every patient, respectively. RESULTS: Twenty patients were treated by IMRT for pituitary adenomas, and a total of 231 measurements were obtained. Sigma and sigma were 0.6 and 1.3 mm, 0.8 and 1 mm, 1.2 and 1.5 mm in the AP, LL and CC direction, respectively. Larger setup margin was 2.4, 2.7 and 4 mm in the AP, LL and CC direction, respectively (van Herk formula). CONCLUSIONS: IMRT is a highly sophisticated treatment technique that requires precise definition and optimisation of local setup errors and, finally, of the irradiated volumes. The role of image-guided RT in these kinds of treatments should be prospectively evaluated. PMID- 23090245 TI - Endovascular treatment of transplanted renal artery stenosis with PTA/stenting. AB - PURPOSE: We evaluated the effectiveness of endovascular treatment with percutaneous transluminal balloon angioplasty (PTA)/stenting of transplanted renal artery stenosis (TRAS). MATERIALS AND METHODS: Between January 2005 and December 2010, 17 patients (4 women, 13 men; mean age 60.9 years) with TRAS underwent PTA/stenting. The parameters analysed were: technical success, pre- and post-treatment serum creatinine (SCr) and blood pressure (BP), average number of antihypertensive drugs administered before and after treatment and vessel patency on colour Doppler ultrasound (CDUS) at 1, 3, 6 and 12 months and once a year thereafter. RESULTS: Technical success was 100%. During a mean follow-up of 28.3+/-18.7 months, there was a statistically significant reduction in SCr and BP values. In 18 % of cases, moderate (<60%) restenosis was observed on CDUS without renal failure and not requiring new treatment. There was a reduction in antihypertensive drugs from an average of 3.5+/-0.5 to 1.5+/-0.5. CONCLUSIONS: Consistent with the literature data, our experience shows that endovascular treatment with PTA/stenting is a safe and effective option for managing TRAS and can thus be considered the method of choice. PMID- 23090246 TI - Percutaneous radiological gastrostomy: single-puncture double-anchor technique. AB - PURPOSE: We evaluated technical success, safety and effectiveness of percutaneous radiological gastrostomy (PRG) with a modified technique: single puncture and double anchor. MATERIALS AND METHODS: From January 2008 to June 2011, 163 patients underwent PRG with a single-puncture double-anchor technique. The stomach was punctured with a 17-gauge Chiba needle, and gastropexy was performed by placing two anchors in the gastric lumen. Finally, a 12-F Wills-Oglesby percutaneous gastrostomy catheter was inserted. Technical success and complications at 30 days were evaluated on the basis of imaging and patients' medical records. RESULTS: PRG was successfully completed in all 163 patients. Only a single puncture was required in all patients. The average PRG procedure time was 9 min. Three patients had major complications: haemorrhage (n=2) and pneumoperitoneum (n=1). Ten patients had minor complications: tube malfunction/breakage (n=9), and leakage through the insertion site (n=1). Two patients died 30 days after the procedure. CONCLUSIONS: Single-puncture double anchor PRG is a fast, safe and effective technique. PMID- 23090247 TI - Chest radiography in intensive care: an irreplaceable survey? AB - PURPOSE: This study evaluated the impact and value of bedside chest X-ray in intensive care units. MATERIALS AND METHODS: This observational study considered the bedside chest X-rays performed on 258 consecutive patients (160 men, 98 women; mean age, 58 years) admitted to intensive care units. Stratification of patients according to the reason for hospitalisation and analysis of the reasons for chest X-ray examinations were performed to assess the diagnostic efficacy (DE). RESULTS: DE for chest X-rays was 84.5%, with 15.5% of tests remaining unchanged over time. Patient stratification by disease indicated that the DE was 85.27% in transplant, 90.79% in postoperative care after general surgery, 83.89% in respiratory failure, 82.42% in polytrauma, 90.54% in postoperative care after neurosurgery, 86.6% in postoperative care after vascular surgery, 83.3% in neurological conditions and 93.4% in other diseases. CONCLUSIONS: Chest X-rays performed at the bedside are the most widely used imaging method in the follow-up of critically ill patients. DE is approximately 84.5%. Radiologists should maintain familiarity with the interpretation of this examination. PMID- 23090248 TI - Preoperative vascular mapping with multislice CT of deep inferior epigastric artery perforators in planning breast reconstruction after mastectomy. AB - PURPOSE: Our aim was to evaluate the usefulness of computed tomography angiography (CTA) in vascular mapping for planning breast reconstruction after mastectomy using a free flap made with the deep inferior epigastric perforators (DIEP). MATERIALS AND METHODS: We retrospectively evaluated 41 patients, mean age 57 years, scheduled for mastectomy. CTA was performed with a 64-row scanner (Aquilion 64, Toshiba Medical Systems, Japan), with injection of 100 ml of contrast medium (iomeprol 350 mgI/ml, Bracco, Italy) at 4.5 ml/s. Maximum intensity projection (MIP) and three-dimensional volume-rendering (VR) reconstructions were made to mark perforator positions. Presentation frequency, anatomy and artery opacification quality were evaluated. RESULTS: DIEP were always depicted (n=81) and subdivided according to Taylor's classification into type I (65%), type II (28%), and type III (7%). We observed a mean of three (range, 1-5) DIEP arteries on the right and two (range, 1-5) on the left side. The superficial inferior epigastric artery (SIEA) was depicted in 6/41 patients, bilaterally in three cases. Opacification was optimal in 30/41 cases, venous contamination due to late arterial phase in eight and low opacification due to early scan in three. CONCLUSIONS: Studying DIEP with CTA is useful in the surgical planning of breast reconstruction, even though it requires careful optimisation owing to the critical timing of opacification typical of that vascular district. PMID- 23090249 TI - Bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography and gene-mutation-associated pancreatitis (GMAP). AB - PURPOSE: This study prospectively assessed whether the presence of a bull's-eye pattern of pancreatic-duct stones on multidetector computed tomography (MDCT) correlated with gene-mutation-associated pancreatitis (GMAP) and whether other signs suggestive of GMAP can be detected with MDCT. MATERIALS AND METHODS: Forty seven patients with chronic calcific pancreatitis underwent genetic testing for CFTR, SPINK1 and PRSS1 mutations and an MDCT scan of the abdomen. Qualitative analysis assessed the presence or absence of pancreatic-duct stones with bull's eye appearance. Quantitative analysis included the number and maximum diameter of stones and the diameter of the main pancreatic duct. RESULTS: Fifteen of 47 patients (32%) were positive for gene mutations (GMAP patients). The bull's-eye pattern was found in 10/15 patients (67%) with GMAP and in 4/32 (12%) patients with chronic pancreatitis not associated with GMAP (NGMAP; p<0.0001). The mean diameter of duct stones was 15 mm in patients with GMAP and 10 mm in patients with NGMAP (p<0.04). CONCLUSIONS: The presence of duct stones with a bull's-eye pattern correlates with GMAP. Duct stones with diameter >=15 mm are another sign suggestive of GMAP. PMID- 23090250 TI - Chest MR imaging in the follow-up of pulmonary alterations in paediatric patients with middle lobe syndrome: comparison with chest X-ray. AB - PURPOSE: The authors evaluated the role of magnetic resonance (MR) imaging of the chest in comparison with chest X-ray in the follow-up of pulmonary abnormalities detected by computed tomography (CT) in paediatric patients with middle lobe syndrome. MATERIALS AND METHODS: Seventeen patients with middle lobe syndrome (mean age 6.2 years) underwent chest CT at the time of diagnosis (100 kV, CARE dose with quality reference of 70 mAs; collimation 24*1.2 mm; rotation time 0.33 s; scan time 5 s); at follow-up after a mean of 15.3 months, all patients were evaluated with chest MR imaging with a respiratory-triggered T2-weighted BLADE sequence (TR 2,000; TE 27 ms; FOV 400 mm; flip angle 150 degrees ; slice thickness 5 mm) and chest X-ray. Images from each modality were assessed for the presence of pulmonary consolidations, bronchiectases, bronchial wall thickening and mucous plugging. Hilar and mediastinal lymphadenopathies were assessed on CT and MR images. RESULTS: Baseline CT detected consolidations in 100% of patients, bronchiectases in 35%, bronchial wall thickening in 53% and mucous plugging in 35%. MR imaging and chest X-ray identified consolidations in 65% and 35%, bronchiectases in 35% and 29%, bronchial wall thickening in 59% and 6% and mucous plugging in 25% and 0%, respectively. Lymphadenopathy was seen in 64% of patients at CT and in 47% at MR imaging. CONCLUSIONS: Patients with middle lobe syndrome show a wide range of parenchymal and bronchial abnormalities at diagnosis. Compared with MR imaging, chest X-ray seems to underestimate these changes. Chest MR imaging might represent a feasible and radiation-free option for an overall assessment of the lung in the follow-up of patients with middle lobe syndrome. PMID- 23090251 TI - Nasopharyngeal carcinoma: correlation of apparent diffusion coefficient value with prognostic parameters. AB - PURPOSE: The aim of this study was to correlate the apparent diffusion coefficient (ADC) value with the prognostic parameters of nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: This was a prospective study conducted on 30 consecutive patients (19 men, 11 women; mean age 61 years) with NPC. Patients underwent diffusion-weighted magnetic resonance (DW-MR) singleshot echoplanar imaging at 1.5 Tesla. NPC ADC value was correlated with pathological tumour type, pathological tumour grade, tumour volume and nodal status. RESULTS: Mean NPC ADC value was 0.99 +/- 0.11 * 10(-3)mm(2)/s. ADC values of well-differentiated and moderately differentiated tumours differed significantly (p=0.005) from those of poorly differentiated and undifferentiated NPC. There was also a significant difference in ADC value among small, medium and large tumour volume (p=0.03). ADC value was also significantly lower (p=0.003) when metastatic cervical lymph nodes were present. ADC value correlated inversely with tumour volume (r=-0.799, p=0.03). CONCLUSIONS: ADC value can be considered a noninvasive prognostic parameter that correlates well with prognostic parameters of NPC. PMID- 23090252 TI - Magnetic resonance imaging in the complications of kidney transplantation. AB - Kidney transplantation is currently the treatment of choice in most patients with end-stage chronic renal failure owing to the excellent results in terms of both graft and patient survival. However, surgical complications are still very frequent. Although urological (stricture, urinary fistulas, vesico-ureteral reflux) and lymphatic complications (lymphocoele) have a high incidence, they only rarely lead to graft loss. By contrast, vascular complications (stenosis, arterial and venous thrombosis, arterio-venous fistulas, pseudoaneurysms) are relatively rare, but potentially serious and may affect graft survival. Finally, medical complications such as acute tubular necrosis (ATN), rejection and de novo neoplasms may also arise in kidney transplantation. The purpose of this pictorial review is to illustrate the increasingly significant contribution of magnetic resonance angiography (MRA) in the management of complications of kidney transplantation, and emphasise how this method should now be considered a mandatory step in the diagnostic workup of selected cases. Moreover, the application and role in this setting of new magnetic resonance imaging (MRI) techniques, such as diffusion-weighted and blood oxygen level-dependent (BOLD) MRI, are also discussed. PMID- 23090253 TI - Optimisation of radiological protocols for chest imaging using computed radiography and flat-panel X-ray detectors. AB - PURPOSE: Digital radiography technology has replaced conventional screen-film systems in many hospitals. Despite the different characteristics of new detector materials, frequently, the same radiological protocols previously optimised for screen film are still used with digital equipment without any critical review. This study addressed optimisation of exposure settings for chest examinations with digital systems, considering both image quality and patient dose. MATERIALS AND METHODS: Images acquired with direct digital radiography equipment and a computed radiography system were analysed with specially developed commercial software with a four-alternative forced-choice method: the most promising protocols were then scored by two senior radiologists. RESULTS: Digital technology offers a wide dynamic range and the ability to postprocess images, allowing use of lower tube potentials in chest examinations. The computed radiography system showed both better image quality and lower dose at lower energies (85 kVp and 95 kVp) than those currently used (125 kVp). Direct digital radiography equipment confirmed both its superior image quality and lower dose requirements compared with the storage phosphor plate system. CONCLUSIONS: Generally, lowering tube potentials in chest examinations seems to allow better image quality/effective dose ratio when using digital equipment. PMID- 23090254 TI - Removable vena cava filter: single-centre experience with a single device. AB - PURPOSE: The aim of our study was to evaluate the safety of retrieving both short and long-term permanent/ retrievable ALN vena cava filters (VCF). MATERIALS AND METHODS: From 2002 to 2010, 201 permanent/retrievable VCF were percutaneously placed in 201 patients (age range, 18-80 years). Sixty-seven were placed through the jugular vein, 61 through the brachial vein and 63 through the femoral vein. In 109 patients, the VCF was placed for absolute indications, in 77 for relative indications, and in 15 for temporary filtration. Follow-up was carried out with colour Doppler ultrasound (CDUS) and abdominal X-ray at 3 and 12 months, then annually. Indications for removal included: lack of contraindications to anticoagulant therapy, absence of pulmonary embolism and iliocaval venous patency. All candidates for VCF removal underwent computed tomography angiography (CTA). RESULTS: VCF placement with correct position (tilting up to 15 degrees ) was achieved in 99.01% of cases. In two (0.99%) cases, tilting >15 degrees was present. Haematomas, which resolved spontaneously, occurred in only eight jugular access sites. A total of 26 of 201 VCF were removed, with 96.16% technical success. The removal procedure failed in one case only. In seven cases, a double approach through the right jugular and femoral veins was necessary. VCF was removed 6 months after deployment in 11 patients, 12 months in eight, 24 months in four after 36 months in three (range, 180-1,155 days.) There were no periprocedural complications. Of the 26 removed VCF, 21 were infrarenal and five suprarenal. Of the 15 VCF placed for temporary use, 12 were removed; the remaining three not removed owing to persistence of the neoplastic thrombus after nephrectomy for kidney cancer. Of the 186 VCF placed for permanent use, with absolute and relative indications, 14 were removed (4/109 and 10/77, respectively). Only one showed thrombi occluding the cranial end. CONCLUSIONS: VCF removal is certainly more difficult than placement. Technical failure of the removal procedure is directly proportional to the VCF tilt, and the VCF is as yet unable to ensure absolute removal safety, with the result that failure may occasionally occur. The morphological and structural features of permanent/retrievable VCF allow for unlimited time from placement to removal, documented to be up to 3 years after placement. PMID- 23090255 TI - Placement of port-a-cath through the right internal jugular vein under ultrasound guidance. AB - PURPOSE: This study was undertaken to demonstrate the effectiveness of ultrasound (US)-guided placement of porta-cath (PC) through the right internal jugular vein (RIJV) by evaluating the onset of early and late complications. MATERIALS AND METHODS: From 30 June 2008 to 30 June 2011, we placed 695 port-a-caths in 694 patients with a mean age of 58 years. Exclusion criteria were active infection, bleeding disorders and life expectancy <6 months. The procedures were performed in the angiography suite under local anaesthesia. After US-guided puncture of the RIJV, the subcutaneous pocket was prepared, followed by tunnelling of the vein and closure of the surgical wound. In order to evaluate pneumothorax (PNX), all patients underwent chest X-ray a few hours after the end of the procedure unless there were clinical indications. We evaluated the technical success of the procedure and the rate of complications. RESULTS: Technical success was achieved in all cases. The device was kept in place for an average of 168 days. There was one case of PNX (0.14%) as shown on chest X-ray and five cases of late complications (0.70%): one case of intracatheter thrombosis (0.14%), two cases of disconnection between the reservoir and catheter (0.28%) and two cases of PC infection (0.28%). CONCLUSIONS: This procedure incurs very small number of complications compared with other positioning techniques using accesses such as the subclavian vein. Complications recorded in our study are comparable, in type and incidence, to those found by other authors, with the most frequent being device infection. PMID- 23090256 TI - Optimisation of low-dose CT with adaptive statistical iterative reconstruction in total body examination. AB - PURPOSE: The aim of this study was to assess the feasibility of low-dose computed tomography (CT) with the adaptive statistical iterative reconstruction (ASIR) algorithm in whole-body imaging with low tube voltage and current. MATERIALS AND METHODS: Twenty-three patients underwent whole-body CT with 40% of ASIR and parameters modulated according to body mass index (BMI). All had previously undergone conventional-dose CT with 100% filtered back projection (FBP). Two radiologists jointly assessed image quality (sharpness, noise, artefacts) and diagnostic quality blinded to the scanning technique. The effective dose and image quality obtained with the ASIR protocol were compared with those obtained with the FBP algorithm. RESULTS: The mean effective dose achieved with ASIR was 15.6 +/- 5 mSv versus 21.8 +/- 5.3 mSv with the FBP protocol (p<0.0001). Image quality was good in all low-dose CT scans, and diagnostic quality was comparable with or superior to that of conventional-dose CT. CONCLUSIONS: Low-dose CT with the ASIR algorithm is feasible and ensures significant reduction in effective dose. PMID- 23090258 TI - Disease genetics: mitochondrial mutation mixtures. PMID- 23090257 TI - ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. AB - Chromatin immunoprecipitation experiments followed by sequencing (ChIP-seq) detect protein-DNA binding events and chemical modifications of histone proteins. Challenges in the standard ChIP-seq protocol have motivated recent enhancements in this approach, such as reducing the number of cells that are required and increasing the resolution. Complementary experimental approaches - for example, DNaseI hypersensitive site mapping and analysis of chromatin interactions that are mediated by particular proteins - provide additional information about DNA binding proteins and their function. These data are now being used to identify variability in the functions of DNA-binding proteins across genomes and individuals. In this Review, I describe the latest advances in methods to detect and functionally characterize DNA-bound proteins. PMID- 23090259 TI - Tumor dormancy and the neuroendocrine system: an undisclosed connection? AB - Tumor dormancy is a poorly understood phenomenon conceptualized as a protracted quiescent state during which cancer cells are present but clinical disease is not apparent, a condition referred to as "cancer without disease" by Folkman. Examples include the incidental detection of occult in situ tumors in post-mortem organ analysis and cancer recurrence after long disease-free periods. Lack of angiogenic competency has been proposed as a major determinant of the fate of dormant tumors. Other proposed processes include establishment of homeostatic equilibrium between tumor cells and the host's immune system response and a non permissive microenvironment for tumor growth. Recent cellular and molecular studies suggest that neuroendocrine mediators regulate the biology of tumor progression and act as endogenous modulators of angiogenesis, inflammation, and other molecular processes involved in tumor reactivation from dormancy. We review experimental and clinical evidence and propose that neuroendocrine dynamics of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis might contribute to the loss of tumor dormancy. PMID- 23090260 TI - The role of the tissue omega-6/omega-3 fatty acid ratio in regulating tumor angiogenesis. AB - Angiogenesis is a necessary step in tumor growth and metastasis. It is well established that the metabolites of omega-6 and omega-3 fatty acids, which must be obtained through the diet and cannot be synthesized de novo in mammals, have differential effects on cellular processes. Omega-6 fatty acid (n-6 FA)-derived metabolites promote angiogenesis by increasing growth factor expression whereas omega-3 fatty acids (n-3 FA) have anti-angiogenic and antitumor properties. However, most studies thus far have failed to account for the role of the n-6 FA/n-3 FA ratio in angiogenesis and instead examined the absolute levels of n-6 and n-3 FA. This review highlights the biochemical interactions between n-6 and n 3 FA and focuses on how the n-6/n-3 FA ratio in tissues modulates tumor angiogenesis. We suggest that future work should consider the n-6/n-3 FA ratio to be a key element in experimental design and analysis. Furthermore, we recommend that clinical interventions should aim to both reduce n-6 metabolites and simultaneously increase n-3 FA intake. PMID- 23090262 TI - Analysis of fMRI time-series by entropy measures. AB - Entropy is a measure of information content or complexity. Information-theoretic modeling has been successfully used in various biological data analyses including functional magnetic resonance (fMRI). Several studies have tested and evaluated entropy measures on simulated datasets and real fMRI data. The efficiency of entropy algorithms has been compared to classical methods based on the linear model. Here we explain and summarize entropy algorithms that have been used in fMRI analysis, their advantages over classical methods and their potential use in event-related and block design fMRI. PMID- 23090263 TI - Clinical and psychological features of normal-weight women with subthreshold anorexia nervosa: a pilot case-control observational study. AB - OBJECTIVE: Weight preoccupations have been frequently reported in normal-weight subjects. Subthreshold anorexia nervosa (s-AN, all DSM IV TR criteria except amenorrhea or underweight) is a form of eating disorder not otherwise specified that has received scarce scientific attention. Under a case-control design we compared the general characteristics, body composition, and psychopathological features of normal-weight patients with s-AN with those of BMI- and sex-matched controls. DESIGN: Participants in this pilot study included 9 normal-weight women who met the DSM IV TR criteria for s-AN and 18 BMI-matched normal-weight controls. The general characteristics of the study participants were collected by questionnaire. Body composition was measured by bioelectrical impedance. Behavioral and psychological measures included the standardized symptom checklist (SCL-90-R) and the eating disorder inventory (EDI-2). RESULTS: There were no differences in age, education, employment status, marital status, and history of previous slimming treatment in the two study groups. In addition, anthropometric measures and body composition of s-AN patients and BMI-matched normal weight controls were not significantly different. In the s-AN subgroup, we found a significant relationship between waist circumference and the SCL-90-R obsessivity compulsivity scale (n=9, r=-0.69, p<0.05). After multiple regression analysis, the SCL-90-R obsessivity-compulsivity scale (beta = 0.61, t=2.7, p=0.017) was the only independent predictor of the presence s-AN in our study cohort. CONCLUSIONS: These pilot results suggest that psychopathological criteria (particularly related to the obsessivity-compulsivity dimension) may be more useful than anthropometric measures for screening of s-AN in normal-weight women. PMID- 23090264 TI - Transsphenoidal surgery for a life-threatening prolactinoma apoplexy during pregnancy. AB - Prolactinoma is the most common secreting pituitary adenoma. It is typically diagnosed in women of reproductive age and is common cause of infertility. Currently the treatment of choice is pharmacotherapy with dopamine agonists, whereas surgical treatment is reserved for a selected group of patients. Pituitary-tumor apoplexy is a rare, life-threatening condition associated with significant morbidity and mortality. The authors present the case of a 25-year old woman with prolactinoma treated with dopamine agonist. In course of such a treatment the patient became pregnant. The bromocriptine was gradually withdrawn. In the 14th week of pregnancy she was admitted for symptoms suggesting pituitary tumor apoplexy. The treatment with bromocriptine was reinitiated. In the 20th week of pregnancy further deterioration of the patient's neurological condition and visual-field abnormalities were observed. The patient was qualified for surgical treatment - selective transsphenoidal adenomectomy. The successful surgery led to improvement of neurological condition. The early postoperative PRL level decreased significantly and hormonal function of the pituitary was preserved. The pregnancy ended in 38th week with a caesarean section. Endocrinological evaluation conducted after the uneventful delivery confirmed normal function of the pituitary. Magnetic resonance imaging (MRI) did not reveal tumor re-growth. The patient is kept under constant medical care. In this case study the authors discussed therapeutic management and reviewed literature regarding gestational pituitary-tumor apoplexy with particular emphasis on surgical treatment. PMID- 23090265 TI - Hemichorea associated with nonketotic hyperglycemia in a female. AB - A case of a 61-year-old woman with hemichorea associated with nonketotic hyperglycemia is reported. The typical presentation of this disease is nonketotic hyperglycemia, hemichorea, hyper-intense signal on T1-weighted magnetic resonance imaging (MRI) and high-density on computed tomography (CT) in the contralateral striatum. With good glycemic control, the clinical symptoms disappeared. PMID- 23090266 TI - Metabolic parameters and long-term antipsychotic treatment: a comparison between patients treated with clozapine or olanzapine. AB - OBJECTIVES: This study was undertaken to examine if patients exhibit more pronounced metabolic abnormalities after 8-year treatment with clozapine or olanzapine than before, and also to investigate whether there exist any differences between long-term clozapine and olanzapine therapies regarding metabolic side- effects. METHODS: Fifty psychiatric outpatients diagnosed with schizophrenia or schizoaffective disorder and on treatment with clozapine or olanzapine were studied during 8 years. Fasting blood or serum samples for glucose, lipids, prolactin and antipsychotic drug concentrations were analyzed. In addition, body mass index was calculated. RESULTS: More patients treated with olanzapine compared with those treated with clozapine ended with their medication, in most cases because of diabetes mellitus and/or hyperlipidemia, during the 8-year follow-up. Also more patients treated with olanzapine compared with those treated with clozapine developed manifest diabetes mellitus during the 8-year period. Prolactin levels were higher in the patients treated with olanzapine compared with in those treated with clozapine at study start, but there were no differences in the other parameters between the treatment groups at study start. In the patients remaining on their medication all 8 years, the glucose level increased over time in the clozapine group, but not in the olanzapine group, whereas body mass index and lipids were unchanged over time in both treatment groups. CONCLUSIONS: Our findings point to that both olanzapine and clozapine long-term treatments cause development of hyperglycemia and/or hyperlipidemia. Furthermore, olanzapine long-term treatment seems to more often lead to development of manifest diabetes mellitus than long-term treatment with clozapine. PMID- 23090267 TI - The relationship between the C677T polymorphism of the MTHFR gene and serum levels of luteinizing hormone in males with erectile dysfunction. AB - OBJECTIVES: The methylenetetrahydrofolate reductase (MTHFR) enzyme activity plays an important role in the metabolism of folate within methionine-homocysteine pathway and, consequently, in the development of vascular diseases. The C677T polymorphism (rs1801133) of the MTHFR gene affects the MTHFR activity, modifies the homocysteine plasma concentration and, among others, increases the risks for idiopathic male infertility, including erectile dysfunction (ED). As this sexual dysfunction is related to sex hormone levels, we investigated a possible relationship between the C677T polymorphism of the MTHFR gene and plasma concentrations of follicle-stimulating hormone (FSH) as well as luteinizing hormone (LH) in male patients with ED. METHODS: We conducted our study on 90 healthy men with ED between the age of 32 and 61 (mean age was 51.1 +/- 11.5) years. The subjects were genotyped and their FSH and LH plasma levels were analysed. RESULTS: The analysis results of ED patients and their genotypes of the MTHFR gene did not provide evidence supporting any causal association of T allele in CT and TT genotypes with studied clinical parameters. However, we found that patients with the CC genotype had significantly higher plasma levels of LH than patients with the CT and/or TT genotypes. CONCLUSIONS: Our observations suggest that the C677T polymorphism of MTHFR gene has no direct relationship to erectile dysfunction, but does exhibit a relationship between this rs1801133 polymorphism and plasma LH concentrations. PMID- 23090268 TI - Comparison of tibolone and 17beta-estradiol administration on the expression of zonula occludens-1, occludin, glial fibrillary acidic protein and c-fos levels in the brain cortex and hippocampus of female rats. AB - OBJECTIVES: To compare the effect exerted by oral tibolone or intramuscular 17beta-estradiol administration on the expression of ZO-1, occludin, GFAP and c fos levels in the brain cortex and hippocampus of ovariectomized rats. RESULTS: Immunostaining for ZO-1 and occludin revealed similar staining patterns between controls and tibolone rats and between controls and E2 rats. When staining in tibolone and E2 rats were compared both for ZO-1 and occludin, staining patterns were again identical. Positive staining for the GFAP was detected in the controls, tibolone rats and E2 rats. Staining was more intense in the tibolone rats than controls and in the E2 rats than controls. In sections from the controls, tibolone rats and E2 rats, number of reactive cells for c-fos were 1.75+/-0.25, 3.75+/-0.36 and 4.50+/-0.50, respectively. There was a statistically significant difference between the three groups (p=0.0001). Comparison of tibolone and E2 rats revealed no statistically significant difference (p=0.246). CONCLUSIONS: It is well known that natural hormones like E2 regulate brain development and function. Our results provide further information on the mechanism of action of tibolone in the brain cortex and hippocampus. These results will allow us to continue with further studies with different post ovariectomy intervals, because tibolone can be proposed as an attractive alternative for hormone replacement therapy, acting as a neuroprotective agent for the prevention of neurodegenerative diseases in menopausal women. PMID- 23090269 TI - The prognostic value of fine-needle aspiration biopsy of the thyroid gland - analysis of results of 1078 patients. AB - OBJECTIVE: We aimed to evaluate the prognostic value of thyroid fine needle aspiration biopsy (FNAB) in the diagnosis of pathologic lesions. METHODS: Data from 1 078 consecutive patients (female : male ratio, 9:1) who underwent thyroidectomy were retrospectively analyzed. All patients had preoperative thyroid FNAB. Unilateral and bilateral FNAB were performed in 872 and 206 patients, respectively, resulting in 1 284 cytologic aspirates, which were compared to postoperative histology. Risk factors for malignancy (age, sex, single nodule, or nodule in multinodular goiter) were evaluated. RESULTS: 203 (15.81%) aspirates were non-diagnostic. 768 (59.81%) were benign; 112 (8.72%) were atypical; 170 (13.24%) were follicular neoplasms, 5 (0.4%) had suspicion of malignancy; and 26 (2.02%) were malignant tumors on FNAB. The calculated risk of malignancy in each group was: 1.97%, 1.84%, 7.15%, 12.35%, 60%, and 100%. There were 2.02% false negative and 0.15% false positive results. Diagnostic discrepancies occurred in the follicular neoplasm group, of 86 biopsies (0.15%). CONCLUSION: FNAB is the primary method of preoperative diagnostics of thyroid tumors, as it allows many patients to avoid thyroidectomy. In addition, it helps the operating surgeon to decide the extent of surgical resection. PMID- 23090271 TI - Loneliness depends on salivary estradiol levels in adolescent females. AB - OBJECTIVE: Loneliness is one of the psychological characteristics in adolescence, during which sex hormones are elevated. The elevation of sex steroid hormones is known to sculpture and remodel neuronal circuits, which cause behavioral characteristics in adolescence. The aim of the present study is to investigate the relationship between loneliness and sex steroid hormones, testosterone (T) and 17beta-estradiol (E2). METHODS: Fifty-eight adolescents (28 boys and 30 girls) participated in this study. The salivary levels of T and E2 were measured by Enzyme-Linked Immunosorbent Assay (ELISA). Loneliness was assessed by the UCLA loneliness scale, which is widely used as a self-administered questionnaire. RESULTS: The results showed that Salivary E2 levels had positive relevance to loneliness in females, whereas there was no relationship in males. Salivary T level was not shown to be relevant with loneliness in either sex group. CONCLUSIONS: These findings suggest that E2 has gender specific effects on loneliness in adolescent females. PMID- 23090270 TI - The impact of high iodine intake on thyroid function in ewes and lambs. AB - OBJECTIVES: The objective of the study was to assess the metabolic risk of excessive dietary iodine intake in ewes and neonatal lambs. DESIGN: Pregnant Sumava ewes received an experimental diet containing 3.1 mg iodine per kg of dietary dry matter in Group A (control, n=13, 6 ewes and 7 lambs) and 5.1 mg iodine per kg of dietary dry matter in Group B (experimental, n=12, 6 ewes, 6 lambs) for eight months. Iodine was administered to ewes as calcium iodate. TSH in blood serum; TT3, TT4, fT3, and fT4 in blood plasma were examined in both groups of ewes and lambs to assess the risks of iodine intake above the permitted limit, as it applies to thyroid gland activity. RESULTS: Group B ewes showed a significant increase in TSH and TT4 only on day 1 after parturition. The highest values of TT4, TT3, and fT3 in lambs were recorded on day 1 after birth. The lowest values of fT3 and fT4 in lambs were measured on day 60 after birth with no differences observed between the groups. In lambs of Group B the lower concentration of TSH until day 3 after birth was followed by a significant increase from day 10 after birth. CONCLUSION: Our results indicate a risk of postnatal hypothyroidism among lambs from pregnant and lactating ewes having a high iodine intake. PMID- 23090272 TI - Ascorbic acid and alpha-tocopherol protect age-dependently from hypoxia-induced changes of cortical excitability in developing rats. AB - OBJECTIVES: The effects of ascorbic acid and alpha-tocopherol pre-treatment on hypoxia induced changes in brain cortex excitability were tested in immature rats exposed chronically to simulated altitude of 7 000 m. METHODS: Rat pups were kept together with their mothers for 8 hours a day in hypobaric chamber since the day of the birth till the postnatal day 11 or 17. Each day immediately before placing to hypobaric chamber pups were pretreated intraperitoneally either with ascorbic acid (100 mg/kg) or alpha-tocopherol (1 500 mg/kg). Cortical afterdischarges were elicited by repeated stimulation of the right sensorimotor cortex. The duration of evoked cortical afterdischarges was analyzed. RESULTS: Duration of cortical afterdischarges progressively declines with age. Hypoxia prolonged the duration of afterdischarges in 12-, 18- and 25-day-old animals. Pretratment with ascorbic acid or alpha-tocopherol shorted afterdischarges duration in youngest experimental group when compared with animals exposed to hypoxia only. CONCLUSION: Hypoxia significantly affects the brain cortex excitability by prolonging afterdischarges duration. This effect differs with age. Antioxidant pre-treatment brought about shorter duration of cortical afterdischarges only in the youngest experimental group. The antioxidant effect is therefore age dependent. PMID- 23090273 TI - Relationship between lipid peroxidation or carcinoembryonic antigen and risk factors for non-communicable diseases in women at midlife and beyond. AB - BACKGROUND: Non-communicable diseases (NCDs) constitute leading cause of morbidity, disability and premature mortality. Oxidative processes are involved in the pathogenesis of NCDs. OBJECTIVES: To investigate the relationship between lipid peroxidation (LPO), an index of oxidative damage to membrane lipids, or carcinoembryonic antigen (CEA), a tumor marker, and potential risk factors for NCDs in women at midlife and beyond. METHODS: Data on lifestyle, such as dietary habits, smoking, physical activity, etc. and medical history, were assessed by a questionnaire in 323 female outpatients of the Regional Centre of Menopause and Osteoporosis - Outpatient Department of Endocrinology, Lodz (Poland), at midlife and beyond. Blood serum LPO and CEA levels, as well as anthropometric measurements were evaluated. RESULTS: Positive correlations between LPO level and body mass or body mass index or hip circumference were found. LPO level was increased in women who did not declare regular menstrual cycles. CEA level was increased in women who smoked (and positively correlated with duration of smoking), who consumed pickled food every day and over-consumed animal fats, who had not breastfed in the past, as well as in women with malignancy in anamnesis. Logistic regression analysis has revealed that LPO constitutes the independent positive determinant, whereas CEA constitutes the independent negative determinant, of obesity. Moreover, CEA was independently associated with malignancy in anamnesis, cigarette smoking and animal fat over-consumption. CONCLUSION: Both LPO and CEA are independently associated with certain modifiable risk factors for NCDs. PMID- 23090274 TI - Thr136Ile polymorphism of human vesicular monoamine transporter-1 (SLC18A1 gene) influences its transport activity in vitro. AB - OBJECTIVES: Although single nucleotide polymorphisms of the human vesicular monoamine transporter 1 (hVMAT1) gene SLC18A1 have been associated with neuropsychiatric disorders, there is limited information on the function of naturally occurring hVMAT1 variant proteins. This study evaluated transport activity of full length hVMAT1 isoform-a (NP_003044.1) with a threonine (Thr) or isoleucine (Ile) at amino acid 136 and hVMAT1 isoform-b (NP_00135796.1) with a 136-Thr and deletion of 32 amino acids in the central region of the protein. Genetic studies have previously linked the 136-Thr to bipolar disorder. METHODS: Expression vectors with hVMAT1 DNA coding for isoform variants were transfected into COS-1 cells. Expression of immunoreactive proteins was assessed by Western blotting, and function was assayed by ATP-dependent transport of radiolabeled serotonin and concentration-dependent inhibition by reserpine. RESULTS: Immunoreactive isoform-a proteins were observed as a major doublet (68-71 Kd) and a minor 39 Kd protein. The major isoform-b protein was 47 Kd with minor 57 and 115 Kd proteins. Isoform-b had no detectable transport activity, despite a large amount of immunoreactive protein. Transport activity of isoform-a with 136-Thr was 20-50% lower than with 136-Ile in time course studies (2.5-5 min) and in additional 5 min assays repeated with 5-6 transfections per variant. Kinetic analyses indicated a lower transport Vmax of isoform-a with 136-Thr but no significant differences in the transport Km or reserpine IC50. CONCLUSIONS: Deletion of amino acids 307-338 in hVMAT1 isoform-b abolishes transport activity, and a 136-Thr partially reduces activity of isoform-a. PMID- 23090275 TI - Development of the "Playing-in-Touch" (PiT) questionnaire: a measure of musical intouchness in people with low-functioning autism. AB - BACKGROUND: There is accumulating evidence that people with autism have a particular affinity with music. METHODS: This study developed the "Playing-in Touch" (PiT) questionnaire as an objective measure of musical intouchness - defined as the degree of engagement in creative exchange while playing ensemble music pieces - in persons with low-functioning autism. RESULTS: A 3-facet Rasch model supported the content and construct validity of the PiT scale. The items verified a one-dimensional hierarchical model. CONCLUSIONS: The PiT questionnaire is a convenient complement to other research methodologies exploring the attitudes of people with low-functioning autism in terms of active music making. PMID- 23090276 TI - Serum visfatin levels are decreased in schoolchildren with atopic asthma. AB - OBJECTIVES: Very little is known about the role of adipokines in atopic asthma in children. Studies about the potential role of novel proinflammatory adiopcytokine - visfatin are lacking. DESIGN AND SETTING: In this cross-sectional study serum visfatin (VISF) levels were measured in 89 asthmatic out-patients (61 boys and 28 girls aged 7.0-17.0 years) and in 33 healthy children. MATERIAL AND METHODS: Among examined asthmatics 59 (19 girls and 40 boys) had normal weight and 30 (9 girls and 21 boys) were obese. Serum VISF was evaluated using standard ELISA tests and the results were analysed in relation to body weight, asthma severity, and gender were analysed. RESULTS: The mean serum levels of visfatin were significantly (p<0.001) lower both in obese (2.13+/-0.07npg/ml) and non-obese asthmatic children (2.05+/-0.06 npg/ml) than in healthy children (2.57+/-0.07 pg/ml) regardless of gender. After stratifying by gender, there was a significant decrease (p<0.001) in visfatin levels in obese asthmatic girls (2.30+/-0.08 ng/ml) and asthmatic girls with normal weight girls (2.21+/-0,09 ng/ml) compared with girls from control group (2.69 +/-0.06 ng/ml). In obese asthmatic boys and non-obese asthmatic boys also significantly lower (p<0.01) mean values of visfatin (2.03+/-0.06 ng/ml and 1.9+/-0.06 pg/ml respectively) were observed than in control boys (2.391+/-0.09 ng/ml). No relationships between examined adipokine levels and asthma severity, spirometric parameters, degree of allergic sensitization, BMI, were observed. CONCLUSION: Visfatin is not potential biomarker in atopic asthma in children and further studies evaluating the possible role of this proinflammatory adipokine in childhood atopic asthma pathogenesis are needed. PMID- 23090277 TI - Frequency of some psychosomatic symptoms in informal caregivers of Alzheimer's disease individuals. Prague's experience. AB - BACKGROUND: This study was motivated by the growth in the number of elderly with dementia and consequent need to help family caregivers who face the daily stress for long periods of time. The aim was to describe the frequency of some common psychosomatic symptoms in self-assessed health status and to determine whether there are gender differences in these symptoms and the perception of one's own health in family caregivers. METHODS: The first results of cross-sectional survey design as the first phase of a longitudinal cohort study are presented. The participants in this investigation (n=73) were family caregivers of outpatients suffering from moderate (59 cases = 80.8%) or mild (14 cases = 19.2%) stage of Alzheimer' s disease (AD). RESULTS: The group of caregivers consisting of 61 (83.6%) women and 12 men (16.4%). Participants of this study were recruited from the Department of Psychiatry, Prague, Czech Republic. Data from caregivers were collected by using a self-administered questionnaire containing various items to measure self-perceived health including some common psychosomatic symptoms in relationship with their caregiving role. CONCLUSIONS: The following symptoms appeared the most frequent among family caregivers: chronic fatigue and sleeping disturbances. Most caregivers of patients with moderate stage of AD evaluated their own health as poor and experienced more symptoms in comparison with caregivers of patients with mild stage of Alzheimer's disease, who scored their own health as good or very good. A follow-up of the survey population seems to be necessary. PMID- 23090279 TI - Visceral obesity and colorectal cancer: are we missing the boat with BMI? AB - INTRODUCTION: Compared to subcutaneous fat, visceral fat is more metabolically active, leading to chronic inflammation and tumorigenesis. The aim of this study is to describe the effect of visceral obesity on colorectal cancer outcomes using computed tomography (CT) imaging to measure visceral fat. MATERIALS AND METHODS: We conducted a retrospective chart review of patients who underwent surgical resection for colorectal cancer. Visceral fat volume was measured by preoperative CT scans. Final analysis was performed by stratifying patients based on oncologic stage. RESULTS: Two hundred nineteen patients met the inclusion criteria, 111 viscerally obese and 108 nonobese. Body mass index (BMI) weakly correlated with visceral fat volume measurements (R (2) = 0.304). Whereas obese patients had no difference in survival when categorizing obesity by BMI, categorizing based on visceral fat volume resulted in significant differences in stage II and stage III patients. In stage II cancer, viscerally obese patients had a nearly threefold decrease in disease-free survival (hazard ratio (HR) = 2.72; 95 % confidence interval (CI) = 1.21, 6.10). In stage III cancer, viscerally obese patients had a longer time to recurrence (HR = 0.39; 95 % CI = 0.16, 0.99). CONCLUSION: This study shows that viscerally obese patients with stage II colorectal cancer are at higher risk for poor outcomes and should be increasingly considered for adjuvant chemotherapy. PMID- 23090280 TI - Gastroesophageal reflux disease and antireflux surgery-what is the proper preoperative work-up? AB - BACKGROUND: Many surgeons feel comfortable performing antireflux surgery (ARS) on the basis of symptomatic evaluation, endoscopy, and barium esophagography. While esophageal manometry is often obtained to assess esophageal peristalsis, pH monitoring is rarely considered necessary to confirm the diagnosis of gastroesophageal reflux disease (GERD). AIMS: The aim of this study was to analyze the sensitivity and specificity of symptoms, endoscopy, barium esophagography, and manometry as compared to pH monitoring in the preoperative evaluation of patients for ARS. PATIENTS AND METHODS: One hundred and thirty eight patients were referred for ARS with a diagnosis of GERD based on symptoms, endoscopy, and/or barium esophagography. Barium esophagography, esophageal manometry, and ambulatory 24-h pH monitoring were performed preoperatively in every patient. RESULTS: Four patients were found to have achalasia and were excluded from the analysis. Based on the presence or absence of gastroesophageal reflux on pH monitoring, the remaining 134 patients were divided into two groups: GERD+ (n = 78, 58 %) and GERD- (n = 56, 42 %). The groups were compared with respect to the incidence of symptoms, presence of reflux and hiatal hernia on esophagogram, endoscopic findings, and esophageal motility. There was no difference in the incidence of symptoms between the two groups. Within the GERD+ group, 37 patients (47 %) had reflux at the esophagogram and 41 (53 %) had no reflux. Among the GERD- patients, 17 (30 %) had reflux and 39 (70 %) had no reflux. A hiatal hernia was present in 40 and 32 % of patients, respectively. Esophagitis was found at endoscopy in 16 % of GERD+ patients and in 20 % of GERD- patients. Esophageal manometry showed no difference in the pressure of the lower esophageal sphincter or quality of peristalsis between the two groups. CONCLUSIONS: The results of this study showed that (a) symptoms were unreliable in diagnosing GERD, (b) the presence of reflux or hiatal hernia on esophagogram did not correlate with reflux on pH monitoring, (c) esophagitis on endoscopy had low sensitivity and specificity, and (d) manometry was mostly useful for positioning the pH probe and rule out achalasia. Ambulatory 24-h pH monitoring should be routinely performed in the preoperative work-up of patients suspected of having GERD in order to avoid unnecessary ARS. PMID- 23090281 TI - The use of over the scope clip (OTSC) device for sleeve gastrectomy leak. PMID- 23090282 TI - Heterochromatin and gene positioning: inside, outside, any side? AB - All cellular processes depend on the expression and repression of the right sets of genes at the right time. As each cell contains the same DNA, transcriptional and epigenetic factors have to maintain tight control over gene expression. Even a small divergence from the correct transcriptional program can lead to severe defects and even death. Having deciphered the complete linear genetic information, we need to clarify how this information is organized into the dynamic and highly heterogeneous three-dimensional space of the eukaryotic cell nucleus. Observations on the higher order organization of DNA into differentiated condensation levels date back to the early twentieth century, and potential implications of these structural features to gene expression were postulated shortly after. In particular, proximity of genes to condensed regions of heterochromatin was proposed to negatively influence their expression and, henceforward, the concept of heterochromatin as subnuclear silencing compartment emerged. Methodological advances fueled a flurry of recent studies, which only, in part, led support to this concept. In this review, we address how (hetero)chromatin structure and proximity might influence gene expression and discuss the challenges and means to unravel this fundamental biological question. PMID- 23090283 TI - Paediatric chronic illness and educational failure: the role of emotional and behavioural problems. AB - BACKGROUND: Chronic illness in childhood is associated with worse educational outcomes. The association is usually explained via lowered cognitive development, decreased readiness to learn and school absence. However, this paper examines whether worse psychological adjustment may also play a role. METHODS: We use data from the Growing Up in Ireland study, a cohort study, which collected data on 8,568 nine-year-old children through the Irish national school system using a two stage sampling method. Maximum likelihood path analytic models are used to assess the direct effect of child chronic illness on reading and maths test scores and the mediating role of emotional and behavioural problems. RESULTS: In unadjusted analyses, children with a mental and behavioural condition scored 14.5 % points less on reading tests and 16.9 % points less on maths tests than their healthy peers. Children with non-mental and behavioural conditions scored 3 % points less on both tests, a significant difference. Mental and behavioural (OR, 9.58) and other chronic conditions (OR, 1.61) were significantly more likely to have 'high' levels of difficulties on the SDQ. Path analysis models showed that the association between chronic illness and educational test scores was completely mediated by emotional and behavioural problems controlling for school absence and bullying by peers. CONCLUSIONS: Child and adolescent chronic illness can have significant effects on educational development and a long-lasting impact on future life-chances. The psychological adjustment of the child is important in mediating the effect of chronic illness on educational outcomes. Interventions should target this developmental pathway. PMID- 23090284 TI - Describing the use of the internet for health, physical activity, and nutrition information in pregnant women. AB - The purpose of this study was to determine how pregnant women in the Midwestern United States use the internet for health information during pregnancy including information related to physical activity and nutrition, and to determine the impact of the internet on women's confidence in making decisions about physical activity participation and eating behaviors during pregnancy. This was a descriptive, exploratory study using a convenient, non-probabilistic sample. Women were recruited through handouts provided in person, fliers posted at venues, or local websites that cater to women who are pregnant or up to 1 year post-partum. Overall, 293 women (28.5 years +/- 4.9) completed the survey online (Survey Monkey) or in-print. Data were analyzed using descriptive statistics, paired t tests, and analyses of covariance. Almost all women used the internet for health information during their pregnancy. Half of women used the internet for information related to physical activity during their pregnancy and some increased their physical activity as a result. Women reported an increase in their confidence for making decisions related to physical activity during pregnancy after using the internet for physical activity information. Women that reported increases in physical activity during pregnancy, had greater increases in confidence for making decisions from using the internet compared to women who decreased or did not change their physical activity. Findings related to nutrition were similar to physical activity. However, there were no significant differences in increases in confidence between those who did or did not change the foods they ate. This study provides health promotional professionals useful information to consider when designing future physical activity and/or nutrition interventions for pregnant women. PMID- 23090285 TI - The influence of maternal smoking and exposure to residential ETS on pregnancy outcomes: a retrospective national study. AB - In a nationwide study of Serbian births, in 2008, we estimated the influence of maternal prenatal smoking and environmental tobacco smoke (ETS) exposure on birth outcomes. Using stratified two-stage random cluster sampling, 2,721 women were interviewed in-person (response rates 98.1 %), and 2,613 singleton live births were included. Date of birth, gender, birthweight, birth height and head circumference were copied from the official hospital Birth Certificate. Six exposure categories were defined according to mother's smoking history and exposure to ETS. We calculated adjusted mean values and group differences by analysis of covariance, and adjusted odds ratios for the low birthweight (LBW < 2,500 g). Compared to the reference category (non-smoking, non-exposed to ETS) we observed birthweight reductions in infants whose mothers smoked continuously during the pregnancy and were exposed to ETS (-162.6 g) and whose mothers were not exposed to ETS (-173 g) (p = 0.000, and p = 0.003, respectively), as well as reduction in birth length (-1.01 and -1.06 cm; p = 0.003 and p = 0.000, respectively). Reduction in birthweight and birth length related to exposure categories was not linear. Adjusted OR for LBW was almost tripled for mothers who smoked over the entire pregnancy and were non-exposed to ETS (aOR 2.85; 95 % CI 1.46-5.08), and who were exposed to ETS (aOR 2.68; 95 % CI 1.15-6.25). Our results showed strong effects of smoking throughout the pregnancy on reduced birthweight, birth length and head circumference, and increased risk for LBW. We were not able to detect an effect for ETS exposure alone. PMID- 23090286 TI - Utilization of agricultural biomass in the production of the biopolymer schizophyllan. AB - Schizophyllan is a homoglucan produced by the fungus Schizophyllum commune, with a beta-1,3-linked backbone and beta-1,6-linked side chains of single glucose units at every other residue. Schizophyllan is commercially produced for pharmaceutical and cosmetics uses. However, the unique physical properties of schizophyllan suggest that it may have biomaterials applications. Schizophyllan is conventionally produced by submerged culture fermentation using glucose as a carbon source. This study demonstrates for the first time the efficient utilization of agricultural biomass substrates, particularly distiller's dried grains with solubles, for schizophyllan production. Sugar composition analysis, NMR, and permethylation linkage analysis confirmed that the recovered product was schizophyllan. Schizophyllan produced from agricultural residues was of a high molecular weight and exhibited solution viscosity properties similar to those of commercially produced material. Utilization of biomass substrates could reduce the cost of schizophyllan production and provide a new value-added bioproduct for integrated biorefineries of the future. PMID- 23090287 TI - From well-defined Pt(II) surface species to the controlled growth of silica supported Pt nanoparticles. AB - Silica-supported Pt nanoparticles were prepared from well-defined surface platinum(II) surface species, obtained by grafting of well-defined Pt(II) molecular precursors with specific ligands (Cl, Me, N(SiMe(3))(2), OSi(OtBu)(3)) onto silica partially dehydroxylated at 200 and 700 degrees C yielding well defined platinum(II) surface species. This approach allowed for testing the effect of Pt density and ligands on nanoparticle size. Higher grafting densities are achieved on silica partially dehydroxylated at 200 degrees C due to its initially higher surface silanol density. Surface species have been synthesized from symmetrical and dissymmetrical complexes, namely (COD)Pt(Me)(2), (COD)Pt(OSi(OtBu)(3))(2), (COD)Pt(Me)(OSi(OtBu)(3)), (COD)Pt(Me)(N(SiMe(3))(2)), (COD)Pt(Cl)(N(SiMe(3))(2)) and (COD)Pt(N(SiMe(3))(2))(OSi(OtBu)(3)) yielding mono grafted complexes of general formula (COD)Pt(R)(OSi=) according to elemental analyses, diffuse reflectance infrared fourier transform (DRIFT) and carbon-13 solid-state nuclear magnetic resonance (NMR) spectroscopies. While the dimethyl complex shows low reactivity towards grafting, bis-siloxy and dissymmetric complexes demonstrate better reactivity yielding platinum loadings up to 7.4 wt%. Upon grafting amido complexes, the surface passivation yielding Me(3)SiOSi= surface species is demonstrated. Nanoparticles have been synthesized from these well-defined surface species by reduction under H(2) at 300 degrees C, under static or flow conditions. This process yields nanoparticles with sizes ranging from 2 to 3.3 nm and narrow size dispersion from 0.5 to 1.2 nm. Interestingly, the chloride complex yields large nanoparticles from 5 to 40 nm demonstrating the strong influence of chloride over the nanoparticles growth. PMID- 23090288 TI - Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer. AB - In the present study, we studied the expression of T-bet, a key marker for type 1 immune responses, within the tumor microenvironment of gastric cancer, and analyzed its association with clinicopathological parameters. One hundred and fifty-two archival paraffin-embedded gastric tumor tissues were collected, and the expression of T-bet in these cancer tissue specimens was examined by immunohistochemistry. T-bet(+) tumor-infiltrating lymphocytes (TILs) in some gastric cancer tissues were further characterized by flow cytometric analysis. The density of T-bet(+) TILs in gastric cancer tissues in relation to patient's clinicopathological parameters and postoperative prognosis has been analyzed. Herein, we have found significant increases in T-bet(+) lymphocytes in tumor tissues as compared with normal stomach tissues, gastritis tissues or gastric polyp specimens. T-bet(+) cells mainly consisted of CD4(+), CD8(+) and CD56(+) TILs. In addition, lower numbers of T-bet(+) TILs were associated with poor clinicopathological parameters such as invasion to muscular layer, larger tumor size and advanced cancer stages. Moreover, patients with higher numbers of T bet(+) TILs have longer disease-free survival and overall survival. Thus, our study supports the idea that tumor growth elicits spontaneous type 1 cellular immune responses and tumor progression is associated with suppression of antitumor immunity. T-bet expression within tumor can serve as a prognostic indicator for gastric cancer and a potential biomarker for immunotherapy. PMID- 23090289 TI - Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance. AB - Expression of monocyte chemoattractant protein-1 (MCP-1) and CC chemokine receptor 2 (CCR2) and its significance has been demonstrated in some cancer cells in recent clinical studies. However, the role of tumor MCP-1 and CCR2 expression in non-small cell lung cancer (NSCLC) remains unknown. The aim of the present study was to investigate the prognostic significance of MCP-1 and CCR2 expression in NSCLC cells. The relationship between MCP-1 and CCR2 expression in NSCLC cancer cells was examined by immunohistochemical staining of surgical specimens from 134 patients. Sixty-five of these patients had follow-up records. Kaplan Meier analysis and Cox regression model were used to assess overall survival according to the presence or absence of MCP-1 and CCR2 expression in tumor cells. MCP-1 was detected in cancer cells of 107 NSCLC (79.9 %) and CCR2 was detected in cancer cells of 39 NSCLC (29.1 %). MCP-1 expression was correlated with sex, smoking habits, histology, and tumor size. Presence of MCP-1 in tumor cells was associated with better overall survival (P = 0.018). By multivariate analysis, MCP-1 expression in cancer cells showed an independent prognostic factor for overall survival (P = 0.002, hazard ratio [HR] = 0.256, 95 % confidence interval [CI] = 0.106-0.616). There was no significant relationship between CCR2 expression in tumor cells and clinical and pathological characteristics. Also, no significant positive correlation between MCP-1 and CCR2 expression was revealed by Spearman correlation analysis. Our data indicate that MCP-1 is overexpressed in NSCLC cells. Its expression in cancer cells is associated with better survival in NSCLC patients. PMID- 23090290 TI - Clinical safety and pharmacological profile of the HLA-DR antibody 1D09C3 in patients with B cell chronic lymphocytic leukemia and lymphoma: results from a phase I study. AB - 1D09C3 is a human monoclonal IgG4-type antibody against human leukocyte antigen DR (HLA-DR) which has demonstrated pro-apoptotic activity against lymphoid tumors in vitro and in vivo. We report results from a phase I dose-escalation study which aimed to identify tolerated dosing, and the pharmacokinetic and pharmacodynamic profile of 1D09C3. Fourteen patients with relapsed/refractory B cell type leukemia/lymphoma were treated and followed after up to 4 weekly infusions of 1D09C3, administered in 6 dose levels at 0.25-8 mg/kg/day. Treatment was tolerated well with mostly mild side effects. The most common grade III-IV toxicities were hematological events observed in 4 patients. In one patient, treated at 8.0 mg/kg/day, a dose limiting toxicity occurred, identified as an invasive catheter-related infection. Adverse events resolved completely without long-term sequelae. 1D09C3 reduced peripheral blood B cells and monocytes by a median of 73-81 % in all patients, with a nadir reached 30-60 min after infusion and sustained for <96 h. Granulocytes and natural killer cells predominantly increased with variable time courses. Pharmacokinetic assessments showed detectable drug concentrations at doses 4-8 mg/kg/day and a terminal half-life of 0.7-7.9 h. Effective saturation of HLA-DR on peripheral blood B cells/monocytes was achieved, varying consistently with available serum concentrations and the cell-reducing activity of 1D09C3. In summary, 1D09C3 could be administered safely in patients with advanced B cell malignancies. Pharmacodynamic studies demonstrated a strong dose dependent but transient reduction of peripheral blood B cells and monocytes, consistent with a short drug serum availability. PMID- 23090291 TI - Chirality transfer based on reversible C-C bond formation/breaking in nickel(II) complexes. AB - The reaction of (1R)-(-)-myrtenal-derived benzothiazoline with nickel(II) acetate in ethanol exclusively gave a Schiff base-type nickel(II) complex having M helical configurational myrtenyl arms, which is reversibly converted to a non innocent-type complex having additional S,S configurational asymmetric carbon centres. PMID- 23090292 TI - The influence of exogenous carbohydrate provision and pre-exercise alkalosis on the heat shock protein response to prolonged interval cycling. AB - The aim of this study was to observe the intracellular heat shock protein 72 (HSP72) and heme oxygenase-1 (HSP32) response to prolonged interval cycling following the ingestion of carbohydrates (CHO) and sodium bicarbonate (NaHCO(3)). Six recreationally active males (mean +/- SD; age 23.2 +/- 2.9 years, height 179.5 +/- 5.5 cm, body mass 76.5 +/- 6.8 kg, and peak power output 315 +/- 36 W) volunteered to complete a 90 min interval cycling exercise on four occasions. The trials were completed in a random and blinded manner following ingestion of either: placebo and an artificial sweetener (P-P), NaHCO(3) and sweetener (B-P), placebo and CHO (P-CHO), and NaHCO(3) and CHO (B-CHO). Both HSP72 and HSP32 were significantly increased in monocytes and lymphocytes from 45 min post-exercise (p <= 0.039), with strong relationships between both cell types (HSP72, r = 0.83; HSP32, r = 0.89). Exogenous CHO had no influence on either HSP72 or HSP32, but the ingestion of NaHCO(3) significantly attenuated HSP32 in monocytes and lymphocytes (p <= 0.042). In conclusion, the intracellular stress protein response to 90 min interval exercise is closely related in monocytes and lymphocytes, and HSP32 appears to be attenuated with a pre-exercise alkalosis. PMID- 23090293 TI - Synthesis, characterization, conformational analysis of a cyclic conjugated octreotate peptide and biological evaluation of (99m)Tc-HYNIC-His(3)-Octreotate as novel tracer for the imaging of somatostatin receptor-positive tumors. AB - Peptides are attracting increasing interest in nuclear oncology for targeted tumor diagnosis and therapy. We therefore synthesized new cyclic octapeptides conjugated with HYNIC by Fmoc solid-phase peptide synthesis. These were purified and analyzed by RP-HPLC, MALDI mass, (1)H NMR, (13)C NMR, HSQC, HMBC, COSY and IR spectroscopy. Conformational analysis of the peptides was performed by circular dichroism spectroscopy, in pure water and trifluoroethanol-water (1:1), revealed the presence of strong secondary structural features like beta-sheet and random coils. Labeling was performed with (99m)Tc using Tricine and EDDA as coligands by SnCl(2) method to get products with excellent radiochemical purity >99.5 %. Metabolic stability analysis did not show any evidence of breaking of the labeled compounds and formation of free (99m)Tc. Internalization studies were done and IC(50) values were determined in somatostatin receptor-expressing C6 glioma cell line and rat brain cortex membrane, and the results compared with HYNIC-TOC as standard. The IC(50) values of (99m)Tc-HYNIC-His(3)-Octreotate (21 +/- 0.93 nM) and (99m)Tc-HYNIC-TOC (2.87 +/- 0.41 nM) proved to be comparable. Biodistribution and image study on normal rat under gamma camera showed very high uptake in kidney and urine, indicating kidney as primary organ for metabolism and route of excretion. Biodistribution and image study on rats bearing C6 glioma tumor found high uptake in tumor (1.27 +/- 0.15) and pancreas (1.71 +/- 0.03). Using these findings, new derivatives can be prepared to develop (99m)Tc radiopharmaceuticals for imaging somatostatin receptor-positive tumors. PMID- 23090294 TI - [Repeated pregnancy among adolescents and negative outcomes of the newborn: study in the city of Rio de Janeiro]. AB - The aim of the study was to evaluate the prevalence of repeated pregnancy among adolescents and identify associated factors and perinatal outcomes. A sample of 1,986 post-partum adolescents was selected from public hospitals in the city of Rio de Janeiro, Brazil. To verify the hypothesis of homogeneity of proportions, chi-square tests (chi2) were used. Odds ratios and correspondent confidence intervals were estimated. Logistic regression procedures were used. A repeated pregnancy prevalence of 31.4% was identified and the principal associated factors were: maternal age 15-19 years; paternal age >19 years; early menarche; black or brown maternal skin color; schooling < 5 years; living with partner during pregnancy. Perinatal death was significantly higher in the adolescent mothers group with repeated pregnancy. The results showed that the most disadvantaged socioeconomic conditions were found among adolescent mothers with repeated pregnancy in comparison to mothers on their first pregnancy. The findings sustain the relevance of social policies for adolescent mothers with repeated pregnancy. PMID- 23090295 TI - [Surveillance of adverse drug events in hospitals: implementation and performance of triggers]. AB - Adverse drug events (ADE) are important causes of impairment of the quality of care for inpatients and therefore should be identified and characterized. Thus, lists of triggers were developed, including the proposal by the Institute for Healthcare Improvement. We analyzed the application of these triggers in a university hospital, with the cooperation of pharmacy and medical students, field training, standardized forms and manuals. Here, we present the process of application and performance of these triggers in a teaching hospital. The information on the triggers and ADE were collected through a retrospective chart review of patients discharged from January to June 2008. Four hundred and ninety seven triggers were identified in 177 charts, and each chart had 2.33 (SD = 2.7) triggers on average. The most frequent triggers were: "antiemetic" (72.1/100 charts), "abrupt cessation of medication" (70.0/100 charts) and "over-sedation, drowsiness, numbness, lethargy, hypotension and fall" (34.6/100 charts). The most effective triggers for capturing ADE were "benzodiazepine antagonist", "antidiarrheal" and "rash", which, when identified in charts, were related to an event. The ADE most commonly found were related to the triggers, "abrupt cessation of medication" (8.3/100 charts), "antiemetic" (4.6/100 charts), "rash" and "anti-allergy" (2.1/100 charts). These results may help to decide which triggers are more useful in each situation. PMID- 23090296 TI - Mortality information system for identifying underreported cases of tuberculosis in Brazil. AB - The aim of the study was to analyze the underreporting of deaths from tuberculosis (TB) in Brazil, as well as to assess the impact these cases would cause in the reporting rate and proportion of TB deaths in 2006. We analyzed the deaths recorded in the Mortality Information System (SIM) in 2006 and all reports of TB in Brazil during the 2001 to 2006 period. The variables used for the relationship were: report number, city and State of residence, patient name, date and year of birth, sex, mother's name and address. Six blocking steps were performed. Scores above 12.4 were considered pairs, and those below 9.7, doubtful pairs. After each step, we performed a manual review of doubtful pairs. The Reportable Disease Information System (Sinan) had 547,589 records. The SIM had 6,924 records, 39.3% (n = 2,727) of which were not found in Sinan during the period evaluated. We observed that 64.5% (2,707) of deaths were reported in 2006 and after analyzing the proportion of deaths underreported by region and federal units, we found that the highest percentage was in the Northern region, followed by the Southeast and Northeast. The addition of deaths that had not been reported to the Sinan database increased the reporting rate 3.7%. Regarding the proportion of deaths due to TB, such inclusion was responsible for a 60.7% increase in this indicator. The relationship between both databases seems to be an important strategy for improving the quality of the TB surveillance system. PMID- 23090297 TI - [Vertical transmission of HIV, syphilis and hepatitis B in the municipality with the highest incidence of AIDS in Brazil: a population-based study from 2002 to 2007]. AB - OBJECTIVE: The objective of this study was to verify the prevalence and vertical transmission rate of HIV, syphilis and hepatitis B in pregnant women in the municipality of Itajai, state of Santa Catarina, Brazil, during the 2002-2007 period. METHODS: Data were collected in a retrospective population-based longitudinal study using computerized medical records of the state and local health authorities during the 2002-2007 period for HIV, and 2004-2007 for syphilis and hepatitis B. RESULTS: The prevalence of HIV, acute hepatitis B, chronic hepatitis B and syphilis in pregnant women was 1.7%, 0.41%, 0.46%, and 0.43%, respectively. Overall, vertical transmission of HIV was 6.28%, although it was less than 5% among women diagnosed with HIV before or during pregnancy, compared to 20% and 55% among women first diagnosed with HIV during and after delivery, respectively. Vertical transmission of syphilis was 68.89%. No trend was confirmed for the transmission rate either regarding the year of diagnosis or age group of pregnant women. Almost 44% of HIV infected pregnant women knew their HIV status before becoming pregnant; the HIV transmission rate for these women was less than 5%. No case of vertical transmission was observed for hepatitis B. CONCLUSIONS: The vertical transmission rate for HIV was within the target of the Ministry of Health when HIV diagnosis was made during pregnancy, but increased sharply when the diagnosis was made only at delivery. Vertical transmission of syphilis was much higher than expected, showing the importance of reinforcing the procedures recommended for its reduction. PMID- 23090298 TI - [Plasmodium vivax malaria recurrence according to the use of primaquine: analysis of longitudinal descriptive studies]. AB - BACKGROUND: primaquine (PQ) is the only drug available in the market to prevent Plasmodium vivax malaria recurrence, but several aspects are still unknown. OBJECTIVE: To compare PQ regimens to prevent recurrence of vivax malaria. METHODS: systematic review and meta-analysis of data. RESULTS: 1. According to descriptive studies, is PQ effective in preventing recurrence of vivax malaria? Yes. The comparison of studies that did not use PQ to others that did, using any regimen, showed that if PQ is not used, recurrence is highly likely. 2. Are equal daily doses effective (mg/kg) but total doses different? The total dose of 75 mg is equally or more effective than 210 mg. 3. Does the efficacy depend on where the infection happens? Yes. There is variation by country and region. 4. Does the recurrence rate depend on the post-treatment time follow-up? The answer is not uniform everywhere. CONCLUSIONS: Although not 100%, PQ is effective in preventing recurrence. Total doses of 210 and 75 mg are equally effective, but 75 mg alone has been evaluated in India, where P. vivax seems to respond better to PQ than elsewhere. The effect of place in the proportion of recurrences seems evident, even using the same total dose. The role of follow-up time is not clear. Although the standard regimen has an average effectiveness of 90% or more, alternative regimens should be assessed. PMID- 23090299 TI - Patterns of heroin use in a sample of consumers in Medellin--Colombia. AB - INTRODUCTION: In Colombia, there are no specific studies on the prevalence of heroin use. This paper reviews the patterns of substance use in a consumer group in the city of Medellin and its metropolitan area, showing that consumption is becoming a threat to public health due to the particular forms of consumption, among which risk practices are included. OBJECTIVE: To evaluate the use of heroin in the city of Medellin and its metropolitan area. METHODS: The study took a mixed approach using multiple-case study to cover each of the variables and categories proposed; 42 heroin users of treatment centers in the city of Medellin and its metropolitan area were accessed between July and September 2008, using the "snowball", technique. Information was collected by a structured, face to face interview, asking about the type of heroin consumed, routes of administration, frequency of consumption, equipment used, consumption practices and rituals that accompany these practices. Quantitative data were analyzed using the EPI-Info statistical package 2,000 and Atlas ti qualitative, version 5.5, for Windows. RESULTS: Consumers were predominantly male, single, aged between 18 and 23 years, childless and many had not completed college. Most respondents were in the middle socioeconomic stratum, had a family history of psychoactive substance use and had started heroin use between 15 and 17 years. There are special forms to name heroine, consumers, and rituals to consume the substance. The article gives details of the heroin consumed, the paraphernalia and associated practices. CONCLUSIONS: The use of heroin is an emerging reality in Colombia. Qualitative quantitative studies are necessary to allow us to acknowledge and understand more about this phenomenon in order to decrease the impact on public health. PMID- 23090300 TI - Assessment of surgical adverse events in Rio de Janeiro hospitals. AB - A study on surgical adverse events (AE) is relevant because of the frequency of these events, because they are in part attributable to deficiencies in health care, because of their considerable impact on patient health and economic consequences on social and health expenditures, and because this study is an assessment tool for quality of care. We aimed to evaluate the incidence and the contributive factors of surgical AE in hospitals of Rio de Janeiro. This retrospective cohort study aimed to perform a descriptive analysis of secondary data obtained from the Adverse Events Computer Program, which was developed for collecting data for the assessment of AE in three teaching hospitals in the state of Rio de Janeiro. Incidence of patients with surgical AE was 3.5% (38 of 1,103 patients) (95% CI 2.4 - 4.4) and the proportion of patients submitted to surgery among patients with surgical AE was 5.9% (38 of 643) (95% CI 4.1 - 7.6). The proportion of avoidable surgical AE was 68.3% (28 of 41 events) and the proportion of patients with avoidable surgical AE was 65.8% (25 of 38 patients). One in five patients with surgical AE had a permanent disability or died. Over 60% of the cases were classified as not complex or of low complexity, and with low risk for care-related AE. PMID- 23090301 TI - Social capital at work: psychometric analysis of a short scale in Spanish among Mexican health workers. AB - Most studies on social capital and health are carried out with large home-based surveys, neglecting that many interactions among individuals occur in the workplace. The objective of this study was to explore the psychometric properties of a scale in Spanish used to measure social capital at work. The scale designed by Kouvonen et al was translated into Spanish and tested under classical test theory, item response theory, and confirmatory factorial analysis; 152 public health workers from different socio-cultural contexts participated in the survey. Internal consistency was high (Chronbach's alpha = 0.88). Social capital at work correlated properly with two Job Content Questionnaire dimensions. A ceiling effect was detected and item difficulty was quantified. The confirmatory factor analysis showed the expected theoretical components of social capital: bonding, bridging and trust. The scale has acceptable psychometric properties, thus it can be used in future studies. PMID- 23090302 TI - [Does orphanhood by aids or by homicide effect nutritional status of children?]. AB - The aims of this paper were to evaluate the nutritional status of children orphaned by aids or homicides in the city of Sao Paulo and to estimate the association of nutritional indexes with orphanhood-related variables. The study was a household survey carried out between 2006 and 2007. We sampled 484 children representative of Sao Paulo, 5-14 years old who lost either or both of their parents from aids or homicides between 2000 and 2004. We selected body-mass-index for-age (BMI) and height-for-age (height) as outcomes for analysis. Multiple linear regression in the light of a conceptual hierarchical approach was used for estimating BMI-for-age and height-for-age associated factors. Children from aids and homicides groups differed in terms of orphanhood-related variables and age. Economic, household, health and nutritional conditions were similar between groups. Underweight accounted for 1.3% and 2.1% of children under the age of 10 and adolescents, respectively. Stunting accounted for 0.7% and 4.0% of children and adolescents, respectively. Overweight accounted for 19% and 20% of children and adolescents, respectively. BMI and height were unaffected by orphanhood related variables after adjusting for selected classical determinants of nutritional status in the hierarchical model. Economic status was the main determinant of the nutritional profile. Nutritional status of children orphaned by aids or homicides in Sao Paulo was similar and mainly influenced by economic status. The nutritional profile, characterized by being overweight, suggests that these orphans have not shown additional risks due to those orphanhood-related variables. PMID- 23090303 TI - Association between housework overload and common mental disorders in women. AB - INTRODUCTION: Common mental disorders (CMD) are more frequent in women. Low reward and lack of visibility in performing housework are the determining factors for these psychological illnesses. OBJECTIVES: To evaluate the association between housework overload and the occurrence of common mental disorders in women living in the urban zone of the municipality of Feira de Santana, Bahia. METHODS: cross-sectional epidemiological study that included 2,057 women aged 15 years or over selected by random sampling in clusters. The housework overload indicator was created from the domestic activities of washing, ironing, cleaning and cooking, weighted according to the number of individuals living in the home. The common mental disorders were assessed using SRQ-20. RESULTS: Women with a high housework overload had a higher prevalence of CMD than women with a low overload (45.6% versus 36.2%). Multiple logistic regression analysis confirmed the association between housework overload and CMD (PR: 1.23; 95% CI: 1.05 - 1.44), adjusted for income, level of schooling and leisure activities. CONCLUSION: The findings support the hypothesis that high housework overload is associated with mental disorders. PMID- 23090304 TI - Clinical and laboratory characteristics in the retreatment of leprosy relapse. AB - OBJECTIVE: To compare clinical and laboratory data of leprosy patients diagnosed in specialized services in the State of Mato Grosso, Brazil, during the initial treatment and the retreatment of relapse. METHODS: A cross-sectional study of patients with diagnosis of leprosy relapse was conducted in specialized health services of five cities, between 2005 and 2007. Initial treatment was described as t1 and relapse treatment as t2. DATA SOURCE: Sistema de Informacao de Agravos de Notificacao (Sinan - Reportable Diseases Information System), medical records, laboratory tests, and files of individual reports and of physical disability assessments. The chi-square test (c2) was applied at a significance level of 5%. RESULTS: The clinical dimorphic form prevailed in t2 when compared with t1 (39.6% versus 11.3%; p = 0.003); 20.8% of relapse cases showed a bacilloscopy index >= 4+ in relation to those in t1 (p = 0.034)]; an increase in the number of (17%) cases of relapse with physical disability at level 0 was found, compared to patients evaluated during the diagnosis (58.5% versus 41.5%); an increase (7.5%) in the recurrence of disabilities at level 2 was observed, when compared to t1 (9.4% versus a 9%); and there was a higher prevalence of cases not evaluated for disability between t1 (45.3%) and t2 (22.6%) (p = 0.040). CONCLUSION: Cases of relapse characterized the aggravation of the disease, indicated by the increase in the bacilloscopy index and level of physical disability. Attention should be paid to the diagnostic confirmation of relapse using bacilloscopy tests, especially in multibacillary cases, and systematic neurological assessment of all leprosy patients. PMID- 23090305 TI - Prevalence and associated factors with alcohol use disorders among adults: a population-based study in southern Brazil. AB - OBJECTIVES: The study aimed to describe the prevalence of alcohol use disorders in an adult population from Brazil and its association with demographic, socioeconomic, behavioral variables and health conditions. METHODS: A population based cross-sectional survey was conducted with adults (20 to 59 years) of a medium-sized city in Southern Brazil with a random sample of 1,720 individuals. Cluster sampling was done in two stages: census tract first and household second. Alcohol use disorders were measured using the Alcohol Use Disorders Identification Test (AUDIT) and associations were tested with selected variables by Poisson Regression. Results of multivariate analysis were expressed as prevalence ratios. RESULTS: The prevalence of alcohol use disorders in the population was 18.4% (95% CI: 16.6% - 20.3%), higher among men (29.9%) than in women (9.3%). The prevalence of abstinence was 30.6%; 6.8% of respondents had already caused problems to themselves or to others after drinking; and 10.3% reported that a relative, friend or doctor had already shown concern on their drinking. After multivariate analysis, an association with alcohol use disorders remained for: being male, age 20 to 29 years, being single, declaring to be light skinned blacks and being an ex-smoker or current smoker. CONCLUSION: The prevalence of alcohol use disorders identified is high compared with other similar studies, with differences according to being male, age 20 to 29, skin color and tobacco use. These issues must be considered in formulating public health policies aimed at reducing problems related to alcohol use. PMID- 23090306 TI - Characteristics of women with breast cancer seen at reference services in the North of Minas Gerais. AB - OBJECTIVE: To describe the main characteristics, including stage of disease and local treatment of patients admitted to two reference services for the treatment of breast cancer in the North of Minas Gerais. METHODS: We conducted a cross sectional descriptive study. We evaluated medical records of 288 female patients with breast cancer admitted between January 2006 and December 2009, referred from a public hospital and a private clinic. Variables were analyzed using the chi square test and multinomial logistic regression. RESULTS: 68.1% of patients were referred from the public hospital. There was a predominance of patients over 50 years old (54.5%), married (59%) and with children (87.8%). The mean age of the population studied was 63 years old. Time between suspected cancer and confirmation of diagnosis was over six months in 42.7% of patients. Cancer diagnosis was late (stage III and IV) in 47.6% of patients. Family history of breast cancer was present in 20.1%, 20.8% of them had performed self-breast examination, and 41% had been submitted to a mammogram. CONCLUSION: There was a higher prevalence of stage III/IV patients from the public service when compared to the private sector. We found that the major factors associated with the late diagnosis of breast cancer were the delay between suspected and confirmed diagnosis, the absence of family history of breast cancer and not having a mammogram. PMID- 23090307 TI - Diet quality among adolescents: a population-based study in Campinas, Brazil. AB - We assessed the overall diet quality and adequacy of diet consumption of each component of the diet of adolescents according to demographic, socioeconomic and body mass index (BMI) data. A cross-sectional population-based study analyzed a representative sample of 409 adolescents, aged 12-19 years, using the Healthy Eating Index (HEI). We estimated the prevalence of diets classified in the first quartile of the HEI and the average scores of each component of the HEI. Linear and Poisson multiple regressions were used in the analysis. The mean score of HEI was 59.7. We observed a lower prevalence of inadequate diets in the segment with heads of household presenting higher schooling. The lower socioeconomic status segments, measured by income and schooling, showed a lower consumption of vegetables, fruits, dairy products and a less diversified diet, and a higher intake of cereals and legumes. Overweight/obese adolescents consume more meat and eggs and less fruit compared to low weight/normal weight adolescents. Girls had a higher intake of total fat and lower sodium intake. The results identified diet components that deserve more attention in the strategies to promote healthy eating, and the more vulnerable segments among adolescents. PMID- 23090308 TI - Magnitude and trend of American Tegumentary Leishmaniasis in the State of Sao Paulo, Brazil, 1975 to 2008. AB - The aim of this study was to analyze the magnitude and trend of American Tegumentary Leishmaniasis (ATL) in the State of Sao Paulo from 1975 to 2008. An ecological study that classified municipalities according to the magnitude of transmission was performed. From 1975 to 1985, 1,281 cases of ATL were registered in 45 municipalities, rising to 258 municipalities and 4,093 cases from 1986 to 1995; and reaching 385 municipalities and 7,604 cases from 1996 to 2008. Lutzomyia intermedia s.l. was collected in most of the entomological surveys. In the classification of municipalities according to magnitude, 67.5% were observed to have a "small magnitude," 19.2% "moderate magnitude" and 13.3% "high magnitude." The highest incidences of ATL have been restricted to underserved areas close to the Atlantic forest. There was an increase in the number of municipalities with small occurrence of cases and expansion in the area of risk. PMID- 23090309 TI - Prevalence of hepatitis C in adult users of the public health service of Sao Jose dos Pinhais--Parana. AB - OBJECTIVES: We aimed to investigate the prevalence of Hepatitis C in adult users of the Public Health Services of Sao Jose dos Pinhais - Parana. METHODS: We performed an epidemiological survey with a probabilistic sample of 5,017 volunteers who answered a questionnaire and were submitted to an anti-HCV quick test. Data were organized using Epi-info 3.5.1. The association between the presence of the disease and the factors of interest in the study were evaluated by the Chi-square test. We used a Logistic Regression Adjusted Model for risk factor analysis and the Wald test for decision making on the importance of the risk factors. RESULTS: The absolute frequency of positive anti-HCV was 13, with a prevalence of 0.30%, (IC = 0.12% - 0.40%). A higher probability of the disease was reported in males (p = 0.008) and in single, separated and widowed subjects (p = 0.045); in subjects with prior HCV symptoms (p < 0.001) and a previous blood transfusion (p < 0.001); and with the presence of a tattoo (p = 0.033). Drug abuse, blood transfusion and age > 40 years increased the risk for disease, regardless of sex, age and marital status. CONCLUSION: We found a low prevalence of Hepatitis C, albeit expected for Southern Brazil. Our results did not differ from other studies as to contamination risks. The study may contribute to highlight the importance of Hepatitis C, the need to implement strategies to cope with it, and stimulate better understanding of Hepatitis C. PMID- 23090310 TI - Monitoring of risk and protective factors for chronic non communicable diseases by telephone survey in Brazilian State Capitals, 2008. AB - OBJECTIVE: To estimate the prevalence of protective and risk factors for the most important chronic non communicable diseases in all Brazilian capitals, including the Federal District. METHODS: Data used were collected in 2008 through VIGITEL, an ongoing population-based telephone survey surveillance system implemented in all Brazilian State capitals since 2006. In 2008, over 54,000 interviews were completed over the phone with a random sample of individuals living in all 27 capitals. RESULTS: The analyses showed differences in the prevalence of determinants of chronic diseases by demographic characteristics such as gender, age and schooling. Men were more likely to be current smokers, overweight, and consumers of soft drinks, fatty meat and alcohol. They were also more likely to be more active in leisure. Women reported being more likely to eat healthy, but also were more likely to have a physician diagnosis of high blood pressure, dyslipidemia, osteoporosis and overall poor health status. In general, the prevalence of risk factors studied increased with decreasing levels of schooling. DISCUSSION: The VIGITEL system was implemented to monitor changes in the prevalence of determinants of chronic diseases over time to inform public health workers and decision makers to adjust existing programs and policies according to the changing profile of consumers. The ultimate goal is to improve the health of the Brazilian population. PMID- 23090311 TI - Factors associated with nutritional status of 7-10 year-old schoolchildren: sociodemographic variables, dietary and parental nutritional status. AB - OBJECTIVE: To estimate the prevalence of overweight / obesity in schoolchildren, and to investigate its association with parents' nutritional status, socioeconomic factors and food consumption. METHODS: Cross-sectional study with 1,223 schoolchildren, 7 to 10 years old from Florianopolis, SC. We collected anthropometric measures directly and dietary intake of previous day; parents' data were collected from a socioeconomic and self-reported anthropometric questionnaire. Schoolchildren's nutritional status was defined using the Body Mass Index (BMI) for age and sex according to the reference data of the World Health Organization (2007), and parents' nutritional status was defined according to the World Health Organization BMI cutoff points (1995). We performed bivariate and multivariate analysis using Poisson regression. RESULTS: Prevalence of overweight/obesity was 36.2% in boys and 32.7% among girls. The prevalence was 56.3% and 27.5% in fathers and mothers, respectively. In the final model, mother's (p = 0.001) and father's nutritional status (p = 0.050) remained directly associated with schoolchildren's overweight/obesity. The prevalence of overweight/obesity was 1.58 times higher in schoolchildren with overweight/obese mothers, and 1.41 times higher in schoolchildren with overweight/obese fathers, compared to mothers and fathers without the condition. CONCLUSION: There was a high prevalence of overweight/obesity among schoolchildren, which was associated with the nutritional status of mothers and fathers. These results confirm the need to prevent overweight/obesity in schoolchildren with actions that also involve the family environment in order to reduce obesity in this population. PMID- 23090312 TI - Factors associated with dietary patterns in adolescents: a school-based study in Cuiaba, Mato Grosso. AB - OBJECTIVE: To identify dietary patterns among adolescents and to assess their association with socioeconomic and lifestyle characteristics and nutritional status. METHODS: A probabilistic clustered two-stage sample of students between 14 and 19 years old from public and private high schools from Cuiaba, Mato Grosso, Brazil, was investigated (n = 1.139). A self-administered food frequency questionnaire was used to obtain information on food intake. Nutritional status was classified according to the Body Mass Index (BMI = weight/height2) z-score. Socioeconomic status was inferred by the education level of head of household and by the presence of electrical appliances in the household. Dietary patterns were identified by applying exploratory factor analysis (extraction method: principal component analysis) and their relationship with socioeconomic conditions, lifestyle variables, and nutritional status was estimated by mutually adjusted multilinear regression models. RESULTS: "Western", "traditional" and "mixed" dietary patterns were identified. Studying in the morning hours and reporting the intake of alcoholic beverages were associated with greater adherence to the "Western" pattern. Male low-income students from public schools who have a BMI in the normal range preferred the "traditional" pattern. The "mixed" pattern was adopted by boys from public schools reporting physical activity. CONCLUSION: Several factors were associated with dietary patterns of adolescents and the Brazilian traditional diet was associated with normal weight. PMID- 23090313 TI - Prevalence and risk factors of anemia in children attending daycare centers in Belo Horizonte--MG. AB - OBJECTIVE: To evaluate the prevalence and risk factors of anemia in children attending daycare centers in the city of Belo Horizonte. METHODS: Cross-sectional study that evaluated 312 children aged 7 to 59 months attending daycare centers of the East Sanitary District of Belo Horizonte. The diagnosis of anemia was determined by finger stick blood samples, using the HemocueTM portable photometer, considering hemoglobin levels below 11.0 g/dL. Weight and height were measured and nutritional status of children was classified according to WHO 2006 criteria. Variables were collected through a questionnaire answered by children's parents or guardians, containing socioeconomic aspects, in addition to information on maternal and children's health. Multiple logistic regression was performed to assess the association between variables and anemia, with control for confounding variables. RESULTS: The prevalence of anemia in the population studied was 30.8%, with a higher prevalence in children <= 24 months of age (71.1%). Risk factors for anemia were age <= 24 months (OR: 9.08 CI: 3.96 to 20.83), and height-for-age < -1 z-score (OR: 2.1, CI: 1.20 to 3.62). CONCLUSIONS: The high prevalence of anemia in children attending day care centers in Belo Horizonte, especially those younger than 24 months and in children with height for-age < - 1 z-score, demonstrates the importance of nutritional care to infants and strengthens the need for commitment of child care institutions in reducing this deficiency. PMID- 23090314 TI - [Education and its relationship with income and health: a reflection on inequality in Chile]. PMID- 23090315 TI - DNA translocating through a carbon nanotube can increase ionic current. AB - Translocation of DNA through a narrow, single-walled carbon nanotube can be accompanied by large increases in ion current, recently observed in contrast to the ion current blockade. We use molecular dynamics simulations to show that large electro-osmotic flow can be turned into a large net current via ion selective filtering by a DNA molecule inside the carbon nanotube. PMID- 23090316 TI - Measuring the dynamics of E. coli ribosome biogenesis using pulse-labeling and quantitative mass spectrometry. AB - The ribosome is an essential organelle responsible for cellular protein synthesis. Until recently, the study of ribosome assembly has been largely limited to in vitro assays, with few attempts to reconcile these results with the more complex ribosome biogenesis process inside the living cell. Here, we characterize the ribosome synthesis and assembly pathway for each of the E. coli ribosomal protein (r-protein) in vivo using a stable isotope pulse-labeling timecourse. Isotope incorporation into assembled ribosomes was measured by quantitative mass spectrometry (qMS) and fit using steady-state flux models. Most r-proteins exhibit precursor pools ranging in size from 0% to 7% of completed ribosomes, and the sizes of these individual r-protein pools correlate well with the order of r-protein binding in vitro. Additionally, we observe anomalously large precursor pools for specific r-proteins with known extra-ribosomal functions, as well as three r-proteins that apparently turnover during steady state growth. Taken together, this highly precise, time-dependent proteomic qMS approach should prove useful in future studies of ribosome biogenesis and could be easily extended to explore other complex biological processes in a cellular context. PMID- 23090317 TI - Postmenopausal effects of resistance training on muscle damage and mitochondria. AB - The purpose of this study was to measure the effects of a 12-month progressive resistance training intervention on muscle morphology and strength gains in postmenopausal women. Skeletal muscle biopsies were obtained from the vastus lateralis of 5 independent community-dwelling women (mean age: 75.6 +/- 4.28 years; mean height: 163 +/- 5.34 cm; mean weight: 72 +/- 17.5 kg) before 6 months and 12 months after progressive resistance training. Muscle strength (1 repetition maximum) was measured at the same time points. After 6 months of training, morphological analysis revealed evidence of increased proteolysis and tissue repair, and rudimentary fiber development. The percent of Z-bands with mild Z-band disruption increased from 43.9% at baseline to 66.7% after 6 months of training (p < 0.01). Mitochondrial volume also increased (percent of mitochondria = 0.86% at baseline, 1.19% at 6 months, and 1.04% at 12 months, p < 0.05), and there was a shift to larger sized mitochondria. The training did not result in statistically significant increases in muscle leg strength (p < 0.18). It appears that mild Z-band disruption acts as a precursor for increased protein synthesis and stimulates an increase in mitochondrial mass. Therefore, although a progressive resistance training program in this population did not increase muscle strength, it did demonstrate clinical applications that lend support to the importance of resistance training in older adults. PMID- 23090318 TI - The effects of a doublet stimulus and force level on the electromechanical delay. AB - The purpose of this study was to examine the effects of a doublet stimulus evoked during isometric submaximal contractions on the electromechanical delay (EMD). Twenty-three healthy individuals performed isometric step contractions ranging from 10 to 70% maximal voluntary contraction (MVC) with a doublet stimulus applied during the contractions. A 2-way repeated-measures analysis of variance (gender [male vs. female] * contraction intensity [10% vs. 20% vs. 30% vs. 40% vs. 50% vs. 60% vs. 70% MVC]) was used to analyze the EMD. The EMD at 10% was significantly less than at 30% (p = 0.022), 40% (p = 0.044), 50% (p = 0.012), 60% (p = 0.041), and 70% MVC (p < 0.001). In addition, the EMD at 70% MVC was significantly higher than at 20% (p = 0.002), 30% (p = 0.006), 40% (p = 0.009), and 50% MVC (p = 0.021). The EMD is the time difference between muscle activation and the onset of muscle force production, with the stretching of the series elastic component (SEC) as the major contributor. A doublet stimulus applied during an isometric contraction minimizes the effects of the SEC during the interpolated twitch technique. Therefore, when the SEC is minimized, the EMD may be lengthened because of mechanisms associated with the excitation-contraction coupling at higher contraction intensities. The EMD measurement, produced with a doublet stimulus, could potentially be a useful tool to examine the effects of fatigue, exercise, stretching, and so on, on the excitation-contraction coupling during various force levels. However, future research is needed to further elucidate the mechanisms that result in a lengthening of the EMD under these conditions. PMID- 23090319 TI - Fitness profiling of elite level adolescent Gaelic football players. AB - The purpose of this study was to evaluate the anthropometric characteristics and fitness levels of elite level under 18 (U-18) Gaelic football players to establish normative centile scores for selected fitness parameters and to compare the physical and fitness characteristics relative to each playing position. A total of 265 male U-18 Gaelic football players (age: 16.96 +/- 0.7 years; height: 178.11 +/- 6.27 cm; weight: 72.07 +/- 8.68 kg) participated in the study. According to positional roles, players were categorized as goalkeepers (n = 13), defenders (n = 113), midfielders (n = 30), and forwards (n = 109). Height and weight were measured, and skinfolds were taken before participants sequentially performed a sit and reach test (S&R), countermovement jump (CMJ), standing long jump (SLJ), 5- and 20-m speed test, and the Yo-Yo Intermittent Recovery Test Level 1 (YYIRT1). The percentage body fat was higher (p < 0.01) in goalkeepers than the other playing positions. Goalkeepers had a higher body mass index than defenders (p < 0.05) and forwards (p < 0.01). Midfielders and goalkeepers were taller (p < 0.01) and heavier (p < 0.01) than defenders and forwards. The total distance covered in the YYIRT1 was significantly lower (p < 0.01) in goalkeepers than the other playing positions. There was no significant positional difference in the performance scores in the S&R test, CMJ, SLJ, and 5- and 20-m running speed. The study findings indicate minimal differences in the anthropometric and physiological characteristics between playing positions in elite youth level Gaelic football players. The norm-referenced percentile scores will enable conditioning coaches to benchmark elite performance and design training programs. PMID- 23090320 TI - Quantifying the physical demands of collision sports: does microsensor technology measure what it claims to measure? AB - The physical demands of rugby league, rugby union, and American football are significantly increased through the large number of collisions players are required to perform during match play. Because of the labor-intensive nature of coding collisions from video recordings, manufacturers of wearable microsensor (e.g., global positioning system [GPS]) units have refined the technology to automatically detect collisions, with several sport scientists attempting to use these microsensors to quantify the physical demands of collision sports. However, a question remains over the validity of these microtechnology units to quantify the contact demands of collision sports. Indeed, recent evidence has shown significant differences in the number of "impacts" recorded by microtechnology units (GPSports) and the actual number of collisions coded from video. However, a separate study investigated the validity of a different microtechnology unit (minimaxX; Catapult Sports) that included GPS and triaxial accelerometers, and also a gyroscope and magnetometer, to quantify collisions. Collisions detected by the minimaxX unit were compared with video-based coding of the actual events. No significant differences were detected in the number of mild, moderate, and heavy collisions detected via the minimaxX units and those coded from video recordings of the actual event. Furthermore, a strong correlation (r = 0.96, p < 0.01) was observed between collisions recorded via the minimaxX units and those coded from video recordings of the event. These findings demonstrate that only one commercially available and wearable microtechnology unit (minimaxX) can be considered capable of offering a valid method of quantifying the contact loads that typically occur in collision sports. Until such validation research is completed, sport scientists should be circumspect of the ability of other units to perform similar functions. PMID- 23090321 TI - Alternative procedures for the three-minute all-out exercise test. AB - The cycling 3-minute all-out exercise test (3 MT) provides the measures of critical power (CP) and the curvature constant (W') for the relationship between power and time limit to exhaustion in the severe exercise domain. The original procedures for the 3 MT required a preliminary graded exercise test (GXT) to establish the linear factor and the fixed load for the test. We evaluated a new procedure of establishing the load for the 3 MT using a percentage of body mass (% BM). Fifteen subjects of varied fitness levels completed a custom GXT verification protocol to establish the gas exchange threshold and V[Combining Dot Above]O2max, a 3 MT using a load derived with the linear factor, and a 3 MT using a % BM. The subjects also completed a subsequent exhaustive bout at 10% above CP. The CP and W' estimated from either protocol did not differ. The CP estimates were consistent (alpha = 0.97, SEM = 7.1 W, coefficient of variation = 4%); however, W' was less reliable, a finding true of any method of measuring W'. The V[Combining Dot Above]O2 evoked during the 3 MT was lower than the values evoked by the exhaustive GXT-verification bouts and the 10% above CP bout after the 3 MT. All individual V[Combining Dot Above]O2 values in the 10% above CP bout were ">=" values measured in the 3 MT. Our findings indicate that several viable procedures for administering the 3 MT are plausible. PMID- 23090322 TI - An inferential and descriptive statistical examination of the relationship between cumulative work metrics and injury in Major League Baseball pitchers. AB - In Major League Baseball (MLB), games pitched, total innings pitched, total pitches thrown, innings pitched per game, and pitches thrown per game are used to measure cumulative work. Often, pitchers are allocated limits, based on pitches thrown per game and total innings pitched in a season, in an attempt to prevent future injuries. To date, the efficacy in predicting injuries from these cumulative work metrics remains in question. It was hypothesized that the cumulative work metrics would be a significant predictor for future injury in MLB pitchers. Correlations between cumulative work for pitchers during 2002-07 and injury days in the following seasons were examined using regression analyses to test this hypothesis. Each metric was then "binned" into smaller cohorts to examine trends in the associated risk of injury for each cohort. During the study time period, 27% of pitchers were injured after a season in which they pitched. Although some interesting trends were noticed during the binning process, based on the regression analyses, it was found that no cumulative work metric was a significant predictor for future injury. It was concluded that management of a pitcher's playing schedule based on these cumulative work metrics alone could not be an effective means of preventing injury. These findings indicate that an integrated approach to injury prevention is required. This approach will likely involve advanced cumulative work metrics and biomechanical assessment. PMID- 23090323 TI - Colorectal cancer: Comparison of colorectal cancer screening strategies. PMID- 23090327 TI - Infection: Activation of Hedgehog pathway promotes fibrogenesis and vascular remodelling in human schistosomiasis. PMID- 23090329 TI - Physical activity: an essential component of lifestyle modification in NAFLD. AB - NAFLD encompasses a spectrum of liver diseases pertaining to fat accumulation in the liver in the absence of significant alcohol consumption. NASH is the most clinically relevant subset of NAFLD, and patients with NASH have an increased risk of progression to cirrhosis or developing liver cancer. No pharmacotherapy is currently approved for NAFLD, and lifestyle modification via diet and exercise is most commonly recommended. The optimal physical activity regimen in terms of both effectiveness and compliance remains to be determined and is the focus of this Review. PMID- 23090330 TI - Agreement between auricular and rectal measurements of body temperature in healthy cats. AB - Measurement of body temperature is a routine part of the clinical assessment of a patient. However, this procedure may be time-consuming and stressful to most animals because the standard site of temperature acquisition remains the rectal mucosa. Although an increasing number of clinicians have been using auricular temperature to estimate core body temperature, evidence is still lacking regarding agreement between these two methods in cats. In this investigation, we evaluated the agreement between temperatures measured in the rectum and ear in 29 healthy cats over a 2-week period. Temperatures were measured in the rectum (using digital and mercury-in-glass thermometers) and ear once a day for 14 consecutive days, producing 406 temperature readings for each thermometer. Mean temperature and confidence intervals were similar between methods, and Bland Altman plots showed small biases and narrow limits of agreement acceptable for clinical purposes. The interobserver variability was also checked, which indicated a strong correlation between two near-simultaneous temperature readings. Results are consistent with auricular thermometry being a reliable alternative to rectal thermometry for assessing core body temperature in healthy cats. PMID- 23090331 TI - Intrathoracic pseudocyst in a kitten. AB - A 2-month-old, intact, female domestic shorthair kitten presented with a history of acute-onset dyspnoea. Severe dyspnoea and tachypnoea were noted on physical examination. Serosanguinous fluid, consistent with a modified transudate, was aspirated from the pleural cavity immediately after the physical examination, with an immediate decrease in respiratory rate and effort. The thorax was radiographed and the entire left hemithorax appeared to be filled with a large soft tissue density mass. Thoracic ultrasound was performed and a cystic structure, measuring 3.0 cm * 1.5 cm, was seen in the left hemithorax. An explorative thoracotomy was performed and a mass obliterating the left hemithorax was found. The mass was removed by a combination of blunt and sharp dissection. A final diagnosis of thoracic pseudocyst was made on histological examination of the tissue. The mass was described as a sterile process characteristic of an organised seroma or haematoma. Recovery from surgery was uneventful and the kitten was discharged 48 h postoperatively. The kitten was still alive with no recurrence of clinical signs at the time of writing this report, 8 months postoperatively. PMID- 23090332 TI - Treatment and long-term follow-up of cats with suspected primary epilepsy. AB - We report an evaluation of the treatment and outcome of cats with suspected primary epilepsy. Phenobarbital therapy was used alone or in combination with other anti-epileptic drugs. Outcome after treatment was evaluated mainly on the basis of number of seizures per year and categorised into four groups: seizure free, good control (1-5 seizures per year), moderate control (6-10 seizures per year) and poor control (more than 10 seizures per year). About 40-50% of cases became seizure-free, 20-30% were considered good-to-moderately controlled and about 30% were poorly controlled depending on the year of treatment considered. The duration of seizure events after treatment decreased in 26/36 cats and was unchanged in eight cats. The subjective severity of seizure also decreased in 25 cats and was unchanged in nine cats. Twenty-six cats had a good quality of life, nine cats an impaired quality of life and one cat a bad quality of life. Despite being free of seizures for years, cessation of treatment may lead to recurrence of seizures in most cats. PMID- 23090333 TI - Application of the tripartite model to a complicated sample of residential youth with externalizing problems. AB - The tripartite model of anxiety and depression has received strong support among child and adolescent populations. Clinical samples of children and adolescents in these studies, however, have usually been referred for treatment of anxiety and depression. This study investigated the fit of the tripartite model with a complicated sample of residential youths with externalizing problems. Structural Equation Modeling was used to test the tripartite model relationships between negative affect, positive affect, and mood symptoms. Multiple fit indices were used to provide a reliable and conservative evaluation of the model. As predicted, the tripartite model provided a good fit for symptoms of emotional disorders in this complicated sample of children and adolescents. Implications of these findings are discussed in terms of the utility of the tripartite model in understanding anxiety and depression in more diverse populations and recommendations for residential assessment. PMID- 23090334 TI - Glycine receptor autoimmune spectrum with stiff-man syndrome phenotype. AB - OBJECTIVES: To determine whether glycine receptor alpha1 subunit-specific autoantibodies (GlyRalpha1-IgG) occur in a broader spectrum of brainstem and spinal hyperexcitability disorders than the progressive encephalomyelitis with rigidity and myoclonus phenotype recognized to date, and to ascertain disease specificity. DESIGN: Retrospective, case-control study. SETTINGS: Mayo Clinic, Rochester, Minnesota, and University of Barcelona, Spain. PATIENTS: Eighty-one patients with stiff-man syndrome phenotype, 80 neurologic control subjects, and 20 healthy control subjects. INTERVENTION: Glycine receptor alpha1-transfected cells to test serum or cerebrospinal fluid from cases and control subjects. MAIN OUTCOME MEASURES: Frequency of GlyRalpha1-IgG positivity among stiff-man syndrome phenotype cases and control subjects. Comparison of GlyRalpha1-IgG seropositive and seronegative cases. RESULTS: Seropositive cases (12% of cases) included 9 with stiff-man syndrome (4 classic; 5 variant; 66% were glutamic acid decarboxylase 65-IgG positive) and 1 with progressive encephalomyelitis with rigidity and myoclonus. Immunotherapy responses were noted more frequently in GlyRalpha1-IgG-positive cases (6 of 7 improved) than in seronegative cases (7 of 25 improved; P= .02). The single seropositive control patient had steroid responsive vision loss and optic atrophy with inflammatory cerebrospinal fluid. CONCLUSIONS: Glycine receptor alpha1-IgG aids identification of autoimmune brainstem/spinal cord hyperexcitability disorders and may extend to the glycinergic visual system. PMID- 23090335 TI - Organic foods: health and environmental advantages and disadvantages. AB - The US market for organic foods has grown from $3.5 billion in 1996 to $28.6 billion in 2010, according to the Organic Trade Association. Organic products are now sold in specialty stores and conventional supermarkets. Organic products contain numerous marketing claims and terms, only some of which are standardized and regulated. In terms of health advantages, organic diets have been convincingly demonstrated to expose consumers to fewer pesticides associated with human disease. Organic farming has been demonstrated to have less environmental impact than conventional approaches. However, current evidence does not support any meaningful nutritional benefits or deficits from eating organic compared with conventionally grown foods, and there are no well-powered human studies that directly demonstrate health benefits or disease protection as a result of consuming an organic diet. Studies also have not demonstrated any detrimental or disease-promoting effects from an organic diet. Although organic foods regularly command a significant price premium, well-designed farming studies demonstrate that costs can be competitive and yields comparable to those of conventional farming techniques. Pediatricians should incorporate this evidence when discussing the health and environmental impact of organic foods and organic farming while continuing to encourage all patients and their families to attain optimal nutrition and dietary variety consistent with the US Department of Agriculture's MyPlate recommendations. This clinical report reviews the health and environmental issues related to organic food production and consumption. It defines the term "organic," reviews organic food-labeling standards, describes organic and conventional farming practices, and explores the cost and environmental implications of organic production techniques. It examines the evidence available on nutritional quality and production contaminants in conventionally produced and organic foods. Finally, this report provides guidance for pediatricians to assist them in advising their patients regarding organic and conventionally produced food choices. PMID- 23090336 TI - Trajectories of autism severity in children using standardized ADOS scores. AB - OBJECTIVES: To plot longitudinal trajectories of autism spectrum disorder (ASD) severity from early childhood to early adolescence. In line with reported trajectories in toddlers, we hypothesize that a substantial minority of children will show marked changes in ASD severity over time, with "Improvers" demonstrating the highest mean baseline and rate of growth in verbal IQ (VIQ). METHODS: Patients included 345 clinic referrals and research participants with best-estimate clinical diagnoses of ASD at 1 or more time points, and repeated Autism Diagnostic Observation Schedule (ADOS), VIQ, and nonverbal IQ scores. Standardized ADOS severity scores were applied to 1026 assessments collected longitudinally between the ages of 2 and 15 (VIQ at most recent assessment: mean = 58, SD = 35). Scores were fitted for latent severity trajectory classes with and without covariates. Adaptive behavior and VIQ trajectories over time were modeled within each of the best-fit latent classes. RESULTS: A 4-class model best represented the observed data. Over 80% of participants were assigned to persistent (stable) high or moderately severe classes; 2 small classes respectively increased or decreased in severity over time. Age, gender, race, and nonverbal IQ did not predict class membership; VIQ was a significant predictor. Baseline VIQ was highest in the improving and worsening classes; it increased at the greatest rate in the improving class. Adaptive behavior declined in all but the improving class, with consistent impairment in all classes. CONCLUSIONS: If replicated, identified trajectory classes of ADOS severity may contribute to clinical prognosis and to subtyping samples for neurobiological and genetic research. PMID- 23090337 TI - You too can teach clinical reasoning! PMID- 23090338 TI - Cord blood 25-hydroxyvitamin D3 and allergic disease during infancy. AB - OBJECTIVE: There has been growing interest in vitamin D insufficiency as a predisposing factor for allergy development based on immunoregulatory properties and epidemiological studies. The aim of this study was to investigate the association between vitamin D exposure in utero and allergic outcomes in the first year of life. METHODS: Cord blood (CB) vitamin D was measured in 231 high risk infants from an Australian prospective birth cohort. CB 25-hydroxyvitamin D(3) (25[OH]D(3)) concentration was analyzed in relation to maternal vitamin D intake and the development of infant eczema, allergen sensitization, and immunoglobulin E-mediated food allergy. RESULTS: Maternal intake of supplemental vitamin D was significantly correlated with CB 25(OH)D(3) concentration (rho = 0.244, P = .003), whereas dietary vitamin D did not influence CB levels. There was significant seasonal variation in CB 25(OH)D(3) concentration suggesting that sunlight exposure was an important determinant. Lower CB vitamin D status was observed in infants that developed eczema (P = .018), and eczema was significantly more likely in those with concentrations <50 nmol/L in comparison with those with concentrations >= 75 nmol/L (odds ratio 2.66; 95% confidence interval 1.24-5.72; P = .012). This association remained significant after adjustment for multiple confounding factors. The associations between CB 25(OH)D(3) concentration and allergen sensitization, immunoglobulin E-mediated food allergy, and eczema severity (SCORing Atopic Dermatitis) were not significant. CONCLUSIONS: Reduced vitamin D status in pregnancy may be a risk factor for the development of eczema in the first year of life, reinforcing the need to explore the role of vitamin D exposure during development for disease prevention. PMID- 23090339 TI - Randomized trial of prongs or mask for nasal continuous positive airway pressure in preterm infants. AB - OBJECTIVE: To determine whether nasal continuous positive airway pressure (NCPAP) given with nasal prongs compared with nasal mask reduces the rate of intubation and mechanical ventilation in preterm infants within 72 hours of starting therapy. METHODS: Infants <31 weeks' gestation treated with NCPAP were randomly assigned to receive it via either prongs or mask. Randomization was stratified by gestational age (<28 weeks, 28-30 weeks) and according to whether NCPAP was started as a primary treatment for respiratory distress or postextubation. Infants were intubated and ventilated if they fulfilled 2 or more of 5 failure criteria (worsening signs of respiratory distress; recurrent apnea treated with mask positive pressure ventilation; fraction of inspired oxygen >0.4 to keep oxygen saturation >88% sustained for 30 minutes; pH <7.2 on 2 blood gases >= 30 minutes apart; Pco(2) >9 kPa [68 mm Hg] on 2 blood gases >= 30 minutes apart) within 72 hours of starting therapy. The groups were treated the same in all other respects. We recorded relevant secondary outcomes and analyzed data by using the intention-to-treat principle. RESULTS: We enrolled 120 infants. Thirty two of 62 (52%) infants randomly assigned to prongs were intubated within 72 hours, compared with 16/58 (28%) of those randomly assigned to mask (P = .007). There were no statistically significant differences between the groups in any secondary outcomes. CONCLUSIONS: In premature infants, NCPAP was more effective at preventing intubation and ventilation within 72 hours of starting therapy when given via nasal masks compared with nasal prongs. PMID- 23090340 TI - Identifying and treating a substandard housing cluster using a medical-legal partnership. AB - BACKGROUND AND OBJECTIVE: There is a documented connection between the home environment and health. Medical-legal partnerships (MLPs) can address social and environmental determinants of health. Our objective was to describe a cluster of substandard housing identified and treated by an MLP based in a pediatric primary care setting. METHODS: Potential cases of poor-quality housing were identified during outpatient primary care. A case was defined as any rented housing unit with a reported unaddressed housing risk within a defined building portfolio (owned by a single developer) in which >= 1 child lived. An on-site MLP offered affected families legal services including ordinance enforcement and connection to resources. They also initiated portfolio-wide advocacy. Legal advocates reported case outcomes. Medical history and household demographics were collected from the medical record and compared with clinic-wide data by using Fisher's exact test or chi(2) statistics. RESULTS: After identification of a single case, an additional 15 cases were identified. Pest infestation was the most common initial risk identified. Of 14 units with outcome data, repairs were completed in 10 (71%). Of the 19 building complexes with the same owner, 11 received significant systemic repairs. Of the 45 children living within the 16 identified case units, 36% had asthma, 33% had developmental delay or behavioral disorder, and 9% had an elevated lead level. Affected children were more likely to have one of these diagnoses than the general clinic population (all P < .01). CONCLUSIONS: An MLP identified and improved home environmental conditions for children living in a cluster of substandard housing. PMID- 23090341 TI - Medicine and law: new opportunities to close the disparity gap. PMID- 23090342 TI - Influence of hospital guidelines on management of children hospitalized with pneumonia. AB - BACKGROUND AND OBJECTIVE: Clinical practice guidelines (CPGs) assist clinicians in making appropriate diagnostic and treatment decisions based on available evidence. The objective of this study was to describe the availability and content of institutional community-acquired pneumonia (CAP) CPGs, and to evaluate the association between institutional CPGs and care utilization, antibiotic administration, and outcomes among children hospitalized with CAP. METHODS: This multicenter retrospective cohort study included children aged 1 to 18 years hospitalized with CAP from July 1, 2009, to June 30, 2011. CPGs from each institution were reviewed to abstract information regarding diagnostic testing and antimicrobial selection. We compared overall and specific utilization patterns, antimicrobial use, and hospital length of stay (LOS) for children with CAP between hospitals with and without CPGs. RESULTS: Thirteen (31.7%) of 41 hospitals had an institutional CPG for nonsevere CAP. There was marked heterogeneity among CPGs. Among the 19,710 children hospitalized with CAP, cost of care, hospital LOS, and 14-day readmission rate were not associated with the presence of a CPG. CPGs did not influence ordering patterns for most diagnostic tests, including blood culture and chest radiographs. Penicillin or aminopenicillins were prescribed to 46.3% of children at institutions where a CPG recommended the use of these antibiotics as first-line agents compared with 23.9% of children at institutions without a CPG (odds ratio = 2.7; 95% confidence interval = 1.4-5.5). CONCLUSIONS: The availability of a CAP CPG had minimal impact on resource utilization and was not associated with cost or hospital LOS. Institutional CPGs, however, did influence patterns of antimicrobial use. PMID- 23090344 TI - Carnitine palmitoyltransferase I and sudden unexpected infant death in British Columbia First Nations. AB - OBJECTIVE: Infant mortality in British Columbia (BC) First Nations remains elevated relative to other residents. The p.P479L (c.1436C>T) variant of carnitine palmitoyltransferase 1 (CPT1A) is frequent in some aboriginal populations and may be associated with increased infant deaths. This work was initiated to determine the performance of acylcarnitine profiling for detecting this variant, to determine its frequency in BC, and to determine if it is associated with sudden infant deaths in this population. METHODS: Newborn screening cards from all BC First Nations infants in 2004 and all sudden unexpected deaths in BC First Nations infants (1999-2009) were genotyped for the CPT1A p.P479L variant and linked to archival acylcarnitine data. RESULTS: The CPT1A p.P479L variant is frequent in BC First Nations but is not evenly distributed, with higher rates in coastal regions (up to 25% homozygosity) with historically increased infant mortality. There is also an overrepresentation of p.P479L homozygotes in unexpected infant deaths from these regions, with an odds ratio of 3.92 (95% confidence interval: 1.69-9.00). Acylcarnitine profiling will identify p.P479L homozygotes with a 94% sensitivity and specificity. CONCLUSIONS: The CPT1A p.P479L variant is common to some coastal BC First Nations, and homozygosity for this variant is associated with unexpected death in infancy. The high frequency of this variant in a wide range of coastal aboriginal communities, however, suggests a selective advantage, raising the possibility that this variant may have differing impacts on health depending on the environmental or developmental context. PMID- 23090343 TI - Influence of stress in parents on child obesity and related behaviors. AB - OBJECTIVE: To assess associations of the number of parent stressors and parent perceived stress with obesity and related behaviors in their children. METHODS: This cross-sectional analysis used data from the 2006 Southeastern Pennsylvania Household Health Survey in which 2119 parents/caregivers answered questions about themselves and their children (ages 3-17 years). Survey data were used to assess the main exposure variables: the number of stressors (measured using a stressor index) and parent-perceived stress (the response to a general stress question); child covariates (age, race/ethnicity, health quality, and gender); adult covariates (education, BMI, gender, poor sleep quality) and study outcomes (child obesity, fast-food consumption, fruit and vegetable consumption, and physical activity). To account for developmental differences, analyses were also stratified by age group (3-5, 6-8, 9-12, and 13-17 years). Analyses used multiple logistic regression, with results expressed as odds ratios and 95% confidence intervals. RESULTS: The number of parent stressors was related to child obesity in unadjusted (1.12, 1.03-1.22, P = .007) and adjusted models (1.12, 1.03-1.23, P = .010). Parent-perceived stress was related to fast-food consumption in unadjusted (1.07, 1.03-1.10, P < .001) and adjusted (1.06, 1.02-1.10, P < .001) models. CONCLUSIONS: The number of parent stressors was directly related to child obesity. Parent-perceived stress was directly related to child fast-food consumption, an important behavioral indicator of obesity risk. Clinical care models and future research that address child obesity should explore the potential benefits of addressing parent stressors and parent-perceived stress. PMID- 23090345 TI - The challenge--and promise--of local clinical practice guidelines. PMID- 23090346 TI - Internet access and attitudes toward online personal health information among detained youth. AB - OBJECTIVE: To assess Internet access and usage patterns among high-risk youth involved in the juvenile justice system, and to determine if health information technology tools might play a useful role in more actively engaging this population in their health care. METHODS: A sample of 79 youth between the ages of 13 and 18 years old underwent a structured interview while detained in a large, Northern California juvenile detention facility. After an institutional review board-approved assent/consent process, youth discussed their typical Internet use when not detained, as well as their attitudes toward online access to their personal health information (PHI). RESULTS: Detained youth from predominantly underserved, minority communities, reported high levels of access to the Internet while outside of the detention setting, with 97% reporting using the Internet at least once per month and 87% at least weekly. Furthermore, 90% of these youth expressed interest in accessing their PHI online and sharing it with either parents or physicians. CONCLUSIONS: Detained adolescents describe unexpectedly high usage of the Internet and online resources when they are outside of the juvenile hall setting. These youth show an interest in, and may benefit from, accessing their PHI online. Further studies are needed to understand the potential health benefits that may be realized by engaging this population through online tools. PMID- 23090347 TI - Electrocardiogram provides a continuous heart rate faster than oximetry during neonatal resuscitation. AB - OBJECTIVE: To compare the time required to obtain a continuous audible heart rate signal from an electrocardiogram (ECG) monitor and pulse oximeter (PO) in infants requiring resuscitation. METHODS: Infants who had both ECG and PO placed during resuscitation were analyzed using video and analog recordings. The median times from arrival until the ECG electrodes and PO sensor were placed, and the time to achieve audible tones from the devices, were compared. RESULTS: Forty-six infants had ECG and PO data. Thirty infants were very low birth weight (23-30 weeks). There was a difference in the median total time to place either device (26 vs 38 seconds; P = .04), and a difference (P < .001) in the time to achieve an audible heart rate signal after ECG lead (2 seconds) versus PO probe (24 seconds) placement. In infants weighing >1500 g (n = 16), the median time (interquartile range) to place the ECG was 20 seconds (14-43) whereas the time to place the PO was 36 seconds (28-56) (P = .74). The median times (interquartile range) to acquire a signal from the ECG and PO were 4 seconds (1-6) and 32 seconds (15-40, P = .001), respectively. During the first minutes of resuscitation, 93% of infants had an ECG heart rate compared with only 56% for PO. CONCLUSIONS: Early application of ECG electrodes during infant resuscitation can provide the resuscitation team with a continuous audible heart rate, and its use may improve the timeliness of appropriate critical interventions. PMID- 23090348 TI - Cheerleading injuries: epidemiology and recommendations for prevention. AB - Over the last 30 years, cheerleading has increased dramatically in popularity and has evolved from leading the crowd in cheers at sporting events into a competitive, year-round sport involving complex acrobatic stunts and tumbling. Consequently, cheerleading injuries have steadily increased over the years in both number and severity. Sprains and strains to the lower extremities are the most common injuries. Although the overall injury rate remains relatively low, cheerleading has accounted for approximately 66% of all catastrophic injuries in high school girl athletes over the past 25 years. Risk factors for injuries in cheerleading include higher BMI, previous injury, cheering on harder surfaces, performing stunts, and supervision by a coach with low level of training and experience. This policy statement describes the epidemiology of cheerleading injuries and provides recommendations for injury prevention. PMID- 23090349 TI - Symptom reports are not reliable during ambulatory reflux monitoring. AB - OBJECTIVES: Patient reporting of symptom events during ambulatory reflux monitoring is commonly performed with little data regarding its accuracy. We employed a novel time-synchronized ambulatory audio recording of symptom events simultaneously with prolonged pH/impedance monitoring to assess temporal accuracy of patient-reported symptoms. METHODS: An acoustic monitoring system was employed to detect cough events via tracheal and chest wall sounds and it was temporally synchronized with an ambulatory impedance/pH monitoring system. Patients were instructed to record their symptoms in the usual manner. Six separate observers independently listened to the 24-h audio recordings and logged the exact timing of each cough event. Patients were blinded to study design and the audio reviewers were blinded to their own reports and those of patients and other reviewers. Concurrence of audio recordings and patient-reported symptoms were tested for three separate time thresholds: 1, 2, and 5 min. RESULTS: The median (interquartile range (IQR)) number of cough events by audio detection was significantly (P<0.001) higher than those reported by patients: 216 (90-275) and 34 (22-60), respectively. There was significantly (P<0.001) higher agreement among the audio recording listeners (substantial to almost perfect agreement; kappa=0.77-0.82) than between the audio recording and patient-reported symptoms (slight to fair agreement; kappa=0.13-0.27). Patients did not report 91, 82, and 71% of audible cough events based on 1-, 2-, and 5-min concordance time windows, respectively. CONCLUSIONS: We found that patients do not report the majority of their symptoms during ambulatory reflux monitoring even within a 5-min time window of the true event and advise caution in clinical decision-making based solely on symptom indices. PMID- 23090350 TI - Risk factors for fecal incontinence in older women. AB - OBJECTIVES: The objectives of this study were to estimate the prevalence of fecal incontinence (FI) in older women and examine associations between potential risk factors and prevalent FI. METHODS: We conducted a cross-sectional study of prevalent FI in 64,559 women, aged 62-87 years, in the Nurses' Health Study. Since 1976, participants provided information on health and lifestyle on mailed biennial questionnaires. Data on FI were collected in 2008. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for FI were calculated using logistic regression models. RESULTS: The reported prevalence of liquid or solid stool incontinence at least monthly increased from 9% in women aged 62 to 64 years to 17% in women aged 85 to 87 years. Prevalent FI was 50% less common in black women compared with white women (6% vs. 12%, respectively). Other variables associated with increased odds of FI at least monthly were pregnancy, higher body mass index (BMI), lower physical activity, functional limitations, current cigarette smoking, type 2 diabetes, high blood pressure, and neurologic disease. Urinary incontinence (UI) was a strong correlate of FI, with 63% of women with FI reporting UI at least monthly compared with 45% of women in the whole study population. CONCLUSIONS: FI is a common condition among older women, and often co occurs with UI. Potentially modifiable risk factors include BMI, physical activity, and cigarette smoking. PMID- 23090353 TI - A highly stable polypyridyl-based cobalt catalyst for homo- and heterogeneous photocatalytic water reduction. AB - Synthesis, characterization and activity in homogeneous photocatalytic hydrogen production of a cobalt polypyridyl complex are reported. TONs up to 9000 H(2)/Co could be achieved. Immobilization of the complex on a swellable resin yielded a recyclable heterogeneous catalyst. PMID- 23090351 TI - Optimum ribavirin exposure overcomes racial disparity in efficacy of peginterferon and ribavirin treatment for hepatitis C genotype 1. AB - OBJECTIVES: Peginterferon and ribavirin treatment is less effective for hepatitis C virus (HCV) genotype 1 infections in African Americans (AA) compared with Caucasian Americans (CA). Host genetic variability near the interleukin-28B (IL28B) gene locus is partly responsible. We investigated the relationship between ribavirin drug exposure and week 24 and 72 (sustained virologic response, SVR) responses (undetected serum HCV RNA) in 71 AA and 74 CA with HCV genotype 1 who received >90% of the prescribed peginterferon and weight-based ribavirin (1,000 or 1,200 mg per day) from week 1 to 24. METHODS: Ribavirin plasma levels were measured at weeks 1, 2, 4, 8, 12 and 24; ribavirin area under the concentration vs. time curve (AUC) was calculated using the linear trapezoidal rule. RESULTS: Compared with CA, AA had lower week 24 (WK24VR) (57.8 vs. 78.1; P<0.05) and week 72 (SVR) (36.6% vs 54.8%; P<0.05) response rates. AA also had significantly lower ribavirin exposure (AUC) from week 1 to 12 (P<0.05). Ribavirin exposures >=4,065 and >=4,480 ng/ml/day in the first week (AUC(0-7)) were thresholds for WK24VR and SVR in receiver-operating characteristic curve analyses. AA were less likely to have a threshold ribavirin AUC(0-7) level than CA (P<0.05). There were no significant racial differences in WK24VR (AA: 77 vs. CA: 84%) and SVR (AA: 52 vs. CA: 60%) rates in patients who met the ribavirin AUC(0-7) thresholds. Ribavirin AUC(0-7) predicted WK24VR and SVR independently of IL28B single-nucleotide polymorphism rs12979860 genotype. Yet, achieving threshold AUC(0-7) levels increased response rates primarily in AA with the less favorable non-C/C genotypes. CONCLUSIONS: Standard weight-based dosing leads to suboptimal ribavirin exposure in AA and contributes to the racial disparity in peginterferon and ribavirin treatment efficacy for HCV genotype 1. PMID- 23090352 TI - Transient ischemic dilation in SPECT myocardial perfusion imaging for prediction of severe coronary artery disease in diabetic patients. AB - BACKGROUND: Transient ischemic dilation (TID) of the left ventricle during stress myocardial perfusion SPECT (MPS) has been shown to be a useful marker of severe coronary artery disease (CAD). However, investigations in diabetic patients with available coronary angiographic data are still limited. We evaluated the incremental diagnostic value of TID in identifying the presence of angiographically severe CAD in diabetic patients. METHODS AND RESULTS: TID ratio values were automatically derived from rest-stress MPS in 242 diabetic patients with available coronary angiography data. A cutoff of >=1.19 was considered to represent TID. Severe CAD (>=70% stenosis in the proximal left anterior descending artery or the left main artery, or >=90% stenosis in two or three vessels) was identified in 69 (29%) patients. At multivariate analysis, the best independent predictors of severe CAD were summed stress score and TID (both P < .001). At incremental analysis, the addition of TID improved the power of a model including clinical data and summed stress score, increasing the global chi(2) value from 14.3 to 28.2 (P < .01). The best cutoff of summed stress score for identifying patients with severe CAD was >=8. When the TID ratio was considered in patients with summed stress score between 3 and 7, the sensitivity for diagnosing severe CAD significantly improved from 71% to 77% (P < .05). In the overall study population, the net reclassification improvement by adding TID to a model including clinical data and summed stress score in the prediction of severe CAD was 0.40 (P < .005). CONCLUSIONS: TID ratios obtained from rest-stress MPS provide incremental diagnostic information to standard perfusion analysis for the identification of severe and extensive CAD in diabetic patients. PMID- 23090354 TI - Les travaux de Margaret Lock. PMID- 23090358 TI - Enhanced field emission from hydrogenated TiO2 nanotube arrays. AB - The field emission (FE) properties of TiO(2) nanotube arrays (TNAs) synthesized by anodization are dramatically improved after hydrogenation at various temperatures in a range of 400-550 degrees C. Compared with pristine TNAs, the turn-on fields of hydrogenated TNAs (H:TNAs) are significantly decreased from 18.23 to 1.75 V MUm(-1), and closely related to hydrogenation temperature. Importantly, the optimized sample of H:TNAs prepared at 550 degrees C shows excellent FE performances involving both a low turn-on field of 1.75 V MUm(-1), a high current density of 4.0 mA cm(-2) at 4.50V MUm(-1), and a remarkable FE stability over 480 min. The substantially enhanced FE properties can be attributed to the combination of a typical tubular morphology, a reduced work function and the improved conductivity of H:TNAs. PMID- 23090357 TI - Pelvic massive allograft reconstruction after bone tumour resection. AB - PURPOSE: The purpose of this report was to retrospectively review a series treated with pelvic tumour resection and massive allograft reconstruction, and determine survival of patients and implants, functional results and morbidity of surgical technique. METHODS: From 1999, 33 patients underwent pelvic tumour resection and massive allograft reconstruction. The mean age was 40 years (range, 14-72) and 29 patients had a primary malignant tumour. The resection involved the acetabular area in all but three patients. RESULTS: At a median follow-up of 33 months (range, two-143) four patients had local recurrence. The morbidity was high: five deep infections (15 %), requiring two allograft removal, six hip dislocations (18 %), eight sciatic nerve palsy (24 %), persistent in six cases, and two loosening of the acetabular component. Implant survival was 87.3 % at last follow up. The cumulative overall patient's survival was 41.5 % at five and ten years. The average MSTS functional score was 70 % (range, 54-100 %) when the acetabulum was preserved while it was 61 % (30-100 %) in patients with acetabular resection. CONCLUSION: In conclusion, pelvic allografts represent a valid option for reconstruction after resection of pelvic tumours but due to the associated morbidity, patients should be carefully selected. PMID- 23090359 TI - NADPH oxidase-dependent formation of reactive oxygen species contributes to transforming growth factor beta1-induced epithelial-mesenchymal transition in rat peritoneal mesothelial cells, and the role of astragalus intervention. AB - OBJECTIVE: To investigate the role of nicotinamide-adenine dinucleotide phosphate (NADPH) oxidasedependent formation of reactive oxygen species (ROS) in the transforming growth factor beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT) in rat peritoneal mesothelial cells (RPMCs), and the effect of Astragalus injection (AGI) intervention. METHODS: Primary RPMCs were cultured to the second generation in vitro. After synchronization for 24 h, the cells were randomly assigned to the following groups: control (Group A), AGI (2 g/mL; Group B), TGF-beta1 (10 ng/mL; Group C), TGF-beta1 (10 ng/mL) + AGI (2 g/mL; Group D; pretreated for 1 h with AGI before TGF-beta1 stimulation). Reverse transcription polymerase chain reaction (RT-PCR) and Western blot analysis were employed to evaluate the mRNA and protein expression of the NADPH oxidase subunit p67phox, alpha-smooth muscle actin (alpha-SMA) and E-cadherin. The dichlorofluorescein sensitive cellular ROS levels were measured by a fluorometric assay and confocal microscopy. RESULTS: TGF-beta1 significantly induced NADPH oxidase subunit p67phox mRNA and protein expression in RPMCs, as well as inducing the production of intracellular ROS. AGI inhibited this TGF-beta1-induced up-regulation by 39.3% and 47.8%, respectively (P<0.05), as well as inhibiting the TGF-beta1-induced ROS generation by 56.3% (P<0.05). TGF-beta1 also induced alpha-SMA mRNA and protein expression, and down-regulated E-cadherin mRNA and protein expression (P<0.05). This effect was suppressed by AGI (P<0.05). CONCLUSIONS: NADPH oxidase-dependent formation of ROS may mediate the TGF-beta1-dependent EMT in RPMCs. AGI could inhibit this process, providing a theoretical basis for AGI in the prevention of peritoneal fibrosis. PMID- 23090360 TI - Effects of different extracts of kanggushu on osteoporosis in model rats and the underlying mechanisms. AB - OBJECTIVE: To investigate the preventive effects and possible underlying mechanism of different extracts of Kanggushu () on osteoporosis in ovariectomized rats. METHODS: One hundred and sixtyfive female SD rats were divided into 11 groups: control, sham, model, Xianling Gubao Capsule (), nilestriol, Kanggushu aqueous extract high-, medium-, and low-dose and suet extract high-, medium-, and low-dose groups. The osteoporosis model was made by ovariectomizing the rats. The latter 8 groups were administered intragastricly with Xianling Gubao Capsule, nilestriol, Kanggushu aqueous extract and suet extract for 12 weeks, respectively, while the other 3 groups were administered orally saline. The whole body bone mineral density, bone mineral content, organ coefficient of uterus, serum estradiol and alkaline phosphatase contents, blood calcium, phosphorus, interleukin 6 and bone Gla-protein levels after treatment were monitored. Additionally, three-point bending test of femur, HE staining, and scanning electron microscope were performed to explore the pharmacodynamics and underlying mechanisms. RESULTS: In comparison with ovariectomized rats of model group, Kanggushu aqueous extract high-dose resulted in an increased bone mineral density, bone mineral content and organ coefficient of uterus, improved estradiol level, and improved maximum load and structural stiffness (P<0.05 or P<0.01). Two dimensional and three-dimensional trabecular structure was also observed under HE staining and scanning electron microscopy, and the number and thickness of trabecular bone in Kanggushu aqueous extract high-dose group was significantly increased compared to the model group, while the lipid droplets in bone marrow cavity were significantly less. However, there were no significant differences in blood calcium, total serum alkaline phosphatase and bone Gla protein among different treatment groups. Overall, the osteoprotective effects of Kanggushu aqueous extract were comparable to those of nilestriol and were significantly more effective than those of Xianling Gubao Capsule. CONCLUSION: The preventive effects of Kanggushu aqueous extract might be partly due to the increased estradiol level, accelerated restoration of bone trabecular reticulate structure, and accordingly increased bone mineral density in osteoporosis rats. PMID- 23090361 TI - Differentiation at autopsy between in vivo gas embolism and putrefaction using gas composition analysis. AB - Gas embolism can arise from different causes (iatrogenic accidents, criminal interventions, or diving related accidents). Gas analyses have been shown to be a valid technique to differentiate between putrefaction gases and gas embolism. In this study, we performed systematic necropsies at different postmortem times in three experimental New Zealand White Rabbits models: control or putrefaction, infused air embolism, and compression/decompression. The purpose of this study was to look for qualitative and quantitative differences among groups and to observe how putrefaction gases mask in vivo gas embolism. We found that the infused air embolism and compression/decompression models had a similar gas composition prior to 27-h postmortem, being typically composed of around 70-80 % of N(2) and 20-30 % of CO(2), although unexpected higher CO(2) concentrations were found in some decompressed animals, putting in question the role of CO(2) in decompression. All these samples were statistically and significantly different from more decomposed samples. Gas composition of samples from more decomposed animals and from the putrefaction model presented hydrogen, which was therefore considered as a putrefaction marker. PMID- 23090362 TI - Mutation rates at 16 Y-chromosome STRs in the South China Han population. AB - Nine hundred eighteen DNA-confirmed father-son pairs were typed for 16 Y chromosomal short tandem repeat (Y-STR) markers by AmpFLSTR(r) YfilerTM PCR Amplification kit. In a total of 15,606 allele transmissions, 36 mutations were detected. The average mutation rate across all 16 Y-STR markers was 0.0023 (95 % confidence interval, 0.0016-0.0032). One two-step mutation was found at DYS389II, and all other mutations were single steps. The losses and gains were balanced at all other loci, excluding DYS385 and DYS458, where losses were more frequent than gains. Mutation rates among different Y-STR loci were significantly different (Chi (2) = 69.05, P = 0.000). Mutation rates were correlated with the lengths of the alleles. Alleles with higher number of repeats were more likely to mutate. Mutation rates were also correlated with the gene diversity of the locus (r (2) = 0.565, P = 0.023). Loci with higher gene diversity had higher mutation rates. In addition, the mutation rate of the older father was found to be notably higher than that of the younger father. PMID- 23090363 TI - Assessment of adult human exposure to phthalate esters in the urban centre of Paris (France). AB - Human exposure to phthalates was assessed through digestive and respiratory intakes. Six phthalates (DMP, DEP, DnBP, BBP, DEHP, DnOP) were investigated in drinking water, in current foodstuff and in ambient air. Digestive intake was prevailing (92 %) with a major contribution of food (95.5 %). Phthalate intake from water was mainly due to bottled water (60 %) in spite of the minor volume absorbed daily. From the respiratory tract, it was dominated by DEP: 30.3 ng kg( 1) bw day(-1) and the part played by indoor air prevailed. Total intake were as ng kg(-1) bw day(-1), for DEHP: 1458, DnBP: 191.8, BBP: 164.3, DEP: 107.7, DMP: 79.1. PMID- 23090364 TI - Quadricuspid pulmonary valve: computed tomography case series and review of relevant literature. AB - Quadricuspid pulmonary valve (QPV) is a rare congenital cardiac entity. The recognition of QPV has clinical significance as it can cause pulmonary valve dysfunction. It is also important to recognize this condition in patients undergoing the Ross procedure. We report a case of QPV diagnosed by computed tomography with associated pulmonary stenosis and right ventricular hypertrophy. PMID- 23090367 TI - Expression of concern: Ahlin E et al.,"Anti-citrullinated peptide antibodies and rheumatoid factor in Sudanese patients with Leishmania donovani infection", Rev Bras Reumatol 2011; 51(6):572-86. PMID- 23090365 TI - Traumatic ventricular septal defect: characterization with electrocardiogram gated cardiac computed tomography angiography. AB - Ventricular septal defects as a result of blunt trauma to the chest have not been frequently reported in the literature. In addition, the majority of these cases have been imaged with echocardiography alone. We report a case in which a ventricular septal defect caused by blunt chest trauma was characterized with electrocardiogram-gated computed tomography angiography. A review of the current literature and theories of injury mechanism are also provided. PMID- 23090368 TI - Improvement in pain, fatigue, and subjective sleep quality through sleep hygiene tips in patients with fibromyalgia. AB - OBJECTIVE: To evaluate the effectiveness of sleep hygiene instructions for women with fibromyalgia. MATERIALS AND METHODS: Seventy women with fibromyalgia completed the study. The assessment comprised the Fibromyalgia Impact Questionnaire (FIQ), the Pittsburgh Sleep Quality Index (PSQI), and a general questionnaire with personal data and lifestyle information. All patients received information about the disease and a sleep diary, but only the experimental group received the sleep hygiene instructions. Patients were asked to practice sleep hygiene, and, after three months, they were reevaluated by use of the same questionnaires. RESULTS: The mean age in the control group was 55.2 +/-7.12 years, and, in the experimental group, 53.5 +/-8.89 years (P = 0.392). The experimental group showed: a decrease in the pain Visual Analogue Scale values (P = 0.028), in fatigue (P = 0.021), and in the PSQI component 1 (P = 0.030); and a significant reduction in the difficulty falling asleep after waking up in the middle of the night (P = 0.031). The experimental group also showed an increase in the reporting percentage of "silent environment" (ranging from 42.9% to 68.6%), a decrease in the reporting percentage of "fairly quiet environment" (ranging from 40% to 22.9%), and a decrease in the reporting percentage of "noisy environment" (ranging from 17.1% to 8.6%). These changes facilitated falling asleep after waking up in the middle of the night. CONCLUSION: The sleep hygiene instructions allowed changing the patients' behavior, which resulted in pain and fatigue improvement, increased subjective quality of sleep, in addition to facilitating falling asleep after waking up in the middle of the night. PMID- 23090369 TI - Epidemiological profile of patients with extra-articular manifestations of rheumatoid arthritis from the city of Curitiba, south of Brazil. AB - OBJECTIVES: To describe the epidemiological profile of patients with extra articular manifestations of rheumatoid arthritis (ExRA) from an university affiliated rheumatology center; to report the prevalence of ExRA and to compare it with available data; and to identify, if possible, ExRA predictors. METHODS: This study reviewed 262 medical charts of patients previously diagnosed with rheumatoid arthritis (RA) according to the 1987 American College of Rheumatology criteria, and attending that rheumatology center in 2010. The statistical analysis comprised simple mathematical calculations, Student t and chi-square tests, and a significance level of 5% (alpha= 0.05). RESULTS: During the course of the disease, 120 patients (45.8%) had ExRA. Pulmonary manifestation, rheumatoid nodules and Sjogren's syndrome were the most common manifestations found. Rheumatoid factor and anti-cyclic citrullinated peptide antibody were positive in most patients tested. Most patients were classified as Steinbrocker functional classes 1 and 2. The mean DAS-28 was 3.629, and the mean HAQ score, 1.12. Patients with ExRA had longer disease duration (P < 0.05), and current smoking habit associated with the presence of ExRA (P < 0.05). CONCLUSIONS: The prevalence of ExRA during disease course was 45.8%, and current smoking habit correlated with the presence of ExRA. PMID- 23090370 TI - Diagnostic performance and clinical associations of antibodies to the chromatin antigenic system in juvenile systemic lupus erythematosus. AB - OBJECTIVES: To determine the frequency of antibodies to chromatin components in juvenile systemic lupus erythematosus (JSLE), and to correlate the presence of these autoantibodies with clinical manifestations and disease activity. METHODS: Anti-chromatin (anti-CHR), anti-nucleosome core particle (anti-NCS) and anti dsDNA antibodies were measured in 175 individuals, including 37 patients with active JSLE and 41 with inactive disease, 47 non-lupus autoimmune disease patients (non-lupus AD), and 50 healthy children. An in-house ELISA was developed with purified nucleosome core particles from calf thymus to determine IgG and IgG3 anti-NCS antibodies. Anti-CHR and anti-dsDNA antibodies were detected by commercial ELISA kits (INOVA). RESULTS: Anti-NCS and anti-CHR antibodies exhibited high specificity for JSLE and similar frequency in active and inactive JSLE. Anti-CHR and IgG/IgG3 anti-NCS serum levels did not differ between active and inactive JSLE. SLEDAI correlated with anti-dsDNA antibodies but not with antibodies to other chromatin components. There was association of anti-dsDNA, anti-CHR and IgG/IgG3 anti-NCS antibodies with proteinuria and low C4 serum levels. Anti-NCS antibodies in the absence of anti-dsDNA were observed in 14% of the JSLE patients. CONCLUSIONS: Our data indicate that anti-NCS and anti-CHR antibodies are relevant diagnostic markers for JSLE and appear to be correlated with JSLE lupus nephritis activity. IgG3 isotype anti-NCS antibodies do not seem to be more relevant than IgG anti-NCS antibodies as markers of disease activity or active nephritis in JSLE. PMID- 23090371 TI - Newly diagnosed dermatomyositis in the elderly as predictor of malignancy. AB - OBJECTIVE: Dermatomyositis (DM) symptoms may be a clue to the existence of a hidden cancer. Enhancing early detection is essential, but there are no studies evaluating short-term predictive factors in this disease. METHODS: This is a single-center retrospective study, including patients diagnosed with DM meeting at least four of the five Bohan and Peter's criteria (1975), from 1991 to 2011. This study assessed malignancies occurring in up to 12 months after the diagnosis of DM. RESULTS: Neoplasm was found in 12 out of 139 patients (skin, gastrointestinal tract, prostate, thyroid, breast, lungs, and genitourinary tract). Patients with neoplasm had a higher mean age than controls (56.8 +/- 15.7 vs. 40.3 +/- 13.1 years, respectively, P = 0.004, odds ratio 1.09; 95% confidence interval: 1.04-1.14). No statistical differences were observed regarding gender, ethnicity, frequency of constitutional symptoms, organ and systemic involvements, and/or laboratory alterations. CONCLUSION: In newly diagnosed DM, age at disease diagnosis was a predictive factor of malignancy. PMID- 23090372 TI - Nailfold capillaroscopy in children and adolescents with rheumatic diseases. AB - OBJECTIVE: To assess nailfold capillaroscopy in children and adolescents with autoimmune rheumatic diseases (juvenile idiopathic arthritis, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma and mixed connective tissue disease) and relate it to clinical and laboratory findings and disease activity. METHODS: Cross-sectional study assessing 147 patients by use of nailfold capillaroscopy as follows: 60 with juvenile idiopathic arthritis; 30 with systemic lupus erythematosus; 30 with juvenile dermatomyositis; 20 with localized scleroderma; four with systemic sclerosis; and three with mixed connective tissue disease. Clinical and laboratory tests and nailfold capillaroscopy were performed in all patients. The nailfold capillaroscopy was performed with an optical microscope (at 10- and 16-time magnifications) by the same observer. RESULTS: Most patients (76.2%) had normal nailfold capillaroscopy. The major changes in nailfold capillaroscopy, characterizing the scleroderma pattern, were observed in patients with juvenile dermatomyositis, systemic scleroderma and mixed connective tissue disease. There was no association between nailfold capillaroscopy and disease activity in patients with juvenile idiopathic arthritis, systemic lupus erythematosus and localized scleroderma. Disease activity and capillaroscopy were associated in patients with juvenile dermatomyositis. CONCLUSION: Nailfold capillaroscopy is a useful method to diagnose autoimmune rheumatic diseases and monitor disease activity. PMID- 23090373 TI - Cross-cultural adaptation and validation of the Brazilian-Portuguese version of the Bath Ankylosing Spondylitis Functional Index (BASFI). AB - OBJECTIVE: To conduct a cross-cultural adaptation of the Bath Ankylosing Spondylitis Functional Index (BASFI) into Brazilian-Portuguese language and to assess its measurement properties. METHODS: The BASFI was translated by four rheumatologists and three English teachers. The translated questionnaire was applied to ankylosing spondylitis patients by trained observers, and self administered in three moments: days 1, 2, and 14. The validity was assessed analyzing the association of BASFI and functional capacity measures (cervical rotation, intermalleolar distance, Schober's test and occiput-to-wall distance). The internal consistence was tested by Cronbach's alpha coefficient and the reliability by test-retest (intraclass correlation coefficient - ICC). RESULTS: A total of 60 patients with ankylosing spondylitis was included: 85% male, mean age 47 +/- 12 years, and mean disease duration 20 +/- 11 years. The intra-observer test-retest (two-week interval) reliability showed a high ICC (0.999, 95% CI: 0.997-0.999) and a high internal consistency (Cronbach's alpha coefficient: 0.86, CI 95%: 0.80-0.90). Considering the validity, the BASFI indices were correlated with cervical rotation (0.53, P < 0.001) and with intermalleolar distance (0.50, P < 0.001). CONCLUSION: The BASFI Brazilian-Portuguese version is reliable and valid for assessment of patients with ankylosing spondylitis. PMID- 23090374 TI - Ankylosing spondylitis and uveitis: overview. AB - The present article reviews the epidemiology, pathogenesis, clinical features, diagnosis, and treatment of ankylosing spondylitis and its association with ocular changes. The authors used the PubMed (MEDLINE), LILACS, and Ophthalmology Library databases. Ankylosing spondylitis is a chronic inflammatory disease that usually affects the axial skeleton and can progress to stiffness and progressive functional limitation. Ankylosing spondylitis usually begins around the second to third decade of life, preferentially in HLA-B27-positive white males. Its etiology and pathogenesis are not completely understood, and its diagnosis is difficult. Clinical control and treatment are frequently satisfactory. Acute anterior uveite is the most common extra-articular manifestation, occurring in 20%-30% of the patients with ankylosing spondylitis. Approximately half of the acute anterior uveite cases are associated with the presence of the HLA-B27 antigen. It can be the first manifestation of an undiagnosed rheumatic disease, usually having a good prognosis and appropriate response to treatment. In conclusion, for better assessment and treatment of patients with uveitis, ophthalmologists and rheumatologists should work together. PMID- 23090375 TI - Imaging diagnosis of early rheumatoid arthritis. AB - Early diagnosis of rheumatoid arthritis is essential for its proper management. Currently, the initial phase of rheumatoid arthritis is known to provide a window of therapeutic opportunity. Although the diagnosis is primarily clinical, the development and improvement of laboratory and imaging methods have contributed to earlier diagnosis and determination of procedures in early rheumatoid arthritis. In this article, the authors review the role of the major imaging methods used for assessing early rheumatoid arthritis, especially conventional radiography, ultrasonography, and magnetic resonance imaging. PMID- 23090376 TI - Selective inhibition of cyclooxygenase-2: risks and benefits. AB - The cyclooxygenase (COX) inhibitors are the most common drugs used worldwide. COX corresponds to an evolutionarily conserved class of enzymes and has two main isoforms: COX-1, which is largely associated with physiological functions, and COX-2, which is largely associated with pathological functions. Their subproducts have an important role in inflammation and pain perception. The COX-2 selective inhibition was designed to minimize gastrointestinal complications of non selective inhibition. However, this exclusive COX-2 inhibition was associated with serious cardiovascular events, for causing an imbalance between prostacyclin and thromboxane production. The objective of this study is to discuss the mechanisms underlying the cardiovascular effects, pointing out the advantages and disadvantages of the selective or nonselective COX inhibitors. PMID- 23090377 TI - Bilateral osteochondrosis of lateral femoral condyles: case report and literature review. AB - Osteochondrosis is an injury on subchondral ossification with predominance of immature skeleton and whose etiology remains unknown. It may affect the femoral condyles (usually the medial condyle) and the involvement is mostly unilateral. The authors draw the attention to this usually late diagnosis due to its infrequent occurrence and report a child's rare case of bilateral osteochondrosis on lateral femoral condyles, stressing that just one similar case has been described in the orthopaedic literature up to the present time. PMID- 23090378 TI - Reactive haemophagocytic syndrome in a systemic lupus erythematosus patient: case report. AB - The macrophagic syndrome or reactive haemophagocytic syndrome (RHS) is a complication resulting from systemic inflammatory diseases and may also be related to malign neoplasias, immunodeficiencies and to a variety of infections caused by virus, bacteria, and fungus. It is characterized by an excessive activation of macrophages and histiocytes along with intense hemophagocytosis in bone marrow and reticulum-endothelial system, causing the phagocytosis of erythrocytes, leukocytes, platelets, and their precursors. The clinical manifestations are fever, hepatosplenomegaly, lymphadenomegalies, neurological involvement, variable degrees of cytopenias, hyperferritinemia, liver disorders, intravascular coagulation, and multiple organs failure. We report a rare case of recurrent RHS complication in a systemic lupus erythematosus male patient after two years. Although extremely rare it has evolved with an improvement after a pulse methilprednisolone and cyclophosphamide therapy. PMID- 23090379 TI - Spontaneous pneumomediastinum associated with laryngeal lesions and tracheal ulcer in dermatomyositis. AB - We described a 41-year-old woman with dermatomyositis, interstitial lung disease, and cutaneous vasculopathy who developed a pneumomediastinum. The routine bronchoscopy investigation found pale lesions in the larynx, that extended to the tracheobronchial tree, and deep ulcers in the membranous wall of the trachea. The histopathology examination revealed an inflammatory process that was diagnosed secondary to the vasculitis, but no infections. Superior and inferior airway lesions in the same patient with dermatomyositis is a very rare condition. The association of dermatomyositis with deep mucosal ulcers and pneumomediastinum is not clear, but a bronchoscopic examination should be used to improve evaluation. PMID- 23090380 TI - Complete heart block in ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic rheumatic disease of young men that affects mainly the axial skeleton and is associated with HLA-B27 in 90% of the cases. Incidence of cardiovascular involvement in AS ranges between 10%-30%; conduction disturbances have been described in 1%-9% of the patients with AS. The majority of the series show a relationship with longstanding disease. To our knowledge, this is the first report of complete heart block in early AS. PMID- 23090381 TI - Posterior reversible encephalopathy syndrome (PRES) and systemic lupus erythematosus: report of two cases. AB - The posterior reversible encephalopathy syndrome (PRES) is a novel entity clinically manifested by headache, changes of sensorium, seizures, and visual loss. PRES pathogenesis has not been fully clarified. The entity can be associated to a variety of clinical conditions, mainly hypertension, renal insufficiency and immunosuppressive therapy. A possible link of autoimmune disorders with PRES has been recently hypothesized. We herein describe two cases of systemic lupus erythematosus whereby PRES was triggered by different factors. PMID- 23090382 TI - APS ACTION in Brazil. PMID- 23090384 TI - Adjuvants for immunotherapy. AB - PURPOSE OF REVIEW: This article gives an overview about the current state of preclinical and clinical studies using different kinds of adjuvants and their effect on allergen-specific immunotherapy (SIT). RECENT FINDINGS: Recently, vectors such as liposomes and microspheres and adjuvants such as Toll-like receptor agonists [e.g. nonmethylated cytosine-guanine dinucleotide (CpG) motifs derived from bacterial DNA or monophosphoryl lipid A (MPL A)] have been used in clinical phase II and III trials demonstrating encouraging clinical effects. SUMMARY: SIT has been optimized for more than 100 years with different approaches. Among these, adjuvants have been shown to amplify the effect of SIT by modulating the immune response to this therapy. In the first part, this article reviews the immunological mechanisms underlying the use of adjuvants targeting key cells of the innate immune system such as dendritic cells. In the second part, it overviews first clinical trials which have been reported so far in both subcutaneous and sublingual allergen-specific immunotherapy investigating the therapeutic potential of adjuvanted extracts. Most of these clinical trials revealed both clinical efficacy and immunological effects. However, more studies are warranted to further focus the specific role of adjuvants in the process of tolerance induction in allergic patients. PMID- 23090387 TI - Wheat Subtilisin/Chymotrypsin Inhibitor (WSCI) as a scaffold for novel serine protease inhibitors with a given specificity. AB - WSCI (Wheat Subtilisin/Chymotrypsin Inhibitor) is a small protein belonging to the Potato inhibitor I family exhibiting a high content of essential amino acid. In addition to bacterial subtilisins and mammalian chymotrypsins, WSCI inhibits chymotrypsin-like activities isolated from digestive traits of a number of insect larvae. In vivo, as suggested for many plant proteinase inhibitors, WSCI seems to play a role of natural defence against attacks of pests and pathogens. The functional region of WSCI, containing the inhibitor reactive site (Met48-Glu49), corresponds to an extended flexible loop (Val42-Asp53) whose architecture is somehow stabilized by a number of secondary interactions established with a small beta-sheet located underneath. The aim of this study was to employ a WSCI molecule as a stable scaffold to obtain recombinant inhibitors with new acquired anti-proteinase activity or, alternatively, inactive WSCI variants. A gene sequence coding for the native WSCI, along with genes coding for muteins with different specficities, could be exploited to obtain transformed non-food use plants with improved insect resistance. On the other hand, the genetic transformation of cereal plants over-expressing inactive WSCI muteins could represent a possible strategy to improve the nutritional quality of cereal-based foods, without risk of interference with human or animal digestive enzymes. Here, we described the characterization of four muteins containing single/multiple amino acid substitutions at the WSCI reactive site and/or at its proximity. Modalities of interaction of these muteins with proteinases (subtilisin, trypsin and chymotrypsin) were investigated by time course hydrolysis and molecular simulations studies. PMID- 23090385 TI - Estrogen effects in allergy and asthma. AB - PURPOSE OF REVIEW: Asthma prevalence and severity are greater in women than in men, and mounting evidence suggests this is in part related to female steroid sex hormones. Of these, estrogen has been the subject of much study. This review highlights recent research exploring the effects of estrogen in allergic disease. RECENT FINDINGS: Estrogen receptors are found on numerous immunoregulatory cells and estrogen's actions skew immune responses toward allergy. It may act directly to create deleterious effects in asthma, or indirectly via modulation of various pathways including secretory leukoprotease inhibitor, transient receptor potential vanilloid type 1 ion channel and nitric oxide production to exert effects on lung mechanics and inflammation. Not only do endogenous estrogens appear to play a role, but environmental estrogens have also been implicated. Environmental estrogens (xenoestrogens) including bisphenol A and phthalates enhance allergic sensitization in animal models and may enhance development of atopic disorders like asthma in humans. SUMMARY: Estrogen's role in allergic disease remains complex. As allergic diseases continue to increase in prevalence and affect women disproportionately, gaining a fuller understanding of its effects in these disorders will be essential. Of particular importance may be effects of xenoestrogens on allergic disease. PMID- 23090388 TI - Steps toward a globally available malaria vaccine: harnessing the potential of algae for future low cost vaccines. AB - Malaria is an infectious disease that threatens half of the world's population. This debilitating disease is caused by infection from parasites of the genus Plasmodium. Insecticides, bed nets and drug therapies have lowered the prevalence and death rate associated with malaria but this disease continues to plague many populations around the world. In recent years, many organizations have suggested developing methods for a complete eradication of malaria. The most straightforward and effective method for this potential eradication will be through the development of a low-cost vaccine. To achieve eradication, it will be necessary to develop new vaccine candidates and novel systems for both the production and delivery of these vaccines. Recently, the green algae Chlamydomonas reinhardtii has been used for the recombinant expression of malaria vaccine candidates including the transmission blocking vaccine candidate Pfs48/45. Here, we discuss the potential of this research on the future development of a low-cost malaria vaccine candidate. PMID- 23090389 TI - Genes encoding homologous antigens in taeniid cestode parasites: Implications for development of recombinant vaccines produced in Escherichia coli. AB - Recombinant vaccine antigens are being evaluated for their ability to protect livestock animals against cysticercosis and related parasitic infections. Practical use of some of these vaccines is expected to reduce parasite transmission, leading to a reduction in the incidence of neurocysticercosis and hydatid disease in humans. We recently showed that an antigen (TSOL16), expressed in Escherichia coli, confers high levels of protection against Taenia solium cysticercosis in pigs, which provides a strategy for control of T. solium parasite transmission. Here, we discuss the characteristics of this antigen that may affect the utility of TSOL16 and related antigens for development as recombinant vaccines. We also report that genes encoding antigens closely related to TSOL16 from T. solium also occur in other related species of parasites. These highly homologous antigens have the potential to be used as vaccines and may provide protection against related species of Taenia that cause infection in other hosts. PMID- 23090390 TI - Quick photo-Fenton degradation of phenolic compounds by Cu/Al2O3-MCM-41 under visible light irradiation: small particle size, stabilization of copper, easy reducibility of Cu and visible light active material. AB - The present study reports the photo-Fenton degradation of phenolic compounds (phenol, 2-chloro-4-nitrophenol and 4-chloro-2-nitrophenol) in aqueous solution using mesoporous Cu/Al(2)O(3)-MCM-41 nanocomposite as a heterogeneous photo Fenton-like catalyst. The in situ incorporation of mesoporous Al(2)O(3) (MA) into the framework of MCM-41 (sol-gel method) forms Al(2)O(3)-MCM-41 and wetness impregnation of Cu(II) on Al(2)O(3)-MCM-41 generates mesoporous Cu/Al(2)O(3)-MCM 41 composite. The effects of pH and H(2)O(2) concentration on degradation of phenol, 2-chloro-4-nitrophenol and 4-chloro-2-nitrophenol are studied. Kinetics analysis shows that the photocatalytic degradation reaction follows a first-order rate equation. Mesoporous 5 Cu/Al(2)O(3)-MCM-41 is found to be an efficient photo Fenton-like catalyst for the degradation of phenolic compounds. It shows nearly 100% degradation in 45 min at pH 4. The combined effect of small particle size, stabilization of Cu(2+) on the support Al(2)O(3)-MCM-41, ease reducibility of Cu(2+) and visible light activeness are the key factors for quick degradation of phenolic compounds by Cu/Al(2)O(3)-MCM-41. PMID- 23090391 TI - Poor physical performance and dementia in the oldest old: the 90+ study. AB - OBJECTIVE: To examine the cross-sectional relationship between physical performance and dementia in the oldest old (those >= 90 years of age). DESIGN: Cross-sectional study. SETTING: The 90+ Study is a population-based, longitudinal, epidemiologic study of aging and dementia performed at the University of California, Irvine, from January 1, 2003, through November 30, 2009. PARTICIPANTS: A total of 629 participants from The 90+ Study were included in the study. The mean age was 94 years, and most (72.5%) were women. MAIN OUTCOME MEASURES: All-cause dementia, based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria, was the main outcome measure. The independent variables were physical performance measures, including 4-m walk, 5 chair stands, standing balance, and grip strength, each scored from 0 to 4 (0, unable to perform; 4, best performance). Odds of dementia in relation to the physical performance measures were estimated by logistic regression after adjustment for age and sex. RESULTS Poor physical performance in all measures was significantly associated with increased odds of dementia (P< .001). Odds ratios for every unit decrease in physical performance score were 2.1 for 4-m walk, 2.1 for chair stands, 1.9 for standing balance, and 1.7 for grip strength. CONCLUSIONS: We found a strong cross-sectional relationship between poor physical performance and dementia in people 90 years and older. Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition. Additional research is necessary to determine the temporal relationship between poor physical performance and cognitive dysfunction. PMID- 23090392 TI - Nobel Prize for Chemistry 2012: GPCRs seen through a crystal ball. PMID- 23090393 TI - Structures of haemoglobin from woolly mammoth in liganded and unliganded states. AB - The haemoglobin (Hb) of the extinct woolly mammoth has been recreated using recombinant genes expressed in Escherichia coli. The globin gene sequences were previously determined using DNA recovered from frozen cadavers. Although highly similar to the Hb of existing elephants, the woolly mammoth protein shows rather different responses to chloride ions and temperature. In particular, the heat of oxygenation is found to be much lower in mammoth Hb, which appears to be an adaptation to the harsh high-latitude climates of the Pleistocene Ice Ages and has been linked to heightened sensitivity of the mammoth protein to protons, chloride ions and organic phosphates relative to that of Asian elephants. To elucidate the structural basis for the altered homotropic and heterotropic effects, the crystal structures of mammoth Hb have been determined in the deoxy, carbonmonoxy and aquo-met forms. These models, which are the first structures of Hb from an extinct species, show many features reminiscent of human Hb, but underline how the delicate control of oxygen affinity relies on much more than simple overall quaternary-structure changes. PMID- 23090394 TI - A new crystal form of MshB from Mycobacterium tuberculosis with glycerol and acetate in the active site suggests the catalytic mechanism. AB - MshB, a zinc-based deacetylase, catalyses a step in the mycothiol biosynthetic pathway that involves the deacetylation of 1-O-(2-acetamido-2-deoxy-alpha-D glucopyranosyl)-D-myo-inositol (GlcNAc-Ins), via cleavage of an amide bond, to 1 O-(2-amino-2-deoxy-alpha-D-glucopyranosyl)-D-myo-inositol (GlcN-Ins) and acetate. In this study, MshB was expressed, purified and crystallized. A new crystal form was encountered in 0.1 M sodium acetate, 0.2 M ammonium sulfate, 25% PEG 4000 pH 4.6. The crystals diffracted to 1.95 A resolution and the resulting electron density map revealed glycerol and the reaction product, acetate, in the active site. These ligands enabled the natural substrate GlcNAc-Ins to be modelled in the active site with some certainty. One acetate O atom is hydrogen bonded to Tyr142 and is located 2.5 A from the catalytic zinc. The other acetate O atom is located 2.7 A from a carboxylate O atom of Asp15. This configuration strongly suggests that Asp15 acts both as a general base catalyst in the nucleophilic attack of water on the amide carbonyl C atom and in its protonated form acts as a general acid to protonate the amide N atom. The configuration of Tyr142 differs from that observed previously in crystal structures of MshB (PDB entries 1q74 and 1q7t) and its location provides direct structural support for recently published biochemical and mutational studies suggesting that this residue is involved in a conformational change on substrate binding and contributes to the oxyanion hole that stabilizes the tetrahedral intermediate. PMID- 23090395 TI - Structural insights into the broadened substrate profile of the extended-spectrum beta-lactamase OXY-1-1 from Klebsiella oxytoca. AB - Klebsiella oxytoca is a pathogen that causes serious infections in hospital patients. It shows resistance to many clinically used beta-lactam antibiotics by producing chromosomally encoded OXY-family beta-lactamases. Here, the crystal structure of an OXY-family beta-lactamase, OXY-1-1, determined at 1.93 A resolution is reported. The structure shows that the OXY-1-1 beta-lactamase has a typical class A beta-lactamase fold and exhibits greater similarity to CTX-M-type beta-lactamases than to TEM-family or SHV-family beta-lactamases. It is also shown that the enzyme provides more space around the active cavity for the R(1) and R(2) substituents of beta-lactam antibiotics. The half-positive/half-negative distribution of surface electrostatic potential in the substrate-binding pocket indicates the preferred properties of substrates or inhibitors of the enzyme. The results reported here provide a structural basis for the broadened substrate profile of the OXY-family beta-lactamases. PMID- 23090397 TI - A monomeric TIM-barrel structure from Pyrococcus furiosus is optimized for extreme temperatures. AB - The structure of phosphoribosyl anthranilate isomerase (TrpF) from the hyperthermophilic archaeon Pyrococcus furiosus (PfTrpF) has been determined at 1.75 A resolution. The PfTrpF structure has a monomeric TIM-barrel fold which differs from the dimeric structures of two other known thermophilic TrpF proteins. A comparison of the PfTrpF structure with the two known bacterial thermophilic TrpF structures and the structure of a related mesophilic protein from Escherichia coli (EcTrpF) is presented. The thermophilic TrpF structures contain a higher proportion of ion pairs and charged residues compared with the mesophilic EcTrpF. These residues contribute to the closure of the central barrel and the stabilization of the barrel and the surrounding alpha-helices. In the monomeric PfTrpF conserved structural water molecules are mostly absent; instead, the structural waters are replaced by direct side-chain-main-chain interactions. As a consequence of these combined mechanisms, the P. furiosus enzyme is a thermodynamically stable and entropically optimized monomeric TIM-barrel enzyme which defines a good framework for further protein engineering for industrial applications. PMID- 23090396 TI - Endo-beta-D-1,4-mannanase from Chrysonilia sitophila displays a novel loop arrangement for substrate selectivity. AB - The crystal structure of wild-type endo-beta-D-1,4-mannanase (EC 3.2.1.78) from the ascomycete Chrysonilia sitophila (CsMan5) has been solved at 1.40 A resolution. The enzyme isolated directly from the source shows mixed activity as both an endo-glucanase and an endo-mannanase. CsMan5 adopts the (beta/alpha)(8) barrel fold that is well conserved within the GH5 family and has highest sequence and structural homology to the GH5 endo-mannanases. Superimposition with proteins of this family shows a unique structural arrangement of three surface loops of CsMan5 that stretch over the active centre, promoting an altered topography of the binding cleft. The most relevant feature results from the repositioning of a long loop at the extremity of the binding cleft, resulting in a shortened glycone binding region with two subsites. The other two extended loops flanking the binding groove produce a narrower cleft compared with the wide architecture observed in GH5 homologues. Two aglycone subsites (+1 and +2) are identified and a nonconserved tryptophan (Trp271) at the +1 subsite may offer steric hindrance. Taken together, these findings suggest that the discrimination of mannan substrates is achieved through modified loop length and structure. PMID- 23090398 TI - Structures of the ribosome-inactivating protein from barley seeds reveal a unique activation mechanism. AB - Ribosome-inactivating protein (RIP), a defence protein found in various plants, possesses different chain architectures and activation mechanisms. The RIP from barley (bRIP) is a type I RIP and has sequence features that are divergent from those of type I and type II RIPs from dicotyledonous plants and even the type III RIP from maize. This study presents the first crystal structure of an RIP from a cereal crop, barley, in free, AMP-bound and adenine-bound states. For phasing, a codon-optimized synthetic brip1 gene was used and a vector was constructed to overexpress soluble bRIP fusion proteins; such expression has been verified in a number of cases. The overall structure of bRIP shows folding similar to that observed in other RIPs but also shows significant differences in specific regions, particularly in a switch region that undergoes a structural transition between a 3(10)-helix and a loop depending on the liganded state. The switch region is in a position equivalent to that of a proteolytically susceptible and putative ribosome-binding site in type III RIPs. Thus, the bRIP structure confirms the detailed enzymatic mechanism of this N-glycosidase and reveals a novel activation mechanism for type I RIPs from cereal crops. PMID- 23090399 TI - Structural studies on the folded domain of the human prion protein bound to the Fab fragment of the antibody POM1. AB - Prion diseases are neurodegenerative diseases characterized by the conversion of the cellular prion protein PrP(c) into a pathogenic isoform PrP(sc). Passive immunization with antiprion monoclonal antibodies can arrest the progression of prion diseases. Here, the crystal structure of the Fab fragment of an antiprion monoclonal antibody, POM1, in complex with human prion protein (huPrP(c)) has been determined to 2.4 A resolution. The prion epitope of POM1 is in close proximity to the epitope recognized by the purportedly therapeutic antibody fragment ICSM18 Fab in complex with huPrP(c). POM1 Fab forms a 1:1 complex with huPrP(c) and the measured K(d) of 4.5 * 10(-7) M reveals moderately strong binding between them. Structural comparisons have been made among three prion antibody complexes: POM1 Fab-huPrP(c), ICSM18 Fab-huPrP(c) and VRQ14 Fab ovPrP(c). The prion epitopes recognized by ICSM18 Fab and VRQ14 Fab are adjacent to a prion glycosylation site, indicating possible steric hindrance and/or an altered binding mode to the glycosylated prion protein in vivo. However, both of the glycosylation sites on huPrP(c) are positioned away from the POM1 Fab binding epitope; thus, the binding mode observed in this crystal structure and the binding affinity measured for this antibody are most likely to be the same as those for the native prion protein in vivo. PMID- 23090400 TI - Modeling the SHG activities of diverse protein crystals. AB - A symmetry-additive ab initio model for second-harmonic generation (SHG) activity of protein crystals was applied to assess the likely protein-crystal coverage of SHG microscopy. Calculations were performed for 250 proteins in nine point-group symmetries: a total of 2250 crystals. The model suggests that the crystal symmetry and the limit of detection of the instrument are expected to be the strongest predictors of coverage of the factors considered, which also included secondary-structural content and protein size. Much of the diversity in SHG activity is expected to arise primarily from the variability in the intrinsic protein response as well as the orientation within the crystal lattice. Two or more orders-of-magnitude variation in intensity are expected even within protein crystals of the same symmetry. SHG measurements of tetragonal lysozyme crystals confirmed detection, from which a protein coverage of ~84% was estimated based on the proportion of proteins calculated to produce SHG responses greater than that of tetragonal lysozyme. Good agreement was observed between the measured and calculated ratios of the SHG intensity from lysozyme in tetragonal and monoclinic lattices. PMID- 23090401 TI - Error-estimation-guided rebuilding of de novo models increases the success rate of ab initio phasing. AB - Recent advancements in computational methods for protein-structure prediction have made it possible to generate the high-quality de novo models required for ab initio phasing of crystallographic diffraction data using molecular replacement. Despite those encouraging achievements in ab initio phasing using de novo models, its success is limited only to those targets for which high-quality de novo models can be generated. In order to increase the scope of targets to which ab initio phasing with de novo models can be successfully applied, it is necessary to reduce the errors in the de novo models that are used as templates for molecular replacement. Here, an approach is introduced that can identify and rebuild the residues with larger errors, which subsequently reduces the overall C(alpha) root-mean-square deviation (CA-RMSD) from the native protein structure. The error in a predicted model is estimated from the average pairwise geometric distance per residue computed among selected lowest energy coarse-grained models. This score is subsequently employed to guide a rebuilding process that focuses on more error-prone residues in the coarse-grained models. This rebuilding methodology has been tested on ten protein targets that were unsuccessful using previous methods. The average CA-RMSD of the coarse-grained models was improved from 4.93 to 4.06 A. For those models with CA-RMSD less than 3.0 A, the average CA-RMSD was improved from 3.38 to 2.60 A. These rebuilt coarse-grained models were then converted into all-atom models and refined to produce improved de novo models for molecular replacement. Seven diffraction data sets were successfully phased using rebuilt de novo models, indicating the improved quality of these rebuilt de novo models and the effectiveness of the rebuilding process. Software implementing this method, called MORPHEUS, can be downloaded from http://www.riken.jp/zhangiru/software.html. PMID- 23090402 TI - The structure of L-amino-acid ligase from Bacillus licheniformis. AB - L-Amino-acid ligases (LALs) are enzymes which catalyze the formation of dipeptides by linking two L-amino acids. Although many dipeptides are known and expected to have medical and nutritional benefits, their practical use has been limited owing to their low availability and high expense. LALs are potentially desirable tools for the efficient production of dipeptides; however, the molecular basis of substrate recognition by LAL has not yet been sufficiently elucidated for the design of ideal LALs for the desired dipeptides. This report presents the crystal structure of the LAL BL00235 derived from Bacillus licheniformis NBRC 12200 determined at 1.9 A resolution using the multi wavelength anomalous dispersion method. The overall structure of BL00235 is fairly similar to that of YwfE, the only LAL with a known structure, but the structure around the catalytic site contains some significant differences. Detailed structural comparison of BL00235 with YwfE sheds some light on the molecular basis of the substrate specificities. PMID- 23090403 TI - Severe diffraction anisotropy, rotational pseudosymmetry and twinning complicate the refinement of a pentameric coiled-coil structure of NSP4 of rotavirus. AB - The crystal structure of the region spanning residues 95-146 of the rotavirus nonstructural protein NSP4 from the asymptomatic human strain ST3 was determined at a resolution of 2.5 A. Severe diffraction anisotropy, rotational pseudosymmetry and twinning complicated the refinement of this structure. A systematic explanation confirming the crystal pathologies and describing how the structure was successfully refined is given in this report. PMID- 23090404 TI - Structure of the corrinoid:coenzyme M methyltransferase MtaA from Methanosarcina mazei. AB - The zinc-containing corrinoid:coenzyme M methyltransferase MtaA is part of the methanol-coenzyme M-methyltransferase complex of Methanosarcina mazei. The whole complex consists of three subunits: MtaA, MtaB and MtaC. The MtaB-MtaC complex catalyses the cleavage of methanol (bound to MtaB) and the transfer of the methyl group onto the cobalt of cob(I)alamin (bound to MtaC). The MtaA-MtaC complex catalyses methyl transfer from methyl-cob(III)alamin (bound to MtaC) to coenzyme M (bound to MtaA). The crystal structure of the MtaB-MtaC complex from M. barkeri has previously been determined. Here, the crystal structures of MtaA from M. mazei in a substrate-free but Zn(2+)-bound state and in complex with Zn(2+) and coenzyme M (HS-CoM) are reported at resolutions of 1.8 and 2.1 A, respectively. A search for homologous proteins revealed that MtaA exhibits 23% sequence identity to human uroporphyrinogen III decarboxylase, which has also the highest structural similarity (r.m.s.d. of 2.03 A for 306 aligned amino acids). The main structural feature of MtaA is a TIM-barrel-like fold, which is also found in all other zinc enzymes that catalyse thiol-group alkylation. The active site of MtaA is situated at the narrow bottom of a funnel such that the thiolate group of HS CoM points towards the Zn(2+) ion. The Zn(2+) ion in the active site of MtaA is coordinated tetrahedrally via His240, Cys242 and Cys319. In the substrate-free form the fourth ligand is Glu263. Binding of HS-CoM leads to exchange of the O ligand of Glu263 for the S-ligand of HS-CoM with inversion of the zinc geometry. The interface between MtaA and MtaC for transfer of the methyl group from MtaC bound methylcobalamin is most likely to be formed by the core complex of MtaB MtaC and the N-terminal segment (a long loop containing three alpha-helices and a beta-hairpin) of MtaA, which is not part of the TIM-barrel core structure of MtaA. PMID- 23090405 TI - Structure analysis of geranyl pyrophosphate methyltransferase and the proposed reaction mechanism of SAM-dependent C-methylation. AB - In the typical isoprenoid-biosynthesis pathway, condensation of the universal C(5)-unit precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) occurs via the common intermediates prenyl pyrophosphates (C(10)-C(20)). The diversity of isoprenoids reflects differences in chain length, cyclization and further additional modification after cyclization. In contrast, the biosynthesis of 2-methylisonorneol (2-MIB), which is responsible for taste and odour problems in drinking water, is unique in that it primes the enzymatic methylation of geranyl pyrophosphate (GPP) before cyclization, which is catalyzed by an S-adenosyl-L-methionine-dependent methyltransferase (GPPMT). The substrate of GPPMT contains a nonconjugated olefin and the reaction mechanism is expected to be similar to that of the steroid methyltransferase (SMT) family. Here, structural analysis of GPPMT in complex with its cofactor and substrate revealed the mechanisms of substrate recognition and possible enzymatic reaction. Using the structures of these complexes, methyl-group transfer and the subsequent proton-abstraction mechanism are discussed. GPPMT and SMTs contain a conserved glutamate residue that is likely to play a role as a general base. Comparison with the reaction mechanism of the mycolic acid cyclopropane synthase (MACS) family also supports this result. This enzyme represented here is the first model of the enzymatic C-methylation of a nonconjugated olefin in the isoprenoid biosynthesis pathway. In addition, an elaborate system to avoid methylation of incorrect substrates is proposed. PMID- 23090406 TI - Structural characterization of a modification subunit of a putative type I restriction enzyme from Vibrio vulnificus YJ016. AB - In multifunctional type I restriction enzymes, active methyltransferases (MTases) are constituted of methylation (HsdM) and specificity (HsdS) subunits. In this study, the crystal structure of a putative HsdM subunit from Vibrio vulnificus YJ016 (vvHsdM) was elucidated at a resolution of 1.80 A. A cofactor-binding site for S-adenosyl-L-methionine (SAM, a methyl-group donor) is formed within the C terminal domain of an alpha/beta-fold, in which a number of residues are conserved, including the GxGG and (N/D)PP(F/Y) motifs, which are likely to interact with several functional moieties of the SAM methyl-group donor. Comparison with the N6 DNA MTase of Thermus aquaticus and other HsdM structures suggests that two aromatic rings (Phe199 and Phe312) in the motifs that are conserved among the HsdMs may sandwich both sides of the adenine ring of the recognition sequence so that a conserved Asn residue (Asn309) can interact with the N6 atom of the target adenine base (a methyl-group acceptor) and locate the target adenine base close to the transferred SAM methyl group. PMID- 23090407 TI - Alteration of fluorescent protein spectroscopic properties upon cryoprotection. AB - Cryoprotection of a protein crystal by addition of small-molecule compounds may sometimes affect the structure of its active site. The spectroscopic and structural effects of the two cryoprotectants glycerol and ethylene glycol on the cyan fluorescent protein Cerulean were investigated. While glycerol had almost no noticeable effect, ethylene glycol was shown to induce a systematic red shift of the UV-vis absorption and fluorescence emission spectra. Additionally, ethylene glycol molecules were shown to enter the core of the protein, with one of them binding in close vicinity to the chromophore, which provides a sound explanation for the observed spectroscopic changes. These results highlight the need to systematically record spectroscopic data on crystals of light-absorbing proteins and reinforce the notion that fluorescent proteins must not been seen as rigid structures. PMID- 23090409 TI - Professor Dame Louise Napier Johnson (26 September 1940-25 September 2012). PMID- 23090408 TI - Nanoflow electrospinning serial femtosecond crystallography. AB - An electrospun liquid microjet has been developed that delivers protein microcrystal suspensions at flow rates of 0.14-3.1 ul min(-1) to perform serial femtosecond crystallography (SFX) studies with X-ray lasers. Thermolysin microcrystals flowed at 0.17 ul min(-1) and diffracted to beyond 4 A resolution, producing 14,000 indexable diffraction patterns, or four per second, from 140 ug of protein. Nanoflow electrospinning extends SFX to biological samples that necessitate minimal sample consumption. PMID- 23090410 TI - Saline as the sole contrast agent for successful MRI-guided epidural injections. AB - PURPOSE: To assess the performance of sterile saline solution as the sole contrast agent for percutaneous magnetic resonance imaging (MRI)-guided epidural injections at 1.5 T. METHODS: A retrospective analysis of two different techniques of MRI-guided epidural injections was performed with either gadolinium enhanced saline solution or sterile saline solution for documentation of the epidural location of the needle tip. T1-weighted spoiled gradient echo (FLASH) images or T2-weighted single-shot turbo spin echo (HASTE) images visualized the test injectants. Methods were compared by technical success rate, image quality, table time, and rate of complications. RESULTS: 105 MRI-guided epidural injections (12 of 105 with gadolinium-enhanced saline solution and 93 of 105 with sterile saline solution) were performed successfully and without complications. Visualization of sterile saline solution and gadolinium-enhanced saline solution was sufficient, good, or excellent in all 105 interventions. For either test injectant, quantitative image analysis demonstrated comparable high contrast-to noise ratios of test injectants to adjacent body substances with reliable statistical significance levels (p < 0.001). The mean table time was 22 +/- 9 min in the gadolinium-enhanced saline solution group and 22 +/- 8 min in the saline solution group (p = 0.75). CONCLUSION: Sterile saline is suitable as the sole contrast agent for successful and safe percutaneous MRI-guided epidural drug delivery at 1.5 T. PMID- 23090416 TI - Calcification of combined hamartoma of the retina and retinal pigment epithelium over 15 years. PMID- 23090417 TI - Rosai-Dorfman disease presenting as choroidal melanoma: a case report and review of the literature. AB - BACKGROUND: Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy, is a rare non-malignant proliferation of histiocytes of unknown aetiology. It was first recognised as a distinct clinicopathologic entity in 1969, and is classified as an idiopathic non-Langerhans cell histiocytosis. The disease process is usually self-limiting and often involves lymph nodes, but extranodal involvement is well-described and any anatomic site can be involved. METHODS: We describe a unique case of a 40-year-old male who presented with a fundus mass diagnosed clinically as choroidal melanoma. The tumour showed rapid growth. The patient developed a total retinal detachment and underwent enucleation. The globe contained a choroidal tumour with histologic and immunophenotypic features characteristic of RDD. The literature of ocular Rosai Dorfman disease was reviewed. RESULTS: This is the first case in the English literature of intraocular choroidal RDD, mimicking choroidal melanoma. CONCLUSIONS: Rosai-Dorfman disease can present as a mass-producing lesion in the choroid and may mimic other choroidal tumours. The case emphasises the need to consider diagnostic biopsy prior to definitive treatment of choroidal tumours. PMID- 23090414 TI - Nuclear pore complex composition: a new regulator of tissue-specific and developmental functions. AB - Nuclear pore complexes (NPCs) are multiprotein aqueous channels that penetrate the nuclear envelope connecting the nucleus and the cytoplasm. NPCs consist of multiple copies of roughly 30 different proteins known as nucleoporins (NUPs). Due to their essential role in controlling nucleocytoplasmic transport, NPCs have traditionally been considered as structures of ubiquitous composition. The overall structure of the NPC is indeed conserved in all cells, but new evidence suggests that the protein composition of NPCs varies among cell types and tissues. Moreover, mutations in various nucleoporins result in tissue-specific diseases. These findings point towards a heterogeneity in NPC composition and function. This unexpected heterogeneity suggests that cells use a combination of different nucleoporins to assemble NPCs with distinct properties and specialized functions. PMID- 23090418 TI - De novo design of N-(pyridin-4-ylmethyl)aniline derivatives as KDR inhibitors: 3D QSAR, molecular fragment replacement, protein-ligand interaction fingerprint, and ADMET prediction. AB - Vascular endothelial growth factor (VEGF) and its receptor tyrosine kinase VEGFR 2 or kinase insert domain receptor (KDR) have been identified as promising targets for novel anticancer agents. To achieve new potent inhibitors of KDR, we conducted molecular fragment replacement (MFR) studies for the understanding of 3D-QSAR modeling and the docking investigation of arylphthalazines and 2-((1H Azol-1-yl)methyl)-N-arylbenzamides-based KDR inhibitors. Two favorable 3D-QSAR models (CoMFA with q(2), 0.671; r(2), 0.969; CoMSIA with q(2), 0.608; r(2), 0.936) have been developed to predict the biological activity of new compounds. The new molecular database generated by MFR was virtually screened using Glide (docking) and further evaluated with CoMFA prediction, protein-ligand interaction fingerprint (PLIF) and ADMET analysis. 44 N-(pyridin-4-ylmethyl)aniline derivatives as novel potential KDR inhibitors were finally obtained. In this paper, the work flow developed could be applied to de novo drug design and virtual screening potential KDR inhibitors, and use hit compounds to further optimize and design new potential KDR inhibitors. PMID- 23090419 TI - Synthesis of trans-1,3-diaryl-2-(5-methylisoxazol-3-yl)-2,3-dihydro-1H naphtho[1,2-e][1,3]oxazines via bismuth(III)-catalyzed one-pot pseudo-four component reaction. AB - An expeditious, straightforward and efficient synthesis of diversely naphtho[1,2 e][1,3]oxazines via one-pot condensation reaction of beta- naphthol, 3-amino-5 methylisoxazole and arylaldehydes catalyzed by bismuth(III) trifluoromethanesulfonate is described. The reaction preferentially afforded 1,3 trans oxazines. PMID- 23090420 TI - Size-invariant representation of face in infant brain: an fNIRS-adaptation study. AB - We studied whether 5-month-old to 8-month-old infants process faces in a size invariant manner by applying the fNIRS-adaptation paradigm used in our previous study. We used near-infrared spectroscopy to measure hemodynamic responses in the temporal regions of infants' brains during the repeated presentation of an identical face and different faces while changing the size of the faces. As a result, we found that (a) the hemodynamic responses in the channels around the T5 and T6 positions increased significantly during the presentation of different faces and (b) the hemodynamic responses in these channels showed attenuation to the presentation of the same face compared with the presentation of different faces even when the size of the faces altered. Our findings indicated that infants could show adaptation to the same face despite size alterations and that this processing occurred in the bilateral temporal areas. PMID- 23090421 TI - Consumption of diagnostic procedures and other cardiology care in chest pain patients after presentation at the emergency department. AB - OBJECTIVE: The HEART score serves risk stratification of chest pain patients at the emergency department (ED). Quicker and more solid decisions may be taken in these patients with application of this score. An analysis of medical consumption of 122 acute chest pain patients admitted before the introduction of this score may be indicative of possible savings. METHODS: Numbers of cardiology investigations and clinical admission days were counted. Charged cost of medicine was divided into three categories: ED, in-hospital, and outpatient clinic. RESULTS: The total cost of care was 469,631, with an average of 3849 per patient. Seventy-five percent of this cost was due to hospitalisation under the initial working diagnosis of acute coronary syndrome (ACS). This diagnosis was confirmed in only 29/122 (24 %) of the patients. The low-risk group (41 patients with HEART scores 0-3) included one patient with a previously scheduled CABG. In the remaining 40 patients, hospitalisation occurred in 12/40 (30 %) patients and 30/40 (75 %) patients visited the outpatient clinic. The total cost of medical care after presentation of these 40 patients was 37,641; there were no cases where a new diagnosis of coronary artery disease was made. When medical care in this subgroup is declared redundant, major savings on national medical care budgets could be made. CONCLUSION: If the HEART score were to be routinely applied, diagnostic pathways could be shortened and costs reduced, in particular in low-risk patients. PMID- 23090422 TI - Visualizing highly localized luminescence in GaN/AlN heterostructures in nanowires. AB - The optical properties of a stack of GaN/AlN quantum discs (QDiscs) in a GaN nanowire have been studied by spatially resolved cathodoluminescence (CL) at the nanoscale (nanoCL) using a scanning transmission electron microscope (STEM) operating in spectrum imaging mode. For the electron beam excitation in the QDisc region, the luminescence signal is highly localized, with spatial extent as low as 5 nm, due to the high band gap difference between GaN and AlN. This allows the discrimination between the emission of neighbouring QDiscs and evidencing the presence of lateral inclusions, about 3 nm thick and 20 nm long rods (quantum rods, QRods), grown unintentionally on the nanowire sidewalls. These structures, also observed by STEM dark-field imaging, are proved to be optically active in nanoCL, emitting at similar, but usually shorter, wavelengths with respect to most QDiscs. PMID- 23090423 TI - Psoriasis triggered by infliximab in a patient with Behcet's disease. AB - PURPOSE: To report a case of psoriasis triggered by anti-tumor necrosis factor alpha (TNF-alpha) therapy in a uveitis patient with Behcet's disease. CASE REPORT: A 34-year-old man with established Behcet's disease was started on infliximab therapy for recurrent uveitis and showed an excellent response. After 2 years of infliximab treatment, he developed erythematous scaly plaques on both of his palms and heels. No clinical or serological evidence of infection was found, and there was no personal/family history of psoriasis. Histological examination of one lesion showed that it was consistent with psoriasis. Because of the development of hyperkeratotic skin lesions consistent with guttate psoriasis, the infliximab treatment was discontinued. Six months later, the psoriasis had resolved. CONCLUSIONS: Blockade of TNF-alpha is an effective treatment for psoriasis as well as Behcet's disease. However, we have to consider new-onset psoriasis as an adverse side effect that can be triggered by anti-TNF alpha therapy in Behcet's disease. PMID- 23090424 TI - No difference in total blood loss, haemoglobin and haematocrit between continues and intermittent wound drainage after total knee arthroplasty. AB - PURPOSE: The purpose of this prospective randomized study was to compare the visible, hidden, total blood loss and postoperative haemodynamic change of 4-h clamping and nonclamping of the drain after TKA. The hypothesis in the present study was that intermittent drain clamping with injection of diluted epinephrine solution would decrease the visible, hidden blood loss and reduction of postoperative haemoglobin or haematocrit change after TKA. METHODS: From January 2010 to January 2011, 100 TKAs were performed at our hospital. In group I (50 knees), drainage was clamped for the first 4 postoperative hours with injection of diluted epinephrine solution. In group II (50 knees), drainage was not clamped without injection of diluted epinephrine solution. Two drains with an external diameter of 3.2 mm were inserted into the knee joint. We checked the amount of drainage recorded at 6, 12, 24, and 48 h postoperatively. Also, we checked the haemoglobin and haematocrit on the preoperation, first, 5th and 10th postoperative days. We analysed the transfusion rate, the possible adverse issues with clamping drainage, and the range of motion of the knee. RESULTS: The mean total bloody drainage was significantly less in group I than group II (560.7 +/- 249.9 mL vs 978.3 +/- 327.5 mL) (p < 0.001). The decrease of haemoglobin and haematocrit after surgery was not significant between the two groups (n.s.). The hidden blood loss was significantly more in group I than group II (541.1 +/- 439.4 mL vs 32.1 +/- 21.9 mL) (p < 0.001). So, total blood loss showed no significant difference between the two groups (1,101.8 +/- 373.6 mL vs 1,010.4 +/ 385.9 mL) (n.s.). The postoperative range of motion and transfusion rate between the two groups were not significant (n.s.). But immediate wound problem, such as oozing, was significantly more in group I (p < 0.001). CONCLUSION: It is not necessary to perform the intermittent drain clamping with injection of the diluted epinephrine solution in TKA because there is no impact on the postoperative haemoglobin and haematocrit. If anything, the intermittent drain clamping with injection of the diluted epinephrine solution increased the hidden blood loss and immediate wound problem than nonclamping without injection of the diluted epinephrine solution. PMID- 23090426 TI - Enhanced gastric ghrelin-induced c-Kit protein expression in rats with gastric outlet obstruction. PMID- 23090427 TI - Endoscopic removal of large common bile duct stones: time to arm the laser? PMID- 23090425 TI - Acute and acute severe (fulminant) autoimmune hepatitis. AB - Autoimmune hepatitis frequently has an abrupt onset of symptoms, and it can present with acute liver failure. The abrupt presentation can indicate spontaneous exacerbation of a pre-existent chronic disease, newly created disease, a superimposed infectious or toxic injury, or new disease after viral infection, drug therapy, or liver transplantation. Deficiencies in the classical phenotype may include a low serum immunoglobulin G level and low or absent titers of the conventional autoantibodies. The original revised diagnostic scoring system of the International Autoimmune Hepatitis Group can guide the diagnostic evaluation, but low scores do not preclude the diagnosis. Liver tissue examination is valuable to exclude viral-related or drug-induced liver injury and support the diagnosis by demonstrating centrilobular necrosis (usually with interface hepatitis), lymphoplasmacytic infiltration, hepatocyte rosettes, and fibrosis. Conventional therapy with prednisone and azathioprine induces clinical and laboratory improvement in 68-75 % of patients with acute presentations, and high dose prednisone or prednisolone (preferred drug) is effective in 20-100 % of patients with acute severe (fulminant) presentations. Failure to improve or worsening of any clinical or laboratory feature within 2 weeks of treatment or worsening of a mathematical model of end-stage liver disease within 7 days justifies liver transplantation in acute liver failure. Liver transplantation for acute severe (fulminant) autoimmune hepatitis is as successful as liver transplantation for autoimmune hepatitis with a chronic presentation and other types of acute liver failure (patient survival >1 year, 80-94 %). Liver transplantation should not be delayed or superseded by protracted corticosteroid therapy or the empiric institution of nonstandard medications. PMID- 23090428 TI - Biochemical and structural analysis of aminoglycoside acetyltransferase Eis from Anabaena variabilis. AB - The Mycobacterium tuberculosis enhanced intracellular survival (Eis_Mtb) protein is a clinically important aminoglycoside (AG) multi-acetylating enzyme. Eis homologues are found in a variety of mycobacterial and non-mycobacterial species. Variation of the residues lining the AG-binding pocket and positions of the loops bearing these residues in the Eis homologues dictates the substrate specificity and, thus, Eis homologues are Nature-made tools for elucidating principles of AG recognition by Eis. Here, we demonstrate that the Eis from Anabaena variabilis (Eis_Ava), the first non-mycobacterial Eis homologue reported, is a multi acetylating AG-acetyltransferase. Eis_Ava, Eis from Mycobacterium tuberculosis (Eis_Mtb), and Eis from Mycobacterium smegmatis (Eis_Msm) have different structures of their AG-binding pockets. We perform comparative analysis of these differences and investigate how they dictate the substrate and cosubstrate recognition and acetylation of AGs by Eis. PMID- 23090429 TI - Overweight/obese patients referring to plastic surgery: temperament and personality traits. AB - BACKGROUND: Correlations between psychiatric disorders and overweight/obesity are reported in the literature. However, temperament/personality traits have been less frequently studied even though the correlation with Axis-1 diseases is well defined. The present study aims to detect correlations between psychiatric disorders, temperament traits and body image perception in overweight and obese patients who seek surgical lipostructuring treatment. METHODS: Seventy overweight/obese patients (age 18-60 years, BMI 25-34.9 at recruitment) referring to the outpatient service for obesity-related lipodystrophism were enrolled in the period March 2008-March 2012. Psychiatric disorders, temperament traits, and body image perception were evaluated and compared with a control group (N = 33) from the general population sharing clinical/demographic features. RESULTS: Patients had higher scores in lifetime depression, with moderate/mild concern with body shape. Regarding personality traits, tests revealed higher scores on subscale RD4 (dependence/independence) in patients, whereas controls scored higher on the "openness to experience" NEO Five Factory Inventory sub-scale. Obese patients had a higher prevalence of obsessive characteristics. CONCLUSIONS: The affective sphere is an important feature in obese patients, as are obsessive traits, since negative body shape perception and temperament and personality characteristics appear to be involved in leading patients to seek surgical advice. These aspects should be involved in medical/surgical outcomes and compliance with treatment. The future possibility of identifying patients who show alterations in these traits or psychic characteristics may represent a possible instrument to avoid early post-treatment relapse and to implement the service offered to patients, with appropriate psychiatric care before and after surgery. PMID- 23090430 TI - Weight-related quality of life in Spanish obese subjects suitable for bariatric surgery is lower than in their North American counterparts: a case-control study. AB - BACKGROUND: Obesity impairs quality of life, but the perception of the impairment could be different from one country to another. The purpose was to compare weight related quality of life (QOL) between cohorts from Spain and North America. METHODS: A cross-sectional case-control study was performed between two populations. Four hundred Spanish and 400 North American obese subjects suitable for bariatric surgery closely matched for race, gender, age, and body mass index (BMI) were included. Two non-obese control groups matched for gender, age, and BMI from each population were also evaluated (n = 400 in each group). The participants completed the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire, a measure of weight-related QOL. RESULTS: Spanish morbidly obese patients showed poorer QOL than their North American counterparts in physical function, sexual life, work, and total score. By contrast, Spanish non-obese control subjects reported better QOL in all domains than their North American counterparts. Women, both in Spain and North America, reported reduced QOL compared to men on the domain of self-esteem. In addition, North American women reported reduced QOL on the sexual life domain compared to men. BMI correlated negatively with all domains of QOL except for self-esteem in both national groups. CONCLUSIONS: Spanish obese subjects suitable for bariatric surgery report poorer weight-related quality of life than their North American counterparts, and obese women, regardless of nationality, perceive a reduced quality of life compared to men. PMID- 23090431 TI - Microscopic characterization of individual particles from multicomponent ship exhaust. AB - Particles sampled from the main and auxiliary ship diesel engine exhausts during a measurement campaign aboard a cargo ship are studied by SEM and energy dispersive X-ray (EDX) microanalysis. Cluster analysis (CA) is applied to characterize the particles by separating them into distinct groups of similar morphology and chemical composition, representative of the particle types in the exhaust from the main and auxiliary engines. Raman microspectroscopy, Fourier transform infrared (FTIR) spectroscopy, inductively coupled plasma mass spectrometry and ion chromatography provide the criteria for the clustering of a large data set of individual particles. To identify chemical and morphological features of heavy and distillate fuel oil-derived PM emissions, micromarkers discriminating between the different types of emitted particles are proposed. These micromarkers could enable the classification of multicomponent aerosols according to a source type. This characterization of complex multicomponent aerosols emitted by ship diesel engines improves the quantification of the contribution of shipping to ambient air particulates, and can help to identify a source type in apportionment studies. PMID- 23090433 TI - High rate delithiation behaviour of LiFePO4 studied by quick X-ray absorption spectroscopy. AB - A novel in situ time-resolved synchrotron X-ray absorption spectroscopy (XAS) was introduced for the dynamic studies during fast chemical and electrochemical delithiation of LiFePO(4). The lithium diffusion in LiFePO(4) and the reaction mechanisms for both processes were investigated. This approach opens new opportunities for dynamic studies of various energy storage systems. PMID- 23090432 TI - Cytokinin signaling regulates pavement cell morphogenesis in Arabidopsis. AB - The puzzle piece-shaped Arabidopsis leaf pavement cells (PCs) with interdigitated lobes and indents is a good model system to investigate the mechanisms that coordinate cell polarity and shape formation within a tissue. Auxin has been shown to coordinate the interdigitation by activating ROP GTPase-dependent signaling pathways. To identify additional components or mechanisms, we screened for mutants with abnormal PC morphogenesis and found that cytokinin signaling regulates the PC interdigitation pattern. Reduction in cytokinin accumulation and defects in cytokinin signaling (such as in ARR7-over-expressing lines, the ahk3cre1 cytokinin receptor mutant, and the ahp12345 cytokinin signaling mutant) enhanced PC interdigitation, whereas over-production of cytokinin and over activation of cytokinin signaling in an ARR20 over-expression line delayed or abolished PC interdigitation throughout the cotyledon. Genetic and biochemical analyses suggest that cytokinin signaling acts upstream of ROPs to suppress the formation of interdigitated pattern. Our results provide novel mechanistic understanding of the pathways controlling PC shape and uncover a new role for cytokinin signaling in cell morphogenesis. PMID- 23090434 TI - Obstructive sleep apnoea: quantifying its association with obesity and snoring. PMID- 23090435 TI - Adolescents and anaphylaxis. PMID- 23090436 TI - Splenic hypofunction in patients with an incidental finding of small-sized spleen at abdominal ultrasound. PMID- 23090437 TI - Do patients achieve normal gait patterns 3 years after total knee arthroplasty? AB - STUDY DESIGN: Longitudinal cross-sectional study. BACKGROUND: In the early stages after total knee arthroplasty (TKA), quadriceps strength of the operated limb decreases and is substantially less than that of the nonoperated limb. This asymmetry in strength is related to asymmetrical movement patterns that increase reliance on the nonoperated limb. Over time, quadriceps strength in the operated limb increases but remains less than that in age-matched controls without knee pathology, whereas the quadriceps strength in the nonoperated limb gradually decreases. The purpose of this study was to investigate the changes in quadriceps strength and function of both limbs up to 3 years after TKA and to evaluate change in interlimb kinematic and kinetic parameters over time compared to that in age-matched individuals without knee pathology. METHODS: Fourteen individuals after TKA and 14 healthy individuals matched for age, weight, height, and sex participated in the study. Outcome measures included kinematics, kinetics, quadriceps strength, and functional performance. RESULTS: In participants who underwent TKA, quadriceps strength was significantly different between limbs at 3 months and 1 year after TKA, but not at 3 years after TKA. In this group, there was also a significant improvement in self-reported function between 3 months and 1 year after TKA, but a significant decrease between years 1 and 3 for the physical component summary score of the Medical Outcomes Study 36-Item Short-Form Health Survey. In the TKA group, there were few interlimb differences in joint kinematics and kinetics 3 years after TKA, which may be attributed to a combination of worsening in the nonoperated limb, as well as improvement in the operated limb. Differences between participants without knee pathology and those 3 years after TKA still existed for kinematic, kinetic, and spatiotemporal variables. CONCLUSION: As interlimb differences in quadriceps strength decrease after TKA, there are concomitant symmetrical improvements in temporospatial and kinetic gait parameters. The symmetry 3 years after TKA in quadriceps strength is primarily the result of progressive weakness in the nonoperated limb. PMID- 23090438 TI - Novel transformation of alpha,beta-unsaturated aldehydes and ketones into gamma amino alcohols or 1,3-oxazines via a 4 or 5 step, one-pot sequence. AB - An efficient, 4-step, one-pot, highly stereoselective route to gamma-amino alcohols has been developed via an in situ alpha,beta-unsaturated imine formation, beta-boration, reduction (C=N) and oxidation (C-B) sequence and especially for certain water-soluble gamma-amino alcohols, a further step can be added to directly access the corresponding 1,3-oxazine derivatives. PMID- 23090439 TI - Incidence and risk factors for reoperation of surgically treated urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The objective of our study was to estimate the incidence and to identify the risk factors for reoperation of surgically treated stress urinary incontinence (SUI). METHODS: We conducted a nested case-control study among 1,132 women who underwent SUI surgery from January 1988 to June 2007. Cases (n=35) were women who required reoperation for SUI following the first intervention up to December 2008. Controls (n=89) were women randomly selected from the same cohort who did not require reoperation. RESULTS: The cumulative incidence of SUI reoperation was 3.1 % with a mean follow-up of 10.9 years (range 1.7-21.0). The main risk factor was the history of more than one vaginal delivery [adjusted odds ratio (OR) 3.5; 95 % confidence interval (CI) 1.0-12.6]. The use of synthetic midurethral slings was a protective factor compared to other surgical procedures for urinary incontinence (adjusted OR 0.1; 95 % CI 0.0-0.6). CONCLUSIONS: The risk of reoperation after SUI surgery appears to be low and associated with multiple vaginal deliveries. Synthetic slings at index surgery are associated with a lower risk of reoperation. PMID- 23090440 TI - A ferrocene nucleic acid oligomer as an organometallic structural mimic of DNA. AB - The design, synthesis and electrochemical behaviour of an oligomer consisting of linked thymine-functionalised ferrocene units are reported, which, as a so-called form of ferrocene nucleic acid (FcNA), acts as a structural mimic of DNA. PMID- 23090441 TI - ZIP14 and ZIP8 zinc/bicarbonate symporters in Xenopus oocytes: characterization of metal uptake and inhibition. AB - The highly conserved human and mouse SLC39A14 and SLC39A8 genes encode the ZIP14 and ZIP8 transporters, respectively-functioning as divalent cation/bicarbonate symporters and expressed in dozens of tissues. Due to alternative splicing of exons 4, human and mouse SLC39A14 genes each encode two distinct gene products, whereas SLC39A8 produces a single product. This lab previously noted that ZIP14A and ZIP14B show highly variable expression in different cell types, suggesting differences in metal uptake function. We ligated mouse ZIP14A, ZIP14B and ZIP8 cDNA coding regions into the Xenopus-specific vector pXFRM, transcribed these in vitro, and microinjected the capped RNAs into Xenopus oocytes. K(m) and V(max) values for Cd, Zn and Fe uptake were determined. Electrogenicity studies using a potassium gradient confirmed that (just as we found previously for ZIP8) ZIP14A- and ZIP14B-mediated divalent Cd- or Zn-bicarbonate complexes are electroneutral. Competitive inhibition of Cd and Zn uptake with ten additional divalent cations showed a unique gradient of patterns for each of ZIP14A, ZIP14B and ZIP8. ZIP14 proteins are prominent in the gastrointestinal tract and ZIP8 protein is located on the surface of renal proximal tubular epithelial cells. It is known that renal Fanconi syndrome can be caused by five nonessential heavy metals: Cd(2+), Hg(2+), Pb(2+), Pt(2+) and U(2+). In the present study we show that these five divalent cations are usually competitors of ZIP14- and/or ZIP8-mediated Zn uptake; our data thus support the possible involvement of intestinal ZIP14 for uptake of these five metals into the body and ZIP8 for efficient uptake into the kidney. PMID- 23090442 TI - The promise of the state space approach to time series analysis for nursing research. AB - BACKGROUND: Nursing research, particularly related to physiological development, often depends on the collection of time series data. The state space approach to time series analysis has great potential to answer exploratory questions relevant to physiological development but has not been used extensively in nursing. OBJECTIVES: The aim of the study was to introduce the state space approach to time series analysis and demonstrate potential applicability to neonatal monitoring and physiology. METHODS: We present a set of univariate state space models; each one describing a process that generates a variable of interest over time. Each model is presented algebraically and a realization of the process is presented graphically from simulated data. This is followed by a discussion of how the model has been or may be used in two nursing projects on neonatal physiological development. RESULTS: The defining feature of the state space approach is the decomposition of the series into components that are functions of time; specifically, slowly varying level, faster varying periodic, and irregular components. State space models potentially simulate developmental processes where a phenomenon emerges and disappears before stabilizing, where the periodic component may become more regular with time, or where the developmental trajectory of a phenomenon is irregular. DISCUSSION: The ultimate contribution of this approach to nursing science will require close collaboration and cross disciplinary education between nurses and statisticians. PMID- 23090443 TI - Neurologic and vascular abnormalities in Klippel-Trenaunay-Weber syndrome. PMID- 23090445 TI - Paediatric nephrology: Bone changes in children with chronic kidney disease. PMID- 23090447 TI - Risk factors: Plasma renin activity predicts renal impairment. PMID- 23090448 TI - Diabetic nephropathy: Netrin-1 expression in proximal tubular epithelial cells protects against kidney inflammation and injury. PMID- 23090444 TI - Water quality in conventional and home haemodialysis. AB - Dialysis water can be contaminated by chemical and microbiological factors, all of which are potentially hazardous to patients on haemodialysis. The quality of dialysis water has seen incremental improvements over the years, with advances in water preparation, monitoring and disinfection methods, and high standards are now readily achievable in clinical practice. Advances in dialysis membrane technology have refocused attention on water quality and its potential role in the bioincompatibility of haemodialysis circuits and adverse patient outcomes. The role of ultrapure dialysate is increasingly being advocated, given its proposed clinical benefits and relative ease of production as a result of the widespread use of reverse osmosis and ultrafiltration. Many of the issues pertaining to water quality in hospital-based dialysis units are also pertinent to haemodialysis in the home. Furthermore, an increased awareness of the environmental and financial consequences of home haemodialysis has resulted in the development of automated and more efficient dialysis machines. These new machines have an increased emphasis on water conservation and recycling along with a decreased need for a complex infrastructure for water purification and maintenance. PMID- 23090446 TI - Assessing and improving the health-related quality of life of patients with ESRD. AB - Impairment of the health-related quality of life (HRQOL) of patients with end stage renal disease (ESRD) is now well documented. These impairments involve a wide variety of domains and can be assessed using an array of well-validated instruments. Incorporation of at least some of these instruments into routine patient care is important in order to measure the physical and psychological impact of a disease and its treatment on the HRQOL of patients. How this implementation can be achieved in a practical way is, however, a challenge. As more research focuses on improving the HRQOL of patients with ESRD, the systematic evaluation of HRQOL and incorporation into patient care is becoming increasingly important. Whether strategies to improve the HRQOL of patients will translate into improved patient outcomes--as evidenced by reduced mortality and hospitalizations--and lower costs, remains to be determined. PMID- 23090449 TI - Chronic kidney disease: Do patients with CKD benefit from lipid-lowering therapy? PMID- 23090451 TI - Real-time ultrasound-guided spinal anesthesia using the SonixGPS(r) needle tracking system: a case report. AB - PURPOSE: The SonixGPS(r) is an electromagnetic needle tracking system for ultrasound-guided needle intervention. Both current and predicted needle tip position are displayed on the ultrasound screen in real-time, facilitating needle beam alignment and guidance to the target. This case report illustrates the use of the SonixGPS system for successful performance of real-time ultrasound-guided spinal anesthesia in a patient with difficult spinal anatomy. CLINICAL FEATURES: A 67-yr-old male was admitted to our hospital to undergo revision of total right hip arthroplasty. His four previous arthroplasties for hip revision were performed under general anesthesia because he had undergone L3-L5 instrumentation for spinal stenosis. The L4-L5 interspace was viewed with the patient in the left lateral decubitus position. A 19G 80-mm proprietary needle (Ultrasonix Medical Corp, Richmond, BC, Canada) was inserted and directed through the paraspinal muscles to the ligamentum flavum in plane to the ultrasound beam. A 120-mm 25G Whitacre spinal needle was then inserted through the introducer needle in a conventional fashion. Successful dural puncture was achieved on the second attempt, as indicated by a flow of clear cerebrospinal fluid. The patient tolerated the procedure well, and the spinal anesthetic was adequate for the duration of the surgery. CONCLUSION: The SonixGPS is a novel technology that can reduce the technical difficulty of real-time ultrasound-guided neuraxial blockade. It may also have applications in other advanced ultrasound-guided regional anesthesia techniques where needle-beam alignment is critical. PMID- 23090452 TI - Formation of oriented nanostructures in diamond using metallic nanoparticles. AB - A simple, fast and cost-effective etching technique to create oriented nanostructures such as pyramidal and cylindrical shaped nanopores in diamond membranes by self-assembled metallic nanoparticles is proposed. In this process, a diamond film is annealed with thin metallic layers in a hydrogen atmosphere. Carbon from the diamond surface is dissolved into nanoparticles generated from the metal film, then evacuated in the form of hydrocarbons and, consequently, the nanoparticles enter the crystal volume. In order to understand and optimize the etching process, the role of different parameters such as type of catalyst (Ni, Co, Pt, and Au), hydrogen gas, temperature and time of annealing, and microstructure of diamond (polycrystalline and nanocrystalline) were investigated. With this technique, nanopores with lateral sizes in the range of 10-100 nm, and as deep as about 600 nm, in diamond membranes were produced without any need for a lithography process, which opens the opportunities for fabricating porous diamond membranes for chemical sensing applications. PMID- 23090453 TI - Serious infections in obstetrics and gynecology. Introduction. PMID- 23090454 TI - Early recognition of serious infections in obstetrics and gynecology. AB - Pelvic infections commonly occur in pregnant and postoperative women. Most of these infections are readily diagnosed because of their typical clinical manifestations and prompt antimicrobial therapy that leads to the resolution of disease. However, uncommon cases may escape detection and the severity of the process may also go unrecognized without a careful assessment of clues available through physical examination and laboratory testing. In some cases a particularly virulent pathogen can lead to severe infection, septic shock and its consequences, even death, despite clinicians acting appropriately. PMID- 23090455 TI - Group A streptococcal infections in obstetrics and gynecology. AB - Group A streptococcal (GAS) infections continue to be an infrequent, but potentially lethal infections in women despite the victory over childbed fever in the 1800s. Invasive group A streptococcal infection still causes 40% of septic deaths among patients with postpartum endometritis, necrotizing fasciitis, and toxic shock syndrome. Many times symptoms and signs of this infection are nonspecific, but laboratory evaluation can suggest serious infection. The prudent combination of antibiotic and surgical therapy can be lifesaving. PMID- 23090456 TI - Necrotizing soft-tissue infections in obstetric and gynecologic patients. AB - For the clinician, necrotizing soft-tissue infections have remained a daunting opponent since the first writings on the subject over 2000 years ago. Early disease may be incorrectly diagnosed as cellulitis, and this delay in correctly diagnosing and expeditiously proceeding to radical surgical debridement may lead to a high degree of mortality. Although several inciting events and risk factors have been described that allow for the development and progression of this disease, the diagnosis is still made clinically. Only aggressive surgical management in combination with broad-spectrum antibiotics will offer a chance at improving patient outcomes. PMID- 23090457 TI - Serious infection associated with induced abortion in the United States. AB - Though serious infection after induced abortion is rare, infections account for one third of abortion-related deaths in the United States. Most fatal cases of infection after induced medical abortion have involved clostridial species. These reported cases share important clinical features that may guide clinicians to earlier recognition and institution of therapy. This article reviews our current knowledge regarding serious clostridial infections postabortion including the typical clinical presentation, pathophysiology, modes of diagnosis, and available treatment. PMID- 23090458 TI - Pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and tuboovarian abscess. AB - Severe pelvic inflammatory disease and tuboovarian abscesses (TOAs) are common pelvic infections requiring inpatient admission. There are few large randomized trials guiding appropriate clinical management of TOA, including antibiotic selection and timing of surgical management and drainage. The pathogenesis, diagnosis, and management of severe pelvic inflammatory disease and TOA are summarized and reviewed from the most current literature. PMID- 23090459 TI - Postoperative infections in obstetrics and gynecology. AB - Postoperative infection is the most commonly seen complication of surgery in obstetrics and gynecology. The use of antibiotic prophylaxis has greatly decreased though not completely eliminated this adverse outcome. Postoperative infections include wound cellulitis, wound abscess, endomyometritis, pelvic cellulitis, and pelvic abscess. Infections usually manifest as fever and greater than normal postoperative pain. Refractory fevers maybe because of septic pelvic vein thrombophlebitis or maybe noninfectious in origin. Broad-spectrum antibiotics should be initiated as soon as possible when diagnosis of postoperative infection is made; most patients will respond to treatment within 24 to 48 hours when appropriate antibiotics are selected. PMID- 23090460 TI - Influenza during pregnancy: a cause of serious infection in obstetrics. AB - Influenza infection during pregnancy imparts disproportionate morbidity and mortality. This has been primarily noted during occasional influenza pandemics but also during seasonal epidemics. The majority of pregnant women who contract influenza appear to have a mild, self-limited course. However, influenza produces a severe life-threatening respiratory illness among a non-negligible and partially unpredictable portion of susceptible pregnant women. Influenza vaccination is the most effective way to prevent this occasionally fatal infection and is recommended for all pregnant women lacking contraindication. Antiviral medications are indicated for both prophylaxis and treatment for suspected and/or confirmed influenza infection during pregnancy. PMID- 23090461 TI - Opportunistic infections in women with HIV AIDS. AB - Women account for half of the global human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) infections. Heterosexual contact is the leading risk factor in women. Over 50% of patients are significantly immunosuppressed at the time of diagnosis. Women with advanced HIV infection are at a risk for opportunistic infections (OIs). OIs lead to significant morbidity and cost. Some of OIs may impact women more significantly than men, that is, human papillomavirus infection and cervical cancer. OIs during pregnancy can increase the risk of maternal-to-child transmission of HIV and some OIs, such as Hepatitis C. This chapter will review of OIs that are most important in women's health. PMID- 23090463 TI - Update on vaginal birth after cesarean. PMID- 23090462 TI - Neonatal herpes simplex virus infection. AB - Neonatal herpes, seen roughly in 1 of 3000 live births in the United States, is the most serious manifestation of herpes simplex virus (HSV) infection in the perinatal period. Although acyclovir therapy decreases infant mortality associated with perinatal HSV transmission, development of permanent neurological disabilities is not uncommon. Mother-to-neonate HSV transmission is most efficient when maternal genital tract HSV infection is acquired proximate to the time of delivery, signifying that neonatal herpes prevention strategies need to focus on decreasing the incidence of maternal infection during pregnancy and more precisely identifying infants most likely to benefit from prophylactic antiviral therapy. PMID- 23090464 TI - Managing the primary cesarean delivery rate. AB - One third of deliveries in the United States are by cesarean, a rate that far exceeds that recommended by professional organizations and experts. A dominant reason for the high overall cesarean rate is the rising primary cesarean rate. The high primary cesarean rate results from multiple factors, both clinical and nonclinical. This review outlines proposed interventions to lower the primary cesarean rate. We focus on those implementable at a facility level and would likely yield immediate results, including aligning provider incentives for vaginal birth, limiting elective induction of labor, and improving labor management of dystocia and abnormal fetal heart rate tracings. PMID- 23090465 TI - VBAC: what does the evidence show? AB - Declining rates of vaginal birth after cesarean (VBAC) are contributing to rising total cesarean delivery rates. The reasons behind the decreased utilization of VBAC are complex, but concerns about the safety of a trial of labor after cesarean are often cited. This manuscript will present a summary of existing evidence on maternal and fetal/neonatal outcomes associated with trial of labor after cesarean/VBAC, and highlight findings from recent contributions to this literature. PMID- 23090466 TI - Vaginal birth after cesarean delivery: comparison of ACOG practice bulletin with other national guidelines. AB - Evidence-based guidelines regarding vaginal birth after cesarean from 3 countries (United States, Canada, and United Kingdom) were reviewed. The similarities in the 3 national guidelines (trial of labor after 1 previous cesarean, informed consent, delivery facility and available resources, epidural analgesia, continuous fetal monitoring, and induction and augmentation of labor) are understandable. Differences in recommendations (uterine rupture risk, success rate, intrauterine pressure catheter, and mechanical cervical ripening) are not explained. The likelihood of recommendations being categorized as level A differed: United States, 27% (3/11); Canada, 32% (6/19); and United Kingdom, 0% (0/17). Only 6 publications were cited by all 3 guidelines. PMID- 23090467 TI - Uterine rupture associated with VBAC. AB - Uterine rupture during attempted vaginal birth after cesarean is a rare, but serious complication and can result in death or long-term disability. Several factors can increase the risk of uterine rupture during vaginal birth after cesarean and adequate counseling is necessary. Current literature suggests that timely diagnosis and delivery of the fetus is necessary for optimal outcome. PMID- 23090468 TI - Cesarean scar imaging and prediction of subsequent obstetric complications. AB - It has long been hoped that cesarean hysterotomy scar imaging data could predict obstetric complications in subsequent pregnancies with sufficient precision to be used for clinical decision-making. Although large visualized defects in nonpregnant uteri, and thinning of the lower uterine segment late in subsequent pregnancies, may be associated with increased risk of uterine rupture, the paucity of available clinical correlation data still preclude any clinical utility. There is an ongoing need for prospective adequately powered registries that include clinical factors related to the previous cesarean deliveries that can inform subsequent practice decisions. PMID- 23090469 TI - VBAC in the trenches: a community perspective. AB - Is vaginal birth after cesarean in the community a disappearing practice? Since 1996 the rate of trial of labor after cesarean for low-risk women has dropped precipitously. This paper reviews the current literature and summarizes opinions of community obstetricians and midwives. Descriptive data are presented to document the scope of the problem and identify barriers: liability concerns, provider biases, and institutional restrictions. Our perspective draws on experience in our community hospital with a previously high vaginal birth after cesarean rate and a subsequent ban. Strategies to reduce the skyrocketing cesarean rate and encourage trial of labor after cesarean for low-risk women are outlined. PMID- 23090470 TI - The anesthesiologist's role during attempted VBAC. AB - American College of Obstetricians and Gynecologists' guidelines on vaginal birth after cesarean had both intended and unintended consequences for anesthesiologists. Epidural analgesia continues to play an important role in patient acceptance of a trial of labor after prior cesarean delivery. It does not impact the success rate of vaginal birth after cesarean and may be a diagnostic tool when uterine rupture occurs. Preanesthesia evaluation and counseling should occur early in the patient's care. Intrapartum management includes appropriate oral intake and close communication between anesthesiologist and obstetrician. If uterine rupture or postpartum hemorrhage occur, appropriate algorithms should be followed. PMID- 23090471 TI - How do we deal with the legal risks? AB - Do obstetricians as a profession risk losing credibility as cesarean section rates continue to rise to once unimaginable levels? Physician practice style and fear of litigation have contributed to the escalation in abdominal delivery but so have societal expectations and patient perspectives. At the same time, some patients are so motivated for a vaginal delivery that they choose to have a home birth after cesarean section as opposed to submitting to a repeat cesarean delivery. Amid a medical-legal environment that "exerts a chilling effect on a trial of labor," what is the obstetrician to do? PMID- 23090472 TI - Why VBAC in Northern New England is still viable: the Northern New England perinatal quality improvement network. AB - Under the strong leadership of Maternal-Fetal Medicine specialists and the support of the tertiary care centers serving the region, Northern New England (NNE) initiated a collaborative project to improve the availability and safety of trial of labor after cesarean delivery. The project involved over 250 individuals from over 30 organizations and resulted in a strong regional guideline that has been implemented by institutions across the nation. The availability of trial of labor after cesarean in NNE has increased. The work led to the creation of the NNE Perinatal Quality Improvement Network, whose work has improved regional outcomes. PMID- 23090473 TI - Contemporary management of VBAC. AB - Elective repeat cesarean contributes substantially to the overall rising rate of cesarean delivery in the United States. Many women opting for an elective repeat cesarean are good candidates for a trial of labor after cesarean (TOLAC). Physicians should be able to identify women who are good candidates for TOLAC and provide accurate patient counseling to women considering TOLAC. Currently, evidence-based recommendations regarding intrapartum management should be followed in a well-equipped facility with all necessary personnel. With the selection of proper candidates and appropriate intrapartum management, outcome can be optimized for both mother and fetus. PMID- 23090476 TI - In vivo mutagenesis reveals that OriL is essential for mitochondrial DNA replication. AB - The mechanisms of mitochondrial DNA replication have been hotly debated for a decade. The strand-displacement model states that lagging-strand DNA synthesis is initiated from the origin of light-strand DNA replication (OriL), whereas the strand-coupled model implies that OriL is dispensable. Mammalian mitochondria cannot be transfected and the requirements of OriL in vivo have therefore not been addressed. We here use in vivo saturation mutagenesis to demonstrate that OriL is essential for mtDNA maintenance in the mouse. Biochemical and bioinformatic analyses show that OriL is functionally conserved in vertebrates. Our findings strongly support the strand-displacement model for mtDNA replication. PMID- 23090477 TI - Defining a new role of GW182 in maintaining miRNA stability. AB - GW182 binds to Argonaute (AGO) proteins and has a central role in miRNA-mediated gene silencing. Using lentiviral shRNA-induced GW182 knockdown in HEK293 cells, this study identifies a new role of GW182 in regulating miRNA stability. Stably knocking down GW182 or its paralogue TNRC6B reduces transfected miRNA-mimic half lives. Replenishment of GW182 family proteins, as well as one of its domain Delta12, significantly restores the stability of transfected miRNA-mimic. GW182 knockdown reduces miRNA secretion via secretory exosomes. Targeted siRNA screening identifies a 3'-5' exoribonuclease complex responsible for the miRNA degradation only when GW182 is knocked down. Immunoprecipitation further confirms that the presence of GW182 in the RISC complex is critical in protecting Argonaute-bound miRNA. PMID- 23090478 TI - ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. AB - Intratumoral hypoxia is associated with poor prognosis, regardless of the mode of therapy. Cancer cells survive this condition through activating several adaptive signaling pathways, including the integrated stress response (ISR) and autophagy. Activating transcription factor 4 (ATF4) is the major transcriptional mediator of the ISR, which we have shown to be involved in autophagy regulation to protect cells from severe hypoxia. Here we demonstrate that ATF4 orchestrates a program of BH3-only protein expression in severe hypoxia. We find that the BH3-only proteins HRK, PUMA, and NOXA are transcriptionally induced in severe hypoxia and that their expression is abrogated by RNA interference against ATF4. In particular, we show that the BH3-only protein harakiri (HRK) is transactivated by ATF4 in severe hypoxia through direct binding of ATF4 to the promoter region. Furthermore, we demonstrate through siRNA knockdown that HRK induces autophagy and promotes cancer cell survival in severe hypoxia. PMID- 23090479 TI - Identification of a new gene encoding 5-enolpyruvylshikimate-3-phosphate synthase using genomic library construction strategy. AB - Applying the genomic library construction strategy and colony screening, a new aroA gene encoding 5-enolpyruvylshikimate-3-phosphate synthase has been identified, cloned and overexpressed in Escherichia coli, and the enzyme was purified to homogeneity. Kinetic analysis of the AroA( P.fluorescens ) indicated that the full-length enzyme exhibits 10-fold increased IC50 and an approximately 38-fold increased K ( i ) for glyphosate compared to those of the AroA( E.coli ), while retaining high affinity for the substrate phosphoenolpyruvate. Furthermore, we have transformed the new aroA ( P.fluorescens ) gene into Arabidopsis thaliana via a floral dip method, and demonstrated that transgenic A. thaliana plants exhibit significant glyphosate resistance when compared with the wild type. PMID- 23090480 TI - Effects of magnetic field on cell dedifferentiation and callus induction derived from embryo culture in bread wheat (Triticum aestivum. L) genotypes. AB - Current study was conducted to investigation of effect of magnetic field on cell dedifferentiation and follow it callus induction derived from mature embryo culture in bread wheat genotypes. For this purpose, a factorial experiment based on completely randomized design was carried out with two wheat genotypes and three level of magnetic field strength (0.0, 8.8 and 17.6 Tesla) in three replications. Callus growth rate (CGR), relative growth rate (RGR), callus relative growth rate (CRGR), percentage of callus water content and percentage of callus induction traits were measured. To sum up, the results showed that differences between wheat genotypes and level of magnetic field strength were significant for some studied treats related to callus induction. The effect of magnetic field levels on CGR (from 0.181 to 0.175), RGR (from 1.442 to 0.655) and CRGR (from 0.052 to 0.022) were decreased with increment of magnetic field intensity. PMID- 23090481 TI - Analyzing the promoters of two CYP9A genes in the silkworm Bombyx mori by dual luciferase reporter assay. AB - Cytochrome P450s (CYPs) are widespread proteins that interact with exogenous chemicals from the diet or the environment. CYP9A subfamily genes are important in the silkworm Bombyx mori. We previously reported transcriptional levels of two CYP9A genes in different tissues and their responses to sodium fluoride (NaF). In this study, promoter truncation analysis using a dual-luciferase reporter assay in B. mori ovary cells (BmN) showed that the regions -1,496 to -1,102 bp for CYP9A19, and -1,630 to -1,210 bp for CYP9A22 were essential for basal transcriptional activity. Sequence analysis of these regions revealed several transcriptional regulatory elements but no typical promoter elements. Promoter activities were regulated after NaF induction and with an obvious dose effect. Although the dual-luciferase assay has been widely used to determine the activity of a given promoter in cell lines, problems with it still exist. Our results indicate that both plasmid size and construct protocols affect the experimental results. PMID- 23090484 TI - Sex differences in central and peripheral mechanisms of fatigue in cyclists. AB - We examined peripheral versus central contributions to fatigue in men and women during prolonged cycling using a peripheral nerve magnetic stimulation-based technique. 11 men (41 +/- 3 years) and 9 women (38 +/- 2 years) cycled for 2 h at ventilatory threshold with 5, 1-min sprints interspersed, followed by a 3-km time trial. Quadriceps strength testing was performed isometrically in a semi-reclined position pre- and post-cycling: (1) MVC; (2) MVC with superimposed 3-s magnetic stimulation to measure central activation ratio (CAR), a measure of central fatigue; (3) peripheral magnetic stimulation (PMS) alone of the femoral nerve in a 4-s pulse train, a measure of peripheral fatigue. Data were analyzed with mixed model ANOVA. When adjusted for body mass, men and women had similar strength (p = 0.876), and changes in MVC with time were similar between sexes, declining 22 % in men and 16 % in women (p = 0.360). CAR was similar between sexes and decreased 15 % (effect of time, p < 0.001). Changes in PMS-elicited force were different between sexes: only men lost stimulated strength (6.30 to 5.21 vs. 5.48 to 5.53 N kg(-1), interaction p = 0.036). Results clearly demonstrate that quadriceps fatigue after >2 h of cycling was of both central and peripheral origin in men but solely due to central mechanisms in women. PMID- 23090483 TI - Costs of living in metal polluted areas: respiration rate of the ground beetle Pterostichus oblongopunctatus from two gradients of metal pollution. AB - To address the question about costs of living in polluted areas, biomarkers linked to metabolism were measured in Pterostichus oblongopunctatus (Coleoptera: Carabidae) collected along two metal-pollution gradients in the vicinity of the two largest Polish zinc smelters: 'Boleslaw' and 'Miasteczko Slaskie' in southern Poland. Both gradients covered a broad range of Zn and Cd concentrations in the humus layer (109-6151 and 1.48-71.4 mg kg(-1), respectively) and body metal concentrations increased with increasing soil metal concentrations. The whole organism respiration rate was measured as oxygen consumption with Micro-Oxymax respirometer, and cellular energy consumption-as the activity of electron transport system, which is linked to cellular respiration rate. The significant increase in the whole-organism respiration rate with the body metal concentration was found when taking into account other factors such as body mass, gradient (or year of sampling as the beetles were collected on the gradients in different years) and the interactions: body metal concentrations * collection date, body metal concentrations * body mass, and body mass * gradient/sampling year. However, no relationships between metal concentrations in soil or body metal concentrations and the whole-organism or cellular respiration rate could be detected when using mean values per site, underlining the crucial importance of incorporating individual variability in such analyses. The observed increase of the whole-organism respiration rate with increasing body contamination with metals suggests that P. oblongopunctatus incurs energetic expenditures resulting from the necessity to facilitate metal elimination or repair of toxicant-induced damage. PMID- 23090482 TI - The melanocortin 1 receptor (MC1R) inhibits the inflammatory response in Raw 264.7 cells and atopic dermatitis (AD) mouse model. AB - The alpha melanocyte stimulating hormone receptor (MC1R) is one of five G-protein coupled receptors belonging to the melanocortin subfamily, MC1R gene has been known to play a major role in regulating of fur color in mammals, and alpha-MSH and ACTH are endogenous nonselective agonists for MC1R. However, we found that MC1R was highly expressed in Raw 264.7 cells which were important inflammatory cells involved in the initiation of inflammatory responses. In addition, Cyclic AMP is not only a key molecule in the MC1R signal transduction pathway, but dampen innate immune-mediated responses. These intriguing biological results triggered the further conformation studies; it suggested that MC1R was very likely to be an important role in immunoregulation. In this study, we were to investigate the immunosuppressive effects of MC1R on inflammation in lipopolysaccharide (LPS) stimulated Raw 264.7 cells and LPS induced vivo 2-chloro 1,3,5-trinitrobenzene (TNCB)-induced atopic dermatitis (AD) model. The effects of the MC1R antagonist psoralen on pro-inflammatory cytokines and signaling pathways were analyzed by enzyme-linked immunosorbent assay, western blot, real-time fluorescence quantitative PCR and Histological analysis. Our results show a consistent and marked effect of high concentrations of MC1R antagonist psoralen increased the level of MC1R mRNA in Raw 264.7 cells by cumulative feedback regulation through preferential binding of MC1R. Moreover, as evidenced by inhibiting the LPS-induced TNF-alpha, IL-6 and enhancing the expression level of cyclic AMP protein in vitro. In vivo study it was also observed that psoralen promoted on histopathologic changes in the skin tissue of TNCB-induced AD mice. Taken together, our results suggest that MC1R decrease the inflammation in vitro and vivo, and might be a therapeutic signaling pathway to against inflammatory diseases. PMID- 23090485 TI - Variables associated with level of disability in working individuals with nonacute low back pain: a cross-sectional investigation. AB - STUDY DESIGN: Single-site, exploratory, cross-sectional design. OBJECTIVE: To identify variables associated with disability related to low back pain (LBP), as measured by the modified Oswestry Low Back Pain Disability Questionnaire (mOSW), in a sample of working adults with nonacute LBP. BACKGROUND: Compared to acute LBP, there is little information available in the literature to identify variables associated with LBP-related disability in working individuals with stage 2 and stage 3 LBP. METHODS: Data analyzed were from working individuals with nonacute LBP (n = 235). The response variable was dichotomized by mOSW score (less than 20 or 20 or greater), and the regressor variables included 27 self report, sociodemographic, impairment-based, and kinematic measures used to assess individuals with LBP. Logistic regression was used to identify variables associated with mOSW. RESULTS: One hundred eleven subjects had a mOSW score of 20 or greater, and 124 subjects had a mOSW score of less than 20. Logistic regression analysis identified 4 variables associated with LBP-related disability (mOSW): duration of LBP (P = .006), numeric pain rating (P<.0001), Fear-Avoidance Beliefs Questionnaire physical activity subscale (P = .0007), and limits of stability movement velocity in the forward direction (P = .02). The best model had an R2(u) of 0.25. CONCLUSION: The odds of LBP-related disability (mOSW) in this sample of nonacute working individuals were found to increase with longer duration of LBP, higher numeric pain rating scores, higher Fear-Avoidance Beliefs Questionnaire physical activity subscale scores, and slower limits of stability movement velocity in the forward direction. The identification of limits of stability movement velocity is a novel finding that may support a link between sensorimotor balance deficits and disability in working individuals with nonacute LBP. PMID- 23090486 TI - Electron holography characterization as a method for measurements of diameter and mean inner potential of hollow nanomaterials. AB - In this paper, we provide a method for the simultaneous measurement of the inner diameter of nanotubes with a regular shape and calculation of their mean inner potential (MIP) using electron holography. This method contains 4 steps: (i)phase profile characterization from electron holography; (ii) shape assumption from prepared data; (iii) thickness simulation from a shape assumption and fitting method; (iv) calculation of MIP of the simulated and fitted parameters. By this method, as an example, the shape and the outer and inner diameters of a tube formed from C(60) molecules were characterized. The MIP of the tube was also calculated through this method. The MIP calculation from another nano whisker formed from C(60) molecules supports the feasibility of our method and it could be extended to other nanomaterials. This work provides a convenient method for morphology characterization of hollow nanomaterials, such as diameter measurements and cross-sectional shape determination, which are the most basic and important characteristics of the nanomaterials. In addition, it also provides a method for MIP calculation without a thickness measurement if the samples have relatively regular shapes. Thus this method should be more convenient for closely combining the tomography and physical properties of samples, which could be essential for in situ TEM studies of nanomaterials. PMID- 23090487 TI - Mechanisms of mesenchymal stromal cell immunomodulation. AB - Multipotent mesenchymal stromal cells (MSCs) have generated considerable interest in the fields of regenerative medicine, cell therapy and immune modulation. Over the past 5 years, the initial observations that MSCs could enhance regeneration and modulate immune responses have been significantly advanced and we now have a clearer picture of the effects that MSCs have on the immune system particularly in the context of inflammatory-mediated disorders. A number of mechanisms of action have been reported in MSC immunomodulation, which encompass the secretion of soluble factors, induction of anergy, apoptosis, regulatory T cells and tolerogenic dendritic cells. It is clear that MSCs modulate both innate and adaptive responses and evidence is now emerging that the local microenvironment is key in the activation or licensing of MSCs to become immunosuppressive. More recently, studies have suggested that MSCs have the capacity to sense their environment and have a role in pathogen clearance in conjunction with the resolution of insult or injury. This review focuses on the mechanisms of MSC immunomodulation discussing the multistep process of MSC localisation at sites of inflammation, the cross talk between MSCs and the local microenvironment as well as the subsequent mechanisms of action used to resolve inflammation. PMID- 23090488 TI - Transient Foxp3(+) regulatory T-cell depletion enhances therapeutic anticancer vaccination targeting the immune-stimulatory properties of NKT cells. AB - The natural killer T (NKT) cell ligand, alpha-galactosylceramide (alpha-GalCer), represents a potential adjuvant to boost immunotherapeutic vaccination strategies against poorly immunogenic cancers. The objective of this study was to assess the therapeutic potential of an alpha-GalCer-loaded tumor-cell vaccine against solid tumors in mice and to enhance the effectiveness of this approach by removing immune suppression associated with the activity of Foxp3(+) regulatory T cells (Tregs). In the B16F10 melanoma model, we show that single vaccination with irradiated, alpha-GalCer-loaded tumor cells resulted in suppression of established subcutaneous (s.c.) B16F10 tumor growth, which was mediated by NKT cell-dependent IFN-gamma production and enhanced in the absence of IL-17 A. Selective depletion of Foxp3(+) Tregs in transgenic DEpletion of REGulatory T cells (DEREG) mice led to significant inhibition of B16F10 tumor growth and enhanced survival of mice receiving vaccination. Short-term elimination of Foxp3(+) Tregs (<7 days) was sufficient to boost vaccine-induced immunity. Enhanced antitumor activity with combination therapy was associated with an increase in systemic NK cell and effector CD8(+) T-cell activation and IFN-gamma production, as well as infiltration of effector CD8(+) T cells into the tumor. Overall, these findings demonstrate that transient depletion of Foxp3(+) Tregs constitutes a highly effective strategy to improve the therapeutic efficacy of anticancer vaccination with NKT cell adjuvants. PMID- 23090489 TI - Susceptible electron spin adhering to an yttrium cluster inside an azafullerene C79N. AB - Highly impressionable electron spin was found in endohedral azafullerene Y(2)@C(79)N at low temperature or upon exohedral chemical modification. These external stimulations can be employed to manipulate the spin-active Y(2)@C(79)N and can further be used in quantum processes for promising information-carrying spin systems and molecular devices. PMID- 23090490 TI - [Sixty years after Hsiang-Tung Chang's presentation on dendrite at the Cold Spring Harbor Symposium]. AB - Sixty years elapsed since Chang (Hsiang-Tung Chang, Xiang-Tong Zhang) presented his seminal report "Cortical neurons with particular reference to the apical dendrite" at the Cold Spring Harbor Symposium. Thanks to the development of elaborated techniques through the 6 decades, our understanding of the dendrite has been pushed forward greatly: the backward and forward conductions during excitation, sodium and calcium conductances, chemical excitation by uncaging glutamate at a dimension of micrometer, and the quantitative study of chemical organization of postsynaptic density (PSD), etc. Though the progression is great, there are still tough problems in dendritic research, especially the integration through dendritic spine. PMID- 23090492 TI - Inwardly rectifying potassium channels in Drosophila. AB - Inwardly rectifying potassium channels (Kir) are a special subset of potassium selective ion channels which pass potassium more easily into rather than out of the cell. These channels mediate a variety of cellular functions, including control of membrane resting potential, maintenance of potassium homeostasis and regulation of cellular metabolism. Given the existence of fifteen Kir genes in mammals, current genetic studies using mutant animals that lack a single channel may have missed many important physiological functions of these channels due to gene redundancy. This issue can be circumvented by using a simple model organism like Drosophila, whose genome encodes only 3 Kir proteins. The sophisticated genetic approaches of Drosophila may also provide powerful tools to identify additional regulation mechanisms of Kir channels. Here we provide an overview of the progress made in elucidating the function of Drosophila Kir channels. The knowledge of Drosophila Kir channels may lead us to uncover novel functions and regulation mechanisms of human Kir channels and help on pathological studies of related diseases. PMID- 23090493 TI - New tricks for an old slug: descending serotonergic system in pain. AB - A large body of research including animal and human studies has confirmed the crucial role of the serotonin (5-HT) system in the regulation of nociception and chronic pain-related behaviors. In recent years, the functional status of the 5 HT system in descending inhibition and facilitation of spinal nociceptive processing has been reevaluated by novel genetic manipulation techniques and selective agents for 5-HT receptor subtypes. Although these studies shed more light on several aspects of descending 5-HT and spinal 5-HT receptors functioning in descending modulation in pain perception, the current knowledge about the specific role of descending 5-HT system in the induction and maintenance of persistent pain remains fragmentary. In this paper, we review the available data from recent studies of the inhibitory or facilitatory influence from descending 5 HT-spinal 5-HT receptor system in acute and persistent pain, attempt to dissect the involvement of this signaling pathway in neural circuits of maintenance of persistent pain and discuss some issues that need to be considered for further pain research. PMID- 23090491 TI - Regulation of voltage-gated calcium channels by proteolysis. AB - Voltage gated calcium channels (VGCCs) are multi-subunit membrane proteins present in a variety of tissues and control many essential physiological processes. Due to their vital importance, VGCCs are regulated by a myriad of proteins and signaling pathways. Here we review the literature on the regulation of VGCCs by proteolysis of the pore-forming alpha1 subunit, Ca(v)alpha(1). This form of regulation modulates channel function and degradation and affects cellular gene expression and excitability. L-type Ca(2+) channels are proteolyzed in two ways, depending on tissue localization. In the heart and skeletal muscle, the distal C-terminus of Ca(v)alpha(1) is cleaved and acts as an autoinhibitor when it reassociates with the proximal C-terminus. Relief of this autoinhibition underlies the beta-adrenergic stimulation-induced enhancement of cardiac and skeletal muscle calcium currents, part of the "fight or flight" response. Proteolysis of the distal C-terminus of L-type channels also occurs in the brain and is probably catalyzed by a calpain-like protease. In some brain regions, the entire C-terminus of L-type Ca(2+) channels can be cleaved by an unknown protease and translocates to the nucleus acting as a transcription factor. The distal C terminus of P/Q-channel Ca(v)alpha(1) is also proteolyzed and translocates to the nucleus. Truncated forms of the PQ-channel Ca(v)alpha(1) are produced by many disease-causing mutations and interfere with the function of full-length channels. Truncated forms of N-type channel Ca(v)alpha(1), generated by mutagenesis, affect the expression of full-length channels. New forms of proteolysis of VGCC subunits remain to be discovered and may represent a fruitful area of VGCC research. PMID- 23090494 TI - Purinergic P2X receptors and diabetic neuropathic pain. AB - Diabetic peripheral neuropathy (DPN), one of the most common chronic complications of diabetes, is characterized by allodynia, hyperalgesia and spontaneous pain. Chinese epidemiological studies have shown that at least 25% diabetic patients suffered from painful DPN, which compromises patients' daily functioning and becomes a major health care problem. Although the pathogenesis of painful DPN is not fully understood and current treatment options are very limited, research in the field has advanced our understanding on the mechanism of painful DPN in the past Decade of Pain Research and Control. This review will mainly focus on evaluation of current diabetic animal models, possible molecular pathways and available therapies, with an emphasis on roles of purinergic receptor and its signaling transduction pathways. Common therapies address one or two DPN symptoms, while others offer wider symptom control, presumably by targeting pathophysiological mechanisms of DPN. Purinergic receptor signaling transduction pathways might become potential targets for treatment for painful DPN. PMID- 23090495 TI - Aberrant plasticity and "learned" motor inhibition in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by severe loss of substantia nigra dopamine (DA) neurons. The target region of substantia nigra DA neurons is the dorsal striatum. According to the classic model, activation of DA receptors on striatal medium spiny neurons (MSNs) modulates their intrinsic excitability. Activation of D1 receptors makes MSNs in the direct "Go" pathway more excitable, whereas activation of D2 receptors makes MSNs in the indirect "NoGo" pathway less excitable. Therefore increased DA increases the responsiveness of the Go pathway while decreases the responsiveness of the NoGo pathway. Both mechanisms increase motor output. Conversely, diminished DA will favor the inhibitory NoGo pathway. Therefore, DA has direct, "on-line" effect on motor performance. However, in addition to modulating the intrinsic excitability of MSNs "on-line", DA also modulates corticostriatal plasticity, therefore could potentially produce cumulative and long-lasting changes in corticostriatal throughput. Studies in my lab suggest that DA blockade leads to both direct motor performance impairment and D2 receptor dependent NoGo learning ("learned" motor inhibition) that gradually deteriorates motor performance. NoGo learning is experience dependent and task specific. It is different from blocked learning since NoGo learning impairs future performance even after DA is restored. More recent data from my lab suggest that NoGo learning in the absence of DA arises from increased LTP at the indirect pathway corticostriatal synapses and contributes significantly to PD like motor symptoms. Our data and hypotheses suggest a novel therapeutic strategy for PD that targets directly signaling molecules for corticostriatal plasticity (e.g. the cAMP pathway and downstream signaling molecules) and prevents aberrant plasticity under conditions of DA denervation. PMID- 23090496 TI - A review on the current neuroligin mouse models. AB - Neuroligins (NLs) are postsynaptic membrane proteins expressed in the brain and mediate synaptogenesis. Neuroligin family proteins can specifically induce either excitatory or inhibitory synapses. Deletions or point mutations in neuroligin genes are found in patients with autism spectrum disorders (ASD) or mental retardations. The dysfunctions of these mutations have been tested in multiple neuroligin mouse models. In most of the models, including the human autism-linked NL3 and NL4 mutation mice, there are social interaction defects, memory impairment and repetitive behaviors. Researchers also found the excitatory/inhibitory synapse ratio altered in those mice, as well as receptor subunit composition. However, inconsistencies and debates also exist between different research approaches. In this review, we summarize the neuroligin mouse models currently available, examine the detailed alterations detected in those mice and compare the differences within different mouse models or different investigation methods, to obtain an overall picture of the current progress on neuroligin mouse models. PMID- 23090497 TI - Activation of cGMP-PKG signaling pathway contributes to neuronal hyperexcitability and hyperalgesia after in vivo prolonged compression or in vitro acute dissociation of dorsal root ganglion in rats. AB - Injury or inflammation affecting sensory neurons in the dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spinal central sensitization and neuropathic pain. Recent studies have indicated that, following chronic compression of DRG (CCD) or acute dissociation of DRG (ADD) treatment, both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by activity in cGMP-PKG signaling pathway. Here, we provide evidence supporting the idea that CCD or ADD treatment activates cGMP-PKA signaling pathway in the DRG neurons. The results showed that CCD or ADD results in increase of levels of cGMP concentration and expression of PKG-I mRNA, as well as PKG-I protein in DRG. CCD or ADD treated-DRG neurons become hyperexcitable and exhibit increased responsiveness to the activators of cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMP. Hyperexcitability of the injured neurons is inhibited by cGMP-PKG pathway inhibitors, ODQ and Rp-8-pCPT-cGMPS. In vivo delivery of Rp-8-pCPT-cGMPS into the compressed ganglion within the intervertebral foramen suppresses CCD induced thermal hyperalgesia. These findings indicate that the in vivo CCD or in vitro ADD treatment can activate the cGMP-PKG signaling pathway, and that continuing activation of cGMP-PKG pathway is required to maintain DRG neuronal hyperexcitability and/or hyperalgesia after these two dissimilar forms of injury related stress. PMID- 23090498 TI - Interferon-stimulated gene 15 as a general marker for acute and chronic neuronal injuries. AB - Activation of interferon (IFN) signaling in the central nervous system (CNS) is usually associated with inflammation. However, a robust activation of type I IFN stimulated genes (ISGs) at pre-symptomatic stages occurs in the spinal cord of SOD1(G93A) mice, an amyotrophic lateral sclerosis (ALS) animal model, without obvious signs of inflammation. To determine if the same signaling pathway is elevated in other types of neuronal injuries, we examined the protein expression levels of an IFN-stimulated gene, ISG15, in mouse models of acute and chronic neuronal injuries. We found that ISG15 protein was dramatically increased in the brains of mice subjected to global ischemia and traumatic brain injury, and in transgenic mice overexpressing HIV gp120 protein. These results suggest that activation of ISGs is a shared feature of neuronal injuries and that ISG15 may be a suitable biomarker for detecting neuronal injuries in the CNS. PMID- 23090500 TI - Simulation of homology models for the extracellular domains (ECD) of ErbB3, ErbB4 and the ErbB2-ErbB3 complex in their active conformations. AB - Epidermal growth factor receptors (EGFR) are associated with a number of biological processes and are becoming increasingly recognized as important therapeutic targets against cancer. In this work, we provide models based on homology for the extracellular domains (ECD) of ErbB3 and ErbB4 in their active conformations, including a Heregulin ligand, followed by further refinement of the models by molecular dynamics simulations at atomistic scale. We compare the results with a model built for ErbB2 based on crystallographic information and analyze the common features observed among members of the family, namely, the periscope movement of the dimerization arm and the hinge displacement of domain IV. Finally, we refine a model for the interaction of the ECDs corresponding to a ErbB2-ErbB3 heterodimer, which is widely recognized to have a high impact in cancer development. PMID- 23090499 TI - Outcome of elderly patients with acute promyelocytic leukemia: results of the German Acute Myeloid Leukemia Cooperative Group. AB - Despite improvement of prognosis, older age remains a negative prognostic factor in acute promyelocytic leukemia (APL). Reports on disease characteristics and outcome of older patients are conflicting. We therefore analyzed 91 newly diagnosed APL patients aged 60 years or older (30 % of 305 adults with APL) registered by the German AML Cooperative Group (AMLCG) since 1994; 68 patients (75 %) were treated in studies, 23 (25 %) were non-eligible, and 31 % had high risk APL. Fifty-six patients received induction therapy with all-trans retinoic acid and TAD (6-thioguanine, cytarabine, daunorubicin), and consolidation and maintenance therapy. Treatment intensification with a second induction cycle (high dose cytarabine, mitoxantrone; HAM) was optional (n = 14). Twelve patients were randomized to another therapy not considered in this report. The early death rate was 48 % in non-eligible and 19 % in study patients. With the AMLCG regimen, 7-year overall, event-free and relapse-free survival (RFS) and cumulative incidence of relapse were 45 %, 40 %, 48 %, and 24 %, respectively. In patients treated with TAD-HAM induction, 7-year RFS was superior (83 %; p = 0.006) compared to TAD only, and no relapse was observed. In our registered elderly patients, we see a high rate of non-eligibility for treatment in studies and of high-risk APL. In patients who can undergo a curative approach, intensified chemotherapy is highly effective, but is restricted to a selection of patients. Therefore, new less toxic treatment approaches with broader applicability are needed. Elderly patients might be a particular target group for concepts with arsenic trioxide. PMID- 23090501 TI - Topological analysis of tetraphosphorus oxides (P4O 6+n (n = 0-4)). AB - Quantum chemical calculations were used to analyze the chemical bonding and the reactivity of phosphorus oxides (P4O6+n (n = 0-4)). The chemical bonding was studied using topological analysis such as atoms in molecules (AIM), electron localization function (ELF), and the reactivity using the Fukui function. A classification of the P-O bonds formed in all structures was done according to the coordination number in each P and O atoms. It was found that there are five P O bond types and these are distributed among the five phosphorus oxides structures. Results showed that there is good agreement among the evaluated properties (length, bond order, density at the critical point, and disynaptic population) and each P-O bond type. It was found that regardless of the structure in which a P-O bond type is present the topological and geometric properties do not have a significant variation. The topological parameters electron density and Laplacian of electron density show excellent linear correlation with the average length of P-O bond in each bond type for each structure. From the Fukui function analysis it was possible to predict that from P4O6 until P4O8 the most reactive regions are basins over the P. PMID- 23090503 TI - Photoisomerisation quantum yield and non-linear cross-sections with femtosecond excitation of the photoactive yellow protein. AB - The quantum yield of photoisomerisation of the photoactive yellow protein (PYP) strongly depends on peak power and wavelength with femtosecond optical excitation. Using systematic power titrations and addition of second order dispersion resulting in 140, 300 and 600 fs pulse durations, the one and multi photon cross-sections at 400, 450 and 490 nm have been assessed from transient absorption spectroscopy and additionally the Z-scan technique. Applying a target model that incorporates photoselection theory, estimates for the cross-sections for stimulated emission and absorption of the first excited state, the amount of ultrafast internal conversion and the underlying species associated dynamics have been determined. The final quantum yields for photoisomerisation were found to be 0.06, 0.14-0.19 and 0.02 for excitation wavelengths 400, 450 and 490 nm and found to increase with increasing pulse durations. Transient absorption measurements and Z-scan measurements at 450 nm, coinciding with the maximum wavelength of the ground state absorption, indicate that the photochemical quantum yield is intrinsically limited by an ultrafast internal conversion reaction as well as by stimulated emission cross-section. With excitation at 400 nm photoisomerisation quantum yield is further significantly limited by competing multi-photon excitation into excited state absorption at 385 nm previously proposed to result in photoionisation. With excitation at 490 nm the photoisomerisation quantum yield is predominantly limited further by the significantly higher stimulated emission cross-section compared to ground state cross-section as well as multi photon processes. In addition to photoionisation, a second product of multi photon excitation is identified and characterised by an induced absorption at 500 nm and a time constant of 2 ps for relaxation. With power densities up to 138 GW cm(-2) the measurements have not provided indication for coherent multi-photon absorption of PYP. In the saturation regime with 450 nm excitation, the limit for the photoisomerisation quantum yield was found to be 0.14-0.19 and the excited state absorption cross-section 6.1 * 10(-17) cm(2) or 0.36 times the ground state cross-section of 1.68 * 10(-16) cm(2) per molecule. This places a fundamental restriction on the maximum populations and sample penetration that may be achieved for instance in femtosecond pump-probe experiments with molecular crystals of PYP. PMID- 23090502 TI - In pursuit of negative Fukui functions: examples where the highest occupied molecular orbital fails to dominate the chemical reactivity. AB - In our quest to explore molecules with chemically significant regions where the Fukui function is negative, we explored reactions where the frontier orbital that indicates the sites for electrophilic attack is not the highest occupied molecular orbital. The highest occupied molecular orbital (HOMO) controls the location of the regions where the Fukui function is negative, supporting the postulate that negative values of the Fukui function are associated with orbital relaxation effects and nodal surfaces of the frontier orbitals. Significant negative values for the condensed Fukui function, however, were not observed. PMID- 23090504 TI - Experiences of parents with a child with Down syndrome in Pakistan and their views on termination of pregnancy. AB - It has been argued that Down syndrome (DS) is as much a cultural creation as a biomedical condition, yet the majority of research in this area has been conducted in 'Western' cultures. This study explored parents' experiences of their child with DS in Pakistan and their views on abortion for the condition. Thirty mothers and fathers of children with DS took part in qualitative interviews. Transcripts were thematically analysed. Parents used Islamic discourse to frame positive personal meanings of their child's condition. These were contrasted with personal experiences of stigmatisation and rejection by family and community. An ambivalent cultural stereotype was revealed that characterised people with DS as abnormal and objects of pity but also as being closer to God and bringers of good fortune. Views on termination varied, but parents were generally supportive of the availability of abortion for DS due to the social stigmatisation they experienced. The findings reveal how parents negotiated their religious beliefs alongside personal experiences to inform personal views on abortion for DS. Advice to other parents about termination was rooted in Islamic discourse but emphasised pragmatic concerns about the impact of having a family member with intellectual disability in Pakistan. PMID- 23090505 TI - Rheumatoid arthritis: Genetic variants in DKK1 linked to severity of joint damage in RA. PMID- 23090506 TI - siRNA-based therapeutic approaches for rheumatic diseases. AB - RNA interference (RNAi) is one of the most exciting and important discoveries of the past few decades. Small interfering RNAs (siRNAs) can silence gene activity and be used to interfere with pathophysiological processes. Substantial research has focused on introducing 'drug-like' properties-stability, selectivity and potency-to RNAi molecules, and clinical trials have been initiated. Despite initial success, the current challenge that remains is to develop optimized vehicles that avoid off-target effects whilst efficiently delivering the therapeutic siRNA to specific cell types. As for many other diseases, siRNA-based therapy is emerging as a promising approach for the treatment of rheumatic disorders. Although the pathogenesis of rheumatic diseases is complex, identification of candidate genes able to influence either inflammation or structural damage has been successful. Here, we will discuss advances in the field and potential applications of siRNA therapeutics in clinical trials for rheumatic conditions. PMID- 23090509 TI - Punctal occlusion in Sjogren's syndrome needs clarification. PMID- 23090508 TI - Syndecans in cartilage breakdown and synovial inflammation. AB - Syndecans are transmembrane heparan sulphate proteoglycans (HSPGs) that have gained increasing interest as regulators of a variety of tissue responses, including cartilage development and remodelling. These proteoglycans are composed of a core protein to which extracellular glycosaminoglycan (GAG) chains are attached. Through these GAG chains, syndecans can interact with a variety of extracellular matrix molecules and bind to a number of soluble mediators including morphogens, growth factors, chemokines and cytokines. The structure and post-translational modification of syndecan GAG chains seem to differ not only from cell to cell, but also during different stages of cellular differentiation, leading to a complexity of syndecan function that is unique among membrane-bound HSPGs. Unlike other membrane-bound HSPGs, syndecans contain intracellular signalling motifs that can initiate signalling mainly through protein kinase C. This Review summarizes our knowledge of the biology of syndecans and the mechanisms by which binding of molecules to syndecans exert different biological effects, particularly in the joints. On the basis of the structural and functional peculiarities of syndecans, we discuss the regulation of syndecans and their roles in the developing joint as well as during degenerative and inflammatory cartilage remodelling as understood from expression studies and functional analyses involving syndecan-deficient mice. PMID- 23090510 TI - Possible roles of IL-12-family cytokines in rheumatoid arthritis. AB - The IL-12 family members, IL-12, IL-23, IL-27 and IL-35, are heterodimeric cytokines that share subunits and have important roles in autoimmunity. As well as their structural relationship the IL-12 family cytokines share some biological characteristics but have functional differences. These cytokines contribute to immune-mediated inflammation and our improved knowledge of their actions has led to alteration of the T(H)1-T(H)2 paradigm. In rheumatoid arthritis (RA), leukocyte migration, bone erosions and angiogenesis are modulated by an IL-23-IL 17 cascade, which can be negated in part by IL-12, IL-27 and IL-35 function. However, the IL-12 family members are a relatively new area of research and data have been generated mostly at the preclinical stage. Further studies in patients with RA are, therefore, required to determine whether these cytokines are valid targets for RA therapy. PMID- 23090511 TI - Early occurrence of obstructive sleep apnea in infants and children with cystic fibrosis. AB - OBJECTIVES: To assess the occurrence of sleep-disordered breathing, hypoxemia, and sleep architecture in a cohort of infants and children with cystic fibrosis (CF) and normal or mildly impaired lung function in stable clinical condition. DESIGN: Case-control study. SETTING: Cystic Fibrosis Unit of a university hospital and pediatric sleep laboratory. PARTICIPANTS: A total of 40 children (aged 6 months to 11 years) with CF in stable condition and 18 healthy age matched control subjects. INTERVENTION: Nocturnal sleep and cardiorespiratory monitoring was performed using a full polysomnographic recording in a sleep laboratory. MAIN OUTCOMES MEASURES: Sleep architecture and respiratory variables. RESULTS: Although awake oxyhemoglobin saturation (SaO2) values were similar in the 2 groups (98%), the CF group had significantly lower values of nocturnal mean SaO2. The apnea-hypopnea index was significantly higher in the CF group compared with the controls (mean [SE], 7.3 [1.3] vs 0.5 [0.4], respectively, P < .001), particularly in preschool-aged children and in children with upper airway abnormalities. In addition, 28 (70%) of the 40 children with CF had mild to moderate obstructive sleep apnea (defined as an apnea-hypopnea index >2). Children with CF compared with controls also had reduced sleep efficiency (CF group vs controls mean [SE], 80% [41%] vs 88% [13.1%], P < .001), rapid eye movement sleep duration (11% [0.9%] vs 13% [1%], P < .05), and increased number of arousals per hour (11.0 [10] vs 8.2 [0.7], P < .001). CONCLUSIONS: This study showed an early occurrence of obstructive sleep apnea in children with CF in stable condition, associated with a mild level of sleep disruption. Early routine nocturnal respiratory monitoring is advised in children with CF. PMID- 23090512 TI - Missed opportunities for primary endometrial cancer prevention: how to optimize early identification and treatment of high-risk women. PMID- 23090513 TI - Peripartum cardiomyopathy: we've come a long way, but.... PMID- 23090514 TI - Patient engagement and shared decision making in maternity care. PMID- 23090516 TI - Awareness of endometrial cancer risk and compliance with screening in hereditary nonpolyposis colorectal cancer. AB - OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer (HNPCC) have a 40 60% lifetime risk for endometrial cancer. Guidelines in Denmark recommend gynecologic screening for female members of families with HNPCC. We estimated the knowledge of endometrial cancer risk and identified possible predictors of compliance with the screening among women from families with HNPCC. METHODS: A questionnaire exploring the knowledge of endometrial cancer risk and compliance with screening was sent to 707 women from families with HNPCC who had been recommended endometrial cancer surveillance. The response rate after one reminder was 86% (606 of 707). Data were analyzed by simple and multivariable logistic regression models. RESULTS: Four hundred seventy-one women were included in the final analyses; 65% reported being aware of the increased risk of endometrial cancer. The awareness was significantly greater among women with high educational level (81%; P<.001), women who had received genetic counseling (75%; P<.001), women with family history of gynecologic cancer (76%; P<.001), and those with high perceived endometrial cancer risk (77%; P<.001). Overall, 67% had participated in gynecologic screening. No significant differences were found in compliance regarding women's educational level or their family risk classification. Analyses of data in a multivariable logistic regression model showed that knowledge of endometrial cancer risk was the most important predictor for positive compliance with the gynecologic screening (odds ratio 4.86, 95% confidence interval 3.05-7.74). CONCLUSION: Women's awareness of endometrial cancer risk is the most important predictor of their compliance with gynecologic screening in families with HNPCC. LEVEL OF EVIDENCE: II. PMID- 23090515 TI - Risk factors for developing endometrial cancer after benign endometrial sampling. AB - OBJECTIVE: To identify risk factors for endometrial cancer after benign results of endometrial biopsy or dilation and curettage (D&C). METHODS: Nested case control study from Rochester Epidemiology Project data. Among 370 Olmsted County, Minnesota, residents who received an endometrial cancer diagnosis between 1970 and 2008, we identified 90 patients (24.5%) who had previous benign endometrial biopsy or D&C results (no atypical hyperplasia). We compared them with 172 matched control group participants who had benign endometrial biopsy or D&C results without subsequent endometrial cancer. RESULTS: Using a multivariable conditional logistic regression model, we found that oral contraceptive pill (OCP) use was protective (odds ratio [OR] 0.18, 95% CI [CI] 0.08-0.45; P<.001), and personal history of colorectal cancer (OR 4.44, 95% CI 1.02-19.31; P<.05), endometrial polyp (OR 4.12, 95% CI 1.40-12.17; P=.01), and morbid obesity (OR 3.40, 95% CI 1.18-9.78; P<.03) were independently associated with subsequent endometrial cancer. Compared with the presence of no risk factor, presence of one and two or more risk factors increased the risk of endometrial cancer by 8.12 (95% CI 3.08-21.44) and 17.87 (95% CI 5.57-57.39) times, respectively. Assuming a 2.6% lifetime risk of endometrial cancer, ORs of 8.12 and 17.87 for one and two or more of the four aforementioned risk factors confer a lifetime risk of approximately 18% and 32%, respectively. CONCLUSION: One fourth of patients with endometrial cancer had previous benign endometrial biopsy or D&C results. Personal history of colorectal cancer, presence of endometrial polyps, and morbid obesity are the strongest risk factors for having endometrial cancer after a benign endometrial biopsy or D&C result, and OCP use is the strongest protective factor. LEVEL OF EVIDENCE: II. PMID- 23090517 TI - Peripartum cardiomyopathy: population-based birth prevalence and 7-year mortality. AB - OBJECTIVE: To estimate the birth prevalence and 7-year case-fatality rate of peripartum cardiomyopathy for a statewide population by applying the National Institutes of Health Workshop on Peripartum Cardiomyopathy definition, including echocardiographic criteria for left ventricular dysfunction. METHODS: This was an epidemiologic study of residents of North Carolina experiencing an obstetric delivery or a pregnancy-related death before delivery in 2002 through 2003 including 235,599 live births. Potential cases were identified from International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM), pregnancy and cardiovascular codes followed by medical record review, and from the state pregnancy-related mortality file. Only women meeting the established definition including echocardiographic criteria for left ventricular dysfunction and women with diagnoses at autopsy were included. The state death file and the U.S. Social Security Death Index were searched for the years 2002 through 2010 for all cases. RESULTS: A total of 740 potential cases from 70 hospitals were identified from discharge ICD-9-CM codes. The medical records for 698 (94.3%) were located and reviewed. Seventy-eight met inclusion criteria. An additional seven women had diagnoses only at autopsy. The birth prevalence was 1 case for every 2,772 live births or 3.61 cases per 10,000 live births (95% confidence interval 2.88-4.46). The 7-year case-fatality rate was 16.5% (95% confidence interval 10--25.9%). Black non-Hispanic women experienced an almost fourfold increased prevalence and fatality compared with white women. Women older than age 35 years had the highest prevalence. CONCLUSIONS: The racial disparity in both birth prevalence and case-fatality is striking; one in six women died within 7 years. LEVEL OF EVIDENCE: II. PMID- 23090518 TI - Pelvic muscle strength after childbirth. AB - OBJECTIVE: The objective was to estimate the effect of vaginal childbirth and other obstetric exposures on pelvic muscle strength 6-11 years after delivery and to investigate the relationship between pelvic muscle strength and pelvic floor disorders. METHODS: Among 666 parous women, pelvic muscle strength was measured with a perineometer 6-11 years after delivery. Obstetric exposures were classified by review of hospital records. Pelvic floor outcomes, including stress incontinence, overactive bladder, anal incontinence, and prolapse symptoms, were assessed with a validated questionnaire. Pelvic organ support was assessed using the Pelvic Organ Prolapse Quantification system. Kruskal-Wallis tests were used to estimate the univariable associations of obstetric exposures and pelvic floor outcomes with peak muscle strength. Stepwise multivariable linear regression models were used to estimate the association between obstetric exposures and muscle strength. RESULTS: In comparison with women who delivered all of their children by cesarean, peak muscle strength and duration of contraction were reduced among women with a history of vaginal delivery (39 compared with 29 cm H2O, P<.001). Pelvic muscle strength was further reduced after history of forceps delivery (17 cm H2O, P<.001). After vaginal delivery, reduced pelvic muscle strength was associated with symptoms of anal incontinence (P=.028) and pelvic organ prolapse on examination (P=.025); these associations were not observed among those who had delivered exclusively by cesarean. CONCLUSION: Pelvic muscle strength almost a decade after childbirth is affected by vaginal delivery and by forceps delivery. Although statistically significant, some of the differences observed were small in magnitude. LEVEL OF EVIDENCE: II. PMID- 23090519 TI - Severe maternal morbidity among delivery and postpartum hospitalizations in the United States. AB - OBJECTIVES: To propose a new standard for monitoring severe maternal morbidity, update previous estimates of severe maternal morbidity during both delivery and postpartum hospitalizations, and estimate trends in these events in the United States between 1998 and 2009. METHODS: Delivery and postpartum hospitalizations were identified in the Nationwide Inpatient Sample for the period 1998-2009. International Classification of Diseases, 9 Revision codes indicating severe complications were used to identify hospitalizations with severe maternal morbidity and related in-hospital mortality. Trends were reported using 2-year increments of data. RESULTS: Severe morbidity rates for delivery and postpartum hospitalizations for the 2008-2009 period were 129 and 29, respectively, for every 10,000 delivery hospitalizations. Compared with the 1998-1999 period, severe maternal morbidity increased by 75% and 114% for delivery and postpartum hospitalizations, respectively. We found increasing rates of blood transfusion, acute renal failure, shock, acute myocardial infarction, respiratory distress syndrome, aneurysms, and cardiac surgery during delivery hospitalizations. Moreover, during the study period, rates of postpartum hospitalization with 13 of the 25 severe complications examined more than doubled, and the overall mortality during postpartum hospitalizations increased by 66% (P<.05). CONCLUSIONS: Severe maternal morbidity currently affects approximately 52,000 women during their delivery hospitalizations and, based on current trends, this burden is expected to increase. Clinical review of identified cases of severe maternal morbidity can provide an opportunity to identify points of intervention for quality improvement in maternal care. LEVEL OF EVIDENCE: III. PMID- 23090520 TI - Chlorhexidine-alcohol compared with povidone-iodine for surgical-site antisepsis in cesarean deliveries. AB - OBJECTIVE: To estimate the incidence of surgical-site infection with use of chlorhexidine-alcohol compared with povidone-iodine among women undergoing cesarean deliveries. METHODS: This was a retrospective cohort review of 1,000 consecutive cases in women who underwent cesarean delivery over a 1-year interval. The primary outcome was any surgical-site infection within 30 days (Centers for Disease Control and Prevention criterion). RESULTS: Mean age and parity were equivalent (29.8+/-5.9 years; 2.6+/-1.4). Women were similar regarding baseline characteristics, including acknowledged surgical-site infection comorbidities (body mass index [BMI, calculated as weight (kg)/[height (m)]2], gestational diabetes, smoking; P>.05). Method of skin incision closure was different, with 91% among povidine-iodine compared with 81% among chlorhexidine-alcohol using staples (P<.001). Although the duration of surgical time was higher among chlorhexidine women (67.2 compared with 60.0 minutes; P<.001), fewer women in the chlorhexidine group were classified as having undergone an "urgent" cesarean delivery (29% compared with 46%; P<.001). Concerning surgical-site infection, the overall rate was similar between the two groups (5% [n=25] chlorhexidine and 5.8% [n=29] povidone-iodine; P=.58). In multivariable analysis and after control for potential confounders, odds for surgical-site infection remained similar between the two groups (adjusted odds ratio 0.74, 95% confidence interval 0.41-1.33; P=.32). The only significant predictor of surgical-site infection was duration of cesarean delivery, in which every 1-minute increase in duration increased the odds for infection by 1.3% (adjusted odds ratio 1.013, 95% CI 1.004-1.022; P=.004). CONCLUSION: The single significant predictor of surgical-site infection is operative time. Cleansing with povidone-iodine may be a cost-effective and equally efficacious alternative to chlorhexidine-alcohol among women undergoing cesarean deliveries. LEVEL OF EVIDENCE: II. PMID- 23090521 TI - Antibiotic prophylaxis in premature rupture of membranes at term: a randomized controlled trial. AB - OBJECTIVE: To determine whether prophylactic antibiotic administration in women presenting with premature rupture of membranes (PROM) at term can alter the rates of maternal and neonatal infections. METHODS: In a randomized, controlled, nonblinded trial, women at low risk with singleton term pregnancies presenting with PROM were assigned to either antibiotic administration or no treatment. Main outcomes evaluated were rates of maternal infection (chorioamnionitis and endometritis) and neonatal infection. RESULTS: A total of 161 patients were evaluated, 78 in the antibiotic group and 83 in the control group. Maternal infection was significantly lower when antibiotics were administered (2.6% compared with 13.2%; relative risk 0.89, 95% confidence interval 0.81-0.98; P=.013). All cases of maternal infection occurred in women with more than 12 hours of PROM. Newborns of mothers receiving antibiotics had fewer infections (3.8%) compared with those in the control group (6.0%), but the difference was not statistically significant (P=.375). CONCLUSION: Prophylactic use of antibiotics in PROM at term significantly reduced the risk of maternal infection in our population. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT01633294. LEVEL OF EVIDENCE: I. PMID- 23090522 TI - Continuation of the etonogestrel implant in women undergoing immediate postabortion placement. AB - OBJECTIVE: To estimate whether women who receive an immediate postabortion etonogestrel subdermal implant have higher discontinuation rates than women who undergo an interval insertion (insertion not associated with a recent pregnancy). METHODS: This was a secondary analysis of the Contraceptive CHOICE Project. We compared 12-month continuation rates for the subdermal implant between women undergoing immediate postabortion placement and women who underwent an interval placement. Continuation rates were compared using Kaplan-Meier estimator of survival function and Cox proportional hazard models. RESULTS: Over the study period, 141 women received the implant immediately postabortion and 935 women underwent an interval placement. The 12-month continuation rates were similar: 81.5% among women undergoing immediate postabortion placement and 82.8% among women undergoing interval placement (P=.54). In the survival analysis, women who received an immediate postabortion implant were no more likely to discontinue their method than women who had an interval placement (adjusted hazard ratio 1.04, 95% confidence interval 0.68-1.60). The most common reason given for discontinuation was frequent or irregular bleeding, which was reported by 65.4% of women discontinuing in the immediate postabortion group and 56.7% in the interval group. CONCLUSION: Women who undergo immediate postabortion placement of the subdermal implant have high rates of continuation that are equivalent to women undergoing interval insertion. Immediate postabortion long-acting reversible contraceptives should be available to women undergoing induced abortion to decrease the risk of repeat unplanned pregnancy. LEVEL OF EVIDENCE: II. PMID- 23090523 TI - Hydrocodone-acetaminophen for pain control in first-trimester surgical abortion: a randomized controlled trial. AB - OBJECTIVE: Although hydrocodone-acetaminophen is commonly used for pain control in first-trimester abortion, the efficacy of oral opioids for decreasing pain has not been established. Our objective was to estimate the effect of hydrocodone acetaminophen on patient pain perception during first-trimester surgical abortion. METHODS: We conducted a randomized, double-blinded, placebo-controlled trial. Patients (before 11 weeks of gestation) received standard premedication (ibuprofen and lorazepam) and a paracervical block with the addition of 10 mg hydrocodone and 650 mg acetaminophen or placebo 45-90 minutes before surgical abortion. A sample size of 120 was calculated to provide 80% power to show a 15 mm difference (alpha=0.05) in the primary outcome of pain with uterine aspiration (100-mm visual analog scale). Secondary outcomes were pain at additional time points, satisfaction, side effects, adverse events, and need for additional pain medications. RESULTS: There were no significant differences in demographics or baseline pain between groups. There were no differences in pain scores between patients receiving hydrocodone-acetaminophen compared with placebo during uterine aspiration (65.7 mm compared with 63.2 mm, P=.59) or other procedural time points. There were no differences in satisfaction or need for additional pain medications. Patients who received hydrocodone-acetaminophen had more postoperative nausea than those receiving placebo (P=.03) when controlling for baseline nausea. No medication-related adverse events were noted. CONCLUSION: Hydrocodone-acetaminophen does not decrease pain during first-trimester abortion and may increase postoperative nausea. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, www.clinicaltrials.gov, NCT01330459. LEVEL OF EVIDENCE: I. PMID- 23090524 TI - Extending outpatient medical abortion services through 70 days of gestational age. AB - OBJECTIVE: To estimate the efficacy and acceptability of medical abortion at 64 70 days from last menstrual period (LMP) and to compare it with the already proven 57-63 days from LMP gestational age range. METHODS: This prospective, comparative, open-label trial enrolled 729 women with pregnancies 57-70 days from LMP requesting abortion at six U.S. clinics. Medical abortions were managed with 200 mg mifepristone and 800 micrograms buccal misoprostol and sites' service delivery protocols. Follow-up visits occurred 7-14 days after mifepristone, with an abortion considered complete if surgical intervention was not performed. Success, ongoing pregnancy, and acceptability rates were compared. RESULTS: A total of 629 cases were analyzable for efficacy. Success rates were similar in the two groups (57-63 days group: 93.5%, 95% confidence interval [CI] 90-96; 64 70 days group: 92.8%, 95% CI 89-95). Ongoing pregnancy rates also did not differ significantly (57-63 days: 3.1%, 95% CI 1.6-5.8; 64-70 days: 3.0%, 95% CI 1.5 5.7). Acceptability was high and similar in both arms, with most women (57-63 days: 87.4%; 64-70 days: 88.3%) reporting that their experience was either very satisfactory or satisfactory. CONCLUSION: Medical abortion with mifepristone and misoprostol in current outpatient settings is an efficacious and acceptable method of ending pregnancies 64-70 days from LMP and can be offered without alteration of existing services. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT00997347. LEVEL OF EVIDENCE: II. PMID- 23090525 TI - Incidence of venous thromboembolism after minimally invasive surgery in patients with newly diagnosed endometrial cancer. AB - OBJECTIVE: To estimate the incidence of postoperative venous thromboembolism among patients undergoing minimally invasive surgery for endometrial cancer, and to characterize risk factors associated with the development of venous thromboembolism. METHODS: Patients with newly diagnosed endometrial cancer who were scheduled to undergo a planned minimally invasive surgery procedure from May 1, 2007 to December 31, 2010 were identified. The incidence of symptomatic postoperative venous thromboembolism was estimated in the patients who did not require conversion to laparotomy. Various clinicopathologic variables were tested for an association with the development of a postoperative venous thromboembolism using standard statistical tests. RESULTS: A total of 573 cases were identified. Postoperative low molecular weight heparin was administered to 125 (22%) patients during their immediate postoperative hospital stay. All patients had sequential compression devices placed intraoperatively. Seven (1.2%) patients had development of a symptomatic venous thromboembolism. The factors associated with development of a postoperative venous thromboembolism were: body mass index (BMI) (P=.005); estimated blood loss (P=.03); and operative time (P=.01). A high-risk group was determined to be patients with BMIs of 40 or higher and an operative time of 180 minutes or more. In this group, the incidence of venous thromboembolism was 9.5% (4 of 42) compared with 0.6% (3 of 531) in all others (P=.001). CONCLUSION: The incidence of venous thromboembolism in patients with newly diagnosed endometrial cancer undergoing minimally invasive surgery is very low. There appears to be no clear justification for the routine use of a heparin for perioperative thromboprophylaxis in the majority of these patients. Thromboprophylaxis with heparin, however, may be a consideration in morbidly obese patients (BMI of 40 or higher) after a procedure that lasts 3 hours or more. LEVEL OF EVIDENCE: II. PMID- 23090526 TI - Perinatal outcomes associated with obstructive sleep apnea in obese pregnant women. AB - OBJECTIVE: To investigate the associations between obstructive sleep apnea (OSA) and maternal and neonatal morbidities in a cohort of obese gravid women. METHODS: Participants were enrolled in a prospective observational study designed to screen for OSA and describe the possible risk factors for and outcomes of OSA among obese (body mass index [BMI, calculated as weight (kg)/[height (m)]2] 30 or higher) pregnant women. Women underwent an overnight sleep study using a portable home monitor. Studies were manually scored by a central masked sleep reading center using American Academy of Sleep Medicine diagnostic criteria. An apnea hypopnea index of 5 or more was considered diagnostic of OSA. Perinatal outcomes were compared between women with and without OSA. RESULTS: Among 175 women, OSA prevalence was 15.4% (13 mild, 9 moderate, 5 severe). Compared with no OSA (apnea hypopnea index less than 5), the OSA group had a higher BMI (46.8+/-12.2 compared with 38.1+/-7.5; P=.002) and more chronic hypertension (55.6% compared with 32.4%, P=.02). Maternal complications included maternal death (n=1, amniotic fluid embolus [no OSA group]) and cardiac arrest (n=1, intraoperative at cesarean delivery [OSA group]). One previable birth and two stillbirths occurred in the no OSA group. Among live births, OSA was associated with more frequent cesarean delivery (65.4% compared with 32.8%; P=.003), preeclampsia (42.3% compared with 16.9%; P=.005), and neonatal intensive care unit admission (46.1% compared with 17.8%; P=.002). After controlling for BMI, maternal age, and diabetes, OSA (odds ratio [OR] 3.55, 95% confidence interval [CI] 1.1-11.3), previous preeclampsia (OR 2.79, 95% CI 1.09-7.19), and hypertension (OR 4.25, 95% CI 1.67-10.77) were associated with development of preeclampsia. CONCLUSION: Obstructive sleep apnea among obese pregnant women is associated with more frequent preeclampsia, neonatal intensive care unit admissions, and cesarean delivery. LEVEL OF EVIDENCE: II. PMID- 23090527 TI - Acetabular labral tear and postpartum hip pain. AB - OBJECTIVE: To educate the obstetrics community regarding postpartum labral tears, an avoidable and treatable potential complication of pregnancy in the postpartum period. METHODS: From 2009 to 2011, 10 women presented to the second author's office with persistent hip pain that had begun during pregnancy or during delivery. These 10 postpartum women presented with signs and symptoms of labral tears, which were subsequently confirmed with arthroscopy and surgically repaired. RESULTS: Each patient experienced relief of symptoms within 4 months after the procedure. All patients were satisfied with surgery, and all patients had improvement in modified Harris hip score. The average preoperative modified Harris hip score was 53.1 and the average postoperative modified Harris hip score was 84.3 (P<.001). CONCLUSION: An acetabular labral tear should be considered part of the differential diagnosis for hip pain in postpartum women. Additionally, freeing the distal lower extremity to externally rotate during labor may prevent an acute labral tear. When nonoperative management fails, surgery may lead to positive outcomes. LEVEL OF EVIDENCE: II. PMID- 23090529 TI - Trends in surgical mesh use for pelvic organ prolapse from 2000 to 2010. AB - OBJECTIVE: To describe trends in and predictors of surgical mesh use for pelvic organ prolapse (POP) repair and to estimate the influence of safety advisories on mesh use. METHODS: Analysis of women aged 18 years and older recorded in a health care quality and resource utilization database who underwent POP repair from 2000 to 2010, identified by International Classification of Diseases, 9th Revision, Clinical Modification procedure codes, and stratified by mesh use. Odds ratios were calculated with adjustments for patient, physician, and hospital-level characteristics. RESULTS: Among 273,275 women in the cohort, 64,968 (23.8%) underwent a mesh-augmented repair. Concurrent incontinence surgery was a strong predictor of mesh use (odds ratio [OR] 9.95; 95% confidence interval [CI] 9.70 10.21). Mesh use increased from 7.9% in 2000 to a peak of 32.1% in 2006, and declined slightly to 27.5% in 2010. Among women without incontinence, mesh use increased from 3.3% in 2000 to 13.5% in 2006, and remained stable at 12.8% in 2010. Intermediate-volume (OR 1.53; 95% CI 1.44-1.62) and high-volume (OR 2.74; 95% CI 2.58-2.92) surgeons were more likely to use mesh than low-volume surgeons. Compared with women who underwent operation by gynecologists, those treated by urologists were more than three times more likely to undergo mesh-augmented prolapse repair (OR 3.36; 95% CI 3.09-3.66). Black women were 27% less likely to undergo mesh repair (OR 0.73; 95% CI 0.66-0.82). CONCLUSIONS: Mesh-augmented prolapse repairs increased substantially over the past decade, and this increase was most pronounced in the years before the publication of safety advisories. Physician specialty and surgical volume are important factors underlying mesh use. Additional measures must ensure evidence-based use of mesh for pelvic reconstruction. LEVEL OF EVIDENCE: II. PMID- 23090530 TI - Cervical carcinoma rates among young females in the United States. AB - OBJECTIVE: All national organizations now recommend that women be screened for cervical cancer beginning at age 21 years, regardless of age of sexual initiation; however, studies have shown that providers continue to screen much earlier than recommended. Two federal cancer surveillance systems were used to quantify the burden of invasive cervical carcinoma among women younger than 40 years of age. METHODS: We examined combined data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program covering 92% of the U.S. population. We calculated the age-adjusted incidence of cervical carcinoma among women younger than age 40 years by age, race, ethnicity, and histology for the time period of 1999-2008. RESULTS: For women younger than age 40 years, 78% of the cervical cancer cases were diagnosed in women aged 30 39, 21% were diagnosed in women 20-29 years of age, and 1% was diagnosed in women younger than age 20 years. There was an average of 3,063 cases of invasive cervical carcinomas annually from 1999 through 2008, with an average of 14 carcinomas per year (rate of 0.15 per 100,000 females) among those aged 15-19 years, and 125 carcinomas per year (rate of 1.4 per 100,000 females) among those aged 20-24 years. CONCLUSION: Cervical cancer is very rare in young women. Widespread implementation of Pap testing over the past four decades has detected very few cases of cervical cancer in women younger than 25 while potentially causing harm with unnecessary follow-up interventions. LEVEL OF EVIDENCE: III. PMID- 23090531 TI - Endometrioid endometrial carcinoma with atrophic endometrium and poor prognosis. AB - OBJECTIVE: Type I endometrial carcinomas are characterized by endometrioid histology, develop from hyper-plastic endometrium, and have a good prognosis. Type II, nonendometrioid carcinomas, arise in atrophic endometrium and have a poor prognosis. However, approximately 20% of cases do not fit within this dualistic model and include endometrioid carcinomas associated with recurrence and possibly with atrophy. We aimed to evaluate grade 1 endometrioid endometrial carcinomas with atrophic endometrium, a putative third type of endometrial carcinoma. METHODS: Histologic slides of all grade 1 endometrioid endometrial cancers from the Radboud University Medical Centre and Canisius-Wilhelmina Hospital from 1999-2009 and from the Mayo Clinic from 2002-2008 were reviewed. Comparisons were made between patients with atrophic and hyperplastic endometrium. RESULTS: After review, 527 patients were identified. In 88 patients (16.8%), background endometrium was atrophic and 387 patients (73.3%) had hyperplastic endometrium. Fifty-two patients (9.9%) had proliferative endometrium or no background endometrium and were excluded. Atrophy correlated with older age, low body mass index, advanced International Federation of Gynecology and Obstetrics stage, malignant cells in peritoneal cytology, lymph node metastases, cervical involvement, lymphovascular space invasion, and deep myometrial invasion. Multivariable analysis showed that age (hazard ratio 1.06, 95% confidence interval [Cl] 1.01-1.12), International Federation of Gynecology and Obstetrics stage (hazard ratio 8.47, 95% Cl 1.73-41.57), and background endometrium (hazard ratio 3.11, 95% Cl 1.11-8.70) were predictors of progression free survival. CONCLUSION: Atrophic endometrium is an independent prognostic factor for patients with grade 1 endometrioid endometrial carcinoma. Endometrioid carcinoma with atrophy may not follow the hypothesized progression model for type I tumors and may arise through unique carcinogenic pathways. LEVEL OF EVIDENCE: II. PMID- 23090532 TI - Management and prevention of red cell alloimmunization in pregnancy: a systematic review. AB - OBJECTIVE: To evaluate the application of new technologies to the management of the red cell alloimmunized pregnancy. DATA SOURCES: We searched three computerized databases for studies that described treatment or prevention of alloimmunization in pregnancy (MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials [1990 to July 2012]). The text words and MeSH included Rhesus alloimmunization, Rhesus isoimmunization, Rhesus prophylaxis, Rhesus disease, red cell alloimmunization, red cell isoimmunization, and intrauterine transfusion. METHODS OF STUDY SELECTION: Of the 2,264 studies initially identified, 246 were chosen after limiting the review to those articles published in English and crossreferencing to eliminate duplication. TABULATION, INTEGRATION, AND RESULTS: Both authors independently reviewed the articles to eliminate publications involving less than six patients. Special emphasis was given to publications that have appeared since 2008. CONCLUSION: Quantitative polymerase chain reaction can be used instead of serology to more accurately determine the paternal RHD zygosity. In the case of unknown or a heterozygous paternal RHD genotype, new DNA techniques now make it possible to diagnose the fetal blood type through cell-free fetal DNA in maternal plasma. Serial Doppler assessment of the peak systolic velocity in the middle cerebral artery is now the standard to detect fetal anemia and determine the need for the first intrauterine transfusion. Assessment of the peak systolic velocity in the middle cerebral artery can be used to time the second transfusion, but its use to decide when to perform subsequent procedures awaits further study. New data suggest normal neurologic outcome in 94% of cases after intrauterine transfusion, although severe hydrops fetalis may be associated with a higher risk of impairment. Recombinant Rh immune globulin is on the horizon. Cell-free fetal DNA for fetal RHD genotyping may be used in the future to decide which patients should receive antenatal Rh immune globulin. PMID- 23090528 TI - Perinatal outcomes in Hispanic and non-Hispanic white women with mild gestational diabetes. AB - OBJECTIVE: To compare perinatal outcomes between self-identified Hispanic and non Hispanic white women with mild gestational diabetes mellitus (GDM) or glucose intolerance. METHODS: In a secondary analysis of a mild GDM treatment trial, we compared perinatal outcomes by race and ethnicity for 767 women with glucose intolerance (abnormal 50-g 1-hour screen, normal 100-g 3-hour oral glucose tolerance test), 371 women with mild GDM assigned to usual prenatal care, and 397 women with mild GDM assigned to treatment. Outcomes included: composite adverse perinatal outcome (neonatal death, hypoglycemia, hyperbilirubinemia, hyperinsulinemia, stillbirth, birth trauma), gestational age at delivery, birth weight, and hypertensive disorders of pregnancy. Adjusted regression models included: 100-g 3-hour oral glucose tolerance test results, parity, gestational age, body mass index, maternal age at enrollment, and current tobacco use. RESULTS: The sample of 1,535 women was 68.3% Hispanic and 31.7% non-Hispanic white. Among women with glucose intolerance, Hispanic women had more frequent composite outcome (37% compared with 27%, adjusted odds ratio [OR] 1.62, 95% confidence interval [CI] 1.10-2.37) with more neonatal elevated C-cord peptide (19% compared with 13%, adjusted OR 1.79, 95% CI 1.04-3.08) and neonatal hypoglycemia (21% compared with 13%, adjusted OR 2.04, 95% CI 1.18-3.53). Among women with untreated mild GDM, outcomes were similar by race and ethnicity. Among Hispanic women with treated mild GDM, composite outcome was similar to non Hispanic white women (35% compared with 25%, adjusted OR 1.62, 95% CI 0.92-2.86), but Hispanic neonates had more frequent hyperinsulinemia (21% compared with 10%, adjusted OR 2.96, 95% CI 1.33-6.60). CONCLUSION: Individual components of some neonatal outcomes were more frequent in Hispanic neonates, but most perinatal outcomes were similar between Hispanic and non-Hispanic ethnic groups. LEVEL OF EVIDENCE: II. PMID- 23090533 TI - Risk of fever after misoprostol for the prevention of postpartum hemorrhage: a meta-analysis. AB - OBJECTIVE: To estimate the incidence and risk of misoprostol-induced fever with different doses and routes when used for the prevention of postpartum hemorrhage. DATA SOURCES: We searched MEDLINE, the Cochrane CENTRAL, and PubMed free-text terms "misoprostol AND third stage of labor," "misoprostol AND third stage of labour," "misoprostol AND postpartum hemorrhage," and "misoprostol AND postpartum haemorrhage." Randomized trials with at least one group randomized to misoprostol administered by any route to prevent postpartum hemorrhage were included. METHODS OF STUDY SELECTION: Two hundred thirty-one studies were initially identified and 61 of them were assessed for eligibility. We excluded nonrandomized trials, studies without a control group, and trials that did not record the rate of fever. The date of last search was July 20, 2010. Data were extracted, tabulated, and analyzed with Reviewer Manager software. TABULATION, INTEGRATION, AND RESULTS: We included 33 trials with 38,478 participants in the final analysis. The highest reported incidence of fever was in the sublingual route (15%) with lower rates with the oral (11.4%) and rectal (4%) routes. The overall risk ratio of fever with misoprostol in comparisons with placebo and other uterotonics was approximately 5. There was frequent heterogeneity, however, which could not be explained by study quality or publication date. CONCLUSION: The incidence of fever with misoprostol is related to both its dosage and route with the highest incidences found in the high-dose sublingual routes. However, this is not the only influence on postnatal fever. There appear also to be other effects that could be genetic or cultural. PMID- 23090534 TI - Patient safety: some progress and many challenges. AB - Progress in patient safety has been exceedingly slow, hampered by lack of both clarity regarding the definition and standard methodology to assess iatrogenic patient harm in obstetrics and gynecology. Understanding the causes of medical error and strategies to reduce harm is simple compared with the complexity of clinical practice. On the other hand, patient safety interventions will not be successful without a receptive culture of safety. This culture can only occur with engaged organizational and individual leaders who understand the importance of patient safety. Transforming groups of individual experts into expert teams is central to this cultural transformation. Strategic pathways to accelerate future improvement in patient safety include fundamental changes in health care education, patient engagement, transparency, care coordination, and improving health care providers' morale. PMID- 23090535 TI - Management of endometrial precancers. AB - In the United States, endometrial cancer is the most commonly diagnosed cancer of the female reproductive system. Strategies to sensitively and accurately diagnose premalignant endometrial lesions are sorely needed. We reviewed studies pertaining to the diagnostic challenges of endometrial precancers, their predictive value, and evidence to support management strategies. Currently, two diagnostic schemas are in use: the four-class 1994 World Health Organization hyperplasia system, based on morphologic features of architectural complexity and nuclear atypia and, more recently, the two-class endometrial intraepithelial neoplasia system, which is quantitative. Diagnosis should use criteria and terminology that distinguish between clinicopathologic entities that can be managed differently. In some instances, such as for women with hereditary nonpolyposis colon cancer, biomarkers may aid in diagnosis, but the clinical utility of biomarkers has yet to be determined. Total hysterectomy is curative for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, and provides a definitive standard for assessment of a concurrent carcinoma, when clinically appropriate. If hysterectomy is performed for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, then intraoperative assessment of the uterine specimen for occult carcinoma is desirable, but optional. Nonsurgical management may be appropriate for patients who wish to preserve fertility or those for whom surgery is not a viable option. Treatment with progestin therapy may provide a safe alternative to hysterectomy; however, clinical trials of hormonal therapies for atypical endometrial hyperplasia or endometrial intraepithelial neoplasia have not yet established a standard regimen. Future studies will need to determine the optimal nonsurgical management of atypical endometrial hyperplasia or endometrial intraepithelial neoplasia, standardizing agent, dose, schedule, clinical outcomes, and appropriate follow up. PMID- 23090536 TI - Pharmacogenetics and other reasons why drugs can fail in pregnancy: higher dose or different drug? AB - Changes in maternal physiology during pregnancy can alter the absorption, distribution, and clearance of many drugs. When presented with a clinical situation in which it does not appear that a prescribed drug is working, clinicians must either change drugs or increase the dose of the current drug to achieve the desired clinical effect. A case highlighting antihypertensive medication in pregnancy and the effect of changed drug-metabolizing enzymes is presented. Understanding pregnancy's effect on drug-metabolizing enzymes, transporters, and receptors can help clinicians make individualized pharmacotherapeutic decisions for patients. Pharmacogenetics potentially can aid clinicians in treating pregnant women in the future as more data are generated and individualized therapeutic models are constructed. PMID- 23090537 TI - Preventing the first cesarean delivery: summary of a joint Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal Fetal Medicine, and American College of Obstetricians and Gynecologists Workshop. AB - With more than one third of pregnancies in the United States being delivered by cesarean and the growing knowledge of morbidities associated with repeat cesarean deliveries, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Society for Maternal-Fetal Medicine, and the American College of Obstetricians and Gynecologists convened a workshop to address the concept of preventing the first cesarean delivery. The available information on maternal and fetal factors, labor management and induction, and nonmedical factors leading to the first cesarean delivery was reviewed as well as the implications of the first cesarean delivery on future reproductive health. Key points were identified to assist with reduction in cesarean delivery rates including that labor induction should be performed primarily for medical indication; if done for nonmedical indications, the gestational age should be at least 39 weeks or more and the cervix should be favorable, especially in the nulliparous patient. Review of the current literature demonstrates the importance of adhering to appropriate definitions for failed induction and arrest of labor progress. The diagnosis of "failed induction" should only be made after an adequate attempt. Adequate time for normal latent and active phases of the first stage, and for the second stage, should be allowed as long as the maternal and fetal conditions permit. The adequate time for each of these stages appears to be longer than traditionally estimated. Operative vaginal delivery is an acceptable birth method when indicated and can safely prevent cesarean delivery. Given the progressively declining use, it is critical that training and experience in operative vaginal delivery are facilitated and encouraged. When discussing the first cesarean delivery with a patient, counseling should include its effect on future reproductive health. PMID- 23090538 TI - Creating a public agenda for maternity safety and quality in cesarean delivery. AB - Cesarean delivery rates in California and the United States rose by 50% between 1998 and 2008 and vary widely among states, regions, hospitals, and health care providers. The leading driver of both the rise and the variation is first-birth cesarean deliveries performed during labor. With the large increase in primary cesarean deliveries, repeat cesarean delivery now has emerged as the largest single indication. The economic costs, health risks, and negligible benefits for most mothers and newborns of these higher rates point to the urgent need for a new approach to working with women in labor. This commentary analyzes the high rates and wide variations and presents evidence of costs and risks associated with cesarean deliveries (complete discussion provided in the California Maternal Quality Care Collaborative White Paper at www.cmqcc.org/white_paper). All stakeholders need to ask whether society can afford the costs and complications of this high cesarean delivery rate and whether they can work together toward solutions. The factors involved in the rise in cesarean deliveries point to the need for a multistrategy approach, because no single strategy is likely to be effective or lead to sustained change. We outline complementary strategies for reducing the rates and offer recommendations including clinical improvement strategies with careful examination of labor management practices; payment reform to eliminate negative or perverse incentives; education to recognize the value of vaginal birth; and full transparency through public reporting and continued public engagement. PMID- 23090539 TI - Patients, doctors, and legislators. PMID- 23090540 TI - At the threshold. PMID- 23090541 TI - What is new in female pelvic medicine and reconstructive surgery? Best articles from the past year. AB - This month, we focus on current research in female pelvic medicine and reconstructive surgery. Dr. Rogers discusses four recent publications, and each is concluded with a "bottom line" that is the take-home message. The complete reference for each can be found in on this page, along with direct links to the abstracts. PMID- 23090542 TI - Cosmetic gynecology and the elusive quest for the "perfect" vagina. PMID- 23090543 TI - Cosmetic gynecology and the elusive quest for the "perfect" vagina. PMID- 23090545 TI - Effect of vaginal lubricants on natural fertility. PMID- 23090547 TI - Buttock necrosis and paraplegia after bilateral internal iliac artery embolization for postpartum hemorrhage. PMID- 23090549 TI - Incidence and risk factors for clinical failure of uterine leiomyoma embolization. PMID- 23090551 TI - Risk of stillbirth and infant death stratified by gestational age. PMID- 23090559 TI - The following College document has been withdrawn: Committee opinion no. 502: primary ovarian insufficiency in the adolescent (Obstet Gynecol. 2011;118(3):741 5). PMID- 23090553 TI - Hyperosmolar glucose injection for the treatment of heterotopic ovarian pregnancy. PMID- 23090560 TI - ACOG Practice Bulletin Number 131: Screening for cervical cancer. AB - The incidence of cervical cancer in the United States has decreased more than 50% in the past 30 years because of widespread screening with cervical cytology. In 1975, the rate was 14.8 per 100,000 women. By 2008, it had been reduced to 6.6 per 100,000 women. Mortality from the disease has undergone a similar decrease from 5.55 per 100,000 women in 1975 to 2.38 per 100,000 women in 2008 (1). The American Cancer Society (ACS) estimates that there will be 12,170 new cases of cervical cancer in the United States in 2012, with 4,220 deaths from the disease (2). Cervical cancer is much more common worldwide, particularly in countries without screening programs, with an estimated 530,000 new cases of the disease and 275,000 resultant deaths each year (3, 4). When cervical cancer screening programs have been introduced into communities, marked reductions in cervical cancer incidence have followed (5, 6). New technologies for cervical cancer screening continue to evolve as do recommendations for managing the results. In addition, there are different risk-benefit considerations for women at different ages, as reflected in age-specific screening recommendations. The ACS, the American Society for Colposcopy and Cervical Pathology (ASCCP), and the American Society for Clinical Pathology (ASCP) have recently updated their joint guidelines for cervical cancer screening (7), and an update to the U.S. Preventive Services Task Force recommendations also has been issued (8). The purpose of this document is to provide a review of the best available evidence regarding screening for cervical cancer. PMID- 23090561 TI - ACOG Committee Opinion Number 540: Risk of venous thromboembolism among users of drospirenone-containing oral contraceptive pills. AB - Although the risk of venous thromboembolism is increased among oral contraceptive users compared with nonusers who are not pregnant and not taking hormones, and some data have suggested that use of drospirenone-containing pills has a higher risk of venous thromboembolism, this risk is still very low and is much lower than the risk of venous thromboembolism during pregnancy and the immediate postpartum period. When prescribing any oral contraceptive, clinicians should consider a woman's risk factors for venous thromboembolism and refer to the U.S. Medical Eligibility Criteria for Contraceptive Use issued by the Centers for Disease Control and Prevention. Patient education materials, including product labeling, should place information regarding oral contraceptive use and venous thromboembolism risks in context by also providing information about overall venous thromboembolism risks and venous thromboembolism risks during pregnancy and the postpartum period. Decisions regarding choice of oral contraceptive should be left to clinicians and their patients, taking into account the possible minimally increased risk of venous thromboembolism, patient preference, and available alternatives. PMID- 23090562 TI - ACOG Committee Opinion Number 541: Professional relationships with industry. AB - The American College of Obstetricians and Gynecologists (the College) has a long history of leadership in ensuring that its educational mission is evidence based and unbiased. A predecessor to this Committee Opinion was published in 1985, making the College one of the first professional associations to provide guidance on this issue. The College has continued to update the ethical guidance on physician interactions with industry periodically. Obstetrician-gynecologists' relationships with industry should be structured in a manner that will enhance, rather than detract from, their obligations to their patients. The ideal behaviors set forth in this Committee Opinion will contribute toward maintaining patient trust in the specialty and avoiding conflicts of interest by College members. PMID- 23090563 TI - ACOG Committee Opinion Number 542: Access to emergency contraception. AB - Emergency contraception includes contraceptive methods used to prevent pregnancy in the first few days after unprotected intercourse, sexual assault, or contraceptive failure. Although the U.S. Food and Drug Administration approved the first dedicated product for emergency contraception in 1998, numerous barriers to access to emergency contraception remain. The purpose of this Committee Opinion is to examine the barriers to the use of oral emergency contraception methods and to highlight the importance of increasing access. PMID- 23090564 TI - ACOG Patient Safety Checklist Number 8: Appropriateness of trial of labor after previous cesarean delivery (antepartum period). PMID- 23090565 TI - ACOG Patient Safety Checklist Number 9: Trial of labor after previous cesarean delivery (intrapartum admission). PMID- 23090566 TI - Coagulation management. AB - PURPOSE OF REVIEW: Trauma-induced coagulopathy is a frequent complication in severely injured patients. To correct coagulopathy and restore haemostasis, these patients have traditionally been treated with fresh frozen plasma, but in the last decade, there has been a shift from empirical therapy to targeted therapy with coagulation factor concentrates and other haemostatic agents. This review highlights emerging therapeutic options and controversial topics. RECENT FINDINGS: Early administration of the antifibrinolytic medication tranexamic acid was shown in the multicentre CRASH-2 trial to be an effective and inexpensive means of decreasing blood loss. Numerous retrospective and experimental studies have shown that the use of coagulation factor concentrates decreases blood loss and may be useful in reducing the need for transfusion of allogeneic blood products. In particular, early use of fibrinogen concentrate and thrombin generators has a positive impact on haemostasis. However, the use of prothrombin complex concentrate to correct trauma-induced coagulopathy has also been associated with a potential risk of serious adverse events. SUMMARY: Current evidence in trauma resuscitation indicates a potential role for coagulation factor concentrates and other haemostatic agents in correcting trauma-induced coagulopathy. Despite a shift towards such transfusion strategy, there remains a shortage of data to support this approach. PMID- 23090567 TI - Time to watch out for the bleeding trauma patient. PMID- 23090568 TI - Medicare, swing beds, and critical access hospitals. AB - Critical Access Hospitals (CAHs) receive cost-based reimbursement from Medicare for inpatient care, including post-acute skilled care provided in swing beds (skilled swing days). Because the reimbursement formula treats swing bed and acute days equally, there is concern that CAH skilled swing days are "overreimbursed" as compared with skilled days provided in other settings. The reimbursement formula is complex; thus, empirical estimates are needed to identify the marginal cost per day to the hospital and the implied Medicare expenditure per day, accounting for fixed cost transfers between services. Using Medicare cost report data, we find that Medicare paid, on average, $581 for the routine portion of a CAH skilled swing day in 2009--more than the estimated marginal cost of $262, but less than the 2009 average per diem of $1,302. Estimates varied widely across the 1,300 CAHs; therefore, payment policy changes would likely have a broad range of effects. PMID- 23090569 TI - Controllable growth of Prussian blue nanostructures on carboxylic group functionalized carbon nanofibers and its application for glucose biosensing. AB - Glucose detection is very important in biological analysis, clinical diagnosis and the food industry, and especially for the routine monitoring of diabetes. This work presents an electrochemical approach to the detection of glucose based on Prussian blue (PB) nanostructures/carboxylic group-functionalized carbon nanofiber (FCNF) nanocomposites. The hybrid nanocomposites were constructed by growing PB onto the FCNFs. The obtained PB-FCNF nanocomposites were characterized by scanning electron microscopy, x-ray diffraction and x-ray photoelectron spectroscopy. The mechanism of formation of PB-FCNF nanocomposites was investigated and is discussed in detail. The PB-FCNF modified glassy carbon electrode (PB-FCNF/GCE) shows good electrocatalysis toward the reduction of H(2)O(2), a product from the reduction of O(2) followed by glucose oxidase (GOD) catalysis of the oxidation of glucose to gluconic acid. Further immobilizing GOD on the PB-FCNF/GCE, an amperometric glucose biosensor was achieved by monitoring the generated H(2)O(2) under a relatively negative potential. The resulting glucose biosensor exhibited a rapid response of 5 s, a low detection limit of 0.5 MUM, a wide linear range of 0.02-12 mM, a high sensitivity of 35.94 MUA cm(-2) mM(-1), as well as good stability, repeatability and selectivity. The sensor might be promising for practical application. PMID- 23090570 TI - Wavelength dependence of biological damage induced by UV radiation on bacteria. AB - The biological effects of UV radiation of different wavelengths (UVA, UVB and UVC) were assessed in nine bacterial isolates displaying different UV sensitivities. Biological effects (survival and activity) and molecular markers of oxidative stress [DNA strand breakage (DSB), generation of reactive oxygen species (ROS), oxidative damage to proteins and lipids, and the activity of antioxidant enzymes catalase and superoxide dismutase] were quantified and statistically analyzed in order to identify the major determinants of cell inactivation under the different spectral regions. Survival and activity followed a clear wavelength dependence, being highest under UVA and lowest under UVC. The generation of ROS, as well as protein and lipid oxidation, followed the same pattern. DNA damage (DSB) showed the inverse trend. Multiple stepwise regression analysis revealed that survival under UVA, UVB and UVC wavelengths was best explained by DSB, oxidative damage to lipids, and intracellular ROS levels, respectively. PMID- 23090571 TI - Isolation and characterization of acyl homoserine lactone-producing bacteria during an urban river biofilm formation. AB - The presence and diversity of acyl homoserine lactone (AHL)-producers in an urban river biofilm were investigated during 60-day biofilm formation. AHL biosensors detected the presence of AHL-producers in 1-60-day river biofilms. Screening for AHL-producers resulted in 17 Aeromonas spp., 3 Pseudomonas spp., 3 Ensifer spp., and 1 Acinetobacter sp. Among these isolates, six of them were closely related to Acinetobacter tjernbergiae, Aeromonas allosaccharophila, Aeromonas aquariorum, Aeromonas jandaei, Pseudomonas panipatensis, and Ensifer adhaerens and represented novel AHL-producing species. Thin layer chromatography revealed that C4-homoserine lactone was prevailing in Aeromonas spp., whereas C6- and C8 homoserine lactones and their derivatives were prevailing in other strains. Using degenerate primers, novel AHL synthetase genes from the three Ensifer spp. were successfully amplified. This study reports for the first time the diversity of AHL-producers from a river biofilm and the variety of novel AHL synthetase genes in Ensifer group. PMID- 23090572 TI - Definition of patients presenting a high risk of developing peritoneal carcinomatosis after curative surgery for colorectal cancer: a systematic review. AB - BACKGROUND: In colorectal cancer, complete cytoreductive surgery associated with hyperthermic intraperitoneal chemotherapy achieves encouraging results in early peritoneal carcinomatosis (PC), but this early detection can only be accurately accomplished during a systematic second-look surgery. This costly and invasive approach can only be proposed to selected patients. The objective of this study was to identify risk factors predictive of developing PC after curative surgery for colorectal cancer. METHODS: After a systematic review of the literature published between 1940 and 2011, all clinical studies reporting the incidence of PC after curative surgery for colorectal cancer were searched for factors associated with the primary tumor that were likely to influence the incidence of recurrent PC. RESULTS: Sixteen clinical studies were considered informative, all nonrandomized, three prospective and 13 retrospective, including 4-395 patients. Overall, the methodological quality of the reported studies was low. Data were available for the following factors: synchronous PC, synchronous ovarian metastases, perforated primary tumor, serosal and/or adjacent organ invasion, histological subtype, and positive peritoneal cytology with reported incidences of recurrent PC between 8 and 75%. No study was found that mentioned an impact of lymph node invasion, tumor location, laparoscopy, occlusive tumors, or bleeding tumor on recurrent PC. CONCLUSIONS: Evidence regarding the incidence of recurrent PC after curative surgery for colorectal cancer is poor. Emerging data indicate three situations that could result in a real higher risk of recurrent PC: synchronous PC, synchronous isolated ovarian metastases, and a perforated primary tumor. PMID- 23090574 TI - The modular modality frame model: continuous body state estimation and plausibility-weighted information fusion. AB - Humans show admirable capabilities in movement planning and execution. They can perform complex tasks in various contexts, using the available sensory information very effectively. Body models and continuous body state estimations appear necessary to realize such capabilities. We introduce the Modular Modality Frame (MMF) model, which maintains a highly distributed, modularized body model continuously updating, modularized probabilistic body state estimations over time. Modularization is realized with respect to modality frames, that is, sensory modalities in particular frames of reference and with respect to particular body parts. We evaluate MMF performance on a simulated, nine degree of freedom arm in 3D space. The results show that MMF is able to maintain accurate body state estimations despite high sensor and motor noise. Moreover, by comparing the sensory information available in different modality frames, MMF can identify faulty sensory measurements on the fly. In the near future, applications to lightweight robot control should be pursued. Moreover, MMF may be enhanced with neural encodings by introducing neural population codes and learning techniques. Finally, more dexterous goal-directed behavior should be realized by exploiting the available redundant state representations. PMID- 23090573 TI - Adrenal histologic findings show no difference in clinical presentation and outcome in primary hyperaldosteronism. AB - BACKGROUND: Primary hyperaldosteronism is most commonly due to a solitary cortical adenoma. Thus, some surgeons have suggested a subtotal adrenalectomy is a reasonable approach when a mass can be identified. On the other hand, adrenal vein sampling (AVS) is being used more frequently to distinguish patients with unilateral disease for adrenalectomy, even if a discrete mass is not identified on axial imaging. In these cases, surgical pathology may reveal a cortical adenoma, a cortical adenoma with hyperplasia, or cortical hyperplasia. The goal of this study was to compare the presentation and outcome among patients undergoing adrenalectomy and found to have different histologic features. METHODS: We performed a retrospective analysis of 136 patients with primary hyperaldosteronism. A total of 95 patients had an adrenalectomy for unilateral disease. The preoperative clinical and laboratory, and postoperative outcome of the three aforementioned histologic groups were compared. RESULTS: A total of 95 patients underwent an adrenalectomy. We found no significant difference in age, gender, body mass index, duration of hypertension, number of antihypertensive medications, serum aldosterone level, serum renin level, or adrenal vein sampling ratios among the three histologic categories. We also found no significant difference among the three categories in postoperative cure rate. CONCLUSION: The rate of unilateral hyperplasia in patients with primary hyperaldosteronism (16%) is likely higher than previously reported, which may be due to the increasing use of AVS. The clinical presentation and outcome of patients regardless of the histologic findings are similar. Our data also suggests that subtotal adrenalectomy would not be appropriate in patients with primary hyperaldosteronism. PMID- 23090575 TI - High energy expenditure masks low physical activity in obesity. AB - OBJECTIVE: To investigate energy expenditure in lean and obese individuals, focusing particularly on physical activity and severely obese individuals. DESIGN: Total daily energy expenditure (TDEE) was assessed using doubly labeled water, resting metabolic rate (RMR) by indirect calorimetry, activity energy expenditure (AEE) by difference and time spent in physical activity by multisensor activity monitors. SUBJECTS: In all, 177 lean, Class I and severely obese individuals (age 31-56 years, body mass index 20-64 kg m(-2)) were analyzed. RESULTS: All components of energy expenditure were elevated in obese individuals. For example, TDEE was 2404+/-95 kcal per day in lean and 3244+/-48 kcal per day in Class III obese individuals. After appropriate adjustment, RMR was similar in all groups. Analysis of AEE by body weight and obesity class indicated a lower AEE in obese individuals. Confirming lower physical activity, obese individuals spent less time engaged in moderate-to-vigorous physical activity (2.7+/-1.3, 1.8+/-0.6, 2.0+/-1.4 and 1.2+/-1.0 h per day in lean, Class I, Class II and Class III individuals) and more time in sedentary behaviors. CONCLUSIONS: There was no indication of metabolic efficiency in even the severely obese, as adjusted RMR was similar across all groups. The higher AEE observed in the obese is consistent with a higher cost of activities due to higher body weight. However, the magnitude of the higher AEE (20-25% higher in obese individuals) is lower than expected (weight approximately 100% higher in Class III individuals). Confirming a lower volume of physical activity in the obese, the total time spent in moderate-to-vigorous physical activity and average daily metabolic equivalent of task level were lower with increasing obesity. These findings demonstrate that high body weight in obese individuals leads to a high TDEE and AEE, which masks the fact that they are less physically active, which can be influenced by duration or intensity of activity, than in lean individuals. PMID- 23090576 TI - Long-term weight changes in obese young adult men and subsequent all-cause mortality. AB - BACKGROUND: Although the expectation is that weight gain increases mortality and weight loss among those overweight reduces mortality, results on weight gain and mortality in young adults are conflicting, and weight loss is less explored. We investigated the association between long-term weight change and all-cause mortality in a broad range of body mass index (BMI) in young men. METHODS: Among 362200 Danish draftees, examined between 1943 and 1977, all obese (BMI ?31.0 kg m(-2); n=1930), and a random 1% sample of the others (n=3601) were identified at a mean age of 20 years (range: 18-25 years). All the obese and half the controls were re-examined between 4 and 40 years later (mean age 35 years). Weight changes were defined as: weight loss <-0.1 kg m(-2) per year, weight stability within +/ 0.1 kg m(-2) per year and weight gain >0.1 kg m(-2) per year. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. RESULTS: Among the 908 obese and 1073 controls followed for 30 years after re-examination 220 and 232 died. HR of the weight stable obese was 2.32 (CI: 1.56-3.44) compared with the weight stable controls. In the obese cohort there was no association between weight loss, adjusted for initial BMI, and mortality (HR: 0.99; CI: 0.68 1.45) compared with weight stable obese. Too few controls lost weight to allow assessment of weight loss. Weight gain was associated with increased mortality in the obese (HR: 1.50; CI: 1.07-2.10) and controls (HR: 1.54; CI: 1.14-2.09) compared with weight stable obese and controls, respectively. Neither the time between the two examinations, life-style factors nor exclusion of diseased individuals influenced the results. CONCLUSIONS: Although there were increased mortality of the weight-stable obese compared with controls, there was no association between weight loss and mortality in the obese. Weight gain increased mortality regardless of the initial weight. PMID- 23090577 TI - Contribution of 24 obesity-associated genetic variants to insulin resistance, pancreatic beta-cell function and type 2 diabetes risk in the French population. AB - CONTEXT: Obesity is the major determinant of type 2 diabetes (T2D), presumably through its effect on insulin resistance. Genome-wide association studies reported many single-nucleotide polymorphisms (SNPs) that increase obesity risk and body mass index (BMI), but their impact on T2D-related traits and risk is unclear. OBJECTIVE: We aimed at analyzing the effect of 24 obesity risk alleles, separately and in combination, on variation of both insulin resistance and beta cell dysfunction, and on T2D risk. DESIGN: We genotyped 24 obesity-associated SNPs and calculated an obesity genotype score (sum of the obesity risk alleles per individual). We analyzed the contribution of each SNP and this score to the variation of four metabolic indices: homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of the pancreatic beta-cell function (HOMA-B), insulin sensitivity index (ISI) and insulinogenic index (II) (in up to 8050 nondiabetic French individuals) and to T2D risk (in 2077 T2D cases and 3085 controls). RESULTS: We found a highly significant effect of the obesity genotype score on increased insulin resistance adjusted for age and gender (beta=0.02; P-value=7.16 * 10(-9) for HOMA-IR). Individually, we identified nominal or significant association between increased insulin resistance and risk alleles in FAIM2, FTO, GNPDA2, MC4R, NPC1, PTER and SH2B1. Most signals, including the obesity genotype score and FTO SNP, were also associated with increased beta-cell function (beta=0.01; P-value=1.05 * 10(-6) and beta=0.04; P value=3.45 * 10(-4), respectively). In our T2D case-control study, only the obesity genotype score and the well-known FTO locus significantly contributed to T2D risk (OR=1.03; P-value=9.99 * 10(-3) and OR=1.15; P-value=9.46 * 10(-4), respectively). Adjustment for BMI abolished all significant associations. CONCLUSIONS: Genetic predisposition to obesity contributes to increased insulin resistance and to its compensation through increased beta-cell function, and weakly increases the T2D risk. These associations are mediated by BMI. PMID- 23090578 TI - The environmental obesogen bisphenol A promotes adipogenesis by increasing the amount of 11beta-hydroxysteroid dehydrogenase type 1 in the adipose tissue of children. AB - BACKGROUND: Bisphenol A (BPA) is considered as an environmental obesogen. The enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts the inactive hormone cortisone to the active hormone cortisol in adipose tissues and promotes adipogenesis. OBJECTIVE: To examine whether environmentally relevant concentrations of BPA could increase the expression of 11beta-HSD1, as well as that of the adipogenesis-related genes peroxisome proliferator-activated receptor gamma (PPAR-gamma) and lipoprotein lipase (LPL), in the adipose tissue of children. METHODS: Omental fat biopsies were obtained from 17 children (7 boys and 10 girls between 3 and 13 years of age) undergoing abdominal surgery. The effects of BPA (10 nM, 1 MUM, and 80 MUM) on 11beta-HSD1, PPAR-gamma and LPL mRNA expression, and 11beta-HSD1 enzymatic activity in adipose tissue and adipocytes were assessed in vitro. Moreover, the effects of carbenoxolone (CBX), an 11beta HSD1 inhibitor, or RU486, a glucocorticoid (GC) receptor antagonist, on 11beta HSD1, PPAR-gamma and LPL mRNA expression were assessed in human visceral preadipocytes and adipocytes. RESULTS: BPA, even at the lowest concentration tested (10 nM), increased the mRNA expression and enzymatic activity of 11beta HSD1 in the omental adipose tissue samples and the visceral adipocytes. Similar effects on PPAR-gamma and LPL mRNA expression and lipid accumulation were observed in the adipocytes. CBX treatment inhibited the stimulatory effects of BPA (at 10 nM) on PPAR-gamma and LPL mRNA expression, whereas RU486 inhibited 11beta-HSD1 mRNA expression in the adipocytes. CONCLUSION: BPA, at environmentally relevant levels, increased the mRNA expression and enzymatic activity of 11beta-HSD1 by acting upon a GC receptor, which may lead to the acceleration of adipogenesis. PMID- 23090579 TI - Breaking the regioselectivity of indole prenyltransferases: identification of regular C3-prenylated hexahydropyrrolo[2,3-b]indoles as side products of the regular C2-prenyltransferase FtmPT1. AB - The prenyltransferase FtmPT1 from Aspergillus fumigatus is involved in the biosynthesis of fumitremorgin-type alkaloids and catalysed the regular C2 prenylation of brevianamide F (cyclo-L-Trp-L-Pro). It has been shown that FtmPT1 also accepted a number of other tryptophan-containing cyclic dipeptides and prenylated them, in the presence of dimethylallyl diphosphate, at C-2 of the indole nucleus. Detailed analysis of the incubation mixtures of FtmPT1 with these cyclic dipeptides revealed the presence of additional product peaks in the HPLC chromatograms. Seven regularly C3-prenylated hexahydropyrrolo[2,3-b]indoles were isolated and identified by HR-ESI-MS and NMR analyses including HMBC, HMQC and NOESY experiments. Further experiments proved that the C2- and C3-prenylated products are both independent enzyme products. To the best of our knowledge, this is the first report on the enzymatic formation of regularly C3-prenylated indolines. A reaction mechanism for both C2- and C3-prenylated derivatives was proposed. PMID- 23090580 TI - Management of hyperglycemia in hospitalized patients with renal insufficiency or steroid-induced diabetes. AB - Pharmacologic doses of glucocorticoids and chronic renal failure are challenging comorbidities and complications for safe and effective dosing of insulin for the management of hospitalized patients with diabetes. Glucocorticoids are used widely in hospitalized patients and will commonly provoke new-onset hyperglycemia in patients without a prior history of diabetes or will provoke severely uncontrolled hyperglycemia in patients with known diabetes. Insulin therapy is invariably necessary for the treatment of glucocorticoid-induced hyperglycemia and must be tailored to the pharmacodynamics of the glucocorticoid being given. Renal failure causes a decrease in the clearance of insulin, especially exogenous injected insulin. Dosing algorithms for hospitalized patients should be adjusted for patients with renal failure in order to minimize hypoglycemia. Many patients with type 2 diabetes will need little or no therapy after the development of end stage renal failure. Care must be taken to avoid the overtreatment of hyperglycemia. PMID- 23090581 TI - RETRACTED ARTICLE: Using remote sensing to quantify the fractional cover of vegetation and exposed bedrock within a complex landscape: applications for karst rocky desertification monitoring. PMID- 23090582 TI - Corynebacterium glutamicum CsoR acts as a transcriptional repressor of two copper/zinc-inducible P(1B)-type ATPase operons. AB - The mechanism of regulation of the expression of copA and copB, encoding putative copper-translocating P(1B)-type ATPases in Corynebacterium glutamicum, was investigated. The levels of copA and copB mRNAs were upregulated in response to excess copper as well as excess zinc. Disruption of csoR, encoding a transcriptional regulator, resulted in constitutive expression of copA and copB. The CsoR protein bound to the promoter regions of the copA-csoR and the cgR_0124 copB-cgR_0126 operon. In vitro DNA binding activity was strongly inhibited by copper, but much less inhibited by zinc. A csoR-deficient mutant showed slightly increased resistance to copper, but slightly decreased resistance to zinc. These findings indicate that CsoR acts as a transcriptional repressor not only of the cognate copA-csoR operon but also of the cgR_0124-copB-cgR_0126 operon, which is not physically linked to csoR on the chromosome, and that CsoR plays a major role in copper homeostasis. PMID- 23090583 TI - Prussian blue nanoparticles operate as a new generation of photothermal ablation agents for cancer therapy. AB - Herein, prussian blue nanoparticles, an ancient dye, were explored as a new generation of near-infrared laser-driven photothermal ablation agents for cancer therapy alternative to traditional agents due to their good photothermal efficiency and high photothermal stability but low cost and particularly clinically approved biosafety. PMID- 23090585 TI - Action of gibberellins on growth and metabolism of Arabidopsis plants associated with high concentration of carbon dioxide. AB - Although the positive effect of elevated CO(2) concentration [CO(2)] on plant growth is well known, it remains unclear whether global climate change will positively or negatively affect crop yields. In particular, relatively little is known about the role of hormone pathways in controlling the growth responses to elevated [CO(2)]. Here, we studied the impact of elevated [CO(2)] on plant biomass and metabolism in Arabidopsis (Arabidopsis thaliana) in relation to the availability of gibberellins (GAs). Inhibition of growth by the GA biosynthesis inhibitor paclobutrazol (PAC) at ambient [CO(2)] (350 umol CO(2) mol(-1)) was reverted by elevated [CO(2)] (750 umol CO(2) mol(-1)). Thus, we investigated the metabolic adjustment and modulation of gene expression in response to changes in growth of plants imposed by varying the GA regime in ambient and elevated [CO(2)]. In the presence of PAC (low-GA regime), the activities of enzymes involved in photosynthesis and inorganic nitrogen assimilation were markedly increased at elevated [CO(2)], whereas the activities of enzymes of organic acid metabolism were decreased. Under ambient [CO(2)], nitrate, amino acids, and protein accumulated upon PAC treatment; however, this was not the case when plants were grown at elevated [CO(2)]. These results suggest that only under ambient [CO(2)] is GA required for the integration of carbohydrate and nitrogen metabolism underlying optimal biomass determination. Our results have implications concerning the action of the Green Revolution genes in future environmental conditions. PMID- 23090587 TI - Dynamic changes in the distribution of minerals in relation to phytic acid accumulation during rice seed development. AB - Phytic acid (inositol hexakisphosphate [InsP(6)]) is the storage compound of phosphorus in seeds. As phytic acid binds strongly to metallic cations, it also acts as a storage compound of metals. To understand the mechanisms underlying metal accumulation and localization in relation to phytic acid storage, we applied synchrotron-based x-ray microfluorescence imaging analysis to characterize the simultaneous subcellular distribution of some mineral elements (phosphorus, calcium, potassium, iron, zinc, and copper) in immature and mature rice (Oryza sativa) seeds. This fine-imaging method can reveal whether these elements colocalize. We also determined their accumulation patterns and the changes in phosphate and InsP(6) contents during seed development. While the InsP(6) content in the outer parts of seeds rapidly increased during seed development, the phosphate contents of both the outer and inner parts of seeds remained low. Phosphorus, calcium, potassium, and iron were most abundant in the aleurone layer, and they colocalized throughout seed development. Zinc was broadly distributed from the aleurone layer to the inner endosperm. Copper localized outside the aleurone layer and did not colocalize with phosphorus. From these results, we suggest that phosphorus translocated from source organs was immediately converted to InsP(6) and accumulated in aleurone layer cells and that calcium, potassium, and iron accumulated as phytic acid salt (phytate) in the aleurone layer, whereas zinc bound loosely to InsP(6) and accumulated not only in phytate but also in another storage form. Copper accumulated in the endosperm and may exhibit a storage form other than phytate. PMID- 23090588 TI - MP2 energy and density for large molecular systems with internal error control using the Divide-Expand-Consolidate scheme. AB - Divide-Expand-Consolidate (DEC) is a local correlation method where the inherent locality of the electron correlation problem is used to express the correlated calculation on a large molecular system in terms of small independent fragment calculations employing small subsets of local HF orbitals. A crucial feature of the DEC scheme is that the sizes of the local orbital spaces are determined in a black box manner during the calculation. In this way it is ensured that the correlation energy has been determined to a predefined precision compared to a conventional calculation. In the present work we apply the DEC scheme to calculate the correlation energy as well as the electron density matrix for the insulin molecule using second order Moller-Plesset (MP2) theory. This is the first DEC calculation on a molecular system which is too large to be treated using a conventional MP2 implementation. The fragmentation errors for the insulin DEC calculation are carefully analyzed using internal consistency checks. It is demonstrated that size-intensive properties are determined to the same precision for small and large molecules. For example, the percentage of correlation energy recovered and the error per electron in the correlated density matrix depend only on the predefined precision and not on the molecular size. PMID- 23090586 TI - Systems dynamic modeling of a guard cell Cl- channel mutant uncovers an emergent homeostatic network regulating stomatal transpiration. AB - Stomata account for much of the 70% of global water usage associated with agriculture and have a profound impact on the water and carbon cycles of the world. Stomata have long been modeled mathematically, but until now, no systems analysis of a plant cell has yielded detail sufficient to guide phenotypic and mutational analysis. Here, we demonstrate the predictive power of a systems dynamic model in Arabidopsis (Arabidopsis thaliana) to explain the paradoxical suppression of channels that facilitate K(+) uptake, slowing stomatal opening, by mutation of the SLAC1 anion channel, which mediates solute loss for closure. The model showed how anion accumulation in the mutant suppressed the H(+) load on the cytosol and promoted Ca(2+) influx to elevate cytosolic pH (pH(i)) and free cytosolic Ca(2+) concentration ([Ca(2+)](i)), in turn regulating the K(+) channels. We have confirmed these predictions, measuring pH(i) and [Ca(2+)](i) in vivo, and report that experimental manipulation of pH(i) and [Ca(2+)](i) is sufficient to recover K(+) channel activities and accelerate stomatal opening in the slac1 mutant. Thus, we uncover a previously unrecognized signaling network that ameliorates the effects of the slac1 mutant on transpiration by regulating the K(+) channels. Additionally, these findings underscore the importance of H(+) coupled anion transport for pH(i) homeostasis. PMID- 23090589 TI - A unique interactive cognitive behavioral training program for front-line cancer care professionals. AB - For between one third and one half of all cancer survivors, disturbances in mood and cognition do not end with the conclusion of treatment. Recognizing this problem, the Institute of Medicine emphasized in its 2008 report, the importance of addressing psychosocial issues, such as distress, to providing quality cancer care. The National Cancer Institute (NCI) has recognized that there is a severe lack of trained professionals who can address these needs. In response to this need, an interactive training program was developed and implemented to teach frontline cancer care professionals Cognitive Behavioral Therapy (CBT) skills. This training includes a structured curriculum, centered around a 3-day training workshop that includes didactic discussion, small group interactive sessions, role playing, post course support, and follow-up evaluation. Four of the planned eight workshops have been conducted thus far and indicate successful recruitment and implementation of a unique training model related to the CBT skills learned. PMID- 23090592 TI - Introduction to antibiotic resistance. AB - The inexorable rise in multidrug-resistant Gram-negative bacteria has been widely reported. Multiple modes of resistance often present in a single strain of bacteria, and this may also be combined with an increase in virulence, both of which are leading to a significant increase in morbidity and mortality in patients. Against this background, the absolute number of new antibiotics licensed has declined especially for Gram-negative multidrug-resistant pathogens. The reasons for this failure are presented here: market issues, big pharma changes, regulatory constraints, difficulties in finding drugable targets and, lastly, suitable compounds worthy of full development. PMID- 23090591 TI - Development and preliminary evaluation of a training workshop for the collection of patient-reported outcome (PRO) interview data by research support staff. AB - This paper describes the development and initial evaluation of a didactic curriculum to prepare research support staff with the core knowledge and skills required to collect patient-reported outcomes (PROs) via interviews. Research support staff members (N = 77) were recruited for eight separate workshops, each consisting of a didactic presentation followed by role-play scenarios with trained actors depicting common scenarios they may encounter as part of patient interaction. Trainees were observed and received feedback on their performance from trained facilitators and peers. In comparison to their pre-training assessment, trainees showed significant improvement in their confidence to conduct a research interview, handle a distressed participant, manage a wandering interview, ask participants sensitive questions, and handle irritated patients. Training research support staff in the effective collection of PROs via patient interviews can improve the confidence of these individuals in interacting with patients, which can ultimately lead to increased accuracy of data collection. PMID- 23090593 TI - The origins of antibiotic resistance. AB - Antibiotics remain one of our most important pharmacological tools for the control of infectious disease. However, unlike most other drugs, the use of antibiotics selects for resistant organisms and erodes their clinical utility. Resistance can emerge within populations of bacteria by mutation and be retained by subsequent selection or by the acquisition of resistance elements laterally from other organisms. The source of these resistance genes is only now being understood. The evidence supports a large bacterial resistome-the collection of all resistance genes and their precursors in both pathogenic and nonpathogenic bacteria. These genes have arisen by various means including self-protection in the case of antibiotic producers, transport of small molecules for various reasons including nutrition and detoxification of noxious chemicals, and to accomplish other goals, such as metabolism, and demonstrate serendipitous selectivity for antibiotics. Regardless of their origins, resistance genes can rapidly move through bacterial populations and emerge in pathogenic bacteria. Understanding the processes that contribute to the evolution and selection of resistance is essential to mange current stocks of antibiotics and develop new ones. PMID- 23090594 TI - Surveillance programmes and antibiotic resistance: worldwide and regional monitoring of antibiotic resistance trends. AB - Since the introduction of the penicillins many decades ago, multiple species of bacteria have responded to the use of antimicrobial agents in their ability to develop and transmit antimicrobial resistance. Increased consumption of antimicrobial agents, their misappropriate use among other factors have further catalysed this resistance phenomenon. As bacterial resistance is a global healthcare issue, appropriate monitoring through governmental, institutional and industry or pharmaceutical led surveillance programmes is essential. This chapter describes the resistance issue, factors affecting this issue and examples of such ongoing resistance surveillance programmes. PMID- 23090595 TI - Current and future challenges in the development of antimicrobial agents. AB - Micro-organisms exist to survive. Even in the absence of antimicrobial agents, many have determinants of resistance that may be expressed phenotypically, should the need arise. With the advent of the antibiotic age, as more and more drugs were developed to treat serious infections, micro-organisms (particularly bacteria) rapidly developed resistance determinants to prevent their own demise.The most important determinants of resistance have been in the Gram positive and Gram-negative bacteria. Among Gram-positive bacteria, methicillin resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae (PRSP) have taxed researchers and pharmaceutical companies to develop new agents that are effective against these resistant strains. Among the Gram-negative bacteria, extended-spectrum beta lactamase (ESBL) enzymes, carbapenemases (CREs) and the so-called amp-C enzymes that may be readily transferred between species of enterobacteriaceae and other facultative species have created multi-drug resistant organisms that are difficult to treat. Other resistance determinants have been seen in other clinically important bacterial species such as Neisseria gonorrhoeae, Clostridium difficile, Haemophilus influenzae and Mycobacterium tuberculosis. These issues have now spread to fungal agents of infection.A variety of modalities have been used to stem the tide of resistance. These include the development of niche compounds that target specific resistance determinants. Other approaches have been to find new targets for antimicrobial activity, use of combination agents that are effective against more than one target in the cell, or new delivery mechanism to maximize the concentration of antimicrobial agents at the site of infection without causing toxicity to the host. It is important that such new modalities have been proved effective for clinical therapy. Animal models and non mammalian systems have been developed to determine if new agents will reach sufficient concentrations at infection sites to predict clinical efficacy without toxicity. It will also be key to consider antimicrobial stewardship as an important component of the continuing battle to prevent the development of antimicrobial resistance. PMID- 23090596 TI - The role of the outer membrane of Gram-negative bacteria in antibiotic resistance: Ajax' shield or Achilles' heel? AB - There has been an enormous increase in our knowledge of the fundamental steps in the biosynthesis and assembly of the outer membrane of Gram-negative bacteria. Lipopolysaccharide is a major component of the outer membrane of Gram-negative bacteria as is peptidoglycan. Porins, efflux pumps and other transport proteins of the outer membrane are also present. It is clear that there are numerous essential proteins that have the potential to be targets for novel antimicrobial agents. Progress, however, has been slow. Much of the emphasis has been on cytoplasmic processes that were better understood earlier on, but have the drawback that two penetration barriers, with different permeability properties, have to be crossed. With the increased understanding of the late-stage events occurring in the periplasm, it may be possible to shift focus to these more accessible targets. Nevertheless, getting drugs across the outer membrane will remain a challenge to the ingenuity of the medicinal chemist. PMID- 23090597 TI - Prevention of drug resistance by combined drug treatment of tuberculosis. AB - Treatment with a combination of anti-tuberculosis drugs is thought to work by the first drug killing mutants resistant to the second drug, while the second drug kills those resistant to the first drug. Combined treatment has been remarkably successful in preventing the emergence of resistance during the treatment of tuberculosis. This success has led to the introduction of multi-drug treatment for leprosy, HIV infections and cancer. Its success in tuberculosis depends on a number of conditions such as the chromosomal nature of drug resistance in Mycobacterium tuberculosis and the absence of plasmids carrying resistance factors as well as the manner in which the bacterial population in tuberculosis does not come into contact with other potentially resistant bacteria. For multi drug treatment to be effective in preventing resistance, the drugs must be sufficiently active so that each can inhibit all the bacteria in lesions. There must also be effective post-antibiotic lags in growth restarting to prevent growth between doses. Special bacterial populations that are drug tolerant or survive drug action unusually successfully are also a potential source of resistance. PMID- 23090598 TI - Nonmultiplying bacteria are profoundly tolerant to antibiotics. AB - Bacteria survive treatments with antimicrobial agents; they achieve this in two ways. Firstly, bacteria quickly become tolerant to these agents. This tolerance is temporary, reversible, and associated with slowing of the multiplication rate. Secondly, bacteria can undergo genetic mutations leading to permanent clonal resistance to antimicrobial agents. In patients with infections, nonmultiplying bacteria, some of which may be viable but nonculturable, exist side by side with multiplying bacteria. Current antibiotics capable of killing actively multiplying bacteria have very limited or no effect against nonmultiplying bacteria. Treatment of such infections requires a regimen of multiple antimicrobial agents in order to control nonmultiplying persistent bacteria. This is especially important in tuberculosis where there is co-existence of slowly multiplying tolerant bacteria with fast growing sensitive organisms. For this reason, a prolonged length of chemotherapy, lasting 6 months, is necessary to achieve cure. This long duration of treatment is due to the slow, inadequate effect of antibiotics on nonmultiplying persistent bacteria. Similar problems with eradication of persistent bacteria are evident in the treatment of biofilms. These bacteria serve as a pool for recurrent infections. Extended courses of antibiotics increase the likelihood of genetic resistance, raise the cost of treatments, and lead to more side effects. PMID- 23090599 TI - Persister cells: molecular mechanisms related to antibiotic tolerance. AB - It is a given that new antibiotics are needed to combat drug-resistant pathogens. However, this is only a part of the need-we actually never had antibiotics capable of eradicating an infection. All pathogens produce a small subpopulation of dormant persister cells that are highly tolerant to killing by antibiotics. Once an antibiotic concentration drops, surviving persisters re-establish the population, causing a relapsing chronic infection. Persisters are especially significant when the pathogen is shielded from the immune system by biofilms, or in sites where the immune components are limited-in the nervous system, the stomach, or inside macrophages.Antibiotic treatment during a prolonged chronic infection of P. aeruginosa in the lungs of patients with cystic fibrosis selects for high-persister (hip) mutants. Similarly, treatment of oral thrush infection selects for hip mutants of C. albicans. These observations suggest a direct causality between persisters and recalcitrance of the disease. It appears that tolerance of persisters plays a leading role in chronic infections, while resistance is the leading cause of recalcitrance to therapy in acute infections. Studies of persister formation in E. coli show that mechanisms of dormancy are highly redundant. Isolation of persisters produced a transcriptome which suggests a dormant phenotype characterized by downregulation of energy-producing and biosynthetic functions. Toxin-antitoxin modules represent a major mechanism of persister formation. The RelE toxin causes dormancy by cleaving mRNA; the HipA toxin inhibits translation by phosphorylating elongation factor Ef-Tu, and the TisB toxin forms a membrane pore, leading to a decrease in pmf and ATP. PMID- 23090600 TI - Antimicrobial textiles. AB - Bacteria have evolved unique mechanisms that allow them survive in the presence of strong selection pressures. Included in these mechanisms is the ability to share genetic determinants among and between species of bacteria thus spreading metal or antibiotic resistance traits quickly. The textile industry in response to demand has developed antimicrobial fabrics by the addition of bactericidal compounds during production. Some of these antimicrobials include metal nanoparticles, quaternary ammonia compounds, and broad spectrum compounds like triclosan. Bacteria have already expressed resistance to each of these bactericides. Here we discuss the evolutionary and ecological consequences of antimicrobial textiles in terms of co-selection. We predict that continued use of such materials could result in increased and widespread resistance to specific antimicrobials, especially metals, with an increased resistance to antibiotics. Such increases have the potential to find their way into other bacterial populations of human pathogens leading to serious and unintended public health consequences. PMID- 23090601 TI - Efflux: how bacteria use pumps to control their microenvironment. AB - Efflux pumps are a potent and clinically important cause of antibiotic resistance. The particular focus of this chapter is on the efflux pump as a target for antimicrobial therapy and the development of new antibacterials to address the efflux problem.Tigecycline is an example of how old antibiotics, in this case tetracyclines, which have become substrates for efflux pumps, can be extensively modified to restore antimicrobial activity and clinical efficacy. PMID- 23090602 TI - Antibiotics in phase II and III clinical trials. AB - There are 19 compounds in late-stage clinical trials, of which ten may be suitable for Gram-positive infections. However, there are only five compounds in development for Gram-negative infections, in addition to four broad-spectrum ones. There are two new classes in late-stage clinical development. This chapter discusses in some detail each of the antibiotics in Phase II and Phase III clinical trials. Only those that appear in the literature are covered. The shortage of compounds in development for Gram-negatives and the small number of new classes in the pipeline is of serious concern; this matter needs to be addressed by governments, the regulatory authorities, the pharmaceutical industry and academia urgently. PMID- 23090603 TI - Selective, sensitive and reversible "turn-on" fluorescent cyanide probes based on 2,2'-dipyridylaminoanthracene-Cu2+ ensembles. AB - 2,2'-Dipyridylamine and anthracene units were linked to afford highly emissive compounds whose Cu(2+) ensembles were developed as effective fluorescence turn-on CN(-) probes. PMID- 23090605 TI - Spin and boasting in research articles. PMID- 23090604 TI - Relevance of brown adipose tissue in infancy and adolescence. AB - Brown adipose tissue (BAT) was thought to disappear after infancy. Recent findings of BAT in patients undergoing positron emission tomography/computed tomography (PET/CT) have renewed the interest in deciphering the relevance of this tissue in humans. Available data suggest that BAT is more prevalent in children than in adults and that its activation during adolescence is associated with significantly lower gains in weight and adiposity. Data also show that pediatric patients with metabolically active BAT on PET/CT examinations have significantly greater muscle volume than patients without identifiable BAT. Both the activity and the amount of BAT increase during puberty. The magnitude of the increase is higher in boys as compared with girls and is closely related to gains in muscle volume. Hence, concurrent with the gains in skeletal muscle during infancy and puberty, all infants and adolescents accumulate large amounts of BAT. These observations are consistent with in vitro investigations suggesting close interactions between brown adipocytes, white adipocytes, and myocytes. In this review, we discuss the potential role of this tissue in regulating weight and musculoskeletal development in children. PMID- 23090606 TI - Cardiac sympathetic neurons provide trophic signal to the heart via beta2 adrenoceptor-dependent regulation of proteolysis. AB - AIMS: Increased cardiac sympathetic neuron (SN) activity has been associated with pathologies such as heart failure and hypertrophy, suggesting that cardiac innervation regulates cardiomyocyte trophism. Whether continuous input from the SNs is required for the maintenance of the cardiomyocyte size has not been determined thus far. METHODS AND RESULTS: To address the role of cardiac innervation in cardiomyocyte size regulation, we monitored the effect of pharmacological sympathetic denervation in mice on cardiac structure, function, and signalling from 24 h to 30 days in the absence of other pathological stimuli. SN ablation caused an immediate reduction in the cardiomyocyte size with minimal consequences on the resting contractile function. Atrophic remodelling was mediated by the ubiquitin-proteasome system through FOXO-dependent early induction of the muscle-specific E3 ubiquitin ligases Atrogin-1/MAFbx and MuRF1, which was followed by activation of the autophagy-lysosome system. MuRF1 was found to be determinant in denervation atrophy as remodelling did not develop in denervated MuRF1 knock-out (KO) hearts. These effects were caused by decreased basal stimulation of cardiomyocyte beta2-adrenoceptor (AR), as atrophy was prevented by treatment of denervated mice with the beta2-AR agonist clenbuterol. Consistent with these data, we also observed that beta2-AR KO mice showed cardiac atrophy at rest. CONCLUSION: Cardiac SNs are strong regulators of the cardiomyocyte size via beta2-AR-dependent repression of proteolysis, demonstrating that the neuro-cardiac axis operates constitutively for the determination of the physiological cardiomyocyte size. These results are of great clinical relevance given the role of beta-AR in cardiovascular diseases and their modulation in therapy. PMID- 23090607 TI - Regulation of JAK/STAT signalling by SOCS in the myocardium. PMID- 23090608 TI - The future application of induced pluripotent stem cells in vascular regenerative medicine. PMID- 23090609 TI - Nitric oxide synthase 2 is required for conversion of pro-fibrogenic inflammatory CD133(+) progenitors into F4/80(+) macrophages in experimental autoimmune myocarditis. AB - AIMS: Experimental autoimmune myocarditis (EAM) model mirrors important mechanisms of inflammatory dilated cardiomyopathy (iDCM). In EAM, inflammatory CD133(+) progenitors are a major cellular source of cardiac myofibroblasts in the post-inflammatory myocardium. We hypothesized that exogenous delivery of macrophage-colony-stimulating factor (M-CSF) can stimulate macrophage lineage differentiation of inflammatory progenitors and, therefore, prevent their naturally occurring myofibroblast fate in EAM. METHODS AND RESULTS: EAM was induced in wild-type (BALB/c) and nitric oxide synthase 2-deficient (Nos2(-/-)) mice and CD133(+) progenitors were isolated from inflamed hearts. In vitro, M-CSF converted inflammatory CD133(+) progenitors into nitric oxide-producing F4/80(+) macrophages and prevented transforming growth factor-beta-mediated myofibroblast differentiation. Importantly, only a subset of heart-infiltrating CD133(+) progenitors expresses macrophage-specific antigen F4/80 in EAM. These CD133(+)/F4/80(hi) cells show impaired myofibrogenic potential compared with CD133(+)/F4/80(-) cells. M-CSF treatment of wild-type mice with EAM at the peak of disease markedly increased CD133(+)/F4/80(hi) cells in the myocardium, and CD133(+) progenitors isolated from M-CSF-treated mice failed to differentiate into myofibroblasts. In contrast, M-CSF was not effective in converting CD133(+) progenitors from inflamed hearts of Nos2(-/-) mice into macrophages, and M-CSF treatment did not result in increased CD133(+)/F4/80(hi) cell population in hearts of Nos2(-/-) mice. Accordingly, M-CSF prevented post-inflammatory fibrosis and left ventricular dysfunction in wild-type but not in Nos2(-/-) mice. CONCLUSION: Active and NOS2-dependent induction of macrophage lineage differentiation abrogates the myofibrogenic potential of heart-infiltrating CD133(+) progenitors. Modulating the in vivo differentiation fate of specific progenitors might become a novel approach for the treatment of inflammatory heart diseases. PMID- 23090610 TI - Bistable Gestalts reduce activity in the whole of V1, not just the retinotopically predicted parts. AB - Activity in the primary visual cortex reduces when certain stimuli can be perceptually organized as a unified Gestalt. This reduction could offer important insights into the nature of feedback computations within the human visual system; however, the properties of this response reduction have not yet been investigated in detail. Here we replicate this reduced V1 response, but find that the modulation in V1 (and V2) to the perceived organization of the input is not specific to the retinotopic location at which the sensory input from that stimulus is represented. Instead, we find a response modulation that is equally evident across the primary visual cortex. Thus in contradiction to some models of hierarchical predictive coding, the perception of an organized Gestalt causes a broad feedback effect that does not act specifically on the part of the retinotopic map representing the sensory input. PMID- 23090611 TI - Calculation of the mean circle size does not circumvent the bottleneck of crowding. AB - Visually, we can extract a statistical summary of sets of elements efficiently. However, our visual system has a severe limitation in that the ability to recognize an object is remarkably impaired when it is surrounded by other objects. The goal of this study was to investigate whether the crowding effect obstructs the calculation of the mean size of objects. First, we verified that the crowding effect occurs when comparing the sizes of circles (Experiment 1). Next, we manipulated the distances between circles and measured the sensitivity when circles were on or off the limitation of crowding (Experiment 2). Participants were asked to compare the mean sizes of the circles in the left and right visual fields and to judge which was larger. Participants' sensitivity to mean size difference was lower when the circles were located in the nearer distance. Finally, we confirmed that crowding is responsible for the observed results by showing that displays without a crowded object eliminated the effects (Experiment 3). Our results indicate that the statistical information of size does not circumvent the bottleneck of crowding. PMID- 23090612 TI - Depth perception from point-light biological motion displays. AB - Humans have a clear impression of facing in depth for point-light biological motion. However, this has not been measured systematically nor is it known on which cues humans rely for their judgment. In the present study subjects judged the facing orientation-in-depth of point-light displays. The displays represented natural walking and modified versions in which the time sequence was reversed, action was perturbed, the limbs and joints were nonrigid, the temporal sequence was scrambled, or the joint positions were scrambled. We found that the subjects were best at judging the facing direction of normal and reversed walking with an accuracy of 6 degrees and 10 degrees precision. The results show that pendular motion of the limb segments and the implicit knowledge of the human body play an important role for the precision of the judgment. Three further factors were relevant for the judgment of facing direction: (a) the discrimination of the front and back side, (b) the facing bias, and (c) the impression of depth from the display, probably due to the kinetic depth effect. The latter influences the accuracy, which differed strongly between subjects. The results suggest that the facing bias, to perceive the figure as facing toward the observer rather than away, is not related to the recognition of a human figure but rather to the presence of oscillating movements of the dots in the display. PMID- 23090613 TI - Disparity-based stereomotion detectors are poorly suited to track 2D motion. AB - A study was conducted to examine the time required to process lateral motion and motion-in-depth for luminance- and disparity-defined stimuli. In a 2 * 2 design, visual stimuli oscillated sinusoidally in either 2D (moving left to right at a constant disparity of 9 arcmin) or 3D (looming and receding in depth between 6 and 12 arcmin) and were defined either purely by disparity (change of disparity over time [CDOT]) or by a combination of disparity and luminance (providing CDOT and interocular velocity differences [IOVD]). Visual stimuli were accompanied by an amplitude-modulated auditory tone that oscillated at the same rate and whose phase was varied to find the latency producing synchronous perception of the auditory and visual oscillations. In separate sessions, oscillations of 0.7 and 1.4 Hz were compared. For the combined CDOT + IOVD stimuli (disparity and luminance [DL] conditions), audiovisual synchrony required a 50 ms auditory lag, regardless of whether the motion was 2D or 3D. For the CDOT-only stimuli (disparity-only [DO] conditions), we found that a similar lag (~60 ms) was needed to produce synchrony for the 3D motion condition. However, when the CDOT-only stimuli oscillated along a 2D path, the auditory lags required for audiovisual synchrony were much longer: 170 ms for the 0.7 Hz condition, and 90 ms for the 1.4 Hz condition. These results suggest that stereomotion detectors based on CDOT are well suited to tracking 3D motion, but are poorly suited to tracking 2D motion. PMID- 23090614 TI - Differential effects of alcohol on contrast processing mediated by the magnocellular and parvocellular pathways. AB - This study investigated how acute alcohol intake affects contrast processing mediated by inferred magnocellular (MC) and parvocellular (PC) pathways. Achromatic contrast discrimination thresholds were measured in 16 young healthy participants using a steady-pedestal, pulsed-pedestal or pedestal-Delta-pedestal paradigm designed to favor the inferred MC or the PC pathway. Each participant completed two randomized sessions that included consumption of either 0.8 g/kg alcohol or a placebo beverage, with each session consisting of contrast discrimination measurements at baseline and at 60 min following beverage consumption. The results showed that, compared to placebo, alcohol significantly reduced MC contrast sensitivity and PC contrast gain but had no effect on PC contrast sensitivity for the majority of the participants; and did not alter MC contrast gain consistently across participants. The decrease in contrast gain in the PC pathway can be interpreted as a degradation of the postretinal signal-to noise ratio, whereas the decrease of sensitivity in the MC pathway likely results from a change of cortical processing. PMID- 23090617 TI - The patient-centered medical home and accountable care organizations: an overview. AB - PURPOSE OF REVIEW: As the crisis regarding the cost of medical care in the United States continues to spiral out of control, new models of care are being touted as a means to fix the economics of healthcare. This review will examine newly proposed models of healthcare. RECENT FINDINGS: The patient-centered medical home (PCMH) and accountable care organizations (ACOs) are two models that have leapt to the forefront of healthcare reform. The PCMH or medical home is a model predicated upon a primary care provider who will provide and coordinate comprehensive healthcare for the patient across the continuum with care that is evidence based and patient centered. The PCMH provides coordinated care, allowing for more appropriate utilization of resources resulting in improved care and outcomes while decreasing costs. The ACO agrees to be accountable for the overall care, quality and cost of the patients enrolled. The model links patient care to quality, safety and improved outcomes. This coordination reduces the costs of care, thus making it economically appealing to the patients, the providers, the ACO and the payer, whether it be government or private. SUMMARY: Healthcare reform will require implementation of new models of care. The PCMH and ACO are two such models. Although both models have their share of supporters as well as detractors, both will play a significant role in the next chapter of healthcare reform in this country. PMID- 23090615 TI - Hand-related rather than goal-related source of gaze-dependent errors in memory guided reaching. AB - Mechanisms for visuospatial cognition are often inferred directly from errors in behavioral reports of remembered target direction. For example, gaze-centered target representations for reach were first inferred from reach overshoots of target location relative to gaze. Here, we report evidence for the hypothesis that these gaze-dependent reach errors stem predominantly from misestimates of hand rather than target position, as was assumed in all previous studies. Subjects showed typical gaze-dependent overshoots in complete darkness, but these errors were entirely suppressed by continuous visual feedback of the finger. This manipulation could not affect target representations, so the suppressed gaze dependent errors must have come from misestimates of hand position, likely arising in a gaze-dependent transformation of hand position signals into visual coordinates. This finding has broad implications for any task involving localization of visual targets relative to unseen limbs, in both healthy individuals and patient populations, and shows that response-related transformations cannot be ignored when deducing the sources of gaze-related errors. PMID- 23090618 TI - Leadership. AB - PURPOSE OF REVIEW: To discuss leadership. RECENT FINDINGS: Leadership in healthcare has many similarities to other industries. SUMMARY: Given that now is a time of great transition in healthcare, leadership in healthcare is needed now more than ever from physicians. However, physicians have never had much training in leadership. This primer aims to give an overview of some basics of leadership and resources to begin the path to leadership. PMID- 23090619 TI - Association between KRAS codon 13 mutations and clinical response to anti-EGFR treatment in patients with metastatic colorectal cancer: results from a meta analysis. AB - PURPOSE: To comparatively evaluate whether metastatic colorectal cancer (mCRC) patients with KRAS codon 13 mutations (codon 13 muts) can benefit from anti-EGFR treatment. METHODS: We performed a meta-analysis of relevant studies. Systematic searches of the PubMed, Embase, and Cochrane databases, as well as ASCO conference papers up to July 30, 2012, were retrieved, and the authors of included studies were contacted to obtain more individual data. Fixed effects meta-analytical models were used where indicated, and between-study heterogeneity was assessed. The primary study end points were the overall response rate (ORR). Secondary end points were progress-free survival (PFS) and overall survival (OS). RESULTS: A total of 7 studies were included in the final meta-analysis, consisting of 2,802 mCRC patients, 1,679 of whom were treated with anti-EGFR monoclonal antibodies. The ORR of mCRC patients with codon 13 mutation was 25.2 % (29/115), compared to 17.6% (98/558) for other KRAS mutations (other mut) and 42.6% (429/1,006) for KRAS WT patients. The overall pooled RR for ORRs of codon 13 mut versus other mut was 1.52 (95% CI 1.10-2.09, P = 0.003), whereas the pooled RR for codon 13 mut versus WT was 0.61 (95% CI 0.45-0.83, P = 0.002). The pooled progression-free survival (PFS) times were 6.4 months for codon 13 mut, 4.1 months for other mut, and 6.6 months for WT, whereas the pooled OS durations were 14.6, 11.8, and 17.3 months, respectively. Subgroup analysis was conducted on the basis of the line of treatment, anti-EGFR drug, study design, and detection method, respectively. The results implicated that KRAS codon 13 mut patients gain more benefit from Cetuximab in further line treatment. CONCLUSIONS: Metastatic colorectal cancer patients with KRAS codon 13 mutations demonstrate a greater clinical response to anti-EGFR treatment than patients with other KRAS mutations. PMID- 23090620 TI - Comparison of pharmacokinetics and safety profiles of two capecitabine tablet formulations in patients with colon, colorectal or breast cancer. AB - PURPOSE: The objective of this study was to compare the pharmacokinetics and safety of two tablet formulations containing 500 mg of capecitabine (CAS number 154361-50-9) in patients with colon, colorectal or breast cancer. METHODS: The study was a multicentric, open label, randomized, two-treatment, two-period, two sequence, single dose, crossover bioequivalence study in patients of either sex with colon, colorectal or breast cancer. Eligible patients received each treatment in a crossover manner under fed conditions according to the randomization schedule. The pre-dose blood sample was taken within 90 min prior to dosing, and serial blood sampling was done up to 10.00 h post-dose under monochromatic light. The analysis of plasma samples for concentrations of capecitabine and 5'-deoxy-5-fluorocytidine (5'-DFCR) was carried out using a validated liquid chromatography mass spectrometry method. Bioequivalence was to be concluded if the confidence intervals so constructed were within the range of 80-125 % for C(max), AUC(0-t) and AUC(0-infinity) of capecitabine and 5'-DFCR. Patients were monitored for safety and tolerability throughout the study. RESULTS: The 90 % confidence intervals for the "test/reference" mean ratios of the ln-transformed pharmacokinetic variables C(max), AUC(0-t) and AUC(0-infinity) were clearly within the conventional bioequivalence range of 80-125 %. Both the formulations were reasonably tolerated after a single oral dose in patients. CONCLUSIONS: Both the capecitabine tablet formulations demonstrated equivalent rate and extent of systemic absorption, and hence were considered bioequivalent. Therefore, the two formulations can be considered as equivalent in terms of pharmacokinetics and safety profiles. PMID- 23090621 TI - Modeling stented coronary arteries: where we are, where to go. AB - In the last two decades, numerical models have become well-recognized and widely adopted tools to investigate stenting procedures. Due to limited computational resources and modeling capabilities, early numerical studies only involved simplified cases and idealized stented arteries. Nowadays, increased computational power allows for numerical models to meet clinical needs and include more complex cases such as the implantation of multiple stents in bifurcations or curved vessels. Interesting progresses have been made in the numerical modeling of stenting procedures both from a structural and a fluid dynamics points of view. Moreover, in the drug eluting stents era, new insights on drug elution capabilities are becoming essential in the stent development. Lastly, image-based methods able to reconstruct realistic geometries from medical images have been proposed in the recent literature aiming to better describe the peculiar anatomical features of coronary vessels and increase the accuracy of the numerical models. In this light, this review provides a comprehensive analysis of the current state-of-the-art in this research area, discussing the main methodological advances and remarkable results drawn from a number of significant studies. PMID- 23090622 TI - Advanced gastric cancer patients with lymphoid stroma have better survival than those without. AB - BACKGROUND: Lymphoid stroma is a specific pathologic appearance in gastric cancer. This study aims to compare the clinicopathological characteristics of gastric cancer patients with and without lymphoid stroma. METHODS: From January 1988 to February 2009, 222 out of 1,959 patients with lymphoid stroma of gastric cancer received gastrectomy at the Department of Surgery, Taipei Veterans General Hospital. Clinicopathological characteristics and survival rates were analyzed and compared among the gastric cancer patients with and without lymphoid stroma. For patients with lymphoid stroma, CD20 expression of B lymphocytes and CD3 expression of T lymphocytes were examined using immunohistochemical stains. RESULTS: Advanced gastric cancer patients with lymphoid stroma had better 5-year survival status than those without lymphoid stroma (44.5% vs. 20.5%, P < 0.001). Univariate and multivariate analyses showed that male gender (P = 0.034), tumor invasion depth (P = 0.001), pathological staging (P = 0.006), and Ming's histological classification (P = 0.041) were significantly correlated with patients with lymphoid stroma. B lymphocytes appeared more in Borrmann type III and IV, diffuse Lauren's histological type, and lymph nodes metastases. CONCLUSION: Advanced gastric cancer patients with lymphoid stroma had better prognosis than those without lymphoid stroma. B lymphocytes appeared more in aggressive gastric cancer tissues with lymphoid stroma. PMID- 23090624 TI - The effect of nicotine on sign-tracking and goal-tracking in a Pavlovian conditioned approach paradigm in rats. AB - RATIONALE: Nicotine (NIC) potently increases operant responding for non-NIC reinforcers, and this effect may depend on drug-mediated increases in incentive motivation. According to this hypothesis, NIC should also potently increase approach to Pavlovian-conditioned stimuli associated with rewards. OBJECTIVE: The present studies explored the effects of NIC on Pavlovian-conditioned approach responses. METHOD: To do so, liquid dippers were used to deliver an unconditioned stimulus (US; 0.1 ml sucrose) after presentation of a conditioned stimulus (CS; 30 s illumination of a stimulus light)-both the CS and US were presented in receptacles equipped to monitor head entries. RESULTS: In experiment 1, the CS and US were presented in the same receptacle, but NIC pretreatment (0.4 mg/kg base) did not increase conditioned approach responses. Delivery of the sucrose US was then shifted to receptacle in a different location. All rats learned to approach the new US location (goal-tracking) at similar rates. Approach to the CS receptacle (sign-tracking) declined for saline-pretreated rats, but NIC pretreatment increased sign-tracking. In experiment 2, NIC pretreatment increased sign-tracking when the CS and US were spatially separated during acquisition. In experiment 3, NIC pretreatments were replaced with saline, but the effect of NIC persisted for an additional 24 test sessions. CONCLUSION: The findings suggest that NIC increases incentive motivation and that this effect is long-lasting, persisting beyond the pharmacological effects of NIC. PMID- 23090626 TI - Anion-directed assembly of a rectangular supramolecular cage in the solid state with electron-deficient phenoxylated oxacalix[2]arene[2]triazine. AB - Chloride-pi interaction along with lone-pair electrons-pi interaction, hydrogen bonding and pi-pi stacking induced the hexameric assembly of the parent macrocycle into a rectangular supramolecular cage in the solid state. PMID- 23090625 TI - SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study. AB - INTRODUCTION: Serotonin and norepinephrine reuptake inhibitors (SNRIs) are antidepressants which have high affinity to both serotonin transporter (SERT) and norepinephrine transporter (NET). In studies in vitro, SNRIs have been reported to show a large variability in the affinity ratio between SERT and NET. For instance, the reported affinity ratio is about 30 for venlafaxine and 1.6 for milnacipran. In this study in nonhuman primates, we aimed to investigate the relationship between SERT and NET affinity by measuring the in vivo occupancy at both transporters of venlafaxine and milnacipran. METHODS: PET measurements with [(11)C]MADAM and [(18)F]FMeNER-D(2) were performed in two female cynomolgus monkeys at baseline and after pretreatment with venlafaxine and milnacipran, respectively. Relationships between dose, plasma concentration, and transporter occupancy were evaluated by saturation analysis using a hyperbolic function. Binding affinity (Kd(plasma)) was expressed by the dose or plasma concentration at which 50 % of the transporter was occupied. RESULTS: SERT and NET occupancy by venlafaxine and milnacipran increased in a dose and plasma concentration dependent manner. The Kd(plasma) ratio of SERT to NET was 1.9 for venlafaxine and 0.6 for milnacipran. CONCLUSIONS: In this nonhuman primate PET study, the affinity in vivo for SERT and NET, respectively, was shown to be at a similar level for venlafaxine and milnacipran. Both drugs were found to produce balanced inhibition of SERT and NET binding. This observation is not consistent with previous in vitro binding data and illustrates the need to characterize antidepressants at in vivo condition. PMID- 23090627 TI - Bilateral Sertoli cell tumors of the testis-a likely new extracolonic manifestation of familial adenomatous polyposis. AB - Testicular Sertoli cell tumors are rare and usually sporadic and unifocal. The large cell calcifying Sertoli cell tumor variant is known to be associated with Carney and Peutz-Jeghers syndromes and can be bilateral in these patient populations. There has been no documented association of Sertoli cell tumor with familial adenomatous polyposis (FAP) in the literature. The case presented is a bilateral Sertoli cell tumor occurring in a 34-year-old patient with FAP. The tumor had a conventional Sertoli cell tumor morphology, but with different morphology in the left and right sites. Beta-catenin immunostain showed strong nuclear reactivity in the tumor cells but not the nonneoplastic Sertoli cells. The presence of bilaterality as well as overexpression of beta-catenin by this tumor supports an association of the development of Sertoli cell tumor with the patient's FAP syndrome and adenomatous polyposis coli inactivation. PMID- 23090628 TI - Primary benign vascular tumors and tumorlike lesions of the kidney: a clinicopathologic analysis of 15 cases. AB - Primary benign vascular lesions of the kidney are uncommonly encountered in routine surgical pathology practice. They can, however, mimic malignancy or be an incidental finding adjacent to a malignancy. Fifteen specimens harboring 16 primary benign renal lymphatic/vascular lesions were identified from our files from 1999 to 2011 and subjected to a detailed pathologic evaluation and clinicopathologic correlation. Clinical and demographic data were available for all the 15 cases. There were ten males and five female patients with age range of 33-74 years (mean 54 years). Lesions ranged from 0.5 cm to 40 cm (average, 6.6 cm). There were six arteriovenous malformations (AVMs), four hemangiomas, three anastomosing hemangiomas, two lymphangiomas, and one solid intravascular papillary endothelial hyperplasia (IPEH). Five AVMs were located in the kidney parenchyma and one in the pelviureteric system. Additional associated lesions ranged from renal stones to renal cell carcinoma in two cases (one lymphangioma and one AVM). One AVM was associated with a capillary hemangioma in the vicinity, and another with a history of renal cell carcinoma in the contralateral kidney. Capillary hemangiomas and lymphangiomas were noninfiltrative and lacked cytological atypia and mitotic activity. Except for a renal pelvic AVM, all other renal AVMs radiologically mimicked malignancy. The patients had undergone partial or radical nephrectomies except for the renal pelvic AVM which was laparoscopically excised. To the best of our knowledge, none of the cases had any syndromic/systemic associations. Benign vascular lesions of the kidney are rarely seen in routine surgical pathology practice, partly because a vast majority of them are medically treated by embolization. However, lesions mimicking renal malignancy are subjected to surgery. They may exist as isolated lesions or coexist with malignant lesions either in the ipsilateral or the contralateral kidney. PMID- 23090629 TI - Effect of azadirachtin on haematological and biochemical parameters of Argulus infested goldfish Carassius auratus (Linn. 1758). AB - Argulosis hampers aquaculture production and alters the host physiology and growth. Azadirachtin is recognized as a potential antiparasitic agent against Argulus sp. The present study aimed to investigate the effect of different concentration of azadirachtin solution on haematological and serum biochemical parameters of Argulus-infested goldfish Carassius auratus. Ninety Argulus infested goldfish were randomly divided into six equal groups. Fish of group 1-5 were treated with azadirachtin solution through bath of 1, 5, 10, 15 and 20 mg L( 1) as T1, T2, T3, T4 and T5, respectively, and group 6 was exposed to 2% DMSO solution without azadirachtin and considered as negative control T0(-). Along with six treatment groups, a positive control T0(+) of healthy goldfish free from Argulus infestation was also maintained. Parasitic mortality was evaluated after 3 days of consecutive bath treatment. After 7 days of post-treatment, the blood and serum were drawn from each of the treatment groups and haematological and serum biochemical parameters were evaluated. Total leucocyte count (TLC), mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), blood glucose, total protein (TP), globulin, serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) were significantly (p < 0.05) high in negative control group when compared with positive control group. It could be concluded that Argulus infestation altered marked haematological and serum biochemical parameters. However, in treated groups complete elimination of Argulus was found in T4 and T5 groups. Also significant (p < 0.05) reduction in haematological and serum biochemical parameters of all the treatment groups were recorded in comparison with negative control group. In addition, T4 and T5 groups showed significantly (p < 0.05) high superoxide dismutase (SOD), catalase, total erythrocyte count (TEC) and haemoglobin (Hb). However, higher mean corpuscular haemoglobin concentration (MCHC), blood glucose and lactate dehydrogenase (LDH) levels in T5 group revealed that higher concentration of azadirachtin have notable effects on activity of vital tissues function and physiology of the host. Argulus spp. from infested goldfish could be eliminated using bath treatment with solution of azadirachtin having concentration of 15 mg L(-1) and that also shifted haematological and serum biochemical parameters towards homeostasis. PMID- 23090630 TI - Soil column leaching of pesticides. AB - In this review, I address the practical and theoretical aspects of pesticide soil mobility.I also address the methods used to measure mobility, and the factors that influence it, and I summarize the data that have been published on the column leaching of pesticides.Pesticides that enter the unsaturated soil profile are transported downwards by the water flux, and are adsorbed, desorbed, and/or degraded as they pass through the soil. The rate of passage of a pesticide through the soil depends on the properties of the pesticide, the properties of the soil and the prevailing environmental conditions.Because large amounts of many different pesticides are used around the world, they and their degradates may sometimes contaminate groundwater at unacceptable levels.It is for this reason that assessing the transport behavior and soil mobility of pesticides before they are sold into commerce is important and is one indispensable element that regulators use to assess probable pesticide safety. Both elementary soil column leaching and sophisticated outdoor lysimeter studies are performed to measure the leaching potential for pesticides; the latter approach more reliably reflects probable field behavior, but the former is useful to initially profile a pesticide for soil mobility potential.Soil is physically heterogeneous. The structure of soil varies both vertically and laterally, and this variability affects the complex flow of water through the soil profile, making it difficult to predict with accuracy. In addition, macropores exist in soils and further add to the complexity of how water flow occurs. The degree to which soil is tilled, the density of vegetation on the surface, and the type and amounts of organic soil amendments that are added to soil further affect the movement rate of water through soil, the character of soil adsorption sites and the microbial populations that exist in the soil. Parameters that most influence the rate of pesticide mobility in soil are persistence (DT50) of the pesticide, and its sorption/desorption(Koc) characteristics. These parameters may vary for the same pesticide from geographic site-to-site and with soil depth. The interactions that normally occur between pesticides and dissolved organic matter (DOM) or WDC are yet other factors that may complicate pesticide leaching behavior.The soil mobility of pesticides is normally tested both in the laboratory and in the field. Lab studies are initially performed to give researchers a preliminary appraisal of the relative mobility of a pesticide. Later, field lysimeter studies can be performed to provide more natural leaching conditions that emulate the actual field use pattern. Lysimeter studies give the most reliable information on the leaching behavior of a pesticide under field conditions, but these studies are time-consuming and expensive and cannot be performed everywhere. It is for this reason that the laboratory soil column leaching approach is commonly utilized to profile the mobility of a pesticide,and appraise how it behaves in different soils, and relative to other pesticides.Because the soil structure is chemically and physically heterogenous, different pesticide tests may produce variable DT50 and Koc values; therefore, initial pesticide mobility testing is undertaken in homogeneously packed columns that contain two or more soils and are eluted at constant flow rates. Such studies are done in duplicate and utilize a conservative tracer element. By fitting an appropriate mathematical model to the breakthrough curve of the conservative tracer selected,researchers determine key mobility parameters, such as pore water velocity, the column-specific dispersion coefficient, and the contribution of non equilibrium transport processes. Such parameters form the basis for estimating the probable transport and degradation rates that will be characteristic of the tested pesticide. Researchers also examine how a pesticide interacts with soil DOM and WDC, and what contribution from facilitated transport to mobility is made as a result of the effects of pH and ionic strength. Other methods are used to test how pesticides may interact with soil components to change mobility. Spectroscopic approaches are used to analyze the nature of soil pesticide complexes. These may provide insight into the mechanism by which interactions occur. Other studies may be performed to determine the effect of agricultural practices (e.g., tillage) on pesticide leaching under controlled conditions using intact soil cores from the field. When preferential flow is suspected to occur, dye staining is used to examine the contribution of macropores to pesticide transport. These methods and others are addressed in the text of this review. PMID- 23090631 TI - Behavior and impact of zirconium in the soil-plant system: plant uptake and phytotoxicity. AB - Zirconium (Zr) is a transition metal that has both stable and radioactive isotopes.This metal has gained significant attention as a major pollutant of concern, partly because it has been prominent in the debate concerning the growing anthropogenic pressure on the environment. Its numerous past and present uses have induced significant soil and water pollution. Zr is generally considered to have low mobility in soils. The behavior of Zr particularly depends on the characteristics of the media in which it exists, and even its presence in the biosphere as a contaminate may affect its behavior. In this chapter, we describe the relationship between the behavior of Zrand its speciation in soils, its uptake and accumulation by plants, its translocation and toxicity inside plants, and mechanisms by which plants detoxify it.Zr is abundant and occurs naturally in the earth's crust. Zr emissions to the atmosphere are increasing from anthropogenic activities such as its use in industry and nuclear reactors. Zr forms various complexes with soil components, which reduces its soil mobility and phytoavailabilty. The mobility and phytoavailabilty of Zr in soil depend on its speciation and the physicochemical properties of soil that include soil pH, texture, and organic contents. Despite having low soil mobility and phytoavailability,amounts of Zr are absorbed by plants, mainly through the root system and can thereby enter the food chain.After plant uptake, Zr mainly accumulates in root cells. Zr does not have any known essential function in plant or animal metabolism. Although little published data are available, we conclude that the phytotoxicity of Zr is generally low.Notwithstanding, Zr can significantly reduce plant growth and can affect plantenzyme activity. When exposed to Zr-induced toxicity, plants possess numerous defense mechanisms to cope with the toxicity. Such strategies include Zr sequestration in plant roots and activation of various antioxidants. Because Zr may have impact on the biosphere, we believe it deserves to be evaluated in supplementary studies that will enhance the understanding of its behavior in soil-plant systems. PMID- 23090633 TI - The interaction between smoking and GSTM1 variant on lung cancer in the Chinese population. AB - Smoking and the deletion of GSTM1 variant are two risk factors of lung cancer. This meta-analysis was performed to examine the GSTM1-smoking interaction on lung cancer in the Chinese population. PubMed, Web of Science, and other Chinese databases were searched to include all the related studies. The number of subjects with two GSTM1 genotypes across different smoking status was extracted. The pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were calculated using fixed- or random-effect model. A total of 4,345 cases and 5,031 controls from 30 studies were included in the meta-analysis. Compared with nonsmokers having power GSTM1, the pooled ORs with 95 % CIs for lung cancer in smokers with power GSTM1, in nonsmokers with null GSTM1, and in smokers with null GSTM1 were 2.24 (1.82-2.76), 1.48 (1.23-1.79), and 4.18 (3.38-5.16), respectively. This meta analysis showed that there was an interaction between the GSTM1 and smoking on the risk of lung cancer in the Chinese. Further studies are needed to examine the interactions between other environmental factors and GSTM1 on the risk of lung cancer. PMID- 23090632 TI - Staging and neuroprogression in bipolar disorder. AB - The apparently progressive nature of a considerable proportion of cases of bipolar disorder (BD) has been acknowledged in recently proposed clinical staging models. This has been part of an attempt to facilitate and refine diagnosis, treatment selection, and establish a prognosis. The study of the progressive nature of some cases of BD has given raise to the hypothesis of neuroprogression, which postulates that different stages of BD are associated with distinct neurobiological underpinnings. Given that BD may be intimately associated with chronic stress response and coping mechanisms over the course of illness, we propose that cellular resilience mechanisms may play a key role in the neuroprogression in BD. In the present study, we review neuroanatomical evidence of the progression that occurs in many cases of BD, as well as cellular resilience mechanisms and peripheral biomarkers associated with distinct stages of this disorder. In summary, cellular resilience mechanisms seem to be less efficient at later stages of BD, especially mitochondrial and endoplasmic reticulum-related responses to stress. These insights may help in developing staging models of BD, with a special emphasis on the search for biomarkers associated with illness progression. PMID- 23090634 TI - Proton transfer reactions between nitric acid and acetone, hydroxyacetone, acetaldehyde and benzaldehyde in the solid phase. AB - The heterogeneous and homogeneous reactions of acetone, hydroxyacetone, acetaldehyde and benzaldehyde with solid nitric acid (HNO(3)) films have been studied with Reflection-Absorption Infrared Spectroscopy (RAIRS) under Ultra-High Vacuum (UHV) conditions in the 90-170 K temperature range. In the bulk or at the surface of the films, nitric acid transfers its proton to the carbonyl function of the organic molecules, producing protonated acetone-H(+), hydroxyacetone-H(+), acetaldehyde-H(+) and benzaldehyde-H(+), and nitrate anions NO(3)(-), a reaction not observed when nitric acid is previously hydrated [J. Lasne, C. Laffon and Ph. Parent, Phys. Chem. Chem. Phys., 2012, 14, 697]. This provides a molecular-scale description of the carbonyl protonation reaction in an acid medium, the first step of the acid-catalyzed condensation of carbonyl compounds, fuelling the growth of secondary organic aerosols (SOA) in the atmosphere. PMID- 23090635 TI - Will the 2012 presidential election change health care? PMID- 23090636 TI - Sonic Hedgehog contributes to gastric mucosal restitution after injury. AB - Eradication of Helicobacter pylori correlates with regeneration of the gastric epithelium, ulcer healing and re-expression of the gastric morphogen Sonic Hedgehog (Shh). We sought to identify the role of Shh as a regulator of gastric epithelial regeneration during wound healing. A mouse model expressing a parietal cell-specific, tamoxifen-inducible deletion of Shh (HKCre(ERT2);Shh(flox/flox) or PC-iShhKO) was developed. Stomachs were collected and compared 7-150 days after the final vehicle or tamoxifen injection. Ulcers were induced in both controls and PC-iShhKO mice using acetic acid and ulcer size compared 1 and 7 days post induction. (1) Re-expression of Shh correlates with decreased hyperproliferation: Compared to controls, PC-iShhKO mice developed foveolar hyperplasia. Restoration of normal gastric epithelial architecture and differentiation correlated with the re-expression of Shh in PC-iShhKO mice 150 days after the final tamoxifen injection. At the tamoxifen dose used to induce Cre recombination there was no genotoxicity reported in either HKCre(ERT2) or Shh(flox/flox) control mouse stomachs. (2) Delayed wound healing in PC-iShhKO mouse stomachs: To identify the role of Shh in gastric regeneration, an acetic acid ulcer was induced in control and PC-iShhKO mice. Ulcers began to heal in control mice by 7 days after induction. Ulcer healing was documented by decreased ulcer size, angiogenesis, macrophage infiltration and formation of granulation tissue that correlated with the re-expression of Shh within the ulcerated tissue. PC-iShhKO mice did not show evidence of ulcer healing. Re-expression of Shh contributes to gastric regeneration. Our current study may have clinical implications given that eradication of H. pylori correlates with re-expression of Shh, regeneration of the gastric epithelium and ulcer healing. PMID- 23090637 TI - Transgenic mouse model with deficient mitochondrial polymerase exhibits reduced state IV respiration and enhanced cardiac fibrosis. AB - Mitochondria produce the energy required for proper cardiac contractile function, and cardiomyocytes that exhibit reduced mitochondrial electron transport will have reduced energy production and decreased contractility. Mitochondrial DNA (mtDNA) encodes the core subunits for the protein complexes of the electron transport chain (ETC). Reduced mtDNA abundance has been linked to reduced ETC and the development of heart failure in genetically engineered mice and in human diseases. Nucleoside reverse-transcriptase inhibitors for HIV/AIDS are used in antiretroviral regimens, which cause decreased mtDNA abundance by inhibiting the mitochondrial polymerase, pol-gamma, as a limiting side effect. We explored consequences of AZT (1-[(2R,4S,5S)-4-azido-5-(hydroxymethyl)oxolan-2-yl]-5 methylpyrimidine-2,4-dione) exposure on mtDNA abundance in an established transgenic mouse model (TG) in which a cardiac-targeted mutant form of pol-gamma displays a dilated cardiomyopathy (DCM) phenotype with increased left ventricle (LV)-mass and increased LV-end diastolic dimension. TG and wild-type littermate mice received 0.22 mg per day AZT or vehicle for 35 days, and were subsequently analyzed for physiological, histological, and molecular changes. After 35 days, Y955C TGs exhibited cardiac fibrosis independent of AZT. Reduced mtDNA abundance was observed in the Y955C mouse; AZT treatment had no effect on the depletion, suggesting that Y955C was sufficient to reduce mtDNA abundance maximally. Isolated mitochondria from AZT-treated Y955C hearts displayed reduced mitochondrial energetic function by oximetric measurement. AZT treatment of the Y955C mutation further reduced basal mitochondrial respiration and state IV(0) respiration. Together, these results demonstrate that defective pol-gamma function promotes cardiomyopathy, cardiac fibrosis, mtDNA depletion, and reduced mitochondrial energy production. PMID- 23090639 TI - Carbon heterogeneous surface modification on a mesoporous TiO2-supported catalyst and its enhanced hydrodesulfurization performance. AB - In this work, we report a novel surface modification which can improve the desorption of a hydrodesulfurization product (H(2)S) from mesoporous TiO(2). The corresponding catalyst exhibits a significantly enhanced hydrodesulfurization performance compared with an unmodified catalyst, and the dibenzothiophene conversion increases from 65% to 98%. PMID- 23090638 TI - Preprocedural therapeutic international normalized ratio influence on bleeding complications in atrial fibrillation ablation with continued anticoagulation with warfarin. AB - BACKGROUND: Safety of atrial fibrillation (AF) ablation in conditions of periprocedural therapeutic international normalized ratio (INR) in combination with heparin is still uncertain, and little is known about the pre-procedural therapeutic INR influence on bleeding complications (BC) in this method. METHODS AND RESULTS: The subjects were 150 consecutive patients who underwent catheter ablation for AF with therapeutic INR. The patients were classified into 2 groups, BC (Group BC) and no BC (Group No BC), by whether they did or did not have BC, respectively. Differences in various parameters, including pre- and post procedural prothrombin time-INR and activated partial thromboplastin time (APTT), were compared between the 2 groups. None of the patients experienced stroke or transient ischemic attack. In the 22 patients (15%) who had BC (Group BC), 3 patients had major and 19 patients had minor BC. There were no significant differences between the 2 groups in pre-procedural INR, APTT, and amount of heparin administered during the procedure. However, post-procedural INR and APTT were significantly prolonged in Group BC (2.5 +/- 0.5 vs. 2.2 +/- 0.5, P=0.016, 65 +/- 45 vs. 44 +/- 11, P<0.0001 respectively). Multivariable analysis showed that post-procedural APTT was the only independent bleeding risk factor (P=0.022). CONCLUSIONS: AF ablation with peri-procedural therapeutic INR in combination with heparin seems to be safe. Presence or absence of BC are not related to the pre-procedural INR level, but to post-procedural APTT. PMID- 23090640 TI - Highly regioselective nitrile oxide dipolar cycloadditions with ortho-nitrophenyl alkynes. AB - The dipolar cycloadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated. A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated. PMID- 23090641 TI - Recent victimization exposure and suicidal ideation in adolescents. AB - OBJECTIVE: To examine the independent and cumulative effects of past-year exposure to several different types of child victimization (peer victimization, witnessing family violence, community violence, sexual assault, and maltreatment) on suicidal ideation in a nationally representative sample of adolescents. DESIGN: The study used 2 waves of longitudinal data from the National Survey of Children's Exposure to Violence. SETTING: Conducted in 2008 and 2010 on the telephone with respondents from the contiguous United States. PARTICIPANTS: National sample of 1186 youth aged 10 to 17 years in wave 1. MAIN EXPOSURES: Peer victimization, sexual assault, witnessing family violence, exposure to community violence, and maltreatment by a parent/caregiver. OUTCOME MEASURE: Self-report suicidal ideation in the past month. RESULTS: Controlling for demographic characteristics, internalizing disorder diagnoses, and wave 1 suicidal ideation, findings showed independent effects of peer victimization, sexual assault, and maltreatment by a parent/caregiver on suicidal ideation at wave 2. The risk of suicidal ideation was 2.4 times greater among youth who experienced peer victimization in the past year, 3.4 times greater among those who were sexually assaulted, and 4.4 times greater among those exposed to maltreatment, relative to children who were not exposed to these types of victimization. Findings also showed substantial effects of polyvictimization (exposure to 7 or more individual types of victimization in the past year), with polyvictims almost 6 times more likely to report suicidal ideation. CONCLUSION: Findings point to the importance of recent victimization in increasing risk of suicidal ideation in adolescents and suggest the need for victimization assessments among all youth who are believed to be at risk for suicidal ideation. PMID- 23090642 TI - Diagnostic value of thyroglobulin assay in cervical lymph node fine-needle aspirations for metastatic differentiated thyroid cancer. AB - PURPOSE OF REVIEW: Differentiated thyroid cancers (DTCs) have generally an indolent behavior. However, in a minority of these patients cervical metastasis at diagnosis or recurrence during follow-up may occur. Then, in suspicious neck lymph nodes fine-needle aspiration (FNA) is warranted. Thyroglobulin measurement in needle washout fluids (FNA-Tg) since its first description has been reported to increase the diagnostic accuracy of cytology in neck lymph nodes suspicious for metastatic DTC. RECENT FINDINGS: Recent literature suggests that FNA-Tg can substitute conventional cytology and, in turn, simplifies clinical management of DTC patients. However, because of the large difference between these clinical studies, the data are sparse. Thus, neither procedures nor assay method for FNA Tg have been standardized. SUMMARY: FNA-Tg measurement is the more accurate tool to detect neck recurrences and metastases from DTC. Providing strict standardization of preanalytical and analytical phase, FNA-Tg may suffice to confirm or exclude neck DTC recurrence in patients with concurrent well differentiated papillary cancer type, suspicious neck ultrasound findings and increased serum thyroglobulin after thyroidectomy. On the contrary, FNA-Tg accuracy increases by adding cytological examination when FNA is performed before thyroidectomy, in patients with more aggressive histological types, and if low undetectable serum thyroglobulin and/or positive serum antithyroglobulin antibodies occur. PMID- 23090643 TI - Influence of Pseudomonas aeruginosa pvdQ gene on altering antibiotic susceptibility under swarming conditions. AB - In Pseudomonas aeruginosa PAO1, the pvdQ gene has been shown to have at least two functions. It encodes the acylase enzyme and hydrolyzes 3-oxo-C12-HSL, the key signaling molecule of quorum sensing system. In addition, pvdQ is involved in swarming motility. It is required and up-regulated during swarming motility, which is triggered by high cell densities. As high density bacterial populations also display elevated antibiotics resistance, studies have demonstrated swarm cell differentiation in P. aeruginosa promotes increased resistance to various antibiotics. PvdQ acts as a signal during swarm-cell differentiation, and thus may play a role in P. aeruginosa antibiotic resistance. The aim of this study was to examine whether pvdQ was involved in modifying antibiotic susceptibility during swarming conditions and to investigate the mechanism by which this occurred. We constructed the PAO1pMEpvdQ strain, which overproduces PvdQ. PAO1pMEpvdQ promotes swarming motility, while PAO1DeltapvdQ abolishes swarming motility. In addition, both PAO1 and PAO1pMEpvdQ acquired resistance to ceftazidime, ciprofloxacin, meropenem, polymyxin B, and gentamicin, though PAO1pMEpvdQ exhibited a twofold to eightfold increase in antibiotic resistance compared to PAO1. These results indicate that pvdQ plays an important role in elevating antibiotic resistance via swarm-cell differentiation and possibly other mechanisms as well. We analyzed outer membrane permeability. Our data also suggest that pvdQ decreases P. aeruginosa outer membrane permeability, thereby elevating antibiotic resistance under swarming conditions. Our results suggest new approaches for reducing P. aeruginosa resistance. PMID- 23090644 TI - Characterization of plasmid pML21 of Enterococcus faecalis ML21 from koumiss. PMID- 23090645 TI - High-fat feeding induces angiogenesis in skeletal muscle and activates angiogenic pathways in capillaries. AB - High-fat diet (HFD) increases fatty acid oxidation in skeletal muscles. We hypothesized that this leads to increased oxygen demand and thus to increased capillarization. We determined the effects of high-fat diet on capillarization and angiogenic factors in skeletal muscles of mice that were either active or sedentary. Fifty-eight C57BL/6 J mice were divided into four groups: low-fat diet sedentary (LFS), low-fat diet active (LFA), high-fat diet sedentary (HFS), and high-fat diet active (HFA). The mice in active groups were housed in cages with running wheels and the sedentary mice were housed in similar cages without running wheels. After 19 weeks HFS, LFA and HFA had higher capillary density and capillary-to-fiber-ratio in quadriceps femoris muscles than LFS. Capillarization was similar in HFS and HFA. To reveal possible mechanisms of HFD induced angiogenesis, we measured protein and mRNA levels of angiogenic factors VEGF-A, HIF-1alpha, PGC-1alpha and ERRalpha. VEGF-A protein levels were higher in muscles of HFS, LFA and HFA compared to LFS. However, no significant differences were observed between HFA and HFS. Protein levels of HIF-1alpha, PGC-1alpha, and ERRalpha were similar in all groups. However, the mRNA expression of HIF-1alpha and VEGF-A was up-regulated in capillaries but not in muscle fibers of HFS. The sedentary and active mice groups had similar mRNA expression levels of angiogenesis regulators studied. We conclude that high-fat feeding induces angiogenesis in skeletal muscle and up-regulates the gene expression of HIF 1alpha and VEGF-A in capillaries. PMID- 23090647 TI - Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. AB - Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology. PMID- 23090648 TI - Methadone concentrations in blood, plasma, and oral fluid determined by isotope dilution gas chromatography-mass spectrometry. AB - Methadone (MTD) is widely used for detoxification of heroin addicts and also in pain management programs. Information about the distribution of methadone between blood, plasma, and alternative specimens, such as oral fluid (OF), is needed in clinical, forensic, and traffic medicine when analytical results are interpreted. We determined MTD and its metabolite 2-ethylidene-1,5-dimethyl-3,3 diphenylpyrrolidine (EDDP) in blood, plasma, blood cells, and OF by gas chromatography-mass spectrometry (GC-MS) after adding deuterium-labeled internal standards. The analytical limits of quantitation for MTD and EDDP by this method were 20 and 3 ng/mL, respectively. The amounts of MTD and EDDP were higher in plasma (80.4 % and 76.5 %) compared with blood cells (19.6 % and 23.5 %) and we found that repeated washing of blood cells with phosphate-buffered saline increased the amounts in plasma (93.6 % and 88.6 %). Mean plasma/blood concentration ratios of MTD and EDDP in spiked samples (N = 5) were 1.27 and 1.21, respectively. In clinical samples from patients (N = 46), the concentrations of MTD in plasma and whole blood were highly correlated (r = 0.92, p < 0.001) and mean (median) plasma/blood distribution ratios were 1.43 (1.41). The correlations between MTD in OF and plasma (r = 0.46) and OF and blood (r = 0.52) were also statistically significant (p < 0.001) and the mean OF/plasma and OF/blood distribution ratios were 0.55 and 0.77, respectively. The MTD concentration in OF decreased as salivary pH increased (more basic). These results will prove useful in clinical and forensic medicine when MTD concentrations in alternative specimens are compared and contrasted. PMID- 23090646 TI - Assessment of attention in preschoolers. AB - In the past two decades, there has been an increased interest in the assessment and treatment of preschool children presenting with concerns about attention problems. This article reviews the research and clinical literature involving assessment of attention and related skills in the preschool years. While inattention among preschoolers is common, symptoms alone do not necessarily indicate a disorder, and most often represent a normal variation in typical preschool child development. Thus, accurate identification of "disordered" attention in preschoolers can be challenging, and development of appropriate, norm-referenced tests of attention for preschoolers is also difficult. The current review suggests that comprehensive assessment of attention and related functions in the preschool child should include thorough review of the child's history, planned observations, and formal psychometric testing. The three primary methods of psychometric assessment that have been used to characterize attentional functioning in preschool children include performance-based tests, structured caregiver interviews, and rating scales (parent, teacher, and clinician). Among performance-based methods for measurement of attention in the preschool years, tests have been developed to assess sustained attention, selective (focused) attention, span of attention (encoding/manipulation), and (top-down) controlled attention--including freedom from distractibility and set shifting. Many of these tests remain experimental in nature, and review of published methods yields relatively few commercially available, nationally normed tests of attention for preschoolers, and an overall dearth of reliability and validity studies on the available measures. PMID- 23090649 TI - Covalent attachment of functionalized cardiolipin on a biosensor gold surface allows repetitive measurements of anticardiolipin antibodies in serum. AB - Antiphospholipid antibodies (aPL) are a relevant serological indicator of antiphospholipid syndrome (APS). A solid-state surface with covalently bound omega-amine-functionalized cardiolipin was established and the binding of beta2 glycoprotein I (beta2-GPI) was investigated either by use of surface plasmon resonance (SPR) biosensor, by electrically switchable DNA interfaces (switchSENSE) and by scanning tunneling microscopy (STM). STM could clearly visualize the attachment of beta2-GPI to the cardiolipin surface. Using the switchSENSE sensor, beta2-GPI as specific ligand could be identified by increased hydrodynamic friction. The binding of anti-cardiolipin antibodies (aCL) was detected against the omega-amine-functionalized cardiolipin-modified SPR biosensor (aCL biosensor) using sera from healthy donors, APS patients and syphilis patients. Our results showed that the aCL biosensor is a much more sensitive diagnostic device for APS patients compared to previous methods. The specificity between beta2-GPI-dependent autoimmune- and beta2-GPI-independent infection-associated types of aPLs was also studied and they can be distinguished by the different binding kinetics and patterns. PMID- 23090650 TI - Characterization of nanochannel delivery membrane systems for the sustained release of resveratrol and atorvastatin: new perspectives on promoting heart health. AB - Novel drug delivery systems capable of continuous sustained release of therapeutics have been studied extensively for use in the prevention and management of chronic diseases. The use of these systems holds promise as a means to achieve higher patient compliance while improving therapeutic index and reducing systemic toxicity. In this work, an implantable nanochannel drug delivery system (nDS) is characterized and evaluated for the long-term sustained release of atorvastatin (ATS) and trans-resveratrol (t-RES), compounds with a proven role in managing atherogenic dyslipidemia and promoting cardioprotection. The primary mediators of drug release in the nDS are nanofluidic membranes with hundreds of thousands of nanochannels (up to 100,000/mm(2)) that attain zero order release kinetics by exploiting nanoconfinement and molecule-to-surface interactions that dominate diffusive transport at the nanoscale. These membranes were characterized using gas flow analysis, acetone diffusion, and scanning and transmission electron microscopy (SEM, TEM). The surface properties of the dielectric materials lining the nanochannels, SiO(2) and low-stress silicon nitride, were further investigated using surface charge analysis. Continuous, sustained in vitro release for both ATS and t-RES was established for durations exceeding 1 month. Finally, the influence of the membranes on cell viability was assessed using human microvascular endothelial cells. Morphology changes and adhesion to the surface were analyzed using SEM, while an MTT proliferation assay was used to determine the cell viability. The nanochannel delivery approach, here demonstrated in vitro, not only possesses all requirements for large-scale high yield industrial fabrication, but also presents the key components for a rapid clinical translation as an implantable delivery system for the sustained administration of cardioprotectants. PMID- 23090651 TI - Supramolecular immobilization of glucose oxidase on gold coated with cyclodextrin modified cysteamine core PAMAM G-4 dendron/Pt nanoparticles for mediatorless biosensor design. AB - Cysteamine core polyamidoamine G-4 dendron branched with beta-cyclodextrins was chemisorbed on the surface of Au electrodes and further coated with Pt nanoparticles. Adamantane-modified glucose oxidase was subsequently immobilized on the nanostructured electrode surface by supramolecular association. This enzyme electrode was used to construct a reagentless amperometric biosensor for glucose, making use of the electrochemical oxidation of H2O2 generated in the enzyme reaction. The amperometric response of the biosensor was rapid (6 s) and a linear function of glucose concentration between 5 and 705 MUmol L(-1). The biosensor had a low detection limit of 2.0 MUmol L(-1), sensitivity of 197 mA mol(-1) L cm(-2), and retained 94% of its initial response after storage for nine days at 4 degrees C. PMID- 23090652 TI - Negative ion tandem mass spectrometry of prenylated fungal metabolites and their derivatives. AB - Liquid chromatography negative ion electrospray ionisation tandem mass spectrometry has been used for characterisation of naturally occurring prenylated fungal metabolites and synthetic derivatives. The fragmentation studies allow an elucidation of the decomposition pathways for these compounds. It could be shown, that the prenyl side chain is degraded by successive radical losses of C(5) units. Both the benzoquinones and the phenolic derivatives display significant key ions comprising the aromatic ring. In some cases, the formation of significant oxygen-free key ions could be evidenced by high-resolution MS/MS measurements. Furthermore, the different types of basic skeletons, benzoquinones and phenol type as well as cyclic prenylated compounds, can be differentiated by their MS/MS behaviour. Figure Fruiting bodies of Suillus bovinus, the structure of boviquinone-4 and its negative ion MS2 spectrum. PMID- 23090653 TI - Medical management of hunger strikers. AB - Hunger strikes are not infrequent occurrences in military and civilian prisons. Although practicing clinicians are familiar with the management of patients who have limited oral intake, managing hunger strikers is unfamiliar to most. The psychological, physiological, and social events that surround hunger strikes are very complex and need to be understood by those caring for hunger strike patients. To provide adequate medical care to hunger strike patients, clinicians most understand the physiological events that ensue after prolonged starvation. Careful vigilance for development of refeeding syndrome is of key importance. A multidisciplinary approach to hunger strikes is of utmost importance, and involvement of a multidisciplinary clinical team as well as prison officials is essential. PMID- 23090654 TI - Home parenteral nutrition: safe transition from hospital to home. AB - Parenteral nutrition (PN) is a complex therapy that may result in serious harm if not properly prescribed, prepared, and administered. The patient who is discharged home on PN for the first time poses significant safety challenges and requires coordination of care between several healthcare disciplines within and outside the hospital. Use of an experienced prescriber and multidisciplinary team to oversee the home PN therapy is an important measure to optimize safety. Referrals should be made to home health and home infusion agencies with qualified staff; however, this may at times be difficult to assess. A safe discharge also requires transition of care between inpatient clinicians caring for the patient and designated outpatient follow-up. Home PN and lab orders upon discharge should be clear and comprehensive. The use of a standardized home PN order format is an important measure to ensure accuracy of the order. Patient and/or caregiver education is another vital component to safely providing PN in the home setting and should ideally be initiated prior to discharge. This should include instructions to the patient regarding self-monitoring and when to call if problems develop. Specific criteria should be identified for the patients regarding when and who to contact for problems that develop after they are discharged home. PMID- 23090656 TI - Does patellectomy jeopardize function after TKA? AB - BACKGROUND: The patella provides important mechanical leverage to the knee extensor mechanism. Patellectomy does not exclude the development of tibiofemoral arthrosis. QUESTIONS/PURPOSES: We asked whether (1) TKA provides improvements in clinical outcome scores in patellectomized knees and (2) the scores of TKA in patellectomized knees are comparable to those in knees with intact patellae. METHODS: We evaluated 50 patients (52 primary TKAs) with patellectomized knees and a control group of 52 patients (52 primary TKAs) with intact patellae matched for age, sex, implant, and surgical year between 1984 and 2009. We compared the preoperative and latest postoperative SF-12, WOMAC, and Knee Society score (KSS). Minimum followup was 24 months (mean, 69 months; range, 24-204 months). RESULTS: The mean WOMAC score in the control group improved from 41.8 (range, 7.5-72.4) preoperatively to 69.1 (range, 17.0-100.0) postoperatively, while that in the patellectomized group improved from 35.8 (range, 5.2-62.2) to 61.3 (range, 17.5 96.2). The mean KSS improved from 80.4 (range, 4.0-143.0) preoperatively to 161.4 (range, 69.0-200.0) postoperatively in the control group and from 76.9 (range, 5 134) to 136.8 (range, 7-199) in the patellectomized group. Mean postoperative WOMAC scores were comparable between the two groups, while the mean KSS was lower in the patellectomized group. The mean SF-12 scores were not different after TKA or between groups. CONCLUSIONS: Despite the mechanical disadvantage to the knee extensor mechanism rendered by a previous patellectomy, TKA for tibiofemoral arthrosis in these patients relieved pain and restored function, but function was on average lower than that in patients with intact patellae. LEVEL OF EVIDENCE: Level III, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 23090655 TI - The DAS28-ESR cutoff value necessary to achieve remission under the new Boolean based remission criteria in patients receiving tocilizumab. AB - To seek the cutoff value of the 28-joint disease activity score using erythrocyte sedimentation rate (DAS28-ESR) that is necessary to achieve remission under the new Boolean-based criteria, we analyzed the data for 285 patients with rheumatoid arthritis registered between May 2008 and November 2009 by the Michinoku Tocilizumab Study Group and observed for 1 year after receiving tocilizumab (TCZ) in real clinical practice. Remission rates under the DAS28-ESR criteria and the Boolean criteria were assessed every 6 months after the first TCZ dose. The DAS28 ESR cutoff value necessary to achieve remission under the new criteria was analyzed by receiver operating characteristic (ROC) analysis. Data were analyzed using last observation carried forward. After 12 months of TCZ use, remission was achieved in 164 patients (57.5 %) by DAS28-ESR and 71 patients (24.9 %) under the new criteria for clinical trials. CRP levels scarcely affected remission rates, and the difference between remission rates defined by DAS28-ESR and by the new criteria was mainly due to patient global assessment (PGA). Improvement of PGA was inversely related to disease duration. ROC analysis revealed that the DAS28 ESR cutoff value necessary to predict remission under the new criteria for clinical trials was 1.54, with a sensitivity of 88.7 %, specificity of 85.5 %, positive predictive value of 67.0 %, and negative predictive value of 95.8 %. A DAS28-ESR cutoff value of 1.54 may be reasonable to predict achievement of remission under the new Boolean-based criteria for clinical trials in patients receiving TCZ. PMID- 23090657 TI - ABJS Carl T. Brighton workshop on hip preservation surgery: editorial comment. PMID- 23090658 TI - Reply to letter to the editor: operating room traffic is a major concern during total joint arthroplasty. PMID- 23090659 TI - Characteristics of metabolic syndrome based on clustering pattern among Korean adolescents: findings from the Korean National Health and Nutrition Examination Survey, 2007-2008. AB - To define the factors that influence the development of metabolic syndrome (MetS) characteristics in adolescents, this study assessed the clustering pattern for MetS using confirmatory factor analysis (CFA). Components of metabolic syndrome, including abdominal obesity, insulin resistance, high blood pressure, and dyslipidemia, were analyzed in 1,514 Korean adolescents aged 10 to 18 years. The validities of one-factor models underlying a unifying etiology and a four-factor model based on more than one physiologic process for MetS across sex and age groups were assessed using the CFA method. The one-factor model, which incorporated waist circumference (WC), homeostasis model assessment-insulin resistance (HOMA-IR), systolic blood pressure (SBP), and high-density lipoprotein (HDL) values, had the best goodness-of-fit indices among the models (comparative fit index 0.99, root mean square error of approximation 0.04), with stability over sex and age groups. MetS was mainly defined by WC, SBP, HOMA-IR, and HDL values, with factor loadings of 0.78, 0.47, 0.44, and -0.37, respectively. WC contributed the most to MetS, with the highest factor loading value across sex and age groups. In conclusion, a single underlying factor representing the common pathway linking abdominal obesity, SBP, HOMA-IR, and HDL may explain MetS in Korean adolescents with stability across sex and age groups. PMID- 23090661 TI - Mercury-thymine interaction with a chair type G-quadruplex architecture. AB - The T-Hg-T bond was utilized to cross-link two lateral loops of chair-type G quadruplex DNA (G4-DNA) structures. Two out of five cross-linking geometries are able to increase the melting temperature and simultaneously reduce the polymorphism of the G4-DNA conformations. PMID- 23090660 TI - Insulin-sensitive obese children display a favorable metabolic profile. AB - Most of what is known about the metabolically healthy obese phenomenon is derived from studies in the adult population and no standardized criteria to identify these individuals exist to date. The aim of this study was to determine if the preserved insulin sensitivity evaluated by homeostatic model assessment of insulin resistance (HOMA-IR) index is associated with favorable metabolic profile in the obese children. We studied a group of 248 children and adolescents (150 female, 98 male), aged 5.9-18.9 years with diet-induced obesity (BMI >95th percentile). The entire cohort was divided into quartiles based on levels of insulin resistance determined by HOMA-IR index. Subjects in the lower quartile of HOMA-IR were classified as insulin-sensitive group (ISG), whereas children in the upper quartile were categorized as insulin-resistant group (IRG). The ISG subjects had values of HOMA-IR <=2.75 while the children from the IRG group had HOMA-IR >=6.16. Subjects from ISG group had lower basal beta-cell activity and were less likely to have impaired fasting glucose or impaired glucose tolerance. Concentrations of LDL and total cholesterol, triglycerides, and transaminases were lower and HDL cholesterol levels were higher in ISG subjects. Findings obtained by the use of Matsuda index correlated well with the findings obtained by the use of HOMA-IR. CONCLUSION: Lower HOMA-IR values were significantly associated with favorable metabolic profile in studied children, which correlates with findings in the adult population and emphasizes the need for further, longitudinal studies of insulin resistance development in childhood obesity. PMID- 23090662 TI - Comparison of autonomic J-wave modulation in patients with idiopathic ventricular fibrillation and control subjects. AB - BACKGROUND: Although J-waves are seen in both patients with idiopathic ventricular fibrillation (IVF) and the general population, their genesis remains unclear. To assess the relationship between J-waves and autonomic tone we investigated the circadian variation of J-waves in individuals with and without IVF. METHODS AND RESULTS: In study 1, we obtained resting 12-lead ECG and Holter ECG recordings in 258 individuals undergoing screening for heart disease. In 60 of these subjects (23.3%), we detected J-waves on Holter ECGs; 40 of them (66.7%) had shown no J-waves on 12-lead ECGs. In study 2, we measured the J-wave amplitude, heart rate (HR), and HR variability [high frequency (HF) and the ratio of low- to high-frequency (LF/HF)] on Holter ECGs recorded in 5 patients with IVF and 20 control subjects who had manifested J-waves. The J-wave amplitude increased at night and decreased during the day in both groups; it was significantly higher in the IVF patients (P<0.0001). In both groups, the J-wave amplitude showed a significant negative correlation with HR and LF/HF and a significant positive correlation with HF. The slope of the J/HR and J/(LF/HF) relationship was significantly steeper in the IVF patients. CONCLUSIONS: The J wave amplitude was more significantly influenced by the autonomic balance in IVF patients than in the controls. Autonomic J-wave modulation may yield important information on the genesis of J-waves. PMID- 23090663 TI - Conduction recovery after electrical isolation of superior vena cava--prevalence and electrophysiological properties. AB - BACKGROUND: Superior vena cava (SVC) is an infrequent yet an important source of atrial fibrillation (AF). The data on SVC reconnection are limited. METHODS AND RESULTS: Following pulmonary vein (PV) antrum isolation for AF, SVC isolation was systemically performed under angiographic and mapping guidance using 4-mm non irrigated tip catheter. SVC reconnection could be evaluated in 76 consecutive patients (65 +/- 9 years, 59 male) who underwent repeat AF ablation after 16 +/- 16 months. SVC was isolated at the 1(st), 2(nd), 3(rd) and 4(th) AF ablation procedure in 63, 7, 5 and 1 patient by 7.3 +/- 3.1 radiofrequency applications. SVC reconnection was observed in 56 patients (74%). In the majority, the conduction gap was located at the anterolateral SVC-right atrium (RA) junction. After re-isolation of SVC, 2/7 patients (29%) had reconnection at the following procedure. Among 63 patients who underwent PV and SVC isolation at the initial procedure, the prevalence of reconnection for PV and that for SVC were similar (53/63, 84% vs. 46/63, 73%; P=0.129). Dissociated activity, however, was more frequently observed in the PVs than in the SVC (47/63, 73% vs. 10/63, 16%; P<0.0001). During the procedure, AF initiation from a thoracic vein was identified in 19/63 patients (30%). CONCLUSIONS: SVC reconnection is common after 1 or more previous isolation procedures undertaken for AF ablation. Its prevalence is similar to that of PV reconnection. The location of the conduction gap varies widely but is most frequently found at the anterolateral SVC-RA junction. PMID- 23090664 TI - Tradeoffs in cardiovascular disease prevention, treatment, and research. AB - It is widely believed that the US health care system needs to transition from a culture of reactive treatment of disease to one of proactive prevention. As a tool for understanding the appropriate allocation of spending to prevention versus treatment (including research into improved prevention and treatment), a simple Markov model is used to represent the flow of individuals among states of health, where the transition rates are governed by the magnitude of appropriately lagged expenditures in each of these categories. The model estimates the discounted cost and discounted effectiveness (measured in quality adjusted life years or QALYs) associated with a given spending mix, and it allows computing the marginal cost-effectiveness associated with additional spending in a category. We apply the model to explore interactions of alternative investments in cardiovascular disease (CVD) and to identify an optimal spending mix. Under the assumptions of our model structure, we find that the marginal cost-effectiveness of prevention of CVD varies with changes in spending on treatment (and vice versa), and that the optimal mix of CVD spending (i.e., the spending mix that maximizes the overall QALYs achieved) would, indeed, shift spending from treatment to prevention. PMID- 23090665 TI - Prefrontal cortical deficits in type 1 diabetes mellitus: brain correlates of comorbid depression. AB - CONTEXT Neural substrates that may be responsible for the high prevalence of depression in type 1 diabetes mellitus (T1DM) have not yet been elucidated. OBJECTIVE To investigate neuroanatomic correlates of depression in T1DM. DESIGN Case-control study using high-resolution brain magnetic resonance images. SETTINGS Joslin Diabetes Center and McLean Hospital, Massachusetts, and Seoul National University Hospital, South Korea. PARTICIPANTS A total of 125 patients with T1DM (44 subjects with >=1 previous depressive episodes [T1DM-depression group] and 81 subjects who had never experienced depressive episodes [T1DM-only group]), 23 subjects without T1DM but with 1 or more previous depressive episodes (depression group), and 38 healthy subjects (control group). MAIN OUTCOME MEASURES Spatial distributions of cortical thickness for each diagnostic group were compared with the control group using a surface-based approach. Among patients with T1DM, associations between metabolic control measures and cortical thickness deficits were examined. RESULTS Thickness reduction in the bilateral superior prefrontal cortical regions was observed in the T1DM-depression, T1DM only, and depression groups relative to the control group at corrected P < .01. Conjunction analyses demonstrated that thickness reductions related to the influence of T1DM and those related to past depressive episode influence were observed primarily in the superior prefrontal cortical region. Long-term glycemic control levels were associated with superior prefrontal cortical deficits in patients with T1DM (beta = -0.19, P = .02). CONCLUSIONS This study provides evidence that thickness reduction of prefrontal cortical regions in patients with T1DM, as modified by long-term glycemic control, could contribute to the increased risk for comorbid depression. PMID- 23090666 TI - Effects of pyridoxine on the intestinal absorption and pharmacokinetics of isoniazid in rats. AB - Pyridoxine is always simultaneously administered orally with isoniazid for tuberculosis patients in the clinic to prevent or treat the nervous system side effects induced by isoniazid. So the aim of this research was to investigate the effects of pyridoxine on the intestinal absorption and pharmacokinetics of isoniazid. The intestinal absorption of isoniazid with or without pyridoxine was investigated by the rat single-pass intestinal perfusion model in situ, and a high-performance liquid chromatographic method was applied to study the pharmacokinetics of isoniazid with or without pyridoxine. The results suggested that the intestinal apparent permeability (P app) and intestinal absorption rate constant (K a) for isoniazid (30 MUg/ml) were decreased by 43.7 and 36.4 %, respectively, by co-perfused pyridoxine (40 MUg/ml). In vivo, the effect of pyridoxine on isoniazid pharmacokinetic correlated with the doses of pyridoxine. The blood concentrations of isoniazid at the absorption phase were affected by co administered pyridoxine, but the AUC and C max of isoniazid were not greatly affected by pyridoxine as expected from the inhibition by pyridoxine of the intestinal absorption of isoniazid, which could be caused by its rapid absorption phase. Therefore, although the intestinal absorption of isoniazid could be significantly inhibited by pyridoxine, the pharmacokinetics of isoniazid oral administration was not greatly affected by the decreased intestinal absorption of isoniazid due to its rapid absorption. PMID- 23090668 TI - Soft conductive elastomer materials for stretchable electronics and voltage controlled artificial muscles. AB - Block copolymer elastomer conductors (BEC) are mixtures of block copolymers grafted with conducting polymers, which are found to support very large strains, while retaining a high level of conductivity. These novel materials may find use in stretchable electronics. The use of BEC is demonstrated in a capacitive strain sensor and in an artificial muscle of the dielectric elastomer actuator type, supporting more than 100% actuation strain and capacity strain sensitivity up to 300%. PMID- 23090667 TI - Prostaglandin E2 regulates pancreatic stellate cell activity via the EP4 receptor. AB - OBJECTIVES: Pancreatic stellate cells are source of dense fibrotic stroma, a constant pathological feature of chronic pancreatitis and pancreatic adenocarcinoma. We observed correlation between levels of cyclooxygenase 2 (COX 2) and its product prostaglandin E2 (PGE2) and the extent of pancreatic fibrosis. The aims of this study were to delineate the effects of PGE2 on immortalized human pancreatic stellate cells (HPSCs) and to identify the receptor involved. METHODS: Immunohistochemistry, reverse transcription-polymerase chain reaction and quantitative reverse transcription-polymerase chain reaction were used to assess COX-2, extracellular matrix, and matrix metalloproteinase gene expression. Eicosanoid profile was determined by liquid chromatography-tandem mass spectrometry. Human pancreatic stellate cell proliferation was assessed by MTS assay, migration by Boyden chamber assay, and invasion using an invasion chamber. Transient silencing was obtained by small interfering RNA. RESULTS: Human pancreatic stellate cells express COX-2 and synthesize PGE2. Prostaglandin E2 stimulated HPSC proliferation, migration, and invasion and stimulated expression of both extracellular matrix and matrix metalloproteinase genes. Human pancreatic stellate cells expressed all 4 EP receptors. Only blocking the EP4 receptor resulted in abrogation of PGE2-mediated HPSC activation. Specificity of EP4 for the effects of PGE2 on stellate cells was confirmed using specific antagonists. CONCLUSIONS: Our data indicate that PGE2 regulates pancreatic stellate cell profibrotic activities via EP4 receptor, thus suggesting EP4 receptor as useful therapeutic target for pancreatic cancer to reduce desmoplasia. PMID- 23090670 TI - Structures and stabilities of group 17 fluorides EF3 (E = I, At, and element 117) with spin-orbit coupling. AB - In this work, a recently developed CCSD(T) approach with spin-orbit coupling (SOC) as well as density functional theory (DFT) using various exchange correlation (XC) functionals are employed to investigate structures and stabilities of group 17 fluorides EF(3) (E = I, At, and element 117). These molecules are predicted to have bent T-shaped C(2v) structures according to the second-order Jahn-Teller (SOJT) effects or the valance shell electron pair repulsion (VSEPR) theory. For IF(3) and (117)F(3), our results are consistent with previous SOC-DFT calculations. However, different XC functionals provide different results for AtF(3) and our SOC-CCSD(T) calculations show that both the C(2v) and D(3h) structures are minima on the potential energy surface and the C(2v) structure is the global minimum for AtF(3). The performance of XC functionals on structures and stabilities of IF(3) and AtF(3) is found to depend on the fraction of the Hartree-Fock exchange (HFX) included in the XC functionals and the M06-2X functional with 54% of HFX providing results that agree best with CCSD(T) results. In addition, although both the C(2v) and D(3h) structures are minima for AtF(3), the energy barrier between them is only 8 kJ mol(-1) for the C(2v) structure and 0.05 kJ mol(-1) for the D(3h) structure. This indicates that the D(3h) structure could not possibly be observed experimentally and AtF(3) can convert easily between the three C(2v) structures. The SOJT term is shown to be reduced by electron correlation for IF(3) and AtF(3). On the other hand, although SOC decreases the energy difference between the C(2v) and D(3h) structures and reduces the deviation of the C(2v) structure from the D(3h) structure, it decreases the frequency of the bond bending mode, which may indicate that SOC actually increases the SOJT term. This could be related to mixing of spin-singlet E' states to low-energy spin-triplet states due to SOC. PMID- 23090669 TI - Identification of novel activators of constitutive androstane receptor from FDA approved drugs by integrated computational and biological approaches. AB - PURPOSE: The constitutive androstane receptor (CAR, NR1I3) is a xenobiotic sensor governing the transcription of numerous hepatic genes associated with drug metabolism and clearance. Recent evidence suggests that CAR also modulates energy homeostasis and cancer development. Thus, identification of novel human (h) CAR activators is of both clinical importance and scientific interest. METHODS: Docking and ligand-based structure-activity models were used for virtual screening of a database containing over 2000 FDA-approved drugs. Identified lead compounds were evaluated in cell-based reporter assays to determine hCAR activation. Potential activators were further tested in human primary hepatocytes (HPHs) for the expression of the prototypical hCAR target gene CYP2B6. RESULTS: Nineteen lead compounds with optimal modeling parameters were selected for biological evaluation. Seven of the 19 leads exhibited moderate to potent activation of hCAR. Five out of the seven compounds translocated hCAR from the cytoplasm to the nucleus of HPHs in a concentration-dependent manner. These compounds also induce the expression of CYP2B6 in HPHs with rank-order of efficacies closely resembling that of hCAR activation. CONCLUSION: These results indicate that our strategically integrated approaches are effective in the identification of novel hCAR modulators, which may function as valuable research tools or potential therapeutic molecules. PMID- 23090671 TI - On the basic reproduction number in a random environment. AB - The concept of basic reproduction number R0 in population dynamics is studied in the case of random environments. For simplicity the dependence between successive environments is supposed to follow a Markov chain. R0 is the spectral radius of a next-generation operator. Its position with respect to 1 always determines population growth or decay in simulations, unlike another parameter suggested in a recent article (Hernandez-Suarez et al., Theor Popul Biol, doi: 10.1016/j.tpb.2012.05.004 , 2012). The position of the latter with respect to 1 determines growth or decay of the population's expectation. R0 is easily computed in the case of scalar population models without any structure. The main emphasis is on discrete-time models but continuous-time models are also considered. PMID- 23090672 TI - Osteoarthritis, inflammation and obesity. AB - PURPOSE OF REVIEW: Obesity is one of the main risk factors of the incidence and prevalence of knee osteoarthritis. Recent epidemiological data showing an increased risk of hand osteoarthritis in obese patients opened the door to a role of systemic inflammatory mediators, adipokines, released by adipose tissue. RECENT FINDINGS: Recent experimental studies confirm the critical roles of adipokines in the pathophysiologic features of osteoarthritis, with an emphasis on a new member, chemerin. Animal models of diet-induced obesity show that overload cannot completely explain the aggravation of spontaneous or posttraumatic knee osteoarthritis. We now have data suggesting that some adipokines may be surrogate biomarkers for severity of osteoarthritis. SUMMARY: Preclinical studies targeting adipokines are now expected to provide new hope for patients with osteoarthritis, especially those with metabolic syndrome. PMID- 23090674 TI - The GDF5 gene and anterior cruciate ligament rupture. AB - A recent genetic association study has revealed that a variant (rs143383) within the 5'-untranslated region of the growth differentiation factor 5 gene (GDF5) associates with the risk of Achilles tendon pathology. The aim of this study was to determine whether this variant associates with the risk of ACL rupture. A cohort of 126 Caucasians with ACL rupture (ACL group), including 51 subjects who ruptured their ACL through a non-contact mechanism (NON sub-group), and 214 controls (CON group) were genotyped for the rs143383 variant. We report no significant GDF5 rs143383 genotype (P=0.396) or allele (P=0.810) frequency differences between the ACL (TT genotype, n=37, 29%; CT genotype, n=72, 57%; CC genotype, n=17, 14%) and CON (TT genotype, n=73, 34%; CT genotype, n=106, 50%; CC genotype, n=35, 16%) groups. There were also no significant differences between the NON sub-group and the CON group (allele; P=0.710, genotype; P=0.771). Furthermore, in gender specific analysis we found no association between rs143383 and ACL in either males (allele; P=0.988, genotype; P=0.407) or females (allele; P=0.643, genotype; P=0.885), respectively. Nor were there any gender specific associations between the NON sub-group and either genotype or allele. In conclusion, the rs143383 variant was not found to associate with the risk of ACL rupture. PMID- 23090675 TI - ACE activity and endurance performance during the South African Ironman triathlons. AB - The insertion allele of the angiotensin-converting enzyme (ACE) gene has been associated with endurance performance. Since a large portion of the variance seen in circulatory ACE levels is unaccounted for by the insertion/deletion polymorphism it is likely that the ACE phenotype would serve as a more informative marker in assessing elite endurance performance. The aim of this study was to correlate plasma ACE activity with performance of a homogenous population of South African-born Caucasian male triathletes. Plasma ACE activity was determined in 145 triathletes, representing the fastest and slowest subgroups who completed either the 2000 or 2001 South African Ironman Triathlon. There was a trend for lower mean plasma ACE activity in the fastest (28.85+/-8.60 mU/ml) when compared to the slowest finisher subgroup (31.65+/-8.75 mU/ml, P=0.055). There was a significant positive correlation between plasma ACE activity and overall finishing time within the participants who completed the event in under 15 h (r=0.192, P=0.029). There was also a positive correlation with cycle (r=0.195, P=0.034) and run (r=0.184, P=0.040) stages but not the swim stage (r=0.084, P=0.353). In conclusion, this is the first study to report a relationship between plasma ACE activity and endurance performance in humans. PMID- 23090676 TI - Sexual partner's age as a risk factor for HIV seroconversion in a cohort of HIV negative homosexual men in Sydney. AB - Increasing partner age may be an important risk factor for HIV infection in homosexual men. About 20 % of 1,427 participants in the Health in Men study in Sydney, Australia, reported that half or more of their partners were much older. Having more partners who were much older was associated with an increased risk of HIV seroconversion (p trend = 0.002), and this remained significant after adjustment for participants' age, number of regular and casual partners, and sexual risk behaviour (p trend = 0.027). Men who reported much older partners were at increased risk of HIV infection, independent of unprotected anal intercourse with sero-nonconcordant partners. PMID- 23090678 TI - Oral ibandronate in postmenopausal osteoporotic women alters micromechanical properties independently of changes in mineralization. AB - Postmenopausal osteoporotic (PMOP) women treated with ibandronate had higher bone mineral density, lower bone turnover, and decreased incidence of new vertebral fractures. The aim of this study was to investigate the effect of daily or intermittent oral ibandronate on the degree of mineralization (DMB) of bone and microhardness (Hv) at the bone tissue and bone structural unit (BSU) levels. A total of 110 iliac biopsies were taken from patients treated for 22 or 34 months with an oral placebo (n = 36), 2.5 mg daily oral ibandronate (n = 40), or 20 mg intermittent oral ibandronate (n = 34). These regimens provide annual cumulative exposures (ACEs) that are about half of the therapeutic doses currently licensed for PMOP women. DMB and Hv were measured at the global level (i.e., cortical or cancellous) and the focal level (i.e., BSU). At the global level, DMB and its distribution were not significantly different from placebo after 22 and 34 months of treatment. Hv was significantly higher in the cortical, cancellous, and total bone after 22 and 34 months of ibandronate versus placebo for both regimens. At the focal level, DMB and Hv, measured simultaneously in 3,760 BSUs, were significantly and positively correlated in all groups (r = 0.59-0.65, p < 0.0001). However, analysis of covariance highlighted the differences in the y intercepts of the linear regressions of the placebo- and ibandronate-treated groups. We infer that a low ACE of oral ibandronate altered the bone micromechanical properties irrespective of changes in secondary mineralization. PMID- 23090677 TI - Recruitment of urban US women at risk for HIV infection and willingness to participate in future HIV vaccine trials. AB - Enrollment of US women with sufficient risk of HIV infection into HIV vaccine efficacy trials has proved challenging. A cohort of 799 HIV-negative women, aged 18-45, recruited from three US cities was enrolled to assess recruitment strategies based on geographic risk pockets, social and sexual networks and occurrence of sexual concurrency and to assess HIV seroincidence during follow-up (to be reported later). Among enrolled women, 90 % lived or engaged in risk behaviors within a local risk pocket, 64 % had a male partner who had concurrent partners and 50 % had a male partner who had been recently incarcerated. Nearly half (46 %) were recruited through peer referral. At enrollment, 86 % of women said they were willing to participate in a vaccine efficacy trial. Results indicate that participant and partner risk behaviors combined with a peer referral recruitment strategy may best identify an at-risk cohort willing to participate in future trials. PMID- 23090680 TI - PAX5/ETV6 alters the gene expression profile of precursor B cells with opposite dominant effect on endogenous PAX5. PMID- 23090679 TI - Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. AB - The mechanistic target of rapamycin (mTOR) is a serine/threonine kinase whose activity contributes to leukemia proliferation and survival. Compounds targeting the mTOR active site inhibit rapamycin-resistant functions and have enhanced anticancer activity in mouse models. MLN0128 (formerly known as INK128) is a novel, orally active mTOR kinase inhibitor currently in clinical development. Here, we evaluated MLN0128 in preclinical models of B-cell acute lymphoblastic leukemia (B-ALL). MLN0128 suppressed proliferation of B-ALL cell lines in vitro and reduced colony formation by primary human leukemia cells from adult and pediatric B-ALL patients. MLN0128 also boosted the efficacy of dasatinib (DA) in Philadelphia Chromosome-positive (Ph+) specimens. In a syngeneic mouse model of lymphoid BCR-ABL+ disease, daily oral dosing of MLN0128 rapidly cleared leukemic outgrowth. In primary xenografts of Ph+ B-ALL specimens, MLN0128 significantly enhanced the efficacy of DA. In non-Ph B-ALL xenografts, single agent MLN0128 had a cytostatic effect that was most pronounced in mice with low disease burden. In all in vivo models, MLN0128 was well tolerated and did not suppress endogenous bone marrow proliferation. These findings support the rationale for clinical testing of MLN0128 in both adult and pediatric B-ALL and provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors. PMID- 23090682 TI - Domestic dogs (Canis familiaris) coordinate their actions in a problem-solving task. AB - Cooperative hunting is a cognitively challenging activity since individuals have to coordinate movements with a partner and at the same time react to the prey. Domestic dogs evolved from wolves, who engage in cooperative hunting regularly, but it is not clear whether dogs have kept their cooperative hunting skills. We presented pairs of dogs with a reward behind a fence with two openings in it. A sliding door operated by the experimenter could block one opening but not both simultaneously. The dogs needed to coordinate their actions, so that each was in front of a different opening, if one of them was to cross through and get food. All 24 dog pairs solved the problem. In study 1, we demonstrated that dogs understood how the apparatus worked. In study 2, we found that, although the performance of the pairs did not depend on the divisibility of the reward, pairs were quicker at coordinating their actions when both anticipated rewards. However, the dogs did not monitor one another, suggesting that their solutions were achieved by each individual attempting to maximize for itself. PMID- 23090683 TI - Agrobacterium-mediated gene transfer in plants and biosafety considerations. AB - Agrobacterium, the natures' genetic engineer, has been used as a vector to create transgenic plants. Agrobacterium-mediated gene transfer in plants is a highly efficient transformation process which is governed by various factors including genotype of the host plant, explant, vector, plasmid, bacterial strain, composition of culture medium, tissue damage, and temperature of co-cultivation. Agrobacterium has been successfully used to transform various economically and horticulturally important monocot and dicot species by standard tissue culture and in planta transformation techniques like floral or seedling infilteration, apical meristem transformation, and the pistil drip methods. Monocots have been comparatively difficult to transform by Agrobacterium. However, successful transformations have been reported in the last few years based on the adjustment of the parameters that govern the responses of monocots to Agrobacterium. A novel Agrobacterium transferred DNA-derived nanocomplex method has been developed which will be highly valuable for plant biology and biotechnology. Agrobacterium mediated genetic transformation is known to be the preferred method of creating transgenic plants from a commercial and biosafety perspective. Agrobacterium mediated gene transfer predominantly results in the integration of foreign genes at a single locus in the host plant, without associated vector backbone and is also known to produce marker free plants, which are the prerequisites for commercialization of transgenic crops. Research in Agrobacterium-mediated transformation can provide new and novel insights into the understanding of the regulatory process controlling molecular, cellular, biochemical, physiological, and developmental processes occurring during Agrobacterium-mediated transformation and also into a wide range of aspects on biological safety of transgenic crops to improve crop production to meet the demands of ever-growing world's population. PMID- 23090684 TI - Immobilization of lipase from grey mullet. AB - Grey mullet (Mugil cephalus) lipase was isolated using para-aminobenzamidine agarose and immobilized on octyl Sepharose CL-4B (o-Sep). Immobilized grey mullet lipase (GMLi) had a 10 degrees C higher optimum temperature compared to the free enzyme and showed remarkable thermal stability. GMLi was most active within the pH range of 8.0-9.5 with an optimum at 8.5. Immobilization also enhanced the storage stability and reusability of the enzyme with minimal changes in efficiency during repeated batches. GMLi showed variable stabilities in various organic solvents. A signal in the amide I absorption region of the FTIR spectrum of GMLi was attributed to the protein layer on o-Sep. The surface morphology of o Sep was visualized on a Zeiss stereomicroscope as globular-shaped beads. PMID- 23090685 TI - Genotypic variability among soybean genotypes under NaCl stress and proteome analysis of salt-tolerant genotype. AB - The present investigation was conducted to evaluate salt tolerance in ten genotypes of soybean (Glycine max L.). Twelve-day-old seedlings, grown hydroponically, were treated with 0, 25, 50, 75, 100, 125 and 150 mM NaCl for 10 days. Growth, lipid peroxidation and antioxidant enzyme activities were evaluated. Growth, measured in terms of length, fresh weight and dry weight of plants, was drastically reduced in Pusa-24 while there was little effect of NaCl treatment on Pusa-37 genotype of soybean. High level of lipid peroxidation was observed in Pusa-24 as indicated by increased level of malondialdehyde. Activities of superoxide dismutase, catalase, ascorbate peroxidase and glutathione reductase were maximum in Pusa-37 where 9-, 1-, 5- and 6-fold increase over control were observed, respectively. The results suggested that Pusa-24 and Pusa-37 are salt-sensitive and salt-tolerant genotype of soybean, respectively, and antioxidant defence system is involved in conferring the sensitiveness and tolerance in these genotypes. Salt-tolerant genotype Pusa-37, was further analysed by 2-dimensional gel electrophoresis to analyse the differential expression of proteins at high salt stress. In the present study, 173 protein spots were identified. Of these, 40 proteins were responsive to salinity in that they were either up- or downregulated. This study could help us in identifying the possible regulatory switches (gene/s) controlling novel proteins of the salt-tolerant genotype of the crop plants and their possible role in defence mechanism. PMID- 23090686 TI - Weismann versus morgan revisited: clashing interpretations on animal regeneration. AB - This paper has three principal aims: first, through a detailed analysis of the hypotheses and assumptions underlying Weismann's and Morgan's disagreement on the nature of animal regeneration, it seeks to readdress the imbalance in coverage of their discussion, providing, at the same time, a fascinating case-study for those interested in general issues related to controversies in science. Second, contrary to Morgan's beliefs according to which Weismann employed a speculative and unempirical method of scientific investigation, the article shows that Weismann performed experiments, made observations and proposed 'undogmatic' theories open to refutation. Third, through the reconstruction of Weismann's and Morgan's disagreement, this study illustrates how biology, during the very late nineteenth and early twentieth centuries, was undergoing important changes. I argue that this controversy clearly and convincingly demonstrates how some important epistemic assumptions became increasingly problematic for some members of the younger generations of biologists. At the end of my discussion I will also argue that Weismann and Morgan both had strong well-grounded arguments supporting their conclusions; for this reason I suggest a few factors ("taken-for-granted" beliefs or assumptions) that could explain why their disagreement was doomed to remain unresolved. In particular, I will analyze their diverse explicative interests, their different theoretical concerns and their distinct use of the available evidence. PMID- 23090687 TI - CuAAC click functionalization of azide-modified nanodiamond with a photoactivatable CO-releasing molecule (PhotoCORM) based on [Mn(CO)3(tpm)]+. AB - The copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition (CuAAC) was used for the first time to attach a biologically active carbon monoxide delivery agent to modified nanodiamond (ND) as a highly biocompatible carrier. The [Mn(CO)(3)(tpm)](+) photoactivatable CO-releasing molecule (PhotoCORM) on the surface retained the carbon monoxide release properties of the parent compound as shown with the myoglobin assay. PMID- 23090688 TI - Cationic complexes of hydrogen with helium. AB - High-resolution mass spectra of helium nanodroplets doped with hydrogen or deuterium reveal that copious amounts of helium can be bound to H(+), H(2)(+), H(3)(+), and larger hydrogen-cluster ions. All conceivable He(n)H(x)(+) stoichiometries are identified if their mass is below the limit of ~120 u set by the resolution of the spectrometer. Anomalies in the ion yields of He(n)H(x)(+) for x=1, 2, or 3, and n<=30 reveal particularly stable cluster ions. Our results for He(n)H(1)(+) are consistent with conclusions drawn from previous experimental and theoretical studies which were limited to smaller cluster ions. The He(n)H(3)(+) series exhibits a pronounced anomaly at n=12 which was outside the reliable range of earlier experiments. Contrary to findings reported for other diatomic dopant molecules, the monomer ion (i.e. H(2)(+)) retains helium with much greater efficiency than hydrogen-cluster ions. PMID- 23090689 TI - Genetic and molecular analyses of resistance to a variant of Puccinia striiformis in barley. AB - Seedlings of 62 Australian barley cultivars and two exotic barley genotypes were assessed for resistance to a variant of Puccinia striiformis, referred to as "Barley Grass Stripe Rust" (BGYR), first detected in Australia in 1998, which is capable of infecting wild Hordeum species and some genotypes of cultivated barley. Fifty-three out of 62 cultivated barley cultivars tested were resistant to the pathogen. Genetic analyses of seedling resistance to BGYR in six Australian barley cultivars and one Algerian barley landrace indicated that they carried either one or two major resistance genes to the pathogen. A single recessive seedling resistance gene, rpsSa3771, identified in Sahara 3771, was located on the long arm of chromosome 1 (7 H), flanked by the restriction fragment length polymorphism (RFLP) markers Xwg420 and Xcdo347 at genetic distances of 12.8 and 21.9 cM, respectively. Mapping resistance to BGYR at adult plant growth stages using the doubled haploid (DH) population Clipper * Sahara 3771 identified two major quantitative trait loci (QTL), one on the long arm of chromosome 3 (3 H) and the second on the long arm of chromosome 1 (7 H), accounting for 26 % and 18 % of the total phenotypic variation, respectively. The QTL located on chromosome 7HL corresponded to seedling resistance gene rpsSa3771 and the second QTL was concluded to correspond to a single APR gene, designated rpsCl, contributed by cultivar Clipper. PMID- 23090690 TI - Evaluation of motion correction processing in equine bone scintigraphy by Scheffe's method of paired comparisons. AB - Equine bone scintigraphy is usually performed with horses in standing position under sedation. However, swaying motion often leads to poor-quality images. To examine the usefulness of motion correction (MC) processing, equine bone scintigrams were evaluated using Scheffe's method of paired comparisons. A significant difference in evaluation scores was detected by analysis of variance (F test, P<0.01). According to all observers, Yardstick analysis scores were higher for images use of MC processing than for those no use of MC processing, for all parts. Overall scores of 5 observers were as follows: without MC 100% acquisition time (AT, lowest), use of MC with 25% AT, MC 50% AT, MC 75% AT and MC 100% AT (highest). Thus, MC processing shortens AT in equine bone scintigraphy, and it contributes to a reduction in the external radiation exposure of nurses/technicians. PMID- 23090691 TI - Negative inotropic effect of carbachol and interaction between acetylcholine receptor-operated potassium channel (K.ACh channel) and GTP binding protein in mouse isolated atrium--a novel methodological trial. AB - Interaction between acetylcholine receptor-operated potassium channel (K.ACh channel) and GTP binding protein was examined by an immunoprecipitation-Western blotting system in mouse isolated atrium. The carbachol-induced negative inotropic action in indomethacin-pretreated mouse atrium was significantly inhibited by a K.ACh channel blocker, tertiapin or atropine. Kir3.1 K.ACh channel (Kir3.1) was immunoprecipitated with a mouse anti-Kir3.1 antibody. Coprecipitating Gbeta with Kir3.1, detected by Western blotting, was significantly augmented by carbachol. Atropine, but not tertiapin, significantly inhibited the carbachol-induced coprecipitating Gbeta with Kir3.1. The data indicate that immunoprecipitation with Kir3.1 and Western blotting of Gbeta system is a useful method for assessing interaction between K.ACh channel and GTP binding protein in mouse atrium. PMID- 23090692 TI - Possible involvement of neuropeptide Y in photo-induced suppression of growth hormone pulses. AB - It is well established that growth hormone (GH) is secreted in a pulsatile manner. Although the GH pulse-generating mechanism is not fully understood, we have previously reported that neuropeptide Y (NPY) profiles in the cerebrospinal fluid were negatively correlated with serum GH pulses. In addition, it is known that photic stimulation suppresses GH pulses for a certain period of time. In the present study, to investigate the involvement of NPY in regulating GH pulse generation, NPY gene expression in the arcuate nucleus (ARC) of the hypothalamus in rats was analyzed at around the lights on. First, we confirmed that GH pulses did not occur for around 1.5 hr after the start of the light phase. Then, we analyzed the activity of neurons and expression of NPY mRNA 1 hr before and 0.5 and 2 hr after lights on. Both the activity of neurons, which was evaluated by immunohistochemical detection for phosphorylated-cAMP response element binding protein (pCREB), and NPY mRNA levels in the caudal ARC were higher at 0.5 hr after lights on than the other two time points, while pCREB-positive cell numbers in the rostral ARC remained unchanged throughout the experimental period. In addition, NPY immunoreactivity in the periventricular nucleus (PeVN) was also higher at 0.5 hr after lights on than the other time points. These results suggest that NPY neurons in the caudal ARC projecting to the PeVN play a role in inhibiting GH pulses at the commencement of the light phase. PMID- 23090693 TI - Identification of G protein alpha subunits in the main olfactory system and vomeronasal system of the Japanese Striped snake, Elaphe quadrivirgata. AB - In the olfactory system, G proteins couple to the olfactory receptors, and G proteins expressed in the main olfactory system and vomeronasal system vary according to animal species. In this study, G protein alpha subunits expressed in the main olfactory system and vomeronasal system of the snake were identified by immunohistochemistry. In the olfactory epithelium, only anti-Galphaolf/s antibody labeled the cilia of the receptor cells. In the vomeronasal epithelium, only anti Galphao antibody labeled the microvilli of the receptor cells. In the accessory olfactory bulb, anti-Galphao antibody stained the whole glomerular layer. These results suggest that the main olfactory system and the vomeronasal system of the snake express Galphaolf and Galphao as G proteins coupling to the olfactory receptors, respectively. PMID- 23090694 TI - Response of Holstein cows with milk fever to first treatment using two calcium regimens: a retrospective clinical study. AB - The responses of 64 Holstein cows with milk fever to first treatment with 500 ml of either of 2 intravenous calcium (Ca) solutions, one containing Ca alone (group A, n = 32) or 1 containing Ca, phosphate and magnesium (group B, n = 32), were evaluated by selected clinical signs and serum biochemical data. Based on the cow's ability to stand, treatment response was categorized into "immediate response" (stood after single treatment), "delayed response" (stood after repeated treatments) and "non-response" (slaughtered despite repeated treatments). No significant differences among the response categories were found between the two groups, suggesting that the solution containing Ca borogluconate alone was sufficient for the first treatment of milk fever. PMID- 23090695 TI - Heme oxygenase-1 is involved in nitric oxide- and cGMP-induced alpha-Amy2/54 gene expression in GA-treated wheat aleurone layers. AB - Here, alpha-Amy2/54 gene expression was used as a molecular probe to investigate the interrelationship among nitric oxide (NO), cyclic GMP (cGMP), and heme oxygenase-1 (HO-1) in GA-treated wheat aleurone layers. The inducible expressions of alpha-Amy2/54 and alpha-amylase activity were respectively amplified by two NO releasing compounds, sodium nitroprusside (SNP) and spermine NONOate, in a GA dependent fashion. Similar responses were observed when an inducer of HO-1, hemin or one of its catalytic products, carbon monoxide (CO) in aqueous solution-was respectively added. The SNP-induced responses, mimicked by 8-bromoguanosine 3',5' cyclic monophosphate (8-Br-cGMP), a cGMP derivative, were NO-dependent. This conclusion was supported by the fact that endogenous NO overproduction was rapidly induced by SNP, and thereafter induction of alpha-Amy2/54 gene expression and increased alpha-amylase activity were sensitive to the NO scavenger. We further observed that the above induction triggered by SNP and 8-Br-cGMP was partially prevented by zinc protoporphyrin IX (ZnPPIX), an inhibitor of HO-1. These blocking effects were clearly reversed by CO, confirming that the above response was HO-1-specific. Further analyses showed that both SNP and 8-Br-cGMP rapidly up-regulated HO-1 gene expression and increased HO activity, and SNP responses were sensitive to cPTIO and the guanylate cyclase inhibitor 6-anilino 5,8-quinolinedione (LY83583). Molecular evidence confirmed that GA-induced GAMYB and ABA-triggered PKABA1 transcripts were up-regulated or down-regulated by SNP, 8-Br-cGMP or CO cotreated with GA. Contrasting changes were observed when cPTIO, LY83583, or ZnPPIX was added. Together, our results suggested that HO-1 is involved in NO- and cGMP-induced alpha-Amy2/54 gene expression in GA-treated aleurone layers. PMID- 23090696 TI - Systematic analysis and validation of differential gene expression in ovarian serous adenocarcinomas and normal ovary. AB - PURPOSE: Cancer of the ovary confers the worst prognosis among women with gynecological malignancies, primarily because most ovarian cancers are diagnosed at late stage. Hence, there is a substantial need to develop new diagnostic biomarkers to enable detection of ovarian cancer at earlier stages, which would confer better prognosis. In addition, the identification of druggable targets is of substantial interest to find new therapeutic strategies for ovarian cancer. METHODS: The expression of 22,500 genes in a series of 67 serous papillary carcinomas was compared with 9 crudely enriched normal ovarian tissue samples by RNA hybridization on oligonucleotide microarrays. Multiple genes with near uniformly expression were elevated in carcinomas of varying grade and malignant potential, including several previously described genes (e.g., MUC-1, CD9, CD24, claudin 3, and mesothelin). We performed immunohistochemical staining with antibodies against several of the proteins encoded by differentially expressed genes in an independent cohort of 71 cases of paraffin-embedded ovarian cancer samples. RESULTS: We found striking differences in EpCAM (p < 0.005), CD9 (p < 0.001), MUC-1 (p < 0.001), and claudin 3 proteins (p < 0.001) but not for mesothelin (p > 0.05) using the Mann-Whitney U test. CONCLUSIONS: Protein expression of a majority of the differentially expressed genes tested was found to be elevated in ovarian carcinomas and, as such, define potential new biomarkers or targets. PMID- 23090698 TI - Discontinuation of anticoagulant care during admission to a psychiatric hospital. AB - PURPOSE: Continuation of coumarin therapy is important to prevent thromboembolic events. Continuation of medication, unrelated to the reason for hospital admission, may be at risk due to the patient's psychiatric status and the involvement of several physicians in patient care. METHODS: We performed a retrospective follow-up study of users of orally administered anticoagulants who were admitted to a psychiatric hospital. Information on patient characteristics, anticoagulant use, and International Normalized Ratio (INR) measurements was collected. Discontinuation of anticoagulant care was defined as no anticoagulant dispensing during the first 7 days of hospitalization and/or no INR measurement during hospitalization. Relative risks (RR) of discontinuation, overall and stratified by patient characteristics, was estimated using Cox regression analysis. RESULTS: Of 111 patients, 24.3 % had their anticoagulant care discontinued. For 17.1 %, no anticoagulant was dispensed during the first week, and 13.5 % had no INR measurement during hospitalization. CONCLUSIONS: Admission to a psychiatric hospital leads to discontinuation of anticoagulant care in 24.3 % of patients, with highest risk of discontinuation in patients admitted to nonpsychogeriatric wards. More research is needed to evaluate the clinical impact of this finding. PMID- 23090699 TI - The fuzzy line between needs, coverage, and excess in the Mexican Formulary List: an example of qualitative market width analysis. AB - PURPOSE: To assess the rationality of the Mexican Formulary List (MEX-LIST). METHODS: MEX-LIST was compared with the World Health Organization Essential Medicines List (WHO-LIST) to identify drugs classified as unmet needs. For the MEX-LIST rationality evaluation, the assessment of a non-sponsored, systematic and unbiased source (Prescrire Journal) was used for medicines not listed in WHO LIST. The rating scale of Prescrire classifies medicines as Bravo, Real Advance, Offers an Advance, Possibly Helpful, Nothing New (NN), Judgment Reserved (JR), or Not Acceptable (NA) depending on their comparative therapeutic value. The NN, JR, and NA categories of medicines are further classified as non-added value. RESULTS: The MEX-LIST contains 771 medicines, which is 2.4-fold more than the WHO LIST (n = 321). Up to 236 medicines in the MEX-LIST perfectly match the WHO-LIST medicines, 40 could be considered as reasonable substitutes, but 45 (14.0 %) present in the WHO-LIST are not present in the MEX-LIST, including an oversupply of 495 medicines. Rationality level could be analyzed for 353 of these: 43.1 % (n = 152) were classified as NN, 12.2 % (n = 43) as NA, and 6.2 % (n = 22) as JR due to limited available information. In summary, 61.5 % of the evaluated medicines present in the MEX-LIST but not included in the WHO-LIST (n = 217) can be considered drugs that do not add substantial therapeutic benefits, this accounts for 28.1 % of the medicines in the MEX-LIST. CONCLUSIONS: MEX-LIST is characterized by a twofold irrationality in that essential medicines to treat prevalent diseases are missing and medicines without any rational added value are in oversupply. This type of study can be easily applied to other countries with the aim of providing a forum for further discussion and improvement of the medicines offered by their national formularies. PMID- 23090700 TI - Impact of regional copayment policy on selective serotonin reuptake inhibitor (SSRI) consumption and expenditure in Italy. AB - PURPOSE: The continuous growth of antidepressant consumption and expenditure, especially for selective serotonin reuptake inhibitors (SSRIs), has led to the adoption of several policy measures directed toward cost control in Western countries. In Italy, copayment policies have been heterogeneously introduced at a regional level as part of a strategy designed to reduce drug consumption. The aim of our study was to evaluate whether regional copayment policies have affected trends in the consumption of and expenditure for SSRIs from 2001 to 2007. METHODS: The consumption of SSRIs was measured in terms of defined daily doses per 1,000 inhabitants (DDD/1000) per day from May 2001 to December 2007. Time trends in consumption and expenditure before and after the introduction of copayment policies were examined using segmented regression analysis of interrupted time-series, adjusting for seasonal components. The study was conducted for 17 regions, nine of which had implemented a copayment policy. RESULTS: The overall consumption of SSRIs in Italy increased during the study period, from a monthly consumption of 12.85 DDD/1000 per day in May 2001 to 23.40 DDD/1000 per day in December 2007. The average monthly increase in SSRI use was 0.82 % in regions with a copayment policy versus 0.77 % in regions without a copayment policy (P = 0.329). According to the multivariable analysis, copayment was associated with a 1 % reduction in the monthly growth rate of SSRI consumption (P = 0.01). The impact of copayment on expenditure was statistically significant (P < 0.005) on both the level and the trend, even though the estimate of the effect was negligible. CONCLUSIONS: The implementation of copayment policies in Italy affected both the use and expenditure of SSRIs between 2001 and 2007 to only to a minor extent. PMID- 23090701 TI - Orphan drugs, orphan diseases. The first decade of orphan drug legislation in the EU. AB - PURPOSE: To assess the methodological quality of Orphan Medicinal Product (OMP) dossiers and discuss possible reasons for the small number of products licensed. METHODS: Information about orphan drug designation, approval, refusal or withdrawal was obtained from the website of the European Medicines Agency and from the European Public Assessment Reports. RESULTS: From 2000 up to 2010, 80.9 % of the 845 candidate orphan drug designations received a positive opinion from the European Medicines Agency (EMA)'s Committee on Orphan Medicinal Products. Of the 108 OMP marketing authorizations applied for, 63 were granted. Randomised clinical trials were done for 38 OMPs and placebo was used as comparator for nearly half the licensed drugs. One third of the OMPs were tested in trials involving fewer than 100 patients and more than half in trials with 100-200 cases. The clinical trials lasted less than one year for 42.9 % of the approved OMPs. CONCLUSION: Although there may have been some small improvements over time in the methods for developing OMPs, in our opinion, the number of patients studied, the use of placebo as control, the type of outcome measure and the follow-up have often been inadequate. The present system should be changed to find better ways of fostering the development of effective and sustainable treatments for patients with orphan diseases. Public funds supporting independent clinical research on OMPs could bridge the gap between designation and approval. More stringent criteria to assess OMPs' efficacy and cost/effectiveness would improve the clinical value and the affordability of products allowed onto the market. PMID- 23090702 TI - Potentially inappropriate medications in a large cohort of patients in geriatric units: association with clinical and functional characteristics. AB - OBJECTIVE: With the aim of reducing the risk of adverse drug effects, expert groups have defined lists of potentially inappropriate medications (PIM) for drug therapy in the elderly. However, it is unclear whether use of PIM at discharge from specialized geriatric units is associated with altered clinical characteristics. METHODS: A post-hoc analysis of 376,335 drug prescriptions in 45,809 patients aged 70 years or older at discharge from 44 geriatric units located in Bavaria was performed (1 January 2009 to 31 December 2010). The main outcome measures were patient-related characteristics including functional status, which were independently associated in a multivariable logistic regression model with PIM at discharge. RESULTS: Male gender was associated with a lower odds ratio (OR) for the use of PIM [OR 0.72, 95 % confidence interval (CI) 0.67-0.76, P < 0.001]. The Barthel score at discharge was associated with a modestly increased odds ratio for receiving at least one PIM (OR 1.00, 95 % CI 1.00-1.01, P < 0.001). Patients who were only able to walk with assistant or who were unable to walk in the Timed Up-and-Go-Test, had adjusted odds ratios of 1.18 (95 % CI 1.08-1.28, P < 0.001) and 1.22 (95 % CI 1.07-1.39, P = 0.003), respectively, for receiving PIM. In additional multivariate analyses we found no evidence for a significant impact of PIM use on the change in the Barthel score during the hospital stay and on the ability to walk. CONCLUSIONS: Several factors, including gender and Barthel score, are associated with the use of drugs classified as potentially inappropriate for drug therapy in the elderly. However, the use of potentially inappropriate medications is not a clinically meaningful indicator of functional status at discharge. PMID- 23090703 TI - CYP2C19 genotype has a major influence on labetalol pharmacokinetics in healthy male Chinese subjects. AB - PURPOSE: The pharmacokinetics (PK) of labetalol show wide inter-subject variability, but the genetic causes for this are largely undetermined. This study was performed to examine whether common polymorphisms in UGT1A1, UGT2B7, CYP2C19 and ABCB1 affect the PK of labetalol. METHODS: The PK of labetalol were determined in 37 Chinese healthy male subjects who took a single oral dose of 200 mg labetalol. Plasma concentrations of labetalol were determined by a high performance liquid chromatographic method. Subjects were genotyped for the CYP2C19 2 and 3, UGT1A1 6, 28 and 60, UGT2B7 2 and ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms. RESULTS: Subjects with the CYP2C19 2/ 2 genotype had a higher peak concentration (255.5 +/- 80.1 vs. 156.0 +/- 66.3 ng/mL; P < 0.05) and area under the concentration-time curve (AUC0-infinity; 1,473.7 +/- 493.6 vs. 502.8 +/- 176.1 ng[Symbol: see text]h/mL; P < 0.001) than subjects with 60 or 28, and UGT2B7 2 did not result in a significant effect. Subjects with ABCB1 2677TA or TT or ABCB1 3435TT genotypes had higher AUC0-infinity and lower total clearance than the wild-types (P < 0.05), but this appeared to be related to the distribution of CYP2C19 genotypes. The CYP2C19 genotype appeared to be the only predictor of labetalol concentrations, accounting for approximately 60 % of the total variance in the AUC0-infinity. CONCLUSION: Our results suggest that the PK of labetalol are significantly affected by the common CYP2C19 polymorphisms in individuals of Chinese ethnicity. Future larger studies are needed to evaluate the effect of CYP2C19 and UGT1A1 polymorphisms on the PK of labetalol stereoisomers and the pharmacodynamic effects. PMID- 23090704 TI - Influence of the VKORC1 3730 G > A polymorphism on warfarin dose. PMID- 23090705 TI - Medication errors in the Middle East countries: a systematic review of the literature. AB - BACKGROUND: Medication errors are a significant global concern and can cause serious medical consequences for patients. Little is known about medication errors in Middle Eastern countries. The objectives of this systematic review were to review studies of the incidence and types of medication errors in Middle Eastern countries and to identify the main contributory factors involved. METHODS: A systematic review of the literature related to medication errors in Middle Eastern countries was conducted in October 2011 using the following databases: Embase, Medline, Pubmed, the British Nursing Index and the Cumulative Index to Nursing & Allied Health Literature. The search strategy included all ages and languages. Inclusion criteria were that the studies assessed or discussed the incidence of medication errors and contributory factors to medication errors during the medication treatment process in adults or in children. RESULTS: Forty-five studies from 10 of the 15 Middle Eastern countries met the inclusion criteria. Nine (20 %) studies focused on medication errors in paediatric patients. Twenty-one focused on prescribing errors, 11 measured administration errors, 12 were interventional studies and one assessed transcribing errors. Dispensing and documentation errors were inadequately evaluated. Error rates varied from 7.1 % to 90.5 % for prescribing and from 9.4 % to 80 % for administration. The most common types of prescribing errors reported were incorrect dose (with an incidence rate from 0.15 % to 34.8 % of prescriptions), wrong frequency and wrong strength. Computerised physician rder entry and clinical pharmacist input were the main interventions evaluated. Poor knowledge of medicines was identified as a contributory factor for errors by both doctors (prescribers) and nurses (when administering drugs). Most studies did not assess the clinical severity of the medication errors. CONCLUSION: Studies related to medication errors in the Middle Eastern countries were relatively few in number and of poor quality. Educational programmes on drug therapy for doctors and nurses are urgently needed. PMID- 23090707 TI - Medial prefrontal cortex: multiple roles in fear and extinction. AB - Anxiety disorders are among the most common mental health problems; deficits in extinction have been implicated as a possible risk factor for the development of these disorders. Fear extinction refers to the ability to adapt as situations change by learning to suppress a previously acquired fear. Attention is directed toward the medial prefrontal cortex (mPFC) and the interaction it has with the amygdala as this circuit has crucial roles in both the acquisition and the extinction of fear associations. Here, we review converging evidence from different laboratories pointing to multiple roles that the mPFC has in fear regulation. Research on rodents indicates opposing roles that the different subregions of the mPFC have in exciting and inhibiting fear. In addition, this review aims to survey the findings addressing the mechanisms by which the mPFC regulates fear. Data from our laboratory and others show that changes in plasticity in the mPFC could be one of the mechanisms mediating extinction of fear. Recent findings on rodents and nonhuman primates report that modifying plasticity in the mPFC alters fear and affects extinction, suggesting that targeting plasticity in the mPFC could constitute a therapeutic tool for the treatment of anxiety disorders. PMID- 23090706 TI - Hyphal differentiation induced via a DNA damage checkpoint-dependent pathway engaged in crosstalk with nutrient stress signaling in Schizosaccharomyces japonicus. AB - DNA damage response includes DNA repair, nucleotide metabolism and even a control of cell fates including differentiation, cell death pathway or some combination of these. The responses to DNA damage differ from species to species. Here we aim to delineate the checkpoint pathway in the dimorphic fission yeast Schizosaccharomyces japonicus, where DNA damage can trigger a differentiation pathway that is a switch from a bidirectional yeast growth mode to an apical hyphal growth mode, and the switching is regulated via a checkpoint kinase, Chk1. This Chk1-dependent switch to hyphal growth is activated with even low doses of agents that damage DNA; therefore, we reasoned that this switch may depend on other genes orthologous to the components of the classical Sz. pombe Chk1 dependent DNA checkpoint pathway. As an initial test of this hypothesis, we assessed the effects of mutations in Sz. japonicus orthologs of Sz. pombe checkpoint genes on this switch from bidirectional to hyphal growth. The same set of DNA checkpoint genes was confirmed in Sz. japonicus. We tested the effect of each DNA checkpoint mutants on hyphal differentiation by DNA damage. We found that the Sz. japonicus hyphal differentiation pathway was dependent on Sz. japonicus orthologs of Sz. pombe checkpoint genes-(SP)rad3, (SP)rad26, (SP)rad9, (SP)rad1, (SP)rad24, (SP)rad25, (SP)crb2, and (SP)chk1-that function in the DNA damage checkpoint pathway, but was not dependent on orthologs of two Sz. pombe genes-(SP)cds1 or (SP)mrc1-that function in the DNA replication checkpoint pathway. These findings indicated that although the role of each component of the DNA damage checkpoint and DNA replication checkpoint is mostly same between the two fission yeasts, the DNA damage checkpoint was the only pathway that governed DNA damage-dependent hyphal growth. We also examined whether DNA damage checkpoint signaling engaged in functional crosstalk with other hyphal differentiation pathways because hyphal differentiation can also be triggered by nutritional stress. Here, we discovered genetic interactions that indicated that the cAMP pathway engaged in crosstalk with Chk1-dependent signaling. PMID- 23090708 TI - Thermal and photochemical reactions of NO2 on chromium(III) oxide surfaces at atmospheric pressure. AB - While many studies of heterogeneous chemistry on Cr(2)O(3) surfaces have focused on its catalytic activity, less is known about chemistry on this surface under atmospheric conditions. We report here studies of the thermal and photochemical reactions of NO(2) on Cr(2)O(3) at one atm in air. In order to follow surface species, the interaction of 16-120 ppm NO(2) with a 15 nm Cr(2)O(3) thin film deposited on a germanium crystal was monitored in a flow system using attenuated total reflectance (ATR) coupled to a Fourier transform infrared (FTIR) spectrometer. Gas phase products were monitored in the effluent of an ~285 ppm NO(2)-air mixture that had passed over Cr(2)O(3) powder in a flow system. A chemiluminescence NO(y) analyzer, a photometric O(3) analyzer and a long-path FTIR spectrometer were used to probe the gaseous products. In the absence of added water vapor, NO(2) formed nitrate (NO(3)(-)) ions coordinated to Cr(3+). These surface coordinated NO(3)(-) were reversibly solvated by water under humid conditions. In both dry and humid cases, nitrate ions decreased during irradiation of the surface at 302 nm, and NO and NO(2) were generated in the gas phase. Under dry conditions, NO was the major gaseous product while NO(2) was the dominant species in the presence of water vapor. Heating of the surface after exposure to NO(2) led to the generation of both NO(2) and NO under dry conditions, but only NO(2) in the presence of water vapor. Elemental chromium incorporated into metal alloys such as stainless steel is readily oxidized in contact with ambient air, forming a chromium-rich metal oxide surface layer. The results of these studies suggest that active photo- and thermal chemistry will occur when boundary layer materials containing chromium(III) or chromium oxide such as stainless steel, roofs, automobile bumpers etc. are exposed to NO(2) under tropospheric conditions. PMID- 23090709 TI - Effect of cryogenic burnishing on surface integrity modifications of Co-Cr-Mo biomedical alloy. AB - Severe plastic deformation (SPD) processes have been used to modify the surface integrity properties of many materials by generating ultrafine or even nanometer sized grains in the surface and subsurface region. These fine grained materials created by SPD and dynamic recrystallization in a thin layer near the surface usually have higher hardness and frequently exhibit enhanced mechanical properties (wear resistance, corrosion resistance, fatigue life, etc.). Cryogenic burnishing, a SPD process, was used to improve several surface integrity parameters of a Co-Cr-Mo biomedical alloy. Application of liquid nitrogen during the burnishing process significantly suppressed the temperature rise within and outside the nitrogen application zone. Better surface finish, high hardness value, thick burnishing-influenced surface layer, and significant grain refinement were simultaneously achieved with the application of cryogenic cooling. Current results show that cryogenic burnishing can be an effective processing method for modifying the studied surface integrity properties of Co-Cr Mo biomedical alloy. PMID- 23090710 TI - [Mental distress and quality of life in tinnitus patients]. AB - BACKGROUND: Tinnitus is a disease with a high prevalence that is often combined with psychiatric comorbidity. The aim of this study was to identify the dimensions of quality of life in which tinnitus patients are especially affected, and how these affections change during a therapy, including a hyperbaric oxygen therapy. MATERIAL AND METHODS: 120 patients suffering from tinnitus were examined at 3 time points: at the beginning (t1) and the end (t2) of a 2-week hyperbaric oxygen therapy, and 4 weeks later (t3). The following questionnaires were adopted: Hospital Anxiety and Depression Scale, Multidimensional Fatigue Inventory, and the quality of life instrument EORTC QLQ-C30. RESULTS: Compared with the general population, tinnitus patients were impaired in all areas of quality of life. The greatest differences were found in the scales Social, Cognitive, Emotional and Role Functioning and in the field of financial difficulties with effect sizes of about 1.5. During the therapy, the scores improved, reaching roughly the middle between the initial patients' scores and the values of the general population. The directly assessed subjective improvement due to the therapy was only marginally correlated with the differences in the questionnaires. CONCLUSION: Since there was no control group without hyperbaric oxygen therapy, the results do not justify conclusions about the effectiveness of this therapy. However, the findings document multiple impairments of the patients (especially psycho-social disturbances) and show hints for supportive offers. PMID- 23090711 TI - Menopausal hormone therapy for the primary prevention of chronic conditions: U.S. Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Update of the 2005 U.S. Preventive Services Task Force (USPSTF) recommendation statement on hormone therapy for the prevention of chronic conditions in postmenopausal women. METHODS: The USPSTF commissioned a review of the literature to update evidence about the benefits and harms of using menopausal hormone therapy to prevent chronic conditions, as well as whether the benefits and harms of hormone therapy differ by population subgroups defined by age; the presence of comorbid medical conditions; and the type, dose, and method of hormonal delivery. POPULATION: This recommendation applies to postmenopausal women who are considering hormone therapy for the primary prevention of chronic medical conditions. It does not apply to women who are considering hormone therapy for the management of menopausal symptoms, such as hot flashes or vaginal dryness. It also does not apply to women younger than 50 years who have had surgical menopause. RECOMMENDATION: The USPSTF recommends against the use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women. (Grade D recommendation).The USPSTF recommends against the use of estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy. (Grade D recommendation). PMID- 23090712 TI - Lanthanum (III) regulates the nitrogen assimilation in soybean seedlings under ultraviolet-B radiation. AB - Ultraviolet-B (UV-B, 280-320 nm) radiation has seriously affected the growth of plants. Finding the technology/method to alleviate the damage of UV-B radiation has become a frontal topic in the field of environmental science. The pretreatment with rare earth elements (REEs) is an effective method, but the regulation mechanism of REEs is unknown. Here, the regulation effects of lanthanum (La(III)) on nitrogen assimilation in soybean seedlings (Glycine max L.) under ultraviolet-B radiation were investigated to elucidate the regulation mechanism of REEs on plants under UV-B radiation. UV-B radiation led to the inhibition in the activities of the key enzymes (nitrate reductase, glutamine synthetase, glutamate synthase) in the nitrogen assimilation, the decrease in the contents of nitrate and soluble proteins, as well as the increase in the content of amino acid in soybean seedlings. The change degree of UV-B radiation at the high level (0.45 W m(-2)) was higher than that of UV-B radiation at the low level (0.15 W m(-2)). The pretreatment with 20 mg L(-1) La(III) could alleviate the effects of UV-B radiation on the activities of nitrate reductase, glutamine synthetase, glutamate synthase, and glutamate dehydrogenase, promoting amino acid conversion and protein synthesis in soybean seedlings. The regulation effect of La(III) under UV-B radiation at the low level was better than that of UV-B radiation at the high level. The results indicated that the pretreatment with 20 mg L(-1) La(III) could alleviate the inhibition of UV-B radiation on nitrogen assimilation in soybean seedlings. PMID- 23090713 TI - Decreased bioelements content in the hair of patients with Fahr's disease (idiopathic bilateral calcification in the brain). AB - The remarkable calcification of the basal ganglia and cerebellum has been traditionally called Fahr's disease, but this nomenclature is criticized for including heterogeneous diseases. To determine the pattern of some biological metals in the hair of patients with Fahr's disease, we investigated the levels of 24 bioelements in the hair of 28 patients (17 males and 11 females) with Fahr's disease and compared them with those of three age-, sex-, and living region matched controls (84 controls in total). Interestingly, we found decreases in the levels of several bioelements [calcium (Ca), copper (Cu), iron (Fe), mercury (Hg), iodine (I), nickel (Ni), phosphate (P), lead (Pb), and selenium (Se)] in the hair of patients. This is in contrast to our previous finding of increases of Cu, Fe, zinc (Zn), and magnesium (Mg) in the cerebrospinal fluid (CSF) of patients. The decreased level of Cu in the hair was the most prominent and pathognomonic, while the increased level of Cu in the CSF had been found to be the most significant in patients. More significant correlations between two bioelements in the hair were recognized in patients than controls. Although Fahr's disease has been considered to be a heterogenous entity, the significant tendencies of several bioelements in the hair of patients in this study suggest metabolic disorders of bioelements, especially biometals, on the background. Some transporters, especially P transporter such as PiT2, of bioelements will be involved in the different distribution of bioelements in the body of patients. PMID- 23090714 TI - Photoionization of Yb(NH3)n complexes. AB - The ionization energies of complexes between a rare-earth metal (Yb) and ammonia were measured for the first time. Using photoionization mass spectrometry under molecular-beam conditions, the adiabatic ionization energies of Yb(NH3)n were determined for n=1-10. Ab initio calculations were also carried out in support of this work and were found to be in excellent agreement with experiment. The combined findings from theory and experiment are consistent with formation of "interior" complexes in which the Yb atom is embedded within a shell of NH3 molecules, rather than sitting on the surface of an (NH3)n cluster. The calculations also suggest that Yb can accommodate up to eight NH3 molecules in its first solvation shell before steric repulsion makes occupancy of the second solvation shell more favourable energetically. The experimental ionization data are consistent with this prediction, as demonstrated by below-trend adiabatic ionization energies for the n=9 and 10 complexes. The ionization energies of Yb(NH3)n complexes closely follow those for complexes of alkali metal atoms with NH3, which suggests that a valence electron will eventually detach from the Yb atom to form a solvated electron in Yb(NH3)n when n is sufficiently large. PMID- 23090715 TI - Adiponectin: key role and potential target to reverse energy wasting in chronic heart failure. AB - The concept of skeletal muscle myopathy as a main determinant of exercise intolerance in chronic heart failure (HF) is gaining acceptance. Symptoms that typify HF patients, including shortness of breath and fatigue, are often directly related to the abnormalities of the skeletal muscle in HF. Besides muscular wasting, alterations in skeletal muscle energy metabolism, including insulin resistance, have been implicated in HF. Adiponectin, an adipocytokine with insulin-sensitizing properties, receives increasing interest in HF. Circulating adiponectin levels are elevated in HF patients, but high levels are paradoxically associated with poor outcome. Previous analysis of m. vastus lateralis biopsies in HF patients highlighted a striking functional adiponectin resistance. Together with increased circulating adiponectin levels, adiponectin expression within the skeletal muscle is elevated in HF patients, whereas the expression of the main adiponectin receptor and genes involved in the downstream pathway of lipid and glucose metabolism is downregulated. In addition, the adiponectin-related metabolic disturbances strongly correlate with aerobic capacity (VO2 peak), sub maximal exercise performance and muscle strength. These observations strengthen our hypothesis that adiponectin and its receptors play a key role in the development and progression of the "heart failure myopathy". The question whether adiponectin exerts beneficial rather than detrimental effects in HF is still left unanswered. This current research overview will elucidate the emerging role of adiponectin in HF and suggests potential therapeutic targets to tackle energy wasting in these patients. PMID- 23090716 TI - Paclitaxel increases high voltage-dependent calcium channel current in dorsal root ganglion neurons of the rat. AB - Peripheral neuropathic pain is a serious side effect of paclitaxel treatment. However, the mechanism of this paclitaxel-induced neuropathic pain is unknown. In this study, we investigated the effects of paclitaxel on the voltage-dependent calcium channel (VDCC) current in rat dorsal root ganglion (DRG) neurons using the whole-cell patch clamp technique. Behavioral assessment using von Frey filament stimuli showed that 2 and 4 mg/kg paclitaxel treatment induced mechanical allodynia/hyperalgesia. Paclitaxel-induced mechanical hyperalgesia was significantly inhibited by gabapentin (100 mg/kg). Using the patch clamp method, we observed that paclitaxel (4 mg/kg) treatment significantly increased the VDCC current in small- and medium-diameter DRG neurons. Moreover, paclitaxel-induced increase in the VDCC current in medium-diameter DRG neurons was completely inhibited by 10 and 100 MUM gabapentin. Similar effects in small-diameter DRG neurons were only seen with 100 MUM gabapentin. Western blotting revealed that paclitaxel increased protein levels of the VDCC subunit alpha2delta-1 (Ca(v)alpha2delta-1) in DRG neurons. Immunohistochemistry showed that paclitaxel treatment increased Ca(v)alpha2delta-1 protein expression in DRG neurons. Thus, paclitaxel treatment increases the VDCC current in small- and medium-diameter DRG neurons and upregulates Ca(v)alpha2delta-1. The antihyperalgesic action of gabapentin may be due to inhibition of paclitaxel-induced increases in the VDCC current in DRG neurons. PMID- 23090717 TI - Affective value and associative processing share a cortical substrate. AB - The brain stores information in an associative manner so that contextually related entities are connected in memory. Such associative representations mediate the brain's ability to generate predictions about which other objects and events to expect in a given context. Likewise, the brain encodes and is able to rapidly retrieve the affective value of stimuli in our environment. That both contextual associations and affect serve as building blocks of numerous mental functions often makes interpretation of brain activation ambiguous. A critical brain region where such activation has often resulted in equivocal interpretation is the medial orbitofrontal cortex (mOFC), which has been implicated separately in both affective and associative processing. To characterize its role more unequivocally, we tested whether activity in the mOFC was most directly attributable to affective processing, associative processing, or a combination of both. Subjects performed an object recognition task while undergoing fMRI scans. Objects varied independently in their affective valence and in their degree of association with other objects (associativity). Analyses revealed an overlapping sensitivity whereby the left mOFC responded both to increasingly positive affective value and to stronger associativity. These two properties individually accounted for mOFC response, even after controlling for their interrelationship. The role of the mOFC is either general enough to encompass associations that link stimuli both with reinforcing outcomes and with other stimuli or abstract enough to use both valence and associativity in conjunction to inform downstream processes related to perception and action. These results may further point to a fundamental relationship between associativity and positive affect. PMID- 23090718 TI - Positive emotion broadens attention focus through decreased position-specific spatial encoding in early visual cortex: evidence from ERPs. AB - Recent evidence has suggested that not only stimulus-specific attributes or top down expectations can modulate attention selection processes, but also the actual mood state of the participant. In this study, we tested the prediction that the induction of positive mood can dynamically influence attention allocation and, in turn, modulate early stimulus sensory processing in primary visual cortex (V1). High-density visual event-related potentials (ERPs) were recorded while participants performed a demanding task at fixation and were presented with peripheral irrelevant visual textures, whose position was systematically varied in the upper visual field (close, medium, or far relative to fixation). Either a neutral or a positive mood was reliably induced and maintained throughout the experimental session. The ERP results showed that the earliest retinotopic component following stimulus onset (C1) strongly varied in topography as a function of the position of the peripheral distractor, in agreement with a near far spatial gradient. However, this effect was altered for participants in a positive relative to a neutral mood. On the contrary, positive mood did not modulate attention allocation for the central (task-relevant) stimuli, as reflected by the P300 component. We ran a control behavioral experiment confirming that positive emotion selectively impaired attention allocation to the peripheral distractors. These results suggest a mood-dependent tuning of position specific encoding in V1 rapidly following stimulus onset. We discuss these results against the dominant broaden-and-build theory. PMID- 23090719 TI - Acceptance and commitment therapy for fibromyalgia: a randomized controlled trial. AB - BACKGROUND: Fibromyalgia (FM) is characterized by widespread pain and co-morbid symptoms such as fatigue and depression. For FM, medical treatments alone appear insufficient. Recent meta-analyses point to the utility of cognitive behaviour therapy (CBT), but effects are moderate. Within the continuous development of CBT, the empirical support for acceptance and commitment therapy (ACT) has increased rapidly. ACT focuses on improving functioning by increasing the patient's ability to act in accordance with personal values also in the presence of pain and distress (i.e., psychological flexibility). However, no study has yet explored the utility of ACT in FM. OBJECTIVES: To evaluate the efficacy of ACT for FM and the role of psychological inflexibility as a mediator of improvement. METHODS: In this randomized controlled trial, ACT was evaluated in comparison to a waiting list control condition. Forty women diagnosed with FM participated in the study. Assessments were made pre- and post-treatment and at 3 months of follow-up. The ACT intervention consisted of 12 weekly group sessions. RESULTS: Significant differences in favour of ACT were seen in pain-related functioning, FM impact, mental health-related quality of life, self-efficacy, depression, anxiety and psychological inflexibility. Changes in psychological inflexibility during the course of treatment were found to mediate pre- to follow-up improvements in outcome variables. CONCLUSIONS: The results correspond with previous studies on ACT for chronic pain and suggest the utility of ACT for FM as well as the role of psychological inflexibility as a mediator of improvement. PMID- 23090720 TI - Safety and early efficacy of irreversible electroporation for hepatic tumors in proximity to vital structures. AB - INTRODUCTION: Irreversible electroporation (IRE) has shown promise for ablation of lesions in proximity to vital structures in the preclinical setting. This study aims to evaluate the safety and efficacy of IRE for hepatic tumors in the clinical setting. METHODS: An IRB approved prospective registry of patients undergoing IRE for hepatic tumors over a 2-year period. Factors analyzed included patient and tumor characteristics, treatment related complications, and local recurrence free survival (LRFS) for ablated lesions. LRFS was calculated according to Kaplan-Meier, with secondary analyses stratified by procedural approach (laparotomy, laparoscopy, and percutaneous) and tumor histology. RESULTS: There were 44 patients undergoing 48 total IRE procedures, 20 colorectal mets, 14 hepatocellular, and 10 other metastatsis. Initial success was achieved in 46 (100%) treatments. Five patients had 9 adverse events, with all complications resolving within 30 days. LRFS at 3, 6, and 12 months was 97.4%, 94.6%, and 59.5%. There was a trend toward higher recurrence rates for tumors over 4 cm (HR 3.236, 95% CI: 0.585-17.891; P = 0.178). CONCLUSIONS: IRE appears to be a safe treatment for hepatic tumors in proximity to vital structures. Further prospective evaluation is needed to determine the optimal effectiveness of IRE in relation to size and technique for IRE of the liver. PMID- 23090721 TI - Introduction to the special issue: subgroup analysis in prevention and intervention research. PMID- 23090722 TI - The acaricidal efficacy of peracetic acid and deltamethrin against the fowl tick, Argas persicus, infesting laying hens. AB - The fowl tick, Argas persicus (Oken), is of veterinary importance as a parasite of poultry and wild birds. The antitick efficacy, in vitro and in vivo, of peracetic acid (PAA) and deltamethrin (DMT) was tested separately against A. persicus through the dipping technique. PAA (0.5 %) was highly efficient against soft tick larvae (A. persicus), resulting in 100 % mortality after 2 min. The lethal concentrations LC(50) and LC(95) were 0.310 and 0.503 %, respectively. The lethal time values LT(50) and LT(95) were 5.34 and 40.00 min, respectively, after treatment with PAA (0.25 %). Two minutes after exposure to DMT, LC(50) and LC(95) values were 0.033 and 0.052 % (33.204 and 51.527 mg/L), respectively. The LT(50) and LT(95) values were 27.03 and 305.46 min, respectively, after treatment with 0.025 % DMT (25 mg/L). After dipping in PAA (0.5 %), the chickens did not show respiratory signs or inflammation on the eyes and/or skin. By contrast, temporary coughing, sneezing, and ocular inflammations without dermatitis were observed in chickens dipped in DMT (0.05 % or 50 mg /L). Seven days posttreatment (PT), the reduction in the percentages of A. persicus infesting laying hens were 99.15 and 63.42 % after dipping in PAA and DMT, respectively. However, complete elimination of the number of ticks occurred after 28 days PT with DMT. PAA inhibits molting effectively (28 %) when compared with that of DMT (52 %). Results indicated that PAA is a more potent and promising acaricide against A. persicus (in vitro and in vivo) than DMT. PMID- 23090723 TI - Detection and characterization of urinary metabolites of boldione by LC-MS/MS. Part I: Phase I metabolites excreted free, as glucuronide and sulfate conjugates, and released after alkaline treatment of the urine. AB - Boldione (1,4-androstadien-3,17-dione) is included in the list of prohibited substances, issued by the World Anti-Doping Agency (WADA). Endogenous production of low concentrations of boldione has also been reported. The objective of this study was to assess boldione metabolism in humans. Detection of boldione metabolites was accomplished by analysis by liquid chromatography coupled to tandem mass spectrometry of urine samples obtained after administration of the drug and subjected to different sample preparation procedures to analyze the different metabolic fractions (free, glucuronides, sulpfates and released in basic media). In addition to boldione, eight metabolites were detected in the free fraction. Four of them were identified by comparison with standards: 6beta hydroxy-boldenone (M3), androsta-1,4,6-triene-3,17-dione (M5), (5alpha)-1 androstenedione (M6) and (5alpha)-1-testosterone (M8). Metabolite M7 was identified as the 5beta-isomer of 1-androstenedione, and metabolites M1, M2 and M4 were hydroxylated metabolites and tentative structures were proposed based on mass spectrometric data. After beta-glucuronidase hydrolysis, five additional metabolites excreted only as conjugates with glucuronic acid were detected: boldenone, (5beta)-1-testosterone (M9), and three metabolites resulting from reduction of the 3-keto group. Boldenone, epiboldenone, and hydroxylated metabolites of boldione, boldenone and 1-testosterone were detected as conjugates with sulfate. In addition, boldione and seven metabolites (boldenone, M2, M3, M4, M5, M7 and M9) increased their concentration in urine after treatment of the urine in alkaline conditions. In summary, 15 boldione metabolites were detected in all fractions. The longer detection time was observed for metabolite M4 after alkaline treatment of the urine, which was detected up to 5 days after boldione administration. PMID- 23090724 TI - Cholesteric liquid crystals with a broad light reflection band. AB - The cholesteric-liquid-crystalline structure, which concerns the organization of chromatin, collagen, chitin, or cellulose, is omnipresent in living matter. In technology, it is found in temperature and pressure sensors, supertwisted nematic liquid crystal displays, optical filters, reflective devices, or cosmetics. A cholesteric liquid crystal reflects light because of its helical structure. The reflection is selective - the bandwidth is limited to a few tens of nanometers and the reflectance is equal to at most 50% for unpolarized incident light, which is a consequence of the polarization-selectivity rule. These limits must be exceeded for innovative applications like polarizer-free reflective displays, broadband polarizers, optical data storage media, polarization-independent devices, stealth technologies, or smart switchable reflective windows to control solar light and heat. Novel cholesteric-liquid-crystalline architectures with the related fabrication procedures must therefore be developed. This article reviews solutions found in living matter and laboratories to broaden the bandwidth around a central reflection wavelength, do without the polarization-selectivity rule and go beyond the reflectance limit. PMID- 23090725 TI - In vitro generation of somaclonal variant plants of sugarcane for tolerance to Fusarium sacchari. AB - KEY MESSAGE : A combination of in vitro culture and mutagenesis using ethyl methanesulfonate (EMS) followed by culture filtrate-mediated selection produced variant sugarcane plants tolerant and resistant to Fusarium sacchari. Eldana saccharina is a destructive pest of the sugarcane crop in South Africa. Fusarium sacchari PNG40 (a fungal strain harmful to E. saccharina) has the potential to be an endophytic biological control agent of the stalk borer. However, the fungus causes Fusarium stalk rot in sugarcane. In the current study, sugarcane plants tolerant and resistant to F. sacchari PNG40 were produced by exposing embryogenic calli to the chemical mutagen ethyl methanesulfonate (EMS), followed by in vitro selection during somatic embryogenesis and plantlet regeneration on media containing F. sacchari culture filtrates (CF). The incorporation of 100 ppm CF in the culture media at the embryo maturation stage, at germination, or at both, resulted in callus necrosis and consequent reduced plantlet yield. Subsequent trimming of the roots of regenerated plants and their exposure to 1,500 ppm CF served as a further selection treatment. Plants produced from EMS-treated calli displayed improved root re-growth in the presence of CF pressure compared with those from non-treated calli. The tolerance of CF-selected plants was confirmed in greenhouse tests by inoculation with F. sacchari PNG40, re-isolation of Fusarium spp. from undamaged tissue of asymptomatic plants and establishment of the identity of fungal isolates as PNG40 using molecular analysis. The restriction of PNG40 presence to the inoculation lesion in some plants suggested their resistance to the fungus. Genotypes exhibiting symptomless endophytic colonization by PNG40 were identified and will be utilised for testing biological control strategies against E. saccharina. PMID- 23090726 TI - Identification of wild soybean (Glycine soja) TIFY family genes and their expression profiling analysis under bicarbonate stress. AB - Wild soybean (Glycine soja L. G07256) exhibits a greater adaptability to soil bicarbonate stress than cultivated soybean, and recent discoveries show that TIFY family genes are involved in the response to several abiotic stresses. A genomic and transcriptomic analysis of all TIFY genes in G. soja, compared with G. max, will provide insight into the function of this gene family in plant bicarbonate stress response. This article identified and characterized 34 TIFY genes in G. soja. Sequence analyses indicated that most GsTIFY proteins had two conserved domains: TIFY and Jas. Phylogenetic analyses suggested that these GsTIFY genes could be classified into two groups. A clustering analysis of all GsTIFY transcript expression profiles from bicarbonate stress treated G. soja showed that there were five different transcript patterns in leaves and six different transcript patterns in roots when the GsTIFY family responds to bicarbonate stress. Moreover, the expression level changes of all TIFY genes in cultivated soybean, treated with bicarbonate stress, were also verified. The expression comparison analysis of TIFYs between wild and cultivated soybeans confirmed that, different from the cultivated soybean, GsTIFY (10a, 10b, 10c, 10d, 10e, 10f, 11a, and 11b) were dramatically up-regulated at the early stage of stress, while GsTIFY 1c and 2b were significantly up-regulated at the later period of stress. The frequently stress responsive and diverse expression profiles of the GsTIFY gene family suggests that this family may play important roles in plant environmental stress responses and adaptation. PMID- 23090727 TI - A new radiopaque embolizing agent for the treatment of endoleaks after endovascular repair: influence of contrast agent on chitosan thermogel properties. AB - A new injectable radiopaque embolizing agent has been developed, based on chitosan thermogelling properties. Different commercial contrast agents (Isovue(r), Visipaque(r), and Conray(r)) were associated with chitosan-beta glycerophosphate. Their impact on gelation kinetic, mechanical properties, radiopacity, and cytotoxicity was tested to evaluate the best candidate and its feasibility for the treatment of endoleaks after endovascular aneurysm repair (EVAR). Addition of contrast agents did not prevent gelation at body temperature, but it significantly increased the viscosity of the solution before gelation, delayed gelation, and reduced the gelation rate. However, using chitosan with a high degree of deacetylation and 20 vol % contrast agent made it possible to obtain a gel with rapid gelation that was visible during X-ray based guided intervention. Hydrogels exhibit relatively low mechanical properties, which are only slightly modified by the addition of contrast agents. In vitro studies have demonstrated rapid release of contrast agents from hydrogels when immersed in a saline solution (>50% within 4 h). This is suitable for embolization, as radiopacity is required only to follow the embolization procedure, while long term radiopacity would hamper further imaging and endoleak detection. Cytotoxicity and osmolality testing of extracts demonstrated some toxicity of products released by the gel during the first few hours, which is mainly related to their hypertonicity. After the first 24 h incubation, hydrogels released no more cytotoxic compounds, suggesting that the hydrogel rapidly becomes biocompatible. Altogether, this study suggests that the new radiopaque thermogels present interesting characteristics as embolizing agents for EVAR, although their mechanical properties require improvement. PMID- 23090728 TI - Real-life evaluation of a human immunodeficiency virus screening algorithm using a single combined p24 antigen-antibody assay. AB - Since May 2010, human immunodeficiency virus (HIV) screening in France has been performed using a single combined fourth-generation assay. One of our major concerns is to verify that this screening strategy is able to diagnose HIV primary infection as soon as possible. Thus, the sensitivity and specificity of this strategy were evaluated on 49,623 serum samples, including 29 primary infections, received for routine HIV testing between September 2010 and November 2011. Specimens were screened using the Enzygnost HIV Integral II enzyme-linked immunosorbent assay (ELISA) kit. All positive sera, according to the manufacturer's recommendations [signal-to-cutoff ratio (S/CO) >= 1] were retested using the Architect HIV Ag/Ab Combo. Moreover, we defined a grey zone (0.5 < S/CO < 1) and sera within this grey zone were retested using the VIDAS HIV DUO Ultra test and HIV-1 RNA was checked by the Abbott RealTime PCR kit. Screening tests were positive for all primary infections. All samples within the grey zone proved VIDAS HIV DUO Ultra and HIV-1 RNA negative. Overall, the ELISA test sensitivity and specificity were 100 and 99.79 %, respectively. The false positive rate was higher when S/CO was in the low range (1 to 5). Adding a second screening test for positive sera reduced the false-positive rate from 0.20 to 0.02 %. HIV screening with a single combined assay did not miss any documented primary infection during this evaluation period, even without extending the positivity zone. PMID- 23090729 TI - Early passage neonatal and adult keratinocytes are sensitive to apoptosis induced by infection with an ICP27-null mutant of herpes simplex virus 1. AB - Herpes simplex virus 1 (HSV-1) is a enveloped, double stranded DNA virus that is the causative agent of various diseases including cold sores, encephalitis, and ocular keratitis. Previous research has determined that HSV-1 modulates cellular apoptotic pathways. Apoptosis is triggered in infected cells early in infection; however, later in the infection the apoptotic response is suppressed due to the expression of several viral apoptotic antagonists. This sets us a delicate balance between pro- and anti-apoptotic processes during the lytic phase of infection. Several studies have demonstrated that the apoptotic balance can be shifted during infection of certain cell types, leading to apoptosis of the infected cells (HSV-1-dependent apoptosis). For example, HEp-2 cells infected with an ICP27-null recombinant HSV-1 virus undergo HSV-1-dependent apoptosis. Differences in the sensitivity to HSV-1-dependent apoptosis have been revealed. Although many tumor cells have been found to be highly sensitive to this apoptotic response, with the exception hematological cells, all primary human cells tested prior to this study have been shown to be resistant to HSV-1 dependent apoptosis. Here, we demonstrate that early passage neonatal and adult human keratinocytes, which are usually the first cells to encounter HSV-1 in human infection and support the lytic stage of the life cycle, display membrane blebbing and ballooning, chromatin condensation, caspase activation, and cleavage of cellular caspase substrates when infected with an ICP27-null recombinant of HSV-1. Furthermore, caspase activation is needed for the efficient apoptotic response. These results suggest that apoptotic machinery may be a target for modulating HSV-disease in patients. PMID- 23090730 TI - Hepatitis C genotype analysis: results in a large veteran population with review of the implications for clinical practice. AB - CONTEXT: Hepatitis C virus (HCV) infects up to 1.8% of the US general population, although the rate is significantly higher in military veterans at 5.4-20%. Early detection and accurate diagnosis are critical as chronic HCV infection can lead to liver cirrhosis and hepatocellular carcinoma. Genotype analysis has both therapeutic and prognostic importance in patients with HCV infections. OBJECTIVE: We compare two versions of a commonly utilized platform for genotype analysis in HCV infections and review the implications of the results for clinical practice. DESIGN: A retrospective review of 9401 genotype results from 2001-2010 were analyzed. All results were obtained from the James A. Haley VA Medical Center, a large referral veterans' healthcare facility. RESULTS: Genotype 1 was identified in 80.1% of samples, genotype 2 in 11.1%, genotype 3 in 7.4%, and genotype 4 in 1.2%. Genotypes 5 and 6 were rarely present in our patient population. Improvements in diagnostic methodologies over the study period resulted in shifts in genotype subtyping. Specifically, upgrading from the Versant HCV genotype assay (LIPA) (Siemens, Tarrytown, NY) to the newer version 2.0 assay resulted in an increase in identification of genotype 1a by 18.5%. CONCLUSIONS: Improved technologies lead to accurate genotype identification and subtyping, both of which have increasingly important prognostic and therapeutic implications. The clinical importance of these results in patients with HCV infections is reviewed. PMID- 23090731 TI - Host genomics and HCV personalized medicine. AB - It is estimated that there are 4.0 million individuals chronically infected with Hepatitis C virus (HCV) in the US. Due to the slow progression of disease, the incidence of HCV has declined in the last two decades. However, it is anticipated that the number of individuals requiring treatment for liver disease associated with HCV will increase for years to come. Until 2011, HCV genotype 1 infections were treated with 48 weeks of pegylated interferon and ribavirin combination therapy; only 50% of patients had a successful outcome. Moreover, patients often withdraw from treatment prematurely because of the high cost and adverse effects of therapy. All of these factors make HCV infection a serious healthcare issue. Recent advances in HCV management include the discovery of host genetic polymorphisms that can predict treatment outcome, as well as the availability of the first direct acting antiviral agents that promise to revolutionize HCV management and increase the likelihood of a favorable treatment outcome. In 2009, multiple independent groups performed genome-wide association studies in HCV infected individuals and identified several single-nucleotide polymorphisms (SNPs) near the IL28B gene that predict the likelihood of both spontaneous and treatment-induced HCV clearance. This article provides an overview of the genome wide association studies that uncovered the role of the IL28B genotype and reviews the clinical utility of IL28B genotyping. PMID- 23090732 TI - Comparison of MagNA Pure 96, Chemagic MSM1, and QIAamp MinElute for hepatitis B virus nucleic acid extraction. AB - This study was designed to compare two automated systems and one manual system for hepatitis B virus (HBV) nucleic acid extraction. The two automated systems were the MagNA Pure 96 system (Roche Applied Science, Manheim, Germany) and the Chemagic system (Chemagen, Baesweiler, Germany), and the manual system was the QIAamp system (Qiagen, Hilden, Germany). Sixty-eight samples that were within the detection range of the Cobas Ampliprep/Cobas TaqMan (CAP/CTM) platform (Roche Molecular Systems, Manheim, Germany) were selected. Extracted viral nucleic acids from the three systems were quantified using an AccuPower HBV Quantitative PCR kit (Bioneer, Daejon, Korea). The MagNA Pure 96 system and QIAamp system did not detect viral loads in one sample. The Chemagic system did not detect low viral loads in nine samples (range, 26-290 IU/mL by the CAP/CTM platform). Comparisons of the viral loads of the samples from the MagNA Pure 96 system, the Chemagic system, and the QIAamp system with those from the CAP/CTM platform yielded correlation coefficients of 0.977, 0.914, and 0.967, respectively. Comparisons of the MagNA Pure 96 system and the Chemagic system with the QIAamp system yielded correlation coefficients of 0.987 and 0.939, respectively. The MagNA Pure 96 system demonstrated better performance than the Chemagic system for HBV nucleic acid extraction. The MagNA Pure 96 system demonstrated comparable performance with the QIAamp system. PMID- 23090733 TI - Cardiovascular risk factors in suburban American late-adolescents: a cross sectional, community-based study. AB - An opportunity for low cost, population-based screening has resulted from the recent promotion of blood donor "value-added" testing. We utilized this opportunity to evaluate key data on cardiovascular risk factors (CVRF) obtained from a sample of late adolescents (16 to 19 years old) from generally affluent suburban communities. We examined non-fasting serum cholesterol and glucose, body mass index (BMI), mean arterial pressure (MAP), determined percentile-based values for these variables for the suburban late-teenage population represented by this sample, and examined potential associations among these parameters. Data were obtained on a cohort of 7,464 males and females divided by age and gender. Percentile values at the 25(th), 50(th), 75(th), 95(th) and 97.5(th) levels were calculated by nonparametric methods. Within gender groups, several small but statistically significant differences in CVRF were noted for different ages. In general, levels of CVRF were substantially higher than expected. BMI data were compared with year 2000 United States Centers for Disease Control and Prevention (CDC) norms, and for all age groups and both genders, significantly higher percentile-based values were noted for the adolescents in this study. Elevations in glucose and cholesterol levels associated significantly with MAP and BMI in the older (18 and 19) age groups. We conclude that late adolescents are displaying a disturbing trend toward dangerous levels of CVRF and that teenagers from affluent suburbs are not exempt from this trend. These data also point out the utility of blood donor "value-added" screening programs in this population. PMID- 23090734 TI - Determination of myeloperoxidase-induced apoAI-apoAII heterodimers in high density lipoprotein. AB - Myeloperoxidase secreted by macrophages and neutrophils in atherosclerotic lesions generates a tyrosyl radical in apolipoprotein (apo) AI, a major protein component of high-density lipoprotein (HDL), thus inducing the formation of apoAI apoAII heterodimers. It can also cause nitration and chlorination of tyrosine residues. Determining the apoAI-apoAII heterodimer could provide useful information as to functional changes in HDL and/or the progression of atherosclerotic lesions. To this end, the apoAI-apoAII heterodimer was identified in normal human serum by immunoblotting; the band intensity was increased by treatment with myeloperoxidase. This apparent increase in heterodimer formation was quantitatively confirmed by ELISA. In normal human serum, a significant correlation between the concentrations of apoAI-apoAII heterodimer and free apoAII (r=0.763), but not free apoAI (r=0.093), was observed, indicating that heterodimer formation is likely induced on HDL particles carrying both apoAI and apoAII (Lp-AI/AII). In preliminary studies, the levels of apoAI-apoAII heterodimer were statistically higher in plasma from subjects with acute myocardial infarction (AMI) as compared to controls. These findings indicate the possibility that the apoAI-apoAII heterodimer, including nitration and chlorination modifications, may serve as an indicator of atherosclerotic lesions. PMID- 23090735 TI - Establishment of two novel ELISA methods for Dermatophagoides farinae-specific IgE detection with recombinant group 2 allergen. AB - Dermatophagoides farinae, or the American house dust mite, is a common cause of allergy and asthma. Current tests for sensitization to D. farinae include an indirect enzyme-linked immunosorbent assay (ELISA) method for specific IgE detection, which, while clinically useful, is time-consuming and has low sensitivity since it uses crude mite extracts. We developed two new ELISA methods to detect the group 2 allergen from D. farinae (Der f 2) and the Der f 2-specific IgE in sera of patients with asthma. Using recombinant Der f 2 protein for the analysis of Der f 2-specific IgE, we tested both indirect ELISA and avidin biotin complex ELISA (ABC-ELISA) methods in 46 patients who were also tested by Pharmacia UniCap. Both of these approaches are more specific than traditional methods using crude mite extracts. These new tests could aid in the laboratory diagnosis of asthma due to sensitization to D. farinae. PMID- 23090736 TI - Comparison of GeneXpert PCR to BD GeneOhm for detecting C. difficile toxin gene in GDH positive toxin negative samples. AB - The need for rapid diagnosis of Clostridium difficile (C. difficile) associated infection in a clinical microbiology laboratory has provided the stimulus for new diagnostic tests and testing protocols. A two-test algorithm has been proposed using assays such as Quik Chek Complete, which detects both C. difficile glutamate dehydrogenase (GDH) and C. difficile toxins A and B, followed by reflex testing of samples having inconclusive results (GDH positive and toxin negative) with PCR for identification of toxin gene specific DNA. The goal of this study was to compare the outcome and efficiency of PCR assays, BD GeneOhm and GeneXpert, for detecting C. difficile toxin B gene in samples that have tested indeterminate for C. difficile by the Quik Chek Complete test. Over a three-month period, a total of 41 cases tested indeterminate by Quik Chek Complete test and were retested by the aforementioned PCR assays. Out of the 41 samples, 36 had matching results in both assays; 19 negative samples and 17 positive samples. In terms of efficiency, GeneXpert was user-friendly and had a turnaround time (TAT) of 45 minutes with two-minute specimen processing compared to BD GeneOhm which had a TAT of 75 to 90 minutes. PMID- 23090737 TI - SMAD4 haploinsufficiency associates with augmented colonic inflammation in select humans and mice. AB - SMAD4 is a common mediator of the TGF-beta signaling pathway. One of the members of this pathway, TGF-beta 1, has an important role in controlling gut inflammation in relation to the continuous stimulation of the intestinal microbiota. SMAD4 haploinsufficiency in humans has been linked to juvenile polyposis hereditary hemorrhagic telangiectasia syndrome (JP/HHT; OMIM#17505). Hematochezia and colonic mucosal inflammation suggestive of inflammatory bowel diseases (IBD) have been reported in JP/HHT. Stimulated by recent experience with two affected pediatric patients presented here, we explored the potential role of Smad4 haploinsufficiency in a murine model of colonic inflammation. Smad4(+/-) mice were maintained on a mixed C57/129SvEv background. Chronic colitis was induced with repeated administration of dextran sulfate sodium (DSS) in drinking water. The colonic mucosal microbiota was interrogated by massively parallel pyrosequencing of the bacterial 16S rRNA gene. 66.7% of Smad4(+/-) mice were sensitive to DSS colitis compared to 14.3% of wild type (Chi-Square p=0.036). The augmented colitis was associated with microbiota separation in the Smad4(+/-) mice. Enterococcus and Enterococcus faecalis specifically was increased in abundance in the colitis-prone animals. Smad4 haploinsufficiency can associate with increased susceptibility to large bowel inflammation in mammals with variable penetrance in association with the colonic mucosal microbiota. These findings may reveal implications not only towards colonic inflammation in the setting of SMAD4 haploinsufficiency, but for colorectal cancer as well. PMID- 23090738 TI - Rhabdomyomatous differentiation in Wilms tumor pulmonary metastases: a case report and literature review. AB - While sparsely reported in the literature, Wilms tumor may differentiate into more mature mesenchymal tissue types, such as skeletal muscle, following chemotherapy. The frequency of this event is unknown. Chemotherapy and radiation may induce cytodifferentiation of Wilms tumor cells or select for the survival of less mitotically active cells. In follow-up biopsies, the presence of rhabdomyomatous differentiation can confound the histologic diagnosis. Furthermore, these differentiated tumors appear to be more resistant to chemotherapy, thus biopsy and positron emission tomography scans following chemotherapy and radiation may prevent unnecessary treatment. We report an unusual case of Wilms tumor in a 21- year-old man with rhabdomyomatous differentiation of pulmonary metastases after chemotherapy, which presented a challenge during frozen section diagnosis. PMID- 23090739 TI - Littoral cell angioma: diagnosis by image-guided biopsy. AB - We report a case of littoral cell angioma (LCA) diagnosed by percutaneous core needle biopsy during the workup of a patient with multiple splenic lesions. Splenectomy was not performed. The patient has remained asymptomatic during 4 years of follow-up. Our findings raise interesting questions about the feasibility of core needle biopsy for the diagnosis of LCA. Clinicians should be aware of LCA as an unusual benign entity in the differential diagnosis of multiple splenic lesions. PMID- 23090740 TI - Parotid gland abscess caused by Haemophilus paraphrophilus: a case report. AB - Human diseases caused by Haemophilus paraphrophilus (H.paraphrophilus) are unusual. The following case report describes a 67-year-old man who presented with pain and swelling of the right side of the face. Fine needle aspiration suggested a parotid gland abscess. Microbiological studies identified H.paraphrophilus. This is the first time a parotid abscess has been found to be caused by this organism. PMID- 23090741 TI - SLC22A5 mutations in a patient with systemic primary carnitine deficiency: the first Korean case confirmed by biochemical and molecular investigation. AB - Systemic primary carnitine deficiency (CDSP) is a rare autosomal recessive disorder that presents episodic periods of hypoketotic hypoglycemia. The main symptoms of CDSP are skeletal and cardiac myopathy. CDSP is caused by a defect in plasma membrane uptake of carnitine, ultimately caused by the SLC22A5 gene. We report the case of a Korean patient with CDSP. He had an abnormal free carnitine level of 5.56 MUmol/L (reference range, RR 10.4~87.1 MUmol/L) and a palmitoylcarnitine level of 0.27 MUmol/L (RR 0.5~9.7 MUmol/L) in a newborn screening test. The patient showed an ammonia level of 129.4 ug/dL (RR, 25~65 ug/dL), a lactate level of 4.5 mmol/L (RR, 0.5-2.2 mmol/L), and a free carnitine level of 10.3 MUmol/L (RR, 36-74 MUmol/L) in blood. After PCR-sequencing analysis of the SLC22A5 gene, the patient was found to be a compound heterozygote for c.506G>A (p.R169Q) and c.1400C>G (p.S467C) mutations. These missense mutations are reported previously. The patient was started on L-carnitine supplement after CDSP diagnosis. The patient was treated with L-carnitine to reach a normal free carnitine level and has remained asymptomatic up to the current age of 21 months. The plasma free carnitine level normalized to 66.6 MUmol/L at 4 weeks after treatment. To the best of our knowledge, this is the first report of a CDSP patient confirmed by molecular genetic investigation. PMID- 23090742 TI - Detection of a UL97 gene mutation conferring ganciclovir resistance in human cytomegalovirus: prevalence of the D605E polymorphism in Korean immunocompromised patients. AB - The purpose of this study was to determine the prevalence of ganciclovir (GCV) resistance-conferring human cytomegalovirus (HCMV) UL97 gene mutations and UL97 polymorphisms in Korean immunocompromised patients. A partial sequence of the HCMV UL97 gene spanning codons 430 to 644 was amplified in 77 samples from 32 patients by nested polymerase chain reaction (PCR) and sequenced directly. A cysteine-to-glycine mutation at codon 592 (C592G) conferring GCV resistance was detected in a 2-year-old girl after a 40-day GCV treatment, but overall, UL97 gene mutations associated with GCV resistance were rare in GCV-treated patients. An aspartate-to-glutamate substitution at codon 605 (D605E) was detected in 29 of 32 patients (90.6%), but 17 of 19 (89.5%) GCV-naive patients also possessed D605E. These findings indicate that the D605E polymorphism, which is frequent in Korean patients and thus may be a natural sequence variant, could be a genetic marker for HCMV in Asian countries. PMID- 23090743 TI - Pedometer step counts and oxidized low-density lipoprotein levels among asymptomatic subjects. AB - While daily step counts are considered to be a useful measure of cardiovascular health, the biochemical predictors of step counts have not been fully characterized. This study investigated the correlation between pedometer determined daily step counts and cardiometabolic variables, including the serum level of malondialdehyde-modified low-density lipoprotein (MDA-LDL), among asymptomatic subjects (n = 50, mean age 63 years). Simple and stepwise multiple linear correlation tests revealed that there was a significant inverse correlation between the step counts and MDA-LDL levels (r = -0.41, P < 0.01; beta = -0.38, P < 0.01). The data suggest that daily steps may be beneficially associated with atherosclerosis in correlation with reduced oxidized low-density lipoprotein, and in addition that the MDA-LDL level may be used as a measure reflective of the daily steps. PMID- 23090744 TI - Generation and characterization of a tamoxifen inducible Msx1(CreERT2) knock-in allele. AB - Msx1, a member of the Msx gene family, encodes a homeodomain transcription factor and plays critical roles during mouse development in numerous organs. By homologous recombination, we generated a new Msx1 allele (Msx1(CreERT2) ) in which the CreERT2 fusion protein is produced in place of the endogenous Msx1 protein. Using different reporter mouse strains and appropriate tamoxifen treatments, we show that, in mice bearing the Msx1(CrERT2) allele, CreERT2 is capable to induce loxP genomic recombination specifically in Msx1-expressing cells and that this can be obtained during embryonic development as well as after birth. These results show that this new mouse line can be used for lineage tracing of Msx1-expressing cells and their descendants and, combined with Cre inducible Msx null alleles, for the analysis of Msx1 and/or Msx2 functions in the Msx1-expressing organs, in a time-dependant manner. PMID- 23090745 TI - (1)H NMR based profiling of spent culture media cannot predict success of implantation for day 3 human embryos. AB - BACKGROUND: Identification of a non-invasive technique to assess embryo implantation potential in assisted reproduction would greatly increase success rates and lead more efficiently to single embryo transfer. Early studies suggested metabonomic analysis of spent culture media could improve embryo selection. The goal of this study is to assess if embryo implantation can be predicted based on proton nuclear magnetic resonance ((1)H NMR) profiles of spent embryo culture media from patients undergoing transfer of multiple embryos on cycle day 3. METHOD: We conducted a retrospective study in an academic assisted reproduction technology (ART) program and analyzed the data in a university research center. Two hundred twenty-eight spent culture media samples originating from 108 patients were individually analyzed. Specifically, five distinct sets (1 to 5) of different types of spent media samples (volume ~14 MUL) from embryos that resulted in clinical pregnancy (positive heart rate at 6 weeks gestation) (n (1) = 29; n (2) = 19; n (3) = 9; n (4) = 12; n (5) = 33; n (total) = 102) and from embryos that did not implant (n (1) = 28; n (2) = 29; n (3) = 18; n (4) = 15; n (5) = 36; n (total) = 126) were collected on day 3 of embryo growth. The media samples were profiled using (1)H NMR spectroscopy, and the NMR profiles of sets 1 to 5 were subject to standard uni- and multi-variate data analyses in order to evaluate potential correlation of profiles with implantation success. RESULTS: For set 1 of the media samples, a borderline class separation of NMR profiles was obtained by use of principal component analysis (PCA) and logistic regression. This tentative class separation could not be repeated and validated in any of the other media sets 2 to 5. CONCLUSIONS: Despite the rigorous technical approach, (1)H NMR based profiling of spent culture media cannot predict success of implantation for day 3 human embryos. PMID- 23090748 TI - Successful implementation of the stepwise layer-by-layer growth of MOF thin films on confined surfaces: mesoporous silica foam as a first case study. AB - Here we report the successful growth of highly crystalline homogeneous MOF thin films of HKUST-1 and ZIF-8 on mesoporous silica foam, by employing a layer-by layer (LBL) method. The ability to control and direct the growth of MOF thin films on confined surfaces, using the stepwise LBL method, paves the way for new prospective applications of such hybrid systems. PMID- 23090747 TI - The psychometric testing of the Thai version of the Health Utilities Index in patients with ischemic heart disease. AB - The HEALTH UTILITIES INDEX((r)) (HUI((r))) is a family of systems designed to measure utility scores of health-related quality of life for comprehensive health states. There are two current HUI systems: HUI2 and HUI3. Since no Thai version of self-administered HUI was available, the study objective was to translate and test the psychometric properties of the HUI self-complete Thai-language questionnaire in terms of practicality, reliability, validity and responsiveness. A convenience sample of 216 outpatients with ischemic heart disease (IHD) was selected. Mean age was 60.3 +/- 7.2 (range 37-77) and 37.2% were males. The floor and ceiling effects of the total scores for both HUI were <15%. The intraclass correlation coefficients were from moderate to high for all attributes and total scores. The correlations of HUI2 and HUI3 when compared with the EQ-5D and MacNew global scores were high (Spearman's rho > 0.5, P < 0.001). Discriminant validity was proved among three groups of different specific activity scale classes (P < 0.001). The effect size was the highest (0.92) in the patients reporting worsened health status assessed by the HUI2. In conclusion, both of the HUIs demonstrated conditionally satisfactory psychometric properties in the patients with IHD. PMID- 23090749 TI - Decisional separability, model identification, and statistical inference in the general recognition theory framework. AB - Recent work in the general recognition theory (GRT) framework indicates that there are serious problems with some of the inferential machinery designed to detect perceptual and decisional interactions in multidimensional identification and categorization (Mack, Richler, Gauthier, & Palmeri, 2011). These problems are more extensive than previously recognized, as we show through new analytic and simulation-based results indicating that failure of decisional separability is not identifiable in the Gaussian GRT model with either of two common response selection models. We also describe previously unnoticed formal implicational relationships between seemingly distinct tests of perceptual and decisional interactions. Augmenting these formal results with further simulations, we show that tests based on marginal signal detection parameters produce unacceptably high rates of incorrect statistical significance. We conclude by discussing the scope of the implications of these results, and we offer a brief sketch of a new set of recommendations for testing relationships between dimensions in perception and response selection in the full-factorial identification paradigm. PMID- 23090751 TI - Summaries for patients. Menopausal hormone therapy to prevent chronic conditions: U.S. Preventive Services Task Force recommendation statement. PMID- 23090750 TI - Action enhances auditory but not visual temporal sensitivity. AB - People naturally dance to music, and research has shown that rhythmic auditory stimuli facilitate production of precisely timed body movements. If motor mechanisms are closely linked to auditory temporal processing, just as auditory temporal processing facilitates movement production, producing action might reciprocally enhance auditory temporal sensitivity. We tested this novel hypothesis with a standard temporal-bisection paradigm, in which the slope of the temporal-bisection function provides a measure of temporal sensitivity. The bisection slope for auditory time perception was steeper when participants initiated each auditory stimulus sequence via a keypress than when they passively heard each sequence, demonstrating that initiating action enhances auditory temporal sensitivity. This enhancement is specific to the auditory modality, because voluntarily initiating each sequence did not enhance visual temporal sensitivity. A control experiment ruled out the possibility that tactile sensation associated with a keypress increased auditory temporal sensitivity. Taken together, these results demonstrate a unique reciprocal relationship between auditory time perception and motor mechanisms. As auditory perception facilitates precisely timed movements, generating action enhances auditory temporal sensitivity. PMID- 23090752 TI - The role of attribution of trauma responsibility in posttraumatic stress disorder following motor vehicle accidents. AB - BACKGROUND: Motor vehicle accidents (MVAs) are highly prevalent and associated with adverse psychological outcomes. METHODS: The present study used data from the National Comorbidity Survey-Replication (NCS-R) to examine the association between injury, role in an MVA (driver/nondriver), attributions of responsibility for the accident, and posttraumatic stress disorder (PTSD), amongst 165 MVA survivors. RESULTS: Findings indicated that drivers with external attributions of the MVA (i.e. who considered others to be at fault for the MVA) were significantly more likely to have a diagnosis of PTSD than drivers with internal attributions (i.e. considering themselves to be at fault) and nondrivers with external attributions of the accident. Further, serious injury sustained in the accident was related to greater likelihood of developing PTSD. CONCLUSIONS: External attributions for the MVA among drivers, as well as serious injury during the accident, were related to higher rates of PTSD. The present findings have implications for models that highlight the importance of posttraumatic cognitions in contributing to mental health following a traumatic event. PMID- 23090753 TI - Immunohistochemical evidence for the relationship between microglia and GnRH neurons in the preoptic area of ovariectomized rats with and without steroid replacement. AB - Prostaglandins (PGs), whose synthesis is catalyzed by the rate-limiting enzyme cyclooxygenase (COX) including COX-1 and COX-2, are among the important mediators involved in the regulation of gonadotropin-releasing hormone (GnRH) secretion. However, the cellular origin of PGs remains obscure in terms of its relationship to GnRH neurons. The present study was therefore aimed to clarify the anatomical relationship between COX-1-producing microglia and GnRH neurons in the preoptic area (POA), and to examine possible influence of ovarian steroids. We performed a triple labeled immunofluorescent histochemistry of COX-1, CD11b (a specific marker for microglia) and GnRH in the POA of ovarian steroid-primed and non primed ovariectomized rats. The result confirmed our previous study suggesting COX-1 immunoreactivity in the vicinity of, but not within, GnRH neurons in the POA. COX-1 around GnRH cells was entirely (100%) localized in cells containing CD11b regardless of steroid replacement in ovariectomized rats. These CD11b immunoreactive cells had small cell bodies and highly branched fibers characteristic of ramified microglia. Three-dimensional reconstruction of confocal images revealed close proximity of some COX-1-containing microglia and GnRH neurons. These results showed selective and constitutive expression of COX-1 in ramified microglia in the vicinity of GnRH neurons, providing evidence for intercellular communication, mediated by PGs, from microglia to GnRH cells. PMID- 23090755 TI - Preserving integrity in the face of performance threat: self-affirmation enhances neurophysiological responsiveness to errors. AB - Self-affirmation produces large effects: Even a simple reminder of one's core values reduces defensiveness against threatening information. But how, exactly, does self-affirmation work? We explored this question by examining the impact of self-affirmation on neurophysiological responses to threatening events. We hypothesized that because self-affirmation increases openness to threat and enhances approachability of unfavorable feedback, it should augment attention and emotional receptivity to performance errors. We further hypothesized that this augmentation could be assessed directly, at the level of the brain. We measured self-affirmed and nonaffirmed participants' electrophysiological responses to making errors on a task. As we anticipated, self-affirmation elicited greater error responsiveness than did nonaffirmation, as indexed by the error-related negativity, a neural signal of error monitoring. Self-affirmed participants also performed better on the task than did nonaffirmed participants. We offer novel brain evidence that self-affirmation increases openness to threat and discuss the role of error detection in the link between self-affirmation and performance. PMID- 23090756 TI - The gargle effect: rinsing the mouth with glucose enhances self-control. PMID- 23090754 TI - Expression of glucocorticoid-induced leucine zipper (GILZ) in cardiomyocytes. AB - Glucocorticoids (GCs) are frequently prescribed pharmacological agents most notably for their immunosuppressive effects. Endogenous GCs mediate biological processes such as energy metabolism and tissue development. At the cellular level, GCs bind to the glucocorticoid receptor (GR), a cytosolic protein that translocates to the nuclei and functions to alter transcription upon ligand binding. Among a long list of genes activated by GCs is the glucocorticoid induced leucine zipper (GILZ). GC-induced GILZ expression has been well established in lymphocytes and mediates GC-induced apoptosis. Unlike lymphocytes, cardiomyocytes respond to GCs by gaining resistance against apoptosis. We determined GILZ expression in cardiomyocytes in vivo and in vitro. Expression of GILZ in mouse hearts as a result of GC administration was confirmed by Western blot analyses. GCs induced dose- and time-dependent elevation of GILZ expression in primary cultured rat cardiomyocytes, with dexamethasone (Dex) as low as 0.1 MUM being effective. Time course analysis indicated that GILZ protein levels increased at 8 h and peaked at 48 h after exposure to 1 MUM Dex. H9c2(2-1) cell line showed a similar response of GILZ induction by Dex as primary cultured rat cardiomyocytes, providing a convenient model for studying the biological significance of GILZ expression. With corticosterone (CT), an endogenous form of corticosteroids in rodents, 0.1-2.5 MUM was found to induce GILZ in H9c2(2-1) cells. Time course analysis with 1 MUM CT indicated induction of GILZ at 6 h with peak expression at 18 h. Inhibition of the GR by mifepristone led to blunting of GILZ induction by GCs. Our data demonstrate GILZ induction in cardiomyocytes both in vivo and in vitro by GCs, pointing to H9c2(2-1) cells as a valid model for studying the biological function of GILZ in cardiomyocytes. PMID- 23090757 TI - Female sex is an independent risk factor for reduced overall survival in bladder cancer patients treated by transurethral resection and radio- or radiochemotherapy. AB - PURPOSE: To evaluate sex as a possible prognostic factor in bladder cancer patients treated with transurethral resection (TURBT) and radio- (RT) or radiochemotherapy (RCT). METHODS: Kaplan-Meier analyses and multiple Cox proportional hazards regression analyses were performed to analyze sex as a possible prognostic factor on the overall (OS) and cancer-specific (CSS) survival of 386 male and 105 female patients who underwent TURBT and RCT or RT with curative intent between 1982 and 2007. RESULTS: After a follow-up of 5 years, female sex demonstrated a hazard ratio (HR) of 1.79 (95 % CI 1.24-2.57) for OS; for CSS, the HR was 2.4 (95 % CI 1.52-3.80). Sex was an adverse prognosticator of both OS and CSS independent from age at diagnosis, cT stage, grading, concurrent cis, LVI, focality, therapy response, resection status and therapy mode. Kaplan Meier analysis showed significantly reduced OS of women compared with men, with a median survival of 2.3 years for female patients and 5.1 years for male patients (p = 0.045, log-rank test). The estimated median CSS was 7.1 years for female patients and 12.7 years for male patients (p = 0.11, log-rank test). CONCLUSIONS: Female sex is an independent prognostic factor for reduced OS and CSS in bladder cancer patients treated by TURBT and RT or RCT. These data are in agreement with those reported for OS after radical cystectomy in muscle-invasive bladder cancers. Therefore, further studies are strongly warranted to obtain more information about molecular differences regarding sex-specific carcinogenesis in bladder cancer and about possible therapeutic considerations. PMID- 23090758 TI - Growth of calcium phosphates on magnesium substrates for corrosion control in biomedical applications via immersion techniques. AB - Magnesium (Mg) has been suggested as a revolutionary biodegradable replacement for current permanent metals used in orthopedic applications. Current investigations concentrate on the control of the corrosion rate to match bone healing. Calcium phosphate coatings have been a recent focus of these investigations through various coating protocols. Within this investigation, an in situ crystallization technique was utilized as an inexpensive and relatively simple method to produce a brushite and monetite coating on pure Mg. Coatings were characterized using energy dispersive spectroscopy, glancing angle X-ray diffraction and field emission scanning electron microscopy. Corrosion protection properties of the coatings were assessed in physiological buffers, Earles balanced salt solution, minimum essential media, and minimum essential media containing serum albumin, over a 4-week period. Using this novel coating protocol, our findings indicate brushite and monetite coated Mg to have significant corrosive protective effects when compared with its uncoated counterpart whilst maintaining high coating substrate adhesion, homogeneity, and reproducibility. PMID- 23090760 TI - Enhanced charge carrier mobility in two-dimensional high dielectric molybdenum oxide. AB - We demonstrate that the energy bandgap of layered, high-dielectric alpha-MoO(3) can be reduced to values viable for the fabrication of 2D electronic devices. This is achieved through embedding Coulomb charges within the high dielectric media, advantageously limiting charge scattering. As a result, devices with alpha MoO(3) of ~11 nm thickness and carrier mobilities larger than 1100 cm(2) V(-1) s( 1) are obtained. PMID- 23090759 TI - Contrasting impacts of different-sized herbivores on species richness of Mediterranean annual pastures differing in primary productivity. AB - Vertebrate herbivores can be key determinants of grassland plant species richness, although the magnitude of their effects can largely depend on ecosystem and herbivore characteristics. It has been demonstrated that the combined effect of primary productivity and body size is critical when assessing the impact of herbivores on plant richness of perennial-dominated grasslands; however, the interaction of site productivity and herbivore size as determinants of plant richness in annual-dominated pastures remains unknown. We experimentally partitioned primary productivity and herbivore body size (sheep and wild rabbits) to study the effect of herbivores on the plant species richness of a Mediterranean semiarid annual plant community in central Spain over six years. We also analyzed the effect of grazing and productivity on the evenness and species composition of the plant community, and green cover, litter, and plant height. We found that plant richness was higher where the large herbivore was present at high-productivity sites but barely changed at low productivity. The small herbivore did not affect species richness at either productivity site despite its large effects on species composition. We propose that adaptations to resource scarcity and herbivory prevented plant richness changes at low-productivity sites, whereas litter accumulation in the absence of herbivores decreased plant richness at high productivity. Our results are consistent with predictions arising from a long history of grazing and highlight the importance of both large and small herbivores to the maintenance of plant diversity of Mediterranean annual-dominated pastures. PMID- 23090761 TI - Remembrance of Ray Rappaport, pioneer in the study of cytokinesis. PMID- 23090763 TI - Down regulation of CAII is associated with tumor differentiation and poor prognosis in patients with pancreatic cancer. AB - BACKGROUND AND OBJECTIVES: Altered expression of carbonic anhydrase (CA)I and II associated with human carcinogenesis. But there was no definite study investigating their expression for clinical significance in pancreatic cancer and effect of the CA inhibitor acetazolamide (AZ) on regulation biological behavior of pancreatic cancer cells. METHODS: Immunohistochemistry, immunofluorescence, immunoblot, and qRT-PCR were used to detect CAI, II, and p53 expression. Tumor cell viability, apoptosis, and invasion assays were used to investigate the effect of AZ on pancreatic cancer cells. RESULTS: Expression of CAI and p53 was increased in pancreatic cancer than that in paired non-cancerous tissues (P = 0.021; P = 0.007), whereas CAII was down-regulated in pancreatic cancer (P = 0.001). CAI overexpression was associated with tumor differentiation and negatively with vascular invasion (P = 0.015 and P = 0.018, respectively), while overexpression of CAII was associated with tumor differentiation (P = 0.017) and a better prognosis of pancreatic cancer patients (P = 0.017), and was an independent prognostic indicator (P = 0.011). p53 overexpression was related with lymph node metastasis (P = 0.032) and TNM stage (P = 0.016). Treatment with AZ inhibited tumor cell validity, invasion, and induced apoptosis in some of six pancreatic cancer cells. CONCLUSION: This study suggests the clinical significance of CAI, CAII and p53 expression in pancreatic cancer and provides evidence for AZ as a potential target for controlling pancreatic cancer. PMID- 23090764 TI - Confidence intervals for the difference in paired Youden indices. AB - Comparison of accuracy between two diagnostic tests can be implemented by investigating the difference in paired Youden indices. However, few literature articles have discussed the inferences for the difference in paired Youden indices. In this paper, we propose an exact confidence interval for the difference in paired Youden indices based on the generalized pivotal quantities. For comparison, the maximum likelihood estimate-based interval and a bootstrap based interval are also included in the study for the difference in paired Youden indices. Abundant simulation studies are conducted to compare the relative performance of these intervals by evaluating the coverage probability and average interval length. Our simulation results demonstrate that the exact confidence interval outperforms the other two intervals even with small sample size when the underlying distributions are normal. A real application is also used to illustrate the proposed intervals. PMID- 23090765 TI - An electrospun polydioxanone patch for the localisation of biological therapies during tendon repair. AB - Rotator cuff tendon pathology is thought to account for 30-70 % of all shoulder pain. For cases that have failed conservative treatment, surgical re-attachment of the tendon to the bone with a non-absorbable suture is a common option. However, the failure rate of these repairs is high, estimated at up to 75 %. Studies have shown that in late disease stages the tendon itself is extremely degenerate, with reduced cell numbers and poor matrix organisation. Thus, it has been suggested that adding biological factors such as platelet rich plasma (PRP) and mesenchymal stem cells could improve healing. However, the articular capsule of the glenohumeral joint and the subacromial bursa are large spaces, and injecting beneficial factors into these sites does not ensure localisation to the area of tendon damage. Thus, the aim of this study was to develop a biocompatible patch for improving the healing rates of rotator cuff repairs. The patch will create a confinement around the repair area and will be used to guide injections to the vicinity of the surgical repair. Here, we characterised and tested a preliminary prototype of the patch utilising in vitro tools and primary tendon derived cells, showing exceptional biocompatibility despite rapid degradation, improved cell attachment and that cells could migrate across the patch towards a chemo-attractant. Finally, we showed the feasibility of detecting the patch using ultrasound and injecting liquid into the confinement ex vivo. There is a potential for using this scaffold in the surgical repair of interfaces such as the tendon insertion in the rotator cuff, in conjunction with beneficial factors. PMID- 23090766 TI - Operating characteristics of alternative statistical methods for detecting gene by-measured environment interaction in the presence of gene-environment correlation in twin and sibling studies. AB - It is likely that all complex behaviors and diseases result from interactions between genetic vulnerabilities and environmental factors. Accurately identifying such gene-environment interactions is of critical importance for genetic research on health and behavior. In a previous article we proposed a set of models for testing alternative relationships between a phenotype (P) and a putative moderator (M) in twin studies. These include the traditional bivariate Cholesky model, an extension of that model that allows for interactions between M and the underling influences on P, and a model in which M has a non-linear main effect on P. Here we use simulations to evaluate the type I error rates, power, and performance of the Bayesian Information Criterion under a variety of data generating mechanisms and samples sizes (n = 2,000 and n = 500 twin pairs). In testing the extension of the Cholesky model, false positive rates consistently fell short of the nominal Type I error rates ([Formula: see text]). With adequate sample size (n = 2,000 pairs), the correct model had the lowest BIC value in nearly all simulated datasets. With lower sample sizes, models specifying non linear main effects were more difficult to distinguish from models containing interaction effects. In addition, we provide an illustration of our approach by examining possible interactions between birthweight and the genetic and environmental influences on child and adolescent anxiety using previously collected data. We found a significant interaction between birthweight and the genetic and environmental influences on anxiety. However, the interaction was accounted for by non-linear main effects of birthweight on anxiety, verifying that interaction effects need to be tested against alternative models. PMID- 23090767 TI - High-fat food, sympathetic nerve activity, and hypertension: danger soon after the first bite? PMID- 23090768 TI - Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension. AB - The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type-specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40(fl/fl)). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40(fl/fl):Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40(fl/fl):Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40(fl/fl) controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40. PMID- 23090769 TI - Large artery stiffening and remodeling are independently associated with all cause mortality and cardiovascular events in chronic kidney disease. AB - Chronic kidney disease, even at moderate stages, is characterized by a high incidence of cardiovascular events. Subclinical damage to large arteries, such as increased arterial stiffness and outward remodeling, is a classical hallmark of patients with chronic kidney disease. Whether large artery stiffness and remodeling influence the occurrence of cardiovascular events and the mortality of patients with chronic kidney disease (stages 2-5) is still debated. This prospective study included 439 patients with chronic kidney disease (mean age, 59.8 +/- 14.5 years) with a mean measured glomerular filtration rate of 37 mL/min per 1.73 m(2). Baseline aortic stiffness was estimated through carotid-femoral pulse wave velocity measurements; carotid stiffness, diameter, and intima-media thickness were measured with a high-resolution echotracking system. For the overall group of patients, the 5-year estimated survival and cumulative incidence of cardiovascular events were 87% and 16%, respectively. In regression analyses adjusted on classical cardiovascular and renal risk factors, aortic stiffness remained significantly associated with all-cause mortality (for 1 SD, Cox model derived relative risk [95% CI], 1.48 [1.09-2.02]) and with fatal and nonfatal cardiovascular events (for 1 SD, Fine and Gray competing risks model-derived relative risk [95% CI], 1.35 [1.05-1.75]). Net reclassification improvement index was significant (29.0% [2.3-42.0%]). Carotid internal diameter was also independently associated with all-cause mortality. This study shows that increased aortic stiffness and carotid internal diameter are independent predictors of mortality in patients with stages 2 to 5 chronic kidney disease and that aortic stiffness improves the prediction of the risk. PMID- 23090770 TI - Leukocyte-dependent responses of the microvasculature to chronic angiotensin II exposure. AB - Angiotensin II (Ang II) contributes to the pathogenesis of hypertension and other cardiovascular diseases. Ang II induces a pro-oxidative, proinflammatory, and prothrombogenic phenotype in vascular endothelial cells. Although the peptide promotes the recruitment of leukocytes and platelets and induces oxidative stress in the microvasculature, it remains unclear whether and how the blood cell recruitment is linked to the production of reactive oxygen species. In this study, we addressed the contributions of Ang II type 1 receptors (AT(1)r) and gp91(phox) to the recruitment of leukocytes and platelets and reactive oxygen species production in venules during chronic (2-week) infusion of Ang II in wild type (WT) and mutant mice. Intravital video microscopy was used to measure the adhesion and emigration of leukocytes, the adhesion of fluorescently labeled platelets, and dihydrorhodamine oxidation (a measure of oxidative stress) in cremaster muscle postcapillary venules. In WT mice, Ang II infusion induced a time-dependent increase in the adhesion of leukocytes and platelets and enhanced reactive oxygen species production in venules. These changes in blood cell adhesion and reactive oxygen species production were not observed in AT(1)r(-/-) mice, AT(1)r(-/-) bone marrow chimeras (blood cells deficient in AT(1)r), gp91(phox-/-) mice, gp91(phox-/-) chimeras (blood cells or endothelial cells deficient in gp91(phox)), and in WT mice rendered granulocytopenic via intraperitoneal injection of antimouse granulocyte receptor 1 antibody. Thrombocytopenic WT mice (platelets depleted by intraperitoneal injection of rabbit antimouse thrombocyte antiserum) responded similar to WT mice. These findings implicate leukocyte-associated AT(1)r and gp91(phox) in the induction of the pro-oxidative, proinflammatory, and prothrombogenic phenotype assumed by microvessels that is chronically exposed to elevated Ang II. PMID- 23090771 TI - Quantitative polymerase chain reaction-based analysis of podocyturia is a feasible diagnostic tool in preeclampsia. AB - Preeclampsia is a significant cause of maternal and fetal morbidity and mortality worldwide. A clinically useful screening test that can predict development of preeclampsia at an early stage is urgently needed. The detection of podocyturia by immunohistochemistry after cell culture has been noted as a reliable marker for preeclampsia. However, this method is laborious and carries the risk of cell culture contamination. The aim of this study was to investigate the diagnostic value of quantitative polymerase chain reaction as a rapid method to detect preeclampsia. Clean-catch urine samples were collected from preeclamptic (n=35), healthy pregnant (n=34), and healthy nonpregnant (n=12) women. Furthermore, a control group of women with gestational hypertension (n=5) was included. Quantitative polymerase chain reaction analysis was performed for podocyte specific markers. Receiver operating characteristic curve analyses were performed. Significantly elevated mRNA levels of nephrin, podocin, and vascular endothelial growth factor were detected in preeclamptic women compared with healthy pregnant and healthy nonpregnant controls. In addition, significantly elevated levels of nephrin mRNA were detected in urine of preeclamptic women compared with women with gestational hypertension. A positive correlation (rho=0.82; P<0.0001) was observed between nephrin and vascular endothelial growth factor mRNA levels in preeclamptic women. Receiver operating characteristic curve analyses demonstrated a strong ability of this method to discriminate between the different study groups. Quantitative polymerase chain reaction analysis of podocyte-specific molecules in urine samples is a rapid and reliable method to quantify podocyturia. We demonstrate that this method distinguishes preeclamptic patients from healthy controls and women with gestational hypertension. This method may be a tool for the detection of preeclampsia at an earlier stage, thereby preventing maternal and fetal morbidity and mortality. PMID- 23090772 TI - Angiotensin II type 2 receptor stimulation initiated after stroke causes neuroprotection in conscious rats. AB - We have demonstrated previously that pretreatment with an angiotensin II type 2 receptor (AT(2)R) agonist is neuroprotective against a subsequent stroke independent of any changes in blood pressure. Therefore, in the current study, we have examined the potential neuroprotective effect of AT(2)R stimulation initiated after stroke induction to mimic the clinical setting. Intracerebroventricular administration of the AT(2)R agonist CGP42112 was commenced 6 hours after an ischemic stroke had been induced in conscious spontaneously hypertensive rats. CGP42112 given over 4 doses in the same rats (3 ug/kg per dose centrally) at 6, 24, 48, and 72 hours after stroke induction reduced total infarct volume (32 +/- 13 mm(3) versus vehicle, 170 +/- 49 mm(3); P<0.05) and improved motor function. Furthermore, we have demonstrated that AT(2)R stimulation after stroke increased neuronal survival, decreased apoptosis, and caused an increase in the number of activated microglia in the core region of damage. The effects of CGP42112 were partially reversed with the coadministration of an AT(2)R antagonist, PD123319. Thus, the current study has shown for the first time that delayed central AT(2)R stimulation after a cerebral incident is neuroprotective in a conscious rat model of stroke. PMID- 23090773 TI - Exercise training attenuates placental ischemia-induced hypertension and angiogenic imbalance in the rat. AB - An imbalance between proangiogenic (vascular endothelial growth factor) and antiangiogenic (soluble fms-like tyrosine kinase 1) factors plays an important role in hypertension associated with reduced uteroplacental perfusion (RUPP). Exercise has been shown to stimulate proangiogenic factors, such as vascular endothelial growth factor, in both the pregnant and nonpregnant state; thus, we hypothesized that exercise training would attenuate both angiogenic imbalance and hypertension attributed to RUPP. Four groups of animals were studied, RUPP and normal pregnant controls and normal pregnant and RUPP+exercise training. Exercise training attenuated RUPP-induced hypertension (P<0.05), decreased soluble fms like tyrosine kinase 1 (P<0.05), increased VEGF (P<0.05), and elevated the soluble fms-like tyrosine kinase 1:vascular endothelial growth factor ratio. The positive effects of exercise on angiogenic balance in the RUPP rats were confirmed by restoration (P<0.05) of the RUPP-induced decrease in endothelial tube formation in human umbilical vascular endothelial cells treated with serum from each of the experimental groups. Placental prolyl hydroxylase 1 was increased (P<0.05) in RUPP+exercise training rats. Decreased trolox equivalent antioxidant capacity in the placenta, amniotic fluid, and kidney of the RUPP rats was reversed by exercise. RUPP-induced increase in renal thiobarbituric acid reactive species was attenuated by exercise. The present data show that exercise training before and during pregnancy attenuates placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress in the RUPP rat and reveals that increased prolyl hydroxylase 1 is associated with decreased soluble fms-like tyrosine kinase 1, thus revealing several potential pathways for exercise training to mitigate the effects of placental ischemia-induced hypertension. Lastly, the present study demonstrates that exercise training may be a useful approach to attenuate the development of placental ischemia-induced hypertension during pregnancy. PMID- 23090774 TI - Cafeteria diet increases fat mass and chronically elevates lumbar sympathetic nerve activity in rats. AB - Obesity causes sympathetic activation that promotes atherosclerosis, end-organ damage, and hypertension. Because high-fat induced weight gain in rats elevates plasma leptin at 1 to 3 days after the onset of calorie-dense diets, we hypothesized that diet-induced overfeeding will increase sympathetic activity within 1 week after the onset of the regimen. To test this, we continuously measured sympathetic activity and blood pressure before and during the onset of diet-induced obesity using a high-calorie, cafeteria-style diet. Female Wistar rats, in which radiotelemeters had been implanted for continuous monitoring of lumbar sympathetic activity, mean arterial pressure, and heart rate, were randomly assigned to groups that received regular chow (control) or a cafeteria diet for a period of 15 days. This short-term, cafeteria-feeding regimen caused modest but nonsignificant increases in body weight (P=0.07) and a doubling of brown and white adipose tissue (P<0.01). The increases in fat mass were accompanied by elevations in plasma leptin (P<0.001) but no change in glucose. Overall heart rates and blood pressure were higher in cafeteria rats compared with controls (P<0.05). Cafeteria diet-induced weight gain caused increases in lumbar sympathetic nerve activity that became significant by the 12th day of the diet (P<0.001). These data show, for the first time, that the high-fat, cafeteria style diet stimulates sustained increases in lumbar sympathetic neural drive in rats. PMID- 23090775 TI - Impaired role of epoxyeicosatrienoic acids in the regulation of basal conduit artery diameter during essential hypertension. AB - In young healthy subjects, epoxyeicosatrienoic acids synthesized by endothelial cytochrome P450 epoxygenases maintain basal conduit artery diameter during altered NO availability. Whether this compensatory mechanism is effective during essential hypertension is unknown. Radial artery diameter, blood flow, and mean wall shear stress were determined in 14 nontreated essential hypertensive patients and 14 normotensive control subjects during 8 minutes of brachial infusion for inhibitors of cytochrome P450 epoxygenases (fluconazole, 0.4 umol/min) and NO synthase (N(G)-monomethyl-L-arginine, 8 umol/min) alone and in combination. In controls, the radial artery diameter was reduced by fluconazole ( 0.034 +/- 0.012 mm) and N(G)-monomethyl-L-arginine (-0.037 +/- 0.010 mm) and to a larger extent by their combination (-0.137 +/- 0.011 mm), demonstrating a synergic effect. In contrast, the radial diameter in hypertensive patients was not affected by fluconazole (0.010 +/- 0.014 mm) but was reduced by N(G) monomethyl-L-arginine (-0.091 +/- 0.008 mm) to a larger extent than in controls. In parallel, N(G)-monomethyl-L-arginine decreased local plasma nitrite to a lesser extent in hypertensive patients (-14 +/- 5 nmol/L) than in controls (-50 +/- 10 nmol/L). Moreover, the addition of fluconazole to N(G)-monomethyl-L arginine did not further decrease radial diameter in patients (-0.086 +/- 0.011 mm). Accordingly, fluconazole significantly decreased local epoxyeicosatrienoic acid plasma level in controls (-2.0 +/- 0.6 ng/mL) but not in patients (-0.9 +/- 0.4 ng/mL). Inhibitors effects on blood flow and endothelium-independent dilatation to sodium nitroprusside were similar between groups. These results show that, in contrast to normotensive subjects, epoxyeicosatrienoic acids did not contribute to the regulation of basal conduit artery diameter and did not compensate for altered NO availability to maintain this diameter in essential hypertensive patients. PMID- 23090776 TI - Angiotensin II type 2 receptor agonists as therapies for ischemic stroke. PMID- 23090777 TI - Reversal of cardiomyopathy in patients with congestive heart failure secondary to tachycardia. AB - OBJECTIVES: Tachycardia-induced cardiomyopathy (TCM) is a reversible cause of heart failure. Little is known of the characteristics of tachycardia associated with the development of left ventricular (LV) dysfunction and the reversal of cardiomyopathy after cure of tachycardia. This study aimed to examine the reversal of cardiomyopathy in patients undergoing ablation with congestive heart failure secondary to tachycardia. METHODS: A total of 625 patients underwent radiofrequency ablation for tachycardiarrhymias between January 2009 and July 2011. Echocardiography analysis was performed to identify patients with depressed LV function, defined as a left ventricular ejection fraction <50 %. Patients with preexisting structural heart disease (n = 10) were excluded. NT-pro-B-type natriuretic peptide (NT-proBNP) assessment was performed before ablation in patients considered to have TCM (n = 17). Repeated echocardiography study and NT proBNP assessment were measured after a mean follow-up of 3 months. Levels of NT proBNP before and after ablation were compared. Reversal of cardiomyopathy was also assessed. RESULTS: The incidence of TCM was 2.7 % (12 males; age, 35.8 +/- 17.1 years). Successful ablation was performed in 16 of 17 patients (94.1 %). There was a significant improvement in left ventricular ejection fraction (36.7 +/- 7.5 vs. 59.4 +/- 9.7 %; P < 0.001). The mean left ventricular end-diastolic diameter before treatment was 59.5 +/- 8.3 mm (range, 43 to 70), compared with 51.9 +/- 7.4 mm (range, 40 to 67) (P = 0.009) after 3 months follow-up. The levels of NT-proBNP decreased after ablation procedure, from 4,092.6 +/- 3,916.6 to 478.9 +/- 881.9 pg/ml (P < 0.001). After successful ablation, ventricular function normalized in 15 of 17 (88.2 %) patients at a mean of 3 months. CONCLUSIONS: Restoration of LV function and reversal of LV remodeling can be achieved with successful elimination of tachycardia in the majority of patients. NT-proBNP level elevates in subjects with TCM and decreases sharply after ablation. PMID- 23090778 TI - Phrenic nerve palsy during ablation of atrial fibrillation using a 28-mm cryoballoon catheter: predictors and prevention. AB - PURPOSE: The purposes of this study were to determine whether predictors of phrenic nerve palsy (PNP) exist and to test whether a standardized ablation protocol may prevent PNP during cryoballoon (CB) ablation using the 28 mm CB. METHODS: Three-dimensional (3D) geometry of the pulmonary veins (PV) and their relationship to the superior vena cava (SVC) was analyzed. Phrenic nerve (PN) stimulation was performed during ablation of the right-sided PVs with a 28-mm CB. The freezing cycle was immediately terminated in case of loss of PN capture. RESULTS: Sixty-five patients (age, 58 +/- 11 years; ejection fraction, 0.59 +/- 0.06; left atrial size, 40 +/- 5 mm) with paroxysmal atrial fibrillation were included. No persistent PNP was observed. Transient PNP occurred in 4 of 65 patients (6 %). PN function normalized within 24 h in all four patients. A short distance between the right superior PV and the SVC was significantly associated with PNP, but left atrial and 3D PV anatomy were not. Low temperature early during the freezing cycle (<-41 degrees C at 30 s) predicted PNP with a sensitivity and a specificity of 100 and 98 %, respectively. CONCLUSION: The anatomical relationship between the right superior PV and the SVC is a preprocedural predictor for the development of transient PNP, and low temperature early during ablation at the right superior PV is a sensitive warning sign of impending PNP. Despite the use of the 28 mm CB, transient PNP occurred in 6 % of patients undergoing CB ablation. PMID- 23090779 TI - Peripheral tumor necrosis factor alpha regulation of adipose tissue metabolism and adipokine gene expression in neonatal pigs. AB - The neonatal pig is susceptible to stress and infection, conditions which favor tumor necrosis factor alpha (TNFalpha) secretion. This study examined whether TNFalpha can alter metabolic activity and cytokine gene expression within neonatal pig adipose tissue. Cell cultures were prepared from neonatal subcutaneous adipose tissue using standard procedures. Cultures (5 experiments) were incubated with medium containing (14)C-glucose for 4 h to measure glucose conversion to lipid in the presence of combinations of TNFalpha (10 ng), insulin (10 nM) and an anti-pig TNFalpha antibody (5 MUg). Basal lipogenesis was not affected by TNFalpha treatment (P > 0.05). However, insulin stimulated lipogenesis was reduced by TNFalpha (P < 0.02). For gene expression studies, cultures were incubated with 0, 2.5, 5.0 or 10 ng TNFalpha for 2, 4 or 24 h (n = 4 experiments). Interleukin 6 and TNFalpha gene expression were acutely (2-4 h) stimulated by exogenous TNFalpha treatment (P < 0.05), as analyzed by real-time PCR. Adiponectin mRNA abundance was reduced (P < 0.001) while monocyte chemotactic gene expression was increased by TNFalpha treatment at all time points (P < 0.001). Chronic treatment (24 h) was required to increase monocyte multiplication inhibitory factor or suppress lipoprotein lipase gene expression (P < 0.02). These data suggest conditions which increase serum TNFalpha, like sepsis, could suppress lipid accumulation within adipose tissue at a time of critical need in the neonate and induce a variety of adipose derived cytokines which may function to alter adipose physiology. PMID- 23090780 TI - Optimal remifentanil dosage for intubation without muscle relaxants in elderly patients. AB - BACKGROUND: Remifentanil used in combination with propofol provides adequate conditions for tracheal intubation without muscle relaxants. Delivery of the optimal dose is important to prevent poor intubation conditions and drug-related complications. No previous study has investigated the use of a remifentanil propofol combination in elderly patients. OBJECTIVE: The aim of the present study was to determine the dose of remifentanil necessary for rapid tracheal intubation without the use of muscle relaxants in elderly patients. METHODS: A total of 24 patients >65 years of age with American Society of Anesthesiologists status I-II who were scheduled to undergo elective surgery under general anaesthesia were enrolled. After premedication with glycopyrrolate and midazolam, anaesthesia was induced with 1 mg/kg propofol, and a blinded dose of remifentanil was then infused over 30 s after confirming the patient's loss of consciousness. The remifentanil dose was determined using Dixon's up-and-down method, starting at 2 ug/kg. Intubation was performed 60 s after the loss of consciousness. Intubation conditions were assessed with the Stockholm score and an assessment of excellent or good condition was regarded as being clinically acceptable. The effective dose needed for acceptable intubation conditions in 50 % of the subjects (ED(50)) was determined by Dixon's up-and-down method, and the ED(50) and the effective dose needed for acceptable intubation conditions in 95 % of the subjects (ED(95)) with 95 % confidence intervals (CIs) were determined by probit analysis. RESULTS: In total, 24 patients were recruited and the median age (interquartile range) was 70 (66-74) years. The ED(50) of remifentanil for tracheal intubation was 1.15 (standard deviation 0.13) ug/kg. The ED(50) and ED(95) of remifentanil obtained from the probit analyses were 1.16 (95 % CI 1.01, 1.29) ug/kg and 1.39 (95 % CI 1.27, 2.13) ug/kg, respectively. Blood pressure and heart rate decreased significantly after propofol and remifentanil administration, but were within 30 % of baseline values. CONCLUSIONS: Combined with 1 mg/kg propofol, 1.39 (95 % CI 1.27, 2.13) ug/kg remifentanil resulted in acceptable intubation conditions within 60 s in 95 % of elderly patients without major complications. PMID- 23090781 TI - Exposure to titanium dioxide nanoparticles induces autophagy in primary human keratinocytes. AB - Understanding the mechanisms of cell-nanomaterial interactions is vital in harnessing the potential of using nanomaterials in biomedical applications. By immuno-labeling of LC3 and TEM analysis, it is found that titanium dioxide nanoparticles are internalized by human keratinocytes and induce autophagy. Autophagy appears to play a cytoprotective role in response to toxicity influence exerted by the nanoparticles. PMID- 23090782 TI - Can a single molecule of water be completely isolated within the subnano-space inside the fullerene C60 cage? A quantum chemical prospective. AB - Based on an experimental observation, it has been controversially suggested in a study (Kurotobi et al., Science 2011, 33, 613) that a single molecule of water can completely be localized within the subnano-space inside the fullerene C(60) cage and, that neither the H atoms nor the O lone-pairs are linked, either via hydrogen bonding or through dative bonding, with the interior C-framework of the C(60) cage. To resolve the controversy, electronic structure calculations were performed by using the density functional theory, together with the quantum theory of atoms in molecules, the natural population and bond orbital analyses, and the results were analyzed by using varieties of recommended diagnostics often used to interpret noncovalent interactions. The present results reveal that the mechanically entrapped H(2)O molecule is not electronically innocent of the presence of the cage; each H atom of H(2)O is weakly O-H...C(60) bonded, whereas the O lone-pairs are O...C(60) bonded regardless of the conformations investigated. Exploration of various featured properties suggests that H(2)O@C(60) may be regarded as a unique system composed of both inter- and intramolecular interactions. PMID- 23090783 TI - Burden of comorbidities among patients with atrial fibrillation. AB - OBJECTIVE: This study examined comorbidity prevalence and general medication use among individuals with atrial fibrillation in the United States to convey a more comprehensive picture of their total disease burden. METHODS: This was a retrospective, observational evaluation of responses to the 2009 wave of the annual Internet-based National Health and Wellness survey, which collects health data including epidemiologic data and information on medical treatment from a representative nationwide sample of adults in the United States. Responses were assessed to determine three measures of comorbidity: mean number of comorbidities, CHADS2 score reflecting stroke risk (0-6 points; low risk: 0; moderate risk: 1; high risk: >= 2), and scores on the Charlson Comorbidity Index, which is a measure of general comorbidity reflecting presence of a wide range of comorbidities. RESULTS: Of the overall sample, 1297 participants reported having been diagnosed with atrial fibrillation. Almost all (98%) of the predominantly male (65.1%) and older (>= 65 years of age, 65.7%) population with atrial fibrillation had at least one additional comorbidity, and 90% had cardiovascular comorbidities. On the Charlson Comorbidity Index, 44.9% of the respondents had scores of 1-2 and 20.5% had scores of 3 or higher. High risk for stroke, demonstrated by a CHADS2 score of at least 2, was present in 45% and moderate risk (CHADS2 score 1) in 36%. Of the respondents with atrial fibrillation, 71% reported current use of medication to manage the condition, but only 48% of individuals at high risk for stroke reported use of anticoagulation therapy. Of those who reported having common risk factors for stroke, the majority reported receiving prescription therapy for these conditions. CONCLUSIONS: The health burden carried by patients often extends far beyond atrial fibrillation. Physicians should carefully consider comorbidities and concomitant medications when managing patients with atrial fibrillation. PMID- 23090785 TI - The activity of SV40 promoter can be inhibited by overexpression of heme oxygenase-1 in tumor cells. AB - Heme oxygenase-1 (HO-1) is both beneficial and detrimental to the host in some viral infections by catalyzing the conversion of heme to biliverdin, iron, and carbon monoxide. Simian Virus 40 (SV40) early promoter plays an important role in transforming many cells as it can drive the transcription of large T antigen, which is a potent oncogene. In order to determine the effect of HO-1 on the SV40 early promoter, tumor cells overexpressing HO-1 and HO-1 dominant-negative mutant (glycine143 mutated to histidine) (HO-1G143H) were used. Western blot and HO activity for HO-1/HO-1G143H expression, cell growth, and luciferase activity driven by SV40 promoter were detected in this study. The luciferase activity was suppressed notably in BGC-823 cells transiently overexpressing HO-1, but significantly increased in BGC-823 cells transiently overexpressing HO-1G143H, compared with the mock, respectively. HO-1 overexpression in BGC-823 cells caused the cells containing Blasticidin-resistant gene driven by SV40 promoter to grow slowly under Blasticidin screening, compared with control groups. The luciferase activities were also suppressed in BGC-823, A549, and HepG2 cells stably overexpressing HO-1, and increased in these cell lines stably overexpressing HO 1G143H, compared with the mock, respectively. The results demonstrated that overexpression of HO-1 suppressed transcription driven by SV40 promoter in tumor cells and that HO-1 catalysates might play a major role in the process. Our preliminary results suggested that HO-1 might possess promising counteraction in cell transformation by suppressing SV40 large T-antigen expression, potentially applicable to therapeutic interventions in some virus diseases. PMID- 23090784 TI - Prevention of hemodynamic instability in extra-cranial carotid angioplasty and stenting using temporary transvenous cardiac pacemaker. AB - Hemodynamic instability is a common condition during extra-cranial carotid angioplasty and stenting (CAS). We evaluated the safety and efficacy of prophylactic placement of temporary cardiac pacemaker during extra-cranial CAS for the prevention of hemodynamic instability. For this, forty-seven carotid artery stents were deployed in 41 high-risk patients. Temporary transvenous cardiac pacemakers were inserted before CAS procedure. The pacers were set to capture a heart rate <60 bpm. Clinical symptoms, blood pressure, heart rate, and pacing activation were monitored and data were collected. We found that pacing occurred in 25 carotid lesions during balloon predilatation; pacemakers were activated transiently in 25 patients. The longest pacing continued for 1 day. Among cases with pacemaker activation, 1 patient developed post-procedural symptomatic hypotension that lasted for 4 days. No related complications were observed. It was, therefore, concluded that pacing was technically effective in producing electrical ventricular responses and was hemodynamically effective in 25 carotid lesions which underwent balloon predilatation. The prophylactic use of a temporary transvenous cardiac pacemaker during CAS was rapid and effective in controlling peri-operative hemodynamic instability and preventing stroke and other complications. The prophylactic use of temporary pacemaker is particularly recommended for patients at high risk for developing hemodynamic instability. PMID- 23090786 TI - Novel macrocyclic monoterpene glycosides from bioactive extract of Parkinsonia aculeata L. AB - Five novel macrocyclic monoterpene O-glycosides, parkinsenes A-E (1-5), and eleven known phenolic metabolites including three 3-O-glycosylflavonols (6-8), five C-glycosylflavones (9-13), p-hydroxybenzoic acid (14), esculetin (15), and diosmetin (16) were isolated from the leaves and small twigs of Parkinsonia aculeata L. (Fabaceae). Their structures were established by chemical and spectroscopic analyses (UV, ESI-MS, and 1D/2D NMR). The investigated 80 % aqueous methanol extract (AME) showed significant analgesic, antipyretic, anti inflammatory, hepatoprotective, hypoglycemic, hypocholesterolemic, and antioxidant activities in a dose-dependent manner using two different doses 250 and 500 mg/kg b. wt. PMID- 23090787 TI - Recurrence network analysis of the synchronous EEG time series in normal and epileptic brains. AB - We sought to analyze the dynamic properties of brain electrical activity from healthy volunteers and epilepsy patients using recurrence networks. Phase-space trajectories of synchronous electroencephalogram signals were obtained through embedding dimension in phase-space reconstruction based on the distance set of space points. The recurrence matrix calculated from phase-space trajectories was identified with the adjacency matrix of a complex network. Then, we applied measures to characterize the complex network to this recurrence network. A detailed analysis revealed the following: (1) The recurrence networks of normal brains exhibited a sparser connectivity and smaller clustering coefficient compared with that of epileptic brains; (2) the small-world property existed in both normal and epileptic brains consistent with the previous empirical studies of structural and functional brain networks; and (3) the assortative property of the recurrence network was found by computing the assortative coefficients; their values increased from normal to epileptic brain which accurately suggested the difference of the states. These universal and non-universal characteristics of recurrence networks might help clearly understand the underlying neurodynamics of the brain and provide an efficient tool for clinical diagnosis. PMID- 23090789 TI - Evaluation of stem cell-to-tenocyte differentiation by atomic force microscopy to measure cellular elastic moduli. AB - In the present study, we evaluated whether stem cell-to-tenocyte differentiation could be evaluated via measurement of the mechanical properties of the cell. We used mechanical uniaxial cyclic stretching to induce the differentiation of human bone marrow mesenchymal stem cells into tenocytes. The cells were subjected to cyclic elongation of 10 or 15 % at a cyclic frequency of 1 Hz for 24 or 48 h, and differentiation was assessed by real-time PCR (rtPCR) determination of messenger RNA expression levels for four commonly used markers of stem cell-to-tenocyte differentiation: type I collagen, type III collagen, tenascin-C, and scleraxis. The rtPCR results showed that cells subjected to 10 % cyclic elongation for 24 or 48 h differentiated into tenocytes. Atomic force microscopy (AFM) was then used to measure the force curves around the cell nuclei, and the AFM data were used to calculate the elastic moduli of the cell surfaces. The elastic modulus values of the control (non-stretched) cells differed significantly from those of cells stretched at 10 % for 24 or 48 h (P < 0.01). Confocal fluorescence microscopic observations of actin stress fibers suggested that the change in elastic modulus was ascribable to the development of the cellular cytoskeleton during the differentiation process. Therefore, we conclude that the atomic force microscopic measurement of the elastic modulus of the cell surface can be used to evaluate stem cell-to-tenocyte differentiation. PMID- 23090788 TI - Neuroprotective effect of atorvastatin involves suppression of TNF-alpha and upregulation of IL-10 in a rat model of intracerebral hemorrhage. AB - We evaluated the neuroprotective effects of atorvastatin (2, 5, and 10 mg/kg) on experimentally induced intracerebral hemorrhage (ICH) in adult rats; controls were administered PBS. Plasma TNF-alpha and IL-10 levels before and after ICH were analyzed at various time points by enzyme-linked immunosorbent assay (ELISA) and neurological behavior of rats was assessed by climbing scores. At 3-days postoperatively, brain water contents and TNF-alpha/IL-10 expression in brain tissue were determined. Histopathological changes and microglial cells in the brain tissue were evaluated by light-microscopy. Post-ICH neurological deficits differed significantly between sham-operated group A and experimental-ICH group B (P < 0.05). Brain water contents were significantly less in group A than in group B (P < 0.05). Significant differences (P < 0.05) between two groups were observed regarding activated microglia, TNF-alpha and IL-10 levels. Compared with group B, neurological deficits, brain water contents, pathological changes, and activated microglia were reduced (P < 0.05) in groups C (Experimental-ICH + atorvastatin 2 mg/kg), D (Experimental-ICH + atorvastatin 5 mg/kg) and E (Experimental-ICH + atorvastatin 10 mg/kg). Atorvastatin-induced a dose-dependent reduction of TNF alpha and increase of IL-10 levels (P < 0.05). Therefore, it was concluded that atorvastatin improved neurofunctional rehabilitation in rats through the suppression of cytokines-mediated inflammatory response and attenuation of brain damage following intracerebral hemorrhage. PMID- 23090790 TI - Contribution of hydrogenase 2 to stationary phase H2 production by Escherichia coli during fermentation of glycerol. AB - Escherichia coli has four hydrogenases (Hyd), three genes of which are encoded by the hya, hyb, and hyc operons. The proton-reducing and hydrogen-oxidizing activities of Hyd-2 (hyb) were analyzed in whole cells grown to stationary phase and cell extracts, respectively, during glycerol fermentation using novel double mutants. H2 production rate at pH 7.5 was decreased by ~3.5- and ~7-fold in hya and hyc (HDK 103) or hyb and hyc (HDK 203) operon double mutants, respectively, compared with the wild type. At pH 6.5, H2 production decreased by ~2- and ~5 fold in HDK103 and HDK203, respectively, compared with the wild type. At pH 5.5, H2 production was reduced by ~4.5-fold in the mutants compared with the wild type. The total hydrogen-oxidizing activity was shown to depend on the pH of the growth medium in agreement with previous findings and was significantly reduced in the HDK103 or HDK203 mutants. At pH 7.5, Hyd-2 activity was 0.26 U (mg protein)(-1) and Hyd-1 activity was 0.1 U (mg protein)(-1). As the pH of the growth medium decreased to 6.5, Hyd-2 activity was 0.16 U (mg protein)(-1), and Hyd-1 was absent. Surprisingly, at pH 5.5, there was an increase in Hyd-2 activity (0.33 U mg protein)(-1) but not in that of Hyd-1. These findings show a major contribution of Hyd-2 to H2 production during glycerol fermentation that resulted from altered metabolism which surprisingly influenced proton reduction. PMID- 23090791 TI - Outcomes of surgery aiming at curative resection in good responder to induction chemotherapy for gastric cancer with distant metastases. AB - BACKGROUND: The aim of this study is to analyze the outcome of surgery with curative intent in good responder to induction chemotherapy for gastric cancer with distant metastases (M1 gastric cancer). MATERIALS AND METHODS: We reviewed M1 gastric cancer patients in whom radiologic evaluation suggests disappearance of metastatic lesion after chemotherapy and received operation from January 2000 to December 2009. Clinicopathologic variables and oncologic outcomes were evaluated. RESULTS: Of the 34 patients who underwent surgery with curative intent after chemotherapy, overall R0 resection rate was 76.5% (26/34). R0 resection rate was 88.0% (22/25) in initial one metastatic site and 44.4% (4/9) in two metastatic sites (P = 0.017). Postoperative morbidity and mortality rate were 14.7% and 0%. Recurrence rate was 61.5% (16/26) after R0 resection. Median survival was 22.9 and 7.8 months according to R0 versus non-R0 resection (P = 0.033). After R0 resection, 3-year overall survival was 51.7% in ypN0-2 stage group. CONCLUSION: The present study provides evidence that in patients with M1 gastric cancer which confined to one site who respond well to induction chemotherapy, a higher rate of R0 resection and longer survival can be expected. A multicenter cohort study is needed to explore this concept further. PMID- 23090792 TI - Modulation of chondrocyte migration and aggregation by insulin-like growth factor 1 in cultured cartilage. AB - The effect of insulin-like growth factor-1 (IGF-1) on the behavior of rabbit chondrocytes in cultured collagen (CL) gels initially seeded with 2 * 10(5) cells/ml was examined. On day 5, the frequency of migrating cells cultured in presence of 100 ng IGF-1/ml was 0.04, which was 54 % of the frequency in IGF-1 free culture. The presence of IGF-1 caused an increase in the frequency of dividing cells from 0.09 to 0.13. These results suggest that IGF-1 suppressed the migration of chondrocytes in the CL gels while stimulating cell division in the initial culture phase. The proteolytic migration of cells was thought to be suppressed by the down-regulation of membrane type 1 matrix metalloproteinase by IGF-1. This contributed to the formation of aggregates with spherical-shaped cells that produced collagen type II. PMID- 23090793 TI - Adsorption of multimeric T cell antigens on carbon nanotubes: effect on protein structure and antigen-specific T cell stimulation. AB - Antigen-specific activation of cytotoxic T cells can be enhanced up to three-fold more than soluble controls when using functionalized bundled carbon nanotube substrates ((b) CNTs). To overcome the denaturing effects of direct adsorption on (b) CNTs, a simple but robust method is demonstrated to stabilize the T cell stimulus on carbon nanotube substrates through non-covalent attachment of the linker neutravidin. PMID- 23090794 TI - Unilateral ovarian metastasis from gastric mucinous adenocarcinoma visualized on FDG PET/CT. AB - BACKGROUND: Krukenberg tumor is a metastatic ovarian tumor with primary focus usually seen in the gastrointestinal tract. Metastatic involvement of the ovary is an uncommon manifestation of malignancy. We report a [18F]-fluoro-2-deoxy-D glucose positron-emission tomography/computed tomography (FDG PET/CT) appearance of solitary unilateral ovarian metastasis in a 44-year-old woman with a history of mucinous adenocarcinoma type of gastric carcinoma. Total hysterectomy with bilateral salpingo-oophorectomy was performed. Histopathological verification determined metastasis of mucinous adenocarcinoma with components of signet-ring cell carcinoma in the right ovary. PMID- 23090795 TI - Lymphoma of cheek: a case report. AB - Lymphoma of cheek is a rare ad uncommon disease, representing 2,5% of malignant lymphoma. The cause is unknown but there are a lot of risk factors such as Helicobacter pylori and Epstein Barr virus. Symptoms are aspecific and may be confused with otolaryngological benign diseases. We present a case of B cell lymphoma of the cheek, which presented with a history of a slowly growing swelling of 3 months duration, resistant to NSAIDs and antibiotic therapy. Biopsy of the mass led to diagnosis of lymphoma. Blood investigations, ultrasonography and CT scan helped to reach this result. This case report shows that an accurate clinical examination, a cytohistological and immune-histochemical diagnosis by fine-needle aspiration biopsy (FNAB) are fundamental to obtain a diagnosis and to decide therapy.
PMID- 23090796 TI - Trigeminal and facial schwannoma: a case load and review of the literature. AB - Schwannoma or neurilemmoma are benign tumours originating from Schwann cells of the nerve sheath. They can arise from any peripheral, cranial, or autonomic nerve The treatment of extracranial head and neck schwannomas is surgical and the approach depends on the location and extent of the tumor and the nerve involved. The Authors report the case load of surgical managements of three different extracranial nerve schwannomas involved facial and trigeminal nerves, and a review of the literature. PMID- 23090797 TI - Multiple primary laryngotracheal adenoid cystic and left thyroid follicular carcinoma with right vocal cord paralysis: the crucial role of surgery. AB - BACKGROUND: Primary tracheal tumors are rare, accounting for only 0.2% of all thoracic cancers. Adenoid cystic carcinoma (ACC) diagnosed in the trachea is very uncommon and its coexistence with second histologically distinct malignant tumors of he neck region has never been reported. SUMMARY: We now report a case of multiple primary laryngotracheal ACC and thyroid follicular carcinoma surgically successful treated with an incidental 8 years follow-up. CONCLUSIONS: The laringotracheal resection with en-bloc thyroidectomy can be adopted for treating multiple primary tumor of tracheal and thyroid carcinoma with good long-term prognosis. PMID- 23090798 TI - Osteoblastoma of cervical spine causing an unusual neck pain. AB - Osteoblastoma is a rare benign tumor of bone that accounts for approximately 1% of primary skeletal neoplasms, with around 90% of cases diagnosed in the second and third decades of life. Cervical spine is an usual localization of osteoblastoma. The main clinical manifestation in case of cervical spine location is a progressive and resistant pain, possibly accompanied by stiffness, scoliosis or other ailments, including severe neurological deficits. Owing to a non specific clinical presentation of osteoblastoma, the delay in diagnosis is common. Osteoblastomas may have an aggressive behavior, tend to enlarge and damage the bone and adjacent structures. The treatment of choice is, therefore, a wide and complete surgical excision of the lesion in order to achieve full recovery and prevent recurrence or, in some cases, malignant transformation. In the case of persistent neck pain, not readily relieved by aspirin and possibly accompanied by stiffness, scoliosis or neurological deficits, especially in young subjects, osteoblastoma of cervical spine may be one of the diagnostic options to be considered, in order to avoid delay in diagnosis. We report the case of a 41 year-old male affected by cervical spine osteoblastoma causing a lasting neck pain.
PMID- 23090799 TI - Malignant solitary fibrous tumour of the chest wall: a challenging case. AB - Solitary fibrous tumors are very rare neoplasms that seldomly appear in extra serosal soft tissues. In such cases, an accurate preoperative diagnosis is often difficult and challenging, especially in extrapleural ones. Traditionally, extrapleural solitary fibrous tumours have been regarded as indolent neoplasms similar to their intra-thoracic counterparts, although there has been some evidence that this subgroup could be a subset of more aggressive malignant tumours. For these reasons, surgical excision is mandatory and represents, to date, the best therapeutic option. In this article we report a case of a malignant solitary fibrous tumor of the chest wall in a 58-year-old man. Problems related to differential diagnosis and the possible pitfalls that can be encountered in the diagnostic process of such rare tumors are discussed. PMID- 23090800 TI - Primary cutaneous mucoepidermoid carcinoma infiltrating the parotid gland. AB - Mucoepidermoid carcinoma (MEC) of the skin is an extremely rare neoplasm but is common in the major and minor salivary glands accounting of approximately 30% of all malignant tumors arising from these glands. Cutaneous involvement should be carefully assessed to exclude the possibility of metastases from distant sites. We report an 81 year-old man presenting a primary cutaneous mucoepidermoid carcinoma infiltrating his left parotid gland. Excision of the affected skin and a total parotidectomy with supraomohyoid neck dissection (level I-III) was performed followed by radiotherapy. No relapse after 2 years follow up has been observed. Since the primary cutaneous mucoepidermoid carcinoma is an aggressive neoplasm that frequently develops metastases it is important to distinguish it from primary MEC originating from the salivary glands for better management and suitable therapeutic decisions. PMID- 23090801 TI - Unusual case of extraovarian granulosa cell tumor. AB - We present a case of adult type extraovarian granulosa cell tumor in 22 years old woman. The pelvic and radiographic examination revealed right adnexial solid mass in patient who complaining from menstrual disregulation and pelvic pain. The patient underwent exploratory laparotomy which showed pelvic mass adjacent urinary bladder and fixed to the behind of pubic bone at pre-peritoneal area. PMID- 23090802 TI - Successful embolectomy in a femoral artery thrombosis caused by femoral artery catheterization in a infant. AB - In infants, the most common cause of femoral artery is thrombosis and iatrogenic arterial injuries usually occur after femoral artery catheterization procedures. Management of this complication includes heparin infusion, thrombolytic agents, interventional radiologic procedures, surgical thrombectomy and by-pass surgery. Signs of arterial thrombosis developed after femoral artery catheterization procedure in the right lower extremity of 9-month-old female infant with methyl malonic acidemia. Heparin infusion was started after confirming the diagnosis of femoral artery thrombosis by ultrasonography. Because of there was no response to heparin treatment, thrombolytic therapy (t-PA) was started after 24 hours. Again, because of there was no response to all medication, surgical thrombectomy was performed. Was entered right common femoral artery with 3.0 F Fogarty catheter and fresh thrombus material was removed from the proximal and distal segments of the femoral artery. Antegrade and retrograde blood flow was achieved. After the procedure clinical signs and the symptoms of the thrombosis were resolved rapidly. There were no any complications in the postoperative period.This case encouraged us for using surgical thrombectomy in the treatment of femoral artery thrombosis in infants who do not respond to medication. PMID- 23090803 TI - First case of bronchiolar-pleural fistula repair with platelet-leukocyte rich gel. AB - Bronchiolar-pleural fistulas are a frequent complication of thoracic surgery. Current treatment strategies and their invasiveness are quiet different, but often surgeons decide for a new surgical intervention and definitive closure of the breach. We report the case of a bronchiolar-pleural fistula in a 75 years old man with important co-morbidities that we treated with instillation of platelet leukocyte rich gel (PLR-G). We discuss actual indications for PLR-G as well as its possible role in thoracic surgery. PMID- 23090804 TI - A woman with a solitary pulmonary nodule: is it a lung cancer? AB - BACKGROUND: Solitary pulmonary nodules present a real challenge for physicians. Due to the clinical implications and prognosis of a certain diagnosis, it should be pursued with any cost; a clear definition is not always simple and further investigations are often necessary to exclude the possibility of a malignancy. A diagnostic path must be followed and the clinical hypothesis should be reconsidered on the basis of the new information provided by the tests, always keeping in mind their limits! Sometimes only the surgical resection permits a definitive diagnosis. A 68 year-old non-smoker female with a pulmonary solitary nodule highly suspicious to be malignant at the chest CT, performed a FBS with BAL, negative for neoplastic cells and for infective agents, and a CT guided pulmonary biopsy that was inconclusive. The patient underwent then a video thoracoscopic atypical lung resection that demonstrated the reactive nature of the lesion, definitely excluding the presence of a malignancy. PMID- 23090805 TI - Complete transmural gastric migration of PTFE mesh after surgery for a recurrent hiatal hernia. AB - Complications directly associated with the use of prosthetic materials in large hiatal hernia repair are rarely cited events in the literature. We herein report a case of a 47 year-old woman who came to our attention for a subacute onset of severe dysphagia and weight loss. She previously underwent laparotomic Nissen fundoplication with PTFE dual-mesh cruroplasty for a large recurrent hiatal hernia. With the clinical suspicious of "Tight Nissen", an endoscopy was performed and revealed a circular stenosis in the lower esophagus, a rotation of the stomach and, surprisingly, the presence of PTFE mesh free-moving in the gastric lumen With the use of rattooth forceps, the foreign body was removed and, after few days, the patient underwent a surgical debridement of hiatal scar tissue and a gastropexy procedure. In conclusion, dysphagia may manifest during the early postoperative period after mesh repair antireflux surgery, but such dysphagia usually resolves; if it doesn't or if it worsens, mesh migration must be excluded. PMID- 23090806 TI - A case of vomiting in an anorexic achalasic patient. AB - Wernicke's encephalopathy is a neurological disorder caused by thiamine (vitamin B1) deficiency characterized by vertigo, ataxia, and mental confusion. Wernicke's encephalopathy has a causative association with alcoholism but recently there has been an increased prevalence also in other clinical conditions. In literature potentially fatal Wernicke's encephalopathy onset in an advanced achalasia has been previously reported only once. We describe for the first time an improvement of achalasic symptoms in a young patient affected by end-stage achalasia and anorexia nervosa (coming from ineffective Heller-Dor myotomy) after vitamin B1 supplementation. This case report suggest a potential positive impact of B1 supplementation on end-stage achalasic patients and requires systematic studies to confirm this observation. PMID- 23090807 TI - Ultrasonography and magnetic resonance imaging findings of abdominal complications of cystic fibrosis. AB - In this study, our aim is to discuss the imaging findings of the abdominal complications seen in Cystic Fibrosis (CF), with ultrasonography (US) and magnetic resonance imaging (MRI). Our first case, a 22 year-old female showed changes characterized by severe biliary involvement such as cholelithiasis and cholangitis. Our second case was a 36 year-old male with severe hepatic manifestations. In this case signs of severe cirrhosis, portal hypertension and marked splenomegaly were seen. Micro-gallbladder, cholecystolithiasis and diffuse fatty infiltration of the pancreas were seen in both cases. IN CONCLUSION: US and MRI are effective and noninvasive imaging techniques to evaluate the abdominal complications of cystic fibrosis. PMID- 23090808 TI - Urgent surgical management of a prenatally diagnosed midgut volvulus with malrotation. AB - Midgut volvulus is a life-threatening condition that commonly presents during the first year of life rarely antenatally. Here we report successful urgent surgical management of an unusual case with malrotation exhibiting the sonographic findings of volvulus in utero that leads to premature birth. This 34-wk, 2700 g infant was born via spontaneous vaginal delivery. Prenatal ultrasound showed polyhydramnios and 30 x 40 mm cystic lesion showing whirlpool sign in abdomen that made us think midgut volvulus. The patient had distended abdomen with skin discoloration. An emergency surgical management was performed showing malrotation, volvulus and a 15 cm ischemic necrotic region of terminal ileum. PMID- 23090809 TI - Cystic hygroma of the breast in a 5 year old boy presenting as a gynecomastia. AB - Cystic hygroma, also known as lymphangioma, are unusual congenital malformations of the lymphatic system. Cystic lymphangioma is a rare lesion in the breast of children. Only a few cases have been documented in literature. We report a rare case of a 5-year-old boy presented with a gradually enlarging, painless breast mass which was identified sonographically and histologically as a breast lymphangioma and treated by surgical excision. A local excision of the lump was performed and a diagnosis of cystic lymphangioma was made. Cyst was surgically removed, with preservation of normal tissue, and histopathologic findings showed a lymphangioma. The patient is well, after one year of follow-up, with no complaints or recurrence. PMID- 23090810 TI - Well-known but rare pathogen in neonates: Listeria monocytogenes. AB - Listeria monocytogenes is a very important life-threatening bacteria in certain risk groups such as neonates, pregnant women, elderly people, transplant recipients and others with impaired cell-mediated immunity. However, its infections are very rare in healthy children. Reports of listeriosis in newborn period are limited. We report a case of neonatal listeriosis with erythematous rash, intractable convulsions, severe early neonatal sepsis, disseminated intravascular coagulation, multiple organ dysfunction syndrome and death. Although an empirical antibiotic therapy including ampicillin (semisentetic penicillin) and aminoglycoside combination is effective by the means of a probable Listeria infection, the progression of the very early-onset disease may be fatal, despite vigorous treatment efforts as in our case. PMID- 23090811 TI - An infant with congenital fibula deficiency accompanying with deafness. AB - Congenital longitudinal deficiency of the fibula (CLDF) is the most common congenital defect involving the long bones. There have been many different classifications developed for fibula deficiency. Achterman and Kalamchi's classification is most commonly used and will be described. Our case was complied with type II. Other anomalies includes cardiac anomalies, thrombocytopenia absent radius (TAR) syndrome, thoracoabdominal schisis, spina bifida and renal anomalies, but most associated anomalies are skeletal. We here presented firstly in literature an infant with congenital fibula deficiency accompanying with deafness. PMID- 23090812 TI - Control of persistent auditory hallucinations through audiotape therapy (three case reports). AB - Auditory hallucinations are found in patients with schizophrenia. For some patients with persistent psychotic symptoms, hallucinations are unresponsive to medications. We report three cases with schizophrenia and persistent auditory hallucinations. In this study three types of tapes were used: pure music, music and speech, blank tapes. The patients were asked to record the duration and severity of their auditory hallucinations when they were listening to tapes. Audiotape therapy led to a significant decrease in the duration and severity of the hallucinations (p < 0.05). This study supports treating persistent auditory hallucination by altering external stimulation. Therefore, audiotape therapy could be helpful. PMID- 23090813 TI - Methylphenidate as a treatment for stuttering: a case report. AB - INTRODUCTION: A randomized placebo controlled trial with methylphenidate (MPH) was set up to identify the effects of MPH on cognition in healthy young adults (ea. without attention deficit hyperactivity disorder, ADHD). Subjects repeatedly performed tests of the immediate and delayed memory and vigilance tasks after administration of placebo or 20 mg MPH. CASE PRESENTATION: We report the case of an 18 year old man who participated in the study. He suffered from stuttering since childhood. During the study phase he reported a remarkable relief of the stuttering after the intake of 20 mg MPH. CONCLUSIONS: For D-amphetamine the beneficial effect on stuttering has been demonstrated but it was never implemented in clinical practice because of important adverse events. MPH, an amphetamine analogue, doesn't present these side effects. For this reason, MPH seems to merit further investigation in a randomized-controlled trial as a possible agent in the treatment of stuttering.Methylphenidate, Stuttering. PMID- 23090814 TI - Supersensitivity psychosis in a case with clozapine tolerance. AB - Despite its serious side effects, clozapine is still the golden standard in treatment of schizophrenia due to its effectiveness and lack of extrapyramidal side effects. Some studies have mentioned withdrawal symptoms, including withdrawal psychosis after stopping clozapine, and have tried to explain this severe symptom through dopamine receptor supersensitivity. This phenomenon, called supersensitivity psychosis, can be explained by the development of tolerance towards the effect of the medication. In literature, there are several cases of supersensitivity psychosis while using other neuroleptics. However, to our knowledge, there are no published cases reporting an association between clozapine and supersensitivity psychosis. The current patient, who has been diagnosed as resistant schizophrenia, responded well to the clozapine in the beginning of treatment. Due to an effective dose of clozapine, he had psychotic exacerbation with significant positive symptoms. We discuss the probable reasons causing this situation and the relationship between tolerance to the treatment effect and the dopamine supersensitivity.
PMID- 23090815 TI - Asymptomatic and isolated accessory mitral valve tissue in adult population: three case reports and review of the literature. AB - Accessory mitral valve tissue is a rare congenital cardiac anomaly and commonly it may cause left ventricular outflow tract obstruction (LVOTO). This anomaly occurs as a part of other congenital cardiac anomalies. However, it may be seen isolated. Structures in LVOT such as tumor, vegetation, cysts may have attention for differential diagnosis. The number of cases is increasing with the routinely using of two-dimensional echocardiography. Accessory mitral valve tissue is detected first early in children with symptoms of LVOT and is very rarely diagnosed in adults. One third of cases may asymptomatic, but commonly significant left ventricular outflow tract gradient can be detected in these cases, especially adult period. Optimal treatment of this anomaly is surgery if there is a significant LVOTO. In this report, we presented the three asymptomatic adult cases with accessory mitral valve tissue, without increased gradient in LVOT. Surgical excision was recommended to the first case in another hospital with diagnosis of cardiac cyst. Two cases are presented. PMID- 23090816 TI - Managing a left pleural effusion after aortic surgery. PMID- 23090817 TI - Giant right atrial thrombus in hepatocellular carcinoma: real-time characterization by cardiac magnetic resonance and real time three-dimensional echocardiography. AB - Hepatocellular carcinoma (HCC) with extension to the right atrium is an uncommon form of cardiac involvement. We report a case of a 67-year-old man admitted to our Department for the incidental findings of a mass in the right atrium. Physical examination revealed leg edema, distention of external jugular vein and ascites. The anamnestic collection revealed HCC occurred on post-alcoholic liver cirrhosis 3 years earlier. Transthoracic echocardiography revealed a dilated RA containing a mass, with superficial apposition of a thrombotic material. Bi dimensional echocardiography is the most commonly used noninvasive tool for evaluating intracardiac masses. Although MRI is considered the gold standard, real-time three-dimensional echocardiography has the capability to obtain the entire volume reconstruction of an intracardiac mass, even with an irregular shape. Moreover, it permits an hemodynamic evaluation of the potential obstructive effects visualized from different angles and planes.
PMID- 23090818 TI - Ocular toxoplasmosis and retinal detachment: five case reports. AB - BACKGROUND: Ocular toxoplasmosis is a potentially blinding cause of posterior uveitis. Retinal detachment is rare complication of ocular toxoplasmosis. AIM: To report the clinical course and prognosis of retinal breaks and detachments occurring in patients with ocular toxoplasmosis. PATIENTS AND METHODS: This study was a retrospective, non-comparative case series of five patients with ocular toxoplasmosis who had consulted us with retinal detachment. RESULTS: All of the participants had retinal detachment after severe and treatment resistant toxoplasmic retinochoroiditis, leaving one of them with decreased visual acuity to light perception in spite of treatment and final visual acuity was 20/100 or better in four patients. CONCLUSIONS: The functional prognosis for the patients with retinal detachment was poor. Careful retinal examination in ocular toxoplasmosis is warranted, especially in patients with severe intraocular inflammation. PMID- 23090819 TI - Pleomorphic adenoma of the lacrimal gland: two clinical cases. AB - INTRODUCTION: Pleomorphic adenoma of the lacrimal gland is uncommon but it is the most common benign epithelial tumor of this gland. In the literature few cases have been reported in patients aged between 6 years and 80 years with a mean age of 39 years. A correct diagnosis and treatment is fundamental in order to avoid a relapse and sometimes their malignant transformation. An incisional biopsy is better to be avoided because it could injure the capsule, leading to dissemination of tumoral cells in the orbital tissues with a recurrence rate of 30% over 5 years. AIM: This papers want to support the use of mini-invasive surgery for the treatment of orbital lesions when it is possible. MATERIALS AND METHODS: We report two clinical cases of pleomorphic adenoma affecting the lacrimal gland treated with two different surgery approaches. The radiographic and photographic documentation of the patients was collected in the pre-and post operatively. All patients underwent a CT scan and MRI. CONCLUSIONS: This lesions requires a well-grounded clinical and therapeutic protocol to avoid the risk of malignant transformation or disease recurrence, very dangerous at this site. CT scan and MRI scan are very important to recognize different types of lesions involving the lacrimal gland and fossa. A mini-invasive surgery reduces hospitalization, risk of complications, surgical times and bleedings and guarantees an excellent functional and esthetic result when performed by a skilled surgeon. PMID- 23090820 TI - Chronic adrenal failure and hypergonadotropic hypogonadism in a patient with abetalipoproteinemia. AB - INTRODUCTION: Abetalipoproteinemia is a rare inherited disorder characterized by very low plasma levels of cholesterol and triglycerides, secondary to a dramatic decrease in apolipoprotein B-containing lipoproteins, which is induced by a mutation in the microsomal triglyceride transfer protein gene. CASE: In our paper, we describe an atypical clinical manifestation of this condition in a young man, which included the presence of hypogonadism and chronic adrenal failure. We connect the development of both endocrine disorders with very low plasma levels of cholesterol, which is uptaken by the gonads and adrenal cortex and used as a substrate for steroidogenesis, accentuated by carbamazepine treatment. Testosterone treatment and administration of hydrocortisone, fludrocortisone and dehydroepiandrosterone resulted in a significant improvement in a patient's condition. CONCLUSIONS: This case shows that untreated or inaccurately managed long-lasting abetalipoproteinemia may impair the production of steroid hormones and lead to the development of some endocrine disorders. PMID- 23090821 TI - Digital clubbing as an unusual complication of the secondary hyperparathyroidism associated with atypical neutrophils: a case report. AB - Digital clubbing is a rare clinical finding and usually represents a sign of underlying disease.There are only few cases of digital clubbing in patients with primary hyperparathyroidism or with secondary hyperparathyroidism (SHPT) during long-term hemodialysis. We haven't come across papers dealing with the relation of digital clubbing and SHPT caused by vitamin D deficiency. In this article, we report a case of 43 year-old female patient with prominent clubbing of the fingers and toes, and 22 year history of SHPT caused by vitamin D deficiency. Current radiographic findings of the hands and feet are actually uncommon, and they show massive osteolytic lesions of numerous phalanges, which is the consequence of long-time untreated SHPT. Besides, our patient has a rare case of neutrophils with bilobed nuclei and decreased cytoplasmic granularity. This paper for the first time describes digital clubbing as an unusual complication of the SHPT caused by vitamin D deficiency associated with atypical neutrophils. PMID- 23090822 TI - Promontory hemangioma mimics glomus tympanicum in the middle ear (promontory hemangioma). AB - Hemangiomas, common benign vascular tumors, have been well reported in the head and neck region. They have rarely been reported in the ear. Ear involvement hemangiomas are usually seen in the together with external auditory channel and middle ear. We presented a 62-year-old woman of capillary promontory hemangioma which was mimicking as glomus tympanicum with a review of the literature. PMID- 23090823 TI - Upper airway study should always come before any sleep study in OSAS evaluation: a giant parapharyngeal lipoma behind OSAS. AB - BACKGROUND: The parapharyngeal space (PPS) is a rare site for neoplasms in the head and neck and lipoma represents 0.5% of all head and neck tumors. CASE REPORT: We describe a case of a giant parapharyngeal lipoma in obese adult patient causing anatomic pharyngeal obstruction with severe obstructive sleep apnea (OSA) syndrome. The patient was successfully operated with transcervical approach. CONCLUSIONS: In patients presenting with symptoms suggestive of OSA, it is essential to rule out any physical cause and perform a comprehensive ear, nose and throat examination including fibro-endoscopic upper airway examination before referral for sleep study and management. The ideal management for OSA involves treating the underlying cause. If no definitive cause is identified, management should begin with conservative measures such as lifestyle changes and a weight loss program; if these are unsuccessful, continuous positive airway pressure (CPAP), oral appliances or upper airway surgery could be considered. Better diagnostic methods should be developed to identify the main OSA causes and improve therapeutic outcomes. PMID- 23090824 TI - Magnetic resonance imaging contrast agent related pulmonary edema: a case report. AB - Gadobutrol is a contrast agent often used during magnetic resonance imaging (MRI). The agent has several side effects, some of which can be serious. It has extremely rare life-threatening systemic complications, which can lead to bronchospasm, hypersensitivity reactions and cardiovascular arrest. However, there is no data available on the development of noncardiogenic pulmonary edema following use of gadobutrol. This paper examines the case of a 37-year-old male patient reported to have developed noncardiogenic pulmonary edema after intravenous injection of gadobutrol during MRI. PMID- 23090825 TI - Complete improvement in a patient with multiple irreversible defects of the left ventricle on 99m technetium-sestamibi SPECT after percutaneous coronary intervention. AB - 99mTc-sestamibi has been investigated as a potential viability marker; initial studies have shown good concordance between 201Tl and 99mTc-sestamibi activities in both viable and nonviable myocardium. However, assessment of myocardial viability by 99mTc-sestamibi remains controversial for tissue recovery after revascularization. Here, we present a patient with several regions of severely diminished and irreversible (defect persisting in both early and delay images of each set scanning) defects on initial scan which were dissolved completely on the follow up scan after an intervention. In a 75 year-old Asian woman with acute myocardial infarction who received thrombolytic therapy and subjected to percutaneous coronary angiography (PCI) on day 28 after acute myocardial infarction(MI), resting 99mTc-sestamibi SPECT was applied on day 4 (initial scan) and 138 (follow up scan) after acute MI at 30 and 180 min after injection of tracer (740 MBq); Two-dimensional echocardiography was carried out at the same time. On the initial image set, there was irreversible defects in the apex, anteroapical, inferoapical, anteroseptal, septal and also anterior walls, while the follow up image was normal in all regions.The angiography intervention showed just significant stenosis on left anterior descending (LAD) vessel (95%). This may highlight the failure of 99mTc-sestamibi as a marker of myocardial viability and also mandate further validating of the procedure with follow up scan or other modalities for myocardial viability investigation. PMID- 23090826 TI - An orbital roof and anterior skull base fracture: case report. AB - Blow-out fractures usually involve the orbit in the floor or in the medial wall. Anyway, if the roof of the orbit is thin and direct compressive or buckling forces impact the orbit the fracture can involve the upper roof. We describe the case of a blow-out fracture of the orbital roof with enophtalmus and cerebrospinal fluid leak from lacero-contusive subciliar wound PMID- 23090827 TI - Le Fort III osteotomic variants. AB - INTRODUCTION: Midface hypoplasia is a skeletal defect involving all three space planes, hence needing a three-dimensional repositioning. This research study shows two cases of cranio-facial dysostosis, on which two Le Fort III variants were performed. CASE REPORT: In the first case we report the performing the two types of osteotomy simultaneously. Le Fort I, however, has been performed without any pterygomaxillary disjunctions, thus accomplishing a complete midface mobilization without any variation of the occlusal ratios. In the second case a modified Le Fort III osteotomy has been performed with median disjunction; reduction of the transverse interdacryal diameters and of the pyriform opening. DISCUSSION: Among all osteotomic variants we would like to mention the one introduced by Obwegeser in 1969 where, in patients with acceptable dental occlusal ratios, Le Fort III and Le Fort I have been performed in conjunction. This technique allows a different midface and dental occlusion repositioning. CONCLUSIONS: In adult patients with permanent dentition and normal occlusal ratios this technique may be chosen for a midface advancement without compromising the dento-skeletal relations, in order to achieve the best functional and aesthetical results. PMID- 23090828 TI - Odontoameloblastoma: five years follow up of a surgical case and review of literature. AB - The odontoameloblastoma (OA), also known as ameloblastic odontoma, is a rare neoplasm of jaws which includes odontogenic ectomesenchyme in addition to odontogenic epithelium that resembles an ameloblastoma both in structure and in behaviour. The exact incidence is difficult to determine. Since 1944, only 24 cases have been reported in English literature which fulfill both histological and clinical features of this lesion. The Authors report a case report of an odontoameloblastoma in a 15-year-old caucasian man treated with a surgical excision. The five years follow-up shows no evidence of recurrence confirming the validity of a conservative surgery with enucleation of OA, followed by periodical clinical and radiographical controls. PMID- 23090829 TI - The new retained foreign body! Case report and review of the literature on retained foreign bodies in laparoscopic bariatric surgery. AB - The advent of laparoscopic surgery has created a set of peculiar morbidities. As the laparoscopic devices, also the type of retained foreign bodies has changed. We present a case of unusual, apparently isolated and recurrent lung abscess, pleural effusion and poorly evident subphrenic abscess after laparoscopic gastric bypass, due to a retained Endo-Catch bag. A 27-year-old obese female underwent an uneventful laparoscopic Roux-en-Y gastric bypass. After surgery she developed a left basal lung abscess, that resolved in two weeks with heavy antibiotic therapy, while radiological abdominal imaging was apparently normal. Patient was discharged on p.o. day 30. After two months, she presented with fever and dyspnoea and no gastrointestinal complaints. Chest and abdominal computer tomography showed a left recurrent abscess with effusion but this time a 3 cm subphrenic mass with metallic clips inside was demonstrated on CT scan. Patient was treated with an explorative laparoscopy that identified an Endo-Catch bag with the jejunal blind loop inside. Postoperative left lung abscess can be a warning of a suphrenic surgical complication. Laparoscopic surgery requires even more attention to retained foreign bodies due to the reduced visibility of the surgical field. The recommendation to enforce recording of laparoscopic maneuvers is mandatory. PMID- 23090830 TI - Angioleiomyoma of the oral cavity extended to submandibular space; an unusual tumor in an unusual deep-seated space: a case report. AB - Angioleiomyoma (AL) is a benign neoplasia originating from smooth muscle and very uncommon in the oral cavity. The most frequent subtype in the oral cavity is the vascular one. AL usually occurs in the extremities: only around 12% are found in other areas such as head and neck. It presents as an asymptomatic, slow growing nodule lodging in the palate, tongue or lips. The diagnosis is essentially by histological exam and special specific stains are helpful to confirm the origin and to distinguish it from other tumors. We present a case of AL found in unusual site: attached to the submandibular region in a deep-seated space. PMID- 23090831 TI - Improvement of renal function in epidermolysis bullosa patients after gluten free diet: two cases. AB - Epidermolysis bullosa (EB) is a rare inherited genetic disease characterized by an abnormal response of the skin and mucosa to mechanical trauma. Dystrophic EB (DEB) is very often associated with many extra cutaneous complications. Those complications involve either epithelial associated tissues or other organs. In particular, several renal complications have been described for DEB in the recessive form, such as amyloidosis, post-infection glomerulonephritis, upper and lower urinary tract obstruction and IgA-Nephropathy (IgAN). In the cases reported below we have two patients diagnosed with DEB that showed compromised renal function and proteinuria. The switch of the normal diet toward a gluten free diet resulted beneficial for both patients, since renal function was rescued and proteinuria cured. Moreover, a general health status improvement was recognised, given that nutritional condition was ameliorated and bone growing enhanced. Furthermore, in both patients the presence of autoantibodies anti-COL7 indicating an autoimmune form of the disease. Therefore, patients received low doses of betametasone useful to reduce inflammatory state and to control immune system function. In conclusion, our results prompt us to hypothesized that in these patients, due to the fragility of the intestinal mucosa, the absence in the diet of gluten may be beneficial. PMID- 23090832 TI - The confirmation of three repeated sequence elements in the 3' untranslated region of Chikungunya virus. AB - In this study, the complete genomic nucleotide sequence of Chikungunya virus (CHIKV) strain S27 African prototype was determined and three 21 nucleotides repeated sequence elements (RSEs) at positions 11398-11418, 11533-11553, and 11620-11640 in the 3' untranslated region (3'UTR) were confirmed. In addition, the 3'UTRs of all CHIKV strains deposited in GenBank were analyzed. The results displayed that the majority of the CHIKV strains consisted of the three 21 nucleotides RSEs in the 3'UTRs, and the third RSE was the most conservative. The conservation of the three RSEs of 21 nucleotides within the 3'UTR of CHIKV genome may play an important role on the virus replication cycle. PMID- 23090833 TI - A new begomovirus-betasatellite complex is associated with chilli leaf curl disease in Sri Lanka. AB - Leaf curl disease of chilli (LCDC) is a major constraint in production of chilli in the Indian subcontinent. The objective of this study was to identify the begomovirus species occurring in chilli in Sri Lanka, where the LCDC was initially recorded in 1938. The virus samples were collected from the North Central Province, the major chilli growing region in Sri Lanka with a history of epidemic prevalence of LCDC. The virus could be readily transmitted by Bemisia tabaci to chilli, tomato and tobacco, where vein clearing followed by leaf curl developed. The genome analysis of two isolates obtained from two distantly located fields showing 100 % LCDC, revealed that the DNA-A genome (2754 nucleotides) shared 89.5 % sequence identity with each other and 68.80-84.40 % sequence identity with the other begomoviruses occurring in the Indian subcontinent. The closest identity (84.40 %) of the virus isolates was with Tomato leaf curl Sri Lanka virus (ToLCLKV). The results support that a new begomovirus species is affecting chilli in Sri Lanka and the name Chilli leaf curl Sri Lanka virus (ChiLCSLV) is proposed. Recombination analysis indicated that ChiLCSLV was a recombinant virus potentially originated from the begomoviruses prevailing in southern India and Sri Lanka. The genome of betasatellite associated with the two isolates consisted of 1366 and 1371 nucleotides and shared 95.2 % sequence identity with each other and 41.50-73.70 % sequence identity with the other betasatellite species. The results suggest that a new begomovirus betasatellite, Chilli leaf curl Sri Lanka betasatellite is associated with LCDC in Sri Lanka. This study demonstrates a new species of begomovirus and betasatellite complex is occurring in chilli in Sri Lanka and further shows that diverse begomovirus species are affecting chilli production in the Indian subcontinent. PMID- 23090834 TI - Comparison of tenocytes and mesenchymal stem cells seeded on biodegradable scaffolds in a full-size tendon defect model. AB - In order to investigate cell-based tendon regeneration, a tendon rupture was simulated by utilizing a critical full-size model in female rat achilles tendons. For bridging the defect, polyglycol acid (PGA) and collagen type I scaffolds were used and fixed with a frame suture to ensure postoperatively a functional continuity. Scaffolds were seeded with mesenchymal stem cells (MSC) or tenocytes derived from male animals, while control groups were left without cells. After a healing period of 16 weeks, biomechanical, PCR, histologic, and electron microscopic analyses of the regenerates were performed. Genomic PCR for male specific gene was used to detect transplanted cells in the regenerates. After 16 weeks, central ossification and tendon-like tissue in the superficial tendon layers were observed in all study groups. Biomechanical test showed that samples loaded with tenocytes had significantly better failure strength/cross-section ratio (P < 0.01) compared to MSC and the control groups whereas maximum failure strength was similar in all groups. Thus, we concluded that the application of tenocytes improves the outcome in this model concerning the grade of ossification and the mechanical properties in comparison to the use of MSC or just scaffold materials. PMID- 23090835 TI - Nanoparticles of cobalt-substituted hydroxyapatite in regeneration of mandibular osteoporotic bones. AB - Indications exist that paramagnetic calcium phosphates may be able to promote regeneration of bone faster than their regular, diamagnetic counterparts. In this study, analyzed was the influence of paramagnetic cobalt-substituted hydroxyapatite nanoparticles on osteoporotic alveolar bone regeneration in rats. Simultaneously, biocompatibility of the material was tested in vitro, on osteoblastic MC3T3-E1 and epithelial Caco-2 cells in culture. The material was shown to be biocompatible and nontoxic when added to epithelial monolayers in vitro, while it caused a substantial decrease in the cell viability as well as deformation of the cytoskeleton and cell morphology when incubated with the osteoblastic cells. In the course of 6 months after the implantation of the material containing different amounts of cobalt, ranging from 5 to 12 wt%, in the osteoporotic alveolar bone of the lower jaw, the following parameters were investigated: histopathological parameters, alkaline phosphatase and alveolar bone density. The best result in terms of osteoporotic bone tissue regeneration was observed for hydroxyapatite nanoparticles with the largest content of cobalt ions. The histological analysis showed a high level of reparatory ability of the nanoparticulate material implanted in the bone defect, paralleled by a corresponding increase in the alveolar bone density. The combined effect of growth factors from autologous plasma admixed to cobalt-substituted hydroxyapatite was furthermore shown to have a crucial effect on the augmented osteoporotic bone regeneration upon the implantation of the biomaterial investigated in this study. PMID- 23090837 TI - A 3D AgCl hierarchical superstructure synthesized by a wet chemical oxidation method. AB - A novel 3D AgCl hierarchical superstructure, with fast growth along the <111> directions of cubic seeds, is synthesized by using a wet chemical oxidation method. The morphological structures and the growth process are investigated by scanning electron microscopy and X-ray diffraction. The crystal structures are analyzed by their crystallographic orientations. The surface energy of AgCl facets {100}, {110}, and {111} with absorbance of Cl(-) ions is studied by density functional theory calculations. Based on the experimental and computational results, a plausible mechanism is proposed to illustrate the formation of the 3D AgCl hierarchical superstructures. With more active sites, the photocatalytic activity of the 3D AgCl hierarchical superstructures is better than those of concave and cubic ones in oxygen evolution under irradiation by visible light. PMID- 23090836 TI - Role of leptin receptor (LEPR) gene polymorphisms and haplotypes in susceptibility to hepatocellular carcinoma in subjects with chronic hepatitis B virus infection. AB - AIM: The reported association of the leptin receptor (LEPR) protein with hepatocellular carcinoma (HCC) carcinogenesis prompted us to evaluate whether genetic polymorphisms of the LEPR gene affect susceptibility to HCC and its clinicopathologic characteristics. METHODS: A total of 417 subjects who were diagnosed with HCC and 551 age- and sex-matched subjects without HCC were enrolled in this study. All subjects had chronic hepatitis B virus (HBV) infection. Three single nucleotide polymorphisms (SNPs) of the LEPR gene were determined. RESULTS: The genotype frequencies of Lys109Arg and Gln223Arg differed significantly between HCC and non-HCC subjects (both p < 0.001). For the Lys109Arg polymorphism, HCC subjects had a higher prevalence of 109Arg/Arg than non-HCC subjects. The 109Arg/Arg carriers had a significantly higher adjusted risk of HCC than the 109Lys/Lys carriers. For the Gln223Arg polymorphism, subjects with the 223Arg/Arg genotype had a significantly higher risk of HCC than those with the 223Gln/Gln genotype. The Lys656Asn SNP did not affect the HCC risk. Haplotype analyses showed that subjects with 109Lys-656Lys-223Arg and 109Arg-656Asn-223Arg haplotypes had an increased HCC risk, while the 109Lys 656Lys-223Gln and 109Lys-656Asn-223Gln haplotypes had protective effects against HCC development. None of these polymorphisms were related to the clinicopathologic features of HCC. CONCLUSION: The Lys109Arg and Gln223Arg polymorphisms of the LEPR gene are associated with susceptibility to HCC but not with its clinicopathologic features. These polymorphisms may represent genetic markers for the risk of HCC in the context of chronic HBV infection. PMID- 23090838 TI - Craniosynostosis with wormian bone, bowing of the long bones, unilateral short femur, and focal fibula deficiency: a prenatal diagnostic dilemma. AB - The prenatal detection in the second trimester of pregnancy of a fetus with craniosynostosis, wide metopic suture, and wormian bone associated with bowing of the long bones, unilateral short femur, and focal fibula deficiency is reported. These ultrasonographic findings when not supported by a diagnostic molecular biology result represent a prenatal dilemma in term of both parent's counseling and management of potential overlapping skeletal diseases. PMID- 23090839 TI - Systematic review of efficacy, pharmacokinetics, and administration of intraventricular vancomycin in adults. AB - Central nervous system infections requiring treatment with intraventricular (IVT) vancomycin are becoming increasingly common with advent of intracranial devices and increasing prevalence of multi-drug resistant and nosocomial organisms. Administering vancomycin via IVT route bypasses the blood-brain barrier to allow localized and controlled delivery directly to the desired site of action, achieving high concentrations for more reliable bactericidal action. This article systematically reviews current literature on IVT vancomycin in adults, compiles current knowledge, and integrates available evidence to serve as a practical reference.Medline (1946-July 2012), Embase (1974-July 2012), and International Pharmaceutical Abstracts (1970-July 2012) were searched using terms vancomycin, intraventricular, shunt infection, cerebrospinal fluid, and intraventriculitis. Seventeen articles were included in this review. Indications for IVT vancomycin included meningitis unresponsive to intravenous antibiotics, ventriculitis, and intracranial device infections. No serious adverse effects following IVT vancomycin have been reported. Dosages reported in literature ranged from 0.075 50 mg/day, with the most evidence for dosages of 5 to 20 mg/day. Duration of therapy most commonly ranged from 7 to 21 days. Therapeutic drug monitoring was reported in 11 studies, with CSF vancomycin levels varying widely from 1.1 to 812.6 mg/L, without clear relationships between CSF levels and efficacy or toxicity. Using IVT vancomycin to treat meningitis, ventriculitis, and CNS device associated infections appears safe and effective based on current evidence. Optimal regimens are still unclear, and dosing of IVT vancomycin requires intricate consideration of patient specific factors and their impact on CNS pathophysiology. Higher-quality clinical trials are necessary to characterize the disposition of vancomycin within CNS, and to determine models for various pathophysiological conditions to facilitate better understanding of effects on pharmacokinetic and pharmacodynamic parameters. PMID- 23090841 TI - Possible genetic component to the etiology of perigraft hygromas. AB - Perigraft hygroma is a known complication of prosthetic graft implantation. The specific etiology of perigraft hygromas is still unknown. We report 2 brothers who underwent open abdominal aortic aneurysm repairs with polytetrafluoroethylene grafts that developed progressively enlarging perigraft hygromas. This is the first case report of 2 brothers developing sac hygromas after open abdominal aortic aneurysm repair. This case demonstrates that there could be a genetic component associated with the development of perigraft hygromas and further investigation of genetic etiologies should be considered. PMID- 23090840 TI - Anti-N-methyl-D-aspartate receptor encephalitis with favorable outcome despite prolonged status epilepticus. AB - BACKGROUND: To describe a case of auto-immune encephalitis in an adolescent with favorable outcome despite prolonged status epilepticus. METHODS: A 17 year old Asian man without previous medical history developed alteration of consciousness and partial seizures. The diagnosis of anti-N-methyl-D-aspartate receptor encephalitis was confirmed by the detection of specific antibodies in both cerebrospinal fluid and serum. RESULTS: The clinical course was complicated by prolonged status epilepticus which was refractory to a large number of antiepileptic drugs, including barbiturate coma. Immunomodulatory therapy included steroids, plasma exchanges, and intravenous immunoglobulins. After 86 days of intensive therapy, the patient regained consciousness progressively. Brain magnetic resonance imaging never demonstrated any lesion. Extensive search for a tumor was negative. At 12 month follow-up, the patient had made an excellent recovery. CONCLUSION: Auto-immune encephalitis is likely underdiagnosed in adolescents. In their most severe presentation, seizures may be resistant to a large number of anti-epileptic drugs, and the clinical improvement seems to be mainly because of the immunomodulatory therapy. Relapse is possible, as well as the delayed development of a teratoma or other tumor. PMID- 23090842 TI - Proteome-wide analysis of temporal phosphorylation dynamics in lysophosphatidic acid-induced signaling. AB - Most growth factor receptors trigger phosphorylation-based signal transduction to translate environmental stimuli into defined biological responses. In addition to comprehensive and reliable assessment of growth factor-induced phosphoregulation, temporal resolution is needed to gain insights into the organizing principles of the cellular signaling machinery. Here, we introduce a refined experimental design for MS-based phosphoproteomics to reconcile the need for high comprehensiveness and temporal resolution with the key requirement of monitoring biological reproducibility. We treated SILAC-labeled SCC-9 cells with the seven transmembrane receptor ligand lysophosphatidic acid (LPA) and identified more than 17 000 phosphorylation sites. Filtering for biological replicate quantification yielded five-time point profiles for 6292 site-specific phosphorylations, which we analyzed for statistically significant regulation. Notably, about 30% of these sites changed significantly upon LPA stimulation, indicating extensive phosphoproteome regulation in response to this growth factor. Analysis of time series data identified distinct temporal profiles for different kinase substrate motifs, likely reflecting temporal orchestration of cellular kinase activities. Our data further indicated coordinated regulation of biological processes and phosphoprotein networks upon LPA stimulation. Finally, we detected regulation of functionally characterized phosphorylation sites not yet implicated in LPA signaling, which may foster a better understanding how LPA regulates cellular physiology on the molecular level. PMID- 23090844 TI - Hard X-ray nanotomography of catalytic solids at work. PMID- 23090843 TI - Early alterations in mitochondrial reserve capacity; a means to predict subsequent photoreceptor cell death. AB - Although genetic and environmental factors contribute to neurodegenerative disease, the underlying etiology common to many diseases might be based on metabolic demand. Mitochondria are the main producer of ATP, but are also the major source of reactive oxygen species. Under normal conditions, these oxidants are neutralized; however, under environmental insult or genetic susceptibility conditions, oxidative stress may exceed cellular antioxidant capacities, leading to degeneration. We tested the hypothesis that loss in mitochondrial reserve capacity plays a causative role in neuronal degeneration and chose a cone photoreceptor cell line as our model. 661W cells were exposed to agents that mimic oxidant stress or calcium overload. Real-time changes in cellular metabolism were assessed using the multi-well Seahorse Biosciences XF24 analyzer that measures oxygen consumption (OCR) and extracellular acidification rates (ECAR). Cellular stress resulted in an early loss of mitochondrial reserve capacity, without affecting basal respiration; and ECAR was increased, representing a compensatory shift of ATP productions toward glycolysis. The degree of change in energy metabolism was correlated with the amount of subsequent cell death 24-hours post-treatment, the concentration-dependent loss in mitochondrial reserve capacity correlated with the number of live cells. Our data suggested first, that loss in mitochondrial reserve capacity is a major contributor in disease pathogenesis; and second, that the XF24 assay might represent a useful surrogate assay amenable to the screening of agents that protect against loss of mitochondrial reserve capacity. In future experiments, we will explore these concepts for the development of neuroprotective agents. PMID- 23090845 TI - Efficiency of different Agrobacterium rhizogenes strains on hairy roots induction in Solanum mammosum. AB - This article presents the abilities and efficiencies of five different strains of Agrobacterium rhizogenes (strain ATCC 31798, ATCC 43057, AR12, A4 and A13) to induce hairy roots on Solanum mammosum through genetic transformation. There is significant difference in the transformation efficiency (average number of days of hairy root induction) and transformation frequency for all strains of A. rhizogenes (P < 0.05). Both A. rhizogenes strain AR12 and A13 were able to induce hairy root at 6 days of co-cultivation, which were the fastest among those tested. However, the transformation frequencies of all five strains were below 30 %, with A. rhizogenes strain A4 and A13 showing the highest, which were 21.41 +/- 10.60 % and 21.43 +/- 8.13 % respectively. Subsequently, the cultures for five different hairy root lines generated by five different strains of bacteria were established. However, different hairy root lines showed different growth index under the same culture condition, with the hairy root lines induced by A. rhizogenes strain ATCC 31798 exhibited largest increase in fresh biomass at 45 days of culture under 16 h light/8 h dark photoperiod in half-strength MS medium. The slowest growing hairy root line, which was previously induced by A. rhizogenes strain A13, when cultured in optimized half-strength MS medium containing 1.5 times the standard amount of ammonium nitrate and potassium nitrate and 5 % (w/v) sucrose, had exhibited improvement in growth index, that is, the fresh biomass was almost double as compared to its initial growth in unmodified half-strength MS medium. PMID- 23090846 TI - A fast-initiating ionically tagged ruthenium complex: a robust supported pre catalyst for batch-process and continuous-flow olefin metathesis. AB - In this study, a new pyridinium-tagged Ru complex was designed and anchored onto sulfonated silica, thereby forming a robust and highly active supported olefin metathesis pre-catalyst for applications under batch and continuous-flow conditions. The involvement of an oxazine-benzylidene ligand allowed the reactivity of the formed Ru pre-catalyst to be efficiently controlled through both steric and electronic activation. The oxazine scaffold facilitated the introduction of the pyridinium tag, thereby affording the corresponding cationic pre-catalyst in good yield. Excellent activities in ring-closing (RCM), cross (CM), and enyne metathesis were observed with only 0.5 mol % loading of the pre catalyst. When this powerful pre-catalyst was immobilized onto a silica-based cationic-exchange resin, a versatile catalytically active material for batch reactions was generated that also served as fixed-bed material for flow reactors. This system could be reused at 1 mol % loading to afford metathesis products in high purity with very low ruthenium contamination under batch conditions (below 5 ppm). Scavenging procedures for both batch and flow processes were conducted, which led to a lowering of the ruthenium content to as little as one tenth of the original values. PMID- 23090847 TI - The effects of rejection sensitivity on reactive and proactive aggression. AB - The aim of this research was to use a pure measure of aggression to clarify whether rejection sensitive children exhibit higher levels of aggressive behavior than those who are not as rejection sensitive and to examine whether the components of rejection sensitivity (RS) vary according to the types of aggression. A total of 287 Australian primary school students aged between 9 and 12 completed self-report measures of RS and aggression. As expected, RS and its components, angry and anxious expectations of rejection, were linked to generalized aggression (GA) in adolescents, with angry expectations being more strongly associated with GA and in particular, proactive aggression. As expected, RS predicted reactive aggression better than it did proactive aggression and a three-way interaction was found whereby the relationship between the type of RS and aggression differed as a function of the type of aggression. The present study offers new evidence to support the theory that RS is predictive of aggressive behavior in children and clarifies some confusion about the attributional affect and processes behind this behavior. The findings both support and extend existing research in the areas of RS and aggression. PMID- 23090848 TI - Enzyme-cleavable tandem peptides for quantitative studies in MS-based proteomics. AB - A novel type of peptide standard is introduced that consists of two peptides combined in one synthetic molecule and separated by a proteolytic cleavage site. Upon enzymatic digestion, the two peptides are released in a molar one-to-one ratio. This method enables the generation of exact equimolar mixtures of two peptides of any nature and origin, thereby providing a valuable tool for the investigation of fundamental phenomena in MS. The applicability of the method is exemplified by the analysis of the effect of peptide sequence variations on the relative ionization efficiency in ESI- and MALDI-MS. PMID- 23090850 TI - Effect of BDNF-plasma-collagen matrix controlled delivery system on the behavior of adult rats neural stem cells. AB - The neurogenesis amount in central nervous system (CNS) stimulated by the injury or diseases is so small that neural stem cells (NSCs) cannot specifically differentiate into the ideal phenotypes to repair the injured CNS. The transplanted exogenous NSCs also have such problems as poor survival and insufficient neuronal differentiation. In this study, the behavior of NSCs from the spinal cord of adult rats was compared at the neurosphere level after the respective addition of the brain-derived neurotrophic factor (BDNF) daily, the BDNF-loaded plasma-collagen matrix, the plasma-collagen matrix alone, or the defined medium alone. The results suggested that the BDNF, either in the control release form or in the soluble form, initiated NSCs proliferation and differentiation by activating receptors Trk B and p75NTR. BDNF also increased the differentiation percentage of adult NSCs into neurons and supported the long-term cell survival and growth. The BDNF was stably released by the plasma-collagen matrix for up to 21 days. The plasma-collagen matrix alone showed its biocompatibility with cells by facilitating the adhesion, survival, and differentiation of NSCs. The NSCs in the defined medium alone group showed poor survival and a very low level of neuronal differentiation and proliferation abilities than above three groups. This study suggested that the BDNF-loaded plasma-collagen matrix may provide a promising means to resolve either the poor survival and insufficient neuronal differentiation of transplanted exogenous NSCs, or stimulating the intrinsic NSCs to proliferate and differentiate into neurons so as to repair the injured adult CNS. PMID- 23090849 TI - Testing for phytochemical synergism: arthropod community responses to induced plant volatile blends across crops. AB - Using herbivore-induced plant volatiles (HIPVs) to attract specific natural enemies in the field has proven challenging, partly because of a poor understanding of: (i) which compound(s) to manipulate to attract specific taxa, and (ii) the ecological conditions over which HIPVs are effective. To address these issues, we quantified the response of a complex arthropod community to three common HIPVs (methyl salicylate, cis-3-hexen-1-ol, and phenylethyl alcohol) as individual compounds and equal part blends in corn and soybean fields. Of 119 arthropod taxa surveyed, we found significant responses by four species in corn fields (2 parasitoids, 1 herbivore, and 1 detritivore) and 16 in soybean fields (8 parasitoids, 3 predators, 4 herbivores, and 1 detritivore), with both attractive and repellent effects of the HIPVs observed. For example, tachinid flies were highly attracted to cis-3-hexen-1-ol (ca. 3-fold increase), but repelled by methyl salicylate (ca. 60 % decrease). Surprisingly, we found very few cases in which HIPVs acted synergistically; only two arthropod groups (ichneumonid wasps and phorid flies) were more attracted by a blend of the HIPVs than by the individual compounds composing the blend. Crop type, however, had a strong impact on the strength of arthropod responses to HIPVs. A few arthropod species were broadly affected across both crops (i.e., the herbivore Halticus bractatus was repelled by most of our treatments, regardless of crop background), but overall more arthropod groups responded to HIPVs released in soybean fields compared with corn. This was true despite the fact that taxa responding to HIPVs were present and abundant in both systems, suggesting that crop-based outcomes were likely driven by the plant matrix rather than mere differences in taxonomic composition of the arthropod community in corn vs. soybean fields. As a whole, these results suggest that: (i) repellent effects of HIPVs on natural enemies of herbivorous insects can be observed as frequently as attractive effects; (ii) odor blends may be no more effective than single-compound lures for some taxa; and (iii) crop background alters the magnitude of attraction to HIPVs, depending on the species being targeted. PMID- 23090851 TI - Structure-selective catalytic alkylation of DNA and RNA. PMID- 23090852 TI - High-resolution optical mapping of inflammatory macrophages following endovascular arterial injury. AB - PURPOSE: Inflammation following arterial injury mediates vascular restenosis, a leading cause of cardiovascular morbidity. Here we utilize intravital microscopy (IVM) and a dextran-coated nanosensor to spatially map inflammatory macrophages in vivo following endovascular injury of murine carotid arteries. PROCEDURES: C57Bl/6 mice (n = 23) underwent endovascular guidewire carotid arterial injury. At day 14 or day 28 post-injury, mice underwent fluorescence IVM, 24 h after injection with the near-infrared fluorescent macrophage nanosensor CLIO-VT680. Adventitial collagen was concomitantly imaged using second harmonic generation (SHG) IVM. Correlative fluorescence microscopy and immunohistochemistry were performed. RESULTS: Two-plane IVM reconstructions detected macrophage inflammation in the arterial wall that was elevated at day 14 compared to day 28 animals (P < 0.05). SHG-based collagen imaging of the outer arterial wall facilitated analysis of the macrophage-rich, inflamed neointima. Histological analyses and fluorescence microscopy data demonstrated increased macrophage infiltration in day 14 compared to day 28 neointima. CONCLUSIONS: We demonstrate that the macrophage response to arterial injury can be imaged in vivo using IVM based molecular imaging, and shows a higher macrophage influx at day 14 compared to day 28 post-injury. PMID- 23090853 TI - Dynamic changes of FDG uptake and clearance in normal tissues. AB - PURPOSE: This study aims to evaluate dynamic 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake in normal tissues. PROCEDURES: Thirty male patients underwent FDG positron emission tomography (PET)/computed tomography imaging at 1, 2, and 3 h after tracer injection. Standardized uptake values (SUV) were obtained in regions of interest of normal tissues. RESULTS: The aorta (blood pool), liver, and spleen FDG activity demonstrated significantly and continuously decreased activity from 1 to 2 and 2 to 3 h, while FDG uptake in the lungs, pancreas, lymph nodes, and skeletal muscle decreased from 1 to 2 h only. In contrast, the left ventricular myocardium demonstrated two patterns of dynamic changes: myocardium with higher FDG uptake (SUVmax >= 3.25) on the initial images had more remarkable increased activity on the delayed images, while myocardium with lower FDG uptake (SUVmax < 3.25) on the initial imaging had no increased uptake on delayed imaging. Increased FDG uptake was also observed in the bones on the delayed images. No significant changes of FDG uptake were noted in the parotid gland, thyroid gland, and prostate gland. CONCLUSIONS: These findings may help nuclear medicine physicians when comparing images performed at different time points, when using FDG uptake in internal reference regions as a relative indicator of FDG uptake in a specific lesion, and when reading a delayed FDG PET imaging. PMID- 23090854 TI - Postnatal longitudinal evaluation of children diagnosed with prenatal hydronephrosis: insights in natural history and referral pattern. AB - OBJECTIVES: Clinical significance and management of prenatal hydronephrosis (PNH) are sources of debate. Existing studies are flawed with biased cohorts or inconsistent follow-up. We aimed to evaluate the incidence of pathology in a large cohort of PNH and assess the biases and outcomes of this population. METHODS: We reviewed 1034 charts of fetuses with PNH. Records of delivered offspring were reviewed at a pediatric center and analyzed with respect to prenatal and postnatal pathology and management. RESULTS: Prenatal resolution of hydronephrosis occurred in 24.7% of pregnancies. On first postnatal ultrasound, some degree of dilatation was present in 80%, 88% and 95% of mild, moderate and severe PNH cases, respectively. At the end of follow-up, hydronephrosis persisted in 10%, 25% and 72% of children, respectively. Incidence of vesicoureteral reflux did not correlate with severity of PNH. Children with postnatal workup had more severe PNH than those without. CONCLUSIONS: Despite prenatal resolution totalizing 25%, pelvic dilatation persisted on first postnatal imaging in most cases, thus justifying postnatal ultrasound evaluation. Whereas most mild cases resolved spontaneously, a quarter of moderate and more than half of severe cases required surgery. Patients with postnatal imaging and referral had more severe PNH, which could result in overestimation of pathology. PMID- 23090855 TI - Prospective study on metabolic factors and risk of prostate cancer. AB - BACKGROUND: There are inconsistent data regarding the association between metabolic factors, separately and combined, and the risk of prostate cancer and death from prostate cancer. METHODS: In the Metabolic Syndrome and Cancer Project (Me-Can), data on body mass index (BMI); blood pressure; and blood levels of glucose, cholesterol, and triglycerides were collected for 289,866 men. Cox proportional hazard models were used to calculate relative risks (RRs) by exposures in quintiles as well as for z scores (with a mean of 0 and a standard deviation of 1) together with a composite sum of scores to assess the combined effect of metabolic factors. RRs were corrected for random errors in measurement. RESULTS: During a mean follow-up of 12 years, 6673 men were diagnosed with prostate cancer and 961 died of the disease. Men with high levels of glucose and triglycerides were found to have a decreased risk of prostate cancer: top versus bottom quintile of glucose: RR, 0.82 (95% confidence interval [95% CI], 0.62 1.08; P value for trend = .03) and top versus bottom quintile of triglycerides: RR, 0.88 (95% CI, 0.74-1.04; P value for trend = .001). High BMI, elevated blood pressure, and a high composite z score were found to be associated with an increased risk of death from prostate cancer: top versus bottom quintile of BMI: RR, 1.36 (95% CI, 1.08-1.71); systolic blood pressure: RR, 1.62 (95% CI, 1.07 2.45); and per 1-unit increase of the composite z score: RR, 1.13 (95% CI, 1.03 1.25). CONCLUSIONS: The authors found no evidence of an association between high levels of metabolic factors and the risk of prostate cancer, but high BMI, elevated blood pressure, and a composite score of all metabolic factors were associated with an increased risk of death from prostate cancer. PMID- 23090856 TI - Solvent- and light-controlled unidirectional transit of a nonsymmetric molecular axle through a nonsymmetric molecular wheel. AB - The development of a pseudorotaxane motif capable of performing unidirectional threading and dethreading processes under control of external stimuli is particularly important for the construction of processive linear motors based on rotaxanes and, at least in principle, it discloses the possibility to access to rotary motors based on catenanes. Here, we report a strategy to obtain the solvent-controlled unidirectional transit of a molecular axle through a molecular wheel. It is based on the use of appropriately designed molecular components, the essential feature of which is their non-symmetric structure. Specifically they are an axle containing a central electron-acceptor 4,4'-bipyridinium core functionalized with a hexanol chain at one side, and a stilbene unit connected through a C6 chain at the other side, and a heteroditopic tris(phenylureido) calix[6]arene wheel. In apolar solvents the axle threads into the wheel from its upper rim and with the end carrying the OH group, giving an oriented pseudorotaxane structure. After a stoppering reaction, which replaces the small hydroxy group with a bulky diphenylacetyl moiety, and replacement of the apolar solvent with a polar one, dethreading occurs through the slippage of the stilbene unit from the lower rim of the wheel, that is, in the same direction of the threading process. The essential role played by the stilbene unit to achieve the unidirectional transit of the axle through the wheel, and to tune the dethreading rate by light is also demonstrated. PMID- 23090858 TI - Facilitating responsible gambling: the relative effectiveness of education-based animation and monetary limit setting pop-up messages among electronic gaming machine players. AB - Although most gamblers set a monetary limit on their play, many exceed this limit -an antecedent of problematic gambling. Responsible gambling tools may assist players to gamble within their means. Historically, however, the impact of such tools has been assessed in isolation. In the current research, two responsible gambling tools that target adherence to a monetary limit were assessed among 72 electronic gaming machine (EGM) players. Participants watched an educational animation explaining how EGMs work (or a neutral video) and then played an EGM in a virtual reality environment. All participants were asked to set a monetary limit on their play, but only half were reminded when that limit was reached. Results showed that both the animation and pop-up limit reminder helped gamblers stay within their preset monetary limit; however, an interaction qualified these main effects. Among participants who did not experience the pop-up reminder, those who watched the animation stayed within their preset monetary limits more than those who did not watch the animation. For those who were reminded of their limit, however, there was no difference in limit adherence between those who watched the animation and those who did not watch the animation. From a responsible gambling perspective, the current study suggests that there is no additive effect of exposure to both responsible gambling tools. Therefore, for minimal disruption in play, a pop-up message reminding gamblers of their preset monetary limit might be preferred over the lengthier educational animation. PMID- 23090857 TI - Emerging genetics of COPD. AB - Since the discovery of alpha-1 antitrypsin in the early 1960s, several new genes have been suggested to play a role in chronic obstructive pulmonary disease (COPD) pathogenesis. Yet, in spite of those advances, much about the genetic basis of COPD still remains to be discovered. Unbiased approaches, such as genome wide association (GWA) studies, are critical to identify genes and pathways and to verify suggested genetic variants. Indeed, most of our current understanding about COPD candidate genes originates from GWA studies. Experiments in form of cross-study replications and advanced meta-analyses have propelled the field towards unravelling details about COPD's pathogenesis. Here, we review the discovery of genetic variants in association with COPD phenotypes by discussing the available approaches and current findings. Limitations of current studies are considered and future directions provided. PMID- 23090859 TI - Effect of Ni(II) on inflammatory gene expression in THP1 monocytic cells. AB - Nickel-containing alloys are in common use for dental restorations, but tend to corrode and release Ni(II) in service. Ni(II) increases secretion of several inflammatory cytokines from activated monocytic cells, suggesting that nickel alloys may exaggerate inflammatory responses in adjacent periodontal tissues. In this work, the effects of Ni(II) on expression of inflammatory cytokine and receptor genes as well as nuclear factor-kappa B (NFkappaB)-related genes were assessed using quantitative real-time polymerase chain reaction (PCR) and PCR based arrays in the human THP1 monocytic cell line pre-exposed to Ni(II) for 72 h, then activated by lipopolysaccharide. The expression of 10 inflammatory genes was down-regulated >=50% by Ni(II) versus non-Ni(II) controls, whereas some genes like IL8 were up-regulated significantly by Ni(II). Expression of seven NFkappaB related genes was up-regulated by Ni(II) by >=50%, and HMOX1 expression, a redox protein regulated by NRF2, was increased by >500%. The current results suggest that Ni(II) has diverse effects on inflammatory gene expression, which may partly account for previous reports of Ni(II)-induced changes in inflammatory cytokine secretion from monocytes and alterations in NFkappaB regulation. Further work is needed to verify these effects in primary cells and to ascertain how Ni(II) alters gene expression. PMID- 23090860 TI - The generation, detection, and effects of reactive drug metabolites. AB - The decline in approval of new drugs during the past decade has led to a close analysis of the drug discovery process. One of the main reasons for attrition is preclinical toxicity, frequently attributed to the generation of protein-reactive drug metabolites. In this review, we present a critique of such reactive metabolites and evaluate the evidence linking them to observed toxic effects. Methodology for the characterization of reactive metabolites has advanced greatly in recent years, and is summarized first. Next, we consider the inhibition of key metabolic enzymes by electrophilic metabolites, as well as unfavorable drug-drug interactions that may ensue. One important class of protein-reactive metabolites, not linked conclusively to a toxic event, is acyl glucuronides. Their properties are discussed in light of the safety characteristics of carboxylic acid containing drugs. Many adverse drug reactions (ADRs) are known collectively as idiosyncratic events, that is, not predictable from knowledge of the pharmacology and pharmacokinetics of the parent compound. Observed ADRs may take various forms. Specific organ injury, particularly of the liver, is the most direct: we examine this in some detail. Moving to the cellular level, we also consider the upregulation of induced cellular processes. The related, but distinct, issue of hypersensitivity or allergic reactions to drugs and their metabolites, possibly via the immune system, is considered next. Finally, we discuss the impact of such data on the drug discovery process, both through early detection of reactive metabolites and informed synthetic design, which eliminates unfavorable functionality from drug candidates. PMID- 23090862 TI - Light-driven coordination-induced spin-state switching: rational design of photodissociable ligands. AB - The bistability of spin states (e.g., spin crossover) in bulk materials is well investigated and understood. We recently extended spin-state switching to isolated molecules at room temperature (light-driven coordination-induced spin state switching, or LD-CISSS). Whereas bistability and hysteresis in conventional spin-crossover materials are caused by cooperative effects in the crystal lattice, spin switching in LD-CISSS is achieved by reversibly changing the coordination number of a metal complex by means of a photochromic ligand that binds in one configuration but dissociates in the other form. We present mathematical proof that the maximum efficiency in property switching by such a photodissociable ligand (PDL) is only dependent on the ratio of the association constants of both configurations. Rational design by using DFT calculations was applied to develop a photoswitchable ligand with a high switching efficiency. The starting point was a nickel-porphyrin as the transition-metal complex and 3 phenylazopyridine as the photodissociable ligand. Calculations and experiments were performed in two iterative steps to find a substitution pattern at the phenylazopyridine ligand that provided optimum performance. Following this strategy, we synthesized an improved photodissociable ligand that binds to the Ni porphyrin with an association constant that is 5.36 times higher in its trans form than in the cis form. The switching efficiency between the diamagnetic and paramagnetic state is efficient as well (72% paramagnetic Ni-porphyrin after irradiation at 365 nm, 32% paramagnetic species after irradiation at 440 nm). Potential applications arise from the fact that the LD-CISSS approach for the first time allows reversible switching of the magnetic susceptibility of a homogeneous solution. Photoswitchable contrast agents for magnetic resonance imaging and light-controlled magnetic levitation are conceivable applications. PMID- 23090861 TI - Obstructive sleep apnea and acute myocardial infarction severity: ischemic preconditioning? AB - BACKGROUND: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH). In animal models, IH has been shown to protect the myocardium during periods of ischemia by reducing infarct size. However, this phenomenon of "ischemic preconditioning" has not been investigated among OSA patients with acute myocardial infarction (MI). This study investigates the role of OSA on MI severity as measured by cardiac enzymes, specifically troponin-T, among patients with an acute MI. METHODS: This is an observational cohort study of patients >=18 years of age who were hospitalized with an acute MI. Each participant underwent portable sleep monitoring (Apnea Link Plus); OSA was defined as an apnea-hypopnea index >=5/h. Multivariable regression analysis was conducted to assess the relationship between OSA and highly sensitive troponin-T levels. RESULTS: In our entire cohort of acute MI patients (n = 136), 77 % of the sample had evidence of sleep disordered breathing, with 35 % of the sample having OSA (i.e., an AHI >5). Higher AHI was associated with lower peak troponin-T levels in partially adjusted models (beta = -0.0320, p = 0.0074, adjusted for age, gender, and race) and fully adjusted models (beta = -0.0322, p = 0.0085) (additionally adjusted for smoking, hypertension, hyperlipidemia, body mass index, history of prior cardiovascular or cerebrovascular disease, diabetes and baseline admission creatinine levels). The mean value of the log-transformed peak troponin-T variable was used to dichotomize the outcome variable. In both partially (OR 0.949, CI 0.905-0.995, p = 0.03) and fully adjusted (OR 0.918, CI 0.856-0.984, p = 0.0151) logistic regression models, the OR for AHI suggests a protective effect on high troponin-T level. CONCLUSIONS: Our study demonstrates that patients with OSA have less severe cardiac injury during an acute non-fatal MI when compared to patients without OSA. This may suggest a cardioprotective role of sleep apnea during acute MI via ischemic preconditioning. PMID- 23090863 TI - Design of an active site towards optimal electrocatalysis: overlayers, surface alloys and near-surface alloys of Cu/Pt(111). PMID- 23090864 TI - Local extraction and condensation under a microscope using the optically controlled phase separation of a thermoresponsive polymer. AB - In-situ extraction and condensation of various dyes were carried out in a phase separation region of a thermoresponsive polymer aqueous solution generated by near infrared (NIR) laser heating under a microscope. The NIR laser irradiation was directed at a chromium line deposited on a glass substrate, thereby causing local heating of the solution due to the photothermal effect. A phase-separation region was formed by dehydration of the thermoresponsive polymer followed by ejection of water outside of the phase-separation region. When various dyes were included in the solution, some dye molecules were extracted into the phase separation region, where they condensed. In the case of poly(N isopropylacrylamide) (PNIPAM, 10 wt% in an aqueous solution) as the thermoresponsive polymer and crystal violet (CV) as the dye (0.1 mM), CV condensed by about 25 times. It was found that one of the necessary conditions for the extraction/condensation is the hydrophobicity of the dye molecule; however, the dominant cause for accumulating inside the PNIPAM chain is the molecular interaction between the amide group in the side chain of PNIPAM and the functional groups such as carbonyl or amino groups in the dye molecules. PMID- 23090865 TI - Development of D-lysine-assisted 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide/N hydroxysuccinimide-initiated cross linking of collagen matrix for design of scaffold. AB - This work discusses the preparation and characterization of collagen scaffold with presence of D-Lysine (Coll-D-Lys)-assisted 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC)/N-hydroxysuccinimide (NHS)-initiated cross linking. The mechanical strength, thermal and structural stability, resistance to biodegradation and cell viability of this scaffold was investigated. The results of the Coll-D-Lys-EDC/NHS scaffold also indicate an increase in the tensile strength (T(S)), percentage of elongation (% E), denaturation temperature (T(d)), and decrease the decomposition rate. Scanning electron microscopic (SEM) and atomic force microscopic (AFM) analyses revealed a well ordered with properly oriented and well-aligned structure of scaffold. The D-Lys stabilizes the scaffold against degradation by collagenase than L-Lys. The cell assay showed more than 98 +/- 2% fibroblast viability (NIH 3T3) after 72 h of culture Coll-D Lys-scaffold when compared with native Coll and Coll-L-Lys-scaffold. The proteolytic machinery is not well equipped to deal with Coll-D-Lys-scaffold than Coll-L-Lys-scaffold. Incorporating D-Lys in scaffold design has the potential to improve existing collagen stability and create new topologies inaccessible to homochiral molecules. This method may assist in the functionalization of the scaffold for regenerative applications. PMID- 23090866 TI - High magnetic moments in manganese-doped silicon clusters. AB - We report on the structural, electronic, and magnetic properties of manganese doped silicon clusters cations, Si(n)Mn(+) with n=6-10, 12-14, and 16, using mass spectrometry and infrared spectroscopy in combination with density functional theory computations. This combined experimental and theoretical study allows several structures to be identified. All the exohedral Si(n)Mn(+) (n=6-10) clusters are found to be substitutive derivatives of the bare Si(n+1)(+) cations, while the endohedral Si(n)Mn(+) (n=12-14 and 16) clusters adopt fullerene-like structures. The hybrid B3P86 functional is shown to be appropriate in predicting the ground electronic states of the clusters and in reproducing their infrared spectra. The clusters turn out to have high magnetic moments localized on Mn. In particular the Mn atoms in the exohedral Si(n)Mn(+) (n=6-10) clusters have local magnetic moments of 4 MU(B) or 6 MU(B) and can be considered as magnetic copies of the silicon atoms. Opposed to other 3d transition-metal dopants, the local magnetic moment of the Mn atom is not completely quenched when encapsulated in a silicon cage. PMID- 23090867 TI - Genomic and post-genomic effects of cigarette smoke: mechanisms and implications for risk assessment and prevention strategies. PMID- 23090868 TI - [(=SiO)Ta(V)Cl2Me2]: a well-defined silica-supported tantalum(V) surface complex as catalyst precursor for the selective cocatalyst-free trimerization of ethylene. PMID- 23090869 TI - Biorecognition on graphene: physical, covalent, and affinity immobilization methods exhibiting dramatic differences. AB - The preparation of biorecognition layers on the surface of a sensing platform is a very crucial step for the development of sensitive and selective biosensors. Different protocols have been used thus far for the immobilization of biomolecules onto various electrode surfaces. In this work, we investigate how the protocol followed for the immobilization of a DNA aptamer affects the performance of the fabricated thrombin aptasensor. Specifically, the differences in selectivity and optimum amount of immobilized aptamer of the fabricated aptasensors adopting either physical, covalent, or affinity immobilization were compared. It was discovered that while all three methods of immobilization uniformly show a similar optimum amount of immobilized aptamer, physical, and covalent immobilization methods exhibit higher selectivity than affinity immobilization. Hence, it is believed that our findings are very important in order to optimize and improve the performance of graphene-based aptasensors. PMID- 23090871 TI - Molecular gauge blocks for building on the nanoscale. AB - Molecular gauge blocks, based on 1-7, 9-11 paraxylene rings, have been synthesized as part of a homologous series of oligoparaxylenes (OPXs) with a view to providing a molecular tool box for the construction of nano architectures-such as spheres, cages, capsules, metal-organic frameworks (MOFs), metal-organic polyhedrons (MOPs) and covalent-organic frameworks (COFs), to name but a few-of well-defined sizes and shapes. Twisting between the planes of contiguous paraxylene rings is generated by the steric hindrance associated with the methyl groups and leads to the existence of soluble molecular gauge blocks without the need, at least in the case of the lower homologues, to introduce long aliphatic side chains onto the phenylene rings in the molecules. Although soluble molecular gauge blocks with up to seven consecutive benzenoid rings have been prepared employing repeating paraxylene units, in the case of the higher homologues it becomes necessary to introduce hexyl groups instead of methyl groups onto selected phenylene rings to maintain solubility. A hexyl-doped compound with seven substituted phenylene rings was found to be an organogelator, exhibiting thermally reversible gelation and a critical gelation concentration of 10 mM in dimethyl sulfoxide. Furthermore, control over the morphology of a series of hexyl doped OPXs to give microfibers, microaggregates, or nanofibers, was observed as a function of their lengths according to images obtained by scanning electron microscopy. The modular syntheses of the paraphenylene derivatives rely heavily on Suzuki-Miyaura cross-coupling reactions. The lack of pi-pi conjugation in these derivatives that is responsible for their enhanced solubilities was corroborated by UV/Vis and fluorescent spectroscopy. In one particular series of model OPXs, dynamic (1)H NMR spectroscopy was used to probe the stereochemical consequences of having from one up to five axes of chirality present in the same molecule. The Losanitsch sequence for the compounds with 1-3 chiral axes was established, and a contemporary mathematical way was found to describe the sequence. The development of the ways and means to make molecular gauge building blocks will have positive repercussions on the control of nanostructures in general. Their incorporation into extended structures with the MOF-74 topology provides an excellent demonstration of the potential usefulness of these molecular gauge blocks. PMID- 23090870 TI - Effectiveness of a web-based protocol for the screening and phenotyping of individuals with Tourette syndrome for genetic studies. AB - Genome-wide association studies (GWAS) and other emerging technologies offer great promise for the identification of genetic risk factors for complex psychiatric disorders, yet such studies are constrained by the need for large sample sizes. Web-based collection offers a relatively untapped resource for increasing participant recruitment. Therefore, we developed and implemented a novel web-based screening and phenotyping protocol for genetic studies of Tourette syndrome (TS), a childhood-onset neuropsychiatric disorder characterized by motor and vocal tics. Participants were recruited over a 13-month period through the membership of the Tourette Syndrome Association (TSA; n = 28,878). Of the TSA members contacted, 4.3% (1,242) initiated the questionnaire, and 79.5% (987) of these were enrollment eligible. 63.9% (631) of enrolled participants completed the study by submitting phenotypic data and blood specimens. Age was the only variable that predicted study completion; children and young adults were significantly less likely to be study completers than adults 26 and older. Compared to a clinic-based study conducted over the same time period, the web based method yielded a 60% larger sample. Web-based participants were older and more often female; otherwise, the sample characteristics did not differ significantly. TS diagnoses based on the web-screen demonstrated 100% accuracy compared to those derived from in-depth clinical interviews. Our results suggest that a web-based approach is effective for increasing the sample size for genetic studies of a relatively rare disorder and that our web-based screen is valid for diagnosing TS. Findings from this study should aid in the development of web based protocols for other disorders. PMID- 23090873 TI - Tailored mesostructured copper/ceria catalysts with enhanced performance for preferential oxidation of CO at low temperature. PMID- 23090872 TI - The association of intergroup encounters, dominance status, and fecal androgen and glucocorticoid profiles in wild male white-faced capuchins (Cebus capucinus). AB - Androgens play a role in male reproductive competition, frequently via aggression, while glucocorticoids are associated with the stress response. However, the relationships of these hormones with different sources of competition (intra- vs. intergroup) and dominance status are highly variable. Here, we consider the fecal androgen (fA) and glucocorticoid (fGC) profiles of alpha and subordinate male Cebus capucinus in the context of intergroup competition during a rare period of low intragroup competition (i.e. all females were either pregnant or lactating). Intergroup encounters (IGEs) are a long-term reproductive strategy in male white-faced capuchins, enabling them to assess the composition of neighboring groups. IGEs pose a threat to resident males as these can result in injury or death, loss of dominance rank, group eviction, and group takeovers that are frequently associated with infanticide. From February to July 2007, fecal samples were collected from eight males in three groups of white faced capuchins in the Santa Rosa Sector of the Area de Conservacion Guanacaste, Costa Rica. IGE rate was positively associated with both fA and fGC levels, indicating that IGEs are perceived as reproductive challenges by resident males, and may be associated with elevated metabolic costs. Alpha males sire the majority of group offspring and, accordingly, the threat of IGEs to both future (via rank loss or eviction) and current (via infanticide) reproductive success is greater than for subordinate males. Consistent with this observation, alpha males had higher fA and fGC levels than subordinate males. Given that all females were either pregnant or lactating and pronounced overt intragroup competition was absent, we interpret the difference in hormone profiles of alpha and subordinate males as being primarily associated with variation in the perceived threats of IGEs according to dominance status. Future studies should focus on the interaction of intra- and intergroup competition by examining hormone levels in the presence of periovulatory females. PMID- 23090874 TI - Synthesis and photocatalytic activity of poly(triazine imide). AB - Poly(triazine imide) was synthesized with incorporation of Li(+) and Cl(-) ions (PTI/Li(+)Cl(-)) to form a carbon nitride derivative. The synthesis of this material by the temperature-induced condensation of dicyandiamide was examined both in a eutectic mixture of LiCl-KCl and without KCl. On the basis of X-ray diffraction measurements of the synthesized materials, we suggest that a stoichiometric amount of LiCl is necessary to obtain the PTI/Li(+)Cl(-) phase without requiring the presence of KCl at 873 K. PTI/Li(+)Cl(-) with modification by either Pt or CoO(x) as cocatalyst photocatalytically produced H(2) or O(2), respectively, from water. The production of H(2) or O(2) from water indicates that the valence and conduction bands of PTI/Li(+)Cl(-) were properly located to achieve overall water splitting. The treatment of PTI/Li(+)Cl(-) with [Pt(NH(3))(4)](2+) cations enabled the deposition of Pt through ion exchange, demonstrating photocatalytic activity for H(2) evolution, while treatment with [PtCl(6)](2-) anions resulted in no Pt deposition. This was most likely because of the preferential exchange between Li(+) ions and [Pt(NH(3))(4)](2+) cations. PMID- 23090875 TI - P-glycoprotein and cytochrome P450 3A act together in restricting the oral bioavailability of paclitaxel. AB - Paclitaxel is avidly transported by P-glycoprotein (P-gp/MDR1/ABCB1). This results in low oral bioavailability, which can be boosted by coadministration of P-gp inhibitors. Unlike paclitaxel, docetaxel is extensively metabolized by CYP3A4 and its oral bioavailability can be enhanced in mice and humans by coadministration of the potent CYP3A inhibitor ritonavir. Unexpectedly, ritonavir also enhances the oral bioavailability of paclitaxel in humans. We aimed to resolve the mechanism underlying this enhancement. Using mice lacking Cyp3a and/or P-gp, we investigated the combined and separate restricting roles of Cyp3a and P-gp in the oral bioavailability of paclitaxel, and the boosting effect of ritonavir. CYP3A4-humanized mice were used for translation to the human situation. P-gp had a dominant effect (11.6-fold, p < 0.001) over Cyp3a (<1.5 fold, n.s.) in limiting plasma concentrations of oral paclitaxel. However, in the absence of P-gp, Cyp3a decreased paclitaxel plasma concentrations twofold (p < 0.001). Coadministered ritonavir inhibited Cyp3a-mediated metabolism, but not P gp-mediated transport of paclitaxel. Owing to the dominant effect of P-gp, ritonavir enhanced only paclitaxel plasma concentrations in P-gp-deficient mice. Mouse liver microsomes metabolized paclitaxel far less efficiently than human or CYP3A4-transgenic liver microsomes, revealing much lower efficiency of paclitaxel metabolism by mouse than by human CYP3As. Accordingly, ritonavir could enhance the oral bioavailability of paclitaxel in CYP3A4-humanized mice, despite the fact that these mice are P-gp-proficient. Our results show that CYP3A4 inhibition most likely underlies the boosting effect of ritonavir on oral paclitaxel bioavailability in humans. Furthermore, CYP3A4-humanized mice allow improved understanding of CYP3A4-mediated paclitaxel metabolism in humans. PMID- 23090876 TI - Template-free fabrication of Bi2O3 and (BiO)2CO3 nanotubes and their application in water treatment. AB - Uniform bismuth oxide (Bi(2)O(3)) and bismuth subcarbonate ((BiO)(2)CO(3)) nanotubes were successfully synthesized by a facile solvothermal method without the need for any surfactants or templates. The synergistic effect of ethylene glycol (EG) and urea played a critical role in the formation of the tubular nanostructures. These Bi(2)O(3) and (BiO)(2)CO(3) nanotubes exhibited excellent Cr(VI)-removal capacity. Bi(2)O(3) nanotubes, with a maximum Cr(VI)-removal capacity of 79 mg g(-1), possessed high removal ability in a wide range of pH values (3-11). Moreover, Bi(2)O(3) and (BiO)(2)CO(3) nanotubes also displayed highly efficient photocatalytic activity for the degradation of RhB under visible light irradiation. This work not only demonstrates a new and facile route for the fabrication of Bi(2)O(3) and (BiO)(2)CO(3) nanotubes, but also provides new promising adsorbents for the removal of heavy-metal ions and potential photocatalysts for environmental remediation. PMID- 23090877 TI - Maternal prenatal smoking and offspring emotional problems: no moderating effect of maternal or child 5-HTTLPR genotype. PMID- 23090878 TI - Constrained parametric model for simultaneous inference of two cumulative incidence functions. AB - We propose a parametric regression model for the cumulative incidence functions (CIFs) commonly used for competing risks data. The model adopts a modified logistic model as the baseline CIF and a generalized odds-rate model for covariate effects, and it explicitly takes into account the constraint that a subject with any given prognostic factors should eventually fail from one of the causes such that the asymptotes of the CIFs should add up to one. This constraint intrinsically holds in a nonparametric analysis without covariates, but is easily overlooked in a semiparametric or parametric regression setting. We hence model the CIF from the primary cause assuming the generalized odds-rate transformation and the modified logistic function as the baseline CIF. Under the additivity constraint, the covariate effects on the competing cause are modeled by a function of the asymptote of the baseline distribution and the covariate effects on the primary cause. The inference procedure is straightforward by using the standard maximum likelihood theory. We demonstrate desirable finite-sample performance of our model by simulation studies in comparison with existing methods. Its practical utility is illustrated in an analysis of a breast cancer dataset to assess the treatment effect of tamoxifen, adjusting for age and initial pathological tumor size, on breast cancer recurrence that is subject to dependent censoring by second primary cancers and deaths. PMID- 23090879 TI - Total synthesis of (+/-)-pentalenolactone A methyl ester. PMID- 23090880 TI - Facile synthesis of high-quality plasma-reduced graphene oxide with ultrahigh 4,4'-dichlorobiphenyl adsorption capacity. AB - High-quality reduced graphene, termed PG, has been synthesized by a simple, low cost, and green plasma approach, and applied as adsorbent to remove 4,4' dichloribiphenyl (4,4'-DCB) from aqueous solutions. As a comparison, the adsorption of 4,4'-DCB on graphene oxide (GO) and multiwalled carbon nanotubes (MWCNTs) was also studied under the same experimental conditions. PG performs significantly better with regard to 4,4'-DCB adsorption than GO and MWCNTs, or any reported nanomaterials, with a maximum adsorption capacity (q(max)) of 1552 mg g(-1) at pH 7.0. The high affinity of 4,4'-DCB to PG is mainly a result of strong pi-pi interactions, as also confirmed by DFT calculations. The results reveal that PG sheets hold promise for the removal of persistent organic pollutants. We expect possible applications of this fast and mild plasma technique in the fabrication of nanomaterials and envisage their use in a variety of advanced chemical processes. PMID- 23090883 TI - Light-induced modular ligation of conventional RAFT polymers. AB - Making light work of RAFT conjugation: a non-activated RAFT agent at the end of RAFT polymers can readily be coupled with ortho-quinodimethanes (photoenols) in a photo-triggered Diels-Alder reaction under mild conditions without catalyst. The method is universal and opens the door for the conjugation of a large number of RAFT-prepared polymers with photoenol-functionalized (macro)molecules. (RAFT=reversible addition-fragmentation chain transfer.). PMID- 23090882 TI - Molecular genetics research in ADHD: ethical considerations concerning patients' benefit and resource allocation. AB - Immense resource allocations have led to great data output in genetic research. Concerning ADHD resources spent on genetic research are less than those spent on clinical research. But there are successful efforts made to increase support for molecular genetics research in ADHD. Concerning genetics no evidence based conclusive results have significant impact on prevention, diagnosis or treatment yet. With regard to ethical aspects like the patients' benefit and limited resources the question arises if it is indicated to think about a new balance of resource allocation between molecular genetics and non-genetics research in ADHD. An ethical reflection was performed focusing on recent genetic studies and reviews based on a selective literature search. There are plausible reasons why genetic research results in ADHD are somehow disappointing for clinical practice so far. Researchers try to overcome these gaps systematically, without knowing what the potential future benefits for the patients might be. Non-genetic diagnostic/therapeutic research may lead to clinically relevant findings within a shorter period of time. On the other hand, non-genetic research in ADHD may be nurtured by genetic approaches. But, with the latter there exist significant risks of harm like stigmatization and concerns regarding data protection. Isolated speeding up resources of genetic research in ADHD seems questionable from an ethical point of view. There is a need to find a new balance of resource allocation between genetic and non-genetic research in ADHD, probably by integrating genetics more systematically into clinical research. A transdisciplinary debate is recommended. PMID- 23090881 TI - Height, age at menarche and risk of hormone receptor-positive and -negative breast cancer: a cohort study. AB - Associations of breast cancer overall with indicators of exposures during puberty are reasonably well characterized; however, uncertainty remains regarding the associations of height, leg length, sitting height and menarcheal age with hormone receptor-defined malignancies. Within the European Prospective Investigation into Cancer and Nutrition cohort, Cox proportional hazards models were used to describe the relationships of adult height, leg length and sitting height and age at menarche with risk of estrogen and progesterone receptor negative (ER-PR-) (n = 990) and ER+PR+ (n = 3,524) breast tumors. Height as a single risk factor was compared to a model combining leg length and sitting height. The possible interactions of height, leg length and sitting height with menarche were also analyzed. Risk of both ER-PR- and ER+PR+ malignancies was positively associated with standing height, leg length and sitting height and inversely associated with increasing age at menarche. For ER+PR+ disease, sitting height (hazard ratios: 1.14[95% confidence interval: 1.08-1.20]) had a stronger risk association than leg length (1.05[1.00-1.11]). In comparison, for ER-PR- disease, no distinct differences were observed between leg length and sitting height. Women who were tall and had an early menarche (<=13 years) showed an almost twofold increase in risk of ER+PR+ tumors but no such increase in risk was observed for ER-PR- disease. Indicators of exposures during rapid growth periods were associated with risks of both HR-defined breast cancers. Exposures during childhood promoting faster development may establish risk associations for both HR-positive and -negative malignancies. The stronger associations of the components of height with ER+PR+ tumors among older women suggest possible hormonal links that could be specific for postmenopausal women. PMID- 23090884 TI - Synthesis and promising properties of a new family of high-nitrogen compounds: polyazido- and polyamino-substituted N,N'-azo-1,2,4-triazoles. AB - A new family of high-nitrogen compounds, that is, polyazido- and polyamino substituted N,N'-azo-1,2,4-triazoles, were synthesized in a safe and convenient manner and fully characterized. The structures of 3,3',5,5'-tetra(azido)-4,4'-azo 1,2,4-triazole (15) and 3,3',5,5'-tetra(amino)-4,4'-azo-1,2,4-triazole (23) were also confirmed by X-ray diffraction. Differential scanning calorimetry (DSC) was performed to determine their thermal stability. Their heats of formation and density, which were calculated by using Gaussian 03, were used to determine the detonation performances of the related compounds (EXPLO 5.05). The heats of formation of the polyazido compounds were also derived by using an additive method. Compound 15 has the highest heat of formation (6933 kJ kg(-1)) reported so far for energetic compounds and a detonation performance that is comparable to that of octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX), while compound 23 has a decomposition temperature of up to 290 degrees C. PMID- 23090886 TI - Pharmacokinetic and pharmacodynamic comparability study of moxetumomab pasudotox, an immunotoxin targeting CD22, in cynomolgus monkeys. AB - Moxetumomab pasudotox is an immunotoxin currently being investigated in patients for the treatment of CD22-expressing B-cell malignancies. A single-cycle pharmacokinetic (PK)-pharmacodynamic (PD) study was conducted in cynomolgus monkeys for PK comparability assessment and population PK-PD modeling after major manufacturing process and site changes. Primates were randomized by body weight and baseline CD22 lymphocyte counts to receive intravenous administrations of 1 mg/kg moxetumomab pasudotox (n = 12/group) on Days 1, 3, and 5. PK and B lymphocyte count data were modeled using a population approach. The 90% confidence intervals of the geometric mean ratios of PK exposure were within the 80%-125% range. The B lymphocytes were depleted to a similar extent, and the immunogenicity incidences were similar across the two groups. The B-cell depletion was described by a novel lifespan model in which moxetumomab pasudotox induced random destruction of B cells in each aging compartment. The endogenous de novo influx from bone marrow was subject to a negative feedback mechanism. The estimated B cell apparent lifespan was 51 days. Covariate analysis confirmed that the manufacturing change had no impact on PK or PD of moxetumomab pasudotox. Results from this study supported continued clinical investigation of moxetumomab pasudotox using the new material. PMID- 23090885 TI - Solid-phase glycan isolation for glycomics analysis. AB - Glycosylation is one of the most significant protein PTMs. The biological activities of proteins are dramatically changed by the glycans associated with them. Thus, structural analysis of the glycans of glycoproteins in complex biological or clinical samples is critical in correlation with the functions of glycans with diseases. Profiling of glycans by HPLC-MS is a commonly used technique in analyzing glycan structures and quantifying their relative abundance in different biological systems. Methods relied on MS require isolation of glycans from negligible salts and other contaminant ions since salts and ions may interfere with the glycans, resulting in poor glycan ionization. To accomplish those objectives, glycan isolation and clean-up methods including SPE, liquid phase extraction, chromatography, and electrophoresis have been developed. Traditionally, glycans are isolated from proteins or peptides using a combination of hydrophobic and hydrophilic columns: proteins and peptides remain on hydrophobic absorbent while glycans, salts, and other hydrophilic reagents are collected as flowthrough. The glycans in the flowthrough are then purified through graphite-activated carbon column by hydrophilic interaction LC. Yet, the drawback in these affinity-based approaches is nonspecific binding. As a result, chemical methods by hydrazide or oxime have been developed for solid-phase isolation of glycans with high specificity and yield. Combined with high resolution MS, specific glycan isolation techniques provide tremendous potentials as useful tools for glycomics analysis. PMID- 23090887 TI - Hypoalbuminemia is an independent prognostic factor for overall survival in myelodysplastic syndromes. AB - We hypothesized that hypoalbuminemia is an independent prognostic factor in patients with myelodysplastic syndromes (MDS). We analyzed records of 767 patients treated at Moffitt Cancer Center between January 2001 and December 2009 to evaluate the relationship between serum albumin (SA) at the time of presentation and overall survival (OS). Patients (median age of 69 years) were stratified into three groups based on SA concentration (<=3.5, 3.6-4.0, and >4.0 g/dL). Two-thirds of the patients had low or intermediate-1 International Prognostic Scoring System (IPSS)-based risk for MDS. Median OS by SA concentration of <=3.5, 3.6-4.0, and >4.0 g/dL was 11, 23, and 34 months, respectively (P < 0.005), whereas rate of acute myeloid leukemia progression was highest in patients with low SA (<=3.5 g/dL). The SA level offered prognostic discrimination for outcomes within the lower and higher IPSS risk groups, as well as with the MD Anderson risk model. In multivariable analysis, SA was a significant independent co-variate for OS after adjustment for IPSS, age, serum ferritin, and transfusion dependence (hazard ratio = 0.8; 95% CI 0.6-0.9; P = 0.004). Our findings indicate that hypoalbuminemia is an independent prognostic biomarker that may serve as a surrogate representative of disease biology or comorbidities in patients with MDS. PMID- 23090888 TI - Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management. AB - DISEASE OVERVIEW: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of one-two cases per 100,000 adults and accounts for ~15% of newly diagnosed cases of leukemia in adults. DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. FRONTLINE THERAPY: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. SALVAGE THERAPY: For patients who fail standard-dose imatinib therapy, imatinib dose escalation is a second-line option. Alternative second-line options include 2nd generation TKIs. Although both are potent and specific BCR-ABL TKIs, dasatinib and nilotinib exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as disease stage and BCR-ABL mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs and are candidate for clinical trials. Allogeneic transplantation remains an important therapeutic option for CML-CP harboring the T315I mutation, patients who fail 2nd generation TKIs, and for all patients in advanced phase disease. PMID- 23090889 TI - Persistent A-antigen after stem cell transplantation of blood group A patient with non-A donor. AB - Patients receiving an ABO-incompatible hematopoietic stem cell transplantation (SCT) are at an increased risk for immune-mediated hematological complications including immediate and delayed hemolysis, late red blood cell engraftment, and pure red cell aplasia. Much research effort has been invested in the unraveling of the immunological mechanisms underyling these complications and approaches to prevent them. Only minimal attention has been paid to the fact that in some SCT patients, even after years, a persistent patient A- and/or B-antigen is detected in the clinical laboratory, despite 100% white cell donor chimerism. The impact for the patient can be substantial: fear that the transplantation was not successful, concern of relapse, and other anxieties influence the quality of life. Little is known about the possible causes of this phenomenon, making appropriate counseling and reassurance of patients by the clinician difficult. In this letter, we describe two cases and a short review on the putative causes of persistent blood group antigens after SCT. PMID- 23090890 TI - Pentadecker supramolecules with a lithium alkoxo nanobelt sandwiched between two highly charged buckybowl surfaces. PMID- 23090892 TI - Improved selectivity by stabilizing and exposing active phases on supported Pd nanoparticles in acetylene-selective hydrogenation. AB - Palladium dynamics: Under hydrogenation conditions, saturating over-active palladium by carbon diffusion leads to a stable and selective particle surface. By choosing supports with suitable geometric structures and establishing a strong interaction between supports and metal particles, accumulated species can be regularly rearranged and reaction-selective phases can be exposed (see figure). PMID- 23090893 TI - Hypertension cure rate after adrenalectomy for unilateral primary aldosteronism. PMID- 23090891 TI - Aptamers and the next generation of diagnostic reagents. AB - Antibodies have been extensively used as capture and detection reagents in diagnostic applications of proteomics-based technologies. Proteomic assays need high sensitivity and specificity, a wide dynamic range for detection, and accurate, reproducible quantification with small confidence values. However, several inherent limitations of monoclonal antibodies in meeting the emerging challenges of proteomics led to the development of a new class of oligonucleotide based reagents. Natural and derivatized nucleic acid aptamers are emerging as promising alternatives to monoclonal antibodies. Aptamers can be effectively used to simultaneously detect thousands of proteins in multiplex discovery platforms, where antibodies often fail due to cross-reactivity problems. Through chemical modification, vast range of additional functional groups can be added at any desired position in the oligonucleotide sequence, therefore the best features of small molecule drugs, proteins, and antibodies can be brought together into aptamers, making aptamers the most versatile reagent in proteomics. In this review, we discuss the recent developments in aptamer technology, including new selection methods and the aptamers' application in proteomics. PMID- 23090894 TI - In the realm for standardization in immunophenotyping. PMID- 23090899 TI - Application of 2D-DIGE to formalin-fixed diseased tissue samples from hospital repositories: results from four case studies. AB - PURPOSE: In the recent past, the potential suitability of fixed samples to 2D DIGE studies has been demonstrated on model tissues, but not on "real-world" archival tissues. Therefore, this study was aimed to assess the quality of the results delivered by 2D-DIGE on samples retrieved from hospital tissue repositories. EXPERIMENTAL DESIGN: Diseased and normal tissue samples (namely, human gastric adenocarcinoma and normal gastric tissue, human lung neuroendocrine tumors, canine mammary tubulo-papillary carcinoma and normal mammary tissue, sheep liver with cloudy swelling degeneration and normal liver tissue) were retrieved from human and veterinary biorepositories and subjected to full-length protein extraction, cyanine labeling, 2D-DIGE separation, image analysis, MS analysis, and protein identification. RESULTS: Archival samples could be successfully subjected to 2D-DIGE, providing maps of satisfactory resolution, although with varying pattern complexity (possibly influenced by preanalytical variables). Moreover, differentially expressed protein identities were consistent with the disease biology. CONCLUSIONS AND CLINICAL RELEVANCE: 2D-DIGE can support biomarker discovery and validation studies on large sample cohorts. In fact, although some information complexity is lost when compared to fresh-frozen tissues, their vast availability and the associated patient information can considerably boost studies suffering limited sample availability or involving long-distance exchange of samples. PMID- 23090901 TI - Synthesis and immunological evaluation of self-assembling and self-adjuvanting tricomponent glycopeptide cancer-vaccine candidates. AB - Self-adjuvanting tricomponent vaccines were prepared and assessed for their self assembly and immunological activity in mouse models. The vaccines each consisted of a peptide or glycopeptide antigen that corresponds to a complete copy of the variable-number tandem repeat (VNTR) of the tumor-associated mucin 1 (MUC1) glycoprotein, the universal T-cell helper peptide epitope PADRE, and the immunoadjuvant Pam(3)CysSer. The vaccines were shown to spontaneously self assemble in water to form isotropic particles varying in size from 17 to 25 nm and elicited robust humoral responses in murine models without the addition of an external adjuvant. The serum antibodies could recognize tumor-associated MUC1 epitopes on the surface of MCF7 breast-cancer cells and B16 melanoma cells, which overexpress this tumor-associated glycoprotein. PMID- 23090902 TI - Expression of survivin and livin predicts early recurrence in non-muscle invasive bladder cancer. AB - BACKGROUND: Survivin and livin are novel members of the inhibitor of apoptosis gene family (IAP) that controls mitotic progression and induces tumor cell invasion. This study aims to evaluate the association of both expression with clinical outcomes and risk of recurrence in patients with non-muscle invasive bladder cancer (NIMBC). PATIENTS AND METHODS: We investigated the expression of survivin and livin in 72 NMIBC samples using immunohistochemical staining (Envision Method). Survivin and livin were considered high-expressed when more than 10% of the cells expressed. The archival bladder tissue specimens from 11 normal controls were examined and studied. All patients with a follow-up of at most 5 years following initial transurethral resection (TUR) were included in the study. The association of both expression with established clinicopathologic factors and recurrence free survival (RFS) was analyzed using log-rank test and Cox regression analysis. RESUTS: Neither survivin nor livin was expressed in normal bladder urothelium. Survivin and livin were high-expressed in 84.7 and 75.0% of NIMBC. And in cases of recurrence, the high-expression (H-exp.) rates were 98.3 and 91.7% (P < 0.01), respectively. The recurrence of NIMBC was significantly associated with high expression of survivin and livin (P < 0.01, P < 0.01), and G-3 tumors had a significantly greater proportion of high survivin expression than G-1 or/and G-2 tumors (P = 0.01); however, no association was found between expression of both and age, gender, pathology stage, or adjuvant therapy. High expression of survivin (RR:9.818, 95% CI: 1.109-86.911, P = 0.040) and livin (RR: 4.199; 95% CI: 1.018-17.321; P = 0.047) was significantly powerful prognostic factors in Cox regression analysis for RFS. CONCLUSIONS: Expression of survivin and livin may influence the prognosis of NIMBC. This finding opens new perspectives for Survivin and livin prediction of early recurrence in NIMBC. PMID- 23090904 TI - Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines. AB - The recently emerged concept of cancer stem cell (CSC) has led to a new hypothesis on the basis for tumor progression. Basically, the CSC theory hypothesizes the presence of a hierarchically organized and relatively rare cell population, which is responsible for tumor initiation, self-renewal, and maintenance, in addition to accumulation of mutation and resistance to chemotherapy. CSCs have recently been described in breast cancer. Different genetic markers have been used to isolate breast CSCs, none of which have been correlated with the tumorigenicity or metastatic potential of the cells, limiting their precise characterization and clinical application in the development of therapeutic protocols. Here, we sought for subpopulations of CSCs by analyzing 10 judiciously chosen stem cell markers in a normal breast cell line (MCF10-A) and in four human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435, and Hs578 T) displaying different degrees of metastatic and invasiveness potential. We were able to identify two markers, which are differentially expressed in nontumorigenic versus tumor cells. The CD90 marker was highly expressed in the malignant cell lines. Interestingly, the CD14 molecule displayed higher expression levels in the nontumorigenic cell line. Therefore, we demonstrated that these two markers, which are more commonly used to isolate and characterize stem cells, are differentially expressed in breast tumor cells, when compared with nontumorigenic breast cells. PMID- 23090905 TI - Proteomic workflow for analysis of archival formalin-fixed and paraffin-embedded clinical samples to a depth of 10 000 proteins. AB - PURPOSE: Archival formalin-fixed and paraffin-embedded clinical samples represent a very diverse source of material for proteomic investigation of diseases, often with follow-up patient information. Here, we describe an analytical workflow for analysis of laser-capture microdissected formalin-fixed and paraffin-embedded samples that allows studying proteomes to a depth of 10 000 proteins per sample. EXPERIMENTAL DESIGN: The workflow involves lysis of tissue in SDS-containing buffer, detergent removal, and consecutive digestion of the proteins with two enzymes by the multienzyme digestion filter-aided sample preparation method. Resulting peptides are fractionated by pipette-tip based strong anion exchange into six fractions and analyzed by LC-MS/MS on a bench top quadrupole Orbitrap mass spectrometer. RESULTS: Analysis of the data using the MaxQuant software resulted in the identification of 9502 +/- 28 protein groups per a 110 nL sample of microdissected cells from human colonic adenoma. This depth of proteome analysis enables systemic insights into the organization of the adenoma cells and an estimation of the abundances of known biomarkers. It also allows the identification of proteins expressed from tumor suppressors, oncogenes, and other key players in the development and progression of the colorectal cancer. CONCLUSION AND CLINICAL RELEVANCE: Our proteomic platform can be used for quantitative comparisons between samples representing different stages of diseases and thus can be applied to the discovery of biomarkers or drug targets. PMID- 23090906 TI - Thermally driven nanofuses based on organometallic rotors. AB - Molecular design of chromium arenes are theoretically studied as a model for the development of novel thermally-driven molecular fuses. This study correlates the switching event with a partial disconnection of the molecule from the metallic electrode mediated by changes in the conformational states of the molecule directed by external stimuli. Moreover, the reversibility of the process (the reconnection to the metallic electrode) is also considered for these systems when a reversal voltage pulse (reset) is applied. The energetic requirements of the on and off states are correlated with temperature through the Arrhenius equation. To carry out this study we performed density functional theory (DFT) calculations. PMID- 23090907 TI - Fetal obstructive uropathy complicated by urinary ascites: outcome and prognostic value of fetal serum beta-2-microglobulin. AB - OBJECTIVES: To determine whether the prognostic value of fetal serum beta-2 microglobulin is altered and whether the occurrence of fetal urinary ascites prevents kidney damage in cases of fetal obstructive uropathy with urinary ascites. METHODS: This was a retrospective study of cases of fetal bilateral obstructive uropathy that occurred between 2006 and 2010, for which both fetal serum and ascites samples were sent to our laboratory for analysis. beta-2 microglobulin was assayed in both fetal serum and the corresponding ascites. Renal outcome was analyzed. Histological features of the kidney in cases of termination of pregnancy and renal function of liveborn infants were recorded. RESULTS: Fourteen cases with analysis of fetal serum and fetal ascites in a context of urinary obstruction were included. Renal outcome was unfavorable in eight cases (57%) and favorable in six (43%). When fetal serum beta-2 microglobulin was < 5 mg/L, renal outcome was favorable in all cases (4/4). When fetal serum beta-2-microglobulin was >= 5 mg/L, 8/10 cases (80%) had an unfavorable renal outcome (sensitivity, 100%; specificity, 66%). CONCLUSION: Fetal serum beta-2-microglobulin reliably predicts postnatal renal outcome in obstructive uropathy complicated by urinary ascites. Moreover, urine extravasation does not seem to protect fetal renal function. PMID- 23090908 TI - Follow-up of early stage melanoma: specialist clinician perspectives on the functions of follow-up and implications for extending follow-up intervals. AB - BACKGROUND: There is limited evidence on the relative effectiveness of different follow-up schedules for patients with AJCC stage I or II melanoma, but less frequent follow-up than is currently recommended has been proposed. OBJECTIVES: To describe melanoma clinicians' perspectives on the functions of follow-up, factors that influence follow-up intervals, and important considerations for extending intervals. METHODS: Qualitative interviews with 16 clinicians (surgical oncologists, dermatologists, melanoma unit physicians) who conduct follow-up at two of Australia's largest specialist centers. RESULTS: Follow-up is conducted for early detection of recurrences or new primary melanomas, to manage patient anxiety, support patient self-care, and as part of shared care. Recommended intervals are based on guidelines but account for each patient's clinical risk profile, level of anxiety, patient education requirements, capacity to engage in skin self-examination, and how the clinician prefers to manage any suspicious lesions. CONCLUSIONS: To revise guidelines and implement change it is important to understand the rationale underpinning existing practice. Extended follow-up intervals for early stage melanoma are more likely to be adopted after the first year when patients are less anxious and sufficiently prepared to conduct self examination. Clinicians may retain existing schedules for highly anxious patients or those unable to examine themselves. PMID- 23090909 TI - Structure and strength of the distal radius in female patients with rheumatoid arthritis: a case-control study. AB - The purpose of this work was to investigate the volumetric bone mineral density (vBMD), bone microstructure, and mechanical indices of the distal radius in female patients with rheumatoid arthritis (RA). We report a cross-sectional study of 66 middle-aged female RA patients and 66 age-matched healthy females. Areal BMD (aBMD) of the hip, lumbar spine, and distal radius was measured by dual energy X-ray absorptiometry (DXA). High-resolution peripheral quantitative computed tomography (HR-pQCT) was performed at the distal radius, yielding vBMD, bone microstructure, and mechanical indices. Cortical and trabecular vBMD were 3.5% and 10.7% lower, respectively, in RA patients than controls, despite comparable aBMD. Trabecular microstructural indices were -5.7% to -23.1% inferior, respectively, in RA patients compared to controls, with significant differences in trabecular bone volume fraction, separation, inhomogeneity, and structural model index. Cortical porosity volume and percentage were 128% and 93% higher, respectively, in RA patients, with stress being distributed more unevenly. Fourteen RA patients had exaggerated periosteal bone apposition primarily affecting the ulnovolar aspect of the distal radius. These particular patients were more likely to have chronic and severe disease and coexisting wrist deformity. The majority of the differences in density and microstructure between RA patients and controls did not depend on menstrual status. Recent exposure to glucocorticoids did not significantly affect bone density and microstructure. HR pQCT provides new insight into inflammation-associated bone fragility in RA. It detects differences in vBMD, bone microstructure, and mechanical indices that are not captured by DXA. At the distal radius, deterioration in density and microstructure in RA patients involved both cortical and trabecular compartments. Excessive bone resorption appears to affect cortical more than trabecular bone at distal radius, particularly manifested as increased cortical porosity. Ulnovolar periosteal apposition of the distal radius is a feature of chronic, severe RA with wrist deformity. PMID- 23090910 TI - Parallel interactions at large horizontal displacement in pyridine-pyridine and benzene-pyridine dimers. AB - A study of crystal structures from the Cambridge Structural Database (CSD) and DFT calculations reveals that parallel pyridine-pyridine and benzene-pyridine interactions at large horizontal displacements (offsets) can be important, similar to parallel benzene-benzene interactions. In the crystal structures from the CSD preferred parallel pyridine-pyridine interactions were observed at a large horizontal displacement (4.0-6.0 A) and not at an offset of 1.5 A with the lowest calculated energy. The calculated interaction energies for pyridine pyridine and benzene-pyridine dimers at a large offset (4.5 A) are about 2.2 and 2.1 kcal mol(-1), respectively. Substantial attraction at large offset values is a consequence of the balance between repulsion and dispersion. That is, dispersion at large offsets is reduced, however, repulsion is also reduced at large offsets, resulting in attractive interactions. PMID- 23090911 TI - Issue highlights November 2012. PMID- 23090912 TI - Clinical cytometry in Europe, 2012. PMID- 23090913 TI - MALDI MS imaging as a tool for biomarker discovery: methodological challenges in a clinical setting. AB - MALDI MS imaging (MSI) is an analytical tool capable of providing spatial distribution and relative abundance of biomolecules directly in tissue. After 15 years of intense efforts to improve the acquisition and quality of molecular images, MSI has matured into an asset of the proteomic toolbox. The power of MSI lies in the ability to differentiate tissue regions that are not histologically distinct but are characterized by different MS profiles. Recently, MSI has been gaining momentum in biomedical research and has found applications in disease diagnosis and prognosis, biomarker discovery, and drug therapy. Although the technology holds great promise, MSI is still faced with a set of methodological challenges presented by the clinical setting. There is a growing awareness regarding this topic and efforts are being taken to develop clear and practical standards to overcome these challenges. This review presents an overview of MALDI MSI as a biomarker discovery tool and recent methodological progress in the field. PMID- 23090914 TI - 4D flow MRI. AB - Traditionally, magnetic resonance imaging (MRI) of flow using phase contrast (PC) methods is accomplished using methods that resolve single-directional flow in two spatial dimensions (2D) of an individual slice. More recently, three-dimensional (3D) spatial encoding combined with three-directional velocity-encoded phase contrast MRI (here termed 4D flow MRI) has drawn increased attention. 4D flow MRI offers the ability to measure and to visualize the temporal evolution of complex blood flow patterns within an acquired 3D volume. Various methodological improvements permit the acquisition of 4D flow MRI data encompassing individual vascular structures and entire vascular territories such as the heart, the adjacent aorta, the carotid arteries, abdominal, or peripheral vessels within reasonable scan times. To subsequently analyze the flow data by quantitative means and visualization of complex, three-directional blood flow patterns, various tools have been proposed. This review intends to introduce currently used 4D flow MRI methods, including Cartesian and radial data acquisition, approaches for accelerated data acquisition, cardiac gating, and respiration control. Based on these developments, an overview is provided over the potential this new imaging technique has in different parts of the body from the head to the peripheral arteries. PMID- 23090915 TI - MRI of the pancreas: problem solving tool. AB - Advances in MR hardware and pulse sequence design over the years have improved the quality and robustness of MR imaging of the pancreas. Today, MRI is an indispensible tool for studying the pancreas and can provide useful information not attainable with other noninvasive or minimally invasive imaging techniques. In the present review, specific cases are reviewed where the strengths of MRI demonstrate the utility of this imaging modality as a problem solving tool. PMID- 23090916 TI - MRI of cardiac iron overload. AB - Transfusion therapy has greatly improved the survival of transfusion dependent thalassemia major (TM) patients; however, the resultant iron load damages tissues including the heart, liver and endocrine organs. Among these, heart complication still remains the leading cause of mortality. Myocardial iron deposition can occur independently of other solid organ involvement; conversely, the heart may be spared despite heavy siderosis in other tissues. Iron chelation treatment diminishes the risk of hemosiderosis; however, the chelation treatment has its own toxicities and might not be available to all patients due to costs. Close monitoring of individual organ iron concentration and function is thus important for optimization of individual patient care. This review outlines the importance and clinical significance of recently available MRI techniques for monitoring cardiac iron load. PMID- 23090917 TI - MRI contrast agents: basic chemistry and safety. AB - Magnetic resonance imaging (MRI) contrast agents are pharmaceuticals used widely in MRI examinations. Gadolinium-based MRI contrast agents (GBCAs) are by far the most commonly used. To date, nine GBCAs have been commercialized for clinical use, primarily indicated in the central nervous system, vasculature, and whole body. GBCAs primarily lower the T(1) in vivo to create higher signal in T(1) weighted MRI scans where GBCAs are concentrated. GBCAs are unique among pharmaceuticals, being water proton relaxation catalysts whose effectiveness is characterized by a rate constant known as relaxivity. The relaxivity of each GBCAs depends on a variety of factors that are discussed in terms of both the existing agents and future molecular imaging agents under study by current researchers. Current GBCAs can be divided into four different structural types (macrocyclic, linear, ionic, and nonionic) based on the chemistry of the chelating ligands whose primary purpose is to protect the body from dissociation of the relatively toxic Gd(3+) ion from the ligand. This article discusses how the chemical structure influences inherent and in vivo stability toward dissociation, and how it affects important formulation properties. Although GBCAs have a lower rate of serious adverse events than iodinated contrast agents, they still present some risk. PMID- 23090920 TI - Laser mass spectrometry with circularly polarized light: circular dichroism of molecular ions. AB - In recent experiments of resonance-enhanced laser ionization, large differences between circular dichroism measured for molecular and fragment ions were found by several research groups for different molecular systems. In the case of 3 methylcyclopentanone (3-MCP) we attributed this effect to a large circular dichroism of the molecular ion. In the work presented here, this effect in 3-MCP is studied by ion spectroscopy, by varying the neutral intermediate excited state involved in resonance-enhanced multiphoton ionization (REMPI) and by performing REMPI-induced measurements of circular dichroism at different laser pulse energies. It turns out that the dynamics of structural changes in the ionic ground state strongly influences the observed ionic circular dichroism. PMID- 23090919 TI - Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. AB - Myelin loss is frequently observed in human Alzheimer's disease (AD) and may constitute to AD-related cognitive decline. A potential source to repair myelin defects are the oligodendrocyte progenitor cells (OPCs) present in an adult brain. However, until now, little is known about the reaction of these cells toward amyloid plaque deposition neither in human AD patients nor in the appropriate mouse models. Therefore, we analyzed cells of the oligodendrocyte lineage in a mouse model with chronic plaque deposition (APPPS1 mice) and samples from human patients. In APPPS1 mice defects in myelin integrity and myelin amount were prevalent at 6 months of age but normalized to control levels in 9-month-old mice. Concomitantly, we observed an increase in the proliferation and differentiation of OPCs in the APPPS1 mice at this specific time window (6-8 months) implying that improvements in myelin aberrations may result from repair mechanisms mediated by OPCs. However, while we observed a higher number of cells of the oligodendrocyte lineage (Olig2+ cells) in APPPS1 mice, OLIG2+ cells were decreased in number in postmortem human AD cortex. Our data demonstrate that oligodendrocyte progenitors specifically react to amyloid plaque deposition in an AD-related mouse model as well as in human AD pathology, although with distinct outcomes. Strikingly, possible repair mechanisms from newly generated oligodendrocytes are evident in APPPS1 mice, whereas a similar reaction of oligodendrocyte progenitors seems to be strongly limited in final stages of human AD pathology. PMID- 23090921 TI - Adipose tissue engineering with human adipose tissue-derived adult stem cells and a novel porous scaffold. AB - We investigated the effect of a novel porous scaffold composed with water-soluble poly(L-glutamic acid) (PLGA) and chitosan (CS) on the attachment, proliferation, and adipogenic differentiation of human adipose tissue-derived adult stem cells (ADSCs) in vitro and in vivo. Scanning electron microscope and fluorescent Dil labeling were used to reveal the attachment and growth of ADSCs on scaffolds; cell proliferation was detected by DNA assay. The adipogenic differentiation potential of ADSCs on the scaffolds was assayed by Oil-red O staining and further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) for adipogenic gene markers (peroxisome proliferator-activated receptor gamma2, lipoprotein lipase, fatty acid-binding protein, adiponectin). Cell-seeded constructs exposed to adipogenic medium for 2 weeks in vitro were implanted in severe combined immunodeficient (SCID) mice for 6 weeks. It was shown that ADSCs attached and spread well on scaffolds with good proliferation behaviors and abundance of extracellular matrix deposition. Oil-red O staining and RT-PCR showed adipogenic differentiation potential of ADSCs on scaffolds. Newly formed adipose-like tissue was confirmed in vivo in SCID mice by Oil-red O staining. PLGA/CS porous scaffolds exhibit good compatibility to ADSCs and can be promising biomaterials for adipose tissue engineering. PMID- 23090922 TI - Optimizing the deposition of hydrogen evolution sites on suspended semiconductor particles using on-line photocatalytic reforming of aqueous methanol solutions. AB - The deposition of hydrogen evolution sites on photocatalysts is a crucial step in the multistep process of synthesizing a catalyst that is active for overall photocatalytic water splitting. An alternative approach to conventional photodeposition was developed, applying the photocatalytic reforming of aqueous methanol solutions to deposit metal particles on semiconductor materials such as Ga2O3 and (Ga0.6 Zn0.4)(N0.6O0.4). The method allows optimizing the loading of the co-catalysts based on the stepwise addition of their precursors and the continuous online monitoring of the evolved hydrogen. Moreover, a synergetic effect between different co-catalysts can be directly established. PMID- 23090923 TI - Topographical anatomy of the radial nerve and its muscular branches related to surface landmarks. AB - Understanding of the anatomy of the radial nerve and its branches is vital to the treatment of humeral fracture or the restoration of upper extremity function. In this study, we dissected 40 upper extremities from adult cadavers to locate the course of the radial nerve and the origins and insertions of the branches of the radial nerve using surface landmarks. The radial nerve reached and left the radial groove and pierced the lateral intermuscular septum, at the levels of 46.7, 60.5, and 66.8% from the acromion to the transepicondylar line, respectively. Branches to the long head of the triceps brachii originated in the axilla, and branches to the medial and lateral heads originated in the axilla or in the arm. The muscular attachments to the long, medial, and lateral heads were on average 34.0 mm proximal, 16.4 mm distal, and 19.3 mm proximal to the level of inferior end of the deltoid muscle, respectively. The radial nerve innervated 65.0% of the brachialis muscles. Branches to the brachioradialis and those to the extensor carpi radialis longus arose from the radial nerve above the transepicondylar line. Branches to the extensor carpi radialis brevis usually arose from the deep branch of radial nerve (67.5%); however, in some cases, branches to the extensor carpi radialis brevis arose from either the radial nerve (20.0%) or the superficial branch of the radial nerve (12.5%). Using these data, the course of the radial nerve can be estimated by observing the surface of the arm. PMID- 23090924 TI - Antidepressant use, serotonin transporter affinity, and reinfarction among patients receiving clopidogrel: a population-based study. AB - PURPOSE: Conflicting evidence exists regarding the association between antidepressant use and reinfarction among high-risk cardiovascular patients. Recent evidence suggests that clinical benefit associated with antidepressants may be related to serotonergic activity, suggesting that some antidepressants may offer greater advantages than others. METHODS: We conducted a population-based nested case-control study among patients aged 66 years or older who commenced clopidogrel between April 1, 2002 and December 31, 2009, following hospital discharge for acute myocardial infarction (AMI). Cases were those who were readmitted for AMI, underwent percutaneous coronary intervention (PCI), or died within 90 days of discharge. Three controls were matched to each case on age, PCI, and the date of hospital discharge. We categorized exposure to antidepressants as current or no use within 120 days before the index date, and the serotonergic activity of antidepressants was further categorized as low, medium, and high according to their affinity for the serotonin transporter. RESULTS: Among 24 090 patients who received clopidogrel following AMI, we identified 2494 cases. Of these, 2444 (98%) were successfully matched to 7045 controls. After extensive multivariable adjustment, antidepressant use was not associated with lower risk of the composite outcome (adjusted odds ratio [OR] 1.11 and 95% confidence interval [CI] 0.98-1.27). The absence of association was consistent across the different antidepressant groups categorized by serotonin transporter affinity. CONCLUSION: In high-risk cardiovascular patients with a history of AMI and treated with clopidogrel, antidepressant use is associated with no additional reduction in risk of reinfarction irrespective of serotonin transporter affinity. PMID- 23090926 TI - Association between colistin dose and microbiologic outcomes in patients with multidrug-resistant gram-negative bacteremia. AB - BACKGROUND: Colistin is increasingly used for the treatment of multidrug resistant gram-negative infections. However, colistin dosing varies greatly and the optimal regimen is unknown. The purpose of this study was to determine if colistin dosing correlates with patient outcomes. METHODS: This retrospective study included patients with gram-negative bacteremia treated with intravenous colistin for at least 72 hours. The primary objective was to determine if colistin dose (mg of colistin base activity/kg/day) independently predicts day-7 microbiological success. Secondary objectives included evaluation for an association between colistin dose and 7-day mortality, 28-day mortality, and the development of acute kidney insufficiency (AKI). RESULTS: Seventy-six patients were included in the analysis, with 52 patients (68%) achieving 7-day microbiological success. The median colistin dose was significantly higher in patients who achieved microbiological success (2.9 vs 1.5 mg/kg/day; P = .011). After adjusting for baseline severity of illness and concomitant tigecyline use, higher colistin dose independently correlated with microbiological success (adjusted odds ratio per 1 mg/kg/day = 1.74; 95% confidence interval, 1.11-2.71; P = .015). The median colistin dose was also significantly higher among survivors at day 7 (2.7 vs 1.5 mg/kg/day; P = .007). However, no difference was observed in colistin dose when comparing survivors and nonsurvivors at day 28. A significantly higher colistin dose was given to patients who developed AKI during therapy (3.8 vs 1.6 mg/kg/day; P < .001). CONCLUSIONS: Higher colistin dose independently predicted microbiological success, which may partially explain the similar association with 7-day mortality. However, higher colistin doses may also precipitate worsening renal function. PMID- 23090925 TI - Antiretroviral drug-related liver mortality among HIV-positive persons in the absence of hepatitis B or C virus coinfection: the data collection on adverse events of anti-HIV drugs study. AB - BACKGROUND: Liver diseases are the leading causes of death in human immunodeficiency virus (HIV)-positive persons since the widespread use of combination antiretroviral treatment (cART). Most of these deaths are due to hepatitis C (HCV) or B (HBV) virus coinfections. Little is known about other causes. Prolonged exposure to some antiretroviral drugs might increase hepatic mortality. METHODS: All patients in the Data Collection on Adverse Events of Anti HIV Drugs study without HCV or HBV coinfection were prospectively followed from date of entry until death or last follow-up. In patients with liver-related death, clinical charts were reviewed using a structured questionnaire. RESULTS: We followed 22 910 participants without hepatitis virus coinfection for 114 478 person-years. There were 12 liver-related deaths (incidence, 0.10/1000 person years); 7 due to severe alcohol use and 5 due to established ART-related toxicity. The rate of ART-related deaths in treatment-experienced persons was 0.04/1000 person-years (95% confidence interval, .01, .10). CONCLUSIONS: We found a low incidence of liver-related deaths in HIV-infected persons without HCV or HBV coinfection. Liver-related mortality because of ART-related toxicity was rare. PMID- 23090927 TI - Predictors of the isolated hepatitis B core antibody pattern in HIV-infected and uninfected men in the multicenter AIDS cohort study. AB - BACKGROUND: The significance of hepatitis B core antibody (anti-HBc) without hepatitis B surface antigen (HBsAg) or hepatitis B surface antibody (anti-HBs) is unclear. METHODS: This cohort study included men enrolled in the Multicenter AIDS Cohort to determine clinical and laboratory predictors of isolated anti-HBc. RESULTS: A total of 2286 subjects (51% human immunodeficiency virus [HIV] infected) were followed over 3.9 years. Overall, 16.9% (387) had at least 1 visit with isolated anti-HBc. The isolated anti-HBc pattern was stable 84% of the time, and transitioned to or from a pattern of past infection (anti-HBc and anti-HBs). Isolated anti-HBc was associated with HIV infection (odds ratio [OR], 2.19; 95% confidence interval [CI], 1.73-2.79) and hepatitis C virus (HCV; OR, 4.21; 95% CI; 2.99-5.91). The HCV association was stronger for chronic HCV infection (OR, 6.76; 95% CI, 5.08-8.99) than for cleared HCV (OR, 3.03; 95% CI, 1.83-5.03). HIV infection, chronic HCV, and cleared HCV infection all remained associated with isolated anti-HBc in multivariable models (OR, 1.74; 95% CI, 1.33-2.29; OR, 6.24; 95% CI, 4.62-8.42; and OR, 2.77; 95% CI, 1.65-4.66, respectively). Among HIV infected subjects, highly active antiretroviral therapy was negatively associated (OR, 0.79; 95% CI, .66-.95) with isolated anti-HBc. CONCLUSIONS: Isolated anti HBc is associated with HIV and HCV coinfection, especially active HCV replication, and most commonly occurs as a transition to or from the pattern of natural immunity (anti-HBc and anti-HBs). The isolated anti-HBc pattern likely represents resolved HBV infection with low or undetected anti-HBs. PMID- 23090928 TI - Implementation of genotype MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa. AB - BACKGROUND: Diagnosis of drug resistance and timely initiation of multidrug resistant (MDR) tuberculosis therapy are essential to reduce transmission and improve patient outcomes. We sought to determine whether implementation of the rapid MTBDRplus diagnostic shortened the time from specimen collection to patient MDR tuberculosis therapy initiation. METHODS: We conducted a retrospective cohort analysis of 197 MDR tuberculosis patients treated at Brewelskloof, a rural tuberculosis hospital in Western Cape Province, South Africa, between 2007 and 2011. RESULTS: Eighty-nine patients (45%) were tested using conventional liquid culture and drug susceptibility testing (DST) on solid medium and 108 (55%) were tested using the MTBDRplus assay after positive acid-fast bacilli or culture. Median time from sample taken to therapy initiation was reduced from 80 days (interquartile range [IQR] 62-100) for conventional DST to 55 days (IQR 37.5-78) with the MTBDRplus. Although the laboratory processing time declined significantly, operational delays persisted both in the laboratory and the clinical infrastructure for getting patients started on treatment. In multivariate analysis, patients tested using the MTBDRplus test had a reduced risk of starting treatment 60 days or more after sputum collection of 0.52 (P < .0001) compared with patients tested with culture-based DST, after adjustment for smear status and site of disease. CONCLUSIONS: Use of MTBDRplus significantly reduced time to MDR tuberculosis treatment initiation. However, DST reporting to clinics was delayed by more than 1 week due, in part, to laboratory operational delays, including dependence on smear and culture positivity prior to MTBDRplus performance. In addition, once MDR tuberculosis was reported, delays in contacting patients and initiating therapy require improvements in clinical infrastructure. PMID- 23090929 TI - (1->3) beta-D-glucan as a prognostic marker. PMID- 23090931 TI - Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. AB - BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae isolates are important clinical pathogens. In addition, the efficacy of cefepime for such infections is controversial. METHODS: We performed a retrospective study of monomicrobial bacteremia caused by ESBL producers at 2 medical centers between May 2002 and August 2007. The patients definitively treated with in vitro active cefepime (cases) were compared with those treated with a carbapenem (controls) in a propensity score-matched analysis to assess therapeutic effectiveness. The 30 day crude mortality is the primary endpoint. RESULTS: A total of 178 patients were eligible for the study. Patients who received cefepime (n = 17) as definitive therapy were more likely to have a clinical failure (odds ratio [OR] 6.2; 95% confidence interval [CI], 1.7-22.5; P = .002), microbiological failure (OR 5.5; 95% CI, 1.3-25.6; P = .04), and 30-day mortality (OR 7.1; 95% CI, 2.5 20.3; P < .001) than those who received carbapenem therapy (n = 161). Multivariate regression revealed that a critical illness with a Pitt bacteremia score >= 4 points (OR 5.4; 95% CI, 1.4-20.9; P = .016), a rapidly fatal underlying disease (OR 4.4; 95% CI, 1.5-12.6; P = .006), and definitive cefepime therapy (OR 9.9; 95% CI, 2.8-31.9; P < .001) were independently associated with 30-day crude mortality. There were 17 case-control pairs in the propensity scores matched analysis. The survival analysis consistently found that individuals who received cefepime therapy had a lower survival rate (log-rank test, P = .016). CONCLUSIONS: Based on the current Clinical and Laboratory Standards Institute susceptible breakpoint of cefepime (minimum inhibitory concentration <= 8 MUg/mL), cefepime definitive therapy is inferior to carbapenem therapy in treating patients with so-called cefepime-susceptible ESBL-producer bacteremia. PMID- 23090932 TI - Hepatitis C therapy: highlights from the 2012 annual meeting of the European Association for the Study of the Liver. AB - The results from clinical trials testing new direct-acting antivirals (DAAs) for chronic hepatitis C were the major focus of interest at the 2012 annual meeting of the European Association for the Study of the Liver. Besides triple combinations, in which any one of the new DAAs is given along with peginterferon alpha/ribavirin, clinical trials exploring interferon-free oral regimens combining several DAAs attracted major attention. The good tolerance, broad hepatitis C virus (HCV) genotype activity, and high resistance barrier of sofosbuvir make this nucleotide analogue one of the most promising DAAs. Among HCV protease inhibitors, the safety, potency, and convenient dosing of simeprevir, asunaprevir, faldaprevir, and ABT-450/r were particularly highlighted. Among NS5A inhibitors, the good performance of daclatasvir encourages further clinical development. Finally, intriguing results were released about the role of interleukin 28B (IL-28B) polymorphisms using interferon-free regimens, indirectly supporting the role of innate immunity for clearing HCV definitively. PMID- 23090930 TI - Frequent longitudinal sampling of hepatitis C virus infection in injection drug users reveals intermittently detectable viremia and reinfection. AB - BACKGROUND: Detection of hepatitis C virus (HCV) reinfection and intercalation (ie, intermittent recurrent bouts of viremia with homologous virus interspersed with aviremic periods) requires extensive and frequent evaluation and viral sequencing. METHODS: HCV infection outcomes were studied prospectively in active injection drug users with recurrent HCV RNA-positive tests after serial negative results. HCV viremia and viral sequences (Core/E1) were assessed from monthly blood samples. RESULTS: Viral clearance, reinfection, and intercalating infection were all detected. Among 44 participants with apparently resolved HCV (26 incident HCV clearers and 18 enrolled with already resolved infection), 36 (82%) remained persistently HCV RNA negative, but 8 demonstrated intermittent recurrent viremia. Four of these (50%) had confirmed reinfection with a heterologous virus; 3 demonstrated viral intercalation, and 1 was not classifiable as either. Estimated incidence of first reinfection was 5.4 per 100 person-years (95% confidence interval, 2.0-14.5). Six (75%) participants, including 3 of 4 with reinfection, demonstrated sustained viral clearance for a median of 26 months since last HCV RNA test. CONCLUSIONS: These results show that frequent monitoring and viral sequencing are required to correctly assess HCV outcomes and estimate incidence of reinfection (which was previously overestimated). Sustained clearance may take many months and occur after episodes of reinfection and viral intercalation. Three of 4 subjects who had confirmed reinfection showed evidence of long-term clearance. Viral intercalation occurs with significant frequency. Further studies of these events, especially immunological, are needed to inform HCV clinical care and vaccine development. PMID- 23090933 TI - Antimicrobial stewardship lessons: know when to say no to vancomycin. PMID- 23090934 TI - Reply to Chow and Hurley. PMID- 23090935 TI - Nitroanilines as quenchers of pyrene fluorescence. AB - The quenching of pyrene and 1-methylpyrene fluorescence by nitroanilines (NAs), such as 2-, 3-, and 4-nitroaniline (2-NA, 3-NA, and 4-NA, respectively), 4-methyl 3-nitroaniline (4-M-3-NA), 2-methyl-4-nitroaniline (2-M-4-NA), and 4-methyl-3,5 dinitroaniline (4-M-3,5-DNA), are studied in toluene and 1,4-dioxane. Steady state fluorescence data show the higher efficiency of the 4-NAs as quenchers and fit with a sphere-of-action model. This suggests a 4-NA tendency of being in close proximity to the fluorophore, which could be connected with their high polarity/hyperpolarizability. In addition, emission and excitation spectra evidence the formation of emissive pyrene-NA ground-state complexes in the case of the 4-NAs and, in a minor degree, in the 2-NA. Moreover, time-resolved fluorescence experiments show that increasing amounts of NA decrease the pyrene fluorescence lifetime to a degree that depends on the NA nature and is larger in the less viscous solvent (toluene). Although the NA absorption and the pyrene (Py) emission overlap, we found no evidence of dipole-dipole energy transfer from the pyrene singlet excited state ((1)Py) to the NAs; this could be due to the low NA concentration used in these experiments. Transient absorption spectra show that the formation of the pyrene triplet excited state ((3)Py) is barely affected by the presence of the NAs in spite of their efficiency in (1)Py quenching, suggesting the involvement of (1)Py-NA exciplexes which--after intersystem crossing--decay efficiently into (3)Py. PMID- 23090936 TI - Comparative in vivo study of commercially pure Ti implants with surfaces modified by laser with and without silicate deposition: biomechanical and scanning electron microscopy analysis. AB - The purpose of this study was to evaluate commercially pure titanium implant surfaces modified by laser beam (LS) and LS associated with sodium silicate (SS) deposition, and compare them with machined surface (MS) and dual acid-etching surfaces (AS) modified. Topographic characterization was performed by scanning electron microscopy-X-ray energy dispersive spectroscopy (SEM-EDX), and by mean roughness measurement before surgery. Thirty rabbits received 60 implants in their right and left tibias. One implant of each surface in each tibia. The implants were removed by reverse torque for vivo biomechanical analysis at 30, 60, and 90 days postoperative. In addition, the surface of the implants removed at 30 days postoperative was analyzed by SEM-EDX. The topographic characterization showed differences between the analyzed surfaces, and the mean roughness values of LS and SS were statistically higher than AS and MS. At 30 days, values removal torque LS and SS groups showed a statistically significant difference (p < 0.05) when compared with MS and AS. At 60 days, groups LS and SS showed statistically significant difference (p < 0.05) when compared with MS. At 90 days, only group SS presented statistically higher (p < 0.05) in comparison with MS. The authors can conclude that physical chemistry properties and topographical of LS and SS implants increases bone-implant interaction and provides higher degree of osseointegration when compared with MS and AS. PMID- 23090937 TI - Acceleration of disproportionation of aromatic alcohols through self emulsification of reactants in water. AB - Exploration of new and effective routes to conduct organic reactions in water using the special properties of water/organics is of great importance. In this work, we performed the disproportionation of various aromatic alcohols in water and in different organic solvents. It was demonstrated that the disproportionation reactions of the alcohols were accelerated more effectively in water than organic-solvent-based or solvent-free reactions. A series of control experiments were conducted to study the mechanism of the accelerated reaction rate in water. It was shown that the reactants could emulsify the reactant/water systems at the reaction conditions owing to their amphiphilic nature. The regularly orientated reactant molecules at the water/reactant droplet interface improved the contact probability of the reactive groups and the Pd nanocatalysts, which is one of the main reasons for the enhanced reaction rate in water. Controlling the self-emulsification of amphiphilic reactant/water systems has great application potential for optimizing the rate and/or selectivity of many organic reactions. PMID- 23090938 TI - Bio-assembled nanocomposites in conch shells exhibit giant electret hysteresis. AB - Giant electric polarization (2000-4000 MUC cm(-2)) is observed in natural conch shells. The nanolaminas and biopolymer layers of their unique hierarchical microstructures exhibit ferroelectret behavior and account for the observed polarization. Such huge polarization leads to extremely high pyroelectric coefficients, 2-3 orders of magnitude larger than those of conventional ferroelectric materials. The possibility of tailoring the giant polarization for various applications is considered. PMID- 23090939 TI - L-tryptophan-induced electron transport across supported lipid bilayers: an alkyl chain tilt-angle, and bilayer-symmetry dependence. AB - Molecular orientation-dependent electron transport across supported 1,2 dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) lipid bilayers (SLBs) on semiconducting indium tin oxide (ITO) is reported with an aim towards potential nanobiotechnological applications. A bifunctional strategy is adopted to form symmetric and asymmetric bilayers of DPPC that interact with L-tryptophan, and are analyzed by surface manometry and atomic force microscopy. Polarization dependent real-time Fourier transform infrared reflection absorption spectroscopy (FT-IRRAS) analysis of these SLBs reveals electrostatic, hydrogen-bonding, and cation-pi interactions between the polar head groups of the lipid and the indole side chains. Consequently, a molecular tilt arises from the effective interface dipole, facilitating electron transport across the ITO-anchored SLBs in the presence of an internal Fe(CN)(6)(4-/3-) redox probe. The incorporation of tryptophan enhances the voltammetric features of the SLBs. The estimated electron transfer rate constants for symmetric and asymmetric bilayers (k(s) = 2.0*10(-2) and 2.8*10(-2) s(-1)) across the two-dimensional (2D) ordered DPPC/tryptophan SLBs are higher compared to pure DPPC SLBs (k(s) = 3.2*10(-3) and 3.9*10(-3) s( 1)). In addition, they are molecular tilt-dependent, as it is the case with the standard apparent rate constants k(app)(0), estimated from electrochemical impedance spectroscopy and bipotentiostatic experiments with a Pt ultramicroelectrode. Lower magnitudes of k(s) and k(app)(0) imply that electrochemical reactions across the ITO-SLB electrodes are kinetically limited and consequently governed by electron tunneling across the SLBs. Standard theoretical rate constants (k(th)(0)) accrued upon electron tunneling comply with the potential-independent electron-tunneling coefficient beta = 0.15 A(-1). Insulator-semiconductor transitions moving from a liquid-expanded to a condensed 2D-phase state of the SLBs are noted, adding a new dimension to their transport behavior. These results highlight the role of tryptophan in expediting electron transfer across lipid bilayer membranes in a cellular environment and can provide potential clues towards patterned lipid nanocomposites and devices. PMID- 23090940 TI - Synthesis and characterization of Bi2O3/HSA core-shell nanoparticles for X-ray imaging applications. AB - Bismuth oxide nanoparticles of 12.1 +/- 3.0 nm diameter were prepared by thermal decomposition of bismuth acetate dissolved in ethylene glycol in the presence of an oxidizing agent. Functionalization and stabilization of the hydrophobic Bi(2)O(3) nanoparticles was accomplished by coating these core nanoparticles with human serum albumin (HSA), via a precipitation process. The formed Bi(2)O(3)/HSA core-shell nanoparticles were of 15.2 +/- 3.5 nm diameter. Elemental analysis measurements indicated that the bismuth weight % of the Bi(2)O(3)/HSA core-shell nanoparticles is 72.9. The crystalline structure of these nanoparticles was examined by XRD. The radiopacity of these nanoparticles was demonstrated in vitro and in vivo by a CT scanner. In ovo and in vivo trials proved the safety of these Bi(2)O(3)/HSA core-shell nanoparticles. In the future, we plan to extend this study particularly for molecular imaging applications. PMID- 23090941 TI - High-efficiency panchromatic hybrid Schottky solar cells. AB - Nanostructured Schottky inorganic-organic solar cells provide overall power conversion efficiencies exceeding 3%, with extremely large short-circuit photocurrents. The device EQE faithfully tracks the absorptance of the CdSe nanorods, and the IQE is approximately constant over the entire visible spectrum as opposed to a p-n junction hybrid solar cell fabricated with a highly absorbing organic polymer. PMID- 23090942 TI - Autozygosity mapping with exome sequence data. AB - Autozygosity mapping is a powerful method for the identification of recessively inherited disease genes using small inbred families. Typically, microarray SNP genotype data are first used to identify autozygous regions as extended runs of homozygous genotypes. Next, candidate disease loci are found by defining regions that are autozygous in all affected patients. Finally, the disease gene is identified by sequencing the genes within the candidate disease loci. However, with the advent of massively parallel sequencing, it is now possible to sample or to completely sequence an individual's genome, or, more commonly, exome. This opens up the possibility of concurrently defining autozygous regions and identifying possibly deleterious sequence variants, using data from a single sequencing experiment. Consequently, we have developed a set of computer programs that identify autozygous regions using exome sequence data. These programs derive their genotyping data either by the ab initio detection of all sequence variants or by the assessment of 0.53 million known polymorphic positions within each exome dataset. Using genotype data derived solely from exome sequence data, it was possible to identify the majority of autozygous regions found by microarray SNP genotype data. PMID- 23090944 TI - Do calcium waves propagate between cells and synchronize alternating calcium release in rat ventricular myocytes? AB - The aim was to investigate the propagation of Ca(2+) waves between cells and determine whether this synchronizes alternating Ca(2+) release between cells. Experiments were carried out on electrically coupled cell pairs; spontaneous Ca(2+) waves were produced by elevating external Ca(2+). There was a significant difference in the ability of these waves to propagate between cells depending on the orientation of the pairs. Although almost all pairs connected by side-to-side contacts showed propagating Ca(2+) release, this was very uncommon in end-to-end cell pairs. Confocal studies showed that there was a gap at the intercalated disc consisting of cell membranes and a region of cytoplasm devoid of sarcoplasmic reticulum. This gap was 2.3 MUm in length and is suggested to interfere with Ca(2+) wave propagation. The gap measured was much smaller between side-to-side contacts: 1.5 MUm and so much less likely to interfere with propagation. Subsequent experiments investigated the synchronization between cells of Ca(2+) alternans produced by small depolarizing pulses. Although this alternation results from beat-to-beat alternation of intracellular Ca(2+) wave propagation, there was no evidence that propagation of Ca(2+) waves between cells contributed to synchronization of this alternans. PMID- 23090943 TI - Astrocytic GABA transporter GAT-1 dysfunction in experimental absence seizures. AB - An enhanced tonic GABA(A) inhibition in the thalamus plays a crucial role in experimental absence seizures and has been attributed, on the basis of indirect evidence, to a dysfunction of the astrocytic GABA transporter-1 (GAT-1). Here, the GABA transporter current was directly investigated in thalamic astrocytes from a well-established genetic model of absence seizures, the genetic absence epilepsy rats from Strasbourg (GAERS), and its non-epileptic control (NEC) strain. We also characterized the novel form of GABAergic and glutamatergic astrocyte-to-neuron signalling by recording slow outward currents (SOCs) and slow inward currents (SICs), respectively, in thalamocortical (TC) neurons of both strains. In patch-clamped astrocytes, the GABA transporter current was abolished by combined application of the selective GAT-1 and GAT-3 blocker, NO711 (30 MUm) and SNAP5114 (60 MUm), respectively, to GAERS and NEC thalamic slices. NO711 alone significantly reduced (41%) the transporter current in NEC, but had no effect in GAERS. SNAP5114 alone reduced by half the GABA transporter current in NEC, whilst it abolished it in GAERS. SIC properties did not differ between GAERS and NEC TC neurons, whilst moderate changes in SOC amplitude and kinetics were observed. These data provide the first direct demonstration of a malfunction of the astrocytic thalamic GAT-1 transporter in absence epilepsy and support an abnormal astrocytic modulation of thalamic ambient GABA levels. Moreover, while the glutamatergic astrocyte-neuron signalling is unaltered in the GAERS thalamus, the changes in some properties of the GABAergic astrocyte-neuron signalling in this epileptic strain may contribute to the generation of absence seizures. PMID- 23090945 TI - Regulation of synaptic transmission at the photoreceptor terminal: a novel role for the cation-chloride co-transporter NKCC1. AB - The Na(+)-K(+)-2Cl(-) co-transporter type 1 (NKCC1) is localized primarily throughout the outer plexiform layer (OPL) of the distal retina, a synaptic lamina that is comprised of the axon terminals of photoreceptors and the dendrites of horizontal and bipolar cells. Although known to play a key role in development, signal transmission and the gating of sensory signals in other regions of the retina and in the CNS, the contribution of NKCC1 to synaptic transmission within the OPL is largely unknown. In the present study, we investigated the function of NKCC1 at the photoreceptor-horizontal cell synapse by recording the electrical responses of photoreceptors and horizontal cells before and after blocking the activity of the transporter with bumetanide (BMN). Because NKCC1 co-transports 1 Na(+), 1 K(+) and 2 Cl(-), it is electroneutral and its activation had little effect on membrane conductance. However, recordings from postsynaptic horizontal cells revealed that inhibiting NKCC1 with BMN greatly increased glutamate release from both rod and cone terminals. In addition, we found that NKCC1 directly regulates Ca(2+)-dependent exocytosis at the photoreceptor synapse, raising the possibility that NKCC1 serves to suppress bulk release of glutamate vesicles from photoreceptor terminals in the dark and at light offset. Interestingly, NKCC1 gene and protein expressions were upregulated by light, which we attribute to the light-induced release of dopamine acting on D1-like receptors. In sum, our study reveals a new role for NKCC1 in the regulation of synaptic transmission in photoreceptors. PMID- 23090946 TI - Human phase response curve to a single 6.5 h pulse of short-wavelength light. AB - The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18-30 years) were studied for 9-10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 MUW cm(-2), 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of -2.6 h and 1.3 h, respectively. The 480 nm PRC induced ~75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure. PMID- 23090947 TI - Ion channels in genetic and acquired forms of epilepsy. AB - Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na(+) channels of inhibitory neurons, or GABA(A) receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K(+) channels, hyperpolarization-activated cation channels and T-type Ca(2+) channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K(+) channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis. PMID- 23090948 TI - Hypoxia-reoxygenation-induced endothelial barrier failure: role of RhoA, Rac1 and myosin light chain kinase. AB - Hypoxia-reoxygenation induces loss of endothelial barrier function and oedema formation, which presents a major impediment for recovery of the organ. The integrity of the endothelial barrier is highly dependent on its contractile machinery and actin dynamics, which are precisely regulated by Rho GTPases. Perturbed activities of these Rho-GTPases under hypoxia-reoxygenation lead to derangement of the actin cytoskeleton and therefore may affect the integrity of the endothelial barrier. The aim of the present study was to analyse the role of these GTPases in regulating endothelial barrier function during hypoxia reoxygenation in cultured porcine aortic endothelial cells and isolated perfused rat hearts. Hypoxia-reoxygenation induced an increase in albumin permeability of endothelial monolayers accompanied by an activation of the endothelial contractile machinery, derangement of the actin cytoskeleton and loss of VE cadherin from cellular junctions. Inhibition of contractile activation with ML-7 partially protected against hypoxia-reoxygenation-induced hyperpermeability. Likewise, reoxygenation caused an increase in RhoA and a reduction in Rac1 activity accompanied by enhanced stress fibre formation and loss of peripheral actin. Inhibition of RhoA/rho kinase (Rock) signalling with RhoA or Rock inhibitors led to a complete depolymerisation and derangement of the actin cytoskeleton and worsened hypoxia-reoxygenation-induced hyperpermeability. Activation of Rac1 using a cAMP analogue, 8-CPT-O-Me-cAMP, which specifically activates Epac/Rap1 signalling, restored peripheral localisation of actin and VE cadherin at cellular junctions and abrogated reoxygenation-induced hyperpermeability. Similar results were reproduced in isolated saline-perfused rat hearts. These data show that activation of Rac1 but not the inhibition of RhoA preserves endothelial integrity against reoxygenation-induced loss of barrier function. PMID- 23090949 TI - Spatial gradients in action potential duration created by regional magnetofection of hERG are a substrate for wavebreak and turbulent propagation in cardiomyocyte monolayers. AB - Spatial dispersion of action potential duration (APD) is a substrate for the maintenance of cardiac fibrillation, but the mechanisms are poorly understood. We investigated the role played by spatial APD dispersion in fibrillatory dynamics. We used an in vitro model in which spatial gradients in the expression of ether-a go-go-related (hERG) protein, and thus rapid delayed rectifying K(+) current (I(Kr)) density, served to generate APD dispersion, high-frequency rotor formation, wavebreak and fibrillatory conduction. A unique adenovirus-mediated magnetofection technique generated well-controlled gradients in hERG and green fluorescent protein (GFP) expression in neonatal rat ventricular myocyte monolayers. Computer simulations using a realistic neonatal rat ventricular myocyte monolayer model provided crucial insight into the underlying mechanisms. Regional hERG overexpression shortened APD and increased rotor incidence in the hERG overexpressing region. An APD profile at 75 percent repolarization with a 16.6 +/- 0.72 ms gradient followed the spatial profile of hERG-GFP expression; conduction velocity was not altered. Rotors in the infected region whose maximal dominant frequency was 12.9 Hz resulted in wavebreak at the interface (border zone) between infected and non-infected regions; dominant frequency distribution was uniform when the maximal dominant frequency was <12.9 Hz or the rotors resided in the uninfected region. Regularity at the border zone was lowest when rotors resided in the infected region. In simulations, a fivefold regional increase in I(Kr) abbreviated the APD and hyperpolarized the resting potential. However, the steep APD gradient at the border zone proved to be the primary mechanism of wavebreak and fibrillatory conduction. This study provides insight at the molecular level into the mechanisms by which spatial APD dispersion contributes to wavebreak, rotor stabilization and fibrillatory conduction. PMID- 23090950 TI - Activation of metabotropic glutamate receptors improves the accuracy of coincidence detection by presynaptic mechanisms in the nucleus laminaris of the chick. AB - Interaural time difference (ITD) is a major cue for localizing a sound source and is processed in the nucleus laminaris (NL) in birds. Coincidence detection (CD) is a crucial step for processing ITD and critically depends on the size and time course of excitatory postsynaptic potentials (EPSPs). Here, we investigated a role of metabotropic glutamate receptors (mGluRs) in the regulation of EPSP amplitude and CD in the NL of chicks. A non-specific agonist of mGluRs ((+/-)-1 aminocyclopentane-trans-1,3-dicarboxylic acid; t-ACPD) reduced the amplitude and extent of depression of excitatory postsynaptic currents (EPSCs) during a stimulus train, while the paired pulse ratio and coefficient of variation of EPSC amplitude were increased. In contrast, the amplitudes of spontaneous EPSCs were not affected, but the frequency was reduced. Thus, the effects of t-ACPD were presynaptic and reduced the release of neurotransmitter from terminals in the NL. Expression of group II mGluRs was graded along the tonotopic axis and was stronger towards the low frequency region in the NL. Both group II (DCG-IV) and group III (l-AP4) specific agonists reduced EPSC amplitude by presynaptic mechanisms, and the reduction was larger in the low frequency region; however, we could not find any effects of group I-specific agonists on EPSCs. The reduced EPSP amplitude in DCG-IV improved CD. A specific antagonist of group II mGluRs (LY341495) increased the amplitude of both EPSCs and EPSPs and enhanced the depression during a stimulus train, indicating constitutive activation of mGluRs in the NL. These observations indicate that mGluRs may work as autoreceptors and regulate EPSP size to improve CD in the NL. PMID- 23090951 TI - Cerebral network disorders after stroke: evidence from imaging-based connectivity analyses of active and resting brain states in humans. AB - Stroke causes a sudden disruption of physiological brain function which leads to impairments of functional brain networks involved in voluntary movements. In some cases, the brain has the intrinsic capacity to reorganize itself, thereby compensating for the disruption of motor networks. In humans, such reorganization can be investigated in vivo using neuroimaging. Recent developments in connectivity analyses based on functional neuroimaging data have provided new insights into the network pathophysiology underlying neurological symptoms. Here we review recent neuroimaging studies using functional resting-state correlations, effective connectivity models or graph theoretical analyses to investigate changes in neural motor networks and recovery after stroke. The data demonstrate that network disturbances after stroke occur not only in the vicinity of the lesion but also between remote cortical areas in the affected and unaffected hemisphere. The reorganization of motor networks encompasses a restoration of interhemispheric functional coherence in the resting state, particularly between the primary motor cortices. Furthermore, reorganized neural networks feature strong excitatory interactions between fronto-parietal areas and primary motor cortex in the affected hemisphere, suggesting that greater top-down control over primary motor areas facilitates motor execution in the lesioned brain. In addition, there is evidence that motor recovery is accompanied by a more random network topology with reduced local information processing. In conclusion, Stroke induces changes in functional and effective connectivity within and across hemispheres which relate to motor impairments and recovery thereof. Connectivity analyses may hence provide new insights into the pathophysiology underlying neurological deficits and may be further used to develop novel, neurobiologically informed treatment strategies. PMID- 23090952 TI - Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. AB - Mice deficient for CELF4, a neuronal RNA-binding protein, have a complex seizure disorder that includes both convulsive and non-convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the physiological and molecular basis of this, we studied Celf4-deficient neurons in brain slices. Assessment of intrinsic properties of layer V cortical pyramidal neurons showed that neurons from mutant heterozygotes and homozygotes have a lower action potential (AP) initiation threshold and a larger AP gain when compared with wild-type neurons. Celf4 mutant neurons also demonstrate an increase in persistent sodium current (I(NaP)) and a hyperpolarizing shift in the voltage dependence of activation. As part of a related study, we find that CELF4 directly binds Scn8a mRNA, encoding sodium channel Na(v)1.6, the primary instigator of AP at the axon initial segment (AIS) and the main carrier of I(NaP). In the present study we find that CELF4 deficiency results in a dramatic elevation in the expression of Na(v)1.6 protein at the AIS in both null and heterozygous neurons. Together these results suggest that activation of Na(v)1.6 plays a crucial role in seizure generation in this complex model of neurological disease. PMID- 23090953 TI - In vitro and in vivo studies on radiobiological effects of prolonged fraction delivery time in A549 cells. AB - Intensity-modulated radiation therapy, when used in the clinic, prolongs fraction delivery time. Here we investigated both the in vivoand in vitroradiobiological effects on the A549 cell line, including the effect of different delivery times with the same dose on A549 tumor growth in nude mice. The in vitroeffects were studied with clonogenic assays, using linear-quadratic and incomplete repair models to fit the dose-survival curves. Fractionated irradiation of different doses was given at one fraction per day, simulating a clinical dose-time fractionation pattern. The longer the interval between the exposures, the more cells survived. To investigate the in vivoeffect, we used sixty-four nude mice implanted with A549 cells in the back legs, randomly assigned into eight groups. A 15 Gy radiation dose was divided into different subfractions. The maximum and minimum tumor diameters were recorded to determine tumor growth. Tumor growth was delayed for groups with prolonged delivery time (40 min) compared to the group receiving a single dose of 15 Gy (P< 0.05), and tumors with a 20 min delivery time had delayed growth compared to those with a 40 min delivery time [20' (7.5 Gy * 2 F) vs 40' (7.5 Gy * 2 F), P= 0.035; 20' (3 Gy * 5 F) vs 40' (3 Gy * 5 F); P= 0.054; 20' (1.67 Gy * 9 F) vs 40' (1.67 Gy * 9 F), P= 0.028]. A prolonged delivery time decreased the radiobiological effects, so we strongly recommend keeping the delivery time as short as possible. PMID- 23090955 TI - Role of YopK in Yersinia pseudotuberculosis resistance against polymorphonuclear leukocyte defense. AB - The enteropathogen Yersinia pseudotuberculosis can survive in the harsh environment of lymphoid compartments that abounds in immune cells. This capacity is dependent on the plasmid-encoded Yersinia outer proteins (Yops) that are delivered into the host cell via a mechanism involving the Yersinia type III secretion system. We show that the virulence protein YopK has a role in the mechanism by which Y. pseudotuberculosis avoids the polymorphonuclear leukocyte or neutrophil (PMN) defense. A yopK mutant, which is attenuated in the mouse infection model, where it fails to cause systemic infection, was found to colonize Peyer's patches and mesenteric lymph nodes more rapidly than the wild type strain. Further, in mice lacking PMNs, the yopK mutant caused full disease with systemic spread and typical symptoms. Analyses of effects on PMNs revealed that both the wild-type strain and the yopK mutant inhibited internalization and reactive oxygen species production, as well as neutrophil extracellular trap formation by PMNs. However, the wild-type strain effectively avoided induction of PMN death, whereas the mutant caused a necrosis-like PMN death. Taken together, our results indicate that YopK is required for the ability of Yersinia to resist the PMN defense, which is critical for the virulence of the pathogen. We suggest a mechanism whereby YopK functions to prevent unintended Yop delivery and thereby PMN disruption, resulting in necrosis-like cell death, which would enhance the inflammatory response favoring the host. PMID- 23090956 TI - A purified capsular polysaccharide markedly inhibits inflammatory response during endotoxic shock. AB - Capsular material of the opportunistic fungus Cryptococcus neoformans is composed mainly of a polysaccharide named glucuronoxylomannan (GXM). In this study, the effects of GXM were analyzed in an in vivo experimental system of lipopolysaccharide (LPS)-induced shock. Endotoxic shock was induced in mice by a single intraperitoneal injection of LPS from Escherichia coli. GXM treatment reduced the mortality of mice at early stages. Mice treated with LPS alone showed markedly increased plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6, whereas mice that were also treated with GXM showed significantly lower plasma levels of these cytokines. This effect was related to a marked suppression of Akt and IkappaBalpha activation. Importantly, the inhibitory effect of GXM on proinflammatory cytokine secretion was reproduced by treatment with wortmannin, an inhibitor of the Akt transcription pathway. Our results indicate that GXM has a beneficial effect on endotoxic shock, resulting in a significant increase in the rate of survival by dampening the hyperinflammatory response. PMID- 23090954 TI - Inactivation of epidermal growth factor by Porphyromonas gingivalis as a potential mechanism for periodontal tissue damage. AB - Porphyromonas gingivalis is a Gram-negative bacterium associated with the development of periodontitis. The evolutionary success of this pathogen results directly from the presence of numerous virulence factors, including peptidylarginine deiminase (PPAD), an enzyme that converts arginine to citrulline in proteins and peptides. Such posttranslational modification is thought to affect the function of many different signaling molecules. Taking into account the importance of tissue remodeling and repair mechanisms for periodontal homeostasis, which are orchestrated by ligands of the epidermal growth factor receptor (EGFR), we investigated the ability of PPAD to distort cross talk between the epithelium and the epidermal growth factor (EGF) signaling pathway. We found that EGF preincubation with purified recombinant PPAD, or a wild-type strain of P. gingivalis, but not with a PPAD-deficient isogenic mutant, efficiently hindered the ability of the growth factor to stimulate epidermal cell proliferation and migration. In addition, PPAD abrogated EGFR-EGF interaction dependent stimulation of expression of suppressor of cytokine signaling 3 and interferon regulatory factor 1. Biochemical analysis clearly showed that the PPAD exerted effects on EGF activities were solely due to deimination of the C terminal arginine. Interestingly, citrullination of two internal Arg residues with human endogenous peptidylarginine deiminases did not alter EFG function, arguing that the C-terminal arginine is essential for EGF biological activity. Cumulatively, these data suggest that the PPAD-activity-abrogating EGF function in gingival pockets may at least partially contribute to tissue damage and delayed healing within P. gingivalis-infected periodontia. PMID- 23090957 TI - Transcriptional responses of uropathogenic Escherichia coli to increased environmental osmolality caused by salt or urea. AB - Uropathogenic Escherichia coli (UPEC) is the most common causative agent of urinary tract infections in humans. The majority of urinary infections develop via ascending route through the urethra, where bacterial cells come in contact with human urine prior to reaching the bladder or kidneys. Since urine contains significant amounts of inorganic ions and urea, it imposes osmotic and denaturing stresses on bacterial cells. In this study, we determined the transcriptional adaptive responses of UPEC strain CFT073 to the presence of 0.3 M NaCl or 0.6 M urea in the growth medium. The cell responses to these two osmolytes were drastically different. Although most of the genes of the osmotically inducible regulon were overexpressed in medium with salt, urea failed to stimulate osmotic stress response. At the same time, UPEC colonization genes encoding type 1 and F1C fimbriae and capsule biosynthesis were transcriptionally induced in the presence of urea but did not respond to increased salt concentration. We speculate that urea can potentially be sensed by uropathogenic bacteria to initiate infection program. In addition, several molecular chaperone genes were overexpressed in the presence of urea, whereas adding NaCl to the medium led to an upregulation of a number of anaerobic metabolism pathways. PMID- 23090958 TI - Schistosoma mansoni hemozoin modulates alternative activation of macrophages via specific suppression of Retnla expression and secretion. AB - The trematode Schistosoma mansoni is one of the etiological agents of schistosomiasis, a key neglected tropical disease responsible for an estimated annual loss of 70 million disability-adjusted life years. Hematophagy represents the primary nutrient acquisition pathway of this parasite, but digestion of hemoglobin also liberates toxic heme. Schistosomes detoxify heme via crystallization into hemozoin, which is subsequently regurgitated into the host's circulation. Here we demonstrate that during experimental schistosomiasis, hemozoin accumulating in the mouse liver is taken up by phagocytes at a time coincident with the development of the egg-induced T-helper 2 (Th2) granulomatous immune response. Furthermore, the uptake of hemozoin also coincides with the hepatic expression of markers of alternative macrophage activation. Alternatively activated macrophages are a key effector cell population associated with protection against schistosomiasis, making hemozoin well placed to play an important immunomodulatory role in this disease. To systematically explore this hypothesis, S. mansoni hemozoin was purified and added to in vitro bone marrow derived macrophage cultures concurrently exposed to cytokines chosen to reflect the shifting state of macrophage activation in vivo. Macrophages undergoing interleukin-4 (IL-4)-induced alternative activation in the presence of hemozoin developed a phenotype specifically lacking in Retnla, a characteristic alternatively activated macrophage product associated with regulation of Th2 inflammatory responses. As such, in addition to its important detoxification role during hematophagy, we propose that schistosome hemozoin also provides a potent immunomodulatory function in the coevolved network of host-parasite relationships during schistosomiasis. PMID- 23090959 TI - Genome expression analysis of nonproliferating intracellular Salmonella enterica serovar Typhimurium unravels an acid pH-dependent PhoP-PhoQ response essential for dormancy. AB - Genome-wide expression analyses have provided clues on how Salmonella proliferates inside cultured macrophages and epithelial cells. However, in vivo studies show that Salmonella does not replicate massively within host cells, leaving the underlying mechanisms of such growth control largely undefined. In vitro infection models based on fibroblasts or dendritic cells reveal limited proliferation of the pathogen, but it is presently unknown whether these phenomena reflect events occurring in vivo. Fibroblasts are distinctive, since they represent a nonphagocytic cell type in which S. enterica serovar Typhimurium actively attenuates intracellular growth. Here, we show in the mouse model that S. Typhimurium restrains intracellular growth within nonphagocytic cells positioned in the intestinal lamina propria. This response requires a functional PhoP-PhoQ system and is reproduced in primary fibroblasts isolated from the mouse intestine. The fibroblast infection model was exploited to generate transcriptome data, which revealed that ~2% (98 genes) of the S. Typhimurium genome is differentially expressed in nongrowing intracellular bacteria. Changes include metabolic reprogramming to microaerophilic conditions, induction of virulence plasmid genes, upregulation of the pathogenicity islands SPI-1 and SPI-2, and shutdown of flagella production and chemotaxis. Comparison of relative protein levels of several PhoP-PhoQ-regulated functions (PagN, PagP, and VirK) in nongrowing intracellular bacteria and extracellular bacteria exposed to diverse PhoP-PhoQ-inducing signals denoted a regulation responding to acidic pH. These data demonstrate that S. Typhimurium restrains intracellular growth in vivo and support a model in which dormant intracellular bacteria could sense vacuolar acidification to stimulate the PhoP-PhoQ system for preventing intracellular overgrowth. PMID- 23090960 TI - Innate immune response to Streptococcus iniae infection in zebrafish larvae. AB - Streptococcus iniae causes systemic infection characterized by meningitis and sepsis. Here, we report a larval zebrafish model of S. iniae infection. Injection of wild-type S. iniae into the otic vesicle induced a lethal infection by 24 h postinfection. In contrast, an S. iniae mutant deficient in polysaccharide capsule (cpsA mutant) was not lethal, with greater than 90% survival at 24 h postinfection. Live imaging demonstrated that both neutrophils and macrophages were recruited to localized otic infection with mutant and wild-type S. iniae and were able to phagocytose bacteria. Depletion of neutrophils and macrophages impaired host survival following infection with wild-type S. iniae and the cpsA mutant, suggesting that leukocytes are critical for host survival in the presence of both the wild-type and mutant bacteria. However, zebrafish larvae with impaired neutrophil function but normal macrophage function had increased susceptibility to wild-type bacteria but not the cpsA mutant. Taking these findings together, we have developed a larval zebrafish model of S. iniae infection and have found that although neutrophils are important for controlling infection with wild-type S. iniae, neutrophils are not necessary for host defense against the cpsA mutant. PMID- 23090961 TI - Cytotoxic necrotizing factor 1 and hemolysin from uropathogenic Escherichia coli elicit different host responses in the murine bladder. AB - Cytotoxic necrotizing factor 1 (CNF1) and hemolysin (HlyA1) are toxins produced by uropathogenic Escherichia coli (UPEC). We previously showed that these toxins contribute to the inflammation and tissue damage seen in a mouse model of ascending urinary tract infection. CNF1 constitutively activates small Rho GTPases by deamidation of a conserved glutamine residue, and HlyA1 forms pores in eukaryotic cell membranes. In this study, we used cDNA microarrays of bladder tissue isolated from mice infected intraurethrally with wild-type CP9, CP9cnf1, or CP9DeltahlyA to further evaluate the role that each toxin plays in the host response to UPEC. Regardless of the strain used, we found that UPEC itself elicited a significant change in host gene expression 24 h after inoculation. The largest numbers of upregulated genes were in the cytokine and chemokine signaling and Toll-like receptor signaling pathways. CNF1 exerted a strong positive influence on expression of genes involved in innate immunity and signal transduction and a negative impact on metabolism- and transport-associated genes. HlyA1 evoked an increase in expression of genes that encode innate immunity factors and a decrease in expression of genes involved in cytoskeletal and metabolic processes. Multiplex cytokine and myeloperoxidase assays corroborated our finding that a strong proinflammatory response was elicited by all strains tested. Bladders challenged intraurethrally with purified CNF1 displayed pathology similar to but significantly less intense than the pathology that we observed in CP9-challenged mice. Our data demonstrate substantial roles for CNF1 and HlyA1 in initiation of a strong proinflammatory response to UPEC in the bladder. PMID- 23090962 TI - Characterization of the AggR regulon in enteroaggregative Escherichia coli. AB - AggR is a transcriptional regulator of enteroaggregative Escherichia coli (EAEC) and has been proposed as the defining factor for typical EAEC strains. Expression of multiple putative virulence factors, including the aggregative adherence fimbriae (AAF), dispersin, the dispersin translocator Aat, and the Aai type VI secretion system, have been found to be regulated by AggR. Here, we confirm the existence of at least 44 AggR-regulated genes using DNA microarray and real-time quantitative reverse transcription-PCR (qRT-PCR); these genes include chromosomal and plasmid-borne loci and 19 previously unsuspected genes. Two previously uncharacterized virulence plasmid-encoded open reading frames (ORFs) (designated ORF3 and ORF4) exhibit significant identity with isoprenoid biosynthesis genes of Bacteria and Archaea. The predicted ORF4 product is closely related to isopentenyl isomerase (IDI) enzymes, whereas the predicted product of the adjacent ORF3 exhibits an aspartate-rich region that is common among trans isoprenyl phosphate synthases. We show that mutations in these ORFs confer changes in bacterial surface properties. AggR coordinately controls expression of a large number of EAEC genes. PMID- 23090964 TI - Reading vocabulary in children with and without hearing loss: the roles of task and word type. AB - PURPOSE: To address the problem of low reading comprehension scores among children with hearing impairment, it is necessary to have a better understanding of their reading vocabulary. In this study, the authors investigated whether task and word type differentiate the reading vocabulary knowledge of children with and without severe hearing loss. METHOD: Seventy-two children with hearing loss and 72 children with normal hearing performed a lexical and a use decision task. Both tasks contained the same 180 words divided over 7 clusters, each cluster containing words with a similar pattern of scores on 8 word properties (word class, frequency, morphological family size, length, age of acquisition, mode of acquisition, imageability, and familiarity). RESULTS: Whereas the children with normal hearing scored better on the 2 tasks than the children with hearing loss, the size of the difference varied depending on the type of task and word. CONCLUSIONS: Performance differences between the 2 groups increased as words and tasks became more complex. Despite delays, children with hearing loss showed a similar pattern of vocabulary acquisition as their peers with normal hearing. For the most precise assessment of reading vocabulary possible, a range of tasks and word types should be used. PMID- 23090963 TI - Identification of Burkholderia cenocepacia strain H111 virulence factors using nonmammalian infection hosts. AB - Burkholderia cenocepacia H111, a strain isolated from a cystic fibrosis patient, has been shown to effectively kill the nematode Caenorhabditis elegans. We used the C. elegans model of infection to screen a mini-Tn5 mutant library of B. cenocepacia H111 for attenuated virulence. Of the approximately 5,500 B. cenocepacia H111 random mini-Tn5 insertion mutants that were screened, 22 showed attenuated virulence in C. elegans. Except for the quorum-sensing regulator cepR, none of the mutated genes coded for the biosynthesis of classical virulence factors such as extracellular proteases or siderophores. Instead, the mutants contained insertions in metabolic and regulatory genes. Mutants attenuated in virulence in the C. elegans infection model were also tested in the Drosophila melanogaster pricking model, and those also attenuated in this model were further tested in Galleria mellonella. Six of the 22 mutants were attenuated in D. melanogaster, and five of these were less pathogenic in the G. mellonella model. We show that genes encoding enzymes of the purine, pyrimidine, and shikimate biosynthesis pathways are critical for virulence in multiple host models of infection. PMID- 23090965 TI - Effects of noise suppression on intelligibility: experts' opinions and naive normal-hearing listeners' performance. AB - PURPOSE: In this study, the authors investigated how well experts can adjust the settings of a commercial noise-reduction system to optimize the intelligibility for naive normal-hearing listeners. METHOD: In Experiment 1, 5 experts adjusted parameters for a noise-reduction system while aiming to optimize intelligibility. The stimuli consisted of speech presented in car-cabin noise or babble at 5 different signal-to-noise ratios (SNRs). In Experiment 2, the effects of processing with these settings were measured with 10 listeners undertaking an intelligibility test. In Experiment 3, the intelligibility of a broad range of settings was investigated with another 10 listeners to determine whether the experts' chosen settings could have been improved. RESULTS: Low Cronbach's alphas indicated that parameter settings varied considerably within and across experts. For very low SNRs, mean proposed settings differed from those for higher SNRs. The different settings had no significant effects on intelligibility for naive normal-hearing listeners. At high SNRs, the settings proposed by experts were found to deteriorate intelligibility. Superior intelligibility for naive normal hearing listeners was achievable from settings other than the ones proposed by the experts. CONCLUSION: While attempting to enhance noisy speech, experts may propose settings that deteriorate intelligibility for naive normal-hearing listeners. PMID- 23090966 TI - EKLF/KLF1, a tissue-restricted integrator of transcriptional control, chromatin remodeling, and lineage determination. AB - Erythroid Kruppel-like factor (EKLF or KLF1) is a transcriptional regulator that plays a critical role in lineage-restricted control of gene expression. KLF1 expression and activity are tightly controlled in a temporal and differentiation stage-specific manner. The mechanisms by which KLF1 is regulated encompass a range of biological processes, including control of KLF1 RNA transcription, protein stability, localization, and posttranslational modifications. Intact KLF1 regulation is essential to correctly regulate erythroid function by gene transcription and to maintain hematopoietic lineage homeostasis by ensuring a proper balance of erythroid/megakaryocytic differentiation. In turn, KLF1 regulates erythroid biology by a wide variety of mechanisms, including gene activation and repression by regulation of chromatin configuration, transcriptional initiation and elongation, and localization of gene loci to transcription factories in the nucleus. An extensive series of biochemical, molecular, and genetic analyses has uncovered some of the secrets of its success, and recent studies are highlighted here. These reveal a multilayered set of control mechanisms that enable efficient and specific integration of transcriptional and epigenetic controls and that pave the way for proper lineage commitment and differentiation. PMID- 23090967 TI - CD2AP links cortactin and capping protein at the cell periphery to facilitate formation of lamellipodia. AB - Understanding the physiology of complex relationships between components of signaling pathways and the actin cytoskeleton is an important challenge. CD2AP is a membrane scaffold protein implicated in a variety of physiological and disease processes. The physiological function of CD2AP is unclear, but its biochemical interactions suggest that it has a role in dynamic actin assembly. Here, we report that CD2AP functions to facilitate the recruitment of actin capping protein (CP) to the Src kinase substrate, cortactin, at the cell periphery, and that this is necessary for formation of the short branched filaments that characterize lamellipodium formation and are required for cell migration. Superresolution fluorescence microscopy demonstrated that the efficient colocalization of CP and cortactin at the cell periphery required CD2AP. As both cortactin and CP function to enhance branched actin filament formation, CD2AP functions synergistically to enhance the function of both proteins. Our data demonstrate how the interplay between specialized actin regulatory molecules shapes the actin cytoskeleton. PMID- 23090968 TI - A-kinase-anchoring protein-Lbc anchors IkappaB kinase beta to support interleukin 6-mediated cardiomyocyte hypertrophy. AB - In response to stress, the heart undergoes a pathological remodeling process associated with hypertrophy and the reexpression of a fetal gene program that ultimately causes cardiac dysfunction and heart failure. In this study, we show that A-kinase-anchoring protein (AKAP)-Lbc and the inhibitor of NF-kappaB kinase subunit beta (IKKbeta) form a transduction complex in cardiomyocytes that controls the production of proinflammatory cytokines mediating cardiomyocyte hypertrophy. In particular, we can show that activation of IKKbeta within the AKAP-Lbc complex promotes NF-kappaB-dependent production of interleukin-6 (IL-6), which in turn enhances fetal gene expression and cardiomyocyte growth. These findings provide a new mechanistic hypothesis explaining how hypertrophic signals are coordinated and conveyed to interleukin-mediated transcriptional reprogramming events in cardiomyocytes. PMID- 23090969 TI - An unusual two-step control of CPEB destruction by Pin1. AB - Cytoplasmic polyadenylation is a conserved mechanism that controls mRNA translation and stability. A key protein that promotes polyadenylation-induced translation of mRNAs in maturing Xenopus oocytes is the cytoplasmic polyadenylation element binding protein (CPEB). During this meiotic transition, CPEB is subjected to phosphorylation-dependent ubiquitination and partial destruction, which is necessary for successive waves of polyadenylation of distinct mRNAs. Here we identify the peptidyl-prolyl cis-trans isomerase Pin1 as an important factor mediating CPEB destruction. Pin1 interacts with CPEB in an unusual manner in which it occurs prior to CPEB phosphorylation and prior to Pin1 activation by serine 71 dephosphorylation. Upon induction of maturation, CPEB becomes phosphorylated, which occurs simultaneously with Pin1 dephosphorylation. At this time, the CPEB-Pin1 interaction requires cdk1-catalyzed CPEB phosphorylation on S/T-P motifs. Subsequent CPEB ubiquitination and destruction are mediated by a conformational change induced by Pin1 isomerization of CPEB. Similar to M phase progression in maturing Xenopus oocytes, the destruction of CPEB during the mammalian cell cycle requires Pin1 as well. These data identify Pin1 as a new and essential factor regulating CPEB degradation. PMID- 23090970 TI - Quantification of the N-glycosylated secretome by super-SILAC during breast cancer progression and in human blood samples. AB - Cells secrete a large number of proteins to communicate with their surroundings. Furthermore, plasma membrane proteins and intracellular proteins can be released into the extracellular space by regulated or non-regulated processes. Here, we profiled the supernatant of 11 cell lines that are representative of different stages of breast cancer development by specifically capturing N-glycosylated peptides using the N-glyco FASP technology. For accurate quantification we developed a super-SILAC mix from several labeled breast cancer cell lines and used it as an internal standard for all samples. In total, 1398 unique N glycosylation sites were identified and quantified. Enriching for N-glycosylated peptides focused the analysis on classically secreted and membrane proteins. N glycosylated secretome profiles correctly clustered the different cell lines to their respective cancer stage, suggesting that biologically relevant differences were detected. Five different profiles of glycoprotein dynamics during cancer development were detected, and they contained several proteins with known roles in breast cancer. We then used the super-SILAC mix in plasma, which led to the quantification of a large number of the previously identified N-glycopeptides in this important body fluid. The combination of quantifying the secretome of cancer cell lines and of human plasma with a super-SILAC approach appears to be a promising new approach for finding markers of disease. PMID- 23090971 TI - Comparative proteomics of two life cycle stages of stable isotope-labeled Trypanosoma brucei reveals novel components of the parasite's host adaptation machinery. AB - Trypanosoma brucei developed a sophisticated life cycle to adapt to different host environments. Although developmental differentiation of T. brucei has been the topic of intensive research for decades, the mechanisms responsible for adaptation to different host environments are not well understood. We developed stable isotope labeling by amino acids in cell culture in trypanosomes to compare the proteomes of two different life cycle stages. Quantitative comparison of 4364 protein groups identified many proteins previously not known to be stage specifically expressed. The identification of stage-specific proteins helps to understand how parasites adapt to different hosts and provides new insights into differences in metabolism, gene regulation, and cell architecture. A DEAD-box RNA helicase, which is highly up-regulated in the bloodstream form of this parasite and which is essential for viability and proper cell cycle progression in this stage is described as an example. PMID- 23090976 TI - Accurate model selection of relaxed molecular clocks in bayesian phylogenetics. AB - Recent implementations of path sampling (PS) and stepping-stone sampling (SS) have been shown to outperform the harmonic mean estimator (HME) and a posterior simulation-based analog of Akaike's information criterion through Markov chain Monte Carlo (AICM), in bayesian model selection of demographic and molecular clock models. Almost simultaneously, a bayesian model averaging approach was developed that avoids conditioning on a single model but averages over a set of relaxed clock models. This approach returns estimates of the posterior probability of each clock model through which one can estimate the Bayes factor in favor of the maximum a posteriori (MAP) clock model; however, this Bayes factor estimate may suffer when the posterior probability of the MAP model approaches 1. Here, we compare these two recent developments with the HME, stabilized/smoothed HME (sHME), and AICM, using both synthetic and empirical data. Our comparison shows reassuringly that MAP identification and its Bayes factor provide similar performance to PS and SS and that these approaches considerably outperform HME, sHME, and AICM in selecting the correct underlying clock model. We also illustrate the importance of using proper priors on a large set of empirical data sets. PMID- 23090977 TI - Characterization of methicillin-resistant non-Staphylococcus aureus staphylococci carriage isolates from different bovine populations. AB - OBJECTIVES: This study aimed at investigating bovine non-Staphylococcus aureus staphylococci for their role as a potential reservoir for methicillin resistance. METHODS: Nasal swab samples were collected from 150 veal calves on 15 veal farms, 100 dairy cows on 10 dairy farms and 100 beef cows on 10 beef farms. Suspected staphylococcal isolates were investigated by PCR for the presence of the classic mecA and mecA(LGA251). Methicillin-resistant non-S. aureus staphylococci (MRNAS) were genotypically identified and were characterized by broth microdilution antimicrobial susceptibility testing and staphylococcal cassette chromosome mec (SCCmec) typing. RESULTS: The MRNAS (n = 101) carriage rate was estimated as 30.29% (95% CI 6.14%-74.28%) in veal calves, 13.1% (95% CI 1.28%-63.72%) in dairy cows and 24.8% (95% CI 11.97%-44.42%) in beef cows. Carriage rates were not significantly different between the three populations (P > 0.05). mecA(LGA251) was not detected. Most (n = 80) MRNAS were identified as Staphylococcus sciuri, Staphylococcus lentus or Staphylococcus fleurettii. Resistance to aminoglycosides, macrolide-lincosamide-streptogramin antimicrobials, tetracycline and ciprofloxacin was frequently detected. Two linezolid-resistant MRNAS from veal calves carried the multidrug-resistance gene cfr. SCCmec cassettes of type III predominated (n = 46); another 40 SCCmec cassettes harboured a class A mec complex without identifiable ccr complex; type IVa, type V and several other non typeable cassettes were detected in low frequencies, especially in methicillin resistant Staphylococcus epidermidis. CONCLUSIONS: The SCCmec types predominating in bovine MRNAS differ from those mostly detected in livestock-associated methicillin-resistant S. aureus strains. Yet, the detection of cfr and the high level of other antimicrobial resistances suggest a potentially important role of bovine MRNAS as a reservoir for resistance determinants other than SCCmec. PMID- 23090978 TI - Analysis of the quinolone-resistance determining region of the gyrA gene and the analogous region of the parC gene in Ureaplasma parvum and Ureaplasma urealyticum detected in first-void urine of men with non-gonococcal urethritis. PMID- 23090979 TI - The anticancer ruthenium complex KP1019 induces DNA damage, leading to cell cycle delay and cell death in Saccharomyces cerevisiae. AB - The anticancer ruthenium complex trans-[tetrachlorobis(1H indazole)ruthenate(III)], otherwise known as KP1019, has previously been shown to inhibit proliferation of ovarian tumor cells, induce DNA damage and apoptosis in colon carcinoma cells, and reduce tumor size in animal models. Notably, no dose limiting toxicity was observed in a Phase I clinical trial. Despite these successes, KP1019's precise mechanism of action remains poorly understood. To determine whether Saccharomyces cerevisiae might serve as an effective model for characterizing the cellular response to KP1019, we first confirmed that this drug is internalized by yeast and induces mutations, cell cycle delay, and cell death. We next examined KP1019 sensitivity of strains defective in DNA repair, ultimately showing that rad1Delta, rev3Delta, and rad52Delta yeast are hypersensitive to KP1019, suggesting that nucleotide excision repair (NER), translesion synthesis (TLS), and recombination each play a role in drug tolerance. These data are consistent with published work showing that KP1019 causes interstrand cross-links and bulky DNA adducts in mammalian cell lines. Published research also showed that mammalian cell lines resistant to other chemotherapeutic agents exhibit only modest resistance, and sometimes hypersensitivity, to KP1019. Here we report similar findings for S. cerevisiae. Whereas gain-of-function mutations in the transcription activator-encoding gene PDR1 are known to increase expression of drug pumps, causing resistance to structurally diverse toxins, we now demonstrate that KP1019 retains its potency against yeast carrying the hypermorphic alleles PDR1-11 or PDR1-3. Combined, these data suggest that S. cerevisiae could serve as an effective model system for identifying evolutionarily conserved modulators of KP1019 sensitivity. PMID- 23090980 TI - The AIDS pandemic in historic perspective. AB - Potent antiretroviral drugs (ART) have changed the nature of AIDS, a once deadly disease, into a manageable illness and offer the promise of reducing the spread of HIV. But the pandemic continues to expand and cause significant morbidity and devastation to families and nations as ART cannot be distributed worldwide to all who need the drugs to treat their infections, prevent HIV transmission, or serve as prophylaxis. Furthermore, conventional behavioral prevention efforts based on theories that individuals can be taught to modify risky behaviors if they have the knowledge to do so have been ineffective. Noting behavioral strategies targeting individuals fail to address broader social and political structures that create environments vulnerable to HIV spread, social scientists and public health officials insist that HIV policies must be comprehensive and also target a variety of structures at the population and environmental level. Nineteenth century public health programs that targeted environmental susceptibility are the historical analogues to today's comprehensive biomedical and structural strategies to handle AIDS. Current AIDS policies underscore that those fighting HIV using scientific advances in virology and molecular biology cannot isolate HIV from its broader environment and social context any more than their nineteenth-century predecessors who were driven by the filth theory of disease. PMID- 23090981 TI - Accurate human microsatellite genotypes from high-throughput resequencing data using informed error profiles. AB - Repetitive sequences are biologically and clinically important because they can influence traits and disease, but repeats are challenging to analyse using short read sequencing technology. We present a tool for genotyping microsatellite repeats called RepeatSeq, which uses Bayesian model selection guided by an empirically derived error model that incorporates sequence and read properties. Next, we apply RepeatSeq to high-coverage genomes from the 1000 Genomes Project to evaluate performance and accuracy. The software uses common formats, such as VCF, for compatibility with existing genome analysis pipelines. Source code and binaries are available at http://github.com/adaptivegenome/repeatseq. PMID- 23090982 TI - Accumulation of retained nonfunctional arteriovenous grafts correlates with severity of inflammation in asymptomatic ESRD patients. AB - BACKGROUND: The contribution of multiple retained nonfunctional arteriovenous grafts (AVGs) to the burden of chronic inflammation in chronic hemodialysis patients has not been well studied. Here, we sought to evaluate the association between plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha) and albumin and the number of retained nonfunctional AVGs. METHODS: This cross-sectional study enrolled 91 prevalent patients undergoing in-center hemodialysis without evidence of infection or inflammation. A baseline blood sample was obtained at study enrollment. A general linear model (GLM) was used to compare levels of biomarkers of systemic inflammation across groups defined by the number of retained, nonfunctional AVGs. RESULTS: A total of 43 patients had one or more retained thrombosed AVG and had significantly greater plasma log-CRP levels compared with patients without a previous AVG (P= 0.036), regardless of the current AV access type. Using a GLM, we found that for every additional retained thrombosed AVG, plasma log-CRP, log IL-6 and TNF-alpha concentrations increased significantly by 0.30 mg/L (P= 0.011), 0.18 pg/mL (P= 0.046) and 0.72 pg/mL (P= 0.046), respectively, following adjustment. CONCLUSIONS: Hence, the severity of inflammation increases with the number of retained nonfunctional AVG's, suggesting that AVG accumulation may contribute to the cardiovascular morbidity and mortality associated with chronic inflammation in asymptomatic end-stage renal disease (ESRD) patients. Further study is indicated to determine whether patients with one or more thrombosed, retained AVG may benefit from periodic screening with CRP monitoring to identify those patients who may benefit from AVG resection. PMID- 23090983 TI - Molecular classification of gliomas based on whole genome gene expression: a systematic report of 225 samples from the Chinese Glioma Cooperative Group. AB - Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to molecularly targeted therapy. However, prior studies attempting to classify glioma subtypes have given conflicting results. We aim to complement and validate the existing molecular classification system on a large number of samples from an East Asian population. A total of 225 samples from Chinese patients was selected for whole genome gene expression profiling. Consensus clustering was applied. Three major groups of gliomas were identified (referred to as G1, G2, and G3). The G1 subgroup correlates with a good clinical outcome, young age, and extremely high frequency of IDH1 mutations. Relative to the G1 subgroup, the G3 subgroup is correlated with a poorer clinical outcome, older age, and a very low rate of mutations in the IDH1 gene. Correlations of the G2 subgroup with respect to clinical outcome, age, and IDH1 mutation fall between the G1 and G3 subgroups. In addition, the G2 subtype was associated with a higher percentage of loss of 1p/19q when compared with G1 and G3 subtypes. Furthermore, our classification scheme was validated on 2 independent datasets derived from the cancer genome atlas (TCGA) and Rembrandt. With use of the TCGA classification system, proneural, neural, and mesenchymal, but not classical subtype, associated gene signatures were clearly defined. In summary, our results reveal that 3 main subtypes stably exist in Chinese patients with glioma. Our classification scheme may reflect the clinical and genetic alterations more clearly. Classical subtype-associated gene signature was not found in our dataset. PMID- 23090985 TI - Detection of 2-hydroxyglutaric acid in vivo by proton magnetic resonance spectroscopy in U87 glioma cells overexpressing isocitrate dehydrogenase-1 mutation. AB - The arginine 132 (R132) mutation of isocitrate dehydrogenase -1 (IDH1(R132)) results in production of 2-hydroxyglutarate (2-HG) and is associated with a better prognosis compared with wild-type (WT) in glioma patients. The majority of lower-grade gliomas express IDH1(R132), whereas this mutation is rare in grade IV gliomas. The aim of this study was to noninvasively investigate metabolic and physiologic changes associated with the IDH1 mutation in a mouse glioma model. Using a 7T magnet, we compared MRI and proton magnetic resonance spectroscopy (MRS) in U87 glioma cells overexpressing either the mutated IDH1(R132) or IDH1 wild-type (IDH1(WT)) gene in a mouse flank xenograft model. Flank tumors overexpressing IDH1(R132) showed a resonance at 2.25 ppm corresponding to the 2 HG peak described for human IDH1(R132) gliomas. WT tumors lacked this peak in all cases. IDH1 mutant tumors demonstrated significantly reduced glutamate by in vivo MRS. There were no significant differences in T(2), apparent diffusion coefficient (ADC), or perfusion values between the mutant and IDH1(WT) tumors. The IDH1(R132) mutation results in 2-HG resonance at 2.25 ppm and a reduction of glutamate levels as determined by MRS. Our results establish a model system where 2-HG can be monitored noninvasively, which should be helpful in validating 2-HG levels as a prognostic and/or predictive biomarker in glioma. PMID- 23090984 TI - The molecular biology of WHO grade I astrocytomas. AB - World Health Organization (WHO) grade I astrocytomas include pilocytic astrocytoma (PA) and subependymal giant cell astrocytoma (SEGA). As technologies in pharmacologic neo-adjuvant therapy continue to progress and as molecular characteristics are progressively recognized as potential markers of both clinically significant tumor subtypes and response to therapy, interest in the biology of these tumors has surged. An updated review of the current knowledge of the molecular biology of these tumors is needed. We conducted a Medline search to identify published literature discussing the molecular biology of grade I astrocytomas. We then summarized this literature and discuss it in a logical framework through which the complex biology of these tumors can be clearly understood. A comprehensive review of the molecular biology of WHO grade I astrocytomas is presented. The past several years have seen rapid progress in the level of understanding of PA in particular, but the molecular literature regarding both PA and SEGA remains nebulous, ambiguous, and occasionally contradictory. In this review we provide a comprehensive discussion of the current understanding of the chromosomal, genomic, and epigenomic features of both PA and SEGA and provide a logical framework in which these data can be more readily understood. PMID- 23090986 TI - Prediction of oligodendroglial histology and LOH 1p/19q using dynamic [(18)F]FET PET imaging in intracranial WHO grade II and III gliomas. AB - Oligodendroglial components (OC) and loss of heterozygosity on chromosomes 1p and 19q (LOH 1p/19q) are associated with better outcome in patients with glioma. We aimed to assess the fitness of [(18)F]fluoroethyltyrosine positron-emission tomography (FET-PET) for noninvasively identifying these important prognostic/predictive factors. One hundred forty-four patients with MRI-suspected WHO grade II and III glioma underwent FET-PET scans prior to histological diagnosis. FET-PET analyses included maximal tumoral uptake (SUV(max)/BG), biological tumor volume (BTV), mean tumoral uptake (SUV(mean)/BG), total tumoral uptake (SUV(total)/BG), and kinetic analysis. Suspicion of OC was based on static and dynamic FET-uptake parameters. PET results were correlated with histology and 1p/19q status. OC tumors exhibited significantly higher uptake values, compared with astrocytomas (AC) (SUV(max)/BG 3.1 vs 2.3, BTV 15.5 mL vs 7.2 mL, SUV(total)/BG 38.5 vs 17.4, P < .01 each; SUV(mean)/BG 2.2 vs 2.1, P < .05). These differences were more pronounced in WHO grade II gliomas. Comparable results were found with respect to 1p/19q status. Kinetic analysis misclassified 18 of 34 low-grade OC tumors as high-grade glioma but misclassified only 5 of 45 of the low-grade ACs. FET-based suspicion of OC resulted in concordance rates of both 76% for the prediction of OC and LOH 1p/19q. FET-uptake was significantly higher in gliomas with OC, compared with AC, and likewise in 1p/19q codeleted, compared with noncodeleted tumors. However, FET-PET analysis did not reliably predict the presence of OC/LOH 1p/19q in the individual patient, mostly because of an overlap in PET characteristics of OC tumors and high-grade AC. Histological examination is still required for an accurate diagnosis. PMID- 23090987 TI - EORTC 26083 phase I/II trial of dasatinib in combination with CCNU in patients with recurrent glioblastoma. AB - The treatment of patients with recurrent glioblastoma remains a major oncologic problem, with median survival after progression of 7-9 months. To determine the maximum tolerated dose and dose-limiting toxicity (DLT), the combination of dasatinib and cyclonexyl-chloroethyl-nitrosourea (CCNU) was investigated in this setting. The study was designed as multicenter, randomized phase II trial, preceded by a lead-in safety phase. The safety component reported here, which also investigated pharmacokinetics and preliminary clinical activity, required expansion and is therefore considered a phase I part to establish a recommended dosing regimen of the combination of CCNU (90-110 mg/m(2)) and dasatinib (100-200 mg daily). Overall, 28 patients were screened, and 26 patients were enrolled. Five dose levels were explored. DLTs, mainly myelosuppression, occurred in 10 patients. Grade 3 or 4 neutropenia was recorded in 7 patients (26.9%) and thrombocytopenia in 11 patients (42.3%). No significant effect of CCNU coadministration on dasatinib pharmacokinetics was found. Median progression-free survival (PFS) was 1.35 months (95% confidence interval: 1.2-1.4) and 6-month PFS was 7.7%. In this phase I study of recurrent glioblastoma patients, the combination of CCNU and dasatinib showed significant hematological toxicities and led to suboptimal exposure to both agents. PMID- 23090988 TI - Simplified mechanism for new particle formation from methanesulfonic acid, amines, and water via experiments and ab initio calculations. AB - Airborne particles affect human health and significantly influence visibility and climate. A major fraction of these particles result from the reactions of gaseous precursors to generate low-volatility products such as sulfuric acid and high molecular weight organics that nucleate to form new particles. Ammonia and, more recently, amines, both of which are ubiquitous in the environment, have also been recognized as important contributors. However, accurately predicting new particle formation in both laboratory systems and in air has been problematic. During the oxidation of organosulfur compounds, gas-phase methanesulfonic acid is formed simultaneously with sulfuric acid, and both are found in particles in coastal regions as well as inland. We show here that: (i) Amines form particles on reaction with methanesulfonic acid, (ii) water vapor is required, and (iii) particle formation can be quantitatively reproduced by a semiempirical kinetics model supported by insights from quantum chemical calculations of likely intermediate clusters. Such an approach may be more broadly applicable in models of outdoor, indoor, and industrial settings where particles are formed, and where accurate modeling is essential for predicting their impact on health, visibility, and climate. PMID- 23090989 TI - Sulfur record of rising and falling marine oxygen and sulfate levels during the Lomagundi event. AB - Carbonates from approximately 2.3-2.1 billion years ago show markedly positive delta(13)C values commonly reaching and sometimes exceeding +100/00. Traditional interpretation of these positive delta(13)C values favors greatly enhanced organic carbon burial on a global scale, although other researchers have invoked widespread methanogenesis within the sediments. To resolve between these competing models and, more generally, among the mechanisms behind Earth's most dramatic carbon isotope event, we obtained coupled stable isotope data for carbonate carbon and carbonate-associated sulfate (CAS). CAS from the Lomagundi interval shows a narrow range of delta(34)S values and concentrations much like those of Phanerozoic and modern marine carbonate rocks. The delta(34)S values are a close match to those of coeval sulfate evaporites and likely reflect seawater composition. These observations are inconsistent with the idea of diagenetic carbonate formation in the methanic zone. Toward the end of the carbon isotope excursion there is an increase in the delta(34)S values of CAS. We propose that these trends in C and S isotope values track the isotopic evolution of seawater sulfate and reflect an increase in pyrite burial and a crash in the marine sulfate reservoir during ocean deoxygenation in the waning stages of the positive carbon isotope excursion. PMID- 23090990 TI - Modulation of voltage-gated K+ channels by the sodium channel beta1 subunit. AB - Voltage-gated sodium (Na(V)) and potassium (K(V)) channels are critical components of neuronal action potential generation and propagation. Here, we report that Na(V)beta1 encoded by SCN1b, an integral subunit of Na(V) channels, coassembles with and modulates the biophysical properties of K(V)1 and K(V)7 channels, but not K(V)3 channels, in an isoform-specific manner. Distinct domains of Na(V)beta1 are involved in modulation of the different K(V) channels. Studies with channel chimeras demonstrate that Na(V)beta1-mediated changes in activation kinetics and voltage dependence of activation require interaction of Na(V)beta1 with the channel's voltage-sensing domain, whereas changes in inactivation and deactivation require interaction with the channel's pore domain. A molecular model based on docking studies shows Na(V)beta1 lying in the crevice between the voltage-sensing and pore domains of K(V) channels, making significant contacts with the S1 and S5 segments. Cross-modulation of Na(V) and K(V) channels by Na(V)beta1 may promote diversity and flexibility in the overall control of cellular excitability and signaling. PMID- 23090991 TI - Metabolic constraint imposes tradeoff between body size and number of brain neurons in human evolution. AB - Despite a general trend for larger mammals to have larger brains, humans are the primates with the largest brain and number of neurons, but not the largest body mass. Why are great apes, the largest primates, not also those endowed with the largest brains? Recently, we showed that the energetic cost of the brain is a linear function of its numbers of neurons. Here we show that metabolic limitations that result from the number of hours available for feeding and the low caloric yield of raw foods impose a tradeoff between body size and number of brain neurons, which explains the small brain size of great apes compared with their large body size. This limitation was probably overcome in Homo erectus with the shift to a cooked diet. Absent the requirement to spend most available hours of the day feeding, the combination of newly freed time and a large number of brain neurons affordable on a cooked diet may thus have been a major positive driving force to the rapid increased in brain size in human evolution. PMID- 23090992 TI - Climate variability and conflict risk in East Africa, 1990-2009. AB - Recent studies concerning the possible relationship between climate trends and the risks of violent conflict have yielded contradictory results, partly because of choices of conflict measures and modeling design. In this study, we examine climate-conflict relationships using a geographically disaggregated approach. We consider the effects of climate change to be both local and national in character, and we use a conflict database that contains 16,359 individual geolocated violent events for East Africa from 1990 to 2009. Unlike previous studies that relied exclusively on political and economic controls, we analyze the many geographical factors that have been shown to be important in understanding the distribution and causes of violence while also considering yearly and country fixed effects. For our main climate indicators at gridded 1 degrees resolution (~100 km), wetter deviations from the precipitation norms decrease the risk of violence, whereas drier and normal periods show no effects. The relationship between temperature and conflict shows that much warmer than normal temperatures raise the risk of violence, whereas average and cooler temperatures have no effect. These precipitation and temperature effects are statistically significant but have modest influence in terms of predictive power in a model with political, economic, and physical geographic predictors. Large variations in the climate-conflict relationships are evident between the nine countries of the study region and across time periods. PMID- 23090994 TI - Break-up dynamics of fluctuating liquid threads. AB - The thinning dynamics of a liquid neck before break-up, as may happen when a drop detaches from a faucet or a capillary, follows different rules and dynamic scaling laws depending on the importance of inertia, viscous stresses, or capillary forces. If now the thinning neck reaches dimensions comparable to the thermally excited interfacial fluctuations, as for nanojet break-up or the fragmentation of thermally annealed nanowires, these fluctuations should play a dominant role according to recent theory and observations. Using near-critical interfaces, we here fully characterize the universal dynamics of this thermal fluctuation-dominated regime and demonstrate that the cross-over from the classical two-fluid pinch-off scenario of a liquid thread to the fluctuation dominated regime occurs at a well-defined neck radius proportional to the thermal length scale. Investigating satellite drop formation, we also show that at the level of the cross-over between these two regimes it is more probable to produce monodisperse droplets because fluctuation-dominated pinch-off may allow the unique situation where satellite drop formation can be inhibited. Nonetheless, the interplay between the evolution of the neck profiles from the classical to the fluctuation-dominated regime and the satellites' production remains to be clarified. PMID- 23090993 TI - Structural and functional characterization of the nitrite channel NirC from Salmonella typhimurium. AB - Nitrite (NO(2)(-)) is a central intermediate in the nitrogen metabolism of microorganisms and plants, and is used as a cytotoxin by macrophages as part of the innate immune response. The bacterial membrane protein NirC acts as a specific channel to facilitate the transport of nitrite anions across lipid bilayers for cytoplasmic detoxification. Despite NirC's importance in nitrogen metabolism and in the pathogenicity of enteric bacteria, available biochemical data are scarce. Here we present a functional and structural characterization of NirC from Salmonella typhimurium by lipid bilayer electrophysiology and X-ray crystallography. NirC is a pentameric member of the formate/nitrite transporter family of membrane proteins that operates as a channel with high conductance. Single-channel measurements reveal fast and slow gating events but, in contrast to the related FocA formate channel, no pH-dependent gating. A 2.4A crystal structure of NirC at pH 5 shows similarity to FocA and aquaporins, but lacks the structural asymmetry observed in the formate channel at similarly low pH. Resolved water molecules in the protomers suggest a transport mechanism that also permits a facultative NO(2)(-)/H(+) symport. PMID- 23090995 TI - Tissue-specific opposing functions of the inflammasome adaptor ASC in the regulation of epithelial skin carcinogenesis. AB - A chronic inflammatory microenvironment favors tumor progression through molecular mechanisms that are still incompletely defined. In inflammation-induced skin cancers, IL-1 receptor- or caspase-1-deficient mice, or mice specifically deficient for the inflammasome adaptor protein ASC (apoptosis-associated speck like protein containing a CARD) in myeloid cells, had reduced tumor incidence, pointing to a role for IL-1 signaling and inflammasome activation in tumor development. However, mice fully deficient for ASC were not protected, and mice specifically deficient for ASC in keratinocytes developed more tumors than controls, suggesting that, in contrast to its proinflammatory role in myeloid cells, ASC acts as a tumor-suppressor in keratinocytes. Accordingly, ASC protein expression was lost in human cutaneous squamous cell carcinoma, but not in psoriatic skin lesions. Stimulation of primary mouse keratinocytes or the human keratinocyte cell line HaCaT with UVB induced an ASC-dependent phosphorylation of p53 and expression of p53 target genes. In HaCaT cells, ASC interacted with p53 at the endogenous level upon UVB irradiation. Thus, ASC in different tissues may influence tumor growth in opposite directions: it has a proinflammatory role in infiltrating cells that favors tumor development, but it also limits keratinocyte proliferation in response to noxious stimuli, possibly through p53 activation, which helps suppressing tumors. PMID- 23090996 TI - Evolutionary analyses of non-genealogical bonds produced by introgressive descent. AB - All evolutionary biologists are familiar with evolutionary units that evolve by vertical descent in a tree-like fashion in single lineages. However, many other kinds of processes contribute to evolutionary diversity. In vertical descent, the genetic material of a particular evolutionary unit is propagated by replication inside its own lineage. In what we call introgressive descent, the genetic material of a particular evolutionary unit propagates into different host structures and is replicated within these host structures. Thus, introgressive descent generates a variety of evolutionary units and leaves recognizable patterns in resemblance networks. We characterize six kinds of evolutionary units, of which five involve mosaic lineages generated by introgressive descent. To facilitate detection of these units in resemblance networks, we introduce terminology based on two notions, P3s (subgraphs of three nodes: A, B, and C) and mosaic P3s, and suggest an apparatus for systematic detection of introgressive descent. Mosaic P3s correspond to a distinct type of evolutionary bond that is orthogonal to the bonds of kinship and genealogy usually examined by evolutionary biologists. We argue that recognition of these evolutionary bonds stimulates radical rethinking of key questions in evolutionary biology (e.g., the relations among evolutionary players in very early phases of evolutionary history, the origin and emergence of novelties, and the production of new lineages). This line of research will expand the study of biological complexity beyond the usual genealogical bonds, revealing additional sources of biodiversity. It provides an important step to a more realistic pluralist treatment of evolutionary complexity. PMID- 23090997 TI - Meiosis arrest female 1 (MARF1) has nuage-like function in mammalian oocytes. AB - Orderly regulation of meiosis and protection of germline genomic integrity from transposable elements are essential for male and female gamete development. In the male germline, these processes are ensured by proteins associated with cytoplasmic nuage, but morphologically similar germ granules or nuage have not been identified in mammalian female germ cells. Indeed, many mutations affecting nuage-associated proteins such as PIWI and tudor domain containing proteins 5 and 7 (TDRD5/7) can result in failure of meiosis, up-regulation of retrotransposons, and infertility only in males and not in females. We recently identified MARF1 (meiosis arrest female 1) as a protein essential for controlling meiosis and retrotransposon surveillance in oocytes; and in contrast to PIWI-pathway mutations, Marf1 mutant females are infertile, whereas mutant males are fertile. Here we put forward the hypothesis that MARF1 in mouse oocytes is a functional counterpart of the nuage-associated components of spermatocytes. We describe the developmental pattern of Marf1 expression and its roles in retrotransposon silencing and protection from DNA double-strand breaks. Analysis of MARF1 protein domains compared with PIWI and TDRD5/7 revealed that these functional similarities are reflected in remarkable structural analogies. Thus, functions that in the male germline require protein interactions and cooperative scaffolding are combined in MARF1, allowing a single molecule to execute crucial activities of meiotic regulation and protection of germline genomic integrity. PMID- 23090998 TI - MDA5 assembles into a polar helical filament on dsRNA. AB - Melanoma differentiation-associated protein 5 (MDA5) detects viral dsRNA in the cytoplasm. On binding of RNA, MDA5 forms polymers, which trigger assembly of the signaling adaptor mitochondrial antiviral-signaling protein (MAVS) into its active fibril form. The molecular mechanism of MDA5 signaling is not well understood, however. Here we show that MDA5 forms helical filaments on dsRNA and report the 3D structure of the filaments using electron microscopy (EM) and image reconstruction. MDA5 assembles into a polar, single-start helix around the RNA. Fitting of an MDA5 homology model into the structure suggests a key role for the MDA5 C-terminal domain in cooperative filament assembly. Our study supports a signal transduction mechanism in which the helical array of MDA5 within filaments nucleates the assembly of MAVS fibrils. We conclude that MDA5 is a polymerization dependent signaling platform that uses the amyloid-like self-propagating properties of MAVS to amplify signaling. PMID- 23090999 TI - Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. AB - Activating transcription factor 5 (ATF5) is a member of the ATF/cAMP response element-binding family of transcription factors, which compose a large group of basic region leucine zipper proteins whose members mediate diverse transcriptional regulatory functions. ATF5 has a well-established prosurvival activity and has been found to be overexpressed in several human cancers, in particular glioblastoma. However, the role(s) of ATF5 in development and normal physiology are unknown. Here we address this issue by deriving and characterizing homozygous Atf5 knockout mice. We find that Atf5(-/-) pups die neonatally, which, as explained below, is consistent with an olfactory defect resulting in a competitive suckling deficit. We show that Atf5 is highly expressed in olfactory sensory neurons (OSNs) in the main olfactory epithelium starting from embryonic stage 11.5 through adulthood. Immunostaining experiments with OSN-specific markers reveal that ATF5 is expressed in some immature OSNs and in all mature OSNs. Expression profiling and immunostaining experiments indicate that loss of Atf5 leads to a massive reduction in mature OSNs resulting from a differentiation defect and the induction of apoptosis. Ectopic expression of Atf5 in neural progenitor cells induces expression of multiple OSN-specific genes. Collectively, our results suggest a model in which Atf5 is first expressed in immature OSNs and the resultant ATF5 functions to promote differentiation into mature OSNs. Thus, ATF5 is required for terminal differentiation and survival of OSNs. PMID- 23091000 TI - Structural insights into the mechanisms of Mg2+ uptake, transport, and gating by CorA. AB - Despite the importance of Mg(2+) for numerous cellular activities, the mechanisms underlying its import and homeostasis are poorly understood. The CorA family is ubiquitous and is primarily responsible for Mg(2+) transport. However, the key questions-such as, the ion selectivity, the transport pathway, and the gating mechanism-have remained unanswered for this protein family. We present a 3.2 A resolution structure of the archaeal CorA from Methanocaldococcus jannaschii, which is a unique complete structure of a CorA protein and reveals the organization of the selectivity filter, which is composed of the signature motif of this family. The structure reveals that polar residues facing the channel coordinate a partially hydrated Mg(2+) during the transport. Based on these findings, we propose a unique gating mechanism involving a helical turn upon the binding of Mg(2+) to the regulatory intracellular binding sites, and thus converting a polar ion passage into a narrow hydrophobic pore. Because the amino acids involved in the uptake, transport, and gating are all conserved within the entire CorA family, we believe this mechanism is general for the whole family including the eukaryotic homologs. PMID- 23091001 TI - MED12 mutations link intellectual disability syndromes with dysregulated GLI3 dependent Sonic Hedgehog signaling. AB - Recurrent missense mutations in the RNA polymerase II Mediator subunit MED12 are associated with X-linked intellectual disability (XLID) and multiple congenital anomalies, including craniofacial, musculoskeletal, and behavioral defects in humans with FG (or Opitz-Kaveggia) and Lujan syndromes. However, the molecular mechanism(s) underlying these phenotypes is poorly understood. Here we report that MED12 mutations R961W and N1007S causing FG and Lujan syndromes, respectively, disrupt a Mediator-imposed constraint on GLI3-dependent Sonic Hedgehog (SHH) signaling. We show that the FG/R961W and Lujan/N1007S mutations disrupt the gene-specific association of MED12 with a second Mediator subunit, CDK8, identified herein to be a suppressor of GLI3 transactivation activity. In FG/R961W and Lujan/N1007S patient-derived cells, we document enhanced SHH pathway activation and GLI3-target gene induction coincident with impaired recruitment of CDK8 onto promoters of GLI3-target genes, but not non-GLI3-target genes. Together, these findings suggest that dysregulated GLI3-dependent SHH signaling contributes to phenotypes of individuals with FG and Lujan syndromes and further reveal a basis for the gene-specific manifestation of pathogenic mutations in a global transcriptional coregulator. PMID- 23091002 TI - Structural insight into HIV-1 capsid recognition by rhesus TRIM5alpha. AB - Tripartite motif protein isoform 5 alpha (TRIM5alpha) is a potent antiviral protein that restricts infection by HIV-1 and other retroviruses. TRIM5alpha recognizes the lattice of the retrovirus capsid through its B30.2 (PRY/SPRY) domain in a species-specific manner. Upon binding, TRIM5alpha induces premature disassembly of the viral capsid and activates the downstream innate immune response. We have determined the crystal structure of the rhesus TRIM5alpha PRY/SPRY domain that reveals essential features for capsid binding. Combined cryo electron microscopy and biochemical data show that the monomeric rhesus TRIM5alpha PRY/SPRY, but not the human TRIM5alpha PRY/SPRY, can bind to HIV-1 capsid protein assemblies without causing disruption of the capsid. This suggests that the PRY/SPRY domain alone constitutes an important pattern-sensing component of TRIM5alpha that is capable of interacting with viral capsids of different curvatures. Our results provide molecular insights into the mechanisms of TRIM5alpha-mediated retroviral restriction. PMID- 23091003 TI - High-resolution, low-dose phase contrast X-ray tomography for 3D diagnosis of human breast cancers. AB - Mammography is the primary imaging tool for screening and diagnosis of human breast cancers, but ~10-20% of palpable tumors are not detectable on mammograms and only about 40% of biopsied lesions are malignant. Here we report a high resolution, low-dose phase contrast X-ray tomographic method for 3D diagnosis of human breast cancers. By combining phase contrast X-ray imaging with an image reconstruction method known as equally sloped tomography, we imaged a human breast in three dimensions and identified a malignant cancer with a pixel size of 92 MUm and a radiation dose less than that of dual-view mammography. According to a blind evaluation by five independent radiologists, our method can reduce the radiation dose and acquisition time by ~74% relative to conventional phase contrast X-ray tomography, while maintaining high image resolution and image contrast. These results demonstrate that high-resolution 3D diagnostic imaging of human breast cancers can, in principle, be performed at clinical compatible doses. PMID- 23091005 TI - AAA ATPase p97/VCP is essential for TRIM21-mediated virus neutralization. AB - Tripartite motif-containing 21 (TRIM21) is a cytosolic IgG receptor that mediates intracellular virus neutralization by antibody. TRIM21 targets virions for destruction in the proteasome, but it is unclear how a substrate as large as a viral capsid is degraded. Here, we identify the ATPase p97/valosin-containing protein (VCP), an enzyme with segregase and unfoldase activity, as a key player in this process. Depletion or catalytic inhibition of VCP prevents capsid degradation and reduces neutralization. VCP is required concurrently with the proteasome, as addition of inhibitor after proteasomal degradation has no effect. Moreover, our results suggest that it is the challenging nature of virus as a substrate that necessitates involvement of VCP, since intracellularly expressed IgG Fc is degraded in a VCP-independent manner. These results implicate VCP as an important host factor in antiviral immunity. PMID- 23091004 TI - Cryo-EM structure of the mammalian eukaryotic release factor eRF1-eRF3-associated termination complex. AB - Eukaryotic translation termination results from the complex functional interplay between two eukaryotic release factors, eRF1 and eRF3, and the ribosome, in which GTP hydrolysis by eRF3 couples codon recognition with peptidyl-tRNA hydrolysis by eRF1. Here, using cryo-electron microscopy (cryo-EM) and flexible fitting, we determined the structure of eRF1-eRF3-guanosine 5'-[beta,gamma-imido]triphosphate (GMPPNP)-bound ribosomal pretermination complex (pre-TC), which corresponds to the initial, pre-GTP hydrolysis stage of factor attachment. Our results show that eukaryotic translation termination involves a network of interactions between the two release factors and the ribosome. Our structure provides mechanistic insight into the coordination between GTP hydrolysis by eRF3 and subsequent peptide release by eRF1. PMID- 23091006 TI - One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor. AB - Natural products represent valuable lead structures for drug discovery. However, for most bioactive compounds no cellular target is yet identified and many substances predicted from genome analysis are inaccessible due to their life stage-dependent biosynthesis, which is not reflected in common isolation procedures. In response to these issues, an NMR-based and target-directed protease assay for inhibitor detection of the proteasome was developed. The methodology is suitable for one-shot identification of inhibitors in conglomerates and crude culture broths. The technique was applied for analysis of the different life stages of the bacterium Photorhabdus luminescens, which resulted in the isolation and characterization of cepafungin I (CepI), the strongest proteasome inhibitor described to date. Its biosynthesis is strictly regulated and solely induced by the specific environmental conditions determined by our methodology. The transferability of the developed technique to other drug targets may disclose an abundance of novel compounds applicable for drug development. PMID- 23091008 TI - Action as an innate bias for visual learning. PMID- 23091007 TI - Structural analysis of human Cdc20 supports multisite degron recognition by APC/C. AB - The anaphase-promoting complex/cyclosome (APC/C) promotes anaphase onset and mitotic exit through ubiquitinating securin and cyclin B1. The mitotic APC/C activator, the cell division cycle 20 (Cdc20) protein, directly interacts with APC/C degrons--the destruction (D) and KEN boxes. APC/C(Cdc20) is the target of the spindle checkpoint. Checkpoint inhibition of APC/C(Cdc20) requires the binding of a BubR1 KEN box to Cdc20. How APC/C recognizes substrates is not understood. We report the crystal structures of human Cdc20 alone or bound to a BubR1 KEN box. Cdc20 has a disordered N-terminal region and a C-terminal WD40 beta propeller with a preformed KEN-box-binding site at its top face. We identify a second conserved surface at the side of the Cdc20 beta propeller as a D-box binding site. The D box of securin, but not its KEN box, is critical for securin ubiquitination by APC/C(Cdc20). Although both motifs contribute to securin ubiquitination by APC/C(Cdh1), securin mutants lacking either motif are efficiently ubiquitinated. Furthermore, D-box peptides diminish the ubiquitination of KEN-box substrates by APC/C(Cdh1), suggesting possible competition between the two motifs. Our results indicate the lack of strong positive cooperativity between the two degrons of securin. We propose that low cooperativity, multisite target recognition enables APC/C to robustly ubiquitinate diverse substrates and helps to drive cell cycle oscillations. PMID- 23091009 TI - Genotype of a historic strain of Mycobacterium tuberculosis. AB - The use of ancient DNA in paleopathological studies of tuberculosis has largely been restricted to confirmation of disease identifications made by skeletal analysis; few attempts at obtaining genotype data from archaeological samples have been made because of the need to perform different PCRs for each genetic locus being studied in an ancient DNA extract. We used a next generation sequencing approach involving hybridization capture directed at specific polymorphic regions of the Mycobacterium tuberculosis genome to identify a detailed genotype for a historic strain of M. tuberculosis from an individual buried in the 19th century St. George's Crypt, Leeds, West Yorkshire, England. We obtained 664,500 sequencing by oligonucleotide ligation and detection (SOLiD) reads that mapped to the targeted regions of the M. tuberculosis genome; the coverage included 218 of 247 SNPs, 10 of 11 insertion/deletion regions, and the repeat elements IS1081 and IS6110. The accuracy of the SOLiD data was checked by conventional PCRs directed at 11 SNPs and two insertion/deletions. The data placed the historic strain of M. tuberculosis in a group that is uncommon today, but it is known to have been present in North America in the early 20th century. Our results show the use of hybridization capture followed by next generation sequencing as a means of obtaining detailed genotypes of ancient varieties of M. tuberculosis, potentially enabling meaningful comparisons between strains from different geographic locations and different periods in the past. PMID- 23091011 TI - Fiber orientation-dependent white matter contrast in gradient echo MRI. AB - Recent studies have shown that there is a direct link between the orientation of the nerve fibers in white matter (WM) and the contrast observed in magnitude and phase images acquired using gradient echo MRI. Understanding the origin of this link is of great interest because it could offer access to a new diagnostic tool for investigating tissue microstructure. Since it has been suggested that myelin is the dominant source of this contrast, creating an accurate model for characterizing the effect of the myelin sheath on the evolution of the NMR signal is an essential step toward fully understanding WM contrast. In this study, we show by comparison of the results of simulations and experiments carried out on human subjects at 7T, that the magnitude and phase of signals acquired from WM in vivo can be accurately characterized by (i) modeling the myelin sheath as a hollow cylinder composed of material having an anisotropic magnetic susceptibility that is described by a tensor with a radially oriented principal axis, and (ii) adopting a two-pool model in which the water in the sheath has a reduced T(2) relaxation time and spin density relative to its surroundings, and also undergoes exchange. The accuracy and intrinsic simplicity of the hollow cylinder model provides a versatile framework for future exploitation of the effect of WM microstructure on gradient echo contrast in clinical MRI. PMID- 23091010 TI - Adaptation to a new environment allows cooperators to purge cheaters stochastically. AB - Cooperation via production of common goods is found in diverse life forms ranging from viruses to social animals. However, natural selection predicts a "tragedy of the commons": Cheaters, benefiting from without producing costly common goods, are more fit than cooperators and should destroy cooperation. In an attempt to discover novel mechanisms of cheater control, we eliminated known ones using a yeast cooperator-cheater system engineered to supply or exploit essential nutrients. Surprisingly, although less fit than cheaters, cooperators quickly dominated a fraction of cocultures. Cooperators isolated from these cocultures were superior to the cheater isolates they had been cocultured with, even though these cheaters were superior to ancestral cooperators. Resequencing and phenotypic analyses revealed that evolved cooperators and cheaters all harbored mutations adaptive to the nutrient-limited cooperative environment, allowing growth at a much lower concentration of nutrient than their ancestors. Even after the initial round of adaptation, evolved cooperators still stochastically dominated cheaters derived from them. We propose the "adaptive race" model: If during adaptation to an environment, the fitness gain of cooperators exceeds that of cheaters by at least the fitness cost of cooperation, the tragedy of the commons can be averted. Although cooperators and cheaters sample from the same pool of adaptive mutations, this symmetry is soon broken: The best cooperators purge cheaters and continue to grow, whereas the best cheaters cause rapid self extinction. We speculate that adaptation to changing environments may contribute to the persistence of cooperative systems before the appearance of more sophisticated mechanisms of cheater control. PMID- 23091012 TI - Hepatitis B virus X protein targets Bcl-2 proteins to increase intracellular calcium, required for virus replication and cell death induction. AB - Infection with the hepatitis B virus (HBV) promotes the development of hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) and is a leading cause of morbidity and mortality worldwide. HBV X protein (HBx) is an important effector for HBV pathogenesis, but its cellular targets and acting mechanisms remain elusive. We show here that HBx interacts with the anti-apoptotic proteins Bcl-2 and Bcl-xL through a Bcl-2 homology 3 (BH3)-like motif in mammalian cells. Importantly, mutations in the BH3-like motif that prevent HBx binding to Bcl-2 and Bcl-xL abrogate cytosolic calcium elevation and cell death induced by HBx expression in hepatocytes and severely impair HBV viral replication, which can be substantially rescued by restoring cytosolic calcium. These results suggest that HBx binding to Bcl-2 family members and subsequent elevation of cytosolic calcium are important for HBV viral replication. Consistently, RNAi knockdown of Bcl-2 or Bcl-xL results in reduced calcium elevation by HBx and decreased viral replication in hepatocytes. Our results suggest that HBx targets Bcl-2 proteins through its BH3 like motif to promote cytosolic calcium elevation, cell death, and viral replication during HBV pathogenesis, which presents an excellent therapeutic intervention point in treating patients with chronic HBV. PMID- 23091013 TI - Sleep spindles are locally modulated by training on a brain-computer interface. AB - The learning of a motor task is known to be improved by sleep, and sleep spindles are thought to facilitate this learning by enabling synaptic plasticity. In this study subjects implanted with electrocorticography (ECoG) arrays for long-term epilepsy monitoring were trained to control a cursor on a computer screen by modulating either the high-gamma or mu/beta power at a single electrode located over the motor or premotor area. In all trained subjects, spindle density in posttraining sleep was increased with respect to pretraining sleep in a remarkably spatially specific manner. The pattern of increased spindle activity reflects the functionally specific regions that were involved in learning of a highly novel and salient task during wakefulness, supporting the idea that sleep spindles are involved in learning to use a motor-based brain-computer interface device. PMID- 23091015 TI - Euler and Navier-Stokes equations on the hyperbolic plane. AB - We show that nonuniqueness of the Leray-Hopf solutions of the Navier-Stokes equation on the hyperbolic plane (2) observed by Chan and Czubak is a consequence of the Hodge decomposition. We show that this phenomenon does not occur on (n) whenever n >= 3. We also describe the corresponding general Hamiltonian framework of hydrodynamics on complete Riemannian manifolds, which includes the hyperbolic setting. PMID- 23091014 TI - Isoform-specific antagonists of exchange proteins directly activated by cAMP. AB - The major physiological effects of cAMP in mammalian cells are transduced by two ubiquitously expressed intracellular cAMP receptors, protein kinase A (PKA) and exchange protein directly activated by cAMP (EPAC), as well as cyclic nucleotide gated ion channels in certain tissues. Although a large number of PKA inhibitors are available, there are no reported EPAC-specific antagonists, despite extensive research efforts. Here we report the identification and characterization of noncyclic nucleotide EPAC antagonists that are exclusively specific for the EPAC2 isoform. These EAPC2-specific antagonists, designated as ESI-05 and ESI-07, inhibit Rap1 activation mediated by EAPC2, but not EPAC1, with high potency in vitro. Moreover, ESI-05 and ESI-07 are capable of suppressing the cAMP-mediated activation of EPAC2, but not EPAC1 and PKA, as monitored in living cells through the use of EPAC- and PKA-based FRET reporters, or by the use of Rap1-GTP pull down assays. Deuterium exchange mass spectroscopy analysis further reveals that EPAC2-specific inhibitors exert their isoform selectivity through a unique mechanism by binding to a previously undescribed allosteric site: the interface of the two cAMP binding domains, which is not present in the EPAC1 isoform. Isoform-specific EPAC pharmacological probes are highly desired and will be valuable tools for dissecting the biological functions of EPAC proteins and their roles in various disease states. PMID- 23091016 TI - Benzodiazepine treatment induces subtype-specific changes in GABA(A) receptor trafficking and decreases synaptic inhibition. AB - Benzodiazepines potentiate gamma-aminobutyric acid type A receptor (GABA(A)R) activity and are widely prescribed to treat anxiety, insomnia, and seizure disorders. Unfortunately, clinical use of benzodiazepines (BZs) is severely limited by tolerance. The mechanisms leading to BZ tolerance are unknown. BZs bind at the interface between an alpha and gamma subunit of GABA(A)Rs, preferentially enhancing synaptic receptors largely composed of alpha(1-3, 5), beta3, and gamma2 subunits. Using confocal imaging and patch-clamp approaches, we show that treatment with the BZ flurazepam decreases GABA(A)R surface levels and the efficacy of neuronal inhibition in hippocampal neurons. A dramatic decrease in surface and total levels of alpha2 subunit-containing GABA(A)Rs occurred within 24 h of flurazepam treatment, whereas GABA(A)Rs incorporating alpha1 subunits showed little alteration. The GABA(A)R surface depletion could be reversed by treatment with the BZ antagonist Ro 15-1788. Coincident with decreased GABA(A)R surface levels, flurazepam treatment reduced miniature inhibitory postsynaptic current amplitude, which returned to control levels with acute Ro 15-1788 treatment. GABA(A)R endocytosis and insertion rates were unchanged by flurazepam treatment. Treatment with leupeptin restored flurazepam lowered receptor surface levels, strongly suggesting that flurazepam increases lysosomal degradation of GABA(A)Rs. Together, these data suggest that flurazepam exposure enhances degradation of alpha2 subunit-containing GABA(A)Rs after their removal from the plasma membrane, leading to a reduction in inhibitory synapse size and number along with a decrease in the efficacy of synaptic inhibition. These reported subtype-specific changes in GABA(A)R trafficking provide significant mechanistic insight into the initial neuroadaptive responses occurring with BZ treatment. PMID- 23091018 TI - Linking water quality and well-being for improved assessment and valuation of ecosystem services. AB - Despite broad recognition of the value of the goods and services provided by nature, existing tools for assessing and valuing ecosystem services often fall short of the needs and expectations of decision makers. Here we address one of the most important missing components in the current ecosystem services toolbox: a comprehensive and generalizable framework for describing and valuing water quality-related services. Water quality is often misrepresented as a final ecosystem service. We argue that it is actually an important contributor to many different services, from recreation to human health. We present a valuation approach for water quality-related services that is sensitive to different actions that affect water quality, identifies aquatic endpoints where the consequences of changing water quality on human well-being are realized, and recognizes the unique groups of beneficiaries affected by those changes. We describe the multiple biophysical and economic pathways that link actions to changes in water quality-related ecosystem goods and services and provide guidance to researchers interested in valuing these changes. Finally, we present a valuation template that integrates biophysical and economic models, links actions to changes in service provision and value estimates, and considers multiple sources of water quality-related ecosystem service values without double counting. PMID- 23091017 TI - Persistent loss of IL-27 responsiveness in CD8+ memory T cells abrogates IL-10 expression in a recall response. AB - CD8+ T cells are central to the eradication of intracellular pathogens, but they can also act to limit inflammation and immunopathology. During primary respiratory viral infection CD8+ effector T cells release the immunosuppressive cytokine IL-10, which is essential for host survival. Here we report that CD8+ T cell-derived IL-10 is absent in a recall response. We show in mice that the lack of IL-10 is due to a persistent loss of IL-27 responsiveness in CD8+ memory T cells, caused by down-regulation of the common cytokine receptor, glycoprotein 130. CD8+ memory T cells secreted less IL-10 when activated in the presence of IL 27 than did naive controls, and retroviral expression of glycoprotein 130 restored IL-10 and reduced IFN-gamma production upon restimulation. We demonstrate that human CD8+ memory cells are also characterized by impaired IL-27 responsiveness. Our data suggest that CD8+ T-cell activation involves a persistent loss of specific cytokine receptors that determines the functional potential of these cells during rechallenge infection. PMID- 23091019 TI - Capturing fleeting intermediates in a catalytic C-H amination reaction cycle. AB - We have applied an ambient ionization technique, desorption electrospray ionization MS, to identify transient reactive species of an archetypal C-H amination reaction catalyzed by a dirhodium tetracarboxylate complex. Using this analytical method, we have detected previously proposed short-lived reaction intermediates, including two nitrenoid complexes that differ in oxidation state. Our findings suggest that an Rh-nitrene oxidant can react with hydrocarbon substrates through a hydrogen atom abstraction pathway and raise the intriguing possibility that two catalytic C-H amination pathways may be operative in a typical bulk solution reaction. As highlighted by these results, desorption electrospray ionization MS should have broad applicability for the mechanistic study of catalytic processes. PMID- 23091020 TI - Size and complexity in model financial systems. AB - The global financial crisis has precipitated an increasing appreciation of the need for a systemic perspective toward financial stability. For example: What role do large banks play in systemic risk? How should capital adequacy standards recognize this role? How is stability shaped by concentration and diversification in the financial system? We explore these questions using a deliberately simplified, dynamic model of a banking system that combines three different channels for direct transmission of contagion from one bank to another: liquidity hoarding, asset price contagion, and the propagation of defaults via counterparty credit risk. Importantly, we also introduce a mechanism for capturing how swings in "confidence" in the system may contribute to instability. Our results highlight that the importance of relatively large, well-connected banks in system stability scales more than proportionately with their size: the impact of their collapse arises not only from their connectivity, but also from their effect on confidence in the system. Imposing tougher capital requirements on larger banks than smaller ones can thus enhance the resilience of the system. Moreover, these effects are more pronounced in more concentrated systems, and continue to apply, even when allowing for potential diversification benefits that may be realized by larger banks. We discuss some tentative implications for policy, as well as conceptual analogies in ecosystem stability and in the control of infectious diseases. PMID- 23091021 TI - Complete mitochondrial DNA genome sequences from the first New Zealanders. AB - The dispersal of modern humans across the globe began ~65,000 y ago when people first left Africa and culminated with the settlement of East Polynesia, which occurred in the last 1,000 y. With the arrival of Polynesian canoes only 750 y ago, Aotearoa/New Zealand became the last major landmass to be permanently settled by humans. We present here complete mitochondrial genome sequences of the likely founding population of Aotearoa/New Zealand recovered from the archaeological site of Wairau Bar. These data represent complete mitochondrial genome sequences from ancient Polynesian voyagers and provide insights into the genetic diversity of human populations in the Pacific at the time of the settlement of East Polynesia. PMID- 23091022 TI - Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes. AB - Adult stem cells are believed to be maintained by a specialized microenvironment, the niche, which provides short-range signals that either instruct stem cells to self-renew or inhibit execution of preprogrammed differentiation pathways. In Drosophila testes, somatic cyst stem cells (CySCs) and the apical hub form the niche for neighboring germline stem cells (GSCs), with CySCs as the proposed source of instructive self-renewal signals [Leatherman JL, Dinardo S (2010) Nat Cell Biol 12(8):806-811]. In contrast to this model, we show that early germ cells with GSC characteristics can be maintained over time after ablation of CySCs and their cyst cell progeny. Without CySCs and cyst cells, early germ cells away from the hub failed to initiate differentiation. Our results suggest that CySCs do not have a necessary instructive role in specifying GSC self-renewal and that the differentiated progeny of CySCs provide an environment necessary to trigger GSC differentiation. This work highlights the complex interaction between different stem cell populations in the same niche and how the state of one stem cell population can influence the fate of the other. PMID- 23091023 TI - Nonsymbolic number and cumulative area representations contribute shared and unique variance to symbolic math competence. AB - Humans and nonhuman animals share the capacity to estimate, without counting, the number of objects in a set by relying on an approximate number system (ANS). Only humans, however, learn the concepts and operations of symbolic mathematics. Despite vast differences between these two systems of quantification, neural and behavioral findings suggest functional connections. Another line of research suggests that the ANS is part of a larger, more general system of magnitude representation. Reports of cognitive interactions and common neural coding for number and other magnitudes such as spatial extent led us to ask whether, and how, nonnumerical magnitude interfaces with mathematical competence. On two magnitude comparison tasks, college students estimated (without counting or explicit calculation) which of two arrays was greater in number or cumulative area. They also completed a battery of standardized math tests. Individual differences in both number and cumulative area precision (measured by accuracy on the magnitude comparison tasks) correlated with interindividual variability in math competence, particularly advanced arithmetic and geometry, even after accounting for general aspects of intelligence. Moreover, analyses revealed that whereas number precision contributed unique variance to advanced arithmetic, cumulative area precision contributed unique variance to geometry. Taken together, these results provide evidence for shared and unique contributions of nonsymbolic number and cumulative area representations to formally taught mathematics. More broadly, they suggest that uniquely human branches of mathematics interface with an evolutionarily primitive general magnitude system, which includes partially overlapping representations of numerical and nonnumerical magnitude. PMID- 23091024 TI - Functional eukaryotic nuclear localization signals are widespread in terminal proteins of bacteriophages. AB - A number of prokaryotic proteins have been shown to contain nuclear localization signals (NLSs), although its biological role remains sometimes unclear. Terminal proteins (TPs) of bacteriophages prime DNA replication and become covalently linked to the genome ends. We predicted NLSs within the TPs of bacteriophages from diverse families and hosts and, indeed, the TPs of Phi29, Nf, PRD1, Bam35, and Cp-1, out of seven TPs tested, were found to localize to the nucleus when expressed in mammalian cells. Detailed analysis of Phi29 TP led us to identify a bona fide NLS within residues 1-37. Importantly, gene delivery into the eukaryotic nucleus is enhanced by the presence of Phi29 TP attached to the 5' DNA ends. These findings show a common feature of TPs from diverse bacteriophages targeting the eukaryotic nucleus and suggest a possible common function by facilitating the horizontal transfer of genes between prokaryotes and eukaryotes. PMID- 23091025 TI - Cxcr4 regulation of interneuron migration is disrupted in 22q11.2 deletion syndrome. AB - Interneurons are thought to be a primary pathogenic target for several behavioral disorders that arise during development, including schizophrenia and autism. It is not known, however, whether genetic lesions associated with these diseases disrupt established molecular mechanisms of interneuron development. We found that diminished 22q11.2 gene dosage-the primary genetic lesion in 22q11.2 deletion syndrome (22q11.2 DS)-specifically compromises the distribution of early generated parvalbumin-expressing interneurons in the Large Deletion (LgDel) 22q11.2DS mouse model. This change reflects cell-autonomous disruption of interneuron migration caused by altered expression of the cytokine C-X-C chemokine receptor type 4 (Cxcr4), an established regulator of this process. Cxcr4 is specifically reduced in LgDel migrating interneurons, and genetic analysis confirms that diminished Cxcr4 alters interneuron migration in LgDel mice. Thus, diminished 22q11.2 gene dosage disrupts cortical circuit development by modifying a critical molecular signaling pathway via Cxcr4 that regulates cortical interneuron migration and placement. PMID- 23091026 TI - Regulation of actin-myosin interaction by conserved periodic sites of tropomyosin. AB - Cooperative activation of actin-myosin interaction by tropomyosin (Tm) is central to regulation of contraction in muscle cells and cellular and intracellular movements in nonmuscle cells. The steric blocking model of muscle regulation proposed 40 y ago has been substantiated at both the kinetic and structural levels. Even with atomic resolution structures of the major players, how Tm binds and is designed for regulatory function has remained a mystery. Here we show that a set of periodically distributed evolutionarily conserved surface residues of Tm is required for cooperative regulation of actomyosin. Based on our results, we propose a model of Tm on a structure of actin-Tm-myosin in the "open" (on) state showing potential electrostatic interactions of the residues with both actin and myosin. The sites alternate with a second set of conserved surface residues that are important for actin binding in the inhibitory state in the absence of myosin. The transition from the closed to open states requires the sites identified here, even when troponin + Ca(2+) is present. The evolutionarily conserved residues are important for actomyosin regulation, a universal function of Tm that has a common structural basis and mechanism. PMID- 23091027 TI - Optical tweezers reveal relationship between microstructure and nanoparticle penetration of pulmonary mucus. AB - In this study, the mobility of nanoparticles in mucus and similar hydrogels as model systems was assessed to elucidate the link between microscopic diffusion behavior and macroscopic penetration of such gels. Differences in particle adhesion to mucus components were strongly dependent on particle coating. Particles coated with 2 kDa PEG exhibited a decreased adhesion to mucus components, whereas chitosan strongly increased the adhesion. Despite such mucoinert properties of PEG, magnetic nanoparticles of both coatings did not penetrate through native respiratory mucus, resisting high magnetic forces (even for several hours). However, model hydrogels were, indeed, penetrated by both particles in dependency of particle coating, obeying the theory of particle mobility in an external force field. Comparison of penetration data with cryogenic scanning EM images of mucus and the applied model systems suggested particularly high rigidity of the mucin scaffold and a broad pore size distribution in mucus as reasons for the observed particle immobilization. Active probing of the rigidity of mucus and model gels with optical tweezers was used in this context to confirm such properties of mucus on the microscale, thus presenting the missing link between micro- and macroscopical observations. Because of high heterogeneity in the size of the voids and pores in mucus, on small scales, particle mobility will depend on adhesive or inert properties. However, particle translocation over distances larger than a few micrometers is restricted by highly rigid structures within the mucus mesh. PMID- 23091028 TI - The ABO blood group is a trans-species polymorphism in primates. AB - The ABO histo-blood group, the critical determinant of transfusion incompatibility, was the first genetic polymorphism discovered in humans. Remarkably, ABO antigens are also polymorphic in many other primates, with the same two amino acid changes responsible for A and B specificity in all species sequenced to date. Whether this recurrence of A and B antigens is the result of an ancient polymorphism maintained across species or due to numerous, more recent instances of convergent evolution has been debated for decades, with a current consensus in support of convergent evolution. We show instead that genetic variation data in humans and gibbons as well as in Old World monkeys are inconsistent with a model of convergent evolution and support the hypothesis of an ancient, multiallelic polymorphism of which some alleles are shared by descent among species. These results demonstrate that the A and B blood groups result from a trans-species polymorphism among distantly related species and has remained under balancing selection for tens of millions of years-to date, the only such example in hominoids and Old World monkeys outside of the major histocompatibility complex. PMID- 23091029 TI - Functional MYCN signature predicts outcome of neuroblastoma irrespective of MYCN amplification. AB - Neuroblastoma is a pediatric tumor of the sympathetic nervous system. MYCN (V-myc myelocytomatosis viral-related oncogene, neuroblastoma derived [avian]) is amplified in 20% of neuroblastomas, and these tumors carry a poor prognosis. However, tumors without MYCN amplification also may have a poor outcome. Here, we identified downstream targets of MYCN by shRNA-mediated silencing MYCN in neuroblastoma cells. From these targets, 157 genes showed an expression profile correlating with MYCN mRNA levels in NB88, a series of 88 neuroblastoma tumors, and therefore represent in vivo relevant MYCN pathway genes. This 157-gene signature identified very poor prognosis tumors in NB88 and independent neuroblastoma cohorts and was more powerful than MYCN amplification or MYCN expression alone. Remarkably, this signature also identified poor outcome of a group of tumors without MYCN amplification. Most of these tumors have low MYCN mRNA levels but high nuclear MYCN protein levels, suggesting stabilization of MYCN at the protein level. One tumor has an MYC amplification and high MYC expression. Chip-on-chip analyses showed that most genes in this signature are directly regulated by MYCN. MYCN induces genes functioning in cell cycle and DNA repair while repressing neuronal differentiation genes. The functional MYCN-157 signature recognizes classical neuroblastoma with MYCN amplification, as well as a newly identified group marked by MYCN protein stabilization. PMID- 23091030 TI - Acid-base chemical reaction model for nucleation rates in the polluted atmospheric boundary layer. AB - Climate models show that particles formed by nucleation can affect cloud cover and, therefore, the earth's radiation budget. Measurements worldwide show that nucleation rates in the atmospheric boundary layer are positively correlated with concentrations of sulfuric acid vapor. However, current nucleation theories do not correctly predict either the observed nucleation rates or their functional dependence on sulfuric acid concentrations. This paper develops an alternative approach for modeling nucleation rates, based on a sequence of acid-base reactions. The model uses empirical estimates of sulfuric acid evaporation rates obtained from new measurements of neutral molecular clusters. The model predicts that nucleation rates equal the sulfuric acid vapor collision rate times a prefactor that is less than unity and that depends on the concentrations of basic gaseous compounds and preexisting particles. Predicted nucleation rates and their dependence on sulfuric acid vapor concentrations are in reasonable agreement with measurements from Mexico City and Atlanta. PMID- 23091031 TI - Elucidating secondary organic aerosol from diesel and gasoline vehicles through detailed characterization of organic carbon emissions. AB - Emissions from gasoline and diesel vehicles are predominant anthropogenic sources of reactive gas-phase organic carbon and key precursors to secondary organic aerosol (SOA) in urban areas. Their relative importance for aerosol formation is a controversial issue with implications for air quality control policy and public health. We characterize the chemical composition, mass distribution, and organic aerosol formation potential of emissions from gasoline and diesel vehicles, and find diesel exhaust is seven times more efficient at forming aerosol than gasoline exhaust. However, both sources are important for air quality; depending on a region's fuel use, diesel is responsible for 65% to 90% of vehicular-derived SOA, with substantial contributions from aromatic and aliphatic hydrocarbons. Including these insights on source characterization and SOA formation will improve regional pollution control policies, fuel regulations, and methodologies for future measurement, laboratory, and modeling studies. PMID- 23091032 TI - Histone H3K4 demethylation is negatively regulated by histone H3 acetylation in Saccharomyces cerevisiae. AB - Histone H3 lysine 4 trimethylation (H3K4me3) is a hallmark of transcription initiation, but how H3K4me3 is demethylated during gene repression is poorly understood. Jhd2, a JmjC domain protein, was recently identified as the major H3K4me3 histone demethylase (HDM) in Saccharomyces cerevisiae. Although JHD2 is required for removal of methylation upon gene repression, deletion of JHD2 does not result in increased levels of H3K4me3 in bulk histones, indicating that this HDM is unable to demethylate histones during steady-state conditions. In this study, we showed that this was due to the negative regulation of Jhd2 activity by histone H3 lysine 14 acetylation (H3K14ac), which colocalizes with H3K4me3 across the yeast genome. We demonstrated that loss of the histone H3-specific acetyltransferases (HATs) resulted in genome-wide depletion of H3K4me3, and this was not due to a transcription defect. Moreover, H3K4me3 levels were reestablished in HAT mutants following loss of JHD2, which suggested that H3 specific HATs and Jhd2 serve opposing functions in regulating H3K4me3 levels. We revealed the molecular basis for this suppression by demonstrating that H3K14ac negatively regulated Jhd2 demethylase activity on an acetylated peptide in vitro. These results revealed the existence of a general mechanism for removal of H3K4me3 following gene repression. PMID- 23091033 TI - Evidence for the role of endosymbionts in regional-scale habitat partitioning by hydrothermal vent symbioses. AB - Deep-sea hydrothermal vents are populated by dense communities of animals that form symbiotic associations with chemolithoautotrophic bacteria. To date, our understanding of which factors govern the distribution of host/symbiont associations (or holobionts) in nature is limited, although host physiology often is invoked. In general, the role that symbionts play in habitat utilization by vent holobionts has not been thoroughly addressed. Here we present evidence for symbiont-influenced, regional-scale niche partitioning among symbiotic gastropods (genus Alviniconcha) in the Lau Basin. We extensively surveyed Alviniconcha holobionts from four vent fields using quantitative molecular approaches, coupled to characterization of high-temperature and diffuse vent-fluid composition using gastight samplers and in situ electrochemical analyses, respectively. Phylogenetic analyses exposed cryptic host and symbiont diversity, revealing three distinct host types and three different symbiont phylotypes (one epsilon proteobacteria and two gamma-proteobacteria) that formed specific associations with one another. Strikingly, we observed that holobionts with epsilon proteobacterial symbionts were dominant at the northern fields, whereas holobionts with gamma-proteobacterial symbionts were dominant in the southern fields. This pattern of distribution corresponds to differences in the vent geochemistry that result from deep subsurface geological and geothermal processes. We posit that the symbionts, likely through differences in chemolithoautotrophic metabolism, influence niche utilization among these holobionts. The data presented here represent evidence linking symbiont type to habitat partitioning among the chemosynthetic symbioses at hydrothermal vents and illustrate the coupling between subsurface geothermal processes and niche availability. PMID- 23091034 TI - Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. AB - The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH(2) but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design. PMID- 23091035 TI - Structure of Sputnik, a virophage, at 3.5-A resolution. AB - "Sputnik" is a dsDNA virus, referred to as a virophage, that is coassembled with Mimivirus in the host amoeba. We have used cryo-EM to produce an electron density map of the icosahedral Sputnik virus at 3.5-A resolution, sufficient to verify the identity of most amino acids in the capsid proteins and to establish the identity of the pentameric protein forming the fivefold vertices. It was also shown that the virus lacks an internal membrane. The capsid is organized into a T = 27 lattice in which there are 260 trimeric capsomers and 12 pentameric capsomers. The trimeric capsomers consist of three double "jelly-roll" major capsid proteins creating pseudohexameric capsomer symmetry. The pentameric capsomers consist of five single jelly-roll proteins. The release of the genome by displacing one or more of the pentameric capsomers may be the result of a low pH environment. These results suggest a mechanism of Sputnik DNA ejection that probably also occurs in other big icosahedral double jelly-roll viruses such as Adenovirus. In this study, the near-atomic resolution structure of a virus has been established where crystallization for X-ray crystallography was not feasible. PMID- 23091036 TI - Conformation of receptor-bound visual arrestin. AB - Arrestin-1 (visual arrestin) binds to light-activated phosphorylated rhodopsin (P Rh*) to terminate G-protein signaling. To map conformational changes upon binding to the receptor, pairs of spin labels were introduced in arrestin-1 and double electron-electron resonance was used to monitor interspin distance changes upon P Rh* binding. The results indicate that the relative position of the N and C domains remains largely unchanged, contrary to expectations of a "clam-shell" model. A loop implicated in P-Rh* binding that connects beta-strands V and VI (the "finger loop," residues 67-79) moves toward the expected location of P-Rh* in the complex, but does not assume a fully extended conformation. A striking and unexpected movement of a loop containing residue 139 away from the adjacent finger loop is observed, which appears to facilitate P-Rh* binding. This change is accompanied by smaller movements of distal loops containing residues 157 and 344 at the tips of the N and C domains, which correspond to "plastic" regions of arrestin-1 that have distinct conformations in monomers of the crystal tetramer. Remarkably, the loops containing residues 139, 157, and 344 appear to have high flexibility in both free arrestin-1 and the P-Rh*complex. PMID- 23091037 TI - Hepatitis B virus X protein targets the Bcl-2 protein CED-9 to induce intracellular Ca2+ increase and cell death in Caenorhabditis elegans. AB - HBx is a multifunctional hepatitis B virus (HBV) protein that is crucial for HBV infection and pathogenesis and a contributing cause of hepatocyte carcinogenesis. However, the host targets and mechanisms of action of HBx are poorly characterized. We show here that expression of HBx in Caenorhabditis elegans induces both necrotic and apoptotic cell death, mimicking an early event of liver infection by HBV. Genetic and biochemical analyses indicate that HBx interacts directly with the B-cell lymphoma 2 (Bcl-2) homolog CED-9 (cell death abnormal) through a Bcl-2 homology 3 (BH3)-like motif to trigger both cytosolic Ca(2+) increase and cell death. Importantly, Bcl-2 can substitute for CED-9 in mediating HBx-induced cell killing in C. elegans, suggesting that CED-9 and Bcl-2 are conserved cellular targets of HBx. A genetic suppressor screen of HBx-induced cell death has produced many mutations, including mutations in key regulators from both apoptosis and necrosis pathways, indicating that this screen can identify new apoptosis and necrosis genes. Our results suggest that C. elegans could serve as an animal model for identifying crucial host factors and signaling pathways of HBx and aid in development of strategies to treat HBV-induced liver disorders. PMID- 23091038 TI - Multimolecule test-tube simulations of protein unfolding and aggregation. AB - Molecular dynamics simulations of protein folding or unfolding, unlike most in vitro experimental methods, are performed on a single molecule. The effects of neighboring molecules on the unfolding/folding pathway are largely ignored experimentally and simply not modeled computationally. Here, we present two all atom, explicit solvent molecular dynamics simulations of 32 copies of the Engrailed homeodomain (EnHD), an ultrafast-folding and -unfolding protein for which the folding/unfolding pathway is well-characterized. These multimolecule simulations, in comparison with single-molecule simulations and experimental data, show that intermolecular interactions have little effect on the folding/unfolding pathway. EnHD unfolded by the same mechanism whether it was simulated in only water or also in the presence of other EnHD molecules. It populated the same native state, transition state, and folding intermediate in both simulation systems, and was in good agreement with experimental data available for each of the three states. Unfolding was slowed slightly by interactions with neighboring proteins, which were mostly hydrophobic in nature and ultimately caused the proteins to aggregate. Protein-water hydrogen bonds were also replaced with protein-protein hydrogen bonds, additionally contributing to aggregation. Despite the increase in protein-protein interactions, the protein aggregates formed in simulation did not do so at the total exclusion of water. These simulations support the use of single-molecule techniques to study protein unfolding and also provide insight into the types of interactions that occur as proteins aggregate at high temperature at an atomic level. PMID- 23091039 TI - Cryo-EM structure of gastric H+,K+-ATPase with a single occupied cation-binding site. AB - Gastric H(+),K(+)-ATPase is responsible for gastric acid secretion. ATP-driven H(+) uptake into the stomach is efficiently accomplished by the exchange of an equal amount of K(+), resulting in a luminal pH close to 1. Because of the limited free energy available for ATP hydrolysis, the stoichiometry of transported cations is thought to vary from 2H(+)/2K(+) to 1H(+)/1K(+) per hydrolysis of one ATP molecule as the luminal pH decreases, although direct evidence for this hypothesis has remained elusive. Here, we show, using the phosphate analog aluminum fluoride (AlF) and a K(+) congener (Rb(+)), the 8-A resolution structure of H(+),K(+)-ATPase in the transition state of dephosphorylation, (Rb(+))E2~AlF, which is distinct from the preceding Rb(+)-free E2P state. A strong density located in the transmembrane cation-binding site of (Rb(+))E2~AlF highly likely represents a single bound Rb(+) ion, which is clearly different from the Rb(+)-free E2AlF or K(+)-bound (K(+))E2~AlF structures. Measurement of radioactive (86)Rb(+) binding suggests that the binding stoichiometry varies depending on the pH, and approximately half of the amount of Rb(+) is bound under acidic crystallization conditions compared with at a neutral pH. These data represent structural and biochemical evidence for the 1H(+)/1K(+)/1ATP transport mode of H(+),K(+)-ATPase, which is a prerequisite for generation of the 10(6)-fold proton gradient in terms of thermodynamics. Together with the released E2P-stabilizing interaction between the beta subunit's N terminus and the P domain observed in the (Rb(+))E2~AlF structure, we propose a refined vectorial transport model of H(+),K(+)-ATPase, which must prevail against the highly acidic state of the gastric lumen. PMID- 23091040 TI - Force measurements on cargoes in living cells reveal collective dynamics of microtubule motors. AB - Many cellular cargoes move bidirectionally along microtubules, driven by teams of plus- and minus-end-directed motor proteins. To probe the forces exerted on cargoes during intracellular transport, we examined latex beads phagocytosed into living mammalian macrophages. These latex bead compartments (LBCs) are encased in membrane and transported along the cytoskeleton by a complement of endogenous kinesin-1, kinesin-2, and dynein motors. The size and refractive index of LBCs makes them well-suited for manipulation with an optical trap. We developed methods that provide in situ calibration of the optical trap in the complex cellular environment, taking into account any variations among cargoes and local viscoelastic properties of the cytoplasm. We found that centrally and peripherally directed forces exerted on LBCs are of similar magnitude, with maximum forces of ~20 pN. During force events greater than 10 pN, we often observe 8-nm steps in both directions, indicating that the stepping of multiple motors is correlated. These observations suggest bidirectional transport of LBCs is driven by opposing teams of stably bound motors that operate near force balance. PMID- 23091041 TI - T-cell receptor (TCR) interaction with peptides that mimic nickel offers insight into nickel contact allergy. AB - T cell-mediated allergy to Ni(++) is one of the most common forms of allergic contact dermatitis, but how the T-cell receptor (TCR) recognizes Ni(++) is unknown. We studied a TCR from an allergic patient that recognizes Ni(++) bound to the MHCII molecule DR52c containing an unknown self-peptide. We identified mimotope peptides that can replace both the self-peptide and Ni(++) in this ligand. They share a p7 lysine whose epsilonNH(2) group is surface-exposed when bound to DR52c. Whereas the TCR uses germ-line complementary-determining region (CDR)1/2 amino acids to dock in the conventional diagonal mode on the mimotope DR52c complex, the interface is dominated by the TCR Vbeta CDR3 interaction with the p7 lysine. Mutations in the TCR CDR loops have similar effects on the T-cell response to either the mimotope or Ni(++) ligand. We suggest that the mimotope p7 lysine mimics Ni(++) in the natural TCR ligand and that MHCII beta-chain flexibility in the area around the peptide p7 position forms a common site for cation binding in metal allergies. PMID- 23091044 TI - Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. AB - The guideline is intended for use by healthcare providers who care for adult and pediatric patients with group A streptococcal pharyngitis. The guideline updates the 2002 Infectious Diseases Society of America guideline and discusses diagnosis and management, and recommendations are provided regarding antibiotic choices and dosing. Penicillin or amoxicillin remain the treatments of choice, and recommendations are made for the penicillin-allergic patient, which now include clindamycin. PMID- 23091043 TI - T cell receptor/CARMA1/NF-kappaB signaling controls T-helper (Th) 17 differentiation. AB - IL-17-producing CD4 T cells play a key role in immune responses against extracellular bacteria and autoimmunity. Nuclear factor kappaB (NF-kappaB) is required for T-cell activation and selected effector functions, but its role in Th17 differentiation is controversial. Using genetic mouse models that impede T cell-NF-kappaB signaling either downstream of the T-cell receptor (TCR) or of IkappaB kinase beta (IKKbeta), we demonstrate that NF-kappaB signaling controls not only survival and proliferation of activated T cells, but, if cell survival and cell-cycle progression are enabled, has an additional role in promoting completion of Th17 differentiation. CARD-containing MAGUK protein 1 (CARMA1), an adapter required for TCR/NF-kappaB signaling, was necessary for acquisition of IL 17A, IL-17F, IL-21, IL-22, IL-23R, and CCR6 expression in T cells cultured under Th17 conditions. In proliferating cells, lack of CARMA1 selectively prevented Th17, but not Th1 or Th2 differentiation, in a cell-intrinsic manner. Consistent with these data, CARMA1-KO mice were resistant to experimental autoimmune encephalomyelitis. Surprisingly, transcription factors essential for Th17 differentiation such as RORgammat, AHR, and IRF4 were normally induced in CARMA1 KO T cells activated under Th17 conditions, suggesting that the Th17 differentiation program was initiated normally. Instead, chromatin loci of Th17 effector molecules failed to acquire an open conformation in CARMA1-KO T cells. Our results demonstrate that TCR/CARMA1/NF-kappaB controls completion of Th17 differentiation by enabling chromatin accessibility of Th17 effector molecule loci. PMID- 23091045 TI - Photo quiz. Verrucous lesions and ectropion in an immunocompetent individual. PMID- 23091049 TI - Prevalence and presentation of externalized conductors and electrical abnormalities in Riata defibrillator leads after fluoroscopic screening: report from the Netherlands Heart Rhythm Association Device Advisory Committee. AB - BACKGROUND: The Riata family of implantable cardioverter-defibrillator (ICD) leads is prone to a specific insulation abrasion characterized by externalization of conductor cables. The objective of this study was to determine the prevalence of externalized conductors and electrical abnormalities in Riata ICD leads by fluoroscopic screening and standard ICD interrogation. METHODS AND RESULTS: All ICD implantation centers were contacted by the Netherlands Heart Rhythm Association Device Advisory Committee to identify all patients with an active Riata ICD lead and to perform fluoroscopic screening of the lead. In addition, the electrical integrity of the lead was assessed. As of March 1, 2012, data for 1029 active Riata leads were available; 47% of these were 8-F Riata and 53% were 7-F Riata ST. Externalized conductors were observed in 147 leads (14.3%). Proportion of externalized conductors was higher in 8-F Riata compared with 7-F Riata ST (21.4% vs 8.0%; P<0.001). Median time from implantation to detection of externalized conductors was 65.3 months. The estimated rates of externalized conductors were 6.9% and 36.6% at 5 and 8 years after implantation, respectively. Of the 147 leads with externalized conductors, 10.9% had abnormal electrical parameters vs 3.5% in nonexternalized leads (P<0.001). CONCLUSIONS: The prevalence of externalized conductors in Riata leads is significantly high (14.3%) using fluoroscopic screening. The majority of externalized conductors are not detectable with standard ICD interrogation. Screening with fluoroscopy is reasonable. PMID- 23091050 TI - Regulation of endothelial nitric-oxide synthase (NOS) S-glutathionylation by neuronal NOS: evidence of a functional interaction between myocardial constitutive NOS isoforms. AB - Myocardial constitutive No production depends on the activity of both endothelial and neuronal NOS (eNOS and nNOS, respectively). Stimulation of myocardial beta(3) adrenergic receptor (beta(3)-AR) produces a negative inotropic effect that is dependent on eNOS. We evaluated whether nNOS also plays a role in beta(3)-AR signaling and found that the beta(3)-AR-mediated reduction in cell shortening and [Ca(2+)](i) transient amplitude was abolished both in eNOS(-/-) and nNOS(-/-) left ventricular (LV) myocytes and in wild type LV myocytes after nNOS inhibition with S-methyl-L-thiocitrulline. LV superoxide (O(2)(.-)) production was increased in nNOS(-/-) mice and reduced by L-N(omega)-nitroarginine methyl ester (L-NAME), indicating uncoupling of eNOS activity. eNOS S-glutathionylation and Ser-1177 phosphorylation were significantly increased in nNOS(-/-) myocytes, whereas myocardial tetrahydrobiopterin, eNOS Thr-495 phosphorylation, and arginase activity did not differ between genotypes. Although inhibitors of xanthine oxidoreductase (XOR) or NOX2 NADPH oxidase caused a similar reduction in myocardial O(2)(.-), only XOR inhibition reduced eNOS S-glutathionylation and Ser 1177 phosphorylation and restored both eNOS coupled activity and the negative inotropic and [Ca(2+)](i) transient response to beta(3)-AR stimulation in nNOS(-/ ) mice. In summary, our data show that increased O(2)(.-) production by XOR selectively uncouples eNOS activity and abolishes the negative inotropic effect of beta(3)-AR stimulation in nNOS(-/-) myocytes. These findings provide unequivocal evidence of a functional interaction between the myocardial constitutive NOS isoforms and indicate that aspects of the myocardial phenotype of nNOS(-/-) mice result from disruption of eNOS signaling. PMID- 23091042 TI - A resurrected mammalian hAT transposable element and a closely related insect element are highly active in human cell culture. AB - Chromosome structure and function are influenced by transposable elements, which are mobile DNA segments that can move from place to place. hAT elements are a superfamily of DNA cut and paste elements that move by excision and integration. We have characterized two hAT elements, TcBuster and Space Invaders (SPIN), that are members of a recently described subfamily of hAT elements called Buster elements. We show that TcBuster, from the red flour beetle Tribolium castaneum, is highly active in human cells. SPIN elements are currently inactive elements that were recently highly active in multiple vertebrate genomes, and the high level of sequence similarity across widely diverged species and patchy phylogenetic distribution suggest that they may have moved between genomes by horizontal transfer. We have generated an intact version of this element, SPIN(ON), which is highly active in human cells. In vitro analysis of TcBuster and SPIN(ON) shows that no proteins other than transposase are essential for recombination, a property that may contribute to the ability of SPIN to successfully invade multiple organisms. We also analyze the target site preferences of de novo insertions in the human genome of TcBuster and SPIN(ON) and compare them with the preferences of Sleeping Beauty and piggyBac, showing that each superfamily has a distinctive pattern of insertion. The high-frequency transposition of both TcBuster and SPIN(ON) suggests that these transposon systems offer powerful tools for genome engineering. Finally, we describe a Saccharomyces cerevisiae assay for TcBuster that will provide a means for isolation of hyperactive and other interesting classes of transposase mutants. PMID- 23091051 TI - Crystal structure of bovine coronavirus spike protein lectin domain. AB - The spike protein N-terminal domains (NTDs) of bovine coronavirus (BCoV) and mouse hepatitis coronavirus (MHV) recognize sugar and protein receptors, respectively, despite their significant sequence homology. We recently determined the crystal structure of MHV NTD complexed with its protein receptor murine carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), which surprisingly revealed a human galectin (galactose-binding lectin) fold in MHV NTD. Here, we have determined at 1.55 A resolution the crystal structure of BCoV NTD, which also has the human galectin fold. Using mutagenesis, we have located the sugar-binding site in BCoV NTD, which overlaps with the galactose-binding site in human galectins. Using a glycan array screen, we have identified 5-N acetyl-9-O-acetylneuraminic acid as the preferred sugar substrate for BCoV NTD. Subtle structural differences between BCoV and MHV NTDs, primarily involving different conformations of receptor-binding loops, explain why BCoV NTD does not bind CEACAM1 and why MHV NTD does not bind sugar. These results suggest a successful viral evolution strategy in which coronaviruses stole a galectin from hosts, incorporated it into their spike protein, and evolved it into viral receptor-binding domains with altered sugar specificity in contemporary BCoV or novel protein specificity in contemporary MHV. PMID- 23091052 TI - A trapping approach reveals novel substrates and physiological functions of the essential protease FtsH in Escherichia coli. AB - Proteolysis is a universal strategy to rapidly adjust the amount of regulatory and metabolic proteins to cellular demand. FtsH is the only membrane-anchored and essential ATP-dependent protease in Escherichia coli. Among the known functions of FtsH are the control of the heat shock response by proteolysis of the transcription factor RpoH (sigma(32)) and its essential role in lipopolysaccharide biosynthesis by degradation of the two key enzymes LpxC and KdtA. Here, we identified new FtsH substrates by using a proteomic-based substrate trapping approach. An FtsH variant (FtsH(trap)) carrying a single amino acid exchange in the proteolytic center was expressed and purified in E. coli. FtsH(trap) is devoid of its proteolytic activity but fully retains ATPase activity allowing for unfolding and translocation of substrates into the inactivated proteolytic chamber. Proteins associated with FtsH(trap) and wild type FtsH (FtsH(WT)) were purified, separated by two-dimensional PAGE, and subjected to mass spectrometry. Over-representation of LpxC in the FtsH(trap) preparation validated the trapping strategy. Four novel FtsH substrates were identified. The sulfur delivery protein IscS and the d-amino acid dehydrogenase DadA were degraded under all tested conditions. The formate dehydrogenase subunit FdoH and the yet uncharacterized YfgM protein were subject to growth condition dependent regulated proteolysis. Several lines of evidence suggest that YfgM serves as negative regulator of the RcsB-dependent stress response pathway, which must be degraded under stress conditions. The proteins captured by FtsH(trap) revealed previously unknown biological functions of the physiologically most important AAA(+) protease in E. coli. PMID- 23091053 TI - Solution structure of IseA, an inhibitor protein of DL-endopeptidases from Bacillus subtilis, reveals a novel fold with a characteristic inhibitory loop. AB - In Bacillus subtilis, LytE, LytF, CwlS, and CwlO are vegetative autolysins, DL endopeptidases in the NlpC/P60 family, and play essential roles in cell growth and separation. IseA (YoeB) is a proteinaceous inhibitor against the DL endopeptidases, peptidoglycan hydrolases. Overexpression of IseA caused significantly long chained cell morphology, because IseA inhibits the cell separation DL-endopeptidases post-translationally. Here, we report the first three-dimensional structure of IseA, determined by NMR spectroscopy. The structure includes a single domain consisting of three alpha-helices, one 3(10) helix, and eight beta-strands, which is a novel fold like a "hacksaw." Noteworthy is a dynamic loop between beta4 and the 3(10)-helix, which resembles a "blade." The electrostatic potential distribution shows that most of the surface is positively charged, but the region around the loop is negatively charged. In contrast, the LytF active-site cleft is expected to be positively charged. NMR chemical shift perturbation of IseA interacting with LytF indicated that potential interaction sites are located around the loop. Furthermore, the IseA mutants D100K/D102K and G99P/G101P at the loop showed dramatic loss of inhibition activity against LytF, compared with wild-type IseA, indicating that the beta4 3(10) loop plays an important role in inhibition. Moreover, we built a complex structure model of IseA-LytF by docking simulation, suggesting that the beta4 3(10) loop of IseA gets stuck deep in the cleft of LytF, and the active site is occluded. These results suggest a novel inhibition mechanism of the hacksaw-like structure, which is different from known inhibitor proteins, through interactions around the characteristic loop regions with the active-site cleft of enzymes. PMID- 23091054 TI - Characterization and structure of the Aquifex aeolicus protein DUF752: a bacterial tRNA-methyltransferase (MnmC2) functioning without the usually fused oxidase domain (MnmC1). AB - Post-transcriptional modifications of the wobble uridine (U34) of tRNAs play a critical role in reading NNA/G codons belonging to split codon boxes. In a subset of Escherichia coli tRNA, this wobble uridine is modified to 5 methylaminomethyluridine (mnm(5)U34) through sequential enzymatic reactions. Uridine 34 is first converted to 5-carboxymethylaminomethyluridine (cmnm(5)U34) by the MnmE-MnmG enzyme complex. The cmnm(5)U34 is further modified to mnm(5)U by the bifunctional MnmC protein. In the first reaction, the FAD-dependent oxidase domain (MnmC1) converts cmnm(5)U into 5-aminomethyluridine (nm(5)U34), and this reaction is immediately followed by the methylation of the free amino group into mnm(5)U34 by the S-adenosylmethionine-dependent domain (MnmC2). Aquifex aeolicus lacks a bifunctional MnmC protein fusion and instead encodes the Rossmann-fold protein DUF752, which is homologous to the methyltransferase MnmC2 domain of Escherichia coli MnmC (26% identity). Here, we determined the crystal structure of the A. aeolicus DUF752 protein at 2.5 A resolution, which revealed that it catalyzes the S-adenosylmethionine-dependent methylation of nm(5)U in vitro, to form mnm(5)U34 in tRNA. We also showed that naturally occurring tRNA from A. aeolicus contains the 5-mnm group attached to the C5 atom of U34. Taken together, these results support the recent proposal of an alternative MnmC1-independent shortcut pathway for producing mnm(5)U34 in tRNAs. PMID- 23091055 TI - The zinc finger protein ZNF268 is overexpressed in human cervical cancer and contributes to tumorigenesis via enhancing NF-kappaB signaling. AB - Cervical cancer is one of the most common tumors affecting women's health worldwide. Although human papillomavirus can be detected in nearly all cases, the mechanism of cervical carcinogenesis remains to be further addressed. Here, we demonstrated that ZNF268, a Kruppel-associated box-containing zinc finger protein, might contribute to the development of cervical cancer. We found that ZNF268b2, an isoform of ZNF268, was overexpressed in human squamous cervical cancer specimens. Knockdown of ZNF268 in cervical cancer cells caused cell cycle arrest at the G(0)/G(1) phase, reduced colony formation, and increased sensitivity to TNFalpha-induced apoptosis. In addition, HeLa cell growth in xenograft nude mice was suppressed by ZNF268 knockdown, with increased apoptosis. Furthermore, ZNF268b2 was shown to increase NF-kappaB signaling in vitro and in vivo. Reconstitution of NF-kappaB activity restored proliferation in ZNF268 knockdown HeLa cells. Of note, we observed a high frequency of NF-kappaB activation in ZNF268-overexpressing cervical cancer tissues, suggesting a pathological coincidence of ZNF268b2 overexpression and NF-kappaB activation. Taken together, our results reveal a novel role of ZNF268b2 that contributes to cervical carcinogenesis in part through enhancing NF-kappaB signaling. PMID- 23091056 TI - Ric1-Rgp1 complex is a guanine nucleotide exchange factor for the late Golgi Rab6A GTPase and an effector of the medial Golgi Rab33B GTPase. AB - Rab GTPases are master regulators of membrane trafficking events and template the directionality of protein transport through the secretory and endocytic pathways. Certain Rabs recruit the guanine nucleotide exchange factor (GEF) that activates a subsequent acting Rab protein in a given pathway; this process has been termed a Rab cascade. We show here that the medial Golgi-localized Rab33B GTPase has the potential to link functionally to the late Golgi, Rab6 GTPase, by its capacity for association with Ric1 and Rgp1 proteins. In yeast, Ric1p and Rgp1p form a complex that catalyzes guanine nucleotide exchange by Ypt6p, the Rab6 homolog. Human Ric1 and Rgp1 both bind Rab6A with preference for the GDP-bound conformation, characteristic of a GEF. Nevertheless, both Ric1 and Rgp1 proteins are needed to catalyze nucleotide exchange on Rab6A protein. Ric1 and Rgp1 form a complex, but unlike their yeast counterparts, most of the subunits are not associated, and most of the proteins are cytosolic. Loss of Ric1 or Rgp1 leads to destabilization of Rab6, concomitant with a block in Rab6-dependent retrograde transport of mannose 6-phosphate receptors to the Golgi. The C terminus of Ric1 protein contains a distinct binding site for Rab33B-GTP, supporting the existence of a Rab cascade between the medial and trans Golgi. This study thus identifies a GEF for Rab6A in human cells. PMID- 23091057 TI - Munc18-1 controls SNARE protein complex assembly during human sperm acrosomal exocytosis. AB - The spermatozoon is a very specialized cell capable of carrying out a limited set of functions with high efficiency. Sperm are then excellent model cells to dissect fundamental processes such as regulated exocytosis. The secretion of the single dense-core granule of mammalian spermatozoa relies on the same highly conserved molecules and goes through the same stages as exocytosis in other types of cells. In this study, we describe the presence of Munc18-1 in human sperm and show that this protein has an essential role in acrosomal exocytosis. We observed that inactivation of endogenous Munc18-1 with a specific antibody precluded the stabilization of trans-SNARE complexes and inhibited acrosomal exocytosis. Addition of recombinant Munc18-1 blocked secretion by sequestering monomeric syntaxin, an effect that was rescued by alpha-soluble NSF attachment protein. By electron microscopy, we observed that both the anti-Munc18-1 antibody and recombinant Munc18-1 inhibited the docking of the acrosome to the plasma membrane. In conclusion, our results indicate that Munc18-1 plays a key role in the dynamics of trans-SNARE complex assembly and/or stabilization, a process that is necessary for the docking of the outer acrosomal membrane to the plasma membrane and subsequent fusion pore opening. PMID- 23091058 TI - Network reconstruction and systems analysis of cardiac myocyte hypertrophy signaling. AB - Cardiac hypertrophy is managed by a dense web of signaling pathways with many pathways influencing myocyte growth. A quantitative understanding of the contributions of individual pathways and their interactions is needed to better understand hypertrophy signaling and to develop more effective therapies for heart failure. We developed a computational model of the cardiac myocyte hypertrophy signaling network to determine how the components and network topology lead to differential regulation of transcription factors, gene expression, and myocyte size. Our computational model of the hypertrophy signaling network contains 106 species and 193 reactions, integrating 14 established pathways regulating cardiac myocyte growth. 109 of 114 model predictions were validated using published experimental data testing the effects of receptor activation on transcription factors and myocyte phenotypic outputs. Network motif analysis revealed an enrichment of bifan and biparallel cross-talk motifs. Sensitivity analysis was used to inform clustering of the network into modules and to identify species with the greatest effects on cell growth. Many species influenced hypertrophy, but only a few nodes had large positive or negative influences. Ras, a network hub, had the greatest effect on cell area and influenced more species than any other protein in the network. We validated this model prediction in cultured cardiac myocytes. With this integrative computational model, we identified the most influential species in the cardiac hypertrophy signaling network and demonstrate how different levels of network organization affect myocyte size, transcription factors, and gene expression. PMID- 23091059 TI - Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering. AB - The T-cell antigen receptor (TCR) exists in monomeric and nanoclustered forms independently of antigen binding. Although the clustering is involved in the regulation of T-cell sensitivity, it is unknown how the TCR nanoclusters form. We show that cholesterol is required for TCR nanoclustering in T cells and that this clustering enhances the avidity but not the affinity of the TCR-antigen interaction. Investigating the mechanism of the nanoclustering, we found that radioactive photocholesterol specifically binds to the TCRbeta chain in vivo. In order to reduce the complexity of cellular membranes, we used a synthetic biology approach and reconstituted the TCR in liposomes of defined lipid composition. Both cholesterol and sphingomyelin were required for the formation of TCR dimers in phosphatidylcholine-containing large unilamellar vesicles. Further, the TCR was localized in the liquid disordered phase in giant unilamellar vesicles. We propose a model in which cholesterol and sphingomyelin binding to the TCRbeta chain causes TCR dimerization. The lipid-induced TCR nanoclustering enhances the avidity to antigen and thus might be involved in enhanced sensitivity of memory compared with naive T cells. Our work contributes to the understanding of the function of specific nonannular lipid-membrane protein interactions. PMID- 23091060 TI - Dual regulation of diacylglycerol kinase (DGK)-theta: polybasic proteins promote activation by phospholipids and increase substrate affinity. AB - Diacylglycerol kinases are important mediators of lipid signaling cascades, and insight into their regulation is of increasing interest. Using purified DGK theta, we show that this isoform is subject to dual regulation and that the previously characterized stimulation by acidic phospholipids is dependent on the presence of a positively charged protein or peptide. Polybasic cofactors lowered the K(m) for diacylglycerol at the membrane surface (K(m)((surf))), and worked synergistically with acidic phospholipids to increase activity 10- to 30-fold, suggesting that the purified enzyme is autoinhibited. Vesicle pulldown studies showed that acidic phospholipids recruit polybasic cofactors to the vesicle surface but have little effect on the membrane association of DGK-theta, suggesting that a triad of enzyme, acidic lipid and basic protein are necessary for interfacial activity. Importantly, these data demonstrate that the interfacial association and catalytic activity of DGK-theta are independently regulated. Finally, we show that DGK-theta directly interacts with, and is activated by, basic proteins such as histone H1 and Tau with nm affinity, consistent with a potential role for a polybasic protein or protein domain in the activation of this enzyme. PMID- 23091061 TI - The DNAJA2 substrate release mechanism is essential for chaperone-mediated folding. AB - DNAJA1 (DJA1/Hdj2) and DNAJA2 (DJA2) are the major J domain partners of human Hsp70/Hsc70 chaperones. Although they have overall similarity with the well characterized type I co-chaperones from yeast and bacteria, they are biologically distinct, and their functional mechanisms are poorly characterized. We identified DJA2-specific activities in luciferase folding and repression of human ether-a-go go-related gene (HERG) trafficking that depended on its expression levels in cells. Mutations in different internal domains of DJA2 abolished these effects. Using purified proteins, we addressed the mechanistic defects. A mutant lacking the region between the zinc finger motifs (DJA2-Deltam2) was able to bind substrate similar to wild type but was incapable of releasing substrate during its transfer to Hsc70. The equivalent mutation in DJA1 also abolished its substrate release. A DJA2 mutant (DJA-221), which had its C-terminal dimerization region replaced by that of DJA1, was inactive but retained its ability to release substrate. The release mechanism required the J domain and ATP hydrolysis by Hsc70, although the nucleotide dependence diverged between DJA2 and DJA1. Limited proteolysis suggested further conformational differences between the two wild type co-chaperones and the mutants. Our results demonstrate an essential role of specific DJA domains in the folding mechanism of Hsc70. PMID- 23091062 TI - The lipoprotein LpqW is essential for the mannosylation of periplasmic glycolipids in Corynebacteria. AB - Phosphatidylinositol mannosides (PIM), lipomannan (LM), and lipoarabinomannan (LAM) are essential components of the cell wall and plasma membrane of mycobacteria, including the human pathogen Mycobacterium tuberculosis, as well as the related Corynebacterineae. We have previously shown that the lipoprotein, LpqW, regulates PIM and LM/LAM biosynthesis in mycobacteria. Here, we provide direct evidence that LpqW regulates the activity of key mannosyltransferases in the periplasmic leaflet of the cell membrane. Inactivation of the Corynebacterium glutamicum lpqW ortholog, NCgl1054, resulted in a slow growth phenotype and a global defect in lipoglycan biosynthesis. The NCgl1054 mutant lacked LAMs and was defective in the elongation of the major PIM species, AcPIM2, as well as a second glycolipid, termed Gl-X (mannose-alpha1-4-glucuronic acid-alpha1-diacylglycerol), which function as membrane anchors for LM-A and LM-B, respectively. Elongation of AcPIM2 and Gl-X was found to be dependent on expression of polyprenol phosphomannose (ppMan) synthase. However, the DeltaNCgl1054 mutant synthesized normal levels of ppMan, indicating that LpqW is not required for synthesis of this donor. A spontaneous suppressor strain was isolated in which lipoglycan synthesis in the DeltaNCgl1054 mutant was partially restored. Genome-wide sequencing indicated that a single amino acid substitution within the ppMan dependent mannosyltransferase MptB could bypass the need for LpqW. Further evidence of an interaction is provided by the observation that MptB activity in cell-free extracts was significantly reduced in the absence of LpqW. Collectively, our results suggest that LpqW may directly activate MptB, highlighting the role of lipoproteins in regulating key cell wall biosynthetic pathways in these bacteria. PMID- 23091064 TI - Medical director responsibilities for outpatient cardiac rehabilitation/secondary prevention programs: 2012 update: a statement for health care professionals from the American Association of Cardiovascular and Pulmonary Rehabilitation and the American Heart Association. AB - Medical directors of cardiac rehabilitation/secondary prevention (CR/SP) programs are responsible for the safe and effective delivery of high-quality CR/SP services to eligible patients. Yet, the training and resources for CR/SP medical directors are limited. As a result, there appears to be considerable variability throughout CR/SP programs in the United States in the roles, responsibilities, and engagement of CR/SP medical directors. Since the publication of the 2005 scientific statement from the American Heart Association and American Association of Cardiovascular and Pulmonary Rehabilitation regarding medical director responsibilities for outpatient CR/SP programs, significant changes have occurred. This statement updates the responsibilities of CR/SP medical directors, in view of changes in federal legislation and regulations and changes in health care delivery and clinical practice that impact the roles and responsibilities of CR/SP medical directors. PMID- 23091063 TI - Endothelial nuclear factor-kappaB-dependent regulation of arteriogenesis and branching. AB - BACKGROUND: Arteriogenesis and collateral formation are complex processes requiring integration of multiple inputs to coordinate vessel branching, growth, maturation, and network size. Factors regulating these processes have not been determined. METHODS AND RESULTS: We used an inhibitor of NFkappaB activation (IkappaBalphaSR) under control of an endothelial-specific inducible promoter to selectively suppress endothelial nuclear factor-kappaB activation during development, in the adult vasculature, or in vitro. Inhibition of nuclear factor kappaB activation resulted in formation of an excessively branched arterial network that was composed of immature vessels and provided poor distal tissue perfusion. Molecular analysis demonstrated reduced adhesion molecule expression leading to decreased monocyte influx, reduced hypoxia-inducible factor-1alpha levels, and a marked decrease in delta-like ligand 4 expression with a consequent decrease in Notch signaling. The latter was the principal cause of increased vascular branching as treatment with Jagged-1 peptide reduced the size of the arterial network to baseline levels. CONCLUSIONS: These findings identify nuclear factor-kappaB as a key regulator of adult and developmental arteriogenesis and collateral formation. Nuclear factor-kappaB achieves this by regulating hypoxia inducible factor-1alpha-dependent expression of vascular endothelial growth factor-A and platelet-derived growth factor-BB, which are necessary for the development and maturation of the arterial collateral network, and by regulating delta-like ligand 4 expression, which in turn determines the size and complexity of the network. PMID- 23091065 TI - The safety of cardiopulmonary exercise testing in a population with high-risk cardiovascular diseases. AB - BACKGROUND: Cardiopulmonary exercise testing (CPX) with measurement of peak oxygen uptake (Vo(2)) is a powerful test for assessment and quantification of functional impairment resulting from cardiovascular disease. The safety of CPX has been established in patients with coronary artery disease and congestive heart failure, but clinical use of CPX in other cardiac diseases has been limited, in part because of a paucity of safety data. This study investigates the safety of CPX in a heterogeneous cohort of patients with a wide variety of underlying high-risk cardiac diagnoses. METHODS AND RESULTS: This single-center retrospective review examined 5060 CPX studies performed in 4250 unique patients, including 1748 (35%) female subjects and 686 (14%) subjects aged >=75 years. The primary end point was major adverse event during stress testing. The study population included patients with a variety of high-risk cardiac diseases, including congestive heart failure (n=1289, 25.5%), hypertrophic cardiomyopathy (n=598, 11.8%), pulmonary hypertension (n=194, 3.8%), and aortic stenosis (n=212, 4.2%). This patient population generally had severe functional impairment, including 1192 (24%) patients with peak Vo(2)<14 mL/kg/min. Eight adverse events occurred during CPX, for an adverse event rate of 0.16%. The most common adverse event (n=6) was sustained ventricular tachycardia. There were no fatal events. CONCLUSIONS: CPX is generally a safe procedure, even in a population with underlying high-risk cardiovascular diagnoses. PMID- 23091066 TI - TspanC8 tetraspanins regulate ADAM10/Kuzbanian trafficking and promote Notch activation in flies and mammals. AB - The metalloprotease ADAM10/Kuzbanian catalyzes the ligand-dependent ectodomain shedding of Notch receptors and activates Notch. Here, we show that the human tetraspanins of the evolutionary conserved TspanC8 subfamily (Tspan5, Tspan10, Tspan14, Tspan15, Tspan17, and Tspan33) directly interact with ADAM10, regulate its exit from the endoplasmic reticulum, and that four of them regulate ADAM10 surface expression levels. In an independent RNAi screen in Drosophila, two TspanC8 genes were identified as Notch regulators. Functional analysis of the three Drosophila TspanC8 genes (Tsp3A, Tsp86D, and Tsp26D) indicated that these genes act redundantly to promote Notch signaling. During oogenesis, TspanC8 genes were up-regulated in border cells and regulated Kuzbanian distribution, Notch activity, and cell migration. Furthermore, the human TspanC8 tetraspanins Tspan5 and Tspan14 positively regulated ligand-induced ADAM10-dependent Notch1 signaling. We conclude that TspanC8 tetraspanins have a conserved function in the regulation of ADAM10 trafficking and activity, thereby positively regulating Notch receptor activation. PMID- 23091067 TI - Substrate stiffness regulates cadherin-dependent collective migration through myosin-II contractility. AB - The mechanical microenvironment is known to influence single-cell migration; however, the extent to which mechanical cues affect collective migration of adherent cells is not well understood. We measured the effects of varying substrate compliance on individual cell migratory properties in an epithelial wound-healing assay. Increasing substrate stiffness increased collective cell migration speed, persistence, and directionality as well as the coordination of cell movements. Dynamic analysis revealed that wounding initiated a wave of motion coordination from the wound edge into the sheet. This was accompanied by a front-to-back gradient of myosin-II activation and establishment of cell polarity. The propagation was faster and farther reaching on stiff substrates, indicating that substrate stiffness affects the transmission of directional cues. Manipulation of myosin-II activity and cadherin-catenin complexes revealed that this transmission is mediated by coupling of contractile forces between neighboring cells. Thus, our findings suggest that the mechanical environment integrates in a feedback with cell contractility and cell-cell adhesion to regulate collective migration. PMID- 23091068 TI - Critical role for the kinesin KIF3A in the HIV life cycle in primary human macrophages. AB - Macrophages are long-lived target cells for HIV infection and are considered viral reservoirs. HIV assembly in macrophages occurs in virus-containing compartments (VCCs) in which virions accumulate and are stored. The regulation of the trafficking and release of these VCCs remains unknown. Using high resolution light and electron microscopy of HIV-1-infected primary human macrophages, we show that the spatial distribution of VCCs depended on the microtubule network and that VCC-limiting membrane was closely associated with KIF3A+ microtubules. Silencing KIF3A strongly decreased virus release from HIV-1-infected macrophages, leading to VCC accumulation intracellularly. Time-lapse microscopy further suggested that VCCs and associated KIF3A move together along microtubules. Importantly, KIF3A does not play a role in HIV release from T cells that do not possess VCCs. These results reveal that HIV-1 requires the molecular motor KIF3 to complete its cycle in primary macrophages. Targeting this step may lead to novel strategies to eliminate this viral reservoir. PMID- 23091069 TI - N-WASP coordinates the delivery and F-actin-mediated capture of MT1-MMP at invasive pseudopods. AB - Metastasizing tumor cells use matrix metalloproteases, such as the transmembrane collagenase MT1-MMP, together with actin-based protrusions, to break through extracellular matrix barriers and migrate in dense matrix. Here we show that the actin nucleation-promoting protein N-WASP (Neural Wiskott-Aldrich syndrome protein) is up-regulated in breast cancer, and has a pivotal role in mediating the assembly of elongated pseudopodia that are instrumental in matrix degradation. Although a role for N-WASP in invadopodia was known, we now show how N-WASP regulates invasive protrusion in 3D matrices. In actively invading cells, N-WASP promoted trafficking of MT1-MMP into invasive pseudopodia, primarily from late endosomes, from which it was delivered to the plasma membrane. Upon MT1 MMP's arrival at the plasma membrane in pseudopodia, N-WASP stabilized MT1-MMP via direct tethering of its cytoplasmic tail to F-actin. Thus, N-WASP is crucial for extension of invasive pseudopods into which MT1-MMP traffics and for providing the correct cytoskeletal framework to couple matrix remodeling with protrusive invasion. PMID- 23091070 TI - Noncentrosomal microtubules and type II myosins potentiate epidermal cell adhesion and barrier formation. AB - During differentiation, many cells reorganize their microtubule cytoskeleton into noncentrosomal arrays. Although these microtubules are likely organized to meet the physiological roles of their tissues, their functions in most cell types remain unexplored. In the epidermis, differentiation induces the reorganization of microtubules to cell-cell junctions in a desmosome-dependent manner. Here, we recapitulate the reorganization of microtubules in cultured epidermal cells. Using this reorganization assay, we show that cortical microtubules recruit myosin II to the cell cortex in order to engage adherens junctions, resulting in an increase in mechanical integrity of the cell sheets. Cortical microtubules and engaged adherens junctions, in turn, increase tight junction function. In vivo, disruption of microtubules or loss of myosin IIA and B resulted in loss of tight junction-mediated barrier activity. We propose that noncentrosomal microtubules act through myosin II recruitment to potentiate cell adhesion in the differentiating epidermis, thus forming a robust mechanical and chemical barrier against the external environment. PMID- 23091071 TI - Phosphocaveolin-1 is a mechanotransducer that induces caveola biogenesis via Egr1 transcriptional regulation. AB - Caveolin-1 (Cav1) is an essential component of caveolae whose Src kinase dependent phosphorylation on tyrosine 14 (Y14) is associated with regulation of focal adhesion dynamics. However, the relationship between these disparate functions remains to be elucidated. Caveola biogenesis requires expression of both Cav1 and cavin-1, but Cav1Y14 phosphorylation is dispensable. In this paper, we show that Cav1 tyrosine phosphorylation induces caveola biogenesis via actin dependent mechanotransduction and inactivation of the Egr1 (early growth response 1) transcription factor, relieving inhibition of endogenous Cav1 and cavin-1 genes. Cav1 phosphorylation reduces Egr1 binding to Cav1 and cavin-1 promoters and stimulates their activity. In MDA-231 breast carcinoma cells that express elevated levels of Cav1 and caveolae, Egr1 regulated Cav1, and cavin-1 promoter activity was dependent on actin, Cav1, Src, and Rho-associated kinase as well as downstream protein kinase C (PKC) signaling. pCav1 is therefore a mechanotransducer that acts via PKC to relieve Egr1 transcriptional inhibition of Cav1 and cavin-1, defining a novel feedback regulatory loop to regulate caveola biogenesis. PMID- 23091073 TI - Neuroprotective lifestyles and the aging brain: activity, atrophy, and white matter integrity. AB - OBJECTIVES: Increased participation in leisure and physical activities may be cognitively protective. Whether activity might protect the integrity of the brain's white matter, or reduce atrophy and white matter lesion (WML) load, was examined in the Lothian Birth Cohort 1936 (n = 691), a longitudinal study of aging. METHODS: Associations are presented between self-reported leisure and physical activity at age 70 years and structural brain biomarkers at 73 years. For white matter integrity, principal components analysis of 12 major tracts produced general factors for fractional anisotropy (FA) and mean diffusivity. Atrophy, gray and normal-appearing white matter (NAWM) volumes, and WML load were assessed using computational image processing methods; atrophy and WML were also assessed visually. RESULTS: A higher level of physical activity was associated with higher FA, larger gray and NAWM volumes, less atrophy, and lower WML load. The physical activity associations with atrophy, gray matter, and WML remained significant after adjustment for covariates, including age, social class, and health status. For example, physical activity (standardized beta = -0.09, nonstandardized beta = -0.09, p = 0.029) and stroke (standardized beta = 0.18, nonstandardized beta = 0.69, p = 0.003) each had an independent effect on rated WML load. Leisure activity was associated with NAWM volume, but was nonsignificant after including covariates. CONCLUSIONS: In this large, narrow-age sample of adults in their 70s, physical activity was associated with less atrophy and WML. Its role as a potential neuroprotective factor is supported; however, the direction of causation is unclear from this observational study. PMID- 23091072 TI - Rbms3 functions in craniofacial development by posttranscriptionally modulating TGF-beta signaling. AB - Cranial neural crest cells form much of the facial skeleton, and abnormalities in their development lead to severe birth defects. In a novel zebrafish protein trap screen, we identified an RNA-binding protein, Rbms3, that is transiently expressed in the cytoplasm of condensing neural crest cells within the pharyngeal arches. Morphants for rbms3 displayed reduced proliferation of prechondrogenic crest and significantly altered expression for chondrogenic/osteogenic lineage markers. This phenotype strongly resembles cartilage/crest defects observed in Tgf-betar2:Wnt1-Cre mutants, which suggests a possible link with TGF-beta signaling. Consistent with this are the findings that: (a) Rbms3 stabilized a reporter transcript with smad2 3' untranslated region, (b) RNA immunoprecipitation with full-length Rbms3 showed enrichment for smad2/3, and (c) pSmad2 levels were reduced in rbms3 morphants. Overall, these results suggest that Rbms3 posttranscriptionally regulates one of the major pathways that promotes chondrogenesis, the transforming growth factor beta receptor (TGF-betar) pathway. PMID- 23091074 TI - Outcomes after thrombolysis in AIS according to prior statin use: a registry and review. AB - BACKGROUND: The impact of prior statin use on outcomes after thrombolysis is unclear. We evaluated outcomes of patients treated by IV, intra-arterial (IA) thrombolysis, or combined therapy, according to prior statin use. METHODS: We analyzed data from a patient registry (606 patients) and conducted a systematic review. RESULTS: We identified 11 previous studies (6,438 patients) that evaluated the effect of statin use on outcomes after IV thrombolysis (8 studies), IA thrombolysis (2 studies), or a single/combined approach (1 study). In our registry and in most of the retrieved studies, statin users had more risk factors and concomitant antiplatelet treatment than nonstatin users. Regardless of treatment strategy, prior statin use was not associated with favorable outcome (adjusted odds ratio [OR] 1.36; 95 confidence interval [CI] 0.86-2.16), symptomatic intracranial hemorrhage (sICH) (OR 0.57; 95% CI 0.22-1.49), or recanalization (OR 1.87; 95% CI 0.69-5.03). In meta-analysis, prior statin use was not associated with favorable outcome (crude OR 0.99; 95% CI 0.88-1.12), but was associated with an increased risk of sICH (crude OR 1.55; 95% CI 1.23-1.95). However, when the available multivariable associations were combined (5 studies), the effect of prior statin use on risk of sICH was not significant (OR 1.31; 95% CI 0.97-1.76). CONCLUSIONS: These results suggest no beneficial or detrimental effect of prior statin use in acute stroke patients treated by IV thrombolysis, IA thrombolysis, or combined therapy, although the numbers of patients treated by IA thrombolysis or combined therapy are too small to exclude an effect. PMID- 23091075 TI - Mouse brain kaleidoscope. PMID- 23091076 TI - Frontal lobotomy. PMID- 23091077 TI - Education research: neurology training reassessed. The 2011 American Academy of Neurology Resident Survey results. AB - OBJECTIVE: To assess the strengths and weaknesses of neurology resident education using survey methodology. METHODS: A 27-question survey was sent to all neurology residents completing residency training in the United States in 2011. RESULTS: Of eligible respondents, 49.8% of residents returned the survey. Most residents believed previously instituted duty hour restrictions had a positive impact on resident quality of life without impacting patient care. Most residents rated their faculty and clinical didactics favorably. However, many residents reported suboptimal preparation in basic neuroscience and practice management issues. Most residents (71%) noted that the Residency In-service Training Examination (RITE) assisted in self-study. A minority of residents (14%) reported that the RITE scores were used for reasons other than self-study. The vast majority (86%) of residents will enter fellowship training following residency and were satisfied with the fellowship offers they received. CONCLUSIONS: Graduating residents had largely favorable neurology training experiences. Several common deficiencies include education in basic neuroscience and clinical practice management. Importantly, prior changes to duty hours did not negatively affect the resident perception of neurology residency training. PMID- 23091078 TI - Clinical features of Parkinson disease when onset of diabetes came first: a case control study. PMID- 23091079 TI - Clinical reasoning: a 55-year-old woman with vertigo. A dizzying conundrum. PMID- 23091080 TI - Teaching NeuroImages: alternating ptosis and Marcus Gunn jaw-winking phenomenon with PHOX2B mutation. PMID- 23091081 TI - Teaching NeuroImages: dorsal midbrain (Parinaud) syndrome with corectopia. PMID- 23091082 TI - Ca(2+) entry through TRP-C channels regulates fibroblast biology in chronic atrial fibrillation. PMID- 23091083 TI - Na(+) channel I-II loop mediates parallel genetic and phosphorylation-dependent gating changes. PMID- 23091084 TI - Trends in antihypertensive medication use and blood pressure control among United States adults with hypertension: the National Health And Nutrition Examination Survey, 2001 to 2010. AB - BACKGROUND: The monitoring of national trends in hypertension treatment and control can provide important insight into the effectiveness of primary prevention efforts for cardiovascular disease. The objective of this study was to examine recent trends in antihypertensive medication use and its impact on blood pressure control among US adults with hypertension. METHODS AND RESULTS: A total of 9320 hypertensive people aged >=18 years from the National Health and Nutrition Examination Survey 2001 to 2010 were included in this study. The prevalence of antihypertensive medication use increased from 63.5% in 2001 to 2002 to 77.3% in 2009 to 2010 (P(trend)<0.01). Most notably, there was a large increase in the use of multiple antihypertensive agents (from 36.8% to 47.7%, P(trend)<0.01). Overall, the use of thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers increased by 23%, 57%, 31%, and 100%, respectively. In comparison with monotherapy, single-pill combinations and multiple-pill combinations were associated with 55% and 26% increased likelihoods of blood pressure control, respectively. By the 2009 to 2010 time period, 47% of all hypertensive people and 60% of treated hypertensive people had blood pressure controlled. However, higher treated but uncontrolled hypertension rates continued to persist among older Americans, non-Hispanic blacks, diabetic people, and those with chronic kidney disease. Also, Mexican Americans with hypertension were still less likely to take antihypertensive medication than non-Hispanic whites with hypertension. CONCLUSIONS: Antihypertensive medication use and blood pressure control among US adults with hypertension significantly increased over the past 10 years. Combination therapy regimens can facilitate achievement of blood pressure goals. PMID- 23091086 TI - Optical coherence tomography. PMID- 23091087 TI - Coronary artery fistula after cardiac transplantation. PMID- 23091088 TI - Cardiac tamponade from compression of the pulmonary arterial outflow graft of a biventricular assist device. PMID- 23091090 TI - Letter by Peverill regarding article, "The heart in Friedreich ataxia: definition of cardiomyopathy, disease severity, and correlation with neurological symptoms". PMID- 23091085 TI - New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII). PMID- 23091091 TI - Letter by Mc Loughlin and Mc Loughlin regarding article, "sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men". PMID- 23091092 TI - Letter by Malavazos et al regarding article, "sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men". PMID- 23091093 TI - Letter by Vranckx and Valgimigli regarding article, "validation of the bleeding academic research consortium definition of bleeding in patients with coronary artery disease undergoing percutaneous coronary intervention". PMID- 23091094 TI - Breeding strategies for forage and grass improvement. PMID- 23091095 TI - The production of a key floral volatile is dependent on UV light in a sexually deceptive orchid. AB - BACKGROUND AND AIMS: Plants use a diverse range of visual and olfactory cues to advertize to pollinators. Australian Chiloglottis orchids employ one to three related chemical variants, all 2,5-dialkylcyclohexane-1,3-diones or 'chiloglottones' to sexually attract their specific male pollinators. Here an investigation was made of the physiological aspects of chiloglottone synthesis and storage that have not previously been examined. METHODS: The location of chiloglottone production was determined and developmental and diurnal changes by GC-MS analysis of floral tissue extracts was monitored in two distantly related Chiloglottis species. Light treatment experiments were also performed using depleted flowers to evaluate if sunlight is required for chiloglottone production; which specific wavelengths of light are required was also determined. KEY RESULTS: Chiloglottone production only occurs in specific floral tissues (the labellum calli and sepals) of open flowers. Upon flower opening chiloglottone production is rapid and levels remain more or less stable both day and night, and over the 2- to 3-week lifetime of the flower. Furthermore, it was determined that chiloglottone production requires continuous sunlight, and determined the optimal wavelengths of sunlight in the UV-B range (with peak of 300 nm). CONCLUSIONS: UV B light is required for the synthesis of chiloglottones - the semiochemicals used by Chiloglottis orchids to sexually lure their male pollinators. This discovery appears to be the first case to our knowledge where plant floral odour production depends on UV-B radiation at normal levels of sunlight. In the future, identification of the genes and enzymes involved, will allow us to understand better the role of UV-B light in the biosynthesis of chiloglottones. PMID- 23091096 TI - Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. AB - PURPOSE: Chemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome. PATIENTS AND METHODS: This was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750*10(6)/L and a platelet count greater than 75*10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734). RESULTS: Five hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar. CONCLUSION: For localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity. PMID- 23091097 TI - Biallelic ATM inactivation significantly reduces survival in patients treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 trial. AB - PURPOSE: The prognostic significance of ATM mutations in chronic lymphocytic leukemia (CLL) is unclear. We assessed their impact in the context of a prospective randomized trial. PATIENTS AND METHODS: We analyzed the ATM gene in 224 patients treated on the Leukemia Research Fund Chronic Lymphocytic Leukemia 4 (LRF-CLL4) trial with chlorambucil or fludarabine with and without cyclophosphamide. ATM status was analyzed by denaturing high-performance liquid chromatography and was related to treatment response, survival, and the impact of TP53 alterations for the same patient cohort. RESULTS: We identified 36 ATM mutations in 33 tumors, 16 with and 17 without 11q deletion. Mutations were associated with advanced disease stage and involvement of multiple lymphoid sites. Patients with both ATM mutation and 11q deletion showed significantly reduced progression-free survival (median, 7.4 months) compared with those with ATM wild type (28.6 months), 11q deletion alone (17.1 months), or ATM mutation alone (30.8 months), but survival was similar to that in patients with monoallelic (6.7 months) or biallelic (3.4 months) TP53 alterations. This effect was independent of treatment, immunoglobulin heavy chain variable gene (IGHV) status, age, sex, or disease stage. Overall survival for patients with biallelic ATM alterations was also significantly reduced compared with those with ATM wild type or ATM mutation alone (median, 42.2 v 85.5 v 77.6 months, respectively). CONCLUSION: The combination of 11q deletion and ATM mutation in CLL is associated with significantly shorter progression-free and overall survival following first line treatment with alkylating agents and purine analogs. Assessment of ATM mutation status in patients with 11q deletion may influence the choice of subsequent therapy. PMID- 23091098 TI - Incidence of HIV-related anal cancer remains increased despite long-term combined antiretroviral treatment: results from the french hospital database on HIV. AB - PURPOSE: To study recent trends in the incidence of anal cancer in HIV-infected patients receiving long-term combined antiretroviral treatment (cART) compared with the general population. PATIENTS AND METHODS: From the French Hospital Database on HIV, we identified 263 cases of invasive anal squamous cell carcinoma confirmed histologically between 1992 and 2008. We compared incidence rates of anal cancer across four calendar periods: 1992-1996 (pre-cART period), 1997-2000 (early cART period), and 2001-2004 and 2005-2008 (recent cART periods). Standardized incidence ratios (SIRs) were calculated by using general population incidence data from the French Network of Cancer Registries. RESULTS: In HIV infected patients, the hazard ratio (HR) in the cART periods versus the pre-cART period was 2.5 (95% CI, 1.28 to 4.98). No difference was observed across the cART calendar periods (HR, 0.9; 95% CI, 0.6 to 1.3). In 2005-2008, HIV-infected patients compared with the general population had an excess risk of anal cancer, with SIRs of 109.8 (95% CI, 84.6 to 140.3), 49.2 (95% CI, 33.2 to 70.3), and 13.1 (95% CI, 6.8 to 22.8) for men who have sex with men (MSM), other men, and women, respectively. Among patients with CD4 cell counts above 500/MUL for at least 2 years, SIRs were 67.5 (95% CI, 41.2 to 104.3) when the CD4 nadir was less than 200/MUL for more than 2 years and 24.5 (95% CI, 17.1 to 34.1) when the CD4 nadir was more than 200/MUL. CONCLUSION: Relative to that in the general population, the risk of anal cancer in HIV-infected patients is still extremely high, even in patients with high current CD4 cell counts. cART appears to have no preventive effect on anal cancer, particularly in MSM. PMID- 23091099 TI - Predictors of early death risk in older patients treated with first-line chemotherapy for cancer and the importance of geriatric assessment. PMID- 23091100 TI - Yield of screening for long-term complications using the children's oncology group long-term follow-up guidelines. AB - PURPOSE: The Children's Oncology Group Long-Term Follow-Up (COG-LTFU) Guidelines use consensus-based recommendations for exposure-driven, risk-based screening for early detection of long-term complications in childhood cancer survivors. However, the yield from these recommendations is not known. METHODS: Survivors underwent COG-LTFU Guideline-directed screening. Yield was classified as negligible/negative (< 1%), intermediate (>= 1% to < 10%), or high (>= 10%). For long-term complications with high yield, logistic regression was used to identify subgroups more likely to screen positive. RESULTS: Over the course of 1,188 clinic visits, 370 childhood cancer survivors (53% male; 47% Hispanic; 69% leukemia/lymphoma survivors; median age at diagnosis, 11.1 years [range, 0.3 to 21.9 years]; time from diagnosis, 10.5 years [range, 5 to 55.8 years]) underwent 4,992 screening tests. High-yield tests included thyroid function (hypothyroidism, 10.1%), audiometry (hearing loss, 22.6%), dual-energy x-ray absorptiometry scans (low bone mineral density [BMD], 23.2%), serum ferritin (iron overload, 24.0%), and pulmonary function testing/chest x-ray (pulmonary dysfunction, 84.1%). Regression analysis failed to identify subgroups more likely to result in high screening yield, with the exception of low BMD (2.5-fold increased risk for males [P = .04]; 3.3-fold increased risk for nonobese survivors [P = .01]). Screening tests with negligible/negative (< 1%) yield included complete blood counts (therapy-related leukemia), dipstick urinalysis for proteinuria and serum blood urea nitrogen/creatinine (glomerular defects), microscopic urinalysis for hematuria (hemorrhagic cystitis, bladder cancer), ECG (anthracycline-related conduction disorder), and hepatitis B and HIV serology. CONCLUSION: Screening tests with a high yield are appropriate for risk groups targeted for screening by the COG-LTFU Guidelines. Elimination of screening tests with negligible/negative yield should be given consideration. PMID- 23091102 TI - When hope hinders science and patient-centered care. PMID- 23091101 TI - Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. AB - PURPOSE: The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. PATIENTS AND METHODS: In total, 477 patients with CD20(+) DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. RESULTS: After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). CONCLUSION: In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT. PMID- 23091103 TI - Patterns of use and short-term complications of breast brachytherapy in the national medicare population from 2008-2009. AB - PURPOSE: Brachytherapy has disseminated into clinical practice as an alternative to whole-breast irradiation (WBI) for early-stage breast cancer; however, current national treatment patterns and associated complications remain unknown. PATIENTS AND METHODS: We constructed a national sample of Medicare beneficiaries ages 66 to 94 years who underwent breast-conserving surgery from 2008 to 2009 and were treated with brachytherapy or WBI. We used hospital referral regions (HRRs) to assess national treatment variation and an instrumental variable analysis to compare complication rates between treatment groups, adjusting for patient and clinical characteristics. We compared overall, wound and skin, and deep-tissue and bone complications between brachytherapy and WBI at 1 year of follow-up. RESULTS: Of 29,648 women in our sample, 4,671 (15.8%) received brachytherapy. The percent of patients receiving brachytherapy varied substantially across HRRs, ranging from 0% to over 70% (interquartile range, 7.5% to 23.3%). Of women treated with brachytherapy, 34.3% had a complication compared with 27.3% of women undergoing WBI (P < .001). After adjusting for patient and clinical characteristics, 35.2% of women treated with brachytherapy (95% CI, 28.6 to 41.9) had a complication compared with 18.4% treated with WBI (95% CI, 15.5 to 21.3; P value for difference, <.001). Brachytherapy was associated with a 16.9% higher rate of wound and skin complications compared with WBI (95% CI, 10.0 to 23.9; P < .001), but there was no difference in deep-tissue and bone complications. CONCLUSION: Brachytherapy is commonly used among Medicare beneficiaries and varies substantially across regions. After 1 year, wound and skin complications were significantly higher among women receiving brachytherapy compared with those receiving WBI. PMID- 23091104 TI - Frequency of triple-negative breast cancer in BRCA1 mutation carriers: comparison between common Ashkenazi Jewish and other mutations. PMID- 23091105 TI - New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. AB - PURPOSE: To identify the criteria for hematologic and cardiac response to treatment in immunoglobulin light chain (AL) amyloidosis based on survival analysis of a large patient population. PATIENTS AND METHODS: We gathered for analysis 816 patients with AL amyloidosis from seven referral centers in the European Union and the United States. A different cohort of 374 patients prospectively evaluated at the Pavia Amyloidosis Research and Treatment Center was used for validation. Data was available for all patients before and 3 and/or 6 months after initiation of first-line therapy. The prognostic relevance of different criteria for hematologic and cardiac response was assessed. RESULTS: There was a strong correlation between the extent of reduction of amyloidogenic free light chains (FLCs) and improvement in survival. This allowed the identification of four levels of response: amyloid complete response (normal FLC ratio and negative serum and urine immunofixation), very good partial response (difference between involved and uninvolved FLCs [dFLC] < 40 mg/L), partial response (dFLC decrease > 50%), and no response. Cardiac involvement is the major determinant of survival, and changes in cardiac function after therapy can be reliably assessed using the cardiac biomarker N-terminal natriuretic peptide type B (NT-proBNP). Changes in FLC and NT-proBNP predicted survival as early as 3 months after treatment initiation. CONCLUSION: This study identifies and validates new criteria for response to first-line treatment in AL amyloidosis, based on their association with survival in large patient populations, and offers surrogate end points for clinical trials. PMID- 23091106 TI - Risks of less common cancers in proven mutation carriers with lynch syndrome. AB - PURPOSE: Patients with Lynch syndrome are at high risk for colon and endometrial cancer, but also at an elevated risk for other less common cancers. The purpose of this retrospective cohort study was to provide risk estimates for these less common cancers in proven carriers of pathogenic mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6. PATIENTS AND METHODS: Data were pooled from the German and Dutch national Lynch syndrome registries. Seven different cancer types were analyzed: stomach, small bowel, urinary bladder, other urothelial, breast, ovarian, and prostate cancer. Age-, sex- and MMR gene-specific cumulative risks (CRs) were calculated using the Kaplan-Meier method. Sex-specific incidence rates were compared with general population incidence rates by calculating standardized incidence ratios (SIRs). Multivariate Cox regression analysis was used to estimate the impact of sex and mutated gene on cancer risk. RESULTS: The cohort comprised 2,118 MMR gene mutation carriers (MLH1, n = 806; MSH2, n = 1,004; MSH6, n = 308). All cancers were significantly more frequent than in the general population. The highest risks were found for male small bowel cancer (SIR, 251; 95% CI, 177 to 346; CR at 70 years, 12.0; 95% CI, 5.7 to 18.2). Breast cancer showed an SIR of 1.9 (95% CI, 1.4 to 2.4) and a CR of 14.4 (95% CI, 9.5 to 19.3). MSH2 mutation carriers had a considerably higher risk of developing urothelial cancer than MLH1 or MSH6 carriers. CONCLUSION: The sex- and gene-specific differences of less common cancer risks should be taken into account in cancer surveillance and prevention programs for patients with Lynch syndrome. PMID- 23091107 TI - Research participants' high expectations of benefit in early-phase oncology trials: are we asking the right question? AB - PURPOSE: To determine whether patients' expectations of benefit in early-phase oncology trials depend on how patients are queried and to explore whether expectations are associated with patient characteristics. PATIENTS AND METHODS: Participants were 171 patients in phase I or II oncology trials in the United States. After providing informed consent for a trial but before receiving the investigational therapy, participants answered questions about expectations of benefit. We randomly assigned participants to one of three groups corresponding to three queries about expectations: frequency type, belief type, or both. Main outcomes were differences in expectations by question type and the extent to which expectations were associated with demographic characteristics, numeracy, dispositional optimism, religiousness/spirituality, understanding of research, and other measures. RESULTS: The belief-type group had a higher mean expectation of benefit (64.4 of 100) than the combination group (51.6; P = .01) and the frequency-type group (43.1; P < .001). Mean expectations in the combination and frequency groups were not significantly different (P = .06). Belief-type expectations were associated with a preference for nonquantitative information (r = -0.19; 95% CI, -0.19 to -0.36), knowledge about research (r = -0.21; 95% CI, 0.38 to -0.03), dispositional optimism (r = 0.20; 95% CI, 0.01 to 0.37), and spirituality (r = 0.22; 95% CI, 0.03 to 0.38). Frequency-type expectations were associated with knowledge about clinical research (r = -0.27; 95% CI, -0.27 to 0.51). CONCLUSION: In early-phase oncology trials, patients' reported expectations of benefit differed according to how patients were queried and were associated with patient characteristics. These findings have implications for how informed consent is obtained and assessed. PMID- 23091109 TI - Randomized phase II study of bortezomib, thalidomide, and dexamethasone with or without cyclophosphamide as induction therapy in previously untreated multiple myeloma. AB - PURPOSE: Bortezomib-thalidomide-dexamethasone (VTD) is an effective induction therapy in multiple myeloma (MM). This phase II, noncomparative study sought to determine whether addition of cyclophosphamide to this regimen (VTDC) could further increase efficacy without compromising safety. PATIENTS AND METHODS: Patients age 18 to 70 years with previously untreated, measurable MM, who were eligible for high-dose chemotherapy-autologous stem-cell transplantation (HDCT ASCT), were randomly assigned to bortezomib 1.3 mg/m(2), thalidomide 100 mg, and dexamethasone 40 mg, with (n = 49) or without (n = 49) cyclophosphamide 400 mg/m(2) for four 21-day cycles, followed by HDCT-ASCT. The primary end point was postinduction combined rate of near-complete response (nCR) or better (including complete response [CR] with normalized serum kappa:lambda free light chain ratio, CR, and nCR). RESULTS: Postinduction, 51% (VTD) and 44% (VTDC) of patients achieved combined CR/nCR, with bone marrow-confirmed CR in 29% and 31%, overall response rates of 100% and 96%, respectively, and very good partial response or better rates of 69% per arm. Post-HDCT-ASCT, combined CR/nCR rates were 85% (VTD) and 77% (VTDC). In all, 35% (VTD) and 27% (VTDC) of patients were negative for minimal residual disease (MRD) during induction and postinduction. Three-year overall survival was 80% (both arms). Grade 3 to 4 adverse events (AEs) and serious AEs were observed in 47% and 22% (VTD) and 57% and 41% (VTDC) of patients, respectively. The primary health-related quality of life end point (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30] Global Health score) steadily increased with VTD during induction and reached a clinically relevant difference post transplantation versus baseline. CONCLUSION: Both VTD and VTDC are highly active induction regimens producing high combined CR/nCR and MRD-negative rates; however, VTDC was associated with increased toxicity and suggestion of transient decreases in Global Health score, without an increase in activity. PMID- 23091108 TI - Tamoxifen use in postmenopausal breast cancer: CYP2D6 matters. PMID- 23091110 TI - Airborne emissions of carcinogens and respiratory sensitizers during thermal processing of plastics. AB - OBJECTIVES: Thermoplastics may contain a wide range of additives and free monomers, which themselves may be hazardous substances. Laboratory studies have shown that the thermal decomposition products of common plastics can include a number of carcinogens and respiratory sensitizers, but very little information exists on the airborne contaminants generated during actual industrial processing. The aim of this work was to identify airborne emissions during thermal processing of plastics in real-life, practical applications. METHODS: Static air sampling was conducted at 10 industrial premises carrying out compounding or a range of processes such as extrusion, blown film manufacture, vacuum thermoforming, injection moulding, blow moulding, and hot wire cutting. Plastics being processed included polyvinyl chloride, polythene, polypropylene, polyethylene terephthalate, and acrylonitrile-butadiene-styrene. At each site, static sampling for a wide range of contaminants was carried out at locations immediately adjacent to the prominent fume-generating processes. RESULTS: The monitoring data indicated the presence of few carcinogens at extremely low concentrations, all less than 1% of their respective WEL (Workplace Exposure Limit). No respiratory sensitizers were detected at any sites. CONCLUSIONS: The low levels of process-related fume detected show that the control strategies, which employed mainly forced mechanical general ventilation and good process temperature control, were adequate to control the risks associated with exposure to process-related fume. This substantiates the advice given in the Health and Safety Executive's information sheet No 13, 'Controlling Fume During Plastics Processing', and its broad applicability in plastics processing in general. PMID- 23091111 TI - Occupational trichloroethylene exposure and cervical pathology: a case-control study. AB - OBJECTIVES: Trichloroethylene (TCE) is suspected of association with elevated risk of cervical cancer. A case-control study was performed in a geographical area in which occupational TCE exposure is high. The study objective was to analyze the correlation between occupational TCE exposure and cervical cancer (including precancerous conditions). METHODS: Case and control subjects were recruited by gynecologists. General and occupational data were collected by telephonic interviews. An industrial hygienist assessed occupational TCE exposure on a task-exposure matrix. Analysis focused on occupational TCE exposure at various levels and on cumulative dose. Multivariate analysis was performed to take account of the various risk factors. RESULTS: In total, 67 case and 67 age matched control subjects were included. Mean age was 36 years in both groups. Five of the possible general risk factors correlated significantly with cervical dysplasia or cancer: number of partners, history of genital or anal wart, interval between first period and first sexual relation, parity, and body mass index, the last three showing inverse correlation. Elevated risk was found in women who had had jobs as manual workers according to the PCS French classification (professions and socioprofessional categories), and production and related workers according to ISCO classification (International Standard Classification of Occupations), with odds ratios (ORs), adjusted on general and medical risk factors, of 7.68 [95% confidence interval (CI): 1.39-42.54] and 7.48 (1.30-43.24), respectively, among skilled service sector workers; the adjusted OR was close to significance, at 4.67 (95% CI: 0.92-23.67). No occupational sectors were significantly associated with elevated risk. In all, 17 (25.4%) case and 15 (22.4%) control subjects were exposed to TCE: raw OR = 1.17 (95% CI: 0.54-2.52), adjusted OR = 1.51 (95% CI: 0.42-5.41). There was no significant correlation between cumulative dose and exposure time. CONCLUSIONS: The study found no significantly increased risk of cervical dysplasia or cancer associated with occupational TCE exposure. PMID- 23091112 TI - Environmental and biological monitoring of platinum-containing drugs in two hospital pharmacies using positive air pressure isolators. AB - Environmental and biological monitoring of platinum containing drugs was implemented in two French hospital pharmacies using positive air pressure isolators and having similar working procedures when preparing antineoplastic drugs. Wipe sampling of surfaces, gloves, and vials was performed in the preparation room and in storage areas. All employees involved in the preparation of antineoplastic drugs were tested for urinary platinum on Monday before work and Friday after shift. Only traces of platinum were detected on surfaces in the preparation room outside the isolators (less than 1.61 pg cm(-2)). However, in one center, significant contamination was found in the storage area of the drug vials, which can most likely be linked to the rupture of a platinum vial and due to inefficient cleaning procedures. Surfaces inside the isolators were found to be contaminated (maximum: 198.4 pg cm(-2)). A higher level of contamination was detected in one pharmacy and could be explained by the lack of overgloving with regular changes during the preparation process. Nitrile gloves used during drug handling outside the isolator showed the highest platinum concentration (maximum: 5.86 ng per pair). With regards to platinum urine concentration, no significant difference was found between exposed and unexposed pharmacy personnel. Isolator technology combined with individual protective measures seems to be efficient to protect workers from occupational exposure to antineoplastic drugs, whereas specific individual protective procedures implemented were focussing on the risk of handling vials outside the isolator (e.g. high frequency of glove changing). Moreover, overgloving inside the isolator would contribute to substantially decrease inner surface contamination and should be recommended in order to limit the transfer of chemical contamination to the end products. PMID- 23091113 TI - A novel therapeutic regimen to eradicate established solid tumors with an effective induction of tumor-specific immunity. AB - PURPOSE: The efficacy of oncolytic viruses depends on multiple actions including direct tumor lysis, modulation of tumor perfusion, and stimulation of tumor directed immune responses. In this study, we investigated whether a sequential combination of immunologically distinct viruses might enhance antitumor efficacy through the induction of tumor-specific immunity and circumvention or mitigation of antiviral immune responses. EXPERIMENTAL DESIGN: The Syrian hamster as an immune-competent model that supports replication of both adenovirus and vaccinia virus was evaluated in vitro and in vivo. The antitumor efficacy of either virus alone or sequential combination of the two viruses was examined in pancreatic and kidney cancer models. The functional mechanism of the regimen developed here was investigated by histopathology, immunohistochemistry staining, CTL assay, and T cell depletion. RESULTS: The Syrian hamster is a suitable model for assessment of oncolytic adenovirus and vaccinia virus. Three low doses of adenovirus followed by three low doses of vaccinia virus resulted in a superior antitumor efficacy to the reverse combination, or six doses of either virus alone, against pancreatic and kidney tumors in Syrian hamsters. A total of 62.5% of animals bearing either tumor type treated with the sequential combination became tumor-free, accompanied by the induction of effective tumor-specific immunity. This enhanced efficacy was ablated by CD3+ T-cell depletion but was not associated with humoral immunity against the viruses. CONCLUSION: These findings show that sequential treatment of tumors with oncolytic adenovirus and vaccinia virus is a promising approach for cancer therapy and that T-cell responses play a critical role. PMID- 23091114 TI - HER2-associated radioresistance of breast cancer stem cells isolated from HER2 negative breast cancer cells. AB - PURPOSE: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2(-/low) breast cancers. EXPERIMENTAL DESIGN: HER2 expressing BCSCs (HER2(+)/CD44(+)/CD24(-/low)) were isolated from radiation treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24( /low) BCSCs was conducted with two-dimensional difference gel electrophoresis (2 D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. RESULTS: Compared with HER2-negative BCSCs, HER2(+)/CD44(+)/CD24(-/low) cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2(+)/CD44(+)/CD24(-/low) cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/MS-MS of HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. CONCLUSION: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy resistant HER2(-/low) breast cancer. PMID- 23091116 TI - Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer? AB - The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte colony stimulating factor support. PMID- 23091115 TI - An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance. AB - PURPOSE: Epithelial-mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non-small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study. EXPERIMENTAL DESIGN: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified. RESULTS: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI 7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies. CONCLUSION: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype. PMID- 23091117 TI - Sequence dependence of MEK inhibitor AZD6244 combined with gemcitabine for the treatment of biliary cancer. AB - PURPOSE: MEK inhibition has clinical activity against biliary cancers and might therefore be successfully combined with gemcitabine, one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the extracellular signal-regulated kinase (ERK) pathway has a major role driving cell-cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 using a series of biliary cancer models. EXPERIMENTAL DESIGN: Primary xenografts were established from patients with gallbladder and distal bile duct cancer and grown in severe combined immunodeficient (SCID) mice at the subcutaneous site. Plasma and tumor drug levels and the time course for recovery of ERK signaling and S-phase were measured in tumor-bearing mice treated for 48 hours with AZD6244 and then monitored for 48 hours off treatment. On the basis of these results, two different treatment schedules combining AZD6244 with gemcitabine were tested in four different biliary cancer models. RESULTS: DNA synthesis was suppressed during treatment with AZD6244, and reentry into S-phase was delayed by approximately 48 hours after treatment. Strong schedule dependence was seen in all four biliary cancer models tested, suggesting that combined treatment with AZD6244 plus gemcitabine would be more active in patients with biliary cancer when gemcitabine is given following a 48-hour interruption in AZD6244 dosing, rather than concurrently. CONCLUSIONS: The combination of AZD6244 plus gemcitabine is highly schedule dependent, and predicted to be more effective in the clinic using sequential rather than simultaneous dosing protocols. PMID- 23091119 TI - Cerebrovascular reserve and stroke risk in patients with carotid stenosis or occlusion: a systematic review and meta-analysis. AB - BACKGROUND AND PURPOSE: Impairments in cerebrovascular reserve (CVR) have been variably associated with increased risk of ischemic events and may stratify stroke risk in patients with high-grade internal carotid artery stenosis or occlusion. The purpose of this study is to perform a systematic review and meta analysis to summarize the association of CVR impairment and stroke risk. METHODS: We performed a literature search evaluating the association of impairments in CVR with future stroke or transient ischemic attack in patients with high-grade internal carotid artery stenosis or occlusion. We included studies with a minimum of 1-year patient follow-up with baseline CVR measures performed by any modality and primary outcome measures of stroke and/or transient ischemic attack. A meta analysis with assessment of study heterogeneity and publication bias was performed. Results were presented in a forest plot and summarized using a random effects model. RESULTS: Thirteen studies met the inclusion criteria, representing a total of 1061 independent CVR tests in 991 unique patients with a mean follow up of 32.7 months. We found a significant positive relationship between impairment of CVR and development of stroke with a pooled random effects OR of 3.86 (95% CI, 1.99-7.48). Subset analysis showed that this association between CVR impairment and future risk of stroke/transient ischemic attack remained significant regardless of ischemic outcome measure, symptomatic or asymptomatic disease, stenosis or occlusion, or CVR testing method. CONCLUSIONS: CVR impairment is strongly associated with increased risk of ischemic events in carotid stenosis or occlusion and may be useful for stroke risk stratification. PMID- 23091120 TI - Persistent hemodynamic changes in ruptured brain arteriovenous malformations. AB - BACKGROUND AND PURPOSE: Hemodynamic properties of brain arteriovenous malformations (AVMs) with risk factors for a future hemorrhage are essentially unknown. We hypothesized that AVMs with anatomic properties, which are associated with an increased rupture risk, exhibit different hemodynamic characteristics than those without these properties. METHODS: Seventy-two consecutive patients with AVMs diagnosed by conventional angiography underwent MRI examination, including time-resolved 3-dimensional MR angiography. Signal-intensity curves derived from the time-resolved 3-dimensional MR angiography datasets were used to calculate relative blood flow transit times through the AVM nidus based on the time-to-peak parameter. For identification of characteristics associated with altered transit times, a multiple normal regression model was fitted with stepwise selection of the following regressors: intracranial hemorrhage, deep nidus location, infratentorial location, deep drainage, associated aneurysm, nidus size, draining venous stenosis, and number of draining veins. RESULTS: A previous intracranial hemorrhage is the only characteristic that was associated with a significant alteration of the relative transit time, leading to an increase of 2.4 seconds (95% CI, 1.2-3.6 seconds;, P<0.001) without adjustment and 2.1 seconds (95% CI, 0.6-3.6 seconds; P=0.007) with adjustment for all other regressors considered. The association was independent of the bleeding age. CONCLUSIONS: Hemodynamic parameters do not seem useful for risk assessment of an AVM-related hemorrhage because only a previous AVM rupture leads to a significant and permanent alteration of the hemodynamic situation. PMID- 23091121 TI - Multivoxel MR spectroscopy in acute ischemic stroke: comparison to the stroke protocol MRI. AB - BACKGROUND AND PURPOSE: Few patients with stroke have been imaged with MR spectroscopy (MRS) within the first few hours after onset. We compared data from current MRI protocols to MRS in subjects with ischemic stroke. METHODS: MRS was incorporated into the standard clinical MRI stroke protocol for subjects <24 hours after onset. MRI and clinical correlates for the metabolic data from MRS were sought. RESULTS: One hundred thirty-six MRS voxels from 32 subjects were analyzed. Lactate preceded the appearance of the lesion on diffusion-weighted imaging in some voxels but in others lagged behind it. Current protocols may predict up to 41% of the variance of MRS metabolites. Serum glucose concentration and time to maximum partially predicted the concentration of all major metabolites. CONCLUSIONS: MRS may be helpful in acute stroke, especially for lactate detection when perfusion-weighted imaging is unavailable. Current MRI protocols do provide surrogate markers for some indices of metabolic activity. PMID- 23091122 TI - Assessment of cortical hemodynamics by multichannel near-infrared spectroscopy in steno-occlusive disease of the middle cerebral artery. AB - BACKGROUND AND PURPOSE: In a pilot study we evaluated near-infrared spectroscopy as to its potential benefit in monitoring patients with steno-occlusive disease of a major cerebral artery for alterations in cortical hemodynamics. METHODS: Cortical maps of time-to-peak (TTP) in 10 patients unilaterally affected by severe stenosis or occlusion of the middle cerebral artery were acquired by multichannel near-infrared spectroscopy after bolus application of indocyanine green. Hemodynamic manifestations were assessed by comparison between affected and unaffected hemisphere and evaluated for common constituents by principal component analysis. In one patient, TTP values were compared with those obtained by dynamic susceptibility contrast imaging. RESULTS: TTP was increased on the affected hemisphere in 9 patients. Mean difference in TTP between hemispheres was 0.44 second (P<0.05) as compared with a mean lateral difference of 0.12 second found in a control group of 10 individuals. In group analysis a significant rise in TTP was found in the distribution of the affected middle cerebral artery, whereas principal component analysis suggests augmentation of hemodynamic effects toward the border zones as a dominant pattern. A linear correlation of 0.61 between TTP values determined by dynamic susceptibility contrast MRI and near infrared spectroscopy was found to be statistically significant (P<0.001). CONCLUSIONS: Multichannel near-infrared spectroscopy might facilitate detection of disease-related hemodynamic changes as yet only accessible by tomographic imaging modalities. Being indicative for hypoperfusion and collateral flow increased values of TTP, as found to a varying extent in the present patient group, might be of clinical relevance. PMID- 23091124 TI - Letter by Meves and Neubauer regarding article "Clinical outcomes using a platelet function-guided approach for secondary prevention in patients with ischemic stroke or transient ischemic attack". PMID- 23091125 TI - Polyphasic characterization of Salmonella Enteritidis isolates on persistently contaminated layer farms during the implementation of a national control program with obligatory vaccination: a longitudinal study. AB - Since 2007, a national Salmonella control program including obligatory vaccination has been ongoing in Belgium. In this context, the aim of the present study was to investigate the diversity of Salmonella enterica serovar Enteritidis isolates on 5 persistently contaminated Belgian layer farms and to examine the potential sources and transmission routes of Salmonella Enteritidis contamination on the farms during successive laying rounds. A collection of 346 Salmonella isolates originating from the sampled farms were characterized using a combination of multilocus variable number of tandem repeat analysis (MLVA) and phage typing (PT). On each farm, one or 2 dominant MLVA-PT types were found during successive laying cycles. The dominant MLVA type was different for each of the individual farms, but some farms shared the same dominant phage type. Isolates recovered from hens' feces and ceca, egg contents, eggshells, vermin (mice, rats, red mites, and flies), and pets (dog and cat feces) had the same MLVA-PT type also found in the inside henhouse environment of the respective layer farm. Persistent types were identified in the layer farm inside environment (henhouse and egg collecting area). Furthermore, this study demonstrated cross contamination of Salmonella between henhouses and between the henhouse and the egg collecting area. Additional isolates with a different MLVA-PT type were also recovered, mainly from the egg collecting area. A potential risk for cross contamination of Salmonella between the individual layer farms and their egg trader was identified. PMID- 23091126 TI - The morphological, material-level, and ash properties of turkey femurs from 3 different genetic strains during production. AB - Femoral fractures are observed in selective-bred commercial turkeys; however, the etiology of such fractures is unknown. The current study investigated the whole bone morphological, material-level mechanical, and bone ash properties to determine the effect of selective breeding on bone strength. Femora from 3 divergent strains of turkeys, a commercial line, a different selectively bred heavy line (F-line), and a lighter age or weight matched random-bred line (RBC2/R EQ, respectively), were compared. Bone geometric properties were measured with micro-CT and bone mechanical properties were measured using 3-point bending tests. Whole bone ash quantities were also recorded. Statistics were run using a general linear model multivariate ANOVA (GLM ANOVA). Results showed that at similar ages, the faster growing birds (commercial and F-line) had femurs twice the size of the RBC2 line as measured by cross-sectional area as early as 8 wk into the study. The femurs of the commercial and F-lines also exhibited as much as 20% greater mechanical strength than femurs from the RBC2 line at 16 and 20 wk of age as measured by properties such as elastic modulus and ultimate tensile strength. However, at similar BW, the slower growing R-EQ line had higher mechanical properties than the other lines, with the elastic modulus being 40% greater and the ultimate tensile strength being 37% greater at weights equivalent to those of the commercial and F-lines at 12 wk of age. Moreover, it was observed that the morphological properties (i.e., cross-sectional area, moments of inertia) are largely governed by BW, as there is little difference in the amount gained per week of age across the different lines. Conversely, the mechanical properties, as well as the related ash content, appear to be governed at least in part by time. Therefore, whereas modulation of bone geometry is the key responder for changes in BW, sufficient time for matrix mineralization or maturation or both to occur is also essential for mechanical competence of bone. PMID- 23091127 TI - Antioxidant effects of ovotransferrin and its hydrolysates. AB - Food protein-derived peptides are important components for nutraceuticals, with many biological functions as well as substantial nutritional benefits. The aim of this study was to investigate the antioxidant effects of ovotransferrin (OTF) derived from egg white and its hydrolysates (OH) prepared by hydrolyzing either with acid or enzymes (protamex, alkalase, trypsin, neutrase, flavorzyme, maxazyme, collupulin, protex, promod 278, and alpha-chymotrypsin). All OH showed approximately 3.2 to 13.5 times higher superoxide anion scavenging activity than OTF, with the maximum activity found in the OH-protamex. Similar results were obtained for oxygen radical absorbance capacity assay, with the highest value in OH-alpha-chymotrypsin [1.6 MUM trolox equivalents (TE)] and the lowest value in OTF (0.2 MUM TE). However, OTF showed the most powerful 2,2-diphenyl-2 picrylhydrazyl radical scavenging activity, which reached 78.2% after 36 h of reaction. Both OTF and OH showed protective effects against the oxidative stress induced DNA damages in human leukocytes. Overall, OTF possessed antioxidant abilities and hydrolyzation of OTF with acid or enzymes improved these abilities. PMID- 23091128 TI - Different combinations of probiotics improve the production performance, egg quality, and immune response of layer hens. AB - To evaluate the effects of different combinations of probiotics on performance, egg quality, and immune response of layer hens, a trial was carried out with 1,800 white feather layer hens of the Lohmann variety. The experiment was conducted by using a completely randomized design with 9 treatments, 4 replicates, and 50 hens in each replicate. Compared with the control group, group F, which added a composition of heat-inactivated Lactobacillus salivarius(CB) and Bacillus subtilis to the diets of layer hens, caused highly significant (P < 0.05) increases in egg production, daily egg yield, damaged egg ratio, combined with a significant (P < 0.05) decrease in feed conversion and damaged egg ratio. Group G, adding a combination of inactivated Lactobacillus salivarius and sodium butyrate, resulted in a significant increase (P < 0.05) in daily egg yield, feed conversion, damaged egg ratio and Haugh unit. Meanwhile, groups D and H had significantly decreased feed conversion (P < 0.05), and groups B, H, and I had a significantly decreased damaged egg ratio. In serum levels, no significant difference was observed except a significant decrease (P < 0.05) in total cholesterol (groups D, E, and G) and low-density lipoprotein cholesterol (group E and G) and a significant increase (P < 0.05) in total cholesterol (groups D, E, and G) compared with group A. According to the hemagglutination inhibition test, the antibody titer of antibody against the avian influenza virus was significantly (P < 0.05) higher in most treated groups such as groups B, C, E, G, and I after d 15 fed to layers with probiotics and groups B, C, D, E, F, G, and H after d 45 compared with the control group. No significant difference was observed in the antibody titer against the Newcastle disease virus at d 15, but significantly (P < 0.05) higher at d 45 in groups F and G. These results demonstrate that several combinations of probiotics used in this experiment have a positive impact on the performance, egg quality, and immune response of layer hens, and the following work will continue to focus on these groups. PMID- 23091129 TI - Optimized culturing and nucleic acid-based methods for the detection of Salmonella enterica in poultry environments. AB - The main objective of this trial was to set up a series of assays following quantified inoculation of Salmonella samples in 2 initial enrichment methods to ultimately determine the most effective and fastest detection method for recovery of Salmonella in a poultry environment matrix. Samples were randomly split into 2 different containers containing either buffered peptone water (BPW) + yeast extract, or tetrathionate broth (TT) with added iodine and Brilliant Green solution 0.1%. A frozen stock Salmonella culture was thawed and serially diluted 10-fold to inoculate 100 uL of the dilution into the enriched samples. The samples were incubated at 42 and 37 degrees C, respectively, for 24 h and secondarily enriched in modified semi-solid Rappaport Vassiliadis (MSRV) incubated at 42 degrees C. All samples then were reincubated under the same conditions. After secondary enrichment, the samples were streaked onto Chromogenic agar/ XLT4 bi-plates and incubated under the same conditions. After initial inoculation and each 24-h incubation, a portion of the enriched samples was analyzed using a real-time PCR assay. The results of this trial indicate that recovery of Salmonella in a culture-based assay may be enhanced by up to 3 logs by using the TT as the initial enrichment media compared with BPW. The incorporation of MSRV as a secondary cultural selective media after the TT gave the best recovery of Salmonella. These data indicate that considerable time can be saved by using TT as an initial media for Salmonella recovery. PMID- 23091130 TI - Pinon shell polysaccharide enhances immunity against H9N2 avian influenza virus in chickens. AB - This study investigated the potential of pinon shell polysaccharide (PSP) to enhance immunity against H9N2 subtype avian influenza virus (H9N2 AIV) in chickens. The effect of PSP treatment and H9N2 virus infection after PSP pretreatment were investigated by [3-(4, 5-dimethylthiazol-2-yl)-2, 3-diphenyl tetrazolium bromide] assay and analysis of major histocompatibility complex and cytokine mRNA expression. The in vivo effects on lymphocytes and serum antibody titers were also investigated. The IL-6 expression and antibody titers were enhanced in the first week after PSP treatment. These data indicate that prophylactic PSP administration reduces H9N2 AIV replication and promotes early humoral immune responses in young birds. PMID- 23091131 TI - Survey on tetracycline resistance and antibiotic-resistant genotype of avian Escherichia coli in North China. AB - The experiment was performed to investigate the tetracycline resistance and antibiotic-resistant genotype of avian Escherichia coli in North China and to analyze the correlation of genotype and phenotype. The resistance of 164 E. coli isolates (from Beijing, Tianjin, inner Mongolia, Shanxi, and Hebei regions of China) to tetracycline, doxycycline, and minocycline was investigated by using a drug susceptibility test. The results show that the rate of resistance to tetracycline antibiotics was 89.63% (147/164). The higher resistance rate was 84.76% (139/164) to tetracycline and 70.12% (115/164) to doxycycline, and the lowest resistance rate was 4.88% (8/164) to minocycline. The distribution of tetracycline resistance (Tcr) genes (tetA, tetB, tetC, and tetM) in avian E. coli isolates was detected by PCR. Of the isolates, 82.32% (135/164) carried tetracycline resistance genes. The positive rates of tetA, tetB, and tetM were 57.93% (95/164), 38.41% (63/164), and 10.97% (18/164), respectively. No tetC was amplified in avian E. coli isolates. The total positive rate of resistance genes (82.32%) was almost equal to the total rate of resistance to tetracycline antibiotics (89.63%). Thus, the positive rate of genotype was basically in line with that of phenotype for tetracycline resistance. The tetracycline resistance genes are widely distributed in E. coli and their main resistance mechanism to tetracycline is the active efflux effect mediated by tetA and tetB. PMID- 23091132 TI - Influence of chlorine added to drinking water during the preslaughter feed withdrawal on microbiology and morphology of the broiler gastrointestinal tract. AB - The objective of this experiment was to test the effects of the addition of chlorine to broiler drinking water during a 12-h preslaughter feed withdrawal period on reduction of the quantities of microorganisms, such as Escherichia coli and enterococci, in broiler crops and ceca. Reduction of these microorganisms would likely also reduce contamination of broiler meat by pathogenic bacteria during processing. It was also investigated if the chlorine caused some intestinal damage that could disseminate the microorganisms to the carcass. A total of 40 Cobb male broilers were used. Samples of crop and cecal content were collected for microbiological analysis, and duodenum and jejunum were used for morphological analysis from 10 birds in each treatment. The most probable number (MPN) of E. coli and enterococci in the collected samples of crop and ceca and the measure of the free residual chlorine in water were determined. The scanning electron microscopy from duodenum and jejunum was used to illustrate the mucosa integrity. The chlorine added to water was efficient in reducing the quantities of microorganisms in broiler crops and improved the integrity of the mucosa. Therefore, preslaughter feed withdrawal should be coupled with crop disinfection, because preslaughter feed withdrawal increases the MPN of enterococci and E. coli in broiler crops. So, it presents a higher risk for carcass contamination during slaughterhouse processing and, consequently, a higher risk for public health. PMID- 23091133 TI - Individual and combined effects of Salmonella typhimurium lipopolysaccharide and fumonisin B1 in broiler chickens. AB - The aim of this research was to evaluate the individual and combined effects of Salmonella typhimurium lipopolysaccharide (sLPS) and fumonisin B(1) (FB) on performance, relative weight of liver, biological parameters, and histological evaluation of several tissues from four hundred thirty-two 1-d-old male broiler chickens divided into 9 treatments according to the dose of FB (0, 100, or 200 mg/kg, from d 1 to d 28) and sLPS (0, 250, or 500 ug/application per bird, every other day, from d 15 to 27) administered. At the end of the experiment (28 d), significant effects caused by sLPS, FB, and the interaction of sLPS * FB were observed on several parameters. Histopathological evaluations showed significant lesions in liver and kidney caused by sLPS, FB, and their association. According to these results, both sLPS and FB (isolated or in association) cause significant effects on performance and biological parameters of broilers at 28 d of age. PMID- 23091134 TI - Effects of feeding corn naturally contaminated with aflatoxin B1 and B2 on hepatic functions of broilers. AB - The purpose of this study was to evaluate the effects of feeding corn naturally contaminated with aflatoxin B(1) (AFB(1)) and aflatoxin B(2) (AFB(2)) on serum biochemical parameters, hepatic antioxidant enzyme activities, and pathological lesions of broilers. In total, 1,200 Cobb male broilers were randomly allocated into 5 treatments, with 8 replicates per treatment and 30 birds per replicate, in a 42-d experiment. The dietary treatments were as follows: control, 25, 50, 75, and 100% contaminated corn groups. Results showed that serum aspartate aminotransferase activity in the 75 and 100% contaminated groups were higher than that in the control group on d 21 (P < 0.05). Decreased content of hepatic total protein and increased activities of hepatic glutathione reductase and glutathione S-transferase were observed as the percentage of contaminated corn increased (P < 0.05). The activity of superoxide dismutase and the content of hepatic malondialdehyde increased when the broilers were fed with more than 50% contaminated corn (P < 0.05). A reduction in glutathione peroxidase level was observed in the AFB(1)- and AFB(2)-contaminated groups on d 21 (P < 0.05). The average pathological lesion scores and apoptosis rate of liver cells increased as the concentration of dietary AFB(1) and AFB(2) increased. Ultrastructural changes were found in the livers of broilers fed 100% contaminated corn. In conclusion, diets containing AFB(1) and AFB(2) could induce pathological lesions in the livers, slightly change the serum biochemical parameters, and damage the hepatic antioxidant functions when the inclusion of AFB(1)- and AFB(2)-contaminated corn reached or exceeded 50%. PMID- 23091135 TI - Antiviral activity and mode of action of extracts from neem seed kernel against duck plague virus in vitro1. AB - Four fractions obtained from alcohol extracts of neem (Azadirachta indica) seed kernel by column chromatography were investigated for antivirus activity against the duck plague virus (DPV) in vitro. Duck embryo fibroblasts (DEF) infected with DPV were treated with the neem seed kernel extracts, and the effect of antivirus was judged by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide colorimetric method assay and direct immunofluorescence assay. The mode of action was tested by the plaque reduction assay. The results showed that fractions 1 to 3 were inactive. The median inhibitory concentration (IC(50)) of fraction 4 was 10.9 MUg/mL and inhibited the virus protein expression in the direct immunofluorescence assay. In the plaque reduction assay, fraction 4 could significantly reduce the number of plaques compared with the negative control (P < 0.01) in all modes of action. This study indicated that the fourth fraction obtained from neem seed kernel could improve the viability of infected cells, and reduce the cytopathic effects caused by DPV and the amount of the virus protein expressed in virus-infected cells. The antiviral activity works in the whole process of virus infecting the normal cells. PMID- 23091136 TI - Ivermectin residues in squab. AB - No drugs have been approved for the treatment of parasitic nematodes in pigeons, but ivermectin, a broad-spectrum endectocide, has been used extra-label by prescription. Producers currently allow for a 2-wk withdrawal time before marketing squabs. However, because its use is extra-label there is no legal maximum residue limit for ivermectin in squab meat. The purpose of this study was to examine the depletion of ivermectin (passed by the parents to the squabs) from the tissues of squab. Adult pigeons brooding squab were treated with ivermectin in their drinking water (3.3 ug/mL) for 3 d. After dosing the parents, the ivermectin concentration of the breast meat and liver of squabs was found to be greater than the maximum residual limits established for livestock, indicating that ivermectin was transferred from the parents to the squabs. However, ivermectin was not detected in either the breast meat or the livers of squabs 1 wk after dosing. These results indicate that there is a rapid decline in tissue levels of ivermectin in squab. PMID- 23091137 TI - Mycoplasma infection of ducks and geese. AB - Production of ducks and geese in certain parts of the world is very important. Mycoplasma diseases cause significant losses to the duck and goose industry. This review summarizes the epidemiological, clinical, and pathomorphological characteristics of mycoplasma diseases of ducks and geese and the involvement of the various mycoplasma species in their pathogenesis. The role of mycoplasma infections in the development of clinical signs, pathological lesions, and mortality of challenged birds is demonstrated in challenge experiments. Transmission of mycoplasma in the ovary and eggs resulting in the reduction of egg production and an increase of embryo mortality has been shown in challenge experiments as well as in field studies. The susceptibility of many mycoplasma isolates of the most important mycoplasma species of duck and goose origin were tested and showed relatively high average minimum inhibitory concentrations of lincomycin, tilosin, oxytetracycline, chlortetracycline, and enrofloxacin but not for tiamulin. The successful treatment of mycoplasma infections with antibiotics in ducks and geese should be selected based on the minimum inhibitory concentration values against the mycoplasmas isolated from the flock. PMID- 23091138 TI - Effects of a blend of essential oil compounds and benzoic acid on performance of broiler chickens as revealed by a meta-analysis of 4 growth trials in various locations. AB - A series of growth trials with broiler chicks was conducted in various geographical locations to evaluate the efficacy of a novel eubiotic feed additive (EFA) at various dietary inclusion levels on performance of growing chicks. The EFA product consisted of a blend of essential oil compounds (thymol, eugenol, piperine) with benzoic acid, all belonging to the group of flavoring substances. Although variable in responses, the overall results indicated that 300 mg/kg of this EFA represented an optimum supplementation dose for generation of beneficial performance effects in broilers. A meta-analysis with all data from the 300 mg/kg EFA-supplemented treatments in comparison with the non-supplemented controls revealed that the eubiotic product significantly improved BW on d 21 (+2.0%; P = 0.0021) and on d 42 (+1.4%; P = 0.0151). Furthermore, the birds on the EFA 300 mg/kg treatment expressed a higher average daily gain in the starter phase (d 1 21; +2.1%; P = 0.0023) and over the entire experimental period (d 1-42; +1.5%; P = 0.0154). Feed conversion ratio was more favorable with dietary EFA supplementation (-0.6%; P = 0.0414), when compared with the control birds. Mortality was considered normal and was not affected by the dietary treatment (control = 3.09%; EFA 300 mg/kg = 3.26%). In conclusion, 300 mg/kg of this new eubiotic product demonstrated to effectively improve performance of broiler chicks under various husbandry conditions. PMID- 23091139 TI - Phosphorus utilization in finishing broiler chickens: effects of dietary calcium and microbial phytase. AB - A decrease in dietary P, especially in finishing broilers (21 to 38 d old), is a crucial issue in poultry production from an environmental and economic point of view. Nevertheless, P must be considered together with other dietary components such as Ca and microbial phytase. Different corn and soybean meal-based diets varying in Ca [low (LCa) 0.37, medium (MCa) 0.57, and high (HCa) 0.77%], and nonphytate P [nPP; low (LnPP) 0.18 and high (HnPP) 0.32%] content were tested with and without microbial phytase [0 or 500 phytase units (FTU)/kg]. Feed intake, BW gain, bone mineralization, and mineral retention were examined in 144 Ross PM3 broilers (22 to 38 d old) reared in individual cages. Growth performance was not significantly affected by the treatments. Nevertheless, a numerical decrease of ADG and ADFI was observed in HCa-LnPP and LCa-HnPP associated with an increase of feed conversion ratio. Decreased dietary Ca reduced tibia ash content (Ca, linear: P < 0.001; quadratic: P = 0.034) and tibia ash weight for the highest level of nPP (Ca * nPP; P = 0.035). In parallel, increasing dietary Ca reduced the flow of retained P (P = 0.022) but also tibia ash weight in LnPP diets (Ca * nPP; P = 0.035). The responses of the animals in terms of tibia ash content and P retention were improved by the addition of microbial phytase especially for the lowest P diets (nPP * phytase, P = 0.021 and P = 0.009; respectively). Phytase increased dry tibia weight, bone breaking strength, and tibia diameter in broilers fed the highest Ca diets (Ca * phytase; P < 0.05). We conclude that is possible to decrease P levels in finishing broilers, if the Ca content is appropriate. Nevertheless, decreasing the dietary P and Ca cannot allow a maximization of bone mineralization, but the optimal threshold remains to be determined. PMID- 23091140 TI - Influence of feed form and source of soybean meal of the diet on growth performance of broilers from 1 to 42 days of age. 1. Floor pen study. AB - In total, 3,120 broilers were used to study the effects of feed form and source of soybean meal (SBM) of the diet on growth performance. From 1 to 21 d of age, there were 12 treatments arranged factorially with 3 feed forms (mash, crumbles, and pellets) and 4 commercial sources of SBM that differed in the CP content [48.1 and 46.2% CP from the United States (USA-1 and USA-2), 47.6% CP from Brazil (BRA), and 46.3% CP from Argentina (ARG)]. From 21 to 42 d of age, diets were fed as pellets. Diets were formulated assuming that all SBM had similar digestible amino acid content per unit of CP. From 1 to 21 d of age, chicks fed crumbles or pellets had higher (P < 0.001) ADG than chicks fed mash. Also, chicks fed pellets had better (P < 0.001) feed-to-gain ratio (F:G) than chicks fed crumbles, and both were better than chicks fed mash. However, from 21 to 42 d of age, F:G was best (P < 0.001) for chicks previously fed mash. For the entire experimental period, broilers that were fed crumbles or pellets from 1 to 21 d of age had higher (P < 0.001) ADG than broilers that were fed mash. Also, broilers that were fed pellets had better (P < 0.05) F:G than broilers fed mash, with broilers fed crumbles being intermediate. Broilers fed the USA-2 meal had higher (P < 0.01) ADG than broilers fed the BRA or the ARG meals, with broilers fed the USA-1 meal being intermediate. Feed efficiency tended (P = 0.07) to be hindered in broilers fed the BRA meal. The results show that pelleting improved growth performance of broilers from 1 to 42 d of age with effects being less evident at 42 d than at 21 d of age. Source of SBM affected growth performance suggesting the need for a better control of chemical composition and quality of this ingredient before diet formulation. PMID- 23091141 TI - Effect of dietary supplementation of Lactobacillus-fermented Artemisia princeps on growth performance, meat lipid peroxidation, and intestinal microflora in Hy line Brown male chickens. AB - The objective of this experiment was to investigate the effect of dietary supplementation of Lactobacillus-fermented Artemisia princeps (LFA) on growth performance, meat lipid peroxidation, and intestinal microflora in Hy-line Brown male chickens. A total of six hundred twenty-four 1-d-old Hy-Line Brown male chicks were randomly allotted to 3 dietary treatments with 4 replicated pens consisting of 52 chicks. The control diet was formulated to be adequate in energy and nutrients. Two additional diets were prepared by adding 2.5 or 5.0 g/kg of LFA to the control diet. The experimental diets were fed on an ad libitum basis to the birds during 7 wk. Body weight gain and feed intake were recorded at 2 and 7 wk. At the end of the experiment, 2 birds from each treatment were killed by cervical dislocation and the samples for ileal content, breast, and thigh meat were collected for the determination of meat lipid peroxidation and microbial population. Results indicated that increasing inclusion level of LFA in diets improved BW gain (linear and quadratic, P < 0.05) and tended to improve feed efficiency (linear and quadratic, P < 0.10) of birds during 0 to 7 wk. Feeding the diets containing increasing amounts of LFA to birds reduced (quadratic, P < 0.05) thiobarbituric acid-reactive substance (TBARS) values in breast and thigh meat during 15 d of storage. The concentrations of Lactobacillus spp. in the ileal content of birds increased (linear and quadratic, P < 0.05), but those of Salmonella spp. tended to be decreased (quadratic, P < 0.10) as inclusion level of LFA in diets increased. These results suggest that dietary LFA may be used as a functional ingredient to improve growth performance, meat lipid stability, and intestinal health of birds. PMID- 23091142 TI - Protective effect of Bacillus subtilis ANSB060 on egg quality, biochemical and histopathological changes in layers exposed to aflatoxin B1. AB - Bacillus subtilis ANSB060 from the fish gut had strong ability to detoxify aflatoxins. The aim of this research was to investigate the protective effect of B. subtilis ANSB060 (ANSB060) on egg quality and biochemical and histopathological changes of liver and kidney in laying hens when exposed to aflatoxin B(1). Treatments (C20, C40, and C60) were prepared by substituting corn contaminated by aflatoxin B(1) (AFB1) at different proportions (20, 40, and 60%) for normal corn in basic diets. The aflatoxin degradation enzyme (E) treatments (E20, E40, and E60) were mixed with the fermentation liquor of ANSB060 with C20, C40, and C60, respectively. The results showed that ANSB060 can improve the eggshell strength in E60 compared with C60 (P <= 0.05), and toxin reduced the content of total protein (in groups C20, C40, and C60) and albumin (in C20 and C40; P < 0.05) and heightened the activities of GPT (in C60) and GOT (in C40 and C60) in serum (P < 0.05). In the liver, AFB1 inhibited the activity of superoxide dismutase and glutathione peroxidase (C40 and C60; P < 0.05) and increased the content of malonaldehyde (in C40 and C60), which induced the damage in the liver and kidney as shown in the photomicrographs of hematoxylin and eosin-stained sections. The addition of ANSB060 can enhance the activity of antioxidant enzymes, and it recovered the protein synthesis in liver. Moreover, ANSB060 also ameliorated the damage of liver and kidney tissue and restored them to normal. Hence, ANSB060 had the ability to inhibit the damage induced by AFB1; it will have a great potential in industrial applications. PMID- 23091143 TI - A comparison of long bone development in historical and contemporary ducks. AB - The selection for growth and carcass traits in poultry meat species has contributed to increased interest in understanding and characterizing skeletal growth as the birds struggle to balance skeletal development with increased BW and muscle mass. The objective of this study was to compare the physical characteristics and mineralization of the tibia and femur from commercial Pekin ducks representing circa 1993 and 2010 commercial strains. In 1993, the femur and tibia were collected from 8 ducks at 11 ages between 11 and 53 d. A similar study was done in 2010 in which the femur and tibia were collected from 8 ducks at 12 sample ages between 10 and 49 d. All bones were weighed and the length and width at 50% of length were measured. Each bone was subsequently cut into epiphyseal (top 25% of length) and diaphyseal (midregion at 50% of length) sections. Each bone segment was extracted with ether, hot weighed, and ashed. The 2010 contemporary ducks reached market weight faster than the 1993 ducks. Therefore, statistical comparisons were made at common BW as well as at common ages. The mean tibia length of the 2010 duck was 0.75 cm greater (P < 0.05) at similar ages and similar BW. The percentage ash in the diaphyseal region of the tibia was 3% greater (P < 0.05) in the 2010 versus 1993 ducks. The percentage epiphyseal ash in the femur was 10% lower (P < 0.01) at 10 d and 14 d in the 2010 ducks but there were no significant differences by 18 d of age. The lower epiphyseal ash values at both younger ages and smaller BW in the 2010 contemporary ducks suggests that it is critical to monitor those factors that influence bone mineralization in contemporary ducklings that can achieve market BW at earlier chronological ages. PMID- 23091144 TI - Culture of chicken embryo in interspecific surrogate egg white. AB - The effect of interspecific egg white on the development of chicken embryos was investigated in a surrogate eggshell culture system. Egg yolks were separated from fertile White Leghorn chicken eggs and cultured in different egg whites from turkey (group TK), guineafowl (group GF), and duck (group DK), and chicken (group CK) was used as control. The viability of chicken embryos in groups CK, TK, GF, and DK after 3 d culture in system II was 98.3, 90.2, 96.1, and 91.1%. The whole contents (egg yolk and surrogate egg white) were further transferred into an eggshell from a 1.5 times heavier chicken egg with air space (system III), and incubated for further 16 d, before moving them to a hatcher. No significant difference between the 4 groups was found in their viabilities, which ranged between 72.9 and 81.3%, until 14 d postincubation (P > 0.05). After 21 d, the viability decreased to 60.4, 57.4, 50.0, and 27.7% in groups CK, TK, GF, and DK. The viability in group DK was significantly lower than in the other groups (P < 0.05). Weight loss in system III was approximately 12% in all the 4 groups without significant difference (P > 0.05). Hatchability of the chicken embryo was 60.4, 55.3, 47.9, and 19.1% in groups CK, TK, GF, and DK, respectively, and that in group DK was significantly lower than in the other groups (P < 0.05). There was no difference between the other groups (P > 0.05). These results show that chicken embryos can develop to hatch in duck, guineafowl, and turkey egg whites. However, the hatchability decreases according to the phylogenetic distance. The present study will provide a tool for manipulation of avian embryos and eventual conservation of endangered wild birds. PMID- 23091145 TI - Temporal myosin heavy chain isoform expression transitions faster in broiler chickens compared with Single Comb White Leghorns. AB - Myosin heavy chain (MyHC), one of the major components in the contractile machinery of skeletal muscle fibers, is found in several isoforms during myogenesis. During chicken development, embryonic, neonatal, and adult MyHC isoforms are expressed. Broiler chickens have been selected for fast and large muscle growth, whereas Single Comb White Leghorn (SCWL) chickens have been selected for egg laying capabilities. This has led to an obvious difference in muscle growth and development with broilers being much larger than SCWL. The objective of this study was to determine if differences in muscle growth and development of SCWL and broilers are associated with differences in temporal expression of MyHC isoforms in skeletal muscle between the 2 breeds. Pectoralis major muscle (PM) was collected from SCWL and broilers at embryonic d 15, 17, and 19 and 1, 5, 11, 20, 27, and 33 d posthatch with n = 3 samples per time point and breed. Western blotting using 3 monoclonal antibodies (EB165, 2E9, and AB8) was performed to compare the expression patterns of embryonic/adult, neonatal, and adult isoforms of MyHC, respectively, for all time points in both SCWL and broiler chickens. Both broiler and SCWL chickens began expressing the neonatal MyHC isoform on d 5; however, SCWL chickens expressed the neonatal isoform much longer than broilers. The SCWL chickens had sustained expression of the neonatal MyHC isoform through d 27, whereas in broiler chickens the neonatal isoform was not expressed at d 20. Pectoralis major tissue from broiler chickens expressed the adult MyHC isoform as early as d 20, whereas the SCWL chickens began expressing the adult isoform later. The rate of transition to neonatal and adult MyHC isoforms in broilers and Leghorns is consistent with the faster maturation and growth of broilers relative to Leghorns. This relationship between faster growth of the PM and the rate of transition of MyHC isoforms within the fast skeletal muscle of the PM may indicate a selection marker for improvement of broiler PM growth. PMID- 23091146 TI - Effects of lipopolysaccharide and interleukins on the expression of avian beta defensins in hen ovarian follicular tissue. AB - The aim of this study was to determine the mechanism by which expression of avian beta-defensins (AvBD) in the follicular theca tissue was regulated. It was examined whether their expression was stimulated directly by LPS or indirectly through proinflammatory cytokines (IL-1beta and IL-6) induced by LPS. Theca tissues of ovarian follicles were collected from White Leghorn hens. The specimens of those theca tissues were cultured in TCM-199 culture medium and stimulated by lipopolysaccharide from Salmonella minnesota (LPS), recombinant chicken IL-1beta, or recombinant chicken IL-6. In the first experiment, changes in the expression of IL-1beta, IL-6, AvBD10, and AvBD12 in response to LPS stimulation were examined by quantitative reverse-transcription PCR. The AvBD10 and 12 had been known to be expressed in the theca. In the second experiment, changes in the expression of AvBD10 and 12 in response to recombinant chicken IL 1beta or IL-6 stimulation were examined by quantitative reverse-transcription PCR. Density of AvBD12 protein after IL-1beta stimulation that showed changes in the gene expression was analyzed by Western blotting. In the first experiment, LPS was able to induce IL-1beta and IL-6, but not AvBD10 or AvBD12. In the second experiment, IL-1beta was able to upregulate significantly the expression of AvBD12 mRNA and protein. However, IL-6 did not exert significant effects on the expression of AvBD10 and AvBD12. It is suggested that LPS may stimulate theca cells to produce proinflammatory cytokines, whereas, in turn, IL-1beta stimulates those cells to synthesize AvBD12, which may be able to attack infectious gram negative bacteria. PMID- 23091147 TI - Characterization of chicken visfatin gene: cDNA cloning, tissue distribution, and promoter analysis. AB - Here we report the cloning and characterization of chicken visfatin (also called pre-B cell enhancing factor; PBEF, or nicotinamide phosphoribosyltransferase; Nampt) gene. Sequence analyses revealed that the coding region of visfatin is 1,482 bp in length and encodes a protein of 493 amino acids, which shares high amino acid sequence identity not only to visfatin of human (94%), rat (94%), carp (89%), and zebrafish (89%), but also to Nampt of sponge (58%) and cyanobacterium (48%). The reverse transcription PCR assay and Northern-blot analysis demonstrated that visfatin was widely expressed in all chicken tissues examined. Using a dual luciferase reporter system, we further demonstrated that the cloned 1,372-bp fragment upstream of the putative translation start site (ATG) displayed the maximal promoter activity in cultured CHO, DF-1, and HEK293 cells, whereas the removal of its 5'-region (1,075 bp) or 3'-region (297 bp) could only partially reduce its promoter activity, implying that visfatin gene transcription was likely controlled by multiple promoters near the translation start site. Taken together, results from present study will contribute to our better understanding of the expression and roles of visfatin gene in chickens. PMID- 23091148 TI - The effects of allopurinol, uric acid, and inosine administration on xanthine oxidoreductase activity and uric acid concentrations in broilers. AB - The purpose of these studies was to determine the effects of uric acid (UA) and inosine administration on xanthine oxidoreductase activity in broilers. In experiment one, 25 broilers were assigned to 5 treatment groups: control, AL (25 mg of allopurinol/kg of body mass), AR (AL for 2 wk followed by allopurinol withdrawal over wk 3), UAF (AL plus 6.25 g of UA sodium salt/kg of feed), and UAI (AL plus 120 mg of UA sodium salt injected daily). The UA administration had no effect on plasma concentration of UA (P > 0.05), and all allopurinol-treated birds had lower (P < 0.05) UA levels than controls. The UA concentrations were restored in both plasma and kidney of AR birds at wk 3, but liver UA concentrations remained lower. Whereas xanthine oxidoreductase (XOR) activity in the liver (LXOR) was reduced (P < 0.05) by allopurinol treatment, XOR activity in the kidney (KXOR) was not affected (P = 0.05). In experiment two, 3 groups of 5 birds each were fed 0 (control), 0.6 M inosine/kg of feed (INO), or INO plus 50 mg of allopurinol/kg of body mass (INOAL). The INOAL birds showed lower total LXOR activity, but KXOR activity was not affected. Both INO and INOAL birds had higher plasma and kidney UA concentrations than controls. The results suggest that regulation of UA production is tissue dependent. PMID- 23091149 TI - Pulmonary vascular remodeling in broiler and Leghorn chickens after unilateral pulmonary artery occlusion. AB - Morphological and physiological responses to unilateral pulmonary artery occlusion (PAO) were evaluated in male broiler (B) and Leghorn (L) chickens. All birds were fed a diet containing 3,200 kcal of ME/kg of feed and 23% CP. Broilers (18-21 d old; 507 +/- 40 g of BW) and L (61-64 d old, 861 +/- 87 g of BW) had surgical PAO (n = 40 each strain) or were sham-operated (SHAM; n = 40 each strain). Hematocrit (%, Hc), relative lung weight (wet right + left lung weight/BW * 100), right ventricle to total ventricle weight ratio (RV/TV), and resistance pulmonary arterioles (RPA) thickness were measured in 6 chickens per group one day presurgery, and at 7 and 14 d postsurgery. Data were analyzed using one-way ANOVA. Relative lung weight was higher in L-chickens than in B-chickens at all sampling times. There were no differences in Hc between B and L presurgery, but at d 7 and 14, L-PAO chickens had the highest Hc (35 +/- 1.4 and 40 +/- 1.9, respectively); the B-SHAM had a lower Hc (28 +/- 1.2, and 29 +/- 1.0) than the L-SHAM (32 +/- 1.2 and 34 +/- 1.1) and the B-PAO (32 +/- 1.2 and 34 +/- 2.0) chickens, with no differences between L-SHAM and B-PAO. The RV/TV ratio was highest in the B-PAO at d 7 and d 14, with no differences among the other groups. The B-PAO chickens had the thickest RPA at 7 d and 14 d postsurgery than the rest of the groups, whereas B had thicker RPA than L at presurgery. Broilers had a lower ventilation capacity than L, and after PAO they developed right ventricular hypertrophy and small arteriole remodeling, whereas the L-PAO showed a higher degree of hypoxemia (high Hct), but without changes in RV/TV ratios or small arterial remodeling, suggesting that L-chickens had a better pulmonary arterial vasodilation even after chronic increases in blood flow through a single lung. PMID- 23091150 TI - Photoperiodic lighting (16 hours of light:8 hours of dark) programs during incubation: 1. Effects on growth and circadian physiological traits of embryos and early stress response of broiler chickens. AB - This study was conducted to evaluate the effect of a 16L:8D photoperiod during incubation, either during the whole incubation period (Inc(0-21d)) or the last week of incubation (Inc(14-21d)), on embryo growth, incubation performance, and light:dark rhythm of plasma melatonin and corticosterone in relation to early stress responses of newly hatched chicks to the posthatching environment. A dark incubation condition (Inc(Dark)) served as control. Three batches of eggs (n = 1,080, 1,320, 720) from Ross 308 broiler breeders were used in the experiment. Embryos from Inc(0-21d) presented a daily rhythm of melatonin at internal pipping and hatching, but Inc(Dark) embryos did not. The Inc(14-21d) group had rhythmic plasma melatonin at hatching only. A L:D rhythm of corticosterone was apparent at hatching. A significant incubation * sampling time interaction suggested that a lower increment in blood corticosterone level in Inc(0-21d) at 8 h posthatching (light period), as compared with hatching (dark period) values, might be associated with probable changes in the hypothalamic-pituitary-adrenal axis in Inc(0-21d) through incubation lighting. This finding may also suggest improved adaptation to the posthatching environment. Incubation lighting did not consistently affect brain malondialdehyde concentration; the only difference between groups was higher concentrations at hatching in Inc(14-21d), whereas incubation groups at the internal pipping stage had similar values. Mean relative asymmetry (RA) did not differ with incubation lighting. The malondialdehyde and RA results indicate that neither lighting nor darkness during the overall incubation exacerbated embryo oxidative and developmental stress. An increased breast muscle weight was observed at hatching only in Inc(14-21d). The Inc(0-21d) group had increased embryo weights relative to egg weight and decreased residual yolk but had no effect on chick weight, relative heart and liver (% of embryo weight), hatchability, embryo mortality, incubation time, oxidative stress, or mean RA. In conclusion, these results provide further evidence that photoperiodic lighting during incubation (Inc(0-21d)) may improve adaptation of chicks to a novel environment at hatching, possibly giving birds a better start for early posthatching development. PMID- 23091151 TI - Photoperiodic lighting (16 hours of light:8 hours of dark) programs during incubation: 2. Effects on early posthatching growth, blood physiology, and production performance in broiler chickens in relation to posthatching lighting programs. AB - Photoperiodic incubation lighting might improve bird adaptation to a novel environment at hatching for a better start in early posthatching development. We evaluated the effect of 16L:8D lighting for either the whole incubation period (Inc(0-21d)) or the last week of incubation (Inc(14-21d)) on early posthatching growth, blood melatonin, and corticosterone at 6 d as well as malondialdehyde levels in brain tissue, relative asymmetry, and overall broiler performance as an interaction with the posthatching lighting programs. Dark incubation conditions (Inc(Dark)) served as control. There were 3 incubation batches in the experiment. Chicks from 2 of 3 batches were reared either at 16L:8D or under continuous lighting (24 h) through 6 d posthatching. Batch 3 chicks were reared to 35 d under either 16L:8D or 23L:1D. The main finding was a significant incubation * posthatching lighting interaction for 35-d BW in broilers. Although groups had similar BW under continuous lighting, Inc(0-21d) and Inc(14-21d) broilers were respectively 94 and 78 g heavier than Inc(Dark) birds under 16L:8D at 35 d. Lighted incubation groups increased 0 to 6 d of gain and had higher d-6 breast muscle weights with no effect on other traits measured. Posthatching 16L:8D reduced the gain and d-6 breast muscle. Significant incubation * posthatching lighting and posthatching lighting * sampling time interactions for blood melatonin may indicate that Inc(0-21d) affects melatonin diurnal rhythms even at 6 d under continuous light. Lower blood corticosterone levels on d 6 in Inc(0 21d) chicks reared under 16L:8D posthatching may support our hypothesis that incubation lighting can modify the bird stress response, probably affecting the hypothalamic-pituitary-adrenal axis during ontogeny, and may improve adaptation to a similar environment posthatching. The lower malondialdehyde concentration in brain tissue of Inc(0-21d) birds on d 6 may indicate lower lipid peroxidation and thus lower oxidative stress compared with Inc(Dark). These results provide further evidence that Inc(0-21d) may improve both bird adaptation to a similar photoperiodic environment and growth, probably through early entrainment of circadian physiology. PMID- 23091152 TI - Effects of constant and cyclic heat stress on muscle metabolism and meat quality of broiler breast fillet and thigh meat. AB - This study investigated the effects of constant and cyclic heat stress on muscle metabolism and meat quality of broiler breast fillet and thigh meat from 4 to 6 wk of age. Male Arbor Acres (AA) broilers (n = 270, 4 wk old) were raised under different temperature conditions: standard (temperature was 23 degrees C); constant high temperature (temperature was 34 degrees C); and cyclic high temperature (temperature was 36 degrees C from 1000 h to 1600 h and 23 degrees C from 1600 h to 1000 h). On d 42, broilers were stunned and sampled. The results showed that chronic high temperature significantly decreased the proportion of breast muscle and significantly increased the proportion of thigh muscle (P < 0.05). The moisture concentration was significantly higher in the breast muscle of the birds exposed to constant high temperature (P < 0.05), whereas the protein content was significantly lower (P < 0.05) and fat deposition was significantly higher (P < 0.05) in the breast muscle of the birds exposed to constant or diurnal cyclic high temperature than those grown under standard temperature. The breast and thigh muscle of the birds grown under constant high temperature had significantly higher lightness, cook loss, and shear force (P < 0.05) and significantly lower initial pH (pH(i)), ultimate pH (pH(u)), and redness compared with those grown under standard temperature (P < 0.05). The pH(i), pH(u), and redness were significantly lower (P < 0.05) while the lightness and shear force were significantly higher for the breast muscle of the chickens raised under diurnal cyclic high temperature (P < 0.05) than those grown under standard temperature. In contrast, lightness and yellowness of thigh muscle were significantly higher (P < 0.05) in the chickens grown under diurnal cyclic high temperature than under standard temperature. Breast and thigh muscle of broilers exposed to constant high temperature produced higher (P < 0.05) lactic acid and pyruvate kinase activities than those exposed to the standard temperature. These results indicated that chronic heat stress significantly increased lactate production, reduced meat pH value by accelerating meat glycolysis, and eventually reduced meat quality. PMID- 23091153 TI - Deboning broiler chicken legs and wings by dislocation of articular cartilage followed by stripping periosteum. AB - The yield of deboned meat is an important economic factor affecting the profit of the meat industry. This study was undertaken to determine whether the yield of boneless meat from broiler chicken leg (thigh and drumstick) and wing (drumette and winglet) is improved by introducing a new deboning method consisting of articular cartilage dislocation followed by stripping periosteum. A total of 44 broiler chicken carcasses were used in the deboning experiment. Right and left legs or wings from the first 22 carcasses were assigned to the new and ordinary hand deboning methods, respectively. For the remaining 22 carcasses, right and left legs or wings were assigned to the ordinary and new methods, respectively. The weight of residue, composed of bone and small amounts of cartilage and noncartilaginous tissues obtained after deboning, was then compared between the right and left legs or wings to see the difference between the 2 methods. The removal of tibia, fibula, humerus, radius, or ulna resulted in formation of a hollow in boneless meat obtained. There was no difference (P > 0.05) between the right and left legs or wings in the weight of residue obtained after deboning as expected. The weight of residue was less (P < 0.05) with the new method compared with the ordinary method in all chicken parts examined. The difference of residue weight between the 2 methods accounted for 10, 12, 14, and 21% of the weight of residue obtained by the ordinary method in thigh, drumstick, drumette, and winglet, respectively. The new method may be useful to deboners at home kitchens as well as the poultry meat industry. The present study also showed the development of a secondary ossification center at the proximal end of the carpometacarpus of chickens. This is, to our knowledge, the first report of development of secondary ossification center in chicken wings. PMID- 23091154 TI - Strain and sex effects on growth performance and carcass traits of contemporary commercial broiler crosses. AB - In total, 3,840 sexed birds from 6 commercial cross broiler strains (4 male and 3 female) were raised and processed to analyze the effect of strain and sex on growth performance and carcass traits. Chicks from M1 * F1, M2 * F1, M3 * F1, M4 * F1, M3 * F2, and M4 * F3 crosses were sexed. Fifty female and 40 male chicks were randomly allocated to 24 floor pens (119 * 300 cm) covered with pine shavings in each of 4 rooms. The FCR was adjusted for the weight of dead birds (AFCR). Four birds/pen were processed at 7 wk of age. Carcasses were deboned after 2 h of chilling (n = 32 birds per treatment). There were significant strain by sex interactions for BW gain from 0 to 21 and 0 to 48 d. Strain differences in growth rate and mortality increased with age. The cross with the fastest growth rate also had the highest mortality. Because of differences in mortality and carcass yields, birds with the fastest growth (0-48 d) did not produce the most salable meat. Both the heaviest live BW per bird at 48 d (3.45 kg) and highest mortality (13.40%) were observed with the M4 * F3 cross. However, the heaviest live BW per 1,000 chicks placed was from the M3 * F2 cross (3,107 kg). The highest chilled carcass yield was from the M3 * F2 cross (76.05% of live BW) as was the highest meat yield (2,364 kg per 1,000 chicks placed) and highest pectoralis meat yield (805 kg per 1,000 chicks placed). The M3 * F2 cross produced the most total white meat (1,058 kg per 1,000 chicks placed), but interestingly the slowest-growing strain (M1 * F1) produced more white meat (breast + tenders + wings) than did the fastest-growing M4 * F3 strain (980 kg vs. 1,002 kg per 1,000 chicks placed). These results demonstrate the complexity of choosing between commercial strain crosses. The most profitable choice will be dependent on whether whole birds or parts are marketed and the relative values of the parts. PMID- 23091155 TI - Intestinal epithelial responses to Salmonella enterica serovar Enteritidis: effects on intestinal permeability and ion transport. AB - Salmonella infection of chickens that leads to potential human foodborne salmonellosis continues to be a major concern. Chickens serve as carriers but, in contrast to humans, rarely show any clinical signs including diarrhea. The present investigations aimed to elucidate whether the absence of diarrhea during acute Salmonella enterica serovar Enteritidis (Salmonella Enteritidis) infection may be linked to specific changes in the electrophysiological properties of the chicken gut. Immediately after slaughter, intestinal pieces of the mid-jejunum and cecum of either commercial broiler or specific pathogen-free (SPF) chickens were mounted in Ussing chambers in 2 separate experimental series. Living Salmonella Enteritidis (3 * 10(9)) or Salmonella Enteritidis endotoxin (20 mg/L), or both, were added to the mucosal side for 1 h. In both experimental series, the Salmonella infection decreased the trans-epithelial ion conductance G(t) (P < 0.05). In the jejunum of SPF chickens, there was also a marked decrease in net charge transfer across the epithelium, evidenced by decreased short-circuit current (I(sc), P < 0.05). Interestingly, the mucosal application of Salmonella endotoxin to the epithelial preparations from jejunum and cecum of SPF chicken had an effect similar to living bacteria. However, the endotoxin had no additional effect on the intestinal function in the presence of bacteria. The decreasing effect of Salmonella and or its endotoxin on G(t) could be partly reversed by serosal addition of histamine. To our knowledge, this is the first study to address the functional response of native intestinal epithelium of chicken to an in vitro Salmonella infection. For the first time, it can be reported that intestinal ion permeability of chicken decreases acutely by the presence of Salmonella. This type of response could counteract ion and fluid secretion and may thus, at least in part, explain why chickens do not develop overt diarrhea after Salmonella infection. PMID- 23091156 TI - Response surface of dietary energy and protein in Japanese quail from 7 to 14 days of age. AB - An experiment was conducted to determine dietary energy (ME) and CP requirements of quail chicks using response surface methodology. A total of 40 floor pens of 20 birds each were assigned to 9 diets of central composite design (CCD) containing 5 levels of ME (2,809 to 3,091 kcal/kg) and CP (19 to 24.8% of diet) from 7 to 14 d of age. The experimental results of CCD were fitted with quadratic response models, and ridge analysis was used to compute the optimal response for BW gain (BWG) and feed conversion ratio (FCR). Regression analysis showed that the linear effect of independent variables was significant on bird responses. The quadratic and cross-product effects did not have significant effects on performance. Dietary levels of CP linearly affected BWG and FCR, but the effect of dietary ME was not significant. The ridge maximum analysis on BWG and minimum analysis on FCR models revealed that the maximum BWG may be achieved with 2,950 kcal of ME/kg and 25% CP; and minimum FCR may be obtained with 2,878 kcal of ME/kg and 24.4% CP. The results of this study showed that response surface analysis with the CCD platform was successfully used to optimize dietary requirements of Japanese quail and this methodology could be used for other nutrients. PMID- 23091157 TI - Influence of in ovo prebiotic and synbiotic administration on meat quality of broiler chickens. AB - A trial was conducted to evaluate the effect of in ovo injection of prebiotic and synbiotics on growth performance, meat quality traits (cholesterol content, intramuscular collagen properties, fiber measurements), and the presence of histopathological changes in the pectoral muscle (PS) of broiler chickens. On d 12 of incubation, 480 eggs were randomly divided into 5 experimental groups treated with different bioactives, in ovo injected: C, control with physiological saline; T1 with 1.9 mg of raffinose family oligosaccharides; T2 and T3 with 1.9 mg of raffinose family oligosaccharides enriched with different probiotic bacteria, specifically 1,000 cfu of Lactococcus lactis ssp. lactis SL1 and Lactococcus lactis ssp. cremoris IBB SC1, respectively; T4 with commercially available synbiotic Duolac, containing 500 cfu of both Lactobacillus acidophilus and Streptococcus faecium with the addition of lactose (0.001 mg/embryo). Among the hatched chickens, 60 males were randomly chosen (12 birds for each group) and were grown to 42 d in collective cages (n = 3 birds in each 4 cages: replications for experimental groups). Broilers were fed ad libitum commercial diets according to age. In ovo prebiotic and synbiotic administration had a low effect on investigated traits, but depend on the kind of bioactives administered. Commercial synbiotic treatment (T4) reduced carcass yield percentage, and the feed conversion ratio was higher in T3 and T4 groups compared with other groups. The abdominal fat, the ultimate pH, and cholesterol of the PS were not affected by treatment. Broiler chickens of the treated groups with both slightly greater PS and fiber diameter had a significantly lower amount of collagen. The greater thickness of muscle fibers (not significant) and the lower fiber density (statistically significant), observed in treated birds in comparison with those of the C group, are not associated with histopathological changes in the PS of broilers. The incidence of histopathological changes in broiler chickens from examined groups was low, which did not affect the deterioration of meat quality obtained from these birds. PMID- 23091158 TI - Does preincubational in ovo injection of buffers or antioxidants improve the quality and hatchability in long-term stored eggs? AB - A hypothesis was tested that providing buffer solutions or antioxidants during egg storage may help embryos in combating the harmful effect of longer holding periods. Hatching eggs were obtained from a breeder flock (35 wk) and stored for 13 d before setting. In experiment 1, the eggs were injected (d 4) with bicarbonate buffer solution (BBS) or PBS. For experiment 2, l-carnitine (LC), vitamin E (VE), and vitamin C (VC) were injected (d 7) at 3 different doses. The egg internal quality characteristics were evaluated at 2-d intervals after injection and the remaining eggs were incubated for 21 d under standard conditions. At 21 d, hatchability was recorded and unhatched eggs were broken open to assess the fertility and stage of embryonic mortality. No differences were noted in albumen pH due to using buffer solutions or antioxidants except for a decreased pH at 2 d postinjection of the high dose of VC (75 mg). In ovo injection of BBS increased the albumen index and Haugh unit at d 6 postinjection; however, the response to PBS was not different from that in the control group. In ovo injection of antioxidants did not influence the albumen index, Haugh unit, and yolk index; however, the yolk percentage was partly affected. Irrespective of the dosage, hatchability was greatly decreased following in ovo injection of buffers or antioxidants (as low as 4.3 vs. 87.5% in control), with the highest mortality percentage recorded at early embryonic stages (d 0 to 6). Data suggested that, despite improvement in certain egg internal qualities, preincubational in ovo injection of BBS, PBS, LC, VE, or VC was associated with a profoundly decreased hatchability for which the underlying mechanism(s) remain(s) to be clarified. PMID- 23091159 TI - Egg production curve fitting using nonlinear models for selected and nonselected lines of White Leghorn hens. AB - Egg production curves describe the laying patterns of hen populations over time. The objectives of this study were to fit the weekly egg production rate of selected and nonselected lines of a White Leghorn hen population, using nonlinear and segmented polynomial models, and to study how the selection process changed the egg-laying patterns between these 2 lines. Weekly egg production rates over 54 wk of egg production (from 17 to 70 wk of age) were measured from 1,693 and 282 laying hens from one selected and one nonselected (control) genetic line, respectively. Six nonlinear and one segmented polynomial models were gathered from the literature to investigate whether they could be used to fit curves for the weekly egg production rate. The goodness of fit of the models was measured using Akaike's information criterion, mean square error, coefficient of determination, graphical analysis of the fitted curves, and the deviations of the fitted curves. The Logistic, Yang, Segmented Polynomial, and Grossman models presented the best goodness of fit. In this population, there were significant differences between the parameter estimates of the curves fitted for the selected and nonselected lines, thus indicating that the effect of selection changed the shape of the egg production curves. The selection for egg production was efficient in modifying the birds' egg production curve in this population, thus resulting in genetic gain from the 5th to the 54th week of egg laying and improved the peak egg production and the persistence of egg laying. PMID- 23091160 TI - Growth performance and carcass characteristics of guinea fowl broilers fed micronized-dehulled pea (Pisum sativum L.) as a substitute for soybean meal. AB - This study was conducted to evaluate the effect of substitution of soybean meal (SBM) with dehulled-micronized peas (Pisum sativum) in diets of guinea fowl broilers on their growth performance, carcass yields, and fatty acid composition of meat. One hundred forty 1-d-old guinea fowl keets were randomly assigned to 2 dietary treatments, which were fed from hatch to 12 wk. The birds were fed 2 wheat middling-based diets comprising a control diet, which contained SBM (78 g/kg) and a test diet containing dehulled-micronized peas (180 g/kg) as the main protein source. The substitution of SBM with peas had no adverse effect on growth performance, dressing percentage, or breast and thigh muscle relative weights of the guinea broilers. However, a reduction of abdominal fat content (P < 0.05) was observed in birds fed the pea diet compared with the control. Breast and thigh meat of birds fed the pea diet had higher lightness scores (P < 0.05) and water holding capacity (P < 0.01) than the control. Meat from guinea fowls fed the pea diet had less cholesterol (P < 0.01) and lipids (P < 0.05), and higher concentrations of phospholipids (P < 0.05). Feeding peas increased polyunsaturated fatty acid concentration in breast and thigh muscles, and decreased the saturated fatty acid concentration. Feeding the pea diet also lowered the n-6/n-3 polyunsaturated fatty acid ratio of the guinea broiler muscles. Our results suggest that replacing the conventional SBM as the protein source with dehulled-micronized pea meal in diets of guinea fowls broilers can improve carcass quality and favorable lipid profile without adversely affecting growth performance traits. PMID- 23091161 TI - Pro-smoking apps for smartphones: the latest vehicle for the tobacco industry? AB - BACKGROUND: Smartphone use is growing exponentially and will soon become the only mobile phone handset for about 6 billion users. Smartphones are ideal marketing targets as consumers can be reached anytime, anywhere. Smartphone application (app) stores are global shops that sell apps to users all around the world. Although smartphone stores have a wide collection of health-related apps they also have a wide set of harmful apps. In this study, the availability of 'pro smoking' apps in two of the largest smartphone app stores (Apple App store and Android Market) was examined. METHOD: In February 2012, we searched the Apple App Store and Android Market for pro-smoking apps, using the keywords Smoke, Cigarette, Cigar, Smoking and Tobacco. We excluded apps that were not tobacco related and then assessed the tobacco-related apps against our inclusion criteria. RESULT: 107 pro-smoking apps were identified and classified into six categories based on functionality.42 of these apps were from the Android Market and downloaded by over 6 million users. Some apps have explicit images of cigarette brands. CONCLUSIONS: Tobacco products are being promoted in the new 'smartphone app' medium which has global reach, a huge consumer base of various age groups and underdeveloped regulation. The paper also provides two examples of app store responses to country-specific laws and regulations that could be used to control the harmful contents in the app stores for individual countries. PMID- 23091162 TI - Advanced evolutionary molecular engineering to produce thermostable cellulase by using a small but efficient library. AB - We aimed at constructing thermostable cellulase variants of cellobiohydrolase II, derived from the mesophilic fungus Phanerochaete chrysosporium, by using an advanced evolutionary molecular engineering method. By aligning the amino acid sequences of the catalytic domains of five thermophilic fungal CBH2 and PcCBH2 proteins, we identified 45 positions where the PcCBH2 genes differ from the consensus sequence of two to five thermophilic fungal CBH2s. PcCBH2 variants with the consensus mutations were obtained by a cell-free translation system that was chosen for easy evaluation of thermostability. From the small library of consensus mutations, advantageous mutations for improving thermostability were found to occur with much higher frequency relative to a random library. To further improve thermostability, advantageous mutations were accumulated within the wild-type gene. Finally, we obtained the most thermostable variant Mall4, which contained all 15 advantageous mutations found in this study. This variant had the same specific cellulase activity as the wild type and retained sufficient activity at 50 degrees C for >72 h, whereas wild-type PcCBH2 retained much less activity under the same conditions. The history of the accumulation process indicated that evolution of PcCBH2 toward improved thermostability was ideally and rapidly accomplished through the evolutionary process employed in this study. PMID- 23091163 TI - Cellular origin and pathophysiology of chronic lymphocytic leukemia. AB - The cellular origin of chronic lymphocytic leukemia (CLL) is still debated, although this information is critical to understanding its pathogenesis. Transcriptome analyses of CLL and the main normal B cell subsets from human blood and spleen revealed that immunoglobulin variable region (IgV) gene unmutated CLL derives from unmutated mature CD5(+) B cells and mutated CLL derives from a distinct, previously unrecognized CD5(+)CD27(+) post-germinal center B cell subset. Stereotyped V gene rearrangements are enriched among CD5(+) B cells, providing independent evidence for a CD5(+) B cell derivation of CLL. Notably, these CD5(+) B cell populations include oligoclonal expansions already found in young healthy adults, putatively representing an early phase in CLL development before the CLL precursor lesion monoclonal B cell lymphocytosis. Finally, we identified deregulated proteins, including EBF1 and KLF transcription factors, that were not detected in previous comparisons of CLL and conventional B cells. PMID- 23091164 TI - The alpha7nACh-NMDA receptor complex is involved in cue-induced reinstatement of nicotine seeking. AB - Smoking is the leading preventable cause of disease, disability, and premature death. Nicotine, the main psychoactive drug in tobacco, is one of the most heavily used addictive substances, and its continued use is driven through activation of nicotinic acetylcholine receptors (nAChRs). Despite harmful consequences, it is difficult to quit smoking because of its positive effects on mood and cognition that are strong reinforcers contributing to addiction. Furthermore, a formidable challenge for the treatment of nicotine addiction is the high vulnerability to relapse after abstinence. There is no currently available smoking cessation product able to achieve a >20% smoking cessation rate after 52 wk, and there are no medications that directly target the relapse process. We report here that the alpha7nAChR forms a protein complex with the NMDA glutamate receptor (NMDAR) through a direct protein-protein interaction. Chronic nicotine exposure promotes alpha7nAChR-NMDAR complex formation. Interestingly, administration of an interfering peptide that disrupts the alpha7nAChR-NMDAR complex decreased extracellular signal-regulated kinase (ERK) activity and blocked cue-induced reinstatement of nicotine seeking in rat models of relapse, without affecting nicotine self-administration or locomotor activity. Our results may provide a novel therapeutic target for the development of medications for preventing nicotine relapse. PMID- 23091166 TI - Are differences in microRNA regulation implicated in species-dependent response to toxicological exposures? AB - Equivalent exposures can result in qualitatively or quantitatively dissimilar toxic effects across species, with the underlying molecular mechanisms being often not well defined. In many cases, differences in metabolic handling of the chemical (metabolism and disposition) provide an explanation of these differences, but in other cases the explanation is less obvious. This variability in the outcome of toxicant exposures complicates the interspecies extrapolation of human hazard from animal testing data. MicroRNAs (miRNAs) are a family of noncoding RNAs that posttranscriptionally regulate the expression of their target genes that have fundamental roles in physiology, disease, and toxicological responses. Importantly, these noncoding genes are characterized by a high evolutionary flux, in terms of miRNA repertoire and functioning, even among closely related species. Furthermore, evidence is emerging that the enzymes of drug metabolism are also under miRNA regulation and thus offer a new twist to an old para digm, whereby manipulation of the expression of these enzymes affects toxic outcomes. In this review, we discuss how miRNA may contribute to the interspecies variability observed in the response to toxicant exposures. Although few studies have so far specifically examined the contribution of differences in miRNA regulation to species-dependent responses to toxicological exposures, we believe that this will be an area of intense research in the coming years. PMID- 23091165 TI - ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. AB - Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro-nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75(NTR) in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up regulation of proNGF by cardiomyocytes and p75(NTR) by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75(NTR) in proNGF-expressing mice rescues the phenotype, confirming the importance of p75(NTR)-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75(NTR) limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction. PMID- 23091167 TI - Pharmacoelectrophysiology of viral-free induced pluripotent stem cell-derived human cardiomyocytes. AB - Development of pharmaceutical agents for cardiac indication demands elaborate safety screening in which assessing repolarization of cardiac cells remains a critical path in risk evaluations. An efficient platform for evaluating cardiac repolarization in vitro significantly facilitates drug developmental programs. In a proof of principle study, we examined the effect of antiarrhythmogenic drugs (Vaughan Williams class I-IV) and noncardiac active drugs (terfenadine and cisapride) on the repolarization profile of viral-free human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Extracellular field potential (FP) recording using microelectrode arrays demonstrated significant delayed repolarization as prolonged corrected FP durations (cFPDs) by class I (quinidine and flecainide), class III (sotalol and amiodarone), and class IV (verapamil), whereas class II drugs (propranolol and nadolol) had no effects. Consistent with their sodium channel-blocking ability, class I drugs also significantly reduced FPmin and conduction velocity. Although lidocaine (class IB) had no effects on cFPDs, verapamil shortened cFPD and FPmin by 25 and 50%, respectively. Furthermore, verapamil reduced beating frequencies drastically. Importantly, the examined drugs exhibited dose-response curve on prolongation of cFPDs at an effective range that correlated significantly with therapeutic plasma concentrations achieved clinically. Consistent with clinical outcomes, drug induced arrhythmia of tachycardia and bigeminy-like waveforms by quinidine, flecainide, and sotalol was demonstrated at supraphysiological concentrations. Furthermore, off-target effects of terfenadine and cisapride on cFPD and Na( + ) channel blockage were similarly revealed. These results suggest that hiPSC-CMs may be useful for safety evaluation of cardioactive and noncardiac acting drugs for personalized medicine. PMID- 23091168 TI - Multiple NSAID-induced hits injure the small intestine: underlying mechanisms and novel strategies. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause serious gastrointestinal (GI) injury including jejunal/ileal mucosal ulceration, bleeding, and even perforation in susceptible patients. The underlying mechanisms are largely unknown, but they are distinct from those related to gastric injury. Based on recent insights from experimental models, including genetics and pharmacology in rodents typically exposed to diclofenac, indomethacin, or naproxen, we propose a multiple-hit pathogenesis of NSAID enteropathy. The multiple hits start with an initial pharmacokinetic determinant caused by vectorial hepatobiliary excretion and delivery of glucuronidated NSAID or oxidative metabolite conjugates to the distal small intestinal lumen, where bacterial beta-glucuronidase produces critical aglycones. The released aglycones are then taken up by enterocytes and further metabolized by intestinal cytochrome P450s to potentially reactive intermediates. The "first hit" is caused by the NSAID and/or oxidative metabolites that induce severe endoplasmic reticulum stress or mitochondrial stress and lead to cell death. The "second hit" is created by the significant subsequent inflammatory response that would follow such a first-hit injury. Based on these putative mechanisms, strategies have been developed to protect the enterocytes from being exposed to the parent NSAID and/or oxidative metabolites. Among these, a novel strategy already demonstrated in a murine model is the selective disruption of bacteria-specific beta-glucuronidases with a novel small molecule inhibitor that does not harm the bacteria and that alleviates NSAID induced enteropathy. Such mechanism-based strategies require further investigation but provide potential avenues for the alleviation of the GI toxicity caused by multiple NSAID hits. PMID- 23091169 TI - Identification of Dlk1-Dio3 imprinted gene cluster noncoding RNAs as novel candidate biomarkers for liver tumor promotion. AB - The molecular events during nongenotoxic carcinogenesis and their temporal order are poorly understood but thought to include long-lasting perturbations of gene expression. Here, we have investigated the temporal sequence of molecular and pathological perturbations at early stages of phenobarbital (PB) mediated liver tumor promotion in vivo. Molecular profiling (mRNA, microRNA [miRNA], DNA methylation, and proteins) of mouse liver during 13 weeks of PB treatment revealed progressive increases in hepatic expression of long noncoding RNAs and miRNAs originating from the Dlk1-Dio3 imprinted gene cluster, a locus that has recently been associated with stem cell pluripotency in mice and various neoplasms in humans. PB induction of the Dlk1-Dio3 cluster noncoding RNA (ncRNA) Meg3 was localized to glutamine synthetase-positive hypertrophic perivenous hepatocytes, suggesting a role for beta-catenin signaling in the dysregulation of Dlk1-Dio3 ncRNAs. The carcinogenic relevance of Dlk1-Dio3 locus ncRNA induction was further supported by in vivo genetic dependence on constitutive androstane receptor and beta-catenin pathways. Our data identify Dlk1-Dio3 ncRNAs as novel candidate early biomarkers for mouse liver tumor promotion and provide new opportunities for assessing the carcinogenic potential of novel compounds. PMID- 23091170 TI - Neutrophil and eosinophil granulocytes as key players in a mouse model of chemical-induced asthma. AB - Diisocyanates are an important cause of chemical-induced occupational asthma. This type of immunologically mediated asthma is often characterized by a predominant granulocytic inflammation in the airways, rather than an infiltration by lymphocytes. We sought to determine the contribution of granulocytes in the outcome of chemical-induced asthma using general and specific leukocyte depletion strategies in an established mouse model of isocyanate asthma. On days 1 and 8, BALB/c mice received dermal applications with toluene-2,4-diisocyanate (TDI) or vehicle (acetone olive oil), followed by two ip injections of cyclophosphamide (CP, days 11 and 13), or one iv injection of antigranulocyte receptor 1 (aGR1, day 13) monoclonal antibody (mAb), or two ip injections of Ly6G-specific mAb (1A8, days 13 and 14). On day 15, the mice were challenged (oropharyngeal administration) with TDI or vehicle. The next day, we assessed methacholine airway hyperreactivity (AHR); bronchoalveolar lavage differential cell count; histopathology and total serum IgE; and auricular lymphocyte subpopulations and release of interleukin (IL)-2, IL-4, IL-10, IL-13, and gamma interferon by these lymphocytes. CP depleted all leukocyte types and completely prevented AHR and airway inflammation. aGR1 depleted granulocytes and CD8(+) lymphocytes, which resulted in a partial prevention in AHR but no decrease in airway inflammation. Depletion of Ly6G-positive granulocytes, i.e., both neutrophils and eosinophils, prevented AHR and lung epithelial damage and significantly reduced airway inflammation. Injection of aGR1 or 1A8 led to significantly changed cytokine release patterns in TDI-treated mice. Granulocytes, both neutrophils and eosinophils, are key cellular players in this model of chemical-induced asthma. PMID- 23091171 TI - Computer-aided detection of masses at mammography: interactive decision support versus prompts. AB - PURPOSE: To compare effectiveness of an interactive computer-aided detection (CAD) system, in which CAD marks and their associated suspiciousness scores remain hidden unless their location is queried by the reader, with the effect of traditional CAD prompts used in current clinical practice for the detection of malignant masses on full-field digital mammograms. MATERIALS AND METHODS: The requirement for institutional review board approval was waived for this retrospective observer study. Nine certified screening radiologists and three residents who were trained in breast imaging read 200 studies (63 studies containing at least one screen-detected mass, 17 false-negative studies, 20 false positive studies, and 100 normal studies) twice, once with CAD prompts and once with interactive CAD. Localized findings were reported and scored by the readers. In the prompted mode, findings were recorded before and after activation of CAD. The partial area under the location receiver operating characteristic (ROC) curve for an interval of low false-positive fractions typical for screening, from 0 to 0.2, was computed for each reader and each mode. Differences in reader performance were analyzed by using software. RESULTS: The average partial area under the location ROC curve with unaided reading was 0.57, and it increased to 0.62 with interactive CAD, while it remained unaffected by prompts. The difference in reader performance for unaided reading versus interactive CAD was statistically significant (P = .009). CONCLUSION: When used as decision support, interactive use of CAD for malignant masses on mammograms may be more effective than the current use of CAD, which is aimed at the prevention of perceptual oversights. PMID- 23091173 TI - Size-specific dose estimates for adult patients at CT of the torso. AB - PURPOSE: To determine relationships among patient size, scanner radiation output, and size-specific dose estimates (SSDEs) for adults who underwent computed tomography (CT) of the torso. MATERIALS AND METHODS: Informed consent was waived for this institutional review board-approved study of existing data from 545 adult patients (322 men, 223 women) who underwent clinically indicated CT of the torso between April 1, 2007, and May 13, 2007. Automatic exposure control was used to adjust scanner output for each patient according to the measured CT attenuation. The volume CT dose index (CTDI(vol)) was used with measurements of patient size (anterioposterior plus lateral dimensions) and the conversion factors from the American Association of Physicists in Medicine Report 204 to determine SSDE. Linear regression models were used to assess the dependence of CTDI(vol) and SSDE on patient size. RESULTS: Patient sizes ranged from 42 to 84 cm. In this range,CTDI(vol) was significantly correlated with size (slope = 0.34 mGy/cm; 95% confidence interval [CI]: 0.31, 0.37 mGy/cm; R(2) = 0.48; P < .001), but SSDE was independent of size (slope = 0.02 mGy/cm; 95% CI: -0.02, 0.07 mGy/cm; R(2) = 0.003; P = .3). These R(2) values indicated that patient size explained 48% of the observed variability in CTDI(vol) but less than 1% of the observed variability in SSDE. The regression of CTDI(vol) versus patient size demonstrated that, in the 42-84-cm range, CTDI(vol) varied from 12 to 26 mGy. However, use of the evaluated automatic exposure control system to adjust scanner output for patient size resulted in SSDE values that were independent of size. CONCLUSION: For the evaluated automatic exposure control system,CTDI(vol) (scanner output) increased linearly with patient size; however, patient dose (as indicated by SSDE) was independent of size. PMID- 23091174 TI - Cognition and sensation in very high static magnetic fields: a randomized case crossover study with different field strengths. AB - PURPOSE: To establish the extent to which representative cognitive functions in subjects undergoing magnetic resonance (MR) imaging are acutely impaired by static magnetic fields of varying field strengths. MATERIALS AND METHODS: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. In this single-blind case-crossover study, 41 healthy subjects underwent an extensive neuropsychologic examination while in MR units of differing field strengths (1.5, 3.0, and 7.0 T), including a mock imager with no magnetic field as a control condition. Subjects were blinded to field strength. Tests were performed while subjects were lying still in the MR unit and while the examination table was moved. The tests covered a representative set of cognitive functions, such as memory, eye-hand coordination, attention, reaction time, and visual discrimination. Subjective sensory perceptions were also assessed. Effects were analyzed with a repeated-measures analysis of variance; the within-subject factors were field strength (0, 1.5, 3.0, and 7.0 T) and state (static, dynamic). RESULTS: Static magnetic fields were not found to have a significant effect on cognitive function at any field strength. However, sensory perceptions did vary according to field strength. Dizziness, nystagmus, phosphenes, and head ringing were related to the strength of the static magnetic field. CONCLUSION: Static magnetic fields as high as 7.0 T did not have a significant effect on cognition. PMID- 23091172 TI - T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy. AB - PURPOSE: To determine the utility of cardiac magnetic resonance (MR) T1 mapping for quantification of diffuse myocardial fibrosis compared with the standard of endomyocardial biopsy. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board. Cardiomyopathy patients were retrospectively identified who had undergone endomyocardial biopsy and cardiac MR at one institution during a 5-year period. Forty-seven patients (53% male; mean age, 46.8 years) had undergone diagnostic cardiac MR and endomyocardial biopsy. Thirteen healthy volunteers (54% male; mean age, 38.1 years) underwent cardiac MR as a reference. Myocardial T1 mapping was performed 10.7 minutes +/- 2.7 (standard deviation) after bolus injection of 0.2 mmol/kg gadolinium chelate by using an inversion-recovery Look-Locker sequence on a 1.5-T MR imager. Late gadolinium enhancement was assessed by using gradient-echo inversion-recovery sequences. Cardiac MR results were the consensus of two radiologists who were blinded to histopathologic findings. Endomyocardial biopsy fibrosis was quantitatively measured by using automated image analysis software with digital images of specimens stained with Masson trichrome. Histopathologic findings were reported by two pathologists blinded to cardiac MR findings. Statistical analyses included Mann-Whitney U test, analysis of variance, and linear regression. RESULTS: Median myocardial fibrosis was 8.5% (interquartile range, 5.7-14.4). T1 times were greater in control subjects than in patients without and in patients with evident late gadolinium enhancement (466 msec +/- 14, 406 msec +/- 59, and 303 msec +/- 53, respectively; P < .001). T1 time and histologic fibrosis were inversely correlated (r = -0.57; 95% confidence interval: -0.74, -0.34; P < .0001). The area under the curve for myocardial T1 time to detect fibrosis of greater than 5% was 0.84 at a cutoff of 383 msec. CONCLUSION: Cardiac MR with T1 mapping can provide noninvasive evidence of diffuse myocardial fibrosis in patients referred for evaluation of cardiomyopathy. PMID- 23091175 TI - Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow up. AB - PURPOSE: To determine the long-term (10-year) survival of patients with colorectal liver metastases treated with radiofrequency (RF) ablation and systemic chemotherapy with intention to treat. MATERIALS AND METHODS: Institutional review board approval was obtained for this study. From 1997 to 2006, 99 consecutive patients with 202 small (0.8-4.0 cm; mean: 2.2 cm +/- 1.1) metachronous colorectal liver metastases underwent ultrasonography-guided percutaneous RF ablation with internally-cooled electrodes in association with systemic chemotherapy. Patients ineligible for surgery (n = 80) or whose lesions were potentially resectable and who refused surgery (n = 19) were included. Patients were followed up with contrast agent-enhanced computed tomography and/or magnetic resonance imaging for a minimum of 3 years to more than 10 years after RF ablation (n = 99, 67, 49, and 25 for 3, 5, 7, and 10 or more years, respectively). Overall local response rates and long-term survival rates were assessed. For each of these primary endpoints, Kaplan-Meier curves were generated and log-rank tests were used to assess for statistically significant differences. RESULTS: Primary and secondary technical success rates were 93.1% (188 of 202) and 100% (14 of 14), respectively. Local tumor progression occurred in 11.9% (24 of 202) metastases, and 54.2% (13 of 24) of these were re-treated. Patient survival rates increased with re-treatment versus no re-treatment (P < .001). At follow-up, 125 new liver metastases were found, and of these 32.8% (41 of 125) were treated with RF ablation. Overall survival rates were 98.0%, 69.3%, 47.8%, 25.0%, and 18.0% (median: 53.2 months) at 1, 3, 5, 7, and 10 years, respectively. The major complication rate was 1.3% (two of 156), and there were no procedure related deaths. At the time this article was written, 32.3% (32 of 99) of the patients were alive, and 67.7% (67 of 99) were deceased, with a median follow-up of 72 months. CONCLUSION: Adding RF ablation to systemic chemotherapy achieved local control in a large majority of metachronous colorectal liver metastases. The 3- to 10-year survival rates of this relatively large series of patients were essentially equivalent to those of most surgical series reported in the literature. PMID- 23091176 TI - Lamellated hyperintense synovitis: potential MR imaging sign of an infected knee arthroplasty. AB - PURPOSE: To determine the sensitivity and specificity of lamellated hyperintense synovitis for infection following knee arthroplasty and to determine the inter- and intraobserver variability of this sign at magnetic resonance (MR) imaging. MATERIALS AND METHODS: The purpose of the retrospective case control study was approved by the hospital's institutional review board. MR images from 28 patients with proved infected total knee arthroplasty and 28 patients with noninfected arthroplasty were reviewed by two musculoskeletal radiologists for the presence of lamellated hyperintense synovitis. Cases were rereviewed 2 weeks later by each reader. The sensitivity and specificity were calculated with the initial reads. The kappa statistic was used to assess inter- and intraobserver reliability. RESULTS: The sensitivity of lamellated hyperintense synovitis for infection was 0.86-0.92 (95% confidence interval [CI]: 0.75, 0.97) and the specificity was 0.85 0.87 (95% CI: 0.74, 0.94). There was almost perfect interobserver agreement (kappa = 0.82; 95% CI: 0.72, 0.93; P < .001) and intraobserver agreement (for reader 1, kappa = 0.89 [95% CI: 0.78, 1.00; P < .001] and for reader 2, kappa = 0.89 [95% CI: 0.77, 1.00; P < .001]) in the classification of the synovial pattern. CONCLUSION: In this selected series of patients, the presence of lamellated hyperintense synovitis at MR imaging of knee arthroplasty had a high sensitivity and specificity for infection. This sign had high inter- and intraobserver reliability. PMID- 23091177 TI - The boundaries of mental health first aid. PMID- 23091178 TI - A solution to inappropriate self-citation via peer review. PMID- 23091179 TI - Tourette syndrome. PMID- 23091180 TI - Maternal and neonatal separation and mortality associated with concurrent admissions to intensive care units. AB - BACKGROUND: Concurrent admission of a mother and her newborn to separate intensive care units (herein referred to as co-ICU admission), possibly in different centres, can magnify family discord and stress. We examined the prevalence and predictors of mother-infant separation and mortality associated with co-ICU admissions. METHODS: We completed a population-based study of all 1 023 978 singleton live births in Ontario between Apr. 1, 2002, and Mar. 31, 2010. We included data for maternal-infant pairs that had co-ICU admission (n = 1216), maternal ICU admission only (n = 897), neonatal ICU (NICU) admission only (n = 123 236) or no ICU admission (n = 898 629). The primary outcome measure was mother-infant separation because of interfacility transfer. RESULTS: The prevalence of co-ICU admissions was 1.2 per 1000 live births and was higher than maternal ICU admissions (0.9 per 1000). Maternal-newborn separation due to interfacility transfer was 30.8 (95% confidence interval [CI] 26.9-35.3) times more common in the co-ICU group than in the no-ICU group and exceeded the prevalence in the maternal ICU group and NICU group. Short-term infant mortality (< 28 days after birth) was higher in the co-ICU group (18.1 per 1000 live births; maternal age-adjusted hazard ratio [HR] 27.8, 95% CI 18.2-42.6) than in the NICU group (7.6 per 1000; age-adjusted HR 11.5, 95% CI 10.4-12.7), relative to 0.7 per 1000 in the no-ICU group. Short-term maternal mortality (< 42 days after delivery) was also higher in the co-ICU group (15.6 per 1000; age-adjusted HR 328.7, 95% CI 191.2-565.2) than in the maternal ICU group (6.7 per 1000; age adjusted HR 140.0, 95% CI 59.5-329.2) or the NICU group (0.2 per 1000; age adjusted HR 4.6, 95% CI 2.8-7.4). INTERPRETATION: Mother-infant pairs in the co ICU group had the highest prevalence of separation due to interfacility transfer and the highest mortality compared with those in the maternal ICU and NICU groups. PMID- 23091182 TI - Alcohol intolerance associated with Hodgkin lymphoma. PMID- 23091183 TI - Making sense of the world's highest HIV rate. PMID- 23091185 TI - Lost in transition at discharge. PMID- 23091186 TI - Senior suicide: an overlooked problem. PMID- 23091184 TI - Influence of individual and combined healthy behaviours on successful aging. AB - BACKGROUND: Increases in life expectancy make it important to remain healthy for as long as possible. Our objective was to examine the extent to which healthy behaviours in midlife, separately and in combination, predict successful aging. METHODS: We used a prospective cohort design involving 5100 men and women aged 42 63 years. Participants were free of cancer, coronary artery disease and stroke when their health behaviours were assessed in 1991-1994 as part of the Whitehall II study. We defined healthy behaviours as never smoking, moderate alcohol consumption, physical activity (>= 2.5 h/wk moderate physical activity or >= 1 h/wk vigorous physical activity), and eating fruits and vegetables daily. We defined successful aging, measured over a median 16.3-year follow-up, as good cognitive, physical, respiratory and cardiovascular functioning, in addition to the absence of disability, mental health problems and chronic disease (coronary artery disease, stroke, cancer and diabetes). RESULTS: At the end of follow-up, 549 participants had died and 953 qualified as aging successfully. Compared with participants who engaged in no healthy behaviours, participants engaging in all 4 healthy behaviours had 3.3 times greater odds of successful aging (95% confidence interval [CI] 2.1-5.1). The association with successful aging was linear, with the odds ratio (OR) per increment of healthy behaviour being 1.3 (95% CI 1.2-1.4; population-attributable risk for 1-4 v. 0 healthy behaviours 47%). When missing data were considered in the analysis, the results were similar to those of our main analysis. INTERPRETATION: Although individual healthy behaviours are moderately associated with successful aging, their combined impact is substantial. We did not investigate the mechanisms underlying these associations, but we saw clear evidence of the importance of healthy behaviours for successful aging. PMID- 23091187 TI - Rural life hardly healthier. PMID- 23091188 TI - Combination lopinavir and ritonavir alter exogenous and endogenous bile acid disposition in sandwich-cultured rat hepatocytes. AB - Inhibition of the bile salt export pump (BSEP) can cause intracellular accumulation of bile acids and is a risk factor for drug-induced liver injury in humans. Antiretroviral protease inhibitors lopinavir (LPV) and ritonavir (RTV) are reported BSEP inhibitors. However, the consequences of LPV and RTV, alone and combined (LPV/r), on hepatocyte viability, bile acid transport, and endogenous bile acid disposition in rat hepatocytes have not been examined. The effect of LPV, RTV, and LPV/r on cellular viability and the disposition of [(3)H]taurocholic acid (TCA) and [(14)C]chenodeoxycholic acid (CDCA) was determined in sandwich-cultured rat hepatocytes (SCRH) and suspended rat hepatocytes. Lactate dehydrogenase and ATP assays revealed a concentration dependent effect of LPV and RTV on cellular viability. LPV (5 uM), alone and combined with 5 uM RTV, significantly decreased [(3)H]TCA accumulation in cells + bile of SCRHs compared with control. LPV/r significantly increased [(3)H]TCA cellular accumulation (7.7 +/- 0.1 pmol/mg of protein) compared with vehicle and 5 uM LPV alone (5.1 +/- 0.7 and 5.0 +/- 0.5 pmol/mg of protein). The [(3)H]TCA biliary clearance was reduced significantly by LPV and RTV and further reduced by LPV/r. LPV and RTV did not affect the initial uptake rates of [(3)H]TCA or [(14)C]CDCA in suspended rat hepatocytes. LPV (50 uM), RTV (5 uM), and LPV/r (5 and 50 uM/5 uM) significantly decreased the accumulation of total measured endogenous bile acids (TCA, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, and alpha/beta-tauromuricholic acid) in SCRH. Quantification of endogenous bile acids in SCRH may reveal important adaptive responses associated with exposure to known BSEP inhibitors. PMID- 23091189 TI - Pharmacokinetic mechanism involved in the prolonged high retention of laninamivir in mouse respiratory tissues after intranasal administration of its prodrug laninamivir octanoate. AB - Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 MUmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 MUM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery. PMID- 23091190 TI - Community health workers' experiences and perspectives on mass drug administration for schistosomiasis control in western Kenya: the SCORE Project. AB - Abstract. The Schistosomiasis Consortium for Operational Research and Evaluation (SCORE) includes communitywide treatment in areas with >= 25% prevalence of schistosomiasis along the shores of Lake Victoria using community health workers (CHWs). The CHWs are key drivers in community-owned mass drug administration (MDA) intervention programs. We explored their experiences and perceptions after initial MDA participation. Unstructured open-ended group discussions were conducted after completion of MDA activities. Narratives were obtained from CHWs using a digital audio recorder during the group discussion, transcribed verbatim and translated into English where applicable. Thematic decomposition of data was done using ATLAS.t.i. software. From the perspective of the CHWs, factors influencing MDA compliance included drug side effects, food supply stability, and conspiracy theories about the "real" purpose of treatment. The interest of CHWs to serve as community drug distributors stemmed from both intrinsic and extrinsic factors. Feedback from CHWs can promote more effective MDA in rural Kenyan communities. PMID- 23091191 TI - Endemic transmission of visceral leishmaniasis in Bhutan. AB - Visceral leishmaniasis was first reported in Bhutan in 2006. We conducted studies of the parasite, possible vectors and reservoirs, and leishmanin skin test and risk factor surveys in three villages. Nineteen cases were reported from seven districts. Parasite typing yielded two novel microsatellite sequences, both related to Indian L. donovani. In one case village, 40 (18.5%) of 216 participants had positive leishmanin skin test results, compared with 3 (4.2%) of 72 in the other case village and 0 of 108 in the control village. Positive results were strongly associated with the village and increasing age. None of the tested dogs were infected. Eighteen sand flies were collected, 13 Phlebotomus species and 5 Sergentomyia species; polymerase chain reaction for leishmanial DNA was negative. This assessment suggests that endemic visceral leishmaniasis transmission has occurred in diverse locations in Bhutan. Surveillance, case investigations, and further parasite, vector, and reservoir studies are needed. The potential protective impact of bed nets should be evaluated. PMID- 23091192 TI - Acute Chagas disease in a returning traveler. AB - Acute Chagas disease is rarely recognized, and the risk for acquiring the disease is undefined in travelers to Central America. We describe a case of acute Chagas disease in a traveler to Costa Rica and highlight the need for increased awareness of this infection in travelers to Chagas-endemic areas. PMID- 23091193 TI - Scrub typhus: surveillance, clinical profile and diagnostic issues in Shandong, China. AB - To elucidate the epidemic status, clinical profile, and current diagnostic issues of scrub typhus in Shandong Province, we analyzed the surveillance data of scrub typhus from 2006 to 2011 and conducted a hospital-based disease survey in 2010. Scrub typhus was clustered in mountainous and coastal areas in Shandong Province, with an epidemic period from September to November. The most common manifestations were fever (100%), eschar or skin ulcer (86.3%), fatigue (71.6%), anorexia (71.6%), and rash (68.6%). Predominant complications included bronchopneumonia, toxic hepatitis, and acute cholecystitis in 21.6%, 3.9%, and 2.9% of the cases, respectively. Severe complications including toxic myocarditis, heart failure, pneumonedema, pleural effusion, and emphysema were first reported in Shandong. Missed and delayed diagnosis of scrub typhus was common in local medical institutions. Alarm should be raised for changes of clinical features and current diagnostic issues of scrub typhus in newly developed endemic areas. PMID- 23091194 TI - Use of rapid diagnostic tests in malaria school surveys in Kenya: does their under-performance matter for planning malaria control? AB - Malaria rapid diagnostic tests (RDTs) are known to yield false-positive results, and their use in epidemiologic surveys will overestimate infection prevalence and potentially hinder efficient targeting of interventions. To examine the consequences of using RDTs in school surveys, we compared three RDT brands used during a nationwide school survey in Kenya with expert microscopy and investigated the cost implications of using alternative diagnostic approaches in identifying localities with differing levels of infection. Overall, RDT sensitivity was 96.1% and specificity was 70.8%. In terms of classifying districts and schools according to prevalence categories, RDTs were most reliable for the < 1% and > 40% categories and least reliable in the 1-4.9% category. In low-prevalence settings, microscopy was the most expensive approach, and RDT results corrected by either microscopy or polymerase chain reaction were the cheapest. Use of polymerase chain reaction-corrected RDT results is recommended in school malaria surveys, especially in settings with low-to-moderate malaria transmission. PMID- 23091195 TI - Treatment of Dientamoeba fragilis in patients with irritable bowel syndrome. AB - The role of Dientamoeba fragilis in irritable bowel syndrome (IBS) is incompletely known. We aimed to investigate whether eradication of D. fragilis alleviates symptoms in IBS. Twenty-five D. fragilis-positive IBS patients were treated with Metronidazole (MZ) or Tetracycline. The patients were mostly female (89%), and mean age (SD) was 35.1 (8.2) years. Microbiological response, evaluated 2 weeks post-treatment, was observed in 15 of 25 patients (60%), all by MZ. Clinical response, defined as adequate relief of symptoms, was observed in 7 of 22 patients (32%), all by MZ. In a logistic regression analysis, we found no significant association between clinical and microbiological response. This case study did not support our hypothesis of a simple association between D. fragilis and IBS. Some D. fragilis-infections were insufficiently treated by MZ. Further studies into the prevalence and effect of eradication of D. fragilis in IBS and into efficient treatments of D. fragilis are warranted. PMID- 23091196 TI - Peridomiciliary breeding sites of phlebotomine sand flies (Diptera: Psychodidae) in an endemic area of American cutaneous leishmaniasis in southeastern Brazil. AB - The occurrence of American cutaneous leishmaniasis (ACL) in areas modified by humans indicates that phlebotomine sand fly vectors breed close to human habitations. Potential peridomiciliary breeding sites of phlebotomines were sampled in an area of transmission of Leishmania (Viannia) braziliensis in Southeastern Brazil. Three concentric circles rounding houses and domestic animal shelters, with radii of 20, 40, and 60 m, defined the area to be monitored using adult emergence traps. Of the 67 phlebotomines collected, Lutzomyia intermedia comprised 71.6%; Lutzomyia schreiberi, 20.9%; and Lutzomyia migonei, 4.5%. The predominance of L. intermedia, the main species suspected of transmitting L. (V.) braziliensis in Southeastern Brazil, indicates its participation in the domiciliary transmission of ACL, providing evidence that the domiciliary ACL transmission cycle might be maintained by phlebotomines that breed close to human habitations. This finding might also help in planning measures that would make the peridomiciliary environment less favorable for phlebotomine breeding sites. PMID- 23091198 TI - TRAIL: not just for tumors anymore? AB - Since the discovery of TNF-related apoptosis-inducing ligand (TRAIL) and its network of receptors, the majority of attention has focused on the clinical potential of manipulating this pathway in cancer therapy. However, the widespread expression of TRAIL under inflammatory conditions and the ability to induce both apoptotic and prosurvival signaling pathways has suggested that TRAIL plays broader roles in regulating immune processes. Two new studies now show that expression of TRAIL by neutrophils in the lung facilitates defenses against bacterial pathogens, whereas expression of TRAIL by cells within arterioles exacerbates vascular disease. These differentiating results highlight that the context of TRAIL signaling can determine whether the outcome is beneficial or pathogenic for the host. PMID- 23091197 TI - Brucellosis among hospitalized febrile patients in northern Tanzania. AB - Acute and convalescent serum samples were collected from febrile inpatients identified at two hospitals in Moshi, Tanzania. Confirmed brucellosis was defined as a positive blood culture or a >= 4-fold increase in microagglutination test titer, and probable brucellosis was defined as a single reciprocal titer >= 160. Among 870 participants enrolled in the study, 455 (52.3%) had paired sera available. Of these, 16 (3.5%) met criteria for confirmed brucellosis. Of 830 participants with >= 1 serum sample, 4 (0.5%) met criteria for probable brucellosis. Brucellosis was associated with increased median age (P = 0.024), leukopenia (odds ratio [OR] 7.8, P = 0.005), thrombocytopenia (OR 3.9, P = 0.018), and evidence of other zoonoses (OR 3.2, P = 0.026). Brucellosis was never diagnosed clinically, and although all participants with brucellosis received antibacterials or antimalarials in the hospital, no participant received standard brucellosis treatment. Brucellosis is an underdiagnosed and untreated cause of febrile disease among hospitalized adult and pediatric patients in northern Tanzania. PMID- 23091199 TI - Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials. AB - AIMS: The aim of this study was to evaluate benefits and risks of extending dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in the drug-eluting stent era. METHODS AND RESULTS: We searched electronic databases (Medline, EMBASE, the Cochrane Central Register of Controlled Trials), relevant websites, reference lists, conference abstracts, reviews, chapters in books, and proceedings of advisory panels for the US Food and Drug Administration, for randomized controlled trials investigating the clinical impact of extending DAPT duration in patients undergoing PCI. The primary endpoint was all-cause death. The secondary endpoints were myocardial infarction (MI), stent thrombosis (ST), cerebrovascular accidents (CVAs), and thrombolysis in myocardial infarction (TIMI) major bleeding. We included four trials that randomized 8231 patients (50.2%, extended DAPT duration vs. 49.8%, control duration). A total of 8158 patients (99.1%) were available for final analyses. The median DAPT duration was 16.8 vs. 6.2 months for the extended DAPT and control groups, respectively. At follow-up (median 16.8 months) extending DAPT duration did not reduce all-cause death [odds ratio (95% confidence interval) = 1.15 (0.85-1.54), P = 0.36], MI [0.95 (0.66-1.36), P = 0.77], ST [0.88 (0.43-1.81), P = 0.73], or CVAs [1.51 (0.92-2.47), P = 0.10]. Conversely, extended DAPT duration clearly increased the risk of TIMI major bleeding [2.64 (1.31-5.30), P = 0.006]. CONCLUSIONS: The extension of DAPT duration after percutaneous coronary interventions may increase the risk of bleeding without reducing ischaemic events. These results need corroboration from large ongoing trials. PMID- 23091200 TI - What is the atrium trying to tell us? PMID- 23091202 TI - Potential lifetime cost-effectiveness of catheter-based renal sympathetic denervation in patients with resistant hypertension. AB - AIMS: Recent studies have demonstrated the safety and efficacy of catheter-based renal sympathetic denervation (RDN) for the treatment of resistant hypertension. We aimed to determine the cost-effectiveness of this approach separately for men and women of different ages. METHODS AND RESULTS: A Markov state-transition model accounting for costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness was developed to compare RDN with best medical therapy (BMT) in patients with resistant hypertension. The model ran from age 30 to 100 years or death, with a cycle length of 1 year. The efficacy of RDN was modelled as a reduction in the risk of hypertension-related disease events and death. Analyses were conducted from a payer's perspective. Costs and QALYs were discounted at 3% annually. Both deterministic and probabilistic sensitivity analyses were performed. When compared with BMT, RDN gained 0.98 QALYs in men and 0.88 QALYs in women 60 years of age at an additional cost of ?2589 and ?2044, respectively. As the incremental cost-effectiveness ratios increased with patient age, RDN consistently yielded more QALYs at lower costs in lower age groups. Considering a willingness-to-pay threshold of ?35 000/QALY, there was a 95% probability that RDN would remain cost-effective up to an age of 78 and 76 years in men and women, respectively. Cost-effectiveness was influenced mostly by the magnitude of effect of RDN on systolic blood pressure, the rate of RDN non responders, and the procedure costs of RDN. CONCLUSION: Renal sympathetic denervation is a cost-effective intervention for patients with resistant hypertension. Earlier treatment produces better cost-effectiveness ratios. PMID- 23091201 TI - Drug-induced arrhythmia: pharmacogenomic prescribing? AB - Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from www.qtdrugs.org up to January 2012, case reports and articles from www.pubmed.com up to January 2012, and the British National Formulary edition at www.bnf.org. PMID- 23091204 TI - Complications of cardiac implants: handling device infections. AB - Managing patients with cardiac implantable electrophysiological devices (CIED) infections can be challenging. The first step should be prevention, which involves patient selection, timing of implantation, and the procedure itself. After implantation, a high degree of suspicion should be applied in order to correctly diagnose patients with infected implanted devices. It is necessary to recognize that patients can present with a wide variety of signs and symptoms. Once diagnosed, the next step is determining if it is a local pocket infection or system infection. In almost every patient, in addition to antibiotics, complete removal of ALL hardware is required. Transvenous lead extraction is now safe and effective, but should only be performed at experienced centres with a practiced extraction team, all possible needed equipment, and cardiothoracic surgical backup. After extraction, the indication for CIED therapy should be re-evaluated to determine re-implantation is warranted. Timing of re-implantation depends on a variety of factors such as type of infection or valvular involvement and should be made in concordance with an infectious disease specialist. This review is aimed at introducing the steps needed to manage patients with infected cardiac devices. PMID- 23091203 TI - Liver function abnormalities, clinical profile, and outcome in acute decompensated heart failure. AB - AIMS: The aim of this study was to assess the prevalence of abnormal liver function tests (LFTs) and the associated clinical profile and outcome(s) in acute decompensated heart failure (ADHF) patients. Alteration in LFTs is a recognized feature of ADHF, but prevalence and outcomes data from a broad contemporary cohort of ADHF are scarce and the mechanism(s) of ADHF-induced cholestasis is unknown. METHODS AND RESULTS: We conducted a post hoc analysis of SURVIVE, a large clinical trial including ADHF patients treated with levosimendan or dobutamine. All LFTs were available in 1134 patients at baseline. Abnormal LFTs were seen in 46% of ADHF patients: isolated abnormal alkaline phosphatase (AP) was noted in 11%, isolated abnormal transaminases in 26%, and a combination of abnormal AP and transaminases in 9%. Abnormal AP was associated with marked signs of systemic congestion and elevated right-sided filling pressure. Abnormal AP had no relationship with 31-day mortality but was associated with worse 180-day mortality (23.5 vs. 34.9%, P = 0.001 vs. patients with normal AP). Abnormal transaminases were associated with clinical signs of hypoperfusion and with greater 31-day and 180-day mortality compared with normal transaminase profiles (17.6 vs. 8.4% and 31.6 vs. 22.4%, respectively; both P < 0.001). There was no additive value of abnormal AP plus abnormal transaminase on a long-term outcome. CONCLUSION: Abnormal LFTs were present in about a half of patients presenting with ADHF treated with inotropes. Abnormal AP and abnormal transaminases were associated with specific clinical, biological, and prognostic features, including a short-term overmortality with increased transaminases but not with biological signs of cholestasis, in ADHF patients. PMID- 23091205 TI - Principles and applications of quantum control engineering. PMID- 23091206 TI - Principles and applications of quantum control engineering. AB - This is a brief survey of quantum feedback control and specifically follows on from the two-day conference Principles and applications of quantum control engineering, which took place in the Kavli Royal Society International Centre at Chicheley Hall, on 12-13 December 2011. This was the eighth in a series of principles and applications of control to quantum systems workshops. PMID- 23091207 TI - Stabilizing entangled states with quasi-local quantum dynamical semigroups. AB - We provide a solution to the problem of determining whether a target pure state can be asymptotically prepared using dissipative Markovian dynamics under fixed locality constraints. Besides recovering existing results for a large class of physically relevant entangled states, our approach has the advantage of providing an explicit stabilization test solely based on the input state and constraints of the problem. Connections with the formalism of frustration-free parent Hamiltonians are discussed, as well as control implementations in terms of a switching output-feedback law. PMID- 23091208 TI - Specification of photonic circuits using quantum hardware description language. AB - Following the simple observation that the interconnection of a set of quantum optical input-output devices can be specified using structural mode VHSIC hardware description language, we demonstrate a computer-aided schematic capture workflow for modelling and simulating multi-component photonic circuits. We describe an algorithm for parsing circuit descriptions to derive quantum equations of motion, illustrate our approach using simple examples based on linear and cavity-nonlinear optical components, and demonstrate a computational approach to hierarchical model reduction. PMID- 23091209 TI - Qubit purification speed-up for three complementary continuous measurements. AB - We consider qubit purification under simultaneous continuous measurement of the three non-commuting qubit operators sigma(x), sigma(y), sigma(z). The purification dynamics is quantified by (i) the average purification rate and (ii) the mean time of reaching a given level of purity, 1-epsilon. Under ideal measurements (detector efficiency eta=1), we show in the first case an asymptotic mean purification speed-up of 4 when compared with a standard (classical) single detector measurement. However, by the second measure-the mean time of first passage T(epsilon) of the purity-the corresponding speed-up is only 2. We explain these speed-ups using the isotropy of the qubit evolution that provides an equivalence between the original measurement directions and three simultaneous measurements, one with an axis aligned along the Bloch vector and the other with axes in the two complementary directions. For inefficient detectors, eta=1 - delta < 1, the mean time of first passage T(delta,epsilon)increases because qubit purification competes with an isotropic qubit dephasing. In the asymptotic high purity limit (epsilon,delta?1), we show that the increase possesses a scaling behaviour: DeltaT(delta,epsilon) is a function only of the ratio delta/epsilon. The increase DeltaT(delta,epsilon) is linear for small arguments, but becomes exponential ~exp(delta,2epsilon) for delta/epsilon large. PMID- 23091210 TI - Asymptotic inference in system identification for the atom maser. AB - System identification is closely related to control theory and plays an increasing role in quantum engineering. In the quantum set-up, system identification is usually equated to process tomography, i.e. estimating a channel by probing it repeatedly with different input states. However, for quantum dynamical systems such as quantum Markov processes, it is more natural to consider the estimation based on continuous measurements of the output, with a given input that may be stationary. We address this problem using asymptotic statistics tools, for the specific example of estimating the Rabi frequency of an atom maser. We compute the Fisher information of different measurement processes as well as the quantum Fisher information of the atom maser, and establish the local asymptotic normality of these statistical models. The statistical notions can be expressed in terms of spectral properties of certain deformed Markov generators, and the connection to large deviations is briefly discussed. PMID- 23091211 TI - Pure Gaussian state generation via dissipation: a quantum stochastic differential equation approach. AB - Recently, the complete characterization of a general Gaussian dissipative system having a unique pure steady state was obtained. This result provides a clear guideline for engineering an environment such that the dissipative system has a desired pure steady state such as a cluster state. In this paper, we describe the system in terms of a quantum stochastic differential equation (QSDE) so that the environment channels can be explicitly dealt with. Then, a physical meaning of that characterization, which cannot be seen without the QSDE representation, is clarified; more specifically, the nullifier dynamics of any Gaussian system generating a unique pure steady state is passive. In addition, again based on the QSDE framework, we provide a general and practical method to implement a desired dissipative Gaussian system, which has a structure of quantum state transfer. PMID- 23091212 TI - The quantum trajectory approach to quantum feedback control of an oscillator revisited. AB - We revisit the stochastic master equation approach to feedback cooling of a quantum mechanical oscillator undergoing position measurement. By introducing a rotating wave approximation for the measurement and bath coupling, we can provide a more intuitive analysis of the achievable cooling in various regimes of measurement sensitivity and temperature. We also discuss explicitly the effect of backaction noise on the characteristics of the optimal feedback. The resulting rotating wave master equation has found application in our recent work on squeezing the oscillator motion using parametric driving and may have wider interest. PMID- 23091213 TI - Robust stability of uncertain linear quantum systems. AB - This paper considers the problem of robust stability for a class of uncertain linear quantum systems subject to unknown perturbations in the system Hamiltonian. The case of a nominal linear quantum system is considered with quadratic perturbations to the system Hamiltonian. A robust stability condition is given in terms of a strict bounded real condition. PMID- 23091214 TI - Quantum measurements in continuous time, non-Markovian evolutions and feedback. AB - In this article, we reconsider a version of quantum trajectory theory based on the stochastic Schrodinger equation with stochastic coefficients, which was mathematically introduced in the 1990s, and we develop it in order to describe the non-Markovian evolution of a quantum system continuously measured and controlled, thanks to a measurement-based feedback. Indeed, realistic descriptions of a feedback loop have to include delay and thus need a non Markovian theory. The theory allows us to put together non-Markovian evolutions and measurements in continuous time, in agreement with the modern axiomatic formulation of quantum mechanics. To illustrate the possibilities of such a theory, we apply it to a two-level atom stimulated by a laser. We introduce closed loop control too, via the stimulating laser, with the aim of enhancing the 'squeezing' of the emitted light, or other typical quantum properties. Note that here we change the point of view with respect to the usual applications of control theory. In our model, the 'system' is the two-level atom, but we do not want to control its state, to bring the atom to a final target state. Our aim is to control the 'Mandel Q-parameter' and the spectrum of the emitted light; in particular, the spectrum is not a property at a single time, but involves a long interval of times (a Fourier transform of the autocorrelation function of the observed output is needed). PMID- 23091215 TI - Quantum system characterization with limited resources. AB - The construction and operation of large-scale quantum information devices presents a grand challenge. A major issue is the effective control of coherent evolution, which requires accurate knowledge of the system dynamics that may vary from device to device. We review strategies for obtaining such knowledge from minimal initial resources and in an efficient manner, and apply these to the problem of characterization of a qubit embedded into a larger state manifold, made tractable by exploiting prior structural knowledge. We also investigate adaptive sampling for estimation of multiple parameters. PMID- 23091216 TI - Quantum demolition filtering and optimal control of unstable systems. AB - A brief account of the quantum information dynamics and dynamical programming methods for optimal control of quantum unstable systems is given to both open loop and feedback control schemes corresponding respectively to deterministic and stochastic semi-Markov dynamics of stable or unstable systems. For the quantum feedback control scheme, we exploit the separation theorem of filtering and control aspects as in the usual case of quantum stable systems with non demolition observation. This allows us to start with the Belavkin quantum filtering equation generalized to demolition observations and derive the generalized Hamilton-Jacobi-Bellman equation using standard arguments of classical control theory. This is equivalent to a Hamilton-Jacobi equation with an extra linear dissipative term if the control is restricted to Hamiltonian terms in the filtering equation. An unstable controlled qubit is considered as an example throughout the development of the formalism. Finally, we discuss optimum observation strategies to obtain a pure quantum qubit state from a mixed one. PMID- 23091217 TI - Single photon quantum filtering using non-Markovian embeddings. AB - We determine quantum master and filter equations for continuous measurement of systems coupled to input fields in certain non-classical continuous-mode states, specifically single photon states. The quantum filters are shown to be derivable from an embedding into a larger non-Markovian system, and are given by a system of coupled stochastic differential equations. PMID- 23091218 TI - On structure-preserving transformations of the Ito generator matrix for model reduction of quantum feedback networks. AB - Two standard operations of model reduction for quantum feedback networks, elimination of internal connections under the instantaneous feedback limit and adiabatic elimination of fast degrees of freedom, are cast as structure preserving transformations of Ito generator matrices. It is shown that the order in which they are applied is inconsequential. PMID- 23091219 TI - Non-abelian Weyl commutation relations and the series product of quantum stochastic evolutions. AB - We show that the series product, which serves as an algebraic rule for connecting state-based input-output systems, is intimately related to the Heisenberg group and the canonical commutation relations. The series product for quantum stochastic models then corresponds to a non-abelian generalization of the Weyl commutation relation. We show that the series product gives the general rule for combining the generators of quantum stochastic evolutions using a Lie-Trotter product formula. PMID- 23091220 TI - Establishment of local diagnostic reference levels in paediatric screen-film radiography at a children's hospital. AB - To assess the frequency of examination, image quality (IQ) and establishment of local diagnostic reference levels (LDRLs) in paediatric radiographic examinations. The X-ray device performance, film reject rate and IQ grading were assessed at Radiology Department of a referral and teaching children's hospital in Kenya. A questionnaire method was developed and used in recording the exposure factors used to indirectly calculate patient doses. The study established the first age- and technique-specific diagnostic reference levels (DRLs) for paediatric patients with respect to grid and non-grid radiographic techniques. The mean doses in most grid examinations exceeded the available international DRLs. The non-grid radiography imaging technique provided better IQ and an optimal patient dose. In this study, the preliminary age-specific paediatric DRLs, based on the mean values of the dose distribution, have been suggested for the type of examination considered. They form the preliminary LDRLs, which are lower than the few available international DRLs. PMID- 23091221 TI - A A field test for extremity dose assessment during outages at Korean nuclear power plants. AB - During maintenance on the water chamber of a steam generator, the pressuriser heater and the pressure tube feeder in nuclear power plants, workers are likely to receive high radiation doses due to the severe workplace conditions. In particular, it is expected that workers' hands would receive the highest radiation doses because of their contact with the radioactive materials. In this study, field tests for extremity dose assessments in radiation workers undertaking contact tasks with high radiation doses were conducted during outages at pressurised water reactors and pressurised heavy water reactors in Korea. In the test, the radiation workers were required to wear additional thermoluminescent dosemeters (TLDs) on their backs and wrists and an extremity dosemeter on the finger, as well as a main TLD on the chest while performing the maintenance tasks. PMID- 23091222 TI - The impact of past introductions on an iconic and economically important species, the red deer of Scotland. AB - The red deer (Cervus elaphus) is an iconic species in Scotland and, due to its value as a game species, an important element of the Scottish rural economy. The native status of this species is sometimes questioned because of many recorded introductions of nonnative deer in the past that were an attempt to improve trophy size. In this study, we assessed the impact of past introductions on the genetic makeup of Scottish red deer by genotyping at 15 microsatellite loci a large number of samples (n = 1152), including mainland and island Scottish red deer and individuals from several putative external source populations used in introductions to improve trophy size. Population structure and introgression assessment analyses revealed that the impact of introductions was weak in Highland red deer populations but more prominent on the islands, especially on those where current red deer populations are mostly or entirely derived from introductions (Harris & Lewis, Arran, and Rum). Frequent imports of Central Eastern European red deer into English deer parks were reflected in the higher genetic introgression values found in some of the individuals collected in parks. PMID- 23091223 TI - Localization of a new gene for bitterness in cucumber. AB - Bitterness in cucumber fruit and foliage is due to the presence of cucurbitacins. Several genes have been described that control the trait, with bi (bi-1) making fruit and foliage bitter free and Bt (Bt-1) making the fruit highly bitter. Previous studies have reported the inheritance and molecular markers linked to bi 1 or Bt-1, but we were interested in studying the inheritance of fruit bitterness in the progeny of 2 nonbitter fruit inbred lines. The objective was to determine the inheritance of cucumber fruit and foliage bitterness and to locate them on a current linkage map using a recombinant inbred lines (RILs) population derived by crossing 9110Gt and 9930. It was concluded from the inheritance analysis that there were 2 loci controlling fruit bitterness in the population. One locus was in the same position as the location previously identified for bi-1, and another locus was for bi-3. Using a simple sequence repeat (SSR) linkage map, 2 loci for fruit bitterness in this RILs population were mapped. The locus of bi-1 was located at the region between SSR0004 and SSR02309 within the genetic distance of 5.2 cM on chromosome 6. The locus of bi-3 was placed in the region of SSR00116 SSR05321 within the genetic distance of 6.3 cM on chromosome 5. The physical distances for the regions of bi-1 and bi-3 were 11,430.94 Kb with 160 predicted genes and 1528.23 Kb with 198 predicted genes, respectively. Among 160 predicted genes for bi-1, there is a terpene synthase gene named Csa008595, which was speculated as the candidate gene of bi-1. PMID- 23091224 TI - Nucleotide sequence diversity of floral pigment genes in Mexican populations of Ipomoea purpurea (morning glory) accord with a neutral model of evolution. AB - The common morning glory (Ipomoea purpurea) is an annual vine native to Central and Southern Mexico. The genetics of flower color polymorphisms and interactions with the biotic environment have been extensively studied in I. purpurea and in its sister species I. nil. In this study, we examine nucleotide sequence polymorphism in 11 loci, 9 of which are known to participate in a pathway that produces floral pigments. A sample of 30 I. purpurea accessions from the native range of Central and Southern Mexico comprise the data, along with one accession from each of the two sister species I. alba and I. nil. We observe moderate levels of nucleotide sequence polymorphism of ~1%. The ratio of recombination to mutation parameter estimates (rho/theta) of ~2.5 appears consistent with a mixed mating system. Ipomoea resequencing data from these genic regions are noteworthy in providing a good fit to the standard neutral model of molecular evolution. The derived silent site frequency spectrum is very close to that predicted by coalescent simulations of a drift-mutation process, and Tajima's D values are not significantly different from expectations under neutrality. PMID- 23091225 TI - Heterozygosity-fitness correlations in adult and juvenile Zenaida Dove, Zenaida aurita. AB - Understanding how fitness is related to genetic variation is of crucial importance in both evolutionary ecology and conservation biology. We report a study of heterozygosity-fitness correlations in a wild, noninbred population of Zenaida Doves, Zenaida aurita, based on a sample comprising 489 individuals (382 adults and 107 juveniles) typed at 13 microsatellite loci, resulting in a data set comprising 5793 genotypes. In both adults and juveniles, and irrespective of sex, no evidence was found for an effect of either multilocus or single-locus heterozygosity on traits potentially related to fitness such as foraging tactic, competitive ability, and fluctuating asymmetry. In contrast, a significant negative correlation between body condition and multilocus heterozygosity, indicative of outbreeding depression, was found in juveniles, whereas no such trend was observed in adults. However, the frequency distribution of heterozygosity did not differ between the two age classes, suggesting compensatory growth by heterozygous juveniles. We discuss our results in relation to some practical limitations associated with studies of heterozygosity-fitness correlations, and suggest that tropical bird species with allopatric divergence between island populations may provide a good biological model for the detection of outbreeding depression. PMID- 23091226 TI - Validation of the EuroSCORE II: should we be concerned with retrospective performance? PMID- 23091227 TI - Long-term outcomes of bilateral lobar lung transplantation. AB - OBJECTIVES: Lobar lung transplantation is an option that provides the possibility of transplanting an urgent listed recipient of small size with a size-mismatched donor lung by surgically reducing the size of the donor lung. We report our short and long-term results with bilateral lobar lung transplantation (BLLT) and compare it with the long-term outcomes of our cohort. METHODS: Retrospective analyses of 75 lung transplant recipients who received downsized lungs with a special focus on 23 recipients with BLLT performed since January 2000. Postoperative surgical complications, lung function tests, late complications and survival were analyzed. The decision to perform lobar transplantation was considered during allocation and finally decided prior to implantation. RESULTS: Cystic fibrosis was the most common indication (43.5%) followed by pulmonary fibrosis (35%). Median age at transplantation was 41 (range 13-66) years. Fifteen were females. Nineteen of the transplantations (83%) were done with extracorporeal membrane oxygenation (ECMO) support; 3 of them were already on ECMO prior to transplantation. There was no 30-day or in-hospital mortality. No bronchial complications occurred. The most common early complication was haematothorax (39%), which required surgical intervention. The rate of postoperative atrial arrhythmias was 30%. Forced expiratory volumes in 1 s (% predicted) at 1 and 2 years were 76 +/- 23 and 76 +/- 22, respectively (mean +/- standard deviation). By 2-year follow-up, bronchiolitis obliterans syndrome was documented in 3 patients with a median follow-up of 1457 days. Overall survivals at 1 and 5 years were 82 +/- 8 and 64 +/- 11%, respectively and were comparable with those of 219 other recipients who received bilateral lung transplantation during the same period (log rank test, P = 0.56). CONCLUSIONS: This study demonstrates that BLLT has short- and long-term outcomes comparable with those of standard bilateral lung transplantation. The limitation of lung transplantation due to size-mismatch, particularly in smaller recipients, could be overcome by utilizing lobar lung transplantation. PMID- 23091228 TI - Intravascular plasma cell granuloma of the pulmonary artery. PMID- 23091229 TI - Preoperative quality of life predicts survival following pulmonary resection in stage I non-small-cell lung cancer. AB - OBJECTIVES: The objective of this study was to assess the prognostic role of preoperative quality of life (QoL) in patients operated on for early-stage non small-cell lung cancer (NSCLC). METHODS: This is an observational analysis of 131 consecutive patients (2003-08) submitted to pulmonary lobectomy and systematic nodal dissection for pathological pT1N0 or pT2N0 stages NSCLC with a complete follow-up (median 40 months). QoL was measured by the Short Form 36v2, a multidimensional survey assessing eight domains and two composite scales (physical component score [PCS] and mental component score [MCS]). Survival was calculated by the Kaplan-Meier method. The log-rank test was used to assess differences between groups. The relationships between survival and QoL composite scales were determined by Cox proportional hazards regression analysis adjusting for the effect of several baseline and clinical variables. PCS and MCS were categorized according to their values greater or lower than 50 percentiles (general population norms). RESULTS: Fifty-three (40%) patients had PCS <50 and 71 (54%) had MCS <50. Results from physical functioning (P = 0.03) and general health (P = 0.03) scales were directly associated with survival. Multivariable regression showed that significant factors associated with overall survival were age >70 (hazard ratio [HR] 2.4, 95% confidence interval [95% CI] 1.2-4.8, P = 0.01) and PCS <50 (HR 2.3, 95% CI 1.4-4.4, P = 0.01). MCS, pT stage, histology, forced expiratory volume in 1 s, DLCO were not associated with prognosis. Patients with PCS >50 lived longer than those with PCS <50 (5-year overall survival 79 vs 49%, P = 0.01), in both pT1 (5-year overall survival 80 vs 49%) and pT2 stages (5-year overall survival 78 vs 48%). Cancer-specific 5-year survival was better in patients with a preoperative PCS >50 compared with those with PCS <50 (89 vs 73%, P = 0.05). Deaths due to cancer recurrence were similar in patients with PCS <50 and >50 (55 vs 53%, P = 0.9). CONCLUSIONS: The physical component of QoL was associated with overall and cancer-specific survivals in patients operated on for early-stage NSCLC. Supportive interventions aimed at improving the perception of physical well-being should be tested to verify whether they can improve long-term prognosis after lung cancer surgery. PMID- 23091230 TI - Giant coronary artery aneurysm arising from the sinus node artery with a fistula into the left atrium. AB - Giant sinus node artery aneurysms with a fistula into the left atrium are extremely rare. A 76-year old woman was admitted to our hospital for an abnormality on her chest X-ray. Coronary computed tomography (CT) angiogram revealed a giant coronary aneurysm with feeding arteries arising from the sinus node artery and the left circumflex artery. Additionally, the aneurysm had a fistula into the left atrium. The size of aneurysm was 70 * 50 mm. Coronary angiography showed contrast dye drained from the aneurysm to the left atrium through the fistula. Surgical treatment was performed. After feeding arteries were ligated, the aneurysm was opened under routine cardiopulmonary bypass. The diameter of the fistula entry was found to be 2 cm, and it was closed using a patch material. Since we were not able to identify the anatomical relationship of the fistula, mitral valve and pulmonary veins through the origin of the fistula, we used an additional right lateral left atriotomy approach. The aneurysmal wall was resected, and the cause of aneurysmal change was histopathologically diagnosed as atherosclerosis. The patient's postoperative course was uneventful, with a postoperative CT showing a complete exclusion of the aneurysm. PMID- 23091231 TI - Reply to Rychlik and McManus. PMID- 23091232 TI - Adjuvant endocrine therapy with tamoxifen: side-effects on the female genital tract are not always what they seem. PMID- 23091233 TI - CT differentiation of abscess and non-infected fluid in the postoperative neck. AB - BACKGROUND: Differentiation of postoperative neck abscess from non-infected fluid is important because the treatment is different. PURPOSE: To determine specific CT findings that might help to differentiate abscesses from non-infected fluid collections in the postoperative neck. MATERIAL AND METHODS: We retrospectively reviewed CT scans of 50 patients (43 men and 7 women; mean age, 62.5 +/- 8.9 years) who had postoperative fluid collections in the neck (26 abscesses and 24 non-infected fluid collections). Diagnosis of an abscess was determined by a positive bacteria culture from the fluid collection. Diagnoses were correlated with the following CT findings: anatomic spaces involved, the maximum transverse diameter, margin, attenuation, rim enhancement, gas bubbles, and manifestations of soft tissue adjacent to a fluid collection. RESULTS: Rim enhancement pattern and soft tissue manifestations showed significant differences between abscess and non-infected fluid. The reliable CT findings for abscess were: (i) rim enhancement > 50% of the circumference, 54% sensitive, 71% specific, and 62% accurate; and (ii) severe soft tissue manifestations, 39% sensitive, 92% specific, and 64% accurate. There were no significant differences in the anatomic spaces involved, the maximum transverse diameter, margin, attenuation, and gas bubbles between abscess and non-infected fluid. CONCLUSION: CT findings that may help differentiate postoperative neck abscess from non-infected fluid were rim enhancement > 50% of the circumference and severe soft tissue manifestations. PMID- 23091235 TI - Computed tomography characterization of neuroendocrine tumors of the thymus can aid identification and treatment. AB - BACKGROUND: Neuroendocrine tumors of the thymus are extremely rare anterior mediastinal tumors. The few studies reporting these tumors have focused on the clinical manifestations and do not provide a summary of characteristic computed tomography (CT) findings. PURPOSE: To investigate the CT appearances of neuroendocrine tumors of the thymus in order to improve the diagnostic and resection efficacy. MATERIAL AND METHODS: Nine cases of pathologically identified thymic neuroendocrine tumors were retrospectively analyzed by CT. All the patients underwent non-enhanced and contrast-enhanced CT. Multiple CT features were examined, including tumor location, shape, margins, CT attenuation, involvement of surrounding structures, and distant metastasis. RESULTS: A total of nine masses were examined in this study. The maximum tumor diameter ranged from 5 to 14 cm (average, 9 cm). The shapes of six masses were lobulated and three were rounded or oval and the margins of seven masses were unclear while two masses were sharp. All the masses showed hypodensity or isodensity compared to muscles in the anterior thoracic wall on non-enhanced CT images. Two masses showed homogeneous attenuation by non-enhanced CT imaging and moderate homogeneous enhancement after contrast administration, while seven masses showed heterogeneous attenuation with patchy low-attenuation foci and showed moderate to strong heterogeneous enhancement. Involvement of adjacent structures was observed in six cases. Five cases were observed to have lymph node metastases and four cases had distant metastases. CONCLUSION: Neuroendocrine tumors of the thymus are rare tumors of the anterior mediastinum with a number of distinct CT characteristics. Most importantly, the density of the tumors was heterogeneous with necrosis or cystic degeneration and moderately or strongly enhancement after bolus injection of contrast medium, which may allow for more efficient tumor identification. Thus, CT can improve of the diagnosis of neuroendocrine tumors and provide critical information for surgical planning. PMID- 23091236 TI - Diagnosis of pericardial effusion with a new generation hand-carried ultrasound device in cardiothoracic intensive care unit patients. AB - BACKGROUND: Technological advances introduced hand-carried ultrasound (HCU) imagers in daily clinical workflow providing several benefits such as fast bedside availability and prompt diagnosis. PURPOSE: To evaluate the diagnostic yield of a latest generation HCU imager compared to contrast-enhanced multidetector computed tomography (MDCT) for the detection of pericardial effusion (PE) in cardiothoracic intensive care unit (ICU) patients. MATERIAL AND METHODS: Thirty-six patients from a cardiothoracic ICU were enrolled to this study irrespective of their underlying disease. All patients were examined with a new generation HCU for the presence of PE. Definite diagnosis of PE was based on findings of MDCT as standard of reference. Statistical analysis was performed using PASW 18. RESULTS: PE was identified in 20 patients by MDCT (prevalence 56%). The HCU examination was carried out technically successfully in all patients. Sensitivity, specificity, positive and negative predictive value of HCU for the diagnosis of PE were 75%, 88%, 88%, and 74%, respectively. CONCLUSION: HCU provides rapid, practical, reliable, and cost-effective diagnosis of PE in patients on cardiothoracic ICU. PMID- 23091237 TI - Arterial spin labeling in patients with chronic cerebral artery steno-occlusive disease: correlation with (15)O-PET. AB - BACKGROUND: Heterogeneity of arterial transit time due to cerebral artery steno occlusive lesions hampers accurate regional cerebral blood flow measurement by arterial spin labeling (ASL). PURPOSE: To assess the feasibility of regional cerebral blood flow measurement by ASL with multiple-delay time sampling in patients with steno-occlusive diseases by comparing with positron emission tomography (PET), and to determine whether regional arterial transit time measured by this ASL technique is correlated with regional mean transit time, a PET index of perfusion pressure. MATERIAL AND METHODS: Sixteen patients with steno-occlusive diseases received both ASL and (15)O-PET. The mean regional cerebral blood flow measured by ASL and PET, regional arterial transit time by ASL, and regional mean transit time by PET were obtained by a region-of-interest analysis. Correlation between regional cerebral blood flow by ASL and that by PET, and correlation between regional arterial transit time by ASL and regional mean transit time by PET were tested using Pearson's correlation coefficient for both absolute and relative values. A multivariate regression analysis was performed to test whether regional arterial transit time by ASL was a significant contributor in modeling regional mean transit time by PET after controlling the effect of regional cerebral blood flow by ASL. RESULTS: A significant positive correlation was found between regional cerebral blood flow by ASL and that by PET for both absolute (r = 0.520, P < 0.0001) and relative (r = 0.691, P < 0.0001) values. A significant positive correlation was found between regional arterial transit time by ASL and regional mean transit time by PET both for absolute (r = 0.369, P = 0.0002) and relative (r = 0.443, P < 0.0001) values. The regression analysis revealed that regional arterial transit time by ASL was a significant contributor in modeling regional mean transit time by PET after controlling regional cerebral blood flow by ASL (P = 0.0011). CONCLUSION: The feasibility of regional cerebral blood flow measurement using ASL with multiple-delay time sampling was confirmed in patients with cerebral artery steno-occlusive diseases. Moreover, it was suggested that mapping of regional arterial transit time has the potential to detect hemodynamic impairment. PMID- 23091239 TI - Use of sonographic guidance for selected biopsies in the lung and superior mediastinum. PMID- 23091238 TI - Early results of real-time qualitative sonoelastography in the evaluation of parotid gland masses: a study with histopathological correlation. AB - BACKGROUND: Sonoelastography has been used to differentiate malignant from benign lesions in numerous types of tissues including breast, prostate, liver, blood vessels, thyroid, musculoskeletal structures, and salivary glands. PURPOSE: To evaluate the efficacy and application of real-time qualitative sonoelastography in the differentiation of benign and malignant focal parotid gland lesions. MATERIAL AND METHODS: A total of 75 patients (36 boys/men, 39 girls/women; age range, 10-83 years) with 81 lesions were evaluated prospectively by sonoelastography performed and interpreted by two expert radiologists. The results of these experts classification and scoring of lesions according to relative stiffness of the mass were compared with each other and with histopathological findings. The interpretation of sonoelastography scores of 1-4 were as follows: 1, soft; 2, mostly soft; 3, mostly stiff; and 4, stiff. RESULTS: The kappa statistic of 0.508 (P < 0.001) indicated moderate agreement between the two radiologists. The sonoelastography scores correctly diagnosed 30 of 49 benign tumors (sensitivity, 61.2%) and 19 of 32 malignant tumors (specificity, 59.4%). The area under the receiver-operating characteristic curve was 0.603. The diagnostic value of sonoelastography for evaluating pleomorphic adenomas, Warthin tumors, adenoid cystic carcinoma, and high-grade tumors was low, whereas the diagnostic rates for low-grade tumors such as mucoepidermoid carcinoma, acinic cell carcinoma, and metastases of basal cell carcinoma were better with sonoelastography. CONCLUSION: Although sonoelastography seems to be promising in the differentiating of low-grade malignancies, the primary role of radiology is currently limited to determination of localization, size, and morphology of parotid tumors. PMID- 23091240 TI - Sonography first for acute flank pain? PMID- 23091241 TI - Sonographic evaluation of acute pelvic pain. PMID- 23091242 TI - Accuracy, agreement, and reliability of fetal cardiac measurements using 4 dimensional spatiotemporal image correlation. AB - OBJECTIVES: The purpose of this study was to evaluate the accuracy, agreement, and reliability of 4-dimensional sonography using spatiotemporal image correlation (STIC) in fetal cardiac measurements during the second and third trimesters. METHODS: Four-dimensional cardiac STIC volumes were acquired from 150 low-risk singleton pregnancies at gestational ages of 18 to 38 weeks. A total of 11 dimensions of the fetal heart and great vessels were analyzed by two different observers. Accuracy was assessed by comparing the measurements acquired by 4 dimensional STIC with those determined by 2-dimensional echocardiography by calculating the mean error and mean percent error and depicted by Bland-Altman plots. Absolute agreement and reliability of STIC-based measurements were evaluated on the basis of an intraclass correlation coefficient (ICC). RESULTS: For STIC-based measurements of cardiac dimensions, good accuracy was achieved by the two experienced observers (mean percent error, -3.10% to 0.87% for observer A; -2.49% to -0.33% for observer B), and absolute agreement was almost perfect (ICC, 95% confidence interval, 0.916-0.993 for observer A; 0.957-0.990 for observer B). Interobserver ICCs among the two observers were between 0.909 and 0.990 (95% confidence interval), whereas intraobserver ICCs for observer A were between 0.894 and 0.989, and those for observer B were between 0.893 and 0.985, showing no significant differences in the reliability of SITC with regard to observers. CONCLUSIONS: Four-dimensional sonography with STIC is a feasible and accurate method for fetal cardiac dimension measurements in the second and third trimesters. It is in good agreement with 2-dimensional echocardiography and can be performed by different observers. PMID- 23091243 TI - Three-dimensional ultrasonographic assessment of fetal total lung volume as a prognostic factor in primary pleural effusion. AB - OBJECTIVES: The purpose of this study was to predict perinatal outcomes using fetal total lung volumes assessed by 3-dimensional ultrasonography (3DUS) in primary pleural effusion. METHODS: Between July 2005 and July 2010, total lung volumes were prospectively estimated in fetuses with primary pleural effusion by 3DUS using virtual organ computer-aided analysis software. The first and last US examinations were considered in the analysis. The observed/expected total lung volumes were calculated. Main outcomes were perinatal death (up to 28 days of life) and respiratory morbidity (orotracheal intubation with mechanical respiratory support >48 hours). RESULTS: Twelve of 19 fetuses (63.2%) survived. Among the survivors, 7 (58.3%) had severe respiratory morbidity. The observed/expected total lung volume at the last US examination before birth was significantly associated with perinatal death (P < .01) and respiratory morbidity (P < .01) as well as fetal hydrops (P < .01) and bilateral effusion (P = .01). CONCLUSIONS: Fetal total lung volumes may be useful for the prediction of perinatal outcomes in primary pleural effusion. PMID- 23091244 TI - Reference ranges for vertebral body areas of the fetal lumbosacral spine on 3 dimensional sonography using volume contrast imaging with OmniView. AB - OBJECTIVES; The purpose of this study was to establish reference ranges for vertebral body areas of the fetal lumbosacral spine in the coronal plane on 3 dimensional sonography using volume contrast imaging with OmniView (GE Healthcare, Zipf, Austria). METHODS; An observational cross-sectional study was conducted on 576 healthy pregnant women at gestational ages of 20 weeks to 34 weeks 6 days. Volume contrast imaging with OmniView was used to measure the vertebral body areas (L1-L5, S1, and S2) by positioning a curved line along the fetal lumbosacral spine. To create reference ranges, first- and second-degree linear regression models adjusted using residual analysis and the coefficient of determination (R(2)) were created. To assess reproducibility, two examiners evaluated 40 random volumes using the intraclass correlation coefficient. RESULTS; The mean areas of the vertebral bodies were 102.72 (range, 25-254), 107.29 (range, 30-245), 105.10 (range, 31-231), 99.09 (range, 31-211), 87.74 (range, 11-178), 65.80 (range, 18-161), and 46.54 (range, 12-129) mm(2) for L1, L2, L3, L4, L5, S1, and S2, respectively. In the intraobserver and interobserver reproducibility assessments, intraclass correlation coefficients of greater than 0.80 were found for all fetal vertebral body areas. CONCLUSIONS; Reference values for fetal lumbosacral spine vertebral body areas were determined by 3-dimensional sonography using volume contrast imaging with OmniView, and they were shown to be reproducible. PMID- 23091245 TI - Accuracy of sonography to predict estimated weight in fetuses with gastroschisis. AB - OBJECTIVES: The purpose of this study was to determine whether sonographic formulas for estimating fetal weight are as accurate for fetuses affected with gastroschisis as they are for healthy fetuses. We hypothesized that because the most commonly used Hadlock formulas rely on the abdominal circumference as a biometric variable, estimates of birth weight are less reliable in fetuses with gastroschisis than in healthy fetuses. METHODS: We performed a chart review of all fetuses with a prenatal diagnosis of gastroschisis at 3 tertiary care institutions from 1990 to 2008. Charts were reviewed for clinical and sonographic data. The estimated fetal weight at the prenatal sonogram closest to delivery was compared to the birth weight. Published Hadlock formulas using 4 biometric parameters were used to calculate the estimated fetal weight. Data analysis was performed using the Student t test and chi(2) test for continuous and categorical variables, respectively. RESULTS: One hundred eleven patients with gastroschisis were identified. Sixty-six patients had a prenatal sonogram with a calculated estimated fetal weight within 7 days of delivery; 88 patients had a sonogram within 14 days. The mean birth weights +/- SD were 2292 +/- 559 and 2477 +/- 531 g in the 0- to 7- and 8- to 14-day groups, respectively. Sonographic biometric measurements underestimated the birth weight by an average of 5.6%. Intrauterine growth restriction was predicted in 72% of all pregnancies but was only present in 52%. CONCLUSIONS: Our study shows a systematic error of birth weight underestimation when using the Hadlock formulas in fetuses affected with gastroschisis. PMID- 23091246 TI - Volumetric contrast-enhanced ultrasound imaging to assess early response to apoptosis-inducing anti-death receptor 5 antibody therapy in a breast cancer animal model. AB - OBJECTIVES: The objective of this study was to determine whether volumetric contrast-enhanced ultrasound (US) imaging could detect early tumor response to anti-death receptor 5 antibody (TRA-8) therapy alone or in combination with chemotherapy in a preclinical triple-negative breast cancer animal model. METHODS: Animal experiments had Institutional Animal Care and Use Committee approval. Thirty breast tumor-bearing mice were administered Abraxane (paclitaxel; Celgene Corporation, Summit, NJ), TRA-8, TRA-8 + Abraxane, or saline as a controlon days 0, 3, 7, 10, 14, and 17. Volumetric contrast-enhanced US imaging was performedon days 0, 1, 3, and 7 before dosing. Changes in parametric maps of tumor perfusion were compared with the tumor volume and immunohistologic findings. RESULTS: Therapeutic efficacy was detected within 7 days after drug administration using parametric volumetric contrast-enhanced US imaging. Decreased tumor perfusion was observed in both the TRA-8-alone- and TRA-8 + Abraxane-dosed animals compared to control tumors (P = .17; P = .001, respectively). The reduction in perfusion observed in the TRA-8 + Abraxane group was matched with a corresponding regression in tumor size over the same period. Survival curves illustrate that the combination of TRA-8 + Abraxane improves drug efficacy compared to the same drugs administered alone. Immunohistologic analysis revealed increased levels of apoptotic activity in the TRA-8-dosed tumors, confirming enhanced antitumor effects. CONCLUSIONS: Preliminary results are encouraging, and volumetric contrast-enhanced US-based tumor perfusion imaging may prove clinically feasible for detecting and monitoring the early antitumor effects in response to combination TRA-8 + Abraxane therapy. PMID- 23091247 TI - Likelihood ratio-based differentiation of nodular Hashimoto thyroiditis and papillary thyroid carcinoma in patients with sonographically evident diffuse hashimoto thyroiditis: preliminary study. AB - OBJECTIVES: To assess the efficacy of sonography for discriminating nodular Hashimoto thyroiditis from papillary thyroid carcinoma in patients with sonographically evident diffuse Hashimoto thyroiditis. METHODS: This study included 20 patients with 24 surgically confirmed Hashimoto thyroiditis nodules and 40 patients with 40 papillary thyroid carcinoma nodules; all had sonographically evident diffuse Hashimoto thyroiditis. A retrospective review of the sonograms was performed, and significant benign and malignant sonographic features were selected by univariate and multivariate analyses. The combined likelihood ratio was calculated as the product of each feature's likelihood ratio for papillary thyroid carcinoma. We compared the abilities of the original sonographic features and combined likelihood ratios in diagnosing nodular Hashimoto thyroiditis and papillary thyroid carcinoma by their sensitivity, specificity, and Youden index. RESULTS: The diagnostic capabilities of the sonographic features varied greatly, with Youden indices ranging from 0.175 to 0.700. Compared with single features, combinations of features were unable to improve the Youden indices effectively because the sensitivity and specificity usually changed in opposite directions. For combined likelihood ratios, however, the sensitivity improved greatly without an obvious reduction in specificity, which resulted in the maximum Youden index (0.825). With a combined likelihood ratio greater than 7.00 as the diagnostic criterion for papillary thyroid carcinoma, sensitivity reached 82.5%, whereas specificity remained at 100.0%. With a combined likelihood ratio less than 1.00 for nodular Hashimoto thyroiditis, sensitivity and specificity were 90.0% and 92.5%, respectively. CONCLUSIONS: Several sonographic features of nodular Hashimoto thyroiditis and papillary thyroid carcinoma in a background of diffuse Hashimoto thyroiditis were significantly different. The combined likelihood ratio may be superior to original sonographic features for discrimination of nodular Hashimoto thyroiditis from papillary thyroid carcinoma; therefore, it is a promising risk index for thyroid nodules and warrants further investigation. PMID- 23091248 TI - Real-time elastography: a useful tool for predicting malignancy in thyroid nodules with nondiagnostic cytologic findings. AB - OBJECTIVES: The aim of this study was to evaluate the predictive value of sonography and sonographic elastography in thyroid nodules with nondiagnostic cytologic findings. METHODS: The study included 101 patients (74 female, mean age +/- SD, 55 +/- 11 years [range, 27-70 years]; and 27 male, mean age, 62 +/- 9 years [range, 42-72 years]) who had at least 1 nodule with nondiagnostic cytologic findings at two different fine-needle aspiration cytologic evaluations and with an indication for hemi or total thyroidectomy for clinical suspicion of malignancy, nodule size, or the occurrence of a coexisting nodule with cytologic findings suspicious for malignancy. All of the patients underwent sonography and elastography 2 months after the second fine-needle aspiration and before surgery. The elastogram was matched with an elasticity color scale and classified as follows: score 1, nodules with high elasticity (soft); score 2, nodules with indeterminate elasticity; and score 3, nodules with low elasticity (hard). RESULTS: A total of 135 nodules (93.7%) were hyperplastic; 15 (9.4%) were papillary carcinomas; and 9 (6.3%) were follicular adenomas. The association of scores 2 and 3 identified 12 of 15 thyroid cancers (sensitivity, 80.0%; specificity, 93.7%; positive predictive value, 57.1%; negative predictive value, 97.8%; and accuracy, 92.4%), whereas the association of conventional sonographic features plus scores 2 and 3 identified all of the cancers (specificity, 70.8%; positive predictive value, 26.3%; negative predictive value, 100%; and accuracy, 73.6%). CONCLUSIONS: Our data suggest that elastography could be a promising tool in the management of nodules that are nondiagnostic at cytologic evaluation, reducing unnecessary surgery. PMID- 23091249 TI - Effects of hemodialysis on brachial artery endothelial function: a clinical study. AB - OBJECTIVES: The purposes of this study were to determine brachial artery endothelial function in patients at varying times during hemodialysis and to evaluate the influence and time-dependent effects of hemodialysis on the vascular endothelium. METHODS: The brachial artery systolic and diastolic dimensions and diameter after reactive hyperemia in patients undergoing hemodialysis (dialysis group), uremic patients who had not yet undergone hemodialysis (predialysis group), and healthy volunteers (control group) were measured by high-frequency sonography. The distensibility coefficient, degree of brachial artery stiffness, and flow-mediated dilatation were calculated. RESULTS: The distensibility coefficient and flow-mediated dilatation of the brachial artery were significantly decreased, whereas the degree of stiffness was significantly increased, in the dialysis and predialysis groups compared with the control group (P < .01). There were no significant differences in these parameters between the dialysis group at 12 months and the predialysis group (P> .05). The distensibility coefficient and flow-mediated dilatation at 36 months were significantly lower (P < .01), whereas the degree of stiffness was significantly higher, than that at 12 months after starting hemodialysis (P < .01) but not between 36 and 60 months after hemodialysis (P > .05). CONCLUSIONS: Hemodialysis could aggravate endothelial dysfunction in uremic patients and this effect is associated with the duration of hemodialysis. PMID- 23091250 TI - Changes in middle cerebral artery blood flow velocity during sonolysis using a diagnostic transcranial probe with a 2-MHz Doppler frequency in healthy volunteers. AB - OBJECTIVES: Ultrasound has various biological effects in the human body. The effects of continuous monitoring with ultrasound (sonolysis) on vasodilatation of the radial artery were described recently. We wanted to ascertain whether similar changes in the blood flow velocity during sonolysis could also be detected in the middle cerebral artery. METHODS: Fifteen healthy volunteers (6 male and 9 female; age range, 23-68 years; mean +/- SD, 47.1 +/- 15.1 years) were subjected to 1 hour of middle cerebral artery sonolysis using a diagnostic transcranial probe with a 2-MHz Doppler frequency and measurement of the blood flow velocity at 2 minute intervals. During a second session, a flow curve was recorded for 10 seconds at 2-minute intervals. The peak systolic velocity, end-diastolic velocity, mean flow velocity, pulsatility index, and resistive index were recorded during both measurements. RESULTS: Irregular changes in the measured blood flow parameters were recorded during both sessions. Changes in particular hemodynamic parameters during both measurements were similar. The changes in the peak systolic velocity, end-diastolic velocity, mean flow velocity, pulsatility index, and resistive index were not significantly different between the two measurements (P < .05 in all cases). CONCLUSIONS: As opposed to sonolysis of the radial artery, sonolysis of the middle cerebral artery using a diagnostic 2-MHz frequency in healthy volunteers did not lead to changes in the flow curve or peripheral vasodilatation. PMID- 23091251 TI - Development of a flexible implantable sensor for postoperative monitoring of blood flow. AB - We have developed a blood flow measurement system using Doppler ultrasound flow sensors fabricated of thin and flexible piezoelectric-polymer films. These flow sensors can be wrapped around a blood vessel and accurately measure flow. The innovation that makes this flow sensor possible is the diffraction-grating transducer. A conventional transducer produces a sound beam perpendicular to its face; therefore, when placed on the wall of a blood vessel, the Doppler shift in the backscattered ultrasound from blood theoretically would be 0. The diffraction grating transducer produces a beam at a known angle to its face; therefore, backscattered ultrasound from the vessel will contain a Doppler signal. Flow sensors were fabricated by spin coating a poly(vinylidene fluoride trifluoroethylene) copolymer film onto a flexible substrate with patterned gold electrodes. Custom-designed battery-operated continuous wave Doppler electronics along with a laptop computer completed the system. A prototype flow sensor was evaluated experimentally by measuring blood flow in a flow phantom and the infrarenal aorta of an adult New Zealand White rabbit. The flow phantom experiment demonstrated that the error in average velocity and volume blood flow was less than 6% for 30 measurements taken over a 2.5-hour period. The peak blood velocity through the rabbit infrarenal aorta measured by the flow sensor was 118 cm/s, within 1.7% of the measurement obtained using a duplex ultrasound system. The flow sensor and electronics operated continuously during the course of the 5 hour experiment after the incision on the animal was closed. PMID- 23091252 TI - Follicular ring sign: a simple sonographic sign for early diagnosis of ovarian torsion. AB - The follicular ring sign is a novel, easily identifiable sonographic finding of ovarian torsion consisting of hyperechoic rings around the antral follicles. In a retrospective analysis of 15 consecutive patients with torsion undergoing surgery, the follicular ring sign was frequently present, starting early in the disease course. This sign could be valuable for accurate and early diagnosis of torsion in the absence of specific conventional sonographic features. PMID- 23091253 TI - Asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum (AVID): an imaging triad. AB - A series of 20 cases from 2 academic institutions is presented with a characteristic imaging triad of asymmetric ventriculomegaly, a large interhemispheric cyst, and partial or complete agenesis of the corpus callosum. Most cases were initially referred as aqueduct stenosis and hydrocephalus or focal porencephaly. We describe the imaging findings that identify an abnormal or absent corpus callosum associated with a type 1 interhemispheric cyst in fetuses initially thought to have hydrocephalus attributable to aqueductal stenosis. We suggest that the acronym AVID (asymmetric ventriculomegaly, interhemispheric cyst, and dysgenesis of the corpus callosum) may be useful in recognition of these cases. All cases presented with markedly asymmetric ventriculomegaly on initial sonography, with progressive hydrocephalus throughout gestation. Fetal magnetic resonance imaging was performed in 15 of 20 cases. Thirteen of 20 cases were identified in male fetuses. Associated fetal and postnatal abnormalities are also reported. Technological improvements in sonography and fetal magnetic resonance imaging allow improved characterization of associated intracranial anomalies in the setting of hydrocephalus. Accurate diagnosis can aid parental counseling, especially because isolated aqueductal stenosis suggests a better prognosis than hydrocephalus with anomalies. Markedly asymmetric ventriculomegaly in this series was the key to excluding isolated aqueductal stenosis and was associated with callosal malformation with a type 1a interhemispheric cyst. PMID- 23091254 TI - Fetal cardiac rhabdomyoma with hydrops fetalis: report of 2 cases and literature review. AB - Rhabdomyoma is the most common cardiac tumor in fetuses, often associated with the tuberous sclerosis complex, especially when multiple tumors and a positive family history of tuberous sclerosis are noted. The tumor is often benign and has a tendency to regress but may increase in size until the early third trimester. Fetal cardiac rhabdomyoma complicated by hydrops fetalis and leading to fetal death is rare. We report 2 cases of fetal cardiac rhabdomyoma with hydrops fetalis and provide a review of the literature. PMID- 23091255 TI - Intrapericardial diaphragmatic hernia: report of 2 cases with prenatal diagnosis. AB - An intrapericardial diaphragmatic hernia is a very rare congenital abnormality, with only a few cases reported in the English literature. The triad includes a massive pericardial effusion, bilateral pulmonary compression with or without pulmonary hypoplasia, and herniation of part of the liver into the pericardium. We report 2 cases of intrapericardial diaphragmatic hernias diagnosed prenatally in our obstetrics and gynecology unit. PMID- 23091256 TI - Prenatal diagnosis of a rare sonographic appearance of duodenal atresia: report of 2 cases and literature review. AB - We report 2 cases of a rare sonographic appearance of duodenal atresia. The first was associated with severe hydramnios and a small, centrally located stomach. After birth due to recurrent pneumonia, bronchoscopy revealed a type 4 laryngotracheoesophageal cleft. The second case had an enlarged stomach without dilatation of the duodenum or hydramnios. After birth, radiography showed an enlarged stomach and duodenum: the classic "double bubble." The appearance of duodenal atresia on sonography is diverse. It may show a double bubble but may also show a single bubble: the stomach. The stomach may be normal in size or enlarged. In any case of a subjective abnormal size or position of the stomach or an abnormal amount of amniotic fluid, duodenal atresia should be considered. PMID- 23091257 TI - Identifying sonographic markers for placenta accreta in the first trimester. AB - Our study attempted to identify whether sonographic markers for placenta accreta may be present as early as the first trimester. We reviewed 10 cases with pathologically proven accreta and retrospectively analyzed their first-trimester images. The gestational ages ranged from 8 weeks 4 days to 14 weeks 2 days. Sonographic findings included anechoic placental areas (9 of 10), low implantation of the gestational sac (9 of 10), an irregular placental-myometrial interface (9 of 10), and placenta previa (7 of 10). Nine patients had at least 1 prior cesarean delivery; 3 had additional uterine surgical procedures. One patient underwent hysteroscopic myomectomy. Our case series suggests that signs of placenta accreta may be present in the first trimester. PMID- 23091258 TI - Cloacal malformation: embryology, anatomy, and prenatal imaging features. AB - Cloacal malformation is a rare but important anomaly. Prenatal diagnosis is possible with knowledge of the distinctive imaging features. The purpose of this case series is to illustrate characteristic prenatal sonographic and magnetic resonance imaging features of cloacal malformation using imaging from 6 cases seen at a single academic center to augment published data. The imaging feature common to all cases was a central cystic pelvic mass containing a characteristic fluid-fluid level. Additional anomalies include uterine and vaginal duplication, hydronephrosis, and lumbosacral anomalies. Prenatal magnetic resonance imaging showed the absence of the normal T1-hyperintense meconium-filled rectum in all cases. Prenatal diagnosis may affect immediate neonatal care (eg, immediate drainage of hydrocolpos) with an ultimate improved outcome. PMID- 23091259 TI - Unilateral hand oligodactyly: prenatal diagnosis with 3-dimensional sonography. PMID- 23091260 TI - Mirror-image artifact of early pregnancy on transvaginal sonography. PMID- 23091261 TI - What it means to be a cardiovascular sonographer. PMID- 23091263 TI - Vascular surgery: recognition at last. PMID- 23091264 TI - Inflammation in abdominal aortic aneurysms: cellular infiltrate and cytokine profiles. AB - Abdominal aortic aneurysm (AAA) pathogenesis occurs as a result of the altered homeostasis of the aortic vessel wall structural proteins. This results in weakening, and subsequent expansion, of the aorta leading to aneurysm formation. Multiple mechanisms are involved in this process, including genetic abnormalities, biomechanical wall stress, apoptosis, and proteolytic degradation of the aortic wall. One key hallmark of this pathology, which orchestrates the interaction of the various pathologic processes, is inflammation. The inflammatory process is characterized by the infiltration of a variety of cells, which leads to the upregulation of multiple cytokines. The balance of the cellular type and resultant cytokine milieu determines the ultimate fate of the aortic wall - healing, atherosclerosis or aneurysm formation. This review highlights some of the known cellular and cytokine inflammatory events that are involved in aortic aneurysm formation. PMID- 23091268 TI - gamma' Fibrinogen as a novel marker of thrombotic disease. AB - gamma' Fibrinogen is an isoform of fibrinogen that normally constitutes about 7% of total plasma fibrinogen, and arises from an alternative processing event in the gamma chain mRNA. gamma' Fibrinogen is a newly-emerging cardiovascular disease (CVD) risk factor that appears to have an independent association with CVD from that of total fibrinogen, which is itself a well-established CVD risk factor. gamma' Fibrinogen shows a significant association with coronary artery disease and myocardial infarction in at least four case-control studies, including the Stockholm Coronary Artery Risk Factor study and the Framingham Heart Study. gamma' Fibrinogen is also significantly associated with stroke, as shown in the Erasmus Stroke Study and others. The role of genetic polymorphisms in the association between gamma' fibrinogen and CVD is under active investigation. gamma' Fibrinogen increases during inflammation, and is differentially regulated from total fibrinogen under pathologic conditions, as demonstrated in the Periodontitis and Vascular Events study. The association between gamma' fibrinogen and venous thromboembolism remains unclear, however, with some studies showing an inverse association with gamma' fibrinogen levels and other studies showing the opposite. PMID- 23091267 TI - Social disadvantage: cause or consequence of impending psychosis? AB - BACKGROUND: An association between social disadvantage and established psychosis is well documented in the literature, but there remains a lack of data on the social circumstances of patients before they became ill. We investigated whether social disadvantage at, and prior to, first contact with psychiatric services, is associated with psychosis. METHOD: We collected information on social disadvantage in childhood and adulthood from 278 cases presenting with their first episode of psychosis to the South London and Maudsley National Health Service Foundation Trust and from 226 controls recruited from the local population. Three markers of childhood social disadvantage and 3 markers of disadvantage in adulthood were analyzed. RESULTS: Long term separation from, and death of, a parent before the age of 17 years were both strongly associated with a 2- to 3-fold-increased odds of psychosis. Cases were also significantly more likely to report 2 or more markers of adult social disadvantage than healthy controls (OR = 9.03) at the time of the first presentation with psychosis, independent of a number of confounders. When we repeated these analyses for long standing adult social disadvantage, we found that the strength of the association decreased but still remained significant for 1 year (OR = 5.67) and 5 years (OR = 2.57) prior to the first contact. CONCLUSIONS: Social disadvantage indexes exposure to factors operating prior to onset that increase the risk of psychosis, both during childhood and adulthood. PMID- 23091269 TI - I hear a song in my head. A memoir in stories of love, fear, doctoring and flight. AB - No abstract available. PMID- 23091270 TI - Effect of silver nanoparticles on human primary keratinocytes. AB - Silver nanoparticles (AgNPs) have many biological applications in biomedicine, biotechnology and other life sciences. Depending on the size, shape and the type of carrier, AgNPs demonstrate different physical and chemical properties. AgNPs have strong antimicrobial, antiviral and antifungal activity, thus they are used extensively in a range of medical settings, particularly in wound dressings but also in cosmetics. This study was undertaken to examine the potential toxic effects of 15 nm polyvinylpyrrolidone-coated AgNPs on primary normal human epidermal keratinocytes (NHEK). Cells were treated with different concentrations of AgNPs and then cell viability, metabolic activity and other biological and biochemical aspects of keratinocytes functioning were studied. We observed that AgNPs decrease keratinocyte viability, metabolism and also proliferatory and migratory potential of these cells. Moreover, longer exposure resulted in activation of caspase 3/7 and DNA damage. Our studies show for the first time, that AgNPs may present possible danger for primary keratinocytes, concerning activation of genotoxic and cytotoxic processes depending on the concentration. PMID- 23091271 TI - Heart rate variability exhibits complication-dependent changes postsurgery. AB - "Surgical stress response" is tissue damage postsurgery, leading to a systemic response (inflammation, sympathetic upregulation, and release of vasoactive chemicals), which is typically measured by C-reactive protein (CRP). We assessed arterial stiffness and heart rate variability (HRV)-additional parameters reflecting autonomic and vascular functions-in this response and their potential associations with postoperative complications. In 47 participants undergoing abdominal surgery, CRP, arterial stiffness, and HRV were measured pre- and postoperatively (days 1 and 2). C-reactive protein was significantly higher postoperatively in participants experiencing complications but not preoperatively. Compared to participants without complications, those with complications had increased HRV and pnn50 (time domain) and tendency toward increasing low-frequency/high-frequency ratio (frequency domain) on postoperative day 2. Therefore, time and frequency domain HRV parameters show perioperative changes in relation to complication development. These findings suggest the applicability of this noninvasive technology to a variety of abdominal operations. Larger studies need to confirm these findings. PMID- 23091272 TI - Simulating the trabecular bone structure around dental implants: a case presentation. AB - The effect of bone remodeling on the long-time success of dental implants is becoming critical for implant design and presurgical assessments. This study applies a previously presented remodeling simulation scheme on a computer tomography (CT)-based finite element model. The CT data of a dental implant at the upper right central incisor region 6 years after implant insertion was used. The time-dependent density change of the trabecular bone after osseointegration was studied. The trabecular structure, by means of density distribution, around the implant showed similarities to the CT images at many regions. PMID- 23091273 TI - Role of NMDA and opioid receptors in neuropathic pain induced by chronic constriction injury of sciatic nerve in rats. AB - BACKGROUND: The efficacy of opioids in neuropathic pain is still controversial. Earlier studies have suggested that N-methyl-D-aspartate (NMDA) receptor binding can be affected by opioids and vice versa. The present study aims to explore the interactions between NMDA and opioid receptors using various combinations of drugs acting on these receptors. METHODS: We used an animal model of sciatic nerve ligation to induce neuropathic pain, and a hot-plate test was used to assess pain response. RESULTS: It was observed that NMDA and naloxone increased the pain response. Ketamine reduced the pain response, which was further reduced when ketamine was administered in combination with naloxone, but not with NMDA, thus highlighting the activity of the NMDA receptor system. In addition, morphine was also found to increase latency to hind-paw lick, which was further reduced when given in combination with naloxone. Furthermore, triple drug combinations using ketamine+morphine+naloxone and ketamine+NMDA+naloxone demonstrated some significant interactions at these receptors. CONCLUSIONS: Thus, our study establishes that neuropathic pain can probably be overcome using higher doses of opioids, and there exists some intimate relationships between NMDA and opioid systems that lead to pain modulation. PMID- 23091274 TI - Auditory working memory and early reading skills in Hebrew-speaking preschool children. AB - The hypothesis that different subcomponents of auditory working memory are differentially related to early reading skills was tested in 63 Hebrew speaking 4 year-old children, using a battery of early reading (phonological processing and familiarity with written language) and memory (simple and complex spans) tasks. Complex spans accounted for significant amounts of variance on both facets of early reading even after the contribution of simple spans was accounted for. These findings suggest that the unique contribution of complex working memory to early reading can be identified as early as preschool and that the structure of correlations between reading and memory is similar across ages. PMID- 23091275 TI - Rustless translation. AB - ATP binding cassette proteins are a large and diverse family of molecular machines and include transmembrane transporter, chromosome maintenance and DNA repair proteins, and translation factors. However, the function of the ABCE1, the only member of subfamily E of ABC proteins, remained mysterious for over a decade, even though it is perhaps the most conserved ABC protein in eukaryotes and archaea. Recent results have now identified ABCE1 as the ribosome-recycling factor of eukaryotes and archaea. Thus, two iron-sulfur clusters - the hallmark feature of ABCE1 - help catalyze an integral step of the translational cycle at the core of the protein synthesis machinery. PMID- 23091276 TI - Covalent and non-covalent reversible proteasome inhibition. AB - The 20S proteasome core particle (CP) is the proteolytically active key element of the ubiquitin proteasome system that directs the majority of intracellular protein degradation in eukaryotic cells. Over the past decade, the CP has emerged as an anticancer therapy target after approval of the first-in-class drug bortezomib (Velcade((r))) by the US Food and Drug Administration. However, bortezomib and all second-generation CP inhibitors that are currently explored in clinical phase studies react covalently and most often irreversibly with the proteolytic sites of the CP, hereby causing permanent CP blockage. Furthermore, reactive head groups result in unspecific binding to proteasomal active centers and in substantial enzymatic off-target activities that translate to severe side effects. Thus, reversible proteasome inhibitors might be a promising alternative, overcoming these drawbacks, but are challenging with respect to their urge for thorough enthalpic and entropic optimization. This review describes developments in the hitherto neglected field of reversible proteasome inhibitors focusing on insights gained from crystal structures, which provide valuable knowledge and strategies for future directions in drug development. PMID- 23091277 TI - N-terminal acetylation of annexin A2 is required for S100A10 binding. AB - Annexin A2 (AnxA2), a Ca2+-regulated phospholipid binding protein involved in membrane-cytoskeleton contacts and membrane transport, exists in two physical states, as a monomer or in a heterotetrameric complex mediated by S100A10. Formation of the AnxA2-S100A10 complex is of crucial regulatory importance because only the complex is firmly anchored in the plasma membrane, where it functions in the plasma membrane targeting/recruitment of certain ion channels and receptors. The S100A10 binding motif is located in the first 12 residues of the AnxA2 N-terminal domain, but conflicting reports exist as to the importance of N-terminal AnxA2 acetylation with regard to S100A10 binding. We show here that AnxA2 is subject to N-terminal modification when expressed heterologously in Escherichia coli. Met1 is removed and Ser2 is acetylated, yielding the same modification as the authentic mammalian protein. Bacterially expressed and N terminally acetylated AnxA2 binds S100A10 with an affinity comparable to AnxA2 from porcine tissue and is capable of forming the AnxA2-S100A10 heterotetramer. Complex formation is competitively inhibited by acetylated but not by non acetylated peptides covering the N-terminal AnxA2 sequence. These results demonstrate that N-terminal acetylation of AnxA2 is required for S100A10 binding and that this common eukaryotic modification is also obtained upon expression in bacteria. PMID- 23091278 TI - Withaferin A binds covalently to the N-terminal domain of annexin A2. AB - Annexin A2 (AnxA2), a 38-kDa member of the Ca2+-binding annexin family, has been implicated in numerous cancer pathways. Withaferin A (WithfA), a natural plant compound, has been reported previously to bind covalently to Cys133 of the AnxA2 core domain leading to a reduction of the invasive capabilities of cancer cells by altering their cytoskeleton. We show here that AnxA2 has an inhibitory effect on actin polymerization, and a modification with WithfA significantly increases this inhibitory role of AnxA2. Using mass spectrometry and single-site mutants, we localized the WithfA-AnxA2 interaction to the N-terminal domain of AnxA2 where WithfA binds covalently to Cys9. Whereas binding to F-actin filaments has been mapped to the C terminus of AnxA2, our results suggest that the N-terminal domain modified by WithfA may also play a role in the AnxA2-actin interaction. The binding of WithfA may regulate the AnxA2-mediated actin dynamics in two distinct ways: (i) the increase of F-actin bundling activity by the Anx2/p11 heterotetramer and (ii) the decrease of actin polymerization as a result of the increased affinity of AnxA2 to the barbed end of actin microfilaments. We demonstrate the susceptibility of Cys9 of AnxA2 to chemical modifications and exclude Cys133 as a binding site for WithfA. PMID- 23091280 TI - Culturally diverse nursing students in Finland: some experiences. AB - Around the world, student populations are internationalizing and diversifying. The purpose of this study was to research culturally and linguistically diverse nursing students' experiences in Finland. The data were collected from 27 students in four polytechnics through focus group interviews. The findings highlight the importance of concreteness in theoretical instruction. In clinical settings, language barriers and negative attitudes towards students and their cultural background lead to social and professional isolation. The findings suggest that development of culturally sensitive pedagogy requires further investigation with strong research designs. Intensified language instruction for those who need it is essential. Strategies that increase cultural competence and promote appreciation of cultural diversity in health care settings should be developed. PMID- 23091281 TI - Noninvasive imaging in pulmonary embolism according to age and gender. AB - Some now recommend a lung scan if the plain chest radiograph is normal instead of computed tomographic (CT) angiography to minimize the risks of radiation in younger patients with suspected pulmonary embolism. The purpose of this investigation is to determine practice standards according to age and gender in regard to noninvasive imaging. Data are from the Nationwide Inpatient Patient, 1998 to 2009. In 2006 to 2009, the proportion of females with pulmonary embolism imaged with CT angiography was 275 (90%) of 305 among teenagers and girls, 3990 (87%) of 4570 among women 20 to 40 years, and 25 650 (85%) of 30 160 among women >40 years. Among males the proportion imaged with CT angiography was 175 (92%) of 190 among teenagers and boys, 3000 (89%) of 3370 among men 20 to 40 years, and 21 280 (86%) of 24 800 among men >40 years. In conclusion, contrary to the recommendations of some, CT angiography is usually obtained in young patients. PMID- 23091282 TI - Comparison of the impact of four generations of progestins on hemostatic variables. AB - This study was undertaken to evaluate the impact of progestins as part of low estrogen (ethinyl estradiol [EE2] <=35 MUg) combined oral contraceptives (COCs) on hemostatic variables. One hundred ninety-five healthy women took oral contraceptives with following formulations: 35 EE2/norgestimate (NGM), 35 EE2/cyproterone acetate, 35 EE2/norethisterone, 30 EE2/levonorgestrel, 30 EE2/drospirenone (DRSP), 20 EE2/gestodene, and 20 EE2/DRSP, for 6 months. Hemostatic assays (prothrombin time, activated partial thromboplastin time, fibrinogen, resistance to activated protein C ratio, protein C, protein S, factor VIII [FVIII], antithrombin, plasminogen, alpha2-antiplasmin, inhibitor of plasminogen activator type 1 [PAI-1] and d-dimers) were performed in 3 time points: at baseline, after 3, and 6 cycles. For each formulation, results were compared according to baseline values, intergroup analysis, and the amount of estrogen or progestin component. Most of the variables were changed except FVIII. Significant difference between oral contraceptives was found in antithrombin, protein C, protein S activities, and PAI-1 values, but changes were mostly within reference range. PMID- 23091283 TI - Comparative studies on branded enoxaparin and a US generic version of enoxaparin. AB - Enoxaparin, a complex, biologically derived low-molecular-weight heparin, is approved for a range of clinical indications. This study was carried out to compare the potency profile and pharmacodynamic responses of branded enoxaparin (Lovenox; Sanofi, US) with a generic enoxaparin (enoxaparin sodium injection, USP). Five batches of each product were tested. Although the average molecular weight, anti-factor Xa, and anti-factor IIa potencies were similar for the two products, differences were observed in the in vitro thrombin generation and kinetics of clot formation (P = .01) and in the ex vivo pharmacodynamics regarding thrombin generation inhibition (P = .029), tissue factor pathway inhibitor release (P = .006), and inhibition of the active form of thrombin activated fibrinolysis inhibitor (P = .023). These findings suggest that simple analytical characterization can establish good quality control in manufacturing, but they may not assure similarity in biological performance between the branded and the generic enoxaparin. PMID- 23091284 TI - Treatment with low-dose atorvastatin, losartan, and their combination increases expression of vasoactive-related genes in rat aortas. AB - Recently it has been shown that statins and angiotensin receptor blockers (ARBs) at low doses express beneficial pleiotropic vascular effects. We aimed to explore whether these drugs at low doses induce the expression of vasoactive-related genes. Sixty adult Wistar rats were treated with low-dose atorvastatin (2 mg/kg), low-dose losartan (5 mg/kg), their combination or saline daily for 4, 6, or 8 weeks. Expression of the vasoactive-related genes endothelin receptor type A (EDNRA), endothelial nitric oxide synthase 3 (NOS3), inducible nitric oxide synthase 2 (NOS2), and angiotensin II receptor type 1 (AGTRL1a) was measured in isolated thoracic aortas. Expression of EDNRA gradually decreased, the lowest values being obtained after 8 weeks (low-dose atorvastatin, losartan [1.6- and 1 7-fold vs controls, respectively; both P < .05], and the combination [2.3-fold vs control, P < .001]). The highest values of NOS3 were obtained after 6 weeks (low dose atorvastatin, losartan, and their combination, 3.1-fold, P < .01; 3.4-fold, P < .001; and 3.6-fold, P < .001 vs controls, respectively) and then declined after 8 weeks. The combination was more effective in inducing total NOS3 expression when compared to the separate drugs (1.4-fold; P < .05). Importantly, expression of NOS3 was associated with increased plasma NO levels and positively correlated with thoracic aorta relaxation. No changes in expression of NOS2 and AGTRL1a were observed. We showed that low-dose atorvastatin or losartan and especially their combination increases the expression of NOS3 and decreases the expression of EDNRA. These findings are valuable in explaining the effectiveness of the "low-dose pharmacological approach" for improvement in arterial function. PMID- 23091285 TI - Pentosidine as a biomarker for microvascular complications in type 2 diabetic patients. AB - Serum soluble receptor for advanced glycation end product (sRAGE) may reflect the activity of the advanced glycation end product (AGE)-receptor for advanced glycation end product (RAGE) axis, which has been proposed as a potential mechanism linking hyperglycaemia to vascular complications in diabetes. We have investigated whether serum AGEs, sRAGE and pentosidine levels were increased and correlated with microvascular complications in type 2 diabetes mellitus (DM). We included 30 healthy control subjects, and 200 diabetic patients were divided into two subgroups: 100 patients with diabetic retinopathy and 100 patients with diabetic nephropathy. AGEs, sRAGE and pentosidine were measured in serum by enzyme-linked immunosorbent assay (ELISA). Serum AGEs, sRAGE and pentosidine levels were significantly increased in diabetic patients with retinopathy and in diabetic patients with nephropathy compared to control subjects (p < 0.001). Serum AGEs, sRAGE and pentosidine levels are positively associated with microvascular complications in type 2 DM. Multiple regression analysis reveals serum pentosidine as an independent determinant of the presence of diabetic retinopathy (p = 0.004) and the presence of hypertension (p = 0.018) and hyperlipidaemia (p = 0.036). Pentosidine levels may be a biomarker for microvascular complications in type 2 diabetic patients. PMID- 23091286 TI - The underlying osseous deformity in plantar plate tears: a radiographic analysis. AB - PURPOSE: Plantar plate tears can cause pain and deformity of the forefoot. The purpose of this study is to correlate common radiographic findings with observed intra-operative pathology in patients with plantar plate pathology. METHODS: Bilateral weight-bearing radiographs were reviewed for 88 patients (106 feet) who underwent surgical repair of suspected plantar plate pathology. Parameters reviewed included the first intermetatarsal angle, the metatarsus adductus angle, the second and third metatarsophalangeal angles, splaying of the second and third toes, evaluation of the metatarsal parabola by 3 different methods, the first and second lateral declination angles, and the second lateral metatarsophalangeal angle. RESULTS: Of 106 feet, 97 had intra-operative plantar plate tears. The radiographs of patients with plantar plate tears had an increased amount of digital splay on the anteroposterior radiograph compared to patients without pathology. For patients with unilateral plantar plate pathology, the metatarsal parabola of the symptomatic foot was compared with that of the asymptomatic foot. A significantly increased second metatarsal protrusion distance as measured by 2 different methods was noted in the symptomatic foot. Odds ratios revealed that patients with an intermetatarsal angle >12, medial deviation of the second toe, and splaying of the digits were more likely to be diagnosed with a plantar plate tear intra-operatively. CONCLUSION: Although radiographs do not definitively diagnose plantar plate tears, understanding osseous forefoot architecture will aid with diagnosis in the absence of other osseous pathology. Furthermore, these data suggest that parabola should be corrected to maintain long-term correction of plantar plate pathology. LEVEL OF EVIDENCE: Prognostic, Level II. PMID- 23091287 TI - Ultrasound elastography for musculoskeletal applications. AB - Ultrasound elastography (EUS) is a method to assess the mechanical properties of tissue, by applying stress and detecting tissue displacement using ultrasound. There are several EUS techniques used in clinical practice; strain (compression) EUS is the most common technique that allows real-time visualisation of the elastographic map on the screen. There is increasing evidence that EUS can be used to measure the mechanical properties of musculoskeletal tissue in clinical practice, with the future potential for early diagnosis to both guide and monitor therapy. This review describes the various EUS techniques available for clinical use, presents the published evidence on musculoskeletal applications of EUS and discusses the technical issues, limitations and future perspectives of this method in the assessment of the musculoskeletal system. PMID- 23091288 TI - "Black bone" MRI: a potential alternative to CT when imaging the head and neck: report of eight clinical cases and review of the Oxford experience. AB - OBJECTIVE: The potential risks associated with ionising radiation are well documented. We have previously reported the "black bone" MRI sequence, useful when imaging cortical bone. The objective of this paper is to report our initial experience of this technique in patients undergoing imaging of the head and neck region. METHODS: Using the departmental database those patients having had "black bone" sequences of the head and neck performed as part of their MRI examination in the preceding 5 years were identified. The radiological reports were reviewed to identify those cases where "black bone" or conventional MRI sequences had been performed in place of the requested CT, and the patient medical records for these cases were reviewed. Medical record review was also conducted for those cases where it was considered that the pathological condition requiring imaging would ordinarily be investigated with CT. RESULTS: The "black bone" sequence had been performed in 69 patients as part of routine MRI of the head and neck. Of these, 67% (n=46) were performed in combination with CT imaging, the majority of cases being primary tumours. In four cases, an MRI was performed in place of the requested CT scan. We present eight clinical cases illustrating the potential benefits of the "black bone" sequence. CONCLUSIONS: "Black bone" MRI offers a radiation-free method of imaging the head and neck, and has been successfully utilised in a range of benign and malignant conditions affecting this region. Advances in knowledge Adoption of this approach, where feasible, would be a significant advance in radiation protection. PMID- 23091289 TI - Contrast-enhanced MRI of the subdeltoid, subacromial bursa in painful and painless rotator cuff tears. AB - OBJECTIVE: Although shoulder pain is often associated with rotator cuff tears, many tears are asymptomatic and are not the cause of the patient's pain. This may explain the persistence of symptoms in some patients despite technically successful rotator cuff repair. It has been proposed that rotator cuff tears cause pain through subdeltoid/subacromial bursal inflammation. The aim of this study was to determine whether bursal inflammation seen on MRI is associated with pain in patients with rotator cuff tears of the shoulder. METHODS: The shoulders of 255 patients were screened with ultrasound. 33 full-thickness rotator cuff tears (18 with shoulder pain and 15 without pain) were identified and subsequently studied using contrast-enhanced MRI of the shoulder. Enhancement of the subacromial bursa was scored independently by two musculoskeletal radiologists. Logistic regression was used to determine whether bursal enhancement was independently associated with pain. RESULTS: There was a significant association between pain and age, with greater likelihood of pain in younger patients. Bursal enhancement was common in both painful and painless tears. No statistically significant link between pain and bursal enhancement was seen, even after accounting for age. CONCLUSION: Although enhancement of the subdeltoid/subacromial bursa was common, no evidence was found to support the hypothesis that bursal enhancement is associated with pain in rotator cuff tears. It is therefore unlikely to determine reliably which patients would benefit from rotator cuff repair. Advances in knowledge Bursal enhancement and thickening does not reliably correlate with symptoms or presence of rotator cuff tear. PMID- 23091290 TI - Dosimetric advantages of generalised equivalent uniform dose-based optimisation on dose-volume objectives in intensity-modulated radiotherapy planning for bilateral breast cancer. AB - OBJECTIVE: We compared and evaluated the differences between two models for treating bilateral breast cancer (BBC): (i) dose-volume-based intensity-modulated radiation treatment (DV plan), and (ii) dose-volume-based intensity-modulated radiotherapy with generalised equivalent uniform dose-based optimisation (DV-gEUD plan). METHODS: The quality and performance of the DV plan and DV-gEUD plan using the Pinnacle(3) system (Philips, Fitchburg, WI) were evaluated and compared in 10 patients with stage T2-T4 BBC. The plans were delivered on a Varian 21EX linear accelerator (Varian Medical Systems, Milpitas, CA) equipped with a Millennium 120 leaf multileaf collimator (Varian Medical Systems). The parameters analysed included the conformity index, homogeneity index, tumour control probability of the planning target volume (PTV), the volumes V(20 Gy) and V(30 Gy) of the organs at risk (OAR, including the heart and lungs), mean dose and the normal tissue complication probability. RESULTS: Both plans met the requirements for the coverage of PTV with similar conformity and homogeneity indices. However, the DV gEUD plan had the advantage of dose sparing for OAR: the mean doses of the heart and lungs, lung V(20) (Gy), and heart V(30) (Gy) in the DV-gEUD plan were lower than those in the DV plan (p<0.05). CONCLUSIONS: A better result can be obtained by starting with a DV-generated plan and then improving it by adding gEUD-based improvements to reduce the number of iterations and to improve the optimum dose distribution. Advances to knowledge The DV-gEUD plan provided superior dosimetric results for treating BBC in terms of PTV coverage and OAR sparing than the DV plan, without sacrificing the homogeneity of dose distribution in the PTV. PMID- 23091291 TI - An unusual case of duodenal beaking. PMID- 23091292 TI - Medial meniscal root tears and meniscal extrusion transverse length ratios on MRI. AB - OBJECTIVE: To evaluate the clinical utility of the meniscal extrusion transverse ratio of the medial meniscus in the diagnosis of meniscal root tear compared with the gold standard of arthroscopic diagnosis. METHODS: This retrospective study sample included 32 males and 35 females who underwent MRI at our institution. There were 24 meniscal root tear cases. The control groups were 18 cases of medial meniscal tears without root tears and 25 cases of negative meniscal findings on arthroscopy. Meniscal extrusion (L) and maximal transverse lengths (T) of the medial meniscus were measured, and L/T ratios were calculated. These results were correlated with arthroscopic findings and analysed statistically. With arthroscopic findings used as the standard of reference, the sensitivity and specificity of 10%, 11% and 12% extrusion thresholds, and 3 mm of medial meniscal extrusion (MME) as diagnostic thresholds, were calculated. RESULTS: The mean length of the meniscal extrusions of meniscal root tears was twice as long as the control group. The mean L/T ratio of the meniscal root tears was approximately 13%, while those of the control groups were 5%. The differences in the L and L/T between the meniscal root tears and normal and meniscal root tears and other meniscal tears were statistically significant (p<0.001), but those between normal and other meniscal tears were not. The best diagnostic discrimination was achieved using an extrusion ratio threshold of 10% (79% sensitivity, 86% specificity). The 3 mm of MME threshold demonstrated high specificity (98%), but not high sensitivity (54%). CONCLUSION: The mean L/T ratio of the meniscal root tears was approximately 13% and was statistically significant. The best diagnostic discrimination was achieved using an extrusion ratio threshold of 10%. Advances in knowledge The use of the L/T ratio in combination with MME can be a useful method for evaluating medial meniscal root tears. PMID- 23091293 TI - Dynamic conformal arc cranial stereotactic radiosurgery: implications of multileaf collimator margin on dose-volume metrics. AB - OBJECTIVE: The effect of multileaf collimator (MLC) margin on target and normal tissue dose-volume metrics for intracranial stereotactic radiosurgery (SRS) was assessed. METHODS: 118 intracranial lesions of 83 SRS patients formed the basis of this study. For each planning target volume (PTV), five separate treatment plans were generated with MLC margins of -1, 0, 1, 2 and 3 mm, respectively. Identical treatment planning parameters were employed with a median of five dynamic conformal arcs using the Varian/BrainLab high-definition MLC for beam shaping. Prescription dose (PD) was such that 22 Gy covered at least 95% of the PTV. Dose-volume and dose-response comparative metrics included conformity index, heterogeneity index, dose gradient, tumour control probability (TCP) and normal tissue complication probability (NTCP). RESULTS: Target dose heterogeneity decreased with increasing MLC margin (p<0.001); mean heterogeneity index decreased from 70.4 +/- 12.7 to 10.4 +/- 2.2%. TCP decreased with increasing MLC margin (p<0.001); mean TCP decreased from 81.0 +/- 2.3 to 62.2 +/- 1.8%. Normal tissue dose fall-off increased with MLC margin (p<0.001); mean gradient increased from 3.1 +/- 0.9 mm to 5.3 +/- 0.7 mm. NTCP was optimal at 1 mm MLC margin. No unambiguous correlation was observed between NTCP and PTV volume. Plan delivery efficiency generally improved with larger margins (p<0.001); mean monitor unit per centigray of the PD decreased from 3.60 +/- 1.30 to 1.56 +/- 0.13. Conclusion Use of 1 mm MLC margins for dynamic conformal arc-based cranial radiosurgery resulted in optimal tumour control and normal tissue sparing. Clinical significance of these comparative findings warrants further investigation. PMID- 23091294 TI - Differentiation of myocardial scar from potential pitfalls and artefacts in delayed enhancement MRI. AB - Delayed enhancement cardiac magnetic resonance (DE-CMR) imaging is used increasingly to identify and quantify focal myocardial scar. Our objective is to describe factors used in the interpretation of DE-CMR images and to highlight potential pitfalls and artefacts that mimic myocardial scar. Inversion recovery gradient recalled echo sequence is commonly accepted as the standard of reference for DE-CMR. There are also alternative sequences that can be performed in a single breath-hold or with free breathing. Radiologists need to be aware of factors affecting image quality, and potential pitfalls and artefacts that may generate focal hyperintense areas that mimic myocardial scar. PMID- 23091295 TI - PI3K-PKB hyperactivation augments human plasmacytoid dendritic cell development and function. AB - Plasmacytoid dendritic cells (pDCs) are considered potential tools or targets for immunotherapy. However, current knowledge concerning methodologies to manipulate their development or function remains limited. Here, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)-mammalian target of rapamycin (mTOR) axis in human pDC development, survival, and function. In vitro pDC generation from human cord blood-derived CD34(+) hematopoietic progenitors was reduced by pharmacologic inhibition of PI3K, PKB, or mTOR activity, and peripheral blood pDCs required PI3K-PKB-mTOR signaling to survive. Accordingly, activity of this pathway in circulating pDCs correlated with their abundance in peripheral blood. Importantly, introduction of constitutively active PKB or pharmacologic inhibition of negative regulator phosphatase and tensin homolog (PTEN) resulted in increased pDC numbers in vitro and in vivo. Furthermore, MHC class II and costimulatory molecule expression, and production of IFN-alpha and TNF-alpha, were augmented, which could be explained by enhanced IRF7 and NF-kappaB activation. Finally, the numerically and functionally impaired pDCs of chronic hepatitis B patients demonstrated reduced PI3K-PKB-mTOR activity. In conclusion, intact PI3K-PKB-mTOR signaling regulates development, survival, and function of human pDCs, and pDC development and functionality can be promoted by PI3K-PKB hyperactivation. Manipulation of this pathway or its downstream targets could be used to improve the generation and function of pDCs to augment immunity. PMID- 23091296 TI - Small sizes and indolent evolutionary dynamics challenge the potential role of P2RY8-CRLF2-harboring clones as main relapse-driving force in childhood ALL. AB - The P2RY8-CRLF2 fusion defines a particular relapse-prone subset of childhood acute lymphoblastic leukemia (ALL) in Italian Association of Pediatric Hematology and Oncology Berlin-Frankfurt-Munster (AIEOP-BFM) 2000 protocols. To investigate whether and to what extent different clone sizes influence disease and relapse development, we quantified the genomic P2RY8-CRLF2 fusion product and correlated it with the corresponding CRLF2 expression levels in patients enrolled in the BFM ALL 2000 protocol in Austria. Of 268 cases without recurrent chromosomal translocations and high hyperdiploidy, representing approximately 50% of all cases, 67 (25%) were P2RY8-CRLF2 positive. The respective clone sizes were >= 20% in 27% and < 20% in 73% of them. The cumulative incidence of relapse of the entire fusion-positive group was clone size independent and significantly higher than that of the fusion-negative group (35% +/- 8% vs 13% +/- 3%, P = .008) and primarily confined to the non-high-risk group. Of 22 P2RY8-CRLF2-positive diagnosis/relapse pairs, only 4/8 had the fusion-positive dominant clone conserved at relapse, whereas none of the original 14 fusion-positive small clones reappeared as the dominant relapse clone. We conclude that the majority of P2RY8-CRLF2-positive clones are small at diagnosis and virtually never generate a dominant relapse clone. Our findings therefore suggest that P2RY8-CRLF2-positive clones do not have the necessary proliferative or selective advantage to evolve into a disease-relevant relapse clone. PMID- 23091297 TI - Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress. AB - The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steady-state hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reactive oxygen species scavenging by N-acetyl cysteine or stabilization of hypoxia signaling by knockdown of the von-Hippel-Lindau (VHL) protein led to reversal of the effects of Meis1 deletion. The results of the present study demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism. PMID- 23091298 TI - Targeted genomic sequencing of pediatric Burkitt lymphoma identifies recurrent alterations in antiapoptotic and chromatin-remodeling genes. AB - To ascertain the genetic basis of pediatric Burkitt lymphoma (pBL), we performed clinical-grade next-generation sequencing of 182 cancer-related genes on 29 formalin-fixed, paraffin embedded primary pBL samples. Ninety percent of cases had at least one mutation or genetic alteration, most commonly involving MYC and TP53. EBV(-) cases were more likely than EBV(+) cases to have multiple mutations (P < .0001). Alterations in tumor-related genes not previously described in BL were identified. Truncating mutations in ARID1A, a member of the SWI/SNF nucleosome remodeling complex, were seen in 17% of cases. MCL1 pathway alterations were found in 22% of cases and confirmed in an expanded panel. Other clinically relevant genomic alterations were found in 20% of cases. Our data suggest the roles of MCL1 and ARID1A in BL pathogenesis and demonstrate that comprehensive genomic profiling may identify additional treatment options in refractory disease. PMID- 23091299 TI - Marketing the HIV test to MSM: ethnic differences in preferred venues and sources. AB - Lack of awareness of HIV status is associated with an increased likelihood of HIV transmission. We surveyed 633 men who have sex with men (MSM) from diverse ethnic groups recruited from a variety of community venues in a U.S. Midwestern city with rising HIV infection rates. Our first aim was to describe patterns of sexual risk, annual HIV testing frequency, and venues where information about HIV and HIV testing could be disseminated to inner-city MSM. Our second aim was to identify preferred sources to receive information about HIV testing and determine whether these preferences differed by ethnic background. Results indicated that despite similar proportions of high-sexual risk behaviors, compared with African American and Latino MSM, smaller proportions of non-Hispanic White MSM had received an HIV test in the last 12 months. Despite ethnic differences in health care access, a physician's office was the most common HIV testing site. Overall, a majority conveyed a preference to see advertisements in mainstream media outlets. However, when preferences were stratified by ethnicity, African American MSM were the least likely to prefer receiving information from mainstream media and conveyed a stronger preference to receive information from authority figures than non-Hispanic White and Hispanic MSM. PMID- 23091300 TI - Stage of change and other predictors of participant retention in a behavioral weight management program in primary care. AB - High attrition often limits the efficacy of weight management programs, particularly those that serve primary care patients. We investigated stage of change and other predictors of retention in a behavioral intervention program that enrolled adult obese patients at three primary care sites. The program included practice improvements and provider training, as well as individual lifestyle counseling and educational group classes for participants. We analyzed predictors of whether participants returned for counseling visits and whether they attended group classes. The 461 participants were mainly women (84%) and minorities (87%), and most of them were in the preparation stage for dietary and physical activity changes. A total of 134 (29%) participants returned for at least one follow-up visit with their counselor and 85 (18%) attended at least one class. Baseline stage of change was not significantly associated with either return visits or class attendance (p = .875 and .182, respectively). Men and participants with children in the household were less likely to return for subsequent counseling sessions (p = .012 and .027, respectively). Age and employment were associated with class attendance (p = .099 and .034, respectively). Focus groups with participants confirmed that reasons for dropout included physical limitations or health issues, family issues, stress, and lack of social support. We conclude that prescreening of patients for readiness to participate and attention to personal barriers related to family and work might improve program retention. More frequent contacts between visits and stronger provider engagement might also strengthen the intervention. PMID- 23091301 TI - Worksite translation of the Diabetes Prevention Program: formative research and pilot study results from FUEL Your Life. AB - This article summarizes formative research and pilot study findings from a workplace translation of the Diabetes Prevention Program (DPP). The overarching goal was to devise a relatively straightforward weight management intervention suitable for use in a wide array of work settings. This project was conducted in conjunction with Union Pacific Railroad at one of their locomotive maintenance facilities. Participating employees were predominately male and middle-aged. Formative data were collected through stakeholder interviews, focus groups, and direct observation of the work environment. These results were used to adapt the DPP into a largely self-directed intervention augmented by peer health coaches and the on-site nurse. A small pilot test of the adapted program (n = 67) produced modest but statistically significant weight reductions at both 6 (core intervention period) and 12 months (maintenance period). These results are discussed in terms of the original DPP and other DPP translation studies. PMID- 23091302 TI - Physical Activity and Nutrition Program for Seniors (PANS): process evaluation. AB - ISSUE ADDRESSED: The Physical Activity and Nutrition Program for Seniors (PANS) program aimed to increase levels of physical activity and improve the diet of insufficiently active community-based seniors aged 60 to 70 years using a range of strategies. Comprehensive process evaluation was used to determine the suitability and appropriateness of the resources and effectiveness of the strategies. METHOD: Process evaluation data (qualitative and quantitative) were collected on the program strategies and resources throughout, and at the conclusion of the intervention period. RESULTS: The program strategies/resources were found to be relevant to the population, assisting participants to increase their level of physical activity and improve their diet. Participants reported that the program resources were suitable for their age-group (84%), encouraged them to think about physical activity (78%), and nutrition (70%). Participants reported that they used the pedometer (91%) and recorded daily steps (78%). Moreover, the provision of group guides facilitated individuals to set and achieve personal goals. CONCLUSION: The PANS strategies and resources were appropriate, which supported the seniors in identifying, establishing, and achieving their physical activity and nutrition goals. Minor refinements of the program were recommended based on the findings. PMID- 23091303 TI - Training partnership dyads for community-based participatory research: strategies and lessons learned from the Community Engaged Scholars Program. AB - This article describes the development, implementation, evaluation framework, and initial outcomes of a unique campus-community training initiative for community based participatory research (CBPR). The South Carolina Clinical & Translational Research Center for Community Health Partnerships, which functions as the institution's Clinical Translational and Science Award Community Engagement Program, leads the training initiative known as the Community Engaged Scholars Program (CES-P). The CES-P provides simultaneous training to CBPR teams, with each team consisting of at least one community partner and one academic partner. Program elements include 12 months of monthly interactive group sessions, mentorship with apprenticeship opportunities, and funding for a CBPR pilot project. A modified RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework guides the process, impact, and outcome evaluation plan. Lessons learned include challenges of group instruction with varying levels of readiness among the CBPR partners, navigating the institutional review board process with community co-investigators, and finding appropriate academic investigators to match community research interests. Future directions are recommended for this promising and unique dyadic training of academic and community partners. PMID- 23091304 TI - Working inside the firehouse: developing a participant-driven intervention to enhance health-promoting behaviors. AB - Cardiovascular disease (CVD) is the most common cause of on-duty death among U.S. firefighters among whom volunteers comprise 71% of the fire service. We sought to understand CVD risk among volunteer firefighters and to develop a CVD intervention based on their input. To accomplish these aims, we conducted a series of focus groups with volunteer firefighters and firefighters who serve with volunteers in Maryland. We conducted two additional focus groups with fire service leaders. Ninety-eight people participated in 15 focus groups. Participants discussed health and wellness, stress and the demanding nature of the volunteer fire service, and the challenges associated with healthy eating. They talked about food in the firehouse and the lack of quick, healthy, satisfying, and affordable food. Several suggestions for interventions to improve the food environment and firefighters' ability to choose and prepare healthy meals and snacks emerged. An intervention reflecting the participants' recommendations resulted. The way volunteer firefighters understand health and wellness and the specific factors that influence their food intake are valuable insights for addressing CVD risks in this population. To our knowledge, this is the first study that systematically brings firefighters into the process of developing an intervention to reduce CVD risk among this high-risk population. PMID- 23091305 TI - IL-17 and IL-22 in cerebrospinal fluid and plasma are elevated in Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acute autoimmune-mediated inflammatory demyelinating disease that causes rapidly progressing paralysis and occasionally respiratory failure. We hypothesized that interleukin (IL)-17 and IL-22 are elevated in GBS and participate in the autoimmune inflammatory response of GBS. We used sandwich enzyme-linked immunosorbent assay (ELISA) to measure the IL-17 and IL-22 levels in the CSF, and plasma from 22 GBS patients at the acute phase and 18 healthy controls (HC). The results show that CSF and plasma levels of IL 17 and IL-22 are elevated in GBS patients compared with HC. IL-17 and IL-22 levels in CSF, respectively, are correlated with GBS disability scale scores (GDSs). Meanwhile, IL-17 and IL-22 levels in CSF, IL-22 in CSF, and plasma of GBS patients have positive correlation, respectively. The increased levels of IL-17 and IL-22 in CSF may be explained by the disruption of blood-brain barrier (BBB) and peripheral nervous system (PNS) local inflammation in GBS. Meanwhile, the elevated levels of these two cytokines in plasma suggest the activation of Th17 and Th22 cells in the systemic immune response of GBS. Our data provide preliminary evidence that GBS is associated with high levels of IL-17 and IL-22 in CSF and plasma. These cytokines display pathogenic potential and may serve as useful biomarkers for GBS. PMID- 23091307 TI - Prediction of microbial infection of cultured cells using DNA microarray gene expression profiles of host responses. AB - Infection by microorganisms may cause fatally erroneous interpretations in the biologic researches based on cell culture. The contamination by microorganism in the cell culture is quite frequent (5% to 35%). However, current approaches to identify the presence of contamination have many limitations such as high cost of time and labor, and difficulty in interpreting the result. In this paper, we propose a model to predict cell infection, using a microarray technique which gives an overview of the whole genome profile. By analysis of 62 microarray expression profiles under various experimental conditions altering cell type, source of infection and collection time, we discovered 5 marker genes, NM_005298, NM_016408, NM_014588, S76389, and NM_001853. In addition, we discovered two of these genes, S76389, and NM_001853, are involved in a Mycolplasma-specific infection process. We also suggest models to predict the source of infection, cell type or time after infection. We implemented a web based prediction tool in microarray data, named Prediction of Microbial Infection (http://www.snubi.org/software/PMI). PMID- 23091308 TI - Quantitative determination of Plasmodium parasitemia by flow cytometry and microscopy. AB - The traditional light microscopy has limitations for precise growth assays of malaria parasites in culture or for assessment of new compounds for antimalarial activity; the speed and high reproducibility of flow cytometry can overcome these limitations. A flow cytometric method using PicoGreen, a DNA-binding fluorochrome, was developed with optimal precision suitable for performing growth assays of low-parasitemia field isolates. In addition, intra- and inter-person reproducibility of the flow cytometric and the microscopic method were compared in order to quantitatively demonstrate the improved precision. RNase treatment contributed to the precision of the flow cytometric measurements by enhancing the signal-to-noise ratios. Coefficients of variation of the method were smaller than 10% for 0.1% or higher parasitemia samples. The intra- and inter-person coefficients of variation of the flow cytometric method were three to six times smaller than those of the microscopic method. The flow cytometric method developed in this study yielded substantially more precise results than the microscopic method, allowing determination of parasitemia levels of 0.1% or higher, with coefficients of variation smaller than 10%. Thus, the PicoGreen method could be a reliable high sensitivity assay for analysis of low parasitemia samples and might be applied to a high throughput system testing antimalarial drug activity. PMID- 23091306 TI - Does inflammation determine whether obesity is metabolically healthy or unhealthy? The aging perspective. AB - Obesity is a major health issue in developed as well as developing countries. While obesity is associated with relatively good health status in some individuals, it may become a health issue for others. Obesity in the context of inflammation has been studied extensively. However, whether obesity in its various forms has the same adverse effects is a matter of debate and requires further research. During its natural history, metabolically healthy obesity (MHO) converts into metabolically unhealthy obesity (MUHO). What causes this transition to occur and what is the role of obesity-related mediators of inflammation during this transition is discussed in this paper. PMID- 23091309 TI - Proportion of multidrug-resistant tuberculosis in human immunodeficiency virus/mycobacterium tuberculosis co-infected patients in Korea. AB - Much controversy surrounds the issue of whether HIV infection is a risk factor for developing multidrug-resistant tuberculosis (MDR-TB). In this study, we evaluated the prevalence of and risk factors for MDR-TB in HIV-infected patients at the National Medical Center of Korea. We reviewed the medical records of HIV/TB co-infected patients from January 2005 to May 2011; the drug susceptibility profiles were available for 55 patients. Of these, 32.7% had MDR TB, which was approximately 3.6 times higher than the prevalence among the general population. Additionally, there were more additional AIDS-defining clinical illnesses in the MDR-TB group than in the non-MDR-TB group (27.8% vs 5.4%, P = 0.032). These results suggest that HIV infection and HIV-related immunosuppresion may contribute to the development of MDR-TB. PMID- 23091310 TI - Hepatocellular carcinoma in the elderly: clinical characteristics, treatment, survival analysis in Korean patients older than 70 years. AB - The prevalence of hepatocellular carcinoma (HCC) has increased in recent years. However, HCC remains poorly characterized in elderly patients, and comprehensive data are limited. This study aimed to investigate the clinical characteristics, prognostic features and survival outcome of elderly HCC patients. We retrospectively analyzed 992 HCC patients treated at Dongsan Hospital from January 2003 to December 2007. The patients were divided into two age groups: < 70 yr (n = 813) and >= 70 yr (n = 179). Elderly HCC patients, compared to younger patients, had significantly higher incidence of females (31.3% vs 18.9%, P = 0.001), hepatitis C-related disease (HCV antibody positivity 26.3% vs 9.2%, P = 0.001) and comorbid condition (53.6% vs 32.1%), but lower rates of hepatitis B related disease (HBs antigen positivity 31.3% vs 69.4%, P = 0.001). There were no significant differences in underlying liver function, stage and survival outcomes. Factors significantly influencing the prognosis of HCC were Child-Pugh grade, number of HCC, level of alpha-fetoprotein, presence of metastasis. The survival outcome of older patients with HCC was not different from that of younger patients. There were no differences between groups in independent factors influencing the prognosis of HCC. Therefore, determining the optimal management strategy for elderly HCC patients is important to improve survival and long-term outcomes. PMID- 23091311 TI - Rapid detection of prognostically significant fusion transcripts in acute leukemia using simplified multiplex reverse transcription polymerase chain reaction. AB - Multiplex reverse transcription polymerase chain reaction (mRT-PCR) has recently emerged as an alternative to cytogenetics. We designed and used simplified mRT PCR system as a molecular screen for acute leukemia. Fifteen fusion transcripts were included: BCR-ABL1, PML-RARA, ZBTB16-RARA, RUNX1-RUNX1T1, CBFB-MYH11, DEK NUP214, TCF3-PBX1, ETV6-RUNX1, MLL-AFF1, MLL-MLLT4, MLL-MLLT3, MLL-MLLT10, MLL ELL, MLL-MLLT1, and MLL-MLLT6. A total of 121 diagnostic acute leukemia specimens were studied, comparing the mRT-PCR system with standard cytogenetics. Fifty-six cases (46.3%) had fusion transcripts revealed by our mRT-PCR assay. The concordance rate between mRT-PCR and cytogenetics was 91.7%. However, false negative results were found in three cases who have inv(16), t(4;11) or t(11;19)(q23;p13.1), respectively. Seven cryptic translocations including ETV6 RUNX1, MLL-MLLT3, MLL-MLLT4, and PML-RARA were detected. This mRT-PCR assay is a useful screening tool in acute leukemia because it provides rapid and reliable detection of clinically important chimeric transcripts. In addition, cryptic translocations provide additional genetic information that could be clinically useful. PMID- 23091312 TI - Serum thioredoxin 1 level has close relation with myocardial damage amount in acute myocardial infarction patients. AB - Thioredoxin-1 (Trx-1) is one of important anti-oxidative molecules to overcome the oxidative stress. The aim of the present study is to investigate the clinical relationship between serum concentration of Trx-1 on the pre-percutaneous coronary intervention (prePCI) and myocardial damage amount in the patients with acute myocardial infarction with the culprit lesion in only the left anterior descending artery on coronary angiography (n = 100). Initial value of creatine kinase (CK) was 368.3 +/- 531.4 U/L, and MB isoenzyme of CK (CK-MB) level was 22.92 +/- 33.8 ng/mL, and cardiac specific troponin T (cTnT) level was 0.61 +/- 1.6 ng/mL. Positive correlations were observed between prePCI Trx-1 level and initial CK (P = 0.005, r = 0.281), and cTnT (P < 0.001, r = 0.453), peak CK (P = 0.001, r = 0.316) in all patients, but the statistical relation was observed only in ST segment elevation myocardial infarction (STEMI) patients (P = 0.008, r = 0.329 for initial CK, P = 0.001, r = 0.498 for initial cTnT, P = 0.005, r = 0.349 for peak CK), not in Non-STEMI patients. Conclusively, we consider prePCI serum Trx-1 as a predictor for myocardial damage amount in patients with STEMI. PMID- 23091313 TI - Tissue responses to endovascular stent grafts for saccular abdominal aortic aneurysms in a canine model. AB - We investigated tissue responses to endoskeleton stent grafts for saccular abdominal aortic aneurysms (AAAs) in canines. Saccular AAAs were made with Dacron patch in 8 dogs, and were excluded by endoskeleton stent grafts composed of nitinol stent and expanded polytetrafluoroethylene graft. Animals were sacrificed at 2 months (Group 1; n = 3) or 6 months (Group 2; n = 5) after the placement, respectively. The aortas embedding stent grafts were excised en bloc for gross inspection and sliced at 5 to 8 mm intervals for histopathologic evaluation. Stent grafts were patent in all except a dog showing a thrombotic occlusion in Group 2. In the 7 dogs with patent lumen, the graft overhanging the saccular aneurysm was covered by thick or thin thrombi with no endothelial layer, and the graft over the aortic wall was completely covered by neointima with an endothelial layer. Transgraft cell migration was less active at an aneurysm than at adjacent normal aorta. In conclusion, endoskeleton stent grafts over saccular aneurysms show no endothelial coverage and poor transgraft cell migration in a canine model. PMID- 23091314 TI - Early start of dialysis has no survival benefit in end-stage renal disease patients. AB - The timing for dialysis initiationis still debated. The aim of this study was to compare mortality rates, using a propensity-score approach, in dialysis patients with early or late starts. From January 2000 to June 2009, incident adult patients (n = 836) starting dialysis for end-stage renal disease (ESRD) were enrolled. The patients were assigned to either an early- or late-start group depending on the initiation time of the dialysis. After propensity-score basedmatching, 450 patients remained. At the initiation of dialysis, the mean estimated glomerular filtration rate (eGFR) was 11.1 mL/min/1.73 m(2) in the early-start group compared with 6.1 mL/min/1.73 m(2) in the late-start group. There were no significant differences in survival between the patients in the early- and late-start groups (Log rank tests P = 0.172). A higher overall mortality risk was observed in the early-start group than in the late-start group for the patients aged >= 70 yr (hazard ratio [HR]: 3.29; P = 0.048) and/or who had albumin levels >= 3.5 g/dL (HR: 2.53; P = 0.046). The survival of the ESRD patients was comparable between the patients in the early and late-start groups. The time to initiate dialysis should be determined based on clinical findings as well as the eGFR. PMID- 23091315 TI - Change in body compositions of Asian recipients after kidney transplantation. AB - Kidney transplantation and accompanying medical conditions may result in changes in body composition. Such changes have been evaluated in Caucasian recipients, but not in Asian recipients. Herein, we conducted a study on Asian recipients because Asians have a different body composition from Caucasians. A total of 50 Asian recipients was enrolled as a prospective cohort. Using bioelectrical impedance analysis, body composition (muscle and fat mass) was assessed after 2 weeks (baseline), and at 1, 3, 6, 9, and 12 months following kidney transplantation. To find predictors related to changes, the data were analyzed by multivariate analysis using forward selection. All of the patients had good graft function during the study period. Patients gained approximately 3 kg within 1 yr of kidney transplantation. The proportion of muscle mass significantly decreased (P(trend) = 0.001) and the proportion of fat mass significantly increased over time (P(trend) = 0.002). The multivariate results revealed that male recipients, deceased donor type, and low protein intake were associated with an increase in fat mass and a decrease in muscle mass. The results from this study may help to investigate differences in body composition changes between races, as well as the factors related to these changes. PMID- 23091316 TI - Association between nutrient intake and obesity in type 2 diabetic patients from the Korean National Diabetes Program: a cross-sectional study. AB - The aim of the study was to assess the association between usual dietary nutrient intake and obesity in Korean type 2 diabetic patients. We examined 2,832 type 2 diabetic patients from the Korean National Diabetes Program cohort who completed dietary assessment and clinical evaluation in this cross-sectional study. In men, higher dietary fiber intake was associated with a lower odds of being obese (P(trend) = 0.003) and in women, higher protein intake was associated with a lower odds of being obese (P(trend) = 0.03) after adjustment for age, diabetes duration, HbA1c, alcohol drinking, income, education level, and calorie intake. In men, higher fiber intake was associated with lower odds of obesity after further adjustment for diastolic blood pressure, physical activity, and possible confounding nutritional intake and medication. The multivariable adjusted odds ratio for the highest quintile of fiber intake was 0.37 (P(trend) < 0.001). In women, protein intake was not associated with obesity after further adjustment. In conclusion, higher intake of dietary fiber is associated with lower odds of being obese in type 2 diabetic men, suggesting a role for dietary fiber in the management and prevention of obesity in type 2 diabetes (ClinicalTrials.gov: NCT 01212198). PMID- 23091317 TI - Association between total bilirubin and hemoglobin A1c in Korean type 2 diabetic patients. AB - Recent studies have shown that bilirubin is negatively associated with hemoglobin A1c (HbA1c) in the general population. The association between bilirubin and HbA1c in serum of diabetes patients has not yet been studied. The aim of the present study was to evaluate the association between total bilirubin and HbA1c in Korean patients with type 2 diabetes. A total of 690 of the 1,275 type 2 diabetes patients registered with the public health centers in Seo-gu, Gwangju and Gokseong-gun, Jeollanam-do participated in this study. Following an overnight fast, venous blood and urine samples were collected and analyzed. The mean HbA1c values differed significantly according to total bilirubin (<= 0.4 mg/dL, 7.6%; 0.5 mg/dL, 7.3%; 0.6-0.7 mg/dL, 7.2%; and >= 0.8 mg/dL, 7.1%; P for trend = 0.016) after we adjusted for other confounding factors. When the odds ratio (OR) was adjusted for other confounding factors, there was a significant association between total bilirubin and HbA1c (OR, 0.4 [95% confidence interval, 0.2-0.8] for total bilirubin >= 0.8 mg/dL versus <= 0.4 mg/dL. In conclusion, total bilirubin concentrations in serum are negatively associated with HbA1c levels after adjustment for sex, age, and other confounding factors in type 2 diabetes patients. PMID- 23091318 TI - Effect of Helicobacter pylori eradication according to the IL-8-251 polymorphism in Koreans. AB - Previous studies suggested that polymorphisms of proinflammatory cytokine genes are important host genetic factors in Helicobacter pylori infection. The present study evaluated whether IL-8-251 polymorphism affected H. pylori eradication rate and to investigate the effect of H. pylori eradication on angiogenesis and the inflammatory process according to the IL-8-251 polymorphism. A total of 250 H. pylori-positive patients treated by endoscopic resection of the gastric neoplasm were classified into 3 groups (134 H. pylori-eradicated group, 19 H. pylori eradication failure group, and 97 H. pylori-infected group). H. pylori status, histology, and angiogenic factor levels were evaluated at baseline, 6 months, and 18 months. H. pylori eradication rate was 92.9% in AA genotype, 85.7% in AT genotype and 88.4% in TT genotype (P value = 0.731). Elevated IL-8 and matrix metalloproteinase-9 concentrations in H. pylori-infected gastric mucosa were reversible by successful eradication of H. pylori, independent of the IL-8-251 polymorphism. It is suggested that elevated IL-8 and MMP-9 concentrations in H. pylori-infected gastric mucosa are altered significantly after successful eradication and these conditions continue for 18 months. However, IL-8-251 polymorphism does not affect H. pylori eradication rate and the sequential changes of related angiogenic factors after H. pylori eradication in Koreans. PMID- 23091319 TI - Clinical characteristics of an esophageal fish bone foreign body from Chromis notata. AB - Damselfish Chromis notata is a small fish less than 15 cm long and it is widespread in the Indo-Pacific Ocean. Of all the cases of fish bone foreign body (FBFB) disease at our hospital, a damselfish FBFB was very common, and a specific part of the bone complex was involved in the majority of cases. This study was performed to evaluate the clinical characteristics of damselfish FBFB in Jeju Island. We retrospectively reviewed the medical records from March 2004 to March 2011 for foreign body diseases. Among 126 cases of foreign body diseases, there were 77 (61.1%) cases of FBFB. The mean age +/- standard deviation was 57.8 +/- 12.7 yr, and this was higher in females 60.9 +/- 14.6 yr vs 54.1 +/- 8.7 yr. Damselfish was the most common origin of a FBFB 36 out of total 77 cases. The anal fin spine-pterygiophore complex of damselfish was most commonly involved and cause more severe clinical features than other fish bone foreign bodies; deep 2.7 +/- 0.8 cm vs 2.3 +/- 0.8 cm; P < 0.01, more common mural penetration 23/36 vs 10/41; P < 0.01, and longer hospital stay 12.6 +/- 20.0 days 4.7 +/- 4.8 days; P = 0.02. We recommend removing the anal fin spine-pterygiophore complex during cleaning the damselfish before cooking. PMID- 23091320 TI - Dense deposit disease in Korean children: a multicenter clinicopathologic study. AB - The purpose of this study was to investigate the clinical, laboratory, and pathologic characteristics of dense deposit disease (DDD) in Korean children and to determine whether these characteristics differ between Korean and American children with DDD. In 2010, we sent a structured protocol about DDD to pediatric nephrologists throughout Korea. The data collected were compared with previously published data on 14 American children with DDD. Korean children had lower 24-hr urine protein excretion and higher serum albumin levels than American children. The light microscopic findings revealed that a higher percentage of Korean children had membranoproliferative glomerulonephritis patterns (Korean, 77.8%; American, 28.6%, P = 0.036), whereas a higher percentage of American children had crescents (Korean, 0%; American, 78.6%, P < 0.001). The findings from the electron microscopy revealed that Korean children were more likely to have segmental electron dense deposits in the lamina densa of the glomerular basement membrane (Korean, 100%; American, 28.6%, P = 0.002); mesangial deposit was more frequent in American children (Korean, 66.7%; American, 100%, P = 0.047). The histological findings revealed that Korean children with DDD were more likely to show membranoproliferative glomerulonephritis patterns than American children. The degree of proteinuria and hypoalbuminemia was milder in Korean children than American children. PMID- 23091321 TI - Utilization of emergency department by children in Korea. AB - This study was conducted to examine the nation-wide emergency department (ED) utilization pattern by children in Korea. Most referral hospital EDs provide their essential ED information to the National Emergency Medical Center through the National Emergency Department Information System (NEDIS). We analyzed the NEDIS data on pediatric visits (< 19 yr old) during three years, from June 1, 2008 to May 31, 2010. A total of 2,072,664 children visited 124 EDs during the study period, and this patient population comprised 31.2% of the total ED visits. Male patients with a mean age of 5.44 (+/- 5.40 SD) yr comprised 59.1% of the ED pediatric visits. Among all age groups, the 1-4-yr-old group was the largest (42.3%). The most common mode of arrival was non-emergency medical service (EMS) (90.7%), and only 4.2% of patients used EMS transport. Common chief complaints in infants were fever (37.4%), whereas many older children presented to the EDs with abdominal pain (15.4%). The ratio of disease versus injury as the cause of ED visits was 2.5:1. Most patients were discharged (81.2%), and 15.3% were admitted. In conclusion, the most common age group who are brought to EDs in Korea is 1 to 4 yr-old young children, and common chief complaints of the visiting children are age-dependent, such as fever in younger children and abdominal pain and headache in older children. We need more improved and organized emergency medicine service system for children in Korea. PMID- 23091322 TI - Attention deficit hyperactivity disorder in epileptic children. AB - It is well-known that the prevalence of attention deficit hyperactivity disorder (ADHD) is higher in epileptic children than in the general pediatric population. The aim of this study was to compare the accompaniment of ADHD in epileptic children with well-controlled seizures and no significant intellectual disability with that in healthy controls. We included epileptic children between the ages of 6 and 12 yr visiting our clinic for six consecutive months and controls without significant medical or psychiatric illnesses. We excluded patients with intellectual disability or persistent seizures during the recent three months. The diagnosis of ADHD was based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). After exclusion of 84 patients, we enrolled 102 (54.8%) children (mean age, 9.4 +/- 2.0 yr). Seven (7 of 102, 6.9%) were diagnosed with ADHD. As compared to control group (4 of 110, 3.6%), there was no difference in ADHD accompaniment (P = 0.29). No difference was observed in ADHD accompaniment according to seizure type and epilepsy syndrome. In conclusion, the accompaniment of ADHD in epileptic children with well-controlled seizures and no intellectual disability may not differ from that of the general pediatric population. PMID- 23091323 TI - Prevalence of birth defects in Korean livebirths, 2005-2006. AB - We investigated the livebirths prevalence and occurrence pattern of birth defects in Korea. After the survey on birth defects was done in 2,348 medical institutions around the nation, the birth defect prevalence of livebirths in 2005 2006 was calculated. This study was based on the medical insurance claims database of the National Health Insurance Corporation. The number of livebirths in Korea was 883,184 from 2005-2006, and 25,335 cases of birth defects were notified to our study, equivalent to a prevalence of 286.9 per 10,000 livebirths. Anomalies of the circulatory system were the most common defects, accounting for 43.4% of birth defects with a prevalence of 124.5 per 10,000 livebirths. It was followed by the musculoskeletal system anomalies, the digestive system anomalies, and the urinary system anomalies. The five major birth defects based on the ranking of prevalence were atrial septal defect, ventricular septal defect, hydronephrosis, patent ductus arteriosus, and cleft lip/palate. Birth defects in livebirths were associated with a high proportion of low birthweight, prematurity, multiple births and advanced maternal age. The prevalence of birth defects in Korea is similar to or lower than those reported in developed countries. Our study suggests baseline data to explain the current status of birth defects and to establish a registry system of birth defects in Korea. PMID- 23091325 TI - Prevalence of common skin diseases and their associated factors among military personnel in Korea: a cross-sectional study. AB - This study was conducted to clarify the prevalence of common skin diseases and their associated factors among military personnel in Korea. Four dermatologists visited adjacent military units and examined soldiers. A structured questionnaire that included questions about known skin diseases, demographic information, and questions for the Perceived Stress Index was completed for each participant. The soldiers that had been diagnosed with a skin disease answered one additional questionnaire (Skindex-29) which assess the influence of an individual's skin disease on daily life. Of 1,321 soldiers examined, 798 (60.4%) had one or more skin diseases. The three most common skin problems were acne (35.6%), tinea pedis (15.2%) and atopic dermatitis (5.1%). The diseases closely related to the period of military service were acne, tinea pedis, viral warts and corns. The diseases related to the amount of stress were atopic dermatitis, seborrheic dermatitis, and acne. The most troublesome skin diseases were atopic dermatitis, tinea cruris, and seborrheic dermatitis. These results demonstrated that the prevalence of skin disease among military personnel in Korea is very high, and that some of the skin disorders may have a significant influence on their daily lives. PMID- 23091324 TI - Dendritic eIF4E-binding protein 1 (eIF4E-BP1) mRNA is upregulated by neuronal activation. AB - Long-term synaptic plasticity requires addition of new proteins at the synaptic site. The local protein synthesis at subsynaptic sites confers advantageous mechanisms that would regulate the protein composition in local domains on a moment-by-moment basis. However, our information on the identities of 'dendritic' mRNAs is very limited. In this study we investigated the expression of the protein and mRNA for eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) in cultured rat hippocampal neurons. Immunocytochemistry (ICC) showed that 4EBP1 protein is highly localized to the nucleus. In dendrites most 4EBP1 punctae were not colocalized with those of eIF4E. In situ hybridization (ISH) and Fluorescence ISH (FISH) revealed that 4EBP1 mRNA was present in dendrites. The FISH signals formed clusters along dendrites that colocalized with ICC signals for Staufen, a marker for RNA granules. The neuronal activation by KCl (60 mM, 10 min) significantly increased the density of 4EBP1 FISH signals in the nucleus after 2 hr, and both in the nucleus and dendrites after 6 hr. Our results indicate that 4EBP1 and its mRNA are present in dendrites, and the mRNA is upregulated and transported to dendritic domains in RNA granules upon neuronal activation. PMID- 23091326 TI - Evaluating the accuracy of emergency medicine resident interpretations of abdominal CTs in patients with non-traumatic abdominal pain. AB - Abdominal computed tomography (CT) is widely used as a diagnostic tool in emergency medicine (EM) to accurately diagnose abdominal pain. EM residents must be able to offer preliminary interpretations of CT imaging. In this study, we evaluated the preliminary interpretation ability of a sample of emergency residents presented with adult abdominal CT images, and compared their results with those of radiology residents. We conducted a prospective observational study from November 16, 2008 to June 30, 2009. During this time, we gathered preliminary interpretations of consecutive abdominal CT made by emergency and radiology residents. We assessed the discrepancy rates of both samples by comparing their findings to the final reports from attending radiologists. A total of 884 cases were enrolled in the present study. The discrepancy rates of emergency and radiology residents were 16.7% and 12.2%, respectively. When female genital organs, peritoneum, adrenal glands, or the musculoskeletal system were abnormal, we found that emergency residents' preliminary interpretations of CT images were insufficient compared to those of radiology residents. Therefore more formal education is needed to emergency residents. If possible, the preliminary interpretations of radiology attending physicians are ideal until improving the ability of interpretations of emergency residents in abdomen CT. PMID- 23091327 TI - Successful treatment of chronic eosinophilic pneumonia with anti-IgE therapy. AB - Anti-IgE therapy, using recombinant humanized anti-IgE antibodies, is clinically effective in patients with eosinophil-related disorders such as allergic asthma, allergic rhinitis, and chronic urticaria. Chronic eosinophilic pneumonia tends to respond promptly to systemic corticosteroid therapy, however; relapses are common following corticosteroid tapering. We treated two patients (17- and 19-yr-old males) of chronic eosinophilic pneumonia whose symptoms were cough and dyspnea on exertion. The symptoms were recurrent while tapering off corticosteroid. They were treated with anti-IgE antibody without recurrence for 2 yr and 15 months. Here, we first describe clinical experience of the 2 cases of chronic eosinophilic pneumonia. PMID- 23091328 TI - Unintended cannulation of the subclavian artery in a 65-year-old-female for temporary hemodialysis vascular access: management and prevention. AB - Ultrasound-guided cannulation of a large-bore catheter into the internal jugular vein was performed to provide temporary hemodialysis vascular access for uremia in a 65-yr-old woman with acute renal failure and sepsis superimposed on chronic renal failure. Despite the absence of any clinical evidence such as bleeding or hematoma during the procedure, a chest x-ray and computed tomographic angiogram of the neck showed that the catheter had inadvertently been inserted into the subclavian artery. Without immediately removing the catheter and applying manual external compression, the arterial misplacement of the hemodialysis catheter was successfully managed by open surgical repair. The present case suggests that attention needs to be paid to preventing iatrogenic arterial cannulation during central vein catheterization with a large-bore catheter and to the management of its potentially devastating complications, since central vein catheterization is frequently performed by nephrologists as a common clinical procedure to provide temporary hemodialysis vascular access. PMID- 23091329 TI - A case report on 30-week premature twin babies with congenital myotonic dystrophy conceived by in vitro fertilization. AB - Congenital myotonic dystrophy type 1 (DM1) presents severe generalized weakness, hypotonia, and respiratory compromise after delivery with high mortality and poor prognosis. We presented a congenital DM1 of premature twins in the 30th week of gestation. These twins were conceived by in vitro fertilization (IVF). Both babies presented apnea and hypotonia and had characteristic facial appearance. They were diagnosed DM1 by genetic method. They were complicated by chylothorax and expired at 100 and 215 days of age, respectively. Mother was diagnosed DM1 during the evaluation of babies. This is the first report on congenital DM1 which accompanied the chylothorax. More investigation on the association with chylothorax and congenital DM1 is recommended. With a case of severe neonatal hypotonia, congenital DM1 should be differentiated in any gestational age. Finally, since DM1 is a cause of infertility, we should consider DM1 in infertility clinic with detailed history and physical examination. PMID- 23091330 TI - A case of 9.7 Mb terminal Xp deletion including OA1 locus associated with contiguous gene syndrome. AB - Terminal or interstitial deletions of Xp (Xp22.2->Xpter) in males have been recognized as a cause of contiguous gene syndromes showing variable association of apparently unrelated clinical manifestations such as Leri-Weill dyschondrosteosis (SHOX), chondrodysplasia punctata (CDPX1), mental retardation (NLGN4), ichthyosis (STS), Kallmann syndrome (KAL1), and ocular albinism (GPR143). Here we present a case of a 13.5 yr old boy and sister with a same terminal deletion of Xp22.2 resulting in the absence of genes from the telomere of Xp to GPR143 of Xp22. The boy manifested the findings of all of the disorders mentioned above. We began a testosterone enanthate monthly replacement therapy. His sister, 11 yr old, manifested only Leri-Weill dyschondrosteosis, and had engaged in growth hormone therapy for 3 yr. To the best of our knowledge, this is the first report of a male with a 9.7 Mb terminal Xp deletion including the OA1 locus in Korea. PMID- 23091333 TI - Reducing the risk of deadly mixups with epidural and intravenous drugs. AB - Mixups of epidural and intravenous drugs can be deadly. PMID- 23091334 TI - Congress passes unambitious user fee reauthorization and expansion: act omits key provisions sought by pharmacy groups. AB - The FDA's PDUFA reauthorization bill passes but omits significant safety provisions. PMID- 23091331 TI - An intrathecally located broken catheter used for an intrathecal drug delivery system. AB - The intrathecal drug delivery system (ITDDS), an effective treatment tool for intractable spasticity and pain, is associated with various complications but breakage of the catheter is rare. We report the case of a 50-yr-old man with ITDDS, in whom an intrathecal catheter was severed, resulting in a 28.6-cm-long intrathecal fragment. The catheter completely retracted into the intrathecal space from the anchor site. The catheter was severed during spine flexion, and the total distal fragment was repositioned in the intrathecal space. Although the outcome of ITDDS was associated with the length or diameter of the broken catheter, no neurologic complications occurred in our patient. Thus, we inserted another catheter instead of removing the old one. Thereafter, the patient has been regularly followed up, and no neurologic complications have developed during the 28 months. PMID- 23091336 TI - Cabazitaxel (jevtana): a novel agent for metastatic castration-resistant prostate cancer. AB - OBJECTIVE: This article presents current clinical evidence supporting the use of cabazitaxel (Jevtana) in men with metastatic castration-resistant prostate cancer (mCRPC). DATA SOURCES: We conducted a literature search using abstracts from MEDLINE and PubMed (from January 1966 to December 2011) and the American Society of Clinical Oncology (from January 2000 to December 2011). The search included clinical studies and abstracts in the English language that described the pharmacology, pharmacokinetics, clinical activity, and safety of cabazitaxel in mCRPC. RESULTS: Cabazitaxel, a semisynthetic microtubule inhibitor that induces cell death by microtubule stabilization, was approved in combination with prednisone for the treatment of mCRPC in patients who had been treated with a docetaxel-(Taxotere)-containing regimen. The approval of this taxane derivative was based primarily on the results of a randomized, open-label trial in patients with mCRPC who were treated with either cabazitaxel 25 mg/m(2) or mitoxantrone (Novantrone) 12 mg/m(2) intravenously every 3 weeks, both in combination with prednisone 10 mg/day. The median survival period was 15.1 months with cabazitaxel and 12.7 months with mitoxantrone. Neither group experienced complete responses. Cabazitaxel has also shown activity in breast cancer and other malignancies. In clinical trials, common grade 3 or grade 4 adverse reactions were myelosuppression, febrile neutropenia, diarrhea, fatigue, and asthenia. Other adverse effects included abdominal pain, back pain, arthralgia, and peripheral neuropathy. CONCLUSION: Cabazitaxel appeared to be an effective second-line agent in patients with mCRPC refractory to a docetaxel-containing regimen. Studies comparing cabazitaxel with existing first-line regimens for mCRPC are under way. Until the results of these head-to-head trials are published, it remains uncertain whether cabazitaxel is more effective or more tolerable than the currently available first-line regimens. PMID- 23091337 TI - Don'T know much about health insurance exchanges: the next critical step: educating consumers and small businesses. AB - By the end of 2012, states must figure out how they will provide exchanges for citizens to buy health care insurance. Much work remains to be done, including removing information barriers, to make health care accessible to all citizens by 2014. PMID- 23091338 TI - The changing landscape of treatment options for metastatic castrate-resistant prostate cancer: challenges and solutions for physicians and patients. AB - Four recently approved drugs (cabazitaxel, sipuleucel-T, abiraterone, and denosumab), along with emerging therapies, bone-building therapies, hormonal treatments, and immunotherapies, have all demonstrated promise in advanced prostate cancer. It appears that the best outcomes will be achieved from the sequential use of multiple agents. PMID- 23091339 TI - Adherence to 5-alpha reductase inhibitor therapy for benign prostatic hyperplasia: clinical and economic outcomes. AB - OBJECTIVE: Our goal was to quantify relationships between adherence to 5-alpha reductase inhibitors (5-ARIs), the risk of acute urinary retention (AUR) and prostate surgery, and medical costs related to patients with benign prostatic hyperplasia (BPH). METHODS: Claims recorded over a period of 6.5 years in a nationwide managed care database were analyzed. We conducted time-to-event multivariate analysis to evaluate relationships between adherence (medication possession ratio [MPR] thresholds of 70% or higher, 75% or higher, and 80% or higher), persistence (length of therapy), and the risk of AUR and surgery. We compared mean monthly BPH-related medical costs in patients with MPRs at or above thresholds and those with MPRs below thresholds and determined changes in BPH related costs associated with 30-day increments of therapy. RESULTS: In AUR analyses (N = 17,293), meeting or exceeding MPR thresholds was associated with a reduced likelihood of AUR for 70% (hazard ratio [HR], 0.380), 75% (HR, 0.613), and 80% (HR, 0.519) (P < 0.05 for all). In prostate surgery analyses (N = 17,739), the likelihood of surgery was reduced with MPR thresholds of 70% or above (HR, 0.294), 75% or above (HR, 0.542), and 80% or above (HR, 0.436) (P < 0.05 for all). A longer duration of therapy was associated with a reduced likelihood of AUR (HR, 0.860) and surgery (HR, 0.884) (P < 0.05 for both). In both populations, adherence and persistence were also associated with significantly decreased BPH-related medical costs. CONCLUSION: In patients with BPH who received 5-ARI therapy, greater adherence and persistence were associated with significantly reduced risks of AUR and prostate surgery and with significantly lower medical costs. Maximizing adherence may enable patients to realize the potential long-term benefits of 5ARIs. PMID- 23091340 TI - 2012 american society of clinical oncology and american society of hypertension: 27th annual scientific meeting and exposition. AB - Selected ASCO topics include drugs for melanoma, gastrointestinal tumors, non small-cell lung cancer, and advanced breast cancer. ASH presentations cover ambulatory blood pressure in type-2 diabetes, triple therapy in obese patients, the effect of body mass on cardiovascular outcomes, and a novel glucagon-like peptide agonist for diabetes. PMID- 23091341 TI - Management of Complications during Gastric Endoscopic Submucosal Dissection. AB - Popularity of endoscopic submucosal dissection (ESD) has shown an increase during the last decade, and may, for the time being, be the most important technique in treatment of early gastrointestinal cancer or a premalignant lesion. This technique has advantages in the aspect of en bloc resection, which enables evaluation of the completeness of resection and other pathologic characteristics; however, it has limitation in terms of complications, compared to endoscopic mucosal resection (EMR). Bleeding and perforation are the most common complications encountered during the procedure. These complications can cause embarrassment for the endoscopist and hamper performance of the procedure, which can result in an incomplete resection. To overcome these obstacles during performance of the procedure, we should be familiar with management of complications. In particular, beginners who start performing ESD should have full knowledge of and be in good handling of the method of hemostasis using hemoclips or electrocoagulation for management of complications. Various methods, procedures, and equipment are under development, which will provide us with powerful tools for achievement of successful ESD without complications in the near future. PMID- 23091342 TI - Treatment of mycoplasma contamination in cell cultures with Plasmocin. AB - A high percentage of cell lines are chronically infected with various mycoplasma species. The addition of antibiotics that are particularly effective against these contaminants to the culture medium during a limited period of time is a simple, inexpensive, and very practical approach for decontaminating cell cultures. Here, we examined the effectiveness of the new antimycoplasma compound Plasmocin that has been employed routinely to cleanse chronically infected cell lines. In a first round of treatment 45 out of 58 (78%) mycoplasma-positive cell lines could be cured. In a second attempt using back-up cryopreserved original cells, four additional cell lines were cured; thus, the overall cure rate was 84%. Even if the mycoplasma contamination was not eradicated by Plasmocin, the parallel treatment with several other antibiotics (Baytril, BM-Cyclin, Ciprobay, MRA, or MycoZap) led to the cure of all 58 cell lines. The successful decontamination was permanent as mycoplasmas were no longer detected at day +14 posttreatment and at later time points as examined by PCR which is the most sensitive and specific mycoplasma detection method. Collectively, our results highlight certain antibiotics as effective antimycoplasma reagents and support the therapeutic rationale for their use in the eradication of this notorious cell culture contaminant. PMID- 23091343 TI - Antihyperglycemic effects of fermented and nonfermented mung bean extracts on alloxan-induced-diabetic mice. AB - Mung bean was reported as a potential antidiabetic agent while fermented food has been proposed as one of the major contributors that can reduce the risk of diabetes in Asian populations. In this study, we have compared the normoglycemic effect, glucose-induced hyperglycemic effect, and alloxan-induced hyperglycemic effect of fermented and nonfermented mung bean extracts. Our results showed that fermented mung bean extracts did not induce hypoglycemic effect on normal mice but significantly reduced the blood sugar levels of glucose- and alloxan-induced hyperglycemic mice. The serum levels of cholesterol, triglyceride (TG), and low density lipoprotein (LDL) were also lowered while insulin secretion and antioxidant level as measured by malonaldehyde (MDA) assays were significantly improved in the plasma of the fermented mung bean-treated group in alloxan induced hyperglycemic mouse. These results indicated that fermentation using Mardi Rhizopus sp. strain 5351 inoculums could enhance the antihyperglycemic and the antioxidant effects of mung bean in alloxan-treated mice. The improvement in the antihyperglycemic effect may also be contributed by the increased content of GABA and the free amino acid that are present in the fermented mung bean extracts. PMID- 23091344 TI - A new candidate substrate for cell-matrix adhesion study: the acellular human amniotic matrix. AB - In vivo adhesions between cells and the extracellular matrix play a crucial role in cell differentiation, proliferation, and migration as well as tissue remodeling. Natural three-dimensional (3D) matrices, such as self-assembling matrices and Matrigel, have limitations in terms of their biomechanical properties. Here, we present a simple method to produce an acellular human amniotic matrix (AHAM) with preserved biomechanical properties and a favorable adhesion potential. On the stromal side of the AHAM, human foreskin fibroblasts (HFFs) attached and extended with bipolar spindle-shaped morphology proliferated to multilayer networks, invaded into the AHAM, and migrated in a straight line. Moreover, alphaV integrin, paxillin, and fibronectin were observed to colocalize after 24 h of HFF culture on the stromal side of the AHAM. Our results indicate that the AHAM may be an ideal candidate as a cell-matrix adhesion substrate to study cell adhesion and invasion as well as other functions in vitro under a tensile force that mimics the in vivo environment. PMID- 23091345 TI - Frequency of TLR 2, 4, and 9 gene polymorphisms in Chinese population and their susceptibility to type 2 diabetes and coronary artery disease. AB - Toll-like receptors (TLRs) are pivotal components of the innate immune response. Activation of the innate immune system and subsequent chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and type 2 diabetes. In the study, we genotyped TLRs gene polymorphisms, including TLR2 Arg677Trp and Arg753Gln, TLR4 Asp299Gly and Thr399Ile, TLR9 1486T/C and -1237T/C. The frequencies of TT, TC and CC genotype of TLR9-1486T/C mutation were 39.6%, 45.8% and 14.6%, respectively; the frequencies of T allele and C allele were 62.5% and 37.5%. However, neither of these parameters was statistically significant among study groups. In addition, we were surprised to find that the commonly reported TLR SNPs in the Western countries, like TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C, were not polymorphic at all in all study subjects. In conclusion, our data suggests that TLR2 Arg677Trp or Arg753Gln, TLR4 Asp299Gly or Thr399Ile and TLR9-1237T/C polymorphisms have low frequency and TLR9-1486T/C polymorphism may not be a suitable marker in predicting the susceptibility to type 2 diabetes or coronary artery disease in the Chinese Han population. PMID- 23091346 TI - Proteomic profiling of the dioxin-degrading bacterium Sphingomonas wittichii RW1. AB - Sphingomonas wittichii RW1 is a bacterium of interest due to its ability to degrade polychlorinated dioxins, which represent priority pollutants in the USA and worldwide. Although its genome has been fully sequenced, many questions exist regarding changes in protein expression of S. wittichii RW1 in response to dioxin metabolism. We used difference gel electrophoresis (DIGE) and matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to identify proteomic changes induced by growth on dibenzofuran, a surrogate for dioxin, as compared to acetate. Approximately 10% of the entire putative proteome of RW1 could be observed. Several components of the dioxin and dibenzofuran degradation pathway were shown to be upregulated, thereby highlighting the utility of using proteomic analyses for studying bioremediation agents. This is the first global protein analysis of a microorganism capable of utilizing the carbon backbone of both polychlorinated dioxins and dibenzofurans as the sole source for carbon and energy. PMID- 23091347 TI - Alterations and chromosomal variants in the Ecuadorian population. AB - Medical genetics is a field marked by fast progress. Even though it was at one point confined to a group of relatively rare diseases, today it has become a central component in the understanding of disorders and it is the subject of interest for all medical specialties. This paper, shares data on the chromosomal alterations and variations that have been diagnosed in Ecuadorian patients since 1998. A total of 2,636 individual cases have been analyzed by G-banding technique until February 2012. The present work shows this collection of data and the important findings that have appeared throughout these years in hopes that it can contribute to have a deeper understanding of the incidence of chromosomal aberrations and alterations in the Ecuadorian population. PMID- 23091348 TI - Antioxidant, antinociceptive, and anti-inflammatory effects of carotenoids extracted from dried pepper (Capsicum annuum L.). AB - Carotenoids extracted from dried peppers were evaluated for their antioxidant, analgesic, and anti-inflammatory activities. Peppers had a substantial carotenoid content: guajillo 3406 +/- 4 MUg/g, pasilla 2933 +/- 1 MUg/g, and ancho 1437 +/- 6 MUg/g of sample in dry weight basis. A complex mixture of carotenoids was discovered in each pepper extract. The TLC analysis revealed the presence of chlorophylls in the pigment extract from pasilla and ancho peppers. Guajillo pepper carotenoid extracts exhibited good antioxidant activity and had the best scavenging capacity for the DPPH(+) cation (24.2%). They also exhibited significant peripheral analgesic activity at 5, 20, and 80 mg/kg and induced central analgesia at 80 mg/kg. The results suggest that the carotenoids in dried guajillo peppers have significant analgesic and anti-inflammatory benefits and could be useful for pain and inflammation relief. PMID- 23091349 TI - Comprehensive evaluation of different T-helper cell subsets differentiation and function in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is the most common autoimmune disorder. Loss of Th1/Th2 and Th17/Treg balance has been reported in several inflammatory autoimmune diseases. This study was to investigate Th1, Th2, Th17, and Treg differentiation and related cytokines in RA patients. The frequencies of Th1, Th2, Th17, and Treg cells in peripheral blood of RA patients (n = 76) and healthy controls (n = 18) were determined by flow cytometry. Eight serum cytokines were analyzed using cytometric bead array. The results demonstrated that RA patients exhibited increased peripheral Th1/Th17 cells and Th1/Th17-related cytokines. However, Th1 cells only reached significant difference at advanced stage, but Th17 at all stages, suggesting more important roles in Th17 cells. For Th2 and Treg cells, there was a different function pattern in RA progression. Although with the increase of DAS28 score, Th2 cell experienced some degree of decrease in RA patients, no significant difference was observed. IL-4 and IL-10 showed a significant increase in RA patients. These indicated that Th2 cells might exert immunosuppression effects mainly by secreting cytokines. Treg cells were found significantly decreased in RA patients, but no difference was observed in TGF beta expression, indicating a cell-cell interaction pattern in Treg cell. PMID- 23091350 TI - Evaluation of bovine embryo biopsy techniques according to their ability to preserve embryo viability. AB - The purpose of this research was to evaluate three embryo biopsy techniques used for preimplantation genetic diagnosis (PGD) in cattle and to recommend the least invasive one for current use, especially when PGD is followed by embryo cryopreservation. Three hundred bovine embryos were biopsied by either one of the needle, aspiration or microblade method, and then checked for viability by freezing/thawing and transplantation to recipient cows. The number of pregnancies obtained after the transfer of biopsied frozen/thawed embryos was assessed 30 days later using ultrasounds. The results were significantly different between the three biopsy methods: the pregnancy rate was of 57% in cows that received embryos biopsied by needle, 43% in cows that received embryos biopsied by aspiration, and 31% in cows that received embryos biopsied by microblade. Choosing an adequate biopsy method is therefore of great importance in embryos that will undergo subsequent cryopreservation, as it significantly influences their viability after thawing. PMID- 23091351 TI - Improvement of coenzyme Q10 production: mutagenesis induced by high hydrostatic pressure treatment and optimization of fermentation conditions. AB - Coenzyme Q10 (CoQ10, ubiquinone), a potent antioxidative dietary supplement, was produced by submerged fermentation using Agrobacterium tumefaciens instead of chemical synthesis or solvent extraction. Agrobacterium tumefaciens 1.2554 was subjected to mutagenesis using a series of treatments including high hydrostatic pressure (HHP) treatment, UV irradiation, and diethyl sulfate (DES) treatment to obtain mutant strains showing higher CoQ10 production than wild-type strains. A mutant strain PK38 with four genetic markers was isolated: the specific CoQ10 content of the mutant strain increased by 52.83% compared with the original strain. Effects of carbon and nitrogen sources on CoQ10 production with PK38 were studied. Sucrose at concentration of 30 g/l was tested as the best carbon source, and yeast extract at concentration of 30 g/l supplemented with 10 g/l of ammonium sulfate was identified to be the most favorable for CoQ10 production using PK38. Fed-batch culture strategy was then used for increasing production of CoQ10 in 5 l fermentor. Using the exponential feeding fed-batch culture of sucrose, cell growth and CoQ10 formation were significantly improved. With this strategy, the final cell biomass, CoQ10 production, and specific CoQ10 production increased by 126.11, 173.12, and 22.76%, respectively, compared to those of batch culture. PMID- 23091353 TI - Genome-wide analysis of mir-548 gene family reveals evolutionary and functional implications. AB - mir-548 is a larger, poorly conserved primate-specific miRNA gene family. 69 human mir-548 genes located in almost all human chromosomes whose widespread distribution pattern implicates the evolutionary origin from transposable elements. Higher level of nucleotide divergence was detected between these human miRNA genes, which mainly derived from divergence of multicopy pre-miRNAs and homologous miRNA genes. Products of mir-548, miR-548-5p, and miR-548-3p showed inconsistent evolutionary patterns, which partly contributed to larger genetic distances between pre-miRNAs. "Seed shifting" events could be detected among miR 548 sequences due to various 5' ends. The events led to shift of seed sequences and target mRNAs, even generated to new target mRNAs. Additionally, the phenomenon of miRNA:miRNA interaction in the miRNA gene family was found. The potential interaction between miRNAs may be contributed to dynamic miRNA expression profiles by complementarily binding events to form miRNA:miRNA duplex with 5'-/3'-overhangs. The miRNA gene family had important roles in multiple biological processes, including signaling pathways and some cancers. The potential abundant roles and functional implication further led to the larger and poorly conserved gene family with genetic variation based on transposable elements. The evolutionary pattern of the primate-specific gene family might contribute to dynamic expression profiles and regulatory network. PMID- 23091354 TI - Shifts in nitrification kinetics and microbial community during bioaugmentation of activated sludge with nitrifiers enriched on sludge reject water. AB - This study used two laboratory-scale sequencing batch reactors (SBRs) to evaluate the shifts in nitrification kinetics and microbial communities of an activated sludge sewage treatment system (main stream) during bioaugmentation with nitrifiers cultivated on real sludge reject water (side stream). Although bioaugmentation exerted a strong influence on the microbial community and the nitrification kinetics in the main stream, there was 58% of maximum ammonia uptake rate (AUR) and 80% of maximum nitrite uptake rate (NUR) loss of the seed source after bioaugmentation. In addition, nitrite accumulation occurred during bioaugmentation due to the unequal and asynchronous increase of the AUR (from 2.88 to 13.36 mg N/L . h) and NUR (from 0.76 to 4.34 mg N/L . h). FISH results showed that ammonia oxidizing bacteria (AOB) was inclined to be washed out with effluent in contrast to nitrite oxidizing bacteria (NOB), and Nitrosococcus mobilis lineage was the dominant AOB, while the dominant NOB in the main stream gradually transferred from Nitrospira to Nitrobacter. Nitrospina and Nitrococcus which existed in the seed source could not be detected in the main stream. It can be inferred that nitrite accumulation occurred due to the mismatch of NOB structure but washed out with effluent. PMID- 23091352 TI - Rabbit and mouse models of HSV-1 latency, reactivation, and recurrent eye diseases. AB - The exact mechanisms of HSV-1 establishment, maintenance, latency, reactivation, and also the courses of recurrent ocular infections remain a mystery. Comprehensive understanding of the HSV-1 disease process could lead to prevention of HSV-1 acute infection, reactivation, and more effective treatments of recurrent ocular disease. Animal models have been used for over sixty years to investigate our concepts and hypotheses of HSV-1 diseases. In this paper we present descriptions and examples of rabbit and mouse eye models of HSV-1 latency, reactivation, and recurrent diseases. We summarize studies in animal models of spontaneous and induced HSV-1 reactivation and recurrent disease. Numerous stimuli that induce reactivation in mice and rabbits are described, as well as factors that inhibit viral reactivation from latency. The key features, advantages, and disadvantages of the mouse and rabbit models in relation to the study of ocular HSV-1 are discussed. This paper is pertinent but not intended to be all inclusive. We will give examples of key papers that have reported novel discoveries related to the review topics. PMID- 23091355 TI - Assessment of genotoxic and cytotoxic hazards in brain and bone marrow cells of newborn rats exposed to extremely low-frequency magnetic field. AB - The present study aimed to evaluate the association between whole body exposure to extremely low frequency magnetic field (ELF-MF) and genotoxic , cytotoxic hazards in brain and bone marrow cells of newborn rats. Newborn rats (10 days after delivery) were exposed continuously to 50 Hz, 0.5 mT for 30 days. The control group was treated as the exposed one with the sole difference that the rats were not exposed to magnetic field. Comet assay was used to quantify the level of DNA damage in isolated brain cells. Also bone marrow cells were flushed out to assess micronucleus induction and mitotic index. Spectrophotometric methods were used to measure the level of malondialdehyde (MDA) and the activity of glutathione (GSH) and superoxide dismutase (SOD). The results showed a significant increase in the mean tail moment indicating DNA damage in exposed group (P < 0.01, 0.001, 0.0001). Moreover ELF-MF exposure induced a significant (P < 0.01, 0.001) four folds increase in the induction of micronucleus and about three folds increase in mitotic index (P < 0.0001). Additionally newborn rats exposed to ELF-MF showed significant higher levels of MDA and SOD (P < 0.05). Meanwhile ELF-MF failed to alter the activity of GSH. In conclusion, the present study suggests an association between DNA damage and ELF-MF exposure in newborn rats. PMID- 23091356 TI - Characterization of flavonol inhibition of DnaB helicase: real-time monitoring, structural modeling, and proposed mechanism. AB - DnaB helicases are motor proteins essential for DNA replication, repair, and recombination and may be a promising target for developing new drugs for antibiotic-resistant bacteria. Previously, we established that flavonols significantly decreased the binding ability of Klebsiella pneumoniae DnaB helicase (KpDnaB) to dNTP. Here, we further investigated the effect of flavonols on the inhibition of the ssDNA binding, ATPase activity, and dsDNA-unwinding activity of KpDnaB. The ssDNA-stimulated ATPase activity of KpDnaB was decreased to 59%, 75%, 65%, and 57%, in the presence of myricetin, quercetin, kaempferol, and galangin, respectively. The ssDNA-binding activity of KpDnaB was only slightly decreased by flavonols. We used a continuous fluorescence assay, based on fluorescence resonance energy transfer (FRET), for real-time monitoring of KpDnaB helicase activity in the absence and presence of flavonols. Using this assay, the flavonol-mediated inhibition of the dsDNA-unwinding activity of KpDnaB was observed. Modeled structures of bound and unbound DNA showed flavonols binding to KpDnaB with distinct poses. In addition, these structural models indicated that L214 is a key residue in binding any flavonol. On the basis of these results, we proposed mechanisms for flavonol inhibition of DNA helicase. The resulting information may be useful in designing compounds that target K. pneumoniae and other bacterial DnaB helicases. PMID- 23091357 TI - Attenuating effect of Ginkgo biloba leaves extract on liver fibrosis induced by thioacetamide in mice. AB - The purpose of this study is to investigate the effect of Ginkgo biloba leaves extract on experimental liver fibrosis induced by thioacetamide (TAA) in male albino mice. The experimental mice were divided into four groups. The mice of the first group were served as control. The experimental animals of the second group were given 150 mg/kg body weight of TAA by intraperitoneal injection, twice weekly, for 9 weeks. The mice of the third group were exposed to TAA and supplemented with G. biloba leaves extract. The animals of the fourth group were supplemented with G. biloba leaves extract. The levels of plasma alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, triglycerides, cholesterol, and low-density lipoprotein cholesterol were statistically increased while the levels of plasma total protein, albumin, glucose, and high-density lipoprotein cholesterol were significantly decreased. The levels of liver superoxide dismutase, glutathione, glycogen and total protein were notably declined, whereas the level of total lipid was increased in mice of the second group. Furthermore, microscopic examination of liver sections from mice treated with TAA showed an abnormal morphology characterized by nodular transformations in liver parenchyma which surrounded by fibrous septa. Administration of G. biloba leaves extract reduced extent and development of fibrous septa, liver cells change, and biochemical alterations in mice exposed to TAA. This study showed that G. biloba leaves extract has a potential activity against TAA-induced liver fibrosis and suggested that the chemical constituents of G. biloba are effective in modulation of oxidative stress induced by TAA. PMID- 23091359 TI - Identification of physiologically active substances as novel ligands for MRGPRD. AB - Mas-related G-protein coupled receptor member D (MRGPRD) is a G protein-coupled receptor (GPCR) which belongs to the Mas-related GPCRs expressed in the dorsal root ganglia (DRG). In this study, we investigated two novel ligands in addition to beta-alanine: (1) beta-aminoisobutyric acid, a physiologically active substance, with which possible relation to tumors has been seen together with beta-alanine; (2) diethylstilbestrol, a synthetic estrogen hormone. In addition to the novel ligands, we found that transfection of MRGPRD leads fibroblast cells to form spheroids, which would be related to oncogenicity. To understand the MRGPRD novel character, oncogenicity, a large chemical library was screened in order to obtain MRGPRD antagonists to utilize in exploring the character. The antagonist in turn inhibited the spheroid proliferation that is dependent on MRGPRD signaling as well as MRGPRD signals activated by beta-alanine. The antagonist, a small-molecule compound we found in this study, is a potential anticancer agent. PMID- 23091358 TI - Controlling self-renewal and differentiation of stem cells via mechanical cues. AB - The control of stem cell response in vitro, including self-renewal and lineage commitment, has been proved to be directed by mechanical cues, even in the absence of biochemical stimuli. Through integrin-mediated focal adhesions, cells are able to anchor onto the underlying substrate, sense the surrounding microenvironment, and react to its properties. Substrate-cell and cell-cell interactions activate specific mechanotransduction pathways that regulate stem cell fate. Mechanical factors, including substrate stiffness, surface nanotopography, microgeometry, and extracellular forces can all have significant influence on regulating stem cell activities. In this paper, we review all the most recent literature on the effect of purely mechanical cues on stem cell response, and we introduce the concept of "force isotropy" relevant to cytoskeletal forces and relevant to extracellular loads acting on cells, to provide an interpretation of how the effects of insoluble biophysical signals can be used to direct stem cells fate in vitro. PMID- 23091361 TI - Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome. AB - The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH. PMID- 23091360 TI - Generation of a Chinese hamster ovary cell line producing recombinant human glucocerebrosidase. AB - Impaired activity of the lysosomal enzyme glucocerebrosidase (GCR) results in the inherited metabolic disorder known as Gaucher disease. Current treatment consists of enzyme replacement therapy by administration of exogenous GCR. Although effective, it is exceptionally expensive, and patients worldwide have a limited access to this medicine. In Brazil, the public healthcare system provides the drug free of charge for all Gaucher's patients, which reaches the order of $ 84 million per year. However, the production of GCR by public institutions in Brazil would reduce significantly the therapy costs. Here, we describe a robust protocol for the generation of a cell line producing recombinant human GCR. The protein was expressed in CHO-DXB11 (dhfr(-)) cells after stable transfection and gene amplification with methotrexate. As expected, glycosylated GCR was detected by immunoblotting assay both as cell-associated (~64 and 59 kDa) and secreted (63-69 kDa) form. Analysis of subclones allowed the selection of stable CHO cells producing a secreted functional enzyme, with a calculated productivity of 5.14 pg/cell/day for the highest producer. Although being laborious, traditional methods of screening high-producing recombinant cells may represent a valuable alternative to generate expensive biopharmaceuticals in countries with limited resources. PMID- 23091362 TI - Persistent dystrophin protein restoration 90 days after a course of intraperitoneally administered naked 2'OMePS AON and ZM2 NP-AON complexes in mdx mice. AB - In Duchenne muscular dystrophy, the exon-skipping approach has obtained proof of concept in animal models, myogenic cell cultures, and following local and systemic administration in Duchenne patients. Indeed, we have previously demonstrated that low doses (7.5 mg/Kg/week) of 2'-O-methyl-phosphorothioate antisense oligoribonucleotides (AONs) adsorbed onto ZM2 nanoparticles provoke widespread dystrophin restoration 7 days after intraperitoneal treatment in mdx mice. In this study, we went on to test whether this dystrophin restoration was still measurable 90 days from the end of the same treatment. Interestingly, we found that both western blot and immunohistochemical analysis (up to 7% positive fibres) were still able to detect dystrophin protein in the skeletal muscles of ZM2-AON-treated mice at this time, and the level of exon-23 skipping could still be assessed by RT real-time PCR (up to 10% of skipping percentage). In contrast, the protein was undetectable by western blot analysis in the skeletal muscles of mdx mice treated with an identical dose of naked AON, and the percentage of dystrophin-positive fibres and exon-23 skipping were reminiscent of those of untreated mdx mice. Our data therefore demonstrate the long-term residual efficacy of this systemic low-dose treatment and confirm the protective effect nanoparticles exert on AON molecules. PMID- 23091363 TI - The inhibitory effect of Prunella vulgaris L. on aldose reductase and protein glycation. AB - To evaluate the aldose reductase (AR) enzyme inhibitory ability of Prunella vulgaris L. extract, six compounds were isolated and tested for their effects. The components were subjected to in vitro bioassays to investigate their inhibitory assays using rat lens aldose reductase (rAR) and human recombinant AR (rhAR). Among them, caffeic acid ethylene ester showed the potent inhibition, with the IC(50) values of rAR and rhAR at 3.2 +/- 0.55 MUM and 12.58 +/- 0.32 MUM, respectively. In the kinetic analyses using Lineweaver-Burk plots of 1/velocity and 1/concentration of substrate, this compound showed noncompetitive inhibition against rhAR. Furthermore, it inhibited galactitol formation in a rat lens incubated with a high concentration of galactose. Also it has antioxidative as well as advanced glycation end products (AGEs) inhibitory effects. As a result, this compound could be offered as a leading compound for further study as a new natural products drug for diabetic complications. PMID- 23091364 TI - Depigmenting effect of Kojic acid esters in hyperpigmented B16F1 melanoma cells. AB - The depigmenting effect of kojic acid esters synthesized by the esterification of kojic acid using Rhizomucor miehei immobilized lipase was investigated in B16F1 melanoma cells. The depigmenting effect of kojic acid and kojic acid esters was evaluated by the inhibitory effect of melanin formation and tyrosinase activity on alpha-stimulating hormone- (alpha-MSH-) induced melanin synthesis in B16F1 melanoma cells. The cellular tyrosinase inhibitory effect of kojic acid monooleate, kojic acid monolaurate, and kojic acid monopalmitate was found similar to kojic acid at nontoxic doses ranging from 1.95 to 62.5 MUg/mL. However, kojic acid monopalmitate gave slightly higher inhibition to melanin formation compared to other inhibitors at doses ranging from 15.63 to 62.5 MUg/mL. Kojic acid and kojic acid esters also show antioxidant activity that will enhance the depigmenting effect. The cytotoxicity of kojic acid esters in B16F1 melanoma cells was significantly lower than kojic acid at high doses, ranging from 125 and 500 MUg/mL. Since kojic acid esters have lower cytotoxic effect than kojic acid, it is suggested that kojic acid esters can be used as alternatives for a safe skin whitening agent and potential depigmenting agents to treat hyperpigmentation. PMID- 23091366 TI - Role of TGF-beta1/Smad3 signaling pathway in secretion of type I and III collagen by vascular smooth muscle cells of rats undergoing balloon injury. AB - Antisense Smad3 adenoviral vectors were used to transfect vascular smooth muscle cells (VSMCs) from rats with balloon injury or infused into the rat balloon catheter injured carotid arteries, and the role of TGF-beta1/Smad3 signaling pathway in the secretion of type I and III collagen by VSMCs following balloon injury was investigated. Antisense Smad3 adenoviral vectors were used to transfect these VSMCs (antisense Smad3 group). A total 90 rats were randomly assigned into blank control group, experiment group, negative control group. In the in vitro study, the expression of type I and III collagen was markedly reduced in the antisense Smad3 group when compared with the control groups (P < 0.05). In the in vivo study, the expression of type I and III collagen was significantly lower than that in the negative control group at 3 days, 1 week and 2 weeks after injury (P < 0.05). At 2 weeks and 3 months after injury, the lumen area in the antisense Smad3 group was markedly increased but the intimal area dramatically reduced when compared with the negative control (P < 0.05). We conclude that transfection of VSMCs with antisense Smad3 can reduce the secretion of type I and III collagen which then inhibit intimal hyperplasia. PMID- 23091365 TI - Cytotoxicity of bacterial metabolic products, including listeriolysin O, on leukocyte targets. AB - Bacterial toxins can exhibit anticancer activities. Here we investigated the anticancer effects of the listeriolysin O toxin produced by Listeria monocytogenes. We found that supernatants of Listeria monocytogenes strains (wild type, 1189, and 1190) were cytotoxic to the Jurkat cell line and human peripheral blood mononuclear cells (PBMC) in a concentration-dependent manner. The supernatant of strain 1044, not producing listeriolysin O, was inactive. The supernatants of Listeria strains were also cytotoxic toward B cells of chronic leukemia patients, with no significant differences in activities between strains. We also tested supernatants of Bacillus subtilis strains BR1-90, BR1-S, and BR1 89 producing listeriolysin O. BR1-S and BR1-89 were cytotoxic to PBMC and to Jurkat cells, the latter being more sensitive to the supernatants. BR1-90 was not hemolytic or cytotoxic to PBMC, but was cytotoxic to Jurkat cells in the concentration range of 10-30%, suggesting that listeriolysin O is selectively effective against T cells. Overall, the response of human peripheral blood mononuclear and human leukemia cell lines to bacteria supernatants containing listeriolysin O depended on the bacteria strain, target cell type, and supernatant concentration. PMID- 23091367 TI - Differential temporal evolution patterns in brain temperature in different ischemic tissues in a monkey model of middle cerebral artery occlusion. AB - Brain temperature is elevated in acute ischemic stroke, especially in the ischemic penumbra (IP). We attempted to investigate the dynamic evolution of brain temperature in different ischemic regions in a monkey model of middle cerebral artery occlusion. The brain temperature of different ischemic regions was measured with proton magnetic resonance spectroscopy ((1)H MRS), and the evolution processes of brain temperature were compared among different ischemic regions. We found that the normal (baseline) brain temperature of the monkey brain was 37.16 degrees C. In the artery occlusion stage, the mean brain temperature of ischemic tissue was 1.16 degrees C higher than the baseline; however, this increase was region dependent, with 1.72 degrees C in the IP, 1.08 degrees C in the infarct core, and 0.62 degrees C in the oligemic region. After recanalization, the brain temperature of the infarct core showed a pattern of an initial decrease accompanied by a subsequent increase. However, the brain temperature of the IP and oligemic region showed a monotonously and slowly decreased pattern. Our study suggests that in vivo measurement of brain temperature could help to identify whether ischemic tissue survives. PMID- 23091368 TI - Serum peptidome patterns of colorectal cancer based on magnetic bead separation and MALDI-TOF mass spectrometry analysis. AB - Background. Colorectal cancer (CRC) is one of the most common cancers in the world, identification of biomarkers for early detection of CRC represents a relevant target. The present study aims to determine serum peptidome patterns for CRC diagnosis. Methods. The present work focused on serum proteomic analysis of 32 health volunteers and 38 CRC by ClinProt Kit combined with mass spectrometry. This approach allowed the construction of a peptide patterns able to differentiate the studied populations. An independent group of serum (including 33 health volunteers, 34 CRC, 16 colorectal adenoma, 36 esophageal carcinoma, and 31 gastric carcinoma samples) was used to verify the diagnostic and differential diagnostic capability of the peptidome patterns blindly. An immunoassay method was used to determine serum CEA of CRC and controls. Results. A quick classifier algorithm was used to construct the peptidome patterns for identification of CRC from controls. Two of the identified peaks at m/z 741 and 7772 were used to construct peptidome patterns, achieving an accuracy close to 100% (>CEA, P < 0.05). Furthermore, the peptidome patterns could differentiate validation group with high accuracy. Conclusions. These results suggest that the ClinProt Kit combined with mass spectrometry yields significantly higher accuracy for the diagnosis and differential diagnosis of CRC. PMID- 23091369 TI - Genome-wide survey of ds exonization to enrich transcriptomes and proteomes in plants. AB - Insertion of transposable elements (TEs) into introns can lead to their activation as alternatively spliced cassette exons, an event called exonization which can enrich the complexity of transcriptomes and proteomes. Previously, we performed the first experimental assessment of TE exonization by inserting a Ds element into each intron of the rice epsps gene. Exonization of Ds in plants was biased toward providing splice donor sites from the beginning of the inserted Ds sequence. Additionally, Ds inserted in the reverse direction resulted in a continuous splice donor consensus region by offering 4 donor sites in the same intron. The current study involved genome-wide computational analysis of Ds exonization events in the dicot Arabidopsis thaliana and the monocot Oryza sativa (rice). Up to 71% of the exonized transcripts were putative targets for the nonsense-mediated decay (NMD) pathway. The insertion patterns of Ds and the polymorphic splice donor sites increased the transcripts and subsequent protein isoforms. Protein isoforms contain protein sequence due to unspliced intron-TE region and/or a shift of the reading frame. The number of interior protein isoforms would be twice that of C-terminal isoforms, on average. TE exonization provides a promising way for functional expansion of the plant proteome. PMID- 23091370 TI - Increased macular choroidal blood flow velocity during systemic corticosteroid therapy in a patient with acute macular neuroretinopathy. AB - PURPOSE: The precise mechanism causing outer retinal damage in acute macular neuroretinopathy (AMN) remains unclear. In this study, choroidal blood flow velocity was quantitatively evaluated using laser speckle flowgraphy (LSFG) in a patient with AMN who received systemic corticosteroid therapy. METHODS: Corticosteroids were systemically administrated across 4 months for an AMN patient. LSFG measurements were taken ten consecutive times before treatment and at 1 week and 1, 3, and 10 months after the onset of therapy. The square blur rate, a quantitative index of relative blood flow velocity, was calculated using LSFG in three regions: Square 1, the macular lesion with findings of severe multifocal electroretinography amplitude reduction, and Squares 2 and 3, funduscopically normal-appearing retinal areas with findings of moderate and mild multifocal electroretinography amplitude reduction, respectively. RESULTS: The AMN lesion gradually decreased after treatment and improved results were detected on the Amsler chart, as well as on optical coherence tomography and scanning laser ophthalmoscopy. When the changing rates of the macular flow were compared with the mean square blur rate level before treatment (100%), 14.6%, 24.5%, 12.9%, and 16.3% increases were detected in Square 1 (macular lesion) at 1 week and 1, 3, and 10 months after treatment, respectively. Similarly, in Square 2 (normal-appearing area next to the lesion), 12.6%, 18.6%, 6.7%, and 8.3% increases were also noted at 1 week and 1, 3, and 10 months after treatment, respectively. In Square 3 (normal-appearing area apart from the lesion), 16.0%, 15.1%, 19.1%, and 3.8% increases were measured at 1 week and 1, 3, and 10 months after treatment, respectively. CONCLUSION: In a patient with AMN, choroidal blood flow velocity at the lesion site, which was examined with LSFG, sequentially increased during systemic corticosteroid therapy, together with improvement of visual function. The present findings suggest that choroidal circulation impairment relates to the pathogenesis of AMN, extending over a wider area in the posterior pole than the site of an AMN lesion per se. PMID- 23091371 TI - Clinical evaluation of sivelestat for acute lung injury/acute respiratory distress syndrome following surgery for abdominal sepsis. AB - BACKGROUND: The efficacy of sivelestat in the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has not been established. In part, this is due to the wide variety of factors involved in the etiology of ALI/ARDS. In this study, we examined the efficacy of sivelestat in patients with ALI/ARDS associated with abdominal sepsis. METHODS: The subjects were 49 patients with ALI/ARDS after surgery for abdominal sepsis. The efficacy of sivelestat was retrospectively assessed in two treatment groups, ie, a sivelestat group (n = 34) and a non-sivelestat group (n = 15). RESULTS: The sivelestat group showed significant improvements in oxygenation, thrombocytopenia, and multiple organ dysfunction score. The number of ventilator days (6.6 +/- 6.1 versus 11.1 +/- 8.4 days; P = 0.034) and length of stay in the intensive care unit (8.5 +/- 6.2 versus 13.3 +/- 9.5 days; P = 0.036) were significantly lower in the sivelestat group. The hospital mortality rate decreased by half in the sivelestat group, but was not significantly different between the two groups. CONCLUSION: Administration of sivelestat to patients with ALI/ARDS following surgery for abdominal sepsis resulted in early improvements of oxygenation and multiple organ dysfunction score, early ventilator weaning, and early discharge from the intensive care unit. PMID- 23091372 TI - Efficacy of two novel 2,2'-bifurans to inhibit methicillin-resistant Staphylococcus aureus infection in male mice in comparison to vancomycin. AB - The therapeutic efficacy of two novel bifurans and vancomycin in an animal model of a methicillin-resistant Staphylococcus aureus (MRSA) infection was compared. Adult male CF-1 mice (25-35 g) were intraperitoneally injected with 200 MUL/mouse containing 10(7) cell-forming units of MRSA. After 16 hours, animals were treated with 110 mg/kg of vancomycin, or 5 mg/kg of mononitrile bifuran (1A) or monocationic bifuran (1B) and killed after 8 hours. Treatment with bifurans did not cause any toxicity. Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen. Colonies recovered from livers and kidneys of mice injected with 1A or 1B lost the initial resistance pattern and became susceptible to methicillin and ciprofloxacin. MRSA elevated the serum urea level and activities of alanine aminotransferase and gamma-glutamyl transpeptidase. MRSA also elevated the hepatic level of malondialdehyde, and serum levels of tumor necrosis factor and interleukin-6. MRSA also reduced the glutathione content and activities of catalase and glutathione S-transferase in liver. Similar to vancomycin, bifurans ameliorated most of the previous effects. Compound 1B was superior to 1A, and sometimes both provided better antistaphylococcal agents than vancomycin against MRSA pathogenesis. The present findings along with our previous studies support further evaluation of the efficacy of these bifurans in clinical studies. PMID- 23091373 TI - Effects of oral valganciclovir prophylaxis for cytomegalovirus infection in heart transplant patients. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a serious complication following heart transplantation. This study (June 2003-January 2010) retrospectively assessed the effects of oral valganciclovir prophylaxis in adult heart transplant recipients during the first year after transplantation. METHODS: In patients with normal renal function, 900 mg of oral valganciclovir was administered twice daily for 14 days after heart transplant followed by 900 mg per day for following 6 months. In the event of renal insufficiency, valganciclovir was adjusted according to the manufacturer's recommendations. Antigenemia testing for pp65 antigen and simultaneous polymerase chain reaction (PCR) were used to document exposure to CMV. From 2003 to 2010, 146 patients (74.0% men) of mean age 50.7 +/- 10.3 years at the time of heart transplant were included. RESULTS: A total of 16 patients (11.0% of total, 75.0% male) had a positive pp65 and PCR result (ie, CMV infection) during the year following heart transplant; three of these patients had discontinued valganciclovir prophylaxis within the first 6 months following transplant because of leukopenia, including one patient developed CMV colitis. Two further patients developed CMV pneumonia during prophylactic valganciclovir therapy. Eight patients had positive pp65 and PCR tests in the 6-12 months after heart transplant following cessation of routine prophylaxis. One of these patients developed CMV pneumonia and another developed CMV colitis and CMV pneumonia. Thirty-seven of the 146 (25.3%) patients were CMV donor seropositive/recipient-seronegative, and seven (18.9% of this subgroup) had a positive CMV test. In patients who were CMV donor-seropositive/recipient seronegative, the risk of a positive CMV test (ie, CMV infection) was significantly elevated (P = 0.023). CONCLUSION: CMV prophylaxis with oral valganciclovir for 6 months following heart transplant is clinically feasible. In line with previous studies, CMV donor-seropositive/recipient-seronegative patients have a significantly elevated risk of CMV infection. In patients who prematurely discontinue valganciclovir, close monitoring of CMV antigenemia appears warranted. No significantly elevated rate of CMV infection was observed after 6 months of valganciclovir prophylaxis. PMID- 23091374 TI - Variability of glomerular filtration rate estimation equations in elderly Chinese patients with chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is recognized worldwide as a public health problem, and its prevalence increases as the population ages. However, the applicability of formulas for estimating the glomerular filtration rate (GFR) based on serum creatinine (SC) levels in elderly Chinese patients with CKD is limited. MATERIALS AND METHODS: Based on values obtained with the technetium-99m diethylenetriaminepentaacetic acid ((99m)Tc-DTPA) renal dynamic imaging method, 319 elderly Chinese patients with CKD were enrolled in this study. Serum creatinine was determined by the enzymatic method. The GFR was estimated using the Cockroft-Gault (CG) equation, the Modification of Diet in Renal Disease (MDRD) equations, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, the Jelliffe-1973 equation, and the Hull equation. RESULTS: The median of difference ranged from -0.3-4.3 mL/min/1.73 m(2). The interquartile range (IQR) of differences ranged from 13.9-17.6 mL/min/1.73 m(2). Accuracy with a deviation less than 15% ranged from 27.6%-32.9%. Accuracy with a deviation less than 30% ranged from 53.6%-57.7%. Accuracy with a deviation less than 50% ranged from 74.9%-81.5%. None of the equations had accuracy up to the 70% level with a deviation less than 30% from the standard glomerular filtration rate (sGFR). Bland-Altman analysis demonstrated that the mean difference ranged from -3.0-2.4 mL/min/1.73 m(2). However, the agreement limits of all the equations, except the CG equation, exceeded the prior acceptable tolerances defined as 60 mL/min/1.73 m(2). When the overall performance and accuracy were compared in different stages of CKD, GFR estimated using the CG equation showed promising results. CONCLUSIONS: Our study indicated that none of these equations were suitable for estimating GFR in the elderly Chinese population investigated. At present, based on overall performance, as well as performance in different CKD stages, the CG equation may be the most accurate for estimating GFR in elderly Chinese patients with CKD. PMID- 23091375 TI - Efficacy of percutaneous transluminal renal angioplasty with stent in elderly male patients with atherosclerotic renal artery stenosis. AB - OBJECTIVES: Percutaneous transluminal renal angioplasty with stent implantation (PTRAS) has become the treatment of choice for atherosclerotic renal artery stenosis (ARAS). This study evaluates the long-term effects of PTRAS on hypertension and renal function in elderly patients with ARAS. METHODS: We conducted a retrospective cohort study of all patients who underwent PTRAS in the geriatric division of a tertiary medical center during the period 2003-2010. The clinical data were extracted from the medical records of each patient. Changes in blood pressure, antihypertensive treatment, and estimated glomerular filtration rate were analyzed before and after PTRAS. RESULTS: Eighty-six stents in 81 elderly patients were placed successfully. The average age of the patients was 76.2 years (65-89 years). Mean follow-up was 31.3 months (range 12 -49 months). There was a significant decrease in both systolic and diastolic blood pressure at the third day after the PTRAS procedure and the reduction in blood pressure was constant throughout the follow-up period until 36 months after PTRAS. However, there was no marked benefit to renal function outcome during the follow-up period. The incidence of contrast-induced nephropathy was 9.9% in this study group. The rate of renal artery restenosis was 14.8%. The survival rate was 96.3% for 4 years after the procedure. CONCLUSION: It is beneficial to control blood pressure in elderly patients with ARAS up to 36 months after a PTRAS procedure. However, their renal function improvement is limited. PMID- 23091376 TI - An optimized molecular inclusion complex of diferuloylmethane: enhanced physical properties and biological activity. AB - OBJECTIVE: The purpose of this study was to explore and evaluate the enhanced physical properties and biological activity of a molecular inclusion complex (MICDH) comprising diferuloylmethane (DFM) and hydroxypropyl-beta-cyclodextrin. METHODS: The preparation conditions of MICDH were optimized using an orthogonal experimental design. The solubility, in vitro release and model fitting, microscopic morphology, molecular structure simulation, anti-lung cancer activity, and action mechanism of MICDH were evaluated. RESULTS: The solubility of DFM was improved 4400-fold upon complexation with hydroxypropyl-beta cyclodextrin. The release rate of DFM was significantly higher from MICDH than from free DFM. MICDH exhibited higher antitumor activity against human lung adenocarcinoma A549 cells than free DFM. More cells were arrested in the S/G2 phase of the cell cycle or were induced to undergo apoptosis when treated with MICDH than when treated with free DFM. Furthermore, increased reactive oxygen species and intracellular calcium ion levels and decreased mitochondrial membrane potential were observed in cells treated with MICDH. CONCLUSION: MICDH markedly improved the physical properties and antitumor activity of DFM. MICDH may prove to be a preferred alternative to free DFM as a formulation for DFM delivery in lung cancer treatment. PMID- 23091377 TI - Chondroitin sulfate functionalized mesostructured silica nanoparticles as biocompatible carriers for drug delivery. AB - Mesoporous silica nanoparticles (MSNs) have garnered a great deal of attention as potential carriers for therapeutic payloads. Here, we report a pH-responsive drug carrier based on chondroitin sulfate functionalized mesostructured silica nanoparticles (NMChS-MSNs) ie, the amidation between NMChS macromer and amino group functionalized MSNs. The prepared nanoparticles were characterized using dynamic light scattering, fourier transform infrared spectroscopy and transmission electron microscopy. The resultant NMChS-MSNs were uniform spherical nanoparticles with a mean diameter of approximately 74 nm. Due to the covalent graft of hydrophilic and pH responsive NMChS, the NMChS-MSNs could be well dispersed in aqueous solution, which is favorable to being utilized as drug carriers to construct a pH-responsive controlled drug delivery system. Doxorubicin hydrochloride (DOX), a well-known anticancer drug, could be effectively loaded into the channels of NMChS-MSNs through electrostatic interactions between drug and matrix. The drug release rate of DOX@NMChS-MSNs was pH dependent and increased with the decrease of pH. The in vitro cytotoxicity test indicated that NMChS-MSNs were highly biocompatible and suitable to use as drug carriers. Our results imply that chondroitin sulfate functionalized nanoparticles are promising platforms to construct the pH-responsive controlled drug delivery systems for cancer therapy. PMID- 23091378 TI - Encapsulation of cisplatin in long-circulating and pH-sensitive liposomes improves its antitumor effect and reduces acute toxicity. AB - Cisplatin (CDDP) is one of the most effective and potent anticancer drugs used as first-line chemotherapy against several solid tumors. However, the severe side effects and its tendency to provoke chemoresistance often limit CDDP therapy. To avoid these inconveniences, the present study's research group developed long circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). The present study aimed to evaluate the antitumor effect and toxicity of SpHL-CDDP, as compared with that of free CDDP, and long-circulating and non- pH-sensitive liposomes containing CDDP (NSpHL-CDDP), after their intravenous administration in solid Ehrlich tumor-bearing mice. Antitumor activity was evaluated by analysis of tumor volume and growth inhibition ratio, serum vascular endothelial growth factor (VEGF) levels, and histomorphometric and immunohistochemical studies. Body weight variation and the histological examination of bone marrow and kidneys were used as toxicity indicators. A significant reduction in the tumor volume and a higher tumor growth inhibition ratio was observed after SpHL-CDDP treatment, compared with free CDDP and NSpHL-CDDP treatments. In addition, complete remission of the tumor was detected in 18.2% of the mice treated with SpHL- CDDP (16 mg/kg). As such, the administration of SpHL-CDDP, as compared with free CDDP and NSpHL-CDDP, led to a decrease in the area of necrosis and in the percentage of positive CDC 47 tumor cells. A significant reduction in the VEGF serum level was also observed after SpHL-CDDP treatment, as compared with free-CDDP treatment. SpHL-CDDP administered in a two-fold higher dose than that of free CDDP presented a loss in body weight and changes in the hematopoietic tissue morphology, which proved to be similar to that of free CDDP. No changes could be verified in the renal tissue after any formulations containing CDDP had been administered. These findings showed that SpHL-CDDP allowed for the administration of higher doses of CDDP, significantly improving its antitumor effect. PMID- 23091379 TI - Targeting nanomaterials: future drugs for cancer chemotherapy. PMID- 23091381 TI - Gold and silver nanoparticles from Trianthema decandra: synthesis, characterization, and antimicrobial properties. AB - BACKGROUND: There is an increasing commercial demand for nanoparticles due to their wide applicability in various markets, including medicine, catalysis, electronics, chemistry, and energy. In this report, a simple and ecofriendly chemical reaction for the synthesis of gold and silver nanoparticles from Trianthema decandra (Aizoaceae) has been developed. METHODS AND RESULTS: On treatment of aqueous solutions containing chloroauric acid or silver nitrate with root extract of T. decandra, stable gold or silver nanoparticles were rapidly formed. The kinetics of reduction of gold and silver ions during the reaction was analyzed by ultraviolet-visible spectroscopy. Field emission-scanning electron microscopy showed formation of gold nanoparticles in various shapes, including spherical, cubical, triangular, and hexagonal, while silver nanoparticles were spherical. The size of the gold nanoparticles was 33-65 nm and that of the silver nanoparticles was 36-74 nm. Energy dispersive x-ray and Fourier transform infrared spectroscopy confirmed the presence of metallic gold and metallic silver in the respective nanoparticles. The antimicrobial properties of the synthesized nanoparticles were analyzed using the Kirby-Bauer method. The results show varied susceptibility of microorganisms to the gold and silver nanoparticles. CONCLUSION: It is believed that phytochemicals present in T. decandra extract reduce the silver and gold ions into metallic nanoparticles. This strategy reduces the cost of production and the environmental impact. The silver and gold nanoparticles formed showed strong activity against all microorganisms tested. PMID- 23091380 TI - Functionalized carbon nanotubes: biomedical applications. AB - Carbon nanotubes (CNTs) are emerging as novel nanomaterials for various biomedical applications. CNTs can be used to deliver a variety of therapeutic agents, including biomolecules, to the target disease sites. In addition, their unparalleled optical and electrical properties make them excellent candidates for bioimaging and other biomedical applications. However, the high cytotoxicity of CNTs limits their use in humans and many biological systems. The biocompatibility and low cytotoxicity of CNTs are attributed to size, dose, duration, testing systems, and surface functionalization. The functionalization of CNTs improves their solubility and biocompatibility and alters their cellular interaction pathways, resulting in much-reduced cytotoxic effects. Functionalized CNTs are promising novel materials for a variety of biomedical applications. These potential applications are particularly enhanced by their ability to penetrate biological membranes with relatively low cytotoxicity. This review is directed towards the overview of CNTs and their functionalization for biomedical applications with minimal cytotoxicity. PMID- 23091382 TI - In vitro characterization and in vivo evaluation of nanostructured lipid curcumin carriers for intragastric administration. AB - BACKGROUND: Curcumin has a variety of pharmacological effects. However, poor water solubility and low oral bioavailability limit its clinical utility. A delivery system for nanostructured lipid carriers has been reported to be a promising approach to enhancing the oral absorption of curcumin. The aim of the present study was to investigate the pharmacokinetics, tissue distribution, and relative bioavailability of curcumin in rats after a single intragastric dose of a nanostructured lipid curcumin carrier formulation. METHODS: Nanostructured lipid curcumin carriers were prepared using the ethanol dripping method and characterized in terms of the particle size, polydispersity index, zeta potential, differential scanning calorimetry, drug-loading capacity, encapsulation efficiency, and in vitro release. The pharmacokinetics and tissue distribution of nanostructured lipid curcumin carriers and curcumin suspension were compared after intragastric administration. RESULTS: Nanostructured lipid curcumin carriers showed a significantly higher peak plasma concentration (564.94 +/- 14.98 ng/mL versus 279.43 +/- 7.21 ng/mL, P < 0.01), a shorter time taken to reach peak plasma concentration (0.5 +/- 0.01 hour versus 1.0 +/- 0.12 hour, P < 0.01), and a greater AUC(0-infinity) (820.36 +/- 25.11 mg * hour/L versus 344.11 +/- 10.01 mg * hour/L, P < 0.05) compared with curcumin suspension. In the tissue distribution studies, curcumin could be detected in the spleen, heart, liver, kidneys, lungs, and brain. Following intragastric administration of the nanostructured lipid curcumin carrier formulation, tissue concentrations of curcumin also increased, especially in the brain. The nanostructured lipid curcumin carrier formulation improved the ability of curcumin to cross the blood brain barrier, with an 11.93-fold increase in the area under the curve achieved in the brain when compared with curcumin suspension. CONCLUSION: The nanostructured lipid carrier formulation significantly improved the oral bioavailability of curcumin and represents a promising method for its oral delivery. PMID- 23091384 TI - Impact of surface coating and particle size on the uptake of small and ultrasmall superparamagnetic iron oxide nanoparticles by macrophages. AB - PURPOSE: Magnetic resonance imaging (MRI) using contrast agents like superparamagnetic iron oxide (SPIO) is an extremely versatile technique to diagnose diseases and to monitor treatment. This study tested the relative importance of particle size and surface coating for the optimization of MRI contrast and labeling efficiency of macrophages migrating to remote inflammation sites. MATERIALS AND METHODS: We tested four SPIO and ultrasmall superparamagnetic iron oxide (USPIO), alkali-treated dextran magnetite (ATDM) with particle sizes of 28 and 74 nm, and carboxymethyl dextran magnetite (CMDM) with particle sizes of 28 and 72 nm. Mouse macrophage RAW264 cells were incubated with SPIOs and USPIOs, and the labeling efficiency of the cells was determined by the percentage of Berlin blue-stained cells and by measuring T(2) relaxation times with 11.7-T MRI. We used trypan blue staining to measure cell viability. RESULTS: Analysis of the properties of the nanoparticles revealed that ATDM coated 74 nm particles have a lower T(2) relaxation time than the others, translating into a higher ability of MRI negative contrast agent. Among the other three candidates, CMDM-coated particles showed the highest T(2) relaxation time once internalized by macrophages. Regarding labeling efficiency, ATDM coating resulted in a cellular uptake higher than CMDM coating, independent of nanoparticle size. None of these particle formulations affected macrophage viability. CONCLUSION: This study suggests that coating is more critical than size to optimize the SPIO labeling of macrophages. Among the formulations tested in this study, the best MRI contrast and labeling efficiency are expected with ATDM-coated 74 nm nanoparticles. PMID- 23091383 TI - Bone repair by periodontal ligament stem cellseeded nanohydroxyapatite-chitosan scaffold. AB - BACKGROUND: A nanohydroxyapatite-coated chitosan scaffold has been developed in recent years, but the effect of this composite scaffold on the viability and differentiation of periodontal ligament stem cells (PDLSCs) and bone repair is still unknown. This study explored the behavior of PDLSCs on a new nanohydroxyapatite-coated genipin-chitosan conjunction scaffold (HGCCS) in vitro as compared with an uncoated genipin-chitosan framework, and evaluated the effect of PDLSC-seeded HGCCS on bone repair in vivo. METHODS: Human PDLSCs were cultured and identified, seeded on a HGCCS and on a genipin-chitosan framework, and assessed by scanning electron microscopy, confocal laser scanning microscopy, MTT, alkaline phosphatase activity, and quantitative real-time polymerase chain reaction at different time intervals. Moreover, PDLSC-seeded scaffolds were used in a rat calvarial defect model, and new bone formation was assessed by hematoxylin and eosin staining at 12 weeks postoperatively. RESULTS: PDLSCs were clonogenic and positive for STRO-1. They had the capacity to undergo osteogenic and adipogenic differentiation in vitro. When seeded on HGCCS, PDLSCs exhibited significantly greater viability, alkaline phosphatase activity, and upregulated the bone-related markers, bone sialoprotein, osteopontin, and osteocalcin to a greater extent compared with PDLSCs seeded on the genipin-chitosan framework. The use of PDLSC-seeded HGCCS promoted calvarial bone repair. CONCLUSION: This study demonstrates the potential of HGCCS combined with PDLSCs as a promising tool for bone regeneration. PMID- 23091385 TI - Positively charged cholesterol-recombinant human gelatins foster the cellular uptake of proteins and murine immune reactions. AB - PURPOSE: Recombinant human gelatins with defined molecular weights were modified with cholesterol to make them amphiphilic in nature. We investigated the feasibility of these modified human gelatins acting as a carrier of antigenic proteins for inducing cellular immunity. The aim of this study was to synthesize novel and effective compounds for vaccine delivery in vivo. METHODS: Two types of cholesterol-modified gelatin micelles, anionic cholesterol-modified gelatin (aCMG) and cationic-cholesterol modified gelatin (cCMG), were synthesized using different cholesterol derivatives such as the cholesterol-isocyanate (Ch-I) for aCMG and amino-modified cholesterol for cCMG. One was anionic and the other cationic, and therefore they differed in terms of their zeta potential. The aCMG and cCMG were characterized for their size, zeta potential, and in their ability to form micelles. Cytotoxicity was also evaluated. The modified human gelatins were then investigated as a carrier of antigenic proteins for inducing cellular immunity both in vitro in DC 2.4 cells, a murine dendritic cell line, as well as in vivo. The mechanism of entry of the polymeric micelles into the cells was also evaluated. RESULTS: It was found that only cCMG successfully complexed with the model antigenic protein, fluorescein-isothiocyanate ovalbumin (OVA) and efficiently delivered and processed proteins in DC 2.4 cells. It was hypothesized that cCMG enter the cells predominantly by a caveolae-mediated pathway that required tyrosine kinase receptors on the cell surface. Animal testing using mice showed that the cationic cholesterol-modified gelatin complexed with OVA produced significantly high antibody titers against OVA: 2580-fold higher than in mice immunized with free OVA. CONCLUSION: Conclusively, cCMG has shown to be very effective in stimulating an immune response due to its high efficiency, stability, and negligible cytotoxicity. PMID- 23091386 TI - Controlled-release approaches towards the chemotherapy of tuberculosis. AB - Tuberculosis (TB), caused by the bacteria Mycobacterium tuberculosis, is notorious for its lethality to humans. Despite technological advances, the tubercle bacillus continues to threaten humans. According to the World Health Organization's 2011 global report on TB, 8.8 million cases of TB were reported in 2010, with a loss of 1.7 million human lives. As drug-susceptible TB requires long-term treatment of between 6 and 9 months, patient noncompliance remains the most important reason for treatment failure. For multidrug-resistant TB, patients must take second-line anti-TB drugs for 18-24 months and many adverse effects are associated with these drugs. Drug-delivery systems (DDSs) seem to be the most promising option for advancement in the treatment of TB. DDSs reduce the adverse effects of drugs and their dosing frequency as well as shorten the treatment period, and hence improve patient compliance. Further advantages of these systems are that they target the disease area, release the drugs in a sustained manner, and are biocompatible. In addition, targeted delivery systems may be useful in dealing with extensively drug-resistant TB because many side effects are associated with the drugs used to cure the disease. In this paper, we discuss the DDSs developed for the targeted and slow delivery of anti-TB drugs and their possible advantages and disadvantages. PMID- 23091387 TI - Parkinson's disease patients' subjective descriptions of characteristics of chronic pain, sleeping patterns and health-related quality of life. AB - OBJECTIVE: Nonmotor symptoms are common in Parkinson's disease (PD). Health related quality of life (HRQoL) is negatively affected by different factors, of which pain and sleep disturbances are important contributors. This study was performed to evaluate and describe subjective experiences of pain, sleeping patterns, and HRQoL in a cohort of PD patients with chronic pain. METHODS: A total of 45 participants with established PD for more than 2 years, and PD related pain for the preceding three months, were recruited from three sites in Sweden. Data regarding time point for onset, duration and degree of pain parameters, body localization of pain, external influences, and treatments were obtained. HRQoL was evaluated with the Short Form-36((r)) Health Survey, and sleeping patterns were registered with the Parkinson's disease Sleep Scale, both completed along with a questionnaire. RESULTS: In one-third of participants, pain preceded the PD diagnosis. Median pain score measured with a visual analog scale was 6.6 and 5.9 (for females and males, respectively) the week before the study. In almost half of the participants, pain was present during all their waking hours. Significantly more females described their pain as troublesome, while more males described their pain as irritating. Feelings of numbness and creeping sensations at night were strongly associated with the maximal visual analog scale scores. Polypharmacy was common; 89% used medication for anxiety/insomnia, and 18% used antidepressants. Only one-third of patients who reported pain relief with analgesics had these prescribed on their drug lists. Sleep was characterized by frequent awakenings. Urinary urgency and restless legs were frequently reported as troublesome. Patients rated HRQoL as significantly worse in all items compared with a healthy reference population matched for age and sex. CONCLUSIONS: Experiences of chronic PD-related pain are complex; there is substantial sleep fragmentation and negative impact on HRQoL. PMID- 23091388 TI - EACOL (Scale of Evaluation of Reading Competence by the Teacher): evidence of concurrent and discriminant validity. AB - AIM: The study aimed to provide information about the concurrent and discriminant validation of the Scale of Evaluation of Reading Competence by the Teacher (EACOL), which is composed of 27 dichotomous items concerning reading aloud (17 items) and reading silently (10 items). SAMPLES: Three samples were used in this validation study. The first was composed of 335 students with an average age of 9.75 years (SD = 1.2) from Belo Horizonte (Minas Gerais State), Brazil, where the full spectrum of reading ability was assessed. The second two samples were from Sao Paulo city (Sao Paulo State), Brazil, where only children with reading difficulties were recruited. The first Sao Paulo sample was labeled "SP screening" and had n = 617, with a mean age of 9.8 years (SD = 1.0), and the other sample was labeled "SP-trial" and had n = 235, with a mean age of 9.15 years (SD = 0.05). METHODS: Results were obtained from a latent class analysis LCA, in which two latent groups were obtained as solutions, and were correlated with direct reading measures. Also, students' scores on the Wechsler Intelligence Scale and on the Strengths and Difficulties Questionnaire tested the discriminant validation. RESULTS: Latent groups of readers underlying the EACOL predicted all direct reading measures, while the same latent groups showed no association with behavior and intelligence assessments, giving concurrent and discriminant validity to EACOL, respectively. CONCLUSION: EACOL is a reliable screening tool which can be used by a wide range of professionals for assessing reading skills. PMID- 23091389 TI - The potential benefit of stem cell therapy after stroke: an update. AB - Stroke is a leading cause of death and disability worldwide. Stem cell therapy is an emerging therapeutic modality with evidence of significant benefits in preclinical stroke models. A number of phase I and II clinical trials have now been completed, with several more currently under way. Translation to the bedside, however, remains a long way off, and there are many questions that remain unanswered. This review will summarize the current evidence and ongoing clinical trials worldwide, and explore the challenges to making this a realistic treatment option for the future. PMID- 23091390 TI - Clinicopathological and prognostic significance of epithelial mesenchymal transition-related protein expression in intrahepatic cholangiocarcinoma. AB - BACKGROUND: The aim of this study was to examine the patterns of expression of epithelial-mesenchymal transition (EMT)-related proteins in intrahepatic cholangiocarcinoma. The clinicopathological and prognostic value of these markers was also evaluated. METHODS: We detected the expression status of three EMT related proteins, ie, E-cadherin, vimentin, and N-cadherin, by immunohistochemistry in consecutive intrahepatic cholangiocarcinoma specimens from 96 patients. RESULTS: The frequency of loss of the epithelial marker E cadherin, and acquisition of mesenchymal markers, vimentin and N-cadherin, in intrahepatic cholangiocarcinoma was 43.8%, 37.5% and 57.3%, respectively. Altered expression of EMT markers was associated with aggressive tumor behavior, including lymph node metastasis, undifferentiated-type histology, advanced tumor stage, venous invasion, and shorter overall survival. Moreover, loss of E cadherin was retained as an independent prognostic factor for patients with intrahepatic cholangiocarcinoma in multivariate analysis. CONCLUSION: Our results suggest that the EMT process is associated with tumor progression and a poor outcome in patients with intrahepatic cholangiocarcinoma, and inhibition of EMT might offer novel promising molecular targets for the treatment of affected patients. PMID- 23091391 TI - Impact of dry eye on work productivity. AB - BACKGROUND: The purpose of this study was to evaluate the impact of dry eye on work productivity of office workers, especially in terms of presenteeism. METHODS: A total of 396 individuals aged >=20 years (258 men and 138 women, mean age 43.4 +/- 13.0 years) were recruited through an online survey. Data from 355 responders who did not have missing values were included in the analysis. They were classified into the following four groups according to the diagnostic status and subjective symptoms of dry eye: a definite dry eye group; a marginal dry eye group; a self-reported dry eye group; and a control group. The impact of dry eye on work productivity was evaluated using the Japanese version of the Work Limitations Questionnaire. The cost of work productivity loss associated with dry eye and the economic benefits of providing treatment for dry eye were also assessed. RESULTS: The degree of work performance loss was 5.65% in the definite dry eye group, 4.37% in the marginal dry eye group, 6.06% in the self-reported dry eye group, and 4.27% in the control group. Productivity in the self-reported dry eye group was significantly lower than that in the control group (P < 0.05). The annual cost of work productivity loss associated with dry eye was estimated to be USD 741 per person. CONCLUSION: Dry eye impairs work performance among office workers, which may lead to a substantial loss to industry. Management of symptoms of dry eye by providing treatment may contribute to improvement in work productivity. PMID- 23091392 TI - Sleep quality, depression, and quality of life in elderly hemodialysis patients. AB - OBJECTIVE: Both the incidence and the prevalence of end-stage renal disease (ESRD) in elderly patients are increasing worldwide. Elderly ESRD patients have been found to be more prone to depression than the general population. There are many studies that have addressed the relationship between sleep quality (SQ), depression, and health related quality of life (HRQoL) in ESRD patients, but previous studies have not confirmed the association in elderly hemodialysis (HD) patients. Therefore, the aim of the present study was to demonstrate this relationship in elderly HD patients. PATIENTS AND METHODS: Sixty-three elderly HD patients (32 females and 31 males aged between 65 and 89 years) were included in this cross-sectional study. A modified Post-Sleep Inventory (PSI), the Medical Outcomes Study 36-item short form health survey, and the Beck Depression Inventory (BDI) were applied. RESULTS: The prevalence of poor sleepers (those with a PSI total sleep score [PSI-4 score] of 4 or higher) was 71% (45/63), and the prevalence of depression was 25% (16/63). Of the 45 poor sleepers, 15 had depression, defined as a BDI score of 17 or higher. Poor sleepers had a significantly higher rate of diabetes mellitus (P = 0.03), significantly higher total BDI scores, and lower Physical Component Scale scores (ie, lower HRQoL) than good sleepers. The PSI-4 score correlated negatively with Physical Component Scale (r = -0.500, P < 0.001) and Mental Component Scale scores (r = -0.527, P < 0.001) and it correlated positively with the BDI score (r = 0.606, P < 0.001). In multivariate analysis, independent variables of PSI-4 score were BDI score (beta value [beta] = 0.350, P < 0.001), Mental Component Scale score (beta = -0.291, P < 0.001), and age (beta = 0.114, P = 0.035). CONCLUSION: Poor SQ is a very common issue and is associated with both depression and lower HRQoL in elderly HD patients. PMID- 23091393 TI - Primary care physician attitudes and perceptions of the impact of FDA-proposed REMS policy on prescription of extended-release and long-acting opioids. AB - With increasing numbers of patients experiencing chronic pain, opioid therapy is becoming more common, leading to increases in concern about issues of abuse, diversion, and misuse. Further, the US Food and Drug Administration recently released a statement notifying sponsors and manufacturers of extended-release and long-acting opioids of the need to develop Risk Evaluation and Mitigation Strategies (REMS) programs in order to ensure that the benefits of this therapy choice outweigh the potential risks. There is little research on physician opinions concerning opioid-prescribing and education policies. To assess attitudes surrounding new opioid policies, a survey was designed and distributed to primary care physicians in October 2011. Data collected from 201 primary care physicians show that most are not familiar with the REMS requirements proposed by the Food and Drug Administration for extended-release and long-acting opioids; there is no consensus among primary care physicians on the impact of prescribing requirements on patient education and care; and increasing requirements for extended-release and long-acting opioid education may decrease opioid prescribing. Physician attitudes toward increased regulatory oversight of opioid therapy prescriptions should be taken into consideration by groups developing these interventions to ensure that they do not cause undue burden on already busy primary care physicians. PMID- 23091394 TI - Assessing the role of cognitive behavioral therapy in the management of chronic nonspecific back pain. AB - PURPOSE: The aim of this study is to provide a narrative review of the current state of knowledge of the role of cognitive behavioral therapy (CBT) in the management of chronic nonspecific back pain. METHODS: A literature search on all studies published up until July 2012 (PubMed and PsycINFO) was performed. The search string consisted of 4 steps: cognitive behavioral therapy/treatment/management/modification/intervention, chronic, back pain (MeSH term) or low back pain (MeSH term), and randomized controlled trial (MeSH term). The conclusions are based on the results from randomized controlled trials (RCTs) and reviews of RCTs. Interventions were not required to be pure CBT interventions, but were required to include both cognitive and behavioral components. RESULTS: The search yielded 108 studies, with 46 included in the analysis. Eligible intervention studies were categorized as CBT compared to wait list controls/treatment as usual, physical treatments/exercise, information/education, biofeedback, operant behavioral treatment, lumbar spinal fusion surgery, and relaxation training. The results showed that CBT is a beneficial treatment for chronic back pain on a wide range of relevant variables, especially when compared to wait-list controls/treatment as usual. With regards to the other comparison treatments, results were mixed and inconclusive. CONCLUSION: The results of this review suggest that CBT is a beneficial treatment for chronic nonspecific back pain, leading to improvements in a wide range of relevant cognitive, behavioral and physical variables. This is especially evident when CBT is compared to treatment as usual or wait-list controls, but mixed and inconclusive when compared with various other treatments. Multidisciplinary and transdisciplinary interventions that integrate CBT with other approaches may represent the future direction of management of chronic back pain, with treatments modified for specific circumstances and stakeholders. There is a need for future intervention studies to be specific in their use of cognitive behavioral elements, in order for results to be comparable. PMID- 23091395 TI - Fluoroscopic caudal epidural injections in managing chronic axial low back pain without disc herniation, radiculitis, or facet joint pain. AB - BACKGROUND: Chronic low back pain without disc herniation is common. Various modalities of treatments are utilized in managing this condition, including epidural injections. However, there is continued debate on the effectiveness, indications, and medical necessity of any treatment modality utilized for managing axial or discogenic pain, including epidural injections. METHODS: A randomized, double-blind, actively controlled trial was conducted. The objective was to evaluate the ability to assess the effectiveness of caudal epidural injections of local anesthetic with or without steroids for managing chronic low back pain not caused by disc herniation, radiculitis, facet joints, or sacroiliac joints. A total of 120 patients were randomized to two groups; one group did not receive steroids (group 1) and the other group did (group 2). There were 60 patients in each group. The primary outcome measure was at least 50% improvement in Numeric Rating Scale and Oswestry Disability Index. Secondary outcome measures were employment status and opioid intake. These measures were assessed at 3, 6, 12, 18, and 24 months after treatment. RESULTS: Significant pain relief and functional status improvement (primary outcome) defined as a 50% or more reduction in scores from baseline, were observed in 54% of patients in group 1 and 60% of patients in group 2 at 24 months. In contrast, 84% of patients in group 1 and 73% in group 2 saw significant pain relief and functional status improvement in the successful groups at 24 months. CONCLUSION: Caudal epidural injections of local anesthetic with or without steroids are effective in patients with chronic axial low back pain of discogenic origin without facet joint pain, disc herniation, and/or radiculitis. PMID- 23091396 TI - Antihyperalgesic activity of nucleoside transport inhibitors in models of inflammatory pain in guinea pigs. AB - BACKGROUND AND METHODS: The role of the endogenous purine nucleoside, adenosine, in nociception is well established. Inhibition of the equilibrative nucleoside transporter (ENT1) prevents adenosine uptake into cells, and could therefore enhance the antinociceptive properties of adenosine. The effects of ENT1 inhibition were studied in two animal models of inflammatory pain. Analgesic activity was assessed in a complete Freund's adjuvant (CFA)-induced and carrageenan-induced mechanical and thermal hyperalgesia model in the guinea pig. RESULTS: Draflazine, dipyridamole, dilazep, lidoflazine, soluflazine, and KF24345 showed efficacy in the CFA thermal hyperalgesia model. Draflazine, the most potent compound in this test, was further characterized in the CFA model of mechanical hyperalgesia and the carrageenan inflammation model of thermal and mechanical hyperalgesia, where it completely reversed the hypersensitivity. The antihyperalgesic effects of draflazine (10 mg/kg, administered subcutaneously) were attenuated by the A1 receptor antagonist, cyclopentyltheophylline (5-40 mg/kg, administered intraperitoneally), by the nonselective adenosine antagonist, caffeine (10-40 mg/kg intraperitoneally), and by the A2 antagonist, DMPX (10 mg/kg administered intraperitoneally). CONCLUSION: ENT1 inhibition is an effective way of reversing mechanical and thermal inflammatory hyperalgesia in the guinea pig, and these effects are mediated by enhancement of endogenous adenosine levels. Both A1 and A2 adenosine receptor subtypes are likely to be involved. PMID- 23091397 TI - The effect of CyberKnife therapy on pulmonary function tests used for treating non-small cell lung cancer: a retrospective, observational cohort pilot study. AB - INTRODUCTION: The current standard for treating operable early stage non-small cell lung cancer is surgical resection and for inoperable cases it is external beam radiotherapy. Lung functions are adversely affected with both the above treatments. CyberKnife treatment limits radiation damage by tracking targets moving with each breath. The effect of CyberKnife treatment on pulmonary function tests has not been well documented. METHODS: Lung cancer patients who underwent CyberKnife treatment and had pre- and post-treatment pulmonary function tests were included. Paired t-tests were conducted. We also conducted subgroup analysis. RESULTS: Thirty-seven patients were included. Median age was 73 years. No statistical difference between mean pre- and post-CyberKnife pulmonary function tests was found. DISCUSSION: We observed that CyberKnife better preserves lung function status compared to current standards of care. It has shown to have very minimal side effects. PMID- 23091398 TI - Pelvic exenteration for colorectal cancer: oncologic outcome in 59 patients at a single institution. AB - BACKGROUND: Pelvic exenteration (PE) continues to be the only curative option in selected patients with advanced or recurrent pelvic neoplasms. A current debate exists concerning the appropriate selection of patients for PE, with the most important factor being the absence of extrapelvic disease. AIM: To evaluate the outcome of patients submitted to exenterative surgery. PATIENTS AND METHODS: A review of the clinical charts of patients with colorectal cancer who underwent PE between January 1994 and June 2010 at the Institute National of Cancerologia in Mexico City was performed. RESULTS: We selected 59 patients, 53 of whom were females (90%), and six of whom were males (10%). Mean age at the time of diagnosis was 50 years (range, 21-77 years). A total of 51 patients underwent posterior PE (86%), and eight patients underwent total PE (14%). Operative mortality occurred in two cases (3%), and 29 patients developed complications (49%). Overall, 11 patients (19%) experienced local failure with mean disease free survival time of 10.2 months. After a mean follow-up of 28.3 months, nine patients are still alive without evidence of the disease (15%). CONCLUSIONS: PE should be considered in advanced colorectal cancer without extrapelvic metastatic disease. PE is accompanied by considerable morbidity (49%) and mortality (3%), but local control is desirable. Overall survival justifies the use of this procedure in patients with primary or recurrent locally advanced rectal cancer. PMID- 23091400 TI - Advantages of the association of resveratrol with oral contraceptives for management of endometriosis-related pain. AB - BACKGROUND: The effect of resveratrol on the management of endometriosis-related pain was investigated in 12 patients who failed to obtain pain relief during use of an oral contraceptive containing drospirenone + ethinylestradiol. METHODS AND RESULTS: The addition of 30 mg of resveratrol to the contraceptive regimen resulted in a significant reduction in pain scores, with 82% of patients reporting complete resolution of dysmenorrhea and pelvic pain after 2 months of use. In a separate experiment, aromatase and cyclo-oxygenase-2 expression were investigated in the endometrial tissue of 42 patients submitted to laparoscopy and hysteroscopy for the management of endometriosis. Sixteen of these patients were using oral contraceptives alone prior to hospital admission, while the remaining 26 were using them in combination with resveratrol. Inhibition of both aromatase and cyclo-oxygenase-2 expression was significantly greater in the eutopic endometrium of patients using combined drospirenone + resveratrol therapy compared with the endometrium of patients using oral contraceptives alone. CONCLUSION: These results suggest that resveratrol potentiates the effect of oral contraceptives in the management of endometriosis-associated dysmenorrhea by further decreasing aromatase and cyclo-oxygenase-2 expression in the endometrium. PMID- 23091399 TI - Autophagy as a target for cancer therapy: new developments. AB - Autophagy is an evolutionarily conserved lysosomal degradation pathway that eliminates cytosolic proteins, macromolecules, organelles, and protein aggregates. Activation of autophagy may function as a tumor suppressor by degrading defective organelles and other cellular components. However, this pathway may also be exploited by cancer cells to generate nutrients and energy during periods of starvation, hypoxia, and stress induced by chemotherapy. Therefore, induction of autophagy has emerged as a drug resistance mechanism that promotes cancer cell survival via self-digestion. Numerous preclinical studies have demonstrated that inhibition of autophagy enhances the activity of a broad array of anticancer agents. Thus, targeting autophagy may be a global anticancer strategy that may improve the efficacy of many standard of care agents. These results have led to multiple clinical trials to evaluate autophagy inhibition in combination with conventional chemotherapy. In this review, we summarize the anticancer agents that have been reported to modulate autophagy and discuss new developments in autophagy inhibition as an anticancer strategy. PMID- 23091401 TI - Overcoming resistance and barriers to the use of local estrogen therapy for the treatment of vaginal atrophy. AB - The purpose of this review is to summarize current information regarding the pathophysiology and management of vaginal atrophy (sometimes called "atrophic vaginitis") and to identify barriers to its treatment with local (or "topical") vaginal estrogen therapy. Relevant clinical trials, meta-analyses, and reviews were identified through the PubMed database. Local estrogen therapy is effective and safe for treatment of vaginal atrophy; however, barriers to treatment (eg, patient reluctance to discuss the condition, misinformation, incomplete understanding of the effectiveness and safety of available therapies) result in its underuse. Health care providers can help overcome barriers to effective treatment of vaginal atrophy by facilitating discussion with women about vaginal health. Discussions should occur at routine preventive health care examinations and during episodic visits when patients present with symptoms of vaginal atrophy. Education and counseling should include information on the importance of maintaining vaginal health and the benefits and risks of treatment, including the demonstrated effectiveness and safety profile of low-dose local estrogen therapy. PMID- 23091402 TI - Brief cognitive-behavioral therapy for weight loss in midlife women: a controlled study with follow-up. AB - OBJECTIVE: Cognitive-behavioral therapy (CBT) has proven to be effective in weight reduction. This study explores whether individual, 8-session CBT can promote weight loss in midlife women. METHODS: Anthropometric (weight, abdominal perimeter, and body mass index calculation), psychological (health-related and sexual quality of life, stress, anxiety, and depression), and behavioral measures (binge eating disorder and restrained, external, and emotional eating) were assessed at baseline (T1), posttreatment (T2), and 4-month follow-up (T3), for a total of 21 women at baseline; the CBT group (n = 11) and the control group (n = 10; waiting list) were compared. RESULTS: Statistically significant effects that were dependent on the intervention were observed on weight (F = 4.402; P = 0.035; eta(p) (2) = 0.404; pi = 0.652) and body mass index (F = 3.804; P = 0.050; eta(p) (2) = 0.369; pi = 0.585); furthermore, marginally significant effects were observed on external eating (F = 2.844; P = 0.095; eta(p) (2) = 0.304; pi = 0.461). At follow-up, women in the CBT group presented with lower weight, abdominal perimeter, body mass index, and external eating; higher health-related quality-of-life and restrained eating were also observed in this group. Most differences identified were at a marginally significant level. Moreover, at follow-up, none of the participants of the CBT group met the criteria for binge eating disorder, whereas the number of women with binge eating disorder in the control group remained the same through all three assessments. CONCLUSION: An effective, though small, weight loss was achieved. Changes in quality of life were also observed. Moreover, changes in external eating behavior were successful. PMID- 23091403 TI - A Novel Role of IGF1 in Apo2L/TRAIL-Mediated Apoptosis of Ewing Tumor Cells. AB - Insulin-like growth factor 1 (IGF1) reputedly opposes chemotoxicity in Ewing sarcoma family of tumor (ESFT) cells. However, the effect of IGF1 on apoptosis induced by apoptosis ligand 2 (Apo2L)/tumor necrosis factor (TNF-) related apoptosis-inducing ligand (TRAIL) remains to be established. We find that opposite to the partial survival effect of short-term IGF1 treatment, long-term IGF1 treatment amplified Apo2L/TRAIL-induced apoptosis in Apo2L/TRAIL-sensitive but not resistant ESFT cell lines. Remarkably, the specific IGF1 receptor (IGF1R) antibody alpha-IR3 was functionally equivalent to IGF1. Short-term IGF1 incubation of cells stimulated survival kinase AKT and increased X-linked inhibitor of apoptosis (XIAP) protein which was associated with Apo2L/TRAIL resistance. In contrast, long-term IGF1 incubation resulted in repression of XIAP protein through ceramide (Cer) formation derived from de novo synthesis which was associated with Apo2L/TRAIL sensitization. Addition of ceramide synthase (CerS) inhibitor fumonisin B1 during long-term IGF1 treatment reduced XIAP repression and Apo2L/TRAIL-induced apoptosis. Noteworthy, the resistance to conventional chemotherapeutic agents was maintained in cells following chronic IGF1 treatment. Overall, the results suggest that chronic IGF1 treatment renders ESFT cells susceptible to Apo2L/TRAIL-induced apoptosis and may have important implications for the biology as well as the clinical management of refractory ESFT. PMID- 23091404 TI - The role of invasive and non-invasive procedures in diagnosing fever of unknown origin. AB - BACKGROUND: The etiology of fever of unknown origin has changed because of the recent advances in and widespread use of invasive and non-invasive diagnostic tools. However, undiagnosed patients still constitute a significant number. OBJECTIVE: To determine the etiological distribution and role of non-invasive and invasive diagnostic tools in the diagnosis of fever of unknown origin. MATERIALS & METHODS: One hundred patients who were hospitalized between June 2001 and 2009 with a fever of unknown origin were included in this study. Clinical and laboratory data were collected from the patients' medical records retrospectively. RESULTS: Fifty three percent of the patients were male, with a mean age of 45 years. The etiology of fever was determined to be infectious diseases in 26, collagen vascular diseases in 38, neoplastic diseases in 14, miscellaneous in 2 and undiagnosed in 20 patients. When the etiologic distribution was analyzed over time, it was noted that the rate of infectious diseases decreased, whereas the rate of rheumatological and undiagnosed diseases relatively increased because of the advances in imaging and microbiological studies. Seventy patients had a definitive diagnosis, whereas 10 patients had a possible diagnosis. The diagnoses were established based on clinical features and non-invasive tests for 61% of the patients and diagnostic benefit was obtained for 49% of the patients undergoing invasive tests. Biopsy procedures contributed a rate of 42% to diagnoses in patients who received biopsies. CONCLUSION: Clinical features (such as detailed medical history-taking and physical examination) may contribute to diagnoses, particularly in cases of collagen vascular diseases. Imaging studies exhibit certain pathologies that guide invasive studies. Biopsy procedures contribute greatly to diagnoses, particularly for malignancies and infectious diseases that are not diagnosed by non-invasive procedures. PMID- 23091405 TI - Aberrant TRPV1 expression in heat hyperalgesia associated with trigeminal neuropathic pain. AB - Trigeminal neuropathic pain is a facial pain syndrome associated with trigeminal nerve injury. However, the mechanism of trigeminal neuropathic pain is poorly understood. This study aimed to determine the role of transient receptor potential vanilloid 1 (TRPV1) in heat hyperalgesia in a trigeminal neuropathic pain model. We evaluated nociceptive responses to mechanical and heat stimuli using a partial infraorbital nerve ligation (pIONL) model. Withdrawal responses to mechanical and heat stimuli to vibrissal pads (VP) were assessed using von Frey filaments and a thermal stimulator equipped with a heat probe, respectively. Changes in withdrawal responses were measured after subcutaneous injection of the TRP channel antagonist capsazepine. In addition, the expression of TRPV1 in the trigeminal ganglia was examined. Mechanical allodynia and heat hyperalgesia were observed in VP by pIONL. Capsazepine suppressed heat hyperalgesia but not mechanical allodynia. The number of TRPV1-positive neurons in the trigeminal ganglia was significantly increased in the large-diameter-cell group. These results suggest that TRPV1 plays an important role in the heat hyperalgesia observed in the pIONL model. PMID- 23091406 TI - Correlation between the digital cervicography and pathological diagnosis performed at private clinics in Korea. AB - OBJECTIVE: To evaluate the correlation tendency between abnormal findings of digital cervicography and cervical pathology at private clinics in Korea. METHODS: Abnormal finding of digital cervicography performed at private clinics in Korea between January 1, 2010 and May 31, 2012 were analysed retrospectively. The patient's age, abnormal findings of digital cervicography, cervical cytology, human papillomaviru (HPV) test and cervical pathology were investigated and the rate of agreement between abnormal finding of digital cervicography and cervical pathology results was calculated. Abnormal findings of digital cervicography were divided into 4 categories: atypical, compatible with CIN1, compatible with CIN2/3 and compatible with cancer. RESULTS: The study group was composed of 1547 women with a mean (range) age of 37.4 (14-91 years). The agreement rate between abnormal findings of digital cervicography and cervical pathology was 52.0% in "compatible with CIN1", 78.9% in "compatible with CIN2/3", and 90.2% in "compatible with cancer". CONCLUSIONS: Abnormal findings of digital cervicography were highly concordant with cervical intraepithelial neoplasia (CIN) and cancer examined at outpatient clinics in Korea. Therefore, abnormal interpretations of digital cervicography can be used as an excellent auxiliary technique with cervical cytology for CIN and cancer. PMID- 23091407 TI - Monitoring reasons for encounter via an electronic patient record system: the case of a rural practice initiative. AB - The objective of this brief communication was to tabulate common reasons for encounter in a Greek rural general practice, as result of a recently adopted electronic patient record (EPR) application. Twenty encounter reasons accounted for 3,797 visits (61% of all patient encounters), whereas 565 other reasons accounted for the remaining 2,429 visits (39%). Number one reason for encounter was health maintenance or disease prevention seeking services, including screening examinations for malignancies, immunization and provision of medical opinion reports. Hypertension, lipid disorder and ischemic heart disease without angina were among the most common reasons for seeking care. A strengths/weaknesses/opportunities/threats (SWOT) analysis on the key role of an EPR system in collecting data from rural and remote primary health care settings is also presented. PMID- 23091408 TI - Gross total resection of glioma with the intraoperative fluorescence-guidance of fluorescein sodium. AB - OBJECTIVE: High dose fluorescein sodium has been utilized for fluorescence-guided tumor resection with conflicting reports on the efficacy of this procedure. The aim of this study was to reevaluate the utility and clinical limitations of using fluorescein sodium for the treatment and resection of glioma brain tumors. METHODS: Patients diagnosed with glioma were divided into two groups with a total of 22 patients enrolled in the study: 1) the study group (n=10), patients that received intravenous injection of fluorescein sodium and 2) the control group (n=12), patients that did not receive injections during surgical resection. Quality of life was evaluated according to Karnofsky Performance Scale (KPS) score and neurological status. Fluorescein sodium was intravenously injected at a dose of 15-20mg/kg of body weight. Glioma resection was evaluated preoperative and postoperatively with enhanced Magnetic Resonance Imaging (MRI). RESULTS: Significant differences in the gross total resection (GTR) rates were observed between the two patient groups (Fisher's Exact Test p=0.047). Progressive free survival was significantly longer in the study group (Student's T-Test p=0.033) as well as in the GTR group (Student's T-Test p=0.0001) compared to the control and non-GTR groups, respectively. Three patients in the study group and four patients in the control group had transient neurological deterioration. One patient in the control group had permanent hemiplegia. CONCLUSION: The intraoperative utility of using fluorescein sodium can significantly increase the GTR rate without obvious deterioration. In addition, we find that it is better to apply the fluorescein sodium in the cases with BBB (blood-brain barrier) disruption, which had been enhanced in preoperative MRI. PMID- 23091409 TI - The SCARB1 rs5888 SNP and serum lipid levels in the Guangxi Mulao and Han populations. AB - BACKGROUND: The associations of scavenger receptor class B type 1 (SCARB1) rs5888 single nucleotide polymorphism (SNP) and serum lipid levels are inconsistant among diverse ethnic populations. The present study was undertaken to detect the association of rs5888 SNP and serum lipid levels in the Guangxi Mulao and Han populations. METHODS: Genotypes of the SCARB1 rs5888 SNP in 801 subjects of Mulao and 807 subjects of Han Chinese were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: Serum apolipoprotein (Apo) B levels and the T allelic frequency were higher in Mulao than in Han. Serum high-density lipoprotein cholesterol (HDL-C) levels in Mulao were different among the genotypes, the subjects with TT genotype had lower HDL-C levels than the subjects with CC or CT genotype in female (P < 0.05). For the Han population, serum triglyceride (TG), HDL-C, ApoAI, ApoB levels and the ratio of ApoAI to ApoB in males were different among the genotypes, the T allele carriers had lower serum HDL-C, ApoAI levels and ApoAI/ApoB ratio and higher serum ApoB levels than the T allele noncarriers (P < 0.05 for all), the subjects with TT genotype had higher serum TG levels than the subjects with CC or CT genotype. Serum HDL-C levels in Mulao females and serum HDL-C, ApoAI, ApoB levels and the ApoAI/ApoB ratio in Han males were correlated with genotypes by the multiple linear regression analysis. Serum lipid parameters were also influenced by genotype-environmental interactions in Han but not in Mulao populations. CONCLUSIONS: These results suggest that the rs5888 SNP is associated with serum HDL-C levels in Mulao females, and TG, HDL-C, ApoAI, ApoB levels and the ApoAI/ApoB ratio in Han males. The differences in serum ApoB levels between the two ethnic groups might partially attribute to different SCARB1 genotype-environmental interactions. PMID- 23091410 TI - Clinical effect of acute complete acromioclavicular joint dislocation treated with micro-movable and anatomical acromioclavicular plate. AB - OBJECTIVES: We evaluated the long-term clinical results of acute complete acromioclavicular dislocations treated with micro-movable and anatomical acromioclavicular plate. METHODS: Open reduction and internal fixation was performed using the MAAP in 16 patients (10 males, 6 females; mean age 36 years; range 16 to 63 years) with acute complete acromioclavicular joint dislocation. Radiographic evaluations were routinely conducted every 3 weeks until 3 months postoperatively. The MAAP were removed under local anesthesia after 3 months postoperatively. We evaluated the functional results by using the constant scoring system and radiological results in the last follow-up time. The mean follow up was 26 months (range 16 to 38 months). RESULTS: The mean Constant score was 94 (range, 78 to 100). The results were excellent in 12 patients (75.0%), good in 3 patients (18.8%) and satisfactory in 1 patient (6.2%). Three patients with scores of 80 to 90 had mild pain during activity, but have not affected the shoulder range of motion. One patient has both some pain and limited range of motion of shoulder joint. All patients but one have returned to their preoperative work without any limitations. Compared to the contralateral side, radiography showed anatomical reposition in the vertical plane in 14 cases, slight loss of reduction in 2 older patients. CONCLUSION: We recommend the MAAP fixation for surgical treatment of acute complete acromioclavicular joint dislocation as it could provide satisfactory shoulder functions and clinical results, with lower complication rate. However, it is necessary to continue to observe the clinical effects of this fixation technique. PMID- 23091411 TI - Age- and gender dependent association between components of metabolic syndrome and subclinical arterial stiffness in a Chinese population. AB - BACKGROUND: The aim of this study was to estimate the relationship between arterial stiffness and components of metabolic syndrome (MetS) in different age- and gender groups. METHODS: A total of 12,900 Chinese adults aged 20-79 years were recruited and stratified on the basis of gender and age. All participants underwent the measurement of waist circumference, blood pressure (BP), brachial ankle pulse wave velocity (baPWV; an indicator of arterial stiffness), and blood chemistry. Multiple linear regression analysis was performed to evaluate the relationship between baPWV and above variables, to determine the relative influence of each component of MetS on baPWV. RESULTS: The prevalence of metabolic disorders except for low high-density lipoprotein cholesterol (HDL-C) was much higher in men than in women. All participants with MetS or any component of MetS except for low HDL-C had higher baPWV. BP was positively correlated with baPWV in all groups, while HDL-C was not correlated with baPWV in any groups. In addition, fasting glucose was related to baPWV in middle-aged adults and the elderly. Waist circumference had a positive association with baPWV in middle-aged adults and young men, triglyceride levels showed a significant correlation with baPWV in middle-aged women and young men. Of the MetS components, elevated BP was the strongest predictor of baPWV. CONCLUSION: The prevalence of metabolic disorders and the association between baPWV and metabolic variables are dependent on age and gender. Different components of MetS exert distinct impacts on the baPWV in different age- and gender groups, with BP being the strongest predictor. It is suggested that age and gender should be taken into accounted in the management of MetS aiming to reduce subsequent complications. PMID- 23091412 TI - Tissue-specific transcriptome profiling of Plutella xylostella third instar larval midgut. AB - The larval midgut of diamondback moth, Plutella xylostella, is a dynamic tissue that interfaces with a diverse array of physiological and toxicological processes, including nutrient digestion and allocation, xenobiotic detoxification, innate and adaptive immune response, and pathogen defense. Despite its enormous agricultural importance, the genomic resources for P. xylostella are surprisingly scarce. In this study, a Bt resistant P. xylostella strain was subjected to the in-depth transcriptome analysis to identify genes and gene networks putatively involved in various physiological and toxicological processes in the P. xylostella larval midgut. Using Illumina deep sequencing, we obtained roughly 40 million reads containing approximately 3.6 gigabases of sequence data. De novo assembly generated 63,312 ESTs with an average read length of 416 bp, and approximately half of the P. xylostella sequences (45.4%, 28,768) showed similarity to the non-redundant database in GenBank with a cut-off E-value below 10(-5). Among them, 11,092 unigenes were assigned to one or multiple GO terms and 16,732 unigenes were assigned to 226 specific pathways. In-depth analysis identified genes putatively involved in insecticide resistance, nutrient digestion, and innate immune defense. Besides conventional detoxification enzymes and insecticide targets, novel genes, including 28 chymotrypsins and 53 ABC transporters, have been uncovered in the P. xylostella larval midgut transcriptome; which are potentially linked to the Bt toxicity and resistance. Furthermore, an unexpectedly high number of ESTs, including 46 serpins and 7 lysozymes, were predicted to be involved in the immune defense.As the first tissue-specific transcriptome analysis of P. xylostella, this study sheds light on the molecular understanding of insecticide resistance, especially Bt resistance in an agriculturally important insect pest, and lays the foundation for future functional genomics research. In addition, current sequencing effort greatly enriched the existing P. xylostella EST database, and makes RNAseq a viable option in the future genomic analysis. PMID- 23091413 TI - Insights on FoxN1 biological significance and usages of the "nude" mouse in studies of T-lymphopoiesis. AB - Mutation in the "nude" gene, i.e. the FoxN1 gene, induces a hairless phenotype and a rudimentary thymus gland in mice (nude mouse) and humans (T-cell related primary immunodeficiency). Conventional FoxN1 gene knockout and transgenic mouse models have been generated for studies of FoxN1 gene function related to skin and immune diseases, and for cancer models. It appeared that FoxN1's role was fully understood and the nude mouse model was fully utilized. However, in recent years, with the development of inducible gene knockout/knockin mouse models with the loxP-Cre(ER(T)) and diphtheria toxin receptor-induced cell abolished systems, it appears that the complete repertoire of FoxN1's roles and deep-going usage of nude mouse model in immune function studies have just begun. Here we summarize the research progress made by several recent works studying the role of FoxN1 in the thymus and utilizing nude and "second (conditional) nude" mouse models for studies of T-cell development and function. We also raise questions and propose further consideration of FoxN1 functions and utilizing this mouse model for immune function studies. PMID- 23091414 TI - High level of COP1 expression is associated with poor prognosis in primary gastric cancer. AB - COP1 (constitutive photomorphogenic 1, also known as RFWD2) is a p53-targeting E3 ubiquitin ligase containing RING-finger, coiled-coil, and WD40-repeat domains. Recent studies have identified that COP1 is overexpressed in several cancer types and that increased COP1 expression promotes cell proliferation, cell transformation, and tumor progression. In the present study, we investigated the expression and prognostic value of COP1 in primary gastric cancer. To investigate the role of the COP1 gene in primary gastric cancer pathogenesis, real-time quantitative PCR and western blotting were performed to examine COP1 expression in paired cancerous and matched adjacent noncancerous gastric tissues. The results revealed high COP1 mRNA (P=0.030) and protein (P=0.008) expression in most tumor-bearing tissues compared with the matched adjacent non-tumor tissues. The correlated protein expression analysis revealed a negative correlation between COP1 and p53 in gastric cancer samples (P=0.005, r=-0.572). Immunohistochemical staining of gastric cancer tissues from the same patient showed a high COP1 expression and a low p53 expression. To further investigate the clinicopathological and prognostic roles of COP1 expression, we performed immunohistochemical analysis of 401 paraffin-embedded gastric cancer tissue blocks. The data revealed that high COP1 expression was significantly correlated with T stage (P=0.030), M stage (P=0.048) and TNM stage (P=0.022). Consistent with these results, we found that high expression of COP1 was significantly correlated with poor survival in gastric cancer patients (P<0.001). Cox regression analyses showed that COP1 expression was an independent predictor of overall survival (P<0.001). Our data suggest that COP1 could play an important role in gastric cancer and might serve as a valuable prognostic marker and potential target for gene therapy in the treatment of gastric cancer. PMID- 23091415 TI - DLX4 upregulates TWIST and enhances tumor migration, invasion and metastasis. AB - The distal-less homeobox gene 4 (DLX4) is a member of the DLX family of homeobox genes. Although absent from most normal adult tissues, DLX4 is widely expressed in leukemia, lung, breast, ovarian and prostate cancers. However the molecular targets, mechanisms and pathways that mediate the role of DLX4 in tumor metastasis are poorly understood. In this study, we found that DLX4 induces cancer cells to undergo epithelial to mesenchymal transition (EMT) through TWIST. Overexpression of DLX4 increased expression of TWIST expression in cancer cell lines, resulting in increased migratory and invasive capacity. Likewise, knocking down expression of DLX4 decreased TWIST expression and the migration ability of cancer cell lines. DLX4 bound to regulatory regions of the TWIST gene. Both western blotting and immunohistochemistry staining showed that the expression of DLX4 and TWIST are correlated in most of breast tumors. Taken together, these data from both cell models and tumor tissues demonstrate that DLX4 not only upregulates TWIST expression but also induces EMT and tumor metastasis. Altogether, we propose a new pathway in which DLX4 drives expression of TWIST to promote EMT, cancer migration, invasion and metastasis. PMID- 23091416 TI - Hydrophobic properties of tRNA with varied conformations evaluated by an aqueous two-phase system. AB - The surface properties of transfer RNA (tRNA) were analyzed using a poly(ethylene glycol)/dextran aqueous two-phase system (ATPS), where the surface net hydrophobicity (HFS) and the local hydrophobicity (LH) were evaluated based on the partition coefficient of tRNA in the ATPS. According to the evaluated HFS values, the surface of the tRNA molecule was hydrophilic at 20 degrees -40 degrees C, and it became hydrophobic at 50 degrees -80 degrees C because of the exposure of the intrinsic nucleobases of tRNA. In contrast, the LH values were found to be maximal at 20 degrees -40 degrees C. The conformation of tRNA was investigated by Raman and circular dichroism (CD) spectroscopies, corroborating the results with the calculated prediction of its secondary structure (Mfold). It was shown that 66% of A-form structure existed at room temperature; the base stacking (theta(265)) was gradually decreased, and the A-form structure (theta(208)) was denatured along with a sigmoid curve against the temperature increase; the denatured secondary structures were observed above 50 degrees C by Mfold prediction. The HFS value of the DNA duplex was found to be hydrophilic, compared to that of the single-stranded DNA, indicating that the exposure of nucleobases is a key factor of the hydrophobic properties of nucleotides. We conclude that the hydrophobic property of the tRNA surface was directly affected by its conformational transition. PMID- 23091418 TI - Comment on: "hepatitis C virus in Arab world: a state of concern". PMID- 23091417 TI - ACE/ACE2 ratio and MMP-9 activity as potential biomarkers in tuberculous pleural effusions. AB - OBJECTIVE: Pleural effusion is common problem, but the rapid and reliable diagnosis for specific pathogenic effusions are lacking. This study aimed to identify the diagnosis based on clinical variables to differentiate pleural tuberculous exudates from other pleural effusions. We also investigated the role of renin-angiotensin system (RAS) and matrix metalloproteinase (MMPs) in the pathogenesis of pleural exudates. EXPERIMENTAL DESIGN: The major components in RAS and extracellular matrix metabolism, including angiotensin converting enzyme (ACE), ACE2, MMP-2 and MMP-9 activities, were measured and compared in the patients with transudative (n = 45) and exudative (n = 80) effusions. The exudative effusions were come from the patients with tuberculosis (n = 20), pneumonia (n = 32), and adenocarcinoma (n = 28). RESULTS: Increased ACE and equivalent ACE2 activities, resulting in a significantly increased ACE/ACE2 ratio in exudates, were detected compared to these values in transudates. MMP-9 activity in exudates was significantly higher than that in transudates. The significant correlation between ACE and ACE2 activity that was found in transudates was not found in exudates. Advanced analyses showed significantly increased ACE and MMP-9 activities, and decreased ACE2 activity in tuberculous pleural effusions compared with those in pneumonia and adenocarcinoma effusions. The results indicate that increased ACE and MMP-9 activities found in the exudates were mainly contributed from a higher level of both enzyme activities in the tuberculous pleural effusions. CONCLUSION: Interplay between ACE and ACE2, essential functions in the RAS, and abnormal regulation of MMP-9 probably play a pivotal role in the development of exudative effusions. Moreover, the ACE/ACE2 ratio combined with MMP-9 activity in pleural fluid may be potential biomarkers for diagnosing tuberculous pleurisy. PMID- 23091419 TI - OneZoom: a fractal explorer for the tree of life. PMID- 23091421 TI - On the hunt for vascular endothelial stem cells. PMID- 23091420 TI - Generation of functional blood vessels from a single c-kit+ adult vascular endothelial stem cell. AB - In adults, the growth of blood vessels, a process known as angiogenesis, is essential for organ growth and repair. In many disorders including cancer, angiogenesis becomes excessive. The cellular origin of new vascular endothelial cells (ECs) during blood vessel growth in angiogenic situations has remained unknown. Here, we provide evidence for adult vascular endothelial stem cells (VESCs) that reside in the blood vessel wall endothelium. VESCs constitute a small subpopulation within CD117+ (c-kit+) ECs capable of undergoing clonal expansion while other ECs have a very limited proliferative capacity. Isolated VESCs can produce tens of millions of endothelial daughter cells in vitro. A single transplanted c-kit-expressing VESC by the phenotype lin CD31+CD105+Sca1+CD117+ can generate in vivo functional blood vessels that connect to host circulation. VESCs also have long-term self-renewal capacity, a defining functional property of adult stem cells. To provide functional verification on the role of c-kit in VESCs, we show that a genetic deficit in endothelial c-kit expression markedly decreases total colony-forming VESCs. In vivo, c-kit expression deficit resulted in impaired EC proliferation and angiogenesis and retardation of tumor growth. Isolated VESCs could be used in cell-based therapies for cardiovascular repair to restore tissue vascularization after ischemic events. VESCs also provide a novel cellular target to block pathological angiogenesis and cancer growth. PMID- 23091422 TI - Human rights research and ethics review: protecting individuals or protecting the state? PMID- 23091424 TI - Seeing daylight. PMID- 23091426 TI - Biologics clinical trials, research, and FDA actions. PMID- 23091423 TI - Genetic predictors of response to serotonergic and noradrenergic antidepressants in major depressive disorder: a genome-wide analysis of individual-level data and a meta-analysis. AB - BACKGROUND: It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way. METHODS AND FINDINGS: The NEWMEDS consortium, an academia industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5*10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5*10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D. CONCLUSIONS: No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary. PMID- 23091425 TI - Innovation flourishes at a time of benefit coverage uncertainty. PMID- 23091427 TI - ASCO: The Science Was Grand, But What Will Payers Think? PMID- 23091428 TI - Showdown in steel city. AB - Healthcare reform is encouraging the vertical integration of payers and providers. How far can this go in any one market before such efforts risk being deemed illegal? Pittsburgh provides a case study. PMID- 23091429 TI - Connecting Patients With Specialty Products: Part 2: The future of specialty drug distribution. AB - Previously, this series described distribution channels through which specialty drugs move to patients. This installment discusses changes and challenges that lie ahead, especially at the dispensing end. PMID- 23091430 TI - Putting oncology patients at risk. AB - Using genomic tests to personalize oncology treatment is a worthy endeavor. But when the rush to capitalize on biomedical research overcomes the rules of evidence, it's the patients who suffer. PMID- 23091432 TI - Drug shortages ease, but have we gotten to the root of the problem? PMID- 23091431 TI - Will comparative effectiveness research finally succeed? AB - Autonomy, innovation, and drug access may be at stake along with personalized medicine. Can all stakeholders be satisfied and should cost be a factor? PMID- 23091433 TI - Myriad: debate over gene patents continues. PMID- 23091434 TI - iSPOT-D Trial Has Potential To Personalize Antidepressant Treatment. PMID- 23091435 TI - Employers target rising specialty drug costs. PMID- 23091436 TI - Immune disorders and its correlation with gut microbiome. AB - Allergic disorders such as atopic dermatitis and asthma are common hyper-immune disorders in industrialized countries. Along with genetic association, environmental factors and gut microbiota have been suggested as major triggering factors for the development of atopic dermatitis. Numerous studies support the association of hygiene hypothesis in allergic immune disorders that a lack of early childhood exposure to diverse microorganism increases susceptibility to allergic diseases. Among the symbiotic microorganisms (e.g. gut flora or probiotics), probiotics confer health benefits through multiple action mechanisms including modification of immune response in gut associated lymphoid tissue (GALT). Although many human clinical trials and mouse studies demonstrated the beneficial effects of probiotics in diverse immune disorders, this effect is strain specific and needs to apply specific probiotics for specific allergic diseases. Herein, we briefly review the diverse functions and regulation mechanisms of probiotics in diverse disorders. PMID- 23091438 TI - Calcium/Calmodulin-Dependent Protein Kinase is Involved in the Release of High Mobility Group Box 1 Via the Interferon-beta Signaling Pathway. AB - Previously, we have reported that high mobility group box 1 (HMGB1), a proinflammatory mediator in sepsis, is released via the IFN-beta-mediated JAK/STAT pathway. However, detailed mechanisms are still unclear. In this study, we dissected upstream signaling pathways of HMGB1 release using various molecular biology methods. Here, we found that calcium/calmodulin-dependent protein kinase (CaM kinase, CaMK) is involved in HMGB1 release by regulating IFN-beta production. CaMK inhibitor, STO609, treatment inhibits LPS-induced IFN-beta production, which is correlated with the phosphorylation of interferon regulatory factor 3 (IRF3). Additionally, we show that CaMK-I plays a major role in IFN-beta production although other CaMK members also seem to contribute to this event. Furthermore, the CaMK inhibitor treatment reduced IFN-beta production in a murine endotoxemia. Our results suggest CaMKs contribute to HMGB1 release by enhancing IFN-beta production in sepsis. PMID- 23091437 TI - The past, present, and future of adoptive T cell therapy. AB - Although adoptive T cell therapy (ACT) has become a promising immunotherapeutic regime for cancer treatment, its effectiveness has been hindered by several inherent shortcomings regarding safety and efficacy. During the past few decades, several strategies for enhancing the efficacy of ACT have been developed and introduced in clinic. This review will summarize not only the past approaches but also the latest strategies which have been shown to enhance the anticancer activity of ACT. PMID- 23091439 TI - Affinity Maturation of an Epidermal Growth Factor Receptor Targeting Human Monoclonal Antibody ER414 by CDR Mutation. AB - It is well established that blocking the interaction of EGFR with growth factors leads to the arrest of tumor growth, resulting in tumor cell death. ER414 is a human monoclonal antibody (mAb) derived by guided selection of the mouse mAb A13. The ER414 exhibited a ~17-fold lower affinity and, as a result, lower efficacy of inhibition of the EGF-mediated tyrosine phosphorylation of EGFR when compared with mAb A13 and cetuximab. We performed a stepwise in vitro affinity maturation to improve the affinity of ER414. We obtained a 3D model of ER414 to identify the amino acids in the CDRs that needed to be mutated. Clones were selected from the phage library with randomized amino acids in the CDRs and substitution of amino acids in the HCDR3 and LCDR1 of ER414 led to improved affinity. A clone, H3-14, with a ~20-fold increased affinity, was selected from the HCDR3 randomized library. Then three clones, ER2, ER78 and ER79, were selected from the LCDR1 randomized library based on the H3-14 but did not show further increased affinities compared to that of H3-14. Of the three, ER2 was chosen for further characterization due to its better expression than others. We successfully performed affinity maturation of ER414 and obtained antibodies with a similar affinity as cetuximab. And antibody from an affinity maturation inhibits the EGF mediated tyrosine phosphorylation of EGFR in a manner similar to cetuximab. PMID- 23091440 TI - Epithelial mesenchymal transition in drug resistance and metastasis of lung cancer. AB - Among all types of cancer, incidence of lung cancer remains the highest with regard to cancer-related mortality. Problems contributing to recurrence of the disease include metastasis and drug resistance. Mounting evidence has demonstrated involvement of epithelial mesenchymal transition (EMT) in cancer progression. EMT is a critical mechanism ensuring tissue remodeling during morphogenesis of multicellular organisms. Therefore, understanding of the biology of this process for identification of potential EMT-targeted therapeutic strategies for the benefit cancer patients is necessary. This review describes recent evidence of EMT involvement in drug resistance and metastasis of cancers, with an emphasis on lung cancer. PMID- 23091441 TI - Current Trends of the Incidence and Pathological Diagnosis of Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs) in Korea 2000-2009: Multicenter Study. AB - PURPOSE: As a result of various independently proposed nomenclatures and classifications, there is confusion in the diagnosis and prediction of biological behavior of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A comprehensive nationwide study is needed in order to understand the biological characteristics of GEP-NETs in Korea. MATERIALS AND METHODS: We collected 4,951 pathology reports from 29 hospitals in Korea between 2000 and 2009. Kaplan-Meier survival analysis was used to determine the prognostic significance of clinicopathological parameters. RESULTS: Although the GEP-NET is a relatively rare tumor in Korea, its incidence has increased during the last decade, with the most significant increase found in the rectum. The 10-year survival rate for well differentiated endocrine tumor was 92.89%, in contrast to 85.74% in well differentiated neuroendocrine carcinoma and 34.59% in poorly differentiated neuroendocrine carcinoma. Disease related death was most common in the biliary tract (62.2%) and very rare in the rectum (5.2%). In Kaplan-Meier survival analysis, tumor location, histological classification, extent, size, mitosis, Ki 67 labeling index, synaptophysin expression, lymphovascular invasion, perineural invasion, and lymph node metastasis showed prognostic significance (p<0.05), however, chromogranin expression did not (p=0.148). The 2000 and 2010 World Health Organization (WHO) classification proposals were useful for prediction of the prognosis of GEP-NET. CONCLUSION: The incidence of GEP-NET in Korea has shown a remarkable increase during the last decade, however, the distribution of tumors in the digestive system differs from that of western reports. Assessment of pathological parameters, including immunostaining, is crucial in understanding biological behavior of the tumor as well as predicting prognosis of patients with GEP-NET. PMID- 23091442 TI - Is There a Role of Postoperative Radiation Therapy in Completely Resected Stage I/II Thymic Epithelial Tumor? AB - PURPOSE: Retrospective analyses of patients with stage I-II thymic epithelial tumors (TET) who were treated with either surgery alone (S) or surgery plus postoperative radiation therapy (SRT) were conducted to evaluate the role of adjuvant radiation therapy (RT). MATERIALS AND METHODS: A total of 110 stage I-II TET patients following complete resection were included in this study. Postoperative radiation therapy was recommended for those with aggressive histologic type and/or invasive features according to the surgeons' judgment during the operation. A median dose of 54.0 Gy (range, 44 to 60 Gy) focused on the primary tumor bed was administered to 57 patients (51.8%). RESULTS: In all patients, the rates of overall survival, disease-specific survival, and disease free survival at 10 years were 91.7%, 97.1%, and 95.8%, respectively. No significant differences in disease-specific survival (100% in the S group and 93.5% in the SRT group at 10 years, p=0.12) and disease-free survival (98.1% in the S group and 94.5% in the SRT group at 10 years, p=0.41) were observed between the treatment groups, although a significantly larger number of World Health Organization (WHO)-type B2-C (p<0.001) and Masaoka stage II (p=0.03) tumors were observed in the SRT group than in the S group. No local recurrence was observed in the SRT group. No grade 2 or greater RT-related toxicities were observed in the SRT group. CONCLUSION: Excellent outcomes were achieved in patients with stage I-II TET who underwent complete resection. Considering excellent local control and low morbidity, adjuvant RT may be considered in high risk patients with WHO-type B2-C histology and Masaoka stage II. PMID- 23091443 TI - Metachronous double primary cancer after diagnosis of gastric cancer. AB - PURPOSE: The pattern of double primary cancers after treatment for gastric cancer is important for a patient's survival. MATERIALS AND METHODS: We analyzed the clinicopathologic data of 214 gastric cancer patients from October 1996 to November 2007 with regard to metachronous second primary cancers. RESULTS: Out of 5,778 patients with gastric cancer, metachronous second primary cancers occurred in 214 patients. The median age was 61.8 years, the number of male and female patients was 140 (65.4%), 74 (34.6%), respectively. The median time to the occurrence of second cancers after diagnosis of the first was 39.2 months (standard deviation, 31.2 months). The most common cancer was colorectal cancer, which occurred in 44 patients (20.6%), and lung cancer in 33 patients (15.4%), hepatocellular carcinoma in 26 patients (12.1%), ovarian cancer in 15 patients (7.0%), cervical cancer in 12 patients (7.0%), breast cancer in 11 patients (5.1%), and esophageal cancer in 11 patients (5.1%). The observed/expected (O/E) ratio showed a significant increase in colorectal (1.25), male biliary (1.60), ovarian (8.72), and cervical cancer (3.33) with primary gastric cancer. After five years from diagnosis of gastric cancer, secondary cancer occurred in 50 patients (23.4%), and breast cancer, prostate cancer, laryngeal cancer, lung cancer, and hepatocellular carcinoma were the most frequent. CONCLUSION: The O/E ratio showed a significant increase in colorectal, male biliary, ovarian, and cervical cancer with primary gastric cancer, and second primary cancer as the main cause of death for these patients. A follow-up examination for metachronous double primary cancer is needed in order to improve the survival time in patients with gastric cancer. PMID- 23091444 TI - Clinico-pathologic Parameters for Prediction of Microsatellite Instability in Colorectal Cancer. AB - PURPOSE: Although the incidence of microsatellite instability (MSI) accounts for 10-15% of cases of colorectal cancer, its clinical application for all colorectal cancers has widened. We attempted to identify clinical and pathological parameters that may be helpful in selection of patients with MSI-high (MSI-H). MATERIALS AND METHODS: A total of 120 resected colorectal cancers were enrolled retrospectively for this MSI study. Polymerase chain reaction (PCR) and denaturing high performance liquid chromatography and/or real time PCR methods with five markers and immunohistochemistry (IHC) for MLH1 and MSH2 were performed for analysis of cancer and blood specimens. Clinico-pathologic parameters, including IHC, were investigated in order to determine their usefulness as predictive factors of MSI. RESULTS: Among 120 cases of colorectal cancer, MSI was observed in 15 cases (12.5%), including 11 cases of MSI-H and four cases of MSI low. Patients with MSI were younger, less than 50 years old, had a family history of cancer, Rt. sided colon cancer and/or synchronous multiple colorectal cancer, mucinous histologic type, and serum carcinoembryonic antigen group in the normal range. Results of multivariate analysis showed Bethesda guidelines, Rt. sided and/or synchronous multiple colorectal cancer, and negative expression of IHC for MLH1, which was consistently associated with MSI-H. MSI-H colorectal tumors have met at least one of these three parameters and their sensitivity and specificity were 100% and 72.5%, respectively. CONCLUSION: Bethesda guidelines, tumor location, and negative expression of MLH1 protein are important parameters for selection of patients with colorectal cancers for MSI testing. MSI testing is recommended for patients showing any of these three parameters. PMID- 23091445 TI - Interval between Surgery and Radiation Therapy Is an Important Prognostic Factor in Treatment of Rectal Cancer. AB - PURPOSE: The purpose of this study is to evaluate survival and prognostic factors for rectal cancer, including interval between surgery and radiation therapy after surgery, radiation therapy, and chemotherapy. MATERIALS AND METHODS: We conducted a retrospective study of 153 patients with rectal cancer who were treated with surgery, radiotherapy with/without chemotherapy at Keimyung University Dongsan Medical Center from January, 1988 to December, 2005. The study included 89 males and 64 females, with a median age of 56 years (range, 23 to 81 years). Tumor, node and metastasis (TNM) was I in 23 patients, II in 39, and III in 91. Radiation therapy was performed on pelvic fields using a median dose of 54 Gy five days per week, 1.8 Gy once per day. Ninety two patients were treated with radiotherapy, 43 with concurrent chemo-radiation therapy and 18 with sequential therapy after surgery. The median follow-up period was 52 months (range, 4 to 272 months). The interval between surgery and radiation was 1-25 weeks (median, 5 weeks). RESULTS: Two-year and five-year overall survival rate was 64.7% and 46.4%, respectively. Two-year and five-year disease-free-survival (DFS) rate was 58.6% and 43.1%, respectively. Median DFS was 39 months. Loco-regional failure was evident in 10.5% of patients, 8.4% had distant metastasis, and 9.2% had both. In multivariate analysis, TNM stage and interval between surgery and radiation therapy (<=5 weeks vs. >5 weeks; 95% confidence interval, 1.276 to 2.877; hazard ratio, 1.916; p=0.002) were significant prognostic factors of DFS. CONCLUSION: Survival rates for rectal cancer after surgery, chemotherapy, and radiation therapy were similar to those reported in previous studies. Starting radiation therapy as soon as possible after surgery, especially within the first five weeks after surgery, is suggested. PMID- 23091446 TI - Constitutive Expression of MAP Kinase Phosphatase-1 Confers Multi-drug Resistance in Human Glioblastoma Cells. AB - PURPOSE: Current treatment of glioblastoma after surgery consists of a combination of fractionated radiotherapy and temozolomide. However, it is difficult to completely remove glioblastoma because it has uncertain boundaries with surrounding tissues. Moreover, combination therapy is not always successful because glioblastoma has diverse resistances. To overcome these limitations, we examined the combined effects of chemotherapy and knockdown of mitogen-activated protein kinase phosphatase-1 (MKP-1). MATERIALS AND METHODS: We used ten different anti-cancer drugs (cisplatin, cyclophosphoamide, doxorubicin, epirubicin, etoposide, 5-fluorouracil, gemcitabine, irinotecan, mitomycin C, and vincristine) to treat glioblastoma multiforme (GBM) cells. Knockdown of MKP-1 was performed using siRNA and lipofectamine. The basal level of MKP-1 in GBM was analyzed based on cDNA microarray data obtained from the Gene Expression Omnibus (GEO) databases. RESULTS: Anti-cancer drug-induced cell death was significantly enhanced by knockdown of MKP-1, and this effect was most prominent in cells treated with irinotecan and etoposide. Treatment with these two drugs led to significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in a time-dependent manner, while pharmacological inhibition of JNK partially inhibited drug-induced cell death. Knockdown of MKP-1 also enhanced drug-induced phosphorylation of JNK. CONCLUSION: Increased MKP-1 expression levels could be the cause of the high resistance to conventional chemotherapeutics in human GBM. Therefore, MKP-1 is an attractive target for overcoming drug resistance in this highly refractory malignancy. PMID- 23091447 TI - Epidermal growth factor receptor: is it a feasible target for the treatment of osteosarcoma? AB - PURPOSE: Features of epidermal growth factor receptor (EGFR) expression in osteosarcoma and in vitro efficacies of EGFR inhibitors against osteosarcoma cells were evaluated. MATERIALS AND METHODS: Thirty biopsy samples of osteosarcoma patients were retrospectively analyzed for EGFR protein expression by immunohistochemistry. Relationships between EGFR expression and clinicopathologic characteristics and treatment outcomes were evaluated. Four osteosarcoma cell lines were analyzed for EGFR and p-EGFR expression by western blotting. Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tyrosine kinase domains in exons 18 to 21 were sequenced and gene expression analyses of EGFR and PTEN were performed in four osteosarcoma cell lines. RESULTS: EGFR protein was expressed in 27 (90%) samples (6 low, 12 intermediate, 9 high) and in three cell lines. Intermediate or high staining for EGFR was related to a tumor volume<150 mL (p<0.001) and histologic subtype other than osteoblastic type (p=0.03). However, EGFR expression was not associated with histologic response to preoperative chemotherapy or survival. Gefitinib and BIBW 2992 did not have any significant inhibitory effect on cell viabilities. DNA sequencing analysis revealed three osteosarcoma cell lines have single base changes at codon 2361 of exon 20 (G to A), without affecting translation results. Furthermore, no mutation was found to be associated with constitutive EGFR activation. CONCLUSION: In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells. However, as osteosarcoma cells express EGFR, further studies are necessary to explore the potential of other therapeutic agents targeting EGFR. PMID- 23091448 TI - A case of paratesticular leiomyosarcoma successfully treated with orchiectomy and chemotherapy. AB - A 50-year-old male patient presented with a right scrotal mass that had been growing rapidly for more than one year. A heterogeneous enhancing right scrotal mass (12*9 cm) with para-aortic and peri-caval lymphadenopathies was found on abdominal computed tomography (CT). Right orchiectomy was performed and the gross finding had shown intact testis with a well-defined, huge, whitish solid mass adjacent to the testis. According to pathology, the mass was characterized as a leiomyosarcoma, grade 3 (by National Cancer Instituted [NCI] system). Therefore, the diagnosis was stage III, grade 3 paratesticular leiomyosarcoma. The patient underwent additional systemic chemotherapy using ifosfamide and adriamycin. After nine cycles of chemotherapy, positron emission tomography-CT was performed and no FDP uptake was observed. The patient has been followed up for 12 months after systemic chemotherapy, and he has maintained a complete response. We report here on a rare case of paratesticular leiomyosarcoma treated successfully with orichiectomy and additional systemic chemotherapy. PMID- 23091449 TI - Metastatic renal cell carcinoma in a supraclavicular lymph node with no known primary: a case report. AB - Although metastasis is relatively frequent in cases of renal cell carcinoma (RCC), metastasis in the cervical or supraclavicular lymph node (LN) is relatively rare. Moreover, cases of metastatic RCC with a non-identifiable kidney mass are extremely rare. Here, the authors report a case of metastatic RCC in a supraclavicular LN without a primary kidney lesion. A 69-year-old man presented with a progressively enlarging right supraclavicular mass. Incisional biopsy of the affected supraclavicular LN was performed, and histological examination revealed metastatic RCC. However, no tumor was found in either kidney, despite various examinations. The patient was treated with radiotherapy followed by sunitinib. After three months on sunitinib, a follow-up computed tomography scan revealed that the supraclavicular LN had markedly decreased, and after 20 months, the disease had not progressed. This case suggests that, even when there is no primary kidney lesion, clinicians must consider the possibility of metastatic RCC when evaluating patients with clear cell carcinoma with an unknown primary site. PMID- 23091450 TI - Mapping local structural perturbations in the native state of stefin B (cystatin B) under amyloid forming conditions. AB - Unlike a number of amyloid-forming proteins, stefins, and in particular stefin B (cystatin B) form amyloids under conditions where the native state predominates. In order to trigger oligomerization processes, the stability of the protein needs to be compromised, favoring structural re-arrangement however, accelerating fibril formation is not a simple function of protein stability. We report here on how optimal conditions for amyloid formation lead to the destabilization of dimeric and tetrameric states of the protein in favor of the monomer. Small, highly localized structural changes can be mapped out that allow us to visualize directly areas of the protein which eventually become responsible for triggering amyloid formation. These regions of the protein overlap with the Cu (II)-binding sites which we identify here for the first time. We hypothesize that in vivo modulators of amyloid formation may act similarly to painstakingly optimized solvent conditions developed in vitro. We discuss these data in the light of current structural models of stefin B amyloid fibrils based on H-exchange data, where the detachment of the helical part and the extension of loops were observed. PMID- 23091451 TI - Monosynaptic functional connectivity in cerebral cortex during wakefulness and under graded levels of anesthesia. AB - The balance between excitation and inhibition is considered to be of significant importance for neural computation and cognitive function. Excitatory and inhibitory functional connectivity in intact cortical neuronal networks in wakefulness and graded levels of anesthesia has not been systematically investigated. We compared monosynaptic excitatory and inhibitory spike transmission probabilities using pairwise cross-correlogram (CCG) analysis. Spikes were measured at 64 sites in the visual cortex of rats with chronically implanted microelectrode arrays during wakefulness and three levels of anesthesia produced by desflurane. Anesthesia decreased the number of active units, the number of functional connections, and the strength of excitatory connections. Connection probability (number of connections per number of active unit pairs) was unaffected until the deepest anesthesia level, at which a significant increase in the excitatory to inhibitory ratio of connection probabilities was observed. The results suggest that the excitatory-inhibitory balance is altered at an anesthetic depth associated with unconsciousness. PMID- 23091452 TI - How quantum brain biology can rescue conscious free will. AB - Conscious "free will" is problematic because (1) brain mechanisms causing consciousness are unknown, (2) measurable brain activity correlating with conscious perception apparently occurs too late for real-time conscious response, consciousness thus being considered "epiphenomenal illusion," and (3) determinism, i.e., our actions and the world around us seem algorithmic and inevitable. The Penrose-Hameroff theory of "orchestrated objective reduction (Orch OR)" identifies discrete conscious moments with quantum computations in microtubules inside brain neurons, e.g., 40/s in concert with gamma synchrony EEG. Microtubules organize neuronal interiors and regulate synapses. In Orch OR, microtubule quantum computations occur in integration phases in dendrites and cell bodies of integrate-and-fire brain neurons connected and synchronized by gap junctions, allowing entanglement of microtubules among many neurons. Quantum computations in entangled microtubules terminate by Penrose "objective reduction (OR)," a proposal for quantum state reduction and conscious moments linked to fundamental spacetime geometry. Each OR reduction selects microtubule states which can trigger axonal firings, and control behavior. The quantum computations are "orchestrated" by synaptic inputs and memory (thus "Orch OR"). If correct, Orch OR can account for conscious causal agency, resolving problem 1. Regarding problem 2, Orch OR can cause temporal non-locality, sending quantum information backward in classical time, enabling conscious control of behavior. Three lines of evidence for brain backward time effects are presented. Regarding problem 3, Penrose OR (and Orch OR) invokes non-computable influences from information embedded in spacetime geometry, potentially avoiding algorithmic determinism. In summary, Orch OR can account for real-time conscious causal agency, avoiding the need for consciousness to be seen as epiphenomenal illusion. Orch OR can rescue conscious free will. PMID- 23091453 TI - Competing visual flicker reveals attention-like rivalry in the fly brain. AB - There is increasing evidence that invertebrates such as flies display selective attention (van Swinderen, 2011a), although parallel processing of simultaneous cues remains difficult to demonstrate in such tiny brains. Local field potential (LFP) activity in the fly brain is associated with stimulus selection and suppression (van Swinderen and Greenspan, 2003; Tang and Juusola, 2010), like in other animals such as monkeys (Fries et al., 2001), suggesting that similar processes may be working to control attention in vastly different brains. To investigate selective attention to competing visual cues, I recorded brain activity from behaving flies while applying a method used in human attention studies: competing visual flicker, or frequency tags (Vialatte et al., 2010). Behavioral fixation in a closed-loop flight arena increased the response to visual flicker in the fly brain, and visual salience modulated responses to competing tags arranged in a center-surround pattern. Visual competition dynamics in the fly brain were dependent on the rate of pattern presentation, suggesting that attention-like switching in insects is tuned to the pace of visual changes in the environment rather than simply the passage of time. PMID- 23091455 TI - Neuro-impressions: interpreting the nature of human creativity. AB - Understanding the creative process is essential for realizing human potential. Over the past four decades, the author has explored this subject through his brain-inspired drawings, paintings, symbolic sculptures, and experimental art installations that present myriad impressions of human creativity. These impressionistic artworks interpret rather than illustrate the complexities of the creative process. They draw insights from empirical studies that correlate how human beings create, learn, remember, innovate, and communicate. In addition to offering fresh aesthetic experiences, this metaphorical art raises fundamental questions concerning the deep connections between the brain and its creations. The author describes his artworks as embodiments of everyday observations about the neuropsychology of creativity, and its all-purpose applications for stimulating and accelerating innovation. PMID- 23091454 TI - Neighborhood disadvantage and adolescent stress reactivity. AB - Lower socioeconomic status (SES) is associated with higher levels of life stress, which in turn affect stress physiology. SES is related to basal cortisol and diurnal change, but it is not clear if SES is associated with cortisol reactivity to stress. To address this question, we examined the relationship between two indices of SES, parental education and concentrated neighborhood disadvantage, and the cortisol reactivity of African-American adolescents to a modified version of the Trier Social Stress Test (TSST). We found that concentrated disadvantage was associated with cortisol reactivity and this relationship was moderated by gender, such that higher concentrated disadvantage predicted higher cortisol reactivity and steeper recovery in boys but not in girls. Parental education, alone or as moderated by gender, did not predict reactivity or recovery, while neither education nor concentrated disadvantage predicted estimates of baseline cortisol. This finding is consistent with animal literature showing differential vulnerability, by gender, to the effects of adverse early experience on stress regulation and the differential effects of neighborhood disadvantage in adolescent males and females. This suggests that the mechanisms underlying SES differences in brain development and particularly reactivity to environmental stressors may vary across genders. PMID- 23091456 TI - Dual processing streams in chemosensory perception. AB - Higher order sensory processing follows a general subdivision into a ventral and a dorsal stream for visual, auditory, and tactile information. Object identification is processed in temporal structures (ventral stream), whereas object localization leads to activation of parietal structures (dorsal stream). To examine whether the chemical senses demonstrate a similar dissociation, we investigated odor identification and odor localization in 16 healthy young subjects using functional MRI. We used two odors-(1) eucalyptol; (2) a mixture of phenylethanol and carbon dioxide)-which were delivered to only one nostril. During odor identification subjects had to recognize the odor; during odor localization they had to detect the stimulated nostril. We used general linear model (GLM) as a classical method as well as independent component analysis (ICA) in order to investigate a possible neuroanatomical dissociation between both tasks. Both methods showed differences between tasks-confirming a dual processing stream in the chemical senses-but revealed complementary results. Specifically, GLM identified the left intraparietal sulcus and the right superior frontal sulcus to be more activated when subjects were localizing the odorants. For the same task, ICA identified a significant cluster in the left parietal lobe (paracentral lobule) but also in the right hippocampus. While GLM did not find significant activations for odor identification, ICA revealed two clusters (in the left central fissure and the left superior frontal gyrus) for this task. These data demonstrate that higher order chemosensory processing shares the general subdivision into a ventral and a dorsal processing stream with other sensory systems and suggest that this is a global principle, independent of sensory channels. PMID- 23091457 TI - Computational model of neuron-astrocyte interactions during focal seizure generation. AB - Empirical research in the last decade revealed that astrocytes can respond to neurotransmitters with Ca(2+) elevations and generate feedback signals to neurons which modulate synaptic transmission and neuronal excitability. This discovery changed our basic understanding of brain function and provided new perspectives for how astrocytes can participate not only to information processing, but also to the genesis of brain disorders, such as epilepsy. Epilepsy is a neurological disorder characterized by recurrent seizures that can arise focally at restricted areas and propagate throughout the brain. Studies in brain slice models suggest that astrocytes contribute to epileptiform activity by increasing neuronal excitability through a Ca(2+)-dependent release of glutamate. The underlying mechanism remains, however, unclear. In this study, we implemented a parsimonious network model of neurons and astrocytes. The model consists of excitatory and inhibitory neurons described by Izhikevich's neuron dynamics. The experimentally observed Ca(2+) change in astrocytes in response to neuronal activity was modeled with linear equations. We considered that glutamate is released from astrocytes above certain intracellular Ca(2+) concentrations thus providing a non-linear positive feedback signal to neurons. Propagating seizure-like ictal discharges (IDs) were reliably evoked in our computational model by repeatedly exciting a small area of the network, which replicates experimental results in a slice model of focal ID in entorhinal cortex. We found that the threshold of focal ID generation was lowered when an excitatory feedback-loop between astrocytes and neurons was included. Simulations show that astrocytes can contribute to ID generation by directly affecting the excitatory/inhibitory balance of the neuronal network. Our model can be used to obtain mechanistic insights into the distinct contributions of the different signaling pathways to the generation and propagation of focal IDs. PMID- 23091458 TI - Extracting functionally feedforward networks from a population of spiking neurons. AB - Neuronal avalanches are a ubiquitous form of activity characterized by spontaneous bursts whose size distribution follows a power-law. Recent theoretical models have replicated power-law avalanches by assuming the presence of functionally feedforward connections (FFCs) in the underlying dynamics of the system. Accordingly, avalanches are generated by a feedforward chain of activation that persists despite being embedded in a larger, massively recurrent circuit. However, it is unclear to what extent networks of living neurons that exhibit power-law avalanches rely on FFCs. Here, we employed a computational approach to reconstruct the functional connectivity of cultured cortical neurons plated on multielectrode arrays (MEAs) and investigated whether pharmacologically induced alterations in avalanche dynamics are accompanied by changes in FFCs. This approach begins by extracting a functional network of directed links between pairs of neurons, and then evaluates the strength of FFCs using Schur decomposition. In a first step, we examined the ability of this approach to extract FFCs from simulated spiking neurons. The strength of FFCs obtained in strictly feedforward networks diminished monotonically as links were gradually rewired at random. Next, we estimated the FFCs of spontaneously active cortical neuron cultures in the presence of either a control medium, a GABA(A) receptor antagonist (PTX), or an AMPA receptor antagonist combined with an NMDA receptor antagonist (APV/DNQX). The distribution of avalanche sizes in these cultures was modulated by this pharmacology, with a shallower power-law under PTX (due to the prominence of larger avalanches) and a steeper power-law under APV/DNQX (due to avalanches recruiting fewer neurons) relative to control cultures. The strength of FFCs increased in networks after application of PTX, consistent with an amplification of feedforward activity during avalanches. Conversely, FFCs decreased after application of APV/DNQX, consistent with fading feedforward activation. The observed alterations in FFCs provide experimental support for recent theoretical work linking power-law avalanches to the feedforward organization of functional connections in local neuronal circuits. PMID- 23091459 TI - On the Kinematic Motion Primitives (kMPs) - Theory and Application. AB - Human neuromotor capabilities guarantee a wide variety of motions. A full understanding of human motion can be beneficial for rehabilitation or performance enhancement purposes, or for its reproduction on artificial systems like robots. This work aims at describing the complexity of human motion in a reduced dimensionality, by means of kinematic Motion Primitives (kMPs). A set of five invariant kMPs are identified for periodic motions, and a set of two kMPs for discrete motions. It is shown how these two sets of kMPs can be combined to synthesize more complex motion as the simultaneous execution of the periodic and the discrete motions. The results reported are an evidence of the theory of Central Pattern Generators (CPG), showing its effects on the kinematics, and are related to what presented in the literature on the Motor Primitives extracted from EMG signals. Experimental tests with the COmpliant huMANoid (COMAN) were performed to show that the kMPs extracted from human subjects can be used to transfer the features of human locomotion to the gait of a robot. PMID- 23091462 TI - II.1.5 Phenotyping pearl millet for adaptation to drought. AB - Pearl millet is highly resilient to some of the driest areas of the world, like the Sahel area or fringes of the Thar desert in India. Despite this, there is a wealth of variation in pearl millet genotypes for their adaptation to drought and the object of this paper was to review some related work in the past 25 years to harness these capacities toward the breeding of better adapted cultivars. Work on short duration cultivars has been a major effort. Pearl millet has also some development plasticity thanks to a high tillering ability, which allows compensating for possible drought-related failure of the main culm under intermittent drought. The development of molecular tools for breeding has made great progress in the last 10-15 years and markers, maps, EST libraries, BACs are now available and a number of quantitative trait loci (QTLs) for different traits, including drought, have been identified. Most of the work on drought has focused on the drought tolerance index (DTI), an index that reflect the genetic differences in drought adaptation that are independent of flowering time and yield potential. The DTI is closely associated to the panicle harvest index (PNHI), a trait that relates to a better grain setting and grain filling capacity. Initial work on the DTI involved empirical breeding and selection based on PNHI. A QTL for PNHI has then been identified and introgressed by marker assisted backcrossing. More recently, a thorough dissection of that QTL has been carried out and shows that high PNHI is related to the constitutive ability of tolerant lines to save water (lower leaf conductance and sensitivity of transpiration to high vapor pressure deficit) at a vegetative stage and use it for the grain filling period. However, there is no contribution of root traits in this QTL. Current work is taking place to map these water saving traits, understand their genetic interactions, and design ideotypes having specific genetic make-up toward adaptation to specific rainfall environments. PMID- 23091460 TI - Group 1 metabotropic glutamate receptor function and its regulation of learning and memory in the aging brain. AB - Normal aging is generally characterized by a slow decline of cognitive abilities albeit with marked individual differences. Several animal models have been studied to explore the molecular and cellular mechanisms underlying this phenomenon. The excitatory neurotransmitter glutamate and its receptors have been closely linked to spatial learning and hippocampus-dependent memory processes. For decades, ionotropic glutamate receptors have been known to play a critical role in synaptic plasticity, a form of adaptation regulating memory formation. Over the past 10 years, several groups have shown the importance of group 1 metabotropic glutamate receptor (mGluR) in successful cognitive aging. These G protein-coupled receptors are enriched in the hippocampal formation and interact physically with other proteins in the membrane including glutamate ionotropic receptors. Synaptic plasticity is crucial to maintain cognitive abilities and long-term depression (LTD) induced by group 1 mGluR activation, which has been linked to memory in the aging brain. The translation and synthesis of proteins by mGluR-LTD modulate ionotropic receptor trafficking and expression of immediate early genes related to cognition. Fragile X syndrome, a genetic form of autism characterized by memory deficits, has been associated to mGluR receptor malfunction and aberrant activation of its downstream signaling pathways. Dysfunction of mGluR could also be involved in neurodegenerative disorders like Alzheimer's disease (AD). Indeed, beta-amyloid, the main component of insoluble senile plaques and one of the hallmarks of AD, occludes mGluR-dependent LTD leading to diminished functional synapses. This review highlights recent findings regarding mGluR signaling, related synaptic plasticity, and their potential involvement in normal aging and neurological disorders. PMID- 23091463 TI - Measuring group synchrony: a cluster-phase method for analyzing multivariate movement time-series. AB - A new method for assessing group synchrony is introduced as being potentially useful for objectively determining degree of group cohesiveness or entitativity. The cluster-phase method of Frank and Richardson (2010) was used to analyze movement data from the rocking chair movements of six-member groups who rocked their chairs while seated in a circle facing the center. In some trials group members had no information about others' movements (their eyes were shut) or they had their eyes open and gazed at a marker in the center of the group. As predicted, the group level synchrony measure was able to distinguish between situations where synchrony would have been possible and situations where it would be impossible. Moreover, other aspects of the analysis illustrated how the cluster phase measures can be used to determine the type of patterning of group synchrony, and, when integrated with multi-level modeling, can be used to examine individual-level differences in synchrony and dyadic level synchrony as well. PMID- 23091461 TI - Functional role of monocytes and macrophages for the inflammatory response in acute liver injury. AB - Different etiologies such as drug toxicity, acute viral hepatitis B, or acetaminophen poisoning can cause acute liver injury or even acute liver failure (ALF). Excessive cell death of hepatocytes in the liver is known to result in a strong hepatic inflammation. Experimental murine models of liver injury highlighted the importance of hepatic macrophages, so-called Kupffer cells, for initiating and driving this inflammatory response by releasing proinflammatory cytokines and chemokines including tumor necrosis factor (TNF), interleukin-6 (IL 6), IL-1beta, or monocyte-chemoattractant protein-1 (MCP-1, CCL2) as well as activating other non-parenchymal liver cells, e.g., endothelial or hepatic stellate cells. Many of these proinflammatory mediators can trigger hepatocytic cell death pathways, e.g., via caspase activation, but also activate protective signaling pathways, e.g., via nuclear factor kappa B (NF-kappaB). Recent studies in mice demonstrated that these macrophage actions largely depend on the recruitment of monocytes into the liver, namely of the inflammatory Ly6c+ (Gr1+) monocyte subset as precursors of tissue macrophages. The chemokine receptor CCR2 and its ligand MCP-1/CCL2 promote monocyte subset infiltration upon liver injury. In contrast, the chemokine receptor CX3CR1 and its ligand fractalkine (CX3CL1) are important negative regulators of monocyte infiltration by controlling their survival and differentiation into functionally diverse macrophage subsets upon injury. The recently identified cellular and molecular pathways for monocyte subset recruitment, macrophage differentiation, and interactions with other hepatic cell types in the injured liver may therefore represent interesting novel targets for future therapeutic approaches in ALF. PMID- 23091465 TI - The timing of change detection and change perception in complex acoustic scenes. AB - We investigated how listeners perceive the temporal relationship of a light flash and a complex acoustic signal. The stimulus mimics ubiquitous events in busy scenes which are manifested as a change in the pattern of on-going fluctuation. Detecting pattern emergence inherently requires integration over time; resulting in such events being detected later than when they occurred. How does delayed detection time affect the perception of such events relative to other events in the scene? To model these situations, we use rapid sequences of tone pips with a time-frequency pattern that changes from random to regular ("REG-RAND") or vice versa ("RAND-REG"). REG-RAND transitions are detected rapidly, but RAND-REG take longer to detect (~880 ms post nominal transition). Using a Temporal Order Judgment task, we instructed subjects to indicate whether the flash appeared before or after the acoustic transition. The point of subjective simultaneity between the flash and RAND-REG does not occur at the point of detection (~880 ms post nominal transition) but ~470 ms closer to the nominal acoustic transition. In a second experiment we halved the tone pip duration. The resulting pattern of performance was qualitatively similar to that in Experiment 1, but scaled by half. Our results indicates that the brain possesses mechanisms that survey the proximal history of an on-going stimulus and automatically adjust perception so as to compensate for prolonged detection time, thus producing more accurate representations of scene dynamics. However, this readjustment is not complete. PMID- 23091466 TI - A cue from the unconscious - masked symbols prompt spatial anticipation. AB - Anticipating where an event will occur enables us to instantaneously respond to events that occur at the expected location. Here we investigated if such spatial anticipations can be triggered by symbolic information that participants cannot consciously see. In two experiments involving a Posner cueing task and a visual search task, a central cue informed participants about the likely location of the next target stimulus. In half of the trials, this cue was rendered invisible by pattern masking. In both experiments, visible cues led to cueing effects, that is, faster responses after valid compared to invalid cues. Importantly, even masked cues caused cueing effects, though to a lesser extent. Additionally, we analyzed effects on attention that persist from one trial to the subsequent trial. We found that spatial anticipations are able to interfere with newly formed spatial anticipations and influence orienting of attention in the subsequent trial. When the preceding cue was visible, the corresponding spatial anticipation persisted to an extent that prevented a noticeable effect of masked cues. The effects of visible cues were likewise modulated by previous spatial anticipations, but were strong enough to also exert an impact on attention themselves. Altogether, the results suggest that spatial anticipations can be formed on the basis of unconscious stimuli, but that interfering influences like still active spatial anticipations can suppress this effect. PMID- 23091467 TI - Computational constraints in cognitive theories of forgetting. AB - This article highlights some of the benefits of computational modeling for theorizing in cognition. We demonstrate how computational models have been used recently to argue that (1) forgetting in short-term memory is based on interference not decay, (2) forgetting in list-learning paradigms is more parsimoniously explained by a temporal distinctiveness account than by various forms of consolidation, and (3) intrusion asymmetries that appear when information is learned in different contexts can be explained by temporal context reinstatement rather than labilization and reconsolidation processes. PMID- 23091468 TI - Insights on the marine microbial nitrogen cycle from isotopic approaches to nitrification. AB - The microbial nitrogen (N) cycle involves a variety of redox processes that control the availability and speciation of N in the environment and that are involved with the production of nitrous oxide (N(2)O), a climatically important greenhouse gas. Isotopic measurements of ammonium (NH(+) (4)), nitrite (NO(-) (2)), nitrate (NO(-) (3)), and N(2)O can now be used to track the cycling of these compounds and to infer their sources and sinks, which has lead to new and exciting discoveries. For example, dual isotope measurements of NO(-) (3) and NO( ) (2) have shown that there is NO(-) (3) regeneration in the ocean's euphotic zone, as well as in and around oxygen deficient zones (ODZs), indicating that nitrification may play more roles in the ocean's N cycle than generally thought. Likewise, the inverse isotope effect associated with NO(-) (2) oxidation yields unique information about the role of this process in NO(-) (2) cycling in the primary and secondary NO(-) (2) maxima. Finally, isotopic measurements of N(2)O in the ocean are indicative of an important role for nitrification in its production. These interpretations rely on knowledge of the isotope effects for the underlying microbial processes, in particular ammonia oxidation and nitrite oxidation. Here we review the isotope effects involved with the nitrification process and the insights provided by this information, then provide a prospectus for future work in this area. PMID- 23091464 TI - Cognition-emotion dysinteraction in schizophrenia. AB - Evolving theories of schizophrenia emphasize a "disconnection" in distributed fronto-striatal-limbic neural systems, which may give rise to breakdowns in cognition and emotional function. We discuss these diverse domains of function from the perspective of disrupted neural circuits involved in "cold" cognitive vs. "hot" affective operations and the interplay between these processes. We focus on three research areas that highlight cognition-emotion dysinteractions in schizophrenia: First, we discuss the role of cognitive deficits in the "maintenance" of emotional information. We review recent evidence suggesting that motivational abnormalities in schizophrenia may in part arise due to a disrupted ability to "maintain" affective information over time. Here, dysfunction in a prototypical "cold" cognitive operation may result in "affective" deficits in schizophrenia. Second, we discuss abnormalities in the detection and ascription of salience, manifest as excessive processing of non-emotional stimuli and inappropriate distractibility. We review emerging evidence suggesting deficits in some, but not other, specific emotional processes in schizophrenia - namely an intact ability to perceive emotion "in-the-moment" but poor prospective valuation of stimuli and heightened reactivity to stimuli that ought to be filtered. Third, we discuss abnormalities in learning mechanisms that may give rise to delusions, the fixed, false, and often emotionally charged beliefs that accompany psychosis. We highlight the role of affect in aberrant belief formation, mostly ignored by current theoretical models. Together, we attempt to provide a consilient overview for how breakdowns in neural systems underlying affect and cognition in psychosis interact across symptom domains. We conclude with a brief treatment of the neurobiology of schizophrenia and the need to close our explanatory gap between cellular-level hypotheses and complex behavioral symptoms observed in this illness. PMID- 23091469 TI - Phytoplankton chytridiomycosis: fungal parasites of phytoplankton and their imprints on the food web dynamics. AB - Parasitism is one of the earlier and common ecological interactions in the nature, occurring in almost all environments. Microbial parasites typically are characterized by their small size, short generation time, and high rates of reproduction, with simple life cycle occurring generally within a single host. They are diverse and ubiquitous in aquatic ecosystems, comprising viruses, prokaryotes, and eukaryotes. Recently, environmental 18S rDNA surveys of microbial eukaryotes have unveiled major infecting agents in pelagic systems, consisting primarily of the fungal order of Chytridiales (chytrids). Chytrids are considered the earlier branch of the Eumycetes and produce motile, flagellated zoospores, characterized by a small size (2-6 MUm), and a single, posterior flagellum. The existence of these dispersal propagules includes chytrids within the so-called group of zoosporic fungi, which are particularly adapted to the plankton lifestyle where they infect a wide variety of hosts, including fishes, eggs, zooplankton, algae, and other aquatic fungi but primarily freshwater phytoplankton. Related ecological implications are huge because chytrids can killed their hosts, release substrates for microbial processes, and provide nutrient-rich particles as zoospores and short fragments of filamentous inedible hosts for the grazer food chain. Furthermore, based on the observation that phytoplankton chytridiomycosis preferentially impacts the larger size species, blooms of such species (e.g., filamentous cyanobacteria) may not totally represent trophic bottlenecks. Besides, chytrid epidemics represent an important driving factor in phytoplankton seasonal successions. In this review, I summarize the knowledge on the diversity, community structure, quantitative importance, and functional roles of fungal chytrids, primarily those who are parasites of phytoplankton, and infer the ecological implications and potentials for the food web dynamics and properties. I reach the conclusion that phytoplankton chytridiomycosis represents an important but as yet overlooked ecological driving force in aquatic food web dynamics and network organization. PMID- 23091470 TI - Vitamin b(1) and b(12) uptake and cycling by plankton communities in coastal ecosystems. AB - While vitamin B(12) has recently been shown to co-limit the growth of coastal phytoplankton assemblages, the cycling of B-vitamins in coastal ecosystems is poorly understood as planktonic uptake rates of vitamins B(1) and B(12) have never been quantified in tandem in any aquatic ecosystem. The goal of this study was to establish the relationships between plankton community composition, carbon fixation, and B-vitamin assimilation in two contrasting estuarine systems. We show that, although B-vitamin concentrations were low (pM), vitamin concentrations and uptake rates were higher within a more eutrophic estuary and that vitamin B(12) uptake rates were significantly correlated with rates of primary production. Eutrophic sites hosted larger bacterial and picoplankton abundances with larger carbon normalized vitamin uptake rates. Although the >2 MUm phytoplankton biomass was often dominated by groups with a high incidence of vitamin auxotrophy (dinoflagellates and diatoms), picoplankton (<2 MUm) were always responsible for the majority of B(12)-vitamin uptake. Multiple lines of evidence suggest that heterotrophic bacteria were the primary users of vitamins among the picoplankton during this study. Nutrient/vitamin amendment experiments demonstrated that, in the Summer and Fall, vitamin B(12) occasionally limited or co-limited the accumulation of phytoplankton biomass together with nitrogen. Combined with prior studies, these findings suggest that picoplankton are the primary producers and users of B-vitamins in some coastal ecosystems and that rapid uptake of B-vitamins by heterotrophic bacteria may sometimes deprive larger phytoplankton of these micronutrients and thus influence phytoplankton species succession. PMID- 23091471 TI - Functional characterization and evolution of the isotuberculosinol operon in Mycobacterium tuberculosis and related Mycobacteria. AB - Terpenoid metabolites are important to the cellular function, structural integrity, and pathogenesis of the human-specific pathogen Mycobacterium tuberculosis (Mtb). Genetic and biochemical investigations have indicated a role for the diterpenoid isotuberculosinol (isoTb) early in the infection process. There are only two genes (Rv3377c and Rv3378c) required for production of isoTb, yet these are found in what appears to be a five-gene terpenoid/isoprenoid biosynthetic operon. Of the three remaining genes (Rv3379c, Rv3382c, and Rv3383c), previous work has indicated that Rv3379c is an inactive pseudo-gene. Here we demonstrate that Rv3382c and Rv3383c encode biochemically redundant machinery for isoprenoid metabolism, encoding a functional 4-hydroxy-3-methylbut 2-enyl diphosphate reductase (LytB) for isoprenoid precursor production and a geranylgeranyl diphosphate (GGPP) synthase, respectively, for which the Mtb genome contains other functional isozymes (Rv1110 and Rv0562, respectively). These results complete the characterization of the isoTb biosynthetic operon, as well as further elucidating isoprenoid metabolism in Mtb. In addition, we have investigated the evolutionary origin of this operon, revealing Mtb-specific conservation of the diterpene synthase genes responsible for isoTb biosynthesis, which supports our previously advanced hypothesis that isoTb acts as a human specific pathogenic metabolite and is consistent with the human host specificity of Mtb. Intriguingly, our results revealed that many mycobacteria contain orthologs for both Rv3383c and Rv0562, suggesting a potentially important role for these functionally redundant GGPP synthases in the evolution of terpenoid/isoprenoid metabolism in the mycobacteria. PMID- 23091472 TI - The sensitivity of marine N(2) fixation to dissolved inorganic nitrogen. AB - The dominant process adding nitrogen (N) to the ocean, di-nitrogen (N(2)) fixation, is mediated by prokaryotes (diazotrophs) sensitive to a variety of environmental factors. In particular, it is often assumed that consequential rates of marine N(2) fixation do not occur where concentrations of nitrate (NO(-) (3)) and/or ammonium (NH(+) (4)) exceed 1MUM because of the additional energetic cost associated with assimilating N(2) gas relative to NO(-) (3) or NH(+) (4). However, an examination of culturing studies and in situ N(2) fixation rate measurements from marine euphotic, mesopelagic, and benthic environments indicates that while elevated concentrations of NO(-) (3) and/or NH(+) (4) can depress N(2) fixation rates, the process can continue at substantial rates in the presence of as much as 30MUM NO(-) (3) and/or 200MUM NH(+) (4). These findings challenge expectations of the degree to which inorganic N inhibits this process. The high rates of N(2) fixation measured in some benthic environments suggest that certain benthic diazotrophs may be less sensitive to prolonged exposure to NO(-) (3) and/or NH(+) (4) than cyanobacterial diazotrophs. Additionally, recent work indicates that cyanobacterial diazotrophs may have mechanisms for mitigating NO(-) (3) inhibition of N(2) fixation. In particular, it has been recently shown that increasing phosphorus (P) availability increases diazotroph abundance, thus compensating for lower per-cell rates of N(2) fixation that result from NO(-) (3) inhibition. Consequently, low ambient surface ocean N:P ratios such as those generated by the increasing rates of N loss thought to occur during the last glacial to interglacial transition may create conditions favorable for N(2) fixation and thus help to stabilize the marine N inventory on relevant time scales. These findings suggest that restricting measurements of marine N(2) fixation to oligotrophic surface waters may underestimate global rates of this process and contribute to uncertainties in the marine N budget. PMID- 23091473 TI - Influence of vitamin B auxotrophy on nitrogen metabolism in eukaryotic phytoplankton. AB - While nitrogen availability is known to limit primary production in large parts of the ocean, vitamin starvation amongst eukaryotic phytoplankton is becoming increasingly recognized as an oceanographically relevant phenomenon. Cobalamin (B(12)) and thiamine (B(1)) auxotrophy are widespread throughout eukaryotic phytoplankton, with over 50% of cultured isolates requiring B(12) and 20% requiring B(1). The frequency of vitamin auxotrophy in harmful algal bloom species is even higher. Instances of colimitation between nitrogen and B vitamins have been observed in marine environments, and interactions between these nutrients have been shown to impact phytoplankton species composition. This review surveys available data, including relevant gene expression patterns, to evaluate the potential for interactive effects of nitrogen and vitamin B(12) and B(1) starvation in eukaryotic phytoplankton. B(12) plays essential roles in amino acid and one-carbon metabolism, while B(1) is important for primary carbohydrate and amino acid metabolism and likely useful as an anti-oxidant. Here we will focus on three potential metabolic interconnections between vitamin, nitrogen, and sulfur metabolism that may have ramifications for the role of vitamin and nitrogen scarcities in driving ocean productivity and species composition. These include: (1) B(12), B(1), and N starvation impacts on osmolyte and antioxidant production, (2) B(12) and B(1) starvation impacts on polyamine biosynthesis, and (3) influence of B(12) and B(1) starvation on the diatom urea cycle and amino acid recycling through impacts on the citric acid cycle. We evaluate evidence for these interconnections and identify oceanographic contexts in which each may impact rates of primary production and phytoplankton community composition. Major implications include that B(12) and B(1) deprivation may impair the ability of phytoplankton to recover from nitrogen starvation and that changes in vitamin and nitrogen availability may synergistically impact harmful algal bloom formation. PMID- 23091474 TI - Dynamic Evolution of the LPS-Detoxifying Enzyme Intestinal Alkaline Phosphatase in Zebrafish and Other Vertebrates. AB - Alkaline phosphatases (Alps) are well-studied enzymes that remove phosphates from a variety of substrates. Alps function in diverse biological processes, including modulating host-bacterial interactions by dephosphorylating the Gram-negative bacterial cell wall component lipopolysaccharide (LPS). In animals, Alps are encoded by multiple genes characterized by either ubiquitous expression (named Alpls for their liver expression, but a key to proper bone mineralization), or their tissue-specific expression, for example in the intestine (Alpi). We previously characterized a zebrafish alpi gene (renamed here alpi.1) that is regulated by Myd88-dependent innate immune signaling and that is required to prevent a host's excessive inflammatory reactions to its resident microbiota. Here we report the characterization of two new alp genes in zebrafish, alpi.2 and alp3. To understand their origins, we investigated the phylogenetic history of Alp genes in animals. We find that vertebrate Alp genes are organized in three clades with one of these clades missing from the mammals. We present evidence that these three clades originated during the two vertebrate genome duplications. We show that alpl is ubiquitously expressed in zebrafish, as it is in mammals, whereas the other three alps are specific to the intestine. Our phylogenetic analysis reveals that in contrast to Alpl, which has been stably maintained as a single gene throughout the vertebrates, the Alpis have been lost and duplicated multiple times independently in vertebrate lineages, likely reflecting the rapid and dynamic evolution of vertebrate gut morphologies, driven by changes in bacterial associations and diet. PMID- 23091475 TI - Translating Tolerogenic Therapies to the Clinic - Where Do We Stand and What are the Barriers? PMID- 23091476 TI - Multiple actin isotypes in plants: diverse genes for diverse roles? AB - Plant actins are encoded by a gene family. Despite the crucial significance of the actin cytoskeleton for plant structure and function, the importance of individual actin isotypes and their specific roles in various plant tissues or even single cells is rather poorly understood. This review summarizes our current knowledge about the plant actin gene family including its evolution, gene and protein structure, and the expression profiles and regulation. Based on this background information, we review mutant and complementation analyses in Arabidopsis to draw an emerging picture of overlapping and specific roles of plant actin isotypes. Finally, we examine hypotheses explaining the mechanisms of isotype-specific functions. PMID- 23091477 TI - Evolution and Structural Diversification of PILS Putative Auxin Carriers in Plants. AB - The phytohormone auxin contributes to virtually every aspect of the plant development. The spatiotemporal distribution of auxin depends on a complex interplay between auxin metabolism and intercellular auxin transport. Intracellular auxin compartmentalization provides another link between auxin transport processes and auxin metabolism. The PIN-LIKES (PILS) putative auxin carriers localize to the endoplasmic reticulum (ER) and contribute to cellular auxin homeostasis. PILS proteins regulate intracellular auxin accumulation, the rate of auxin conjugation and, subsequently, affect nuclear auxin signaling. Here, we investigate sequence diversification of the PILS family in Arabidopsis thaliana and provide insights into the evolution of these novel putative auxin carriers in plants. Our data suggest that PILS proteins are conserved throughout the plant lineage and expanded during higher plant evolution. PILS proteins diversified early during plant evolution into three clades. Besides the ancient Clade I encompassing non-land plant species, PILS proteins evolved into two clades. The diversification of Clade II and Clade III occurred already at the level of non-vascular plant evolution and, hence, both clades contain vascular and non-vascular plant species. Nevertheless, Clade III contains fewer non- and increased numbers of vascular plants, indicating higher importance of Clade III for vascular plant evolution. Notably, PILS proteins are distinct and appear evolutionarily older than the prominent PIN-FORMED auxin carriers. Moreover, we revealed particular PILS sequence divergence in Arabidopsis and assume that these alterations could contribute to distinct gene regulations and protein functions. PMID- 23091479 TI - The Effect of Dysregulation of tRNA Genes and Translation Efficiency Mutations in Cancer and Neurodegeneration. PMID- 23091478 TI - MicroRNAs as Novel Biomarkers in Colorectal Cancer. AB - MicroRNAs (miRNAs) play an important role in various physiologic and developmental processes and in the initiation and progression of cancer. This class of small, non-coding RNAs critically regulate gene expression at the post transcriptional level and evidence suggests that they may function as both oncogenes and tumor suppressors. Colorectal cancer (CRC) is a major healthcare concern worldwide and in order to reduce CRC related deaths, research is aimed into the search for some novel screening approaches. In this sense, miRNAs are rapidly emerging as a novel class of biomarkers, with good potential as diagnostic and therapeutic targets. This review summarizes the recent findings of the clinicopathological relevance that miRNAs have in CRC initiation, development, and progress, highlighting their potential diagnostic, prognostic, and therapeutic use in CRC, focusing on the group of microsatellite instable and the group of hypermethylated CRCs, as well as discussing future prospects. PMID- 23091481 TI - Induction of p53-inducible microRNA miR-34 by gamma radiation and bleomycin are different. AB - microRNAs (miRNAs) are small molecules in their mature form and master regulators of gene expression. Recent work has shown that miRNAs are involved in the p53 network. Of the various miRNAs, miR-34 is regulated by the p53 protein. miR-34 can be induced by ionizing radiation (IR) in vitro and in vivo. However, there is no data in the literature for induction of miR-34 by a chemical agent inducing DNA damage. Here we studied the expression of miR-34 in HeLa and MCF-7 cells exposed to genotoxic stress-induced by bleomycin (BLM) or gamma-radiation. We first analyzed p53 accumulation upon DNA damage induction. The basal level of p53 in MCF-7 cells was higher (approx. 6-fold) than in HeLa cells, and its accumulation was similar for both DNA-damaging agents in both cell lines. We have shown that miR-34 is significantly induced by gamma-radiation in HeLa cells, but not in MCF-7 cells. BLM did not significantly affect miR-34 expression in both cell types. In conclusion, our findings reveal that miR-34 induction by genotoxic stress may be cell-type specific. PMID- 23091480 TI - Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: a novel candidate SNP approach. AB - OBJECTIVES: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. METHODS: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. RESULTS: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing or conducting meta-analysis. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. CONCLUSION: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns. PMID- 23091482 TI - Effect of pioglitazone on the fructose-induced abdominal adipose tissue dysfunction. AB - Aim. To test the potential role of PPARgamma in the endocrine abdominal tissue dysfunction induced by feeding normal rats with a fructose rich diet (FRD) during three weeks. Methodology. Adult normal male rats received a standard commercial diet (CD) or FRD, (10% in drinking water) without or with pioglitazone (PIO) (i.p. 0.25 mg/Kg BW/day; CD-PIO and FRD-PIO). Thereafter, we measured circulating metabolic, endocrine, and oxidative stress (OS) markers, abdominal adipose tissue (AAT) mass, leptin (LEP) and plasminogen activator inhibitor-1 (PAI-1) tissue content/expression, and leptin release by isolated adipocytes incubated with different concentrations of insulin. Results. Plasma glucose, insulin, triglyceride, TBARS, LEP, and PAI-1 levels were higher in FRD rats; PIO coadministration fully prevented all these increments. AAT adipocytes from FRD rats were larger, secreted a higher amount of LEP, and displayed decreased sensitivity to insulin stimulation; these effects were significantly ameliorated by PIO. Whereas AAT LEP and PAI-1 (mRNA) concentrations increased significantly in FRD rats, those of insulin-receptor-substrate- (IRS-) 1 and IRS-2 were reduced. PIO coadministration prevented FRD effects on LEP, PAI-1, and IRS-2 (fully) and IRS-1 (partially) mRNAs in AAT. Conclusion. PPARgamma would play a relevant role in the development of the FRD-induced metabolic-endocrine dysfunction. PMID- 23091483 TI - Comparison of diagnostic accuracies of various endoscopic examination techniques for evaluating the invasion depth of colorectal tumors. AB - This study was designed to assess the clinical value of magnifying endoscopy combined with EUS for estimating the invasion depth of colorectal tumors. We studied 168 colorectal adenomas and carcinomas that were sequentially examined by conventional endoscopy followed by magnifying endoscopy and EUS in the same session to evaluate invasion depth. Endoscopic images obtained by each technique were reassessed by 3 endoscopists to determine whether endoscopic resection (adenoma, mucosal cancer, or submucosal cancer with slight invasion) or colectomy (submucosal cancer with massive invasion or advanced cancer) was indicated. The accuracy of differential diagnosis was compared among the examination techniques. The rate of correct differential diagnosis according to endoscopic examination technique was similar. The proportion of lesions that were difficult to diagnose was significantly higher for EUS (15.5%) than for conventional endoscopy and magnifying endoscopy. Among lesions that could be diagnosed, the rate of correct differential diagnosis was the highest for EUS (89.4%), but did not significantly differ among three endoscopic examination techniques. When it is difficult to evaluate the invasion depth of colorectal tumors on conventional endoscopy alone, the combined use of different examination techniques such as EUS may enhance diagnostic accuracy in some lesions. PMID- 23091484 TI - Effect of Aqueous Extract of Crocus sativus L. on Morphine-Induced Memory Impairment. AB - In the present study, the effect of aqueous extracts of saffron on morphine induced memory impairment was investigated. On the training trial, the mice received an electric shock when the animals were entered into the dark compartment. Twenty-four and forty-eight hours later, the time latency for entering the dark compartment was recorded and defined as the retention trial. The mice were divided into (1) control, (2) morphine which received morphine before the training in the passive avoidance test, (3-5) three groups treated by 50, 150 and 450 mg/kg of saffron extract before the training trial, and (6 and 7) the two other groups received 150 and 450 mg/kg of saffron extract before the retention trial. The time latency in morphine-treated group was lower than control (P < 0.01). Treatment of the animals by 150 and 450 mg/kg of saffron extract before the training trial increased the time latency at 24 and 48 hours after the training trial (P < 0.05 and P < 0.01). Administration of both 150 and 450 mg/kg doses of the extract before retention trials also increased the time latency (P < 0.01). The results revealed that the saffron extract attenuated morphine-induced memory impairment. PMID- 23091487 TI - CMD: A Database to Store the Bonding States of Cysteine Motifs with Secondary Structures. AB - Computational approaches to the disulphide bonding state and its connectivity pattern prediction are based on various descriptors. One descriptor is the amino acid sequence motifs flanking the cysteine residue motifs. Despite the existence of disulphide bonding information in many databases and applications, there is no complete reference and motif query available at the moment. Cysteine motif database (CMD) is the first online resource that stores all cysteine residues, their flanking motifs with their secondary structure, and propensity values assignment derived from the laboratory data. We extracted more than 3 million cysteine motifs from PDB and UniProt data, annotated with secondary structure assignment, propensity value assignment, and frequency of occurrence and coefficiency of their bonding status. Removal of redundancies generated 15875 unique flanking motifs that are always bonded and 41577 unique patterns that are always nonbonded. Queries are based on the protein ID, FASTA sequence, sequence motif, and secondary structure individually or in batch format using the provided APIs that allow remote users to query our database via third party software and/or high throughput screening/querying. The CMD offers extensive information about the bonded, free cysteine residues, and their motifs that allows in-depth characterization of the sequence motif composition. PMID- 23091486 TI - Cardiac autonomic control mechanisms in the pathogenesis of chagas' heart disease. AB - Primary abnormalities of the autonomic nervous system had been postulated as the pathogenic mechanisms of myocardial damage, in patients with Chagas disease. However, recent investigations indicate that these abnormalities are secondary and amenable to treatment with beta-adrenergic blockers. Moreover, muscarinic cardiac autoantibodies appear to enhance parasympathetic activity on the sinus node. Therefore, the purpose of this paper is to analyze how knowledge on Chagas' disease evolved from being initially considered as a primary cardioneuromyopathy to the current status of a congestive cardiomyopathy of parasitic origin. PMID- 23091488 TI - Comment on "influence of orotate phosphoribosyl transferase levels on tumor prognosis and response to chemotherapy". PMID- 23091485 TI - Epidemiology of Rhodotorula: an emerging pathogen. AB - This is an updated paper focusing on the general epidemiological aspects of Rhodotorula in humans, animals, and the environment. Previously considered nonpathogenic, Rhodotorula species have emerged as opportunistic pathogens that have the ability to colonise and infect susceptible patients. Rhodotorula species are ubiquitous saprophytic yeasts that can be recovered from many environmental sources. Several authors describe the isolation of this fungus from different ecosystems, including sites with unfavourable conditions. Compared to R. mucilaginosa, R. glutinis and R. minuta are less frequently isolated from natural environments. Among the few references to the pathogenicity of Rhodotorula spp. in animals, there are several reports of an outbreak of skin infections in chickens and sea animals and lung infections and otitis in sheep and cattle. Most of the cases of infection due to Rhodotorula in humans were fungemia associated with central venous catheter (CVC) use. The most common underlying diseases included solid and haematologic malignancies in patients who were receiving corticosteroids and cytotoxic drugs, the presence of CVC, and the use of broad spectrum antibiotics. Unlike fungemia, some of the other localised infections caused by Rhodotorula, including meningeal, skin, ocular, peritoneal, and prosthetic joint infections, are not necessarily linked to the use of CVCs or immunosuppression. PMID- 23091489 TI - Long-term survival in young women: hazards and competing risks after thyroid cancer. AB - Background. Differentiated thyroid cancers (DTCs) are one of the most common and survivable cancers diagnosed in women. We examine factors associated with long term survival and competing risks of death in women diagnosed with DTC under the age of 40 (<40) and aged 40 and older (40+). Methods. SEER data was used to identify DTCs diagnosed in women from 1975 to 2009. We examined overall (OS), disease-specific (DSS), other cancer (OCS), and non-cancer-related (NCS) survival using multivariate Cox proportional hazards modeling. Results. Observed survival was 97.2% for <40 (n = 14,540) and 82.5% for 40+ (n = 20,513). Distant stage (HR = 1.96, 95% CI 1.23-3.07), non-Hispanic Black (HR = 2.04, 95% CI 1.45-2.87), being unmarried (HR = 1.26, 95% 1.03-1.54), and subsequent primary cancers (HR = 4.63, 95% CI 3.76-5.71) were significant for OS in women <40. Age was an effect modifier for all survival outcomes. Racial disparities in NCS were most pronounced for young non-Hispanic black women (HR = 3.36, 95% CI 2.17-5.22). Women in both age groups were more likely to die from other causes. Conclusions. Age at diagnosis remains one of the strongest prognostic factors for thyroid cancer survival. More directed efforts to ensure effective care for comorbid conditions are needed to reduce mortality from other causes. PMID- 23091491 TI - Er:YAG Laser and Fractured Incisor Restorations: An In Vitro Study. AB - Introduction. The aim of this study was to analyse the effects of an Er:YAG laser on enamel and dentine in cases of dental restorations involving fractured teeth, utilizing the dental fragment. Materials and Methods. Seventy-two freshly extracted bovine incisors were fractured at the coronal level by using a hammer applied with a standardized method, and the fragment was reattached by using three different methods: Er:YAG laser, orthophosphoric acid, and laser plus acid. The different groups were evaluated by a test realized with the dynamometer to know the force required to successfully detach the reattached fragment and by a microinfiltration test by using a 0.5% methylene blue solution followed by the optic microscope observation. Results. The compression test showed only a slight difference between the three groups, without any statistical significance. The infiltration test used to evaluate the marginal seal between the fracture fragment and the tooth demonstrated that etching with Er:YAG laser alone or in combination with orthophosphoric acid gives better results than orthophosphoric acid alone, with a highly significant statistical result. Discussion. Reattaching a tooth fragment represents a clinically proven methodology, in terms of achieving resistance to detachment, and the aim of this work was to demonstrate the advantages of Er:YAG laser on this procedure. Conclusion. This "in vitro" study confirms that Er:YAG laser can be employed in dental traumatology to restore frontal teeth after coronal fracture. PMID- 23091490 TI - Dental approach to craniofacial syndromes: how can developmental fields show us a new way to understand pathogenesis? AB - The paper consists of three parts. Part 1: Definition of Syndromes. Focus is given to craniofacial syndromes in which abnormal traits in the dentition are associated symptoms. In the last decade, research has concentrated on phenotype, genotype, growth, development, function, and treatment. Part 2: Syndromes before Birth. How can the initial malformation sites in these syndromes be studied and what can we learn from it? In this section, deviations observed in syndromes prenatally will be highlighted and compared to the normal human embryological craniofacial development. Specific focus will be given to developmental fields studied on animal tissue and transferred to human cranial development. Part 3: Developmental Fields Affected in Two Craniofacial Syndromes. Analysis of primary and permanent dentitions can determine whether a syndrome affects a single craniofacial field or several fields. This distinction is essential for insight into craniofacial syndromes. The dentition, thus, becomes central in diagnostics and evaluation of the pathogenesis. Developmental fields can explore and advance the concept of dental approaches to craniofacial syndromes. Discussion. As deviations in teeth persist and do not reorganize during growth and development, the dentition is considered useful for distinguishing between syndrome pathogenesis manifested in a single developmental field and in several fields. PMID- 23091492 TI - Peri-implant crestal bone loss: a putative mechanism. AB - Purpose. The immunological mechanisms of peri-implant crestal bone loss have, hitherto, not been elucidated. We hypothesized that bacterial products from the microgap cause upregulation of cytokines in otherwise healthy peri-implant cells, which results in osteoclast formation and, ultimately, in bone resorption. Materials and Methods. We used RT-PCR and ELISA to assay mediators of osteoclastogenesis in rat and human macrophages (r-and hMO); bone marrow derived stromal cells (r-and hBMCs); and human gingival fibroblasts (hGF)-with or without stimulation by LPS. TRAP positive multinucleate cells were assessed for their resorptive ability. Results. We show that IL-1alpha, IL-1beta, and IL-6 were expressed by all examined cell types, and TNF-alpha was upregulated in hGF. Secretion of IL-1alpha and IL-1beta proteins was stimulated in hMO by LPS, and IL 6 protein secretion was highly stimulated in hBMCs and hGF. Both LPS and RANKL stimulated macrophages to form osteoclast-like TRAP positive cells, which resorbed calcium phosphate substrates. Conclusion. Taken together, the results of our study support the hypothesis that bacterial endotoxins upregulate enhanced mediators of osteoclastogenesis in resident cells found in the healthy peri implant compartment and that the local synergistic action of cytokines secreted by such cells results in the genesis of resorptively active osteoclasts. PMID- 23091493 TI - Dimensional Ridge Preservation with a Novel Highly Porous TiO(2) Scaffold: An Experimental Study in Minipigs. AB - Despite being considered noncritical size defects, extraction sockets often require the use of bone grafts or bone graft substitutes in order to facilitate a stable implant site with an aesthetically pleasing mucosal architecture and prosthetic reconstruction. In the present study, the effect of novel TiO(2) scaffolds on dimensional ridge preservation was evaluated following their placement into surgically modified extraction sockets in the premolar region of minipig mandibles. After six weeks of healing, the scaffolds were wellintegrated in the alveolar bone, and the convex shape of the alveolar crest was preserved. The scaffolds were found to partially preserve the dimensions of the native buccal and lingual bone walls adjacent to the defect site. A tendency towards more pronounced vertical ridge resorption, particularly in the buccal bone wall of the nongrafted alveoli, indicates that the TiO(2) scaffold may be used for suppressing the loss of bone that normally follows tooth extraction. PMID- 23091494 TI - Microbial translocation and infectious diseases: what is the link? PMID- 23091495 TI - Processing load induced by informational masking is related to linguistic abilities. AB - It is often assumed that the benefit of hearing aids is not primarily reflected in better speech performance, but that it is reflected in less effortful listening in the aided than in the unaided condition. Before being able to assess such a hearing aid benefit the present study examined how processing load while listening to masked speech relates to inter-individual differences in cognitive abilities relevant for language processing. Pupil dilation was measured in thirty two normal hearing participants while listening to sentences masked by fluctuating noise or interfering speech at either 50% and 84% intelligibility. Additionally, working memory capacity, inhibition of irrelevant information, and written text reception was tested. Pupil responses were larger during interfering speech as compared to fluctuating noise. This effect was independent of intelligibility level. Regression analysis revealed that high working memory capacity, better inhibition, and better text reception were related to better speech reception thresholds. Apart from a positive relation to speech recognition, better inhibition and better text reception are also positively related to larger pupil dilation in the single-talker masker conditions. We conclude that better cognitive abilities not only relate to better speech perception, but also partly explain higher processing load in complex listening conditions. PMID- 23091496 TI - Acquired Umbilico-Inguinal Fistula with Persistent Discharge due to Suture Reaction: A Case Report and Review of the Literature. AB - The aim of this paper is to stay a very rare umbilico-inguinal fistula (UIF) resulting from a delayed suture reaction after the use of silk suture to repair an inguinal hernia. A 3-year-old boy presented with persistent umbilical discharge. The initial diagnosis was omphalitis and he was treated with broad spectrum antibiotics but a UIF was subsequently diagnosed. Surgery was performed to ascertain the cause of the UIF. This case demonstrates that silk suture used in inguinal hernia repair can lead to a UIF, which should be considered in the differential diagnosis of a patient presenting with persistent umbilical discharge. PMID- 23091497 TI - Bowel Obstruction due to Migration of an Intragastric Balloon Necessitating Surgical Removal before Completion of the Recommended 6 Months. AB - We report a 25-year-old man with small bowel obstruction due to migration of a saline-filled intragastric balloon before the completion of the recommended 6 months of treatment who presented to the emergency department with abdominal pain. The patient had received a gastric balloon insertion 5 months prior. Within 24 hours of the original procedure, he noticed urine staining. The results of an endoscopy conducted the next day were normal. After ruling out other possible complications using endoscopy and confirming the diagnosis by computed tomography (CT) scan and conservative treatment for 48 hours the patient underwent surgery and the balloon was extracted. Due to the growing prevalence of obesity and the modalities used for treating it, physicians should be familiar with the side effects of each option and their presenting symptoms as well as the differential diagnosis they should not miss. Physicians must also improve their knowledge of how to approach these patients to avoid life-threatening complications caused by these modalities. PMID- 23091498 TI - Retrograde Instillation of Methylene Blue in the Difficult Diagnosis of BPF. AB - We report two cases in which we were able to diagnose bronchopleural fistula through retrograde methylene blue instillation during bronchoscopy. In the first case, methylene blue was injected through an abdominal drain, followed by air instillation and detected in the left bronchial tree, demonstrating the presence of a fistula in the lingula's bronchus. In the second case, methylene blue was injected into a pleural drain, through a breach on a surgical suture and detected in the right bronchial tree, demonstrating the presence of a fistula in the right inferior bronchus. The retrograde instillation of methylene blue, through a drain in the abdomen or the thoracic wall, is a safe, cheap, and practical method that allows the bronchoscopist to identify the presence of a fistula and, more importantly, to identify the exact point on the bronchial tree where a fistula is located. This provides the possibility of sealing the fistula with a variety of devices. It is our opinion that this procedure should be considered a primary method of diagnosis when a bronchopleural fistula is suspected and a drain on the thoracic or abdominal wall is positioned such that effusions are able to drain. PMID- 23091500 TI - Can we find better bronchodilators to relieve asthma symptoms? AB - Bronchodilators are the first line therapy during acute asthmatic exacerbations to reverse airway obstruction primarily by relaxing airway smooth muscle. Only three categories of bronchodilators exist in clinical practice: beta-adrenergic agonists, anticholinergics, and methylxanthines. Each of these categories have specific drugs dating back to the early 20th century, raising the question of whether or not we can find better bronchodilators. While caffeine, theophylline, atropine, and epinephrine were the first generations of therapeutics in each of these drug classes, there is no question that improvements have been made in the bronchodilators in each of these classes. In the following editorial, we will briefly describe new classes of potential bronchodilators including: novel PDE inhibitors, natural phytotherapeutics, bitter taste receptor ligands, and chloride channel modulators, which have the potential to be used alone or in combination with existing bronchodilators to reverse acute airway obstruction in the future. PMID- 23091499 TI - The potential for cellular therapy combined with growth factors in spinal cord injury. AB - Any traumatic spinal cord injury (SCI) may cause symptoms ranging from pain to complete loss of motor and sensory functions below the level of the injury. Currently, there are over 2 million SCI patients worldwide. The cost of their necessary continuing care creates a burden for the patient, their families, and society. Presently, few SCI treatments are available and none have facilitated neural regeneration and/or significant functional improvement. Research is being conducted in the following areas: pathophysiology, cellular therapies (Schwann cells, embryonic stem cells, induced pluripotent stem cells, mesenchymal stem cells, olfactory ensheathing cells), growth factors (BDNF), inhibitory molecules (NG2, myelin protein), and combination therapies (cell grafts and neurotrophins, cotransplantation). Results are often limited because of the inhibitory environment created following the injury and the limited regenerative potential of the central nervous system. Therapies that show promise in small animal models may not transfer to nonhuman primates and humans. None of the research has resulted in remarkable improvement, but many areas show promise. Studies have suggested that a combination of therapies may enhance results and may be more effective than a single therapy. This paper reviews and discusses the most promising new SCI research including combination therapies. PMID- 23091502 TI - Anti-inflammatory effects of statins beyond cholesterol lowering. PMID- 23091501 TI - Personalized medicine in cardiovascular diseases. AB - Personalized medicine is a novel medical model with all decisions and practices being tailored to individual patients in whatever ways possible. In the era of genomics, personalized medicine combines the genetic information for additional benefit in preventive and therapeutic strategies. Personalized medicine may allow the physician to provide a better therapy for patients in terms of efficiency, safety and treatment length to reduce the associated costs. There was a remarkable growth in scientific publication on personalized medicine within the past few years in the cardiovascular field. However, so far, only very few cardiologists in the USA are incorporating personalized medicine into clinical treatment. We review the concepts, strengths, limitations and challenges of personalized medicine with a particular focus on cardiovascular diseases (CVDs). There are many challenges from both scientific and policy perspectives to personalized medicine, which can overcome them by comprehensive concept and understanding, clinical application, and evidence based practices. Individualized medicine serves a pivotal role in the evolution of national and global healthcare reform, especially, in the CVDs fields. Ultimately, personalized medicine will affect the entire landscape of health care system in the near future. PMID- 23091503 TI - The effect of doubling the statin dose on pro-inflammatory cytokine in patients with triple-vessel coronary artery disease. AB - BACKGROUND AND OBJECTIVES: Statin prevents atherosclerotic progression and helps to stabilize the plaque. According to a recent study, statin reduces inflammation in blood vessels. However, it has not been demonstrated to have any anti inflammation reaction in patients who have been diagnosed as having a triple vessel coronary artery disease (CAD). SUBJECTS AND METHODS: This study included a total of thirty (30) patients who had been diagnosed by coronary angiogram as having a triple-vessel CAD. Patients who already had been taking statin were given doubled dosage. An interview, physical examination and blood test were performed at the beginning of this study and three months later. RESULTS: After doubling the dose of statin, there was no statistically significant decrease in total cholesterol, low density lipoprotein-cholesterol, (increase in) high density lipoprotein-cholesterol and triglyceride in the blood test. C-reactive protein (CRP), an acute phase reactant, significantly decreased from 0.34 mg/dL at the beginning of the study to 0.12 mg/dL at the end of study (p<0.01). The interleukin-6 concentration also significantly decreased from 8.55 pg/dL to 4.81 pg/dL (p<0.001). No major cardiovascular events occurred and the dosage regimen was not modified during the close observation period. There was no difference in the symptoms of angina pectoris, established by World Health Organization Angina Questionnaires, before and after the dose increase. Liver enzymes remained within normal range with no significant increase before and after conducting this study. CONCLUSION: Doubling the dose of statin alone significantly lowers pro inflammatory cytokine concentration, which is closely related to the potential acute coronary syndrome, and CRP, a marker of vascular inflammation. PMID- 23091504 TI - Cardiodynamics and infarct size in regional and global ischemic isolated heart model: comparison of 1 hour and 2 hours reperfusion. AB - BACKGROUND AND OBJECTIVES: We investigated whether 1 hour reperfusion is enough to assess cardiodynamics and infarct size in both regional ischemia (RI) and global ischemia (GI) in isolated rat heart models. MATERIALS AND METHODS: Hearts were randomly assigned to one of the following groups (each n=14): 1) Sham hearts for 1 hour; 2) Sham hearts for 2 hours; 3) 30 minutes RI followed by 1 hour reperfusion; 4) 30 minutes of RI followed by 2 hours reperfusion; 5) 30 minutes GI followed by 1 hour reperfusion; and 6) 30 minutes GI followed by 2 hours reperfusion. RESULTS: There were no significant differences in infarct size between 1 hour and 2 hours reperfusion in both RI and GI. Left ventricular developed pressure was significantly decreased at both 1 hour and 2 hours reperfusion in groups of RI and GI compared to baseline (p<0.01). Rate-pressure product and +dP/dt(max) also significantly decreased compared to baseline level at both 1 hour and 2 hours reperfusion in groups of RI and GI (p<0.05). CONCLUSION: There was no significant difference in infarct size between 1 hour and 2 hours reperfusion in groups of RI and GI. Cardiodynamic variables measured at 1 hour and 2 hours reperfusion significantly decreased compared to baseline level. Our data suggests that reperfusion of 1 hour is sufficient to assess cardiodynamics in both regional and global ischemic isolated hearts model. PMID- 23091505 TI - A comparison of cornell and sokolow-lyon electrocardiographic criteria for left ventricular hypertrophy in korean patients. AB - BACKGROUND AND OBJECTIVES: Electrocardiography (ECG) is a cost-effective and useful method for diagnosing left ventricular hypertrophy (LVH) in a large-scale study or in clinical practice. Among ECG criteria, the Cornell product (Cor P) and Sokolow-Lyon criteria were adopted by the European Society of Hypertension European Society of Cardiology Guidelines but have different performances among races. The aim of this study was to compare the diagnostic performance of two voltage criteria in Korean patients. SUBJECTS AND METHODS: Electrocardiography and echocardiographic LV mass of 332 (159 male, 173 female) consecutive patients were analyzed. Cornell voltage criteria and the Cor P were compared with Sokolow Lyon voltage (Sok V) and the Sokolow-Lyon product (Sok P). The sensitivities and specificities were estimated using a receiver-operating characteristics (ROC) curve in relation to the LVH diagnosis. The sensitivities and revised cut-off values were derived at specificity levels of 90, 95, and 100%. RESULTS: The Cornell-based criteria generally showed better performance than that of the Sok V criteria and Sok P in the area under the ROC curve analysis. The revised cut-off values for the Cornell voltage criteria (20 and 16 mm for males and females, respectively) showed an improved sensitivity (19.7 and 30.3% for males and females, respectively), with a high specificity of 95%. CONCLUSION: The Cornell based criteria had better performance than that of the Sokolow-Lyon criteria in both Korean men and women. However, revised cut-off values are needed to improve accuracy. PMID- 23091506 TI - Urinary levels of 8-iso-prostaglandin f2alpha and 8-hydroxydeoxyguanine as markers of oxidative stress in patients with coronary artery disease. AB - BACKGROUND AND OBJECTIVES: The objective of this study was to determine if urinary levels of 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha) and 8 hydroxydeoxyguanine (8-OHdG) could be used as markers of the oxidative stress in significant coronary artery disease (CAD). SUBJECTS AND METHODS: We conducted a case-control study in 104 subjects assessed by coronary angiography with the following diagnoses: 35 consecutive cases of significant CAD and 69 cases of non CAD with stable angina. We compared the urinary levels of 8-iso-PGF 2alpha and 8 OHdG, as measured by immunoassay between the 2 groups. RESULTS: History of hypertension was significantly higher and high density lipoprotein-cholesterol level significantly lower in the CAD group compared with those in the non-CAD group. Median levels of 8-iso-PGF2alpha were significantly higher in the CAD group compared with the non-CAD group (9.2 vs. 6.0 ng/mg, p=0.001). There were no significant differences in 8-OHdG values between the 2 groups. The odds ratio of 8-iso-PGF2alpha for CAD in the highest tertile compared with that in the lowest tertile was 7.39 (95% confidence interval; 1.71-31.91). There was no significant difference in median values of 8-iso-PGF2alpha between single- and multi-vessel CAD. CONCLUSION: Urinary 8-iso-PGF 2alpha was independently associated with significant CAD in this case-control study. PMID- 23091507 TI - Relation Between RR Intervals and Early Diastolic Mitral Annular Velocities in Atrial Fibrillation. AB - BACKGROUND AND OBJECTIVES: Irregular RR intervals in atrial fibrillation (AF) make beat-to-beat changes in left ventricular (LV) systolic performance. Early diastolic mitral annular velocity (E') is one of the well-established parameters for evaluating LV diastolic function. The relation between RR intervals and E's is unknown. The aim of this study was to observe the influence of continuous changes in RR interval on the parameter for diastolic function in AF. SUBJECTS AND METHODS: Echocardiography was performed in 117 patients with AF. E' was adjusted for the effect of pre-preceding RR interval (RR-2) using the logarithmic equation between RR-2 and E'. The logarithmic equation between adjusted E' and preceding RR interval (RR-1) was calculated. RESULTS: The slope in the relation between RR-1 and E' varied from -2.5 to 2.6. The slope was lower (more likely negative) in patients with higher ratio of early diastolic mitral flow velocity (E) to E' (r=-0.21, p=0.023), ischemic heart disease (IHD, r=0.21, p=0.026), and higher systolic blood pressure (r=-0.19, p=0.046). When patients were divided into these 3 groups on the basis of slope, the lowest slope group (<-0.55, n=39) was associated with higher E'/E (p=0.004) and IHD (p=0.018) compared with the highest slope group (>0.57, n=39). The slope with regards to the relationship between RR-2 and E' also varied from -3.4 to 3.1. CONCLUSION: Changes in RR intervals had variable effects on E's according to clinical variables in AF. PMID- 23091508 TI - Reverse controlled antegrade and retrograde subintimal tracking in chronic total occlusion of right coronary artery. AB - Passage failure of guidewire is still remained most common reason for percutaneous coronary intervention (PCI) failure in chronic total occlusion (CTO). Intravascular ultrasound study (IVUS) and cardiac CT angiography can help identify features that most influence current success rates of PCI. We report our experience using the reverse controlled antegrade and retrograde subintimal tracking technique under the aid of IVUS, cardiac CT angiography for an ambiguous CTO of proximal right coronary artery. PMID- 23091509 TI - A case of aortic dissection with fistula from aorta to right ventricle. AB - Aorto-right ventricular fistula is a very rare complication of aortic dissection. We report a case of acute aortic dissection extending into the right ventricle as documented by echocardiography. The patient survived after successful surgical repair. PMID- 23091510 TI - Catheter Ablation of Ventricular Arrhythmias via the Radial Artery in a Patient With Prior Myocardial Infarction and Peripheral Vascular Disease. AB - Herein, we present a case of a successful catheter ablation of ventricular tachycardia (VT) using a radial artery approach in a post-myocardial infarction patient, who had an implantable cardioverter-defibrillator and peripheral artery disease. Although the patient did not use antiarrhythmic drugs, the patient experienced no recurrence of VT during the following 3-year period. PMID- 23091511 TI - Placement of Endovascular Stent Graft in Acute Malperfusion Syndrome After Acute Type II Aortic Dissection. AB - Acute malperfusion syndrome is a serious complication of acute aortic dissection. A 76-year-old female patient was admitted with acute type B aortic dissection and developed renal malperfusion during medical therapy. We are reporting a clinically successful result from the thoracic endovascular aortic repair used for malperfusion syndrome that occurred by acute type B aortic dissection. PMID- 23091512 TI - Acute myocardial infarction in a young man; fatal blow of the marijuana: a case report. AB - Marijuana is known to have been used for medicinal and recreational purposes for thousands of years. Although marijuana has some diverse effects on cardiovascular system, there is insufficient knowledge concerning acute myocardial infarction (AMI) associated with marijuana and its underlying mechanism. We report the case of a 26 year-old young man suffering from ST-elevated AMI caused by marijuana abuse, which was successfully treating with percutaneous coronary intervention. It should be kept in mind that marijuana could be one of the most probable causes of AMI observed in apparently healthy young persons who use this drug. PMID- 23091513 TI - Acute Stent Thrombosis and Heparin Induced Thrombocytopenia in a Patient With ST Segment Elevation Myocardial Infarction. AB - Heparin is an essential drug in the treatment of acute coronary syndrome and it is used during percutaneous coronary intervention (PCI). Heparin-induced thrombocytopenia (HIT), albeit a serious complication of heparin therapy characterized by thrombocytopenia and high risk for venous and arterial thrombosis, has rarely been previously reported during PCI. We report a case of an acute stent thrombosis due to an unusual cause, HIT during primary PCI, in a patient with acute myocardial infarction. PMID- 23091514 TI - Heavy metal concentrations in hair of newly imported China-origin rhesus macaques (Macaca mulatta). AB - Macaque monkeys are good sentinel to humans for environmental pollutions because their similarities in genetic and physiological characteristics. So, their reference values about exposures to heavy metals are required for proper data interpretation. Here, we report several heavy metals concentrations in the hair of rhesus monkeys which are widely used in biomedical research. The hair of 28 imported rhesus monkeys from an animal farm in southwest China were examined for the presence of eight heavy metals (Arsenic, Beryllium, Cadmium, Chromium, Iron, Lead, Mercury, and Selenium). The analyzed data in parts per million (ppm) for hair concentrations of heavy metals in rhesus monkeys were as follow: As (0.654+/ 0.331), Be (0.005+/-0.003), Cd (0.034+/-0.022), Cr (11.329+/-4.259), Fe (87.106+/ 30.114), Pb (0.656+/-0.613), Hg (0.916+/-0.619), and Se (3.200+/-0.735). The concentrations of Be, Cr, and As showed significant higher in females than in males (P<0.05). We present here the reference values of several heavy metals in healthy China-origin rhesus monkeys. These data may provide valuable information for veterinarians and investigators using rhesus monkeys in experimental studies. PMID- 23091515 TI - Effects of Red Liriope platyphylla on NGF secretion ability, NGF receptor signaling pathway and gamma-secretase components in NSE/hAPPsw transgenic mice expressing Alzheimer's Disease. AB - Liriope platyphylla (LP) has long been regarded as a curative herb for the treatment of diabetes, asthma, and neurodegenerative disorders. To examine the therapeutic effects of Red LP (RLP) manufactured by steaming process on neurodegenerative disorders, significant alteration of the key factors influencing Alzheimer's Disease (AD) was detected in NSE/hAPPsw transgenic (Tg) mice after RLP treatment. The concentration of nerve growth factor (NGF) in serum increased in RLP-treated NSE/hAPPsw Tg mice compared with vehicle-treated Tg mice. However, downstream effectors of the NGF receptor signaling pathway, including TrkA and p75(NTR) proteins, were suppressed in RLP-treated NSE/hAPPsw Tg mice. Especially, Tg mice showed decreased levels of TrkA, p75(NTR), and RhoA expression. Production of Abeta-42 peptides was lower in RLP-treated NSE/hAPPsw Tg mice than in vehicle-treated Tg mice. Further, analysis of gamma-secretase components showed that Abeta-42 peptide expression was downregulated. Of the four components, the expression of APH-1 and Nicastrin (NCT) decreased in RLP-treated NSE/hAPPsw Tg mice, whereas expression of PS-2 and Pen-2 was maintained or increased within the same group. Overall, these results suggest that RLP can help relieve neurodegenerative diseases, especially AD, through upregulation of NGF secretion ability, activation of NGF signaling pathway, downregulation of Abeta 42 peptide deposition, and alteration of gamma-secretase components. PMID- 23091516 TI - Comparison of alpha-synuclein immunoreactivity in the spinal cord between the adult and aged beagle dog. AB - Alpha-synuclein (alpha-syn) is a presynaptic protein that is richly expressed in the central and peripheral nervous systems of mammals, and it is related to the pathogenesis of Parkinson's disease and other neurodegenerative disorders. In the present study, we compared the distribution of the immunoreactivity of alpha-syn and its related gliosis in the spinal cord of young adult (2-3 years) and aged (10-12 years) beagle dogs. We discovered that alpha-syn immunoreactivity was present in many neurons in the thoracic level of the aged spinal cord, however, its protein level was not distinct inform that of the adult spinal cord. In addition, ionized calcium-binding adapter molecule-1 (a marker for microglia) immunoreactivity, and not glial fibrillary acidic protein (a marker for astrocytes) immunoreactivity, was somewhat increased in the aged group compared to the adult group. These results indicate that alpha-syn immunoreactivity was not dramatically changed in the dog spinal cord during aging. PMID- 23091517 TI - Prophylactic effects of swimming exercise on autophagy-induced muscle atrophy in diabetic rats. AB - Diabetes decreases skeletal muscle mass and induces atrophy. However, the mechanisms by which hyperglycemia and insulin deficiency modify muscle mass are not well defined. In this study, we evaluated the effects of swimming exercise on muscle mass and intracellular protein degradation in diabetic rats, and proposed that autophagy inhibition induced by swimming exercise serves as a hypercatabolic mechanism in the skeletal muscles of diabetic rats, supporting a notion that swimming exercise could efficiently reverse the reduced skeletal muscle mass caused by diabetes. Adult male Sprague-Dawley rats were injected intraperitoneally with streptozotocin (60 mg/kg body weight) to induce diabetes and then submitted to 1 hr per day of forced swimming exercise, 5 days per week for 4 weeks. We conducted an intraperitoneal glucose tolerance test on the animals and measured body weight, skeletal muscle mass, and protein degradation and examined the level of autophagy in the isolated extensor digitorum longus, plantaris, and soleus muscles. Body weight and muscle tissue mass were higher in the exercising diabetic rats than in control diabetic rats that remained sedentary. Compared to control rats, exercising diabetic rats had lower blood glucose levels, increased intracellular contractile protein expression, and decreased autophagic protein expression. We conclude that swimming exercise improves muscle mass in diabetes-induced skeletal muscle atrophy, suggesting the activation of autophagy in diabetes contributes to muscle atrophy through hypercatabolic metabolism and that aerobic exercise, by suppressing autophagy, may modify or reverse skeletal muscle wasting in diabetic patients. PMID- 23091519 TI - Anticoccidial effects of Galla rhois extract on Eimeria tenella-infected chicken. AB - Anticoccidial effects of Galla rhois (GR) extract were evaluated in chickens after oral infection with Eimeria tenella. This study was performed using 3-day old chickens (n=30). The animals were divided into 3 groups as follows: GR 0.5%/infected (n=10), untreated/infected (n=10), and non-infected control (n=10). The chickens were fed a standard diet supplemented with or without GR for 1 week before infection with E. tenella (10,000 sporulated oocysts per chicken). The effects of GR on E. tenella infection were assessed by 2 parameters, number of fecal oocysts and body weight gain, and the results of the polymerase chain reaction (PCR). The GR-fed chickens produced significantly lower number of fecal oocysts (P<0.05) than the E. tenella-infected chickens who were fed the standard diet. In addition, GR-based diet improved the loss of body weight caused by E. tenella infection. Positive findings of PCR were identified by distinct bands in the samples of E. tenella-inoculated chickens. However, PCR analysis revealed no E. tenella oocysts in the feces of GR-fed chickens. Our data showed that GR extracts had remarkable anticoccidial activities against E. tenella. This finding might have implications for the development of novel anticoccidial drugs. PMID- 23091518 TI - Aqueous extract of Liriope platyphylla, a traditional Chinese medicine, significantly inhibits abdominal fat accumulation and improves glucose regulation in OLETF type II diabetes model rats. AB - Liriope platyphylla is a medical herb that has long been used in Korea and China to treat cough, sputum, neurodegenerative disorders, obesity, and diabetes. The aims of this study were to determine the antidiabetic and antiobesity effects of aqueous extract of L. platyphylla (AEtLP) through glucose and lipid regulation in both pre-diabetes and obesity stage of type II diabetes model. Two concentrations of AEtLP were orally administrated to OLETF (Otsuka Long-Evans Tokushima Fatty) rats once a day for 2 weeks, after which changes in glucose metabolism and fat accumulation were measured. Abdominal fat mass dramatically decreased in AEtLP treated OLETF rats, whereas glucose concentration slightly decreased in all AEtLP treated rats. However, compared to vehicle-treated OLETF rats, only AEtLP10 (10% concentration)-treated OLETF rats displayed significant induction of insulin production, whereas AEtLP5 (5% concentration)-treated OLETF rats showed a lower level of insulin. Although serum adiponectin level increased in only AEtLP5 treated rats, significant alteration of lipid concentration was detected in AEtLP5-treated OLETF rats. Expression of Glut-1 decreased in all AEtLP-treated rats, whereas Akt phosphorylation increased only in AEtLP10-treated OLETF rats. Furthermore, the pattern of Glut-3 expression was very similar with that of Glut 1 expression, which roughly corresponded with the phosphorylation of c-Jun N teminal kinase (JNK) and p38 in the mitogen-activated protein kinase pathway. Therefore, these findings suggest that AEtLP should be considered as a therapeutic candidate during pre-diabetes and obesity stage capable of inducing insulin secretion from pancreatic beta-cells, glucose uptake in liver cells, as well as a decrease in fat and lipid accumulation. PMID- 23091520 TI - Gingko biloba extract (EGb 761) attenuates ischemic brain injury-induced reduction in Ca(2+) sensor protein hippocalcin. AB - Gingko biloba extract 761 (EGb 761) protects neuronal cells from ischemic brain injury via a number of neuroprotective mechanisms. Hippocalcin is a calcium sensor protein that regulates intracellular calcium concentrations and apoptotic cell death. We investigated whether EGb 761 regulates hippocalcin expression in cerebral ischemia. Male Sprague-Dawley rats were treated with vehicle or EGb 761 (100 mg/kg) prior to middle cerebral artery occlusion (MCAO), and cerebral cortex tissues were collected 24 h after MCAO. A proteomic approach demonstrated reduction in hippocalcin expression in vehicle-treated animals during MCAO, whereas EGb 761 treatment prevented injury-induced decreases in hippocalcin expression. RT-PCR and Western blot analyses indicated that EGb 761 attenuates injury-induced decrease in hippocalcin. These results suggest that the maintenance of hippocalcin during cerebral ischemia contributes to the neuroprotective role of EGb 761. PMID- 23091521 TI - Development of a type II diabetic mellitus animal model using Micropig(r). AB - Diabetes, which has shown an explosive increase in terms of its incidence, is regarded as a serious disease that must be overcome for the sake of human life. Among animal models used for testing of drug efficacy, the mini-pig model has shown a rapid upload due to its many similarities with human, particularly concerning the pharmacokinetics of compounds after subcutaneous administration, the structure and function of the gastrointestinal tract, the morphology of the pancreas, and overall metabolic status. Based on these various advantages, we sought to develop an animal model of type II diabetic mellitus using the Micro pig, which differs from other miniature pigs. We used six male Micro-pigs for induction of a moderate insulin deficient model with nicotinamide (NIA)/streptozotocin (STZ) treatment and three animals for control. For evaluation of incidence of type II diabetes, we measured blood glucose level, and performed oral glucose tolerance test and immunohistochemistry on pancreatic tissue using insulin antibody. Compared to control animals, all animals treated with NIA/STZ showed high levels of glucose and low levels of insulin. In addition, we observed the partially destroyed beta cell population from tissue of the pancreas in treated animals. Based on these results, we report that the Micro pig model developed in this study can be used for testing of the efficacy of therapeutic agents for treatment of Type 2 diabetic mellitus. PMID- 23091522 TI - Evaluating the effects of pentoxifylline administration on experimental pressure sores in rats by biomechanical examinations. AB - This study used a biomechanical test to evaluate the effects of pentoxifylline administration on the wound healing process of an experimental pressure sore induced in rats. Under general anesthesia and sterile conditions, experimental pressure sores generated by no. 25 Halsted mosquito forceps were inflicted on 12 adult male rats. Pentoxifylline was injected intraperitoneally at a dose of 50 mg/kg daily from the day the pressure sore was generated, for a period of 20 days. At the end of 20 days, rats were sacrificed and skin samples extracted. Samples were biomechanically examined by a material testing instrument for maximum stress (N mm(2)), work up to maximum force (N), and elastic stiffness (N/mm). In the experimental group, maximum stress (2.05+/-0.15) and work up to maximum force (N/mm) (63.75+/-4.97) were significantly higher than the control group (1.3+/-0.27 and 43.3+/-14.96, P=0.002 and P=0.035, respectively). Pentoxifylline administration significantly accelerated the wound healing process in experimental rats with pressure sores, compared to that of the control group. PMID- 23091523 TI - Acute gastrointestinal dilation in laboratory rhesus monkeys in the Korea National Primate Research Center. AB - Acute gastrointestinal dilation is a medical condition in which the stomach and intestine become overstretched by excessive gas content. In laboratory monkeys, cases of bloating involving gastrointestinal dilation are rarely seen, and the cause thereof is not clearly defined. Two rhesus monkeys in the Korea National Primate Research Center were found to suffer from acute gastrointestinal dilation. One of the monkeys showed severe gastric bloating after recovering from general anesthesia with isoflurane, where after it died suddenly. During necropsy, severe congestion of the lung was observed. The other monkey showed gastrointestinal dilation and died after treatment. During necropsy, severe dilation of the large intestine was observed. Severe congestion was detected in small and large intestines. Histopathologically, erythrocytes were found to fill the alveoli and alveolar capillaries of the lung. In stomach, epithelial cells were found to be sloughed from the mucosal layer, and erythrocytes were found to fill the blood vessels of the submucosal and mucosal layers. In small and large intestines, epithelial cells were also found to be sloughed from the mucosal layer, and inflammatory cells were found to have infiltrated in the submucosa (only large intestine) and mucosa. Microbiologically, Enterococcus faecalis and the pathogenic Staphylococcus haemolyticus, which do not form gas in the gastrointestinal tract, were detected in the gastrointestinal contents of both monkeys. These results suggest that the cause of the acute gastrointestinal dilation in these monkeys was not infection by gas-forming bacteria, but rather multiple factors such as diet, anesthesia, and excessive water consumption. PMID- 23091525 TI - Transesophageal echocardiographic findings are independent and relevant predictors of ischemic stroke in patients with nonvalvular atrial fibrillation. AB - BACKGROUND AND PURPOSE: Not only clinical factors, including the CHADS(2) score, but also echocardiographic findings have been reported to be useful for predicting the risk of ischemic stroke in patients with nonvalvular atrial fibrillation (NVAF). However, it remains to be determined which of these factors might be more relevant for evaluation of the risk of stroke in each patient. METHODS: In 490 patients with NVAF who underwent transesophageal echocardiography (TEE), we examined the long-term incidence of ischemic stroke events (mean follow up time, 5.7+/-3.3 years). For each patient, the predictive values of gender, the CHADS(2) risk factors (congestive heart failure, hypertension, age >=75 years, diabetes mellitus, history of cerebral ischemia), the CHADS(2) score, and the findings on echocardiography, including TEE risk markers, were assessed. RESULTS: The ischemic stroke rate was significantly correlated with the CHADS(2) score (p<0.05). According to the results of univariate analyses, age >=75 years, history of cerebral ischemia, CHADS(2) score >=2, and presence of TEE risk were significantly correlated with the incidence of ischemic stroke. Cox proportional hazards regression analyses identified age >=75 years and presence of TEE risk as significant predictors of subsequent ischemic stroke events in patients with NVAF. As compared with that in persons below 75 years of age without TEE risk, the ischemic stroke rate was significantly higher in persons who were >=75 years of age with TEE risk (4.3 vs. 0.56%/year, adjusted hazard ratio=8.94, p<0.001). CONCLUSIONS: TEE findings might be more relevant predictors of ischemic stroke than the CHADS(2) score in patients with NVAF. The stroke risk was more than 8 fold higher in patients aged >=75 years with TEE risk. PMID- 23091524 TI - Incidence of thymoma in myasthenia gravis: a systematic review. AB - BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is usually comorbid with thymoma. More accurate estimates of the incidence thymoma in MG will help inform patients and their physicians, facilitate health policy discussions, provide etiologic clues, and optimize the management of MG. METHODS: We conducted a systematic review search of relevant English-language studies published between 1960 and 2012 using MEDLINE and Embase. We identified additional studies by reviewing the bibliographies of the retrieved articles and hand searched the main neurology journals. Only incidence studies and case series of unselected MG patients in which information about thymoma were included. RESULTS: Out of 2206 potentially relevant studies, 49 met the inclusion criteria. Although there was a considerable degree of heterogeneity, the pooled estimate of the incidence of thymoma in MG was 21% (95% confidence interval, 20-22%). The pooled incidence was significantly higher for surgery-based studies than for population- and hospital based studies. A large proportion of the reported thymomas were noninvasive. Furthermore, thymoma appears to occur significantly more frequently among male MG patients and those older than 40 years at the onset of MG. CONCLUSIONS: Thymoma is common in MG patients, but appears to be found more often in male MG patients and those older than 40 years at the onset of MG. Further research is needed to expand our understanding of these association conditions. PMID- 23091526 TI - Validity and reliability of a korean version of the national institutes of health stroke scale. AB - BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) is a clinical assessment tool that is widely used in clinical trials and practice to evaluate stroke-related neurological deficits. The aim of this study was to determine the validity and reliability of the Korean version of the NIHSS (K NIHSS) for evaluating Korean stroke patients. METHODS: The K-NIHSS was translated and adapted with regard to cultural and linguistic peculiarities. To examine its content validity, we quantified the Content Validity Index (CVI), which was rated by 11 stroke experts. The validity of the K-NIHSS was assessed by comparison with the Glasgow Coma Scale (GCS), the modified Rankin Scale (mRS), and the Barthel Index. The reliability of the K-NIHSS was evaluated using the unweighted kappa statistics for multiple raters and an intraclass correlation coefficient (ICC). RESULTS: The CVI of the K-NIHSS reached 0.91-1.00. The median K-NIHSS score at baseline was 3 (interquartile range, 2-7), and the mean+/-SD score was 6.0+/-6.6. The baseline K-NIHSS had a significantly negative correlation with the GCS at baseline and the Barthel Index after 90 days. The K-NIHSS also had a significantly positive correlation with the mRS after 90 days. Facial paresis and dysarthria had moderate interrater reliability (unweighted kappa, 0.41-0.60); kappa values were substantial to excellent (unweighted kappa, >0.60) for all the other items. The ICC for the overall K-NIHSS score was 0.998. The intrarater reliability was acceptable, with a median kappa range of 0.524-1.000. CONCLUSIONS: The K-NIHSS is a valid and reliable tool for assessing neurological deficits in Korean acute stroke patients. PMID- 23091527 TI - Anorectal manometric dysfunctions in newly diagnosed, early-stage Parkinson's disease. AB - BACKGROUND AND PURPOSE: Anorectal dysmotility is common in advanced Parkinson's disease (PD), but there have been few evaluations in newly diagnosed PD patients. METHODS: We conducted anorectal manometric evaluations in 19 newly diagnosed, drug-naive, early-stage PD patients. All of the PD patients were questioned regarding the presence of anorectal symptoms. RESULTS: Anorectal manometry was abnormal in 12 of the 19 patients. These abnormalities were more common in patients with more severe anorectal symptoms, as measured using a self-reported scale. However, more than 40% of patients with no or minimal symptoms also exhibited manometric abnormalities. CONCLUSIONS: These results suggest that anorectal dysmotility manifests in many early-stage PD patients, which this represent evidence for the involvement of neuronal structures in such nonmotor manifestations in PD. PMID- 23091528 TI - The effect of cognitive training in patients with mild cognitive impairment and early Alzheimer's disease: a preliminary study. AB - BACKGROUND AND PURPOSE: The objective of this study was to determine the benefits of cognitive training in patients with amnestic mild cognitive impairment (aMCI) and those with early Alzheimer's disease (AD). METHODS: Eleven patients with aMCI and nine with early AD (stage 4 on the Global Deterioration Scale) participated in this study. Six participants with aMCI and six with AD were allocated to the cognitive training group, while five participants with aMCI and three with AD were allocated to a wait-list control group. Multicomponent cognitive training was administered in 18 weekly, individual sessions. Outcome measures were undertaken at baseline, and at 2 weeks and 3 months of follow-up. RESULTS: In the trained MCI group, there were significant improvements in the delayed-recall scores on the Seoul Verbal Learning Test at both the 2-week and 3-month follow ups compared with baseline (baseline, 1.6+/-1.5; 2 weeks, 4.4+/-1.5, p=0.04; 3 months, 4.6+/-2.3, p=0.04). The phonemic fluency scores (1.0+/-0.8 vs. 5.0+/-1.8, p=0.07) and Korean Mini-Mental State Examination scores (18.8+/-0.5 vs. 23.8+/ 2.2, p=0.07) also showed a tendency toward improvement at the 2-week follow-up compared to baseline in the trained AD group. CONCLUSIONS: This study provides evidence of the effectiveness of cognitive training in aMCI and early AD. The efficacy of cognitive training programs remains to be verified in studies with larger samples and a randomized design. PMID- 23091529 TI - Differences in Clinical Features and Disability according to the Frequency of Medication Use in Patients with Chronic Migraine. AB - BACKGROUND AND PURPOSE: Chronic migraine (CM) has a significant impact on daily activities, and analgesic overuse is a major contributing factor to migraine transformation. Limited information is available on the functional consequences of CM stemming from analgesic overuse. This study evaluated the impact of the frequency of analgesic medication use on headache-related disability and clinical features in patients with CM. METHODS: PATIENTS WITH CM WERE ENROLLED CONSECUTIVELY AND CLASSIFIED INTO TWO GROUPS ACCORDING TO THEIR FREQUENCY OF MEDICATION USE: <15 days/month (CM-ML, n=52) and >=15 days/month (CM-MH, n=68). All patients completed a structured questionnaire concerning the clinical features of their migraine, a validated version of the Migraine Disability Assessment questionnaire (MIDAS), and the Headache Impact Test-6 (HIT-6). RESULTS: The pain intensity, as measured by a visual analog scale, was greater in the CM-MH group than in the CM-ML group (8.5+/-0.2 vs. 7.7+/-0.3, mean+/-SD; p<0.05). In the disability domain, the MIDAS scores were significantly higher for CM-MH patients than for CM-ML patients (47.6+/-4.8 vs. 26.8+/-4.5, p<0.01). The impact from migraine, as measured by the HIT-6, was greater for CM-MH patients than for CM-ML patients (65.6+/-1.0 vs. 62.1+/-1.0, p<0.05). CONCLUSIONS: Our results indicate that the headache pain intensity and disability are greater in patients with CM who use medication frequently. PMID- 23091530 TI - Prevalence and impact of migraine and tension-type headache in Korea. AB - BACKGROUND AND PURPOSE: The epidemiology and impact of headache disorders are only partially documented for Asian countries. We investigated the prevalence and impact of migraine and tension-type headache - which are the two most common primary headache disorders - in a Korean population. METHODS: A stratified random population sample of Koreans older than 19 years was selected and evaluated using a 29-item, semistructured interview. The questionnaire was designed to classify headache types according to the criteria of the International Classification of Headache Disorders, second edition, including migraine and tension-type headache. The questionnaire also included items on basic demographics such as age, gender, geographical region, education level, and income, and the impact of headache on the participant. RESULTS: Among the 1507 participants, the 1-year prevalence of all types of headaches was 61.4% (69.9% in women and 52.8% in men). The overall prevalence rates of migraine and tension-type headaches were 6.1% (9.2% in women and 2.9% in men) and 30.8% (29.3% in women and 32.2% in men), respectively. The prevalence of migraine peaked at the age of 40-49 years in women and 19-29 years in men. In contrast to migraine, the prevalence of tension-type headache was not influenced by either age or gender. Among individuals with migraine and tension type headache, 31.5% and 7% reported being substantially or severely impacted by headache, respectively (Headache Impact Test score >=56). Overall, 13.4% of all headache sufferers reported being either substantially or severely impacted by headache. CONCLUSIONS: The 1-year prevalence rates of migraine and tension-type headache in the studied Korean population were 6.1% and 30.8%, respectively. One third of migraineurs and some individuals with tension-type headache reported being either substantially or severely impacted by headache. PMID- 23091531 TI - Clinical Characteristics and Analysis of CLCN1 in Patients with "EMG Disease". AB - BACKGROUND AND PURPOSE: While the etiology and clinical features of "EMG disease" - which is characterized by diffusely increased insertional activity on needle electromyography (EMG) in the absence of neuromuscular disease - are not well known, some authorities believe it may be a form of myotonia congenita (MC). The aims of this study were to determine the clinical features of EMG disease and its relationship with CLCN1 mutations in patients. METHODS: The detailed clinical and electrophysiological features of EMG disease were evaluated in six patients. All 23 coding exons and exon-intron boundaries in CLCN1 gene were analyzed by direct sequencing to detect nucleotide changes. RESULTS: The common clinical symptoms of EMG disease were chronic muscle stiffness or generalized myalgia, which were aggravated in a cold environment. Four patients complained of action myotonia several times a year. Short trains of provoked positive sharp waves were documented on needle EMG, but myotonic discharges, fibrillation potentials, and fasciculations were not. Increased insertional activity was identified at the asymptomatic muscles studied. One novel heterozygous mutation was identified in one patient following genetic testing for CLCN1 mutations (c.1679T>C, p.Met560Thr). CONCLUSIONS: The clinical features of EMG disease might be quite similar to those of MC, but CLCN1 mutation was found in only one subject. It is thus difficult to accept that EMG disease lies within the phenotypic spectrum of MC. Additional testing is needed to verify the pathogenetic cause of the diffusely increased insertional activity associated with this condition. PMID- 23091532 TI - Acute spinal-cord ischemia: evolution of MRI findings. AB - BACKGROUND AND PURPOSE: Magnetic resonance (MR) findings in acute spinal-cord ischemia can be summarized as focal cord enlargement and hyperintensities on T2 weighted images and gadolinium enhancement, especially of the central gray matter. However, in analogy with acute brain ischemia, it is to be expected that the findings of MR imaging (MRI) may be normal in the first hours after symptom onset. We evaluated the clinical and MRI findings in a series of patients with acute spinal-cord ischemia, and tested the hypothesis that the development and course of MR abnormalities are predictable. METHODS: Five patients with acute spinal-cord ischemia were admitted to our hospital over a 2-year period. Repeated MRI (1.5 T) was performed in all patients. Clinical data were retrieved from the patients' charts. RESULTS: Four women and one man with a median age of 52 years (range, 31-75 years) were admitted. Three patients had anterior spinal artery infarction and two patients had transverse infarctions. All patients underwent spinal MRI within 24 hours; the findings were normal in four of the five patients. After 1-2 days, T2-weighted MRI generally exhibited focal cord enlargement and hyperintensity in all patients, while spinal-cord enhancement appeared after 2-11 days. CONCLUSIONS: Acute spinal-cord ischemia may have a typical course on MRI. MRI findings are usually normal in the acute phase, but spinal cord swelling and T2 abnormality are expected after several days, while gadolinium enhancement appears even later after symptom onset. The sensitivity and specificity of MRI can be increased by repeated MRI in patients suspected of acute spinal-cord ischemia. PMID- 23091533 TI - Prediction of outcome after traumatic brain injury using clinical and neuroimaging variables. AB - BACKGROUND AND PURPOSE: The functional outcome of traumatic brain injury (TBI) varies widely. The aim of this study was to identify the factors predicting outcome following TBI. METHODS: We prospectively enrolled acute TBI patients, and assessed them clinically and radiologically using brain magnetic resonance imaging (MRI). Functional outcome was measured using the Glasgow Outcome Scale (GOS) at 3 months after TBI. A GOS score of <=4 was regarded as an unfavorable outcome. We performed multivariate analysis to investigate the association between clinicoradiological variables and outcome. RESULTS: Forty-two patients completed the clinical evaluation in the acute phase and outcome measurement at 3 months. Motorcycle accident was associated with unfavorable outcome [odds ratio (OR)=38.3, p=0.022]. If the patients were the victims of the accident, they were more likely to have an unfavorable outcome (OR=21.3, p=0.037). All seven patients with a low Glasgow Coma Scale (GCS) score (i.e., <=8) at 24 or 48 h after TBI were also found to have an unfavorable outcome. The presence of diffuse axonal injury (DAI) was a significant predicting factor of an unfavorable outcome (OR=8.48, p=0.042). CONCLUSIONS: Motorcycle accident, being an accident victim, and a lower GCS score at 24 hours or more after the accident were found to be unfavorable prognostic variables. DAI was the only radiologic variable predicting an unfavorable outcome. Thus, it is important to identify DAI by applying MRI in the acute phase. PMID- 23091534 TI - Leber's Hereditary Optic Neuropathy with Olivocerebellar Degeneration due to G11778A and T3394C Mutations in the Mitochondrial DNA. AB - BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported. CASE REPORT: The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. CONCLUSIONS: These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype. PMID- 23091535 TI - A patient with coexisting myasthenia gravis and lambert-eaton myasthenic syndrome. AB - BACKGROUND: The coexistence of myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) is very rare and remains controversial. CASE REPORT: A 48-year-old woman initially presented with noticeable right ptosis and intermittent diplopia. She then developed fluctuating proximal limb weakness and difficulty in swallowing. The serum titer of anti-acetylcholine-receptor antibody was elevated and the edrophonium (Tensilon) test was positive. However, repetitive nerve stimulation revealed abnormalities typical of LEMS. The patient exhibited a good response to treatment with anticholinesterase inhibitors and steroids, and long-term evaluation disclosed that she presented with the clinical, electrophysiological, and immunological characteristics of both diseases. CONCLUSIONS: The reported clinical and electrophysiological features suggest that this patient was a very rare case of combined MG and LEMS. PMID- 23091536 TI - Medial temporal activation in mal de debarquement syndrome revealed by standardized low-resolution brain electromagnetic tomography. AB - BACKGROUND: Mal de debarquement (MdD) literally means "sickness of disembarkation", and refers to the illusion of movement perceived as an after effect of traveling on a boat, train, or airplane. The pathophysiology of MdD is currently unknown. CASE REPORT: A 20-year-old man presented with dizziness and swaying sensation for 3 days after a boat trip. Compared with the follow-up EEG without symptoms, the EEG recorded while having MdD symptoms disclosed a significantly decreased alpha-band current source density at the precentral gyrus of the left frontal lobe and increased beta-2 activity at the parahippocampal gyrus of right mesial temporal region. CONCLUSIONS: Our results provide evidence of deranged cortical activity in MdD. To the best of our knowledge this is the first study to document cortical correlates of MdD using an EEG source localization method. PMID- 23091538 TI - Personalized medicine in breast cancer: a systematic review. AB - The recent advent of "-omics" technologies have heralded a new era of personalized medicine. Personalized medicine is referred to as the ability to segment heterogeneous subsets of patients whose response to a therapeutic intervention within each subset is homogeneous. This new paradigm in healthcare is beginning to affect both research and clinical practice. The key to success in personalized medicine is to uncover molecular biomarkers that drive individual variability in clinical outcomes or drug responses. In this review, we begin with an overview of personalized medicine in breast cancer and illustrate the most encountered statistical approaches in the recent literature tailored for uncovering gene signatures. PMID- 23091539 TI - Stem Cell Implants for Cancer Therapy: TRAIL-Expressing Mesenchymal Stem Cells Target Cancer Cells In Situ. AB - PURPOSE: Tumor-specific delivery of tumor necrosis factor-related apoptosis inducing ligand (TRAIL), an apoptosis-inducing peptide, at effective doses remains challenging. Herein we demonstrate the utility of a scaffold-based delivery system for sustained therapeutic cell release that capitalizes on the tumor-homing properties of mesenchymal stem cells (MSCs) and their ability to express genetically-introduced therapeutic genes. METHODS: Implants were formed from porous, biocompatible silk scaffolds seeded with full length TRAIL expressing MSCs (FLT-MSCs). under a doxycycline inducible promoter. In vitro studies with FLT-MSCs demonstrated TRAIL expression and antitumor effects on breast cancer cells. Next, FLT-MSCs were administered to mice using three administration routes (mammary fat pad co-injections, tail vein injections, and subcutaneous implantation on scaffolds). RESULTS: In vitro cell-specific bioluminescent imaging measured tumor cell specific growth in the presence of stromal cells and demonstrated FLT-MSC inhibition of breast cancer growth. FLT MSC implants successfully decreased bone and lung metastasis, whereas liver metastasis decreased only with tail vein and co-injection administration routes. Average tumor burden was decreased when doxycycline was used to induce TRAIL expression for co-injection and scaffold groups, as compared to controls with no induced TRAIL expression. CONCLUSION: This implant-based therapeutic delivery system is an effective and completely novel method of anticancer therapy and holds great potential for clinical applications. PMID- 23091540 TI - Associations between BRCA Mutations in High-Risk Breast Cancer Patients and Familial Cancers Other than Breast or Ovary. AB - PURPOSE: We investigated the relationship between BRCA mutations and the distribution of familial cancers other than breast or ovary in high-risk breast cancer patients. METHODS: PATIENTS WITH BREAST CANCER WHO HAD AT LEAST ONE OF THE FOLLOWING RISK FACTORS WERE ENROLLED: reported family history of breast or ovarian cancer; 40 years of age or younger age at diagnosis; bilateral breast cancer; or male gender. Genetic testing for BRCA mutation and questionnaires about personal and family histories of malignancies were performed. RESULTS: Among the 238 eligible patients, 49 (20.6%) patients had BRCA1/2 mutations, which were more frequent in patients with multiple risk factors (p<0.0001). There were 271 members of 156 (65.5%) families who had histories of other primary cancer. The distribution of the families was 119 (63.0%) and 37 (75.5%) in the BRCA negative and positive group, respectively (p=0.0996). Multiple familial cancers occurred in 70 families, which were significantly more frequent in BRCA-positive families (p=0.0034). By ordinal logistic regression, the occurrence of multiple familial cancers was associated with BRCA mutations (p=0.0045), not with other risk factors. The most common site of disease was the stomach, which is the most common in nationwide. And the proportional incidence of pancreatic cancer (6.8%) was significantly higher than that of nationwide cancer statistics (2.4%, p=0.0137). CONCLUSION: BRCA mutations in high-risk breast cancer patients were associated with multiple risk factors and multiple family members with other primary cancers. Genetic counseling based on accurate information should be provided to families with BRCA mutation carriers. PMID- 23091541 TI - Survival benefit of tamoxifen in estrogen receptor-negative and progesterone receptor-positive low grade breast cancer patients. AB - PURPOSE: This study aimed to analyze the efficacy and prognostic significance of adjuvant tamoxifen in breast cancer patients with various hormone receptor statuses. METHODS: Typically, 1,260 female breast cancer patients were recruited in this study. The correlation between estrogen receptor (ER)/progesterone receptor (PR) phenotypes and clinical characteristics was investigated, and the survival rate was assessed after 5-year follow-up. RESULTS: The 5-year overall survival (85%) was better in women under the age of 50 years. Patients with ER+/PR+ tumors had a better 5-year survival rate (94%); those with ER-/PR- tumors experienced the worst outcome (74% survival rate); whereas single-positive cases were in between. In 97 out of 128 patients with ER-/PR+ tumors, tamoxifen was given as adjuvant hormonal therapy, and it increased the survival benefit in the lower grade group in terms of overall survival and disease-free survival (p=0.01 and p=0.03, respectively). CONCLUSION: For high-grade tumors with ER-/PR+, adjuvant tamoxifen therapy may have no survival benefit, whereas for the patients with low-grade ER-/PR+ tumors, adjuvant tamoxifen therapy is highly suggestive. PMID- 23091542 TI - Adjuvant chemotherapy and survival of elderly korean patients with breast carcinoma. AB - PURPOSE: The available research work on types of treatment and the efficacy of adjuvant chemotherapy in older Korean patients is insufficient. Henceforth, this report assessed treatment patterns and the relationship between chemotherapy and survival in elderly Korean breast cancer patients. METHODS: We identified women over 55 years of age diagnosed with breast cancer from the period 1995 to 2006. Clinicopathologic features and treatment methods were compared for three groups divided on the basis of age: 55 to 59 years, 60 to 69 years, and over 70 years old. The effects of chemotherapy on survival were compared overall and individually for each group. RESULTS: A total of 832 patients over 55 years of age were included in the present investigation. No statistical differences were observed between the three age groups in clinicopathologic features including tumor size, grade, and stage. However, patients in the elderly group received mastectomy more often when compared to the younger groups (p<0.001). In contrast, there was a decline in radiation treatment and chemotherapy with older age (p<0.001). Overall, patients who received chemotherapy had a significantly increased breast cancer specific survival and overall survival rate when compared to the non-chemotherapy groups (p=0.022). Among the estrogen receptor positive group, no statistical significance was achieved in the survival benefit of chemotherapy. However, in estrogen receptor-negative patients, overall, the chemotherapy groups showed a better survival rate than the non-chemotherapy patients and a similar trend was observed in each age group except in the group comprising of 70 years old patients. CONCLUSION: This study describes the survival benefit of adjuvant chemotherapy in Korean patients over 55 years of age, especially in hormone receptor-negative patients. Hence, based on the results of the present report and considering the similarity of clinicopathologic features between age groups, it is proposed that age alone should not be a determinant factor of treatment methods. PMID- 23091543 TI - Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers. AB - PURPOSE: Carcinoma of the breast is the most prevalent cancer among Egyptian women and constitutes 29% of National Cancer Institute cases. The aim of this study was to determine the effect of breast cancer on oxidative stress, cardiac markers and liver function tests, moreover the role of 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) in the treatment of breast cancer and its mechanism through changing the measured markers. METHODS: Forty female breast cancer patients who were admitted to the Department of Oncology of the Beni-Suef University Hospital were enrolled in the study. This study included three arms: a control group of healthy age-matched females (n=20), breast cancer patients who weren't receiving treatment (n=20), and patients undergoing treatment with anticancer combination drugs FAC (n=20). Blood samples collected from the control subjects and patients were analysed to determine levels of catalase, reduced glutathione (GSH), uric acid, nitric oxide (NO), malondialdehyde, creatine kinase (CK), lactate dehydrogenase (LDH), liver enzymes (alanine aminotransferase and aspartate aminotransferase), and creatinine. RESULTS: The levels of catalase and GSH were significantly reduced (p<0.05) in breast carcinoma and FAC treated breast cancer patients. The lipid peroxidation and NO levels were significantly enhanced in both untreated and FAC treated breast cancer patients. The CK and LDH were significantly enhanced (p<0.05) in the FAC group. CONCLUSION: The results from the present study show that oxidative stress is implicated in breast carcinoma and chemotherapy aggravates this oxidative stress which causes damage to many cellular targets and has the main side effect of cardiotoxicity. PMID- 23091544 TI - Invasive pleomorphic lobular carcinoma of the breast: clinicopathologic characteristics and prognosis compared with invasive ductal carcinoma. AB - PURPOSE: Invasive pleomorphic lobular carcinoma (IPLC) is a very rare and distinct morphological variant of invasive lobular carcinoma (ILC), characterized by nuclear atypia and pleomorphism contrasted with the cytologic uniformity of ILC. This study evaluated clinicopathologic characteristics and prognosis of IPLC compared with invasive ductal carcinoma (IDC). METHODS: We retrospectively reviewed the medical records of 35 patients with IPLC and 6,184 patients with IDC, not otherwise specified. We compared the clinicopathologic characteristics, relapse-free survival (RFS) and disease specific survival (DSS) of patients who were surgically treated between January 1997 and December 2010. RESULTS: Patients with IPLC presented at an older age with larger tumor size, worse histologic grade, higher rates of N3 stage, more multifocal/multicentric tumors, and more nipple-areolar complex involvement than those of patients with IDC. During the follow-up period, the IPLC group experienced five cases (14.3%) of disease recurrence and three cases (8.6%) of disease specific mortality compared with 637 cases (10.4%) of recurrence and 333 cases (5.4%) of disease specific mortality in the IDC group. Univariate analysis using the Kaplan-Meier method revealed that the IPLC group showed a significantly poorer prognosis than that of the IDC group (RFS, p=0.008; DSS, p<0.001). However, after adjusting for clinicopathologic factors, a multivariate analysis showed no statistical differences in RFS (p=0.396) and DSS (p=0.168) between the IPLC and the IDC groups. CONCLUSION: Our data suggest that patients with IPLC present with poor prognostic factors such as large tumor size, poor histologic grade and advanced stage at diagnosis. These aggressive clinicopathologic characteristics may result in poor clinical outcomes. Although our study could not link IPLC histology to poor prognosis, considering the aggressive characteristics of IPLC, early detection and considerate treatment, including proper surgical and adjuvant intervention, could be helpful for disease progression and survival. PMID- 23091545 TI - Correlation of conventional and conformal plan parameters for predicting radiation pneumonitis in patients treated with breast cancer. AB - PURPOSE: The purpose of this study is to evaluate the correlation between the conventional plan parameters and dosimetric parameters obtained from conformal radiotherapy (RT) planning, and between these parameters and radiation pneumontitis (RP) incidence. METHODS: Clinical and dosimetric data of 122 patients that were treated with mastectomy and adjuvant 3D conformal RT (39% received 2-field RT [2-FRT], and in addition, 61% received 4-field RT [4-FRT]) were retrospectively analyzed. Central lung depth (CLD), maximum lung depth (MLD), and lung length were measured by the conventional plan. Lung dose-volume histograms (DVH) were created with conformal planning, and the lung volumes receiving 5 to 50 Gy (V(5Gy) to V(50Gy)) were calculated. Minimum (D(min)), maximum (D(max)), and mean doses (D(mean)) for the ipsilateral lung and bilateral lungs were measured by DVH. Correlations between 3D dosimetric data and 2D radiographic parameters were analyzed. RESULTS: The conventional plan parameters did not significantly differ between 2-FRT and 4-FRT. The conformal plan D(min), D(max), and D(mean) values were higher in 4-FRT versus 2-FRT. CLD and MLD were correlated with DVH parameter V(5Gy) to V(45Gy) values for ipsilateral, as well as bilateral lungs for 2-FRT. MLD and ipsilateral D(mean) via 2-FRT planning had the strongest positive correlation (r=0.76, p<0.01). Moderate correlations existed between CLD and ipsilateral and bilateral lung V(5Gy-45Gy), and between MLD and bilateral lung V(5Gy-45Gy) values in 2-FRT. Only four patients developed symptomatic RP, 4 with 4-FRT and one with 2-FRT. CONCLUSION: The conformal plan parameters were strongly correlated with dose-volume parameters for breast 2-FRT. With only 4 cases of Grade 3 RP observed, our study is limited in its ability to provide definitive guidance, however assuming that CLD is an indicator for RP, V(20Gy) could be used as a predictor for RP and for 2-FRT. A well-defined parameters are still required to predict RP in 4-FRT. PMID- 23091546 TI - Radiation treatment in pathologic n0-n1 patients treated with neoadjuvant chemotherapy followed by surgery for locally advanced breast cancer. AB - PURPOSE: This study evaluated the treatment results and the necessity to irradiate the supraclavicular lymph node (SCN) region in pathological N0-N1 (pN0 N1) patients with locally advanced breast cancer treated with neoadjuvant chemotherapy (NAC) followed by surgery and radiotherapy (RT). METHODS: Between 1996 and 2008, 184 patients with initial tumor size >5 cm or clinically positive lymph nodes were treated with NAC followed by surgery and RT. Among these patients, we retrospectively reviewed 98 patients with pN0-N1. Mastectomy was performed in 55%. The pathological lymph node stage was N0 in 49% and N1 in 51%. All patients received adjuvant RT to chest wall or breast and 56 patients (57%) also received RT to the SCN region (SCNRT). RESULTS: At 5 years, locoregional recurrence (LRR)-free survival, distant metastasis-free survival, disease-free survival (DFS), and overall survival rates were 93%, 83%, 81%, and 91%, respectively. In pN0 patients, LRR was 7% in SCNRT- group and 5% in SCNRT+ group. In pN1 patients, LRR was 7% in SCNRT- group and 6% in SCNRT+ group. There was no significant difference of LRR, regardless of SCNRT. However, in pN1 patients, there were more patients with poor prognostic factors in the SCNRT+ group compared to SCNRT- group. These factors might be associated with worse DFS in the SCNRT+ group, even though RT was administered to the SCN region. CONCLUSION: Our study showed the similar LRR, regardless of SCNRT in pN0-pN1 breast cancer patients after NAC followed by surgery. Prospective randomized trial is called for to validate the role of SCNRT. PMID- 23091547 TI - Radiation pneumonitis in breast cancer patients who received radiotherapy using the partially wide tangent technique after breast conserving surgery. AB - PURPOSE: We assessed the risk of radiation pneumonitis (RP) in terms of dosimetric parameters in breast cancer patients, who received radiotherapy using the partially wide tangent technique (PWT), following breast conservation surgery (BCS). METHODS: We analyzed the data from 100 breast cancer patients who underwent radiotherapy using PWT. The entire breast, supraclavicular lymph node, and internal mammary lymph node (IMN) were irradiated with 50.4 Gy in 28 fractions. RP was scored on a scale of 0 to 5, based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. The dosimetric parameters, used in analysis for the ipsilateral lung, were the mean lung dose (MLD), V(5) (percentage of lung volume that received a dose of 5 Gy or more)-V(50), and normal tissue complication probability (NTCP). RESULTS: Of the 100 patients, three suffered from symptomatic RP (symptom grade >=2), but were relieved by supportive care. The risk of RP was not correlated with the treatment regimen. RP associated mostly with asymptomatic minimal pulmonary radiologic change or mild dry cough developed more frequently in the group with MLD >=20.5 Gy or NTCP >=23% than in the group with MLD <20.5 Gy and NTCP <23% (48.6% vs. 25.4%, p=0.018). CONCLUSION: Dosimetric parameters of MLD and NTCP were correlated with the incidence of RP, but the clinical impact was minimal. We suggest that PWT is a safe technique for the treatment of IMN for BCS patients with low risk of symptomatic RP. PMID- 23091548 TI - Ultrasonographic characteristics of mammographically occult small breast cancer. AB - PURPOSE: To analyze significant ultrasonographic findings of small malignant breast mass (<=10 mm) which were occult on mammography. METHODS: The study included 190 small breast masses (<=10 mm), demonstrated on breast ultrasonography, but not mammography. Histopathology (when the masses were biopsied) or serial breast ultrasonography (for at least 24 months) were used to confirm benign or malignant condition of the masses. Univariate and multivariate logistic regression analysis were used to identify significant characteristic malignant findings on ultrasonography. RESULTS: Of 190 masses, 46 were cancer, and 144 were benign. On multivariate analyses, irregular shape (odds ratio [OR], 10.4) and not circumscribed margin (OR, 31.6) were significant features to differentiate between benign and malignant breast masses. However, low width/anteroposterior ratio, echogenic halo, hypoechogenecity and posterior acoustic shadow, which were predictors for malignancy in large breast mass, were not documented in small mass. CONCLUSION: In conclusion, irregular shape and not circumscribed margin detected during ultrasonography were strong predictive signs of malignancy for small malignant breast mass. PMID- 23091549 TI - Oncoplastic reconstruction with superior based lateral breast rotation flap after lower quadrant tumor resection. AB - PURPOSE: Poor cosmetic outcome have been reported as a result of breast cancer operation due to lower quadrant breast tumors; this is particularly true for women with small, firm breasts. Herein, we report here on the use of superior based lateral breast rotation flap reconstruction to improve cosmetic outcome in patients with lower quadrant breast cancer. METHODS: We enrolled 33 patients with invasive breast cancer located in the lower quadrant of the breast, which were located more than 2 cm apart from the nipple. After completing a quadrantectomy, a single S-shaped or reverse S-shaped incision was made from axilla to tumor site. Two triangular skin islands, one on the axilla and one overlying the tumor were marked for excision. Once the fibroglandular tissues and the additional fatty tissue of the lateral chest wall were appropriately mobilized, the breast defect was closed at the mid-point of the parenchymal thickness in order to keep the natural position of the infra mammary fold. RESULTS: Median tumor size was 2.3 cm (range, 0.7-3.5 cm) and median resected volume was 35.5 g (range, 27.0 51.0 g). With a mean follow-up of 24.5 months (range, 9.0-33.5 months), cosmetic outcomes were good (94.0%) to fair (6.0%) at 6 months after the procedure, and there was no local or systemic recurrence during the short term follow-up period. CONCLUSION: Clearly, this type of rotation flap reconstruction is an oncologically safe and a cosmetically sound procedure. Hopefully this rotation flap reconstruction technique will become more widely available and perhaps a standard procedure for lower quadrant breast tumors, especially for cosmetic treatment of small to medium-sized breasts. PMID- 23091550 TI - An unusual case of gastric cancer presenting with breast metastasis with pleomorphic microcalcifications. AB - Breast metastasis from gastric carcinoma is rare. We present a case of right breast mass with microcalcification in which the diagnosis of poorly differentiated adenocarcinoma from the stomach was made after a biopsy. Pleomorphic microcalcification was noted in the ill-defined breast mass, which is a rare feature in breast metastasis. Since breast metastasis usually signifies advanced metastatic disease, differentiating primary breast cancer from metastasis is important for appropriate treatment. PMID- 23091551 TI - Occult breast cancers manifesting as axillary lymph node metastasis in men: a two case report. AB - Occult breast cancer is a type of breast cancer without any symptoms on the breasts or any abnormalities upon radiologic examination such as mammography. In males, there are few cases of breast cancer, the rate of diagnosis of occult breast cancer is very low, and little is known about this disease. We experienced two cases of occult breast cancers manifesting as axillary lymph node metastasis in men. They had a palpable lesion on axillary area several years ago and had not seen a doctor about it. As such there was no abnormality on evaluations for cancer except for axillary lymph node showing signs of carcinoma (primary or metastatic) on biopsy and estrogen receptor-positive and progesterone receptor positive on immunohistochemistry. The patients were diagnosed with occult breast cancer, and treatments were performed. Herein, we report the rare cases of occult breast cancers in men. PMID- 23091552 TI - Two cases of post-radiation sarcoma after breast cancer treatment. AB - We describe two cases of post-radiation sarcoma after breast cancer treatment. The first patient was a 61-year-old woman who underwent partial mastectomy of the right breast and adjuvant whole breast irradiation 7 years previously. Subsequently, a rapidly growing mass from the anterior arc of the right fifth rib was incidentally detected on an abdomino-pelvic computed tomography scan. The second patient was a 70-year-old woman who received neoadjuvant chemotherapy and a partial mastectomy of the left breast 9 years ago. Adjuvant irradiation was delivered to the whole breast and supraclavicular region. Subsequently, an approximate 8 cm mass developed in the left axillary area. Both patients received wide excision of the tumor with negative resection margins. The pathological diagnoses were osteosarcoma and undifferentiated pleomorphic sarcoma, respectively. Although post-radiation sarcomas are rare complications with a poor prognosis, enhanced awareness and early detection by clinicians are essential to improve outcomes via curative surgical resection. PMID- 23091553 TI - Granulomatous Mastitis during Chronic Antidepressant Therapy: Is It Possible a Conservative Therapeutic Approach? AB - Granulomatous mastitis is a rare benign inflammatory disease of the breast with multiple etiologies such as tuberculosis, sarcoidosis, foreign body reaction, and mycotic and parasitic infections. In contrast, idiopathic granulomatous mastitis (IGM) is characterized by the presence of chronic granulomatous lobulitis in the absence of an obvious etiology. Clinically and radiologically it may mimic breast carcinoma and so awareness of surgeons, pathologists, and radiologists is essential to avoid unnecessary mastectomies. Cases of IGM are reported during antidepressant therapy in patients also showing high levels of prolactinemia. In these cases, we believe that surgical excision must be avoided being replaced with a conservative management of the pathological condition based on a corticosteroid treatment. PMID- 23091554 TI - The genetic polymorphisms of HLA are strongly correlated with the disease severity after Hantaan virus infection in the Chinese Han population. AB - The polymorphism of human leukocyte antigen (HLA), which is a genetic factor that influences the progression of hemorrhagic fever with renal syndrome (HFRS) after Hantaan virus (HTNV) infection, was incompletely understood. In this case-control study, 76 HFRS patients and 370 healthy controls of the Chinese Han population were typed for the HLA-A, -B, and -DRB1 loci. The general variation at the HLA DRB1 locus was associated with the onset of HFRS (P < 0.05). The increasing frequencies of HLA-DRB1*09 and HLA-B*46-DRB1*09 in HFRS patients were observed as reproducing a previous study. Moreover, the HLA-B*51-DRB1*09 was susceptible to HFRS (P = 0.037; OR = 3.62; 95% CI: 1.00-13.18). The increasing frequencies of HLA-B*46, HLA-B*46-DRB1*09, and HLA-B*51-DRB1*09 were observed almost in severe/critical HFRS patients. The mean level of maximum serum creatinine was higher in HLA-B*46-DRB1*09 (P = 0.011), HLA-B*51-DRB1*09 (P = 0.041), or HLA-B*46 (P = 0.011) positive patients than that in the negative patients. These findings suggest that the allele HLA-B*46 and haplotypes HLA-B*46-DRB1*09 and HLA-B*51 DRB1*09 in patients could contribute to a more severe degree of HFRS and more serious kidney injury, which improve our understanding of the HLA polymorphism for a different outcome of HTNV infection. PMID- 23091556 TI - HIV-associated tuberculosis 2012. PMID- 23091555 TI - The phenotype of circulating follicular-helper T cells in patients with rheumatoid arthritis defines CD200 as a potential therapeutic target. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting synovial joints in which the development of autoantibodies represents a failure of normal tolerance mechanisms, suggesting a role for follicular helper T cells (T(FH)) in the genesis of autoimmunity. To determine whether quantitative or qualitative abnormalities in the circulating T(FH) cell population exist, we analysed by flow cytometry the number and profile of these cells in 35 patients with RA and 15 matched controls. Results were correlated with patient characteristics, including the presence of autoantibodies, disease activity, and treatment with biologic agents. Circulating T(FH) cells from patients with RA show significantly increased expression of the immunoglobulin superfamily receptor CD200, with highest levels seen in seropositive patients (P = 0.0045) and patients treated with anti-TNFalpha agents (P = 0.0008). This occurs in the absence of any change in T(FH) numbers or overt bias towards Th1, Th2, or Th17 phenotypes. CD200 levels did not correlate with DAS28 scores (P = 0.887). Although the number of circulating T(FH) cells is not altered in the blood of patients with RA, the T(FH) cells have a distinct phenotype. These differences associate T(FH) cells with the pathogenesis of RA and support the relevance of the CD200/CD200R signalling pathway as a potential therapeutic target. PMID- 23091557 TI - Momordica charantia Extract Induces Apoptosis in Human Cancer Cells through Caspase- and Mitochondria-Dependent Pathways. AB - Plants are an invaluable source of potential new anti-cancer drugs. Momordica charantia is one of these plants with both edible and medical value and reported to exhibit anticancer activity. To explore the potential effectiveness of Momordica charantia, methanol extract of Momordica charantia (MCME) was used to evaluate the cytotoxic activity on four human cancer cell lines, Hone-1 nasopharyngeal carcinoma cells, AGS gastric adenocarcinoma cells, HCT-116 colorectal carcinoma cells, and CL1-0 lung adenocarcinoma cells, in this study. MCME showed cytotoxic activity towards all cancer cells tested, with the approximate IC(50) ranging from 0.25 to 0.35 mg/mL at 24 h. MCME induced cell death was found to be time-dependent in these cells. Apoptosis was demonstrated by DAPI staining and DNA fragmentation analysis using agarose gel electrophoresis. MCME activated caspase-3 and enhanced the cleavage of downstream DFF45 and PARP, subsequently leading to DNA fragmentation and nuclear condensation. The apoptogenic protein, Bax, was increased, whereas Bcl-2 was decreased after treating for 24 h in all cancer cells, indicating the involvement of mitochondrial pathway in MCME-induced cell death. These findings indicate that MCME has cytotoxic effects on human cancer cells and exhibits promising anti cancer activity by triggering apoptosis through the regulation of caspases and mitochondria. PMID- 23091558 TI - Are Primo Vessels (PVs) on the Surface of Gastrointestine Involved in Regulation of Gastric Motility Induced by Stimulating Acupoints ST36 or CV12? AB - Previous studies showed primo vessels (PVs), which were referred to as Bonhan ducts (BHDs) and a part of circulatory system by Kim, located in different places of the body. The BHDs system was once considered as the anatomical basis of classical acupuncture meridian but not clearly identified by other investigators. In the present study, we tried to address the relationship between PVs and meridians through detecting the modulation of gastric motility by stimulating the PVs on the surface of stomach or intestine, as well as acupoints Zusanli (ST36) and Zhongwan (CV12). The results showed electric stimulation of the PVs had no effect on the gastric motility. While stimulating CV12 inhibited gastric motility significantly in PVs-intact and PVs-cut rats, there is no significant difference between the inhibition rate of the PVS-intact and the PVS-cut rats. Stimulating at ST36 increased gastric motility significantly in both the PVs-intact and the PVs-cut rats, yet there was no significant difference between the facilitation rate of the both groups. Taken together, the PVs on the surface of stomach or intestine did not mediate the regulation of gastric motility induced by stimulating at the acupoints ST36 or CV12. PMID- 23091559 TI - Dentatin Induces Apoptosis in Prostate Cancer Cells via Bcl-2, Bcl-xL, Survivin Downregulation, Caspase-9, -3/7 Activation, and NF-kappaB Inhibition. AB - This study was set to investigate antiproliferative potential of dentatin (a natural coumarin isolated from Clausena excavata Burm. F) against prostate cancer and to delineate the underlying mechanism of action. Treatment with dentatin dose dependently inhibited cell growth of PC-3 and LNCaP prostate cancer cell lines, whereas it showed less cytotoxic effects on normal prostate epithelial cell line (RWPE-1). The inhibitory effect of dentatin on prostate cancer cell growth was due to induction of apoptosis as evidenced by Annexin V staining and cell shrinkage. We found that dentatin-mediated accumulation of reactive oxygen species (ROS) and downregulated expression levels of antiapoptotic molecules (Bcl 2, Bcl-xL, and Survivin), leading to disruption of mitochondrial membrane potential (MMP), cell membrane permeability, and release of cytochrome c from the mitochondria into the cytosol. These effects were associated with induction of caspase-9, -3/7 activities, and subsequent DNA fragmentation. In addition, we found that dentatin inhibited TNF-alpha-induced nuclear translocation of p65, suggesting dentatin as a potential NF-kappaB inhibitor. Thus, we suggest that dentatin may have therapeutic value in prostate cancer treatment worthy of further development. PMID- 23091560 TI - Association of perceived stress with stressful life events, lifestyle and sociodemographic factors: a large-scale community-based study using logistic quantile regression. AB - OBJECTIVE: The present paper aimed at investigating the association between perceived stress and major life events stressors in Iranian general population. METHODS: In a cross-sectional large-scale community-based study, 4583 people aged 19 and older, living in Isfahan, Iran, were investigated. Logistic quantile regression was used for modeling perceived stress, measured by GHQ questionnaire, as the bounded outcome (dependent), variable, and as a function of most important stressful life events, as the predictor variables, controlling for major lifestyle and sociodemographic factors. This model provides empirical evidence of the predictors' effects heterogeneity depending on individual location on the distribution of perceived stress. RESULTS: The results showed that among four stressful life events, family conflicts and social problems were more correlated with level of perceived stress. Higher levels of education were negatively associated with perceived stress and its coefficients monotonically decrease beyond the 30th percentile. Also, higher levels of physical activity were associated with perception of low levels of stress. The pattern of gender's coefficient over the majority of quantiles implied that females are more affected by stressors. Also high perceived stress was associated with low or middle levels of income. CONCLUSIONS: The results of current research suggested that in a developing society with high prevalence of stress, interventions targeted toward promoting financial and social equalities, social skills training, and healthy lifestyle may have the potential benefits for large parts of the population, most notably female and lower educated people. PMID- 23091561 TI - Fast parameters estimation in medication efficacy assessment model for heart failure treatment. AB - INTRODUCTION: Heart failure (HF) is a common and potentially fatal condition. Cardiovascular research has focused on medical therapy for HF. Theoretical modelling could enable simulation and evaluation of the effectiveness of medications. Furthermore, the models could also help predict patients' cardiac response to the treatment which will be valuable for clinical decision-making. METHODS: This study presents a fast parameters estimation algorithm for constructing a cardiovascular model for medicine evaluation. The outcome of HF treatment is assessed by hemodynamic parameters and a comprehensive index furnished by the model. Angiotensin-converting enzyme inhibitors (ACEIs) were used as a model drug in this study. RESULTS: Our simulation results showed different treatment responses to enalapril and lisinopril, which are both ACEI drugs. A dose-effect was also observed in the model simulation. CONCLUSIONS: Our results agreed well with the findings from clinical trials and previous literature, suggesting the validity of the model. PMID- 23091562 TI - Global stability analysis of SEIR model with holling type II incidence function. AB - A deterministic model for the transmission dynamics of a communicable disease is developed and rigorously analysed. The model, consisting of five mutually exclusive compartments representing the human dynamics, has a globally asymptotically stable disease-free equilibrium (DFE) whenever a certain epidemiological threshold, known as the basic reproduction number (R0), is less than unity; in such a case the endemic equilibrium does not exist. On the other hand, when the reproduction number is greater than unity, it is shown, using nonlinear Lyapunov function of Goh-Volterra type, in conjunction with the LaSalle's invariance principle, that the unique endemic equilibrium of the model is globally asymptotically stable under certain conditions. Furthermore, the disease is shown to be uniformly persistent whenever R0 > 1. PMID- 23091563 TI - Quick fix or long-term cure? Pros and cons of bariatric surgery. AB - The past decade has seen an enormous increase in the number of bariatric, or weight loss, operations performed. This trend is likely to continue, mirroring the epidemic of obesity around the world and its rising prevalence among children. Bariatric surgery is considered by many to be the most effective treatment for obesity in terms of maintenance of long-term weight loss and improvement in obesity-related comorbid conditions. Although overly simplified, the primary mechanisms of the surgical interventions currently utilized to treat obesity are the creation of a restrictive or malabsorptive bowel anatomy. Operations based on these mechanisms include the laparoscopic adjustable gastric band and laparoscopic vertical sleeve gastrectomy (considered primarily restrictive operations), the laparoscopic biliopancreatic diversion with or without a duodenal switch (primarily malabsorptive operation), and the laparoscopic Roux-en-Y gastric bypass (considered a combination restrictive and selective malabsorptive procedure). Each operation has pros and cons. Important considerations, for the patient and surgeon alike, in the decision to proceed with bariatric surgery include the technical aspects of the operation, postoperative complications including long-term nutritional problems, magnitude of initial and sustained weight loss desired, and correction of obesity-related comorbidities. Herein, the pros and cons of the contemporary laparoscopic bariatric operations are reviewed and ongoing controversies relating to bariatric surgery are discussed: appropriate patient selection, appropriate operation selection for an individual patient, surgeon selection, and how to measure success after surgery. PMID- 23091564 TI - The CNS and bladder dysfunction. AB - The brain's role in the development and maintenance of bladder control is critical, although its precise role in patient-reported complaints such as urgency and urine leakage is unknown. Functional brain imaging studies have advanced our knowledge of brain activity during the micturition cycle, showing multiple neuronal circuits involved as parts of a 'brain-bladder control network.' Yet, new advances need to be made in order to incorporate this knowledge into existing models of neuroanatomy and of clinical syndromes of bladder dysfunction and related clinical practice. This short article explains why and how brain imaging methods are poised to achieve that goal and decode the role of the brain in widely prevalent clinical conditions related to bladder dysfunction. PMID- 23091565 TI - The numbers of Libyan doctors in diaspora: Myths and facts. PMID- 23091566 TI - Effect of rotating acoustic stimulus on heart rate variability in healthy adults. AB - Acoustic stimulus can modulate the Autonomic Nervous System. However, previous reports on this topic are conflicting and inconclusive. In this study we have shown, how rotating acoustic stimulus, a novel auditory binaural stimulus, can change the autonomic balance of the cardiac system. We have used Heart rate Variability (HRV), an indicator of autonomic modulation of heart, both in time and frequency domain to analyze the effect of stimulus on 31 healthy adults.A decrease in the heart rate accompanied with an increase in SD and RMSSD indices on linear analysis was observed post-stimulation. In the Poincare Plot, Minor Axis (SD1), Major Axis (SD2) and the ratio SD12 (SD1/SD2) increased after the stimulation. Post stimulus greater increment of SD12 with higher lag numbers of (M) beat to beat intervals, when compared to pre stimulus values, resulted in increased curvilinearity in the SD12 vs. Lag number plot. After stimulation,value of exponent alpha of Dretended Flactuation Analysis of HRV was found to be decreased. From these characteristic responses of the heart after the stimulus, it appears that rotating acoustic stimulus may be beneficial for the sympathovagal balance of the heart. PMID- 23091567 TI - Chronic or late lyme neuroborreliosis: present and future. PMID- 23091568 TI - A reappraisal of the u.s. Clinical trials of post-treatment lyme disease syndrome. AB - Four federally funded randomized placebo-controlled treatment trials of post treatment Lyme syndrome in the United States have been conducted. Most international treatment guidelines summarize these trials as having shown no acute or sustained benefit to repeated antibiotic therapy. The goal of this paper is to determine whether this summary con-clusion is supported by the evidence. METHODS: The methods and results of the 4 U.S. treatment trials are described and their critiques evaluated. RESULTS: 2 of the 4 U.S. treatment trials demonstrated efficacy of IV ceftriaxone on primary and/or secondary outcome measures. CONCLUSIONS: Future treatment guidelines should clarify that efficacy of IV ceftriaxone for post-treatment Lyme fatigue was demonstrated in one RCT and supported by a second RCT, but that its use was not recommended primarily due to adverse events stemming from the IV route of treatment. While repeated IV antibiotic therapy can be effective, safer modes of delivery are needed. PMID- 23091569 TI - The psychoimmunology of lyme/tick-borne diseases and its association with neuropsychiatric symptoms. AB - Disease progression of neuropsychiatric symptoms in Lyme/tick-borne diseases can be better understood by greater attention to psychoimmunology. Although there are multiple contributors that provoke and weaken the immune system, infections and persistent infections are significant causes of pathological immune reactions. Immune mediated ef-fects are a significant contributor to the pathophysiological processes and disease progression. These immune effects in-clude persistent inflammation with cytokine effects and molecular mimicry and both of these mechanisms may be present at the same time in persistent infections. Sickness syndrome associated with interferon treatment and autoimmune limbic encephalopathies are models to understand inflammatory and molecular mimicry effects upon neuropsychiatric symp-toms. Progressive inflammatory reactions have been proposed as a model to explain disease progression in depression, psychosis, dementia, epilepsy, autism and other mental illnesses and pathophysiological changes have been associated with oxidative stress, excitotoxicity, changes in homocysteine metabolism and altered tryptophan catabolism. Lyme dis-ease has been associated with the proinflammatory cytokines IL-6, IL-8, IL-12, IL-18 and interferon-gamma, the chemokines CXCL12 and CXCL13 and increased levels proinflammatory lipoproteins. Borrelia burgdorferi surface gly-colipids and flagella antibodies appear to elicit anti-neuronal antibodies and anti-neuronal antibodies and Borrelia burgdorferi lipoproteins can disseminate from the periphery to inflame the brain. Autism spectrum disorders associated with Lyme/tick-borne diseases may be mediated by a combination of inflammatory and molecular mimicry mechanisms. Greater interaction is needed between infectious disease specialists, immunologists and psychiatrists to benefit from this awareness and to further understand these mechanisms. PMID- 23091570 TI - Evolving perspectives on lyme borreliosis in Canada. AB - With cases now documented in every province, Lyme borreliosis (LB) is emerging as a serious public health risk in Canada. Controversy over the contribution of LB to the burden of chronic disease is maintained by difficulty in capturing accurate Canadian statistics, especially early clinical cases of LB. The use of dogs as sentinel species demon-strates that potential contact with Borrelia burgdorferi spirochetes, as detected by C6 peptide, extends across the country. Dissemination of infected ticks by migratory birds and rapid establishment of significant levels of infection have been well described. Canadian public health response has focused on identification of established populations of the tick vectors, Ixodes scapularis and I. pacificus, on the assumption that these are the only important vectors of the disease across Canada. Strains of B. burgdorferi circulating in Canada and the full range of their reservoir species and coinfections remain to be explored. Ongoing surveys and historical records demonstrate that Borrelia-positive Ixodes species are regu-larly present in regions of Canada that have previously been considered to be outside of the ranges of these species in re-cent modeling efforts. We present data demonstrating that human cases of LB are found across the nation. Consequently, physician education and better early diagnoses are needed to prevent long term sequelae. An international perspective will be paramount for developing improved Canadian guidelines that recognize the complexity and diversity of Lyme borreliosis. PMID- 23091571 TI - The lymphocyte transformation test for borrelia detects active lyme borreliosis and verifies effective antibiotic treatment. AB - Borrelia-specific antibodies are not detectable until several weeks after infection and even if they are present, they are no proof of an active infection. Since the sensitivity of culture and PCR for the diagnosis or exclusion of borreliosis is too low, a method is required that detects an active Borrelia infection as early as possible. For this purpose, a lymphocyte transformation test (LTT) using lysate antigens of Borrelia burgdorferi sensu stricto, Borrelia afzelii and Borrelia garinii and recombinant OspC was developed and validated through investigations of seronegative and seropositive healthy individuals as well as of seropositive patients with clinically manifested borreliosis. The sensitivity of the LTT in clinical borreliosis before antibiotic treatment was determined as 89,4% while the specificity was 98,7%. In 1480 patients with clinically suspected borreliosis, results from serology and LTT were comparable in 79.8% of cases. 18% were serologically positive and LTT-negative. These were mainly patients with borreliosis after antibiotic therapy. 2.2% showed a negative serology and a positive LTT result. Half of them had an early erythema migrans. Following antibiotic treatment, the LTT became negative or borderline in patients with early manifestations of borreliosis, whereas in patients with late symptoms, it showed a regression while still remaining positive. Therefore, we propose the follow-up monitoring of dis-seminated Borrelia infections as the main indication for the Borrelia-LTT. PMID- 23091572 TI - Diagnosis of infectious or inflammatory psychosyndromes. AB - Before an outline of the process of diagnosis and differential diagnosis in infectious and/or inflammatory psy-chosyndromes is given, a more general overview onto the approach to organic psychosyndromes seems useful, because in both entities similar principles of causality conclusion are applied. Correlation does not demonstrate causality. Therefore the principles and consensus recommendations, and limitations of causal inference to categorize psychosyndromes as be-ing 'organic', is to be discussed in detail. PMID- 23091573 TI - How do lyme borrelia organisms cause disease? The quest for virulence determinants(). AB - Lyme disease Borrelia are invasive, nontoxigenic, persistent pathogens, and little is known about their mechanisms of pathogenesis. In our laboratory, a signature-tagged mutagenesis (STM) library of over 4,000 Borrelia burgdorferi transposon mutants has been constructed and is being screened for infectivity in mice. In this manner, a global view of the virulence determinants (factors required for full infectivity) is being developed. Additionally, the mechanisms of immune evasion involving the VMP-like system (vls) are under analysis, and cryo-electron microscopy is providing a detailed view of the three-dimensional structure of B. burgdorferi. These approaches will contribute to the improved understanding of how Lyme disease Borrelia cause disease. PMID- 23091574 TI - "Pyogenic granuloma - Hyperplastic lesion of the gingiva: case reports". AB - Pyogenic granuloma is a reactive hyperplasia of connective tissue in response to local irritants. It is a tumourlike growth of the oral cavity, frequently located surrounding the anterior teeth or skin that is considered to be neoplastic in nature. It usually arises in response to various stimuli such as low-grade local irritation, traumatic injury, hormonal factors, or certain kinds of drugs. Histologically, the surface epithelium may be intact, or may show foci of ulcerations or even exhibiting hyperkeratosis. It overlies a mass of dense connective tissue composed of significant amounts of mature collagen. Gingiva is the most common site affected followed by buccal mucosa, tongue and lips. Pyogenic granuloma in general, does not occur when excised along with the base and its causative factors. This paper presents some cases of a pyogenic granuloma managed by surgical intervention. PMID- 23091575 TI - Effects on dentin treated with eluted multi-mineral varnish in vitro. AB - PURPOSE: The purpose of this pilot study was to assess the non-contact effects of a NaF varnish on the morphology and elemental compositions of sound and demineralized dentin in an in vitro pH cycling model. METHODS: 3 mm diameter dentin cores were extracted from bovine teeth, mounted in acrylic rods, and ground and polished. Sound and demineralized (in 10 mL unstirred 50% citric acid (pH = 1.2) for two minutes) specimens were divided into four groups (N=6) corresponding to treatments with either water (control group) or non-contact Vanish(r) 5% NaF White Varnish with tri-calcium phosphate (3M ESPE). For the non contact varnish group, one 0.50 ml unit-dose was applied to acrylic rods and positioned in the same stopper as three dentin specimens. The four groups were then cycled in a regimen consisting of three rounds of one-hour treatments with each round followed by immersion in a three-minute static acid challenge (0.3% citric acid, pH = 3.8). For each one-hour treatment immersion the test groups were immersed in distilled water. The specimens were thoroughly rinsed with distilled water after each treatment and after each acid challenge. After the last challenge, specimens were rinsed with distilled water and immersed in artificial saliva (AS) overnight. All treatments, acid challenges and immersion in AS solution were performed in an incubator set at 37 degrees C. After three days, the specimens were assessed using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). RESULTS: SEM and EDS results demonstrated the non-contact varnish group can provide mineralization benefits relative to the control group for both sound and demineralized dentin substrates. Depositions from mineral eluting from the varnish developed on the intertubular and intratubular regions alike, with the most prominent depositions appearing on initially demineralized dentin. CONCLUSIONS: In this observational study, acid resistant mineral depositions were produced on the sound and dentin surfaces without direct application from a multi-mineral varnish containing fluoride, calcium and phosphate. PMID- 23091576 TI - Postextraction implant placement with immediate provisionalisation and finalisation, using a simplified technique: technical notes and a case report. AB - Trauma of maxillary teeth is a common accident. In most cases, the result is a root or crown fracture requiring tooth extraction and implant placement. Immediate postextraction implants are considered an effective option for restoring missing teeth in order to achieve successful aesthetic and functional outcomes. The aim of this article is to describe a clinical case in which a fractured maxillary canine was replaced by an osseointegrated implant using a simplified technique in a patient who was a smoker and presented poor oral hygiene. The technique adopted permits a reduction of the number of implant components and consequently a lower cost of treatment, while at the same time maintaining acceptable aesthetic and functional outcomes. PMID- 23091577 TI - Is the deficit in pain inhibition in fibromyalgia influenced by sleep impairments? AB - It has been proposed that a deficit in inhibitory conditioned pain modulation (ICPM) underlies the pathophysiology of fibromyalgia (FM), but there is high variability in ICPM efficacy in this syndrome that remains poorly understood. Based on emerging data showing that age, anxiety, depression and sleep can modulate ICPM efficacy, the main objective of this study was to determine the clinical correlates of experimentally-induced pain perception in FM. Fifty FM patients and 39 healthy controls (HC) were tested. Anxiety, depression, sleep and FM symptoms were measured with questionnaires or interview-type scales. Experimental pain testing consisted of two tonic heat pain stimulations separated by a 2-minute cold pressor test (CPT). Thermal pain thresholds and tolerance were higher in HC compared to FM patients. Pain ratings during the CPT were lower in HC relative to FM patients. ICPM efficacy was stronger in HC compared to FM patients. Finally, sleep quality was the only factor significantly related to ICPM efficacy. To our knowledge, this is the first study to report this association in FM. Future studies will need to replicate this finding, to determine whether impaired sleep is primary or secondary to deficient pain inhibition, and to characterize the neurobiological mechanisms underlying this association. PMID- 23091579 TI - A Three-dimensional Deformable Brain Atlas for DBS Targeting. I. Methodology for Atlas Creation and Artifact Reduction. AB - BACKGROUND: Targeting in deep brain stimulation (DBS) relies heavily on the ability to accurately localize particular anatomic brain structures. Direct targeting of subcortical structures has been limited by the ability to visualize relevant DBS targets. METHODS AND RESULTS: In this work, we describe the development and implementation, of a methodology utilized to create a three dimensional deformable atlas for DBS surgery. This atlas was designed to correspond to the print version of the Schaltenbrand-Bailey atlas structural contours. We employed a smoothing technique to reduce artifacts inherent in the print version. CONCLUSIONS: We present the methodology used to create a three dimensional patient specific DBS atlas which may in the future be tested for clinical utility. PMID- 23091578 TI - Tuberculous coxitis: diagnostic problems and varieties of treatment: a case report. AB - Although the prevalence of tuberculosis reduces, it still belongs to the most important infectious diseases worldwide even in industrial countries.We report an unusual case of tuberculous coxitis in a 28-year-old healthy native female with recurrent hip pain. While X-ray and microbiological examination of the aspirate showed no abnormality, only extended diagnostic measurements and detailed history led to the diagnosis of TBC. Although the patient did not show any pulmonary symptoms open tuberculosis was confirmed. After a course of antibiotic treatment she underwent reconstructive surgery which consecutively improved range of motion. This case report emphasizes that tuberculosis should still be considered as a significant disease even in healthy patients with uncertain complaints in joints without significant initial radiographic abnormalities. We recommend the described diagnostic procedures as well as an antibiotic and surgical treatment. PMID- 23091580 TI - Developing a Web-Based HIV Behavioral Surveillance Pilot Project Among Men Who Have Sex with Men. AB - BACKGROUND: A web-based HIV behavioral surveillance system (WHBS) has potential to collect behavioral data from men who have sex with men (MSM) not reached through traditional sampling methods. Six U.S. cities conducted a WHBS pilot in 2005-2007 to determine the feasibility to conduct a behavioral surveillance project entirely on the internet. METHODS: THREE SAMPLING METHODS OF ADULT MSM ON THE INTERNET WERE EXPLORED: direct marketing (DM) using banner advertisements; respondent-driven sampling (RDS) using peer recruitment; and venue-based sampling (VBS) using internet venues. RESULTS: A total of 8,434 complete MSM surveys were obtained: 8,109 through DM, 130 through RDS, and 195 through VBS. By methods, enrollment rates ranged from 70-90%; completion rates ranged from 67-95%. DM obtained the largest proportions of racial/ethnic minority MSM (36%) and MSM 18 20 years (19%). CONCLUSIONS: Only the DM method achieved a substantial number of complete MSM surveys. Successful implementation of an internet-based systematic sampling method may be problematic, but a convenience sample of MSM using banner advertisements is feasible and may produce useful and timely behavioral information from a large number of MSM. PMID- 23091582 TI - Trichophyton rubrum-induced Majocchi's Granuloma in a heart transplant recipient. A therapeutic challenge. AB - BACKGROUND: Solid organ transplant recipients are at an increased risk for infections because of long-term immunosuppression to prevent graft rejection. Fungal infections with dermatophytes are a common cause of cutaneous infections seen in organ transplant recipients and cutaneous dermatophyte infections may progress to Majocchi's granuloma. Itraconazole is an anti-fungal compound used for the treatment of infections of the skin, nails and mucous membranes. MAIN OBSERVATION: We report on a heart transplant recipient who developed widespread Trichophyton rubrum infection presenting as Majocchi's granuloma. Itraconazole treatment was complicated by drug interactions. Tricho-phyton rubrum infection progressed, while itraconazole treatment was varied in dose and delivery form. CONCLUSIONS: In patients with Trichophyton rubrum infections, refractory to itraconazole treatment, altered drug absorption or drug interactions has to be considered. Careful monitoring and adjustment of itraconazole is of vital importance. PMID- 23091581 TI - Lobomycosis: A case from Southeastern Europe and review of the literature. AB - BACKGROUND: Lobomycosis, also known as Jorge Lobo's disease, represents a rare chronic subcutaneous mycosis caused by the fungus Lacazia loboi, an organism that is found within lesions but has not been cultured to date. The natural reservoir of L. loboi is unknown but it is believed to be aquatic, or associated with soil and vegetation. More than 550 human cases have been reported, especially in patients with a history of travel or residence in endemic areas (Central and South America, particularly Brazil) or in communities along rivers. MAIN OBSERVATIONS: We describe a 64-year-old Greek female farmer living in a coastal region, who presented with an erythematous plaque on her left inner thigh resembling a keloid. The diagnosis was based on the triad: 1) absence of fungal growth in cultures, 2) positive direct microscopic examination of the lesion and 3) histopathology, all consistent with lobomycosis. Particularly, skin biopsy showed deep cutaneous fungal infection with granulomatous reaction. Fungal cells were found inside giant cells. The fungi were thick-walled with some budding, isolated or in short chains. Dermal fibrosis was present. Our patient had a medical history of common variable immunodeficiency but no history of travel to South or Central America. She probably acquired this rare infection by injury during her agricultural works. CONCLUSION: Our case represents probably the first documented case of human lobomycosis in Southeastern Europe. This case is unusual due to the rarity of lobomycosis in Mediterranean countries, particularly in Southeastern Europe. PMID- 23091583 TI - Post-Irradiation Morphea: Case report and review of the literature. AB - BACKGROUND: Post-irradiation morphea (PIM) is an entity documented in the literature although still not mentioned in most of the dermatological textbooks with a frequency approximately 2 out of every 1000 patients who received radiotherapy. Most of the cases are misdiagnosed as recurrent or metastatic carcinoma. MAIN OBSERVATIONS: We report on a 64-year-old woman who was treated with radiotherapy for breast cancer. Two years and eight months after the first dose of radiotherapy, she developed localized morphea in the irradiated area. CONCLUSION: We report on a new case with a literature review and discuss pathogenesis, treatment modalities and post irradiation subcutaneos reactions mimicking PIM. Around 54 cases of post-irradiation morphea (PIM) were identified in the literature. PMID- 23091584 TI - Ichthyosis bullosa of Siemens. AB - BACKGROUND: Ichthyosis bullosa of Siemens (IBS) is a rare hyperkeratotic blistering condition caused by mutations in keratin 2e gene. MAIN OBSERVATIONS: This is a case of a 18-year-old female with generalized blisters, erosions and thickened skin since she was 3 months old. As she aged, there was decrease in development of blisters and erosions, with accompanying increase in severity of hyperkeratosis. Skin punch biopsy showed overlying basket weave hyperkeratosis and acanthosis, prominent vacuolization of the granular cell layer, and intraepidermal blisters with the split at the granular layer. The patient was treated with emollients, with marked improvement. CONCLUSIONS: Mutations in the different keratin genes have been shown to underlie a wide range of disorders of keratinization. Epidermolytic hyperkeratosis and ichthyosis bullosa of Siemens are distinct disorders with mutations in different genes. Although molecular genetic testing should ideally be done for confirmation of diagnosis, ichthyosis bullosa of Siemens could be diagnosed in this patients based on key clinical characteristics. PMID- 23091585 TI - Kikuchi disease with skin lesions mimicking lupus erythematosus. AB - BACKGROUND: Kikuchi disease (Kikuchi-Fujimoto disease, histiocytic necrotizing lymphadenitis) is a systemic illness of unkown etiology. It is characterized by cervical lymphadenopathy and fever. The skin is the most frequently affected extranodal organ. Cuta-neous Kikuchi-Fujimoto disease can mimic both clinically and histolo-gically skin lesions in lupus erythema-tosus, a disorder with which it seems to be closely related. A close follow up is required as systemic lupus erythema-tosus develop-ment has been reported. MAIN OBSERVATION: We report a case of a 23-year-old woman, who was admitted to our depart-ment with high fever, skin lesions and arthralgia. Scaly and erythematous plaques were noted on both cheeks and earlobes. In pads of feet and hands and periungual area, multiple purple papules with a perilesional erythematous halo were evident. A thoraco-abdominal computed tomography scan revealed lateral cervical, mediastinal, paratracheal, subcarinal and submandi-bular lympha-denopathy. Excisional node biopsy was consisten with Kikuchi disease with skin involvement. CONCLUSION: It has to be kept in mind that Kikuchi disease is a differential diag-nosis in case of fever, lymphade-nopathy and lupus-like skin lesions. Skin lesions in this disease and may resemble clinically and histologically to those of subacute lupus erythema tosus or systemic erythema-tosus lupus. PMID- 23091586 TI - Sezary syndrome, Kaposi sarcoma and generalized dermatophytosis 15 years after sulfur mustard gas exposure. AB - BACKGROUND: The relationship between compromised immune system and the development of malignancy, generalized dermatitis, and infection after sulfur mustard gas exposure has been established. MAIN OBSERVATION: We introduce a 58 year-old man with an abrupt, de novo and erythrodermic eruption in 2002 that was previously exposed to sulfur mustard during the Iran - Iraq war in 1987. Six weeks after the onset of diffuse eruption, he developed papules on the glans penis and generalized dermatophytosis. A biopsy of his eruption was consistent with cutaneous T-cell lymphoma/Sezary syndrome. A complete blood count demonstrated leukocytosis, eosinophilia and atypical lymphocytosis. Subsequently, Sezary syndrome was confirmed and T-cell count with increased CD4/CD8 in flow cytometry. The biopsy of his penile papules was consistent with Kaposi's sarcoma. CONCLUSION: These findings suggest a causative relationship between sulfur mustard gas exposure, cutaneous T cell lymphoma and immune compromised state with opportunistic infections. PMID- 23091587 TI - Photoletter to the editor: Pityriasis Rotunda. AB - Pityriasis rotunda is described as persistent, large, sharply defined circular patches of dry ichthyosiform scaling with no inflammatory changes. Pityriasis rotunda may be associated with systemic diseases (eg. hepatocellular carcinoma). We report a case of pityriasis rotunda in a 19-year-old, otherwise healthy male. The condition started one year prior to his referral. Lesions were distributed over the trunk and upper extremities. Histopathological examination revealed hyperkeratosis, absent granular layer, pigmented basal layer, pigmentary incontinence and perivascular lymphocytic infiltrate. PAS staining for fungi was negative. Treatment of pityriasis rotunda in this case was challenging. When there's an underlying disease, successful treatment of the original disease leads to clearance of pityriasis rotunda lesions. PMID- 23091588 TI - Photoletter to the editor: Hyperkeratosis lenticularis perstans (Flegel's disease) with unusual clinical presentation. Response to isotretinoin therapy. AB - Hyperkeratosis lenticularis perstans also known as Flegel's disease is a keratinisation disorder characterized by small keratotic papules with horny scales. Most cases have been reported in Europe with age of presentation between 35 and 60 years. We report a case of a 25-year-old man, who presented with 1-5 mm multiple asymptomatic hyperkeratotic papules of 15 years duration on both legs and hand along with lichenified plaques with Koebner phenomenon in the axillary folds, anticubital and popliteal fossae. Similar lesions were present in the eyelids also. There was no involvement elsewhere. Similar illness was found in the younger brother aged 13 years with the duration of illness for the past 5 years. Histopathology confirmed the clinical diagnosis. Patient was treated with oral isotretinoin in a daily dose of 20 mg per day to which he responded immediately with clearing of the lesions in two weeks. PMID- 23091589 TI - Photoletter to the editor: Dyschromatosis universalis hereditaria: an infrequently occurring entity in Europe. AB - Dyschromatosis universalis hereditaria (DUH) is a rare genodermatosis mainly described in asian subjects. Here, we report a case of a caucasian 11-year-old boy with DUH and an unaffected twin brother. Parents were not consanguineous. A review of the main phenotical, clinical and hystological aspects of this rare entity is exhibited. Differential diagnose might be stablished with several pigmentary disorders, so Dermatologist might have this entity in mind to make a correct diagnose, specially in cases with no response to typical treatments. PMID- 23091590 TI - Photoletter to the editor: Localized pyoderma gangrenosum after interferon alpha2b injections. AB - We present a male patient with polycythemia vera (PV) in whom pyoderma gangrenosum (PG) was induced by subcutaneous injections of interferon-alpha2beta (IFN-alpha2b).The patient presented with a 6 cm wide necrotic ulcer on the external aspect of his left thigh, which was surrounded by an erythematous and indurated plaque. He also had a simetrical but smaller 2 cm of size ulcer on the external aspect of the right thigh. Histopathological examination showed a massive perivascular and interstitial inflammatory infiltrate. It was vastly composed of neutrophils and secondary formation of interstitial neutrophilic microabscesses was also observed.To our knowledge only two cases of PG secondary to IFN-alpha2b injections have been reported, none of them in a patient with PV. Physicians should be aware of these IFN-alpha2b-related local adverse effects as they might become extremely severe. Immediate local discontinuation of drug administration is mandatory. In order to avoid these complications, alternating injection sites is highly advisable. PMID- 23091591 TI - Photoletter to the editor: Exogenous pigmentation of the sole mimicking in situ acral melanoma on dermoscopy. AB - The parallel ridge pattern, characterized by a parallel band-like pigmentation of the ridges of the surface skin markings, represents the most important dermoscopic feature of in situ acral melanoma. A case of a young girl who showed a plantar pigmented brown macule likely due to prolonged contact with black rubber shoes, revealing a parallel ridge pattern on dermoscopy, is reported and discussed. Although parallel ridge pattern is highly suspicious of early melanoma, exogenous pigmentation should be considered as differential diagnosis in case of rapid onset acral pigmented macules. PMID- 23091592 TI - Consequences of increasing hypoxic disturbance on benthic communities and ecosystem functioning. AB - Disturbance-mediated species loss has prompted research considering how ecosystem functions are changed when biota is impaired. However, there is still limited empirical evidence from natural environments evaluating the direct and indirect (i.e. via biota) effects of disturbance on ecosystem functioning. Oxygen deficiency is a widespread threat to coastal and estuarine communities. While the negative impacts of hypoxia on benthic communities are well known, few studies have assessed in situ how benthic communities subjected to different degrees of hypoxic stress alter their contribution to ecosystem functioning. We studied changes in sediment ecosystem function (i.e. oxygen and nutrient fluxes across the sediment water-interface) by artificially inducing hypoxia of different durations (0, 3, 7 and 48 days) in a subtidal sandy habitat. Benthic chamber incubations were used for measuring responses in sediment oxygen and nutrient fluxes. Changes in benthic species richness, structure and traits were quantified, while stress-induced behavioral changes were documented by observing bivalve reburial rates. The initial change in faunal behavior was followed by non linear degradation in benthic parameters (abundance, biomass, bioturbation potential), gradually impairing the structural and functional composition of the benthic community. In terms of ecosystem function, the increasing duration of hypoxia altered sediment oxygen consumption and enhanced sediment effluxes of NH(4)(+) and dissolved Si. Although effluxes of PO(4)(3-) were not altered significantly, changes were observed in sediment PO(4)(3-) sorption capability. The duration of hypoxia (i.e. number of days of stress) explained a minor part of the changes in ecosystem function. Instead, the benthic community and disturbance driven changes within the benthos explained a larger proportion of the variability in sediment oxygen- and nutrient fluxes. Our results emphasize that the level of stress to the benthic habitat matters, and that the link between biodiversity and ecosystem function is likely to be affected by a range of factors in complex, natural environments. PMID- 23091593 TI - Integrating chemical footprinting data into RNA secondary structure prediction. AB - Chemical and enzymatic footprinting experiments, such as shape (selective 2' hydroxyl acylation analyzed by primer extension), yield important information about RNA secondary structure. Indeed, since the [Formula: see text]-hydroxyl is reactive at flexible (loop) regions, but unreactive at base-paired regions, shape yields quantitative data about which RNA nucleotides are base-paired. Recently, low error rates in secondary structure prediction have been reported for three RNAs of moderate size, by including base stacking pseudo-energy terms derived from shape data into the computation of minimum free energy secondary structure. Here, we describe a novel method, RNAsc (RNA soft constraints), which includes pseudo-energy terms for each nucleotide position, rather than only for base stacking positions. We prove that RNAsc is self-consistent, in the sense that the nucleotide-specific probabilities of being unpaired in the low energy Boltzmann ensemble always become more closely correlated with the input shape data after application of RNAsc. From this mathematical perspective, the secondary structure predicted by RNAsc should be 'correct', in as much as the shape data is 'correct'. We benchmark RNAsc against the previously mentioned method for eight RNAs, for which both shape data and native structures are known, to find the same accuracy in 7 out of 8 cases, and an improvement of 25% in one case. Furthermore, we present what appears to be the first direct comparison of shape data and in line probing data, by comparing yeast asp-tRNA shape data from the literature with data from in-line probing experiments we have recently performed. With respect to several criteria, we find that shape data appear to be more robust than in-line probing data, at least in the case of asp-tRNA. PMID- 23091594 TI - Frequency of infant stroking reported by mothers moderates the effect of prenatal depression on infant behavioural and physiological outcomes. AB - Animal studies find that prenatal stress is associated with increased physiological and emotional reactivity later in life, mediated via fetal programming of the HPA axis through decreased glucocorticoid receptor (GR) gene expression. Post-natal behaviours, notably licking and grooming in rats, cause decreased behavioural indices of fear and reduced HPA axis reactivity mediated via increased GR gene expression. Post-natal maternal behaviours may therefore be expected to modify prenatal effects, but this has not previously been examined in humans. We examined whether, according to self-report, maternal stroking over the first weeks of life modified associations between prenatal depression and physiological and behavioral outcomes in infancy, hence mimicking effects of rodent licking and grooming. From a general population sample of 1233 first time mothers recruited at 20 weeks gestation we drew a stratified random sample of 316 for assessment at 32 weeks based on reported inter-partner psychological abuse, a risk to child development. Of these 271 provided data at 5, 9 and 29 weeks post delivery. Mothers reported how often they stroked their babies at 5 and 9 weeks. At 29 weeks vagal withdrawal to a stressor, a measure of physiological adaptability, and maternal reported negative emotionality were assessed. There was a significant interaction between prenatal depression and maternal stroking in the prediction of vagal reactivity to a stressor (p = .01), and maternal reports of infant anger proneness (p = .007) and fear (p = .043). Increasing maternal depression was associated with decreasing physiological adaptability, and with increasing negative emotionality, only in the presence of low maternal stroking. These initial findings in humans indicate that maternal stroking in infancy, as reported by mothers, has effects strongly resembling the effects of observed maternal behaviours in animals, pointing to future studies of the epigenetic, physiological and behavioral effects of maternal stroking. PMID- 23091595 TI - MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. AB - MicroRNA (miR)-155 is a critical player in both innate and adaptive immune responses. It can influence CD4(+) T cell lineage choice. To clarify the role of miR-155 in CD4(+) CD25(+) regulatory T (Treg)/T helper (Th)17 cell differentiation and function, as well as the mechanism involved, we performed gain-and loss-of-function analysis by transfection pre-miR-155 and anti-miR-155 into purified CD4(+) T cells. The results showed that miR-155 positively regulated both Treg and Th17 cell differentiation. It also induced the release of interleukin (IL)-17A by Th17 cells, but not the release of IL-10 and transforming growth factor (TGF)-beta1 by Treg cells. Furthermore, we found that miR-155 reacted through regulating Janus kinase/signal transducer and activator of transcription (JAK/STAT) rather than TGF-beta/mothers against decapentaplegic homolog (SMAD) signaling pathway in the process of Treg and Th17 cells differentiation. This may because suppressors of cytokine signaling (SOCS)1, the important negative regulator of JAK/STAT signaling pathway, was the direct target of miR-155 in this process, but SMAD2 and SMAD5 were not. Therefore, we demonstrated that miR-155 enhanced Treg and Th17 cells differentiation and IL-17A production by targeting SOCS1. PMID- 23091596 TI - Fractional flow reserve is not associated with inflammatory markers in patients with stable coronary artery disease. AB - BACKGROUND: Atherosclerosis is an inflammatory condition and increased blood levels of inflammatory biomarkers have been observed in acute coronary syndromes. In addition, high expression of inflammatory markers is associated with worse prognosis of coronary artery disease. The presence and extent of inducible ischemia in patients with stable angina has previously been shown to have strong prognostic value. We hypothesized that evidence of inducible myocardial ischemia by local lesions, as measured by fractional flow reserve (FFR), is associated with increased levels of blood based inflammatory biomarkers. METHODS: Whole blood samples of 89 patients with stable angina pectoris and 16 healthy controls were analyzed. The patients with stable angina pectoris underwent coronary angiography and FFR of all coronary lesions. We analyzed plasma levels of cytokines IL-6, IL-8 and TNF-alpha and membrane expression of Toll-like receptor 2 and 4, CD11b, CD62L and CD14 on monocytes and granulocytes as markers of inflammation. Furthermore, we quantified the severity of hemodynamically significant coronary artery disease by calculating Functional Syntax Score (FSS), an extension of the Syntax Score. RESULTS: For the majority of biomarkers, we observed lower levels in the healthy control group compared with patients with stable angina who underwent coronary catheterization. We found no difference for any of the selected biomarkers between patients with a positive FFR (<= 0.75) and negative FFR (>0.80). We observed no relationship between the investigated biomarkers and FSS. CONCLUSION: The presence of local atherosclerotic lesions that result in inducible myocardial ischemia as measured by FFR in patients with stable coronary artery disease is not associated with increased plasma levels of IL-6, IL-8 and TNF-alpha or increased expression of TLR2 and TLR4, CD11b, CD62L and CD14 on circulating leukocytes. PMID- 23091597 TI - Site directed mutagenesis of Schizosaccharomyces pombe glutathione synthetase produces an enzyme with homoglutathione synthetase activity. AB - Three different His-tagged, mutant forms of the fission yeast glutathione synthetase (GSH2) were derived by site-directed mutagenesis. The mutant and wild type enzymes were expressed in E. coli DH5alpha and affinity purified in a two step procedure. Analysis of enzyme activity showed that it was possible to shift the substrate specificity of GSH2 from Gly (k(m) 0,19; wild-type) to beta-Ala or Ser. One mutation (substitution of Ile471, Cy472 to Met and Val and Ala 485 and Thr486 to Leu and Pro) increased the affinity of GSH2 for beta-Ala (k(m) 0,07) and lowered the affinity for Gly (k(m) 0,83), which is a characteristic of the enzyme homoglutathione synthetase found in plants. Substitution of Ala485 and Thr486 to Leu and Pro only, increased instead the affinity of GSH2 for Ser (k(m) 0,23) as a substrate, while affinity to Gly was preserved (k(m) 0,12). This provides a new biosynthetic pathway for hydroxymethyl glutathione, which is known to be synthesized from glutathione and Ser in a reaction catalysed by carboxypeptidase Y. The reported findings provide further insight into how specific amino acids positioned in the GSH2 active site facilitate the recognition of different amino acid substrates, furthermore they support the evolutionary theory that homoglutathione synthetase evolved from glutathione synthetase by a single gene duplication event. PMID- 23091598 TI - A loud auditory stimulus overcomes voluntary movement limitation in cervical dystonia. AB - BACKGROUND: Patients with cervical dystonia (CD) present with an impaired performance of voluntary neck movements, which are usually slow and limited. We hypothesized that such abnormality could involve defective preparation for task execution. Therefore, we examined motor preparation in CD patients using the StartReact method. In this test, a startling auditory stimulus (SAS) is delivered unexpectedly at the time of the imperative signal (IS) in a reaction time task to cause a faster execution of the prepared motor programme. We expected that CD patients would show an abnormal StartReact phenomenon. METHODS: Fifteen CD patients and 15 age matched control subjects (CS) were asked to perform a rotational movement (RM) to either side as quick as possible immediately after IS perception (a low intensity electrical stimulus to the II finger). In randomly interspersed test trials (25%) a 130 dB SAS was delivered simultaneously with the IS. We recorded RMs in the horizontal plane with a high speed video camera (2.38 ms per frame) in synchronization with the IS. The RM kinematic-parameters (latency, velocity, duration and amplitude) were analyzed using video-editing software and screen protractor. Patients were asked to rate the difficulty of their RMs in a numerical rating scale. RESULTS: In control trials, CD patients executed slower RMs (repeated measures ANOVA, p<0.10(-5)), and reached a smaller final head position angle relative to the midline (p<0.05), than CS. In test trials, SAS improved all RMs in both groups (p<0.10(-14)). In addition, patients were more likely to reach beyond their baseline RM than CS (chi(2), p<0.001) and rated their performance better than in control trials (t-test, p<0.01). CONCLUSION: We found improvement of kinematic parameters and subjective perception of motor performance in CD patients with StartReact testing. Our results suggest that CD patients reach an adequate level of motor preparation before task execution. PMID- 23091599 TI - Characterization of bacteria associated with pinewood nematode Bursaphelenchus xylophilus. AB - Pine Wilt Disease (PWD) is a complex disease integrating three major agents: the pathogenic agent, the pinewood nematode Bursaphelenchus xylophilus; the insect vector Monochamus spp.; and the host pine tree, Pinus sp. Since the early 80's, the notion that another pathogenic agent, namely bacteria, may play a role in PWD has been gaining traction, however the role of bacteria in PWD is still unknown. The present work supports the possibility that some B. xylophilus-associated bacteria may play a significant role in the development of this disease. This is inferred as a consequence of: (i) the phenotypic characterization of a collection of 35 isolates of B. xylophilus-associated bacteria, in different tests broadly used to test plant pathogenic and plant growth promoting bacteria, and (ii) greenhouse experiments that infer the pathogenicity of these bacteria in maritime pine, Pinus pinaster. The results illustrate the presence of a heterogeneous microbial community associated with B. xylophilus and the traits exhibited by at least, some of these bacteria, appear to be related to PWD symptoms. The inoculation of four specific B. xylophilus-associated bacteria isolates in P. pinaster seedlings resulted in the development of some PWD symptoms suggesting that these bacteria likely play an active role with B. xylophilus in PWD. PMID- 23091600 TI - Plasma-derived exosomal survivin, a plausible biomarker for early detection of prostate cancer. AB - BACKGROUND: Survivin is expressed in prostate cancer (PCa), and its downregulation sensitizes PCa cells to chemotherapeutic agents in vitro and in vivo. Small membrane-bound vesicles called exosomes, secreted from the endosomal membrane compartment, contain RNA and protein that they readily transport via exosome internalization into recipient cells. Recent progress has shown that tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions via immune escape, tumor invasion and angiogenesis. Furthermore, exosome analysis may provide novel biomarkers to diagnose or monitor PCa treatment. METHODS: Exosomes were purified from the plasma and serum from 39 PCa patients, 20 BPH patients, 8 prostate cancer recurrent and 16 healthy controls using ultracentrifugation and their quantities and qualities were quantified and visualized from both the plasma and the purified exosomes using ELISA and Western blotting, respectively. RESULTS: Survivin was significantly increased in the tumor-derived samples, compared to those from BPH and controls with virtually no difference in the quantity of Survivin detected in exosomes collected from newly diagnosed patients exhibiting low (six) or high (nine) Gleason scores. Exosome Survivin levels were also higher in patients that had relapsed on chemotherapy compared to controls. CONCLUSIONS: These studies demonstrate that Survivin exists in plasma exosomes from both normal, BPH and PCa subjects. The relative amounts of exosomal Survivin in PCa plasma was significantly higher than in those with pre-inflammatory BPH and control plasma. This differential expression of exosomal Survivin was seen with both newly diagnosed and advanced PCa subjects with high or low-grade cancers. Analysis of plasma exosomal Survivin levels may offer a convenient tool for diagnosing or monitoring PCa and may, as it is elevated in low as well as high Gleason scored samples, be used for early detection. PMID- 23091601 TI - Single liver lobe repopulation with wildtype hepatocytes using regional hepatic irradiation cures jaundice in Gunn rats. AB - BACKGROUND AND AIMS: Preparative hepatic irradiation (HIR), together with mitotic stimulation of hepatocytes, permits extensive hepatic repopulation by transplanted hepatocytes in rats and mice. However, whole liver HIR is associated with radiation-induced liver disease (RILD), which limits its potential therapeutic application. In clinical experience, restricting HIR to a fraction of the liver reduces the susceptibility to RILD. Here we test the hypothesis that repopulation of selected liver lobes by regional HIR should be sufficient to correct some inherited metabolic disorders. METHODS: Hepatocytes (10(7)) isolated from wildtype F344 rats or Wistar-RHA rats were engrafted into the livers of congeneic dipeptidylpeptidase IV deficient (DPPIV(-)) rats or uridinediphosphoglucuronateglucuronosyltransferase-1A1-deficient jaundiced Gunn rats respectively by intrasplenic injection 24 hr after HIR (50 Gy) targeted to the median lobe, or median plus left liver lobes. An adenovector expressing hepatocyte growth factor (10(11) particles) was injected intravenously 24 hr after transplantation. RESULTS: Three months after hepatocyte transplantation in DPPIV(-) rats, 30-60% of the recipient hepatocytes were replaced by donor cells in the irradiated lobe, but not in the nonirradiated lobes. In Gunn rats receiving median lobe HIR, serum bilirubin declined from pretreatment levels of 5.17 +/- 0.78 mg/dl to 0.96 +/- 0.30 mg/dl in 8 weeks and remained at this level throughout the 16 week observation period. A similar effect was observed in the group, receiving median plus left lobe irradiation. CONCLUSIONS: As little as 20% repopulation of 30% of the liver volume was sufficient to correct hyperbilirubinemia in Gunn rats, highlighting the potential of regiospecific HIR in hepatocyte transplantation-based therapy of inherited metabolic liver diseases. PMID- 23091602 TI - Beneficial effects of sitostanol on the attenuated immune function in asthma patients: results of an in vitro approach. AB - BACKGROUND: In vitro and animal studies have suggested that plant sterols and stanols increase cytokine production by T-helper-1 cells. This may be beneficial for patient groups characterized by a T-helper-2 dominant immune response, e.g. asthma patients. (1) to evaluate whether sitostanol induces a T-helper-1 shift in peripheral blood mononuclear cells (PBMCs) from asthma patients, and (2) to unravel the role of regulatory T-cells in this respect. METHODOLOGY/PRINCIPAL FINDINGS: PBMCs from 10 asthma patients and 10 healthy subjects were isolated and incubated with 1.2 uM sitostanol, while stimulated with 5 ug/ml PHA. Similar amounts of cholesterol were used to determine whether effects were specific for plant stanols or for sterols in general. Changes in cytokine production were measured using antibody arrays and ELISAs. Changes in regulatory T-cell population size were measured by flow cytometry, using intracellular Foxp3 staining. Sitostanol increased production of IFNgamma by 6.5% and IL-2 by 6.0% compared to cholesterol (p<0.01). No changes in IL-4 and IL-13 were found. Interestingly, this effect was only present in PBMCs from asthma patients. The number of Foxp3+ cells tended to increase and their activity, measured by IL-10 production, increased after sitostanol treatment in PBMCs from asthma patients compared to controls by 32.3% (p = 0.077) and 13.3% (p<0.05), respectively. CONCLUSIONS/SIGNIFICANCE: Altogether, the sitostanol-induced Thelper-1 shift in PBMCs from asthma patients and the stimulating effects of sitostanol on Treg cell numbers and activity indicate a possible novel approach for plant stanol ester enriched functional foods in the amelioration of asthmatic symptoms. Functional effects, however, require further evaluation. PMID- 23091604 TI - Oxidized LDL triggers pro-oncogenic signaling in human breast mammary epithelial cells partly via stimulation of MiR-21. AB - Dyslipidemia and obesity are primary risk factors for the development of atherosclerosis and are also epidemiologically linked to increased susceptibility to a variety of cancers including breast cancer. One of the prominent features of dyslipidemia is enhanced production of oxidized LDL (ox-LDL), which has been shown to be implicated in key steps of atherogenesis including inflammatory signaling and proliferation of vascular cells. In this study we analyzed the effects of ox-LDL in human mammary epithelial cells (MCF10A). MCF10A cells avidly internalized dil-ox-LDL and exhibited increased proliferative response to ox-LDL within the range of 1-50 ug/ml in a dose-dependent manner. Treatment of cells with 20 ug/ml ox-LDL for 2 and 12 hours was associated with upregulation of LOX-1 and CD36 scavenger receptors while MSR1 and CXLC16 receptors did not change. Ox LDL-treated cells displayed significant upregulation of NADPH oxidases (subunits P22(phox) and P47(phox)), lipoxygenases-12 and -15, and cytoplasmic, but not mitochondrial, SOD. Ox-LDL also triggered phosphorylation of IkappaBalpha coupled with nuclear translocation of NF-kappaB and stimulated p44/42 MAPK, PI3K and Akt while intracellular PTEN (PI3K/Akt pathway inhibitor and target of miR-21) declined. Quantitative PCR revealed increased expression of hsa-miR-21 in ox-LDL treated cells coupled with inhibition of miR-21 target genes. Further, transfection of MCF10A cells with miR-21 inhibitor prevented ox-LDL mediated stimulation of PI3K and Akt. We conclude that, similarly to vascular cells, mammary epithelial cells respond to ox-LDL by upregulation of proliferative and pro-inflammatory signaling. We also report for the first time that part of ox-LDL triggered reactions in MCF10A cells is mediated by oncogenic hsa-miR-21 through inhibition of its target gene PTEN and consequent activation of PI3K/Akt pathway. PMID- 23091605 TI - Vapor of volatile oils from Litsea cubeba seed induces apoptosis and causes cell cycle arrest in lung cancer cells. AB - Non-small cell lung carcinoma (NSCLC) is a major killer in cancer related human death. Its therapeutic intervention requires superior efficient molecule(s) as it often becomes resistant to present chemotherapy options. Here we report that vapor of volatile oil compounds obtained from Litsea cubeba seeds killed human NSCLC cells, A549, through the induction of apoptosis and cell cycle arrest. Vapor generated from the combined oils (VCO) deactivated Akt, a key player in cancer cell survival and proliferation. Interestingly VCO dephosphorylated Akt at both Ser(473) and Thr(308); through the suppression of mTOR and pPDK1 respectively. As a consequence of this, diminished phosphorylation of Bad occurred along with the decreased Bcl-xL expression. This subsequently enhanced Bax levels permitting the release of mitochondrial cytochrome c into the cytosol which concomitantly activated caspase 9 and caspase 3 resulting apoptotic cell death. Impairment of Akt activation by VCO also deactivated Mdm2 that effected overexpression of p53 which in turn upregulated p21 expression. This causes enhanced p21 binding to cyclin D1 that halted G1 to S phase progression. Taken together, VCO produces two prong effects on lung cancer cells, it induces apoptosis and blocked cancer cell proliferation, both occurred due to the deactivation of Akt. In addition, it has another crucial advantage: VCO could be directly delivered to lung cancer tissue through inhalation. PMID- 23091606 TI - Complement depletion deteriorates clinical outcomes of severe abdominal sepsis: a conspirator of infection and coagulopathy in crime? AB - BACKGROUND: The complement depletion commonly occurred during sepsis, but it was often underestimated compared with severe infection or coagulation dysfunction. OBJECTIVE: This study was designed to investigate the alteration of complement system in patients with severe abdominal sepsis and evaluate the role of complement depletion in prognosis of such patients. The relationship between complement depletion and infection or coagulopathy was also explored. METHODS: Forty-five patients with severe abdominal sepsis were prospectively conducted among individuals referral to SICU. Currently recommended treatments, such as early goal-directed resuscitation, source control and antibiotics therapy, were performed. Acute physiology and chronic health evaluation II (APACHE II) and sepsis related organ failure assessment (SOFA) scores were employed to evaluate severity. Plasma levels of C3, C4, CRP, PCT, D-dimer and other parameters were detected within eight times of observation. The 28-day mortality, length of stay, and postoperative complications were compared between complement depletion and non-complement depletion groups. RESULTS: Within the study period, eight (17.8%) patients died, five of them suffering from complement depletion. The overall incidence of complement depletion was 64.4%. At admission, mean complement C3 and C4 levels were 0.70 and 0.13 mg/mL, respectively. Using ROC analysis for mortality prediction, the area under the curve of C3 was 0.926 (95% CI, 0.845 0.998, P<0.001), with optimal cutpoint value of 0.578 mg/mL. Complement C3 depletion was shown to be no correlation to severity scores, however, strongly correlated with elevated D-dimer, PCT concentrations and increased postoperative complications. CONCLUSIONS: Complement C3 depletion was found to be connected to poor prognosis in severe abdominal sepsis. This depletion seems to be associated with coagulopathy and aggravated infection during sepsis, which should be paid close attention in critical care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01568853. PMID- 23091607 TI - Modulation of self-esteem in self- and other-evaluations primed by subliminal and supraliminal faces. AB - BACKGROUND: Past research examining implicit self-evaluation often manipulated self-processing as task-irrelevant but presented self-related stimuli supraliminally. Even when tested with more indirect methods, such as the masked priming paradigm, participants' responses may still be subject to conscious interference. Our study primed participants with either their own or someone else's face, and adopted a new paradigm to actualize strict face-suppression to examine participants' subliminal self-evaluation. In addition, we investigated how self-esteem modulates one's implicit self-evaluation and validated the role of awareness in creating the discrepancy on past findings between measures of implicit self-evaluation and explicit self-esteem. METHODOLOGY/PRINCIPAL FINDINGS: Participants' own face or others' faces were subliminally presented with a Continuous Flash Suppression (CFS) paradigm in Experiment 1, but supraliminally presented in Experiment 2, followed by a valence judgment task of personality adjectives. Participants also completed the Rosenberg Self-Esteem Scale in each experiment. Results from Experiment 1 showed a typical bias of self positivity among participants with higher self-esteem, but only a marginal self positivity bias and a significant other-positivity bias among those with lower self-esteem. However, self-esteem had no modulating effect in Experiment 2: All participants showed the self-positivity bias. CONCLUSIONS/SIGNIFICANCE: Our results provide direct evidence that self-evaluation manifests in different ways as a function of awareness between individuals with different self-views: People high and low in self-esteem may demonstrate different automatic reactions in the subliminal evaluations of the self and others; but the involvement of consciousness with supraliminally presented stimuli may reduce this dissociation. PMID- 23091603 TI - De novo assembly, characterization and functional annotation of pineapple fruit transcriptome through massively parallel sequencing. AB - BACKGROUND: Pineapple (Ananas comosus var. comosus), is an important tropical non climacteric fruit with high commercial potential. Understanding the mechanism and processes underlying fruit ripening would enable scientists to enhance the improvement of quality traits such as, flavor, texture, appearance and fruit sweetness. Although, the pineapple is an important fruit, there is insufficient transcriptomic or genomic information that is available in public databases. Application of high throughput transcriptome sequencing to profile the pineapple fruit transcripts is therefore needed. METHODOLOGY/PRINCIPAL FINDINGS: To facilitate this, we have performed transcriptome sequencing of ripe yellow pineapple fruit flesh using Illumina technology. About 4.7 millions Illumina paired-end reads were generated and assembled using the Velvet de novo assembler. The assembly produced 28,728 unique transcripts with a mean length of approximately 200 bp. Sequence similarity search against non-redundant NCBI database identified a total of 16,932 unique transcripts (58.93%) with significant hits. Out of these, 15,507 unique transcripts were assigned to gene ontology terms. Functional annotation against Kyoto Encyclopedia of Genes and Genomes pathway database identified 13,598 unique transcripts (47.33%) which were mapped to 126 pathways. The assembly revealed many transcripts that were previously unknown. CONCLUSIONS: The unique transcripts derived from this work have rapidly increased of the number of the pineapple fruit mRNA transcripts as it is now available in public databases. This information can be further utilized in gene expression, genomics and other functional genomics studies in pineapple. PMID- 23091608 TI - Accurate simulation and detection of coevolution signals in multiple sequence alignments. AB - BACKGROUND: While the conserved positions of a multiple sequence alignment (MSA) are clearly of interest, non-conserved positions can also be important because, for example, destabilizing effects at one position can be compensated by stabilizing effects at another position. Different methods have been developed to recognize the evolutionary relationship between amino acid sites, and to disentangle functional/structural dependencies from historical/phylogenetic ones. METHODOLOGY/PRINCIPAL FINDINGS: We have used two complementary approaches to test the efficacy of these methods. In the first approach, we have used a new program, MSAvolve, for the in silico evolution of MSAs, which records a detailed history of all covarying positions, and builds a global coevolution matrix as the accumulated sum of individual matrices for the positions forced to co-vary, the recombinant coevolution, and the stochastic coevolution. We have simulated over 1600 MSAs for 8 protein families, which reflect sequences of different sizes and proteins with widely different functions. The calculated coevolution matrices were compared with the coevolution matrices obtained for the same evolved MSAs with different coevolution detection methods. In a second approach we have evaluated the capacity of the different methods to predict close contacts in the representative X-ray structures of an additional 150 protein families using only experimental MSAs. CONCLUSIONS/SIGNIFICANCE: Methods based on the identification of global correlations between pairs were found to be generally superior to methods based only on local correlations in their capacity to identify coevolving residues using either simulated or experimental MSAs. However, the significant variability in the performance of different methods with different proteins suggests that the simulation of MSAs that replicate the statistical properties of the experimental MSA can be a valuable tool to identify the coevolution detection method that is most effective in each case. PMID- 23091609 TI - The shape of the urine stream--from biophysics to diagnostics. AB - We develop a new computational model of capillary-waves in free-jet flows, and apply this to the problem of urological diagnosis in this first ever study of the biophysics behind the characteristic shape of the urine stream as it exits the urethral meatus. The computational fluid dynamics model is used to determine the shape of a liquid jet issuing from a non-axisymmetric orifice as it deforms under the action of surface tension. The computational results are verified with experimental modelling of the urine stream. We find that the shape of the stream can be used as an indicator of both the flow rate and orifice geometry. We performed volunteer trials which showed these fundamental correlations are also observed in vivo for male healthy volunteers and patients undergoing treatment for low flow rate. For healthy volunteers, self estimation of the flow shape provided an accurate estimation of peak flow rate (+/- 2%). However for the patients, the relationship between shape and flow rate suggested poor meatal opening during voiding. The results show that self measurement of the shape of the urine stream can be a useful diagnostic tool for medical practitioners since it provides a non-invasive method of measuring urine flow rate and urethral dilation. PMID- 23091612 TI - Mirrored prominent deck B phenomenon: frequent small losses override infrequent large gains in the inverted Iowa Gambling Task. AB - Since Bechara et al. pioneered its development, the Iowa Gambling Task (IGT) has been widely applied to elucidate decision behavior and medial prefrontal function. Although most decision makers can hunch the final benefits of IGT, ventromedial prefrontal lesions generate a myopic choice pattern. Additionally, the Iowa group developed a revised IGT (inverted IGT, iIGT) to confirm the IGT validity. Each iIGT trial was generated from the trial of IGT by multiplying by a "-" to create an inverted monetary value. Thus, bad decks A and B in the IGT become good decks iA and iB in the iIGT; additionally, good decks C and D in the IGT become bad decks iC and iD in the iIGT. Furthermore, IGT possessed mostly the gain trials, and iIGT possessed mainly the loss trials. Therefore, IGT is a frequent-gain-based task, and iIGT is a frequent-loss-based task. However, a growing number of IGT-related studies have identified confounding factors in IGT (i.e., gain-loss frequency), which are demonstrated by the prominent deck B phenomenon (PDB phenomenon). Nevertheless, the mirrored PDB phenomenon and guiding power of gain-loss frequency in iIGT have seldom been reexamined. This experimental finding supports the prediction based on gain-loss frequency. This study identifies the mirrored PDB phenomenon. Frequent small losses override occasional large gains in deck iB of the iIGT. Learning curve analysis generally supports the phenomenon based on gain-loss frequency rather than final outcome. In terms of iIGT and simple versions of iIGT, results of this study demonstrate that high-frequency loss, rather than a satisfactory final outcome, dominates the preference of normal decision makers under uncertainty. Furthermore, normal subjects prefer "no immediate punishment" rather than "final reward" under uncertainty. PMID- 23091610 TI - Integrative analysis of somatic mutations altering microRNA targeting in cancer genomes. AB - Determining the functional impact of somatic mutations is crucial to understanding tumorigenesis and metastasis. Recent sequences of several cancers have provided comprehensive lists of somatic mutations across entire genomes, enabling investigation of the functional impact of somatic mutations in non coding regions. Here, we study somatic mutations in 3'UTRs of genes that have been identified in four cancers and computationally predict how they may alter miRNA targeting, potentially resulting in dysregulation of the expression of the genes harboring these mutations. We find that somatic mutations create or disrupt putative miRNA target sites in the 3'UTRs of many genes, including several genes, such as MITF, EPHA3, TAL1, SCG3, and GSDMA, which have been previously associated with cancer. We also integrate the somatic mutations with germline mutations and results of association studies. Specifically, we identify putative miRNA target sites in the 3'UTRs of BMPR1B, KLK3, and SPRY4 that are disrupted by both somatic and germline mutations and, also, are in linkage disequilibrium blocks with high scoring markers from cancer association studies. The somatic mutation in BMPR1B is located in a target site of miR-125b; germline mutations in this target site have previously been both shown to disrupt regulation of BMPR1B by miR-125b and linked with cancer. PMID- 23091611 TI - Methylation of p15INK4b and expression of ANRIL on chromosome 9p21 are associated with coronary artery disease. AB - BACKGROUND: Genome-wide association studies have identified that multiple single nucleiotide polymorphisms on chromosome 9p21 are tightly associated with coronary artery disease (CAD). However, the mechanism linking this risk locus to CAD remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: The methylation status of six candidate genes (BAX, BCL-2, TIMP3, p14(ARF), p15(INK4b) and p16(INK4a)) in 205 patients and controls who underwent coronary angiography were analyzed by quantitative MethyLight assay. Rs10757274 was genotyped and expression of INK4/ARF and antisense non-coding RNA in the INK4 locus (ANRIL) was determined by real-time RT-PCR. Compared with controls, DNA methylation levels at p15(INK4b) significantly increased in CAD patients (p = 0.006). To validate and dissect the methylation percentage of each target CpG site at p15(INK4b), pyrosequencing was performed, finding CpG +314 and +332 remarkably hypermethylated in CAD patients. Further investigation determined that p15(INK4b) hypermethylation prevalently emerged in lymphocytes of CAD patients (p = 0.013). The rs10757274 genotype was significantly associated with CAD (p = 0.003) and GG genotype carriers had a higher level of ANRIL exon 1-5 expression compared among three genotypes (p = 0.009). There was a stepwise increase in p15(INK4b) and p16(INK4a) methylation as ANRIL exon 1-5 expression elevated (r = 0.23, p = 0.001 and r = 0.24, p = 0.001, respectively), although neither of two loci methylation was directly linked to rs10757274 genotype. CONCLUSIONS/SIGNIFICANCE: p15(INK4b) methylation is associated with CAD and ANRIL expression. The epigenetic changes in p15(INK4b) methylation and ANRIL expression may involve in the mechanisms of chromosome 9p21 on CAD development. PMID- 23091613 TI - Germ cells are not required to establish the female pathway in mouse fetal gonads. AB - The fetal gonad is composed of a mixture of somatic cell lineages and germ cells. The fate of the gonad, male or female, is determined by a population of somatic cells that differentiate into Sertoli or granulosa cells and direct testis or ovary development. It is well established that germ cells are not required for the establishment or maintenance of Sertoli cells or testis cords in the male gonad. However, in the agametic ovary, follicles do not form suggesting that germ cells may influence granulosa cell development. Prior investigations of ovaries in which pre-meiotic germ cells were ablated during fetal life reported no histological changes during stages prior to birth. However, whether granulosa cells underwent normal molecular differentiation was not investigated. In cases where germ cell loss occurred secondary to other mutations, transdifferentiation of granulosa cells towards a Sertoli cell fate was observed, raising questions about whether germ cells play an active role in establishing or maintaining the fate of granulosa cells. We developed a group of molecular markers associated with ovarian development, and show here that the loss of pre-meiotic germ cells does not disrupt the somatic ovarian differentiation program during fetal life, or cause transdifferentiation as defined by expression of Sertoli markers. Since we do not find defects in the ovarian somatic program, the subsequent failure to form follicles at perinatal stages is likely attributable to the absence of germ cells rather than to defects in the somatic cells. PMID- 23091614 TI - Air bubble contact with endothelial cells causes a calcium-independent loss in mitochondrial membrane potential. AB - OBJECTIVE: Gas microembolism remains a serious risk associated with surgical procedures and decompression. Despite this, the signaling consequences of air bubbles in the vasculature are poorly understood and there is a lack of pharmacological therapies available. Here, we investigate the mitochondrial consequences of air bubble contact with endothelial cells. METHODS AND RESULTS: Human umbilical vein endothelial cells were loaded with an intracellular calcium indicator (Fluo-4) and either a mitochondrial calcium indicator (X-Rhod-1) or mitochondrial membrane potential indicator (TMRM). Contact with 50-150 um air bubbles induced concurrent rises in intracellular and mitochondrial calcium, followed by a loss of mitochondrial membrane potential. Pre-treating cells with 1 umol/L ruthenium red, a TRPV family calcium channel blocker, did not protect cells from the mitochondrial depolarization, despite blocking the intracellular calcium response. Mitigating the interactions between the air-liquid interface and the endothelial surface layer with 5% BSA or 0.1% Pluronic F-127 prevented the loss of mitochondrial membrane potential. Finally, inhibiting protein kinase C-alpha (PKCalpha), with 5 umol/L Go6976, protected cells from mitochondrial depolarization, but did not affect the intracellular calcium response. CONCLUSIONS: Our results indicate that air bubble contact with endothelial cells activates a novel, calcium-independent, PKCalpha-dependent signaling pathway, which results in mitochondrial depolarization. As a result, mitochondrial dysfunction is likely to be a key contributor to the pathophysiology of gas embolism injury. Further, this connection between the endothelial surface layer and endothelial mitochondria may also play an important role in vascular homeostasis and disease. PMID- 23091615 TI - Oleanolic acid: a novel cardioprotective agent that blunts hyperglycemia-induced contractile dysfunction. AB - Diabetes constitutes a major health challenge. Since cardiovascular complications are common in diabetic patients this will further increase the overall burden of disease. Furthermore, stress-induced hyperglycemia in non-diabetic patients with acute myocardial infarction is associated with higher in-hospital mortality. Previous studies implicate oxidative stress, excessive flux through the hexosamine biosynthetic pathway (HBP) and a dysfunctional ubiquitin-proteasome system (UPS) as potential mediators of this process. Since oleanolic acid (OA; a clove extract) possesses antioxidant properties, we hypothesized that it attenuates acute and chronic hyperglycemia-mediated pathophysiologic molecular events (oxidative stress, apoptosis, HBP, UPS) and thereby improves contractile function in response to ischemia-reperfusion. We employed several experimental systems: 1) H9c2 cardiac myoblasts were exposed to 33 mM glucose for 48 hr vs. controls (5 mM glucose); and subsequently treated with two OA doses (20 and 50 uM) for 6 and 24 hr, respectively; 2) Isolated rat hearts were perfused ex vivo with Krebs-Henseleit buffer containing 33 mM glucose vs. controls (11 mM glucose) for 60 min, followed by 20 min global ischemia and 60 min reperfusion +/- OA treatment; 3) In vivo coronary ligations were performed on streptozotocin treated rats +/- OA administration during reperfusion; and 4) Effects of long-term OA treatment (2 weeks) on heart function was assessed in streptozotocin-treated rats. Our data demonstrate that OA treatment blunted high glucose-induced oxidative stress and apoptosis in heart cells. OA therapy also resulted in cardioprotection, i.e. for ex vivo and in vivo rat hearts exposed to ischemia reperfusion under hyperglycemic conditions. In parallel, we found decreased oxidative stress, apoptosis, HBP flux and proteasomal activity following ischemia reperfusion. Long-term OA treatment also improved heart function in streptozotocin-diabetic rats. These findings are promising since it may eventually result in novel therapeutic interventions to treat acute hyperglycemia (in non-diabetic patients) and diabetic patients with associated cardiovascular complications. PMID- 23091616 TI - Accelerated growth plate mineralization and foreshortened proximal limb bones in fetuin-A knockout mice. AB - The plasma protein fetuin-A/alpha2-HS-glycoprotein (genetic symbol Ahsg) is a systemic inhibitor of extraskeletal mineralization, which is best underscored by the excessive mineral deposition found in various tissues of fetuin-A deficient mice on the calcification-prone genetic background DBA/2. Fetuin-A is known to accumulate in the bone matrix thus an effect of fetuin-A on skeletal mineralization is expected. We examined the bones of fetuin-A deficient mice maintained on a C57BL/6 genetic background to avoid bone disease secondary to renal calcification. Here, we show that fetuin-A deficient mice display normal trabecular bone mass in the spine, but increased cortical thickness in the femur. Bone material properties, as well as mineral and collagen characteristics of cortical bone were unaffected by the absence of fetuin-A. In contrast, the long bones especially proximal limb bones were severely stunted in fetuin-A deficient mice compared to wildtype littermates, resulting in increased biomechanical stability of fetuin-A deficient femora in three-point-bending tests. Elevated backscattered electron signal intensities reflected an increased mineral content in the growth plates of fetuin-A deficient long bones, corroborating its physiological role as an inhibitor of excessive mineralization in the growth plate cartilage matrix--a site of vigorous physiological mineralization. We show that in the case of fetuin-A deficiency, active mineralization inhibition is a necessity for proper long bone growth. PMID- 23091617 TI - Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem-like glioma cells. AB - We asked whether inhibitors of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, which is highly active in cancer stem cells (CSCs) and upregulated in response to genotoxic treatments, promote gamma-irradiationgammaIR)-induced cell death in highly radioresistant, patient-derived stem-like glioma cells (SLGCs). Surprisingly, in most cases the inhibitors did not promote gammaIR-induced cell death. In contrast, the strongly cytostatic Ly294002 and PI-103 even tended to reduce it. Since autophagy was induced we examined whether addition of the clinically applicable autophagy inhibitor chloroquine (CQ) would trigger cell death in SLGCs. Triple therapy with CQ at doses as low as 5 to 10 uM indeed caused strong apoptosis. At slightly higher doses, CQ alone strongly promoted gammaIR-induced apoptosis in all SLGC lines examined. The strong apoptosis in combinations with CQ was invariably associated with strong accumulation of the autophagosomal marker LC3-II, indicating inhibition of late autophagy. Thus, autophagy-promoting effects of PI3K/Akt pathway inhibitors apparently hinder cell death induction in gamma-irradiated SLGCs. However, as we show here for the first time, the late autophagy inhibitor CQ strongly promotes gammaIR-induced cell death in highly radioresistant CSCs, and triple combinations of CQ, gammaIR and a PI3K/Akt pathway inhibitor permit reduction of the CQ dose required to trigger cell death. PMID- 23091618 TI - Critical role of heat shock protein 27 in bufalin-induced apoptosis in human osteosarcomas: a proteomic-based research. AB - Bufalin is the primary component of the traditional Chinese herb "Chan Su". Evidence suggests that this compound possesses potent anti-tumor activities, although the exact molecular mechanism(s) is unknown. Our previous study showed that bufalin inhibited growth of human osteosarcoma cell lines U2OS and U2OS/MTX300 in culture. Therefore, this study aims to further clarify the in vitro and in vivo anti-osteosarcoma effects of bufalin and its molecular mechanism of action. We found bufalin inhibited both methotrexate (MTX) sensitive and resistant human osteosarcoma cell growth and induced G2/M arrest and apoptosis. Using a comparative proteomics approach, 24 differentially expressed proteins following bufalin treatment were identified. In particular, the level of an anti-apoptotic protein, heat shock protein 27 (Hsp27), decreased remarkably. The down-regulation of Hsp27 and alterations of its partner signaling molecules (the decrease in p-Akt, nuclear NF-kappaB p65, and co-immunoprecipitated cytochrome c/Hsp27) were validated. Hsp27 over-expression protected against bufalin-induced apoptosis, reversed the dephosphorylation of Akt and preserved the level of nuclear NF-kappaB p65 and co-immunoprecipitated Hsp27/cytochrome c. Moreover, bufalin inhibited MTX-resistant osteosarcoma xenograft growth, and a down-regulation of Hsp27 in vivo was observed. Taken together, bufalin exerted potent anti-osteosarcoma effects in vitro and in vivo, even in MTX resistant osteosarcoma cells. The down-regulation of Hsp27 played a critical role in bufalin-induced apoptosis in osteosarcoma cells. Bufalin may have merit to be a potential chemotherapeutic agent for osteosarcoma, particularly in MTX-resistant groups. PMID- 23091619 TI - A pilot investigation of visceral fat adiposity and gene expression profile in peripheral blood cells. AB - Evidence suggests that visceral fat accumulation plays a central role in the development of metabolic syndrome. Excess visceral fat causes local chronic low grade inflammation and dysregulation of adipocytokines, which contribute in the pathogenesis of the metabolic syndrome. These changes may affect the gene expression in peripheral blood cells. This study for the first time examined the association between visceral fat adiposity and gene expression profile in peripheral blood cells. The gene expression profile was analyzed in peripheral blood cells from 28 obese subjects by microarray analysis. Reverse transcription polymerase chain reaction (RT-PCR) was performed using peripheral blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m(2) according to the Japanese criteria, and the estimated visceral fat area (eVFA) was measured by abdominal bioelectrical impedance. Analysis of gene expression profile was carried out with Agilent whole human genome 4 * 44 K oligo DNA microarray. The expression of several genes related to circadian rhythm, inflammation, and oxidative stress correlated significantly with visceral fat accumulation. Period homolog 1 (PER1) mRNA level in blood cells correlated negatively with visceral fat adiposity. Stepwise multiple regression analysis identified eVFA as a significant determinant of PER1 expression. In conclusion, visceral fat adiposity correlated with the expression of genes related to circadian rhythm and inflammation in peripheral blood cells. PMID- 23091620 TI - Love thy neighbour: group properties of gaping behaviour in mussel aggregations. AB - By associating closely with others to form a group, an animal can benefit from a number of advantages including reduced risk of predation, amelioration of environmental conditions, and increased reproductive success, but at the price of reduced resources. Although made up of individual members, an aggregation often displays novel effects that do not manifest at the level of the individual organism. Here we show that very simple behaviour in intertidal mussels shows new effects in dense aggregations but not in isolated individuals. Perna perna and Mytilus galloprovincialis are gaping (periodic valve movement during emersion) and non-gaping mussels respectively. P. perna gaping behaviour had no effect on body temperatures of isolated individuals, while it led to increased humidity and decreased temperatures in dense groups (beds). Gaping resulted in cooler body temperatures for P. perna than M. galloprovincialis when in aggregations, while solitary individuals exhibited the highest temperatures. Gradients of increasing body temperature were detected from the center to edges of beds, but M. galloprovincialis at the edge had the same temperature as isolated individuals. Furthermore, a field study showed that during periods of severe heat stress, mortality rates of mussels within beds of the gaping P. perna were lower than those of isolated individuals or within beds of M. galloprovincialis, highlighting the determinant role of gaping on fitness and group functioning. We demonstrate that new effects of very simple individual behaviour lead to amelioration of abiotic conditions at the aggregation level and that these effects increase mussel resistance to thermal stress. PMID- 23091621 TI - Influence of climate change and trophic coupling across four trophic levels in the Celtic Sea. AB - Climate change has had profound effects upon marine ecosystems, impacting across all trophic levels from plankton to apex predators. Determining the impacts of climate change on marine ecosystems requires understanding the direct effects on all trophic levels as well as indirect effects mediated by trophic coupling. The aim of this study was to investigate the effects of climate change on the pelagic food web in the Celtic Sea, a productive shelf region in the Northeast Atlantic. Using long-term data, we examined possible direct and indirect 'bottom-up' climate effects across four trophic levels: phytoplankton, zooplankton, mid trophic level fish and seabirds. During the period 1986-2007, although there was no temporal trend in the North Atlantic Oscillation index (NAO), the decadal mean Sea Surface Temperature (SST) in the Celtic Sea increased by 0.66 +/- 0.02 degrees C. Despite this, there was only a weak signal of climate change in the Celtic Sea food web. Changes in plankton community structure were found, however this was not related to SST or NAO. A negative relationship occurred between herring abundance (0- and 1-group) and spring SST (0-group: p = 0.02, slope = 0.305 +/- 0.125; 1-group: p = 0.04, slope = -0.410 +/- 0.193). Seabird demographics showed complex species-specific responses. There was evidence of direct effects of spring NAO (on black-legged kittiwake population growth rate: p = 0.03, slope = 0.0314 +/- 0.014) as well as indirect bottom-up effects of lagged spring SST (on razorbill breeding success: p = 0.01, slope = -0.144 +/- 0.05). Negative relationships between breeding success and population growth rate of razorbills and common guillemots may be explained by interactions between mid trophic level fish. Our findings show that the impacts of climate change on the Celtic Sea ecosystem is not as marked as in nearby regions (e.g. the North Sea), emphasizing the need for more research at regional scales. PMID- 23091622 TI - Comparing proteomics and RISC immunoprecipitations to identify targets of Epstein Barr viral miRNAs. AB - Epstein-Barr virus is a gamma-herpes virus that is causally associated with several lymphomas and carcinomas. This virus encodes at least 25 pre-miRNAs, which are expressed in infected cells to yield more than 50 detected mature miRNAs. miRNAs are small, non-coding RNAs that inhibit gene expression by promoting the inhibition of translation or of degradation of mRNAs. Currently, the function of these viral miRNAs and the contribution they provide to EBV's life-cycle remain largely unknown, due to difficulties in identifying cellular and viral genes regulated by these miRNAs. We have compared and contrasted two methods to identify targets of viral miRNAs in order to identify the advantages and limitations of each method to aid in uncovering the functions of EBV's miRNAs. PMID- 23091623 TI - Acute cardiac disorder or pneumonia and concomitant presence of pulmonary embolism. AB - PURPOSE: To determine the frequency of apparent acute pulmonary embolism (PE) and of concomitant disease in computed tomography pulmonary angiography (CTPA); to compare the frequency of PE in patients with pneumonia or acute cardiac disorder (acute coronary syndrome, tachyarrhythmia, acute left ventricular heart failure or cardiogenic shock), with the frequency of PE in patients with none of these alternative chest pathologies (comparison group). METHODS: Retrospective analysis of all patients who received a CTPA at the emergency department (ED) within a period of four years and 5 months. RESULTS: Of 1275 patients with CTPA, 28 (2.2%) had PE and concomitant radiologic evidence of another chest disease; 3 more (0.2%) had PE and an acute cardiac disorder without radiological evidence of heart failure. PE was found in 11 of 113 patients (10%) with pneumonia, in 5 of 154 patients (3.3%) with an acute cardiac disorder and in 186 of 1008 patients (18%) in the comparison group. After adjustment for risk factors for thromboembolism and for other relevant patient's characteristics, the proportion of CTPAs with evidence of PE in patients with an acute cardiac disorder or pneumonia was significantly lower than in the comparison group (OR 0.13, 95% CI 0.05-0.33, p<0.001 for patients with an acute cardiac disorder, and OR 0.45, 95% CI 0.23-0.89, p = 0.021 for patients with pneumonia). CONCLUSION: The frequency of PE and a concomitant disease that can mimic PE was low. The presence of an acute cardiac disorder or pneumonia was associated with decreased odds of PE. PMID- 23091624 TI - The bite of the honeybee: 2-heptanone secreted from honeybee mandibles during a bite acts as a local anaesthetic in insects and mammals. AB - Honeybees secrete 2-heptanone (2-H) from their mandibular glands when they bite. Researchers have identified several possible functions: 2-H could act as an alarm pheromone to recruit guards and soldiers, it could act as a chemical marker, or it could have some other function. The actual role of 2-H in honeybee behaviour remains unresolved. In this study, we show that 2-H acts as an anaesthetic in small arthropods, such as wax moth larva (WML) and Varroa mites, which are paralysed after a honeybee bite. We demonstrated that honeybee mandibles can penetrate the cuticle of WML, introducing less than one nanolitre of 2-H into the WML open circulatory system and causing instantaneous anaesthetization that lasts for a few minutes. The first indication that 2-H acts as a local anaesthetic was that its effect on larval response, inhibition and recovery is very similar to that of lidocaine. We compared the inhibitory effects of 2-H and lidocaine on voltage-gated sodium channels. Although both compounds blocked the hNav1.6 and hNav1.2 channels, lidocaine was slightly more effective, 2.82 times, on hNav.6. In contrast, when the two compounds were tested using an ex vivo preparation-the isolated rat sciatic nerve-the function of the two compounds was so similar that we were able to definitively classify 2-H as a local anaesthetic. Using the same method, we showed that 2-H has the fastest inhibitory effect of all alkyl-ketones tested, including the isomers 3- and 4-heptanone. This suggests that natural selection may have favoured 2-H over other, similar compounds because of the associated fitness advantages it confers. Our results reveal a previously unknown role of 2-H in honeybee defensive behaviour and due to its minor neurotoxicity show potential for developing a new local anaesthetic from a natural product, which could be used in human and veterinary medicine. PMID- 23091625 TI - Synaptotagmin I regulates patterned spontaneous activity in the developing rat retina via calcium binding to the C2AB domains. AB - BACKGROUND: In neonatal binocular animals, the developing retina displays patterned spontaneous activity termed retinal waves, which are initiated by a single class of interneurons (starburst amacrine cells, SACs) that release neurotransmitters. Although SACs are shown to regulate wave dynamics, little is known regarding how altering the proteins involved in neurotransmitter release may affect wave dynamics. Synaptotagmin (Syt) family harbors two Ca(2+)-binding domains (C2A and C2B) which serve as Ca(2+) sensors in neurotransmitter release. However, it remains unclear whether SACs express any specific Syt isoform mediating retinal waves. Moreover, it is unknown how Ca(2+) binding to C2A and C2B of Syt affects wave dynamics. Here, we investigated the expression of Syt I in the neonatal rat retina and examined the roles of C2A and C2B in regulating wave dynamics. METHODOLOGY/PRINCIPAL FINDINGS: Immunostaining and confocal microscopy showed that Syt I was expressed in neonatal rat SACs and cholinergic synapses, consistent with its potential role as a Ca(2+) sensor mediating retinal waves. By combining a horizontal electroporation strategy with the SAC-specific promoter, we specifically expressed Syt I mutants with weakened Ca(2+)-binding ability in C2A or C2B in SACs. Subsequent live Ca(2+) imaging was used to monitor the effects of these molecular perturbations on wave-associated spontaneous Ca(2+) transients. We found that targeted expression of Syt I C2A or C2B mutants in SACs significantly reduced the frequency, duration, and amplitude of wave associated Ca(2+) transients, suggesting that both C2 domains regulate wave temporal properties. In contrast, these C2 mutants had relatively minor effects on pairwise correlations over distance for wave-associated Ca(2+) transients. CONCLUSIONS/SIGNIFICANCE: Through Ca(2+) binding to C2A or C2B, the Ca(2+) sensor Syt I in SACs may regulate patterned spontaneous activity to shape network activity during development. Hence, modulating the releasing machinery in presynaptic neurons (SACs) alters wave dynamics. PMID- 23091626 TI - Virotherapy of canine tumors with oncolytic vaccinia virus GLV-1h109 expressing an anti-VEGF single-chain antibody. AB - Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients. PMID- 23091627 TI - Hepatitis B virus-specific miRNAs and Argonaute2 play a role in the viral life cycle. AB - Disease-specific serum miRNA profiles may serve as biomarkers and might reveal potential new avenues for therapy. An HBV-specific serum miRNA profile associated with HBV surface antigen (HBsAg) particles has recently been reported, and AGO2 and miRNAs have been shown to be stably associated with HBsAg in serum. We identified HBV-associated serum miRNAs using the Toray 3D array system in 10 healthy controls and 10 patients with chronic hepatitis B virus (HBV) infection. 19 selected miRNAs were then measured by quantitative RT-PCR in 248 chronic HBV patients and 22 healthy controls. MiRNA expression in serum versus liver tissue was also compared using biopsy samples. To examine the role of AGO2 during the HBV life cycle, we analyzed intracellular co-localization of AGO2 and HBV core (HBcAg) and surface (HBsAg) antigens using immunocytochemistry and proximity ligation assays in stably transfected HepG2 cells. The effect of AGO2 ablation on viral replication was assessed using siRNA. Several miRNAs, including miR-122, miR-22, and miR-99a, were up-regulated at least 1.5 fold (P<2E-08) in serum of HBV-infected patients. AGO2 and HBcAg were found to physically interact and co localize in the ER and other subcellular compartments. HBs was also found to co localize with AGO2 and was detected in multiple subcellular compartments. Conversely, HBx localized non-specifically in the nucleus and cytoplasm, and no interaction between AGO2 and HBx was detected. SiRNA ablation of AGO2 suppressed production of HBV DNA and HBs antigen in the supernatant. CONCLUSION: These results suggest that AGO2 and HBV-specific miRNAs might play a role in the HBV life cycle. PMID- 23091628 TI - Hepatitis C VLPs delivered to dendritic cells by a TLR2 targeting lipopeptide results in enhanced antibody and cell-mediated responses. AB - Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. In this study, we have evaluated the use of an anionic self-adjuvanting lipopeptide containing the TLR2 agonist Pam(2)Cys (E(8)Pam(2)Cys) to enhance the immunogenicity of VLPs containing the HCV structural proteins (core, E1 and E2) of genotype 1a. While co formulation of this lipopeptide with VLPs only resulted in marginal improvements in dendritic cell (DC) uptake, its ability to concomitantly induce DC maturation at very small doses is a feature not observed using VLPs alone or in the presence of an aluminium hydroxide-based adjuvant (Alum). Dramatically improved VLP and E2 specific antibody responses were observed in VLP+E(8)Pam(2)Cys vaccinated mice where up to 3 doses of non-adjuvanted or traditionally alum-adjuvanted VLPs was required to match the antibody titres obtained with a single dose of VLPs formulated with this lipopeptide. This result also correlated with significantly higher numbers of specific antibody secreting cells that was detected in the spleens of VLP+E(8)Pam(2)Cys vaccinated mice and greater ability of sera from these mice to neutralise the binding and uptake of VLPs by Huh7 cells. Moreover, vaccination of HLA-A2 transgenic mice with this formulation also induced better VLP-specific IFN-gamma-mediated responses compared to non-adjuvanted VLPs but comparable levels to that achieved when coadministered with complete freund's adjuvant. These results suggest overall that the immunogenicity of HCV VLPs can be significantly improved by the addition of this novel adjuvant by targeting their delivery to DCs and could therefore constitute a viable vaccine strategy for the treatment of HCV. PMID- 23091629 TI - Multiple implants do not aggravate the tissue reaction in rat brain. AB - Chronically implanted microelectrodes are an invaluable tool for neuroscientific research, allowing long term recordings in awake and behaving animals. It is known that all such electrodes will evoke a tissue reaction affected by its' size, shape, surface structure, fixation mode and implantation method. However, the possible correlation between tissue reactions and the number of implanted electrodes is not clear. We implanted multiple wire bundles into the brain of rats and studied the correlation between the astrocytic and microglial reaction and the positioning of the electrode in relation to surrounding electrodes. We found that an electrode implanted in the middle of a row of implants is surrounded by a significantly smaller astrocytic scar than single ones. This possible interaction was only seen between implants within the same hemisphere, no interaction with the contralateral hemisphere was found. More importantly, we found no aggravation of tissue reactions as a result of a larger number of implants. These results highlight the possibility of implanting multiple electrodes without aggravating the glial scar surrounding each implant. PMID- 23091630 TI - Housekeeping gene selection advisory: glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin are targets of miR-644a. AB - Results of overexpression or downregulation of a microRNA (miRNA) on its target mRNA expression are often validated by reverse-transcription and quantitative PCR analysis using an appropriate housekeeping gene as an internal control. The possible direct or indirect effects of a miRNA on the expression of housekeeping genes are often overlooked. Among many housekeeping genes, expressions of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin have been used extensively for normalization of gene expression data. Here, we show that GAPDH and beta-actin are direct targets of miR-644a. Our data demonstrate the unsuitability of GAPDH and beta-actin as internal controls in miR-644a functional studies and emphasize the need to carefully consider the choice of a reference gene in miRNA experiments. PMID- 23091632 TI - Regeneration of a coastal pine (Pinus thunbergii Parl.) forest 11 years after thinning, Niigata, Japan. AB - To examine the effects of thinning intensity on wind vulnerability and regeneration in a coastal pine (Pinus thunbergii) forest, thinning with intensities of 20%, 30% and 50% was conducted in December 1997; there was an unthinned treatment as the control (total 8 stands). We re-measured the permanent sites to assess the regeneration characteristics 11 years after thinning. In the 50% thinned stand, seedlings aged from 2 to 10 years exhibited the highest pine seedling density and growth. The age composition ranged from 1-3 years with densities of 9.9 and 5.1 seedlings m(-2) in 30% and 20% thinned stands; only 1 year-old seedlings with a density of 6.1 seedlings m(-2) in the unthinned stand. Similar trends were found for the regeneration of broadleaved species such as Robinia pseudoacacia and Prunus serrulata. We speculate that the canopy openness and moss coverage contributed to the regeneration success in the 50% thinned stand, while the higher litter depth and lack of soil moisture induced the regeneration failure in the unthinned stand. The stands thinned at 20% or 30% were less favourable for pine regeneration than the stands thinned at 50%. Therefore, thinning with less than 30% canopy openness (20% and 30% thinned stands) should be avoided, and thinning at higher than 30% canopy openness (50% thinned stand, approximately 1500 stems ha(-1) at ages 40-50 years) is suggested for increasing regeneration in the coastal pine forest. The implications of thinning-based silviculture in the coastal pine forest management are also discussed. The ongoing development of the broadleaved seedlings calls for further observations. PMID- 23091631 TI - Modulation of V1 spike response by temporal interval of spatiotemporal stimulus sequence. AB - The spike activity of single neurons of the primary visual cortex (V1) becomes more selective and reliable in response to wide-field natural scenes compared to smaller stimuli confined to the classical receptive field (RF). However, it is largely unknown what aspects of natural scenes increase the selectivity of V1 neurons. One hypothesis is that modulation by surround interaction is highly sensitive to small changes in spatiotemporal aspects of RF surround. Such a fine tuned modulation would enable single neurons to hold information about spatiotemporal sequences of oriented stimuli, which extends the role of V1 neurons as a simple spatiotemporal filter confined to the RF. In the current study, we examined the hypothesis in the V1 of awake behaving monkeys, by testing whether the spike response of single V1 neurons is modulated by temporal interval of spatiotemporal stimulus sequence encompassing inside and outside the RF. We used two identical Gabor stimuli that were sequentially presented with a variable stimulus onset asynchrony (SOA): the preceding one (S1) outside the RF and the following one (S2) in the RF. This stimulus configuration enabled us to examine the spatiotemporal selectivity of response modulation from a focal surround region. Although S1 alone did not evoke spike responses, visual response to S2 was modulated for SOA in the range of tens of milliseconds. These results suggest that V1 neurons participate in processing spatiotemporal sequences of oriented stimuli extending outside the RF. PMID- 23091633 TI - In-vivo imaging of the Drosophila wing imaginal disc over time: novel insights on growth and boundary formation. AB - In developmental biology, the sequence of gene induction and pattern formation is best studied over time as an organism develops. However, in the model system of Drosophila larvae this oftentimes proves difficult due to limitations in imaging capabilities. Using the larval wing imaginal disc, we show that both overall growth, as well as the creation of patterns such as the distinction between the anterior(A) and posterior(P) compartments and the dorsal(D) and ventral(V) compartments can be studied directly by imaging the wing disc as it develops inside a larva. Imaged larvae develop normally, as can be seen by the overall growth curve of the wing disc. Yet, the fact that we can follow the development of individual discs through time provides the opportunity to simultaneously assess individual variability. We for instance find that growth rates can vary greatly over time. In addition, we observe that mechanical forces act on the wing disc within the larva at times when there is an increase in growth rates. Moreover, we observe that A/P boundary formation follows the established sequence and a smooth boundary is present from the first larval instar on. The division of the wing disc into a dorsal and a ventral compartment, on the other hand, develops quite differently. Contrary to expectation, the specification of the dorsal compartment starts with only one or two cells in the second larval instar and a smooth boundary is not formed until the third larval instar. PMID- 23091634 TI - Mycoplasma pneumoniae large DNA repetitive elements RepMP1 show type specific organization among strains. AB - Mycoplasma pneumoniae is the smallest self-replicating bacterium with a streamlined genome of 0.81 Mb. Complete genome analysis revealed the presence of multiple copies of four large repetitive elements (designated RepMP1, RepMP2/3, RepMP4 and RepMP5) that are implicated in creating sequence variations among individual strains. Recently, we described RepMP1-associated sequence variations between reference strain M129 and clinical isolate S1 that involved three RepMP1 genes (i.e. mpn130, mpn137 and mpn138). Using PCR and sequencing we analyze 28 additional M. pneumoniae strains and demonstrate the existence of S1-like sequence variants in nine strains and M129-like variants in the remaining nineteen strains. We propose a series of recombination steps that facilitates transition from M129- to S1-like sequence variants. Next we examined the remaining RepMP1-genes and observed no other rearrangements related to the repeat element. The only other detected difference was varying numbers of the 21 nucleotide tandem repeats within mpn127, mpn137, mpn501 and mpn524. Furthermore, typing of strains through analysis of large RepMPs localized within the adhesin P1 operon revealed that sequence divergence involving RepMP1-genes mpn130, mpn137 and mpn138 is strictly type-specific. Once more our analysis confirmed existence of two highly conserved groups of M. pneumoniae strains. PMID- 23091635 TI - New surfactant with SP-B and C analogs gives survival benefit after inactivation in preterm lambs. AB - BACKGROUND: Respiratory distress syndrome in preterm babies is caused by a pulmonary surfactant deficiency, but also by its inactivation due to various conditions, including plasma protein leakage. Surfactant replacement therapy is well established, but clinical observations and in vitro experiments suggested that its efficacy may be impaired by inactivation. A new synthetic surfactant (CHF 5633), containing synthetic surfactant protein B and C analogs, has shown comparable effects on oxygenation in ventilated preterm rabbits versus Poractant alfa, but superior resistance against inactivation in vitro. We hypothesized that CHF 5633 is also resistant to inactivation by serum albumin in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Nineteen preterm lambs of 127 days gestational age (term = 150 days) received CHF 5633 or Poractant alfa and were ventilated for 48 hours. Ninety minutes after birth, the animals received albumin with CHF 5633 or Poractant alfa. Animals received additional surfactant if P(a)O(2) dropped below 100 mmHg. A pressure volume curve was done post mortem and markers of pulmonary inflammation, surfactant content and biophysiology, and lung histology were assessed. CHF 5633 treatment resulted in improved arterial pH, oxygenation and ventilation efficiency index. The survival rate was significantly higher after CHF 5633 treatment (5/7) than after Poractant alfa (1/8) after 48 hours of ventilation. Biophysical examination of the surfactant recovered from bronchoalveolar lavages revealed that films formed by CHF 5633-treated animals reached low surface tensions in a wider range of compression rates than films from Poractant alfa-treated animals. CONCLUSIONS: For the first time a synthetic surfactant containing both surfactant protein B and C analogs showed significant benefit over animal derived surfactant in an in vivo model of surfactant inactivation in premature lambs. PMID- 23091636 TI - Effects of increased spatial complexity on behavioural development and task performance in Lister Hooded rats. AB - Enhancing laboratory animal welfare, particularly in rodents, has been achieved through environmental enrichment in caging systems. Traditional enrichment such as adding objects has shown to impact development, reproductive and maternal performance as well as cognition. However, effects of increased spatial complexity as part of larger novel caging systems have not been investigated. While adoption of caging systems with increased spatial complexity seems uncontroversial from a welfare perspective, effects of such housing on the development and task performance of experimental animals remains unclear. In this study, we investigate differences in key behaviours and cognitive performance between Lister Hooded rats housed in traditional (single-shelf) cages ('basic') and those housed in larger cages with an additional shelf ('enriched'). We found minor differences in maternal behaviour, such as nursing and offspring development. Further, we compared task performance in females, using a hippocampus-dependent task (T-maze) and a hippocampus-independent task (Novel Object Recognition, NOR). While in the T-maze no differences in either the rate of learning or probe trial performance were found, in the NOR task females housed in enriched cages performed better than those housed in basic cages. Our results show that increased spatial complexity does not significantly affect development and maternal performance but may enhance learning in females for a non-spatial task. Increased spatial complexity does not appear to have the same effects on behaviour and development as traditional enrichment. Thus, our results suggest no effect of housing conditions on the development of most behaviours in experimental animals housed in spatially enriched caging systems. PMID- 23091637 TI - Human embryonic stem cell-derived oligodendrocyte progenitors aid in functional recovery of sensory pathways following contusive spinal cord injury. AB - BACKGROUND: Transplantations of human stem cell derivatives have been widely investigated in rodent models for the potential restoration of function of neural pathways after spinal cord injury (SCI). Studies have already demonstrated cells survival following transplantation in SCI. We sought to evaluate survival and potential therapeutic effects of transplanted human embryonic stem (hES) cell derived oligodendrocyte progenitor cells (OPCs) in a contusive injury in rats. Bioluminescence imaging was utilized to verify survivability of cells up to 4 weeks, and somatosensory evoked potential (SSEPs) were recorded at the cortex to monitor function of sensory pathways throughout the 6-week recovery period. PRINCIPAL FINDINGS: hES cells were transduced with the firefly luciferase gene and differentiated into OPCs. OPCs were transplanted into the lesion epicenter of rat spinal cords 2 hours after inducing a moderate contusive SCI. The hES treatment group showed improved SSEPs, including increased amplitude and decreased latencies, compared to the control group. The bioluminescence of transplanted OPCs decreased by 97% in the injured spinal cord compared to only 80% when injected into an uninjured spinal cord. Bioluminescence increased in both experimental groups such that by week 3, no statistical difference was detected, signifying that the cells survived and proliferated independent of injury. Post-mortem histology of the spinal cords showed integration of human cells expressing mature oligodendrocyte markers and myelin basic protein without the expression of markers for astrocytes (GFAP) or pluripotent cells (OCT4). CONCLUSIONS: hES-derived OPCs transplanted 2 hours after contusive SCI survive and differentiate into OLs that produce MBP. Treated rats demonstrated functional improvements in SSEP amplitudes and latencies compared to controls as early as 1 week post-injury. Finally, the hostile injury microenvironment at 2 hours post injury initially caused increased cell death but did not affect the long-term cell proliferation or survival, indicating that cells can be transplanted sooner than conventionally accepted. PMID- 23091638 TI - Effects of silver nanoparticle exposure on germination and early growth of eleven wetland plants. AB - The increasing commercial production of engineered nanoparticles (ENPs) has led to concerns over the potential adverse impacts of these ENPs on biota in natural environments. Silver nanoparticles (AgNPs) are one of the most widely used ENPs and are expected to enter natural ecosystems. Here we examined the effects of AgNPs on germination and growth of eleven species of common wetland plants. We examined plant responses to AgNP exposure in simple pure culture experiments (direct exposure) and for seeds planted in homogenized field soils in a greenhouse experiment (soil exposure). We compared the effects of two AgNPs-20-nm polyvinylpyrrolidine-coated silver nanoparticles (PVP-AgNPs) and 6-nm gum arabic coated silver nanoparticles (GA-AgNPs)-to the effects of AgNO(3) exposure added at equivalent Ag concentrations (1, 10 or 40 mg Ag L(-1)). In the direct exposure experiments, PVP-AgNP had no effect on germination while 40 mg Ag L(-1) GA-AgNP exposure significantly reduced the germination rate of three species and enhanced the germination rate of one species. In contrast, 40 mg Ag L(-1) AgNO(3) enhanced the germination rate of five species. In general root growth was much more affected by Ag exposure than was leaf growth. The magnitude of inhibition was always greater for GA-AgNPs than for AgNO(3) and PVP-AgNPs. In the soil exposure experiment, germination effects were less pronounced. The plant growth response differed by taxa with Lolium multiflorum growing more rapidly under both AgNO(3) and GA-AgNP exposures and all other taxa having significantly reduced growth under GA-AgNP exposure. AgNO(3) did not reduce the growth of any species while PVP-AgNPs significantly inhibited the growth of only one species. Our findings suggest important new avenues of research for understanding the fate and transport of NPs in natural media, the interactions between NPs and plants, and indirect and direct effects of NPs in mixed plant communities. PMID- 23091639 TI - Performance deficits in a voluntary saccade task in Chinese "express saccade makers". AB - Differences in behaviour and cognition have been observed in different human populations. It has been reported that in various types of complex visual task, eye movement patterns differ systematically between Chinese and non-Chinese participants, an observation that has been related to differences in culture between groups. However, we confirm here that, in healthy, naive adult Chinese participants, a far higher proportion (22%) than expected (1-5%) exhibit a pattern of reflexive eye movement behaviour (high numbers of low latency express saccades) in circumstances designed to inhibit such responses (prosaccade overlap tasks). These participants are defined as "express saccade makers" (ESMs). We then show using the antisaccade paradigm, which requires the inhibition of reflexive responses and the programming and execution of voluntary saccades, that the performance of ESMs is compromised; they have higher antisaccade directional error rates, and the latency distributions of their error saccades again exhibit a higher proportion of low latency express saccade errors consistent with a reduced ability to inhibit reflexive responses. These results are difficult to reconcile with a cultural explanation as they relate to important and specific performance differences within a particular population. They suggest a potential unexpected confound relevant to those studies of Chinese versus other groups which have investigated group differences using oculomotor measures, and explained them in terms of culture. The confirmation of higher numbers of ESMs among Chinese participants provides new opportunities for examining oculomotor control. PMID- 23091640 TI - High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. AB - BACKGROUND & AIMS: While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet. METHODS: C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high-fat (60 kcal % fat) diet (HFD) for 8 weeks. RESULTS: HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-kappaB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4 deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4 deficient mice. CONCLUSIONS: HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity. PMID- 23091641 TI - Measurement and 3D-visualization of cell-cycle length using double labelling with two thymidine analogues applied in early heart development. AB - Organ development is a complex spatial process in which local differences in cell proliferation rate play a key role. Understanding this role requires the measurement of the length of the cell cycle at every position of the three dimensional (3D) structure. This measurement can be accomplished by exposing the developing embryo to two different thymidine analogues for two different durations immediately followed by tissue fixation. This paper presents a method and a dedicated computer program to measure the resulting labelling indices and subsequently calculate and visualize local cell cycle lengths within the 3D morphological context of a developing organ. By applying this method to the developing heart, we show a large difference in cell cycle lengths between the early heart tube and the adjacent mesenchyme of the pericardial wall. Later in development, a local increase in cell size was found to be associated with a decrease in cell cycle length in the region where the chamber myocardium starts to develop. The combined application of halogenated-thymidine double exposure and image processing enables the automated study of local cell cycle parameters in single specimens in a full 3D context. It can be applied in a wide range of research fields ranging from embryonic development to tissue regeneration and cancer research. PMID- 23091642 TI - Beyond Streptococcus mutans: dental caries onset linked to multiple species by 16S rRNA community analysis. AB - Dental caries in very young children may be severe, result in serious infection, and require general anesthesia for treatment. Dental caries results from a shift within the biofilm community specific to the tooth surface, and acidogenic species are responsible for caries. Streptococcus mutans, the most common acid producer in caries, is not always present and occurs as part of a complex microbial community. Understanding the degree to which multiple acidogenic species provide functional redundancy and resilience to caries-associated communities will be important for developing biologic interventions. In addition, microbial community interactions in health and caries pathogenesis are not well understood. The purpose of this study was to investigate bacterial community profiles associated with the onset of caries in the primary dentition. In a combination cross-sectional and longitudinal design, bacterial community profiles at progressive stages of caries and over time were examined and compared to those of health. 16S rRNA gene sequencing was used for bacterial community analysis. Streptococcus mutans was the dominant species in many, but not all, subjects with caries. Elevated levels of S. salivarius, S. sobrinus, and S. parasanguinis were also associated with caries, especially in subjects with no or low levels of S. mutans, suggesting these species are alternative pathogens, and that multiple species may need to be targeted for interventions. Veillonella, which metabolizes lactate, was associated with caries and was highly correlated with total acid producing species. Among children without previous history of caries, Veillonella, but not S. mutans or other acid-producing species, predicted future caries. Bacterial community diversity was reduced in caries as compared to health, as many species appeared to occur at lower levels or be lost as caries advanced, including the Streptococcus mitis group, Neisseria, and Streptococcus sanguinis. This may have implications for bacterial community resilience and the restoration of oral health. PMID- 23091643 TI - Degenerate human nucleus pulposus cells promote neurite outgrowth in neural cells. AB - Innervation of nociceptive nerve fibres into the normally aneural nucleus pulposus (NP) of the intervertebral disc (IVD) occurs during degeneration resulting in discogenic back pain. The neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which are associated with stimulation of axonal outgrowth and nociception by neuronal cells, are both expressed by NP cells, with BDNF levels increasing with disease severity. However the mechanism of interaction between human NP cells and neural cells has yet to be fully elucidated. Therefore the aim of this study was to determine whether non degenerate or degenerate human NP cells inhibit or stimulate neural outgrowth and whether any outgrowth is mediated by NGF or BDNF. Human NP cells from non degenerate and degenerate IVD were cultured in alginate beads then co-cultured for 48 hours with human SH-SY5Y neuroblastoma cells. Co-culture of non-degenerate NP cells with neural cells resulted in both an inhibition of neurite outgrowth and reduction in percentage of neurite expressing cells. Conversely co-culture with degenerate NP cells resulted in an increase in both neurite length and percentage of neurite expressing cells. Addition of anti-NGF to the co-culture with degenerate cells resulted in a decrease in percentage of neurite expressing cells, while addition of anti-BDNF resulted in a decrease in both neurite length and percentage of neurite expressing cells. Our findings show that while non degenerate NP cells are capable of inhibiting neurite outgrowth from human neural cells, degenerate NP cells stimulate outgrowth. Neurotrophin blocking studies demonstrated that both NGF and BDNF, secreted by degenerate NP cells, may play a role in this stimulation with BDNF potentially playing the predominant role. These findings suggest that NP cells are capable of regulating nerve ingrowth and that neoinnervation occurring during IVD degeneration may be stimulated by the NP cells themselves. PMID- 23091644 TI - Both STING and MAVS fish orthologs contribute to the induction of interferon mediated by RIG-I. AB - Viral infections are detected in most cases by the host innate immune system through pattern-recognition receptors (PRR), the sensors for pathogen-associated molecular patterns (PAMPs), which induce the production of cytokines, such as type I interferons (IFN). Recent identification in mammalian and teleost fish of cytoplasmic viral RNA sensors, RIG-I-like receptors (RLRs), and their mitochondrial adaptor: the mitochondrial antiviral signaling (MAVS) protein, also called IPS-1, highlight their important role in the induction of IFN at the early stage of a virus infection. More recently, an endoplasmic reticulum (ER) adaptor: the stimulator of interferon genes (STING) protein, also called MITA, ERIS and MPYS, has been shown to play a pivotal role in response to both non-self cytosolic RNA and dsDNA. In this study, we cloned STING cDNAs from zebrafish and showed that it was an ortholog to mammalian STING. We demonstrated that overexpression of this ER protein in fish cells led to a constitutive induction of IFN and interferon-stimulated genes (ISGs). STING-overexpressing cells were almost fully protected against RNA virus infection with a strong inhibition of both DNA and RNA virus replication. In addition, we found that together with MAVS, STING was an important player in the RIG-I IFN-inducing pathway. This report provides the demonstration that teleost fish possess a functional RLR pathway in which MAVS and STING are downstream signaling molecules of RIG-I. The Sequences presented in this article have been submitted to GenBank under accession numbers: Zebrafish STING (HE856619); EPC STING (HE856620); EPC IRF3 (HE856621); EPC IFN promoter (HE856618). PMID- 23091645 TI - Apocynin-treatment reverses hyperoxaluria induced changes in NADPH oxidase system expression in rat kidneys: a transcriptional study. AB - PURPOSE: We have previously shown that production of reactive oxygen species (ROS) is an important contributor to renal injury and inflammation following exposure to oxalate (Ox) or calcium-oxalate (CaOx) crystals. The present study was conducted, utilizing global transcriptome analyses, to determine the effect of Apocynin on changes in the NADPH oxidase system activated in kidneys of rats fed a diet leading to hyperoxaluria and CaOx crystal deposition. APPROACH: Age-, sex- and weight-matched rats were either fed regular rat chow or regular rat chow supplemented with 5% w/w hydroxy-L-proline (HLP). Half of the rats on the HLP diet were also placed on Apocynin-supplemented H(2)O. After 28 days, each rat was euthanized, their kidneys freshly explanted and dissected to obtain both cortex and medulla tissues. Total RNA was extracted from each tissue and subjected to genomic microarrays to obtain global transcriptome data. KEGG was used to identify gene clusters with differentially expressed genes. Immunohistochemistry was used to confirm protein expressions of selected genes. RESULTS: Genes encoding both membrane- and cytosolic-NADPH oxidase complex-associated proteins, together with p21rac and Rap1a, were coordinately up-regulated significantly in both renal medulla and cortex tissues in the HLP-fed rats compared to normal healthy untreated controls. Activation of NADPH oxidase appears to occur via the angiotensin-II/angiotensin-II receptor-2 pathway, although the DAG-PKC pathway of neutrophils may also contribute. Immuno histochemical staining confirmed up regulated gene expressions. Simultaneously, genes encoding ROS scavenger proteins were down-regulated. HLP-fed rats receiving Apocynin had a complete reversal in the differential-expression of the NADPH oxidase system genes, despite showing similar levels of hyperoxaluria. CONCLUSIONS: A strong up-regulation of an oxidative/respiratory burst involving the NADPH oxidase system, activated via the angiotensin-II and most likely the DAG-PKC pathways, occurs in kidneys of hyperoxaluric rats. Apocynin treatment reversed this activation without affecting the levels of hyperoxaluria. PMID- 23091646 TI - Site-specific expression of gelatinolytic activity during morphogenesis of the secondary palate in the mouse embryo. AB - Morphogenesis of the secondary palate in mammalian embryos involves two major events: first, reorientation of the two vertically oriented palatal shelves into a horizontal position above the tongue, and second, fusion of the two shelves at the midline. Genetic evidence in humans and mice indicates the involvement of matrix metalloproteinases (MMPs). As MMP expression patterns might differ from sites of activity, we used a recently developed highly sensitive in situ zymography technique to map gelatinolytic MMP activity in the developing mouse palate. At embryonic day 14.5 (E14.5), we detected strong gelatinolytic activity around the lateral epithelial folds of the nasopharyngeal cavity, which is generated as a consequence of palatal shelf elevation. Activity was concentrated in the basement membrane of the epithelial fold but extended into the adjacent mesenchyme, and increased in intensity with lateral outgrowth of the cavity at E15.5. Gelatinolytic activity at this site was not the consequence of epithelial fold formation, as it was also observed in Bmp7-deficient embryos where shelf elevation is delayed. In this case, gelatinolytic activity appeared in vertical shelves at the exact position where the epithelial fold will form during elevation. Mmp2 and Mmp14 (MT1-MMP), but not Mmp9 and Mmp13, mRNAs were expressed in the mesenchyme around the epithelial folds of the elevated palatal shelves; this was confirmed by immunostaining for MMP-2 and MT1-MMP. Weak gelatinolytic activity was also found at the midline of E14.5 palatal shelves, which increased during fusion at E15.5. Whereas MMPs have been implicated in palatal fusion before, this is the first report showing that gelatinases might contribute to tissue remodeling during early stages of palatal shelf elevation and formation of the nasopharynx. PMID- 23091647 TI - Common variants of FTO are associated with childhood obesity in a cross-sectional study of 3,126 urban Indian children. AB - BACKGROUND: FTO variants are robustly associated with obesity and related traits in many population and shown to have variable impact during life course. Although studies have shown association of FTO variants with adiposity in adult Indian, its association in Indian children is yet to be confirmed. METHODS: Here we examined association of FTO variants (rs9939609 and rs8050136) with obesity and related anthropometric and biochemical traits in 3,126 Indian children (aged 11 17 years) including 2,230 normal-weight and 896 over-weight/obese children. We also compared effects observed in the present study with that observed in previous studies on South Asian adults and children of other ethnic groups. RESULTS: The variant rs9939609 showed significant association with risk of obesity [OR = 1.21, P = 2.5 * 10(-3)] and its measures BMI, weight, waist circumference and hip circumference [beta range = 0.11 to 0.14 Z-score units; P range = 1.3 * 10(-4) to 1.6 * 10(-7)] in children. The observed effect sizes in Indian children were similar to those reported for European children. Variant rs9939609 explained 0.88% of BMI variance in Indian children. The effect sizes of rs9939609 on BMI and WC were ~2 fold higher in children than adults. Interestingly rs9939609 was also associated with serum levels of thyroid stimulating hormone (TSH) [beta = 0.10 Z-score, P = 5.8 * 10(-3)]. The other variant rs8050136 was in strong linkage disequilibrium with rs9939609 (r(2) = 0.97) and provided similar association results. CONCLUSION: The study provides first report of association of FTO variants with obesity and related anthropometric traits in Indian children with higher impact in children compared to adults. We also demonstrated association of FTO variant with serum levels of TSH, indicating putative influence of FTO in hypothalamic-pituitary-thyroid axis. PMID- 23091648 TI - Identification of differentially-expressed genes associated with pistil abortion in Japanese apricot by genome-wide transcriptional analysis. AB - The phenomenon of pistil abortion widely occurs in Japanese apricot, and imperfect flowers with pistil abortion seriously decrease the yield in production. Although transcriptome analyses have been extensively studied in the past, a systematic study of differential gene expression has not been performed in Japanese apricot. To investigate genes related to the pistil development of Japanese apricot, high-throughput sequencing technology (Illumina) was employed to survey gene expression profiles from perfect and imperfect Japanese apricot flower buds. 3,476,249 and 3,580,677 tags were sequenced from two libraries constructed from perfect and imperfect flower buds of Japanese apricot, respectively. There were 689 significant differentially-expressed genes between the two libraries. GO annotation revealed that highly ranked genes were those implicated in small molecule metabolism, cellular component organisation or biogenesis at the cellular level and fatty acid metabolism. According to the results, we assumed that late embryogenesis abundant protein (LEA), Dicer-like 3 (DCL3) Xyloglucan endotransglucosylase/hydrolase 2 (XTH2), Pectin lyase-like superfamily protein (PPME1), Lipid transfer protein 3 (LTP3), Fatty acid biosynthesis 1 (FAB1) and Fatty acid desaturase 5 (FAD5) might have relationships with the pistil abortion in Japanese apricot. The expression patterns of 36 differentially expressed genes were confirmed by real-time (RT)-PCR. This is the first report of the Illumina RNA-seq technique being used for the analysis of differentially-expressed gene profiles related to pistil abortion that both computationally and experimentally provides valuable information for the further functional characterisation of genes associated with pistil development in woody plants. PMID- 23091649 TI - Spatial structure and climatic adaptation in African maize revealed by surveying SNP diversity in relation to global breeding and landrace panels. AB - BACKGROUND: Climate change threatens maize productivity in sub-Saharan Africa. To ensure food security, access to locally adapted genetic resources and varieties is an important adaptation measure. Most of the maize grown in Africa is a genetic mix of varieties introduced at different historic times following the birth of the trans-Atlantic economy, and knowledge about geographic structure and local adaptations is limited. METHODOLOGY: A panel of 48 accessions of maize representing various introduction routes and sources of historic and recent germplasm introductions in Africa was genotyped with the MaizeSNP50 array. Spatial genetic structure and genetic relationships in the African panel were analysed separately and in the context of a panel of 265 inbred lines representing global breeding material (based on 26,900 SNPs) and a panel of 1127 landraces from the Americas (270 SNPs). Environmental association analysis was used to detect SNPs associated with three climatic variables based on the full 43,963 SNP dataset. CONCLUSIONS: The genetic structure is consistent between subsets of the data and the markers are well suited for resolving relationships and admixture among the accessions. The African accessions are structured in three clusters reflecting historical and current patterns of gene flow from the New World and within Africa. The Sahelian cluster reflects original introductions of Meso-American landraces via Europe and a modern introduction of temperate breeding material. The Western cluster reflects introduction of Coastal Brazilian landraces, as well as a Northeast-West spread of maize through Arabic trade routes across the continent. The Eastern cluster most strongly reflects gene flow from modern introduced tropical varieties. Controlling for population history in a linear model, we identify 79 SNPs associated with maximum temperature during the growing season. The associations located in genes of known importance for abiotic stress tolerance are interesting candidates for local adaptations. PMID- 23091650 TI - Effects of feeding Bt maize to sows during gestation and lactation on maternal and offspring immunity and fate of transgenic material. AB - BACKGROUND: We aimed to determine the effect of feeding transgenic maize to sows during gestation and lactation on maternal and offspring immunity and to assess the fate of transgenic material. METHODOLOGY/PRINCIPAL FINDINGS: On the day of insemination, sows were assigned to one of two treatments (n = 12/treatment); 1) non-Bt control maize diet or 2) Bt-MON810 maize diet, which were fed for ~143 days throughout gestation and lactation. Immune function was assessed by leukocyte phenotyping, haematology and Cry1Ab-specific antibody presence in blood on days 0, 28 and 110 of gestation and at the end of lactation. Peripheral-blood mononuclear cell cytokine production was investigated on days 28 and 110 of gestation. Haematological analysis was performed on offspring at birth (n = 12/treatment). Presence of the cry1Ab transgene was assessed in sows' blood and faeces on day 110 of gestation and in blood and tissues of offspring at birth. Cry1Ab protein presence was assessed in sows' blood during gestation and lactation and in tissues of offspring at birth. Blood monocyte count and percentage were higher (P<0.05), while granulocyte percentage was lower (P<0.05) in Bt maize-fed sows on day 110 of gestation. Leukocyte count and granulocyte count and percentage were lower (P<0.05), while lymphocyte percentage was higher (P<0.05) in offspring of Bt maize-fed sows. Bt maize-fed sows had a lower percentage of monocytes on day 28 of lactation and of CD4(+)CD8(+) lymphocytes on day 110 of gestation, day 28 of lactation and overall (P<0.05). Cytokine production was similar between treatments. Transgenic material or Cry1Ab-specific antibodies were not detected in sows or offspring. CONCLUSIONS/SIGNIFICANCE: Treatment differences observed following feeding of Bt maize to sows did not indicate inflammation or allergy and are unlikely to be of major importance. These results provide additional data for Bt maize safety assessment. PMID- 23091651 TI - Centrosome aberrations associated with cellular senescence and p53 localization at supernumerary centrosomes. AB - Centrosome overduplication or amplification has been observed in many human cancers and in premalignant tissue, but the mechanisms leading to such centrosome aberrations are not fully understood. We previously showed that abnormal mitotic cells with supernumerary centrosomes increase with replicative senescence in human fibroblasts, especially in a polyploid subpopulation. This study examines localization of p53 protein at centrosomes in mitotic cells, which is often observed in association with DNA damage response, to investigate a possible association between p53 localization and numerical centrosome aberrations induced by cellular senescence. Cultures at later passages or the 4th day after exposure to H(2)O(2) showed increased frequencies of mitotic cells with supernumerary centrosomes, especially in a polyploid subpopulation. Immunohistochemical analysis frequently showed p53-positive foci in mitotic cells, and some were localized at centrosomes. The number of p53-positive foci in mitotic cells and its localization to centrosomes increased with replicative and premature senescence. Supernumerary centrosomes showed higher frequencies of p53 localization compared to normally duplicated centrosomes. Centrosome-associated p53 protein was phosphorylated at Ser15. These data suggest a possible association between localization of p53 protein and numerical centrosome aberrations in replicatively or prematurely senescent cells. PMID- 23091652 TI - The Singapore field epidemiology service: insights into outbreak management. AB - Field epidemiology involves the implementation of quick and targeted public health interventions with the aid of epidemiological methods. In this article, we share our practical experiences in outbreak management and in safeguarding the population against novel diseases. Given that cities represent the financial nexuses of the global economy, global health security necessitates the safeguard of cities against epidemic diseases. Singapore's public health landscape has undergone a systemic and irreversible shift with global connectivity, rapid urbanization, ecological change, increased affluence, as well as shifting demographic patterns over the past two decades. Concomitantly, the threat of epidemics, ranging from severe acute respiratory syndrome and influenza A (H1N1) to the resurgence of vector-borne diseases as well as the rise of modern lifestyle-related outbreaks, have worsened difficulties in safeguarding public health amidst much elusiveness and unpredictability. One critical factor that has helped the country overcome these innate and man-made public health vulnerabilities is the development of a resilient field epidemiology service, which includes our enhancement of surveillance and response capacities for outbreak management, and investment in public health leadership. We offer herein the Singapore story as a case study in meeting the challenges of disease control in our modern built environment. PMID- 23091653 TI - Effect of preexisting musculoskeletal diseases on the 1-year incidence of fall related injuries. AB - OBJECTIVES: People who have chronic diseases, as well as gait imbalance or psychiatric drug use, may be susceptible to injuries from falls and slips. The purpose of this study was to evaluate the effect of musculoskeletal diseases on incidental fall-related injuries among adults in Korea. METHODS: We analyzed data from the 4th Korea National Health and Nutrition Examination Survey (2007-2009), which are national data obtained by a rolling survey sampling method. The 1-year incidence of fall-related injuries was defined by health service utilization within the last year due to injury occurring after a slip and fall, and musculoskeletal diseases included osteoarthritis, rheumatoid arthritis, osteoporosis, and back pain. To evaluate the effects of preexisting musculoskeletal diseases, adults diagnosed before the last year were considered the exposed group, and adults who had never been diagnosed were the unexposed group. RESULTS: The weighted lifetime prevalence of musculoskeletal disease was 32 540 per 100 000 persons. Musculoskeletal diseases were associated with a higher risk of fall-related injury after adjustment for sex, age, residence, household income, education, occupation, visual disturbance, paralysis due to stroke, and medication for depression (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.03 to 1.93). As the number of comorbid musculoskeletal diseases increased, the risk of fall-induced injuries increased (p-value for trend <0.001). In particular, patients who had any musculoskeletal condition were at much higher risk of recurrent fall-related injuries (OR, 6.20; 95% CI, 1.06 to 36.08). CONCLUSIONS: One must take into account the risk of fall-related injuries and provide prevention strategies among adults who have musculoskeletal diseases. PMID- 23091654 TI - The socioeconomic burden of coronary heart disease in Korea. AB - OBJECTIVES: We aimed to estimate the annual socioeconomic burden of coronary heart disease (CHD) in Korea in 2005, using the National Health Insurance (NHI) claims data. METHODS: A prevalence-based, top-down, cost-of-treatment method was used to assess the direct and indirect costs of CHD (International Classification of Diseases, 10th revision codes of I20-I25), angina pectoris (I20), and myocardial infarction (MI, I21-I23) from a societal perspective. RESULTS: Estimated national spending on CHD in 2005 was $2.52 billion. The majority of the spending was attributable to medical costs (53.3%), followed by productivity loss due to morbidity and premature death (33.6%), transportation (8.1%), and informal caregiver costs (4.9%). While medical cost was the predominant cost attribute in treating angina (74.3% of the total cost), premature death was the largest cost attribute for patients with MI (66.9%). Annual per-capita cost of treating MI, excluding premature death cost, was $3183, which is about 2 times higher than the cost for angina ($1556). CONCLUSIONS: The total insurance-covered medical cost ($1.13 billion) of CHD accounted for approximately 6.02% of the total annual NHI expenditure. These findings suggest that the current burden of CHD on society is tremendous and that more effective prevention strategies are required in Korea. PMID- 23091655 TI - Alcohol consumption and mortality in the Korean Multi-Center Cancer Cohort Study. AB - OBJECTIVES: To examine the association between alcohol consumption habit, types of beverages, alcohol consumption quantity, and overall and cancer-specific mortality among Korean adults. METHODS: The alcohol consumption information of a total of 16 320 participants who were 20 years or older from the Korean Multi center Cancer Cohort were analyzed to examine the association between alcohol consumption habit and mortality (median follow-up of 9.3 years). The Cox proportional hazard model was used to estimate the hazard ratio (HR) of alcohol consumption to mortality adjusting for age, sex, geographic areas, education, smoking status, and body mass index. RESULTS: Alcohol drinkers showed an increased risk for total mortality compared with never drinkers (HR, 1.72; 95% confidence interval [CI], 1.38 to 2.14 for past drinkers; HR, 1.21; 95% CI, 1.06 to 1.39 for current drinkers), while past drinkers only were associated with higher risk for cancer deaths (HR, 1.84; 95% CI, 1.34 to 2.53). The quantity of alcohol consumed per week showed a J-shaped association with risk of mortality. Relative to light drinkers (0.01 to 90 g/wk), never drinkers and heavy drinkers (>504 g/wk) had an increased risk for all-cause and cancer deaths: (HR, 1.18; 95% CI, 0.96 to 1.45) and (HR, 1.39; 95% CI, 1.05 to 1.83) for all-cause mortality; and (HR, 1.55; 95% CI, 1.15 to 2.11) and (HR, 2.07; 95% CI, 1.39 to 3.09) for all cancer mortality, respectively. Heavy drinkers (>504 g/wk) showed an elevated risk for death from stomach and liver cancers. CONCLUSIONS: The present study supports the existence of a J-shaped association between alcohol consumption quantity and the risk of all-cause and cancer deaths. Heavy drinkers had an increased risk of death from cancer overall and liver and stomach cancer. PMID- 23091656 TI - Changes in air temperature and its relation to ambulance transports due to heat stroke in all 47 prefectures of Japan. AB - OBJECTIVES: Changes in air temperature and its relation to ambulance transports due to heat stroke in all 47 prefectures, in Japan were evaluated. METHODS: Data on air temperature were obtained from the Japanese Meteorological Agency. Data on ambulance transports due to heat stroke was directly obtained from the Fire and Disaster Management Agency, Japan. We also used the number of deaths due to heat stroke from the Ministry of Health, Labour and Welfare, Japan, and population data from the Ministry of Internal Affairs and Communications. Chronological changes in parameters of air temperature were analyzed. In addition, the relation between air temperature and ambulance transports due to heat stroke in August 2010 was also evaluated by using an ecological study. RESULTS: Positive and significant changes in the parameters of air temperature that is, the mean air temperature, mean of the highest air temperature, and mean of the lowest air temperature were noted in all 47 prefectures. In addition, changes in air temperature were accelerated when adjusted for observation years. Ambulance transports due to heat stroke was significantly correlated with air temperature in the ecological study. The highest air temperature was significantly linked to ambulance transports due to heat stroke, especially in elderly subjects. CONCLUSIONS: Global warming was demonstrated in all 47 prefectures in Japan. In addition, the higher air temperature was closely associated with higher ambulance transports due to heat stroke in Japan. PMID- 23091657 TI - Smoking is associated with abdominal obesity, not overall obesity, in men with type 2 diabetes. AB - OBJECTIVES: Abdominal obesity increases mortality and morbidity from cardiovascular disease and there is a possibility that smoking effects obesity. However, previous studies concerning the effects of smoking on obesity are inconsistent. The objective of this study was to examine whether smoking is positively related to abdominal obesity in men with type 2 diabetes. METHODS: Subjects consisted of 2197 type 2 diabetic patients who visited Huh's Diabetes Center from 2003 to 2009. Indices of abdominal obesity were defined as visceral fat thickness (VFT) measured by ultrasonography and waist circumference (WC). Overall obesity was defined as body mass index (BMI). RESULTS: Statistically significant differences in WC and VFT by smoking status were identified. However, there was no statistical difference in BMI according to smoking status. Means of WC and VFT were not significantly higher in heavy smokers and lower in mild smokers. Compared to nonsmokers, the BMI confounder adjusted odds ratio and 95% confidence interval for VFT in ex-smokers and current-smokers were 1.70 (1.21 to 2.39) and 1.86 (1.27 to 2.73), respectively. CONCLUSIONS: Smoking status was positively associated with abdominal obesity in type 2 diabetic patients. PMID- 23091658 TI - Trends in ischemic heart disease mortality in Korea, 1985-2009: an age-period cohort analysis. AB - OBJECTIVES: Economic growth and development of medical technology help to improve the average life expectancy, but the western diet and rapid conversions to poor lifestyles lead an increasing risk of major chronic diseases. Coronary heart disease mortality in Korea has been on the increase, while showing a steady decline in the other industrialized countries. An age-period-cohort analysis can help understand the trends in mortality and predict the near future. METHODS: We analyzed the time trends of ischemic heart disease mortality, which is on the increase, from 1985 to 2009 using an age-period-cohort model to characterize the effects of ischemic heart disease on changes in the mortality rate over time. RESULTS: All three effects on total ischemic heart disease mortality were statistically significant. Regarding the period effect, the mortality rate was decreased slightly in 2000 to 2004, after it had continuously increased since the late 1980s that trend was similar in both sexes. The expected age effect was noticeable, starting from the mid-60's. In addition, the age effect in women was more remarkable than that in men. Women born from the early 1900s to 1925 observed an increase in ischemic heart mortality. That cohort effect showed significance only in women. CONCLUSIONS: The future cohort effect might have a lasting impact on the risk of ischemic heart disease in women with the increasing elderly population, and a national prevention policy is need to establish management of high risk by considering the age-period-cohort effect. PMID- 23091659 TI - Letter to the editor: the increasing hepatitis a incidence in Korea: is it possible within a limited time? PMID- 23091662 TI - Intravenous magnesium infusion for the prevention of symptomatic cerebral vasospasm after aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: The study examined the difference in the incidence of symptomatic cerebral vasospasm with magnesium supplementation in aneurysmal subarachnoid hemorrhage (SAH) in a Korean population. METHODS: This retrospective analysis was performed in 157 patients diagnosed with aneurysmal SAH from January 2007 to December 2011 at a single center. Seventy patients (44.6%) received a combination treatment of nimodipine with magnesium and 87 patients (55.4%) received only nimodipine. A matched case-control study using propensity scores was conducted and 41 subjects were selected from each group. A dosage of 64 mmol/day of magnesium was administrated. RESULTS: The infusion of magnesium did not reduce the incidence of symptomatic cerebral vasospasm (n=7, 17.1%, p=0.29) compared with simple nimodipine injection (n=11, 26.8%). The ratios of good clinical outcome (modified Rankin scale 0-2) at 6 months were similar, being 78% in the combination treatment group and 80.5% in the nimodipine only group (p=0.79). The proportions of delayed cerebral infarction was not significantly lower in patients with combination treatment (n=2, 4.9% vs. n=3, 7.3%; p=0.64). There was no difference in the serum magnesium concentrations between the patients with symptomatic vasospasm and without vasospasm who had magnesium supplementation. No major complications associated with intravenous magnesium infusion were observed. CONCLUSION: Magnesium supplementation (64 mmol/day) may not be beneficial for the reduction of the incidence of symptomatic cerebral vasospasm in patients with aneurysmal SAH. PMID- 23091663 TI - The meaning of the prognostic factors in ruptured middle cerebral artery aneurysm with intracerebral hemorrhage. AB - OBJECTIVE: This study analyzed the relationship between prognosis and multiple clinical factors of ruptured middle cerebral artery (MCA) aneurysm with intracerebral hemorrhage (ICH), to aid in predicting the results of surgical treatment. METHODS: Enrolled subjects were 41 patients with ruptured MCA aneurysm with ICH who were treated with surgical clipping. Clinical factors such as gender, age, and initial Glasgow coma scale were assessed while radiological factors such as the volume and location of hematoma, the degree of a midline shift, and aneurysm size were considered retrospectively. Prognosis was evaluated postoperatively by Glasgow outcome scale. RESULTS: Age and prognosis were correlated only in the groups with ICH over 31 mL or ICH at the frontal lobe or sylvian fissure. When initial mental status was good, only patients with ICH on the temporal lobe had a better prognosis. If the midline shift was less than 4.5 mm, the probability of better prognosis was 95.5% (21 of 22). If the midline shift was more than 4.5 mm, the probability of poor prognosis was 42.1% (8 of 19). Patients with ICH less than 31 mL had higher survival rates, whereas if the ICH was more than 31 mL, 41.2% (7 of 17) had a poor clinical pathway. CONCLUSION: Even if the initial clinical condition of the patient was not promising, by carefully examining and taking into account all factors, neurosurgeons can confidently recommend surgical treatment for these patients. PMID- 23091664 TI - The effect of microvascular decompression for hemifacial spasm caused by vertebrobasilar dolichoectasia. AB - OBJECTIVE: Hemifacial spasm (HFS) caused by vertebrobasilar dolichoectasia (VBD) is very rare, and in theses cases, it is difficult to decompress the nerve from its vascular compression. The objective of this study was to investigate the outcome of microvascular decompression (MVD) for HFS caused by VBD. METHODS: There were 10 patients of HFS caused by VBD at our hospital between September 1978 and September 2008. We evaluated magnetic resonance angiography (MRA) and time of flight magnetic resonance imaginge (TOF MRI) findings using the criteria for VBD. We compared the clinical outcomes of MVD for the 10 patients with VBD with the overall outcomes of the total 2058 MVDs performed for HFS. RESULTS: The results of MVD for HFS caused by VBD were successful in 90.9% of cases. The postoperative complication rate in VBD was 45.5%. Offending vessels in patients with VBD were identified visually during surgery. Adverse effects after MVD were found in 4 patients. We found that the diameter of VBD was significantly greater in patients with complications than in those with no complications (p=0.028). CONCLUSION: Our data shows that MVD may be a good treatment modality for HFS caused by VBD but care must be taken to avoid adverse effects from the procedure. It is important to detach the dolichoectatic artery from its surrounding structures sufficiently to allow it to be easily movable. In addition, attempts should be made to lessen the retraction of the cerebellum during release of the dolichoectatic artery. PMID- 23091665 TI - Temozolomide during and after Radiotherapy for Newly Diagnosed Glioblastomas : A Prospective Multicenter Study of Korean Patients. AB - OBJECTIVE: This study was performed to determine the safety and outcome of concurrent chemoradiotherapy (CCRT) and adjuvant chemotherapy with temozolomide for Korean patients with a newly diagnosed glioblastoma. METHODS: Patients were recruited from four institutions between 2004 and 2007. The patients received fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks and daily temozolomide, followed by 6 cycles of adjuvant temozolomide. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response, and safety. RESULTS: A total of 103 patients were enrolled in this study. Ninety-six patients (93%) completed the CCRT and 54 patients (52%) received 6 cycles of adjuvant temozolomide. The response rate was 73% (53/73) and the tumor control rate was 92% (67/73). Of the 96 patients who completed the CCRT, the median OS was 18.0 months and the 1- and 2-year OS rates were 74 and 38%, respectively. The median PFS was 10.0 months and the 1- and 2-year PFS rates were 33 and 16%, respectively. The only significant prognostic factor of survival was the extent of surgical resection (p<0.05). CCRT resulted in grade 3 or 4 hematologic toxic effects in 8% of patients. No opportunistic infections were noted. CONCLUSION: This study is the first prospective multi-institutional report of CCRT and adjuvant chemotherapy with temozolomide for patients with a newly diagnosed glioblastoma in Korea. The current protocol may prolong the survival of Korean patients with a glioblastoma and may be tolerable in terms of toxicity. PMID- 23091666 TI - Radiation-induced intratumoral necrosis and peritumoral edema after gamma knife radiosurgery for intracranial meningiomas. AB - OBJECTIVE: To study the clinical significance and relevant factors of radiation induced intratumoral necrosis (RIN) and peritumoral edema (PTE) after Gamma knife radiosurgery (GKRS) for intracranial meningiomas. METHODS: We retrospectively analyzed the data of 64 patients who underwent GKRS for intracranial meningioma. The mean lesion volume was 4.9 cc (range, 0.3-20), and the mean prescription dose of 13.4 Gy (range, 11-18) was delivered to the mean 49.9% (range, 45-50) isodose line. RIN was defined as newly developed or enlarged intratumoral necrosis after GKRS. RESULTS: RIN and new development or aggravation of PTE were observed in 21 (32.8%) and 18 (28.1%) cases of meningioma, respectively during the median follow up duration of 19.9+/-1.0 months. Among various factors, maximum dose (>25 Gy) and target volume (>4.5 cc) were significantly related to RIN, and RIN and maximum dose (>24 Gy) were significantly related to the development or aggravation of PTE. In 21 meningiomas with development of RIN after GKRS, there was no significant change of the tumor volume itself between the times of GKRS and RIN. However, the PTE volume increased significantly compared to that at the time of GKRS (p=0.013). The median interval to RIN after GKRS was 6.5+/-0.4 months and the median interval to new or aggravated PTE was 7.0+/-0.7 months. CONCLUSION: A close observation is required for meningiomas treated with a maximum dose >24 Gy and showing RIN after GKRS, since following or accompanying PTE may deteriorate neurological conditions especially when the location involves adjacent critical structures. PMID- 23091667 TI - New Diagnostic Tool for Far Lateral Lumbar Disc Herniation : The Clinical Usefulness of 3-Tesla Magnetic Resonance Myelography Comparing with the Discography CT. AB - OBJECTIVE: To prospectively assess the diagnostic and clinical value of a new technique (3-tesla magnetic resonance myelography, 3T MRM) as compared to computed tomographic discography (disco-CT) in patients with far lateral disc herniation. METHODS: We evaluated 3T MRM and disco-CT of 25 patients, whom we suspected of suffering from far lateral disc herniation. Using an assessment scale, 4 observers examined independently both 3T MRM and disco-CT images. We analyzed observer agreement and the accentuation of each image. RESULTS: We found complete matching, and observer agreement, between high resolution images of 3T MRM and disco-CT for diagnosing far lateral disc herniation. CONCLUSION: We think noninvasive 3T MRM is an appropriate diagnostic tool for far lateral disc herniation as compared to disco-CT. PMID- 23091668 TI - Long-term follow-up radiologic and clinical evaluation of cylindrical cage for anterior interbody fusion in degenerative cervical disc disease. AB - OBJECTIVE: Various procedures have been introduced for anterior interbody fusion in degenerative cervical disc disease including plate systems with autologous iliac bone, carbon cages, and cylindrical cages. However, except for plate systems, the long-term results of other methods have not been established. In the present study, we evaluated radiologic findings for cylindrical cervical cages over long-term follow up periods. METHODS: During 4 year period, radiologic findings of 138 patients who underwent anterior cervical fusion with cylindrical cage were evaluated at 6, 12, 24, and 36 postoperative months using plain radiographs. We investigated subsidence, osteophyte formation (anterior and posterior margin), cage direction change, kyphotic angle, and bone fusion on each radiograph. RESULTS: Among the 138 patients, a minimum of 36 month follow-up was achieved in 99 patients (mean follow-up : 38.61 months) with 115 levels. Mean disc height was 7.32 mm for preoperative evaluations, 9.00 for immediate postoperative evaluations, and 4.87 more than 36 months after surgery. Osteophytes were observed in 107 levels (93%) of the anterior portion and 48 levels (41%) of the posterior margin. The mean kyphotic angle was 9.87 degrees in 35 levels showing cage directional change. There were several significant findings : 1) related subsidence [T-score (p=0.039) and anterior osteophyte (p=0.009)], 2) accompanying posterior osteophyte and outcome (p=0.05). CONCLUSION: Cage subsidence and osteophyte formation were radiologically observed in most cases. Low T-scores may have led to subsidence and kyphosis during bone fusion although severe neurologic aggravation was not found, and therefore cylindrical cages should be used in selected cases. PMID- 23091669 TI - Clinical outcome of modified cervical lateral mass screw fixation technique. AB - OBJECTIVE: The purpose of this study was 1) to analyze clinically-executed cervical lateral mass screw fixation by the Kim's technique as suggested in the previous morphometric and cadaveric study and 2) to examine various complications and bicortical purchase that are important for b-one fusion. METHODS: A retrospective study was done on the charts, operative records, radiographs, and clinical follow up of thirty-nine patients. One hundred and seventy-eight lateral mass screws were analyzed. The spinal nerve injury, violation of the facet joint, vertebral artery injury, and the bicortical purchases were examined at each lateral mass. RESULTS: All thirty-nine patients received instrumentations with poly axial screws and rod systems, in which one hundred and seventy-eight screws in total. No vertebral artery injury or nerve root injury were observed. Sixteen facet joint violations were observed (9.0%). Bicortical purchases were achieved on one hundred and fifty-six (87.6%). Bone fusion was achieved in all patients. CONCLUSION: The advantages of the Kim's technique are that it is performed by using given anatomical structures and that the complication rate is as low as those of other known techniques. The Kim's technique can be performed easily and safely without fluoroscopic assistance for the treatment of many cervical diseases. PMID- 23091670 TI - Posterior atalntoaxial fusion with c1 lateral mass screw and c2 pedicle screw supplemented with miniplate fixation for interlaminar fusion : a preliminary report. AB - OBJECTIVE: To investigate the feasibility of C1 lateral mass screw and C2 pedicle screw with polyaxial screw and rod system supplemented with miniplate for interlaminar fusion to treat various atlantoaxial instabilities. METHODS: After posterior atlantoaxial fixation with lateral mass screw in the atlas and pedicle screw in the axis, we used 2 miniplates to fixate interlaminar iliac bone graft instead of sublaminar wiring. We performed this procedure in thirteen patients who had atlantoaxial instabilities and retrospectively evaluated the bone fusion rate and complications. RESULTS: By using this method, we have achieved excellent bone fusion comparing with the result of other methods without any complications related to this procedure. CONCLUSION: C1 lateral mass screw and C2 pedicle screw with polyaxial screw and rod system supplemented with miniplate for interlaminar fusion may be an efficient alternative method to treat various atlantoaxial instabilities. PMID- 23091671 TI - Imaging findings of solitary spinal bony lesions and the differential diagnosis of benign and malignant lesions. AB - OBJECTIVE: The purpose of this study was to present the MRI and CT findings of solitary spinal bone lesions (SSBLs) with the aims of aiding the differential diagnoses of malignant tumors and benign lesions, and proposing a diagnostic strategy for obscure SSBLs. METHODS: The authors retrospectively reviewed the imaging findings of 19 patients with an obscure SSBL on MRI at our hospital from January 1994 to April 2011. The 19 patients were divided to benign groups and malignant groups according to final diagnosis. MRI and CT findings were evaluated and the results of additional work-up studies were conducted to achieve a differential diagnosis. RESULTS: At final diagnoses, 10 (52.6%) of the 19 SSBLs were malignant tumors and 9 (47.4%) were benign lesions. The malignant tumors included 6 metastatic cancers, 3 multiple myelomas, and 1 chordoma, and the benign lesions included 4 osteomyelitis, 2 hemangiomas, 2 nonspecific chronic inflammations, and 1 giant cell tumor. No MRI characteristics examined was found to be significantly different in the benign and malignant groups. Reactive sclerotic change was observed by CT in 1 (10.0%) of the 10 malignant lesions and in 7 (77.8%) of the 9 benign lesions (p=0.005). CONCLUSION: Approximately half of the obscure SSBLs were malignant tumors. CT and MRI findings in combination may aid the differential diagnosis of obscure SSBLs. In particular, sclerotic change on CT images was an important finding implying benign lesion. Finally, we suggest a possible diagnostic strategy for obscure SSBLs on MRI. PMID- 23091672 TI - Indications and surgical results of twist-drill craniostomy at the pre-coronal point for symptomatic chronic subdural hematoma patients. AB - OBJECTIVE: Twist-drill craniostomy (TDC) with closed-system drainage and burr hole drainage (BHD) with a closed system are effective treatment options for chronic subdural hematoma (CSDH). The aim of this study was to analyze clinical data and surgical results from symptomatic CSDH patients who underwent TDC with closed-system drainage at the pre-coronal point (PCP). METHODS: We analyzed data for 134 symptomatic CSDH patients who underwent TDC at the PCP with closed-system drainage. We defined the PCP for TDC to be 1 cm anterior to the coronal suture at the level of superior temporal line. TDC at the PCP with closed-system drainage was selected in patients with CSDH that extended beyond the coronal suture, confirmed by preoperative CT scans. Medical records, radiological findings, and clinical performance were reviewed retrospectively. RESULTS: Of the 134 CSDH patients, 114 (85.1%) showed improved clinical performance and imaging findings after surgery. Catheter failures were seen in two cases (1.4%); the catheters were inserted in the epidural space. Recurrent cases were seen in eight patients (5.6%), and they were improved with a second BHD with a closed-system operation. CONCLUSION: TDC at the PCP with closed-system drainage is safe and effective for patients with symptomatic CSDH whose hematomas extend beyond the coronal suture. PMID- 23091673 TI - Brachial plexus tumors in a consecutive series of twenty one patients. AB - OBJECTIVE: This is a retrospective review of 22 surgically treated benign and malignant tumors of brachial plexus region to describe clinical presentation, the characteristics of brachial plexus tumor and clinical outcomes with a literature review. METHODS: Twenty-one patients with consecutive 22 surgeries for primary brachial plexus tumors were enrolled between February 2002 and November 2011 were included in this study. The medical records of all patients were reviewed. RESULTS: Eleven male and 10 female patients were enrolled. Mean age was 39 years. Three patients had brachial plexus tumor associated with neurofibromatosis (13.6%). Presenting signs and symptoms included parenthesis and numbness (54.5%), radiating pain (22.7%), direct tenderness and pain (27.2%), palpable mass (77.3%). Twelve patients presented preoperative sensory deficit (54.5%) and 9 patients presented preoperative motor deficit (40.9%). Twenty tumors (90.9%) were benign and 2 tumors (9.1%) were malignant. Benign tumors included 15 schwannomas (68.2%), 4 neurofibromas (18.2%) and 1 granular cell tumor (4.5%). There were 1 malignant peripheral nerve sheath tumor (MPNST) and 1 malignant granular cell tumor. Gross total resection was achieved in 16 patients (72.7%), including all schwannomas, 1 neurofibroma. Subtotal resection was performed in 6 tumors (27.3%), including 3 neurofibromatosis associated with brachial plexus neurofibromas, 1 MPNST and 2 granular cell tumor in one patient. CONCLUSION: Resection of tumor is the choice of tumor in the most of benign and malignant brachial plexus tumors. Postoperative outcomes are related to grade of resection at surgery and pathological features of tumor. PMID- 23091674 TI - Intraventricular cavernous hemangiomas located at the foramen of monro. AB - Intraventricular cavernous hemangiomas are uncommon. Among them, those occurred at the foramen of Monro in the third ventricle may be of particular interest because of its rarity, development of hydrocephalus, being differentiated from other brain lesions. We present a rare case of intraventricular cavernous hemangioma at foramen of Monro which was resected through microsurgery and also review the relevant literatures. PMID- 23091675 TI - Malignant transformation of an epidermoid cyst in the cerebellopontine angle. AB - Intracranial squamous cell carcinoma is extremely rare, with most of the cases arising from malignant transformation of an epidermoid or a dermoid cyst. The patient presented with facial weakness. Initial magnetic resonance imaging revealed a mass in the right cerebellopontine angle. A subtotal resection was performed via right retrosigmoid suboccipital approach. Histopathological findings were consistent with an epidermoid tumor. Five months later, the patient underwent gamma knife radiosurgery due to highly probable recurrent epidermoid tumor. Two years after, the patient's neurological deficit had been newly developed, and follow-up magnetic resonance imaging demonstrated a large contrast enhancing tumor in the left cerebellopontine angle, which compressed the brainstem. After resection of the tumor, histopathological examinations revealed a squamous cell carcinoma probably arising from an underlying epidermoid cyst. We report a case of an epidermoid tumor in the cerebellopontine angle that transformed into a squamous cell carcinoma. PMID- 23091676 TI - A Case of Ectopic Rathke's Cleft Cyst in the Prepontine Cistern. AB - A Rathke's cleft cyst (RCC) is a benign pituitary cyst derived from the remnant of Rathke's pouch, and usually presents as an intrasellar lesion with varying degrees of suprasellar extension. However, to date, a description of a primary prepontine RCC with no intrasellar component has not been reported. The author describes an exceptional case of a symptomatic RCC located behind the sella turcica in a 41-year-old woman who presented with severe headache. The author also provides an embryological hypothesis of the development of an ectopic RCC, with a special emphasis on radiologic characteristics. PMID- 23091677 TI - Intradural migration of a sequestrated lumbar disc fragment masquerading as a spinal intradural tumor. AB - Intervertebral intradural lumbar disc herniation (ILDH) is a quite rare pathology, and isolated intradural lumbar disc herniation is even more rare. Magnetic resonance imaging (MRI) may not be able to reveal ILDHs, especially if MRI findings show an intact lumbar disc annulus and posterior longitudinal ligament. Here, we present an exceedingly rare case of an isolated IDLH that we initially misidentified as a spinal intradural tumor, in a 54-year-old man hospitalized with a 2-month history of back pain and right sciatica. Neurologic examination revealed a positive straight leg raise test on the right side, but he presented no other sensory, motor, or sphincter disturbances. A gadolinium enhanced MRI revealed what we believed to be an intradural extramedullary tumor compressing the cauda equina leftward in the thecal sac, at the L2 vertebral level. The patient underwent total L2 laminectomy, and we extirpated the intradural mass under microscopic guidance. Histologic examination of the mass revealed a degenerated nucleus pulposus. PMID- 23091679 TI - Infiltrating spinal angiolipoma. AB - Spinal angiolipomas are rare lesions usually found in the epidural space of the thoracic spine. The infiltrating type of spinal angiolipomas is extremely rare. This report presents the case and reviews the related literature. A 58-year-old man was presented with a 7-month history of progressive weakness and sensory change of lower extremities. Magnetic resonance images showed a well-enhanced mass infiltrating the vertebral foramen at the T4-5 level. Resection of the tumor was performed. Histological study revealed the tumor as an angiolipoma. The patient was relieved from symptoms after tumor resection. PMID- 23091678 TI - Congenital osseus bridging of lumbar transverse processes. AB - Osseous bridging between lumbar transverse processes is an uncommon condition that may cause low back pain. In most cases, its etiology is alleged to be trauma to the back and only rarely has a congenital origin been indicated. Furthermore, most reported cases involved adults, the majority of whom were middle-aged. Here, the authors describe the case of the youngest girl reported to date with congenital transverse process bridging. As far as the authors' knowledge, there has been no report of congenital bridging of transverse processes in children or adolescents in Korea. PMID- 23091680 TI - Pulsed Radiofrequency of Non-neural Tissues. PMID- 23091681 TI - Effects of Ethyl Pyruvate on Allodynia, TNF-alpha Expression, and Apoptosis in the Dorsal Root Ganglion after Spinal Nerve Ligation Injury. AB - BACKGROUND: It has been demonstrated that the expression of tumor necrosis factor alpha (TNF-alpha) and apoptotic cell death in the dorsal root ganglion (DRG) following spinal nerve constriction injury play a role in the initiation and continuation of hyperalgesia and allodynia. The present study was designed to investigate the effects of ethyl pyruvate (EP) on mechanical and cold allodynia, TNF-alpha expression, and apoptosis in DRG after spinal nerve ligation injury. METHODS: Rats were divided into 3 groups: control, pre-EP, and post-EP. EP (50 mg/kg) was intraperitoneally injected 30 minutes before (pre-EP) or after (post EP) surgery. Behavioral tests to determine mechanical and cold allodynia were conducted before surgery and 4 and 7 days after surgery. Seven days after surgery, TNF-alpha protein levels in DRG were evaluated by enzyme-linked immunosorbent assay, and DRG apoptosis was determined by immunohistochemical detection of activated caspase-3. RESULTS: Treatment with EP significantly reduced mechanical and cold allodynia following spinal nerve ligation injury. TNF alpha protein levels in the pre-EP (4.7 +/- 1.2 pg/200 ug; P < 0.001) and post-EP (6.4 +/- 1.8 pg/200 ug; P < 0.001) groups were 2-3 times lower than the control group (14.4 +/- 1.2 pg/200 ug). The percentages of neurons and satellite cells that co-localized with caspase-3 were also significantly lower in the pre-EP and post-EP groups than the control group. CONCLUSIONS: These results demonstrate that EP has a strong anti-allodynic effect that acts through the inhibition of TNF-alpha expression and apoptosis in DRG after spinal nerve ligation injury. PMID- 23091682 TI - Evidence for the Participation of ATP-sensitive Potassium Channels in the Antinociceptive Effect of Curcumin. AB - BACKGROUND: It has been reported that curcumin, the main active compound of Curcuma longa, also known as turmeric, exhibits antinociceptive properties. The aim of this study was to examine the participation of ATP-sensitive potassium channels (K(ATP) channels) and, in particular, that of the L-arginine-nitric oxide-cyclic GMP-K(ATP) channel pathway, in the antinociceptive effect of curcumin. METHODS: Pain was induced by the intraplantar injection of 1% formalin in the right hind paw of Wistar rats. Formalin-induced flinching behavior was interpreted as an expression of nociception. The antinociceptive effect of oral curcumin was explored in the presence and absence of local pretreatment with L NAME, an inhibitor of nitric oxide synthase, ODQ, an inhibitor of soluble guanylyl cyclase, and glibenclamide, a blocker of K(ATP) channels. RESULTS: Oral curcumin produced a dose-dependent antinociceptive effect in the 1% formalin test. Curcumin-induced antinociception was not altered by local L-NAME or ODQ, but was significantly impaired by glibenclamide. CONCLUSIONS: Our results confirm that curcumin is an effective antinociceptive agent. Curcumin-induced antinociception appears to involve the participation of K(ATP) channels at the peripheral level, as local injection of glibenclamide prevented its effect. Activation of K(ATP) channels, however, does not occur by activation of the L arginine-nitric oxide-cGMP-K(ATP) channel pathway. PMID- 23091683 TI - Evaluation of the neurological safety of epidural milnacipran in rats. AB - BACKGROUND: Milnacipran is a balanced serotonin norepinephrine reuptake inhibitor with minimal side effects and broad safety margin. It acts primarily on the descending inhibitory pain pathway in brain and spinal cord. In many animal studies, intrathecal administration of milnacipran is effective in neuropathic pain management. However, there is no study for the neurological safety of milnacipran when it is administered neuraxially. This study examined the neurotoxicity of epidural milnacipran by observing behavioral and sensory-motor changes with histopathological examinations of spinal cords in rats. METHODS: Sixty rats were divided into 3 groups, with each group receiving epidural administration of either 0.3 ml (3 mg) of milnacipran (group M, n = 20), 0.3 ml of 40% alcohol (group A, n = 20), or 0.3 ml of normal saline (group S, n = 20). RESULTS: There were no abnormal changes in the behavioral, sensory-motor, or histopathological findings in all rats of groups M and S over a 3-week observation period, whereas all rats in group A had abnormal changes. CONCLUSIONS: Based on these findings, the direct epidural administration of milnacipran in rats did not present any evidence of neurotoxicity in behavioral, sensory-motor and histopathological evaluations. PMID- 23091684 TI - Antinociceptive effects of intraperitoneal and intrathecal vitamin e in the rat formalin test. AB - BACKGROUND: Vitamin E is widely known to be one of the reactive oxygen species (ROS) scavengers and a drug that can easily be obtained, and it has been shown to attenuate the pain responses induced by various causes in animal pain models. Thus, this experiment was conducted to assess the antinociceptive effects of vitamin E by comparing intraperitoneal and intrathecal injections in rats subjected to the formalin test. METHODS: AFTER THE INTRAPERITONEAL AND INTRATHECAL INJECTIONS OF VITAMIN E WERE CARRIED OUT, RESPECTIVELY (IP: 500 mg/kg, 1 g/kg, and 2 g/kg, IT: 3 mg/kg, 10 mg/kg, and 30 mg/kg), the formalin test was perfumed. As soon as 5% formalin was injected into left hind paw, the number of flinches induced by pain was measured at 5-minute intervals for 1 hour. RESULTS: Formalin injected into the left hind paw induced biphasic nociceptive behavior in all animals. Intraperitoneal injection of vitamin E diminished the nociceptive behavior in a dose-dependent manner during the early and late phase. Intrathecal vitamin E diminished nociceptive behavior dose dependently during the late phase but showed no significant difference in the early phase. CONCLUSIONS: Vitamin E attenuated acute nociception when it was injected systemically, while both systemic and intrathecal injection produced analgesia in a rat model of formalin-induced hyperalgesia. PMID- 23091685 TI - Chronic Pain and Its Determinants: A Population-based Study in Southern Iran. AB - BACKGROUND: Prevalence of chronic pain and its association with demographic characteristics have been reported by different studies from different geographical regions in the world. However, data from many Middle East countries including Iran (especially southern Iran) are scare. The aim of the present study was to demonstrate the prevalence of chronic pain and its association with demographic, psychological and socioeconomic factors in an Iranian population. METHODS: In this population-based survey, the target population was comprised of subjects aged 20 to 85 years residing in Jahrom, southern Iran during 2009-2011. All eligible subjects were invited to participate in the study. Before a detailed questionnaire was given; face to face interviews were done for each individual. RESULTS: There were 719 men and 874 women with an average age of 40.5 years at the onset of the study. Among the study population, 38.9% (620/1,593) complained of chronic pain, of whom 40.8% (253/620) were men and 59.2% (367/620) were women. Foot and joint pain were observed in 31.9%. Hip and spine pain, migraine and tension headaches, heart pain, and abdomen pain were observed in 21.5%, 15.5%, 9.5%, and 8.0% of chronic pain cases, respectively. There was a significant association among the covariables age, sex, overweight, educational level, income, and type of employment with chronic pain as the dependent variable (P < 0.0001). CONCLUSIONS: Our findings show the prevalence of chronic pain and its association with demographic, psychological and socioeconomic factors. Individuals with low incomes and less education became accustomed to pain due to a lack of knowledge. PMID- 23091686 TI - Preconsent video-assisted instruction improves the comprehension and satisfaction in elderly patient visiting pain clinic. AB - BACKGROUND: Elderly patients visiting pain clinic may be at greater risk of misunderstanding the explanation because of age-related cognitive decline. Video instruction may provide a consistent from of teaching in a visual and realistic manner. We evaluated the effect of educational video on the patient understanding and satisfaction in a group of geriatric patients visiting pain clinic. METHODS: Ninety two patients aged more than 60 years old who were scheduled for transforaminal epidural block were recruited. After exposure to either video or paper instruction process, each patient was asked 5-item comprehension questions, overall satisfaction and preference question. During follow-up period, number of outpatient referral-line call for further explanation was counted. RESULTS: We observed significantly better comprehension in the video education compared with paper instruction (P < 0.001). Patient satisfaction was also higher in the video group (P = 0.015), and patients visiting pain clinic were more preferred video instruction (P < 0.001). Proportion of referral-line call for further explanation were similar (P = 0.302). CONCLUSIONS: Video approach to instruction process before consent improves treatment comprehension in geriatric patient visiting pain clinic. PMID- 23091687 TI - Unrecognized c1 lateral mass fracture without instability; the origin of posterior neck pain. AB - Posterior neck pain is a common complaint of patients in the pain clinic. The atlas (C1) burst fracture is known to be a cause of posterior neck pain and instability. Although the atlas burst fracture and instability can be discovered by plain X-rays which show lateral mass displacement or widening of the atlantodental interval, assessment of an atlas burst fracture can be difficult if there is no instability in the imaging study. Here we report a case of a 46-year old female patient who had complained of sustained posterior neck pain for 6 months. Plain X-rays showed only disc space narrowing at C4/5 and C5/6, without any cervical instability. However, an unrecognized C1 lateral mass fracture was detected by CT and MRI. The patient's pain was then successfully treated after atlantoaxial joint injection with a C2 DRG block. PMID- 23091688 TI - Pneumocephalus in a patient with no cerebrospinal fluid leakage after lumbar epidural block - a case report -. AB - Several complications are possible after a lumbar epidural block. However pneumocephalus are rare. In this case, we report a case of pneumocephalus. A 68 year-old male patient received lumbar epidural block with the loss of resistance technique using air, and after 35 minutes, apnea, unconsciousness, hypotension, and bradycardia occurred. Immediately, brain CT was done, and we found pneumocephalus. The patient complained of severe occipital headache and itchiness due to pneumocehalus. After conservative treatment, the patient recovered without neurologic complications, and on the seventh day of his hospitalization, he was discharged from the hospital. PMID- 23091689 TI - Pain and anxiety management in minimally invasive repair of pectus excavatum. AB - The Nuss procedure for the correction of Pectus Excavatum (PE) is associated with intense postoperative pain. Our strategy to control early postoperative pain is to combine epidural with intravenous analgesia. Our aim was to analyse our pain control strategy by reviewing all the PE cases treated at our institution. Sixty consecutive patients, aged between 12 and 26 years old, received the PE operation at our institution from January, 2007 to September, 2010. The median age was 16 (12-27) with a male/female ratio of about 7/1. An epidural catheter was employed in all the cases, with 38 patients (63%) requiring additional drugs to control pain, which remained in place for 74 hours (72-96). The pain score was higher in male patients, but lower in those younger than 16 years old. Moreover, patients that consumed benzodiazepines had a significant decrease in cumulative opioid intake (P = 0.0408). Both gender and age had an impact on pain control, while we noticed a synergistic effect between opiates and tranquillizers. PMID- 23091690 TI - Mirror therapy for phantom limb pain. AB - Phantom limb pain is a painful sensation that is perceived in a body part that no longer exists. To control this pain, many methods have been used such as medication, physical treatment, nerve block, neuromodulation, surgical treatment and mirror therapy. However, until now, there effects have been uncertain. We report the successful reduction of phantom limb pain using mirror therapy when other treatments initially failed to control the pain. PMID- 23091691 TI - Popliteal Fossa Pain in 24 Year-old Female. AB - The pain around the posterior knee, called 'popliteal fossa', has been known to be caused by a variety of disease entities. Venous malformation is a very rare cause of popliteal area pain, and its diagnosis is frequently delayed, missed, or given incorrectly. Here, we report a case of a patient with popliteal fossa pain for 2 years and was diagnosed as intramuscular venous malformation using ultrasound. PMID- 23091692 TI - Efficacy of stellate ganglion block in cholinergic urticaria with acquired generalized hypohidrosis. AB - Cholinergic urticaria with acquired generalized hypohidrosis, and its pathophysiology is not well known. Autoimmunity to sweat glands or to acetylcholine receptors on sweat glands has been mentioned as one of the possible etiologies. Systemic steroid therapy, antihistamines, anticholinergics, and avoidance of the stimulatory situations are recommended for treatment. We experienced a case of cholinergic urticaria with acquired generalized hypohidrosis in a patient who had no other associated disease, and the symptoms eased after repeated bilateral stellate ganglion block. Stellate ganglion block normalized the elevated sympathetic tone and may relieve symptoms in patients with this condition. PMID- 23091693 TI - Rare Complications of Kikuchi's Disease: Beyond Pain Control. PMID- 23091694 TI - Rare clinical presentations of perineural cysts besides radicular pain. PMID- 23091695 TI - Quantum tunneling of magnetization in ultrasmall half-metallic V3O4 quantum dots: displaying quantum superparamagnetic state. AB - Quantum tunneling of magnetization (QTMs), stemming from their importance for understanding materials with unconventional properties, has continued to attract widespread theoretical and experimental attention. However, the observation of QTMs in the most promising candidates of molecular magnets and few iron-based compounds is limited to very low temperature. Herein, we first highlight a simple system, ultrasmall half-metallic V(3)O(4) quantum dots, as a promising candidate for the investigation of QTMs at high temperature. The quantum superparamagnetic state (QSP) as a high temperature signature of QTMs is observed at 16 K, which is beyond absolute zero temperature and much higher than that of conventional iron based compounds due to the stronger spin-orbital coupling of V(3+) ions bringing high anisotropy energy. It is undoubtedly that this ultrasmall quantum dots, V(3)O(4), offers not only a promising candidate for theoretical understanding of QTMs but also a very exciting possibility for computers using mesoscopic magnets. PMID- 23091697 TI - Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases. AB - The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases. PMID- 23091698 TI - High mobility conduction at (110) and (111) LaAlO3/SrTiO3 interfaces. AB - In recent years, striking discoveries have revealed that two-dimensional electron liquids (2DEL) confined at the interface between oxide band-insulators can be engineered to display a high mobility transport. The recognition that only few interfaces appear to suit hosting 2DEL is intriguing and challenges the understanding of these emerging properties not existing in bulk. Indeed, only the neutral TiO(2) surface of (001)SrTiO(3) has been shown to sustain 2DEL. We show that this restriction can be surpassed: (110) and (111) surfaces of SrTiO(3) interfaced with epitaxial LaAlO(3) layers, above a critical thickness, display 2DEL transport with mobilities similar to those of (001)SrTiO(3). Moreover we show that epitaxial interfaces are not a prerequisite: conducting (110) interfaces with amorphous LaAlO(3) and other oxides can also be prepared. These findings open a new perspective both for materials research and for elucidating the ultimate microscopic mechanism of carrier doping. PMID- 23091696 TI - High-performance method for specific effect on nucleic acids in cells using TiO2~DNA nanocomposites. AB - Nanoparticles are used to solve the current drug delivery problem. We present a high-performance method for efficient and selective action on nucleic acid target in cells using unique TiO(2).PL-DNA nanocomposites (polylysine-containing DNA fragments noncovalently immobilized onto TiO(2) nanoparticles capable of transferring DNA). These nanocomposites were used for inhibition of human influenza A (H3N2) virus replication in infected MDCK cells. They showed a low toxicity (TC(50) ~ 1800 MUg/ml) and a high antiviral activity (>99.9% inhibition of the virus replication). The specificity factor (antisense effect) appeared to depend on the delivery system of DNA fragments. This factor for nanocomposites is ten-times higher than for DNA in the presence of lipofectamine. IC(50) for nanocomposites was estimated to be 1.5 MUg/ml (30 nM for DNA), so its selectivity index was calculated as ~1200. Thus, the proposed nanocomposites are prospective for therapeutic application. PMID- 23091699 TI - Theoretical investigation of the magnetic exchange interactions in copper(II) oxides under chemical and physical pressures. AB - It remains a challenge to understand the unconventional mechanisms that cause high-T(C) superconductivity in cuprate superconductors, high-T(C) multiferroicity in CuO, or low-dimensional magnetism in the spin-Peierls transition compounds such as CuGeO(3). A common feature of all these copper oxide compounds (containing Cu(2+) ions) is the presence of large magnetic superexchange interactions J. It is a general strategy to apply chemical and/or physical pressure in order to tune these exotic properties. Here we show theoretically, for the first time, the impact of physical pressure on J on CuO, for which we predict a strong enhancement of the low-dimensionality of the magnetic interactions and the spin-frustration at high-pressures. Such modifications are expected to strongly influence the multiferroic properties of CuO. We finally demonstrate that PBE0 hybrid DFT calculations provide reliable J values for a wide range of copper(II) oxides compounds, i.e. CuGeO(3), BaCu(2)Si(2)O(7), BaCu(2)Ge(2)O(7), and La(2)CuO(4). PMID- 23091700 TI - Phylogeny rather than ecology or lifestyle biases the construction of Escherichia coli-Shigella genetic exchange communities. AB - Genetic material can be transmitted not only vertically from parent to offspring, but also laterally (horizontally) from one bacterial lineage to another. Lateral genetic transfer is non-uniform; biases in its nature or frequency construct communities of genetic exchange. These biases have been proposed to arise from phylogenetic relatedness, shared ecology and/or common lifestyle. Here, we test these hypotheses using a graph-based abstraction of inferred genetic-exchange relationships among 27 Escherichia coli and Shigella genomes. We show that although barriers to inter-phylogenetic group lateral transfer are low, E. coli and Shigella are more likely to have exchanged genetic material with close relatives. We find little evidence of bias arising from shared environment or lifestyle. More than one-third of donor-recipient pairs in our analysis show some level of fragmentary gene transfer. Thus, within the E. coli-Shigella clade, intact genes and gene fragments have been disseminated non-uniformly and at appreciable frequency, constructing communities that transgress environmental and lifestyle boundaries. PMID- 23091701 TI - Impaired coenzyme A synthesis in fission yeast causes defective mitosis, quiescence-exit failure, histone hypoacetylation and fragile DNA. AB - Biosynthesis of coenzyme A (CoA) requires a five-step process using pantothenate and cysteine in the fission yeast Schizosaccharomyces pombe. CoA contains a thiol (SH) group, which reacts with carboxylic acid to form thioesters, giving rise to acyl-activated CoAs such as acetyl-CoA. Acetyl-CoA is essential for energy metabolism and protein acetylation, and, in higher eukaryotes, for the production of neurotransmitters. We isolated a novel S. pombe temperature-sensitive strain ppc1-537 mutated in the catalytic region of phosphopantothenoylcysteine synthetase (designated Ppc1), which is essential for CoA synthesis. The mutant becomes auxotrophic to pantothenate at permissive temperature, displaying greatly decreased levels of CoA, acetyl-CoA and histone acetylation. Moreover, ppc1-537 mutant cells failed to restore proliferation from quiescence. Ppc1 is thus the product of a super-housekeeping gene. The ppc1-537 mutant showed combined synthetic lethal defects with five of six histone deacetylase mutants, whereas sir2 deletion exceptionally rescued the ppc1-537 phenotype. In synchronous cultures, ppc1-537 cells can proceed to the S phase, but lose viability during mitosis failing in sister centromere/kinetochore segregation and nuclear division. Additionally, double-strand break repair is defective in the ppc1-537 mutant, producing fragile broken DNA, probably owing to diminished histone acetylation. The CoA-supported metabolism thus controls the state of chromosome DNA. PMID- 23091703 TI - Association of HLA-DQB1*05:02 and DRB1*16 Alleles with Late-Onset, Nonthymomatous, AChR-Ab-Positive Myasthenia Gravis. AB - An association of several HLA alleles with myasthenia gravis (MG) has been reported. Aim of this work was to analyze the HLA allele profile in a survey of 76 unselected Italian MG patients and in a subgroup characterized by disease onset after the age of 50 years, absence of thymoma, and presence of antiacetylcholine receptor antibodies. We defined this subgroup by the acronym LOAb. Typing was performed at low resolution for HLA-A, -B, and -DRB1 loci with sequence-specific oligonucleotide probe (PCR-SSO); at high resolution for HLA DQB1 locus by PCR with sequence-specific primers (PCR-SSPS). HLA allele frequencies were compared with 100 healthy controls. No correlation was observed between MG and the studied HLA class I alleles. On the contrary, a strong positive association was found for the HLA class II alleles DQB1*05:02 (P(c) = 0.00768) and DRB1*16 (P(c) = 0.0211) in the LOAb subgroup (n = 27) of MG patients. Association between DQB1*05:02 and some subtypes of MG has been previously reported but not in patients with the LOAb characteristics. Therefore, the HLA allele DQB1*05:02 might be considered as a susceptibility marker for LOAb among Italians. PMID- 23091702 TI - Epidemiology of Enterocytozoon bieneusi Infection in Humans. AB - A review was conducted to examine published works that focus on the complex epidemiology of Enterocytozoon bieneusi infection in humans. Studies on the prevalence of these emerging microsporidian pathogens in humans, in developed and developing countries, the different clinical spectra of E. bieneusi intestinal infection in children, in different settings, and the risk factors associated with E. bieneusi infection have been reviewed. This paper also analyses the impact of the recent application of PCR-based molecular methods for species specific identification and genotype differentiation has had in increasing the knowledge of the molecular epidemiology of E. bieneusi in humans. The advances in the epidemiology of E. bieneusi, in the last two decades, emphasize the importance of epidemiological control and prevention of E. bieneusi infections, from both the veterinary and human medical perspectives. PMID- 23091704 TI - Role of hsp90 in systemic lupus erythematosus and its clinical relevance. AB - Heat shock proteins (HSP) are a family of ubiquitous and phylogenically highly conserved proteins which play an essential role as molecular chaperones in protein folding and transport. Heat Shock Protein 90 (Hsp90) is not mandatory for the biogenesis of most proteins, rather it participate in structural maturation and conformational regulation of a number of signaling molecules and transcription factors. Hsp90 has been shown to play an important role in antigen presentation, activation of lymphocytes, macrophages, maturation of dendritic cells, and in the enhanceosome mediated induction of inflammation. Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Dysregulated expression of Type I interferon alpha, activation of B cells and production of autoantibodies are hallmarks of SLE. The enhanced levels of Hsp90 were detected in the serum of SLE patients. The elevated level of Hsp90 in SLE has also been correlated with increased levels of IL-6 and presence of autoantibodies to Hsp90. This suggests that Hsp90 may contribute to the inflammation and disease progression and that targeting of Hsp 90 expression may be a potential treatment of SLE. The pharmacologic inhibition of Hsp90 was successfully applied in mouse models of autoimmune encephalomyelitis and SLE-like autoimmune diseases. Thus targeting Hsp90 may be an effective treatment for SLE, especially if combined with other targeted therapeutic approaches. PMID- 23091705 TI - Abdominal obesity is characterized by higher pulse pressure: possible role of free triiodothyronine. AB - Objective. This study examined whether obesity is characterized by higher 24 h mean pulse pressure (24 h mean SBP-24 h mean DBP) and whether free thyroid hormones (FT(3) and FT(4)) have a relationship with 24 h mean pulse pressure. Methods. A total of 231 euthyroid overweight and obese patients, 103 women and 128 men, aged 18-68 yrs, normotensive (n = 69) or with recently developed hypertension (n = 162), never treated with antihypertensive drugs, were investigated. Fasting insulin, TSH, FT(3), FT(4), glucose, and lipid serum concentrations were measured. Waist circumference was measured as an indirect parameter of central fat accumulation. Ambulatory blood pressure monitoring (ABPM) was performed. Results. 24 h mean pulse pressure (PP) showed a significant positive correlation with BMI (P < 0.001), waist circumference (P < 0.001), and FT(3) (P < 0.001) and insulin serum levels (P < 0.05). When a multivariate analysis was performed, and 24 h PP was considered as the dependent variable, and waist circumference, FT(3), insulin, male sex, and age as independent parameters, 24 h mean PP maintained a significant association only with waist circumference (P < 0.001) and FT(3) levels (P < 0.05). Conclusion. Our results suggest that FT(3) per se may contribute to higher pulse pressure in obese subjects. PMID- 23091706 TI - Periconceptional undernutrition in sheep affects adult phenotype only in males. AB - Periconceptional undernutrition (PCUN) in sheep alters fetal growth and metabolism and postnatal growth regulation, but effects on adult body composition are unknown. We investigated the effects of PCUN on adult phenotype. Singleton lambs of ewes fed normally (N, n = 17) or undernourished before (UN-61-0 d, n = 23), before and after (UN-61-30 d, n = 19), or after (UN-2-30d, n = 17) mating (d0) were weighed at birth, 12 weeks, and intermittently to adulthood. At the age of 3-4 years, body composition was assessed by dual-emission X-ray absorptiometry followed by postmortem examination. Compared with N animals, male, but not female, offspring of all UN groups had greater % fat mass (all UN versus N: 9 +/- 1 versus 2 +/- 1%, P < 0.001) and perirenal fat (544 +/- 36 versus 222 +/- 44 g, P = 0.002), and proportionately smaller hearts (4.5 +/- 0.1 versus 5.2 +/- 0.2 g.kg(-1)), lungs (9.1 +/- 0.2 versus 10.6 +/- 0.5 g.kg(-1)), and adrenals (0.06 +/- 0.002 versus 0.08 +/- 0.003 g.kg(-1)). UN males also had larger testes (726 +/- 21 versus 545 +/- 32 g, P = 0.007), but UN females had smaller ovaries (2.7 +/- 0.08 versus 3.4 +/- 0.4 g, P = 0.01). Changes were independent of birth weight or postnatal growth velocity. Brief PCUN has sex-specific effects on adult phenotype, predominantly affecting males, which may contribute to adverse metabolic outcomes. PMID- 23091707 TI - Meal replacements for weight loss in type 2 diabetes in a community setting. AB - Background. There is limited information on the effectiveness of meal replacements (MRs) as a weight-loss strategy in an unsupervised community setting. Aim. To evaluate the use of MR compared with a diet book for 6 months. Subjects and Methods. Obese subjects (n = 120) with type 2 diabetes mellitus were recruited from the community in Adelaide, South Australia, and randomised to intervention or control. Subjects in the intervention were advised to consume 2 MR/day for 3 months and 1 MR/day for 3 months and follow the manufacturers' instructions from printed material and the website. Subjects in the control arm were given a commercially available diet book. Results. Consumption of 2 MR for 3 months and 1 MR for the subsequent 3 months led to weight loss of 5.5 kg (5%) and a 0.26% decrease in HbA1c while the diet book group had a weight loss of 3 kg (3%) (P = 0.027 for difference between groups) and a decrease in HbA1c of 0.15% (between group ns) in those who completed the 6-month study. On intention-to treat (last observation carried forward) weight loss at 6 months was 3.4 kg in MR and 1.8 kg in control (P = 0.07). Decreases in HbA1c were 0.22% and 0.12%, respectively (P = ns). HDL cholesterol increased by 4% in MR and decreased by 1% in control (P = 0.004). Blood pressure decreased equally in both groups. There were reductions in fasting glucose in both groups at 6 months with no changes in LDL-cholesterol or triglyceride concentrations. Conclusion. MR confers benefits in HbA1C reduction and weight loss at 6 months in those who completed the study. PMID- 23091708 TI - Symptom Status Predicts Patient Outcomes in Persons with HIV and Comorbid Liver Disease. AB - Persons living with human immunodeficiency virus (HIV) are living longer; therefore, they are more likely to suffer significant morbidity due to potentially treatable liver diseases. Clinical evidence suggests that the growing number of individuals living with HIV and liver disease may have a poorer health related quality of life (HRQOL) than persons living with HIV who do not have comorbid liver disease. Thus, this study examined the multiple components of HRQOL by testing Wilson and Cleary's model in a sample of 532 individuals (305 persons with HIV and 227 persons living with HIV and liver disease) using structural equation modeling. The model components include biological/physiological factors (HIV viral load, CD4 counts), symptom status (Beck Depression Inventory II and the Medical Outcomes Study HIV Health Survey (MOS-HIV) mental function), functional status (missed appointments and MOS-HIV physical function), general health perceptions (perceived burden visual analogue scale and MOS-HIV health transition), and overall quality of life (QOL) (Satisfaction with Life Scale and MOS-HIV overall QOL). The Wilson and Cleary model was found to be useful in linking clinical indicators to patient-related outcomes. The findings provide the foundation for development and future testing of targeted biobehavioral nursing interventions to improve HRQOL in persons living with HIV and liver disease. PMID- 23091710 TI - Extravascular lung water does not increase in hypovolemic patients after a fluid loading protocol guided by the stroke volume variation. AB - Introduction. Circulatory failure secondary to hypovolemia is a common situation in critical care patients. Volume replacement is the first option for the treatment of hypovolemia. A possible complication of volume loading is pulmonary edema, quantified at the bedside by the measurement of extravascular lung water index (ELWI). ELWI predicts progression to acute lung injury (ALI) in patients with risk factors for developing it. The aim of this study was to assess whether fluid loading guided by the stroke volume variation (SVV), in patients presumed to be hypovolemic, increased ELWI or not. Methods. Prospective study of 17 consecutive postoperative, fully mechanically ventilated patients diagnosed with circulatory failure secondary to presumed hypovolemia were included. Cardiac index (CI), ELWI, SVV, and global end-diastolic volume index (GEDI) were determined using the transpulmonary thermodilution technique during the first 12 hours after fluid loading. Volume replacement was done with a strict hemodynamic protocol. Results. Fluid loading produced a significant increase in CI and a decrease in SVV. ELWI did not increase. No correlation was found between the amount of fluids administered and the change in ELWI. Conclusion. Fluid loading guided by SVV in hypovolemic and fully mechanically ventilated patients in sinus rhythm does not increase ELWI. PMID- 23091709 TI - Management of anemia of inflammation in the elderly. AB - Anemia of any degree is recognized as a significant independent contributor to morbidity, mortality, and frailty in elderly patients. Among the broad types of anemia in the elderly a peculiar role seems to be played by the anemia associated with chronic inflammation, which remains the most complex form of anemia to treat. The origin of this nonspecific inflammation in the elderly has not yet been clarified. It seems more plausible that the oxidative stress that accompanies ageing is the real cause of chronic inflammation of the elderly and that the same oxidative stress is actually a major cause of this anemia. The erythropoietic agents have the potential to play a therapeutic role in this patient population. Despite some promising results, rHuEPO does not have a specific indication for the treatment of anemia in the elderly. Moreover, concerns about their side effects have spurred the search for alternatives. Considering the etiopathogenetic mechanisms of anemia of inflammation in the elderly population, an integrated nutritional/dietetic approach with nutraceuticals that can manipulate oxidative stress and related inflammation may prevent the onset of this anemia and its negative impact on patients' performance and quality of life. PMID- 23091711 TI - Microcirculation. PMID- 23091713 TI - Social support associated with quality of life in home care patients with intractable neurological disease in Japan. AB - The aim of the present study was to investigate what kinds of social supports contribute to the higher quality of life (QOL) of home care patients with intractable neurological disease. We investigated the World Health Organization Quality of Life-BREF (WHOQOL-BREF) and social supports to 74 patients with intractable neurological disease in a city of the Aichi prefecture, Japan. Association between WHOQOL and social supports was examined using multiple logistic regression analyses adjusting activities of daily living (ADL). High WHOQOL scores were associated with "attending patient gatherings held by the public health center," "having someone who will listen empathically to anxieties or troubles," and ADL. Physical health was associated with ADL, while psychological well-being was related to "having a hobby," "having someone who will listen," and "having a hospital for admission in emergencies." Patients not having someone who will listen were more likely to participate in the gatherings. The present findings suggest that having someone who will provide emotional support is important for home care patients with neurological diseases. Patient gatherings held by the public health center were expected to provide patients with emotional support. PMID- 23091714 TI - Nursing home resident symptomatology triggering transfer: avoiding unnecessary hospitalizations. AB - The purpose of this study was to describe nursing home resident symptomatology and medical diagnoses associated with nursing home to hospital transfers. A retrospective chart review of documented transfers was conducted at a 120-bed, nonprofit urban Continuing Care Retirement Center nursing home facility located in the southwestern United States. The transferred residents (n = 101) had seventy different medical diagnoses prior to hospital transfer with hypertension, coronary artery disease, and congestive heart failure most frequently reported. Most frequently reported symptomatology included fatigue, lethargy or weakness, shortness of breath, and change in level of consciousness. Multiple symptomatology was indicative of a wide variety of medical diagnoses. The diagnoses and symptomatology recorded in this paper identify the importance of strategic planning concerning assessment and communication of common nursing home resident symptomatology and the importance of basic nursing and diagnostic procedures for prevention of potentially avoidable hospitalizations. PMID- 23091712 TI - Persistence of avian influenza viruses in various artificially frozen environmental water types. AB - Background. This study investigates the viable persistence of avian influenza viruses (AIVs) in various types of artificially frozen environmental water and evaluates the feasibility of similar occurrence taking place in nature, and allowing for prolonged abiotic virus survival, with subsequent biotic viral recirculation. Methods. Fresh, brackish, and salty water, taken in Japan from aquatic biotopes regularly visited by migratory waterfowl, were seeded with AIVs. We monthly monitored the viability of the seeded viruses in the frozen state at 20 degrees C and -30 degrees C, for 12 months. We also monitored virus viability following repeatedly induced freezing and thawing. Results. The viruses exhibited considerable viable persistence all along that period of time, as well as during freezing-thawing cycles. Appreciable, yet noncrucial variances were observed in relation to some of the parameters examined. Conclusions. As typical waterborne pathogens of numerous northerly aquatic birds, AIVs are innately adapted to both the body temperature of their hosts (40 degrees C to 42 degrees C) and, presumably, to subzero temperatures of frozen lakes (down to -54 degrees C in parts of Siberia) occupied and virus-seeded by subclinically infected birds, prior to freezing. Marked cryostability of AIVs appears to be evident. Preservation in environmental ice has significant ecophylogenetic and epidemiological implications, potentially, and could account for various unexplained phenomena. PMID- 23091715 TI - Extent of East-african nurse leaders' participation in health policy development. AB - This paper reports part of a bigger study whose aim was to develop an empowerment model that could be used to enhance nurse leaders' participation in health policy development. A Delphi survey was applied which included the following criteria: expert panelists, iterative rounds, statistical analysis, and consensus building. The expert panelists were purposively selected and included national nurse leaders in leadership positions at the nursing professional associations, nursing regulatory bodies, ministries of health, and universities in East Africa. The study was conducted in three iterative rounds. The results reported here were gathered as part of the first round of the study and that examined the extent of nurse leaders' participation in health policy development. Seventy-eight (78) expert panelists were invited to participate in the study, and the response rate was 47%. Data collection was done with the use of a self-report questionnaire. Data analysis was done by use of SPSS and descriptive statistics were examined. The findings indicated that nurse leaders participate in health policy development though participation is limited and not consistent across all the stages of health policy development. The recommendations from the findings are that health policy development process needs to be pluralistic and inclusive of all nurse leaders practicing in positions related to policy development and the process must be open to their ideas and suggestions. PMID- 23091716 TI - Hair Analysis for Determination of Isoniazid Concentrations and Acetylator Phenotype during Antituberculous Treatment. AB - Background. Analysis of isoniazid (INH) uptake has been based on measurement of plasma concentrations providing a short-term and potentially biased view. Objectives. To establish hair analysis as a tool to measure long-term uptake of INH and to assess whether acetylator phenotype in hair reflects N acetyltransferase-2 (NAT2) genotype. Design and Methods. INH and acetyl-INH concentrations in hair were determined in patients on INH treatment for M. tuberculosis infection using high pressure liquid chromatography/mass spectrometry. Acetyl-INH/INH ratios were correlated with NAT-2 genotype. Results. Hair concentrations of INH, determined in 40 patients, were not dependent on ethnic group or body mass index and were significantly higher in male compared to female patients (median (range) 2.37 ng/mg (0.76-4.9) versus 1.11 ng/mg (0.02 7.20) (P = 0.02). Acetyl-INH/INH ratios were a median of 15.2% (14.5 to 31.7) in homozygous rapid acetylator NAT-2 genotype and 37.3% (1.73 to 51.2) in the heterozygous rapid acetylator NAT-2 genotype and both significantly higher than in the slow acetylator NAT-2 genotype with 5.8% (0.53 to 14.4) (P < 0.05). Conclusions. Results of hair analysis for INH showed lower concentrations in females. Acetyl-INH/INH ratios were significantly lower in patients with slow acetylator versus rapid acetylator genotypes. PMID- 23091717 TI - (64)Cu-NODAGA-c(RGDyK) Is a Promising New Angiogenesis PET Tracer: Correlation between Tumor Uptake and Integrin alpha(V)beta(3) Expression in Human Neuroendocrine Tumor Xenografts. AB - Purpose. The purpose of this paper is to evaluate a new PET tracer (64)Cu-NODAGA c(RGDyK) for imaging of tumor angiogenesis using gene expression of angiogenesis markers as reference and to estimate radiation dosimetry for humans. Procedures. Nude mice with human neuroendocrine tumor xenografts (H727) were administered (64)Cu-NODAGA-c(RGDyK) i.v. for study of biodistribution as well as for dynamic PET. Gene expression of angiogenesis markers integrin alpha(V), integrin beta(3), and VEGF-A were analyzed using QPCR and correlated to the tracer uptake in the tumors (%ID/g). From biodistribution data human radiation-absorbed doses were estimated using OLINDA/EXM. Results. Tumor uptake was 1.2%ID/g with strong correlations between gene expression and tracer uptake, for integrin alpha(V) R = 0.76, integrin beta(3) R = 0.75 and VEGF-A R = 0.81 (all P < 0.05). The whole body effective dose for humans was estimated to be 0.038 and 0.029 mSv/MBq for females and males, respectively, with highest absorbed dose in bladder wall. Conclusion. (64)Cu-NODAGA-c(RGDyK) is a promising new angiogenesis PET tracer with potential for human use. PMID- 23091718 TI - Influence of Fever and hospital-acquired infection on the incidence of delayed neurological deficit and poor outcome after aneurysmal subarachnoid hemorrhage. AB - Although fever and infection have been implicated in the causation of delayed neurological deficits (DND) and poor outcome after aneurysmal subarachnoid hemorrhage (SAH), the relationship between these two often related events has not been extensively studied. We reviewed these events through of our retrospective database of patients with SAH. Multivariate logistic regression was used to determine independent predictors of DND and poor outcome. A total of 186 patients were analyzed. DND was noted in 76 patients (45%). Fever was recorded in 102 patients (55%); infection was noted in 87 patients (47%). A patient with one infection was more likely to experience DND compared to a patient with no infections (adjusted OR 3.73, 95% CI 1.62, 8.59). For those with more than two infections the likelihood of DND was even greater (adjusted OR 4.24, 95% CI 1.55, 11.56). Patients with 1-2 days of fever were less likely to have a favorable outcome when compared to their counterparts with no fever (adjusted OR 0.19, 95% CI 0.06, 0.62). This trend worsened as the number of days febrile increased. These data suggest that the presence of infection is associated with DND, but that fever may have a stronger independent association with overall outcome. PMID- 23091719 TI - Facing your fears in adolescence: cognitive-behavioral therapy for high functioning autism spectrum disorders and anxiety. AB - Adolescents with high-functioning autism spectrum disorders (ASDs) are at high risk for developing psychiatric symptoms, with anxiety disorders among the most commonly cooccurring. Cognitive behavior therapies (CBTs) are considered the best practice for treating anxiety in the general population. Modified CBT approaches for youth with high-functioning ASD and anxiety have resulted in significant reductions in anxiety following intervention. The purpose of the present study was to develop an intervention for treating anxiety in adolescents with ASD based on a CBT program designed for school-aged children. The Facing Your Fears Adolescent Version (FYF-A) program was developed; feasibility and acceptability data were obtained, along with initial efficacy of the intervention. Twenty-four adolescents, aged 13-18, completed the FYF-A intervention. Results indicated significant reductions in anxiety severity and interference posttreatment, with low rates of anxiety maintained at 3-month follow-up. In addition, nearly 46% of teen participants met criteria for a positive treatment response on primary diagnosis following the intervention. Initial findings from the current study are encouraging and suggest that modified group CBT for adolescents with high functioning ASD may be effective in reducing anxiety symptoms. Limitations include small sample size and lack of control group. Future directions are discussed. PMID- 23091720 TI - Elevated serum levels of homocysteine as an early prognostic factor of psychiatric disorders in children and adolescents. AB - Background and Goal. The aim was to examine the serum levels of homocysteine (Hcy) and their associations with the methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphism in patients with schizophrenia and mood disorders as well as controls. Materials and Methods. There were 198 patients: 82 with schizophrenia spectrum disorders, 22 with mood disorders, and 94 controls. The level of Hcy was determined by an isocratic high-performance liquid chromatography system. MTHFR C677T polymorphism was analysed using the restriction fragment length polymorphism-polymerase chain reaction method. Results. The average level of Hcy was 11.94 +/- 5.6 MUmol/L for patients with schizophrenia, 11.65 +/- 3.3 MUmol/L for patients with affective disorders, versus 6.80 +/- 2.93 MUmol/L in a control. The highest level of Hcy has been observed in patients with episodic-recurrent course of schizophrenia (11.30 +/- 7.74 MUmol/L), paranoid schizophrenia continuous (12.76 +/- 5.25 MUmol/L), and in patients with affective disorders (11.65 +/- 3.26 MUmol/L). An association between the MTHFR gene C677T polymorphism and Hcy level was found by linear regression analysis (r = 1.41, P = 0.029). Conclusions. The data indicate a link between Hcy levels and schizophrenia and mood disorders. No associations between the level of Hcy in patients with schizophrenia and mood disorders and the MTHFR C677T polymorphism were found. PMID- 23091721 TI - Antiepidermal growth factor receptor monoclonal antibodies: applications in colorectal cancer. AB - Patients with metastatic colorectal cancer have a poor prognosis and present a challenge to clinicians. The role of the antiepidermal growth factor receptor (EGFR) pathway in tumorogenesis and tumor progression has been well defined. This paper will review the use of anti-EGFR monoclonal antibodies in the treatment of operable, as well as metastatic colorectal cancer both in the setting of KRAS mutation unselected patients and later in KRAS wild-type patients. Active investigations designed to further identify predictive biomarkers that may be potentially druggable are reviewed as well. PMID- 23091722 TI - Miniaturized mass-spectrometry-based analysis system for fully automated examination of conditioned cell culture media. AB - We present a fully automated setup for performing in-line mass spectrometry (MS) analysis of conditioned media in cell cultures, in particular focusing on the peptides therein. The goal is to assess peptides secreted by cells in different culture conditions. The developed system is compatible with MS as analytical technique, as this is one of the most powerful analysis methods for peptide detection and identification. Proof of concept was achieved using the well-known mating-factor signaling in baker's yeast, Saccharomyces cerevisiae. Our concept system holds 1 mL of cell culture medium and allows maintaining a yeast culture for, at least, 40 hours with continuous supernatant extraction (and medium replenishing). The device's small dimensions result in reduced costs for reagents and open perspectives towards full integration on-chip. Experimental data that can be obtained are time-resolved peptide profiles in a yeast culture, including information about the appearance of mating-factor-related peptides. We emphasize that the system operates without any manual intervention or pipetting steps, which allows for an improved overall sensitivity compared to non-automated alternatives. MS data confirmed previously reported aspects of the physiology of the yeast-mating process. Moreover, matingfactor breakdown products (as well as evidence for a potentially responsible protease) were found. PMID- 23091723 TI - Oxygen versus Reactive Oxygen in the Regulation of HIF-1alpha: The Balance Tips. AB - Hypoxia inducible factor (HIF) is known as the master regulator of the cellular response to hypoxia and is of pivotal importance during development as well as in human disease, particularly in cancer. It is composed of a constitutively expressed beta subunit (HIF-1beta) and an oxygen-regulated alpha subunit (HIF 1alpha and HIF-2alpha), whose stability is tightly controlled by a family of oxygen- and iron-dependent prolyl hydroxylase enzymes. Whether or not mitochondria-derived reactive oxygen species (ROS) are involved in the regulation of Hypoxia Inducible Factor-1alpha has been a matter of contention for the last 10 years, with equally compelling evidence in favor and against their contribution. A number of recent papers appear to tip the balance against a role for ROS. Thus, it has been demonstrated that HIF prolyl hydroxylases are unlikely to be physiological targets of ROS and that the increase in ROS that is associated with downregulation of Thioredoxin Reductase in hypoxia does not affect HIF-1alpha stabilization. Finally, the protein CHCHD4, which modulates cellular HIF-1alpha concentrations by promoting mitochondrial electron transport chain activity, has been proposed to exert its regulatory effect by affecting cellular oxygen availability. These reports are consistent with the hypothesis that mitochondria play a critical role in the regulation of HIF-1alpha by controlling intracellular oxygen concentrations. PMID- 23091724 TI - Benfotiamine counteracts smoking-induced vascular dysfunction in healthy smokers. AB - Background. Smoking induces endothelial dysfunction (ED) mainly by exacerbating oxidative stress (OS) and inflammation. Benfotiamine, a thiamine prodrug with high bioavailability, prevents nicotine-induced vascular dysfunction in rats. It remained unknown whether this effect also occurs in humans. Methods. Therefore, 20 healthy volunteers (mean age: 38 years) were investigated twice, 7-10 days apart in a randomized, cross-over, and investigator-blinded design. Vascular function was assessed by flow-mediated vasodilatation (FMD) of the brachial artery and by measurements of the soluble vascular cell adhesion molecule (sVCAM) 1. Investigations were performed after an overnight fast as well as 20 minutes after one cigarette smoking. On another day, the same procedure was applied following a 3-day oral therapy with benfotiamine (1050 mg/day). Ten patients were randomized to start with smoking alone, and ten started with benfotiamine. Results. Results are expressed as (mean +/- SEM). Smoking acutely induced a decrease in FMD by 50% ((**)P < 0.001 versus baseline) an effect significantly reduced by benfotiamine treatment to 25%(*S) ((*)P < 0.05 versus baseline, (S)P < 0.05 versus smoking alone). Smoking-induced elevation in sVCAM-1 was also prevented by benfotiamine. The endothelium-independent vasodilatation remained unaltered between days. Conclusion. In healthy volunteers, smoking blunts vascular function mirrored by a decrease in FMD and an increase in sVCAM-1. Short term treatment with benfotiamine significantly reduces these effects, showing protective vascular properties. PMID- 23091725 TI - Role of sentinel lymph node biopsy in the management of merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) is a rare and typically aggressive form of skin cancer. It most commonly affects the elderly and has a predilection for the sun exposed skin of the head and neck region. Other etiological factors include immune suppression, organ transplantation, and polyoma virus infection. MCC has a propensity to spread to regional lymphatics with a high locoregional recurrence rate. Since its discovery in 1972, treatment paradigms have shifted, with no consensus on optimal management strategies. Currently, standard of care includes surgical intervention to the primary and locoregional site with adjuvant radiotherapy for high-risk disease. In this paper, we discuss the history, pathology, and epidemiology of this rare disease with a focus on the evidentiary basis of treatment protocols. The use of sentinel lymph node biopsy as a management option will be the focus of this paper. PMID- 23091726 TI - Sun-protection habits of primary students in a coastal area of Greece. AB - Aim. The aim of the present study was to record habits and attitudes of primary school students in Greece regarding sun-protection measures. Materials and Methods. 2,163 students with an average age of 9.9 (+/-1.1) years, studying in 14 schools of a Greek region, constituted our sample. The SPSS 17.0 software was used for the statistical analysis and significance level was set to P <= 0.05. Results. Our sample had an equal gender distribution. 16% of the students belonged to the high-risk group, 70.2% of the participants lived 0-5 km away from the sea (urban area), 84.2% of the students were Greek, and 15.8% had non-Greek nationality. Half of the participants said they wear a hat when under the sun and 72% of them said they use sunscreen. 33.1% of the students said they had a sunburn last summer. Greek students as well as those who lived near the sea had better behaviour patterns regarding sun protection. Finally, children who did not use a sunscreen systematically had suffered sunburns more often than the rest. Conclusions. Health education programmes are necessary for students and parents/teachers alike, in order to raise awareness about everyday sun protection. PMID- 23091727 TI - HOX Gene Aberrant Expression in Skin Melanoma: A Review. AB - The homeobox family and its subset of HOX gene products represent a family of transcription factors directing DNA-protein and protein-protein interactions. In the embryo, they are central regulators in cell differentiation during morphogenesis. A series of genes of the four HOX gene clusters A, B, C, and D were reported to show aberrant expressions in oncogenesis, particularly in cutaneous malignant melanoma (CMM). They are involved in cell proliferation and progression in the CMM metastatic path. We present relevant peer-reviewed literature findings about the aberrant expression of HOX genes in CMM. The number of CMM cell nuclei exhibiting aberrant HOX protein expression appears correlated with tumour progression. PMID- 23091728 TI - Th17 mediated alloreactivity is facilitated by the pre-transplant microbial burden of the recipient. AB - Acute graft-versus-host disease (aGvHD) is a major complication after hematopoietic stem cell transplantation (HSCT) and severity of aGvHD is associated with biological and genetic factors related to donors and recipients. Studies on inflammatory pathways involved in aGvHD have shown a significant impact of the gut microflora on aGvHD development giving increasing evidence in the understanding of the response of innate and adaptive immunity to microbial products. Cytokine deregulation may increase or reduce the risk of aGvHD. Damage of tissues affected by aGvHD reflects the immunological cascade of events in this disease. PMID- 23091729 TI - Rapid Detection and Identification of Yersinia pestis from Food Using Immunomagnetic Separation and Pyrosequencing. AB - Interest has recently been renewed in the possible use of Y. pestis, the causative agent of plague, as a biological weapon by terrorists. The vulnerability of food to intentional contamination coupled with reports of humans having acquired plague through eating infected animals that were not adequately cooked or handling of meat from infected animals makes the possible use of Y. pestis in a foodborne bioterrorism attack a reality. Rapid, efficient food sample preparation and detection systems that will help overcome the problem associated with the complexity of the different matrices and also remove any ambiguity in results will enable rapid informed decisions to be made regarding contamination of food with biothreat agents. We have developed a rapid detection assay that combines the use of immunomagnetic separation and pyrosequencing in generating results for the unambiguous identification of Y. pestis from milk (0.9 CFU/mL), bagged salad (1.6 CFU/g), and processed meat (10 CFU/g). The low detection limits demonstrated in this assay provide a novel tool for the rapid detection and confirmation of Y. pestis in food without the need for enrichment. The combined use of the iCropTheBug system and pyrosequencing for efficient capture and detection of Y. pestis is novel and has potential applications in food biodefence. PMID- 23091730 TI - Androgen Metabolism Gene Polymorphisms, Associations with Prostate Cancer Risk and Pathological Characteristics: A Comparative Analysis between South African and Senegalese Men. AB - Prostate cancer is the most common cancer in men in developed countries and the leading cause of mortality in males in less developed countries. African ethnicity is one of the major risk factors for developing prostate cancer. Pathways involved in androgen metabolism have been implicated in the etiology of the disease. Analyses of clinical data and CYP3A4, CYP3A5, and SRD5A2 genotypes were performed in South African White (120 cases; 134 controls), Mixed Ancestry (207 cases; 167 controls), and Black (25 cases; 20 controls) men, as well as in Senegalese men (86 cases; 300 controls). Senegalese men were diagnosed earlier with prostate cancer and had higher median PSA levels compared to South African men. Metastasis occurred more frequently in Senegalese men. Gene polymorphism frequencies differed significantly between South African and Senegalese men. The CYP3A4 rs2740574 polymorphism was associated with prostate cancer risk and tumor aggressiveness in South African men, after correction for population stratification, and the SRD5A2 rs523349 CG genotype was inversely associated with high-stage disease in Senegalese men. These data suggest that variants previously associated with prostate cancer in other populations may also affect prostate cancer risk in African men. PMID- 23091731 TI - Incidence of occult carcinoma and high-risk lesions in mammaplasty specimens. AB - Objectives. To determine the incidence and type of premalignant or malignant changes in mammaplasty specimens and to determine the incidence of these changes according to age distribution. Methods. Retrospective database review of patients who underwent a reduction mammaplasty between 1999 and 2009 was performed from pathology records at a single institution. Results. 700 patients were identified. Of the 644 patients who had bilateral reductions, 25 (4%) had significant pathologic findings. The likelihood of finding premalignant changes or cancer increased with advancing patient age (0.8 percent for patients <40 years old and 10 percent for patients >60 years old). Of the 56 patients who underwent unilateral mammaplasty, 12 patients (21%) had significant pathologic findings. The incidence of finding premalignant changes or cancer in this population also increased with advancing patient age (0 for patients <40 years old to 25 percent for patients >60 years old). Conclusions. When a unilateral mammaplasty is performed to match a breast reconstructed after cancer surgery, the likelihood of identifying premalignant changes or cancer increases more than fourfold. Therefore, one should consider additional radiologic imaging in the preoperative workup of patients with a history of carcinoma prior to undergoing unilateral mammaplasty. PMID- 23091733 TI - Radiation therapy for locally recurrent breast cancer. AB - Approximately one-third of all breast cancer patients experience local recurrence of their tumor after initial treatment. As initial treatment often employs the use of radiation therapy (RT), the standard of care for local breast cancer recurrence after initial breast conserving therapy has traditionally been surgical intervention with mastectomy. However, recent attempts to preserve the intact breast after recurrence with local excision have revealed a potential need for RT in addition to repeat breast conserving surgery as rates of local failure with resection alone remain high. Additionally, local recurrence following initial mastectomy and chest wall RT can be treated with reirradiation to increase local control. Repeating RT, however, in a previously irradiated area, is a complex treatment strategy, as the clinician must carefully balance maximizing treatment effectiveness while minimizing treatment-related toxicity. As a result, physicians have been hesitant to treat recurrent disease with repeat RT with limited data. Results from the current literature are promising and current clinical trials are underway to explore reirradiation modalities which will provide additional information on treatment-related toxicity and outcomes. This paper will review the current literature on repeat radiation therapy for locally recurrent breast cancer. PMID- 23091732 TI - Metastatic breast cancer to the gastrointestinal tract: report of five cases and review of the literature. AB - Luminal gastrointestinal (GI) metastases from breast cancer are rare, reports are fragmentary and poor. The purposes of this study are to assess the gastrointestinal involvement from breast cancer in a retrospective study at a single institution and reviewing the related literature. Between January 2007 and December 2011 a total of 980 patients with breast cancer were treated at our institution, patients' records and report database were analysed. Institutional Review Board approval was obtained for this study. A search of the literature using PubMed, CancerLit, Embase, was performed. Selected for the present review were papers published in English before June 2012. Five of 980 patients (0.5%) showed gastrointestinal metastases from breast cancer, 3 patients had gastric involvement, 1 jejunum, and 1 rectum. Reviewing the literature, 206 patients affected by gastrointestinal metastasis from breast cancer were identified: the most frequent site of metastasis was the stomach (60%). The majority of the patients underwent chemotherapy and endocrine therapy, someone surgery and radiotherapy. GI metastases from breast cancer are rare, but possible, and a very late recurrence can also occur. Cyto-histological diagnosis is mandatory, to differentiate GI metastases from breast cancer to other diseases and to allow an adequate treatment. PMID- 23091734 TI - Experience Since MELD Implementation: How Does the New System Deliver? AB - Because of increasing waiting-list mortality, the MELD (Model for End-Stage Liver Disease) allocation system was implemented within most countries of the Eurotransplant area on December 16, 2006. Five years have now passed, and we review in this paper the effects of the MELD-based allocation upon the waiting list for liver transplantation, on peri-operative management and on postoperative outcome. Giving priority to sicker patients on the waiting list has resulted in a significant increase in mean MELD score at the time of organ allocation. Consequently, there has also been a significant reduction in waiting-list mortality. However, in Germany a worsening in postoperative outcome, mainly in the group of high-MELD recipients (>=30 points), has been reported. This paper presents comprehensive results following liver transplantation within the MELD era. Especially for the group of high-risk recipients, risk factors for impaired survival are presented and discussed. PMID- 23091736 TI - Skipping posterior dynamic transpedicular stabilization for distant segment degenerative disease. AB - Objective. To date, there is still no consensus on the treatment of spinal degenerative disease. Current surgical techniques to manage painful spinal disorders are imperfect. In this paper, we aimed to evaluate the prospective results of posterior transpedicular dynamic stabilization, a novel surgical approach that skips the segments that do not produce pain. This technique has been proven biomechanically and radiologically in spinal degenerative diseases. Methods. A prospective study of 18 patients averaging 54.94 years of age with distant spinal segment degenerative disease. Indications consisted of degenerative disc disease (57%), herniated nucleus pulposus (50%), spinal stenosis (14.28%), degenerative spondylolisthesis (14.28%), and foraminal stenosis (7.1%). The Oswestry Low-Back Pain Disability Questionnaire and visual analog scale (VAS) for pain were recorded preoperatively and at the third and twelfth postoperative months. Results. Both the Oswestry and VAS scores showed significant improvement postoperatively (P < 0.05). We observed complications in one patient who had spinal epidural hematoma. Conclusion. We recommend skipping posterior transpedicular dynamic stabilization for surgical treatment of distant segment spinal degenerative disease. PMID- 23091737 TI - The dynamic optical breast imaging in the preoperative workflow of women with suspicious or malignant breast lesions: development of a new comprehensive score. AB - Purpose. To determine the diagnostic accuracy of DOBIComfortScan in patients with Breast Imaging Reporting suspect breast lesions (BI-RADS) 4-5 breast lesions. Materials and Methods. One-hundred and thirteen patients underwent DOBIComfortScan examination before surgery. Twelve parameters were taken into consideration to define DOBI findings. Results. Twenty-seven radical mastectomies, 47 quadrantectomies and 39 wide excisions, were performed. Overall, 65 invasive cancer, 9 in situ carcinoma and 39 nonmalignant lesions, were observed. Ten out of 12 considered parameters resulted significantly in association with histology at discriminant analysis. A summation score of 30.5 resulted to be the best cut off at ROC analysis, giving a sensitivity and specificity of 80% and 87%, respectively, and a positive predictive value of 92.2%. Finally the following DOBI-BI-RADS model was developed: malignant B5 >= 38 score); possibly malignant (B4 = 25 - 37 score); benign but the possibility of malignancy cannot be excluded (B3 = 20 - 24 score); benign (B2 < 20 score). Conclusion. definition of other parameters permits to improve the accuracy of this procedure. Further studies are warranted to define the potential role of DOBIComfortScan in breast cancer imaging. PMID- 23091735 TI - Regulation of the g1/s transition in hepatocytes: involvement of the cyclin dependent kinase cdk1 in the DNA replication. AB - A singular feature of adult differentiated hepatocytes is their capacity to proliferate allowing liver regeneration. This review emphasizes the literature published over the last 20 years that established the most important pathways regulating the hepatocyte cell cycle. Our article also aimed at illustrating that many discoveries in this field benefited from the combined use of in vivo models of liver regeneration and in vitro models of primary cultures of human and rodent hepatocytes. Using these models, our laboratory has contributed to decipher the different steps of the progression into the G1 phase and the commitment to S phase of proliferating hepatocytes. We identified the mitogen dependent restriction point located at the two-thirds of the G1 phase and the concomitant expression and activation of both Cdk1 and Cdk2 at the G1/S transition. Furthermore, we demonstrated that these two Cdks contribute to the DNA replication. Finally, we provided strong evidences that Cdk1 expression and activation is correlated to extracellular matrix degradation upon stimulation by the pro-inflammatory cytokine TNFalpha leading to the identification of a new signaling pathway regulating Cdk1 expression at the G1/S transition. It also further confirms the well-orchestrated regulation of liver regeneration via multiple extracellular signals and pathways. PMID- 23091739 TI - Asystole after orthotopic lung transplantation: examining the interaction of cardiac denervation and dexmedetomidine. AB - Dexmedetomidine is an alpha(2)-receptor agonist commonly used for sedation and analgesia in ICU patients. Dexmedetomidine is known to provide sympatholysis and also to have direct atrioventricular and sinoatrial node inhibitory effects. In rare instances, orthotopic lung transplantation has been associated with disruption of autonomic innervation of the heart. The combination of this autonomic disruption and dexmedetomidine may be associated with severe bradycardia and/or asystole. Since orthotopic lung transplant patients with parasympathetic denervation will not respond with increased heart rate to anticholinergic therapy, bradyarrhythmias must be recognized and promptly treated with direct acting beta agonists to avoid asystolic cardiac events. PMID- 23091738 TI - Calcium imaging of living astrocytes in the mouse spinal cord following sensory stimulation. AB - Astrocytic Ca(2+) dynamics have been extensively studied in ex vivo models; however, the recent development of two-photon microscopy and astrocyte-specific labeling has allowed the study of Ca(2+) signaling in living central nervous system. Ca(2+) waves in astrocytes have been described in cultured cells and slice preparations, but evidence for astrocytic activation during sensory activity is lacking. There are currently few methods to image living spinal cord: breathing and heart-beating artifacts have impeded the widespread application of this technique. We here imaged the living spinal cord by two-photon microscopy in C57BL6/J mice. Through pressurized injection, we specifically loaded spinal astrocytes using the red fluorescent dye sulforhodamine 101 (SR101) and imaged astrocytic Ca(2+) levels with Oregon-Green BAPTA-1 (OGB). Then, we studied astrocytic Ca(2+) levels at rest and after right electrical hind paw stimulation. Sensory stimulation significantly increased astrocytic Ca(2+) levels within the superficial dorsal horn of the spinal cord compared to rest. In conclusion, in vivo morphofunctional imaging of living astrocytes in spinal cord revealed that astrocytes actively participate to sensory stimulation. PMID- 23091740 TI - Amelogenesis imperfecta and generalized gingival overgrowth resembling hereditary gingival fibromatosis in siblings: a case report. AB - Amelogenesis imperfecta (AI) is a group of hereditary disorders primarily characterized by developmental abnormalities in the quantity and/or quality of enamel. There are some reports suggesting an association between AI and generalized gingival enlargement. This paper describes the clinical findings and oral management of two siblings presenting both AI and hereditary gingival fibromatosis (HGF) like generalized gingival enlargements. The treatment of gingival enlargements by periodontal flap surgery was successful in the management of the physiologic gingival form for both patients in the 3-year follow-up period. Prosthetic treatment was also satisfactory for the older patient both aesthetically and functionally. PMID- 23091741 TI - Bilateral mandibular premolar dens invaginations: a case report. AB - Dens invaginations are a rare developmental defect most commonly affecting maxillary lateral incisors, with very few reported cases in mandibular teeth. We describe a rare case of bilateral first mandibular premolar dens invaginations type I, where apparently health teeth presented with periapical pathology. PMID- 23091742 TI - A case of nonfunctioning pituitary carcinoma that responded to temozolomide treatment. AB - Pituitary carcinoma is a rare malignancy and is difficult to manage. Pituitary carcinomas commonly produce either PRL or ACTH, but some do not produce pituitary hormones. The alkylating reagent temozolomide (TMZ) was recently shown to be effective as a treatment for pituitary carcinoma. Most of the published reports of TMZ use in pituitary carcinoma cases were against hormone-producing carcinomas. Only a few patients with a nonfunctioning pituitary carcinoma treated with TMZ have been reported. Here we describe our treatment of a patient with nonfunctioning pituitary carcinoma and a background of multiple endocrine neoplasia type 1. The pituitary carcinoma was accompanied by meningeal dissemination with cerebral and L1 spinal bone metastasis. The patient received continuous dosing of TMZ along with external radiation, followed by standard dosing of TMZ. There was an apparent antitumor response seen in MRI. MGMT, an enzyme antagonized by TMZ, was negative in the tumor. The therapeutic efficacy of TMZ and dosing schedules of TMZ in pituitary carcinoma are discussed. PMID- 23091743 TI - A rare cause of acute pancreatitis: intramural duodenal hematoma. AB - We describe an interesting case of intramural duodenal hematoma in an otherwise healthy male who presented to emergency room with gradually progressive abdominal pain, nausea, and vomiting. This condition was missed on initial evaluation and patient was discharged from emergency room with diagnosis of acute gastritis. After 3 days, patient came back to emergency room and abdominal imaging studies were conducted which showed that patient had intramural duodenal hematoma associated with gastric outlet obstruction and pancreatitis. Hematoma was the cause of acute pancreatitis as pancreatic enzymes levels were normal at the time of first presentation, but later as the hematoma grew in size, it caused compression of pancreas and subsequent elevation of pancreatic enzymes. We experienced a case of pancreatitis which was caused by intramural duodenal hematoma. This case was missed on initial evaluation. We suggest that physicians should be more vigilant about this condition. PMID- 23091744 TI - Ischemic colitis in an endurance runner. AB - A 20-year-old female running the Marine Corps Marathon developed diarrhea at mile 12. After finishing the race she noted that she was covered in bloody stool. A local emergency department suspected ischemic colitis. After discharge, her primary care physician instructed her to discontinue the use of all nonsteroidal anti-inflammatory drugs. Her symptoms resolved and she returned to running without any complications. This paper describes the pathophysiology, diagnostic approach, and management options. PMID- 23091745 TI - Duodenal histoplasmosis presenting with upper gastrointestinal bleeding in an AIDS patient. AB - Gastrointestinal histoplasmosis (GIH) is common in patients with disseminated disease but only rarely comes to clinical attention due to the lack of specific signs and symptoms. We report the unusual case of a 33-year-old Caucasian male with advanced AIDS who presented with upper GI bleeding from diffuse erosions throughout the duodenum. Biopsy of the lesions revealed small bowel mucosa with granulomatous inflammation and macrophages with small intracellular yeasts consistent with disseminated histoplasmosis. The patient demonstrated significant clinical improvement following a two-week course of liposomal amphotericin B. To our knowledge, this is the first case report of duodenal histoplasmosis leading to clinically significant bleeding, manifesting with worsening anemia and melanotic stools. Given our findings, we maintain that GIH should be considered on the differential diagnosis for GI bleeding in AIDS patients at risk, specifically those with advanced immunosuppression (i.e., CD4(+) cell counts <100 cells/mm(3)) who reside in endemic areas (Ohio or Mississippi river valleys) and/or have a prior history of histoplasmosis. For diagnostic evaluation, we recommend checking a urine Histoplasma quantitative antigen EIA as well as upper and/or lower endoscopy with biopsy. We recommend treatment with a two-week course of liposomal amphotericin B followed by indefinite itraconazole. PMID- 23091746 TI - Vici syndrome: a rare autosomal recessive syndrome with brain anomalies, cardiomyopathy, and severe intellectual disability. AB - Purpose. The objective of this study was to present and describe two additional patients diagnosed with Vici syndrome. Methods. Clinical, laboratory, and imaging findings of the two siblings are discussed in detail. The two patients' descriptions are compared with the other eleven patients reported in the literature. We also presented detailed autopsy results on the male sibling, which demonstrated cytoplasmic vacuoles of the cardiomyocytes and confirmed the clinical findings. Results. The patients reported here include the 13th and 14th patients reported with Vici syndrome. The summary of findings present in these patients includes postnatal growth retardation, developmental delay, bilateral cataracts, agenesis of the corpus callosum, cerebellar anomalies, gyral abnormalities, seizures, hypotonia, and cardiomyopathy. Conclusion. Vici syndrome should be suspected in any child with agenesis of the corpus callosum and one of the following findings: cardiomyopathy, cataracts, immune deficiency, or cutaneous hypopigmentation. PMID- 23091747 TI - Lymphoma of the cervix. AB - Primary non-Hodgkins lymphoma of the uterine cervix is a very rare diagnosis. A 54-year-old woman presented with a 3-month history of postmenopausal bleeding per vaginum. On examination, a friable, fungating lesion was seen on the cervix. Histology revealed a CD 20 positive high-grade non-Hodgkin's diffuse large B cell lymphoma from cervical biopsies and endometrial curettage. She was diagnosed as stage IE after workup and subsequently treated with six cycles of R-CHOP chemotherapy followed by radiotherapy of the involved field. PMID- 23091748 TI - Long-term survival in a patient with multiple brain metastases from small-cell lung cancer treated with gamma knife radiosurgery on four occasions: a case report. AB - Brain metastases are the most common cancerous neoplasm in the brain. The treatment of these lesions is challenging and often includes a multimodality management approach with whole-brain radiation therapy, stereotactic radiosurgery, and neurosurgery options. Although advances in biomedical imaging technologies and the treatment of extracranial cancer have led to the overall increase in the survival of brain metastases patients, the finding that select patients survive several years remains puzzling. For this reason, we present the case of a 70-year-old patient who was diagnosed with multiple brain metastases from small-cell lung cancer five years ago and is currently alive following treatment with chemotherapy for the primary cancer and whole-brain radiation therapy and Gamma Knife radiosurgery on four separate occasions for the neurological cancer. Since the diagnosis of brain metastases five years ago, the patient's primary cancer has remained controlled. Furthermore, multiple repeat GKRS procedures provided this patient with high levels of local tumor control, which in combination with a stable primary cancer led to an extended period of survival and a highly functional life. Further analysis and clinical research will be valuable in assessing the durability of multiple GKRS for brain metastases patients who experience long-term survival. PMID- 23091749 TI - Parkinsonism following Bee Sting: A Case Report. AB - We are reporting here a rare case of Parkinsonism (Hypokinetic dysarthria) caused after a bee stung, a member of the hymenoptera order. The main aim of this report is to orient the clinicians with the possibility of extrapyramidal syndromes because of hymenoptera stings. PMID- 23091750 TI - A Patient Developed Painful Muscle Cramps due to Overeating Mangos. AB - A 79-year-old woman had a habit to eat a mango every night before sleep and experienced muscle cramps during sleep. Her muscle cramps may be resulted from potassium overload due to overeating mangos. PMID- 23091751 TI - Superficial siderosis and anticoagulation therapy: different presentations, different outcomes. AB - Superficial siderosis is a potentially manageable neurodegenerative disorder, caused by chronic subarachnoid haemorrhage and iron deposition along the central nervous system surfaces. Association with oral anticoagulant therapy is well known, but its definite role as a causative agent is yet to be clarified. Two Caucasian women, both under long-term oral anticoagulation: a 74 year old woman with slowly progressive hearing loss and mild cerebellar ataxia; a 72 year old woman suffering from behavioural changes, rapidly progressive cognitive decline and latter developing paraparesis. Magnetic resonance imaging showed striking hypointensities along the surfaces of cerebellum, brainstem, frontotemporal cortices, spinal cord, and lumbar arachnoid therefore suggesting superficial siderosis. No specific bleeding source was found in any of the patients. Anticoagulation could not be stopped in the first patient due to a mechanic valve and slowly progressive worsening occurred. In contrast, for the second patient anticoagulation withdrawal was feasible and marked motor and cognitive improvement ensued. Superficial siderosis is associated with unvarying progression, mostly when no direct source of bleeding is identified. Nonetheless, we verified striking motor and cognitive improvement after anticoagulants withdrawal in one of the patients. This may reinforce the need to consider such modifiable factor in future patient management. PMID- 23091752 TI - Steroid cell ovarian neoplasm, not otherwise specified: a case report and review of the literature. AB - Background. Steroid cell ovarian tumors, not otherwise specified, represent a unique cause of female virilization. Most commonly encountered in premenopausal women, these tumors can exist throughout a women's lifetime, from before puberty until after menopause. Case. Steroid cell, not otherwise specified, was diagnosed in a 70-year-old female significant for hirsutism. The patient demonstrated elevated total testosterone levels with normal gonadotropins, DHEA, and DHEA-S levels. CT imaging revealed a right ovarian mass and subsequent laparoscopic right oophorectomy yielded clinical improvement promptly. Conclusion. Virilization in females can occur based on ovarian or adrenal pathology. In terms of ovarian-based female virilization, many tumors exist that may induce women to demonstrate masculine features, such as pure Sertoli, pure Leydig, Sertoli-Leydig combinations, and gynandroblastomas. Each of these tumor types possesses a unique histologic pattern that allows for pathologic identification after removal. A rare source of ovarian-based female virilization is steroid cell neoplasms, not otherwise specified, that do not demonstrate these specific histologic characteristics and thus represent a diagnosis of exclusion after other causes of ovarian-based female virilization have been ruled out. PMID- 23091753 TI - Peritoneal mullerian tumor-like (endosalpingiosis-leiomyomatosis peritoneal): a hardly known entity. AB - We describe a case of multiple peritoneal nodules with cysts at the free border of the omento and other locations of the peritoneal surfaces. A total abdominal hysterectomy and bilateral salpingooophorectomy were performed for a myomatous uterus and bilateral ovarian cysts. The omentum and several fragments of the abdominal peritoneum were also removed. Microscopic diagnosis was Disseminated Peritoneal Endosalpingiosis-Leiomyomatosis. PMID- 23091754 TI - Three-dimensional ultrasound findings in cornelia de lange syndrome: a case report. AB - Introduction. The objective is to report a case of Cornelia de Lange syndrome (CdLS) diagnosed by detailed observations using three-dimensional sonography. Case Report. A 33-year-old healthy multipara was referred to our hospital at 34 week gestation after severe fetal growth restriction, congenital heart anomaly, and antebrachium abnormality were diagnosed during the third trimester. Further sonography diagnosis on cardiac abnormalities diagnosed the existence of ventricular septal defect in the outflow tract, atrioventricularis communis, and truncus arteriosus communis where the pulmonary artery branched from the common arterial trunk. As for abnormalities of the forearms, ectrodactylia and monodactylism were suspected and the abnormalities were observed sterically by using three-dimensional sonography. A 1986 g (1.07 percentile) male newborn was delivered by assisted breech extraction at 37-week gestation. After birth, from characteristic facies including bushy eyebrow, broad nasal bridge, micrognathia, and abnormalities of the forearms (ectrodactylia and monodactylism), the case was diagnosed with CdLS. Conclusion. Through detailed observation including abnormalities of fingers, we could exemplify this very rare disease as an antenatal diagnoses for fetal growth retardation. PMID- 23091755 TI - Accurate preoperative diagnosis of ovarian pregnancy with transvaginal scan. AB - Ovarian pregnancy is a rare variant of ectopic pregnancy, and an accurate preoperative diagnosis is very challenging. Dr. Saint Monnissey described the first reported case of ovarian pregnancy in 17th century. Transvaginal ultrasonography is a valuable tool in identifying an ovarian pregnancy from other types of ectopic pregnancies. Management with laparoscopy or laparotomy is required in all cases, and in almost all cases, ovary can be preserved since implantation is usually superficial (Koo et al.; 2011). A single case of an ovarian pregnancy, consistent with Spiegelberg's criteria is presented here. This case history demonstrates the use of ultrasonography (USG) and surgery in the diagnosis and treatment, respectively, of the ovarian pregnancy. As we step into an era where in vitro fertilization rate is on its hike, one should be aware that incidence of ovarian pregnancy is also increasing, necessitating a high index of suspicion. PMID- 23091756 TI - A rare case of an inflammatory myofibroblastic tumor in a middle-aged female. AB - Inflammatory myofibroblastic tumors (IMTs) are distinct entities with specific characteristics immunohistochemically and molecularly. They are regarded as "intermediate malignancy" tumors of unknown etiology. We report a case of a 64 years-old woman with a fever and abdominal discomfort for 3 months; a computer tomography was performed indicating gastrointestinal stromal tumor. Histologically the lesion proved to be IMT of the abdomen. PMID- 23091757 TI - Simultaneous EUS-FNA Diagnosis and TNM Staging of a Pancreatic Neuroendocrine Tumor in a Patient with an Unrecognized MEN Type 1. AB - We report the case of a woman who, during oncological followup for bronchial carcinoid (diagnosed in 2005), papillary thyroid carcinoma, and bilateral parathyroid adenoma (simultaneously diagnosed in 2007), performed a pancreatic endoscopic ultrasonography with fine needle agobiopsy (EUS-FNA) for a positron emission tomography (PET) suspicion of pancreatic and hepatic lesions; during the procedure, the pancreatic and liver lesions were confirmed, and a peripancreatic lymph node involvement was found, allowing a complete pTNM staging during the same procedure. PMID- 23091758 TI - Scalp metastasis from leiomyosarcoma of the inferior vena cava sign as the first clinical sign: a case report. AB - The presentation of scalp metastases from leiomyosarcoma of the vena cava is an extremely infrequent event. There are no other publications that describe such finding and very few of leiomyosarcoma in vessels. About this event we have reviewed the English literature describing studies on scalp metastases and skin metastases in general: their incidence, origin, clinical appearance, meaning, and diagnosis. The case we describe would be the second one presented worldwide because, as far as we know, it has been only one more published in 2005. PMID- 23091759 TI - Primary clear cell chondrosarcoma of the spine: a case report of a rare entity and a review of the literature. AB - Chondrosarcoma is the third most common primary malignant bone tumor after osteosarcoma and Ewing's sarcoma. Clear cell chondrosarcoma is a rare subtype variant of chondrosarcoma, most commonly encountered in the proximal part of the femur or humerus. Vertebral involvement is exceedingly rare and shows a predilection for the thoracic spine. We report the case of a woman with clear cell chondrosarcoma of the thoracic spine, which has been surgically excised, and review the pertinent literature (PubMed). Although it has a reasonably benign biological behavior, clear cell chondrosarcoma needs to be treated as a malignancy. The best treatment for spinal chondrosarcoma is surgery. It should be promptly and adequately resected. Gross-total resection should be the ultimate surgical goal. Radiation therapy should also be considered, especially in the case of subtotal resection or inoperable lesions. In conclusion, it is important to keep in mind this entity in the differential diagnosis of spinal tumors, in order to optimize treatment planning. With adequate treatment, local recurrence rates as low as 20% can be achieved. PMID- 23091760 TI - Development of cerebral metastasis after medical and surgical treatment of anal squamous cell carcinoma. AB - Squamous cell carcinoma of the anus is a relatively uncommon GI malignancy. When it does occur, it metastasizes in only a small minority of patients. Spread of anal squamous cell carcinoma to the brain is exceedingly rare, and has been previously reported only three times in the medical literature. We report the case of a 67 year old male who was diagnosed on presentation with a poorly differentiated anal squamous cell carcinoma that already had a solitary metastasis to the liver. While the tumors were initially responsive to chemoradiotherapy, the patient's primary and liver lesions recurred. The patient then underwent synchronous abdominoperineal resection for the primary lesion and a liver lobectomy for the metastasis. Soon thereafter, the patient developed focal neurologic symptoms and was found to have an intracranial lesion that on biopsy demonstrated metastatic squamous cell carcinoma. This case highlights the fact that patients with a previous history of anal squamous cell carcinoma can occasionally develop cerebral metastasis. Furthermore, cerebral metastases from anal squamous cell carcinoma portend a dismal prognosis even in the face of aggressive medical and surgical therapy. PMID- 23091761 TI - Genetic analysis for two italian siblings with usher syndrome and schizophrenia. AB - Usher syndrome is a group of autosomal recessive genetic disorders characterized by deafness, retinitis pigmentosa, and sometimes vestibular areflexia. The relationship between Usher syndrome and mental disorders, most commonly a "schizophrenia-like" psychosis, is sometimes described in the literature. The etiology of psychiatric expression of Usher syndrome is still unclear. We reported a case of two natural siblings with congenital hypoacusis, retinitis pigmentosa, and psychiatric symptoms. Clinical features and genetic analysis were also reported. We analyzed possible causes to explain the high prevalence of psychiatric manifestations in Usher syndrome: genetic factors, brain damage, and "stress-related" hypothesis. PMID- 23091762 TI - Foreign body embedded in anterior chamber angle. AB - Introduction. We present a case of a metallic foreign body embedded in the anterior chamber angle. After standing in close proximity to a construction worker breaking a tile, a 26-year-old woman using soft contact lens for the correction of mild myopia presented to emergency department for evaluation of a foreign body sensation of her right eye. Methods and Results. Diagnosis was confirmed by gonioscopic examination and a noncontrast CT scan of head and orbits. The foreign body was removed by an external approach without utilizing a magnet. The patient's final outcome was favorable. Discussion. The above is a rare clinical situation, which is impossible to detect on slit-lamp examination without a gonioscopic view. Proper imaging and a specific management are mandatory in order to achieve favorable outcome. PMID- 23091763 TI - Bilateral vitreopapillary traction demonstrated by optical coherence tomography mistaken for papilledema. AB - Purpose. The purpose of this study was to report a case of bilateral vitreopapillary traction, previously misdiagnosed as papilledema. Methods. A case report is presented of a 47-year-old woman with a prior diagnosis of papilledema, who is shown to have bilateral vitreopapillary traction rather than true optic disc swelling, confirmed by optical coherence tomography (OCT). Results. OCT showed vitreous traction surrounding the optic discs of both eyes. Fluorescein angiography demonstrated focal leakage of both discs. Conclusion. Bilateral disc elevation caused by vitreous traction can be confused with papilledema. In such cases, OCT can be used to arrive at the correct diagnosis. Although the phenomenon of vitreopapillary traction is well reported, this case indicates that not all ophthalmologists recognize the condition. PMID- 23091764 TI - Sporadic intra-abdominal desmoid: a rare presentation as a hepatic mass. AB - We report an unusual presentation of a sporadic intra-abdominal desmoid tumour, possibly arising from the diaphragm, masquerading as a hepatic mass in a young female without any history of surgery or trauma. Histopathology ruled out a hepatic origin of the tumour as was inferred from pre- and intraoperative evaluation. Immunohistochemistry showed positivity of lesional fibroblastic cells for beta-catenin and negativity for CD34, CD117, EMA, SMA, desmin, vimentin, cytokeratin, and ALK1 thereby confirming the diagnosis of a desmoid tumour. There exist only a few reports in the literature on desmoids related to the diaphragm, but only one on a diaphragmatic desmoid that is possibly primary. PMID- 23091765 TI - Pott's Puffy Tumor: An Uncommon Clinical Entity. AB - Although first described in 1760, Pott's puffy tumor is a lesser known clinical entity. Often seen as a complication of frontal sinusitis, Pott's is a frontal bone osteomyelitis with an associated subperiosteal abscess. Patients present with a fluctuant swelling of the scalp. The diagnosis is often confirmed with computed tomography (CT). Prompt surgical and medical treatments are the rule as there is the potential for significant morbidity if not quickly diagnosed and treated. Herein, we describe the presentation, diagnosis, and treatment of an 8 year-old female presenting with Pott's puffy tumor. PMID- 23091766 TI - Prenatal diagnosis and postnatal ultrasound findings of cloacal anomaly: a case report. AB - Cloacal malformation is an extremely rare fetal pathological condition that presents as a variety of defects. It predominantly affects females, with prevalence of 1 in 50,000 births. Prenatal ultrasonography on a 20-year-old caucasian woman (G4P1A2) at 33 weeks of pregnancy showed the fetus having a large cystic mass in the lower abdomen with a single septum, bilateral hydronephrosis, ambiguous genitalia, and a single umbilical artery. The pregnancy developed accentuated oligohydramnios, and presence of a fetal brain-sparing effect was diagnosed using arterial Doppler velocimetry. The newborn showed abdominal distension, ambiguous genitalia, and rectal atresia, with a single perineal opening. Pelvic ultrasound done on the first day after delivery revealed the presence of a large retrovesical septated cystic mass of dense content in the fetal abdomen, and bilateral hydronephrosis. Hysterotomy was performed, and 70 mL of dense liquid was drained through an abdominal colostomy. The infant died on the 27th day of life as a result of infectious complications. Prenatal diagnosing of female urogenital anomalies is usually difficult because of their rarity, different types of manifestation, and lack of characteristic ultrasound signs. Presence of a septated cyst with dense content in the fetal abdomen confirms the finding of hydrometrocolpos, thus raising clinical suspicion of a cloacal anomaly. PMID- 23091767 TI - Living donor liver transplantation with renoportal anastomosis for a patient with congenital absence of the portal vein. AB - A congenital absence of the portal vein (CAPV) is a rare disorder that may lead to an intrapulmonary shunt. A 14-year-old male with CAPV underwent living donor liver transplantation with a left lobe graft from his father. The portal vein reconstruction was achieved with a renoportal anastomosis using an interpositional graft from the native collateral vein, because portal venous system directly drains to the left renal vein without constructing the confluence of superior mesenteric vein and splenic vein. The patient is doing well with a normal liver function and mild hypoxemia. PMID- 23091768 TI - Extreme achalasia presenting as anorexia nervosa. AB - Background. Achalasia may lead to cachexia if not diagnosed in an early stage. Surgery in cachectic patients is hazardous and complications may result in a protracted recovery or even death. Different treatment options have been described. In this paper, we report a stepwise surgical laparoscopic approach which appears to be safe and effective. Methods. Over a one-year period, a patient with a body mass index (BMI) below 17 being treated for anorexia nervosa was referred with dysphagia. Because of the extreme cachexia, a laparoscopic feeding jejunostomy (LFJ) was fashioned to enable long-term home enteral feeding. The patient underwent a laparoscopic Heller myotomy (LHM) when the BMI was normal. Results. The patient recovered well following this stepwise approach. Conclusion. Patients with advanced achalasia usually present with extreme weight loss. In this small group of patients, a period of home enteral nutrition (HEN) via a laparoscopically placed feeding jejunostomy allows weight gain prior to safe definitive surgery. PMID- 23091770 TI - Molecular evolutionary routes that lead to innovations. PMID- 23091769 TI - Trends in the prevalence of dementia in Japan. AB - There is a paucity of data regarding trends in dementia and its subtype prevalence in Japan. Our aims in the current paper are to: (1) summarize epidemiological studies of dementia in Japan including relevant details of study protocol and diagnostic criteria, (2) compare the age-specific prevalence of all cause dementia among studies, and (3) assess the trends in Alzheimer's disease (AD) versus vascular dementia (VaD) over time. We reviewed diagnostic criteria, all-cause dementia prevalence, and the AD/VaD ratio from 8 large population studies of dementia in Japan. Compared with the Okinawa 1992 study, studies conducted in 1994, 1998, 2005, and 2008 had a higher prevalence of all-cause dementia using Poisson regression models, after controlling for age and sex. In contrast to the US and some European countries, all-cause dementia prevalence is increasing in Japan. The prevalence of AD as opposed to VaD seems to be increasing over time, but large variability in diagnostic criteria, possible regional variability, and differences in prevalence of subtypes of dementia between men and women make it difficult to draw a conclusion about this trend at the national level. Further studies, for example, comparing the population attributable risk of vascular diseases to the prevalence and incidence of dementia could help to clarify the regional variations in etiological subtypes. PMID- 23091771 TI - Ocular inflammation and infection. PMID- 23091772 TI - Osteoporotic characteristics persist in the spine of ovariectomized sheep after withdrawal of corticosteroid administration. AB - A validated ovine model of osteoporosis achieves severe bone loss in a relatively short period. This study investigated if osteoporotic features persist in this model after cessation of corticosteroid administration. Methods. Osteoporosis was induced in nine ewes by chronic corticosteroid injection, ovariectomy, and low calcium diet. Six ewes were used as controls. Bone mineral density (BMD) of the lumbar spine (LS) and body weight were assessed at regular intervals. After five months, corticosteroid treatment was withdrawn systematically over one month. Three months later, all animals were euthanised, and the LS was collected for histomorphometric analysis. Results. BMD in the LS of osteoporotic sheep was 25% lower than control sheep. Body weight of osteoporotic sheep was reduced in the first month of the corticosteroid withdrawal period but returned to baseline level thereafter. Trabecular bone volume of LS in osteoporotic sheep was 27% lower than controls and showed a heterogeneous structure. Conclusions. Osteoporotic characteristics remain in the vertebra after ceasing corticosteroid administration providing an opportunity to evaluate potential systemic or local treatments in vivo under realistic physiological conditions. The microstructural arrangement of vertebral trabecular bone in sheep is similar to humans demonstrating further relevance of this model for preclinical investigations. PMID- 23091773 TI - Normative data for bone mass in healthy term infants from birth to 1 year of age. AB - For over 2 decades, dual-energy X-ray absorptiometry (DXA) has been the gold standard for estimating bone mineral density (BMD) and facture risk in adults. More recently DXA has been used to evaluate BMD in pediatrics. However, BMD is usually assessed against reference data for which none currently exists in infancy. A prospective study was conducted to assess bone mass of term infants (37 to 42 weeks of gestation), weight appropriate for gestational age, and born to healthy mothers. The group consisted of 33 boys and 26 girls recruited from the Winnipeg Health Sciences Center (Manitoba, Canada). Whole body (WB) as well as regional sites of the lumbar spine (LS 1-4) and femur was measured using DXA (QDR 4500A, Hologic Inc.) providing bone mineral content (BMC) for all sites and BMD for spine. During the year, WB BMC increased by 200% (76.0 +/- 14.2 versus 227.0 +/- 29.7 g), spine BMC by 130% (2.35 +/- 0.42 versus 5.37 +/- 1.02 g), and femur BMC by 190% (2.94 +/- 0.54 versus 8.50 +/- 1.84 g). Spine BMD increased by 14% (0.266 +/- 0.044 versus 0.304 +/- 0.044 g/cm(2)) during the year. This data, representing the accretion of bone mass during the first year of life, is based on a representative sample of infants and will aid in the interpretation of diagnostic DXA scans by researchers and health professionals. PMID- 23091775 TI - Factors influencing the outcome of patients with incidental papillary thyroid microcarcinoma. AB - Objective. To analyze some factors that could influence the outcome of patients with PTMC. Material and Methods. This is a longitudinal observational study. All patients diagnosed and treated for papillary thyroid microcarcinoma at the University Hospital of Vigo, between January 1994 and December 2003, were included in the present study. Demographic characteristics, tumour characteristics, TNM stage, rate of recurrence, and treatment with (131)I were the study variables. Results. Ninety-one patients (75 females) with an average age of 47.7 +/- 13.4 years, range 19-81, were studied. Initial tumour staging was T1 in 90 patients and T4a in 1 case. Initial lymph node involvement was present in 4 cases (4.4%). We only found one case with distant metastases at diagnosis. Postsurgical evaluation of thyroid specimens revealed that 28 (30.7%) tumours were multifocal. The average size of the tumour was 0.44 +/- 0.25 cm, range 0.1 1. Univariate analysis reveals a statistically significant association between tumour multifocality and postsurgical (131)I therapy with the recurrence rate. In the multivariate analysis only multifocality (P = 0.037, HR 5.7) was a significant risk factor for the recurrence rate. Conclusions. Our results indicate that tumour multifocality is an independent predictor of relapse but neither the tumour size nor postsurgical (131)I therapy. PMID- 23091774 TI - The role of purinergic receptors in cancer-induced bone pain. AB - Cancer-induced bone pain severely compromises the quality of life of many patients suffering from bone metastasis, as current therapies leave some patients with inadequate pain relief. The recent development of specific animal models has increased the understanding of the molecular and cellular mechanisms underlying cancer-induced bone pain including the involvement of ATP and the purinergic receptors in the progression of the pain state. In nociception, ATP acts as an extracellular messenger to transmit sensory information both at the peripheral site of tissue damage and in the spinal cord. Several of the purinergic receptors have been shown to be important for the development and maintenance of neuropathic and inflammatory pain, and studies have demonstrated the importance of both peripheral and central mechanisms. We here provide an overview of the current literature on the role of purinergic receptors in cancer-induced bone pain with emphasis on some of the difficulties related to studying this complex pain state. PMID- 23091776 TI - P-cadherin expression in feline mammary tissues. AB - The search for molecular markers in the feline mammary gland, namely, the adhesion molecules belonging to the cadherin family, is useful in the understanding of the development of mammary carcinomas in felines and humans. To study P-cadherin expression in the feline mammary gland, 61 samples of normal (n = 4), hyperplastic (n = 12), and neoplastic (n = 45) feline mammary tissues were examined. In both normal and hyperplastic mammary tissues as well as in benign tumours, P-cadherin immunolabelling was restricted to myoepithelial cells. In malignant tumours, however, there was an aberrant epithelial P-cadherin immunoexpression in 64.1% (n = 25) of cases, with a membranous and/or cytoplasmic pattern of distribution. A statistically significant relationship was seen between epithelial P-cadherin expression and malignant mammary lesions (P = 0.0001). In malignant mammary tumours, there was likewise a statistically significant relationship between aberrant P-cadherin immunoexpression and histological grade (P = 0.0132). Aberrant epithelial P-cadherin expression seems to be related to malignancy in the feline mammary gland. To confirm the results of this investigation, further studies with larger samples and follow-up studies are warranted. PMID- 23091777 TI - Publishing your work in a journal: understanding the peer review process. AB - Manuscripts have been subjected to the peer review process prior to publication for over 300 years. Currently, the peer review process is used by almost all scientific journals, and The International Journal of Sports Physical Therapy is no exception. Scholarly publication is the means by which new work is communicated and peer review is an important part of this process. Peer review is a vital part of the quality control mechanism that is used to determine what is published, and what is not. The purpose of this commentary is to provide a description of the peer review process, both generally, and as utilized by The International Journal of Sports Physical Therapy. It is the hope of the authors that this will assist those who submit scholarly works to understand the purpose of the peer review process, as well as to appreciate the length of time required for a manuscript to complete the process and move toward publication. PMID- 23091778 TI - Evidence - based medicine/practice in sports physical therapy. AB - A push for the use of evidence-based medicine and evidence-based practice patterns has permeated most health care disciplines. The use of evidence-based practice in sports physical therapy may improve health care quality, reduce medical errors, help balance known benefits and risks, challenge views based on beliefs rather than evidence, and help to integrate patient preferences into decision-making. In this era of health care utilization sports physical therapists are expected to integrate clinical experience with conscientious, explicit, and judicious use of research evidence in order to make clearly informed decisions in order to help maximize and optimize patient well-being. One of the more common reasons for not using evidence in clinical practice is the perceived lack of skills and knowledge when searching for or appraising research. This clinical commentary was developed to educate the readership on what constitutes evidence-based practice, and strategies used to seek evidence in the daily clinical practice of sports physical therapy. PMID- 23091779 TI - Levels of evidence in medicine. AB - Levels of evidence allow clinicians to appreciate the quality of a particular research paper quickly. The levels are generally set out in a hierarchical order, which is based largely upon the experimental design. While there are ideal designs for studies examining the effects of interventions, risk factors for a clinical condition or diagnostic testing, in most instances researchers have had to make compromises and these subsequently decrease the quality of their work. This paper provides information concerning how those compromises relate to subsequent levels that are given to a piece of research. It also provides an understanding of issues related to evaluating papers, and suggest ways in which the reader might discern how relevant a paper might be to one's clinical practice. PMID- 23091780 TI - Research designs in sports physical therapy. AB - Research is designed to answer a question or to describe a phenomenon in a scientific process. Sports physical therapists must understand the different research methods, types, and designs in order to implement evidence-based practice. The purpose of this article is to describe the most common research designs used in sports physical therapy research and practice. Both experimental and non-experimental methods will be discussed. PMID- 23091781 TI - Systematic review and meta-analysis: a primer. AB - The use of an evidence-based approach to practice requires "the integration of best research evidence with clinical expertise and patient values", where the best evidence can be gathered from randomized controlled trials (RCTs), systematic reviews and meta-analyses. Furthermore, informed decisions in healthcare and the prompt incorporation of new research findings in routine practice necessitate regular reading, evaluation, and integration of the current knowledge from the primary literature on a given topic. However, given the dramatic increase in published studies, such an approach may become too time consuming and therefore impractical, if not impossible. Therefore, systematic reviews and meta-analyses can provide the "best evidence" and an unbiased overview of the body of knowledge on a specific topic. In the present article the authors aim to provide a gentle introduction to readers not familiar with systematic reviews and meta-analyses in order to understand the basic principles and methods behind this type of literature. This article will help practitioners to critically read and interpret systematic reviews and meta-analyses to appropriately apply the available evidence to their clinical practice. PMID- 23091782 TI - Statistical principles for prospective study protocols:: design, analysis, and reporting. AB - In the design of scientific studies it is essential to decide on which scientific questions one aims to answer, just as it is important to decide on the correct statistical methods to use to answer these questions. The correct use of statistical methods is crucial in all aspects of research to quantify relationships in data. Despite an increased focus on statistical content and complexity of biomedical research these topics remain difficult for most researchers. Statistical methods enable researchers to condense large spreadsheets with data into means, proportions, and difference between means, risk differences, and other quantities that convey information. One of the goals in biomedical research is to develop parsimonious models - meaning as simple as possible. This approach is valid if the subsequent research report (the article) is written independent of whether the results are "statistically significant" or not. In the present paper we outline the considerations and suggestions on how to build a trial protocol, with an emphasis on having a rigorous protocol stage, always leading to a full article manuscript, independent of statistical findings. We conclude that authors, who find (rigorous) protocol writing too troublesome, will realize that they have already written the first half of the final paper if they follow these recommendations; authors simply need to change the protocols future tense into past tense. Thus, the aim of this clinical commentary is to describe and explain the statistical principles for trial protocols in terms of design, analysis, and reporting of findings. PMID- 23091783 TI - How to write a scientific article. AB - Successful production of a written product for submission to a peer-reviewed scientific journal requires substantial effort. Such an effort can be maximized by following a few simple suggestions when composing/creating the product for submission. By following some suggested guidelines and avoiding common errors, the process can be streamlined and success realized for even beginning/novice authors as they negotiate the publication process. The purpose of this invited commentary is to offer practical suggestions for achieving success when writing and submitting manuscripts to The International Journal of Sports Physical Therapy and other professional journals. PMID- 23091784 TI - Avoiding manuscript mistakes. AB - Writing a scientific manuscript can be a consuming, but rewarding task with a number of intrinsic and extrinsic benefits. The ability to write a scientific manuscript is typically not an emphasized component of most entry-level professional programs. The purpose of this overview is to provide authors with suggestions to improve manuscript quality and to provide mechanisms to avoid common manuscript mistakes that are often identified by journal reviewers and editors. PMID- 23091785 TI - Changes in lower extremity movement and power absorption during forefoot striking and barefoot running. AB - PURPOSE/BACKGROUND: Both forefoot strike shod (FFS) and barefoot (BF) running styles result in different mechanics when compared to rearfoot strike (RFS) shod running. Additionally, running mechanics of FFS and BF running are similar to one another. Comparing the mechanical changes occurring in each of these patterns is necessary to understand potential benefits and risks of these running styles. The authors hypothesized that FFS and BF conditions would result in increased sagittal plane joint angles at initial contact and that FFS and BF conditions would demonstrate a shift in sagittal plane joint power from the knee to the ankle when compared to the RFS condition. Finally, total lower extremity power absorption will be least in BF and greatest in the RFS shod condition. METHODS: The study included 10 male and 10 female RFS runners who completed 3-dimensional running analysis in 3 conditions: shod with RFS, shod with FFS, and BF. Variables were the angles of plantarflexion, knee flexion, and hip flexion at initial contact and peak sagittal plane joint power at the hip, knee, and ankle during stance phase. RESULTS: Running with a FFS pattern and BF resulted in significantly greater plantarflexion and significantly less negative knee power (absorption) when compared to shod RFS condition. FFS condition runners landed in the most plantarflexion and demonstrated the most peak ankle power absorption and lowest knee power absorption between the 3 conditions. BF and FFS conditions demonstrated decreased total lower extremity power absorption compared to the shod RFS condition but did not differ from one another. CONCLUSIONS: BF and FFS running result in reduced total lower extremity power, hip power and knee power and a shift of power absorption from the knee to the ankle. CLINICAL RELEVANCE: Alterations associated with BF running patterns are present in a FFS pattern when wearing shoes. Additionally, both patterns result in increased demand at the foot and ankle as compared to the knee. PMID- 23091786 TI - Comparison of different trunk endurance testing methods in college-aged individuals. AB - OBJECTIVE: Determine the reliability of two different modified (MOD1 and MOD2) testing methods compared to a standard method (ST) for testing trunk flexion and extension endurance. PARTICIPANTS: Twenty-eight healthy individuals (age 26.4 +/- 3.2 years, height 1.75 +/- m, weight 71.8 +/- 10.3 kg, body mass index 23.6 +/- 3.4 m/kg(2)). METHOD: Trunk endurance time was measured in seconds for flexion and extension under the three different stabilization conditions. The MOD1 testing procedure utilized a female clinician (70.3 kg) and MOD2 utilized a male clinician (90.7 kg) to provide stabilization as opposed to the ST method of belt stabilization. RESULTS: No significant differences occurred between flexion and extension times. Intraclass correlations (ICCs(3,1)) for the different testing conditions ranged from .79 to .95 (p <.000) and are found in Table 3. Concurrent validity using the ST flexion times as the gold standard coefficients were .95 for MOD1 and .90 for MOD2. For ST extension, coefficients were .91 and .80, for MOD1 and MOD2 respectively (p <.01). CONCLUSIONS: These methods proved to be a reliable substitute for previously accepted ST testing methods in normal college aged individuals. These modified testing procedures can be implemented in athletic training rooms and weight rooms lacking appropriate tables for the ST testing. LEVEL OF EVIDENCE: 3. PMID- 23091787 TI - The acute effects of various types of stretching static, dynamic, ballistic, and no stretch of the iliopsoas on 40-yard sprint times in recreational runners. AB - BACKGROUND AND PURPOSE: The potential adverse effects of static stretching on athletic performance are well documented, but still appears to be controversial, especially as they relates to sprinting. The prevalence of this practice is demonstrated by the number of competitive and recreational athletes who regularly engage in stretching immediately prior to sprinting with the mindset of optimizing their performance. The purpose of this study was to examine the effects of acute static, dynamic, and ballistic stretching, and no stretching of the iliopsoas muscle on 40-yard sprint times in 18-37 year-old non-competitive, recreational runners. METHODS: Twenty-five healthy recreational runners (16 male and 9 female) between the ages of 24 and 35 (Mean = 26.76 yrs., SD = 2.42 yrs.) completed this study. A repeated measures design was used, which consisted of running a 40-yard sprint trial immediately following each of 4 different stretching conditions aimed at the iliopsoas muscle and lasting 1 minute each. The 4 conditions were completed in a randomized order within a 2-week time period, allowing 48-72 hours between each condition. Prior to each 40-yard sprint trial, a 5-minute walking warm-up was performed at 3.5 mph on a treadmill. The subject then ran a baseline 40-yard sprint. After a 10-minute self-paced walk, each subject performed one of the 4 stretching conditions (ballistic, dynamic, static, and no stretch) and then immediately ran a timed 40-yard sprint. RESULTS: There was a significant interaction between stretching conditions and their effects on sprint times, F(3,72) = 9.422, p<.0005. To break down this interaction, simple main effects were performed with 2 repeated measures ANOVAs and 4 paired t-tests using a Bonferroni corrected alpha (alpha = .0083). There were no significant differences between the 4 pre-condition times, p = 0.103 (Greenhouse-Geisser) or the post-condition times, p = 0.029. In the no stretch condition, subjects improved significantly from pre- to post- sprint times (p<0.0005). There were no statistically significant differences in pre- and post stretch condition sprint times among the static (p = 0.804), ballistic (p = 0.217), and dynamic (p = 0.022) stretching conditions. CONCLUSIONS: Sprint performance may show greatest improvement without stretching and through the use of a walking generalized warmup on a treadmill. These findings have clinically meaningful implications for runners who include iliopsoas muscle stretching as a component of the warm-up. LEVEL OF EVIDENCE: Level 2. PMID- 23091788 TI - Shoulder range of motion, pitch count, and injuries among interscholastic female softball pitchers: a descriptive study. AB - BACKGROUND/PURPOSE: Injury rates for softball players are similar to baseball players yet information regarding risk factors, pitching, and physical characteristics for high school windmill softball pitchers is limited. This information is needed to guide prevention, training, and rehabilitation efforts. The purpose of this study was to report descriptive data regarding the physical characteristics and pitching volume experienced by high school softball pitchers during one academic season. A secondary aim was to track and describe upper extremity injuries suffered by high school softball pitchers throughout the course of the 2009 season. METHODS: Twelve uninjured female softball pitchers (13 18y) from 5 Greenville, South Carolina high schools participated. Prior to the 2009 season, the pitchers' shoulder internal, external, total arc of rotation and horizontal adduction PROM was measured. During the 10-week season, aggregate pitch counts (pitch volume) and occurrence of upper extremity injury were tracked for each pitcher. RESULTS: Mean preseason internal, external, and total arc of rotation PROM was observed to be similar between the pitchers' dominant and non dominant shoulders. The PROM measures of horizontal abduction (HA) appear to demonstrate a side-to-side difference with less HA on the dominant arm of the pitchers who were examined. Subjects threw in an average of 10.1 games (+/-4.9) during the season. Six pitchers threw in 60% or more of the team's games and 3 of 12 pitchers pitched less than 25% of games. Pitchers averaged 61.8 pitches per game (+/-31.5) and 745.8 (+/-506.4) per season. Pitch count data did not appear to be different between injured and non-injured pitchers. CONCLUSIONS: Knowledge of pitch volume can be used to prepare windmill softball pitchers for the seasonal stresses, guide establishment of goals when recovering from injury, or assist in training for an upcoming season. Further research is needed to examine larger samples of pitchers over multiple seasons and years. LEVEL OF EVIDENCE: III. PMID- 23091789 TI - Acute management concepts of the acromioclavicular joint: a case report. AB - Acromioclavicular injuries are quite common and approaches to early management of those that are described as a Type III are controversial. The Rockwood Type III classification implies complete disruption of the acromioclavicular and coracoclavicular ligaments, resulting in inferior positioning of the scapula and, thus, the glenohumeral complex while the clavicle appears more superiorly prominent. Clinical management can include surgical or conservative techniques. This case report outlines the decision making process related to this type of injury, as applied in the diagnosis and management of 61 year-old recreational athlete. LEVEL OF EVIDENCE: 5 (Single Case report). PMID- 23091790 TI - Outcome of triple-negative breast cancer in patients with or without markers regulating cell cycle and cell death. AB - PURPOSE: The genes p53 and B-cell lymphoma (bcl)-2 play an important role in regulating the mechanisms of apoptosis. In this paper, we retrospectively applied these factors to our series of triple negative breast cancer (TNBC) patients, in conjunction with an evaluation of the prognostic significance of these factors' influence on TNBC survival rate. Particular focus was placed on the role of bcl 2, p53, Ki-67. METHODS: The study subjects, 94 women with TNBC, were a subset of patients operated at Kosin University Gospel Hospital from January 2000 to December 2005. Chi-squared tests were used for statistical analysis. RESULTS: Positive staining for cytokeratin (CK)5/6 in 23 cases (24.5%), epidermal growth factor receptor in 15 cases (16.0%), bcl-2 in 26 cases (27.7%), p53 in 55 cases (58.5%) and Ki-67 in 74 cases (78.7%) was determined. Lymph node status, tumor size and expression of CK5/6 or Ki-67 were independent prognostic factors for patients with TNBC. CONCLUSION: Markers regulating cell cycle and cell death such as p53 and bcl-2 cannot be used to classify TNBCs into two subtypes with differing disease-free survival. But because our study is small in size, more abundant patient data will be needed to evaluate the factors' predictive role in regulating cell cycle and cell death. PMID- 23091791 TI - Observational study of central metastases following thyroid lobectomy without a completion thyroidectomy for papillary carcinoma. AB - PURPOSE: There are no guidelines for the optimal timing of the decision of when to perform completion thyroidectomy, and controversy exists regarding how the timing of completion thyroidectomy impacts survival patterns. We investigated the legitimacy of an observational strategy in central node metastasis after thyroid lobectomy for papillary thyroid cancer (PTC). METHODS: We retrospectively evaluated 522 consecutive patients who underwent thyroid lobectomy. Of the 69 patients with central metastasis, 61 patients (88.4%) were included in an observational study under cautious evaluation with informed consent by the patients, and compared with an observation arm of 180 postlobectomy N0 (node negative proven) patients. RESULTS: Of the 522 patients, six (1.1%) thyroid, five (0.9%) central, and two (0.4%) lateral recurrences were observed. Lateral recurrences occurred in the immediate completion N0 and Nx groups but not in the N1a observation arms. There were two (3.3%) central recurrences without thyroid or lateral recurrence on the observation arm of N1a observation patients. But two (1.1%) thyroid and three (1.7%) central recurrences were on the observation arm of N0 patients. In Kaplan-Meier survival curves for central or lateral recurrences between observation arms for the N1a and N0 groups, no significant difference was found between the N1a and N0 observation arms (P = 0.365). CONCLUSION: The timing of when to perform completion thyroidectomy in central metastases-proven patients after lobectomy for PTC should be based on the patient's risk category. PMID- 23091792 TI - The Effects of Helicobacter pylori on the prognosis of patients with curatively resected gastric cancers in a population with high infection rate. AB - PURPOSE: The goal of this study was to assess the correlation between the Helicobacter pylori status of patients who underwent curative resection for gastric adenocarcinoma and their prognosis in Eastern societies where H. pylori infection is prevalent. METHODS: Between 2006 and 2007, 192 patients who had a curative resection for the treatment of gastric adenocarcinoma were enrolled in the study. Of these patients, 18 were excluded due to an inexact evaluation of the H. pylori status, thereby leaving 174 patients in the final analysis. Serologic testing for H. pylori was assessed using an enzyme-linked immunosorbent assay kit for immunoglobulin G, and the histological presence of H. pylori was identified using the Giemsa stain. RESULTS: Of the 174 patients, 111 patients (63.8%) were confirmed for H. pylori infection. H. pylori status did not correlate with the overall or disease-free survival. For patients with stage III or IV gastric cancer, a positive H. pylori status was a significant predictive factor for recurrence over that of a negative H. pylori status (P = 0.019). Negative H. pylori status was a predictive factor for recurrence in multivariable analysis (relative risk, 2.724; 95 confidence interval, 1.192 to 6.228). CONCLUSION: Helicobacter pylori status did not correlate with the clinicopathologic factors of gastric adenocarcinoma. However, a negative Helicobacter pylori status may be a predictive factor for recurrence in patients diagnosed with advanced gastric adenocarcinoma. PMID- 23091793 TI - Transumbilical single port laparoscopic appendectomy using basic equipment: a comparison with the three ports method. AB - PURPOSE: Single port laparoscopic surgery is a rapidly evolving laparoscopic surgical approach. We report a comparison of transumbilical single port laparoscopic appendectomy (TUSPLA) and conventional laparoscopic appendectomy (CLA) in a Korean military hospital. METHODS: This single-center retrospective study of 63 patients who received laparoscopic appendectomy was conducted between May 2011 and October 2011. Nineteen patients received TUSPLA and 44 patients received CLA. Clinical outcomes such as operation time, hospital stay, postoperative pain, diet, and postoperative complication were reviewed. RESULTS: There were no statistically significant differences between TUSPLA and CLA patients, respectively, in operation time (58.9 minutes vs. 52.3 minutes, P = 0.262), duration of hospitalization (10.2 days vs. 10.6 days, P = 0.782), mean visual analogue scale score (2.6 vs. 2.5, P = 0.894), and return to diet (1.6 days vs. 1.7 days, P = 0.776). There were two cases (10.5%) of short-term complications in the TUSPLA group and four cases (9.1%) of short-term complications in the CLA group. All patients were fully recovered at discharge. CONCLUSION: TUSPLA is a feasible alternative for CLA. When a glove port is used, no special instruments are needed. Thus, it can be performed in a hospital equipped with basic laparoscopic surgical instruments. PMID- 23091794 TI - Proposal of an endoscopic retrograde cholangiopancreatography-related perforation management guideline based on perforation type. AB - PURPOSE: Consensus for endoscopic retrograde cholangiopancreatography (ERCP) related perforation management is lacking. We aimed to identify candidate patients for conservative management by examining treatment results and to introduce a simple, algorithm-based management guideline. METHODS: A retrospective review of 53 patients with ERCP-related perforation between 2000 and 2010 was conducted. Data on perforation site (duodenum lateral wall or jejunum, type I; para-Vaterian, type II), management method, complication, mortality, hospital stay, and hospital cost were reviewed. Comparative analysis was done according to the injury types and management methods. RESULTS: The outcome was greater in the conservative group than the operative group with shorter hospital stay (20.6 days vs. 29.8 days, P = 0.092), less cost (10.6 thousand United States Dollars [USD] vs. 19.9 thousand USD, P = 0.095), and lower morbidity rate (22.9% vs. 55.6%, P = 0.017). Eighty-one percent (17/21) of type I injuries were operatively managed and 96.9% (31/32) of type II injuries were conservatively managed. Between the types, type II showed better results over type I with shorter hospital stay (19.3 days vs. 30.6 days, P = 0.010), less cost (9.5 thousand USD vs. 20.1 thousand USD, P = 0.028), and lower complication rate (18.8% vs. 57.1%, P = 0.004). There was no difference in mortality. CONCLUSION: Type II injuries were conservatively manageable and demonstrated better outcomes than type I injuries. The management algorithm suggests conservative management in type II injuries without severe peritonitis or unsolved problem requires immediate surgical correction, including operative management in type I injuries unless endoscopic intervention is possible. Conservative management offers socio medical benefits. Conservative management is recommended in well-selected patients. PMID- 23091795 TI - Prognostic factors for gallbladder cancer in the laparoscopy era. AB - PURPOSE: Hepatobiliary surgery has changed dramatically in recent decades with the advent of laparoscopic techniques. The aim of this retrospective study was to compare survival rates according to stages, adjusting for important prognostic factors. METHODS: A retrospective study of a 17-year period from January 1994 to April 2011 was carried out. The cases studied were divided into two time period cohorts, those treated in the first 9-years (n = 109) and those treated in the last 7-years (n = 109). RESULTS: An operation with curative intent was performed on 218 patients. The 5-year survival rates according to the depth of invasion were 86% (T1), 56% (T2), 45% (T3), and 5% (T4). The number of cases of incidental gallbladder cancer found during 3,919 laparoscopic cholecystectomies was 96 (2.4%). Incidental gallbladder cancer revealed a better survival rate (P = 0.003). Iatrogenic bile spillage was found in 20 perforations of the gallbladder during laparoscopic cholecystectomies, 16 preoperative percutaneous transhepatic gallbladder drainages and 16 percutaneous transhepatic biliary drainages; only percutaneous transhepatic biliary drainage patients showed a significantly lower survival rate than patients without iatrogenic bile spillage (P < 0.034). Chemoradiation appeared to improve overall survival (P < 0.001). Multivariate analysis also revealed that time period, type of surgery, surgical margin, lymphovascular invasion, lymph node involvement, and chemoradiation therapy had significant effects. CONCLUSION: This study found that the prognosis of gallbladder cancer is still determined by the stage at presentation due to the aggressive biology of this tumor. Early diagnosis, radical resection and appropriate adjuvant therapy can increase overall survival. PMID- 23091796 TI - The diagnostic values of preoperative laboratory markers in children with complicated appendicitis. AB - PURPOSE: Accurate diagnosis and optimal management of acute appendicitis, despite being the most common surgical emergency encountered in emergency departments, is often delayed in pediatric patients due to nonspecific symptoms and communication barriers, often leading to more complicated cases. The aim of this study is to investigate the diagnostic significance of common laboratory markers. METHODS: A total of 421 patients aged 15 and younger underwent surgical treatment for acute appendicitis. We conducted a retrospective analysis for white blood cell (WBC), C reactive protein (CRP) and bilirubin. All patients were classified into simple or complicated appendicitis groups based on postoperative histology. RESULTS: The mean age of the patients in the complicated appendicitis group was younger than that in the simple group (P = 0.005). WBC, CRP and bilirubin levels were significantly higher in the complicated appendicitis group (P < 0.001, <0.001, 0.002). The relative risk for complicated appendicitis was calculated using age, WBC, CRP and bilirubin. Elevated CRP levels were associated with the highest risk for complicated appendicitis (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.38 to 4.65) followed by WBC (HR, 2.42; 95% CI, 1.07 to 5.46) and bilirubin (HR, 2.04; 95% CI, 1.09 to 3.82). The most sensitive markers for diagnosing complicated appendicitis were WBC (95.2%) and CRP (86.3%). Bilirubin levels showed the highest specificity at 74.8%. CONCLUSION: The risk of complicated appendicitis was significantly higher in patients younger than 10 years old. Preoperative WBC, CRP and bilirubin have clinical value in diagnosing complicated appendicitis with a HR of 2.0 to 2.5. Our results suggest that the utilization of WBC, CRP, and bilirubin can assist in the diagnosis of complicated appendicitis in pediatric patients, allowing prompt diagnosis and optimal management. PMID- 23091797 TI - A rare reason of abdominal compartment syndrome: non-Hodgkin lymphoma. AB - Abdominal compartment syndrome (ACS) is characterized by intra-abdominal hypertension (IAH) which affects all body systems. In healthy individuals, normal intra-abdominal pressure (IAP) is <5 to 7 mmHg. The upper limit of IAP is generally accepted to be 12 mmHg. ACS has been classified into primary, secondary, and tertiary subtypes. Non-Hodgkin lymphoma (NHL) is a rare reason for ACS. We report here one case of NHL as a primary retroperitoneal mass in an 80 year-old male patient who presented with IAH. PMID- 23091798 TI - Liver abscess developed after cadaveric liver transplantation due to ligation of an accessory right hepatic artery of the donor graft. AB - It is important that extrahepatic arteries are identified precisely at the time of graft procurement. We present a case where the accessory right hepatic artery of the liver was ligated leading to postoperative liver abscess formation in the liver graft. A forty-seven-year-old female patient diagnosed with liver cirrhosis underwent orthotopic cadaveric liver transplantation due to altered mentality. The donor graft showed a variant of the hepatic artery anatomy where an accessory right hepatic artery arose from the superior mesenteric artery. This artery was accidentally transected during procurement. Since the back bleeding test using perfusion fluid was good, the artery was ligated. Postoperative abdominal computed tomography scan revealed a 6 cm low attenuating lesion in the liver. The patient underwent conservative treatment. We believe that even small accessory arteries (1 to 2 mm) should be reconstructed whenever possible to avoid postoperative complications such as liver abscess. PMID- 23091799 TI - Endovascular treatment of ruptured infected aortic aneurysm with sepsis. AB - The generally accepted treatment for infected aortic aneurysms involves open surgical resection and debridement, with in situ or extra-anatomical bypass. Occasionally, endovascular management can be substituted for the standard operation dependent on the patient's condition. We report the case of an 81-year old female with a ruptured infected aortic aneurysm and sepsis, successfully treated endovascularly. She had been on oral antibiotics for one year and is doing well 2 years after discharge. PMID- 23091800 TI - Urachal cyst presenting with huge abscess formation in adults. AB - Urachal disease, a disorder where embryonic remnant of the cloaca and the allantois present after birth as a midline fibrous cord, is usually detected in infancy and childhood. But urachal disease in adults is rare. We report a case of a huge abscess derived from a urachal cyst in an adult. A 52-year-old man presented with peri-umbilical distension and abdominal pain for 2 weeks. Ultrasonography and abdominal computed tomography scan demonstrated a huge abscess derived from the abdominal wall. After prompt incision and drainage, the remaining abscess cavity was removed completely under general anesthesia. Pathologic report was consistent with urachal duct cyst, and the patient was discharged in a week without complication. PMID- 23091801 TI - Acute myeloid leukemia as a model for cancer therapy. PMID- 23091802 TI - Molecular mechanisms of MYCN-dependent apoptosis and the MDM2-p53 pathway: an Achille's heel to be exploited for the therapy of MYCN-amplified neuroblastoma. AB - The p53 oncosuppressor is very seldom mutated in neuroblastoma, but several mechanisms cooperate to its functional inactivation in this tumor. Increased MDM2 levels, due to genetic amplification or constitutive inhibition of p14( ARF), significantly contribute to this event highlighting p53 reactivation as an attractive perspective for neuroblastoma treatment. In addition to its role in tumorigenesis, MYCN sensitizes untransformed and cancer cells to apoptosis. This is associated to a fine modulation of the MDM2-p53 pathway. Indeed MYCN induces p53 and MDM2 transcription, and, by evoking a DNA damage response (DDR), it stabilizes p53 and its proapoptotic kinase Homeodomain Interacting Protein Kinase 2 (HIPK2). Through the regulation of the HIPK2-p53 inhibitor High Mobility Group protein A1 (HMGA1) and the homeobox proteins BMI-1 and TWIST-1, MYCN establishes a delicate balance between pro- and antiapoptotic molecules that might be easily perturbed by a variety of insults, leading to cell death. MDM2-p53 antagonists, such as Nutlin-3, are strikingly prone to inducing death in MYCN-amplified neuroblastoma, by further pushing on HIPK2 accumulation. Here we discuss implications and caveats of exploiting this pathway and its connections to MYCN induced DDR for a tailored therapy of MYCN-amplified neuroblastoma. PMID- 23091803 TI - Microbial genomics challenge Darwin. PMID- 23091804 TI - Drug-induced liver injury: present and future. AB - Liver injury due to prescription and nonprescription medications is a growing medical, scientific, and public health problem. Worldwide, the estimated annual incidence rate of drug-induced liver injury (DILI) is 13.9-24.0 per 100,000 inhabitants. DILI is one of the leading causes of acute liver failure in the US. In Korea, the annual extrapolated incidence of cases hospitalized at university hospital is 12/100,000 persons/year. Most cases of DILI are the result of idiosyncratic metabolic responses or unexpected reactions to medication. There is marked geographic variation in relevant agents; antibiotics, anticonvulsants, and psychotropic drugs are the most common offending agents in the West, whereas in Asia, 'herbs' and 'health foods or dietary supplements' are more common. Different medical circumstances also cause discrepancy in definition and classification of DILI between West and Asia. In the concern of causality assessment, the application of the Roussel Uclaf Causality Assessment Method (RUCAM) scale frequently undercounts the cases caused by 'herbs' due to a lack of previous information and incompatible time criteria. Therefore, a more objective and reproducible tool that could be used for the diagnosis of DILI caused by 'herbs' is needed in Asia. In addition, a reporting system similar to the Drug Induced Liver Injury Network (DILIN) in the US should be established as soon as possible in Asia. PMID- 23091805 TI - Changes of guidelines diagnosing hepatocellular carcinoma during the last ten year period. AB - Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths in the world. There have been many advances in the diagnosis of HCC during the last ten years, especially in the imaging techniques. The Korean Liver cancer study group (KLCSG), European Association for the Study of the Liver (EASL), American Association for the Study of Liver disease (AASLD), and Asian-Pacific Association for the Study of Liver (APASL) have made and changed the HCC guidelines with the advances in the imaging techniques and according to the results of the researches on HCC. We reviewed the changes of the imaging guidelines in HCC diagnosis according to the advances in the imaging techniques. Further studies will be necessary to resolve the controversies in the diagnosis of HCC smaller than 1 cm in size. PMID- 23091806 TI - Impact of ribavirin dose reduction during treatment in chronic hepatitis C genotype 1 patients. PMID- 23091807 TI - A reduced dose of ribavirin does not influence the virologic response during pegylated interferon alpha-2b and ribavirin combination therapy in patients with genotype 1 chronic hepatitis C. AB - BACKGROUND/AIMS: When combined with pegylated interferon alpha-2b (Peg-IFN alpha 2b) for the treatment of genotype 1 chronic hepatitis C (CHC) in Korea, the current guideline for the initial ribavirin (RBV) dose is based on body weight. However, since the mean body weight is lower for Korean patients than for patients in Western countries, current guidelines might result in Korean patients being overdosed with RBV. METHODS: We retrospectively reviewed the medical records of patients with genotype 1 CHC who were treated with Peg-IFN alpha-2b and RBV combination therapy. We divided the patients into groups A (>=15 mg/kg/day, n=23) and B (<15 mg/kg/day, n=26), given that the standard dose is 15 mg/kg/day. The clinical course in terms of the virologic response, adverse events, and dose modification rate was compared between the two groups after therapy completion. RESULTS: The early response rates (92.0% vs. 83.3%, P=0.634) and sustained virologic response rates (82.6% vs. 73.1%, P=0.506) did not differ significantly between the two groups. During the treatment period, the RBV dose reduction rate was significantly higher in group A than in group B (60.9% vs. 23.1%, P=0.01). CONCLUSIONS: RBV dose reduction is performed frequently when patients are treated according to the current Korean guidelines. Given that lowering the RBV dose did not appear to decrease the virologic response during therapy, reducing RBV doses below the current Korean guideline may be effective for treatment, especially in low-weight patients. PMID- 23091808 TI - Enhanced A-FABP expression in visceral fat: potential contributor to the progression of NASH. AB - BACKGROUND/AIMS: Adipose tissue is an active endocrine organ that secretes various metabolically important substances including adipokines, which represent a link between insulin resistance and nonalcoholic steatohepatitis (NASH). The factors responsible for the progression from simple steatosis to steatohepatitis remain elusive, but adipokine imbalance may play a pivotal role. We evaluated the expressions of adipokines such as visfatin, adipocyte-fatty-acid-binding protein (A-FABP), and retinol-binding protein-4 (RBP-4) in serum and tissue. The aim was to discover whether these adipokines are potential predictors of NASH. METHODS: Polymerase chain reaction, quantification of mRNA, and Western blots encoding A FABP, RBP-4, and visfatin were used to study tissue samples from the liver, and visceral and subcutaneous adipose tissue. The tissue samples were from biopsy specimens obtained from patients with proven NASH who were undergoing laparoscopic cholecystectomy due to gallbladder polyps. RESULTS: PATIENTS WERE CLASSIFIED INTO TWO GROUPS: NASH, n=10 and non-NASH, n=20 according to their nonalcoholic fatty liver disease Activity Score. Although serum A-FABP levels did not differ between the two groups, the expressions of A-FABP mRNA and protein in the visceral adipose tissue were significantly higher in NASH group than in non NASH group (104.34 vs. 97.05, P<0.05, and 190.01 vs. 95.15, P<0.01, respectively). Furthermore, the A-FABP protein expression ratio between visceral adipose tissue and liver was higher in NASH group than in non-NASH group (4.38 vs. 1.64, P<0.05). CONCLUSIONS: NASH patients had higher levels of A-FABP expression in their visceral fat compared to non-NASH patients. This differential A-FABP expression may predispose patients to the progressive form of NASH. PMID- 23091810 TI - Association between apolipoprotein E genotype, chronic liver disease, and hepatitis B virus. AB - BACKGROUND/AIMS: Apolipoprotein E (ApoE) plays an important role in regulating lipid and lipoprotein metabolism, and ApoE genotypes are known to affect plasma lipoprotein concentrations. We investigated whether ApoE genotype determines the disease outcome in hepatitis B virus (HBV)-infected individuals, and verified the association between ApoE genotype and the occurrence of hepatocellular carcinoma (HCC) in patients with chronic liver diseases of various etiologies. METHODS: This hospital-based, case-controlled study enrolled 156 subjects (47 healthy controls, 50 HBV-related liver cirrhosis patients, and 59 HCC patients). ApoE genotypes were determined using PCR-based ApoE genotyping kits. The biological significance of ApoE genotype was verified by measuring serum ApoE levels using an ELISA kits. RESULTS: The epsilon3 allele was the most common allele, with allele frequencies among the entire cohort of 5.8%, 84.3%, and 9.9% for the epsilon2, epsilon3, and epsilon4 alleles, respectively. Significantly more of those patients carrying the epsilon3/3 genotype had developed liver cirrhosis compared to the control subjects. Being an ApoE4 carrier was associated with a lower probability of developing liver cirrhosis. The allele frequencies and genotype distribution of ApoE did not differ significantly between the liver cirrhosis and HCC patients. The serum level of ApoE was significantly higher in patients with liver cirrhosis than in the healthy controls, but did not differ significantly with the ApoE genotype. CONCLUSIONS: The ApoE epsilon3/3 genotype frequency was higher in patients with HBV-associated liver cirrhosis than in the controls. PMID- 23091809 TI - Cyclooxygenase-2 and vascular endothelial growth factor in chronic hepatitis, cirrhosis and hepatocellular carcinoma. AB - BACKGROUND/AIMS: Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are up-regulated in hepatocellular carcinoma (HCC). To investigate the levels of COX-2 and VEGF expression in chronic hepatitis (CH), cirrhosis, and HCC. METHODS: The immunohistochemical expressions of COX-2 and VEGF were evaluated in tissues from patients with CH (n=95), cirrhosis (n=38), low-grade HCC (LG-HCC; n=6), and high-grade HCC (HG-HCC; n=29). RESULTS: The COX-2 expression scores in CH, cirrhosis, LG-HCC, and HG-HCC were 3.3+/-1.9 (mean+/ SD), 4.2+/-1.7, 5.5+/-1.0, and 3.4+/-2.4, respectively (CH vs. cirrhosis, P=0.016; CH vs. LG-HCC, P=0.008; LG-HCC vs. HG-HCC, P=0.004), and the corresponding VEGF expression scores were 0.9+/-0.8, 1.5+/-0.7, 1.8+/-0.9, and 1.6+/-1.1 (CH vs. cirrhosis, P<0.001; CH vs. LG-HCC, P=0.011; LG-HCC vs. HG-HCC, P=0.075). Both factors were correlated with the fibrosis stage in CH and cirrhosis (COX-2: r=0.427, P<0.001; VEGF: r=0.491, P<0.001). There was a significant correlation between COX-2 and VEGF in all of the tissue samples (r=0.648, P<0.001), and between high COX-2 and VEGF expression scores and survival (COX-2: P=0.001; VEGF: P<0.001). CONCLUSIONS: The expressions of both COX-2 and VEGF are significantly higher in cirrhosis and LG-HCC than in CH. High COX-2 and high VEGF expressions are associated with a high survival rate. PMID- 23091811 TI - Thrombocytopenia represents a risk for deterioration of liver function after radiofrequency ablation in patients with hepatocellular carcinoma. AB - BACKGROUND/AIMS: We evaluated changes in liver function parameters and risk factors for the deterioration of liver function 12 months after percutaneous radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC). METHODS: The subjects in this retrospective study comprised 102 patients with HCC who had undergone RFA therapy and exhibited no recurrence of HCC 12 months thereafter. Serial changes in serum total bilirubin and albumin, prothrombin time, and Child-Pugh score were evaluated before RFA and 3, 6, 9, and 12 months thereafter. Deterioration of liver function was defined when the Child Pugh score increased by at least 2 at 12 months after RFA therapy. We determined the factors related to aggravation of liver function after RFA therapy. RESULTS: Liver function had deteriorated 12 months after RFA in 29 patients (28.4%). Serum albumin levels decreased significantly from before (3.7+/-0.1 g/dL, mean+/-SD) to 12 months after RFA therapy (3.3+/-0.1 g/dL, P=0.002). The Child-Pugh score increased significantly during the same time period (from 6.1+/-0.2 to 7.2+/-0.3, P<0.001). Pre-RFA thrombocytopenia (<=100,000/mm(3)) was revealed as a significant risk factor for the deterioration of liver function after RFA. However, no patients had episodes of bleeding as a complication of RFA. CONCLUSIONS: Among the liver-function parameters, serum albumin level was markedly decreased in HCC patients over the course of 24 months after RFA therapy. A pre-RFA thrombocytopenia represents a major risk factor for the deterioration of liver function. PMID- 23091812 TI - Type and cause of liver disease in Korea: single-center experience, 2005-2010. AB - BACKGROUND/AIMS: The aim of this study was to describe the types and causes of liver disease in patients from a single community hospital in Korea between April 2005 and May 2010. METHODS: A cohort of patients who visited the liver clinic of the hospital during the aforementioned time period were consecutively enrolled (n=6,307). Consistent diagnostic criteria for each liver disease were set by a single, experienced hepatologist, and the diagnosis of all of the enrolled patients was confirmed by retrospective review of their medical records. RESULTS: Among the 6,307 patients, 528 (8.4%) were classified as acute hepatitis, 3,957 (62.7%) as chronic hepatitis, 767 (12.2%) as liver cirrhosis, 509 (8.1%) as primary liver cancer, and 546 (8.7%) as a benign liver mass or other diseases. The etiologies in the acute hepatitis group in decreasing order of prevalence were hepatitis A (44.3%), toxic hepatitis (32.4%), other hepatitis viruses (13.8%), and cryptogenic hepatitis (9.1%). In the chronic hepatitis group, 51.2% of cases were attributed to viral hepatitis, 33.3% to nonalcoholic fatty liver disease, and 13.0% to alcoholic liver disease (ALD). Of the cirrhoses, 73.4% were attributable to viral causes and 18.1% to alcohol. Of the hepatocellular carcinoma cases, 86.6% were attributed to viral hepatitis and 11.6% to ALD. Among the benign tumors, hemangioma comprised 52.2% and cystic liver disease comprised 33.7%. CONCLUSIONS: Knowledge of the current status of the type and cause of liver disease in Korea may be valuable as a basis for evaluating changing trends in liver disease in that country. PMID- 23091813 TI - Spinal cord injury after conducting transcatheter arterial chemoembolization for costal metastasis of hepatocellular carcinoma. AB - Transcatheter arterial chemoembolization (TACE) has been used widely to treat patients with unresectable hepatocellular carcinoma. However, this method can induce various adverse events caused by necrosis of the tumor itself or damage to nontumor tissues. In particular, neurologic side effects such as cerebral infarction and paraplegia, although rare, may cause severe sequelae and permanent disability. Detailed information regarding the treatment process and prognosis associated with this procedure is not yet available. We experienced a case of paraplegia that occurred after conducting TACE through the intercostal artery to treat hepatocellular carcinoma that had metastasized to the rib. In this case, TACE was attempted to relieve severe bone pain, which had persisted even after palliative radiotherapy. A sudden impairment of sensory and motor functions after TACE developed in the trunk below the level of the sternum and in both lower extremities. The patient subsequently received steroid pulse therapy along with supportive care and continuous rehabilitation. At the time of discharge the patient had recovered sufficiently to enable him to walk by himself, although some paresthesia and spasticity remained. PMID- 23091814 TI - A case of necrotizing pancreatitis subsequent to transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma. AB - Necrotizing pancreatitis is one of the rare complications of transcatheter arterial chemoembolization (TACE). Necrotizing pancreatitis after TACE may result from the development of ischemia caused by regurgitation of embolic materials into the vessels supplying the pancreas. We report a case of post-TACE necrotizing pancreatitis with abscess formation in a patient with hepatocellular carcinoma. The patient had suffered hepatic artery injury due to repetitive TACE; during his 25th TACE procedure he had submitted to selective catheterization of the feeding vessel from the dorsal pancreatic artery with a cytotoxic agent and Gelfoam particles. The patient complained of abdominal pain after the TACE procedure, and a CT scan led to a diagnosis of necrotizing pancreatitis with abscess formation. The pancreatic abscess progressed despite general management of the pancreatitis, including antibiotics. Percutaneous catheter drainage was performed, and the symptoms of the patient improved. PMID- 23091815 TI - Adenosquamous carcinoma of the liver. PMID- 23091817 TI - A highly fluorescent pH sensing membrane for the alkaline pH range incorporating a BODIPY dye. AB - A robust and re-usable dipstick-type fluorescent pH sensor for the alkaline pH range was developed by embedding a brightly fluorescent boron-dipyrromethene (BODIPY) dye bearing an acidic phenol moiety into a polyurethane matrix immobilized on a 3D epoxy-functionalized polymer support. The sensor strip has a dynamic working range of pH 10.0-13.1, i.e., operates in strongly basic media where pH glass electrodes can suffer from alkaline errors, and tolerates a high electrolyte background such as simulated seawater and sewage. This work describes the preparation of the sensing material and provides insight into the features that a hydrogel sensing membrane can bestow on an embedded pH-responsive dye by means of optical spectroscopic investigations. PMID- 23091816 TI - Hepatic angiomyolipoma with minimal fat, mimicking hepatocellular carcinoma. PMID- 23091818 TI - Voltammetric reduction and re-oxidation of solid coordination polymers of dihydroxybenzoquinone. AB - Crystalline (PMePh(3))(2)[Cd(2)(dhbq)(3)], (dhbq(2-) = deprotonated 2,5 dihydroxybenzoquinone, H(2)dhbq), attached to electrode surfaces, survives repeated cycles of reduction followed by re-oxidation when placed in contact with aqueous electrolyte media. The results afford encouragement that a range of coordination networks containing redox active connecting ligands and/or redox active metal centres may be reducible or oxidisable in the solid state. PMID- 23091819 TI - Production of large graphene sheets by exfoliation of graphite under high power ultrasound in the presence of tiopronin. AB - Under ultrasonication, the production of high quality graphene layers by exfoliation of graphite was achieved via addition of tiopronin as an antioxidant. PMID- 23091820 TI - Oxo-sulfido- and oxo-selenido-molybdenum(VI) complexes possessing a dithiolene ligand related to the active sites of hydroxylases of molybdoenzymes: low temperature preparation and characterisation. AB - Oxo-sulfido- and oxo-selenido-molybdenum(VI) complexes with an ene-1,2-dithiolate ligand are generated as models of the active sites of molybdenum hydroxylases. The sulfide and selenide groups are highly reactive toward triphenylphosphine in the order of Se > S. PMID- 23091821 TI - Delivery, stabilization, and spatiotemporal activation of cargo molecules in cells with positively charged nanoparticles. AB - Positively charged photodegradable nanoparticles that simultaneously encapsulated various compounds including small and large molecules were prepared. The nanoparticles were internalized to the cell by endocytosis and were stable within the cells for at least 4 days. The encapsulated molecules were released into the cytosol using light stimuli. PMID- 23091822 TI - Positioning NAPNAP for the future: focus on health policy. PMID- 23091823 TI - Obituary: Professor John Daniel Collins MVB MVM MS (Calif.) PhD MRCVS. PMID- 23091824 TI - ORIGIN trial shows safety and efficacy of insulin glargine: no adverse cardiovascular outcomes after a 6.2-year follow up of early insulin use. PMID- 23091825 TI - [What is your diagnosis? Dysembryoplastic neuroepithelial tumor (DNET) WHO grade 1]. PMID- 23091826 TI - Hypertension, chronic kidney disease, atrial fibrillation and the newer anticoagulants: Prof Brian Rayner comments. PMID- 23091827 TI - Faculty of Consulting Physicians of South Africa (FCPSA): saving brain with dabigatran. PMID- 23091828 TI - Managing neuropathic pain: first expert recommendation for South Africa places emphasis on stepwise pharmacological intervention. PMID- 23091829 TI - Rheumatoid arthritis management options for 2012. PMID- 23091830 TI - Benefit versus risk in the use of non-selective NSAIDs and selective COX-2 inhibitors. PMID- 23091831 TI - US medical researchers brace themselves for budget cuts. PMID- 23091832 TI - Syria's refugees face a bleak winter. PMID- 23091833 TI - Thomas Szasz: rebel with a questionable cause. PMID- 23091834 TI - [What is your diagnosis? Combined glioneuronal tumor with DNET structure and ganglioglioma, WHO grade 1]. PMID- 23091835 TI - [What is your diagnosis? Pilocytic astrocytoma, WHO grade 1]. PMID- 23091836 TI - Effects of cigarette smoke and nicotine on cell viability, migration and myofibroblastic differentiation. AB - BACKGROUND AND OBJECTIVE: Several studies have analysed the role of nicotine as a prominent agent affecting wound repair in smokers. However, tobacco smoke contains several components that may alter gingival wound healing. The present study aimed to analyse the roles of cigarette smoke condensate (CSC) and nicotine on cell viability, cell migration/invasion and myofibroblastic differentiation using primary cultures of human gingival fibroblasts. MATERIAL AND METHODS: To compare the effects of CSC and nicotine, gingival fibroblasts were stimulated with CSC (0.4-500 lg/mL) and the corresponding nicotine concentrations (0.025-32 lg/mL) present in research cigarettes (1R3F). Cell viability was evaluated through the MTS assay. Cell migration and invasion were assessed through scratch wound assays, collagen nested matrices and trans well migration. a-Smooth muscle actin production was evaluated by western blotting. RESULTS: Cigarette smoke condensate at 50 lg/mL induced a moderate increase in cell viability, whereas the corresponding nicotine concentration (3.2 lg/mL) did not produce this response. Cigarette smoke condensate at 250 lg/mL, but not nicotine at 16 lg/mL (the corresponding nicotine concentration), induced cell death. Both nicotine and CSC stimulated cell migration (50 lg/mL CSC; 3.2 lg/mL nicotine). At 150 lg/mL, CSC inhibited cell migration; however, the corresponding concentration of nicotine (9.6 lg/mL), did not have this effect. Although both nicotine and CSC inhibited a smooth muscle actin production, only the latter induced a statistically significant effect on this response. CONCLUSION: Cigarette smoke condensate may stimulate cell survival and migration at low concentrations and inhibit these cell responses at higher levels of exposure. Moreover, CSC may interfere in myofibroblastic differentiation.These results show that cigarette smoke, but not nicotine, may significantly alter cell viability, cell migration and myofibroblastic differentiation in gingival mesenchymal cells. PMID- 23091837 TI - The future of technologies for personalised medicine. AB - Personalised medicine promises prediction, prevention and treatment of illness that is targeted to individuals' needs. New technologies for detailed biological profiling of individuals at the molecular level have been crucial in initiating the move to personalised medicine; further novel technologies will be necessary if the vision is to become a reality. We will need to develop new technologies to collect and analyse data in a way that is not just linear but integrated (understanding system level functioning) and dynamic (understanding system in flux). Key factors in the development of technologies for personalised medicine are standardisation, integration and harmonisation. For example, the tools and processes for data collection and analysis must be standardised across research sites. Research activity at different sites must be integrated to maximise synergies, and scientific research must be integrated with healthcare to ensure effective translation. There must also be harmonisation between scientific practices in different research sites, between science and healthcare and between science, healthcare and wider society, including the ethical and regulatory frameworks, the prevailing political and cultural ethos and the expectations of patients/citizens. PMID- 23091838 TI - CM experts: hospitals need ED case managers now more than ever. AB - It's no longer a luxury for hospitals to have case managers in their emergency departments, according to some case management experts--it's a necessity to make sure patients are admitted in the proper status and to ensure that those being discharged from the emergency department have what they need to manage their conditions. Hospitals need to ensure that patients meet medical necessity criteria to avoid losing reimbursement. Case managers can help provide a smooth transition from the emergency department back to the community and connect patients with post-discharge services. Case managers can work with patients who frequently utilize the emergency department and educate them about more appropriate venues of care. PMID- 23091839 TI - It takes data to justify ED case management. AB - When it comes to justifying staff in the emergency department, case management directors need to provide financial data, not anecdotal information to the hospital's finance department. Experts recommend the following: Track your facility's avoidable admissions and patients admitted in the wrong status and calculate how much reimbursement the hospital lost. Collect information on people treated for non-emergent conditions who didn't pay and what the hospital lost. Add up the number of frequent utilizers who use the emergency department to manage their chronic conditions and how many could have benefitted from a referral to community services. PMID- 23091840 TI - ED of future must connect patients, services. AB - In today's healthcare system, emergency departments can no longer be a gateway to the hospital. They must be a place where people can be triaged to the proper venue for care, says Karen Zander, RN, MS, CCMAC, FAAN, principal and co-owner of The Center for Case Management in Wellesley, MA. Patients are going to continue using the emergency department for primary care because of a shortage of primary care providers, making it difficult to get timely appointments. Many primary care practices will not take Medicaid recipients, leaving those patients no alternative for treatment besides the emergency department. Hospitals need to be able to connect patients to services such as home health and durable medical equipment and to help them get follow-up appointments. PMID- 23091841 TI - CMS continues to shift emphasis to quality of care. AB - The Centers for Medicare & Medicaid Services' (CMS) Inpatient Prospective Payment System final rule for 2013 makes it clear that in the future, hospital reimbursement is going to hinge even more on the quality of care patients receive. CMS announced its intentions to add more risk-adjusted measures to the reimbursement reduction and value-based purchasing initiatives in future years, penalizing hospitals that do not do as well as their peers on these measures. Case managers must make sure that patients are in the appropriate level of care and that documentation clearly reflects how sick patients are and the care they receive. Even though some measures won't be added to value-based purchasing until fiscal 2015, the performance period starts as early as Oct. 1, 2012, making it imperative for hospitals to make improvements now. PMID- 23091842 TI - Hospitals collaborate to reduce ED overuse. AB - ED Connections, a joint project of two competing hospitals in Lincoln, NE, has reduced the number of emergency visits by uninsured and underinsured frequent users by 56%, saving the two hospitals about $700,000 in uncompensated care costs. When patients being treated in the emergency department say they can't afford their medication or have other needs, they receive a card with the ED Connections phone number that they can call for help. When patients enroll in the program, staff conduct a psychosocial assessment and work with them to create an action plan and goals. The team works closely with patients to help them follow their plan of care. PMID- 23091843 TI - Intensive CM cuts ED visits, hospitalizations. AB - The Intensive Case Management Program at Community Memorial Hospital in Ventura, CA, connects frequent emergency department users with community-based services and has cut emergency department visits by 42% and acute care admissions by 44%. Patients are young with multiple physical illnesses, substance abuse, and mental health issues. Intensive case management coordinators work closely with patients on a treatment plan, help them access community resources, and go with them to physician visits. They visit patients in the emergency department and the hospital and revise their treatment plan. PMID- 23091844 TI - Program for uninsured cuts ED visits, admissions. AB - MetroHealth Medical Center in Cleveland has saved about $18 per member a month by enrolling uninsured patients in an HMO-like system developed by the health system. Patients pay on a sliding scale based on their income. Uninsured patients are signed up for the program when they come to the emergency department and cannot have a clinic visit unless they enroll. The hospital embeds case managers in the health system's clinic to work with uninsured patients to help them avoid emergency department visits and hospitalizations. PMID- 23091845 TI - The inexorable march toward accountable care. AB - Although they got off to a slow start, Medicare accountable care organizations (ACOs) are being viewed more favorably as a result of the Centers for Medicare & Medicaid Services's promotion of the Pioneer ACO pilot. Commercial ACOs are successfully reducing costs and improving health outcomes. Because of the early positive results of pilot programs, ACOs are expected to increase in the years ahead. PMID- 23091846 TI - [Experience in preventing cardiovascular diseases in our country]. AB - The paper gives concise historic information on the prevention of non communicable diseases and characterizes the-state-of-the-art of cardiovascular disease prevention in Russia. PMID- 23091847 TI - [Deformation, rotation, and axial torsion of the left ventricle in coronary heart disease patients with its severe dysfunction]. AB - AIM: To evaluate global left ventricular (LV) systolic longitudinal and circumferential strain rates, rotation, and axial torsion in relation to the type of postinfarction LV remodeling in patients with coronary heart disease (CHD) and severe LV dysfunction. SUBJECTS AND METHODS: Studies were performed in 58 patients with sustained anterior myocardial infarction, an ejection fraction of less than 40%, and NYHA Functional Class IlI-IV heart failure. Three types of postinfarction LV remodeling were identified: 1) with LV apical aneurysm; 2) an intermediate type; 3) with ischemic cardiomyopathy. Global LV systolic longitudinal and circumferential strain rates, end-systolic basal (RotMV/RottMV) and apical (Rot(apex)/RotRapex) rotation, and axial torsion axis were estimated as an indicator of global LV systolic function. RESULTS: No differences were found in the basal global LV longitudinal and circumferential strain rates, basal rotation, and rotation rate between the patients with 3 types of LV remodeling. In the patients with type 1 LV remodeling, the basal rotation was higher than the apical one (RotMV - Rot(apex): -3.085 +/- 2.821 versus 2.293 +/- 1.021; p = 0,002; RotR(MV)--RotRapex: -22.452 +/- 19.823/c(-1) versus 13.641 +/- 10.745/c( 1); p = 0.003). In type 2 postinfarction LV remodeling, the basal and apical rotation values did not differ statistically significantly. Impaired apical rotation (in a clockwise direction) was identified in 5 of the 16 patients with type 3 LV remodeling (Rot(apex): -1.477 +/- 0.392; RotRapex: -30.572 +/- 13.735/c(-1)). There were no differences in the value of LV axial torsion between types 1 and 2 LV postinfarction remodeling (Type 1, 6.714 +/- 3.017; Type 2, 7.463 +/- 5.416). CONCLUSION: It was shown for the first time that there were no differences in global LV longitudinal and circumferential strain rates and end systolic LV rotation between the patients with types 1 and 2 postinfarction LV remodeling. PMID- 23091848 TI - [Prognostic value of SYNTAX score for outcomes and revascularization strategy choice in ST-segment elevation myocardial infarction patients with multivessel coronary artery disease]. AB - AIM: To study the prognostic significance of the SYNTAX score in the evaluation of outcomes of primary percutaneous coronary interventions (PCIs) and revascularization strategy choice in patients with ST-elevation myocardial infarction (STEMI) with multivessel coronary artery disease. MATERIAL AND METHODS: The long-term outcomes of primary PCIs were analyzed in 163 patients with STEMI in terms of the objective assessment of the severity of the coronary bed lesion according to SYNTAX scores. RESULTS: In a cohort of STEMI patients who had undergone primary PCI, the SYNTAX score of > or = 23 (a severe lesion) was associated with the higher incidence of acute heart failure (Killip class II) and three-vessel coronary artery disease (odds ratio (OR) 2.8), with the higher risk of death (OR 7.5) and the higher rate of the combined endpoint of death, myocardial infarction, and target vessel revascularization (OR 2.8) as compared with patients with a SYNTAX score of < or = 22 (a moderate lesion). CONCLUSION: The SYNTAX score has a prognostic value in assessing the outcomes of primary PCIs in the cohort of STEMI patients with multivessel disease, which can find use in the differential choice of the optimal revascularization strategy and improve treatment results. In the group of patients with a SYNTAX score of > or = 23, the incomplete revascularization strategy shows the least favorable results as compared to multivessel stenting and staged revascularization. PMID- 23091849 TI - [Aspects of risk stratification in acute coronary syndrome: prognostic value of evaluation of left ventricular myocardial viability according to the data of pharmacological stress echocardiography]. AB - AIM: To define the prognostic value of the indicators of left ventricular myocardial viability according to the data of pharmacological stress echocardiography in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: The results of examinations were analyzed in a total of 91 patients with ACS; 71 of them were found to have areas of asynergy (these cases formed the key basis for statistical processing). An analysis of the outcomes registered in the established follow-up period (mean 14.3 +/- 0.7 months) took into consideration death from cardiac diseases, a recurrent acute coronary episode (nonfatal myocardial infarction (MI), unstable angina (UA)). RESULTS: Risk stratification for cardiac events in patients with ACS requires both the assessment of a myocardial viability testing result and the detection of stress-induced ischemia. An analysis of the impact of the indicators of myocardial viability on prognosis in the ACS group showed that the most important predictors of cardiac death were impaired segmental contractility index (ISCI), number of asynergic segments, and total ejection fraction (TEF) at rest; TEF, ISCI, number of segments with a negative response to low-dose drug infusion; TEF, deltaTEF (as compared to the baseline data), and a positive or negative peak stress testing result. The most important predictors of major cardiac events (death MI, UA) were ascertained to be ISCI, number of asynergic segments, resting TEF; TEF, ISCI, number of segments with a negative response to low-dose drug infusion; a positive or negative testing result, TEF, deltaTEF (as compared to the baseline data), and ISCI during the peak stress test. CONCLUSION: The low myocardial/coronary reserve increases mortality rates; the high one worsens the prognosis of major cardiac events, particularly when the test is positive, which tacitly transfers these patients to a very high risk group. PMID- 23091850 TI - [Time course of changes in brachial artery function in patients with unstable angina pectoris during perindopril therapy]. AB - AIM: To estimate the time course of changes in brachial artery (BA) functional parameters in patients with unstable angina (UA) treated with angiotensin converting enzyme inhibitors. SUBJECTS AND METHODS: After examination, 30 patients with Braunwald Classes IB and IIB UA were randomized to two groups to receive perindopril or enalapril as part of combination therapy (Group 1 and Group 2, respectively). The authors carried out BA duplex scanning with a reactive hyperemia test, calculated the values of its viscoelastic properties, and determined pulse wave velocity (PWV) at baseline and after 3 months. RESULTS: The patients of both groups did not differ in BA functional parameters at baseline. Following 3 months, Group 1 showed a reduction in Young's (p = 0.046) and Peterson's (p = 0.049) modules, an increase in compliance (p = 0.016) and distensibility (p = 0.02) coefficients, and a decrease in PWV (p = 0.23). Estimation of endothelium-dependent vasodilation of BA revealed a significant increase in its diameter increment both at testing minutes 1 (p = 0.047) and 2 (p = 0.049). In Group 2, only did the distensibility coefficient change significantly (p = 0.041). After the reactive hyperemia test, there was a significant rise in BA diameter increment at minute 1 (p = 0.047) and no change in this indicator at minute 2. CONCLUSION: After 3-month treatment, the viscoelastic properties of BA improved in all indicators in the patients taking perindopril as part of combination therapy. The use of enalapril improved only an arterial distensibility index. The BA endothelial function estimated by its diameter increment also displayed better changes in the patients receiving perindopril. PMID- 23091851 TI - [Pharmacogenetic features of the effect of metformin in patients with coronary heart disease in the presence of metabolic syndrome and type 2 diabetes mellitus in terms of PPAR-gamma2 gene polymorphism]. AB - AIM: To define the pharmacogenetic features of the effect of metformin in coronary heart disease (CHD) patients with metabolic syndrome (MS) or type 2 diabetes mellitus (T2DM), by taking into consideration PPAR-gamma2 Pro1 2Ala polymorphism. SUBJECTS AND METHODS: Twenty-four men with CHD and MS and 28 men with CHD and T2DM were examined. The effect of metformin as a short course in combination therapy was evaluated. A population control group consisted of 46 apparently healthy men. The genetic PPRA-gamma2 Pro12Ala polymorphism was studied. A number of indicators (total cholesterol (TC), high-density lipoprotein cholesterol, total lipids, triglycerides, beta-lipoproteins, glycated hemoglobin, C-peptide) and proinflammatory markers, such as interleukin (IL)-1beta, IL-6, IL 8, and tumor necrosis factor-alpha (TNF-alpha) were determined in the blood. RESULTS: Analysis of the frequencies of Pro and Ala alleles indicated a decrease in the latter in CHD patients with T2DM. The CHD and MS patients who carried the Pro allele showed a significant metformin-induced reduction in weight, waist circumference, body mass index, and concentrations of TC, C-peptide, and cytokines, such IL-1beta, IL-6, IL-8, and TNF-alpha. CONCLUSION: Metformin exhibits a high therapeutic efficacy in patients with CHD in the presence of T2DM or MS who have the Pro/Pro genotype, which is of interest in terms of pharmacogenetics and calls for further investigation. PMID- 23091852 TI - [Risk of cardiovascular death in relation to blood lipid composition in male inhabitants of Tyumen: results of a 12-year prospective study]. AB - AIM: To evaluate the impact of the blood levels of lipoproteins, such as total cholesterol (TC), high-density lipoproteins (HDL), triglycerides (TG), on the risk for cardiovascular death in an open Tyumen male population on the basis of a 12-year prospective follow-up study. SUBJECTS AND METHODS: Standard methods were used to conduct an epidemiological study of a representative sample of Tyumen males aged 25-64 years in 1996. The cardiological screening response rate was 79.5% (n = 795). Eighty-five cardiovascular deaths (CVD) were registered in the male cohort during 12 years of the prospective follow-up study. The Cox proportional hazard regression model was employed to assess the relative risk (RR) of CVD. Survival rates were analyzed with the Kaplan-Meier method; the significance of lifespan differences in two groups was estimated using the log rank test. RESULTS: In the male cohort, a statistically significant increase in the RR of CVD occurred, starting with a TC level of > or = 230 mg/dl. The lowest survival rates were noted in the males with hypercholesterolemia (HC). The statistically significant increase in the RR of CVD depending on the levels of TG was found in its 5th quintile (138 mg/dl or more). Lower survival rates were stated in the males with hypertriglyceridemia (HTG) than in those with normal blood TG levels. There were neither statistically significant results in the assessment of RR and survival rates in relation to the level of low-density lipoprotein cholesterol, no data on the effect of the level of HDL cholesterol on the RR of CVD in the males. CONCLUSION: According to the data of a 12-year cohort study, the open Tyumen male population was found to have a high RR of CVD in those who had TC levels > or = 230 mg/dl and TG levels > or = 138 mg/dl, which determined the lowest survival rates in males with HC and HTG. PMID- 23091853 TI - [Comparative analysis of the serum level of autoantibodies as a diagnostic tool of myocardial inflammatory diseases]. AB - AIM: To assess whether the serum levels of autoantibodies (auto-Abs) interacting with myocardial and vascular wall antigens might be used for the differential diagnosis of myocardial inflammatory diseases. Subjects and methods. Seventeen patients with morphologically documented myocarditis were examined. A comparison group comprised 9 patients with acute myocardial infarction (AMI). A control group included 18 apparently healthy individuals and 8 patients with chronic erosive gastritis (CEG). Serum auto-Abs levels were estimated by the ELI test systems standardized for enzyme immunoassay. RESULTS: The individual profiles that reflect relative changes in the levels of 16 study auto-Abs and characterize the integral autoreactivity of a patient have clear intergroup differences. Using the profiles of auto-Abs could confirm the diagnosis of myocarditis in 94% of cases or assign the patient to a group of apparently healthy individuals. The informative value of the method in patients with AMI and CEG was 81.8 and 87.5%, respectively. CONCLUSION: The proposed method may be used for the noninvasive screening diagnosis of myocardial inflammatory diseases. PMID- 23091854 TI - [Nonspecific inflammation and structural changes in the arteries of hypertensive males at high and moderate risk for cardiovascular events]. AB - AIM: To study relationships between nonspecific inflammation (NI) of the arterial wall and its structural changes in Stages I-II hypertensive disease (HD) males at moderate and high risks of cardiovascular events (CVE). SUBJECTS AND METHODS: Sixty hypertensive males aged 30 to 65 years (mean age 44 +/- 2 years), including 35 patients with grade 1 arterial hypertension (AH) and 25 with grade 2 AH at moderate and high risks of CVE, were examined. The concentrations of C-reactive protein (CRP) and methylglyoxal (MG) were measured. Pulse wave propagation velocity (PWPV) and ankle brachial index (ABI) were studied. Normal PWPV values were calculated in terms of gender and age features. RESULTS: The examined HD group showed a positive correlation of PWPV with systolic blood pressure over 24 hours (r=0.39; p < 0.02) and age (r = 0.47; p < 0.01). In smoking and nonsmoking hypertensive men, PWPV differences failed to achieve statistical significance (14.05 +/- 0.53 and 13.07 +/- 0.38 m/sec, respectively). PWPW was found to be correlated with CRP values weakly (r = 0.31; p = 0.07) and with MG levels moderately (r = 0.62; p < 0.01); there were also positive relationships of ABI to the levels of CRP (r = 0.50; p < 0.01) and MG (r = 0.46; p < 0.05). There was a positive correlation between CRP and MG levels (r = 0.45; p = 0.01). CONCLUSION: In middle-aged men with grades 1-2 AH at moderate and high risks of CVE, NI processes are not only related to MG metabolism, but also they have a substantial effect on the elastic properties of the wall of predominantly muscle-elastic type arteries, which validates the hypothesis of the involvement of NI processes in the course of HD. PMID- 23091855 TI - [Trends in the risk factors and signs of subclinical atherosclerosis in subjects at low and moderate risk according to the SCORE scale in different medical management tactics: two-year follow-up results]. AB - AIM: To comparatively analyze the following parameters of the subclinical manifestations of atherosclerosis: carotid intima-media thickness (IMT), the presence and number of carotid atherosclerotic plaques (ASP), ankle brachial pulse wave velocity (ABPWV) in patients from 2 (active and conventional observation) groups at low and moderate risks according to the SCORE scale in two year outpatient practice. SUBJECTS AND METHODS: A screening could select 600 able bodied persons (445 women and 155 men) aged 30 to 65 years at low and moderate risks (according to the SCORE scale without atherosclerosis-associated diseases who were divided into 2 groups: A) active observation (n =400) and B) conventional medical management tactics (n = 200). Five hundred and seven (85%) persons (339 in Group A and 168 in Group B) completed the study following 2 years. Carotid duplex scanning, computed sphygmography, and biochemical tests for blood lipid composition were performed. The delta index (%) calculated by the special formula, by subtracting the results during the first visit from those obtained 2 years later, was used to statistically analyze the time course of changes in the parameters under study. RESULTS: Delta IMT (%) statistically significantly increased in Group B men as compared to that in Group A men (p = 0.042). The delta parameter of total carotid stenosis, which reflected the percentage of the latter, proved to be high in both Group B women and men (p = 0.0001) and the persons with a larger number of ASP were statistically significantly more in Group B (p = 0.035). Delta ABPWV (%) was also greater in Group B (p = 0.001). CONCLUSION: Just after 2 years, the active medical observation tactics in patients at low and moderate risks (according to the SCORE scale) can result in a reduction in the rate of subclinical atherosclerosis progression in the carotid artery. PMID- 23091857 TI - [Prognostic value of pathogenetic therapy-induced changes in NT-proBNP in patients with chronic heart failure]. AB - AIM: To study the prognostic value of therapy-induced changes in plasma NT-proBNP levels in patients with left ventricular (LV) systolic dysfunction. SUBJECTS AND METHODS: The study covered 84 patients aged 23 to 70 years (mean 54 +/- 8.1 years) with LV systolic dysfunction (an ejection fraction of < 40%). Plasma NT proBNP levels were determined in all the patients at baseline and 3 months later to evaluate the efficiency of therapy for heart failure (HF). The median follow up was 18 months. The follow-up recorded the following outcomes (end points): death from decompensated HF and unplanned hospital admissions for progressive HF symptoms. RESULTS: The baseline and therapy high plasma levels of NT-proBNP (more than 3000 pg/ml) were associated with worsening prognosis. The therapy-induced decrease in NT-proBNP levels was associated with more favorable prognosis. CONCLUSION: Repeat dynamic determination of plasma NT-proBNP levels allows identification of patients at increased risk of poor outcomes for a more intensive observation and more aggressive pathogenetic therapy. PMID- 23091856 TI - [Vascular remodeling indicators and their impact on prognosis in patients with chronic heart failure]. AB - AIM: To estimate vascular remodeling indicators and their impact on prognosis in patients with chronic heart failure (CHF). SUBJECTS AND METHODS: The study enrolled 128 patients with prior myocardial infarction and CHF and 40 individuals as a comparison group. Endothelium-dependent and -independent vasodilation (EDV and EIDV) was studied in the reactive hyperemia (RH) test and nitroglycerin (NTG) test. Carotid artery (CA) intima-media thickness (IMT) and great arterial rigidity were studied. RESULTS: As compared to the control subjects, the patients with CHF were found to have EDV and EIVD reductions that were more pronounced in those with Functional Class IV CHF, more CA IMT, and abnormal arterial rigidity. There were relationships of EDV and EIDV to CA IMT (r = -0.30; p = 0.02) and aortic pulse wave velocity (APWV) (r = -0.30; p = 0.05). Multivariate analysis showed that the risk for cardiovascular events (CVE) in the CHF patients with an APWV of > 12 m/sec during a year was 2.02 times higher than in those with an APWV of < or = 12 m/sec (relative risk 2.02, 95 confidence interval, 1.01-4.03). CONCLUSION: APWV is an independent risk factor of CVE in patients with CHF. PMID- 23091859 TI - [Radionuclide evaluation of renal function in essential hypertensive patients with chronic kidney disease]. AB - AIM: To carry out radionuclide evaluation of renal function in patients with arterial hypertension (AH) and chronic kidney disease (CKD). SUBJECTS AND METHODS: Thirty-one AH patients with CKD were examined using dynamic nephroscintigraphy. A control group consisted of 8 CKD patients without AH. RESULTS: The scintigraphic findings reflected statistically significant differences in renal secretory and excretory functions depending on the level of glomerular filtration rate (GFR) decrease in AH patients with CKD. If GFR was 30 59 ml/min, there was a deceleration in the secretory phase in the histogram; but when it was lower than 30 ml/min, the secretory function tended to accelerate, which appeared as a 3-fold reduction in achieving the peak radio tracer concentration (p < 0.001). CONCLUSION: Dynamic nephroscintigraphy can detect early renal secretory and excretory dysfunctions and it is of prognostic value in assessing renal dysfunction, which necessitates early drug correction of revealed disorders. PMID- 23091858 TI - [Total risk for coronary events in cardiac patients due to snoring, daytime drowsiness, and obstructive sleep apnea syndrome]. AB - AIM: To assess the risk of cardiovascular events due to obstructive sleep apnea syndrome (OSAS) in persons without organic heart diseases. SUBJECTS AND METHODS: Two hundred and forty men complaining about their sleep snoring and/or daytime drowsiness and 209 men without this symptomatology were examined. The presence of OSAS was verified by cardiorespiratory monitoring. Blood lipid composition, blood pressure, heart rate, and body mass index were determined in all the examinees. The risk for cardiovascular diseases (CVD) was assessed using the SCORE and PROCAM scales. RESULTS: When only the subjective manifestations of OSAS were present, there was a preponderance of hypercholesterolemia and an increased risk for CVD as possible markers of preclinical atherosclerosis. Hypertension and smoking, as well as a combination of 4 traditional CVD risk factors are recognized the worst. At the same time, the PROCAM scale allows identification of a high-risk group, the size of which is 1.6 times more than that of the group rated by the SCORE scal CONCLUSION: OSAS is an important CVD risk factor and the PROCAM scale is more preferable to identify a group at high risk for CVD among subjects with OSAS. PMID- 23091860 TI - [Possibilities of using levosimendan in patients with idiopathic pulmonary hypertension]. AB - AIM: To evaluate the efficiency and safety of intravenous infusion of levosimendan in patients with idiopathic pulmonary hypertension (IPH) and its clinical, hemodynamic, and neurohumoral effects. SUBJECTS AND METHODS: The study included 9 patients (mean age 31.8 +/- 8.7 years) with Functional Class III and IV IPH and severe right ventricular failure (RVF). Levosimendan was administered as dropwise intravenous infusion. The patients' general condition, blood pressure, heart rate, and 6-minute walk test results were assessed at baseline and 24 hours after levosimendan infusion, and then following 12 weeks. The time course of changes in blood neurohumoral mediators was determined and transthoracic echocardiography performed. RESULTS: At 24 hours after initiation of levosimendan infusion, there were substantial reductions in pulmonary artery systolic pressure, mean pulmonary artery pressure, mean right atrial pressure, and pulmonary vascular resistance. There was a significant increase in exercise tolerance. The blood exhibited lower norepinephrine and NT-proBNP and higher epinephrine concentrations. At 12 weeks after termination of levosimendan infusion, the improved functional status was preserved in the patients with IPH. There were no noticeable changes in the achieved key hemodynamic parameters. Only one patient needed re-administration of the drug 12 weeks later. The achieved changes in vasoactive mediators were retained 12 weeks following levosimendan infusion. Levosimendan treatment was not followed by clinically relevant adverse reactions requiring infusion termination and therapy discontinuation. CONCLUSION: 24-hour intravenous levosimendan infusion in patents with FC III-IV IPH and severe RVF causes positive changes in the key hemodynamic parameters and neurohumoral status of the patients and promotes stabilization in those with IPH at 12-week follow-up. PMID- 23091861 TI - [Pulmonary hypertension in rheumatic heart disease: current approaches to diagnosis and therapy]. AB - Pulmonary hypertension is a complex multidisciplinary problem in modern medicine. This review discusses its clinical and pathophysiological type associated with rheumatic heart disease. Current approaches to the pathogenesis and diagnosis of the disease are reflected; basic approaches to its treatment are discussed in terms of current clinical guidelines and new scientific achievements. PMID- 23091862 TI - [The pathogenetic bases of cardiorenal syndrome]. AB - The term "cardiorenal syndrome" has been introduced to denote the mutual influences of the cardiovascular system and kidneys. According to the definition, the cardiorenal syndrome is a pathophysiological condition of the heart and kidney, in which acute or chronic dysfunction of one of these organs leads to that of the other. The community of pathogenetic components allows one to apply a comprehensive approach to diagnosing, treating, and preventing cardiovascular and renal diseases. PMID- 23091863 TI - [Sergey Petrovich Botkin is the founder of Russian therapeutic school]. AB - The paper gives basic facts from the life and work of Sergey Petrovich Botkin, one of the coryphaei of Russian medicine, who played a prominent role in the formation and development of Russian clinical medicine and became the founder of the most well-known therapeutic school in Russia. S.P. Botkin's greatest merit is emphasized to be his neurogenic theory of medicine, which has played a great role in the understanding of physiological and pathological processes in the entire organism. PMID- 23091864 TI - Few women are exercising one year after heart attack. Failure to make healthy lifestyle changes could jeopardize their future. PMID- 23091865 TI - Understand how some medications can lower your triglycerides. PMID- 23091866 TI - I take glucosamine and chondroitin every day for my knees. Will it interfere with any of my heart medications? PMID- 23091867 TI - Can taking statins to help control my cholesterol cause diabetes? PMID- 23091868 TI - I am considering using an on-line pharmacy to get my heart medications at less cost. Are there any drawbacks with this? PMID- 23091869 TI - Last week, I had chest pain and called 911. The hospital did a lot of tests, and said it wasn't a heart attack. Could this be so? What should I do if it happens again? PMID- 23091870 TI - New device lowers post-surgery blood clot risk. It's especially helpful for hip surgery patients who must remain flat for an extended period after the operation. PMID- 23091871 TI - I'm 79 and I have a pacemaker. Soon after receiving my first one, I developed persistent atrial fibrillation. In the past few months, though, I have had eight episodes of ventricular tachycardia. Within a year, my pacemaker battery will be exhausted and I'll need a replacement. What would be the benefit of an ICD over continuing with a pacemaker, or would there be any advantage? PMID- 23091872 TI - I sometimes notice that my pulse...but I don't feel my heart pounding....I keep my blood pressure under control with medications and exercise. Why then would my pulse be going fast when my heart seems to be pumping normally? PMID- 23091873 TI - Notch signaling pathway and human placenta. PMID- 23091874 TI - When patient health is at risk, doctors would do well to follow the example of their California peers. PMID- 23091875 TI - Binuclear manganese (III) complexes as electron donors in D1/D2/cytochrome b559 preparations isolated from spinach photosystem II membrane fragments. AB - The capability of different manganese complexes to act as PS II electron donors in D1/D2/cytochrome b559 complexes has been analyzed by measuring actinic light induced absorption changes at 680 nm (650 nm) and 340 nm, reflecting the photoaccumulation of Pheophytin- (Pheo-) and the reduction of NADP+, respectively. The data obtained revealed: a) the donor capacity of synthetic binuclear Mn (III)2complexes containing aromatic ligands significantly exceeds that for MnCl2 in both cases, i.e. Pheo- photoaccumulation and NADP+ reduction; b) manganese complexes can serve as suitable electron donors for light-induced NADP+ reduction catalyzed by D1/D2/cytochrome b559 complexes and ferredoxin plus ferredoxin-NADP+ reductase under anaerobic conditions and c) the specific turnover rate of the system leading to NADP+ reduction is extremely small. The implications of these findings are briefly discussed. PMID- 23091876 TI - Acute gastrointestinal syndrome in high-dose irradiated mice. AB - The most detailed reports of the response of the gastrointestinal system to high dose acute radiation have focused mainly on understanding the histopathology. However, to enable medical countermeasure assessment under the animal rule criteria, it is necessary to have a robust model in which the relationship between radiation dose and intestinal radiation syndrome incidence, timing, and severity are established and correlated with histopathology. Although many mortality studies have been published, they have used a variety of mouse strains, ages, radiation sources, and husbandry conditions, all of which influence the dose response. Further, it is clear that the level of bone marrow irradiation and supportive care can influence endpoints. In order to create robust baseline data, the authors have generated dose response data in adult male mice maintained under identical conditions and exposed to either total or partial-body irradiation. Partial-body irradiation includes both extensive (40%) and minimal (5%) bone marrow sparing models, the latter designed to correlate with an established primate model and allow assessment of effects of any medical countermeasure on all three major radiation syndromes (intestinal, bone marrow, and lung) in the surviving mice. Lethal dose (LD(30), LD(50), and LD(70)) data are described in the various models, along with the impact of enteric flora and response to supportive care. Correlation with diarrhea severity and histopathology are also described. These data can be used to aid the design of good laboratory practice (GLP)-compliant Animal Rule studies that are reflective of the conditions following accidental radiation exposure. PMID- 23091878 TI - Development and dosimetry of a small animal lung irradiation platform. AB - Advances in large scale screening of medical countermeasures for radiation induced normal tissue toxicity are currently hampered by animal irradiation paradigms that are both inefficient and highly variable among institutions. Here, a novel high-throughput small animal irradiation platform is introduced for use in orthovoltage small animal irradiators. Radiochromic film and metal oxide semiconductor field effect transistor detectors were used to examine several parameters, including 2D field uniformity, dose rate consistency, and shielding transmission. The authors posit that this setup will improve efficiency of drug screens by allowing for simultaneous targeted irradiation of multiple animals to improve efficiency within a single institution. Additionally, they suggest that measurement of the described parameters in all centers conducting countermeasure studies will improve the translatability of findings among institutions. The use of tissue equivalent phantoms in performing dosimetry measurements for small animal irradiation experiments was also investigated. Though these phantoms are commonly used in dosimetry, the authors recorded a significant difference in both the entrance and target tissue dose rates between euthanized rats and mice with implanted detectors and the corresponding phantom measurement. This suggests that measurements using these phantoms may not provide accurate dosimetry for in vivo experiments. Based on these measurements, the authors propose that this small animal irradiation platform can increase the capacity of animal studies by allowing for more efficient animal irradiation. They also suggest that researchers fully characterize the parameters of whatever radiation setup is in use in order to facilitate better comparison among institutions. PMID- 23091877 TI - Evidence of delayed gastrointestinal syndrome in high-dose irradiated mice. AB - The acute effects of irradiation on the gastrointestinal (GI) system are well documented, but the longer-term effects are less well known. Increased incidence of adenocarcinoma has been noted, but apart from descriptions of fibrosis, the development of other pathologies specific to survivors of acute radiation is poorly understood. Samples were taken from C57BL/6 mice irradiated with partial body irradiation where the thorax, head, and forelimbs were shielded (i.e., sparing 40% of the bone marrow). Tissue from age-matched controls was also collected. There were clear pathological changes in the intestine associated with DEARE (Delayed Effects of Acute Radiation Exposure) at doses greater than 12 Gy, with a dose-related increase in observed pathologies. Mice maintained on the synthetic antibiotic ciprofloxacin during the acute phase (days 4 to 20), however, had a lower or delayed incidence of symptoms. After 20 d, mice developed structures similar to early adenomas. Abnormally high levels of apoptotic and mitotic cells were present in some crypts, along with the early adenomas, suggesting tissue regeneration and areas of deregulated cell turnover. Over time, there was inhibited crypt cell proliferation in animals with advanced symptoms, a blunting of the crypts and villi, and an enlargement of villus girth, with an increasingly acellular and fibrotic extracellular matrix (a characteristic that has been demonstrated previously in aging mice). Together these changes may lead to a reduced functional surface area and less motile intestine. These observations are similar to those seen in geriatric animals, suggesting a premature aging of the GI tract. PMID- 23091879 TI - HIV treatment strategies. PMID- 23091880 TI - Jamar's voice. Interview by Jeff Berry. PMID- 23091881 TI - PrEP'ing. PMID- 23091882 TI - Leather, porn, and kink. PMID- 23091883 TI - Exploring the therapist's use of self: enactments, improvisation and affect in psychodynamic psychotherapy. AB - Psychoanalytic psychotherapists, drawing upon intersubjective and attachment theories, recognize that mutual influence impacts the treatment process. Mutual influence generates enactments--emotionally intense joint creations stemming from the unconscious of both therapist and patient--which often leave both patient and therapist feeling confused and stuck. The author presents a case in which the therapist's use of improvisational role play was a critical therapeutic response to an enactment. The therapist's self-expression through the displacement of the role play 1) modeled a safe, affectively genuine engagement in relationship, 2) provided the patient with an unexpected and powerful window into the therapist's emotional world, 3) shifted the patient's fundamental belief that fathers and men are cold and unfeeling, and 4) led the patient to uncover "new" early memories and to become aware of his role as an agent of vitality and intimacy. The author concludes that using improvisation as a flexible response to rigid patterns of enactment may provide a catalyst for therapeutic change. PMID- 23091884 TI - Some limitations on the external validity of psychotherapy efficacy studies and suggestions for future research. AB - Increased emphasis on identifying empirically supported treatments (ESTs) has enhanced the scientific basis for psychotherapy practice, but uncritical acceptance of ESTs as the basis for credentialing and policy decisions risks stifling innovation and creativity in the field. There are limitations inherent in efficacy studies of psychotherapy that can constrain external validity. This article discusses several limitations on the external validity of efficacy studies, as well as other issues related to evaluating psychotherapy outcome research. These limitations and concerns include: 1) the practice of maximizing homogeneity by selecting participants diagnosed with a single Axis I disorder; 2) the practice of requiring manualized therapies for efficacy research; 3) the assumption that lasting and meaningful changes occur and can be assessed within a relatively short time frame; 4) the assumption that valid assessments of outcome can be conducted in randomized control trials studies without concern for researcher allegiance; and 5) the view that evidence of effectiveness from non RCT design studies can be ignored. Finally, alternative research approaches for studying psychotherapy that can potentially supplement knowledge gained from efficacy studies and foster continued innovation and creativity in the field are discussed. PMID- 23091885 TI - Five analogies between a King's Speech treatment and contemporary play therapies. AB - OBJECTIVE: Psychiatric patients frequently respond positively to play therapy, which may rely on psychoanalytic, Jungian, cognitive-behavioral, familial, school based, or other theories. I wished to determine if there were unifying principles that tie together these various types of play treatments. METHODS: The fact-based film, The King's Speech, vividly illustrates play utilized by Lionel Logue in his speech treatment (1926-1939) of the future King of England. In the film I found five analogies to the play therapy I employ in office practice. RESULTS: The play scenes in The King's Speech point to five unifying principles among contemporary play therapies: (1) the crucial nature of the relationship, (2) the centrality of having fun, (3) the occasional reliance on others, (4) the interjection of pithy talk, and (5) the usefulness of a little drama. CONCLUSION: No matter what theory a play therapist ascribes to, these five unifying principles should be kept in mind during treatment. PMID- 23091886 TI - Emotional stocks and bonds: a metaphorical model for conceptualizing and treating codependency and other forms of emotional overinvesting. AB - Codependent behaviors are associated with an unhealthy reliance on others for meeting emotional needs. This over-reliance on others often leads to dysfunctional interpersonal relationships. This article presents emotional stocks and bonds (ESB), a metaphorical model for use with clients who display codependent behaviors. Emotional stocks and bonds incorporates theoretical tenets from Bowen family systems and attachment theory and aids clients in understanding and changing unhealthy relationship behavior patterns. In addition to an overview of the model's key concepts and its use in clinical practice, we provide a case illustration and a discussion of practice implications and limitations. PMID- 23091887 TI - Educating psychotherapy supervisors. AB - What do we know clinically and empirically about the education of psychotherapy supervisors? In this paper, I attempt to address that question by: (1) reviewing briefly current thinking about psychotherapy supervisor training; and (2) examining the available research where supervisor training and supervision have been studied. The importance of such matters as training format and methods, supervision topics for study, supervisor development, and supervisor competencies are considered, and some prototypical, competency-based supervisor training programs that hold educational promise are identified and described. Twenty supervisor training studies are critiqued, and their implications for practice and research are examined. Based on this review of training programs and research, the following conclusions are drawn: (1) the clinical validity of supervisor education appears to be strong, solid, and sound, (2) although research suggests that supervisor training can have value in stimulating the development of supervisor trainees and better preparing them for the supervisory role, any such base of empirical support or validity should be regarded as tentative at best; and (3) the most formidable challenge for psychotherapy supervisor education may well be correcting the imbalance that currently exists between clinical and empirical validity and "raising the bar" on the rigor, relevance, and replicability of future supervisor training research. PMID- 23091888 TI - Longitudinal outcomes of high-risk human papillomavirus (HPV) infections as competing-risks events following cervical HPV test at baseline visit in the NIS LAMS cohort. AB - BACKGROUND: The complex natural history of human papillomavirus (HPV) infections following a single HPV test can be modeled as competing-risks events (i.e., no-, transient- or persistent infection) in a longitudinal setting. The covariates associated with these competing events have not been previously assessed using competing-risks regression models. OBJECTIVES: To gain further insights in the outcomes of cervical HPV infections, we used univariate- and multivariate competing-risks regression models to assess the covariates associated with these competing events. STUDY DESIGN AND METHODS: Covariates associated with three competing outcomes (no-, transient- or persistent HR-HPV infection) were analysed in a sub-cohort of 1,865 women prospectively followed-up in the NIS (n = 3,187) and LAMS Study (n = 12,114). RESULTS: In multivariate competing-risks models (with two other outcomes as competing events), permanently HR-HPV negative outcome was significantly predicted only by the clearance ofASCUS+ Pap during FU, while three independent covariates predicted transient HR-HPV infections: i) number of recent (< 12 months) sexual partners (risk increased), ii) previous Pap screening history (protective), and history of previous CIN (increased risk). The two most powerful predictors of persistent HR-HPV infections were persistent ASCUS+ Pap (risk increased), and previous Pap screening history (protective). In pair-wise comparisons, number of recent sexual partners and previous CIN history increase the probability of transient HR-HPV infection against the HR-HPV negative competing event, while previous Pap screening history is protective. Persistent ASCUS+ Pap during FU and no previous Pap screening history are significantly associated with the persistent HR-HPV outcome (compared both with i) always negative, and ii) transient events), whereas multiparity is protective. CONCLUSIONS: Different covariates are associated with the three main outcomes of cervical HPV infections. The most significant covariates of each competing events are probably distinct enough to enable constructing of a risk-profile for each main outcome. PMID- 23091889 TI - Efficacy of neoadjuvant chemotherapy followed by radical hysterectomy in locally advanced non-squamous carcinoma of the uterine cervix: a retrospective multicenter study of Tohoku Gynecologic Cancer Unit. AB - OBJECTIVE: Radical hysterectomy (RH) is a standard treatment for locally advanced non-squamous cell carcinoma (N-SCC) of the uterine cervix, but there have been no reports on whether neoadjuvant chemotherapy (NAC) followed by radical hysterectomy could improve the outcome of patients with this disease. MATERIALS AND METHODS: This multicenter retrospective study enrolled 77 patients with Stage IB2 to IIB N-SCC of the uterine cervix. Of these, 27 patients were treated with NAC prior to radical hysterectomy (NAC group) and 50 with RH alone (RH group). The two-year recurrence-free survival (RFS) rate, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Clinical parameters such as clinical stage, histological type, and postoperative treatment were also examined between the groups. RESULTS: While the two-year RFS rates were 81.5% and 70.0% in NAC and RH groups, respectively (p = 0.27) and the median PFS was 51 months and 35 months in NAC and RH groups, respectively (p = 0.35), the median OS was 58 months and 48 months in NAC and RH groups, respectively, which was significant (p = 0.0014). The median OS of patients with mucinous adenocarcinoma in NAC group was significantly higher than that in RH group: 58 months versus 37 months (p = 0.03). CONCLUSION: NAC prior to RH may offer the prognostic advantage of patients with locally advanced N-SCC of the uterine cervix, especially mucinous adenocarcinoma. PMID- 23091890 TI - Expression of p53, p27 and Jab1 protein in epithelial ovarian tumors. AB - OBJECTIVE: The study aimed to investigate expression of p53, p27 and Jun activation domain-binding protein 1 (Jab1) proteins in epithelial ovarian tumors and the values of these factors as discriminating markers for the transformation of borderline tumors to cancers. METHODS: Forty-seven cases of paraffin-embedded tissues of epithelial ovarian tumors including 22 cases of benign ovarian tumors, nine cases of borderline tumors, and 16 cases of invasive cancers were used to evaluate expression of p53, p27 and Jab1 proteins by immunohistochemical methods. RESULTS: p53 protein was expressed in 13.6% of the benign tumors, 44.4% of the borderline tumors and 62.5% of the malignant tumors and p27 protein was expressed in 95.5% of the benign tumors, 66.7% of the borderline tumors, and 37.5% of the malignant tumors. Expression of Jab1 protein was observed in 22.7% of the benign tumors, 77.8% of the borderline tumors and 62.5% of the malignant tumors. Expressions of p53, p27 and Jab1 proteins in malignant tumors were all higher than in benign tumors and the expression of p27 protein in malignant tumors was lower than in benign tumors (p < 0.05). Expression of Jab1 protein in borderline tumors was significantly higher than in benign tumors (p < 0.05). CONCLUSIONS: Expression of p53, p27 and Jab1 proteins can be used to discriminate between benign and malignant tumors in epithelial ovarian tumors. PMID- 23091891 TI - Expression of inflammatory cytokines by adipose tissue from patients with endometrial cancer. AB - Obesity results in increased mortality from many forms of cancer. We looked at the levels of gene expression for TNFalpha, IL-6, IkappaB kinase (inhibitor of NF kappaB), CD 68 (glycoprotein expressed on macrophages) and leptin in samples of adipose tissue from individuals with endometrial cancer versus patients with benign conditions. This is a prospective study which included patients of a gynecologic oncology group. A piece of omental tissue was harvested from them during surgery. RNA was purified from all samples. Relative amounts of RNA for IkappaB, TNFalpha, IL-6, CD68 and leptin were calculated. Pearson's correlation method was used to correlate RNA levels with BMI. Logistic regression method was used to compare gene expression for cancer and control groups. The total sample size was 56 (24 endometrial cancer and 32 controls). IkappaB, TNFalpha and IL-6 levels increased linearly with increasing BMI in the control group. There was no correlation of IkappaB, TNFalpha, IL-6 or CD-68 levels with cancer status of the patients. Leptin had a weak protective effect against endometrial cancer (odds ratio = 0.92). Obesity is associated with increased expression of certain inflammatory cytokines in the adipose tissue. However, increased levels of these inflammatory markers in the adipose tissue of the omentum are not associated with presence of endometrial cancer. PMID- 23091892 TI - Wortmannin inhibits proliferation and induces apoptosis of MCF-7 breast cancer cells. AB - OBJECTIVE: The present study aimed to explore the effects of wortmannin in the proliferation and apoptosis of human breast cancer MCF-7 cells. METHODS: The authors treated cells with 0, 1, 6.25, 12.5, 25, and 50 nM wortmannin for 24, 48, and 72 hours. Inhibition of proliferation was measured by cell counting kit-8 assay (CCK8). Apoptosis was detected with Annexin V-fluorescein isothiocyanate/propidium iodide double staining by flow cytometry. Additionally, expression of proteins involved in the PI3K pathway, specifically total Akt, phosphorylated Akt (p-Akt), and NF-kappaB was detected by Western blotting following 24 hours of wortmannin exposure. RESULTS: Higher doses (6.25, 12.5, 25, and 50 nM) of wortmannin significantly inhibited proliferation of MCF-7 cells after 24, 48, and 72 hours of exposure compared with control MCF-7 cells incubated with DMSO alone in DMEM (p < 0.05). This inhibition increased with concentration and duration of treatment. Similarly, wortmannin at 6.25, 12.5, 25, and 50 nM concentrations significantly increased apoptosis of MCF-7 cells following 24 hours of exposure (p < 0.05). Western blotting revealed that increasing concentrations of wortmannin (6.25, 12.5, 25, and 50 nM, 24 hours) increasingly reduced expression of p-Akt and NF-kappaB; however, expression of total Akt was unaffected at any concentration of wortmannin. CONCLUSIONS: Wortmannin inhibits proliferation and induces apoptosis of MCF-7 cells in a dose and time-dependent manner, likely through down-regulation of PI3K/Akt signaling and NF-kappaB protein expression. PMID- 23091893 TI - Effective multidisciplinary treatment for ovarian granulosa cell tumor with multiple metastases--a case report. AB - Ovarian granulosa cell tumor (GCT) is among the ovarian sex-cord stromal tumors that are classified as borderline malignancies. We report a case of GCT with multiple metastases for which multidisciplinary treatment including surgery, chemotherapy and radiotherapy was effective. A 41-year-old woman underwent left salpingo-oophorectomy because of an ovarian tumor in 2004. Final pathology confirmed a granulosa cell tumor adult type, FIGO Stage IC. In 2008, tumorectomy of the lower abdominal wall metastases was also performed. After three cycles of BEP chemotherapy for metastases of the right lung, liver, paraaortic lymph node and rectus, surgical resection was performed in 2009. In 2010, local radiation was performed for the first lumbar vertebral metastasis. Ovarian GCTs exhibit slow growth but if the surgical stage is IC or higher, there is the possibility of recurrence. It is important to treat recurrent tumors with the combination of surgery, chemotherapy, and radiation therapy. PMID- 23091894 TI - Laparoscopic versus laparotomic approach to endometrial cancer. AB - OBJECTIVE: The aim of our study was to compare the feasibility, morbidity, long term safety, disease-free survival, and overall survival of the laparoscopic (LPS) approach to early-stage endometrial cancer (EC) compared to the traditional laparotomic approach. METHODS: We reviewed retrospective data of patients who underwent primary surgery from 1997 to 2009. We recorded clinical parameters, surgical stage, histological type, operative and peri-operative complications, time to resumption of normal functions, conversion to laparotomy, overall survival, and disease-free survival. RESULTS: LPS, did not increase operative risk and peri-operative complications even in obese and older women. The number of pelvic lymph and aortic nodes removed was similar for the two groups. One hundred and eight patients had a follow-up of 60 months. The two groups were similar for disease-free survival and overall survival. CONCLUSIONS: Laparoscopic approach to EC provides a reduction in postoperative complications and hospital stay compared to the laparotomic approach. PMID- 23091895 TI - Human epididymal protein 4 (HE4) is a novel biomarker and a promising prognostic factor in ovarian cancer patients. AB - PURPOSE OF INVESTIGATION: The aim of this work was to compare serum concentrations of HE4 in patients with benign and malignant epithelial tumors and to determine the association of preoperative concentrations of HE4 with some clinicopathologic factors. METHODS: We enrolled 94 patients, including 39 females with freshly diagnosed ovarian cancer. HE4 concentrations were measured with ELISA HE4 EIA assay from Fujirebio Diagnostics. RESULTS: Serum concentrations of HE4 differed significantly in patients with ovarian cancer (324.1 pM) compared with benign epithelial tumors (26.1 pM; p < 000.1). There was also a significant difference between HE4 concentrations at diagnosis of ovarian cancer (324.1 pM) and in patients with complete clinical remission (23.3 pM; p < 0.0001). Patients with poorly differentiated tumors had significantly higher concentrations of HE4. Preoperative HE4 levels were higher in patients in whom relapse was noted and who died before the end of the two-year follow-up period. CONCLUSION: On the basis of these findings and reports in the literature it appears likely that HE4 can complement CA125 in the monitoring of therapy in ovarian cancer and may also serve for prognostication. PMID- 23091896 TI - Model for predicting the burden and cost of treatment in cervical cancer and HPV related diseases in Thailand. AB - PURPOSE: Cervical cancer is a significant health burden in many countries. Long term cost of care is still not well understood. We aimed to evaluate the long term burden of illness and healthcare resource utilization associated with cervical cancer, cervical intraepithelial neoplasia (CIN) and genital warts from the care provider perspective. METHOD: We developed a health state-transition Markov model to portray the algorithm of treatment of stages of cervical cancer, CIN and genital warts by tracking a hypothetical lifetime cohort of 12-year-old girls. Costs in this study were unit cost; capital costs and labor costs were included in the unit cost for inpatients and out-patients. RESULTS: The highest incidence of CIN and genital warts was observed in women aged 20-30 years old. For cervical cancer, the highest incidence was 45-55 years. Death rate was estimated at 2%, 8%, 84% and 94% in cervical cancer Stage IA1, IA2-IIA, IIB-IVA and IVB, respectively. The estimated mean direct cost per patient with cervical cancer Stage IA1, IA2-IIA, IIB-IVA, IVB, CIN1, CIN2/3 and genital warts were 41,117 Thai Baht ($1,277 US), 97,250 Thai Baht ($3,020 US), 402,683 Thai Baht ($12,506 US), 322,619 Thai Baht ($10,019 US), 5,381 Thai Baht ($167 US), 49,933 Thai Baht ($1.551 US) and 3,585 Thai Baht ($111 US), respectively. Cost for survival or death case was indifferent. The overall lifetime costs from the provider perspective were evaluated at 859.1 million Baht ($26.7 million US) per a cohort of 100,000 women which corresponds to approximately 4,244 million Baht ($131.8 million US) for the current number of Thai 12-year-old girls. CONCLUSIONS: HPV-related diseases impose health and cost burdens in Thailand. The national immunization programme to reduce this burden as well as further research to evaluate the impact is keenly expected. PMID- 23091897 TI - Laparoscopic surgery compared to traditional abdominal surgery in the management of early stage cervical cancer. AB - The purpose of the study was to compare laparoscopic total radical hysterectomy with classic radical hysterectomy regarding parametrial, and vaginal resection, and lymphadenectomy. METHODS: Laparoscopic or laparotomic total radical hysterectomy with advantages and disadvantages was offered to the patients diagnosed as having operable cervical cancer between 2007 and 2010. Lymph node status, resection of the parametria and vagina, and margin positivity were recorded for both groups. Data were collected prospectively. Statistical analysis was performed with the SPSS statistical software program. RESULTS: Totally, 53 cases had classical abdominal radical hysterectomy and 35 laparoscopic radical hysterectomy, respectively. Parametrial involvement was detected in four (11.4%) cases in laparoscopic radical surgery versus nine (16.9%) in laparatomic surgery. All the cases with parametrial involvement had free surgical margins of tumor. Also there were no significant statistical differences in lymph node number and metastasis between the two groups. CONCLUSION: There is no difference in anatomical considerations between laparoscopic and laparatomic radical surgery in the surgical management of cervical cancer. PMID- 23091898 TI - Labeling of microvessel density, lymphatic vessel density and potential role of proangiogenic and lymphangiogenic factors as a predictive/prognostic factors after radiotherapy in patients with cervical cancer. AB - INTRODUCTION: Angiogenesis, formation of a new blood vessel from the existing vascular network, is essential for tumor growth, progression and metastasis. Vascular endothelial growth factor (VEGF) has been identified to be one of the most important factors of angiogenesis. VEGF-C, a novel member of the family, is a relatively specific lymphangiogenic growth factor. It is tempting to suggest that cervical cancer is one of the most common malignancies in a woman's life. Its prognostic factors are tumor stage, lymph node status, histologic type, level of hemoglobin. However, little is known about prognostic or/and predictive significance of angiogenesis in cervical cancer. OBJECTIVE: This prospective study is an attempt to evaluate serum VEGF-A, VEGF-C, microvessel density (MVD), and lymphatic vessel density (LMVD) in cervical cancer and the correlations with clinicopathologic features. MATERIAL AND METHODS: Blood samples were collected from 58 patients affected by FIGO I-IV stage cervical cancer, who were admitted to the Department of Oncology and Brachytherapy Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University. Serum VEGF-A/VEGF-C concentrate was determined by means of a quantitative sandwich enzyme immunoassay (ELISA). All tumor samples were taken from cross section during the first brachytherapy. Then they were examined by immunohistochemical studies with podoplanin antibody and anti-CD31 antibody. The present analysis was used to evaluate MVD and LMVD. RESULTS: The median serum VEGF-A was 734.76 pg/ml (range from 86.39 pg/ml - 2200.00 pg/ml), and VEGF-A was only correlated with after treatment hemoglobin concentration (p = 0.046, R = -0.3450). The median serum VEGF-C was 145.72 pg/ml (range 131.08 - 233.60 pg/ml). Serum VEGF-C levels measured in patients were associated with primary tumor size. We observed significantly higher serum VEGF-C in localized disease (FIGO I, II) in comparison to advanced tumors (232.44 pg/ml vs 152.45 pg/ml; p = 0.034). The median LMVD was 6.25 (range 3.5-10.0) and median blood vessel density was 12.5 (range 9.5-23.0). We found significantly higher lymphatic vessel density in patients with Gl/G2 grade of differentiation than in those with G3 (9.93 vs 6.25; p = 0.0398). We observed a statistically significant correlation between MVD and LMVD; (p = 0.032). CONCLUSION: In conclusion, our study suggests that serum VEGF-A, VEGF-C, LMVD and MVD play an important role in tumor growth and progression in cervical cancer. Nonetheless, further studies are essential to explore the underlying mechanism. PMID- 23091899 TI - A single nucleotide polymorphism in the 5' untranslated region of RAD51 and ovarian cancer risk in Polish women. AB - BACKGROUND: DNA repair gene polymorphisms are known to influence cancer risk. The RAD51 gene encodes proteins essential for maintaining genomic stability by playing a central role in holmology-dependent recombinational repair of the DNA double-strand breaks. Aims. We investigated the association of polymorphisms in the DNA repair genes RAD51-135G > C and 172G >T with ovarian cancer risk. METHODS: 120 Polish ovarian cancer patients and 120 healthy controls were genotyped for RAD51 (135G > C and 172G > T) by PCR-RFLP. RESULTS: In the present work no association was detected between ovarian cancer risk and 172G > T polymorphism of the RAD51 gene. The 135G > C polymorphism was associated with ovarian cancer risk. We found evidence of an increased ovarian cancer risk in CC homozygotes (OR 12.97 [95% confidence interval {CI} (5.73-29.36)]) but not in heterozygotes (OR 0.55 [95% CI 0.23-1.29]). We demonstrated a significant positive association between the RAD51 variant 135C allele and ovarian carcinoma, with an adjusted odds ratio (OR) of 6.24 (p < .0001). CONCLUSION: The results indicated that the polymorphism 135G > C of RAD51 may be positively associated with ovarian carcinoma in the Polish population. Further studies on the role of the RAD51 gene on ovarian cancer are warranted. PMID- 23091900 TI - Metastatic bone involvement in vulvar cancer: report of a rare case and review of the literature. AB - PURPOSE: Bone metastasis secondary to vulvar carcinoma is an infrequent clinical entity. Only ten cases have been published in the literature. We describe a case of squamous vulvar carcinoma, that presented with cervical vertebral involvement, as a part of distant spread. CASE: A 69-year-old woman presented with radicular pain and a painful cervical mass. MRI of the cervical spine was performed, showing an osteolytic lesion with spinal cord compression. CONCLUSION: This case was unique in presenting vertebral metastasis eight months after chemotherapy and radiotherapy. PMID- 23091901 TI - Large cell neuroendocrine carcinoma arising in mature cystic teratoma: a case report and review of the literature. AB - BACKGROUND: Malignant transformation of ovarian mature cystic teratoma is rare, and occurs in approximately 1% of all cases. The most common histology arising in mature cystic teratoma is squamous cell carcinoma. Less frequently, malignant transformation is represented by an endocrine tumor. To date, only five cases of large cell neuroendocrine carcinoma (LCNC) arising in a mature cystic teratoma of the ovary have been reported. CLINICAL CASE: A 69-year-old woman presented with a 15-cm left ovarian mass, and was diagnosed with Stage IV large cell carcinoma neuroendocrine carcinoma (LCNC) arising in mature cystic teratoma (MCT) of the left ovary. The patient received adjuvant chemotherapy with paclitaxel and carboplatin, however, residual tumors increased in size. Six months after the debulking surgery she succumbed to the disease. A literature review revealed LCNC of the ovary showed excessively aggressive phenotype in malignant transformation from ovarian mature cystic teratoma. CONCLUSION: The present case of LCNC arising in MCT had an exceedingly poor prognosis, which was suggested in the previous five cases reported. PMID- 23091902 TI - Successful response to docetaxel treatment in recurrent ovarian granulosa cell tumor: a case report. AB - BACKGROUND: Ovarian granulosa cell tumor (GCT) is primarily treated surgically. Treatment for advanced or recurrent disease includes primary or adjuvant chemotherapy. Data about the efficacy of treatment with paclitaxel are limited, without data about the role of docetaxel in treating recurrent GCT. CASE: A 68 year-old patient with Stage IA ovarian GCT diagnosed ten years earlier, presented with a third episode of recurrent disease. Following the first event of recurrent disease, she underwent a second laparotomy followed by BEP chemotherapy. Because of new liver masses, she was treated with paclitaxel, with complete response. Following diagnosis of new liver lesions, third-line chemotherapy with docetaxel was initiated, resulting in stable disease and a PFI of 24 months. CONCLUSION: Docetaxel might be a good alternative for treating recurrent GCT. PMID- 23091903 TI - Cisplatin-gemcitabine as palliative chemotherapy in advanced squamous vulvar carcinoma: report of two cases. AB - Vulvar cancer (VC) is a rare disease, usually diagnosed in a stage still amenable to potentially curative treatments, including surgery and/or radiation therapy with or without chemotherapy. Several patients however present at diagnosis with metastatic disease and another 30-50% will relapse. Prognosis of metastatic or recurrent disease not amenable to salvage surgery or radiotherapy is very poor. Evidence about the efficacy of chemotherapy in this setting is limited and its role still remains unclear. At present there is no standard treatment for advanced VC and patients are usually treated with schedules adopted for chemoradiation or extrapolated from cervical cancer. We report our experience using a cisplatin-gemcitabine regimen in two cases of metastatic squamous cell VC. No response was obtained with this schedule. No other data are available in the literature about the choice of a cisplatin-gemcitabine regimen in this patient subset. The paucity of evidence about the role of palliative chemotherapy in metastatic VC justifies any effort to implement knowledge. For this reason we think it is notable to also report a negative experience. It is not possible for us to conclude that this chemotherapy would be unable to provide any benefit in a larger sample of patients; nonetheless we think that new agents, rather than combinations of older drugs, could hopefully provide more benefit. PMID- 23091904 TI - A case of extramedullary solitary plasmacytoma arising at the uterine cervix. AB - Extramedullary plasmacytomas are localized plasma cell neoplasms that arise in tissues other than bone and bone marrow. Primary plasmacytomas of the female genital tract are extremely rare and present a substantial diagnostic challenge. We report a case of a 38-year-old woman who presented with an endocervical polypoid. Surgical removal of the polyp was carried out. The final pathological report revealed primary plasmacytoma of the uterine cervix. The diagnosis was further facilitated by the use of immunohistochemistry and clonal immunoglobulin heavy-chain gene rearrangement. We performed a simple hysterectomy by laparoscopy on the patient and kept a close follow-up. She has remained well for more than eight years. The clinical characteristics and histopathologic findings of plasmacytoma of the uterine cervix are discussed. PMID- 23091905 TI - Primary endometrial natural killer (NK)/T cell lymphoma: case report and review of literature. AB - Primary natural killer (NK)/T cell lymphoma of the uterus is extremely rare. A case of primary NK/T cell lymphoma arising from the endometrium of the uterus was diagnosed by curettage which demonstrated the typical pathological characteristics of NK/T cell lymphoma. The patient received induction chemotherapy but refused hysterectomy. Later she developed bone marrow infiltration and eventually died on day 76 after diagnosis. The natural course of primary endometrial (NK)/T cell lymphoma was very aggressive. Conventional cytotoxic chemotherapy may be ineffective for this aggressive disease. PMID- 23091906 TI - Mullerian papilloma in a patient with Proteus syndrome: case report and review of the literature. AB - BACKGROUND: Mullerian papilloma is a rare benign tumor of the female genital tract. It mostly affects girls less than five years old. After the treatment long term follow-up is needed as there is a chance of recurrence, but even then the prognosis is excellent. CASE: A 19-year-old girl with Proteus syndrome presented with vaginal bleeding. The histological examination revealed Mullerian papilloma of the uterine cervix and large bilateral ovarian cystadenomas. The patient was treated with a radical operation, because there were signs of more aggressive behavior in the tumor. The patient is alive and free of disease five years after the operation. CONCLUSION: The medical care of patients affected by rare disorders depends heavily on experiences gained from cases published in the medical literature. Since there is not much experience with tumors in Proteus syndrome we believe that this case can aid in shedding light on this subject. PMID- 23091907 TI - "Intestinal-type" mucinous adenocarcinoma of the vulva: a report of two cases. AB - BACKGROUND: "Intestinal-type" mucinous carcinoma of the vulva is extremely rare with very few cases reported in the literature. CASE REPORT: The authors report two patients who had diagnosis of intestinal-type mucinous adenocarcinoma of the vulva after excisional biopsy. In both cases, restaging was perfomed with total body computed tomography (CT) scan, gastroscopy, and colonoscopy that showed no other site of disease. A radical vulvectomy with bilateral systematic inguinal lymphadenectomy was performed, and in both cases no residual disease was found. A patient developed metastatic (liver, bone marrow) colonic cancer 36 months after primary surgery, received multiple lines of chemotherapy, and died of disseminated disease 18 months after diagnosis. The other patient was found to have dysplastic polyp in the sigmoid colon, and is alive without disease at 39 months after primary diagnosis. CONCLUSION: Intestinal-type mucinous carcinoma of the vulva has a poor prognosis. Strict endoscopic follow-up of the colon is mandatory in such cases, considering the high propensity of associated gastrointestinal (GI) tumors. PMID- 23091908 TI - A rare case of umbilical and vaginal metastasis from endometrial cancer--review of the literature. AB - INTRODUCTION: Metastases from primary endometrial cancer to the umbilicus are extremely rare. This unusual site of metastases has been described as Sister Joseph's nodule. MATERIAL AND METHOD: We present a case of a 73-year-old Caucasian woman with a BMI of 30, type II diabetes mellitus, hypertension, and umbilical and vaginal metastasis of endometroid endometrial adenocarcinoma (FIGO Stage IIIa, G2). Total abdominal hysterectomy and bilateral salpingo-oophorectomy by Pfannenstiel dissection, had been performed eight months before. The size of the umbilical mass was 2 x 2 cm. A second laparotomy including full recession of the umbilical ring, omentectomy, bilateral inguinal lymph nodes and excision of the upper one-third of the vagina was performed. Histological diagnosis revealed metastases of the same origin with her primary disease. CONCLUSION: The exact mechanism of implantation of cancer cells at the site of the umbilical ring is still unclear. Perhaps malignant cells penetrated the thickness of the uterine wall and spread intraperitoneally to reach the umbilical ring. The exfoliation of cells from the primary tumor via the fallopian tubes could be another possible explanation. Unfortunately, the presence of umbilical metastasis is a poor prognostic feature and sign of advanced neoplastic disease. The survival rate of these patients is influenced by the type of treatment and time of the diagnosis. PMID- 23091909 TI - Hydatidiform mole in a perimenopausal and primary infertility patient: case report. AB - We present a case of a 56-year-old woman with primary infertility who complained of amenorrhea for five months and vaginal bleeding for two months. Initially she was misdiagnosed with endometrial cancer due to her disease history and older age, but eventually a diagnosis of complete hydatidiform mole was confirmed and then laparoscopic total hysterectomy was performed. The patient has been followed up as an outpatient for more than one year, and hads an excellent prognosis. To our knowledge, this is the first case of hydatidiform mole in a woman with primary infertility during the perimenopausal stage. Even though hydatidiform mole is rare in primary infertility patients during perimenopause, it should always be considered in case of misdiagnosis. PMID- 23091910 TI - An apparently benign vulvar mass: possibly a rare malignancy. AB - BACKGROUND: Vulvar dermatofibrosarcoma is a rare fibrous tumor of intermediate grade malignancy, with a tendency for local recurrence, and rarely metastasizes. Management should be multidisciplinary. This is a report of an apparently benign vulvar mass with delayed diagnosis of vulvar dermatofibrosarcoma. CASE REPORT: A 42-year-old woman was referred to our hospital because of a vulvar tumor lasting 16 years, although several gynecological procedures and a total laparoscopic hysterectomy had been performed two years before. During this long period the lesion did not change morphological features and remained asymptomatic. Only a benign vulvar mass was diagnosed. Then, the swelling became evident showing erythematous skin with an aspect of "peau d'orange", leading the patient to consult a specialist. A firm vulvar swelling was observed in the anterior third of right labia majora continuing with about 3 cm of cord on top, quite movable above the underlying tissue but not on the overlying tissue. A wide excision was performed. The pathological examination showed positive margins. One month later an extensive deeper excision was performed. Histology confirmed a diagnosis of dermatofibrosarcoma. Immunohistochemistry was strongly positive for CD34. CONCLUSION: Vulvar lesions always require complete pathologic examination even in case of features of benign tumor to exclude a dermatofibrosarcoma. The role of the pathologist is essential to ensure negative microscopic margins and to avoid local recurrence. PMID- 23091912 TI - [A focus on self-directiveness in the training and support approach of caregivers]. AB - The aim of this paper is to quickly define the notion of "self-nomativity", a central element of my thinking and the impact this notion of the patient's link to his disease and the norm has on the health care relation. Its active and paradoxical aspect is highligthed as well as the difficutly for the caregiver to detect it as a normative process, even in the framework of apparently pathological behaviours. I therefore invite the caregivers to open their mind to the listening of the chronically ill patient during clinical examination. PMID- 23091911 TI - [Research communication: an opportune time to revitalize the profession]. PMID- 23091913 TI - [The support approach as a specific professionnal position: example of patient education]. AB - The support approach was progressivley introduced in most professional sectors, namely those where the human relation is significant. The patient's therapeutic education is without any doubt an aspect of the support approach in the health sector. It is often presented as a help, in other words a psychological and/or social complement of the mediacl treatment. This support approach is expected to have useful and necessary effects, even economical results thanks to a better compliance with the treatment. But this support approach cannot be limited to prescriptions optimization nor to a goodwill device. Even though there is a risk of it being diverted from the values which characterize it, it is also a means of bringing change to which we have to be attentive. The aim of this paper is to establish some guidelines to understand first of all what support means and what characterizes this support position. We shall then identify the framework of interaction of this support approach. We shall also try to focus on the patient's therapeutic education. PMID- 23091914 TI - [The role of law in human rights: illustrations in the field of healthcare]. AB - This work gives the opportunity to search where the law stands in the question of right in the philosophical modern and contemporain reflection. This step is not neutral because to accept a confrontation betwenn law and right, is also to choose putting down the following hypothesis, law is not right, although the proposal of the juridical positivism maintains that right exists only by law, even though right, it is what complies with law. When we assume that the right equals the law, we allow to maintain that law puts down a guarantee. This assumption is totally different from the law is the right. The boarder betwen the two ideas is very thin, changing according to ideological meanings and the relationships, thus there are questions on the maining and the shape. Reflection suggestions in the health field and more particularly the ones related to the decision-making process could be drawn from the essay dealing with the understanding of the norms on the individual or on groups of individuals. PMID- 23091915 TI - [A holistic approach and typology for the health promotion of women with breast cancer]. AB - The aim of this research is to better understand how women with breast cancer protect themselves against their disease in a holistic approach taking into account cognitive, subjective, biologic and social factors. This approach leads to the development of a typology of feminine protection, typology today absent of the French health system. THEORY: The protection concept refers to the salutogenesis theory. It brings together factors which help explain the way women think while going through their cancer and how they try to maintain themselves in good health in such an extreme situation. METHODOLOGY: The research is based on a mix method. This article discusses the results of the quantitative data analysis with some insights from the qualitative data. Our findings identify three distinctive types of women with regard to the types of protection they put in place (cluster analysis). RESULTS: The typology demonstrates three types of protection: (1) an ineffective protection characterised by weak SOC and stress, an internal control over the cause of cancer, a medium self-efficacy and the recourse to the protection's instinct; (2) a mixed protection marked by a weak SOC and a strong stress, an internal control over the cause of cancer, a low self efficacy and a strong difficulty to confront authority; and (3) an effective protection expressed by a strong SOC and a weak stress, an internal control over the course of cancer, a high self-efficacy and the capacity to act in face of danger. In short, in our sample, one woman in two encounter difficulties to protect herself against breast cancer and one woman in four does not manage to do it. CONCLUSION: The typology offers a clinical framework to help women to maintain their health in face of cancer, allowing health professionals to identify those who have difficulties to protect themselves efficiently. PMID- 23091916 TI - [Patient education: between complex knowledge, educators, heterogeneous learners and multiple contexts]. AB - Therapeutic patient education questions the links between medical and social sciences through epistemological, praxeological, and ethical issues. Its development in France and abroad necessary invites to consider the complexity of the particularities and variations of numerous contexts. The present contribution examines the theoretical foundations and the conditions required for the development of integrative learning situations, which involve both persons with chronic diseases and educators who have beneficiated from diverse socialisations. These learning situations have been worked out across three distinct stages: prerequisite analysis of specific knowledge at stake and of learners' representations preceding the thorough design of procedures that can yield results with heterogeneous individuals of various cultural and social origins. More than ten thousands persons have beneficiated from these learning situations courses. Results underline the development of emerging social dynamics and organisations beyond the learning process. These analysis invite to the reflection on social and contextual dimensions of learning, on the access to knowledge for persons with chronic diseases and the opportunities to develop the approach by diverse educators and trainers from various areas. PMID- 23091917 TI - [Prenatal monitoring and health education]. AB - Contrary to not so far away times, today in Portugal the pregnant woman is precociously accompanied by health professionals within whom it is important to focus the intervention of the midwives who accompanies, gives advice and even more and more frequently gives adequate formation on how to live in a healthy and balanced way this period of her life. This study is part of the core of a comprehensive sociology. The method of collecting empirical data involves the semi-structured interview and direct observation. The midwives had been unanimous in affirming that the Education for the Health is an activity with priority. However, there seems to be some confusion in the concepts of "prevention and promotion". These practices are divided into two models, which we designate as traditional and dialogic. The first model points to the prevention of diseases and damages in accordance with the information of biometric contents in order to reduce individual risks. The second is focused on the individual and its reality, thus considered as subject of the educational practice. Therefore is pertinent to question on how the schools should train form the professionals of health in relation to this intention. PMID- 23091918 TI - [Perception and attitude toward pain]. AB - Traditionally, the pain sends back to the infringement of the flesh and the suffering on the infringement of the psyche. The relation of care and the accompanying are due to nature a social fact of relation. In the right line of a first study (Peoc'h et al., 2007) concerning professional representations of health care professionals with respect to the care of the pain, we studied in the context of the theoretical model of the "social thought" (Rouquette, 1973), attitudes, perceptions and the ideological positions of patients about their pain's living. 244 patients hospitalized within the Hospitals of Toulouse have completed a questionnaire included free associations tasks, attitude answers, and answers concerning the ideological dimension of pain (beliefs, religious or anthropological orientation), in fine, a fourth party entered into a phenomenological perspective. The object "pain" will be suspected under the angle of the consciousness and the lived of the patient by using the protocol of the "narrative story of life" (Le Grand, 1989), with a praxeological design. Results indicate that the conceptions of the pain proposed by the patient make references to two different areas: that of the body (evil, handicap) and that of the psyche (evil-being, suffering). The term suffering reveal the social face of the pain in a double constituent: existential (solitude, incomprehension) and ideological (" it is necessary to take its evil in patience ", P = 73,3 %; chi2 = 39,83, p. < .05). The representation universe of the pain comes along with a certain indecision between these two events of the disease : pain versus suffering. PMID- 23091919 TI - [Hypnosis as a resource in palliative care. A qualitative study of the contribution of hypnosis to the care of oncology patients]. AB - Hypnosis is recognised in medicine as an effective complementary therapy. However, few qualitative data are available concerning the benefits it may bring. This qualitative exploratory study aimed to examine the contribution of hypnosis to the care of advanced cancer patients. Results demonstrate that hypnosis is an effective and efficient means of developing the resources of people suffering from serious illness. After an average of four hypnotherapy sessions, patients said they were able to locate previously unexploited resources within themselves and were able to become autonomous in the use of self-hypnosis. The major benefit reported concerned a reduction in anxiety. For patients experiencing anxiety about death, hypnosis allowed them, within a therapeutic environment perceived as safe, to explore different facets of their fears and to develop adaptive strategies. Aside from slight fatigue experienced during the sessions, no adverse side-effects were reported. In conclusion, this study exploring the effects of hypnosis allowed us to identify important benefits for patients suffering from advanced cancer. Consequently, replication on a larger scale is recommended in order to ascertain the extent to which it is possible to generalise from these results and in order better to define the characteristics of patients most likely to benefit from this therapy. PMID- 23091920 TI - [Portfolio in nursing school: myth or reality]. AB - CONTEXT: The portfolio is a new tool that has been introduced for the setting up of a new program concerning the nurse training. It aims at the would-be nurse to improve their self-reliance and make them assess themselves through a critical and reflexive approach. Indeed, the portfolio is mostly made up of sheets that the student has to fill in when describing and analysing several professional conditions. AIM: This study is about the assessment of the relevance in the portfolio that each nurse student owns in order to make them improve their reflexive practical. The work will, thus, suggest different ways of thinking and improving the use of the tool. METHODS: 30 portfolios were chosen randomly among the 2nd year students, because 180 analysis were assessed thanks to a grid. 10 viewpoints from volunteer students were gathered after several semi directive interviews. RESULTS: The qualitative and evaluative analysis shows that the students develop the reflexive practical throughout their trainings. It seems, indeed, relevant to choose the portfolio in order to help the students to develop this way of working. According to them, there are several positive points such as the distance towards an event, an awareness-raising of the acquisition, feedbacks about the quality of the text by the trainer and an ability to assess oneself. Yet, even though it was created 18 months ago, there are some limits such as the too short period of mentoring and feedback, the lack of time for the students to write their analysis, the fact that it is not a practical tool, and the unclear description of assessment criteria. In order to fulfil the needs, some solutions are to be found. CONCLUSION: The portfolio is clearly helpful for the students who wish to increase/improve gradually their reflexive practice. Thus, the trainer's role is crucial, when he is a supervisor. PMID- 23091921 TI - [Nursing observation chart: between the objectives targeted by this model and actual practice, where should we place the reflective process of the nurse? Results of the study. Future prospects of teaching tools]. AB - The research presented below examines the focus charting model in French nursing practice. Between the objectives targeted by this model and actual practice, where to place the reflective process of the nurse? To answer this question, the methodology used is the comprehensive approach. It is characterized by the production of semi-structured interviews of nurses using the model studied, but also by the in situ observation of practices. The results show that nurses engaged a reflexive process in the use of the focus charting model. This reflexive process is "in" the action rather than "on" or "for" the action. Nurse's position vis a vis at their disposal is investigated. PMID- 23091922 TI - [Non alcoholic fatty liver disease assessment]. AB - Non alcoholic Fatty Liver Disease (NAFLD) is the leading cause of consultation in hepatology department. It is a manifestation of the metabolic syndrome. If the simple steatosis is considered as benign, Non Alcoholic Steato Hepatitis (NASH) is associated with increased mortality linked to cardiovascular, metabolic and liver diseases. The diagnosis of NAFLD is based on simple clinical and biological data often corroborated by a liver imaging. The main issues in the assessment of these diseases are firstly to exclude secondary causes of steatosis and secondly to establish the severity of the disease. The assessment of the severity of NAFLD implies the determination of the degree of fibrosis. Combination of biological tests and elastography allows to determine indirectly fibrosis, reserving liver biopsy for doubtful cases. Comorbidities associated with metabolic syndrome (insulin resistance and cardiovascular diseases) must be researched and screening measures for colon and breast cancers should be considered. Eventually, NASH monitoring should include, like for others chronic hepatitis, the screening for the complications of end-stage liver diseases, including portal hypertension and hepatocarcinoma. PMID- 23091923 TI - [Management of alcoholic hepatitis]. AB - Alcoholic hepatitis is a severe form of alcoholic liver disease. Diagnosis is based on the association of new onset of jaundice and a compatible liver biopsy. Alcoholic hepatitis is severe when the Maddrey is up to 32 and, in this case, is associated with a mortality of 40-50% at 2 months. Corticosteroids improve survival of patients suffering from severe alcoholic hepatitis. The decrease of total bilirubin at day 7 of treatment and the Lille score are markers of response to corticosteroids. The absence of response is associated with a dramatic outcome (mortality rate of 75% at 6 months). Liver transplantation could be an alternative in a strictly selected group of non-responders. PMID- 23091924 TI - [Hepatitis B: screening and treatment]. AB - Hepatitis B virus infection is more prevalent than human immunodeficiency virus (HIV) infection and hepatitis C virus infection. Chronic hepatitis B (CHB) is a serious disease that can lead to severe complications as cirrhosis and hepatocellular carcinoma. The vast majority of people with chronic HBV infection are asymptomatic and as many as 2 in 3 people do not know they are infected. This is an indication of under screening by healthcare professionals. However, early treatment and intervention can prevent progression of liver disease. HBV infection is a vaccine-preventable disease. Until recently, there were few treatment options for patients with CHB, but now there are a number of antiviral agents available that are both effective against hepatitis B virus (HBV) and tolerable for the patient. This review paper attempts to provide some answers regarding the prevention, diagnosis and treatment of hepatitis B. PMID- 23091925 TI - [Management of chronic hepatitis C in 2012 in Belgium]. AB - Chronic hepatitis C virus infection is a major public health problem. It is estimated that 15 to 35% of infected patients will develop cirrhosis after a period of 30 years. Fibrosis stage must be evaluated in all hepatitis-C-infected patients. Noninvasive methods for the evaluation of liver fibrosis have been developed, mainly serum markers and transient elastography or Fibroscan. The goal of therapy is to achieve a sustained virological response, defined by hepatitis C RNA undetectable in serum 6 months after the end of therapy. This indicates viral eradication. Treatment of chronic hepatitis C has considerably improved. The association of pegylated interferon with ribavirin remains the standard of care for non-genotype-1-infected patients. Genotype-1-infected patients (who represent the majority of cases) are preferentially treated by triple therapy pegylated interferon plus ribavirin plus a first generation protease inhibitor (telaprevir or boceprevir). While triple therapy represents a major advance, by increasing the possibility of viral eradication, such therapy also presents new challenges, including the need for strict compliance, risk of additional side effects and development of resistant variants, drug-drug interactions, etc., which call for first-rate expertise in management of chronic hepatitis C therapy. Several new antiviral compounds are currently in clinical development and might lead to viral eradication in the vast majority of infected patients in the near future. PMID- 23091927 TI - [Subclinical hyperthyroidism: from diagnosis to treatment]. AB - Subclinical hyperthyroidism is a common clinical entity. Subclinical hyperthyroidism is defined as a serum TSH below the reference range but a normal T4 and T3 level in an asymptomatic patient. Whether or not subclinical hyperthyroidism should be treated remains a matter of debate. Cross-sectional studies and longitudinal population-based studies demonstrate association between subclinical hyperthyroidism and risk of atrial fibrillation, osteoporosis and cardiovascular and global mortality. However, there are no randomized clinical trials answering the question whether long term-health outcomes are improved by the treatment of subclinical hyperthyroidism. Therefore in the absence of evidence for or against treatment of subclinical hyperthyroidism, it seems appropriate to follow algorithms that consider the level of TSH and the presence of risks factors (age > 65 years, osteoporosis, post menopause and cardiac disease). PMID- 23091926 TI - [Multidisciplinary management of hepatocellular carcinoma in cirrhotic patients]. AB - The treatment of hepatocellular carcinoma (HCC) in cirrhotic patients is challenging: the incidence is increasing, the cirrhosis dramatically limits the tolerance to treatment possibilities, there are many therapeutic modalities but resources are limited, namely in the context of organ shortage for transplantation. Liver transplantation (LT) is the optimal treatment as it combines the largest tumor resection possible and the correction of the underlying liver disease. Due to organ shortage however, LT is reserved for early stages HCC. Surgical resection and radiofrequency destruction represent potentially curative options in highly selected patients. Arterial embolizations, chemo- or radio-embolizations, allow local tumor control but are not curative. These techniques could be performed before surgical resection or LT, to downstage the tumor and/or to control tumor progression while waiting for a graft. Finally, sorafenib is the only systemic treatment which has shown a survival benefit in advanced HCC. The benefit of combination of sorafenib and surgical treatments remains undetermined. The challenge in the management of HCC in cirrhotic patients is to integrate both individual (age, comorbidities, cirrhosis stage, tumor stage, specific contraindications to LT, etc.) and collective variables (expected waiting time before LT) to determine the best therapeutic option for each patient. In this process, multidisciplinarity is a key for success. PMID- 23091928 TI - [Blood tests and imaging in thyroid pathology]. AB - Circulating analytes used in the exploration of thyroid function are TSH and free thyroid hormones (FT4 and FT3). TSH is used as first line analysis in diagnosis because a normal value excludes almost always a thyroid dysfunction. However in the follow up of a treatment for hypo- or hyperthyroidism, free hormones are to be determined since TSH reaction is delayed and does not reflect precisely the restoration of euthyroidism. The measurement of anti-thyroperoxidase antibodies (anti-TPO) will show the presence of an autoimmune thyroiditis and that of thyroid stimulating antibodies (TSI) will establish the diagnosis of Graves' disease. The measurement of circulating thyroglobulin has no place in the diagnostic of thyroid dysfunction nor in the evaluation of a goitre but it is now the golden standard in the follow up of patients with a differentiated thyroid cancer after surgery and radioiodine ablation in patients without antithyroglobulin antibodies. Echography is the first line examination to evaluate thyroid morphology. It shows tiny thyroid nodules and gives precious informations on their structure, as well as paremchymatous diffuse abnormalities associated with thyroiditis. Thyroid scintigraphy with 99mTc allows establishing the functional characteristics of thyroid nodules (warm or cold) and to precise the origin of a thyrotoxicosis (autonomous toxic nodule vs Graves-Basedow, sub acute or silent thyroiditis). Whole body scintigraphy is mandatory after radioiodine treatment with 131I in order to visualize possible metastasis and establish their avidity for iodine. PMID- 23091929 TI - [Thyroid nodule: benign or malignant?]. AB - A thyroid nodule is a frequent occurrence. Its prevalence in a general adult population is about 50% and can even reach 67% when a cervical echography is performed. Only 5% of these nodules are cancers, and it is therefore important to avoid an useless and riskful surgery. This presentation is based on the Medical Guidelines for Clinical Practice: American Association of Clinical Endocrinologists (AACE), Associazione Medici Endocrinologi (AME) and European Thyroid Association (ETA) in 2010 for the Diagnosis and Management of Thyroid Nodules. In the absence of prospective randomized studies, these recommendations are established on the best evidence level. The patient history and clinical signs give some informations about potential risks. Thyroid tests not only evaluate thyroid functional status but TSH value and the presence of antithyroglobuline antibody seem to be associated with a higher risk of malignancy. A thyroid scintigraphy detects the presence of hot thyroid nodules. The thyroid echography is a key element before fine needle aspiration cytology. Some echographic criteria in the TIRADS (Thyroid Imaging Reporting and Data System), classification can reach an 88% sensitivity, a 49% specificity, a 49% positive predictive value, an 88% negative predictive value and a 94% diagnostic accuracy. The fine needle aspiration cytology performed with echography will be crucial to decide if the patient is to be eligible for surgery. In 70 to 80% of the cases, nodules can be classified as benign or malignant with a 92% negative predictive value for a benign diagnosis and a 100% positive predictive value for a diagnosis of cancer. The discovery of a follicular proliferation (cancer incidence of 20-30%) is a grey zone. Follicular proliferation and definite cancer lead of course to a surgical option. A decisional tree summarizes the different steps leading to a therapeutic decision. PMID- 23091930 TI - [Primary hyperparathyroidism: diagnosis and management]. AB - The prevalence of primary hyperparathyroidism (HPT) varies between 1 and 4/1.000 in the general population. HPT is nowadays most often asymptomatic. The classical bone disease has been replaced by osteopenia or osteoporosis with a preferential bone loss in cortical sites. The incidence of nephrolithiasis has been considerably lowered, but renal lithiasis is still the most frequent complication of HPT. The diagnosis is most often made by chance or during the workup of an abnormal bone mass. Hypercalcemia and an elevated PTH concentration, or at least a PTH level in the upper part of the normal range, generally point to a diagnosis of HPT. Additional tests include an evaluation of renal function, vitamin D measurement, determination of 24-hour urinary calcium and bone densitometry. Besides symptomatic HPT, classical recommendations for surgery include age less than 50, serum Ca at least 1 mg/dl above the upper limit of normal, creatinine clearance < 60 ml/min and osteoporosis. Surgical referral will, however, take into account patient age and comorbidities, as well as patient preferences. In the hands of an experienced surgeon, the success rate of parathyroidectomy is 95 98% and the rate of permanent complications is 1-3%. Parathyroid scintigraphy is the best preoperative localization technique of the adenoma. When surgery is contraindicated or refused by the patient, bisphosphonates or cinacalcet can be indicated in cases of osteoporosis or clinically significant hypercalcemia, respectively. PMID- 23091931 TI - [How to improve the management of heart failure by the general practitioner?]. AB - Current treatment of heart failure remains suboptimally implemented, leading to less favorable outcome. Readmission due to decompensation, remains frequent, in about 20% of patients at one month and 50% at six months. Precipitating factors of deterioration are known, including inappropriate drug interactions, and the early detection can be facilitated by simple clinical features (weight, heart rate, dyspnea) that can be confirmed by biomarkers (BNP, Nt-ProBNP). Medical treatment relies upon the proper use of drugs that have been demonstrated efficacious in the randomized clinical trials, and have been proposed in the international clinical guidelines. The basic principle of their titration consists on a gradual increase of the dosage, up to the target dosages, or maximal clinically tolerated dosages. Particular attention shall be paid to renal function and kaliemia, besides clinical parameters; close monitoring is mandatory along the treatment. PMID- 23091932 TI - [Pulmonary hypertension: a rare cause of unexplained dyspnea]. AB - Pulmonary hypertension (PH) is defined by an increase in mean pulmonary artery pressure above 25 mmHg, measured at right heart catheterization. The various conditions (up to 37) leading to PH are described in a clinical classification identifying 5 groups, including pulmonary arterial hypertension (PAH). With an incidence of 2-4 cases/million/year, PAH is a rare, rapidly progressive and incurable form or PH. The differential diagnosis of PH relies on a decision tree, which is typically triggered by the presence of unexplained dyspnea and followed by a non invasive approach that includes simple tests such as EKG, chest radiography, pulmonary function tests and echocardiography. Other tests have some value to exclude chronic thromboembolic pulmonary hypertension, such as ventilation/perfusion scintigraphy, angio CT scanner and pulmonary angiogram. Finally, right heart catheterization is mandatory to establish the diagnosis of PH. PMID- 23091933 TI - [Aortic stenosis in the elderly: what to monitor, when and how to treat? The place of TAVI]. AB - Because of population ageing, the frequency of calcified aortic stenosis in the elderly is constantly rising. In this article we will attempt to answer the questions a General Practitioner might ask himself when treating this disease that remains symptomless for quite some time. We will discuss the diagnosis of this pathology and the various medical and surgical therapeutic options including the newly developed technique of trans catheter aortic valve replacement. We will list the elements determining treatment choice and optimal timing for intervention. Finally, we will highlight the utmost importance of communication between the patient, the general practitioner and the cardiology team. PMID- 23091934 TI - [Renal denervation: new treatment for refractory hypertension?]. AB - Sympathetic renal hyperactivity is involved hypertension and in its progression towards organ damages. Using femoral access, a dedicated ablation catheter can be inserted into the renal vessels to deliver high frequency energy in the arterial wall. This therapy leads to a focal heating, which ablates the renal nerve fibers running in the adventitia. First clinical results (Simplicity HTN 1 and HTN 2 trials) have demonstrated a significant and sustained decrease in office blood pressure. The response rate to this therapy was about 85 to 90%. This procedure did not cause serious adverse event and seems to have also positive impact on glucose metabolism and exercise capacity. Based on these first results, renal denervation appears as a new interesting therapy, which requires further studies to better define its place in the antihypertensive therapeutic arsenal. Actually, it should not be considered as an alternative to pharmacological therapy and renal denervation should be only proposed to patients with resistant hypertension. Prior to renal denervation, an upstream work has to be done to ensure an adequate patient selection. The mandatory point is to ensure that patient scheduled for this therapy respond to the definition of arterial resistant hypertension. Because of the narrowed limit between the very common situation of "uncontrolled" hypertension and the "true resistant" group, we proposed a 3 steps algorithm that can help for patient selection. PMID- 23091935 TI - [Electrocardiographic tracings]. PMID- 23091936 TI - [Breast milk: its nutritional composition and functional properties]. AB - Human milk is a complex biological fluid with thousands of components. The milk composition in the mammalian species is specific and adapted to the needs of the offspring. It contains macronutrients (proteins, lipids and carbohydrates), micronutrients (minerals and vitamins) and numerous biologically active substrates. Human milk not only covers the nutritional needs of the newborn but protects the baby against infection, inflammation and oxidative stress. It has immunomodulation properties and confers trophical protection to the intestinal mucosa. The newborn infant is particularly immature: innate immunity, adaptive immunity and intestinal immaturity. Human milk will offer this exogenous protective and immunomodulating source. The development of the composition of the intestinal microflora of the neonate will be impacted by pre- and probiotic components of human milk. Current scientific knowledge of human milk properties highlights interdependency of the different components, ontogeny of the intestinal function, development of the mucosal intestinal immune system, colonization by the intestinal microbiota and protection against pathogens. Quality of these interactions influences the newborn's short and long-term health status. The promotion of breastfeeding with the support of the Baby Friendly Hospital Initiative (BFHI) program and labeling has been shown to have positive impact in public health. PMID- 23091937 TI - [Breastfeeding: from physiology to practical aspects]. AB - Exclusive breastfeeding is recommended up to 6 months of age, and may be continued in combination with a more diversified diet until 2 years of age. It represents the ideal natural diet for the newborn. The current change of maternity care policy and the adherence to the Baby Friendly Hospital Initiative (BFHI) project, have been associated with a significant improvement of patient information. This positive aspect combined with the effect of perinatal education were major contributors for breastfeeding promotion. This article presents the physiology of breastfeeding and its practical aspects, useful for the family doctor. The doctor plays a central role both in the information, which might influence the choice of breastfeeding, and also in the support of the mother or her baby. The duration of breastfeeding represents the new goal to be emphasized. Lactating mothers should be encouraged to consult competent caregivers, including the family doctor in case of breastfeeding difficulties. PMID- 23091938 TI - [Infant feeding]. AB - Infants are vulnerable: their growth and their development depend largely on their nutritional status. It is important to propose for them an optimal food. The human milk is unquestionably the best choice for the infant. When breastfeeding is not possible, the choice of the milk is made among hundreds of formulas for infants. They are regulated by a European directive. The healthcare professionals have to recommend as often as possible an infant formula: low protein content, predominance of whey proteins, enrichment with long chain fatty acids, lactose, addition of pre- or probiotics. The formulas for specific indications will be recommended in case of particular situations after verification that the complaints (constipation, regurgitations, stomach pains) cannot be corrected by simple dietary measures (increasing of the intakes of meals with a concomitant reduction of the volume of the meals). The food diversification is recommended between 17 and 26 weeks according to the neuromuscular capacities of the infant. These meals must be presented with a spoon to assure a sufficient nutritional intake. In Belgium, the use is to begin with fruits. One should avoid adding biscuits or sugar. The meal of vegetables will be introduced a little later. It should consist of starchy foods, vegetables with some fat to which the meat will be added. Numerous foods (biscuits, croissants and similar products, chips) should never be part of the ordinary menu, but should be reserved for particular occasions. The education of the children should begin from this age on. PMID- 23091939 TI - [Food allergies in children: which diet?]. AB - Food allergies are very frequent in children (between 4 and 8% of population). There are many clinical manifestations, that can be lifethreatening. In children, compared to adults, a limited number of food allergens are responsible for the disease: egg, cow milk, peanuts, nuts (hazelnut, nut, ...), fish, cereals, exotic fuits, and soya. Eviction of the offending food is the first treatment of allergy. This eviction diet is sometimes difficult to organize and can alter the quality of life (child and family). Diagnosis must be well established; sensitivity to an allergen must be differenciated from real allergy. This can lead to perform a provocation test (oral challenge) in the hospital. It is now proposed that the eviction diet will be less strict than before, adapted according to the allergen, symptoms in each case, age of patient and ideally to the reacted dose of the offending allergen. A collaboration with a dietist is necessary to optimalize the nutritionnal schedule. Induction of oral tolerance seems to be an interesting optional treatment for patients presenting persistant food allergy. PMID- 23091940 TI - [Vitamins in pediatrics]. AB - Vitamins are organic substances essential to the maintenance of many physiological functions, and necessary for growth. They are subdivided into two groups: the fat soluble vitamins which include vitamins A, D, E and K and the water-soluble vitamins which include Group B vitamins and vitamin C. The recommendations for vitamins intake must be evaluated at regular intervals, and vary according to the different methods used and the different environments assessed. The shortcomings, but equally the measures of prevention must be taken into account. In industrialized countries, provided that the diet is balanced and in the absence of chronic disease, the majority of needs are covered. Vitamin requirements vary depending on age, sex, state of pregnancy, chronic disease or a specific diet. In industrialized countries, chronic alcoholics and malabsorption cases represent groups at risk of vitamin deficiency. Dietary anamnesis remains the best tool to assess needs and nutritional deficiencies. In infants fed exclusively on milk, the required intake is easy to deduce; on the other hand, the needs assessment becomes more difficult with dietary diversification. In industrialized countries, vitamin D should be administered throughout one's life, and vitamin K during the first three months of life for breast-fed new-borns. In developing countries, nutritional status is precarious and supplementation needs to be adapted accordingly. PMID- 23091941 TI - [Feeding and adolescence]. AB - Adolescence is a transition period during which young people face many changes. Their desire to assert and differentiate themselves is reflected even in their food choices. These choices may have impacts until their adult lives. Moreover the media affect them in contradictory ways from images of extreme thinnesses to enticing advertisements of calorie food. A lack of self-esteem may appear, and in case of fertile ground may cause either diet, either addiction, or eating disorder. A comforting family as well as empathetic physicians have a main role in the medical care. PMID- 23091942 TI - [Neurosurgical treatments for pain]. AB - Pain represents the most frequent symptom faced by general practitioners and is associated with 60% of neurological troubles. Pain consists in a conscious, subjective, unpleasant and protective sensory experience transmitted by thermoalgic pathways in the central nervous system (nociceptive pain). Lesioning of peripheral or central sensory pathways can also generate pain associated with hypoesthesia (phantom or neuropathic pain). Since the 1920's, neurosurgeons have attempted to alleviate nociceptive and neuropathic chronic pain by interrupting (irreversible interruptive techniques) thermoalgic fibers (neurotomies, rhizotomies, cordotomies, tractotomies, thalamotomies, cingulotomies). Some of them (neurotomies, rhizotomies) are still used today when all medications have failed. They can provide immediate and tremendous pain relief like in trigeminal neuralgia. However, the technique, when not sufficiently selective, can generate a neuropathic pain and then a short-lating pain relief. Increasing knowledge on pathophysiological mechanisms of pain allowed surgery to interfere with the functioning of the sensory circuits without lesioning and to modulate neuronal activity in order to reduce pain (neuromodulation). Non-lesioning modulating techniques (then reversible) appeared (deep brain stimulation, epidural spinal cord or motor cortex stimulation, intrathecal infusion, radiosurgery) and are currently applied to efficiently alleviate neuropathic pain. PMID- 23091943 TI - [Gamma knife radiosurgery]. AB - Gamma Knife radiosurgery can be used as an alternative or complementary therapy to neurosurgery or radiotherapy for the treatment of some brain disorders or tumors of small volume. The most frequent indications are brain metastases, vestibular schwannomas, meningiomas, trigeminal neuralgia, arteriovenous malformations, some gliomas, and pituitary adenomas. Created in 1999, the Gamma Knife Center of the ULB remains currently the unique center in Belgium where a Gamma Knife radiosurgery treatment can be performed. PMID- 23091944 TI - [Treatment of brain metastases]. AB - Brain metastases (BC) are the cause of important mortality and morbidity in cancer patients. Corticoids and Whole Brain Radiotherapy (WBRT) remains the standard treatment but, at the long-term, the results are disappointing. In patients with a single metastase, the survival and the Quality of Life (QoL) can be improved by surgery combined with WBRT. Unfortunately, if surgery (S) is impossible because of the number and/or the site of the metastases or any contraindication for surgery, radiosurgery (RS) remains a good alternative choice. RS allows an excellent local control of the lesions and can be applied to several lesions at the same time. There is no advantage in in terms of survival between RS + WBRT and S + WBRT or RS alone. RS can therefore be recommended as a first treatment approach, namely when favourable prognostic factors are present. This approach allows to avoid WBRT and its potential toxicity, namely in long term survival. PMID- 23091945 TI - [Aneurysms and other intracranial vascular malformations]. AB - The objective is to present the management of patients with aneurysms and other intracranial vascular malformations by interventional neuroradiology (INR) techniques. Interventional neuroradiology is dedicated to the treatment of patients who present with pathologies of the brain, the face, and the spinal cord that are treatable by direct percutaneous or endovascular approaches. Indications of INR have dramatically increased over the last 20 years thanks to innovations in radiological equipments (angio suite, 3D images, etc.) and embolic materials. The endovascular treatment alone is generally curative but sometimes it will be performed before surgery to decrease its risks. Interventional neuroradiology is thus part of several multidisciplinary teams including departments of neurosurgery, neurology, intensive care, anesthesiology, vascular surgery, ENT, etc. We will present the main indication of INR that is the treatment of patients with aneurysms and other intracranial vascular malformations. In conclusion, interventional neuroradiology plays nowadays the main role for the management of patients with neurovascular diseases. Interventional neuroradiology belongs to several multidisciplinary teams and allows to diagnose, to treat, and to follow up these patients. PMID- 23091946 TI - [Conceptual structure of the electronic health record]. AB - The file is the daily work tool for any physician, general practitioner or specialist. The general practitioner's must of course contribute to the quality of care for his patients, but also has to be used to communicate and exchange relevant clinical information to ensure continuity. A common structure for all the files of first line is therefore essential. For several years, Belgium has played a pioneering role in this matter and several successive working groups led to the development of a standard, which is described in this article. This one became a label and quality criterion for all electronic health records of family doctors. PMID- 23091947 TI - [The global medical record + (DMG+), tool for prevention in first line care]. AB - The "global medical record +" can be offered to all 45 to 75 year-old patients in the form of a prevention module within the global medical record and which the general practitioner and the patient will regularly update. It will include in particular an assessment of cardiovascular risk, cervical, breast and colon cancer screening, a check of main adult vaccinations, as well as a primary prevention section focused on smoking, alcohol consumption and various hygiene and dietary measures. The inclusion of this module in a computerized medical record will make it more efficient and will lighten the practitioner's workload. PMID- 23091948 TI - [From library to clinical decision support systems: access of general practitioner to quality information]. AB - Since 2003, the following tools have been implemented in Belgium for improving the access of general practioners to the EBM literature: the Digital Library for Health and the evidence-linker of the CEBAM, the portal EBMPracticeNet.be and the multidimensional electronic clinical decision support EBMeDS. The aim of this article is to show the progress achieved in the information dissemination toward the belgian general practioners, particularly the access from the electronic health record. From the literature published these last years, the opportunities cited by the users are for using EBM and the strong willingness for using these literature access in the future; the limits are the medical data coding, the irrelevance of the search results, the alerts fatigue induced by EBMeDS. The achievements done and planned for the new EBMPracticeNet guidelines portal and the EBMeDS system are explained in the aim of informing belgian healthcare professionals. These projects are claiming for lauching a participatory process in the production and dissemination of EBM information. The discussion is focused on the belgian healthcare system advantages, the solutions for a reasonable implementation of these projects and for increasing the place of an evidence based information in the healthcare decision process. Finally the input of these projects to the continuing medical education and to the healthcare quality are discussed, in a context of multifactorial interaction healthcare design (complexity design). PMID- 23091949 TI - [GP practice in Belgium: strengths and weaknesses. Potential improvement by electronic patient record]. AB - In July 2012, NIHDI (National Institute for Health and Disease Insurance) has published a GP's performance report under the umbrella of the quality promotion Council, addressed to policymakers, stake holders and general practitioners (GP). This article is summarizing the performance measurement, strengths and weaknesses. Main findings are a pretty high level of population satisfaction, a good accessibility and the central role of GP's within the health organization. The report points out weaknesses in quality variation and sustainability. Electronic medical file could be helpful to improve quality. PMID- 23091950 TI - [EHealth, health networks and electronic health record: towards a culture of sharing and trust]. AB - In Belgium, the computerization of the ambulatory care sector and general practice in particular has been continuously progressing over the last ten years. Although regional differences exist, 75% of the Belgian general practitioners own today a software to assist them in the management of their patients. To date however, general practitioners have been hardly using their electronic system to share or communicate with other actors of the system. The silo culture remains the norm. Aside from certain group practices, computerization has thus not yet contributed to improve in a significant way the quality of care of the patient. The implementation in 2012 of the "shared electronic health record" thanks to the deployment in production of the 5 health networks connected via the federal directory of references is due to deeply change this situation. Communication flows between health care professionals will thus rapidly intensify and the amount of information available at the point of care will increase significantly. This is however only the first step. The future electronic patient record (EPR) will need to make room for a deep integration of the actors around the patient thanks--among other things--to the implementation of a global semantic interoperability strategy. This integration of actors together with the empowerment of the patient are indeed essential preliminary conditions in order to adapt our health system to the enormous challenges that we will all have to face in the next 10 years. PMID- 23091951 TI - [Management of gastroparesis and functional dyspepsia after cisapride withdrawal]. AB - Dyspepsia is a common symptom frequently encountered in general practice. Functional dyspepsia is an exclusion diagnosis after an organic cause has been ruled out, and is a defined entity which can be subdivised in two different subtypes based on the cluster of symptoms, namely epigastric pain and postprandial distress syndromes. The term gastroparesis is used when persistently and severly delayed gastric emptying is found in the absence of mechanical obstruction. Helicobacter pylori infection should be treated, although symptomatic benefice is small. Proton pumps inhibitors offer a clinical benefit in epigastric pain syndrome, whereas prokinetics are probably useful in postprandial distress syndrome. Cisapride has been withdrawn last year due to the risk of potential severe cardiac arrythmies. Domperidone is safer, although caution has to be paid in long-term use because of potential ventricular arrythmies. Dietary advice and psychological therapies might be a useful adjunct. There are difficulties with new treatment development for functional dyspepsia, due to pathophysiological heterogeneity, lack of well-accepted endpoints, a huge placebo effect, and unconfirmed results in large clinical studies after early positive results for promising drugs. Acotiamide, a new cholinesterase inhibitor improving dyspeptic symptoms is not yet available in Europe. PMID- 23091952 TI - [Irritable bowel syndrome: diet and complementary medicine therapies?]. AB - Irritable bowel syndrome (IBS) is a frequent and invalidating functional bowel disorder with entangled mechanisms. Its therapeutic approach is therefore complex. Classical therapies, prescribed alone or in combination in light of the predominant symptom, consist of antispasmodics, fibers, laxatives, antidiarrheals, and psychotropic agents. Other emerging pharmacological therapies, such as prokinetics, prosecretory or serotoninergic agents, bile acid modulators and antibiotics have been recently studied in clinical trials. Dietary measures can include reduction of short-chain poorly absorbed carbohydrates (FODMAPs) and gluten restriction. Assessment of food allergy can be proposed in a subgroup of IBS patients. Complementary and alternative medicine therapies, that are generally low cost and safe, appear to be appreciated by patients. Probiotics have demonstrated action on the gut microbiote modulation, and may be helpful in a subset of patients. Peppermint oil has an established visceral analgesic effect. Hypnotherapy represents an original, global and effective approach. Finally, education, reassurance and listening to the patient, leading to a solid therapeutic relationship, represents an essential backdrop of remedy or diet effectiveness. PMID- 23091953 TI - [Positron emission tomography in inflammatory disorders]. AB - Value of positron emission tomography (PET) applied to the metabolic evaluation of inflammatory disorders is increasingly recognized. PET with fluorodeoxyglucose (FDG) has now taken the place occupied by citrate of Gallium-67 in this domain, in which it has several advantages compared to other diagnostic imaging methods such as scintigraphy with labelled leucocytes. Visualization of inflammatory lesions does not just rely on the presence of immune cells. Uptake of the tracer actually requires the activation of these immune cells, an important point to consider to adequately interpreting PET imaging in this context. For systemic inflammatory disorders, FDG-PET has the advantage to provide whole body evaluation. This advantage, combined to the fact that the tracer used reveals infectious, non-infectious inflammatory diseases on one hand, and malignant diseases on the other hand, is crucial for the etiologic diagnosis of fever of unknown origin. Various chronic infectious diseases that are frequent clinical challenges are better diagnosed with the use of PET, particularly when this imaging method is combined with X-ray computed tomography (CT). Such infectious diseases are osteomyelitis, infection of orthopaedic and vascular prostheses, and infectious diseases with systemic distribution such as tuberculosis. For what concerns noninfectious inflammatory diseases, FDG-PET has proved particularly helpful for the diagnosis and management of large vessels arteritis and inflammatory bowel disease. PMID- 23091955 TI - Automated urinalysis in the clinical lab. PMID- 23091954 TI - [Andropause and testosterone deficiency: how to treat in 2012?]. AB - Age-related hypogonadism is a clinical syndrome defined as a low serum testosterone level (< 11 nmol/l) with precise clinical symptoms: diminished libido, erectile dysfunction, and loss of morning erection. Testosterone supplementation has been shown to have a beneficial effect on muscle and fat mass as well as on bone mineral density, with more conflicting effects observed on muscle strength, sexual function, mood and quality of life. In spite of an inverse relationship between testosterone levels and various cardiovascular risk factors (obesity, insulin resistance and type 2 diabetes mellitus), there is no evidence of a positive effect of testosterone replacement therapy towards these risk factors. So far, the long-term safety of testosterone replacement therapy has not been established. Evidence has been found that testosterone replacement therapy has a causative and worsening role in prostate cancer urging not to treat patients with a history of prostate cancer. Finally, patients with high cardiovascular risk, including those with congestive heart failure, should not be treated. PMID- 23091956 TI - CDC recommends expanded patient testing. PMID- 23091957 TI - Intelligent automation. PMID- 23091958 TI - Middleware: don't rule it out. PMID- 23091959 TI - Laboratory developed tests: what may be coming. PMID- 23091960 TI - Gene sequencing in the clinical laboratory--benefits and dilemmas. PMID- 23091961 TI - Meaningful use: today and tomorrow. PMID- 23091962 TI - Helping to shape drug shortage provision in FDA user fee legislation. PMID- 23091963 TI - Damaging diarrhea. PMID- 23091964 TI - Networking and the power of being connected. PMID- 23091965 TI - Altitude and environmental climate effects on bronchiolitis severity among children presenting to the emergency department. AB - Bronchiolitis, a respiratory illness, is the leading cause of hospitalization for infants. The authors examined whether environmental factors contributed to the severity of the bronchiolitis illness. They compiled environmental data (temperature, dew point, wind speed, precipitation, altitude, and barometric pressure) to augment clinical data from a 30-center prospective cohort study of emergency department patients with bronchiolitis. They analyzed these data using multivariable logistic regression. Higher altitude was modestly associated with increased retractions (odds ratio [OR] = 1.6; 95% confidence interval [CI] = 1.1 2.1; p < .001) and decreased air entry (OR = 2.0; 95% CI = 1.6-2.6; p < .001). Increasing wind speed had a minor association with more severe retractions (OR = 1.3; 95% CI = 1.1-1.7; p = .02). Higher dew points had a minor association with lower admission rates (OR = 0.9; 95% CI = 0.8-0.996; p = .04). Altitude and environmental climate variables appear to have modest associations with the severity of bronchiolitis in the emergency department. Further studies need to be conducted, however, on limiting exposure to these environmental variables or increasing humidity before making broad recommendations. PMID- 23091966 TI - Evaluation of fecal coliform samples from Oakland Bay, Washington, using a new sanitation model. AB - The study described in this article analyzed the current statistical procedure used by the National Shellfish Sanitation Program (NSSP) to manage opening and closing of conditionally approved shellfish harvest areas and identified a deficiency in the statistical analytical method used by NSSP. The authors propose a new statistical model to address this deficiency. Over 2,100 fecal coliform samples, collected by the Washington Department of Public Health from 15 shellfish stations in Oakland Bay, Washington, over 10 years from January 13, 2000, to December 9, 2009, were analyzed. The results suggest that the estimated 90th percentile criterion, which is currently used by NSSP, is not sufficient to protect the public from risks caused by consumption of biologically contaminated shellfish. To reduce this risk, the NSSP procedure should be augmented by applying the upper limit of the estimated 90th percentile of fecal coliform samples at the .05 significance level. PMID- 23091967 TI - The presence of asbestos-contaminated vermiculite attic insulation or other asbestos-containing materials in homes and the potential for living space contamination. AB - Asbestos-contaminated vermiculite attic insulation (VAI) produced from a mine near Libby, Montana, may be present in millions of homes along with other commercial asbestos-containing materials (ACM). The primary goal of the research described here was to develop and test procedures that would allow for the safe and effective weatherization of low-income homes with asbestos. The presence of asbestos insulation was confirmed by bulk sampling of the suspect asbestos material. The homes were then tested for the presence of asbestos fibers in the living spaces. All 40 homes containing VAI revealed the presence of amphibole asbestos in bulk samples. Asbestos (primarily chrysotile) was confirmed in bulk samples of ACM collected from 18 homes. Amphibole asbestos was detected in the living space of 12 (26%) homes, while chrysotile asbestos was detected in the living space of 45 (98%) homes. These results suggest that asbestos sources in homes can contribute to living space contamination. PMID- 23091968 TI - Tattooing regulations in U.S. States, 2011. AB - Tattooing's popularity has led to regulatory concerns because medical complications linked to unsanitary practices can have a lasting health impact. The authors' study sought to determine whether existing state tattooing laws and regulations (rules) effectively protect public health. A 10-item checklist was created for each of three types of rules (sanitation, training, and infection control) identified as having the greatest public health impact. State rules were classified as effective if the state scored > or = 7 on all three categories, moderate if > or = 4 in all three categories, minimal if < 4 in one or more categories, and ineffective if < or = 2 in all three categories. Forty-one states have at least one state statute regulating tattooing practice. On the basis of the authors' study criteria, 36 states regulate sanitation effectively; 15 states regulate training effectively; and 26 states regulate infection control effectively. Fourteen states meet the criteria for regulating all three categories effectively. Specific rules vary substantially by state. Public health agencies should encourage states to adopt and enforce effective, evidence-based tattooing rules. PMID- 23091969 TI - From conversation to action: implementation of the National Conversation on Public Health and Chemical Exposures. PMID- 23091970 TI - The food-water nexus: irrigation water quality, risks to food safety, and the need for a systems-based preventive approach. PMID- 23091972 TI - Workerless businesses--an explosive new trend dancing with the inner entrepreneur. PMID- 23091971 TI - 2012 environmental health legislation. PMID- 23091973 TI - State of the association. PMID- 23091974 TI - The problem with apathy... PMID- 23091975 TI - Have we won the drug war yet? PMID- 23091976 TI - In adults with Restless Legs Syndrome, which treatments have been found to be effective? PMID- 23091977 TI - Interfaces between electronic medical record (EMR/EHR) technology and people in American medicine: insight. imagination, and relationships in clinical practice. AB - This paper explores the contexts and relationships in which EMR/EHR technology is used in healthcare settings. It approaches the EMR/EHR as an issue in clinical ethics. The author recognizes the immense contribution that healthcare informatics makes to coordinating and integrating medical care at the level of individual physician, nurse, and institutions. At the same time the author raises a cautionary note about some unrecognized dimensions of the use and experience of the EMR/EHR. The author argues that the EMR/EHR can consciously and unconsciously become an instrument of assembly line-like physician "productivity" and "production reports" that depersonalize patient and physician alike. Construed this way, the EMR/EHR can narrow the clinician's imagination, relationships, clinical decision-making, and documentation into oversimplified, and potentially distorting, clinical narratives and categories such as fit into CPT, ICD-9, DRG, DSM-IV and other codes, EBM protocols, and clinical algorithms. By contrast, the author uses a vignette and one of his own clinical poems to illustrate the rich weave of relationship and meaning that are foreground rather than background in clinical assessment, decision-making, treatment, outcome, and satisfaction. The author concludes with a call to imaginatively use the EMR/EHR as an instrument of physician-patient communication, and to include in it and make available vital narrative data (evidence) about patient, family, culture, occupation, socioeconomic status, physician, disease, and their relationships. PMID- 23091979 TI - What is fragile X syndrome? Fact sheet. PMID- 23091978 TI - OHCA supports docs with best practice for atypical antipsychotics. PMID- 23091980 TI - MNA goes to Washington: ANA House of Delegates. PMID- 23091981 TI - Everything antiretroviral: 5th IAS conference, Cape Town, South Africa. PMID- 23091982 TI - Improving influenza vaccination rates in pregnant women. AB - OBJECTIVE: To determine whether a provider-focused reminder improved vaccination rates as compared with no reminder. STUDY DESIGN: This was a retrospective cohort study comparing vaccination rates among pregnant patients seen in October and November 2003 (no reminder) and October and November 2005 (provider-focused reminder). Charts of all patients presenting for prenatal care during those months were reviewed for vaccination order. Vaccination rates were calculated and compared by year, provider, age, race, education, primary language, insurance type, and presence or absence of medical risk factors. RESULTS: A total of 1,367 records were reviewed: 504 from 2003 and 863 from 2005. Overall vaccination rate increased from 15-52% with a provider-focused reminder in place. In our study population medical risk factors were identified in 396 patients (29%). Vaccination rates for patients with medical risk factors increased from 18-47%. All provider groups demonstrated significant increases in the rates of vaccination with a reminder, however, there were no differences in age, race, education, primary language, or insurance. CONCLUSION: Although a low-cost, provider-focused reminder improved vaccination rates to 52%, additional measures including patient and provider education, dedicated vaccination clinics, and standing orders will be needed to achieve the ACOG goal of 100% vaccination. PMID- 23091983 TI - Clinical significance of inadequate endometrial biopsies prior to hysterectomy. AB - OBJECTIVE: To evaluate preoperative clinical risk factors associated with significant uterine histopathologic abnormalities in final hysterectomy specimens in patients with inadequate preoperative endometrial biopsies. STUDY DESIGN: This is an institutional review board-approved, retrospective cohort analysis of 469 consecutive patients who underwent preoperative endometrial biopsies with subsequent hysterectomy from January 1, 2005, to December 31, 2009, at the University of Louisville Medical Center. We analyzed risk factors for inadequate biopsy and for final diagnosis of endometrial pathology (defined as endometrial hyperplasia or uterine cancer). RESULTS: Of the 469 preoperative endometrial biopsies reviewed, 26.2% (123/469) were inadequate (IBx) and 73.8% (346/469) were adequate and benign. IBx on endometrial biopsies was associated with a greater risk of having significant uterine histopathologic abnormalities on final hysterectomy specimens (6.5% vs. 2.3%, RR 2.8 [95% CI 1.1-7.3], p = 0.04). CONCLUSION: Although inadequate endometrial biopsies are a common finding, they can be associated with significant uterine histopathologic abnormalities on final hysterectomy specimens. PMID- 23091984 TI - Urinary retention and voiding dysfunction in women with uterine leiomyoma: a case series. AB - OBJECTIVE: To examine urinary retention as an underreported complication of uterine leiomyoma. Reproductive-aged women with uterine leiomyoma often describe pelvic pressure and menorrhagia, however few complain of complete urinary retention. STUDY DESIGN: We dis-cuss the cases of 8 women who presented to our emergency room with acute urinary retention over a 4-year period. RESULTS: Patients had a mean age of 39 (range, 25-51) and median parity of 1 (range, 0-5). Seven of 8 patients (88%) had posterior-fundal leiomyomas. All patients underwent either myomectomy or hysterectomy with resolution of their urinary retention. CONCLUSION: Incarceration of the posterior or fundal leiomyoma beyond the pelvic brim can push the cervix against the pubic bone, resulting in compression of the bladder neck or urethra. This may explain the etiology of retention and/or voiding dysfunction in some cases. Urinary retention, as a result of leiomyoma, may be overlooked in the initial management of symptomatic patients. PMID- 23091985 TI - Use of complementary and alternative medications among patients in an obstetrics and gynecology clinic. AB - OBJECTIVE: To evaluate the current use of complementary and alternative medication (CAM) products among women in obstetrics and gynecology outpatient clinics. STUDY DESIGN: This study was performed at a major academic center among patients seen at either a faculty-led private clinical practice site (n = 250) or a resident-led clinical practice site (n = 250). Patients were requested to bring a written list and the medication bottles (prescriptions, over-the-counter medications and CAM products) to the clinic, where a survey was then administered. RESULTS: Overall, 18.6% of participants were using CAM products. Significantly more patients reported using CAM products in the faculty private practice as compared to the resident clinic practice (28.4% vs. 8.8%, respectively, p value < 0.05). Only 29.0% of CAM products users had spoken to a healthcare provider regarding CAM products. Multivariate logistic regression model determined that older age (p < 0.0001) and Caucasian ethnicity (p = 0.0245) were associated with higher rates of CAM products use. CONCLUSION: In this study CAM products use was not as prevalent as anticipated for this patient population, however it continues to be underreported to providers. Healthcare professionals should continue to increase their knowledge about CAM products, take a proactive role to improve documentation, and develop an open communication with patients regarding appropriate use of CAM products. PMID- 23091986 TI - Pregnancy outcomes in type 2 diabetic patients as compared with type 1 diabetic patients and nondiabetic controls. AB - OBJECTIVE: To characterize the neonatal and maternal outcomes of type 2 diabetic patients as compared with type 1 diabetic patients and nondiabetic controls. STUDY DESIGN: We performed a retrospective cohort study reviewing perinatal outcomes of type 1 and type 2 diabetic patients and nondiabetic controls from July 2000 to August 2006. Analysis of variance, t testing and chi2 analysis were used to compare groups. Post hoc power analysis indicated 80% power was necessary to detect a 15% difference in composite poor neonatal outcomes. RESULTS: A total of 64 type 2 and 64 type 1 diabetic patients were compared with 256 controls. Type 1 diabetic patients had higher incidences of composite poor neonatal outcome and congenital anomalies than did type 2 diabetic and control patients. Both diabetic groups had similarly higher incidences of cesarean delivery, preeclampsia, preterm delivery, polyhydramnios and macrosomia than did controls. CONCLUSION: Type 2 diabetic patients have a decreased incidence of adverse neonatal outcomes when compared with that of type 1 diabetic patients. No difference was observed between the diabetic groups in the incidence of a majority of the adverse maternal outcomes examined, however both diabetic groups had overall worse outcomes that did nondiabetic controls. PMID- 23091987 TI - Assessment of vascular endothelial growth factor, basic fibroblast growth factor, and transforming growth factor levels in amniotic fluid. AB - OBJECTIVE: To measure amniotic fluid levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-beta2 and to characterize their levels with respect to advancing gestational age and pregnancy-related complications. STUDY DESIGN: Amniotic fluid was collected from a total of 37 patients, 2 of whom had twin pregnancies. Twenty seven specimens were collected in the second trimester and 10 specimens were collected in the third trimester. VEGF, bFGF and TGF-beta2 were isolated from centrifuged amniotic fluid and quantified using commercially available ELISA kits. Concentrations of growth factors were expressed in pg/mL. RESULTS: The growth factors under investigation were present in most but not all amniotic fluid specimens throughout pregnancy. The levels of VEGF, bFGF and TGF-beta2 were inconsistent and did not show a statistically significant association with gestational age, number of fetuses, or the presence of hypertension and/or diabetes. One significant finding emerged from the data: smokers had significantly higher amniotic fluid levels of VEGF compared to nonsmokers (p = 0.03). CONCLUSION: VEGF, bFGF and TGF-beta2 are detectable in second and third trimester amniotic fluid. Smoking appears to correlate with increased amniotic fluid VEGF during pregnancy. VEGF may represent a molecular marker of hypoxia and is an interesting focus for future investigation. PMID- 23091988 TI - Methotrexate on a 21-day cycle for low-risk gestational trophoblastic neoplasia. AB - OBJECTIVE: To perform an outcome analysis of patients with low-risk gestational trophoblastic neoplasia (GTN) treated with a 5-day intramuscular methotrexate (MTX) regimen on a 21-day cycle. STUDY DESIGN: A retrospective review of 31 patients with low-risk GTN treated with a 5-day MTX regimen. RESULTS: A total of 31 patients with low-risk GTN (WHO score < 7) received single-agent MTX at a dose of 0.4 mg/kg daily for 5 days every 21 days (mean number of cycles, 3; 83% remission). The only significant toxicity encountered was grade 2 stomatitis in 8 (26%) patients. CONCLUSION: A 5-day MTX regimen given every 21 days is convenient, well-tolerated and effective for patients with low-risk GTN. PMID- 23091989 TI - Effect of length of controlled ovarian hyperstimulation using a gonadotropin releasing hormone antagonist on in vitro fertilization pregnancy rates. AB - OBJECTIVE: To compare pregnancy outcomes between shorter and longer in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) cycles using GnRH antagonist protocol. STUDY DESIGN: Retrospective cohort analysis at a large military academic hospital. A total of 351 patients underwent 412 IVF/ICSI cycles using a GnRH antagonist protocol from September 2002 through May 2008. Clinical pregnancy and live birth rates for all IVF/ICSI cycles were compared independently for both total length of ovarian stimulation with gonadotropins (< 10 days vs. > or = 10 days) and GnRH antagonist use (< 4 days vs. > or = 4 days), respectively. RESULTS: Clinical pregnancy rates were 54.6% among cycles with total gonadotropin use <10 days vs. 48.6% for those cycles > or = 10 days, odds ratio 0.82 (0.53-1.27); live birth rates were 50.0% vs. 47.7%, odds ratio 0.91 (0.59-1.42). Clinical pregnancy rates were 54.0% among cycles with GnRH antagonist use < 4 days vs. 52.8% with GnRH antagonist use > or = 4 days, odds ratio 0.95 (0.62-1.45); live birth rates were 46.8% vs. 50.4%, odds ratio 1.15 (0.76-1.76). CONCLUSION: Clinical pregnancy and live birth rates are not adversely affected by longer IVF/ICSI cycles using GnRH antagonists. PMID- 23091990 TI - Effect of sperm chromatin condensation on the outcome of intrauterine insemination in patients with male factor infertility. AB - OBJECTIVE: To study the effect of sperm nuclear chromatin condensation on pregnancy rates and rates of abortion in infertile couples with male factor infertility undergoing intrauterine insemination. STUDY DESIGN: A total of 195 infertile couples with male factor infertility undergoing intrauterine insemination (IUI) were included in this prospective study. They were divided into two groups according to sperm chromatin staining by aniline blue stain. The first group included 109 patients having a positive aniline blue staining in < 30% of sperm. The second group included 86 infertile couples in whom > or = 30% spermatozoa were positively stained. All cases were assessed clinically and underwent semen analysis and assessment of chromatin condensation by aniline blue staining. IUI with the partner's sperm was done after semen processing and induction of ovulation; pregnancy rate and rate of abortion were recorded. RESULTS: The pregnancy rate in the first group was 21.6% (24/111), and abortions occurred in 29.2% (6/24). In the second group the pregnancy rate was 18.6% (16/84) and abortions occurred in 56.3% (9/16). There was no statistically significant difference in pregnancy rate between the two groups, while the rate of abortion increased with increased sperm chromatin decondensation. CONCLUSION: Our study concluded that sperm chromatin condensation has no effect on the pregnancy rate, but it has a profound effect on fertilization failure after IUI, therefore assessment of sperm chromatin condensation may be useful as a predictive test for successful pregnancy after intrauterine insemination. PMID- 23091991 TI - Medical student knowledge of global health problems: obstetric fistulas in developing countries. AB - OBJECTIVE: To evaluate medical students in the United States at several medical schools regarding their knowledge of the global health burden of obstetric fistulas. STUDY DESIGN: A cross-sectional survey was conducted in 8 schools across the United States over a period of 6 months. The survey was composed of 18 questions on epidemiology, pathology, and treatment of fistulas. It was a web based module accessed through an emailed link. It was sent to 5,103 medical students' email addresses at the 8 institutions once a week for 4 weeks. SPSS paired student t tests was used for statistical analysis. RESULTS: Of the 1,089 students from 8 medical schools that initially began the survey, 965 completed this voluntary and anonymous survey, with a 21% response rate and 19% completion rate. Overall the students averaged 11/18 (60.7%) correct on this survey. The knowledge of obstetric fistula improved, but not significantly, with increasing level of medical school education, with first-year medical students achieving 10/18 (55%) correct and senior medical students achieving 12/18 (67%) correct (p = 0.1). CONCLUSION: U.S. medical students' knowledge of obstetric fistulas in developing countries does not increase significantly over 4 years of medical school education. While this condition presents largely in the developing world, given rapid globalization as well as increased international health experiences for U.S.-trained health professionals,further effort should be placed in improving medical student knowledge of this devastating condition. PMID- 23091992 TI - Fertility cryopreservation for female cancer patients: attitudes and clinical practices of oncologists in Riyadh, Saudi Arabia. AB - OBJECTIVE: To study and report on the attitudes and clinical practices of oncologists regarding fertility cryopreservation for female cancer patients. STUDY DESIGN: Data was collected using a self administered questionnaire distributed to oncologists in different institutions in Riyadh, Saudi Arabia, during the period May through August 2010. The questionnaire covered their attitudes and clinical practices regarding fertility cryopreservation for female cancer patients. RESULTS: Almost half of the respondents (45.6%) were not familiar with any female fertility preservation options. Although most of the respondents had a positive attitude toward the topic, their referral practice was very poor. About three-quarters (76%) perceived that fertility preservation was very important, and 90% thought that patients would benefit from referral to an infertility specialist for counseling, yet 80% believed that cryopreservation was a complicated process. Almost half of respondents (55.3%) mentioned that they always discuss future fertility with their patients. The most prominent reasons for not discussing this issue were the emergent need to start therapy (50.5%) and the concern about the well-being of future children (34.5%). The majority (86.4%) did not refer their cancer patients to an infertility specialist. CONCLUSION: Oncologists' knowledge about female cryopreservation was lacking, and their attitudes and clinical practice on the topic needed enhancement. PMID- 23091993 TI - Fallopian tubal patency diagnosed by magnetic resonance hysterosalpingography. AB - OBJECTIVE: To discuss the value of magnetic resonance hysterosalpingography (MR HSG) in diagnosing tubal patency of the fallopian tube. STUDY DESIGN: Conventional pelvic magnetic resonance imaging (MRI) and MR HSG were performed on 20 infertile women who had all undergone conventional X-ray HSG or laparoscopy within the previous 6 months. Conventional scanning sequences included T2 weighted axial, T2-weighted sagittal, T2-weighted coronal and T1-weighted axial scans. A balloon catheter was placed into the uterine cavity, and then flash 3D coronal scanning by MRI was performed with the uterine injection of a diluted mixture of Gadodiamide (1:100), and data was reconstructed after digital subtraction scan. RESULTS: Except for a failure caused by a uterine malformation in which the left side of the cervix was not exposed, all patients successfully completed MR HSG inspection. Test results were compared with the previous conventional HSG or laparoscopy inspection results. One patient's results indicated interstitial tubal obstruction on the left side with conventional HSG, but the MR HSG results suggested tubal patency on the same side. A patient with supposed bilateral hydrosalpinx and fallopian tube obstruction under the previous conventional HSG was diagnosed with bilateral hydrosalpinx without obstruction with MR HSG. Another patient with tubal obstruction under conventional X-ray inspection was found to have tubal patency on the right side with MR HSG. The remaining test results in patients were consistent with the previous normal HSG or laparoscopy. Endometrial and pelvic conditions could be well displayed in the course of pelvic MR scan; uterine malformations, uterine fibroids and pelvic conditions such as hydrosalpinx were also well displayed. CONCLUSION: Routine MRI scan with MR-facilitated HSG can better display the fallopian tubes, ovaries, uterus and pelvic-related structures and therefore has clinical value in the diagnosis of infertility. PMID- 23091994 TI - Risk factors associated with cesarean section in a Chinese rural population: a cross sectional study. AB - OBJECTIVE: To identify individual and clinical risk factors associated with cesarean section (CS) delivery in a Chinese rural population. STUDY DESIGN: A cross-sectional study was conducted with data from hospital medical records in Henan Province and Anhui Province, China, using univariate and multiple logistic regression analyses. RESULTS: Between January 1 and December 31, 2008, 46.3% (4,823/10,425) of deliveries were via CS in the study population. After adjustment for other variables, pregnant women in the 25-29-year-old (odds ratio [OR] 1.41, 95% confidence interval [CI] 1.24-1.61) and > or = 30-year-old (OR 1.73, 95% CI 1.46-2.04) age groups were more likely to give birth by CS as compared to the 20-24-year-old age group. Other independent factors related to a higher risk of CS included nonagricultural occupation (OR 1.44, 95% CI 1.27 1.62), gestational hypertension (OR 5.22, 95% CI 3.93-6.93), breech presentation (OR 10.47, 95% CI 6.37-17.20), dystocia (OR 28.62, 95% CI 24.62-33.28), and preterm delivery (OR 1.28, 95% CI 1.06-1.54). CONCLUSION: Age, occupation, gestational hypertension, breech presentation, and dystocia may play an important role in the high level of CS among women in a Chinese rural population. Further comprehensive studies on both medical and nonmedical reasons for CS delivery are needed. PMID- 23091995 TI - Uterine cyst as a cause of chronic pelvic pain: a case report. AB - BACKGROUND: Cystic adenomyosis is a rare form of adenomyosis. Presently, these cysts are generally considered to be of a benign nature and result from cyclical response to menstrual dynamics. CASE: A 31-year-old, African-American female presented for a second opinion with a chief complaint of pelvic pain. She had recently undergone an exploratory laparoscopy with findings suggestive of endometriosis. She was never pregnant and had been taking oral contraceptive pills for over 3 months with little relief This patient had no history of uterine surgery. Pelvic ultrasound performed after her surgery revealed a cystic structure, homogeneously echogenic in the anterior corpus of the uterus, measuring 2.7 x 2.4 x 3.5 cm. This structure appeared consistent with an adenomyotic cyst. The patient's symptoms improved after the transvaginal aspiration, and she no longer required narcotics. CONCLUSION: Of all the possibilities considered, this cyst most closely resembled an adenomyotic cyst in its clinical presentation, location within the myometrium and gross appearance of the chocolate cyst fluid. Imaging is key in distinguishing this process from other congenital and acquired gynecologic entities. Awareness of this condition is important for timely and accurate diagnosis followed by appropriate intervention. PMID- 23091996 TI - Congenital endocardial cushion defect detected during uncomplicated pregnancy: a case report. AB - BACKGROUND: The first symptoms of previously undiagnosed congenital heart disease may become apparent during pregnancy. It is important to recognize structural heart lesions since they require additional monitoring during the prenatal, peripartum, and postpartum periods and are associated with increased maternal and fetal morbidity and mortality. CASE: We report a case of a new diagnosis of an endocardial cushion defect in an otherwise healthy woman in her third trimester whose presenting complaint was dyspnea in the left lateral decubitus position. CONCLUSION: We located only one other case report of a congenital heart lesion first diagnosed during pregnancy. While rare, since the signs and symptoms of congenital heart disease may also occur in normal pregnant women, it is important for the clinician to be aware that structural heart lesions are part of the differential diagnosis. PMID- 23091997 TI - Diabetic ketoacidosis occurring with lower blood glucose levels in pregnancy: a report of two cases. AB - BACKGROUND: Euglycemic diabetic ketoacidosis (DKA) during pregnancy is an unusual condition, but it can occur with normal or modest elevations in blood glucose levels. It is usually a complication of type I diabetes. CASES: We report two cases of euglycemic DKA, in type II diabetes mellitus and in gestational diabetes. Both patients showed blood glucose levels up to 9 mmoL/L (164 mg/dL), ketonuria and metabolic acidosis. They responded to initiation of correct insulin dosages. CONCLUSION: Euglycemic DKA in pregnancy may occur with type II diabetes or in gestational diabetes and requires prompt recognition and treatment. PMID- 23091998 TI - Complete mole with a coexistent normal fetus: a case report. AB - BACKGROUND: The incidence of a coexistent normal fetus is quoted in literature as 1 in 22,000 to 100,000 pregnancies and may be associated with multiple complications including persistent trophoblastic neoplasia. CASE: A 35-year-old woman with a complete mole and a coexistent normal fetus presented with multiple complications but was successfully managed until 30 weeks' gestation and gave birth to a healthy, normal female fetus. After delivery the mother recovered completely with no evidence of persistent trophoblastic disease. CONCLUSION: Although termination of pregnancy is an option chosen by most patients, continuing the pregnancy while optimizing the maternal condition by appropriate management of complications can result in a successful outcome. PMID- 23091999 TI - Do placentas from hysterectomies performed for placenta accreta show adherent muscle? PMID- 23092000 TI - Anisakis simplex: current knowledge. AB - Anisakiasis, firstly described in 1960s in the Netherlands, is a fish-borne parasitic disease caused by the consumption of raw or undercooked fish or cephalopods contaminated by third stage (13) larvae of the Anisakidae family, in particular Anisakis simplex (As), A. pegreffii and Pseudoterranova decipiens. Every year, approximately 20,000 cases of anisakiasis were reported worldwide, over 90% are from Japan and most others in Spain, the Netherlands and Germany, depending on the habits of fish consuming. Live As larvae can elicit i) a parasitic infection of the digestive tract or, occasionally, other organs, causing erosive and/or haemorrhagic lesions, ascites, perforations until granulomas and masses, if larva is not removed, and ii) allergic reactions, as anaphylaxis, acute/chronic urticaria and angioedema. Like other parasite infestations, As larva induces an immune adaptive response characterised by T lymphocyte proliferation with polyclonal and monoclonal (responsible for As allergic symptoms) IgE production, eosinophilia and mastocytosis. Several As allergens, many of which thermostable, were described In particular the major allergen Ani s 1 and Ani s 7 could characterized a past or a recent infection. There is a general agreement that an active infection is required to initiate allergic sensitivity to Anisakis. Until now, the only effective treatment for anisakiasis is the endoscopic removal of live larvae and the best protection against anisakiasis is to educate consumers about the dangers of eating raw fish and to recommend avoiding the consumption of raw or inadequately thermally treated marine fish or cephalopods. PMID- 23092001 TI - Ragweed allergy in northern Italy: are patterns of sensitization changing? AB - BACKGROUND: Previous surveys performed in this area showed that the age at onset of ragweed allergy in monosensitized subjects is about 35. OBJECTIVE: To detect whether a reduction in the mean age of ragweed sensitization in the area of Milan has taken place after the last survey. METHODS: All patients developing clinical ragweed pollen allergy in the years 2007-2010 and monosensitized to this allergen seen were included. 30 randomly selected subjects already sensitized to at least one other allergen source among grass, pellitory, or mite who developed ragweed allergy during the same period served as controls. RESULTS: The 137 patients showed a median age at onset of ragweed allergy of 36-40 years in the years 2007 2010 with no tendency to reduction. About 10% of patients were < 20 years old in 3 of the 4 study years. 15% of patients were > 50 years old at onset, and 3 of them were > 70. In the control group the mean age at onset of ragweed allergy was 31,6 years (median 32,5 years; range 10-60; p < 0.001 vs patients). CONCLUSION: In this area monosensitization to ragweed occurs steadily at an adult age. In already allergic subjects it occurs at a younger age. The age at onset of allergy to one specific airborne allergen source seems to depend on several variables, including exposure duration, atopic status, and specific features of the allergen. PMID- 23092002 TI - Aspirin challenge/desensitisation before coronary stenting in subjects with history of hypersensitivity. A pragmatic approach. AB - BACKGROUND: Aspirin hypersensitivity may represent a major problem in patients with ischemic coronary disease who need a stenting procedure. In those patients, clinically unsettled reasonably quick desensitisation procedures are needed. In our study we attempted to select the most suitable procedure on the basis of characteristics and severity of ASA hypersensitivity. METHODS: Thirty patients with a history of mild reactions to anti-inflammatory doses of aspirin (> 325 mg) were considered at low risk and underwent a tolerance test in 5 steps. Thirty-one patients, with a history of severe reactions to anti-platelet doses of aspirin 0 mg) underwent a slow desensitisation in 12 steps, reaching a cumulative dose of 150 mg ASA in 220 minutes. RESULTS: In the first group, 29 patients tolerated the challenge. One developed urticaria, thus underwent challenge/desensitisation and achieved tolerance. In the second group, 3 patients did not tolerate the procedure and had to discontinue. CONCLUSION. Our approach to aspirin hypersensitivity in patients needing coronary stenting, based on a severity stratification, allowed to achieve an effective tolerance to aspirin in the majority of subject in a reasonable short time. PMID- 23092003 TI - Selective anaphylaxis to paracetamol in a child. AB - Paracetamol anaphylaxis is a very rare event, with only a few cases described in literature and even less reported in children. We report the case of a 15-year old boy, referred to Immunoallergy Department due to four reproducible episodes of anaphylaxis after paracetamol administration, since the age of 8 years. The most severe episode occurred at 12 years, characterized by glottis edema with respiratory distress, hypotension, generalized urticaria and facial edema, immediately after intravenous administration of paracetamol during a post operatory recovery. He had always and still tolerates ibuprofen; an oral challenge test with meloxicam was negative. Skin prick and intradermal tests with paracetamol were negative. Serum-specific IgE and CAST to paracetamol were also negative. This report provides an alert to health-care professionals regarding the potential severity of reactions occurring within the therapeutic range of this widely used drug. PMID- 23092004 TI - Monosensitization to a novel plane pollen allergen. AB - A patient monosensitized to plane pollen is described On ISAC 103 the patients showed IgE reactivity to both Pla a 1 and Pla a 2, but on immunoblot analysis the serum showed a single IgE reactivity at about 50 kDa allergen. PMID- 23092005 TI - Onset of oral allergic syndrome during birch sublingual immunotherapy. AB - Pollen allergy may be frequently associated with oral allergy to fruits and/or vegetables (the so called oral allergic syndrome). Some studies reported a possible positive effect exerted by allergen-specific immunotherapy on OAS course, while others did not. A case of OAS case onset after starting sublingual immunotherapy is reported. PMID- 23092006 TI - Sudden loss of cow's milk tolerance in a long-sensitized patient. AB - The prevalence of food allergy and anaphylaxis in children is reported to be increasing in recent years. Evidence suggests that exposure to large doses of antigen favors the maintenance of tolerance. We report a case of sudden loss of cow's milk tolerance in a long-sensitized girl with celiac disease after a short period of milkless diet. We hypothesize that the continuous intake of high quantities of antigen sustained tolerance despite high levels of specific IgE and that, in the presence of epithelial barrier dysfunction caused by celiac disease, the few weeks of allergen-free diet led to a rapid loss of tolerance. PMID- 23092007 TI - Fever of unknown origin as unique symptom of an indolent mastocytosis. AB - A 39-years-old man afferred to our hospital for a fever lasting for more than 6 months, without abnormalities at physical examination (in particular no skin alterations); a recent laboratory and instrumental investigation was ineffective and so a fever of unknown origin (FUO) was diagnosed Since he reported an history of infantile mastocytosis (usually auto-resolving) we evaluated his serum tryptase levels that resulted of 49 ug/L (normal value 20 ug/L), raising the doubt of the presence of an active mastocytosis. The following bone marrow evaluation showed aggregates of CD117 positive cells and a c-Kit point mutation at codon D 816V confirming the diagnosis of indolent mastocytosis.The present case confirm that FUO can be caused by an otherwise asymptomatic indolent mastocytosis, thus suggesting to include the serum-tryptase level measurement in the diagnostic approach to this pathological condition, at least in selected cases. PMID- 23092008 TI - Acquired C1-inhibitor deficiency: a case report. AB - Angioedema due to C1--inhibitor deficiency may be hereditary (HAE) or acquired (AAE). AAE is a very rare condition, whose prevalence is possibly underestimated, as it is often unrecognized. AAE usually occurs after the fourth decade of life, and it is commonly associated to an underlying disease, mainly lymphoproliferative disorders. We report a 74-years old woman with recurrent episodes of angioedema involving upper airways in which diagnosis was obtained a long time after symptoms onset. A concomitant B cell leukaemia was also diagnosed This report stresses the importance of the recognition of AAE: a delayed diagnosis is indeed associated to the risk of severe life-threatening episodes, unresponsive to the usual therapy of common form of angioedema. AAE should be considered as a possible diagnosis in subjects with adult onset of angioedema: a careful clinical history is basic, since the clinical features and the time course are often suggestive of the disease. PMID- 23092009 TI - Assessing the effects of large mobile predators on ecosystem connectivity. AB - Large predators are often highly mobile and can traverse and use multiple habitats. We know surprisingly little about how predator mobility determines important processes of ecosystem connectivity. Here we used a variety of data sources drawn from Palmyra Atoll, a remote tropical marine ecosystem where large predators remain in high abundance, to investigate how these animals foster connectivity. Our results indicate that three of Palmyra's most abundant large predators (e.g., two reef sharks and one snapper) use resources from different habitats creating important linkages across ecosystems. Observations of cross system foraging such as this have important implications for the understanding of ecosystem functioning, the management of large-predator populations, and the design of conservation measures intended to protect whole ecosystems. In the face of widespread declines of large, mobile predators, it is important that resource managers, policy makers, and ecologists work to understand how these predators create connectivity and to determine the impact that their depletions may be having on the integrity of these linkages. PMID- 23092010 TI - Seed dispersal by a captive corvid: the role of the 'Alala (Corvus hawaiiensis) in shaping Hawai'i's plant communities. AB - Species loss can lead to cascading effects on communities, including the disruption of ecological processes such as seed dispersal. The endangered 'Alala (Corvus hawaiiensis), the largest remaining species of native Hawaiian forest bird, was once common in mesic and dry forests on the Big Island of Hawai'i, but today it exists solely in captivity. Prior to its extinction in the wild, the 'Alala may have helped to establish and maintain native Hawaiian forest communities by dispersing seeds of a wide variety of native plants. In the absence of 'Alala, the structure and composition of Hawai'i's forests may be changing, and some large-fruited plants may be dispersal limited, persisting primarily as ecological anachronisms. We fed captive 'Alala a variety of native fruits, documented behaviors relating to seed dispersal, and measured the germination success of seeds that passed through the gut of 'Alala relative to the germination success of seeds in control groups. 'Alala ate and carried 14 native fruits and provided germination benefits to several species by ingesting their seeds. Our results suggest that some plants rely heavily on 'Alala for these services. In captivity, juvenile birds displayed seed dispersal behaviors more often than adult birds for most fruiting plants in our study. We introduced captive 'Alala to two large-fruited, dry-forest plants, not previously recorded as 'Alala food resources, but which may once have been part of their natural diet. The seed dispersal behavior that 'Alala displayed toward these species supports the inclusion of dry and mesic forests in 'Alala habitat restoration plans and adds weight to the idea that plant dispersal limitation may contribute to the rarity of these plants. Our study provides evidence that 'Alala have the capacity to play a vital role in maintaining the diversity of fruiting plants in native Hawaiian forests through seed dispersal and enhanced seed germination, thus adding greater urgency to efforts to restore 'Alala to their former range. PMID- 23092011 TI - Survival analysis of a critical resource for cavity-nesting communities: patterns of tree cavity longevity. AB - Tree cavities are a vital multi-annual resource used by cavity-nesting birds and mammals for nesting and shelter. The abundance of this resource will be influenced by the rates at which cavities are created and destroyed. We applied the demographic concepts of survival and longevity to populations of tree holes to investigate rates of loss for cavities in three tree species, as well as how characteristics of nest trees, habitat type, and species of excavator affected the persistence of tree cavities in trembling aspen, Populus tremuloides (95% of cavities were in aspen trees), in interior British Columbia, Canada. By modeling survival of 1635 nesting cavities in aspen over a time span of 16 years, we found that the decay stage of the nest tree was the most important factor determining cavity longevity. Cavities in trees with advanced decay had a relatively short median longevity of 7 years (95% CI 6-9 years), whereas those in living trees had a median longevity of more than 15 years. We found that cavity longevity was greater in continuous forest than in aspen grove habitat. Interestingly, cavities formed by weak excavators survived as long as those created by Northern Flickers (Colaptes auratus), despite occurring in more decayed tree stems. Thus, weak excavators may be selecting for characteristics that make a tree persistent, such as a broken top. Our results indicate that retention of cavities in large, live aspen trees is necessary to conserve persistent cavities, and that cavity longevity will have a large effect on the structure and function of cavity-using vertebrate communities. PMID- 23092012 TI - Predicted eelgrass response to sea level rise and its availability to foraging Black Brant in Pacific coast estuaries. AB - Managers need to predict how animals will respond to habitat redistributions caused by climate change. Our objective was to model the effects of sea level rise on total eelgrass (Zostera marina) habitat area and on the amount of that area that is accessible to Brant geese (Branta bernicla), specialist grazers of eelgrass. Digital elevation models were developed for seven estuaries from Alaska, Washington, California (USA), and Mexico. Scenarios of future total eelgrass area were derived from combinations of estuarine specific sediment and tectonic rates (i.e., bottom change rate) with three rates of eustatic sea level rise (ESLR). Percentages of total eelgrass areas that were accessible to foraging Brant were determined for December when the birds overwinter at more southerly sites and in April as they move north to sites where they build body stores on their way to nesting areas in Alaska. The modeling showed that accessible eelgrass area could be lower than total area due to how daytime low-tide height, eelgrass shoot length, and the upper elevation of eelgrass determined Brant reaching depth. Projections of future eelgrass area indicated that present-day ESLR (2.8 mm/yr) and bottom change rates should sustain the current pattern of estuarine use by Brant except in Morro Bay, where use should decrease because eelgrass is being ejected from this estuary by a positive bottom change rate. Higher ESLR rates (6.3 and 12.7 mm/yr) should result in less Brant use of estuaries at the northern and southern ends of the flyway, particularly during the winter, but more use of mid-latitude estuaries. The capacity of mid-latitude estuaries to function as Brant feeding refugia, or for these estuaries and Izembek Lagoon to provide drift rather than attached leaves, is eventually limited by the decrease in total eelgrass area, which is a result of a light extinction affect on the eelgrass, or the habitat being pushed out of the estuary by positive tectonic rates. Management responses are limited to the increase or decrease of sediment supply and the relocation of levees to allow for upslope migration of eelgrass habitat. PMID- 23092013 TI - Biological surrogacy in tropical seabed assemblages fails. AB - Surrogate taxa are used widely to represent attributes of other taxa for which data are sparse or absent. Because surveying and monitoring marine biodiversity is resource intensive, our understanding and management of marine systems will need to rely on the availability of effective surrogates. The ability of any marine taxon to adequately represent another, however, is largely unknown because there are rarely sufficient data for multiple taxa in the same region(s). Here, we defined a taxonomic group to be a surrogate for another taxonomic group if they possessed similar assemblage patterns. We investigated effects on surrogate performance of (1) grouping species by taxon at various levels of resolution, (2) selective removal of rare species from analysis, and (3) the number of clusters used to define assemblages, using samples for 11 phyla distributed across 1189 sites sampled from the seabed of Australia's Great Barrier Reef. This spatially and taxonomically comprehensive data set provided an opportunity for extensive testing of surrogate performance in a tropical marine system using these three approaches for the first time, as resource and data constraints were previously limiting. We measured surrogate performance as to how similarly sampling sites were divided into assemblages between taxa. For each taxonomic group independently, we grouped sites into assemblages using Hellinger distances and medoid clustering. We then used a similarity index to quantify the concordance of assemblages between all pairs of taxonomic groups. Surrogates performed better when taxa were grouped at a phylum level, compared to taxa grouped at a finer taxonomic resolution, and were unaffected by the exclusion of spatially rare species. Mean surrogate performance increased as the number of clusters decreased. Moreover, no taxonomic group was a particularly good surrogate for any other, suggesting that the use of any one (or few) group(s) for mapping seabed biodiversity patterns is imprudent; sampling several taxonomic groups appears to be essential for understanding tropical/subtropical seabed communities. Consequently, where resource constraints do not allow complete surveying of biodiversity, it may be preferable to exclude rare species to allow investment in a broader range of taxonomic groups. PMID- 23092014 TI - Regime shift indicators fail under noise levels commonly observed in ecological systems. AB - Ecological regime shifts are rapid, potentially devastating changes in ecosystem state that last for extended periods of time. Previous theoretical work has generated numerous early-warning indicators of regime shifts, some of which have been empirically demonstrated in closed ecological systems. Here we evaluated a suite of indicators using a previously studied three-species model under conditions likely to be observed in field studies of open ecological systems. Simulations included large correlated fluctuations in extrinsic noise and a rapidly changing driving variable, while indicators were calculated using sparsely sampled time series. All indicators performed poorly under these conditions, particularly during the beginning of the regime shift. Overall, the best performing indicator was a rise in variance. Future research should focus on methods for setting benchmark values of early warning indicators and for identifying indicators that work for sparsely sampled data sets. PMID- 23092015 TI - Causes of recruitment failure in freshwater mussel populations in southeastern New York. AB - Populations of freshwater mussels (Unionoida) are declining or disappearing from many waters around the world. In many declining populations, recruitment fails before adult mortality occurs, resulting in relict populations that can persist for decades. We tested whether recruitment failure in populations of the freshwater mussel Elliptio complanata was associated with invasion of nonnative crayfish, loss of a primary fish host (American eel Anguilla rostrata), excessive inputs of fine sediments, or unfavorable interstitial water chemistry (too little dissolved oxygen or too much un-ionized ammonia). We sampled mussel populations, crayfish populations, and environmental conditions at 14 sites on wadeable streams in southeastern New York. Five of the mussel populations had little or no recent recruitment. We found no association between recruitment failure and crayfish, American eels, fine sediments, or interstitial dissolved oxygen. In contrast, recruitment failure was strongly associated with high concentrations (>0.2 microg N/L) of un-ionized ammonia. This threshold is much lower than thresholds for acute ammonia toxicity identified in laboratory studies. We suggest that excessive concentrations of interstitial un-ionized ammonia may be responsible for widespread declines of freshwater mussel populations, especially in agricultural areas. PMID- 23092016 TI - Making leaps in amphibian ecotoxicology: translating individual-level effects of contaminants to population viability. AB - Concern that environmental contaminants contribute to global amphibian population declines has prompted extensive experimental investigation, but individual-level experimental results have seldom been translated to population-level processes. We used our research on the effects of mercury (Hg) on American toads (Bufo americanus) as a model for bridging the gap between individual-level contaminant effects and amphibian population viability. We synthesized the results of previous field and laboratory studies examining effects of Hg throughout the life cycle of B. americanus and constructed a comprehensive demographic population model to evaluate the consequences of Hg exposure on population dynamics. Our model explicitly considered density-dependent larval survival, which is known to be an important driver of amphibian population dynamics, and incorporated two important factors that have seldom been considered in previous amphibian modeling studies: environmental stochasticity and sublethal effects. We demonstrated that decreases in embryonic survival and sublethal effects (e.g., reduced body size) that delay maturation have minor effects on population dynamics, whereas contaminant effects that reduce late-larval or post-metamorphic survival have important population-level consequences. We found that excessive Hg exposure through maternal transfer or larval diet, alone, had minor effects on B. americanus populations. Simultaneous maternal and dietary exposure resulted in reduced population size and a dramatic increase in extinction probability, but explicit prediction of population-level effects was dependent on the strength of larval density dependence. Our results suggest that environmental contaminants can influence amphibian population viability, but that highly integrative approaches are needed to translate individual-level effects to populations. PMID- 23092017 TI - Cascading effect of economic globalization on human risks of scrub typhus and tick-borne rickettsial diseases. AB - The increase in global travel and trade has facilitated the dissemination of disease vectors. Globalization can also indirectly affect vector-borne diseases through the liberalization of cross-border trade, which has far-reaching, worldwide effects on agricultural practices and may in turn influence vectors through the modification of the ecological landscape. While the cascading effect of economic globalization on vector-borne diseases, sometimes acting synergistically with regional agricultural policy, could be substantial and have significant economic, agricultural, and public health implications, research into this remains very limited. We evaluated how abandonment of rice paddies in Taiwan after joining the World Trade Organization, along with periodic plowing, an agricultural policy to reduce farm pests in abandoned fields can unexpectedly influence risks to diseases transmitted by ticks and chiggers (larval trombiculid mites), which we collected from their small-mammal hosts. Sampling was limited to abandoned (fallow) and plowed fields due to the challenge of trapping small mammals in flooded rice paddies. Striped field mice (Apodemus agrarius) are the main hosts for both vectors. They harbored six times more ticks and three times more chiggers in fallow than in plowed plots. The proportion of ticks infected with Rickettsia spp. (etiologic agent of spotted fever) was three times higher in fallow plots, while that of Orientia tsutsugamushi (scrub typhus) in chiggers was similar in both treatments. Fallow plots had more ground cover and higher vegetation than plowed ones. Moreover, ticks and chiggers in both field types were dominated by species known to infest humans. Because ticks and chiggers should exhibit very low survival in flooded rice paddies, we propose that farm abandonment in Taiwan, driven by globalization, may have inadvertently led to increased risks of spotted fever and scrub typhus. However, periodic plowing can unintentionally mitigate vector burdens. Economic globalization can have unexpected consequences on disease risk through modification of the agricultural landscape, but the outcome may also be influenced by agricultural policies, calling for further research on vector-borne diseases and their control from broader perspectives. PMID- 23092018 TI - Mixtures of genetically modified wheat lines outperform monocultures. AB - Biodiversity research shows that diverse plant communities are more stable and productive than monocultures. Similarly, populations in which genotypes with different pathogen resistance are mixed may have lower pathogen levels and thus higher productivity than genetically uniform populations. We used genetically modified (GM) wheat as a model system to test this prediction, because it allowed us to use genotypes that differed only in the trait pathogen resistance but were otherwise identical. We grew three such genotypes or lines in monocultures or two line mixtures. Phenotypic measurements were taken at the level of individual plants and of entire plots (population level). We found that resistance to mildew increased with both GM richness (0, 1, or 2 Pm3 transgenes with different resistance specificities per plot) and GM concentration (0%, 50%, or 100% of all plants in a plot with a Pm3 transgene). Plots with two transgenes had 34.6% less mildew infection and as a consequence 7.3% higher seed yield than plots with one transgene. We conclude that combining genetic modification with mixed cropping techniques could be a promising approach to increase sustainability and productivity in agricultural systems, as the fitness cost of stacking transgenes within individuals may thus be avoided. PMID- 23092019 TI - Shape of patch edges affects edge permeability for meadow voles. AB - Human development typically fragments natural habitats into patches, affecting population and metapopulation dynamics via changes in animal behavior. Emigration from one habitat patch to another has a large effect on population and metapopulation dynamics. One factor that affects emigration is permeability of patch edges. This study looks at the effects of edge shape (convex, concave, and straight) on edge permeability for meadow voles (Microtus pennsylvanicus).. I tested five hypotheses for responses of animal movement to patch shape: (1) neutral edge response; (2) edge attraction; (3) edge avoidance; (4) time minimizing, in which an animal attempts to minimize the time spent in inhospitable matrix, and thus travels as far as possible in the patch before crossing the edge; and (5) protection, in which an animal attempts to maximize protection while in the inhospitable matrix by keeping the patch close by. These hypotheses were tested by an experimental manipulation of meadow vole habitats. A strip was mowed with different edge shapes through an old field, and vole response was measured by tracking plates. Voles crossed edges at concave treatments twice as often compared to convex and straight shapes. Hypotheses (2) and (5) were supported. Although edge attraction causes a passive effect of a decrease in edge-crossing at concavities, this effect was eclipsed by the active effect of voles choosing to cross at concavities. The results can be generalized to edge tortuosity in general. Conservation biologists should consider edge shapes when exploring the effects of habitat fragmentation on animal populations. PMID- 23092020 TI - Gauging climate change effects at local scales: weather-based indices to monitor insect harassment in caribou. AB - Climate change is occurring at an accelerated rate in the Arctic. Insect harassment may be an important link between increased summer temperature and reduced body condition in caribou and reindeer (both Rangifer tarandus). To examine the effects of climate change at a scale relevant to Rangifer herds, we developed monitoring indices using weather to predict activity of parasitic insects across the central Arctic. During 2007-2009, we recorded weather conditions and used carbon dioxide baited traps to monitor activity of mosquitoes (Culicidae), black flies (Simuliidae), and oestrid flies (Oestridae) on the post calving and summer range of the Bathurst barren-ground caribou (Rangifer tarandus groenlandicus) herd in Northwest Territories and Nunavut, Canada. We developed statistical models representing hypotheses about effects of weather, habitat, location, and temporal variables on insect activity. We used multinomial logistic regression to model mosquito and black fly activity, and logistic regression to model oestrid fly presence. We used information theory to select models to predict activity levels of insects. Using historical weather data, we used hindcasting to develop a chronology of insect activity on the Bathurst range from 1957 to 2008. Oestrid presence and mosquito and black fly activity levels were explained by temperature. Wind speed, light intensity, barometric pressure, relative humidity, vegetation, topography, location, time of day, and growing degree-days also affected mosquito and black fly levels. High predictive ability of all models justified the use of weather to index insect activity. Retrospective analyses indicated conditions favoring mosquito activity declined since the late 1950s, while predicted black fly and oestrid activity increased. Our indices can be used as monitoring tools to gauge potential changes in insect harassment due to climate change at scales relevant to caribou herds. PMID- 23092021 TI - Ecosystem greenspots: identifying potential drought, fire, and climate-change micro-refuges. AB - In response to climate change and other threatening processes there is renewed interest in the role of refugia and refuges. In bioregions that experience drought and fire, micro-refuges can play a vital role in ensuring the persistence of species. We develop and apply an approach to identifying potential micro refuges based on a time series of remotely sensed vegetation greenness (fraction of photosynthetically active radiation intercepted by the sunlit canopy; fPAR). The primary data for this analysis were NASA MODIS 16-day L3 Global 250 m (MOD13Q1) satellite imagery. This method draws upon relevant ecological theory (source sink habitats, habitat templet) to calculate a micro-refuge index, which is analyzed for each of the major vegetation ecosystems in the case-study region (the Great Eastern Ranges of New South Wales, Australia). Potential ecosystem greenspots were identified, at a range of thresholds, based on an index derived from: the mean and coefficient of variance (COV) of fPAR over the 10-year time series; the minimum mean annual fPAR; and the COV of the 12 values of mean monthly fPAR. These greenspots were mapped and compared with (1) an index of vascular plant species composition, (2) environmental variables, and (3) protected areas. Potential micro-refuges were found within all vegetation ecosystem types. The total area of ecosystem greenspots within the upper 25% threshold was 48 406 ha; around 0.2% of the total area of native vegetation (23.9 x 10(6) ha) in the study region. The total area affected by fire was 3.4 x 10(6) ha. The results of the environmental diagnostic analysis suggest deterministic controls on the geographical distribution of potential micro-refuges that may continue to function under climate change. The approach is relevant to other regions of the world where the role of micro-refuges in the persistence of species is recognized, including across the world's arid zones and, in particular, for the Australian, southern African, and South American continents. Micro-refuge networks may play an important role in maintaining beta-diversity at the bio-region scale and contribute to the stability, resilience, and adaptive capacity of ecosystems in the face of ever-growing pressures from human-forced climate change, land use, and other threatening processes. PMID- 23092022 TI - [Application of fascia of the temporal muscle and cartilage of the auricular tragus in myringoplasty in children]. AB - INTRODUCTION: Perforation of the tympanic membrane in children may be the cause of recurrent middle ear infection and loss of hearing. OBJECTIVE: The aim of this study was to analyze the application of different reconstructive materials in surgical technique myringoplasty. METHODS: We performed 88 myringoplasties due to auricular tragus perforation in 76 children (aged 4 to 16 years, mean 11.9 years) from July 2001 to July 2009. Age, gender, size and the site of perforation, status of the contra lateral ear, underlying cause of the perforations, surgical technique, preoperative and postoperative hearing levels and postoperative complications were recorded and analyzed. In performing myringoplasty we used fascia of the temporal muscle and cartilage of the auricular tragus. RESULTS: In 43 (48%) patients we used fascia of the temporal muscle and in 45 (52%) cartilage of the auricular tragus. Graft success was defined as an intact eardrum at 12 months postoperatively and improvement in the perception of air-bone gap of 10 dB, which we recorded in 73 (83%) cases. Re-perforations were recorded in 12 (13%) patients, of whom in 8 (18.6%) cases we used the temporal fascia and in 4 (9.3%) cases a tragal cartilage. Retraction of the tympanic membrane was recorded in 3 (4%) cases with the temporal fascia. CONCLUSION: Myringoplasty is a reasonably successful method with good functional results in pediatric patients. Risk factors of surgical failure are young age, the size of auricular tragus perforation and pathological conditions of the contra lateral ear. The tragal cartilage gives better results in cases with bilateral perforations because the possibility of retractions and re-perforations is lower. Relatively small number of patients is probably the reason that, exept for young age, differences between the two groups did not reach the level of statistical significance. PMID- 23092023 TI - [Analysis of soft tissue thickness in persons with malocclusions of Class II division 1 and Class II division 2]. AB - INTRODUCTION: Different malocclusions indicate different thickness of facial soft tissue. OBJECTIVE: The aim of the study was to establish the differences in the thickness of facial soft tissue profile in persons with dentoskeletal Class II/1 and II/2 relationship. METHODS: In the study we used cephalometric rendgenograms profile analysis of 60 patients aged 12-18 years of the Dental Clinic in Nis who had not previously undergone orthodontical treatment. According to the dentoskeletal jaws relations the patients were divided into two groups with Class II division 1 and Class II class division 2. In all of them the standard dentoskeletal profile analysis by Steiner and soft tissue profile analysis by Burston was done. The obtained findings were statistically analyzed and the comparison between the studied groups was performed. RESULTS: The results indicated the following: in the patients with Class II/1 relationship there was a significantly thinner upper lip (t=5.741; p<0.0001), thinner upper lip sulcus (t=3.858; p<0.001) and significantly thinner lower lip (t=2.009; p<0.05) in relation to the patients with Class 11/2. Compensatory effect in the Class II/1 patients was more distinctive in females, as their soft tissue profiles were thicker. In Class 11/2 patients this relationship was in favor of males. CONCLUSION: The facial soft tissue profile indicated significant differences in the thickness dependant on the type of malocclusion and gender. Because of their great variability and a significant participation in the formation of the profile, while planning orthodontic therapy, it is necessary to pay them full attention, with obligatory analysis of the dentoskeletal profile. PMID- 23092024 TI - [Teeth size reduction in the prehistoric populations in Serbia]. AB - INTRODUCTION: Anthropological studies show craniofacial changes with a reduction in teeth size during evolution of the human population. OBJECTIVE: The objective was to measure and compare the sizes of teeth in the population of the Mesolithic Neolithic sites in the Iron Gate Gorge and the population from the Early Bronze Age site of Mokrin. METHODS: The study included teeth without advanced wear near the pulp. The material was divided according to the site of the skeletal population in two groups. Group 1 comprised 107 teeth from the Mesolithic Neolithic sites Lepenski Vir and Vlasac. Group 2 included 158 teeth from the Mokrin graveyard dated in the Early Bronze Age. The mesio-distal diameter was measured in all teeth, while the vestibulo-oral diameter was measured in the molars only. Using the two-factor analysis of variance, the influence of sex, site and their interaction on the size of the teeth were investigated. RESULTS: The vestibulo-oral diameter of the upper third molar was significantly higher in males compared to females. The comparison between the groups showed that the vestibulooral diameter of the lower first molar was significantly higher in group 1. CONCLUSION: The present difference in teeth size indicates the existence of reduction during the prehistoric times. However, the time period between the populations studied is probably too short to be manifested on a large number of teeth. PMID- 23092025 TI - [Prospective follow-up of nebivolol in the treatment of arterial hypertension]. AB - INTRODUCTION: Nebivolol, a third-generation beta-blocker (BB) shows a highly selective beta-blockade and specific vasodilating effects due to getting free nitro-oxide from the dysfunctional endothelium. OBJECTIVE: The aim of the study was to investigate the antihypertensive effect of nebivolol in patients with arterial hypertension (AH) of both sexes. METHODS: Systolic and diastolic blood pressure (BP), heart rate and serum glycemia, creatinin, cholesterol and trygliceride were measured after a 6-week treatment with a single 5 mg dose of nebivolol once daily so as to assess its efficacy and metabolic effects, as well as its tolerance by using a questionnaire answered by physicians and patients. RESULTS: Out of 520 patients with mild or moderate AH, 430 (82.7%) were treated with nebivolol as monotherapy. After a 6-week treatment with nebivolol, with very good tolerability and neutral metabolic effects, systolic BP was significantly decreased (in male from initial 165 +/- 19 to 129 +/- 12 mm Hg, and female from initial 169 +/- 22 to 132 +/- 15 mm Hg at the end of the study; average decrease 22.3%, p<0.001) and as well as diastolic BP (male from initial 103 +/- 12 to 79 +/- 6 mm Hg and female from initial 100 +/- 9 to 82 +/- 7 mm Hg, average decrease 22.6%; p<0.001). CONCLUSION: After a 6-week treatment nebivolol significantly decreased systolic and diastolic BP in patients with mild and moderate AH, independently of the sex. PMID- 23092026 TI - [Physiological adaptation of anthropometric and cardiovascular parameters on physical activity of elite athletes]. AB - INTRODUCTION: Specific morphological and functional characteristics of athletes have a significant role in determining athletes' sports results and can be also used to assess the athlete's individual potential. OBJECTIVE: The aim of the study was to compare anthropometric characteristics and cardiovascular parameters in trained subjects to those of untrained subjects. METHODS: A total number of 25 trained (17.30 +/- 0.83 years) and 21 (18.52 +/- 1.52 years) untrained male subjects participated in this study. Body weight and height were measured and these values were used to compute body mass index (BMI).The bioelectrical impedance analysis (BIA) method was used to estimate body fat percentage (%BF). Cardiovascular parameters were monitored in rest (rest heart rate, systolic and diastolic blood pressure) during ergospirometric testing (maximal oxygen consumption, maximal heart rate) and in recovery (heart rate in the first and third minute of recovery). RESULTS: Body mass, height and BMI (p<0.01) were significantly higher, although BF% was lower in trained group when compared to untrained, but the difference was not statistically significant. Heart rate in rest and recovery were significantly lower (p<0.05) in trained group when compared to untrained, although maximal oxygen consumption and maximal heart rate were significantly higher in trained group (p<0.01, p<0.05, respectevely). CONCLUSION: Our results show that in trained subjects, water polo players, regular intense physical activity lead to adaptive changes of anthropometric parameters and adaptive changes on the cardiovascular system. PMID- 23092027 TI - [Correlation between arterial and venous blood gas analysis parameters in patients with acute exacerbation of chronic obstructive pulmonary disease]. AB - INTRODUCTION: Arterial blood gas (ABG) analyses have an important role in the assessment and monitoring of the metabolic and oxygen status of patients with acute exacerbation of chronic obstructive pulmonary disease (COPD). Arterial puncture could have a lot of adverse effects, while sampling of venous blood is simpler and is not so invasive. OBJECTIVE: The aim of this study was to evaluate whether venous blood gas (VBG) values of pH, partial pressure of carbon dioxide (PCO2), partial oxygen pressure (PO2), bicarbonate (HCO3), and venous and arterial blood oxygen saturation (SO2) can reliably predict ABG levels in patients with acute exacerbation of COPD. METHODS: Forty-seven patients with a prior diagnosis of COPD were included in this prospective study. The patients with acute exacerbation of this disease were examined at the General Hospital EMS Department in Prijepolje. ABG samples were taken immediately after venous sampling, and both were analyzed. RESULTS: The Pearson correlation coefficients between arterial and venous parameters were 0.828, 0.877, 0.599, 0.896 and 0.312 for pH, PCO2, PO2, HCO3 and SO2, respectively. The statistically significant correlation between arterial and venous pH, PCO2 and HCO3, values was found in patients with acute exacerbation of COPD (p<0.001). CONCLUSION: When we cannot provide arterial blood for analysis, venous values of the pH, Pv,CO2 and HCO3 parameters can be an alternative to their arterial equivalents in the interpretation of the metabolic status in patients with acute exacerbation of COPD, while the values of venous Pv,O, and Sv,O2 cannot be used as predictors in the assessment of oxygen status of such patients. PMID- 23092028 TI - [Risk factors for acute respiratory distress syndrome development in patients with type A influenza (H1N1)]. AB - INTRODUCTION: Acute respiratory distress syndrome (ARDS) is a significant complication in patients with type A influenza (H1N1) due to the severity of the disease and adverse outcome. OBJECTIVE: The aim of the study was to identify risk factors for the development of ARDS in patients with type A influenza (H1N1) and outcome of ARDS. METHODS: The research was conducted as a case series study, and included patients admitted at the Clinical Center in Kragujevac during the 2009 and 2010 flu season. Data for the study were obtained from patients' medical records, inclusion criteria having been determined in accordance with recommendations of the Expert Methodological Guide for Controlling Spread of Pandemic Influenza in the Republic of Serbia. Primary data analysis was performed using descriptive statistics and a statistical method for testing hypotheses. Dependence analysis was performed using simple logistic regression. The statistical hypotheses were tested at the 0.05 level of significance. RESULTS: The case group consisted of 14 patients who developed ARDS, while the control group was composed of 34 patients with influenza but without ARDS (group alignment performed by age). Simple logistic regression analysis identified the following risk factors for the development of ARDS: diabetes mellitus type 1 or 2 (p=0.028), high levels of C-reactive protein (p=0.004), aspartate aminotransferase (p=0.006), urea (p=0.028), creatine kinase (p=0.001), lactate dehydrogenase (p=0.005) and longer time elapsed from disease symptoms onset to the administration of specific antiviral therapy administration (p=0.021). CONCLUSION: The research showed that diabetes, late initiation of antiviral therapy and some laboratory tests are risk factors for ARDS development in patients with type A influenza (H1N1). PMID- 23092029 TI - [Efficacy and safety of peginterferon alfa-2a and ribavirin treatment of chronic hepatitis C in the Republic of Serbia]. AB - INTRODUCTION: Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. Pegylated interferon alfa-2a or 2b (PEG IFN alfa 2a or 2b) and ribavirin (RBV) represent a standard treatment of chronic hepatitis C (CHC). Sustained virological response (SVR), defined as continued undetectable HCV RNA 24 weeks after completion of treatment, is universally considered as an indicator of treatment efficacy. OBJECTIVE: The aim of this study was to determine efficacy and safety of PEG IFN alfa-2a and RBV treatment in patients with CHC in Serbia. METHODS: One hundred seventy-six patients with CHC were included in this multicenter trial from 8 reference centers in Serbia. The patients were treated with standard PEG IFN alfa-2a and RBV protocol. We performed the following virological testing: anti-HCV (ELISA), HCV RNK (quantitative PCR), HCV genotype (type-specific PCR), HBsAg, anti-HBs, anti-HBc and anti-HIV (ELISA). Histological activity and the degree of fibrosis were determined according to the Metavir scoring system. Potential predictors for achieving SVR were evaluated using multivariable logistic regression analysis. RESULTS: Of the treated patients with CHC 65.9% were male, and 60.2% of them aged over 40 years. Of the treated patients 68.2% had infection over 5 years, 63% had HCV RNA >400.000 IU/mL, 76.1% had HCV G1/4, and 60.1% had a mild to moderate liver fibrosis. SVR was achieved in 78.9% of patients (G1/4 79.1%; G2/3 78.1%). The factors that indicated a poorer efficacy of the treatment were age >40 (p<0.05), high basal viremia (p=0.013), and the reduction of PEG IFN alfa-2a and RBV doses, with interruption of therapy (p<0.001). Of the treated patients 45.9% had adverse affects (G1/4 50.8%; G2/3 29.7%). CONCLUSION: Treatment of CHC with PEG IFN alfa-2a and RBV was efficient in 78.9% of patients. The safety profile of therapy was satisfactory. Longer therapy increases the possibility of the development of adverse affects. No life-threatening adverse effects were recorded in our patients. PMID- 23092030 TI - [Higher dose of erythropoietin for anemia correction in balkan endemic nephropathy patients]. AB - INTRODUCTION: Balkan endemic nephropathy (BEN) patients maintained with hemodialysis have more severe anemia than patients with other kidney diseases. OBJECTIVE: The aim of the study was to compare the improvement of anemia in BEN patients and those with other kidney diseases during treatment with human recombinant erythropoietin (rHuEpo). METHODS: The study involved 240 patients on regular hemodialysis for more than one year. Out of them 146 had BEN and 94 other kidney diseases (21 glomerulonephritis, 20 hypertension, 18 diabetes, 10 policystic kidney disease, 5 obstructive nephropathy, 18 other diseases). Treatment with rHuEpo was carried out according to European guidelines for the management of anemia. RESULTS: Patients with BEN were older and were less frequently treated with ACEi than patients with other kidney diseases. At the onset of the study mean hemoglobin level (109.6 +/- 22.3 vs. 112.7 +/- 11.3 g/l) was significantly lower, but serum ferritin level and rHuEpo dose (65.4 +/- 22.3 vs. 57.5 +/- 22.5 U/kg/week) were significantly higher in BEN patients than in others. In prospective four months study these differences in hemoglobin levels and rHuEpo doses maintained.The rate of anemia improvement was examined in 15 BEN patients and 10 patients with other kidney diseases at the beginning of rHuEpo treatment. No difference in the rate of anemia improvement was found between the two groups but higher rHuEpo doses were used in BEN patients. CONCLUSION: Patients with BEN on regular hemodialysis had more severe anemia and required higher rHuEpo doses for maintaining target hemoglobin level. PMID- 23092031 TI - [Quality of life and results of total androgen blockade alone and with radiotherapy in the treatment of nonmetastatic prostate cancer]. AB - INTRODUCTION: Hormonal treatment of prostate cancer (CaP) in the form of total androgen blockade (TAB) with or without radiotherapy is applied in metastatic disease and in patients with nonmetastatic and localized disease as well. OBJECTIVE: The aim of the study was to compare oncological results, residual and newly developed symptoms during treatment and the quality of life in patients with nonmetastatic CaP treated by using TAB and in a group treated both with TAB and radiotherapy (RT+TAB). METHODS: Retrospective analysis of 126 patients with nonmetastatic CaP was performed. Follow-up was 36 months. Seventy-nine out of 126 patients were treated with TAB alone and 47 with TAB and radiotherapy (TAB+RT). Overall survival, metabolic syndrome appearance and the frequency of nonmalignant complications during treatment were analyzed. Urinary, digestive and sexual symptoms were analyzed, as well as the overall health condition of the patients. RESULTS: Fatal outcome and/or disease progression occurred in 29 out of 126 patients (23%). High risk patients were significantly more frequent in the TAB+RT group (p=0.04). Mortality rate was not different in both groups indicating that better results of treatment were achieved in patients treated with TAB+RT. Metabolic syndrome appeared in 51.6% of TAB patients and in 51.1 of TAB+RT patients, and was significantly more frequent at the end of the follow-up than at the beginning of the treatment (p=0.003 in TAB and p=0.01 in TAB+RT group). Urinary symptoms were more frequent than digestive symptoms in both groups. The quality of life was slightly improved after the beginning of therapy to be followed by the tendency of gradual decrease. CONCLUSION: Both modalities of treatment were efficient. Therapy TAB+RT was more efficient in high risk patients. Metabolic syndrome was more frequent after a long-term administration of therapy than at the beginning. The quality of life was the most affected in sexually active patients. PMID- 23092032 TI - [Efficiency of fenticonazole for the treatment of vaginal candidiasis]. AB - INTRODUCTION: Uncomplicated vulvovaginal candidiasis appears in 75% women of reproductive age. The most frequent causes are Candida albicans (85-95%) or C. glabrata, and infrequently C. krusei, C. tropicalis, C. parapsilosis, C. pseudotropicalis, etc. OBJECTIVE: The aim of the study was to investigate efficiency and safety of fenticonazole for vaginal candidiasis treatment. METHODS: Therapeutic effect of a single 600 mg fenticonasole vaginal capsule was observed in 417 women, aged 16-67, in five centers in Serbia. In all women, before the treatment, vaginal candidiasis was confirmed by testing of vaginal smear. Based on smear findings and associated symptoms observed on the 7th and 28th day after therapy administration, treatment results were evaluated. On the next day after drug application the patients recorded by using a questionnaire their own feelings on withdrawal symptoms and possible side effects in the period prior to the first control. RESULTS: Control after seven days showed a statistically significant decrease of symptoms. In 385 women, vaginal smear was found negative to yeast and yeast blastospores. Within the first seven days after treatment 84 women had to repeat therapy due to the persistence of symptoms or positive vaginal smear. After 28 days we recorded full recovery in 392 patients, clinical improvement in eight, no change in 16, and deterioration in one patient only. Side effects were very seldom, mostly in the form of a slight redness of the vulva and vagina, and mild itching during several days. CONCLUSION: Our observations confirmed good efficacy and safety of fenticonazole in the treatment of vaginal candidiasis. PMID- 23092033 TI - [Ability of the Childhood Health Assessment Questionnaire in predicting outcome of patients with juvenile idiopathic arthritis]. AB - INTRODUCTION: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease associated with decreased functional capacity and potentially long-term consequences. The establishment of early prognostic factors could help in the prevention of joint damage and improve the quality of life in children with JIA. OBJECTIVE: The aim of the study was to evaluate the functional status of children with JIA by using the Childhood Health Assessment Questionnaire (CHAQ) and to assess its ability in predicting the outcome of the disease. METHODS: The study included 87 patients, average age 14 years, under follow-up on the average of 3.7 years. Parents/ patients over 12 years completed CHAQ based on which disability index (DI) was calculated. Disease outcome was determined according to the preliminary criteria for clinical remission. RESULTS: At the end of the follow-up period, functional ability improved significantly (0.541 vs. 0.398; p<0.05). During the study, in 52.8% of patients treatment with biologic drug etanercept was introduced. CHAQ showed good predictive validity when a baseline DI was compared with disease outcome at the final examination (F=18.349; p<0.001). Using the patients with normal functional ability (DI=0) as the reference group, in patients with moderate and more severe functional disability the odds ratio for the disease to be active at the end of the follow-up period (DI> or =0.6) was 4.6 (p=0.044). CONCLUSION: Functional ability of patients with JIA significantly improved during the follow-up period owing to the efficient therapy. The questionnaire for the assessment of the functional status is a simple tool, with good ability to predict disease outcome, and should thus be used in everyday clinical practice with the aim to identify patients with poor prognosis. PMID- 23092034 TI - Evaluation of utilization and efficacy of general hospitals in Serbia: is there a shift forward? AB - INTRODUCTION: In the Republic of Serbia the activity of general hospitals has not been sufficiently evaluated. OBJECTIVE: The aim of this study was to evaluate, by analyzing the basic indicators of general hospitals condition and functioning, the network, utilization and efficacy of general hospitals for further improvement of their organization and work. METHODS: The paper is a part of a retrospective-prospective analysis of hospital healthcare services which we performed in 2011. The research involved all 40 general hospitals in Serbia evaluated as a general hospitals system. We selected seven basic indicators of hospitals condition and functioning that we followed-up in the period 2000-2009. As the data source we used the Reports of the Office for Hospital Stationary Treatment of general hospitals and the Report of the Republican Institution for Statistics entitled Vital Events in the Republic of Serbia. Numerical data were analyzed using the methods of descriptive statistics and the program Microsoft Office Excel 2007 and SPSS for Windows. Statistical significance indicators of differences were determined by Student's t-test. RESULTS: In general hospitals during the studied years, the number of beds decreased by 16.5% (p(t)=0.057). The number of discharged patients was increased by 11.8% (p(t)=0.035). The number of hospitalization days was reduced by 11.2% (p(t)=0.038).The average length of treatment was reduced by 1.9 days (p(t)=0.074). The average daily bed occupancy was increased by 4% (p(t)=0.020). The utilization of beds was increased by 4.5% (p(t)=0.019). Throughput capacity of beds increased by 8.5 patients per bed or by 27.8% (p(t)=0.091). CONCLUSION: The most significant indicators of the utilization and efficacy of general hospitals were improved. Nevertheless, European and domestic guidelines were achieved only in the average length of treatment. PMID- 23092035 TI - Teaching about quality improvement in specialist training for family medicine in Slovenia. AB - INTRODUCTION: Quality is a part of curricula in medical schools worldwide. It has a special position in family medicine, because it follows specific rules that are adapted to this discipline. Because of its specificities, teaching quality is even more important to become a part of specialist training curricula. OBJECTIVE: Our aim was to describe quality improvement in family medicine specialist training curriculum in Slovenia and its practical implications and experiences. METHODS: The paper describes the family medicine specialist training curriculum also including the topic on the ways quality improvement. Assignments and research protocols are used to enhance the usage of quality methods in everyday practice. An example of such a research protocol, developed by one of the trainees, is used to illustrate the process. Trainees' evaluations of the quality improvement curriculum are analyzed. RESULTS: In the quality improvement project, 199 patients with arterial hypertension younger than 80 years were included. At the first measurement only 21 patients (10.6%) had their blood pressure within the recommended level. Six months after the quality improvement intervention 77 patients (38.9%) had controlled their blood pressure, a statistically significant improvement (p<0.001). CONCLUSION: Teaching quality in family medicine must be a generic part of specialist training curriculum. The use of specific assignments can underpin the necessity to use methods that follow the principles of modern education. The result of teaching process can be even measured in actual improvement in the quality of care. PMID- 23092036 TI - Orthograde endodontic retreatment of teeth with individual cast posts: report of two cases. AB - INTRODUCTION: The failure of primary endodontic treatment is manifested by various clinical symptoms following endodontic therapy or, more frequently, by the development of chronic inflammatory process in the apex region without any subjective symptoms. In case of unfavorable outcome of the primary endodontic treatment, orthograde endodontic retreatment is the method of choice for a prolonged therapy. OUTLINE OF CASES: Two female patients, 47 and 44 years old, were presented at the Dental Clinic of Vojvodina for endodontic retreatment of teeth 22, 23 and 13, within the repeated prosthetic restoration. Intraradicular individual cast posts were removed using ultrasonic instruments. Remains of gutta percha were removed by engine driven rotary re-treatment files, root canals were shaped and cleaned using the crown-down technique, and obturated with gutta percha and epoxy-resin-based sealer using the lateral compaction technique. CONCLUSION: When there are metal posts or broken instruments in the root canal, the use of ultrasonic instruments is considered a safe method characterized by negligible tooth substance loss and minimal root damage causing fractures and perforations, and the entire procedure is effective and predictable. Non-surgical orthograde endodontic retreatment, when properly performed in accessible and penetrable root canals, achieves a high cure rate, good and lasting results and eliminates the need for radical procedures, such as apical surgery or tooth extraction. When nonsurgical endodontic retreatment is done, treated teeth must be restored by full coronal coverage as soon as possible, to prevent coronal leakage or fracture. PMID- 23092037 TI - Adrenocorticotrophin-dependent hypercortisolism: imaging versus laboratory diagnosis. AB - INTRODUCTION: Cushing's syndrome results from inappropriate exposure to excessive glucocorticoids. Untreated, it has significant morbidity and mortality. CASE OUTLINE: A 38-year-old woman with a typical appearance of Cushing's syndrome was admitted for further evaluation of hypercortisolism. The serum cortisol level was elevated without diurnal rhythm, without adequate suppression of cortisol after 1 mg dexamethasone suppression test. 24-hour urinary-free cortisol level was elevated. Differential diagnostic testing indicated adrenocorticotrophin (ACTH) dependent lesion of the pituitary origin. Pituitary abnormalities were not observed during repeated MRI scanning. Inferior petrosal sinus sampling (IPSS) was performed: 1) Baseline ratio ACTH inferior petrosal sinus/peripheral was <2; 2) Corticotropin-releasing hormone (CRH) stimulated ratio ACTH inferior petrosal sinus/peripheral was <3; 3) Baseline intersinus ratio of ACTH was <1.4; 4) Increase in inferior petrosal sinus and peripheral ACTH of more than 50 percent above basal level after CRH; 5) Baseline ratio ACTH vena jugularis interna/peripheral was >1.7. Transsphenoidal exploration and removal of the pituitary tumor was performed inducing iatrogenic hypopituitarism. Postoperative morning serum cortisol level was less than 50 nmol/l on adequate replacement therapy with hydrocortisone, levothyroxine and estro-progestagen. CONCLUSION: No single test provides absolute distinction, but the combined results of several tests generally provide a correct diagnosis of Cushing's syndrome. PMID- 23092038 TI - Successful non-standard approaches to massive hemoptysis in invasive pulmonary aspergillosis. AB - INTRODUCTION: Invasive pulmonary aspergillosis (IA) is the most frequent invasive fungal infection in patients with hematological malignancies. Massive hemoptysis (MH) with blood loss more than 300-600 ml in 24 hours is a rare (5-10% of IA patients) but frequently fatal complication. Standard treatment of MH, such as oxygenation, a semi-sitting position with the bleeding site down, bronchoscopical suctioning, antifungal therapy, transfusion support and surgical resection might be either ineffective or not feasible in some cases. OUTLINE OF CASES: We report two patients with life threatening, non-controlled, massive hemoptysis who were successfully managed by non-standard measures. A 61-year-old male with acute myeloid leukemia developed pulmonary IA and massive hemoptysis after consolidation cure by chemotherapy. The bleeding site was localized in the VI lung segment by bronchoscopy. Local application of fibrinogen-thrombin concentrate (fibrin glue) stopped the bleeding. A 22-year-old female patient with the diagnosis of severe aplastic anemia developed IA and massive hemoptysis early after application of immunosuppressive therapy (antilymphocyte globulin, cyclosporine and corticosteroids). Conventional transfusion therapy, desmopresine and antifibrinolytics were ineffective. This urgent condition was successfully treated with human activated recombinant factor VII (rFVIIa, NovoSeven). CONCLUSION: Our experience together with data from the available literature suggests a potential benefit of fibrinogen-thrombin concentrate and rFVIIa in the treatment of refractory critical bleeding in hemato-oncological patients. PMID- 23092039 TI - Congenital arteriovenous fistula of the horseshoe kidney with multiple hemangiomas. AB - INTRODUCTION: Congenital renal arteriovenous fistulas (AVF) are rare, especially if they are associated with other developmental renal anomalies. CASE OUTLINE: A 34-year-old female was hospitalized due to total painless hematuria and bladder tamponade. Excretory urography revealed a horseshoe kidney with normal morphology of pyelocaliceal system and ureters. Aortography and selective renovasography detected a cluster-like vascular formation with multiple arteriovenous fistulas (AVF). Due to a large AVF gauge and poor flow of the efferent vein to the inferior vena cava, a surgical procedure of two renal artery segmentary branches ligation and division was performed. During the operative procedure, the presence of multiple superficial renal hemangiomas was detected. CONCLUSION: Although selective arterial embolization represents the preferable treatment option, conventional surgery remains favorable alternative in selected cases with large and complex AVF. PMID- 23092040 TI - Heterotopic pregnancy after in vitro fertilization and embryo transfer: a case report. AB - INTRODUCTION: Heterotopic pregnancy is a life-threatening complication of pregnancy defined as coexistent intrauterine and ectopic gestation. Its diagnosis is frequently overlooked and delayed. CASE OUTLINE: A 28-year-old woman experienced acute abdominal pain in pregnancy achieved by in vitro fertilization. Since all previous checkups indicated a normal course of pregnancy, the ectopic pregnancy was not suspected on admission. However, due to persistent hypotension, this diagnosis was also considered.Transvaginal ultrasound performed by an experienced obstetrician revealed an adnexal mass highly indicative of ectopic pregnancy. No fetal heart beats were visualized and the diagnosis of a missed abortion was made. A prompt laparotomy revealed a ruptured right ampullary pregnancy, and salpingectomy was performed. CONCLUSION: Although rare, heterotopic pregnancy should be considered in the differential diagnosis of abdominal pain in pregnancy. Every physician treating women of reproductive age should bear in mind the possibility of heterotopic pregnancy not only in patients with predisposing risk factors but also in those without them. PMID- 23092041 TI - [Surgical treatment of tibial nonunion after wounding by high velocity missile and external fixators: a case report]. AB - INTRODUCTION: The missiles of modern firearms can cause severe fractures of the extremity. High velocity missile fractures of the tibia are characterized by massive tissue destruction and primary contamination with polymorphic bacteria. Treatment of these fractures is often complicated by delayed healing, poor position healing, nonhealing and bone tissue infection. CASE OUTLINE: We present the management of tibial nonunion after wounding by high velocity missile and primary treatment by external fixation in a 25-year-old patient. The patient was primarily treated with external fixation and reconstructive operations of the soft tissue without union of the fracture. Seven months after injury we placed a compression-distraction external fixator type Mitkovic and started with compression and distraction in the fracture focus after osteotomy of the fibula and autospongioplasty. We recorded satisfactory fracture healing and good functional outcome. CONCLUSION: Contamination and devitalization of the soft tissue envelope increase the risk of infection and nonunion in fractures after wounding by high velocity missile. The use of the compression-distraction external fixator type Mitkovic may be an effective method in nonunions of the tibia after this kind of injury. PMID- 23092042 TI - [Atrial fibrillation after coronary artery bypass surgery: possibilities of prevention]. AB - Atrial fibrillation occurs as a frequent complication after cardiac interventions. It can be found in 5% of all surgical patients, and it is far more common in cardiac (10% - 65% of patients) than in non-cardiac procedures. In a number of patients it remains asymptomatic, but may be accompanied by very severe symptoms of hypotension, heart failure, syncope, systemic or pulmonary embolism, perioperative myocardial infarction, cerebrovascular insult and increased operative mortality. Patients whose postoperative course is complicated by atrial fibrillation require longer hospitalization. Possible predisposing factors of this arrhythmia are numerous and are associated with surgery, extensive coronary heart disease and revascularization, and preoperative diseases. According to the recommendations of the European Society of Cardiology orally applied beta blocker, amiodarone and sotalol can be used for prophylaxis of atrial fibrillation. Following the recommendations, treatment of postoperative atrial fibrillation should include beta-blockers, amiodarone, and in patients with heart failure and left ventricular dysfunction, digoxin. Due to the increased risk of stroke, an anticoagulant protection is necessary. Many studies have been conducted with results supporting the prophylactic use of amiodarone and beta blockers, while the treatment with new agents such as magnesium, statins, omega-3 fatty acids and inhibitors of the renin-angiotensin-aldosterone system is still being investigated. PMID- 23092043 TI - [Clinical significance of internal carotid artery restenosis following carotid endarterectomy]. AB - Carotid endarterectomy has been established as the preferred treatment for symptomatic and asymptomatic high-grade carotid stenosis. Internal carotid artery restenosis is defined as a specific entity with a great clinical significance in carotid surgery due to accompanied increased future cerebral ischemic events risk. Carotid restenosis is the result of neointimal hyperplasia in the early postoperative period (within 36 months) or recurrent atherosclerotic lesions at a later date. While the restenotic lesions caused by neointimal hyperplasia are determined by ultrasound as smooth lesions, atherosclerotic carotid stenosis has almost the same ultrasound and angiographic characteristics as primary atherosclerotic lesions. Some authors believe that patients with internal carotid artery restenosis have insignificant risk of stroke or progression to total occlusion, and suggest conservative treatment only. On the other hand, many surgeons have more aggressive attitude towards the treatment of asymptomatic carotid stenosis and indicate surgical treatment in asymptomatic patients with carotid restenosis above 80%. The aim of our paper was to present a review of literature available data concerning etiology, pathophysiology, clinical significance and treatment of carotid restenosis following endarterectomy. Numerous studies have reported satisfactory results of redo endarterectomy and carotid angioplasty as treatment options of carotid restenosis. Carotid angioplasty for primary atherosclerotic lesions treatment is accompanied by a high carotid restenosis rate and therefore its role in primary carotid symptomatic and asymptomatic stenosis treatment is still the issue of numerous debates and the subject of extensive ongoing clinical studies worldwide. PMID- 23092044 TI - [Bunion foot]. AB - Hallux valgus deformity is a complex chronic progressive disease primarily characterized by a lateral great toe deviation and deformity of the first metatarsophalageal joint. Numerous etiological factors are related with the expression of this disease, and they are divided into two categories: endogenous and exogenous. Complexity of the hallux valgus deformity is reflected with the progression of the disease that gives rise to numerous forefoot deformities. The diagnosis is first of all affirmed by clinical examination and x-ray of the feet in a standing position. Treatment could be either operative or conservative. Conservative treatment has shown to be totally unsuccessful. Before decision making on the type of operative treatment, the patient's complaints, age, profession, clinical and x-ray findings must be taken into consideration. Until now, over two hundred different operative procedures have been described, which clearly supports the observation that there is no single method which could resolve all clinical varieties of this deformity. Therefore, today, when making a choice on the surgical procedure of hallux valgus deformity, the utilization of surgical algorithm is recommended. PMID- 23092045 TI - [Dr. Elizabeth Ross: heroine and victim of the World War I in Serbia]. AB - At the beginning of 1915, several months after the World War I started, Serbia was in an extremely difficult situation.The country was war-ravaged, full of sick and wounded soldiers, there was a desperate shortage of doctors, nurses and other medical personnel, and the epidemic of typhus fever exploded and violently attacked the entire country. At that time, however, a number of both foreign allied medical missions and individual volunteers, from various countries, mostly from Great Britain, came to Serbia to help. Among them mostly were women, and they were of enormous support to Serbia in that grave situation. It is estimated that there were more than 600 foreign women volunteers in Serbia at that time and that 22 of them died there. Dr. Elizabeth Ross was one of those brave volunteers who came to Serbia early in 1915. That noble Scottish lady doctor was born in 1878 and finished her medical studies at the University of Glasgow in 1901. After graduation she worked in various places in Great Britain until 1909, when she went to Persia (Iran), where she worked until the beginning of the so called Great War. When she heard of the urgent need in Serbia she left Persia as soon as she could and volunteered to serve in Serbia. She came to Kragujevac at the beginning of January 1915, where she worked at the First Military Reserve Hospital, which at that time was actually a typhus hospital. Working there intensively and devotedly for several weeks under shocking conditions she contracted typhus herself and died there on her 37th birthday on February 14th, 1915. She was buried in Kragujevac, next to two British ladies who also died in Serbia of typhus. Her grave was restored in 1980 when the town of Kragujevac started holding commemorations at the graveside every February 14th at noon to honor her and all other brave and noble women who lost their lives helping Serbia at that unfortunate time. PMID- 23092046 TI - Understanding participation by African Americans in cancer genetics research. AB - PURPOSE: Understanding genetic factors that contribute to racial differences in cancer outcomes may reduce racial disparities in cancer morbidity and mortality. Achieving this goal will be limited by low rates of African American participation in cancer genetics research. METHOD: We conducted a qualitative study with African American adults (n = 91) to understand attitudes about participating in cancer genetics research and to identify factors that are considered when making a decision about participating in this type of research. RESULTS: Participants would consider the potential benefits to themselves, family members, and their community when making a decision to participate in cancer genetics research. However, concerns about exploitation, distrust of researchers, and investigators' motives were also important to participation decisions. Individuals would also consider who has access to their personal information and what would happen to these data. Side effects, logistical issues, and the potential to gain knowledge about health issues were also described as important factors in decision making. CONCLUSION: African Americans may consider a number of ethical, legal, and social issues when making a decision to participate in cancer genetics research. These issues should be addressed as part of recruitment efforts. PMID- 23092047 TI - Analysis of multiple risk factors for the recurrence of nondisabling stroke. AB - BACKGROUND: Recurrent stroke is one of severe outcomes of transient ischemic attack (TIA) and minor ischemic stroke (MIS), which are collectively termed as nondisabling stroke. However, the association between multiple risk factors and nondisabling stroke has not been fully studied. Here, we aimed to identify predicative risk factors in TIA and MIS in order to prevent recurrent nondisabling stroke. METHODS: We used logistic regression methods to analysis risk factors in 620 patients with TIA or MIS between August 2006 and january 2009 and followed up to 90 days. We selected 20 factors, including age, gender, body mass index (BMI), smoking and alcohol history, blood pressure, limb weakness, speech impairment, diabetes, ischemic brain lesions, previous history of stroke (> 24 hours), coronary atherosclerotic heart disease, cardiac function insufficiency, duration of symptoms of at least 1 hour, blood lipids, lysophosphatidic acid, C-reactive protein, atrial fibrillation, and carotid artery plaque in ultrasound examination. RESULTS: We found that limb weakness, history of cerebrovascular events, and carotid artery plaque in ultrasound examination were risk factors of recurrent stroke within 14 days, whereas the factors for the recurrence within 90 days were duration of symptoms of at least 1 hour, speech impairment, limb weakness, BMI of at least 25 kg/m2, history of cerebrovascular events, and carotid artery plaque in ultrasound examination. CONCLUSION: Six risk factors are associated with recurrent nondisabling stroke, including symptom duration of at least 1 hour, speech impairment, limb weakness, BMI of at least 25 kg/m2, history of cerebrovascular events, and carotid artery plaque in ultrasound examination. Thus, identification and prevention of these risk factors may reduce recurrent stroke. PMID- 23092048 TI - Setting the agenda for quality improvement in pediatric sickle cell disease. AB - OBJECTIVE: Despite recent scientific advances, children with sickle cell disease (SCD) continue to experience high mortality and significant morbidity, in part due to variations in the care provided. We sought to identify and compare drivers for quality improvement among clinical staff and parents of children with SCD. METHODS: We interviewed clinical staff across care settings in an urban teaching hospital to elicit their perspectives on improving care for children with SCD. Concurrently, we invited parents of children with SCD to participate in focus groups to identify their needs. Findings are reported according to Consolidated Criteria for Reporting Qualitative Research guidelines. RESULTS: We conducted 29 interviews with clinical staff and 4 focus groups with parents. Both groups identified the need for effective communication of relevant patient information across disciplines as a key area for improvement. Clinical staff cited standardization of care delivery as a top priority through increased accessibility of pertinent clinical information, enhanced pain assessment and management, and improved availability of clinical decision-making tools. Parents listed the need for increased community awareness about SCD, including school and day care staff, enhanced parental education and peer support, and self-management skills for their children as opportunities to improve pediatric SCD care. CONCLUSIONS: Identifying drivers for quality improvement is a critical first step in transforming the care provided to children with SCD. Using a systematic approach that includes eliciting the perspectives of both clinicians and parents may significantly enhance the development of a patient-centered quality improvement agenda. PMID- 23092050 TI - The role of trust in health decision making among African American men recruited from urban barbershops. AB - OBJECTIVE: To examine factors within the patient-provider relationship that influence which role African American men aged 40-70 years prefer when making health care decisions. METHODS: We recruited 40 African American men from barbershops in the Richmond, Virginia, metropolitan area to participate in semistructured interviews. At the completion of each interview, participants completed a brief self-administered demographic survey. The semistructured interviews were audiotaped and transcribed verbatim and then imported into a qualitative software program for organizing, sorting, and coding data. The principles of thematic analysis and template approach were used in this study. The survey data were analyzed using descriptive statistics. RESULTS: Trust was a major theme that emerged from the semistructured interviews. The men listed trust in the health care provider as the primary reason for choosing a collaborative or active role in the decision-making process. Within the theme of trust, 4 subthemes emerged: expertise, information sharing, active listening, and relationship length. Thirty-five out of the 40 men interviewed preferred an active or collaborative role in the decision-making process; only 5 preferred passive decision making. CONCLUSIONS: Trust emerged as an important factor that influenced role preference for African American men when making health care decisions in the context of the patient-provider relationship. Future studies that help identify which other factors influence health care decision-making roles among African American men may have implications for addressing health disparities among this population and improve the quality of their health care. PMID- 23092049 TI - Opioid addiction and abuse in primary care practice: a comparison of methadone and buprenorphine as treatment options. AB - Opioid abuse and addiction have increased in frequency in the United States over the past 20 years. In 2009, an estimated 5.3 million persons used opioid medications nonmedically within the past month, 200000 used heroin, and approximately 9.6% of African Americans used an illicit drug. Racial and ethnic minorities experience disparities in availability and access to mental health care, including substance use disorders. Primary care practitioners are often called upon to differentiate between appropriate, medically indicated opioid use in pain management vs inappropriate abuse or addiction. Racial and ethnic minority populations tend to favor primary care treatment settings over specialty mental health settings. Recent therapeutic advances allow patients requiring specialized treatment for opioid abuse and addiction to be managed in primary care settings. The Drug Addiction Treatment Act of 2000 enables qualified physicians with readily available short-term training to treat opioid-dependent patients with buprenorphine in an office-based setting, potentially making primary care physicians active partners in the diagnosis and treatment of opioid use disorders. Methadone and buprenorphine are effective opioid replacement agents for maintenance and/or detoxification of opioid-addicted individuals. However, restrictive federal regulations and stigmatization of opioid addiction and treatment have limited the availability of methadone. The opioid partial agonist-antagonist buprenorphine/naloxone combination has proven an effective alternative. This article reviews the literature on differences between buprenorphine and methadone regarding availability, efficacy, safety, side effects, and dosing, identifying resources for enhancing the effectiveness of medication-assisted recovery through coordination with behavioral/psychological counseling, embedded in the context of recovery-oriented systems of care. PMID- 23092051 TI - A qualitative study of the perspectives of individuals with disabilities about their health care experiences: implications for culturally appropriate health care. AB - PURPOSE: This study explores the health care experience of individuals with disabilities and how this knowledge can guide health care professionals in providing effective and compassionate care for persons with disabilities. METHODS: Participants' experiences about the health care they received were quantitatively analyzed for common themes. RESULTS: Participants most often discussed the process of how they came to receive their official disability diagnosis. Another recurrent theme was disability etiology, in which participants described the events or process that resulted in a disability. Two other frequent themes, normality and others' perceptions of disability, centered upon what it means to be "normal" or others' assumptions about what it means to be "nor mal" (as opposed to having a disability). Family support and struggles, experiences with medical professionals and hospitals, and barriers to inclusion and accommodations were the other key themes. CONCLUSION: This study provides insights to aspects of living with a disability that individuals with disabilities felt were important for health care professionals to know. Being aware of these topics may help health care providers in establishing good communication with their patients who have a disability. PMID- 23092052 TI - Assessing darunavir/ritonavir-based therapy in a racially diverse population: 48 week outcomes from GRACE. AB - The Gender, Race, and Clinical Experience (GRACE) study was designed to assess sex-based differences in darunavir/ ritonavir-based therapy and to enroll a female population representative of the racial demographics of women with human immunodeficiency virus (HIV)/AIDS in the United States. Here, we report week 48 results, stratified by race. GRACE was a multicenter, open-label, phase 3b study. Patients received 600 mg of darunavir and 100 mg of ritonavir twice daily plus an investigator-selected optimized background regimen. Virologic response (HIV-1 RNA < 50 copies/ mL) and safety were assessed over 48 weeks. Post hoc multivariate analyses were performed to investigate factors associated with response. Of 429 patients enrolled, 61.5% were black, 22.4% were Hispanic, and 15.2% were white. Black patients had more advanced disease at baseline, and more black patients discontinued (32.6%) than Hispanic (24%) or white (26.2%) patients. In the intent to-treat population, similar response rates were seen in Hispanic (61.5%) and white patients (60.0%); lower response rates were observed in black patients (48.5%). Similar trends were observed in the nonvirologic failure censored population. The multivariate analysis revealed that being of a nonblack race was significantly associated with improved response (P = .009). Overall, darunavir/ritonavir-based therapy was well tolerated, regardless of race. Diarrhea, nausea, and rash were the most commonly reported grade 2 to 4 adverse events (at least possibly related to darunavir/ritonavir). Darunavir/ritonavir treatment is safe and effective in treatment-experienced patients, irrespective of sex or race. Despite the controlled trial environment, more black patients discontinued and experienced virologic failure than Hispanic or white patients. PMID- 23092053 TI - Saturday Morning Science programs: a model to increase diversity in the biosciences. AB - PURPOSE: To examine a pathway program for middle and high school students from underrepresented backgrounds designed to foster career interest in the biomedical sciences. In 2002, the Institute of Medicine released a report entitled Unequal Treatment, which examined the racial and ethnic disparities in health and health care within the United States and encouraged the development of a diverse health care workforce as a means to reduce health care disparities. PROCEDURES: Saturday Morning Science (SMS) is a program model presented as a pipeline strategy that addresses this specific recommendation. SMS is a 10-week program that emphasized the importance of science and math. Post-SMS evaluations were conducted to assess biomedical career knowledge, attitudes regarding future career plans, and the effectiveness of the program. FINDINGS: A total of 87.5% of middle and high school students who were enrolled in SMS completed the program (113 of 130). Seventy percent of SMS participants were underrepresented minorities. Snapshot program evaluation data exposed new ideas about science (strongly agree/agree, 98%; 64 of 65), exposed new ideas about medicine (strongly agree/agree, 97%; 63 of 65, and increased desire to enter science related field (strongly agree/agree 82% (53 of 65). CONCLUSIONS: SMS was designed to motivate students of underrepresented ethnic backgrounds from middle through high school to attend college and prepare for careers in the health sciences. SMS students had the opportunity to interact with scientists, physicians, medical and graduate students, and other academicians. They provided direction and guidance to ensure that students had meaningful experiences specifically designed to expose them to opportunities in the biosciences. PMID- 23092054 TI - Management of AIDS-associated Kaposi's sarcoma in Nigerian children: a case series and review of literature. AB - INTRODUCTION: There is a paucity of published studies on the management and outcome of AIDS-associated Kaposi's sarcoma (AAKS) in African children. In this study, we reviewed the management and literature of AAKS in Nigerian children. PATIENTS AND METHODS: A prospective review of children aged 1 to 14 years and adolescents aged 15 to 18 years who presented with AAKS. Following clinical evaluation and resuscitation, patients were treated with highly active antiretroviral therapy (HAART). Stable patients were further treated with chemotherapy consisting of vincristine, doxorubicin, and bleomycin. Patients were monitored until death or loss to follow-up. RESULTS: There were 9 patients: 6 children and 3 adolescents. Three children had vertical transmission of HIV infection. Kaposi's sarcoma was the AIDS-defining disease in 5 patients. One patient was on HAART at the time of diagnosis. There were multiple skin lesions in all patients, and cervical lymph nodes and oropharynx were frequently affected. The CD4 counts at the time of AAKS diagnosis ranged 78 to 601 cells/ uL, mean of 317. Five patients had best palliative care. Three had anticancer chemotherapy, of which 2 were alive 4 years after diagnosis. Three patients died at the initial hospitalization 2 to 6 weeks after diagnosis. CONCLUSION: Children and adolescents with AAKS presented with generalized skin lesions and lymphadenopathy, which facilitated the diagnosis. The majority of the patients presented with advanced disease that was rapidly fatal. However, patients with good immunity may have a prolonged control of symptoms if treated with HAART and appropriate anticancer chemotherapy. PMID- 23092055 TI - Health disparities from future genetic research efforts: breast cancer as a case study. PMID- 23092056 TI - What you need to know about HIV/AIDS. PMID- 23092057 TI - Biochemia medica appoints research integrity editor. AB - Biochemia Medica has just established the Research integrity editor who will act as the Editorial team member responsible for all matters related to the various aspects of scientific misconduct. The major reason for this is the increasing number of various types of scientific misconduct in manuscripts submitted to our Journal. Research integrity editor will: a) strive to continuously raise awareness for research and publication integrity issues; b) educate our authors, reviewers and readers, by providing educational articles on various topics related to responsible research and writing; c) aim to prevent unethical research and publication practices; and d) responsibly deal with research and publication misconduct attempts in accordance with internationally accepted policies and recommendations. This initiative provides firm evidence of our commitment and respect for publishing ethical and responsible research. By this we hope to further increase the scientific quality of the journal content as well as the quality of the editorial work. PMID- 23092058 TI - Our profession now has a European name: specialist in laboratory medicine. AB - We need a common name to have a clear identity which best describes the scope of the work we carry out for the patients. A clear and easily understood name which reflects the level of education and training of a specialist in the medical laboratory, and hence eligibility to be on the EC4 Register, is therefore needed, whatever academic background and whether polyvalent or sub-specialised. PMID- 23092059 TI - Taxonomy of quantities. AB - The adjectives "generic", "subgeneric", "specific", and "individual" are proposed to be added to the term "quantity", depending on the case, in order to diminish the ambiguity of this term and to classify the different types of quantities. PMID- 23092060 TI - Interrater reliability: the kappa statistic. AB - The kappa statistic is frequently used to test interrater reliability. The importance of rater reliability lies in the fact that it represents the extent to which the data collected in the study are correct representations of the variables measured. Measurement of the extent to which data collectors (raters) assign the same score to the same variable is called interrater reliability. While there have been a variety of methods to measure interrater reliability, traditionally it was measured as percent agreement, calculated as the number of agreement scores divided by the total number of scores. In 1960, Jacob Cohen critiqued use of percent agreement due to its inability to account for chance agreement. He introduced the Cohen's kappa, developed to account for the possibility that raters actually guess on at least some variables due to uncertainty. Like most correlation statistics, the kappa can range from -1 to +1. While the kappa is one of the most commonly used statistics to test interrater reliability, it has limitations. Judgments about what level of kappa should be acceptable for health research are questioned. Cohen's suggested interpretation may be too lenient for health related studies because it implies that a score as low as 0.41 might be acceptable. Kappa and percent agreement are compared, and levels for both kappa and percent agreement that should be demanded in healthcare studies are suggested. PMID- 23092061 TI - Bowels control brain: gut hormones and obesity. AB - Peptide hormones are released from the gastrointestinal tract in response to nutrients and communicate information regarding the current state of energy balance to the brain. These hormones regulate appetite, energy expenditure and glucose homeostasis. They can act either via the circulation at target peripheral tissues, by activation of the vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothalamus and brainstem. This review gives an overview of the main gut hormones implicated in the regulation of food intake and how some of these are being targeted to develop anti obesity treatments. PMID- 23092062 TI - Inherited prothrombotic risk factors in children with first ischemic stroke. AB - Stroke in children is a heterogeneous disorder. Over 100 risk factors for stroke have been reported and genetic predisposition to stroke has been established. The most frequently reported risk factors are congenital heart malformations, hemolytic anemias, collagen vascular diseases, some rare inborn metabolic disorders, trauma, infection and thrombophilia. The aim of this article is to provide an overview of investigated inherited prothrombotic risk factors in children with first ischemic stroke. Various prothrombotic risk factors have been investigated in pediatric stroke including elevated homocysteine and lipoprotein (a), antithrombin, protein C and protein S deficiency, Factor V Leiden, Factor II G20210A and plasminogen activator inhibitor-1 4G/5G polymorphism. Despite similar criteria for inclusion of different studies in meta-analyses investigating first ischemic stroke in children, the obtained results were not consistent for all prothrombotic risk factors. The discrepancies found could be explained by methodological issues like different sample sizes, patient populations included and lack of controls. In order to provide the necessary power for randomized control trials, multi-center, multi-national approaches like International Pediatric Stroke Study have been initiated with the aim to describe risk factors for childhood stroke and explore their relationship with presentation, age, geography, and infarct characteristics. Although it is evident from numerous studies that the frequency of inherited prothrombotic factors is increased in pediatric stroke, single thrombophilia does not fully explain stroke in a child as it represents only a mild risk factor. Further studies are needed, as improved understanding of underlying mechanisms will improve primary and secondary prevention of childhood stroke. PMID- 23092063 TI - Iron metabolism: current facts and future directions. AB - Iron metabolism has been intensively examined over the last decade and there are many new players in this field which are worth to be introduced. Since its discovery many studies confirmed role of liver hormone hepcidin as key regulator of iron metabolism and pointed out liver as the central organ of system iron homeostasis. Liver cells receive multiple signals related to iron balance and respond by transcriptional regulation of hepcidin expression. This liver hormone is negative regulator of iron metabolism that represses iron efflux from macrophages, hepatocytes and enterocytes by its binding to iron export protein ferroportin. Ferroportin degradation leads to cellular iron retention and decreased iron availability. At level of a cell IRE/IRP (iron responsive elements/iron responsive proteins) system allows tight regulation of iron assimilation that prevents an excess of free intracellular iron which could lead to oxidative stress and damage of DNA, proteins and lipid membranes by ROS (reactive oxygen species). At the same time IRE/IRP system provides sufficient iron in order to meet the metabolic needs. Recently a significant progress in understanding of iron metabolism has been made and new molecular participants have been characterized. Article gives an overview of the current understanding of iron metabolism: absorption, distribution, cellular uptake, release, and storage. We also discuss mechanisms underlying systemic and cellular iron regulation with emphasis on central regulatory hormone hepcidin. PMID- 23092064 TI - The new oral anticoagulants and the future of haemostasis laboratory testing. AB - The tests currently employed within most haemostasis laboratories to monitor anticoagulant therapy largely comprise the prothrombin time (PT)/ International Normalised Ratio (INR) and the activated partial thromboplastin time (APTT). These are respectively used to monitor Vitamin K antagonists (VKAs) such as warfarin, and unfractionated heparin. Additional tests that laboratories may also employ for assessing or monitoring unfractionated heparin include thrombin time (TT) and the anti-Xa assay, which can also be used to monitor low molecular weight heparin. Several new anti-thrombotic agents have recently emerged, or are in the final process of clinical evaluation. These novel drugs that include Dabigatran etexilate and Rivaroxaban would not theoretically require monitoring; however, testing is useful in specific situations. The tests currently used to monitor VKAs and heparin are typically either too sensitive or too insensitive to the new drugs to be used as 'typically performed in laboratories', and may thus require some methodological adjustments to increase or decrease their sensitivity. Alternately, different tests may be better employed in these assessments. Whatever the case, laboratories may soon be performing a reduced or possibly increased number of tests, the same kind of tests but perhaps differently, or conceivably different assay panels. Specific laboratory guidance on the choice of the appropriate test to be ordered according to the drug being administered, as well as on appropriate interpretation of test results, will also be necessary. The current report reviews the current state of play and provides a glimpse to the possible future of the coagulation laboratory. PMID- 23092066 TI - Investigation of unusual high serum indices for lipemia in clear serum samples on siemens analysers dimension. AB - INTRODUCTION: We present our work of monitoring 202 different patients with markedly elevated serum index for lipemia whereby serum samples were clear. We tried to clarify the cause of occurrence of these indices which were detected in the years 2006-2010 on Siemens Dimension analyzers. MATERIALS AND METHODS: In samples with unusual lipemia index we measured the concentration of lipids (total cholesterol, triglycerides, HDL and LDL cholesterol, Lp(a), ApoA1, ApoB), total proteins and checked for possible interferents (rheumatoid factor, immunoglobulins). We performed serum protein and immuno- electrophoresis. We investigated the repeatability of unusual lipemia indices during the day and after different time periods and we compared them on four different analyzers (RXL Max, Vista, Hitachi 911 and former Olympus AU640). RESULTS: In 87% of 202 samples we found a monoclonal or biclonal peak in serum protein electrophoresis. Different types of paraproteins were confirmed with immunofixation electrophoresis. In the remaining 13%, polyclonal elevated concentrations of immunoglobulins were measured. Other parameters had no influence on appearing of these indices. The repeatability of indices was good during the first day of measurements (P values > 0.05) and markedly lower in the next days or after 3 and 12 months (P values <0.05). The indices were elevated only on Dimension analyzers, but not on Hitachi and former Olympus analysers. CONCLUSION: A markedly elevated lipemia index in a clear serum sample measured on Siemens analyzers Dimension indicates a high possibility for the presence of a paraprotein in the sample. PMID- 23092065 TI - Impact of the phlebotomy training based on CLSI/NCCLS H03-a6 - procedures for the collection of diagnostic blood specimens by venipuncture. AB - INTRODUCTION: The activities involving phlebotomy, a critical task for obtaining diagnostic blood samples, are poorly studied as regards the major sources of errors and the procedures related to laboratory quality control. The aim of this study was to verify the compliance with CLSI documents of clinical laboratories from South America and to assess whether teaching phlebotomists to follow the exact procedure for blood collection by venipuncture from CLSI/NCCLS H03-A6 - Procedures for the Collection of Diagnostic Blood Specimens by Venipuncture might improve the quality of the process. MATERIALS AND METHODS: A survey was sent by mail to 3674 laboratories from South America to verify the use of CLSI documents. Thirty skilled phlebotomists were trained with the CLSI H03-A6 document to perform venipuncture procedures for a period of 20 consecutive working days. The overall performances of the phlebotomists were further compared before and after the training program. RESULTS: 2622 from 2781 laboratories that did answer our survey used CLSI documents to standardize their procedures and process. The phlebotomists' training for 20 days before our evaluation completely eliminated non-conformity procedures for: i) incorrect friction of the forearm, during the cleaning of the venipuncture site to ease vein location; ii) incorrect sequence of vacuum tubes collection; and iii) inadequate mixing of the blood in primary vacuum tubes containing anticoagulants or clot activators. Unfortunately the CLSI H03-A6 document does not caution against both unsuitable tourniquet application time (i.e., for more than one minute) and inappropriate request to clench the fist repeatedly. These inadequate procedures were observed for all phlebotomists. CONCLUSION: We showed that strict observance of the CLSI H03-A6 document can remarkably improve quality, although the various steps for collecting diagnostic blood specimens are not a gold standard, since they may still permit errors. Tourniquet application time and forearm clench should be verified by all quality laboratory managers in the services. Moreover, the procedure for collecting blood specimens should be revised to eliminate this source of laboratory variability and safeguard the quality. PMID- 23092067 TI - Serum thyroglobulin antibody levels within or near to the reference range may interfere with thyroglobulin measurement. AB - High concentration of thyroglobulin antibodies (TgAb) is a major limiting factor of thyroglobulin measurements in patients with differentiated thyroid cancer. We investigated whether thyroglobulin antibody added to serum samples could interfere with the thyroglobulin assay. Thyroglobulin levels in serum samples with different concentrations of thyroglobulin were measured by electrochemiluminescence immunoassay before and after the addition of increasing concentrations of thyroglobulin antibody using the secondary calibrator solution of the thyroglobulin assay kit containing sheep thyroglobulin antibody to reach thyroglobulin antibody levels within or near to the reference range. Thyroglobulin and thyroglobulin antibody concentrations were also measured in 134 serum samples from 27 patients after thyroid ablation. There was a strong negative association (slope = -1.179) between thyroglobulin antibody and thyroglobulin concentrations in samples with added thyroglobulin antibody (beta = -0.86; P <0.001). Changes in thyroglobulin concentrations were described mathematically as loss of thyroglobulin% = -0.2408 x Ln(thyroglobulin antibody IU/ml) + 0.1944. Thyroglobulin concentrations were significantly lower than those calculated from experiments with added thyroglobulin antibody in 26/134 samples from patients after thyroid ablation. We conclude that if the same TgAb interference exists in the presence of naturally occurring human TgAb, our observation may prove to be useful during follow-up of patients with differentiated thyroid cancer. However, further studies are needed to explore the clinical relevance of thyroglobulin antibody levels within or near to the reference range in monitoring these patients. PMID- 23092068 TI - Gamma heavy chain disease in a patient with rheumatoid arthritis--a laboratory evaluation. AB - INTRODUCTION: Heavy chain diseases (HCD) are neoplastic proliferations of B cells which secrete truncated immunoglobulin heavy chains without associated light chains. Being rare and probably underdiagnosed diseases the aim of this report is to show an additional case of gamma heavy chain disease in a 48 year old female patient with rheumatoid arthritis focusing on the laboratory presentation. MATERIALS AND METHODS: Laboratory work-up included agarose gel electrophoresis (AGE), capillary zone electrophoresis (CZE), immunofixation and nephelometrically determined immunoglobulin and immunoglobulin subclasses of the patient's serum. Urine samples were also subjected to immunofixation and to a SDS-PAGE with consecutive immunoblot. RESULTS: Nephelometrically measured elevated IgG concentrations were noted in combination with a decreased gamma globulin region and an increased beta globulin region on AGE. A definite monoclonal spike was not identified on AGE but at least suspected on CZE; finally serum and urine immunofixation demonstrated a monoclonal gamma heavy chain devoid of any corresponding light chains confirming the diagnosis of HCD. Analysis of the gamma heavy chain (HC) with means of SDS-PAGE revealed proteins of 40 kD and 80 kD most likely presenting a truncated HC in its monomeric and dimeric form and possibly leading to the failure of IgG-subclass typing with the applied IgG subclass antisera. CONCLUSION: This case report illustrates a new case of gamma HCD demonstrating variable laboratory manifestations and therefore the need for heightened awareness concerning this disease when confronted with abnormal and discrepant protein profiles in routinely applied laboratory tests. PMID- 23092069 TI - Accidental digitoxin intoxication: an interplay between laboratory and clinical medicine. AB - INTRODUCTION: Two Italian adults arrived at the Emergency Department referring diarrhea, nausea and vomiting for 4 days; weakness, fatigue and visual hallucinations were also complained of. Patients reported the ingestion of some leaves of a plant, which they supposed to be "donkey ears", a week before. Physical examination showed hypotension and bradycardia and ECG examination disclosed sinus rhythm and repolarization abnormalities (scooping of the ST-T complex) in both patients and a 2:1 AV block in the man. MATERIALS AND METHODS: Digoxin concentration was evaluated twice for each patient (at the admission and after 4 hours) by the automated immunoassay system ADVIA Centaur. Digitoxin concentration was evaluated by liquid chromatography-mass spectrometry (LC MS/MS). RESULTS: Despite clinical picture was suggestive of digitalis intoxication, digoxin levels were undetectable. Due to the more severe clinical picture, the male patient was treated with anti-digoxin antibodies (Digifab) achieving a good clinical improvement and remission of the AV block within two hours. Initial diagnosis was confirmed by LC-MS/MS showing high digitoxin concentrations, but digoxin was undetectable. Patients remained stable and 48 hours later were discharged from the hospital. CONCLUSION: Whereas digoxin determination frequently relies on monoclonal antibodies which do not cross-react to digitoxin, polyclonal antibodies constituting Digifab recognize a large spectrum of cardiac glycosides, including digitoxin. This report emphasizes the primary role of the clinical approach to patients in the emergency setting and how an active communication and a continuous sharing of professional experiences between Laboratory and Clinicians ensure an early and correct diagnosis. PMID- 23092070 TI - [Assisting these newly immigrant colleagues]. PMID- 23092071 TI - [Improving the safety of medical devices]. PMID- 23092072 TI - [Evaluation of the new reference book for nursing training]. PMID- 23092073 TI - [New reflection mission on the End of Life]. PMID- 23092074 TI - [Lung cancer, a worrying epidemiological evolution]. AB - As no screening test exists, most cases of lung cancer are diagnosed when the disease is already at a locally advanced or metastatic stage, which has a negative impact on the prognosis. The epidemiological evolution of this cancer is worrying, notably with regard to the explosion in the number of women affected. PMID- 23092075 TI - [The non-surgical treatment of lung cancer]. AB - Advances in the treatment of lung cancer concern mainly non-small cell cancers. Surgery, radiotherapy or drugs are offered alone or in combination depending on the patient and the extent of the disease. Involved in their implementation, the oncology nurse supports the patient throughout his or her treatment pathway. PMID- 23092076 TI - [Thoracic surgery for lung cancer]. AB - There are two main types of lung cancer. The reference treatment for small cell lung cancer is chemotherapy combined or not with radiotherapy. Generally multimodal, the treatment for non-small cell cancer combines surgery, chemotherapy and radiotherapy. A major procedure for patients, surgery is a stage in their fight against the cancer. PMID- 23092077 TI - [The role of the nurse in lung cancer surgery]. AB - The surgical period of the treatment of lung cancer is gruelling for the patient. Close to the patient from the pre-operative care onwards, nursing teams take turns in listening and providing technical care through to the patient's discharge. The optimal treatment of pain favours the early rehabilitation of the patient. PMID- 23092078 TI - [Preventing lung cancer]. AB - Lung cancer is one cancer for which preventative measures can be most effective. Unfortunately the strategies developed, in particular in terms of smoking, whether with regard to primary prevention, treatment by healthcare professionals or regulations, are insufficient or poorly adapted. PMID- 23092079 TI - [An Auriculotherapy protocol to enrich substance addictions's management]. PMID- 23092080 TI - [A guide to advance health care directives]. AB - Since the law of 22nd April 2005, any patient at the end of their life can draw up advance health care directives indicating their wishes with regard to the care and treatments they would like or not like to receive if they are no longer able to communicate. Valid for three years and included in the patient's records, the doctor must consult them but is not obliged to follow them. PMID- 23092082 TI - [The role of the nurse in the administering of chemotherapy at home]. AB - The global treatment of cancer patients has become a public health issue. To meet growing nursing needs, home hospitalisation teams provide an important contribution. Experts in administering chemotherapy at home, the nurses of the Sante Service association support patients in their wish to remain at home. PMID- 23092081 TI - [Dignity and the elderly: age makes no difference]. AB - Elderly people are human beings, dependent maybe, but still with a right to their dignity. However, in an institute, it is difficult to carry out care and monitor the residents at the same time as ensuring they have space for privacy and freedom. Overprotection and the sacralisation of autonomy can slide towards mistreatment. We must ensure that we are not submerged by the prevailing ideology which would have us believe that a dependent elderly person is a burden on society and that the solution to suffering is death. PMID- 23092083 TI - [Music therapy, a partner in patient care]. AB - Long time the preserve of psychiatry, music therapy is today used in general care. At Necker University Children's Hospital in Paris, it forms part of the treatment of multifactorial pain, with the collaboration of nursing teams. PMID- 23092084 TI - [Galenic forms for oral medication]. AB - Galenic science is interested in the art and the way of formulating an active principle with an excipient in order for it to be administered to the patient. The pharmaceutical forms envisage different administration routes, including by mouth. Nurses need to handle and sometimes modify the pharmaceutical form of a drug to make it easier for the patient to take. This requires vigilance. PMID- 23092085 TI - Receiving family of a patient in intensive care. AB - Pierre is currently working in the intensive care unit (ICU). The rules for visitors are strict. Visiting time is short and only two persons are allowed at a time, in the patient's ward. Standards of hygiene have to be respected carefully. This evening Pierre accompanies the husband of a Japanese tourist whose health is in a critical condition. PMID- 23092086 TI - [The nurse facing acute coronary syndrome ]. PMID- 23092087 TI - [Different psychotherapies]. PMID- 23092088 TI - [Deontology in situation of hospital care]. PMID- 23092089 TI - [Utilization of Meopa to ease pain]. PMID- 23092090 TI - [A brief review of glaucoma surgery and its recent topics]. PMID- 23092091 TI - [Incidence of uveitis in the northern Kyushu region of Japan --comparison between the periods of 1996-2001 and 2003-2008]. AB - PURPOSE: To report the clinical statistical analysis of patients with uveitis in the northern Kyushu region of Japan. SUBJECTS AND METHODS: This retrospective study involved 735 new patients with uveitis who visited the Kyushu university hospital from January 2003 to December 2008. The subjects were classified into four groups; adolescent (0-19 years), young (20-39 years), middle-aged (40-59 years) and old (60 years or older) and were compared with the results of our previous studies. RESULT: This study comprised 343 men and 392 women. The age averaged 47.2 years. Definitive diagnosis was made in 385 cases (52.4%). The most frequent clinical entity was sarcoidosis (9.8%), followed by Vogt-Koyanagi-Harada disease (7.9%), Behcet's disease (7.6%), acute anterior uveitis associated with human leukocyte antigen (HLA)-B27 (4.5%), herpetic iridocyclitis (3.1%), human T lymphotropic virus type I associated uveitis (HU) (2.7%), and intraocular lymphoma (2.3%). The proportion of unclassified uveitis was large among females in general, and among adolescents in the four groups. The incidence of secondary glaucoma in the whole group of 735 patients with uveitis was 22.2%. Among the patients with ocular hypertension, the proportion of steroid responders was large in the adolescent group. CONCLUSION: Compared with our previous report, this study shows increasing frequency of sarcoidosis and decreasing frequency of Behcet's disease except in the young group. HU showed a decreasing incidence. PMID- 23092092 TI - [A prospective study of postoperative aqueous flare in trabeculectomy alone versus phacotrabeculectomy]. AB - PURPOSE: To compare trabeculectomy alone with phacotrabeculectomy in postoperative aqueous flare. SUBJECTS AND METHODS: Aqueous flare was prospectively measured using a laser flare-cell meter in open-angle glaucoma patients with cataract undergoing trabeculectomy with either mitomycin C or phacotrabeculectomy with mitomycin C. Flare was measured before surgery and at 2 and 4 weeks after surgery. RESULTS: Twenty-four patients who underwent trabeculectomy and 26 patients who underwent phacotrabeculectomy completed the study. There were no significant differences in flare values between the two groups at any point. Logistic regression analysis demonstrated that exfoliation glaucoma (odds ratio = 8.978; p = 0.0028) and postoperatively shallow anterior chamber (odds ratio = 15.539 ; p = 0.0074) were risk factors for high values of aqueous flare at 2 weeks after surgery. CONCLUSIONS: Combined phacoemulsification does not enhance postoperative aqueous flare in trabeculectomy. Exfoliation glaucoma and postoperative shallow anterior chamber are factors in the elevation of aqueous flare. PMID- 23092093 TI - [Measurement of age-related changes in human blinks using a high-speed blink analysis system]. AB - PURPOSE: To measure the spontaneous and voluntary blinks of both younger and older people using a new device that simplifies the detailed recording of eye blinking. METHODS: Fifty healthy volunteers (10 women and 15 men under 40 years of age, range: 22-38 years, and 20 women and 5 men above 60 years of age, range: 63-85 years) were examined after obtaining informed consent from each subject. Eyelid movements of all subjects were recorded using a high-speed blink analysis system. The spontaneous eye-blinks of the subjects were recorded during sessions consisting of a 40 seconds' period following which the subjects were instructed to blink as rapidly as possible for 5 seconds in which the blinks were again recorded. The upper lid position and movement data were plotted every millisecond by processing the recorded images. RESULTS: The frequency of the spontaneous blinks did not differ between the younger and older subjects. The women tended to blink more frequently in both age groups. The average amplitude and duration time of the spontaneous blinks in the younger subjects were greater than those in the older subjects. Voluntary blinks in the younger subjects were more frequent than in the older subjects. Women tended to make deeper and faster voluntary blinks. CONCLUSION: Whereas the frequency of the voluntary blinks differed between the younger and older subjects, that of the spontaneous blinks did not differ. The findings of this study also revealed the gender-related differences in spontaneous and voluntary blinks. PMID- 23092094 TI - [A 10-week safety and efficacy evaluation of olopatadine, 0.2% instilled twice daily in patients with allergic conjunctivitis in Japan]. AB - PURPOSE: Olopatadine hydrochloride ophthalmic solution, 0.2% (olopatadine 0.2%) is a multi-action agent approved in Japan for allergic conjunctivitis when used as a dose of 1 to 2 drops twice-daily. The objective of this study was to evaluate the long-term (10 weeks) safety and efficacy of olopatadine 0.2% in Japanese patients with allergic conjunctivitis when used as a dose of 2 drops twice-daily. SUBJECTS AND METHODS: This was a single-insititution, open-label, single-group study of symptomatic patients > or = 12 years of age with allergic conjunctivitis. RESULTS: A total of 110 Japanese patients were enrolled. From baseline to week 10, the mean (95% confidence interval) absolute changes were 2.4 (-2.7, -2.2) in ocular itching and the total hyperemia scores were -3.2 ( 3.4, -2.9). Mean scores for all other efficacy variables were low at baseline (< or = 2.4) and decreased to < or = 0.6 by week 10. There were no serious adverse events. Mild eye irritation (1 patient) was the only treatment-related event. No safety concerns were identified in a review of the safety results. CONCLUSIONS: Based on this study, olopatadine 0.2% is generally safe, well tolerated and effective when instilled as 2 drops in both eyes twice-daily in Japanese patients with allergic conjunctivitis and is a useful new option for ocular allergy management. PMID- 23092095 TI - Immunoregulation of hepatitis B virus infection--rationale and clinical application. AB - Hepatitis B virus (HBV) is susceptible to the cellular immune responses, especially to the signal of interferon (IFN)-gamma. The action of IFN-gamma is pleiotropic, and causes downregulation of HBV in protein, RNA, and possibly DNA levels. Therefore, therapeutic vaccination to induce cellular immune responses to HBV is a promising approach for controlling chronic HBV infection. A number of clinical trials with this approach have been conducted to date, however, they have not been as successful as initially expected. T-cell exhaustion induced by the excessive HBV antigens caused by persistent infection is thought to be one of the main causes of poor responses to therapeutic vaccination. In this review, the mechanisms behind immunoregulation of HBV replication and immunodysfunction during chronic HBV infection are summarized, and novel approaches to improve the efficacy of therapeutic vaccination, from basic research to clinical trials, are introduced. PMID- 23092097 TI - Postoperative function following radical surgery in gastric and colorectal cancer patients over 80 years of age--an objection to "ageism". AB - PURPOSE: With rapid growth in the elderly population, the number of elderly cancer patients who should be offered life-prolonging radical surgery has been increasing. The aim of this report is to demonstrate the outcome of elective radical surgery for gastric or colorectal cancer patients 80 years of age or older, including the natural course of recovery of functional independence, in order to avoid the negative attitude held toward surgery that is due only to patients' high chronological age. METHODS: Physical condition, ADL, and QOL of 108 patients 80 years of age or older with gastric or colorectal cancer were evaluated preoperatively and at the 1st, 3rd, and 6th postoperative months. RESULTS: There were no operative deaths, and the morbidity rate was 27.9%. Only 6% of the patients showed a decrease in ADL at the 6th postoperative month. This decrease typically occurred following discharge from the hospital. Patient QOL showed recovery to an extent equal to or better than average preoperative scores. CONCLUSIONS: Of the patients who underwent elective surgery for gastric or colorectal cancer, only a few showed a protracted decline in ADL, and most exhibited better QOL after surgery. Surgical treatment should therefore be considered, whenever needed, for elderly patients 80 years of age or older with gastric or colorectal cancer. PMID- 23092096 TI - Improvements in the status of women and increased use of maternal health services in rural Egypt. AB - This research investigated the association between the household status of women and their use of maternal health services in rural Egypt. Face-to-face interviews with a structured questionnaire to 201 married women were carried out in a village, posing questions about their health service utilization and their household socio-economic status. The association between service utilization and other variables was statistically analysed. Older ages at first marriage and higher education levels showed significant positive associations with the three outcome variables--regular antenatal care (ANC), deliveries attended by skilled health professionals, and deliveries at heath facilities--of the use of maternal health services. Women who had not experienced physical assaults by husbands and had knowledge of community activities were more likely to receive ANC regularly; however, there were no significant association with the other two outcome variables. Participation in household decision-making and availability of assistance with household chores had no significant linkage to the use of maternal health services. Marriages to husbands with secondary or higher levels of education and residence in extended families were significantly associated with greater maternal health service usage. Our results suggest that the improved status of women in the household and moral support from family members contributes to an increase in the use of maternal health services. PMID- 23092098 TI - Morphologic characterization and quantification of superficial calcifications of the coronary artery--in vivo assessment using optical coherence tomography. AB - Coronary calcification is proportional to the extent and severity of atherosclerotic disease, and is a predictor of cardiac events. Furthermore, coronary calcification protruding into the lumen is considered as one type of vulnerable plaque. Optical coherence tomography (OCT) can provide in vivo imaging of the detailed vessel wall structure of the coronary artery with high resolution, as in the histological approach. We analyzed coronary calcification in that fashion using OCT in vivo. This study consisted of 70 superficial coronary calcifications of 39 consecutive patients who underwent percutaneous coronary intervention. After revascularization, OCT was performed in the treated vessel. We analyzed morphologic characteristics and the quantification of OCT determined coronary calcification. Superficial coronary calcifications were classified into two groups depending on whether they did not intrude the lumen (type I) or did (type II). The distance from the lumen and the volume of each calcification were then measured. Superficial coronary calcifications were classified into two groups; type I, n = 39 (56%) and type II, n = 31 (44%). Type II calcifications were located significantly closer to the lumen [80 microm (60 130) vs.130 microm (90-260), p = 0.015], and tended to be smaller, but did not show a significant difference [0.65 (0.2631.3) mm3 vs. 1.2 (0.47-1.9) mm3, p = 0.153] compared to those of type I. In conclusion, OCT could visualize superficial coronary calcifications in detail and enable us to evaluate in vivo morphologic characterizations and quantify them. PMID- 23092100 TI - Social correlates of female infertility in Uzbekistan. AB - The purpose of this matched case-control study was to investigate the social correlates of primary infertility among females aged 35 years or less. The study was conducted in the Clinics of Samarkand Medical Institute, Uzbekistan, among 120 infertile and 120 healthy women matched by age, residential area, and occupation from January to June 2009. Data were collected by face-to-face interviews using a structured questionnaire. Median duration of infertility was 10.0 months (interquartile range = 6.0-13.0). The rate of remarriage was 3.5 times higher among infertile women compared with healthy subjects. Insufficient family income, poor quality of life, life stress, and discontentment with daily routines as well as 'bad' relationships with family members (husband, mother- and father-in-law) were significant correlates of female infertility. Infertile women were more likely to underestimate the importance of sexual intimacy, and a negative attitude to sex. Female infertility is associated with various social correlates leading to higher remarriage rates and to further complicating the problem of infertility. Thus, a correction of women's basic attitudes and their relationships to their surrounding social habitat should be an essential component of any program of infertility management. PMID- 23092099 TI - Involvement of KRAS G12A mutation in the IL-2-independent growth of a human T-LGL leukemia cell line, PLT-2. AB - Cytokine-dependent cell lines have been used to analyze the cytokine-induced cellular signaling and the mechanism of oncogenesis. In the current study, we analyzed MOTN-1 and PLT-2 cell lines established from different stages of a T cell large granular lymphocyte leukemia patient (Daibata et al. 2004). MOTN-1 is IL-2-dependent derived from the chronic phase, whereas IL-2-independent PLT-2 is from the aggressive and terminal stage. They shared considerable chromosome abnormalities and the pattern of T-cell receptor rearrangement, presuming that the cytokine independence of PLT-2 was due to the additive genetic abnormality. Besides IL-2, IL-15 supported MOTN-1 cell growth, because these receptors share beta- and gamma-subunits. IL-2 activated ERK, AKT and STAT pathway of MOTN-1. STAT3 pathway of PLT-2 was also activated by IL-2, suggesting intact IL-2 induces signal transduction of PLT-2. However, ERK1/2 but not AKT, was continuously activated in PLT-2, consistent with the increased Ras-activity of PLT-2. Sequence analysis revealed KRAS G12A mutation but not NRAS and HRAS mutation of PLT-2 but not MOTN-1. Another signaling molecule affecting Ras-signaling pathway, SHP2, which has been frequently mutated in juvenile myelomonocytic leukemia (JMML), did not show mutation. Moreover, MEK inhibitor, PD98059, as well as farnesylation inhibitor inhibited PLT-2 cell growth. Using NIH3T3 and MOTN-1, ERK activation, increased cell proliferation and survival by KRAS G12A were shown, suggesting the important role of KRAS G12A in IL-2-independent growth of PLT-2. Taken together, KRAS G12A is important for IL-2-independent growth of PLT-2 cells and suggests the possibility of involvement of KRAS mutation with disease progression. PMID- 23092101 TI - Association of obesity and diabetes with serum prostate-specific antigen levels in Japanese males. AB - Patients with diabetes have been reported to be at an increased risk for cancers of the pancreas, liver, and colon; however, recent studies have suggested that men with diabetes are at a decreased risk for prostate cancer. Previous studies have found that obese men have lower serum prostate-specific antigen (PSA) concentrations than do non-obese men. Further understanding of how obesity and diabetes affect the PSA concentration may improve our ability to detect clinically relevant prostate tumors. This study examined the relationships among serum PSA level, obesity, and diabetes in apparently healthy Japanese males. We analyzed the baseline data from 2,172 Japanese males (age, 56.8 +/- 6.1 years [mean +/- SD]) who participated in the Japan Multi-Institutional Collaborative Cohort Study. Diabetes was defined as the presence of both a hemoglobin A1c (JDS) of > or = 6.1% and a fasting plasma glucose level of > or = 126 mg/dL, or a positive medical history. After adjusting for age, the PSA levels were elevated among males with a higher normal BMI (ranging from 23.0 to 24.9) and lowered among men with a BMI of > or = 25.0. In the stratified analysis, these significant differences in BMI categories were absent among diabetics. The mean PSA levels were significantly lower in diabetics than in non-diabetics among subjects aged 60 and over. Our findings suggest that the pre-overweight men had increased PSA levels, and the diabetes was associated with a reduction of PSA levels in elderly. PMID- 23092102 TI - CFTR polymorphisms of healthy individuals in two Chinese cities--Changchun and Nanjing. AB - BACKGROUND AND AIM: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel, cause cystic fibrosis. In order to investigate the polymorphic backgrounds of CFTR genes of healthy populations in different Chinese cities (Changchun and Nanjing), we analyzed 119 blood samples (Changchun 64, Nanjing 55) of randomly selected healthy individuals for poly T, TG-repeats and M470V polymorphisms. We analyzed the differences of CFTR polymorphic distributions between the two Chinese cities from the south and the north. Methods Genomic DNA was extracted from whole blood. DNA fragments of CFTR gene were amplified by polymerase chain reaction (PCR). Poly-T and TG repeats were directly sequenced by auto sequencer (ABI 310). M470V was detected by a HphI restriction enzyme. RESULTS: The T7 allele was the most common haplotype in Changchun (0.938) and Nanjing (0.927) populations. The T5 allele was present in only 7 Changchun and 3 Nanjing subjects. The TG11 and TG12 alleles were dominant haplotypes in Changchun (TG11 0.500, TG12 0.453) and Nanjing (TG11 0.345, TG12 0.609). The frequency of the V470 allele was 0.633 in Changchun, which was higher than that in Nanjing (0.500) (p < 0.05). There were three major haplotypes: T7-TG11-V470, T7-TG12-M470 and T7-TG12-V470. The T7-TG11-V470 was the most common haplotype in Changchun (0.514), while T7-TG12-M470 was the most common haplotype in Nanjing (0.500). CONCLUSION: Though Changchun and Nanjing are in the same country, their polymorphic backgrounds of CFTR gene are very different. Most of the two populations have genotypes that cause lower CFTR function. PMID- 23092103 TI - Restricted expression of new guanine nucleotide exchange factor Zizimin2 in aged acquired immune system. AB - The activity of various biological functions, such as nervous, endocrine and immune systems including acquired immunity, is known to decline along with aging. To elucidate the molecular mechanism of this phenomenon, we here compared the number of thymocytes, splenocytes, and bone marrow lymphocytes in young and aged mice and found the age-related functional fragility of the immune system. However, the molecular mechanisms or even the key molecules remain elusive. Therefore, we further focused on a candidate for immunosenesence-related molecules, Zizimin2, which we have recently isolated and identified as a novel guanine nucleotide exchange factor that is highly expressed in murine splenic germinal center B cells after immunization with a T cell-dependent antigen. Here, we showed that endogenous Zizimin2 protein as well as mRNA expression levels in immune organs are strictly suppressed in aged mice. We further observed that the serum antigen specific antibody response is hampered in aged mice compared to that in young animals. Moreover, the Zizimin2 mRNA expression level was not activated after immunization in aged mice. Taken together, these data suggested that Zizimin2 is associated with the reduction of immune response in acquired immunity along with aging. PMID- 23092104 TI - Inflammatory index and treatment of brain abscess. AB - This study retrospectively analyzed 12 patients with brain abscesses. Half of the patients were diagnosed inaccurately in the initial stage, and 7.2 days were required to achieve the final diagnosis of brain abscess. The patients presented only with a moderately elevated leukocyte count, serum CRP levels, or body temperatures during the initial stage. These markers changed, first with an increase in the leukocyte count, followed by the CRP and body temperature. The degree of elevation tended to be less prominent, and the time for each inflammatory index to reach its maximum value tended to be longer in the patients without ventriculitis than in those with it. The causative organisms of a brain abscess were detected in 10 cases. The primary causative organisms from dental caries were Streptococcus viridians or milleri, and Fusobacterium nucleatum. Nocardia sp. or farcinica were common when the abscess was found in other regions. The primary causative organisms of unrecognized sources of infection were Streptococcus milleri and Prolionibacterium sp. Nocardia is resistant to many antibiotics. However, carbapenem, tetracycline and quinolone were effective for Nocardia as well as many other kinds of bacteria. In summary, the brain abscesses presented with only mildly elevated inflammatory markers of body temperature, leukocyte and CRP. These inflammatory markers were less obvious in the patients without ventriculitis and/or meningitis. The source of infection tended to suggest some specific primary causative organism. It was reasonable to initiate therapy with carbapenem. PMID- 23092105 TI - Treatment of a cerebral dissecting aneurysm in anterior circulation: report of 11 subarachnoid hemorrhage cases. AB - This report presents 8 cases of internal carotid artery aneurysms, 1 case of a middle cerebral artery aneurysm, and 2 cases of anterior cerebral artery aneurysms, together with a discussion of the treatment of aneurysms in anterior circulation. All cases showed subarachnoid hemorrhage. Two of the 8 internal carotid artery aneurysms were trapped with a low-flow bypass; however, both patients died of an immediate hemodynamic infarction or vasospasm-induced infarction. Five of the 8 internal carotid artery aneurysms were trapped after revascularization with high flow bypass. Four of those patients were self supporting at discharge, but one patient was discharged in a vegetative state due to the sacrifice of arterial branches which were included in the dissecting portion. One case of the dissecting aneurysm in the M2 portion of the middle cerebral artery was trapped after low-flow bypass. This patient was self supporting at discharge. In 2 cases of anterior cerebral artery aneurysms, the lesions were first wrapped with Bemsheets, and then the aneurysmal clip was applied on the wrapped dome. Trapping following high-flow bypass is the best method for treating a dissecting aneurysm in the internal carotid artery. Trapping also can be used to treat a dissecting aneurysm of the middle cerebral artery, after low-flow bypass. Clipping on the wrapped aneurysm can also be performed successfully in the anterior cerebral artery aneurysm. PMID- 23092106 TI - Air vent of vein graft in extracranial-intracranial bypass surgery. AB - Revascularization with a vein graft is a mandatory method for treatment of dissecting or pseudoaneurysms of the internal carotid artery. We report the necessity for an air vent from the vein graft and explain its use in our two cases. In Case 1, we searched for a great saphenous vein around its junction with a femoral vein during the harvest of vein graft. An accessory branch of that great saphenous vein was also found around the junctional region with a femoral vein, and was temporarily ligated. At first, anastomosis was completed on both the distal and proximal sides. After the proximal side of a vein graft was opened and the ligation of the branch was loosened, an air vent could be made through the branch of the vein graft. Multiple air bubbles and a large quantity of white microemboli were discharged through this branch. The postoperative course was uneventful. In Case 2, the air vent was omitted to shorten ischemia. During the opening of the vein graft, the migrated air was observed to move to the middle cerebral artery. A computed tomography scan demonstrated that brain infarction and dysarthria occurred postoperatively. The air vent of the vein graft is essential in extracranial-intracranial bypass surgery, because the air bubbles or microthrombi are easily trapped around the valve and cause cerebral infarction. An air vent can be easily made if the branch of a vein graft exists in the outflow pathway, because intraluminal air or thrombus can be washed out through the branch at the final stage of surgery. PMID- 23092107 TI - Metastatic breast cancer to the uterine cervix mimicking a giant cervical leiomyoma. AB - Metastasis to the uterine cervix is a complication of breast cancer that is not commonly known. Detection of cervical metastasis before the diagnosis of the primary tumor is even rarer. The present report describes a case of a 52-year-old woman who had a large cervical tumor appearing as a leiomyoma. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy. Histopathological examination of the cervical tumor showed patterns characteristic of invasive lobular carcinoma of the breast, leading to the discovery of the primary in the left breast. She subsequently underwent mastectomy, hormone therapy and chemotherapy, and is alive at 7-year follow-up. PMID- 23092108 TI - Intravascular lymphoma of the central nervous system presenting as multiple cerebral infarctions. AB - A 67-year-old woman presented with an acute onset of left-sided weakness. Magnetic resonance (MR) imaging revealed multiple cerebral infarctions and gadolinium-enhanced lesions in both cerebral hemispheres. Her symptoms once improved after starting steroid treatment; however, soon developed consciousness disturbance and hemiparesis on the left side. She was referred to our hospital where she underwent stereotactic needle biopsy, that revealed an intravascular large B-cell lymphoma in the cerebrum. She received high-dose methotrexate chemotherapy followed by whole-brain radiation therapy, and the MR findings improved. However, her medical condition gradually worsened, and she died 6 months after disease onset. Intravascular lymphoma (IVL) limited to the central nervous system (CNS) is very rare, and the optimal treatment for this medical condition has not been established yet. IVLs showing only neurologic manifestations might be overlooked or misdiagnosed as cerebral infarctions. Here, we present a case of CNS IVL, with its radiographic and pathologic features and treatment with high-dose methotrexate chemotherapy. PMID- 23092109 TI - Pilot study on the effects of a 1-day sleep education program: influence on sleep of stopping alcohol intake at bedtime. AB - The aim of this pilot study was to evaluate whether sleep was improved by a 1-day sleep education program in an occupational setting and whether stopping alcohol intake at bedtime might influence sleep. Subjects were 40 high school employees. The sleep education program lasted 4.5 hours and consisted of sleep science information, and sleep hygiene education including the risk of sleep related breathing disorder resulting from alcohol intake. Sleep conditions were evaluated by self-administered questionnaires at baseline and approximately 1 month later. The mean the Epworth Sleepiness Scale (ESS) score was significantly decreased by 1.2 points (P = 0.04), while the mean sleep duration was significantly decreased by 10 minutes (P = 0.02). Shortened sleep duration coincided with a decrease in sleepiness. This may indicate an improvement in sleep quality. The percentage of habitual alcohol intake at bedtime was significantly decreased (from 38.5% (15/39) to 20.5% (8/39), P = 0.04). Subjects who stopped alcohol intake at bedtime (n = 8) received the most benefit, with decreased scores of ESS and Insomnia Severity Index (ISI), although the reductions were not significant. This education program offers the possibility of improving sleep conditions among the general population, especially in those who cease habitual alcohol intake at bedtime. Further larger, randomized, controlled studies are warranted. PMID- 23092110 TI - Measurement of CO2 diffusivity for carbon sequestration: a microfluidic approach for reservoir-specific analysis. AB - Predicting carbon dioxide (CO(2)) security and capacity in sequestration requires knowledge of CO(2) diffusion into reservoir fluids. In this paper we demonstrate a microfluidic based approach to measuring the mutual diffusion coefficient of carbon dioxide in water and brine. The approach enables formation of fresh CO(2) liquid interfaces; the resulting diffusion is quantified by imaging fluorescence quenching of a pH-dependent dye, and subsequent analyses. This method was applied to study the effects of site-specific variables--CO(2) pressure and salinity levels--on the diffusion coefficient. In contrast to established, macro-scale pressure-volume-temperature cell methods that require large sample volumes and testing periods of hours/days, this approach requires only microliters of sample, provides results within minutes, and isolates diffusive mass transport from convective effects. The measured diffusion coefficient of CO(2) in water was constant (1.86 [+/- 0.26] * 10(-9) m(2)/s) over the range of pressures (5-50 bar) tested at 26 degrees C, in agreement with existing models. The effects of salinity were measured with solutions of 0-5 M NaCl, where the diffusion coefficient varied up to 3 times. These experimental data support existing theory and demonstrate the applicability of this method for reservoir-specific testing. PMID- 23092111 TI - Hyaluronic acid-gold nanoparticle/interferon alpha complex for targeted treatment of hepatitis C virus infection. AB - Gold nanoparticles (AuNPs) have been extensively investigated as an emerging delivery carrier of various biopharmaceuticals. Instead of nonspecific polyethylene glycol (PEG) conjugated interferon alpha (IFNalpha) for the clinical treatment of hepatitis C virus (HCV) infection, in this work, a target-specific long-acting delivery system of IFNalpha was successfully developed using the hybrid materials of AuNP and hyaluronic acid (HA). The HA-AuNP/IFNalpha complex was prepared by chemical binding of thiolated HA and physical binding of IFNalpha to AuNP. According to antiproliferation tests in Daudi cells, the HA AuNP/IFNalpha complex showed a comparable biological activity to PEG-Intron with a highly enhanced stability in human serum. Even 7 days postinjection, HA AuNP/IFNalpha complex was target-specifically delivered and remained in the murine liver tissue, whereas IFNalpha and PEG-Intron were not detected in the liver. Accordingly, HA-AuNP/IFNalpha complex significantly enhanced the expression of 2',5'-oligoadenylate synthetase 1 (OAS1) for innate immune responses to viral infection in the liver tissue, which was much higher than those by IFNalpha, PEG-Intron, and AuNP/IFNalpha complex. Taken together, the target-specific HA-AuNP/IFNalpha complex was thought to be successfully applied to the systemic treatment of HCV infection. PMID- 23092112 TI - Hybrid energy-minimization simulation of equilibrium droplet shapes on hydrophilic/hydrophobic patterned surfaces. AB - We have developed an efficient algorithm for simulating the equilibrium shape of a microdroplet placed on a flat substrate that has a fine, discontinuous, and arbitrarily shaped hydrophilic/hydrophobic patterned surface. The method uses a hybrid energy-minimization technique that combines the direct search method to determine the droplet shape around solid/liquid contact lines with the gradient descent method for the other parts of the droplet surface. The method provides high-convergence at a low computational cost with sufficient mesh resolution, providing a useful tool for the optimal design of printed electronic devices. PMID- 23092113 TI - Photocleavable DNA barcode-antibody conjugates allow sensitive and multiplexed protein analysis in single cells. AB - DNA barcoding is an attractive technology, as it allows sensitive and multiplexed target analysis. However, DNA barcoding of cellular proteins remains challenging, primarily because barcode amplification and readout techniques are often incompatible with the cellular microenvironment. Here we describe the development and validation of a photocleavable DNA barcode-antibody conjugate method for rapid, quantitative, and multiplexed detection of proteins in single live cells. Following target binding, this method allows DNA barcodes to be photoreleased in solution, enabling easy isolation, amplification, and readout. As a proof of principle, we demonstrate sensitive and multiplexed detection of protein biomarkers in a variety of cancer cells. PMID- 23092115 TI - Antioxidation of decellularized stem cell matrix promotes human synovium-derived stem cell-based chondrogenesis. AB - Clinical treatment of cartilage defects is challenging due to concomitant post traumatic joint inflammation. This study was to demonstrate that the antioxidant ability of human adult synovium-derived stem cells (SDSCs) could be enhanced by ex vivo expansion on a decellularized stem cell matrix (DSCM). Microarray was used to evaluate oxidative, antioxidative, and chondrogenic status in SDSCs after expansion on the DSCM and induction in the chondrogenic medium. Hydrogen peroxide (H2O2) was added to create oxidative stress in either expanded SDSCs or chondrogenically induced premature pellets. The effect of H2O2 on SDSC proliferation was evaluated using flow cytometry. Chondrogenic differentiation of expanded SDSCs was evaluated using histology, immunostaining, biochemical analysis, and real-time polymerase chain reaction. Mitogen-activated protein kinase signaling pathways and p21 were compared in the DSCM and plastic-flask expanded SDSCs with or without H2O2 treatment. We found that expansion on the DSCM upregulated antioxidative gene levels and chondrogenic potential in human SDSCs (hSDSCs), retarded the decrease in the cell number and the increase in apoptosis, and rendered SDSCs resistant to cell-cycle G1 arrest resulting from H2O2 treatment. Treatment with 0.05 mM H2O2 during cell expansion yielded pellets with increased chondrogenic differentiation; treatment in premature SDSC pellets showed that the DSCM-expanded cells had a robust resistance to H2O2-induced oxidative stress. Extracellular signal-regulated kinases 1 and 2 and p38 were positively involved in antioxidative and chondrogenic potential in SDSCs expanded on the DSCM in which p21 was downregulated. DSCM could be a promising cell expansion system to provide a large number of high-quality hSDSCs for cartilage regeneration in a harsh joint environment. PMID- 23092116 TI - Internet trials: participant experiences and perspectives. AB - BACKGROUND: Use of the Internet to conduct randomised controlled trials is increasing, and provides potential to increase equity of access to medical research, increase the generalisability of trial results and decrease the costs involved in conducting large scale trials. Several studies have compared response rates, completeness of data, and reliability of surveys using the Internet and traditional methods, but very little is known about participants' attitudes towards Internet-based randomised trials or their experience of participating in an Internet-based trial. OBJECTIVE: To obtain insights into the experiences and perspectives of participants in an Internet-based randomised controlled trial, their attitudes to the use of the Internet to conduct medical research, and their intentions regarding future participation in Internet research. METHODS: All English speaking participants in a recently completed Internet randomised controlled trial were invited to participate in an online survey. RESULTS: 1246 invitations were emailed. 416 participants completed the survey between May and October 2009 (33% response rate). Reasons given for participating in the Internet RCT fell into 4 main areas: personal interest in the research question and outcome, ease of participation, an appreciation of the importance of research and altruistic reasons. Participants' comments and reflections on their experience of participating in a fully online trial were positive and less than half of participants would have participated in the trial had it been conducted using other means of data collection. However participants identified trade-offs between the benefits and downsides of participating in Internet-based trials. The main trade-off was between flexibility and convenience - a perceived benefit - and a lack connectedness and understanding - a perceived disadvantage. The other tradeoffs were in the areas of: ease or difficulty in use of the Internet; security, privacy and confidentiality issues; perceived benefits and disadvantages for researchers; technical aspects of using the Internet; and the impact of Internet data collection on information quality. Overall, more advantages were noted by participants, consistent with their preference for this mode of research over others. The majority of participants (69%) would prefer to participate in Internet-based research compared to other modes of data collection in the future. CONCLUSION: Participants in our survey would prefer to participate in Internet-based trials in the future compared to other ways of conducting trials. From the participants' perspective, participating in Internet-based trials involves trade-offs. The central trade-off is between flexibility and convenience - a perceived benefit - and lack of connectedness and understanding - a perceived disadvantage. Strategies to maintain the convenience of the Internet while increasing opportunities for participants to feel supported, well-informed and well-understood would seem likely to increase the acceptability of Internet based trials. PMID- 23092114 TI - Novel directions for diabetes mellitus drug discovery. AB - INTRODUCTION: Diabetes mellitus impacts almost 200 million individuals worldwide and leads to debilitating complications. New avenues of drug discovery must target the underlying cellular processes of oxidative stress, apoptosis, autophagy, and inflammation that can mediate multi-system pathology during diabetes mellitus. AREAS COVERED: The authors examine the novel directions for drug discovery that involve: the beta-nicotinamide adenine dinucleotide (NAD(+)) precursor nicotinamide, the cytokine erythropoietin, the NAD(+)-dependent protein histone deacetylase SIRT1, the serine/threonine-protein kinase mammalian target of rapamycin (mTOR), and the wingless pathway. Furthermore, the authors present the implications for the targeting of these pathways that oversee gluconeogenic genes, insulin signaling and resistance, fatty acid beta-oxidation, inflammation, and cellular survival. EXPERT OPINION: Nicotinamide, erythropoietin, and the downstream pathways of SIRT1, mTOR, forkhead transcription factors, and wingless signaling offer exciting prospects for novel directions of drug discovery for the treatment of metabolic disorders. Future investigations must dissect the complex relationship and fine modulation of these pathways for the successful translation of robust reparative and regenerative strategies against diabetes mellitus and the complications of this disorder. PMID- 23092117 TI - In-silico prediction of blood-brain barrier permeability. AB - The ability of penetration of the blood-brain barrier is one of the significant properties of a drug or drug-like compound for the central nervous system (CNS), which is commonly expressed by log BB (log BB = log (C (brain)/C (blood))). In this work, a dataset of 320 compounds with log BB values was split into a training set including 198 compounds and a test set including 122 compounds according to their structure properties by a Kohonen's self-organizing map (SOM). Each molecule was represented by global and shape descriptors, 2D autocorrelation descriptors and RDF descriptors calculated by ADRIANA.Code. Several quantitative models for prediction of log BB were built by a multilinear regression (MLR), a support vector machine (SVM) and an artificial neural network (ANN) analysis. The models show good prediction performance on the test set compounds. PMID- 23092118 TI - Modulating the photoisomerization of N,C-chelate organoboranes with triplet acceptors. AB - Triplet acceptors such as naphthalene, pyrene, and anthracene have been found to be highly effective in controlling the photoisomerization efficiency of N,C chelate boryl chromophores, establishing the involvement of a photoactive triplet state in the isomerization of this class of photochromic compounds. PMID- 23092119 TI - In vitro demonstration of apoptosis mediated photodynamic activity and NIR nucleus imaging through a novel porphyrin. AB - We synthesized a novel water-soluble porphyrin THPP and its metalated derivative Zn-THPP having excellent triplet excited state quantum yields and singlet oxygen generation efficiency. When compared to U.S. Food and Drug Administration approved and clinically used sensitizer Photofrin, THPP showed ca. 2-3-fold higher in vitro photodynamic activity in different cell lines under identical conditions. The mechanism of the biological activity of these porphyrin systems has been evaluated through a variety of techniques: 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) assay, comet assay, poly(ADP ribose)polymerase (PARP) cleavage, CM-H(2)DCFDA assay, DNA fragmentation, flow cytometric analysis, fluorescence, and confocal microscopy, which confirm the apoptotic cell death through predominantly reactive oxygen species (ROS). Moreover, THPP showed rapid cellular uptake and are localized in the nucleus of the cells as compared to Hoechst dye and Photofrin, thereby demonstrating its use as an efficient sensitizer in photodynamic therapy and live cell NIR nucleus imaging applications. PMID- 23092120 TI - The clinical instructor role in nursing education: a structured literature review. AB - A structured literature review was conducted to understand clinical instructors' perceptions of their role and the factors that facilitate and constrain their teaching in undergraduate nursing programs. The literature published in English between 2000 and 2011 was searched, and data were extracted from 15 articles that met the inclusion criteria. The analysis identified four themes-characteristics of the role, characteristics of effective clinical teaching, influence of the clinical context on the role, and influence of the academic context on the role. Clinical instructors are portrayed as needing to be good educators, as well as excellent clinicians. However, they often lack formal education and professional development opportunities related to the role and must draw on their individual personal and professional experiences to guide their teaching to meet the demands of both the clinical and academic contexts in which they simultaneously work. PMID- 23092121 TI - Terahertz plasmon and surface-plasmon modes in hollow nanospheres. AB - : We present a theoretical study of the electronic subband structure and collective electronic excitation associated with plasmon and surface plasmon modes in metal-based hollow nanosphere. The dependence of the electronic subband energy on the sample parameters of the hollow nanosphere is examined. We find that the subband states with different quantum numbers l degenerate roughly when the outer radius of the sphere is r2 >= 100 nm. In this case, the energy spectrum of a sphere is mainly determined by quantum number n. Moreover, the plasmon and surface plasmon excitations can be achieved mainly via inter-subband transitions from occupied subbands to unoccupied subbands. We examine the dependence of the plasmon and surface-plasmon frequencies on the shell thickness d and the outer radius r2 of the sphere using the standard random-phase approximation. We find that when a four-state model is employed for calculations, four branches of the plasmon and surface plasmon oscillations with terahertz frequencies can be observed, respectively. PMID- 23092123 TI - Corkscrew angiopathy of intracranial vessels in a young stroke patient: a case report. AB - INTRODUCTION: We present a rare finding of a 'corkscrew appearance' of the distal cerebral vessels in a young Asian woman who presented with acute stroke. CASE PRESENTATION: A 32-year-old Asian woman presented with a 3-month history of recurrent right-sided transient ischemic attacks. Her clinical workup and brain imaging results were normal. A digital subtraction angiogram revealed an abnormal corkscrew appearance of all intracranial distal vessels. She was discharged on a single antiplatelet drug. She had no further transient ischemic attacks on clinical follow-up. A digital subtraction angiogram performed 1 year later revealed no changes in the appearance of these vessels. CONCLUSION: To the best of our knowledge no similar previous reports exist in the literature. The present report describes a unique case of an unusual corkscrew appearance of the distal intracranial vessels. However, the underlying etiology in the present case remains unknown. PMID- 23092122 TI - SAMHD1 restricts HIV-1 reverse transcription in quiescent CD4(+) T-cells. AB - BACKGROUND: Quiescent CD4+ T lymphocytes are highly refractory to HIV-1 infection due to a block at reverse transcription. RESULTS: Examination of SAMHD1 expression in peripheral blood lymphocytes shows that SAMHD1 is expressed in both CD4+ and CD8+ T cells at levels comparable to those found in myeloid cells. Treatment of CD4+ T cells with Virus-Like Particles (VLP) containing Vpx results in the loss of SAMHD1 expression that correlates with an increased permissiveness to HIV-1 infection and accumulation of reverse transcribed viral DNA without promoting transcription from the viral LTR. Importantly, CD4+ T-cells from patients with Aicardi-Goutieres Syndrome harboring mutation in the SAMHD1 gene display an increased susceptibility to HIV-1 infection that is not further enhanced by VLP-Vpx-treatment. CONCLUSION: Here, we identified SAMHD1 as the restriction factor preventing efficient viral DNA synthesis in non-cycling resting CD4+ T-cells. These results highlight the crucial role of SAMHD1 in mediating restriction of HIV-1 infection in quiescent CD4+ T-cells and could impact our understanding of HIV-1 mediated CD4+ T-cell depletion and establishment of the viral reservoir, two of the HIV/AIDS hallmarks. PMID- 23092124 TI - Mass spectrometry-based identification of native cardiac Nav1.5 channel alpha subunit phosphorylation sites. AB - Cardiac voltage-gated Na+ (Nav) channels are key determinants of action potential waveforms, refractoriness and propagation, and Nav1.5 is the main Nav pore forming (alpha) subunit in the mammalian heart. Although direct phosphorylation of the Nav1.5 protein has been suggested to modulate various aspects of Nav channel physiology and pathophysiology, native Nav1.5 phosphorylation sites have not been identified. In the experiments here, a mass spectrometry (MS)-based proteomic approach was developed to identify native Nav1.5 phosphorylation sites directly. Using an anti-NavPAN antibody, Nav channel complexes were immunoprecipitated from adult mouse cardiac ventricles. The MS analyses revealed that this antibody immunoprecipitates several Nav alpha subunits in addition to Nav1.5, as well as several previously identified Nav channel associated/regulatory proteins. Label-free comparative and data-driven phosphoproteomic analyses of purified cardiac Nav1.5 protein identified 11 phosphorylation sites, 8 of which are novel. All the phosphorylation sites identified except one in the N-terminus are in the first intracellular linker loop, suggesting critical roles for this region in phosphorylation-dependent cardiac Nav channel regulation. Interestingly, commonly used prediction algorithms did not reliably predict these newly identified in situ phosphorylation sites. Taken together, the results presented provide the first in situ map of basal phosphorylation sites on the mouse cardiac Nav1.5 alpha subunit. PMID- 23092126 TI - Proteasome inhibitors: a new perspective for treating autoimmune diseases. AB - Since the discovery of proteasome in the late 1980s, the ubiquitin-proteasome system has been found to exert an important physiological function in all the cells of living organisms - that of ensuring homeostasis. All cell cycle, apoptosis, differentiation, transcription, protein quality control and antigen processing activities require the efficiency of this system. As a matter of fact, several pathological conditions are characterized by deregulation of the ubiquitinproteasome system. These include cancer, neurodegenerative diseases, viral infections and autoimmune diseases. This has stimulated interest in developing proteasome inhibitors for their treatment, but clinical application has been limited due to the toxicity of these compounds. Following experiences with the first proteasome inhibitor, bortezomib, in the treatment of hematologic malignancies, several molecules with proteasome inhibitor properties were discovered and they were also exploited for the treatment of experimental models of human autoimmunity. Autoimmune disorders are a heterogeneous group of conditions, both organ- and non-organ-specific, whose incidence is increasing worldwide. This has stimulated interest in discovering novel predictive strategies and therapeutics. Here we provide a review of the use of proteasome inhibitors in treating autoimmune conditions and, in particular, systemic autoimmune diseases, inflammatory bowel disease, multiple sclerosis and organ specific autoimmune diseases. We also present perspectives derived from more recently discovered compounds with proteasome inhibitor activity and discuss their potential in the management of these disorders. PMID- 23092125 TI - Awareness of the 2009 US Preventive Services Task Force recommended changes in mammography screening guidelines, accuracy of awareness, sources of knowledge about recommendations, and attitudes about updated screening guidelines in women ages 40-49 and 50+. AB - BACKGROUND: The US Preventive Services Task Force updated mammography recommendations in 2009, recommending against routine screening for women ages 40 49 and reducing recommended frequency for women 50+. The recommendation changes were highly controversial and created conflicting recommendations across professional organizations. This study examines overall awareness of the changes, accuracy of knowledge about changes, factors related to both overall awareness and accuracy, sources of knowledge about changes, and attitudes about the new recommendations. METHOD: National telephone survey of 508 women, half aged 40-49 and half 50+, conducted one year after the update (November/December 2010; cooperation rate was 36%). Measures include awareness, accuracy, source of knowledge, interactions with providers, and attitudes about the changes. RESULTS: Fewer than half of women were aware of the guideline changes. Younger, more educated, and higher income women were more aware. Of those who were aware, only 12% correctly reported both change in age and frequency. Accuracy was not associated with demographics. The majority learned of changes through the media and the majority had negative attitudes about the changes. CONCLUSIONS: Despite widespread coverage of the recommendation changes, overall awareness in the relevant population is low. Increasing awareness and addressing attitudes about the changes is necessary to ensure the use of recommendations to impact screening behavior. PMID- 23092127 TI - Advances in mycobacterial isocitrate lyase targeting and inhibitors. AB - Isocitrate lyase plays a key role for survival of Mycobacterium tuberculosis in the latent form during a chronic stage of infection. This enzyme is important for M. tuberculosis during steady stage growth when it converts isocitrate to succinate and glyoxylate. Then, the glyoxylate is condensed with acetyl-CoA to form malate by malate synthase. The carbon conserving glyoxylate pathway has not been observed in mammals; therefore, it has been determined as a potential drug target for discovery of a new antituberculosis agent. Novel active molecules should shorten the duration of therapy, prevent resistance development and eliminate latent disease. The review summarizes recent progresses in isocitrate lyase inhibitors, overviews structural analogues of several metabolic intermediates (3-nitropropionate, 3-bromopyruvate, itaconate, itaconic anhydride), peptide inhibitors, and recently developed inhibitors with various chemical structures. The largest inhibitory activity against isocitrate lyase (IC(50) of 0.10 +/- 0.01 MUM) and concomitantly a significant antimycobacterial activity has been presented by fluoroquinolone derivative 1-cyclopropyl-7-[3,5 dimethyl-4-(3-nitropropanoyl)piperazin-1-yl]-6-fluoro-8-methoxy-4-oxo-1,4 dihydroquinoline-3-carboxylic acid, which has incorporated 3-nitropropionyl group as one of the structural analogue of succinate, a metabolic intermediate. PMID- 23092128 TI - New pentamidine analogues in medicinal chemistry. AB - Sixty years after its introduction, 1,5-bis(4-amidinophenoxy)pentane (Pentamidine) is still one of the most used drugs for the treatment of the first stage of Human African trypanosomiasis and other neglected diseases such as malaria and leishmaniasis. These protozoan infections are prevalent in the poorest world areas such as sub-saharian and developing countries, however the increasing immigration from these countries to the richest part of the world and the overlap of HIV with parasitic infections result in a growing number of cases in developed nations. A great effort has been made to develop new generations of diamidines for the treatment of these infections transmitted by insects. This review summarises the synthesis and evaluation of pentamidine analogues reported in the last years in the effort to find new drugs with better pharmaceutical activity, higher lipophilicity and lower citotoxycicty. PMID- 23092129 TI - Cytotoxicity and genotoxicity of cationic phosphorus-containing dendrimers. AB - Cationic phosphorus-containing dendrimers (CPDs) are a class of highly-branched polymers with potential medical relevance. However, little is known about CPD modes of interactions with cell and its components, including DNA. In the present work we investigated cytotoxicity and genotoxicity of CPDs generation 3 and 4 (CPD G3 and CPD G4) in human mononuclear blood cells, A549 human cancer cells and human gingival fibroblasts (HGFs). CPD G3 and CPD G4 at concentrations up to 10 MUM induced a concentration-dependent decrease in cell viability as assessed by flow cytometry. Both compounds did not induce breaks in isolated DNA as evaluated by the plasmid relaxation assay but they induced DNA cross-links in the cells, as examined by comet assay. CPD G3 and 4 induced slight perturbations in the cell cycle leading to a decrease in the G2/M cell population accompanied by an increase in the S cell population. Upon treatment with CPDs, the cells showed changes in their morphology, including loss of cell attachment, disruption of cell membrane and nucleus condensation. Our results indicate that CPD G3 and G4 are cytotoxic and genotoxic for the assorted human cells. Therefore, CPDs may form stable complexes with DNA and interfere with cellular processes. PMID- 23092131 TI - Correlation between central corneal thickness, anterior chamber depth, and corneal keratometry as measured by Oculyzer II and WaveLight OB820 in preoperative cataract surgery patients. AB - PURPOSE: To compare and correlate central corneal thickness (CCT), anterior chamber depth (ACD), and keratometric (flat and steep K) measurements using two anterior segment imaging methods, a Scheimpflug camera system (Oculyzer II [Oculus Optikgerate GmbH]) and a partial coherence biometry system (WaveLight OB820 [Alcon Laboratories Inc]) in eyes undergoing cataract surgery. METHODS: Ninety patients (mean age: 66+/-13 years [range: 32 to 88 years]) underwent preoperative measurement of CCT, ACD, and keratometric measurements by Scheimpflug tomography (Oculyzer II) and optical low coherence reflectometry (WaveLight OB820). Interdevice agreement and correlation between the two techniques were assessed. RESULTS: All measurements were highly correlated and showed no clinically significant difference between methods. Mean CCT was 554.21+/-39.07 MUm and 546.59+/-37.75 MUm for the Oculyzer II and WaveLight OB820, respectively (R2=0.9268). Mean ACD was 2.63+/-0.44 mm and 2.63+/-0.43 mm for the Oculyzer II and WaveLight OB820, respectively (R(2)=0.9488). The principal meridian keratometric values were also highly correlated. Mean flat K was 42.88+/-1.50 diopters (D) and 42.96+/-1.40 D for the Oculyzer II and WaveLight OB820, respectively (R2=0.8741). Mean steep K was 44.08+/-1.79 D and 44.26+/-1.95 D for the Oculyzer II and WaveLight OB820, respectively (R(2)=0.9159). CONCLUSIONS: Our data show that the Oculyzer II and WaveLight OB820 provide measurements that are in agreement with published values for CCT and ACD in patients. Excellent agreement for CCT and ACD was found between the two devices, as demonstrated by a high degree of correlation and linearity, in addition to minimal bias. Thus, CCT, ACD, and K measurements by these instruments can both be used in clinical preparation, and their agreement is an ensuring precision factor for cataract and refractive surgeons. PMID- 23092130 TI - Thermosensitive polymeric hydrogels as drug delivery systems. AB - Thermosensitive hydrogels are very important biomaterials used in drug delivery systems (DDSs), which gained increasing attention of researchers. Thermosensitive hydrogels have great potential in various applications, such as drug delivery, cell encapsulation, tissue engineering, and etc. Especially, injectable thermosensitive hydrogels with lower sol-gel transition temperature around physiological temperature have been extensively studied. By in vivo injection, the hydrogels formed non-flowing gel at body temperature. Upon incorporation of pharmaceutical agents, the hydrogel systems could act as sustained drug release depot in situ. Injectable thermosensitive hydrogel systems have a number of advantages, including simplicity of drug formulation, protective environment for drugs, prolonged and localized drug delivery, and ease of application. The objective of this review is to summarize fundamentals, applications, and recent advances of injectable thermosensitive hydrogel as DDSs, including chitosan and related derivatives, poly(N-isopropylacrylamide)-based (PNIPAAM) copolymers, poly(ethylene oxide)/poly(propylene oxide) (PEO/PPO) copolymers and its derivatives, and poly(ethylene glycol)/ biodegradable polyester copolymers. PMID- 23092132 TI - Orbital infarction syndrome after transcanalicular dacryocystorhinostomy with diode laser. AB - Orbital infarction syndrome is a rare but devastating disorder resulting in sudden visual loss. A patient with orbital infarction syndrome due to orbital cellulitis after transcanalicular dacryocystorhinostomy with diode laser is described. A 55-year-old woman presented 3 days after transcanalicular dacryocystorhinostomy. Initial examination revealed significant eyelid swelling, marked proptosis, total ophthalmoplegia, and no light perception in the right eye. Fundus examination revealed ophthalmic artery occlusion. The clinical findings of the patient were consistent with orbital infarction syndrome. Clinical findings improved with antibiotic therapy, but visual acuity did not change. PMID- 23092133 TI - Purification and characterization of a novel lectin with antiphytovirus activities from the wild mushroom Paxillus involutus. AB - A novel lectin was isolated from the dried fruiting bodies of the wild mushroom Paxillus involutus. Isolation was conducted by anion exchange chromatography on DEAE-Cellulose, Q-Sepharose and gel filtration on Superdex 75 using a fast protein liquid chromatography (FPLC) system. This lectin had a molecular mass of 28 kDa and was composed of four identical subunits, each with a molecular mass of 7 kDa. N-terminal amino acid sequence of the P. involutus lectin was determined to be CTCAVFLNNTTVKS, which showed a low level of similarity to mushroom lectin sequences reported previously. The biochemical properties of this lectin were determined, and the hemagglutinating activity was inhibited by inulin and O Nitrophenyl-beta-D-galacto-pyranoside. Additionally, Ca2+, Zn2+, Cd2+, Fe2+, and Al3+ inhibited its hemagglutinating activity, while Cu2+ promoted this activity. This lectin exhibited poor thermostability and was sensitive to HCl, but it had a high tolerance to NaOH exposure. In terms of biological properties, this lectin manifested antiphytovirus activity towards tobacco mosaic virus (TMV) with a 70.61% inhibition at a concentration of 200 ug/mL. This lectin was devoid of inhibitory activities toward pathogenic fungi and HIV-1 reverse transcriptase, and antiproliferative activities were observed in tumor cell lines including lung cancer A-549 and human colon cancer HCT-8 cells. PMID- 23092134 TI - Clearance of genetic variants of amyloid beta peptide by neuronal and non neuronal cells. AB - The presence of senile plaques in the brain is one of the pathological hallmarks of Alzheimer's disease (AD). The biogenesis and clearance of the amyloid beta peptide (A beta ), the main component of the lesions, lie at the center of the pathogenesis of AD. In sporadic AD, the increase of A beta levels seems to be indicative of failure of clearance mechanisms. We previously showed that the clearance of the wild type A beta40 peptide by various neuronal and non-neuronal cells occurs through a same proteolytic process and that A beta degradation was primarily dictated by its conformational state (Panchal et al., 2007). To gain further insights on the role of the peptide conformation in the clearance mechanism of A beta , two A beta40 peptides, known to be associated with amyloid angiopathy (Dutch and Flemish mutations), and the rodent A beta40 peptide were catabolized by several cells by using the same experimental approach. The peptide fragments, generated by proteolytic cleavage of substrates in cell supernatants, were identified by LC-MS and the cleavage sites of proteases were deduced. In parallel, conformational states of wild type A beta 40 peptide and of the three A beta 40 variants were characterized by circular dichroism spectroscopy. We provide data suggesting that discrete conformational changes of A beta 40 peptide regulate its clearance rate by neuronal and non-neuronal cells. PMID- 23092135 TI - The expression and induction of heat shock proteins in molluscs. AB - Living cells respond to stress stimuli by triggering rapid changes in the protein profiles, and the induction of heat shock proteins (HSPs) plays an important part in this process. HSPs, mainly acting as molecular chaperones, are constitutively expressed in cells and involved in protein folding, assembly, degradation, and intracellular localization. The overexpression of HSPs represents a ubiquitous molecular mechanism to cope with stress. Compared to vertebrates, molluscs have a biphasic life cycle where pelagic larvae go through settlement and metamorphosis. HSPs may play an important role in the survival strategy of molluscs during the biphasic life stages. Since aquatic environments are highly dynamic, molluscs may be subject to a variety of sources of stress and HSPs might play a more important role in the adaptation of these animals. Moreover, the mechanisms of stress tolerance in molluscs can offer fundamental insights into the adaptation of organisms for a wide range of environmental challenges. The cDNA of HSPs has been cloned from some molluscs, and HSPs can be induced by heat stress, hypoxia, heavy metal contamination, and aestivation, etc. The expression of HSPs was detected in the neuroendocrine system, mollusc development, and reproductive process. Furthermore, the induction of HSPs is related with the phosphorylation of stress activated p38 mitogen-activated protein kinase (p38 MAPK) and cJun-N-terminal kinases (JNKs) in molluscs. PMID- 23092136 TI - A metabolomic study reveals novel plasma lyso-Gb3 analogs as Fabry disease biomarkers. AB - Fabry disease is an X-linked, multisystemic lysosomal storage disorder due to alpha-galactosidase A deficiency. It is characterized by the accumulation of glycosphingolipids, mainly globotriaosylceramide (Gb(3)), in biological fluids, vascular endothelium, heart, and kidneys. Treatment by enzyme replacement therapy has been shown to be beneficial in both males and females affected with the disease. In addition to Gb(3), increased concentrations of globotriaosylsphingosine (lyso-Gb(3)) have recently been reported in urine and plasma of Fabry patients. The overall objective of this metabolomic study was to identify and characterize new potential plasma biomarkers in treated and untreated males and females affected with Fabry disease which might better reflect disease severity and progression. We employed a time-of-flight mass spectrometry metabolomic approach using plasma samples of Fabry patients compared to age-matched controls. We found three new lyso-Gb(3) analogs in Fabry patients presenting m/z ratios at 802, 804, and 820. As previously detected by our group, we also found a m/z ratio of 784 corresponding to the lyso-Gb(3) molecule minus two hydrogen atoms. Using exact mass measurements and tandem mass spectrometry, we confirmed that these analogs result from modifications of the lyso-Gb(3) sphingosine moiety. We evaluated the relative plasma concentration by measuring area counts for each lyso-Gb(3) analog. None of these analogs was detected in the majority of healthy controls. The relative concentration of each analog was higher in males compared to female Fabry patients. We demonstrated that mass spectrometry combined to a metabolomic approach is a powerful tool to detect and identify new potential biomarkers. PMID- 23092137 TI - Are retinoids a promise for Alzheimer's disease management? AB - Retinoids regulate several physiological and pathological processes through the interaction with nuclear receptors. Retinoid-associated signaling which plays an essential role in neurodevelopment appears to remain active in the adult central nervous system (CNS), thus assuming a high significance in the context of neurodegeneration, and indeed retinoid analogs are thought to be promising therapeutic agents for the treatment of neurodegenerative disorders. The ability of retinoids to exert antioxidant effects, inhibit amyloid-beta (Abeta) deposits and likely Abeta-induced mitochondrial dysfunction, tau hyperphosphorylation, Abeta-induced IL6 production and neuroinflammation, increase survival in hippocampal neurons, and reverse cognitive deficits in animal models of Alzheimer's disease (AD) is discussed. Although retinoids with their multi-target activity are revealing to be promising for management of AD which is a multifaceted biochemical phenomenon, timing as well as appropriate dosage and safety remain, however, a challenge. The end-stage lesions, namely senile plaques and neurofibrillary tangles, are, at present, considered an adaptive response to oxidative stress underlying AD, thus paradoxically late administration of retinoids could even suppress a protective mechanism by inhibiting Abeta deposits. PMID- 23092138 TI - Liposomal delivery of proteins and peptides. AB - INTRODUCTION: A number of delivery issues exist for biotech molecules including peptides, proteins and gene-based medicines that now make up over 60% of the drug pipeline. The problems comprise pharmaceutical ad biopharmaceutical issues. One of the common approaches to overcome these issues is the use of a carrier and liposomes as carriers have been investigated extensively over the last decade. AREAS COVERED: The review has been discussed in terms of formulation and preclinical development studies and in vivo studies encompassing different delivery routes including parenteral, oral, buccal, pulmonary, intranasal, ocular and transdermal involving liposomes as carriers. Important research findings have been tabulated under each side heading and an expert opinion has been summarised for each delivery route. EXPERT OPINION: The conclusion and expert opinion - conclusion sections discuss in detail troubleshooting aspects related to the use of liposomes as carriers for delivery of biopharmaceutical moieties and scrutinises the aspects behind the absence of a protein/peptide-containing liposome in market. PMID- 23092139 TI - Scaffolds for tympanic membrane regeneration in rats. AB - Tympanic membrane (TM) perforations lead to significant hearing loss and result in possible infection of the middle ear. Myringoplasty is commonly performed to repair chronic perforations. Although various grafts and materials have been used to promote TM regeneration, all have associated limitations. The aim of this study was to evaluate the efficacy and feasibility of two graft materials, silk fibroin scaffold (SFS) and porcine-derived acellular collagen type I/III scaffold (ACS), compared with two commonly used graft materials (paper patch and Gelfoam) for the promotion of TM regeneration. These scaffolds were implanted using on-lay myringoplasty in an acute TM perforation rat model. Surface morphology of the scaffolds was observed with scanning electron microscopy. The morphology of the TM was assessed at various time points postimplantation using otoscopy, light and electron microscopy, and functional outcomes by auditory brainstem responses. We found that SFS and ACS significantly accelerated the TM perforation closure, obtained optimal TM thickness, and resulted in better trilaminar morphology with well-organized collagen fibers and early restoration of hearing. However, paper patch and Gelfoam lost their scaffold function in the early stages and showed an inflammatory response, which may have contributed to delayed healing. This study indicates that compared with paper patch and Gelfoam, SFS and ACS are more effective in promoting an early TM regeneration and an improved hearing, suggesting that these scaffolds may be potential substitutes for clinical use. PMID- 23092141 TI - Cuspal deflection in premolar teeth restored using current composite resins with and without resin-modified glass ionomer liner. AB - AIM: To evaluate the effects of four different types of composite resins and a resin modified glass ionomer cement (RMGIC) liner on the cuspal deflection of large MOD cavities in vitro. MATERIALS & METHODS: One hundred twenty-eight extracted human upper premolar teeth were used. After the teeth were divided into eight groups (n=16), standardized large MOD cavities were prepared. The distance between cusp tips was measured before and after the cavity preparations with a digital micrometer. Then the teeth were restored with different resin composites (Filtek Supreme XT, Filtek P60, Filtek Z250, Filtek Silorane - 3M ESPE, St Paul, MN, USA) with and without a RMGIC liner (Vitrebond, 3M ESPE, St Paul, MN, USA). Cuspal deflection was measured 5 min, 24 h, and 48 h after the completion of restorations. The data were statistically analyzed with Friedman and Kruskal Wallis tests. RESULTS: A significant reduction in cuspal deflection was observed in Filtek Silorane restorations with and without RMGIC liner (p<0.05). In all restored teeth, the distance between cusps was reduced but they did not return to their original positions during the 48 h period. All teeth showed cuspal deflection, but placement of RMGIC liner reduced it. CONCLUSION: The use of silorane-based composites and the placement of RMGIC liner under the composite resin restorations resulted in significantly reduced cuspal deflection. PMID- 23092140 TI - Labeled vs actual concentration of bleaching agents. AB - The purpose of this study was to determine if the actual concentration of bleaching agents available in four different countries were the same as the label indicated and within the recommendations of the International Standard on Tooth Whitening. The method recommended for assaying peroxide by the United States Pharmacopeia was used to determine concentrations. All products in the United States and China were within the standard when products were tested immediately upon delivery at testing sites. One product in Saudi Arabia and three products in Brazil had greater than 30% concentration loss. Three of 24 products in the United States did not meet the International Standard when they were tested at month of expiration. PMID- 23092142 TI - The effect of a 10% carbamide peroxide bleaching agent on the microhardness of four types of direct resin-based restorative materials. AB - PURPOSE: This in vitro study was undertaken to evaluate the effect of a 10% carbamide peroxide bleaching agent on the microhardness of four types of direct resin-based restorative materials. MATERIALS AND METHODS: Thirty disk-shaped specimens (10.0 mm diameter * 2.0 mm depth) of each material, including a microhybrid resin composite (Z250), a nanofilled resin composite (Z350), a silorane-based low-shrink resin composite (P90), and a hybrid resin composite (Valux Plus), were fabricated and then polished with medium, fine, and superfine polishing discs. After being polished, specimens were cleaned with distilled water for 2 min in an ultrasonic bath to remove any surface debris and then stored in distilled water at 37 degrees C for 24 hours. Specimens from each material were divided into three groups (n=10). One group was selected as a control group (nontreated with bleaching agent). The other two groups were treated with bleaching agent for 14 days (group A) and for 14 days followed by immersion in artificial saliva for 14 days (group B). The top surfaces of the specimens in the different groups were also subjected to the Vickers hardness test with a load of 300 g and 15-second dwell time. Data were analyzed with a one way analysis of variance and Tukey's HSD test (alpha = 0.05). RESULTS: There was a general reduction of Vickers hardness numbers (VHN) values of treated groups compared with the control group for each material used, but this reduction was minimal, with no significant difference between groups in Z250, whereas the other three materials (Z350, P90, and Valux Plus) showed a significant reduction of VHN of treated groups compared with the control group. Conversely, the findings showed no significant difference between treated groups A and B in all materials used except P90. CONCLUSION: A 10% carbamide peroxide bleaching agent had an adverse effect on the microhardness of nanofilled, silorane-based low-shrink, and hybrid types of resin-based composite materials compared with the microhybrid type. PMID- 23092143 TI - Clinical effectiveness of a hydrophobic coating used in conjunction with a one step self-etch adhesive: an 18-month evaluation. AB - The purpose of this randomized clinical trial was to evaluate the clinical performance of a one-step self-etch adhesive in noncarious cervical lesions with inclusion of a hydrophobic bonding layer not included in the original bonding system as a test of potentially improved bonding. Patients with noncarious cervical lesions received two or four restorations after being randomly assigned to two adhesive technique protocols (n=32): EB, application of Adper Easy Bond (3M ESPE) following manufacturer's instructions; and EB+B, application of Adper Easy Bond, immediately followed by the application of a hydrophobic resin coat (Scotchbond Multi-Purpose Bonding Agent, 3M ESPE). All restorations were restored with a microhybrid composite (Filtek Z250, 3M ESPE). Clinical effectiveness was recorded in terms of retention, marginal discoloration, marginal integrity, postoperative sensitivity, recurrent caries, periodontal health, and pulpal vitality, according to the modified USPHS criteria, for 18 months. Data were analyzed using chi-square, Fisher exact, and McNemar tests at alpha=0.05. Two restorations of each group were debonded after six months, leading to an overall clinical success rate of 93.8% for both groups. At the 18-month evaluation period, no new restoration was debonded. However, one restoration of the EB group displayed recurrent caries at the dentin margin, decreasing the overall success rate to 90.6% in comparison to 93.8% of EB+B. The success rate between EB and EB+B was not statistically significant (p=0.5). The application of a hydrophobic resin coat over EB did not increase bonding effectiveness in noncarious cervical lesions after 18 months. PMID- 23092144 TI - Radiopacity of flowable composite by a digital technique. AB - The aim of this in vitro study was to evaluate the radiopacity of 19 current dental flowable composite materials by a digital technique. Digital radiographs were obtained with a CCD sensor using an aluminum step wedge, a 1-mm-thick tooth slice, and a 1-mm-thick flowable composite specimen using five different combinations of exposure and voltage. The radiopacity in pixels was determined using Digora 2.6. software. The equivalent thickness of aluminum for each material was then calculated based on the calibration curve. All of the tested flowable composite materials had higher radiopacities than that of dentin, but in almost every combination of exposure and voltage, there were some composite materials that exhibited radiopacities equal to or slightly greater than enamel p>alpha; alpha=0.01). Of the flowable composite materials tested, 37% showed lower radiopacities than enamel, and 21% of the tested materials had higher radiopacities than the 3-mm aluminum equivalent. The highest radiopacity at all exposure values was produced by the Majesty Flow and Charisma Opal Flow materials, which had radiopacities almost twice that of enamel. Flowable composite materials should have radiopacities greater than that of enamel (ISO 4049), an important consideration for the introduction of new materials to the market. The digital radiopacity analysis techniques used in this study provide an easy, reliable, rapid, and precise method to characterize radiopacity of dental flowable composite materials. PMID- 23092145 TI - Temperature increase at the light guide tip of 15 contemporary LED units and thermal variation at the pulpal floor of cavities: an infrared thermographic analysis. AB - In this study, a comprehensive investigation on the temperature increase at the light guide tip of several commercial light-emitting diode (LED) light-curing units (LCUs) and the associated thermal variation (DeltaT) at the pulpal floor of dental cavities was carried out. In total, 15 LEDs from all generations were investigated, testing a quartz-tungsten-halogen (QTH) unit as a reference. The irradiance level was measured with a power meter, and spectral distribution was analyzed using a spectrometer. Temperature increase at the tip was measured with a type-K thermocouple connected to a thermometer, while DeltaT at the pulpal floor was measured by an infrared photodetector in class V cavities, with a 1-mm thick dentin pulpal floor. The relationship among measured irradiance, DeltaT at the tip, and DeltaT at the pulpal floor was investigated using regression analyses. Large discrepancies between the expected and measured irradiances were detected for some LCUs. Most of the LCUs showed an emission spectrum narrower than the QTH unit, with emission peaks usually between 450 and 470 nm. The temperature increase at the tip followed a logarithmic growth for LCUs with irradiance >=1000 mW/cm(2), with DeltaT at the tip following the measured irradiance linearly (R(2)=0.67). Linear temperature increase at the pulpal floor over the 40-second exposure time was observed for several LCUs, with linear association between DeltaT at the pulpal floor and measured irradiance (R(2)=0.39) or DeltaT at the tip (R(2)=0.28). In conclusion, contemporary LED units show varied irradiance levels that affect the temperature increase at the light guide tip and, as a consequence, the thermal variation at the pulpal floor of dental cavities. PMID- 23092146 TI - Effect of postoperative peroxide bleaching on the stability of composite to enamel and dentin bonds. AB - This study investigated the effect of peroxide bleaching gel on the durability of the adhesive bond between composite material, enamel, and dentin created with the etch-and-rinse adhesive Gluma Comfort Bond (GLU) and with the self-etch adhesives Clearfil SE Bond (CLE), Adper Prompt (ADP), and iBond (IBO). The adhesives were applied to flattened enamel and dentin of extracted human molars and built up with a microhybrid composite (Charisma). After 25 eight-hour cycles of bleaching with a 20% carbamide peroxide bleaching gel (Opalescence PF 20), the shear bond strength was measured and compared with one-day and two-month control specimens stored in water. The data were analyzed using nonparametric Mann-Whitney and Kruskal-Wallis statistics (p<0.05). Detailed fractographic analysis was performed using scanning electron microscopy. The bleaching gel significantly decreased the bond strength on both enamel and dentin for the simplified single-step self-etch adhesives ADP and IBO and markedly affected a fracture pattern of ADP specimens at the periphery of their bonded area. The results of our study indicate that the durability of adhesive restorations can be detrimentally influenced by carbamide peroxide bleaching and that different adhesives show varying sensitivity levels to the bleaching gel. PMID- 23092147 TI - Dimensional accuracy of optical bite registration in single and multiple unit restorations. AB - The dimensional accuracy of optical bite registration in the CEREC system was compared to that of the conventional physical method in vitro using a bite registration material. Maxillary and mandibular full-arch dentate epoxy models mounted on an articulator were used to measure the interarch distance and the angles created by the occlusal planes. The preparations for a single restoration on the maxillary first molar or for multiple restorations on the maxillary posterior quadrant were made on the model. Optical impression and bite registration data were collected to construct virtual models using computer-aided design software. A silicone material was used for the physical method, and the dimensional accuracy was measured by means of the coordinate measuring machine. The discrepancy relative to the baseline before preparation was analyzed in each registration record. For the single restoration, the optical method created a mean discrepancy of 243.2 MUm relative to baseline at the prepared tooth, which was insignificantly but slightly lower than the mean discrepancy of 311.1 MUm obtained with the physical method. The mean rotational deviation in the horizontal plane was significantly lower for the optical method. For the multiple preparations, the optical method showed significantly larger discrepancy on the right molar and on the left premolar and molar sites. In the frontal view, the optical method created significantly larger rotational deviation than the physical method. The result indicates that the optical bite registration was effective in terms of dimensional accuracy for single posterior restorations. PMID- 23092148 TI - Comparison of acid versus laser etching on the clinical performance of a fissure sealant: 24-month results. AB - OBJECTIVE: To compare the clinical performance of a pit and fissure sealant placed with the use of different enamel preparation methods, i.e. acid or Er,Cr:YSGG laser etching, over 24 months. METHODS: Sixteen subjects (15 female, 1 male) with no restorations or sealant present on their fissures and no detectable caries participated. Using a table of random numbers, a total of 112 sealants (56 with acid-etching, 56 with laser etching) were placed on the permanent premolar and molar teeth. All restorative procedures except for application of the laser were performed by the same dentist. After completion of the fissure preparation either with acid or laser, the adhesive was applied; then a pit and fissure sealant, Clinpro Sealant, was placed and polymerized. Clinical evaluations were done at baseline and at 6-, 12-, 18-, and 24-month follow-up visits by two calibrated examiners, who were unaware of which etching method had been used. The retention of sealants and caries were evaluated with the aid of a dental explorer and an intra-oral mirror. Each sealant was evaluated using the following criteria: 1=completely retained; 2= partial loss; 3= total loss. The Pearson chi square test was used to evaluate differences in the retention rates among the sealants used with different etching methods. RESULTS: All patients attended the 24-month follow-up visit and all sealants were evaluated (total recall rate 100%). At the end of 24 months, 83.9% of the sealants from laser group and 85.7% of those from acid-etch group were recorded as "completely retained". There were no statistically significant differences in retention rates among the preparation methods after all evaluation periods (p>0.05). No statistically significant differences were found between the retention rates of premolar and molars at each evaluation period. No secondary caries was detected in association with any sealants. CONCLUSION: The clinical performance of fissure sealants placed after acid or Er,Cr:YSGG laser etching was similar. PMID- 23092149 TI - The vented crown: a pictorial case report. AB - The venting of crowns has been shown to be one of the important factors in achieving the optimal marginal fit that can lead to improved longevity. This case report describes the technique and demonstrates the preparation, laboratory work, seating, and finishing of the vented cast gold crown. This technique can also be used on porcelain fused to metal crowns. PMID- 23092150 TI - A new ATRX mutation in a patient with acquired alpha-thalassemia myelodysplastic syndrome. AB - Acquired alpha-thalassemia (alpha-thal) myelodysplastic syndrome (ATMDS) is a rare acquired syndrome characterized by a somatic point mutation in the ATRX gene in patients with chronic myeloid disorders. We describe the case of a 78-year-old man with myelodysplastic syndrome (MDS) and striking microcytic, hypochromic anemia. Brilliant cresyl blue supravital stain of the peripheral blood and hemoglobin (Hb) electrophoresis showed the presence of Hb H. Sequence analysis of unfractionated peripheral blood DNA identified a G>T transition at codon 524 in exon 7 of the ATRX gene. To the best of our knowledge, it is the first description of this point mutation of the ATRX gene in an ATMDS. PMID- 23092151 TI - Porous graphitized carbon for adsorptive removal of benzene and the electrothermal regeneration. AB - Graphitized carbons with mesoporous and macroporous structures were synthesized by a facile template-catalysis procedure using resorcinol and formaldehyde as carbon precursors and particulate hydrated metal oxides as both template and catalyst precursors. The materials were used as novel adsorbents for low concentration benzene vapor. Furthermore, on the basis of the good electrical conductivities associated with the graphitized structures, an electrothermal desorption technique, which involved passing electric currents through the adsorbents to generate Joule heat, was employed to regenerate the saturated adsorbents and produce enriched benzene vapors. In comparison to microporous activated carbon, the porous graphitized carbons could afford a much quicker and more efficient regeneration by electrothermal desorption technique due to their enhanced conductivity and larger pore sizes. In addition, the concentration of the desorbed organics could be controlled by adjusting the applied voltages, which might be interesting for practical secondary treatment. It is promising that the joint utilization of porous graphitized carbon adsorbents and electrothermal desorption technique might develop effective and energy-saving processes for VOCs removal. PMID- 23092152 TI - Probing surface band bending of surface-engineered metal oxide nanowires. AB - We in situ probed the surface band bending (SBB) by ultraviolet photoelectron spectroscopy (UPS) in conjunction with field-effect transistor measurements on the incompletely depleted ZnO nanowires (NWs). The diameter range of the NWs is ca. 150-350 nm. Several surface treatments (i.e., heat treatments and Au nanoparticle (NP) decoration) were conducted to assess the impact of the oxygen adsorbates on the SBB. A 100 degrees C heat treatment leads to the decrease of the SBB to 0.74 +/- 0.15 eV with 29.9 +/- 3.0 nm width, which is attributed to the removal of most adsorbed oxygen molecules from the ZnO NW surfaces. The SBB of the oxygen-adsorbed ZnO NWs is measured to be 1.53 +/- 0.15 eV with 43.2 +/- 2.0 nm width. The attachment of Au NPs to the NW surface causes unusually high SBB (2.34 +/- 0.15 eV with the wide width of 53.3 +/- 1.6 nm) by creating open circuit nano-Schottky junctions and catalytically enhancing the formation of the charge O(2) adsorbates. These surface-related phenomena should be generic to all metal oxide nanostructures. Our study is greatly beneficial for the NW-based device design of sensor and optoelectronic applications via surface engineering. PMID- 23092153 TI - Coordination chemistry and antisolvent strategy to rare-earth solid solution colloidal spheres. AB - We have devised in this work a general synthetic strategy for preparation of single- and multicomponent rare-earth coordination polymer colloidal spheres (RE CPCSs). This strategy is based on an integration of coordination chemistry and antisolvent effect for synchronized precipitation. Highly monodisperse RE-CPCSs with homogeneous mixing of RE elements, which are not readily attainable by any existing methods, have been successfully prepared for the first time. In addition, the type and molar ratio of these colloidal spheres can be adjusted easily in accordance to the variety and dosage of precursor salts. The molar ratio of RE elements in as-prepared colloidal spheres shows a linear relationship to that of starting reactants. Furthermore, the RE-based core/shell colloidal spheres can be facilely prepared by introducing other metal salts (beyond lanthanide elements) owing to their different coordination chemistry and precipitation behavior. By adjusting concentrations of the ionic activators, luminescent properties can be tuned accordingly. Moreover, the RE-CPCSs can be transformed to monodisperse lanthanide oxide spheres via simple heat treatment. We believe that the present synthetic strategy provides a viable route to prepare other lanthanide-containing colloidal spheres that have enormous potential for future applications as optoelectronic devices, catalysts, gas sensors, and solar cells. PMID- 23092154 TI - Water-soluble Pd nanoparticles capped with glutathione: synthesis, characterization, and magnetic properties. AB - The synthesis, characterization, and magnetic properties of water-soluble Pd nanoparticles capped with glutathione are described. The glutathione-capped Pd nanoparticles were synthesized under argon and air atmospheres at room temperature. Whereas the former exhibits a bulklike lattice parameter, the lattice parameter of the latter is found to be considerably greater, indicating anomalous lattice expansion. Comparative structural and compositional studies of these nanoparticles suggest the presence of oxygen in the core lattice when Pd nanoparticles are prepared under an air atmosphere. Both Pd nanoparticles prepared under argon and air show ferromagnetism at 5 K, but the latter exhibits significantly greater coercivity (88 Oe) and magnetization (0.09 emu/g at 50 kOe). The enhanced ferromagnetic properties are explained by the electronic effect of the incorporated oxygen that increases the 4d density of holes at the Pd site and localizes magnetic moments. PMID- 23092155 TI - Sexual life and fertility desire in long-term HIV serodiscordant couples in Addis Ababa, Ethiopia: a grounded theory study. AB - BACKGROUND: Even though remarkable progress has been achieved, HIV/AIDS continues to be a major global health priority. HIV discordant relationship is one of the emerging issues in HIV prevention endeavour. In Ethiopia, very little is known about HIV-serodiscordant couples particularly how they manage their sexual relationship and fertility desire. Therefore, we conduct this study with the aim of exploring the experiences of HIV discordant couples about their sexual life, and fertility desire in the context of long-term relationships in Addis Ababa, Ethiopia. METHODS: A grounded theory approach was employed using in-depth interviews among 36 informants in ART/PMTCT centers of three public hospitals, a health center and one PLHIV association in Addis Ababa. Theoretical sampling was used to recruit 28 clients who lived in a discordant relationship and eight health care providers as key informants. Data collection and analysis were undertaken simultaneously using a constant comparison. The analysis was facilitated using OpenCode software. RESULTS: A grounded theory pertaining to sexual life and desire to have a child among HIV discordant couples emerged as "maintaining the relationship" as a core category. Couples pass through a social process of struggle to maintain their relationship. The causal conditions for couples to enter into the process of struggle to maintain their relationship were collectively categorized as "Entering in-to a transition" (knowing HIV serostatus) and this includes mismatch of desire to have a child, controversy on safe sex versus desire to have a child, and undeniable change in sexual desire and practice through time were the features in entering into-transition. Then after the transition, couples engaged in certain actions/strategies that are categorized as "dealing with discordancy" such as entertaining partner's interest by scarifying once self interest to maintain their relationship. CONCLUSIONS: HIV discordant couples' relationship is filled with controversies of maintaining relationship versus fear of getting infected. The findings of this study have suggested the need to view discordant couple's actions as a process of maintaining their relationship in the context of eminent risks. Further study should be done among HIV discordant couples to assess the fitness of the current model in different setups and population. In addition, a study could begin to test the hypotheses proposed in this study. PMID- 23092156 TI - One-pot C-N/C-C cross-coupling of methyliminodiacetic acid boronyl arenes enabled by protective enolization. AB - Iterative cross-coupling is a highly efficient and versatile strategy for modular construction in organic synthesis, though this has historically been demonstrated solely in the context of C-C bond formation. A C-N cross-coupling of haloarene methyliminodiacetic acid (MIDA) boronates with a wide range of aromatic and aliphatic amines is reported. Successful cross-coupling of aliphatic amines was realized only through protective enolization of the MIDA group. This reaction paradigm was subsequently utilized to achieve a one-pot C-N/C-C cross-coupling sequence. PMID- 23092157 TI - Development of a 2,4-dinitrotoluene-responsive synthetic riboswitch in E. coli cells. AB - Riboswitches are RNA sequences that regulate expression of associated downstream genes in response to the presence or absence of specific small molecules. A novel riboswitch that activates protein translation in E. coli cells in response to 2,4 dinitrotoluene (DNT) has been engineered. A plasmid library was constructed by incorporation of 30 degenerate bases between a previously described trinitrotoluene aptamer and the ribosome binding site. Screening was performed by placing the riboswitch library upstream of the Tobacco Etch Virus (TEV) protease coding sequence in one plasmid; a second plasmid encoded a FRET-based construct linked with a peptide containing the TEV protease cleavage site. Addition of DNT to bacterial culture activated the riboswitch, initiating translation of TEV protease. In turn, the protease cleaved the linker in the FRET-based fusion protein, causing a change in fluorescence. This new riboswitch exhibited a 10 fold increase in fluorescence in the presence of 0.5 mM DNT compared to the system without target. PMID- 23092158 TI - Effect of TiO2 nanotubes with TiCl4 treatment on the photoelectrode of dye sensitized solar cells. AB - In this study, we used the electrochemical anodization to prepare TiO2 nanotube arrays and applied them on the photoelectrode of dye-sensitized solar cells. In the field emission scanning electron microscopy analysis, the lengths of TiO2 nanotube arrays prepared by electrochemical anodization can be obtained with approximately 10 to 30 MUm. After titanium tetrachloride (TiCl4) treatment, the walls of TiO2 nanotubes were coated with TiO2 nanoparticles. XRD patterns showed that the oxygen-annealed TiO2 nanotubes have a better anatase phase. The conversion efficiency with different lengths of TiO2 nanotube photoelectrodes is 3.21%, 4.35%, and 4.34% with 10, 20, and 30 MUm, respectively. After TiCl4 treatment, the efficiency of TiO2 nanotube photoelectrode for dye-sensitized solar cell can be improved up to 6.58%. In the analysis of electrochemical impedance spectroscopy, the value of Rk (charge transfer resistance related to recombination of electrons) decreases from 26.1 to 17.4 Omega when TiO2 nanotubes were treated with TiCl4. These results indicate that TiO2 nanotubes treated with TiCl4 can increase the surface area of TiO2 nanotubes, resulting in the increase of dye adsorption and have great help for the increase of the conversion efficiency of DSSCs. PMID- 23092159 TI - Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn. AB - BACKGROUND: We previously reported that immune activation in the spinal dorsal horn contributes to pain induced by chronic pancreatitis (CP). Targeting immune response in the CNS may provide effective treatments for CP-induced pain. Recent findings demonstrate that resolvin D1 (RvD1) can potently dampen inflammatory pain. We hypothesized that intrathecal injection of RvD1 may inhibit pain of CP. METHODS: Rat CP model was built through intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). All the rats were divided into three groups: TNBS, sham, and naive controls and were further divided for intrathecal RvD1 administration. Pain behavior of rats was tested with von Frey filaments. Anxiety-like behavior and free locomotor and exploration of rats were evaluated by open field test and elevated plus maze. Pancreatic histology was evaluated with hematoxylin and eosin staining. Phosphorylation of NMDA receptor and expression of inflammatory cytokines were examined with Western blot, real-time RT-PCR and ELISA. RESULTS: Behavioral study indicated that compared to the vehicle control, RvD1 (100 ng/kg) significantly decreased TNBS-induced mechanical allodynia at 2 h after administration (response frequencies: 49.2 +/- 3.7% vs 71.3 +/- 6.1%), and this effect was dose-dependent. Neither CP nor RvD1 treatment could affect anxiety-like behavior. CP or RvD1 treatment could not affect free locomotor and exploration of rats. Western blot analysis showed that compared with that of naive group, phosphorylated NR1 (pNR1) and pNR2B in TNBS rats were significantly increased in the spinal cord (pNR1: 3.87+/-0.31 folds of naive control, pNR2B: 4.17 +/- 0.24 folds of naive control). Compared to vehicle control, 10 ng/kg of RvD1 could significantly block expressions of pNR1 (2.21 +/- 0.26 folds of naive) and pNR2B (3.31 +/- 0.34 folds of naive). Real-time RT-PCR and ELISA data showed that RvD1 (10 ng/kg) but not vehicle could significantly block expressions of TNF-alpha, IL-1beta and IL-6. In addition, RvD1 did not influence pain behavior, NMDA receptor phosphorylation or cytokines production in sham-operated rats. CONCLUSIONS: These data highly suggest that RvD1 could be a novel and effective treatment for CP-induced chronic pain. PMID- 23092160 TI - Where are the parasites in food webs? AB - This review explores some of the reasons why food webs seem to contain relatively few parasite species when compared to the full diversity of free living species in the system. At present, there are few coherent food web theories to guide scientific studies on parasites, and this review posits that the methods, directions and questions in the field of food web ecology are not always congruent with parasitological inquiry. For example, topological analysis (the primary tool in food web studies) focuses on only one of six important steps in trematode life cycles, each of which requires a stable community dynamic to evolve. In addition, these transmission strategies may also utilize pathways within the food web that are not considered in traditional food web investigations. It is asserted that more effort must be focused on parasite centric models, and a central theme is that many different approaches will be required. One promising approach is the old energetic perspective, which considers energy as the critical resource for all organisms, and the currency of all food web interactions. From the parasitological point of view, energy can be used to characterize the roles of parasites at all levels in the food web, from individuals to populations to community. The literature on parasite energetics in food webs is very sparse, but the evidence suggests that parasite species richness is low in food webs because parasites are limited by the quantity of energy available to their unique lifestyles. PMID- 23092162 TI - Geochemical implications of gas leakage associated with geologic CO2 storage--a qualitative review. AB - Gas leakage from deep storage reservoirs is a major risk factor associated with geologic carbon sequestration (GCS). A systematic understanding of how such leakage would impact the geochemistry of potable aquifers and the vadose zone is crucial to the maintenance of environmental quality and the widespread acceptance of GCS. This paper reviews the current literature and discusses current knowledge gaps on how elevated CO(2) levels could influence geochemical processes (e.g., adsorption/desorption and dissolution/precipitation) in potable aquifers and the vadose zone. The review revealed that despite an increase in research and evidence for both beneficial and deleterious consequences of CO(2) migration into potable aquifers and the vadose zone, significant knowledge gaps still exist. Primary among these knowledge gaps is the role/influence of pertinent geochemical factors such as redox condition, CO(2) influx rate, gas stream composition, microbial activity, and mineralogy in CO(2)-induced reactions. Although these factors by no means represent an exhaustive list of knowledge gaps we believe that addressing them is pivotal in advancing current scientific knowledge on how leakage from GCS may impact the environment, improving predictions of CO(2) induced geochemical changes in the subsurface, and facilitating science-based decision- and policy-making on risk associated with geologic carbon sequestration. PMID- 23092161 TI - Anti-cancer effects of a new docosahexaenoic acid monoacylglyceride in lung adenocarcinoma. AB - Lung cancer is the leading cause of cancer-related deaths worldwide. Despite advances in research, diagnosis and treatment, lung cancer remains a highly lethal disease, often diagnosed at advanced stages and with a very poor prognosis. Therefore, new strategies for the prevention and treatment of lung cancer are urgently needed. The aim of the present study was to determine the anti-tumorigenic effects of docosahexaenoic acid monoacylglyceride (MAG-DHA), a newly patented DHA derivative in lung adenocarcinoma. Our results demonstrate that MAG-DHA treatments decreased cell proliferation and induced apoptosis in A549 human lung carcinoma cells whereas MAG-DHA treatment did not induce apoptosis of normal bronchial epithelial BEAS-2B cells. MAG-DHA decreased NFkappaB activation leading to a reduction in COX-2 expression level in both A549 cells and lung adenocarcinoma tissues. Furthermore, MAG-DHA treatment increased PTEN expression and activation concomitant with a decrease in AKT phosphorylation levels and enhanced apoptosis. Oral administration of MAG-DHA significantly reduced tumor growth in a mouse A549 xenograft model. Lastly, MAG-DHA markedly decreased COX-2 and enhanced PTEN protein expression in tumor tissue sections. Altogether, these data provide new evidence regarding the mode of action of MAG DHA and strongly suggest that this compound could be of clinical interest in cancer treatment. PMID- 23092163 TI - SAMHD1: a new contributor to HIV-1 restriction in resting CD4+ T-cells. AB - Resting CD4+ T-cells are critical for establishing HIV-1 reservoirs. It has been known for over two decades that resting CD4+ T-cells are refractory to HIV-1 infection, but the underlying mechanisms are not fully understood. Compared with activated CD4+ T-cells that support HIV-1 infection, resting CD4+ T-cells have lower levels of dNTPs, which limit HIV-1 reverse transcription. The dNTPase SAMHD1 has been identified as an HIV-1 restriction factor in non-cycling myeloid cells. Two recent studies revealed that SAMHD1 restricts HIV-1 infection in resting CD4+ T-cells, suggesting a common mechanism of HIV-1 restriction in non cycling cells that may contribute to viral immunopathogenesis. PMID- 23092164 TI - Redox behaviour of verbascoside and rosmarinic acid. AB - The electrochemical oxidation mechanisms of rosmarinic acid (RA) and verbascoside (VB), both caffeic acid esters with two catechol moieties, were investigated. The redox mechanism is associated with the oxidation of the catechol groups, and was studied over a wide pH range by cyclic, differential pulse and square wave voltammetry, using a glassy carbon electrode. The voltammetric study revealed that both molecules, RA and VB, are reversibly oxidized in two successive pH dependent steps each with the transfer of two electrons and two protons. Moreover, it was found that the first oxidation step is associated with the caffeic acid moiety, whereas the second oxidation step corresponds to the oxidation in VB of the hydroxytyrosol group and in RA of the 3,4-dihydroxyphenyl lactic acid residue. PMID- 23092165 TI - Cocos nucifera Linn. (Palmae) husk fiber ethanolic extract: antioxidant capacity and electrochemical investigation. AB - The present study aims to determine the antioxidant capacity of the ethanolic extracts of husk fiber of four coconut (Cocos nucifera L.) varieties (yellow dwarf, green dwarf, giant and hybrid) and to evaluate the electrochemical behavior of these extracts on a glassy carbon electrode and on a modified glassy carbon electrode. The highest values of total phenolic content were obtained for the hybrid (531 +/- 24 mg GAE g(-1) dry extract) and yellow dwarf (501 +/- 29 mg GAE g(-1) dry extract) varieties and the lowest was for the green dwarf variety with 58 +/- 9 mg GAE g(-1) dry extract. The ability of the extracts to scavenge DPPH radicals was in the order of giant > yellow dwarf > hybrid > green dwarf and the IC50 values varied from 8.6 to 55.9 MUg mL(-1). All varieties showed reducing potential by the use of FRAP and CUPRAC methods, with the lowest performance obtained for the green dwarf variety. Additionally, through the use of mimetic biomembranes, ethanolic extracts of coconut husk were shown to protect lipids against oxidative damage independent of the variety. The main antioxidants identified in the extract of yellow dwarf variety by UPLC-MS were quercetin and catechin. Cyclic voltammetric studies of the ethanolic extracts on glassy carbon electrode confirmed the presence of easily oxidized compounds, and the high antioxidant capacity of the varieties. This capacity was expressed as mg quercetin equivalents g(-1) dry extract and ranged from 25.9 up to 53.5 mg QE g( 1). A poly-xanthurenic acid (poly-Xa)/multi-walled carbon nanotube (MWCNT) / glassy carbon modified electrode (poly-Xa/MWCNT/GCE) was used for this purpose. Our findings suggest that these extracts are potentially important antioxidant supplements for the everyday human diet, pharmaceutical and cosmetic industries, thereby aggregating value to the enormous amount of waste from the coconut industry, mostly used for burning purposes. PMID- 23092166 TI - Simultaneous assay of ascorbate and urate antioxidants in human blood serum using PEDOT-based electrochemical microsensor. AB - An electrochemical microsensor has been developed for the simultaneous assay of ascorbate (AA) and urate (UA) antioxidants in human blood serum. The electrode surface was modified by means of electropolymerized conductive poly(3,4 ethylenedioxythiophene) PEDOT organic films. Highly selective responses (detection potential difference more than 250 mV) were obtained for both biomarkers by optimizing the PEDOT thickness. Contrary to most previous studies the analytical performances were recorded by testing the microsensor directly in blood serum without any pretreatment of the samples. Using differential pulse voltammetry (DPV) the sensitivity and detection limit were 0.481 MUA MUM(-1) cm( 2) and 4.2 MUmol L(-1) for AA and 1.815 MUA MUM(-1) cm(-2) and 2.0 MUmol L(-1) for UA. The calibration curves were linear in the concentration range 5-200 MUmol L(-1) for AA and 3-700 MUmol L-1 for UA. The accuracy of the sensor was satisfactorily compared with the reference analytical methods provided that the synergic effect between both antioxidants was considered. The sensor response was unmodified in the presence of the major biochemical interfering species. PMID- 23092167 TI - Electrochemical study of DNA damaged by oxidation stress. AB - Many compounds can interact with DNA leading to changes of DNA structure as point mutation and bases excision, which could trigger some metabolic failures, which leads to the changes in DNA structure resulting in cancer. Oxidation of nucleic acid bases belongs to the one of the mostly occurred type of DNA damaging leading to the above mentioned phenomena. The investigation of processes of DNA oxidation damage is topical and electrochemical methods include a versatile and sensitive tool for these purposes. 8-hydroxydeoxyguanosine (8-OHdG) is the most widely accepted marker of DNA damage. Oxidative damage to DNA by free radicals and exposure to ionizing radiation generate several other products within the double helix besides mentioned oxidation products of nucleic acid bases. The basic electrochemical behaviour of nucleic acids bases on various types of carbon electrodes is reviewed. Further, we address our attention on description of oxidation mechanisms and on detection of the most important products of nucleic bases oxidation. The miniaturization of detector coupled with some microfluidic devices is suggested and discussed. The main aim of this review is to report the advantages and features of the electrochemical detection of guanine oxidation product as 8-OHdG and other similarly produced molecules as markers for DNA damage. PMID- 23092168 TI - Electrochemical approaches employed for sensing the antioxidant capacity exhibited by vegetal extracts: a review. AB - Vegetal extracts are among the most important source of polyphenols in the diet, highlighting the importance of their characterization and determination. For this reason, analytical methods have gained increasing interest, with many publications devoted to this subject. Among the wide possibilities of analytical methods, electroanalytical techniques can provide valuable information, since the antioxidant activity of polyphenols is related to their electrochemical properties. This review analyzes and highlights the role of electroanalytical approaches for sensing the antioxidant capacity exhibited by vegetal extracts, as well as focuses on their importance for human health. The analytical capacity of the electrochemistry is comprehensively stated with the selected results found in the literature, mainly from 2000 up to the present date. PMID- 23092169 TI - Biosensors for antioxidant evaluation in biological systems. AB - The prevention of oxidative reactions in a biological medium as well as the role of reactive oxygen species (ROS) in chronic degenerative diseases are questions that continue to be investigated. Electrochemical biosensors have shown attractive features to evaluate the oxidative stress condition at a level comparable to chromatographic and spectroscopic techniques. The biosensors developed so far are based on direct analysis of specific indicators such as biomarkers of oxidative stress on the monitoring of reactive oxygen species the free radicals in cells or tissues, aiming to obtain a correlation between the index obtained from these indicators with the oxidative stress levels in cells. In this review we will provide an overview of the development of electrochemical biosensors to evaluate the content of antioxidants and reactive oxygen species in physiological systems. Some discussion regarding the analysis of antioxidant capacity at the single cell level is also presented. PMID- 23092170 TI - Three-component green reaction of arylaldehydes, 6-amino-1,3- dimethyluracil and active methylene compounds catalyzed by Zr(HSO4)4 under solvent-free conditions. AB - A convenient one-pot, three-component reaction of aromatic aldehydes, 6-amino-1,3 dimethyluracil and active methylene compounds in the presence of Zr(HSO4)4 as a heterogeneous catalyst, under solvent-free conditions brings a very simple and highly efficient method for the preparation of pyrimido[4,5-b]quinolines, pyrimido[5',4':5,6]pyrido[2,3- d]pyrimidines, indeno[2',1':5,6]pyrido[2,3 d]pyrimidines and a new class of pyrimidinedione derivatives in excellent yields. This approach is general and provides several advantages such as simple reaction set-up, very mild reaction conditions, high yields, recyclability of the catalyst and environmentally friendly benign. PMID- 23092171 TI - Effect of chlorhexidine application on the long-term shear bond strength to dentin of a resin-modified glass ionomer. AB - PURPOSE: The aim of this study was to investigate the effect of chlorhexidine digluconate (CHX) application on the shear bond strength (SBS) of a resin modified glass ionomer cement (RMGIC) to polyalkenoic acid-preconditioned dentin after 24 hours, six months, and 12 months of water storage at 37 degrees C. MATERIALS AND METHODS: Cylindrical molds, placed on flat, polyalkenoic acid (Cavity Conditioner(r) [GC]) preconditioned dentin surfaces of 90 human teeth embedded in resin, were filled with Fuji II LC(r) (GC), a RMGIC, with (n=45) or without (n=45) the prior application of a 0.05% CHX solution. Within each group, SBS was determined after 24 hours (n=15), six months (n=15), and 12 months (n=15) of storage in water at 37 degrees C. The results were analyzed with two-way analysis of variance followed by Tukey multiple means comparisons (p<0.05). The type of bond failure (adhesive/cohesive/mixed) was noted and the results were analyzed with chi-square test (p<0.05). RESULTS: After 24 hours, the SBS of RMGIC was not significantly different with (9.0 +/- 2.8 MPa) or without (8.3+/-0.6 MPa) the application of CHX. After six months, however, SBS increased significantly in the group without CHX (12.7+/-3.4 MPa) but remained unchanged in the CHX group (9.4+/-4.0 MPa). Similar results without CHX (12.6+/-3.8 MPa) and with CHX (9.5+/ 3.2 MPa) were obtained after 12 months. No significant differences in the type of debonding were found between the various groups tested. CONCLUSION: The application of 0.05% CHX after dentin preconditioning did not seem to have affected the 24-hour SBS of RMGIC. However, the six- and 12-month SBS was significantly lower for CHX-treated samples, possibly as a result of CHX interference with both the bonding mechanism and the maturation reaction of RMGIC. PMID- 23092173 TI - Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure to assess psoriasis symptom severity. AB - BACKGROUND: The objective of this study was to evaluate the measurement properties of the Psoriasis Symptom Inventory (PSI), an eight-item patient reported outcome measure for assessing severity of plaque psoriasis symptoms. METHODS: In this prospective, randomized study using data from adults with moderate-to-severe plaque psoriasis, patients completed the PSI, Dermatology Life Quality Index (DLQI), SF-36v2 Acute, and Patient Global Assessment (PtGA). PSI construct validity was assessed using Spearman rank correlations between PSI and DLQI and SF-36; test-retest reliability and sensitivity to change were evaluated using PtGA as an anchor. Daily 24-h and weekly 7-day PSI versions were evaluated. RESULTS: Eight US sites enrolled 143 patients; 139 (97.2%) completed the study. All symptoms (itch, redness, scaling, burning, cracking, stinging, flaking, and pain) were reported across all response options (not at all severe, mild, moderate, severe, very severe). Test-retest reliability was acceptable (intraclass correlation coefficients range = 0.70-0.80). A priori hypotheses of convergent and discriminant validity were confirmed by correlations of PSI with DLQI items and SF-36 domains. The PSI demonstrated good construct validity and was sensitive to within-subject change (p < 0.0001). CONCLUSIONS: The PSI is brief, valid, reproducible, and responsive to change and has the potential to be a useful PRO measure in psoriasis clinical trials. PMID- 23092172 TI - Human embryonic stem cell-derived mesenchymal stem cell seeding on calcium phosphate cement-chitosan-RGD scaffold for bone repair. AB - Calcium phosphate cement (CPC) has in situ-setting ability and excellent osteoconductivity. Human embryonic stem cells (hESCs) are exciting for regenerative medicine due to their strong proliferative ability and multilineage differentiation capability. However, there has been no report on hESC seeding with CPC. The objectives of this study were to obtain hESC-derived mesenchymal stem cells (hESCd-MSCs), and to investigate hESCd-MSC proliferation and osteogenic differentiation on novel CPC with chitosan immobilized with RGD (CPC chitosan-RGD). RGD was covalently bonded with chitosan, which was then incorporated into CPC. The CPC-chitosan-RGD scaffold had higher strength and toughness than CPC-chitosan control without RGD (p<0.05). hESCs were cultured to form embryoid bodies (EBs), and the MSCs were then migrated out of the EBs. Flow cytometry indicated that the hESCd-MSCs expressed typical surface antigen profile of MSCs. hESCd-MSCs had good viability when seeded on CPC scaffolds. The percentage of live cells and the cell density were significantly higher on CPC chitosan-RGD than CPC-chitosan control. Scanning electron microscope examination showed hESCd-MSCs with a healthy spreading morphology adherent to CPC. hESCd-MSCs expressed high levels of osteogenic markers, including alkaline phosphatase, osteocalcin, collagen I, and Runx2. The mineral synthesis by the hESCd-MSCs on the CPC-chitosan-RGD scaffold was twice that for CPC-chitosan control. In conclusion, hESCs were successfully seeded on CPC scaffolds for bone tissue engineering. The hESCd-MSCs had good viability and osteogenic differentiation on the novel CPC-chitosan-RGD scaffold. RGD incorporation improved the strength and toughness of CPC, and greatly enhanced the hESCd-MSC attachment, proliferation, and bone mineral synthesis. Therefore, the hESCd-MSC-seeded CPC-chitosan-RGD construct is promising to improve bone regeneration in orthopedic and craniofacial applications. PMID- 23092174 TI - Monitoring drug use among HIV/AIDS patients in Brazil: should we combine self report and urinalysis? AB - Illicit drug use in HIV-infected patients can be linked to impairment of physical and mental health, low health related quality of life, and suboptimal adherence to HIV treatment. This study aimed to evaluate the correlation of self report illicit drug use, urinalysis for cocaine and cannabis metabolites, and severity of dependence among HIV-infected patients on antiretroviral therapy (ART) in a treatment center in Brazil. Four hundred and thirty-eight outpatients of an HIV referral center were interviewed and assessed for drug use (lifetime, last year and last month). Urinalysis was performed to detect the presence of cocaine and cannabis metabolites in urine samples. Overall agreement between self report and urinalysis was almost 68% for cannabis and higher than 85% for cocaine. Positive urinalysis was significantly associated with more than once a week cannabis (p< .0001) and cocaine (p< .0001) use during the last-month. Severity of Dependence Scale (SDS) properly predicted positive cocaine urinalysis results (area under the curve [AUC] = .81, p = .0001). Frequency of cannabis and cocaine use, SDS score degree and positive urinalysis for both drugs were correlated. Our findings suggest that positive self-report is a reliable predictor of positive urine sample both for cannabis and cocaine, but since the agreement was not perfect, there is a role for urine drug screening in the care of patients with HIV-related conditions. PMID- 23092175 TI - Histone deacetylase inhibitor MC1293 induces latent HIV-1 reactivation by histone modification in vitro latency cell lines. AB - HIV-1 latency remains a major problem for the eradication of viruses in infected individuals. We evaluated the effect of MC1293 on the epigenetic change at HIV-1 LTR and the induction of the latent viruses in the latency Jurkat T cell line. We found MC1293 can activate HIV-1 gene expression, increase the acetylation level of H3 and H4 at the nuc-1 site of HIV-1 LTR. In addition, MC1293 can synergize with prostratin to activate the HIV-1 promoter, and has relatively lower toxicity compared to Trichostatin A (TSA). The results suggest that the acetylation of histone plays an important role in regulating HIV-1 LTR gene expression, and MC1293 is potential drug candidate for antilatency therapies. PMID- 23092176 TI - Workplace hand hygiene and wellness: a survey of knowledge, beliefs, and practices. AB - Community hand hygiene interventions have reduced the spread of infectious disease in elementary schools, daycare centers, and private homes. Despite this success, and the potential for reducing workplace absenteeism and presenteeism, few peer-reviewed hand hygiene intervention studies among workers have been published. This research used the Theory of Planned Behavior (TPB) to guide the development of a model to understand and predict motivations for performing hand hygiene, and to examine related illness, absenteeism, and presenteeism among employees from 39 bank branches in Ohio. Although the TPB has been used extensively to elucidate hand hygiene practices among employees in the health care and food industries, little is known about the ability of the TPB to predict hand hygiene practices among workers in public settings. These survey findings indicate a need for hand hygiene improvement, and support the use of attitudinal beliefs and social norms to guide multimodal approaches for workplace hand hygiene interventions. PMID- 23092177 TI - Occupational trajectories and immigrant worker health. AB - During their initial years in the receiving country, many immigrants experience occupational downgrading. Downgrading is a loss of occupational status between one's last job in the home country and first job in the receiving country, often resulting in overeducation or overqualification. Although the extent and determinants of such occupational trajectories have been characterized, the connection to immigrant worker health has not been widely examined. However, an emerging body of knowledge indicates that negative health outcomes are associated with overeducation and overqualification in general worker populations, suggesting similar experiences by immigrant workers. This article provides an overview of the magnitude and conceptualization of occupational downgrading, overeducation, and overqualification and discusses implications for immigrant worker health. Occupational health professionals should spearhead research efforts on occupational downgrading, raise public awareness about the issue, and serve as advocates for immigrant workers' rights. PMID- 23092179 TI - Surface-enhanced Raman trajectories on a nano-dumbbell: transition from field to charge transfer plasmons as the spheres fuse. AB - By taking advantage of the tensor nature of surface-enhanced Raman scattering (SERS), we track trajectories of the linker molecule and a CO molecule chemisorbed at the hot spot of a nano-dumbbell consisting of dibenzyldithio linked silver nanospheres. The linear Stark shift of CO serves as an absolute gauge of the local field, while the polyatomic spectra characterize the vector components of the local field. We identify surface-enhanced Raman optical activity due to a transient asperity in the nanojunction in an otherwise uneventful SERS trajectory. During fusion of the spheres, we observe sequential evolution of the enhanced spectra from dipole-coupled Raman to quadrupole- and magnetic dipole-coupled Raman, followed by a transition from line spectra to band spectra, and the full reversal of the sequence. From the spectrum of CO, the sequence can be understood to track the evolution of the junction plasmon resonance from dipolar to quadrupolar to charge transfer as a function of intersphere separation, which evolves at a speed of ~1 A/min. The crossover to the conduction limit is marked by the transition of line spectra to Stark broadened and shifted band spectra. As the junction closes on CO, the local field reaches 1 V/A, limited to a current of 1 electron per vibrational cycle passing through the molecule, with associated Raman enhancement factor via the charge transfer plasmon resonance of 10(12). The local field identifies that a sharp protrusion is responsible for room-temperature chemisorption of CO on silver. The asymmetric phototunneling junction, Ag-CO-Ag, driven by the frequency-tunable charge transfer plasmon of the dumbbell antenna, combines the design elements of an ideal rectifying photocollector. PMID- 23092180 TI - Nanodimensionally driven analyte response reversal in gold nanocluster chemiresistor sensing. AB - The modulation of electron transport through an ensemble of ligand-stabilized gold nanoclusters by the sorption of vapors is made exceptionally sensitive and selective by terminal carboxylic acid functionalization of the alkanethiol ligand. Of further importance, the directionality of the response (conductance increase or decrease) is strongly dependent on the nanoscale dimensions of the gold core and ligand shell thickness. Films of gold nanoclusters composed of a 2 nm metal core with a 0.5 nm -S(CH(2))(5)COOH shell are compared to those based on an 8 nm core and a 1.5 nm -S(CH(2))(15)COOH shell with the finding of very strong and selective responses to amine vapors but with a reversal of response in the direction of the conductance transduction. This unexpected result cannot be accommodated by known vapor response transduction mechanisms based on a swelling expansion and a dielectric alteration of the ligand shell to modulate conductance in the ensemble. A speculative new mechanism is proposed on the basis of intercluster nanodomains of low and high dielectric character whose domain dimensions are determined by the ligand molecular structure and dielectric character that can range up to that associated with an ionic capacitance if generated by a vapor interaction. PMID- 23092181 TI - Photoluminescence properties of graphene versus other carbon nanomaterials. AB - Photoluminescent nanomaterials continue to garner research attention because of their many applications. For many years, researchers have focused on quantum dots (QDs) of semiconductor nanocrystals for their excellent performance and predictable fluorescence color variations that depend on the sizes of the nanocrystals. Even with these advantages, QDs can present some major limitations, such as the use of heavy metals in the high-performance semiconductor QDs. Therefore, researchers continue to be interested in developing new QDs or related nanomaterials. Recently, various nanoscale configurations of carbon have emerged as potential new platforms in the development of brightly photoluminescent materials. As a perfect pi-conjugated single sheet, graphene lacks electronic bandgaps and is not photoluminescent. Therefore, researchers have created energy bandgaps within graphene as a strategy to impart fluorescence emissions. Researchers have explored many experimental techniques to introduce bandgaps, such as cutting graphene sheets into small pieces or manipulating the pi electronic network to form quantum-confined sp(2) "islands" in a graphene sheet, which apparently involve the formation or exploitation of structural defects. In fact, defects in graphene materials not only play a critical role in the creation of bandgaps for emissive electronic transitions, but also contribute directly to the bright photoluminescence emissions observed in these materials. Researchers have found similar defect-derived photoluminescence in carbon nanotubes and small carbon nanoparticles, dubbed carbon "quantum" dots or "carbon dots". However, they have not systematically examined the emissions properties of these different yet related carbon nanomaterials toward understanding their mechanistic origins. In this Account, we examine the spectroscopic features of the observed photoluminescence emissions in graphene materials. We associate the structural characteristics in the underlying graphene materials with those emission properties as a way of classifying them into two primary categories: emissions that originate from created or induced energy bandgaps in a single graphene sheet and emissions that are associated with defects in single- and/or multiple-layer graphene. We highlight the similarities and differences between the observed photoluminescence properties of graphene materials and those found in other carbon nanomaterials including carbon dots and surface defect-passivated carbon nanotubes, and we discuss their mechanistic implications. PMID- 23092182 TI - Fast and accurate procedure for the determination of Cr(VI) in solid samples by isotope dilution mass spectrometry. AB - We present here a new environmental measurement method for the rapid extraction and accurate quantification of Cr(VI) in solid samples. The quantitative extraction of Cr(VI) is achieved in 10 minutes by means of focused microwave assisted extraction using 50 mmol/L Ethylendiamintetraacetic acid (EDTA) at pH 10 as extractant. In addition, it enables the separation of Cr species by anion exchange chromatography using a mobile phase which is a 1:10 dilution of the extracting solution. Thus, neutralization or acidification steps which are prone to cause interconversion of Cr species are not needed. Another benefit of using EDTA is that it allows to measure Cr(III)-EDTA complex and Cr(VI) simultaneously in an alkaline extraction solution. The application of a 10 minutes focused microwave assisted extraction (5 min at 90 degrees C plus 5 min at 110 degrees C) has been shown to quantitatively extract all forms of hexavalent chromium from the standard reference materials (SRM) candidate NIST 2700 and NIST 2701. A double spike isotope dilution mass spectrometry (IDMS) procedure was employed to study chromium interconversion reactions. It was observed that the formation of a Cr(III)-EDTA complex avoided Cr(III) oxidation for these two reference materials. Thus, the use of a double spiking strategy for quantification is not required and a single spike IDMS procedure using isotopically enriched Cr(VI) provided accurate results. PMID- 23092183 TI - Targeted nanotheranostics for personalized cancer therapy. AB - INTRODUCTION: The development of nanomedicine, during the last 10 years have given rise to novel delivery systems among which multifunctional platforms called nanotheranostics that are designed to simultaneously diagnose and cure cancer. These systems can be built using the large panel of biocompatible and biodegradable materials. The recent advances of imaging modalities even enable targeted nanotheranostics to probe molecular structures on specific cells opening the doors to personalized cancer therapy. AREAS COVERED: This review presents the different requirements nanotheranostics should fulfill to achieve an optimized anticancer therapy. It focuses on two imaging modalities: MRI and ultrasonography used to visualize drug delivery, release, and efficacy. The advantages and limitations of these two methods are considered. The review will enable the readers to virtually tune a nanotheranostic system according to the nature of the targeting tissue and the availability of imaging modality. EXPERT OPINION: Despite great perspectives, described for nanotheranostic systems in personalized cancer therapy, the imaging techniques still face technological issues, such as high sensitivity and good spatial and temporal resolutions. Active targeting should consider better specificity and low immunogenicity of the ligand selected, to be more efficient. PMID- 23092184 TI - Combination of QuEChERS and DLLME for GC-MS determination of pesticide residues in orange samples. AB - A new method combining QuEChERS (quick, easy, cheap, effective, rugged and safe) and DLLME (dispersive liquid-liquid microextraction) followed by gas chromatography-mass spectrometry with selected ion monitoring (SIM) was developed for the simultaneous determination of 19 pesticides from nine chemical groups exhibiting or suspected to exhibit endocrine-disrupting properties in orange samples. Acetonitrile extract obtained from QuEChERS extraction was used for DLLME as dispersive solvent and carbon tetrachloride as extractive solvent to increase the enrichment factor of the extraction procedure. The effect of several extraction parameters, such as volume extract achieved by the QuEChERS method and subsequently used for DLLME, selection of extractive solvent and its volume, was tested. Under optimum conditions, good linearity, satisfactory recoveries and repeatability were obtained. Limits of quantification (LOQs) achieved (ranging from 0.02 to 47 ng/g) were below the maximum residue limits established by the European Union. The proposed method was applied to the monitoring of pesticide residue levels in oranges commercialised in Portugal. PMID- 23092185 TI - High-performance flexible thin-film transistors exfoliated from bulk wafer. AB - Mechanically flexible integrated circuits (ICs) have gained increasing attention in recent years with emerging markets in portable electronics. Although a number of thin-film-transistor (TFT) IC solutions have been reported, challenges still remain for the fabrication of inexpensive, high-performance flexible devices. We report a simple and straightforward solution: mechanically exfoliating a thin Si film containing ICs. Transistors and circuits can be prefabricated on bulk silicon wafer with the conventional complementary metal-oxide-semiconductor (CMOS) process flow without additional temperature or process limitations. The short channel MOSFETs exhibit similar electrical performance before and after exfoliation. This exfoliation process also provides a fast and economical approach to producing thinned silicon wafers, which is a key enabler for three dimensional (3D) silicon integration based on Through Silicon Vias (TSVs). PMID- 23092187 TI - Cellular heterogeneity and molecular evolution in cancer. AB - Intratumor heterogeneity represents a major obstacle to effective cancer treatment and personalized medicine. However, investigators are now elucidating intratumor heterogeneity at the single-cell level due to improvements in technologies. Better understanding of the composition of tumors, and monitoring changes in cell populations during disease progression and treatment, will improve cancer diagnosis and therapeutic design. Measurements of intratumor heterogeneity may also be used as biomarkers to predict the risk of progression and therapeutic resistance. We summarize important considerations related to intratumor heterogeneity during tumor evolution. We also discuss experimental approaches that are commonly used to infer intratumor heterogeneity and describe how these methodologies can be translated into clinical practice. PMID- 23092189 TI - Progressive multifocal leukoencephalopathy: why gray and white matter. AB - Since it was first described in 1958, progressive multifocal leukoencephalopathy (PML), a demyelinating disease of the brain caused by the polyomavirus JC (JCV), has evolved tremendously. It was once considered a noninflammatory disease that affected exclusively oligodendrocytes and astrocytes in the white matter of immunosuppressed individuals and was almost always fatal. Today, we understand that PML can present during the course of an immune reconstitution inflammatory syndrome and that it affects a broader range of individuals, including patients with minimal immunosuppression and those who are treated with novel immunomodulatory medications. Furthermore, JCV-infected glial cells are frequently located at the gray matter-white matter junction or within the gray matter, causing demyelinating lesions within cortical areas. Finally, JCV variants can also infect neurons, leading to the recognition of two distinct clinical entities: JCV granule cell neuronopathy and JCV encephalopathy. PMID- 23092188 TI - IgA nephropathy: molecular mechanisms of the disease. AB - Studies of molecular and cellular interactions involved in the pathogenesis of IgA nephropathy have revealed the autoimmune nature of this most common primary glomerulonephritis. In patients with this disease, altered glycan structures in the unique hinge region of the heavy chains of IgA1 molecules lead to the exposure of antigenic determinants, which are recognized by naturally occurring antiglycan antibodies of the IgG and/or IgA1 isotype. As a result, nephritogenic immune complexes form in the circulation and deposit in the glomerular mesangium. Deposited immune complexes induce proliferation of resident mesangial cells, increased production of extracellular matrix proteins and cytokines, and ultimately loss of glomerular function. Structural elucidation of the nature of these immune complexes and their biological activity should provide a rational basis for an effective, immunologically mediated inhibition of the formation of nephritogenic immune complexes that could be used as a disease-specific therapeutic approach. PMID- 23092190 TI - Respiratory viruses from hospitalized children with severe pneumonia in the Philippines. AB - BACKGROUND: Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined. METHODS: The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively. RESULT: Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated. CONCLUSION: Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries. PMID- 23092192 TI - Effect of the degree of dissociation of molecules in a monolayer at an air/water interface on the force between the monolayer and a like-charged particle in the subphase. AB - We used the monolayer particle interaction apparatus to measure the force between a monolayer of stearic acid or octadecanol at the air/water interface and a colloidal silica sphere. The silica sphere approached the monolayer from the aqueous subphase. The aim was to analyze how the magnitude of the charge of a deformable interface affects the interaction between that interface and a like charged hard particle. The charge density of the stearic acid monolayer was controlled by adjusting the pH (5.8-9) and the surface pressure. The octadecanol monolayer acted as a reference; the alcohol headgroup did not dissociate between pH 5.8-9.0. Stable monolayers of dissociated stearic acid molecules were formed at the air/water interface by dissolving stearic acid into the subphase to give a saturated concentration at each pH value studied. The approach force curve showed that the electrostatic repulsion increased with an increasing degree of dissociation and therefore the charge of the monolayer. The strength of the repulsion corresponded to that measured between two like-charged hard surfaces, but the apparent range of the repulsion was larger for a deformable interface. Retracting force curves displayed a significant adhesion, whose magnitude and range depended on the surface pressure and subphase pH. PMID- 23092186 TI - Host responses in tissue repair and fibrosis. AB - Myofibroblasts accumulate in the spaces between organ structures and produce extracellular matrix (ECM) proteins, including collagen I. They are the primary "effector" cells in tissue remodeling and fibrosis. Previously, leukocyte progenitors termed fibrocytes and myofibroblasts generated from epithelial cells through epithelial-to-mesenchymal transition (EMT) were considered the primary sources of ECM-producing myofibroblasts in injured tissues. However, genetic fate mapping experiments suggest that mesenchyme-derived cells, known as resident fibroblasts, and pericytes are the primary precursors of scar-forming myofibroblasts, whereas epithelial cells, endothelial cells, and myeloid leukocytes contribute to fibrogenesis predominantly by producing key fibrogenic cytokines and by promoting cell-to-cell communication. Numerous cytokines derived from T cells, macrophages, and other myeloid cell populations are important drivers of myofibroblast differentiation. Monocyte-derived cell populations are key regulators of the fibrotic process: They act as a brake on the processes driving fibrogenesis, and they dismantle and degrade established fibrosis. We discuss the origins, modes of activation, and fate of myofibroblasts in various important fibrotic diseases and describe how manipulation of macrophage activation could help ameliorate fibrosis. PMID- 23092191 TI - Ano-genital human papillomavirus type 97 infection is detected in Canadian men but not women at risk or infected with the human immunodeficiency virus. AB - BACKGROUND: Human papillomavirus type 97 (HPV97) DNA was detected in nearly 5% of anal samples collected from HIV-seropositive men living in Montreal, Canada. The rate of detection of HPV97 in the genital tract of Canadian women is unknown. Whether HPV97 is a local epidemic in HIV-seropositive men living in Montreal is also unknown. The prevalence of human papillomavirus type 97 (HPV97) was assessed in cervicovaginal cells from women living in Canada and in anal samples from HIV seropositive men living in Toronto. FINDINGS: Cervicovaginal lavages collected from 904 women (678 HIV-seropositive, 226 HIV-seronegative) women living in Canada and anal cells collected from 123 HIV-seropositive men living in Toronto were tested for the presence of HPV97 with PCR. HPV97-positive samples were further tested by PCR-sequencing for molecular variant analysis to assess if all HPV97-positive men were infected with the same strain. All cervicovaginal samples were negative for HPV97. HPV97 was detected in anal samples from 6 HIV seropositive men (4.9%, 95% confidence interval 2.0-10.5%), of whom five had high grade and one had low-grade anal intraepithelial neoplasia, in addition to 2 to 8 HPV genital genotypes per sample. Four HPV97 variants were defined by four variation sites in the viral control region. CONCLUSION: These findings indicate that HPV97 infects in the anal canal of HIV-seropositive men but is not detected in the genital tract of women. PMID- 23092193 TI - Cloning, sequence analysis, expression of Cyathus bulleri laccase in Pichia pastoris and characterization of recombinant laccase. AB - BACKGROUND: Laccases are blue multi-copper oxidases and catalyze the oxidation of phenolic and non-phenolic compounds. There is considerable interest in using these enzymes for dye degradation as well as for synthesis of aromatic compounds. Laccases are produced at relatively low levels and, sometimes, as isozymes in the native fungi. The investigation of properties of individual enzymes therefore becomes difficult. The goal of this study was to over-produce a previously reported laccase from Cyathus bulleri using the well-established expression system of Pichia pastoris and examine and compare the properties of the recombinant enzyme with that of the native laccase. RESULTS: In this study, complete cDNA encoding laccase (Lac) from white rot fungus Cyathus bulleri was amplified by RACE-PCR, cloned and expressed in the culture supernatant of Pichia pastoris under the control of the alcohol oxidase (AOX)1 promoter. The coding region consisted of 1,542 bp and encodes a protein of 513 amino acids with a signal peptide of 16 amino acids. The deduced amino acid sequence of the matured protein displayed high homology with laccases from Trametes versicolor and Coprinus cinereus. The sequence analysis indicated the presence of Glu 460 and Ser 113 and LEL tripeptide at the position known to influence redox potential of laccases placing this enzyme as a high redox enzyme. Addition of copper sulfate to the production medium enhanced the level of laccase by about 12-fold to a final activity of 7200 U L-1. The recombinant laccase (rLac) was purified by ~4 fold to a specific activity of ~85 U mg(-1) protein. A detailed study of thermostability, chloride and solvent tolerance of the rLac indicated improvement in the first two properties when compared to the native laccase (nLac). Altered glycosylation pattern, identified by peptide mass finger printing, was proposed to contribute to altered properties of the rLac. CONCLUSION: Laccase of C. bulleri was successfully produced extra-cellularly to a high level of 7200 U L( 1) in P. pastoris under the control of the AOX1 promoter and purified by a simple three-step procedure to homogeneity. The kinetic parameters against ABTS, Guaiacol and Pyrogallol were similar with the nLac and the rLac. Tryptic finger print analysis of the nLac and the rLac indicated altered glycosylation patterns. Increased thermo-stability and salt tolerance of the rLac was attributed to this changed pattern of glycosylation. PMID- 23092194 TI - From triclosan toward the clinic: discovery of nonbiocidal, potent FabI inhibitors for the treatment of resistant bacteria. AB - In this paper, we present some elements of our optimization program to decouple triclosan's specific FabI effect from its nonspecific cytotoxic component. The implementation of this strategy delivered highly specific, potent, and nonbiocidal new FabI inhibitors. We also disclose some preclinical data of one of their representatives, 83, a novel antibacterial compound active against resistant staphylococci and some clinically relevant Gram negative bacteria that is currently undergoing clinical trials. PMID- 23092195 TI - Controllable fabrication of PS/Ag core-shell-shaped nanostructures. AB - In this paper, based on the previous steps, a facile in situ reduction method was developed to controllably prepare polystyrene/Ag (PS/Ag) core-shell-shaped nanostructures. The crucial procedure includes surface treatment of polystyrene core particles by cationic polyelectrolyte polyethyleneimine, in situ formation of Ag nanoparticles, and immobilization of the Ag nanoparticles onto the surface of the polystyrene colloids via functional group NH from the polyethyleneimine. The experimental parameters, such as the reaction temperature, the reaction time, and the silver precursors were optimized for improvement of dispersion and Ag coat coverage of the core-shell-shaped nanostructures. Ultimately, the optimum parameters were obtained through a series of experiments, and well-dispersed, uniformly coated PS/Ag core-shell-shaped nanostructures were successfully fabricated. The formation mechanism of the PS/Ag core-shell-shaped nanostructures was also explained. PMID- 23092196 TI - Unusual pediatric co-morbility: autoimmune thyroiditis and cortico-resistant nephrotic syndrome in a 6-month-old Italian patient. AB - We report on a case of autoimmune thyroiditis in a 6-month-old patient with cortico-resistant nephrotic syndrome. Normal serum levels of thyroid hormons and thyroid-stimulating hormone were detected with high titers of circulant antithyroid antibodies and a dysomogeneous ultrasound appearance of the gland, typical of autoimmune thyroiditis. The research of maternal thyroid antibodies was negative. This is the first case of autoimmune thyroiditis found in such a young patient with pre-existing nephrotic syndrome ever described in literature. This association is random because nephrotic syndrome does not have an autoimmune pathogenesis and the genes involved in autoimmune thyroiditis are not related to those of nephrotic syndrome. PMID- 23092197 TI - Expeditious microwave-assisted synthesis of functionalized oxaphosphaphenanthrenes and chromenes via multicomponent reactions of trivalent phosphorus nucleophiles. AB - Stable derivatives of oxaphosphaphenanthrenes were prepared by using the reactions of dialkyl acetylenedicarboxylate with 3-bromo-2-naphthol in the presence of trimethyl or triphenyl phosphite under microwave conditions at 70 degrees C in good yields. Under similar conditions, chromene derivatives were produced by using triethyl phosphite and dialkyl acetylenedicarboxylate in the presence of OH-acids in excellent yields. PMID- 23092198 TI - A cross-sectional epidemiological study of chronic HCV liver disease stage in HIV coinfected patients using noninvasive techniques: CoTrans- GEENI Study. AB - BACKGROUND & AIMS: Considering the disadvantages of liver biopsy, alternative noninvasive methods have been sought to assess the stage of liver fibrosis. The aim of this study is to determine the prevalence of different stages of chronic liver disease using noninvasive methods (transition elastography (Fibroscan(r)) and Forns and AST-to-platelet ratio index-APRI-indexes) in HCV/HIV-coinfected patients. MATERIALS & METHODS: An observational, cross-sectional, multicenter study conducted between September 2007 and May 2008. The study enrolled coinfected patients who had a transient elastography performed in the year of the study and/or biochemical markers (Forns/APRI indexes) to assess the stage of liver fibrosis. RESULTS: A total of 109 patients were finally enrolled. Mean elastography velocity was 15.3 kPa, and mean APRI and Forns indexes were 1.4 and 6.1, respectively. According to transient elastography: 41% had mild, 24% moderate, and 35% severe fibrosis; 35% with significant fibrosis. According to the APRI index: 29% had mild, 45% moderate, and 26% severe fibrosis; 28% with significant fibrosis. According to the Forns index: 16% had mild, 54% moderate, and 30% severe fibrosis; 30% with significant fibrosis. The Kappa concordance index between the three methods was 0.42 for fibrosis stage and 0.52 for significant fibrosis detection (p < 0.001 in both cases). CONCLUSIONS: There is concordance between the APRI and Forns indexes and elastography in the detection of different fibrosis stages and it is significant. Transient elastography agrees with these indexes in the detection of significant and severe fibrosis. PMID- 23092199 TI - Terpenoids: natural products for cancer therapy. AB - INTRODUCTION: Terpenoids constitute the largest class of natural products and are a rich reservoir of candidate compounds for drug discovery. Recent efforts into the research and development of anti-cancer drugs derived from natural products have led to the identification of a variety of terpenoids that inhibit cancer cell proliferation and metastasis via various mechanisms. Despite the increasing number of research reports, there lacks a comprehensive review of anti-cancer activity of terpenoids. AREAS COVERED: The present article provides an overview of the recent progress in the anti-cancer studies on terpenoids. Over a dozen naturally originated terpenoid compounds, in particular those derived from traditional Chinese medicine, were classified into five categories according to the structures, namely monoterpenoids, sesquiterpenoids, diterpenoids, triterpenoids and tetraterpenoids. The anti-cancer activities and relevant mechanistic insights of these compounds are discussed in this review. EXPERT OPINION: The anti-cancer activity of terpenoids appears promising and will potentially open more opportunities for cancer therapy. However, current studies are restricted to descriptive findings and lack mechanistic insights and systematic structure-activity relationship (SAR) studies. Future efforts into the systematic identification of the targets of terpenoids are believed to increase chances of gaining breakthrough insights in the field. PMID- 23092200 TI - Effect of ionic liquid impurities on the synthesis of silver nanoparticles. AB - Imidazolium-based ionic liquids have been widely utilized as versatile solvents for metal nanoparticle synthesis; however, reactions to synthesize silver nanoparticles that are performed identically in different commercially obtained lots of 1-butyl-3-methylimidazolium tetrafluoroborate (BMIM-BF(4)) give divergent results. This suggests that impurities in these nominally identical solvents play an important role in the resulting silver nanoparticle quality. To test the effect that impurities have on the quality of silver nanoparticles synthesized in BMIM-BF(4), silver nanoparticles were synthesized in carefully prepared and purified BMIM-BF(4) and compared against silver nanoparticles that were synthesized in the purified BMIM-BF(4) that had been spiked with trace amounts of water, chloride, and 1-methylimidazole. It was clearly demonstrated that trace amounts of these common ionic liquid impurities cause significant deviation in size and shape (creating polydisperse and irregularly shaped ensembles of both large and small particles), and also negatively impact the stabilization of the resulting silver nanoparticles. PMID- 23092201 TI - Detailed electrochemical studies of the tetraruthenium polyoxometalate water oxidation catalyst in acidic media: identification of an extended oxidation series using Fourier transformed alternating current voltammetry. AB - The electrochemistry of the water oxidation catalyst, Rb(8)K(2)[{Ru(4)O(4)(OH)(2)(H(2)O)(4)}(gamma-SiW(10)O(36))(2)] (Rb(8)K(2)-1(0)) has been studied in the presence and absence of potassium cations in both hydrochloric and sulfuric acid solutions by transient direct current (dc) cyclic voltammetry, a steady state dc method in the rotating disk configuration and the kinetically sensitive technique of Fourier transformed large-amplitude alternating current (ac) voltammetry. In acidic media, the presence of potassium ions affects the kinetics (apparent rate of electron transfer) and thermodynamics (reversible potentials) of the eight processes (A'/A to H/H') that are readily detected under dc voltammetric conditions. The six most positive processes (A'/A to F/F'), each involve a one electron ruthenium based charge transfer step (A'/A, B'/B are Ru(IV/V) oxidation and C/C' to F/F' are Ru(IV/III) reduction). The apparent rate of electron transfer of the ruthenium centers in sulfuric acid is higher than in hydrochloric acid. The addition of potassium cations increases the apparent rates and gives rise to a small shift of reversible potential. Simulations of the Fourier transformed ac voltammetry method show that the B'/B, E/E', and F/F' processes are quasi-reversible, while the others are close to reversible. A third Ru(IV/V) oxidation process is observed just prior to the positive potential limit via dc methods. Importantly, the ability of the higher harmonic components of the ac method to discriminate against the irreversible background solvent process allows this (process I) as well as an additional fourth reversible ruthenium based process (J) to be readily identified. The steady-state rotating disk electrode (RDE) method confirmed that all four Ru centers in Rb(8)K(2)-1(0) are in oxidation state IV. The dc and ac data indicate that reversible potentials of the four ruthenium centers are evenly spaced, which may be relevant to understanding of the water oxidation electrocatalysis. A profound effect of the potassium cation is observed for the one-electron transfer process (G/G') assigned to Ru(III/II) reduction and the multiple electron transfer reduction process (H/H') that arise from the tungstate polyoxometalate framework. A significant shift of E degrees ' to a more positive potential value for process H/H' was observed on removal of K(+) (~100 mV in H(2)SO(4) and ~50 mV in HCl). PMID- 23092202 TI - Root resorption diagnosed with cone beam computed tomography after 6 months and at the end of orthodontic treatment with fixed appliances. AB - OBJECTIVE: To investigate the prevalence of orthodontically induced root resorption after treatment and the correlation with resorption found after 6 months of treatment. MATERIALS AND METHODS: One hundred fifty-six patients (11-18 years) treated with fixed appliances and extraction of four premolars were examined with cone beam computed tomography before treatment, after 6 months of treatment (n = 97), and at the end of active treatment. The Malmgren Index was used to describe the degree of root resorption. RESULTS: Severe root resorption (>2 mm, score 3) was found in 25.6% of the patients at the end of treatment. Extreme root resorption was found in one patient. Root resorption was seen more frequently in the maxillary incisor region. There was no correlation between the severity of root resorption after 6 months and the amount observed at the end of treatment. Furthermore, no correlation was seen between treatment duration and the severity of root resorption. CONCLUSIONS: Clinically significant resorption was diagnosed in 25.6% of the patients, but no correlations, either with the resorption seen after 6 months or with the length of treatment, were found. Radiographic examination after 3 to 6 months of orthodontic treatment is too early and will not reduce the number of patients who will have teeth with severe root resorption. PMID- 23092203 TI - Artificial insemination in pigs: predicting male fertility. AB - Efficient artificial insemination (AI) is essential for future challenges in the pig industry. Knowledge on the exact relation between semen quality characteristics and fertility can have a major impact on both the genetic merit of future animals and the efficiency of AI. Variation in fertility is caused not only by farm- or sow-related parameters but also by boar- and semen-related parameters. In pig AI there is no gold standard concerning semen quality assessment. Assessing semen quality characteristics objectively and relating them to large field fertility datasets leads to an efficient production of insemination doses, which results in an efficient dissemination/descent of the breeding program required genes. Overall, this contributes to the development of semen quality assessments, which improves the prediction of porcine male fertility. Knowing which semen characteristics, and to what extent, contribute to male fertility and makes the field fertility more predictable. PMID- 23092204 TI - Subcutaneous Panniculitis-like T-cell lymphoma in two pediatric patients: an HIV positive adolescent and a 4-month-old infant. AB - Subcutaneous Panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of childhood non-Hodgkin lymphoma. Subcutaneous Panniculitis-like T-cell lymphoma has an aggressive variant associated with the hemophagocytic syndrome (HPS). Patients without HPS show resolution of the disease with prednisone or immunosuppressive therapy unlike other T-cell lymphomas. One HIV-positive adolescent and one infant with multiple subcutaneous masses are presented and the literature is reviewed. Lesional cells were consistent with SPTCL alpha-beta type. Our cases, without HPS, showed complete resolution of their lesions when treated with non-aggressive therapies. Patients with SPTCL alpha-beta should be treated conservatively. PMID- 23092206 TI - Monitoring the electrophoretic migration and adsorption of single insulating nanoparticles at ultramicroelectrodes. AB - The individual adsorption events of sub-MUm silica and polystyrene spheres (310 530 nm in diam.) were detected by monitoring the blocking of redox mediator diffusion to Pt ultramicroelectrode (UME) substrates by the adsorbing spheres. Under the diffusion limited oxidation of FcMeOH and at low supporting electrolyte concentrations, the negatively charged spheres arrive at the electrode by electrophoretic migration. Sphere adsorption monitoring experiments consisted of long-time (1000-5000 s) chronoamperograms recorded in solutions with fM concentrations of spheres and different concentrations of supporting electrolyte. Trends in the heights of the step features with time reflect changing surface coverage of spheres, and coupled step features in the chronoamperograms suggest dynamic rearrangement of spheres on the surface. Numerical simulations of diffusion blocking at electrodes by adsorbing particles as well as mass transport of particles under migration were also performed, and show good agreement with the experimental data collected. PMID- 23092208 TI - Charge density waves in exfoliated films of van der Waals materials: evolution of Raman spectrum in TiSe2. AB - A number of the charge-density-wave materials reveal a transition to the macroscopic quantum state around 200 K. We used graphene-like mechanical exfoliation of TiSe(2) crystals to prepare a set of films with different thicknesses. The transition temperature to the charge-density-wave state was determined via modification of Raman spectra of TiSe(2) films. It was established that the transition temperature can increase from its bulk value to ~240 K as the thickness of the van der Waals films reduces to the nanometer range. The obtained results are important for the proposed applications of such materials in the collective-state information processing, which require room-temperature operation. PMID- 23092207 TI - Impact of organised cervical screening on cervical cancer incidence and mortality in migrant women in Australia. AB - BACKGROUND: Organised cervical screening, introduced in 1991, appears to have reduced rates of cervical cancer incidence and mortality in women in Australia. This study aimed to assess whether cervical cancer rates in migrant women in the state of New South Wales (NSW) showed a similar pattern of change to that in Australian-born women after 1991. METHODS: Data from the NSW Central Cancer Registry were obtained for females 15+ years diagnosed with invasive cervical cancer from 1973 to 2008 (N=11,485). We used joinpoint regression to assess annual percent changes (APC) in cervical cancer incidence and mortality before and after the introduction of organised cervical screening in 1991. RESULTS: APC in incidence fell more rapidly after than before 1991 (p<0.001) amongst women from seven groups defined by country of birth (including Australia). There was only weak evidence that the magnitude of this incidence change varied by country of-birth (p=0.088). The change in APC in mortality after 1991, however, was heterogeneous by country of birth (p=0.004). For Australian and UK or Ireland born women the mortality APC fell more rapidly after 1991 than before (p=0.002 and p=0.001 respectively), as it did for New Zealand, Middle East, North Africa and Asian-born (p>=0.05), but in other European-born and women from the 'Rest of the World' it appeared to rise (p=0.40 and p=0.013 respectively). CONCLUSIONS: Like Australian-born women, most, but not all, groups of migrant women experienced an increased rate of fall in incidence of cervical cancer following introduction of organised cervical screening in 1991. An apparent rise in mortality in women in a 'Rest of the World' category might be explained by a recent rise in migration from countries with high cervical cancer incidence and mortality rates. PMID- 23092210 TI - Inter-dimensional effects in nano-structures. AB - : We report on two extensions of the traditional analysis of low-dimensional structures in terms of low-dimensional quantum mechanics. On one hand, we discuss the impact of thermodynamics in one or two dimensions on the behavior of fermions in low-dimensional systems. On the other hand, we use both quantum wells and interfaces with different effective electron or hole mass to study the question when charge carriers in interfaces or layers exhibit two-dimensional or three dimensional behavior. We find in particular that systems with different effective masses in the bulk and in the interface exhibit separation of two-dimensional and three-dimensional behavior on different length scales, whereas quantum wells exhibit linear combination of two-dimensional and three-dimensional behavior on short length scales while the behavior on large length scales cannot be associated with either two-dimensional or three-dimensional behavior. PMID- 23092209 TI - Phylogenetic analysis of complete genome sequences of hepatitis B virus from an Afro-Colombian community: presence of HBV F3/A1 recombinant strain. AB - BACKGROUND: Hepatitis B virus (HBV) infection is one of the most prevalent viral infections in humans and represents a serious public health problem. In Colombia, our group reported recently the presence of subgenotypes F3, A2 and genotype G in Bogota. The aim of this study was to characterize the HBV genotypes circulating in Quibdo, the largest Afro-descendant community in Colombia. Sixty HBsAg positive samples were studied. A fragment of 1306 bp (S/POL) was amplified by nested PCR. Positive samples to S/POL fragment were submitted to PCR amplification of the HBV complete genome. FINDINGS: The distribution of HBV genotypes was: A1 (52.17%), E (39.13%), D3 (4.3%) and F3/A1 (4.3%). An HBV recombinant strain subgenotype F3/A1 was found for the first time. CONCLUSIONS: This study is the first analysis of complete HBV genome sequences from Afro Colombian population. It was found an important presence of HBV/A1 and HBV/E genotypes. A new recombinant strain of HBV genotype F3/A1 was reported in this population. This fact may be correlated with the introduction of these genotypes in the times of slavery. PMID- 23092211 TI - Why does the G117H mutation considerably improve the activity of human butyrylcholinesterase against sarin? Insights from quantum mechanical/molecular mechanical free energy calculations. AB - Human butyrylcholinesterase (BChE) is recognized as the most promising bioscavenger for organophosphorus (OP) warfare nerve agents. The G117H mutant of human BChE has been identified as a potential catalytic bioscavenger with a remarkably improved activity against OP nerve agents such as sarin, but it still does not satisfy the clinical use. For further design of the higher-activity mutants against OP nerve agents, it is essential to understand how the G117H mutation improves the activity. The reaction mechanisms and the free energy profiles for spontaneous reactivation of wild-type BChE and its G117H mutant phosphorylated by sarin have been explored, in this study, by performing first principles quantum mechanical/molecular mechanical free energy calculations, and the remarkable role of the G117H mutation on the activity has been elucidated. For both the wild-type and G117H mutant enzymes, H438 acts as a general base to initiate the spontaneous reactivation that consists of two reaction steps: the nucleophilic attack at the phosphorus by a water molecule and decomposition of the pentacoordinated phosphorus intermediate. The calculated overall free energy barriers, i.e., 30.2 and 23.9 kcal/mol for the wild type and G117H mutant, respectively, are in good agreement with available experimental kinetic data. On the basis of the calculated results, the mutated residue (H117 in the G117H mutant) cannot initiate the spontaneous reactivation as a general base. Instead, it skews the oxyanion hole and makes the phosphorus more open to the nucleophilic water molecule, resulting in a remarkable change in the rate-determining step and significantly improved catalytic activity of human BChE. PMID- 23092212 TI - No effect modification of serum bilirubin or coffee consumption on the association of gamma-glutamyltransferase with glycated hemoglobin in a cross sectional study of Japanese men and women. AB - BACKGROUND: Oxidative stress has been implicated in the development of type 2 diabetes mellitus. Bilirubin is a potent endogenous antioxidant, and coffee is a major source of exogenous antioxidants. Serum gamma-glutamyltransferase (GGT), a marker of oxidative stress, is a strong predictor of the risk of type 2 diabetes mellitus. This study evaluated the effect modification of bilirubin and coffee consumption on the association of serum GGT with glycated hemoglobin (HbA1c) and the combined effect of bilirubin and coffee on HbA1c concentrations. METHODS: The subjects were 4492 men and 6242 women aged 49-76 years who participated in the baseline survey of an on-going cohort study on lifestyle-related diseases in Fukuoka, Japan. Geometric means of HbA1c were examined according to quartile categories of GGT, with stratification by serum total bilirubin (>= 0.6 mg/dL versus less in men and >= 0.5 mg/dL versus less in women) and coffee consumption (< 1, 1-3 and >= 4 cups of per day). Statistical adjustment was made for age, smoking, alcohol use and body mass index by using analysis of covariance. RESULTS: HbA1 concentrations increased progressively with increasing levels of GGT in both men and women. The increasing trend of HbA1c concentrations associated with GGT did not differ by either bilirubin status or coffee consumption. Both men and women with high bilirubin had consistently lower concentrations of HbA1c across the GGT quartiles. Higher coffee consumption was associated with lower concentrations of HbA1c in women with low bilirubin (trend P = 0.04), but not with high bilirubin (trend P = 0.37). There was no such association between coffee and HbA1c in men with either low or high bilirubin levels. CONCLUSIONS: Bilirubin is possibly protective against deterioration of glucose metabolism. Further studies are needed regarding the combined effect of bilirubin and coffee on glucose metabolism. PMID- 23092213 TI - A differentiation account of recognition memory: evidence from fMRI. AB - Differentiation models of recognition memory predict a strength-based mirror effect in the distributions of subjective memory strength. Subjective memory strength should increase for targets and simultaneously decrease for foils following a strongly encoded list compared with a weakly encoded list. An alternative explanation for the strength-based mirror effect is that participants adopt a stricter criterion following a strong list than a weak list. Behavioral experiments support the differentiation account. The purpose of this study was to identify the neural bases for these differences. Encoding strength was manipulated (strong, weak) in a rapid event-related fMRI paradigm. To investigate the effect of retrieval context on foils, foils were presented in test blocks containing strong or weak targets. Imaging analyses identified regions in which activity increased faster for foils tested after a strong list than a weak list. The results are interpreted in support of a differentiation account of memory and are suggestive that the angular gyrus plays a role in evaluating evidence related to the memory decision, even for new items. PMID- 23092215 TI - Contrast-enhanced ultrasound for the evaluation of the cryolesion after laparoscopic renal cryoablation: an initial report. AB - PURPOSE: Stringent radiological follow-up is essential after renal tumor ablation. Drawbacks of postablation follow-up by contrast-enhanced computed tomography (CECT) are the associated ionizing radiation and nephrotoxic contrast agent. Contrast-enhanced ultrasound (CEUS) has shown potential to demonstrate microvasculature without using either ionizing radiation or toxic contrast agent. We assessed the concordance of enhancement patterns of CEUS and CECT/MRI in cryolesion assessment after laparoscopic renal cryoablation (LCA). METHODS: From 01/2006 to 01/2009, a CEUS was performed before and after LCA (3 and 12 months) in addition to regular CECT/MRI. Using an enhancement score (0=no enhancement, 1=rim enhancement, 2=diffuse enhancement, 3=localized enhancement, 4=no enhancement defect), the cryolesion was assessed by both modalities, and concordance of enhancement score was assessed. RESULTS: In total, 45 tumors were included (29 biopsy proven renal cell carcinoma (RCC), mean size 2.66 cm). One cryoablation failed, resulting in a nonenhancing cryolesion apart from the persisting renal tumor. There were no postablation recurrences during the study period. Pre-LCA: Both modalities were available in 26 cases. In 20 out of 26, there was concordance of enhancement score (77%, all cases score 3 or 4). Three months: Both modalities were available in 32 cases. Enhancement score corresponded in 23 out of 32 cases (72%). Seven cases showed enhancement on CECT/MRI ("1" in six cases, "4" in one case) with enhancement score "0"on CEUS. Two cases showed enhancement on CEUS without enhancement on CECT/MRI (specificity 92%, negative predictive value [NPV] 77%). Except one case, all enhancement resolved on subsequent imaging. Twelve months: Both modalities were available in 21 tumors. Enhancement score corresponded in 19 out of 21 cases (91%). Two cases showed enhancement on CEUS without enhancement on CECT/MRI (specificity 90%, NPV 100%). CONCLUSION: This pilot study shows that CEUS is a safe imaging technique with high concordance of enhancement score between CEUS and CECT/MRI. While cross sectional imaging seems sensible to demonstrate successful ablation at first follow-up, CEUS might be used to diminish the burden of contrast-enhanced cross sectional imaging in the long-term follow-up. PMID- 23092214 TI - Characterization and burden of Campania children health migration across Italian regions during years 2006-2010: chance and/or necessity? AB - BACKGROUND: To evaluate medical, economical and sociological variables underlying avoidable pediatric migration from Campania region. METHODS: Analysis of years 2006-2010 hospital discharge records, extracted from the archive of Regional Health Agency (ArSan), classified by Major Diagnostic Categories, Aggregate Clinical Codes, Discipline of dismissal, Local Health Authorities of residence, and age group 0-14 years (excluding those of healthy newborns). Sociological variables were evaluated by questionnaires. RESULTS: A total of 68,316 hospital discharge records were released by extra-regional structures. Major diagnostic categories and Discipline of dismissal indicated that the most implicated diseases (nervous system and mental disorders, hematology-oncology, and bone diseases) were not always of very high complexity. The total cost paid by the Campania Region was 124.700.000 Euros. The need for more specialized hospital pediatric units and/or with more pediatric subspecialties in the native region was pointed out by most of the self-administered questionnaires. CONCLUSIONS: Pediatric migration is an important phenomenon with evident implications. The identification of the most concerned sub-specialties here reported can give useful information aiming to assist in the improvement of the existing pediatric resources in Campania region in the wider context of the national global child health advancement. PMID- 23092216 TI - Clustered drug and sexual HIV risk among a sample of middle-aged injection drug users, Houston, Texas. AB - Recent studies have reported a clustered pattern of high-risk drug using and sexual behaviors among younger injection drug users (IDUs), however, no studies have looked at this clustering pattern in relatively older IDUs. This analysis examines the interplay and overlap of drug and sexual HIV risk among a sample of middle-aged, long-term IDUs in Houston, Texas. Our study includes 452 eligible IDUs, recruited into the 2009 National HIV Behavioral Surveillance project. Four separate multiple logistic regression models were built to examine the odds of reporting a given risk behavior. We constructed the most parsimonious multiple logistic regression model using a manual backward stepwise process. Participants were mostly male, older (mean age: 49.5+/-6.63), and nonHispanic Black. Prevalence of receptive needle sharing as well as having multiple sex partners and having unprotected sex with a partner in exchange for money, drugs, or other things at last sex were high. Unsafe injecting practices were associated with high-risk sexual behaviors. IDUs, who used a needle after someone else had injected with it had higher odds of having more than three sex partners (odds ratio (OR) = 2.10, 95% confidence interval (CI): 1.40-3.12) in last year and who shared drug preparation equipment had higher odds of having unprotected sex with an exchange partner (OR = 3.89, 95% CI: 1.66-9.09) at last sex. Additionally, homelessness was associated with unsafe injecting practices but not with high risk sexual behaviors. Our results show that a majority of the sample IDUs are practicing sexual as well as drug-using HIV risk behaviors. The observed clustering pattern of drug and sexual risk behavior among this middle-aged population is alarming and deserve attention of HIV policy-makers and planners. PMID- 23092217 TI - A crystal structure analysis and magnetic investigation on highly ordered mesoporous Cr2O3. AB - A series of highly ordered mesoporous Cr(2)O(3) were prepared through the nanocasting pathway from decomposition of chromium(VI) oxide using KIT-6 as a hard template. The effects of the calcination temperature on the crystal structure, textural parameters and magnetic properties of the material were investigated. It was found that with increasing calcination temperature, surface area and pore volume of the mesoporous Cr(2)O(3) decreased slightly. Unpredictably, increasing calcination temperature also influences the lattice parameters of the Cr(2)O(3) crystal, and this rearrangement in the lattice parameter leads to changes in the value of the Neel temperature. A spin-flop transition has been observed at a magnetic field smaller than that of bulk material. PMID- 23092218 TI - An evidence-based review of risk-reductive strategies for osteonecrosis of the jaws among cancer patients. AB - PURPOSE: Bone antiresorptive treatment is associated with osteonecrosis of the jaws. Interventions used to treat this complication are diverse, controversial, and largely empirical but certain risk factors could help in its avoidance. The aim of this evidence-based review is to elucidate any interventions that are effective in reducing the risk for development of ONJ in cancer patients receiving bone antiresorptive therapy and to quantify the effectiveness of such interventions. MATERIALS & METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2012. We selected randomized controlled trials (RCTs). Cohort studies were included only as long as there are no RCTs on the same modality. RESULTS: Twelve studies were included in the systematic review while nine studies contributed to the various comparisons. Prescribing denosumab (DSB) instead of zoledronic acid (ZA) may not be expected to reduce risk ONJ (RR:0.71 [99% CI: 0.41-1.24], I2=0%). Prescribing clodronate (RR:10.15 [99% CI: 2.43-42.35], I2=0%) or pamidronate (RR:4.41 [99% CI: 1.90-10.24], I2=16%) instead of ZA may reduce risk for ONJ. Dental extractions remain the most potent risk factor for ONJ (RR:14.04, [99% CI: 10.36-19.03], I2=0%) and their avoidance can be considered an effective risk-reductive intervention. ONJ risk can be reduced by dental prophylactic measures (RR:0.45, [99% CI: 0.23-0.85], I2=7%). CONCLUSIONS: DSB and ZA might cause ONJ more frequently compared with chlodornate or pamidronate. Prescription pamidronate and clodronate helps avoid the complication. Reducing the administered dose for denosumab and zoledronic acid might reduce risk for ONJ as well. More randomized clinical trials comparing reduced doses of these regimens against those currently approved are needed. PMID- 23092219 TI - Cross-task compatibility and age-related dual-task performance. AB - BACKGROUND/STUDY CONTEXT: This study examined the effects of stimulus-stimulus and response-response cross-task compatibility and aging on dual-task performance. Hypothesis 1 predicted that the response code compatibility effect in both experiments would benefit older adults comparably to younger adults. Hypothesis 2 predicted that stimulus-stimulus compatibility would be additive to the effects of cross-task compatibility. METHODS: Younger and older adults participated in two dual-task experiments. Experiment 1 utilized a cross-task compatibility design identical to that of Koch and Prinz ( 2002 , Journal of Experimental Psychology: Human Perception and Performance, 28, 192-201). Experiment 2 added a stimulus-stimulus compatibility condition. RESULTS: The results of both experiments supported Hypothesis 1. Older adults displayed comparable cross-task compatibility effects to younger adults. The data did not support Hypothesis 2. The response-response compatibility effect from Experiment 1 was replicated, but the effect of stimulus-stimulus compatibility was not significant. CONCLUSION: The results of both experiments showed that older adults were able to take advantage of cross-task compatibility as a task design to improve dual-task performance. The lack of stimulus-stimulus compatibility effects in Experiment 2 suggested that the benefit of task design may be limited in effect. PMID- 23092220 TI - Understanding within-group variability of everyday cognition in aging Black/African American adults: a mimic (multiple indicators, multiple causes) model approach. AB - BACKGROUND/STUDY CONTEXT: Everyday cognition represents the ability to solve problems within domains that are representative of issues faced by adults on a daily basis. The current study examined individual differences in everyday cognitive ability among aging Black/African American adults. METHODS: Demographic data on age, gender, education, physical functioning, chronic illnesses, self reported health, and depression were collected from 248 African American adults (mean age = 67.8 years, standard deviation = 8.47 years). A multiple indicators, multiple causes (MIMIC) modeling approach was used to examine the associations of individual characteristics with latent everyday cognitive ability and composite score indicators. RESULTS: Age, depressive symptoms, and number of chronic illnesses were negatively related to latent everyday cognition. The individual characteristics of age, depressive symptoms, self-rated health, and education were directly associated with composite indicators of latent everyday cognition. This suggests that within this sample of older Black/African American adults that certain composite scores (i.e., telephone use, food preparation, and finances) may be particularly sensitive to these individual characteristics. CONCLUSION: These results identify specific sources of variability in everyday cognitive ability among aging Blacks/African Americans. These individual differences should be accounted for when studying everyday cognition among Blacks/African Americans and when comparing the everyday cognitive ability of Blacks/African Americans with other groups. PMID- 23092221 TI - Preserved spatial memory for reaching to remembered three-dimensional targets in aging. AB - BACKGROUND/STUDY CONTEXT: Compared with the large literature on the impact of aging on spatial memory span, far fewer studies have examined the influence of aging on spatial memory processes required to reach a remembered target. This study assessed the ability of seniors to accurately reach to three-dimensional (3D) memorized targets in four conditions in which the memory delay and the attentional demands varied. METHODS: The accuracy and variability of reaching movements (3D absolute, 3D variable, and spatial component errors) were analyzed to evaluate the performance of 12 young adults aged 20 to 30 and 12 older adults aged 62 to 69 in the different delay conditions (short passive delay, long passive delay, long cognitive delay, and long spatial delay). Variance analyses were applied on each error measure as well as on kinematic features of the movements (movement time, deceleration time, and peak velocity). RESULTS: Results revealed that older participants were as capable as their younger counterpart to maintain target location in memory regardless of task complexity. CONCLUSION: Although memory deficits have been found in older adults in several previous studies, the current results support the idea that healthy aging does not produce a breakdown in all memory tasks. Hence, a specific spatial memory channel seems to remain unaffected in normal aging. PMID- 23092222 TI - The role of supportive messages and distracting thoughts on everyday problem solving performance. AB - BACKGROUND/STUDY CONTEXT: An increasing number of studies have examined factors related to everyday problem-solving performance across adulthood. The current study examined the role of experimentally provided supportive messages intended to provide practical or emotional support on everyday problem-solving performance. Other factors such as participant age and distracting thoughts experienced during task completion were also investigated. METHODS: Everyday problem-solving performance, verbal ability performance, inductive reasoning performance, and self-reports of distracting thoughts were obtained from 54 middle-aged and 48 older adults. Participants were also exposed to practically supportive messages, emotionally supportive messages, or no supportive messages prior to completing the everyday problem-solving task. RESULTS: Exposure to emotionally supportive messages increased task performance and lowered levels of distracting thoughts. Distracting thoughts mediated the relation between exposure to emotionally supportive messages and everyday problem-solving performance. Distracting thoughts also mediated the relation between age and everyday problem solving performance. CONCLUSION: Study findings indicate that emotionally supportive messages may increase everyday problem-solving performance by decreasing the amount of distracting thoughts experienced by participants. This finding suggests that consistent administration of emotionally supportive messages could result in more optimal everyday problem-solving performance among middle-aged and older adults. PMID- 23092223 TI - Age-related differences in motor imagery: working memory as a mediator. AB - BACKGROUND/STUDY CONTEXT: Although motor imagery is a well-established phenomenon in healthy younger adults, it seems necessary to determine if older adults are still able to accurately perform imagery tasks before investigating the application of motor imagery in rehabilitation. Therefore, the purpose of this study was to determine if there is a progressive decline in motor imagery performance with age. Furthermore, we wanted to verify whether the effects of age on motor imagery were due to (or mediated by) deficits of working memory. METHODS: This study examined the key characteristics of the motor imagery ability in three groups of healthy older men and women (60-69, 70-79, and >=80 years; mean age M = 73.8, SD = 8.3) and 40 younger subjects aged 20 to 30 years (M = 28.87, SD = 2.5). Imagery ability was measured using the Movement Imagery Questionnaire (MIQ), the Controllability of Motor Imagery (CMI) test, and two different chronometry tests. To estimate the mediational effect of working memory on age differences in the imagery measures, we employed latent variable structural equation modeling (SEM). RESULTS: The main findings indicated that motor imagery ability (generation, visual and kinesthetic imagery ability, controllability, and temporal organization) were better in young adults compared with older adults 70 years and older, but not in older adults 60 to 69 years of age. The analysis of the mediational effect of working memory on age differences in the motor imagery measures showed that the inclusion of working memory increased the amount of explained variance in the MIQ (DeltaR (2) = .03), in the CMI test (DeltaR (2) = .15), as well as in the mental chronometry tests (DeltaR (2) = .16) CONCLUSION: Our findings suggest that there is potential for motor imagery to be compromised in the older age ranges, which may limit motor imagery as a rehabilitative strategy in older and in cognitively impaired individuals. PMID- 23092225 TI - Bimodal surface ligand engineering: the key to tunable nanocomposites. AB - Tuning the dispersion of inorganic nanoparticles within organic matrices is critical to optimizing polymer nanocomposite properties and is intrinsically difficult due to their strong enthalpic incompatibility. Conventional attempts to use polymer brushes to control nanoparticle dispersion are challenged by the need for high graft density to reduce particle core-core attractions and the need for low graft density to reduce the entropic penalty for matrix penetration into the brush. We validated a parametric phase diagram previously reported by Pryamtisyn et al. (Pryamtisyn, V.; Ganesan, V.; Panagiotopoulos, A. Z.; Liu, H.; Kumar, S. K. Modeling the Anisotropic Self-Assembly of Spherical Polymer-Grafted Nanoparticles. J. Chem. Phys.2009, 131, 221102) for predicting dispersion of monomodal-polymer-brush-modified nanoparticles in polymer matrices. The theoretical calculation successfully predicted the experimental observation that the monomodal-poly(dimethyl siloxane) (PDMS)-brush-grafted TiO(2) nanoparticles can only be well dispersed within a small molecular weight silicone matrix. We further extended the parametric phase diagram to analyze the dispersion behavior of bimodal-PDMS-brush-grafted particles, which is also in good agreement with experimental results. Utilizing a bimodal grafted polymer brush design, with densely grafted short brushes to shield particle surfaces and sparsely grafted long brushes that favor the entanglement with matrix chains, we dispersed TiO(2) nanoparticles in high molecular weight commercial silicone matrices and successfully prepared thick (about 5 mm) transparent high-refractive-index TiO(2)/silicone nanocomposites. PMID- 23092224 TI - 1936A->G (I646 V) polymorphism in the AKAP10 gene encoding A-kinase-anchoring protein 10 in very long-lived poles is similar to that in newborns. AB - BACKGROUND/STUDY CONTEXT: The common 1936A->G transition (rs203462) in the AKAP10 gene encoding the A-kinase-anchoring protein 10 has been recently associated with negative prognosis in the aging European American population (60 to 79 years old). The aim of this study was to see the effects of this transition on allele frequency in very long-lived Poles. METHODS: AKAP10 genotype and allele distributions were analyzed in Polish subjects: 148 nonagenarians (95 to 103 years old) and 200 healthy newborn controls, using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Distributions were separated according to gender and chi(2) tests used to analyze possible differences. RESULTS: No significant differences were found in genotype or allele distribution between the age groups, for either gender. Percentages of GG AKAP10 homozygotes were slightly greater in the very old subjects than in the newborns (12.2% vs. 9.0%, respectively), and the G allele percentages were very similar (males, 30.7% and 33.0%; females, 34.1% and 35.8%; respectively). CONCLUSION: The authors conclude that differences in study results between European Americans (60 to 79 years old) and Poles (>=95 years old) result from either (1) geographical location; or (2) the influence of this polymorphism on groups of people differing in genetic background or environmental history; or (3) the time window affected, including extreme age. Further studies with full age-frequency distributions are needed to clarify these results. PMID- 23092226 TI - The integral nuclear membrane protein nurim plays a role in the suppression of apoptosis. AB - As an essential component of eukaryotic cells, the nuclear envelope (NE) plays a crucial role in many physiological processes. At present, a few membrane proteins from NE have been functionally characterized. To determine whether the inner nuclear membrane (INM) protein Nurim is expressed in cancer cells with evidence of apoptosis, we identified three isoforms of this protein that are specific for human testicular seminoma and are generated by alternative splicing. We observed that Nurim is expressed in a broad range of cancer types and that its expression level is correlated with a higher tumor grade. Biochemical analysis showed that Nurim b, like a, is tightly bound to the nuclear envelope. Furthermore, knockdown using miR-Nurim resulted in an abnormal shape change of the nuclear envelope. Notably, Nurim knockdown obviously increased apoptosis induced by ultraviolet in HeLa cells. Together, these findings implicate that the INM protein Nurim plays an important role in the suppression of apoptosis. PMID- 23092227 TI - Technology preferences among caregivers of children with hydrocephalus. AB - OBJECT: The Internet and social media are powerful disseminators of medical information, providing new portals for patient care. The authors of this study evaluated current technology hardware, Internet, and social media use and their socioeconomic relationships among caregivers of children with hydrocephalus. METHODS: A written survey was completed in the neurosurgical clinics at the University of Alabama at Birmingham by 300 parents of children with shunted hydrocephalus between October 26, 2010, and July 26, 2011. RESULTS: Computer use (94.6%), Internet use (91.7%), smartphone use (56.9%), and Internet research on hydrocephalus (81.9%) were prevalent. However, for each of these four utilizations there was significantly lower access by caregivers of minority races (p = 0.04, 0.03, 0.002, and < 0.0001, respectively), lower income (p = 0.02, 0.01, < 0.0001, and < 0.0001, respectively), and lower level of education (p = 0.001, 0.002, < 0.0001, and 0.001, respectively). Personal use of social media was prevalent (95.1% of all Internet users) with use being more prevalent among less-educated than higher-educated caregivers (p = 0.017). Hydrocephalus-related social media use (59.5% of Internet users) was not associated with socioeconomic factors. For hydrocephalus education on the Internet, caregivers chose information websites such as Wikipedia or the Hydrocephalus Association as preferred platforms; these preferences were followed by use of social media websites. Facebook and YouTube were the preferred social media platforms for personal and hydrocephalus-related use. Parents indicate moderate skepticism about the trustworthiness of the Internet; only 21.7% always trust the online sources. Most parents (89.8%) say that they would visit neurosurgeon-recommended websites. Of Internet-using caregivers, 28.6% use the Internet or social media to find hydrocephalus support groups, and 34.8% have used the Internet to communicate with other caregivers who have children with similar conditions. CONCLUSIONS: Technology hardware, the Internet, and social media are widely used with some skepticism by parents of children with shunted hydrocephalus. Caregivers are interested in physician-recommended Internet resources. Socioeconomic factors including race, income, and level of education reveal a disparity in access to some of these resources, although all groups have relatively high use. Unlike typical technology use, social media use is breaking down the digital divide among ethnic and socioeconomic groups. PMID- 23092229 TI - Randomized controlled clinical trials in mild-moderate ulcerative colitis. AB - The Authors review and critically discuss the most recent published evidence on treatment of mild-moderate ulcerative colitis both in the induction and maintenance of remission. Evidence on each drug is introduced by the related statement of ECCO guidelines. A brief introduction on disease classification and the need of standardizing indexes of clinical and endoscopic activity is also provided. Concluding remarks stress the heterogeneity of available studies both in the selection of patients and the outcomes evaluated and suggest the development of an international consensus in setting standards which will allow studies' results to be compared and combined to produce high quality clinical recommendations. PMID- 23092228 TI - Facilitators and barriers to screening for child abuse in the emergency department. AB - BACKGROUND: To identify facilitators of, and barriers to, screening for child abuse in emergency departments (ED) through interviews with ED staff, members of the hospital Board, and related experts. METHODS: This qualitative study is based on semi-structured interviews with 27 professionals from seven Dutch hospitals (i.e. seven pediatricians, two surgeons, six ED nurses, six ED managers and six hospital Board members). The resulting list of facilitators/barriers was subsequently discussed with five experts in child abuse and one implementation expert. The results are ordered using the Child Abuse Framework of the Dutch Health Care Inspectorate that legally requires screening for child abuse. RESULTS: Lack of knowledge of child abuse, communication with parents in the case of suspected abuse, and lack of time for development of policy and cases are barriers for ED staff to screen for child abuse. For Board members, lack of means and time, and a high turnover of ED staff are impediments to improving their child abuse policy. Screening can be promoted by training ED staff to better recognize child abuse, improving communication skills, appointing an attendant specifically for child abuse, explicit support of the screening policy by management, and by national implementation of an approved protocol and validated screening instrument. CONCLUSIONS: ED staff are motivated to work according to the Dutch Health Care Inspectorate requirements but experiences many barriers, particularly communication with parents of children suspected of being abused. Introduction of a national child abuse protocol can improve screening on child abuse at EDs. PMID- 23092230 TI - Methodological problems in RCTs on IBD. AB - Randomized controlled trials (RCTs) are the gold standard method for developing evidence-based medicine in inflammatory bowel disease (IBD). Methodological problems in RCTs in IBD concern different aspects such as the definition of the study population due to the extreme variability of patients with IBD, the indices of disease activity, a clearly defined outcome, the environmental risk factors (i.e smoking behaviour) that may influence the randomization, the heterogeneous placebo rate of remission and the different statistical methods used to analyze the results. It is important that trials are designed efficiently, done well and complement clinical practice with a careful subject selection, standardization of disease activity indices, and precise outcome measurement in order to continue the improvement of the IBD research process. PMID- 23092231 TI - Randomized controlled trials in maintenance of remission in Crohn's disease. AB - Maintenance of medically induced remission is a clinical challenge in Crohn's disease (CD), since it is a chronic disease and that often occurs in young people. The introduction of immunosuppressors and biologics has significantly improved the management of these patients, however efficacy and safety of these treatments in the very long term still needs clarification. Furthermore, scientific research is driven more into new drugs to induce remission rather then maintenance. PMID- 23092232 TI - Randomized controlled trials in active luminal Crohn's disease. AB - Many trials focused on the treatment of active luminal Crohn's disease (CD) have been published in literature. A critical reevaluation of the main trials regarding the use of 5-ASA derivates has shown a not significant benefit of such molecules in treating CD and, as a consequence, the European Crohn's and Colitis Organization's (ECCO) therapeutic statements highlight that 5-ASA should be considered clinically no more effective than placebo for active disease. The main evidence regarding the efficacy of conventional steroids as inductive therapy in active CD is still based on the old but fundamental Cooperative studies which can be considered at low risk for biases in spite of the date of publication. Most probably these RCTs will remain unsurpassed. Current data do not support the use of antibiotics for active luminal CD as primary therapeutic strategy in view of very conflicting results. In accordance with these conclusions current guidelines dot not suggest this kind of treatment in active CD. Even if frequently used, data about the role of conventional immunosuppressors for the therapy of active luminal CD ara scanty. Azathioprine/6-MP should be no more considered as remission-inductive agents for active CD while methotrexate could be considered an effective therapeutic option in inducing remission in this setting particular setting. A number of clinical trials are available about the use of anti-TNF alpha agents (infliximab, adalimumab) in active luminal CD. Both drugs are surely effective in inducing remission even if safety and economic concerns should be better considered and investigated. PMID- 23092233 TI - Randomized controlled trials in perianal Crohn's disease. AB - Crohn's disease can be complicated by the development of fistulas, 54% of which involve the perianal region. The presence of perianal fistulas predicts a disabling course of Crohn's disease. The treatment of complex perianal disease is difficult and the chance of complete fistula healing is no more than 50%. The best management of this condition is a combining medical and surgical therapy. Studies which evaluated the efficacy of medical treatments in this setting are small, open label and considered the efficacy on perianal disease as a second outcome or as the result of a subgroup analysis. In the few available trials the efficacy outcomes were evaluated by the Fistula Drainage Assessment but recently it was observed that inflamed fistula tracks often persist, despite the apparent closure of external orifices. Up to now the most strongly evaluated medical treatments for perianal Crohn's disease are the anti-TNFalpha antibodies. In presence of complex fistulas they are considered the first choice of medical treatment, in combination with surgical therapy. Antibiotics and immunomodulators have not been demonstrated to result in sustained closure of fistulas in Crohn's disease. Their use is recommended as a second line medical treatment. The use of tacrolimus and thalidomide is limited by its side effects. A few evidences support the use of methotrexate and cyclosporine but they are insufficient. PMID- 23092234 TI - Randomized controlled trials in prevention of postsurgical recurrence in Crohn's disease. AB - Most patients with Crohn's disease will require surgery during the course of their disease. However, surgery is not curative and post-operative recurrence is quite inexorable. One year after resection up to 80% of patients have new lesions at the neo-terminal ileum and after 10 years approximately 50% of patients will experience recurrence of symptoms and 35% will need further surgery. Prevention of post-operative recurrence has, therefore, a central role in the management of Crohn's Disease. Several drugs have been evaluated to decrease the risk of both endoscopic and clinical recurrence but the overall results are largely not impressive. Among the different drugs evaluated, mesalazine, antibiotics (metronidazole and ornidazole), thiopurines and anti-TNFalpha antibodies have been shown to be effective whereas budesonide, probiotics and interleukin 10 are not effective. This review focuses on the actual evidence on the prevention of postoperative recurrence: randomised controlled trials and meta-analyses are critically reviewed and discussed with particular attention to the methodological aspects. PMID- 23092235 TI - Randomized controlled trials in steroid dependent and in severe colitis. AB - Intravenous steroids are considered the mainstay of treatment in patients with severe ulcerative colitis. Several randomized controlled trials have been designed to evaluate drugs that, as an adjunct to intravenous steroids, could obtain a clinical response and avoid colectomy in patients who do not respond to corticosteroids. For steroid refractory patients, cyclosporine and infliximab seem to be an effective alternative to colectomy in the short term, but more data are needed to evaluate if they can prevent colectomy also in the long term. Although there is no evidence from the published trials that antibiotics as adjunctive therapy may have an additional benefit, therapeutic protocols for severe ulcerative colitis generally include antibiotics for patients with signs of toxicity, or with worsening of symptoms despite the medical treatment. No additional benefit over steroids has been shown from bowel rest. Moreover, as bowel rest deprives the colonic enterocytes of the short-chain fatty acids vital to their metabolism and repair, it may even be harmful. Conflicting results have been published on heparin as primary treatment of severe ulcerative colitis; at the present time there is no evidence supporting its use. Although "steroid-free" clinical remission is, at this time, the most important end point of clinical studies in inflammatory bowel disease, only few data are available in steroid dependent colitis patients. Azathioprine seems to be effective in inducing steroid-free remission. PMID- 23092236 TI - Randomized controlled trials in pouchitis. AB - Pouchitis is the most common complication of Proctocolectomy with ileal pouch anal anastomosis (IPAA) in patients with ulcerative colitis (UC). The diagnosis of pouchitis requires the presence of symptoms, together with characteristic endoscopic and histological abnormalities. The exact cause of pouchitis is not known. Whereas 'acute' pouchitis can be treated rapidly and successfully in the majority of patients, "refractory" and 'chronic pouchitis' remain therapeutic challenges to patients and physicians. Metronidazole and Ciprofloxacin budesonide enemas and oral probiotic therapy with VSL#3 all appear to be effective therapies for acute and/or chronic pouchitis. The medical therapy of pouchitis remains largely empiric, and additional multicenter, randomized, double-blind, placebo con- trolled, dose-ranging trials are needed. In future trials, treatment indications such as active acute or chronic pouchitis and maintenance of remission for acute or chronic pouchitis should be clearly defined. PMID- 23092237 TI - Pump-probe microscopy: spatially resolved carrier dynamics in ZnO rods and the influence of optical cavity resonator modes. AB - Femtosecond pump-probe microscopy is used to investigate the charge recombination dynamics at different points within a single needle-shaped ZnO rod. Recombination in the tips of the rod occurs through an excitonic or electron-hole plasma state, taking place on a picosecond time scale. Photoexcitation in the larger diameter sections of the interior exhibit dramatically slower recombination that occurs primarily through defects sites, i.e., trap mediated recombination. Transient absorption imaging shows that the spatial variation in the dynamics is also influenced by the cavity resonances supported within the hexagonal cross section of the rod. Finite element simulations suggest that these optical resonator modes produce qualitatively different intensity patterns in the two different locations. Near the end of the rod, the intensity pattern has significant standing-wave character, which leads to the creation of photoexcited carriers in the core of the structure. The larger diameter regions, on the other hand, exhibit intensity distributions in which the whispering gallery (WG) mode character dominates. At these locations, the photoexcited carriers are produced in subsurface depletion zone, where the internal fields separate the electrons and holes and lead to a greater degree of trap recombination on longer time scales. PMID- 23092238 TI - Microstructural evolution of tin nanoparticles during in situ sodium insertion and extraction. AB - The microstructural changes and phase transformations of tin nanoparticles during electrochemical sodiation were studied with a nanosized sodium ion battery using in situ transmission electron microscopy. It was found that the first sodiation process occurred in two steps; that is, the crystalline Sn nanoparticles were initially sodiated via a two-phase mechanism with a migrating phase boundary to form a Na-poor, amorphous Na(x)Sn alloy (x ~ 0.5), which was further sodiated to several Na-rich amorphous phases and finally to the crystallized Na(15)Sn(4) (x = 3.75) via a single-phase mechanism. The volumetric expansion was about 60% in the first step and 420% after the second step. However, despite the huge expansion, cracking or fracture was not observed, which is attributed to the second step of the single-phase sodiation that accommodates large portion of the sodiation induced stress over the entire particle. Excellent cyclability was also observed during the reversible sodiation/desodiation cycles, showing great potential of Sn nanoparticles as a robust electrode material for rechargeable batteries. PMID- 23092239 TI - Acid production in dental plaque after exposure to probiotic bacteria. AB - BACKGROUND: The increasing interest in probiotic lactobacilli in health maintenance has raised the question of potential risks. One possible side effect could be an increased acidogenicity in dental plaque. The aim of this study was to investigate the effect of probiotic lactobacilli on plaque lactic acid (LA) production in vitro and in vivo. METHODS: In the first part (A), suspensions of two lactobacilli strains (L. reuteri DSM 17938, L. plantarum 299v) were added to suspensions of supragingival dental plaque collected from healthy young adults (n=25). LA production after fermentation with either xylitol or fructose was analyzed. In the second part (B), subjects (n=18) were given lozenges with probiotic lactobacilli (L. reuteri DSM 17938 and ATCC PTA 5289) or placebo for two weeks in a double-blinded, randomized cross-over trial. The concentration of LA in supragingival plaque samples was determined at baseline and after 2 weeks. Salivary counts of mutans streptococci (MS) and lactobacilli were estimated with chair-side methods. RESULTS: Plaque suspensions with L. reuteri DSM 17938 produced significantly less LA compared with L. plantarum 299v or controls (p<0.05). Fructose gave higher LA concentrations than xylitol. In part B, there were no significant differences in LA production between baseline and follow up in any of the groups and no differences between test and placebo were displayed. The salivary MS counts were not significantly altered during the intervention but the lactobacilli counts increased significantly in the test group (p<0.05). CONCLUSION: Lactic acid production in suspensions of plaque and probiotic lactobacilli was strain-dependant and the present study provides no evidence of an increase in plaque acidity by the supply of selected probiotic lactobacilli when challenged by fructose or xylitol. The study protocol was approved by The Danish National Committee on Biomedical Research Ethics (protocol no H-2-2010 112). TRIAL REGISTRATION: NCT01700712. PMID- 23092241 TI - Syntheses and characterization of salts with the [Al(D)4F2]+ cation (D = pyridine or water). AB - Our approach for preparation of tetrakis-(pyridine)-difluoro-aluminum chloride was successfully deployed for the synthesis of corresponding Br and I compounds, respectively. By reacting AlX(3).3Py (X = Cl, Br, I) with Me(3)SiF in pyridine, two of the three halogens X were substituted by fluorine atoms forming the "aluminum mixed halide" complexes AlF(2)X.4Py with the ionic solid-state structures [Al(Py)(4)F(2)]X. Whereas the (27)Al solid state NMR spectra of AlX(3).3Py (X = Cl, Br) confirmed the existence of the expected singular sigma(6)lambda(3)-Al centers in their structures, the corresponding spectrum of AlI(3).3Py does not contain any signal that belongs to a 6-fold coordinated Al atom. The elemental analysis data strongly support the 1:2-stoichiometry of the complex (AlI(3).2Py), which in accord to the (27)Al MAS NMR spectra possessed only one sigma(4)lambda(3)-Al side as in the ionic structure [Al(Py)(2)I(2)]I. AlBr(3).3Py was also transformed by pyridine into the ionic complex [Al(Py)(4)Br(2)]Br. The later was isolated from pyridine solutions, and its structure was determined by X-ray single crystal analysis. On the basis of our results, solvated [Al(Py)(n)X(2)](+) cations are most probably the dominating species in pyridine solutions of AlX(3). Thus, only two Al-X covalent bonds underwent X/F- exchange and the halogen exchange reactions were terminated at " [Al(Py)(4)F(2)](+) stage". The hydrolysis of [Al(Py)(4)F(2)]Cl by very diluted hydrochloric acid in methanol proceeded smoothly under preservation of the Al-F bonds and displacement of pyridine by water. The formation of the stable helical trans-octahedron [Al(H(2)O)(4)F(2)](+) cation was confirmed by single-crystal XRD analysis. By reacting [Al(Py)(4)F(2)]Cl with the cyclo-n-propyl-phosphonic acid anhydride [CH(3)CH(2)CH(2)-PO(2)](3), an unexpected F-migration from Al- to P- atoms was observed. PMID- 23092242 TI - Intrinsic inter- and intraspecific competition in parasitoid wasps. AB - Immature development of parasitoid wasps is restricted to resources found in a single host that is often similar in size to the adult parasitoid. When two or more parasitoids of the same or different species attack the same host, there is competition for monopolization of host resources. The success of intrinsic competition differs between parasitoids attacking growing hosts and parasitoids attacking paralyzed hosts. Furthermore, the evolution of gregarious development in parasitoids reflects differences in various developmental and behavioral traits, as these influence antagonistic encounters among immature parasitoids. Fitness-related costs (or benefits) of competition for the winning parasitoid reveal that time lags between successive attacks influence the outcome of competition. Physiological mechanisms used to exclude competitors include physical and biochemical factors that originate with the ovipositing female wasp or her progeny. In a broader multitrophic framework, indirect factors, such as plant quality, may affect parasitoids through effects on immunity and nutrition. PMID- 23092240 TI - Trigeminal-rostral ventromedial medulla circuitry is involved in orofacial hyperalgesia contralateral to tissue injury. AB - BACKGROUND: Our previous studies have shown that complete Freund's adjuvant (CFA) induced masseter inflammation and microinjection of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) into the subnucleus interpolaris/subnucleus caudalis transition zone of the spinal trigeminal nucleus (Vi/Vc) can induce contralateral orofacial hyperalgesia in rat models. We have also shown that contralateral hyperalgesia is attenuated with a lesion of the rostral ventromedial medulla (RVM), a critical site of descending pain modulation. Here we investigated the involvement of the RVM-Vi/Vc circuitry in mediating contralateral orofacial hyperalgesia after an injection of CFA into the masseter muscle. RESULTS: Microinjection of the IL-1 receptor antagonist (5 nmol, n=6) into the ipsilateral Vi/Vc attenuated the CFA-induced contralateral hyperalgesia but not the ipsilateral hyperalgesia. Intra-RVM post-treatment injection of the NK1 receptor antagonists, RP67580 (0.5-11.4 nmol) and L-733,060 (0.5-11.4 nmol), attenuated CFA-induced bilateral hyperalgesia and IL-1beta induced bilateral hyperalgesia. Serotonin depletion in RVM neurons prior to intra-masseter CFA injection prevented the development of contralateral hyperalgesia 1-3 days after CFA injection. Inhibition of 5-HT(3) receptors in the contralateral Vi/Vc with direct microinjection of the select 5-HT(3) receptor antagonist, Y-25130 (2.6-12.9 nmol), attenuated CFA-induced contralateral hyperalgesia. Lesions to the ipsilateral Vc prevented the development of ipsilateral hyperalgesia but did not prevent the development of contralateral hyperalgesia. CONCLUSIONS: These results suggest that the development of CFA-induced contralateral orofacial hyperalgesia is mediated through descending facilitatory mechanisms of the RVM-Vi/Vc circuitry. PMID- 23092243 TI - A must for NIOSH: certify fit performance of the half mask particulate respirator. AB - The National Institute for Occupational Safety and Health has proposed to amend the certification rules for half mask air-purifying particulate respirators. The amendment would require the certified respirator to fit a minimum percentage of the intended users. The fail/pass rate for a respirator fitting a worker population has not been part of the certification process for particulate respirators since 1995. The amendment would also add a new requirement for the manufacturer to inform whom the respirator is intended to fit. PMID- 23092244 TI - Regulation of both the reactive oxygen species level and antioxidant enzyme activity in drought-stressed rice organs by benzimidazolate-based SOD1 mimics. AB - In the study, three benzimidazolate-based Cu2+ complexes were identified as SOD1 mimics to explore their effects on the levels of reactive oxygen species (ROS) and activities of antioxidant enzymes in drought-stressed rice organs. Superoxide dismutase (SOD) activity of the mimics was found to be controlled by unsaturated coordination, auxiliary ligands, and counter-anions. In comparison to the control, SOD1 mimic treatment for rice seeds significantly reduced ROS (O2*-, H2O2, and *OH) levels in the rice leaf and root while notably increased activities of antioxidant enzymes, including SOD1 and catalase. It can enhance the tolerance of plant organs to drought stress and, thus, has a practical potency of application in rice production on arid land. PMID- 23092245 TI - Right sided arcus aorta as a cause of dyspnea and chronic cough. AB - BACKGROUND: Right sided arcus aorta (RSAA) is a rare condition that is usually asymptomatic. Patients may present with exertional dyspnea and chronic cough. A recent article suggested that RSAA should be included in the differential diagnosis of asthma, especially in patients with intractable exertional dyspnea. We aimed to present the clinical, radiologic and spirometric features of thirteen patients with RSAA observed in four years at the Rize Education and Research Hospital and Samsun Chest Diseases and Thoracic Surgery Hospital. METHODS: The characteristics of patients with RSAA, including age, gender, symptoms, radiologic and spirometric findings, were retrospectively evaluated. RESULTS: A total of thirteen patients were diagnosed with RSAA. Their ages ranged from 17 to 86 years and the male to female ratio was 11:2. Seven of the patients (54%) were symptomatic. The most common symptoms were exertional dyspnea, dysphagia and chronic cough. Five patients had received treatment for asthma with bronchodilators. Spirometry showed intrathoracic tracheal obstruction in five patients. CONCLUSIONS: The RSAA anomaly occurs more frequently than might be estimated from the number of patients who are detected. Patients with intractable exertional dyspnea and chronic cough should be evaluated for the RSAA anomaly by thoracic CT. PMID- 23092246 TI - Conformational, dynamical. and tensional study of tethered bilayer lipid membranes in coarse-grained molecular simulations. AB - Tethered bilayer lipid membranes (tBLMs) have attracted great interest recently due to their crucial roles in elucidating fundamental membrane characteristics and the implications in biochemical sensors and pharmaceutical drug carriers. Nevertheless, they have not yet been investigated computationally on the molecular scale. Here, we study tBLMs consisting of DOPCs (1,2-dioleoyl-sn glycero-3-phosphocholine) as free lipids and pegylated DOPCs (on phosphate group) as tethers in water by a variation of the MARTINI model. By varying grafting densities and tether lengths, distinct conformational changes from planar to undulated bilayers are observed. Lateral diffusivities and lateral pressure profiles show that the dynamical and tensional states are specific to the system configurations. These results suggest that the conformations, fluidity, and elasticity of the tBLMs can be tuned and manipulated to conform to various requirements in theoretical investigations and technological applications. PMID- 23092248 TI - Novel photoinduced phase transitions in transition metal oxides and diluted magnetic semiconductors. AB - Some transition metal oxides have frustrated electronic states under multiphase competition due to strongly correlated d electrons with spin, charge, and orbital degrees of freedom and exhibit drastic responses to external stimuli such as optical excitation. Here, we present photoemission studies on Pr0.55(Ca1 - ySry)0.45MnO3 (y = 0.25), SrTiO3, and Ti1 - xCoxO2 (x = 0.05, 0.10) under laser illumination and discuss electronic structural changes induced by optical excitation in these strongly correlated oxides. We discuss the novel photoinduced phase transitions in these transition metal oxides and diluted magnetic semiconductors on the basis of polaronic pictures such as orbital, ferromagnetic, and ferroelectric polarons. PMID- 23092250 TI - Sulfur-carbon nanocomposite cathodes improved by an amphiphilic block copolymer for high-rate lithium-sulfur batteries. AB - A sulfur-carbon nanocomposite consisting of a commercial high-surface-area carbon (i.e., Black Pearls 2000, BET surface area >1000 m2 g-1) and sulfur has been synthesized by an in situ deposition method. The nanocomposite is in the form of agglomerated nanoparticles, with the micropores within the carbon filled with sulfur and the mesopores on the carbon surface almost completely covered by sulfur. The BET surface area of the nanocomposite containing a sulfur content of 63.5 wt % is significantly reduced to only 40 m2 g-1. Cathodes containing the nanocomposite and Pluronic F-127 block copolymer, which partially replaces the polyvinylidene fluoride binder, were prepared and evaluated in lithium cells by cyclic voltammetry and galvanostatic cycling. The nanocomposite cathodes with the copolymer show improved electrochemical stability and cyclability. The Pluronic copolymer helps retain a uniform nanocomposite structure within the electrodes, improving the electrochemical contact, which was manifested by scanning electron microscopy and electrochemical impedance spectroscopy. The sulfur-Black Pearls nanocomposite with the Pluronic copolymer as an additive in the electrodes is promising for high-rate rechargeable lithium-sulfur batteries. PMID- 23092249 TI - Rapid and versatile construction of diverse and functional nanostructures derived from a polyphosphoester-based biomimetic block copolymer system. AB - A rapid and efficient approach for the preparation and modification of a versatile class of functional polymer nanoparticles has been developed, for which the entire engineering process from small molecules to polymers to nanoparticles bypasses typical slow and inefficient procedures and rather employs a series of steps that capture fully the "click" chemistry concepts that have greatly facilitated the preparation of complex polymer materials over the past decade. The construction of various nanoparticles with functional complexity from a versatile platform is a challenging aim to provide materials for fundamental studies and also optimization toward a diverse range of applications. In this paper, we demonstrate the rapid and facile preparation of a family of nanoparticles with different surface charges and functionalities based on a biodegradable polyphosphoester block copolymer system. From a retrosynthetic point of view, the nonionic, anionic, cationic, and zwitterionic micelles with hydrodynamic diameters between 13 and 21 nm and great size uniformity were quickly formed by suspending, independently, four amphiphilic diblock polyphosphoesters into water, which were functionalized from the same parental hydrophobic-functional AB diblock polyphosphoester by click-type thiol-yne reactions. The well-defined (PDI < 1.2) hydrophobic-functional AB diblock polyphosphoester was synthesized by an ultrafast (<5 min) organocatalyzed ring opening polymerization in a two-step, one-pot manner with the quantitative conversions of two kinds of cyclic phospholane monomers. The whole programmable process starting from small molecules to nanoparticles could be completed within 6 h, as the most rapid approach for the anionic and nonionic nanoparticles, although the cationic and zwitterionic nanoparticles required ca. 2 days due to purification by dialysis. The micelles showed high biocompatibility, with even the cationic micelles exhibiting a 6-fold lower cytotoxicity toward RAW 264.7 mouse macrophage cells, as compared to the commercial transfection agent Lipofectamine. PMID- 23092251 TI - Temperature-dependence of the DnaA-DNA interaction and its effect on the autoregulation of dnaA expression. AB - The DnaA protein is a key factor for the regulation of the timing and synchrony of initiation of bacterial DNA replication. The transcription of the dnaA gene in Escherichia coli is regulated by two promoters, dnaAP1 and dnaAP2. The region between these two promoters contains several DnaA-binding sites that have been shown to play an important role in the negative auto-regulation of dnaA expression. The results obtained in the present study using an in vitro and in vivo quantitative analysis of the effect of mutations to the high-affinity DnaA sites reveal an additional effect of positive autoregulation. We investigated the role of transcription autoregulation in the change of dnaA expression as a function of temperature. While negative auto-regulation is lost at dnaAP1, the effects of both positive and negative autoregulation are maintained at the dnaAP2 promoter upon lowering the growth temperature. These observations can be explained by the results obtained in vitro showing a difference in the temperature-dependence of DnaA-ATP binding to its high- and low-affinity sites, resulting in a decrease in DnaA-ATP oligomerization at lower temperatures. The results of the present study underline the importance of the role for autoregulation of gene expression in the cellular adaptation to different growth temperatures. PMID- 23092247 TI - Molecular mechanisms deployed by virally encoded G protein-coupled receptors in human diseases. AB - G protein-coupled receptors (GPCRs) represent the largest family of cell surface molecules involved in signal transduction. Surprisingly, open reading frames for multiple GPCRs were hijacked in the process of coevolution between Herpesviridae family viruses and their human and mammalian hosts. Virally encoded GPCRs (vGPCRs) evolved as parts of viral genomes, and this evolution allowed the power of host GPCR signaling circuitries to be harnessed in order to ensure viral replicative success. Phylogenetically, vGPCRs are distantly related to human chemokine receptors, although they feature several unique characteristics. Here, we describe the molecular mechanisms underlying vGPCR-mediated viral pathogenesis. These mechanisms include constitutive activity, aberrant coupling to human G proteins and beta-arrestins, binding and activation by human chemokines, and dimerization with other GPCRs expressed in infected cells. The likely structural basis for these molecular events is described for the two closest viral homologs of human GPCRs. This information may aid in the development of novel targeted therapeutic strategies against viral diseases. PMID- 23092253 TI - Cells, micro- and nanosystems in reconstructive medicine: past, present, and future. PMID- 23092252 TI - The 'other' in patterns of drinking: a qualitative study of attitudes towards alcohol use among professional, managerial and clerical workers. AB - BACKGROUND: Recent evidence shows that workers in white collar roles consume more alcohol than other groups within the workforce, yet little is known about their views of drinking. METHODS: Focus groups were conducted in five workplaces to examine the views of white collar workers regarding the effect of alcohol use on personal and professional lives, drinking patterns and perceived norms. Analysis followed the method of constant comparison. RESULTS: Alcohol use was part of everyday routine. Acceptable consumption and 'excess' were framed around personal experience and ability to function rather than quantity of alcohol consumed. Public health messages or the risk of adverse health consequences had little impact on views of alcohol consumption or reported drinking. CONCLUSIONS: When developing public health alcohol interventions it is important to consider the views of differing groups within the population. Our sample considered public health messages to be of no relevance to them, rather they reinforced perceptions that their own alcohol use was controlled and acceptable. To develop effective public health alcohol interventions the views of this group should be examined in more detail. PMID- 23092254 TI - Myocardial tissue engineering and heart muscle repair. AB - Cardiovascular diseases, including myocardial infarction and heart failure, are the main causes of death worldwide. Classical pharmacological treatment may halt, but cannot reverse the underlying disease process. Cellular cardiomyoplasty has the potential to reconstruct myocardium in situ; yet, it is hampered by poor cell survival, engraftment, and differentiation. Tissue engineering has emerged as an alternative cell-based approach, aiming at partial or full replacement of damaged organs with in vitro generated tissue equivalents. However, limited availability of therapeutic cardiomyocytes poses a major challenge on cell-based and in particular tissue engineering-based therapies. Rapidly evolving stem cell technologies, enabling mass cultures may overcome this limitation. Translating available experimental concepts into clinical reality will be the ultimate challenge. This review discusses potentially therapeutic cells for cardiac repair, current stem cell-based myocardial tissue engineering strategies, and the requirements for a translation of myocardial tissue engineering into clinical practice. PMID- 23092255 TI - Stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease. AB - Chronic ischemic heart disease remains a major cause of morbidity and mortality worldwide. Although revascularisation strategies and pharmaceutical therapy are able to delay ventricular remodelling, until today no therapeutic strategy is available that might prevent or even reverse this process of remodelling and consequent ventricular failure. In the recent past, experimental and clinical studies have demonstrated the capacity of bone marrow stem cells in cardiac repair and regeneration of compromised heart muscle. Several clinical trials showed the safety and efficacy of autologous bone marrow stem cell transplantation in the patients with acute myocardial infarction or chronic ischemic heart disease. Today the therapeutic strategy of cell administration during cardiac surgery or coronary artery intervention is entering the clinical practice. In the following Review we will highlight biological as well as methodological backgrounds, indications and clinical results of cardiac stem cell therapy for the treatment of acute myocardial infarction and chronic ischemic heart disease. PMID- 23092256 TI - Small molecules in stem cell research. AB - Stem cells possess great promise as therapeutic tools for neurological disorders such as neurodegenerative diseases (Parkinson's disease and Huntington's disease), cerebrovascular diseases (stroke), neurotraumata (spinal cord injury) and demyelinating diseases (multiple sclerosis). This aspiration is based on the cells' ability to maintain a status of self-renewal and to differentiate into the various cell types of an organism. The use of the cells ranges from in vitro to in vivo studies in animal models, ending with clinical applications in humans. The self-renewal and commitment of stem/progenitor cells to differentiate and mature involves complex events leading to the generation of different phenotypes via distinctive developmental programs. Small molecules provide a tool with which to influence these regulatory changes in a controlled manner and to help understand the underlying mechanisms. Furthermore, substantial progress in generating induced pluripotent stem cells has been made using small molecules to replace reprogramming factors and enhance the reprogramming efficiency and kinetics, thus generating cells more compatible with the requirements for cell replacement therapies. In this review we will present the recent progress on the use of small molecules in embryonic and induced pluripotent stem cell research. In the final section we will give a short summary of the clinical approaches using these cells. PMID- 23092257 TI - Neural stem cells: from neurobiology to clinical applications. AB - In spite of increasing numbers of publications about cell replacement therapies in various neurodegenerative diseases, reports on therapeutic benefits are still rare due to the huge array of parameters affecting the clinically relevant outcome. Limiting conditions can be attributed to origin and number of cells used for transplantation, their in vitro storage, propagation and/or predifferentiation. In addition, the ability of these cells for a site directed differentiation and functional integration in sufficient numbers is known to depend on extrinsic factors including intracerebral position of graft(s). Thus, obstacles to the use of cells in replacement therapies of neurological disorders reflect the molecular as well as cellular complexity of affected functional systems. This review will highlight central aspects of cell replacement strategies that are currently regarded as the most limiting issues in respect to survival, cell identity and site directed differentiation as well as functional integration of grafts. Special attention will be paid to neural stem cells, derived from either fetal or adult central nervous tissue. Unravelling the molecular biology of these proliferating cells in combination with instructive environmental cues for their site directed differentiation will pave the way to high reproducibility in collection, propagation, and predifferentiation of transplantable cells in vitro. In addition, this knowledge of intrinsic and extrinsic cues for a site directed neural differentiation during development will broaden the perspective for any pluripotent stem cell, namely embryonic stem and induced pluripotent stem cells, as an alternate source for a cell based therapy of neurodegenerative diseases. PMID- 23092258 TI - Clonogenic CD15 immunoreactive radial glial cells from the developing human lateral ganglionic eminence. AB - Radial glial cells represent a subpopulation of secondary neural precursor cells that differentiate from neuroepithelial progenitors and are transiently found in the developing CNS of mammals. There is ample evidence for a temporal and spatial arrangement of increasingly committed radial glial cells that is of critical importance for the organisation and specification of different brain regions. For the human ganglionic eminence, recent findings have shown an early molecular specification of this cell type by the CD15 carbohydrate epitope, beginning already at the end of the first trimester. Here we further characterise the CD15+ radial glia cells as bFGF/EGF responsive progenitors allowing its propagation in vitro. By magnet activated cell sorting, its trilineage differentiation potential can be shown by differentiation into (PSA-NCAM beta3 tubulin immunoreactive) neurones, GFAP expressing cells of astrocytic morphology, and O4 positive oligodendrocytes. Subcloning experiments under proliferation conditions reveal ongoing CD15 expression by dividing cells. Although the relative number of CD15+ progenitor cells is found to decrease in favour of CD15- precursor cells during continuous passaging, cell sorting experiments allow the repetitive purification of high numbers of positively selected precursor cells for up to 12 weeks. In conclusion, expression of the cell adhesion molecule CD15 by a subpopulation of proliferative cells from the lateral ganglionic eminence allows easy and reproducible purification of progenitor cells by cell sorting, enabling the generation of a compartment-specific cell pool as a prerequisite for a safe and standardised therapy of neurodegenerative basal forebrain diseases. PMID- 23092259 TI - In vitro dissolution testing of drug-eluting stents. AB - Drug-eluting stents (DES) have revolutionized the treatment of coronary artery blockage by tremendously reducing the rate of in-stent restenosis and the necessity of repeat revascularization compared to bare-metal stents. They are also gaining increasing importance in other medical fields such as the treatment of certain localized tumors and in glaucoma therapy. DES generally contain most potent drugs, e.g. immunosuppressants or cytostatics, which are supposed to be released in a well controlled manner over time spans which are chosen according to disease progression. Typically, this means that fairly small amounts of drug are released over long periods of time. Therefore, quantification of in vivo plasma levels is often not feasible. Due to this limitation and the fact that tissue levels cannot be determined in humans, in vitro dissolution testing is one of the most powerful tools to gain insight into the release behaviour of DES. This article focuses on the methods for in vitro dissolution testing of DES which are available up to date and highlights the specific characteristics of drug release from stents arising from the composition and the in vivo localization of the dosage form. PMID- 23092260 TI - Advances in coronary stent technology--active drug-loaded stent surfaces for prevention of restenosis and improvement of biocompatibility. AB - Beyond their originally sole mechanical function, current drug-eluting stents (DES) implement the concept of local drug delivery for the re-opening of stenotic arterial vessels, and for prevention of in-stent restenosis as one of the major limitations of conventional bare metal stents (BMS). Current DES consist of a permanent metallic stent platform and an active agent being released from a drug incorporated polymer coating or a porous stent surface. Although DES have impressively demonstrated their capability of reducing in-stent restenosis, their safety remains under debate due to potential risks, such as delayed healing, late thrombosis and hypersensitivity demanding further development. Current advancements in the stent design address the stent platform, the pharmacologically active substance and/or the drug carrier. For instance, novel biocompatible absorbable stent platforms and drug carriers are developed and novel drugs with a differential effect on vascular endothelial and smooth muscle cells, providing efficient inhibition of muscle cells without altering the endothelial cell function, are identified. Moreover, biofunctionalization of the stent's surface with capture molecules for endothelial progenitor cells are under investigation in order to achieve an in situ endothelialization of the implant. In this context, this review paper discusses the current advances in coronary stent technology with a special focus on novel stent platforms, drugs and stent coatings for the prevention of restenosis and improvement of biocompatibility. PMID- 23092261 TI - Cochlear implants. AB - Cochlear implants have evolved to become the treatment of choice for severely hearing-impaired patients. Speech signals are picked up by a microphone, processed and then delivered to the stimulating electrodes (the current maximum number being 22) that are placed on an electrode array implanted into the scala tympani of the cochlea. The target cells of electrical stimulation, the spiral ganglion cells (SGCs), are located some distance away in the central axis of the cochlea. SGCs start to degenerate after the onset of deafness. Additionally, fibrous tissue is formed around the electrode array after implantation. If cochlear implants are to deliver sound that is closer to natural hearing, the number of independent stimulation channels has to be increased. Optimization of the interface between the electrode array and the surrounding tissue is, therefore, the focus of current research. Promising approaches relating to cells, micro- and nanosystems will be reviewed. PMID- 23092262 TI - New concepts for glaucoma implants--controlled aqueous humor drainage, encapsulation prevention and local drug delivery. AB - Glaucoma is a common cause of blindness in industrialized countries and is the most frequent cause of irreversible blindness worldwide. Since raised intraocular pressure (IOP) has been implicated as the major risk factor, the main goal of all glaucoma treatment is to reduce IOP sufficiently to prevent continuous irreversible retinal ganglion cell damage and progression of visual field loss. Pharmacological reduction of IOP is first-line therapy, followed by laser treatment of the trabecular meshwork and filtering glaucoma surgery, and cyclophotocoagulation of the ciliary body or allogenic implants. The most important glaucoma implants are presented (MOLTENO, AHMED, BAERVELDT, KRUPIN) together with more recent developments (Ex-Press, Eyepass, iStent, Gold micro shunt). Drainage into the suprachoroidal space is a promising option, but is also limited by scarring of the new created outflow route due to proliferation and adhesion of fibroblasts. A deeper understanding of fibroblasts in the related eye compartments is required. Characterization of scleral, choroidal, and, as a reference, Tenon fibroblast subtypes, is possible based on gene expression patterns. Alongside mitomycin C and 5-fluorouracil, newer drugs to prevent fibrosis have been proposed, offering effects that are more specific and more physiological. Effectors involved in wound healing phases and signaling pathways are potential targets for pharmaceutical intervention. Downregulation of growth factors like TGF-beta and their downstream effectors may suppress proliferation and differentiation of fibroblasts, extracellular matrix deposition, wound contraction, and neovascularization. Furthermore, current approaches to local drug delivery in glaucoma implant technology are briefly summarized. PMID- 23092263 TI - Cochlear Implants. AB - Cochlear implants have evolved to become the treatment of choice for severely hearing-impaired patients. Speech signals are picked up by a microphone, processed and then delivered to the stimulating electrodes (the current maximum number being 22) that are placed on an electrode array implanted into the scala tympani of the cochlea. The target cells of electrical stimulation, the spiral ganglion cells (SGCs), are located some distance away in the central axis of the cochlea. SGCs start to degenerate after the onset of deafness. Additionally, fibrous tissue is formed around the electrode array after implantation. If cochlear implants are to deliver sound that is closer to natural hearing, the number of independent stimulation channels has to be increased. Optimization of the interface between the electrode array and the surrounding tissue is, therefore, the focus of current research. Promising approaches relating to cells, micro- and nanosystems will be reviewed. PMID- 23092264 TI - Intracerebrally applied botulinum neurotoxin in experimental neuroscience. AB - The use of botulinum neurotoxins (BoNTs) for therapeutic purposes in neuromuscular disorders and peripheral hypercholinergic conditions as well as in aesthetic medicine is widespread and common. BoNTs are also able to block the release of a wide range of transmitters from presynaptic boutons. Therefore, application of BoNTs directly in the central nervous system (CNS) is currently under study with respect to basic research and potentially as a new therapeutic strategy of neurological diseases. Investigations concentrate on effects of intracerebral and intraspinal application of BoNTs in rodents on the impact on spinal, nuclear, limbic and cortical neuronal circuits. In animal model first promising BoNT-induced therapeutical benefit has been shown in the treatment of pain, epilepsy, stroke and Parkinson's disease. PMID- 23092265 TI - Dispersion of linear, nonlinear optical susceptibilities and hyperpolarizability of C11H8N2O (o-methoxydicyanovinylbenzene) crystals. AB - Linear and nonlinear optical susceptibility dispersion and hyperpolarizability of C(11)H(8)N(2)O, o-methoxydicyanovinylbenzene, crystals were performed by means of density functional theory (DFT). The exchange and correlation potential was described within a framework of the local density approximation (CA-LDA) and gradient approximation (GGA) based on exchange-correlation energy optimization to calculate the total energy. Engel-Vosko generalized gradient approximation (EV GGA) and the modified Becke-Johnson potential (mBJ) were used for the electronic crystal structure and optical susceptibility dispersion calculations. We have established systematically increasing energy gap from 2.25 eV (LDA), 2.34 eV (GGA), 2.50 eV (EVGGA), and 2.96 eV (mBJ). The crystal possesses a direct band gap which is an important key factor to make the crystal optically active with high linear and nonlinear optical susceptibilities and hyperpolarizability. Additionally, the studied crystal has a considerable anisotropy of birefringence which is necessary for phase matching conditions during the optical second harmonicexperiments. We have found that the theoretically evaluated second harmonic generation achieves about 5.8 * 10(-8) esu in good agreement with the experimental value (4.9 * 10(-8) esu). Additionally, we have found that our calculated value of beta(222) is about 2.3 * 10(-30) esu at zero energy and 6.6 * 10(-30) esu at lambda = 1.064 MUm. We should emphasize that our calculated value of beta(222) (6.60 * 10(-30) esu at lambda = 1.064 MUm) shows better agreement with the experimental data (5.04 * 10(-30) esu at lambda = 1.064 MUm) than other calculations. PMID- 23092266 TI - Advances in the systemic treatment of neuroendocrine tumors in the era of molecular therapy. AB - Neuroendocrine tumors (NETs) are heterogeneous in underlying tumor biology and clinical presentations. They are generally classified according to their degree of differentiation and sites of origin. Moreover, NETs are further characterized by their secreted bioactive neuroamine. The treatment paradigm used to be surgical intervention in early disease and mostly palliative nature in the metastatic setting. With an increase in the understanding of the molecular signaling pathways involved in tumor growth, there are various emerging treatment options for patients with advanced NETs. Somatostatin analogs have both anti tumor effects as well as symptom palliation associated with the secreted neuropeptides. Peptide-radio-receptor treatment (PRRT) using radio-labeled peptides which binds to somatostatin receptor is a useful anti-tumor treatment but limited by general availability. Sunitinib, a multi-targeted tyrosine kinase inhibitor, has recently been shown to improve the survival of pancreatic NETs patients. Similarly, the use of an mTOR inhibitor--everolimus, either alone or in combination with somatostatin analogs have demonstrated encouraging efficacy in treating advanced NETs. The success of these two agents in pancreatic NETS supports the notion that targeting angiogenesis and/or PI3K/AKT/mTOR pathway is an important strategy for making therapeutic advances in this disease. There are now many ongoing trials in exploring the role of other novel agents in treating patients with pancreatic NETs or carcinoid. The major plaguing problem in this era is the differential response to biological agents amongst NETs of different anatomical origins. Pancreatic NETs are generally more responsive to both chemotherapy and targeted agents than NETs of other sites. Thus, the development of potential predictive and prognostic biomarkers to tailor various molecular therapies to different NETs populations is a major unmet need. PMID- 23092267 TI - Molecular targeted therapies in the management of head and neck squamous cell carcinoma: recent developments and perspectives. AB - Current development of molecular targeted therapies in oncology is particularly active. This paper is a review of the recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). We analyze not only the recently published and ongoing clinical trials, but also the relevant preclinical studies, in order to identify the future directions of research in the field of HNSCC. As epidermal growth factor receptor (EGFR) signaling pathway plays a key role in the growth of HNSCC, EGFR, with its downstream effectors, represents the main target of the new therapeutic agents currently in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic disease, in association with platinum-based chemotherapy. Future advances are expected with the integration of cetuximab and other anti EGFR agents into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors. Besides EGFR inhibition, new molecular targeted therapies such as mTOR, Src kinase, or IGF-1R inhibitors, acting on other activated molecular signaling pathways, are being developed. As these innovative molecules are beginning to be used in clinical practice, the identification of predictive markers for efficacy and toxicity is now a crucial issue. PMID- 23092268 TI - Multifunctionalized microbubbles for cancer diagnosis and therapy. AB - Microbubbles (MBs) are gas-filled hollow microparticles. Under the ultrasound field, the difference of acoustic characteristics between gas and plasma in the blood vessel will cause strong impedance mismatch and echogenicity to enhance ultrasonic grey scale imaging. The linear or nonlinear resonance of MB shell in the ultrasound field would lead to repeated expansion-contraction till destruction. In this case, the pre-loaded drug in the MB shell will be released in an accelerated manner triggered by the ultrasound at a probe-given site. Sonoporation effect of the cell membrane would also help increase the uptake of substances into cells. This paper is dedicated to review recent developments on MBs, especially multifunctionalized MBs, as a potential drug/gene delivery microdevices for both diagnosis and therapy of malignant tumors. PMID- 23092270 TI - Recent development of molecular targeted anti-cancer agents. PMID- 23092269 TI - Cytotoxicity and cell death mechanisms induced by a novel bisnaphthalimidopropyl derivative against the NCI-H460 non-small lung cancer cell line. AB - Some polyamine derivatives, namely the bisnaphthalimidopropyl polyamines (BNIPPs) may have potential as anticancer drugs. Indeed, previous work from some of us had shown that the ability of these molecules to bind to DNA may contribute to their cytotoxicity. However, their precise mode of action has not been fully understood. In the present work, we report for the first time the effect of the previously synthesised compounds, BNIPDaCHM and NPA, together with a new BNIP derivative (BNIP-3,4-DaDPM) in the in vitro growth of a non-small cell lung cancer cell line (NCI-H460). In addition, for the most potent compound (BNIPDaCHM), its activity as sirtuin inhibitor was investigated in vitro and further confirmed in silico. Results in the NCI-H460 cells showed that, from the compounds tested, BNIPDaCHM was the most potent (GI50 of 1.3 MUM). In addition, a concentration-dependent alteration in the normal NCI-H460 cell cycle profile was observed following treatment with BNIPDaCHM as well as an increase in the sub-G1 peak (suggestive of apoptotis). This effect was further supported by Annexin V/PI staining and by analysing the expression of proteins related to apoptosis (cleaved PARP and Caspase-3) by Western blot. It was also observed that BNIPDaCHM inhibited the activity of SIRT2 in vitro, but not of SIRT1. Accordingly, this compound also caused a small increase in tubulin acetylation in NCI-H460 cells. To determine the binding potential of BNIPDaCHM on hSIRT2 and to further validate its inhibitory action, in silico docking studies were carried out, which revealed that BNIPDaCHM is composed of an entirely new SIRT2- inhibiting structural scaffold. In conclusion, this study indicates that BNIP derivatives with a novel structural backbone, such as BNIPDaCHM, may have potential as building blocks for novel antitumour agents which might selectively bind to hSIRT-2. PMID- 23092271 TI - Overcoming the blood-brain barrier for chemotherapy: limitations, challenges and rising problems. AB - Treatment of brain tumors with chemotherapy is limited mostly because of delivery impediments related to the blood-brain barrier (BBB). For gliomas, the most common and aggressive primary brain tumor, treatment includes surgery, radiotherapy, and chemotherapy usually administered orally or intravenously. These routes do not deliver effective concentrations. To complicate matters, chemotherapy is usually a long treatment. Therefore, transient disruption of the BBB is likely insufficient to deliver effective intratumoral concentrations of anticancer drugs. This review briefly updates current strategies for overcoming the BBB with emphasis on their limitations and challenges intrinsic to the biology of cancer cells. PMID- 23092272 TI - General strategy for designing core-shell nanostructured materials for high-power lithium ion batteries. AB - Because of its extreme safety and outstanding cycle life, Li(4)Ti(5)O(12) has been regarded as one of the most promising anode materials for next-generation high-power lithium-ion batteries. Nevertheless, Li(4)Ti(5)O(12) suffers from poor electronic conductivity. Here, we develop a novel strategy for the fabrication of Li(4)Ti(5)O(12)/carbon core-shell electrodes using metal oxyacetyl acetonate as titania and single-source carbon. Importantly, this novel approach is simple and general, with which we have successfully produce nanosized particles of an olivine-type LiMPO(4) (M = Fe, Mn, and Co) core with a uniform carbon shell, one of the leading cathode materials for lithium-ion batteries. Metal acetylacetonates first decompose with carbon coating the particles, which is followed by a solid state reaction in the limited reaction area inside the carbon shell to produce the LTO/C (LMPO(4)/C) core-shell nanostructure. The optimum design of the core-shell nanostructures permits fast kinetics for both transported Li(+) ions and electrons, enabling high-power performance. PMID- 23092273 TI - The right ventricle: biologic insights and response to disease: updated. AB - Despite ample evidence that right ventricular function is a critical determinant of the clinical response to a spectrum of cardiovascular diseases, there has been only a limited analysis of the unique and distinguishing physiologic properties of the RV under normal circumstances and in response to pathologic insults. This knowledge deficit is increasingly acknowledged. This review highlights some of these features and underscores the fact that rational therapy in RV failure needs to acknowledge its unique physiology and ought to be chamber specific. That is proven therapies for LV dysfunction do not necessarily apply to the RV. The updated version of this review now acknowledges recent advances in the understanding of metabolic, inflammatory and gender-specific influences on the right ventricle. PMID- 23092274 TI - A multidisciplinary atrial fibrillation clinic. AB - BACKGROUND: Reports in the literature indicate that specialty clinics focusing on management of patients with specific chronic disorders have a significant positive impact on patient outcomes. Atrial fibrillation (AF), one of the most common forms of cardiac arrhythmia, affects millions of patients. Outcome data regarding the impact of managing patients with AF are limited. We established a specialty clinic focusing on management of patients with AF. The objective of our study was to evaluate the outcomes of treating AF patients in this clinic. METHODS: A team consisting of electrophysiologists and pharmacists designed a specific plan for managing and educating patients. This plan consisted of evaluation, implementation of an individualized treatment plan, patient education, medication management, and follow-up care. We reviewed the outcomes of patients who had clinic visits between November 2011 and March 2012. The primary outcome was the incidence of AF-related hospitalizations and stroke. RESULTS: Seventy one patients were included in the analysis. Out of 71 patients, we identified 17 (23.9%) patients who were hospitalized. Two of these 17 hospitalized patients had ischemic stroke events. CONCLUSION: When compared to published data in the existing literature, managing AF patients in specialty clinics reduces the incidence of AF-related hospitalizations and stroke. PMID- 23092276 TI - Development of small molecule HIV-1 fusion inhibitors: linking biology to chemistry. AB - Human immunodeficiency virus type 1 (HIV-1) primarily infects and then destroys CD4-positive lymphocytes, leading to the acquired immunodeficiency syndrome (AIDS). Over 20 drugs, most small and orally bioavailable, have been approved, and include reverse transcriptase and protease inhibitors. In 2003, the US-FDA approved enfuvirtide (T-20), a 36-amino acid peptide derived from the C-terminal heptad repeat of the HIV-1 gp41 ectodomain. T-20 was initially identified in 1992 from biological studies, and can effectively suppress HIV-1 infection with multi drug resistance. Currently, numerous fusion inhibitory peptides have been designed and synthesized. Some of these peptides show strong inhibition even towards HIV-1 strains resistant to T-20. These developments also facilitate basic research into the mechanisms of HIV-1 fusion, because peptide inhibition resembles the process of viral fusion with the cellular membrane. In this review, we focus on HIV-1 fusion inhibitors and the application of their development and clinical findings to the concept of "biology to chemistry" to support rational drug design for small bioavailable compounds. PMID- 23092277 TI - Synthesized peptide inhibitors of HIV-1 gp41-dependent membrane fusion. AB - Fusion of viral and cellular membranes is an essential step for HIV-1 infection. This process offers an attractive target for developing antiviral agents. T20 (Enfuvirtide, Fuzeon), a 36-amino acid peptide derived from the C-terminal heptad repeat region of HIV-1 gp41, is the first and only clinically approved HIV-1 fusion inhibitor that being used for treatment of HIV/AIDS patients failed to respond to current antiretroviral drugs. However, T20-resistance can be acquired rather easily in vitro and in vivo. T1249 is considered as a representative of the second generation fusion inhibitors, but its clinical evaluation was halted due to the problem of drug formulation. To overcome these challenges, a number of strategies have been applied to develop the third or next-generation inhibitors with the significantly improved antiviral activity and pharmacokinetic profiles. Promisingly, several peptides are currently under clinical trials, such as Sifuvirtide and VIR-576. Recently, several high resolution crystal structures of HIV-1 fusion inhibitor peptides were reported, which reveal the key residues or motifs underlying their potency against diverse HIV-1 variants. This review highlights the development of the representative peptide inhibitors of HIV-1 fusion toward providing some insights into the future of this class of anti-HIV drugs. PMID- 23092279 TI - Blocking HIV-1 replication by targeting the Tat-hijacked transcriptional machinery. AB - HIV-1 infection can be effectively controlled by HAART, which improves the quality of lives of infected individuals, but fails to completely eradicate the virus, even after decades of treatment. This issue, together with the emergence of multi-drug-resistant viruses, clearly underscores the continuing need to find novel agents able to target vulnerable steps in the viral replication cycle. HIV transcriptional regulation is a crucial step required to re-initiate viral replication from post-integration latency after interruption of therapy and to keep the virus in circulation. In this step, the viral protein Tat plays a central role by dramatically increasing the production of elongated transcripts through its unique interaction with the viral TAR RNA and the cellular cofactor P TEFb, together with a myriad of other host factors which are recruited to the viral promoter to ensure efficient transcription. The transcriptional machinery, involving an intricate interplay of many viral and cellular components, offers a plethora of potential therapeutic targets that have not yet been exploited by any of the antiretroviral drugs used in therapy. In this review we explore the state of-the-art of Tat-mediated transcription inhibitors which target the well consolidated Tat/TAR/PTEFb axis, together with novel therapeutics that interfere with various host-cell factors, including some pioneer inhibitors designed on the basis of recent molecular and structural studies. PMID- 23092275 TI - Obesity pharmacotherapy: current perspectives and future directions. AB - The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis. PMID- 23092278 TI - From the chemistry of epoxy-sugar nucleosides to the discovery of anti-HIV agent 4'-ethynylstavudine-Festinavir. AB - Branched sugar nucleosides have attracted much attention due to their biological activities. We have demonstrated that epoxysugar nucleosides serve as versatile precursor for the stereo-defined synthesis of these nucleoside derivatives on the basis of its ring opening with organoaluminum or organosilicon reagents. In this review article, novel methods for the synthesis of nucleoside analogues branched at the 1' and 4'-position will be described. During this study, we could discover an anti-HIV agent, 4'-ethynylstavudine (Festinavir). Festinavir showed more potent anti-HIV activity than the parent compound stavudine (d4T). Other significant properties of Festinavir are as follows: 1) much less toxic to various cells and also to mitochondorial DNA synthesis than d4T, 2) better substrate for human thymidine kinase than d4T, 3) resistant not only to chemical glycosidic bond cleavage but also to catabolism by thymidine phosphorylase, 4) the activity improves in the presence of a major mutation, K103N, associated with resistance to non-nucleoside reverse transcriptase inhibitors. Detailed profile of the antiviral activities, biology and pharmacology of Festinavir are also described. PMID- 23092280 TI - Inhibitors of HIV-1 entry. AB - Since the discovery of human immunodeficiency virus (HIV) as a causative agent of acquired immune deficiency syndrome (AIDS) various strategies were employed to counter its devastating actions. One such concept relies on the prevention of HIV entry into host's "competent" cells by means of compounds known as entry inhibitors. HIV entry inhibitors comprise a group of immensely diverse compounds ranging from proteins/antibodies to small organic molecules and capable of targeting various stages of viral entry. Although already in clinical use, this approach to HIV therapy is still being investigated to produce new promising antiviral compounds. Here, we review the latest advances in this area. PMID- 23092281 TI - Quinoline-based HIV integrase inhibitors. AB - HIV integrase became an important target for drug development more than twenty years ago. However, progress has been hampered by the lack of assays suitable for high throughput screening, a reliable crystal structure or pharmacophore. Thus, a real breakthrough was only observed in 2007 with the introduction of the first integrase inhibitor, raltegravir, into treatment. To date, the armament of integrase inhibitors is broad and covers several drugs from different classes that are under clinical trials. Among them, quinoline-based compounds and analogues occupy an important place. This review is focused on those compounds that have a quinoline scaffold and attempts to answer the question of whether quinoline is privileged for these activities. In fact, quinoline has been claimed as a privileged structure several times for different fields of activities. A closer look at its structural features may reveal the prerequisites responsible for the popularity of quinoline-based inhibitors of HIV integrase. PMID- 23092282 TI - Anti-HIV drug development: structural features and limitations of present day drugs and future challenges in the successful HIV/AIDS treatment. AB - Acquired Immune Deficiency Syndrome (AIDS), an immuno-compromized condition, a sequel to untreated human immunodeficiency virus (HIV) infection, inviting several life-threatening diseases, has become one of the most fatal disorders in the recent past because of HIV strain variance due to mutations, passive latency and reservoirs helping in replenishing and reviving the HIV-1 proviral DNA. Scientific efforts have led to the discovery of several effective drugs against HIV and lowered the morbidity and mortality all over the world. However, despite availability of a good number of anti-HIV drugs, the problem, for the foreseeable reasons, stands out as the most chronic disease due to the less tolerability and low accessibility of drugs, life-long expensive treatment, and above all, the emergence of drug resistant viral strains. This review dwells upon HIV infection and its proliferation inside the host system, drug targets, different types of drugs, their structural features and mode of interaction with viral targets and drug regimens. It further focuses on topics of latest interest regarding drug development, fixed dose combinations (FDCs), the limitations of present day drugs with their structural features along with their pharmacodynamics, pharmacokinetics and pharmacogenomics and the challenges in finding a permanent cure for HIV/AIDS. PMID- 23092283 TI - The current status and challenges in the development of fusion inhibitors as therapeutics for HIV-1 infection. AB - HIV-1 membrane fusion as a part of the process of viral entry in the target cells is facilitated by gp41 and gp120, which are encoded by Env gene of HIV-1. Based on the structure and the mechanism researches, new treatment options targeting HIV-1 entry process have been proposed. Enfuvirtide, which mimics amino acid sequences of viral envelope glycoprotein gp41, is the first HIV-1 fusion inhibitor approved by FDA. Although it fulfills vital functions by binding to gp41 and abolishing the membrane fusion reaction when used in combination, it could induce drug resistant virus variants. Currently, a number of design and modification schemes have been presented, a large number of prospective fusion peptides have emerged. For these fusion inhibitors, multiple mutations in gp41 have been associated with the loss of susceptibility to agents. This review reported the current developments and innovative designs of HIV-1 membrane fusion inhibitors. PMID- 23092284 TI - Discovery of small molecule fusion inhibitors targeting HIV-1 gp41. AB - Gp41 is regarded as an attractive target for development of HIV-1 entry inhibitors since it mediates the fusion process of HIV- 1 entry into the target cell through the six-helix bundle (6-HB) formation between its N-heptad repeat (NHR) and C-heptad repeat (CHR). Any chemical entity that disrupts the six-helix bundle formation may inhibit the fusion process, thereby blocking HIV-1 entry into the target cells. A brief review of discovering small molecule inhibitors targeting gp41 is presented here, including the development of assay methods, current known small molecule inhibitors and their binding mode studies. Lessons learned and challenges remained in view of blocking protein-protein interaction between NHR and CHR are also discussed. PMID- 23092285 TI - Editorial: the development of novel inhibitors for the treatment of HIV infection. PMID- 23092286 TI - Molecular aspects of the RT/drug interactions. Perspective of dual inhibitors. AB - The HIV-1 reverse transcriptase (RT) is one of the most attracting targets for the development of early phase infection inhibitors. Although many RT inhibitors have been approved for the treatment of HIV-1 infection, they all target the polymerase function of this enzyme. So far, no drugs are available for the inhibition of the RT associated ribonuclease H function (RNase H), which plays an essential role in the HIV replication cycle. Moreover it should be reported that many of the known RT inhibitors, targeting the polymerase function, enhance the RNase H activity, indicating that, although spatially distinct, a close relation occurs between the two functions. The aim of this review is to summarise the efforts in the design of new inhibitors either characterized by a novel mechanism of action or capable of blocking both RT associated functions, as well as pointing out the main binding features of the known RT inhibitors. PMID- 23092287 TI - Transcriptional profiling of Saccharomyces cerevisiae exposed to propolis. AB - BACKGROUND: Propolis is a natural product of plant resins collected by honeybees (Apis mellifera) from various plant sources. Our previous studies indicated that propolis sensitivity is dependent on the mitochondrial function and that vacuolar acidification and autophagy are important for yeast cell death caused by propolis. Here, we extended our understanding of propolis-mediated cell death in the yeast Saccharomyces cerevisiae by applying systems biology tools to analyze the transcriptional profiling of cells exposed to propolis. METHODS: We have used transcriptional profiling of S. cerevisiae exposed to propolis. We validated our findings by using real-time PCR of selected genes. Systems biology tools (physical protein-protein interaction [PPPI] network) were applied to analyse the propolis-induced transcriptional bevavior, aiming to identify which pathways are modulated by propolis in S. cerevisiae and potentially influencing cell death. RESULTS: We were able to observe 1,339 genes modulated in at least one time point when compared to the reference time (propolis untreated samples) (t-test, p-value 0.01). Enrichment analysis performed by Gene Ontology (GO) Term finder tool showed enrichment for several biological categories among the genes up-regulated in the microarray hybridization such as transport and transmembrane transport and response to stress. Real-time RT-PCR analysis of selected genes showed by our microarray hybridization approach was capable of providing information about S. cerevisiae gene expression modulation with a considerably high level of confidence. Finally, a physical protein-protein (PPPI) network design and global topological analysis stressed the importance of these pathways in response of S. cerevisiae to propolis and were correlated with the transcriptional data obtained thorough the microarray analysis. CONCLUSIONS: In summary, our data indicate that propolis is largely affecting several pathways in the eukaryotic cell. However, the most prominent pathways are related to oxidative stress, mitochondrial electron transport chain, vacuolar acidification, regulation of macroautophagy associated with protein target to vacuole, cellular response to starvation, and negative regulation of transcription from RNA polymerase II promoter. Our work emphasizes again the importance of S. cerevisiae as a model system to understand at molecular level the mechanism whereby propolis causes cell death in this organism at the concentration herein tested. Our study is the first one that investigates systematically by using functional genomics how propolis influences and modulates the mRNA abundance of an organism and may stimulate further work on the propolis-mediated cell death mechanisms in fungi. PMID- 23092288 TI - Antitumoral activity of indole-3-carbinol cyclic tri- and tetrameric derivatives mixture in human breast cancer cells: in vitro and in vivo studies. AB - Indole-3-carbinol (I3C) and its oligomeric derivatives have been widely studied for their chemopreventive and chemotherapeutic properties. We have previously shown that the I3C cyclic tetrameric derivative CTet inhibits breast cancer cell proliferation in vitro and in xenotrasplanted tumor. Here we report the antitumoral activity of a mixture of tri- and tetrameric cyclic I3C derivatives (CTr/CTet) both in vitro (MCF-7 and MDA-MB-231 breast cancer cell lines) and in vivo in a tumor xenograft model. CTr/CTet mixture avoids the low solubility drawbacks of CTet, thus favouring its solubilization, and reducing purification process, time and costs. CTr/CTet mixture has been shown to inhibit breast cancer cell proliferation (IC50 = 1.3 and 1.6 MUg/ml in MCF-7 and MDAMB- 231, respectively) inducing the G0/1 cell cycle phase accumulation. The main molecular events related to CTr/CTet activity are the overexpression of p21, p27 and GADD45A, nuclear translocation of FOXO3a, inhibition of Akt activity and downregulation of estrogen receptor. In vivo, the growth of xenotransplanted tumor has been inhibited and the pro-tumoral low molecular weight cyclin E downregulation has been detected. Our data indicate that CTr/CTet is a potential anticancer combination agent for both hormone-responsive and triple-negative breast tumors. PMID- 23092290 TI - The effects of beta-glucans on dendritic cells and implications for cancer therapy. AB - beta-Glucans are polysaccharides of beta-D-glucose extracted from the cell walls of different species of mushrooms, yeast, oat, barley, seaweeds, algae and bacteria. Modern biomedical research has identified beta-glucans as biological response modifiers (BRM) with anti-tumor properties that elicit potent immune responses through their recognition by a variety of pattern recognition receptors (PRRs) on dendritic cells (DCs), macrophages and neutrophils. Complement receptor 3 (CR3), lactosylceramides, scavenger receptors and dectin-1 are involved in beta glucan recognition, triggering a series of signaling events that modulate innate and subsequently adaptive immune responses. beta-Glucan binding to specific receptors in DCs and macrophages triggers their activation and maturation, increases their antigen-presentation ability and enhances the production of proinflammatory cytokines that stimulate the polarization of TH1 or TH17 responses, and induces the activation of antigen-specific CD8+ cytotoxic T lymphocytes (CTL). Moreover, large beta-glucans can be degraded by macrophages into smaller moieties, when released, prime CR3 receptor on neutrophils and natural killer (NK) cells mediating CR3-dependent cellular cytotoxicity (CR3-DCC) of iC3b opsonized tumor cells. Elucidating the molecular mechanisms of beta- glucan-induced signaling in immune cells is essential for the design of new therapeutic strategies against cancer. Future studies should be done to translate beta-glucan research to the clinic. PMID- 23092291 TI - Health-related and social factors predicting non-reemployment amongst newly unemployed. AB - BACKGROUND: Many researchers have examined the effect that mental health has on reemployment opportunities amongst the unemployed, but the results are inconclusive. Our aim in this study is to investigate the effects that different aspects of mental and physical health, as well as socio-demographic, social, and economic factors, have on reemployment. METHODS: A questionnaire was administered to 1,000 and answered by 502 newly registered unemployed Swedes, who were followed for one year using data from the Swedish National Labour Market Board. The differences between those reemployed and those not reemployed was analysed using stepwise logistic regression. RESULTS: General mental ill health amongst unemployed individuals measured by the General Health Questionnaire scale was associated with lower levels of reemployment after one year. This effect could not be explained by any of the scales measuring specific aspects of mental disease such as health-related level of function, rate of depression, burnout, or alcohol misuse. Instead being above 45, low control over one's financial situation, being an immigrant, and visiting a physician during the last three months were better predictors of failure to be reemployed. CONCLUSION: There are theoretical reasons to assume that psychological distress leads to a decreased reemployment rate amongst the unemployed. The results of this study partly endorse this hypothesis empirically, showing that general subjective mental distress decreases the rate of reemployment amongst newly unemployed individuals, although this effect was mediated by social and economic factors. Indicators of psychiatric disease had no significant effect on reemployment. The results of this study lead us to suggest the early introduction of financial counselling, psychological support, and other interventions for groups with lower reemployment rates. PMID- 23092289 TI - The use of lentinan for treating gastric cancer. AB - Natural compounds containing fungal beta-glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of beta-(1, 3)-glucan with beta-(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by beta-glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review. PMID- 23092292 TI - Novel M(1) allosteric ligands: a patent review. AB - INTRODUCTION: There is substantial evidence from preclinical and early proof-of concept studies suggesting that selective modulation of the M(1) muscarinic receptor is efficacious in cognitive models of Alzheimer's disease (AD) and antipsychotic models of schizophrenia. For example, a number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive function in AD patients, but were limited due to cholinergic adverse events thought to be mediated by pan activation of the M(2) to M(5) subtypes. Thus, there is a need to identify selective activators of the M(1) receptor to evaluate their potential in cognitive disorders. One strategy to confer selectivity for M(1) is the identification of allosteric agonists or positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. AREAS COVERED: This review discusses the M(1) muscarinic receptor and its potential therapeutic value in the treatment of CNS disorders such as AD and schizophrenia. Specifically, novel allosteric ligands that activate or positively modulate the M(1) receptor are examined and peer-reviewed articles associated with these patents publications are also described. EXPERT OPINION: There is substantial evidence supporting activation of the M(1) receptor might be effective in treating symptoms of AD and schizophrenia, but therapeutic success has been elusive and is hypothesized to be due to the lack of selectivity among orthosteric agonists. During the past decade, allosteric modulation of GPCRs has evolved as a viable strategy toward generating subtype selective molecules. A number of novel, selective ligands in the form of allosteric agonists and positive allosteric modulators of the M(1) receptor have been identified offering the potential for clinical evaluation of M(1)-specific receptor activation. PMID- 23092295 TI - Development and optimization of hydroxyapatite-ofloxacin implants for possible bone delivery in osteomyelitis treatment. AB - The present study deals with preparation, optimization and in-vitro drug release study of hydroxyapatite (HAp)- ofloxacin for bone-implantable delivery in osteomyelitis treatment. The effect of drug amount added, and orthophosphoric acid addition rate as process parameters on the drug loading into HAp-system by precipitation method was optimized by using 32 factorial design. The response surface methodology utilizing polynomial equation was used to search for optimal drug loading into HAp-system. The responses observed coincided well with the predicted values obtained through optimization technique. HAp-ofloxacin bone implants were manufactured using synthesized HAp-ofloxacin composite powders and 2 % w/v aqueous solution of sodium alginate was used as binder. Characterization of the delivery system was done by FTIR spectroscopy. The in-vitro ofloxacin release from optimized HAp-ofloxacin bone-implants was slow and sustained over 10 weeks. The drug release pattern was correlated well with Korsmeyer-Peppas model and was followed by Fickian (diffusional) release mechanism. PMID- 23092293 TI - Investigations on the oxygen dependence of a 2-oxoglutarate histone demethylase. AB - Histone N(epsilon)-methyl lysine demethylases are important in epigenetic regulation. KDM4E (histone lysine demethylase 4E) is a representative member of the large Fe(II)/2-oxoglutarate- dependent family of human histone demethylases. In the present study we report kinetic studies on the reaction of KDM4E with O2. Steady-state assays showed that KDM4E has a graded response to O2 over a physiologically relevant range of O2 concentrations. Pre-steady state assays implied that KDM4E reacts slowly with O2 and that there are variations in the reaction kinetics which are dependent on the methylation status of the substrate. The results demonstrate the potential for histone demethylase activity to be regulated by oxygen availability. PMID- 23092294 TI - Discovery of highly potent and selective alpha4beta2-nicotinic acetylcholine receptor (nAChR) partial agonists containing an isoxazolylpyridine ether scaffold that demonstrate antidepressant-like activity. Part II. AB - In our continued efforts to develop alpha4beta2-nicotinic acetylcholine receptor (nAChR) partial agonists as novel antidepressants having a unique mechanism of action, structure-activity relationship (SAR) exploration of certain isoxazolylpyridine ethers is presented. In particular, modifications to both the azetidine ring present in the starting structure 4 and its metabolically liable hydroxyl side chain substituent have been explored to improve compound druggability. The pharmacological characterization of all new compounds has been carried out using [(3)H]epibatidine binding studies together with functional assays based on (86)Rb(+) ion flux measurements. We found that the deletion of the metabolically liable hydroxyl group or its replacement by a fluoromethyl group not only maintained potency and selectivity but also resulted in compounds showing antidepressant-like properties in the mouse forced swim test. These isoxazolylpyridine ethers appear to represent promising lead candidates in the design of innovative chemical tools containing reporter groups for imaging purposes and of possible therapeutics. PMID- 23092296 TI - Sensory discrimination between innocuous and noxious cold by TRPM8-expressing DRG neurons of rats. AB - The TRPM8 channel is a principal cold transducer that is expressed on some primary afferents of the somatic and cranial sensory systems. However, it is uncertain whether TRPM8-expressing afferent neurons have the ability to convey innocuous and noxious cold stimuli with sensory discrimination between the two sub-modalities. Using rat dorsal root ganglion (DRG) neurons and the patch-clamp recording technique, we characterized membrane and action potential properties of TRPM8-expressing DRG neurons at 24 degrees C and 10 degrees C. TRPM8-expressing neurons could be classified into TTX-sensitive (TTXs/TRPM8) and TTX-resistant (TTXr/TRPM8) subtypes based on the sensitivity to tetrodotoxin (TTX) block of their action potentials. These two subtypes of cold-sensing cells displayed different membrane and action potential properties. Voltage-activated inward Na(+) currents were highly susceptible to cooling temperature and abolished by ~95% at 10 degrees C in TTXs/TRPM8 DRG neurons, but remained substantially large at 10 degrees C in TTXr/TRPM8 cells. In both TTXs/TRPM8 and TTXr/TRPM8 cells, voltage-activated outward K(+) currents were substantially inhibited at 10 degrees C, and the cooling-sensitive outward currents resembled A-type K(+) currents. TTXs/TRPM8 neurons and TTXr/TRPM8 neurons were shown to fire action potentials at innocuous and noxious cold temperatures respectively, demonstrating sensory discrimination between innocuous and noxious cold by the two subpopulations of cold-sensing DRG neurons. The effects of cooling temperatures on voltage-gated Na(+) channels and A-type K(+) currents are likely to be contributing factors to sensory discrimination of cold by TTXs/TRPM8 and TTXr/TRPM8 afferent neurons. PMID- 23092298 TI - Ionization, transport, separation, and detection of ions in non-electrolyte containing liquids. AB - Liquid phase ion mobility spectrometry (LPIMS) has the potential to be miniaturized such that it can be incorporated into chip based technology, providing higher performance in terms of both detection sensitivity and resolving power than is currently available by other separation technologies such as gas phase IMS, chromatography, or electrophoresis. This work presents modeling, simulation, and experimental investigations to characterize the mobility of ions in a liquid phase. This study included the ionization, transfer, separation, and detection of ions in non-electrolyte liquids. Using a resistive glass tube, mobility spectra were obtained by pulsed ionization for several different analytes, namely, tetramethylammonium chloride, tetrabutylammonium chloride, and dimethyl methylphosphonate (DMMP). Ion separation was demonstrated by separating solvent ions from the ions generated from the test compounds. Simulation and theoretical resolving power calculations were made to validate the experimental mobility measurements. A parametric study on the dependence of IMS resolving power on drift length, voltage across drift cell, and pulse width determined the requirements for designing a miniaturized IMS system, approximately the centimeter scale, with high performance, resolving power approaching 100 or higher. Mobility spectra are used for the first time to determine the diffusion coefficients of ions in a liquid. PMID- 23092297 TI - Atorvastatin sensitises vascular smooth muscle cells, but not endothelial cells, to TNF-alpha-induced cell death. AB - OBJECTIVE: Stimuli activating vascular smooth muscle cell death can constrain the neointimal response to arterial damage and prevent vascular thickening. Conversely, endothelial cell death increases endothelial dysfunction and thrombosis risk. We investigated the combined effect of atorvastatin and TNF alpha on vascular cell death. METHODS AND RESULTS: Cell death was investigated in cultures of human aortic smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). Atorvastatin downregulated NF-kappaB and enhanced JNK activity and cell death in VSMC cultured with TNF- alpha. In the absence of TNF alpha, percentages (mean and StDev) of annexin V positive cells were 17.4 +/- 6.6%, 19.3 +/- 5.9%, 22.9 +/- 9.4% and 35.0 +/- 20.0 % with 0, 1, 3 and 10 uM atorvastatin, respectively. The cytotoxic effect of statin was significant at the highest dose of 10 MUM (p=0.001). In the presence of TNF-alpha, percentages of annexin V positive cells were 27.1 +/- 10.6%, 34.2 +/- 8.5%, 37.4 +/- 14.6, and 54.1 +/- 20.0% with 0, 1, 3 and 10 uM atorvastatin, respectively. The cytotoxic effect of statin was significant at each dose used (p<=0.02), in the presence of TNF-alpha. The cell death sensitising effect of atorvastatin was apparently mediated by down modulation of PKCbeta activity, because it was reproduced by the specific PKCbeta inhibitor LY317615 and prevented by the PKC activator phorbol-12 myristate-13-acetate (PMA). This effect was cell context dependent because it was not observed in HUVECs. PKCbeta was found to be constitutively active in VSMCs but not in HUVECs, thereby explaining the differential effect among the two cell types. Measurement of phosphoPKCbeta protein levels in arterial specimens confirmed increased activation of this kinase in the smooth muscle layer, in comparison with endothelium. We show that PKCbeta provides survival signals to vascular smooth muscle cells and not the endothelium. CONCLUSION: Our study suggests that atorvastatin enhances TNF-alpha-induced cell death in vascular smooth muscle- but not endothelial - cells; by a cell-context-dependent mechanism, involving PKCbeta inhibition. PMID- 23092301 TI - Recent advance in the studies of beta-glucans for cancer therapy. PMID- 23092300 TI - Ferritin ion channel disorder inhibits Fe(II)/O2 reactivity at distant sites. AB - Ferritins, a complex, mineralized, protein nanocage family essential for life, provide iron concentrates and oxidant protection. Protein-based ion channels and Fe(II)/O(2) catalysis initiate conversion of thousands of Fe atoms to caged, ferritin Fe(2)O(3).H(2)O minerals. The ion channels consist of six helical segments, contributed by 3 of 12 or 24 polypeptide subunits, around the 3-fold cage axes. The channel structure guides entering Fe(II) ions toward multiple, catalytic, diiron sites buried inside ferritin protein helices, ~20 A away from channel internal exits. The catalytic product, Fe(III)-O(H)-Fe(III), is a mineral precursor; mineral nucleation begins inside the protein cage with mineral growth in the central protein cavity (5-8 nm diameter). Amino acid substitutions that changed ionic or hydrophobic channel interactions R72D, D122R, and L134P increased ion channel structural disorder (protein crystallographic analyses) and increased Fe(II) exit [chelated Fe(II) after ferric mineral reduction/dissolution]. Since substitutions of some channel carboxylate residues diminished ferritin catalysis with no effect on Fe(II) exit, such as E130A and D127A, we investigated catalysis in ferritins with altered Fe(II) exit, R72D, D122R and L134P. The results indicate that simply changing the ionic properties of the channels, as in the R72D variant, need not change the forward catalytic rate. However, both D122R and L134P, which had dramatic effects on ferritin catalysis, also caused larger effects on channel structure and order, contrasting with R72D. All three amino acid substitutions, however, decreased the stability of the catalytic intermediate, diferric peroxo, even though overall ferritin cage structure is very stable, resisting 80 degrees C and 6 M urea. The localized structural changes in ferritin subdomains that affect ferritin function over long distances illustrate new properties of the protein cage in natural ferritin function and for applied ferritin uses. PMID- 23092302 TI - Genesis of enhanced Raman bands in SERS spectra of 2-mercaptoimidazole: FTIR, Raman, DFT, and SERS. AB - The surface enhanced Raman scattering (SERS) spectra of biologically and industrially significant, 2-mercaptoimidazole (2-MI) molecule have been investigated. The SERS spectra of the molecule at different concentrations of the adsorbate are compared with its Fourier transform infrared (FTIR) and normal Raman spectra (NRS) in varied environments. The optimized molecular structures and vibrational wavenumbers of the various forms (ca. cationic, neutral, ylidic, anionic) of the molecule have been estimated from the density functional theory (DFT). The vibrational signatures of the molecule have been assigned for the first time from the potential energy distributions (PEDs). The analyses of the Raman vibrational signatures reveal the coexistence of all the different forms of the molecule in the solid state and in aqueous solution. Concentration dependent SERS spectra of the molecule at neutral pH of the medium together with the multivariate data analyses techniques also suggest the concomitance of all the probable forms of the molecule in the surface adsorbed state. The genesis of selective enhancements of the Raman bands in the SERS spectra emanating from the cationic, neutral, ylidic and anionic forms of the molecule have been divulged from the view of the Albretcht's "A" and Herzberg-Teller (HT) charge transfer (CT) contribution. PMID- 23092303 TI - Ionic liquid-stabilized non-spherical gold nanofluids synthesized using a one step method. AB - Ionic liquid (IL)-stabilized non-spherical gold nanofluids have been synthesized by a one-step method in aqueous solution. The whole reaction proceeded in room temperature. In the presence of amino-functionalized ionic liquids, gold nanofluids with long-wave surface plasmon resonance (SPR) absorption (>600 nm) could be obtained by adopting tannic acid as the reductant. The specific SPR absorption was related to the non-spherical gold nanoparticles including gold triangle, decahedra, and icosahedra nanocrystals. All the nanocrystals were observed by transmission electron microscopy. It was deduced that the formation of non-spherical gold nanofluids was related to the hydroxyls in tannic acid while IL acted as the synthesis template. PMID- 23092304 TI - On the pH-responsive, charge-selective, polymer-brush-mediated transport probed by traditional and scanning fluorescence correlation spectroscopy. AB - The complete and reversible charge-selective sequestration of fluorophores by a weak polyelectrolyte brush, poly(2-(dimethylamino)ethylmethacrylate) (PDMAEMA) was demonstrated using fluorescence correlation spectroscopy (FCS). The chemistry and thickness of the weak polyelectrolyte PDMAEMA was tuned reversibly between neutral and cationic polymer forms. Thus, by switching the pH successively, the brush architecture was tuned to selectively trap and release anionic dye probes while continuously excluding cationic molecules. In addition, line-scan FCS was implemented and applied for the first time to a synthetic polymer system and used to identify a new, slower diffusion time on the order of seconds for the sequestered anionic probe under acidic conditions. These results, which quantify the selective sequestration properties of the PDMAEMA brush, are important because they enable a better understanding of transport in polymers and establish a spectroscopic means of evaluating materials with proposed applications in separations science, charge storage/release, and environmental remediation. PMID- 23092305 TI - Quartz concentration trends in metal and nonmetal mining. AB - From 1974 through 2010, the Mine Safety and Health Administration (MSHA) collected nearly 147,000 respirable dust samples with a mass of at least 0.1 mg and a minimum of 1% quartz. These samples represent about 50% of all respirable dust compliance samples collected by MSHA. Analysis of these data shows that pockets of high concentrations and overexposure continue to exist. At underground mines, from 2005 to 2010, occupations with >20% of the samples exceeding the permissible exposure limit (PEL) and geometric mean quartz concentrations exceeding the ACGIH threshold limit value of 25 MUg/m(3) included mucking, crusher operator, general laborer/utility, and front-end loader operator. During the same period, stone and rock saw operators and bagger and packers working at surface mines and mills also had >20% of the samples exceeding the PEL and geometric mean quartz concentrations >25 MUg/m(3). Regardless of mine type or location, slow but steady improvement in exposure levels is seen in jobs involving crushing operations, which are widespread in the mining industry. Crusher operators are more likely to work in an enclosed area where it is easier to apply dust controls and air conditioning. A downward trend is also observed for vehicle equipment operators who drive load-haul-dumps, front-end loaders, trucks, and similar equipment. Crusher operators and vehicle equipment operators represent occupational categories that are widely sampled by MSHA inspectors. A small but statistically significant reduction in the overall mean respirable quartz dust and quartz concentrations from 1993 to 2010 was observed in most commodity groups. Variability from year to year and between commodities is high. Reduction in respirable quartz dust concentration does not necessarily correspond to a reduction in quartz concentration within the same commodity group. These trends are consistent with those reported in previous studies. PMID- 23092306 TI - Preparation and characterization of supported bimetallic Pd(IV)-Co(III) model catalyst from organometallic single source precursor for aerobic oxidation of alcohols. AB - The bimetallic paddlewheel catalyst precursor, [Pd(II)Co(II)(MU-OOCCH(3))(4)] H(2)O.2CH(3)COOH (1), prepared from [Pd(3)(MU-OOCCH(3))(6)] and [Co(OOCCH(3))(2)], was used as a single source precursor to prepare, after binding to a surface-hydroxylated silicon wafer and oxidation, the bimetallic oxides of Pd(IV)Co(III)/SiO(2) catalyst supported on a model planar (i.e., two dimensional) silicon wafer. This catalyst catalyzes the aerobic oxidation of alcohols to its corresponding carbonyl compounds. The bimetallic tetracarboxylato catalyst precursor was bonded to the surface-hydroxylated silicon wafer by spin coating and also by grafting. X-ray photoelectron spectroscopy (XPS) revealed that one of the four MU-acetato bridging ligands was substituted by Si-O fragments in a covalent bond formation process during grafting of 1 onto the wafer. In contrast, during the spin-coating process, all four acetato ligands remained intact during fixation on the silicon surface. Upon oxidation and workup, the grafted sample's Pd:Co ratio remained unchanged (1.0:1.3), whereas the spin-coated sample's Pd content decreased with respect to Co content. XPS determined binding energies were interpreted to imply that after oxidation in an oxygen/argon mixture of the grafted sample both Pd(II) and Co(II) were oxidized to produce PdO(2) (337.5 eV) and Co(III)(2)O(3) (781.1 eV) which most probably interacts with the silicon surface via Pd(IV)-O-Si and Co(III)-O-Si bonds. Solvent free aerobic oxidation of octadecanol to its corresponding carbonyl compound was achieved on this oxidized Pd(IV)Co(III)/SiO(2) model catalyst using molecular oxygen as oxidant under solvent-free conditions. The use of the single source catalyst precursor, 1, resulted in a Pd(IV)Co(III)/SiO(2) catalyst with superior catalytic activity toward the oxidation of octadecanol over a catalyst prepared from a physical mixture of the separate reactant compounds tripalladium(II) hexaacetate and cobalt(II) diacetate. PMID- 23092307 TI - Evaluation of micronuclei induction capacity and mutagenicity of organochlorine and organophosphate pesticides. AB - The genotoxic and mutagenic effects of two commonly used organochlorine pesticides, lindane (LND) and endosulfan (ENS), and two commonly used organophosphate pesticides, chlorpyrifos (CPF) and monocrotophos (MCP) were assessed using in vivo mouse bone marrow micronucleus test and in vitro Ames Salmonella/ microsome mutagenicity test. The results showed that these pesticides alone or in combination, induced significantly high frequency of micronuclei (MN) formation that increased with concentration of pesticides. All these four pesticides produced significant increase in the frequencies of micronucleated polychromatic erythrocytes (MN-PCE) and decrease infrequencies of PCE in dose dependent manner. The results indicate the suppression of proliferative activity of the bone marrow and increase in the extent of cell death. ENS and MCP showed mutagenic potential in Salmonella/ microsome assay. ENS induced mutagenic and nontoxic response only in TA98 tester strain of S.typhimurium at the dose of 500 MUg/plate and in the absence of metabolic activation. MCP showed weak mutagenic and nontoxic effect only in TA100 tester strain at the dose of 5000 MUg/plate in both assays, with or without metabolic activation when compared with negative control. MCP was toxic in TA98 tester strain at the dose of 5000 MUg/plate in absence of metabolic activation while reduction in toxicity was seen on addition of S9 mixture. The study clearly showed the genotoxic potential of all these four pesticides and mutagenic response of endosulfan and monocrotophos. PMID- 23092308 TI - Single vesicle analysis reveals nanoscale membrane curvature selective pore formation in lipid membranes by an antiviral alpha-helical peptide. AB - Using tethered sub-100 nm lipid vesicles that mimic enveloped viruses with nanoscale membrane curvature, we have in this work designed a total internal reflection fluorescence microscopy-based single vesicle assay to investigate how an antiviral amphipathic alpha-helical (AH) peptide interacts with lipid membranes to induce membrane curvature-dependent pore formation and membrane destabilization. Based on a combination of statistics from single vesicle imaging, binding kinetics data, and theoretical analysis, we propose a mechanistic model that is consistent with the experimentally observed peptide association and pore formation kinetics at medically relevant peptide concentrations (10 nM to 1 MUM) and unusually low peptide-to-lipid (P/L) ratio (~1/1000). Importantly, the preference of the AH peptide to selectively rupture virions with sub-100 nm diameters appears to be related to membrane strain dependent pore formation rather than to previously observed nanoscale membrane curvature facilitated binding of AH peptides. Compared to other known proteins and peptides, the combination of low effective P/L ratio and high specificity for nm-sized membrane curvature lends this particular AH peptide great potential to serve as a framework for developing a highly specific and potent antiviral agent for prophylactic and therapeutic applications while avoiding toxic side effects against host cell membranes. PMID- 23092309 TI - Ag nanoparticle decorated nanoporous ZnO microrods and their enhanced photocatalytic activities. AB - Nanostructured Ag nanoparticles (Ag-NPs)/nanoporous ZnO micrometer-rods (n-ZnO MRs) have been synthesized by a two-step method. The n-ZnO MRs was initially prepared by solvothermal-assisted heat treatment. The rods had the diameter ranged from 90 to 150 nm and length between 0.5 and 3 MUm. They were found to be porous and were composited of ZnO nanopartiles with size of about 20 nm. In the second stage, Ag-NPs with a diameter of 20-50 nm were anchored onto the surface of the as-prepared n-ZnO MRs by a photoreduction method. The Ag-NPs/n-ZnO MRs were evaluated for their ability to degrade methylene blue (MB) solution under visible to ultraviolet (UV) light irradiation. The rate of degradation of the as prepared Ag-NPs/n-ZnO MRs was more than twice and nearly 5.6 times faster than that of using bare n-ZnO MRs under the UV and solar light irradiation, respectively. The formation of Schottky barriers in the regions between the Ag NPs and n-ZnO MRs had improved the charge separation and consequently enhanced the efficiency of the degradation process. Moreover, the as-prepared hybrid structure exhibited high photostability, and 98% of degradation efficiency could be maintained even after being used five times. This endurance was attributed to the retardation of photocorrosion of ZnO as a result of the low concentration of surface defects in the as-prepared n-ZnO MRs. It also minimized the surface defects of the as-prepared n-ZnO MRs and consequently further inhibited the photocorrosion of ZnO when the deposited Ag-NPs were much more inclined to combine with the chemisorbed oxygen. PMID- 23092310 TI - Visual AIDS for multimodal treatment options to support decision making of patients with colorectal cancer. AB - BACKGROUND: A variety of multimodal treatment options are available for colorectal cancer and many patients want to be involved in decisions about their therapies. However, their desire for autonomy is limited by lack of disease specific knowledge. Visual aids may be helpful tools to present complex data in an easy-to-understand, graphic form to lay persons. The aim of the present study was to evaluate the treatment preferences of healthy persons and patients using visual aids depicting multimodal treatment options for colorectal cancer. METHODS: We designed visual aids for treatment scenarios based on four key studies concerning multimodal treatment of colorectal cancer. The visual aids were composed of diagrams depicting outcome parameters and side effects of two treatment options. They were presented to healthy persons (n = 265) and to patients with colorectal cancer (n = 102). RESULTS: Most patients and healthy persons could make immediate decisions after seeing the diagrams (range: 88% 100%). Patients (79%) chose the intensive-treatment option in the scenario with a clear survival benefit. In scenarios without survival benefit, all groups clearly preferred the milder treatment option (range: 78% - 90%). No preference was seen in the scenario depicting equally intense treatment options with different timing (neoadjuvant vs. adjuvant) but without survival benefit. CONCLUSIONS: Healthy persons' and patients' decisions using visual aids seem to be influenced by quality-of-life aspects rather than recurrence rates especially in situations without survival benefit. In the future visual aids may help to improve the management of patients with colorectal cancer. PMID- 23092311 TI - Effect of alpha-1-acid glycoprotein binding on pharmacokinetics and pharmacodynamics. AB - Alpha-1-acid glycoprotein (AGP, also known as AAG or orosomucoid) is an important plasma protein involved in the binding and transport of many drugs, especially basic compounds. AGP has some unique drug-binding properties that differ from those of albumin. For example, the plasma concentration of AGP is relatively low and there is only one drug-binding site in each AGP molecule. Thus, binding to AGP is saturable and displaceable. This could have potential implications for drug-drug interactions or toxicological consequences. Furthermore, AGP is an acute phase protein and the concentration of AGP in plasma can significantly increase in various diseases (such as cancer and inflammatory diseases) or following trauma (burns, surgery). Changes in AGP concentration could potentially alter the free fraction of drugs in plasma or at their target sites and eventually affect their pharmacokinetic disposition and pharmacological action. Given that an increasing number of drugs have been shown to bind preferrentially to AGP, a better understanding of this unique interaction may provide great benefit for drug discovery and development. In this review, we will focus on the effect of altered AGP binding on the pharmacokinetics and pharmacodynamics (PK/PD) of drugs, as well as the species differences in AGP binding. PMID- 23092312 TI - Coronary risk assessment among intermediate risk patients using a clinical and biomarker based algorithm developed and validated in two population cohorts. AB - BACKGROUND: Many coronary heart disease (CHD) events occur in individuals classified as intermediate risk by commonly used assessment tools. Over half the individuals presenting with a severe cardiac event, such as myocardial infarction (MI), have at most one risk factor as included in the widely used Framingham risk assessment. Individuals classified as intermediate risk, who are actually at high risk, may not receive guideline recommended treatments. A clinically useful method for accurately predicting 5-year CHD risk among intermediate risk patients remains an unmet medical need. OBJECTIVE: This study sought to develop a CHD Risk Assessment (CHDRA) model that improves 5-year risk stratification among intermediate risk individuals. METHODS: Assay panels for biomarkers associated with atherosclerosis biology (inflammation, angiogenesis, apoptosis, chemotaxis, etc.) were optimized for measuring baseline serum samples from 1084 initially CHD free Marshfield Clinic Personalized Medicine Research Project (PMRP) individuals. A multivariable Cox regression model was fit using the most powerful risk predictors within the clinical and protein variables identified by repeated cross validation. The resulting CHDRA algorithm was validated in a Multiple-Ethnic Study of Atherosclerosis (MESA) case-cohort sample. RESULTS: A CHDRA algorithm of age, sex, diabetes, and family history of MI, combined with serum levels of seven biomarkers (CTACK, Eotaxin, Fas Ligand, HGF, IL-16, MCP-3, and sFas) yielded a clinical net reclassification index of 42.7% (p < 0.001) for MESA patients with a recalibrated Framingham 5-year intermediate risk level. Across all patients, the model predicted acute coronary events (hazard ratio = 2.17, p < 0.001), and remained an independent predictor after Framingham risk factor adjustments. LIMITATIONS: These include the slightly different event definition with the MESA samples and inability to include PMRP fatal CHD events. CONCLUSIONS: A novel risk score of serum protein levels plus clinical risk factors, developed and validated in independent cohorts, demonstrated clinical utility for assessing the true risk of CHD events in intermediate risk patients. Improved accuracy in cardiovascular risk classification could lead to improved preventive care and fewer deaths. PMID- 23092314 TI - Pharmaco-economic impact of demographic change on pharmaceutical expenses in Germany and France. AB - BACKGROUND: Most European health care systems are suffering from the impact of demographic change. In short, aging of society is leading to higher costs of treatment per capita, while reproduction rates below 2.1 children per woman lead to a reduced number of younger people to provide for the necessary contributions into the health insurance system.This research paper addresses the questions what impact the demographic development will have on one particular spending area, what are pharmaceutical expenditure in two of Europe's largest health care systems, Germany and France, and what the implications are for pharmaceutical companies. METHODS: The research is based on publicly available data from German and French health ministries, the OECD, and institutes which focus on projection of demographic development in those countries. In a first step, data was clustered into age groups, and average spending on pharmaceuticals was allocated to that. In the second step, these figures were extrapolated, based on the projected change in the demographic structure of the countries from 2004 until 2050. This leads to a deeper understanding of demand for pharmaceutical products in the future due to the demographic development as a single driving factor. RESULTS: - Pharmaceutical expenses per head (patient) will grow only slightly until 2050 (0.5% p.a. in both countries). - Demographic change alone only provides for a slowly growing market for pharmaceutical companies both in Germany and in France, but for a relevant change in the consumption mix of pharmaceutical products, based on a shift of relevance of different age groups. CONCLUSIONS: Despite demographic changes pharmaceutical expenses per head (patient) and the overall pharmaceutical markets will grow only slightly until 2050 in Germany as well as in France. Nevertheless, the aging of society implies different challenges for pharmaceutical companies and also for the health care system. Companies have to cope with the shift of relevance of different age groups and within the health care system new options for financing the slowly growing expenses have to be found. PMID- 23092315 TI - Sexual dimorphism in renal heme-heme oxygenase system in the streptozotocin diabetic rats. AB - Heme Oxygenase (HO) -1 and -2 exert antioxidant, cytoprotective and vascular actions in male diabetic rats. However, there is no information about the expression and functional significance of the renal HO system in diabetic females. The present study tested the hypothesis that the HO system is differentially regulated in the kidney of female Sprague Dawley diabetic rats, protecting it from nitrosative and glomerular functional damage. Two weeks after the administration of streptozotocin (STZ; 65 mg/kg. i.p), males (DM) and females (DF) showed hyperglycemia, polyuria and elevated kidney/body weight ratio, compared to their control males (CM) and females (CF). In conscious animals, creatinine clearance was higher (0.5 +/- 00 vs. 0.3 +/- 00; ml/min/100g BW; p<0.05) and urinary albumin excretion was lower (0.7 +/- 0.3 vs 3.1 +/- 0.7; mg/day) in DF compared to DM. Acute administration of a HO inhibitor stannous mesoporphyrin (SnMP 40 mol/kg, i.v.) induced a greater renal vasoconstrictor response in DF than in DM. Western blot analysis of renal tissue revealed higher renal cortex HO-1 protein levels in DF compared to all other groups; by immunohistochemistry this induction of HO-1 in DF was localized in tubular segments and glomeruli. Furthermore, renal cortical concentration of nitrosylated protein was higher in DM than in DF animals and inversely related with HO-1 levels in both renal cortex and medulla. These data demonstrate that the HO-1 protein is induced in females, associated with renal vasodilation, decreased renal nitrosative stress and reduced albuminuria, indicating that the HO system is protecting the kidney from diabetes-induced damage specifically in females. PMID- 23092313 TI - Role of the CAI-1 fatty acid tail in the Vibrio cholerae quorum sensing response. AB - Quorum sensing is a mechanism of chemical communication among bacteria that enables collective behaviors. In V. cholerae, the etiological agent of the disease cholera, quorum sensing controls group behaviors including virulence factor production and biofilm formation. The major V. cholerae quorum-sensing system consists of the extracellular signal molecule called CAI-1 and its cognate membrane bound receptor called CqsS. Here, the ligand binding activity of CqsS is probed with structural analogues of the natural signal. Enabled by our discovery of a structurally simplified analogue of CAI-1, we prepared and analyzed a focused library. The molecules were designed to probe the effects of conformational and structural changes along the length of the fatty acid tail of CAI-1. Our results, combined with pharmacophore modeling, suggest a molecular basis for signal molecule recognition and receptor fidelity with respect to the fatty acid tail portion of CAI-1. These efforts provide novel probes to enhance discovery of antivirulence agents for the treatment of V. cholerae. PMID- 23092317 TI - Novel penetrating cations for targeting mitochondria. AB - Novel penetrating cations were used for the design of mitochondria-targeted compounds and tested in model lipid membranes, in isolated mitochondria and in living human cells in culture. Rhodamine-19, berberine and palmatine were conjugated by aliphatic linkers with plastoquinone possessing antioxidant activity. These conjugates (SkQR1,SkQBerb, SkQPalm) and their analogs lacking plastoquinol moiety (C12R1,C10Berb and C10Palm) penetrated bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria of living cells due to membrane potential negative inside. Reduced forms of SkQR1, SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In human fibroblasts SkQR1, SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by hydrogen peroxide. SkQR1 was effective at subnanomolar concentrations while SkQberb, SkQPalm and SkQ1 (prototypic conjugate of plastoquinone with dodecyltriphenylphosphonium) were effective at 10-times higher concentrations. The aliphatic conjugates of berberine and palmatine (as well as the conjugates of triphenylphosphonium) induced proton transport mediated by free fatty acids (FA) both in the model and mitochondrial membrane. In mitochondria this process was facilitated by the adenine nucleotide carrier. In contrast to the other cationic conjugates, SkQR1 and C12R1 induced FA-independent proton conductivity due to protonation/deprotonation of the rhodamine residue. This property in combination with the antioxidant activity probably makes rhodamine conjugates highly effective in protection against oxidative stress. The novel cationic conjugates described here are promising candidates for drugs against various pathologies and aging as mitochondria-targeted antioxidants and selective mild uncouplers. PMID- 23092316 TI - Hsp60, a novel target for antitumor therapy: structure-function features and prospective drugs design. AB - Heat shock protein 60 kDa (Hsp60) is a chaperone classically believed to be involved in assisting the correct folding of other mitochondrial proteins. Hsp60 also plays a role in cytoprotection against cell stressors, displaying for example, antiapoptotic potential. Despite the plethora of studies devoted to the mechanism of Hsp60's function, especially in prokaryotes, fundamental issues still remain unexplored, including the definition of its role in cancer. Key questions still unanswered pertain to the differences in structure-function features that might exist between the well-studied prokaryotic GroEL and the largely unexplored eukaryotic Hsp60 proteins. In this article we discuss these differences in sequence, structure, and roles of Hsp60, focusing on the human ortholog with the view of devising compounds to block its ability to favour tumor cell growth and survival. Compounds currently known to directly or indirectly affect Hsp60 functions, such as protein folding, HIF-1alpha accumulation, or Hsp60-induced cell proliferation, are discussed along with strategies that might prove effective for developing Hsp60-targeting drugs for anticancer therapy. PMID- 23092318 TI - The p53-p66Shc apoptotic pathway is dispensable for tumor suppression whereas the p66Shc-generated oxidative stress initiates tumorigenesis. AB - Reactive oxygen species (ROS) are regarded as hazardous by-products of mitochondrial respiration. In addition to the respiratory chain, specific ROS generating systems have evolved. In particular, p66Shc is a mitochondrial redox protein that oxidizes cytochrome c to generate H2O2. Consistently, the deletion of p66Shc in cells and tissue results in reduced levels of ROS and oxidative stress. Taking advantage of the p66Shc knock out (p66KO) mouse model of decreased ROS production, we assessed the role of endogenously-produced ROS in tumorigenesis. Spontaneous tumor incidence was investigated and found unaltered in two different strains, 129Sv and C57Bl/6J, p66KO mice. In addition, papilloma formation upon exposure to ultraviolet radiation (UV) or 7,12 Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol- 13-acetate (DMBA/TPA) was found to be slightly lower in the absence of p66Shc. The role of p66Shc in tumorigenesis was also investigated in the absence of the tumor suppressor gene p53 (p53KO) by generating p53-p66Shc double knock out (DKO) mice. Notably, DKO mice displayed a significantly increased lifespan compared to p53KO mice. In addition, 2-deoxy-2-(18F)fluoro-D-glucose Positron Emission Tomography ([18F]FDG PET) analysis allowed to determine that disease onset occurred later in life in DKO mice compared to p53KO and that a low percentage of these mice did not develop tumors. Overall, these results indicate that although tumor incidence is not decreased in p66KO mice, p66Shc contributes to tumor initiation, in particular upon activation by carcinogens as well as when p53- mediated tumor suppression mechanisms defect. PMID- 23092319 TI - Hydrogen sulfide prevents hyperoxia-induced lung injury by downregulating reactive oxygen species formation and angiopoietin-2 release. AB - Oxygen therapy is a life-sustaining treatment for patients with respiratory failure. However, prolonged exposure to high oxygen concentrations often results in hyperoxia-induced acute lung injury (HALI). At present, no effective therapeutic intervention can attenuate the development of HALI. In the present study, we investigated whether hydrogen sulfide (H2S) can confer lung protection in a mouse model of HALI. C57BL/6 mice were either exposed to room air or 90 vol% oxygen and received either the H2S donor sodium hydrosulfide (NaHS, 10 mg/kg) or vehicle. Lung injury was assessed by an HALI score in tissue sections. Bronchoalveolar lavage fluid was analyzed for protein content and cellular infiltration. Reactive oxygen species (ROS) were detected by dihydroethidium staining. Angiopoietin- 2 was detected by Western Blotting. Pulmonary epithelial, endothelial, and macrophage cells were stimulated to produce ROS either in the absence or presence of NaHS. Mice exposed to hyperoxia developed substantial lung injury, characterized by an elevated HALI score, cellular infiltration, protein leakage, ROS production, and overexpression of angiopoietin-2. NaHS treatment abolished morphological indices of HALI. Angiopoietin-2 expression was significantly reduced by NaHS in vivo. In endothelial cells and macrophages, angiopoietin-2 was released due to ROS formation and decreased in the presence of NaHS. In conclusion, H2S protects from HALI by preventing ROS production and angiopoietin-2 release. PMID- 23092320 TI - Periodontitis and redox status: a review. AB - Periodontal diseases are common inflammatory conditions of the supporting apparatus of the teeth which lead to early tooth loss. This review discusses the evidence for a role of reactive oxygen species in inducing periodontal tissue damage and focuses on recent evidence showing increased local and systemic alterations in the redox balance of periodontitis. An appraisal of the methods for analysis of oxidative stress in periodontal disease research is provided, showing an increase in oxidative stress measures and oxidative damage fingerprints detected in studies investigating periodontitis cases compared to healthy controls. Hypotheses on the relationships between oxidative stress and inflammatory responses and on the role of redox status in periodontal medicine are discussed. Finally, the review provides an overview of possible intervention pathways for the use of antioxidants as adjuncts to mechanical biofilm removal for the treatment of periodontitis. PMID- 23092321 TI - Carbon Monoxide and the brain: time to rethink the dogma. AB - Carbon Monoxide (CO), long thought to be a simple environmental pollutant is now known to have a critical role in cellular functions ranging from vasodilation to circadian rhythms. In this review, we will begin with a discussion of the enzyme responsible for CO production: heme oxygenase. Because this review will focus on the effects of CO in the brain, we will transition to CO toxicology and determine if this simple diatomic gas has really earned its nefarious reputation. An in depth analysis of the roles for CO in circadian rhythms and as a gasotransmitter will be provided in the neurological functional role section, followed by its vascular effects derived mainly from interactions with soluble guanylyl cyclase. We will then describe the evidence for CO's protective roles through the MAPK pathway, and finally touch upon the potential therapeutic roles for CO in neurological diseases including ischemic stroke, multiple sclerosis, and neuropathic pain. PMID- 23092322 TI - Regulation of autophagy in oxygen-dependent cellular stress. AB - Oxidative stress caused by supraphysiological production of reactive oxygen species (ROS), can cause cellular injury associated with protein and lipid oxidation, DNA damage, and mitochondrial dysfunction. The cellular responses triggered by oxidative stress include the altered regulation of signaling pathways that culminate in the regulation of cell survival or cell death pathways. Recent studies suggest that autophagy, a cellular homeostatic process that governs the turnover of damaged organelles and proteins, may represent a general cellular and tissue response to oxidative stress. The autophagic pathway involves the encapsulation of substrates in double-membraned vesicles, which are subsequently delivered to the lysosome for enzymatic degradation and recycling of metabolic precursors. Autophagy may play multifunctional roles in cellular adaptation to stress, by maintaining mitochondrial integrity, and removing damaged proteins. Additionally, autophagy may play important roles in the regulation of inflammation and immune function. Modulation of the autophagic pathway has been reported in cell culture models of oxidative stress, including altered states of oxygen tension (i.e., hypoxia, hyperoxia), and exposure to oxidants. Furthermore, proteins that regulate autophagy may be subject to redox regulation. The heme oxygenase- 1 (HO)-1 enzyme system may have a role in the regulation of autophagy. Recent studies suggest that carbon monoxide (CO), a reaction product of HO activity which can alter mitochondrial function, may induce autophagy in cultured epithelial cells. In conclusion, current research suggests a central role for autophagy as a mammalian oxidative stress response and its interrelationship to other stress defense systems. PMID- 23092323 TI - Reactive oxygen and nitrogen species in the renal ischemia/reperfusion injury. AB - Renal ischemia is the most common cause of acute kidney injury (AKI) still associated with high mortality rates of about 50% in the intensive care unit. Postischemic AKI is characterized by decreased glomerular filtration rate and high renal vascular resistance with endothelial activation and dysfunction, a process of critical importance that is followed by a reduction in microvascular blood flow mainly affecting the renal outer medulla. The pathophysiology of postischemic AKI remains incompletely understood, although it seems to be a phenomenon of altered renal hemodynamics, linked critically to the production of high amounts of nitric oxide and free radicals. On the other hand, and depending on the severity of renal ischemia, tubular epithelial cells undergo a varying degree of necrosis or apoptosis with tubular obstruction followed by both, anatomical and functional recovery. The way in which vascular and tubular epithelium recover determines the final status of the renal function, ranging from full recovery to chronic renal failure and ultimately to end-stage renal disease. In this review we will revise the mechanisms responsible for these pathophysiologic alterations, including the role of heme oxygenase system and sex differences in the susceptibility to ischemic acute renal failure, and we will also review the pre- and postconditioning phenomena, in which brief episodes of ischemia before (pre-conditioning) or after (post-conditioning) the prolonged ischemia have a protective effect on AKI after reperfusion. Interestingly, these protective responses can be elicited by ischemizing distant tissues (remote conditioning). A better understanding of these mechanisms may help to improve the clinical outcome of those patients. PMID- 23092324 TI - Synergistic effect of L-Carnosine and EGCG in the prevention of physiological brain aging. AB - The benefits of multi-target action are well established in a variety of pathological models. Many dietary supplements and nutraceuticals may be useful to slow age-related cognitive declines and the risk of developing neurodegenerative disease. L-Carnosine and EGCG are natural compounds that have received particular attention because of their potential role in modulating oxidative stress associated with aging and chronic conditions. The biological activities of these naturally occurring substances have frequently been used to prevent or reduce senile features; however they have never been evaluated as a combined treatment. In the present study we investigated the combined effect of L-Carnosine and EGCG on the activation of two stress-responsive pathways: HO-1 and Hsp72 (the inducible form of Hsp70), which play an important role in cytoprotection against oxidative stress-induced cell damage. We demonstrated that the neuroprotective effects of EGCG and L-Carnosine are achieved through the modulation of HO-1/Hsp72 systems. Furthermore, the combined action of both compounds resulted in a synergistic increase of HO-1 expression which suggests a crosstalk between the HO 1 and the Hsp72-mediated pathways. Our results indicate that the combined administration of EGCG and L-Carnosine would benefit the treatment and prevention of neurodegenerative diseases by reducing the neuronal damage caused by oxidative stress. PMID- 23092325 TI - Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells. AB - Identification of imatinib mesylate as a potent inhibitor of the Abl kinase and the subsequent findings that this compound displays growth inhibitory and pro apoptotic effects in Bcr-Abl+ cells, has deeply conditioned CML treatment. Unfortunately the initial striking efficacy of this drug has been overshadowed by the development of clinical resistance. A wide variety of molecular mechanisms can underlie such resistance mechanisms. In the recent years, heme oxygenase-1 (HO-1) expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress and this cytoprotective role has already been demonstrated for several solid tumors and acute leukemias. The aim of the present study was to investigate the effect of HO 1 expression on cell proliferation and apoptosis in chronic myeloid leukemia cells, K562 and LAMA-84 cell lines following imatinib treatment. Cells were incubated for 24h with Imatinib (1 MUM) alone or in combination with Hemin (10MUM), an inducer of HO-1. In addition, cells were also treated with HO byproducts, bilirubin and carbon monoxide (CO), or with a protease inhibitor (Ed64) to inhibit HO-1 nuclear translocation. Pharmacological induction of HO-1 was able to overcome the effect of imatinib. The cytoprotective effect of HO-1 was further confirmed after silencing HO-1 by siRNA. Interestingly, neither bilirubin nor CO was able to protect cells from Imatinib-induced toxicity. By contrast, the protective effect of HO-1 was mitigated by the addition of E64d, preventing HO-1 nuclear translocation. Finally, imatinib was able to increase the formation of cellular reactive oxygen species (ROS) and this effect was reversed by HO-1 induction or the addition of N-acetylcisteine (NAC). In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve its enzymatic byproducts, but rather the nuclear translocation of HO-1 following proteolytic cleavage. PMID- 23092326 TI - Ellagic acid: cytodifferentiating and antiproliferative effects in human prostatic cancer cell lines. AB - BACKGROUND: Recently, increasing attention has been given to neuroendocrine differentiation (NED) of Prostate Cancer and its diagnostic, prognostic and therapeutic potential. During multistep carcinogenesis, cytodifferentiation of malignant/premalignant cells into more mature or normal-like cells, has become an attractive modality of treatment and promises to be a less toxic and a more specific targeting strategy than conventional chemotherapy. In this study we investigated the capacity of a polyphenol, ellagic acid (EA), to induce differentiation of two prostate cancer cell lines: LnCap and DU145. METHODS: NED markers, Chromogranin A (CgA) and p75NGFR levels were evaluated by immunocytochemistry. DNA methyltransferase- 1 (DNMT-1) and phospho-Rb (p-Rb) expression were evaluated by western blotting. Akt activation was evaluated by ELISA. Finally the ability of EA to induce DNA damage in cancer cells was examined using the COMET assay. RESULTS: Treatment with EA significantly reduced CgA levels and increased p75NGFR expression. Moreover p-Rb, DNMT-1 levels and Akt activation/phosphorylation were decreased. EA treatment induced, in a dose dependent manner, a marked increase in DNA damage, both in LnCap and DU145 cell lines. CONCLUSIONS: The results of this study demonstrate that EA treatment represents a new approach and highly effective strategy in reducing carcinogenesis. Therefore, EA may be considered in a promising new class of cancer therapeutic agent, with both antiproliferative and pro-differentiation properties. PMID- 23092327 TI - Redox homeostasis and epigenetics in non-alcoholic fatty liver disease (NAFLD). AB - Non-alcoholic fatty liver disease (NAFLD), an accumulation of intra-hepatic triglycerides that is often considered the hepatic manifestation of insulin resistance, is the most common cause of chronic liver disease in the Western countries with up to one third of the population affected. NAFLD is a spectrum of disturbances that encompasses various degrees of liver damage ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH is characterized by hepatocellular injury/inflammation with or without fibrosis. The individuals with NAFLD develop NASH in 10% of the cases, and are also at risk of developing hepatocellular carcinoma (HCC). Epigenetic mechanisms of nuclear chromatin remodeling, such as DNA methylation, post-translational modifications of histones, and incorporation of histone variants into the chromatin are increasingly recognized as crucial factors in the pathophysiology of NAFLD. NAFLD is often accompanied by oxidative stress: reactive oxygen species (ROS) are implicated in altered reduction/oxidation (redox) reactions that attack cellular macromolecules and are detected in the liver of patients and animal models of NAFLD. In this review, we summarize recent knowledge advancements in the hepatic epigenetic and redox mechanisms, and their possible links, involved in the pathogenesis and treatment of NAFLD. PMID- 23092329 TI - Pharmacological and molecular targets in cellular redox status maintenance. PMID- 23092328 TI - Heme Oxygenase-1 and breast cancer resistance protein protect against heme induced toxicity. AB - Heme is the functional group of diverse hemoproteins and crucial for many cellular processes. However, heme is increasingly recognized as a culprit for a wide variety of pathologies, including sepsis, malaria, and kidney failure. Excess of free heme can be detrimental to tissues by mediating oxidative and inflammatory injury. Protective mechanisms against free heme are therefore pivotal for cellular survival. We postulated that overexpression of Heme Oxygenase-1 (HO-1) and Breast Cancer Resistance Protein (BCRP) would protect against heme-induced cytotoxicity. HO-1 is a heme-degrading enzyme generating carbon monoxide, iron, and biliverdin/bilirubin, while BCRP is a heme efflux transporter. Human embryonic kidney cells were transduced using a baculovirus system as a novel strategy to efficiently overexpress HO-1 and BCRP. Exposing cells to heme resulted in a dose-dependent increase in reactive oxygen species formation, DNA damage and cell death. Heme-induced cell death was significantly attenuated when cells overexpressed HO-1, BCRP, or both. The protective effects of HO-1 overexpression were most pronounced, while co-treatment with the HO activity inhibitor tin mesoporphyrin reversed these protective effects. Also cells treated with the anti-oxidants N-acetylcysteine or HO-effector molecule bilirubin showed protection against heme insults, which may explain the increased protection by HO-1 compared to BCRP. In conclusion, both HO-1 and BCRP protect against heme-induced toxicity and may thus form novel therapeutic targets for heme-mediated pathologies. PMID- 23092330 TI - ETM and ANN study for polysubstituted 2H-pyran-2-ones. AB - The structure glutamate pyruvate transaminase (GPT), glutamate oxaloacetate transaminase (GOT), acid phosphatase (ACP), alkaline phosphatase (ALP) and glutamate dehydrogenase (GlDH) activity relationships of 2H-pyran-2- ones polysubstitutes being a new class of hepatoprotective agents have been investigated by means of the Electronic- Topological Method (ETM) and two Statistical Analysis. Molecular fragments specific for active compounds were calculated for 2H-pyran-2-ones polysubstitutes by applying the ETM. QSAR descriptors such as molecular weight, EHOMO, ELUMO, DeltaE, chemical potential, softness, electrophilicity index, dipole moment, etc were calculated. In order to examine the relationship between independent and dependent variables, both Partial Least Squares Regression and ANNs are employed to determine the relationship since the data set consists of highly nonlinearity and multicolinearity. It is observed that ANN has surpassed both PLS2 and PLS1 in terms of better modeling and validation. PMID- 23092331 TI - Synthesis and effects of pyrazolines and isoxazoles on the phagocytic chemotaxis and release of reactive oxygen species by zymosan stimulated human neutrophils. AB - A series of novel isoxazole and pyrazoline derivatives has been synthesized and evaluated for their effects on the chemiluminescence and chemotactic activity of human phagocytes. Their effects on the chemotactic migration of isolated polymorphonuclear leukocytes (PMNs) and on the release of reactive oxygen species (ROS) during respiratory burst of human whole blood and PMNs were carried out using the Boyden chamber technique and luminol-based chemiluminescence assay, respectively. Of the compounds tested, compounds 8, 9, 11 and 12 exhibited higher inhibitory activity on the release of ROS (with IC50 values ranging from 5.6 to 8.4 MUM) than acetylsalicylic acid (IC50 = 9.5 MU M). These compounds also showed strong inhibitory activity on the migration of PMNs with compound 8 exhibiting an IC50 value lower than that of ibuprofen. The results suggest that some of these isoxazole and pyrazoline derivatives have ability to modulate the innate immune response of phagocytes at different steps, indicating their potential as a source of new immunomodulatory agents. PMID- 23092332 TI - Imidazolium hydrogen carbonates versus imidazolium carboxylates as organic precatalysts for N-heterocyclic carbene catalyzed reactions. AB - Imidazolium-2-carboxylates (NHC-CO(2) adducts, 3) and (benz)imidazolium hydrogen carbonates ([NHC(H)][HCO(3)], 4) were independently employed as organic precatalysts for various molecular N-heterocyclic carbene (NHC) catalyzed reactions. NHC-CO(2) adducts were obtained by carboxylation in THF of related free NHCs (2), while the synthesis of [NHC(H)][HCO(3)] precursors was directly achieved by anion metathesis of imidazolium halides (1) using potassium hydrogen carbonate (KHCO(3)) in methanolic solution, without the need for the prior preparation of free carbenes. Thermogravimetric analysis (TGA) and TGA coupled with mass spectrometry (TGA-MS) of most [NHC(H)][HCO(3)] precursors 4 showed a degradation profile in stages, with either a concomitant or a stepwise release of H(2)O and CO(2), between 108 and 280 degrees C, depending on the nature of the azolium and substituents. In solution, NHC generation from both [NHC(H)][HCO(3)] salts and NHC-CO(2) adducts could be achieved at room temperature, most likely by a simple solvation effect. Both types of precursors proved efficient for organocatalyzed molecular reactions, including cyanosilylation, benzoin condensation, and transesterification reactions. The catalytic efficiencies of NHC-CO(2) adducts 3 were found to be approximately 3 times higher than those of their [NHC(H)][HCO(3)] counterparts 4. PMID- 23092333 TI - TRPM channels phosphorylation as a potential bridge between old signals and novel regulatory mechanisms of insulin secretion. AB - Transient receptor potential channels, especially the members of the melastatin family (TRPM), participate in insulin secretion. Some of them are substrates for protein kinases, which are involved in several neurotransmitter, incretin and hormonal signaling cascades in beta cells. The functional relationships between protein kinases and TRPM channels in systems of heterologous expression and native tissues rise issues about novel regulation pathways of pancreatic beta cell excitability. The aim of the present work is to review the evidences about phosphorylation of TRPM channels in beta cells and to discuss the perspectives on insulin secretion. PMID- 23092335 TI - Measuring nanoscale forces with living probes. AB - Optical trapping techniques have been used to investigate fundamental biological processes ranging from the identification of the processive mechanisms of kinesin and myosin to understanding the mechanics of DNA. To date, these investigations have relied almost exclusively on the use of isotropic probes based on colloidal microspheres. However, there are many potential advantages in utilizing more complex probe morphologies: use of multiple trapping points enables control of the interaction volume; increasing the distance between the optical trap and the sample minimizes photodamage in sensitive biological materials; and geometric anisotropy introduces the potential for asymmetric surface chemistry and multifunctional probes. Here we demonstrate that living cells of the freshwater diatom Nitzschia subacicularis Hustedt can be exploited as advanced probes for holographic optical tweezing applications. We characterize the optical and material properties associated with the high shape anisotropy of the silica frustule, examine the trapping behavior of the living algal cells, and demonstrate how the diatoms can be calibrated for use as force sensors and as force probes in the presence of rat B-cell hybridoma (11B11) cells. PMID- 23092334 TI - Phosphatase of regenerating liver-3 directly interacts with integrin beta1 and regulates its phosphorylation at tyrosine 783. AB - BACKGROUND: Phosphatase of regenerating liver-3 (PRL-3 or PTP4A3) has been implicated in controlling cancer cell proliferation, motility, metastasis, and angiogenesis. Deregulated expression of PRL-3 is highly correlated with cancer progression and predicts poor survival. Although PRL-3 was categorized as a tyrosine phosphatase, its cellular substrates remain largely unknown. RESULTS: We demonstrated that PRL-3 interacts with integrin beta1 in cancer cells. Recombinant PRL-3 associates with the intracellular domain of integrin beta1 in vitro. Silencing of integrin alpha1 enhances PRL-3-integrin beta1 interaction. Furthermore, PRL-3 diminishes tyrosine phosphorylation of integrin beta1 in vitro and in vivo. With site-specific anti-phosphotyrosine antibodies against residues in the intracellular domain of integrin beta1, tyrosine-783, but not tyrosine 795, is shown to be dephosphorylated by PRL-3 in a catalytic activity-dependant manner. Phosphorylation of Y783 is potentiated by ablation of PRL-3 or by treatment with a chemical inhibitor of PRL-3. Conversely, depletion of integrin alpha1 decreases the phosphorylation of this site. CONCLUSIONS: Our results revealed a direct interaction between PRL-3 and integrin beta1 and characterized Y783 of integrin beta1 as a bona fide substrate of PRL-3, which is negatively regulated by integrin alpha1. PMID- 23092337 TI - Roles of miRNA in the initiation and development of colorectal carcinoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs exhibiting critical functions as post-transcriptional regulators. Due to the importance and extensive influence of miRNAs on genes, dysregulation of miRNAs has been associated with various types of cancer, with more prominent being colorectal carcinoma (CRC). Increasing evidence suggests that miRNAs mediate the initiation and development of CRC and also act as potential biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the miRNAs which interact with critical pathways such as p53, NF kappa B, beta-catenin pathways and also play a significant role in the regulation of EMT and maintenance of cancer stem cell. PMID- 23092336 TI - Cognitive behavioural therapy (CBT) for anxiety in people with dementia: study protocol for a randomised controlled trial. AB - BACKGROUND: Many people with dementia experience anxiety, which can lead to decreased independence, relationship difficulties and increased admittance to care homes. Anxiety is often treated with antipsychotic medication, which has limited efficacy and serious side effects. Cognitive behavioural therapy (CBT) is widely used to treat anxiety in a range of populations, yet no RCTs on CBT for anxiety in dementia exist. This study aims to develop a CBT for anxiety in dementia manual and to determine its feasibility in a pilot RCT. METHODS/DESIGN: Phase I involves the development of a CBT for anxiety in dementia manual, through a process of (1) focus groups, (2) comprehensive literature reviews, (3) expert consultation, (4) a consensus conference and (5) field testing. Phase II involves the evaluation of the manual with 50 participants with mild to moderate dementia and anxiety (and their carers) in a pilot, two-armed RCT. Participants will receive either ten sessions of CBT or treatment as usual. Primary outcome measures are anxiety and costs. Secondary outcome measures are participant quality of life, behavioural disturbance, cognition, depression, mood and perceived relationship with the carer, and carer mood and perceived relationship with the person with dementia. Measures will be administered at baseline, 15 weeks and 6 months. Approximately 12 qualitative interviews will be used to gather service-users' perspectives on the intervention. DISCUSSION: This study aims to determine the feasibility of CBT for people with anxiety and dementia and provide data on the effect size of the intervention in order to conduct a power analysis for a definitive RCT. The manual will be revised according to qualitative and quantitative findings. Its publication will enable its availability throughout the NHS and beyond. TRIAL REGISTRATION: ISRCTN64806852. PMID- 23092338 TI - Therapeutically targeting microRNAs in liver cancer. AB - MicroRNAs are small non-coding RNAs that negatively regulate gene expression through binding on the 3' untranslated region (UTR) of genes. Although microRNAs constitute a small fraction of the human genome, multiple studies have indicated their involvement in the pathogenesis of different types of cancer. Hepatocellular carcinoma (liver) is one of the most aggressive types of cancer with very few therapeutic options. Several studies have revealed that microRNAs are deregulated during liver cancer development and affect central oncogenic and anti-apoptotic liver cancer signaling pathways. Furthermore, the expression levels of specific microRNAs have been identified to be correlated with clinicopathological parameters and treatment responses in liver cancer patients. Here, we review how different epidemiological and liver cancer risk factors, such as the hepatitis B and C viruses, deregulate microRNA-gene circuits in the liver, contributing to liver cancer development. Furthermore, we describe how the most frequently deregulated microRNAs identified in liver cancer patients control their down-stream signaling pathways in liver cancer cells. In addition, we provide examples of microRNAs or microRNA inhibitors that have been used as liver cancer therapeutics and describe novel delivery technologies that could be potentially used in order to optimize the delivery of microRNAs in the liver without having any toxicity or side effects in other major organs. Taken together, there is ample evidence suggesting the deregulation of microRNA-gene circuits in liver, promising that the development of microRNA-based therapeutics could be a clinically viable approach for liver cancer patients. PMID- 23092340 TI - The role of microRNAs in the pathogenesis and treatment of hematopoietic malignancies. AB - microRNAs (miRNAs) comprise a recently discovered class of non-coding RNAs with regulatory functions in post-transcriptional gene expression control. Many miRNAs are located in genomic regions that are frequently deleted in cancer, or are subject to epigenetic and transcriptional deregulation in cancer cells. The miRNA transcriptome of cancer cells is very different from that of their normal cell counterparts. miRNAs can exhibit oncogenic or tumor suppressive or even both properties depending on the specific targets and cellular context. It is becoming increasingly clear that miRNAs not only serve as useful tumor biomarkers with implications for diagnosis, prognosis and the prediction of treatment responses, but may also be used for targeted cancer treatment and even as therapeutics. In this review, we provide an overview of recent advances in our understanding of the tumor suppressor miRNAs and oncomiRs involved in the pathogenesis of leukemias and lymphomas, and their target transcripts in cancer signaling networks. In particular, we focus on the role of miRNAs in chronic lymphocytic and acute lymphoblastic leukemia and in B-cell lymphomas. In the second part, we review the various alternative strategies of targeting miRNAs in cancer therapy. Methods of oncomiR antagonization by antagomiRs or locked nucleid acids are contrasted with strategies that harness the tumor suppressive properties of certain miRNAs for cancer treatment. Preclinical progress, also with regard to delivery strategies, possible side effects and other pharmacological aspects, is presented along with results from the first human trials assessing the safety and efficacy of miRNA-targeting therapeutics. PMID- 23092339 TI - Epigenetic deregulation of microRNAs: new opportunities to target oncogenic signaling pathways in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the few cancers with a worldwide increasing trend of incidence, representing the third largest cause of cancer related death. The initiation and progression of HCC depend on progressive accumulation of genetic and epigenetic defects that alter an array of signaling cascades via deregulation of signal activators and inhibitors. MicroRNAs (miRNAs) are small RNA molecules that post-transcriptionally repress gene expression including those signal molecules and thus are critical for many cellular pathways. However, the balance of this fine-tuning function is broken by the abnormal expression of miRNAs in various cancers through genomic alterations or epigenetic mechanisms. This review summarizes the current knowledge of the role of epigenetic aberrations, including histone methylation and deacetylation as well as DNA hypermethylation and hypomethylation in the aberrant regulation of miRNAs leading to activation of signaling pathways such as Ras, STAT3 and AKT/mTOR in HCC. Conceivably, the therapeutic efficacy of current chromatin modifying drugs might be related to their capacity to reactivate previously silenced tumor-suppressive miRNAs and cause down-regulation of target oncogenes. Better understanding of the epigenetics-miRNA regulatory cascades in the control of the functionally significant pathways will provide new opportunities for the development of more effective therapeutic modality for HCC. PMID- 23092341 TI - miRNAs in gastrointestinal and liver cancers: their perspectives and clinical applications. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post transcriptionally. They have been found to be dysregulated in many pathological conditions including cancer and play an important role during the progression of such disease. Recent efforts have been directed in translating the primary findings of miRNAs into clinical uses. This article gives a general overview on the potential of miRNAs as diagnostic and prognostic markers and also as therapeutic targets for gastrointestinal and liver cancers in animals and humans. Other contributors in this special series would focus in discussing the roles of specific miRNAs and their pathogenic mechanisms and therapeutic applications in different types of cancer in the gastrointestinal tract and liver. PMID- 23092342 TI - MicroRNAs and esophageal cancer--implications for pathogenesis and therapy. AB - There are several microRNAs that have been consistently reported to be differentially expressed in esophageal squamous cell carcinoma vs. normal squamous tissue, with prognostic associations for miR-21 (invasion, positive nodes, decreased survival), miR-143 (disease recurrence, invasion depth), and miR 375 (inversely correlated with advanced stage, distant metastasis, poor overall survival, and disease-free survival). There is also evidence that miR-375 regulates gene expression associated with resistance to chemotherapy. Hence, microRNA expression assays have the potential to provide clinically relevant information about prognosis and potential response to chemotherapy in patients with esophageal squamous cell carcinoma. Results are inconsistent, however, for microRNAs across different studies for esophageal adenocarcinoma (EAC) vs. its precursor lesion Barrett's esophagus. These inconsistencies may partly result from pathological and/or molecular heterogeneity in both Barrett's esophagus and EAC, but may also result from differences in study designs or different choices of comparator tissues. Despite these inconsistencies, however, several mRNA/protein targets have been identified, the cancer related biology of some of these targets is well understood, and there are clinico-pathological associations for some of these mRNA targets. MicroRNAs also have potential for use in therapy for esophageal cancers. The development of new delivery methods, such as minicells and autologous microvesicles, and molecular modifications such as the addition of aromatic benzene pyridine analogs, have facilitated the exploration of the effects of therapeutic microRNAs in vivo. These approaches are producing encouraging results, with one technology in a phase I/IIa clinical trial. PMID- 23092343 TI - MicroRNA involvement in gastrointestinal stromal tumor tumorigenesis. AB - Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The molecular mechanism of GIST formation is among the best characterized of all human tumors. Activating mutations of the c-Kit-kinase (KIT), a member of the receptor tyrosine kinase III family, are present in 80% of GISTs. Gain-of-function mutations of platelet-derived growth factor receptor A (PDGFRA), a member of the same kinase family, are present in 35% of GISTs that lack KIT mutations. These mutations induce the overexpression and autophosphorylation of KIT and PDGFRA, and result in the activation of downstream signaling pathways. Imatinib, a KIT receptor inhibitor, was developed to treat GIST patients by inactivating signaling pathways. However, some GISTs, especially cases with mutations in exon 13 and 17 of KIT, are resistant to imatinib treatment. Therefore, another approach is needed to develop drugs for GIST treatment. Data also support dysregulation of microRNAs in the progression of many types of cancers. Studies demonstrate that microRNAs directly regulate KIT expression levels in GISTs, and inhibit GIST cell proliferation. This review summarizes the characteristics of GISTs, their molecular and clinical implications, the role of microRNAs in GIST tumorigenesis, and their possible therapeutic potential. PMID- 23092344 TI - Roles of miRNA in the initiation and development of colorectal carcinoma. AB - MicroRNAs (miRNAs) are small non-coding RNAs exhibiting critical functions as post-transcriptional regulators. Due to the importance and extensive influence of miRNAs on genes, dysregulation of miRNAs has been associated with various types of cancer, with more prominent being colorectal carcinoma (CRC). Increasing evidence suggests that miRNAs mediate the initiation and development of CRC and also act as potential biomarkers for both diagnosis and prognosis. In this review, we summarize the recent advancement of miRNA research in CRC, in particular, the miRNAs which interact with critical pathways such as p53, NF kappa B, beta-catenin pathways and also play a significant role in the regulation of EMT and maintenance of cancer stem cell. PMID- 23092345 TI - The expression patterns and clinical significance of microRNAs in liver diseases and hepatocellular carcinoma. AB - MicroRNAs (miRNAs) are approximately 22-nucleotide noncoding RNAs that constitute silencers of target gene expression and have emerged as key regulatory molecules of mammalian cell functions. Aberrant miRNA expression promotes pathologic conditions including hepatocellular carcinoma (HCC) and a variety of precancerous liver diseases, especially chronic hepatitis B and C, and liver cirrhosis. miRNAs may contribute to HCC development by acting as oncogenes or tumor suppressors. Specific alterations of miRNA expression have also been related to clinical features of HCC, such as stage, differentiation, prognosis, and response to adjuvant therapy. miRNA signatures may help define molecular profiles of liver diseases as biomarkers, and allow classification of different stages of cirrhosis and HCC progression. Either miRNAs, or anti-miRNA oligonucleotides (antagomirs) could be used for in vivo modulation of miRNA actions, and thus have significant potential in molecularly targeted therapy. PMID- 23092346 TI - MicroRNA dysregulation in gastric cancer. AB - Gastric carcinogenesis is a complex multistep process involving genetic dysregulation of proto-oncogenes and tumorsuppressor genes, and has recently entered the era of microRNAs (miRNAs), a class of small non-coding RNAs that posttranscriptionally regulate gene expression and control various cellular functions. MicroRNAs are small (approximately 22 nucleotides) non-coding RNAs that play fundamental roles in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. MicroRNAs have been revealed to be involved in various stages of cancer development, showing that abnormal miRNA expressions play critical roles in modulating expression of known oncogenes or tumor suppressor genes during cancer progression. Therefore, microRNAs can perform the function of onco-miRs or tumor suppressor-miRs in gastric carcinogenesis. This review summarizes a current understanding of the connection between miRNAs and gastric cancer. Additionally, this paper outlines the applications of miRNAs in clinical practice, such as diagnosis, prognosis, detection, and therapy of gastric cancer. PMID- 23092347 TI - MicroRNA dysregulation in esophageal neoplasia: the biological rationale for novel therapeutic options. AB - While the phenotypic changes involved in the esophageal oncogenic "cascade" are now well established, the molecular profiling of this pathway remains unreliable. Our understanding of the molecular dysregulations underlying the development/progression of cancer has recently been expanded by the characterization of a new class of small, noncoding RNA gene products, the microRNAs (or miRNAs). These "endogenous silencers" target a large number of genes, functioning as tumor suppressors or tumor promoters, depending on the activity of the targeted genes. In esophageal cancer, miRNA dysregulation plays a significant part in the molecular oncogenic pathway, in cancer prognosis, and in patients' responsiveness to neo-adjuvant and adjuvant therapies. In addition to these valuable features, miRNAs have been proposed as innovative therapeutics per se and as plausible biological targets in new treatment strategies. PMID- 23092348 TI - MicroRNAs: small molecules with a potentially role in oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC) is one of the most common cancers worldwide. MicroRNAs (miRNAs) are small noncoding RNAs that post-transcriptionally modulate gene expression by degrading or repressing the translation of target messenger RNAs (mRNA). Aberrant miRNA expression has been reported in OSCC, and this altered expression may be useful for the early detection of oral cancer. In this review we highlight the miRNAs profile of OSCC, the possible mechanisms underlying their altered expression together with their function in oral cancer development and progression. The modulation of miRNAs makes these small molecules potential markers for early oral cancer diagnosis and prognostic prediction as well as potential molecular tools for its treatment. Translational studies focusing on miRNAs could lead to the development of new tools for the management of patients with OSCC. PMID- 23092349 TI - MicroRNA in the pathogenesis and prognosis of esophageal cancer. AB - Esophageal cancer (EC) is a deadly disease. EC usually occurs as either adenocarcinoma (EAC) or squamous cell carcinomas (ESCC). The development of EAC generally follows the metaplasia-dysplasia-carcinoma sequence. Barrett's esophagus (BE) is a metasplastic precursor of EAC. Multiple global miRNA expression profiling and candidate gene studies have been performed in EAC and ESCC that clearly support the important roles of miRNAs in the pathogenesis of EAC and ESCC. A number of consistently dysregulated miRNAs have been identified in EAC and/or ESCC, including upregulation of miR-21, miR-192, miR-194, miR-106 25 polycistron (miR-25, miR-93, and miR-106b), miR-10b, miR-151, and miR-93, and downregulation of miR-375, miR-203, miR-205, miR-145, miR- 27b, miR-100, miR 125b, let-7c, etc. Most of these miRNAs are also dysregulated in other cancer types and their target genes have been extensively studied in different cancers. The prognostic value of miR-21 and miR-375 has been replicated in independent studies. Circulating miRNAs as potential biomarkers for early detection, prognosis, and treatment response have only been scarcely studied in EC. The association of genetic variations in miRNA regulatory pathway with EC risk or outcome is a largely uncharted territory. Future studies should be focused on the role of miRNAs in the prognosis of EC, the identification of circulating miRNAs and miRNA-related genetic variations as biomarkers in EC, and the biological mechanisms underlying the contribution of miRNA dysreguation to EC. A better understanding of roles of miRNA in EC developemnt may provide new avenues for the early detection, diagnosis, prognosis, and therapy of this deadly disease. PMID- 23092350 TI - Editorial: miRNA in the pathogenesis and therapy for gastrointestinal and hepatic cancers. PMID- 23092351 TI - Nanotwinning and structural phase transition in CdS quantum dots. AB - Nanotwin structures are observed in high-resolution transmission electron microscopy studies of cubic phase CdS quantum dots in powder form by chemical co precipitation method. The deposition of thin films of nanocrystalline CdS is carried out on silicon, glass, and TEM grids keeping the substrates at room temperature (RT) and 200 degrees C by pulsed laser ablation. These films are then subjected to thermal annealing at different temperatures. Glancing angle X-ray diffraction results confirm structural phase transitions after thermal annealing of films deposited at RT and 200 degrees C. The variation of average particle size and ratio of intensities in Raman peaks I2LO/I1LO with annealing temperature are studied. It is found that electron-phonon interaction is a function of temperature and particle size and is independent of the structure. Besides Raman modes LO, 2LO and 3LO of CdS at approximately 302, 603, and 903 cm-1 respectively, two extra Raman modes at approximately 390 and 690 cm-1 are studied for the first time. The green and orange emissions observed in photoluminescence are correlated with phase transition. PMID- 23092352 TI - Drug discovery and development.Preface. PMID- 23092353 TI - Submovement organization, pen pressure, and muscle activity are modulated to precision demands in 2D tracking. AB - The authors investigated how tracking performance, submovement organization, pen pressure and muscle activity in forearm and shoulder muscles were affected by target size in a 2D tracking task performed with a pen on a digitizer tablet. Twenty-six subjects took part in an experiment, in which either a small dot or a large dot was tracked, while it moved quasirandomly across a computer screen at a constant velocity of 2 cm/s. The manipulation of precision level was successful, because mean distance to target and the standard deviation of this distance were significantly smaller with the small target than with the large target. With a small target, subjects trailed more behind the center of target and used submovements with larger amplitudes and of shorter duration, resulting in higher tracking accuracy. This change in submovement organization was accompanied by higher pen pressure, while at the same time muscle activity in the forearm extensors and flexors was increased, indicating higher endpoint stability. In conclusion, increased precision demands were accommodated by both a different organization of submovements and higher endpoint stability in a 2D tracking task performed with a pen on a digitizer tablet. PMID- 23092354 TI - (IP)2Ga(III) complexes facilitate net two-electron redox transformations (IP = alpha-iminopyridine). AB - Reaction of M(+)[(IP(2-))(2)Ga](-) (IP = iminopyridine, M = Bu(4)N, 1a; (DME)(3)Na, 1b) with pyridine N-oxide affords two-electron-oxidized (IP( ))(2)Ga(OH) (2) in reactions where the product outcome is independent of the cation identity, M(+). In a second example of net two-electron chemistry, outer sphere oxidation of M(+)[(IP(2-))(2)Ga](-) using either 1 or 2 equiv of the one electron oxidant ferrocenium afforded [(IP(-))(2)Ga](+) (3) in either 44 or 87% yield, respectively. Reaction with 1 equiv of TEMPO, a one-electron oxidant, afforded the two-electron-oxidized product (IP(-))(2)Ga(TEMPO) (4). Reduction of 2IP by 3Na and subsequent reaction with GaCl(3) yielded a 1:1 mixture of (IP( ))(2)GaCl and 1. Most remarkably, all of these reactions are overall two-electron processes and only the (IP(-))(2)GaX and [(IP(2-))(2)Ga](-) oxidation states are thermodynamically accessible to us. Analogous aluminum chemistry previously afforded either one-electron or two-electron reactions and mixed-valent states. The thermodynamic accessibility of the mixed-valent states of (IP(2-))(IP(-))E, where E = Al or Ga, can be compared using cyclic voltammetry measurements. These measurements indicated that the mixed-valent state [(IP(2-))(IP(-))Ga](+) is not significantly stabilized with respect to disproportionation on the time scale of the electrochemistry experiment. The electrochemically observed differences in thermodynamic stability of the mixed-valent state [(IP(2-))(IP(-))E](+) can be rationalized by the observation that the dihedral angle between the ligand planes containing the pi-system of IP is roughly 5 degrees larger in all gallium complexes compared with aluminum analogs. Presumably, a larger dihedral angle provides weaker electronic coupling between the pi-systems of IP via the E-X sigma* orbital. Alternatively, the observed difference may be a result of the "inert pair effect": a contracted Ga component in the E-X sigma* orbital would also afford weaker electronic coupling. PMID- 23092355 TI - Large assembly formation via a two-step process in a chromonic liquid crystal. AB - IR-806 is a near-infrared cyanine dye that forms assemblies in aqueous solutions which in turn orientationally order into a liquid crystal phase at concentrations as low as 0.5 wt %. Unlike many chromonic liquid crystals, the absorption spectrum of IR-806 changes dramatically with concentration, showing an isodesmic assembly process at lower concentrations followed by a second process at higher concentrations that is not isodesmic. The lower concentration assembly process is characterized by a free energy change per molecule of about 9 k(B)T, not unlike other chromonic systems. However, X-ray scattering measurements suggest that the assemblies that form during the higher concentration process are much larger than what is observed for many chromonic liquid crystals. Although there is a transitional region between the liquid crystal and isotropic phases of 10-15 degrees C, unlike most chromonic liquid crystals, no biphasic region is observed using polarizing microscopy. PMID- 23092356 TI - Neural activity in superior parietal cortex during rule-based visual-motor transformations. AB - Cognition allows for the use of different rule-based sensorimotor strategies, but the neural underpinnings of such strategies are poorly understood. The purpose of this study was to compare neural activity in the superior parietal lobule during a standard (direct interaction) reaching task, with two nonstandard (gaze and reach spatially incongruent) reaching tasks requiring the integration of rule based information. Specifically, these nonstandard tasks involved dissociating the planes of reach and vision or rotating visual feedback by 180 degrees . Single unit activity, gaze, and reach trajectories were recorded from two female Macaca mulattas. In all three conditions, we observed a temporal discharge pattern at the population level reflecting early reach planning and on-line reach monitoring. In the plane-dissociated task, we found a significant overall attenuation in the discharge rate of cells from deep recording sites, relative to standard reaching. We also found that cells modulated by reach direction tended to be significantly tuned either during the standard or the plane-dissociated task but rarely during both. In the standard versus feedback reversal comparison, we observed some cells that shifted their preferred direction by 180 degrees between conditions, reflecting maintenance of directional tuning with respect to the reach goal. Our findings suggest that the superior parietal lobule plays an important role in processing information about the nonstandard nature of a task, which, through reciprocal connections with precentral motor areas, contributes to the accurate transformation of incongruent sensory inputs into an appropriate motor output. Such processing is crucial for the integration of rule-based information into a motor act. PMID- 23092357 TI - Orienting block copolymer microdomains with block copolymer brushes. AB - A simple, rapid, and robust technique for controlling the self-assembly of block copolymers (BCPs) with a large segmental interaction parameter, chi, is described using a surface modified with anchored BCP brushes. End-functionalized poly(styrene-b-ethylene oxide)s (PS-b-PEOs), where the fraction of PS (f(PS)) was varied, end-functionalized neat PS, and end-functionalized neat PEO were end grafted onto Si substrates modifying the surface with polymer brushes. Thin films of cylinder-forming PS-b-PEO were prepared on modified Si substrates and thermally annealed. When neat PS and PEO were used as the anchored brushes, the microdomains of the PS-b-PEO oriented parallel to the substrate upon thermal annealing due to the preferential interactions of one block to the anchored brushes. However, when end-functionalized PS-b-PEOs were used to modify the substrate, hexagonally packed cylindrical PEO microdomains oriented normal to the substrate, having long-range lateral ordering, were obtained over a very wide range of f(PS) (0.32 to 0.77). PMID- 23092358 TI - Ability of a biomarker-based score to predict death from circulatory disease and cancer in NHANES III. AB - BACKGROUND: A score based on serum concentrations of C-reactive protein (CRP), albumin, gamma-glutamyl transferase (GGT), and HDL cholesterol was positively associated with death from cancer, circulatory disease, and all-cause mortality. We replicated this in the third National Health and Nutrition Examination Survey (NHANES III), a US nationally representative survey conducted between 1988-1994. METHODS: Baseline measurements of CRP, albumin, GGT, and HDL were available for participants with mortality follow-up (n=13,056). A biomarker score, ranging 0-4, was created by adding number of markers with abnormal values (cut-off: CRP>10mg/L, albumin<35mg/L, GGT>36U/L, HDL<1.04mmol/L). Its association with mortality was analyzed with multivariate Cox proportional hazards models. RESULTS: The score was positively associated with death from all causes, cancer and circulatory disease [e.g. HR all-cause mortality: 1.21 (95% CI: 1.09, 1.35), 1.92 (1.67, 2.20), 3.38 (2.62, 4.36), and 7.93 (5.77, 10.89), for score 1, 2, 3, 4 vs.0]. These patterns were found across the Charlson Comorbidity Index (CCI). Where CCI =3, risk of cancer death was 1.09 (0.93, 1.28), 1.81 (1.43, 2.29), 4.67 (3.05, 7.14), and 6.97 (5.32, 9.14) for score 1, 2, 3, 4 vs. 0. No effect modification by sex or race/ethnicity was observed. CONCLUSIONS: These findings correlate with results from a Swedish study. This biomarker-based score could help clinicians make decisions in prevention and disease management. PMID- 23092359 TI - Hierarchically structured metal oxide/silica nanofibers by colloid electrospinning. AB - We present herein a new concept for the preparation of nanofibrous metal oxides based on the simultaneous electrospinning of metal oxide precursors and silica nanoparticles. Precursor fibers are prepared by electrospinning silica nanoparticles (20 nm in diameter) dispersed in an aqueous solution of poly(acrylic acid) and metal salts. Upon calcination in air, the poly(acrylic acid) matrix is removed, the silica nanoparticles are cemented, and nanocrystalline metal oxide particles of 4-14 nm are nucleated at the surface of the silica nanoparticles. The obtained continuous silica fibers act as a structural framework for metal oxide nanoparticles and show improved mechanical integrity compared to the neat metal oxide fibers. The hierarchically nanostructured materials are promising for catalysis applications, as demonstrated by the successful degradation of a model dye in the presence of the fibers. PMID- 23092360 TI - General synthesis of beta-alanine-containing spider polyamine toxins and discovery of nephila polyamine toxins 1 and 8 as highly potent inhibitors of ionotropic glutamate receptors. AB - Certain spiders contain large pools of polyamine toxins, which are putative pharmacological tools awaiting further discovery. Here we present a general synthesis strategy for this class of toxins and prepare five structurally varied polyamine toxins. Electrophysiological testing at three ionotropic glutamate receptor subtypes reveals that two of these, Nephila polyamine toxins 1 (NPTX-1) and 8 (NPTX-8), comprise intriguing pharmacological activities by having subnanomolar IC(50) values at kainate receptors. PMID- 23092361 TI - Reactive molecular dynamics of the initial oxidation stages of Ni111 in pure water: effect of an applied electric field. AB - Corrosion processes occurring in aqueous solutions are critically dependent upon the interaction between the metal electrode and the solvent. In this work, the interaction of a nickel substrate with water molecules has been investigated using reactive force field (ReaxFF) molecular dynamics simulations. This approach was originally developed by van Duin and co-workers to study hydrocarbon chemistry and the catalytic properties of organic compounds. To our knowledge, this method has not previously been used to study the corrosion of nickel. In this work, we studied the interaction of 480 molecules of water (rho = 0.99 g.cm( 3)) with Ni(111) surfaces at 300 K. The results showed that a water "bilayer" was adsorbed on the nickel surface. In the absence of an applied electric field, no dissociation of water was observed. However, the nickel atoms at the surface were charged positively, whereas the first water layer was charged negatively, indicating the formation of an electric double layer. To study the corrosion of nickel in pure water, we introduced an external electric field between the metal and the solution. The electric field intensity varied between 10 and 20 MeV/cm. The presence of this electric field led to oxidation of the metal surface. The structural and morphological differences associated with the growth of this oxide film in the presence of the electric field were evaluated. The simulated atomic trajectories were used to analyze the atomic displacement during the reactive process. The growth of the oxide scale on the nickel surface was primarily due to the movement of anions toward the interior of the metal substrate and the migration of nickel toward the free surface. We found that increasing the electric field intensity sped up the corrosion of nickel. The results also showed that the oxide film thickness increased linearly with increasing electric field intensity. PMID- 23092363 TI - Treatment of obstructive sleep apnea in infants with trisomy 21 using oral appliances. AB - Objective : To perform a retrospective study to evaluate the effect of oral appliances, aimed at increasing the pharyngeal space, on obstructive sleep apnea (OSA) in infants with trisomy 21 (TS21). Design and Setting : Retrospective study in a tertiary referral center. Intervention : We analyzed data from 51 consecutive infants (mean age, 2.7 months) who underwent polysomnography (PSG) and were offered our treatment concept. Primary study variable was the mixed obstructive apnea index (MOAI); OSA was defined as a MOAI >= 1. Results : Twenty seven infants (53%) had OSA. Their median MOAI improved from 2.3 (1 to 13) to 0 (0 to 0.2; P < .05). Seven of these infants were treated with an appliance that included some type of velar extension to move the tongue base forward. Of the 24 infants without OSA at admission, follow-up PSG results were available for 13. Three infants from this group had developed OSA by the time of a repeat PSG. Conclusion : In patients with TS21, OSA may already develop in infancy. Early treatment may improve OSA. Oral appliances with some type of velar extension may be considered as an alternative to other treatment procedures. PMID- 23092362 TI - High-risk long QT syndrome mutations in the Kv7.1 (KCNQ1) pore disrupt the molecular basis for rapid K(+) permeation. AB - Type 1 long QT syndrome (LQT1) is caused by loss-of-function mutations in the KCNQ1 gene, which encodes the K(+) channel (Kv7.1) that underlies the slowly activating delayed rectifier K(+) current in the heart. Intragenic risk stratification suggests LQT1 mutations that disrupt conserved amino acid residues in the pore are an independent risk factor for LQT1-related cardiac events. The purpose of this study is to determine possible molecular mechanisms that underlie the loss of function for these high-risk mutations. Extensive genotype-phenotype analyses of LQT1 patients showed that T322M-, T322A-, or G325R-Kv7.1 confers a high risk for LQT1-related cardiac events. Heterologous expression of these mutations with KCNE1 revealed they generated nonfunctional channels and caused dominant negative suppression of WT-Kv7.1 current. Molecular dynamics simulations of analogous mutations in KcsA (T85M-, T85A-, and G88R-KcsA) demonstrated that they disrupted the symmetrical distribution of the carbonyl oxygen atoms in the selectivity filter, which upset the balance between the strong attractive and K(+)-K(+) repulsive forces required for rapid K(+) permeation. We conclude high risk LQT1 mutations in the pore likely disrupt the architectural and physical properties of the K(+) channel selectivity filter. PMID- 23092364 TI - The ionic liquid 1-alkyl-3-methylimidazolium demonstrates comparable antimicrobial and antibiofilm behavior to a cationic surfactant. AB - Biofilms are problematic in health and industry because they are resistant to various antimicrobial treatments. Ionic liquids are a novel class of low temperature liquid salts consisting of discrete anions and cations, and have attracted considerable interest as safer alternatives to organic solvents. Ionic liquids have interesting antimicrobial properties and some could find use in the development of novel antiseptics, biocides and antifouling agents. The antimicrobial and antibiofilm activity of 1-dodecyl-3-methylimiazolium iodide ([C(12)MIM]I) was studied using the clinically important bacterial pathogens, Staphylococcus aureus SAV329 and Pseudomonas aeruginosa PAO1. The ionic liquid increased cell membrane permeability in both S. aureus and P. aeruginosa cells and impaired their growth, attachment and biofilm development. The ionic liquid exhibited superior antimicrobial and antibiofilm activity against the Gram positive S. aureus compared to the Gram-negative P. aeruginosa cells. BacLightTM staining and confocal microscope imaging confirmed that the ionic liquid treatment increased the cell membrane permeability of both the Gram-positive and Gram-negative bacteria. In addition, the antimicrobial and antibiofilm properties of [C(12)MIM]I were similar or superior to those of cetyltrimethylammonium bromide (CTAB), a well-known cationic surfactant. It is concluded that the ionic liquid induced damage to bacterial cells by disrupting cell membrane, leading to inhibition of growth and biofilm formation. Overall, the results indicate that the ionic liquid 1-dodecyl-3-methylimiazolium iodide was effective in preventing S. aureus and P. aeruginosa biofilms and could have applications in the control of bacterial biofilms. PMID- 23092365 TI - Allopurinol hypersensitivity reactions: desensitization strategies and new therapeutic alternative molecules. AB - Allopurinol, an analog of hypoxanthine has been worldwide used for the treatment of hyperuricemia and gout for over 40 years. Unfortunately some patients assuming this medication have developed hypersensitivity reactions ranging from mild cutaneous eruption to more severe clinical manifestations such as allopurinol hypersensitivity syndrome or Steven-Johnson syndrome and lethal toxic epidermal necrolysis. Various strategies of slow desensitization have been elaborated to reintroduce allopurinol in a part of these patients, mainly patients affected by mild skin reactions as fixed drug eruption or exanthema. However, several new uricosuric therapies have been recently introduced. Actually drugs as recombinant urate oxidase and febuxostat are under post-marketing surveillance to control potential adverse effects related to their immunogenicity even. PMID- 23092366 TI - Factors influencing the development of evidence-based practice among nurses: a self-report survey. AB - BACKGROUND: Health authorities in several countries have decided that the health care services should be evidence-based. Recent research indicates that evidence based practice may be more successfully implemented if the interventions overcome identified barriers. AIMS: The present study aimed to examine factors influencing the implementation of evidence-based practice among nurses in a large Norwegian university hospital. METHODS: Cross-sectional data was collected from 407 nurses during the period November 8 to December 3, 2010, using the Norwegian version of Developing Evidence-based Practice questionnaire (DEBP). The DEBP included data on various sources of information used for support in practice, on potential barriers for evidence-based practice, and on self-reported skills on managing research-based evidence. The DEBP was translated into Norwegian in accordance with standardized guidelines for translation and cultural adaptation. RESULTS: Nurses largely used experienced-based knowledge collected from their own observations, colleagues and other collaborators for support in practice. Evidence from research was seldom used. The greatest barriers were lack of time and lack of skills to find and manage research evidence. The nurse's age, the number of years of nursing practice, and the number of years since obtaining the last health professional degree influenced the use of sources of knowledge and self-reported barriers. Self-reported skills in finding, reviewing and using different sources of evidence were positively associated with the use of research evidence and inversely related to barriers in use of research evidence. CONCLUSION: Skills in evidence-based practice seem to reduce barriers to using research evidence and to increase use of research evidence in clinical practice. PMID- 23092368 TI - Concise total synthesis and stereochemical analysis of tetraponerines T3 and T4. AB - An efficient stereocontrolled preparation of tetraponerines T3 and T4 is detailed. The sequence takes advantage of two consecutive stereoselective aminoallylations of appropriate aldehydes with chiral tert-butanesulfinamide and in situ generated allyl indium species. The absolute configuration of the carbon stereogenic center at the aminal moiety is thermodynamically controlled. This was ascertained on the basis of an exhaustive DFT configurational study of tetraponerines, which fulfils the lack of detailed structural information for these systems. It was found that the trans-transoid-configuration of the AB rings is the most stable geometry for T3 and T4. However, the C ring prefers a cis configuration in T3 (ttc-T3) and a trans-fusion in T4 (ttt-T4). Regarding their dynamic behavior, low activation barriers were found by DFT calculations for the inversion of the nitrogen at the indolizidine framework, allowing rapid equilibration between the major configurations (ttc and ttt) in T3 and T4. PMID- 23092367 TI - Association between faecal load of lawsonia intracellularis and pathological findings of proliferative enteropathy in pigs with diarrhoea. AB - BACKGROUND: The study was designed to investigate correlation between histological findings of Lawsonia intracellularis in porcine cases of diarrhoea and the quantitative detection of Lawsonia intracellularis in faeces. A total of 156 pigs (10 to 70 days post weaning) with diarrhoea were randomly selected from 20 herds: The pigs were subjected to necropsy, histopathology, immunohistochemistry and faecal quantification of Lawsonia intracellularis by real time PCR. RESULTS: The median Lawsonia intracellularis excretion was significantly higher in pigs with gross lesions of proliferative enteropathy (median excretion: 5.92 log10 bacteria/g faeces) compared to pigs without gross lesions of proliferative enteropathy (median excretion: <3.3 log10 bacteria/g faeces) (P<0.001). Spearman's correlation coefficient between the measureable PE lesions and L. intracellularis excretion was 0.50 (P<0.001). A significantly increasing trend in Lawsonia intracellularis excretion level for increasing proliferative enteropathy histopathology and immunohistochemistry scores was demonstrated (P<0.001; P<0.001). Spearman's correlation coefficient between the histopathology scores and L. intracellularis excretion was 0.67 (P<0.001). Spearman's correlation coefficient between the IHC scores and L. intracellularis excretion was 0.77 (P<0.001). CONCLUSIONS: The histological and quantitative PCR detection of Lawsonia intracellularis were correlated in pigs with diarrhoea. Overall the results suggest that clinically important levels for Lawsonia intracellularis excretion in faeces may be established. Such clinical threshold levels may be used in practice to confirm a diagnosis of Lawsonia intracellularis associated diarrhoea. PMID- 23092369 TI - Rearrangements of N-acyl isothioureas. Alternate access to acylguanidines from cyanamides. AB - We report a tin-free one-pot radical approach to the synthesis of N-acyl isothioureas and acylguanidines from N-acyl cyanamides. Photoactivated reduction of aromatic disulfides in the presence of Hunig's base results in hydrothiolation of the cyanamide moiety, followed by spontaneous 1,3-migration of the acyl group. Onward reaction of the isothioureas obtained with amines led to the corresponding N-acylguanidines, where the acyl group is attached to the nitrogen atom formerly at the cyano-end of the starting material. PMID- 23092370 TI - Effectiveness of nanometer-sized extracellular matrix layer-by-layer assembled films for a cell membrane coating protecting cells from physical stress. AB - In recent approaches to tissue engineering, cells face various stresses from physical, chemical, and environmental stimuli. For example, coating cell membranes with nanofilms using layer-by-layer (LbL) assembly requires many cycles of centrifugation, causing physical (gravity) stress. Damage to cell membranes can cause the leakage of cytosol molecules or sometimes cell death. Accordingly, we evaluated the effectiveness of LbL films prepared on cell membranes in protecting cells from physical stresses. After two steps of LbL assembly using Tris-HCl buffer solution without polymers or proteins (four centrifugation cycles including washing), hepatocyte carcinoma (HepG2) cells showed extremely high cell death and the viability was ca. 15%. Their viability ultimately decreased to 6% after 9 steps of LbL assembly (18 cycles of centrifugation), which is the typical number of steps involved in preparing LbL nanofilms. However, significantly higher viability (>85%) of HepG2 cells was obtained after nine steps of LbL assembly employing fibronectin (FN)-gelatin (G) or type IV collagen (Col IV) laminin (LN) solution combinations, which are typical components of an extracellular matrix (ECM), to fabricate 10-nm-thick LbL films. When LbL films of synthetic polymers created via electrostatic interactions were employed instead of the ECM films described above, the viability of the HepG2 cells after the same nine steps slightly decreased to 61%. The protective effects of LbL films were strongly dependent on their thickness, and the critical thickness was >5 nm. Surprisingly, a high viability of over 85% was achieved even under extreme physical stress conditions (10,000 rpm). We evaluated the leakage of lactate dehydrogenase (LDH) during the LbL assembly processes to clarify the protective effect, and a reduction in LDH leakage was clearly observed when using FN-G nanofilms. Moreover, the LbL films do not inhibit cell growth during cell culturing, suggesting that these coated cells can be useful for other experiments. LbL nanofilm coatings, especially ECM nanofilm coatings, will be important techniques for protecting cell membranes from physical stress during tissue engineering. PMID- 23092372 TI - Scanning tunneling microscopy and theoretical study of water adsorption on Fe3O4: implications for catalysis. AB - The reduced surface of a natural Hematite single crystal alpha-Fe(2)O(3)(0001) sample has multiple surface domains with different terminations, Fe(2)O(3)(0001), FeO(111), and Fe(3)O(4)(111). The adsorption of water on this surface was investigated via Scanning Tunneling Microscopy (STM) and first-principle theoretical simulations. Water species are observed only on the Fe-terminated Fe(3)O(4)(111) surface at temperatures up to 235 K. Between 235 and 245 K we observed a change in the surface species from intact water molecules and hydroxyl groups bound to the surface to only hydroxyl groups atop the surface terminating Fe(III) cations. This indicates a low energy barrier for water dissociation on the surface of Fe(3)O(4) that is supported by our theoretical computations. Our first principles simulations confirm the identity of the surface species proposed from the STM images, finding that the most stable state of a water molecule is the dissociated one (OH + H), with OH atop surface terminating Fe(III) sites and H atop under-coordinated oxygen sites. Attempts to simulate reaction of the surface OH with coadsorbed CO fail because the only binding sites for CO are the surface Fe(III) atoms, which are blocked by the much more strongly bound OH. In order to promote this reaction we simulated a surface decorated with gold atoms. The Au adatoms are found to cap the under-coordinated oxygen sites and dosed CO is found to bind to the Au adatom. This newly created binding site for CO not only allows for coexistence of CO and OH on the surface of Fe(3)O(4) but also provides colocation between the two species. These two factors are likely promoters of catalytic activity on Au/Fe(3)O(4)(111) surfaces. PMID- 23092371 TI - Systems mapping of HIV-1 infection. AB - Mathematical models of viral dynamics in vivo provide incredible insights into the mechanisms for the nonlinear interaction between virus and host cell populations, the dynamics of viral drug resistance, and the way to eliminate virus infection from individual patients by drug treatment. The integration of these mathematical models with high-throughput genetic and genomic data within a statistical framework will raise a hope for effective treatment of infections with HIV virus through developing potent antiviral drugs based on individual patients' genetic makeup. In this opinion article, we will show a conceptual model for mapping and dictating a comprehensive picture of genetic control mechanisms for viral dynamics through incorporating a group of differential equations that quantify the emergent properties of a system. PMID- 23092373 TI - Charge transfer magnetoexciton formation at vertically coupled quantum dots. AB - A theoretical investigation is presented on the properties of charge transfer excitons at vertically coupled semiconductor quantum dots in the presence of electric and magnetic fields directed along the growth axis. Such excitons should have two interesting characteristics: an extremely long lifetime and a permanent dipole moment. We show that wave functions and the low-lying energies of charge transfer exciton can be found exactly for a special morphology of quantum dots that provides a parabolic confinement inside the layers. To take into account a difference between confinement potentials of an actual structure and of our exactly solvable model, we use the Galerkin method. The density of energy states is calculated for different InAs/GaAs quantum dots' dimensions, the separation between layers, and the strength of the electric and magnetic fields. A possibility of a formation of a giant dipolar momentum under external electric field is predicted. PMID- 23092374 TI - Implementing a Modified Version of Parent Management Training (PMT) with an intellectually disabled client in a special education setting. AB - In this article the author discusses how an evidence-based practice was modified to treat an intellectually disabled client with oppositional behavior. Parent Management Training was modified to treat the client. A single-subject A-B design was used. Behavior improved from 1.57 (SD = .78) to 0.63 (SD = .71) episodes of negative behavior per day from baseline to intervention, and findings were significant (t = 2.83, p = .01). Follow-up with the family indicated sustained improvement one year after the intervention was discontinued. Consideration should be given to using principles of Parent Management Training to create formal plans for addressing problem behaviors across settings with intellectually disabled clients. PMID- 23092375 TI - Transitional education for child laborers. A review of residential bridge camps for mainstreaming ex-child laborers into the formal education system. AB - Residential bridge camps provide intensive education in residential settings with the aim of preparing hard-core child laborers to be integrated in mainstream schools. The author reviews the extent to which residential bridge camps are effective interventions for integrating former child laborers into the mainstream schools at age appropriate levels. The research was based on a thorough review of secondary data, with 786 abstracts being screened. Given the methodological limitations of the studies, the only reliable inferences the author can advance through this review are on the aspects that appear to be promising, but which require further research. PMID- 23092376 TI - Gregory research beliefs scale: discriminant construct, concurrent criterion, and known-groups validity. AB - The purpose of the author in this study was to evaluate the discriminant construct, concurrent criterion, and known-groups validity of the Gregory Research Beliefs Scale (GRBS). Data was collected from masters and bachelors level social work students via online and traditional classroom settings. The Gregory Research Beliefs Scale's discriminant construct validity was supported via principal component and confirmatory factor analysis. A correlation coefficient provided some evidence for the concurrent criterion validity. The Gregory Research Beliefs Scale's known-groups validity was not supported. Strengths, limitations, future research, and implications for evidence-based social work practice are discussed. PMID- 23092377 TI - Holocaust survivors: three waves of resilience research. AB - Three waves of resilience research have resulted in resilience-enhancing educational and therapeutic interventions. In the first wave of inquiry, researchers explored the traits and environmental characteristics that enabled people to overcome adversity. In the second wave, researchers investigated the processes related to stress and coping. In the third wave, studies examined how people grow and are transformed following adverse events, often leading to self actualize, client creativity and spirituality. In this article the authors examined data from a study, "Forgiveness, Resiliency, and Survivorship among Holocaust Survivors" funded by the John Templeton Foundation ( Greene, Armour, Hantman, Graham, & Sharabi, 2010 ). About 65% of the survivors scored on the high side for resilience traits. Of the survivors, 78% engaged in processes considered resilient and felt they were transcendent or had engaged in behaviors that help them grow and change over the years since the Holocaust, including leaving a legacy and contributing to the community. PMID- 23092378 TI - The value of daily money management: an analysis of outcomes and costs. AB - For vulnerable and frail older adults, management of daily financial obligations can become an overwhelming burden spiraling into at-risk situations. Social service agencies have developed community-based Daily Money Management programs to assist these adults in protecting their financial security. Through this study the authors present the first economic estimates of the costs of Daily Money Management programs which, along with case management programs, save $60,000 per individual when compared with the cost of nursing home placement, making them highly cost effective. Most importantly, individuals are able to remain in their homes. The authors address the current gap between cost-effective community-based practice and public policy support. PMID- 23092379 TI - Improving outcomes for at-risk youth: findings from the Prodigy Cultural Arts Program. AB - Through this study the authors evaluate the Prodigy Cultural Arts Program, an early prevention program for adjudicated youth. A quasi experimental pre- and posttest was conducted. A significant reduction in mental health symptoms (particularly for females) and behavioral dysregulation (particularly for males), and increases in academic performance and family functioning were found. There was also a relationship between decreased mental health symptomology and perceived academic performance. The Prodigy Cultural Arts Program appears to be successful in intervening with youth who present challenges to the juvenile justice system due to the complexity of their mental health symptoms, behavioral regulation difficulties, and/or gender. PMID- 23092381 TI - Characterization of DMSO coordination to palladium(II) in solution and insights into the aerobic oxidation catalyst, Pd(DMSO)2(TFA)2. AB - Recent studies have shown that Pd(DMSO)(2)(TFA)(2) (TFA = trifluoroacetate) is an effective catalyst for a number of different aerobic oxidation reactions. Here, we provide insights into the coordination of DMSO to palladium(II) in both the solid state and in solution. A crystal structure of Pd(DMSO)(2)(TFA)(2) confirms that the solid-state structure of this species has one O-bound and one S-bound DMSO ligand, and a crystallographically characterized mono-DMSO complex, trans Pd(DMSO)(OH(2))(TFA)(2), exhibits an S-bound DMSO ligand. (1)H and (19)F NMR spectroscopic studies show that, in EtOAc and THF-d(8), Pd(DMSO)(2)(TFA)(2) consists of an equilibrium mixture of Pd(S-DMSO)(O-DMSO)(TFA)(2) and Pd(S DMSO)(2)(TFA)(2). The O-bound DMSO is determined to be more labile than the S bound DMSO ligand, and both DMSO ligands are more labile in THF relative to EtOAc as the solvent. DMSO coordination to Pd(II) is substantially less favorable when the TFA ligands are replaced with acetate. An analogous carboxylate ligand effect is observed in the coordination of the bidentate sulfoxide ligand, 1,2 bis(phenylsulfinyl)ethane to Pd(II). DMSO coordination to Pd(TFA)(2) is shown to be incomplete in AcOH-d(4) and toluene-d(8), resulting in Pd(II)/DMSO adducts with <2:1 DMSO/Pd(II) stoichiometry. Collectively, these results provide useful insights into the coordination properties of DMSO to Pd(II) under catalytically relevant conditions. PMID- 23092382 TI - Automating knowledge discovery for toxicity prediction using jumping emerging pattern mining. AB - The design of new alerts, that is, collections of structural features observed to result in toxicological activity, can be a slow process and may require significant input from toxicology and chemistry experts. A method has therefore been developed to help automate alert identification by mining descriptions of activating structural features directly from toxicity data sets. The method is based on jumping emerging pattern mining which is applied to a set of toxic and nontoxic compounds that are represented using atom pair descriptors. Using the resulting jumping emerging patterns, it is possible to cluster toxic compounds into groups defined by the presence of shared structural features and to arrange the clusters into hierarchies. The methodology has been tested on a number of data sets for Ames mutagenicity, oestrogenicity, and hERG channel inhibition end points. These tests have shown the method to be effective at clustering the data sets around minimal jumping-emerging structural patterns and finding descriptions of potentially activating structural features. Furthermore, the mined structural features have been shown to be related to some of the known alerts for all three tested end points. PMID- 23092383 TI - Harnessing the power of the immune system to target cancer. AB - For many years, immunotherapeutic approaches for cancer held more promise than actual clinical benefit for the majority of patients. However, several recent key advances in tumor immunology have now turned the tide in favor of immunotherapy for the treatment of many different cancer types. In this review, we describe four of the most effective immunotherapeutic approaches currently used in the clinic: cancer vaccines, immunostimulatory agents, adoptive T cell therapy, and immune checkpoint blockade. In addition, we discuss some of the most promising future strategies that aim to utilize multiple immunotherapies or combine them with other approaches to more effectively target cancer. PMID- 23092384 TI - Hyperaldosteronism as a common cause of resistant hypertension. AB - Resistant hypertension affects an estimated 10-15 million American adults and is increasing in prevalence. The etiology of resistant hypertension is almost always multifactorial, including obesity, older age, high dietary salt, chronic kidney disease, and aldosterone excess. Classical primary aldosteronism and lesser degrees of aldosterone excess, possibly originating from visceral adipocytes, contribute broadly to antihypertensive treatment resistance. Treatment of resistant hypertension is predicated on appropriate lifestyle changes and use of effective combinations of antihypertensive agents from different classes. Blockade of aldosterone with spironolactone has been shown to be particularly effective for treatment of resistant hypertension. The antihypertensive benefit of spironolactone is not limited to patients with demonstrable hyperaldosteronism but instead can be effective in resistant hypertensive patients regardless of aldosterone levels. Chlorthalidone is a potent, long-acting thiazide-like diuretic and should be used preferentially to treat resistant hypertension as it is superior to normally used doses of hydrochlorothiazide. PMID- 23092386 TI - Fano resonant ring/disk plasmonic nanocavities on conducting substrates for advanced biosensing. AB - By introducing a conducting metal layer underneath a Fano resonant asymmetric ring/disk plasmonic nanocavity system, we demonstrate that electromagnetic fields can be strongly enhanced. These large electromagnetic fields extending deep into the medium are highly accessible and increase the interaction volume of analytes and optical fields. As a result, we demonstrate high refractive index sensitivities as large as 648 nm/RIU. By exciting Fano resonances with much sharper spectral features, as narrow as 9 nm, we experimentally show high figure of merits as large as 72 and reliable detection of protein mono- and bilayers. Furthermore, the conducting substrate enables strong interaction between fundamental and higher order modes of the system by minor structural asymmetries. This is very advantageous for experimental realization of systems supporting resonances with well-defined Fano-like line shape without requiring challenging fabrication resolution. Exploiting conducting metallic substrates and the associated propagating surface plasmons at their interface could be extended to other Fano resonant cavity geometries for improved biosensing performance. PMID- 23092385 TI - Circulating tumor cells: from bench to bedside. AB - Circulating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases. In recent years, their detection has gained increasing interest. There is ample evidence regarding the ability to detect CTCs and their prognostic relevance, but their demonstrated predictive value in therapeutic response monitoring is clinically even more meaningful. Many clinical trials in the early and metastatic cancer setting now include CTCs as a monitoring parameter, and numerous translational studies attempting their molecular characterization are under way. There has been great progress in defining the clinical importance of CTCs, and it now seems likely that we may expect wider implementation of CTCs as a diagnostic oncology tool to monitor therapeutic response in real time. Novel technologies may further facilitate molecular characterization of CTCs and development of novel therapeutic targets, possibly leading to more powerful treatment strategies for cancer patients. As the detection and evaluation of CTCs are becoming an increasingly important diagnostic and prognostic tool, the goal of this review is to communicate the knowledge obtained through analysis of primary tumors and CTCs to oncologists and medical specialists in managing patients with cancer. PMID- 23092388 TI - On the origin of large two-photon activity of DANS molecule. AB - In this work, using the quadratic response theory and two-state model approach, we have explained the origin of high two-photon activity and the corresponding solvent dependence of 4,4'-dimethyl-amino-nitro-stilbene (DANS) molecule. For this purpose, we have made two structural modifications in the DANS molecule (1) at the donor-acceptor part and (2) at the unsaturated bridge between the two rings and calculated the one- and two-photon (OP and TP) absorption parameters of all the systems in gas phase and in three different solvents, viz., MeCN, THF, and toluene. We found that the removal of donor-acceptor groups from the original DANS molecule vanishes the transition moment between the ground and excited states and also the corresponding dipole moment difference, and the saturation of the pi-conjugation bridge between the two rings keeping the donor-acceptor groups intact causes a large decrease in the ground to excited state transition moment. These changes, in turn, decrease the overall TP activity of the molecules as compared to DANS. On the basis of our analysis, we have concluded that neither the donor-acceptor pair nor the pi-conjugation bridge between the two, rather their cooperative involvement leads to a large overlap between the ground and virtual and also the virtual and charge-transfer states, which are eventually responsible for the very large TP activity of DANS. PMID- 23092387 TI - Sitting time and health outcomes among Mexican origin adults: obesity as a mediator. AB - BACKGROUND: Sitting time and sedentary behaviors have been associated with adverse health outcomes including obesity, diabetes and cardiovascular disease (CVD) within non- Hispanic White populations. Similar associations have not been described within Hispanic populations despite their high CVD risk profile. This study aimed to assess the association between sitting time and obesity, self reported diagnosed diabetes, hypertension and high cholesterol among a large cohort (N=11,268) of Mexican origin adults and to assess whether obesity mediated these associations. METHODS: Using a cross-sectional design, data collected between 2004 and 2010 were analyzed in late 2010. Regression analyses evaluated associations between self-reported daily sitting hours and disease outcomes, controlling for demographics, employment status, family disease history, and light, moderate and strenuous physical activity. RESULTS: Participants were mostly female (81.1%) Mexican origin adults. Sitting time was associated with increased odds of being obese, having diabetes and having hypertension, but not high cholesterol. Adjusted odds ratios of participants who reported sitting > 4 hours/day compared to those sitting 1-2 hours/day were for obesity OR=1.55 (95% CI 1.39, 1.73), p<.001, for diabetes OR=1.29 (95% CI, 1.09, 1.52), p=.003, for hypertension OR=1.17 (95% CI, 1.01, 1.37), p=.041. Associations controlled for physical activity and employment status. Effects on hypertension and diabetes were mediated by obesity. CONCLUSIONS: Sitting time was significantly associated with detrimental health outcomes, independent of physical activity. Obesity mediated these relationships for diabetes and hypertension. Future research should assess whether interventions addressing sitting time are feasible and effective among Mexican origin populations. PMID- 23092389 TI - Lanostanoids from fungi: a group of potential anticancer compounds. AB - Lanostanes are a group of tetracyclic triterpenoids derived from lanosterol. They have relevant biological and pharmacological properties, such as their cytotoxic effects via induction of apoptosis. This review compiles the most relevant lanostanoids studied from 2000 to 2011, principally those isolated from Ganoderma lucidum and other related fungi, such as Poria cocos, Laetiporus sulphureus, Inonotus obliquus, Antrodia camphorata, Daedalea dickinsii, and Elfvingia applanata, which have great potential as anticancer agents because of their cytotoxic or apoptotic effects. The compounds were selected on the basis of their proapoptotic mechanisms, through their ability to modify transcriptional activities via nuclear factors or genes and the activation or inhibition of pro- or antiapoptotic proteins; studies based only on their cytotoxicity were excluded from this review in the absence of complementary studies on their mechanisms of action. A total of 81 compounds from Ganoderma lucidum and other species from this genus are included, as well as 96 compounds isolated from other fungi, principally Poria cocos. Some of these compounds were found to arrest the cell cycle in the G1 phase, increase levels of p53 and Bax, or inhibit the phosphorylation of Erk1/2 or the activation of NF-kappaB and AP-1. Other lanostanes have inhibitory effects on the growth of androgen prostate carcinoma through increasing the expression of p21, which activates the tumor suppressor protein p53, while other compounds have been shown to selectively inhibit topo II activity without affecting topo I. General considerations concerning the chemical structure-biological activities of these compounds are also discussed. PMID- 23092391 TI - Synthesis of cis-octahydroindoles via intramolecular 1,3-dipolar cycloaddition of 2-acyl-5-aminooxazolium salts. AB - A concise method for the diastereoselective synthesis of octahydroindoles is presented. The products contain 2-amido and 7-hydroxyl substituents. A series of 2-acyl-5-aminooxazoles were prepared in one step. Upon methylation of the oxazole nitrogen atom, the substrates underwent rapid intramolecular 1,3-dipolar cycloaddition with a tethered alkene and, after reduction with excess hydride, produced octahydroindoles with excellent diastereoselectivity. The method allows for the installation of alpha-quaternary stereogenic carbon atoms. PMID- 23092392 TI - Sexual dysfunction during methadone maintenance treatment and its influence on patient's life and treatment: a qualitative study in South China. AB - Methadone maintenance treatment (MMT) has become an important modality of substitution treatment for opioid addicts in China since 2006. However, data are limited regarding the change in sexual function from heroin use to MMT and the influence of sexual dysfunction (SD) during MMT on patient's life and treatment. Face-to-face in-depth interviews were conducted with 13 male and 14 female MMT patients, five of their partners, and three clinicians. The interviews took place in four MMT clinics in Guangdong Province between August 2010 and February 2011. The patients and their partners were asked separately for their perceptions of patient's sexual function during MMT, and the influence of SD on personal/family life and treatment. The main SD problems patients perceived were libido inhibition and decreased sexual pleasure. Methadone was thought to have a stronger inhibition effect on sexual desire than heroin. SD decreased quality of patient's sexual life and damaged intimate relationships. There was a gender difference in coping with SD. Men generally tended to refuse, escape, or alienate their partners. Women tended to hide sexual listlessness, endure sexual activity and tried to satisfy their partners. SD might increase risk of voluntary dropout from treatment and illicit drug use during treatment. Patients with SD did not get any effective therapy from clinicians and they also lacked skills on coping with SD-related problems. Sexual dysfunction prevented patients from reconstructing a normal intimate relationship, and affected stability of maintenance treatment. Response to patient's SD and SD-related problems from clinicians was inadequate. There is a need to develop a clinical guide to deal with both SD itself and SD-related problems. PMID- 23092390 TI - Metabolic engineering of the purine biosynthetic pathway in Corynebacterium glutamicum results in increased intracellular pool sizes of IMP and hypoxanthine. AB - BACKGROUND: Purine nucleotides exhibit various functions in cellular metabolism. Besides serving as building blocks for nucleic acid synthesis, they participate in signaling pathways and energy metabolism. Further, IMP and GMP represent industrially relevant biotechnological products used as flavor enhancing additives in food industry. Therefore, this work aimed towards the accumulation of IMP applying targeted genetic engineering of Corynebacterium glutamicum. RESULTS: Blocking of the degrading reactions towards AMP and GMP lead to a 45 fold increased intracellular IMP pool of 22 MUmol g(CDW)-1. Deletion of the pgi gene encoding glucose 6-phosphate isomerase in combination with the deactivated AMP and GMP generating reactions, however, resulted in significantly decreased IMP pools (13 MUmol g(CDW)-1). Targeted metabolite profiling of the purine biosynthetic pathway further revealed a metabolite shift towards the formation of the corresponding nucleobase hypoxanthine (102 MUmol g(CDW)-1) derived from IMP degradation. CONCLUSIONS: The purine biosynthetic pathway is strongly interconnected with various parts of the central metabolism and therefore tightly controlled. However, deleting degrading reactions from IMP to AMP and GMP significantly increased intracellular IMP levels. Due to the complexity of this pathway further degradation from IMP to the corresponding nucleobase drastically increased suggesting additional targets for future strain optimization. PMID- 23092394 TI - Crankshafts: using simple, flat C2h-symmetric molecules to direct the assembly of chiral 2D nanopatterns. AB - Linear D2h-symmetric bisisophthalic acids 1 and 2 and related substances have well-defined flattened structures, high affinities for graphite, and strong abilities to engage in specific intermolecular interactions. Their adsorption produces characteristic nanopatterns that reveal how 2D molecular organization can be controlled by reliable interadsorbate interactions such as hydrogen bonds when properly oriented by molecular geometry. In addition, the behavior of these compounds shows how large-scale organization can be obstructed by programming molecules to associate strongly according to competing motifs that have similar stability and can coexist smoothly without creating significant defects. Analogous new bisisophthalic acids 3a and 4a have similar associative properties, and their unique C2h-symmetric crankshaft geometry gives them the added ability to probe the poorly understood effect of chirality on molecular organization. Their adsorption shows how nanopatterns composed predictably of a single enantiomer can be obtained by depositing molecules that can respect established rules of association only by accepting neighbors of the same configuration. In addition, an analysis of the adsorption of crankshaft compounds 3a and 4a and their derivatives by STM reveals directly on the molecular level how kinetics and thermodynamics compete to control the crystallization of chiral compounds. In such ways, detailed studies of the adsorption of properly designed compounds on surfaces are proving to be a powerful way to discover and test rules that broadly govern molecular organization in both 2D and 3D. PMID- 23092393 TI - Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis. AB - BACKGROUND: Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC). METHODS: PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC) in SJIA or POLY samples. These transcripts were used to find related biological pathways. RESULTS: Combining Pearson and t-test analyses, we found 91 ESR-related and 92 JC related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF) of SJIA compared to samples from the later arthritis-predominant phase (AF). Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF) subgroup. CONCLUSIONS: The strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with differences in clinically appreciated target organs. The limited number of ESR-related SJIA genes that also are associated with elevations of ESR in POLY implies that the SJIA associations are specific for SJIA, at least to some degree. The distinct pathways associated with arthritis in early and late SJIA raise the possibility that different immunobiology underlies arthritis over the course of SJIA. PMID- 23092396 TI - Amino alcohol-derived reduced Schiff base V(IV)O and V(V) compounds as catalysts for asymmetric sulfoxidation of thioanisole with hydrogen peroxide. AB - We report the synthesis and characterization of several amino alcohol-derived reduced Schiff base ligands (AORSB) and the corresponding V(IV)O and V(V) complexes. Some of the related Schiff base variants (amino alcohol derived Schiff base = AOSB) were also prepared and characterized. With some exceptions, all compounds are formulated as dinuclear compounds {V(IV)O(L)}(2) in the solid state. Suitable crystals for X-ray diffraction were obtained for two of the AORSB compounds, as well as a rare X-ray structure of a chiral V(IV)O compound, which revealed a dinuclear {V(IV)O(AOSB)}(2) structure with a rather short V-V distance of 3.053(9) A. Electron paramagnetic resonance (EPR), (51)V NMR, and density functional theory (DFT) studies were carried out to identify the intervenient species prior to and during catalytic reactions. The quantum-chemical DFT calculations were important to determine the more stable isomers in solution, to explain the EPR data, and to assign the (51)V NMR chemical shifts. The V(AORSB) and V(AOSB) complexes were tested as catalysts in the oxidation of thioanisole, with H(2)O(2) as the oxidant in organic solvents. In general, high conversions of sulfoxide were obtained. The V(AOSB) systems exhibited greater activity and enantioselectivity than their V(AORSB) counterparts. Computational and spectroscopic studies were carried out to assist in the understanding of the mechanistic aspects and the reasons behind such marked differences in activity and enantioselectivity. The quantum-chemical calculations are consistent with experimental data in the assessment of the differences in catalytic activity between V(AOSB) and V(AORSB) peroxido variants because the V(AORSB) peroxido transition states correspond to ca. 22 kJ/mol higher energy activation barriers than their V(AOSB) counterparts. PMID- 23092395 TI - Chemical profile and biological activities of Deguelia duckeana A.M.G. Azevedo (Fabaceae). AB - Deguelia duckeana is popularly known as timbo and used by indigenous people as ictiotoxic. On account of there being no literature pertaining to the chemical profile or biological activity of this plant, the hexane, methanol and aqueous crude extracts from leaves, stems and roots were assayed that presented very high cytotoxic potential against Artemia salina, achieving 100% mortality in up to 5.0 ug mL(-1) concentration, but lower antioxidant potential on 2,2-diphenyl-1-picryl hydrazyl and Fe(3+)/Phenanthroline assays. The phytochemical analysis of crude extracts showed the presence of flavonoids and related compounds as major constituents as well as steroids in all of them, and tannins in polar extracts. All the extracts were assayed for antibacterial activity but only the hexane extract of stems showed moderate activity on Staphylococcus aureus, which was fractionated and yielded a mixture of 3,5,4'-trimethoxy-4-prenylstilbene, lonchocarpine, 4-hydroxylonchocarpine and derricidine, reported for the first time in D. duckeana and other fraction with beta-sitosterol and stigmasterol mixture. PMID- 23092397 TI - admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. AB - Absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties play key roles in the discovery/development of drugs, pesticides, food additives, consumer products, and industrial chemicals. This information is especially useful when to conduct environmental and human hazard assessment. The most critical rate limiting step in the chemical safety assessment workflow is the availability of high quality data. This paper describes an ADMET structure activity relationship database, abbreviated as admetSAR. It is an open source, text and structure searchable, and continually updated database that collects, curates, and manages available ADMET-associated properties data from the published literature. In admetSAR, over 210,000 ADMET annotated data points for more than 96,000 unique compounds with 45 kinds of ADMET-associated properties, proteins, species, or organisms have been carefully curated from a large number of diverse literatures. The database provides a user-friendly interface to query a specific chemical profile, using either CAS registry number, common name, or structure similarity. In addition, the database includes 22 qualitative classification and 5 quantitative regression models with highly predictive accuracy, allowing to estimate ecological/mammalian ADMET properties for novel chemicals. AdmetSAR is accessible free of charge at http://www.admetexp.org. PMID- 23092398 TI - Reversible absorption of CO2 triggered by phase transition of amine-containing micro- and nanogel particles. AB - Herein we report that an aqueous solution of temperature-responsive micro- and nanogel particles (GPs) consisting of N-isopropylacrylamide (NIPAm) and N-[3 (dimethylamino)propyl]methacrylamide (DMAPM) reversibly absorbs and desorbs CO(2) via a phase transition induced by cooling and heating cycles (30-75 degrees C). Below the phase-transition temperature, most of the amines in the swollen GPs are capable of forming ion pairs with absorbed bicarbonate ions. However, above the phase-transition temperature, shrinkage of the GPs lowers the pK(a) and the number of amine groups exposed to water, thereby resulting in almost complete desorption of CO(2). The GPs can reversibly absorb more than the DMAPM monomer and polymer without NIPAm, which indicates the importance of the temperature responsive phase transition of polymers in determining the degree of absorption. The results show the potential of temperature-responsive polymer solutions as absorbents to sequester CO(2) at a low energy cost. PMID- 23092400 TI - Nanoscale perturbations of room temperature ionic liquid structure at charged and uncharged interfaces. AB - The nanoscale interactions of room temperature ionic liquids (RTILs) at uncharged (graphene) and charged (muscovite mica) solid surfaces were evaluated with high resolution X-ray interface scattering and fully atomistic molecular dynamics simulations. At uncharged graphene surfaces, the imidazolium-based RTIL ([bmim(+)][Tf(2)N(-)]) exhibits a mixed cation/anion layering with a strong interfacial densification of the first RTIL layer. The first layer density observed via experiment is larger than that predicted by simulation and the apparent discrepancy can be understood with the inclusion of, dominantly, image charge and pi-stacking interactions between the RTIL and the graphene sheet. In contrast, the RTIL structure adjacent to the charged mica surface exhibits an alternating cation-anion layering extending 3.5 nm into the bulk fluid. The associated charge density profile demonstrates a pronounced charge overscreening (i.e., excess first-layer counterions with respect to the adjacent surface charge), highlighting the critical role of charge-induced nanoscale correlations of the RTIL. These observations confirm key aspects of a predicted electric double layer structure from an analytical Landau-Ginzburg-type continuum theory incorporating ion correlation effects, and provide a new baseline for understanding the fundamental nanoscale response of RTILs at charged interfaces. PMID- 23092402 TI - Ruthenium- and sulfonamide-catalyzed cyclization between N-sulfonyl imines and alkynes. AB - Ruthenium(II)-catalyzed redox-neutral annulative coupling of N-sulfonyl imines with alkynes has been achieved for the synthesis of indenamines, where a sulfonamide cocatalyst is necessary. PMID- 23092401 TI - Estimates of marker effects for measures of milk flow in the Italian brown Swiss dairy cattle population. AB - BACKGROUND: Milkability is a complex trait that is characterized by milk flow traits including average milk flow rate, maximum milk flow rate and total milking time. Milkability has long been recognized as an economically important trait that can be improved through selection. By improving milkability, management costs of milking decrease through reduced labor and improved efficiency of the automatic milking system, which has been identified as an important factor affecting net profit. The objective of this study was to identify markers associated with electronically measured milk flow traits, in the Italian Brown Swiss population that could potentially improve selection based on genomic predictions. RESULTS: Sires (n = 1351) of cows with milk flow information were genotyped for 33,074 single nucleotide polymorphism (SNP) markers distributed across 29 Bos taurus autosomes (BTA). Among the six milk flow traits collected, ascending time, time of plateau, descending time, total milking time, maximum milk flow and average milk flow, there were 6,929 (time of plateau) to 14,585 (maximum milk flow) significant SNP markers identified for each trait across all BTA. Unique regions were found for each of the 6 traits providing evidence that each individual milk flow trait offers distinct genetic information about milk flow. This study was also successful in identifying functional processes and genes associated with SNPs that influences milk flow. CONCLUSIONS: In addition to verifying the presence of previously identified milking speed quantitative trait loci (QTL) within the Italian Brown Swiss population, this study revealed a number of genomic regions associated with milk flow traits that have never been reported as milking speed QTL. While several of these regions were not associated with a known gene or QTL, a number of regions were associated with QTL that have been formerly reported as regions associated with somatic cell count, somatic cell score and udder morphometrics. This provides further evidence of the complexity of milk flow traits and the underlying relationship it has with other economically important traits for dairy cattle. Improved understanding of the overall milking pattern will aid in identification of cows with lower management costs and improved udder health. PMID- 23092404 TI - Beyond reproductive effects of sex steroids. AB - In this special issue of Minireviews in Medicinal Chemistry, called Beyond Reproductive Effects of Sex Steroids, the reader will find representative papers of the state of the art in the field of non-reproductive effects of sex steroids. For instance, Teran-Perez and co-workers discuss the role of steroid hormones in the sleep-waking cycle. Cabrera-Munoz et al., review the role of estradiol and progesterone in the susceptibility and disease progression of one of the most important health problems on the last decade: HIV infection. Furthermore, Gonzalez-Arenas and Agramonte-Hevia make a review on the effects that sex steroid hormones have on normal and pathologic conditions of the lung. The effects of sex steroids on the maternal brain is very nicely reviewed by Kinsley et al. The role of sex steroid hormones in immunoregulation, particularly in the establishment, growth and reproduction of parasites is reviewed by Hernandez-Bello et al. De Nicola et al., make an interesting contribution regarding the role of estradiol in neuroprotection during hypertensive encephalopathy. The regulation of morphological and functional characteristics of the amygdala regulated by sex steroids in the adult rat is a topic boarded by Rasia-Filho and co-workers. Finally, Bautista et al., talk about the role of sex steroid hormones in one of the most important functions of organisms: appetitive behavior. We hope that our readers will find fascinating this Special Issue devoted to the wide non-typical functions in vertebrates. PMID- 23092403 TI - Effects of being uninsured or underinsured and living in extremely poor neighborhoods on colon cancer care and survival in California: historical cohort analysis, 1996-2011. AB - BACKGROUND: We examined the mediating effects of health insurance on poverty colon cancer care and survival relationships and the moderating effects of poverty on health insurance-colon cancer care and survival relationships among women and men in California. METHODS: We analyzed registry data for 3,291 women and 3,009 men diagnosed with colon cancer between 1996 and 2000 and followed until 2011 on lymph node investigation, stage at diagnosis, surgery, chemotherapy, wait times and survival. We obtained socioeconomic data for individual residences from the 2000 census to categorize the following neighborhoods: high poverty (30% or more poor), middle poverty (5-29% poor) and low poverty (less than 5% poor). Primary health insurers were Medicaid, Medicare, private or none. RESULTS: Evidence of mediation was observed for women, but not for men. For women, the apparent effect of poverty disappeared in the presence of payer, and the effects of all forms of health insurance seemed strengthened. All were advantaged on 6-year survival compared to the uninsured: Medicaid (RR = 1.83), Medicare (RR = 1.92) and private (RR = 1.83). Evidence of moderation was also only observed for women. The effects of all forms of health insurance were stronger for women in low poverty neighborhoods: Medicaid (RR = 2.90), Medicare (RR = 2.91) and private (RR = 2.60). For men, only main effects of poverty and payers were observed, the advantaging effect of private insurance being largest. Across colon cancer care processes, Medicare seemed most instrumental for women, private payers for men. CONCLUSIONS: Health insurance substantially mediates the quality of colon cancer care and poverty seems to make the effects of being uninsured or underinsured even worse, especially among women in the United States. These findings are consistent with the theory that more facilitative social and economic capital is available in more affluent neighborhoods, where women with colon cancer may be better able to absorb the indirect and direct, but uncovered, costs of care. PMID- 23092405 TI - Steroid hormones and sleep regulation. AB - In the search of the sleep substance, many studies have been addressed for different hormones, responsible for sleep-wake cycle regulation. In this article we mentioned the participation of steroid hormones, besides its role regulating sexual behavior, they influence importantly in the sleep process. One of the clearest relationships are that estrogen and progesterone have, that causing changes in sleep patterns associated with the hormonal cycles of women throughout life, from puberty to menopause and specific periods such as pregnancy and the menstrual cycle, including being responsible for some sleep disorders such as hypersomnia and insomnia. Another studied hormone is cortisol, a hormone released in stressful situations, when an individual must react to an extraordinary demand that threatens their survival, but also known as the hormone of awakening because the release peak occurs in the morning, although this may be altered in some sleep disorders like insomnia and mood disorders. Furthermore neurosteroids such as pregnanolone, allopregnanolone and pregnenolone are involved in the generation of slow wave sleep, the effect has been demonstrated in experimental animal studies. Thus we see that the sleep and the endocrine system saved a bidirectional relationship in which depends on each other to regulate different physiological processes including sleep. PMID- 23092406 TI - Beneficial effects of herbs, spices and medicinal plants on the metabolic syndrome, brain and cognitive function. AB - Herbs and spices have been used since ancient times to not only improve the flavor of edible food but also to prevent and treat chronic health maladies. While the scientific evidence for the use of such common herbs and medicinal plants then had been scarce or lacking, the beneficial effects observed from such use were generally encouraging. It is, therefore, not surprising that the tradition of using such herbs, perhaps even after the advent of modern medicine, has continued. More recently, due to an increased interest in understanding the nutritional effects of herbs/spices more comprehensively, several studies have examined the cellular and molecular modes of action of the active chemical components in herbs and their biological properties. Beneficial actions of herbs/spices include anti-inflammatory, antioxidant, anti-hypertensive, gluco regulatory, and anti-thrombotic effects. One major component of herbs and spices is the polyphenols. Some of the aforementioned properties are attributed to the polyphenols and they are associated with attenuating the metabolic syndrome. Detrimental changes associated with the metabolic syndrome over time affect brain and cognitive function. Metabolic syndrome and type-2 diabetes are also risk factors for Alzheimer's disease and stroke. In addition, the neuroprotective effects of herbs and spices have been demonstrated and, whether directly or indirectly, such beneficial effects may also contribute to an improvement in cognitive function. This review evaluates the current evidence available for herbs/spices in potentially improving the metabolic syndrome, as well as their neuroprotective effects on the brain, and cognitive function in animal and human studies. PMID- 23092407 TI - Neuroprotective actions of flavones and flavonols: mechanisms and relationship to flavonoid structural features. AB - Epidemiological studies have shown positive preventive action of flavonoids on cardiovascular and neurodegenerative events. Among the six groups in which flavonoids are classified, the flavones and flavonols, based on the backbone of 2 phenylchromen-4-one (2-phenyl-1-benzopyran-4-one) are the most commonly encountered within the families and genera of the higher plants. Numerous studies support a neuroprotective activity of flavones such as luteolin and flavonols such as kaempherol and quercetin in experimental focal ischemia and models of neurodegeneration. Antioxidation, modulation of signaling cascades and gene expression as well as anti-inflammation appear as the main protective mechanisms and mitochondria are a likely main target mediating the preventive actions against oxidative stress. Flavones and flavonols re-establish the redox regulation of proteins, transcription factors and signaling cascades that are otherwise inhibited by elevated oxidative stress. The final survival or death of the neuron depends on flavone and flavonol concentrations, time of exposure and, mainly, metabolic and oxidative neuronal circumstances. Neuroprotection appears to be linked to specific structural motifs, beyond those involved in antioxidation. By themselves or as templates for synthetic compounds, flavone and flavonol molecules show potential as multi-targeted therapeutic tools for protecting the brain. Nonetheless, more research needs to be done on the correlation of potential beneficial effects of flavones and flavonols and their mechanisms of action. PMID- 23092408 TI - Prophylaxis with Bacopa monnieri attenuates acrylamide induced neurotoxicity and oxidative damage via elevated antioxidant function. AB - Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications. Exposure to ACR causes neuropathy and associated neurological defects including gait abnormalities and skeletal muscle weakness, due to impaired neurotransmitter release and eventual neurodegeneration. Using in vivo and in vitro models, we examined whether oxidative events are involved in ACR-mediated neurotoxicity and whether these could be prevented by natural plant extracts. Administration (i.p.) of ACR in mice (40 mg/kg bw/ d for 5d) induced significant oxidative damage in the brain cortex and liver as evidenced by elevated lipid peroxidation, reactive oxygen species and protein carbonyls. This was associated with lowered antioxidant activities including antioxidant enzymes (catalase, glutathione-s-transferase) and reduced glutathione (GSH) compared to untreated controls. Similarly, exposure of N27 neuronal cells in culture to ACR (1-5 mM) caused dose-dependent neuronal death and lowered GSH. Interestingly, dietary supplementation with the leaf powder of Bacopa monnieri (BM) (which possesses neuroprotective properties and nootropic activity) in mice for 30 days offered significant protection against ACR toxicity and oxidative damage in vivo. Similarly, pretreatment with BM protected the N27 cells against ACR-induced cell death and associated oxidative damage. Co-treatment and pre-treatment of Drosophila melanogaster with BM extract protected against ACR-induced locomotor dysfunction and GSH depletion. We infer that BM displays prophylactic effects against ACR induced oxidative damage and neurotoxicity with potential therapeutic application in human pathology associated with neuropathy. PMID- 23092409 TI - Changes in gene expression in the rat hippocampus following exposure to 56Fe particles and protection by berry diets. AB - Exposing young rats to particles of high energy and charge, such as (56)Fe, enhances indices of oxidative stress and inflammation and disrupts behavior, including spatial learning and memory. In the present study, we examined whether gene expression in the hippocampus, an area of the brain important in memory, is affected by exposure to 1.5 Gy or 2.5 Gy of 1 GeV/n high-energy (56)Fe particles 36 hours after irradiation. We also determined if 8 weeks of pre-feeding with 2% blueberry or 2% strawberry antioxidant diets could ameliorate irradiation-induced changes in gene expression. Alterations in gene expression profile were analyzed by pathway-focused microarrays for inflammatory cytokines and genes involved in nuclear factor-kappa B (NF-kappaB) signal transduction pathways. We found that genes that are directly or indirectly involved in the regulation of growth and differentiation of neurons were changed following irradiation. Genes that regulate apoptosis were up-regulated whereas genes that modulate cellular proliferation were down-regulated. The brains of animals supplemented with berry diets demonstrated an up-regulation of some protective stress signal genes. Therefore, these data suggest that (56)Fe particle irradiation causes changes in gene expression in rats that are ameliorated by berry fruit diets. PMID- 23092410 TI - Effect of Withania somnifera supplementation on rotenone-induced oxidative damage in cerebellum and striatum of the male mice brain. AB - Withania somnifera (WS) an ayurvedic medicinal herb is widely known for its memory enhancing ability and improvement of brain function. In the present study, we tested the hypothesis that WS prophylaxis could offset neurotoxicant-induced oxidative dysfunctions in developing brain employing a rotenone (ROT) mouse model. Initially, we assessed the potential of WS oral supplements (100-400 mg/ kg b.w/ d, 4wks) to modulate the endogenous levels of oxidative markers in cerebellum (cb) and striatum (st) of prepubertal (PP) mice. Further, we assessed the induction of oxidative stress in cb and st of mice administered with ROT (i.p. 0.5 and 1mg/ kg b.w, 7d). ROT caused significant elevation in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), hydroperoxides (HP) and nitric oxide (NO) levels in both brain regions. Further ROT caused significant perturbations in the levels of reduced glutathione (GSH), activity levels of antioxidant enzymes, acetylcholinesterase and mitochondrial dysfunctions suggesting a state of oxidative stress. In a satellite study, we examined the protective effects of WS root powder (400mg/ kg b.w/ d, 4wks) in PP mice challenged with ROT (0.5 mg/ kg b.w/ d, 7 d). WS prophylaxis significantly offset ROT-induced oxidative damage in st and cb as evident by the normalized levels of oxidative markers (MDA, ROS levels and HP) and restoration of depleted GSH levels. Further, WS effectively normalized the NO levels in both brain regions suggesting its antiinflammatory action. Furthermore, WS prophylaxis restored the activity levels of cytosolic antioxidant enzymes, neurotransmitter function and dopamine levels in st. Taken together, these findings suggest that WS prophylaxis has the propensity to modulate neurotoxicant-mediated oxidative impairments and mitochondrial dysfunctions in specific brain regions of mice. While the exact mechanism/s underlying the neuroprotective effects of WS merit further investigation, based on our findings, we hypothesize that it may be wholly or in part due to its ability to enhance GSH, thiols and antioxidant defences in the brain of mice. PMID- 23092411 TI - Chloride in vesicular trafficking and function. AB - Luminal acidification is of pivotal importance for the physiology of the secretory and endocytic pathways and its diverse trafficking events. Acidification by the proton-pumping V-ATPase requires charge compensation by counterion currents that are commonly attributed to chloride. The molecular identification of intracellular chloride transporters and the improvement of methodologies for measuring intraorganellar pH and chloride have facilitated the investigation of the physiology of vesicular chloride transport. New data question the requirement of chloride for pH regulation of various organelles and furthermore ascribe functions to chloride that are beyond merely electrically shunting the proton pump. This review surveys the currently established and proposed intracellular chloride transporters and gives an overview of membrane trafficking steps that are affected by the perturbation of chloride transport. Finally, potential mechanisms of membrane-trafficking modulation by chloride are discussed and put into the context of organellar ion homeostasis in general. PMID- 23092412 TI - Statin treatment and carotid plaque composition: a review of clinical studies. AB - The impact on cardiovascular events achieved by statin therapy seems to be mostly attributable to their cholesterol- lowering effect, with a highly debated contribution of the lipid-independent pleiotropic effects. Statins have an established role in the treatment of hypercholesterolemia with a clear and robust reduction in cardiovascular morbidity and mortality. Nevertheless, the pathophysiologic effect of statins on inflammatory responses and local atherosclerotic plaque morphology in humans remains a matter of debate. In particular, the question remains whether statin-induced alterations in plaque composition can be ascribed mainly to low density lipoprotein cholesterol (LDL-C) lowering or an antiinflammatory pleiotropic effect, or both. This review summarizes the available evidence of the effects of statins on carotid plaque cellular composition in clinical settings, focusing on lipid-related and lipid independent effects of statin therapy. A systematic review of the web online databases was performed. Studies in humans evaluating the effect of statins on composition of carotid plaque removed at endarterectomy were eligible for inclusion. Data support the view that plaque composition even after a short-term lipid lowering therapy is significantly modulated by the degree of LDL-C lowering. A contribution of LDL-C independent, anti-inflammatory mechanisms of statins on plaque stability is only suggested by some of the studies. Actually, data strongly support the current guidelines based on progressively lower LDL-C targets depending upon the cardiovascular risk of individual patients. PMID- 23092413 TI - The clopidogrel-PPI interaction: an updated mini-review. AB - Proton pump inhibitors (PPIs) are recommended in patients with prior upper gastrointestinal bleeding and considered appropriate in patients with multiple other risk factors who require dual antiplatelet treatment (DAPT). During the past few years, however, concerns have been raised about the potential for PPIs, especially omeprazole, to decrease the efficacy of clopidogrel, and both the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued warnings regarding the concomitant use of these medications. A review of the literature revealed that the pharmacodynamic studies support an interaction, whereas the clinical evidence, which is mainly based on nonrandomized, observational studies and secondary analyses of randomized trials, is conflicting. We conclude that PPIs should be prescribed together with DAPT for patients in whom they are recommended according to the guidelines and for patients with other indications. With respect to omeprazole, current evidence does not allow clear recommendations to be provided. PMID- 23092414 TI - Rethinking Responsible Literature Searching using LibGuides. AB - Drawing from the Responsible Literature Searching project developed by the Health Sciences Library System-University of Pittsburgh, the Mayo Clinic Libraries utilized Springshare's LibGuides software to create an Effective Database Searching Guide for its diverse set of users. Library databases are organized under broad subject categories with overview information, links to help materials, and news on system updates. Additionally, the guide features a visual site map, searching best practices, a database comparison chart, responsible literature searching guidelines, classic evidence-based practice articles, and recommendations on when to contact a librarian for assistance. The self-guided tool is both easy to use and maintain. PMID- 23092415 TI - Literature searching in medical education: online tutorial development from idea to creation. AB - The medical education literature is growing, and the result is not only greater knowledge, but an increasing complexity in locating quality evidence-based information. In 2008, eight librarians partnered with the Association of American Medical Colleges to research, conceptualize, and build an online module to develop medical educators' search skills. Developing an online instructional module is a time-consuming, multi-stage process requiring the expertise of content, technical, and design specialists working in concert. Many lessons were learned, including the power of collaborative tools; the benefits of including specialists, such as graphic designers; the benefit of thoroughly surveying existing resources; and the importance of choosing technology wisely. PMID- 23092416 TI - Combined use of online tutorials and hands-on group exercises in bibliographic instruction for pharmacy students. AB - This study describes the new blended learning methodology implemented in a Drug Literature Evaluation course for pharmacy students that involves combined use of online tutorials and in-class group exercises. Assignment grades earned by 909 students enrolled in the course before and after the new methods were implemented (2008-2010) were studied to measure student performance. Course evaluations were analyzed in order to ascertain students' perceptions. The hybrid approach used to deliver the course content allowed students to perform at the same level as traditional didactic teaching. Students' evaluations reported a positive educational experience and favorable perceptions of the new course design. PMID- 23092418 TI - VisualDx: a visual diagnostic decision support tool. AB - VisualDx is a clinical decision support tool that uses images and searchable clinical features to assist physicians in the diagnostic decision-making process. VisualDx is a database of more than 24,000 high-quality images covering a wide variety of conditions and drug eruptions. In addition, VisualDx integrates within both UpToDate and many electronic medical records and features a mobile version. This column includes a sample search and a review of the features of VisualDx. PMID- 23092417 TI - The Frontera Collaboration: a preliminary report of health sciences librarians promoting evidence-based practice in U.S.-Mexico border communities. AB - This article reviews the formation of the Frontera Collaboration, a coalition of health sciences librarians serving clinicians and public health personnel in the U.S.-Mexico border region. Based on findings from an assessment of the target populations' learning needs, the Frontera Collaboration participants developed a shared set of training materials that have been used in pilot training sessions. The Frontera Collaboration's participants learned several lessons related to collaborative health information outreach and increased their understanding of the concerns and needs of clinicians and public health personnel serving border communities. PMID- 23092419 TI - Evaluation: theoretical underpinnings and web resources. AB - Librarians may benefit from understanding research theory more fully, looking at the services they offer as a program, and using program evaluation to understand the program value more completely. The process of program evaluation is research, and, as such, it should be situated within theory. This article reviews two of the basic theoretical concepts of research: ontology and epistemology. These concepts work together to help craft the research questions, and the questions drive the selection of methodology. The article also provides a list of web resources useful for understanding research theory in evaluation. PMID- 23092420 TI - Hospital clinicians' iPad use: an interim report. AB - An increasing number of hospital libraries are supporting the use of tablet computers such as iPads for access to information resources. To date, this adoption of tablets is not supported by high-quality research evidence. This article provides an interim report on a formal study of clinicians' use of iPads in the hospital setting, currently being conducted at Pennsylvania Hospital in Philadelphia. Other hospital librarians may wish to consider similar factors when beginning to support the use of tablet computers at their own institutions. PMID- 23092421 TI - MRSQ informatics education columns: passing the baton. AB - This is the last Informatics Education column under the current editors. The outgoing co-editor identifies several key themes that describe the column during her tenure. The main theme discovered while reviewing the columns published over the last five years is technology. Technological changes and advances have affected the way in which librarians conduct instruction, such as incorporating e learning with traditional workshops and in-class sessions. Technology plays a key role in all of the themes that emerged. The incoming editors imagine what the future themes will be for the Informatics Education column. PMID- 23092429 TI - Uvaridacols E-H, highly oxygenated antiausterity agents from Uvaria dac. AB - Chemical investigation of the stems of Uvaria dac yielded four new highly oxygenated cyclohexene derivatives named uvaridacols E-H (1-4). Their structures were established through NMR and circular dichroism spectroscopic analysis. Uvaridacols E (1), F (2), and H (4) displayed weak preferential cytotoxicity against PANC-1 human pancreatic cancer cells under nutrition-deprived conditions in a concentration-dependent manner, without causing toxicity in normal nutrient rich conditions. PMID- 23092428 TI - Opposing effects of Toll-like receptors 2 and 4 on synaptic stability in the spinal cord after peripheral nerve injury. AB - BACKGROUND: Glial cells are involved in the synaptic elimination process that follows neuronal lesions, and are also responsible for mediating the interaction between the nervous and immune systems. Neurons and glial cells express Toll-like receptors (TLRs), which may affect the plasticity of the central nervous system (CNS). Because TLRs might also have non-immune functions in spinal-cord injury (SCI), we aimed to investigate the influence of TLR2 and TLR4 on synaptic plasticity and glial reactivity after peripheral nerve axotomy. METHODS: The lumbar spinal cords of C3H/HePas wild-type (WT) mice, C3H/HeJ TLR4-mutant mice, C57BL/6J WT mice, and C57BL/6J TLR2 knockout (KO) mice were studied after unilateral sciatic nerve transection. The mice were killed via intracardiac perfusion, and the spinal cord was processed for immunohistochemistry, transmission electron microscopy (TEM), western blotting, cell culture, and reverse transcriptase PCR. Primary cultures of astrocytes from newborn mice were established to study the astrocyte response in the absence of TLR2 and the deficiency of TLR4 expression. RESULTS: The results showed that TLR4 and TLR2 expression in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord. First, TLR4 contributed to synaptic preservation of terminals in apposition to lesioned motor neurons after peripheral injury, regardless of major histocompatibility complex class I (MHC I) expression. In addition, in the presence of TLR4, there was upregulation of glial cell-derived neurotrophic factor and downregulation of interleukin-6, but no morphological differences in glial reactivity were seen. By contrast, TLR2 expression led to greater synaptic loss, correlating with increased astrogliosis and upregulation of pro-inflammatory interleukins. Moreover, the absence of TLR2 resulted in the upregulation of neurotrophic factors and MHC I expression. CONCLUSION: TLR4 and TLR2 in the CNS may have opposite effects on the stability of presynaptic terminals in the spinal cord and in astroglial reactions, indicating possible roles for these proteins in neuronal and glial responses to injury. PMID- 23092430 TI - Synthesis and characterization of a series of annelated benzotriazole based polymers with variable bandgap. AB - Here we report the synthesis and characterization of a series of annelated benzotriazole based polymers with variable bandgap. Benzobistriazole monomers reported by us previously were desymmetrized using partial reduction ring opening followed by ring closure to produce a wide range of annelated benzotriazole based monomers. These monomers were co-polymerized with a fluorene moiety to give polymers with bandgaps ranging from 1.16 to 2.41 eV. PMID- 23092432 TI - Modulation of cellular Mg2+ content in cardiac cells by alpha1-adrenoceptor stimulation and anti-arrhythmic agents. AB - Magnesium (Mg(2+)) is used pharmacologically to sedate specific forms of arrhythmias. Administration of pharmacological doses of catecholamine or adrenergic receptor agonists often results in arrhythmias onset. Results from the present study indicate that stimulation of cardiac adrenergic receptors elicits an extrusion of cellular Mg(2+) into the extracellular space. This effect occurs in both perfused hearts and isolated cells within 5-6 min following either beta- or alpha1- adrenergic receptor stimulation, and is prevented by specific adrenergic receptors antagonists. Sequential stimulation of the two classes of adrenergic receptor results in a larger mobilization of cellular Mg(2+) provided that the two agonists are administered together or within 1-2 min from each other. A longer delay in administering the second stimulus results in the abolishment of Mg(2+) extrusion. Hence, these data suggest that the stimulation of beta- and alpha1-adrenergic receptors mobilizes Mg(2+) from two distinct cellular pools, and that Mg(2+) loss from either pool triggers a Mg(2+) redistribution within the cardiac myocyte. At the sarcolemmal level, Mg(2+) extrusion occurs through a Na(+)/Mg(2+) exchange mechanism phosphorylated by cAMP. Administration of quinidine, a patent anti-arrhythmic agent, blocks Na(+) transport in a non-specific manner and prevents Mg(2+) extrusion. Taken together, these data indicate that catecholamine administration induces dynamic changes in total and compartmentalized Mg(2+) pools within the cardiac myocytes, and suggest that prevention of Mg(2+) extrusion and redistribution may be an integral component of the effectiveness of quinidine and possibly other cardiac antiarrhythmic agents. Confirmation of this possibility by future experimental and clinical studies might result in new patents of these compounds as Mg(2+) preserving agents. PMID- 23092434 TI - Lessons learned from muscle fatigue: implications for treatment of patients with hyperkalemic periodic paralysis. AB - Hyperkalemic periodic paralysis (HyperKPP) is a disease characterized by periods of myotonic discharges and paralytic attacks causing weakness, the latter associated with increases in plasma [K(+)]. The myotonic discharge is due to increased Na(+) influx through defective Na(+) channels that triggers generation of several action potentials. The subsequent increase in extracellular K(+) concentration causes excessive membrane depolarization that inactivates Na(+) channels triggering the paralysis. None of the available treatments is fully effective. This paper reviews the capacity of Na(+) K(+)ATPase pumps, KATP and ClC-1 Cl(-) channels in improving membrane excitability during muscle activity and how using these three membrane components we can study future and more effective treatments for HyperKPP patients. The review of current patents related to HyperKPP reinforces the need of novel approaches for the treatment of this channelopathy. PMID- 23092431 TI - Ryanodine receptor patents. AB - Research over the past two decades has implicated dysfunction of the ryanodine receptor (RyR), a Ca(2+) release channel on the sarcoplasmic reticulum (SR) required for excitation-contraction (EC) coupling, in the pathogenesis of cardiac and skeletal myopathies. These discoveries have led to the development of novel drugs, screening tools, and research methods. The patents associated with these advances tell the story of the initial discovery of RyRs as a target for plant alkaloids, to their central role in cardiac and skeletal muscle excitation contraction coupling, and ongoing clinical trials with a novel class of drugs called RycalsTM that inhibit pathological intracellular Ca(2+) leak. Additionally, these patents highlight questions, controversies, and future directions of the RyR field. PMID- 23092433 TI - Prostaglandin E2: from clinical applications to its potential role in bone- muscle crosstalk and myogenic differentiation. AB - Prostaglandin E(2) (PGE(2)), a prostanoid synthesized from arachidonic acid via the cyclooxygenase pathway, is a modulator of physiological responses including inflammation, fever, and muscle regeneration. Several patents have been filed that are related to PGE(2), one of them being directly related to skeletal muscles. In this report, we first summarize the key patents describing inventions for the utilization of PGE(2) for either diagnostic or therapeutic purposes, including skeletal muscle. In the second part of our work we present new and exciting data that demonstrates that PGE(2) accelerates skeletal muscle myogenic differentiation. Our discovery resulted from our recent and novel concept of bone muscle crosstalk. Bone and muscle are anatomically intimate endocrine organs and we aimed to determine whether this anatomical intimacy also translates into a biochemical communication from bone cells to muscle cells at the in vitro level. The effects of MLOY4 osteocyte-like cell conditioned medium (CM) and three osteocyte-secreted factors, PGE(2), sclerostin and monocyte chemotactic protein (MCP-3), on C2C12 myogenic differentiation were evaluated using morphological analyses, a customized 96-gene PCR array, and measurements of intracellular calcium levels. MLO-Y4 CM and PGE(2), but not sclerostin and MCP-3, induced acceleration of myogenesis of C2C12 myoblasts that was linked with significant modifications in intracellular calcium homeostasis. This finding should further stimulate the pursuit of new patents to explore the use of PGE(2) and the new concept of bone-muscle crosstalk for the development and application of inventions designed to treat muscle diseases characterized by enhanced muscle wasting, such as sarcopenia. PMID- 23092435 TI - Jatropha curcas: from biodiesel generation to medicinal applications. AB - Jatropha curcas (JC) is a multipurpose perennial plant that belongs to the Euphorbiaceae family and is native to arid and semiarid tropical regions worldwide. It has many attributes and considerable potential for renewable energy, fish and livestock feeding. Despite its rich application as a renewable source and for animal feeding, JC has barely been explored for its medicinal potential. Here we review several patents related to JC that show it has been underused for medicinal purposes. For example, only one invention disclosure to date utilizes JC, combined with three other plants, in a preparation for wound healing. Motivated by support from the Brazilian funding agencies and anecdotal accounts in Brazil of the medicinal value of JC, we performed a series of pilot studies that demonstrate that JC is able to protect skeletal muscle cells in vitro against the deleterious effects of ethanol. We were able to determine that JC's effects are mediated by the up regulation of HSP60, a critical mitochondrial heat shock related protein that is essential for intracellular REDOX regulation. Given the fact that ethanol myopathy accounts for more than 50% of all cases of myopathy worldwide, we hope that our studies will sparkle new interest from the scientific community to explore the medicinal properties of Jatropha curcas, including the development of new patents leading to new drugs and new targets for the treatment of muscle diseases and other human diseases. PMID- 23092437 TI - Myokines in myogenesis and health. AB - Although some myokines exert their actions on other organs in a hormone-like fashion, many of them operate locally on skeletal muscle themselves. Myokines may thereby provide a feedback loop for the muscle to regulate its own growth and regeneration allowing for adaptation to exercise training. The myokine concept provides a conceptual basis and a whole new paradigm for understanding how muscles communicate with other organs within the muscle itself. New biotechnological patents are published based on the identification of new myokines, and these myokines and their receptors will potentially serve as pharmacological targets for treating muscle diseases, metabolic disorders and other diseases associated with muscle disuse. PMID- 23092436 TI - Poloxamer 188 (p188) as a membrane resealing reagent in biomedical applications. AB - Maintenance of the integrity of the plasma membrane is essential for maintenance of cellular function and prevention of cell death. Since the plasma membrane is frequently exposed to a variety of mechanical and chemical insults the cell has evolved active processes to defend against these injuries by resealing disruptions in the plasma membrane. Cell membrane repair is a conserved process observed in nearly every cell type where intracellular vesicles are recruited to sites of membrane disruption where they can fuse with themselves or the plasma membrane to create a repair patch. When disruptions are extensive or there is an underlying pathology that reduces the membrane repair capacity of a cell this defense mechanism may prove insufficient and the cell could die due to breakdown of the plasma membrane. Extensive loss of cells can compromise the integrity and function of tissues and leading to disease. Thus, methods to increase membrane resealing capacity could have broad utility in a number of disease states. Efforts to find reagents that can modulate plasma membrane reseal found that specific tri-block copolymers, such as poloxamer 188 (P188, or Pluronic F68), can increase the structural stability and resealing of the plasma membrane. Here we review several current patents and patent applications that present inventions making use of P188 and other copolymers to treat specific disease states such as muscular dystrophy, heart failure, neurodegenerative disorders and electrical injuries, or to facilitate biomedical applications such as transplantation. There appears to be promise for the application of poloxamers in the treatment of various diseases, however there are potential concerns with toxicity with long term application and bioavailability in some cases. PMID- 23092439 TI - Dithiocarbamate complexes with metals in cancer therapy. PMID- 23092438 TI - Hyperthermia: from diagnostic and treatments to new discoveries. AB - Hyperthermia is an important approach for the treatment of several diseases. Hyperthermia is also thought to induce hypertrophy of skeletal muscles in vitro and in vivo, and has been used as a therapeutic tool for millennia. In the first part of our work, we revise several relevant patents related to the utilization of hyperthermia for the treatment and diagnostic of human diseases. In the second part, we present exciting new data on the effects of forced and natural overexpression of HSP72, using murine in vitro (muscle cells) and ex vivo (primary skeletal muscles) models. These studies help to demonstrate that hyperthermia effects are orchestrated by tight coupling between gene expression, protein function, and intracellular Ca2+ signaling pathways with a key role for calcium-induced calcium release. We hope that the review of current patents along with previous unknown information on molecular signaling pathways that underlie the hypertrophy response to hyperthermia in skeletal muscles may trigger the curiosity of scientists worldwide to explore new inventions that fully utilize hyperthermia for the treatment of muscle diseases. PMID- 23092440 TI - The Davis-Beirut Reaction: a novel entry into 2H-indazoles and indazolones. Recent biological activity of indazoles. AB - A novel, easy method for the syntheses of richly diversified 2H-indazoles and indazolones, called the Davis-Beirut reaction, and other recent 2H-indazole synthetic routes are briefly reviewed. An update on the biological activity of indazoles is also surveyed. PMID- 23092441 TI - Construction of a novel selection system for endoglucanases exhibiting carbohydrate-binding modules optimized for biomass using yeast cell-surface engineering. AB - To permit direct cellulose degradation and ethanol fermentation, Saccharomyces cerevisiae BY4741 (Deltased1) codisplaying 3 cellulases (Trichoderma reesei endoglucanase II [EG], T. reesei cellobiohydrolase II [CBH], and Aspergillus aculeatus beta-glucosidase I [BG]) was constructed by yeast cell-surface engineering. The EG used in this study consists of a family 1 carbohydrate binding module (CBM) and a catalytic module. A comparison with family 1 CBMs revealed conserved amino acid residues and flexible amino acid residues. The flexible amino acid residues were at positions 18, 23, 26, and 27, through which the degrading activity for various cellulose structures in each biomass may have been optimized. To select the optimal combination of CBMs of EGs, a yeast mixture with comprehensively mutated CBM was constructed. The mixture consisted of yeasts codisplaying EG with mutated CBMs, in which 4 flexible residues were comprehensively mutated, CBH, and BG. The yeast mixture was inoculated in selection medium with newspaper as the sole carbon source. The surviving yeast consisted of RTSH yeast (the mutant sequence of CBM: N18R, S23T, S26S, and T27H) and wild-type yeast (CBM was the original) in a ratio of 1:46. The mixture (1 RTSH yeast and 46 wild-type yeasts) had a fermentation activity that was 1.5-fold higher than that of wild-type yeast alone in the early phase of saccharification and fermentation, which indicates that the yeast mixture with comprehensively mutated CBM could be used to select the optimal combination of CBMs suitable for the cellulose of each biomass. PMID- 23092442 TI - Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension. METHODS: We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy. RESULTS: Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant. CONCLUSION: Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible. PMID- 23092443 TI - The antibacterial effects of silver, titanium dioxide and silica dioxide nanoparticles compared to the dental disinfectant chlorhexidine on Streptococcus mutans using a suite of bioassays. AB - Metal-containing nanomaterials have the potential to be used in dentistry for infection control, but little is known about their antibacterial properties. This study investigated the toxicity of silver (Ag), titanium dioxide and silica nanoparticles (NPs) against the oral pathogenic species of Streptococcus mutans, compared to the routine disinfectant, chlorhexidine. The bacteria were assessed using the minimum inhibitory concentration assay for growth, fluorescent staining for live/dead cells, and measurements of lactate. All the assays showed that Ag NPs had the strongest antibacterial activity of the NPs tested, with bacterial growth also being 25-fold lower than that in chlorhexidine. The survival rate of bacteria under the effect of 100 mg l(-1) Ag NPs in the media was 2% compared to 60% with chlorhexidine, while the lactate concentration was 0.6 and 4.0 mM, respectively. Silica and titanium dioxide NPs had limited effects. Dialysis experiments showed negligible silver dissolution. Overall, Ag NPs were the best disinfectant and performed better than chlorhexidine. Improvements to the MIC assay are suggested. PMID- 23092444 TI - Multiple interaction regions in the orthosteric ligand binding domain of the alpha7 neuronal nicotinic acetylcholine receptor. AB - Neuronal nicotinic receptors (nAChRs) belong to the Cys-loop family of ligand gated ion channels and are formed from five subunits either as homologous or heterologous, oligomeric receptors, and are of interest as targets for treatment of a variety of central and peripheral nervous system disorders. Using a model of the homopentameric alpha7 nAChR extracellular region derived from the homologous acetylcholine binding protein (AChBP) from Aplysia California, binding modes of structurally diverse, high affinity alpha7 ligands were examined by docking to the orthosteric ligand binding domain. While all alpha7 ligands show similar interactions between the essential positively charged cationic center of the ligand and alphaTRP147 of the receptor (i.e., hydrogen bond to the tryptophan backbone carbonyl and cation-pi interaction), docked poses of various ligands show the potential to interact with three additional regions within the binding domain, identified as regions 1, 2, and 3. Region 1 is located in the vicinity of Loop-E, involves ligand-protein interactions via a network of water-mediated hydrogen bonds, and is analogous to the region where pyridinyl groups are located in many of the AChBP-nicotinic ligand cocrystal structures. Ligands interacting with region 2 probe an area that spans from Loop-E to Loops-D and -F and may contribute to alpha7-selectivity over other nAChR subtypes. Several high affinity alpha7 ligands show strong interactions in this region. Region 3 is located near Loop-F of the protein and is analogous to an area involved in binding of an active metabolite derived from DMXBA, in an AChBP cocrystal structure. It appears that pi-pi interactions contribute to binding affinities of alpha7 nAChR ligands in this latter region, and further, this region may also contribute to alpha7 selectivity over other nAChR subtypes. Analysis of the resulting poses suggests that compounds with high alpha7 binding affinity do not require interactions across all regions simultaneously, but that interactions in multiple regions may enhance ligand binding and increase selectivity. Our results provide insight for further development of selective alpha7 nAChR ligands and may prove useful for the design of novel scaffolds for specific nicotinic therapeutic agents. PMID- 23092445 TI - Brownian dynamics simulation of comicellization of amphiphilic block copolymers with different tail lengths. AB - Brownian dynamics simulations were performed to study the self-assembly of mixed linear amphiphilic block copolymers. The molecules consist of similar hydrophilic heads and hydrophobic tails of different lengths. The model amphiphilic diblock copolymers have been selected to gain insight into the comicellization process in concentrated regimes, and the micelles were not kinetically frozen on the time scale of simulation. The critical micelle concentration (cmc), micelle size distribution, radius of gyration distribution, density profile of comicelles, shape anisotropy, and dynamics of comicellization have been studied as a function of the varying molar fraction of components. The cmc's of systems rich in the molar fraction of each type were found to be close to the cmc of that component. It has also been found that at a certain concentration comicellization affects the cmc in mixed systems. The weight-average aggregate size distribution of mixed copolymers was found to be between the aggregate distributions of short and long copolymers and becomes broader because of mixing. Moreover, values of the most probable aggregate size and radius of gyration of comicelles follow the mixing rule. Results show that small aggregates are mainly made from shorter block copolymers, whereas longer block copolymers form the major portion of large clusters. Furthermore, the cores of the micelles are mainly composed of longer block copolymers, and in all cases, the concentrations of shorter block copolymers are more dominant in the outer part than in the interior regions. In addition, the dynamics of polymeric micelles was studied using tracer and extraction autocorrelation functions and their relaxation times. The tracer correlation time increases with increasing longer copolymer concentration and deviates positively from the mixing rule. We also find that the total extraction correlation time increases exponentially from short to long copolymers, but the presence of long block copolymers linearly increases the short copolymer extraction correlation times. Short block copolymers, however, linearly decrease the long copolymer correlation times. PMID- 23092447 TI - A new triterpene saponin from the roots of Ilex pubescens. AB - A new triterpene saponin, ilexoside P (1), along with three known triterpene saponins, ilexoside O (2), ilexsaponin B3 (3) and ilexpublesnin A (4) was isolated from the roots of Ilex pubescens. Their chemical structures were elucidated on the basis of UV, IR, MS, and NMR spectroscopic analyses coupled with chemical degradation. In addition, the xanthine oxidase (XOD) inhibitory activity of the isolated saponins was reported. Compound 1 exhibited weak XOD inhibitory activity in the test. PMID- 23092446 TI - The adipokine adiponectin has potent anti-fibrotic effects mediated via adenosine monophosphate-activated protein kinase: novel target for fibrosis therapy. AB - INTRODUCTION: Fibrosis in scleroderma is associated with collagen deposition and myofibroblast accumulation. Peroxisome proliferator activated receptor gamma (PPAR-gamma), a master regulator of adipogenesis, inhibits profibrotic responses induced by transforming growth factor-beta (TGF-beta), and its expression is impaired in scleroderma. The roles of adiponectin, a PPAR-gamma regulated pleiotropic adipokine, in regulating the response of fibroblasts and in mediating the effects of PPAR-gamma are unknown. METHODS: Regulation of fibrotic gene expression and TGF-beta signaling by adiponectin and adenosine monophosphate protein-activated (AMP) kinase agonists were examined in normal fibroblasts in monolayer cultures and in three-dimensional skin equivalents. AdipoR1/2 expression on skin fibroblasts was determined by real-time quantitative PCR. RESULTS: Adiponectin, an adipokine directly regulated by PPAR-gamma, acts as a potent anti-fibrotic signal in normal and scleroderma fibroblasts that abrogates the stimulatory effects of diverse fibrotic stimuli and reduces elevated collagen gene expression in scleroderma fibroblasts. Adiponectin responses are mediated via AMP kinase, a fuel-sensing cellular enzyme that is necessary and sufficient for down-regulation of fibrotic genes by blocking canonical Smad signaling. Moreover, we demonstrate that endogenous adiponectin accounts, at least in part, for the anti-fibrotic effects exerted by ligands of PPAR-gamma. CONCLUSIONS: These findings reveal a novel link between cellular energy metabolism and extracellular matrix homeostasis converging on AMP kinase. Since the levels of adiponectin as well as its receptor are impaired in scleroderma patients with progressive fibrosis, the present results suggest a potential role for defective adiponectin expression or function in progressive fibrogenesis in scleroderma and other chronic fibrosing conditions. Restoring the adiponectin signaling axis in fibroblasts might, therefore, represent a novel pharmacological approach to controlling fibrosis. PMID- 23092448 TI - Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson's disease. AB - BACKGROUND: Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. METHODS: Both pre treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), gp91phox and inducible nitric oxide synthase (iNOS), were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH)-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE) and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. RESULTS: Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN). MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in this pre-clinical model of PD. Importantly, diapocynin administered 3 days after initiation of the disease restored the neurochemical deficits. Diapocynin also halted the disease progression in a chronic mouse model of PD. CONCLUSIONS: Collectively, these results demonstrate that diapocynin exhibits profound neuroprotective effects in a pre-clinical animal model of PD by attenuating oxidative damage and neuroinflammatory responses. These findings may have important translational implications for treating PD patients. PMID- 23092449 TI - Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy. AB - BACKGROUND: Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. METHODS: We reviewed the clinical, pathological and genetic features of twenty four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females. RESULTS: Symptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found. CONCLUSIONS: Skewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene. PMID- 23092450 TI - The role of the 5-hydroxytryptamine pathway in reflux-induced esophageal mucosal injury in rats. AB - BACKGROUND: Dysfunction of the 5-hydroxytryptamine (5-HT) signaling pathway can lead to gastrointestinal motility and secretion abnormalities and to visceral hypersensitivity. The aim of this study is to investigate the role of 5-HT in reflux-induced esophageal mucosal injury. METHODS: Fifty 8-week-old male Sprague Dawley (SD) rats were randomly divided into a gastroesophageal reflux (GER) model group (30 rats) and a sham surgery control group (20 rats). Four weeks after surgery, the esophageal mucosa was collected for histological evaluation, 5-HT concentrations, and 5-HT selective reuptake transporter (SERT) mRNA and 5-HT4 receptor (5-HT4R) protein expressions. RESULTS: Twenty-seven rats in the GER model group survived, and three rats died. Histologically, in the GER model group, 20 rats had reflux esophagitis (RE group), and 7 rats had non-erosive reflux disease (NERD group). The 5-HT levels in the esophageal tissue from the RE group were significantly higher than those from the control and NERD groups. Both the RE and NERD groups showed significant increases in SERT mRNA expression of the esophageal mucosa than that of the controls, and the SERT mRNA level in the RE group was significantly higher than that in the NERD group. The 5-HT4R protein level of the esophageal mucosa in the RE group was significantly lower than that in the controls and the NERD group. CONCLUSIONS: We conclude that a 5-HT signaling pathway disorder could be a major factor in the pathogenesis of GER and RE. PMID- 23092502 TI - Segregated versus mixed interchain stacking in highly oriented films of naphthalene diimide bithiophene copolymers. AB - Highly oriented films of an electron accepting polymer semiconductor, poly{[N,N' bis(2-octyldodecyl)-1,4,5,8-naphthalenedicarboximide-2,6-diyl]-alt-5,5'-(2,2' bithiophene)} (PNDI2OD-T2), are obtained by two different methods, namely directional epitaxial crystallization (DEC) on 1,3,5-trichlorobenzene (TCB) and epitaxy on friction transferred poly(tetrafluoroethylene) (PTFE) substrates. Two distinct polymorphs with unprecedented intrachain resolution are identified by high-resolution transmission electron microscopy (HR-TEM). Form I is obtained by DEC on TCB, whereas highly oriented films of form II are obtained on PTFE substrates after melting at T = 300 degrees C and cooling at 0.5 K/min. In form I, both electron diffraction and HR-TEM indicate a segregated stacking of bithiophene (T2) and naphthalene diimide (NDI) units forming separate columns. In form II, a ~c/2 shift between successive pi-stacked chains leads to mixed pi overlaps of T2 and NDI. Form I can be transformed into form II by annealing at T > 250 degrees C. The different pi-stacking of NDI and T2 in the two polymorphs have characteristic signatures in the UV-vis spectra, especially in the charge transfer band around 750 nm which is also observed in spin-coated films. PMID- 23092451 TI - Rationale, design, methodology and sample characteristics for the Vietnam pre conceptual micronutrient supplementation trial (PRECONCEPT): a randomized controlled study. AB - BACKGROUND: Low birth weight and maternal anemia remain intractable problems in many developing countries. The adequacy of the current strategy of providing iron folic acid (IFA) supplements only during pregnancy has been questioned given many women enter pregnancy with poor iron stores, the substantial micronutrient demand by maternal and fetal tissues, and programmatic issues related to timing and coverage of prenatal care. Weekly IFA supplementation for women of reproductive age (WRA) improves iron status and reduces the burden of anemia in the short term, but few studies have evaluated subsequent pregnancy and birth outcomes.The Preconcept trial aims to determine whether pre-pregnancy weekly IFA or multiple micronutrient (MM) supplementation will improve birth outcomes and maternal and infant iron status compared to the current practice of prenatal IFA supplementation only. This paper provides an overview of study design, methodology and sample characteristics from baseline survey data and key lessons learned. METHODS/DESIGN: We have recruited 5011 WRA in a double-blind stratified randomized controlled trial in rural Vietnam and randomly assigned them to receive weekly supplements containing either: 1) 2800 MUg folic acid 2) 60 mg iron and 2800 MUg folic acid or 3) MM. Women who become pregnant receive daily IFA, and are being followed through pregnancy, delivery, and up to three months post-partum. Study outcomes include birth outcomes and maternal and infant iron status. Data are being collected on household characteristics, maternal diet and mental health, anthropometry, infant feeding practices, morbidity and compliance. DISCUSSION: The study is timely and responds to the WHO Global Expert Consultation which identified the need to evaluate the long term benefits of weekly IFA and MM supplementation in WRA. Findings will generate new information to help guide policy and programs designed to reduce the burden of anemia in women and children and improve maternal and child health outcomes in resource poor settings. TRIAL REGISTRATION: NCT01665378. PMID- 23092503 TI - Fragility of reconstituted type V collagen fibrils with the chain composition of alpha1(V)alpha2(V)alpha3(V) respective of the D-periodic banding pattern. AB - The triple-helical domains of two subtypes of type V collagen were prepared from human placenta, one with the chain composition of [alpha1(V)](2)alpha2(V) (Vp112) and the other with the chain composition of alpha1(V)alpha2(V)alpha3(V) (Vp123) with limited pepsin treatment. In order to characterize the triple-helical domain of the type Vp123 collagen molecule, the reconstituted aggregate structure formed from the pepsin-treated collagen was compared by using transmission electron microscopy. The diameter of the fibrils reconstituted from types pepsin-treated type Vp123 collagen and type Vp112 collagen was highly uniform and less than the D-periodicity at all the temperatures examined, suggesting that the major triple helical domain of both subtypes has a potency to limit their lateral growth. Both fibrils were approximately 45 nm in width and showed the D-periodic banding pattern along their axes at 34 degrees C. In contrast to type Vp112, the reconstituted type Vp123 fibrils showed no banding pattern along their axes when they were reconstituted at 37 degrees C. The banded fibrils once reconstituted from type Vp123 at 34 degrees C tend to lose their characteristic pattern within 60 min when they were incubated at 37 degrees C. One explanation is that a slightly higher content of hydrophobic residues of type Vp123 collagen than those of type V112p collagen augmented the intermolecular interaction that disturbs the D-periodicity governed essentially by electrostatic interactions. Taken together with recent data in Col5a3 gene-targeted mice, the results suggest that type V123 collagen exists not only as a periodic banded fibril but also as nonfibrillar meshwork structures. PMID- 23092505 TI - Rapid intracellular growth of gold nanostructures assisted by functionalized graphene oxide and its application for surface-enhanced Raman spectroscopy. AB - Hybridization of metal nanoparticles with graphene oxide for high performance surface-enhanced Raman scattering (SERS) has attracted overwhelming attention in recent years. Herein, a one-pot green route for intracellular synthesis of gold nanostructures assisted by poly(vinylpyrrolidone) (PVP)-functionalized graphene oxide (GO) was proposed. The hybrids obtained [GO/PVP/intracellularly grown gold nanoparticles (IGAuNs)] randomly scattered throughout the cell. Compared with the IGAuNs, the growth of GO/PVP/IGAuNs was remarkably accelerated, which could be attributed to the coordination of PVP enriched on GO. GO/PVP/IGAuNs could serve as excellent SERS probes for ultrasensitive detection of cellular components of cancer cells located in the cytoplasm, nucleoplasm, and nucleolus. The random intracellular distribution of GO/PVP/IGAuNs facilitated the effective Raman characterization of cellular components, which was confirmed by the uniform distribution of SERS signals in the Raman image. The SERS signals induced by GO/PVP/IGAuNs could be collected as early as 15 h, which allowed rapid detection of tumor cells. In conclusion, this facile and green strategy for fast intracellular growth of GO/PVP/IGAuNs offered great potential for biomedical applications. PMID- 23092504 TI - Photoaddition reactions of acetylpyridines with silyl ketene acetals: SET vs [2 + 2]-cycloaddition pathways. AB - Photoaddition reactions of silyl ketene acetals with 2-, 3- and 4-acetylpyridine have been explored. The results show that the acetylpyridines react with an electron rich, dimethyl-substituted silyl ketene acetal via a pathway in which excited state single electron transfer (SET) takes place to produce beta hydroxyesters in high yields. In contrast, photochemical reactions of the acetylpyridines with an electron deficient, nonmethyl-substituted silyl ketene acetal generate oxetanes as major products, which arise via a route involving excited state [2 + 2]-cycloaddition. In addition, an increase in solvent polarity significantly enhances the relative efficiencies of the SET processes versus [2 + 2]-cycloaddition reactions. Importantly, the carbonyl groups rather than the pyridine moieties in the acetylpyridine substrates participate in both types of addition reactions. Finally, the results demonstrate that photoinduced electron transfer (PET)-promoted chemical reactions between acetylpyridines and electron rich silyl ketene acetals in polar solvent serve as useful methods to promote beta-hydroxyester forming, Claisen or Mukaiyama condensation reactions under mild conditions. PMID- 23092506 TI - PPh3-catalyzed (3 + 3) annulations of 5-acetoxypenta-2,3-dienoate with 1C,3O bisnucleophiles: facile entry to stable monocyclic 2H-pyrans. AB - Phosphine-catalyzed (3 + 2) and (3 + 3) annulations between 5-acetoxypenta-2,3 dienoate and 1C,3O-bisnucleophiles are presented. The former cases can be achieved with the assistance of base while the latter is dominant without any additive. A series of deuterium-labeling experiments disclosed that the divergence in annulations is likely determined by the involved proton transfer processes. PMID- 23092507 TI - Influence of activated charcoal on desorption kinetics and biodegradation of phenanthrene in soil. AB - The observed strong sorption of polycyclic aromatic hydrocarbons (PAHs) to black carbon (BC) presents potential implications for PAH bioaccessibility in soils. The effects of BC on the desorption kinetics and mineralization of phenanthrene in four soils was investigated after 1, 25, 50, and 100 d soil-PAH contact time, using sequential hydroxypropyl-beta-cyclodextrin (HPCD) extractions in soils amended with 0, 0.1, 1, and 5% (dry wt. soil) activated charcoal (AC, a form of BC). The rapidly (%F(rap)) and slowly (%F(slow)) desorbing phenanthrene fractions and their rate constants were determined using a first-order two-compartment (biphasic) desorption model. A minimum 7.8-fold decrease in %F(rap) occurred when AC was increased from 0 to 5%, with a corresponding increase in %F(slow). Desorption rate constants followed the progression k(rap) (% h(-1)) > k(slow) (% h(-1)) and were in the order of 10(-1) to 10(-2) and 10(-3) to 10(-4), respectively. Linear regressions between %F(rap) and the fractions degraded by a phenanthrene-degrading inoculum (%F(min)) indicated that slopes did not approximate 1 at concentrations greater than 0% AC; %F(min) often exceeded %F(rap), indicating a fraction of sorbed phenanthrene (%F(slow)) remained microbially accessible. Therefore, HPCD-desorption kinetics alone may not be an adequate basis for the prediction of the bioaccessibility of PAHs to microorganisms or bioremediation potential in AC-amended soils. PMID- 23092509 TI - Doping human serum albumin with retinoate markedly enhances electron transport across the protein. AB - Electrons can migrate via proteins over distances that are considered long for nonconjugated systems. The nanoscale dimensions of proteins and their enormous structural and chemical flexibility makes them fascinating subjects for exploring their electron transport (ETp) capacity. One particularly attractive direction is that of tuning their ETp efficiency by "doping" them with small molecules. Here we report that binding of retinoate (RA) to human serum albumin (HSA) increases the solid-state electronic conductance of a monolayer of the protein by >2 orders of magnitude for RA/HSA >= 3. Temperature-dependent ETp measurements show the following with increasing RA/HSA: (a) The temperature-independent current magnitude of the low-temperature (<190 K) regime increases significantly (>300 fold), suggesting a decrease in the distance-decay constant of the process. (b) The activation energy of the thermally activated regime (>190 K) decreases from 220 meV (RA/HSA = 0) to 70 meV (RA/HSA >= 3). PMID- 23092510 TI - Retraction: Structure based sequence analysis & epitope prediction of gp41 HIV1 envelope glycoprotein isolated in Pakistan. PMID- 23092511 TI - Endogenous TDP-43, but not FUS, contributes to stress granule assembly via G3BP. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of upper and lower motor neurons, a cell type that is intrinsically more vulnerable than other cell types to exogenous stress. The interplay between genetic susceptibility and environmental exposures to toxins has long been thought to be relevant to ALS. One cellular mechanism to overcome stress is the formation of small dense cytoplasmic domains called stress granules (SG) which contain translationally arrested mRNAs. TDP-43 (encoded by TARDBP) is an ALS-causative gene that we have previously implicated in the regulation of the core stress granule proteins G3BP and TIA-1. TIA-1 and G3BP localize to SG under nearly all stress conditions and are considered essential to SG formation. Here, we report that TDP-43 is required for proper SG dynamics, especially SG assembly as marked by the secondary aggregation of TIA-1. We also show that SG assembly, but not initiation, requires G3BP. Furthermore, G3BP can rescue defective SG assembly in cells depleted of endogenous TDP-43. We also demonstrate that endogenous TDP-43 and FUS do not have overlapping functions in this cellular process as SG initiation and assembly occur normally in the absence of FUS. Lastly, we observe that SG assembly is a contributing factor in the survival of neuronal-like cells responding to acute oxidative stress. These data raise the possibility that disruptions of normal stress granule dynamics by loss of nuclear TDP-43 function may contribute to neuronal vulnerability in ALS. PMID- 23092513 TI - Commercial vehicles and road safety in Pakistan: exploring high-risk attributes among drivers and vehicles. AB - Road traffic injuries are on the rise in developing countries with a disproportionately high number of crashes involving commercial vehicles. Baseline information on risk factors is necessary to develop targeted prevention programmes. A survey of commercial drivers was conducted at the largest bus and truck station in Rawalpindi, Pakistan. Structured interviews elicited information from 857 drivers on their socio-demographics, high-risk driving behaviours, fatigue, use of drugs while driving, vehicle maintenance and health conditions, as well as crash involvement. A binary logistic regression analysis was used to investigate the factors associated with crash involvement in the last five years. Overall, 92 (11.2%) drivers reported having had a road crash in the last 5 years. Factors independently associated with the occurrence of crashes were alcohol use (OR 2.2, 95% CI 1.1-4.4), poor vehicle maintenance (OR 3.4, 95% CI 1.7-7.01) and lack of seat belt use (OR 2.7, 95% CI 1.3-5.6). The high prevalence of high-risk attributes in the study population indicates a great need for targeted risk prevention. PMID- 23092512 TI - Identification and characterization of naturally occurring splice variants of SAMHD1. AB - BACKGROUND: Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1) is a recently identified host factor that restricts HIV-1 replication in dendritic and myeloid cells. SAMHD1 is a dNTPase that presumably reduces the cellular dNTP levels to levels too low for retroviral reverse transcription to occur. However, HIV-2 and SIV encoded Vpx counteracts the antiviral effects of SAMHD1 by targeting the protein for proteasomal degradation. SAMHD1 is encoded by a multiply spliced mRNA and consists of 16 coding exons. RESULTS: Here, we identified two naturally occurring splice variants lacking exons 8-9 and 14, respectively. Like wildtype SAMHD1, both splice variants localize primarily to the nucleus, interact with Vpx, and retain some sensitivity to Vpx-dependent degradation. However, the splice variants differ from full-length SAMHD1 in their metabolic stability and catalytic activity. While full-length SAMHD1 is metabolically stable in uninfected cells, both splice variants were inherently metabolically unstable and were rapidly degraded even in the absence of Vpx. Vpx strongly increased the rate of degradation of full-length SAMHD1 and further accelerated the degradation of the splice variants. However, the effect of Vpx on the splice variants was more modest due to the inherent instability of these proteins. Analysis of dNTPase activity indicates that neither splice variant is catalytically active. CONCLUSIONS: The identification of SAMHD1 splice variants exposes a potential regulatory mechanism that could enable the cell to control its dNTPase activity on a post-transcriptional level. PMID- 23092516 TI - Antiblastic treatment, for solid tumors, during pregnancy: a crucial decision. AB - Cancer is the second leading cause of death during the reproductive years complicating between 0.02 percent and 0.1 percent of pregnancies. The incidence is expected to rise with the increase in age of childbearing. The most common types of pregnancy-associated cancers are: cervical cancer, breast cancer, malignant melanoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma and ovarian cancer. The relatively rare occurrence of pregnancy-associated cancer precludes conducting large, prospective studies to examine diagnostic, management and outcome issues. The treatment of pregnancy-associated cancer is complex since it may be associated with adverse fatal effects. In pregnant patients diagnosed with cancer during the first trimester, treatment with multidrug anti-cancer chemotherapy is associated with an increased risk of congenital malformations, spontaneous abortions or fetal death, and therefore, should follow a strong recommendation for pregnancy termination. Second and third trimester exposure is not associated with teratogenic effect but increases the risk of intrauterine growth retardation and low birth weight. There are no sufficient data regarding the teratogenicity of most cytotoxic drugs. Almost all chemotherapeutic agents were found to be teratogenic in animals and for some drugs only experimental data exist. Moreover, no pharmacokinetic studies have been conducted in pregnant women receiving chemotherapy in order to understand whether pregnant women should be treated with different doses of chemotherapy. This article reviews the available data regarding the different aspects of the treatment of cancer during pregnancy. PMID- 23092514 TI - Lack of cross-protection against Bordetella holmesii after pertussis vaccination. AB - Bordetella holmesii, a species closely related to B. pertussis, has been reported sporadically as a cause of whooping cough-like symptoms. To investigate whether B. pertussis-induced immunity is protective against infection with B. holmesii, we conducted an analysis using 11 human respiratory B. holmesii isolates collected during 2005-2009 from a highly B. pertussis-vaccinated population in Massachusetts. Neither whole-cell (wP) nor acellular (aP) B. pertussis vaccination conferred protection against these B. holmesii isolates in mice. Although T-cell responses induced by wP or aP cross-reacted with B. holmesii, vaccine-induced antibodies failed to efficiently bind B. holmesii. B. holmesii specific antibodies provided in addition to wP were sufficient to rapidly reduce B. holmesii numbers in mouse lungs. Our findings suggest the established presence of B. holmesii in Massachusetts and that failure to induce cross-reactive antibodies may explain poor vaccine-induced cross-protection. PMID- 23092517 TI - Antiblastic treatment of haematological malignancies during pregnancy: a crucial decision. AB - Antiblastic treatment of hematological malignancies during pregnancy poses a number of issues related to the curability of the maternal disease, the need of a prompt treatment and the potential toxicity of chemotherapy for the fetus. Here we report the results of a systematic literature search about the management of the most frequent hematological malignancies that may occur during pregnancy, focusing on specific issues related to gestational age at diagnosis, fetal toxicity and efficacy on the maternal side. The standard approach in non-pregnant women is illustrated as reference. PMID- 23092518 TI - Obstetrical, fetal and postnatal effects of gestational antiblastic chemotherapy: how to counsel cancer patients. AB - At least one in a thousand pregnancies is complicated by cancer and, as the maternal age at pregnancy increases, numbers are growing. If chemotherapy cannot be postponed, both doctors and patients face complex medical and ethical issues. There is a conflict between optimal maternal therapy and fetal wellbeing. Treatment during the first trimester increases the risk of congenital malformations, spontaneous abortions and fetal death. Second and third trimester exposure is less risky, but it can cause intrauterine growth retardation and low birth weight. Other effects on pregnancy after the first trimester include premature birth, stillbirth, impaired functional development, myocardial toxicity and myelosuppression. Counseling and management of these cases are difficult, because literature is mostly represented by case reports or retrospective series while randomized prospective studies or guidelines are lacking. Moreover, personal experience is often scanty due to the rarity of the condition. This article reviews the available data regarding the different aspects of systemic treatment of cancer during pregnancy to help oncologist and obstetricians in counseling their patients and treat them accordingly. PMID- 23092519 TI - Seroprevalence of pandemic influenza viruses, New York, New York, USA, 2004. PMID- 23092520 TI - Vibrio fluvialis in patients with diarrhea, Kolkata, India. AB - We identified 131 strains of Vibrio fluvialis among 400 nonagglutinating Vibrio spp. isolated from patients with diarrhea in Kolkata, India. For 43 patients, V. fluvialis was the sole pathogen identified. Most strains harbored genes encoding hemolysin and metalloprotease; this finding may contribute to understanding of the pathogenicity of V. fluvialis. PMID- 23092521 TI - Virtual screening yields inhibitors of novel antifungal drug target, benzoate 4 monooxygenase. AB - Fungal CYP53 enzymes are highly conserved proteins, involved in phenolic detoxification, and have no homologues in higher eukaryotes, rendering them favorable drug targets. Aiming to discover novel CYP53 inhibitors, we employed two parallel virtual screening protocols and evaluated highest scoring hit compounds by analyzing the spectral binding interactions, by surveying the antifungal activity, and assessing the inhibition of catalytic activity. On the basis of combined results, we selected 3-methyl-4-(1H-pyrrol-1-yl)benzoic acid (compound 2) as the best candidate for hit-to-lead follow-up in the antifungal drug discovery process. PMID- 23092522 TI - Balance of DNA methylation and demethylation in cancer development. AB - Genome-wide 5-hydroxymethylome analysis of a rodent hepatocarcinogen model reveals that 5-hydroxymethylcytosine-dependent active DNA demethylation may be functionally important in the early stages of carcinogenesis. PMID- 23092523 TI - [Multicentric experience with the use of Sheathless 6.5 French-size catheter in coronary angioplasty for bifurcation lesions: feasibility and safety]. AB - BACKGROUND: Transradial intervention of coronary lesion is increasing in frequency and is associated with lower major vascular access site complications. However, the small size of the radial artery is a major limitation of this technique, especially for bifurcation lesions, because 6-French guiding catheters are necessary to optimize the technique. A Sheathless guiding catheter has recently been introduced, optimizing a large lumen with a small size. OBJECTIVES: The aim of this study is to report our preliminary experience performing bifurcated transradial interventions using a 6.5 French Sheathless guide catheter. PATIENTS AND METHODS: From March 2009 to February 2012 in three hospitals, 46 consecutive patients were enrolled in this study who underwent transradial approach (TRA) for percutaneous bifurcation coronary interventions using the 6.5 French Sheathless Eaucath guiding catheter system because of small radial artery caliber. RESULTS: In this study, 46 patients were enrolled with mean age of 72.13 +/- 16.41 years. The majority of patients were females with sex ratio 0.53. Procedural success using the 6.5 French Sheathless guide catheter system was 100 % with no cases requiring conversion to a conventional guide and catheter system. During procedures, adjunctive devices used in this cohort included IVUS (2 patients), 35 bifurcated lesions were treated with a kissing balloon technique in the group of 46 patients undergoing bifurcation PCIs, one patient required rotational atherectomy, thrombus-aspiration catheters had used in four patients, FFR-guided angiography in four patients. We report one case of chronic total occlusion bifurcated lesion successfully treated using this hydrophilic catheter. There were no radial artery site complications. CONCLUSION: The treatment of coronary bifurcation lesions with 6.5 French Sheathless guiding catheter by transradial approach is feasible and appears safe in this multicenter study. PMID- 23092524 TI - Body mass index at the time of diagnosis of autoimmune type 1 diabetes in children. AB - OBJECTIVES: To describe the body mass index (BMI) distribution of children developing autoimmune type 1 diabetes (T1D) compared with the general population and to assess factors associated with BMI at T1D onset. STUDY DESIGN: Children age 2-<19 years enrolled in the Pediatric Diabetes Consortium at 7 US pediatric diabetes centers at T1D onset were included. Eligibility for analysis required a diagnosis of T1D, >=1 positive diabetes autoantibody, and availability of BMI within 14 days of diagnosis. BMI at diagnosis was compared with the general population as described by the 2000 Centers for Disease Control. Regression analysis was used to assess the association between BMI and various participant characteristics. RESULTS: BMI scores for the 490 participants were slightly lower than the 2000 Centers for Disease Control population (P = .04). The median BMI percentile for age and sex was 48(th), 11% of the children were overweight (BMI >=85(th) and <95(th) percentile), 8% obese (BMI >=95(th) and <99(th) percentile), and 2% severely obese (>=99(th) percentile), percentages that were comparable across age and sex groups. Higher BMI Z-scores were associated with African American and Hispanic race/ethnicity (P = .001) and lower hemoglobin A1c (P < .001), and diabetic ketoacidosis, age, and Tanner stage were not associated. CONCLUSIONS: Although the BMI distribution in children developing autoimmune T1D was lower than that of the general population, 21% of children were obese or overweight. Youth who are overweight, obese, racial/ethnic minority, and/or present without diabetic ketoacidosis should not be presumed to have type 2 diabetes because many patients with autoantibody-positive T1D present with the same clinical characteristics. PMID- 23092525 TI - Moth-eaten appearance of tubulointerstitial nephritis and uveitis syndrome on (99m)technetium dimercaptosuccinic acid scintigraphy. PMID- 23092526 TI - Short-term femoral catheter insertion: a promising alternative to consistently allow long-term erythrocytapheresis therapy in children with sickle cell anemia. AB - Erythrocytapheresis procedures, increasingly used in the management of patients with severe complications of sickle cell disease, are limited by adequate venous access. We have successfully used short-term femoral catheter insertion, during a 6.5-year period for a total of 443 procedures, to perform long-term erythrocytapheresis in 18 consecutive children with sickle cell disease. PMID- 23092527 TI - Lone atrial fibrillation in the young - perhaps not so "lone"? AB - OBJECTIVE: To determine if pediatric patients with a history of lone atrial fibrillation (AF) have other forms of supraventricular tachycardia (SVT) that may potentially trigger AF. STUDY DESIGN: A multicenter review of patients with lone AF who underwent electrophysiology (EP) study from 2006-2011 was performed. INCLUSION CRITERIA: age <=21 years, normal ventricular function, structurally normal heart, history of AF, and EP study and/or ablation performed. EXCLUSION CRITERIA: congenital heart disease or cardiomyopathy. Patient demographics, findings at EP study and follow-up data were recorded. RESULTS: Eighteen patients met inclusion criteria. The mean age was 17.9 +/- 2.2 years, weight was 82 +/- 21 kg, body mass index was 27 +/- 6, and 15 (83%) were males. Eleven (61%) were overweight or obese. Seven (39%) had inducible SVT during EP study: 5 atrioventricular nodal re-entry tachycardia (71%) and 2 concealed accessory pathways with inducible atrioventricular re-entry tachycardia (29%). All 7 patients with inducible SVT underwent radiofrequency ablation. There were no complications during EP study and/or ablation for all 18 patients. The mean follow-up was 1.7 +/- 1.5 years and there were no recurrences in the 7 patients who underwent ablation. There were 2 recurrences of AF in patients with no other form of SVT during EP study. CONCLUSIONS: Inducible SVT was found in 39% of pediatric patients undergoing EP study for lone AF. EP study should be considered for pediatric patients presenting with lone AF. PMID- 23092528 TI - Disparities in psychiatric emergency department visits among youth in Hawai'i, 2000-2010. AB - OBJECTIVE: To describe the frequency and patient characteristics of emergency department encounters for mental health among youth, and to examine differences in utilization and treatment patterns. STUDY DESIGN: Data were obtained from the Hawai'i Health Information Corporation database of emergency department records between January 1, 2000, and December 31, 2010. Analyses were limited to records of visits by patients aged <18 years with a diagnosis of mental disorder or a suicide attempt. RESULTS: The annual average rate was 49.7 emergency department visits related to mental health issues per 10 000 youth, accounting for 2.1% of all emergency department visits among youth. Rates of mental health-related visits significantly and steadily increased, from a low of 25.8 in 2000 to a high of 67.4 in 2010. Rural areas consistently exhibited higher rates and acceleration at a steeper incline across time. Rural youth were more likely to be discharged or transferred for inpatient care or outpatient services compared with urban youth (6.3% vs 12.4%; chi(2) = 61.42; df = 3; P < .001). CONCLUSION: The trend in emergency department utilization for mental health-related issues in adolescents is apparently increasing, with significantly higher rate and morbidity for youth in rural areas. Several recommendations are described for creating a responsive and integrated system of mental health care for youth, covering training, consultation, screening, and brief interventions. PMID- 23092530 TI - Air trail of a transilluminant scrotum. PMID- 23092529 TI - A single-blinded randomized clinical trial comparing polymyxin B-trimethoprim and moxifloxacin for treatment of acute conjunctivitis in children. AB - OBJECTIVE: To perform a randomized controlled trial comparing moxifloxacin hydrochloride with polymyxin B-trimethoprim for the treatment of acute conjunctivitis. STUDY DESIGN: Patients ages 1-18 years old with acute conjunctivitis had cultures performed and were randomized to receive either moxifloxacin hydrochloride or polymyxin B-trimethoprim ophthalmic solution for 7 days. Response to treatment was determined by phone query on day 4-6 and by examination with post-treatment conjunctival culture on day 7-10. RESULTS: One hundred and twenty-four patients were enrolled. Eighty patients (65%) had recognized pathogens (55 Haemophilus influenzae, 22 Streptococcus pneumoniae, 4 Moraxella catarrhalis) isolated from their conjunctiva. One hundred fourteen (56/62 moxifloxacin and 58/62 polymyxin B-trimethoprim) completed the 4-6 day evaluation, with 43/56 (77%) of the moxifloxacin group and 42/58 (72%) of the polymyxin B-trimethoprim group clinically cured according to parents (noninferiority test P = .04). Eighty-nine (39/56 moxifloxacin and 50/58 polymyxin B-trimethoprim) patients completed the 7-10 day evaluation. Clinical cure was observed in 37/39 (95%) of the moxifloxacin and 49/51 (96%) of the polymyxin B-trimethoprim treated groups (noninferiority test P <= .01). Clinical cure rates for culture positive and negative conjunctivitis were not different. There was no statistically significant difference in bacteriologic cure rates between the 2 groups. CONCLUSIONS: Polymyxin B-trimethoprim continues to be an effective treatment for acute conjunctivitis with a clinical response rate that does not differ from moxifloxacin. Use of polymyxin B-trimethoprim for the treatment of conjunctivitis would result in significant cost savings compared with fluoroquinolones. PMID- 23092531 TI - Treatment of severe acute malnutrition in infants aged <6 months in Niger. AB - OBJECTIVE: To report a nutritional rehabilitation program in Niger for the management of severe acute malnutrition in infants aged <6 months. STUDY DESIGN: This is a presentation of a case series (n = 632) of young infants who were admitted to a nutrition rehabilitation program in 2010-2011. The main characteristics of the inpatient treatment protocol where the use of diluted F 100 milk via a supplementary suckling technique until exclusive breastfeeding was reinitialized, coaching of mothers on infant feeding, and intensive antibiotic therapy as indicated during the stabilization phase. Semistructured interviews were conducted with 103 mothers. RESULTS: Rates of recovery, mortality, and default were 85% (537 of 632), 6% (37 of 632), and 9% (55 of 632), respectively. The majority of infants had an infectious disease at study entry (81%), particularly acute watery diarrhea and respiratory tract infections. Infection on admission was a predictor of death during treatment (OR, 3.9; 95% CI, 1.6-9.2). Anorexia at entry was a risk factor for treatment failure (OR, 4.4; 95% CI, 1.71 11.1). Interviews revealed a very low rate of exclusive breastfeeding (3%), with delayed initiation in 68% of cases. Traditional beliefs, perceived insufficiency of breast milk, and psychological problems played important roles in feeding choices. CONCLUSION: Severe acute malnutrition in infants aged <6 months can be successfully treated by managing cases as inpatients with an adapted protocol, intensive clinical supervision, and intensive drug treatment if indicated. Whether similar outcomes are achievable in community-based programs remains to be verified. Effective interventions for improving breastfeeding practices are needed. PMID- 23092532 TI - Living on higher ground reduces child neurodevelopment-evidence from South America. AB - OBJECTIVE: To study the effects of altitude on infant neurodevelopment in the first 2 years of life. STUDY DESIGN: Data from a unique study of normal infant neurodevelopment in 5 South American countries were used. The sample included 2116 infants 3-24 months of age who were evaluated for neurodevelopmental problems by study physicians during their routine well-child visits at 31 pediatric practices. We used regression models with country fixed-effects that compare the neurodevelopment of children born at different altitudes within the same country to avoid confounding. The regressions adjust for several socioeconomic and demographic factors. We also evaluated altitude effects stratifying by sex, age, and household wealth. Infant neurodevelopment was evaluated by physicians by using the Bayley Infant Neurodevelopmental Screener. The primary outcome is an indicator for whether the infant is at high risk for neurodevelopmental problems based on the Bayley Infant Neurodevelopmental Screener norms. RESULTS: Altitude significantly increases the probability of being at high risk for neurodevelopmental problems (100-meter increase in altitude: OR 1.02; 95% CI 1.001-1.037; high altitude greater than 2600 meters vs low altitude less than 800 meters: OR 2.01; 95% CI 1.36-2.973). The effects are larger for females and for second than first year of life. The largest effect is for females 12-24 months of age (high vs low altitude: OR 4.147; 95% CI 1.466 12.013). There are no significant differences in altitude effects by household wealth. CONCLUSIONS: Altitude may significantly increase the risk of neurodevelopmental problems during the first 2 years of life, especially for females during their second year of life. PMID- 23092533 TI - Synthesis of coumarins via Pd-catalyzed oxidative cyclocarbonylation of 2 vinylphenols. AB - Palladium-catalyzed oxidative cyclocarbonylation of 2-vinylphenols constitutes a simple, direct method for the synthesis of coumarins. The reaction conditions, employing low pressures of CO, and air or 1,4- benzoquinone as the oxidant, are attractive in terms of environmental considerations and operational simplicity. Coumarins with a variety of functional groups were prepared in yields up to 85%. PMID- 23092534 TI - The 6th drug discovery for neurodegeneration conference: an intensive course on translating research into drugs. AB - Neurodegenerative disorders are rapidly becoming one of the greatest unmet health needs. This annual workshop facilitates innovation and progress in neurodegenerative disease drug discovery by convening stakeholders from charitable foundations, government, academia and industry who introduce scientists to the drug development and approval process. New to the 2012 workshop were candid discussions about re-visiting the CNS therapeutic development process. The continuing challenge is partly due to the poor forecasting potential of models of CNS diseases, as well as the lack of reproducibility of published studies, and greater need to increase focus on pharmacodynamic end points. Significant discussion centered on how to improve discovery approaches using examples of recent successes in the field. For example, the idea of combining reductionist, single-target strategies with functional-approach logic was suggested by several speakers, and widely discussed in the workshop. The didactic aspects of the workshop highlighted underlying concepts, best practices and trends that have characterized successful campaigns. The technical and scientific guidance was complemented by discussions of practical ways to approach the major funding gaps required for translation of projects from basic science to clinical investigations. This workshop has evolved to serve a critical educational need, with a wide range of investigator participation. PMID- 23092535 TI - Topoisomerase II alpha gene amplification is a favorable prognostic factor in patients with HER2-positive metastatic breast cancer treated with trastuzumab. AB - BACKGROUND: The vast majority of patients with HER2-positive metastatic breast cancer (MBC) treated with trastuzumab eventually develop resistance to this agent. There is an unmet need therefore, for identifying biological markers with possible prognostic/predictive value in such patients. The aim of this study was to investigate the prognostic role of topoisomerase II alpha gene (TOP2A) amplification and protein (TopoIIa) expression in patients treated with trastuzumab-containing regimens. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples were retrospectively collected from 225 eligible patients treated with trastuzumab. Protein expression of ER, PgR, Ki67, PTEN, HER2 and TopoIIa were centrally assessed by immunohistochemistry. HER2 and TOP2A gene amplification was evaluated by fluorescence in situ hybridization. PIK3CA mutations were identified by single nucleotide polymorphism genotyping. Survival was evaluated from the initiation of trastuzumab as 1st line treatment to the date of last follow-up or death. RESULTS: Among the 225 samples analyzed, only 137 (61%) were found to be HER2-positive. TOP2A was amplified in 41% and deleted in 16% of such tumors. TOP2A gene amplification was more frequent in ER-negative tumors. TopoIIa protein expression was observed in the majority (65%) of the samples and was associated with ER-positive status, high Ki67 expression, presence of PTEN protein and PIK3CA mutations. Median follow-up for patients treated in the 1st line was 51 months. Survival was more prolonged with trastuzumab-containing treatment in HER2-positive patients (50 months, log-rank, p=0.007). TOP2A non-amplified or deleted tumors were associated with increased risk for death compared to TOP2A amplified tumors (HR=2.16, Wald's p=0.010 and HR=2.67, p=0.009, respectively). In multivariate analysis, a significant interaction of TOP2A with anthracycline treatment (either in the adjuvant or the 1st line setting) was observed for survival (Wald's p=0.015). Among the TOP2A amplified subgroup, anthracycline-treated patients were associated with decreased risk for death. CONCLUSIONS: TOP2A gene amplification was shown to be a favorable prognostic marker in HER2-positive MBC patients treated with trastuzumab, such an effect however, appears to rather be related to treatment with anthracyclines (predictive marker for benefit from anthracyclines). The results of the present retrospective study warrant validation in larger cohorts of patients treated in the context of randomized trials. PMID- 23092536 TI - A microchip device for enhancing capillary zone electrophoresis using pressure driven backflow. AB - A reduction in the electroosmotic flow (EOF) is often desirable in glass microchannels for realizing high resolutions in capillary zone electrophoresis (CZE). While static and dynamic coatings have been commonly employed to accomplish this goal, such chemicals can introduce unwanted interactions of the analyte molecules with the separation medium and/or channel surface. In this article, we report a microfluidic device that can enhance the resolving power of CZE analysis by generating a pressure-driven backflow in the separation channel. This backflow was generated in our current work by fabricating a shallow segment (0.5-4 MUm deep) downstream of the separation duct (5 MUm deep) and applying an electric field across it. A mismatch in EOF transport rate at the interface of this segment was shown to yield a pressure-gradient that counteracted electroosmosis and diminished the net fluid flow in the separation conduit by nearly an order of magnitude. Although the resulting pressure-driven backflow also somewhat increased the band broadening in the analysis channel, overall it allowed us to separate an amino acid mixture with an 8-fold higher resolution. The microchip device presented here is particularly suitable for miniaturization of the CZE method and may be easily integrated into other analytical procedures making it an attractive module for lab-on-a-chip applications. PMID- 23092537 TI - Water-borne infections and warming the sterile water for washing high-risk infants on neonatal intensive care units. PMID- 23092538 TI - Calcium score of small coronary calcifications on multidetector computed tomography: results from a static phantom study. AB - INTRODUCTION: Multi detector computed tomography (MDCT) underestimates the coronary calcium score as compared to electron beam tomography (EBT). Therefore clinical risk stratification based on MDCT calcium scoring may be inaccurate. The aim of this study was to assess the feasibility of a new phantom which enables establishment of a calcium scoring protocol for MDCT that yields a calcium score comparable to the EBT values and to the physical mass. MATERIALS AND METHODS: A phantom containing 100 small calcifications ranging from 0.5 to 2.0mm was scanned on EBT using a standard coronary calcium protocol. In addition, the phantom was scanned on a 320-row MDCT scanner using different scanning, reconstruction and scoring parameters (tube voltage 80-135 kV, slice thickness 0.5-3.0mm, reconstruction kernel FC11-FC15 and threshold 110-150 HU). The Agatston and mass score of both modalities was compared and the influence of the parameters was assessed. RESULTS: On EBT the Agatston and mass scores were between 0 and 20, and 0 and 3mg, respectively. On MDCT the Agatston and mass scores were between 0 and 20, and 0 and 4 mg, respectively. All parameters showed an influence on the calcium score. The Agatston score on MDCT differed 52% between the 80 and 135kV, 65% between 0.5 and 3.0mm and 48% between FC11 and FC15. More calcifications were detected with a lower tube voltage, a smaller slice thickness, a sharper kernel and a lower threshold. Based on these observations an acquisition protocol with a tube voltage of 100 kV and two reconstructions protocols were defined with a FC12 reconstruction kernel; one with a slice thickness of 3.0mm and a one with a slice thickness of 0.5mm. This protocol yielded an Agatston score as close to the EBT as possible, but also a mass score as close to the physical phantom value as possible, respectively. CONCLUSION: With the new phantom one acquisition protocol and two reconstruction protocols can be defined which produces Agatston scores comparable to EBT values and to the physical mass. PMID- 23092539 TI - Value of endovascular stent placement for symptomatic spontaneous isolated superior mesenteric artery dissection. AB - OBJECTIVE: To evaluate the feasibility and efficacy of endovascular stent placement for the treatment of symptomatic spontaneous isolated superior mesenteric artery dissection. MATERIALS AND METHODS: This retrospective study was undertaken in 12 consecutive patients who suffered from symptomatic spontaneous isolated superior mesenteric artery dissection. Seven patients with severe clinical symptoms underwent endovascular stent placement as a primary treatment and the other 5 patients received conservative treatment. The technical results, complications and clinical outcomes were analyzed. Follow-up was performed with computed tomographic angiography. RESULTS: Primary endovascular stent placement was successfully performed in 7 patients with severe clinical symptoms. Successful conservative treatment was achieved in 3 patients. Endovascular stent placement was additionally performed in 2 patients with unsuccessful conservative treatment. A stent was misplaced in the false lumen in one of those two patients due to a severely stenotic true lumen. The fasting time and length of stay were significantly shorter in patients with successful endovascular therapy (median: 3 days and 5.5 days) than in those conducted conservatively (median: 9 days and 14 days) (p<0.05). During the follow-up period (median, 21 months; range, 10-36 months), 1 patient with endovascular stent placement had recurrent abdominal pain because of the wall adherent thrombus in the proximal segment of the superior mesenteric artery during the first follow-up month. No thrombosis or stenosis was found in the lumina of the stents. CONCLUSION: Endovascular stent placement is a safe and feasible therapeutic approach for symptomatic spontaneous isolated superior mesenteric artery dissection with immediate success and satisfactory outcomes. PMID- 23092540 TI - Primary extranodal Non-Hodgkin lymphoma of the orbital and paranasal region-a retrospective study. AB - PURPOSE: Primary extranodal lymphomas of the orbit and sinonasal region are rare and occur almost only as Non-Hodgkin lymphoma (NHL). The purpose of this study was to determine the frequency of different subtypes of NHL in these regions and to describe their radiological features. MATERIALS AND METHODS: Between January 2005 and January 2010, 567 patients with malignant immunoproliferative diseases (MID) were treated at our institution. Primary sinonasal and orbital manifestation was diagnosed in 36 cases. There were 13 women and 23 men with a median age of 67 years. CT and MRI were performed in 14 and 24 patients, respectively. Imaging was re-interpretated and histological subtypes were listed. RESULTS: Among all MID primary sinonasal and orbital NHL occurred with a frequency of 6%. Diffuse large cell lymphoma was identified in 11 cases (30%), marginal cell lymphoma in 6 (16%), and extranodal plasmacytoma in 5 (14%). Other subtypes were rare. On CT, lesions of soft tissue attenuation with homogeneous moderate contrast enhancement were seen in all cases. On T2-weighted fat saturated images 52% of the lesions were slightly hyperintense in comparison to unaffected musculature, 41% were isointense, and 7% slightly hypointense. On T1 weighted sequences most lesions (81%) were homogeneously isointense. After contrast administration marked enhancement was seen in 41%, moderate in 52%, and slight enhancement in 7%. CONCLUSION: The identified radiological features should be included in the differential analysis of lesions in the orbital and sinonasal regions, but they are not specific enough. For exact therapeutic planning histopathological diagnosis of the subtype is required. PMID- 23092541 TI - Is it time to adopt a set of standard abbreviations for patient body positions in the ICU? PMID- 23092542 TI - Reply to Manish Garg, Apul Goel and Jai Prakash's letter to the editor re: Renzo Colombo, Lorenzo Rocchini, Nazareno Suardi, et al. Neoadjuvant short-term intensive intravesical mitomycin C regimen compared with weekly schedule for low grade recurrent non-muscle-invasive bladder cancer: preliminary results of a randomised phase 2 study. Eur Urol 2012;62:797-802. PMID- 23092543 TI - Retrograde versus antegrade nerve sparing during robot-assisted radical prostatectomy: which is better for achieving early functional recovery? AB - BACKGROUND: Although the retrograde approach to nerve sparing (NS) aimed at maximizing NS during robot-assisted radical prostatectomy (RARP) has been described, its significant benefits compared to the antegrade approach have not yet been investigated. OBJECTIVE: To evaluate the impact of NS approaches on perioperative, pathologic, and functional outcomes. DESIGN, SETTING, AND PARTICIPANTS: Five hundred one potent (Sexual Health Inventory for Men [SHIM] score >21) men underwent bilateral full NS and were followed up for a minimum of 1 yr. After propensity score matching, 344 patients were selected and were then categorized into two groups. SURGICAL PROCEDURE: RARP with antegrade NS (n=172) or RARP with retrograde NS (n=172). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Functional outcomes were assessed using validated questionnaires. Multivariable logistic regression models were applied. RESULTS AND LIMITATIONS: Positive margin rates were similar (11.1% vs 6.9%; p=0.192), and no correlation with the NS approach was found on regression analysis. At 3, 6, and 9 mo, the potency rate was significantly higher in the retrograde approach (65% vs 80.8% and 72.1% vs 90.1% and 85.3% vs 92.9%, respectively). The multivariable model indicated that the NS approach was an independent predictor for potency recovery at 3, 6, and 9 mo, along with age, gland size, and hyperlipidemia. After adjusting for these predictors, the hazard ratio (HR) for the retrograde relative to the antegrade approach was 2.462 (95% confidence interval [CI], 1.482-4.089; p=0.001) at 3, 4.024 (95% CI, 2.171-7.457; p<0.001) at 6, and 2.145 (95% CI, 1.019-4.514; p=0.044) at 9 mo. Regarding continence, the recovery rates at each time point and the mean time to regaining it were similar, and the method of NS had no effect on multivariable analysis. The absence of randomization is a major limitation of this study. CONCLUSIONS: In patients with normal erectile function who underwent bilateral full NS, a retrograde NS approach facilitated early recovery of potency compared to that with an antegrade NS approach without compromising cancer control. PMID- 23092544 TI - Contemporary grading for prostate cancer: implications for patient care. AB - CONTEXT: The Gleason grading system is one of the most powerful predictors of outcome in prostate cancer and a cornerstone in counseling and treating patients. Since its inception, it has undergone several modifications triggered by a change in clinical practice and a better understanding of the cancer's histologic spectrum and variants and their prognostic significance. OBJECTIVE: To provide an overview of the implementation and the impact of the Gleason system as a predictive and prognostic tool in all available treatment modalities, and to compare the original and modified Gleason systems in major pathologic and clinical outcome data sets. EVIDENCE ACQUISITION: A comprehensive nonsystematic Medline search was performed using multiple Medical Subject Headings such as Gleason, modified, system, outcome, biopsy, prostatectomy, recurrence, prognosis, radiotherapy, and focal therapy, with restriction to the English language and a preference for publications within the last 10 yr. All Gleason grade-related studies in the last 3 yr were reviewed. For studies before this date, we relied on prior culling of the literature for various recent books, chapters, and original articles on this topic. EVIDENCE SYNTHESIS: Using the modified grading system resulted in disease upgrading with more cancers assigned a Gleason score >= 7 than in the past. It also resulted in a more homogeneous Gleason score 6, which has an excellent prognosis when the disease is organ confined. The vast majority of studies using both systems showed that Gleason grading of adenocarcinomas on needle biopsies and radical prostatectomies was strongly associated with pathologic stage, status of surgical margins, metastatic disease, biochemical recurrence, and cancer-specific survival, with the modified system outperforming the original one in some large series. A description of the continuous incorporation of this parameter in the clinical decision making for treating prostate cancer using all currently used treatment modalities is presented, and the findings of studies before and after the inception of the modified grading system, if available, are compared. The proposed contemporary grading prognostic categories are 3+3, 3+4, 4+3, 8, and 9-10. CONCLUSIONS: The Gleason score is one of the most critical predictive factors of prostate cancer regardless of the therapy used. Modernization of the Gleason grading system has resulted in a more accurate grading system for radical prostatectomy (RP) but has complicated the comparison of data before and after the updating. A better prognostication with the updated Gleason grading system for patients treated with modalities other than surgery can only be postulated at this time because there are limited conflicting data on radiation and no studies on other treatment modalities. Its greatest impact is the uniformly excellent prognosis associated with Gleason score 6 in RPs. PMID- 23092545 TI - Reply from authors re: Camillo Porta, Chiara Paglino. Experience gathered from retrospective series on renal cell carcinoma is useful, but now it is time for a global claim for academically driven prospective studies. Eur Urol 2013;64:71-2: are retrospective data of any value to the specialist treating renal cell carcinoma? PMID- 23092546 TI - The allure of the epigenome. PMID- 23092547 TI - The baby pediatric symptom checklist: development and initial validation of a new social/emotional screening instrument for very young children. AB - OBJECTIVE: To develop and validate the Baby Pediatric Symptom Checklist (BPSC), a brief social/emotional screening instrument for children less than 18 months. The BPSC is modeled after the Pediatric Symptom Checklist (PSC) and is part of the Survey of Wellbeing of Young Children, a comprehensive, freely available screening instrument designed for use in pediatric primary care. METHOD: BPSC items were developed by a team of experts who reviewed existing assessment instruments and relevant research literature. Scale construction and initial validation were conducted with 205 families from pediatric primary care sites and 54 families from referral clinics. A replication sample of 146 additional families were enrolled from an independent set of primary care practices. RESULTS: Exploratory factor analysis revealed 3 dimensions of the BPSC: irritability, inflexibility, and difficulty with routines. Factor structure was confirmed in the replication sample. Retest reliability and internal reliability were adequate (intraclass correlation coefficient >0.70) across subscales, with the exception of the "irritability" subscale's internal reliability in the replication sample. Construct validity of the "irritability" and the "difficulty with routines" subscales is supported by correlations with the Parenting Stress Index and the Ages & Stages Questionnaire: Social/Emotional, but the "inflexibility" subscale seems to be distinct from performance on these instruments. Tests of differential item functioning revealed no significant effects for race/ethnicity, child gender, parent education, or family income. Age based normative data were calculated for each subscale. CONCLUSION: The BPSC assesses 3 domains of behavior for very young children and shows promise as a social/emotional screening instrument for pediatric primary care. PMID- 23092550 TI - Etymologia: coxsackievirus. PMID- 23092548 TI - Seroprevalence of antibodies against Chikungunya, Dengue, and Rift Valley fever viruses after febrile illness outbreak, Madagascar. AB - In October 2009, two-3 months after an outbreak of a febrile disease with joint pain on the eastern coast of Madagascar, we assessed serologic markers for chikungunya virus (CHIKV), dengue virus (DENV), and Rift Valley fever virus (RVFV) in 1,244 pregnant women at 6 locations. In 2 eastern coast towns, IgG seroprevalence against CHIKV was 45% and 23%; IgM seroprevalence was 28% and 5%. IgG seroprevalence against DENV was 17% and 11%. No anti-DENV IgM was detected. At 4 locations, 450-1,300 m high, IgG seroprevalence against CHIKV was 0%-3%, suggesting CHIKV had not spread to higher inland-altitudes. Four women had IgG against RVFV, probably antibodies from a 2008 epidemic. Most (78%) women from coastal locations with CHIKV-specific IgG reported joint pain and stiffness; 21% reported no symptoms. CHIKV infection was significantly associated with high bodyweight. The outbreak was an isolated CHIKV epidemic without relevant DENV co transmission. PMID- 23092549 TI - Pulmonary streptomyces infection in patient with sarcoidosis, France, 2012. AB - TO THE EDITOR: Streptomyces spp. are aerobic, gram-positive bacteria of the order Actinomycetales, known for their ability to produce antimicrobial molecules such as streptomycin. Streptomyces spp., usually saprophytic to humans, can cause local cutaneous fistulized nodules known as actinomycetoma or mycetoma. Severe invasive infections have seldom been reported, but most cases reported have occurred in immunocompromised patients (1-5). We report a case of invasive pulmonary infection caused by a Streptomyces sp. in a splenectomized patient with sarcoidosis. PMID- 23092551 TI - Priorities for young adults when accessing UK primary care: literature review. AB - This literature review focuses on what matters to young adults when they access primary care services in the United Kingdom. Patients' access to and experience of primary care services differs across age groups. Existing research has largely focused on the needs and experiences of children, adolescents, and adults. There is some evidence to suggest the views of young adults (aged 18-25 years) that may differ from the views of other age groups, and research has not previously reported specifically on the views of this group of the population. The literature was reviewed to identify the views and priorities of young UK adults regarding primary healthcare provision, and furthermore, to identify those related topics that would benefit from further research. Relevant academic publications and grey literature published from 2000 onwards was reviewed and synthesised. We identified and reported emerging themes that were of importance to young adults in respect of the UK primary care provision. A total of 19 papers met our inclusion criteria. Young adults access primary care services less frequently than other age groups; this may be because of their experience of primary care throughout childhood and adolescence. Five aspects of primary care provision emerged as being of importance to young adults--the accessibility and availability of services, the confidentiality of health-related information, issues relating to communication with healthcare professionals, continuity of care, and behaviours and attitudes expressed towards young adults by healthcare professionals. There is a lack of focus of current research on the expectations, needs, and primary healthcare experiences of young adults. Young adults may hold views that are distinct from other age groups. Further research is needed to better understand the needs of a young adult population as their needs may impact the future use of services. PMID- 23092552 TI - A bispecific antibody against IL-1beta and IL-17A is beneficial for experimental rheumatoid arthritis. AB - IL-1beta is a pivotal cytokine and plays an important role in rheumatoid arthritis (RA). More recently, the biological therapy targeting this cytokine has been impressively effective for many RA patients, however, it remains insufficient in some patients. One of the reasons for these failures may be due to multiple cytokines involved in the disease process. In the present study, we constructed a single-chain bispecific antibody (scBsAb1/17) against both human IL 1beta and human IL-17A which is the mediator for several key cytokines involved in the RA process such as TNF- and IL-6. A number of in vitro assays demonstrated that scBsAb1/17 simultaneously bound to both targets with a similar antigen binding affinity as an individual single-chain antibody molecule (anti-IL-1beta scFv or anti-IL-17A scFv). Mice with collagen-induced arthritis (CIA) were administrated with either scBsAb1/17 or individual single chain antibody alone, and we noticed that treatment with scBsAb1/17 significantly ameliorated clinical signs and alleviated histological lesion of CIA mice compared to treatments with anti-IL-1beta scFv or anti-IL-17A scFv alone. Production of CII-specific antibodies in scBsAb1/17-treated CIA mice was substantially lower than that of single-chain antibody-treated CIA mice. In addition, scBsAb1/17 was more potent in the inhibition of collagen-specific proliferation of splenocytes and mRNA expression of TNF-, IL-6, IL-2, IL-1beta and IFN-gamma in the spleens of CIA mice compared to a single-chain antibody alone. These results suggest that scBsAb1/17 appears more beneficial in CIA mice than monovalent single-chain antibody molecules. PMID- 23092553 TI - Short and longer-term psychological consequences of Operation Cast Lead: documentation from a mental health program in the Gaza Strip. AB - BACKGROUND: There is growing recognition of the psychological impact of adversity associated with armed conflict on exposed civilian populations. Yet there is a paucity of evidence on the value of mental health programs in these contexts, and of the chronology of psychological sequelae, especially in prolonged conflicts with repeated cycles of extreme violence. Here, we describe changes in the psychological profile of new patients in a mental health program after the military offensive Cast Lead, in the context of the prolonged armed conflict involving the Gaza Strip. METHODS: This study analyses routinely collected program data from a Medecins Sans Frontieres mental health program in the Gaza Strip spanning 2007-2011. Data consist of socio-demographic as well as clinical baseline and follow-up data on new patients entering the program. Comparisons were made through Chi square and Fisher's exact tests, univariate and multivariate logistic and linear regression. RESULTS: PTSD, depression and other anxiety disorders were the most frequent psychopathologies, with 21% having multiple diagnoses. With a median of nine sessions, clinical improvement was recorded for 83% (1122/1357), and more common for those with separation anxiety, acute and posttraumatic disorders as principal diagnosis (855/1005), compared to depression (141/183, p<0.01). Noted changes proximal to Operation Cast Lead were: a doubling in patient case load with a broader socio-economic background, shorter interval from an identified traumatic event to seeking care, and a rise in diagnoses of acute and posttraumatic stress disorders. Sustained changes included: high case load, more distal triggering events, and increase in diagnoses of other anxiety disorders (especially for children 15 years and younger) and depression (especially for patients 16 years and older). CONCLUSION: Evolving changes in patient volume, diagnoses and recall period to triggering events suggest a lengthy and durable effect of an intensified exposure to violence in a context of prolonged conflict. Our findings suggest that mental health related humanitarian relief in protracted conflicts might need to prepare for an increase in patients with changing profiles over an extended period following an acute flare-up in violence. PMID- 23092554 TI - Effects of low-dose ionizing radiation and menadione, an inducer of oxidative stress, alone and in combination in a vertebrate embryo model. AB - Prior work has established the zebrafish embryo as an in vivo model for studying the biological effects of exposure to low doses of ionizing radiation. One of the known effects of radiation is to elevate the levels of reactive oxygen species (ROS) in tissue. However, ROS are also produced as by-products of normal metabolism and, regardless of origin, ROS produce similar chemical damage to DNA. Here we use the zebrafish embryo model to investigate whether the effects of low dose (0-1.5 Gy) radiation and endogenous ROS are mechanistically distinct. We increased levels of endogenous ROS by exposure to low concentrations of the quinone drug, menadione. Imaging studies in live embryos showed that exposure to 3 MUM or higher concentrations of menadione dramatically increased ROS levels. This treatment was associated with a growth delay and morphologic abnormalities, which were partially or fully reversible. By contrast, exposure to low doses of ionizing radiation had no discernable effects on overall growth or morphology, although, there was an increase in TUNEL-positive apoptotic cells, consistent with the results of prior studies. Further studies showed that the combined effect of radiation and menadione exposure are greater than with either agent alone, and that attenuation of the expression of Ku80, a gene important for repair of radiation-induced DNA damage, had only a slight effect on menadione sensitivity. Together, results suggest that ionizing radiation and menadione affect the embryo by distinct mechanisms. PMID- 23092555 TI - Interaction of current alcohol consumption and abdominal obesity on hypertension risk. AB - The high prevalence of alcohol consumption and abdominal obesity and increased incidence of essential hypertension (EH) in China indicates that there may be an interaction between alcohol consumption and abdominal obesity on EH risk. Therefore, we aimed to examine the independent and combined effects of alcohol consumption and abdominal obesity on risk of EH in a Chinese cohort. We analyzed data from a population-based prospective cohort of 2778 participants aged 35-74 years from Jiangsu China who were free of hypertension, diabetes and CVD at enrollment and were followed for hypertension events. Cox proportional hazards regression model was used to calculate the hazard ratio (HR) of hypertension and corresponding 95% confidence interval (CI). Logistic regression model was used to examine the interaction between alcohol consumption and abdominal obesity on risk of hypertension. After adjusting for age, sex, smoking status, family history of hypertension, current alcohol consumption significantly increased EH risk. Compared with those without alcohol consumption, the hazard ratio of EH for participants with alcohol consumption was 1.65 (95% confidence interval 1.29 2.12). There was a statistically significant additive interaction between current alcohol consumption and abdominal obesity on EH risk. The risk of EH for current alcohol consumers with abdominal obesity was 4.49 times as high as the sum of risks in participants with a single condition alone. Both alcohol consumption and abdominal obesity are strong risk factors of EH in the Chinese population. Moreover, this study further demonstrates an additive interaction of alcohol consumption and abdominal obesity on EH risk. PMID- 23092556 TI - Angiotensin II type 1 receptor antagonists inhibit cell proliferation and angiogenesis in breast cancer. AB - Angiotensin II type 1 receptor (AT1R) promotes tumor invasion, migration, metastasis and angiogenesis. We explored the potential antitumor effects of AT1R antagonists in breast cancer. We found that angiotensin II promoted cell proliferation and upregulated the expression of vascular endothelial growth factor A (VEGF-A) in MCF-7 cells. Losartan downregulated the expression of VEGF-A in MCF-7 cells treated with angiotensin II. Candesartan downregulated the expression of VEGF-A in mice bearing MCF-7 xenografts and inhibited tumor growth and angiogenesis. AT1R and VEGF-A expression correlated with increased microvascular density in 102 breast cancer patients. Our data suggest that AT1R antagonists might be useful to suppress breast cancer by inhibiting the angiotensin II. PMID- 23092557 TI - A naked RNA heptamer targeting the human Bcl-2 mRNA induces apoptosis of HL60 leukemia cells. AB - tRNase Z(L)-utilizing efficacious gene silencing is a gene control technology, which is based on the property that tRNase Z(L) can cleave any target RNA under the direction of an appropriate small guide RNA (sgRNA). To find therapeutic sgRNAs to cure hematological malignancies, we investigated behavior of heptamer type sgRNA. We demonstrated that a heptamer, mh1(Bcl-2), which targets the human Bcl-2 mRNA, can be taken up by cells without any transfection reagents and that it can induce apoptosis of the leukemia cells. Mouse xenograft experiments showed that a median survival of the mh1(Bcl-2)-treated mice was longer than that of the control mice. PMID- 23092558 TI - Infectious disease mortality rates, Thailand, 1958-2009. AB - To better define infectious diseases of concern in Thailand, trends in the mortality rate during 1958-2009 were analyzed by using data from public health statistics reports. From 1958 to the mid-1990s, the rate of infectious disease associated deaths declined 5-fold (from 163.4 deaths/100,000 population in 1958 to 29.5/100,000 in 1997). This average annual reduction of 3.2 deaths/100,000 population was largely attributed to declines in deaths related to malaria, tuberculosis, pneumonia, and gastrointestinal infections. However, during 1998 2003, the mortality rate increased (peak of 70.0 deaths/100,000 population in 2003), coinciding with increases in mortality rate from AIDS, tuberculosis, and pneumonia. During 2004-2009, the rate declined to 41.0 deaths/100,000 population, coinciding with a decrease in AIDS-related deaths. The emergence of AIDS and the increase in tuberculosis- and pneumonia-related deaths in the late twentieth century emphasize the need to direct resources and efforts to the control of emerging and re-emerging infectious diseases. PMID- 23092559 TI - Pneumonia after earthquake, Japan, 2011. PMID- 23092560 TI - [Mitochondrial respiratory chain complex II deficiency and diseases]. AB - This article reviews the structure and function of mitochondrial respiratory chain complex II, and the clinical features, diagnosis, treatment and genetic analysis of mitochondrial respiratory chain complex II deficiency. Mitochondrial complex II, known as succinate dehydrogenase, is a part of the mitochondrial respiratory chain. It plays an important role in cellular oxidative phosphorylation. It is associated with oxidative stress and is a sensitive target for toxic substances and abnormal metabolin in cells. Clinical manifestations of respiratory chain complex II deficiency are characterized by a wide variety of abnormalities. Progressive neuromuscular dysfunction is the most common syndrome. Cardiomyopathy, episodic vomit and hemolytic uremic syndrome are also encountered in a few cases. A precise diagnosis is dependent on enzyme activities assay of respiratory chain complexes and genetic analysis. Complex II activities decreased in affected tissues. Pathogenic mutations in SDHA gene and SDHAF1 gene encoding assembly factor have been found so far. Clinical treatment aims at improving the mitochondrial function. PMID- 23092561 TI - [Clinical features of Candida albicans sepsis in preterm infants: an analysis of 13 cases]. AB - OBJECTIVE: To investigate the clinical features of Candida albicans sepsis in preterm infants. METHODS: Retrospective analysis was performed on the clinical data of 13 preterm infants with Candida albicans sepsis, who were born at 28 to 36 weeks of gestational age and who weighed between 1400 and 2815 g. RESULTS: The infants were infected with Candida albicans at the age of 19+/-11 d, with the main clinical manifestations being apnea, poor response, poor skin perfusion, blood oxygen concentration decrease, dark skin, yellowish skin, heart rate increase in the rest state, copious phlegm and difficulty in weaning from the ventilator. The infants showed significantly decreased platelet and increased C reactive protein (CRP), platelet distribution width (PDW), alanine transaminase (ALT), creatine kinase isoenzyme-MB (CK-MB), total bilirubin (TBIL), creatine kinase (CK), and lactate dehydrogenase (LDH). CK and LDH were significantly decreased after 2 weeks of antifungal therapy. Only 3 cases developed drug resistance to fluconazole and these showed response when treated with voriconazole instead. Of the 13 cases, 10 were cured, 2 abandoned therapy and 1 died. CONCLUSIONS: The clinical manifestations of Candida albicans sepsis are nonspecific in preterm infants. Infectious diseases are probably caused by Candida albicans in preterm infants 2-3 weeks after birth. Preterm infants show decreased platelet and increased CRP, PDW, ALT, CK-MB, TBIL, CK, and LDH when infected with Candida albicans. PMID- 23092562 TI - [High-risk factors for parenteral nutrition-associated cholestasis in very low birth weight infants]. AB - OBJECTIVE: To investigate the high-risk factors for parenteral nutrition associated cholestasis (PNAC), which is the most common complication of parenteral nutrition for infants, in very low birth weight infants (VLBWIs). METHODS: Retrospective analysis was performed on the clinical and laboratory data of 204 VLBWIs who received parenteral nutrition for over 2 weeks in the neonatal intensive care unit from August 2006 to December 2011. The infants'liver function was evaluated periodically before and after Parenteral nutrition. Univariate analysis and multivariate analysis were performed in the observation (PNAC) and control (without PNAC) groups. RESULTS: PNAC occurred in 46 (22.5%) of the 204 VLBWIs. Univariate analysis showed that continuous positive airway pressure (CPAP) ventilation, respiration failure, respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) were significantly increased in the observation group compared with the control group. The observation group had lower birth weights, longer duration of ventilation, later breast feeding beginning, longer duration of fasting, longer duration of parenteral nutrition, and higher cumulated amino acid and lipid emulsion intake. Logistic regression analysis revealed that duration of fasting was a high-risk factor for PNAC (OR=1.115, 95%CI: 1.031-1.207). CONCLUSIONS: Many risk factors are associated with PNAC. Early enteral nutrition and short duration of parenteral nutrition are helpful in preventing the incidence of PNAC in VLBWIs. PMID- 23092563 TI - [Prospective study on in-hospital mortality and its risk factors in very low birth weight infants requring mechanical ventilation]. AB - OBJECTIVE: To describe the clinical features, treatments and prognosis of very low birth weight infants (VLBWIs) requring mechanical ventilation, to assess the risk factors associated with the mortality of VLBWIs, and to evaluate the significance of the scoring system based on clinical risk index for babies (CRIB) and the score for neonatal acute physiology-perinatal extension II (SNAPPE-II) for predicting mortality risk for premature infants in China. METHODS: Perinatal data were collected from 127 VLBWIs requring mechanical ventilation who were admitted to the neonatal intensive care unit (NICU) from January 2010 to October 2011. RESULTS: The enrolled infants had a mean gestational age of 31+/-2 weeks, a mean birth weight of 1290+/-170 g, a male/female ratio of 1.23?1, and extremely low birth weight infant accounting for 6.3%. Of the 127 cases, 48.0% were administered with pulmonary surfactant (PS), and 49.6% received endotracheal intubation ventilation. The overall in-hospital mortality was 41.7%. Multivariate logistic regression revealed the following independent risk factors for mortality: low birth weight, multiple birth, cesarean section, and low PaO2/FiO2 ratio (OR = 1.611, 7.572, 4.062, and 0.133 respectively; P<0.05). SNAPPE-II and CRIB showed good performance in predicting prognosis, with areas under the ROC curve of 0.806 and 0.777 respectively. CONCLUSIONS: The overall mortality rate of VLBWIs is still relatively high. The high-risk factors for VLBWI mortality include low birth weight, multiple birth, cesarean section, and low PaO2/FiO2 ratio. The neonatal illness severity scoring system (using SNAPPE-II and CRIB) can be used to quantify illness severity in premature infants. PMID- 23092564 TI - [Investigation on factors related to pyelic separation in early newborns]. AB - OBJECTIVE: To explore the relationship of pyelic separation with gestational age, body weight and sex in early newborns. METHODS: A total of 320 neonates were examined by renal ultrasound 2-7 days after birth. The neonates included 180 boys and 140 girls, with a mean gestational age of 36+/-3 weeks (28-42 weeks) and a mean birth weight of 2430+/-1000 g (900-4870 g). Correlation analysis was performed between renal pelvis anteroposterior diameter (APD) and gestational age/body weight. The newborns were grouped based on gestational age, body weight and sex and the incidence of pyelic separation was compared among the groups. RESULTS: Pyelic separation was found in 100 of the 320 newborns. The incidence of pyelic separation in boys (37.8%, 70 cases) was significantly higher than in girls (22.2%, 30 cases) (P<0.05). The incidence rates of pyelic separation on the left side, right side and both sides were 59%, 13% and 29% respectively in boys, and 53%, 7% and 40% respectively in girls. There was no significant difference in the location of renal pelvis separation between boys and girls (P>0.05). There significant difference in the incidence of pyelic separation between different gestational age groups (P>0.05). APD was positively correlated with gestational age and birth weight (P<0.05). The incidence of pyelic separation was negatively correlated with birth weight in all newborns except those who were macrosomic (P<0.05). CONCLUSIONS: The incidence of pyelic separation in early newborns is closely associated with birth weight and sex. APD is positively correlated to gestational age and birth weight. Pyelic separation often occurs more frequently on the left side or both sides than on the right side. PMID- 23092565 TI - [Clinical and pathological features of 50 children with Duchenne's muscular dystrophy]. AB - OBJECTIVE: To study the clinical and pathological features of children with Duchenne muscular dystrophy (DMD), with the aim of increasing the possibility of early diagnosis. METHODS: The clinical data of 50 children who were definitely diagnosed with DMD, based on clinical manifestations and the results of skeletal muscle biopsies and monoclonal antibody immunohistochemical staining, was reviewed. RESULTS: The children showed similar clinical manifestations, including running slowly in the toddler period, muscle weakness when climbing stairs and standing up followed by squatting down and walking abnormalities a predominant increase in serum creatine kinase level increased dominantly, and myopathic lesions seen on electromyography. Hematoxylin-eosin staining showed similar pathological presentations in all 50 children, including different-sized muscle fibers with rounding, degeneration and necrosis in various degrees, and proliferation of connective tissues. There was some inflammatory cell infiltration in muscle fibers and interstitial tissues. Dystrophin expression was completely absent at the sarcolemma in all 50 children, and sarcoglycan-alpha, beta, -',-delta expression was reduced to various degrees in 33 of them. CONCLUSIONS: For children with the clinical manifestations mentioned above, skeletal muscle biopsies and monoclonal antibody immunohistochemical staining are recommended as these examinations contribute to a definite diagnosis of DMD by demonstrating dystrophin deficiency at the sarcolemma. PMID- 23092566 TI - [Clinical significance of skin prick test for inhalant allergens in 3085 children with allergic diseases]. AB - OBJECTIVE: To investigate the main inhalant allergens and their distribution patterns in children with allergic diseases from Xi'an and the surrounding area and to provide evidence for the prevention and treatment of allergic diseases in children. METHODS: Skin prick test was performed using liquid with 13 standardized allergens (ALK-ABELL, Denmark) on 3085 children from Xi'an and the surrounding area who were treated for allergic diseases between July 2006 and July 2011, to detect inhalant allergens. RESULTS: Of the 3085 patients, 1368 (44.34%) had positive SPT results, with the most prevalent inhalant allergen being Dermatophagoides pteronyssinus (804 cases, 26.06%), followed by Dermatophagoides farinae (793 cases, 25.71%), Blomia tropicalis (440 cases, 14.26%), mugwort (282 cases, 9.14%), and cat hair (204 cases, 6.61%). The positive rates were 28.66% in the <4 years group, 41.85% in the 4-6 years group, and 58.61% in the 7-15 years group (P<0.01). Males had a significantly higher SPT positive rate than females (47.78% vs 38.50%;P<0.05). The SPT positive rate was highest in children with allergic rhinitis (72.41%), followed by bronchial asthma (62-25%), allergic dermatosis (45.83%), and allergic purpura (36.28%). CONCLUSIONS: In children from Xi'an and the surrounding area, the main inhalant allergens for allergic diseases include Dermatophagoides pteronyssinus, Dermatophagoides farinae, Blomia tropicalis, mugwort and cat hair. The SPT positive rate increases with age. Male children have a higher SPT positive rate than female children. The SPT positive rate is highest in children with allergic rhinitis. PMID- 23092567 TI - [Association between suppressors of cytokine signaling mRNA expression and Th1/Th2 balance in children with asthma]. AB - OBJECTIVE: Suppressors of cytokine signaling (SOCS) have been shown to play an important role in regulating cytokines, such as intracellular interferon (IFN) and interleukin (IL), in the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. At present, the association between SOCS and asthma is still under study. The aim of this study is to explore the relationship of SOCS-1 and SOCS-3 mRNA expression in peripheral blood mononuclear cells (PBMCs) with the intracellular IFN-'/IL-4 ratio in CD4+ T cells and specific IgE (sIgE) level in children with asthma. METHODS: BMCs were collected from 44 children with allergic asthma (4-14 years) and 30 healthy children. The intracellular IFN-'/IL-4 ratio in CD4+ T cells was measured by flow cytometry. Total RNAs were extracted from the PBMCs and SOCS-1 and SOCS-3 mRNA expression was measured by SYBR Green I quantitative RT-PCR. RESULTS: Compared with the healthy children, children with allergic asthma showed a lower level of intracellular IFN-' in peripheral blood [(15.7+/-2.0)% vs (19.1+/-2.7)%] and IFN '/IL-4 ratio (3.4+/-1.5 vs 4.8+/-2.9) and higher SOCS-1 mRNA expression (-Ct, 11.1+/-1.9 vs 12.6+/-2.8). There was a negative relationship between SOCS-1 mRNA expression and the percentage of IFN-'-producing CD4+ T cells in peripheral blood in both asthmatic and healthy children (P<0.05). No correlation was found between SOCS-1 and SOCS-3 expression and sIgE level. CONCLUSIONS: Children with allergic asthma have elevated levels of SOCS-1 mRNA in PBMCs, which is associated with Th2 skewed immune response. PMID- 23092568 TI - [Treatment of cerebral palsy with transplantation of human neural progenitor cells]. AB - OBJECTIVE: To study the clinical efficacy of transplantation of human neural progenitor cells (hNPCs) in the treatment of severe cerebral palsy (CP) in children. METHODS: Forty-five children with CP were voluntarily accepted transplantation of hNPCs. The cells obtained from the forebrain of 10 to 12-week fetus were cultured and amplified into hNPCs. Then the hNPCs were injected into the cerebral ventricle of the patients with the supersonic guidance. RESULTS: Dyssomnia, irritability and muscular tension were improved in one patient 3 days after transplantation. The clinical improvements were observed in the majority of the patients 1 month after transplantation. The therapeutic effects slowed down 3 to 6 months after transplantation. One year after transplantation the gross and fine motor skills and the congnition ability in the transplantation group were considerably surpassed to those in the control group. No delayed severe complications were observed after transplantation. No tumorigenesis was noted 5 years after transplantation. CONCLUSIONS: The transplantation of hNPCs as a novel therapy is effective and safe for severe CP. Many investigations are needed to evaluate the effect of the therapy. PMID- 23092569 TI - [ALK gene mutations in childhood neuroblastoma]. AB - OBJECTIVE: To investigate mutations of anaplastic lymphoma kinase (ALK) in Chinese children with neuroblastoma (NB). METHODS: Genomic DNA was extracted from 22 cases of paraffin-embedding NB tumor tissues. Gene mutations in the exons 20 26 which were mutational hotspots of ALK were analyzed by PCR-DNA direct sequencing. RESULTS: A novel synonymous mutation C3586T (Leu1196Leu) and a known synonymous mutation C3375A (Gly1125Gly) were found and located at exon 23 and exon 21 of ALK respectively. There were 10 cases (46%) of known synonymous mutation C3375A in 22 cases of NB. The C3375A allelic frequency was 27%. No statistically significant correlation was found between mutation C3375A and clinical parameters of NB such as age, sex, metastasis and tumor differentiation. Mutation was not found in the other 5 exons. CONCLUSIONS: A novel ALK gene synonymous mutation C3586T was identified using PCR-DNA sequencing. A known mutation C3375A in ALK was successfully identified in children, and its incidence is not influenced by the clinical features of childhood NB. PMID- 23092570 TI - [Role of serum 25-hydroxyvitamin D in the diagnosis of vitamin D deficiency rickets]. AB - OBJECTIVE: To study the role of serum 25-hydroxyvitamin D in the early diagnosis of vitamin D deficiency rickets. METHODS: Concentrations of serum 25(OH)D, calcium, phosphorus and alkaline phosphatase were measured in normal control (n=73), suspected rickets (n=45) and confirmed rickets groups (n=65). Receiver operating characteristic (ROC) curve was used to evaluate the diagnostic value of serum 25(OH)D for rickets. RESULTS: Serum 25(OH)D levels in the suspected and confirmed rickets groups were 83+/-30 and 72+/-31 nmol/L respectively, which was lower than in the normal control group (112+/-37 nmol/L) (P<0.01). There was no significant difference between the suspected and confirmed rickets groups (P>0.05). Vitamin D deficiency rates in the suspected and confirmed rickets groups were higher than in the control group (P<0.01). The ROC curve area of serum 25(OH)D for the diagnosis of rickets was 0.760 (95%CI 0.692-0.820, P<0.01), and the optimal operating point was 90.70 nmol/L (sensitivity 68.49%, specificity 72.73%). There was no significant difference in levels of calcium, phosphorus and alkaline phosphatase between the three groups (P>0.05). CONCLUSIONS: Serum 25(OH)D levels in infants with suspected and confirmed rickets are significantly reduced and this may reflect vitamin D deficiency . Therefore, it may be useful to check serum 25(OH)D levels in screening for rickets. PMID- 23092571 TI - [Causes of unexplained syncope in children]. AB - OBJECTIVE: To investigate the common causes of unexplained syncope in children. METHODS: A total of 434 children with unexplained syncope who were aged from 3.0 to 17.9 years (192 males and 242 females) and who saw the doctor between January 2006 and October 2011. were examined in order to explore the detailed histories and causes of syncope and to analyze variance in causes among different ages, genders, syncope frequencies and head-up tilt test (HUTT) results. RESULTS: (1) The causes of occasional syncope included persistent standing (30%), movement (13%), change in body position(9%), sitting(7%), and playing(6%). Persistent standing was more common as a cause in females than in males (P<0.01). Micturition syncope was mainly seen in males. Sultry weather was the main cause of syncope in females. Change in body position was a more common cause in the >=12 years group than in the <12 years group (P<0.05), while other causes showed no significant differences among different age groups. Change in body position was a more common cause of syncope in children with negative HUTT results than in those with positive HUTT results (P<0.05). (2) All causes of occasional syncope can induce repeated syncope, and most repeated syncope (56%) had the same cause. CONCLUSIONS: The common causes of unexplained syncope include persistent standing, movement and changes of body position in children. Avoiding these causes is helpful for prevention of childhood syncope. PMID- 23092572 TI - [Feasibility of SLEDAI-2000 and BILAG-2004 scoring systems for assessing renal disease activity in children with lupus nephritis]. AB - OBJECTIVE: To study feasibility of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2000) and British Isles Lupus Assessment Group 2004 (BILAG 2004) scoring systems for assessing renal disease activity in children with lupus nephritis (LN). METHODS: The clinical data of 159 children with systemic lupus erythematosus (SLE) and LN were collected, and disease activity was assessed by SLEDAI-2000 and BILAG-2004 scoring systems. The correlations between SLEDAI-2000 and BILAG-2004 scores and 24-hour urinary protein excretion and renal pathology index were analyzed. The SLEDAI-2000 and BILAG-2004 scoring systems were evaluated using ROC curve. RESULTS: Approximately one third (31.5%) of the 159 children had a moderate level of 24-hour urinary protein excretion. Among the 37 patients undergoing renal biopsy, 46.0% had diffuse LN (type IV). 24-hour urinary protein excretion was positively correlated with both SLEDAI-2000 (r=0.36, P<0.05) and BILAG-2004 scores (r= 0.39, P<0.05). Children with types I, II, III, and IV LN had pathology activity index (AI) which positively correlated with SLEDAI-2000 scores (r=0.86, 0.88, 0.84, 0.77 respectively; P<0.05) and BILAG-2004 scores (r= 0.88, 0.98, 0.86, 0.89 respectively; P<0.05). SLEDAI-2000 score showed the best correlation with AI in patients with type II LN, followed by those with type I LN. BIILAG-2004 score showed the best correlation with AI in patients with type II LN, followed by those with type IV LN. The BILAG-2004 scoring system had an area under the ROC curve (AUC) of 0.93, and the SLEDAI-2000 scoring system had an AUC of 0.88. CONCLUSIONS: BILAG-2004 and SLEDAI-2000 scoring systems can be used to assess renal disease activity of patients with LN. The BILAG-2004 scoring system can provide more reliable and comprehensive assessment. PMID- 23092573 TI - [Effects of matrine on the proliferation and apoptosis of human rhabdomyosarcoma RD cells]. AB - OBJECTIVE: To investigate the effects of matrine on the proliferation and apoptosis of human rhabdomyosarcoma RD cells in vitro, and to explore the mechanism of matrine inducing apoptosis of RD cells. METHODS: MTT assay was used to measure the proliferation inhibition rates of RD cells that were treated with matrine (final concentrations= 0.5, 1.0, 1.5, and 2.0 mg/mL). Flow cytometry was used to evaluate the apoptosis of RD cells treated with the four concentrations of matrine. RT-PCR was used to measure the mRNA expression of cyclin D1 and survivin in RD cells treated with 0.5, 1.0, and 1.5 mg/mL of matrine. RESULTS: The RD cells treated with various concentrations of matrine showed significantly higher proliferation inhibition rates and apoptotic rates than those that were not treated with matrine (P<0.01), and with increased matrine concentration, the proliferation inhibition rate of RD cells increased gradually, thus exhibiting a dose dependence. The mRNA expression of cyclin D1 and survivin was seen in all RD cells, but was significantly lower in RD cells treated with matrine than in those that were not treated with matrine (P<0.01). There were significant differences in cyclin D1 mRNA level among the RD cells treated with 0.5, 1.0, and 1.5 mg/mL of matrine (P<0.05), while there was significant difference in survivin mRNA level between the RD cells treated with 0.5 and 1.5 mg/mL of matrine (P<0.05). CONCLUSIONS: Matrine can significantly inhibit proliferation and induce apoptosis of RD cells, which may be related to downregulating the mRNA expression of cyclin D1 and survivin. PMID- 23092574 TI - [Effect of HOXA10 gene silenced by shRNA on proliferation and apoptosis of U937cell line]. AB - OBJECTIVE: To investigate the effects of lentivirus-mediated RNA interference targeting HOXA10 gene on the proliferation, apoptosis and morphology of leukemic cell line U937. METHODS: Four different shRNA plasmids were designed and built to interfere with HOXA10 gene. The four interference plasmids were transfected into 293T cells with the HOXA10 over expression plasmid and then the RNAi efficiency of the four interference plasmids was determined by Western blot. The best one was chosen to transfect 293T cells with lentiviral helping plasmids to produce packaged lentivirus (lenti-shHOXA10). U937 cells were divided into interference group (lenti-shHOXA10), negative control group and untreated group. After infection with the packaged lentivirus, infection efficiency of lentivirus for U937 was detected by flow cytometry, and the expression of HOXA10 gene mRNA and protein was detected by real-time PCR and Western blot. Cell survival was determined by MTT assay. Apoptosis rate was detected by flow cytometry. RESULTS: Lentiviral-shRNA vector of HOXA10 gene was successfully constructed. Compared with the negative control and untreated groups, mRNA level of HOXA10 decreased by (92.3+/-1.3)%, protein levels decreased by 91.1%, and the inhibition rate of U937 cells [(43.9+/-0.7)%] increased in the interference group (P<0.05). Wright's staining showed that the ratio of karyon to cytoplasm was reduced and mitotic phase was rare in the interference group. Apoptosis rate in the interference group [(27.1+/-1.4)%] was significantly higher than in the negative [(19.4+/ 1.9)%] and untreated groups [(5.5+/-1.3)%] (P<0.05). CONCLUSIONS: Lentivirus mediated RNAi can reduce the expression level of HOXA10, effectively inhibit proliferation and promote apoptosis of U937 cells. HOXA10 gene is expected to become a new target for the treatment of leukemia at gene level. PMID- 23092575 TI - [Effect of ginsenoside on apoptosis of human leukemia-60 cells]. AB - OBJECTIVE: To study the effect of ginsenoside on apoptosis of human leukemia-60 (HL-60) cells and its mechanism. METHODS: MTT cytotoxicity assay was used to determine the growth inhibition activity of ginsenoside (100, 50, 25, 12.5, 6.25, 3.125 and 1.5625 MUmol/L) on HL-60 cells. The apoptosis of HL-60 cells after treatment with ginsenoside (0,5,10 and 20 MUmol/L) was determined by Annexin V FITC/PI staining and flow cytometry. The cleavage of total proteins by caspase-8, caspase-9 and caspase-3 was evaluated by Western blot. The cleavage of caspase-3 protein was detected by Western blot after treatment with 10 MUmol/L ginsenoside and caspase-8 and 9 inhibitors. RESULTS: Ginsenoside had potent cytotoxicity on HL-60 cells, with an IC50 value of 7.3+/-1.2 MUmol/L. After treatment with ginsenoside (0, 5, 10 and 20 MUmol/L) for 48 hours, the apoptotic rate displayed a dose dependency, as shown by flow cytometry, with significant differences between the groups (F=12.67, P<0.01). Western blot showed that there were caspase 9 and caspase-3 cleavage bands, but without caspase-8 cleavage band. The specific inhibitor of caspase-9 Z-LEHD-FMK could block the caspase-3 cleavage induced by 10 MUmol/L ginsenoside, but the specific inhibitor of caspase-8 Z-IETD-FMK did not have this effect. CONCLUSIONS: Ginsenoside can induce apoptosis of HL-60 cells, which may be related to a mitochondria-dependent pathway. PMID- 23092576 TI - [Gene diagnosis of alkaptonuria in an infant]. PMID- 23092577 TI - [Neonatal cerebral infarction associated with low levels of protein C and protein S activity: a case report]. PMID- 23092578 TI - [Post-transcriptional protein modification of Gata4]. AB - Gata4 is an important transcription factor in heart development. Gata4 post transcriptional protein modification regulates transcriptional activity and DNA binding, which in turn affects expression of downstream genes and transcription factors, differentiation of embryonic stem cells and cardiogenesis. This article summarizes the effect of post-transcriptional protein modification on transcriptional activity of Gata4 and the relationship between this effect and congenital heart disease. It was shown that acetylation, phosphorylation and SUMOylation upregulate transcriptional activity, DNA binding, downstream gene expression and embryonic stem cell differentiation. On the other hand, methylation and deacetylation downregulate Gata4 transcriptional activity. Post transcriptional protein modification of Gata4 is very important in clinical research on congenital and other heart diseases. PMID- 23092579 TI - Legionella pneumophila serotype 1 pneumonia in patient receiving adalimumab. AB - We describe a case of severe pneumonia caused by Legionella pneumophila serotype 1 in a woman receiving the tumor necrosis factor-alpha antagonist to treat rheumatoid arthritis. As use of tumor necrosis factor-alpha inhibitors increase, clinicians should consider their possible association with legionellosis. PMID- 23092580 TI - Body composition in taller individuals using DXA: A validation study for athletic and non-athletic populations. AB - Dual energy X-ray absorptiometry (DXA) cannot be used to evaluate participants taller than the scan area. We aimed to analyse the accuracy of bone mineral content, fat mass, and lean mass assessed with DXA whole-body scan and from the sum of two scans (head and trunk plus limbs). Participants were 31 athletes (13 males and 18 females) and 65 non-athletes (34 males and 31 females), that fit within the DXA scan area. Three scans were performed using a Hologic Explorer-W fan-beam densitometer: a whole-body scan used as the reference; a head scan; and a trunk and limbs scan. The sum of the head scan and the trunk and limbs scan was used as the alternative procedure. Multiple regression and agreement analysis were performed. Non-significant differences between methods were observed for fat mass (0.06 kg) and lean mass (-0.07 kg) while bone mineral content from the alternative procedure differed from the reference scan (0.009 kg). The alternative procedure explained > 99% of the variance in the reference scan and low limits of agreement were observed. Precision analysis indicated low pure errors and the higher coefficients of variation were found for fat mass (whole body: 3.70%; subtotal: 4.05%). The method proposed is a valid and simple solution to be used in individuals taller than the DXA scan area, including athletes engaged in sports recognised for including very tall competitors. PMID- 23092581 TI - Trends in rural health Clinics and needs during U.S. health care reform. AB - AIM: Rural Health Clinics (RHCs) are primary care clinics certified through Medicare and Medicaid to provide health care to the medically underserved in rural areas of the United States. The purpose of this paper is to describe how the characteristics of RHCs have either changed or remained stable over a 10-year period in the past: from the late 1990s to 2007. In addition, it is also to describe some of the outstanding needs of RHCs as they navigate the transitions of U.S. health care reform. METHODS: Using a panel of RHCs continuously in existence from 2006 through 2007, we calculated and compared statistics with corresponding statistics from the literature. We described the geographic distribution of RHCs, demographics of their counties of location, and characteristics of RHC structure and staffing. We also explored the implications of the recently enacted health reform law (the Patient Protection and Affordable Care Act or ACA) for RHCs, and the improvements that RHCs need as it is implemented. FINDINGS: By the end of the study period, the highest percentages of RHCs were in the South and Midwest, the percentage of RHCs in the West had grown, and that in the South had declined. RHCs served counties with increasing proportions of individuals below poverty and Hispanics/Latinos. The percentage of independent clinics had grown, as had the percentage of for profit clinics. Finally, the percentage of nurse practitioner full-time equivalents had grown as a proportion of the total for three providers. CONCLUSIONS: In investigating the performance of RHCs, many managerial and operational factors are not well understood. It is imperative that RHCs gather the information that could help them maximize the elements of their performance that would keep them financially stable. In addition, a broader awareness of the unique challenges that RHCs face in this era of health care reform is needed. PMID- 23092582 TI - The interaction between CXCL10 and cytokines in chronic inflammatory arthritis. AB - There are several chemokines and their receptors involved in the pathogenesis of chronic inflammatory arthritis. Of those, CXCL10 and its receptor, CXCR3, are increased in many kinds of chronic inflammatory arthritis, especially in rheumatoid arthritis (RA). CXCL10 and CXCR3 play important roles in leukocyte homing to inflamed tissues and in the perpetuation of inflammation, and therefore, tissue damage. In addition to its chemotactic effect, CXCL10 may have pleiotropic functions. Our recent studies show that the crosstalk between CXCL10 and receptor activator of NF-kappaB ligand (RANKL) in inflamed synovial tissue may induce and perpetuate bone destruction in RA. The interaction between CXCL10 and tumor necrosis factor-alpha (TNF-alpha) can also contribute to sustained inflammation in RA. One human trial with anti-CXCL10 monoclonal antibody showed therapeutic potential of blocking CXCL10 in RA treatment. Understanding the novel interaction between this chemokine and other chemokines or cytokines may add possible therapeutic applications in inflammatory arthritis. PMID- 23092583 TI - Severe pneumonia caused by Legionella pneumophila serogroup 11, Italy. PMID- 23092584 TI - HIV infection and geographically bound transmission of drug-resistant tuberculosis, Argentina. AB - During 2003-2009, the National Tuberculosis (TB) Laboratory Network in Argentina gave 830 patients a new diagnosis of multidrug-resistant (MDR) TB and 53 a diagnosis of extensively drug- resistant (XDR) TB. HIV co-infection was involved in nearly one third of these cases. Strain genotyping showed that 7 major clusters gathered 56% of patients within restricted geographic areas. The 3 largest clusters corresponded to epidemic MDR TB strains that have been undergoing transmission for >10 years. The indigenous M strain accounted for 29% and 40% of MDR and XDR TB cases, respectively. Drug-resistant TB trends in Argentina are driven by spread of a few strains in hotspots where the rate of HIV infection is high. To curb transmission, the national TB program is focusing stringent interventions in these areas by strengthening infection control in large hospitals and prisons, expediting drug resistance detection, and streamlining information-sharing systems between HIV and TB programs. PMID- 23092585 TI - [Correlation of apparent diffusion coefficient with histologic type and grade of lung cancer]. AB - BACKGROUND AND OBJECTIVE: The histologic type and grade of lung cancer are significant in assessing the biological behaviour, prognosis and therapeutic regimen. This study investigates the correlation of apparent diffusion coefficient (ADC) with histologic type and grade of lung cancer. METHODS: A total of 115 patients pathologically diagnosed with lung cancer were enrolled in this study. Magnetic resonance (MR)-DWI with a diffusion factor of 500 s/mm2 was performed and the ADC values of lesions were measured. The ADC values among the different histologic types and grades were compared with the values obtained using t-test and one-way ANOVA. The correlation between ADC values and the histologic grades was further evaluated with Spearman correlation coefficient. RESULTS: With a b value of 500 s/mm2, the ADC values significantly differed between small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) (P = 0.017). The ADC values of SCLC were significantly different from those of squamous cell carcinoma and adenocarcinoma (P = 0.011, 0.001, respectively). A significant difference was observed in the ADC values among the different histologic grades of lung cancer (P = 0.003), and the ADC value was correlated with the histologic grades (rs = -0.272, P = 0.003). CONCLUSIONS: ADC value is significant for judgement of histologic type and grade of lung cancer before surgical operation: SCLC has a low ADC value, and ADC value is low for the tumor with poorly-differentiated grade. PMID- 23092586 TI - [Ribonucleotide reductase and non-small cell lung cancer]. PMID- 23092587 TI - [Advanced research on circulating tumor cells in lung cancer]. AB - Lung cancer is the malignant disease with the highest rate in terms of incidence and mortality in China. Early diagnosis and timely monitoring tumor recurrence and metastasis are extremely important for improving 5-year survival rate of lung cancer patients. Circulating tumor cells (CTCs), as a "liquid biopsy specimens" for the primary tumor, provide the possibility to perform real-time, non-invasive histological identification for lung cancer patients. The detection of CTCs contributes to early diagnosis, surveillance of tumor recurrence and metastasis, and prediction of therapeutic efficacy and prognosis. Furthermore, CTCs-dependent detection emerges as a new approach for molecularly pathologic examination, study of molecular mechanisms involved in drug resistance, and resolution for tumor heterogeneity. This study reviewed the recent progress of CTCs in lung cancer research field. PMID- 23092588 TI - Susceptibility of children to sapovirus infections, Nicaragua, 2005-2006. AB - We describe the genetic diversity of sapovirus (SaV) in children in Nicaragua and investigate the role of host genetic factors and susceptibility to SaV infections. Our results indicate that neither ABO blood group, Lewis phenotype, nor secretor status affects susceptibility to SaV infection in Nicaragua. PMID- 23092589 TI - Colorado Twin Registry: an update. AB - The Colorado Twin Registry (CTR) is a population-based registry housed at the Institute for Behavioral Genetics at the University of Colorado. Recruitment began in 1982 and includes twins born from 1968 to the present. Four samples are currently drawn from the CTR: The Community Twin Sample, the Longitudinal Twin Sample, the Early Reading Development Sample, and the Colorado Learning Sample. Criteria for enrollment, recruitment strategies, demographic information, and zygosity assignment are explained for each sample. In addition, five studies in which CTR twins are now participating are highlighted. These include studies of cognition, learning ability, and vulnerability to substance abuse and antisocial behavior. The development of the CTR is an ongoing and evolving process, and it has proven to be a valuable registry, relatively representative of the population from which it was drawn. PMID- 23092590 TI - Novel human enterovirus C infection in child with community-acquired Pneumonia. PMID- 23092591 TI - Risk for travel-associated legionnaires' disease, Europe, 2009. AB - Legionnaires' disease is underreported in Europe; notification rates differ substantially among countries. Approximately 20% of reported cases are travel associated. To assess the risk for travel-associated Legionnaires' disease (TALD) associated with travel patterns in European countries, we retrieved TALD surveillance data for 2009 from the European Surveillance System, and tourism denominator data from the Statistical Office of the European Union. Risk (number cases reported/number nights spent) was calculated by travel country. In 2009, the network reported 607 cases among European travelers, possibly associated with 825 accommodation sites in European Union countries. The overall risk associated with travel abroad was 0.3 cases/million nights. We observed an increasing trend in risk from northwestern to southeastern Europe; Greece had the highest risk (1.7). Our findings underscore the need for countries with high TALD risks to improve prevention and control of legionellosis; and for countries with high TALD risks, but low notification rates of Legionnaires' disease to improve diagnostics and reporting. PMID- 23092592 TI - Loose ends of psychiatric research. PMID- 23092593 TI - Psychopharmacology for the clinician: management of comorbid Tourette syndrome and attention-deficit/hyperactivity disorder: are psychostimulants an option? PMID- 23092594 TI - Effect of latitude on seasonality of tuberculosis, Australia, 2002-2011. AB - Seasonal variation in tuberculosis diagnoses recently has been reported in various populations. In Australia, seasonality of tuberculosis diagnoses was more pronounced in areas where UV exposure is reduced and vitamin D deficiency is more prevalent. Our findings suggest vitamin D deficiency as a factor in disease activation. PMID- 23092595 TI - Memory and communication support strategies in dementia: effect of a training program for informal caregivers. AB - BACKGROUND: People with dementia have a range of needs that are met by informal caregivers. A DVD-based training program was developed using research-based strategies for memory and communication in dementia. The effectiveness of the training on the caregiver experience and the well-being of the person with dementia was evaluated. METHODS: A pre-test/post-test controlled trial was undertaken with caregiver-care-recipient dyads living in the community. Measures of the carers' knowledge of memory and communication strategies, burden, positive perceptions of caregiving, and perceptions of problem behaviors were taken pre- and three months post-intervention. The depression and well-being of the person with dementia were also evaluated. Satisfaction with the training and feedback were measured. RESULTS: Twenty-nine dyads (13 training group, 16 control group) participated. Bonferroni's correction was made to adjust for multiple comparisons, setting alpha at 0.00385. A significant improvement was found in caregivers' knowledge for the training group compared to the control group (p = 0.0011). The training group caregivers reported a reduction in the frequency of care recipient disruptive behaviors (p = 0.028) and increased perceptions of positive aspects of caregiving (p = 0.039), both at a level approaching significance. The training group care recipients had increased frequency of verbally communicated depressive behaviors at a level approaching significance (p = 0.0126). The frequency of observed depressive behaviors was not significantly different between groups. CONCLUSIONS: This approach to training for caregivers of people with dementia appears promising for its impact on knowledge and the caregiving experience. Further research could monitor the impact of the training on broader measures of depression and well-being, with a larger sample. PMID- 23092596 TI - Spirituality and self-efficacy in dementia family caregiving: trust in God and in yourself. AB - BACKGROUND: Research indicates that spirituality and self-efficacy have been associated with higher levels of caregivers' well-being. However, these two concepts have rarely been examined simultaneously. The aim of this study was to analyze the combined effect of spirituality and self-efficacy on the caregiving stress process. METHODS: The study design was cross-sectional. Dementia family caregivers (n = 122) were assessed in relation to the following variables: stressors (time since caregiving began, daily hours caring, frequency of behavioral problems, patient's functional status); appraisal (caregiver's appraisal of behavioral problems), caregiver's personal resources (self-efficacy, spiritual meaning, social support), and outcomes (depression and anxiety). RESULTS: Participants were divided into four groups corresponding to four profiles defined by their scores on spiritual meaning and self-efficacy: LELS = Low self-efficacy and low spirituality; HELS = High self-efficacy and low spirituality; LEHS = Low self-efficacy and high spirituality; and HEHS = High self-efficacy and high spirituality. No differences were found between groups in stressors, appraisal, or personal resources. Caregivers in the HEHS group had significantly less depression compared to the LEHS group. Regression analysis showed that being a HEHS caregiver, low appraisal of behavioral problems and high social support were associated with low caregiver depression. Only high appraisal of behavioral problems was associated with high levels of anxiety. CONCLUSION: The results of this study suggest that spirituality and self-efficacy had an additive effect on caregivers' well-being. A high sense of spiritual meaning and a high self-efficacy, in combination, was associated with lower levels of depression in caregivers. PMID- 23092597 TI - Comparison of the burdens of family caregivers and foreign paid caregivers of the individuals with dementia. AB - BACKGROUND: The caregiver burden on foreign paid caregivers (FPCs) is currently not well understood. This study identified predictors and differences in caregiver burden between FPCs and family caregivers who provided care for patients with dementia. METHODS: We recruited 489 patients with dementia (diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition) and used the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) Scale to assess their neuropsychiatric behavioral problems and severity of dementia. All caregivers [FPCs (n = 42) and family caregivers with (n = 42) and without (n = 447) FPCs] completed three questionnaires: the Zarit Burden Interview (ZBI), the Center for Epidemiological Studies-Depression Scale (CES-D), and caregivers' knowledge of dementia (KD). To understand caregiver burden, we analyzed the correlations between ZBI and other variables and investigated the differences between family caregivers and FPCs. RESULTS: NPI and CDR scores were higher among patients assisted by FPCs than among those whose families did not employ FPCs. Burdens were greater among family caregivers assisted by FPCs than among FPCs and family caregivers who were not assisted by FPCs. Family caregivers had greater knowledge of dementia than did FPCs. For family caregivers, CES-D scores (Spearman's r = 0.650; p < 0.01) and patients' NPI scores (Spearman's r = 0.471; p < 0.01) were correlated with caregiver burden. For FPCs, only CES-D scores (Spearman's r = 0.511; p < 0.01) were correlated with caregiver burden. A linear regression model showed that CES D scores contributed most to caregiver burden in all groups [beta = 0.560 (family caregivers without FPCs), 0.546 (family caregivers with FPCs), and 0.583 (FPCs); p < 0.005]. CONCLUSION: Both family caregivers and FPCs need emotional support. Adequate treatment to reduce the neuropsychiatric symptoms of patients with dementia might reduce the burden on family caregivers. PMID- 23092598 TI - [Non oncologic applications of molecular targeted therapies]. AB - Significant improvements in the knowledge of cancer biology have permitted the development of new molecular targeted therapies. Meanwhile, a better understanding of the physiology of various non-cancerous diseases has allowed developing these agents in other areas. This review intends to illustrate these perspectives through examples corresponding to different strategies of molecular targeted therapies : use of a monoclonal antibody binding a receptor (rituximab and rheumatoid arthritis) or a ligand (bevacizumab and age-related macular degeneration), tyrosine kinase inhibitor (imatinib and systemic sclerosis) or inhibitor of cytoplasmic signal transduction pathways (immunosuppressive and antiproliferative effects of mammalian target of rapamycin [mTOR] inhibitors). Clinical results can draw today what could become molecular medicine of tomorrow. PMID- 23092599 TI - Litchi-associated acute encephalitis in children, Northern Vietnam, 2004-2009. AB - Since the end of the 1990s, unexplained outbreaks of acute encephalitis in children coinciding with litchi harvesting (May-July) have been documented in the Bac Giang Province in northern Vietnam. A retrospective ecologic analysis of data for 2004-2009 involving environmental, agronomic, and climatic factors was conducted to investigate the suspected association between the outbreaks and litchi harvesting. The clinical, biological, and immunologic characteristics of the patients suggested a viral etiology. The ecologic study revealed an independent association between litchi plantation surface proportion and acute encephalitis incidence: Incidence rate ratios were 1.52 (95% CI 0.90-2.57), 2.94 (95% CI 1.88-4.60), and 2.76 (95% CI 1.76-4.32) for second, third, and fourth quartiles, respectively, compared with the lowest quartile. This ecologic study confirmed the suspected association between incidence of acute encephalitis and litchi plantations and should be followed by other studies to identify the causative agent for this syndrome. PMID- 23092600 TI - Genome sequencing of pathogenic Rhodococcus spp. PMID- 23092601 TI - Evaluation of the pilot phase of an Aboriginal and Torres Strait Islander Male Health Module. AB - This article evaluates the pilot phase of an Aboriginal and Torres Strait Islander Male Health Module. Although men experience higher levels of illness and die younger than women, educational programs to support health workers utilise a gender-based approach to increase participation of Aboriginal and Torres Strait Islander males in health care are rare and lack appropriate content. Recognising this gap in service provision, and under the guidance of a Reference Group comprising community leaders in Aboriginal and Torres Strait male health, a comprehensive and culturally appropriate Male Health Module has been developed to enhance the capacity of health workers to improve access to services for Aboriginal and Torres Strait Islander males. Methods used were: in-depth interviews with Module developers, pilot workshops for trainers and health workers, questionnaires and focus group discussions with workshop participants, and participant observations. As well as enhancing capacity to facilitate access to health services for men, the Module was deemed relevant because of its potential to promote health worker empowerment and wellbeing. Findings revealed that improving access to services for men required male and female health workers working in partnership. Despite overall enthusiasm for the Module, the findings also revealed deep fear that it would end up 'collecting dust on shelves'. Strategies to improve the Module quality and accessibility are highlighted. PMID- 23092602 TI - Community outbreak of adenovirus, Taiwan, 2011. AB - In 2011, a large community outbreak of human adenovirus (HAdV) in Taiwan was detected by a nationwide surveillance system. The epidemic lasted from week 11 through week 41 of 2011 (March 14-October 16, 2011). Although HAdV-3 was the predominant strain detected (74%), an abrupt increase in the percentage of infections caused by HAdV-7 occurred, from 0.3% in 2008-2010 to 10% in 2011. Clinical information was collected for 202 inpatients infected with HAdV; 31 (15.2%) had severe infection that required intensive care, and 7 of those patients died. HAdV-7 accounted for 10%, 12%, and 41% of infections among outpatients, inpatients with nonsevere infection, and inpatients with severe infection, respectively (p<0.01). The HAdV-7 strain detected in this outbreak is identical to a strain recently reported in the People's Republic of China (HAdV7 HZ/SHX/CHN/2009). Absence of circulating HAdV-7 in previous years and introduction of an emerging strain are 2 factors that caused this outbreak. PMID- 23092603 TI - Pandemic influenza virus surveillance, Izu-Oshima Island, Japan. AB - A population-based influenza surveillance study (using PCR virus subtyping) on Izu-Oshima Island, Japan, found that the cumulative incidence of influenza A(H1N1)pdm09 virus infections 2 seasons after the pandemic was highest for those 10-14 years of age (43.1%). No postpandemic A(H1N1)pdm09 case-patients had been infected with A(H1N1)pdm09 virus during the pandemic season. PMID- 23092604 TI - Atypical pestivirus and severe respiratory disease in calves, Europe. PMID- 23092605 TI - Analysis of EIF4G1 in Parkinson's disease among Asians. AB - Sequence analysis of all the exons of EIF4G1 in 96 Asian patients with Parkinson's disease (PD) did not reveal any pathogenic mutations. A novel coding variant (Pro693Ser) in exon 15 (position 2077) was detected in one PD patient but not in 539 control subjects. Analysis of a coding polymorphic variant (rs2178403) in 1330 subjects revealed similar frequency between control subjects (0.638) and PD patients (0.640). EIF4G1 is an uncommon cause of PD in our Asian cohort. PMID- 23092606 TI - Pathological analysis of the Candida albicans-infected tongue tissues of a murine oral candidiasis model in the early infection stage. AB - OBJECTIVE: The early pathological process of Candida infection and immunological responses in tongues of the mice with experimental oral candidiasis was analysed. METHODS: CD-1 mice, pretreated by prednisolone were orally inoculated with Candida albicans. Symptoms were monitored by measuring the area of white tongue coating and number of viable Candida cells in oral cavity. The histopathological analysis was carried by PAS-stain and immunofluorescent staining. IL-4, IL-12p70, IFN-gamma, TNF-alpha in recovered from the homogenates of the tongues were measured by ELISA. RESULTS: The fungus invaded the tongue surface of the mice and white patches developed within 24h after inoculation. Histopathological examination indicated the presence of local acute inflammation in superficial tissues of tongues covered by mycelium of C. albicans. Pathological exacerbation was observed from 24 to 48 h after the inoculation and from then the symptoms of oral candidiasis appeared to move into the recovery phase. Inflammatory cells mainly consisting of neutrophils was accumulated and located under the lesions covered by Candida-hyphae. An increase in IL-12p70 and IFN-gamma in tongue homogenates was observed at 48 h after inoculation. CONCLUSIONS: The worst condition in the pathological process in experimental oral candidiasis was found 48 h after C. albicans inoculation. When the surface of the Candida-inoculated tongues was covered with Candida-hyphae, a dense accumulation of neutrophils was observed under the lesions and homogenates of the tongues contained increased levels of IL-12p70 and IFN-gamma. These suggested that local pathological condition of Candida-infected tongues may be affected by neutrophils accumulation and increased levels of some cytokines. PMID- 23092607 TI - Expression and localization of receptor protein tyrosine phosphatase beta and its ligand pleiotrophin in the submandibular gland of mice. AB - OBJECTIVES: The family of receptor protein tyrosine phosphatase beta (RPTPbeta) is composed of 4 splice variants and thought to play roles in the neural migration and outgrowth. Several ligands including the growth factor pleiotrophin (PTN) bind to RPTPbeta and inhibit its phosphatase activity, thereby activating cellular signalling pathways. We examined the expression and localization of RPTPbeta and its ligands in the submandibular gland (SMG) of mice, which is known for a prominent sexual dimorphism in the duct system. DESIGN: The homogenates and tissue sections of male and female mouse SMG were analysed with RT-PCR, Western blotting, and immunohistochemistry. RESULTS: The short receptor type of RPTPbeta (RPTPbeta-S) was dominantly expressed in the SMG, and the male gland had significantly higher levels of RPTPbeta-S expression than the female gland. In the male, RPTPbeta-S was localized predominantly in intercalated duct (ID) cells, but was not found in granular convoluted tubule (GCT) cells or acinar cells. In the female, weaker reactivity was demonstrated in both ID and striated duct (SD) cells. Of the known ligands for RPTPbeta, PTN was expressed in the SMG, without sexual difference in levels. In the male, PTN was localized in ID cells as well as in cells located in the distal ends of GCT that are in close vicinity to the ID, whereas in the female PTN was colocalized with RPTPbeta-S throughout ID and SD cells. CONCLUSIONS: These results indicated that the distribution of RPTPbeta S and its ligand PTN has a close relation to the sexual dimorphism in the duct system of mouse SMG. PMID- 23092608 TI - Effects of enamel matrix derivative on remineralisation of initial enamel carious lesions in vitro. AB - OBJECTIVE: The purpose of this study was to investigate the effect of enamel matrix derivative on remineralisation of initial enamel carious lesions in vitro. DESIGN: Initial enamel carious lesions were created in bovine enamel blocks in vitro. The lesions were subjected to a pH-cycling regime of 24days. Each daily cycle included 4*3-min applications with one of four treatments: 1g/L NaF aqueous solution (positive control), 6% propylene glycol alginate (PGA) or distilled and deionised water (DDW) (both negative controls), and a gel of enamel matrix derivative and PGA (EMDgel). Samples were subjected to surface microhardness (SMH) testing, polarised light microscopy (PLM) and transverse microradiography (TMR) to measure SMH, mineral loss, lesion depth and mineral content of the surface layer and lesion body before and after pH-cycling. RESULTS: NaF samples showed the highest SMH recovery of all the groups (P<0.05). EMDgel samples showed significantly higher SMH recovery than did PGA ones (P<0.05). NaF samples showed significantly less mineral loss and shallower lesions than all other groups (P<0.05). The DDW and EMDgel samples showed significantly less mineral loss and shallower lesions than PGA samples. Mineral deposition predominated much more at the surface layer in the EMDgel group than in the PGA group (P<0.05). CONCLUSIONS: EMD, the active ingredient of EMDgel, may play an essential role in promoting remineralisation of initial enamel carious lesions. However, EMDgel as a whole did not cause detectable remineralisation of such lesions in vitro. PMID- 23092609 TI - Effects of zoledronic acid on odontoblast-like cells. AB - The aim of the study was to evaluate the effects of a highly potent bisphosphonate, zoledronic acid (ZOL), on cultured odontoblast-like cells MDPC 23. The cells (1.5*10(4)cells/cm(2)) were seeded for 48h in wells of 24-well dished. Then, the plain culture medium (DMEM) was replaced by fresh medium without fetal bovine serum. After 24h, ZOL (1 or 5MUM) was added to the medium and maintained in contact with the cells for 24h. After this period, the succinic dehydrogenase (SDH) enzyme production (cell viability - MTT assay), total protein (TP) production, alkaline phosphatase (ALP) activity, and gene expression (qPCR) of collagen type I (Col-I) and ALP were evaluated. Cell morphology was assessed by SEM. Five MUM ZOL caused a significant decrease in SDH production. Both ZOL concentrations caused a dose-dependent significant decrease in TP production and ALP activity. ZOL also produced discret morphological alterations in the MDPC-23 cells. Regarding gene expression, 1MUM ZOL caused a significant increase in Col-I expression. Although 5MUM ZOL did not affect Col-I expression, it caused a significant alteration in ALP expression (ANOVA and Tukey's test, p<0.05). ZOL presented a dose-dependent cytotoxic effect on the odontoblast-like cells, suggesting that under clinical conditions the release of this drug from dentin could cause damage to the pulpo-dentin complex. PMID- 23092610 TI - Salivary markers of oxidative stress in patients with oral premalignant lesions. AB - The aetiology of oral premalignant lesions is unknown. Oxidative stress is associated with inflammation and cancerogenesis. The aim of our study was to compare salivary markers of oxidative and carbonyl stress in patients with oral premalignant lesions and age-matched healthy controls. Unstimulated saliva samples were collected from 16 patients with oral premalignant lesions (leukoplakia, lichen planus, erythroplakia) and 16 age-matched healthy controls. Biochemical analysis included measurement of thiobarbituric acid reacting substances (TBARS), advanced oxidation protein products (AOPP), advanced glycation endproducts (AGEs) and total antioxidant capacity (TAC). Salivary RNA was analyzed using real time PCR. Salivary TBARS and AGEs were significantly higher in patients than in controls. No differences were found in AOPP. TAC and expression of superoxide dismutase were lower in patients than in age-matched controls. Other analyzed transcripts (vascular endothelial growth factor, sialotransferase, neuraminidase) did not differ between patients and the control group. Markers of lipoperoxidation and carbonyl stress were increased in patients with oral premalignant lesions. Decreased antioxidant status potentially due to decreased expression of antioxidant enzymes might be responsible for these findings. Our results might point to the aetiology or pathogenesis of oral premalignant lesions as well as to the mechanism of transition to oral carcinoma. PMID- 23092611 TI - Utilization of waste phosphogypsum to prepare hydroxyapatite nanoparticles and its application towards removal of fluoride from aqueous solution. AB - In the present study, waste phosphogypsum (PG) was utilized firstly to prepare hydroxyapatite nanoparticles (nHAp) via microwave irradiation technology. The nHAp derived from PG exhibited a hexagonal structure with the particle size about 20 nm * 60 nm and high purity. Meanwhile, the adsorption behaviour of fluoride onto the nHAp derived from PG was investigated to evaluate the potential application of this material for the treatment of the wastewater polluted with fluoride. The results indicate that the nHAp derived from PG can be used as an efficient adsorbent for the removal of fluoride from aqueous solution. The maximum adsorption capacities calculated from Langmuir-Freundlich model were 19.742, 26.108, 36.914 and 40.818 mg F(-)/g nHAp for 298, 308, 318 and 328 K, respectively. The pseudo-second order kinetic model was found to provide the best correlation of the used experimental data compared to the pseudo-first order and the adsorption isotherm could be well defined by Langmuir-Freundlich equation. The adsorption mechanism investigation shows that electrostatic interaction and hydrogen bond are the main driving force for fluoride uptake onto nHAp derived from waste PG. PMID- 23092612 TI - Adsorption of toxic metal ion Cr(VI) from aqueous state by TiO2-MCM-41: equilibrium and kinetic studies. AB - This paper deals with the immobilization of various weight percentage of TiO(2) on mesoporous MCM-41, characterization of the materials by X-ray diffraction (XRD), nitrogen adsorption-desorption, Fourier Transform Infrared (FTIR) analysis, UV-vis diffuse reflectance spectroscopy (DRS) and evaluation of the adsorption capacity toward Cr(VI) removal. It is found that the MCM-41 structure retained after loading of TiO(2) but the surface area and pore diameter decreased due to pore blockage. Adsorption of Cr(VI) from aqueous state was investigated on TiO(2)-MCM-41 by changing various parameters such as pH, metal ion concentration, and the temperature. When TiO(2) loading was more than 20 wt.%, the adsorption activity (25)TiO(2)-MCM-41 reduced significantly due to considerable decrease in the surface area. It is also observed that TiO(2) and neat MCM-41 exhibits very less Cr(VI) adsorption compared to TiO(2)-MCM-41. The adsorption of Cr(VI) onto (20)TiO(2)-MCM-41 at pH~5.5 and temperature 323 K was 91% at 100mg/L Cr(VI) metal ion concentration in 80 min. The experimental data fitted well to Langmuir and Freundlich isotherms. The adsorption of Cr(VI) on TiO(2)-MCM-41 followed a second order kinetics with higher values of intra-particle diffusion rate. Thermodynamic parameters suggested that the adsorption process is endothermic in nature and desorption studies indicated a chemisorption mode. PMID- 23092613 TI - Selenite adsorption using leached residues generated by reduction roasting ammonia leaching of manganese nodules. AB - This study was carried out to investigate the adsorption characteristics of leached manganese nodule residue (MNR), generated from the reduction roasting ammonia leaching process, towards aqueous selenite. Physicochemical characterization revealed that the leached residue was a complex mixture of oxides of mainly manganese and iron along with MnCO(3). Adsorption studies of the water washed leached residue (wMNR) at varying the pH, selenite ion concentration, wMNR dosage, heat treatment condition indicated that selenite uptake increased with increasing pH and heat-treatment temperature of wMNR. The maximum value of selenite uptake was obtained at pH ~5.0 with wMNR heat-treated at 400 degrees C and thereafter decreased on increasing the pH and heat-treatment temperature further. The adsorption data were best fitted by the Freundlich isotherm model. The derived monolayer selenite adsorption capacities increased from, X(m)=9.50 mg Se/g (for untreated wMNR) to 15.08 mg Se/g (for wMNR heat treated at 400 degrees C). The results of the studies may be useful for possible utilization of MNR as an adsorbent for the removal of selenite ions from contaminated water bodies. PMID- 23092615 TI - Reflective research: supporting researchers engaged in analyzing end-of-life communication. AB - OBJECTIVES: The objectives of this commentary are to: (1) identify unique aspects of communication at end-of-life as compared to more commonly studied healthcare encounters; (2) outline challenges and opportunities research team members may encounter in coding and analyzing end-of-life communication; and (3) offer recommendations for quantitative communication research teams. This commentary is based on ours and others' experiences in studying the communication among patients with terminal illnesses, their families and their providers. Provider patient/caregiver communication at end-of-life has some differences as compared to other forms of healthcare communication and, thus, has implications for researcher response. Challenges and opportunities for research team members include gaining new knowledge, developing feelings of attachment to study participants, burn-out, and emotional and existential impact on personal life. Practical and psychological considerations for conducting end-of-life communication research are discussed. CONCLUSIONS: Researchers engaged in the study of end-of-life interactions may experience unique challenges, potentially compromising the validity of the research results and interpretation of communication processes. A balance between likely coder emotions and objectivity must be achieved. IMPLICATIONS: Anticipating and facilitating the research teams' reactions to end-of-life interactions while still maintaining scientific standards may be achieved by using a reflective, mindful approach. PMID- 23092614 TI - Improving the spatial resolution of atmospheric polycyclic aromatic hydrocarbons using passive air samplers in a multi-industrial city. AB - The source-receptor relationship of polycyclic aromatic hydrocarbons (PAHs) in the industrial city has been generally investigated using active air samplers (AAS), but they only provide low spatial resolution data. In this study, the spatial resolution of PAHs was improved by the use of polyurethane foam based passive air samplers (PUF-PAS). We deployed 40 passive air samplers in duplicate at 20 sites in the largest industrial city of Ulsan, South Korea during winter (January 7-February 25, 2011). Among the 16 US-EPA priority PAHs, 13 compounds excluding naphthalene, acenaphthylene, and acenaphthene were selected for the calculation of air concentrations. The level of gaseous ?(13)PAHs in Ulsan (mean: 43 ng/m(3)) was not as high as we expected due to prevailing winds which transported large amounts of PAHs to the East Sea. The spatial distribution of PAHs, principal component analysis, and diagnostic ratios suggested the influence of PAH emissions from industrial complexes to the surrounding areas. This study demonstrated that the source-receptor relationship of PAHs in the industrial area can be more clearly understood using passive air samplers. PMID- 23092616 TI - Investigation of outbreaks complicated by universal exposure. AB - Outbreaks in which most or all persons were exposed to the same suspected source of infection, so-called universal exposure, are common. They represent a challenge for public health specialists because conducting analytical studies in such investigations is complicated by the absence of a nonexposed group. We describe different strategies that can support investigations of outbreaks with universal exposure. The value of descriptive epidemiology, extensive environmental investigation, and the hypothesis-generation phase cannot be overemphasized. An exposure that seems universal may in fact not be universal when additional aspects of the exposure are taken into account. Each exposure has unique characteristics that may not be captured when investigators rely on the tools readily at hand, such as standard questionnaires. We therefore encourage field epidemiologists to be creative and consider the use of alternative data sources or original techniques in their investigations of outbreaks with universal exposure. PMID- 23092617 TI - Recurrent solitary fibrous tumour of the thoracic spine. A case-report and literature review. AB - Solitary fibrous tumours (SFTs) are rare tumours originating in the soft tissues. SFT development in the spine is an exceedingly rare event about which little is known. We describe a case of SFT of the thoracic spine in a 56-year-old woman. She presented with neurological deficits that required emergency resection, which was incomplete. Two subsequent local recurrences prompted further surgical procedures. At last follow-up, 12 months after the last procedure, function was satisfactory and there was no evidence of tumour recurrence. The management of SFTs is not well standardised, and no proven adjuvant treatments are available to date. Complete excision is effective in controlling disease progression. Prolonged follow-up is mandatory. PMID- 23092619 TI - Awareness of schizophrenia and intellectual disability and stigma across ethnic groups in the UK. AB - Research has examined the public's understanding of mental illness and stigma, but there is scant evidence on intellectual disabilities. This study investigated whether the public from different ethnic groups can recognise symptoms of schizophrenia and intellectual disability depicted in a vignette, and what factors predict recognition and social distance. A survey of lay people of working age was completed in the UK (N=1002). The sample was ethnically mixed, with the largest groups consisting of white UK residents, and people from Asian and black African/Caribbean backgrounds. Regression analyses were performed to identify predictors of recognition and social distance. Across the whole sample, 25.7% recognised schizophrenia and 28.0% intellectual disability. Ethnicity, gender, education and prior contact predicted recognition of both vignettes. Social distance was higher for schizophrenia than intellectual disability, but overall participants were ambivalent to mildly negative about social contact with individuals with either symptomatology. Familiarity was associated with lower social distance for both conditions. Symptom recognition predicted reduced social distance for intellectual disability, but not for schizophrenia. The low levels of awareness of symptoms and high levels of stigma among some ethnic groups indicate a need for targeted public education efforts and further research. PMID- 23092618 TI - Enhanced absorption of boswellic acids by a lecithin delivery form (Phytosome((r))) of Boswellia extract. AB - The anti-inflammatory potential of Boswellia serrata gum resin extracts has been demonstrated in vitro and in animal studies as well as in pilot clinical trials. However, pharmacokinetic studies have evidenced low systemic absorption of boswellic acids (BAs), especially of KBA and AKBA, in rodents and humans. This observation has provided a rationale to improve the formulation of Boswellia extract. We present here the results of a murine comparative bioavailability study of CasperomeTM, a soy lecithin formulation of standardized B. serrata gum resin extract (BE), and its corresponding non-formulated extract. The concentration of the six major BAs [11-keto-beta-boswellic acid (KBA), acetyl-11 keto-beta-boswellic acid (AKBA), beta-boswellic acid (betaBA), acetyl-beta boswellic acid (AbetaBA), alpha-boswellic acid (alphaBA), and acetyl-alpha boswellic acid (AalphaBA)] was evaluated in the plasma and in a series of tissues (brain, muscle, eye, liver and kidney), providing the first data on tissue distribution of BAs. Weight equivalent and equimolar oral administration of CasperomeTM provided significantly higher plasma levels (up to 7-fold for KBA, and 3-fold for betaBA quantified as area under the plasma concentration time curve, AUC(last)) compared to the non-formulated extract. This was accompanied by remarkably higher tissue levels. Of particular relevance was the marked increase in brain concentration of KBA and AKBA (35-fold) as well as betaBA (3-fold) following CasperomeTM administration. Notably, up to 17 times higher BA levels were observed in poorly vascularized organs such as the eye. The increased systemic availability of BAs and the improved tissue distribution, qualify CasperomeTM for further clinical development to fully exploit the clinical potential of BE. PMID- 23092620 TI - Both mucosal and cutaneous papillomaviruses are in the oral cavity but only alpha genus seems to be associated with cancer. AB - BACKGROUND: Human papillomaviruses are associated with invasive cancers in the cervical, anogenital, and oropharyngeal areas. Persistent HPV infections, particularly with high-risk HPV such as HPV 16, are involved in the carcinogenesis of a subset of oropharyngeal cancers. The majority of published studies on HPV prevalence in these tumors concentrated on identifying high-risk mucosal types. OBJECTIVES: To determine the HPV type specific prevalence in different samples collected from the oral cavity of three groups of patients: (A) healthy (n=25); (B) non-malignant lesions (n=47); and (C) cancers (n=78). STUDY DESIGN: To evaluate the prevalence of HPV genotypes in the oral cavity, samples were analyzed by PCR with: MY09/MY11 followed by GP5+/GP6+, CP65/CP70 followed by CP66/CP69, and FAP59/FAP64 primers. The presence of viral transcripts was ascertained by RT-PCR with specific primers for the E7 region. RESULTS: Mucosal HPV types were associated with the presence of cancers. This trend was statistically significant if the analysis was performed for HPV 16 (p=0.04), which is the most prevalent type detected in oropharyngeal cancers. Conversely, cutaneous HPVs were associated with non-malignant lesions (p=0.007). The multiple correspondence analysis confirmed these data. Viral transcripts of only mucosal HPVs were detected in non-malignant lesions and cancers. CONCLUSIONS: Different types of HPVs infect the oral epithelium, but only the mucosal types, particularly HPV 16, are clearly associated with tumors. The discovery that cutaneous HPVs are associated with potential malignant oral disorders brings other data to understand the significance of their presence in the oral cavity. PMID- 23092621 TI - Detection of false positives with a commonly used Norovirus RT-PCR primer set. PMID- 23092623 TI - Analyzing UV-B narrowband solar irradiance: comparison with erythemal and vitamin D production irradiances. AB - The heliotherapy and the phototherapy are mainly focused on taking benefit of the therapeutic effects of the ultraviolet (UV) irradiance on different skin diseases. The use of UV-B narrowband lamps, with emissions centered at 311 nm, has spread out among the dermatologist community because of its high therapeutic effect in comparison with its low erythema dose. For cloudless sun exposure, the balance of solar erythemal and solar narrowband (NB)-equivalent irradiances depends on several factors such as the solar zenith angle (SZA), the total ozone column (TOC) and the altitude. For SZA below 55 degrees , the ratio of solar UV-B narrowband and erythemal irradiances increases with the SZA whereas the ratio of vitamin D production and erythemal irradiances decreases with the SZA with the maximum around midday. Furthermore, the solar NB ratio also increases with the TOC because the shorter wavelengths of the erythemal action spectrum are more affected by the ozone absorption processes. Considering the daily variations of the ratio between narrowband and erythemal irradiance, sun exposures avoiding midday hours are recommended in order to prevent negative side-effects. However to accumulate great NB doses and sufficient vitamin D in winter months is difficult because the time exposures may be longer than the day duration. PMID- 23092624 TI - The time-dependent accumulation of protoporphyrin IX fluorescence in nodular basal cell carcinoma following application of methyl aminolevulinate with an oxygen pressure injection device. AB - Topical protoporphyrin (PpIX)-induced photodynamic therapy (PDT) relies on the penetration of the prodrug into the skin lesion and subsequent accumulation of the photosensitizer. Methyl aminolevulinate (MAL)-PDT is an established treatment for thinner and superficial non-melanoma skin cancers (NMSCs) but for the treatment of the thicker nodular basal cell carcinoma (nBCC) enhanced penetration of the prodrug is required. This study employed a new higher pressure, oxygen pressure injection (OPI) device, at the time of Metvix(r) application with a view to enhancing the penetration of MAL into the tumors. Each patient had Metvix(r) applied to a single nBCC followed by application of a higher pressure OPI device. Following different time intervals (0, 30, 60, 120 or 180 min) the tumors were excised. The maximum depth and area of MAL penetration achieved in each lesion was measured using PpIX fluorescence microscopy. As expected, an increase in the depth of MAL-induced PpIX accumulation and area of tumor sensitized was observed over time; when the Metvix(r) cream was applied for 0, 30, 60, 120 and 180 min the median depth of PpIX fluorescence was 0%, 21%, 26.5%, 75.5% and 90%, respectively and the median area of tumor sensitized was 0%, 4%, 6%, 19% and 60%, respectively. As the investigation presented here did not include a control arm, the relative depths of fluorescence observed in this study were statistically compared (using the non-parametric Mann Whitney U test) with the results of our previous study where patients had Metvix(r) cream applied either with or without the standard pressure OPI device. When the higher pressure OPI device was employed compared to without OPI this increase was observed to be greater following 30, 120, and 180 min although overall not significantly (p=0.835). In addition, no significant difference between the higher pressure OPI device employed here and the previously investigated standard pressure OPI device was observed (p=0.403). However, when the results for both OPI devices were combined and compared to the standard treatment (no OPI employed) group, although the difference did not reach significance (p=0.531) a consistent and substantial increase in the depth of PpIX fluorescence was observed, therefore employment of an OPI device during topical MAL-PDT protocols warrants further investigation as a technique for enhancing MAL penetration. PMID- 23092625 TI - Comparison of short-term results of modified Karydakis flap and modified Limberg flap for pilonidal sinus surgery. AB - The aim of this study was to compare and analyze the short term results of modified Karydakis flap reconstruction (MKF) and modified Limberg flap reconstruction (MLF). This is a retrospective analysis of 81 patients operated for pilonidal sinus disease. There were 46 patients in MLF group and 35 patients in MKF group. We compared patients age, BMI, operation time, removal time of suction drain, time of feeling completely healed, type of presentation, complications, postoperative 1., 3., 5. Days VAS scores, time to stop analgesic drugs and time to sit on chair or throne without pain. Complication rate, analgesic drug stopping time, postoperative 5. days VAS score were lower in MLF group and there were significant difference between groups. MLF group patients feel better (P: 0.010), they recommended this operation to other pilonidal sinus patients (P: 0.010) and 36 of them rated their satisfaction excellent and 10 of them good (P: 0.010). MLF procedure was more comfortable for patients. Lesser pain, lower complication and recurrence rates and higher patient satisfaction were detected in MLF group. PMID- 23092622 TI - Antigenic diversity of enteroviruses associated with nonpolio acute flaccid paralysis, India, 2007-2009. AB - Because of the broadened acute flacid paralysis (AFP) definition and enhanced surveillance, many nonpolio AFP (NP-AFP) cases have been reported in India since 2005. To determine the spectrum of nonpolio enterovirus (NPEV) serotypes associated with NP-AFP from polio-endemic and -free regions, we studied antigenic diversity of AFP-associated NPEVs. Of fecal specimens from 2,786 children with NP AFP in 1 polio-endemic and 2 polio-free states, 823 (29.5%) were positive for NPEVs in RD cells, of which 532 (64.6%) were positive by viral protein 1 reverse transcription PCR. We identified 66 serotypes among 581 isolates, with enterovirus 71 most frequently (8.43%) detected, followed by enterovirus 13 (7.1%) and coxsackievirus B5 (5.0%). Most strains within a serotype represented new genogropups or subgenogroups. Agents for ~35.0% and 70.0% of culture-positive and -negative cases, respectively, need to be identified. Association of human enterovirus with NP-AFP requires better assessment and understanding of health risks of NPEV infections after polio elimination. PMID- 23092626 TI - Bartonella spp. Bacteremia and rheumatic symptoms in patients from lyme disease endemic region. PMID- 23092633 TI - The development of eye shape and the origin of lower field myopia in the guinea pig eye. AB - In a variety of species, the refractive state of the eye differs in different parts of the visual field (VF) with greater myopia in the region that views the ground ("lower field myopia"). We studied the refraction and eye shape of the normal guinea pig eye to determine what feature(s) underlie this visual adaptation. Guinea pigs (n=67) were either newborn or raised under incandescent light until 14, 37 or 45 days of age (20, 44, 20 and 11 eyes respectively). Refractive error was measured on-axis and 30 degrees off-axis in the superior (SVF), inferior (IVF), temporal (TVF) and nasal (NVF) visual fields. Eye shape was analyzed from images of frozen hemisections in both the horizontal and vertical mid plane in 14 day animals, and in the vertical plane at 0, 14 and 45 days of age. Axial distances in vitro were correlated with in vivo high frequency ultrasound (r(2)=0.90). In the horizontal plane, asymmetry was caused by a +/- 6 degrees conical zone surrounding the optic nerve (12 degrees off-axis in NVF), suggesting significant myopia in this zone. At 30 degrees , there was no asymmetry in eye length, but the NVF was +1.7D more myopic due to asymmetry in corneal power. In the vertical plane at 30 degrees , the IVF was more myopic than the SVF by -3.8D at 0 days, -5.9D at 14 days and -6.0D at 37 days. It resulted from vertical asymmetry in the distance of the retina from the lens center, which was longest in the mid IVF. This non-linear ramp retina was present at birth. In older animals, the peak of the ramp shifted more centrally, and the eye developed longer lengths in the extreme upper periphery (SVF) which may have been caused by the low position of the room ceiling. The vertical asymmetry in eye shape was mirrored by changes in choroid thickness, suggesting a mechanism by which eye shape was refined by vision during development. In early life, ocular growth in the vertical plane was 1.7 times higher in the center relative to the periphery, a pattern that reversed in the following month. Since emmetropization was achieved over this period, local visual cues related to clear vision may provide a switch to change ocular growth from a central to a peripheral emphasis. PMID- 23092634 TI - Clinical evaluation of stereopsis. AB - Principles of the design and administration of clinical stereopsis tests are outlined. Once the presence of the distinct sense of the third dimension by binocular vision alone and without help from monocular cues has been established in a patient, the examination can proceed to the measurement of stereoscopic acuity. Best results are obtained with high-contrast, sharp, well-articulated and uncrowded elements from easily-recognized target sets, displayed with no time constraints. Polarization is the preferred method of right/left eye separation; time-sharing at a minimum of 60 Hz on computer displays with counterphase occluding goggles is a feasible procedure. Random-dot stereograms are problematic because not all observers can disentangle the coherent global disparity on a first view. PMID- 23092635 TI - Fatal respiratory infections associated with rhinovirus outbreak, Vietnam. AB - During an outbreak of severe acute respiratory infections in 2 orphanages, Vietnam, 7/12 hospitalized children died. All hospitalized children and 26/43 children from outbreak orphanages tested positive for rhinovirus versus 9/40 control children (p = 0.0005). Outbreak rhinoviruses formed a distinct genetic cluster. Human rhinovirus is an underappreciated cause of severe pneumonia in vulnerable groups. PMID- 23092636 TI - The cardiovascular risk of gonadotropin releasing hormone agonists in men with prostate cancer: an unresolved controversy. AB - Gonadotropin-releasing hormone agonists (GnRH) play an important role in the treatment of prostate cancer, improving significantly overall survival. GnRH agonists belong to androgen deprivation therapy (ADT) together with surgical castration and, recently, GnRH antagonists. ADT has several side effects, such as sexual dysfunction and osteoporosis. Recently, changes in body composition, obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension have emerged as complications of ADT, perhaps responsible for cardiovascular events, but discussion is still open. Since the majority of men with prostate cancer die of conditions other than their malignancy, recognition of these adverse effects is important. This review serves to focus attention on the pathogenetic mechanisms of ADT-related cardiovascular toxicity with also reference to the possible direct role of GnRH agonist on the cardiac receptors. Furthermore, this paper would generate recommendations for the management of patients treated with GnRH agonists balancing the potential benefits against the possible risks in prostate cancer men. PMID- 23092638 TI - The contribution of Primary Health Care Research, Evaluation and Development supported research to primary health care policy and practice. AB - The importance of primary health care (PHC) research is well understood yet conducting this research can be challenging. Barriers include a lack of funding, support and opportunity. In 2000 the Australian government introduced the Primary Health Care Research, Evaluation and Development (PHCRED) Strategy to address the gap in high-quality research. One component of the strategy, the Research Capacity Building Initiative, provided funding to university departments of general practice and rural health, allowing them to expand their pool of researchers and produce more research relevant to policy and practice. This study investigates the impact of phase two of the PHCRED Strategy by analysing peer reviewed publications from PHCRED-supported departments. Research output was recorded from 2006 to 2010 incorporating 661 publications in 212 journals. Rural departments often had fewer resources than urban departments yet demonstrated steady research contributions focusing on issues relevant to their community. Since its inception the PHCRED Strategy has enabled development of research capacity and contributed to the body of PHC knowledge. While PHC is a diverse field, reflected in the publications produced, the themes underlying much of this work were representative of current health reform and the priority areas and building blocks of the National PHC Strategy. PMID- 23092637 TI - Gene-nutrient interactions on the phosphoenolpyruvate carboxykinase influence insulin sensitivity in metabolic syndrome subjects. AB - BACKGROUND & AIMS: Genetic background may interact with habitual dietary fat composition, and affect development of the metabolic syndrome (MetS). The phosphoenolpyruvate carboxykinase gene (PCK1) plays a significant role regulating glucose metabolism, and fatty acids are key metabolic regulators, which interact with transcription factors and influence glucose metabolism. We explored genetic variability at the PCK1 gene locus in relation to degree of insulin resistance and plasma fatty acid levels in MetS subjects. Moreover, we analyzed the PCK1 gene expression in the adipose tissue of a subgroup of MetS subjects according to the PCK1 genetic variants. METHODS: Insulin sensitivity, insulin secretion, glucose effectiveness, plasma concentrations of C-peptide, fatty acid composition and three PCK1 tag-single nucleotide polymorphisms (SNPs) were determined in 443 MetS participants in the LIPGENE cohort. RESULTS: The rs2179706 SNP interacted with plasma concentration of n - 3 polyunsaturated fatty acids (n - 3 PUFA), which were significantly associated with plasma concentrations of fasting insulin, peptide C, and HOMA-IR. Among subjects with n - 3 PUFA levels above the population median, carriers of the C/C genotype exhibited lower plasma concentrations of fasting insulin (P = 0.036) and HOMA-IR (P = 0.019) as compared with C/C carriers with n - 3 PUFA below the median. Moreover, homozygous C/C subjects with n - 3 PUFA levels above the median showed lower plasma concentrations of peptide C as compared to individuals with the T-allele (P = 0.006). Subjects carrying the T-allele showed a lower gene PCK1 expression as compared with carriers of the C/C genotype (P = 0.015). CONCLUSIONS: The PCK1 rs2179706 polymorphism interacts with plasma concentration of n - 3 PUFA levels modulating insulin resistance in MetS subjects. PMID- 23092639 TI - Using DNA-barcoding for sorting out protist species complexes: a case study of the Nebela tincta-collaris-bohemica group (Amoebozoa; Arcellinida, Hyalospheniidae). AB - Species identification by means of morphology is often problematic in protists. Nebela tincta-collaris-bohemica (Arcellinida) is a species complex of small to medium-sized (ca.100 MUm) testate amoebae common in peat bogs and forest soils. The taxonomic validity of characters used to define species within this group is debated and causes confusion in studies of biogeography, and applications in palaeoecology. We examined the relationship between morphological and genetic diversity within this species complex by combined analyses of light microscopy imaging and Cytochrome Oxidase Subunit 1(COI) sequences obtained from the same individual amoeba cells. Our goals were (1) to clarify the taxonomy and the phylogenetic relationships within this group, and (2) to evaluate if individual genotypes corresponded to specific morphotypes and the extent of phenotypic plasticity. We show here that small variations in test morphology that have been often overlooked by traditional taxonomy correspond to distinct haplotypes. We therefore revise the taxonomy of the group. We redefine Nebela tincta (Leidy) Kosakyan et Lara and N. collaris (Ehrenberg 1848) Kosakyan et Gomaa, change N. tincta var. rotunda Penard to N. rotunda (Penard 1890), describe three new species: N. guttata n. sp. Kosakyan et Lara, N. pechorensis n. sp. Kosakyan et Mitchell, and N. aliciae n. sp. Mitchell et Lara. PMID- 23092640 TI - Transient paralysis from carbon dioxide angiography in a patient after four vessel endovascular thoracoabdominal aortic aneurysm repair. AB - Contrast angiography with carbon dioxide (CO2) is frequently used in patients with renal dysfunction or iodinated contrast allergies, as CO2 is nonallergenic, nontoxic, and rapidly absorbed in the blood. However, when delivered intra arterially, there is a possibility that CO2 may create a vapor lock with resultant transient ischemia. We describe a case of suspected CO2 embolus to the iliolumbar artery after iliac artery stenting resulting in immediate loss of bilateral lower extremity motor and sensory function. After placement of a spinal drain and elevation of mean arterial blood pressure, the patient had complete return of sensation with improvement in motor function. PMID- 23092641 TI - Alterations of baroreflex sensitivity after carotid endarterectomy according to the preoperative carotid plaque echogenicity. AB - OBJECTIVE: Baroreflex sensitivity is lower in patients with echogenic carotid plaques compared with patients with echolucent ones. The purpose of our study was to compare the baroreflex function after carotid endarterectomy (CEA) between patients with different plaque echogenicity. METHOD: Spontaneous baroreflex sensitivity (sBRS), heart rate, and systolic and diastolic arterial pressure were calculated in 51 patients with a severe carotid stenosis (70%-99%) 24 hours before CEA, as well as 24 and 48 hours after CEA. Carotid plaque echogenicity was graded from 1 to 4 according to Gray-Weale classification, after duplex examination, and the patients were divided into two groups: the echolucent (grade 1 or 2) and the echogenic (grade 3 or 4). RESULTS: The postoperative mean systolic arterial pressure values in all 51 patients at 24 and 48 hours (143.2 and 135.5 mm Hg, respectively) were found to be significantly increased compared with the preoperative value (132.5 mm Hg; x2=32, P<.001). Mean sBRS value, in all patients, was significantly reduced postoperatively to 2.1 ms mm Hg(-1), from the mean preoperative value, 3.7 ms mm Hg(-1), independently of plaque echogenicity. Twenty patients (39%) were included in the echolucent group and 31 (61%) in the echogenic. The two groups had significant differences in two parameters: the rate of diabetes mellitus and the rate of symptomatic plaques. After adjusting the two groups for these differences, we found that the preoperative difference in sBRS between the two groups (F[1,51]=11, P<.003) was eliminated 24 and 48 hours after CEA (F[1,51]=.007, P<.9 and F[1,51]=.4, P<.5 for 24 and 48 hours, respectively). CONCLUSIONS: Before the removal of carotid atheroma, baroreflex sensitivity, which is a well established cardiovascular risk factor, seems to be affected by carotid plaque echogenicity. However, CEA has as a result a similar baroreflex response in all patients, regardless of plaque echogenicity, implying no association of plaque morphology and postoperative baroreflex sensitivity. PMID- 23092642 TI - Reconstructive surgery for complex aortoiliac occlusive disease in young adults. AB - BACKGROUND: Although aortoiliofemoral bypass grafting is the optimal revascularization method for patients with severe aortoiliac occlusive disease (AIOD), previous studies have documented poor patency rates in young adults. This study investigated whether young patients with AIOD have worse outcomes in patency, limb salvage, and long-term survival rates after reconstructive surgery than their older counterparts. METHODS: Patients aged<=50 years undergoing reconstructive surgery at our institution for AIOD between 1995 and 2010 were compared with a cohort of randomly selected patients aged>=60 years (two for each of the young patients, matched for year of operation), analyzing demographics, risk factors, indications for surgery, operative details, and outcomes. RESULTS: Among 927 consecutive patients undergoing primary surgery for AIOD, 78 (8.4%) aged<=50 years (mean age, 48.4 years) and 156 older control patients (mean age, 71.2 years) were identified. The younger patients were mainly men (81%) and 59% had surgery for limb salvage and 41% for disabling claudication (P=.02). Compared with older patients, they were significantly more likely to be smokers (90% vs 72%; P=.002) and had previously needed significantly more inflow procedures (28% vs 16%; P=.03). Only one death occurred perioperatively (30-day) among the control patients, and no major amputations or graft infections occurred in either group. The need for subsequent infrainguinal reconstructions was greater in the younger patients (18% vs 7%; P=.01). The primary patency rates were inferior in the younger patients at 5 years (82% and 75%) and 10 years (95% and 90%; P=.01), whereas assisted secondary patency (89% and 82% vs 96% and 91%; P=.08), secondary patency (93% and 86% vs 98% and 92%; P=.19), limb salvage (88% and 83% vs 95% and 91%; P=.13), and survival rates (87% and 76% vs 91% and 84%; P=.32) were comparable in the two groups. CONCLUSIONS: This study shows that despite a higher primary graft failure rate than that in older patients, aortoiliofemoral revascularization for complex AIOD is a safe procedure for younger patients with disabling claudication or limb-threatening ischemia, providing they are willing to follow a regular protocol to complete their postoperative surveillance and to undergo graft revision as necessary. PMID- 23092643 TI - Stent graft composition plays a material role in the postimplantation syndrome. AB - OBJECTIVE: In patients undergoing endovascular aneurysm repair (EVAR), the postimplantation syndrome (PIS), comprising fever and inflammation, occurs frequently. The cause of PIS is unclear, but graft composition and acute thrombus formation may play a role. The objective of this study was to evaluate these possible causes of the inflammatory response after EVAR. METHODS: One hundred forty-nine patients undergoing elective EVAR were included. Implanted stent grafts differed mainly in the type of fabric used: either woven polyester (n=82) or expanded polytetrafluorethylene (ePTFE; n=67). Tympanic temperature and C reactive protein (CRP) were assessed daily during hospitalization. PIS was defined as the composite of a body temperature of >=38 degrees C coinciding with CRP>10 mg/L. Besides graft composition, the size of the grafts and the volume of new-onset thrombus were calculated using dedicated software, and results were correlated to PIS. RESULTS: Implantation of grafts made of polyester was associated with higher postoperative temperature (P<.001), CRP levels (P<.001), and incidence of PIS (56.1% vs 17.9%; P<.001) compared to ePFTE. After multivariate analysis, woven polyester stent grafts were independently associated with an increased risk of PIS (hazard ratio, 5.6; 95% confidence interval, 1.6 19.4; P=.007). Demographics, amount of graft material implanted, or new-onset thrombus had no association with PIS. CONCLUSIONS: The composition of stent grafts may play a material role in the incidence of postimplantation syndrome in patients undergoing EVAR. Implantation of stent grafts based on woven polyester was independently associated with a stronger inflammatory response. PMID- 23092644 TI - Effects of diabetes on small aortic aneurysms under surveillance according to a subgroup analysis from a randomized trial. AB - BACKGROUND: This study aims to investigate the impact of diabetes in the management of patients with small abdominal aortic aneurysms (AAA). METHODS: Three-hundred sixty patients with small AAA (4.1-5.4 cm), enrolled in a randomized trial comparing early endovascular repair versus surveillance and delayed repair (after achievement of >5.5 cm or growth>1 cm/yr), were analyzed with standard survival methods to assess the relation between diabetes and risk of all-cause mortality, complications, and aneurysm growth (on computed tomography as per trial protocol) at 36 months. Baseline covariates were selected with partial likelihood stepwise method to investigate factors (demographic, morphologic, medications) associated with risk of aneurysm growth during surveillance. RESULTS: Prevalence of diabetes was 13.6%. The hazard ratio (HR) for all-cause mortality at 36 months was higher in diabetic compared with nondiabetic patients: (HR, 7.39; 95% confidence interval [CI], 1.55-35.13; P=.012). Baseline aneurysm diameter was comparable between diabetic and nondiabetic patients enrolled in the surveillance arm and was related to subsequent aneurysm growth in covariance analyses adjusted for diabetes (49.3 mm for nondiabetic; 50.2 mm for diabetic). Cox analyses found diabetes as the strongest independent negative predictor of 63% lower probability of aneurysm growth>5 mm during surveillance (HR, 0.37; 95% CI, 0.15-0.92; P=.003). Kaplan Meier cumulative probability of aneurysm growth>5 mm at 36 months was 40.8% in diabetics versus 85.1% in nondiabetics (HR, 0.32; 95% CI, 0.17-0.61). CONCLUSIONS: Progression of small AAA seems to be more than 60% lower in patients with diabetes. This may help to identify high-risk subgroups at higher likelihood of AAA enlargement, such as nondiabetics, for surveillance protocols in patients with small AAA. PMID- 23092645 TI - Coccidioidomycosis-associated Deaths, United States, 1990-2008. AB - Coccidioidomycosis is endemic to the Americas; however, data on deaths caused by this disease are limited. To determine the rate of coccidioidomycosis-associated deaths in the United States, we examined multiple cause-coded death records for 1990-2008 for demographics, secular trends, and geographic distribution. Deaths were identified by International Classification of Diseases, 9th and 10th Revision, codes, and mortality rates were calculated. Associations of deaths among persons with selected concurrent conditions were examined and compared with deaths among a control group who did not have coccidioidomycosis. During the 18 year period, 3,089 coccidioidomycosis-associated deaths occurred among US residents. The overall age-adjusted mortality rate was 0.59 per 1 million person years; 55,264 potential life-years were lost. Those at highest risk for death were men, persons >65 years, Hispanics, Native Americans, and residents of California or Arizona. Common concurrent conditions were HIV and other immunosuppressive conditions. The number of deaths from coccidioidomycosis might be greater than currently appreciated. PMID- 23092646 TI - Livestock density as risk factor for livestock-associated methicillin-resistant Staphylococcus aureus, the Netherlands. AB - To determine whether persons living in areas of high animal density are at increased risk for carrying livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA), we used an existing dataset of persons in the Netherlands with LA-MRSA carriage and controls who carried other types of MRSA. Results of running univariate and multivariate logistic regression models indicated that living in livestock-dense areas increases the odds of nasal carriage of LA-MRSA. We found that doubling pig, cattle, and veal calf densities per municipality increased the odds of LA-MRSA carriage over carriage of other types of MRSA by 24.7% (95% CI 0.9%-54.2%), 76.9% (95% CI 11.3%-81.3%), and 24.1% (95% CI 5.5%-45.9%), respectively, after adjusting for direct animal contact, living in a rural area, and the probable source of MRSA carriage. Controlling the spread of LA-MRSA thus requires giving attention to community members in animal dense regions who are unaffiliated with livestock farming. PMID- 23092647 TI - Laparoscopic-assisted versus conventional ileocolectomy for primary Crohn's disease: results of a comparative study. AB - INTRODUCTION: The laparoscopic approach is becoming the gold standard in the surgical treatment of primary Crohn's disease. The aim of this study was to compare laparoscopic-assisted and open ileocolic resection for primary Crohn's disease. METHODS: We conducted a non-randomized, comparative, retrospective analysis of a prospective database from 1998 to 2010. The remaining 129 patients were divided into two groups: laparoscopic-assisted group (Group L; n=64) and conventional group (Group C; n=65). There were no differences between the two groups as regards preoperative patient characteristics. Complications were graded according to the Clavien-Dindo classification. RESULTS: One hundred and seventeen (90.7%) patients had no complications. Out of 12 patients (9.3%) with complications, four (3.1%) had Grade I, six (4.7%) had Grade II and two (1.6%) had Grade III. There were no postoperative deaths (Grade V). Operating time was longer in Group L compared with Group C (P<0.001). Bowel function returned more quickly in the laparoscopic group in terms of return of bowel movements (P=0.018) and resumption of a regular diet (P=0.06). The mean length of stay was significantly shorter in the laparoscopic group (P=0.001). The mean follow-up was 26 months in Group L versus 34 months in Group C (P=0.06). During follow-up, six patients presented with small bowel obstruction in Group C, which was not statistically different from Group L (3 patients) (P=0.25). During the follow-up period, there have been no recurrences of Crohn's disease in the laparoscopic group while 11 patients (16.9%) have developed a recurrence in the conventional group (P=0.001). CONCLUSION: Laparoscopic-assisted ileocolectomy for primary Crohn's disease of the terminal ileum and/or cecum is safe and successful in most cases. Laparoscopic surgery for Crohn's disease should be considered as the preferred operative approach for primary resections. PMID- 23092648 TI - Anastomotic leakage after colorectal surgery: can it be detected earlier and more easily? PMID- 23092649 TI - The genetics of endurance: frequency of the ACTN3 R577X variant in Ironman World Championship athletes. AB - OBJECTIVES: To investigate the frequency of the ACTN3 R577X polymorphism in elite endurance triathletes, and whether ACTN3 R577X is significantly associated with performance time. DESIGN: Cross-sectional study. METHODS: Saliva samples, questionnaires, and performance times were collected for 196 elite endurance athletes who participated in the 2008 Kona Ironman championship triathlon. Athletes were of predominantly North American, European, and Australian origin. A one-way analysis of variance was conducted to compare performance times between genotype groups. Multiple linear regression analysis was performed to model the effect of questionnaire variables and genotype on performance time. Genotype and allele frequencies were compared to results from different populations using the chi-square test. RESULTS: Performance time did not significantly differ between genotype groups, and age, sex, and continent of origin were significant predictors of finishing time (age and sex: p<5*10(-6); continent: p=0.003) though genotype was not. Genotype and allele frequencies obtained (RR 26.5%, RX 50.0%, XX 23.5%, R 51.5%, X 48.5%) were found to be not significantly different from Australian, Spanish, and Italian endurance athletes (p>0.05), but were significantly different from Kenyan, Ethiopian, and Finnish endurance athletes (p<0.01). CONCLUSIONS: Genotype and allele frequencies agreed with those reported for endurance athletes of similar ethnic origin, supporting previous findings for an association between 577X allele and endurance. However, analysis of performance time suggests that ACTN3 does not alone influence endurance performance, or may have a complex effect on endurance performance due to a speed/endurance trade-off. PMID- 23092650 TI - The relationship between pre-season fitness testing and injury in elite junior Australian football players. AB - OBJECTIVES: Australian Football (AF) is a collision sport containing high injury rates in junior competition. Successful performance at the elite junior level not only requires superior specific football knowledge and skills, but also well developed fitness qualities. However, no studies have examined the link between physical fitness qualities and injury in AF. DESIGN: Prospective cohort. METHODS: Injury data were collected through the use of a Player Movement Record (PMR) and a standardized Injury Report Form (IRF). Fitness test data was collected during the pre-season of the 2010 and 2011 seasons. RESULTS: 382 players consented to participate in the study. The cohort experienced an injury incidence rate of 24.29/standardized club (40 players/club). A faster 5-m sprint was associated with 'injury status' (p=0.016) and a 'knee' region (p<=0.001) injury. A faster planned agility score was associated with an increased risk of a 'hip/groin/thigh' region (p=0.010) injury, and specifically a 'quadriceps strain' (p=0.005). A lower 20-m shuttle run was associated with an increased risk of a 'shin/ankle/foot' (p=0.045) injury. Increased injury severity was associated with a higher left foot running vertical jump (VJ) (p=0.040), and faster 5-m sprint (p=0.043). CONCLUSIONS: Lower aerobic endurance, faster 5-m acceleration and greater planned agility were associated with an increased risk of various injury types in elite junior AF players. Furthermore, a higher left foot running VJ and faster 5-m acceleration were associated with injury severity. These results may largely relate to a greater work capacity placing a higher load upon the musculoskeletal system in contact and non-contact situations. PMID- 23092651 TI - Balance and cognitive performance during a dual-task: preliminary implications for use in concussion assessment. AB - OBJECTIVES: To determine the reliability and effects of a dual-task paradigm on balance and cognitive function compared to a single-task paradigm. DESIGN: Repeated measures. METHODS: Healthy participants (n=23) completed a variation of the Sensory Organization Test and the incongruent Stroop test individually (single-task) and concurrently (dual-task) during two testing sessions. RESULTS: The Sensory Organization Test and incongruent Stroop test had moderate to high reliability (1.00>ICC2,k>0.60) under the dual-task conditions. Reaction time was significantly longer (t21=-2.54, p=0.019) under the dual-task conditions, while balance scores under one of the four conditions of the Sensory Organization Test (sway floor/fixed wall) were statistically better (t22=-3.03, p=0.006) under the dual-task conditions. However, this difference in balance scores may not be clinically meaningful. CONCLUSIONS: These findings illustrate that the Sensory Organization Test and incongruent Stroop task can be reliably incorporated into a dual-task assessment paradigm. The slowed reaction time under the dual-task paradigm indicates that the dual-task provided an additional cost to cognitive function. Dual-task concussion assessment paradigms involving these two tasks are psychometrically appropriate as well as more representative of actual sporting situations. However, more research should be conducted in a concussed population to further validate this claim. PMID- 23092652 TI - Introduction to the special issue autobiographical memory and psychopathology. PMID- 23092653 TI - Science avant-garde. PMID- 23092654 TI - Environmental factors in Tourette syndrome. AB - Environmental exposures during the prenatal period, perinatal stages, and postnatal life may contribute to onset and course of Tourette syndrome (TS). Pregnancy-related noxious exposures may be more frequent in pregnancies of children who will develop TS, particularly maternal smoking and prenatal life stressors. Lower birth weight and use of forceps at delivery may be associated with tic severity in the offspring; moreover, low birth weight and maternal smoking during pregnancy may affect the risk of co-morbid attention deficit/hyperactivity and obsessive-compulsive disorders. Group A streptococcal infections as risk-modifier for TS has not been convincingly demonstrated to date, although an interaction with stressors was suggested. The PANDAS hypothesis is currently undergoing a nosological revision. Only limited anecdotal evidence supports a link of TS to other pathogens. Nevertheless, the relationship between infections and TS may be complex. Recent data point to intrinsically altered immune regulation in TS, which might predispose to both infections and autoimmune mechanisms; however, evidence of cell-mediated and antibody-mediated autoimmunity in TS is still insufficient. Psychosocial stress remains the most important contextual factor influencing tic severity, as confirmed by prospective studies. This might in part be related to enhanced reactivity of the stress response in TS patients, the mechanisms of which need to be explored further. New studies on large prospective cohorts of patients of different age and the identification of reliable biomarkers or endophenotypes indicating early, prenatal exposure to environmental insults are needed. PMID- 23092655 TI - The vigilance regulation model of affective disorders and ADHD. AB - According to the recently proposed vigilance model of affective disorders (vigilance in the sense of "brain arousal"), manic behaviour is partly interpreted as an autoregulatory attempt to stabilise vigilance by creating a stimulating environment, and the sensation avoidance and withdrawal in Major Depressive Disorder (MDD) is seen as an autoregulatory reaction to tonically increased vigilance. Indeed, using a newly developed EEG-based algorithm, hyperstable vigilance was found in MDD, and the contrary, with rapid drops to sleep stages, in mania. Furthermore, destabilising vigilance (e.g. by sleep deprivation) triggers (hypo)mania and improves depression, whereas stabilising vigilance, e.g. by prolonged sleep, improves mania. ADHD and mania have common symptoms, and the unstable vigilance might be a common pathophysiology. There is even evidence that psychostimulants might ameliorate both ADHD and mania. Hyperactivity of the noradrenergic system could explain both the high vigilance level in MDD and, as recently argued, anhedonia and behavioural inhibition. Interestingly, antidepressants and electroconvulsions decrease the firing rate of neurons in the noradrenergic locus coeruleus, whereas many antimanic drugs have opposite effects. PMID- 23092656 TI - Involvement of the primate specific gene G72 in schizophrenia: From genetic studies to pathomechanisms. AB - Schizophrenia is a human mental disorder that affects an individual's thoughts, perception, affect and behavior, which is caused by a complex interaction of genetic and environmental factors. Genetic studies have implicated the evolutionary novel, anthropoid primate-specific gene locus G72/G30 in the etiology of schizophrenia and other psychiatric disorders. This gene encodes the protein LG72, which has been discussed as a modulator of the peroxisomal enzyme d amino-acid-oxidase (DAO), or, alternatively as a mitochondrial protein. Recently, G72 transgenic (G72Tg) mice were generated that express the protein throughout the brain. These mice show several behavioral deficits that are related to schizophrenia. Further, G72Tg mice have a reduced activity of mitochondrial complex I, with a concomitantly increased production of reactive oxygen species, as well as deficits in short-term plasticity. Results from these studies demonstrate that expression of the human G72/G30 gene locus in mice produces behavioral phenotypes that are relevant to schizophrenia. They implicate LG72 induced mitochondrial and synaptic defects as a possible pathomechanism of this disease. PMID- 23092657 TI - Prooxidative toxicity and selenoprotein suppression by cerivastatin in muscle cells. AB - Statins are the most widely used drugs for the treatment of hypercholesterolemia. In spite of their overall favorable safety profile, they do possess serious myotoxic potential, whose molecular origin has remained equivocal. Here, we demonstrate in cultivated myoblasts and skeletal muscle cells that cerivastatin at nanomolar concentrations interferes with selenoprotein synthesis and evokes a heightened vulnerability of the cells toward oxidative stressors. A correspondingly increased vulnerability was found with atorvastatin, albeit at higher concentrations than with cerivastatin. In selenium-saturated cells, cerivastatin caused a largely indiscriminate suppression of selenoprotein biosynthesis and reduced the steady state-levels of glutathione peroxidase 1 (GPx1) and selenoprotein N (SelN). Selenite, ebselen, and ubiquinone were unable to prevent the devitalizing effect of statin treatment, despite the fact that the cellular baseline resistance against tert-butyl hydroperoxide was significantly increased by picomolar sodium selenite. Mevalonic acid, in contrast, entirely prevented the statin-induced decrease in peroxide resistance. These results indicate that muscle cells may be particularly susceptible to a statin-induced suppression of essential antioxidant selenoproteins, which provides an explanation for the disposition of these drugs to evoke adverse muscular side effects. PMID- 23092658 TI - Streptococcus pneumoniae serotype 15A in psychiatric unit, Rhode Island, USA, 2010-2011. AB - During a pneumococcal disease outbreak in a pediatric psychiatric unit in a hospital in Rhode Island, USA, 6 (30%) of 20 patients and staff were colonized with Streptococcus pneumoniae serotype 15A, which is not included in pneumococcal vaccines. The outbreak subsided after implementation of antimicrobial drug prophylaxis and enhanced infection control measures. PMID- 23092659 TI - Microsizing using inside suture placement. A simple and versatile technique for precision adjustment of ring annuloplasties. AB - INTRODUCTION: A new and simple technique for eliminating residual leaks during mitral annuloplasty, called microsizing, is described. METHODS: Microsizing is performed by moving one or more annuloplasty sutures from the outside to the inside of the prosthetic ring. This maneuver advances discrete segments of the annulus toward the opposing leaflet by a distance equal to the thickness of the ring (approximately 3 mm). Microsizing is a simple method for precision adjustment of annular shape and size to eliminate focal gaps, regardless of the cause. RESULTS: A series of 63 consecutive patients with moderate to severe mitral regurgitation (MR) were repaired over a 10 year period, all with intraoperative transesophageal echocardiography guidance. No patient required valve replacement (repair success rate 100%). Concomitant (non-mitral valve) procedures were performed in 53 patients (84.1%). Fifty patients (79.3%, Group 1) underwent successful repair using traditional suture placement in the prosthetic ring. Thirteen patients (20.6%, Group 2) had one or more sutures repositioned to the inside of the ring ("micro-sized") as a new strategy to eliminate residual leaks. Mean post repair MR grade was lower when microsizing was used (0.15 for Group 2 versus 0.30 for Group 1). No micro-sized patient experienced systolic anterior motion (SAM) or mitral stenosis. There were no repairs with greater than trace MR, late ring dehiscences, recurrent regurgitation, or reoperation in the entire series. There was one death (1.6%) in a non-micro-sized patient from intra operative abdominal hemorrhage secondary to an IABP complication. CONCLUSION: Microsizing is a simple variation of suture placement that allows custom shaping of the mitral annulus by advancing selected portions toward the opposing leaflet, eliminating gaps, and improving coaptation. This technique is safe, simple, and reproducible without causing stenosis, SAM, or late failure. PMID- 23092660 TI - Extended myectomy for hypertrophic obstructive cardiomyopathy. AB - BACKGROUND: The purpose of this study was to summarize our experience of extended ventricular septal myectomy in patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS: Thirty-eight patients (26 men, 12 women) with HOCM underwent extended ventricular septal myectomy. The mean age was 36.3 years (range, 18-64 years). Diagnosis was made by echocardiography. The mean (mean +/- SE) systolic gradient between the left ventricle (LV) and the aorta was 89.3 +/- 31.1 mm Hg (range, 50-184 mm Hg) according to echocardiographic assessments before the operations. Moderate or severe systolic anterior motion (SAM) of the anterior leaflet of the mitral valve was found in 38 cases, and mitral regurgitation was present in 29 cases. Extended ventricular septal myectomy was performed in all 38 cases. The results of the surgical procedures were evaluated intraoperatively with transesophageal echocardiography (TEE) and with transthoracic echocardiography (TTE) at 1 to 2 weeks after the operation. All patients were followed up with TTE after their operation. RESULTS: All patients were discharged without complications. The TEE evaluations showed that the mean systolic gradient between the LV and the aorta decreased from 94.8 +/- 35.6 mm Hg preoperatively to 13.6 +/- 10.8 mm Hg postoperatively (P = .0000) and that the mean thickness of the ventricular septum decreased from 28.3 +/- 7.9 mm to 11.8 +/- 3.2 mm (P = .0000). Mitral regurgitation and SAM were significantly reduced or eliminated. During the follow-up, all patients promptly became completely asymptomatic or complained of mild effort dyspnea only, and syncope was abolished. TTE examinations showed that the postoperative pressure gradient either remained the same or diminished. CONCLUSIONS: Extended ventricular septal myectomy is mostly an effective method for patients with HOCM, and good surgical exposure and thorough excision of the hypertrophic septum are of paramount importance for a successful surgery. PMID- 23092661 TI - Impact of gentamicin-collagen sponge (Collatamp) on the incidence of sternal wound infection in high-risk cardiac surgery patients: a propensity score analysis. AB - OBJECTIVE: Local delivery of prophylactic antibiotic to the wound site with an implanted, reabsorbable, gentamicin-containing collagen sponge (Collatamp) is a strategy that has been claimed to prevent sternal wound infection after cardiac surgery. The purpose of this study was to review our experience with Collatamp in cardiac surgery patients deemed at high risk for sternal wound infection. METHODS: From January 2007 to December 2010, Collatamp was used in 107 patients deemed at high risk for sternal wound infection. Applying the propensity score, we matched 97 patients with Collatamp (group I) with 97 patients who did not receive Collatamp (group II). All individuals received routine intravenous antimicrobial prophylaxis. Postoperative wound-infection rates as well as routine outcomes were compared. Information for the study was obtained from the cardiac surgical Patients Analysis and Tracking System (PATS) database and from hospital records. RESULTS: The superficial sternal wound infection rate was 2.1% (2/97) in group I and 6.2% (6/97) in group II (P = .01). The rates of deep sternal wound infection rate were similar (2.1% versus 3.1%, P = .87). There was no mediastinitis in the study population. In addition, more patients in group II received an intra-aortic balloon pump (5.2% versus 2.1%, P = .04) and underwent hemofiltration (7.2% versus 3.1%, P = .02). No side effects were noted. CONCLUSION: Gentamicin-containing collagen sponge (Collatamp) is a useful adjunct to meticulous surgical technique and postoperative wound care in reducing the incidence of sternal wound infection in high-risk cardiac surgery patients. An adequately powered study is needed, however, to validate the safety and efficacy of this strategy. PMID- 23092662 TI - Does payer status impact clinical outcomes after cardiac surgery? A propensity analysis. AB - BACKGROUND: Medicaid patients bear proportionately greater financial responsibility for the cost of outpatient care and medication than non-Medicaid patients. We hypothesized that this difference in provision of continuing care would be associated with adverse clinical outcomes after cardiac surgery. MATERIALS AND METHODS: In a retrospective cohort analysis, 5056 consecutive adult patients undergoing cardiac surgery at a single institution between 2005 and 2010 were divided according to payer status. Propensity scores were calculated using 16 preoperative and demographic variables for each patient, and 461 1:1 propensity score-matched pairs were analyzed. Patient socioeconomic position was determined using aggregate data derived from zip codes. The main outcome measures were early mortality, postoperative complications, and patient survival. RESULTS: In multivariate analysis, Medicaid was found to be an independent predictor of worse survival after cardiac surgery (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2-3.7; P = .01). No significant difference was observed in operative mortality in the 2 groups. After propensity score matching and controlling for socioeconomic position, the only independent predictors of worse midterm survival were an ejection fraction = 30% (HR, 1.7; 95% CI, 1.1-2.7; P = .02) and a higher logistic EuroSCORE (HR, 1.03; 95% CI, 1.0-1.1; P = .02). CONCLUSIONS: Comorbidity and lower socioeconomic status appear to be more important predictors of late mortality after cardiac surgery than payer status, which does not have a significant impact on survival. PMID- 23092663 TI - Transcatheter aortic valve implantation into a stentless prosthetic valve with a low position of the left main coronary artery. AB - Recently during a transcatheter aortic valve implantation (TAVI), we were faced with a problem that seemed to be untreatable by TAVI. It was difficult to decide whether to perform atypical TAVI or to convert to conventional redo aortic valve surgery in an extremely high-risk patient with a degenerated stentless aortic bioprosthesis. PMID- 23092664 TI - Managing port-site bleeding during less invasive coronary artery bypass grafting. AB - INTRODUCTION: Robotic-assisted coronary artery bypass grafting (r-CABG) requires the placement of ports bluntly through the chest wall. When removed, these ports create bleeding sites that can be difficult to detect and treat. This study evaluated whether a topical hemostatic agent placed locally within these sites helps to reduce bleeding and blood product requirements. METHODS: We retrospectively analyzed outcomes for r-CABG cases where 5 mL of a flowable hemostatic agent was injected locally within all port sites (hemostat group, n = 62) compared with patients whose port sites were untreated (controls, n = 131). Outcomes included chest tube output, red blood cell (RBC) transfusions, length of hospital stay, and the risk of reoperation for bleeding. Analyses were adjusted for risk factors known to influence bleeding and Society of Thoracic Surgeons (STS) risk score as a weighted composite of variables, which controls for patient and clinical variables. RESULTS: The 2 study groups had similar baseline characteristics and underwent the same r-CABG procedure. The hemostat group had significant reductions in RBC transfusion (24.2% versus 40.8% receiving blood; P = .026; 0.44 versus 1.39 U transfused postoperatively, P = .024). After adjustment for bleeding risks (using STS risk score), differences in transfusions remained significant. Reoperation rates for bleeding, length of stay, chest tube drainage, and intraoperative transfusions were not significantly different in the 2 groups. CONCLUSIONS: There was significantly reduced postoperative bleeding and less exposure to blood products in the hemostat group. These findings suggest that undetected bleeding from sites used for port access serves as an underappreciated source of morbidity after r-CABG. PMID- 23092665 TI - Is prophylactic intravenous administration of a proton pump inhibitor necessary for perioperative management of cardiac surgery? AB - BACKGROUND: Mortality from gastrointestinal (GI) hemorrhage caused by antiplatelet or anticoagulant therapy (or both) is quite high after cardiac surgery. We previously reported that proton pump inhibitor (PPI) therapy is indispensable in preventing postoperative GI complications. PPIs are usually administered intravenously immediately after surgery and subsequently by oral formulations. We conducted a prospective study to evaluate whether intravenous PPI followed by oral administration is more efficient as prophylaxis than oral only administration. METHODS AND RESULTS: We enrolled 40 patients scheduled to undergo coronary artery bypass grafting with cardiopulmonary bypass and randomly assigned them to receive oral PPIs alone (group 1) or intravenous PPI followed by oral administration (group 2). Postoperative upper GI endoscopy evaluations showed no evidence of GI bleeding. Only gastritis, esophagitis, and hiatal hernia were observed at similar incidences in the groups. Mean hospital stays were also similar, but the cost of PPI treatment was significantly lower in group 1. CONCLUSION: No additional benefits of intravenous PPIs over oral formulations were demonstrated. Oral PPIs alone were effective and economical as prophylaxis against GI complications. Intravenous PPIs might be unnecessary in selected patients after cardiac surgery. PMID- 23092666 TI - Efficacy of thermoreactive nitinol clip implantation in reconstruction of sternal dehiscence. AB - BACKGROUND: Sternal dehiscence is a severe complication of open heart surgery. Reinforced wiring, a system of reinforced sternal closure, fixation of a rigid plate, and implantation of thermoreactive nitinol clips (TRC) are some surgical procedures used. The aim of this study was to evaluate the role of TRC for secondary sternal reconstruction. METHODS: Of 1198 patients who underwent their operations via median sternotomy in 2 separate medical centers, sternal dehiscence was observed in 16 patients overall (1.33%). The mean (SD) age of the patients was 64.06 +/- 9.18 years (range, 40-77 years). Sternal dehiscence was diagnosed in all patients between the fifth and 30th postoperative days. RESULTS: TRC were implanted in all of the patients who developed sternal dehiscence (16 patients). One patient developed severe respiratory failure, became ventilator dependent, and died from pneumonia on postoperative day 24. The other 15 patients were discharged without complications. Postoperative follow-up of the surviving patients revealed adequate and satisfactory sternal stability. CONCLUSION: Implantation of TRC is an effective and easy method for fixing the sternum and can be performed rapidly and securely. PMID- 23092667 TI - Anomalous left coronary artery from the pulmonary arteryin an adult. AB - Anomalous left coronary artery from the pulmonary artery (ALCAPA) is a rare congenital heart defect that usually presents before the age of 1 year. Several surgical options exist for the correction of ALCAPA; however, debate continues regarding the optimal repair technique in adult populations. We report the case of successful surgical repair of ALCAPA with a direct aortic implantation technique in a 44-year-old mother of 4 children. PMID- 23092668 TI - Acute aortic intramural hematoma presenting with painless recurrent syncope. AB - A patient presented with recurrent syncope due to transient severe hypotension. The patient's history, physical examination, and initial baseline investigation did not suggest a cardiovascular cause. After fluid resuscitation, a raised jugular venous pulse was noted. Bedside transthoracic echocardiogram showed a pericardial effusion and a proximally dilated aorta. Computed tomography of the thorax confirmed these findings and also demonstrated an intramural hematoma of the proximal aortic wall.The patient was transferred to a cardiothoracic center, where he was at first treated medically. He then developed sudden cardiogenic shock due to pericardial tamponade and was successfully operated on.It is important to recognize an acute intramural hematoma of the proximal aortic wall as a cardiothoracic emergency. This condition can present atypically, but nevertheless warrants urgent surgical intervention, equal to type A aortic dissection. Echocardiography can help in making the diagnosis. PMID- 23092669 TI - Surgical repair for isolated aortic interruption in a young adult. AB - Interrupted aortic arch (IAA), a rare congenital malformation of the aortic arch, is defined as a loss of luminal continuity between the ascending and descending portions of the aorta. It is rarely diagnosed as an isolated anomaly in adulthood. Surgical repair is feasible through a sternotomy or thoracotomy incision. In this report, we describe the surgical repair of an isolated IAA in a 29-year-old patient by performing an ascending-to-descending aortic bypass via a sternotomy with cardiopulmonary bypass. PMID- 23092670 TI - Giant aneurysmal fistula of the left main coronary artery to the right atrium. AB - A 42-year-old woman presented to our outpatient department with complaints of atypical chest pain and palpitation. On physical examination, the patient's blood pressure was 140/95 mm Hg, and there was a systolic cardiac murmur on the left sternal border. A transthoracic echocardiography examination was performed, and a left-to-right shunt ratio (Qp/Qs) of approximately 1.5 was detected. Computed tomography angiography and coronary angiography examinations confirmed the presence of a large fistula between the left main coronary artery and the right atrium, with giant aneurysm formation and an intact right coronary artery. Surgical closure of the shunt was performed with a good final result. PMID- 23092671 TI - A surgical strategy for cor triatriatum atrial septal defect--A1 lam subclass. AB - Atrial fibrillation and a heart murmur were diagnosed in a 68-year-old woman during a routine medical examination. She presented 2 years later with pulmonary edema. A transthoracic echocardiography examination revealed a tunneled atrial septal defect (ASD) and severe tricuspid regurgitation. Transesophageal echocardiography and 3-dimensional computed tomography evaluations revealed multiple intracardiac defects, including abnormal atrial septation suggestive of a typical cor triatriatum sinistrum (A1 Lam subclass), a rare congenital defect in adults. The patient underwent tricuspid valve repair with concomitant closure of the ASD by using the cor triatriatum curtain to form an autologous transposition flap. The intraoperative transesophageal and predischarge imaging evaluations confirmed an excellent repair. The patient made a swift recovery and demonstrated improvement in her symptoms at follow-up. This previously undescribed technique eliminates the need for a prosthetic implant and is applicable in >80% of cor triatriatum cases in which an ASD exists. PMID- 23092672 TI - Primary intravascular synovial sarcoma: case report. AB - Synovial sarcoma (SS), a mesenchymal spindle cell tumor, displays variable epithelial differentiation, including glandular formation, and features a specific chromosomal translocation, t(X;18)(p11;q11). SS accounts for 5% to 10% of soft-tissue sarcomas. These tumors occur mostly in the joints, especially near the knee, but they also occur in other locations. Primary intravascular SS (IVSS) are extremely rare; only 6 well-documented cases have been reported in the English literature. We describe a new case of primary IVSS of the superior vena cava (SVC) in a 16-year-old boy. A transthoracic echocardiogram confirmed a large (4.8 * 4.6 cm) circumscribed mass filling the right atrium, as well as a moderate pericardial effusion. The mass extended from the SVC to the tricuspid valve but did not prevent valve coaptation. Surgery via a transatrial approach revealed a huge mass (8 to 12 cm) attached to the SVC via a 5-mm pedicle. The tumor was excised, and the patient experienced an uneventful postoperative course. Fluorescence in situ hybridization analysis revealed the presence of the SS specific translocation. PMID- 23092673 TI - Molecular cloning and catalytic activity of a membrane-bound prenyl diphosphate phosphatase from Croton stellatopilosus Ohba. AB - Geranylgeraniol (GGOH), a bioactive acyclic diterpene with apoptotic induction activity, is the immediate precursor of the commercial anti-peptic, plaunotol (18 hydroxy geranylgeraniol), which is found in Croton stellatopilosus (Ohba). From this plant, a cDNA encoding a prenyl diphosphate phosphatase (CsPDP), which catalyses the dephosphorylation of geranylgeranyl diphosphate (GGPP) to GGOH, was isolated using a PCR approach. The full-length cDNA contained 888bp and encoded a 33.6 kDa protein (295 amino acids) that was phylogenetically grouped into the phosphatidic acid phosphatase (PAP) enzyme family. The deduced amino acid sequence showed 6 hydrophobic transmembrane regions with 57-85% homology to the sequences of other plant PAPs. The recombinant CsPDP and its 4 truncated constructs exhibited decreasing dephosphorylation activities relative to the lengths of the N-terminal deletions. While the full-length CsPDP successfully performed the two sequential monodephosphorylation steps on GGPP to form GGOH, the larger N-terminal deletion in the truncated enzymes appeared to specifically decrease the catalytic efficiency of the second monodephosphorylation step. The information presented here on the CsPDP cDNA and factors affecting the dephosphorylation activity of its recombinant protein may eventually lead to the discovery of the specific GGPP phosphatase gene and enzyme that are involved in the formation of GGOH in the biosynthetic pathway of plaunotol in C. stellatopilosus. PMID- 23092674 TI - An analysis of the determinants of the feeling of knowing. AB - Research has demonstrated that feeling-of-knowing (FOK) judgments are affected by the amount of accessible information related to an inaccessible target. Further, studies have demonstrated that, in some situations, FOK judgment magnitude is not only related to the amount (quantity) of accessed features, but also the correctness of those features (Thomas, Bulevich, & Dubois, 2011). The present study examined the conditions under which the correctness of features would influence FOK judgment magnitude. We hypothesized that accuracy of retrieved features would influence FOK judgments, but only in situations where semantically meaningful information was accessible. In three experiments, we manipulated accessibility of semantic information. In all experiments, the quantity, or amount of retrieved partial information had a greater impact on FOK judgments than the accuracy of that information. However, in situations where semantic information was accessible, accuracy of retrieved semantic features also influenced FOK judgment magnitude, and later recognition. PMID- 23092675 TI - Dream recall frequency: impact of prospective measures and motivational factors. AB - Significant individual differences exist in dream recall frequency (DRF) but some variance is likely attributable to instrument choice in measuring DRF. Three hundred and fifty eight participants estimated their weekly DRF and recorded their dreams in either a narrative log (n = 165) or checklist log (n = 193) for 2 5 weeks. There was an early peak in DRF within the first week of both types of prospective logs after which DRF remained relatively stable. Although the two groups did not differ in their estimated DRF, significantly fewer dreams were reported per week on the narrative logs and only checklist logs yielded significantly higher DRF than participants' questionnaire estimates. The interactions between DRF measures did not vary across groups with low, medium or high baseline levels of DRF. Keeping a dream log does not necessarily increase DRF and narrative logs' time consuming nature can impact subjects' motivation to report all of their dreams over time. PMID- 23092677 TI - RNA polymerase I termination: Where is the end? AB - The synthesis of ribosomal RNA (rRNA) precursor molecules by RNA polymerase I (Pol I) terminates with the dissociation of the protein-DNA-RNA ternary complex. Based on in vitro results the mechanism of Pol I termination appeared initially to be rather conserved and simple until this process was more thoroughly re investigated in vivo. A picture emerged that Pol I termination seems to be connected to co-transcriptional processing, re-initiation of transcription and, possibly, other processes downstream of Pol I transcription units. In this article, our current understanding of the mechanism of Pol I termination and how this process might be implicated in other biological processes in yeast and mammals is summarized and discussed. This article is part of a Special Issue entitled: Transcription by Odd Pols. PMID- 23092676 TI - alphaNAC interacts with histone deacetylase corepressors to control Myogenin and Osteocalcin gene expression. AB - In the nucleus of differentiated osteoblasts, the DNA-binding alphaNAC protein acts as a transcriptional coactivator of the Osteocalcin gene. Chromatin immunoprecipitation-microarray assays (ChIP-chip) showed that alphaNAC binds the Osteocalcin promoter but also identified the Myogenin promoter as an alphaNAC target. Here, we confirm these array data using quantitative ChIP and further detected that alphaNAC binds to these promoters in myoblasts. Since these genes are differentially regulated during osteoblastogenesis or myogenesis, these results suggest cell- and promoter-context specific functions for alphaNAC. We hypothesized that alphaNAC dynamically recruits corepressors to inhibit Myogenin expression in cells committing to the osteoblastic lineage or to inhibit Osteocalcin transcription in differentiating myoblasts. Using co immunoprecipitation assays, we detected complexes between alphaNAC and the corepressors HDAC1 and HDAC3, in myoblasts and osteoblasts. Sequential ChIP confirmed HDAC1 recruitment by alphaNAC at the Osteocalcin and Myogenin promoters. Interaction with the corepressors was detectable in pre-osteoblasts and in myoblasts but disappeared as the cells differentiate. Treatment with an HDAC inhibitor caused de-repression of Osteocalcin expression in myoblasts. Overexpression of alphaNAC in myoblasts inhibits expression of Myogenin and differentiation. However, overexpression of an N-terminus truncated alphaNAC mutant allowed myoblasts to express Myogenin and differentiate, and this mutant did not interact with HDAC1 or HDAC3. This study identified an additional DNA binding target and novel protein-protein interactions for alphaNAC. We propose that alphaNAC plays a role in regulating gene transcription during mesenchymal cell differentiation by differentially recruiting corepressors at target promoters. PMID- 23092678 TI - Factors affecting the effectiveness of biomedical document indexing and retrieval based on terminologies. AB - OBJECTIVE: The aim of this work is to evaluate a set of indexing and retrieval strategies based on the integration of several biomedical terminologies on the available TREC Genomics collections for an ad hoc information retrieval (IR) task. MATERIALS AND METHODS: We propose a multi-terminology based concept extraction approach to selecting best concepts from free text by means of voting techniques. We instantiate this general approach on four terminologies (MeSH, SNOMED, ICD-10 and GO). We particularly focus on the effect of integrating terminologies into a biomedical IR process, and the utility of using voting techniques for combining the extracted concepts from each document in order to provide a list of unique concepts. RESULTS: Experimental studies conducted on the TREC Genomics collections show that our multi-terminology IR approach based on voting techniques are statistically significant compared to the baseline. For example, tested on the 2005 TREC Genomics collection, our multi-terminology based IR approach provides an improvement rate of +6.98% in terms of MAP (mean average precision) (p<0.05) compared to the baseline. In addition, our experimental results show that document expansion using preferred terms in combination with query expansion using terms from top ranked expanded documents improve the biomedical IR effectiveness. CONCLUSION: We have evaluated several voting models for combining concepts issued from multiple terminologies. Through this study, we presented many factors affecting the effectiveness of biomedical IR system including term weighting, query expansion, and document expansion models. The appropriate combination of those factors could be useful to improve the IR performance. PMID- 23092679 TI - New insights in the pathogenesis and treatment of normal tension glaucoma. AB - Increased intraocular pressure (IOP) is a major risk factor for glaucomatous damage and reducing IOP improves prognosis. Nevertheless, there is little doubt that other risk factors besides IOP such as unstable ocular perfusion are involved. Blood flow is unstable if either the IOP fluctuates at a high level (or blood pressure fluctuates at a low level) or if the autoregulation of blood flow disturbed. A common cause for a disturbed OBF autoregulation is a primary vascular dysregulation (PVD) frequently observed in normal tension glaucoma patients. An unstable blood flow leads to recurrent mild reperfusion injury (chronic oxidative stress) affecting particularly the mitochondria of the optic nerve head. OBF regulation can be improved by magnesium, calcium channel blockers as well as with carbonic anhydrase inhibitors. PMID- 23092680 TI - Nasopharyngeal bacterial interactions in children. AB - Antimicrobial treatments and vaccines can alter bacterial interactions in the nasopharynx, thereby altering disease processes. To better understand these interactions, we examined colonization rates of 3 respiratory bacterial pathogens among 320 children when healthy and at onset of acute otitis media (AOM). Bacterial interactions were analyzed with a repeated measures logistic regression model. Among healthy children, Streptococcus pneumoniae and Moraxella catarrhalis were synergistically (positively) associated. Colonization with S. pneumoniae when healthy, but not at onset of AOM, was competitively (negatively) associated with Staphylococcus aureus. Among children with AOM, competitive associations were found between Haemophilus influenzae and S. pneumoniae and between H. influenzae and M. catarrhalis; rates of colonization with H. influenzae were higher. Bacterial interactions result in differing pathogen prevalence during periods of health and at onset of AOM. H. influenzae might become a more common cause of AOM among children who receive pneumococcal conjugate vaccine. PMID- 23092681 TI - Seasonal dynamics of Ixodes ricinus on ground level and higher vegetation in a preserved wooded area in southern Europe. AB - Ixodes ricinus is a major vector of pathogens affecting animals and humans in Europe. Despite its wide distribution, data on the ecology of I. ricinus in some areas is meager, which might impair the elaboration of reliable models to predict the risk of pathogen transmission in areas where this tick is currently present. Herein, we analyze some aspects of the ecology of I. ricinus in a wooded area of southern Italy. From March 2010 to March 2012, ticks were collected on a monthly basis by dragging and flagging in three different sites in a wooded area located in southern Italy, within the boundaries of the Gallipoli Cognato Forest, in the Basilicata region, southern Italy. Immature ticks were more abundant than adults (immature:adult ratio, 10.5:1). The abundance of larvae on the ground-level vegetation was generally higher than on higher vegetation (19.1 vs. 8.3 ticks per hour), whereas nymphs, males and females were more abundant on the higher vegetation (22.3 vs. 14.2, 2.9 vs. 0.8, 2.7 vs. 1.0 ticks per hour, respectively). Larvae were most abundant in summer (27.4 ticks per hour), whereas nymphs, females, and males peaked in seasons other than summer. This study underlines that I. ricinus is well adapted to southern Italian conditions, where it remains active during the whole year, displaying spatiotemporal distribution patterns that are different from central and north European populations. Remarkably, it points out that the life cycle of I. ricinus in southern Italy may be completed in approximately 1 year. Data generated will be valuable to elaborate better models to predict the distribution of this tick in Europe and to assess the risk of transmitted diseases, particularly Lyme borreliosis and tick borne encephalitis. PMID- 23092682 TI - Sources of dengue viruses imported into Queensland, australia, 2002-2010. AB - To assess risk for importation of dengue virus (DENV) into Queensland, Australia, and sources of imported viruses, we sequenced the envelope region of DENV isolates from symptomatic patients with a history of travel during 2002-2010. The number of imported dengue cases greatly increased over the surveillance period, some of which were associated with domestic outbreaks. Patients reported traveling to (in order) Asia, Papua New Guinea, Pacific Island countries, and non Asia-Pacific countries. By using phylogenetic methods, we assigned DENV isolates from returning residents and overseas visitors with viremia to a specific genotypic group. Genotypes circulating in Asia were extremely diverse. Genotyping and molecular clock analysis supported Asian origination of a strain that caused an outbreak of DENV-4 in Pacific Island countries during 2007-2009, and subsequently, in Innisfail, Australia, in 2009. Our findings indicate that Asia is a major source of DENVs that are imported into Australia, causing a risk for epidemics. PMID- 23092683 TI - Invasive pneumococcal disease and 7-valent pneumococcal conjugate vaccine, the Netherlands. AB - In the Netherlands, the national immunization program includes 7-valent pneumococcal conjugate vaccine (PCV7) for all newborns born after April 1, 2006. We compared the incidence of invasive pneumococcal disease (IPD) and patient and disease characteristics before PCV7 introduction (June 2004-June 2006) with those after PCV7 introduction (June 2008-June 2010). Culture-confirmed IPD cases were identified by 9 sentinel laboratories covering ~25% of the Dutch population. Significant declines in overall IPD incidence were observed in children <2 (60%) and in persons >65 (13%) years of age. A trend toward gradual increases in non PCV7 serotype IPD infections was observed in all age groups; the largest increases were among persons 50-64 (37%) and >65 (25%) years of age. In adults, the proportion of immunocompromised persons increased among IPD patients. Overall, deaths from IPD decreased from 16% to 12% because of a lower case fatality rate for persons with non-PCV7 serotype IPD. PMID- 23092684 TI - Seroprevalence of influenza A(H1N1)pdm09 virus antibody, England, 2010 and 2011. AB - The intense influenza activity in England during the 2010-11 winter resulted from a combination of factors. Population-based seroepidemiology confirms that the third wave of influenza A(H1N1)pdm09 virus circulation was associated with a shift in age groups affected, with the highest rate of infection in young adults. PMID- 23092685 TI - Rational development and utilization of antibody-based therapeutic proteins in pediatrics. AB - A large number of monoclonal antibody-based therapeutic proteins have emerged from the biopharmaceutical pipelines in recent years. Compared to small-molecule drugs, therapeutic proteins often confer a more targeted mechanism of action, with the potential for greater efficacy and fewer side effects. Over the recent decade, therapeutic proteins have gained an increasingly important place in the management of various diseases, including many of those that are referred to as "refractory" or "recalcitrant" to conventional therapies. In order to improve the well-being of pediatric patients and provide additional options for unmet medical needs, it is imperative to develop these innovative biotherapeutics for clinical use in children. This article provides an overview of the approved and emerging antibody-based therapeutic proteins with pediatric indications, the similarities and dissimilarities in pharmacokinetics, pharmacodynamics and immunogenicity of therapeutic proteins between children and adults, and strategies to develop therapeutic proteins in pediatric settings with emphasis on dose selection and rational use. In the context of a pediatric dosing strategy, the use of quantitative pharmacokinetic/pharmacodynamic modeling approaches to bridge the information gap between children and adults is also discussed. PMID- 23092686 TI - The benign spectrum of hypothalamic hamartomas: infrequent epilepsy and normal cognition in patients presenting with central precocious puberty. AB - PURPOSE: Hypothalamic hamartoma (HH) is the main structural cause of central precocious puberty (CPP). HH is frequently associated with cognitive impairment and epileptic encephalopathies. Disease severity in case series from neurology services may be biased towards more neurologically impaired patients. AIM: To perform a prospective cognitive evaluation in patients with HH presenting with CPP in an endocrinology outpatient clinic setting. METHODS: We evaluated fifteen consecutive patients with CPP due to HH presenting to an endocrinology outpatient clinic. CPP was diagnosed at a median age of 0.7 yr (0.4-7 yr). Mean age at neurologic evaluation was 13.9 yrs. Eight patients (53.3%) were male. Epileptic seizures occurred in 5/15 (33%) patients. Two patients presented a single unprovoked seizure (SUS). Three patients were diagnosed with epilepsy. Cognitive evaluation, using age-appropriate Wechsler Intelligence Scale, was performed in 11 patients. RESULTS: All patients without epilepsy, including two patients with a history of a SUS, had normal neurologic and cognitive evaluation. Epilepsy and SUS were only seen in patients with sessile HH. Three patients with epilepsy presented cognitive or behavioral findings. Reduced intelligence quotients (IQ), in the borderline range, were noted in both patients with epilepsy who underwent full cognitive evaluation. We found no significant correlation between HH diameter or shape and mean full-scale IQ. CONCLUSIONS: Patients who presented with isolated CPP without epilepsy displayed normal cognition when evaluated after a mean period of 13 years. Occurrence of epilepsy, seen in a minority of patients, but not of a single seizure, was associated with mild cognitive deficit and behavioral disturbances in this case series. PMID- 23092687 TI - Survey of pyrethroids resistance in Indian isolates of Rhipicephalus (Boophilus) microplus: identification of C190A mutation in the domain II of the para-sodium channel gene. AB - Monitoring acaricide resistance and understanding the underlying mechanisms are critically important in developing strategies for resistance management and tick control. Eighteen isolates of Rhipicephalus (Boophilus) microplus collected from four agro-climatic regions of India were characterized and the resistant data were correlated with bioassay results, esterase enzyme activities and with the presence/absence of point mutation in the para-sodium channel gene. The adult immersion test was standardized to assess the level of resistance and resistant factors (RF) in the range of 1.2-95.7 were detected. Out of eighteen isolates, three were categorized as susceptible (RF<1.4), five isolates at level I (RF=1.5 <5), eight at level II (RF=5.1-<25), and one isolate each at level III (RF=26 <40) and level IV (RF=>41). The esterase enzyme ratio and survival% of tick isolates was observed significantly (p<0.001) correlated with correlation coefficient (r) in alpha- and beta-esterase activity. The correlation of determination (R(2)) for alpha- and beta-esterase activity indicated that 73.3% and 55.3% data points of field isolates were very close to the correlation lines. For detection of point mutation, three sites (mutation in domain IIS6, T2134A mutation in domain IIIS6 and C190A mutation in domain IIS4-5 linker) of sodium channel gene were amplified and sequenced. Comparative sequence analysis identified a cytosine (C) to adenine (A) nucleotide substitution (CTC to ATC) at position 190 in domain II S4-5 linker region of para-sodium channel gene in six isolates and in reference deltamethrin resistant IVRI-IV line. The occurrence of mutation in the tick isolates having high resistance factor suggested that target site insensitivity and enhanced esterase activity is the possible mechanism of resistance to deltamethrin in the Indian isolates of R. (B.) microplus. These results also concluded that the mutation site in Indian tick isolates is similar to Australian and Brazilian tick isolates while it is different in tick isolates from Mexico and North America. This is the first report of occurrence of mutation in para-sodium channel gene of deltamethrin resistant Indian isolates of R. (B.) microplus. PMID- 23092688 TI - Epidemiology of ascariasis, enterobiasis and giardiasis in a Romanian western county (Timis), 1993-2006. AB - The purpose of this study is to bring new and important data regarding the epidemiology of ascariasis, enterobiasis and giardiasis in the Romanian largest county during a 14-year period. We have performed a retrospective collection and analysis of the available information provided by the general practitioners to the Statistics Department database of the Timis County Public Health Authority. The mean annual incidence of the studied parasitic diseases during 1993-2006 was the following: 194 cases per 100,000 inhabitants (range: 90-304) for ascariasis, 777 cases per 100,000 inhabitants (range: 417-1241) for enterobiasis and 1076 cases per 100,000 inhabitants (range: 93-1770) for giardiasis. Noteworthy is that Romania reported 90.8% of the total cases of giardiasis at the European Union's level during 2006-2008. The general trend of the incidences throughout the studied period was constant for ascariasis (R(2)=0.192, p=0.1), showed no statistically significant variation (R(2)=0.025, p=0.6) for enterobiasis and was upward for giardiasis (R(2)=0.6, p=0.001). Intestinal parasitoses represent an important public health concern in Romania due to the extremely high incidence rates reported. Special attention should be paid to the young population (0-14 years), where the negative disease consequences on children's health and their educational process may be traced for a long-term. Therefore, efficient educational programs and campaigns should be timely implemented. PMID- 23092689 TI - Evaluation of commercial products for personal protection against mosquitoes. AB - Human landing catch studies were conducted in a semi-field setting to determine the efficacy of seven commercial products used for personal protection against mosquitoes. Experiments were conducted in two empty, insecticide free, mesh enclosed greenhouses, in Israel, with either 1500 Aedes albopictus or 1500 Culex pipiens released on consecutive study nights. The products tested in this study were the OFF!((r)) Clip-OnTM Mosquito Repellent (Metofluthrin 31.2%) and the Terminix((r)) ALLCLEAR((r)) Sidekick Mosquito Repeller (Cinnamon oil 10.5%; Eugenol 13%; Geranium oil 21%; Peppermint 5.3%; Lemongrass oil 2.6%), which are personal diffusers; Super BandTM Wristband (22% Citronella oil) and the PIC((r)) Citronella Plus Wristband (Geraniol 15%; Lemongrass oil 5%, Citronella oil 1%); the Sonic Insect Repeller Keychain; the Mosquito Guard Patch (Oil of Lemon Eucalyptus 80mg), an adhesive-backed sticker for use on textiles; and the Mosquito Patch (vitamin B1 300mg), a transdermal patch. It was determined that the sticker, transdermal patch, wristbands and sonic device did not provide significant protection to volunteers compared with the mosquito attack rate on control volunteers who were not wearing a repellent device. The personal diffusers: - OFF!((r)) Clip-OnTM and Terminix((r)) ALLCLEAR((r)) Sidekick - provided superior protection compared with all other devices in this study. These diffusers reduced biting on the arms of volunteers by 96.28% and 95.26% respectively, for Ae. albopictus, and by 94.94% and 92.15% respectively, for Cx. pipiens. In a second trial conducted to compare these devices directly, biting was reduced by the OFF!((r)) Clip-OnTM and the Terminix((r)) ALLCLEAR((r)) by 87.55% and 92.83%, respectively, for Ae. albopictus, and by 97.22% and 94.14%, respectively, for Cx. pipiens. There was no significant difference between the performances of the two diffusers for each species. PMID- 23092690 TI - Characterization of LIC11207, a novel leptospiral protein that is recognized by human convalescent sera and prevents apoptosis of polymorphonuclear leukocytes. AB - We report the study of a predicted outer-membrane leptospiral protein encoded by the gene lic11207. This protein is conserved in several pathogenic leptospiral strains but is absent in the saprophyte Leptospira biflexa. This putative outer membrane protein has a domain of unknown function (DUF) 1565 found in several phylogenetically diverse bacteria and in the archaeon Methanosarcina acetivorans. The gene was cloned and expressed in Escherichia coli BL21 (SI) strain using the expression vector pDEST17. The 34 kDa recombinant protein was tagged with N terminal hexahistidine and purified by metal-charged chromatography. The purified protein was used to assess: reactivity with human convalescent sera; in vivo expression; ability to activate endothelial cells (EC); and ability to modulate the apoptosis of polymorphonuclear cells (PMNs). The LIC11207 coding sequence was identified in vivo in the hamster renal tubules during experimental infection with Leptospira interrogans. The rLIC11207 showed significant antigenicity against human convalescent sera when compared with sera from healthy donors. The recombinant protein did not alter the surface expression of E-selectin or intercellular adhesion molecule 1 (ICAM-1) in EC and failed to induce the release of von Willebrand factor (vWF). Interestingly, rLIC11207 delayed apoptosis of PMNs suggesting a possible role of this protein during the infection. PMID- 23092691 TI - Improved short term surgical outcomes in Scotland for oesophageal cancer. AB - AIM: This study examined the trends in mortality and contributing adverse events associated with death under surgical care for patients with oesophageal cancer. METHODS: Adverse events in surgical care were prospectively audited in patients who died with cancer of the oesophagus or oesophago-gastric junction under surgical care in Scotland from 1994 to 2005 through the Scottish Audit of Surgical Mortality (SASM). RESULTS: Between 1994 and 2005 (inclusive), 1424 patients with oesophageal cancer (median age 72, 62% male) died. The proportion of oesophageal cancer patients dying on a surgical ward fell significantly from 17% to 13% (p = 0.005). There has been a significant decrease in the annual number of major surgical resections for oesophageal cancer in Scotland from 324 in 1994 to 193 in 2005 (p < 0.001). The proportion of patients operated on in specialist cancer centres increased since 2000. In the period 1996 to 2005, 1157 patients died under surgical care with oesophageal cancer and were audited by SASM. One hundred and thirty five patients (12%) had 239 adverse events. Overall, the number of adverse events decreased over time with 65/130 of those who died following a cancer resection had adverse events. An anastomotic leak was a factor in 25 of these patients. There was a significant decrease in the proportion of deaths following therapeutic endoscopy (p = 0.011). CONCLUSION: There has been a significant decrease in the number of cancer resections, adverse events and mortality associated with oesophageal cancer surgery at a time of increasing surgical specialisation. PMID- 23092692 TI - Recovery of probiotic Lactobacillus rhamnosus GG in tonsil tissue after oral administration: randomised, placebo-controlled, double-blind clinical trial. AB - The present randomised, double-blind, placebo-controlled study was conducted to determine whether consumption of probiotic Lactobacillus rhamnosus GG (GG) would lead to the recovery of GG in tonsil tissue. After 3 weeks' daily consumption of GG as a single strain (n 20), GG as a part of a multispecies combination (n 17) or placebo (n 20), tonsil tissue samples were collected from fifty-seven young adults during tonsillectomy due to chronic or recurrent tonsillitis. Strain specific real-time PCR was used to detect GG in the tonsil tissue. GG was recovered in the tonsil sample of 40% of the subjects in the GG group, 41% in the multispecies group and 30% in the placebo group (P value between groups 0.79). In all subjects with positive recovery of GG in the tonsil tissue, GG was also recovered in the faecal sample taken at the start of the intervention and at the time of the tissue sample collection, which indicates more persistent adherence of the probiotic. To conclude, GG can be recovered from tonsil tissue after oral administration as a singlestrain probiotic or as a part of a multispecies probiotic combination. The present results suggest that individual variation exists in the ability of GG to adhere to tonsil tissue. Persistence of GG appears to be high in tonsil tissue as well, in addition to persistence in faecal samples, which has been demonstrated previously. Further clinical trials are warranted to evaluate whether probiotic adherence in the tonsil tissue could have a role in respiratory symptom prevalence. PMID- 23092693 TI - [A single metastasis in the carpal bones as the first clinical manifestation of a hepatocellular carcinoma]. AB - Hepatocellular carcinoma is the most common primary tumor of the liver. Spreading outside the liver usually takes place in advanced stages of the disease, and bone is the third most common site of metastases. We present a case of hepatocellular carcinoma in which the first clinical manifestation was a single metastasis to the carpal bones. The interest of this case lies in the way this hepatocellular carcinoma manifested as well as in the unusual site of the metastasis. PMID- 23092694 TI - Antiepileptic drug effects on mood and behavior: molecular targets. AB - With almost 100 years of clinical experience, antiepileptic drugs (AEDs) remain the mainstay of epilepsy treatment. They suppress epileptic seizures by acting on a variety of mechanisms and molecular targets involved in the regulation of neuronal excitability. These include inhibitory-GABAergic and excitatory glutamatergic neurotransmission, as well as ion (sodium and calcium) conductance through voltage-gated channels. On the other hand, accruing evidence indicates that these mechanisms and targets are also implicated in the regulation of mood and behavior, which may explain why each AED is associated with specific psychotropic effects. These effects, however, cannot be explained solely on the basis of the known mode of action of each AED, and other mechanisms or targets are likely to be implicated. In this article, we review positive and negative effects of AEDs on mood and behavior, discuss putative underlying mechanisms, and highlight knowledge gaps which should be addressed in future studies. PMID- 23092695 TI - Treatment of interictal epileptiform discharges (IEDs) in patients with cerebral palsy for an improved prognostic outcome and quality of life: emerging evidence. PMID- 23092696 TI - Lack of evidence for zoonotic transmission of Schmallenberg virus. AB - The emergence of Schmallenberg virus (SBV), a novel orthobunyavirus, in ruminants in Europe triggered a joint veterinary and public health response to address the possible consequences to human health. Use of a risk profiling algorithm enabled the conclusion that the risk for zoonotic transmission of SBV could not be excluded completely. Self-reported health problems were monitored, and a serologic study was initiated among persons living and/or working on SBV-affected farms. In the study set-up, we addressed the vector and direct transmission routes for putative zoonotic transfer. In total, 69 sheep farms, 4 goat farms, and 50 cattle farms were included. No evidence for SBV-neutralizing antibodies was found in serum of 301 participants. The lack of evidence for zoonotic transmission from either syndromic illness monitoring or serologic testing of presumably highly exposed persons suggests that the public health risk for SBV, given the current situation, is absent or extremely low. PMID- 23092697 TI - Abnormal network connectivity in frontotemporal dementia: evidence for prefrontal isolation. AB - INTRODUCTION: Degraded social function, disinhibition, and stereotypy are defining characteristics of frontotemporal dementia (FTD), manifesting in both the behavioral variant of frontotemporal dementia (bvFTD) and semantic dementia (SD) subtypes. Recent neuroimaging research also associates FTD with alterations in the brain's intrinsic connectivity networks. The present study explored the relationship between neural network connectivity and specific behavioral symptoms in FTD. METHODS: Resting-state functional magnetic resonance imaging was employed to investigate neural network changes in bvFTD and SD. We used independent components analysis (ICA) to examine changes in frontolimbic network connectivity, as well as several metrics of local network strength, such as the fractional amplitude of low-frequency fluctuations, regional homogeneity, and seed-based functional connectivity. For each analysis, we compared each FTD subgroup to healthy controls, characterizing general and subtype-unique network changes. The relationship between abnormal connectivity in FTD and behavior disturbances was explored. RESULTS: Across multiple analytic approaches, both bvFTD and SD were associated with disrupted frontolimbic connectivity and elevated local connectivity within the prefrontal cortex. Even after controlling for structural atrophy, prefrontal hyperconnectivity was robustly associated with apathy scores. Frontolimbic disconnection was associated with lower disinhibition scores, suggesting that abnormal frontolimbic connectivity contributes to positive symptoms in dementia. Unique to bvFTD, stereotypy was associated with elevated default network connectivity in the right angular gyrus. The behavioral variant was also associated with marginally higher apathy scores and a more diffuse pattern of prefrontal hyperconnectivity than SD. CONCLUSIONS: The present findings support a theory of FTD as a disorder of frontolimbic disconnection leading to unconstrained prefrontal connectivity. Prefrontal hyperconnectivity may represent a compensatory response to the absence of affective feedback during the planning and execution of behavior. Increased reliance upon prefrontal processes in isolation from subcortical structures appears to be maladaptive and may drive behavioral withdrawal that is commonly observed in later phases of neurodegeneration. PMID- 23092699 TI - Radiation burn--from mechanism to management. AB - Radiation burn can occur with diagnostic or therapeutic use of ionizing radiation. A nonintentional radiation burn is relatively uncommon. Skin has a specific tolerance to radiation, above which different grades of radiation burn can occur. Being a rare and less studied problem, no precise guideline is present for its management. Because of few unresolved issues in the pathophysiology of deep radiation burn, its management is difficult. To date no specific guidelines are present for the treatment of radiation burn. PMID- 23092700 TI - Topical negative pressure therapy for skin graft fixation in hand and feet defects: a method for quick and easy dressing application--the "sterile glove technique". PMID- 23092698 TI - Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. AB - Osteoporosis and treatment may affect both composition and nanomechanical properties and their spatial distributions within the individual trabeculae of cancellous bone at length scales that cannot be captured by bulk measurements. This study utilized 25 mature adult ewes divided into 5 treatment groups. Four treatment groups were given a dietary model for human high-turnover osteoporosis, and two of these were treated with antiresorptive drugs, either zoledronate (ZOL) or raloxifene (RAL), to examine their effects on bulk tissue properties and nanoscale tissue composition and mechanical properties within trabeculae. Treatment effects were most pronounced at the nanoscale, where RAL increased indentation modulus and hardness throughout trabeculae by 10% relative to the osteoporosis model. In comparison, ZOL increased these properties exclusively at the surfaces of trabeculae (indentation modulus +12%, hardness +16%). Nanomechanical alterations correlated with changes in tissue mineralization, carbonate substitution, crystallinity, and aligned collagen. Despite only minimal changes in bulk tissue tBMD, the nanomechanical improvements within trabeculae with both treatments greatly improved the predicted theoretical bending stiffness of individual trabeculae when idealized as cylindrical struts. Hence, small tissue-level alterations in critical locations for resisting trabecular failure could account for some of the discrepancy between the large reductions in fracture risk and the only modest changes in BMD with antiresorptive treatments. PMID- 23092701 TI - Cushing's syndrome after intralesional triamcinolone acetonide: a systematic review of the literature and multinational survey. AB - BACKGROUND: Intralesional triamcinolone acetonide (TAC) is a well-established treatment for keloids and hypertrophic scars. The present text provides a systematic review of all previously reported cases of Cushing's syndrome resulting from intralesional TAC in an effort to discover whether an association exists between dosage or frequency of injection and the subsequent development of Cushing's syndrome. Data collected from a multinational survey of plastic surgeons is presented and discussed to understand current trends in the use of TAC. Recommendations for early recognition of Cushing's syndrome, TAC dosages in children, and follow up guidelines are presented. METHODS: A systematic review of the literature from 1950 to 2012 was performed to evaluate outcomes following intralesional TAC used for the treatment of scars. A confidential survey was sent to 4125 plastic surgeons, 102 responses from 9 countries were received. RESULTS: A total of 18 cases of Cushing's syndrome after intralesional TAC have been reported in the English world literature. Survey data reveals that at least 30% (25/84) of plastic surgeons exceed the recommended dosage of TAC and 47% (46/97) are not aware of Cushing's syndrome as a possible complication of intralesional TAC. CONCLUSIONS: Cushing's syndrome resulting from intralesional TAC has been reported multiple times in the literature. Published literature suggests that TAC administered within the most recent recommendations does not appear to place adult patients at increased risk for developing Cushing's syndrome. Children appear to be most at risk for developing Cushing's syndrome and yet insufficient recommendations currently exist with regard to their safe dosage. Intralesional dosage should not exceed 30 mg per month in children while noting that at least one reported case of Cushing's syndrome resulted from a smaller dose. Diligent follow up and patient education is advised for any patient treated with TAC so that complications can be recognized and addressed promptly. PMID- 23092702 TI - Assessing paediatric scald injuries using Laser Speckle Contrast Imaging. AB - BACKGROUND: The use of objective methods for assessment of burns is limited. Laser Speckle Contrast Imaging (LSCI) is a non-invasive technique for instant measurement of tissue perfusion, making it potentially valuable for early prediction of burn wound outcome. AIM: To evaluate the influence of technical factors on perfusion and to measure perfusion in burns 0-14 days post-burn and compare this with the outcome of the burn wound at 14 days after burn. METHOD: The effect of room light, camera distance and camera angle was studied using a suspension of polystyrene particles. LSCI measurements were performed on 45 scald burns and 32 uninjured areas 0-14 days after burn. RESULT: Technical factors had no clinically relevant effect on measured perfusion. Burns that healed within 14 days had a higher perfusion during the first week post-burn than burns that healed after 14 days or underwent surgery. The difference in perfusion was largest 4-7 days after burn. CONCLUSION: LSCI allows for robust, instant measurement of burns and can easily be applied in a clinical setting. Differences in perfusion during the first week post-burn are related to the outcome after 14 days. PMID- 23092703 TI - Conditioning the cortical silent period with paired transcranial magnetic stimulation. AB - BACKGROUND: A single supra-threshold pulse of transcranial magnetic stimulation (TMS) over human motor cortex elicits multiple descending volleys (I-waves) that generate a motor evoked potential (MEP) followed by a period of electromyographic silence in the tonically contracted target muscle (silent period; SP). A sub threshold conditioning stimulus (CS) delivered at inter-pulse intervals (IPIs) of 1-5 ms after a supra-threshold test stimulus (TS) conditions I-waves elicited by TS and can increase MEP amplitude (short-interval intracortical facilitation; SICF), however its effect on the SP remains unknown. OBJECTIVE: We investigated whether it is possible to modulate the SP resulting from a TS by delivering a sub threshold CS 1-5 ms later. METHODS: Paired-pulse TMS was delivered while subjects performed slight contraction of the first dorsal interosseous muscle. SICF and SP duration were measured at each IPI and compared to amplitude-matched MEPs evoked by single-pulse TMS. RESULTS: Paired stimulation at IPI 2-5 ms prolonged the SP by 21 +/- 3% (P < 0.001) but had no effect on MEP amplitude. At shorter IPIs the CS increased MEP amplitude (by 170 +/- 31%), but the SP was not prolonged when compared to an amplitude-matched single-pulse stimulus. CONCLUSION: The SP can be modified by a CS applied during the early phase of its genesis. We suggest that this is in keeping with an early GABAA contribution to the SP, and it is possible that this new conditioning paradigm may offer another means for probing the excitability of cortical inhibitory networks in human motor cortex. PMID- 23092704 TI - Spatial distribution assessment of particulate matter in an urban street canyon using biomagnetic leaf monitoring of tree crown deposited particles. AB - Recently, biomagnetic monitoring of tree leaves has proven to be a good estimator for ambient particulate concentration. This paper investigates the usefulness of biomagnetic leaf monitoring of crown deposited particles to assess the spatial PM distribution inside individual tree crowns and an urban street canyon in Ghent (Belgium). Results demonstrate that biomagnetic monitoring can be used to assess spatial PM variations, even within single tree crowns. SIRM values decrease exponentially with height and azimuthal effects are obtained for wind exposed sides of the street canyon. Edge and canyon trees seem to be exposed differently. As far as we know, this study is the first to present biomagnetic monitoring results of different trees within a single street canyon. The results not only give valuable insights into the spatial distribution of particulate matter inside tree crowns and a street canyon, but also offer a great potential as validation tool for air quality modelling. PMID- 23092705 TI - The role of the helper lipid dioleoylphosphatidylethanolamine (DOPE) for DNA transfection cooperating with a cationic lipid bearing ethylenediamine. AB - Gene therapy is expected to treat various incurable diseases including viral infections, autoimmune disorders, and cancers. Cationic lipids (CL) have been used as carriers of therapeutic DNAs for gene therapy because they can form a complex with DNA and such a complex can be incorporated into cells and transport the bound DNA to cytosol. The CL/DNA complexes are called lipoplexes and categorized as a non-viral vector. Lipoplexes are often prepared by adding a neutral phospholipid dioleoylphosphatidylethanolamine (DOPE) to CL in order to enhance transfection. However, the role of DOPE is not fully understood. We synthesized a new CL having an ethylenediamine cationic head group, denoted by DA, and found that addition of DOPE to DA achieved a good efficiency, almost in the similar level of commonly used transfection reagent Lipofectamine 2000 (Invitrogen). The composition of DA:DOPE=1:1 showed the highest efficiency. This lipoplex showed structural transition when pH was changed from 7 to 4, corresponding pH lowering in late endosome, while DOPE itself showed structural transition at more basic pH around 8. The present data showed that the DOPE/DA composition determines the structural transition pH and choosing a suitable pH, i.e., a suitable composition, is essential to increase the transfection efficiency. PMID- 23092706 TI - Phylogeography of dengue virus serotype 4, Brazil, 2010-2011. AB - Dengue virus serotype 4 (DENV-4) reemerged in Roraima State, Brazil, 28 years after it was last detected in the country in 1982. To study the origin and evolution of this reemergence, full-length sequences were obtained for 16 DENV-4 isolates from northern (Roraima, Amazonas, Para States) and northeastern (Bahia State) Brazil during the 2010 and 2011 dengue virus seasons and for an isolate from the 1982 epidemic in Roraima. Spatiotemporal dynamics of DENV-4 introductions in Brazil were applied to envelope genes and full genomes by using Bayesian phylogeographic analyses. An introduction of genotype I into Brazil from Southeast Asia was confirmed, and full genome phylogeographic analyses revealed multiple introductions of DENV-4 genotype II in Brazil, providing evidence for >3 introductions of this genotype within the last decade: 2 from Venezuela to Roraima and 1 from Colombia to Amazonas. The phylogeographic analysis of full genome data has demonstrated the origins of DENV-4 throughout Brazil. PMID- 23092707 TI - Integrating genome-based informatics to modernize global disease monitoring, information sharing, and response. AB - The rapid advancement of genome technologies holds great promise for improving the quality and speed of clinical and public health laboratory investigations and for decreasing their cost. The latest generation of genome DNA sequencers can provide highly detailed and robust information on disease-causing microbes, and in the near future these technologies will be suitable for routine use in national, regional, and global public health laboratories. With additional improvements in instrumentation, these next- or third-generation sequencers are likely to replace conventional culture-based and molecular typing methods to provide point-of-care clinical diagnosis and other essential information for quicker and better treatment of patients. Provided there is free-sharing of information by all clinical and public health laboratories, these genomic tools could spawn a global system of linked databases of pathogen genomes that would ensure more efficient detection, prevention, and control of endemic, emerging, and other infectious disease outbreaks worldwide. PMID- 23092708 TI - Call to action on world pneumonia day. AB - This month, on November 12, the world will recognize the fourth annual World Pneumonia Day. First launched in 2009 by a coalition of global health leaders (1), World Pneumonia Day aims to raise awareness about pneumonia's toll on the world's children and to promote interventions to protect against, treat, and prevent the disease. Pneumonia continues to be the leading killer of young children around the world, causing ~14% of all deaths in children 1 month to 5 years of age (2). It is a critical disease for countries to conquer in order to reach Millennium Development Goal 4: reducing the child mortality rate by two thirds from 1990 to 2015 (3). Most children who die from pneumonia live in developing countries, where such factors as malnutrition, crowding, and lack of access to quality health care increase the risk for death. Pneumonia kills few children in industrialized countries, although it remains among the top 10 causes of deaths in the United States, for example, because of deaths in older adults (4). PMID- 23092709 TI - Environmental and behavioral controls of the expression of clozapine tolerance: evidence from a novel across-model transfer paradigm. AB - Repeated administration of antipsychotic drugs induces a sensitization-like or tolerance-like effect in many behavioral tasks, including the conditioned avoidance response (CAR) and the phencyclidine (PCP)-induced hyperlocomotion, two rodent models with high predictive validity for antipsychotic activity. This study investigated the impacts of contextual and behavioral variables on the expression of clozapine tolerance using a recently validated across-model transfer paradigm (Zhang and Li, 2012 [1]). Male Sprague-Dawley rats were first repeatedly treated with clozapine (2.5-10.0 mg/kg, sc) in the CAR model or PCP (1.6 mg/kg, sc)-induced hyperlocomotion model for five consecutive days. They were then tested for the expression of clozapine tolerance in another model for another 5 days. Finally, all rats were switched back to the original model and tested again for the expression of clozapine tolerance. When tested in the PCP model, rats previously treated with clozapine in the CAR model did not show an immediate weaker inhibition of PCP-induced hyperlocomotion than those treated with clozapine for the first time, but showed a significantly weaker inhibition over time. In contrast, when tested in the CAR model, rats previously treated with clozapine in the PCP model showed an immediate weaker disruption of avoidance response than those treated with clozapine for the first time, but this weaker effect diminished over time. These results suggest that the expression of clozapine tolerance is strongly modulated by the test environment and/or selected behavioral response. Clozapine tolerance and its situational specificity may be related to the drug's low extrapyramidal motor side effect, its superior therapeutic efficacy and/or emergence of clozapine withdrawal syndrome. PMID- 23092710 TI - [Perinatality in the context of addictions]. AB - We must remove bad representations the medical team has upon the pregnant drug users and the same way in reverse. Opiate substitution treatment (OST) improves prenatal prognosis for both mother and child. There is no need to change OST for a stabilized woman discovering pregnancy. Nevertheless, buprenorphine appears to be first-range medication. OST posology is the most important for prenatal prognosis. Practician must never hesitate to adapt it whether increasing or fractionate it. Neonatal abstinence syndrome (NAS) is not linked with OST's posology. OST is not contra-indicated for breast-feeding. Breast-feeding should be encouraged. It does not treat or cure NAS but allows a skin-to-skin contact that could lessens an occurring withdrawal. PMID- 23092712 TI - Effectiveness of a nationwide aftercare program for suicide attempters. AB - BACKGROUND: The effectiveness of large-scale interventions to prevent suicide among persons who previously attempted suicide remains to be determined. The National Suicide Surveillance System (NSSS), launched in Taiwan in 2006, is a structured nationwide intervention program for people who survived their suicide attempts. This naturalistic study examined its effectiveness using data from the first 3 years of its operation. Method Effectiveness of the NSSS aftercare services was examined using a logistic/proportional odds mixture model, with eventual suicide as the outcome of interest. As well, we examined time until death for those who died and factors associated with eventual suicide. RESULTS: Receipt of aftercare services was associated with reduced risk for subsequent suicide; for service recipients who eventually killed themselves, there was a prolonged duration between the index and fatal attempts. Elderly attempters were particularly prone to a shorter duration between the index and fatal attempts. Male gender, the lethality potential of the index attempt, and a history of having had a mental disorder also were associated with higher risk. CONCLUSIONS: The structured aftercare program of the NSSS appears to decrease suicides and to delay time to death for those who remained susceptible to suicide. PMID- 23092713 TI - Unchanged severity of influenza A(H1N1)pdm09 infection in children during first postpandemic season. AB - We conducted a nationwide hospital-based prospective study in Germany of influenza A(H1N1)pdm09 cases among children <15 years of age admitted to pediatric intensive care units and related deaths during the 2009-10 pandemic and the 2010-11 postpandemic influenza seasons. We identified 156 eligible patients: 112 in 2009-10 and 44 in 2010-11. Although a shift to younger patients occurred in 2010-11 (median age 3.2 vs. 5.3 years), infants <1 year of age remained the most affected. Underlying immunosuppression was a risk factor for hospital acquired infections (p = 0.013), which accounted for 14% of cases. Myocarditis was predictive of death (p = 0.006). Of the 156 case-patients, 17% died; the difference between seasons was not significant (p = 0.473). Our findings stress the challenge of preventing severe postpandemic influenza infection in children and the need to prevent nosocomial transmission of influenza virus, especially in immunosuppressed children. PMID- 23092714 TI - Co-expression of Erns and E2 genes of classical swine fever virus by replication defective recombinant adenovirus completely protects pigs against virulent challenge with classical swine fever virus. AB - The objective of this study was to construct a recombinant adenovirus for future CSFV vaccines used in the pig industry for the reduction of losses involved in CSF outbreaks. The Erns and E2 genes of classical swine fever virus (CSFV), which encode the two main protective glycoproteins from the "Shimen" strain of CSFV, were combined and inserted into the replication-defective human adenovirus type-5 and named the rAd-Erns-E2. Nine pigs were randomly assigned to three treatment groups (three pigs in each group) including the rAd-Erns-E2, hAd-CMV control and DMEM control. Intramuscular vaccination with 2*10(6) TCID(50) of the rAd-Erns-E2 was administered two times with an interval of 21 days. At 42 days post inoculation, pigs in all groups were challenged with a lethal dose of 1*10(3) TCID(50) CSFV "Shimen" strain. Observation of clinical signs was made and the existence of CSFV RNA was detected. Animals in the hAd-CMV and DMEM groups showed severe clinical CSF symptoms and were euthanized from 7 to 10 days after the challenge. However, no adverse clinical CSF signs were observed in vaccinated pigs after the administration of rAd-Erns-E2 and even after CSFV challenge. Neither CSFV RNA nor pathological changes were detected in the tissues of interest of the above vaccinated pigs. These results implied that the recombination adenovirus carrying the Erns-E2 genes could be used to prevent swine from classical swine fever. PMID- 23092715 TI - Occupational pesticide exposure and screening tests for neurodegenerative disease among an elderly population in Costa Rica. AB - BACKGROUND: Pesticides have been associated with Parkinson's disease (PD) in many studies, and with Alzheimer's disease (AD) in a few. METHODS: We conducted screening tests for neurologic disease and occupational pesticide use in a population-based sample of 400 elderly subjects at two government-run clinics in Costa Rica; 361 subjects who failed the initial screen were given both the mini mental states exam (MMSE) and a modified version of a 10-item united Parkinson's disease rating motor subscale (UPDRS). Among subjects who failed either test, 144 were then examined by a neurologist. RESULTS: Past occupational pesticide exposure was reported by 18% of subjects. Exposed subjects performed worse on the MMSE than the non-exposed (mean 24.5 versus 25.9, p=0.01, adjusted for age, sex, and education). The exposed had significantly elevated risks of abnormal scores on two UPDRS items, tremor-at-rest (OR 2.58, 1.28-5.23), and finger-tapping (OR=2.94, 95% CI 1.03-8.41). Thirty-three (23%) of those examined by the neurologist were diagnosed with possible/probable PD, 3-4 times the expected based on international data; 85% of these cases had not been previously diagnosed. Among subjects who took the UPDRS, the exposed had an increased risk of PD (OR=2.57, 95% CI 0.91-7.26). No excess risk was found for a diagnosis of AD or mild cognitive impairment. CONCLUSIONS: Elderly subjects with past occupational pesticide exposure performed significantly worse on screening tests for dementia and PD, and had an increased risk of an eventual PD diagnosis. Screening may be particularly appropriate among elderly subjects with past pesticide exposure. PMID- 23092711 TI - A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. AB - Psychological stress is a major provocative factor of symptoms in chronic inflammatory conditions. In recent years, interest in addressing stress responsivity through meditation training in health-related domains has increased astoundingly, despite a paucity of evidence that reported benefits are specific to meditation practice. We designed the present study to rigorously compare an 8 week Mindfulness-Based Stress Reduction (MBSR) intervention to a well-matched active control intervention, the Health Enhancement Program (HEP) in ability to reduce psychological stress and experimentally-induced inflammation. The Trier Social Stress Test (TSST) was used to induce psychological stress and inflammation was produced using topical application of capsaicin cream to forearm skin. Immune and endocrine measures of inflammation and stress were collected both before and after MBSR training. Results show those randomized to MBSR and HEP training had comparable post-training stress-evoked cortisol responses, as well as equivalent reductions in self-reported psychological distress and physical symptoms. However, MBSR training resulted in a significantly smaller post-stress inflammatory response compared to HEP, despite equivalent levels of stress hormones. These results suggest behavioral interventions designed to reduce emotional reactivity may be of therapeutic benefit in chronic inflammatory conditions. Moreover, mindfulness practice, in particular, may be more efficacious in symptom relief than the well-being promoting activities cultivated in the HEP program. PMID- 23092716 TI - Indoor air pollution from solid fuels and risk of upper aerodigestive tract cancers in central and eastern Europe. AB - BACKGROUND: Indoor air pollution from solid fuels is a potentially important risk factor for cancer, yet data on cancers from organs other than the lung are scarce. We investigated if indoor air pollution from coal and wood are risk factors for additional cancers, particularly that of the upper aerodigestive tract (oral cavity, larynx, pharynx and esophagus) in the high-risk areas of central and eastern Europe. METHODS: We used data from multi-center hospital based case-control study of 1065 histologically confirmed upper aerodigestive tract cancer cases and 1346 controls. Standardized questionnaires were used to collect information on residential fuel use for cooking and heating. Using unconditional logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for upper aerodigestive tract cancer risk after adjusting for potential confounders. RESULTS: Lifelong wood use was associated with pharyngeal and esophageal (OR 4.05, 95% CI: 1.30-12.68 and OR 2.71, 95% CI: 1.21-6.10, respectively). We observed an exposure-response relationship between duration of wood use and risk of pharyngeal cancer among those who had never used coal (P(trend)=0.04), ruling out the possibility of residual confounding by coal. Similarly, we observed an increased risk of laryngeal cancers and head & neck cancers among those who always used coal, with a noted exposure-response relationship (P(trend)<0.01). CONCLUSIONS: Our results suggest a possible role of indoor air pollution from solid fuel use in head and neck carcinogenesis in the high risk area of central and eastern Europe. PMID- 23092717 TI - Conflict of interest and professional medical associations: the North American Spine Society experience. AB - BACKGROUND CONTEXT: Recently the financial relationships between industry and professional medical associations have come under increased scrutiny because of the concern that industry ties may create real or perceived conflicts of interest. Professional medical associations pursue public advocacy as well as promote medical education, develop clinical practice guidelines, fund research, and regulate professional conduct. Therefore, the conflicts of interest of a professional medical association and its leadership can have more far-reaching effects on patient care than those of an individual physician. PURPOSE: Few if any professional medical associations have reported their experience with implementing strict divestment and disclosure policies, and among the policies that have been issued, there is little uniformity. We describe the experience of the North American Spine Society (NASS) in implementing comprehensive conflicts of interest policies. STUDY DESIGN: A special feature article. METHODS: We discuss financial conflicts of interest as they apply to professional medical associations rather than to individual physicians. We describe the current policies of disclosure and divestment adopted by the NASS and how these policies have evolved, been refined, and have had no detrimental impact on membership, attendance at annual meetings, finances, or leadership recruitment. No funding was received for this work. The authors report no potential conflict-of-interest associated biases in the text. RESULTS: The NASS has shown that a professional medical association can manage its financial relationships with industry in a manner that minimizes influence and bias. CONCLUSIONS: The NASS experience can provide a template for other professional medical associations to help manage their own possible conflicts of interest issues. PMID- 23092718 TI - The personal and national costs of early retirement because of spinal disorders: impacts on income, taxes, and government support payments. AB - BACKGROUND CONTEXT: Spinal disorders can reduce an individual's ability to participate in the labor force, and this can lead to considerable impacts on both the individual and the state. PURPOSE: This study was aimed to quantify the personal cost of lost income and the cost to the state from lost income taxation, increased benefits payments, and lost gross domestic product (GDP) as a result of early retirement because of spinal disorders in Australians aged 45 to 64 years in 2009. METHODS: This was done using cross-sectional analysis of the base population of Health&WealthMOD, a microsimulation model built on data from the Australian Bureau of Statistics' Survey of Disability, Ageing and Carers, and STINMOD, an income and savings microsimulation model. Linear regression models were used to examine the relationship between spinal disorders, labor force participation, income, taxation, and government support payments. RESULTS: It was found that individuals aged 45 to 64 years who have retired early because of spinal disorders have significantly lower income (79% less; 95% confidence interval [CI], -84.7, -71.1; p<.0001), pay significantly less taxation (100% less; 95% CI, -100.0, 99.9; p<.0001), and receive significantly more in government support payments (21,000% more; 95% CI, 12,767.0, 35,336.4; p<.0001) than those employed full time with no health condition. Individuals who have retired early because of spinal disorders have a median value of total weekly income of only AU$310, whereas those who are employed full time are likely to receive four times this. This has a large national aggregate impact, with AU$4.8 billion lost in annual individual earnings, AU$622 million in additional welfare payments, AU$497 million lost in taxation revenue for governments, and AU$2.9 billion in lost GDP: all attributable to spinal disorders through their impact on labor force participation. CONCLUSIONS: Although the individual has to bear the economic costs of lost income in addition to the burden of the condition itself, the state experiences the impacts of loss of productivity from reduced workforce participation, lost income taxation revenue, and increasing government support payments. PMID- 23092719 TI - Dorsal thoracic spinal cord herniation: report of an unusual case and review of the literature. AB - BACKGROUND CONTEXT: Spinal cord herniation is a rare but well-documented condition that has been associated with tethering through the dural defect. Both spinal cord herniation and cord tethering result in progressive myelopathy that can be improved or stabilized with surgical intervention. Most cases of herniation are caused by dural defects in the ventral or ventrolateral thoracic spine, rarely occurring through the dorsal dura. This is the first reported case of a spontaneous dorsal herniation. PURPOSE: To describe a unique case of thoracic tethered cord resulting from a dorsal dural defect through which there is spinal cord herniation. STUDY DESIGN: A case report and review of the literature. METHODS: A 55-year-old man presented with progressive low back pain, paresthesias, and weakness in his left lower extremity that was exacerbated by walking. Imaging revealed a dorsal dural defect with tethering and herniation of the spinal cord at T7. RESULTS: The patient underwent a T6-T7 laminoplasty to release the tethered cord and repair the dural defect. At 1-year follow-up, the patient noted improvement in strength and back spasticity. CONCLUSIONS: Spinal cord herniation through a dural defect is an uncommon but important cause of symptomatic tethered cord in adults. Surgical intervention can significantly alter the course and prevent further disability. PMID- 23092720 TI - SERS study on adenine using a Ag/poly(t-butylacrylate) nanocomposite. AB - Enhancement of Raman signals of the nucleobase adenine on an Ag based composite was studied using the 1064 nm laser line. The composite comprise emulsions of Ag nanoparticles encapsulated in poly(t-butylacrylate) (PtBA) beads that act as substrate for the Surface-Enhanced Raman Scattering (SERS) of adenine. For this system, Raman enhancement was observed for the ring-stretching vibrational mode of adenine after aggregation of the Ag/poly(t-butylacrylate) emulsion and isolation of the solid composite. This is a convenient and alternative analytical approach to SERS monitoring of solutions of adenine over the more common use of pure Ag colloids. As a consequence, this research contributes to develop innovative studies on DNA fragments using polymeric platforms that can act as highly sensitive SERS substrates. PMID- 23092721 TI - Aorto-enteric fistulas: a physiopathological approach and computed tomography diagnosis. AB - Infection of an abdominal aortic prosthesis with an enteroprosthetic fistula is a very serious, life-threatening complication, leading sometimes to severe functional consequences, the most serious being amputation. Since the symptoms, if there are any, are often rather non-specific, diagnosis is frequently difficult and has always to be based on a whole series of justifications. Early diagnosis is essential and this fistula should be the first possibility considered in a patient with an abdominal aortic prosthesis who is presenting rectorrhagia or melaena (even if only to a slight degree), sepsis and/or abdominal pain. Although rare, the clinical existence of hypertrophic osteoarthropathy may assist diagnosis. A CT scan is the examination of choice, the criteria providing evidence of a fistula being the presence of gaseous images in a periprosthetic fluid collection, thickening and/or retraction of the intestinal walls in contact, the existence of a false aneurysm, and finally, very rarely, extravasation of contrast agent into the intestinal lumen. The differential diagnoses that may mimic a fistula need to be well known, and can include retroperitoneal fibrosis, an infectious aneurysm, inflammatory or infectious aortitis, and above all, a 'simple' prosthesis infection without fistulisation. PMID- 23092722 TI - Comparative in vitro and in vivo antimalarial activity of the indole alkaloids ellipticine, olivacine, cryptolepine and a synthetic cryptolepine analog. AB - Indole alkaloids ellipticine (1), cryptolepine triflate (2a), rationally designed 11-(4-piperidinamino)cryptolepine hydrogen dichloride (2b) and olivacine (3) (an isomer of 1) were evaluated in vitro against Plasmodium falciparum and in vivo in Plasmodium berghei-infected mice. 1-3 inhibited P. falciparum (IC50<=1.4 MUM, order of activity: 2b>1>2a>3). In vitro toxicity to murine macrophages was evaluated and revealed selectivity indices (SI) of 10-12 for 2a and SI>2.8*102 for 1, 2b and 3. 1 administered orally at 50mg/kg/day was highly active against P. berghei (in vivo inhibition compared to untreated control (IVI)=100%, mean survival time (MST)>40 days, comparable activity to chloroquine control). 1 administered orally and subcutaneously was active at 10 mg/kg/day (IVI=70-77%; MST=27-29 days). 3 exhibited high oral activity at >=50 mg/kg/day (IVI=90-97%, MST=23-27 days). Cryptolepine (2a) administered orally and subcutaneously exhibited moderate activity at 50mg/kg/day (IVI=43-63%, MST=24-25 days). At 50 mg/kg/day, 2b administered subcutaneously was lethal to infected mice (MST=3 days) and moderately active when administered orally (IVI=45-55%, MST=25 days). 1 and 3 are promising compounds for development of antimalarials. PMID- 23092723 TI - Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders. AB - Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-kappaB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves was also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate to weak anti-inflammatory activity, while the methanol and especially the water soluble extracts exhibited noticeable cytotoxicity. In contrast, the lipophilic dichloromethane extracts of the roots, stems and leaves exhibited potent anti-inflammatory effects greater than or equal to 1 with minimal cytotoxicity to RAW264.7 cells. Collectively these results suggest that using lipophilic extracts of stinging nettle may be more effective than traditional tinctures (water, methanol, ethanol) in clinical evaluations for the treatment of inflammatory disorders especially arthritis. A chemical investigation into the lipophilic extracts of stinging nettle to identify the bioactive compound(s) responsible for their observed anti-inflammatory activity is further warranted. PMID- 23092724 TI - Infant and fetal mortality among a high fertility and mortality population in the Bolivian Amazon. AB - Indigenous populations experience higher rates of poverty, disease and mortality than non-indigenous populations. To gauge current and future risks among Tsimane Amerindians of Bolivia, I assess mortality rates and growth early in life, and changes in risks due to modernization, based on demographic interviews conducted Sept. 2002-July 2005. Tsimane have high fertility (total fertility rate = 9) and infant mortality (13%). Infections are the leading cause of infant death (55%). Infant mortality is greatest among women who are young, monolingual, space births close together, and live far from town. Infant mortality declined during the period 1990-2002, and a higher rate of reported miscarriages occurred during the 1950-1989 period. Infant deaths are more frequent among those born in the wet season. Infant stunting, underweight and wasting are common (34%, 15% and 12%, respectively) and greatest for low-weight mothers and high parity infants. Regression analysis of infant growth shows minimal regional differences in anthropometrics but greater stunting and underweight during the first two years of life. Males are more likely to be underweight, wasted, and spontaneously aborted. Whereas morbidity and stunting are prevalent in infancy, greater food availability later in life has not yet resulted in chronic diseases (e.g. hypertension, atherosclerosis and diabetes) in adulthood due to the relatively traditional Tsimane lifestyle. PMID- 23092725 TI - Clinical outcomes of biological effective dose-based fractionated stereotactic radiation therapy for metastatic brain tumors from non-small cell lung cancer. AB - PURPOSE: To evaluate the efficacy and toxicity of fractionated stereotactic radiation therapy (FSRT) based on biological effective dose (BED), a novel approach to deliver a fixed BED irrespective of dose fractionation, for brain metastases from non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Between March 2005 and March 2009 we treated 299 patients with 1 to 5 lesions from NSCLC (573 total brain metastases) with FSRT using Novalis. The dose fractionation schedules were individually determined to deliver a peripheral BED10 (alpha/beta ratio = 10) of approximately 80 Gy10. The median number of fractions was 3 (range, 2-10), the median peripheral BED10 was 83.2 Gy (range, 19.1-89.6 Gy). Patients were followed up with magnetic resonance imaging (MRI) studies performed at 1- to 2-month intervals. The local tumor control rate and overall local progression-free and intracranial relapse-free survival were calculated by the Kaplan-Meier method. RESULTS: Local control rates for all 573 lesions at 6 and 12 months were 96.3% and 94.5%, respectively. By multivariate analysis the tumor diameter was the only factor predictive of the local control rate (P=.001). The median overall survival, local progression-free survival, and intracranial relapse-free survival were 17.1, 14.9, and 4.4 months, respectively. The overall survival, local progression-free survival, and intracranial relapse free survival rates at 6 and 12 months were 78.5% and 63.3%, 74.3% and 57.8%, and 41.0% and 21.8%, respectively. Six patients (2%) manifested progressive radiation injury to the brain even during therapy with corticosteroids; they underwent hyperbaric oxygen therapy, and follow-up MRI showed improvement. CONCLUSIONS: This study showed that BED-based FSRT for brain metastases from NSCLC is a promising strategy that may yield excellent outcomes with acceptable toxicity. Criteria must be established to determine the optimal dose fractionation for individual patients. PMID- 23092726 TI - Motexafin-gadolinium and involved field radiation therapy for intrinsic pontine glioma of childhood: a children's oncology group phase 2 study. AB - PURPOSE: To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas. METHODS AND MATERIALS: Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments over 6 weeks. The total dose was 54 Gy. RESULTS: Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18%+/-5%, and the estimated 1-year OS was 53%+/-6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension. CONCLUSIONS: Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas. PMID- 23092728 TI - p21-activated kinases and gastrointestinal cancer. AB - p21-activated kinases (PAKs) were initially identified as effector proteins downstream from GTPases of the Rho family. To date, six members of the PAK family have been discovered in mammalian cells. PAKs play important roles in growth factor signalling, cytoskeletal remodelling, gene transcription, cell proliferation and oncogenic transformation. A large body of research has demonstrated that PAKs are up-regulated in several human cancers, and that their overexpression is linked to tumour progression and resistance to therapy. Structural and biochemical studies have revealed the mechanisms involved in PAK signalling, and opened the way to the development of PAK-targeted therapies for cancer treatment. Here we summarise recent findings from biological and clinical research on the role of PAKs in gastrointestinal cancer, and discuss the current status of PAK-targeted anticancer therapies. PMID- 23092727 TI - A biodistribution and toxicity study of cobalt dichloride-N-acetyl cysteine in an implantable MRI marker for prostate cancer treatment. AB - PURPOSE: C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate. METHODS AND MATERIALS: 9-MUL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated. RESULTS: No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 MUg/g and 268 MUg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 +/- 5.6% (liver), >11.8 +/- 6.5% (prostate), and >5.3 +/- 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 MUg/mL at 5-60 minutes). Excretion in urine was 13.1 +/- 4.6%, with 3.1 +/- 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed. CONCLUSION: C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy. PMID- 23092729 TI - Benchmarking routine psychological services: a discussion of challenges and methods. AB - BACKGROUND: Policy developments in recent years have led to important changes in the level of access to evidence-based psychological treatments. Several methods have been used to investigate the effectiveness of these treatments in routine care, with different approaches to outcome definition and data analysis. AIMS: To present a review of challenges and methods for the evaluation of evidence-based treatments delivered in routine mental healthcare. This is followed by a case example of a benchmarking method applied in primary care. METHOD: High, average and poor performance benchmarks were calculated through a meta-analysis of published data from services working under the Improving Access to Psychological Therapies (IAPT) Programme in England. Pre-post treatment effect sizes (ES) and confidence intervals were estimated to illustrate a benchmarking method enabling services to evaluate routine clinical outcomes. RESULTS: High, average and poor performance ES for routine IAPT services were estimated to be 0.91, 0.73 and 0.46 for depression (using PHQ-9) and 1.02, 0.78 and 0.52 for anxiety (using GAD-7). Data from one specific IAPT service exemplify how to evaluate and contextualize routine clinical performance against these benchmarks. CONCLUSIONS: The main contribution of this report is to summarize key recommendations for the selection of an adequate set of psychometric measures, the operational definition of outcomes, and the statistical evaluation of clinical performance. A benchmarking method is also presented, which may enable a robust evaluation of clinical performance against national benchmarks. Some limitations concerned significant heterogeneity among data sources, and wide variations in ES and data completeness. PMID- 23092730 TI - Effect of lipopolysaccharides from Vibrio alginolyticus on the Mx gene expression and virus recovery from gilthead sea bream (Sparus aurata L.) experimentally infected with Nodavirus. AB - Infections with nodavirus affect a wild and farmed fish species throughout the world, mostly from the marine environment. The aim of this work was to determine the immune status of gilthead sea bream that comes as a result of a Nodavirus infection, induced by activation of the interferon response pathway by lipopolysaccharides from Vibrio alginolyticus and the expression of interferoninduced Mx protein in liver samples. The enhancement of Mx protein gene expression was detected in liver samples of experimentally nodavirus infected fish and, furthermore, the immunostimulant LPS of V. alginolyticus decreased almost three times the virus titration with respect to no-immunized or infected with nodavirus group of fish. PMID- 23092731 TI - Effect of Sophora flavescens on non-specific immune response of tilapia (GIFT Oreochromis niloticus) and disease resistance against Streptococcus agalactiae. AB - The paper describes the effect of a diet supplemented with the Chinese traditional herbal medicine Sophora flavescens on the immunity and disease resistance of an Oreochromis niloticus GIFT strain. Experimental diets containing 0.025%, 0.050%, 0.100%, 0.200%, and 0.400% S. flavescens, as well as a control group without S. flavescens were used. We tested the non-specific humoral immune responses (lysozyme, antiprotease, and complement) and cellular immune responses (reactive oxygen species and nitrogen species production and myeloperoxidase), as well as disease resistance against Streptococcus agalactiae. S. flavescens supplementation at all dose significantly enhanced serum lysozyme, antiprotease, and natural hemolytic complement activity. Similarly, all S. flavescens doses enhanced cellular myeloperoxidase activity. The increased production of reactive oxygen species and reactive nitrogen intermediates by peripheral blood leucocytes was observed in most of the treatment groups throughout the test period. The fish fed 0.100% S. flavescens had a percent mortality of 21.1% and a relative percent survival of 73.3% compared with the group fed the basal diet during the S. agalactiae challenge. The results suggest that S. flavescens can be recommended as a tilapia feed supplement to enhance fish immunity and disease resistance against S. agalactiae. PMID- 23092733 TI - Feeding truncated heat shock protein 70s protect Artemia franciscana against virulent Vibrio campbellii challenge. AB - The 70 kDa heat shock proteins (Hsp70s) are highly conserved in evolution, leading to striking similarities in structure and composition between eukaryotic Hsp70s and their homologs in prokaryotes. The eukaryotic Hsp70 like the DnaK (Escherichia coli equivalent Hsp70) protein, consist of three functionally distinct domains: an N-terminal 44-kDa ATPase portion, an 18-kDa peptide-binding domain and a C-terminal 10-kDa fragment. Previously, the amino acid sequence of eukaryotic (the brine shrimp Artemia franciscana) Hsp70 and DnaK proteins were shown to share a high degree of homology, particularly in the peptide-binding domain (59.6%, the putative innate immunity-activating portion) compared to the N terminal ATPase (48.8%) and the C-terminal lid domains (19.4%). Next to this remarkable conservation, these proteins have been shown to generate protective immunity in Artemia against pathogenic Vibrio campbellii. This study, aimed to unravel the Vibrio-protective domain of Hsp70s in vivo, demonstrated that gnotobiotically cultured Artemia fed with recombinant C-terminal fragment (containing the conserved peptide binding domain) of Artemia Hsp70 or DnaK protein were well protected against subsequent Vibrio challenge. In addition, the prophenoloxidase (proPO) system, at both mRNA and protein activity levels, was also markedly induced by these truncated proteins, suggesting epitope(s) responsible for priming the proPO system and presumably other immune-related genes, consequently boosting Artemia survival upon challenge with V. campbellii, might be located within this conserved region of the peptide binding domain. PMID- 23092734 TI - To BAM or not to BAM?: A closer look at balloon-assisted maturation. AB - BACKGROUND: Balloon assisted maturation (BAM) is a recent, innovative, yet controversial method for developing autogenous arterio-venous fistulae (AVF), with little supportive data. Few retrospective studies have addressed the efficacy of BAM and cofactors affecting successful maturation. We conducted a retrospective analysis of our vascular access database to compare possible factors associated with a successful BAM, as determined by increase in volume flow of the fistulae. METHODS: Between 2009 and 2010, data was prospectively collected on patients undergoing BAM of their AVF under ultrasound guidance at our institution. 30 of these patients, consisting of 143 BAMs, were retrospectively analyzed. Data collection included: past medical history, age, number of BAM procedures preformed, volume flow measurement (VFM) in mid fistulae, size of balloon used, and presence of post procedural wall hematoma. VFM was determined with duplex within one month prior to and subsequent to each BAM performed. RESULTS: Of the 30 patients, consisting of 143 BAMs, the average age was 69 years old + 15 (range 38-92) with 20 males and 10 females. The most common risk factors were hypertension (n = 27) and diabetes mellitus (n = 16). The average BAM per patient was 4.8 (range 1-7). Of the 143 BAM procedures, 4 were excluded due to absence of preoperative or postoperative duplex. In 139 BAMs, 74 developed a post procedural hematoma as observed on duplex, and 76 showed an increase in VFM. In all BAMs analyzed, there was no correlation observed between the presence of a hematoma and increase in VFM (P = 0.87). Hematomas occurred most frequently during the second BAM procedure, with 24.3% of all hematomas observed. In 139 BAMs, 8 different balloon sizes were used, 3 mm-10 mm, with the 7mm balloon being the most frequently used (n = 34). No significant difference was noted between increase in VFM in 3 mm to 7 mm balloons. A 8 mm balloon was used in 31 BAMs with 22 developing hematomas. Of the 8mm balloon group, a statistical difference was noted between percent increase in VFM with presence of a hematoma and percent increase in VFM without presence of a hematoma (P = 0.027). CONCLUSIONS: These preliminary data, suggest that a more aggressive approach to BAM, with use of larger balloons to create hematoma formation and minimizing excessive dilatation procedures, may have a significant impact on performing a successful maturation in respects to increase in VFM. PMID- 23092735 TI - Comparison of precuffed expanded polytetrafluorothylene and heparin-bonded polytetrafluorothylene graft in crural bypass. AB - BACKGROUND: The purpose of this study was to evaluate early and midterm results of tibial bypasses comparing precuffed expanded polytetrafluoroethylene (PTFE) graft (Distaflo) and heparin-bonded PTFE graft (Propaten) with a distal vein patch. METHODS: This is a retrospective cohort analysis evaluating patients who underwent PTFE femorocrural bypasses between April 2004 and December 2010 at the Vascular Surgery Division of the Poliambulanza Foundation Hospital (Brescia, Italy). Results were analyzed in terms of primary and secondary graft patency, limb salvage, and survival with univariate (Kaplan-Meier curves and log-rank test) and multivariate (Cox regression) analyses. RESULTS: After analyzing many patients, we found 79 femorotibial bypass PTFE grafts. We used a Propaten graft and vein patch in 40 patients and a Distaflo graft in 39 patients. The two groups were comparable for main risk factors, except for age. Indication for surgical revascularization was critical limb ischemia in all patients. In 54 cases (68%), it was a redo bypass because of a previously failed revascularization. Perioperative mortality within 30 days from intervention was 2.5%, whereas overall mortality during follow-up was 29%, with a 36-month survival rate of 58% (95% confidence interval [CI]: 0.44-0.77) on life table analysis. We observed a significant difference between two groups in terms of survival at 36 months (Propaten: 0.84 [95% CI: 0.69-1]; Distaflo: 0.21 [95% CI: 0.07-0.63]; P < 0.001; 95% CI: 0.07-0.63; odds ratio [OR]: 0.21). At 24 months, the two groups (Propaten vs. Distaflo) were equivalent in terms of primary patency (Propaten: 0.33 [95% CI: 0.21-0.53]; Distaflo: 0.47 [95% CI: 0.32-0.70]; P = 0.793), secondary patency (Propaten: 0.36 [95% CI: 0.23-0.57]; Distaflo: 0.49 [95% CI: 0.33-0.72]; P = 0.855), and limb salvage (Propaten: 0.65 [95% CI: 0.51-0.84]; Distaflo: 0.57 [95% CI: 0.41-0.79]; P = 0.18). At Cox regression analysis, age of >80 years (P < 0.04; 95% CI: 0.23-0.95; OR: 0.47), peroneal artery distal anastomosis (P < 0.04; 95% CI: 1.04-5.62; OR: 2.42), simultaneous adjunctive procedures (P < 0.02; 95% CI: 1.21-17.74; OR: 4.64), and redo bypass (P < 0.05; 95% CI: 1-6.26; OR: 2.5) were associated with long-term poorer primary patency rates. Postoperative treatment with warfarin therapy compared with antiplatelet therapy was independently associated with better secondary patency (P < 0.04; 95% CI: 0.20 0.95; OR: 0.44) and limb salvage (P < 0.03; 95% CI: 0.11-0.87; OR: 0.32) rates. CONCLUSIONS: Distaflo and Propaten with a distal vein patch in our experience have similar patency and limb salvage results, although further randomized and larger studies are necessary. Postoperative anticoagulation therapy seems better than antiplatelet therapy in terms of patency and limb salvage rate. PMID- 23092736 TI - Challenges and controversies in defining totally drug-resistant tuberculosis. AB - In March 2012, in response to reports of tuberculosis (TB) resistant to all anti TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug resistant TB. Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB. Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB. PMID- 23092737 TI - Coxsackievirus B3, Shandong Province, China, 1990-2010. AB - To determine the cause of a 2008 outbreak of aseptic meningitis in Shandong Province, China, we analyzed samples from outbreak patients and coxsackievirus B3 samples collected during 1990-2010 surveillance. The cause of the outbreak was coxsackievirus B3, genogroup D. Frequent travel might increase importation of other coxsackievirus B3 genogroups. PMID- 23092738 TI - N-cadherin+ HSCs in fetal liver exhibit higher long-term bone marrow reconstitution activity than N-cadherin- HSCs. AB - Adult hematopoietic stem cells (HSCs) are maintained in a microenvironment known as the stem cell niche. The regulation of HSCs in fetal liver (FL) and their niche, however, remains to be elucidated. In this study, we investigated the role of N-cadherin (N-cad) in the maintenance of HSCs during FL hematopoiesis. By using anti-N-cad antibodies (Abs) produced by our laboratory, we detected high N cad expression in embryonic day 12.5 (E12.5) mouse FL HSCs, but not in E15.5 and E18.5 FL. Immunofluorescence staining revealed that N-cad(+)c-Kit(+) and N-cad(+) endothelial protein C receptor (EPCR)(+) HSCs co-localized with Lyve-1(+) sinusoidal endothelial cells (ECs) in E12.5 FL and that some of these cells also expressed N-cad. However, N-cad(+) HSCs were also observed to detach from the perisinusoidal niche at E15.5 and E18.5, concomitant with a down-regulation of N cad and an up-regulation of E-cadherin (E-cad) in hepatic cells. Moreover, EPCR(+) long-term (LT)-HSCs were enriched in the N-cad(+)Lin(-)Sca-1(+)c-Kit(+) (LSK) fraction in E12.5 FL, but not in E15.5 or E18.5 FL. In a long-term reconstitution (LTR) activity assay, higher engraftment associated with N-cad(+) LSK cells versus N-cad(-) LSK cells in E12.5 FL when transplanted into lethally irradiated recipient mice. However, the higher engraftment of N-cad(+) LSK cells decreased subsequently in E15.5 and E18.5 FL. It is possible that N-cad expression conferred higher LTR activity to HSCs by facilitating interactions with the perisinusoidal niche, especially at E12.5. The down-regulation of N-cad during FL hematopoiesis may help us better understand the regulation and mobility of HSCs before migration into BM. PMID- 23092739 TI - Pandemic influenza outbreak on a troop ship--diary of a soldier in 1918. AB - A newly identified diary from a soldier in 1918 describes aspects of a troop ship outbreak of pandemic influenza. This diary is the only known document that describes this outbreak and provides information not officially documented concerning possible risk factors such as overcrowding and the suboptimal outbreak response by military leaders. It also presents an independent personal perspective of this overwhelming experience. PMID- 23092732 TI - Immune gene discovery by expressed sequence tag (EST) analysis of hemocytes in the ridgetail white prawn Exopalaemon carinicauda. AB - The ridgetail white prawn Exopalaemon carinicauda is one of the most important commercial species in eastern China. However, little information of immune genes in E. carinicauda has been reported. To identify distinctive genes associated with immunity, an expressed sequence tag (EST) library was constructed from hemocytes of E. carinicauda. A total of 3411 clones were sequenced, yielding 2853 ESTs and the average sequence length is 436 bp. The cluster and assembly analysis yielded 1053 unique sequences including 329 contigs and 724 singletons. Blast analysis identified 593 (56.3%) of the unique sequences as orthologs of genes from other organisms (E-value < 1e-5). Based on the COG and Gene Ontology (GO), 593 unique sequences were classified. Through comparison with previous studies, 153 genes assembled from 367 ESTs have been identified as possibly involved in defense or immune functions. These genes are categorized into seven categories according to their putative functions in shrimp immune system: antimicrobial peptides, prophenoloxidase activating system, antioxidant defense systems, chaperone proteins, clottable proteins, pattern recognition receptors and other immune-related genes. According to EST abundance, the major immune-related genes were thioredoxin (141, 4.94% of all ESTs) and calmodulin (14, 0.49% of all ESTs). The EST sequences of E. carinicauda hemocytes provide important information of the immune system and lay the groundwork for development of molecular markers related to disease resistance in prawn species. PMID- 23092740 TI - Hemodynamic and psychological responses to laboratory stressors in women: assessing the roles of menstrual cycle phase, premenstrual symptomatology, and sleep characteristics. AB - This study assessed whether premenstrual symptomatology and/or sleep characteristics explain increased luteal phase psychophysiological reactivity to laboratory stressors. We hypothesized that: (1) premenstrual symptoms and sleep characteristics would explain greater luteal versus follicular phase psychophysiological reactivity, (2) symptoms and sleep characteristics would differentially predict psychophysiological reactivity within each cycle phase, and (3) symptoms and sleep characteristics would interact to affect luteal but not follicular reactivity. Freely cycling women (N=87) completed two laboratory sessions, one follicular (cycle days 5-9) and one luteal (days 7-10 post ovulation). We employed two stressors: one physical (cold pressor task) and the other cognitive in nature (Paced Auditory Serial Addition Task). During testing, electrocardiography monitored heart rate (HR) while a timed and auto-inflatable sphygmomanometer assessed blood pressure (BP). Participants also completed a one time self-report measure of sleep characteristics and premenstrual symptomatology as well as a measure of state anxiety pre-post stressor. Results revealed greater luteal HR and systolic BP reactivity compared to follicular reactivity (p<0.001 for both analyses), however neither premenstrual symptoms nor sleep characteristics explained this luteal increase. Within cycle analyses revealed that symptoms and sleep characteristics interacted to affect luteal phase state anxiety reactivity (R(2)=.32, p=.002) with negative affect being associated with more reactivity when sleep hours were low (beta=.333, p=.04). Overall, significant relationships existed during the luteal phase only. Findings are discussed in terms of clinical utility and methodological challenges related to performing laboratory stress testing in women. PMID- 23092741 TI - Comparison of a web-based vs in-person nutrition education program for low-income adults. AB - As access to computers and the Internet by the low-income population is increasing and the "digital divide" is slowly diminishing, other methods of delivering nutrition information to this audience are evolving. This randomized, block equivalence trial sought to determine whether web-based nutrition education could result in equivalent nutrition-related behavior outcomes when compared with traditional in-person nutrition education in low-income adults. A convenience sample of low-income adults (n=123) was randomized to receive in-person education (n=66) or web-based education (n=57) in a community setting within 14 counties of Indiana from April through December 2010. The web-based group received three nutrition education lessons (eg, fruits and vegetables, Nutrition Facts label reading, and whole grains) designed to replicate lessons received by the in person group. Lessons were developed using Kolb's Learning Styles and Experiential Learning Model. Self-reported nutrition-related behaviors were assessed using a previously validated survey for low-income adults. Most nutrition-related behavior outcomes (eg, fruit, vegetable, whole-grain intake, Nutrition Facts label use, breakfast, and meal-planning frequency) improved significantly (P<0.05) from pre to post within both groups, meaning that each intervention was effective. When these nutrition-related behavior improvements were compared between groups, the changes were statistically equivalent (P>0.05), except for one question about use of the Nutrition Facts label. Therefore, web based nutrition education can lead to favorable and equivalent nutrition-related changes when compared with in-person delivery. Most (83%) web-based participants also reported willingness to use the website again. Future application of web based interventions for low-income populations could broaden delivery reach, increase frequency and length of contacts, and possibly decrease costs. PMID- 23092743 TI - [Prophylaxis and treatment of arterial hypotension during caesarean with spinal anaesthesia]. AB - Caesarean section is one of the most common surgical procedures worldwide. Arterial hypotension is the most prevalent adverse effect after spinal anaesthesia. Various methods have been used to prevent or treat hypotension. Since there is no treatment 100% effective by itself, a multimodal management is required to achieve an optimum balance and avoidance of hemodynamic imbalance. Strategies to avoid this side effect are analyzed on the basis of the best evidence available so far, summarized as mechanical factors, anesthetics, fluids and vasopressors. After spinal anaesthesia for caesarean section, the best strategy available for prevention of hypotension appears to be the combination of crystalloids along with an alpha 1 agonist vasopressor. PMID- 23092742 TI - Ethnicity and sepsis characteristics and outcomes. Population based study. AB - BACKGROUND: Two distinct ethnic groups live in Southern Israel: urban Jews and rural Bedouin Arabs. These groups differ in their socioeconomic status, culture and living environment, and are treated in a single regional tertiary care hospital. We hypothesized that these two ethnic groups have different patterns of sepsis-related intensive care admissions. METHODS: The study included all adult patients admitted to the Soroka University Medical Center Intensive Care Units between January 2002 and December 2008, with a diagnosis of sepsis. Demographic data, medical history, and hospitalization and outcomes data were obtained. Primary outcome was all-cause mortality. RESULTS: Jewish patients admitted to the ICU (1343, 87%) were on average 17 years older than Bedouin Arabs (199, 13%). For the population <65 years, Bedouin Arabs had slightly higher age-adjusted prevalence of ICU sepsis admissions than Jewish patients (39.5 vs. 43.0, p=0.25), while for the population >65 years there was a reverse trend (21.8 vs. 19.8 p=0.49). There were no differences in the type of organ failure, sepsis severity or length of hospitalization between the two groups. Twenty eight days/in hospital mortality was 33.9% in Bedouin Arabs vs. 45.5% in Jews, p=0.004. Following adjustment for comorbidities, age and severity of the disease, survival was unrelated to ethnicity, both at 28 days (odds ratio for Bedouin Arabs 0.86, 95% CI 0.66-1.24) and following hospital discharge (hazard ratio 0.86, 95% 0.67 1.09). CONCLUSIONS: Sepsis-related ICU admissions are more prevalent among Bedouin Arabs at younger age compared with the Jewish population. Adjusted for confounders, ethnicity does not influence prognosis. PMID- 23092744 TI - Mycoplasmosis in ferrets. AB - We report an outbreak of severe respiratory disease associated with a novel Mycoplasma species in ferrets. During 2009-2012, a respiratory disease characterized by nonproductive coughing affected ~8,000 ferrets, 6-8 weeks of age, which had been imported from a breeding facility in Canada. Almost 95% became ill, but almost none died. Treatments temporarily decreased all clinical signs except cough. Postmortem examinations of euthanized ferrets revealed bronchointerstitial pneumonia with prominent hyperplasia of bronchiole-associated lymphoid tissue. Immunohistochemical analysis with polyclonal antibody against Mycoplasma bovis demonstrated intense staining along the bronchiolar brush border. Bronchoalveolar lavage samples from 12 affected ferrets yielded fast growing, glucose-fermenting mycoplasmas. Nucleic acid sequence analysis of PCR derived amplicons from portions of the 16S rDNA and RNA polymerase B genes failed to identify the mycoplasmas but showed that they were most similar to M. molare and M. lagogenitalium. These findings indicate a causal association between the novel Mycoplasma species and the newly recognized pulmonary disease. PMID- 23092745 TI - Primary intraosseous squamous cell carcinoma arising in odontogenic cysts: an insight in pathogenesis. AB - PURPOSE: To present a case series of primary intraosseous squamous cell carcinoma arising in odontogenic cysts and review the published data to understand the pathogenesis of the lesion. MATERIALS AND METHODS: The files of the Department of Oral and Maxillofacial Surgery, Government Dental College and Hospital (Jaipur, India) were reviewed, and 3 cases of primary intraosseous squamous cell carcinoma ex odontogenic cyst diagnosed from 2006 to 2011 were identified. The diagnostic inclusion criteria were the presence of a completely intraosseous lesion; the absence of ulceration of the oral mucosa, except when caused by other factors such as tooth extraction or trauma; and the absence of a distant primary tumor. The malignant transformation of the benign cystic lining of an odontogenic cyst to squamous cell carcinoma was identified, and the diagnosis of primary intraosseous squamous cell carcinoma ex odontogenic cyst was confirmed in all cases. The relevant English data were reviewed to determine the possible etiopathologic factors associated with the lesion. RESULTS: It was observed that long-standing chronic inflammation in the benign odontogenic cyst was the most probable etiopathologic factor responsible for malignant transformation of a benign cystic lining. CONCLUSIONS: The signs of chronic inflammation in odontogenic cysts should be taken into consideration, and such lesions should be treated promptly. By doing so, we might reduce the rate of malignant transformation of benign odontogenic cysts. PMID- 23092746 TI - [A female patient with asthma in the emergency room]. AB - A 20-year-old woman, with intolerance to non-steroid anti-inflammatory drugs (NSAIDs) who was diagnosed of asthma 2 years earlier. Both her mother and brother were asthmatic. Non-smoker. Anosmia and rhinosinusitis symptoms. Several hospitalizations for asthmatic attacks, the last one, one month before in the ICU that did not require mechanical ventilation. Skin tests negative to aeroallergens. Better personal PEF: 450 l/min. Previous treatment: salmeterol/fluticasone 50/500 1 inh/12h. and formoterol p.r.n. She came to the emergency room by ambulance due to evolution of fever, expectoration and headache after having gone to her physician, who had prescribed metamizole and azithromycin. She returned at one hour due to difficult breathing and Sat O(2) 89%. The physical examination showed abdominal breathing, 40 rpm and Sat O(2) 92% with nebulizer at 6 bpm, PEF: 180 l/min, tachycardia at 150 bpm, generalized wheezing. Hemodynamically stable. Blood gases with O(2) to 6 bpm: 7.28 pH, 45 pCO(2), 66pO(2), 21.1 HCO(3), Chest X-ray: no consolidations. PMID- 23092747 TI - Communicating the experience of chronic pain and illness through blogging. AB - BACKGROUND: Although more individuals are sharing their experiences with chronic pain or illness through blogging (writing an Internet web log), research on the psychosocial effects and motivating factors for initiating and maintaining a blog is lacking. OBJECTIVE: The objective was to examine via online questionnaire the perceived psychosocial and health benefits of blogging among patients who use this media to communicate their experience of chronic pain or illness. METHODS: A 34-item online questionnaire was created, tested, and promoted through online health/disease forums. The survey employed convenience sampling and was open from May 5 to July 2, 2011. Respondents provided information regarding demographics, health condition, initiation and upkeep of blogs, and dynamics of online communication. Qualitative data regarding respondents' blogging experiences, expectations for blogging, and the perceived effects from blogging on the blogger's health, interpersonal relationships, and quality of life were collected in the form of written narrative. RESULTS: Out of 372 respondents who started the survey, 230 completed the entire questionnaire. Demographic data showed survey respondents to be predominantly female (81.8%) and highly educated (97.2% > high school education and 39.6% with graduate school or professional degrees). A wide spectrum of chronic pain and illness diagnoses and comorbidities were represented. Respondents reported that initiating and maintaining an illness blog resulted in increased connection with others, decreased isolation, and provided an opportunity to tell their illness story. Blogging promoted accountability (to self and others) and created opportunities for making meaning and gaining insights from the experience of illness, which nurtured a sense of purpose and furthered their understanding of their illness. CONCLUSIONS: Results suggest that blogging about chronic pain and illness may decrease a sense of isolation through the establishment of online connections with others and increases a sense of purpose to help others in similar situations. Further study involving a larger sample size, a wider range of education levels, and respondents with different types and magnitudes of illnesses will be needed to better elucidate the mechanism of the observed associations in this understudied area. PMID- 23092749 TI - Early inflammatory response of young rabbits attending natural resistance to calicivirus (RHDV) infection. AB - Young rabbits (i.e. up to 4 weeks of age) are naturally resistant to infection by rabbit haemorrhagic disease virus (RHDV), the same calicivirus that kills more than 90% of adult rabbits in 3 days or less. To characterize this fascinating model of age-related natural resistance to viral infection, we have studied the kinetics (from 6h up to 7 days) of cytokines and of leukocyte subpopulations in the liver (the target organ for calicivirus replication) and spleen (host systemic response) of RHDV infected young rabbits. Infection was associated with early (6h) elevation of proinflammatory cytokines (TNF-alpha, IL-1, IFN-alpha, IFN-gamma, IL-6, IL-8). We found that all three major leukocyte subpopulations (macrophages, B and T lymphocytes) were increased in the liver 48h after the RHDV inoculation. At 7 days of infection, B and T lymphocytes were still elevated in the liver of the rabbits. In the spleen, both macrophages and B lymphocytes (but not T cells) were also enhanced. At 7 days, anti-RHDV specific antibodies were present in sera of all young rabbits infected by the virus. We conclude that natural resistance of young rabbits to RHDV infection is associated with a rapid and effective inflammatory response by the liver, with few hepatocytes being infected, and also with a sustained elevation in local and systemic B and T cells. PMID- 23092748 TI - Effects of dietary yeast strains on immunoglobulin in colostrum and milk of sows. AB - The ban of antibiotic growth promoters in pig diet required the development of alternative strategies and reinforced the importance of maternal immunity to protect neonates from intestinal disorders. Milk from sows fed active dry yeasts during gestation and lactation exhibited higher immunoglobulin (Ig) and protein content in milk at day 21 of lactation. In this study, we investigated whether the administration of Saccharomyces cerevisiae strains of various origins (Sc01, Sc02, Sb03) to sows during late gestation and lactation could induce higher Ig content in colostrum and milk. Results show that yeast supplementation did not increase significantly sow body weight at days 112 of gestation and 18 of lactation as well as piglet body weight gain from birth to weaning. In contrast, the IgG level in colostrum was increased in comparison with the control group when sows were supplemented with Sc01 at both 0.05 and 0.5% (p<0.05) and Sb03 at 0.5% (p<0.01). During the lactation, the level of milk IgG remained significantly higher in comparison with the control group when sows were supplemented with Sc02 at 0.05% and 0.5% and with Sb03 at 0.5%. Furthermore, in comparison with the control sows, the level of milk IgA was significantly maintained in sows supplemented with the 3 yeast strains at 0.05%. The incidence of piglet diarrhoea was decreased in groups Sc01 at both 0.05% and 0.5% and Sc02 at 0.05%. Thus, these results show that the 3 yeast strains display immunostimulatory effects on maternal immunity, but only Sc01 supplementation at 0.05% allowed jointly the increase of IgG level in colostrum, the maintenance of IgA level in milk and the decrease of piglet diarrhoea incidence. This stimulation of maternal immunity could be associated with a better systemic (colostrum IgG) and local (milk IgA) protection of neonates and suggests that dietary yeasts may have stimulated the local gut immune system of sows. PMID- 23092750 TI - Incidence of venous thromboembolism in psychiatric units. AB - INTRODUCTION: Incidence and risk factors of venous thromboembolism (VTE) are well established in surgical and medical settings, but data in psychiatric units are lacking. The aim of this study was to estimate the incidence of VTE in hospitalized psychiatric patients, and to assess the risk factors for VTE in this specific population. MATERIALS AND METHODS: All consecutive adult patients, admitted for a psychiatric disorder for at least seven days in psychiatric units were considered for inclusion. Patients were evaluated for signs and symptoms of VTE during hospitalization. At Day 10, all participants were interviewed and a systematic compression ultrasonography of the lower limbs was performed. Patients were followed-up until Day 90. RESULTS: Among the 471 included patients, 449 were evaluable at Day 10, and 458 were followed-up until Day 90. Ten deep vein thromboses (DVT) were diagnosed by Day 10 leading to an incidence of VTE of 2.2% (95% CI, 1.1%-4.1%). Six additional symptomatic VTE occurred between Day 10 and Day 90, leading to a 3.5% incidence at Day 90 (95% CI, 2.0%-5.6%). The main factors associated with VTE were age, bed rest, and diagnosis of dementia. The incidence of VTE in patients aged 75 or over with a diagnosis of dementia reached 8.2% at Day 10 and 12.5% at Day 90. CONCLUSIONS: The incidence of VTE in psychiatric units appeared low. However, in older patients, especially those with dementia, the incidence of VTE increased considerably. Further studies are needed to confirm these results. PMID- 23092751 TI - An exploration of species boundaries in turret-building tarantulas of the Mojave Desert (Araneae, Mygalomorphae, Theraphosidae, Aphonopelma). AB - Tarantulas in the North American genus Aphonopelma are poorly known due to their challenging patterns of morphological variation and questionable taxonomy; few specimens can be confidently identified using existing keys or comparisons to original descriptions. In an effort to identify new strategies for resolving what has been characterized as a "taxonomic and nomenclatural nightmare", we employed five different approaches for delimiting species in a group of closely related tarantulas from the Mojave Desert in the southwestern United States. These methods included the application of single techniques (morphology, DNA barcoding, shared genealogical exclusivity among independent loci, and generalized mixed Yule coalescent) and an integrative approach that incorporates genealogical and ecological information. Results demonstrate that the taxonomy of these spiders as presently defined underestimates actual species-level diversity and the group is in need of revision. The number of species delimited by each approach, however, was variable and we argue that it is this discordance that emphasizes the importance of incorporating multiple lines of evidence into an integrative taxonomic framework that can be used for constructing robust taxonomic hypotheses for Aphonopelma species. PMID- 23092752 TI - Characterization of methicillin-resistant Staphylococcus aureus from skin and soft tissue infections in patients in Nairobi, Kenya. AB - BACKGROUND: Skin and soft tissue infections (SSTIs) are among the most common infectious diseases and a frequent cause of hospital visits. In this study we sought to assess the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and antibiotic susceptibility patterns in SSTIs in patients attending hospitals in Kenya. METHODS: Eighty-two S. aureus isolates recovered from SSTIs from both inpatients and outpatients were screened for antibiotic susceptibility, possession of staphylococcal cassette chromosome mec (SCCmec) gene type, and the Panton-Valentine leukocidin (PVL) toxin gene. The prevalence of MRSA was investigated in relation to the type of patient and infection type, as well as the type of health care facility. RESULTS: Of 60 boil cultures, 39 (65%) grew S. aureus, of out of which 34 (87.2%) were MRSA. Of the 60 abscess cultures, 14 (23.3%) grew S. aureus, of which 10 (71.4%) were MRSA. Of 34 cellulitis cultures, 18 (52.9%) grew S. aureus, of which 16 (88.8%) were MRSA. Of 25 ulcer cultures, 11 (44%) grew S. aureus, of which nine (81.8%) were MRSA. Sixty-nine of 82 S. aureus (84.1%) were MRSA, with 52 (75.4%) possessing SCCmec II type and 14 (20.3%) being positive for the PVL gene. Based on hospitals, it was noted that most MRSA were isolated at publicly funded health care facilities serving an economically disadvantaged segment of Nairobi's population, such as those living in urban informal settlements. All 82 S. aureus were susceptible to vancomycin and resistant in high numbers to macrolides, aminoglycosides, and quinolones. Bacterial isolates were mostly susceptible to vancomycin, ciprofloxacin and co trimoxazole, and none was resistant to vancomycin. However, most organisms showed decreased susceptibility to erythromycin and clindamycin. CONCLUSIONS: These findings suggest that SCCmec II MRSA and a PVL strain of MRSA are significant pathogens in patients with SSTIs presenting to hospitals in Kenya, and that MRSA cases are prevalent at publicly funded health care facilities. PMID- 23092753 TI - Microtubule catastrophe and rescue. AB - Microtubules are long cylindrical polymers composed of tubulin subunits. In cells, microtubules play an essential role in architecture and motility. For example, microtubules give shape to cells, serve as intracellular transport tracks, and act as key elements in important cellular structures such as axonemes and mitotic spindles. To accomplish these varied functions, networks of microtubules in cells are very dynamic, continuously remodeling through stochastic length fluctuations at the ends of individual microtubules. The dynamic behavior at the end of an individual microtubule is termed 'dynamic instability'. This behavior manifests itself by periods of persistent microtubule growth interrupted by occasional switching to rapid shrinkage (called microtubule 'catastrophe'), and then by switching back from shrinkage to growth (called microtubule 'rescue'). In this review, we summarize recent findings which provide new insights into the mechanisms of microtubule catastrophe and rescue, and discuss the impact of these findings in regards to the role of microtubule dynamics inside of cells. PMID- 23092755 TI - Increased familiarity with eating a food to fullness underlies increased expected satiety. AB - Expected satiety informs self-selected portion sizes and thereby influences energy intake. At present the extent to which these beliefs are learned remains unclear. In an initial study the proposition that familiarity influences expected satiety was explored. Self-report measures of familiarity, along with other measures such as degree of liking, were collected for wine gums and milk chocolate, together with expected satiety estimates obtained using a psychophysical task. Familiarity was indeed significantly correlated with expected satiety, but only in respect of frequency of having eaten the food to fullness. In a second experiment a significant increase in expected satiety was observed after eating a large portion of wine gums at a subsequent test session. Together, these findings indicate that expected satiety changes in response to increased familiarity of eating a food to satiety. PMID- 23092756 TI - Research needs on food marketing to children. Report of the StanMark project. AB - A series of meetings on the topic of children's exposure to the marketing of food and beverages was held between researchers and government officials based in Europe and the Americas during 2010-2011. The meetings resulted in a number of outputs, including observations from policy-makers on the types of evidence they needed to strengthen policy-making. Their observations on the definitions of a child, the specification of foods using nutrient profiling schemes, the types of media carrying marketing messages, and the related policy implementation problems, are summarised in this Short Communication. The paper highlights the need for research which can directly support policy-making and which can evaluate its effectiveness. PMID- 23092754 TI - Signaling networks in human pluripotent stem cells. AB - Maintaining a finely-balanced network of signaling inputs is critical for the maintenance of pluripotent stem cells. Together, signaling pathways achieve this by maintaining a long-term, proliferative state while suppressing differentiation. Although the major pathways involved in pluripotency have been known for some time, it was not previously clear how they function in concert to maintain stem cell identity. Recent work has identified a signaling network involving cross-talk between PI3K, TGFbeta, MAPK and Wnt pathways that culminate in a finely-balanced molecular switch that determines the fate of pluripotent cells. PMID- 23092757 TI - Risk of disordered eating attitudes among adolescents in seven Arab countries by gender and obesity: a cross-cultural study. AB - The objectives were to discover the prevalence of disordered eating attitudes (EAs) among adolescent males and females, and the association of obesity with EA in seven Arab countries. A multistage stratified sampling technique was used to select secondary students aged 15-18 years from cities in Algeria, Jordan, Kuwait, Libya, Palestine, Syria and Sharijah Emirate (United Arab Emirates). The total sample was 4698 (2240 males and 2458 females). The Eating Attitudes Test (EAT-26) was used to measure those at risk of disordered EA. Obesity was calculated according to the International Obesity Taskforce criteria. Participants were grouped into two categories, non-obese and obese (overweight and obese). The risk of disordered EA was twice as high among females as in males in Jordan, Libya, Palestine and Syria. Kuwaiti adolescents (males and females) showed higher prevalence of disordered EA than their counterparts in other countries. The risk of disordered EA among obese adolescents was two to three times higher than that of non-obese adolescents, in both genders. Excepting Kuwaiti females and Palestinian males. The association of obesity with disordered EA was statistically significant. This study highlighted the magnitude of the risk of disordered eating attitudes among both male and female adolescents in Arab countries and identified the need for programmes to prevent and control these disorders in the Arab region. PMID- 23092758 TI - Accessing packaged food and beverages in hospital. Exploring experiences of patients and staff. AB - Food and beverage packaging has been identified as a contributing factor to malnutrition among elderly patients in hospitals. The focus of this research was to describe the types of food and beverage packaging used in NSW hospitals, determine the 'problematic' packaging from the users' perspective, investigate the effect of hand strength on the ability to open the packaging and to survey users' (patients and staff) views on the 'accessibility' of the packaging. The study was conducted in the Illawarra region of NSW, Australia. Participants (140 mostly elderly inpatients and 64 staff members) were recruited from four local public hospitals. Data were collected using interviews, questionnaires, observations and grip strength testing. Several food and beverage packages were found difficult to open by at least 40% of patients. These included milk and juices (52%), cereal (49%), condiments (46%), tetra packs (40%) and water bottles (40%). The difficulties were attributed to 'fiddly' packaging, hand strength and vision; however, only tetra packs demonstrated a relationship between time taken to open and hand strength, suggesting other aspects of hand function may be more important than strength when opening food and beverage packages. PMID- 23092760 TI - Nut consumption and incidence of metabolic syndrome after 6-year follow-up: the SUN (Seguimiento Universidad de Navarra, University of Navarra Follow-up) cohort. AB - OBJECTIVE: To assess the long-term relationship between tree nut consumption and the risk of developing metabolic syndrome (MetS). DESIGN: Nut consumption was collected using a validated 136-item FFQ. The MetS was defined according to the International Diabetes Federation and American Heart Association/National Heart, Lung, and Blood Institute harmonizing definition. The association between nut consumption and MetS was assessed with logistic regression models adjusting for potential confounders. We compared the incidence of MetS between extreme categories of nut intake (> or = 2 servings/week v. never/almost never) after 6 years of follow-up. SETTING: The SUN Project (Seguimiento Universidad de Navarra, University of Navarra Follow-up) is a prospective cohort study, formed of Spanish university graduates. Information is gathered by mailed questionnaires collected biennially. Nut consumption and MetS information was collected by self-reported data. SUBJECTS: Participants (n 9887) initially free of MetS or diabetes and followed up for a minimum of 6 years were included. RESULTS: We observed 567 new cases of MetS during follow-up. Participants who consumed nuts > or = 2 servings/week presented a 32% lower risk of developing MetS than those who never/almost never consumed (adjusted OR = 0.68, 95% CI 0.50, 0.92). The inverse association was stronger among participants who were health professionals. CONCLUSIONS: Nut consumption was significantly associated with lower risk of developing MetS after a 6-year follow-up period in a cohort of Spanish graduates. PMID- 23092761 TI - Dreaming of mathematical neuroscience for half a century. AB - Theoreticians have been enchanted by the secrets of the brain for many years: how and why does it work so well? There has been a long history of searching for its mechanisms. Theoretical or even mathematical scientists have proposed various models of neural networks which has led to the birth of a new field of research. We can think of the 'pre-historic' period of Rashevski and Wiener, and then the period of perceptrons which is the beginning of learning machines, neurodynamics approaches, and further connectionist approaches. Now is currently the period of computational neuroscience. I have been working in this field for nearly half a century, and have experienced its repeated rise and fall. Now having reached very old age, I would like to state my own endeavors on establishing mathematical neuroscience for half a century, from a personal, even biased, point of view. It would be my pleasure if my experiences could encourage young researchers to participate in mathematical neuroscience. PMID- 23092759 TI - Upregulation of phagocyte-like NADPH oxidase by cytokines in pancreatic beta cells: attenuation of oxidative and nitrosative stress by 2-bromopalmitate. AB - Phagocyte-like NADPH oxidase (Nox2) has been shown to play regulatory roles in the metabolic dysfunction of the islet beta-cell under the duress of glucolipotoxic conditions and exposure to proinflammatory cytokines. However, the precise mechanisms underlying Nox2 activation by these stimuli remain less understood. To this end, we report a time-dependent phosphorylation of p47phox, a cytosolic subunit of Nox2, by cytomix (IL-1beta+TNFalpha+IFNgamma) in insulin secreting INS-1 832/13 cells. Furthermore, cytomix induced the expression of gp91phox, a membrane component of Nox2. 2-Bromopalmitate (2-BP), a known inhibitor of protein palmitoylation, markedly attenuated cytokine-induced, Nox2 mediated reactive oxygen species (ROS) generation and inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) generation. However, 2-BP failed to exert any significant effects on cytomix-induced CHOP expression, a marker for endoplasmic reticulum stress. Together, our findings identify palmitoyltransferase as a target for inhibition of cytomix-induced oxidative (ROS generation) and nitrosative (NO generation) stress in the pancreatic beta-cell. PMID- 23092762 TI - Extensively drug-resistant tuberculosis, Central China, 2007-2009. PMID- 23092763 TI - Is there a high incidence of hysterectomy and other nonbladder surgeries before and after onset of interstitial cystitis/bladder pain syndrome? AB - OBJECTIVE: The objective of the study was to compare with controls the incidence of nonbladder pelvic surgeries in the months before and after the onset of interstitial cystitis/bladder pain syndrome (IC/BPS). STUDY DESIGN: The design of the study used an existing database from a retrospective case-control study of 312 incident IC/BPS cases and matched controls plus a longitudinal study of the cases that examined lifetime approximated annual incidence of surgeries with that in the months before and after the onset of IC/BPS. RESULTS: In cases, in the month before the onset of IC/BPS, the approximated annual incidence of nonbladder pelvic surgeries was 15 times higher and of hysterectomy 25 times higher than the incidences of previous years and similarly higher than controls. This rate declined to preindex levels over the first 2 years of IC/BPS. CONCLUSION: There may be a very high incidence of nonbladder surgeries just before IC/BPS onset that decreases to historical levels over the first years of the syndrome. PMID- 23092765 TI - Discussion: 'Risk of repeat clinical chorioamnionitis,' by Cohen-Cline et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. PMID- 23092766 TI - Incidence of gastrointestinal cancers by ethnic group in England, 2001-2007. AB - OBJECTIVE: To compare the incidence of six gastrointestinal cancers (colorectal, oesophageal, gastric, liver, gallbladder and pancreatic) among the six main 'non White' ethnic groups in England (Indian, Pakistani, Bangladeshi, Black African, Black Caribbean and Chinese) to each other and to Whites. METHODS: We analysed all 378 511 gastrointestinal cancer registrations from 2001-2007 in England. Ethnicity was obtained by linkage to the Hospital Episodes Statistics database and we used mid-year population estimates from 2001-2007. Incidence rate ratios adjusted for age, sex and income were calculated, comparing the six ethnic groups (and combined 'South Asian' and 'Black' groups) to Whites and to each other. RESULTS: There were significant differences in the incidence of all six cancers between the ethnic groups (all p<0.001). In general, the 'non-White' groups had a lower incidence of colorectal, oesophageal and pancreatic cancer compared to Whites and a higher incidence of liver and gallbladder cancer. Gastric cancer incidence was lower in South Asians but higher in Blacks and Chinese. There was strong evidence of differences in risk between Indians, Pakistanis and Bangladeshis for cancer of the oesophagus, stomach, liver and gallbladder (all p<0.001) and between Black Africans and Black Caribbeans for liver and gallbladder cancer (both p<0.001). CONCLUSIONS: The risk of gastrointestinal cancers varies greatly by individual ethnic group, including within those groups that have traditionally been grouped together (South Asians and Blacks). Many of these differences are not readily explained by known risk factors and suggest that important, potentially modifiable causes of these cancers are still to be discovered. PMID- 23092767 TI - The many facets of stress urinary incontinence. PMID- 23092768 TI - What causes stress incontinence: Fallacies, fascias and facts. AB - The traditional view of the pathophysiology of stress urinary incontinence (SUI) was that a loss of urethral support was the primary abnormality present. Recent research has challenged this hypothesis, demonstrating that impaired urethral function plays the key causative role. Improving our understanding of the underlying pathologic mechanisms is important to identifying the cause of treatment failures and for developing novel therapies to treat SUI. PMID- 23092769 TI - What is an evidence-based appropriate workup? AB - At the present time, there is no evidence-based guidance available for workup of stress urinary incontinence (SUI). In the absence of such evidence, we must rely on expert consensus, which dictates that a workup should typically include documentation of SUI, assessment of impact on the patient, and information on voiding function. Typical assessment may need to be adjusted for more complicated populations (e.g., those with mixed incontinence, those who have failed previous treatment). PMID- 23092770 TI - Surgical management of stress urinary incontinence: A rational approach to treatment selection. AB - There are a number of operative approaches to correct stress urinary incontinence (SUI). There is clearly not one procedure that "fits all." This review provides a summary of key available data comparing the various interventions. These findings are then incorporated into an algorithm, which attempts to outline a rational approach to select the most appropriate procedures in women seeking surgical treatment of SUI. PMID- 23092771 TI - Complications of midurethral slings and their management. AB - While midurethral slings are associated with a low rate of morbidity, complications can arise intraoperatively or following the procedure. Management of midurethral sling complications is relatively straightforward and urgency is dictated by the severity of the complications, potential for long-term negative effects, and bother to the patient. PMID- 23092772 TI - Evaluation and management of the patient with a failed midurethral synthetic sling. AB - While most women will do well following placement of a midurethral sling (MUS), a substantial minority do experience surgical failure. There are several risk factors that can help identify a patient at higher risk for failure, including body mass index greater than 25 kg/m(2), mixed incontinence, previous continence surgery, intrinsic sphincter deficiency, and diabetes. At the present time, there is no evidence-based guidance for which intervention to use following failure. Careful evaluation of patient characteristics will help guide subsequent management. PMID- 23092773 TI - Stress urinary incontinence: A case-based discussion. AB - At the conclusion of the sessions on stress urinary incontinence (SUI) in women, participants at the 2012 Canadian Urology Forum (academic and clinical urologists from across Canada) engaged in a discussion of optimal SUI evaluation and management. The discussion was led by Dr. Lesley Carr and co-facilitated by the other members of the Forum's steering committee and was based on a patient case. This review provides a summary of the case and the discussion it generated. PMID- 23092774 TI - How do you define success in stress urinary incontinence treatment? AB - At present, there is no consensus on the best way to define treatment success in the context of stress urinary incontinence (SUI). There is, however, a recognition that it is important to include patient-reported outcomes among the core assessments. Going forward, there is a need to unite outcome reporting tools to be able to compare data across studies and perform meaningful meta-analyses. PMID- 23092775 TI - The challenges of lower urinary tract symptoms in men. PMID- 23092776 TI - Benign prostatic hyperplasia and lower urinary tract symptom guidelines. AB - Lower urinary tract symptoms (LUTS) are very common in men, with incidence increasing with age. Several clinical practice guidelines are available as decision-making aids for men with LUTS and the recommendations are based on the presumed etiology of the symptoms (due to obstruction, overactive bladder or a combination of the two). This review presents the various pharmacologic treatment options and summarizes key clinical trial data supporting their use. PMID- 23092777 TI - Lower urinary tract symptoms associated with prostatitis. AB - Approximately 50% to 60% of men with chronic prostatitis experience troublesome lower urinary tract symptoms (LUTS). Individual interventions yield statistically significant but minimally important improvements in clinical trials. Research has shown that categorizing patients with prostatitis by phenotype is an effective way to rationally select therapy and maximize the impact on symptom reduction and improve quality of life. PMID- 23092778 TI - Male lower urinary tract symptoms associated with overactive bladder. AB - Lower urinary tract symptoms (LUTS) associated with overactive bladder (OAB) are more likely to respond to antimuscarinic therapy than to alpha blockade. As such, initial treatment of men with storage symptoms should incorporate an antimuscarinic agent. For men who are truly refractory to current pharmacotherapies, there is emerging evidence to support the use of botulinum toxin A. PMID- 23092779 TI - The dilemma of nocturia. AB - Patients with nocturia are often referred to urologists, but the underlying cause most often lies outside the urinary tract. Nocturia should be considered a systemic disorder and investigated and treated as such. Comprehensive assessment of the symptoms, optimally including a frequency volume chart, can help to determine the potential underlying cause and help to direct the patient to the most suitable medical professional for further management. PMID- 23092780 TI - Appropriate workup for lower urinary tract symptoms in men. AB - For most men with lower urinary tract symptoms (LUTS), the initial workup should consist of a careful history and physical examination, with or without simple adjunctive tests (e.g., uroflowometry, post-void residual, and frequency volume charts). Based on this basic workup, one is usually able to make an informed selection of initial treatment or watchful waiting. Urodynamics, cystoscopy and imaging are most useful in select cases when a specific reason is identified, the diagnosis is uncertain or when patients have failed simple initial treatments and seek further therapy. PMID- 23092781 TI - Overview of interventional treatment options for benign prostatic hyperplasia. AB - Transurethral resection of the prostate (TURP) remains the gold standard surgical intervention for men with benign prostatic hyperplasia (BPH). However, there are other, newer technologies that have also demonstrated safety and efficacy at least equivalent to that of TURP (e.g., Holmium laser, photoselective vaporization of the prostate). These minimally invasive techniques may be particularly useful for selected patient populations (e.g., those on anticoagulant therapy). PMID- 23092783 TI - Stress urinary incontinence in women and lower urinary tract symptoms in men: What are the remaining questions? PMID- 23092782 TI - Lower urinary tract symptoms in men: A case-based discussion. AB - At the conclusion of the sessions on lower urinary tract symptoms (LUTS) in men, participants at the 2012 Canadian Urology Forum (academic and clinical urologists from across Canada) engaged in a discussion of optimal LUTS evaluation and management. The discussion was led by Dr. J. Curtis Nickel and was based on a patient case. This review provides a summary of the case and the discussion it generated. PMID- 23092785 TI - One year intermittent rifaximin plus fibre supplementation vs. fibre supplementation alone to prevent diverticulitis recurrence: a proof-of-concept study. AB - BACKGROUND: Evidence supporting appropriate medical therapy to prevent recurrence of colonic diverticulitis is limited. Our goal was to evaluate the potential of rifaximin given periodically in addition to fibre for the prophylaxis of recurrences. METHODS: We conducted a multicentre, randomized, open controlled study in patients with a recent episode of colonic diverticulitis, currently in remission. Patients received 3.5 g of high-fibre supplementation b.d. with or without one week per month of the non-absorbable antibiotic rifaximin (400 mg b.d.) for 12months. Primary endpoint was recurrence of diverticulitis, encompassing acute symptomatic flare with or without complications, analyzed by multivariable logistic regression analysis and by Cox proportional hazard method. RESULTS: After randomizing 165 patients, the study was interrupted since the recruitment rate was largely below the minimum anticipated, and the trial was switched from evidence-gathering to proof-of-concept. Recurrences occurred in 10.4% of patients given rifaximin plus fibres vs. 19.3% of patients receiving fibres alone. The logistic analysis adjusted for sex, age, illness duration, time from last episode, disease localization and centre recruitment rate, yielded a significant treatment effect (odds ratio 3.20; 95% confidence interval: 1.16 8.82; P=0.025). Patients with diverticulitis diagnosed since >=1 year receiving rifaximin also had a lower incidence of recurrences (10%; 95% confidence interval: 2-47% vs. 67%; 95% confidence interval: 37-100%). Both treatments were safe. CONCLUSIONS: This study represents a proof-of concept of the efficacy of cyclic rifaximin treatment, added to fibre supplements, to reduce the risk of recurrences of diverticulitis in patients in remission. PMID- 23092786 TI - Spontaneous resolution of an inflammatory pseudotumour of the lung subsequent to wedge biopsy. AB - Spontaneous, complete resolution of inflammatory pseudotumour (IPT) of lungs is exceptionally rare. A 44-year-old male was referred for evaluation for "non resolving pneumonitis". He had cough and minimal expectoration for 5 months, chest pain, haemoptysis and fever for a fortnight. Computed tomography of thorax (CT-thorax) confirmed the presence of a homogenous mass with irregular borders in right middle lobe with areas of breakdown and air bronchogram. Transbronchial lung biopsy was suggestive of "plasma cell granuloma". Thoracotomy disclosed a hard mass in right middle lobe adherent to lower lobe, chest wall and mediastinum which could not be removed. A wedge biopsy confirmed IPT. Chest radiograph after 4 weeks revealed significant resolution. CT-thorax a year later showed fibrotic scar. Till date, there are only five reports documenting 6 patients with spontaneous resolution of IPT of lungs and in 4 this occurred within 3 months of an invasive diagnostic intervention. PMID- 23092784 TI - Acute costs and predictors of higher treatment costs of trauma in New South Wales, Australia. AB - BACKGROUND: Accurate economic data are fundamental for improving current funding models and ultimately in promoting the efficient delivery of services. The financial burden of a high trauma casemix to designated trauma centres in Australia has not been previously determined, and there is some evidence that the episode funding model used in Australia results in the underfunding of trauma. AIM: To describe the costs of acute trauma admissions in trauma centres, identify predictors of higher treatment costs and cost variance in New South Wales (NSW), Australia. MATERIALS AND METHODS: Data linkage of admitted trauma patient and financial data provided by 12 Level 1 NSW trauma centres for the 08/09 financial year was performed. Demographic, injury details and injury scores were obtained from trauma registries. Individual patient general ledger costs (actual trauma patient costs), Australian Refined Diagnostic Related Groups (AR-DRG) and state wide average costs (which form the basis of funding) were obtained. The actual costs incurred by the hospital were then compared with the state-wide AR-DRG average costs. Multivariable multiple linear regression was used for identifying predictors of costs. RESULTS: There were 17,522 patients, the average per patient cost was $10,603 and the median was $4628 (interquartile range: $2179-10,148). The actual costs incurred by trauma centres were on average $134 per bed day above AR-DRG costs-determined costs. Falls, road trauma and violence were the highest causes of total cost. Motor cyclists and pedestrians had higher median costs than motor vehicle occupants. As a result of greater numbers, patients with minor injury had comparable total costs with those generated by patients with severe injury. However the median cost of severely injured patients was nearly four times greater. The count of body regions injured, sex, length of stay, serious traumatic brain injury and admission to the Intensive Care Unit were significantly associated with increased costs (p<0.001). CONCLUSION: This multicentre trauma costing study demonstrated the feasibility of trauma registry and financial data linkage. Discrepancies between the observed costs of care in these 12 trauma centres and the NSW average AR-DRG costs suggest that trauma care is currently underfunded in NSW. PMID- 23092787 TI - Patient experience in the pediatric otolaryngology clinic: does the teaching setting influence parent satisfaction? AB - OBJECTIVES: Patient experience scores are now recognized as a chief indicator of healthcare quality. This report compares outpatient pediatric otolaryngology patient satisfaction in the teaching and non-teaching settings. STUDY DESIGN: Cross-sectional, multi-site, patient-level analysis of satisfaction surveys (Press GaneyTM Medical Practice(c)) completed by parents of pediatric otolaryngology patients in FY2010. METHODS: Surveys were stratified by teaching/non-teaching affiliation. The survey has 29 Likert-scaled questions which comprise an overall score and subscores in 6 domains: access, visit, nursing, provider, personal issues, and assessment. The item likelihood-to recommend was measured to indicate practice loyalty. Mean scores were compared by Kruskal-Wallis rank test. Multivariate logistic regression was performed to evaluate the association of teaching status with receipt of highest scores (HI SCORES). RESULTS: 4704 pediatric surveys were analyzed, with 1984 (42%) from the teaching setting. For the teaching setting, mean scores were lower overall (88.1 vs. 89.0; p<0.001) and in domains of access (includes scheduling ease, promptness in returning calls; 86.7 vs. 89.4; p<0.001) and personal issues (includes office hour convenience, sensitivity to needs; 87.0 vs. 88.5; p<0.001). Differences in access scores were largest for young children (0-<6 years; 86.0 vs. 89.5; p<0.001). Children in the teaching setting were less likely to have HI-SCORES overall (OR 0.78; 95%CI 0.65-0.95; p=0.011) and for access (OR 0.8; 95%CI 0.67 0.95; p=0.012); probability of HI-SCORES was similar for the two settings for all other domains. CONCLUSIONS: Parents of pediatric otolaryngology patients evaluated in the teaching setting report lower satisfaction related to access, but similar scores for care providers and practice loyalty. Academic otolaryngology practices might focus on access issues to improve the overall care experience for children and families. PMID- 23092788 TI - Electroacupuncture interferes with bispectral index monitoring. PMID- 23092789 TI - Neoadjuvant chemoradiotherapy for patients with high-risk extremity and truncal sarcomas: a 10-year single institution retrospective study. AB - BACKGROUND: Patients with large, high-grade extremity and truncal soft tissue sarcomas (STS) are at considerable risk for recurrence. A regimen of pre operative chemotherapy consisting of mesna, adriamycin, ifosfamide and dacarbazine (MAID), interdigitated with radiotherapy (RT), followed by resection and post-operative chemotherapy with or without RT, has demonstrated high rates of local and distant control. The goal of this study is to assess outcomes in a recent cohort of patients treated on this regimen. METHODS: We retrospectively reviewed records of 66 consecutive patients with STS of the extremity or trunk who were treated with the aforementioned regimen from May 2000 to April 2011. Clinicopathologic characteristics and patient outcomes were analysed. RESULTS: Sixty-six patients were analysed and were equally divided between grade 2 and 3 tumours. Margins were negative in 57 (89%) patients and positive in seven (11%) patients. At a median follow-up of 46 months, there were six (9%) locoregional and 20 (30%) distant recurrences. The locoregional and distant 5-year recurrence free survival (RFS) rates were 91% and 64%, respectively. The 5-year overall (OS) and disease-specific survival rates were 86% and 89%, respectively. There were no treatment-related deaths or secondary myelodysplasias. Thirty-four (52%) patients had grade 3 or 4 acute haematologic chemotherapy-related toxicity. There were no statistically significant predictors of OS or RFS. CONCLUSIONS: For a contemporary cohort of patients with high-risk extremity and truncal STS, a regimen of neoadjuvant chemoradiotherapy and surgery continues to result in high rates of survival with tolerable short- and long-term toxicity. PMID- 23092790 TI - Identification of the protein target of myelin-binding ligands by immunohistochemistry and biochemical analyses. AB - The ability to visualize myelin is important in the diagnosis of demyelinating disorders and the detection of myelin-containing nerves during surgery. The development of myelin-selective imaging agents requires that a defined target for these agents be identified and that a robust assay against the target be developed to allow for assessment of structure-activity relationships. We describe an immunohistochemical analysis and a fluorescence polarization binding assay using purified myelin basic protein (MBP) that provides quantitative evidence that MBP is the molecular binding partner of previously described myelin selective fluorescent dyes such as BMB, GE3082, and GE3111. PMID- 23092792 TI - The Osteoarthritis Initiative (OAI) magnetic resonance imaging quality assurance update. AB - OBJECTIVE: Longitudinal quantitative evaluation of cartilage disease requires reproducible measurements over time. We report 8 years of quality assurance (QA) metrics for quantitative magnetic resonance (MR) knee analyses from the Osteoarthritis Initiative (OAI) and show the impact of MR system, phantom, and acquisition protocol changes. METHOD: Key 3T MR QA metrics, including signal-to noise, signal uniformity, T2 relaxation times, and geometric distortion, were quantified monthly on two different phantoms using an automated program. RESULTS: Over 8 years, phantom measurements showed root-mean-square coefficient-of variation reproducibility of <0.25% (190.0 mm diameter) and <0.20% (148.0 mm length), resulting in spherical volume reproducibility of <0.35%. T2 relaxation time reproducibility varied from 1.5% to 5.3%; seasonal fluctuations were observed at two sites. All other QA goals were met except: slice thicknesses were consistently larger than nominal on turbo spin echo images; knee coil signal uniformity and signal level varied significantly over time. CONCLUSIONS: The longitudinal variations for a spherical volume should have minimal impact on the accuracy and reproducibility of cartilage volume and thickness measurements as they are an order of magnitude smaller than reported for either unpaired or paired (repositioning and reanalysis) precision errors. This stability should enable direct comparison of baseline and follow-up images. Cross-comparison of the geometric results from all four OAI sites reveal that the MR systems do not statistically differ and enable results to be pooled. MR QA results identified similar technical issues as previously published. Geometric accuracy stability should have the greatest impact on quantitative analysis of longitudinal change in cartilage volume and thickness precision. PMID- 23092791 TI - Endothelial tip cells in ocular angiogenesis: potential target for anti angiogenesis therapy. AB - Endothelial tip cells are leading cells at the tips of vascular sprouts coordinating multiple processes during angiogenesis. In the developing retina, tip cells play a tightly controlled, timely role in angiogenesis. In contrast, excessive numbers of tip cells are a characteristic of the chaotic pathological blood vessels in proliferative retinopathies. Tip cells control adjacent endothelial cells in a hierarchical manner to form the stalk of the sprouting vessel, using, among others, the VEGF-DLL-Notch signaling pathway, and recruit pericytes. Tip cells are guided toward avascular areas by signals from the local extracellular matrix that are released by cells from the neuroretina such as astrocytes. Recently, tip cells were identified in endothelial cell cultures, enabling identification of novel molecular markers and mechanisms involved in tip cell biology. These mechanisms are relevant for understanding proliferative retinopathies. Agents that primarily target tip cells can block pathological angiogenesis in the retina efficiently and safely without adverse effects. A striking example is platelet-derived growth factor, which was recently shown to be an efficacious additional target in the treatment of retinal neovascularization. Here we discuss these and other tip cell-based strategies with respect to their potential to treat patients with ocular diseases dominated by neovascularization. PMID- 23092793 TI - Interspecies scaling of biliary excreted drugs: prediction of human clearance and volume of distribution. AB - BACKGROUND: Interspecies differences in biliary excretion and the differences in bile flow rates make scaling across species difficult for drugs that are excreted in the bile. The objective of this study is to predict clearance (CL) and volume of distribution (V) for humans from animals for drugs that are excreted in the bile. METHODS: Clearance values of 10 drugs known to be excreted in the bile were selected from the literature. Scaling of CL was performed using at least three animal species. Using simple allometry and the rule of exponents (ROE), clearances of studied drugs were predicted in humans. Besides using the ROE, a 'correction factor' was applied adjusting bile flow rate based on the species body weight (bile flow mL/day/kg body weight) or liver weight (bile flow mL/day/kg liver weight). Using the ROE and combining it with the 'correction factor', the clearances of biliary excreted drugs were predicted for humans. V for 15 drugs (without any correction factor) that are excreted in the bile was also predicted for humans. RESULTS: The results of the study indicated that the ROE in association with the correction factors developed for the biliary excreted drugs substantially improved the prediction of human clearance for drugs that are excreted in the bile. In this study, there was no indication (unlike clearance) that the prediction of volume of drug distribution was affected (systematically under- or over-prediction) because of biliary excretion. CONCLUSIONS: The clearance of drugs that are excreted in the bile can be predicted with reasonable accuracy using ROE and a correction factor. PMID- 23092794 TI - Elevated liver enzymes resulting from an interaction between Raltegravir and Panax ginseng: a case report and brief review. AB - BACKGROUND: In the last decade, some evidence has arisen supporting the usefulness of Asian ginseng (Panax ginseng, fam. Araliaceae) as a complementary remedy in patients receiving antiretroviral therapy. However, its role in current therapeutics remains unclear. METHODS: The patient was admitted for an acute elevation of liver enzymes, marked jaundice, and significant weight loss after taking ginseng-based tablets starting approximately 39 days prior. His past medical history (PMH) was also significant for HIV+, long-term hepatitis C, an episode of mitochondrial toxicity, and several comorbidities. His outpatient medications included raltegravir 400 mg plus lopinavir/ritonavir 400/100 mg twice daily, aspirin 100 mg daily, and esomeprazole 40 mg daily as needed. RESULTS: The cessation of the ginseng lozenges led to a progressive improvement in the performance status and laboratory values. Both the Hansten and Horn nomogram and the Roussel Uclaf Causality Assessment Method indicated that the association between the ginseng medicine and the liver injury was probable (six points). CONCLUSIONS: We suggest that ginseng is involved in the episode through an interaction resulting in elevated plasma concentrations of raltegravir. As a consequence, clinicians should be alert when managing patients on other CYP3A4 metabolized drugs or previous liver-damaging conditions. However, larger studies are required to explicitly clarify these statements. PMID- 23092795 TI - alpha-Tocopherol ameliorates nickel induced testicular oxidative and nitrosative stress in albino rats. AB - BACKGROUND: Heavy metals generate free radicals and induce oxidative and nitrosative stress with depletion of antioxidants. In this study, we have evaluated the beneficial effects of alpha-tocopherol against nickel sulfate exposed testicular dysfunction. METHODS: We studied the effect of supplementation of alpha-tocopherol (10 mg/100 g body weight, i.m.) on nickel sulfate (2.0 mg/100 g body weight, i.p.) induced testicular oxidative and nitrosative stress in Wister strain male albino rats. Serum and testicular nitric oxide, L-ascorbic acid and serum alpha-tocopherol concentrations were evaluated. We also evaluated sperm count, motility and histopathology of testes. RESULTS: Nickel treated rats showed significantly decreased body weight, testicular somatic index, sperm count, sperm motility, serum and testicular L-ascorbic acid concentration and serum alpha-tocopherol level as compared to their controls. However, simultaneous treatment with nickel sulfate and alpha-tocopherol produced a remarkable improvement of all the above parameters when compared with treatment with nickel alone. Nickel treated rats also had significantly increased serum and testicular nitric oxide concentrations as compared to their controls. However, simultaneous treatment with nickel sulfate and alpha-tocopherol significantly decreased nitric oxide concentrations in both serum and testes, respectively, as compared to nickel treatment alone. Histopathology of the testes revealed tortuous seminiferous tubules, loss of spermatogenesis process (>75%), congestion and necrosis in nickel sulfate treated rats, whereas rats simultaneously treated with nickel sulfate and alpha-tocopherol had almost normal seminiferous tubules and near normal spermatogenesis as compared to nickel alone treated rats. CONCLUSIONS: Nickel sulfate treatment causes testicular oxidative and nitrosative stress in albino rats, but simultaneous supplementation of alpha-tocopherol was found to be beneficial in combating against such stresses. PMID- 23092796 TI - Functional and structural insights into astacin metallopeptidases. AB - The astacins are a family of multi-domain metallopeptidases with manifold functions in metabolism. They are either secreted or membrane-anchored and are regulated by being synthesized as inactive zymogens and also by co-localizing protein inhibitors. The distinct family members consist of N-terminal signal peptides and pro-segments, zinc-dependent catalytic domains, further downstream extracellular domains, transmembrane anchors, and cytosolic domains. The catalytic domains of four astacins and the zymogen of one of these have been structurally characterized and shown to comprise compact ~200-residue zinc dependent moieties divided into an N-terminal and a C-terminal sub-domain by an active-site cleft. Astacins include an extended zinc-binding motif (HEXXHXXGXXH) which includes three metal ligands and groups them into the metzincin clan of metallopeptidases. In mature, unbound astacins, a conserved tyrosine acts as an additional zinc ligand, which is swung out upon substrate or inhibitor binding in a 'tyrosine switch' motion. Other characteristic structural elements of astacin catalytic domains are three large alpha-helices and a five-stranded beta-sheet, as well as two or three disulfide bonds. The N-terminal pro-segments are variable in length and rather unstructured. They inhibit the catalytic zinc following an 'aspartate-switch' mechanism mediated by an aspartate embedded in a conserved motif (FXGD). Removal of the pro-segment uncovers a deep and extended active-site cleft, which in general shows preference for aspartate residues in the specificity pocket (S1'). Furthermore, astacins undergo major rearrangement upon activation within an 'activation domain,' and show a slight hinge movement when binding substrates or inhibitors. In this review, we discuss the overall architecture of astacin catalytic domains and their involvement in function and zymogenic activation. PMID- 23092797 TI - Structural origins of AGC protein kinase inhibitor selectivities: PKA as a drug discovery tool. AB - The era of structure-based protein kinase inhibitor design began in the early 1990s with the determination of crystal structures of protein kinase A (PKA, or cyclic AMP-dependent kinase). Although many other protein kinases have since been extensively characterized, PKA remains a prototype for studies of protein kinase active conformations. It serves well as a model for the structural properties of AGC subfamily protein kinases, clarifying inhibitor selectivity profiles. Its reliable expression, constitutive activity, simple domain structure, and reproducible crystallizability have also made it a useful surrogate for the discovery of inhibitors of both established and emerging AGC kinase targets. PMID- 23092798 TI - Analytical evaluation of a new automated protein binding assay to determine 25 hydroxyvitamin D concentrations. PMID- 23092799 TI - Revaluating serum ferritin as a marker of body iron stores in the traceability era. AB - Serum ferritin is used for diagnosing iron-related disorders. However, most studies validating this application were performed before the introduction of the 2nd and 3rd WHO International Standards (ISs) to harmonize assay results. We revised the available literature to evaluate if consolidated clinical applications of ferritin and recommended cut-offs have been validated using ISs calibrated assays. All Medline retrieved reviews and individual studies performed since ISs availability were selected and analyzed according to predefined criteria. Concerning ferritin and iron deficiency (ID), only one review, including studies published before 1988, met established criteria. Results showed that ferritin can effectively rule out ID anemia in patients with or without inflammatory disease at cut-offs of 70 and 40 MUg/L, respectively. From two studies using ISs calibrated assays that met inclusion criteria, no information emerged on which cut-off should be employed to obtain similar sensitivity. Regarding iron overload, even when the framework was restricted to hereditary hemochromatosis, no synthesis of scientific evidence, if any, about diagnostic accuracy of ferritin was available both before and after ISs introduction. Available evidence of the ferritin diagnostic effectiveness is limited to ID conditions. Recommended cut-offs for this application are, however, based on studies published from 1970 to the 1980s using non-harmonized assays. PMID- 23092800 TI - Current state of diagnostic technologies in the autoimmunology laboratory. AB - The methods for detecting and measuring autoantibodies have evolved markedly in recent years, encompassing three generations of analytical technologies. Many different immunoassay methods have been developed and used for research and laboratory practice purposes, from the early conventional (or monoplex) analytical methods able to detect single autoantibodies to the more recent multiplex platforms that can quantify tens of molecules. Although it has been in use for over 50 years, indirect immunofluorescence remains the standard method for research on many types of autoantibodies, due to its characteristics of diagnostic sensitivity and also to recent technological innovations which permit it a greater level of automation and standardization. The recent multiplex immunometric methods, with varying levels of automation, present characteristics of higher diagnostic accuracy, but are not yet widely diffused in autoimmunology laboratories due to the limited number of autoantibodies that are detectable, and due to the high cost of reagents and systems. Technological advancement in autoimmunology continues to evolve rapidly, and in the coming years new proteomic techniques will be able to radically change the approach to diagnostics and possibly also clinical treatment of autoimmune diseases. The scope of this review is to update the state of the art of technologies and methods for the measurement of autoantibodies, with special reference to innovations in indirect immunofluorescence and in multiple proteomic methods. PMID- 23092801 TI - Improvement of a prenatal screening program for trisomy 18 in the first trimester of gestation. AB - BACKGROUND: The aim of this study was to evaluate population parameters (medians, standard deviations and coefficients of correlation) different from those used by the commercial software Elipse((r)) v3.0 (Perkin Elmer) in the calculation of prenatal risk of trisomy 18. Moreover, the truncation limits used for extreme values of free beta-human chorionic gonadotropin (fbeta-hCG), pregnancy associated plasma protein-A (PAPP-A) and nuchal translucency (NT) were revised. METHODS: A calculation engine for the prenatal risk of trisomy 18 was developed [called FMF (Fetal Medicine Foundation) calculator]. Recently, published population parameters for fbeta-hCG and PAPP-A as well as new truncation limits were included in this calculator. The patient-specific risks obtained by Elipse((r)) v3.0 and FMF calculators, were compared in 18,801 pregnant women, including 13 cases of trisomy 18, four cases of trisomy 13 and one case of triploidy. RESULTS: Using a cut-off point of 1:250, FMF calculator increased the detection rate of trisomy 18 from 62% to 100% with a 0.31% increase in the false positive rate (FPR). When the detection rate was fixed at 100%, the FPR generated by Elipse v3.0 (1.52%) was significantly higher (p<0.0001) than that generated by the FMF calculator (0.36%). Moreover, an improved detection in cases of trisomy 13 and triploidy was observed. CONCLUSIONS: It is recommended that each laboratory reviews the population parameters and truncation limits used in the risk calculation of trisomy 18, in order to obtain an adequate performance in the screening. PMID- 23092802 TI - Collective opinion paper on findings of the 2011 convocation of experts on laboratory quality. AB - In April of 2011, Bio-Rad Laboratories Quality System Division (Irvine, CA, USA) hosted its third annual convocation of experts on laboratory quality in the city of Salzburg, Austria. As in the past 2 years, over 60 experts from across Europe, Israel, USA and South Africa convened to discuss contemporary issues and topics of importance to the clinical laboratory. This year's conference had EN/ISO 15189 and accreditation as the common thread for most discussions, with topics ranging from how to meet requirements like uncertainty to knowledge gained from those already accredited. The participants were divided into five discussion working groups (WG) with assigned topics. The outcome of these discussions is the subject of this summary. PMID- 23092803 TI - Validation of a new generation POCT glucose device with emphasis on aspects important for glycemic control in the hospital care. AB - BACKGROUND: Point-of-care (POC) glucose devices are widely used for insulin dosage decision-making although such an application is not always permitted. In this study, we have evaluated a new generation of POC glucose device, the HemoCue((r)) Glucose 201DMRT (201DMRT), for its suitability for (tight) glycemic control. MATERIALS AND METHODS: This study was performed according to the CLSI/STARD criteria. The 201DMRT was compared to the laboratory hexokinase glucose method (Siemens Dimension Vista((r))). The variation among different POC devices and cuvette lot numbers was examined. Additionally, the influence of the partial pressure of oxygen and hematocrit on glucose measurement was investigated. RESULTS: The 201DMRT showed a good agreement with the laboratory reference method. This was examined using Deming regression analysis, percentage Bland-Altman plot and a modified Clarke-error grid. The total analytical error at the clinically critical glucose concentrations of 5.6, 7.0 and 11.1 mmol/L (101, 126 and 200 mg/dL) was 6.4%, 4.3% and 3.0%, respectively. The total error among the different POC devices and among different cuvette lot numbers was <6.5%. Glucose measurements on the 201DMRT were not affected by changes in partial pressure of oxygen, whereas changes in hematocrit had influence on the results (3.4% for every 0.10 L/L change in hematocrit). CONCLUSIONS: The 201DMRT device can be used for glycemic control based on analytical results presented. However, the clinical applicability for tight glycemic control must be confirmed in a clinical study. PMID- 23092804 TI - Transforming nursing education: a review of current curricular practices in relation to Benner's latest work. AB - Current societal and healthcare system trends highlight the need to transform nursing education to prepare nurses capable of outstanding practice in the 21st century. Patricia Benner and colleagues urged nurse educators to transform their practice in the 2010 publication Educating Nurses, A Call to Radical Transformation. Frequently utilized pedagogical frameworks in nursing education include behaviorism and constructivism. Much of the structure and basis for instruction and evaluation can be found rooted in these philosophies. By first exploring both behaviorism and constructivism and then relating their use in nursing education to the call to transform, educators can be encourage to examine current practice and possibly modify aspects to include more rich experiential learning. PMID- 23092805 TI - Impact of angiotensin II on skeletal muscle metabolism and function in mice: contribution of IGF-1, Sirtuin-1 and PGC-1alpha. AB - Activation of the renin-angiotensin-aldosterone system and increased levels of angiotensin II (Ang-II) occurs in numerous cardiovascular diseases such as chronic heart failure (CHF). Another hallmark in CHF is a reduced exercise tolerance with impaired skeletal muscle function. The aim of this study was to investigate in an animal model the impact of Ang-II on skeletal muscle function and concomitant molecular alterations. Mice were infused with Ang-II for 4 weeks. Subsequently, skeletal muscle function of the soleus muscle was assessed. Expression of selected proteins was quantified by qRT-PCR and Western blot. Infusion of Ang-II resulted in a 33% reduction of contractile force, despite a lack of changes in muscle weight. At the molecular level an increased expression of NAD(P)H oxidase and a reduced expression of Sirt1, PGC-1alpha and IGF-1 were noticed. No change was evident for the ubiquitin E3-ligases MuRF1 and MafBx and alpha-sarcomeric actin expression. Cytophotometrical analysis of the soleus muscle revealed a metabolic shift toward a glycolytic profile. This study provides direct evidence of Ang-II-mediated, metabolic deterioration of skeletal muscle function despite preserved muscle mass. One may speculate that the Ang-II mediated loss of muscle force is due to an activation of NAD(P)H oxidase expression and a subsequent ROS-induced down regulation of IGF-1, PGC-1alpha and Sirt1. PMID- 23092806 TI - Localization of the stem cell markers LGR5 and Nanog in the normal and the cancerous human ovary and their inter-relationship. AB - LGR5 and Nanog were recently characterized as stem cell markers in various embryonic, adult and cancer stem cells. However, there are no data on their precise localization in the normal adult ovary, which may be important for the initial steps of development of ovarian cancer, the most lethal gynecological cancer. We analyzed by immunocytochemistry the precise localization of these markers in normal ovary (11 specimens, age range 43-76), in borderline specimens (12 specimens), and in serous ovarian cancer (12 specimens of stage II) which comprises the vast majority (80%) of all ovarian cancer. Surprisingly, we revealed that both Nanog and LGR5 are clearly localized in the epithelial cells of the normal ovary. However, in 5 of 12 ovaries there was no labeling at all, while in 3 ovaries staining of Nanog was more prominent with only weak labeling of LGR5. In addition, we found in 3 of 11 ovaries clear labeling in foci of both LGR5 and Nanog antibodies, with partial overlapping. Occasionally, we also found in the stroma foci labeled by either Nanog or LGR5 antibodies. In general, the stroma area of tissue sections labeled with LGR5 was much greater than that labeled with Nanog. In borderline tumors a significant portion of the specimens (7 of 12) was labeled exclusively with Nanog and not with LGR5. In ovarian carcinomas almost 100% of the cells were exclusively labeled only with Nanog (6 of 12 of the specimens) with no labeling of LGR5. These data may suggest the potential of ovaries from postmenopausal women, which express Nanog, to undergo transformation, since Nanog was shown to be oncogenic. We conclude that Nanog, which probably plays an important role in ovarian embryonic development, may be partially silenced in fertile and post-menopausal women, but is re-expressed in ovarian cancer, probably by epigenetic activation of Nanog gene expression. Expression of Nanog and LGR5 in normal ovaries and in borderline tumors may assist in the early detection and improved prognosis of ovarian cancer. Moreover, targeting of Nanog by inhibitory miRNA or other means may assist in treating this disease. PMID- 23092807 TI - [A case of cutaneous mammary re-irradiation]. AB - In early-stage breast cancer, radiotherapy delivered after conservative surgery leads to a reduction in the risk of local recurrences by approximately two thirds. However, some local recurrences can occur in a previously irradiated region and be relevant for a second radiotherapy, exposing to an increased risk of adverse effects. We describe here the observation of a 66-year-old woman treated for a triple negative ductal infiltrative carcinoma of the left breast, who presented an early locoregional recurrence, notably as skin nodules, developed within the irradiated volume and progressing on chemotherapy. The patient was treated by re-irradiation performed concomitantly to oral chemotherapy by capecitabine. PMID- 23092808 TI - [FMEA applied to the radiotherapy patient care process]. AB - PURPOSE: Failure modes and effects analysis (FMEA), is a risk analysis method used at the Radiotherapy Department of Institute Sainte-Catherine as part of a strategy seeking to continuously improve the quality and security of treatments. PATIENTS AND METHODS: The method comprises several steps: definition of main processes; for each of them, description for every step of prescription, treatment preparation, treatment application; identification of the possible risks, their consequences, their origins; research of existing safety elements which may avoid these risks; grading of risks to assign a criticality score resulting in a numerical organisation of the risks. Finally, the impact of proposed corrective actions was then estimated by a new grading round. RESULTS: For each process studied, a detailed map of the risks was obtained, facilitating the identification of priority actions to be undertaken. For example, we obtain five steps in patient treatment planning with an unacceptable level of risk, 62 a level of moderate risk and 31 an acceptable level of risk. CONCLUSION: The FMEA method, used in the industrial domain and applied here to health care, is an effective tool for the management of risks in patient care. However, the time and training requirements necessary to implement this method should not be underestimated. PMID- 23092809 TI - Taurine ameliorate alloxan induced oxidative stress and intrinsic apoptotic pathway in the hepatic tissue of diabetic rats. AB - Oxidative stress is associated with various diabetic complications and taurine plays an important role in ameliorating those difficulties. In the present study we, therefore, investigated whether taurine plays any beneficial role against diabetes induced liver dysfunction and if it does, what cellular mechanism it follows during protective action. Induction of diabetes by alloxan (ALX) (at a dose of 120mg/kg body weight, i.p., once) reduced body weight and plasma insulin level, enhanced blood glucose and serum markers related to hepatic injury, accelerated ROS production, disturbed the intra-cellular antioxidant machineries and disintegrated hepatic cells near central vein. This pathophysiology leads to apoptotic cell death as evidenced from DNA fragmentation and TUNEL aasay. Studies on the mechanism of apoptosis showed that ALX accelerated the markers of mitochondrial dependent apoptotic pathway (enhanced cytochrome C release in cytosol from mitochondria, altered the expression of Bax, Bcl-2, Apaf-1, caspase 9, caspase-3). Treatment with taurine (1% w/v for three weeks) post hyperglycemia, however, could restore all the alteration caused by ALX. Moreover, taurine activates hepatic PI3Kinase, Akt, hexokinase and augments the translocation of GLUT 2 to hepatic membrane in diabetic rats. Combining all, as a potential therapeutic, taurine may normalize the complications of diabetic liver injury. PMID- 23092810 TI - Calcium-dependent neutral cysteine protease and organophosphate-induced delayed neuropathy. AB - A few organophosphorus compounds (OPs) can cause toxic neuropathy known as organophosphorus ester-induced delayed neuropathy (OPIDN). Although the incidents of OPIDN have been documented for over a century, its molecular mechanisms underlying the axonopathy are still unclear. Recently, increasing evidences suggest that proteases are closely associated with OPIDN. Herein, we have summarized the roles of calcium-dependent cysteine proteases (calpains) in OPIDN. The activation of calpains should be an early molecular event during the onset and development of OPIDN. However, the understanding of the mechanism underlying the disruption of Ca(2+) homeostasis and the activation of calpain by neurotoxic OPs is still limited. Therefore, a better understanding of molecular mechanisms that can prevent the disturbance in cellular Ca(2+) homeostasis can facilitate to establish the novel therapeutic strategies for OPIDN. PMID- 23092811 TI - Use of bioluminescence mutant screening for identification of Edwardsiella ictaluri genes involved in channel catfish (Ictalurus punctatus) skin colonization. AB - Initial invasion of the host is the first and vital part of any infection process. We have demonstrated that Edwardsiella ictaluri is capable of colonizing and penetrating catfish skin. Therefore, a mutant library was constructed by random insertion of the Mar2xT7 transposon into the chromosome of E. ictaluri harboring the bioluminescence plasmid pAKgfplux1. This library was then screened through a series of three consecutive challenges for mutants showing a decreased ability to colonize the catfish epithelium. Eighteen mutants were identified that have decreased adhesion and virulence. Mutated genes encoded one sensor protein, two transport proteins, five enzymes, two regulatory proteins, and five hypothetical proteins. Among the mutated genes, the first one identified was a gene encoding for RstA/B, which is known to play a role in regulating the expression of invasion genes in Salmonella enterica Typhimurium. Another mutant was lacking a putative ribonuclease similar to a Shigella protein that regulates the expression of adhesin. A third mutant was defective in a protein similar to a Brucella protein that was initially identified as a transporter, but actually is a member of a newly discovered adhesin family. Results from this study could enable development of a new strategy for blocking E. ictaluri invasion at the initial adherence stage. PMID- 23092812 TI - Immune reconstitution kinetics as an early predictor for mortality using various hematopoietic stem cell sources in children. AB - The severity of complications of allogeneic hematopoietic stem cell transplantation (HSCT) is governed mainly by the status of immune reconstitution. In this study, we investigated differences in immune reconstitution with different cell sources and the association between the kinetics of immune reconstitution and mortality. Immunophenotyping was performed every 2 weeks in children who had undergone HSCT between 2004 and 2008 at University Medical Center Utrecht. Lymphocyte reconstitution in the first 90 days after HSCT was studied in relation to mortality in 3 HSCT groups: matched sibling bone marrow (BM) recipients (35 patients), unrelated BM recipients (32 patients), and unrelated cord blood recipients (36 patients). The median age of recipients was 5.9 years (range, 0.1-21 years). The nature and speed of T cell, B cell, and natural killer (NK) cell reconstitution were highly dependent on the cell source. In the first 90 days after HSCT, faster B cell and NK cell reconstitution and delayed T cell reconstitution were shown in unrelated cord blood recipients compared with matched sibling BM and unrelated BM recipients. Of the lymphocyte subsets investigated, a large number of NK cells and a more rapid CD4(+) immune reconstitution over time, resulting in sustained higher CD4(+) counts, were the only predictors of a lower mortality risk in all cell sources. The final model showed that during the first 90 days, patients with an area under the CD4(+) cell receiver- operating curve of >4,300 cells/day and no peak in CD4(+) cell counts had the highest likelihood of survival (hazard ratio for mortality, 0.2; 95% confidence interval, 0.06-0.5). Our data indicate that CD4(+) kinetics may be used to identify patients at greatest risk for mortality early after HSCT. PMID- 23092813 TI - Viewing transplantation immunology through today's lens: new models, new imaging, and new insights. PMID- 23092815 TI - Impurity and edge roughness scattering in graphene nanoribbons: the Boltzmann approach. AB - The conductivity of graphene nanoribbons in the presence of bulk impurities and edge roughness is studied theoretically using the Boltzmann transport equation for quasi-one-dimensional systems. As the number of occupied subbands increases, the conductivity due to bulk impurities converges towards the two-dimensional case. It is shown that the dependence of the conductivity generated by edge roughness scattering depends in a distinctly different way on the sample parameters than the conductivity due to bulk scattering. The Boltzmann model furthermore predicts the amplitude of the edge-roughness-induced magnetoconductance dip as a function of the amplitude and the correlation length of the edge roughness. PMID- 23092814 TI - Adenovirus viremia and disease: comparison of T cell-depleted and conventional hematopoietic stem cell transplantation recipients from a single institution. AB - Adenovirus (ADV) is an important cause of viral mortality in hematopoietic stem cell transplantation (HSCT). Recipients of T cell-depleted (TCD) HSCT are at increased risk for viral infections. We compared the rates and outcomes of ADV viremia and disease between TCD and conventional (CONV) HSCT at our institution. This was an observational study of 624 adult and pediatric recipients of myeloablative HSCT at Memorial Sloan-Kettering Cancer Center between January 1, 2006, and March 11, 2011. Viral cultures and ADV PCR were ordered as clinically indicated. ADV viremia by quantitative PCR assay was defined as 1 or more positive values >=1,000 copies/mL or 2 or more consecutive positive values. Competing-risk regression analyses were used to identify predictors for ADV viremia. ADV viremia at 1 year after HSCT occurred in 8% of TCD HSCT recipients and in 4.0% of CONV HSCT recipients (P = .041). Among the TCD recipients, ADV viremia was seen in 15% of children, compared with 5% of adults (P = .008). Young age (hazard ratio [HR], 3.0; P < .001) and acute graft-versus-host disease (GVHD) (HR, 3.2; P = .001) were identified as risk factors for ADV viremia. ADV viremia was predictive of mortality (HR, 6.0; P < .001). ADV disease developed in 3.5% of TCD HSCT recipients and in 0.4% of CONV HSCT recipients (P = .022), with an attributable mortality of 27%. Among TCD HSCY recipients, grade II to IV GVHD was a risk factor for ADV disease (HR, 13; P < .001), but age was not. More than 90% of the cases of ADV disease involved a viral load of >=10,000 copies/mL. Rates of ADV disease were 10-fold greater in TCD HSCT recipients compared with CONV HSCT recipients, predominantly in patients who developed acute GVHD. The benefit of preemptive therapy for an ADV viral load >=10,000 copies/mL for preventing ADV disease in TCD HSCT recipients should be evaluated in prospective clinical trials. PMID- 23092816 TI - Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [18F] fluorodeoxyglucose-positron emission tomography/computed tomography. AB - Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (<-30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial. PMID- 23092817 TI - Growth of ultrathin epitaxial Fe/MgO spin injector on (0, 0, 1) (Ga, Mn)As. AB - We have grown an ultrathin epitaxial Fe/MgO bilayer on (Ga, Mn)As by e-beam evaporation in UHV. The system structure has been investigated by high resolution transmission electron microscopy (TEM) experiments which show that the Fe and MgO films, covering completely the (Ga, Mn)As, grow with the epitaxial relationship Fe[100](001) [parallel] MgO[110](001) [parallel] (Ga,Mn)As[110](001). The magnetic reversal process, studied by the magneto-optical Kerr effect (MOKE) at room temperature, demonstrates that the iron is ferromagnetic and possesses a cubic anisotropy, confirming the epitaxy relationship found with TEM. Resistivity measurements across the barrier display a non-Ohmic behavior characterized by cubic conductance as a function of the applied voltage suggesting tunneling dominated transport across the barrier. PMID- 23092818 TI - What is the frailty in elderly? Value and significance of the multidimensional assessments. AB - Authors perform a critical revision of the concept of frailty in elderly going back to its first indication (1978). It is a particular phenotypic condition, characterized by advanced age, clinically unstable polypathologies in evolution, with cognitive disturbances, often very severe, loss of auto sufficiency and the critical socio-economic conditions. The diagnostic validity, both in the definition of the deficits and in the evaluation of the declines in the fundamental functions should be underlined. The first ones are needed particularly for the epidemiological and population studies, and the second one, at the individual level. Today, first of all in the geriatric field, the method of multidimensional evaluation (MDE) is the first choice for the early diagnosis of "elderly frailty" (EF), in order to determine the biological, functional, cognitive and clinical aspects of the elderly subjects, and also for the application of adequate programs of intervention at the sanitary-assistential social levels. PMID- 23092820 TI - [Prevalence of childhood obesity in the Murcia Region; an assessment of different references for body mass index]. AB - INTRODUCTION: Childhood obesity is a problem of high magnitude with serious repercussions on health, which justifies estimating its prevalence at local level to identify conditioning factors and to take preventive actions. The main objective of the present work is to estimate the prevalence of overweight and obesity in the children in the general population of the Murcia Region, using the body mass index (BMI) and applying the International Obesity Task Force (IOTF) criteria, and to compare these results with the ones obtained from other frequently used references in Spain. MATERIAL AND METHODS: The BMI of 178,894 children aged from 2 to 14 years was determined. The prevalence of overweight and obesity was compared to the IOTF, to the studies of the World Health Organization, as well as those of the Orbergozo Foundation (FO), and the Cross sectional Spanish Growth Study (ETEC) references. The agreement between the different results was evaluated using the kappa index. RESULTS: The evaluation using the IOTF cut-off points gave an overweight prevalence of 20.6% (95% CI: 20.4-20.8), an obesity prevalence of 11.4% (95% CI: 11.2-11.5) and an overweight plus obesity prevalence of 32% (95% CI: 31.8-32.2), with this last one being higher in girls (33.2%) than in boys (30.9%). The highest agreement is between IOTF and FO-2011 (kappa=.795) and between FO-2011 and ETEC (kappa=.794). CONCLUSION: A high prevalence of overweight and obesity in children in the Region of Murcia was found. The ETEC and the FO-2011 study showed the highest agreement with the results obtained using the IOTF criteria. PMID- 23092821 TI - [Tropical endomyocardial fibrosis in Spain]. AB - Endomyocardial fibrosis is a restrictive cardiomyopathy of unknown etiology prevalent in tropical regions. It is characterized by fibrotic obliteration of the apex of one or both ventricles, which can be extended to the ventricular inlet chamber. It predominantly affects children and young adults. There is no specific treatment and usually has a poor prognosis. It is uncommon in Spain, but due to immigration, it appears to be increasing. Four cases of endomyocardial fibrosis in children diagnosed and treated in Spain are presented, as a well as a review of this disease. PMID- 23092822 TI - [Otogenic variant of Lemierre syndrome]. PMID- 23092823 TI - Women's post-chemotherapy parity is affected by offspring number and marital status. AB - Childbearing rates post-chemotherapy for breast cancer (BC) are affected by age and chemotherapy-type but may also depend on personal characteristics. In this single institution retrospective study we evaluated post-chemotherapy fertility and its association with offspring number and marital-status at the time of BC diagnosis. We identified 65 fertile BC patients under 38y, who received adjuvant chemotherapy. Menses resumption and pregnancies along with offspring-number and marital-status were recorded. Menses resumed in 95.4% and 33.8% gave birth. Of those who did not give birth 46.5% had at least three children at diagnosis and of those without children 83% were unmarried. Our data associates multiparity with lower childbearing post-chemotherapy, suggesting it as a possible surrogate for women's preferences in retrospective studies. Unlike multiparity, marital status association with lower childbearing may be culture-dependent and not a universal surrogate for women's intentions and would be best investigated prospectively. PMID- 23092819 TI - Integration of cellular bioenergetics with mitochondrial quality control and autophagy. AB - Bioenergetic dysfunction is emerging as a cornerstone for establishing a framework for understanding the pathophysiology of cardiovascular disease, diabetes,cancer and neurodegeneration. Recent advances in cellular bioenergetics have shown that many cells maintain a substantial bioenergetic reserve capacity, which is a prospective index of ' healthy ' mitochondrial populations.The bioenergetics of the cell are likely regulated by energy requirements and substrate availability. Additionally,the overall quality of the mitochondrial population and the relative abundance of mitochondria in cells and tissues also impinge on overall bioenergetic capacity and resistance to stress. Because mitochondria are susceptible to damage mediated by reactive oxygen/nitrogen and lipid species, maintaining a ' healthy ' population of mitochondria through quality control mechanisms appears to be essential for cell survival under conditions of pathological stress. Accumulating evidence suggest that mitophagy is particularly important for preventing amplification of initial oxidative insults, which otherwise would further impair the respiratory chain or promote mutations in mitochondrial DNA (mtDNA). The processes underlying the regulation of mitophagy depend on several factors, including the integrity of mtDNA, electron transport chain activity, and the interaction and regulation of the autophagic machinery. The integration and interpretation of cellular bioenergetics in the context of mitochondrial quality control and genetics is the theme of this review. PMID- 23092824 TI - Disease burden and treatment outcomes in second-line therapy of patients with estrogen receptor-positive (ER+) advanced breast cancer: a review of the literature. AB - OBJECTIVE: To determine the variable burden of disease of patients with advanced estrogen receptor-positive (ER+) breast cancer and assess the current treatment landscape after failure of first-line endocrine therapy. METHODS: A comprehensive literature review was performed (2000-2011) by searching Medline via PubMed, and Embase and Cochrane databases, to assess disease burden (i.e. societal, humanistic, and/or economic burden) and treatment landscape for second-line therapy of ER+ advanced breast cancer in postmenopausal women. RESULTS: Only 1 study was identified that evaluated burden of disease based on ER status (ER+, ER negative, or ER-unknown); this study was a subgroup analysis assessing the impact of breast cancer recurrence over 10 years. The investigators reported that only minor differences in survival and medical costs were noted based on ER status in relapsing patients. Regardless of ER status, patients with breast cancer recurrence consumed more healthcare resources and were associated with more costly care than those without recurrence. A total of 7 studies were identified related to treatment outcomes of second-line therapy in ER+ patients. A combined international population totaled >3800 patients who had progressed on prior hormonal therapy, including tamoxifen and aromatase inhibitors. Three trials performed a comparative efficacy/safety assessment of an ER antagonist vs. aromatase inhibitor, 1 trial compared an aromatase inhibitor to megestrol acetate, and 1 trial compared 2 aromatase inhibitors. Among each of the studies evaluated, no significant differences were observed in the primary efficacy endpoint, and the safety profiles were similar. Two additional studies demonstrated a similar or better efficacy and safety profile based on different dosing evaluations. CONCLUSIONS: Currently, there is insufficient evidence on the economic and humanistic burden associated with ER status, and this gap warrants further research. With increasing drug resistance and greater economic burden associated with breast cancer recurrence, there is an unmet medical need for improved treatment in this patient population. PMID- 23092825 TI - High plasma adiponectin concentration is associated with all-cause mortality in patients with carotid atherosclerosis. AB - BACKGROUND: The role of adiponectin as a risk factor for mortality and recurrent ischemic cardiovascular events in patients with carotid artery disease is unknown. METHODS: Consecutive patients (n = 292) undergoing carotid endarterectomy for symptomatic and asymptomatic carotid stenosis were included in the study. Mortality and cardiovascular ischemic events were recorded during a median follow-up of 5.2 years. Baseline plasma concentrations of adiponectin were measured. Cox regression models stratified for gender were used for estimation of risk of events. RESULTS: Fifty-two patients died and 73 had an ischemic event (ischemic stroke, n = 52 and/or MI, n = 28) during follow-up. In univariate analyses, adiponectin was associated with mortality, hazard ratio (HR) per standard deviation (SD) increase of adiponectin, 1.46 (95% confidence interval [CI], 1.14-1.86). In multivariate analysis age, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), plasma interleukin-6 (IL-6) and plasma adiponectin (HR per SD increase of adiponectin, 1.73 [95% CI, 1.29-2.32]) were independently associated with mortality. T2DM, CHD, fibrinogen, contralateral carotid artery stenosis, systolic blood pressure, symptomatic carotid artery stenosis were independently associated with ischemic events, whereas plasma adiponectin was not (HR per SD increase of adiponectin, 0.96 [95% CI, 0.75-1.23]). CONCLUSIONS: High plasma adiponectin concentration is associated with mortality in patients with established atherosclerosis undergoing surgery for carotid artery stenosis. Further studies to determine the role for adiponectin as a biomarker are warranted. PMID- 23092826 TI - Usefulness of carotid intima-media thickness measurement as an indicator of generalized atherosclerosis: findings from autopsy analysis. AB - BACKGROUND: Ultrasound-determined carotid intima-media thickness (IMT) is widely used as an indicator of generalized atherosclerotic burden, but there are limited autopsy findings in support of the association, directly. METHODS: We performed an autopsy analysis (n = 111, mean 68.8 years; 65.0% men; 86% non-cardiovascular disease death) to examine the associations of microscopy-determined carotid IMT including plaque thickness with the severity of atherosclerosis in the generalized arteries. RESULTS: Microscopy-determined carotid IMT was associated with the extent of intima/media layer ratio of the vasculature, a marker of atherosclerosis, in each structure examined, i.e., coronary artery, cerebrovasculature, thoracic aorta, abdominal aorta, and iliac artery (R = 0.31 0.42; all P < 0.01). The prevalence of a necrotic core in the coronary artery, cerebrovasculature, thoracic aorta, abdominal aorta, and iliac artery increased in accordance with increasing microscopy-determined carotid IMT (all P < 0.05). CONCLUSION: Our autopsy analysis confirms the validity of carotid IMT including plaque thickness as an indicator of generalized atherosclerosis. PMID- 23092827 TI - Asymmetric dimethylarginine predicts clinical outcomes in ischemic chronic heart failure. AB - BACKGROUND: Elevated plasma level of asymmetric dimethylarginine (ADMA) has been reported to be associated with endothelial dysfunction and atherosclerotic risk factors, and may predict adverse cardiovascular events in patients with coronary artery disease. In this study, we aimed to assess the association between plasma ADMA and long-term outcome in patients with angiography-documented ischemic chronic heart failure (HF). METHODS AND RESULTS: We evaluated 285 patients with ischemic chronic HF and measured their plasma ADMA levels by high performance liquid chromatography. The mean age was 70 +/- 12 years and the mean left ventricular ejection fraction was 36 +/- 8%. Plasma ADMA levels were positively correlated with NYHA functional class (p < 0.001) and log N-terminal pro-B type natriuretic peptide (NT-proBNP) level (p < 0.001). During the median follow-up period of 2.2 years, we observed 58 major adverse cardiovascular events (MACE) (20.4%) and 95 MACE plus cardiac decompensation (33.3%). Multivariate Cox regression analysis adjusted for age, ejection fraction, renal function and log NT-proBNP level revealed that ADMA might be a significant independent risk factor and the relative risk of MACE and MACE plus cardiac decompensation would increase by 23% and 25% respectively when plasma ADMA level increased by 1 SD of value (p = 0.05 and 0.007). CONCLUSIONS: In patients with ischemic chronic HF, elevated plasma ADMA levels might be associated with higher NYHA functional classes and elevated NT-proBNP level, and appear to be an independent predictor of long-term adverse clinical outcomes. PMID- 23092828 TI - Left atrium as a dynamic three-dimensional entity: implications for echocardiographic assessment. PMID- 23092829 TI - Evidence of cell damage induced by major components of a diet-compatible mixture of oxysterols in human colon cancer CaCo-2 cell line. AB - Cholesterol oxidation products, termed oxysterols, have been shown to be more reactive than unoxidized cholesterol, possessing marked pro-inflammatory and cytotoxic effects in a number of cells and tissues. Oxysterols, absorbed with the diet as products of cholesterol auto-oxidation, have recently been suggested to potentially interfere with homeostasis of the mucosal intestinal epithelium, by promoting and sustaining irreversible damage. However, the treatment of colon cancer cells with a diet-compatible mixture of oxysterols does not elicit the same responses than individual components added to the cells at the same concentrations at which they are present in the mixture. Sixty MUM oxysterol mixture showed a slight pro-apoptotic effect on human colon cancer CaCo-2 cell line, evaluated in terms of caspase-3 and caspase-7 activation; conversely, 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol and 5alpha,6alpha epoxycholesterol were identified to be able to induce a significant pro-apoptotic effect if added to cell culture singly; 7beta-hydroxycholesterol had stronger action than other compounds. The enhanced production of reactive oxygen species through up-regulation of the colonic NADPH-oxidase isoform NOX1 appeared to be the key event in oxysterol-induced apoptosis in these colon cancer cells. As regards pro-inflammatory effects of oxysterols, IL-8 and MCP-1 were evaluated for their chemotactic activity. Only MCP-1 production was significantly induced by 7beta-hydroxycholesterol, as well as by cholesterol and oxysterol mixture. However, oxysterol-induced inflammation appeared to be NOX1-independent, suggesting a secondary role of this enzyme in inducing inflammation in colon cancer cells. A selective cell death induced by specific oxysterols against colon cancer cells, mainly exploiting their ability to activate NOX1 in generating oxidative reactions, might represent a promising field of investigation in colorectal cancer, and might bring new insights on strategies in anticancer therapy. PMID- 23092830 TI - Measure of keratoconus progression in patients with vernal keratoconjunctivitis using scanning slit topography. AB - PURPOSE: To document topographic changes using Orbscan in patients with keratoconus and vernal keratoconjunctivitis over 1 year. MATERIAL AND METHODS: Retrospective analysis of clinical and Orbscan data of 22 eyes of 11 patients with keratoconus and VKC with follow up over 1 year period was done. The parameters studied included patients demographics, clinical features, visual acuity, refraction and Orbscan IIz. The changes in various Orbscan parameters were studied over the 1-year period. RESULTS: Mean age was 14+/-4.1 years. 20 eyes had clinical keratoconus, while 2 had forme fruste keratoconus. 8 eyes of 22 showed evident progression (>1 diopter change in mean simulated (sim) K over 12 months). There was no significant difference in the visual acuity or clinical features over follow up. In patients with progression, statistically significant change (p<0.05) was found in posterior float curvature, sim K astigmatism and maximum astigmatism. Rest of the parameters did not show significant change. Among the patients without evident progression, none of the parameters showed significant change. On comparing the patients with clinical signs of keratoconus with those with only topographic signs of keratoconus, there was no difference between the two groups with respect to the rate of progression of keratoconus. Patients with both mixed type and pure palpebral type of VKC had comparable Orbscan parameters at baseline and 1 year follow up and similar progression rate of keratoconus. CONCLUSION: Serial topographic analysis provides numerical information about various corneal parameters in patients with vernal keratoconjunctivitis and keratoconus. PMID- 23092831 TI - Novel method for vestibular evoked myogenic potentials: technique and reproducibility. AB - OBJECTIVE: A novel method was employed to control the sternocleidomastoid muscle contraction level during vestibular evoked myogenic potential (VEMP) measurement. STUDY DESIGN: A prospective study to measure the normal VEMP response. SETTINGS: A pressure feedback device composed of a firm rubber bulb and a pressure gauge was employed to monitor the muscular contraction level during measurement. METHODS: Nineteen normal-hearing subjects (12 males; mean age 34.0 +/- 7.7 years) were tested. Subjects were instructed to position the chin on the rubber bulb and use the neck flexors to maintain a pressure of 120 mm Hg during the measurement. MAIN OUTCOME MEASURES: The P13 latencies, N23 latencies, and P13-N23 amplitudes were recorded. In nine subjects, the reproducibility of the technique was tested weekly for 3 consecutive weeks. RESULTS: The average (+/- SD) latency of P13 was 13.97 +/- 1.33 ms, and the latency of N23 was 24.03 +/- 1.79 ms. The average amplitude was 66.89 +/- 44.1 MUV. There was no significant difference between right and left ears in P13 latencies, N23 latencies, and P13-N23 amplitudes. In nine subjects, the average measured interclass correlation coefficient was 0.97 in amplitude, 0.8 in P13 latency, and 0.93 in N23 latency in three consecutive weekly measurements. CONCLUSIONS: The chin-rest pressure feedback method is easy to perform during VEMP testing. Subjects can maintain a constant level of sternocleidomastoid contraction and neck flexion to facilitate this response with a high degree of test-retest reliability. This technique provides a means to compare VEMPs across different clinical scenarios over time. PMID- 23092832 TI - Meta-analysis of the efficacy of amifostine in the prevention of cisplatin ototoxicity. AB - OBJECTIVE: The effectiveness of amifostine in the prevention of cisplatin ototoxicity remains controversial. The objective of this meta-analysis was to determine whether amifostine is successful in preventing ototoxicity secondary to cisplatin chemotherapy. DESIGN: Meta-analysis. METHODS: We conducted a systematic review of all randomized, controlled trials using amifostine in patients of all ages receiving cisplatin chemotherapy. Data extraction was performed by two independent reviewers using predefined data fields, including study quality indicators. Heterogeneity was evaluated using the I2 test. The meta-analysis was performed using the random effect method. MAIN OUTCOME MEASURE: Ototoxicity. RESULTS: Four randomized, controlled trials were included in this meta-analysis. The odds ratio of grade 2 or greater ototoxicity was 0.54 (95% CI 0.27-1.11), and the odds ratio of grade 3 ototoxicity or greater was 0.78 (95% CI 0.29-2.10). The side effects from amifostine use included hypocalcemia, hypotension, vomiting, and sneezing. CONCLUSIONS: This meta-analysis reveals a trend toward decreased ototoxicity in patients receiving amifostine infusion prior to receiving cisplatin chemotherapy. However, the results did not reach statistical significance. Further large randomized, controlled trials of amifostine use to prevent cisplatin-induced ototoxicity are needed. PMID- 23092833 TI - Assessment of the ototoxicity of docusate sodium (colace) in a guinea pig animal model. AB - OBJECTIVE: Docusate sodium (Colace) is an off-label ceruminolytic agent used to soften ear wax and relieve ear canal obstruction. At present, its effect on hearing in the presence of tympanic membrane (TM) perforation is not clear. The present study aimed to assess the safety of ototopic docusate sodium on hearing in the presence of TM perforation. STUDY DESIGN: A prospective, randomized, controlled trial in a guinea pig animal model. MATERIALS AND METHODS: Ten guinea pigs underwent bilateral myringotomy. In each animal, one ear received docusate sodium, serving as the experimental ear, and the other received normal saline as the control. Auditory brain response (ABR) was performed at baseline and then 1, 7, and 14 days following the application. RESULTS: At day 14 following application, there was no significant change in ABR thresholds at 8, 12, 16, 20, or 25 kHz. CONCLUSION: In guinea pigs with perforated TMs, docusate sodium does not seem to cause ototoxicity. Future clinical studies are required. PMID- 23092834 TI - A novel tool for the objective measurement of neck fibrosis: validation in clinical practice. AB - BACKGROUND: Radiotherapy is commonly used to treat neoplasms of the head and neck, and fibrosis is a known side effect. The Cutometer is a device that quantifies properties of the skin. The goal of the study was to validate the Cutometer in normal neck tissues and then quantify fibrosis in radiated necks. METHODS: We performed a prospective study of 251 patients. The elasticity and stiffness parameters were recorded. Control patients were compared to determine the correlation between their left and right sides. Next, the treatment groups were compared using a nonparametric test (Kruskal-Wallis). RESULTS: We found a significant correlation between the left and right sides of the control patients' necks, supporting the view that the Cutometer provides reproducible measurements in the normal neck. Furthermore, the Cutometer demonstrated reduced elasticity in necks treated with radiation, surgery-radiation, and chemoradiation. No significant difference in stiffness was seen. CONCLUSION: The Cutometer may serve as a valuable and valid tool for the measurement of neck skin elasticity. Radiated patients have a quantifiable decrease in their skin elasticity. PMID- 23092835 TI - Prevalence and risk of cancer of thyroid incidentaloma identified by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - OBJECTIVE: To investigate the prevalence and risk of thyroid incidentaloma identified by positron emission tomography/computed tomography (PET/CT). STUDY DESIGN: Historical cohort study. SETTING: Fudan University Shanghai Cancer Center. METHODS: A total of 15 948 non-thyroid disease patients who underwent fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT from November 2006 to September 2010 were included. They were divided into two groups: 12 080 patients for metastatic evaluation and 3868 patients for cancer screening. When thyroid incidentaloma was found, further diagnostic examination was conducted. MAIN OUTCOME MEASURES: Prevalence and risk of thyroid incidentaloma. RESULTS: The prevalence of incidental thyroid 18F-FDG uptake was approximately 2.5% (395 of 15 948). The prevalence of incidentaloma in healthy subjects (118 of 3868; 3.1%) was statistically higher than that in patients with suspected or known cancer (277 of 12 080; 2.3%) (p < .05). Among 395 incidentalomas, 146 patients had further examinations (53 patients with histologic confirmations, 93 patients with clinical monitoring). Finally, 43 lesions were confirmed to be malignancies. Therefore, the cancer risk was 29.5% (43 of 146), and it was higher in cancer screening patients (24 of 59; 40.7%) than in alleged cancer patients (19 of 87; 21.8%) (p < .05). As for FDG uptake pattern, the prevalence of thyroid cancer was 11.6% (5 of 43) and 36.9% (38 of 103) in the group of patients with diffuse and focal uptake, respectively (p < .05). After logistic regression analysis, age, sex, maximal standardized uptake value, and calcification were the potent predictors of differentiation. CONCLUSION: The presence of focal uptake with high SUVmax and calcification detected on CT images correlates with a high likelihood of thyroid malignancy. When a focal thyroid incidentaloma is detected, further examination should be performed. PMID- 23092836 TI - Propranolol as a novel adjunctive treatment for head and neck squamous cell carcinoma. AB - OBJECTIVE: To investigate propranolol as a novel treatment for head and neck squamous cell carcinoma (HNSCC) in vitro. METHODS: HNSCC cell lines were cultured and treated with propranolol alone and in combination with cisplatin or gamma irradiation. The alamarBlue assay was performed to assess cell viability, and apoptosis was confirmed via Western immunoblot for cleaved poly-ADP-ribose polymerase (PARP) and caspase-3/7 assays. RESULTS: Propranolol reduced cell viability and induced apoptosis. In response to propranolol, DeltaNp63alpha decreased, whereas TAp73beta and downstream proapoptotic p53 family target genes increased. Expression of the proangiogenic protein vascular endothelial growth factor (VEGF) also decreased. Combination treatment with propranolol and cisplatin resulted in synergistic effects. Propranolol treatment also enhanced the effects of gamma-irradiation on cell viability. CONCLUSIONS: Our results demonstrate that propranolol reduced HNSCC viability, induced apoptosis, and inhibited production of the proangiogenic protein VEGF. These changes may be due to modulation of p53 family proteins, which are critical regulators of chemotherapy-induced apoptosis in HNSCC. Moreover, propranolol is synergistic in combination with cisplatin and reduces HNSCC viability postradiation in vitro, which may have important implications for novel treatments of HNSCC patients. PMID- 23092837 TI - Morphologic and functional changes in the temporomandibular joint and stomatognathic system after transmandibular surgery in oral and oropharyngeal cancers: systematic review. AB - BACKGROUND: Interruption of mandibular continuity in transmandibular (mandibulotomy and mandibulectomy) surgery for tumour resection in the oral cavity and oropharynx may alter oral and temporomandibular joint (TMJ) morphology and function. OBJECTIVE: To critically analyze available evidence regarding the effects of transmandibular surgeries on morphologic and functional changes in the TMJ and stomatognathic system. DATA SOURCES: Electronic search of Medline, Embase, Evidence-Based Medicine Reviews, Ovid HealthStar, and Scopus and hand searches. INCLUSION CRITERIA: Any article investigating the TMJ morphologic changes and/or functional outcomes following transmandibular surgeries. RESULTS AND SYNTHESIS METHODS: Two hundred seventy-one articles were obtained through the electronic database scan and six articles via a hand search. Twelve full articles were initially selected as potentially meeting the eligibility for this review; however, only five articles finally fulfilled the study inclusion criteria and were analyzed for their methodology. All articles used clinical records and/or patient reports to evaluate TMJ pain, motion, dental occlusion, mouth opening, and deflection during opening as outcome measures. In only four articles was a clinical examination conducted after surgery, with associated patients' interviews and reports. The quality of all included articles was considered poor with a high risk of bias according to the Research Triangle Institute item bank quality of assessment. CONCLUSION: Based on the limited available evidence for this systematic review and a high risk of bias of the analyzed articles, no firm conclusions can be established regarding the effects of transmandibular surgery on morphologic and functional changes in the TMJ and stomatognathic system. PMID- 23092838 TI - Preoperative evaluation of the maxillary sinus roof as a guide for posterior ethmoid and sphenoid sinus surgery. AB - BACKGROUND: The maxillary sinus roof has long been regarded as a reliable reference point for both endoscopic and skull base surgery. OBJECTIVE: This study was designed to evaluate the maxillary sinus roof as a preoperative guide for posterior ethmoid and sphenoid sinus surgery. METHOD: This was a cross-sectional observational study of 50 randomly selected computed tomographic (CT) sinus scans from patients previously seen at a tertiary rhinology clinic. Each side of the sinuses was treated independently, giving a total of 100 sides for analysis. Using the medial maxillary sinus roof as a fixed reference point, the vertical distance to the posterior ethmoid skull base, natural sphenoid ostium, and anterior sphenoid roof and floor were measured. In addition, the maxillary sinus to posterior ethmoid height ratio was calculated for each patient. RESULTS: Relative to the medial maxillary sinus roof, the mean vertical height of the posterior ethmoid skull base was 14.08 +/- 3.03 mm. Using this same reference point, the mean vertical distance to the natural sphenoid ostium, sphenoid roof, and sphenoid floor was 2.76 +/- 2.80 mm, 12.18 +/- 3.20 mm, and 5.94 +/- 2.94 mm, respectively. The mean maxillary sinus to posterior ethmoid height ratio was 2.49:1. CONCLUSION: The medial maxillary sinus roof is a reliable preoperative reference point for guiding safe surgical entry into the posterior ethmoid and sphenoid sinus. In addition to providing a margin of safety away from the skull base, it may also help with localization of the natural sphenoid ostium. A classification scheme for evaluating posterior ethmoid height is proposed. PMID- 23092839 TI - Decision analysis using decision trees for a simple clinical decision. AB - OBJECTIVE: To illustrate the use of decision trees with a utility index in clinical decision making. METHODS: A decision tree was created related to whether or not to perform a tonsillectomy. Data from the literature were applied to a common hypothetical clinical scenario. RESULTS: A decision tree graphically represents the typical decision-making process that many clinicians use. The addition of utility functions permitted consideration of the adverse or beneficial effects of outcomes, altering the treatment decision. CONCLUSION: Quantitative tools such as decision trees may quantify outcome preferences and aid in clinical decision making, but the proper tool and background data are essential. PMID- 23092840 TI - A bone to pick? Fish bones of the upper aerodigestive tract: review of the literature. AB - BACKGROUND: Fish bones are of particular interest to the otolaryngologist as accidental ingestion is one of the most common reasons for otolaryngology-related emergency department referrals. Furthermore, removal of fish bones deeply lodged in the oropharynx or hypopharynx can be both hazardous and technically difficult, and failure to accomplish safe removal could result in considerable morbidity and various critical complications. OBJECTIVE: We present here a literature review on the topic of fish bones in otolaryngology with a focus on selection of patients for intervention and on removal techniques. We emphasize that retained fish bones should be approached with caution as their course can at times be unpredictable, as we describe here. PMID- 23092841 TI - Palatal dysgenesis: a possible influence of corticosteroid use? PMID- 23092842 TI - Atypical presentations of achalasia in the pediatric population. PMID- 23092843 TI - Osteomyelitis and necrosis of the inferior turbinate following submucosal diathermy to the inferior turbinate. PMID- 23092844 TI - Monitoring the Rab27 associated exosome pathway using nanoparticle tracking analysis. AB - Exosomes are secreted by many cell types and display multiple biological functions. The ability to both rapidly detect and quantify exosomes in biological samples would assist in the screening of agents that interfere with their release, and which may therefore be of clinical relevance. Nanoparticle tracking analysis, which detects the size and concentration of exosomes, was used to monitor the inhibition of exosome secretion from MDA-MB-231 breast cancer cells expressing inhibitory RNA targeted for Rab27a, a known component of the exosome pathway. Inhibition of both Rab27a and Rab27b was observed, resulting in alterations to intracellular CD63+ compartments and the release of fewer exosomes into the culture medium, as determined by nanoparticle tracking analysis and confirmed by immunoblotting and protein quantification. These data show that nanoparticle tracking analysis can be used effectively and rapidly to monitor the disruption of exosome secretion. PMID- 23092845 TI - How to invade, replicate, and escape from host organisms. A challenge in defining virulence factors for parasites. AB - During millions of years, parasites have been adapting to different environments and hosts. During this time, they have acquired different molecules and peculiar structures, some absent in other living organisms, in order to successfully invade hosts, resist immune attack, and proliferate in the hosts. Nowadays, several genome sequences and a multitude of new information have been generated for many human and animal parasites, opening new possibilities for understanding in detail how they interact with the host and cause disease. Investigations of these molecules and the associated structures, together with their functional roles, are now emerging, providing key advances in understanding pathology that could be used for developing robust strategies to selectively target the parasites without damaging the host. PMID- 23092846 TI - Electronic structure and transport properties of monatomic Fe chains in a vacuum and anchored to a graphene nanoribbon. AB - The electronic structure and transport properties of monatomic Fe wires of different characteristics are studied within the density functional theory. In both equidistant and dimerized (more stable) isolated wires, magnetism plays an important role since it leads to different shapes of the transmission coefficients for each spin component. In equidistant wires, electron localization around the Fermi level leads to symmetry breaking between d(xy) and d(x(2)-y(2)) bands. The main effect of the structural dimerization is to decrease the number of channels available for the minority spin component. When anchored to the edges of a graphene nanoribbon, the dimerization of the chain is preserved, despite the hybridization of the d states of Fe with the C atoms which gives way to a reduction in the number of d channels around the Fermi level. Most conduction is then led by an electronic channel from the ribbon and the sp(z) bands from the Fe wires. Suggestions to improve the spintronic ability of Fe wires are proposed. PMID- 23092847 TI - Identification, extraction and quantification of the synthetic cannabinoid JWH 018 from commercially available herbal marijuana alternatives. AB - In this work, methods for the rapid identification, extraction, and quantification of the synthetic cannabinoid, JWH-018, from commercially available "Spice" (a herbal marijuana alternative) are presented. JWH-018 was identified in three different products using time-of-flight (TOF) mass spectrometry coupled with a direct analysis in real time (DART) ionization source, a process that was completed in less then five minutes and required no sample preparation. Extraction of the JWH-018 from the spice samples using an automated accelerated solvent extraction (ASE) instrument provided clean extracts with few plant pigments. Subsequent quantification by isocratic HPLC produced the following results (mg JWH-018/g plant material): Weekend Warrior brand "Hash": 90 (+/-3%) mg/g, Weekend Warrior brand "Leaf": 29 (+/-6%) mg/g, TrainWreck Hayze brand: 28 (+/-4%) mg/g. Vegetative samples spiked with JWH-018 gave a recovery of 97% (+/ 1%). PMID- 23092848 TI - DNA sequence analyses of blended herbal products including synthetic cannabinoids as designer drugs. AB - In recent years, various herbal products adulterated with synthetic cannabinoids have been distributed worldwide via the Internet. These herbal products are mostly sold as incense, and advertised as not for human consumption. Although their labels indicate that they contain mixtures of several potentially psychoactive plants, and numerous studies have reported that they contain a variety of synthetic cannabinoids, their exact botanical contents are not always clear. In this study, we investigated the origins of botanical materials in 62 Spice-like herbal products distributed on the illegal drug market in Japan, by DNA sequence analyses and BLAST searches. The nucleotide sequences of four regions were analyzed to identify the origins of each plant species in the herbal mixtures. The sequences of "Damiana" (Turnera diffusa) and Lamiaceae herbs (Mellissa, Mentha and Thymus) were frequently detected in a number of products. However, the sequences of other plant species indicated on the packaging labels were not detected. In a few products, DNA fragments of potent psychotropic plants were found, including marijuana (Cannabis sativa), "Diviner's Sage" (Salvia divinorum) and "Kratom" (Mitragyna speciosa). Their active constituents were also confirmed using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS), although these plant names were never indicated on the labels. Most plant species identified in the products were different from the plants indicated on the labels. The plant materials would be used mainly as diluents for the psychoactive synthetic compounds, because no reliable psychoactive effects have been reported for most of the identified plants, with the exception of the psychotropic plants named above. PMID- 23092849 TI - Conducted energy devices: pilot analysis of (non-)attributability of death using a modified Naranjo algorithm. AB - Alleged fatalities associated with conductive-energy devices (CEDs) are similar to alleged serious adverse events (SAEs) after the use of pharmaceutical products: both types of case arise rarely, in complex (if not unique) combinations of circumstances, frequently when there are multiple concomitant putative aetiologies for the injury, and after the suspected product has been previously well-designed and tested. Attribution (or otherwise) of SAEs to pharmaceutical products is often assessed by use of the Naranjo algorithm. The purpose of this study was to investigate whether an adapted Naranjo algorithm could be used to assess alleged CED-associated fatalities. Unique cases had four independent identifiers. Prospectively, 7 (of the 10) Naranjo algorithm questions were chosen as being potentially applicable to CED use. These had maximum score 9, and the associated ordinal probability scale (doubtful, possible, probable, and definite) was retained by linear proportion to the integral scores. An arbitrary requirement was for database sufficiency>=50%=([n unique cases*7 questions answerable]*0.5); a pilot sample (n=29 unique cases) suggested feasibility (see below). One hundred and seventy-five unique cases were found, with a data sufficiency of 56.8%. Modified Naranjo algorithm scores had an unequally bimodal distribution. CED-attributability was suggested in 21 (12% of 175) cases. Substantial numbers of concomitant conditions existed among cases with low algorithm scores, all being potentially lethal under field conditions without CED exposure. The number of CED-administered shocks sustained was unrelated to CED-attributability of fatality. Two of the Naranjo questions (regarding dechallenge and the effects of challenge with a non-identical but similar agent) proved to be non-contributory. An algorithmic approach to assessment of CED-associated fatality seems feasible. By these pharmacovigilance standards, some published case fatality rates attributable to CED exposure seem exaggerated. CED-attributable deaths have close similarity to Type-B SAEs. The latter are rare, unpredictable, and usually due to a patient idiosyncrasy. In the person being restrained, such idiosyncratic factors may be unavoidable by law enforcement officers (LEO) in the field. These are unlike predictable (Type-A) SAEs, which have their corollary amongst secondary CED-associated deaths, e.g., head injury among cyclists or ignition of an inflammable atmosphere by the CED, and are identifiable risk factors for which LEO can train. Regardless, absolute CED tolerability is obviously greater than that for firearms. A prospective registry of CED deployments would measure this more precisely. PMID- 23092851 TI - Mouth care for orally intubated patients: a critical ethnographic review of the nursing literature. AB - OBJECTIVES: The aim of this critical ethnographic literature review was to explore the evolution of nursing discourse in oral hygiene for intubated and mechanically ventilated patients. METHODS: The online databases CINAHL and MEDLINE were searched for nurse-authored English language articles published between 1960 and 2011 in peer-reviewed journals. Articles that did not discuss oral problems or related care for intubated adult patients were excluded. Articles that met the inclusion criteria were chronologically reviewed to trace changes in language and focus over time. RESULTS: A total of 469 articles were identified, and 84 papers met all of the inclusion criteria. These articles presented an increasingly scientific and evaluative nursing discourse. Oral care originally focused on patient comfort within the literature; now it is emphasized as an infection control practice for the prevention of ventilator-associated pneumonia (VAP). Despite concern for its neglected application, the literature does not sufficiently address mouth care's practical accomplishment. CONCLUSIONS: Mouth care for orally intubated patients is both a science and practice. However, the nursing literature now emphasises a scientific discourse of infection prevention. Inattention to the social and technical complexities of practice may inhibit how nurses learn, discuss and effectively perform this critical aspect of patient care. PMID- 23092852 TI - Nanometric locking of the tight focus for optical microscopy and tip-enhanced microscopy. AB - We have successfully stabilized the tight focus onto the sample surface of an optical microscope within +/-1.0 nm for a virtually unlimited time duration. The time-dependent thermal drift of the tight focus and the mechanical tilt of the sample surface were simultaneously sensed by a non-optical means based on a capacitive sensor and were compensated for in real-time. This non-optical scheme is promising for the suppression of background light sources for optical microscopy. The focus stabilization is crucial for microscopic measurement at an interface, particularly when scanning a large surface area, because there is always a certain amount of mechanical tilt of the sample substrate, which degrades the contrast of the image. When imaging nanoscopic materials such as carbon nanotubes or silicon nanowires, more stringent nanometric stabilization of the focus position relative to such samples is required, otherwise it is often difficult to interpret the results from the observations. Moreover, the smaller the sample volume is, the smaller the signal becomes, resulting in a long exposure time at each position. In this sense, long-term stability of the tight focus is essential for both microscopic large area scanning and nanosized sample scanning (high-resolution/large-area imaging). In addition, the recently developed tip-enhanced microscopy requires long-term stability of the relative position of the tip, sample and focus position. We were able to successfully demonstrate a stability improvement for tip-enhanced microscopy in the same manner. The stabilization of the tight focus enables us to perform long-term and robust measurements without any degradation of optical signal, resulting in the capability of true nanometric optical imaging with good reproducibility and high precision. The technique presented is a simple add-on for any kind of optical microscope. PMID- 23092850 TI - Moderators of the association between exercise identity and obligatory exercise among participants of an athletic event. AB - Previous research has connected exercise identity with obligatory exercise, yet to date no empirical studies have identified moderator variables of this association. The current study included participants of an athletic event (full marathon, n=582; half marathon, n=1,106; shorter distance, n=733) who completed questionnaires about exercise behaviors, obligatory exercise, and internalization of both the thin-ideal and athletic-ideal body shapes. General linear model analyses were conducted to examine the exercise identity-obligatory exercise relationship; moderator variables included gender, internalization of the thin ideal body shape, and internalization of the athletic-ideal body shape. After controlling for the effects of body mass index, age, and distance group, the three-way interaction of exercise identity, gender, and internalization of the athletic-ideal body shape predicted obligatory exercise. Findings suggest that women who report high identification with exercise and high value on having an athletic physique may be vulnerable to obligatory exercise. PMID- 23092853 TI - Electron microscopy in the diagnosis of malignant fibrous histiocytoma of the lung presenting as metastasis to the maxillary gingiva. AB - A rare case of an initial presentation of a metastatic lesion on the gingiva, arising from malignant fibrous histiocytoma (MFH) of the lung is reported. The role of electron microscopy in the diagnosis of soft tissue sarcomas has been studied. The ultrastructural details of a MFH are described and illustrated. The patient died within 9 weeks of the initial presentation with a gingival mass as is normal in these cases. He developed metastatic disease of the liver, lymph nodes, and bone. The role of electron microscopy in the diagnosis of soft tissue sarcomas is discussed. PMID- 23092854 TI - Surgically assisted rapid maxillary expansion: feasibility of not releasing the nasal septum. AB - Surgically assisted rapid maxillary expansion (SARME) is commonly used to correct maxillary transverse deficiency. The aim of this study was to analyse the need for intraoperative liberation of the nasal septum during the procedure. SARME was performed in 25 patients by combining a lateral osteotomy with an inter-radicular maxillary osteotomy. The deviation of the nasal septum after SARME was evaluated by comparing measurements between radiologically defined landmarks on pre- and postoperative computed tomographic images. Two defined angles (angle I, between crista galli-symphysis mandibulae and crista galli-septum nasi; angle II, between maxillary plane and septum nasi) were measured based on four representative planes and septal movement was analysed. The mean changes in angles I (0.03 degrees +/- 0.78 degrees ) and II (0.25 degrees +/- 1.04 degrees ) did not differ significantly from zero (p=0.87 and p=0.24, respectively). Observed variations and displacements were considered to be acceptable because they were insignificant in every respect. Intranasal airway function was also examined pre- and postoperatively to evaluate any loss of ventilation. The described surgical technique is a successful method of maxillary segment distraction. The authors found no compelling reason to release the nasal septum in the context of SARME. PMID- 23092855 TI - CT and MRI findings of sarcomatoid cholangiocarcinoma. AB - Computed tomography (CT) and magnetic resonance imaging (MRI) findings for a case of intrahepatic sarcomatoid cholangiocarcinoma is presented. A 48-year-old man with upper abdominal pain underwent contrast-enhanced CT and MRI. A 13 * 10 * 7 cm mass was seen in the left liver lobe, which had hypodense internal architecture on CT and mixed signal intensities on both T1- and T2-weighted images with an overwhelmingly hypointense signal on T1-weighted images and a hyperintense signal on T2-weighted images. The lesion had heterogeneous enhancement on both CT and MRI. A satellite nodule with the same imaging features was distinctive for the lesion. PMID- 23092857 TI - Cardiovascular abnormalities in Klinefelter syndrome. AB - BACKGROUND: Several epidemiological studies have demonstrated an increased mortality from cardiovascular causes in patients with Klinefelter Syndrome (KS). Little information is available about the nature of the underlying cardiovascular abnormalities. Aim of the study was to investigate exercise performance, left ventricular architecture and function, vascular reactivity, and carotid intima media thickness in a group of patients with KS. MATERIALS AND METHODS: Sixty-nine patients with KS and 48 age-matched controls participated in our population controlled study. Forty-eight Klinefelter subjects were on testosterone treatment at the time of the investigation while 21 were naive and underwent a complete Doppler echocardiographic examination, a cardiopulmonary exercise test as well as a vascular study including measures of carotid intima-media thickness and endothelial function with flow-mediated dilation of the brachial artery. Patients with KS on testosterone therapy (n=48) were also matched against a population of men with treated secondary hypogonadism (n=21). RESULTS: Patients with KS exhibited a wide array of cardiovascular abnormalities including left ventricular diastolic dysfunction, reduced maximal oxygen consumption (p<0.01), increased intima-media thickness (p<0.05) (-34% and +42% vs. controls, respectively) and a high prevalence of chronotropic incompetence (55% of patients, p<0.01). No significant difference was found between treated and untreated KS in variance with men treated for secondary hypogonadism. CONCLUSION: Left ventricular diastolic dysfunction, impaired cardiopulmonary performance, chronotropic incompetence, and increased intima-media thickness suggest that cardiovascular abnormalities are a common finding in KS that is not reversed by testosterone replacement therapy and may represent the pathophysiological underpinnings of the increased risk of dying from heart disease. PMID- 23092858 TI - Long term culture of cells patterned on glass via membrane-tethered oligonucleotides. AB - Oligonucleotide-based membrane inserts can be used as tethers to control attachment of cells to patterned surfaces without interfering with internal cytoskeletal modes of adhesion. Such control can be employed as a means for study of cell-cell interactions or side-by-side co-culture of different cell types without separation/sorting. While there is utility for cell patterning methods decoupled from natural cytoskeletal mechanisms, the consequences of maintaining this artificially induced state of attachment remains unexplored. We present a method for the 2-dimensional patterning of cells via hybridization of membrane tethered single stranded oligonucleotides to complimentary single stranded oligonucleotides bound to optically transparent glass substrates which allowed us to characterize the long term culture of patterned HEK293 cells. Patterned substrates immersed in FBS-containing media are shown to permit the adsorption of adhesive serum proteins which allowed for the spreading and engagement of natural cytoskeletal adhesion modes in cells initially attached only through DNA hybridization. We show that the coexisting modes of attachment result in competition between membrane-bound tethers and natural cytoskeletal adhesion machinery as cells attempt to migrate away from their initial points of attachment. This competition ends in the escape of cells from their designated patterns and the 'winning out' of cytoskeletal migration forces over the affinity of lipid inserts for the cell membrane. PMID- 23092856 TI - Kinetic analysis and evaluation of the mechanisms involved in the resolution of experimental nontypeable Haemophilus influenzae-induced otitis media after transcutaneous immunization. AB - Transcutaneous immunization (TCI) is a simple and needle-free method with which to induce protective immune responses. Using a chinchilla model of nontypeable Haemophilus influenzae (NTHI)-induced otitis media (OM), we examined the efficacy afforded by TCI with a novel chimeric immunogen called 'chimV4' which targets two critical adhesins expressed by NTHI, outer membrane protein P5 and the majority subunit of NTHI Type IV pilus, PilA. Experimental OM was first established in cohorts of animals, and then TCI performed via a therapeutic immunization regime by rubbing vaccine formulations on hydrated pinnae. The kinetics of resolution of established experimental disease was evaluated by clinically-relevant assessments of OM, bacterial culture of planktonic and adherent NTHI within the middle ear and gross examination of the relative amount of NTHI mucosal biofilms within the middle ear space. Within seven days after primary TCI, a significant reduction in the signs of OM, significantly fewer NTHI adherent to the middle ear mucosa and significant resolution of mucosal biofilms was detected in animals that received chimV4+ the adjuvant LT(R192G-L211A), compared to animals administered LT(R192G L211A) alone or saline by TCI (p<0.05) with eradication of NTHI within an additional seven days. The mechanism for rapid disease resolution involved efflux of activated dermal dendritic cells from the pinnae after TCI, secretion of factors chemotactic for CD4(+) T-cells, induction of polyfunctional IFNgamma- and IL-17-producing CD4(+) T-cells and secretion of host defense peptide within the middle ear. These data support TCI as a therapeutic intervention against experimental NTHI-induced OM and begin to elucidate the host response to immunization by this noninvasive regimen. PMID- 23092859 TI - Multifunctional Fe3O4@C@Ag hybrid nanoparticles as dual modal imaging probes and near-infrared light-responsive drug delivery platform. AB - Multifunctional nanocarriers based on Fe(3)O(4)@C@Ag hybrid nanoparticles with a diameter of 200 nm were fabricated by a facile method. Silver (Ag) nanoparticles were deposited onto the surface of Fe(3)O(4)@C nanospheres in dimethyl formamide (DMF) solution by reducing silver nitrate (AgNO(3)) with glucose. The nanocarriers of doxorubicin (DOX) with a high loading content of 997 mg/g and near-infrared (NIR) light-responsive drug delivery based on Ag nanoparticles were realized. Strong fluorescence can be observed in cell nucleus due to the presence of DOX after irradiated by NIR, and most cells were in the state of apoptosis, which indicates NIR-regulated drug release was realized. Moreover, measurements show that the nanocarriers could also be used as magnetic resonance imaging (MRI) contrast agents and fluorescent probes. The combination of synergistic NIR controlled drug release and dual modal imaging of MRI and two-photon fluorescence (TPF) imaging could lead to a potential multifunctional system for biomedical diagnosis and therapy. PMID- 23092860 TI - Multilineage differentiation of human-derived dermal fibroblasts transfected with genes coated on PLGA nanoparticles plus growth factors. AB - Wounded tissues and cells may be treated with growth factors and specific genes for the purpose of tissue repair and regeneration. To deliver specific genes into tissues and cells, this study presents the use of fabricated poly (DL-lactic-co glycolic acid) (PLGA) nanoparticles (NPs) complexed with the cationic polymer poly (ethleneimine) (PEI). Through complexation with PEI, several types of genes (SOX9, Cbfa1, and C/EBP-alpha) were coated into PLGA NPs, which enhanced gene uptake into normal human-derived dermal fibroblast cells (NFDHCs) in vitro and in vivo. Several cell types (293T, HeLa, and fibroblast cells) were transfected with fluorescence-tagged PEI/SOX9, PEI/Cbfa1, and PEI/C/EBP-alpha gene-complexed PLGA NPs. The gene and protein expression levels in the cells were evaluated by RT PCR, real-time quantitative PCR, Western blotting, and confocal laser microscopy. Fibroblast cells encapsulated in fibrin gels were transfected with the gene complexed NPs plus specific growth factors (TGF-beta3, BMP-2, or IGF/bFGF), which induced chondrogenesis, osteogenesis, or adipogenesis both in vitro and after transplantation into nude mouse. PMID- 23092862 TI - Scalable production of controllable dermal papilla spheroids on PVA surfaces and the effects of spheroid size on hair follicle regeneration. AB - Organ size and numbers are vital issues in bioengineering for hair follicle (HF) regeneration. Murine HF dermal papilla (DP) cells are able to induce HF neogenesis when transplanted as aggregates. However, how the preparation of murine and human DP aggregates affects HF inductivity and the size of regenerated HF is yet to be determined. Here we report a scalable method for production of controllable human and rat DP spheroids in general labs for reproducible experiments. Compared with more hydrophobic polyethylene and poly(ethylene-co vinyl alcohol), DP cells are poorly adhesive to hydrophilic polyvinyl alcohol (PVA). Seeded in PVA-coated 96-welled commercial PCR tube arrays, DP cells quickly aggregate into single spheroids with progressive compaction. Varying seeded cell numbers and culture periods enables us to control the size and cell number of the spheroids. The spheroids obtained have high viability and preserve DP characters. A proof of principle experiment was conducted to examine the size effect on the efficiency and efficacy of HF regeneration. We found that both human and rat DP spheroids are able to induce HF neogenesis and larger DP spheroids exhibit higher HF inductivity. However, the average diameter of regenerated hair fiber did not significantly change with the increasing size of transplanted DP spheroids. The result suggests that an appropriate size of DP spheroid is essential for HF inductivity, but its size cannot be directly translated to a thicker regenerated hair. Our results also have implications on the efficiency and efficacy in the regeneration of other epithelial organs. PMID- 23092861 TI - Application of visible light-based projection stereolithography for live cell scaffold fabrication with designed architecture. AB - One-step scaffold fabrication with live cell incorporation is a highly desirable technology for tissue engineering and regeneration. Projection stereolithography (PSL) represents a promising method owing to its fine resolution, high fabrication speed and computer-aided design (CAD) capabilities. However, the majority of current protocols utilize water-insoluble photoinitiators that are incompatible with live cell-fabrication, and ultraviolet (UV) light that is damaging to the cellular DNA. We report here the development of a visible light based PSL system (VL-PSL), using lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP) as the initiator and polyethylene glycol diacrylate (PEGDA) as the monomer, to produce hydrogel scaffolds with specific shapes and internal architectures. Furthermore, live human adipose-derived stem cells (hADSCs) were suspended in PEGDA/LAP solution during the PSL process, and were successfully incorporated within the fabricated hydrogel scaffolds. hADSCs in PEG scaffolds showed high viability (>90%) for up to 7 days after fabrication as revealed by Live/Dead staining. Scaffolds with porous internal architecture retained higher cell viability and activity than solid scaffolds, likely due to increased oxygen and nutrients exchange into the interior of the scaffolds. The VL-PSL should be applicable as an efficient and effective tissue engineering technology for point of-care tissue repair in the clinic. PMID- 23092863 TI - Cationic solid lipid nanoparticles derived from apolipoprotein-free LDLs for target specific systemic treatment of liver fibrosis. AB - Low density lipoprotein (LDL) plays an important role in transporting fat molecules including cholesterols in the body. In this work, cationic solid lipid nanoparticles (CSLNs), bioinspired and reconstituted from natural LDLs, were designed and applied to target specific systemic delivery of connective tissue growth factor siRNA (siCTGF) for the treatment of liver fibrosis. They could form a nuclease-resistant stable nano-complex with siRNA, which was efficiently internalized into cells achieving targeted gene silencing in the presence of serum with a remarkably low cytotoxicity. After intravenous injection, CSLN/siCTGF complex was target specifically delivered to the liver and resulted in a significant reduction in collagen content and pro-fibrogenic factors like tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta (TGF beta), interleukin-6 (IL-6), and CTGF with the dramatic improvement of patho physiological symptoms in liver fibrosis model rats. The bio-distribution study by fluorescence bioimaging and single-photon emission computed tomography (SPECT) confirmed the target specific delivery and accumulation of CSLN/siCTGF complexes to the liver tissues. PMID- 23092864 TI - Approaches to synthetic platelet analogs. AB - Platelet transfusion is routinely used for treating bleeding complications in patients with hematologic or oncologic clotting disorders, chemo/radiotherapy induced myelosuppression, trauma and surgery. Currently, these transfusions mostly use allogeneic platelet concentrates, while products like lyophilized platelets, cold-stored platelets and infusible platelet membranes are under investigation. These natural platelet-based products pose considerable risks of contamination, resulting in short shelf-life (3-5 days). Recent advances in pathogen reduction technologies have increased shelf-life to ~7 days. Furthermore, natural platelets are short in supply and also cause several biological side effects. Hence, there is significant clinical interest in platelet-mimetic synthetic analogs that can allow long storage-life and minimum side effects. Accordingly, several designs have been studied which decorate synthetic particles with motifs that promote platelet-mimetic adhesion or aggregation. Recent refinement in this design involves combining the adhesion and aggregation functionalities on a single particle platform. Further refinement is being focused on constructing particles that also mimic natural platelet's shape, size and elasticity, to influence margination and wall-interaction. The optimum design of a synthetic platelet analog would require efficient integration of platelet's physico-mechanical properties and biological functionalities. We present a comprehensive review of these approaches and provide our opinion regarding the future directions of this research. PMID- 23092865 TI - Emerging rules for inducing organ regeneration. AB - We review the available evidence for regeneration of adult organs of very diverse nature and examine the applicability of simple rules that can be used to summarize these treatments. In the field of regenerative medicine no widely accepted paradigm is currently available that can guide formulation of new theories on the mechanism of regeneration in adults and open new directions for improved regeneration outcomes. The four rules have emerged from multiyear quantitative studies with skin and peripheral nerve regeneration using scaffold libraries based on a simple, well-defined collagen scaffold. These largely quantitative rules distinguish sharply between spontaneously regenerative and nonregenerative tissues, select the two reactants that are required for regeneration, recognize the essential modification of the wound healing process that must be realized prior to regeneration, and identify three structural features of scaffolds that are required for regenerative activity. The combined evidence points at certain requirements for the structure of a collagen scaffold with regenerative activity. An active scaffold emerges as a temporarily insoluble collagen surface, equipped with sufficient ligands for integrins of contractile cells, that inhibits wound contraction while also serving as a topographic template for new stroma synthesis. The four rules, based on studies with just two organs (skin and peripheral nerves), are now viewed in the context of ongoing studies using scaffolds based on decellularized matrices, which are mostly based on collagen. Decellularized matrices have been used during the past few years to regenerate, in whole or in part, the urethra, the abdominal wall, the Achilles tendon, the bladder, the trachea and other organs in several animal models and occasionally in humans. Although these acellular matrices are distinctly different from simple collagen scaffolds, and the methods used by the investigators are still evolving, the results obtained are shown to be broadly consistent with the predictions of the four rules. Future use or adaptations of these largely quantitative rules could account more satisfactorily for problems, such as imperfect function of regenerated organs, that are currently encountered by researchers. It could also further the explanation of the mechanism of regeneration at the cellular and molecular level. PMID- 23092866 TI - Combination therapy for the treatment and prevention of hepatic encephalopathy. AB - OBJECTIVE: To evaluate the efficacy and safety of combination therapy for the treatment and prevention of hepatic encephalopathy (HE). DATA SOURCES: A PubMed MEDLINE search was conducted (1947-June 2012) using the key terms lactulose, lactitol, nonabsorbable disaccharide, metronidazole, rifaximin, neomycin, probiotics, and hepatic encephalopathy. Searches were limited to include articles published in English. STUDY SELECTION AND DATA EXTRACTION: Study selection included published trials, case reports, and case series of humans with HE who were treated with combination therapy of rifaximin, lactulose, lactitol, metronidazole, neomycin, and/or probiotics. DATA SYNTHESIS: Only 6 studies that evaluated the benefits of combination drug therapy in the treatment or prevention of HE were available for review. Four studies addressed the treatment of HE, 2 found no significant difference between lactulose/neomycin versus placebo or rifaximin/lactulose, 1 assessed the use of rifaximin/lactulose without a control group, and the fourth found no significant difference between lactulose/probiotics versus either drug alone, although each group showed improvement from baseline. In the 2 prevention trials, both of which stemmed from the same data, the combination of rifaximin/lactulose was superior to lactulose alone, showing significant improvement in mental status, blood ammonia levels, and health-related quality of life and reductions in HE recurrence and hospitalization. Currently, there are no available clinical studies evaluating dual antibiotic therapy, metronidazole with nonabsorbable disaccharides, or antibiotics with probiotics. CONCLUSIONS: The evidence evaluating the use of combination therapy for the treatment of HE does not support its widespread use. The combination of rifaximin and lactulose may be considered in the treatment of HE and in patients refractory to monotherapy. The combination of rifaximin and lactulose should be considered for the prevention of HE, especially after the second episode of HE recurrence. PMID- 23092867 TI - Tafluprost: the first preservative-free prostaglandin to treat open-angle glaucoma and ocular hypertension. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trial data, efficacy data, and adverse effect incidence of tafluprost. DATA SOURCES: A literature search was completed using PubMed, Web of Science, and Google Scholar. Tafluprost was the primary search term. Articles published between January 2008 and April 2012 were included in this review. Additional limits placed on the searches were "human" and "English." Citations in which tafluprost appeared in the title were 36, 29, and more than 300 in PubMed, Web of Science, and Google Scholar, respectively. STUDY SELECTION AND DATA EXTRACTION: Three clinical trials were included in this review. One trial enrolled more than 500 subjects in a randomized fashion. Another also enrolled more than 500 subjects, although the study design was not randomized. The third trial evaluated the effects of tafluprost on subjects who had recently discontinued use of latanoprost, another prostaglandin that is approved to treat glaucoma and ocular hypertension. The duration of all 3 trials was 12 weeks. DATA SYNTHESIS: Tafluprost 0.0015% is the first topical prostaglandin approved by the Food and Drug Administration for treatment of open-angle glaucoma and ocular hypertension that does not contain the widely used preservative, benzalkonium chloride (BAK). Although some controversy surrounds the long-term safety of exposure to BAK, clinical trial data are inconclusive. Tafluprost, like other prostaglandin analogues, exerts its effects on prostaglandin F receptors to reduce intraocular pressure (IOP). Results from 1 trial demonstrated significant reductions in IOP when monotherapy was switched to tafluprost monotherapy. Reductions in IOP with tafluprost use were compared with those seen with use of timolol and latanoprost in 2 trials, and noninferiority was observed. Significant reductions in tear osmolarity were noted in subjects who changed from latanoprost, another prostaglandin analogue, to tafluprost therapy. Conjunctival hyperemia is the most common adverse effect seen in patients receiving drugs from this class. Many have also reported stinging, ocular pruritus, increased darkening or growth of eyelashes, and darkening of eyelids, as well as irreversible brown pigmentation of the iris. CONCLUSIONS: Clinical trial data suggest that tafluprost is as efficacious as other agents used in the management of ocular hypertension and glaucoma. Its use may be especially advantageous in people with allergies, sensitivities to preservatives, or dry or sensitive eyes. PMID- 23092868 TI - Mixed treatment comparison of the treatment discontinuations of biologic disease modifying antirheumatic drugs in adults with rheumatoid arthritis. AB - BACKGROUND: Introduction of biologic disease-modifying antirheumatic drugs (DMARDs) has considerably changed treatment options for rheumatoid arthritis (RA) over the past decade. Very little information is available on comparative discontinuation rates of the biologics. OBJECTIVE: To compare treatment discontinuations for 9 biologic DMARDs in adults with RA. METHODS: We searched electronic databases through May 2012 to retrieve randomized controlled trials (RCTs) of patients with RA that compared biologic DMARDs with placebo or another biologic DMARD. The primary outcome was treatment discontinuation during the blinded phase of the trials, measured as overall withdrawals, withdrawals resulting from lack of efficacy, and withdrawals resulting from adverse events. Random-effects meta-analysis estimated the effect size for individual agents, and adjusted indirect comparisons were made between biologics using mixed treatment comparisons (MTC) meta-analysis. RESULTS: Forty-four trials were included in the analysis. In comparison with placebo, biologics were less likely to be withdrawn because of lack of efficacy (OR 0.22, 95% CI 0.17 to 0.27) and more likely to be withdrawn because of an adverse event (OR 1.41, 95% CI 1.16 to 1.70). Based on the MTC, certolizumab had the most favorable overall withdrawal profile, followed by etanercept and rituximab. Certolizumab had lower relative withdrawal rates resulting from lack of efficacy than adalimumab, anakinra, and infliximab. Anakinra had higher relative withdrawal rates resulting from lack of efficacy than most other biologics. Certolizumab and infliximab had more, while etanercept had fewer, withdrawals because of adverse events than most other drugs. CONCLUSIONS: Based on MTC using data from RCTs, differences in discontinuation rates were observed, generally favoring certolizumab, etanercept, and rituximab over other biologic DMARDs. These potential differences need to be further explored in head-to-head trials or well-conducted observational studies. PMID- 23092869 TI - Capillary electrophoresis with photodiode array detection of processable poly(3,4 ethylenedioxythiophene)/polystyrene sulfonate aqueous dispersions. AB - The application of capillary electrophoresis (CE) with on-line photodiode array detection to the analysis of processable poly(3,4 ethylenedioxythiophene)/polystyrene sulfonate (PEDOT/PSS) aqueous dispersions is presented. The dispersions were prepared by oxidative polymerization of 3,4 ethylenedioxythiophene (EDOT) in the presence of PSS. The separation of PEDOT/PSS complexes and PSS was achieved using sodium borate (pH 9.2) in a fused silica capillary and positive polarity. The electrophoretic behavior and UV spectra of the negatively charged complexes were correlated to the amount of PEDOT attached to PSS. The ability of CE to predict the conductivity of films produced from spin coating of PEDOT/PSS dispersions was also proposed. PMID- 23092870 TI - New medium-to-high polarity twister coatings for liquid and vapour phase sorptive extraction of matrices of vegetable origin. AB - Stir Bar Sorptive Extraction (SBSE) is a solventless sampling technique first introduced to extract organic analytes from aqueous samples, in the following applied to headspace sampling (HeadSpace Sorptive Extraction - HSSE). In SBSE and HSSE, analytes are sorbed onto a thick film of polydimethylsiloxane (PDMS) coating a glass-coated magnet. However, PDMS is apolar and not highly effective in recovering polar analytes (i.e. with logK(o/w) below 2), making difficult their sampling in complex matrices. A new generation of medium-to-high polarity polymeric coatings for twisters i.e. polyethyleneglycol-modified silicone (EG) and polyacrylate/polyethyleneglycol (PA) has recently been introduced to overcome this limit. In this study, EG and PA twisters have been applied to SBSE and HSSE of a number of dedicated standard mixtures and real-world samples of vegetable origin to evaluate their capability to increase recovery of medium to highly polar analytes. The results obtained, expressed as percent concentration factor (CF%) versus PDMS twisters taken as reference, showed that analyte logK(o/w) is a key-factor driving the choice of the most effective coating. The new twisters showed to be successful for both SBSE and HSSE, although to a different extent. EG twisters gave high recoveries with analytes over a wide range of polarities and in particular with logK(o/w) below 2 and/or containing hydroxyl or carboxylic functional groups independently on their logK(o/w). On the other hand, PA twisters were selectively effective for highly polar compounds with logK(o/w) below 1. PMID- 23092871 TI - Analysis of drug interactions with modified proteins by high-performance affinity chromatography: binding of glibenclamide to normal and glycated human serum albumin. AB - High-performance affinity chromatography (HPAC) was used to examine the changes in binding that occur for the sulfonylurea drug glibenclamide with human serum albumin (HSA) at various stages of glycation for HSA. Frontal analysis on columns containing normal HSA or glycated HSA indicated glibenclamide was interacting through both high affinity sites (association equilibrium constant, K(a), 1.4-1.9 * 10(6)M(-1) at pH 7.4 and 37 degrees C) and lower affinity sites (K(a), 4.4-7.2 * 10(4)M(-1)). Competition studies were used to examine the effect of glycation at specific binding sites of HSA. An increase in affinity of 1.7- to 1.9-fold was seen at Sudlow site I with moderate to high levels of glycation. An even larger increase of 4.3- to 6.0-fold in affinity was noted at Sudlow site II for all of the tested samples of glycated HSA. A slight decrease in affinity may have occurred at the digitoxin site, but this change was not significant for any individual glycated HSA sample. These results illustrate how HPAC can be used as tool for examining the interactions of relatively non-polar drugs like glibenclamide with modified proteins and should lead to a more complete understanding of how glycation can alter the binding of drugs in blood. PMID- 23092872 TI - Comparison of ultra-high performance supercritical fluid chromatography and ultra high performance liquid chromatography for the analysis of pharmaceutical compounds. AB - Currently, columns packed with sub-2 MUm particles are widely employed in liquid chromatography but are scarcely used in supercritical fluid chromatography. The goal of the present study was to compare the performance, possibilities and limitations of both ultra-high performance liquid chromatography (UHPLC) and ultra-high performance supercritical fluid chromatography (UHPSFC) using columns packed with sub-2 MUm particles. For this purpose, a kinetic evaluation was first performed, and van Deemter curves and pressure plots were constructed and compared for columns packed with hybrid silica stationary phases composed of 1.7 and 3.5 MUm particles. As expected, the kinetic performance of the UHPSFC method was significantly better than that of the UHPLC. Indeed, the h(min) values were in the same range with both strategies and were between 2.2 and 2.8, but u(opt) was increased by a factor of >4 in UHPSFC conditions. Another obvious advantage of UHPSFC over UHPLC is related to the generated backpressure, which is significantly lower in the presence of a supercritical or subcritical fluid. However, the upper pressure limit of the UHPSFC system was only ~400 bar vs. ~1000 bar in the UHPLC system, which prevents the use of highly organic mobile phases at high flow rates in UHPSFC. Second, the impact of reducing the particle size (from 3.5 to 1.7 MUm) was evaluated in both UHPLC and UHPSFC conditions. The effect of frictional heating on the selectivity was demonstrated in UHPLC and that of fluid density or decompression cooling was highlighted in UHPSFC. However, in both cases, a change in selectivity was observed for only a limited number of compounds. Third, various types of column chemistries packed with 1.7 MUm particles were evaluated in both UHPLC and UHPSFC conditions using a model mixture of acidic, neutral and basic compounds. It has been shown that more drastic changes in selectivity were obtained using UHPSFC columns compared to those obtained by changing UHPLC columns. In addition, there was a good complementarity between the two separation modes. Finally, by combining the use of small particles with supercritical fluids as a mobile phase, it was possible to achieve the analysis of pharmaceutical compounds in less than 1 min or to attain a peak capacity of more than 250 in approximately 40 min, both with a high degree of repeatability. PMID- 23092873 TI - Phase I and pharmacologic trial of cytosine arabinoside with the selective checkpoint 1 inhibitor Sch 900776 in refractory acute leukemias. AB - PURPOSE: Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776. EXPERIMENTAL DESIGN: Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose. RESULTS: Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage. CONCLUSIONS: These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517. PMID- 23092874 TI - Frequent mutational activation of the PI3K-AKT pathway in trastuzumab-resistant breast cancer. AB - PURPOSE: HER2-amplified breast cancer is sometimes clinically insensitive to HER2 targeted treatment with trastuzumab. Laboratory models of resistance have causally implicated changes in HER2 expression and activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway. We conducted a prospective tissue acquisition study to determine if there is evidence for these lesions in metastatic tumors that have progressed on trastuzumab-containing therapy. EXPERIMENTAL DESIGN: From 2/2007 to 11/2011, 63 patients with HER2-amplified breast cancer with recurrence of disease after adjuvant trastuzumab therapy or World Health Organization-defined progression of metastatic disease on a trastuzumab-containing regimen were prospectively enrolled and underwent tumor biopsy. Specimens were analyzed for activating mutations in PIK3CA and HER2 by Sequenom and analyzed for HER2 and PTEN status by immunohistochemistry. RESULTS: In 53/60 cases (88%, 3 cases not evaluable for HER2), HER2 overexpression persisted in the metastatic tumor following trastuzumab exposure. Among the 7 cases lacking HER2 overexpression, repeat analysis of the pretreatment tumor failed to confirm HER2 overexpression in five cases. Among cases evaluable for PTEN (56) or PI3K mutation (45), absent or significantly diminished PTEN expression was noted in 33 (59%) and activating mutations in PIK3CA in 13 (29%). The combined rate of PTEN loss and PIK3CA mutation in the trastuzumab-refractory tumors was 71% compared with 44% (P = 0.007) in an unexposed cohort of 73 HER2 amplified tumors. CONCLUSIONS: In this series of prospectively collected trastuzumab-refractory human breast cancers, loss of HER2 overexpression was rare, whereas activation of the PI3K-AKT pathway through loss of PTEN or PIK3CA mutation was frequently observed. PMID- 23092875 TI - Do imaging biomarkers relate to outcome in patients treated with VEGF inhibitors? AB - The management of solid tumors has been transformed by the advent of VEGF pathway inhibitors. Early clinical evaluation of these drugs has used pharmacodynamic biomarkers derived from advanced imaging such as dynamic MRI, computed tomography (CT), and ultrasound to establish proof of principle. We have reviewed published studies that used these imaging techniques to determine whether the same biomarkers relate to survival in renal, hepatocellular, and brain tumors in patients treated with VEGF inhibitors. Data show that in renal cancer, pretreatment measurements of K(trans) and early pharmacodynamic reduction in tumor enhancement and density have prognostic significance in patients treated with VEGF inhibitors. A weaker, but significant, relationship is seen with subtle early size change (10% in one dimension) and survival. Data from high-grade glioma suggest that pretreatment fractional blood volume and K(trans) were prognostic of overall survival. However, lack of control data with other therapies prevents assessment of the predictive nature of these biomarkers, and such studies are urgently required. PMID- 23092876 TI - Adoptive transfer of autologous T cells improves T-cell repertoire diversity and long-term B-cell function in pediatric patients with neuroblastoma. AB - PURPOSE: Children with high-risk neuroblastoma have a poor prognosis with chemotherapy alone, and hematopoietic stem cell transplantation offers improved survival. As a dose-escalation strategy, tandem transplants have been used, but are associated with persistent immunocompromise. This study evaluated the provision of an autologous costimulated, activated T-cell product to support immunologic function. EXPERIMENTAL DESIGN: Nineteen subjects with high-risk neuroblastoma were enrolled in a pilot phase and 23 subjects were entered in to the randomized study. Immunologic reconstitution was defined by flow cytometric and functional assays. Next-generation sequencing was conducted to identify changes to the T-cell repertoire. Twenty-two patients were vaccinated to define effects on antibody responses. RESULTS: Subjects who received their autologous costimulated T-cell product on day 2 had significantly superior T-cell counts and T-cell proliferation compared with those who received T cells on day 90. Early administration of autologous T cells suppressed oligoclonality and enhanced repertoire diversity. The subjects who received the day 2 T-cell product also had better responses to the pneumococcal vaccine. CONCLUSIONS: The infusion of activated T cells can improve immunologic function especially when given early after transplant. This study showed the benefit of providing cell therapies during periods of maximum lymphopenia. PMID- 23092877 TI - GH improves spatial memory and reverses certain anabolic androgenic steroid induced effects in intact rats. AB - GH has previously been shown to promote cognitive functions in GH-deficient rodents. In this study we report the effects of GH on learning and memory in intact rats pretreated with the anabolic androgenic steroid nandrolone. Male Wistar rats received nandrolone decanoate (15 mg/kg) or peanut oil every third day for 3 weeks and were subsequently treated with recombinant human GH (1.0 IU/kg) or saline for 10 consecutive days. During the GH/saline treatment spatial learning and memory were tested in the Morris water maze (MWM). Also, plasma levels of IGF1 were assessed and the gene expression of the GH receptors (Ghr), Igf1 and Igf2, in hippocampus and frontal cortex was analyzed. The results demonstrated a significant positive effect of GH on memory functions and increased gene expression of Igf1 in the hippocampus was found in the animals treated with GH. In addition, GH was demonstrated to increase the body weight gain and was able to attenuate the reduced body weight seen in nandrolone-treated animals. In general, the rats treated with nandrolone alone did not exhibit any pronounced alteration in memory compared with controls in the MWM, and in many cases GH did not induce any alteration. Regarding target zone crossings, considered to be associated with spatial memory, the difference between GH- and steroid-treated animals was significant and administration of GH improved this parameter in the latter group. In conclusion, GH improves spatial memory in intact rats and can reverse certain effects induced by anabolic androgenic steroid. PMID- 23092878 TI - Automated recognition and quantification of pancreatic islets in Zucker diabetic fatty rats treated with exendin-4. AB - Type 2 diabetes is characterized by impaired insulin secretion from pancreatic beta-cells. Quantification of the islet area in addition to the insulin-positive area is important for detailed understanding of pancreatic islet histopathology. Here we show computerized automatic recognition of the islets of Langerhans as a novel high-throughput method to quantify islet histopathology. We utilized state of-the-art tissue pattern recognition software to enable automatic recognition of islets, eliminating the need to laboriously trace islet borders by hand. After training by a histologist, the software successfully recognized even irregularly shaped islets with depleted insulin immunostaining, which were quite difficult to automatically recognize. The results from automated image analysis were highly correlated with those from manual image analysis. To establish whether this automated, rapid, and objective determination of islet area will facilitate studies of islet histopathology, we showed the beneficial effect of chronic exendin-4, a glucagon-like peptide-1 analog, treatment on islet histopathology in Zucker diabetic fatty (ZDF) rats. Automated image analysis provided qualitative and quantitative evidence that exendin-4 treatment ameliorated the loss of pancreatic insulin content and gave rise to islet hypertrophy. We also showed that glucagon-positive alpha-cell area was decreased significantly in ZDF rat islets with disorganized structure. This study is the first to demonstrate the utility of automatic quantification of digital images to study pancreatic islet histopathology. The proposed method will facilitate evaluations in preclinical drug efficacy studies as well as elucidation of the pathophysiology of diabetes. PMID- 23092879 TI - Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system. AB - Angiotensin (Ang)-(1-7) is now recognized as a biologically active component of the renin-angiotensin system (RAS). Ang-(1-7) appears to play a central role in the RAS because it exerts a vast array of actions, many of them opposite to those attributed to the main effector peptide of the RAS, Ang II. The discovery of the Ang-converting enzyme (ACE) homolog ACE2 brought to light an important metabolic pathway responsible for Ang-(1-7) synthesis. This enzyme can form Ang-(1-7) from Ang II or less efficiently through hydrolysis of Ang I to Ang-(1-9) with subsequent Ang-(1-7) formation by ACE. In addition, it is now well established that the G protein-coupled receptor Mas is a functional binding site for Ang-(1 7). Thus, the axis formed by ACE2/Ang-(1-7)/Mas appears to represent an endogenous counterregulatory pathway within the RAS, the actions of which are in opposition to the vasoconstrictor/proliferative arm of the RAS consisting of ACE, Ang II, and AT(1) receptor. In this brief review, we will discuss recent findings related to the biological role of the ACE2/Ang-(1-7)/Mas arm in the cardiovascular and renal systems, as well as in metabolism. In addition, we will highlight the potential interactions of Ang-(1-7) and Mas with AT(1) and AT(2) receptors. PMID- 23092880 TI - mTORC1 and mTORC2 regulate insulin secretion through Akt in INS-1 cells. AB - Regulated associated protein of mTOR (Raptor) and rapamycin-insensitive companion of mTOR (rictor) are two proteins that delineate two different mTOR complexes, mTORC1 and mTORC2 respectively. Recent studies demonstrated the role of rictor in the development and function of beta-cells. mTORC1 has long been known to impact beta-cell function and development. However, most of the studies evaluating its role used either drug treatment (i.e. rapamycin) or modification of expression of proteins known to modulate its activity, and the direct role of raptor in insulin secretion is unclear. In this study, using siRNA, we investigated the role of raptor and rictor in insulin secretion and production in INS-1 cells and the possible cross talk between their respective complexes, mTORC1 and mTORC2. Reduced expression of raptor is associated with increased glucose-stimulated insulin secretion and intracellular insulin content. Downregulation of rictor expression leads to impaired insulin secretion without affecting insulin content and is able to correct the increased insulin secretion mediated by raptor siRNA. Using dominant-negative or constitutively active forms of Akt, we demonstrate that the effect of both raptor and rictor is mediated through alteration of Akt signaling. Our finding shed new light on the mechanism of control of insulin secretion and production by the mTOR, and they provide evidence for antagonistic effect of raptor and rictor on insulin secretion in response to glucose by modulating the activity of Akt, whereas only raptor is able to control insulin biosynthesis. PMID- 23092881 TI - Nucleic acid modifications with epigenetic significance. AB - Epigenetic modifications influence gene expression without alterations to the underlying nucleic acid sequence. In addition to the well-known 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5 carboxycytosine (5caC) have recently been discovered in genomic DNA, which all result from iterative oxidation of 5mC by the TET (Ten-Eleven-Translocate) family of enzymes. Recent studies have proposed the roles of these oxidized cytosines in mediating active demethylation of 5mC. Through affinity-based genome-wide sequencing and oxidation-assisted base-resolution sequencing methods, 5hmC is found to be dynamically regulated during development, and is enriched mainly in distal regulatory elements in human and mouse embryonic cells. Among RNA modifications, N(6)-methyladenosine (m(6)A) is a widespread yet poorly studied base modification in mRNA and non-coding RNA. The recent discovery that m(6)A in RNA is the major substrate of the fat mass and obesity associated (FTO) protein draws attention to the potential regulatory functions of reversible RNA methylations, which can be dynamic, and could be important in many fundamental cellular functions. PMID- 23092882 TI - MicroRNA 497 modulates interleukin 1 signalling via the MAPK/ERK pathway. AB - The MAPK/ERK signalling pathway has been described to mediate IL-1 induction of target genes and is known to be regulated by microRNAs (miRNA). We describe a novel miRNA regulating the expression of the MEK1 gene and how it impacts IL-1 induced IL-6 transcription. miR-497 was predicted to target MEK1 3'UTR using bioinformatic tools. Transfection of miR-497 into HeLa cells inhibited MEK1 protein expression by 50%. In transient transfection experiments, the luciferase activity of a MEK1 3'UTR luciferase reporter construct was reduced in the presence of miR-497, and mutation of the predicted miR-497 binding site restored activity. miR-497 also decreased protein levels of RAF1 and ERK1 but not ERK2. Addition of miR-497 was further shown to inhibit IL-1 induced IL-6 gene transcription. PMID- 23092885 TI - Cigarette affordability in Europe. AB - OBJECTIVE: To analyze trends in excise taxes, real price and the affordability of cigarettes in Europe, and to examine the impact of EU wide tax policies on new member states. DESIGN: We use a sample of 37 European countries with data from 2004 to 2010. 27 countries are EU member states of which 12 joined in 2004 or 2007 (new members), while 10 non-EU countries are included as a comparison. Data is sourced from the European Commission and the Economist Intelligence Unit. RESULTS: The excise tax burden increased in all new member states between 2004 and 2010 while remaining relatively unchanged in existing member states. In 2010, the excise tax burden was higher in new (mean 63.8%) than in existing member states (mean 59.4%). Although cigarettes were significant cheaper in new member states the difference in affordability was narrower between the two groups. Excise taxes and prices rose aggressively in new member states while the increases in existing member states were smaller. While cigarettes became less affordable in most EU member states there was little difference between new and existing member states. The average annual percentage change in per-capita cigarette consumption was negative in all existing member states and in 9 of 12 new member states between 2004 and 2010, indicating declining per-capita cigarette consumption. CONCLUSIONS: Joining the EU results in significant increases in excise taxes and prices, and declines in affordability. Additionally, the structure of taxes, specifically the high excise tax floor resulted in higher taxes and prices. PMID- 23092883 TI - Associations between self-reported in-home smoking behaviours and surface nicotine concentrations in multiunit subsidised housing. AB - INTRODUCTION: Smoke-free policies are being increasingly promoted and adopted in subsidised multiunit housing to address disparities in residential secondhand smoke exposure. In order to inform the planning and evaluation of these policies, this study examined associations between self-reported in-home smoking and surface nicotine concentrations. METHODS: A face-to-face, cross-sectional survey was conducted from August to October 2011 with leaseholders in a probability sample of private subsidised housing units in Columbus, Ohio, without an existing smoke-free housing policy (n=301, 64% response rate). After the survey, a wipe sample was collected from a wood surface in the living room to measure surface nicotine concentrations (n=279). RESULTS: In-home smoking was reported by 56.6% of respondents. Geometric mean surface nicotine concentrations differed between non-smoking and smoking homes (11.4 vs 90.9 MUg/m(2); p<0.001), and between homes with complete, partial and no voluntary home smoking restrictions (8.9 vs 56.3 vs 145.6 MUg/m(2); p<0.001). Surface nicotine concentrations were moderately correlated (r=.52) with the total number of cigarettes smoked indoors per week. Smoking behaviours of respondents, other household members and visitors, and length of stay were independently associated with surface nicotine concentrations in a multivariable model, explaining 52% of the variance. CONCLUSIONS: Surface nicotine concentrations were significantly associated with a range of self reported in-home smoking behaviours. This measure should be considered for evaluating changes in in-home smoking behaviours after implementation of smoke free policies by subsidised housing providers. More research is needed about how surface nicotine concentrations differ over space, time and various indoor surfaces. PMID- 23092884 TI - The evolution of health warning labels on cigarette packs: the role of precedents, and tobacco industry strategies to block diffusion. AB - OBJECTIVE: To analyse the evolution and diffusion of health warnings on cigarette packs around the world, including tobacco industry attempts to block this diffusion. METHODS: We analysed tobacco industry documents and public sources to construct a database on the global evolution and diffusion of health warning labels from 1966 to 2012, and also analysed industry strategies. RESULTS: Health warning labels, especially labels with graphic elements, threaten the tobacco industry because they are a low-cost, effective measure to reduce smoking. Multinational tobacco companies did not object to voluntary innocuous warnings with ambiguous health messages, in part because they saw them as offering protection from lawsuits and local packaging regulations. The companies worked systematically at the international level to block or weaken warnings once stronger more specific warnings began to appear in the 1970s. Since 1985 in Iceland, the tobacco industry has been aware of the effectiveness of graphic health warning labels (GWHL). The industry launched an all-out attack in the early 1990s to prevent GHWLs, and was successful in delaying GHWLs internationally for nearly 10 years. CONCLUSIONS: Beginning in 2005, as a result of the World Health Organisation Framework Convention on Tobacco Control (FCTC), GHWLs began to spread. Effective implementation of FCTC labelling provisions has stimulated diffusion of strong health warning labels despite industry opposition. PMID- 23092886 TI - Impact on cardiovascular disease events of the implementation of Argentina's national tobacco control law. AB - BACKGROUND: Argentina's congress passed a tobacco control law that would enforce 100% smoke-free environments for the entire country, strong and pictorial health warnings on tobacco products and a comprehensive advertising ban. However, the Executive Branch continues to review the law and it has not been fully implemented. Our objective was to project the potential impact of full implementation of this tobacco control legislation on cardiovascular disease. METHODS: The Coronary Heart Disease (CHD) Policy Model was used to project future cardiovascular events. Data sources for the model included vital statistics, morbidity and mortality data, and tobacco use estimates from the National Risk Factor Survey. Estimated effectiveness of interventions was based on a literature review. Results were expressed as life-years, myocardial infarctions and strokes saved in an 8-year-period between 2012 and 2020. In addition we projected the incremental effectiveness on the same outcomes of a tobacco price increase not included in the law. RESULTS: In the period 2012-2020, 7500 CHD deaths, 16 900 myocardial infarctions and 4300 strokes could be avoided with the full implementation and enforcement of this law. Annual per cent reduction would be 3% for CHD deaths, 3% for myocardial infarctions and 1% for stroke. If a tobacco price increase is implemented the projected avoided CHD deaths, myocardial infarctions and strokes would be 15 500, 34 600 and 11 900, respectively. CONCLUSIONS: Implementation of the tobacco control law would produce significant public health benefits in Argentina. Strong advocacy is needed at national and international levels to get this law implemented throughout Argentina. PMID- 23092887 TI - Contextual and community factors associated with youth access to cigarettes through commercial sources. AB - OBJECTIVES: This study examines contextual and community-level characteristics associated with youth access to tobacco through commercial sources in 50 non contiguous mid-sized California communities. METHODS: The study is based on data from access surveys conducted by four confederate buyers (two men and two women) in 997 tobacco outlets. City demographics, adult smoking prevalence, and measures of tobacco outlet density, local tobacco retailer licencing and cigarette tax were included. RESULTS: Multilevel regression analyses indicated that buyer's actual age, a male clerk and asking young buyers about their age were related to successful cigarette purchases. Buyer's actual age and minimum age signs increased the likelihood that clerks will request an identification (ID). At the community level, a higher percentage of minors, higher education, and a greater percentage of African-Americans were associated with an increased likelihood of a successful purchase. Lower percentage of minors, lower education, lower percentage of African-Americans, and having a local tobacco retailer licencing were associated with the retailer asking for an ID. Additionally, supermarkets charged significantly more for a pack of cigarettes than small markets, whereas, smoke/tobacco shops and drug stores/pharmacies charged less. Higher prices were associated with higher median household income and greater percentage of Hispanics. Findings about community characteristics, however, differed by cigarette brand. CONCLUSIONS: This study enhances our understanding of the associations between contextual and community characteristics and youth access to tobacco through commercial sources which can help policymakers to identify and target at-risk communities and outlets to decrease youth access to tobacco. PMID- 23092888 TI - The influence of leg length difference on clinical outcome after revision TKA. AB - BACKGROUND: The purpose of this paper was to document the incidence of leg length changes after revision total knee arthroplasty (TKA) and its effect on clinical outcome. METHODS: Leg length difference (LLD) was prospectively measured in 85 patients using digital standing full leg radiography before and after revision TKA. Additionally the patient's subjective perception of LLD was assessed postoperatively. Linear regression models were used to study the correlation between each of these parameters and the clinical outcome after 1 year. Clinical outcome was evaluated by means of the Knee Society Score (KSS). RESULTS: Revision TKA resulted on average in an increased leg length of 5.3 mm. Sixty-five legs (76%) were lengthened with the procedure, 17 (20%) were shortened and three (4%) remained of identical length. Increased leg length after revision was positively correlated with clinical outcome at 3 months (Spearman r=0.22, p=0.044) and 1 year (Spearman r=0.26, p=0.027). The evidence for this correlation remained after correction for age, gender and diagnosis (p=0.012). The most important contributors to improved clinical outcome scores were improved pain score (Spearman r=0.19, p=0.09) and increased stability (Spearman r=0.13, p=0.24), rather than range of motion (Spearman r=-0.02, p=0.85). CONCLUSIONS: The results from our work indicate that revision TKA tends to lengthen the leg by approximately 5mm. Contrary to what might be expected, leg lengthening after revision TKA is correlated with improved clinical outcome. LEVEL OF EVIDENCE: Level 2b. PMID- 23092889 TI - PKR-dependent inflammatory signals. AB - Double-stranded RNA-dependent protein kinase (PKR) is implicated in inflammation and immune dysfunction through its regulation of mitogen-activated protein kinases, interferon regulatory factor 3, nuclear factor kappaB, apoptosis, and autophagy pathways. A study shows that PKR is also required for the activation of inflammasomes and the subsequent release of high-mobility group box 1 (HMGB1) protein, a proinflammatory cytokine. Thus, the cell stress kinase PKR has multifaceted roles in the regulation of inflammatory immune responses, and PKR and HMGB1 are attractive targets for inflammasome-associated diseases. PMID- 23092890 TI - The effects of acute and chronic stress on diabetes control. AB - Stress is an important contributor to pathological conditions in humans. Hormonal changes that occur during acute and chronic stress situations can affect glucose homeostasis in both healthy people and in those with diabetes. Several studies have reported a negative effect of acute stress on maintenance of blood glucose concentrations in patients with type 1 and type 2 diabetes. The effect of stress on glycemic control in people with diabetes may be related to a direct effect of stress hormones on blood glucose levels and an indirect effect of stress on patient behaviors related to diabetes treatment and monitoring and meal and exercise plans. In contrast, there is no clear evidence that stressful life events promote the development of diabetes in children or in adults. Stress hyperglycemia, the development of hyperglycemia during acute illness, represents another interesting connection between the stress system and glucose homeostasis. A large body of evidence supports an association between stress hyperglycemia and increased morbidity and mortality in critically ill patients. Interestingly, there is some evidence supporting a beneficial effect of insulin in reducing morbidity and mortality in patients admitted to intensive care units. Finally, stress can influence the development of type 2 diabetes indirectly by promoting obesity and metabolic syndrome. PMID- 23092891 TI - P450 oxidoreductase deficiency: a disorder of steroidogenesis with multiple clinical manifestations. AB - Cytochrome P450 enzymes catalyze the biosynthesis of steroid hormones and metabolize drugs. There are seven human type I P450 enzymes in mitochondria and 50 type II enzymes in endoplasmic reticulum. Type II enzymes, including both drug metabolizing and some steroidogenic enzymes, require electron donation from a two flavin protein, P450 oxidoreductase (POR). Although knockout of the POR gene causes embryonic lethality in mice, we discovered human POR deficiency as a disorder of steroidogenesis associated with the Antley-Bixler skeletal malformation syndrome and found mild POR mutations in phenotypically normal adults with infertility. Assay results of mutant forms of POR using the traditional but nonphysiologic assay (reduction of cytochrome c) did not correlate with patient phenotypes; assays based on the 17,20 lyase activity of P450c17 (CYP17) correlated with clinical phenotypes. The POR sequence in 842 normal individuals revealed many polymorphisms; amino acid sequence variant A503V is encoded by ~28% of human alleles. POR A503V has about 60% of wild-type activity in assays with CYP17, CYP2D6, and CYP3A4, but nearly wild-type activity with P450c21, CYP1A2, and CYP2C19. Activity of a particular POR variant with one P450 enzyme will not predict its activity with another P450 enzyme: Each POR-P450 combination must be studied individually. Human POR transcription, initiated from an untranslated exon, is regulated by Smad3/4, thyroid receptors, and the transcription factor AP-2. A promoter polymorphism reduces transcription to 60% in liver cells and to 35% in adrenal cells. POR deficiency is a newly described disorder of steroidogenesis, and POR variants may account for some genetic variation in drug metabolism. PMID- 23092892 TI - The effect of acute and chronic stress on growth. AB - Impaired bone growth is observed in many children exposed to stress, but whether the underlying cause is psychological or secondary to a variety of chronic disorders is unclear. The growth plate is specifically targeted by stress through many different mechanisms, including increased serum concentrations of proinflammatory cytokines and cortisol, as well as impaired actions of the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis. Both glucocorticoids, such as cortisol, and proinflammatory cytokines adversely affect several aspects of chondrogenesis in the growth plate, and these effects can be ameliorated by raising local IGF-1 concentrations. However, this intervention does not completely normalize growth. In children with stress related to chronic inflammation, the cornerstone of improving stress-impaired growth remains the judicious use of glucocorticoids while ensuring effective control of the disease process. Specific immunomodulatory therapy that targets the actions of tumor necrosis factor-alpha (TNFalpha) is at least partially effective at rescuing linear growth in many children with juvenile idiopathic arthritis (JIA). Patients who do not respond to anti-TNF treatment may be candidates for therapeutic agents that target other proinflammatory cytokines and for GH intervention. Although GH treatment rescues linear growth in some patients with JIA, it is unknown whether GH can rescue growth in those patients who do not respond to anticytokine therapy. Further experimental and clinical studies are needed to explore these and other new potential treatment strategies that could improve bone growth in patients who do not respond to conventional therapy. PMID- 23092894 TI - PET and SPECT tracers for glutamate receptors. AB - Radioligands for PET imaging of glutamate receptors will have the potential for studying neurological and neuropsychiatric disorders and their diagnosis and therapeutic intervention. Glutamate is the major excitatory neurotransmitter in the brain and is implicated in the pathophysiology of many neurodegenerative and neuropsychiatric disorders. Glutamate and its receptors are potential targets in the treatment of these disorders. Glutamate signaling is mediated through ionotropic and metabotropic receptors. The abundant concentration of these receptors can facilitate their in vivo quantification using positron emission tomography (PET). Glutamate receptors are a potentially important set of targets for monitoring disease progression, for evaluating the effect of therapy and for new treatment development based on the quantification of receptor occupancy. Here, we review the PET and single-photon emission computed tomography (SPECT) radioligands that have been developed for imaging glutamate receptors in living brain. PMID- 23092895 TI - Recent advances in topical ophthalmic drug delivery with lipid-based nanocarriers. AB - Ocular barriers and the poor water solubility of drug candidates present a number of problems for the development of ocular drug delivery systems. Recently, the emergence of lipid-based nanocarriers has provided a viable means of enhancing the bioavailability of ophthalmic formulations. A number of these formulations have been found to be clinically active and several others are currently undergoing clinical trials. In this review, the advantages of lipid-based nanocarriers as non-invasive topical ocular drug delivery systems are presented. Many systems, including emulsions, liposomes, cubosomes, niosomes and other lipid based nanocarriers, are reviewed. PMID- 23092893 TI - Akt phosphorylates the transcriptional repressor bmi1 to block its effects on the tumor-suppressing ink4a-arf locus. AB - The Polycomb group protein Bmi1 is a transcriptional silencer of the Ink4a-Arf locus, which encodes the cell cycle regulator p16(Ink4a) and the tumor suppressor p19(Arf). Bmi1 plays a key role in oncogenesis and stem cell self-renewal. We report that phosphorylation of human Bmi1 at Ser316 by Akt impaired its function by triggering its dissociation from the Ink4a-Arf locus, which resulted in decreased ubiquitylation of histone H2A and the inability of Bmi1 to promote cellular proliferation and tumor growth. Moreover, Akt-mediated phosphorylation of Bmi1 also inhibited its ability to promote self-renewal of hematopoietic stem and progenitor cells. Our study provides a mechanism for the increased abundance of p16(Ink4a) and p19(Arf) seen in cancer cells with an activated phosphoinositide 3-kinase to Akt signaling pathway and identifies crosstalk between phosphorylation events and chromatin structure. PMID- 23092896 TI - Haemodynamic variables and functional outcome in hypothermic patients following out-of-hospital cardiac arrest. AB - AIM OF THE STUDY: To evaluate the association between haemodynamic variables during the first 24h after intensive care unit (ICU) admission and neurological outcome in out-of-hospital cardiac arrest (OHCA) victims undergoing therapeutic hypothermia. METHODS: In a multi-disciplinary ICU, records were reviewed for comatose OHCA patients undergoing therapeutic hypothermia. The hourly variable time integral of haemodynamic variables during the first 24h after admission was calculated. Neurologic outcome was assessed at day 28 and graded as favourable or adverse based on the Cerebral Performance Category of 1-2 and 3-5. Bi- and multivariate regression models adjusted for confounding variables were used to evaluate the association between haemodynamic variables and functional outcome. RESULTS: 67/134 patients (50%) were classified as having favourable outcome. Patients with adverse outcome had a higher mean heart rate (73 [62-86] vs. 66 [60 78]bpm; p=0.04) and received noradrenaline more frequently (n=17 [25.4%] vs. n=9 [6%]; p=0.02) and at a higher dosage (128 [56-1004] vs. 13 [2-162] MUgh(-1); p=0.03) than patients with favourable outcome. The mean perfusion pressure (mean arterial blood pressure minus central venous blood pressure) (OR=1.001, 95% CI =1 1.003; p=0.04) and cardiac index time integral (OR=1.055, 95% CI=1.003-1.109; p=0.04) were independently associated with adverse outcome at day 28. CONCLUSION: Mean perfusion pressure and cardiac index during the first 24h after ICU admission were weakly associated with neurological outcome in an OHCA population undergoing therapeutic hypothermia. Further studies need to elucidate whether norepinephrine-induced increases in perfusion pressure and cardiac index may contribute to adverse neurologic outcome following OHCA. PMID- 23092897 TI - Current path in light emitting diodes based on nanowire ensembles. AB - Light emitting diodes (LEDs) have been fabricated using ensembles of free standing (In, Ga)N/GaN nanowires (NWs) grown on Si substrates in the self-induced growth mode by molecular beam epitaxy. Electron-beam-induced current analysis, cathodoluminescence as well as biased MU-photoluminescence spectroscopy, transmission electron microscopy, and electrical measurements indicate that the electroluminescence of such LEDs is governed by the differences in the individual current densities of the single-NW LEDs operated in parallel, i.e. by the inhomogeneity of the current path in the ensemble LED. In addition, the optoelectronic characterization leads to the conclusion that these NWs exhibit N polarity and that the (In, Ga)N quantum well states in the NWs are subject to a non-vanishing quantum confined Stark effect. PMID- 23092898 TI - Salivary gland swellings. PMID- 23092899 TI - Minor incised traumatic laceration. PMID- 23092900 TI - Rash in a 15 month old girl. PMID- 23092901 TI - BMA's Mark Porter: mastering the thorny issues. Interviewed by Nigel Hawkes. PMID- 23092902 TI - A licence to bill. PMID- 23092903 TI - Girls do not see HPV vaccine as green light for sex, study says. PMID- 23092904 TI - Keloid scars and treatment with Botulinum Toxin Type A: the Belfast experience. PMID- 23092905 TI - Associated anomalies and diagnostic approach in lumbosacral and perineal haemangiomas: case report and review of the literature. PMID- 23092906 TI - Synthesis and screening of novel vitamin E derivatives for anticancer functions. AB - alpha-TEA, RRR-alpha-tocopherol ether linked acetic acid, exhibits potent anticancer actions in vitro and in vivo; whereas, the parent molecule has no anticancer activity. In this study, we incorporated fluorine at the chroman head and/or ether linkage between the chroman head and phytyl tail of alpha-TEA as well as RRR-alpha-tocopherol to synthesize 6 vitamin E derivatives, and evaluated the anticancer actions in vitro for ability to induce cell death by apoptosis of human MCF-7 and MDA-MB-231 breast cancer cell lines and mouse mammary cancer cell line 66cl-4GFP. All derivatives, with the exception of compound 12, exhibited anticancer properties. The modified alpha-TEA ether-type phytyl group exhibited the highest pro-apoptotic activity in comparison with alpha-TEA as well as other vitamin E derivatives. PMID- 23092907 TI - Herd management procedures and factors associated with low farrowing rate of female pigs in Japanese commercial herds. AB - The objective of the present study was to compare management procedures and production factors between low-farrowing-rate herds (LFR herds) and the remaining herds (Non-LFR herds). The questionnaires were sent to the producers of 115 herds that use the same recording system. The questionnaire requested information about management procedures in 2008: (i) daily frequencies of estrus detection: once or twice a day; and (ii) the timing of first insemination. Data from 93 completed questionnaires (80.9%) were coordinated with the reproductive data of individual female pigs from the recording system. The data included 78,321 service records from 37,777 sows and gilts. Herds were classified into two groups on the basis of the lower 25th percentile of farrowing rate: LFR herds (76.5% or lower) and Non LFR herds (76.6% or higher). At the herd level, a two-sample t-test, was used to compare the surveyed management procedures between the two herd groups. At the individual level, two-level mixed-effects models were applied, by using a herd at the level two and an individual record at the level one to determine associations between low farrowing rate and management procedures or production factors in gilts and sows. Gilt and sow models were separately constructed. Means (+/-SEM) of farrowing rate in LFR herds and Non-LFR herds were 71.3+/-0.92 and 85.5+/ 0.54%, respectively. The lower farrowing rates of gilts and sows in LFR herds were associated with once-daily estrus detection, late timing of first insemination and single mating (P<0.05). In LFR herds that detected estrus only once a day, the farrowing rate decreased by 10.5% in first-serviced gilts and by 4.2% in reserviced sows compared with twice daily estrus detection (P<0.05). However, there was no such association in Non-LFR herds (P>0.05). The LFR herds had higher percentages of single-mated gilts and sows than Non-LFR herds (P<0.05). Fewer LFR herds than Non-LFR herds performed first insemination immediately after first estrus detection for gilts or by 6-12h for sows (P<0.05). In order to improve the farrowing rate in LFR herds, we recommend detecting estrus twice a day and performing first insemination earlier after first estrus detection; immediately for gilts and by 6-12h for sows. Additionally, increasing the percentage of multiple inseminations can effectively improve the farrowing rate. PMID- 23092908 TI - Association of TP53 codon 72 polymorphism with susceptibility to ovarian carcinomas in Serbian women. AB - OBJECTIVES: Finding a potential genetic factor associated with a deadly disease, such as ovarian carcinoma, is of particular importance. The aim of this study was to examine the role of the TP53 codon 72 polymorphism in ovarian carcinoma development in Serbian women. STUDY DESIGN: 47 wild-type TP53 gene ovarian carcinoma samples and 70 cervical smears from gynecologically healthy women were analyzed. DNA was extracted by a salting-out procedure. Codon 72 polymorphism was assessed by PCR-RFLP method. chi(2), Fisher exact test and odds ratio were used for statistical analysis. RESULTS: The distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes of codon 72 of the TP53 gene was: 46.8%, 46.8% and 6.4%, respectively in the ovarian carcinomas and 64.3%, 31.4% and 4.3%, respectively in the control group. We observed an increased risk for the development of ovarian carcinoma for Pro homozygotes in relation to heterozygotes plus Arg homozygotes (OR=1.52; 95% CI 0.29-7.89) and a higher one for Pro/Pro plus Arg/Pro genotype in relation to Arg homozygotes (OR=2.04; 95% CI 0.96-4.34). CONCLUSION: The results showed no association between codon 72 TP53 gene polymorphism and risk for development of ovarian carcinoma in Serbian women. However, this observation requires further analysis of a larger case-control study group. PMID- 23092910 TI - Diffuse cerebral language representation in tuberous sclerosis complex. AB - INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder affecting multiple organs, including the brain, and very often associated with epileptic activity. Language acquisition and development seems to be altered in a significant proportion of patients with TSC. In the present study, we used magnetoencephalography (MEG) to investigate spatiotemporal cerebral language processing in subjects with TSC and epilepsy during a reading semantic decision task, compared to healthy control participants. METHODS: Fifteen patients with TSC and 31 healthy subjects performed a lexico-semantic decision task during MEG recording. Minimum-norm estimates (MNE) were computed allowing identification of cerebral generators of language evoked fields (EF) in each subject. RESULTS: Source analysis of the language EF demonstrated early bilateral medial occipital activation (125ms) followed by a fusiform gyrus activation around 135ms. At 270ms post stimuli presentation, a strong cerebral activation was recorded in the left basal temporal language area. Finally, cerebral activations were measured in Wernicke's area followed by Broca's area. The healthy control group showed larger and earlier language activations in Broca and Wernicke's areas compared to TSC patients. Moreover, cerebral activation from Broca's area was greater than activation from Wernicke's area in both groups, but this difference between anterior and posterior regions was smaller in the TSC group. Finally, the activation latency difference between Broca and Wernicke's areas was greater in healthy controls than in TSC patients, which shows that activations in these areas are more serial in control subjects compared to TSC patients in whom activations occur more simultaneously. CONCLUSIONS: This is the first study to investigate cerebral language pattern in patients with TSC. Compared to healthy controls, atypical neuromagnetic language responses may reflect cerebral reorganization in these patients in response to early epileptogenic activity or presence at birth of multiple brain lesions. PMID- 23092909 TI - In utero pesticide exposure and leukemia in Brazilian children < 2 years of age. AB - BACKGROUND: An association between pesticide exposure and cancer has been suggested. Infant leukemia is a rare neoplasm and its association with maternal pesticide exposure has been poorly explored. OBJECTIVES: We investigated the association between pesticide exposure during pregnancy and leukemia in children < 2 years of age. METHODS: A hospital-based case-control study was carried out in 13 Brazilian states during 1999-2007. Mothers of 252 cases and those of 423 controls were interviewed. Information on pesticide exposures 3 months before pregnancy, throughout pregnancy, and during breastfeeding was obtained. Unconditional logistic regression was used to estimate adjusted odds ratios (aORs) for associations between pesticide exposures and leukemia. RESULTS: Associations with ever use of pesticides during pregnancy were observed for acute lymphoid leukemia (ALL) (aOR = 2.10; 95% CI: 1.14, 3.86) and acute myeloid leukemia (AML) (aOR = 5.01; 95% CI: 1.97, 12.7) in children 0-11 months of age, and with ALL (aOR = 1.88; 95% CI: 1.05, 5.23) at 12-23 months of age. According to reported maternal exposure to permethrin, higher risk estimates were verified for children 0-11 months of age (aOR = 2.47; 95% CI: 1.17, 5.25 for ALL; and aOR = 7.28; 95% CI: 2.60, 20.38 for AML). Maternal pesticide exposure related to agricultural activities showed an aOR of 5.25 (95% CI: 1.83, 15.08) for ALL, and an aOR of 7.56 (95% CI: 1.83, 31.23) for AML. CONCLUSIONS: These results support the hypothesis that pesticide exposure during pregnancy may be involved in the etiology of acute leukemia in children < 2 years of age. PMID- 23092912 TI - Maternal calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats. AB - Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies. PMID- 23092911 TI - Delayed development of specific thyroid hormone-regulated events in transthyretin null mice. AB - Thyroid hormones (THs) are vital for normal postnatal development. Extracellular TH distributor proteins create an intravascular reservoir of THs. Transthyretin (TTR) is a TH distributor protein in the circulatory system and is the only TH distributor protein synthesized in the central nervous system. We investigated the phenotype of TTR null mice during development. Total and free 3',5',3,5 tetraiodo-L-thyronine (T(4)) and free 3',3,5-triiodo-L-thyronine (T(3)) in plasma were significantly reduced in 14-day-old (P14) TTR null mice. TTR null mice also displayed a delayed suckling-to-weaning transition, decreased muscle mass, delayed growth, and retarded longitudinal bone growth. In addition, ileums from postnatal day 0 (P0) TTR null mice displayed disordered architecture and contained fewer goblet cells than wild type. Protein concentrations in cerebrospinal fluid from P0 and P14 TTR null mice were higher than in age-matched wild-type mice. In contrast to the current literature based on analyses of adult TTR null mice, our results demonstrate that TTR has an important and nonredundant role in influencing the development of several organs. PMID- 23092913 TI - Defective postnatal endochondral bone development by chondrocyte-specific targeted expression of parathyroid hormone type 2 receptor. AB - The human parathyroid hormone type 2 receptor (PTH2R) is activated by PTH and by tuberoinfundibular peptide of 39 residues (TIP39), the latter likely acting as its natural ligand. Although the receptor is expressed at highest levels in the nervous system, we have observed that both PTH2R and TIP39 are expressed in the newborn mouse growth plate, with the receptor localizing in the resting zone and the ligand TIP39 localizing exclusively in prehypertrophic and hypertrophic chondrocytes. To address the role of PTH2R in postnatal skeletal growth and development, Col2a1-hPTH2R (PTH2R-Tg) transgenic mice were generated. The mice were viable and of nearly normal size at birth. Expression of the transgene in the growth plate was limited to chondrocytes. We found that chondrocyte proliferation was decreased, as determined by in vivo BrdU labeling of proliferating chondrocytes and CDK4 and p21 expression in the growth plate of Col2a1-hPTH2R transgenic mice. Similarly, the differentiation and maturation of chondrocytes was delayed, as characterized by decreased Sox9 expression and weaker immunostaining for the chondrocyte differentiation markers collagen type II and type X and proteoglycans. As well, there was altered expression of Gdf5, Wdr5, and beta-catenin, factors implicated in chondrocyte maturation, proliferation, and differentiation.These effects impacted on the process of endochondral ossification, resulting in delayed formation of the secondary ossification center, and diminished trabecular bone volume. The findings substantiate a role for PTH2R signaling in postnatal growth plate development and subsequent bone mass acquisition. PMID- 23092914 TI - Glucose-dependent insulinotropic polypeptide induces cytokine expression, lipolysis, and insulin resistance in human adipocytes. AB - Obesity-related insulin resistance is linked to a chronic state of systemic and adipose tissue-derived inflammation. Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone also acting on adipocytes. We investigated whether GIP affects inflammation, lipolysis, and insulin resistance in human adipocytes. Human subcutaneous preadipocyte-derived adipocytes, differentiated in vitro, were treated with human GIP to analyze mRNA expression and protein secretion of cytokines, glycerol, and free fatty acid release and insulin-induced glucose uptake. GIP induced mRNA expression of IL-6, IL-1beta, and the IL-1 receptor antagonist IL-1Ra, whereas TNFalpha, IL-8, and monocyte chemotactic protein (MCP) 1 remained unchanged. Cytokine induction involved PKA and the NF-kappaB pathway as well as an autocrine IL-1 effect. Furthermore, GIP potentiated IL-6 and IL-1Ra secretion in the presence of LPS, IL-1beta, and TNFalpha. GIP induced lipolysis via activation of hormone-sensitive lipase and was linked to NF-kappaB activation. Finally, chronic GIP treatment impaired insulin-induced glucose uptake possibly due to the observed impaired translocation of glucose transporter GLUT4. In conclusion, GIP induces an inflammatory and prolipolytic response via the PKA -NF-kappaB-IL-1 pathway and impairs insulin sensitivity of glucose uptake in human adipocytes. PMID- 23092915 TI - Interviewing child witnesses: the effect of forced confabulation on event memory. AB - Age differences in rates of forced confabulation and memory consequences thereof were assessed using a recall task similar to real forensic interview procedures. Children viewed a target video and were tested with the same 18 questions immediately afterward and 1 week later. Of the 18 questions, 12 were answerable; the 6 unanswerable questions referred to information not in the video. Participants in the voluntary confabulation condition had a "don't know" response option; those in the forced confabulation condition did not. Although 6-year-olds and 9-year-olds were equally likely to provide a response to an unanswerable question initially, 1 week later 9-year-olds were significantly more likely than 6-year-olds to repeat their initial confabulated responses. These findings suggest that pressing child witnesses to answer questions they are initially reluctant to answer is not an effective practice, and the consistency of children's responses over time is not necessarily an indication of the accuracy of their eyewitness memory. PMID- 23092916 TI - Stability of the bandgap in Cu-poor CuInSe2. AB - Recent photoluminescence studies report that the bandgap energy E(g) ~ 1.0 eV of CuInSe(2) is stable for Cu-poor compounds [Cu]/[In] < 1, despite the fact that Cu vacancies and (In(Cu) + 2V(Cu)) complexes increase the energy gap. In this work, the impact on E(g) due to the presence of native defects is analyzed using a screened hybrid density functional approach. We demonstrate that the formation energy of neutral (Cu(In) + In(Cu)) anti-site dimers decreases for CuInSe(2) compounds when [Cu]/[In] decreases. This is explained in terms of the octet rule for the Se atoms next to the (In(Cu) + 2V(Cu)) defects. As a consequence, Cu-poor CuInSe(2) involves the large [(In(Cu) + 2V(Cu)) + (Cu(In) + In(Cu))] complexes where the anti-site defects stabilize E(g), in agreement with experimental findings. PMID- 23092917 TI - CD11b expression correlates with monosomal karyotype and predicts an extremely poor prognosis in cytogenetically unfavorable acute myeloid leukemia. AB - Several cytogenetic features, including monosomal karyotype (MK), have been associated with unfavorable prognosis in acute myeloid leukemia (AML). However, little is known about the prognostic significance of immunophenotypes in AML patients with unfavorable-risk cytogenetics. We evaluated immunophenotypes, cytogenetics, clinical features and survival outcomes in 233 uniformly treated AML patients who harbored unfavorable cytogenetics. CD11b expression was observed in 145 (70%) of 208 patients and emerged as an independent prognostic factor for inferior overall survival in multivariate analysis (p=0.024). MK and age >= 60 years were predictors for lower complete remission rate (p=0.017, p<0.0001, respectively) and shorter overall survival (p=0.024, p<0.0001), while complex karyotype (CK) predicted a shorter overall survival (p=0.013). CD11b expression was strongly correlated with MK and identified a subset of patients with MK who had extremely poor overall survival. We proposed a prognostic scoring model using CD11b positivity, age >= 60 years, the presence of MK and the presence of CK to classify the patients into distinct risk groups. We identified the poor prognosis of CD11b expression and validated the adverse influence of MK, CK and age >= 60 years in cytogenetically unfavorable AML patients. Our proposed scoring model may be adapted in clinical practice to further the stratification of this high-risk population. PMID- 23092918 TI - mTOR inhibition modulates epileptogenesis, seizures and depressive behavior in a genetic rat model of absence epilepsy. AB - Several signaling pathways are believed to be involved in the epileptogenic process that triggers the subsequent changes in the brain causing epilepsy. The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that in the brain, regulates several important physiological functions such as neuronal development and synaptic plasticity, and also seems to be involved in many pathologies, including epilepsy and psychiatric disorders. Previous work in animal models of both genetic and acquired generalized convulsive epilepsies, has suggested that modulators of the mTOR signaling pathway may have beneficial neuroprotective and antiepileptogenic effects. Here, we investigated for the first time, the effect of some treatment schedules (i.e. early chronic, sub chronic and acute) with the specific mTOR inhibitor rapamycin, on the development of absence seizures and seizure parameters as well as depressive-like behavior in WAG/Rij rats, a genetic model of absence epilepsy, epileptogenesis and mild depression comorbidity. In addition, we studied the possible interaction between rapamycin treatment and the effects of bacterial lipopolysaccharide (LPS) endotoxin administration, which is known to aggravate absence seizures through generation of increased neuroinflammatory responses. We found that rapamycin (early chronic treatment for 17 weeks, starting at P45) exhibited clear antiepileptogenic properties also in this animal epilepsy model; however, this effect was accompanied by unexpected prodepressant effects. Both acute and sub chronic (7 day) treatments also had anti-absence properties, but the sub-chronic treatment produced contrasting antidepressant properties in the WAG/Rij rats that were not seen in control Wistar rats. The rapamycin/LPS co-administration studies showed that rapamycin blocked or prevented the LPS-dependent increase in absence seizures, suggesting an anti-inflammatory-like protective action. In conclusion, we have demonstrated a novel antiepileptogenic effect of rapamycin in a well established animal model of absence epilepsy, and we suggest that this effect may be mediated by the inhibition of inflammatory processes that are developed in the brain of these specific animals during epileptogenesis and during seizures. Our experiments here suggest new insights into this intriguing field, which deserves to be further explored. This article is part of the Special Issue entitled 'New Targets and Approaches to the Treatment of Epilepsy'. PMID- 23092919 TI - Medial prefrontal cortex lesions in mice do not impair effort-based decision making. AB - The function of the medial prefrontal cortex has previously been determined in the rat to play an important role in effort-based decision making and this, along with functions of other areas, has been assumed largely, to hold true in all rodents. In this study, we attempted to replicate this result in mice and to develop a model for effort-based decision making that could be useful for the study of neurological conditions. Mice were trained on a cost-benefit T-maze paradigm, whereby they chose between a low reward with little effort needed to obtain it or a higher reward, which required increased effort. Following training, the medial prefrontal cortex was lesioned. After surgery, contrary to earlier published rat studies, the performance of the mice did not change. In previous studies, prefrontal cortex lesioned rats chose the low effort/low reward option, but lesioned mice continued to select the high reward/high effort option. However, the other results are in line with previous mouse studies in both the extent of pathology and anxiety-like behaviour. These results illustrate a difference in the functioning of the prefrontal cortex between rats and mice and offer a word of caution on the interpretation of data from studies that employ different species. PMID- 23092920 TI - Genetic control of asexual sporulation in filamentous fungi. AB - Asexual sporulation (conidiation) in the ascomycetous filamentous fungi involves the formation of conidia, formed on specialized structures called conidiophores. Conidiation in filamentous fungi involves many common themes including spatial and temporal regulation of gene expression, specialized cellular differentiation, intra-/inter-cellular communications, and response to environmental factors. The commencement, progression and completion of conidiation are regulated by multiple positive and negative genetic elements that direct expression of genes required for proper vegetative growth and the assembly of the conidiophore and spore maturation. Light is one of the key environmental factors affecting conidiation. Developmental mechanisms in Aspergillus nidulans and Neurospora crassa have been intensively studied, leading to important outlines. Here, we summarize genetic control of conidiation including the light-responding mechanisms in the two model fungi. PMID- 23092921 TI - Recent insights into the export of PEXEL/HTS-motif containing proteins in Plasmodium parasites. AB - Protein export in intra-erythrocytic Plasmodium parasites is of considerable interest in the malaria field because the process is inextricably linked to virulence and survival mechanisms in the human host. Despite many and varied functions, a common link between many exported proteins is their actual mode of export. Most exported proteins must traverse two membranes to their destination in the infected erythrocyte cytosol, the parasite plasma membrane and surrounding parasitophorous vacuole membrane (PVM). In recent years, several studies have shone light on the common molecular mechanism by which the major class of exported proteins, the so-called PEXEL/HTS motif-containing proteins, are translocated across these membranes. Roles for parasite-specific molecular processes in two distinct sites, the endoplasmic reticulum and the PVM have been revealed. PMID- 23092922 TI - Interleukin-6 production in CD40-engaged fibrocytes in thyroid-associated ophthalmopathy: involvement of Akt and NF-kappaB. AB - PURPOSE: CD40-CD40 ligand (CD40L) interactions appear to play pathogenic roles in autoimmune disease. Here we quantify CD40 expression on fibrocytes, circulating, and bone marrow-derived progenitor cells. The functional consequences of CD40 ligation are determined since these may promote tissue remodeling linked with thyroid-associated ophthalmopathy (TAO). METHODS: CD40 levels on cultivated fibrocytes and orbital fibroblasts (GOFB) from patients with Graves' disease (GD), as well as fibrocyte abundance, were determined by flow cytometry. CD40 mRNA expression was evaluated by real-time PCR, whereas response to CD40 ligation was measured by Luminex and RT-PCR. Protein kinase B (Akt) and nuclear factor (NF)-kappa B (NF-kappaB) signaling were determined by Western blot and immunofluorescence. RESULTS: Basal CD40 expression on fibrocytes is greater than that on GOFB. IFN-gamma upregulates CD40 in both cell types and its actions are mediated at the pretranslational level. Fibrocytes produce high levels of cytokines, including interleukin-6 (IL-6), TNF-alpha, IL-8, MCP-1, and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) in response to CD40L. IL-6 induction results from an increase in steady state IL-6 mRNA, and is mediated through Akt and NF-kappaB activation. Circulating CD40(+)CD45(+)Col1(+) fibrocytes are far more frequent in vivo in donors with TAO compared with healthy subjects. CONCLUSIONS: Particularly high levels of functional CD40 are displayed by fibrocytes. CD40L-provoked signaling results in the production of several cytokines. Among these, IL-6 expression is mediated through Akt and NF-kappaB pathways. The frequency of circulating CD40(+) fibrocytes is markedly increased in patients with TAO, suggesting that this receptor might represent a therapeutic target for TAO. PMID- 23092924 TI - Association between choroidal thickness and ocular perfusion pressure in young, healthy subjects: enhanced depth imaging optical coherence tomography study. AB - PURPOSE: To investigate the correlation of choroidal thickness (CT) with ocular perfusion pressure (OPP) in young, healthy subjects using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: A single horizontal section and a single vertical section of EDI-OCT scans in each eye of 69 young, healthy subjects were obtained at the macula. CT was measured at the fovea, and up to 3 mm, at intervals of 0.5 mm, away from the fovea in the superior, inferior, nasal, and temporal choroid. Univariable and multivariable analyses were performed to assess the association of CT with OPP while axial length (AL), refractive error (RE), sex, and/or body mass index (BMI), were taken into consideration. RESULTS: Mean subfoveal CT was 307.03 +/- 91.27 MUm (mean age, 22.3 +/- 3 years; mean axial length, 25.35 +/- 1.14 mm; mean refractive error, -3.89 +/- 2.02 diopters; mean OPP, 44.18 +/- 5.49 mm Hg). Multivariable regression analysis showed that in eyes with <6 diopters of myopia, subfoveal CT (325.92 +/- 88.46 MUm) changed most significantly in association with RE and mean OPP (beta = 25.941, P < 0.001; beta = -3.551, P = 0.042, respectively; adjusted R(2) = 0.249). In subjects with myopia of >6 diopters, subfoveal CT (225.17 +/- 49.37 MUm) was significantly thinner (P < 0.0001), and a significant correlation with OPP was not observed (P > 0.05). CONCLUSIONS: In vivo subfoveal CT as measured by EDI-OCT was significantly associated with OPP in young, healthy subjects when adjusted for RE, suggesting that subfoveal CT may be indirectly indicative of subfoveal ocular perfusion status. This association was not observed in subjects with high myopia. PMID- 23092923 TI - From blood islands to blood vessels: morphologic observations and expression of key molecules during hyaloid vascular system development. AB - PURPOSE: The mode of development of the human hyaloid vascular system (HVS) remains unclear. Early studies suggested that these blood vessels formed by vasculogenesis, while the current concept seems to favor angiogenesis as the mode of development. We examined embryonic and fetal human HVS using a variety of techniques to gain new insights into formation of this vasculature. METHODS: Embryonic and fetal human eyes from 5.5 to 12 weeks gestation (WG) were prepared for immunohistochemical analysis or for light and electron microscopy. Immunolabeling of sections with a panel of antibodies directed at growth factors, transcription factors, and hematopoietic stem cell markers was employed. RESULTS: Light microscopic examination revealed free blood islands (BI) in the embryonic vitreous cavity (5.5-7 WG). Giemsa stain revealed that BI were aggregates of mesenchymal cells and primitive nucleated erythroblasts. Free cells were also observed. Immunolabeling demonstrated that BI were composed of mesenchymal cells that expressed hemangioblast markers (CD31, CD34, C-kit, CXCR4, Runx1, and VEGFR2), erythroblasts that expressed embryonic hemoglobin (Hb-epsilon), and cells that expressed both. Few cells were proliferating as determined by lack of Ki67 antigen. As development progressed (12 WG), blood vessels became more mature structurally with pericyte investment and basement membrane formation. Concomitantly, Hb-epsilon and CXCR4 expression was down-regulated and von Willebrand factor expression was increased with the formation of Weibel-Palade bodies. CONCLUSIONS: Our results support the view that the human HVS, like the choriocapillaris, develops by hemo-vasculogenesis, the process by which vasculogenesis, erythropoiesis, and hematopoiesis occur simultaneously from common precursors, hemangioblasts. PMID- 23092926 TI - DFVF: database of fungal virulence factors. AB - Fungal pathogens cause various diseases for plant and animal hosts. Despite the extensive impact of fungi on human health and life, the threats posed by emerging fungal pathogens are poorly understood. Specifically, there exist few fungal virulence gene databases, which prevent effective bioinformatics studies on fungal pathogens. Therefore, we constructed a comprehensive online database of known fungal virulence factors, which collected 2058 pathogenic genes produced by 228 fungal strains from 85 genera. This database creates a pivotal platform capable of stimulating and facilitating further bench studies on fungal pathogens. PMID- 23092925 TI - The IS/OS junction layer in the natural history of type 2 idiopathic macular telangiectasia. AB - PURPOSE: To document the progression of a break in the photoreceptor inner segment/outer segment (IS/OS) junction layer and its functional correlates over time in the natural history of type 2 idiopathic macular telangiectasia (type 2 MacTel). METHODS: Patients with at least 1 year of follow-up were selected from the MacTel Study. En face images were created by manual segmentation of the IS/OS junctional line in volume scans acquired using a spatial-domain optical coherence tomography retinal imaging unit. Retinal sensitivity thresholds were determined using a retinal microperimeter unit. Aggregate retinal sensitivity loss within IS/OS lesions was calculated. Changes over time in an area of IS/OS defects and retinal sensitivity were analyzed. RESULTS: thirty-nine eyes of 23 patients (mean age: 62.3 +/- 9.2 years) were analyzed. Mean follow-up time was 1.9 years (range: 1-3 years). Mean IS/OS break area at baseline was 0.575 mm(2) (SE = 0.092, 95% confidence interval [CI]: 0.394-0.756 mm(2)). The cluster-adjusted mean annual progression rate in IS/OS break area was 0.140 mm(2) (SE = 0.040, 95% CI: 0.062 0.218 mm(2), P < 0.001). Mean aggregate retinal sensitivity loss was at baseline 28.56 dB (SE = 5.43, 95% CI: 17.32-39.80 dB, n = 28), a positive correlation with IS/OS lesion area was present (P < 0.001). The mean annual rate of change in aggregate sensitivity loss was 5.14 dB (SE = 1.51, 95% CI: 2.19-8.10 dB, P < 0.001, n = 37), a significant correlation with lesion area increase was found (P = 0.006). CONCLUSIONS: Both IS/OS break area and rate of enlargement correlate with aggregate retinal sensitivity loss in type 2 MacTel. En face OCT imaging of the IS/OS layer provides a functionally relevant method for documenting disease progression in type 2 MacTel. PMID- 23092927 TI - Changes in metabolic, inflammatory and coagulation biomarkers after HIV seroconversion--the Health in Men (HIM) Biomarker Substudy. AB - BACKGROUND: Biomarkers of inflammation, coagulation, lipids and vitamin D have been associated with cardiovascular and mortality risk in HIV-infected individuals. Scarce data exist on changes in these markers from pre- to post-HIV seroconversion. METHODS: The study participants were drawn from the Health in Men Study, which recruited HIV-negative homosexual men. Participants with incident HIV infection (n=26) were compared with HIV-negative controls (n=52) matched on age at enrolment, date of visit and reported intravenous drug use. Levels of metabolic (lipids and vitamin D), inflammatory (C-reactive protein and interleukin-6) and coagulation (D-dimer and fibrinogen) biomarkers were measured at pre- and post-HIV seroconversion visits and corresponding visits for controls. Random-effect models were used to compare changes in markers between cases and controls. RESULTS: The median gap between pre- and post-seroconversion or matched first and second visits in controls was 12 months. HIV seroconversion was associated with decline in high density lipoprotein (HDL-C; difference in mean change between cases and controls -0.14 mmol/l; 95% CI -0.22, -0.01; P=0.035). There were no significant differences in changes in other lipids, markers of inflammation, coagulation or vitamin D. CONCLUSIONS: Decline in HDL-C seems to be the main proatherogenic change within 1-1.5 years after HIV seroconversion. HIV seroconversion was not associated with profound changes in other lipids, or markers of inflammation, coagulation and vitamin D. Longitudinal assessment of these markers in comparable population needs further assessment. PMID- 23092928 TI - Deciphering the three-dimensional morphology of free-standing block copolymer thin films by transmission electron microscopy. AB - Block copolymer thin films with distinct morphologies are prepared by spin casting a nominally lamellar assay of poly(styrene-block-ethylene oxide) from a variety of solvents with and without salt doping. The 3-D morphologies of free standing thin-film regions, which are obtained by casting directly onto holey substrates, are investigated in detail using various energy-filtering transmission electron microscopy techniques and by electron tomography. Surface characterization is achieved by atomic force microscopy. Our results demonstrate that in order to fully characterize the unique 3-D morphologies of the block copolymer thin films, a multi-method approach is required. When casting from a binary solvent, an unexpected layered honeycomb-type morphology is revealed, which likely results from an expansion of the poly(ethylene oxide) phase. A dramatic effect of selective cation coordination on the morphology of the as-cast block copolymer films is also directly observed. PMID- 23092929 TI - PECVD based silicon oxynitride thin films for nano photonic on chip interconnects applications. AB - Thin silicon oxynitride (SiO(x)N(y)) films were deposited by low temperature (~300 degrees C) plasma enhanced chemical vapour deposition (PECVD), using SiH(4), N(2)O, NH(3) precursor of the flow rate 25, 100, 30 sccm and subjected to the post deposition annealing (PDA) treatment at 400 degrees C and 600 degrees C for nano optical/photonics on chip interconnects applications. AFM result reveals the variation of roughness from 60.9 A to 23.4 A after PDA treatment with respect to the as-deposited films, favourable surface topography for integrated waveguide applications. A model of decrease in island height with the effect of PDA treatment is proposed in support of AFM results. Raman spectroscopy and FTIR measurements are performed in order to define the change in crystallite and chemical bonding of as-deposited as well as PDA treated samples. These outcomes endorsed to the densification of SiO(x)N(y) thin films, due to decrease in Si-N and Si-O bonds strain, as well the O-H, N-H bonds with in oxynitride network. The increase in refractive index and PL intensity of as deposited SiO(x)N(y) thin films to the PDA treated films at 400 degrees C and 600 degrees C are observed. The significant shift of PL spectra peak positions indicate the change in cluster size as the result of PDA treatment, which influence the optical properties of thin films. It might be due to out diffusion of hydrogen containing species from silicon oxynitride films after PDA treatment. In this way, the structural and optical, feasibility of SiO(x)N(y) films are demonstrated in order to obtain high quality thin films for nano optical/photonics on chip interconnects applications. PMID- 23092930 TI - Differential expression of AURKA and AURKB genes in bone marrow stromal mesenchymal cells of myelodysplastic syndrome: correlation with G-banding analysis and FISH. AB - It has been demonstrated that genomic alterations of cells in the hematopoietic microenvironment could induce myelodysplastic syndromes (MDS) with ineffective hematopoiesis and dysmorphic hematopoietic cells, and subsequent transformation to acute myeloid leukemia. This investigation is the first attempt to correlate the gene expression profile of AURKA and AURKB in a cytogenetically stratified population of mesenchymal stem cells (MSCs) from MDS patients. We found that AURKA messenger RNA was expressed at significantly higher levels in MSCs even with normal/altered karyotype when compared with hematopoietic cells and healthy donors. In addition, we found that the presence of chromosomal abnormalities (mainly aneuploidy) in hematopoietic cells/MSCs was also associated with higher levels of AURKA. Different from previous investigations, our findings, regarding AURKA expression support the hypothesis that the presence of chromosomal abnormalities in MSCs from MDS is not a consequence of the method used for chromosome preparation. They may reflect the genomic instability present in the bone marrow microenvironment of MDS patients. This information is also supported by differences observed in the growth kinetics between MSCs from healthy donors (normal karyotype) and from MDS patients with abnormal karyotype. In summary, our results may not be considered evidence that MDS and MSCs are originated from a single neoplastic clone. In fact, both cells (hematopoietic and MSCs) may probably be altered in response to damage-inducing factors, and the presence of genomic abnormalities in MSCs suggests that an unstable bone marrow microenvironment may facilitate the expansion of MDS/leukemic cells. PMID- 23092931 TI - Leptin modulates lymphocytes' adherence to hepatic stellate cells is associated with oxidative status alterations. AB - We investigated leptin effects on lymphocyte interactions with hepatic-stellate cells (HSCs). Leptin showed pro-fibrotic effects on HSCs with oxidative status imbalance. In co-cultures, leptin activates HSCs and consequently adhered HCV lymphocytes more than healthy ones. Leptin also increased healthy and HCV lymphocyte proliferations; increased their reactive-oxygen-species; decreased antioxidants (reduced-glutathione) levels while inhibited apoptosis only of HCV lymphocytes. The leptin-treated HCV-lymphocytes activated HSCs, increase interleukin-4 while decreased their apoptosis. Leptin-receptor-deficient (db-db) HSCs did not adhere lymphocytes. db/db-lymphocytes however showed fewer adherences to HSCs when compared to WT-counterparts. This study presents immune and oxidative modulatory effects of leptin on lymphocytes and their consequent interaction with HSCs. PMID- 23092932 TI - Nanoimprinted ultrafine line and space nanogratings for liquid crystal alignment. AB - Ultrafine 50 nm line and space nanogratings were fabricated using nanoimprint lithography, and were further used as an alignment layer for liquid crystals. The surface morphologies of the nanogratings were characterized and their surface energies were estimated through the measurement of the contact angles for two different liquids. Experimental results show that the surface energies of the nanogratings are anisotropic: the surface free energy towards the direction parallel to the grating lines is higher than that in the direction perpendicular to the grating lines. Electro-optical characteristics were tested from a twisted nematic liquid crystal cell, which was assembled using two identical nanogratings. Experimental results show that such a kind of nanograting is promising as an alternative to the conventional rubbing process for liquid crystal alignment. PMID- 23092933 TI - The impact of minimum legal drinking age laws on alcohol consumption, smoking, and marijuana use revisited. AB - In volume 30, issue 4 of this journal, we used data from the National Longitudinal Study of Youth, 1997 cohort (NLSY97) to estimate the impact of the minimum legal drinking age (MLDA) laws on alcohol consumption, smoking, and marijuana use among young adults. In our analysis, we used a restricted sample of young adults and considered only those who have consumed alcohol, smoked cigarettes, or used marijuana at least once since the date of their last interview. In this paper, we revisit our original study using the full sample. We show that our results for alcohol consumption in the full sample are similar to those from the restricted sample. However, the effect of the MLDA on smoking and marijuana use is smaller and often statistically insignificant. PMID- 23092934 TI - Big things come in bundled packages: implications of bundled payment systems in health care reimbursement reform. AB - With passage of the Affordable Care Act, the ever-evolving landscape of health care braces for another shift in the reimbursement paradigm. As health care costs continue to rise, providers are pressed to deliver efficient, high-quality care at flat to minimally increasing rates. Inherent systemwide inefficiencies between payers and providers at various clinical settings pose a daunting task for enhancing collaboration and care coordination. A change from Medicare's fee-for service reimbursement model to bundled payments offers one avenue for resolution. Pilots using such payment models have realized varying degrees of success, leading to the development and upcoming implementation of a bundled payment initiative led by the Center for Medicare and Medicaid Innovation. Delivery integration is critical to ensure high-quality care at affordable costs across the system. Providers and payers able to adapt to the newly proposed models of payment will benefit from achieving cost reductions and improved patient outcomes and realize a competitive advantage. PMID- 23092935 TI - Active non-participation among local natural resource-dependent communities: the case of North Carolina fisheries governance. AB - The great emphasis placed on the democratic participation of local user groups as necessary for sustainable natural resource and environmental governance by scholars, advocates, and practitioners of collaborative natural resource management demands a greater focus on who is and who is not participating in governance processes, why, and the potential consequences. This project examines a case where commercial fishers in North Carolina practice active non participation regarding the governance of sea turtles, spotted seatrout and gill nets. Active non-participation is a choice to not participate in formal political activities. Data was collected through observations, interviews and document and policy review. An important finding from this study is that the active non participation of commercial fishers is contributing to their displacement from, as well as the mismanagement of, the fisheries they depend upon for a living. PMID- 23092937 TI - The face-sensitive N170 component in developmental prosopagnosia. AB - Individuals with developmental prosopagnosia (DP) show severe face recognition deficits in the absence of any history of neurological damage. To examine the time-course of face processing in DP, we measured the face-sensitive N170 component of the event-related brain potential (ERP) in a group of 16 participants with DP and 16 age-matched control participants. Reliable enhancements of N170 amplitudes in response to upright faces relative to houses were found for the DP group. This effect was equivalent in size to the effect observed for controls, demonstrating normal face-sensitivity of the N170 component in DP. Face inversion enhanced N170 amplitudes in the control group, but not for DPs, suggesting that many DPs do not differentiate between upright and inverted faces in the typical manner. These N170 face inversion effects were present for younger but not older controls, while they were absent for both younger and older DPs. Results suggest that the early face-sensitivity of visual processing is preserved in most individuals with DP, but that the face processing system in many DPs is not selectively tuned to the canonical upright orientation of faces. PMID- 23092938 TI - Protecting children outside of family care in low and middle income countries: what does the evidence say? PMID- 23092936 TI - Birth weight, head circumference, and prenatal exposure to acrylamide from maternal diet: the European prospective mother-child study (NewGeneris). AB - BACKGROUND: Acrylamide is a common dietary exposure that crosses the human placenta. It is classified as a probable human carcinogen, and developmental toxicity has been observed in rodents. OBJECTIVES: We examined the associations between prenatal exposure to acrylamide and birth outcomes in a prospective European mother-child study. METHODS: Hemoglobin (Hb) adducts of acrylamide and its metabolite glycidamide were measured in cord blood (reflecting cumulated exposure in the last months of pregnancy) from 1,101 singleton pregnant women recruited in Denmark, England, Greece, Norway, and Spain during 2006-2010. Maternal diet was estimated through food-frequency questionnaires. RESULTS: Both acrylamide and glycidamide Hb adducts were associated with a statistically significant reduction in birth weight and head circumference. The estimated difference in birth weight for infants in the highest versus lowest quartile of acrylamide Hb adduct levels after adjusting for gestational age and country was 132 g (95% CI: -207, -56); the corresponding difference for head circumference was -0.33 cm (95% CI: -0.61, -0.06). Findings were similar in infants of nonsmokers, were consistent across countries, and remained after adjustment for factors associated with reduced birth weight. Maternal consumption of foods rich in acrylamide, such as fried potatoes, was associated with cord blood acrylamide adduct levels and with reduced birth weight. CONCLUSIONS: Dietary exposure to acrylamide was associated with reduced birth weight and head circumference. Consumption of specific foods during pregnancy was associated with higher acrylamide exposure in utero. If confirmed, these findings suggest that dietary intake of acrylamide should be reduced among pregnant women. PMID- 23092939 TI - Faulty hip implant shows up failings of EU regulation. PMID- 23092940 TI - Differential relationship between neurological and cognitive dysfunction in first episode psychosis patients and in healthy individuals. AB - The minor neurological and cognitive deficits consistently reported in psychoses may reflect the same underlying brain dysfunction. Still, even in healthy individuals minor neurological abnormalities are associated with worse cognitive function. Therefore, establishing which neurological and cognitive deficits are specific to psychosis is essential to inform the pathophysiology of this disorder. We evaluated a large epidemiological sample of patients with first episode psychosis (n=242) and a population-based sample of healthy individuals (n=155), as part of the AESOP study. We examined neurological soft signs using the Neurological Evaluation Scale (Buchanan and Heinrichs, 1989), and generalized and specific cognitive deficits (memory; verbal abilities; attention, concentration and mental speed; executive functions and working memory; language; visual constructual/perceptual abilities). In patients, more neurological signs across all subscales were associated with worse general cognitive function, while in controls this was only present for sensory integration and sequencing signs. Furthermore, in patients, but not in healthy individuals, more sensory integrative signs were associated with deficits in specific cognitive domains, such as memory, verbal abilities, language, visual/perceptual, executive function (p ranging <0.001-0.002); sequencing signs with language, executive function, and attention (p<0.001-0.004); and motor signs with poorer verbal abilities (p=0.001). These findings indicate the presence of specific associations between neurological and cognitive deficits in psychosis that are distinct from those of healthy individuals. PMID- 23092941 TI - Strain distribution in Si capping layers on SiGe islands: influence of cap thickness and footprint in reciprocal space. AB - We present investigations on the strain properties of silicon capping layers on top of regular SiGe island arrays, in dependence on the Si-layer thickness. Such island arrays are used as stressors for the active channel in field-effect transistors where the desired tensile strain in the Si channel is a crucial parameter for the performance of the device. The thickness of the Si cap was varied from 0 to 30 nm. The results of high resolution x-ray diffraction experiments served as input to perform detailed strain calculations via finite element method models. Thus, detailed information on the Ge distribution within the buried islands and the strain interaction between the SiGe island and Si cap was obtained. It was found that the tensile strain within the Si capping layer strongly depends on its thickness, even if the Ge concentration of the buried dot remains unchanged, with tensile strains degrading if thicker Si layers are used. PMID- 23092943 TI - Surfactant-free scalable synthesis of hierarchically spherical Co3O4 superstructures and their enhanced lithium-ion storage performances. AB - Unique hierarchically porous spherical Co(3)O(4) superstructures were synthesized via a surfactant-free hydrothermal process followed by a calcination treatment, in which the concentration of reactant cobalt (II) nitrate hexahydrate is a key factor affecting the morphology of products. X-ray powder diffraction, electron microscopies (TEM and SEM), and thermogravimetric analysis were employed to investigate the formation of Co(3)O(4) spherical superstructures. Our results suggest that they formed from numerous cubic Co(3)O(4) nanocrystals via an oriented attachment mechanism. These superstructures exhibit a high specific capacity of 1750 mA h g(-1) after the first charge-discharge cycle, and the capacity retention remains at a constant of 1600 mA h g(-1) at 0.2 C after 50 cycles. The facile, scalable, energy-efficient and environmentally friendly nature of the presented approach renders it particularly attractive from a technological standpoint. In addition, this scalable and facile synthesis method could be extended to the preparation of other transition metal oxides with specific morphologies and surface textures. PMID- 23092942 TI - Granulocyte-dependent autoantibody-induced skin blistering. AB - Autoimmune phenomena occur in healthy individuals, but when self-tolerance fails, the autoimmune response may result in specific pathology. According to Witebsky's postulates, one of the criteria in diagnosing a disease as autoimmune is the reproduction of the disease in experimental animals by the passive transfer of autoantibodies. For epidermolysis bullosa acquisita (EBA), a prototypic organ specific autoimmune disease of skin and mucous membranes, several experimental models were recently established. In the animal model described in our present work, purified IgG antibodies against a stretch of 200 amino acids (aa 757-967) of collagen VII are injected repeatedly into mice reproducing the blistering phenotype as well as the histo- and immunopathological features characteristic to human EBA (1). Full-blown widespread disease is usually seen 5-6 days after the first injection and the extent of the disease correlates with the dose of the administered collagen VII-specific IgG. The tissue damage (blister formation) in the experimental EBA is depending on the recruitment and activation of granulocytes by tissue-bound autoantibodies (2,-4). Therefore, this model allows for the dissection of the granulocyte-dependent inflammatory pathway involved in the autoimmune tissue damage, as the model reproduces only the T cell-independent phase of the efferent autoimmune response. Furthermore, its value is underlined by a number of studies demonstrating the blister-inducing potential of autoantibodies in vivo and investigating the mechanism of the blister formation in EBA (1,3,-6). Finally, this model will greatly facilitate the development of new anti-inflammatory therapies in autoantibody-induced diseases. Overall, the passive transfer animal model of EBA is an accessible and instructive disease model and will help researchers to analyze not only EBA pathogenesis but to answer fundamental biologically and clinically essential autoimmunity questions. PMID- 23092944 TI - Laparoscopic retrieval of retained intraperitoneal drain in the immediate postoperative period Report of two cases. AB - AIM: The purpose of this study is to analyze a "rare" complication on the management of abdominal surgical drains: abdominal drainage's retention. Starting from our experience we reviewed literature on this topic MATERIAL OF STUDY: We report two cases (occurred on 2004 and 2010) of retained intraperitoneal drain occurred in the immediate postoperative period after laparoscopic cholecystectomy. RESULTS: Both patients were successfully treated by early laparoscopic removal. DISCUSSION: We compared our experience with literature. Incidence, ethiology, prevention, diagnosis and treatment of this rare complication are analysed. We also considered the guidelines in the placement of intraperitoneal drains, the different fixation techniques, the causes of fragmentation of the drainage and removal techniques. CONCLUSIONS: Retained intraperitoneal drain secondary to fracture and adhesion in the immediate postoperative period is rare but probably underestimated surgical complication. It is impossible to know its real incidence. The role of laparoscopy is emphasized because this approach is cosmetically acceptable, contributes to early recovery and discharge of the patient, and helps to lessen the friction in worsening doctor-patient relationship. KEY WORDS: Abdominal drainage, Drain related complications, Laparoscopy, Retained intraperitoneal drain. PMID- 23092945 TI - Sulforaphane causes a major epigenetic repression of myostatin in porcine satellite cells. AB - Satellite cells function as skeletal muscle stem cells to support postnatal muscle growth and regeneration following injury or disease. There is great promise for the improvement of muscle performance in livestock and for the therapy of muscle pathologies in humans by the targeting of myostatin (MSTN) in this cell population. Human diet contains many histone deacetylase (HDAC) inhibitors, such as the bioactive component sulforaphane (SFN), whose epigenetic effects on MSTN gene in satellite cells are unknown. Therefore, we aimed to investigate the epigenetic influences of SFN on the MSTN gene in satellite cells. The present work provides the first evidence, which is distinct from the effects of trichostatin A (TSA), that SFN supplementation in vitro not only acts as a HDAC inhibitor but also as a DNA methyltransferase (DNMT) inhibitor in porcine satellite cells. Compared with TSA and 5-aza-2'-deoxycytidine (5-aza-dC), SFN treatment significantly represses MSTN expression, accompanied by strongly attenuated expression of negative feedback inhibitors of the MSTN signaling pathway. miRNAs targeting MSTN are not implicated in posttranscriptional regulation of MSTN. Nevertheless, a weakly enriched myoblast determination (MyoD) protein associated with diminished histone acetylation in the MyoD binding site located in the MSTN promoter region may contribute to the transcriptional repression of MSTN by SFN. These findings reveal a new mode of epigenetic repression of MSTN by the bioactive compound SFN. This novel pharmacological, biological activity of SFN in satellite cells may thus allow for the development of novel approaches to weaken the MSTN signaling pathway, both for therapies of human skeletal muscle disorders and for livestock production improvement. PMID- 23092946 TI - An object-mediated updating account of insensitivity to transsaccadic change. AB - Recent evidence has suggested that relatively precise information about the location and visual form of a saccade target object is retained across a saccade. However, this information appears to be available for report only when the target is removed briefly, so that the display is blank when the eyes land. We hypothesized that the availability of precise target information is dependent on whether a post-saccade object is mapped to the same object representation established for the presaccade target. If so, then the post-saccade features of the target overwrite the presaccade features, a process of object mediated updating in which visual masking is governed by object continuity. In two experiments, participants' sensitivity to the spatial displacement of a saccade target was improved when that object changed surface feature properties across the saccade, consistent with the prediction of the object-mediating updating account. Transsaccadic perception appears to depend on a mechanism of object based masking that is observed across multiple domains of vision. In addition, the results demonstrate that surface-feature continuity contributes to visual stability across saccades. PMID- 23092947 TI - Similarity relations in visual search predict rapid visual categorization. AB - How do we perform rapid visual categorization?It is widely thought that categorization involves evaluating the similarity of an object to other category items, but the underlying features and similarity relations remain unknown. Here, we hypothesized that categorization performance is based on perceived similarity relations between items within and outside the category. To this end, we measured the categorization performance of human subjects on three diverse visual categories (animals, vehicles, and tools) and across three hierarchical levels (superordinate, basic, and subordinate levels among animals). For the same subjects, we measured their perceived pair-wise similarities between objects using a visual search task. Regardless of category and hierarchical level, we found that the time taken to categorize an object could be predicted using its similarity to members within and outside its category. We were able to account for several classic categorization phenomena, such as (a) the longer times required to reject category membership; (b) the longer times to categorize atypical objects; and (c) differences in performance across tasks and across hierarchical levels. These categorization times were also accounted for by a model that extracts coarse structure from an image. The striking agreement observed between categorization and visual search suggests that these two disparate tasks depend on a shared coarse object representation. PMID- 23092948 TI - Motor action reduces temporal asynchrony between perceived visual changes. AB - Perceiving a visual object requires binding sensory estimates of its various physical attributes. This process can be facilitated if changes of different attributes are perceived with little asynchronies when they are physically aligned, which is not always the case as revealed by temporal order judgment or perceptual synchronization tasks of visual attributes changes. In this study, we analyzed the effect of performing a motor action on the perceived relative timing between changes of position and color of a visual target by using a temporal order judgment (TOJ) task. Results showed that in the perceptual condition, the change of color must precede (-37.9 ms) the change of position in order to perceive a synchronous change of both target's visual attributes. This physical asynchrony vanished when the same changes took place near the end of a manual reaching action executed towards the visual target (-3.3 ms). The reduction of asynchrony was, however, not observed when participants performed TOJ of visual attributes change in the presence of concomitant tactile information (-36 ms) but with no action. The perceptual relative timing between visual changes was also unaffected when the timing was obtained by comparing each visual change to tactile information resulting from motor action (-33.5 ms) or external stimulation (-27.8 ms). Altogether, these results suggest that signals associated with the organization of a motor action, but not sensory information itself, contribute to reduce the differential delays when processing visual attributes of a single object. Furthermore, the effect of action was not observed when judging relative timing of object-related (visual) versus object-unrelated (tactile) sensory information. PMID- 23092949 TI - The pyridyl group in ligand design for selective metal ion complexation and sensing. AB - Factors in polypyridyl ligands that control their thermodynamic metal ion selectivity in aqueous solution, and their use in selective fluorescent sensing, are examined. Preorganization of polypyridyl ligands ranging from bidentate to tetradentate by bridging benzo groups, as are present in 1,10-phenanthroline (phen) compared to 2,2'-bipyridyl (bpy), is discussed. The role of solvation is considered in relation to the relative affinity of ligands containing pyridyl groups for divalent and trivalent metal ions in aqueous solution. The effects of steric clashes between H atoms on polypyridyl ligands in decreasing complex stability are evaluated, as well as the effect of chelate ring size on metal ion selectivity. Phen ligands with other donor groups present at the 2 and 9 positions, such as alcohols, amides, carboxylates, and oximes are discussed. The design of pyridyl-based ligands for the separation of Am(III) from lanthanide(III) ions is considered, as well as ligands for the removal of metal ions such as Cu(II) or Zn(II) in neurological diseases such as Alzheimer's. The design of pyridyl-based fluorescent sensors for selective sensing of metal ions is examined in terms of the role of spin-orbit coupling constants (zeta), paramagnetism, and steric effects in the development of selective fluorescent sensors that operate via chelation enhanced fluorescence (CHEF). It is concluded that for lighter metal ions with smaller zeta values such as Zn(II) and Ca(II), and to a lesser extent Cd(II), that the CHEF effect can be achieved with pyridyl containing fluorophores that coordinate directly to the metal ion. The way in which steric effects can be used to decrease the CHEF effect in Zn(II) relative to Cd(II) to enable selective sensing of the latter is analyzed. For heavier metal ions such as Hg(II) and Pb(II), because of their large zeta values which quench fluorescence, it is concluded that the fluorophore should be tethered to the metal-binding part of the sensor, and prevented from binding to the metal ion by steric and electronic factors. How Hg(II) can quench the CHEF effect by pi contact with fluorophores such as the anthracenyl group, which at first sight might not seem able to bond with metal ions, is examined. PMID- 23092950 TI - Mode-specificity and transition state-specific energy redistribution in the chemisorption of CH4 on Ni{100}. AB - We have investigated methane (CH(4)) dissociative chemisorption on the Ni{100} surface by first-principles molecular dynamics (MD) simulations. Our results show that this reaction is mode-specific, with the nu(1) state being the most strongly coupled to efficient energy flow into the reaction coordinate when the molecule reaches the transition state. By performing MD simulations for two different transition state (TS) structures we provide evidence of TS structure-specific energy redistribution in methane chemisorption. Our results are compared with recently reported state-resolved measurement of methane adsorption probability on nickel surfaces, and we find that a strong correlation exists between the highest vibrational efficacy measured on Ni{100} for the nu(1) state and the calculated highest fractional vibrational energy content in this mode. PMID- 23092951 TI - Standardized bioenergetic profiling of adult mouse cardiomyocytes. AB - Mitochondria are at the crux of life and death and as such have become ideal targets of intervention in cardiovascular disease. Generally, current methods to measure mitochondrial dysfunction rely on working with the isolated organelle and fail to incorporate mitochondrial function in a cellular context. Extracellular flux methodology has been particularly advantageous in this respect; however, certain primary cell types, such as adult cardiac myocytes, have been difficult to standardize with this technology. Here, we describe methods for using extracellular flux (XF) analysis to measure mitochondrial bioenergetics in isolated, intact, adult mouse cardiomyocytes (ACMs). Following isolation, ACMs were seeded overnight onto laminin-coated (20 MUg/ml) microplates, which resulted in high attachment efficiency. After establishing seeding density, we found that a commonly used assay medium (containing a supraphysiological concentration of pyruvate at 1 mmol/l) produced a maximal bioenergetic response. After performing a pyruvate dose-response, we determined that pyruvate titrated to 0.1 mmol/l was optimal for examining alternative substrate oxidation. Methods for measuring fatty acid oxidation were established. These methods lay the framework using XF analysis to profile metabolism of ACMs and will likely augment our ability to understand mitochondrial dysfunction in heart failure and acute myocardial ischemia. This platform could easily be extended to models of diabetes or other metabolic defects. PMID- 23092952 TI - Molecular aspects of mucin biosynthesis and mucus formation in the bovine cervix during the periestrous period. AB - Mucus within the cervical canal represents a hormonally regulated barrier that reconciles the need to exclude the vaginal microflora from the uterus during progesterone dominance, while permitting sperm transport at estrus. Its characteristics change during the estrous cycle to facilitate these competing functional requirements. Hydrated mucin glycoproteins synthesized by the endocervical epithelium form the molecular scaffold of this mucus. This study uses the bovine cervix as a model to examine functional groups of genes related to mucin biosynthesis and mucus production over the periestrous period when functional changes in cervical barrier function are most prominent. Cervical tissue samples were collected from 30 estrus synchronized beef heifers. Animals were slaughtered in groups starting 12 h after the withdrawal of intravaginal progesterone releasing devices (controlled internal drug releases) until 7 days postonset of estrus (luteal phase). Subsequent groupings represented proestrus, early estrus, late estrus, metestrus, and finally the early luteal phase. Tissues were submitted to next generation RNA-seq transcriptome analysis. We identified 114 genes associated with biosynthesis and intracellular transport of mucins, and postsecretory modifications of cervical; 53 of these genes showed at least a twofold change in one or more experimental group in relation to onset of estrus, and the differences between groups were significant (P < 0.05). The majority of these genes showed the greatest alteration in their expression in the 48 h postestrus and luteal phase groups. PMID- 23092953 TI - Aberrant placenta gene expression pattern in bovine pregnancies established after transfer of cloned or in vitro produced embryos. AB - In the present study, we used the global transcriptome profile approach to identify dysregulated genes, molecular pathways, and molecular functional alterations in bovine placentas derived from somatic cell nuclear transfer (SCNT) and in vitro embryo production (IVP) pregnancies compared with their artificial insemination (AI) counterparts at day 50 of gestation. For this, day 7 blastocysts derived from AI, IVP, or SCNT were transferred to oestrus synchronized cows. The pregnant animals were slaughtered at day 50 of gestation, and the placentas were then recovered and used for transcriptome analysis using Affymetrix GeneChip bovine genome array. Results showed the SCNT placenta to be different from its AI counterpart in the expression of 1,196 transcripts. These genes were found to be associated with alterations in key biological processes and molecular pathways in SCNT placenta, and the dysregulation of 9% (n = 110) of these genes was due to transcriptional reprogramming error. IVP placenta also displayed alterations in the expression of 72 genes, of which 58 were common to SCNT placenta. Gene enrichment analysis revealed that the expression of genes involved in organ development, blood vessel development, extracellular matrix organization, and the immune system was affected in both SCNT and IVP placentas. However, 96% of the affected genes in SCNT were not significantly altered in IVP groups. Thus, the higher transcriptome dysregulation in SCNT placenta followed by IVP would reflect the degree of placental abnormality in SCNT and IVP pregnancies at day 50 of the gestation, which may have a profound effect on subsequent fetal development and health of the offspring. PMID- 23092954 TI - SHAVE: shrinkage estimator measured for multiple visits increases power in GWAS of quantitative traits. AB - Measurement error and biological variability generate distortions in quantitative phenotypic data. In longitudinal studies with repeated measurements, the multiple measurements provide a route to reduce noise and correspondingly increase the strength of signals in genome-wide association studies (GWAS).To optimize noise correction, we have developed Shrunken Average (SHAVE), an approach using a Bayesian Shrinkage estimator. This estimator uses regression toward the mean for every individual as a function of (1) their average across visits; (2) their number of visits; and (3) the correlation between visits. Computer simulations support an increase in power, with results very similar to those expected by the assumptions of the model. The method was applied to a real data set for 14 anthropomorphic traits in ~6000 individuals enrolled in the SardiNIA project, with up to three visits (measurements) for each participant. Results show that additional measurements have a large impact on the strength of GWAS signals, especially when participants have different number of visits, with SHAVE showing a clear increase in power relative to single visits. In addition, we have derived a relation to assess the improvement in power as a function of number of visits and correlation between visits. It can also be applied in the optimization of experimental designs or usage of measuring devices. SHAVE is fast and easy to run, written in R and freely available online. PMID- 23092956 TI - Statistical tests for detecting associations with groups of genetic variants: generalization, evaluation, and implementation. AB - With recent advances in sequencing, genotyping arrays, and imputation, GWAS now aim to identify associations with rare and uncommon genetic variants. Here, we describe and evaluate a class of statistics, generalized score statistics (GSS), that can test for an association between a group of genetic variants and a phenotype. GSS are a simple weighted sum of single-variant statistics and their cross-products. We show that the majority of statistics currently used to detect associations with rare variants are equivalent to choosing a specific set of weights within this framework. We then evaluate the power of various weighting schemes as a function of variant characteristics, such as MAF, the proportion associated with the phenotype, and the direction of effect. Ultimately, we find that two classical tests are robust and powerful, but details are provided as to when other GSS may perform favorably. The software package CRaVe is available at our website (http://dceg.cancer.gov/bb/tools/crave). PMID- 23092955 TI - Dynamin 2 homozygous mutation in humans with a lethal congenital syndrome. AB - Heterozygous mutations in dynamin 2 (DNM2) have been linked to dominant Charcot Marie-Tooth neuropathy and centronuclear myopathy. We report the first homozygous mutation in the DNM2 protein p.Phe379Val, in three consanguineous patients with a lethal congenital syndrome associating akinesia, joint contractures, hypotonia, skeletal abnormalities, and brain and retinal hemorrhages. In vitro membrane tubulation, trafficking and GTPase assays are consistent with an impact of the DNM2p.Phe379Val mutation on endocytosis. Although DNM2 has been previously implicated in axonal and muscle maintenance, the clinical manifestation in our patients taken together with our expression analysis profile during mouse embryogenesis and knockdown approaches in zebrafish resulting in defects in muscle organization and angiogenesis support a pleiotropic role for DNM2 during fetal development in vertebrates and humans. PMID- 23092957 TI - Observation of multiple superconducting gaps in Fe1+yTe1-xSex via a nanoscale approach to point-contact spectroscopy. AB - We report a novel experimental approach to point-contact Andreev reflection spectroscopy with diagnostic capability via a unique design for nanoscale normal metal/superconductor devices with excellent thermomechanical stability, and have employed this method to unveil the existence of two superconducting energy gaps in iron chalcogenide Fe(1+y)Te(1-x)Se(x), which is crucial for understanding its pairing mechanism. This work opens up new opportunities to study gap structures in superconductors and elemental excitations in solids. PMID- 23092958 TI - Selenium intake and nutritional status of children with phenylketonuria in Minas Gerais, Brazil. AB - OBJECTIVE: To evaluate selenium dietary intake and nutritional status of patients with phenylketonuria. METHODS: The study prospectively evaluated 54 children with phenylketonuria, from 4 to10 years old. The study was performed before and after the use of a selenium-supplemented amino acid mixture. The second phase of the study was performed after, at least, 90 days of use of the supplementation. Selenium nutritional status was assessed through the analysis of biochemical parameters: serum free thyroxin and selenium and glutathione peroxidase in erythrocytes. Selenium dietary intake was evaluated by the administration of the Food Frequency Questionnaire. RESULTS: Mean age of the children was of 7.0+/-1.8 years, and 35.2% were female. Mean time of supplementation of selenium, on special formula, was 122.2+/-25.1 days. The selenium-supplemented amino acid mixture represented 72.9% of the daily supply of the mineral. Upon supplementation, mean concentrations of serum selenium and glutathione peroxidase in erythrocytes increased significantly (p < 0.05). The average daily intake of selenium increased significantly (p < 0.001), reaching the levels recommended by the Dietary Reference Intakes. The concentration of free thyroxin, in serum, presented significant reduction (p < 0.001) in all patients during the second phase of the study, and returned to normal limits in those who had changed levels. CONCLUSIONS: Selenium supplementation through protein replacement is effective to improve and adapt the nutritional status of selenium in patients with phenylketonuria. PMID- 23092959 TI - [Sublobar curative resection for non-small-cell lung cancer]. AB - It has been proved that lobectomy for lung cancer of less than 3 cm is superior to sublobar resection (segmentectomy and wedge resection) in the Lung Cancer Study Group trial published in 1995. Lobectomy is therefore recommended, with lymph node resection. Nevertheless, some publications have shown identical or close results after segmentectomy for tumors of less than 2 cm, and after wedge resection for tumors of less than 1 cm. It is likely that local recurrences are avoided by respecting a macroscopic margin of more than 2 cm around the tumor. A new trial comparing lobectomy and sublobar resection has been ongoing since 2007 for tumors of less than 2 cm. Persistent ground glass opacities are now often discovered after screening, either pure or with a small solid component, and correspond to an in situ or a micro-invasive adenocarcinoma, that can be removed with sublobar resection without recurrence. PMID- 23092960 TI - Use of LysoTracker to detect programmed cell death in embryos and differentiating embryonic stem cells. AB - Programmed cell death (PCD) occurs in adults to maintain normal tissue homeostasis and during embryological development to shape tissues and organs(1,2,6,7). During development, toxic chemicals or genetic alterations can cause an increase in PCD or change PCD patterns resulting in developmental abnormalities and birth defects(3-5). To understand the etiology of these defects, the study of embryos can be complemented with in vitro assays that use differentiating embryonic stem (ES) cells. Apoptosis is a well-studied form of PCD that involves both intrinsic and extrinsic signaling to activate the caspase enzyme cascade. Characteristic cell changes include membrane blebbing, nuclear shrinking, and DNA fragmentation. Other forms of PCD do not involve caspase activation and may be the end-result of prolonged autophagy. Regardless of the PCD pathway, dying cells need to be removed. In adults, the immune cells perform this function, while in embryos, where the immune system has not yet developed, removal occurs by an alternative mechanism. This mechanism involves neighboring cells (called "non-professional phagocytes") taking on a phagocytic role-they recognize the 'eat me' signal on the surface of the dying cell and engulf it(8 10). After engulfment, the debris is brought to the lysosome for degradation. Thus regardless of PCD mechanism, an increase in lysosomal activity can be correlated with increased cell death. To study PCD, a simple assay to visualize lysosomes in thick tissues and multilayer differentiating cultures can be useful. LysoTracker dye is a highly soluble small molecule that is retained in acidic subcellular compartments such as the lysosome(11-13). The dye is taken up by diffusion and through the circulation. Since penetration is not a hindrance, visualization of PCD in thick tissues and multi-layer cultures is possible(12,13). In contrast, TUNEL (Terminal deoxynucleotidyl transferase dUTP nick end labeling) analysis(14), is limited to small samples, histological sections, and monolayer cultures because the procedure requires the entry/permeability of a terminal transferase. In contrast to Aniline blue, which diffuses and is dissolved by solvents, LysoTracker Red DND-99 is fixable, bright, and stable. Staining can be visualized with standard fluorescent or confocal microscopy in whole-mount or section using aqueous or solvent-based mounting media(12,13). Here we describe protocols using this dye to look at PCD in normal and sonic hedgehog null mouse embryos. In addition, we demonstrate analysis of PCD in differentiating ES cell cultures and present a simple quantification method. In summary, LysoTracker staining can be a great complement to other methods of detecting PCD. PMID- 23092962 TI - Magnetization and electric transport properties of single-crystal MgB2 nanowires. AB - High quality single-crystal magnesium diboride (MgB(2)) nanowires with lengths exceeding 10 MUm were successfully synthesized by hybrid physical chemical vapor deposition. The magnetization and electrical transport properties of single crystal MgB(2) nanowires (NWs) were measured. The superconducting transition temperature of the NWs was 37 K, as confirmed by magnetization measurements. The disordered behavior of the nanowires was observed by four-terminal current voltage characteristic measurements of an individual NW from T = 10 to 300 K. The temperature-dependent resistivity curves for seven NWs collapsed into a universal curve described by the variable range hopping model, showing intrinsic nonmetallic transport properties. This implies that the granular superconducting defect states are critical to the superconductivity of the individual MgB(2) NWs. PMID- 23092963 TI - Calcification inhibitors in vascular calciphylaxis associated with normal renal function. PMID- 23092965 TI - Determination of colloidal gold nanoparticle surface areas, concentrations, and sizes through quantitative ligand adsorption. AB - Determination of the true surface areas, concentrations, and particle sizes of gold nanoparticles (AuNPs) is a challenging issue due to the nanoparticle morphological irregularity, surface roughness, and size distributions. A ligand adsorption-based technique for determining AuNP surface areas in solution is reported. Using a water-soluble, stable, and highly UV-vis active organothiol, 2 mercaptobenzimidazole (MBI), as the probe ligand, we demonstrated that the amount of ligand adsorbed is proportional to the AuNP surface area. The equivalent spherical AuNP sizes and concentrations were determined by combining the MBI adsorption measurement with Au(3+) quantification of aqua regia-digested AuNPs. The experimental results from the MBI adsorption method for a series of commercial colloidal AuNPs with nominal diameters of 10, 30, 50, and 90 nm were compared with those determined using dynamic light scattering, transmission electron microscopy, and localized surface plasmonic resonance methods. The ligand adsorption-based technique is highly reproducible and simple to implement. It only requires a UV-vis spectrophotometer for characterization of in-house prepared AuNPs. PMID- 23092966 TI - Identifying indoor environmental patterns from bioaerosol material using HPLC. AB - A substantial portion of the atmospheric particle budget is of biological origin (human and animal dander, plant and insect debris, etc.). These bioaerosols can be considered information-rich packets of biochemical data specific to the organism of origin. In this study, bioaerosol samples from various indoor environments were analyzed to create identifiable patterns attributable to a source level of occupation. Air samples were collected from environments representative of human high-traffic- and low-traffic indoor spaces along with direct human skin sampling. In all settings, total suspended particulate matter was collected and the total aerosol protein concentration ranged from 0.03 to 1.2 MUg/m(3). High performance liquid chromatography was chosen as a standard analysis technique for the examination of aqueous aerosol extracts to distinguish signatures of occupation compared to environmental background. The results of this study suggest that bioaerosol "fingerprinting" is possible with the two test environments being distinguishable at a 97% confidence interval. PMID- 23092967 TI - Lessons learned from experimental myocarditis. AB - We have developed murine models of viral myocarditis induced by encephalomyocarditis (EMC) virus in which severe myocarditis, congestive heart failure and dilated cardiomyopathy occur in high incidence. From these models, we have learned the natural history and pathogenesis and assessed not only new diagnostic methods but also therapeutic and preventive interventions. Autoantibodies against cardiac troponin I appeared in spontaneously developing autoimmune myocarditis in PD-1 deficient mice, who lack the T-cell receptor costimulatory molecule PD-1. The passive transfer of this antibody induced myocardial dysfunction. Later, this autoantibody was found in patients with myocarditis. Mast cell deficiency had beneficial effects in the viral myocarditis model, and anti-allergic agents prevented viral myocarditis. Angiotensin converting enzyme inhibitors, angiotensin II receptor blocker and an aldosterone receptor antagonist improved viral myocarditis, suggesting that the renin angiotension-aldosterone system may play an important role in the pathogenesis of viral myocarditis. Differential modulation of cytokine production was seen with various calcium channel blockers, and some calcium channel blocker improved viral myocarditis. Viral infection could lead to increased synthesis of immunoglobulin light chains (FLC). Serum levels of FLC were increased in myocarditis, and exogenously given FLC inhibited viral replication and improved myocarditis. We suggest that a strategy of drug development specifically addressing inflammation in myocarditis may provide increased benefit in terms of target organ damage. PMID- 23092968 TI - Superior long-term cycling stability of SnO2 nanoparticle/multiwalled carbon nanotube heterostructured electrodes for Li-ion rechargeable batteries. AB - We demonstrate the fabrication of hybrid nanocomposite electrodes with a combination of SnO(2) nanoparticles (NPs) and conducting multiwalled carbon nanotube (MWCNT) anodes (SnO(2)@CNT) through the direct anchoring of SnO(2) NPs on the surface of electrophoretically pre-deposited MWCNT (EPD-CNT) networks via a metal-organic chemical vapor deposition process. This SnO(2)@CNT nanocomposite displays large reversible capacities of over 780, 510, and 470 mA h g(-1) at 1 C after 100, 500, and 1000 cycles, respectively. This outstanding long-term cycling stability is a result of the uniform distribution of SnO(2) NPs (~8.5 nm), a nanoscale EPD-CNT network with good electrical conductivity, and the creation of open spaces that buffer a large volume change during the Li-alloying/dealloying reaction of SnO(2). PMID- 23092969 TI - Expression of promyelocytic leukemia protein and vascular endothelial growth factor in aqueous humor and vitreous fluid in patients with proliferative diabetic retinopathy. AB - AIMS: To examine the expression of promyelocytic leukemia protein (PML) in the eye of proliferative diabetic retinopathy (PDR) patients. METHODS: PML mRNA levels were measured in proliferative membranes from 12 PDR patients and idiopathic epiretinal membranes from 5 control patients by quantitative RT-PCR. Protein levels of PML and vascular endothelial growth factor (VEGF) in aqueous humor and vitreous fluid samples from 34 PDR patients and 38 control patients were determined using ELISA. RESULTS: The PML mRNA expression levels in membrane samples, and the PML protein concentrations in aqueous humor and vitreous fluid samples were significantly lower in PDR patients than control patients. We observed a statistically significant inverse correlation between the concentrations of PML and VEGF in the aqueous humor and vitreous fluid of PDR patients. CONCLUSION: PML may be a good candidate as a diagnostic marker and a therapeutic agent for PDR. PMID- 23092971 TI - Interactive versus passive distraction for acute pain management in young children: the role of selective attention and development. AB - OBJECTIVE: To examine whether age and developmental differences in selective attention influence young children's differential responses to interactive and passive distraction. METHODS: 65 3- to 6-year-old children underwent three cold pressor trials while receiving no intervention, playing a video game (interactive distraction), or watching a video game (passive distraction). In addition, children completed a test of selective attention, and parents completed ratings of attention. RESULTS: Consistent with neurocognitive models of pain, children benefited more from interactive distraction than from passive distraction. Although older children demonstrated superior pain tolerance overall, age and selective attention skills did not moderate children's responses to the distraction intervention. CONCLUSIONS: These findings suggest that younger preschoolers can benefit from interactive distraction to manage acute pain, provided that the distraction activity is developmentally appropriate. Research is needed to determine whether developmental issues are more important moderators of children's responses to distraction when faced with more challenging task demands. PMID- 23092970 TI - SUMOylation of hnRNP-K is required for p53-mediated cell-cycle arrest in response to DNA damage. AB - Heterogeneous ribonucleoprotein-K (hnRNP-K) is normally ubiquitinated by HDM2 for proteasome-mediated degradation. Under DNA-damage conditions, hnRNP-K is transiently stabilized and serves as a transcriptional co-activator of p53 for cell-cycle arrest. However, how the stability and function of hnRNP-K is regulated remained unknown. Here, we demonstrated that UV-induced SUMOylation of hnRNP-K prevents its ubiquitination for stabilization. Using SUMOylation defective mutant and purified SUMOylated hnRNP-K, SUMOylation was shown to reduce hnRNP-K's affinity to HDM2 with an increase in that to p53 for p21-mediated cell cycle arrest. PIAS3 served as a small ubiquitin-related modifier (SUMO) E3 ligase for hnRNP-K in an ATR-dependent manner. During later periods after UV exposure, however, SENP2 removed SUMO from hnRNP-K for its destabilization and in turn for release from cell-cycle arrest. Consistent with the rise-and-fall of both SUMOylation and stability of hnRNP-K, its ability to interact with PIAS3 was inversely correlated to that with SENP2 during the time course after UV exposure. These findings indicate that SUMO modification plays a crucial role in the control of hnRNP-K's function as a p53 co-activator in response to DNA damage by UV. PMID- 23092972 TI - Systemic or intrasynovial medication as singular or as combination treatment in horses with (peri-)synovial pain. AB - Records of lame horses (2004-2007) with (peri-)synovial pain of the metacarpophalangeal joint (MCPJ, n = 53), digital flexor tendon sheath (DFTS, n = 20), and distal interphalangeal joint (DIPJ, n = 31) were evaluated (n = 104). Cases were grouped according to the following treatments: (1) systemic administration of NSAIDs (n = 40); (2) intrasynovial administration of glucocorticosteroids (n = 30); (3) combination treatment (n = 34). Outcome was defined as successful when the owner reported that the horse had returned to its previous level of performance within a period of up to six months after treatment. Statistical evaluation was performed using Fisher's Exact tests and multivariable logistic regression analyses at P < 0.05. Successful outcome was significantly higher for horses in treatment group 3 (19/34, 55.9 per cent, P = 0.021) than in treatment groups 1 (11/40, 27.5 per cent, OR 0.21, 95 per cent CI 0.06 to 0.71) and 2 (8/30, 26.6 per cent, OR 0.18, 95 per cent CI 0.06 to 0.56). A significant association was only found with regard to the affected synovial structure (P = 0.025); relative to the DIPJ, involvement of the MCPJ and DFTS was four to five times more likely to provide a successful outcome (OR 4.18 and 5.59, 95 per cent CI 1.24 to 14.08 and 1.42-22.22, respectively). PMID- 23092973 TI - gamma-Glutamyl-transferase (GGT) activity in the urine of clinically healthy domestic rabbits (Oryctolagus cuniculus). AB - Free-catch urine samples were collected from forty-one clinically normal domestic rabbits of various ages, breeds and both sexes. The Test gamma GT Liquid 0018257640 was used for the in vitro quantitative determination of gamma-Glutamyl transferase (GGT) and reference intervals for gamma-glutamyl transferase (gamma glutamyl transpeptidase, gamma-GT, GGT) and GGT index (gamma-glutamyl transferase to creatinine ratio) were established in fresh urine samples. Possible correlations of GGT and GGT index with sex and age were also explored. The stability of GGT after storage at +4 degrees C for one week and -20 degrees C for one month was investigated. The GGT and the GGT index reference intervals in fresh urine samples of healthy domestic rabbits were found to be 2.7-96.5 IU/l and 0.043-1.034, respectively. The urine GGT activity and the GGT index did not differ significantly between sexes in fresh urine samples. Nevertheless, a statistically significant difference was found in the GGT index with neutered status. Short-term storage at 4 degrees C did not alter the enzyme stability, whereas, freezing did. Further investigations are needed to determine whether these parameters may be useful for early detection of renal tubular damage in rabbits, and in enabling better clinical management of affected animals. PMID- 23092974 TI - Peritoneal inflammatory response to surgical correction of left displaced abomasum using different techniques. AB - The objective of this study was to compare the inflammatory response within the abdominal cavity between three surgical methods. The study comprised 45 cows with left displacement of the abomasum, which were allocated into three groups (n = 15). Right flank laparotomy and omentopexy (group R), left flank laparotomy and omentopexy (group L), and laparoscopic abomasopexy (group J) have been applied. Laparoscopic abomasopexy was the only technique that requires perforation of the abomasal wall. Blood and peritoneal fluid (PF) samples were obtained before, and on days 1, 2 and 3 after surgery. Macroscopic and microscopic evaluation of PF were performed. Cytological and biochemical parameters were analysed in blood and PF. No bacteria were present in PF after surgery. The number of PF leukocytes increased in all groups on day 1 after surgery with the highest value after laparoscopy (median, 1st quartile, 3rd quartile, R: 13.1, 6.4, 16.0; L: 13.6, 9.9, 17.4; J: 33.7, 21.1, 46.9 G/l). Laparotomy resulted in an increase of blood and PF CK on day 1 after surgery, whereas, laparoscopy caused an increased PF CK only. All groups had elevated PF D-dimer concentrations before surgery, with further increase in groups R and L on day 1 after surgery. PMID- 23092975 TI - Electrons, phonons and superconductivity in rocksalt and tungsten-carbide phases of CrC. AB - We present results of ab initio theoretical investigations of the electronic structure, phonon dispersion relations, electron-phonon interaction and superconductivity in the rocksalt and tungsten-carbide phases of CrC. It is found that, compared to the stable tungsten-carbide phase, the metastable rocksalt phase is characterized by a much larger electronic density of states at the Fermi level. The phonon spectra of the rocksalt phase exhibit anomalies in the dispersion curves of both the transverse and longitudinal acoustic branches along the main symmetry directions. A combination of these characteristic electronic and phonon properties leads to an order of magnitude larger value of the electron phonon coupling constant (lambda = 2.66) for the rocksalt phase compared to that for the tungsten-carbide phase (lambda = 0.24). Our calculations suggest that superconducting transition temperature values of 0.01 K and 25-35 K may be expected for the tungsten-carbide and rocksalt phases, respectively. PMID- 23092976 TI - The significance of moment-of-inertia variation in flight manoeuvres of butterflies. AB - The objective of this study is to understand the role that changes in body moment of inertia might play during flight manoeuvres of insects. High-speed, high resolution videogrammetry is used to quantify the trajectory and body conformation of Painted Lady butterflies during flight manoeuvres; the 3D kinematics of the centre of masses of the various body parts of the insect is determined experimentally. Measurements of the mass properties of the insect are used to parameterize a simple flight dynamics model of the butterfly. Even though the mass of the flapping wings is small compared to the total mass of the insect, these experiments and subsequent analysis indicate that changes in moment of inertia during flight are large enough to influence the manoeuvres of these insects. PMID- 23092977 TI - Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation. AB - The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis. PMID- 23092978 TI - Sampling bias in an internet treatment trial for depression. AB - Internet psychological interventions are efficacious and may reduce traditional access barriers. No studies have evaluated whether any sampling bias exists in these trials that may limit the translation of the results of these trials into real-world application. We identified 7999 potentially eligible trial participants from a community-based health cohort study and invited them to participate in a randomized controlled trial of an online cognitive behavioural therapy programme for people with depression. We compared those who consented to being assessed for trial inclusion with nonconsenters on demographic, clinical and behavioural indicators captured in the health study. Any potentially biasing factors were then assessed for their association with depression outcome among trial participants to evaluate the existence of sampling bias. Of the 35 health survey variables explored, only 4 were independently associated with higher likelihood of consenting-female sex (odds ratio (OR) 1.11, 95% confidence interval (CI) 1.05-1.19), speaking English at home (OR 1.48, 95% CI 1.15-1.90) higher education (OR 1.67, 95% CI 1.46-1.92) and a prior diagnosis of depression (OR 1.37, 95% CI 1.22-1.55). The multivariate model accounted for limited variance (C-statistic 0.6) in explaining participation. These four factors were not significantly associated with either the primary trial outcome measure or any differential impact by intervention arm. This demonstrates that, among eligible trial participants, few factors were associated with the consent to participate. There was no indication that such self-selection biased the trial results or would limit the generalizability and translation into a public or clinical setting. PMID- 23092979 TI - Short- and long-lasting behavioral and neurochemical adaptations: relationship with patterns of cocaine administration and expectation of drug effects in rats. AB - Cocaine dependence is a significant public health problem, characterized by periods of abstinence. Chronic exposure to drugs of abuse induces important modifications on neuronal systems, including the dopaminergic system. The pattern of administration is an important factor that should be taken into consideration to study the neuroadaptations. We compared the effects of intermittent (once daily) and binge (three times a day) cocaine treatments for 1 (WD1) and 14 (WD14) days after the last cocaine injection on spontaneous locomotor activity and dopamine (DA) levels in the nucleus accumbens (Nac). The intermittent treatment led to a spontaneous increase in DA (WD1/WD14), and in locomotor activity (WD1) at the exact hour which rats were habituated to receive a cocaine injection. These results underline that taking into consideration the hours of the day at which the experiments are performed is crucial. We also investigated these behavioral and neurochemical adaptations in response to an acute cocaine challenge on WD1 and WD14. We observed that only the binge treatment led to sensitization of locomotor effects of cocaine, associated to a DA release sensitization in the Nac, whereas the intermittent treatment did not. We demonstrate that two different patterns of administration induced distinct behavioral and neurochemical consequences. We unambiguously demonstrated that the intermittent treatment induced drug expectation associated with higher basal DA level in the Nac when measured at the time of chronic cocaine injection and that the binge treatment led to behavioral and sensitization effects of cocaine. PMID- 23092980 TI - Dopaminergic involvement during mental fatigue in health and cocaine addiction. AB - Dopamine modulates executive function, including sustaining cognitive control during mental fatigue. Using event-related functional magnetic resonance imaging (fMRI) during the color-word Stroop task, we aimed to model mental fatigue with repeated task exposures in 33 cocaine abusers and 20 healthy controls. During such mental fatigue (indicated by increased errors, and decreased post-error slowing and dorsal anterior cingulate response to error as a function of time-on task), healthy individuals showed increased activity in the dopaminergic midbrain to error. Cocaine abusers, characterized by disrupted dopamine neurotransmission, showed an opposite pattern of response. This midbrain fMRI activity with repetition was further correlated with objective indices of endogenous motivation in all subjects: a state measure (task reaction time) and a trait measure (dopamine D2 receptor availability in caudate, as revealed by positron emission tomography data collected in a subset of this sample, which directly points to a contribution of dopamine to these results). In a second sample of 14 cocaine abusers and 15 controls, administration of an indirect dopamine agonist, methylphenidate, reversed these midbrain responses in both groups, possibly indicating normalization of response in cocaine abusers because of restoration of dopamine signaling but degradation of response in healthy controls owing to excessive dopamine signaling. Together, these multimodal imaging findings suggest a novel involvement of the dopaminergic midbrain in sustaining motivation during fatigue. This region might provide a useful target for strengthening self-control and/or endogenous motivation in addiction. PMID- 23092981 TI - Convergent animal and human evidence suggests the activin/inhibin pathway to be involved in antidepressant response. AB - Despite the overt need for improved treatment modalities in depression, efforts to develop conceptually novel antidepressants have been relatively unsuccessful so far. Here we present a translational approach combining results from hypothesis-free animal experiments with data from a genetic association study in depression. Comparing genes regulated by chronic paroxetine treatment in the mouse hippocampus with genes showing nominally significant association with antidepressant treatment response in two pharmacogenetic studies, the activin pathway was the only one to show this dual pattern of association and therefore selected as a candidate. We examined the regulation of activin A and activin receptor type IA mRNA following antidepressant treatment. We investigated the effects of stereotaxic infusion of activin into the hippocampus and the amygdala in a behavioural model of depression. To analyse whether variants in genes in the activin signalling pathway predict antidepressant treatment response, we performed a human genetic association study. Significant changes in the expression of genes in the activin signalling pathway were observed following 1 and 4 weeks of treatment. Injection of activin A into the hippocampus exerts acute antidepressant-like effects. Polymorphisms in the betaglycan gene, a co receptor mediating functional antagonism of activin signalling, significantly predict treatment outcome in our system-wide pharmacogenetics study in depression. We provide convergent evidence from mouse and human data that genes in the activin signalling pathway are promising novel candidates involved in the neurobiogical mechanisms underlying antidepressant mechanisms of action. Further, our data suggest this pathway to be a target for more rapid-acting antidepressants in the future. PMID- 23092982 TI - Absence of age-related prefrontal NAA change in adults with autism spectrum disorders. AB - Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy ((1)H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=-0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher's r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=-3.23, P=0.001), which indicated that the age-NAA relationship was significantly specific to people with TD. The current (1)H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood. PMID- 23092985 TI - Ileo neo-rectal anastomosis for colitis and familial adenomatous polyposis. PMID- 23092986 TI - Design and synthesis of triazolyl coumarins as Hg2+ selective fluorescent chemosensors. AB - A series of triazolyl coumarin derivatives L1-L4, with and without spacer groups between the coumarin and the triazole groups, were synthesized as fluorescent sensors to study their binding ability and selectivity toward metal ions. Ligand L3, which contains an acetyl linker between the triazole and the coumarin, exhibited a high selectivity toward Hg(2+) in polar protic solvents MeOH-CHCl(3) (9 : 1, v/v) with fluorescent enhancement, furthermore, it was found to bind two Hg(2+) at a high concentration (>12.5 mM) of Hg(ClO(4))(2). In contrast, L4, in which position 4 of the triazole unit was replaced by a benzyl group instead of the 4-tert-butylphenoxymethyl group used in L1-L3, showed a binding stoichiometry toward only one Hg(2+). On the basis of the fluorescent sensing, IR, and (1)H NMR titration results of ligands L1-L4, we proposed that not only the acetyl C=O but also the ether group of the 4-tert-butylphenoxymethyl of assisted the triazole nitrogen atoms in the complexation of Hg(2+) to form a 1 : 2 complex (L3.(Hg(2+))(2)). PMID- 23092983 TI - Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE. AB - The striking excess of affected males in autism spectrum disorders (ASD) suggests that genes located on chromosome X contribute to the etiology of these disorders. To identify new X-linked genes associated with ASD, we analyzed the entire chromosome X exome by next-generation sequencing in 12 unrelated families with two affected males. Thirty-six possibly deleterious variants in 33 candidate genes were found, including PHF8 and HUWE1, previously implicated in intellectual disability (ID). A nonsense mutation in TMLHE, which encodes the E-N trimethyllysine hydroxylase catalyzing the first step of carnitine biosynthesis, was identified in two brothers with autism and ID. By screening the TMLHE coding sequence in 501 male patients with ASD, we identified two additional missense substitutions not found in controls and not reported in databases. Functional analyses confirmed that the mutations were associated with a loss-of-function and led to an increase in trimethyllysine, the precursor of carnitine biosynthesis, in the plasma of patients. This study supports the hypothesis that rare variants on the X chromosome are involved in the etiology of ASD and contribute to the sex ratio disequilibrium. PMID- 23092984 TI - Genome-wide association of mood-incongruent psychotic bipolar disorder. AB - Mood-incongruent psychotic features (MICP) are familial symptoms of bipolar disorder (BP) that also occur in schizophrenia (SZ), and may represent manifestations of shared etiology between the major psychoses. In this study we have analyzed three large samples of BP with imputed genome-wide association data and have performed a meta-analysis of 2196 cases with MICP and 8148 controls. We found several regions with suggestive evidence of association (P<10(-6)), although no marker met genome-wide significance criteria. The top associations were on chromosomes: 6q14.2 within the PRSS35/SNAP91 gene complex (rs1171113, P=9.67 * 10(-8)); 3p22.2 downstream of TRANK/LBA1 (rs9834970, P=9.71 * 10(-8)); and 14q24.2 in an intron of NUMB (rs2333194, P=7.03 * 10(-7)). These associations were present in all three samples, and both rs1171113 and rs2333194 were found to be overrepresented in an analysis of MICP cases compared with all other BP cases. To test the relationship of MICP with SZ, we performed polygenic analysis using the Psychiatric GWAS Consortium SZ results and found evidence of association between SZ polygenes and the presence of MICP in BP cases (meta-analysis P=0.003). In summary, our analysis of the MICP phenotype in BP has provided suggestive evidence for association of common variants in several genes expressed in the nervous system. The results of our polygenic analysis provides support for a modest degree of genetic overlap between BP with MICP and SZ, highlighting that phenotypic correlations across syndromes may be due to the influence of polygenic risk factors. PMID- 23092987 TI - Adolescence: the last frontier. PMID- 23092989 TI - Biomechanical finite element analysis of small diameter and short dental implants: extensive study of commercial implants. AB - In recent years, mini and short dental implants have become increasingly popular as treatment alternatives for patients in whom the bone is unsuitable for a standard implant. As yet, no detailed scientific analysis of the mechanical and biomechanical impact of the reduced diameter and length of these implants has been published. We analysed 21 commercially available implants (13 mini, eight short) with respect to material behaviour and load transfer to the alveolar bone, using finite element (FE) analysis. Following MUCT scanning and geometry reconstruction, FE models of mini implants and short implants were inserted into idealised bone segments. Mini implants were analysed in the anterior mandibular jaw region at a force of 150 N under immediate loading, using a contact analysis in the FE software package Marc Mentat 2007. Short implants were inserted in posterior bone segments and analysed in the osseointegrated state at an occlusal force of 300 N. Von Mises stresses (up to 1150 MPa) in mini implants partly exceeded the ultimate strength. Implant diameter and geometry had a pronounced effect on stresses in the cortical plate (up to 266 MPa). Strains in spongy bone and stresses in cortical bone around short implants were markedly increased compared to those in standard implants. An increased risk of bone damage or implant failure may be assumed in critical clinical situations. PMID- 23092988 TI - The survival and proliferation of fibroblasts on ceramic implants: an in vitro study. AB - To improve osseointegration, different possible dental implant surface modifications, e.g., alterations of surface chemistry and roughness, have been developed. The purpose of this study was to examine the in vitro biocompatibility of newly designed zirconium implants with different surface modifications in comparison with commercially available zirconium and titanium implants. Therefore, cell viability and proliferation were measured after 21 days and correlated with surface structures. In the presence of new ceramic implants with an "mds (blasted/etched)" and a "blasted" surface, cell viability was 1.29- and 1.26-fold increased, respectively, compared to untreated cells, whereas cell viability was unchanged in the presence of reference implants and new ceramic implants with an "etched" surface. The cell viability findings correlate with the results of the cell cytotoxicity assay. The etched implants showed a surface with high roughness and heterogeneity, whereas the mds and blasted implants showed a similar, very rough-textured homogenate surface. The in vitro biocompatibility of two new ceramic implants was significantly better in comparison with the tested reference ceramic and titanium implants. The good biocompatibility may be attributed to the homogenous surface of these implants, and these surfaces might hasten osseointegration. PMID- 23092990 TI - Characterization of hydrogen responsive nanoporous palladium films synthesized via a spontaneous galvanic displacement reaction. AB - A model is presented regarding the mechanistic properties associated with the interaction of hydrogen with nanoporous palladium (np-Pd) films prepared using a spontaneous galvanic displacement reaction (SGDR), which involves PdCl(2) reduction by atomic Ag. Characterization of these films shows both chemical and morphological factors, which influence the performance characteristics of np-Pd microcantilever (MC) nanomechanical sensing devices. Raman spectroscopy, uniquely complemented with MC response profiles, is used to explore the chemical influence of palladium oxide (PdO). These combined techniques support a reaction mechanism that provides for rapid response to H(2) and recovery in the presence of O(2). Post-SGDR processing via reduction of PdCl(2)(s) in a H(2) environment results in a segregated nanoparticle three-dimensional matrix dispersed in a silver layer. The porous nature of the reduced material is shown by high resolution scanning electron microscopy. Extended grain boundaries, typical of these materials, result in a greater surface area conducive to fast sorption/desorption of hydrogen, encouraged by the presence of PdO. X-ray diffraction and inductively coupled plasma-optical emission spectroscopy are employed to study changes in morphology and chemistry occurring in these nanoporous films under different processing conditions. The unique nature of chemical/morphological effects, as demonstrated by the above characterization methods, provides evidence in support of observed nanomechanical response/recovery profiles offering insight for catalysis, H(2) storage and improved sensing applications. PMID- 23092991 TI - Strong differences in genetic structure across disjunct, edge, and core populations of the distylous forest herb Pulmonaria officinalis (Boraginaceae). AB - PREMISE OF THE STUDY: Populations at the edge of a species' distribution area are often small and have low levels of gene flow resulting in lower genetic variation and higher differentiation compared to core populations. This study examined genetic variation among populations of the distylous temperate forest herb Pulmonaria officinalis located in the core, the edge, and outside the species' main distribution range. METHODS: We compared patterns of genetic variation for eight microsatellite loci between disjunct (Belgium), edge (western Germany), and core (eastern Germany) populations of P. officinalis. KEY RESULTS: Disjunct populations contained only a subset of alleles found in edge and core populations and had significantly lower within-population genetic variation. No significant differences, however, in within-population genetic variation were found between edge and core populations, except for allelic and genotypic richness. Genetic differentiation was highest among disjunct (F(ST) = 0.11) and lowest among core populations (F(ST) = 0.03). Significant (P < 0.01) isolation by distance was found for disjunct and edge populations (r(M) = 0.29 and 0.50, respectively), but not for core populations (r(M) = 0.18). CONCLUSIONS: The results are best interpreted from a "dynamic range" point of view in which the observed low levels of genetic diversity and high genetic differentiation in disjunct populations are best explained through historical processes, most likely the introduction of the species in medieval times. Lower levels of gene flow caused by the pronounced fragmentation of forests in Belgium may further have contributed to the genetic structure of P. officinalis in these disjunct populations. PMID- 23092992 TI - Post-pollination barriers and their role in asymmetric hybridization in Rhinanthus (Orobanchaceae). AB - PREMISE OF THE STUDY: Several barriers against hybrid formation exist, and their combined action can affect the evolutionary outcomes of hybridization. To explain the asymmetrical introgression observed between two bumblebee-pollinated plant species (Rhinanthus angustifolius and R. minor), we focused on post-pollination barriers and ethological isolation of hybrids. METHODS: We studied pollen competition in conspecific and heterospecific crosses on both species and analyzed germination rates of hybrid and pure seeds. We also measured bumblebee visitation rates to hybrids relative to their parents using potted Rhinanthus placed in populations of each parental species. KEY RESULTS: In mixed pollinations, there was a conspecific siring advantage in both species, but no difference in pollen tube growth rates in either cross type. F(1) seeds with a R. angustifolius maternal plant germinated poorly, while those with R. minor as the maternal parent germinated better than pure seeds. Interestingly, bumblebees treated hybrids almost as equal to the background species and more often rejected the nonresident Rhinanthus. In a R. angustifolius background, bumblebees preferred R. angustifolius, but visited hybrids more often than R. minor. In contrast, visitation rates were similar on a R. minor background. CONCLUSIONS: Our results suggest that hybridization rates in Rhinanthus remain low because of several leaky barriers that make R. minor the maternal parent of most F(1) offspring. Preference for R. angustifolius and the equal treatment of F(1) and background species by bumblebees induce a visitation pattern that directs gene flow toward R. angustifolius when this species predominates. PMID- 23092993 TI - The complex leaves of the monkey's comb (Amphilophium crucigerum, Bignoniaceae): a climbing strategy without glue. AB - PREMISE OF THE STUDY: Monkey's comb (Amphilophium crucigerum) is a widely spread neotropical leaf climber that develops attachment pads for anchorage. A single complex leaf of the species comprises a basal pair of foliate, assimilating leaflets and apical, attaching leaflet tendrils. This study aims to analyze these leaves and their ontogenetic development for a better understanding of the attachment process, the form-structure-function relationships involved, and the overall maturation of the leaves. METHODS: Thorough morphometrical, morphological, and anatomical analyses incorporated high-resolution microscopy, various staining techniques, SEM, and photographic recordings over the entire ontogenetic course of leaf development. KEY RESULTS: The foliate, assimilating leaflets and the anchorage of the more apical leaflet tendrils acted independently of each other. Attachment was achieved by coiling of the leaflet tendrils and/or development of attachment pads at the tendril apices that grow opportunistically into gaps and fissures of the substrate. In contact zones with the substrate, the cells of the pads differentiate into a vessel element-like tissue. During the entire attachment process of the plant, no glue was excreted. CONCLUSION: The complex leaves of monkey's comb are highly differentiated organs with specialized leaf parts whose functions-photosynthesis or attachment-work independently of each other. The function of attachment includes coiling and maturation process of the leaflet tendrils and the formation of attachment pads, resulting in a biomechanically sound and persistent anchorage of the plant without the need of glue excretion. This kind of glue-less attachment is not only of interest in the framework of analyzing the functional variety of attachment structures evolved in climbing plants, but also for the development of innovative biomimetic attachment structures for manifold technical applications. PMID- 23092994 TI - Neogene-dominated diversification in neotropical montane lichens: dating divergence events in the lichen-forming fungal genus Oropogon (Parmeliaceae). AB - PREMISE OF THE STUDY: Diversification in neotropical regions has been attributed to both Tertiary geological events and Pleistocene climatic fluctuations. However, the timing and processes driving speciation in these regions remain unexplored in many important groups. Here, we address the timing of diversification in the neotropical lichenized fungal genus Oropogon (Ascomycota) and assess traditional species boundaries. METHODS: We analyzed sequence data from three loci to assess phenotypically circumscribed Oropogon species from the Oaxacan Highlands, Mexico. We provide a comparison of dated divergence estimates between concatenated gene trees and a calibrated multilocus species-tree using substitution rates for two DNA regions. We also compare estimates from a data set excluding ambiguously aligned regions and a data set including the hyper-variable regions in two ribosomal markers. KEY RESULTS: Phylogenetic reconstructions were characterized by well-supported monophyletic clades corresponding to traditionally circumscribed species, with the exception of a single taxon. Divergence estimates indicate that most diversification of the sampled Oropogon species occurred throughout the Oligocene and Miocene, although diversification of a single closely related clade appears to have occurred during the late Pliocene and into the Pleistocene. Divergence estimates calculated from a data set with ambiguously aligned regions removed were much more recent than those from the full data set. CONCLUSIONS: Overall, our analyses place the majority of divergence events of Oropogon species from the Oaxacan Highlands within the Neogene and provide strong evidence that climatic changes during the Pleistocene were not a major factor driving speciation in the lichenized genus Oropogon in neotropical highlands. PMID- 23092995 TI - Progress in bismuth vanadate photoanodes for use in solar water oxidation. AB - Harvesting energy directly from sunlight as nature accomplishes through photosynthesis is a very attractive and desirable way to solve the energy challenge. Many efforts have been made to find appropriate materials and systems that can utilize solar energy to produce chemical fuels. One of the most viable options is the construction of a photoelectrochemical cell that can reduce water to H(2) or CO(2) to carbon-based molecules. Bismuth vanadate (BiVO(4)) has recently emerged as a promising material for use as a photoanode that oxidizes water to O(2) in these cells. Significant advancement in the understanding and construction of efficient BiVO(4)-based photoanode systems has been made within a short period of time owing to various newly developed ideas and approaches. In this review, the crystal and electronic structures that are closely related to the photoelectrochemical properties of BiVO(4) are described first, and the photoelectrochemical properties and limitations of BiVO(4) are examined. Subsequently, the latest efforts toward addressing these limitations in order to improve the performances of BiVO(4)-based photoanodes are discussed. These efforts include morphology control, formation of composite structures, composition tuning, and coupling oxygen evolution catalysts. The discussions and insights provided in this review reflect the most recent approaches and directions for general photoelectrode developments and they will be directly applicable for the understanding and improvement of other photoelectrode systems. PMID- 23092996 TI - Adsorption and electron injection of the N3 metal-organic dye on the TiO2 rutile (110) surface. AB - Metal-organic ruthenium-based dyes are often used as a source of photogenerated electrons in dye-sensitised solar cells and photocatalysis. Here, we study the relationship between adsorption geometry and electron injection properties of one of the most successful metal-organic dyes, N3 (cis-bis(isothiocyanato)-bis(4,4' dicarboxy-2,2'-bipyridyl)-ruthenium(II)), on the TiO(2) rutile (110) surface. We systematically construct all possible adsorption configurations of the N3 molecule on this surface. By combining density-functional theory calculations and electron transfer calculations, we find that a large number of adsorption configurations are possible--more than ten structures, which differ in the number of carboxylic and thiocyanate groups adsorbed and in the adsorption mode of the carboxylic groups, have similar adsorption energies and similar electron injection times. Therefore, the observed fast electron injection from this dye may originate either from one adsorption configuration or from several co existing configurations. Our results suggest that related substituted metal organic dyes with fewer anchoring groups will also have good electron injection properties, even if only a small subset of adsorption configurations is available for them. PMID- 23092998 TI - Carcinogenic potential of soils contaminated with polycyclic aromatic hydrocarbons (PAHs) in Xiamen metropolis, China. AB - Xiamen is one of China's most rapidly developing metropolises. The objectives of the present study were: (1) to establish the levels and spatial distribution of polycyclic aromatic hydrocarbons (PAHs) in soil across the Xiamen metropolis, (2) to evaluate the extent to which PAH concentrations were elevated in the high urbanization area (HUA) of the island and how these compared with those in the low urbanization area (LUA) of the mainland, and (3) to evaluate the PAH hazard based upon their Carcinogenic Potential (CP), defined as toxicity equivalence of ?PAHs. Twenty two alternative relative carcinogenic potency schemes were used and compared. Results demonstrated PAH concentrations to be greatly elevated across the entire metropolis. Significantly, the most enriched compounds represented the greatest concern with respect to carcinogenicity. The CP of more than 25% of the industrial samples from the island surpassed the Canadian guidance threshold value (600 MUg kg-1) for an excess lifetime cancer risk (ELCR) of 1 in 10-6. While soil samples from the remaining land uses on the island were all below this threshold, PAH levels in soil were nonetheless elevated (enrichment factors of between 4.1 +/- 1.9 and 16.3 +/- 12.4 in the HUA, and between 1.3 +/- 0.7 and 10.8 +/- 4.4 in the LUA). Results relating to agricultural locations on the island indicated 75% of the samples in HUA and 28% of the samples in LUA to be above the USEPA guidance value for BaP (15 MUg kg-1). Given the exceptionally high population density on the island there is a need for further research to evaluate multiple pathway PAH exposure risks. PMID- 23092997 TI - Genetic interactions controlling sex and color establish the potential for sexual conflict in Lake Malawi cichlid fishes. AB - Sex-determining systems may evolve rapidly and contribute to lineage diversification. In fact, recent work has suggested an integral role of sex chromosome evolution in models of speciation. We use quantitative trait loci analysis of restriction site-associated DNA -tag single nucleotide polymorphisms to identify multiple loci responsible for sex determination and reproductively adaptive color phenotypes in Lake Malawi cichlids. We detect a complex epistatic sex system consisting of a major female heterogametic ZW locus on chromosome 5, two separate male heterogametic XY loci on chromosome 7, and two additional interacting loci on chromosomes 3 and 20. Our data support the known chromosomal linkage between orange blotch color and ZW, as well as novel genetic associations between male blue nuptial color and two sex determining regions (an XY and ZW locus). These results provide further empirical evidence for a complex antagonistic sex-color system in this species flock and suggest a possible role for, and effect of, polygenic sex-determining systems in rapid evolutionary diversification. PMID- 23092999 TI - Preparation of Drosophila central neurons for in situ patch clamping. AB - Short generation times and facile genetic techniques make the fruit fly Drosophila melanogaster an excellent genetic model in fundamental neuroscience research. Ion channels are the basis of all behavior since they mediate neuronal excitability. The first voltage gated ion channel cloned was the Drosophila voltage gated potassium channel Shaker(1,2). Toward understanding the role of ion channels and membrane excitability for nervous system function it is useful to combine powerful genetic tools available in Drosophila with in situ patch clamp recordings. For many years such recordings have been hampered by the small size of the Drosophila CNS. Furthermore, a robust sheath made of glia and collagen constituted obstacles for patch pipette access to central neurons. Removal of this sheath is a necessary precondition for patch clamp recordings from any neuron in the adult Drosophila CNS. In recent years scientists have been able to conduct in situ patch clamp recordings from neurons in the adult brain(3,4) and ventral nerve cord of embryonic(5,6), larval(7,8,9,10), and adult Drosophila(11,12,13,14). A stable giga-seal is the main precondition for a good patch and depends on clean contact of the patch pipette with the cell membrane to avoid leak currents. Therefore, for whole cell in situ patch clamp recordings from adult Drosophila neurons must be cleaned thoroughly. In the first step, the ganglionic sheath has to be treated enzymatically and mechanically removed to make the target cells accessible. In the second step, the cell membrane has to be polished so that no layer of glia, collagen or other material may disturb giga seal formation. This article describes how to prepare an identified central neuron in the Drosophila ventral nerve cord, the flight motoneuron 5 (MN5(15)), for somatic whole cell patch clamp recordings. Identification and visibility of the neuron is achieved by targeted expression of GFP in MN5. We do not aim to explain the patch clamp technique itself. PMID- 23093000 TI - Acute ApoA-I Milano administration induces plaque regression and stabilisation in the long term. PMID- 23093001 TI - The morphological characterization of the forewing of the Manduca sexta species for the application of biomimetic flapping wing micro air vehicles. AB - To properly model the structural dynamics of the forewing of the Manduca sexta species, it is critical that the material and structural properties of the biological specimen be understood. This paper presents the results of a morphological study that has been conducted to identify the material and structural properties of a sample of male and female Manduca sexta specimens. The average mass, area, shape, size and camber of the wing were evaluated using novel measurement techniques. Further emphasis is placed on studying the critical substructures of the wing: venation and membrane. The venation cross section is measured using detailed pathological techniques over the entire venation of the wing. The elastic modulus of the leading edge veins is experimentally determined using advanced non-contact structural dynamic techniques. The membrane elastic modulus is randomly sampled over the entire wing to determine global material properties for the membrane using nanoindentation. The data gathered from this morphological study form the basis for the replication of future finite element structural models and engineered biomimetic wings for use with flapping wing micro air vehicles. PMID- 23093002 TI - Cultural psychiatry considerations in older adults. PMID- 23093003 TI - Complex structural phase transitions in slightly Ca modified Na0.5Bi0.5TiO3. AB - A temperature dependent neutron powder diffraction study, in conjunction with dielectric and ferroelectric characterization, of slightly Ca modified Na(0.5)Bi(0.5)TiO(3) (NBT) revealed an instability with regard to a non-polar orthorhombic (Pbnm) distortion above room temperature. This intermediate orthorhombic phase has earlier been reported for unmodified NBT by electron diffraction studies, but has never been captured by global (x-ray/neutron) diffraction techniques. Calcium substitution seems to amplify the magnitude of this intermediate orthorhombic distortion thereby making the corresponding superlattice reflections become visible in the neutron diffraction pattern. The study revealed the following sequence of very complex structural evolution with temperature: Cc -> Cc + Pbnm -> Pbnm + P4/mbm -> P4/mbm -> PmN3m. PMID- 23093004 TI - Should we perform objective assessment of nasal obstruction in children with chronic rhinitis? PMID- 23093006 TI - New zeolite Al-COE-4: reaching highly shape-selective catalytic performance through interlayer expansion. AB - A ferrierite-type layered aluminosilicate, Al-RUB-36, was prepared for the first time and its interlayer expansion resulted in new zeolite catalysts denoted Al COE-3 and Al-COE-4. Decane hydroconversion tests demonstrated the highly active and shape-selective nature of the new Al-COE-4 catalyst with an unprecedented isomerization yield, highlighting the potential of this material as a hydroisomerization catalyst. This is the first report on achieving shape selectivity via interlayer expansion. PMID- 23093007 TI - Mechanism of selective area growth of GaN nanorods by pulsed mode metalorganic chemical vapor deposition. AB - The growth mechanism for the formation of GaN nanorods using metalorganic chemical vapor deposition (MOCVD) selective area growth by pulsed source injection is proposed. The pulsed mode procedure and the kinetic model are discussed and experiments performed to support the model are described. The achievement of rod shape nanostructures grown by the pulsed mode can be attributed to two mechanisms: (1) the differences in the adsorption/desorption behavior of Ga adatoms on the c-plane (0001) and the boundary m-planes {11[overline]00}, and (2) the growth behavior of the semi-polar planes (especially the semi-polar {11[overline]00} plane). PMID- 23093008 TI - Local blockade of NMDA receptors in the rat prefrontal cortex increases c-Fos expression in multiple subcortical regions. AB - Ketamine, phencyclidine and MK801 are uncompetitive NMDA receptor (NMDAR) antagonists which are used widely to model certain features of schizophrenia in rats. Systemic administration of NMDAR antagonists, in addition to provoking an increase in c-Fos expression, leads to important neurochemical and electrophysiological changes within the medial prefrontal cortex (mPFC). Since the mPFC is considered to exert a top-down regulatory control of subcortical brain regions, we examined the effects of local infusion of the NMDAR antagonist, MK801, into the mPFC on the expression of c-Fos protein (widely used marker of neuronal activation) in several subcortical structures. The experiment was performed on freely moving rats, bilaterally implanted with guide cannulae in the prelimbic mPFC, infused with MK801 or saline. Bilateral administration of MK801 to the mPFC produced changes in the behavior (increased stereotypy and decreased sleep-like behavior) and complex changes in c-Fos protein expression with significant increases observed in the nucleus accumbens (core and shell), amygdala (basolateral and central nuclei), the CA1 field of the hippocampus, and mediodorsal and paraventricular thalamic nuclei, as compared to the saline group. Together, we demonstrate that blockade of NMDA receptors in the mPFC is sufficient to lead to behavioral abnormalities and increased c-Fos expression in many, but not all, of the subcortical structures examined. Our findings suggest that some of the behavioral abnormalities produced by uncompetitive NMDAR antagonists may result from aberrant activity in cortico-subcortical pathways. These data support an increasing body of literature, suggesting that the mPFC is an important site mediating the effects of NMDAR antagonists. PMID- 23093009 TI - Neuronal differentiation of human iPS-cells in a rat cortical primary culture. AB - We tested the neuronal differentiation of human iPS-cells under in vitro conditions. For this purpose we pre-differentiated human (h) iPS-cells into neural stem cells and co-cultivated them with a cortical primary culture from embryonic rats. After 2 days of co-cultivation a certain number of hiPS-cells exhibited a clear neuronal morphology combined with expression of betaIII-tubulin and doublecortin. In addition, we found hiPS-cells without neuronal differentiation and cells already expressing betaIII-tubulin but not having yet distinctive axonal and dendritic processes. Human neuronal progenitors, starting neuronal differentiation, were contacted by both neuronal processes from rat neurons and oligodendrocytes, indicating a possible instructive influence by the primary culture on human cells. After 7 days of co-cultivation, however, we observed a complete degeneration of human iPS-derived cells and phagocytosis by microglial cells. Immunocytochemical stainings surprisingly revealed that microglial cells of the cortical primary culture express both CD8 and T-cell receptors. PMID- 23093010 TI - Effects of adult dysthyroidism on the morphology of hippocampal granular cells in rats. AB - Thyroid hormones are essential for normal brain development and very important in the normal functioning of the brain. Thyroid hormones action in the adult brain has not been widely studied. The effects of adult hyperthyroidism are not as well understood as adult hypothyroidism, mainly in hippocampal granular cells. The purpose of the present study is to assess the consequences of adult hormone dysthyroidism (excess/deficiency of TH) on the morphology of dentate granule cells in the hippocampus by performing a quantitative study of dendritic arborizations and dendritic spines using Golgi impregnated material. Hypo-and hyperthyroidism were induced in rats by adding 0.02 percent methimazole and 1 percent L-thyroxine, respectively, to drinking water from 40 days of age. At 89 days, the animals' brains were removed and stained by a modified Golgi method and blood samples were collected in order to measure T4 serum levels. Neurons were selected and drawn using a camera lucida. Our results show that both methimazole and thyroxine treatment affect granule cell morphology. Treatments provoke alterations in the same direction, namely, reduction of certain dendritic branching parameters that are more evident in the methimazole than in the thyroxine group. We also observe a decrease in spine density in both the methimazole and thyroxine groups. PMID- 23093012 TI - Photoacoustic tomography can detect cerebral hemodynamic alterations in a neonatal rodent model of hypoxia-ischemia. AB - Hypoxic-Ischemic Encephalopathy (HIE) is one of the most recognized causes of neurological deficits in children. Cerebral blood flow (CBF) reductions, as seen with HIE, resulting in neuronal injury have not been evaluated in real-time. Photoacoustic Tomography (PAT) is a form of optical imaging which can detect cerebral hemodynamic alterations in a noninvasive, non-ionizing fashion via changes in hemoglobin optical absorption. Further, this technology has the potential to capture cerebral blood volume (CBV) fluctuations and perhaps CBF changes in real-time. We hypothesized that PAT can detect a reduction in cerebral hemoglobin optical absorption, and therefore CBF, in a neonatal model of hypoxia ischemia. To investigate, P7 rats underwent right carotid artery ligation and exposure to 8 percent oxygen for 60 minutes while imaged with PAT every 20 minutes. Cerebral hemodynamic alterations, as measured by mean optical absorption (MOA), were calculated as a change from baseline. Global and regional MOA was analyzed using a linear mixed model. Global MOA was reduced within the right hemisphere as compared to the left during hypoxia. Regional differences in MOA were detected between the left and right sides for the middle and posterior cortical regions. Injury was confirmed using immunohistochemistry. We conclude that a reduction in global and regional MOA, and hence CBF, could be identified by PAT in a neonatal rat model of HIE. This is the first study described in the literature utilizing a neonatal rat model of HIE to demonstrate in vivo alterations in cerebral hemodynamics in a non-invasive and near real-time fashion. PMID- 23093011 TI - Methylprednisolone improves the survival of new neurons following transient cerebral ischemia in rats. AB - Cerebral ischemia induced the proliferation and differentiation of neural stem cells in discrete regions of brain. However, only a small fraction of the neural stem/progenitor cells survives. In this report, the effects of methylprednisolone (MP) on proliferation, differentiation and survival of neural progenitor cells were explored through early MP administration after occlusion of the middle cerebral artery (MCAo). Transient cerebral ischemia was induced by middle cerebral artery occlusion in Sprague Dawley male rats. One hour, 1 day, 3 days, 14 days, and 28 days after MCAo, neurological examination was performed to evaluate the neurological deficit. MCAo rats were randomly divided into two groups, MP-group was injected MP (30 mg/kg, i.p.) at 3 h, 12 h, and 24 h after MCAo, and vehicle group was injected equal saline (i.p.). Animals were sacrificed at 3 days, 14 days, and 28 days after MCAo. MP was found to decrease apoptosis and TNF-alpha and IL-6 expression at 3 days after MCAo in the ipsilateral striatum. Moreover, MP significantly increased the migrated new neurons (BrdU+/ DCX+) and immature neurons (BrdU+/Tuj1+) at day 14 after MCAo in the ipsilateral striatum. Likewise, MP increased the number of mature neurons (BrdU+/MAP2+) at 28 days after MCAo. However, MP did not affect the progenitor cell proliferation (BrdU+ and Nestin+) at day 3 after MCAo in the subventricular zone (SVZ), but improved the neurological deficit at day 1 and day 3 after MCAo. These results indicate that early MP administration can improve the neurological deficit and enhance the survival of new neurons in the ipsilateral striatum by inhibiting apoptosis and downregulation of inflammatory response after transient cerebral ischemia in rats. PMID- 23093013 TI - Use of cerebrospinal fluid biomarker analysis for improving Alzheimer's disease diagnosis in a non-specialized setting. AB - Low levels of amyloid-beta42 (Abeta42) and high total-tau (t-tau) or phosphorylated-tau (p181-tau) levels in cerebrospinal fluid (CSF) were shown to be characteristic for Alzheimer's disease (AD) patients and for mildly cognitively impaired (MCI) or non-demented individuals who will progress to AD. The goal of this study was to evaluate the benefit of CSF biomarker testing in a setting with no specialized dementia centers, in order to improve the accuracy of AD diagnosis and to identify individuals with incipient AD. Using ELISA assay we analyzed CSF Abeta42, t-tau and p181-tau levels among clinically diagnosed non demented individuals, AD patients and individuals with uncertain dementia (n=36). CSF cut-off values of low Abeta42 (less than or equal to 530 pg/mL) and high t tau (less than or equal to 350 pg/mL) or p181-tau (less than or equal to 52 pg/mL) were used to identify individuals with AD/MCI-CSF profile, regardless of clinical diagnosis. APOE genotyping was performed using PCR-RFLP method. In accord with previous studies we detected significantly decreased levels of CSF Abeta42 and increased tau and p181-tau levels in clinically diagnosed AD group vs. non-demented controls. CSF profiling identified individuals with a typical AD/MCI-CSF pattern in clinically referred non-demented group (9 percent) and among patients with uncertain dementia (41.7 percent). APOE epsilon4-allele was associated with the CSF biomarker changes typical for AD. This study shows that in a non-specialized setting CSF biomarker testing may be used as a screening tool for improving the accuracy of AD diagnosis and for predicting individuals with incipient Alzheimer's disease who need to receive further clinical follow up. PMID- 23093014 TI - The catechol-O-methyltransferase and monoamine oxidase B polymorphisms and levodopa therapy in the Iranian patients with sporadic Parkinson's disease. AB - Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this may be partially genetic in origin. Recent studies suggest that catechol-O-methyltransferase (COMT), G1947A and monoamine oxidase B (MAOB), A644G polymorphisms might influence the risk and treatment of PD. Herein, we aimed to test the possible influence of MAOB and COMT genetic polymorphisms on the effective daily dose of levodopa administered in the fifth year of treatment. We also examined the effect of COMT and MAOB haplotypes on levodopa therapy outcome. There were 31 females and 72 males of Iranian origin diagnosed with sporadic PD included into the study. The patients were divided into two groups. Group 1: patients received daily doses of levodopa below 500 mg in the fifth year of treatment. Group 2: those patients receiving daily doses exceeding 500 mg in the fifth year of treatment. MAOB and COMT polymorphism genotyping was performed by using PCR-based restriction fragment length polymorphism (RFLP) analyses. Our data show that the first group suffered less frequently from dyskinesia than patients from the second group. No statistically significant differences were found in allele frequencies and genotype distributions of the studied genes between two groups. In addition, the incidence of the specific haplotypes between the two groups did not show any difference. The present data suggest that pharmacokinetic or pharmacodynamic factors other than the investigated genetic variants of the MAOB and COMT enzymes seem to determine the response to levodopa in the Iranian PD patients. PMID- 23093015 TI - Electrophysiological differences between high and low frequency rTMS protocols in depression treatment. AB - Repetitive transcranial magnetic stimulation (rTMS) is a rapidly expanding mean in drug resistant depression treatment. Yet, despite vast research in this field, exact neurophysiological mechanism of rTMS therapy still remains unclear. This results in difficulties choosing suitable rTMS parameters in advance and compromises thorough evaluation of efficacy after the treatment. In order to obtain more explicit assessment of rTMS therapy in the psychiatric field, we evaluated and compared the influence of two most widely used antidepressive rTMS protocols on EEG band power spectrum and relation to clinical test scores (MADRS, BDI, HAM-D17). Forty-five patients (12 male, 33 female, mean age 52.16 years) participated in the study. Twenty-three patients received high frequency (10 Hz) stimulation, the rest 22 were stimulated using low frequency (1 Hz) protocol. Both groups received 10 to 15 daily rTMS sessions. EEG recordings and clinical tests were obtained the day before rTMS course and same day after the last session. Majority (57.78%) of patients showed considerable improvement after the treatment. There were no notable differences in clinical test score drop between the two rTMS protocols. However, we found that different protocols resulted in significantly different electrophysiological changes. High frequency (10 Hz) rTMS resulted in widespread changes off EEG band power, including delta power increase on the left hemisphere and alpha power growth on the right. Theta power increase was also obtained in parietal-occipital areas. Low frequency (1 Hz) rTMS showed to have no major effect on basic EEG band power, however, we found a notable shift of frontal alpha power asymmetry towards the right hemisphere, which correlated with the clinical outcome. Our study results suggest that two widely used rTMS protocols strongly differ in their electrophysiological mechanisms. Low frequency stimulation finesse on frontal alpha power asymmetry shift, whereas high frequency protocol acts on wider electrophysiological changes in the brain. PMID- 23093016 TI - From otoacoustic emission to late auditory potentials P300: the inhibitory effect. AB - This study verifies the effects of contralateral noise on otoacoustic emissions and auditory evoked potentials. Short, middle and late auditory evoked potentials as well as otoacoustic emissions with and without white noise were assessed. Twenty-five subjects, normal-hearing, both genders, aged 18 to 30 years, were tested . In general, latencies of the various auditory potentials were increased at noise conditions, whereas amplitudes were diminished at noise conditions for short, middle and late latency responses combined in the same subject. The amplitude of otoacoustic emission decreased significantly in the condition with contralateral noise in comparison to the condition without noise. Our results indicate that most subjects presented different responses between conditions (with and without noise) in all tests, thereby suggesting that the efferent system was acting at both caudal and rostral portions of the auditory system. PMID- 23093017 TI - Jan Bures - obituary. PMID- 23093018 TI - Helium droplets: a chemistry perspective. AB - Helium droplets provide an exotic and unique environment for the study of physical and chemical phenomena. Properties of these droplets include a low temperature (0.37 K), their superfluidity, and the ability to easily add a wide variety of atoms and molecules. This tutorial review provides a concise account of the basic principles of helium droplets, including how to form, dope, and interrogate these objects. There then follows a series of selected applications grouped under particular themes, with strong bias towards topics likely to be of particular interest to chemists. PMID- 23093019 TI - The impact of dental treatment on employment outcomes: a systematic review. AB - OBJECTIVE: Policy advocates in North America argue that access to dental care for low income and unemployed populations can help improve the chances of acquiring a job or attaining a better job, thus having positive economic and social benefits. Our objective is to review the evidence in support of the policy hypothesis that timely access to dental care can improve employment outcomes. METHODS: A systematic review was conducted by searching various scientific databases and search engines. Key words included Dental Care, Dental Intervention, Social Welfare, Unemployment, Employment, and Job. RESULTS: Seven articles were considered eligible for this review. They varied in study design, target population and intervention studied. Overall, they presented low levels of evidence due to small sample sizes, lack of control groups, combined interventions or being based on anecdotal reports. CONCLUSIONS: There is a limited amount of evidence concerning the assumption that dental care can improve employment outcomes. The scarcity of well-conducted studies and the poor quality of evidence makes it difficult to judge the effect of dental care on employment outcomes. More studies need to be conducted in order to confirm or dismiss this generalized assumption. PMID- 23093020 TI - Diffusion and use of health technology assessment in policy making: what lessons for decentralised healthcare systems? AB - OBJECTIVE: The Italian National Healthcare System (NHS) is one of the most decentralised systems since the devolution reform approved in 2001. HTA is spreading as an important tool for decision-making processes both at central and local levels. The aims of this study were to review the state of the health technology assessment (HTA) programmes in Italy - with a focus on regional and central initiatives - and to discuss consequences of a multi-level structure of HTA agencies in highly regionalised healthcare systems. METHODS: Our method combined documentary review with interviews. We reviewed scientific literature about HTA's activities in decentralised systems, legislative and administrative documents from national as well as regional authorities. Semi-structured interviews were conducted with 18 key individuals associated with HTA both at the national and regional levels. Data on HTA programmes implemented or under development in nine regions were collected and analysed according to key principles for the improved conduct of health technology assessments for resource allocation decisions. RESULTS: HTA is in the early stage of development in Italy, although with great heterogeneity across regions. The National Agency for Health Services has certainly contributed to HTA diffusion through supporting and training activities. However, the multi-level structure of HTA in Italy has not yet provided full coordination and harmonisation of practices and outcomes across the country, with a consequent exacerbate inequality of access to services and technologies. CONCLUSIONS: There is probably need to rethink the multi-layer organizational framework of HTA in Italy by leveraging on current knowledge and efficient redistribution of activities across regions. We would advise for different jurisdictions playing different roles while achieving similar health outcomes for their patients, rather than jurisdictions aiming at doing exactly the same things resulting in unequal access to healthcare service provision. PMID- 23093021 TI - Continuity of ambulatory care and health outcomes in adult patients with type 2 diabetes in Korea. AB - OBJECTIVES: Continuity of ambulatory care in chronic disease affects the quality of care and the efficiency of healthcare spending. We assessed the relationship between initial continuity of ambulatory care and subsequent health outcomes (hospitalization, mortality and healthcare costs). METHODS: This was a retrospective cohort study of 68,469 patients enrolled in the Korean National Health Insurance Program, who were 20 years of age or older and first diagnosed with type 2 diabetes in 2004. Patients were followed for 4 years using claims data to measure continuity of ambulatory care for the initial 3 years after first diagnosis and to investigate hospitalization, mortality, and healthcare costs in the fourth year of follow-up. RESULTS: In the group of patients with COCI<0.4, the risk of hospitalization for all causes was higher (odds ratio: 1.37, 95% CI: 1.28-1.47) and healthcare costs increased (beta=0.037, P<0.001) compared with the reference group (COCI=1.0), after adjusting for patient risk factors, such as age, gender, and comorbidity index. CONCLUSIONS: Policies that promote a continuing relationship with the same physician seem to enhance the quality of care and the efficiency of spending in the treatment of diabetic patients. PMID- 23093022 TI - Kinetic quantification of protein polymer nanoparticles using non-invasive imaging. AB - Protein polymers are repetitive amino acid sequences that can assemble monodisperse nanoparticles with potential applications as cancer nanomedicines. Of the currently available molecular imaging methods, positron emission tomography (PET) is the most sensitive and quantitative; therefore, this work explores microPET imaging to track protein polymer nanoparticles over several days. To achieve reliable imaging, the polypeptides were modified by site specific conjugation using a heterobifunctional sarcophagine chelator, AmBaSar, which was subsequently complexed with (64)Cu. AmBaSar/(64)Cu was selected because it can label particles in vivo over periods of days, which is consistent with the timescales required to follow long-circulating nanotherapeutics. Using an orthotopic model of breast cancer, we observed four elastin-like polypeptides (ELPs)-based protein polymers of varying molecular weight, amino acid sequence, and nanostructure. To analyze this data, we developed a six-compartment image driven pharmacokinetic model capable of describing their distribution within individual subjects. Surprisingly, the assembly of an ELP block copolymer (78 kD) into nanoparticles (R(h) = 37.5 nm) minimally influences pharmacokinetics or tumor accumulation compared to a free ELP of similar length (74 kD). Instead, ELP molecular weight is the most important factor controlling the fate of these polymers, whereby long ELPs (74 kD) have a heart activity half-life of 8.7 hours and short ELPs (37 kD) have a half-life of 2.1 hours. These results suggest that ELP-based protein polymers may be a viable platform for the development of multifunctional therapeutic nanoparticles that can be imaged using clinical PET scanners. PMID- 23093023 TI - Phosphoinositide-dependent kinase-1 and protein kinase Cdelta contribute to endothelin-1 constriction and elevated blood pressure in intermittent hypoxia. AB - Obstructive sleep apnea (OSA) is associated with cardiovascular complications including hypertension. Previous findings from our laboratory indicate that exposure to intermittent hypoxia (IH), to mimic sleep apnea, increases blood pressure in rats. IH also increases endothelin-1 (ET-1) constrictor sensitivity in a protein kinase C (PKC) delta-dependent manner in mesenteric arteries. Because phosphoinositide-dependent kinase-1 (PDK-1) regulates PKCdelta activity, we hypothesized that PDK-1 contributes to the augmented ET-1 constrictor sensitivity and elevated blood pressure following IH. Male Sprague-Dawley rats were exposed to either sham or IH (cycles between 21% O(2)/0% CO(2) and 5% O(2)/5% CO(2)) conditions for 7 h/day for 14 or 21 days. The contribution of PKCdelta and PDK-1 to ET-1-mediated vasoconstriction was assessed in mesenteric arteries using pharmacological inhibitors. Constrictor sensitivity to ET-1 was enhanced in arteries from IH-exposed rats. Inhibition of PKCdelta or PDK-1 blunted ET-1 constriction in arteries from IH but not sham group rats. Western analysis revealed similar levels of total and phosphorylated PDK-1 in arteries from sham and IH group rats but decreased protein-protein interaction between PKCdelta and PDK-1 in arteries from IH- compared with sham-exposed rats. Blood pressure was increased in rats exposed to IH, and treatment with the PDK-1 inhibitor OSU-03012 [2-amino-N-{4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H pyrazol-1-yl]-phenyl}-acetamide] (33 mg/day) lowered blood pressure in IH but not sham group rats. Our results suggest that exposure to IH unmasks a role for PDK-1 in regulating ET-1 constrictor sensitivity and blood pressure that is not present under normal conditions. These novel findings suggest that PDK-1 may be a uniquely effective antihypertensive therapy for OSA patients. PMID- 23093025 TI - New EU tobacco legislation is delayed after health commissioner resigns amid claims of knowledge of bribery attempt. PMID- 23093024 TI - Mouse liver protein sulfhydryl depletion after acetaminophen exposure. AB - Acetaminophen (APAP)-induced liver injury is the leading cause of acute liver failure in many countries. This study determined the extent of liver protein sulfhydryl depletion not only in whole liver homogenate but also in the zonal pattern of sulfhydryl depletion within the liver lobule. A single oral gavage dose of 150 or 300 mg/kg APAP in B6C3F1 mice produced increased serum alanine aminotransferase levels, liver necrosis, and glutathione depletion in a dose dependent manner. Free protein sulfhydryls were measured in liver protein homogenates by labeling with maleimide linked to a near infrared fluorescent dye followed by SDS-polyacrylamide gel electrophoresis. Global protein sulfhydryl levels were decreased significantly (48.4%) starting at 1 hour after the APAP dose and maintained at this reduced level through 24 hours. To visualize the specific hepatocytes that had reduced protein sulfhydryl levels, frozen liver sections were labeled with maleimide linked to horseradish peroxidase. The centrilobular areas exhibited dramatic decreases in free protein sulfhydryls while the periportal regions were essentially spared. These protein sulfhydryl depleted regions correlated with areas exhibiting histopathologic injury and APAP binding to protein. The majority of protein sulfhydryl depletion was due to reversible oxidation since the global- and lobule-specific effects were essentially reversed when the samples were reduced with tris(2 carboxyethy)phosphine before maleimide labeling. These temporal and zonal pattern changes in protein sulfhydryl oxidation shed new light on the importance that changes in protein redox status might play in the pathogenesis of APAP hepatotoxicity. PMID- 23093026 TI - Virgin contract to run children's services to go ahead despite non-compliance with law. PMID- 23093027 TI - Health minister agrees to meet academics to discuss access to clinical trial data. PMID- 23093028 TI - Hunt refers reorganisation of children's heart surgery to independent panel. PMID- 23093029 TI - Charge transfer in the weak driving force limit in blends of MDMO-PPV and dithienylthiazolo[5,4-d]thiazoles towards organic photovoltaics with high V(OC). AB - A series of three 5'-aryl-2,5-dithienylthiazolo[5,4-d]thiazole (DTTzTz) semiconducting molecules with different aryl substituents has been investigated as alternative acceptor materials in combination with the donor polymer poly[2 methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene] (MDMO-PPV) in order to evaluate the photoinduced charge transfer (CT) efficiency in the resulting blends, designed towards possible application in organic photovoltaics. Photoluminescence quenching together with polaron detection by electron paramagnetic resonance and photoinduced absorption (PIA) demonstrate an increasing charge transfer efficiency when the DTTzTz substituents are varied from thien-2-yl to 4-trifluoromethylphenyl and 4-cyanophenyl groups, correlating well with the increasing acceptor strength in this series of molecules. In line with this observation, there is a decrease in the effective optical bandgap relative to pure MDMO-PPV that becomes more pronounced along this series of acceptor compounds, reaching 0.12 eV in the blend with 4-CN-Ph-DTTzTz. Intermolecular interactions between the blend components lead to lower energy transitions which are found to contribute significantly to the device external quantum efficiency. The high V(OC) reached in devices based on MDMO-PPV:4-CN-Ph DTTzTz blends meets the expectations for such a donor:acceptor combination. However, thermal activation of charge carrier recombination occurs because of the weak driving force for charge transfer, as shown by time-dependent PIA measurements, and this is suggested as a cause for the observed low photovoltaic performance. PMID- 23093030 TI - Saprolmycins A-E, new angucycline antibiotics active against Saprolegnia parasitica. AB - Saprolmycins A-E, five new anti-Saprolegnia parasitica antibiotics were isolated from the culture broth of Streptomyces sp. strain TK08046. As determined using a combination of NMR and spectroscopic analyses, the structures of these compounds were elucidated as a new group of angucycline compounds closely related to saquayamycin. Saprolmycin A and E exhibited potent anti-S. parasitica selective activities, with MIC values of 3.9 and 7.8 ng ml(-1), respectively, but weak or no activity against fungi, gram-positive or -negative bacteria, and microalgae or zooplankton. Our results suggest these two compounds as highly effective and environmentally safe anti-saprolegniasis candidates. PMID- 23093031 TI - Prevalence and genotypic analysis of plasmid-mediated beta-lactamases among urinary Klebsiella pneumoniae isolates in Moroccan community. AB - The aim of this study is to assess the prevalence and molecular characterization of the extended spectrum beta-lactamases (ESBL)-producing Klebsiella pneumoniae isolated from community acquired urinary tract infections and collected in five Moroccan cities during a 2010 survey. In all, 34 (7.5%) of the 453 K. pneumoniae isolates studied were positive for an ESBL phenotype and 91.1% of these isolates were multidrug resistant. The bla(CTX-M-15) (n=31) was the most frequent ESBL genes detected, followed equally by bla(SHV-28) and bla(SHV-12) (n=3), then bla(TEM-3), bla(SHV-36), bla(SHV-110) and bla(CTX-M-1) with one isolate for each (n=1). Eight isolates co-expressed more than one ESBL with bla(CTX-M-15). The non ESBL genes detected were bla(SHV-1), bla(SHV-11), bla(SHV-32), bla(SHV-26), bla(SHV-76), bla(TEM-1), bla(TEM-1b) and bla(OXA-1). Plasmid-mediated AmpC beta lactamase genes, bla(ACT-2), bla(DHA-1) and a new beta-lacatamase named bla(EBC 1464), were detected in 11.7% of isolates. Fourteen (41.1%) isolates harbored qnr genes; qnrA6 (n=1), qnrB1 (n=8), qnrB2 (n=1) and qnrS1 (n=4) types were detected. Twenty-six isolates (76.4%) were positive for aac(6')-Ib-cr gene. Results of conjugation experiments indicated that bla(CTX-M-15), bla(TEM-1b), bla(OXA-1), aac(6')-Ib-cr and qnrB1 genes were co-transferred and that these genes were carried by a conjugative plasmid of high molecular weight. With the exception of qnrB1, all the antibiotic resistance genes were clustered in a 12-kb region. The results of this work report the genetic diversity of ESBL genes, with the CTX-M 15 enzyme being most common among ESBL-producing K. pneumoniae in Moroccan community. Furthermore, a major finding is that bla(EBC-1464) detection is a first in Morocco. PMID- 23093032 TI - Mycoleptione, a new chromone derivative isolated from the endophytic fungus Mycoleptodiscus sp. MU41. PMID- 23093033 TI - New diketopiperazine derivatives from a deep-sea-derived Nocardiopsis alba SCSIO 03039. AB - The strain SCSIO 03039 was isolated from a sediment sample in the Indian Ocean and was characterized as a Nocardiopsis alba species on the basis of its 16S rRNA gene sequence. Seven diketopiperazines (DKPs), including two new DKPs nocazines D (2a) and E (2b), and five known DKPs (1, 3-6), were isolated from N. alba SCSIO 03039, along with two known compounds 2-methoxy-1,4-naphthoquinone (7) and 1 hydroxy-4-methoxy-2-naphthoic acid (8). Their structures were elucidated by mass and NMR spectroscopic analyses. The structure of methoxyneihumicin (1), previously proposed in a conference poster lacking publicly available experimental data, was validated for the first time by detailed NMR analyses and X-ray diffraction study. The two enantiomers nocazines D (2a) and E (2b) were isolated as a mixture. Compounds 3 and 4 were only known as synthetic compounds before. Methoxyneihumicin (1) exhibited in vitro cytotoxicities against MCF-7 and SF-268 with IC50 values of 4.6 and 12.7 MUM, respectively, better than those of 6 (22.0 and 20.6 MUM). The other compounds showed less pronounced cytotoxities against three tested human cancer cell lines and no compounds displayed antibacterial activities toward four indicator strains. PMID- 23093034 TI - Antimicrobial peptides from arachnid venoms and their microbicidal activity in the presence of commercial antibiotics. AB - Two antimicrobial peptides (AMPs), named La47 and Css54, were isolated from the venom of the spider Lachesana sp. and from the scorpion Centruroides suffusus suffusus, respectively. The primary structures of both La47 and Css54 were determined using N-terminal sequencing and mass spectrometry. La47 is identical to the AMP latarcin 3a obtained previously from the venom of the spider Lachesana tarabaevi, but the primary structure of Css54 is unique having 60% identities to the AMP ponericin-W2 from the venom of the ant Pachycondyla goeldii. Both La47 and Css54 have typical alpha-helix secondary structures in hydrophobic mimicking environments. The biological activities of both La47 and Css54 were compared with the AMP Pin2 isolated from the venom of the scorpion Pandinus imperator. La47 has lower antimicrobial and hemolytic activities compared with Css54 and Pin2. In addition, La47 and Pin2 were evaluated in the presence of the commercial antibiotics, chloramphenicol, ampicillin, novobiocin, streptomycin and kanamycin. Interestingly, the best antimicrobial combinations were obtained with mixtures of La47 and Pin2 with the antibiotics chloramphenicol, streptomycin and kanamycin, respectively. Furthermore, the novel peptide Css54 was evaluated in the presence of antibiotics used for the treatment of tuberculosis, isoniazid, rifampicin, pyrazinamide and ethambutol. Although the mixtures of Css54 with isoniazid, pyrazinamide or ethambutol inhibit the growth of Staphylococcus aureus, the best effect was found with rifampicin. Overall, these data show a motivating outlook for potential clinical treatments of bacterial infections using AMPs and commercial antibiotics. PMID- 23093035 TI - Role of EDTA and CSE1034 in curli formation and biofilm eradication of Klebsiella pneumoniae: a comparison with other drugs. PMID- 23093036 TI - Protoilludane sesquiterpenoids as scaffold structures for new antimicrobials against Mannheimia haemolytica. PMID- 23093037 TI - In vitro activity of Pheroid vesicles containing antibiotics against Plasmodium falciparum. AB - The macrolide antibiotics, erythromycin and azithromycin, have been studied for their potential antimalarial activity, but only modest activity has been demonstrated. In this study, we investigated the enhancement of the efficacy of these antibiotics in combination with a patented lipid-based drug delivery system, Pheroid technology. A chloroquine resistant strain of Plasmodium falciparum (RSA11) was incubated with the formulations for a prolonged incubation time (144 h). Drug efficacy assays were conducted by analyzing the histidine-rich protein II levels of the parasites. The effects of azithromycin and erythromycin were compared with other antibiotics and standard antimalarial drugs. The poor water soluble nature of the drugs led to the formation of micro scale Pheroid vesicles with average particle sizes of 72.76+/-10.73 MUm for azithromycin and 100.62+/-29.27 MUm for erythromycin. The IC(50) values of erythromycin and azithromycin alone and entrapped in Pheroid vesicles decreased statistically significant (P?0.05). Prolonged exposure was also statistically meaningful (P?0.05), although it seems that exposure need not exceed 96 h. Pheroid vesicles also proved successful in decreasing the IC(50) values of doxycycline, tetracycline and triclosan. Pheroid vesicles containing antibiotics could prove successful as a malaria treatment option. PMID- 23093038 TI - [Ventilation in acute respiratory distress. Lung-protective strategies]. AB - Ventilation of patients suffering from acute respiratory distress syndrome (ARDS) with protective ventilator settings is the standard in patient care. Besides the reduction of tidal volumes, the adjustment of a case-related positive end expiratory pressure and preservation of spontaneous breathing activity at least 48 h after onset is part of this strategy. Bedside techniques have been developed to adapt ventilatory settings to the individual patient and the different stages of ARDS. This article reviews the pathophysiology of ARDS and ventilator-induced lung injury and presents current evidence-based strategies for ventilator settings in ARDS. PMID- 23093039 TI - Examination of thymic positive and negative selection by flow cytometry. AB - A healthy immune system requires that T cells respond to foreign antigens while remaining tolerant to self-antigens. Random rearrangement of the T cell receptor (TCR) alpha and beta loci generates a T cell repertoire with vast diversity in antigen specificity, both to self and foreign. Selection of the repertoire during development in the thymus is critical for generating safe and useful T cells. Defects in thymic selection contribute to the development of autoimmune and immunodeficiency disorders(1-4). T cell progenitors enter the thymus as double negative (DN) thymocytes that do not express CD4 or CD8 co-receptors. Expression of the alphabetaTCR and both co-receptors occurs at the double positive (DP) stage. Interaction of the alphabetaTCR with self-peptide-MHC (pMHC) presented by thymic cells determines the fate of the DP thymocyte. High affinity interactions lead to negative selection and elimination of self-reactive thymocytes. Low affinity interactions result in positive selection and development of CD4 or CD8 single positive (SP) T cells capable of recognizing foreign antigens presented by self-MHC(5). Positive selection can be studied in mice with a polyclonal (wildtype) TCR repertoire by observing the generation of mature T cells. However, they are not ideal for the study of negative selection, which involves deletion of small antigen-specific populations. Many model systems have been used to study negative selection but vary in their ability to recapitulate physiological events(6). For example, in vitro stimulation of thymocytes lacks the thymic environment that is intimately involved in selection, while administration of exogenous antigen can lead to non-specific deletion of thymocytes(7-9). Currently, the best tools for studying in vivo negative selection are mice that express a transgenic TCR specific for endogenous self-antigen. However, many classical TCR transgenic models are characterized by premature expression of the transgenic TCRalpha chain at the DN stage, resulting in premature negative selection. Our lab has developed the HY(cd4) model, in which the transgenic HY TCRalpha is conditionally expressed at the DP stage, allowing negative selection to occur during the DP to SP transition as occurs in wildtype mice(10). Here, we describe a flow cytometry-based protocol to examine thymic positive and negative selection in the HY(cd4) mouse model. While negative selection in HY(cd4) mice is highly physiological, these methods can also be applied to other TCR transgenic models. We will also present general strategies for analyzing positive selection in a polyclonal repertoire applicable to any genetically manipulated mice. PMID- 23093040 TI - Parental reporting of adverse drug events and other drug-related problems in children in Finland. AB - PURPOSE: Drug-related problems (DRPs) are common in paediatric pharmacotherapy, but few studies describe them from the parents' perspective. In the present survey, we have investigated the lifetime prevalence and type of DRPs in children in Finland. METHODS: This was a population-based survey of a random sample of 6,000 children below 12 years of age in 2007. A questionnaire was sent to their parents. The final response rate was 67% with a study population of 4,032. The main outcome measure was the lifetime prevalence and type of DRPs. RESULTS: The lifetime prevalence of DRPs was 21% (95% CI 20-22). The most common (82%) of the 1,346 reported DRPs were adverse drug events (ADEs). The prevalence of ADEs was 17% (95% CI 16-19), that of other DRPs 5.2% (95% CI 4.5-5.9). The prevalence of serious ADEs was 0.4% and that of unexpected ADEs was 0.8%. The most common system involved in the ADEs was the gastrointestinal tract, comprising 34% of the 1,106 ADEs. The most common of the 240 other DRPs were problems with the administration and dosing of medicine (86%). Overall, 64% of DRPs were related to anti-infectives. CONCLUSIONS: One fifth of the Finnish children below 12 years of age had experienced DRPs. Appropriate counselling, including possible adverse drug reactions and dosing directions, is important for parents and children at both the prescribing and dispensing of medicines for paediatric patients. Reporting of any suspected serious or unexpected ADEs is an essential part of efficient pharmacovigilance in paediatrics. PMID- 23093041 TI - Population pharmacokinetics of bisoprolol in patients with chronic heart failure. AB - PURPOSE: The aim of the study was to develop a population pharmacokinetic (PK) model for clearance of bisoprolol in patients with congestive heart failure (CHF). METHODS: Parameters associated with the plasma concentrations of bisoprolol at steady-state were analyzed in 61 patients (mean age 66.21 +/- 9.49 years; mean total body weight 8.90 +/- 12.26 kg) with CHF using non-linear mixed effect modeling (NONMEM). A validation set of 17 patients with heart failure was used to estimate the predictive performance of the pharmacokinetic model. RESULTS: The typical mean value for bisoprolol clearance (CL), estimated by the base model (without covariates), in our population was 11.4 l h(-1). In the full model, covariates such as bisoprolol total daily dose (DD) and creatinine clearance were included. The final regression model for the clearance of bisoprolol was the following: CL (l h(-1)) = 4.68 + 0.859 * DD. CONCLUSION: The derived PK model describes the clearance of bisoprolol in patients with CHF, showing that the total daily dose of bisoprolol is the most important covariate. This finding will provide the basis for future PK studies on beta blockers in this specific patient population and lead to better overall management of heart failure. PMID- 23093043 TI - Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects. AB - PURPOSE: Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor. METHODS: Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4-17. Ticagrelor and AR-C124910XX plasma concentrations were quantified for pharmacokinetic analysis (n = 14); inhibition of platelet aggregation (IPA) was also assessed (n = 14). RESULTS: Compared with administration of ticagrelor alone, co-administration of ticagrelor and rifampicin significantly decreased the maximum plasma concentration (Cmax) of ticagrelor from 1091 to 297.8 ng/ml, area under the plasma concentration-time curve from time zero to infinity (AUC) of ticagrelor from 6225 to 864.0 ng.h/ml, and also decreased plasma half-life of ticagrelor from 8.4 to 2.8 h; reductions of 73 %, 86 % and 67 % respectively. With rifampicin, AR-C124910XX Cmax was unaffected, AUC was significantly decreased by 46 %, and metabolite to parent ratio for AUC increased fourfold. Although maximal IPA was unaffected, offset of ticagrelor-mediated IPA was more rapid in the presence of rifampicin; a significant reduction (27 %) in the area under the effect curve between 0 and 24 h was observed following co-administration with rifampicin. CONCLUSION: Co administration with rifampicin reduced ticagrelor exposure and resulted in a more rapid offset of ticagrelor-mediated IPA. Co-administration of strong CYP3A/P glycoprotein inducers with ticagrelor should be discouraged. PMID- 23093044 TI - Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. AB - Chronic heart failure (HF) with either reduced or preserved left ventricular (LV) ejection fraction is common and remains an extremely serious disorder with a high mortality and morbidity. Many complications related to heart failure can be related to thrombosis. Epidemiological and pathophysiological data also link HF to an increased risk of thrombosis, leading to the clinical consequences of sudden death, stroke, systemic thromboembolism and/or venous thromboembolism. This executive summary of a joint consensus document of the Heart Failure Association (EHFA) of the European Society of Cardiology (ESC) and the ESC Working Group on Thrombosis reviews the published evidence, summarises 'best practice', and puts forward consensus statements that may help to define evidence gaps and assist management decisions in everyday clinical practice. In HF patients with atrial fibrillation, oral anticoagulation is clearly recommended, and the CHA2DS2-VASc and HAS-BLED scores should be used to determine the likely risk-benefit ratio (thromboembolism prevention versus risk of bleeding) of oral anticoagulation. In HF patients with reduced LV ejection fraction who are in sinus rhythm there is no evidence of an overall benefit of vitamin K antagonists (e.g. warfarin) on mortality, with risk of major bleeding. Whilst there is the potential for a reduction in ischaemic stroke, there is currently no compelling reason to routinely use warfarin for these patients. Risk factors associated with increased risk of thromboembolic events should be identified and decisions regarding use of anticoagulation individualised. Patient values and preferences are important determinants when balancing the risk of thromboembolism against bleeding risk. Novel oral anticoagulants that offer a different risk-benefit profile compared with warfarin may appear as an attractive therapeutic option, but this would need to be confirmed in clinical trials. PMID- 23093046 TI - Antiferromagnetic ordering in Li2MnO3 single crystals with a two-dimensional honeycomb lattice. AB - Li(2)MnO(3) consists of a layered Mn honeycomb lattice separated by a single layer of LiO(6) octahedra along the c-axis. By using single crystal Li(2)MnO(3) samples, we have examined the physical properties and carried out both powder and single crystal neutron diffraction studies to determine that Mn moments order antiferromagnetically at T(N) = 36 K with an ordered magnetic moment of 2.3 MU(B) perpendicular to the ab plane. We have also discovered that about 35% of the full magnetic entropy is released in the supposedly simple paramagnetic phase, indicative of unusual spin dynamics at higher temperature. PMID- 23093045 TI - Design of highly potent HIV fusion inhibitors based on artificial peptide sequences. AB - Specific interactions were introduced between an artificial heptad repeat peptide template and HIV-1 gp41 for fusion inhibitor design, using a structure based rational design strategy. The designed peptides are nonhomologous with naturally occurring peptide and protein sequences, specifically interact with HIV-1 gp41, and show strong anti-HIV activity. PMID- 23093047 TI - Long term follow-up after a single intravitreal ranibizumab injection for choroidal neovascularisation secondary to optic nerve head drusen in a 5-year-old child. PMID- 23093048 TI - Invited commentary on Pearl and principal stratification. AB - Pearl (2011) posed the question of whether confinement of clinical trial analyses involving post-randomization variables to the principal stratum "framework" of Frangakis and Rubin (2002) unduly restricts the scientific questions that can be asked. Frangakis and Rubin illustrated their proposal through examples involving compliance, mediation, and surrogacy. Here the utility of the principal stratum framework, and the potential outcomes formulation from which it derives, are considered for these topics in the specific setting of the Women's Health Initiative randomized, placebo controlled trials of postmenopausal hormone therapy. It is argued that the essential issues related to study reliability and causal interpretation involve the avoidance of context-specific biases that are typically not closely related to whether or not treatment effects have a representation in terms of potential outcomes contrasts. Also, while the questions posed within principal strata may be of interest, some key questions in the hormone therapy setting would not be addressed if restricted to contrasts within principal strata. PMID- 23093049 TI - Towards realization of multi-terrestrial locomotion: decentralized control of a sheet-like robot based on the scaffold-exploitation mechanism. AB - Autonomous decentralized control is an attractive concept for designing robots that can exhibit highly adaptive animal-like behaviour. However, despite its appeal, previous robots based on this scheme could only adapt to a limited number of environments. Our hypothesis it that this problem can be overcome by simply implementing a scaffold-exploitation mechanism. We draw our inspiration from flatworms, which move over various terrains using their two-dimensional sheet like body, and we design an autonomous decentralized control scheme for a similar robot based on the scaffold-exploitation mechanism. Simulation results show that a robot with the proposed control scheme can move efficiently over various irregular terrains. Our control scheme is not specific to a certain environment, but will be applicable in any environment; it could thus form the basis for developing a multi-terrestrial robot whose working area covers land, sea and even air. PMID- 23093050 TI - Evidence-based neonatal medicine in Latin America: what can we learn from the International Neonatal Immunotherapy Study and trials of IVIg? PMID- 23093051 TI - Designing bimetallic catalysts for a green and sustainable future. AB - This Critical Review provides an overview of the recent developments in the synthesis and characterization of bimetallic nanoparticles. Initially the review follows a materials science perspective on preparing bimetallic nanoparticles with designer morphologies, after which the emphasis shifts towards recent developments in using these bimetallic particles for catalysing either oxidation or reduction. In the final part of this review we present an overview of the utilization of bimetallic catalyst systems for the transformation of bio renewable substrates and reactions related to the realization of a bio-refinery. Because of the sheer number of examples of transformations in this area, a few key examples, namely selective oxidation, hydrogenation/hydrogenolysis and reforming of biomass derived molecules, have been chosen for this review. Reports of bimetallic catalysts being used for the aforementioned transformations are critically analysed and the potential for exploiting such bimetallic catalysts have also been highlighted. A specific objective of this review article is to motivate researchers to synthesize some of the "designer" bimetallic catalysts with specific nanostructures, inspired from recent advances in the area of materials chemistry, and to utilize them for the transformation of biomass derived materials that are very complex and pose different challenges compared to those of simple organic molecules. We consider that supported bimetallic nanoparticles have an important role to play as catalysts in our quest for a more green and sustainable society. PMID- 23093052 TI - Combination therapy with galantamine and memantine improves behavioral and psychological symptoms of dementia (BPSD) in patients with early-onset Alzheimer's disease. PMID- 23093053 TI - The nocebo effect: a clinicians guide. AB - OBJECTIVE: This paper aims to provide an overview on the nocebo effect, focusing on recognition - its phenomenology, at-risk demographic profiles, clinical situations and personality factors, as well as discriminating somatic symptoms in the general population from treatment-related adverse effects. Lastly, the paper addresses available evidence-based strategies for management and minimisation of the nocebo effect. METHOD: Data for this paper were identified by searching PubMed using the search terms "nocebo" and "nocebo effect", augmented by a manual search of the references of the key papers and the related literature. RESULTS: The nocebo effect refers to non-pharmacodynamic, harmful or undesirable effects occurring after inactive treatment, a phenomenon that also occurs in the context of active therapy. Known drivers include classical conditioning and negative expectations concerning treatment. Recent meta-analyses have reported a considerable prevalence, ranging from 18% in the symptomatic treatment of migraine, to more than 74% in multiple sclerosis. Recognition of the nocebo driven adverse effects presents a challenge, especially because of its non specific nature and the similarity to the active medication's expected profile. Traits such as neuroticism, pessimism and type A personalities may predispose individuals to this phenomenon. Clinical management of the nocebo effect includes awareness and recognition, changing the manner of disclosure of potential drug related adverse effects, shaping patients' expectations and enhancing the treatment alliance. CONCLUSION: The nocebo effect is a common, clinically significant, yet covert driver of clinical outcomes. Increased awareness of its features, as well as knowledge of strategies on how to manage it, are fundamental so that clinicians can mitigate its impact on clinical practice. PMID- 23093054 TI - Therapeutic effects of vitamin D as adjunctive therapy to fluoxetine in patients with major depressive disorder. AB - OBJECTIVE: To compare the therapeutic effects of vitamin D3 plus fluoxetine and fluoxetine alone in patients with major depressive disorder. METHODS: In the present double-blind, randomized, placebo-controlled trial, 42 patients with a diagnosis of major depressive disorder based on DSM-IV criteria were randomly assigned into two groups to receive daily either 1500 IU vitamin D3 plus 20 mg fluoxetine or fluoxetine alone for 8 weeks. Depression severity was assessed at 2 week intervals using the 24-item Hamilton Depression Rating Scale (HDRS) as a primary outcome measure and the 21-item Beck Depression Inventory (BDI) as a secondary outcome measure. Serum 25(OH) vitamin D was measured at baseline and after intervention. RESULTS: Forty patients completed the trial. A two-way repeated-measures analysis of variance showed that depression severity based on HDRS and BDI decreased significantly after intervention, with a significant difference between the two groups. The vitamin D + fluoxetine combination was significantly better than fluoxetine alone from the fourth week of treatment. CONCLUSIONS: In the present 8-week trial, the vitamin D + fluoxetine combination was superior to fluoxetine alone in controlling depressive symptoms. PMID- 23093055 TI - Dravet syndrome: a genetic epileptic disorder. AB - Dravet syndrome (DS), or severe myoclonic epilepsy in infancy, is one of the most severe types of genetic epilepsy. It is characterized by the initial occurrence of febrile or afebrile seizures that often evolve into status epilepticus in infants with normal development, and by the subsequent appearance of myoclonic and/or atypical absence seizures as well as complex partial seizures. The key feature that characterizes DS is fever sensitivity, although photosensitivity and pattern-sensitivity are also often seen. The prognosis is unfavorable in most cases. Seizures become drug-resistant and persist, with many patients suffering from motor and cognitive impairment. Mutations of SCN1A, which encodes the voltage-gated sodium channel NaV1.1, are the most frequent genetic cause of this syndrome. SCN1A mutations and/or microchromosomal rearrangements involving SCN1A are detected in about 85? of patients. Mutations of PCDH19 have also been reported in female patients with clinical findings compatible with DS. PCDH19 mutations might account for 5? of overall DS cases. Thirty years after its first description, DS is considered as a model of channelopathy. This survey reviews recent developments in the research literature on DS, focusing on the clinical course, as well as its genetic causes. PMID- 23093056 TI - Relationships between the color-word matching Stroop task and the Go/NoGo task: toward multifaceted assessment of attention and inhibition abilities of children. AB - Both selective attention and response inhibition can be assessed through the Stroop task and the Go/NoGo task (Go/NoGo). The color-word matching Stroop task (cwmStroop) differs from the traditional Stroop task in ways that make it easy to administer, and it enables the examiners to analyze reaction time. It is expected that the cwmStroop and Go/NoGo tasks will be useful as clinical assessments for children with developmental disorders and in combination with functional magnetic resonance imaging studies. The objectives of this study were to elucidate the pattern of developmental change in cwmStroop scores and Go/NoGo scores and to determine whether and how cwmStroop scores are related to Go/NoGo scores. The subjects consisted of 108 healthy Japanese children aged 6-14 years. We found that cwmStroop and Go/NoGo scores displayed clear developmental changes between 6 and 14 years of age. The children's scores on the 2 tasks followed different developmental courses, however, and the correlation between scores on the two tasks was weak on the whole. These results indicate that the cwmStroop and Go/NoGo tasks tap different aspects of selective attention and response inhibition. Therefore it is expected that the combination of both tests will be useful in the multifaceted assessment of selective attention and response inhibition in childhood. PMID- 23093057 TI - Detection of Torque teno virus DNA in exhaled breath by polymerase chain reaction. AB - To determine whether exhaled breath contains Torque teno virus (TTV) or not, we tested exhaled breath condensate (EBC) samples by semi-nested PCR assay. We detected TTV DNA in 35% (7/20) of EBC samples collected from the mouth of one of the authors, demonstrating that TTV DNA is excreted in exhaled breath with moderate frequency. TTV DNA was detected also in oral EBC samples from 4 of 6 other authors, indicating that TTV DNA excretion in exhaled breath is not an exception but rather a common phenomenon. Furthermore, the same assay could amplify TTV DNA from room air condensate (RAC) samples collected at distances of 20 and 40cm from a human face with 40 (8/20) and 35% (7/20) positive rates, respectively. TTV transmission has been reported to occur during infancy. These distances seem equivalent to that between an infant and its household members while caring for the infant. Taken together, it seems that exhaled breath is one of the possible transmission routes of TTV. We also detected TTV DNA in 25% (10/40) of RAC samples collected at a distance of more than 180cm from any human face, suggesting the risk of airborne infection with TTV in a room. PMID- 23093059 TI - Dynamic finite element analysis of impulsive stress waves propagating from distal end of femur. AB - The human femur is subjected to an impulsive load at its distal end during daily life. Femoral bone fracture caused by impact loading is common in elderly women. It is important to clarify the dynamic response of the femur and to evaluate the change in its stress state during impact loading. A 3-dimensional model of the femur was prepared in the present study, and the impulsive stress waves propagating from the distal end of the femur were analyzed by the dynamic finite element method. This model showed that the von Mises equivalent stress is large on the anterior and posterior sides of the mid-diaphysis when the impact direction is different from that of the bone axis. As for the femoral neck, the absolute value of minimum principal stress initially increases on the medial side;slightly later the maximum principal stress increases on the lateral side. In this case, the absolute value of the maximum principal stress was found to be larger than that of the minimum principal stress, and the absolute value of the principal stress decreased as the impact angle increased. Further, the femoral neck and the trochanter were shown to have a higher risk of bone fracture when the impact direction is coincident with the bone axis. PMID- 23093058 TI - HIF-1alpha contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF 1alpha in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1alpha, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1alpha on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1alpha, E cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1alpha protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF 1alpha mRNA showed no significant change. SiRNA could block HIF-1alpha effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1alpha was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1alpha inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line. PMID- 23093060 TI - Esophageal cancer initially thought to be accompanied by a solitary metastasis to an intrathoracic paraaortic lymph node. AB - Esophageal cancers usually exhibit lymph-node metastases. Although a solitary lymph-node metastasis is occasionally found, the involvement of an intrathoracic paraaortic node is rare. We present here an intrathoracic mid-esophageal cancer case in which an accompanying solitary retroaortic mass was found within the posterior mediastinum by integrated positron emission tomography/computed tomography. For diagnosis, thoracoscopic resection of the mass was performed from a left thoracic approach, and histology revealed it to be a squamous cell carcinoma metastasized from the esophageal cancer. Upon radical esophagectomy after neoadjuvant therapy as a T3N1M0 Stage IIIa (AJCC/UICC) cancer, the esophageal cancer was found to have invaded unexpectedly deeply in the vicinity of the descending aorta. Another lymph node within the paraaortic region was also involved (T4N1M0 Stage IIIc). The present case and other cases we review here inform our understanding of metastasis to intrathoracic paraaortic nodes as follows:1) its existence may indicate extensive lymph-node metastasis or direct tumor invasion nearby, and 2) it may be accompanied by other lymph-node involvements in this region, even if it appears solitary upon preoperative investigation. Thus, for radical esophagectomy, sufficient lymph-node dissection is required, even at locations not reached by the usual right thoracic approach. Definitive chemoradiotherapy may be a better choice for preoperatively recognized T3 esophageal cancer when the cancer is accompanied by paraaortic lymph node metastasis. PMID- 23093061 TI - Duodenal carcinoma from a duodenal diverticulum mimicking pancreatic carcinoma. AB - An 81-year-old man was found to have a pancreatic head tumor on abdominal computed tomography (CT) performed during a follow-up visit for sigmoid colon cancer. The tumor had a diameter of 35mm on the CT scan and was diagnosed as pancreatic head carcinoma T3N0M0. The patient was treated with pylorus-preserving pancreaticoduodenectomy. Histopathological examination showed that the tumor had grown within a hollow structure, was contiguous with a duodenal diverticulum, and had partially invaded the pancreas. Immunohistochemistry results were as follows:CK7 negative, CK20 positive, CD10 negative, CDX2 positive, MUC1 negative, MUC2 positive, MUC5AC negative, and MUC6 negative. The tumor was diagnosed as duodenal carcinoma from the duodenal diverticulum. Preoperative imaging showed that the tumor was located in the head of the pancreas and was compressing the common bile duct, thus making it appear like pancreatic cancer. To the best of our knowledge, this is the second report of a case of duodenal carcinoma from a duodenal diverticulum mimicking pancreatic carcinoma. PMID- 23093062 TI - Concentration of various trace elements in the rat retina and their distribution in different structures. AB - Inductively coupled plasma mass spectrometry (ICP-MS) was used to quantify the total amount of trace elements in retina from adult male Sprague-Dawley rats (n = 6). Concentration of trace elements within individual retinal areas in frozen sections of the fellow eye was established with the use of two methodologies: (1) particle-induced X-ray emission (PIXE) in combination with 3D depth profiling with Rutherford backscattering spectrometry (RBS) and (2) synchrotron X-ray fluorescence (SXRF) microscopy. The most abundant metal in the retina was zinc, followed by iron and copper. Nickel, manganese, chromium, cobalt, selenium and cadmium were present in very small amounts. The PIXE and SXRF analysis yielded a non-homogenous pattern distribution of metals in the retina. Relatively high levels of zinc were found in the inner part of the photoreceptor inner segments (RIS)/outer limiting membrane (OLM), inner nuclear layer and plexiform layers. Iron was found to accumulate in the retinal pigment epithelium/choroid layer and RIS/OLM. Copper in turn, was localised primarily in the RIS/OLM and plexiform layers. The trace elements iron, copper, and zinc exist in different amounts and locations in the rat retina. PMID- 23093063 TI - Photocurrent properties of single GaAs/AlGaAs core-shell nanowires with Schottky contacts. AB - Conductivity and photoconductivity properties of individual GaAs/AlGaAs core shell nanowires (NWs) are reported. The NWs were grown by Au-assisted metalorganic vapor phase epitaxy, and then dispersed on a substrate where electrical contacts were defined on the individual NWs by electron beam induced deposition. Under dark conditions, the carrier transport along the NW is found to be limited by Schottky contacts, and influenced by the presence of an oxide layer. Nonetheless, under illumination, the GaAs/AlGaAs core-shell NW shows a significant photocurrent, much higher than the bare GaAs NW. The spatial dependence of the photocurrent within the single core-shell NW, evaluated by a mapping technique, confirms the blocking behavior of the contacts. Moreover, local spectral measurements were performed which allow one to discriminate the contribution of carriers photogenerated in the core and in the shell. PMID- 23093065 TI - Hydrothermal core-shell carbon nanoparticle films: thinning the shell leads to dramatic pH response. AB - Carbon nanoparticles with phenylsulfonate negative surface functionality (Emperor 2000, Cabot Corp.) are coated with positive chitosan followed by hydrothermal carbonization to give highly pH-responsive core-shell nanocarbon composite materials. With optimised core-shell ratio (resulting in an average shell thickness of ca. 4 nm, estimated from SANS data) modified electrodes exhibit highly pH-sensitive resistance, capacitance, and Faradaic electron transfer responses (solution based, covalently bound, or hydrothermally embedded). A shell "double layer exclusion" mechanism is discussed to explain the observed pH switching effects. Based on this mechanism, a broader range of future applications of responsive core-shell nanoparticles are envisaged. PMID- 23093064 TI - Neo-islet formation in liver of diabetic mice by helper-dependent adenoviral vector-mediated gene transfer. AB - Type 1 diabetes is caused by T cell-mediated autoimmune destruction of insulin producing cells in the pancreas. Until now insulin replacement is still the major therapy, because islet transplantation has been limited by donor availability and by the need for long-term immunosuppression. Induced islet neogenesis by gene transfer of Neuogenin3 (Ngn3), the islet lineage-defining specific transcription factor and Betacellulin (Btc), an islet growth factor has the potential to cure type 1 diabetes. Adenoviral vectors (Ads) are highly efficient gene transfer vector; however, early generation Ads have several disadvantages for in vivo use. Helper-dependent Ads (HDAds) are the most advanced Ads that were developed to improve the safety profile of early generation of Ads and to prolong transgene expression(1). They lack chronic toxicity because they lack viral coding sequences(2-5) and retain only Ad cis elements necessary for vector replication and packaging. This allows cloning of up to 36 kb genes. In this protocol, we describe the method to generate HDAd-Ngn3 and HDAd-Btc and to deliver these vectors into STZ-induced diabetic mice. Our results show that co-injection of HDAd-Ngn3 and HDAd-Btc induces 'neo islets' in the liver and reverses hyperglycemia in diabetic mice. PMID- 23093066 TI - Endogenous ovarian hormones affect mitochondrial efficiency in cerebral endothelium via distinct regulation of PGC-1 isoforms. AB - Mitochondria support the energy-intensive functions of brain endothelium but also produce damaging-free radicals that lead to disease. Previously, we found that estrogen treatment protects cerebrovascular mitochondria, increasing capacity for ATP production while decreasing reactive oxygen species (ROS). To determine whether these effects occur specifically in endothelium in vivo and also explore underlying transcriptional mechanisms, we studied freshly isolated brain endothelial preparations from intact and ovariectomized female mice. This preparation reflects physiologic influences of circulating hormones, hemodynamic forces, and cell-cell interactions of the neurovascular unit. Loss of ovarian hormones affected endothelial expression of the key mitochondrial regulator family, peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), but in a unique way. Ovariectomy increased endothelial PGC-1alpha mRNA but decreased PGC-1beta mRNA. The change in PGC-1beta correlated with decreased mRNA for crucial downstream mitochondrial regulators, nuclear respiratory factor 1 and mitochondrial transcription factor A, as well as for ATP synthase and ROS protection enzymes, glutamate-cysteine ligase and manganese superoxide dismutase. Ovariectomy also decreased mitochondrial biogenesis (mitochondrial/nuclear DNA ratio). These results indicate ovarian hormones normally act through a distinctive regulatory pathway involving PGC-1beta to support cerebral endothelial mitochondrial content and guide mitochondrial function to favor ATP coupling and ROS protection. PMID- 23093067 TI - In vivo imaging of cerebral microvascular plasticity from birth to death. AB - Cerebral function and viability are critically dependent on efficient delivery of oxygen and glucose through the microvasculature. Here, we studied individual microvessels in the intact brain using high-resolution confocal imaging and long term time-lapse two-photon microscopy across the lifetime of a mouse. In the first postnatal month, we found large-scale sprouting but to our surprise the majority of sprouts underwent pruning and only a small fraction became perfused capillaries. After the first month, microvessel formation and elimination decreased and the net number of vessels stabilized. Although vascular stability was the hallmark of the adult brain, some vessel formation and elimination continued throughout life. In young adult mice, vessel formation was markedly increased after exposure to hypoxia; however, upon return to normoxia, no vessel elimination was observed, suggesting that new vessels constitute a long-term adaptive response to metabolic challenges. This plasticity was markedly reduced in older adults and aging where hypoxia-induced angiogenesis was absent. Our study describes, for the first time in vivo patterns of cerebral microvascular remodeling throughout life. Disruption of the observed balance between baseline turnover and vascular stability may underlie a variety of developmental and age related degenerative neurological disorders. PMID- 23093068 TI - Neurological basis of AMP-dependent thermoregulation and its relevance to central and peripheral hyperthermia. AB - Therapeutic hypothermia is of relevance to treatment of increased body temperature and brain injury, but drugs inducing selective, rapid, and safe cooling in humans are not available. Here, we show that injections of adenosine 5'-monophosphate (AMP), an endogenous nucleotide, promptly triggers hypothermia in mice by directly activating adenosine A1 receptors (A1R) within the preoptic area (POA) of the hypothalamus. Inhibition of constitutive degradation of brain extracellular AMP by targeting ecto 5'-nucleotidase, also suffices to prompt hypothermia in rodents. Accordingly, sensitivity of mice and rats to the hypothermic effect of AMP is inversely related to their hypothalamic 5' nucleotidase activity. Single-cell electrophysiological recording indicates that AMP reduces spontaneous firing activity of temperature-insensitive neurons of the mouse POA, thereby retuning the hypothalamic thermoregulatory set point towards lower temperatures. Adenosine 5'-monophosphate also suppresses prostaglandin E2 induced fever in mice, having no effects on peripheral hyperthermia triggered by dioxymetamphetamine (ecstasy) overdose. Together, data disclose the role of AMP, 5'-nucleotidase, and A1R in hypothalamic thermoregulation, as well and their therapeutic relevance to treatment of febrile illness. PMID- 23093071 TI - Diffusion-weighted imaging improves prediction in cognitive outcome and clinical phases in patients with carbon monoxide intoxication. AB - INTRODUCTION: Changes in apparent diffusion coefficient (ADC) values often reflect tissue injury. Use of ADC as a surrogate marker to assess clinical phases has not been systemically applied in patients with carbon monoxide (CO) intoxication. METHODS: Fifty-nine magnetic resonance imaging scans and cognitive evaluations were performed in 47 patients with CO intoxication and compared with 22 sex- and age-matched controls. The patients were further classified into three groups based on the clinical phases, namely, acute (within 2 weeks), delayed neuropsychiatric (2 weeks to 6 months), and chronic (>1 year) groups. The ADC values were measured in 16 regions of interests (ROIs) and correlated with cognitive test scores. RESULTS: Among the 59 evaluations, 15 were in the acute, 26 in the delayed neuropsychiatric, and 18 in the chronic groups. Among the ROIs, significant elevations of ADC values were found in the corpus callosum and globus pallidus in all three CO phases compared with the controls, and the ADC values were highest in the chronic phases. In contrast, the ADC values in peripheral gray matter and white matter were highest in the delayed neuropsychiatric group. Both globus pallidus and corpus callosum ADC values correlated with multiple cognitive test scores. CONCLUSION: Using ADC as a surrogate marker, the globus pallidus and corpus callosum can be considered to be two vulnerable structures in the gray and white matter. Significant differences between ADC values correlated well with clinical phase and cognitive performance. PMID- 23093073 TI - Cheap malaria drug is going to wrong people, says charity. PMID- 23093069 TI - The dynamics of the mitochondrial organelle as a potential therapeutic target. AB - Mitochondria play a central role in cell fate after stressors such as ischemic brain injury. The convergence of intracellular signaling pathways on mitochondria and their release of critical factors are now recognized as a default conduit to cell death or survival. Besides the individual processes that converge on or emanate from mitochondria, a mitochondrial organellar response to changes in the cellular environment has recently been described. Whereas mitochondria have previously been perceived as a major center for cellular signaling, one can postulate that the organelle's dynamics themselves affect cell survival. This brief perspective review puts forward the concept that disruptions in mitochondrial dynamics--biogenesis, clearance, and fission/fusion events--may underlie neural diseases and thus could be targeted as neuroprotective strategies in the context of ischemic injury. To do so, we present a general overview of the current understanding of mitochondrial dynamics and regulation. We then review emerging studies that correlate mitochondrial biogenesis, mitophagy, and fission/fusion events with neurologic disease and recovery. An overview of the system as it is currently understood is presented, and current assessment strategies and their limitations are discussed. PMID- 23093072 TI - Effect of carotid artery stenting on cerebral blood flow: evaluation of hemodynamic changes using arterial spin labeling. AB - INTRODUCTION: The purpose of this work was to quantitatively evaluate the hemodynamic changes after carotid artery stenting (CAS) by measuring cerebral blood flow (CBF) using arterial spin labeling (ASL). METHODS: Twenty sets of pre- and postprocedural CBF maps were acquired using ASL in patients who underwent CAS. Vascular territory- and anatomical structure-based regions of interest were applied to the CBF maps. Relative CBF (rCBF) was calculated by adjusting ipsilateral CBF with contralateral CBF. To assess the changes in rCBF after CAS (DeltarCBF), we calculated the following difference: [Formula: see text]. RESULTS: Postprocedural CBFs were significantly higher than preprocedural CBFs for internal carotid artery and middle cerebral artery territories (P < 0.05 in both). Postprocedural rCBFs were also significantly higher than preprocedural rCBFs for internal carotid artery and middle cerebral artery territories (P < 0.05 in both). Significant correlations were observed between preprocedural rCBF and DeltarCBF for the internal carotid artery and middle cerebral artery territories (r = -0.7211, P = 0.0003 and r = -0.6427, P = 0.0022, respectively). Areas in which the DeltarCBF values were >5.00 ml 100 g-1 min-1 were the precentral, postcentral, middle frontal, middle temporal (caudal), superior parietal, and angular gyri. CONCLUSIONS: ASL has potential as a noninvasive imaging tool for the quantitative evaluation of hemodynamic changes after CAS. CAS improves cerebral perfusion in patients with carotid artery stenosis, and patients with greater perfusion deficits prior to CAS have greater improvement in perfusion after CAS. In addition, eloquent areas show the greatest improvement in perfusion. PMID- 23093074 TI - Conserved RNA motifs of EMCV IRES as potential building blocks to design RNA nanostructures. AB - The highly conserved secondary structural RNA motifs endowed by the IRES element of EMCV picornavirus provide an excellent platform to design RNA nanostructures for application in medicine. We have identified a 44mer RNA, hosting distinct 15mer and 11mer RNA stem loop motifs, as potential building blocks for the design of RNA nanostructures. PMID- 23093077 TI - Abdominal aortic aneurysm: an often asymptomatic and fatal men's health issue. AB - Men are more likely than women to develop an abdominal aortic aneurysm (AAA), a disease that is often asymptomatic and has up to a 90% risk of mortality if the aneurysm ruptures. What many men do not know is that an AAA can easily be identified through an ultrasound screening, and if the aneurysm is >5.5 cm, it can be surgically repaired to prevent a life-threatening rupture. Although current AAA screening recommendations focus on men between the ages of 65 and 75 years, who have ever smoked, recent evidence suggest many men of ages 50 to 80 years, regardless of smoking status, may also be at risk for developing an AAA. This article presents a comprehensive overview of AAA disease and summarizes current evidence-based diagnostic and treatment guidelines, the importance of educating men about this health issue, and the need for more widespread AAA ultrasound screening opportunities. PMID- 23093076 TI - The limitations of language: male participants, stoicism, and the qualitative research interview. AB - The semistructured, open-ended interview has become the gold standard for qualitative health research. Despite its strengths, the long interview is not well suited for studying topics that participants find difficult to discuss, or for working with those who have limited verbal communication skills. A lack of emotional expression among male research participants has repeatedly been described as a significant and pervasive challenge by health researchers in a variety of different fields. This article explores several prominent theories for men's emotional inexpression and relates them to qualitative health research. The authors argue that investigators studying emotionally sensitive topics with men should look beyond the long interview to methods that incorporate other modes of emotional expression. This article concludes with a discussion of several such photo-based methods, namely, Photovoice, Photo Elicitation, and Visual Storytelling. PMID- 23093078 TI - Condom use, disclosure, and risk for unprotected sex in HIV-negative midlife and older men who have sex with men. AB - Sexual risk behaviors account for most HIV infections in men who have sex with men (MSM), and the risk of exposure from each sexual encounter increases with age. The focus of this study was to investigate which behaviors in midlife and older MSM influence their sexual risk/protection. Cross-sectional data were collected from a community-based sample of 802 MSM aged 40 years and older from community venues (e.g., bars) who completed an anonymous questionnaire. Data from a subset of 420 MSM who were HIV-negative (aged 40-81 years) were used to investigate which behaviors were associated with greater risk for unprotected anal sex. Regression analyses indicated that erection difficulties (odds ratio [OR] = 4.7; 95% confidence interval [CI] = 1.8-12.2), practicing safe sex with outside partners but not with one's primary partner (OR = 0.54; 95% CI = 0.3 0.94), and recreational drug use (OR = 2.6; 95% CI = 1.3-5.1) were associated with higher risk for unprotected receptive anal intercourse. Younger age (OR = 0.96; 95% CI = 0.9- 0.9), not telling partners about HIV status (OR = 3.2; 95% CI = 1.5-6.5), finding partners in backrooms/sex clubs (OR = 2.8; 95% CI = 1.1- 6.8), and erection difficulties (OR = 10.3; 95% CI = 2.8-37.8) were associated with higher risk for unprotected insertive anal intercourse. These data indicate there may be certain factors specific to older MSM that influence their sexual risk taking behaviors. Programs may be more effective if they are tailored for older cohorts of MSM and address interpersonal communication, erection problems, and substance use to reduce health risks and promote healthier lifestyles. PMID- 23093075 TI - Perceived importance of five different health issues for gay and bisexual men: implications for new directions in health education and prevention. AB - This study assessed the perceived importance of five health issues for gay and bisexual men (N = 660) using time-space sampling in gay bars/clubs and bathhouses in New York City: "HIV & STDs," "Drugs & Alcohol," "Body Image," "Mental Health," and "Smoking." This study compared ratings based on demographic differences, recent substance use, recent sexual risk behavior, and whether or not participants owned a smart device (e.g., "smart" phone, iPad, iPod touch). Contrary to research indicating that gay and bisexual men may be experiencing HIV prevention fatigue, this study identified that HIV and STIs were perceived as most important. Drugs and alcohol and mental health were also rated high, suggesting that providers may be well served to include mental health and drugs and alcohol as part of their comprehensive approach to HIV prevention. A majority of participants (72%) owned a smart device. Smart device owners rated health issues similarly to those who did not, suggesting that such devices may be a useful platform to reach gay and bisexual men for health education and prevention. PMID- 23093079 TI - The evolution of risk factors for respiratory syncytial virus-related hospitalisation in infants born at 32-35 weeks' gestational age: time-based analysis using data from the FLIP-2 study. AB - AIM: The aim of this study was to examine whether the risk for respiratory syncytial virus (RSV)-related hospitalisation changes through the first year of life in infants of 32-35 weeks' gestational age (wGA). METHODS: Risk factors from the FLIP-2 study (190 cases/4566 age-matched controls) were included in a Cox regression analysis wherein time slices were taken at 1-month intervals from birth. RESULTS: Half of all RSV hospitalisations occurred in the first 68 days after birth, with 56% occurring within 90 days. The time taken for 50% of hospitalisations to occur was 148 days for those born outside the RSV season and 58 days for those born within the season. By 90 days old, 84% of infants born in the season and 20% of those born outside the season were hospitalised. In both groups, hospitalisations occurred >=5 months after birth. Male sex, smoking whilst pregnant, month of birth, duration of breastfeeding, number of siblings at school, and number of smokers in household all contributed to the risk of RSV hospitalisation beyond the age of 90 days. CONCLUSIONS: The risk of RSV hospitalisation appears to persist to at least 5-6 months old in 32-35 wGA infants, which has implications for the optimal management of disease prevention. PMID- 23093080 TI - Labour epidural analgesia and anti-infectious management of the neonate: a meta analysis. AB - BACKGROUND: A known side effect of labour epidural analgesia (EDA) is maternal fever. It is unclear whether this has effects on the anti-infectious management of the neonate. METHODS: A systematic literature search and a hand search of abstract publications were conducted. Studies reporting sepsis evaluation or antibiotic treatment were further assessed. For meta-analysis, risk ratio (RR) and 95% confidence interval (CI) were calculated using the random effects model. RESULTS: Five relevant articles reporting on 4667 parturients were identified; three were observational studies and two were randomised controlled trials (RCT). The RR for sepsis workup of all studies analysed together was 2.58 (95% CI, 1.06 6.27, P=0.04). The RR for antibiotic treatment of the neonate was 2.76 (95% CI, 1.20-6.31, P=0.02). When considering the RCTs alone, the RRs for sepsis evaluation and antimicrobial treatment were still significantly elevated. DISCUSSION: Our data suggest that EDA-related maternal hyperthermia results in an increased likelihood of sepsis workup and antibiotic treatment of the infant. A crucial question is whether EDA-related maternal hyperthermia is truly infectious. If not, administration of antibiotics would not be justified and may be dangerous. PMID- 23093081 TI - Carboxyhemoglobin levels in umbilical cord blood of women with pre-eclampsia and intrauterine growth restriction. AB - OBJECTIVE: Pre-eclampsia (PE) and intrauterine growth restriction (IUGR) are associated with abnormal placentation. Heme oxygenase (HO) and carbon monoxide (CO) are involved in normal placental development and function and vasomotor control in the placenta. The objective of our study was to measure CO levels, as assessed by carboxyhemoglobin (COHb) levels in the umbilical cord arterial blood of women with PE, normotensive IUGR (<10th percentile for birth weight), and normotensive pregnancies with appropriate-for-gestational age (AGA) infants. DESIGN AND METHODS: We prospectively analyzed COHb levels in the umbilical arterial blood of women with PE, normotensive IUGR, and normotensive AGA pregnancies. Exclusion criteria included cigarette smoke exposure, hemolytic disorders, a positive direct anti-globulin test, chronic hypertension, fever, and any significant medical illness. COHb levels were measured using the ABL 725 blood gas analyzer. RESULTS: There were 41 women in the normotensive AGA group, 42 in the PE group, and 36 in the normotensive IUGR group. Maternal age, mode of delivery, gravidity, parity, and gender of the infants were similar in the three groups. Gestational age and birth weight were significantly higher in the normotensive AGA group compared with the other two groups. COHb levels were significantly lower in the PE group compared with the normotensive AGA group (0.38+/-0.06% vs. 0.77+/-0.11%, P<0.05). COHb levels, although lower in the normotensive IUGR group compared with the normotensive AGA group, did not reach statistical significance. CONCLUSION: Our data suggests the HO-CO system may have a role in the pathogenesis of PE. We also, for the first time, provide information on umbilical arterial COHb levels in normotensive IUGR pregnancies. PMID- 23093082 TI - Association of the atherogenic index of plasma and oxidative stress status with weight gain during non-complicated pregnancy. AB - BACKGROUND: Pregnancy is a stressful condition linked with altered lipid profile, increased oxidative stress and increased inflammation processes. The purpose of the present study was to determine the associations between those alterations with increased weight gain during pregnancy. METHODS: The atherogenic index of plasma (AIP) and oxidative stress status parameters were determinated in 50 healthy and 172 pregnant women with non-complicated pregnancy. Pregnant women were divided in four groups according to body mass index (BMI) values (BMI quartiles). RESULTS: Oxidative stress parameters were significantly lower in the control group compared with all the pregnant women quartiles. Unexpectedly, differences in oxidative stress parameters between BMI quartiles groups were not significant. The antioxidant defence parameters remained quite similar in the different BMI quartiles. Weight gain and paraoxonase-1 (PON1) activities were independently associated with increased AIP while weight gain and triglyceride concentration were found to be significant predictors of PON1 activities. CONCLUSIONS: The results of our current study indicate the association of maternal weight gain during pregnancy and altered lipid profile, elevated oxidative stress and changed antioxidative capacity of PON1. Taken together all these facts indicate possible increased risk of cardiovascular disease (CVD) development in later life if the weight gain during pregnancy is excessive. PMID- 23093083 TI - Application of mathematical models of system uncertainty to evaluate the utility of assay calibration protocols. AB - BACKGROUND: Laboratory protocols used to calibrate commercial clinical chemistry systems affect test result quality. Mathematical models of system uncertainty can be developed using performance parameters provided by the manufacturer for various subsystems. These models can be used to evaluate protocols for specific laboratory operations. METHODS: A mathematical model was developed to estimate the uncertainty inherent in the Roche Diagnostics P-Modular system, and included uncertainties associated with the sample and reagent pipettes, spectrometer and the calibration process. The model was then used to evaluate various alternate calibration protocols: calibration based on mean of replicate measurements (n=1 6) and calibration based on conditional acceptance when the following quality control specimen was within one standard deviation of target. The effect of calibrator concentrations on assay measurement uncertainty was also studied, and calibrator concentrations that minimize uncertainty at a specific concentration were identified. RESULTS: The simulation model produced uncertainty estimates of 3.5% for the serum cholesterol assay and identified sample pipette (40%) and spectrometer (21%) as the largest contributors to measurement uncertainty. Each additional replicate calibrator measurements result in diminishing reductions in measurement uncertainty, with maximum reductions (19%) achieved with five replicate measurements. The conditional acceptance of calibration only when the control was within 1s resulted in an 18% reduction. CONCLUSIONS: The model can be used to evaluate the utility of laboratory protocols and establish realistic assay performance targets. The model also can help instrument manufacturers and laboratorians identify major contributors to assay measurement uncertainty, which helps improve performance in future assay systems. PMID- 23093084 TI - Phosphoethanolamine normal range in pediatric urines for hypophosphatasia screening. PMID- 23093085 TI - Error reporting in transfusion medicine at a tertiary care centre: a patient safety initiative. AB - BACKGROUND: Errors in the transfusion process can compromise patient safety. A study was undertaken at our center to identify the errors in the transfusion process and their causes in order to reduce their occurrence by corrective and preventive actions. METHODS: All near miss, no harm events and adverse events reported in the 'transfusion process' during 1 year study period were recorded, classified and analyzed at a tertiary care teaching hospital in North India. RESULTS: In total, 285 transfusion related events were reported during the study period. Of these, there were four adverse (1.5%), 10 no harm (3.5%) and 271 (95%) near miss events. Incorrect blood component transfusion rate was 1 in 6031 component units. ABO incompatible transfusion rate was one in 15,077 component units issued or one in 26,200 PRBC units issued and acute hemolytic transfusion reaction due to ABO incompatible transfusion was 1 in 60,309 component units issued. Fifty-three percent of the antecedent near miss events were bedside events. Patient sample handling errors were the single largest category of errors (n=94, 33%) followed by errors in labeling and blood component handling and storage in user areas. CONCLUSIONS: The actual and near miss event data obtained through this initiative provided us with clear evidence about latent defects and critical points in the transfusion process so that corrective and preventive actions could be taken to reduce errors and improve transfusion safety. PMID- 23093086 TI - A mechanical model of stereocilia that demonstrates a shift in the high sensitivity region due to the interplay of a negative stiffness and an adaptation mechanism. AB - Stereocilia are the basic sensory units of nature's inertial sensors and are highly sensitive over broad dynamic ranges, which is a major challenge in the design of conventional engineering sensors. The high sensitivity that is maintained by stereocilia was hypothesized to exist due to a combination of adaptation and negative stiffness mechanisms, which shift the region of highest sensitivity toward the active operation range of the stereocilia bundle. To examine the adaptation hypothesis in terms of its potential applicability to future applications regarding the design of inertial sensors, we developed a mechanical mimicry of the interplay between negative stiffness and the adaptation of the stereocilia that produces spontaneous oscillation of the hair bundle. The mechanical model consists of an inverted pendulum and a fixed T-bar that mimic the interaction of two adjacent stereocilia. To focus on the interaction of one gating spring and the corresponding adaptation motor without the effect of coupling from the other gating springs attached to the neighboring stereocilia, we fixed one bar that contains the adaptation motor. To emulate the negative resistance of the tip-link due to the transient stiffness softening by the gating ion channel, a magnet pair was attached to the top of the inverted pendulum and the fixed T-bar. Readjustment of the tip-link tension by the 'slipping down and climbing up' motion of the adaptation molecular motors was demonstrated by the side-to-side movement of the magnet by a step motor. The negative stiffness region was observed near the equilibrium position and shifted with the activation of the adaptation motor. The temporal demonstration of the stiffness shift was measured as a spontaneous oscillation. The results showed that the interplay between the negative stiffness and the adaptation mechanism was mechanically produced by the combination of a repulsive force and its continuous readjustment and is better understood through a parameter study of a biomimetic mechanical system. PMID- 23093087 TI - The laparoscopic approach for radiofrequency ablation of hepatocellular carcinoma -indication, technique and results. AB - BACKGROUND: The therapeutic regimen for patients suffering of HCC in liver cirrhosis must pay attention to the underlying liver disease. Surgical resection is often limited by liver function and transplantation, as an optimal therapy for many early diagnosed HCC, by the availability of organs. Due to three prospective, randomized trials radiofrequency ablation (RFA) is the standard method of local ablation. RFA compared with resection for HCC in liver cirrhosis yields similar results concerning overall survival but a lower rate of complications. The laparoscopic approach may be advantageous concerning the major drawback of RFA which is still the rate of local failure as shown by a meta analysis of local recurrences. METHOD: Indication for RFA was HCC in liver cirrhosis either as a definite therapy or as a bridging procedure for transplantation if the expected waiting time exceeded 6 months. Laparoscopic ultrasound, standardized algorithm of laparoscopic RFA procedure, track ablation and a Trucut biopsy were performed. The postoperative follow-up was done according to institutional standards. Patient data and parameters of laparoscopic RFA were prospectively documented, analyzed and compared with the results of previously published series found in a Medline search. RESULTS: 34 patients were treated by laparoscopic RFA. The average time of follow-up was 36.9 +/- 28.3 months. There was no procedure-related mortality or surgical complications. An upstaging of the tumor stage by laparoscopic ultrasound was achieved in 32 % of the patients. The overall survival of these patients was 44.7 +/- 6.9 months. The intrahepatic recurrence rate was 61.8 % based on the number of patients treated. The results have been analyzed and compared with six independent papers identified in a Medline search that report on the treatment of patients with HCC in a liver cirrhosis by laparoscopic RFA with a mean follow-up of 12 or more months. CONCLUSIONS: Laparoscopic RFA is a feasible and reliable therapy for unresectable HCCs in patients with cirrhosis. The laparoscopic RFA combines the advantage of a minimally invasive procedure concerning liver dysfunction with the ability of an accurate intraoperative staging by laparoscopic ultrasound. PMID- 23093088 TI - Transplantation with hyper-reduced liver grafts in children under 10 kg of weight. AB - BACKGROUND: We had previously described a left lateral segment hyper-reduction technique capable of sizing the graft according to the volume of the abdominal cavity of the recipient. AIM: The purpose of our study was to evaluate our 14 year live-donor liver transplantation experience with in situ graft hyper reduction in children under 10 kg of weight. PATIENTS AND METHODS: Between January 1997 and May 2011, we performed 881 liver transplants. Two hundred and seventy-seven (n = 277) involved pediatric recipients, of which 102 (37 %) were from live donors. Thirty-five (n = 35) patients under 10 kg of weight underwent hyper-reduced living donor liver transplants. There were 21 females (60 %) and 14 males (40 %), with a median age of 12 months (range 3-23) and a median weight of 7.7 kg (range 5.6-10). RESULTS: Median operative time was 350 min (range 180 510). Median cold ischemia time was 180 min (range 60-300). Twenty-six (n = 26) patients required intraoperative transfusion of blood products. There were 49 postoperative complications involving 26 patients (74 % morbidity rate). One-, 3 , and 5-year survival rates were 87, 79, and 74 %, respectively. Twenty-eight patients are currently alive. CONCLUSIONS: Hyper-reduced grafts provide an alternative approach for low-weight pediatric recipients. The relatively high immediate postoperative morbidity could be related to the complexity of these patients. PMID- 23093089 TI - The use of in situ and ex situ techniques for the study of the formation mechanism of mesoporous silica formed with non-ionic triblock copolymers. AB - Since the discovery of the mesoporous silica material templated by ionic surfactants and the subsequent development of materials templated by non-ionic surfactants and polymers, for example SBA-15, there has been a continuous research effort towards understanding their formation. In situ methodologies, such as Small Angle X-ray Scattering (SAXS), Small Angle Neutron Scattering (SANS), spectroscopic techniques like NMR and EPR, and ex situ methodologies such as electron microscopy techniques (SEM, TEM and cryo-TEM) are powerful and important tools in the investigation of the mechanism by which these materials form. The need for a fundamental understanding of the systems is of academic concern and of great importance when developing materials for applications. In this tutorial review we aim to give the reader a comprehensive overview on the development of the field over the years and an introduction to the experimental in situ and ex situ techniques that have been used. PMID- 23093090 TI - In ovo electroporation of miRNA-based plasmids in the developing neural tube and assessment of phenotypes by DiI injection in open-book preparations. AB - Commissural dI1 neurons have been extensively studied to elucidate the mechanisms underlying axon guidance during development(1,2). These neurons are located in the dorsal spinal cord and send their axons along stereotyped trajectories. Commissural axons initially project ventrally towards and then across the floorplate. After crossing the midline, these axons make a sharp rostral turn and project longitudinally towards the brain. Each of these steps is regulated by the coordinated activities of attractive and repulsive guidance cues. The correct interpretation of these cues is crucial to the guidance of axons along their demarcated pathway. Thus, the physiological contribution of a particular molecule to commissural axon guidance is ideally investigated in the context of the living embryo. Accordingly, gene knockdown in vivo must be precisely controlled in order to carefully distinguish axon guidance activities of genes that may play multiple roles during development. Here, we describe a method to knockdown gene expression in the chicken neural tube in a cell type-specific, traceable manner. We use novel plasmid vectors(3) harboring cell type-specific promoters/enhancers that drive the expression of a fluorescent protein marker, followed directly by a miR30-RNAi transcript(4) (located within the 3'-UTR of the cDNA encoding the fluorescent protein) (Figure 1). When electroporated into the developing neural tube, these vectors elicit efficient downregulation of gene expression and express bright fluorescent marker proteins to enable direct tracing of the cells experiencing knockdown(3). Mixing different RNAi vectors prior to electroporation allows the simultaneous knockdown of two or more genes in independent regions of the spinal cord. This permits complex cellular and molecular interactions to be examined during development, in a manner that is fast, simple, precise and inexpensive. In combination with DiI tracing of commissural axon trajectories in open-book preparations(5), this method is a useful tool for in vivo studies of the cellular and molecular mechanisms of commissural axon growth and guidance. In principle, any promoter/enhancer could be used, potentially making the technique more widely applicable for in vivo studies of gene function during development(6). This video first demonstrates how to handle and window eggs, the injection of DNA plasmids into the neural tube and the electroporation procedure. To investigate commissural axon guidance, the spinal cord is removed from the embryo as an open-book preparation, fixed, and injected with DiI to enable axon pathways to be traced. The spinal cord is mounted between coverslips and visualized using confocal microscopy. PMID- 23093091 TI - Factors influencing prenatal screening for Down's syndrome: evidence from Zhejiang (China). AB - This article attempts to identify the factors that influence prenatal screening uptake. About 1400 postdelivery, still-hospitalized women in 15 hospitals in Zhejiang Province were surveyed from November to December 2007. Univariate analysis was used to describe screening uptake and compare respondents with different characteristics. Stepwise logistic regression (forward) was then used to assess the relative strength of those influencing factors. It was found that 49.7% of the respondents received maternal serum prenatal screening. The factors that influenced prenatal screening service utilization included place of residence (urban vs countryside), migrant versus nonmigrant status, attitudes toward screening, frequency of routine prenatal checkups, and doctor's advice. Migrants had a lower probability of getting screened than permanent residents (odds ratio = 0.456; 95% confidence interval [CI] = 0.31, 0.68). The screening uptake probability of women with doctor's advice was 12 times as great as that of women without doctor's advice (95% CI = 7.91, 18.69). PMID- 23093092 TI - Generation of Ag-Ag(2)O complex nanostructures by excimer laser ablation of Ag in water. AB - Pulsed laser ablation in liquid (PLAL) has been well established as a facile method to produce nanoparticles from bulk materials, but it is still insufficient for fabricating anisotropic and complex nanostructures, especially without the use of surfactants. Here, we demonstrate that silver (Ag) nanosheets can be produced by pulsed excimer laser ablation of bulk Ag in water via laser re processing of the laser-produced primary clusters. We also show that by combining PLAL and drop evaporation, rice-shaped Ag-Ag(2)O particles and their assemblies can be generated on Si substrates, because the interior flow of an evaporating colloidal drop could redistribute the laser-produced primary clusters, which results in the formation of complex nanostructures. These results show that PLAL is able to fabricate novel micro-/nanostructures while keeping its merit of "clean" fabrication. PMID- 23093093 TI - Hydrocarbon oxidation catalyzed by self-folded metal-coordinated cavitands. AB - Functionalized cavitands have been shown to self-fold via coordination of Fe(II) salts and effect catalytic C-H oxidation reactions of unfunctionalized alkanes under mild aqueous conditions in the presence of tert-butyl hydroperoxide as co oxidant. Secondary and tertiary C-H bonds can be converted to ketones and alcohols, respectively, and ethers can be converted to esters. The cavitands retain the catalytic metal throughout the reaction, and can be recovered by filtration. PMID- 23093095 TI - Hierarchically porous germanium-modified carbon materials with enhanced lithium storage performance. AB - In this work, hierarchically porous germanium-modified carbon materials (C/Ge) have been successfully synthesized by a facile hydrothermal method followed with a subsequent annealing treatment. The C/Ge nanocomposites have a unique hierarchically microporous-mesoporous structure, with a surface area of 331 m(2) g(-1). The C/Ge composites exhibit improved capacity, cycling performance and rate capability when used as an anode material, compared with the unmodified carbon and commercial germanium. This superior electrochemical performance could be ascribed to two points. On the one hand, such a hierarchically porous carbon would be beneficial to store and insert the lithium, and therefore the pore transport system would allow the accessibility of those sites by lithium ions. At the same time, the carbon layers can effectively increase the electrode conductivity, and serve as a buffer to accommodate the volume changes of electrode materials during cycling. On the other hand, the Ge also contributes to the enhancement of the capacity of the carbon spheres since Ge is also a promising anode material with large theoretical specific capacity (ca. 1400 mA h g(-1)) for lithium-ion batteries. PMID- 23093094 TI - Acute kidney injury transcriptomics unveils a relationship between inflammation and ageing. AB - There are no pathophysiolgical therapeutic approaches to acute kidney injury (AKI) and the mortality remains high. In addition chronic kidney disease (CKD) predisposes to AKI and AKI contributes to progression of CKD. Recently a transcriptomics approach unveiled a relationship between AKI, inflammation and the regulation of ageing. A transcriptomics analysis of experimental AKI revealed increased kidney expression of Fn14 and transmembrane chemokine CXCL16, as well as a decreased expression of the kidney-secreted anti-ageing hormone Klotho. Fn14 is the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of the TNF superfamily. In AKI kidneys there was a positive correlation between Fn14 and CXCL16 mRNA expression and an inverse correlation between Fn14 and Klotho mRNA. Tubular cells were the site of Fn14, CXCL16 and Klotho expression in vivo. Research on the relationships between these three molecules disclosed that TWEAK activation of Fn14 promoted inflammation through secretion of chemokines such as CXL16 in tubular cells in culture and in vivo. Furthermore, TWEAK activation of Fn14 decreased expression of Klotho mRNA and protein in culture and in vivo. Interestingly, both TWEAK activation of CXCL16 mRNA transcription and suppression of Klotho mRNA transcription were mediated by the NFκB transcription factor. In conclusion, TWEAK engagement of Fn14 is a central event promoting NFκB-mediated activation of inflammation pathways and suppression of anti-inflammatory/anti-ageing pathways. This information may influence future therapeutic approaches to AKI and inflammation/aging. PMID- 23093096 TI - Subsocial behaviour and brood adoption in mixed-species colonies of two theridiid spiders. AB - Cooperation and group living often evolves through kin selection. However, associations between unrelated organisms, such as different species, can evolve if both parties benefit from the interaction. Group living is rare in spiders, but occurs in cooperative, permanently social spiders, as well as in territorial, colonial spiders. Mixed species spider colonies, involving closely related species, have rarely been documented. We examined social interactions in newly discovered mixed-species colonies of theridiid spiders on Bali, Indonesia. Our aim was to test the degree of intra- and interspecific tolerance, aggression and cooperation through behavioural experiments and examine the potential for adoption of foreign brood. Morphological and genetic analyses confirmed that colonies consisted of two related species Chikunia nigra (O.P. Cambridge, 1880) new combination (previously Chrysso nigra) and a yet undescribed Chikunia sp. Females defended territories and did not engage in cooperative prey capture, but interestingly, both species seemed to provide extended maternal care of young and indiscriminate care for foreign brood. Future studies may reveal whether these species adopt only intra-specific young, or also inter-specifically. We classify both Chikunia species subsocial and intra- and interspecifically colonial, and discuss the evolutionary significance of a system where one or both species may potentially benefit from mutual tolerance and brood adoption. PMID- 23093097 TI - Vulnerability and behavioral response to ultraviolet radiation in the components of a foliar mite prey-predator system. AB - Ambient ultraviolet-B (UVB) radiation impacts plant-dwelling arthropods including herbivorous and predatory mites. However, the effects of UVB on prey-predator systems, such as that between the herbivorous spider mite and predatory phytoseiid mite, are poorly understood. A comparative study was conducted to determine the vulnerability and behavioral responses of these mites to ultraviolet (UV) radiation. First, we analyzed dose-response (cumulative irradiance-mortality) curves for the eggs of phytoseiid mites (Neoseiulus californicus, Neoseiulus womersleyi, and Phytoseiulus persimilis) and the spider mite (Tetranychus urticae) to UVB radiation from a UV lamp. This indicated that the phytoseiid mites were more vulnerable than the spider mite, although P. persimilis was slightly more tolerant than the other two phytoseiid mites. Second, we compared the avoidance behavior of adult female N. californicus and two spider mite species (T. urticae, a lower leaf surface user; Panonychus citri, an upper leaf surface user) in response to solar UV and visible light. N. californicus actively avoided both types of radiation, whereas P. citri showed only minimal avoidance behavior. T. urticae actively avoided UV as well as N. californicus but exhibited a slow response to visible light as well as P. citri. Such variation in vulnerability and avoidance behavior accounts for differences in the species adaptations to solar UVB radiation. This may be the primary factor determining habitat use among these mites on host plant leaves, subsequently affecting accessibility by predators and also intraguild competition. PMID- 23093098 TI - Estimation of radiation dose and risk to children undergoing cardiac catheterization for the treatment of a congenital heart disease using Monte Carlo simulations. AB - BACKGROUND: Children diagnosed with congenital heart disease often undergo cardiac catheterization for their treatment, which involves the use of ionizing radiation and therefore a risk of radiation-induced cancer. OBJECTIVE: The purpose of this study was to calculate the effective and equivalent organ doses (H(T)) in those children and estimate the risk of exposure-induced death. MATERIALS AND METHODS: Fifty-three children were divided into three groups: atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA). In all procedures, the exposure conditions and the dose-area product meters readings were recorded for each individual acquisition. Monte Carlo simulations were run using the PCXMC 2.0 code and mathematical phantoms simulating a child's anatomy. The H(T) values to all irradiated organs and the resulting E and risk of exposure-induced death values were calculated. RESULTS: The average dose-area product values were, respectively, 40 +/- 12 Gy.cm(2) for the ASD, 17.5 +/- 0.7 Gy.cm(2) for the VSD and 9.5 +/- 1 Gy.cm(2) for the PDA group. The average E values were 40 +/- 12, 22 +/- 2.5 and 17 +/- 3.6 mSv for ASD, VSD and PDA groups, respectively. The respective estimated risk of exposure induced death values per procedure were 0.109, 0.106 and 0.067%. CONCLUSION: Cardiac catheterizations in children involve a considerable risk for radiation induced cancer that has to be further reduced. PMID- 23093100 TI - Range dependent characteristics in the head-related transfer functions of a bat head cast: part 1. Monaural characteristics. AB - Knowledge of biological sonar systems has revolutionized many aspects of sonar engineering and further advances will benefit from more detailed understanding of their underlying acoustical processes. The anatomically diverse, complex and dynamic heads and ears of bats are known to be important for echolocation although their range-dependent properties are not well understood, particularly across the wide frequency range of some bats' vocalizations. The aim of this and a companion paper Kim et al (2012 Bioinspir. Biomim.) is to investigate bat-head acoustics as a function of bat-target distance, based on measurements up to 100 kHz and more robust examination of hardware characteristics in measurements than previously reported, using a cast of a bat head. In this first paper, we consider the spectral features at either ear (i.e. monaural head-related transfer functions). The results show, for example, that there is both higher magnitude and a stronger effect of distance at close range at relatively low frequencies. This might explain, at least in part, why bats adopt a strategy of changing the frequency range of their vocalizations while approaching a target. There is also potential advantage in the design of bio-inspired receivers of using range dependent HRTFs and utilizing their distinguished frequency characteristics over the distance. PMID- 23093099 TI - A model-based educational intervention to increase physical activity among Iranian adolescents. AB - OBJECTIVE: To conduct an evaluation of an educational program based on the health promotion model (HPM) and stages of change to improve physical activity (PA) behavior among Iranian adolescents. METHODS: This was a group randomized controlled trial with 165 participants in two groups (intervention/control). Data were collected using self-reported questionnaires based upon HPM constructs (benefits and barriers of action, self-efficacy, activity-related affect, interpersonal influences, and situational influences). The stages of change scale was used to select eligible participants (were placed on precontemplation, contemplation, or preparation stages) and to assess the trend. After collecting baseline data, the intervention was administered to the participants and follow up data was collected 3 months after intervention. RESULTS: In all, 88 males and 77 females with a mean age of 13.99+/-0.4 participated in the study. The differences in all HPM constructs, except activity-related affect and social influences, were significant (p < 0.01) between baseline and follow-up measurements. Adolescents in the intervention as compared to the control group were placed in action (70%) or preparation (30%) stages at follow-up. Multiple regression analysis revealed that competing preferences, social norms, role models, (p < 0.001), and commitment to action plan can significantly predict PA behavior. The model accounted for 22.5% of the variance in PA. CONCLUSIONS: The results suggest that educational interventions based on stages of change can have important implications for improving PA among adolescents in more constructs of HPM. PMID- 23093102 TI - Impact of one's own mobile phone in stand-by mode on personal radiofrequency electromagnetic field exposure. AB - When moving around, mobile phones in stand-by mode periodically send data about their positions. The aim of this paper is to evaluate how personal radiofrequency electromagnetic field (RF-EMF) measurements are affected by such location updates. Exposure from a mobile phone handset (uplink) was measured during commuting by using a randomized cross-over study with three different scenarios: disabled mobile phone (reference), an activated dual-band phone and a quad-band phone. In the reference scenario, uplink exposure was highest during train rides (1.19 mW/m(2)) and lowest during car rides in rural areas (0.001 mW/m(2)). In public transports, the impact of one's own mobile phone on personal RF-EMF measurements was not observable because of high background uplink radiation from other people's mobile phone. In a car, uplink exposure with an activated phone was orders of magnitude higher compared with the reference scenario. This study demonstrates that personal RF-EMF exposure is affected by one's own mobile phone in stand-by mode because of its regular location update. Further dosimetric studies should quantify the contribution of location updates to the total RF-EMF exposure in order to clarify whether the duration of mobile phone use, the most common exposure surrogate in the epidemiological RF-EMF research, is actually an adequate exposure proxy. PMID- 23093101 TI - Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico. AB - Exposure to arsenic in drinking water is associated with increased prevalence of diabetes. We previously reported an association of diabetes and urinary concentration of dimethylarsinite (DMAs(III)), a toxic product of arsenic methylation by arsenic (+3 oxidation state) methyltransferase (AS3MT). Here we examine associations between AS3MT polymorphism, arsenic metabolism and diabetes. Fasting blood glucose, oral glucose tolerance and self-reported diagnoses were used to identify diabetic individuals. Inorganic arsenic and its metabolites were measured in urine. Genotyping analysis focused on six polymorphic sites of AS3MT. Individuals with M287T and G4965C polymorphisms had higher levels of urinary DMAs(III) and were more frequently diabetic than the respective wild-type carriers, although the excess was not statistically significant. Odds ratios were 11.4 (95% confidence interval (CI) 2.2-58.8) and 8.8 (95% CI 1.6-47.3) for the combined effects of arsenic exposure >75th percentile and 287T and 4965C genotypes, respectively. Carriers of 287T and 4965C may produce more DMAs(III) and be more likely to develop diabetes when exposed to arsenic. PMID- 23093103 TI - Factors affecting the quality of bottled water. AB - The ever-increasing popularity of bottled water means that it is important to analyze not only its mineral content but also, above all, its content of possible contaminants, especially the organic ones. In this respect, bottled waters are a special case, because apart from organic chemical contaminants derived from the well from which they were acquired, their secondary contamination is always possible, during treatment or storage or transport in unsuitable conditions (sunlight and elevated temperature). This paper describes how various factors, from the area around the well, and the method of drawing and treating water, to the manner in which the finished product is stored and transported may affect the quality of bottled waters. It also summarizes literature information on the levels of organic contaminants in various kinds of bottled water samples. PMID- 23093104 TI - Extermination strategies reported in the NYC Health and Nutrition Examination Survey, 2004: prevalence and predictors. AB - It is likely that household extermination is a major source of pesticide exposure for urban residents. Little is known about the predictors of residential pest control strategies in urban areas, and greater knowledge of these may help identify who is at risk for higher pesticide exposure. Study data is from the 2004 NYC Health and Nutrition Examination Surveys, a cross-sectional, population based study using a three-stage sampling scheme. Logistic regression was used to identify predictors of pesticide use overall, and of application strategy: (1) consumer-applied pesticides only, (2) use of a professional exterminator only, or (3) use of both. Consumer-applied extermination was more prevalent than professional or both professional and consumer (39.9% versus 27.8% and 15.9%, respectively, and non-exclusively). In multivariate models among those who used any extermination, consumer application was associated with age 60 years+, being black or Asian, and being widowed, divorced, or single. Lower income households were more likely to use both strategies, and less likely to use professional extermination only. Urban residents may benefit from targeted education on how and when to self-apply pesticides, and on best-practice pest control to avoid unnecessary pesticide exposure. Higher prevalence of consumer-applied and conjoint consumer and professionally applied extermination in low-income households may reflect both economic determinants of first recourse and higher neighborhood infestation levels. PMID- 23093105 TI - Association of PBEF gene polymorphisms with acute lung injury, sepsis, and pneumonia in a northeastern Chinese population. AB - BACKGROUND: Several studies have suggested that pre-B-cell colony-enhancing factor (PBEF) gene polymorphisms are associated with susceptibility to and prognosis of acute lung injury (ALI) in several populations of Caucasians. The aim of this study was to detect the distribution of PBEF alleles and to evaluate any potential relationship between PBEF polymorphisms and ALI, sepsis, and pneumonia in the Han population of Northeast China. METHODS: Genotyping of two PBEF promoter single-nucleotide polymorphisms (SNPs), rs61330082 (C-1535T) and rs9770242 (T-1001G), were performed in patients with ALI (n=130), sepsis alone (n=107), bacterial pneumonia (n=195) and 150 healthy volunteers using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: We found no variation in the T-1001G allele of PBEF. The homozygous TT genotype was the only genotype. This result is different from that observed in Caucasians. The frequency of the -1543T allele was lower in patients with ALI and sepsis than that in healthy subjects ALI vs. healthy controls: OR=0.60, 95% CI 0.43-0.84, p=0.003; and sepsis vs. healthy controls: OR=0.69, 95% CI 0.49-0.99, p=0.04, respectively). The frequency of TT genotype of -1543T was significantly lower in patients with ALI and sepsis than in healthy subjects (ALI vs. healthy controls: OR=0.23, 95% CI 0.10-0.54, p=0.001; and sepsis vs. healthy controls: OR=0.36, 95% CI 0.15-0.83, p=0.02, respectively). CONCLUSIONS: This study suggested that -1543T allele might be a protective factor for ALI and sepsis, but it apparently had no connection with pneumonia in northeastern Chinese Han patients. PMID- 23093106 TI - Detection of frequent ABCB1 polymorphisms by high-resolution melting curve analysis and their effect on breast carcinoma prognosis. AB - BACKGROUND: The ABCB1 gene encodes P-glycoprotein implicated in the development of cellular drug resistance. The aim of this study was to develop high-resolution melting (HRM) analysis for determination of ABCB1 polymorphisms and evaluate their associations with clinical data of breast carcinoma patients. METHODS: HRM analysis was designed to assess five single nucleotide polymorphisms (SNPs) in ABCB1 (rs2214102, rs1128503, rs2032582, rs2032583 and rs1045642) in genomic DNA from 103 breast carcinoma patients. Results were confirmed by direct DNA sequencing. RESULTS: HRM analysis revealed distinct patterns of melting curves for the respective genotypes of all followed SNPs. Sensitivity of HRM analysis compared with direct DNA sequencing was superior (97.1% vs. 93.9%). The overall accuracy of HRM was 97.6%. The coefficients of variation in replicate experiments encompassed the range 0.002%-0.038%. On the basis of the examined SNPs, one strong haplotype block containing rs2032582 and rs1128503 SNPs was identified. Significant associations of rs2032582 SNP with tumor size, negative HER-2/neu status, and family history of breast carcinoma were found. Patients carrying the ancestral homozygous genotype (GG) in rs2214102 had significantly worse progression-free survival in comparison with carriers of the non-ancestral allele (A) in the adjuvant set (p=0.005). CONCLUSIONS: A rapid, accurate, low-cost and time-effective method for screening ABCB1 SNPs was developed. Significant associations of ABCB1 rs2032582 and rs2214102 SNPs with prognostic factors and survival of patients were found. PMID- 23093107 TI - Far-red to near infrared analyte-responsive fluorescent probes based on organic fluorophore platforms for fluorescence imaging. AB - The long wavelength (far-red to NIR) analyte-responsive fluorescent probes are advantageous for in vivo bioimaging because of minimum photo-damage to biological samples, deep tissue penetration, and minimum interference from background auto fluorescence by biomolecules in the living systems. Thus, great interest in the development of new long wavelength analyte-responsive fluorescent probes has emerged in recent years. This review highlights the advances in the development of far-red to NIR fluorescent probes since 2000, and the probes are classified according to their organic dye platforms into various categories, including cyanines, rhodamine analogues, BODIPYs, squaraines, and other types (240 references). PMID- 23093108 TI - On the unzipping of multiwalled carbon nanotubes. AB - Graphene nanoribbons (GNRs) are very interesting structures which can retain graphene's high carrier mobility while presenting a finite bandgap. These properties make GNRs very valuable materials for the building of nanodevices. Unzipping carbon nanotubes (CNTs) is considered one of the most promising approaches for GNR controlled and large-scale production, although some of the details of the CNT unzipping processes are not completely known. In this work we have investigated CNT unzipping processes through fully atomistic molecular dynamics simulations using reactive force fields (ReaxFF). Multiwalled CNTs of different dimensions and chiralities under induced mechanical stretching were considered. Our results show that fracture patterns and stress profiles are highly CNT chirality dependent. Our results also show that the 'crests' (partially unzipped CNT regions presenting high curvature), originating from defective CNT areas, can act as a guide for the unzipping processes, which can explain the almost perfectly linear cuts frequently observed in unzipped CNTs. PMID- 23093109 TI - Colorectal carcinoma grading by quantifying poorly differentiated cell clusters is more reproducible and provides more robust prognostic information than conventional grading. AB - The most widely used system to define the histological grade of colorectal carcinoma (CRC) is based on the degree of gland formation. This system suffers from significant interobserver variability which may limit its prognostic value and consequently better standardized criteria for the assessment of histological grading of CRC are needed. The present study aims to evaluate and to compare, in a cohort of postsurgical pTNM stage I CRC, conventional histological grading, and a novel grading system based on the number of poorly differentiated clusters of neoplastic cells, in terms of interobserver reproducibility, prognostic significance on progression-free survival, and association with other clinicopathological characteristics. Grading with both systems was performed by two pathologists independently and blinded to the clinicopathological data. Interobserver agreement was higher when grade was assessed by counting poorly differentiated clusters than by assessing the relative proportion of the glandular component. Contrary to conventional grading, the novel system provided significant prognostic information in terms of progression-free survival and was significantly associated with budding, invasive growth, lymphatic invasion, and occult nodal metastases of CRC. In conclusion, our findings suggest that a tumor grading system based on the number of poorly differentiated clusters is more reproducible and provides better prognostic stratification of pTNM stage I CRC patients than conventional grading. PMID- 23093110 TI - CK19 testing prior to OSNA analysis: to stain or not to stain? PMID- 23093111 TI - Highly selective CD44-specific gold nanorods for photothermal ablation of tumorigenic subpopulations generated in MCF7 mammospheres. AB - Heterogeneous stem-like populations within tumor tissues are the primary suspects in causing cancer recurrence and malignancy. It is essential to selectively kill these tumorigenic populations. We created a novel system for photothermally ablating specific cells from three-dimensional mammospheres. A CD44-positive subpopulation, with tumorigenic and self-renewal potential, spontaneously arises in MCF7 breast cancer cell-engineered mammospheres. Using anti-CD44 antibody linked gold nanorods, which strongly absorb near infrared light and increase local temperature, we effectively targeted and photo-ablated atypical cells. This biomarker-specific photothermal ablation model, using a smart nanoplatform, is a promising new strategy for selectively killing cancer cells, while sparing normal tissues. PMID- 23093113 TI - Accurate evaluation of the resonance energies of benzene and pyridine via cyclic reference state. AB - In an attempt to eliminate the stoichiometric arbitrariness in the evaluation of the resonance energy we use benzene and pyridine as an example to illustrate a unique thermodynamic way the resonance energy may and should be evaluated. In doing this, we employ a complete set of possible cyclic reference species and a Tatevski type group additivity model. Three different methods used to evaluate the resonance energies of benzene and pyridine were shown to be identical thus proving the uniqueness of the solution. Based on high level coupled-cluster (estimated CCSD(T)/CBS) computations it was concluded that benzene is more aromatic/stable than pyridine by 2.2 kcal mol(-1). PMID- 23093112 TI - Imaging analysis of neuron to glia interaction in microfluidic culture platform (MCP)-based neuronal axon and glia co-culture system. AB - Proper neuron to glia interaction is critical to physiological function of the central nervous system (CNS). This bidirectional communication is sophisticatedly mediated by specific signaling pathways between neuron and glia(1,2) . Identification and characterization of these signaling pathways is essential to the understanding of how neuron to glia interaction shapes CNS physiology. Previously, neuron and glia mixed cultures have been widely utilized for testing and characterizing signaling pathways between neuron and glia. What we have learned from these preparations and other in vivo tools, however, has suggested that mutual signaling between neuron and glia often occurred in specific compartments within neurons (i.e., axon, dendrite, or soma)(3). This makes it important to develop a new culture system that allows separation of neuronal compartments and specifically examines the interaction between glia and neuronal axons/dendrites. In addition, the conventional mixed culture system is not capable of differentiating the soluble factors and direct membrane contact signals between neuron and glia. Furthermore, the large quantity of neurons and glial cells in the conventional co-culture system lacks the resolution necessary to observe the interaction between a single axon and a glial cell. In this study, we describe a novel axon and glia co-culture system with the use of a microfluidic culture platform (MCP). In this co-culture system, neurons and glial cells are cultured in two separate chambers that are connected through multiple central channels. In this microfluidic culture platform, only neuronal processes (especially axons) can enter the glial side through the central channels. In combination with powerful fluorescent protein labeling, this system allows direct examination of signaling pathways between axonal/dendritic and glial interactions, such as axon-mediated transcriptional regulation in glia, glia mediated receptor trafficking in neuronal terminals, and glia-mediated axon growth. The narrow diameter of the chamber also significantly prohibits the flow of the neuron-enriched medium into the glial chamber, facilitating probing of the direct membrane-protein interaction between axons/dendrites and glial surfaces. PMID- 23093114 TI - Percutaneous reduction and screw fixation of fracture neck talus. AB - BACKGROUND: Fracture neck talus is a rare fracture represents about 1% of all fractures and usually due to high energy trauma. These fractures are usually associated with compromised soft tissues, concomitant skeletal fractures, or life threatening injuries. Talus has a tenuous blood supply which is affected by fracture displacement. Urgent fracture reduction+/-fracture fixation is mandatory. The associated injuries may make the conventional open reduction and internal fixation is impossible to be done in urgent base as it may impacts the already tenuous blood supply of talus increasing the risk of AVN and non union. Percutaneous fracture reduction and fixation can overcome this problem, and decrease complications associated with conventional open reduction and internal fixation. MATERIALS AND METHODS: Between 2006 and 2008, 16 patients with talar neck fractures were operated on by percutaneous reduction of fracture and percutaneous fixation with 3.5mm cannulated screws. Injuries were classified according to modified Hawkins classification system. Patients were followed up over an average of 48 months. RESULTS: 87.5% of the patients were satisfied and resumed their preoperative activities. The mean AOFAS Hind Foot Scale was 89.25 points (range: 74-100) and no poor outcomes. CONCLUSION: Although the number of patients in this study is small, the results showed that, percutaneous reduction and fixation is a good treatment modality in treatment of fracture neck talus, especially in cases with increased risk of soft tissue complications and open reduction should be resort only when percutaneous reduction was failed. PMID- 23093115 TI - Treatment of dynamic claw toe deformity flexor digitorum brevis tendon transfer to interosseous and lumbrical muscles: a literature survey. AB - The authors report the results of a literature survey of corrective surgical treatment based on FDL and FDB tendon transfer for dynamic claw toe deformities. The study revealed that FDL transfer was first described in 1967 by Malcolm A. Brahms in "Common Foot Problems", and FDB transfer was first mentioned in 1993 in the first edition of the treatise by G. Pisani "Trattato di Chirurgia del Piede". The paper also discusses the functional effect of FDB transfer, compared to FDL transfer. PMID- 23093116 TI - Controversies regarding radiological changes and variables predicting amputation in a surgical series of diabetic foot osteomyelitis. AB - BACKGROUND: To investigate if radiological changes have any influence on the outcomes of surgical treatment of diabetic foot osteomyelitis. METHODS: Data of patients included in a prospective cohort who underwent surgical treatment for definitive osteomyelitis were analyzed. Cases were classified according to radiological changes as "early osteomyelitis" when no radiological changes were found or in cases showing periosteal elevation and/or subcortical demineralization and/or cortical disruption. Cases showing sequestra and/or gross bone destruction were classified as "advanced osteomyelitis". RESULTS: Early osteomyelitis was defined according to radiological findings in 37 cases (45.7%) and advanced in 44 (54.3%). Advanced osteomyelitis was not associated with the risk of undergoing amputation. CONCLUSIONS: The bone changes seen in simple X rays in cases of osteomyelitis do not have any prognostic value when surgical treatment is undertaken. The outcomes are more related to soft tissue involvement than bone destruction seen in simple X-rays. PMID- 23093117 TI - Hypermobility of the first ray in patients with planovalgus feet and tarsometatarsal osteoarthritis. AB - BACKGROUND: Hypermobility in the foot is a common observation but difficult to quantify. Primary tarsometatarsal arthritis is less common and its aetiology uncertain. This study introduces a novel means of clinical measurement for range of motion of the medial column and investigates the association between hypermobility, planovalgus foot shape and tarsometatarsal arthritis. METHOD: 32 planovalgus feet with symptomatic tarsometatarsal arthritis were compared with 36 controls. Radiographic angular measurements and arthritic grade were recorded from standing radiographs. Medial column flexion and extension was measured clinically using a validated electronic goniometer. RESULTS: There was a significant difference in medial column range of motion between the patient and control groups (17+/-5 degrees compared to 9+/-3 degrees [P<0.001]). CONCLUSION: Patients with planovalgus feet and tarsometatarsal osteoarthritis have greater range of motion of the medial column than controls with normal feet when measured using this technique. Recognition of this association may lead to progress in prevention and treatment. PMID- 23093118 TI - Touch pressure and sensory density after tarsal tunnel release in diabetic neuropathy. AB - BACKGROUND: Limited quantitative information is available about the improvement of protective sensation after tarsal tunnel release in patients with diabetic peripheral neuropathy. METHODS: Prospective, non-blinded, non-randomized case series of 10 feet in 8 diabetic patients and 24 feet in 22 non-diabetic patients who had tarsal tunnel release. Preoperative and postoperative (average, 8-9 months) anatomic, quantitative sensory testing was done with touch pressure 1 point threshold (Semmes-Weinstein monofilaments) and 2-point discrimination. RESULTS: There was marked, significant postoperative improvement of mean touch pressure 1-point threshold, compared with preoperative values, for medial calcaneal, medial plantar, and lateral plantar nerves in both non-diabetic and diabetic patients. There was minimal improvement in 2-point discrimination only for the medial calcaneal nerve in non-diabetic, but not in diabetic, patients. CONCLUSIONS: Nerve entrapment at the tarsal tunnel is an important component of diabetic peripheral neuropathy. Tarsal tunnel decompression may improve sensory impairment and restore protective sensation. PMID- 23093119 TI - Four-stage regimen for operative treatment of diabetic foot ulcer with deformity a results of 300 patients. AB - BACKGROUND: An operative four-stage regimen (stage 1, debridement; stage 2, closure; stage 3, unloading; stage 4, correction) for operative treatment of diabetic foot ulcer with deformity, and first clinical results are introduced. METHODS AND RESULTS: 335 patients entered stage 1 between 01/09/2006 and 31/08/2010. Stage 1: In 189 cases (56%), one debridement resulted in sterile postoperative specimens. Stage 2: 210 cases (63%) sustained secondary closure, 97 (29%) local shifted skin graft, and 20 (6%) functional amputation. Stage 3: 304 (90%) finished stage 3, 14 (4%) presented with recurrent ulcer. Stage 4: In 185 cases (55%), correction arthrodeses were performed successfully. FOLLOW-UP: 300 (90%) completed follow-up at 26months on average (12-48months). Recurrent ulcer was registered in 46 (15%). Overall amputation rate was 14%, the majority at digital or midfoot level. Four cases (1%) required a below-knee amputation. CONCLUSIONS: The management of diabetic foot ulcer combined with deformity with the introduced regimen showed low major amputation rate and low recurrent ulcer rate compared with the literature. PMID- 23093120 TI - Midfoot arthritis: diagnosis and treatment. AB - BACKGROUND: Midfoot arthritis is a challenging problem causing chronic foot pain and impeding daily activity. There is not much written about this subject in literature and is often not well known by orthopaedic surgeons. The primary aim of treatment is to afford pain relief by enhancing midfoot stability and modifying loads sustained at the inflamed joints. The initial treatment is conservative with inserts and orthoses. Surgery, more specifically midfoot arthrodesis, is the next step when conservative management fails. The arthrodesis should be limited to the symptomatic joints but it is often difficult to determine which joints cause the symptoms. With this manuscript we would like to underline the importance of a precise anatomic preoperative diagnosis, review our surgical experience and discuss the different surgical fixation possibilities in midfoot arthrodesis. METHODS: Between 2006 and 2011 24 patients (26 feet) with midfoot osteoarthritis underwent selective arthrodesis after conservative management had failed. Preoperative examinations, fixation method, complications and outcome were noted. RESULTS: We achieved union in 25 feet. There was one delayed union and one non-union. There were no infections but 3 patients had chronic regional pain syndrome. Reoperation was required in one foot because of non-union and one for symptomatic hardware removal. CONCLUSION: Midfoot arthrodesis is an effective treatment for osteoarthritis of the joint. Identification of the affected joints is important to stipulate the extensiveness of the arthrodesis. PMID- 23093121 TI - How many joints does the 5th toe have? A review of 606 patients of 655 foot radiographs. AB - BACKGROUND: It is a common understanding that the fifth toe has three bones with two interphalangeal joints. However, our experience shows that a significant number have only two phalanges with one interphalangeal joint. METHODS: We identified 676 patients listed as having had a foot radiograph, during an eight week period, of which 606 radiographs were available for the assessment. The radiographs were then assessed counting the number of phalanges in the fifth toe. RESULTS: The patients consisted of 344 females and 262 males. Bilateral radiographs had been performed in 49 patients. 362 radiographs (55.3%) were found to have 3 phalanges in their 5th toe, with 291 (44.4%) having only two phalanges. CONCLUSIONS: We have demonstrated the presence of two phalanges is a common anatomical variant. This finding has clinical implications with regard to the treatment of deformities of the fifth toe and the type of internal fixation device used. PMID- 23093122 TI - Arthroscopic resection of calcaneonavicular coalition/malunion via a modified sinus tarsi approach: an early case series. AB - BACKGROUND: Calcaneonavicular coalition represents abnormal coalescence between calcaneus and navicular bone. It is a congenital anomaly, sometimes becoming symptomatic in young adolescent. This is managed conservatively initially, failing which surgical excision, open or arthroscopic, is considered. We present our arthroscopic technique via a modified sinus tarsi approach, with early results in two adolescent and two young adult patients. METHOD: The patient is placed in a 45 degrees "saggy" lateral position, and entry points for portals are marked around sinus tarsi area. The adequacy of resection is checked with image intensifier at the end of procedure. Patients complete subjective scoring forms, Manchester-Oxford Foot Questionnaire and Visual Analogue Scale, pre operatively and at follow-ups. Paired t test was performed to assess statistical significance. RESULTS: The results of early follow-up of these patients have confirmed complete excision, non-recurrence and symptomatic improvement. The mean difference in MOXFQ scores pre and post surgery is 39.33, with a two-tailed p value of 0.0187. Similarly, the mean difference in VAS score is 5.67 with a two tailed p value of 0.0034. These are statistically significant and confirm symptomatic improvement at an early follow-up. CONCLUSION: The arthroscopic technique provides better access allowing wide excision and causes minimal soft tissue trauma leading to early recovery and mobilisation. PMID- 23093123 TI - A functional outcome study comparing total ankle arthroplasty (TAA) subjects with pain to subjects with absent level of pain by means of videofluoroscopy. AB - BACKGROUND: Total ankle arthroplasty (TAA) subjects often suffer pain on the anteromedial side of their ankle joint. Whether this prevalent pain is caused by a changed motion pattern of the TAA is unclear. Therefore, this study assessed the kinematic differences in the motion of the TAA components during gait, comparing TAA subjects with elevated versus absent levels of pain. METHODS: Eleven TAA subjects (5 with pain vs. 6 without pain), all with unilateral MobilityTM TAA and at least two years post-operation, were recruited and stratified based on standard clinical assessed patient data. The 3D motion of the TAA was assessed by means of videofluoroscopy during level, uphill and downhill walking. RESULTS: The hypothesis that the pain group shows a different kinematic motion pattern than the no pain group could not be confirmed. CONCLUSIONS: The same kinematic motion pattern causes pain in some patients, but not in others. Further investigation concerning ligament stresses is needed. PMID- 23093124 TI - Primary bone tumours of the talus: the Scottish Bone Tumour Registry experience. AB - BACKGROUND: Primary bone tumours of the talus are rare and the existing literature is limited. The aim of this study was to investigate the epidemiology of primary bone tumours affecting this uncommon site and suggest a management protocol for these tumours. METHODS: We retrospectively reviewed the Scottish Bone Tumour Register from January 1954 to May 2010 and included all primary bone tumours of the talus. RESULTS: We identified only twenty three bone tumours over fifty six years highlighting the rarity of these tumours. There were twenty benign and three malignant tumours with a mean age of twenty eight years. A delay in presentation was common with a mean time from onset of symptoms to diagnosis of ten months. CONCLUSIONS: Tumour types identified were consistent with previous literature. We identified cases of desmoplastic fibroma and intraosseous lipodystrophy described for the first time. We suggest an investigatory and treatment protocol for patients with a suspected primary bone tumour of the talus. PMID- 23093125 TI - Effect of a preventive foot care program on lower extremity complications in diabetic patients with end-stage renal disease. AB - BACKGROUND: Lower extremity complications are a major cause of morbidity and mortality in patients with end-stage renal disease (ESRD) and diabetes mellitus. Patient education programs may decrease the risk of diabetic foot complications. METHODS: A preventive program was instituted, consisting of regular assessments by a foot care nurse with expertise in foot care and wound management and patient education about foot care practices and footwear selection. Medical records were reviewed and patients were examined. A comparison was made with data about patients from a previous study done from this institution prior to development of the foot care program. RESULTS: Diabetic subjects more frequently had weakness of the left tibialis anterior, left tibialis posterior, and left peroneal muscles than non-diabetic subjects. A smaller percentage of diabetic subjects had sensory neuropathy compared with the previous study from 5years earlier, but a greater percentage of diabetic subjects had absent pedal pulses in the current study. The frequency of inadequate or poor quality footwear was less in the current study compared with the previous study. CONCLUSIONS: The current data suggest that a foot care program consisting of nursing assessments and patient education may be associated with a decrease in frequency of neuropathy and improved footwear adequacy in diabetic patients with ESRD. PMID- 23093126 TI - Open technique is more effective than percutaneous technique for TOPAZ radiofrequency coblation for plantar fasciitis. AB - BACKGROUND: Microtenotomy coblation using a radiofrequency (RF) probe is a minimally invasive procedure for treating chronic tendinopathy. It has been described for conditions including tennis elbow and rotator cuff tendinitis. There have been no long term studies to show its effectiveness in plantar fasciitis. METHODS: A prospective non-randomised trial was conducted on 48 patients who had failed conservative treatment for plantar fasciitis, between 2007 and 2009. The procedure was performed using the TOPAZ microdebrider device (ArthroCare, Sunnyvale, CA), either via an open or a percutaneous method. Fifty nine feet were treated and followed up for up to 1 year thereafter. Preoperative, 3, 6 and 12 months post-operative VAS pain, American Orthopaedic Foot-Ankle Society (AOFAS) hindfoot and SF-36 scores, patient expectation and satisfaction scores were analysed. RESULTS: VAS scores improved significantly in both groups at 1-year follow-up. The open group had a more significant improvement in the VAS score at 1-year follow-up. AOFAS hindfoot scores improve significantly for both groups pre- and post-operatively, but there was no significant difference between both groups at the 1-year mark. SF-36 scores showed equally significant improvement in both groups 1 year post-operatively. Expectation and satisfaction scores were equally high in both arms. CONCLUSIONS: TOPAZ RF coblation is a good and effective method for the treatment of recalcitrant plantar fasciitis. Clinical results improve with time for up to 1-year post-operatively. The open method seems to have a more significant improvement in pain VAS scores at 1-year postoperatively. PMID- 23093127 TI - Variations in the insertion of peroneus longus tendon-a cadaver study. AB - BACKGROUND: The insertion of peroneus longus is traditionally described to the plantar surface of the 1st cuneiform and 1st metatarsal. It is thought to be the main contributor to the plantarflexed first ray seen in cavus feet. METHODS: We studied the insertion of peroneus longus in 26 feet from 14 adult cadavers. The insertional points, presence of sesamoid bone and variations in insertion were noted. RESULTS: The main insertion was to the base of the 1st metatarsal and the medial cuneiform in the majority of feet but variations were observed. A sesamoid bone was present within the tendon under the cuboid in 16 feet, 12 of which had additional lateral insertion bands. CONCLUSIONS: Variations in the insertion of peroneus longus were found and we have described two new lateral bands. PMID- 23093128 TI - Use of a fenestrated instrument tray intraoperatively allows assessment of plantar contact areas and percutaneous fixation without losing deformity correction. PMID- 23093130 TI - Hawkins's classification of the lateral process fractures of the talus: a letter to the editor. PMID- 23093131 TI - Efficient synthesis of oxazoles by dirhodium(II)-catalyzed reactions of styryl diazoacetate with oximes. AB - An efficient one-step synthesis of multi-functionalized oxazole derivatives is achieved in high yield by dirhodium(II)-catalyzed reactions of styryl diazoacetate with aryl oximes. PMID- 23093132 TI - Spectral-domain optical coherence tomography as a noninvasive method to assess damaged and regenerating adult zebrafish retinas. PMID- 23093133 TI - Low-level laser therapy in meniscal pathology: a double-blinded placebo controlled trial. AB - We performed a randomized, double-blinded, placebo-controlled study (ISRCTN24203769) to assess the effectiveness of low-level laser therapy (LLLT) in patients with meniscal pathology, including only symptomatic patients with tiny focus of grade 3 attenuation (seen only on 0.7 thickness sequences) or intrasubstance tears with spot of grade 3 signal intensity approaching the articular surface. None of the patients in the study group underwent arthroscopy or new magnetic resonance imaging investigation. Paired-samples t test was used to detect significant changes in subjective knee pain over the experimental period within groups, and ANOVA was used to detect any significant differences between the two groups. Pain was significantly improved for the LLLT group than for the placebo group (F = 154, p < 0.0001). Pain scores were significantly better after LLLT. Four (12.5 %) patients did not respond to LLLT. At baseline, the average Lysholm score was 77 +/- 4.6 for the LLLT group and 77.2 +/- 2.6 for the placebo group (p > 0.05). Four weeks after LLLT or placebo therapy, the laser group reported an average Lysholm score of 82.5 +/- 4.6, and the placebo group scored 79.0 +/- 1.9. At 6 months, the laser group had an average Lysholm score of 82.2 +/- 5.7, and after 1 year, they scored 81.6 +/- 6.6 (F = 14.82923, p = 0.002). Treatment with LLLT was associated with a significant decrease of symptoms compared to the placebo group: it should be considered in patients with meniscal tears who do not wish to undergo surgery. PMID- 23093135 TI - Facile and rapid synthesis of RGO-In2S3 composites with enhanced cyclability and high capacity for lithium storage. AB - A sheet-on-sheet reduced graphene oxide-beta-In(2)S(3) (RGO-In(2)S(3)) composite, was successfully synthesized via a one-step mild method. This fresh composite used as an anode material exhibits enhanced cyclability and specific capacity for lithium storage. These results are linked with the intrinsic layered structure of beta-In(2)S(3) sheets and the effective combination of beta-In(2)S(3) and RGO sheets. This results in a high specific surface area and good conductivity of RGO In(2)S(3) composites, with higher transport rates of electrolyte ions and electrons, and a more effective electrochemical reaction of the active material. This facile and rapid synthesis method is a promising route for a large-scale production of graphene-based metal sulfides, which could be used as electrode materials for Li-ion batteries. PMID- 23093134 TI - Lasers for cutaneous congenital vascular lesions: a comprehensive overview and update. AB - The use of laser to treat cutaneous lesions began with Dr. Leon Goldman and his coworkers in 1963. Ten years later, these authors described promising effects on angiomas using the continuous-wave neodymium:yttrium-aluminum-garnet laser. In 1983, Anderson et al. proposed the photothermolysis theory. The selective destruction of vascular lesions is based on this principle, and it is still a guide for treatment of vascular lesions. Over the past 25 years, laser treatment of cutaneous vascular lesions has progressed significantly. Vascular lasers such as argon, tunable dye, krypton, and copper vapor were used in the past and were associated not only with risk of scarring but also hyper- and hypopigmentation. Since then, new devices were developed in order to minimize these side effects. This article presents an overview and update of the current available treatment of cutaneous vascular lesions and covers future directions for vascular laser technology. PMID- 23093136 TI - Improved lifestyle and decreased diabetes risk over 13 years: long-term follow-up of the randomised Finnish Diabetes Prevention Study (DPS). AB - AIMS/HYPOTHESIS: This study aimed to determine whether lifestyle intervention lasting for 4 years affected diabetes incidence, body weight, glycaemia or lifestyle over 13 years among individuals at high risk of type 2 diabetes. METHODS: Overweight, middle-aged men (n = 172) and women (n = 350) with impaired glucose tolerance were randomised in 1993-1998 to an intensive lifestyle intervention group (n = 265), aiming at weight reduction, dietary modification and increased physical activity, or to a control group (n = 257) that received general lifestyle information. The primary outcome was a diagnosis of diabetes based on annual OGTTs. Secondary outcomes included changes in body weight, glycaemia, physical activity and diet. After active intervention (median 4 years, range 1-6 years), participants still free of diabetes and willing to continue their participation (200 in the intervention group and 166 in the control group) were further followed until diabetes diagnosis, dropout or the end of 2009, with a median total follow-up of 9 years and a time span of 13 years from baseline. RESULTS: During the total follow-up the adjusted HR for diabetes (intervention group vs control group) was 0.614 (95% CI 0.478, 0.789; p < 0.001). The corresponding HR during the post-intervention follow-up was 0.672 (95% CI 0.477, 0.947; p = 0.023). The former intervention group participants sustained lower absolute levels of body weight, fasting and 2 h plasma glucose and a healthier diet. Adherence to lifestyle changes during the intervention period predicted greater risk reduction during the total follow-up. CONCLUSIONS/INTERPRETATION: Lifestyle intervention in people at high risk of type 2 diabetes induces sustaining lifestyle change and results in long-term prevention of progression to type 2 diabetes. PMID- 23093138 TI - Does EMLA cream application interfere with the success of venipuncture or venous cannulation? A prospective multicenter observational study. AB - Venipuncture and intravenous cannulation are the most common painful procedures performed on children. The most widely used topical anesthetic is eutectic mixture of local anesthetics (EMLA). EMLA use is associated with a transient cutaneous vasoconstriction which can make it difficult to identify veins. We assessed with a prospective, multicenter, observational study whether EMLA interferes with venipuncture and intravenous cannulation. The primary study outcome was a success at first attempt in the course of venipuncture or venous cannulation. The study enrolled 388 children; 255 of them received EMLA and 133 did not. Eighty-six percent of procedures were successful at the first attempt in the EMLA group and 76.7 % in the no EMLA group. CONCLUSION: In this study, EMLA use did not interfere with the success of venipuncture or venous cannulation in children. PMID- 23093139 TI - Infantile loss of teeth: odontohypophosphatasia or childhood hypophosphatasia. AB - Hypophosphatasia is a hereditary disorder characterized by a deficiency of serum and bone alkaline phosphatase (ALP) activity and defective skeletal mineralization. It is caused by a loss of function mutations in the tissue nonspecific ALP gene (TNSALP) encoding the tissue nonspecific alkaline phosphatase. A 4-year-and-8-month-old girl presented with premature exfoliation of the anterior incisors and canines. Very low ALP level (27 IU/ml) suggested the diagnosis of hypophosphatasia, which was supported by an elevated urine phosphoethanolamine/Cr of 84 MUmol/mmol (reference range, <25 MUmol/mmol) and serum pyridoxal-5'-phosphate of 393 MUg/L (reference range, 3.6-18 MUg/L). The phenotype of the patient was subsequently classified as mild childhood hypophosphatasia. TNSALP gene sequencing revealed the homozygous c.382 G > A (p.V128M) mutation. This mutation was previously observed in a series of patients with severe hypophosphatasia, pointing out the possible role of other genetic or environmental factors in the modulation of the hypophosphatasia phenotype. PMID- 23093141 TI - Range dependent characteristics in the head-related transfer functions of a bat head cast: part 2. Binaural characteristics. AB - Further innovations in bio-inspired engineering based on biosonar systems, such as bats, may arise from more detailed understanding of the underlying acoustic processes. This includes the range-dependent properties of bat heads and ears, particularly at the higher frequencies of bat vocalizations. In a companion paper Kim et al (2012 Bioinspir. Biomim.), range-dependent head-related transfer functions of a bat head cast were investigated up to 100 kHz at either ear (i.e. monaural features). The current paper extends this to consider range-dependent spectral and temporal disparities between the two ears (i.e. binaural features), using experimental data and a spherical model of a bat head to provide insights into the physical basis for these features. It was found that binaural temporal and high-frequency binaural spectral features are approximately independent of distance, having the effect of decreasing their angular resolution at close range. In contrast, low-frequency binaural spectral features are strongly distance-dependent, such that angular sensitivity can be maintained by lowering the frequency of the echolocation emission at close range. Together with the companion paper Kim et al, we speculate that distance-dependent low-frequency monaural and binaural features at short range might help explain why some species of bats that drop the frequency of their calls on target approach while approaching a target. This also provides an impetus for the design of effective emissions in sonar engineering applied to similar tasks. PMID- 23093140 TI - New hospital-based policy for children whose parents present at the ER due to domestic violence, substance abuse and/or a suicide attempt. AB - Child maltreatment is a major social problem with many adverse consequences, and a substantial number of maltreated children are not identified by health care professionals. In 2010, in order to improve the identification of maltreated children in hospitals, a new hospital-based policy was developed in Amsterdam, The Netherlands. This policy was adapted from another policy that was developed in The Hague, the Netherlands, in 2007. In the new Amsterdam policy, all adults presenting at the emergency department due to domestic violence, substance abuse, and/or a suicide attempt are asked whether they have any children in their care. If this is the case, parents are urged to visit the outpatient pediatric department together with all of their children. During this visit, problems are evaluated and voluntary referrals can be arranged to different care organizations. If parents refuse to cooperate, their children are reported to the Dutch Child Abuse Counseling and Reporting Centre. The two aims of this study are to describe (1) characteristics of the identified families and (2) the referrals made to different voluntary and involuntary care organizations during the first 2 years after implementation of the policy. Data were collected from medical records. One hundred and six children from 60 households were included, of which 68 children because their mother was a victim of domestic violence. Referrals to care organizations were arranged for 99 children, of which 67 on a voluntary basis. The Amsterdam policy seems successful in arranging voluntary support for the majority of identified children. PMID- 23093144 TI - The cover. Yellow dance. PMID- 23093147 TI - Hospitals slash central line infections with program that empowers nurses. PMID- 23093148 TI - Young adult cancer survivors face barriers to receiving primary care. PMID- 23093155 TI - Treatment with interferon beta for multiple sclerosis. PMID- 23093157 TI - Requirement to purchase health insurance. PMID- 23093159 TI - A prognostic assay to identify patients at high risk of mortality despite small, node-negative lung tumors. PMID- 23093160 TI - Choosing wisely: low-value services, utilization, and patient cost sharing. PMID- 23093161 TI - What's needed is a health care system that learns: recommendations from an IOM report. PMID- 23093162 TI - A piece of my mind. Cancer survivorship and beyond. PMID- 23093163 TI - Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. AB - CONTEXT: Lung-protective mechanical ventilation with the use of lower tidal volumes has been found to improve outcomes of patients with acute respiratory distress syndrome (ARDS). It has been suggested that use of lower tidal volumes also benefits patients who do not have ARDS. OBJECTIVE: To determine whether use of lower tidal volumes is associated with improved outcomes of patients receiving ventilation who do not have ARDS. DATA SOURCES: MEDLINE, CINAHL, Web of Science, and Cochrane Central Register of Controlled Trials up to August 2012. STUDY SELECTION: Eligible studies evaluated use of lower vs higher tidal volumes in patients without ARDS at onset of mechanical ventilation and reported lung injury development, overall mortality, pulmonary infection, atelectasis, and biochemical alterations. DATA EXTRACTION: Three reviewers extracted data on study characteristics, methods, and outcomes. Disagreement was resolved by consensus. DATA SYNTHESIS: Twenty articles (2822 participants) were included. Meta-analysis using a fixed-effects model showed a decrease in lung injury development (risk ratio [RR], 0.33; 95% CI, 0.23 to 0.47; I2, 0%; number needed to treat [NNT], 11), and mortality (RR, 0.64; 95% CI, 0.46 to 0.89; I2, 0%; NNT, 23) in patients receiving ventilation with lower tidal volumes. The results of lung injury development were similar when stratified by the type of study (randomized vs nonrandomized) and were significant only in randomized trials for pulmonary infection and only in nonrandomized trials for mortality. Meta-analysis using a random-effects model showed, in protective ventilation groups, a lower incidence of pulmonary infection (RR, 0.45; 95% CI, 0.22 to 0.92; I2, 32%; NNT, 26), lower mean (SD) hospital length of stay (6.91 [2.36] vs 8.87 [2.93] days, respectively; standardized mean difference [SMD], 0.51; 95% CI, 0.20 to 0.82; I2, 75%), higher mean (SD) PaCO2 levels (41.05 [3.79] vs 37.90 [4.19] mm Hg, respectively; SMD, 0.51; 95% CI, -0.70 to -0.32; I2, 54%), and lower mean (SD) pH values (7.37 [0.03] vs 7.40 [0.04], respectively; SMD, 1.16; 95% CI, 0.31 to 2.02; I2, 96%) but similar mean (SD) ratios of PaO2 to fraction of inspired oxygen (304.40 [65.7] vs 312.97 [68.13], respectively; SMD, 0.11; 95% CI, -0.06 to 0.27; I2, 60%). Tidal volume gradients between the 2 groups did not influence significantly the final results. CONCLUSIONS: Among patients without ARDS, protective ventilation with lower tidal volumes was associated with better clinical outcomes. Some of the limitations of the meta-analysis were the mixed setting of mechanical ventilation (intensive care unit or operating room) and the duration of mechanical ventilation. PMID- 23093165 TI - Empirical evaluation of very large treatment effects of medical interventions. AB - CONTEXT: Most medical interventions have modest effects, but occasionally some clinical trials may find very large effects for benefits or harms. OBJECTIVE: To evaluate the frequency and features of very large effects in medicine. DATA SOURCES: Cochrane Database of Systematic Reviews (CDSR, 2010, issue 7). STUDY SELECTION: We separated all binary-outcome CDSR forest plots with comparisons of interventions according to whether the first published trial, a subsequent trial (not the first), or no trial had a nominally statistically significant (P < .05) very large effect (odds ratio [OR], >=5). We also sampled randomly 250 topics from each group for further in-depth evaluation. DATA EXTRACTION: We assessed the types of treatments and outcomes in trials with very large effects, examined how often large-effect trials were followed up by other trials on the same topic, and how these effects compared against the effects of the respective meta-analyses. RESULTS: Among 85,002 forest plots (from 3082 reviews), 8239 (9.7%) had a significant very large effect in the first published trial, 5158 (6.1%) only after the first published trial, and 71,605 (84.2%) had no trials with significant very large effects. Nominally significant very large effects typically appeared in small trials with median number of events: 18 in first trials and 15 in subsequent trials. Topics with very large effects were less likely than other topics to address mortality (3.6% in first trials, 3.2% in subsequent trials, and 11.6% in no trials with significant very large effects) and were more likely to address laboratory-defined efficacy (10% in first trials,10.8% in subsequent, and 3.2% in no trials with significant very large effects). First trials with very large effects were as likely as trials with no very large effects to have subsequent published trials. Ninety percent and 98% of the very large effects observed in first and subsequently published trials, respectively, became smaller in meta-analyses that included other trials; the median odds ratio decreased from 11.88 to 4.20 for first trials, and from 10.02 to 2.60 for subsequent trials. For 46 of the 500 selected topics (9.2%; first and subsequent trials) with a very large-effect trial, the meta-analysis maintained very large effects with P < .001 when additional trials were included, but none pertained to mortality-related outcomes. Across the whole CDSR, there was only 1 intervention with large beneficial effects on mortality, P < .001, and no major concerns about the quality of the evidence (for a trial on extracorporeal oxygenation for severe respiratory failure in newborns). CONCLUSIONS: Most large treatment effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller. Well-validated large effects are uncommon and pertain to nonfatal outcomes. PMID- 23093164 TI - Associations between conventional cardiovascular risk factors and risk of peripheral artery disease in men. AB - CONTEXT: Previous studies have examined the associations of individual clinical risk factors with risk of peripheral artery disease (PAD), but the combined effects of these risk factors are largely unknown. OBJECTIVE: To estimate the degree to which the 4 conventional cardiovascular risk factors of smoking, hypertension, hypercholesterolemia, and type 2 diabetes are associated with the risk of PAD among men. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 44,985 men in the United States without a history of cardiovascular disease at baseline in 1986; participants in the Health Professionals Follow-up Study were followed up for 25 years until January 2011. The presence of risk factors was updated biennially during follow-up. MAIN OUTCOME MEASURE: Clinically significant PAD defined as limb amputation or revascularization, angiogram reporting vascular obstruction of 50% or greater, ankle-brachial index of less than 0.90, or physician-diagnosed PAD. RESULTS: During a median follow-up of 24.2 years (interquartile range, 20.8-24.7 years), there were 537 cases of incident PAD. Each risk factor was significantly and independently associated with a higher risk of PAD after adjustment for the other 3 risk factors and confounders. The age-adjusted incidence rates were 9 (95% CI, 6-14) cases/100,000 person-years (n = 19 incident cases) for 0 risk factors, 23 (95% CI, 18-28) cases/100,000 person years (n = 99 incident cases) for 1 risk factor, 47 (95% CI, 39-56) cases/100,000 person-years (n = 176 incident cases) for 2 risk factors, 92 (95% CI, 76-111) cases/100,000 person-years (n = 180 incident cases) for 3 risk factors, and 186 (95% CI, 141-246) cases/100,000 person-years (n = 63 incident cases) for 4 risk factors. The multivariable-adjusted hazard ratio for each additional risk factor was 2.06 (95% CI, 1.88-2.26). Men without any of the 4 risk factors had a hazard ratio of PAD of 0.23 (95% CI, 0.14-0.36) compared with all other men in the cohort. In 96% of PAD cases (95% CI, 94%-98%), at least 1 of the 4 risk factors was present at the time of PAD diagnosis. The population-attributable risk associated with these 4 risk factors was 75% (95% CI, 64%-87%). The absolute incidence of PAD among men with all 4 risk factors was 3.5/1000 person-years. CONCLUSION: Among men in this cohort, smoking, hypertension, hypercholesterolemia, and type 2 diabetes account for the majority of risk associated with development of clinically significant PAD. PMID- 23093166 TI - Multiple cutaneous swellings associated with sudden collapse. PMID- 23093167 TI - Low tidal volumes for all? PMID- 23093168 TI - Improving the health of patients and populations requires humility, uncertainty, and collaboration. PMID- 23093172 TI - JAMA patient page. Age-related macular degeneration. PMID- 23093173 TI - Templated synthesis of nanostructured materials. AB - Templating is one of the most important techniques for the controlled synthesis of nanostructured materials. This powerful tool uses a pre-existing guide with desired nanoscale features to direct the formation of nanomaterials into forms that are otherwise difficult to obtain. As a result, templated synthesis is capable of producing nanostructures with unique structures, morphologies and properties. In this review, we summarize the general principles of templated synthesis and cover recent developments in this area. As a wide variety of synthesis techniques are utilized to produce nanomaterials using template-based methods, the discussion is organized around the various types of common templates. We examine the use of both physical and chemical hard colloidal templates, soft templates, and other non-colloidal templates, followed by our perspective on the state of the field and potential future directions. PMID- 23093174 TI - Lactic acid bacteria producing B-group vitamins: a great potential for functional cereals products. AB - Wheat contains various essential nutrients including the B group of vitamins. However, B group vitamins, normally present in cereals-derived products, are easily removed or destroyed during milling, food processing or cooking. Lactic acid bacteria (LAB) are widely used as starter cultures for the fermentation of a large variety of foods and can improve the safety, shelf life, nutritional value, flavor and overall quality of the fermented products. In this regard, the identification and application of strains delivering health-promoting compounds is a fascinating field. Besides their key role in food fermentations, several LAB found in the gastrointestinal tract of humans and animals are commercially used as probiotics and possess generally recognized as safe status. LAB are usually auxotrophic for several vitamins although certain strains of LAB have the capability to synthesize water-soluble vitamins such as those included in the B group. In recent years, a number of biotechnological processes have been explored to perform a more economical and sustainable vitamin production than that obtained via chemical synthesis. This review article will briefly report the current knowledge on lactic acid bacteria synthesis of vitamins B2, B11 and B12 and the potential strategies to increase B-group vitamin content in cereals-based products, where vitamins-producing LAB have been leading to the elaboration of novel fermented functional foods. In addition, the use of genetic strategies to increase vitamin production or to create novel vitamin-producing strains will be also discussed. PMID- 23093175 TI - Comparison of power output by rice (Oryza sativa) and an associated weed (Echinochloa glabrescens) in vascular plant bio-photovoltaic (VP-BPV) systems. AB - Vascular plant bio-photovoltaics (VP-BPV) is a recently developed technology that uses higher plants to harvest solar energy and the metabolic activity of heterotrophic microorganisms in the plant rhizosphere to generate electrical power. In the present study, electrical output and maximum power output variations were investigated in a novel VP-BPV configuration using the crop plant rice (Oryza sativa L.) or an associated weed, Echinochloa glabrescens (Munro ex Hook. f.). In order to compare directly the physiological performances of these two species in VP-BPV systems, plants were grown in the same soil and glasshouse conditions, while the bio-electrochemical systems were operated in the absence of additional energy inputs (e.g. bias potential, injection of organic substrate and/or bacterial pre-inoculum). Diurnal oscillations were clearly observed in the electrical outputs of VP-BPV systems containing the two species over an 8-day growth period. During this 8-day period, O. sativa generated charge ~6 times faster than E. glabrescens. This greater electrogenic activity generated a total charge accumulation of 6.75 +/- 0.87 Coulombs for O. sativa compared to 1.12 +/- 0.16 for E. glabrescens. The average power output observed over a period of about 30 days for O. sativa was significantly higher (0.980 +/- 0.059 GJ ha(-1) year( 1)) than for E. glabrescens (0.088 +/- 0.008 GJ ha(-1) year(-1)). This work indicates that electrical power can be generated in both VP-BPV systems (O. sativa and E. glabrescens) when bacterial populations are self-forming. Possible reasons for the differences in power outputs between the two plant species are discussed. PMID- 23093177 TI - Microbial degradation of chloroform. AB - Chloroform (CF) is largely produced by both anthropogenic and natural sources. It is detected in ground and surface water sources and it represents the most abundant halocarbon in the atmosphere. Microbial CF degradation occurs under both aerobic and anaerobic conditions. Apart from a few reports describing the utilization of CF as a terminal electron acceptor during growth, CF degradation was mainly reported as a cometabolic process. CF aerobic cometabolism is supported by growth on short-chain alkanes (i.e., methane, propane, butane, and hexane), aromatic hydrocarbons (i.e., toluene and phenol), and ammonia via the activity of monooxygenases (MOs) operatively divided into different families. The main factors affecting CF cometabolism are (1) the inhibition of CF degradation exerted by the growth substrate, (2) the need for reductant supply to maintain MO activity, and (3) the toxicity of CF degradation products. Under anaerobic conditions, CF degradation was mainly associated to the activity of methanogens, although some examples of CF-degrading sulfate-reducing, fermenting, and acetogenic bacteria are reported in the literature. Higher CF toxicity levels and lower degradation rates were shown by anaerobic systems in comparison to the aerobic ones. Applied physiological and genetic aspects of microbial cometabolism of CF will be presented along with bioremediation perspectives. PMID- 23093176 TI - Novel CAD-like enzymes from Escherichia coli K-12 as additional tools in chemical production. AB - In analyzing the reductive power of Escherichia coli K-12 for metabolic engineering approaches, we identified YahK and YjgB, two medium-chain dehydrogenases/reductases subgrouped to the cinnamyl alcohol dehydrogenase family, as being important. Identification was achieved using a stepwise purification protocol starting with crude extract. For exact characterization, the genes were cloned into pET28a vector and expressed with N-terminal His tag. Substrate specificity studies revealed that a large variety of aldehydes but no ketones are converted by both enzymes. YahK and and YjgB strongly preferred NADPH as cofactor. The structure of YjgB was modeled using YahK as template for a comparison of the active center giving a first insight to the different substrate preferences. The enzyme activity for YahK, YjgB, and YqhD was determined on the basis of the temperature. YahK showed a constant increase in activity until 60 degrees C, whereas YjgB was most active between 37 and 50 degrees C. YqhD achieved the highest activity at 50 degrees C. Comparing YjgB and Yahk referring to the catalytic efficiency, YjgB achieved for almost all substrates higher rates (butyraldehyde 221 s-1 mM-1, benzaldehyde 1,305 s-1 mM-1). Exceptions are the two substrates glyceraldehydes (no activity for YjgB) and isobutyraldehyde (YjgB 0.26 s-1 mM-1) which are more efficiently converted by YahK (glyceraldehyde 2.8 s-1 mM 1, isobutyraldehyde 14.6 s-1 mM-1). YahK and even more so YjgB are good candidates for the reduction of aldehydes in metabolic engineering approaches and could replace the currently used YqhD. PMID- 23093178 TI - Angle-resolved photoemission spectroscopy at ultra-low temperatures. AB - The physical properties of a material are defined by its electronic structure. Electrons in solids are characterized by energy (omega) and momentum (k) and the probability to find them in a particular state with given omega and k is described by the spectral function A(k, omega). This function can be directly measured in an experiment based on the well-known photoelectric effect, for the explanation of which Albert Einstein received the Nobel Prize back in 1921. In the photoelectric effect the light shone on a surface ejects electrons from the material. According to Einstein, energy conservation allows one to determine the energy of an electron inside the sample, provided the energy of the light photon and kinetic energy of the outgoing photoelectron are known. Momentum conservation makes it also possible to estimate k relating it to the momentum of the photoelectron by measuring the angle at which the photoelectron left the surface. The modern version of this technique is called Angle-Resolved Photoemission Spectroscopy (ARPES) and exploits both conservation laws in order to determine the electronic structure, i.e. energy and momentum of electrons inside the solid. In order to resolve the details crucial for understanding the topical problems of condensed matter physics, three quantities need to be minimized: uncertainty* in photon energy, uncertainty in kinetic energy of photoelectrons and temperature of the sample. In our approach we combine three recent achievements in the field of synchrotron radiation, surface science and cryogenics. We use synchrotron radiation with tunable photon energy contributing an uncertainty of the order of 1 meV, an electron energy analyzer which detects the kinetic energies with a precision of the order of 1 meV and a He(3) cryostat which allows us to keep the temperature of the sample below 1 K. We discuss the exemplary results obtained on single crystals of Sr2RuO4 and some other materials. The electronic structure of this material can be determined with an unprecedented clarity. PMID- 23093179 TI - Hybrid composites made of multiwalled carbon nanotubes functionalized with Fe3O4 nanoparticles for tissue engineering applications. AB - A straightforward technique for functionalization of multiwalled carbon nanotubes (MWCNTs) with magnetite (Fe(3)O(4)) nanoparticles was developed. Iron oxide nanoparticles were deposited on MWCNT surfaces by a deposition-precipitation method using Fe(3+)/Fe(2+) salts precursors in basic solution. The characterizations by HRTEM, XRD, SEM/EDX, AAS and TPR analyses confirmed the successful formation of magnetic iron oxide nanoparticles on the MWCNT surface. Fe(3)O(4)/MWCNT hybrid composites were analysed in vitro by incubation with mesenchymal stem cells for 1, 3 and 7 days, either in the presence or absence of a static magnetic field. Analysis of cell proliferation was performed by the MTT assay, quantification of cellular stress was performed by the Lactate Dehydrogenase assay and analysis of cell morphology was performed by actin immunofluorescence and scanning electron microscopy. Results demonstrate that the introduction of magnetite into the MWCNT structure increases biocompatibility of oxidized MWCNTs. In addition, the presence of a static magnetic field further increases Fe(3)O(4)/MWCNT influence on cell behaviour. These results demonstrate this novel Fe(3)O(4)/MWCNT hybrid composite has good potential for tissue engineering applications. PMID- 23093180 TI - Similarities between protein folding and granular jamming. AB - Grains and glasses, widely different materials, arrest their motions upon decreasing temperature and external load, respectively, in common ways, leading to a universal jamming phase diagram conjecture. However, unified theories are lacking, mainly because of the disparate nature of the particle interactions. Here we demonstrate that folded proteins exhibit signatures common to both glassiness and jamming by using temperature- and force-unfolding molecular dynamics simulations. Upon folding, proteins develop a peak in the interatomic force distributions that falls on a universal curve with experimentally measured forces on jammed grains and droplets. Dynamical signatures are found as a dramatic slowdown of stress relaxation upon folding. Together with granular similarities, folding is tied not just to the jamming transition, but a more nuanced picture of anisotropy, preparation protocol and internal interactions emerges. Results have implications for designing stable polymers and can open avenues to link protein folding to jamming theory. PMID- 23093181 TI - Spatial control of defect creation in graphene at the nanoscale. AB - Defects in graphene alter its electrical, chemical, magnetic and mechanical properties. The intentional creation of defects in graphene offers a means for engineering its properties. Techniques such as ion irradiation intentionally induce atomic defects in graphene, for example, divacancies, but these defects are randomly scattered over large distances. Control of defect formation with nanoscale precision remains a significant challenge. Here we show control over both the location and average complexity of defect formation in graphene by tailoring its exposure to a focussed electron beam. Divacancies and larger disordered structures are produced within a 10 * 10 nm(2) region of graphene and imaged after creation using an aberration-corrected transmission electron microscope. Some of the created defects were stable, whereas others relaxed to simpler structures through bond rotations and surface adatom incorporation. These results are important for the utilization of atomic defects in graphene-based research. PMID- 23093183 TI - CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease. AB - L-type calcium channels expressed in the brain are heterogeneous. The predominant class of L-type calcium channels has a Ca(V)1.2 pore-forming subunit. L-type calcium channels with a Ca(V)1.3 pore-forming subunit are much less abundant, but have been implicated in the generation of mitochondrial oxidant stress underlying pathogenesis in Parkinson's disease. Thus, selectively antagonizing Ca(V)1.3 L type calcium channels could provide a means of diminishing cell loss in Parkinson's disease without producing side effects accompanying general antagonism of L-type calcium channels. However, there are no known selective antagonists of Ca(V)1.3 L-type calcium channel. Here we report high-throughput screening of commercial and 'in-house' chemical libraries and modification of promising hits. Pyrimidine-2,4,6-triones were identified as a potential scaffold; structure-activity relationship-based modification of this scaffold led to 1-(3 chlorophenethyl)-3-cyclopentylpyrimidine-2,4,6-(1H,3H,5H)-trione (8), a potent and highly selective Ca(V)1.3 L-type calcium channel antagonist. The biological relevance was confirmed by whole-cell patch-clamp electrophysiology. These studies describe the first highly selective Ca(V)1.3 L-type calcium channel antagonist and point to a novel therapeutic strategy for Parkinson's disease. PMID- 23093182 TI - Evolution of the human-specific microRNA miR-941. AB - MicroRNA-mediated gene regulation is important in many physiological processes. Here we explore the roles of a microRNA, miR-941, in human evolution. We find that miR-941 emerged de novo in the human lineage, between six and one million years ago, from an evolutionarily volatile tandem repeat sequence. Its copy number remains polymorphic in humans and shows a trend for decreasing copy-number with migration out of Africa. Emergence of miR-941 was accompanied by accelerated loss of miR-941-binding sites, presumably to escape regulation. We further show that miR-941 is highly expressed in pluripotent cells, repressed upon differentiation and preferentially targets genes in hedgehog- and insulin signalling pathways, thus suggesting roles in cellular differentiation. Human specific effects of miR-941 regulation are detectable in the brain and affect genes involved in neurotransmitter signalling. Taken together, these results implicate miR-941 in human evolution, and provide an example of rapid regulatory evolution in the human linage. PMID- 23093184 TI - Engineering RNA endonucleases with customized sequence specificities. AB - Specific cleavage of RNAs is critical for in vitro manipulation of RNA and for in vivo gene silencing. Here we engineer artificial site-specific RNA endonucleases to function analogously to DNA restriction enzymes. We combine a general RNA cleavage domain with a series of Pumilio/fem-3-binding factor domains that specifically recognize different 8-nucleotide RNA sequences. The resulting artificial site-specific RNA endonucleases specifically recognize RNA substrates and efficiently cleave near their binding sites. The artificial site-specific RNA endonucleases can be devised to recognize and cleave various RNA target sequences, providing a useful tool to manipulate RNAs in vitro. In addition, we generate designer artificial site-specific RNA endonucleases to specifically silence an endogenous gene in Escherichia coli, as well as a mitochondrial encoded gene in human cells, suggesting that artificial site-specific RNA endonucleases can serve as a gene-silencing tool with designed specificity. PMID- 23093186 TI - A high-rate and long cycle life aqueous electrolyte battery for grid-scale energy storage. AB - New types of energy storage are needed in conjunction with the deployment of solar, wind and other volatile renewable energy sources and their integration with the electric grid. No existing energy storage technology can economically provide the power, cycle life and energy efficiency needed to respond to the costly short-term transients that arise from renewables and other aspects of grid operation. Here we demonstrate a new type of safe, fast, inexpensive, long-life aqueous electrolyte battery, which relies on the insertion of potassium ions into a copper hexacyanoferrate cathode and a novel activated carbon/polypyrrole hybrid anode. The cathode reacts rapidly with very little hysteresis. The hybrid anode uses an electrochemically active additive to tune its potential. This high-rate, high-efficiency cell has a 95% round-trip energy efficiency when cycled at a 5C rate, and a 79% energy efficiency at 50C. It also has zero-capacity loss after 1,000 deep-discharge cycles. PMID- 23093187 TI - The convergent evolution of defensive polyacetylenic fatty acid biosynthesis genes in soldier beetles. AB - The defensive and bioactive polyacetylenic fatty acid, 8Z-dihydromatricaria acid, is sequestered within a wide range of organisms, including plants, fungi and soldier beetles. The 8Z-dihydromatricaria acid is concentrated in the defence and accessory glands of soldier beetles to repel avian predators and protect eggs. In eukaryotes, acetylenic modifications of fatty acids are catalysed by acetylenases, which are desaturase-like enzymes that act on existing double bonds. Here we obtained acyl Coenzyme A-linked desaturases from soldier beetle RNA and functionally expressed them in yeast. We show that three genes were sufficient for the conversion of a common monounsaturated fatty acid, oleic acid, to the 18 carbon precursor of 8Z-dihydromatricaria acid, that is, 9Z,16Z octadecadiene-12,14-diynoic acid. These are the first eukaryotic genes reported to produce conjugated polyacetylenic fatty acids. Phylogenetic analysis shows that the genes responsible for 8Z-dihydromatricaria acid synthesis in soldier beetles evolved de novo and independently of the acetylenases of plants and fungi. PMID- 23093188 TI - Active control of electromagnetically induced transparency analogue in terahertz metamaterials. AB - Recently reported metamaterial analogues of electromagnetically induced transparency enable a unique route to endow classical optical structures with aspects of quantum optical systems. This method opens up many fascinating prospects on novel optical components, such as slow light units, highly sensitive sensors and nonlinear devices. In particular, optical control of electromagnetically induced transparency in metamaterials promises essential application opportunities in optical networks and terahertz communications. Here we present active optical control of metamaterial-induced transparency through active tuning of the dark mode. By integrating photoconductive silicon into the metamaterial unit cell, a giant switching of the transparency window occurs under excitation of ultrafast optical pulses, allowing for an optically tunable group delay of the terahertz light. This work opens up the possibility for designing novel chip-scale ultrafast devices that would find utility in optical buffering and terahertz active filtering. PMID- 23093189 TI - Widespread impact of horizontal gene transfer on plant colonization of land. AB - In complex multicellular eukaryotes such as animals and plants, horizontal gene transfer is commonly considered rare with very limited evolutionary significance. Here we show that horizontal gene transfer is a dynamic process occurring frequently in the early evolution of land plants. Our genome analyses of the moss Physcomitrella patens identified 57 families of nuclear genes that were acquired from prokaryotes, fungi or viruses. Many of these gene families were transferred to the ancestors of green or land plants. Available experimental evidence shows that these anciently acquired genes are involved in some essential or plant specific activities such as xylem formation, plant defence, nitrogen recycling as well as the biosynthesis of starch, polyamines, hormones and glutathione. These findings suggest that horizontal gene transfer had a critical role in the transition of plants from aquatic to terrestrial environments. On the basis of these findings, we propose a model of horizontal gene transfer mechanism in nonvascular and seedless vascular plants. PMID- 23093190 TI - Tyrosine sulfation in a Gram-negative bacterium. AB - Tyrosine sulfation, a well-characterized post-translation modification in eukaryotes, has not previously been reported in prokaryotes. Here, we demonstrate that the RaxST protein from the Gram-negative bacterium, Xanthomonas oryzae pv. oryzae, is a tyrosine sulfotransferase. We used a newly developed sulfotransferase assay and ultraviolet photodissociation mass spectrometry to demonstrate that RaxST catalyses sulfation of tyrosine 22 of the Xoo Ax21 (activator of XA21-mediated immunity) protein. These results demonstrate a previously undescribed post-translational modification in a prokaryotic species with implications for studies of host immune responses and bacterial cell-cell communication systems. PMID- 23093191 TI - Imaging the post-fusion release and capture of a vesicle membrane protein. AB - The molecular mechanism responsible for capturing, sorting and retrieving vesicle membrane proteins following triggered exocytosis is not understood. Here we image the post-fusion release and then capture of a vesicle membrane protein, the vesicular acetylcholine transporter, from single vesicles in living neuroendocrine cells. We combine these measurements with super-resolution interferometric photo-activation localization microscopy and electron microscopy, and modelling to map the nanometer-scale topography and architecture of the structures responsible for the transporter's capture following exocytosis. We show that after exocytosis, the transporter rapidly diffuses into the plasma membrane, but most travels only a short distance before it is locally captured over a dense network of membrane-resident clathrin-coated structures. We propose that the extreme density of these structures acts as a short-range diffusion trap. They quickly sequester diffusing vesicle material and limit its spread across the membrane. This system could provide a means for clathrin-mediated endocytosis to quickly recycle vesicle proteins in highly excitable cells. PMID- 23093193 TI - The simple fly larval visual system can process complex images. AB - Animals that have simple eyes are thought to only detect crude visual detail such as light level. However, predatory insect larvae using a small number of visual inputs seem to distinguish complex image targets. Here we show that Drosophila melanogaster larvae, which have 12 photoreceptor cells per hemisphere, are attracted to distinct motions of other, tethered larvae and that this recognition requires the visual system but not the olfactory system. In addition, attraction to tethered larvae still occurs across a clear plastic barrier, does not occur significantly in the dark and attraction occurs to a computer screen movie of larval motion. By altering the artificial attractant movie, we conclude that visual recognition involves both spatial and temporal components. Our results demonstrate that a simple but experimentally tractable visual system can distinguish complex images and that processing in the relatively large central brain may compensate for the simple input. PMID- 23093194 TI - Bursting drops in solid dielectrics caused by high voltages. AB - Fluid drops tend to be spheres--a shape that minimizes surface energy. In thunderstorm clouds, drops can become unstable and emit thin jets when charged beyond certain limits. The instability of electrified drops in gases and liquids has been widely studied and used in applications including ink-jet printing, electrospinning nanofibers, microfluidics and electrospray ionization. Here we report a different scenario: drops in solids become unstable and burst under sufficiently high electric fields. We find the instability of drops in solids morphologically resembles that in liquids, but the critical electric field for the instability follows a different scaling due to elasticity of solids. Our observations and theoretical models not only advance the fundamental understanding of electrified drops, but also suggest a new failure mechanism of high energy density dielectric polymers, which have diverse applications ranging from capacitors for power grids and electric vehicles to muscle-like transducers for soft robots and energy harvesting. PMID- 23093195 TI - Ripple-modulated electronic structure of a 3D topological insulator. AB - Three-dimensional topological insulators host linearly dispersing states with unique properties and a strong potential for applications. An important ingredient in realizing some of the more exotic states in topological insulators is the ability to manipulate local electronic properties. Direct analogy to the Dirac material graphene suggests that a possible avenue for controlling local properties is via a controlled structural deformation such as the formation of ripples. However, the influence of such ripples on topological insulators is yet to be explored. Here we use scanning tunnelling microscopy to determine the effects of one-dimensional buckling on the electronic properties of Bi(2)Te(3.) By tracking spatial variations of the interference patterns generated by the Dirac electrons we show that buckling imposes a periodic potential, which locally modulates the surface-state dispersion. This suggests that forming one- and two dimensional ripples is a viable method for creating nanoscale potential landscapes that can be used to control the properties of Dirac electrons in topological insulators. PMID- 23093196 TI - Emergent quantum confinement at topological insulator surfaces. AB - Bismuth-chalchogenides are model examples of three-dimensional topological insulators. Their ideal bulk-truncated surface hosts a single spin-helical surface state, which is the simplest possible surface electronic structure allowed by their non-trivial Z(2) topology. However, real surfaces of such compounds, even if kept in ultra-high vacuum, rapidly develop a much more complex electronic structure whose origin and properties have proved controversial. Here we demonstrate that a conceptually simple model, implementing a semiconductor like band bending in a parameter-free tight-binding supercell calculation, can quantitatively explain the entire measured hierarchy of electronic states. In combination with circular dichroism in angle-resolved photoemission experiments, we further uncover a rich three-dimensional spin texture of this surface electronic system, resulting from the non-trivial topology of the bulk band structure. Moreover, our study sheds new light on the surface-bulk connectivity in topological insulators, and reveals how this is modified by quantum confinement. PMID- 23093197 TI - The earliest known stem-tetrapod from the Lower Devonian of China. AB - Recent discoveries of advanced fish-like stem-tetrapods (for example, Panderichthys and Tiktaalik) have greatly improved our knowledge of the fin-to limb transition. However, a paucity of fossil data from primitive finned tetrapods prevents profound understanding of the acquisition sequence of tetrapod characters. Here we report a new stem-tetrapod (Tungsenia paradoxa gen. et sp. nov.) from the Lower Devonian (Pragian, ~409 million years ago) of China, which extends the earliest record of tetrapods by some 10 million years. Sharing many primitive features with stem-lungfishes, the new taxon further fills in the morphological gap between tetrapods and lungfishes. The X-ray tomography study of the skull depicts the plesiomorphic condition of the brain in the tetrapods. The enlargement of the cerebral hemispheres and the possible presence of the pars tuberalis in this stem-tetrapod indicate that some important brain modifications related to terrestrial life had occurred at the beginning of the tetrapod evolution, much earlier than previously thought. PMID- 23093199 TI - Implementation of micro-ball nanodiamond anvils for high-pressure studies above 6 Mbar. AB - Since invention of the diamond anvil cell technique in the late 1950s for studying materials at extreme conditions, the maximum static pressure generated so far at room temperature was reported to be about 400 GPa. Here we show that use of micro-semi-balls made of nanodiamond as second-stage anvils in conventional diamond anvil cells drastically extends the achievable pressure range in static compression experiments to above 600 GPa. Micro-anvils (10-50 MUm in diameter) of superhard nanodiamond (with a grain size below ~50 nm) were synthesized in a large volume press using a newly developed technique. In our pilot experiments on rhenium and gold we have studied the equation of state of rhenium at pressures up to 640 GPa and demonstrated the feasibility and crucial necessity of the in situ ultra high-pressure measurements for accurate determination of material properties at extreme conditions. PMID- 23093200 TI - Local structures and Al/Si ordering in lanthanum aluminosilicate glasses explored by advanced 27Al NMR experiments and molecular dynamics simulations. AB - The structures of 15 La-Al-Si-O glasses, whose compositions span 11-28 mol% La(2)O(3), 11-30 mol% Al(2)O(3), and 45-78 mol% SiO(2), are explored over both short and intermediate length-scales by using a combination of solid-state (27)Al magic-angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and molecular dynamics (MD) simulations. MAS NMR reveals Al speciations dominated by AlO(4) groups, with minor but significant fractions of AlO(5) (5-10%) and AlO(6) (?3%) polyhedra present in all La(2)O(3)-Al(2)O(3)-SiO(2) glasses; the amounts of Al([5]) and Al([6]) coordinations increase for decreasing molar fraction of Si. The MD simulations reproduce this compositional trend, with the fractional populations of AlO(p) groups (p = 4, 5, 6) according well with the experimental results. The modeled La speciations mainly involve LaO(6) and LaO(7) polyhedra, giving a range of average La(3+) coordination numbers between 6.0 and 6.6; the latter increases slightly for decreasing Si content of the sample. Besides the expected bridging and non-bridging O species, minor contributions of oxygen triclusters (<=9%) and free O(2-) ions (<=4%) are observed in all MD data. The glass structures exhibit a pronounced Al/Si disorder; the MD simulations reveal essentially random SiO(4)-SiO(4), SiO(4)-AlO(p) and AlO(p)-AlO(q) (p, q = 4, 5, 6) associations, including significant amounts of AlO(4)-AlO(4) contacts, regardless of the n(Al)/n(Si) molar ratio of the glass. The strong violation of Al([4])-Al([4]) avoidance is verified by 2D (27)Al NMR experimentation that correlates double-quantum and single-quantum coherences, here applied for the first time to aluminosilicate glasses, and evidencing AlO(p)-AlO(q) connectivities dominated by AlO(4)-AlO(4) and AlO(4)-AlO(5) pairs. The potential bearings from distinct fictive temperatures of the experimental and modeled glass structures are discussed. PMID- 23093201 TI - Carbon nanotube fibers for electrochemical applications: effect of enhanced interfaces by an acid treatment. AB - Chemical treatment using concentrated nitric acid (16 M) not only induced significant improvement of mechanical and electrical properties of carbon nanotube fibers due to the enhanced interfacial interaction but also allowed much more efficient deposition of polyaniline for developing fiber-shaped supercapacitors. After the 2 h treatment, the acidized fiber had a tensile strength of 1.52 GPa and an electrical conductivity of 1050 S cm(-1), increased by 52% and 128%, respectively, compared with the untreated one. By depositing polyaniline for 10 min around the fiber, the composite fiber had a volumetric capacitance of 239 F cm(-3), 17% higher than that without the acid treatment. For a long time treatment up to 6 h, although the strength and conductivity decreased slightly, the composite fiber had a super high volumetric capacitance up to 299 F cm(-3). The improvement of electrochemical performance is attributed to the increased deposition rate and structural change of polyaniline due to the existence of functional groups on the fiber surface. PMID- 23093202 TI - Biomarkers in an animal model for revealing neural, hematologic, and behavioral correlates of PTSD. AB - Identification of biomarkers representing the evolution of the pathophysiology of Post Traumatic Stress Disorder (PTSD) is vitally important, not only for objective diagnosis but also for the evaluation of therapeutic efficacy and resilience to trauma. Ongoing research is directed at identifying molecular biomarkers for PTSD, including traumatic stress induced proteins, transcriptomes, genomic variances and genetic modulators, using biologic samples from subjects' blood, saliva, urine, and postmortem brain tissues. However, the correlation of these biomarker molecules in peripheral or postmortem samples to altered brain functions associated with psychiatric symptoms in PTSD remains unresolved. Here, we present an animal model of PTSD in which both peripheral blood and central brain biomarkers, as well as behavioral phenotype, can be collected and measured, thus providing the needed correlation of the central biomarkers of PTSD, which are mechanistic and pathognomonic but cannot be collected from people, with the peripheral biomarkers and behavioral phenotypes, which can. Our animal model of PTSD employs restraint and tail shocks repeated for three continuous days - the inescapable tail-shock model (ITS) in rats. This ITS model mimics the pathophysiology of PTSD (17, 7, 4, 10). We and others have verified that the ITS model induces behavioral and neurobiological alterations similar to those found in PTSD subjects (17, 7, 10, 9). Specifically, these stressed rats exhibit (1) a delayed and exaggerated startle response appearing several days after stressor cessation, which given the compressed time scale of the rat's life compared to a humans, corresponds to the one to three months delay of symptoms in PTSD patients (DSM-IV-TR PTSD Criterian D/E (13)), (2) enhanced plasma corticosterone (CORT) for several days, indicating compromise of the hypothalamopituitary axis (HPA), and (3) retarded body weight gain after stressor cessation, indicating dysfunction of metabolic regulation. The experimental paradigms employed for this model are: (1) a learned helplessness paradigm in the rat assayed by measurement of acoustic startle response (ASR) and a charting of body mass; (2) microdissection of the rat brain into regions and nuclei; (3) enzyme-linked immunosorbent assay (ELISA) for blood levels of CORT; (4) a gene expression microarray plus related bioinformatics tools (18). This microarray, dubbed rMNChip, focuses on mitochondrial and mitochondria-related nuclear genes in the rat so as to specifically address the neuronal bioenergetics hypothesized to be involved in PTSD. PMID- 23093204 TI - Phlebotomy, stat testing and laboratory organization: an intriguing relationship. PMID- 23093203 TI - Chlamydia trachomatis: a major agent of respiratory infections in infants from low-income families. AB - OBJECTIVES: To determine the prevalence of lower respiratory tract infection (LRTI) due to Chlamydia trachomatis in newborn infants and to describe the clinical, laboratory, and radiological characteristics of the disease. METHODS: A cross-sectional study carried out over a 12-month period. All infants up to 6 months of age admitted consecutively at the Centro Pediatrico Professor Hosannah de Oliveira of the Universidade Federal da Bahia in Salvador, Brazil, and diagnosed with LRTI according to clinical and/or radiological criteria were included in the study. C. trachomatis infection was diagnosed by the enzyme linked immunosorbent assay (ELISA) for the detection of IgM-class antibodies. The prevalence of LRTI by C. trachomatis was determined and the prevalence ratios for the infection and clinical or laboratory variables were calculated. RESULTS: One hundred and fifty-one infants were submitted to serology for C. trachomatis and 15 (9.9%) tested positive. Chlamydial infection was found only in infants under 5 months of age, mainly in those aged under 2 months. Three of the infants with C. trachomatis infection were born by cesarean section. Conjunctivitis and eosinophilia had occurred in 33.3% of the cases. Chest X rays were abnormal in 92.0% of cases. There was an association between C. trachomatis infection and the duration of hospitalization exceeding 15 days (p = 0.0398) and oxygen therapy (p = 0.0484). CONCLUSIONS: There was a high prevalence of C. trachomatis respiratory infection in the population studied. The infection was associated with a more severe form of the disease, emphasizing the importance of testing pregnant women for this infection to avoid infection in the newborn infant. PMID- 23093205 TI - Hyperhomocysteinemia in health and disease: where we are now, and where do we go from here ? AB - Homocysteine is a sulfur-containing amino acid, which is synthesized from the precursor methionine through a multi-step process, and then reconverted to methionine or catabolyzed into cysteine. The presence of vitamin B9 (folic acid), vitamin B6 (pyridoxine) and vitamin B12 (cobalamin) is essential in homocysteine metabolism, wherein deficiency of one or more of these nutrients is associated with various degree of hyperhomocysteinemia. There is little doubt that hyperhomocysteinemia is associated with several human disorders, such as cardiovascular disease, neurodegenerative disorders, pregnancy complications and fractures, so that its measurement might be useful for risk assessment. Nevertheless, several randomized homocysteine-lowering therapy trials have failed to show that supplementation with vitamins B substantially modifies (and - more importantly - improves) the end points and the related outcomes. According to the current state of scientific knowledge, it seems thus reasonable to conclude that lowering homocysteine alone is probably insufficient to mitigate the risk of thromboembolic, cardiovascular and neurodegenerative disorders inasmuch as this bizarre amino acid acts in strict synergy with other probably more powerful risk factors. Several lines of evidence suggest, however, that its measurement may be helpful for identifying subjects at greater risk of disease, who may thus benefit from a more aggressive treatment of other modifiable risk factors, as recently shown by result of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. PMID- 23093206 TI - Community of arthropod ectoparasites of two species of Turdus Linnaeus, 1758 (Passeriformes: Turdidae) in southern Rio Grande do Sul, Brazil. AB - This study was aimed at describing the community of arthropod ectoparasites associated with sympatric populations of Turdus amaurochalinus and Turdus rufiventris and analyzing the aggregation patterns of the chewing lice species, during reproductive and nonreproductive periods, of both Turdus species in three areas of the Atlantic forest in southern Rio Grande do Sul state (RS), Brazil. Altogether, we captured 36 specimens of T. amaurochalinus and 53 specimens of T. rufiventris. We identified two families of chewing lice, Menoponidae and Philopteridae, with Myrsidea and Brueelia as the most prevalent and abundant on both host birds. The lowest aggregation levels of chewing lice Myrsidea and Brueelia occurred during the reproductive period of both host species, suggesting a reproductive synchronization and a dispersion period. The most prevalent feather mite on T. amaurochalinus was Proctophyllodes weigoldi, and on T. rufiventris, Trouessartia serrana. Analges sp. and Pteronyssoides sp. were not observed on T. rufiventris. We identified three species of ticks; Ixodes auritulus was the most prevalent and abundant on the birds. Ornithoica vicina was the only hippoboscid fly collected, and only on T. amaurochalinus. The richness of ectoparasites was greater on T. amaurochalinus than on T. rufiventris. For T. amaurochalinus, the mean richness was lesser in winter compared to spring and autumn; however, we observed no variation in the mean richness of ectoparasites for T. rufiventris during the same seasons. PMID- 23093208 TI - Graphene-enhanced Raman imaging of TiO2 nanoparticles. AB - The interaction of anatase titanium dioxide (TiO(2)) nanoparticles with chemical vapour deposited graphene sheets transferred on glass substrates is investigated by using atomic force microscopy, Raman spectroscopy and imaging. Significant electronic interactions between the nanoparticles of TiO(2) and graphene were found. The changes in the graphene Raman peak positions and intensity ratios indicate that charge transfer between graphene and TiO(2) nanoparticles occurred, increasing the Raman signal of the TiO(2) nanoparticles up to five times. The normalized Raman intensity of TiO(2) nanoparticles per their volume increased with the disorder of the graphene structure. The complementary reason for the observed enhancement is that due to the higher density of states in the defect sites of graphene, a higher electron transfer occurs from the graphene to the anatase TiO(2) nanoparticles. PMID- 23093207 TI - Diagnostics and epidemiology of alveolar echinococcosis in slaughtered pigs from large-scale husbandries in Germany. AB - By means of the official meat inspection of domestic pigs, exceptionally high proportions of livers affected by encapsulated nodules containing whitish to light yellow, viscous to pasty material ("microabscesses") were detected. The swine had been raised on four different farms, being located in distinct regions of Germany (Brandenburg, Thuringia, Upper Franconia). Macroscopical and histological examination of 77 samples of livers revealed granulomatous to necrotizing hepatitis with attendance of numerous eosinophils. In 61 % (n = 47) of the lesions, eosinophilic, band-like acellular structures resembling the laminated layer of Echinococcus sp. were visible. Moreover, representative samples (n = 11) showed a positive reaction of these structures with Periodic acid-Schiff. Altogether, the findings were consistent with alveolar echinococcosis. Echinococcus multilocularis DNA could be demonstrated in selected samples (n = 7) by polymerase chain reaction. Epidemiological considerations suggest contamination of the forage with fox tapeworm eggs to be the most likely source of infection on two of the farms, as some of the fodder had been stored in the open, being amenable to infected definitive hosts. On the two other farms, mainly straw litter has to be taken into account regarding the transmission route, since carnivores excreting eggs of E. multilocularis could have gained access to the straw storage. The presented cases show that adequate mechanisms of meat inspection may provide important data for the purposes of surveillance and risk assessment of human alveolar echinococcosis. PMID- 23093209 TI - Cell uptake survey of pegylated nanographene oxide. AB - Graphene and more specifically, nanographene oxide (GO) has been proposed as a highly efficient antitumoral therapy agent. Nevertheless, its cell uptake kinetics, its influence in different types of cells and the possibility of controlling cellular internalization timing, is still a field that remains unexplored. Herein, different cell types have been cultured in vitro for several incubation periods in the presence of 0.075 mg ml(-1) pegylated GO solutions. GO uptake kinetics revealed differences in the agent's uptake amount and speed as a function of the type of cell involved. Osteoblast-like cells GO uptake is higher and faster without resulting in greater cell membrane damage. Moreover, the dependence on the commonly used PEG nature (number of branches) also influences the viability and cell uptake speed. These facts play an important role in the future definition of timing parameters and selective cell uptake control in order to achieve an effective therapy. PMID- 23093210 TI - A fluorescent probe for detection of histone deacetylase activity based on aggregation-induced emission. AB - A tetraphenylethylene-derivative fluorescent probe for the one-step detection of histone deacetylases (HDAC) was developed. The deacetylation of the probe triggers electrostatic interaction between the molecules and automatically leads to fluorescence enhancement based on aggregation-induced emission (AIE). PMID- 23093211 TI - Emerging technologies in coloproctology: results of the Italian Society of Colorectal Surgery Logbook of Adverse Events. AB - BACKGROUND: The aim of this paper is to present the results of the Italian Society of Colorectal Surgery [or Societa Italiana di Chirurgia Colorettale (SICCR)] Logbook of adverse events (AE) occurring in relation to emerging technologies in coloproctology (ETCs), over a 3-year period. METHODS: A total of 245 AE were reported (patients age: mean = 49.6 years, range = 20-75 years; gender: 155 = F, 90 = M). The "observations" originated from the same institution of the AEs in 44 cases (18.0%), while 201 patients (82.0%) had been operated on somewhere else. RESULTS: The three most reported ETCs were: Procedure for prolapsed haemorrhoids (PPH) (n = 120-48.9%), stapled transanal rectal resection (STARR (n = 96-39.2%), and transanal haemorrhoidal dearterialization (THD) (n = 11-4.5%). PPH, STARR, and THD together accounted for n = 227 (92.6%) observations. For the three main reported ETCs, the various AEs are listed. Chronic pain after PPH was 46/120 (38.3%), and after STARR of 21/96 (21.9%). The overall re-operation rate was n = 135 (55.1%) versus n = 110 (44.9%) no reoperation. In particular, for the three main reported ETCs, n = 68/120 (56.7%) following an AE after PPH, n = 47/94 (50.0%) following an AE after STARR, and n = 6/11 (54.5) following an AE post-THD. The various types of treatment to solve AE after each of the three most observed ETCs are reported in the text. CONCLUSIONS: Our results do not allow us to draw statistical conclusions; however, this was not the aim of our survey. ETCs are important, yet they are not without major risks. Manufacturers should help colorectal surgeons to convey the right message to patients. PMID- 23093212 TI - Development of a clinical Scandinavian registry for hidradenitis suppurativa; HISREG. PMID- 23093213 TI - Comments on Eusebio et al.: Voxel-based analysis of whole-brain effects of age and gender on dopamine transporter SPECT imaging in healthy subjects. PMID- 23093214 TI - On the horizon: defining the future of sports medicine and the role of the physiatrist. PMID- 23093215 TI - 43rd Walter J. Zeiter Lecture, 2011. The pursuit of excellence in physiatric education and practice. PMID- 23093216 TI - Does preoperative rehabilitation improve patient-based outcomes in persons who have undergone total knee arthroplasty? A systematic review. AB - BACKGROUND: Common clinical practice includes attempts to improve pain, function, motion, and patient independence before total knee arthroplasty (TKA) surgery. Although preoperative rehabilitation often is prescribed, it is unknown whether this care improves patient outcomes after TKA surgery. OBJECTIVE: To focus on how TKA preoperative rehabilitation affects quality of life, pain, and physical outcomes after surgery. DATA SOURCES: A computerized search was performed in February 2011. We searched PubMed, Ageline, CIHNAL, and SPORTDiscus from 1950 through February 2011 using combinations of the terms knee, rehabilitation, arthroplasty, preoperative, and presurgical. Searches were limited to "human" and "English" studies reported in peer-review journals. STUDY SELECTION: Seven studies met the inclusion criteria. For all variables, none was consistently favorable toward preoperative rehabilitation over alternative or control treatment. DATA EXTRACTION: Means and standard deviations (SDs) for each category of the Western Ontario and McMaster Osteoarthritis Index (WOMAC), range of motion, and length of stay (LOS) were obtained and served to calculate point measures and measures of variability. Specifically, bias-adjusted Hedges' g effect sizes, along with 95% confidence intervals, were calculated to assess the magnitude of the treatment effect for each outcome, with separate meta-analyses performed as a summary of the treatment response for each outcome. DATA SYNTHESIS: A total of 240 studies were identified in the search of the literature. On the basis of the title, abstract, or study content, 203 studies were excluded. Of the remaining 37 studies, 30 were excluded on the basis of study design and choice of outcome measures. The results of this review indicate that preoperative rehabilitation likely had no true treatment effect on WOMAC scores, range of motion, and LOS because all effect sizes were weak (<0.4) and confidence intervals crossed zero. CONCLUSION: For all outcomes, none was consistently favorable toward preoperative rehabilitation over the alternative for patients undergoing TKA with the exception of LOS in favor of the treatment group. PMID- 23093217 TI - Physical medicine and rehabilitation: interdisciplinary, interventional, and international. PMID- 23093218 TI - Rehabilitation in Mexico: a dream come true. PMID- 23093219 TI - Ethical challenges of caring for VIPs in the rehabilitation setting: Part II. PMID- 23093220 TI - Use of methylphenidate during inpatient rehabilitation after traumatic brain injury. PMID- 23093221 TI - Identifying loss of function caused by cervical spondylotic myelopathy in young adults with nonathetoid spastic cerebral palsy. PMID- 23093222 TI - A rare cause of scapular pain. PMID- 23093225 TI - Photo- and electro-functional self-assembled architectures of porphyrins. AB - Recent developments in supramolecular strategies have enabled us to construct novel well-defined assemblies of dye molecules. These fundamental researches of such organic materials also entail the synthetic and photophysical processes of molecular aggregates at the nano- and micro-meter scale, since their optical properties significantly differ from those of monomeric species. One of the promising candidates for such functional molecules is a porphyrin dye, which acts as an electron donor as well as a sensitizer. In this perspective, the focus is on the recent advances in the construction of optically and electronically functionalized molecular architectures of porphyrins for light energy conversion and electronics. First, porphyrin aggregates with morphologies such as cube, rod and fiber, which are prepared by three different supramolecular techniques, are reported. Then, we discuss composite molecular nanoarchitectures of porphyrins and carbon nanotubes such as single-wall carbon nanotubes (SWCNTs), stacked-cup carbon nanotubes (SCCNTs) and carbon nanohorns (CNHs). Finally, the structural and photophysical properties of the composite assemblies of porphyrins and graphenes including polycyclic aromatic hydrocarbons (PAH) are presented. PMID- 23093223 TI - Feasibility, safety, and efficacy of the combination of D-serine and computerized cognitive retraining in schizophrenia: an international collaborative pilot study. AB - The combination of pharmacotherapy and cognitive retraining (CRT) for the cognitive deficits of schizophrenia may be more efficacious than either approach alone, but this has not yet been tested. This study evaluated the feasibility, safety, tolerability, and efficacy of 12 weeks of D-serine, combined with CRT in the treatment of cognitive deficits in schizophrenia at two academic sites in parallel, in India and the United States. In a randomized, partial double-blind, placebo-controlled, parallel-group design, 104 schizophrenia subjects (US site=22, Indian site=82) were randomized to: (1) D-serine (30 mg/kg)+CRT (5 h/week), (2) D-serine+control CRT, (3) CRT+placebo D-serine, and (4) placebo+control CRT. Completion rates were 84 and 100% in the Indian and US samples, respectively. On various outcome measures of safety and tolerability, the interventions were well tolerated. D-Serine and CRT did not show any significant effect on the Global Cognitive Index, although both interventions showed differential site effects on individual test performance. CRT resulted in a significant improvement in Verbal Working Memory, and a trend toward improvement in Attention/Vigilance. This is the first study to demonstrating the feasibility, safety, and tolerability of combination pharmacotherapy and CRT in a multicenter international clinical trial. These preliminary findings provide support for future studies using higher doses of D-serine that have been shown to be efficacious or other pharmacotherapies, along with the newer cognitive remediation strategies that are individualized and that target basic information processing. PMID- 23093224 TI - Nature or nurture? Determining the heritability of human striatal dopamine function: an [18F]-DOPA PET study. AB - Striatal dopamine function is important for normal personality, cognitive processes and behavior, and abnormalities are linked to a number of neuropsychiatric disorders. However, no studies have examined the relative influence of genetic inheritance and environmental factors in determining striatal dopamine function. Using [18F]-DOPA positron emission tomography (PET), we sought to determine the heritability of presynaptic striatal dopamine function by comparing variability in uptake values in same sex monozygotic (MZ) twins to dizygotic (DZ) twins. Nine MZ and 10 DZ twin pairs underwent high-resolution [18F]-DOPA PET to assess presynaptic striatal dopamine function. Uptake values for the overall striatum and functional striatal subdivisions were determined by a Patlak analysis using a cerebellar reference region. Heritability, shared environmental effects and non-shared individual-specific effects were estimated using a region of interest (ROI) analysis and a confirmatory parametric analysis. Overall striatal heritability estimates from the ROI and parametric analyses were 0.44 and 0.33, respectively. We found a distinction between striatal heritability in the functional subdivisions, with the greatest heritability estimates occurring in the sensorimotor striatum and the greatest effect of individual specific environmental factors in the limbic striatum. Our results indicate that variation in overall presynaptic striatal dopamine function is determined by a combination of genetic factors and individual-specific environmental factors, with familial environmental effects having no effect. These findings underline the importance of individual-specific environmental factors for striatal dopaminergic function, particularly in the limbic striatum, with implications for understanding neuropsychiatric disorders such as schizophrenia and addictions. PMID- 23093226 TI - A novel nano-scale non-contact temperature measurement technique for crystalline materials. AB - A new high spatial resolution non-contact temperature measurement technique (thermal scanning electron microscopy, ThSEM) is demonstrated. It employs temperature dependent thermal diffuse scattering in electron backscatter diffraction (EBSD) in a scanning electron microscope (SEM). Unlike conventional scanning thermal microscopy, which uses contact probes, ThSEM is a non-contact method. In contrast to optical temperature mapping techniques, ThSEM does not have the spatial resolution limitation that arises from the optical wavelength and theoretically can reach a resolution of <10 nm. The hardware setup is very similar to the EBSD system in an SEM, which can make the integration of temperature mapping into an SEM relatively straightforward. Moreover, multiple signals or contrast mechanisms, such as temperature distributions, grain orientation maps, topographic images and elemental maps can be obtained from the same sample area depending on the specific SEM capability. This technique thus adds a new channel-the temperature signal-to the collection of existing SEM signals. PMID- 23093227 TI - Bay11-7082 inhibits the disintegration of the lymphendothelial barrier triggered by MCF-7 breast cancer spheroids; the role of ICAM-1 and adhesion. AB - BACKGROUND: Many cancers spread through lymphatic routes, and mechanistic insights of tumour intravasation into the lymphatic vasculature and targets for intervention are limited. The major emphasis of research focuses currently on the molecular biology of tumour cells, while still little is known regarding the contribution of lymphatics. METHODS: Breast cancer cell spheroids attached to lymphendothelial cell (LEC) monolayers were used to investigate the process of intravasation by measuring the areas of 'circular chemorepellent-induced defects' (CCID), which can be considered as entry gates for bulky tumour intravasation. Aspects of tumour cell intravasation were furthermore studied by adhesion assay, and siRNA-mediated knockdown of intracellular adhesion molecule-1 (ICAM-1). Replacing cancer spheroids with the CCID-triggering compound 12(S) hydroxyeicosatetraenoic acid (HETE) facilitated western blot analyses of Bay11 7082- and baicalein-treated LECs. RESULTS: Binding of LECs to MCF-7 spheroids, which is a prerequisite for CCID formation, was mediated by ICAM-1 expression, and this depended on NF-kappaB and correlated with the expression of the prometastatic factor S100A4. Simultaneous inhibition of NF-kappaB with Bay11-7082 and of arachidonate lipoxygenase (ALOX)-15 with baicalein prevented CCID formation additively. CONCLUSION: Two mechanisms contribute to CCID formation: ALOX15 via the generation of 12(S)-HETE by MCF-7 cells, which induces directional migration of LECs, and ICAM-1 in LECs under control of NF-kappaB, which facilitates adhesion of MCF-7 cells to LECs. PMID- 23093228 TI - Calprotectin: a novel biomarker for the diagnosis of pleural effusion. AB - BACKGROUND: Novel non-invasive biomarkers for the precise diagnosis of malignancy in pleural effusion (PE) are needed. The aim of this study was to determine the diagnostic accuracy of calprotectin for predicting malignancy in patients with exudative PE. METHODS: Calprotectin concentration was measured in 156 individuals diagnosed with exudative PE (67 malignant and 89 benign). Calprotectin accuracy for discriminating between malignant and benign PE was evaluated using receiver operating characteristic (ROC) curves. Univariate and multivariate logistic regression were performed to test the association between calprotectin levels and malignant PE. RESULTS: Calprotectin levels were significantly lower in malignant pleural fluid (257.2 ng ml(-1), range: 90.7-736.4) than benign effusions (2627.1 ng ml(-1), range: 21-9530.1). The area under the curve was 0.963. A cutoff point of <= 736.4 ng ml(-1) rendered a sensitivity of 100%, with a specificity of 83.15%, which could prove useful to delimit those patients with negative cytology tests that should be referred for more invasive diagnostic procedures. Logistic regression demonstrated a strong association between calprotectin and malignancy (adjusted OR 663.14). CONCLUSION: Calprotectin predicts malignancy in pleural fluid with high accuracy and could be a good complement to cytological methods. PMID- 23093229 TI - EGFR and K-ras gene mutation status in squamous cell anal carcinoma: a role for concurrent radiation and EGFR inhibitors? AB - BACKGROUND: There is a growing appreciation for radio-sensitiser use in multi modal cancer treatment models. Squamous cell anal carcinoma (SCAC) is a rare gastrointestinal tumour traditionally treated with concurrent chemotherapy and radiation. Cetuximab, an epidermal growth factor receptor (EGFR) inhibitor, has demonstrated significant efficacy when combined with radiation in squamous cell carcinoma of the head and neck (SccH&N). We wanted to assess EGFR and Kirsten-ras (K-ras) status in SCAC to see whether it compares with SccH&N. METHODS: Over 90 SCAC paraffin-embedded biopsies were mounted onto a tissue microarray and were assessed for EGFR expression by immunohistochemistry. These samples were also assessed for the most frequently mutated K-ras and EGFR exons by high-resolution melting analysis. RESULTS: The EGFR was present in over 90% of samples tested. The K-ras and EGFR mutations were absent in all samples tested, although a synonymous single-nucleotide polymorphism was found in 3 out of 89 samples tested for EGFR exon 19. CONCLUSION: The low rate of K-ras and EGFR mutations, coupled with the high surface expression of EGFR, suggests similarity in the EGFR signalling pathway between SCAC and SccH&N, and thus a potential role for EGFR inhibitors in SCAC. To our knowledge this is the largest cohort of invasive SCAC samples investigated for EGFR and K-ras mutations reported to date. PMID- 23093230 TI - Hypertensive diseases in pregnancy and subsequent lower risk of breast cancer: the common immune and antiangiogenic profile. PMID- 23093231 TI - Effects of pneumoperitoneum and body position on the morphology of the caudal cava vein analyzed by MRI and plastinated sections. AB - BACKGROUND: Pneumoperitoneum and patient positioning are essential factors during laparoscopic surgical procedures. They cause hemodynamic and anatomical changes in several abdominal organs among which the caudal cava vein (CCV) is involved. Hemodynamic changes in this vein (decreased venous return) have been described in the porcine model, but how the vein morphology and size is affected at different abdominal levels is unknown. We sought to assess the morphological and morphometrical changes in the CCV of the pig caused by pneumoperitoneum and the reverse Trendelenburg position by in vivo magnetic resonance imaging (MRI). METHODS: Six pigs were scanned via MRI under four situations: S1, control (no pneumoperitoneum); S2, control in the reverse Trendelenburg position; S3, pneumoperitoneum (14 mmHg); and S4, pneumoperitoneum in the reverse Trendelenburg position. MRI and plastinated body sections were used to evaluate the topography, morphology and cross-sectional area of the CCV. RESULTS: Two portions of the CCV were differentiated: a prehepatic portion (located between the vertebral levels L1-T15) with flat and irregular morphology, and a hepatic portion (between T14 T11) that was almost rounded. The reverse Trendelenburg position caused an increase in the lumen affecting mainly the prehepatic portion, while pneumoperitoneum caused a decrease in the total vascular lumen, exerting a greater effect on the hepatic portion. The combination of both situations resulted in a further decrease in the vascular area and global morphological changes. CONCLUSIONS: The pneumoperitoneum and reverse Trendelenburg position caused morphological and morphometrical changes in the prehepatic and hepatic portions of the CCV, which should assist in gaining a better understanding of the hemodynamic changes described in the literature. PMID- 23093232 TI - Is transnasal endoscope-assisted endoscopic submucosal dissection for gastric neoplasm useful in training beginners? A prospective randomized trial. AB - BACKGROUND: The main problem in performing endoscopic submucosal dissection (ESD) of gastric neoplasms is that it is technically difficult, especially for beginners. METHODS: A total of 51 patients were randomly assigned to undergo transnasal endoscope-assisted or routine ESD performed by two endoscopists inexperienced in ESD while supervised by one expert. RESULTS: Total procedure time (p = 0.330), complete resection rate (p = 0.977), and complication rate (p = 0.157) were similar for the patients who underwent transnasal endoscope-assisted and routine ESD, but bleeding control time was significantly longer in the transnasal endoscope-assisted ESD group (p = 0.002). Three and six patients in the transnasal endoscope-assisted and routine ESD groups, respectively, were "dropped out" during the procedures (p = 0.291). The endoscopists tended to regard the traction with the transnasal endoscope as more useful for large tumors (p = 0.062). Bleeding control in patients who underwent the transnasal endoscope assisted ESD was significantly longer for patients with tumors located in the anterior wall, posterior wall, and lesser curvature of the stomach (p = 0.001). CONCLUSION: Transnasal endoscope-assisted ESD does not result in improved outcomes when performed by beginners, except for some large tumors. The traction method used by beginners was not superior to proper supervision and advice by an expert during ESD and allowing the expert to perform the procedure when the risk of complications is high or the procedure is delayed. PMID- 23093233 TI - Can EUS elastography improve lymph node staging in esophageal cancer? AB - BACKGROUND: Endoscopic ultrasound (EUS) elastography can assess the hardness of tissue by measuring its elasticity. Few data have been published on EUS elastography for lymph node (LN) staging in patients with esophageal cancer. This study analyzes the value of elastography as an additional diagnostic tool for LN staging. METHODS: Forty patients (mean age 68 years) with known esophageal cancer (34 Barrett's carcinoma, 6 squamous cell carcinoma) were included prospectively. On conventional EUS, suspicious LNs were assessed using sonomorphologic criteria, and EUS elastography was then used to assess their tissue hardness. The sonomorphologic criteria and elastographic images for the LN were later reviewed on recorded video clips by an endosonographer blinded to the histology results. The proportions of color pixels in LNs in selected patients were assessed using computer analysis of the elastography images. Fine-needle aspiration was performed in all of the LNs, and the histological/cytological results were used as the gold standard. RESULTS: Twenty-one of the 40 LNs examined (52.5 %) were positive for neoplasia, confirmed by histology/cytology. The first assessment by the examiner during the procedure, based on sonomorphologic criteria, showed sensitivity of 91.3 % and specificity of 64.7 %. EUS elastography alone had sensitivity of 100 % and specificity of 64.1 %. When computer analysis of the elastographic images was added, the specificity improved significantly to 86.7 %, with a slight decrease in sensitivity to 88.9 %. CONCLUSIONS: EUS elastography is easily included in clinical staging and, particularly with computer-aided pixel analysis, significantly improves the specificity of LN staging. PMID- 23093234 TI - Effect of source of funding on weight loss up to 3 years after gastric banding. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) is a popular choice for patients seeking weight loss surgery. Since behavioural change appears to play a role in weight loss outcomes we postulated that publicly funded patients might not do as well as self-payers. This series examines the effect of public funding versus self-pay on patients undergoing LAGB over 1, 2 and 3 years. METHODS: Consecutive non-randomised cohort series of patient undergoing LAGB over 5 years (September 2003 to December 2008) in a single unit. Age, sex, funding route, body mass index (BMI) and complications were recorded. Per cent excess weight loss (EWL) and the Reinhold criterion for success (proportion achieving 50 % EWL) were assessed. RESULTS: Ninety-nine patients were publicly funded, and 250 patients were self-payers. Initial BMI was significantly higher in publicly funded patients (46.6 vs. 42.3 kg/m(2), p < 0.001) with a higher proportion of males (22.2 vs. 6.0 %, p < 0.001). Mean % EWL was significantly less for publicly funded patients at 1 year (38.1 vs. 53.5 %, p < 0.001) and 2 years (49.6 vs. 64.1 %, p < 0.001), but not at 3 years (59.7 vs. 61.8 %, p = 0.784). Fewer publicly funded patients achieved 50 % EWL at 1 year (24.5 vs. 50.2 %, p < 0.001), but with no significant difference at 2 years (54.8 vs. 67.0 %, p = 0.140) or 3 years (55.2 vs. 66.0 %, p = 0.349). CONCLUSIONS: Self-pay patients initially achieved more % EWL and greater success in reaching 50 % EWL after LAGB, but this difference was not maintained. The results suggest that patient motivation, using self-pay as a surrogate marker, may affect early results, but the operation itself is the main determinant of weight loss at 3 years. PMID- 23093235 TI - Ex vivo comparative study using the Endolifter(r) as a traction device for enhancing submucosal visualization during endoscopic submucosal dissection. AB - BACKGROUND: Endoscopic submucosal dissection (ESD) is a technically demanding procedure, and exposure of the submucosa depends on the action of gravity and submucosal injection. The aim of the study was to investigate the effectiveness of the Endolifter((r)) as a traction device for enhancing submucosal visualization during ESD. METHODS: This was a prospective ex vivo comparative study conducted between September 2010 and March 2011 in the Prince of Wales Hospital. Consecutive ESDs were performed by four experienced endoscopists in an ex vivo ESD model with or without the Endolifter((r)). The Endolifter((r)) allows simultaneous grasping, retracting and lifting of the mucosa during ESD, resulting in exposure of the submucosa. Each of the procedures were recorded and reviewed later by two independent assessors. The outcome measures included the proportion of time that the submucosa was visualized during the procedures (SM ratio), procedural times, perforation rates, amount of submucosal injections, and the difficulty of the procedure. RESULTS: Forty-eight gastric ESD procedures were performed on the model. The SM ratio was higher in the Endolifter((r)) group (P = 0.007), particularly for lesions located at the antrum (P < 0.001). The time required for submucosal dissection and the total procedural time were also less in the Endolifter((r)) group. The endoscopists rated the ESD procedures in the Endolifter((r)) group as less difficult (P = 0.033). CONCLUSIONS: The Endolifter((r)) improved submucosal visualization during gastric ESD and reduces the difficulty of performing the procedures. The device may improve the ease of performing ESD in low-volume centers or large mucosal lesions. PMID- 23093236 TI - Modified triangulating stapling technique for esophagogastrostomy after esophagectomy for esophageal cancer. AB - BACKGROUND: Anastomosis performed during esophagectomy for esophageal cancer is usually involves hand-sewn or circular stapled methods. However, these techniques have been reported to be associated with a high frequency of anastomotic complications, including leakage and benign stenosis. Here a novel triangulating stapling technique for esophagogastrostomy after esophagectomy for esophageal cancer and its retrospective investigation are described. METHODS: Forty-eight patients were underwent esophagectomy for esophageal cancer from January 2006 to December 2009 by the same surgeon using the triangulating stapling technique. The short-term outcomes were evaluated retrospectively. This end-to-end anastomosis used three linear staplers in an everted fashion. RESULTS: Patients comprised 36 men and 12 women with a mean age of 59.4 years. Anastomotic leakage occurred in 4 patients (8.3 %), while anastomotic stenosis was observed in 6 (12.5 %). The average number of endoscopic pneumatic dilatations in patients with anastomotic stenosis was 2.4. The median (range) duration of hospital stay was 40.8 (19-154) days. CONCLUSIONS: Our modified triangulating stapling technique for esophagogastrostomy may be a feasible alternative, resulting in a lower frequency of postoperative anastomotic complications. PMID- 23093237 TI - Robot-assisted renal artery aneurysm repair with a saphenous vein Y-graft interposition. AB - BACKGROUND: Renal artery aneurysms (RAA) treatment includes both surgical repair and endovascular techniques, mostly depending on the location of aneurysm. For complex RAA located at renal artery bifurcation or distally, open surgical repair represents the gold standard of treatment. However, the transperitoneal open access to the renal artery requires a wide laparotomy--hence the attempt to be minimally invasive with the first reports of laparoscopic approach. Even if it represents a possibility, laparoscopy has not yet gained widespread acceptance for the technical difficulties in performing vascular anastomosis. We herein describe the repair of a complex RAA using the Da Vinci Surgical System. METHODS: A 41-year-old woman had an accidentally discovered saccular aneurysm of the right renal artery with a maximum diameter of 20 mm, with one in and four out. A laparoscopic robot-assisted approach was planned. Intraoperatively, we confirm the strategy to group the four output branches in two different patches. Thus, a Y-shaped autologous saphenous graft was prepared and introduced through a trocar. For the three anastomoses, a polytetrafluoroethylene running suture was preferred. RESULTS: The total operation time was 350 min, and the estimated surgical blood loss was about 200 ml. Warm ischemia time was 58 min for the posterior branch and 24 min for the second declamping. The patient resumed a regular diet on postoperative day 2, and the hospital stay lasted 4 days. No intraoperative or postoperative morbidity was noted. A CT scan performed 2 months later revealed the patency of all the reconstructed branches. CONCLUSIONS: The experience of our group counts five other renal aneurysm repair performed with a robot-assisted technique. The presence of five different arterial branches involved in the reconstruction makes this procedure difficult. Robot-assisted laparoscopic technique represents a valid alternative to open surgery in complex cases. PMID- 23093238 TI - GIST: advances in tyrosine kinase inhibitors enhance laparoscopic resection even in advanced disease. PMID- 23093239 TI - Laparoscopic low anterior resection with total mesorectal excision for rectal cancer. Reply. PMID- 23093240 TI - Comparison of hospital costs and length of stay associated with open-mesh, totally extraperitoneal inguinal hernia repair, and transabdominal preperitoneal inguinal hernia repair: an analysis of observational data using propensity score matching. AB - BACKGROUND: Laparoscopic inguinal hernia surgery is increasingly seen as the superior technique in hernia repair. Compared to open-mesh hernia repair, laparoscopic approaches are often reported to be more cost-effective but incur higher costs for the provider. The objective of this study was to analyze the effect of transabdominal preperitoneal (TAPP) and totally extraperitoneal (TEP) repair of nonincarcerated inguinal hernias in men on hospital costs and length of stay (LoS). METHODS: We used routine administrative, highly standardized, patient level cost data from 15 German hospitals participating in the national cost data study. We compared TEP, TAPP, and open-mesh repair. We conducted propensity score matching to account for baseline differences between treatment groups and subsequently estimated the treatment effect on costs and LoS. RESULTS: Total costs for both TEP and TAPP surgery were significantly lower than those for open mesh repair (p < 0.0001 and p < 0.05, respectively). TEP repair also had a slight but nonsignificant advantage in total costs compared to TAPP repair, while TAPP surgery was associated with a significantly shorter LoS than TEP (p < 0.001). CONCLUSION: Results suggest that laparoscopic approaches in hernia repair are not necessarily associated with higher hospital resource consumption than open-mesh repair. PMID- 23093241 TI - The minimally invasive approach is associated with reduced perioperative thromboembolic and bleeding complications for patients receiving preoperative chronic oral anticoagulant therapy who undergo colorectal surgery. AB - BACKGROUND: The data on the perioperative risk of both thromboembolism and hemorrhage for patients receiving chronic oral anticoagulation who undergo colorectal surgery are sparse. In addition, it is uncertain whether the use of the laparoscopic instead of open technique entails additional risk for these patients. This study aimed to evaluate surgical outcomes, with a particular focus on perioperative thromboembolic and bleeding complications for patients receiving chronic oral anticoagulation therapy who undergo open or laparoscopic colorectal resection. METHODS: Patients undergoing colorectal resection between 1994 and 2011 on preoperative chronic oral anticoagulant therapy were included in the study. Patient demographics, characteristics, and perioperative outcomes, with particular emphasis on thromboembolism and bleeding risks, were evaluated comparing laparoscopic and open colectomy. RESULTS: The study enrolled 261 patients receiving chronic anticoagulation therapy (102 laparoscopic colectomy vs 159 open colectomy patients). The patients had a mean age of 57.9 years and a mean body mass index (BMI) of 29.3 kg/m(2). The conversion rate was 8.8 % (n = 9) for laparoscopic operations. Laparoscopic and open cases had comparable BMIs and levels of preoperative hemoglobin. Anastomotic leak, postoperative hospital stay, and surgical-site infection rates were similar for the two groups. Although the laparoscopic group had a significantly greater mean age (p < 0.001) and American Society of Anesthesiology (ASA) score (p = 0.005), the rates for postoperative venous thromboembolism (24.5 vs 2.9 %; p < 0.001), urinary complications (6.9 vs 0 %; p = 0.008), and overall morbidity (44.7 vs 17.7 %; p < 0.001) were lower after laparoscopic surgery. Although the rates for intra- and postoperative blood transfusion were similar, the postoperative hemoglobin levels were significantly higher after laparoscopic surgery. One patient in the laparoscopic group died of sepsis on postoperative day 3. CONCLUSION: For the patients receiving preoperative chronic anticoagulant therapy who underwent colorectal resection, the laparoscopic approach was associated with lower thromboembolic and hemorrhagic complications than open surgery. PMID- 23093242 TI - One surgeon's learning curve for video-assisted thoracoscopic esophagectomy for esophageal cancer with the patient in lateral position: how many cases are needed to reach competence? AB - BACKGROUND: Minimally invasive esophagectomy is a feasible technique shown to be safe and oncologically adequate for the treatment of esophageal cancer. This study aimed to describe one surgeon's learning curve for video-assisted thoracoscopic esophagectomy with the patient in lateral position. METHODS: From May 2010 to June 2012, 89 thoracoscopic esophagectomies for esophageal cancer were performed by one surgeon. The patients were divided into three groups. Group A included the first 30 cases. Group B comprised cases 31 to 60, and group C included the final 29 cases. The demographic characteristics and the intra- and postoperative variables were collected retrospectively and analyzed. RESULTS: One postoperative death occurred. Eight patients required conversion. No significant difference in background or clinicopathologic factors among the three groups was observed. Compared with group A, a significant decrease in intrathoracic operative time (107.7 +/- 16.2 min; P = 0.0000), total operative time (326.3 +/- 40.7 min; P = 0.0002), and blood loss (290.8 +/- 114.3 ml; P = 0.0129) was observed in group B, whereas more retrieved nodes were harvested (20.1 +/- 9.5; P = 0.0002). The last 29 patients (group C) involved significantly less intrathoracic operative time (82.8 +/- 18.4 min; P = 0.0386), total operative time (294.7 +/- 37.4 min; P = 0.0009), and blood loss (234.7 +/- 87.8 ml; P = 0.0125) as well as a shorter postoperative hospital stay (12.4 +/- 3.7 days; P = 0.0125) compared with group B. A significant decline in the overall morbidity from group A to group C (P = 0.0005) also was observed. CONCLUSIONS: The results of this study suggest that at least 30 cases were needed to reach the plateau of thoracoscopic esophagectomy. After more than 60 cases of thoracoscopic esophagectomies had been managed, lower morbidity could be obtained. PMID- 23093243 TI - Hand-sewn gastrojejunostomy using knotless unidirectional barbed absorbable suture during laparoscopic gastric bypass. AB - BACKGROUND: This report describes the authors' institutional experience using knotless unidirectional barbed absorbable suture to close the common enterotomy of the jejunojejunostomy (JJ) and to create a hand-sewn gastrojejunostomy (GJ) during laparoscopic Roux-en-Y gastric bypass. METHODS: A retrospective review of morbidly obese patients who underwent laparoscopic gastric bypass with a hand sewn GJ between April 2011 and 2012 was performed. The authors' traditional technique (TT) consisted of using standard monofilament absorbable suture to close the common JJ enterotomy in a single running layer and to create the GJ with a two-layer anastomosis. A novel technique (NT) was introduced using knotless unidirectional barbed monofilament absorbable suture to perform both tasks. A comparison between these two techniques was performed. RESULTS: In this study, 84 patients with a mean body mass index of 41.7 +/- 4.7 kg/m(2) underwent laparoscopic gastric bypass using a hand-sewn technique. For the 84 patients, 75 primary procedures (89.3 %) and 9 revisional procedures (10.7 %) were performed. In 38 procedures (45.2 %), the TT was used, whereas 46 cases (54.8 %) were managed using the NT. For the primary procedures, the average operating room times were slightly faster in the NT group (178.9 +/- 44.4 vs 154.2 +/- 74.7 min; p = 0.08). The average hospital length of stay was comparable between the two groups (2.3 +/- 0.7 vs 2.6 +/- 1.4 days; p = 0.25). A 30-day follow-up assessment was obtained for all 84 patients, without a significant difference in the overall complication rate between the two groups (TT 18.4 % vs NT 13 %; p = 0.77). No complications were secondary to the JJ closure or gastrojejunostomy. The complications included bleeding (n = 1), small bowel obstruction (n = 1), dehydration (n = 2), esophagitis (n = 1), and subarachnoid hemorrhage (n = 1). No anastomotic leak or stenosis occurred in either group. The mean percentage of excess weight loss at 1 month was 21.3 % +/- 5.4 %, without a significant difference between the two groups. CONCLUSION: In the study cohort, the use of knotless unidirectional barbed suture instead of traditional monofilament absorbable suture had similar 30-day outcomes and appears to be a feasible option for laparoscopic bowel closure and anastomosis creation. PMID- 23093244 TI - Mechanisms of ventilator dependence in children with neuromuscular and respiratory control disorders identified by monitoring diaphragm electrical activity. AB - OBJECTIVES: To report on the monitoring of diaphragm electrical activity (Edi) using neurally adjusted ventilator assist (NAVA) technology to investigate the mechanisms of ventilator dependence in children with neuromuscular and respiratory control disorders. PATIENTS AND METHODS: Using NAVA technology, electrical activity of the diaphragm (Edi) was monitored at the lowest achievable level of respiratory support in six ventilator-dependent patients with neuromuscular and respiratory control disorders, aged 6 weeks to 12 years, admitted to a tertiary paediatric intensive care unit between 2009 and 2011. RESULTS: Edi monitoring identified markedly abnormal respiratory dynamic patterns that were not always apparent clinically. These were associated with disorders of central respiratory control, muscle weakness and diaphragm pathology. CONCLUSIONS: Edi monitoring using NAVA technology is a valuable, minimally invasive, diagnostic adjunct in children with neuromuscular and respiratory control disorders who are ventilator-dependent. PMID- 23093245 TI - Immature platelet fraction in predicting sepsis in critically ill patients. AB - PURPOSE: To establish whether in critically ill patients without sepsis at intensive care unit (ICU) admission the percentage immature platelet fraction (IPF%) is a cellular marker predicting sepsis to verify a possible correlation between IPF% changes and manifest sepsis and describe the IPF% time course after ICU admission. METHODS: Prospective, observational 7-day study of 64 adult patients admitted to a general ICU at a University Hospital with no sepsis criteria. We measured daily IPF%, procalcitonin (PCT), C-reactive protein, platelets, white blood cell count and coagulation variables. Thirty-one patients with sepsis at ICU admission were studied as controls. RESULTS: The only variable we tested at ICU admission that predicted sepsis was plasma IPF% (p < 0.001; >4.7 %: sensitivity 56.2 % IC 37.7-73.6; specificity 90.0 % IC 73.4-97.8). IPF% and PCT values were higher for the patients who had sepsis at admission and during the study than in patients in whom sepsis never developed (IPF%: p = 0.017; PCT: p = 0.030). Among the outcome variables, logistic regression was identified as the only variable related to the development of sepsis, IPF% (r = 0.51; p = 0.004). In patients who developed sepsis IPF% was inversely correlated with platelet count (r = -0.60; p < 0.001) and had high values before sepsis became manifest, decreasing significantly on the 2nd day thereafter. CONCLUSIONS: In patients without sepsis at ICU admission IPF% increases before sepsis becomes manifest. Measuring IPF% through an easily available technology can therefore provide an early cellular marker predicting the development of sepsis. PMID- 23093246 TI - Intensive care unit environment may affect the course of delirium. AB - PURPOSE: Delirium is a common disorder in intensive care unit (ICU) patients. It is unclear whether ICU environment affects delirium. We investigated the influence of ICU environment on the number of days with delirium during ICU admission. METHODS: In this prospective before-after study, ICU delirium was compared between a conventional ICU with wards and a single-room ICU with, among others, improved daylight exposure. We included patients admitted for more than 24 h between March and June 2009 (ICU with wards) or between June and September 2010 (single-room ICU). Patients who remained unresponsive throughout ICU admission were excluded. The presence of delirium in the preceding 24 h was assessed daily with the confusion assessment method for the ICU (CAM-ICU) by research physicians combined with evaluation of medical and nursing charts. The number of days with delirium was investigated with Poisson regression analysis. RESULTS: We included 55 patients (449 observation days) in the ICU with wards and 75 patients (468 observation days) in the single-room ICU. After adjusting for confounding, the number of days with delirium decreased by 0.4 days (95 % confidence interval 0.1-0.7) in the single-room ICU (p = 0.005). The incidence of delirium during ICU stay was similar in the ICU with wards (51 %) and in the single-room ICU (45 %, p = 0.53). CONCLUSIONS: This study is the first to show that ICU environment may influence the course of delirium in ICU patients. PMID- 23093247 TI - The semi-seated position slightly reduces the effort to breathe during difficult weaning. AB - PURPOSE: The influence of posture on breathing effort in patients with difficult weaning is unknown. We hypothesized that posture could modulate the breathing effort in difficult-to-wean patients. METHODS: A prospective, crossover, physiologic study was performed in 24 intubated patients breathing with pressure support who had already failed a spontaneous breathing trial or an extubation episode. Their median duration of mechanical ventilation before measurements was 25 days. Breathing pattern, occlusion pressure (P (0.1)), intrinsic PEEP (PEEP(i)), and inspiratory muscle effort evaluated by the pressure-time product of the respiratory muscles and the work of breathing were measured during three postures: the seated position in bed (90 degrees LD), simulating the position in a chair, the semi-seated (45 degrees ), and the supine (0 degrees ) positions consecutively applied in a random order. A comfort score was obtained in 17 cooperative patients. The influence of position on chest wall compliance was measured in another group of 11 sedated patients. RESULTS: The 45 degrees position was associated with the lowest levels of effort (p <= 0.01) and occlusion pressure (p < 0.05), and tended to be more often comfortable. Respiratory effort was the lowest at 45 degrees in 18/24 patients. PEEP(i) and PEEP(i)-related work were slightly higher in the supine position (p <= 0.01), whereas respiratory effort, heart rate, and P (0.1) values were increased in the seated position (p < 0.05). CONCLUSION: A 45 degrees position helps to unload the respiratory muscles, moderately reduces PEEP(i), and is often considered as comfortable. The semi-seated position may help the weaning process in ventilator dependent patients. PMID- 23093249 TI - TransFLP--a method to genetically modify Vibrio cholerae based on natural transformation and FLP-recombination. AB - Several methods are available to manipulate bacterial chromosomes(1-3). Most of these protocols rely on the insertion of conditionally replicative plasmids (e.g. harboring pir-dependent or temperature-sensitive replicons(1,2)). These plasmids are integrated into bacterial chromosomes based on homology-mediated recombination. Such insertional mutants are often directly used in experimental settings. Alternatively, selection for plasmid excision followed by its loss can be performed, which for Gram-negative bacteria often relies on the counter selectable levan sucrase enzyme encoded by the sacB gene(4). The excision can either restore the pre-insertion genotype or result in an exchange between the chromosome and the plasmid-encoded copy of the modified gene. A disadvantage of this technique is that it is time-consuming. The plasmid has to be cloned first; it requires horizontal transfer into V. cholerae (most notably by mating with an E. coli donor strain) or artificial transformation of the latter; and the excision of the plasmid is random and can either restore the initial genotype or create the desired modification if no positive selection is exerted. Here, we present a method for rapid manipulation of the V. cholerae chromosome(s)(5) (Figure 1). This TransFLP method is based on the recently discovered chitin mediated induction of natural competence in this organism(6) and other representative of the genus Vibrio such as V. fischeri(7). Natural competence allows the uptake of free DNA including PCR-generated DNA fragments. Once taken up, the DNA recombines with the chromosome given the presence of a minimum of 250 500 bp of flanking homologous region(8). Including a selection marker in-between these flanking regions allows easy detection of frequently occurring transformants. This method can be used for different genetic manipulations of V. cholerae and potentially also other naturally competent bacteria. We provide three novel examples on what can be accomplished by this method in addition to our previously published study on single gene deletions and the addition of affinity-tag sequences(5). Several optimization steps concerning the initial protocol of chitin-induced natural transformation(6) are incorporated in this TransFLP protocol. These include among others the replacement of crab shell fragments by commercially available chitin flakes(8), the donation of PCR-derived DNA as transforming material(9), and the addition of FLP-recombination target sites (FRT)(5). FRT sites allow site-directed excision of the selection marker mediated by the Flp recombinase(10). PMID- 23093248 TI - Copeptin as a marker of relative arginine vasopressin deficiency after pediatric cardiac surgery. AB - PURPOSE: Relative arginine vasopressin (AVP) deficiency after pediatric cardiac surgery has recently been described. Copeptin, a more stable and easily measured product of pro-AVP processing, may be a means of identifying these patients. We aimed to determine if copeptin was correlated with AVP in these children and whether it can be a surrogate marker of relative AVP deficiency. METHODS: Patients <6 years of age with basic Aristotle scores >=7 requiring surgery with cardiopulmonary bypass were prospectively enrolled. Plasma AVP and copeptin concentrations were measured pre-cardiopulmonary bypass and 4 and 24 h post cardiopulmonary bypass. Relative AVP deficiency was defined a priori based on our previous work as AVP <9.2 pg/ml at 4 h post-cardiopulmonary bypass. RESULTS: Of 41 children enrolled, relative AVP deficiency was present in 13 (32 %). AVP and copeptin concentrations were significantly lower in these 13 children at 4 h post cardiopulmonary bypass as compared to the other 28 patients. A significant positive association between plasma AVP and copeptin concentrations over time was determined. Based on log-transformed analyses, a 1 % increase in plasma AVP led to a 0.19 % increase in copeptin. Further, copeptin <1.12 ng/ml at 4 h post cardiopulmonary bypass had a sensitivity of 92 % and a negative predictive value of 95 % for relative AVP deficiency. CONCLUSIONS: Plasma AVP and copeptin are positively associated in children undergoing cardiac surgery. Copeptin may represent a useful means of identifying relative AVP deficiency in these patients. PMID- 23093252 TI - The potential of circulating tumor cells as a liquid biopsy to guide therapy in prostate cancer. AB - Miyamoto and colleagues present data that prostate-specific antigen/prostate specific membrane antigen (PSA/PSMA)-based measurements of androgen receptor (AR) signaling in circulating tumor cells (CTC) enable real-time quantitative monitoring of intratumoral AR signaling. This finding indicates that measuring AR signaling within CTCs may help to guide therapy in metastatic prostate cancer and highlights the use of CTCs as liquid biopsy. PMID- 23093250 TI - Assessment of the F9 genotype-specific FIX inhibitor risks and characterisation of 10 novel severe F9 defects in the first molecular series of Argentinian patients with haemophilia B. AB - In haemophilia B (HB) (factor IX [FIX] deficiency), F9 genotype largely determines clinical phenotype. Aimed to characterise Argentinian families with HB, this study presents F9 genotype frequencies and their specific FIX inhibitor risk and 10 novel F9 mutations. Ninety-one DNA samples from HB patients and relatives were subjected to a new scheme: a primary screen for large deletions, a secondary screen for point mutations using conformation sensitive gel electrophoresis, DNA-sequencing and bioinformatic analysis. Our unbiased HB population (N=52) (77% with severe, 11.5% moderate and 11.5% mild HB) showed 32 missense (61.5%), including three novel mutations predicting specific structural/functional defects in silico , seven nonsense (13.5%) (one novel), five large deletions, four splice including three novel mutations affecting predicted splicing scores, three indels (two novel) and one Leiden mutation. Our comprehensive HB population included five patients with long-lasting FIX inhibitors: three nonsense (p.E35* (novel), p.R75*, p.W240*) and two entire- F9 deletions. Another patient with an indel (p.A26Rfs*14) developed transient inhibitors. A case-control analysis, based on our global prevalence of 3.05% for developing inhibitors in HB revealed that missense mutations were associated with a low risk odds ratio (OR) of 0.05 and a prevalence of 0.39%, whereas nonsense and entire- F9 deletions had significantly higher risks (OR 11.0 and 32.7) and prevalence (14.3% and 44.5%, respectively). Our cost-effective practical approach enabled identification of the causative mutation in all 55 Argentine families with HB, analysis of the molecular pathology of novel F9 defects and determination of mutation-associated FIX inhibitor risks. PMID- 23093251 TI - Androgen receptor signaling in circulating tumor cells as a marker of hormonally responsive prostate cancer. AB - Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumor cells (CTC) to measure AR signaling readouts before and after therapeutic interventions. Single-cell immunofluorescence analysis revealed predominantly "AR-on" CTC signatures in untreated patients, compared with heterogeneous ("AR-on, AR-off, and AR-mixed") CTC populations in patients with CRPC. Initiation of first-line ADT induced a profound switch from "AR-on" to "AR-off" CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of "AR-mixed" CTCs and increasing "AR-on" cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer. SIGNIFICANCE: Acquired resistance to first-line hormonal therapy in prostate cancer is heterogeneous in the extent of AR pathway reactivation. Measurement of pre- and posttreatment AR signaling within CTCs may help target such treatments to patients most likely to respond to second-line therapies. PMID- 23093253 TI - High-fidelity simulation increases obstetric self-assurance and skills in undergraduate medical students. AB - OBJECTIVE: Teaching intrapartum care is one of the most challenging tasks in undergraduate medical education. High-fidelity obstetric simulators might support students' learning experience. The specific educational impact of these simulators compared with traditional methods of model-based obstetric teaching has not yet been determined. STUDY DESIGN: We randomly assigned 46 undergraduate medical students to be taught using either a high-fidelity simulator or a scale wood-and-leather phantom. Their self-assessments were evaluated using a validated questionnaire. We assessed obstetric skills and asked students to solve obstetric paper cases. MAIN OUTCOME MEASURES: Assessment of fidelity-specific teaching impact on procedural knowledge, motivation, and interest in obstetrics as well as obstetric skills using high- and low-fidelity training models. RESULTS: High fidelity simulation specifically improved students' feeling that they understood both the physiology of parturition and the obstetric procedures. Students in the simulation group also felt better prepared for obstetric house jobs and performed better in obstetric skills evaluations. However, the two groups made equivalent obstetric decisions. CONCLUSION: This study provides first data on the impact of high-fidelity simulation in an undergraduate setting. PMID- 23093254 TI - Mode of anaesthesia on fetal acid-base status at caesarean section. AB - OBJECTIVE: To study fetal acid-base status and its implications under different modes of anaesthesia for caesarean sections. METHODS: A prospective cohort study was conducted of 196 consecutive women with singleton non-anomalous fetuses who underwent either elective or emergency caesarean section after 36 completed weeks. Immediately after the baby was delivered, blood was drawn from the umbilical vein and one of the umbilical arteries and sent in ice for acid-base analysis. Maternal demographics, pre-existing medical conditions and antenatal complications were retrieved from antenatal records. Apgar scores and admissions to neonatal intensive care units (NICUs) were noted. RESULTS: Six women were excluded from analysis because the umbilical venous blood was either not collected or clotted. Another two were excluded because of placental abruption. The number of subjects that received spinal, epidural and general anaesthesia were 134, 36 and 18, respectively. Apgar scores were higher in spinal anaesthesia and epidural anaesthesia group (P<0.01). General anaesthesia was associated with a higher incidence of fetal acidaemia, both in the umbilical artery and vein. Spinal anaesthesia was associated with the highest pH in umbilical venous blood. Base excess in umbilical venous samples was highest in the spinal anaesthesia group (P=0.006), although pH values were similar for the three groups. There was no difference in admissions to NICU. CONCLUSIONS: This study provided evidence of the advantages of spinal anaesthesia over epidural and general anaesthesia. Our findings are in contrast with recent evidence in the literature. PMID- 23093255 TI - Role of automation in neonatal respiratory support. AB - Premature infants frequently present with respiratory instability, which is associated with fluctuations in ventilation and gas exchange. Adjustment of respiratory support to the infant's needs is limited by staff availability and workload. Hence, automation is being explored as a way to improve the care of the premature infants. New modes of automatic respiratory support are being developed and becoming available for clinical use in preterm infants. These modes are expected to compensate for some of the limitations that presently exist in the conventional forms of respiratory support. Available evidence and preliminary findings are promising, but further investigation is needed to determine the effects of these modalities on the long-term outcome of preterm infants. PMID- 23093256 TI - Vaginal progesterone to prevent preterm birth in multiple pregnancy: a randomized controlled trial. AB - AIM: We sought to assess the effect of progesterone in increasing or decreasing duration of pregnancy for mothers with twins and triplets. METHODS: Women with multiple pregnancy were randomized at 16+0 to 20+6 weeks' gestation to receive daily doses of either 90 mg progesterone vaginal gel or placebo until 35+6 weeks or delivery. Primary outcome was gestational age (GA) at delivery. Secondary outcomes included preterm birth, infant morbidity and mortality, and adverse events up to 28 days after delivery. A sample size of 40 per group was required to detect a 2-week difference in GA at delivery. RESULTS: Eighty-four women were randomized (42 to progesterone, 42 to placebo). Median GA at delivery was 36+3 and 36+2, respectively (difference, 1 day; 95% confidence interval, 4 to -1 days, P=0.585). There were no clinically or statistically significant differences between groups for risk of delivery before 35 or 37 weeks' GA, rates of infant morbidity and mortality, treatment compliance, or adverse events. CONCLUSIONS: Daily treatment with progesterone gel did not prolong multiple pregnancy compared with placebo. Effective prevention strategies are needed to reduce preterm deliveries among women with multiple gestations. PMID- 23093257 TI - Development of integrative autonomic nervous system function: an investigation based on time correlation in fetal heart rate patterns. AB - OBJECTIVE: To describe the development of the integrative capacity of the fetal autonomic nervous system (ANS) according to gestational age and emerging behavioral states, assuming that developing integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate and fetal heart rate variability markers. METHODS: Magnetocardiograms of 114 healthy fetuses (21-40 weeks of gestation) were recorded. Level of fetal activity (quiet/active sleep) was estimated according to characteristic heart rate patterns. Autocorrelation functions of (i) fetal heart rate and (ii) time patterns of SDNN (standard deviation of normal-to-normal intervals) and RMSSD (root mean square of successive differences in normal-to-normal intervals) were calculated and autocorrelation was determined over different time scales. Age and activity related changes were examined using linear regression and non-parametric tests. RESULTS: During pregnancy, autocorrelation increased in fetal heart rate signals and time patterns of SDNN and RMSSD. Short-time correlation (0-20 s) changed between 21 and 31 gestational weeks. Long-time correlation (75-300 s) accelerated later in pregnancy and did not increase in quiet heart rate patterns. Strong state-dependent changes were found with time patterns of SDNN. CONCLUSIONS: Emerging integrative ANS functions are reflected in increasing autocorrelation of fetal heart rate fluctuations over increasing time scales. The period from 21 to 31 gestational weeks seems to be critical to ANS development. Increasing long time correlation is specific to active sleep states. PMID- 23093258 TI - Therapeutic management of fetal anemia: review of standard practice and alternative treatment options. AB - Fetal anemia, mainly due to red cell alloimmunization, is still a significant cause of fetal and neonatal mortality and morbidity. The focus of current clinical research has shifted from an invasive approach to non-invasive management and treatment of affected pregnancies, and the progress in this field is associated with a major improvement in perinatal outcome. During the last 50 years, intrauterine red cells transfusion (IUT), fi rst via the intraperitoneal route and later directly to fetal circulation, is the standard practice in most centers, with survival rates that exceed 90 % , particularly if anemia is diagnosed early and treated in a timely manner. In addition, plasmapheresis and intravenous administration of highdose immunoglobulin have been implicated in the treatment of pregnancies complicated with early-onset severe red cell alloimmunization, alone or in combination with IUTs before the 20(th) week of pregnancy, but there are still issues to be clarified further. This review article aims to provide an overview of the current standard therapeutic management and alternative treatment modalities in pregnancies complicated by fetal anemia. PMID- 23093259 TI - An overview of central fetal monitoring systems in labour. PMID- 23093261 TI - Usefulness of an antiglycolytic granular mixture of sodium fluoride and citrate for stabilizing plasma homocysteine levels. PMID- 23093260 TI - Development of a HPLC method for the determination of losartan urinary metabolic ratio to be used for the determination of CYP2C9 hydroxylation phenotypes. AB - BACKGROUND: Losartan is metabolized to losartan carboxylic acid (E-3174) by the polymorphic cytochrome CYP2C9. The aim of the study was to develop a high performance liquid chromatographic (HPLC) method with fluorescence detection for simultaneously measuring losartan and its metabolite E-3174 in urine to evaluate the losartan urinary metabolic ratio (MR: losartan/E-3174) for CYP2C9 phenotyping in humans. METHODS: The compounds were separated in a reversed-phase chromatographic column and detected by fluorescence at a wavelength of 250 nm for excitation and of 370 nm for emission. RESULTS: No analytical interferences with endogenous compounds were found, and the extraction recoveries were over 88%. Limits of quantification of 2 ng mL-1 for losartan and 5 ng mL-1 for E-3174 were achieved, as well as good reproducibility with coefficients of variation of <9% in all cases. Analyses with the present HPLC method show significant differences (p<0.05) in losartan MRs between the four CYP2C9 genotype groups in 13 Spanish healthy volunteers. CONCLUSIONS: The method developed is simple and affordable, as well as sensitive and reliable to calculate the MR. Therefore, it appears to be useful for CYP2C9 phenotyping using losartan as a drug test in populations, such as Hispanics with different allele combinations. PMID- 23093262 TI - Further insights on the relationship between bilirubin and C-reactive protein. PMID- 23093263 TI - Assessing seasonality in clinical research. AB - BACKGROUND: Seasonal patterns are assumed in many fields of medicine. However, biological processes are full of variations and the possibility of chance findings can often not be ruled out. METHODS: Using simulated data we assess whether auto correlation is helpful to minimize chance findings and test to support the presence of seasonality. RESULTS: Autocorrelation required to cut time curves into pieces. These pieces were compared with one another using linear regression analysis. Four examples with imperfect data are given. In spite of substantial differences in the data between the first and second year of observation, and in spite of otherwise inconsistent patterns, significant positive autocorrelations were constantly demonstrated with correlation coefficients around 0.40 (SE 0.14). CONCLUSIONS: Our data suggest that autocorrelation is helpful to support the presence of seasonality of disease, and that it does so even with imperfect data. PMID- 23093264 TI - Risk of false positive hepatitis C virus RNA due to sample to sample carryover on an automated hematology analyzer. PMID- 23093265 TI - The usefulness of cystatin C and related formulae in pediatrics. AB - Serum creatinine does not share the properties of an ideal marker of glomerular filtration rate (GFR) like inulin, but continues to be the most widely used endogenous marker of GFR. In the search of a better biomarker of GFR, the small molecular weight protein cystatin C has been introduced with features more similar to that of inulin, such as constant production and no non-renal elimination. However,it has not enjoyed widespread use despite its significantly improved diagnostic performance in the detection of impaired GFR and its independence of body composition. A variety of formulae based on either cystatin C or creatinine or both have been developed to estimate GFR. We summarize the currently used methods of GFR measurement, their limitations and analytical errors. The review also summarizes the history, features and the feasibility of cystatin C measurements as well as the most widely used formulae for the estimation of GFR in children. The diagnostic performance of the cystatin C derived eGFR formulae at various levels of GFR is also discussed. An eGFR formula derived from pooled studies analyzing both creatinine and cystatin C, and using a biology-based mathematical approach maybe advantageous. PMID- 23093266 TI - Position paper on laboratory testing for patients taking new oral anticoagulants. Consensus document of FCSA, SIMeL, SIBioC and CISMEL1). AB - At variance with vitamin K antagonists, the new oral anticoagulants(NOAs) can be prescribed at fixed dosage without adjustment by laboratory testing. However, this does not necessarily mean that the laboratory does not play a role for their management. This position paper represents the consensus document of three Italian scientific societies dealing with laboratory issues in thrombosis and hemostasis. It is aimed at reviewing: 1) which test(s) should be used to evaluate the anticoagulant effect of each of the NOAs presently available(i.e., dabigatran, rivaroxaban and apixaban); 2) the patients to be investigated; and 3) the timing of investigation. PMID- 23093267 TI - Comparison of diagnostic and prognostic performance of two assays measuring thymidine kinase 1 activity in serum of breast cancer patients. AB - BACKGROUND: We compared two recently developed immunoassays for serum thymidine kinase 1 (TK1) activity: one manual assay (DiviTum, Biovica((r))) and one fully automated assay (Liaison, Diasorin((r))). METHODS: The study included 368 women: 149 healthy blood donors (control), 59 patients with benign breast disease (BBD) and 160 patients with primary breast cancer (BC). RESULTS: A regression analysis of the Liaison (y) and DiviTum (x) assays for all three groups yielded the equation y=3.93+0.03x (r=0.85, n=368). The r-value in BC was higher than in control and BBD (0.90 vs. 0.81 and 0.64). The correlation between the two assays for TK1 values above the cut-off was higher compared to that below (0.88 and 0.59). Breakdown of the BBD group into subgroups with proliferative and non proliferative lesions was effective only with the measurement of TK1 with DiviTum assay (p=0.03). The TK1 activity determined preoperatively in BC patients with DiviTum and Liaison assays was significantly associated with T-stage (for both p=0.01), presence of vascular invasion (p=0.002 and p=0.02), lack of estrogen receptor (ER) (p=0.001 and p=0.01) and progesterone receptor (PR) (p=0.01 and p=0.03) expression. Only TK1 analyzed with the DiviTum assay was associated with tumor grade and molecular subtype of BC (p=0.02 and p=0.003). Multivariate Cox proportional hazards analyses demonstrated that T-stage, PR status and TK1 activity measured by both methods (DiviTum, RR=3.0, p=0.02 and Liaison, RR=3.1, p=0.01) were independent predictors of disease recurrence. CONCLUSIONS: In spite of differences observed between TK1 activity measured by the DiviTum and Liaison assays, both of them may be used for recurrence prediction in preoperative evaluation of BC patients. PMID- 23093268 TI - Kallikrein-related peptidases (KLKs): a gene family of novel cancer biomarkers. AB - Early diagnosis of cancer and early detection of relapse following surgery are critical for the effective treatment of the disease and for a positive clinical outcome. Identification of novel diagnostic, prognostic and predictive biomarkers will contribute utmost to clinical decision-making. The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. The aberrant expression of KLKs in various malignancies as well as their involvement in many cancer-related processes, such as cell growth regulation, angiogenesis, invasion, and metastasis, has prompted scientists to investigate their potential as cancer biomarkers. Expression of distinct KLKs is associated with clinicopathological parameters of cancer patients. Moreover, several KLKs possess significant favorable or unfavorable prognostic value in various malignancies, with prostate specific antigen (PSA) being the most widely used biomarker in clinical practice, today. KLKs are also considered as very promising biomarkers for cancer personalized medicine, especially for prediction and monitoring of patients' response to chemotherapy, therefore opening up new horizons towards effective patient monitoring post-treatment. This review describes the current status of KLKs as tumor biomarkers. PMID- 23093269 TI - Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. AB - BACKGROUND: Low vitamin D concentrations are detected in patients suffering from various clinical conditions which are characterized also by inflammation and immune activation.We investigated whether vitamin D levels in patients with coronary artery disease (CAD) are related to markers of immune activation. METHODS: Serum concentrations of 25-hydroxyvitamin D[25(OH)D] and 1,25 dihydroxyvitamin D [1,25(OH) 2 D] and the immune activation markers neopterin and high sensitivity C-reactive protein (hsCRP) were measured in 2015 patients derived from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, a cohort study among patients referred for coronary angiography. RESULTS: Serum concentrations of 25(OH)D and 1,25(OH) 2 D did not differ between patients with CAD [mean } SD:25(OH)D: 17.4 } 9.4 MU g/L; 1,25(OH) 2 D: 34.4 } 13.3 ng/L] and controls [25(OH)D: 18.4 } 11.7 MU g/L; 1,25(OH) 2 D: 35.3 } 12.7ng/L; Welch ' s t test: p = n.s.] but CAD patients had higher neopterin (8.6 } 7.4 nmol/L) and hsCRP (9.6 } 19.6 mg/L) concentrations compared to controls (neopterin: 7.5 } 4.8 nmol/L;p = 0.0004; hsCRP: 5.4 } 10.0 mg/L; p < 0.0001). There was an inverse correlation between serum 25(OH)D or 1,25(OH) 2 D concentrations and serum neopterin [Spearman ' s rank correlation:25(OH)D: r s = - 0.183; 1,25(OH)2D: r s = - 0.230] and hsCRP [25(OH)D: r s = - 0.142; 1,25(OH) 2 D: r s = - 0.130; allp < 0.0001] concentrations. CONCLUSIONS: Our results indicate increased inflammatory processes in patients with low vitamin D status. Further studies should clarify the underlying mechanisms for the observed associations of vitamin D status and inflammatory parameters. PMID- 23093270 TI - UrineCART, a machine learning method for establishment of review rules based on UF-1000i flow cytometry and dipstick or reflectance photometer. AB - BACKGROUND: Automated systems have been broadly used in the counting of particles in urine, while manual microscopic analyses are still required for confirming components of urine sediments, especially pathologic casts and other unknown particles. Good review rules can reduce the number of manual urine microscopy examinations safely, thereby increasing productivity. Although several methods have been proposed,establishment of microscopic review rules for fl ow cytometer remains challenging. METHODS: A total of 3014 urine samples from outpatient and inpatient were examined using UF-1000i flow cytometry,Urisys-2400 dipstick and RS 2003 urine sediment workstation,respectively. Based on the results above, three supervised machine learning methods were employed to construct classifiers for screening urine samples. RESULTS: Here, we propose a novel method for construction of microscopic review rules, termed UrineCART, which was based on a classification and regression tree (CART) method.With a cut-off value of 0.0745 for Urine CART, we obtained a sensitivity of 92.0 % , a specificity of 81.5 % and a total review rate of 32.4 % on an independent test set. Comparisons with the existing methods showed that Urine CART gave the acceptable sensitivity and lower total review rate. CONCLUSIONS: An algorithm based on machine learning methods for review criteria can be achieved via systematic comparison of UF-1000i flow cytometry and microscopy.Using Urine CART, our microscopic review rate can be reduced to around 30 % , while decreasing significant losses in urinalysis. PMID- 23093271 TI - Laboratory hemostasis: milestones in Clinical Chemistry and Laboratory Medicine. AB - Hemostasis is a delicate, dynamic and intricate system, in which pro- and anti coagulant forces cooperate for either maintaining blood fluidity under normal conditions, or else will prompt blood clot generation to limit the bleeding when the integrity of blood vessels is jeopardized. Excessive prevalence of anticoagulant forces leads to hemorrhage, whereas excessive activation of procoagulant forces triggers excessive coagulation and thrombosis. The hemostasis laboratory performs a variety of first, second and third line tests, and plays a pivotal role in diagnostic and monitoring of most hemostasis disturbances. Since the leading targets of Clinical Chemistry and Laboratory Medicine include promotion of progress in fundamental and applied research, along with publication of guidelines and recommendations in laboratory diagnostics, this journal is an ideal source of information on current developments in the laboratory technology of hemostasis, and this article is aimed to celebrate some of the most important and popular articles ever published by the journal in the filed of laboratory hemostasis. PMID- 23093272 TI - Lack of commutability between a quality control material and plasma samples in a troponin I measurement system. PMID- 23093273 TI - Plasma homocysteine and the risk of venous thromboembolism: insights from the FIELD study. AB - BACKGROUND: The lipid-lowering effect of fenofibrate is accompanied by a rise in plasma homocysteine (HCY), a potential risk factor for venous thromboembolism (VTE).This study investigated the relationship between HCY and the risk of VTE in patients treated with fenofibrate. METHODS: The relationship between HCY and deep vein thrombosis or pulmonary embolism was investigated in 9522 participants of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. All subjects received fenofibrate during a 6-week active run-in phase before randomization.A Cox proportional-hazards model was used to assess the effect of HCY on risk of venous thromboembolic events. RESULTS: During active-drug run-in, HCY rose on average by 6.5 MU mol/L, accompanied by a substantial rise in plasma creatinine ( + 12 % ). Fenofibrate-induced changes in HCY and creatinine were fully reversible in the placebo group but persisted in the treatment group until reversing at the end of therapy. During follow-up, 1.8 % had at least one episode of deep-vein thrombosis or pulmonary embolism: 103 on fenofibrate and 68 on placebo (log-rank p = 0.006). In multivariate analysis, every 5 MU mol/L higher baseline HCY was associated with 19 % higher risk of VTE. Fenofibrate treatment was associated with 52 % higher risk, but the change in HCY with fenofibrate was not significantly associated with VTE after adjustment for baseline HCY. CONCLUSIONS: Hyperhomocysteinemia is prospectively associated with VTE. Fenofibrate may predispose individuals with high pretreatment HCY towards VTE. The fenofibrate induced increase in HCY did not, however, explain the risk associated with fenofibrate therapy. PMID- 23093275 TI - A predictive equation to adjust for clinical variables in soluble mesothelin related protein (SMRP) levels. AB - BACKGROUND: Malignant mesothelioma (MM) is an aggressive pleural tumor which is difficult to diagnose in its early stages. Thus, biomarkers for MM including soluble mesothelin-related protein (SMRP) are currently an area of intense research interest. However, SMRP is affected by several factors other than malignancy which need to be taken into account in the individual patient. This study aimed to evaluate factors required to adjust SMRP levels for such variables and produce a useful prediction equation for clinical application. METHODS: Serum SRMP levels were measured in 535 subjects formerly exposed to asbestos and silica, including many with asbestos-related disorders (ARDs). Linear regression analyses were used to quantify the strength and " direction " of the relationship between SMRP and several independent variables,and 2 * 2 tables were used to determine the diagnostic accuracy of SMRP levels, taking into account clinical variables. RESULTS: SMRP levels were affected by age and glomerular filtration rate (GFR), which were strong confounders in this study. Body mass index (BMI) was also an initial confounder but lost significance after other factors were taken into account.SMRP was also affected by smoking. Poor sensitivity (15.1 % )for SMRP values among subjects with non-malignant asbestos-related disorders was found when compared to currently healthy subjects with a history of asbestos exposure. CONCLUSIONS: The present study proposes an equation based on age and GFR to improve diagnostic accuracy of SMRP.The poor sensitivity of SMRP found in this study suggests that further work is needed to fi nd new candidate biomarkers for diagnosing early stage MM. PMID- 23093274 TI - Association of acute phase protein-haptoglobin, and epithelial-mesenchymal transition in buccal cancer: a preliminary report. AB - BACKGROUND: The aim of this study was to determine the influence of inflammation on acute phase protein and epithelial-mesenchymal transition (EMT) in buccal cancer. METHODS: Western blotting was carried out to investigate the expression of haptoglobin and epithelial-mesenchymal transition in oral cancer cell lines with or without IL-6 stimulation. We studied patients with buccal cancer patients without distant metastasis at diagnosis. Correlation between cellular haptoglobin, EMT, and clinical characteristics of buccal cancer was analyzed to assess the prognostic value of cellular haptoglobin level and EMT. The relationship of haptoglobin, and EMT expression with survival was assessed using Cox proportional hazard models. RESULTS: Western blotting analysis showed that increased haptoglobin protein was associated with overexpression of vimentin. Under IL-6 stimulation, overexpression of haptoglobin, EMT-associated motile phenotype was noted in OC2 cell lines. Overexpression of haptoglobin was also associated with an increased risk for locoregional recurrence [hazard ratio (HR) 1.04; p=0.011] after adjusting for age, gender, disease site, stage, and treatment modality. CONCLUSIONS: Increased cellular expression of haptoglobin is associated with EMT in oral cancer cell lines and this phenomenon could be exaggerated with IL-6. Cellular expression of haptoglobin is related to locoregional recurrence rate in buccal cancer patients. PMID- 23093276 TI - Human epididymis protein 4 (HE4) in benign and malignant diseases. AB - BACKGROUND: Human epididymis protein 4 (HE4) is described as a useful new biomarker in ovarian cancer. As HE4 is neither tumor nor organ specific, we intensively investigated the occurrence of this protein in female and male patients with various benign and malignant diseases in order to avoid misinterpretation and to identify potential additional clinical relevance. METHODS: We retrospectively investigated HE4(ARCHITECT R , Abbott Diagnostics, US) in the sera of 205 healthy individuals, 654 patients with benign disorders and 720 patients with cancer before initial treatment. RESULTS: The lowest concentrations of HE4 were observed in healthy men (median 26.2 pmol/L) followed by healthy women (median 40.4 pmol/L). In benign diseases, highest HE4 concentrations were seen in both women and men with renal failure (women, median 1041 pmol/L; men, median 1368pmol/L). In women, the highest HE4 levels in malignant diseases were observed in ovarian cancer (median 242 pmol/l),whereas the highest HE4 concentrations in men occurred in lung cancer (median 89.2 pmol/L). The area under the curve(AUC) of HE4 in women was highest in ovarian cancer and borderline tumors as compared to benign gynecological disorders(88.9 % ), with a sensitivity of 67.4 % at 95 % specificity.Also, significantly elevated concentrations of HE4 with reference to the respective group of benign diseases were observed in uterus corpus and breast cancer as well as in lung cancer for men and women. CONCLUSIONS: HE4 has the highest relevance in ovarian cancer but can be elevated in a variety of benign and malignant diseases. PMID- 23093277 TI - HE4 in gynecological cancers: report of a European investigators and experts meeting. AB - The HE4 protein, which belongs to the " four disulfi de " acid protein group, has emerged as one of the most promising biomarkers in gynecologic oncology. An expert meeting on the analytical and clinical performance of the quantitative determination of HE4 was held in November 2011, involving 25 clinical and laboratory specialists from 16 European countries.The aim of the meeting was to present and discuss the results of recent studies on the use of HE4 and on the Risk of Ovarian Malignancy Algorithm (ROMA), which combines the results of HE4 and CA 125. The meeting was structured in separate sessions focusing on ovarian cancer risk stratification, differential diagnosis, prognosis and monitoring and with diagnosis and monitoring of endometrial cancer. We present here a summary of the data and evidence, presented, together with consensus statements on the different topics, where available,and suggestions for further studies and evaluations required to establish optimal use of HE4, either alone or in combination with other markers, for diagnostic and prognostic purposes in gynecological malignancies. Available evidences support the utility of this new cancer biomarker for risk stratification,prognosis and monitoring of epithelial ovarian cancer and of endometrial cancer. PMID- 23093278 TI - An internal validation approach and quality control on hematopoietic chimerism testing after allogeneic hematopoietic cell transplantation. AB - BACKGROUND: Hematopoietic chimerism analysis is important in the follow-up of patients undergoing allogeneic stem cell transplantation. PCR of short tandem repeats is mainly used for monitoring chimerism after transplantation. Validation studies and precision of assay's performance with respect to different mixed chimerism stages is not fully addressed. The aim of the present study was to assess the impact of several microsatellite analytical parameters in the quantification of hematopoietic chimerism after allogeneic hematopoietic stem cell transplantation and to analyze the overall analytical process through the application of internal quality control procedures. METHODS: Artificial DNA mixtures prepared in known proportions and patients samples were analyzed using three microsatellites, together with amplification of amelogenin gene and fluorescence in situ hybridization (FISH) for X and Y chromosomes. Limit of detection, analytical and clinical sensitivity, stochastic threshold and precision profiling was established. Levey-Jennings charts and Westgard rules were applied for quality control evaluation. RESULTS: Analytical and clinical sensitivity of the microsatellite markers was between 0.5% and 1.6%. Amelogenin detection and FISH for X and Y chromosomes showed a similar sensitivity. Severe allelic imbalance resulted in up to 50% difference between the calculated and corrected mixed chimerism. Systematic errors were identified using Levey-Jennings charts and Westgard rules. CONCLUSIONS: Analysis of hematopoietic chimerism performance is a critical step to better understand potential intrinsic errors that may impact the final hematopoietic chimerism results. Implementing quality control tools, such as Levey-Jennings charts together with Westgard rules can identify systematic and random errors so corrective actions can be performed. PMID- 23093279 TI - Clinical Chemistry and Laboratory Medicine: progress and new challenges for our 50-year-old journal. PMID- 23093281 TI - Biological variation in pregnancy-associated plasma protein-A in healthy men and non-pregnant healthy women. PMID- 23093282 TI - Analytical validation of the Roche 25-OH Vitamin D Total assay. AB - BACKGROUND: Vitamin D deficiency is considered a major health issue and therefore there is a need for reliable routine tests for measurement of the vitamin in blood samples. Here we present a validation of the recently released Roche 25-OH Vitamin D Total assay (Vitamin D Total). METHODS: We analyzed control materials (2 levels) and patient serum pools (3 levels) ranging from 34 to 123 nmol/L 84 times over a period of 21 days, and we analyzed five serum pools in 10 separate runs to verify the limit of quantification. We also analyzed 53 paired samples of serum and Li-heparin plasma. We evaluated the 25-OH Vitamin D Total assay in comparison to our in-house liquid chromatography tandem mass spectrometry (LC MS/MS) method [194 patient samples without 25-hydroxy vitamin D(2) (25OHD(2)) and 23 patient samples containing 25OHD(2)]. RESULTS: At concentrations of 34 and 56 nmol/L within-run CVs were 4.8% and 1.9% and total CVs were 8.3% and 6.1%. We verified that the limit of quantification was 22.5 nmol/L, as stated by the manufacturer. No significant difference was observed between serum and plasma samples (Li-heparin). Comparison with LC-MS/MS using 194 samples containing 25OHD(3) only (no 25OHD(2)) showed Vitamin D Total nmol/L=1.07*(LC-MS/MS) nmol/L+4.7 nmol/L, whereas comparison of 25OHD(2) using 23 patient samples showed Vitamin D Total nmol/L=0.55*(LC-MS/MS) nmol/L-2.38 nmol/L (Demings regression). CONCLUSIONS: The Roche Vitamin D Total assay is judged suitable for measurement of 25OHD in serum and Li-heparin plasma. Results for 25OHD(3) are comparable to those obtained by LC-MS/MS, while results for 25OHD(2) are around half of those obtained by LC-MS/MS. PMID- 23093283 TI - Calculating acid-base and oxygenation status during COPD exacerbation using mathematically arterialised venous blood. AB - BACKGROUND: Repeated arterial puncture is painful. A mathematical method exists for transforming peripheral venous pH, PCO 2 and PO 2 to arterial eliminating the need for arterial sampling. This study evaluates this method to monitor acid base and oxygenation during admission for exacerbation of chronic obstructive pulmonary disease (COPD). METHODS: Simultaneous arterial and peripheral venous blood was analysed. Venous values were used to calculate arterial pH, PCO 2 and PO 2, with these compared to measured values using Bland-Altman analysis and scatter plots. Calculated values of PO 2 were assessed with previously defi ned rules.Differences between maximal changes of calculated and measured values were compared using a t-test, with trends analysed by inspection of plots. RESULTS: Fifty-four patients, median age 67 years (range 62 - 75), were studied on average 3 days. Mean values of pH,PCO 2 and PO 2 were 7.432 } 0.047, 6.8 } 1.7 kPa and 9.2 } 1.5kPa, respectively. Calculated and measured arterial pH and PCO 2 agreed well, differences having small bias and SD(0.000 } 0.022 pH, - 0.06 } 0.50 kPa PCO 2 ), significantly better than venous blood alone. Calculated PO 2 obeyed the clinical rules. Calculated values could track patients, with no significant differences in maximal changes in measured and calculated values (pH p = 0.96, PCO 2 p = 0.62, PO 2 p = 0.33), and time-course plots matching quantity and pattern of change in measurements. CONCLUSIONS: This study shows that arterial pH, PCO 2 and PO 2 can be calculated from peripheral venous values so as to characterise changes seen during exacerbation. Application of the method has potential to reduce arterial sampling, decrease discomfort and enable venous sampling as routine practice. PMID- 23093284 TI - A two-base-pairs deletion in the albumin gene causes a new case of analbuminemia. PMID- 23093285 TI - Evaluation of the local temperature of conductive filaments in resistive switching materials. AB - The resistive switching effect in metal oxides and other dielectric materials is among the leading future non-volatile memory technologies. Resistive switching is widely ascribed to the formation and rupture of conductive filaments in the oxide, which are generated by temperature-enhanced nano-scale ion migration or other thermal effects. In spite of the central role of the local filament temperature on the switching effect, as well as on the conduction and reliability physics, no measurement methods of the filament temperature are yet available. In this work, we report on a method for evaluating the conducting filament temperature, using a metal-insulator-semiconductor bipolar transistor structure. The filament temperature is obtained by analyzing the thermal excitation rate of electrons from the filament Fermi level into the conduction band of a p-type semiconductor electrode. Measurements were carried out to obtain the conductive filament temperature in hafnia at varying ambient temperatures in the range of 3 300 K. Significant Joule heating of the filament was observed across the entire measured ambient temperature range. The extracted temperatures provide physical insight into the resistive switching effect. PMID- 23093286 TI - Localized control of light-matter interactions by using nanoscale asymmetric TiO2. AB - This paper reports an asymmetry structure-mediated route for highly localized control of light-matter interactions by using tapered TiO(2). We demonstrate for the first time that the growth habit of Ag nanostructures on tapered TiO(2) can be tuned by controllable photolysis. Site-selective anchoring of Ag nanoparticles or nanowires on tapered TiO(2) can be achieved by simply changing the external light. We further show that the obtained tapered TiO(2)-Ag hetero nanostructures present excellent light-trapping ability over a wide range of wavelengths which is considered to originate from the unique synergistic effects of graded waveguiding and plasmonic light trapping. This improved photon management capability renders the prepared substrate a very promising candidate for optical sensing application. For this purpose, an enhanced sensitivity for trace detection is confirmed. These findings open up promising avenues for tailoring of light-matter interactions which are of special interest for studying controllable photolysis activation processes and diverse applications such as nanostructure growth, trace detection, photocatalysis and solar cells. PMID- 23093287 TI - Does anti-tumour necrosis factor-alpha increase oral candida colonization? A case control study in psoriatic patients. PMID- 23093288 TI - Hysteretic carbon dioxide sorption in a novel copper(II)-indazole-carboxylate porous coordination polymer. AB - The synthesis, structural and gas sorption studies of a porous Cu(II) coordination polymer featuring 1H-indazole-5-carboxylic acid (H(2)L) are presented. [Cu(HL)(2)] is a thermally and hydrolytically robust 4-connected 3D coordination polymer of NbO topology and is replete with 1D channels that permit selective and hysteretic sorption of CO(2). PMID- 23093289 TI - Bosworth hip shelf arthroplasty in adult dysplastic hips: ten to twenty three year results. AB - PURPOSE: Hip shelf arthroplasty is currently considered to be a salvage procedure. The aim of the study is to present outcomes of Bosworth hip shelf arthroplasty in adolescent dysplastic hips with a minimum ten-year follow-up. METHODS: The basic group comprised 25 hips in 18 patients with the mean age of 31 years (range, 16-52) at the time of operation. Subgroup A included 20 hips that were evaluated prior to operation as spherical, centric hips without osteoarthritic changes (acetabular dysplasia). The heterogeneous subgroup B comprised five hips. Of these, three hips were evaluated as aspheric, without osteoarthritic changes, and two hips as aspheric, with osteoarthritic changes of grade 2 according to Tonnis. In addition, two hips in subgroup B were evaluated as decentred (subluxated), one hip without and one hip with osteoarthritic changes. The mean follow-up was 15 years (range, ten-23). RESULTS: In subgroup A, the positive effect of operation had lasted at the time of the final follow-up for ten to 22 years postoperatively (average follow-up 14 years) in 19 hips. Only one female patient, 46 years old at the time of operation, developed hip osteoarthritis within ten years, that was treated by THA. In subgroup B, a lasting positive effect of operation was recorded in two cases at the time of the final follow-up (12 and 15 years). The third female patient with an aspheric and decentred hip developed severe hip osteoarthritis 21 years after shelf procedure that was treated by THA. In two patients who had hip osteoarthritis already before the operation, the positive effect of the shelf procedure survived over 13 and 20 years. Although hip osteoarthritis progressed, THA was performed as late as 15 and 23 years after the shelf procedure. The mean Harris hip score in 21 hips with a still functional hip shelf was 68 (range, 56-82) before and 90 (range, 76-100) after the surgery. CONCLUSION: The best outcomes of Bosworth hip shelf arthroplasty may be expected in a dysplastic spherical centred hip without osteoarthritic changes. In the presence of asphericity, decentration and osteoarthritic changes, neither the effect of the surgery nor its survival can be clearly predicted. PMID- 23093290 TI - Arthroscopic radial head excision in managing elbow trauma. AB - PURPOSE: This study describes a case series of 15 patients with radial head fractures who underwent radial head excision using an arthroscopic technique. METHODS: Over a four year period, 15 patients (average age 49.6 years) who had sustained a radial head or radial neck fracture underwent an arthroscopic excision of the radial head. Four patients had an unreconstructable comminuted fracture (early group; EG) and 11 patients had pain and loss of motion with an associated non- or malunion (late group; LG). RESULTS: The mean time to surgery following injury was three weeks (one to five) for the EG and 27 weeks (eight-58) for the LG. The average visual analogue scale (VAS) was 1.7 (zero to four), and the average Quick Disabilities of the Arm, Shoulder and Hand (Quick-DASH) score was 24.7 (16-44). At final follow-up, average supination was 62.0 degrees (range 45-75 degrees ) and pronation was 63.3 degrees (range 45-75 degrees ). There were no complications. CONCLUSION: This series demonstrates that arthroscopic excision of fractures of the radial head and neck is reliable, reproducible and safe, with similar results to open excision. There may also be additional benefits in the short term with regards to speed of healing and rehabilitation. PMID- 23093292 TI - Narrow intersubband transitions in n-type Ge/SiGe multi-quantum wells: control of the terahertz absorption energy trough the temperature dependent depolarization shift. AB - In this paper we present a detailed study of the intersubband absorption occurring between electron states confined in strained Ge multi-quantum wells as a function of the temperature. The high structural quality of the samples is reflected by the very narrow absorption line-shape constant with temperature. We observe a temperature driven charge transfer occurring between the ground and the first excited subband which, in turn, induces a change in the depolarization shift and consequently in the energy of the absorbance peak. The experimental observations are well accounted for by a multi-valley k.p model. PMID- 23093291 TI - Double incision iso-anatomical ACL reconstruction: the freedom to place the femoral tunnel within the anatomical attachment site without exception. AB - AIM: The present paper describes the rationale behind the surgical technique and the clinical results of the iso-anatomical, single bundle bone patellar-tendon bone anterior cruciate ligament (ACL) reconstruction. METHOD: Using a second incision on the distal lateral femur an outside-in femoral tunnel is drilled. Guided by a special aiming device it is possible to place the femoral tunnel in the centre of the ACL footprint in every single case. CONCLUSION: Since every crucial step of the procedure is under visual control, the technique is safe and reliable, which is mirrored by good clinical results. PMID- 23093293 TI - Theoretical and experimental studies of water interaction in acetate based ionic liquids. AB - Water interactions in 1-ethyl-3-methylimidazolium acetate ([emim][CH(3)COO]) were studied utilizing classical and ab initio simulation methods. The self diffusivities for water and the ionic liquid (IL) were studied experimentally using pulse field gradient NMR spectroscopy and correlated with computational results. Water forms hydrogen bonding networks with the ionic liquid, and depending on the concentration of water, there are profound effects on the self diffusivities of the various species. Both simulation and experiments show that the self-diffusivities for species in the water-[emim][CH(3)COO] system exhibit minima at 40-50 mol% water. Water interaction with the [CH(3)COO](-) anion predominates over the water-water and water-cation interactions at most water concentrations. Simulations further indicate that decreasing water-[CH(3)COO](-) interaction will increase the IL and water self-diffusivities. Self-diffusivities in the water-IL systems are dependent upon the cation in a complex way. Water interactions with [P(4444)][CH(3)COO] are reduced compared to [emim][CH(3)COO]. The [P(4444)](+) cation is bulkier than the [emim](+) cation and has a smaller self-diffusivity, but when water was introduced to [P(4444)] [CH(3)COO], the water-[CH(3)COO](-) hydrogen bonding network in the [P(4444)][CH(3)COO] was much smaller than the one observed in [emim][CH(3)COO]. PMID- 23093294 TI - Development of a screening instrument for risk factors of persistent pain after breast cancer surgery. AB - BACKGROUND: Persistent postsurgical pain can have a significant effect on the quality of life of women being treated for breast cancer. The aim of this prospective study was to develop a screening tool to identify presurgical demographic, psychological and treatment-related factors that predict persistence of significant pain in the operated area after 6 months from surgery. METHODS: Background and self-reported questionnaire data were collected the day before surgery and combined with treatment-related data. Pain in the operated area was assessed 6 months after surgery with a questionnaire. The Bayesian model was used for the development of a screening tool. RESULTS: Report of preoperative chronic pain, more than four or more previous operations, preoperative pain in the area to be operated, high body mass index, previous smoking and older age were included in the six-factor model that best predicted significant pain at the follow-up in the 489 women studied. CONCLUSION: A six-factor risk index was developed to estimate the risk of developing significant pain after breast cancer surgery. Neither treatment- nor mood-related variables were included in the model. Identification of risk factors may lead to prevention of persistent postsurgery pain. This tool could be used for target prevention to those who are at the highest risk of developing persistent postsurgery pain. PMID- 23093295 TI - Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis. AB - BACKGROUND: The objective of this study was to determine the molecular mechanisms responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. METHODS: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. gamma-H2AX foci assays were used to determine the efficiency of DNA double-strand break (DSB) repair in cells. Quantitative PCR (Q-PCR) established the expression levels of key DNA DSB repair genes. Imaging flow cytometry using annexin V-FITC was used to compare artemis expression and apoptosis in cells. RESULTS: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the gamma-H2AX foci assay. The Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene, which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Overexpression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. CONCLUSION: We conclude that elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity. PMID- 23093298 TI - [Accidental levomethadone intoxication in a palliative patient]. AB - Levomethadone is a strong opioid which is used rarely in the treatment of special pain syndromes in Germany. A main field for the usage of Levomethadone, which has be applied as a oral fluid, is the opioid replacement therapy of heroin-addicts. Due to the long plasma half life and its high inter-individual variability, the application implies a risk of cumulation leading to an overdosage. It is not recommended to use a fixed equianalgesic formula for the dosage conversion from other opioids. The conversion starts with a low start dose, an individual titration follows. In this case-report, the difficulty of cumulation, inaccurate drug dispensary and the characteristic of dosage calculation of levomethadone is discussed. PMID- 23093296 TI - NFkappaB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression. AB - BACKGROUND: Cell line models suggest that activation of NFkappaB is associated with progression of prostate cancer. This pathway may be a therapeutic target if these observations translate to clinical specimens. METHODS: Immunohistochemistry measured NFkappaBp65 (p65), NFkappaBp65 nuclear localisation signal (NLS), NFkappaBp65 phosphorylated at ser 276 (p65(ser276)), NFkappaBp65 phosphorylated at ser 536 (p65(ser536)), IkappaBalpha phosphorylated at ser 32/36 (pIkappaBalpha(ser32/36)) and MMP-9 protein expression in 61 matched hormone naive prostate cancer (HNPC) and castrate-resistant prostate cancer (CRPC) tumours. Animal and cell models were used to investigate the role of NFkappaB inhibition in prostate carcinogenesis. RESULTS: In HNPC tumours, NLS expression significantly associated with a shorter time to disease recurrence and disease specific death. In CRPC tumours p65, pIkappaBalpha(ser32/36) and MMP-9 expression significantly associated with shorter time to death from disease recurrence and shorter disease-specific death. MMP-9 and pIkappaBalpha(ser32/36) expression significantly associated with metastases at recurrence and were independent of Gleason sum and prostate-specific antigen at recurrence. Expression of phosphorylated Akt was associated with increased p65 activation in mouse models and inhibition of NFkappaB in LNCaP cells significantly reduced cellular proliferation and induced apoptosis. CONCLUSION: These results provide further evidence that the NFkappaB pathway could be exploited as a target for CRPC. PMID- 23093299 TI - Phenotypic characterisation of pro-inflammatory monocytes and dendritic cells in peripheral arterial disease. AB - Atherosclerosis is a chronic inflammatory process involving antigen-presenting cells like monocytes and dendritic cells (DC). The aim of this study was to perform a phenotypic characterisation of these cell types in patients with different degrees of peripheral arterial disease (PAD). Sixty patients with PAD [N= 30 intermittent claudication (IC), N= 30 critical limb ischemia (CLI)] and 30 controls were included. Peripheral blood leucocytes were analysed from peripheral blood by flow cytometry using different gating strategies to directly identify and analyse monocytes, myeloid DC, (mDC) and plasmacytoid DC (pDC). PAD patients showed a significantly higher proportion of proinflammatory CD14++CD16+ monocytes (p<0.0001) compared with healthy individuals. We found an increased number of mDC/ml and a reduced number of pDC/ml (both p<0.01) in PAD patients, leading to a shift in the mDC/pDC ratio (p<0.01). As compared to patients with intermittent claudication, CLI patients presented a reduced expression of HLA-DR (p<0.01), CD86 and CD40 on both mDCs and pDCs (p<0.01). Peripheral blood monocytes show a proinflammatory phenotype in PAD patients compared to controls. In contrast, CLI patients show a reduced expression of proinflammatory markers. We hypothesise that severe ischaemia and/or prolonged inflammation in CLI might lead to a paradoxical attenuation in the proinflammatory membrane pattern of circulating mononuclear cells, possibly hindering an adequate regulatory function of mDCs and pDCs and favouring the progression of disease. PMID- 23093300 TI - Rapid point-of-care assay of enoxaparin anticoagulant efficacy in whole blood. AB - There is the need for a clinical assay to determine the extent to which a patient's blood is effectively anticoagulated by the low-molecular-weight-heparin (LMWH), enoxaparin. There are also urgent clinical situations where it would be important if this could be determined rapidly. The present assay is designed to accomplish this. We only assayed human blood samples that were spiked with known concentrations of enoxaparin. The essential feature of the present assay is the quantification of the efficacy of enoxaparin in a patient's blood sample by degrading it to complete inactivity with heparinase. Two blood samples were drawn into Vacutainer tubes (Becton-Dickenson; Franklin Lakes, NJ) that were spiked with enoxaparin; one sample was digested with heparinase for 5 min at 37 degrees C, the other sample represented the patient's baseline anticoagulated status. The percent shortening of clotting time in the heparinase-treated sample, as compared to the baseline state, yielded the anticoagulant contribution of enoxaparin. We used the portable, battery operated Hemochron 801 apparatus for measurements of clotting times (International Technidyne Corp., Edison, NJ). The apparatus has 2 thermostatically controlled (37 degrees C) assay tube wells. We conducted the assays in two types of assay cartridges that are available from the manufacturer of the instrument. One cartridge was modified to increase its sensitivity. We removed the kaolin from the FTK-ACT cartridge by extensive rinsing with distilled water, leaving only the glass surface of the tube, and perhaps the detection magnet, as activators. We called this our minimally activated assay (MAA). The use of a minimally activated assay has been studied by us and others. (2-4) The second cartridge that was studied was an activated partial thromboplastin time (aPTT) assay (A104). This was used as supplied from the manufacturer. The thermostated wells of the instrument were used for both the heparinase digestion and coagulation assays. The assay can be completed within 10 min. The MAA assay showed robust changes in clotting time after heparinase digestion of enoxaparin over a typical clinical concentration range. At 0.2 anti-Xa I.U. of enoxaparin per ml of blood sample, heparinase digestion caused an average decrease of 9.8% (20.4 sec) in clotting time; at 1.0 I.U. per ml of enoxaparin there was a 41.4% decrease (148.8 sec). This report only presents the experimental application of the assay; its value in a clinical setting must still be established. PMID- 23093301 TI - What we remember affects how we see: spatial working memory steers saccade programming. AB - Relationships between visual attention, saccade programming, and visual working memory have been hypothesized for over a decade. Awh, Jonides, and Reuter-Lorenz (Journal of Experimental Psychology: Human Perception and Performance 24(3):780 90, 1998) and Awh et al. (Psychological Science 10(5):433-437, 1999) proposed that rehearsing a location in memory also leads to enhanced attentional processing at that location. In regard to eye movements, Belopolsky and Theeuwes (Attention, Perception & Psychophysics 71(3):620-631, 2009) found that holding a location in working memory affects saccade programming, albeit negatively. In three experiments, we attempted to replicate the findings of Belopolsky and Theeuwes (Attention, Perception & Psychophysics 71(3):620-631, 2009) and determine whether the spatial memory effect can occur in other saccade-cuing paradigms, including endogenous central arrow cues and exogenous irrelevant singletons. In the first experiment, our results were the opposite of those in Belopolsky and Theeuwes (Attention, Perception & Psychophysics 71(3):620-631, 2009), in that we found facilitation (shorter saccade latencies) instead of inhibition when the saccade target matched the region in spatial working memory. In Experiment 2, we sought to determine whether the spatial working memory effect would generalize to other endogenous cuing tasks, such as a central arrow that pointed to one of six possible peripheral locations. As in Experiment 1, we found that saccade programming was facilitated when the cued location coincided with the saccade target. In Experiment 3, we explored how spatial memory interacts with other types of cues, such as a peripheral color singleton target or irrelevant onset. In both cases, the eyes were more likely to go to either singleton when it coincided with the location held in spatial working memory. On the basis of these results, we conclude that spatial working memory and saccade programming are likely to share common overlapping circuitry. PMID- 23093303 TI - Comparison of left ventricular cardiac dimensions between small and appropriate for gestational age preterm infants below 30 weeks of gestation. AB - OBJECTIVE: The development of the left cardiac structures in the early life of small for gestational age (SGA) preterm infants has been inadequately studied. The aim of the study was to compare the left ventricular cardiac dimensions between SGA and appropriate for gestational age (AGA) preterm infants. METHODS: Echocardiography was performed on day 2 (T1)and at age 1 month (T2) in 19 SGA preterm infants (birthweight < 3 rd percentile) and 21 AGA controls (P25-50) matched for gestational age (< 30 weeks). RESULTS: The left ventricular cardiac dimensions did not differ significantly between SGA and AGA infants at either T1 or T2 after correction for body length. The left ventricular mass was similar for SGA and AGA infants at T1 and T2 after correction for body weight or body length. The left ventricular output increased significantly from T1 to T2 in both SGA and AGA infants [SGA: 350 (T1) - 640 (T2) mL/kg/min, P < 0.05; AGA: 300 (T1) - 510 (T2) mL/kg/min, P < 0.05]. CONCLUSIONS: The left cardiac structures related to body length are comparable between SGA and AGA preterm infants in the first month of life and show similar development. PMID- 23093302 TI - Effect of maternal vitamin A deficiency during pregnancy on neonatal kidney size. AB - BACKGROUND AND AIMS: In animal studies, vitamin A deficiency (VAD) during pregnancy has been shown to be associated with a decrease in nephron number and kidney weight of the offspring. At present, it is unclear whether these observations are pertinent to humans. Thus, this study was performed to assess the vitamin A status of a cohort of Egyptian pregnant women and their newborns and to determine the potential effect of maternal VAD during pregnancy on the neonatal kidney size. METHODS: The maternal and cord blood samples were collected for the measurement of serum retinol concentration.Within the first 3 days after delivery, an abdominal ultrasound was performed in all newborns to determine the renal dimensions and volume. RESULTS: Sixteen (20%) mothers had VAD. The newborns delivered to VAD mothers had significantly lower mean values of cord retinol concentrations and dimensions of both kidneys than the newborns delivered to mothers with vitamin A sufficiency. The maternal serum retinol concentrations were positively correlated with the cord retinol concentrations, the dimensions of both kidneys, and the combined renal volume of their respective newborns. CONCLUSION: Maternal VAD during pregnancy may decrease renal size in the infant at birth. The functional implications of this effect warrant further study. PMID- 23093304 TI - Urinary voiding symptomatology (micro-incontinence) in male genital lichen sclerosus. PMID- 23093305 TI - Monte Carlo model of the scanning beam digital x-ray (SBDX) source. AB - The scanning-beam digital x-ray (SBDX) system has been developed for fluoroscopic imaging using an inverse x-ray imaging geometry. The SBDX system consists of a large-area x-ray source with a multihole collimator and a small detector. The goal of this study was to build a Monte Carlo (MC) model of the SBDX source as a useful tool for optimization of the SBDX imaging system in terms of its hardware components and imaging parameters. The MC model of the source was built in the EGSnrc/BEAMnrc code and validated using the DOSXYZnrc code and Gafchromic film measurements for 80, 100, and 120 kV x-ray source voltages. The MC simulated depth dose curves agreed with measurements to within 5%, and beam profiles at three selected depths generally agreed within 5%. Exposure rates and half-value layers for three voltages were also calculated from the MC simulations. Patient skin-dose per unit detector-dose was quantified as a function of patient size for all three x-ray source voltages. The skin-dose to detector-dose ratio ranged from 5-10 for a 20 cm thick patient to 1 * 10(3)-1 * 10(5) for a 50 cm patient for the 120 and 80 kV beams, respectively. Simulations of imaging dose for a prostate patient using common imaging parameters revealed that skin-dose per frame was as low as 0.2 mGy. PMID- 23093306 TI - "Antivirals" in the treatment of adult T cell leukaemia- lymphoma (ATLL). AB - Adult T cell leukaemia / lymphoma (ATLL) is a mature (post thymic) T cell lymphoma caused by the human T-lymphotropic virus type 1 (HTLV-1) infection. Overall survival in the aggressive subtypes (Acute Leukaemia and Lymphomatous) remains poor in part due to chemotherapy resistance. To improve treatment outcome for de novo disease, better induction therapies are required and since the pathogenic agent is known it would seem sensible to target the virus. In a recent meta-analysis the use of zidovudine and interferon alpha (ZDV/IFN) has been associated with improved response rates and prolonged overall survival in leukemic subtypes of ATLL (both acute and Chronic) confirmed in a multivariate analysis. In a more recent UK study the overall response rate for patients with aggressive ATLL treated with chemotherapy alone was 49 % compared to 81 % with combined first line therapy (chemotherapy with concurrent or sequential ZDV/IFN). Combined first line therapy prolonged median OS in acute (p = 0.0081) and lymphomatous ATLL (p = 0.001).These data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL. Although the mechanisms of action are incompletely understood, some possible explanations for their efficacy will be discussed. PMID- 23093307 TI - The antimicrobial peptide aurein 1.2 disrupts model membranes via the carpet mechanism. AB - The membrane interactions of the antimicrobial peptide aurein 1.2 were studied using a range of biophysical techniques to determine the location and the mechanism of action in DMPC (dimyristoylphosphatidylcholine) and DMPC/DMPG (dimyristoylphosphatidylglycerol) model membranes that mimic characteristics of eukaryotic and prokaryotic membranes, respectively. Neutron reflectometry and solid-state NMR revealed subtle changes in membrane structure caused by the peptide. Quartz crystal microbalance with dissipation, vesicle dye leakage and atomic force microscopy measurements were used to investigate the global mode of peptide interaction. Aurein 1.2 displayed an enhanced interaction with the anionic DMPC/DMPG membrane while exhibiting primarily a surface interaction with both types of model membranes, which led to bilayer disruption and membrane lysis. The antimicrobial peptide interaction is consistent with the carpet mechanism for aurein 1.2 with discrete structural changes depending on the type of phospholipid membrane. PMID- 23093308 TI - A peptide loop and an alpha-helix N-terminal serving as alternative electron hopping relays in proteins. AB - This work presents a density functional theory calculational study for clarifying that peptide loops (-[peptide](n)-) including the N-terminal and the C-terminal oligopeptides and the alpha-helix N-terminal can serve as an intriguing kind of relay elements, as an addition to the known relay stations served by aromatic amino acids for electron hopping migration. For these protein motifs, an excess electron generally prefers to reside at the -NH(3)(+) group in a Rydberg state for the N-terminal peptides, or at the -COOH group in a dipole-bound state for the C-terminal peptides, and at the N-terminal in a dipole-bound pi*-orbital state for the peptide loops and alpha-helices. The electron binding ability can be effectively enhanced by elongation for the alpha-helix N-terminal, and by bending, twisting, and even beta-turning for the peptide chains. The relay property is determined by the local dipole instead of the total dipole of the peptide chains. Although no direct experiment supports this hypothesis, a series of recent studies regarding charge hopping migration associated with the peptide chains and helices could be viewed as strong evidence. But, further studies are still needed by considering the effects from relative redox potential between the donor and acceptor sites, protein environment, and structure water molecules. PMID- 23093309 TI - Recurrent respiratory infections, specific antibody deficiencies, and memory B cells. AB - OBJECTIVES: To investigate the immunological phenotypes detected in children with recurrent upper and lower respiratory infections that have normal total immunoglobulin concentrations. METHODS: A cohort of over 60 children with recurrent respiration infections was evaluated for specific antibody deficiencies (SAD) and for memory B-cell abnormalities. A control group of children without recurrent infections was also evaluated. Evaluation included a detailed history of immunizations with pneumococcal vaccines; determination of IgM, IgG, IgA, and IgE concentrations; measurement of anti-pneumococcal polysaccharide antibody levels by ELISA and expression of CD27, IgD, and IgM on peripheral CD19(+)B cells by flow cytometry to determine the proportions of naive, IgM-memory B cells, and class-switched memory B cells. RESULTS: Patients were classified as having a SAD to either pure polysaccharides (PPV-SAD) or to conjugate polysaccharides (PCV SAD) based on the number of polysaccharides to which they developed an adequate antibody response. A normal response to only 2 or fewer of 7 PCV or PPV serotypes was considered as evidence of SAD. Forty-one patients without SAD and 26 with SAD were identified. IgM-memory B cells were low in 3 of 41 patients without SAD; in 3 of 5 PPV-SAD patients; and in 10 of 21 PCV-SAD patients. Class-switched memory B cells were low in 19 of 41 patients without SAD; in all 5 patients with PPV SAD; and in 11 of 21PCV-SAD patients. CONCLUSIONS: Patients with recurrent infection with or without SAD may have low IgM- and/or class-switched memory B cells. Ongoing research aims to determine the prognostic implications of these differences in patients with SAD. PMID- 23093310 TI - Toll like receptor 4 D299G associates with disease progression in Caucasian patients with chronic HBV infection: relationship with gender. AB - This study aimed to verify whether rs4986790 A > G single nucleotide polymorphism of toll like receptor 4 (TLR-4) associates with a more severe course of hepatitis B virus (HBV) chronic infection. A cross-sectional study enrolled 191 Caucasian HBV-positive patients: 28 HBsAg + inactive carriers, 121 chronic hepatitis B, 42 HBsAg + transplant candidates. A longitudinal study included 94 patients followed up for a median time of 19.3 years. TLR-4 rs4986790 A/A genotype was carried less frequently in male HBsAg + inactive carriers than in males with HBsAg + active chronic infection (12/17 Vs 109/121, p = 0.022). At stepwise logistic regression analysis, the carriage of TLR-4 rs4986790 A/A genotype was found to be and independent predictor of liver fibrosis (O.R. 14.8, p = 0.019). In conclusion, in HBV-positive Caucasian patients, the A/A genotype of the rs4986790 polymorphism may influence a worse outcome of chronic HBV infection, mainly through a synergistic interaction with male gender. PMID- 23093311 TI - Intravitreal injection of bevacizumab: changes in intraocular pressure related to ocular axial length. AB - PURPOSE: To evaluate the immediate and short-term effects of intravitreal injection of 1.25 mg/0.05 ml of bevacizumab on intraocular pressure related to different ocular axial lengths. DESIGN: A prospective case series of consecutive patients referred to the Department of Ophthalmology, San Pietro-Fatebenefratelli Hospital, from September 2011 through January 2011. METHODS: Twenty-five patients (10 men and 15 women, mean age 70.2 +/- 8.98 years) scheduled for intravitreal injection of bevacizumab for the treatment of neovascular age-related macular degeneration were enrolled in this study. Axial length was measured preoperatively using IOLMaster. Intraocular pressure was measured before injection, after 1 min and after 15 min using Tono-Pen XL tonometry. RESULTS: The mean intraocular pressure change following the intravitreal bevacizumab injection was 21.92 +/- 6.95 mmHg after 1 min and 6.24 +/- 3.77 mmHg after 15 min. The mean axial length of the examined eyes was 23.2 +/- 1.06 mm. A good correlation was observed between the axial length and intraocular pressure rise after both 1 (R (2) = 0.752, p < 0.001) and 15 min (R (2) = 0.559, p < 0.001). CONCLUSIONS: Patients undergoing intravitreal injection of 0.05 ml of bevacizumab can be exposed to intraocular pressure increases correlated to ocular axial length. PMID- 23093312 TI - Differentiation by imaging of superior segmental optic hypoplasia and normal tension glaucoma with inferior visual field defects only. AB - PURPOSE: To differentiate superior segmental optic hypoplasia (SSOH) from normal tension glaucoma (NTG) with inferior visual field defects only. METHODS: Eighteen eyes with SSOH (SSOH group) and 19 eyes with NTG (NTG group) were examined by optical coherence tomography (OCT), Heidelberg retina tomography (Heidelberg Retinal Tomograph II, HRT II) and standard automated perimetry. RESULTS: Retinal nerve fiber layer thickness (RNFLT) based on OCT measurements was significantly reduced (thinner) in the superior to superonasal sectors and significantly greater (thicker) in the inferotemporal sector in the SSOH group than in the NTG group. The cup was significantly smaller and the rim significantly larger in the superotemporal and temporal sectors in the SSOH group than in the NTG group based on HRT II measurements. The greatest area under the receiver operating characteristic curve for discrimination of SSOH from NTG by OCT and HRT II was for the RNFLT ratio of 1 + 2 o'clock/10 + 11 o'clock (0.985) and for the ratio of the superonasal to superotemporal sector of rim to disc area ratio and cup to disc area ratio (0.955), respectively. The frequent location of the inferior visual field defects corresponded to the difference in structural changes in both groups. CONCLUSIONS: Comparison of the superonasal to superotemporal sectors by OCT and HRT II were useful in differentiating SSOH from NTG with only inferior visual field defects. PMID- 23093313 TI - Renin-angiotensin system involvement in the oxidative stress-induced neurodegeneration of cultured retinal ganglion cells. AB - PURPOSE: To analyze the influence of oxidative stress on retinal ganglion cells (RGCs) by using a selective culture system of rat RGCs. METHODS: Rat RGCs were purified by a two-step immunopanning procedure and cultured either with or without antioxidant (AO) compounds. Reactive oxygen species (ROS) in RGCs were analyzed using dihydroethidium. Expression of angiotensin II, cleaved caspase 3, and netrin-1 was analyzed by immunocytochemistry. Live RGCs were detected by use of calcein-acetoxymethyl ester. The roles of angiotensin II type 1 receptor (AT1R) signaling and netrin-1 were analyzed by use of an AT1R blocker (telmisartan) and an anti-netrin-1 neutralizing antibody, respectively. RESULTS: ROS and angiotensin II were induced in RGCs cultured without AO compounds (AO-). In these cultures, the number of live RGCs decreased and expression of cleaved and activated caspase 3 increased, but these changes were attenuated by addition of the AT1R blocker. Reduction in netrin-1 expression under the AO- condition was also prevented by the AT1R blocker. The AT1R blocker's effects on RGC survival and reduction in cleaved caspase 3-positive cells were cancelled by the anti netrin-1 neutralizing antibody. CONCLUSIONS: Oxidative stress induced cell death through AT1R signaling and netrin-1 reduction in cultured RGCs. PMID- 23093314 TI - Photodynamic therapy combined with intravitreal bevacizumab and sub-tenon triamcinolone acetonide injections for age-related macular degeneration. AB - PURPOSE: To report the results of triple therapy with photodynamic therapy (PDT) (PDT combined with intravitreal injection of bevacizumab (IVB) and sub-tenon injection of triamcinolone acetonide (STTA)) for the treatment of age-related macular degeneration (AMD) in Japanese patients. METHODS: This retrospective case series included 38 eyes of 38 patients with exudative AMD treated with PDT combined with IVB (1.25 mg) and STTA (40 mg). Retreatment was performed in the same manner with intervals of at least 3 months. All patients had been treatment naive, with a follow-up period of 12 months. Best-corrected visual acuity (BCVA), macular retinal thickness (MRT) on optical coherence tomography, and the number of treatments were analyzed. RESULTS: The mean logarithm of the minimum angle of resolution BCVA in patients treated with PDT triple therapy was 0.86 +/- 0.55 at baseline and 0.62 +/- 0.55 at 12 months (p < 0.001). The mean MRT was 554.0 +/- 202.6 MUm at baseline and 205.1 +/- 78.6 MUm at 12 months (p < 0.001). During the 1-year follow-up, the average number of PDT triple therapy (treatments per patient) was 1.1. No complications, for example increase in intraocular pressure, cataract, or endophthalmitis, were observed. CONCLUSIONS: In AMD patients, PDT triple therapy significantly improved visual acuity with a minimum number of treatments and a low risk of complications during the 1-year follow-up. PMID- 23093315 TI - The role of diffusion-weighted magnetic resonance imaging in cholesteatoma diagnosis and follow-up. Study with the diffusion PROPELLER technique. AB - INTRODUCTION AND OBJECTIVES: The diagnosis of cholesteatoma is based on clinical evaluation and computed tomography. New non-echo-planar diffusion-weighted magnetic resonance imaging (MRI) techniques, without intravenous contrast, are capable of differentiating cholesteatoma from inflammatory tissue, cholesterol granuloma and granulation tissues. The technique is very helpful in differential diagnosis of cholesteatoma, mainly after canal wall-up tympanoplasty surgery, to avoid routine second-look surgery in these patients. Congenital cholesteatoma and difficult cases can be detected and correctly diagnosed as well. The aim of this study was to evaluate sensitivity, specificity, positive predictive value and negative predictive value of the diffusion-weighted PROPELLER MRI in cholesteatoma diagnosis. METHODS: A prospective study was performed on 52 patients. Clinical and surgical findings were correlated with diffusion-weighted PROPELLER MRI results. RESULTS: Sensitivity, specificity and positive and negative predictive values were 92.85%, 92.30, 92.85 and 92.30%, respectively. CONCLUSIONS: Diffusion-weighted PROPELLER imaging is an effective technique in cholesteatoma diagnosis. It is capable of detecting lesions larger than 2mm. PMID- 23093316 TI - Epigenetic chemical probes. AB - Epigenetic control of gene expression occurs at two distinctlevels: DNA methylation and histone modification. Over thepast 10 years, the discovery of epigenetic targets has acceleratedto the point where more than 400 domains have beenidentified that are involved in either DNA methylation, themodification of histones (and some nonhistones), or translationof these modifications into changes in gene expression PMID- 23093317 TI - Epigenomics and interindividual differences in drug response. AB - Epigenomics is a rapidly growing field. New developments in epigenetics, such as the recently described modified cytosine variants (e.g., 5-hydroxymethylcytosine, 5hmC) and an arsenal of novel noncoding forms of RNA, can be applied in the area of drug pharmacokinetics and pharmacodynamics. Epigenetic aberrations can affect drug treatment by modulating the expressions of key genes involved in the metabolism and distribution of drugs as well as drug targets, thereby contributing to interindividual variation in drug response. These epigenetic alterations, along with the epigenetic profiles of circulating nucleic acids, have great potential to be used as biomarkers for personalized therapy, particularly in the treatment of cancer. In this review we present an update of pharmacoepigenetics with respect to epigenetic regulation of ADME genes (genes related to drug absorption, distribution, metabolism, and excretion) and drug targets, and we illustrate how this information can be used for predicting interindividual variations in drug response. PMID- 23093318 TI - A population-based assessment of the drug interaction between levothyroxine and warfarin. AB - Most drug interaction resources suggest that levothyroxine can dramatically potentiate the effect of warfarin. However, the mechanistic basis of the interaction is speculative, and little evidence supports a meaningful drug interaction. We conducted a population-based nested case-control study to examine the risk of hospitalization for hemorrhage following the initiation of levothyroxine in a cohort of 260,076 older patients receiving warfarin. In this group, we identified 10,532 case subjects hospitalized for hemorrhage and 40,595 controls. In the primary analysis, we found no association between hospitalization for hemorrhage during warfarin therapy and initiation of levothyroxine in the preceding 30 days (adjusted odds ratio 1.11, 95% confidence interval 0.67-1.86). Secondary analyses using more remote initiation of levothyroxine also found no association. These findings suggest that concerns about a clinically meaningful levothyroxine-warfarin drug interaction are not justified. Drug interaction resources that presently characterize this interaction as important should reevaluate this classification. PMID- 23093319 TI - Diagnosis and management of upper extremity deep-vein thrombosis in adults. AB - Upper extremity deep-vein thrombosis (UEDVT) is common and can cause important complications, including pulmonary embolism and post-thrombotic syndrome. An increase in the use of central venous catheters, particularly peripherally inserted central catheters has been associated with an increasing rate of disease. Accurate diagnosis is essential to guide management, but there are limitations to the available evidence for available diagnostic tests. Anticoagulation is the mainstay of therapy, but interventional treatments may be considered in select situations. The risk of UEDVT may be reduced by more careful selection of patients who receive central venous catheters and by use of smaller catheters. Herein we review the diagnosis, management and prevention of UEDVT. Due to paucity of research, some principles are drawn from studies of lower extremity DVT. We present a practical approach to diagnosing the patient with suspected deep-vein thrombosis of the upper extremity. PMID- 23093320 TI - Celiac disease prevalence in children and adolescents with myocarditis and dilated cardiomiopathy. AB - OBJECTIVE: To determine the prevalence of celiac disease in patients with myocarditis and dilated cardiomyopathy. METHODS: Fifty-six patients between 1 and 18 years old with dilated cardiomyopathy or myocarditis were evaluated and followed up at Instituto de Medicina Integral Professor Fernando Figueira. Patients with previous diagnosis of celiac disease were excluded. The functional classification was determined according to the American Heart Association criteria (classes I, II, III and IV). Diagnosis of myocarditis was reported in the patients' medical records. Dilated cardiomyopathy was diagnosed by echocardiogram with systolic dysfunction of one or both ventricles, ejection fraction lower than 55%, ventricular dilatation, and left ventricular diastolic diameter bigger than 112%. Patients answered a questionnaire about gastrointestinal and cardiac symptoms; next, anti-tissue transglutaminase (tTG) and anti-endomysial (EMA) antibodies were dosed. Those with positive antibody results were referred to intestinal biopsy and histological evaluation to detect celiac disease according to Marsh classification. RESULTS: One of the 56 children (1.8%) had positive tTG antibody level, but negative EMA. Intestinal histological evaluation showed total villous atrophy. Approximately, 30% of patients had heart failure. Gastrointestinal symptoms and signs were frequent, especially abdominal pain (70%, 39/56). CONCLUSION: Celiac disease prevalence in pediatric patients with dilated cardiomyopathy or myocarditis was 1.8%. It is important to investigate celiac disease in patients with these conditions to avoid the progression of such diseases and patients' clinical deterioration. PMID- 23093321 TI - Surgical outcomes of anterior trans-obturator mesh and vaginal sacrospinous ligament fixation for severe pelvic organ prolapse in overweight and obese Asian women. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study is to compare the outcomes of patients who underwent surgical repair of advanced pelvic organ prolapse amongst with normal-weight, overweight and obese Asian women. METHODS: Vaginal sacrospinous ligament fixation with anterior mesh repair as primary surgery was performed on 200 patients with advanced pelvic organ prolapse (POP-Q >= stage III). POP-Q < stage II was objective cure and subjective cure was based on POPDI 6 (questions 2 and 3). Patients completed the UDI-6, IIQ-7, POPDI-6, and PISQ-12 pre- and post-surgery. Outcome measures were observed in three categories of Asian BMI (normal weight 18.5 to 23.0 kg/m(2), overweight >23.0 to 27.5 kg/m(2), and obese >= 27.5 kg/m(2)). RESULTS: Postoperative data were available for 195 patients. Objective cure for the normal-weight, overweight, and obese were 93.0%, 92.5% and 90.6% respectively with an overall mean follow-up of 35.69 +/- 18.97 months. The subjective cure was no different. All categories improved significantly with regard to anatomical outcome, UDI-6, IIQ-7, POPDI-6, PISQ-12 after primary surgery (p < 0.05) and none had recurrence requiring further surgery. However, obese patients have significantly less improvement in POPDI-6 (p <0.037) and PISQ-12 (p <0.005) compared with normal weight. There were no differences with regard to perioperative complications and the vaginal mesh exposure rate was 4.1%. CONCLUSIONS: There was no difference in the objective outcome of sacrospinous ligament fixation with anterior mesh repair surgery among the three Asian BMI categories; however, obese patients showed less improvement in POP symptoms and sexual function. PMID- 23093322 TI - Management of ureterovaginal fistulae: an audit. AB - INTRODUCTION AND HYPOTHESIS: A retrospective study was done from January 2008 to January 2011 to analyze the outcome of ureterovaginal fistula management in relation to intervention mode. PATIENTS AND METHODS: Eighteen patients who developed ureterovaginal fistulae following gynecological and obstetric procedures were studied. Ureteroscopic stenting was attempted in 17 cases, and one patient electively underwent ureteral reimplantation. RESULTS: Ureteroscopic stenting was successfully accomplished in 13 of 17 patients; four patients underwent ureteral reimplantation, as stenting was not feasible. The success rate was 100 % at a mean follow-up of 24.6 months, irrespective of modality. CONCLUSION: The majority of iatrogenic ureterovaginal fistulae can be successfully managed by ureteroscopic stenting. Our study also suggests that ureteroscopic stenting should be considered as the primary mode of intervention in all cases. Ureteral reimplantation is required and remains practicable when stenting turns out to be impossible. PMID- 23093323 TI - A repeat mid-urethral sling as valuable treatment for persistent or recurrent stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: The value of a repeat mid-urethral sling (MUS) after a failed primary sling is not generally accepted. We hypothesize that repeat MUS can be performed with favorable results and acceptable complication rates. METHODS: We reviewed the medical records of 80 women (mean age 62 +/- 12.3 years) who underwent repeat MUS surgery from January 2000 to January 2009 at a single tertiary academic centre. Mean follow-up was 44.8 months (range 3-104). Three of these 80 patients were lost to follow-up. Twenty-six (33%) transobturator (TOT), 25 (31%) retropubic (TVT) and 16 (20%) minislings were placed as secondary slings. Thirteen slings (15%) were biological (PelvicolTM). In 4 patients (5%) a release of the primary sling was performed, and in 6 (7.5 %) the extruded sling fragment was totally excised prior to secondary sling placement. RESULTS: The overall subjective cure rate was 61.0%. Of the study group 74.0% reported subjective improvement. The amounts of pads reduced from a mean of 3.8 pads a day to a mean of 0.75 pads a day postoperatively. The objective cure rate was 63.5%. The incidence of de novo urgency was 8.2% (4 patients). When comparing different secondary sling types no difference was found in the overall continence rate, except for the biological sling. More than half (7 out of 13) of the patients from whom the secondary sling was a biological sling, were not satisfied (p=0.01). The subjective improvement rates in patients with recurrent or persistent stress urinary incontinence (SUI) were 68.2% and 75.0% respectively. This difference is not statistically significant (p=0.94). Excision versus release of the MUS showed a slightly higher satisfaction rate after excision, 84.6% and 74.0 % respectively (p=0.63). CONCLUSIONS: Cure rates and improvement rates of a repeat MUS are favorable and complication rates are acceptable. It should be offered to patients with persistent or recurrent SUI after a failed primary sling, even after previous release or excision. PMID- 23093324 TI - The significance of early treatment of exudative age-related macular degeneration: 12 months' results. AB - BACKGROUND: To assess whether the period between initial symptoms and therapy with ranibizumab in patients with choroidal neovascularization (CNV) influences visual outcome after a follow-up of 12 months. METHODS: Fifty patients with CNV were retrospectively split into three groups depending on the duration of visual symptoms: group I: < 1 month, group II: 1-6 months, and group III: > 6 months. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were recorded at baseline, 2, 6, and 12 months. Patients received two initial intravitreal injections of 0.5 mg ranibizumab at baseline and reinjections as needed. RESULTS: The mean time span between initial symptoms and treatment was 66 +/- 63 days. A longer duration of visual symptoms was significantly correlated with a lower BCVA at baseline, but also after 6 and 12 months. CONCLUSIONS: Shorter duration of visual symptoms prior to treatment is associated with a better visual outcome. PMID- 23093325 TI - Fabrication and use of microenvironment microarrays (MEArrays). AB - The interactions between cells and their surrounding microenvironment have functional consequences for cellular behaviour. On the single cell level, distinct microenvironments can impose differentiation, migration, and proliferation phenotypes, and on the tissue level the microenvironment processes as complex as morphogenesis and tumorigenesis(1). Not only do the cell and molecular contents of microenvironments impact the cells within, but so do the elasticity(2) and geometry(3) of the tissue. Defined as the sum total of cell cell, -ECM, and -soluble factor interactions, in addition to physical characteristics, the microenvironment is complex. The phenotypes of cells within a tissue are partially due to their genomic content and partially due to the combinatorial interactions with the microenviroment. A major challenge is to link specific combinations of microenvironmental components with distinctive behaviours. Here, we present the microenvironment microarray (MEArray) platform for cell-based functional screening of interactions with combinatorial microenvironments(4). The method allows for simultaneous control of the molecular composition and the elastic modulus, and combines the use of widely available microarray and micropatterning technologies. MEArray screens require as few as 10,000 cells per array, which facilitates functional studies of rare cell types such as adult progenitor cells. A limitation of the technology is that entire tissue microenvironments cannot be completely recapitulated on MEArrays. However, comparison of responses in the same cell type to numerous related microenvironments, for instance pairwise combinations of ECM proteins that characterize a given tissue, will provide insights into how microenvironmental components elicit tissue-specific functional phenotypes. MEArrays can be printed using a wide variety of recombinant growth factors, cytokines, and purified ECM proteins, and combinations thereof. The platform is limited only by the availability of specific reagents. MEArrays are amenable to time-lapsed analysis, but most often are used for end point analyses of cellular functions that are measureable with fluorescent probes. For instance, DNA synthesis, apoptosis, acquisition of differentiated states, or production of specific gene products are commonly measured. Briefly, the basic flow of an MEArray experiment is to prepare slides coated with printing substrata and to prepare the master plate of proteins that are to be printed. Then the arrays are printed with a microarray robot, cells are allowed to attach, grow in culture, and then are chemically fixed upon reaching the experimental endpoint. Fluorescent or colorimetric assays, imaged with traditional microscopes or microarray scanners, are used to reveal relevant molecular and cellular phenotypes (Figure 1). PMID- 23093326 TI - Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit? AB - Enhanced drug extrusion from cells due to the overexpression of the ATP-binding cassette (ABC) drug transporters inhibits the cytotoxic effects of structurally diverse and mechanistically unrelated anticancer agents and is a major cause of multidrug resistance (MDR) of human malignancies. Multiple compounds can suppress the activity of these efflux transporters and sensitize resistant tumor cells, but despite promising preclinical and early clinical data, they have yet to find a role in oncologic practice. Based on the knowledge of the structure, function, and distribution of MDR-related ABC transporters and the results of their preclinical and clinical evaluation, we discuss probable reasons why these inhibitors have not improved the outcome of therapy for cancer patients. We also outline new MDR-reversing strategies that directly target ABC transporters or circumvent relevant signaling pathways. PMID- 23093327 TI - Mouse models of BRCA1 and their application to breast cancer research. AB - Germline mutations of human breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. In mice, over 20 distinct mutations, including null, hypomorphic, isoform, conditional, and point mutations, have been created to study functions of Brca1 in mammary development and tumorigenesis. Analyses using these mutant mice have yielded an enormous amount of information that greatly facilitates our understanding of the gender- and tissue-specific tumor suppressor functions of BRCA1, as well as enriches our insights into applying these preclinical models of disease to breast cancer research. Here, we review features of these mutant mice and their applications to cancer prevention and therapeutic treatment. PMID- 23093328 TI - Anatomic study of the retaining ligaments of the face and applications for facial rejuvenation. AB - BACKGROUND: The retaining ligaments of the face support the facial soft tissue in a normal anatomic position, thereby resisting gravitational change. In this study, a technique utilizing surgical plication of the superficial musculoaponeurotic system (SMAS) to the retaining ligaments of the face and finger-assisted malar elevation (FAME) dissection of the midface is presented. METHODS: The anatomy of the facial retaining ligaments was studied in 20 half faces of ten fresh cadavers, and the localization of the ligaments was examined macroscopically. Surgical correction of facial aging with plication of the SMAS to the retaining ligaments and FAME dissection of the midface has been performed in 74 face-lift patients since 2006. Outcomes were determined by case notes, clinical review, and a patient questionnaire. RESULTS: The studied ligaments (zygomatic and masseteric) were present in all cadaver dissections. The zygomatic ligament was located 4.3-5.5 cm from the tragus and originates near the inferior border of the anterior zygomatic arch. The masseteric ligament was located 3.7 5.2 cm from the tragus below the junction of the zygomatic arch and masseter muscle. All the patients answered a satisfaction questionnaire and reported high levels of satisfaction at least 1 year after treatment. CONCLUSIONS: We have identified the facial retaining ligaments in all cadaver dissections and their relationship with other structures of the face are described here. This study demonstrates that our face-lift technique is safe and produces highly predictable and natural results. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 23093329 TI - Dementia: new guidelines on disorders associated with dementia. PMID- 23093331 TI - Update on vasectomy protocol. AB - Vasectomy is a commonly practiced form of male contraception with over half a million procedures performed annually. Among urologists who perform the procedure, there is considerable variation in pre-procedure patient counseling, vasectomy technique, and post-procedure practices regarding confirmation of sterility. We report an overview of the vasectomy literature published within the past year with a focus on guidelines that have been recently published by two major organizations, the American Urological Association (AUA) and the European Association of Urology (EAU). PMID- 23093332 TI - Porphyria cutanea tarda and spherocytosis: a non-random association? PMID- 23093333 TI - Counseling customers: emerging roles for genetic counselors in the direct-to consumer genetic testing market. AB - Individuals now have access to an increasing number of internet resources offering personal genomics services. As the direct-to-consumer genetic testing (DTC GT) industry expands, critics have called for pre- and post-test genetic counseling to be included with the product. Several genetic testing companies offer genetic counseling. There has been no examination to date of this service provision, whether it meets critics' concerns and implications it may have for the genetic counseling profession. Considering the increasing relevance of genetics in healthcare, the complexity of genetic information provided by DTC GT, the mediating role of the internet in counseling, and potential conflicts of interest, this is a topic which deserves further attention. In this paper we offer a discourse analysis of ways in which genetic counseling is represented on DTC GT websites, blogs and other online material. This analysis identified four types of genetic counseling represented on the websites: the integrated counseling product; discretionary counseling; independent counseling; and product advice. Genetic counselors are represented as having the following roles: genetics educator; mediator; lifestyle advisor; risk interpreter; and entrepreneur. We conclude that genetic counseling as represented on DTC GT websites demonstrates shifting professional roles and forms of expertise in genetic counseling. Genetic counselors are also playing an important part in how the genetic testing market is taking shape. Our analysis offers important and timely insights into recent developments in the genetic counseling profession, which have relevance for practitioners, researchers and policy makers concerned with the evolving field of personal genomics. PMID- 23093334 TI - Talking to children about maternal BRCA1/2 genetic test results: a qualitative study of parental perceptions and advice. AB - Family communication is the primary, initial means of educating the next, at-risk generation about hereditary cancer risk. In this study, in-depth parent narratives provided self-report of motivations, planning, satisfactions and regrets associated with sharing or not sharing maternal BRCA1/2 test results with young children and advice for parents considering disclosure and for genetic counselors. Interviews were conducted with 32 mothers tested for BRCA1/2 with children ages 8-21 years and 24 of their co-parents; interview narratives were analyzed qualitatively. Parents were concerned with both protecting and educating children about hereditary cancer risk. They expressed confidence that parents can constructively convey genetic information to minor children. Telling relieved most parents and satisfied a sense of parental duty. Parents strongly advised child-specific, age-appropriate tailoring of genetic information and emphasized conveying the positive, preventive utility of genetic information to children. Immunizing effects of disclosure were viewed as providing forewarning about and preparation for possible later family cancer diagnoses. Parents choosing not to tell children were advised to consider future disclosure. Narratives about parental sharing of BRCA1/2 test results with minor children support the feasibility of parental discussion of maternal genetic test results to the next at-risk generation. Results suggest development of intervention tools for parents would support decision-making and family communication and potentially reduce parental worry and regret. Recommendations are made for more active involvement by genetic counselors with tested parents around the topic of delivery of genetic information to children. PMID- 23093335 TI - The structure and formation of hydrogen-bonded molecular networks on Au(111) surfaces revealed by scanning tunnelling and torsional-tapping atomic force microscopy. AB - A comprehensive scanning probe microscopy study has been carried out to characterise 3,4,9,10-Perylenetetracarboxylic diimide (PTCDI)-melamine hydrogen bonded networks deposited on Au(111)-surfaces. Both scanning tunnelling and atomic force microscopy were utilized. Such complementary analysis revealed a multilayered structure of the networks on the Au(111)-surface as opposed to a widely reported monolayer structure. Details of the network formation mechanism are presented. We have also demonstrated that despite the apparent network stability in ambient conditions it is unstable in aqueous solutions of pH 4.5 and 7.1. PMID- 23093336 TI - Homocysteine, folic acid and vitamin B12 levels in females with severe acne vulgaris. PMID- 23093337 TI - No evidence that the skeletal non-response to potassium alkali supplements in healthy postmenopausal women depends on blood pressure or sodium chloride intake. AB - BACKGROUND/OBJECTIVES: In vitro studies demonstrate that bone is degraded in an acidic environment due to chemical reactions and through effects on bone cells. Clinical evidence is insufficient to unequivocally resolve whether the diet net acid or base load bone affects breakdown in humans. Increasing dietary salt (sodium chloride, NaCl) mildly increases blood acidity in humans and in rats with increased sensitivity to the blood pressure effects of salt, whereas increased potassium (K) intake can decrease blood pressure. Blood pressure responses to NaCl or K may potentially be a marker for increased bone turnover or lower bone mineral density (BMD) in women at higher risk for osteoporosis and fracture. SUBJECTS/METHODS: We retrospectively analysed data from two data sets (California and NE Scotland) of postmenopausal women (n=266) enrolled in long-term randomized, placebo-controlled studies of the effects of administration of low- or high-dose dietary K alkali supplementation on bone turnover in relation to sodium or chloride excretion (a marker of dietary salt intake). Mean arterial pressure (MAP) was calculated from blood pressure measures, MAP was divided into tertiles and its influence on the effect of dietary NaCl and K alkali supplementation on deoxypyridinoline markers of bone resorption and BMD by DEXA was tested. Data was analysed for each data set separately and then combined. RESULTS: Percentage change in BMD after 24 months was less for California compared with North East Scotland (hip: -0.6 +/- 2.8% and -1.5 +/- 2.4%, respectively (P=0.027); spine: -0.5 +/- 3.4% and -2.6 +/- 3.5%, (P<0.001). We found no effect of dietary alkali treatment on BMD change or bone resorption for either centre. Adjusting for the possible calcium- or potassium-lowering effects on blood pressure did not alter the results. CONCLUSIONS: Blood pressure responses to Na, Cl or K intake did not help predict a BMD response to diet alkali therapy. PMID- 23093338 TI - Serum 25-hydroxyvitamin D and markers of insulin resistance in a Japanese working population. AB - BACKGROUND/OBJECTIVES: The association between vitamin D status and insulin resistance (IR) has been less studied among Asians, and it remains elusive whether calcium could modify such an association. We examined the association of serum 25-hydroxyvitamin D (25(OH)D) concentrations with IR markers and the potential effect modification by calcium intake among a Japanese population. SUBJECTS/METHODS: The authors analyzed data (n=494) from a cross-sectional survey conducted in 2009 among a Japanese working population aged 20-68 years. Fasting serum 25(OH)D and insulin, as well as fasting plasma glucose were determined, and homeostatic model assessment of IR (HOMA-IR) was calculated. Calcium intake was assessed using a validated diet history questionnaire. Multiple linear regression was done with adjustment of potential confounding variables. RESULTS: Fasting insulin and HOMA-IR were significantly inversely associated with 25(OH)D concentration across quartiles of 25(OH)D after fully adjusting for covariates (P(trend)=0.04 and 0.02, respectively). Across clinically relevant categories of 25(OH)D, compared with participants in the vitamin D sufficiency group, those in the vitamin D insufficiency group had a 5% higher HOMA-IR score, and those in the hypovitaminosis D group had an 18% higher HOMA-IR score (P(trend)=0.01). In an analysis by calcium intake, the HOMA-IR score was highest among participants with both a low calcium intake and lowest 25(OH)D concentrations, with significant inverse trend being observed in the group with lower calcium intake (P(trend)=0.02). CONCLUSIONS: Our findings suggest that low vitamin D status is associated with IR among Japanese adults. PMID- 23093339 TI - Soups increase satiety through delayed gastric emptying yet increased glycaemic response. AB - BACKGROUND/OBJECTIVES: Previous studies have demonstrated the satiating properties of soups compared with solids; however, the mechanisms controlling soup-induced satiety are unknown. This study aimed to understand the physiological mechanisms causing soup to be more satiating. SUBJECTS/METHODS: A total of 12 volunteers were tested on three occasions after a solid meal, chunky soup or smooth soup test meal for gastric emptying (GE) using the sodium [1-13C] acetate breath test, satiety using visual analog scales (VAS) and glycaemic response (GR) using finger prick blood samples. RESULTS: There was a significant difference in GE half-time (P=0.022) and GE ascension time (P=0.018), with the longest GE times for the smooth soup and the shortest for the solid meal. The GR area under the curve was significantly different between meals (P=0.040). The smooth soup had the greatest GR (87.0 +/- 49.5 mmol/l/min), followed by the chunky soup (65.4 +/- 48.0 mmol/l/min), with the solid meal having the lowest GR (61.6 +/- 36.8 mmol/l/min). Volunteers were fuller after the smooth soup compared with solid meal (P=0.034). CONCLUSIONS: The smooth soup induced greater fullness compared with the solid meal because of a combination of delayed GE leading to feelings of gastric distension and rapid accessibility of nutrients causing a greater glycaemic response. PMID- 23093341 TI - Origins for the estimations of water requirements in adults. AB - Water homeostasis generally occurs without conscious effort; however, estimating requirements can be necessary in settings such as health care. This review investigates the derivation of equations for estimating water requirements. Published literature was reviewed for water estimation equations and original papers sought. Equation origins were difficult to ascertain and original references were often not cited. One equation (% of body weight) was based on just two human subjects and another equation (ml water/kcal) was reported for mammals and not specifically for humans. Other findings include that some equations: for children were subsequently applied to adults; had undergone modifications without explicit explanation; had adjusted for the water from metabolism or food; and had undergone conversion to simplify application. The primary sources for equations are rarely mentioned or, when located, lack details conventionally considered important. The sources of water requirement equations are rarely made explicit and historical studies do not satisfy more rigorous modern scientific method. Equations are often applied without appreciating their derivation, or adjusting for the water from food or metabolism as acknowledged by original authors. Water requirement equations should be used as a guide only while employing additional means (such as monitoring short-term weight changes, physical or biochemical parameters and urine output volumes) to ensure the adequacy of water provision in clinical or health-care settings. PMID- 23093342 TI - Higher- versus lower-protein diets. PMID- 23093344 TI - Personalised nutrition: how far has nutrigenomics progressed? AB - The explosion in genetic and biological information presents an opportunity to explore, and ultimately exploit for health benefits, the inter-individual differences in the body's ability to metabolise, and respond to, nutrients. This has led to the concept of personalised nutrition as opposed to public health nutrition-the 'holy grail' of individualised dietary recommendations for optimal health. Using examples from micronutrient and lipid metabolism, this article assesses the scientific progress in our understanding of genetic influences on nutrition and its impact on risk of multifactorial diseases, and identifies the implications of research to date. Genetic variants that influence nutrient metabolism have been identified, but individual variants have not been conclusively linked to the risk of multifactorial diseases such as cancer and cardiovascular disease. Increasingly, it is realised that multiple variants influence nutrient metabolism and health outcomes. There is a need for quantitative assessment and mathematical modelling of multiple genetic effects. It is likely that personalised nutrition will not have the dramatic impact that was once expounded but will in the future, as we understand the complex influences of genetics, and impinge on the work of medical practitioners and dietitians by improving their ability to provide individual dietary advice and by contributing to the development of biomarkers. PMID- 23093345 TI - Multiple-slice magnetic resonance imaging can detect visceral adipose tissue reduction more accurately than single-slice imaging. AB - BACKGROUND/OBJECTIVE: Imaging methods by magnetic resonance imaging are being increasingly used to quantify visceral adipose tissue (VAT), but there is no clear consensus as to a standardized protocol. We compared the ability of two commonly used imaging protocols (multiple slice versus single slice) to detect changes in VAT with diet or exercise. SUBJECTS/METHODS: We utilized data from the participants who completed our diet (n=22) or exercise (n=35) based weight-loss interventions. The intervention mainly comprised of weekly dietary modification sessions or aerobic exercise sessions over 12 weeks. Multiple-slice images obtained from T9 to S1 and a single-slice image at L4-L5 were compared using the effect size of the VAT change. In addition, we calculated the sample size needed to compare the two imaging protocols' ability to detect significant changes in VAT. RESULTS: VAT and subcutaneous adipose tissue volumes and areas, and other anthropometry decreased significantly after both the diet and exercise interventions. For VAT, a single-slice image had a lower effect size (diet: 1.23; exercise: 0.49) than the multiple-slice images (diet: 1.81; exercise: 0.90). The sample size required for multiple slice was substantially lower than for the single-slice with both weight-loss interventions. CONCLUSIONS: The different image protocols may lead to different results in relative VAT changes. Furthermore, single-slice imaging required a substantially larger sample size than multiple-slice imaging, and for researchers to detect smaller changes in VAT with single-slice imaging, a larger sample size would be needed. Thus, multiple slice imaging has advantages for assessing VAT change in future clinical research. PMID- 23093343 TI - Dietary patterns and type 2 diabetes in Japanese men and women: the Japan Public Health Center-based Prospective Study. AB - BACKGROUND/OBJECTIVE: Dietary patterns in Western populations have been linked to type 2 diabetes, but the association of distinctive dietary patterns of Japanese population remains unclear. We prospectively investigated the association between dietary patterns and risk of developing type 2 diabetes among Japanese adults. SUBJECTS/METHODS: Participants were 27, 816 men and 36,889 women aged 45-74 years who participated in the second survey of the Japan Public Health Center-based prospective study and had no history of diabetes. Dietary patterns were derived by using principal component analysis of the consumption of 134 food and beverage items ascertained by a food frequency questionnaire. Odds ratios of self-reported physician-diagnosed type 2 diabetes over 5 year were estimated using logistic regression analysis. RESULTS: A total of 1194 new cases (692 men and 502 women) of type 2 diabetes were self-reported. We identified three dietary patterns: prudent, westernized and traditional Japanese patterns. Any dietary pattern was not significantly associated with type 2 diabetes risk after adjustment for covariates in both men and women. The multivariate-adjusted odds ratios (95% confidence interval) for type 2 diabetes for the highest versus lowest quartile of each dietary pattern score in men and women, respectively, were 0.93 (0.74 1.16) and 0.90 (0.69-1.16) for the prudent pattern, 1.15 (0.90-1.46) and 0.81 (0.61-1.08) for the westernized pattern, and 0.97 (0.74-1.27) and 0.87 (0.66 1.15) for the traditional pattern. CONCLUSIONS: Although a small protective effect of the prudent dietary pattern cannot be excluded, dietary patterns may not be appreciably associated with type 2 diabetes risk in Japanese. PMID- 23093347 TI - Effects of a single injection of teriparatide on bone turnover markers in postmenopausal women. AB - This study investigated the effects of a single administration of teriparatide on bone turnover markers in postmenopausal women. Teriparatide caused a transient increase in bone resorption and inhibition of bone formation followed by a subsequent increase in bone formation and a decrease in resorption that lasted at least 1 week. INTRODUCTION: This study aims to investigate the effects of a single subcutaneous administration of teriparatide on bone turnover markers to elucidate why once weekly intermittent administration of teriparatide is effective on osteoporosis. METHODS: Pharmacokinetics and calcium metabolism and bone turnover parameters were measured in 30 postmenopausal women after two doses of teriparatide (28.2 or 56.5 MUg injection) or placebo in a randomized, double blind, placebo-controlled study. RESULTS: Teriparatide plasma concentration increased in a dose-dependent manner, and the maximum concentration was achieved 1 h after injection. Serum levels of calcium and phosphorus were transiently increased and decreased after teriparatide injection, respectively. Calcium metabolism returned to baseline levels 24 h later. Two days after injection, the serum level of 1,25-dihydroxy vitamin D was increased by ~80 % from baseline for both doses of teriparatide. Serum levels of osteocalcin and procollagen type I N terminal propeptide decreased during the first 24 h followed by a ~10 % increase for 14 days. The serum level of cross-linked N-telopeptide (NTX) of type I collagen increased during the first 24 h followed by a 10 to 12 % dose-dependent suppression from baseline for 14 days. Urinary cross-linked C-telopeptide of type I collagen changes occurred in the same direction as serum NTX, but not dose dependently. CONCLUSION: A single administration of teriparatide caused an immediate, transient increase in bone resorption and inhibited bone formation followed by an increase in bone formation and decrease in resorption for >=1 week. These findings may provide proof for the effect of a once-weekly regimen of teriparatide on bone turnover. PMID- 23093346 TI - Management of remnant pancreatic stump fto prevent the development of postoperative pancreatic fistulas after distal pancreatectomy: current evidence and our strategy. AB - Distal pancreatectomy (DP) is the most common surgical procedure for treating benign and malignant lesions in the body or tail of the pancreas. Although the mortality rate related to DP has recently been reduced, the postoperative morbidity remains high. The most frequent and dismal complication occurring after DP is the development of postoperative pancreatic fistulas (POPF). Several resection methods and closure techniques for treating remnant pancreas have been developed in an effort to reduce the incidence of complications, especially POPF. However, the optimal procedure has not yet been established. In this review, we summarize the current clinical data and evidence for surgical techniques and perioperative management strategies for preventing POPF after DP. Finally, we introduce our non-closure technique for managing remnant pancreatic stumps. PMID- 23093349 TI - How low can you go? Minimum energy pathways for O2 dissociation on Pt(111). AB - Many DFT studies of O(2) dissociation on Pt(111) give conflicting information on preferred paths and final states. Here we report large p(4 * 4) unit cell minimum energy pathway evaluations and compare O(2) adsorption and dissociated states on Pt(111). Calculations reveal how the pathways for O(2) dissociation starting from top-fcc-bridge, top-hcp-bridge, and top-bridge-top sites are interconnected. They also provide a direct reaction pathway for the dissociation of an O(2) molecule from a top-fcc-bridge into an hcp and an fcc site, which is consistent with low temperature scanning tunneling microscope experiments. Such a pathway is shown to be considerably perturbed by the presence of co-adsorbed oxygen atoms. We quantify the coverage dependence through the construction of a Bronsted-Evans Polanyi relationship relating the O(2) dissociation activation energies to the binding energies of the dissociated O atoms. We also show that all pathways starting from a top-fcc-bridge site give the smallest barriers for O(2) dissociation. PMID- 23093348 TI - Racial differences in cortical bone and their relationship to biochemical variables in Black and White children in the early stages of puberty. AB - Osteoporotic fracture rates differ according to race with Blacks having up to half the rate of Whites. The current study demonstrates that racial divergence in cortical bone properties develops in early childhood despite lower serum 25 hydroxyvitamin D in Blacks. INTRODUCTION: Racial differences in bone structure likely have roots in childhood as bone size develops predominantly during growth. This study aimed to compare cortical bone health within the tibial diaphysis of Black and White children in the early stages of puberty and explore the contributions of biochemical variables in explaining racial variation in cortical bone properties. METHODS: A cross-sectional study was performed comparing peripheral quantitative computed tomography-derived cortical bone measures of the tibial diaphysis and biochemical variables in 314 participants (n = 155 males; n = 164 Blacks) in the early stages of puberty. RESULTS: Blacks had greater cortical volumetric bone mineral density, mass, and size compared to Whites (all p < 0.01), contributing to Blacks having 17.0 % greater tibial strength (polar strength-strain index (SSIP)) (p < 0.001). Turnover markers indicated that Blacks had higher bone formation (osteocalcin (OC) and bone-specific alkaline phosphatase) and lower bone resorption (N-terminal telopeptide) than Whites (all p < 0.01). Blacks also had lower 25-hydroxyvitamin D (25(OH)D) and higher 1,25 dihydroxyvitamin D (1,25(OH)2D) and parathyroid hormone (PTH) (all p < 0.05). There were no correlations between tibial bone properties and 25(OH)D and PTH in Whites (all p >= 0.10); however, SSIP was negatively and positively correlated with 25(OH)D and PTH in Blacks, respectively (all p <= 0.02). Variation in bone cross-sectional area and SSIP attributable to race was partially explained by tibial length, 25(OH)D/PTH, and OC. CONCLUSIONS: Divergence in tibial cortical bone properties between Blacks and Whites is established by the early stages of puberty with the enhanced cortical bone properties in Black children possibly being explained by higher PTH and OC. PMID- 23093350 TI - Fluorescence recovery after photobleaching (FRAP) with a focus on F-actin. AB - In this unit on fluorescence recovery after photobleaching (FRAP), an imaging approach to study protein-protein interactions in situ is described. The protocols presented use confocal microscopy to examine the mobility of a fluorescent protein by measuring the recovery of the protein in a bleached area. The data gained in FRAP studies is qualitative and yields insight into relative binding affinity, binding characteristics, and the effect of treatments or mutations on protein mobility. PMID- 23093351 TI - Overview of gene delivery into cells using HSV-1-based vectors. AB - This overview describes the considerations involved in the preparation and use of a herpes simplex virus type 1 (HSV-1) amplicon as a vector for gene transfer into neurons. Strategies for gene delivery into neurons, either to study the molecular biology of brain function or for gene therapy, must utilize vectors that persist stably in postmitotic cells and that can be targeted both spatially and temporally in the nervous system in vivo. This unit describes the biology of HSV 1 along with a discussion covering development of amplicon and genomic HSV-1 vectors. Advantages and disadvantages of current HSV-1 vectors are presented, and HSV-1 vectors are compared with other vectors for gene transfer into neurons. PMID- 23093352 TI - Prime-, stress-, and cue-induced reinstatement of extinguished drug-reinforced responding in rats: cocaine as the prototypical drug of abuse. AB - This unit describes the testing of rats in prime-, footshock-, and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock induced), or by stimuli previously associated with drug administration (cue induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID- 23093353 TI - Rodent models of colorectal distension. AB - Colorectal distension (CRD) is a widely accepted, reproducible method for assessing visceral sensitivity in both clinical and pre-clinical studies. Distension of the colon mirrors the human scenario of visceral pain with regard to intensity and referral of pain in patients. There are several readouts that can be applied to the CRD protocol depending on the species being evaluated, two of which are described in this unit. CRD can be used to measure the impact of novel compounds, strain, or genetic differences as well as the effect of physical and psychological stressors on the sensitivity of the colon. Investigation of the impact of a noxious visceral stimulus (CRD) on other systems within the body can also be carried out. Given that visceral pain is a major clinical problem and one of the most common reasons patients seek out medical advice, the ability to assess this type of pain is essential to the discovery of successful treatments. This unit outlines two protocols that describe CRD of rats and mice. PMID- 23093354 TI - The PAR1 antagonist, SCH79797, alters platelet morphology and function independently of PARs. PMID- 23093355 TI - Efficacy and safety of transarterial radioembolization versus chemoembolization in patients with hepatocellular carcinoma. AB - PURPOSE: Intermediate-stage hepatocellular carcinoma (HCC) is usually treated with locoregional therapy using transarterial chemoembolization (TACE). Transarterial radioembolization (TARE) using beta-emitting yttrium-90 integral to the glass matrix of the microspheres is an alternative to TACE. This retrospective case-control study compared the outcomes and safety of TARE versus TACE in patients with unresectable HCC. MATERIALS AND METHODS: Patients with unresectable HCC without portal vein thrombosis treated with TARE between 2005 and 2008 (n = 61) were retrospectively frequency-matched by age, sex, and liver dysfunction with TACE-treated patients (n = 55) in the Mayo Clinic Hepatobiliary Neoplasia Registry. Imaging studies were reviewed, and clinical and safety outcomes were abstracted from the medical records. RESULTS: Complete tumor response was more common after TARE (12 %) than after TACE (4 %) (p = 0.17). When complete response was combined with partial response and stable disease, there was no difference between TARE and TACE. Median survival did not differ between the two groups (15.0 months for TARE and 14.4 months for TACE; p = 0.47). Two year survival rates were 30 % for TARE and 24 % for TACE. TARE patients received fewer treatments (p < 0.001). Fifty-nine (97 %) TARE patients received outpatient treatment. In contrast, 53 (98 %) TACE patients were hospitalized for >=1 day (p < 0.001). Compared with TACE, TARE was more likely to induce fatigue (p = 0.003) but less likely to cause fever (p = 0.02). CONCLUSION: There was no significant difference in efficacy between TARE and TACE. TARE patients reported more fatigue but had less fever than TACE patients. Treatment with TARE required less hospitalization than treatment with TACE. These findings require confirmation in randomized trials. PMID- 23093356 TI - Experimental investigation of a general real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring. AB - The goal of this work was to experimentally quantify the geometric accuracy of a novel real-time 3D target localization method using sequential kV imaging combined with respiratory monitoring for clinically realistic arc and static field treatment delivery and target motion conditions. A general method for real time target localization using kV imaging and respiratory monitoring was developed. Each dimension of internal target motion T(x, y, z; t) was estimated from the external respiratory signal R(t) through the correlation between R(t(i)) and the projected marker positions p(x(p), y(p); t(i)) on kV images by a state augmented linear model: T(x, y, z; t) = aR(t) + bR(t - tau) + c. The model parameters, a, b, c, were determined by minimizing the squared fitting error ?||p(x(p), y(p); t(i)) - P(theta(i)) . (aR(t(i)) + bR(t(i) - tau) + c)||(2) with the projection operator P(theta(i)). The model parameters were first initialized based on acquired kV arc images prior to MV beam delivery. This method was implemented on a trilogy linear accelerator consisting of an OBI x-ray imager (operating at 1 Hz) and real-time position monitoring (RPM) system (30 Hz). Arc and static field plans were delivered to a moving phantom programmed with measured lung tumour motion from ten patients. During delivery, the localization method determined the target position and the beam was adjusted in real time via dynamic multileaf collimator (DMLC) adaptation. The beam-target alignment error was quantified by segmenting the beam aperture and a phantom-embedded fiducial marker on MV images and analysing their relative position. With the localization method, the root-mean-squared errors of the ten lung tumour traces ranged from 0.7-1.3 mm and 0.8-1.4 mm during the single arc and five-field static beam delivery, respectively. Without the localization method, these errors ranged from 3.1-7.3 mm. In summary, a general method for real-time target localization using kV imaging and respiratory monitoring has been experimentally investigated for arc and static field delivery. The average beam-target error was 1 mm. PMID- 23093358 TI - Arabidopsis COP1 and SPA genes are essential for plant elongation but not for acceleration of flowering time in response to a low red light to far-red light ratio. AB - Plants sense vegetative shade as a reduction in the ratio of red light to far-red light (R:FR). Arabidopsis (Arabidopsis thaliana) responds to a reduced R:FR with increased elongation of the hypocotyl and the leaf petioles as well as with an acceleration of flowering time. The repressor of light signaling, CONSTITUTIVELY PHOTOMORPHOGENIC1 (COP1), has been shown previously to be essential for the shade avoidance response in seedlings. Here, we have investigated the roles of COP1 and the COP1-interacting SUPPRESSOR OF PHYA-105 (SPA) proteins in seedling and adult facets of the shade-avoidance response. We show that COP1 and the four SPA genes are essential for hypocotyl and leaf petiole elongation in response to low R:FR, in a fashion that involves the COP1/SPA ubiquitination target LONG HYPOCOTYL IN FR LIGHT1 but not ELONGATED HYPOCOTYL5. In contrast, the acceleration of flowering in response to a low R:FR was normal in cop1 and spa mutants, thus demonstrating that the COP1/SPA complex is only required for elongation responses to vegetative shade and not for shade-induced early flowering. We further show that spa mutant seedlings fail to exhibit an increase in the transcript levels of the auxin biosynthesis genes YUCCA2 (YUC2), YUC8, and YUC9 in response to low R:FR, suggesting that an increase in auxin biosynthesis in vegetative shade requires SPA function. Consistent with this finding, expression of the auxin response marker gene DR5::GUS did not increase in spa mutant seedlings exposed to low R:FR. We propose that COP1/SPA activity, via LONG HYPOCOTYL IN FR LIGHT1, is required for shade-induced modulation of the auxin biosynthesis pathway and thereby enhances cell elongation in low R:FR. PMID- 23093359 TI - Waterproofing crops: effective flooding survival strategies. PMID- 23093360 TI - RhNAC2 and RhEXPA4 are involved in the regulation of dehydration tolerance during the expansion of rose petals. AB - Dehydration inhibits petal expansion resulting in abnormal flower opening and results in quality loss during the marketing of cut flowers. We constructed a suppression subtractive hybridization library from rose (Rosa hybrida) flowers containing 3,513 unique expressed sequence tags and analyzed their expression profiles during cycles of dehydration. We found that 54 genes were up-regulated by the first dehydration, restored or even down-regulated by rehydration, and once again up-regulated by the second dehydration. Among them, we identified a putative NAC family transcription factor (RhNAC2). With transactivation activity of its carboxyl-terminal domain in yeast (Saccharomyces cerevisiae) cell and Arabidopsis (Arabidopsis thaliana) protoplast, RhNAC2 belongs to the NAC transcription factor clade related to plant development in Arabidopsis. A putative expansin gene named RhEXPA4 was also dramatically up-regulated by dehydration. Silencing RhNAC2 or RhEXPA4 in rose petals by virus-induced gene silencing significantly decreased the recovery of intact petals and petal discs during rehydration. Overexpression of RhNAC2 or RhEXPA4 in Arabidopsis conferred strong drought tolerance in the transgenic plants. RhEXPA4 expression was repressed in RhNAC2-silenced rose petals, and the amino-terminal binding domain of RhNAC2 bound to the RhEXPA4 promoter. Twenty cell wall-related genes, including seven expansin family members, were up-regulated in Arabidopsis plants overexpressing RhNAC2. These data indicate that RhNAC2 and RhEXPA4 are involved in the regulation of dehydration tolerance during the expansion of rose petals and that RhEXPA4 expression may be regulated by RhNAC2. PMID- 23093361 TI - The pepper extracellular xyloglucan-specific endo-beta-1,4-glucanase inhibitor protein gene, CaXEGIP1, is required for plant cell death and defense responses. AB - Plants produce various proteinaceous inhibitors to protect themselves against microbial pathogen attack. A xyloglucan-specific endo-beta-1,4-glucanase inhibitor1 gene, CaXEGIP1, was isolated and functionally characterized in pepper (Capsicum annuum) plants. CaXEGIP1 was rapidly and strongly induced in pepper leaves infected with avirulent Xanthomonas campestris pv vesicatoria, and purified CaXEGIP1 protein significantly inhibited the hydrolytic activity of the glycoside hydrolase74 family xyloglucan-specific endo-beta-1,4-glucanase from Clostridium thermocellum. Soluble-modified green fluorescent protein-tagged CaXEGIP1 proteins were mainly localized to the apoplast of onion (Allium cepa) epidermal cells. Agrobacterium tumefaciens-mediated overexpression of CaXEGIP1 triggered pathogen-independent, spontaneous cell death in pepper and Nicotiana benthamiana leaves. CaXEGIP1 silencing in pepper conferred enhanced susceptibility to virulent and avirulent X. campestris pv vesicatoria, accompanied by a compromised hypersensitive response and lowered expression of defense-related genes. Overexpression of dexamethasone:CaXEGIP1 in Arabidopsis (Arabidopsis thaliana) enhanced resistance to Hyaloperonospora arabidopsidis infection. Comparative histochemical and proteomic analyses revealed that CaXEGIP1 overexpression induced a spontaneous cell death response and also increased the expression of some defense-related proteins in transgenic Arabidopsis leaves. This response was also accompanied by cell wall thickening and darkening. Together, these results suggest that pathogen-inducible CaXEGIP1 positively regulates cell death-mediated defense responses in plants. PMID- 23093363 TI - A galvanotaxis assay for analysis of neural precursor cell migration kinetics in an externally applied direct current electric field. AB - The discovery of neural stem and progenitor cells (collectively termed neural precursor cells) (NPCs) in the adult mammalian brain has led to a body of research aimed at utilizing the multipotent and proliferative properties of these cells for the development of neuroregenerative strategies. A critical step for the success of such strategies is the mobilization of NPCs toward a lesion site following exogenous transplantation or to enhance the response of the endogenous precursors that are found in the periventricular region of the CNS. Accordingly, it is essential to understand the mechanisms that promote, guide, and enhance NPC migration. Our work focuses on the utilization of direct current electric fields (dcEFs) to promote and direct NPC migration - a phenomenon known as galvanotaxis. Endogenous physiological electric fields function as critical cues for cell migration during normal development and wound repair. Pharmacological disruption of the trans-neural tube potential in axolotl embryos causes severe developmental malformations(1). In the context of wound healing, the rate of repair of wounded cornea is directly correlated with the magnitude of the epithelial wound potential that arises after injury, as shown by pharmacological enhancement or disruption of this dcEF(2-3). We have demonstrated that adult subependymal NPCs undergo rapid and directed cathodal migration in vitro when exposed to an externally applied dcEF. In this protocol we describe our lab's techniques for creating a simple and effective galvanotaxis assay for high-resolution, long-term observation of directed cell body translocation (migration) on a single-cell level. This assay would be suitable for investigating the mechanisms that regulate dcEF transduction into cellular motility through the use of transgenic or knockout mice, short interfering RNA, or specific receptor agonists/antagonists. PMID- 23093362 TI - Knockdown of a rice stelar nitrate transporter alters long-distance translocation but not root influx. AB - Root nitrate uptake is well known to adjust to the plant's nitrogen demand for growth. Long-distance transport and/or root storage pools are thought to provide negative feedback signals regulating root uptake. We have characterized a vascular specific nitrate transporter belonging to the high-affinity Nitrate Transporter2 (NRT2) family, OsNRT2.3a, in rice (Oryza sativa ssp. japonica 'Nipponbare'). Localization analyses using protoplast expression, in planta promoter-beta-glucuronidase assay, and in situ hybridization showed that OsNRT2.3a was located in the plasma membrane and mainly expressed in xylem parenchyma cells of the stele of nitrate-supplied roots. Knockdown expression of OsNRT2.3a by RNA interference (RNAi) had impaired xylem loading of nitrate and decreased plant growth at low (0.5 mm) nitrate supply. In comparison with the wild type, the RNAi lines contained both nitrate and total nitrogen significantly higher in the roots and lower in the shoots. The short-term [(15)N]NO(3)(-) influx (5 min) in entire roots and NO(3)(-) fluxes in root surfaces showed that the knockdown of OsNRT2.3a in comparison with the wild type did not affect nitrate uptake by roots. The RNAi plants showed no significant changes in the expression of some root nitrate transporters (OsNRT2.3b, OsNRT2.4, and OsNAR2.1), but transcripts for nia1 (nitrate reductase) had increased and OsNRT2.1 and OsNRT2.2 had decreased when the plants were supplied with nitrate. Taken together, the data demonstrate that OsNRT2.3a plays a key role in long-distance nitrate transport from root to shoot at low nitrate supply level in rice. PMID- 23093364 TI - Difference of interleukin-23 receptor gene haplotype variants in ulcerative colitis compared to Crohn's disease and psoriasis. AB - OBJECTIVE: Polymorphisms of the interleukin-23 receptor (IL23R) gene have been found to play a role in the development of several autoimmune diseases. Our aim was to examine the possible effect of not only simple individual variants, but of haplotypes composed of them. SUBJECTS: We analysed 263 patients with psoriasis, 199 patients with Crohn's disease (CD), 282 patients with ulcerative colitis (UC), and 253 controls for rs1884444, rs11805303, rs7517847, rs2201841, rs10889677 and rs11209032 variants. METHODS: The genotypes were determined by using PCR/RFLP assay. Logistic regression analysis was used to compare the genotype distribution of the polymorphisms and haplotypes between the examined autoimmune diseases and healthy controls. RESULTS: Rs1884444 was found to confer risk for UC and psoriasis, rs10889677 for CD and psoriasis, while rs2201841 and rs7517847 had effect only in CD. Using these SNPs we could study the susceptibility haplotype profiles in these diseases with special attention to UC. Eight different haplotypes could be differentiated. We found that the SNPs exert their susceptibility character in specific haplotype blocks, and the frequency of one haplotype differed significantly in UC compared with both other diseases and also with healthy controls. This haplotype conferred risk for UC, even while it had a somewhat lower frequency in the other diseases than in controls. CONCLUSIONS: The data presented here serve as evidence for the need of haplotype analysis instead of just single standing SNP analysis when susceptibility is interpreted. PMID- 23093365 TI - Dielectric pressure in continuum electrostatic solvation of biomolecules. AB - Continuum solvation representations based on the Poisson-Boltzmann equation have become widely accepted in biomolecular applications after years of basic research and development. Since analytical solution of the differential equation can be achieved only in a few specific cases with simple solute geometry, only numerical solution is possible for biomolecular applications. However, it is conceptually difficult to assign solvation forces in the numerical methods, limiting their applications into direct simulations of energy minimization and molecular dynamics. In this study a dielectric pressure formulation was derived from the general Maxwell stress tensor for continuum solvation of biomolecules modeled with the widely used abrupt-transitioned dielectrics. A charge-central strategy was then proposed to improve the numerical behavior of the computed pressure. An interesting observation is the highly similar charge-central formulations between the smooth-transition dielectric and the abrupt-transition dielectric models utilized in the biomolecular solvation treatments. The connections of the new formulation with both the Davis-McCammon and Gilson et al. approaches were further presented after applying the normal field approximation. The consistency was verified with the numerical tests on a realistic biomolecule. The numerical experiments on the tested biomolecule further indicate that the charge-central strategy combined with the normal field approximation not only improves the accuracy of the dielectric boundary force but also reduces its grid dependence for biomolecular applications. PMID- 23093366 TI - Chemical modifications of laccase from white-rot basidiomycete Cerrena unicolor. AB - Laccases belong to the group of phenol oxidizes and constitute one of the most promising classes of enzymes for future use in various fields. For industrial and biotechnological purposes, laccases were among the first enzymes providing larger scale applications such as removal of polyphenols or conversion of toxic compounds. The wood-degrading basidiomycete Cerrena unicolor C-139, reported in this study, is one of the high-laccase producers. In order to facilitate novel and more efficient biocatalytic process applications, there is a need for laccases with improved biochemical properties, such as thermostability or stability in broad ranges of pH. In this work, modifications of laccase isoforms by hydrophobization, hydrophilization, and polymerization were performed. The hydrophobized and hydrophilized enzyme showed enhanced surface activity and higher ranges of pH and temperatures in comparison to its native form. However, performed modifications did not appear to noticeably alter enzyme's native structure possibly due to the formation of coating by particles of saccharides around the molecule. Additionally, surface charge of modified laccase shifted towards the negative charge for the hydrophobized laccase forms. In all tested modifications, the size exclusion method led to average 80 % inhibition removal for hydrophilized samples after an hour of incubation with fluoride ions. Samples that were hydrophilized with lactose and cellobiose showed an additional 90 % reversibility of inhibition by fluoride ions after an hour of concluding the reaction and 40 % after 24 h. The hydrophobized laccase showed higher level of the reversibility after 1 h (above 80 %) and 24 h (above 70 %) incubation with fluoride ions. The addition of ascorbate to laccase solution before a fluoride spike resulted in more efficient reversibility of fluoride inhibitory effect in comparison to the treatments with reagents used in the reversed sequence. PMID- 23093367 TI - Unique phenotypes in the sperm of the earthworm Eudrilus eugeniae for assessing radiation hazards. AB - The earthworm, Eudrilus eugeniae is a segmented worm. It has two pairs of testes whose cells are highly proliferative. It was found that the earthworm, which is irradiated with X-ray, shows the following phenotypic changes in its sperm: fragmented acrosome in the head, break in the tail, and the appearance of zigzag sperm tail. Sperm morphology can be used as a tool to study radiation hazards in local areas. These three phenotypes were not observed in the sperm of worms exposed to different concentration of toxic chemicals such as sodium arsenate, lead acetate, and mercuric chloride. In contrast, exposure of worms to ethidium bromide caused fragmented acrosome in the head of their sperm cells. PMID- 23093368 TI - Research on the relationship between the fractional coverage of the submerged plant Vallisneria spiralis and observed spectral parameters. AB - The present paper discusses the relationship between the coverage fraction of submerged plants and the observed spectral characteristics. The purpose of this paper is to validate a remote sensing technology to monitor the change in the plant composition of a water body. In the current study, the reflectance spectra of the submerged plant Vallisneria spiralis at different fraction coverages of the wetland in Hangzhou Bay were measured. The relationships between the fraction coverage of V. spiralis and simulated Quickbird normalized difference vegetation index (NDVI), red edge, and other spectral characteristic parameters were established. The results showed that the spectral reflectance characteristics of submerged plant V. spiralis were mainly in the visible light (490-650 nm) and near infrared (700-900 nm). The rate of change of the blue band curve and simulated Quickbird NDVI showed a higher correlation with the V. spiralis coverage, so estimation models of the fraction coverage were constructed using these parameters. The estimated fraction coverage of V. spiralis with different models were validated with ground data, and the accuracy of estimation models was assessed. The most suitable estimated fraction coverage of V. spiralis was obtained using the rate of change of the blue band curve and simulated Quickbird NDVI. The present work demonstrated a method to monitor the distribution and dynamical variation of submerged plants at the large scale. PMID- 23093369 TI - Quantifying the consequences of conifer succession in aspen stands: decline in a biodiversity-supporting community. AB - Quaking aspen (Populus tremuloides Michaux) stands are important for biodiversity in conifer-dominated forest landscapes. Our goal was to quantify the consequences of conifer succession on understory diversity and litter quality, as well as associated changes in aspen stand condition. We studied aspen stands on national park land in the transition zone between the northern Sierra Nevada and southern Cascade mountain ranges. We field-measured ten metrics of aspen stand condition in 29 aspen stands. Along a gradient of increasing current conifer cover, we observed decreases in herbaceous species diversity and richness and an increase in forest floor O horizon depth. We interpreted aerial photos from 1952 and 1998 to determine whether directional changes in conifer cover had occurred in the stands over the past half century, and used regression modeling to associate succession with the observed range of aspen stand condition. From the period 1952 to 1998, we found that conifer encroachment occurred in half the sampled stands, with an average increase in conifer cover of 1% a year. Aspen were persistent in the remaining stands. Stand cover dynamics and percent total canopy cover interacted to influence species richness, diversity, aspen sprouting, and litter quality. In stands with conifer encroachment, both understory species richness and diversity declined. Although aspen sprouting increased, aspen establishment declined and the relative mass of woody to fine soil litter increased. PMID- 23093370 TI - Decrease in heart adrenoceptor gene expression and receptor number as compensatory tool for preserved heart function and biological rhythm in M(2) KO animals. AB - Muscarinic receptors (MR) are main cardioinhibitory receptors. We investigated the changes in gene expression, receptor number, echocardiography, muscarinic/adrenergic agonist/antagonist changes in heart rate (HR) and HR biorhythm in M(2) KO mice (mice lacking the main cardioinhibitory receptors) in the left ventricle (LV) and right ventricle (RV). We hypothesize that the disruption of M(2) MR, key players in parasympathetic bradycardia, would change the number of receptors with antagonistic effects on the heart (beta(1)- and beta(2)-adrenoceptors, BAR), while the function of the heart would be changed only marginally. We have found changes in LV, but not in RV: decrease in M(3) MR, beta(1)- and beta(2)-adrenoceptor gene expressions that were accompanied by a decrease in MR and BAR receptor binding. No changes were found both in LV systolic and diastolic function as assessed by echocardiography (e.g., similar LV end-systolic and end-diastolic diameter, fractional shortening, mitral flow characteristics, and maximal velocity in LV outflow tract). We have found only marginal changes in specific HR biorhythm parameters. The effects of isoprenaline and propranolol on HR were similar in WT and KO (but with lesser extent). Atropine was not able to increase HR in KO animals. Carbachol decreased the HR in WT but increased HR in KO, suggesting the presence of cardiostimulatory MR. Therefore, we can conclude that although the main cardioinhibitory receptors are not present in the heart, the function is not much affected. As possible mechanisms of almost normal cardiac function, the decreases of both beta(1)- and beta(2)-adrenoceptor gene expression and receptor binding should be considered. PMID- 23093371 TI - Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome. AB - Activation of the Wnt signaling pathway has been implicated in the pathogenesis of many tumors as well as in leukemia. However, its role in myelodysplastic syndrome (MDS) is unknown. In this study, we employed methylation-specific PCR to examine the methylation status of six Wnt antagonist genes in 144 MDS patients and in the MDS cell line SKM-1. We also used real-time PCR to examine the expression of Wnt antagonist genes and Wnt pathway genes in the SKM-1 cell line after treatment with 5-aza-2'-deoxycytidine. We found that methylation of the gene promoters of each of the six genes were observed in MDS patients at the following methylation frequencies: 41 % for sFRP1, 89.6 % for sFRP2, 43.1 % for sFRP4, 50.7 % for sFRP5, 44.4 % for DKK-1, and 69.4 % for DKK-3. In the SKM-1 cell line, the gene promoters sFRP1, sFRP2, sFRP5, DKK-1, and DKK-3 were methylated, while sFRP4 was not methylated. Treatment of the SKM-1 cell line with 5-aza-2'-deoxycytidine induced re-expression of methylated Wnt antagonists and inactivation of the Wnt pathway. Survival analysis showed that methylation status of sFRP1, sFRP4, and sFRP5 was associated with worse survival in MDS and sFRP5 methylation also predicted a high risk of leukemia evolution (P = 0.018). Our results indicate that epigenetic regulation of the Wnt pathway in MDS cell line, and the methylation status of Wnt antagonists predicts prognoses of MDS patients. PMID- 23093372 TI - Comparison of different methods of incorporating respiratory motion for lung cancer tumor volume delineation on PET images: a simulation study. AB - The interest of PET complementary information for the delineation of the target volume in radiotherapy of lung cancer is increasing. However, respiratory motion requires the determination of a functional internal target volume (ITV) on PET images for which several strategies have been proposed. The purpose of this study was the comparison of these strategies for taking into account respiratory motion and deriving the ITV: (1) adding fixed margins to the volume defined on a single binned image, (2) segmenting a motion averaged image and (3) considering the union of volumes delineated on binned frames. For this third strategy, binned frames were either non-corrected for motion, or corrected using two different methods: elastic registration or super resolution. The strategies' performances were assessed on realistic simulated datasets combining the NCAT phantom with a PET Philips GEMINI scanner model in GATE, and containing various configurations of tumor to background contrast, with both regular and irregular respiratory motion (with a range of motion amplitudes). The obtained ITVs' sensitivity (SE) and positive predictive value (PVE) with respect to the known true ITV were significantly higher (from 0.8 to 0.95) than all other techniques when using binned frames corrected for motion, independently of motion regularity, amplitude, or tumor to background contrast. Although the absolute difference was small and not always significant, images corrected using super resolution led to systematically better results than using elastic registration. The worst results were obtained when using the motion averaged image for SE (around 0.5-0.6) and using the margins added to a single frame for PPV (0.6-0.7), respectively. The best strategy to account for breathing motion for tumor ITV delineation in radiotherapy planning is to rely on the use of the union of volumes delineated on super resolution-corrected binned images. PMID- 23093373 TI - The angiotensin-converting enzyme 2/angiotensin-(1-7)/Mas receptor axis: a potential target for treating thrombotic diseases. AB - Despite many therapeutic advances leading to increasingly effective drug treatments, thrombotic events (such as ischaemic stroke, pulmonary embolism, deep venous thrombosis and acute myocardial infarction) still represent a major worldwide cause of morbidity and mortality. Remarkable effort has been made to identify new drug targets. There is growing evidence indicating that the recently described counter-regulator axis of the renin-angiotensin system (RAS), composed of Angiotensin-Converting Enzyme 2 (ACE2), Angiotensin-(1-7) and the Mas receptor, has protective effects against thrombosis. In addition, it could be considered as a promising target for treating or preventing this disease. In this narrative review, we focused on the recent findings of the role of the ACE2/Angiotensin-(1-7)/Mas axis on the haemostatic process and its therapeutic potential. PMID- 23093375 TI - Compact quantum dots for single-molecule imaging. AB - Single-molecule imaging is an important tool for understanding the mechanisms of biomolecular function and for visualizing the spatial and temporal heterogeneity of molecular behaviors that underlie cellular biology (1-4). To image an individual molecule of interest, it is typically conjugated to a fluorescent tag (dye, protein, bead, or quantum dot) and observed with epifluorescence or total internal reflection fluorescence (TIRF) microscopy. While dyes and fluorescent proteins have been the mainstay of fluorescence imaging for decades, their fluorescence is unstable under high photon fluxes necessary to observe individual molecules, yielding only a few seconds of observation before complete loss of signal. Latex beads and dye-labeled beads provide improved signal stability but at the expense of drastically larger hydrodynamic size, which can deleteriously alter the diffusion and behavior of the molecule under study. Quantum dots (QDs) offer a balance between these two problematic regimes. These nanoparticles are composed of semiconductor materials and can be engineered with a hydrodynamically compact size with exceptional resistance to photodegradation (5). Thus in recent years QDs have been instrumental in enabling long-term observation of complex macromolecular behavior on the single molecule level. However these particles have still been found to exhibit impaired diffusion in crowded molecular environments such as the cellular cytoplasm and the neuronal synaptic cleft, where their sizes are still too large (4,6,7). Recently we have engineered the cores and surface coatings of QDs for minimized hydrodynamic size, while balancing offsets to colloidal stability, photostability, brightness, and nonspecific binding that have hindered the utility of compact QDs in the past (8,9). The goal of this article is to demonstrate the synthesis, modification, and characterization of these optimized nanocrystals, composed of an alloyed HgxCd1-xSe core coated with an insulating CdyZn1-yS shell, further coated with a multidentate polymer ligand modified with short polyethylene glycol (PEG) chains (Figure 1). Compared with conventional CdSe nanocrystals, HgxCd1-xSe alloys offer greater quantum yields of fluorescence, fluorescence at red and near-infrared wavelengths for enhanced signal-to-noise in cells, and excitation at non cytotoxic visible wavelengths. Multidentate polymer coatings bind to the nanocrystal surface in a closed and flat conformation to minimize hydrodynamic size, and PEG neutralizes the surface charge to minimize nonspecific binding to cells and biomolecules. The end result is a brightly fluorescent nanocrystal with emission between 550-800 nm and a total hydrodynamic size near 12 nm. This is in the same size range as many soluble globular proteins in cells, and substantially smaller than conventional PEGylated QDs (25-35 nm). PMID- 23093376 TI - Induction and inhibition of crystallization in drug-in-adhesive-type transdermal patches. AB - PURPOSE: To screen crystallization inhibitors, perform accelerated stability testing and predict saturation solubility of levonorgestrel in drug-in-adhesive patches. METHODS: Differential scanning calorimetry (DSC) studies were compared against slide crystallization studies for screening additives. Release studies were performed from crystallized and supersaturated patches. Die cutting was used for accelerated stability testing of patches. Time lag experiments were performed to predict saturation solubility of levonorgestrel in acrylate adhesive, DuroTak 2516. RESULTS: DSC studies indicated poloxamer to be the best additive whereas slide crystallization studies showed polyvinylpyrrolidone to be better. Supersaturated patches showed higher release profiles relative to crystallized patches. Crystals were observed in crystallized patches even after 96 h of release studies. Die-cutting of patches helped in development of crystals in less time as compared to uncut sheets indicating its usefulness in accelerated stability testing. Saturation solubility of levonorgestrel in DuroTak-2516 was predicted to be 0.09% w/w which was in close agreement with value of 0.1% w/w from solubility calculator on vendor's website. CONCLUSIONS: Crystallization was shown to have negative impact on drug release and patch performance. Slide crystallization studies, die cutting and time lag experiments can be used as tools to help stabilize the otherwise unstable patches. PMID- 23093378 TI - Characteristics of hydration water around hen egg lysozyme as the protein model in aqueous solution. FTIR spectroscopy and molecular dynamics simulation. AB - In this paper, the hydration of a model protein--hen egg white lysozyme in aqueous solution has been presented. The leading method used was FTIR spectroscopy with an application of a technique of semi-heavy water (HDO) isotope dilution. Analysis of spectra of HDO isotopically diluted in water solution of lysozyme allowed us to isolate HDO spectra affected by lysozyme, and thus to characterise the energetic state of water molecules and their arrangement around protein molecules. The number of water molecules and the shape of the affected HDO spectrum were obtained using a classical and a chemometric method. This shape showed that the HDO spectrum affected by lysozyme may be presented as a superposition of two spectra corresponding to HDO affected by N-methylacetamide and the carboxylate anion (of the formic acid). Moreover, based on the difference in intermolecular distances distribution of water molecules (obtained from spectral data), we demonstrated that the lysozyme molecule causes a decrease in population of weak hydrogen bonds, and concurrently increases the probability of an occurrence of short hydrogen bonds in water affected by lysozyme. This conclusion was also confirmed by the molecular dynamics (MD) simulation. PMID- 23093377 TI - Efficacy of mucoadhesive hydrogel microparticles of whey protein and alginate for oral insulin delivery. AB - PURPOSE: To evaluate the efficacy of mucoadhesive insulin-loaded whey protein (WP) /alginate (ALG) microparticles (MP) for oral insulin administration. METHODS: Insulin-loaded microparticles (ins-MP) made of whey protein and alginate were prepared by a cold gelation technique and an adsorption method, without adjunction of organic solvent in order to develop a biocompatible vehicle for oral administration of insulin. In vitro characterization, evaluations of ins-MP in excised intestinal tissues and hypoglycaemic effects after intestinal administration in healthy rats were performed RESULTS: The release properties and swelling behaviors, investigated in different pH buffers, demonstrated a release based on diffusion mechanism following matrix swelling. Mucoadhesion studies in rabbits and insulin transport experiments with excised intestinal rat tissues revealed that encapsulation in microparticles with mucoadhesive properties promotes insulin absorption across duodenal membranes and bioactivity protection. In vivo experiments reinforced the interest of encapsulation in whey protein/alginate combination. Confocal microscopic observations associated with blood glucose levels bring to light duodenal absorption of insulin biologically active following in vivo administration. CONCLUSIONS: Insulin-loaded WP/ALG MP with high quantities of drug entrapped, in vitro matrix swelling and protective effect as well as excellent mucohadesive properties was developped. Improvement of intestinal delivery of insulin and increased in bioavailability were recorded. PMID- 23093379 TI - A least trimmed square regression method for second level FMRI effective connectivity analysis. AB - We present a least trimmed square (LTS) robust regression method to combine different runs/subjects for second/high level effective connectivity analysis. The basic idea of this method is to treat the extreme nonlinear model variability as outliers if they exceed a certain threshold. A bootstrap method for the LTS estimation is employed to detect model outliers. We compared the LTS robust method with a non-robust method using simulated and real datasets. The difference between LTS and the non-robust method for second level effective connectivity analysis is significant, suggesting the conventional non-robust method is easily affected by the model variability from the first level analysis. In addition, after these outliers are detected and excluded for the high level analysis, the model coefficients of the second level are combined within the framework of a mixed model. The variance of the mixed model is estimated using the Newton Raphson (NR) type Levenberg-Marquardt algorithm. Three sets of real data are adopted to compare conventional methods which do not include random effects in the analysis with a mixed model for second level effective connectivity analysis. The results show that the conventional method is significantly different from the mixed model when greater model variability exists, suggesting there is a strong random effect, and the mixed model should be employed for the second level effective connectivity analysis. PMID- 23093380 TI - Haemophilus parainfluenzae has a limited core lipopolysaccharide repertoire with no phase variation. AB - Cell surface lipopolysaccharide (LPS) is a well characterized virulence determinant for the human pathogen Haemophilus influenzae, so an investigation of LPS in the less pathogenic Haemophilus parainfluenzae could yield important insights. Using a panel of 18 commensal H. parainfluenzae isolates we demonstrate that the set of genes for inner core LPS biosynthesis largely resembles that of H. influenzae, with an additional heptosyltransferase I gene similar to waaC from Pasteurella multocida. Inner core LPS structure is therefore likely to be largely conserved across the two Haemophilus species. Outer core LPS biosynthetic genes are much less prevalent in H. parainfluenzae, although homologues of the H. influenzae LPS genes lpsB, non-phase variable lic2A and lgtC, and losA1, losB1 and lic2C are found in certain isolates. Immunoblotting using antibodies directed against selected LPS epitopes was consistent with these data. We found no evidence for tetranucleotide repeat-mediated phase variation in H. parainfluenzae. Phosphocholine, a phase variable H. influenzae LPS epitope that has been implicated in disease, was absent in H. parainfluenzae LPS as were the respective (lic1) biosynthetic genes. The introduction of the lic1 genes into H. parainfluenzae led to the phase variable incorporation of phosphocholine into its LPS. Differences in LPS structure between Haemophilus species could affect interactions at the bacterial-host interface and therefore the pathogenic potential of these bacteria. PMID- 23093381 TI - Brain RGS4 and RGS10 protein expression in schizophrenia and depression. Effect of drug treatment. AB - RATIONALE: Regulator of G-protein signaling (RGS) proteins, RGS4 and RGS10, may be involved in the pathophysiology of schizophrenia. RGS4 has attracted special interest since the reports of genetic association between SNPs in RGS4 and schizophrenia. However, there is no information about the subcellular distribution of RGS4 and RGS10 proteins in psychiatric disorders. OBJECTIVES: Plasma membrane RGS4 and cytosolic RGS10 protein immunoreactivity in prefrontal cortex from schizophrenic subjects (n = 25), non-diagnosed suicides (n = 13), and control subjects (n = 35), matched by age, gender, and postmortem delay, was analyzed by western blot. A second group of depressed subjects (n = 25) and control subjects (n = 25) was evaluated. The effect of the antipsychotic or antidepressant treatments was also assessed. RESULTS: No significant differences in plasma membrane RGS4 and cytosolic RGS10 protein expression were observed between schizophrenic subjects, non-diagnosed suicides, and control subjects. However, RGS4 immunoreactivity was significantly higher (Delta = 33 +/- 10 %, p < 0.05) in the antipsychotic-treated subgroup (n = 12) than in the antipsychotic free subgroup (n = 13). Immunodensities of plasma membrane RGS4 and cytosolic RGS10 proteins did not differ between depressed and matched control subjects. CONCLUSIONS: Expression of RGS4 and RGS10 proteins at their predominant subcellular location was studied in the postmortem brain of subjects with psychiatric disorders. The results suggest unaltered membrane RGS4 and cytosolic RGS10 proteins levels in schizophrenia and major depression. Antipsychotic treatment seems to increase membrane RGS4 immunoreactivity. Further studies are needed to elucidate RGS4 and RGS10 functional status. PMID- 23093382 TI - A classically conditioned cocaine cue acquires greater control over motivated behavior in rats prone to attribute incentive salience to a food cue. AB - RATIONALE: Cues associated with rewards bias attention towards them and can motivate drug-seeking and drug-taking behavior. There is, however, considerable individual variation in the extent to which cues associated with rewards acquire motivational properties. For example, only in some rats does a localizable food cue become attractive, eliciting approach towards it, and "wanted", in the sense that it serves as an effective conditioned reinforcer. OBJECTIVES: We asked whether the propensity of animals to attribute incentive salience to a food cue predicts the extent to which a classically conditioned cocaine cue acquires incentive motivational properties. METHODS: First, a Pavlovian conditioned approach procedure was used to identify rats prone to attribute incentive salience to a food cue. We then measured the extent to which a classically conditioned cocaine cue acquired two properties of an incentive stimulus: (1) the ability to elicit approach towards it, and (2) the ability to reinstate drug seeking behavior, using an extinction-reinstatement procedure (i.e., to act as a conditioned reinforcer). RESULTS: We found that a classically conditioned cocaine cue became more attractive, in that it elicited greater approach toward it, and more desired, in that it supported more drug-seeking behavior under extinction conditions, in individuals prone to attribute incentive salience to a food cue. CONCLUSIONS: We conclude that rats vary in their propensity to attribute incentive salience to both food and cocaine cues, and it is possible to predict, prior to any drug experience, in which rats a cocaine cue will acquire the strongest motivational control over behavior. PMID- 23093383 TI - Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. AB - RATIONALE: Combinatory therapy is widely used in psychiatry owing to the possibility that drugs with different mechanisms of action may synergize to improve functions deteriorated in schizophrenia, bipolar disorders, and major depression. While combinatory strategies rely on receptor and synaptic mechanisms, it should also be considered that two drugs may also "interact" on the long-term to determine more robust changes in neuronal plasticity, which represents a downstream target important for functional recovery. OBJECTIVE: The aim of the study is to investigate neuroadaptive changes set in motion by chronic concomitant administration of the novel antipsychotic lurasidone and the mood stabilizer valproate. METHODS: Animals were chronically treated with lurasidone, valproate, or the combination of the two drugs and killed 24 h after the last injection to evaluate alterations of different measures of neuronal plasticity such as the neurotrophin brain-derived neurotrophic factor (BDNF), the immediate early gene Activity-regulated cytoskeletal associated protein, and the epigenetic regulators HDAC 1, 2, and 5 in dorsal and ventral hippocampus. RESULTS: The results suggest that coadministration of lurasidone and valproate produces, when compared to the single drugs, a larger increase in the expression of BDNF in the ventral hippocampus, through the regulation of specific neurotrophin transcripts. We also found that the histone deacetylases were regulated by the drug combination, suggesting that some of the transcriptional changes may be sustained by epigenetic mechanisms. CONCLUSIONS: Our results suggest that the beneficial effects associated with combinatory treatment between a second-generation antipsychotic and a mood stabilizer could result from the ability to modulate neuroplastic molecules, whose expression and function is deteriorated in different psychiatric conditions. PMID- 23093384 TI - Enhanced butanol production obtained by reinforcing the direct butanol-forming route in Clostridium acetobutylicum. AB - Butanol is an important industrial solvent and advanced biofuel that can be produced by biphasic fermentation by Clostridium acetobutylicum. It has been known that acetate and butyrate first formed during the acidogenic phase are reassimilated to form acetone-butanol-ethanol (cold channel). Butanol can also be formed directly from acetyl-coenzyme A (CoA) through butyryl-CoA (hot channel). However, little is known about the relative contributions of the two butanol forming pathways. Here we report that the direct butanol-forming pathway is a better channel to optimize for butanol production through metabolic flux and mass balance analyses. Butanol production through the hot channel was maximized by simultaneous disruption of the pta and buk genes, encoding phosphotransacetylase and butyrate kinase, while the adhE1(D485G) gene, encoding a mutated aldehyde/alcohol dehydrogenase, was overexpressed. The ratio of butanol produced through the hot channel to that produced through the cold channel increased from 2.0 in the wild type to 18.8 in the engineered BEKW(pPthlAAD(**)) strain. By reinforcing the direct butanol-forming flux in C. acetobutylicum, 18.9 g/liter of butanol was produced, with a yield of 0.71 mol butanol/mol glucose by batch fermentation, levels which are 160% and 245% higher than those obtained with the wild type. By fed-batch culture of this engineered strain with in situ recovery, 585.3 g of butanol was produced from 1,861.9 g of glucose, with the yield of 0.76 mol butanol/mol glucose and productivity of 1.32 g/liter/h. Studies of two butanol-forming routes and their effects on butanol production in C. acetobutylicum described here will serve as a basis for further metabolic engineering of clostridia aimed toward developing a superior butanol producer. IMPORTANCE Renewable biofuel is one of the answers to solving the energy crisis and climate change problems. Butanol produced naturally by clostridia has superior liquid fuel characteristics and thus has the potential to replace gasoline. Due to the lack of efficient genetic manipulation tools, however, strain improvement has been rather slow. Furthermore, complex metabolic characteristics of acidogenesis followed by solventogenesis in this strain have hampered development of engineered clostridia having highly efficient and selective butanol production capability. Here we report for the first time the results of systems metabolic engineering studies of two butanol-forming routes and their relative importances in butanol production. Based on these findings, a metabolically engineered Clostridium acetobutylicum strain capable of producing butanol to a high titer with high yield and selectivity could be developed by reinforcing the direct butanol-forming flux. PMID- 23093385 TI - Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing. AB - Fecal microbiome transplantation by low-volume enema is an effective, safe, and inexpensive alternative to antibiotic therapy for patients with chronic relapsing Clostridium difficile infection (CDI). We explored the microbial diversity of pre and posttransplant stool specimens from CDI patients (n = 6) using deep sequencing of the 16S rRNA gene. While interindividual variability in microbiota change occurs with fecal transplantation and vancomycin exposure, in this pilot study we note that clinical cure of CDI is associated with an increase in diversity and richness. Genus- and species-level analysis may reveal a cocktail of microorganisms or products thereof that will ultimately be used as a probiotic to treat CDI. IMPORTANCE Antibiotic-associated diarrhea (AAD) due to Clostridium difficile is a widespread phenomenon in hospitals today. Despite the use of antibiotics, up to 30% of patients are unable to clear the infection and suffer recurrent bouts of diarrheal disease. As a result, clinicians have resorted to fecal microbiome transplantation (FT). Donor stool for this type of therapy is typically obtained from a spouse or close relative and thoroughly tested for various pathogenic microorganisms prior to infusion. Anecdotal reports suggest a very high success rate of FT in patients who fail antibiotic treatment (>90%). We used deep-sequencing technology to explore the human microbial diversity in patients with Clostridium difficile infection (CDI) disease after FT. Genus- and species-level analysis revealed a cocktail of microorganisms in the Bacteroidetes and Firmicutes phyla that may ultimately be used as a probiotic to treat CDI. PMID- 23093386 TI - Modulation of Kingella kingae adherence to human epithelial cells by type IV Pili, capsule, and a novel trimeric autotransporter. AB - Kingella kingae is an emerging bacterial pathogen that is being recognized increasingly as an important etiology of septic arthritis, osteomyelitis, and bacteremia, especially in young children. Colonization of the posterior pharynx is a key step in the pathogenesis of K. kingae disease. Previous work established that type IV pili are necessary for K. kingae adherence to the respiratory epithelium. In this study, we set out to identify additional factors that influence K. kingae interactions with human epithelial cells. We found that genetic disruption of the gene encoding a predicted trimeric autotransporter protein called Knh (Kingella NhhA homolog) resulted in reduced adherence to human epithelial cells. In addition, we established that K. kingae elaborates a surface associated polysaccharide capsule that requires a predicted ABC-type transporter export operon called ctrABCD for surface presentation. Furthermore, we discovered that the presence of a surface capsule interferes with Knh-mediated adherence to human epithelial cells by nonpiliated organisms and that maximal adherence in the presence of a capsule requires the predicted type IV pilus retraction machinery, PilT/PilU. On the basis of the data presented here, we propose a novel adherence mechanism that allows K. kingae to adhere efficiently to human epithelial cells while remaining encapsulated and more resistant to immune clearance. IMPORTANCE: Kingella kingae is a Gram-negative bacterium that is being recognized increasingly as a cause of joint and bone infections in young children. The pathogenesis of disease due to K. kingae begins with bacterial colonization of the upper respiratory tract, and previous work established that surface hair-like fibers called type IV pili are necessary for K. kingae adherence to respiratory epithelial cells. In this study, we set out to identify additional factors that influence K. kingae interactions with respiratory epithelial cells. We discovered a novel surface protein called Knh that mediates K. kingae adherence and found that a surface-associated carbohydrate capsule interferes with the Knh-mediated adherence of organisms lacking pili. Further analysis revealed that pilus retraction is necessary for maximal Knh-mediated adherence in the presence of the capsule. Our results may lead to new strategies to prevent disease due to K. kingae and potentially other pathogenic bacteria. PMID- 23093387 TI - Effects of crude oil, dispersant, and oil-dispersant mixtures on human fecal microbiota in an in vitro culture system. AB - The Deepwater Horizon oil spill of 2010 raised concerns that dispersant and dispersed oil, as well as crude oil itself, could contaminate shellfish and seafood habitats with hazardous residues that had potential implications for human health and the ecosystem. However, little is known about the effects of crude oil and dispersant on the human fecal microbiota. The aim of this research was to evaluate the potential effects of Deepwater Horizon crude oil, Corexit 9500 dispersant, and their combination on human fecal microbial communities, using an in vitro culture test system. Fecal specimens from healthy adult volunteers were made into suspensions, which were then treated with oil, dispersant, or oil-dispersant mixtures under anaerobic conditions in an in vitro culture test system. Perturbations of the microbial community, compared to untreated control cultures, were assessed using denaturing gradient gel electrophoresis (DGGE), real-time PCR, and pyrosequencing methods. DGGE and pyrosequencing analysis showed that oil-dispersant mixtures reduced the diversity of fecal microbiota from all individuals. Real-time PCR results indicated that the copy numbers of 16S rRNA genes in cultures treated with dispersed oil or oil alone were significantly lower than those in control incubations. The abundance of the Bacteroidetes decreased in crude oil-treated and dispersed-oil-treated cultures, while the Proteobacteria increased in cultures treated with dispersed oil. In conclusion, the human fecal microbiota was affected differently by oil and dispersed oil, and the influence of dispersed oil was significantly greater than that of either oil or dispersant alone compared to control cultures. IMPORTANCE There have been concerns whether human health is adversely affected by exposure to spilled crude oil, which contains regulated carcinogens, such as polycyclic aromatic hydrocarbons. In this study, we determined the effect of BP Deepwater Horizon crude oil and oil dispersant on the human intestinal microbiota, since there is the potential that low-level residues of petrochemicals could contaminate seafood. The results of this study will increase our understanding of the ecophysiological changes in the microbial communities of the human gastrointestinal tract with respect to crude oil exposure. PMID- 23093388 TI - Vitamin D and the human antimicrobial peptide LL-37 enhance group a streptococcus resistance to killing by human cells. AB - The CsrRS two-component regulatory system of group A Streptococcus (GAS; Streptococcus pyogenes) responds to subinhibitory concentrations of the human antimicrobial peptide LL-37. LL-37 signaling through CsrRS results in upregulation of genes that direct synthesis of virulence factors, including the hyaluronic acid capsule and streptolysin O (SLO). Here, we demonstrate that a consequence of this response is augmented GAS resistance to killing by human oropharyngeal keratinocytes, neutrophils, and macrophages. LL-37-induced upregulation of SLO and hyaluronic acid capsule significantly reduced internalization of GAS by keratinocytes and phagocytic killing by neutrophils and macrophages. Because vitamin D induces LL-37 production by macrophages, we tested its effect on macrophage killing of GAS. In contrast to the reported enhancement of macrophage function in relation to other pathogens, treatment of macrophages with 1alpha,25-dihydroxy-vitamin D3 paradoxically reduced the ability of macrophages to control GAS infection. These observations demonstrate that LL-37 signals through CsrRS to induce a virulence phenotype in GAS characterized by heightened resistance to ingestion and killing by both epithelial cells and phagocytes. By inducing LL-37 production in macrophages, vitamin D may contribute to this paradoxical exacerbation of GAS infection. IMPORTANCE It remains poorly understood why group A Streptococcus (GAS) causes asymptomatic colonization or localized throat inflammation in most individuals but rarely progresses to invasive infection. The human antimicrobial peptide LL-37, which is produced as part of the innate immune response to GAS infection, signals through the GAS CsrRS two-component regulatory system to upregulate expression of multiple virulence factors. This study reports that two CsrRS-regulated GAS virulence factors-streptolysin O and the hyaluronic acid capsule-are critical in LL-37 induced resistance of GAS to killing by human throat epithelial cells and by neutrophils and macrophages. Vitamin D, which increases LL-37 production in macrophages, has the paradoxical effect of increasing GAS resistance to macrophage-mediated killing. In this way, the human innate immune response may promote the transition from GAS colonization to invasive infection. PMID- 23093389 TI - A molecular dynamics study on sI hydrogen hydrate. AB - A molecular dynamics simulation is carried out to explore the possibility of using sI clathrate hydrate as hydrogen storage material. Metastable hydrogen hydrate structures are generated using the LAMMPS software. Different binding energies and radial distribution functions provide important insights into the behavior of the various types of hydrogen and oxygen atoms present in the system. Clathrate hydrate cages become more stable in the presence of guest molecules like hydrogen. PMID- 23093390 TI - CO2 adsorption on polar surfaces of ZnO. AB - Physical and chemical adsorption of CO2 on ZnO surfaces were studied by means of two different implementations of periodic density functional theory. Adsorption energies were computed and compared to values in the literature. In particular, it was found that the calculated equilibrium structure and internuclear distances are in agreement with previous work. CO2 adsorption was analyzed by inspection of the density of states and electron localization function. Valence bands, band gap and final states of adsorbed CO2 were investigated and the effect of atomic displacements analyzed. The partial density of states (PDOS) of chemical adsorption of CO2 on the ZnO(0001) surface show that the p orbitals of CO2 were mixed with the ZnO valence band state appearing at the top of the valence band and in regions of low-energy conduction band. PMID- 23093391 TI - Melanotic neuroectodermal tumour of infancy, a rare cause for a bump on the head. PMID- 23093392 TI - Visual cognitive function in infants with intractable epilepsy before and after surgery. AB - PURPOSE: One purpose of pediatric epilepsy surgery is to improve psychomotor development. However, few methods are available for evaluating cognitive function in infants with severe developmental delays. We used the following battery of tests to evaluate visual cognitive function of infants following surgery for intractable epilepsy. METHODS: The following battery of tests were used to evaluate eight patients before and 1 month after surgery: (1) Erhardt Developmental Vision Assessment (EDVA); (2) evaluation of ocular pursuit for a flashing LED toy; (3) three visual acuity tests preferential looking procedure, optokinetic nystagmus, and Sheridan's Test for Young Children and Retarded balls vision test; and (4) existing developmental test. RESULTS: EDVA scores and ocular pursuit score with a flashing LED toy showed the same trends with developmental age as the existing developmental tests. However, in some patients, the EDVA score and ocular pursuit score improved greatly, whereas the developmental age changed very little. CONCLUSIONS: These tests are suitable for patients with intractable epilepsy and severe developmental delay. By performing these tests before and after surgery, small cognitive changes occurring soon after the surgery may be detected. PMID- 23093393 TI - X-ray phase-contrast CO(2) angiography for sub-10 MUm vessel imaging. AB - X-ray in-line phase contrast has recently been combined with CO(2) angiography for high-resolution small-animal vascular imaging at low radiation dose. In this paper we further investigate the potential and limitations of this method and demonstrate observation of vessels down to 8 MUm in diameter, considerably smaller than the 60 MUm previously reported. Our in-line phase-contrast imaging system is based on a liquid-metal-jet-anode x-ray source and utilizes free-space propagation to convert phase shifts, caused by refractive index variations, into intensity differences. Enhanced refractive index variations are obtained through injection of CO(2) gas into the vascular system to replace the blood. We show rat kidney images with blood vessels down to 27 MUm in diameter and mouse-ear images with vessels down to 8 MUm. The minimum size of observable blood vessels is found to be limited by the penetration of gas into the vascular system and the signal to-noise ratio, i.e. the allowed dose. The diameters of vessels being gas-filled depend on the gas pressure and follow a simple model based on surface tension. A theoretical signal-to-noise comparison shows that this method requires 1000 times less radiation dose than conventional iodine-based absorption contrast for observing sub-50 MUm vessels. PMID- 23093394 TI - [How often are absolute and relative effect measures reported in studies?- Absolute and relative data are still insufficiently reported]. PMID- 23093395 TI - [Influences of medical education on first aid and AED knowledge among laypersons]. AB - BACKGROUND AND AIM: Although most laypersons have incomplete knowledge of first aid, the placement of automated external defibrillators (AED) on public places suggests AED application by laypersons. Unfortunately, previous results are disappointing; many people don't even recognize AED. Therefore, most authors suggest to force medical education about sudden cardiac death and AED use among laypersons. We wanted to find out whether intensive medical education can improve the recognition of AED at public places and the attendance to acquire knowledge in first aid. METHODS: In 2001 eight AED were placed in the amusement swimming park "LAGO - die Therme". Contemporaneously, we started public education regarding sudden cardiac death, resuscitation and AED among layperson visiting the LAGO. After 10 years we interviewed the visitors with special regard to their knowledge of first aid and AED use. RESULTS: 531 persons (260 men, age 48,4 +/- 21,9 [range 8-95] years) fulfilled the questionnaire. 59 (11,1%) stated heart disorder, 219 (41,2%) at least one cardiovascular risk factor. As ten years ago, knowledge of first-aid (59,1%) and AED use (45,2%) was poor, especially among persons younger than 17 years or older than 67 years. 398 (75%) of the interviewed visitors recognized the installed AED, 511 (96,2%) supported the placement of AED. CONCLUSION: The placement of AED on public places in combination with an intensive medical education results in a high acceptance and recognition of AED. Nevertheless, following our date it seems to be doubtful that this results automatically in a higher attendance to acquire knowledge in first aid and AED use. PMID- 23093396 TI - [Transient global amnesia and Tako-Tsubo cardiomyopathy--coincidence or corollary?]. AB - HISTORY: A 69-year-old female patient who had been physically and mentally healthy was admitted to our emergency department because of acute onset of amnesia. INVESTIGATIONS: Inconspicuous diagnostic findings led to the diagnosis of transient global amnesia (TGA). Furthermore bradycardia and elevated troponins were detected. Because of these findings a cardiologic workup was performed resulting in the diagnosis of Tako-Tsubo cardiomyopathy. TREATMENT AND COURSE: The patient recovered completely from TGA as well as from the slight reduction of the left-ventricular ejection fraction as part of the Tako-Tsubo cardiomyopathy. CONCLUSION: There are similarities of the two diseases Tako-Tsubo cardiomyopathy and TGA concerning triggers as well as reversibility. Patients presenting with symptoms suggestive for TGA should be considered to undergo additional cardiologic evaluation. PMID- 23093397 TI - [Progressive malaise and joint pain after travel to Costa Rica]. AB - HISTORY AND ADMISSION FINDINGS: We report on a 57-year-old patient presenting with progressive malaise, joint pain and skin rashes one month after visiting Costa Rica. After exclusion of common tropical diseases empiric antibiotic therapy was initiated, however, the patient's symptoms did not improve. INVESTIGATIONS: CT scan of the chest demonstrated an intrapulmonary nodular lesion. Bronchoscopy revealed no pathological changes. Microbiologic analysis of the bronchoalveolar lavage fluids identified no pathogen. An abdominal ultrasound examination did not reveal pathological findings. Serological tests were positive for Histoplasma capsulatum. TREATMENT AND COURSE: Treatment with itraconazole resulted in a fast initial clinical improvement, but complete resolution of all symptoms only occurred after completion of a 6-months course of itraconazole. Serial CT scans demonstrated a continuous regression of the pulmonary lesion. CONCLUSION: Histoplasmosis has a low incidence among travelers. However, histoplasmosis should be considered in patients with respiratory symptoms and history of travel to endemic countries, specifically when common traveler diseases have been excluded. Diagnosis is confirmed by serology, imaging and ultimately by biopsy for histological, cultural and molecular identification of the pathogen. Antimycotic drug therapy is the recommended treatment of choice for symptomatic cases. PMID- 23093398 TI - [61-year-old woman with formation of nodules after a tropical journey]. PMID- 23093399 TI - [Update pneumonia 2012]. AB - Pneumonia is an infection of the lung parenchyma and defined as combination of a novel radiological infiltrate with typical signs and symptoms. There are 3 distinguished entities of pneumonia: community-acquired pneumonia (CAP), hospital acquired pneumonia (HAP), and pneumonia in the immunocompromised patient. The spectrum of pathogens is increasing from CAP, mostly caused by pneumococci, over HAP (additional multi-drug resistant pathogens) to pneumonia in the immunocompromised (additional opportunistic pathogens). Therefore, each entity demands a specific diagnostic and therapeutic approach. This review compares the 3 forms of pneumonia and presents a guideline based clinical approach in the context of current studies. PMID- 23093400 TI - [Preexposure prophylaxis for HIV infection--current data and recommendations]. PMID- 23093401 TI - Acute effects of pomegranate extract on postprandial lipaemia, vascular function and blood pressure. AB - We investigated whether a test drink enriched in pomegranate polyphenols, consumed with a high-fat meal, can reduce postprandial lipaemia and improve vascular function and blood pressure compared to placebo. Nineteen young, healthy men completed a randomized, controlled crossover trial. The active drink (containing a pomegranate extract) was consumed during a high-fat meal (ET-DUR) or 15 min before (ET-PRE), and the placebo drink (no pomegranate extract) was consumed during the high-fat meal (CONTROL). Postprandial lipaemia was assessed by venous plasma TAG 0-2 h, and capillary plasma TAG 0-4 h. Blood pressure and digital volume pulse, to measure reflection index (DVP-RI) and stiffness index (DVP-SI), were monitored at baseline, 2 and 4 h. There was no inhibition of postprandial lipaemia by the active drink compared to CONTROL. ET-PRE caused a greater increase in the venous plasma TAG at 2 h compared to CONTROL and ET-DUR (treatment effect P = 0.001). The incremental area under the curve 0-4 h for capillary plasma TAG was not significantly different between treatments. Systolic blood pressure (SBP) increased in the ET-PRE and ET-DUR groups to a lesser extent than the CONTROL group (treatment effect P = 0.041). There were no treatment effects for DVP-RI, DVP-SI or diastolic blood pressure. In conclusion, the consumption of a single drink containing ET-rich pomegranate extract did not decrease postprandial plasma TAG concentrations, but suppressed the postprandial increase in SBP following the high-fat meal. PMID- 23093402 TI - Heme-assisted S-nitrosation desensitizes ferric soluble guanylate cyclase to nitric oxide. AB - Nitric oxide (NO) signaling regulates key processes in cardiovascular physiology, specifically vasodilation, platelet aggregation, and leukocyte rolling. Soluble guanylate cyclase (sGC), the mammalian NO sensor, transduces an NO signal into the classical second messenger cyclic GMP (cGMP). NO binds to the ferrous (Fe(2+)) oxidation state of the sGC heme cofactor and stimulates formation of cGMP several hundred-fold. Oxidation of the sGC heme to the ferric (Fe(3+)) state desensitizes the enzyme to NO. The heme-oxidized state of sGC has emerged as a potential therapeutic target in the treatment of cardiovascular disease. Here, we investigate the molecular mechanism of NO desensitization and find that sGC undergoes a reductive nitrosylation reaction that is coupled to the S-nitrosation of sGC cysteines. We further characterize the kinetics of NO desensitization and find that heme-assisted nitrosothiol formation of beta1Cys-78 and beta1Cys-122 causes the NO desensitization of ferric sGC. Finally, we provide evidence that the mechanism of reductive nitrosylation is gated by a conformational change of the protein. These results yield insights into the function and dysfunction of sGC in cardiovascular disease. PMID- 23093403 TI - Electron microscopic analysis of a spherical mitochondrial structure. AB - Mitochondria undergo dynamic structural alterations to meet changing needs and to maintain homeostasis. We report here a novel mitochondrial structure. Conventional transmission electron microscopic examination of murine embryonic fibroblasts treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial uncoupler, found that more than half of the mitochondria presented a ring-shaped or C-shaped morphology. Many of these mitochondria seemed to have engulfed various cytosolic components. Serial sections through individual mitochondria indicated that they formed a ball-like structure with an internal lumen surrounded by the membranes and containing cytosolic materials. Notably, the lumen was connected to the external cytoplasm through a small opening. Electron tomographic reconstruction of the mitochondrial spheroids demonstrated the membrane topology and confirmed the vesicular configuration of this mitochondrial structure. The outside periphery and the lumen were defined by the outer membranes, which were lined with the inner membranes. Matrix and cristae were retained but distributed unevenly with less being kept near the luminal opening. Mitochondrial spheroids seem to form in response to oxidative mitochondrial damage independently of mitophagy. The structural features of the mitochondrial spheroids thus represent a novel mitochondrial dynamics. PMID- 23093404 TI - Sequence determinants of GLUT1-mediated accelerated-exchange transport: analysis by homology-scanning mutagenesis. AB - The class 1 equilibrative glucose transporters GLUT1 and GLUT4 are structurally similar but catalyze distinct modes of transport. GLUT1 exhibits trans acceleration, in which the presence of intracellular sugar stimulates the rate of unidirectional sugar uptake. GLUT4-mediated uptake is unaffected by intracellular sugar. Using homology-scanning mutagenesis in which domains of GLUT1 are substituted with equivalent domains from GLUT4 and vice versa, we show that GLUT1 transmembrane domain 6 is both necessary and sufficient for trans-acceleration. This region is not directly involved in GLUT1 binding of substrate or inhibitors. Rather, transmembrane domain 6 is part of two putative scaffold domains, which coordinate membrane-spanning amphipathic helices that form the sugar translocation pore. We propose that GLUT1 transmembrane domain 6 restrains import when intracellular sugar is absent by slowing transport-associated conformational changes. PMID- 23093405 TI - Targeting of several glycolytic enzymes using RNA interference reveals aldolase affects cancer cell proliferation through a non-glycolytic mechanism. AB - In cancer, glucose uptake and glycolysis are increased regardless of the oxygen concentration in the cell, a phenomenon known as the Warburg effect. Several (but not all) glycolytic enzymes have been investigated as potential therapeutic targets for cancer treatment using RNAi. Here, four previously untargeted glycolytic enzymes, aldolase A, glyceraldehyde 3-phosphate dehydrogenase, triose phosphate isomerase, and enolase 1, are targeted using RNAi in Ras-transformed NIH-3T3 cells. Of these enzymes, knockdown of aldolase causes the greatest effect, inhibiting cell proliferation by 90%. This defect is rescued by expression of exogenous aldolase. However, aldolase knockdown does not affect glycolytic flux or intracellular ATP concentration, indicating a non-metabolic cause for the cell proliferation defect. Furthermore, this defect could be rescued with an enzymatically dead aldolase variant that retains the known F actin binding ability of aldolase. One possible model for how aldolase knockdown may inhibit transformed cell proliferation is through its disruption of actin cytoskeleton dynamics in cell division. Consistent with this hypothesis, aldolase knockdown cells show increased multinucleation. These results are compared with other studies targeting glycolytic enzymes with RNAi in the context of cancer cell proliferation and suggest that aldolase may be a useful target in the treatment of cancer. PMID- 23093406 TI - Metabolic mechanism of mannan in a ruminal bacterium, Ruminococcus albus, involving two mannoside phosphorylases and cellobiose 2-epimerase: discovery of a new carbohydrate phosphorylase, beta-1,4-mannooligosaccharide phosphorylase. AB - Ruminococcus albus is a typical ruminal bacterium digesting cellulose and hemicellulose. Cellobiose 2-epimerase (CE; EC 5.1.3.11), which converts cellobiose to 4-O-beta-D-glucosyl-D-mannose, is a particularly unique enzyme in R. albus, but its physiological function is unclear. Recently, a new metabolic pathway of mannan involving CE was postulated for another CE-producing bacterium, Bacteroides fragilis. In this pathway, beta-1,4-mannobiose is epimerized to 4-O beta-D-mannosyl-D-glucose (Man-Glc) by CE, and Man-Glc is phosphorolyzed to alpha D-mannosyl 1-phosphate (Man1P) and D-glucose by Man-Glc phosphorylase (MP; EC 2.4.1.281). Ruminococcus albus NE1 showed intracellular MP activity, and two MP isozymes, RaMP1 and RaMP2, were obtained from the cell-free extract. These enzymes were highly specific for the mannosyl residue at the non-reducing end of the substrate and catalyzed the phosphorolysis and synthesis of Man-Glc through a sequential Bi Bi mechanism. In a synthetic reaction, RaMP1 showed high activity only toward D-glucose and 6-deoxy-D-glucose in the presence of Man1P, whereas RaMP2 showed acceptor specificity significantly different from RaMP1. RaMP2 acted on D-glucose derivatives at the C2- and C3-positions, including deoxy- and deoxyfluoro-analogues and epimers, but not on those substituted at the C6 position. Furthermore, RaMP2 had high synthetic activity toward the following oligosaccharides: beta-linked glucobioses, maltose, N,N'-diacetylchitobiose, and beta-1,4-mannooligosaccharides. Particularly, beta-1,4-mannooligosaccharides served as significantly better acceptor substrates for RaMP2 than D-glucose. In the phosphorolytic reactions, RaMP2 had weak activity toward beta-1,4-mannobiose but efficiently degraded beta-1,4-mannooligosaccharides longer than beta-1,4 mannobiose. Consequently, RaMP2 is thought to catalyze the phosphorolysis of beta 1,4-mannooligosaccharides longer than beta-1,4-mannobiose to produce Man1P and beta-1,4-mannobiose. PMID- 23093407 TI - Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration. AB - The two members of the Rho-associated coiled-coil kinase (ROCK1 and 2) family are established regulators of actin dynamics that are involved in the regulation of the cell cycle as well as cell motility and invasion. Here, we discovered a novel signaling pathway whereby ROCK regulates microtubule (MT) acetylation via phosphorylation of the tubulin polymerization promoting protein 1 (TPPP1/p25). We show that ROCK phosphorylation of TPPP1 inhibits the interaction between TPPP1 and histone deacetylase 6 (HDAC6), which in turn results in increased HDAC6 activity followed by a decrease in MT acetylation. As a consequence, we show that TPPP1 phosphorylation by ROCK increases cell migration and invasion via modulation of cellular acetyl MT levels. We establish here that the ROCK-TPPP1 HDAC6 signaling pathway is important for the regulation of cell migration and invasion. PMID- 23093408 TI - Eurocin, a new fungal defensin: structure, lipid binding, and its mode of action. AB - Antimicrobial peptides are a new class of antibiotics that are promising for pharmaceutical applications because they have retained efficacy throughout evolution. One class of antimicrobial peptides are the defensins, which have been found in different species. Here we describe a new fungal defensin, eurocin. Eurocin acts against a range of Gram-positive human pathogens but not against Gram-negative bacteria. Eurocin consists of 42 amino acids, forming a cysteine stabilized alpha/beta-fold. The thermal denaturation data point shows the disulfide bridges being responsible for the stability of the fold. Eurocin does not form pores in cell membranes at physiologically relevant concentrations; it does, however, lead to limited leakage of a fluorophore from small unilamellar vesicles. Eurocin interacts with detergent micelles, and it inhibits the synthesis of cell walls by binding equimolarly to the cell wall precursor lipid II. PMID- 23093409 TI - A lectin from the mussel Mytilus galloprovincialis has a highly novel primary structure and induces glycan-mediated cytotoxicity of globotriaosylceramide expressing lymphoma cells. AB - A novel lectin structure was found for a 17-kDa alpha-D-galactose-binding lectin (termed "MytiLec") isolated from the Mediterranean mussel, Mytilus galloprovincialis. The complete primary structure of the lectin was determined by Edman degradation and mass spectrometric analysis. MytiLec was found to consist of 149 amino acids with a total molecular mass of 16,812.59 Da by Fourier transform-ion cyclotron resonance mass spectrometry, in good agreement with the calculated value of 16,823.22 Da. MytiLec had an N terminus of acetylthreonine and a primary structure that was highly novel in comparison with those of all known lectins in the structure database. The polypeptide structure consisted of three tandem-repeat domains of ~50 amino acids each having 45-52% homology with each other. Frontal affinity chromatography technology indicated that MytiLec bound specifically to globotriose (Gb3; Galalpha1-4Galbeta1-4Glc), the epitope of globotriaosylceramide. MytiLec showed a dose-dependent cytotoxic effect on human Burkitt lymphoma Raji cells (which have high surface expression of Gb3) but had no such effect on erythroleukemia K562 cells (which do not express Gb3). The cytotoxic effect of MytiLec was specifically blocked by the co-presence of an alpha-galactoside. MytiLec treatment of Raji cells caused increased binding of anti-annexin V antibody and incorporation of propidium iodide, which are indicators of cell membrane inversion and perforation. MytiLec is the first reported lectin having a primary structure with the highly novel triple tandem repeat domain and showing transduction of apoptotic signaling against Burkitt lymphoma cells by interaction with a glycosphingolipid-enriched microdomain containing Gb3. PMID- 23093410 TI - Human DNA polymerase epsilon is able to efficiently extend from multiple consecutive ribonucleotides. AB - Replicative DNA polymerases (Pols) help to maintain the high fidelity of replication in large part through their strong selectivity against mispaired deoxyribonucleotides. It has recently been demonstrated that several replicative Pols from yeast have surprisingly low selectivity for deoxyribonucleotides over their analogous ribonucleotides. In human cells, ribonucleotides are found in great abundance over deoxyribonucleotides, raising the possibility that ribonucleotides are incorporated in the human genome at significant levels during normal cellular functions. To address this possibility, the ability of human DNA polymerase epsilon to incorporate ribonucleotides was tested. At physiological concentrations of nucleotides, human Pol epsilon readily inserts and extends from incorporated ribonucleotides. Almost half of inserted ribonucleotides escape proofreading by 3' -> 5' exonuclease-proficient Pol epsilon, indicating that ribonucleotide incorporation by Pol epsilon is likely a significant event in human cells. Human Pol epsilon is also efficient at extending from primers terminating in up to five consecutive ribonucleotides. This efficient extension appears to result from reduced exonuclease activity on primers containing consecutive 3'-terminal ribonucleotides. These biochemical properties suggest that Pol epsilon is a likely source of ribonucleotides in human genomic DNA. PMID- 23093411 TI - The involvement of acidic nucleoplasmic DNA-binding protein (And-1) in the regulation of prereplicative complex (pre-RC) assembly in human cells. AB - DNA replication in all eukaryotes starts with the process of loading the replicative helicase MCM2-7 onto chromatin during late mitosis of the cell cycle. MCM2-7 is a key component of the prereplicative complex (pre-RC), which is loaded onto chromatin by the concerted action of origin recognition complex, Cdc6, and Cdt1. Here, we demonstrate that And-1 is assembled onto chromatin in late mitosis and early G(1) phase before the assembly of pre-RC in human cells. And-1 forms complexes with MCM2-7 to facilitate the assembly of MCM2-7 onto chromatin at replication origins in late mitosis and G(1) phase. We also present data to show that depletion of And-1 significantly reduces the interaction between Cdt1 and MCM7 in G(1) phase cells. Thus, human And-1 facilitates loading of the MCM2-7 helicase onto chromatin during the assembly of pre-RC. PMID- 23093412 TI - Mapping histological levels of 8-hydroxy-2'-deoxyguanosine in female reproductive organs. AB - Oxidative stress is associated with many disease states including gynecologic disease. This process can damage lipids, proteins and DNA. The present study highlights the role of oxidative stress induced DNA damage as measured by 8 hydroxy-2-deoxyguanosine in development of benign gynecological conditions (BGC). Our aim was to map the oxidative DNA damage on female reproductive organs and highlight the high amount found in a variety of benign gynecologic disorders. Seventeen biopsy specimens from female pelvic organs were divided in two groups: healthy organs tissue and BGC tissue. Healthy organs biopsy tissue included the cervix, tubes, uterus, peritoneum, and topic endometrium in secretory phase. Benign gynecological biopsy tissue included hydrosalpinges, leiomyoma, adenomyosis and tubal cysts. Immunohistochemical staining showed significantly higher levels of DNA damage between BGC and healthy organs [19.36 % (6.20; 32.51) vs. 4.61 % (0.63; 8.53); P < 0.0344]. Our results highlight the involvement of oxidative stress DNA damage in female benign pelvic disease. Hydrosalpinges, leiomyoma, and adenomyosis exhibit the highest amounts of oxidative DNA damage in the pelvic cavity. PMID- 23093413 TI - Characteristics of colorectal cancer survival in an urban county hospital. AB - PURPOSE: Disparities in colorectal cancer (CRC) survival have been associated with race/ethnicity, screening, and insurance status, but less is known about how geographic and socioeconomic heterogeneity may modulate these factors. We examined CRC outcomes in an urban underserved population with sociodemographic factors distinctly different than those previously studied. METHODS: In this 11 year retrospective study, the demographics and clinical features of 331 CRC patients from a Northern California urban county hospital were reviewed. Cox proportional hazards modeling was used to evaluate differences in 5-year mortality. RESULTS: The study cohort consisted of 38 % Whites, 37 % Asians, 22 % Hispanics, and 4 % Blacks. Most of the patients either had government-sponsored insurance (62.5 %) or were uninsured (21.8 %). Compared to national SEER data, stage IV disease was more prevalent in our study cohort (37 vs 20 %) and the overall 5-year survival rate was worse (52.9 vs 64.3 %). CRC screening was associated with improved survival (hazard ratio (HR) 0.24, P=0.002), while insurance status was not. In the multivariate analysis, advanced age (HR 2.48, confidence interval (CI) 1.39-4.42, P=0.002) and late stage (stage IV: HR 32.46, CI 9.92-106.25, P<0.001) predicted worse outcomes. Contrary to some population based studies, Hispanics in our cohort had significantly better overall mortality compared to Whites (HR 0.46, CI 0.29-0.74, P=0.001). CONCLUSIONS: Disparities in CRC outcomes for urban underserved populations persist. However, there is geographic and socioeconomic heterogeneity in factors that have been previously shown to contribute to mortality. Screening and therapeutic strategies formulated from larger population-based studies may not be generalizable to these unique subpopulations. PMID- 23093414 TI - Distribution of metals and trace elements in adult and juvenile penguins from the Antarctic Peninsula area. AB - The presence of metals in the Antarctic environment is principally a natural phenomenon caused by geochemical characteristics of the region, although some anthropogenic activities can increase these natural levels. Antarctic penguins present several of the characteristics of useful sentinels of pollution in Antarctica such as they are long-lived species situated at the top of food web. The concentrations of Al, Cr, Mn, Fe, Ni, Cu, Zn, As, Se, Cd, and Pb were determined by inductively coupled plasma-mass spectrometry in samples of liver, kidney, muscle, bone, feather, and stomach contents of gentoo, chinstrap, and Adelie penguin (12 adults, five juveniles) from carcasses of naturally dead individuals collected opportunistically in the Antarctic Peninsula area. The obtained results showed that accumulation and magnification of several elements can be occurring, so that Cd and Se reached levels potentially toxic in some specimens. The presence of human activities seems to be increasing the presence of toxic metals such as Mn, Cr, Ni, or Pb in penguins. PMID- 23093415 TI - Biosorption of arsenic (III) from aqueous solution by living cells of Bacillus cereus. AB - In this work, removal of arsenic (III) from aqueous solution by living cells (Bacillus cereus), biosorption mechanism, and characterization studies have been reported. B. cereus cell surface was characterized using SEM-EDX and FTIR. Dependence of biosorption on pH of the solution, biosorbent dose, initial arsenic (III) concentration, contact time, and temperature had been studied to achieve optimum condition. The maximum biosorption capacity of living cells of B. cereus for arsenic (III) was found to be 32.42 mg/g at pH 7.5, at optimum conditions of contact time of 30 min, biomass dosage of 6 g/L, and temperature of 30 +/- 2 degrees C. Biosorption data of arsenic (III) are fitted to linearly transformed Langmuir isotherm with R (2) (correlation coefficient) >0.99. The pseudo-second order model description of the kinetics of arsenic (III) is successfully applied to predict the rate constant of biosorption. Thermodynamic parameters reveal the endothermic, spontaneous, and feasible nature of sorption process of arsenic (III) onto B. cereus biomass. The arsenic (III) ions are desorbed from B. cereus using both 1 M HCl and 1 M HNO(3). PMID- 23093416 TI - Terrestrial and aquatic ecotoxicity assessment of Cr(VI) by the ReCiPe method calculation (LCIA): application on an old industrial contaminated site. AB - The most stable forms of chromium in the environment are chromium (III) and chromium (VI), the former being relatively immobile and necessary for organisms, and the latter being highly soluble and toxic. It is thus important to characterise ecotoxicological impacts of Cr(VI). However, there are still some important uncertainties in the calculation of ecotoxicological impacts of heavy metals in the LCIA global approach. The aim of this paper is to understand how the spatial and dynamic characterization of life cycle inventory (LCI) data can be exploited in life cycle impact assessment and particularly for the evaluation of the aquatic and terrestrial ecotoxicity of Cr(VI). To quantify these impacts, we studied an industrial waste landfill in the North of France that was contaminated with chromium. On the polluted area, the aquatic contamination is due to the slag heap as well as to chromium spots in soil. The soil contamination is mainly due to infiltration of chromium from the infill. The concentration of Cr(VI) in soil and water varies according to seasonal climatic variations and groundwater level. These variations have an effect on the Cr(VI) fate factor, in particular on transfer and residence time of the substance. This study underlines the spatial distribution of aquatic ecotoxicity and the temporal variation of freshwater ecotoxicity. We analysed the correlation between precipitation, temperature, concentration and ecotoxicity impact. With regards to the terrestrial ecotoxicity, the study focused on the vertical variation of the ecotoxicity and the major role of the soil layer composition into terrestrial pollution. PMID- 23093417 TI - Exploring micromycetes biodiversity for screening benzo[a]pyrene degrading potential. AB - Twenty-five strains of filamentous fungi, encompassing 14 different species and belonging mainly to Ascomycetes, were tested for their ability to degrade benzo[a]pyrene (BaP) in mineral liquid medium. The most performing isolates for BaP degradation (200 mg l(-1)) in mineral medium were Cladosporium sphaerospermum with 29 % BaP degradation, i.e., 82.8 MUg BaP degraded per day (day(-1)), Paecilomyces lilacinus with 20.5 % BaP degradation, i.e., 58.5 MUg BaP day(-1), and Verticillium insectorum with 22.3 % BaP degradation, i.e., 64.3 MUg BaP day( 1), after only 7 days of incubation. Four variables, e.g., biomass growth on hexadecane and glucose, BaP solubilization, activities of extracellular- and mycelium-associated peroxidase, and polyethylene glycol degradation, were also studied as selective criteria presumed to be involved in BaP degradation. Among these variables, the tests based on polyethylene glycol degradation and on fungal growth on hexadecane and glucose seemed to be the both pertinent criteria for setting apart isolates competent in BaP degradation, suggesting the occurrence of different mechanisms presumed to be involved in pollutant degradation among the studied micromycetes. PMID- 23093418 TI - Oil spill cleanup using graphene. AB - In this article, we study the use of thermally reduced graphene (TRG) for oil spill cleanup. TRG was synthesized by thermal exfoliation of graphite oxide and characterized by X-ray diffusion, Raman spectroscopy, SEM, TEM, elemental analysis, and Brunauer-Emmett-Teller (BET) surface area measurement. Various aspects of the sorption process have been studied including the sorption capacity, the recovery of the adsorbed oil, and the recyclability of TRG. Our results shows that TRG has a higher sorption capacity than any other carbon-based sorbents, with sorption capacity as high as 131 g of oil per gram TRG. With recovery of the sorbed oil via filtration and reuse of TRG for up to six cycles, 1 g of TRG collectively removes approximately 300 g of crude oil. Moreover, the effects of TRG bulk density, pore volume, and carbon/oxygen ratio and the oil viscosity on the sorption process are also discussed. PMID- 23093419 TI - Assessment of natural sepiolite on cadmium stabilization, microbial communities, and enzyme activities in acidic soil. AB - A pot trial was conducted to assess the efficiency of sepiolite-induced cadmium (Cd) immobilization in ultisoils. Under Cd concentrations of 1.25, 2.5, and 5 mg kg(-1), the available Cd in the soil after the application of 1-10 % sepiolite decreased by a maximum of 44.4, 23.0, and 17.0 %, respectively, compared with no sepiolite treatments. The increase in the values of soil enzyme activities and microbial number proved that a certain metabolic recovery occurred after sepiolite treatment. The dry biomass of spinach (Spinacia oleracea) increased with increasing sepiolite concentration in the soil. However, the concentration (dry weight) of Cd in the spinach shoots decreased with the increase in sepiolite dose, with maximum reduction of 92.2, 90.0, and 84.9 %, respectively, compared with that of unamended soils. Under a Cd level of 1.25 mg kg(-1), the Cd concentration in the edible parts of spinach at 1 % sepiolite amendment was lower than 0.2 mg kg(-1) fresh weight, the maximum permissible concentration (MPC) of Cd in vegetable. Even at higher Cd concentrations (2.5 and 5 mg kg(-1)), safe spinach was produced when the sepiolite treatment was up to 5 %. The results showed that sepiolite-assisted remediation could potentially succeed on a field scale by decreasing Cd entry into the food chain. PMID- 23093420 TI - The ABC model of flower development: then and now. AB - In 1991, we published a paper in Development that proposed the ABC model of flower development, an early contribution to the genetic analysis of development in plants. In this, we used a series of homeotic mutants, and double and triple mutants, to establish a predictive model of organ specification in developing flowers. This model has served as the basis for much subsequent work, especially towards understanding seed plant evolution. Here, we discuss several aspects of this story, that could be a much longer one. One surprising conclusion is that materials and methods that might have led to similar work, and to the same model, were available 100 years before our experiments, belying the belief that progress in biology necessarily comes from improvements in methods, rather than in concepts. PMID- 23093421 TI - The zebrafish issue of Development. AB - In December 1996, a special issue of Development appeared that presented in 37 papers the results of two large screens for zebrafish mutants performed in Tubingen and Boston. The papers describe about 1500 mutations in more than 400 new genes involved in a wide range of processes that govern development and organogenesis. Up to this day, the mutants provide a rich resource for many laboratories, and the issue significantly augmented the importance of zebrafish as vertebrate model organism for the study of embryogenesis, neuronal networks, regeneration and disease. This essay relates a personal account of the history of this unique endeavor. PMID- 23093422 TI - Eph/ephrin signalling during development. AB - Eph receptors and their membrane-tethered ligands have important functions in development. Trans interactions of Eph receptors with ephrins at cell-cell interfaces promote a variety of cellular responses, including repulsion, attraction and migration. Eph-ephrin signalling can be bi-directional and controls actin cytoskeleton dynamics, thereby leading to changes in cellular shape. This article provides an overview of the general structures and signalling mechanisms, and of typical developmental functions along with cell biological principles. PMID- 23093423 TI - In vitro organogenesis in three dimensions: self-organising stem cells. AB - Organ formation during embryogenesis is a complex process that involves various local cell-cell interactions at the molecular and mechanical levels. Despite this complexity, organogenesis can be modelled in vitro. In this article, we focus on two recent examples in which embryonic stem cells can self-organise into three dimensional structures - the optic cup and the pituitary epithelium; and one case of self-organising adult stem cells - the gut epithelium. We summarise how these approaches have revealed intrinsic programs that drive locally autonomous modes of organogenesis and homeostasis. We also attempt to interpret the results of previous in vivo studies of retinal development in light of the self-organising nature of the retina. PMID- 23093424 TI - Glypicans regulate JAK/STAT signaling and distribution of the Unpaired morphogen. AB - In Drosophila, ligands of the Unpaired (Upd) family activate the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. The JAK/STAT pathway controls many developmental events, including multiple functions in the ovary. These include an early role in the germarium for specification of stalk cells and a later role in the vitellarium to pattern the follicular epithelium surrounding each cyst. In this latter role, graded JAK/STAT activation specifies three distinct anterior follicular cell fates, suggesting that Upd is a morphogen in this system. Consistent with the JAK/STAT activation pattern in the vitellarium, Upd forms a concentration gradient on the apical surface of the follicular epithelium with a peak at its source, the polar cells. Like many morphogens, signaling and distribution of Upd are regulated by the heparan sulfate proteoglycans (HSPGs) Dally and Dally-like. Mutations in these glypican genes and in heparan sulfate biosynthetic genes result in disruption of JAK/STAT signaling, loss or abnormal formation of the stalk and significant reduction in the accumulation of extracellular Upd. Conversely, forced expression of Dally causes ectopic accumulation of Upd in follicular cells. Furthermore, biochemical studies reveal that Upd and Dally bind each other on the surface of the cell membrane. Our findings demonstrate that Drosophila glypicans regulate formation of the follicular gradient of the Upd morphogen, Upd. Furthermore, we establish the follicular epithelium as a new model for morphogen signaling in complex organ development. PMID- 23093426 TI - Cytoplasmic Ca2+ changes dynamically during the interaction of the pollen tube with synergid cells. AB - The directional growth of the pollen tube from the stigma to the embryo sac in the ovules is regulated by pollen-pistil interactions based on intercellular communication. Although pollen tube growth is regulated by the cytoplasmic Ca(2+) concentration ([Ca(2+)](cyt)), it is not known whether [Ca(2+)](cyt) is involved in pollen tube guidance and reception. Using Arabidopsis expressing the GFP-based Ca(2+)-sensor yellow cameleon 3.60 (YC3.60) in pollen tubes and synergid cells, we monitored Ca(2+) dynamics in these cells during pollen tube guidance and reception under semi-in vivo fertilization conditions. In the pollen tube growing towards the micropyle, pollen tubes initiated turning within 150 MUm of the micropylar opening; the [Ca(2+)](cyt) in these pollen tube tips was higher than in those not growing towards an ovule in assays with myb98 mutant ovules, in which pollen tube guidance is disrupted. These results suggest that attractants secreted from the ovules affect Ca(2+) dynamics in the pollen tube. [Ca(2+)](cyt) in synergid cells did not change when the pollen tube grew towards the micropyle or entered the ovule. Upon pollen tube arrival at the synergid cell, however, [Ca(2+)](cyt) oscillation began at the micropylar pole of the synergid, spreading towards the chalazal pole. Finally, [Ca(2+)](cyt) in the synergid cell reached a maximum at pollen tube rupture. These results suggest that signals from the pollen tube induce Ca(2+) oscillations in synergid cells, and that this Ca(2+) oscillation is involved in the interaction between the pollen tube and synergid cell. PMID- 23093425 TI - Intercellular calcium signaling in a gap junction-coupled cell network establishes asymmetric neuronal fates in C. elegans. AB - The C. elegans left and right AWC olfactory neurons specify asymmetric subtypes, one default AWC(OFF) and one induced AWC(ON), through a stochastic, coordinated cell signaling event. Intercellular communication between AWCs and non-AWC neurons via a NSY-5 gap junction network coordinates AWC asymmetry. However, the nature of intercellular signaling across the network and how individual non-AWC cells in the network influence AWC asymmetry is not known. Here, we demonstrate that intercellular calcium signaling through the NSY-5 gap junction neural network coordinates a precise 1AWC(ON)/1AWC(OFF) decision. We show that NSY-5 gap junctions in C. elegans cells mediate small molecule passage. We expressed vertebrate calcium-buffer proteins in groups of cells in the network to reduce intracellular calcium levels, thereby disrupting intercellular communication. We find that calcium in non-AWC cells of the network promotes the AWC(ON) fate, in contrast to the autonomous role of calcium in AWCs to promote the AWC(OFF) fate. In addition, calcium in specific non-AWCs promotes AWC(ON) side biases through NSY-5 gap junctions. Our results suggest a novel model in which calcium has dual roles within the NSY-5 network: autonomously promoting AWC(OFF) and non autonomously promoting AWC(ON). PMID- 23093428 TI - Volumetric breast density characteristics as determined from digital mammograms. AB - In this paper we present the results of an automated and entirely reproducible algorithm that estimates the breast volume, dense tissue volume and the volumetric breast density from digital mammograms. The algorithm was applied to 55, 087 digital images (CC view only) from 15 351 individual women, acquired between 2008 and 2011 at the Sunnybrook Health Sciences Centre in Toronto, Canada. The algorithm is based on a prior calibration of the digital image signal versus tissue thickness and composition, and the thickness of the compressed breast is estimated using an empirical model that corrects the thickness readout of the mammography system as a function of compression force. The mean volumetric density and breast volumes for our study group were 30% and 687 cm(3), respectively. The left and right volumetric density and breast volume were strongly correlated, with a Pearson correlation of 0.92 and 0.91, respectively. The volumetric density decreased from 45% to 25% as age increased from 35 to 75 years, with an increase to 30% at 80 years. For a given woman, the volumetric density decreased at an average rate of -2 density percentage points per year while the breast volume increased by 2% per year. PMID- 23093427 TI - Gata2 provides an early anterior bias and uncovers a global positioning system for polarity in the amniote embryo. AB - The first axis to be specified during vertebrate development is that between the site where gastrulation will begin and the opposite pole of the embryo (dorsoventral axis in amphibians and fish, anteroposterior in amniotes). This relies on Nodal activity, but different vertebrates differ in how this activity is positioned. In chick, the earliest known asymmetry is posterior expression of the TGFbeta-related factor Vg1, close to the future Nodal expression domain. Here we show that the transcription factor Gata2 is expressed anteriorly before this stage. Gata2 influences the site of primitive streak formation and its role is independent from, and upstream of, Vg1 and Wnt. However, although Vg1 is required for streak formation, Gata2 does not act as an absolute anterior specifier, but provides an anterior bias. These findings point to previously unsuspected global determinants of polarity of the early amniote embryo. PMID- 23093429 TI - Fatal complication after repair of a congenital diaphragmatic hernia associated with hepatopulmonary fusion, anomalous right pulmonary venous return, and azygos continuation of the inferior vena cava. PMID- 23093431 TI - Testicular exstrophy in a newborn: report of a case and review of literature. PMID- 23093430 TI - Aromatase deficiency: rare cause of virilization. PMID- 23093432 TI - Management of giant omphalocele: a case series. PMID- 23093433 TI - A rare cause for extrahepatic biliary tract obstruction: juvenile hepatic hilar hemangioma. PMID- 23093434 TI - Urachal carcinoid--a new presentation. PMID- 23093435 TI - Quantitative software analysis of ultrasonographic textures in experimental testicular torsion. AB - AIM: Ultrasonography (US) has high diagnostic value in testicular torsion but is vulnerable to several potential errors, especially in the early period. Echotexture (ETX) analysis software provides a numerical expression of B-mode images and allows quantitative evaluation of blood flow due to ischemic damage using power Doppler US (PDUS) analysis. Our aim in this study was to determine the diagnostic value and effective parameters of EXT analysis software in the early period of torsion using B-mode and PDUS images. MATERIALS AND METHODS: In this study, eight rats were used. Following anesthesia, the right testis was rotated to a 1080-degree counterclockwise position whereas the left testis was left in place to have a control group. B-mode and PDUS images of both sides were recorded with a portable US device immediately (0 hour) and 1 and 2 hours after torsion. The B-mode images were analyzed in terms of gradient, homogeneity, and contrast using the BS200pro software (BAB Digital Imaging System 2007, Ankara, Turkey). Intensity (I)-red and area (A)-red values were measured on PDUS images with the Pixelflux (Version 1.0, Chameleon-Software, Leipzig, Germany). The data were evaluated by the Mann-Whitney U and Wilcoxon tests. RESULTS: Data from B mode US image EXT analysis showed no significant difference between the right and left testicles in 0 to 2 hours (p > 0.05). The values obtained from PDUS analysis (I-red and A-red) significantly decreased at the testicular torsion side at the end of the second hour (p < 0.05). I-red and A-red values at 0 to 1 hour of torsion indicated similar blood flow alterations (p > 0.05) whereas the flow was significantly lower at 2 hours (p < 0.05). CONCLUSION: In experimental testicular torsion, ischemic changes can be detected by PDUS power/angio mode using blood flow alterations as early as the second hour. Tissue damage cannot be evaluated within the first 2 hours of torsion with B-mode ETX analysis. PMID- 23093436 TI - Single- and double-lung ventilation in infants and children undergoing thoracoscopic lung resection. AB - INTRODUCTION: Video-assisted thoracoscopic surgery (VATS) has gained wide acceptance for the pediatric population. Single-lung ventilation (SLV) has been suggested for thoracoscopic lung resection to provide better surgical exposure, but its role and sequelae compared with double-lung ventilation (DLV) have not been determined. The aim of this study was to investigate the feasibility and effects of SLV and DLV in infants and children undergoing thoracoscopic lung resection. PATIENTS AND METHODS: Written informed consent from all guardians for anonymized data analysis and approval by the Institutional Review Board were obtained. A retrospective study on a consecutive series of infants and children who underwent thoracoscopic lung resection during an 11 years period was performed. SLV was selected mainly in lesions localized in the upper, middle, and/or central lung for reasons of surgical exposure. Patients with lower lobe lesions and those who underwent atypical resections were preferably operated under DLV. End points were conversion rate, duration of postoperative ventilation, and perioperative complications, such as, atelectasis or pneumonia. RESULTS: Of 114 pediatric patients (58 female and 56 male; ratio 1.04:1) with a mean age of 7.1 years (3 days to 18.1 years), 62 patients underwent DLV and 52 patients underwent SLV for thoracoscopic lung resection. There were no significant differences between the two groups for conversion rate (DLV 8.1 vs. SLV 6.1%; p = 0.53), prompt extubation (DLV 50 vs. SLV 34.6%; p = 0.14), and postoperative atelectasis (DLV 35.5 vs. SLV 25%; p = 0.32). No major cardiorespiratory events, such as bleeding or pneumonia, were observed. No perioperative mortality occurred. CONCLUSIONS: This is the first study on safety, effectiveness, and outcome of SLV and DLV in pediatric patients undergoing thoracoscopic lung resection. Our data suggest that both SLV and DLV can be safely performed with similar low rate of surgical complications, when specific selection criteria are applied. PMID- 23093437 TI - Thoracoscopic repair of oesophageal atresia: results of a selective approach. AB - INTRODUCTION: The repair of oesophageal atresia (OA) and tracheoesophageal fistula (TOF) may be routinely performed via thoracoscopy. However, data on the feasibility and efficacy of thoracoscopic OA/TOF repair are scarce and some authors reported a high rate of anastomotic leak. The aim of this study was to evaluate our concept of OA/TOF repair which includes specific selection of patients and a selective surgical approach. PATIENTS AND METHODS: The study was approved by the Institutional Review Board and written informed consent was obtained from all guardians for anonymized data analysis. All patients undergoing OA/TOF repair from June 2001 to December 2011 were included in this analysis. Thoracoscopy was used in cardiorespiratory stable newborns with OA/TOF and a birthweight of >= 2000 g. In case of any intraoperative adverse events, lack of progress for ~15 minutes, or anastomosis under tension, the procedure was converted to open thoracotomy. Study endpoints were conversion rate and postoperative complications. RESULTS: A total of 44 newborns with OA/TOF were operated, of whom 22 (6 females, 16 males) met our criteria for a thoracoscopic approach. The mean birthweight of thoracoscopically operated patients was 2760 (2020 to 3960) g, 7 were < 36 weeks of gestation. The mean operative time was 142 (75 to 220) minutes. Thoracoscopy was converted to thoracotomy in eight patients due to problems with exposition (n = 2), ventilation (n = 3), anastomosis under tension (n = 2), or bleeding (n = 1, no transfusion). There was no anastomotic leak in the group of patients who underwent successful thoracoscopic repair, but one recurrence of TOF. Two anastomotic leaks emerged in patients in whom the operation was converted. A total of 7 out of the 22 children required endoscopic dilatation. There was no mortality during a mean follow-up of 5.5 years (43 days to 10.6 years). CONCLUSION: Our approach included meticulous patient selection and prompt conversion in case of any adverse events. With this approach, thoracoscopic repair of OA/TOF can be safely performed achieving excellent results and a low rate of complications. PMID- 23093438 TI - Levels of mobility in children and adolescents with spina bifida-clinical parameters predicting mobility and maintenance of these skills. AB - PURPOSE: The retrospective study was performed to apply the "Hoffer criteria" as a suitable classification of mobility in spina bifida patients. We looked at clinical parameters and factors that can be used as predictors for future mobility and development in these patients. MATERIALS AND METHODS: Clinical data about ambulation of 90 spina bifida/myelomeningocele patients were collected using a questionnaire and were completed using the medical records of the patients. The patients were grouped by their walking distances according to "Hoffers criteria" (community walker, household walker, exercise walker, nonwalker). The development of the mobility skills over the years was documented. RESULTS: We grouped 42% of the patients as community walkers, 16% as household, 16% as exercise walkers, and 27% as always wheelchair dependent (nonwalker). We found significant correlations between the Hoffer criteria, the level of lesion the walking distance and the ability to stand upright. There is also a significant relation between the Hoffer criteria and the frequency of fractures and the age of the patients. The occurrence of fractures is directly related to the level of lesion and to the level of mobility in our group of patients. Of all our patients, 39% patients had improved in mobility, 37% patients retained their achieved state, and 24% worsened in their mobility skills. CONCLUSIONS: We could see that a stable and ambitious milieu and care in specialized institutions can achieve a high level of ambulation in spina bifida patients. Most patients are able to maintain this skill over a long period of time. Predictive factors to maintain mobility in patients with myelomeningoceles (spina bifida) are not only dependent on the level of lesion but also rely on the aftercare of the patients too. The data that were collected are used for counseling of parents and patients. PMID- 23093439 TI - Pathological changes and surgical treatment of lipomas of the conus medullaris. AB - OBJECTIVE: To describe the pathological changes of lipomas of the conus medullaris and the appropriate surgical treatment for removing such lipomas for optimal reconstruction of the normal spinal cord anatomy. METHODS: Data were collected on 73 patients, aged 1.5 months to 18 years, who underwent surgical removal of a lipoma of the conus medullaris at Shanghai Children's Medical Center from January 2005 to December 2008. Neurological symptoms included pain, urine and stool incontinence, and bilateral lower limb dysfunction. The surgical procedures consisted of excision of subcutaneous and intradural extramedullary lipoma, partial excision of intramedullary lipoma, detachment of the spinal cord from the dural membrane, relief of tethered spinal cord, and excision of the affected filum terminale. RESULTS: The main pathological changes in patients with lipoma of the conus medullaris were ventral deviation of the spinal cord caused by compression from a dorsal lipoma, traction on the spinal cord from attachment of intradural lipoma and subcutaneous lipoma, increased tight fit between the spinal cord and the dural membrane on both sides, and degeneration of the filum terminale. A total of 67 patients were followed up for 6 months to 4 years. Improvement after surgery varied among the symptomatic patients. A total of 5 patients had transient deterioration of symptoms after surgery. All asymptomatic patients remained asymptomatic. CONCLUSION: Only through thorough understanding of the pathology of the lipoma of the conus medullaris, we could optimally excise the lipoma, untether the spinal cord, reconstruct the normal anatomy of the spinal cord, and rehabilitate neurological function. PMID- 23093440 TI - Is there unity in Europe? First survey of EUPSA delegates on the management of gastroschisis. AB - AIM: To report the first European survey on the current management of gastroschisis and ascertain the degree of variability between centers. METHODS: A 10-question survey was administered at the 2011 European Paediatric Surgeons' Association (EUPSA) Congress. Questionnaires were completed by 205 delegates from 39 countries. A total of 21 responses (10%) were incomplete and voided. The remaining 184 were divided on the basis of following region of practice: Western Europe (WE, n = 102), Eastern Europe (EE, n = 59), and non-European countries (n = 23). Differences between WE and EE were analyzed using contingency tests. p < 0.05 was considered significant. RESULTS: A total of 15% WE and 2% EE responders work in centers where antenatal magnetic resonance imaging scans are routinely used. Nonplanned delivery is the most popular approach (WE 46%, EE 58%). Primary closure is the preferred choice (WE 92%, EE 86%), and it is achieved by operative fascial closure in the majority (WE 80%, EE 75%) rather than by Bianchi technique (WE 20%, EE 25%). Staged reduction and closure is less popular (WE 8%, EE 14%), and it is achieved by custom-made silo (WE 25%, EE 12.5%), preformed silo (PFS) followed by surgical closure (WE 63%, EE 75%), or PFS followed by sutureless closure (WE 12%, EE 12.5%). Objection to PFS in WE is mainly related to surgeons' lack of confidence in the technique (40%), whereas in EE it is due to unavailability and high cost (62%, p = 0.01). In case of associated intestinal atresia, immediate resection and anastomosis is preferred by 60% of WE surgeons versus 35% of EE surgeons (p = 0.03), who equally favor primary closure and delayed surgery (33%). Nutrition is preferably delivered by peripheral long line in WE (64%) and by central line inserted in the first week of life in EE (62%, p = 0.003). CONCLUSIONS: Primary fascial closure is currently the preferred method of gastroschisis closure across Europe. Aspects of care such as strategy for intestinal atresia and delivery of parenteral nutrition differ significantly between WE and EE. Economic considerations appear to influence management strategy particularly in EE. A Europe-wide audit appears warranted to identify whether this survey reflects actual practice. PMID- 23093444 TI - Application of Fourier-wavelet regularized deconvolution for improving image quality of free space propagation x-ray phase contrast imaging. AB - New x-ray phase contrast imaging techniques without using synchrotron radiation confront a common problem from the negative effects of finite source size and limited spatial resolution. These negative effects swamp the fine phase contrast fringes and make them almost undetectable. In order to alleviate this problem, deconvolution procedures should be applied to the blurred x-ray phase contrast images. In this study, three different deconvolution techniques, including Wiener filtering, Tikhonov regularization and Fourier-wavelet regularized deconvolution (ForWaRD), were applied to the simulated and experimental free space propagation x-ray phase contrast images of simple geometric phantoms. These algorithms were evaluated in terms of phase contrast improvement and signal-to-noise ratio. The results demonstrate that the ForWaRD algorithm is most appropriate for phase contrast image restoration among above-mentioned methods; it can effectively restore the lost information of phase contrast fringes while reduce the amplified noise during Fourier regularization. PMID- 23093441 TI - Transactional relationships among cognitive vulnerabilities, stressors, and depressive symptoms in adolescence. AB - The transactional cognitive vulnerability to stress model Hankin & Abramson (Psychological Bulletin, 127:773-796, 2001) extends the traditional diathesis stress model by proposing that the relationships among cognitions, depressive symptoms, and stressors are dynamic and bidirectional. In this study three different pathways among these variables were assessed simultaneously: (1) cognitive vulnerabilities and stressors as predictors of depressive symptoms (vulnerability model), (2) depressive symptoms and cognitive vulnerabilities as predictors of stressors (stress generation model), and (3) depressive symptoms and stressors as predictors of cognitive vulnerabilities (consequence model). A fully cross-lagged design panel was employed with 1,187 adolescents (545 girls and 642 boys, Mean Age = 13.42 years) who were assessed at two time points separated by 6 months. They completed measures of cognitive vulnerabilities (maladaptive schema domains and negative inferential style), stressors, and depressive symptoms. Inferential style and schemas of the disconnection and rejection domain predicted prospective increases in depressive symptoms. Initial levels of depressive symptoms and most cognitive vulnerabilities predicted greater stress generation. Initial levels of stressors and depressive symptoms predicted an increase in negative inferential style and maladaptive schema domains over time. These bidirectional relationships were mostly similar for boys and girls, although there were a few gender differences. The findings support a transactional model with reciprocal relationships among stress, depressive symptoms, and cognitive vulnerabilities. Transactional implications for depression interventions among adolescents are discussed. PMID- 23093443 TI - Using technology in the delivery of mental health and substance abuse treatment in rural communities: a review. AB - Rural communities face tremendous challenges in accessing mental health and substance abuse treatment services. Some of the most promising advancements in the delivery of rural health care services have been in the area of telecommunication technology. These applications have the potential to reduce the disparities in the delivery of substance abuse and mental health services between urban and rural communities. The purpose of this inquiry was to explore the advances and uses of telecommunications technology, and related issues, in the delivery of mental health and substance abuse treatment services within rural areas. A review of the academic literature and other relevant works was conducted and the content was organized into four major themes: (a) advantages of telehealth and applications to rural practice, (b) barriers to implementation in rural practice, (c) utilization in rural areas, and (d) areas for further research. PMID- 23093445 TI - Uncoupling of nucleotide hydrolysis and polymerization in the ParA protein superfamily disrupts DNA segregation dynamics. AB - DNA segregation in bacteria is mediated most frequently by proteins of the ParA superfamily that transport DNA molecules attached via the segrosome nucleoprotein complex. Segregation is governed by a cycle of ATP-induced polymerization and subsequent depolymerization of the ParA factor. Here, we establish that hyperactive ATPase variants of the ParA homolog ParF display altered segrosome dynamics that block accurate DNA segregation. An arginine finger-like motif in the ParG centromere-binding factor augments ParF ATPase activity but is ineffective in stimulating nucleotide hydrolysis by the hyperactive proteins. Moreover, whereas polymerization of wild-type ParF is accelerated by ATP and inhibited by ADP, filamentation of the mutated proteins is blocked indiscriminately by nucleotides. The mutations affect a triplet of conserved residues that are situated neither in canonical nucleotide binding and hydrolysis motifs in the ParF tertiary structure nor at interfaces implicated in ParF polymerization. Instead the residues are involved in shaping the contours of the binding pocket so that nucleotide binding locks the mutant proteins into a configuration that is refractory to polymerization. Thus, the architecture of the pocket not only is crucial for optimal ATPase kinetics but also plays a key role in the polymerization dynamics of ParA proteins that drive DNA segregation ubiquitously in procaryotes. PMID- 23093446 TI - [Update on special surgical approaches in the therapy for lymphedemas]. AB - Despite recent medical progress primary and secondary lymphedemas still represent a therapeutic challenge and they often lead to a significant reduction in quality of life. Lymphedemas usually develop in the extremities, the male external genitals as well as the female breast as a consequence to the axial alignment of the lymphatic collectors. Early stages are characterized by an excess of lymph fluid increasing the volume of the affected part of the body whereas later stages represent an increasing amount of solid tissue. Thus therapeutic efforts can focus on the reduction of the surplus of liquid and/or solid components. Generally there are conservative and operative strategies. Conservative measures mainly focus on the improvement of fluid mobilization and drainage and comprise compression garments, manual lymphatic drainage, and apparative intermittent compression. Operative approaches comprise procedures for surgical tissue reduction (symptomatic/ablative approaches) and/or procedures with the intention of enhancing lymphatic transport (causal approaches). Surgical tissue reduction can be performed by open resection and/or liposuction. Traditional surgical causal techniques such as transposition of local flaps aim at leading lymph away from the congested region of the body. Modern microsurgical causal approaches contain methods of reconstruction of interrupted lymphatic pathways as well as techniques for the conduction of lymph into local veins. In this review we depict and discuss the features of the multiform spectrum of the surgical therapy of lymphedemas on the basis of literature as well as our own clinical and experimental experience. PMID- 23093447 TI - Temporal and spatial expression of KIF3B after acute spinal cord injury in adult rats. AB - The KIF3 subunit KIF3B was proved to be associated with mitosis. It has been known to be engaged in intracellular transport of neurons. To elucidate the certain expression and biological function in central nervous system, we performed an acute spinal cord contusion injury model in adult rats. Western blot analysis indicated a marked upregulation of KIF3B after spinal cord injury (SCI). Immunohistochemistry revealed wide distribution of KIF3B in spinal cord, including neurons and glial cells. Double immunofluorescent staining for proliferating cell nuclear antigen and phenotype-specific markers showed increases of KIF3B expression in proliferating microglia and astrocytes. Our data suggest that KIF3B may be implicated in the proliferation of microglia and astrocytes after SCI. PMID- 23093448 TI - Port-site recurrence of pancreatic adenocarcinoma following laparoscopic pancreaticoduodenectomy. AB - INTRODUCTION: Minimally invasive surgical approaches have only recently been applied to pancreatic adenocarcinoma. DISCUSSION: Significant apprehension exists that minimally invasive pancreatic surgery will not lead to equivalent or superior oncologic outcomes compared to traditional surgical approaches. This is the first case report of a port-site recurrence following laparoscopic pancreaticoduodenectomy. PMID- 23093451 TI - Neuroimaging in neurorehabilitation. AB - Tremendous advances in neuroimaging methods and analytic techniques hold great promise in providing the rehabilitation clinician with a much greater understanding of brain pathology and its potential influence on rehabilitation outcome. This special issues of NeuroRehabilitation overviews the field. Contemporary neuroimaging methods are reviewed specifically in traumatic brain injury (TBI), anoxic brain injury (ABI) and stroke. Innovative methods combined with standard quantitative metrics and traditional clinical assessment provide the rehabilitation clinician with multiple methods to best understand the nature and extent on underlying neuropathology and how to use this information in guiding rehabilitation therapies and predicting outcome. PMID- 23093449 TI - Peri-operative bowel perforation in early stage colon cancer is associated with an adverse oncological outcome. AB - BACKGROUND: The presence of an inflammatory response resulting from bowel perforation or anastomotic leakage has been suggested to enhance recurrence rates in colorectal cancer patients. Currently, it is unknown if bowel perforation or anastomotic leakage has prognostic significance in early stage colon cancer patients. In this study, the impact of peri-operative bowel perforation including anastomotic leakage on disease-free survival of stage I/II colon cancer patients was investigated. METHODS: Prospective follow up data of 448 patients with stages I/II colon cancer that underwent resection were included. Patients who died within 3 months after initial surgery were excluded. RESULTS: Median follow up was 56.0 months. Patients with peri-operative bowel perforation (n = 25) had a higher recurrence rate compared to patients without perforation (n = 423), 36.0 % vs. 16.1 % (p = 0.01). Disease-free survival was significantly worse for the perforation group compared to patients without perforation (p = 0.004). Multivariate analysis including T-stage, histological grade, and adjuvant chemotherapy showed peri-operative bowel perforation to be an independent factor significantly associated with disease recurrence (odds ratio, 2.7; 95 % CI, 1.1 6.7). CONCLUSION: Peri-operative bowel perforation is associated with increased recurrence rates and impaired disease-free survival in early-stage colon cancer patients. PMID- 23093450 TI - Transanal endoscopic microsurgery for rectal neoplasms. How I do it. AB - INTRODUCTION: Transanal endoscopic microsurgery (TEM) has revolutionized the technique and outcomes of transanal surgery, becoming the standard of treatment for large sessile rectal adenomas, and may represent a possible treatment modality for early rectal cancer. METHODS: A full-thickness excision is made on the rectal wall down to the perirectal fatty tissue. The specimen is retrieved transanally. After the parietal defect is disinfected, the wound is closed with one or more running sutures secured with silver clips. RESULTS: Peritoneal perforation during TEM is not associated with adverse short-term or oncologic outcomes. The postoperative morbidity rate ranges between 2 % and 15 %, and in most cases, complications can be conservatively managed. The local recurrence rate of large adenomas is about 6 %, and most recurrences can be safely re resected by TEM. TEM represents an effective treatment for pT1 sm1 rectal malignancies, while pT1 sm2-3 and pT2 should be considered at high risk of recurrence if treated by TEM alone. Finally, TEM does not influence anorectal function or quality of life. CONCLUSION: TEM is a safe procedure and provides excellent functional and oncologic outcomes in the treatment of large sessile benign rectal lesions and selected early rectal cancers. PMID- 23093452 TI - A primer of neuroimaging analysis in neurorehabilitation outcome research. AB - Although most neurological patients that enter a rehabilitation treatment program have had either a computed tomography (CT) or magnetic resonance imaging (MRI) scan, the utilization of neuroimaging in rehabilitation has been limited. However, a number of new MRI methods for image analysis hold great promise to better inform the neurorehabilitation clinician. The current review provides a foundation in neuroimaging fundamentals for neurorehabilitation specialists and examines the progress in using such techniques as quantitative MRI analyses, diffusion tensor imaging (DTI) and functional MRI to better understand the neurologically impaired patient. PMID- 23093453 TI - Pediatric traumatic brain injury: neuroimaging and neurorehabilitation outcome. AB - Brain injury in the pediatric patient not only occurs in an immature brain, but potentially influences all subsequent brain and neurodevelopmental maturation. This presents unique challenges in neuroimaging the developing central nervous system, which is reviewed herein. The most significant neuroimaging advances in assessing pediatric traumatic brain injury (TBI) have occurred with magnetic resonance imaging (MRI), particularly diffusion tensor imaging and the multiple emerging techniques using functional MRI (fMRI). Pediatric neuroimaging findings of TBI are discussed in terms of techniques that can assess underlying neural networks and provide information about neuroplasticity of recovery. Neuroimaging methods also provide insights into the complexities of brain injury, cognitive and neurobehavioral recovery, and how multimodality contemporary neuroimaging methods best demonstrate underlying neuropathology that affects outcome. PMID- 23093454 TI - Detection of hemorrhagic and axonal pathology in mild traumatic brain injury using advanced MRI: implications for neurorehabilitation. AB - INTRODUCTION: There is a need to more accurately diagnose milder traumatic brain injuries with increasing awareness of the high prevalence in both military and civilian populations. Magnetic resonance imaging methods may be capable of detecting a number of the pathoanatomical and pathophysiological consequences of focal and diffuse traumatic brain injury. Susceptibility-weighted imaging (SWI) detects heme iron and reveals even small venous microhemorrhages occurring in diffuse vascular injury. Diffusion tensor imaging (DTI) reveals axonal injury by detecting alterations in water flow in and around injured axons. The overarching hypothesis of this paper is that newer, advanced MR imaging generates sensitive biomarkers of regional brain injury which allows for correlation with clinical signs and symptoms. METHODS: Studies involving subjects with a history of traumatic brain injury as well as healthy, non-trauma controls were used. Analysis involved comparison of TBI patients' imaging results with healthy controls as well as correlation of imaging findings with clinical measures of injury severity. An additional animal study of Sprague-Dawley albino rats compared imaging results with histopathological findings after the animals were sacrificed and stained for b-APP. RESULTS: SWI revealed small foci of hemosiderin for some patients while aggregate lesion volume on SWI correlated with clinical injury severity indices. Similarly, DTI showed striking group differences for fractional anisotropy over the white matter globally, while tract and voxel-based regional results colocalized with SWI and FLAIR lesions in some cases and correlated with clinical deficits. For the rats, correlations were seen between imaging findings and staining of axonal injury. DISCUSSION: Animal data gave important tissue correlations with imaging results. SWI and DTI are commercially available sequences that can improve the diagnostic and prognostic ability of the trauma clinician. These biomarkers of regional brain injury which are present in imaging shortly after acute injury and persist indefinitely can inform clinicians and researchers about not only injury severity but also which neurobehavioral systems were injured. Analogous to stroke rehabilitation, having an understanding of the distribution of brain injury should ultimately allow for development of more effective rehabilitation strategies and more efficient clinical interventional trials. PMID- 23093455 TI - Diffusion tensor imaging of traumatic brain injury review: implications for neurorehabilitation. AB - Diffusion tensor imaging (DTI) has widely been used to investigate the microstructural damage of white matter tracts that occur in individuals with traumatic brain injury (TBI). In the current review, we discuss the white matter regions which are commonly affected in adults with TBI. We also describe the current literature that has utilized DTI to investigate the relationship between microstructural integrity with neuropsychological performance and clinical outcome measures. Finally, a model is presented of the potential utilization of DTI as a biomarker of efficacy in neurorehabilitation for individuals with TBI. PMID- 23093456 TI - Fractional anisotropy helps predicts memory rehabilitation outcome after traumatic brain injury. AB - Traumatic brain injury (TBI) commonly results in residual memory difficulties. Such deficits are amenable to cognitive rehabilitation, but optimal selection of rehabilitation interventions remains a challenge. We hypothesized that diffusion tensor imaging (DTI) could be used to predict which individuals were likely to benefit from a specific memory rehabilitation intervention. Thirty-seven individuals with TBI, of all severities, first underwent DTI scanning, along with 18 matched controls. Participants with TBI then attended a 12-session memory intervention emphasizing internal memory strategies (I-MEMS). Primary outcome measures (HVLT, RBMT) were collected at the time of DTI scanning, and both immediately and one month post-therapy. In contrast to typical neuroimaging analysis, fractional anisotropy (FA) was used to predict long-term outcome scores, adjusting for typical predictors (injury severity, age, education, time since injury, pretest score). FA of the parahippocampal white matter was a significant negative predictor of HVLT, while the anterior corpus callosum, left anterior internal capsule, and right anterior corona radiata were negative predictors of RBMT outcome. The importance of these predictors rivaled those of pretest scores. Thus, FA measures may provide substantial predictive value for other cognitive interventions as well. The reason why higher FA was associated with less successful response to cognitive intervention remains unclear and will require further study. PMID- 23093457 TI - Neuroimaging after critical illness: implications for neurorehabilitation outcome. AB - Survivors of critical illness frequently have severe and long-lasting cognitive impairments and psychiatric disorders, which adversely affect functional outcomes including return to work, and quality of life. While data regarding cognitive outcomes has increased over the last 15 years, neuroimaging data in medical and surgical critical populations is extremely limited. The abrupt development of new significant cognitive impairments after critical illness along with abnormalities on neuroimaging suggest that critical illness results in new acquired brain injury, similar to that observed in other acquired brain injuries. Abnormalities on neuroimaging including cortical and subcortical lesions, brain atrophy, and white matter hyperintensities (WMH) which occur in widely distributed brain regions. Patients admitted to neurorehabilitation who received critical care related to their primary diagnosis may have sustained neurological injury from the nonspecific effects of their critical illness and as demonstrated in this review, generalized, non-specific neuroimaging findings may be observed and quantified. Given the high prevalence rate of cognitive impairments in this population, neuroimaging is important to help elucidate neuropathology of critical illness acquired brain injury and may be beneficial in guiding rehabilitation outcomes in this population. PMID- 23093458 TI - Neuroimaging of anoxic injury: implications for neurorehabilitation. AB - Anoxic brain injury is common and occurs in a wide variety of disorders. The anoxic injury has characteristic pathologies in particular affecting the medial temporal lobe, basal ganglia and deep white matter. The neural injury is associated with significant and persistent cognitive impairments and poor functional outcomes, related in part to the severity of anoxia and assumed to relate to the degree of structural damage evidenced on neuroimaging during the chronic stage. To date neuroimaging following ABI has been used diagnostically with less research focused on guiding or predicting rehabilitation outcome. Because of the distribution of these lesions/abnormalities the degree of damage has practical implications for rehabilitation outcome. Research is needed to understand cognitive and functional outcomes following ABI as well as whether specific rehabilitation techniques or strategies will result in better outcomes. PMID- 23093459 TI - Managing the urban commons: the relative influence of individual and social incentives on the treatment of public space. AB - All communities have common resources that are vulnerable to selfish motives. The current paper explores this challenge in the specific case of the urban commons, defined as the public spaces and scenery of city neighborhoods. A theoretical model differentiates between individual incentives and social incentives for caring for the commons. The quality of a commons is defined as the level of physical (e.g., loose garbage) and social (e.g., public disturbances) disorder. A first study compared levels of disorder across the census block groups of a single city; the second compared the disorder generated by individual addresses in two neighborhoods. Each study found that homeownership, an individual incentive, was the main predictor of disorder. Owner-occupied parcels generated less disorder than their renter-occupied neighbors, but both parcel types produced less disorder in a neighborhood with greater homeownership. The results emphasize the need for considering both individual and social incentives for group-beneficial behaviors. PMID- 23093460 TI - Oxidative stress and reduced antioxidative status, along with endothelial dysfunction in acromegaly. AB - Acromegaly is characterized by high cardiovascular morbidity and mortality. Oxidative stress and endothelial dysfunction are underlying mechanisms of atherosclerosis.The aim of this study was to evaluate the blood redox status and endothelial function by means of nitric oxide (NO) levels in patients with acromegaly. Total antioxidant capacity (TAC), catalase activity and glutathione concentration (GSH), as measures of antioxidative capacity, total oxidized glutathione (GSSG) and thiobarbituric acid reactive substances (TBARS), as indices of oxidative stress, and NO levels were assessed in 15 patients with acromegaly (age 55.4+/-10.5 years; 6 males) and 15 age- and sex-matched controls (age 58.4+/-8.1 years; 7 males). Active disease was present in 12 patients: 11 on current pharmacotherapy and 1 newly diagnosed. Three acromegalics were in remission after successful treatment. Acromegalics as compared with controls had significantly lower levels of catalase activity (8.2+/-5.8 vs. 51.3+/-29.1 mmol/ml/min, p<0.001), GSH (0.97+/-0.54 vs. 1.41+/-0.35 mmol/l, p=0.006), GSSG (0.27+/-0.19 vs. 2.04+/-1.32 mmol/l, p=0.002) and NO levels (6.0+/-3.1 vs. 43.0+/ 29.8 mmol/l, p<0.001), but higher TBARS (16.3+/-8.9 vs. 10.1+/-10.8, nmol/ml, p=0.019). After adjustment for confounders, differences in catalase activity, NO levels and TBARS remained significant (p=0.004, p<0.001 and p=0.025, respectively). No association between IGF-I/GH and oxidative stress markers was noticed, except for a positive correlation between nadir GH and GSSG (r2=0.563, p=0.036). Acromegaly is associated with increased levels of oxidative stress coupled by diminished antioxidant capacity and endothelial dysfunction indicated by the presence of decreased NO levels. PMID- 23093461 TI - Anterior pituitary morphology and hormone production during sustained critical illness in a rabbit model. AB - Prolonged critical illness is hallmarked by striking alterations in the somatrope, thyrotrope, and lactotrope axes, the severity of which is associated with the risk of morbidity and mortality. The exact role of the pituitary gland in these alterations is unknown. We studied the impact of sustained critical illness on pituitary morphology and hormone production in a standardized rabbit model of prolonged (7 days) burn injury-induced critical illness. In healthy and prolonged critically ill rabbits, we determined pituitary weight, size, morphology and orientation of the somatrope, lactotrope and thyrotrope cells and the pituitary expression of GH, PRL, and TSH at gene and protein level. The weight of the pituitary gland was unaltered by 7 days of critical illness. Also, spatial orientation and morphology of the GH, PRL, and TSH producing cells remained normal. In prolonged critically ill rabbits GH mRNA levels were higher and PRL mRNA levels were lower than in healthy controls, whereas TSH mRNA was not affected. The sizes of GH, PRL, or TSH producing cells and the pituitary content of GH, PRL, and TSH proteins were unaltered. In conclusion, in this rabbit model of prolonged critical illness, the morphology of the pituitary gland and the pituitary GH, PRL, and TSH content was normal. The alterations in pituitary hormone mRNA levels with sustained critical illness are compatible with altered hypothalamic and peripheral regulation of pituitary hormone release as previously suggested indirectly by responses to exogenous releasing factors. PMID- 23093462 TI - Laparoscopic treatment of pheochromocytomas smaller or larger than 6 cm. A clinical retrospective study on 44 patients. Laparoscopic adrenalectomy for pheochromocytoma. AB - INTRODUCTION: Laparoscopic adrenalectomy is a gold standard for the treatment of pheochromocytomas less than 6 cm in diameter. Given the difficulty in dissecting the adrenal glands, the presumed increase in the risk of malignancy, and capsular disruption there is controversy regarding minimally invasive surgery for neoplasms greater than 6 cm. The aim of this study was to report laparoscopic adrenalectomy results in 44 patients with pheochromocytomas either larger or smaller than 6 cm. METHODS: The retrospective clinical study was conducted on 44 patients who underwent surgery in the Campania region in Italy, between January 1998 and January 2008. In 30 cases the lesion measured <= 6 cm (group A) in diameter and in 15 > 6 cm (group B). The authors compared cardiovascular instability, operative time, conversion rate, incidence of intra and postoperative complications, length of hospital stay, and medium long term follow up results in the two groups of patients. RESULTS: By comparing group A vs group B no significant differences were observed in operative time, incidence of intra and postoperative complications length of hospital stay or medium long term follow-up results. In patients with pheochromocytomas > 6 cm a higher conversion rate, although not statistically significant, was observed. The same occurred with cardiovascular instability shown by intraoperative sudden bouts of hypertension. One patient underwent "open" reoperation for residual retrocaval glandular tissue, not removed during laparoscopic treatment. CONCLUSIONS: Laparoscopic adrenalectomy for pheochromocytoma by experienced laparoscopic surgeon is safe and probably preferable also in selected cases larger than 6 cm. These patients may have a longer operative time, a greater intraoperative blood loss, a higher conversion rate, more intraoperative hypertensive crises than other patients. Adequate preoperative pharmacological therapy and careful anaesthesia monitoring make possible optimal management of cardiovascular instability. PMID- 23093463 TI - Induction of mouse pancreatic ductal differentiation, an in vitro assay. AB - Despite recent technical advances for studying lineage tracing and gene functions, our knowledge of pancreatic duct progenitor cells and mechanisms involved in their differentiation remains a huge void in our understanding of pancreatic development. A deeper insight into ductal differentiation is needed because ductal cells may harbor pancreatic stem/progenitor cells that could give rise to new islets. Also, since the most common pancreatic tumors form structures expressing ductal cell-specific markers, studies of ductal development may provide better markers for pancreatic tumor classification. One major longstanding problem in the study of pancreatic ductal differentiation has been the lack of an effective in vitro model. We thus wished to develop an in vitro system for the study of pancreatic duct development. In doing so, we have developed a specific culture condition to promote ductal differentiation of E11.5 pancreatic rudiments. Normally, pancreatic explants cultured in vitro develop to form endocrine, acinar, as well as ductal cells. Here, we report that addition of a combination of EGF, fibroblast growth factor-10, and platelet-derived growth factor-AA to the explant cultures promotes ductal differentiation, while preventing endocrine and acinar differentiation. This culture system for differentiation and enrichment of pancreatic ductal cells may allow identification of gene(s) involved in ductal development. PMID- 23093465 TI - Chondracanthus tenellus (Harvey) hommersand extract protects the human keratinocyte cell line by blocking free radicals and UVB radiation-induced cell damage. AB - The aim of this study was to investigate the protective effects of the ethanol extract of the red algae Chondracanthus tenellus (Harvey) Hommersand (CTE) on cultured human keratinocyte cell line. The cellular protection conferred by CTE was evidenced by the ability of the extract to absorb ultraviolet B (UVB; 280-320 nm) and to scavenge the radical 1,1-diphenyl-2-picrylhydrazyl, as well as intracellular reactive oxygen species (ROS), induced by either hydrogen peroxide (H(2)O(2)) or UVB radiation. In addition, both superoxide anion generated by the xanthine/xanthine oxidase system and hydroxyl radical generated by the Fenton reaction (FeSO(4) + H(2)O(2)) were scavenged by CTE, as confirmed using electron spin resonance spectrometry. In the human keratinocyte cell line, CTE decreased the degree of injury resulting from UVB-induced oxidative stress to lipids, proteins, and DNA. CTE-treated cells also showed a reduction in UVB-induced apoptosis, as exemplified by fewer apoptotic bodies and less DNA fragmentation. Taken together, these results suggest that CTE confers protection on the human keratinocyte cell line against UVB-induced oxidative stress by absorbing UVB ray and scavenging ROS, thereby reducing injury to cellular constituents. PMID- 23093464 TI - Effect of mitotic inducers and retinoic acid blocker on expression of pluripotent genes in ES cells derived from early stage in vitro-produced embryos in buffalo. AB - So far, it has been difficult to generate embryonic stem (ES) cell from early stage preimplantation embryos of buffalo. These ES cells will be more helpful for efficient embryo cloning and generation of body cells as they are more primitive than inner cell mass (ICM)-derived ES cells. The present study was conducted to find the effect of lipopolysaccharide (LPS), melatonin (N-acetyl-5 methoxytryptamine, a pineal gland product), and citral (3,7-dimethyl-2,6 octadienal and a retinoic acid synthesis blocker) on establishment of primary ES cell colonies, the comparative size of the ES cell colonies, and expression of pluripotent genes during extended period of culture in buffalo. Zona-free eight cell stage in vitro fertilization (IVF) embryos were cultured in ES cell medium supplemented with none (media I as control), LPS (media II), citral melatonin (media III), or melatonin (media IV). The multiplication of blastomere leading to ES cell colony formation and expression of pluripotent genes were assessed up to day 20 of culture. The primary colony formation, the comparative size of the ES cell colonies, and expression of pluripotent genes in these colonies were better in the medium supplemented with melatonin in all days of culture. Within melatonin supplementation, the colony size was comparatively larger on day 8 and day 12 of culture. Further, with this supplementation, the Oct-4 and Nanog expression was comparatively higher on all days of culture. The results indicated that supplementation of melatonin helped in the formation of better primary ES cell colony as well as in the maintenance of pluripotency. The results also indicated that primary colonies developed on day 8 to day 12 of culture may be better for passaging them for establishment of ES cell line from early stage preimplantation IVF embryos of in buffalo. PMID- 23093466 TI - Osteocutaneous free tissue transplantation for mandibular osteoradionecrosis. AB - OBJECTIVE: To describe the success rate, complications, and functional outcomes of patients who are treated with osteocutaneous free tissue transplantation for grade 4 mandibular osteoradionecrosis (ORN). DESIGN: Retrospective case series. SETTING: Tertiary care academic medical center. PATIENTS: Twelve patients (8 males, 4 females; mean age, 57.6 years) with grade 4 mandibular ORN. Three patients (25%) had a history of primary radiotherapy, two (17%) had previous concurrent chemoradiation, and seven (58%) had undergone postoperative adjuvant radiotherapy. Ten patients (83%) had previous major ablative surgery to treat the primary tumor and five (50%) had been reconstructed with a free tissue transplant prior to the onset of ORN. INTERVENTIONS: All patients underwent reconstruction with an osteocutaneous free tissue transplant for grade 4 mandibular ORN between 1999 and 2006. MAIN OUTCOME MEASURES: Successful treatment of mandibular ORN; major, minor, and late complications; gastrostomy tube (G-tube) dependence; speech and swallowing scores. RESULTS: Grade 4 mandibular ORN was successfully treated in eight (73%) evaluable patients. One patient (8%) died of a second primary tumor before the 12-month assessment. Eight patients (67%) had a major complication, three (25%) had a minor complication, and nine (75%) had a late complication. Three of the five G-tube- dependent patients prior to mandibular reconstruction were able to discontinue the use of their G-tube. Seven of the eight successfully treated patients maintained their nutrition by mouth. Median "range of liquids" score was 6/6 (range, 4 to 6). Median "range of solids" score was 4/6 (range, 3 to 6). Median "understandability of speech" score was 4/5 (range, 2 to 5). CONCLUSIONS: Grade 4 mandibular ORN was treated successfully with an osteocutaneous free tissue transfer in eight evaluable patients (73%). In successfully treated patients, median speech/swallowing scores were highly functional, but the remaining radiated soft tissue resulted in higher local wound complications and a modified diet. PMID- 23093467 TI - Colorimetric examination of typical free flap donor sites and comparison to recipient sites in the extremities. AB - Results after free flap reconstruction in the extremities are often impaired by missing color match of the transferred flap and the recipient site. But pre existing color match is the precondition for satisfying aesthetic results. To obtain suitable free flap donor sites in terms of color for extremity reconstruction and to understand frequent color mismatch, we performed a colorimetric study including 60 healthy volunteers. Ten free flap donor sites were compared with ten recipient sites in the extremities. The results of our study showed that lower extremity sites are markedly lighter than upper extremity sites with the exception of the palmar forearm. We encountered an excellent color match of the radial forearm flap to the back of the hand (4.10 +/- 1.91) and the palm of the hand (5.62 +/- 2.21), and significantly relevant color match to the palmar aspect of the forearm (2.52 +/- 1.23). Additionally, the lateral arm flap showed a remarkable color match to the dorsal aspect of the forearm (3.13 +/- 2.06). Furthermore we encountered significantly relevant color match of the fibula flap to the anterior aspect of the lower leg (2.01 +/- 1.08) and excellent color match of the anterolateral thigh flap (ALT) to the palmar aspect of the forearm (3.66 +/- 2.10). No further significantly relevant color differences between the other donor sites and recipient regions were found. Colorimetric measurements are a helpful tool in reconstructive surgery to compare skin color of different anatomic sites. PMID- 23093468 TI - Early start of the dangling procedure in lower extremity free flap reconstruction does not affect the clinical outcome. AB - Flap loss due to postoperative flap edema and thrombosis of the anastomosis remains the predominant concern of reconstructive microsurgeons. Due to the lack of scientific evidence, there is no unanimous opinion on when to mobilize a reconstructed lower extremity, reflecting the uncertainty of plastic surgeons regarding the effect of the dangling procedure on flap microcirculation. PATIENTS AND METHODS: In this randomized controlled clinical trial, we included 31 patients undergoing free flap transfer to the lower extremity.The patients were randomly divided into two groups. Cohort I consisted of 15 patients starting the dangling procedure at day 7, and cohort II consisted of 16 patients in which an early aggressive postoperative dependency started at day 3.Wrapping and dangling of the flap was performed primarily with a duration of 5 minutes three times a day and increased daily by doubling the duration over a period of 4 days, reaching 60 minutes at day 5.Before and immediately after each dangling procedure the flaps were clinically monitored under direct observation for color, capillary refill, venous congestion, flap turgor, and flap temperature. RESULTS: In all cases the postoperative course was uneventful, resulting in a success rate of 100%. No adverse effects or flap compromise were seen due to the combined dangling/wrapping procedure. CONCLUSION: An early and aggressive start of a combined dangling/wrapping procedure does not compromise flap circulation and allows mobilizing patients after free flap transfer to the lower extremity at an early stage. This approach improves patient comfort, shortens the hospital stay, and therefore reduces socioeconomic costs. PMID- 23093469 TI - Predictive value of SIEV caliber and superficial venous dominance in free DIEP flaps. AB - INTRODUCTION: The superficial inferior epigastric vein (SIEV) is recognized as an important potential venous conduit in deep inferior epigastric artery perforator (DIEP) flaps. Diffuse flap congestion, despite a patent deep inferior epigastric venous anastomosis, occurs in 2% of cases. The SIEV can augment venous outflow and decrease flap congestion. Although a poorly understood phenomenon, the likelihood of its use was thought to be directly proportional to the SIEV size and caliber. Herein we investigate this correlation. AIM: To determine whether the diameter of SIEV in patients undergoing DIEP flaps was predictive of a superficial venous system dominance, necessitating its use in alleviating venous congestion. PATIENTS/METHODS: The in situ SIEV diameter of 39 sequential patients undergoing DIEP flaps was measured on computed tomography (CT) angiography preoperatively as well as intraoperatively from 2008 to 2009. Three patients were excluded for aborted DIEP flap attempt. Six flaps subsequently required venous outflow augmentation with the SIEV. This data was examined using Spearman's correlation analysis. RESULTS: No correlation between SIEV diameter (in situ and radiographic) and eventual use was noted. Other factors such as body mass index (BMI), age, and BMI:SIEV size ratio also failed to predict venous congestion and eventual SIEV use. Flap outcomes are reported herein. CONCLUSION: Our findings suggest that SIEV diameter is not an indicator of superficial epigastric venous dominance and therefore is not predictive of venous congestion nor of its use in increasing venous outflow. This contradicts previously held assumptions that larger caliber SIEVs were indicative of a dominant superficial venous system and more likely to result in their use as an alternate route for venous outflow. Our findings suggest that the SIEV should be prophylactically dissected and harvested in raising every DIEP flap, regardless of its caliber. PMID- 23093470 TI - Letter to the editor: Obesity and inflammation: change in adiponectin, C-reactive protein, tumour necrosis factor-alpha and interleukin-6 after bariatric surgery. PMID- 23093471 TI - Differential changes in exercise performance after massive weight loss induced by bariatric surgery. AB - BACKGROUND: Exercise performance and pulmonary function are often impaired in severely obese subjects. Bariatric surgery represents the most effective therapy for severe obesity, but data on changes in exercise performance after massive weight loss induced by bariatric surgery have rarely been assessed so far. METHODS: Exercise performance was obtained by bicycle spiroergometry in 18 severely obese patients before and at least 1 year after bariatric surgery. Additionally, pulmonary function was assessed by spirometry. RESULTS: BMI was reduced from 46.3 +/- 1.6 to 33.5 +/- 1.4 kg/m(2) after surgery. Pulmonary function (forced expiratory volume within 1 s; inspiratory vital capacity) improved after weight loss (both p <= 0.01). At peak exercise, heart rate (HR) peak, absolute oxygen uptake (VO(2)) peak, and load peak did not differ between both assessments (all p > 0.25). However, relative (related to actual body weight) VO(2) peak and workload peak were higher after than before surgery (both p <= 0.005), while gross efficiency peak and ventilatory equivalent peak remained unchanged (both p > 0.30). At anaerobic threshold (AT), patients showed lower HR AT and absolute VO(2) AT after than before surgery (both p < 0.05), while absolute workload AT did not differ (p = 0.58). In turn, relative VO(2) AT did not change (p = 0.30), whereas relative workload AT was higher after surgery (p = 0.04). Also, ventilatory efficiency AT and gross efficiency AT tended to be improved (both p = 0.08). Before surgery, the patients performed 27.0 % of VO(2) peak above their AT, while this fraction increased to 35.3 % (p = 0.006). CONCLUSIONS: Results indicated differential changes in exercise performance, with the relative but not the absolute peak performance being improved after massive weight loss. Interestingly, anaerobic exercise tolerance was markedly improved after surgery. PMID- 23093472 TI - Ocular myositis. AB - Ocular myositis frequently manifests with orbital pain and diplopia. The diagnosis of ocular myositis falls within the overall classification of idiopathic orbital inflammatory diseases, defined as non-infective non-specific orbital inflammation without identifiable local or systemic causes. Orbital myositis may form part of more widespread systemic inflammatory processes such as Crohn's disease and the more recently described IgG4-related disease. There is also a broad range of ophthalmic differential diagnoses. Diagnosis, assessment and management of ocular myositis requires the cooperation of ophthalmologists and rheumatologists/immunologists in order to achieve the best patient outcomes. The current literature and avenues of future research are reviewed. PMID- 23093473 TI - European guidelines on cardiovascular disease prevention in clinical practice (version 2012) : the fifth joint task force of the European society of cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). PMID- 23093474 TI - Intravenous zolpidem injection in a zolpidem abuser. AB - Zolpidem abuse has been frequently observed in recent years. This study presents a case of zolpidem abuse. Although numerous cases of zolpidem dependence have been reported, this is the first case to report zolpidem intravenous injection without any history of opiate use. Clinicians should monitor patients with a history of zolpidem abuse and be aware that there is a risk of zolpidem injection. PMID- 23093475 TI - Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study. AB - INTRODUCTION: Non-response to an antidepressant monotherapy in unipolar depression is quite common. Therefore strategies for subsequent treatment steps are necessary. However, there is a lack of direct comparisons of these different strategies. In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment. METHODS: Failure of primary antidepressant monotherapy occurred in 135 patients. 98 of these patients have been administered 4 treatment strategies of the physicians' choice: lithium augmentation (Li-Augm), switching to another antidepressant (AD Switch), combination of 2 antidepressants (AD-Comb) or augmentation with second generation antipsychotic (SGA-Augm). Primary outcome measure was the 17-item Hamilton rating scale for depression (HRSD). RESULTS: Patients who received Li Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination. Remission rates for Li-Augm and SGA-Augm were 89.3% and 86.2% compared to 40.7% for AD-Switch and 42.9% for AD-Comb. DISCUSSION: Changing to another pharmacological class (Li-Augm or augmentation with SGAs) showed better treatment results than sticking to the class of antidepressants (AD-Switch and AD Comb) after primary failure in response to antidepressant monotherapy in unipolar depression. The lack of randomization and absence of a non-response definition are design flaws. Controlled studies are required to confirm the findings of this trial. PMID- 23093476 TI - Serum levels of sodium valproate in patients suffering from bipolar disorders: comparing acute and maintenance phases of mania. AB - OBJECTIVES: Bipolar disorders (BD) are characterized by episodes of mania and depression. There is evidence that states of psychiatric disorders impact on neurotransmitters, endocrine system and membrane transport and, therefore, it is possible that specific phases of BD differentially influence the pharmacokinetics of some drugs. The aim of the present study was to investigate the drug-disease interaction between sodium valproate, one of the major drugs used in the treatment of bipolar disorder, and acute versus maintenance states of manic episodes. METHOD: 37 patients (mean age +/- SD = 37.54 +/- 11.27 years; 23 males, 14 females) suffering from bipolar disorder completed the study. Blood samples were taken during both acute and maintenance states. RESULTS: Neither the trough concentration (p = 0.567) nor the internal clearances (p = 0.729) of sodium valproate in the acute phase of mania differed statistically or descriptively from those in the maintenance phase. Marginally significant phase by gender interactions were observed. CONCLUSION: No significant effect of the acute phase of mania was observed in bipolar patients and no relationship could be found between drug pharmacokinetics and disease phase. This may be explained by specific pharmacokinetic features of the drug such as low extraction ratio values. However, phase by gender interactions indicate possible gender-related issues. PMID- 23093477 TI - An update on cross-cultural adaptation of US English SMILEY. AB - We previously developed a health-related quality of life (HRQOL) tool for children with systemic lupus erythematosus (SLE) that is valid in English for the United States, called Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY). In order to determine the effect of SLE on the well-being of children, adolescents and their parents and examine the response to treatment modalities, it is critical to have an HRQOL tool that is applicable for different cultures. After validation in US English, we reported the translation and cultural adaptation process undertaken by our team to make SMILEY available in the following 13 accepted modern language variants: Danish, Dutch, French (France), German (Germany), Hebrew, Italian, Portuguese (Brazil), Slovene, Spanish (USA and Puerto Rico), Spanish (Spain), Spanish (Argentina), Spanish (Mexico) and Turkish. In this report we will describe the translation and adaptation of SMILEY into Afrikaans, Xhosa, Arabic (Saudi Arabia), Arabic (Egypt), Chinese, Czech, English (UK), German (Austria), German (Switzerland), Greek, Hindi, Hungarian, Japanese, Romanian, Serbian and Spanish for Venezuela. We followed the earlier reported procedure in this study consisting of: establishing collaborative relationships with different physicians caring for children with rheumatic diseases; forward and back translation of SMILEY and revisions; and cultural adaptation of SMILEY content. PMID- 23093478 TI - [Lateralized thoracic epidural]. PMID- 23093479 TI - Ketorolac tromethamine improves the analgesic effect of hyoscine butylbromide in patients with intense cramping pain from gastrointestinal or genitourinary origin. AB - The symptomatic treatment of pain associated with spasm of gastrointestinal or genitourinary origin can include the use of spasmolytic agents and/or non steroidal anti-inflammatory drugs. However, the evidence of a superior effectiveness of combination in comparison with individual drugs is scarce and controversial. A double-blind, randomised, clinical trial study was designed to characterize the analgesic effect and safety of ketorolac and hyoscine butylbromide against hyoscine butylbromide alone in patients with ambulatory acute cramping pain of gastrointestinal and genitourinary origin. 160 patients with a pain level >=4 in a 1-10 cm visual analogue scale were allocated to receive a fixed dose of ketorolac/hyoscine butylbromide (10 mg/20 mg) or hyoscine butylbromide (20 mg) alone at 6 h intervals, during a 48 h period. Both treatments were similarly effective when compared as a whole or when groups were classified by pain origin. Conversely, when treatments were grouped by pain intensity, ketorolac/hyoscine butylbromide combination showed a significant better pain relief profile than hyoscine butylbromide alone in pain intensity >=7, but not <7. Data indicate that the oral ketorolac/hyoscine butylbromide mixture could be a better option than hyoscine butylbromide alone in the treatment of some acute intense cramping painful conditions. PMID- 23093480 TI - Interaction of 5-amino-1,3,4-thiadiazole-2-thiol and its violuric acid adduct with Pt(II) - crystals structures, spectroscopic properties and cytotoxic activity. AB - The coordination properties of Pt(II) with 5-amino-1,3,4-thiadiazole-2-thiol [CAS 2349-67-9] (L 1 ) and its novel violurate adduct (L 2 ), both in solution and in solid state, are studied by means of conventional IR-spectroscopy, single crystal X-ray diffraction and thermal methods. The complex compounds of L 1 and L 2 , with general formulas [Pt(C2H2N3S2)2] and [Pt(C6H4N6S2O3)(Cl)]Cl respectively, are obtained. Quantum chemical calculations of the ligands are performed with a view to obtain electronic structure and optical properties of the ligands L 1 and L 2 , respectively. The cell viability of the ligands and metal complexes on a panel of human tumor cell lines is evaluated. PMID- 23093481 TI - In vitro dissolution and in vivo bioequivalence evaluation of two brands of isosorbide 5-mononitrate sustained release tablets. AB - The purpose of the present study was to test a sustained release-tablet newly formulated with synthetic paraffin and compare its bioequivalence to that of the Imdur(r) Long-Acting tablet, based on the guidelines of the Korean Food and Drug Administration.Dissolution test was performed in 4 different dissolution media. A LC/MS/MS method of isosorbide 5-mononitrate in human plasma was validated. In vivo bioequivalence tests of the 2 isosorbide 5-mononitrate tablets were performed in both preprandial and postprandial states.A comparative dissolution test gave similar results for both tablets in all dissolution media tested: 40% dissolution in pH 1.2 at 2 h and 80% dissolution in pH 4.0, pH 6.8, or water at 10 h. In a bioequivalence study to compare 2 tablets, the mean total area under the curve (AUCt) and peak concentration (Cmax) in the fasted state were 8 476.0 ng . h/mL and 540.4 ng/mL, respectively, for the Imdur(r) Long Acting Tablet 60 mg, and 8 701.4 ng . h/mL and 564.2 ng/mL, respectively, for the test tablet. The mean AUCt and Cmax in the fed state were 8 793.5 ng . h/mL and 559.9 ng/mL, respectively, for the Imdur(r) Long-Acting tablet 60 mg, and 8 639.8 ng . h/mL and 617.9 ng/mL, respectively, for the test tablet. The 90% confidence intervals using log transformed data were within the acceptable range of 0.8 - 1.25.Based on these statistical analyses, we conclude that the test tablet is bioequivalent to the Imdur(r) Long-Acting tablet 60 mg in both the preprandial and postprandial states. PMID- 23093482 TI - LC-MS/MS method for determination of epothilone B in rat plasma and its application in pharmacokinetic study. AB - A simple LC-MS/MS method was developed for determination and pharmacokinetic study of Epothilone B in rat plasma.Plasma sample pretreatment involved a one step liquid-liquid extraction of 100 uL plasma. The chromatographic separation was carried out on a Agilent Zobax SB C18 column with a mobile phase consisting of 10 mmol/L ammonium acetate-acetonitrile (35:65, v/v) at a flow rate of 0.2 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer by SRM via electro spray ionization source with positive mode.The standard curve for Epothilone B was linear over the concentration range of 1-100 ng/mL with a lower limit of quantification of 0.5 ng/mL. The intra- and inter-day precision (relative standard deviation) values were not higher than 15% and the accuracy (relative error) was < 10% at 3 quality control levels. Pharmacokinetic parameters were as follows: t1/2, 3.56 (1.12) h; AUC0-24 h, 295.7 (65.3) ng . h/mL and AUC0-infinity, 339.2 (87.4) ng . h/mL, CL, 5.77 (0.67) mL/h; MRT, 7.55 (2.41) h, respectively.This simple, fast and highly sensitive method was fully validated and successfully applied to a preclinical pharmacokinetic study of Epothilone B in rats after i. v. administration. PMID- 23093483 TI - Pharmacokinetics of ginkgolide B injection in beagle dogs. AB - A liquid chromatography-mass spectrometry method was developed, validated, and applied to the pharmacokinetic study with doses of 0.68, 2.73 and 10.92 mg/kg of ginkgolide B in beagle dogs after intravenous infusion.An aliquot of blood samples were -collected, separated and quantitatively analyzed by liquid chromatography-mass spectrometry method with mobile phase of acetonitrile-0.02% ammonia solution (33:67, v/v) at a flow rate of 0.8 mL/min on the UltimateTM XB C18 column (5 MUm, 4.6*150 mm).The method was sensitive, accurate and convenient, and can be used for the determination of ginkgolide B in beagle dogs. The Cmax and AUC0-infinity of GB increased with dose escalation, but ANOVA analyses showed that no significant difference was observed in other pharmacokinetic parameters between different doses.An LC/MS method was developed with good sensitivity, reproducibility and specificity. In the pharmacokinetic study of GB in beagle dogs, linear pharmacokinetics was found at doses from 0.62 to 10.92 mg/kg after a single-dose intravenous infusion. Gender differences were not observed in the pharmacokinetics of GB. PMID- 23093484 TI - "Doctor, what do i have?" Knowledge of cancer diagnosis among immigrant/migrant minorities. AB - This study explores patient knowledge of cancer diagnosis among underserved immigrant/migrant minorities. Patients were recruited at a hospital-based cancer clinic in New York City. Demographic and self-reported diagnosis and treatment information were collected; charts were reviewed to ascertain cancer diagnosis. Four hundred thirty-four patients were included. Eighty-seven percent preferred to speak a language other than English in the health care setting. Sixteen percent had incorrect knowledge of their cancer diagnosis. Multivariate analysis indicated that both preference for a non-English language and diagnosis of a "below the belt" cancer were jointly predictive of incorrect knowledge (LR = 17.01; p = 0.0002). "Below the belt" cancers included bladder, colorectal, gynecological, penile, prostate, and testicular cancers. Among this cohort of immigrant/migrant cancer patients, a considerable proportion was unaware of their correct cancer diagnoses. This may have a significant impact on subsequent cancer education, treatment, and care. Limited-English-proficiency patients may be at particular risk. PMID- 23093485 TI - Cerebrospinal fluid parameters of B cell-related activity in patients with active disease during natalizumab therapy. AB - Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS) restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood-CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients. PMID- 23093486 TI - Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice? AB - BACKGROUND: Tumor spatial heterogeneity is an important prognostic factor, which may be reflected in medical images METHODS: Image texture analysis is an approach of quantifying heterogeneity that may not be appreciated by the naked eye. Different methods can be applied including statistical-, model-, and transform based methods. RESULTS: Early evidence suggests that texture analysis has the potential to augment diagnosis and characterization as well as improve tumor staging and therapy response assessment in oncological practice. CONCLUSION: This review provides an overview of the application of texture analysis with different imaging modalities, CT, MRI, and PET, to date and describes the technical challenges that have limited its widespread clinical implementation so far. With further efforts to refine its application, image texture analysis has the potential to develop into a valuable clinical tool for oncologic imaging. TEACHING POINTS : * Tumor spatial heterogeneity is an important prognostic factor. * Image texture analysis is an approach of quantifying heterogeneity. * Different methods can be applied, including statistical-, model-, and transform based methods. * Texture analysis could improve the diagnosis, tumor staging, and therapy response assessment. PMID- 23093487 TI - Association of type-O blood with neuroendocrine tumors in multiple endocrine neoplasia type 1. AB - CONTEXT: The ABO blood type system describes the expression of human blood group antigens found on both erythrocytes and normal tissue throughout the body. We recently reported an association between O blood type and the manifestation of pancreatic neuroendocrine tumors in a cohort of patients with Von Hippel-Lindau syndrome. OBJECTIVE: The aim of the study was to determine whether there is an association of ABO blood type with the development of neuroendocrine tumors in patients with multiple endocrine neoplasia, type 1 (MEN-1). DESIGN: A retrospective analysis of 105 patients with MEN-1 was performed. Demographic, clinical, and biochemical data were analyzed by ABO blood type. Fisher's exact test was used to determine association between ABO blood type and manifestation of neuroendocrine tumor. RESULTS: Demographic and clinical characteristics were similar amongst blood type cohorts. We found an association between O blood type and the manifestation of a primary neuroendocrine tumor of the gastrointestinal tract, lung, pancreas, and thymus in patients with MEN-1 (P = 0.01). Sixteen of 17 (94%) metastatic tumors had type-O blood, compared to 32 of 43 (74%) with a benign tumor who had non-O blood type. CONCLUSIONS: Our findings suggest an association between O blood type and the manifestation of a primary neuroendocrine tumor in patients with MEN-1. Prospective clinical studies are warranted to see whether patient blood type status may be a useful addition to current screening and surveillance practices. PMID- 23093489 TI - Effects of recombinant follicle-stimulating hormone on bone turnover markers in infertile women undergoing in vitro fertilization procedure. AB - CONTEXT: There is experimental but limited clinical evidence that FSH may have direct effects on bone. OBJECTIVE: The aim of the study was to evaluate the effects of acute FSH stimulation on bone turnover in premenopausal women. DESIGN AND SETTING: We conducted a prospective study at a referral center. PATIENTS: Twenty-nine infertile women (age range, 30-40 yr) undergoing an in vitro fertilization procedure were included in the study. INTERVENTIONS: Pharmacological suppression of endogenous gonadotropin and estradiol (E2) production by GnRH analog (leuprolide 1 mg/d s.c.) was followed by stimulation with recombinant FSH (rFSH; starting dose, 375 IU/d s.c.). MAIN OUTCOME MEASURES: We measured serum osteocalcin, C-telopeptides of type-1 collagen (beta-CTX), FSH, and E2 at the beginning of leuprolide administration (T0), at the beginning of rFSH administration (T1), and 3 d (T2) and 10 d (T3) after the first dose of rFSH. RESULTS: At T1, the suppression of FSH and E2 secretion, as an effect of leuprolide administration, led to a significant increase in serum beta-CTX values vs. T0 (P < 0.001). After the administration of rFSH, a rapid increase in serum FSH was observed, whereas serum E2 values increased more slowly. At T2, the increase in serum FSH values above our reference range for early follicular phase (with E2 in the reference range) did not induce any significant change in median serum beta-CTX values as compared to T1. At T3 (when both FSH and E2 were high), serum beta-CTX values decreased significantly vs. T1 (P < 0.001). Osteocalcin did not change significantly throughout the study period. CONCLUSIONS: Our model suggests that FSH does not acutely exert relevant direct effects on bone metabolism in premenopausal women. PMID- 23093490 TI - Proliferative action of the androgen receptor in human uterine myometrial cells- a key regulator for myometrium phenotype programming. AB - CONTEXT: During pregnancy, the myometrium undergoes a phenotype programming starting from an early proliferative stage, to an intermediate synthetic stage, to a late contractile stage, after which the cells commit to labor. Steroid receptors play important roles in regulating myometrial cell phenotype during pregnancy, although detailed mechanisms are not fully defined. OBJECTIVE: The aim of the study was to investigate the expression and function of the androgen receptor (AR) in myometrial cells during pregnancy. DESIGN AND SETTING: Human primary myometrial cells, immortalized myometrial cells, rat pregnant and tubal ligation models were used. Immunohistochemistry, Western blot and real-time PCR, cell proliferation, and flow cytometry assays were applied. RESULTS: The AR is highly expressed in the proliferative stage of pregnancy, starts to decrease in the synthetic stage, and reaches the lowest levels in the contractile stage. Both the mechanical stretch by the growing fetus and the decreased ratio of progestin:estrogen are responsible for AR protein reduction. AR regulates myometrial cell proliferation ligand-independently. Decreased AR expression delays the G(1)-S phase transition of human myometrial cell cycling and reduces expression of several cyclins. These AR actions are mediated through reducing IGF I receptor protein stability, thus weakening PI3K/Akt signal cascade downstream of IGF-I. AR is required for IGF-I receptor protein stability by preventing the IGF-I receptor from ubiquitylation and protein degradation through both proteosomal and lysosomal pathways. CONCLUSION: AR is a key regulator for myometrial cell proliferation, suggesting its critical role in myometrium phenotype programming during pregnancy. PMID- 23093488 TI - Optic neuropathy in McCune-Albright syndrome: effects of early diagnosis and treatment of growth hormone excess. AB - CONTEXT: GH excess is a serious complication of McCune-Albright syndrome (MAS) and has been associated with craniofacial morbidity. OBJECTIVE: The aim of the study was to determine whether early diagnosis and treatment of MAS-associated GH excess prevents optic neuropathy and hearing impairment, the major morbidities associated with GH excess. DESIGN AND SETTING: A retrospective cross-sectional analysis was conducted at a clinical research center. PATIENTS: Twenty-two subjects with MAS-associated GH excess and 21 control MAS subjects without GH excess were included in the study. INTERVENTION: Biochemical testing included random GH, nadir GH after glucose load, nadir GH on frequent sampling, and IGF-I Z-score. Subjects underwent imaging, ophthalmological, audiological, and otolaryngological assessment. Treatment included octreotide, pegvisomant, transphenoidal surgery, and/or radiotherapy as indicated. MAIN OUTCOME MEASURE: Association of optic neuropathy and hearing impairment to age at GH excess diagnosis/treatment was measured. RESULTS: Of 129 MAS subjects, 26 (20%) were diagnosed with GH excess based on elevation of two measures of GH function. Of these, 22 subjects were candidates for pharmacological intervention. Optic neuropathy was significantly correlated with intervention status, with no cases in the early intervention group (diagnosed/treated before age 18) or the control group, and four of seven (57%) in the late intervention group (diagnosed/treated after age 18) (Fisher's exact test; odds ratio, 0.027; P = 0.0058). Early diagnosis/intervention was not associated with reduction in hearing deficits (odds ratio, 1.25; P = 1.00). Mean head circumference SD score was significantly higher in the late (6.08; range, 2.70 to 22.56) than the early intervention (2.67; range, -0.65 to 6.72) or control groups (2.13; range, -2.06 to 7.79) (P = 0.003). CONCLUSIONS: Early diagnosis/treatment of GH excess in MAS is important to prevent optic neuropathy and craniofacial expansion. The relationship between hearing deficits and GH excess remains less clear and requires further study. PMID- 23093491 TI - Association of female reproductive factors with body composition: the Framingham Heart Study. AB - BACKGROUND: Identifying reproductive risk factors in women offers a life course approach to obesity and cardiovascular disease prevention. The association of female reproductive factors with measures of regional body fat distribution has not been comprehensively studied. METHODS: We examined the association of female reproductive factors (age at menarche, parity, age at natural menopause, menopausal status) in association with body composition data from women who participated in the Offspring and the Third Generation Framingham Heart Study cohorts. Visceral adipose tissue (VAT) and sc adipose tissue (SAT) were measured volumetrically by multidetector computerized tomography. We modeled the relationship between each fat depot and female reproductive factors after adjusting for various factors such as age, smoking status, alcohol intake, physical activity index, hormone replacement therapy, and menopausal status. RESULTS: Earlier age at menarche was associated with increased body mass index (BMI), waist circumference (WC), VAT, and SAT (P < 0.0001). This association of earlier menarche with adiposity measures was attenuated after adjusting for BMI (all P > 0.70). We observed no association between parity and all parameters of adiposity measurements (all P > 0.24). Similarly, age at natural menopause was not associated with measures of body composition. Despite higher mean BMI among the post- (BMI 27.3 kg/m(2)) compared with the premenopausal women (BMI 25.9 kg/m(2)) in an age-matched analysis, mean VAT was not different between the two groups (P = 0.30). CONCLUSIONS: Earlier menarche is associated with overall obesity but not with VAT or SAT after accounting for measures of generalized adiposity. Parity and menopausal age were not associated with adiposity measures. Although postmenopausal women had increased BMI, VAT, and SAT, the association was predominantly due to age. PMID- 23093492 TI - Identification of a CpG island methylator phenotype in adrenocortical carcinomas. AB - PURPOSE: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression. EXPERIMENTAL DESIGN: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium HumanMethylation27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors. RESULTS: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 * 10(-9)). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP high and CIMP-low). This classification could be confirmed by methylation specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2). CONCLUSIONS: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes. PMID- 23093493 TI - A pilot study to explore the safety of perioperative postpyloric enteral nutrition. AB - BACKGROUND: The practice of holding enteral nutrition (EN) 8 hours prior to surgery is common. We hypothesized that it was safe to continue postpyloric EN, and we developed an institutional practice pattern to investigate our hypothesis. METHODS: Our pilot study included intubated patients in the surgical intensive care unit at Froedtert Memorial Lutheran Hospital who received EN via a nasojejunal (NJ) feeding tube and underwent 1 or more surgical procedures. Demographic, illness, and injury information were collected as well as length of time to NJ placement, time to initiation of EN, EN interruptions, and complications. Additional hours of EN were calculated by totaling the number of hours a patient received EN past midnight on the day of surgery. RESULTS: A total of 14 patients with mean (SD) age 44.3 (19.9) were included. Patients had a mean (SD) Injury Severity Score (ISS) of 26.1 (9.2) on admission and underwent a total of 38 operations following placement of a feeding tube. The most frequent operation performed was an orthopedic procedure (n = 17; 46.1%). The mean (SD) length of EN interruptions for a single procedure was 222.4 (206.9) minutes. Patients received an additional 11.9 (4.7) hours of EN over the course of their hospitalization and an additional 1064.9 (490) kcal/d per operation. There were no adverse events. CONCLUSION: Perioperative continuation of postpyloric EN is feasible in some critically ill surgical patients and can result in additional calories provided. A multidisciplinary approach and an institutional policy can increase the likelihood of meeting nutrition goals in these patients. PMID- 23093494 TI - Distinct sensitivity of slo1 channel proteins to ethanol. AB - Ethanol levels reached in circulation during moderate-to-heavy alcohol intoxication (50-100 mM) modify Ca(2+)- and voltage-gated K(+) (BK) channel steady-state activity, eventually altering both physiology and behavior. Ethanol action on BK steady-state activity solely requires the channel-forming subunit slo1 within a bare lipid environment. To identify the protein regions that confer ethanol sensitivity to slo1, we tested the ethanol sensitivity of heterologously expressed slo1 and structurally related channels. Ethanol (50 mM) increased the steady-state activities of mslo1 and Ca(2+)-gated MthK, the latter after channel reconstitution into phospholipid bilayers. In contrast, 50-100 mM ethanol failed to alter the steady-state activities of Na(+)/Cl(-)-gated rslo2, H(+)-gated mslo3, and an mslo1/3 chimera engineered by joining the mslo1 region encompassing the N terminus to S6 with the mslo3 cytosolic tail domain (CTD). Collectively, data indicate that the slo family canonical design, which combines a transmembrane 6 (TM6) voltage-gated K(+) channel (K(V)) core with CTDs that empower the channel with ion-sensing, does not necessarily render ethanol sensitivity. In addition, the region encompassing the N terminus to the S0-S1 cytosolic loop (missing in MthK) is not necessary for ethanol action. Moreover, incorporation of both this region and an ion-sensing CTD to TM6 K(V) cores (a design common to mslo1, mslo3, and the mslo1/mslo3 chimera) is not sufficient for ethanol sensitivity. Rather, a CTD containing Ca(2+)-sensing regulator of conductance for K(+) domains seems to be critical to bestow K(V) structures, whether of TM2 (MthK) or TM6 (slo1), with sensitivity to intoxicating ethanol levels. PMID- 23093495 TI - Requirement of apoptotic protease-activating factor-1 for bortezomib-induced apoptosis but not for Fas-mediated apoptosis in human leukemic cells. AB - Bortezomib is a highly selective inhibitor of the 26S proteasome and has been approved for clinical use in the treatment of relapsing and refractory multiple myeloma and mantle cell lymphoma. Clinical trials are also underway to assess the role of bortezomib in several other human malignancies, including leukemia. However, the mechanism(s) by which bortezomib acts remain to be fully understood. Here, we studied the molecular requirements of bortezomib-induced apoptosis using the human T-cell leukemic Jurkat cells stably transfected with or without shRNA against apoptotic protease-activating factor-1 (Apaf-1). The Apaf-1-deficient Jurkat T cells were resistant to bortezomib-induced apoptosis, as assessed by caspase-3 activity, poly(ADP-ribose) polymerase cleavage, phosphatidylserine externalization, and hypodiploid DNA content. In contrast, Apaf-1-deficient cells were sensitive to Fas-induced apoptosis. Bortezomib induced an upregulation of the pro-apoptotic protein Noxa, loss of mitochondrial transmembrane potential, and release of cytochrome c in cells expressing or not expressing Apaf-1. Transient silencing of Apaf-1 expression in RPMI 8402 T-cell leukemic cells also diminished bortezomib-induced apoptosis. Fas-associated death domain (FADD) deficient Jurkat cells were resistant to Fas-mediated apoptosis yet remained sensitive to bortezomib. Our results show that bortezomib induces apoptosis by regulating pathways that are mechanistically different from those activated upon death receptor ligation. Furthermore, in silico analyses of public transcriptomics databases indicated elevated Apaf-1 expression in several hematologic malignancies, including acute lymphoblastic and myeloid leukemia. We also noted variable Apaf-1 expression in a panel of samples from patients with acute lymphoblastic leukemia. Our results suggest that the expression of Apaf-1 may be predictive of the response to proteasome inhibition. PMID- 23093496 TI - Identification of determinants required for agonistic and inverse agonistic ligand properties at the ADP receptor P2Y12. AB - The ADP receptor P2Y(12) belongs to the superfamily of G protein-coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y(12) displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y(12) have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y(12) and 28 constitutively active mutants. Results showed that ATP and ATP derivatives are agonists at P2Y(12). The potency at P2Y(12) was 2-(methylthio) ADP > 2-(methylthio)-ATP > ADP > ATP. Determinants required for agonistic ligand activity were identified. Molecular docking studies revealed a binding pocket for the ATP derivatives that is bordered by transmembrane helices 3, 5, 6, and 7 in human P2Y(12,) with Y(105), E(188), R(256), Y(259), and K(280) playing a particularly important role in ligand interaction. N-Methyl-anthraniloyl modification at the 3'-OH of the 2'-deoxyribose leads to ligands (mant-deoxy-ATP [dATP], mant-deoxy-ADP) with inverse agonist activity. Inverse agonist activity of mant-dATP was found at the WT human P2Y(12) and half of the constitutive active P2Y(12) mutants. This study showed that, in addition to ADP and ATP, other ATP derivatives are not only ligands of P2Y(12) but also agonists. Modification of the ribose within ATP can result in inverse activity of ATP-derived ligands. PMID- 23093501 TI - Double dislocation of finger interphalangeal joints. AB - A 62-year-old, right-hand-dominant man who had dementia and lived in an Elderly Mentally Infirm (EMI) nursing home was admitted through Accident & Emergency (A&E) department following unwitnessed injury to the left little finger. His examination revealed a swollen and deformed left little finger with a laceration along the middle crease on the volar aspect and head of proximal phalanx visible through this. Distally sensations and capillary refill was normal. X-rays showed a double dislocation of both proximal and distal interphalangeal joints. The finger was reduced under ring block and the laceration was washed with saline in A&E. The patient was taken to the operation theatre next morning for wound exploration and wash-out+/-stabilistion of the finger under general anaesthesia. The wound was thoroughly washed out and closed with 4/0 interrupted nylon. The finger was immobilised with neighbour strapping and bandaged in flexion. PMID- 23093500 TI - Losartan-induced coronary artery spasm. AB - We report a case of coronary artery spasm documented with angiography in a patient with severe chest pain, electrocardiographic ST-segment elevations and highly elevated troponin I. Symptom onset was 15 min after the patient's first ever intake of losartan. Although parts of the clinical presentation suggested allergy or anaphylaxis, laboratory testing did not support this. PMID- 23093504 TI - Laparoscopic management of interstitial pregnancy with automatic stapler. AB - A 36-year-old woman was referred by general practitioner to the early pregnancy unit with pelvic pain in her seventh week of pregnancy. She had a transvaginal ultrasound. Unruptured live twin tubal ectopic pregnancy was diagnosed on. Diagnostic laparoscopy revealed an unruptured left interstitial ectopic pregnancy. The interstitial tubal pregnancy was removed by laparoscopic automatic stapler with minimal blood loss. The patient had an uneventful recovery to health. PMID- 23093505 TI - Inoperable bulky melanoma responds to neoadjuvant therapy with vemurafenib. AB - A patient with a bulky inoperable stage IIIC melanoma involving the left axilla and neck from a primary of the left medial elbow received vemurafenib as neo adjuvant treatment. Based on the molecular analysis, BRAF V600E mutation was present. After 4 months of vemurafinib treatment, the tumours shrank to less than 50% of original clinical size and allowed the surgeons to perform a left modified radical neck dissection and left radical axillary dissection. Pathological analysis of specimen revealed viable metastatic cells only in 1 of 40 nodes resected in the neck and axillary dissection, accounting for over 98% pathological response. Other lymph nodes had a mixture of foamy histiocytic inflammatory reaction fibrosis and islands of necrotic tissues. After recovery from surgery, vemurafenib was resumed and continued for 6 months. He remained disease free 6 months after surgery. PMID- 23093506 TI - Sphenoid sinus mucocele. AB - The authors present their experience of managing an interesting case of a 65-year old woman who presented to their clinic with 1-month history of persistent deep seated headache. The patient sought medical advice in neurology and ophthalmology clinics before being referred to the ear, nose and throat clinic. CT imaging revealed isolated opacification and expansion of both sphenoid sinuses with bony continuity along the periphery of the sinuses features consistent with mucocele. MRI was needed to fully evaluate the extension of the lesion. The lesion was diagnosed as bilateral sphenoid sinuses mucoceles. Transnasal endoscopic drainage of the sphenoid mucoceles leads to gradual improvement of the symptoms. We discuss the clinical presentation, diagnosis and treatment of this case as well as a review of the literature. PMID- 23093507 TI - An interesting finding in a congenital cystic adenomatoid malformation. AB - Here we describe a case of antenatally diagnosed congenital cystic adenomatoid malformation. Due to increasing cyst size and fetal hydrops an antenatal drain was inserted. The lesion was excised surgically soon after birth due to significant respiratory distress. During histological assessment an area of squamous metaplasia was found within the cyst wall. This developed as a result of the drain placement. At 4-year follow-up the child remains well and has experienced no long-term respiratory sequalae. PMID- 23093508 TI - Brilliant crystallisation in the anterior chamber and subretinal space following adjunctive intravitreal ranibizumab for diabetic vitrectomy. AB - To report a unique case of crystallisation in the anterior chamber and subretinal space in a Malay lady following inadvertent subretinal injection of ranibizumab prior to vitrectomy for proliferative diabetic retinopathy. PMID- 23093509 TI - Closure of a large high-output gastrocutaneous fistula with combined postpyloric feeding and aggressive medical therapy. AB - Widening of the exit site of a percutaneous gastrostomy tube is a rare but difficult to manage complication, which leads to significant morbidity as a result of caustic material leak and associated cutaneous injury. Such defects fail to close with conservative measures such that invasive (surgical or endoscopic) intervention is often required. The authors present a 49-year-old woman with neurological dysphagia, 2 years after gastrostomy tube insertion with several months' history of leakage and widening of the hole at the exit site. Following gastrostomy tube removal; the patient was left with a large, high output gastrocutaneous fistula which was treated aggressively with measures to reduce gastric discharge including 'nil-by-mouth', bypassing the stomach with distal feeding, administration of a somatostatin analogue, high-dose proton pump inhibitor and prokinetics with the aim of preoperatively downsizing the wound. This novel approach led to complete closure of the large gastrocutaneous fistula, obviating the need for surgical intervention. PMID- 23093510 TI - Bevacizumab-related osteonecrosis of the mandible is a self-limiting disease process. AB - A female patient with non-small-cell lung cancer presented with a huge area of exposed bone in the mandible following spontaneous teeth loss. She was receiving multimodal chemotherapy containing bevacizumab. No previous treatment with bisphosphonates or comorbid conditions was reported. Pain medications and infection control were offered to the patient who was closely followed up. Initial imaging and histology of bone and surrounding mucosa (8 weeks after bevacizumab cessation) confirmed the clinical suspicion of avascular osteonecrosis of the mandible. Subsequent imaging and histology of bone and gingiva (12 weeks after bevacizumab cessation) revealed the initial sequestration of the mandible with a marked expansion of the mucosal vascular network. Spontaneous bone sequestration eventually occurred few months later, followed by stable and painless mucosal coverage of the mandibular bone. The patient remained disease-free up to 3 years of follow-up. PMID- 23093511 TI - Whole slide images as a platform for initial diagnostics in histopathology in a medium-sized routine laboratory. AB - INTRODUCTION: Whole slide imaging is the process of digitizing glass slides and the creation of Whole Slide Images (WSI), which enable the examination of pathology samples on a computer screen in a manner comparable to light microscopy. WSI have been used for different applications in pathology but their use for primary diagnostics is still limited. Implementing WSI for primary diagnostics would be a turning point necessitating extensive validation to unravel pitfalls and difficulties that could be encountered within the routine workflow. This article is aimed to describe the gradual integration of WSI into routine pathology diagnostics in a medium-sized routine pathology laboratory. METHODS: This project was started with optimizing the digital work environment including the setting up of validation studies, scanning preferences, storing WSI and the implemented adjustments to the workflow for the laboratory and the pathologist. Afterwards scanning glass slides was initiated in the department of pathology at the Atrium Medical Center, Heerlen, The Netherlands, for performing primary diagnostics of breast biopsies. Later this was extended to other specimen types including resections. RESULTS: The validation studies yielded a high concordance rate between WSI and conventional diagnoses. Routine primary WSI based diagnosis was possible in 82.1% of cases. Failure of digital diagnosis was mainly related to poor image quality and logistic problems. CONCLUSION: The quality of the currently produced WSI is sufficient for primary diagnostics in 82.1% of the cases. Improving image quality, adequate retrieval and controlling scanning error will definitely encourage the wide adaptation in routine diagnostics. PMID- 23093512 TI - The Asia-Pacific Journal of Public Health celebrates 25 years. PMID- 23093513 TI - Public health laws and ethics. PMID- 23093514 TI - Public health law and ethics. PMID- 23093515 TI - Globalization of public health law and ethics. AB - The Constitution of the World Health Organization (1946) states that the "enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social position." The international legal framework for this right was laid by the Universal Declaration of Human Rights (1948) and reaffirmed in the International Covenant on Economic, Social, and Cultural Rights (1966) and the Declaration of Alma-Ata (1978). In recent years, the framework has been developed on 10 key elements: national and international human rights, laws, norms, and standards; resource constraints and progressive realization; obligations of immediate effect; freedoms and entitlements; available, accessible, acceptable, and good quality; respect, protect, and fulfill; non discrimination, equality, and vulnerability; active and informed participation; international assistance and cooperation; and monitoring and accountability. Whereas public health law plays an essential role in the protection and promotion of the right to health, the emergence of SARS (2003) highlighted the urgent need to reform national public health laws and international obligations relating to public health in order to meet the new realities of a globalized world, leading to the WHO Framework Convention on Tobacco Control (2003) and the revision of the WHO International Health Regulations (2005). The Asian Institute for Bioethics and Health Law, in conjunction with the Republic of Korea's Ministry of Health and Welfare and the WHO International Digest of Health Legislation, conducted a comparative legal analysis of national public health laws in various countries through a project entitled Domestic Profiles of Public/Population Health Legislation (2006), which underscored the importance of recognizing the political and social contexts of distinct legal cultures, including Western, Asian, Islamic, and African. PMID- 23093516 TI - Elements of Pacific public health laws: an analysis of the public health acts of Papua New Guinea, Vanuatu, the Solomon Islands, and Fiji. AB - Pacific countries are sovereign nations with distinctive histories, ethnicity, customs, primary resources, economies, and health systems. Despite these and other acknowledged differences, similarities exist in many areas such as geography, legal history, and culture. Many share the experience of colonization, with imported British laws and the subsequent experience of independence. Most Pacific countries are also developing countries. This article broadly describes approaches to legislating in public health in Papua New Guinea, Fiji, Vanuatu, and the Solomon Islands and notes common elements in their public health laws, in particular, in relation to administration, allocation of powers and responsibilities, interaction with local government, communicable disease control, and nuisance. The article concludes that many Pacific public health laws could deliver better support for current health policy, more sensitivity to the culture and customs of the region, and better management of public health risk through laws that are better suited to their Pacific environment, easier to understand, more flexible, and more relevant to current health policy. PMID- 23093517 TI - Ethical assessment of national health insurance system of Korea. AB - The current adverse effects of the health insurance system in Korea are considered to be problems that arise from an insufficient reflection of the notion of respecting human rights. The ethical principles most commonly suggested and used in public health are the 4 principles suggested by Beauchamp and Childress in 1994. From the perspective of the community, these 4 principles of medical ethics can be expanded to resolve problems surrounding existing social systems from a socialistic standpoint. This article describes a flexible, easy-to use model for incorporating the 4 medical ethics principles into the National Health Insurance System (NHIS). First, the principle of respect for autonomy involves respecting the decision-making capacities of autonomous medical consumers and providers and enabling individuals to make reasoned and informed choices. Second is the principle of good practice. The government and medical institutions should act in a way that benefits the health care consumers. The principle of prohibiting bad practice involves avoiding causing health problems. The National Health Insurance Corporation and health care providers should not harm the health care consumers. Finally, the principle of justice is concerned with distributing benefits, risks, and costs fairly-that is, the notion that patients in similar positions should be treated in a similar manner. If these problems are solved, health system quality could be better and more accessible and sustainable. The ethical assessment of the NHIS could be a trial to match the 4 medical ethics principles and the NHIS. It can be applied internationally to relevant policy makers in different settings. PMID- 23093518 TI - The 43rd Asia-Pacific Academic Consortium for Public Health Conference 2011 Seoul Declaration. PMID- 23093519 TI - Functional brain changes following cognitive and motor skills training: a quantitative meta-analysis. AB - BACKGROUND: Functional neuroimaging is increasingly used in rehabilitation research to map the neural mechanisms subserving training targets. These data can inform intervention design and improve evaluation of treatment outcomes. Reliable neural markers may provide standard metrics of treatment impact and allow consideration of behavioral outcomes in the context of functional brain changes. OBJECTIVE: To identify common patterns of functional brain changes associated with training across a diverse range of intervention protocols. Reliable brain changes could inform development of candidate neural markers to guide intervention research. METHODS: Taking a quantitative meta-analytic approach, we review the functional neuroimaging studies of cognitive and motor skills training interventions in healthy young adults (N = 38). RESULTS: Reliable decreases in functional brain activity from pretraining to posttraining were observed in brain regions commonly associated with cognitive control processes, including lateral prefrontal, left anterior inferior parietal lobule, and dorsal anterior cingulate cortex. Training-related increases were observed in the medial prefrontal cortex and posterior cingulate and angular gyrus, core regions of the default network. Activity within the subcortical striatum also showed reliable increases pretraining to posttraining. CONCLUSIONS: These data suggest that altered engagement of large-scale, spatially distributed cortical brain networks and subcortical striatal brain regions may serve as candidate neural markers of training interventions. The development of reliable metrics based on activity and functional connectivity among large-scale brain networks may prove fruitful in identifying interactions between domain-general and -specific changes in brain activity that affect behavioral outcomes. PMID- 23093520 TI - Why do young people with CFS/ME feel anxious? A qualitative study. AB - Young people with chronic fatigue syndrome or myalagic encephalopathy (CFS/ME) (CFS/ME) experience higher levels of psychological distress than healthy controls and young people with other chronic illnesses, and it was recently demonstrated that 38% of this population scored above the clinical cut-off on the Spence Child Anxiety Scale. Subscales of social and separation anxiety were consistently high across gender and age groups. In this study, we used qualitative methods to help us understand more about these two types of anxiety in young people with CFS/ME. Eleven young people (age 12-18) were interviewed. Interviews were self-directed by the participants and were wide ranging. The transcripts were analysed using interpretative phenomenological analysis. Five superordinate themes were identified: social loss and adjustment; introduction of uncertainty and unpredictability; the vulnerable self; individual differences; and contributions towards recovery. Many themes were identical to those described in young people coping with other chronic illnesses in adolescence. In addition, young people with CFS/ME describe experiences associated with the perceived illegitimacy of this condition, namely: feeling unable to explain their illness; bullying from peers; disbelief; and distrust from adults around them. This becomes an additional challenge for these young people. Clinicians need to be aware of these problems, and offer appropriate support. PMID- 23093521 TI - Duration of unemployment and suicide in Australia over the period 1985-2006: an ecological investigation by sex and age during rising versus declining national unemployment rates. AB - BACKGROUND: The relationship between unemployment and suicide may be sensitive to demographic factors, national unemployment rates, and length of time without employment. This study investigated these factors in relation to suicide in Australia for the period 1985-2006, in an ecological study. METHODS: The outcome variable was annual suicide rate by age group, sex and the eight states and territories over 22 years of observation (total observations=1760). The main predictor variable was the average duration of unemployment in the population, categorised into three time periods (<2 weeks, 2-4 weeks, >4 weeks). Poisson regression models were used to investigate the relationship between duration of unemployment and suicide over the years 1985-2006 in a series of cross-sectional analyses. Interaction analyses indicated significant differences during periods of declining or increasing labour market opportunity and by age group. RESULTS: During periods of declining unemployment rates in the country, longer durations of unemployment were associated with higher male suicide rates. During periods of increasing unemployment in the country, longer unemployment duration was associated with lower male suicide rates. Effect modification was also apparent by age-group, with stronger associations between unemployment duration and male suicide evident in those aged 25-34 and 55-64, and weaker associations in those aged 15-24 and 44-54 years. Longer length of unemployment was not associated with an increase in female suicide rates. CONCLUSIONS: The labour market opportunities in Australia modified the effect of duration of unemployment on suicide, and the effect was more prominent in men and older age groups. This may reflect social norms and acceptability about unemployment, as well as life-stage influences associated with transitions into and out of the labour market. PMID- 23093523 TI - Publishing in Urology: My 20-year journey. PMID- 23093522 TI - Assessing the effect of regional deprivation on mortality avoiding compositional bias: a natural experiment. AB - BACKGROUND AND OBJECTIVE: We assessed the effect of regional deprivation on individual mortality by making use of a natural experiment: we followed up ethnic German resettlers from Former Soviet Union countries who were quasi-randomly distributed across the socioeconomically heterogeneous counties of Germany's federal state North Rhine-Westphalia (NRW). METHODS: We used data from the retrospective cohort study 'AMOR' on the mortality of resettlers in NRW (n=34 393). Based on the postcode of the last known residence we linked study participants to the 54 counties of NRW, which were aggregated in six deprivation clusters. Mortality rates and standardised mortality ratios (SMRs) were calculated for each cluster. After a mean follow-up of 10 years, 2580 resettlers were deceased. RESULTS: For male and female cohort members, mortality rates and SMRs were highest in the cluster 'poverty poles' (SMR men: 1.21, 95% CI 1.04 to 1.41; SMR women: 1.17, 95% CI 0.99 to 1.37), whereas they were lowest in the cluster 'prospering regions and suburban counties' (SMR women: 0.86, 95% CI 0.70 to 1.05) as well as in the cluster 'heterogeneous counties' (SMR men: 0.73, 95% CI 0.61 to 0.88). CONCLUSIONS: The population which was quasi-randomly distributed to counties of differing socioeconomic status experienced different levels of mortality. It was highest in regions with the highest level of regional deprivation. Previous studies describing this positive relationship between mortality and regional deprivation could not differentiate between compositional and contextual effects. Thus, our findings indicate that in terms of mortality, regional deprivation does matter. PMID- 23093524 TI - Amazing flow rate for an amazing meeting! Niagara 2013. PMID- 23093525 TI - Un debit impressionnant pour une rencontre des plus impressionnantes! Niagara 2013. PMID- 23093526 TI - Mechanism of action of sacral nerve stimulation using a transdermal amplitude modulated signal in a spinal cord injury rodent model. AB - INTRODUCTION: : Sacral neuromodulation (SNM) is an effective treatment modality for several urological problems, including neurogenic bladder. However, the invasiveness of this technique makes it unsuitable for many patients. We present a novel transdermal amplitude-modulated signal (TAMS) that may provide a non invasive alternative to implantable SNM to treat neurogenic detrusor overactivity (NDO). METHODS: : In this study, we investigated the mechanism of action of non invasive SNM using TAMS on our established spinal cord injury (SCI) animal model. We demonstrated that spinally transected rats develop urinary bladder hyper reflexia after 3 weeks of SCI, indicated by the presence of uninhibited contractions, increased resting pressure, increased threshold pressure and increased maximum voiding pressure. RESULTS: : Short-term neurostimulation affected urodynamics parameters by significantly reducing the threshold pressure (p = 0.02). Spinal transection also increased calcitonin gene-related protein (CGRP) concentration in the L6 dorsal root ganglia; whereas, neurostimulation significantly reduced CGRP concentration in L6 (p = 0.03). CONCLUSION: : TAMS caused a reduction in NDO by inhibiting C-fibre activity. PMID- 23093527 TI - Sacral nerve stimulation: 50 years in the making. PMID- 23093528 TI - Laparoscopic partial nephrectomy: The McMaster University experience. AB - INTRODUCTION: : Laparoscopic partial nephrectomy (LPN) remains one of the more challenging procedures in urology. Minimizing warm ischemia time (WIT) and bleeding requires efficient intracorporeal suturing. In addition, achieving negative surgical margins requires complete excision of the tumour. We report a large Canadian series of laparoscopic partial nephrectomy with intermediate follow-up. METHODS: : Between September 2000 and August 2008, 152 consecutive laparoscopic partial nephrectomies were performed at our centre. Demographic, pathological and clinical data were collected through a retrospective review of the charts. RESULTS: : The average tumour size was 2.68 cm (Range: 0.5-8.8. The vast majority of tumours were malignant (80%). All margins were negative, except for 2 patients who underwent an immediate re-resection. There were no local recurrences or distant metastasis during the follow-up period of 44.3 months. Most procedures required hilar clamping (93.4%) with a mean WIT of 34 minutes, with a clear trend for declining WIT with increasing experience. Five procedures were converted to laparoscopic radical nephrectomy, 10 converted to a hand assisted procedure, and 1 was converted to an open partial nephrectomy. The average blood loss was 162 cc. Complications related to the procedure were classified according to the Clavien grading system. The average drop in the glomerular filtration rate was calculated by the Modification of Diet in Renal Disease (MDRD) Study equation between preoperative and 2.5 months postoperative was 8.6 mL/min/1.73 m(2). CONCLUSIONS: : LPN is a challenging procedure that requires advanced laparoscopic skills. LPN is feasible with excellent oncological outcomes, and an acceptable complication profile. The short-term impact on overall renal function is minimal. The most common postoperative complication was pseudo-aneurysm requiring embolization, which reinforces the intra-operative need for meticulous and a quick suture-ligation of blood vessels during LPN. PMID- 23093529 TI - How do asymptomatic toilet-trained children void following tubularized incised plate hypospadias repair? AB - PURPOSE: : To evaluate the functional outcome in the form of urinary flow rates in asymptomatic children following uncomplicated tubularized incised plate urethroplasty (TIPU) hypospadias repair. METHODS: : We reviewed the records of children who underwent TIPU at our institution between April 1997 and September 2007 and included only asymptomatic toilet-trained children who had an uncomplicated postoperative course and had undergone uroflometry not less than 1 year postoperatively. Unfavourable voiding parameters were either a plateau curve, a peak flow below the 5th percentile range in nomogram or a post-void residual (PVR) more than 20% of the total functional capacity of the bladder. Uroflowmetry findings were analyzed against variables, including the surgeon, the severity of hypospadias, the presence of a hypoplastic urethra, the use of double layer closure, the performance of a spongioplasty and the use of a stent. Serial uroflowmetries, when available, were compared with respect to the initial flow study. RESULTS: : In total, 59 patients were eligible for the study. The mean age at surgery was 2.4 years. Hypospadias was distal penile in 50 (85%) and mid and proximal penile in 9 (15%). Mean follow-up was 3.3+/-2 (1-9.5) years. The uroflow curve was bell-shaped in 18 (30%), interrupted in 8 (14%), slightly flattened in 27 (46%) and plateau in 6 (10%). Flow rate nomograms revealed that 40 (68%) were above the 20th percentile, 10 (17%) were below the 5th percentile and 9 (15%) were between these ranges. PVR was >20% of the pre-void volume in 9 children (15%). No patient demonstrated all three unfavourable parameters together. The groups of children with unfavourable functional voiding parameters were compared to the children with favourable parameters specifically with respect to the possible predictors of outcome. Follow-up uroflometry in 17 patients showed improvement in the flow curve, flow rate and PVR with significant improvement of maximum urinary flow rate (Qmax) and PVR values. CONCLUSIONS: : Asymptomatic, urodynamic abnormalities were observed in our study following uncomplicated TIPU repair. These abnormalities were not related to the variation of the technique among surgeons. Spontaneous improvement has been noted on serial flow studies. PMID- 23093530 TI - Monitoring children after hypospadias repair: What is the best plan of action? PMID- 23093531 TI - CUA Annual Meeting Abstracts addition. AB - INTRODUCTION AND OBJECTIVES: : Foley catheters are assumed to drain the bladder to completion. We have previously shown that dependent loops along the drainage tubing create air-locks, which obstruct antegrade urine flow and result in un drained residual bladder urine. We hypothesized that drainage characteristics of Foley catheters remain poorly understood by urologists and general surgeons. We conducted a nationwide survey of general surgery and urology training program faculty and residents, to assess perceptions of Foley catheter drainage. We designed a novel catheter drainage tube/bag that eliminates air-locks. METHODS: : An anonymous illustrated questionnaire assessing Foley catheter use patterns and perception was sent to general surgery and urology residency programs (N=108) nationwide. A modified catheter drainage tube/bag unit was designed and tested. An ex vivo catheterized bladder model was designed to measure and compare urine drainage rates with the standard drainage system, versus with our novel design. RESULTS: : A total of 307 responses were collected from residents (55%) and faculty (45%); responses were similar among both groups (p<0.05). The majority reported that at their centers Foley catheter drainage tubes are generally positioned with a dependent loop (94.1%), and, that positioning with a dependent loop, versus without (78.1%) promoted optimal drainage. Antegrade drainage does not occur with a traditional drainage system when a >5.5 inch dependent loop in place. With our proposed design, which eliminates dependent loops, the bladder model emptied to completion consistently. CONCLUSIONS: : Traditional Foley catheter drainage systems, as commonly used, evacuate the bladder sub- optimally. More reliable and complete bladder drainage may decrease the incidence of catheter related UTI. The novel modified Foley catheter drainage tube/bag design presented here eliminates dependent loops, to optimize antegrade drainage. PMID- 23093532 TI - Impact of academic affiliation on radical cystectomy outcomes in North America: A population-based study. AB - BACKGROUND: : The objective of this study was to examine the rates of blood transfusions, prolonged length of stay, intraoperative and postoperative complications, as well as in-hospital mortality, stratified according to institutional academic status in patients undergoing radical cystectomy (RC). METHODS: : Within the Health Care Utilization Project Nationwide Inpatient Sample (NIS), we focused on patients in whom RC was performed between 1998 and 2007. Multivariable logistic regression analyses were fitted to predict the likelihood of blood transfusions, prolonged length of stay, intraoperative and postoperative complications, and in-hospital mortality. Covariates included age, race, gender, Charlson Comorbidity Index (CCI), hospital region, insurance status, annual hospital caseload (AHC), year of surgery and urinary diversion. RESULTS: : Overall, 12 262 patients underwent RC. Of those, 7892 (64.4%) were from academic institutions. Patients treated at academic institutions were younger and healthier at baseline (all p < 0.001). RCs performed at academic institutions were associated with fewer postoperative complications (28.8% vs. 32.9%, p < 0.001), shorter length of stay (54.0% vs. 56.2%, p = 0.02) and lower in-hospital mortality rates (2.1 vs. 3.0%, p = 0.002). In multivariable analyses, patients who underwent RC at an academic hospital were 12% less likely to succumb to postoperative complications (odds ratio=0.88, p = 0.003). INTERPRETATION: : Even after adjusting for AHC, RCs performed at academic institutions are associated with better postoperative outcomes than RCs performed at non-academic institutions. From a public health prospective, performing RCs at academic institutions may help reduce costs associated with the management of complications and prolonged length of stay. PMID- 23093533 TI - Achieving the achievable in muscle-invasive bladder cancer. PMID- 23093535 TI - The UREThRAL stricture score: A novel method for describing anterior urethral strictures. AB - BACKGROUND: : Urethral stricture description is not standardized. This makes surgical decision-making less reproducible and increases the difficulty of objectively analyzing urethroplasty literature. We developed a standardized system, the UREThRAL stricture score (USS), to quantify the characteristics of anterior urethral stricture disease based on preoperative imaging and intraoperative findings. METHODS: : To develop the USS, we retrospectively analyzed 95 consecutive patients with urethral strictures who underwent open urethroplasty by a single surgeon (SBB) at Barnes-Jewish Hospital from 2009 to 2011. The USS is a numerical score based on five components of anterior urethral stricture disease that help dictate operative decision-making: (1) (UR)ethral stricture (E)tiology; (2) (T) otal number of strictures; (3) (R)etention (luminal obliteration); (4) (A)natomic location; and (5) (L)ength. Stricture management was categorized by increasing surgical complexity: excision/primary anastomosis (EPA), buccal mucosal graft urethroplasty (BMG), augmented anastomotic urethroplasty (AAU), flap urethroplasty, and a combination of flaps and/or grafts. Multinomial logistic regression analysis was used to compare USS to surgical complexity. RESULTS: : The mean USS for EPA, BMG, AAU, flap, and combination flaps/grafts was 5.78, 8.82, 9.23, 11.01, and 14.97, respectively. Increasing USS was significantly associated with surgical complexity (p < 0.0001). INTERPRETATION: : The USS describes the essential factors in determining surgical treatment selection for urethral stricture disease. The USS is a concise, easily applicable system that delineates the clinically significant features of urethral strictures. Valuable comparison of anterior urethral stricture treatments in clinical practice and in the urological literature could be facilitated by using this novel UREThRAL stricture score. PMID- 23093534 TI - Construct validity of the LapSim virtual reality laparoscopic simulator within a urology residency program. AB - OBJECTIVE: : We assessed the construct validity of the LapSim laparoscopic surgical simulator in a urology residency training program. METHODS: : In total, 15 residents participated in the study between July 2007 and July 2008. The subjects were tested six times at one-month intervals on three skill tasks (lifting and grasping, cutting and clip application) using the LapSim laparoscopic simulator. The testing sessions were divided into the first three sessions (seminar 1), and the subsequent three sessions (seminar 2). We evaluated the following parameters: total time, path length, angular path length, tissue damage, maximum damage and stretch damage. The subjects were divided into junior (PGY 1,2) and senior resident groups (PGY 3,4,5). The Wilcoxon Signed-Rank test for paired samples was used to compare the performances of the juniors and seniors during seminar 1 to their performance in seminar 2 to determine whether there was improvement over time. The Wilcoxon Rank-Sum test for independent samples was used to compare the performance of the juniors to that of the seniors for seminar 1, seminar 2 and the combination of both seminars to determine whether the more experienced senior residents performed better than the less experienced juniors. RESULTS: : No significant performance improvement between testing sessions could be demonstrated. Similarly, there was no significant difference in performance between junior and senior residents. CONCLUSIONS: : Construct validity could not be demonstrated for the total time, path length, angular path length and tissue handling parameters of the LapSim laparoscopic surgical simulator when examined within the context of a urology residency program. PMID- 23093536 TI - Urethral stricture disease: Measuring success in treatment. PMID- 23093537 TI - Varicocele surgery or embolization: Which is better? AB - INTRODUCTION: : Varicocele remains the most commonly identified correctable cause of male factor infertility. Surgical correction is the most commonly performed technique to treat varicoceles with a technical failure rate of less than 5%. An attractive alternative to surgery is the selective catheterization and embolization of the gonadal vein. This data are limited by small series. METHODS: : We reviewed a total of 158 patients. These patients underwent embolization for clinical varicoceles and male factor infertility between 2004 and 2008. Of these, 56% underwent attempted bilateral embolization, 43% unilateral left-sided embolization and 1.3% unilateral right-sided embolization. RESULTS: : Of these patients who underwent attempted bilateral embolization, 19.3% did not experience a successful obliteration of the right gonadal vein and 2.3% (2/88) experienced a failure rate in the embolization of the left gonadal vein. Of the 2 attempts at unilateral right-sided embolization, there were no failures. Of the 68 unilateral left-sided embolization attempts, there was a 4.4% failure rate. Of all of the right-sided embolization attempts, 18.9% failed, while 3.2% of the left-sided attempts failed. CONCLUSION: : This review represents the largest contemporary series of varicocele embolization outcomes currently in the literature. Our 19.3% technical failure rate for bilateral varicocele embolization is higher than the current published rate of 13% and is largely related to failure to successfully occlude the right gonadal vein. This supports our belief that bilateral varicoceles are best managed with a primary microsurgical approach, where technical failure rates are expected to be less than 5% based on published data. Men with unilateral left-sided varicoceles should be offered both options as they have similar failure rates, but with embolization offering some clear advantages to the patient. PMID- 23093538 TI - Synergetic effect of testosterone and phophodiesterase-5 inhibitors in hypogonadal men with erectile dysfunction: A systematic review. AB - Testosterone deficiency seems to impair the clinical response to phophodiesterase 5 (PDE-5) inhibitors in patients with erectile dysfunction (ED). In hypogonadal men, testosterone repletion was associated with enhanced sexual function in patients who failed initial treatment with sildenafil or tadalafil. We conducted a systematic review of studies that evaluated combination therapy of testosterone and PDE-5 inhibitors in patients with ED and low, low-normal testosterone levels who failed monotherapy. The studies we examine are heterogeneous with several methodological drawbacks and that, overall, the addition of testosterone to PDE-5 inhibitors might benefit patients with ED associated with testosterone <300 ng/dL (10.4 nmol/L) who failed monotherapy. Further studies, with a randomized placebo controlled and double blind design, are needed to describe the appropriate target patient group, testosterone cut-off and to define the optimal dose and duration of combination therapy. PMID- 23093540 TI - In memoriam. PMID- 23093539 TI - Northeastern Section of the American Urological Association 64(th) Annual Meeting, Niagara Falls, Ontario Scientific Program. AB - BACKGROUND: : Infections following prostate biopsy can be associated with significant morbidity and occasional mortality. Studies have suggested an increased incidence in post-biopsy sepsis. The purpose of this study was to determine the effect of a bacteria sensitivity adapted antimicrobial prophylactic strategy on the incidence of sepsis post prostate biopsy. METHODS: : In October 2008, based on the prevalence of ciprofloxacin-resistant E.coli in the region, our institution modified the prophylactic regimen for prostate biopsy from oral ciprofloxacin alone to a combination of single-dose ciprofloxacin and trimethoprim/sulfamethoxazole. If patients had a history of urosepsis, bacterial prostatitis, organ transplant, or fluoroquinolone use in the preceding 12 months, intramuscular ceftriaxone was administered for prophylaxis. Patients with penicillin allergy received gentamicin. We determined the incidence of ciprofloxacin-resistant bacteremia 16 months before and 16 months after the change in antibiotic protocol. RESULTS: : Between June 2007 and September 2008, 9 of 847 (1.06%) patients were admitted with prostate biopsy induced bacteremia secondary to ciprofloxacin-resistant E. coli. In the 16 months following introduction of the described prophylactic regimen, 1 of 989 (0.10%) patients suffered ciprofloxacin-resistant sepsis. The absolute reduction in E. coli sepsis was 0.96% (95%CI 0.2% to 1.7%; p=0.007). The number needed to treat is 104. CONCLUSIONS: : Bacterial susceptibility to antimicrobial agents is in evolution. Using a regional bacteria sensitivity based approach to biopsy prophylaxis, we have significantly decreased ciprofloxacin-resistant E. coli sepsis in our patients. Regional bacteria sensitivity based protocols may decrease the incidence at other centers and warrants further study. PMID- 23093541 TI - Prednisone for the treatment of withdrawal headache in patients with medication overuse headache: a randomized, double-blind, placebo-controlled study. AB - PURPOSE: To investigate the efficacy of prednisone for treatment of withdrawal headache in patients with medication overuse headache (MOH). PATIENTS AND METHODS: In this prospective double-blind, placebo-controlled, parallel designed multicentre trial, 96 consecutive patients with MOH were randomized to withdrawal treatment with either 100 mg prednisone or placebo over 5 days. Patients were enrolled if they met the International Headache Society criteria for MOH and were diagnosed with migraine or episodic tension-type headache as primary headache. Exclusion criteria comprised significant neurological or psychiatric disorders. Withdrawal symptoms, including headache severity and intake of rescue medication, were documented for 14 days after randomization. RESULTS: Patients treated with prednisone did not experience fewer hours of moderate or severe headache than patients receiving placebo. However, patients requested less rescue medication within the first 5 days. CONCLUSIONS: During withdrawal in MOH, prednisone reduces rescue medication without decreasing the severity and duration of withdrawal headache. PMID- 23093542 TI - Treatment burden among people with chronic illness: what are consumer health organizations saying? AB - OBJECTIVES: To explore the perspectives of consumer health organizations about the burden of chronic illness and multiple treatment regimens experienced by the consumers they represent. METHODS: In-depth interviews (n = 15) were conducted with senior representatives from peak Australian consumer health organizations representing diabetes, asthma, cardiovascular disease, cancer, musculoskeletal illness and mental health. RESULTS: Medication burden, which included aspects such as multiple medications, side effects, stigma and adverse events resulting from medication use, emerged as the most significant and prevalent theme. Carer burden and the negative impact of financial burden was widely discussed, particularly for low-income earners with claims that these consumers were forced to prioritise medications according to how effective they perceived them to be. Time taken to learn about treatment, administer, and monitor or travel to obtain treatment also emerged as being burdensome, however, difficulty accessing treatment was considered to be particularly burdensome. The disjointed nature of care among healthcare services was thought to create a sense of confusion and distress. DISCUSSION: Many of the issues discussed by participants corroborated existing research, underscoring the complementary provider, and advocacy role of these organisations in mitigating treatment burden for people with chronic illness. PMID- 23093545 TI - Screening and breast cancer mortality--letter. PMID- 23093543 TI - Telomere length and pancreatic cancer: a case-control study. AB - BACKGROUND: Telomeres, the ends of chromosomes, are critical for maintaining genomic stability and grow shorter with age. Shortened telomeres in pancreatic tissue play a key role in the pathogenesis of pancreatic cancer, and shorter telomeres in peripheral blood leukocytes (PBL) have been associated with increased risk for several cancer types. We hypothesized that shorter blood telomeres are associated with higher risk for pancreatic cancer. METHODS: Telomere length was measured in PBLs using quantitative real-time PCR in 499 cases with pancreatic cancer and 963 cancer-free controls from the Mayo Clinic. ORs and confidence intervals (CI) were computed using logistic generalized additive models (GAM) adjusting for multiple variables. RESULTS: In multivariable adjusted models, we observed a significant nonlinear association between telomere length in peripheral blood samples and the risk for pancreatic cancer. Risk was lower among those with longer telomeres compared with shorter telomeres across a range from the 1st percentile to 90th percentile of telomere length. There was also some evidence for higher risk among those with telomeres in the longest extreme. CONCLUSIONS: Short telomeres in peripheral blood are associated with an increased risk for pancreatic cancer across most of the distribution of length, but extremely long telomeres may also be associated with higher risk. IMPACT: Although the temporality of this relationship is unknown, telomere length may be useful as either a marker of pancreatic cancer risk or of the presence of undetected pancreatic cancer. If telomere shortening precedes cancer incidence, interventions to preserve telomere length may be an effective strategy to prevent pancreatic cancer. PMID- 23093546 TI - Knowledge integration in cancer: current landscape and future prospects. AB - Knowledge integration includes knowledge management, synthesis, and translation processes. It aims to maximize the use of collected scientific information and accelerate translation of discoveries into individual and population health benefits. Accumulated evidence in cancer epidemiology constitutes a large share of the 2.7 million articles on cancer in PubMed. We examine the landscape of knowledge integration in cancer epidemiology. Past approaches have mostly used retrospective efforts of knowledge management and traditional systematic reviews and meta-analyses. Systematic searches identify 2,332 meta-analyses, about half of which are on genetics and epigenetics. Meta-analyses represent 1:89-1:1162 of published articles in various cancer subfields. Recently, there are more collaborative meta-analyses with individual-level data, including those with prospective collection of measurements [e.g., genotypes in genome-wide association studies (GWAS)]; this may help increase the reliability of inferences in the field. However, most meta-analyses are still done retrospectively with published information. There is also a flurry of candidate gene meta-analyses with spuriously prevalent "positive" results. Prospective design of large research agendas, registration of datasets, and public availability of data and analyses may improve our ability to identify knowledge gaps, maximize and accelerate translational progress or-at a minimum-recognize dead ends in a more timely fashion. PMID- 23093547 TI - Which risk model to use? Clinical implications of the ACS MRI screening guidelines. AB - The American Cancer Society (ACS) guidelines define the appropriate use of MRI as an adjunct to mammography for breast cancer screening. Three risk assessment models are recommended to determine if women are at sufficient risk to warrant the use of this expensive screening tool, however, the real-world application of these models has not been explored. We sought to understand how these models behave in a community setting for women undergoing mammography screening. We conducted a retrospective analysis of 5,894 women, who received mammography screening at a community hospital and assessed their eligibility for MRI according to the ACS guidelines. Of the 5,894 women, 342 (5.8%) were eligible for MRI, but we found significant differences in the number of eligible women identified by each model. Our results indicate that these models identify very different populations, implying that the ACS guidelines deserve further development and consideration. PMID- 23093548 TI - Calcium intake and lung cancer risk among female nonsmokers: a report from the Shanghai Women's Health Study. AB - BACKGROUND: Calcium has been implicated in carcinogenesis and linked to the risk of several cancers in epidemiologic studies; however, few studies have investigated the association of calcium intake with lung cancer risk, particularly among nonsmokers. METHODS: We evaluated the association of intakes of calcium and related minerals, assessed through a food frequency questionnaire, with lung cancer risk among 71,267 female nonsmokers who were cancer free at baseline in the Shanghai Women's Health Study, a population-based, prospective cohort study. Multivariate Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: During follow-up through December 2009 (median follow-up time: 11.2 years), 428 incident lung cancer cases accrued. The median intakes of dietary calcium, magnesium, and phosphorus were 441, 266, and 935 mg/d, respectively. Intakes of calcium, phosphorus, and the calcium-to-magnesium (Ca:Mg) ratio were inversely associated with lung cancer risk. The corresponding HRs (95% CIs) for the highest compared with the lowest quartile were 0.66 (0.48, 0.91) for calcium, 0.55 (0.36, 0.85) for phosphorus, and 0.62 (0.47, 0.82) for the Ca:Mg ratio. No association was observed for dietary magnesium intake or the use of calcium- or vitamin D-containing supplements. CONCLUSIONS AND IMPACT: Our study provides some of the first evidence suggesting a possible role for increasing dietary calcium intake in lung cancer prevention among female nonsmokers, especially in populations with relatively low calcium intake. PMID- 23093549 TI - Measuring plasma fatty acid oxidation with intravenous bolus injection of 3H- and 14C-fatty acid. AB - Accurate measures of plasma FA oxidation can improve our understanding of diseases characterized by impaired FA oxidation. We describe and compare the 24 h time-courses of FA oxidation using bolus injections of [1-(14)C]palmitate versus [9,10-(3)H]palmitate under postabsorptive, postprandial, and walking conditions. Fifty-one men and 95 premenopausal women participated in one condition (postabsorptive, postprandial, or walking), one tracer ((14)C- or (3)H-labeled), and an acetate or palmitate study. Groups were matched for sex, age, and body mass index (BMI). At 24 h, cumulative [(3)H]acetate recovery as (3)H(2)O was 80 +/- 6%, 78 +/- 2%, and 81 +/- 6% in the postabsorptive, postprandial, and walking conditions, respectively (not significant). Model-predicted maximum [1 (14)C]acetate recovery as expired (14)CO(2) was 59 +/- 12%, 52 +/- 8%, and 65 +/- 10% in the postabsorptive, postprandial, and walking condition, respectively (one way ANOVA, P = 0.12). When corrected with the corresponding acetate recovery factors, 24 h time-courses of FFA oxidation were similar between [1 (14)C]palmitate and [9,10-(3)H]palmitate in all three conditions. In contrast to previous meal ingestion studies, an acetate-hydrogen recovery factor was needed to achieve comparable oxidation rates using an intravenous bolus of [(3)H]palmitate. In conclusion, intravenous boluses of [9,10-(3)H]palmitate versus [1-(14)C]palmitate gave similar estimates of 24 h cumulative FFA oxidation in age-, sex- and BMI-matched individuals. PMID- 23093551 TI - The dependence of lipid asymmetry upon phosphatidylcholine acyl chain structure. AB - Lipid asymmetry, the difference in inner and outer leaflet lipid composition, is an important feature of biomembranes. By utilizing our recently developed MbetaCD catalyzed exchange method, the effect of lipid acyl chain structure upon the ability to form asymmetric membranes was investigated. Using this approach, SM was efficiently introduced into the outer leaflet of vesicles containing various phosphatidylcholines (PC), but whether the resulting vesicles were asymmetric (SM outside/PC inside) depended upon PC acyl chain structure. Vesicles exhibited asymmetry using PC with two monounsaturated chains of >14 carbons; PC with one saturated and one unsaturated chain; and PC with phytanoyl chains. Vesicles were most weakly asymmetric using PC with two 14 carbon monounsaturated chains or with two polyunsaturated chains. To define the origin of this behavior, transverse diffusion (flip-flop) of lipids in vesicles containing various PCs was compared. A correlation between asymmetry and transverse diffusion was observed, with slower transverse diffusion in vesicles containing PCs that supported lipid asymmetry. Thus, asymmetric vesicles can be prepared using a wide range of acyl chain structures, but fast transverse diffusion destroys lipid asymmetry. These properties may constrain acyl chain structure in asymmetric natural membranes to avoid short or overly polyunsaturated acyl chains. PMID- 23093550 TI - Sterols in spermatogenesis and sperm maturation. AB - Mammalian spermatogenesis is a complex developmental program in which a diploid progenitor germ cell transforms into highly specialized spermatozoa. One intriguing aspect of sperm production is the dynamic change in membrane lipid composition that occurs throughout spermatogenesis. Cholesterol content, as well as its intermediates, differs vastly between the male reproductive system and nongonadal tissues. Accumulation of cholesterol precursors such as testis meiosis activating sterol and desmosterol is observed in testes and spermatozoa from several mammalian species. Moreover, cholesterogenic genes, especially meiosis activating sterol-producing enzyme cytochrome P450 lanosterol 14alpha demethylase, display stage-specific expression patterns during spermatogenesis. Discrepancies in gene expression patterns suggest a complex temporal and cell type specific regulation of sterol compounds during spermatogenesis, which also involves dynamic interactions between germ and Sertoli cells. The functional importance of sterol compounds in sperm production is further supported by the modulation of sterol composition in spermatozoal membranes during epididymal transit and in the female reproductive tract, which is a prerequisite for successful fertilization. However, the exact role of sterols in male reproduction is unknown. This review discusses sterol dynamics in sperm maturation and describes recent methodological advances that will help to illuminate the complexity of sperm formation and function. PMID- 23093552 TI - Mapping the regioisomeric distribution of fatty acids in triacylglycerols by hybrid mass spectrometry. AB - This study describes the use of hybrid mass spectrometry for the mapping, identification, and semi-quantitation of triacylglycerol regioisomers in fats and oils. The identification was performed based on the accurate mass and fragmentation pattern obtained by data-dependent fragmentation. Quantitation was based on the high-resolution ion chromatograms, and relative proportion of sn 1(3)/sn-2 regioisomers was calculated based on generalized fragmentation models and the relative intensities observed in the product ion spectra. The key performance features of the developed method are inter-batch mass accuracy < 1 ppm (n = 10); lower limit of detection (triggering threshold) 0.1 MUg/ml (equivalent to 0.2 weight % in oil); lower limit of quantitation 0.2 MUg/ml (equivalent to 0.4 weight % in oil); peak area precision 6.5% at 2 MUg/ml concentration and 15% at 0.2 MUM concentration; inter-batch precision of fragment intensities < 1% (n = 10) independent of the investigated concentration; and averaged accuracy using the generic calibration 3.8% in the 1-10 MUg/ml range and varies between 1-23% depending on analytes. Inter-esterified fat, beef tallow, pork lard, and butter fat samples were used to show how well regioisomeric distribution of palmitic acid can be captured by this method. PMID- 23093554 TI - A virtual community: concerns of patients with pulmonary hypertension. AB - Pulmonary Hypertension (PH) is a complex disorder characterized by elevated pressures in the pulmonary artery that cause right heart failure and eventually leads to death. Treatment regimens can be complex and mortality is high. The purpose of this study was to determine how people with PH are using an online Discussion Board. Qualitative descriptive methodology was used to analyze a convenience sample of self-identified patients with PH. Internet posts to an online Discussion Board from January 1, 2010 to December 31, 2010 were analyzed for common themes. Five hundred forty-nine individuals with PH posted to the Discussion Board. Four themes emerged: Uncertainty and Concern, Guidance and Validation, Support, and Refocusing Life. People with PH are using the Internet to answer questions about PH and seeking support. Future research needs to be conducted to further explore the needs and concerns of people with PH to provide tailored interventions. PMID- 23093553 TI - Repeat revascularization after contemporary percutaneous coronary intervention: an evaluation of staged, target lesion, and other unplanned revascularization procedures during the first year. AB - BACKGROUND: Although drug-eluting stents and intensive secondary prevention have contributed to improved outcomes after percutaneous coronary intervention (PCI), repeat revascularization remains relatively common in contemporary practice. We used data from the multicenter Evaluation of Drug-Eluting Stents and Ischemic Events registry to evaluate the relative frequency and timing of staged revascularization, target lesion revascularization (TLR), and other nontarget revascularization during the first year after contemporary PCI. METHODS AND RESULTS: Patients with staged revascularization, TLR, and other unplanned procedures (elsewhere in the target vessel or in other coronary arteries) were evaluated in time-dependent models using Kaplan-Meier life-table estimation. Predictors of TLR and unplanned revascularization at nontarget sites were identified using logistic regression. Between July 2004 to June 2007, 10 144 patients undergoing PCI were enrolled at 55 US hospitals, of whom 86% were treated with at least 1 drug-eluting stent. Twelve percent required repeat revascularization within the first year (3% staged; 9% unplanned). More than 75% of staged revascularizations were performed <30 days after index PCI, although there was significant variation in this practice across hospitals (range, 0% 54%). TLR occurred in 4.5% of patients, with higher hazard rates between 2 to 9 months after PCI, whereas the risk of unplanned non-TLR (4.4% cumulative incidence) was constant over time. CONCLUSIONS: Among unselected patients undergoing PCI in the drug-eluting stent era, the incidence of repeat revascularization at 1 year is ~12%. Among unplanned procedures, only half are performed for TLR. To achieve further improvements in PCI outcomes, future efforts should concentrate as much on identifying ischemia-producing lesions and intensifying secondary prevention therapies as on the prevention of restenosis. PMID- 23093555 TI - Nutritional, hormonal, and depot-dependent regulation of the expression of the small GTPase Rab18 in rodent adipose tissue. AB - There is increasing evidence that proteins associated with lipid droplets (LDs) play a key role in the coordination of lipid storage and mobilization in adipocytes. The small GTPase, RAB18, has been recently identified as a novel component of the protein coat of LDs and proposed to play a role in both beta adrenergic stimulation of lipolysis and insulin-induced lipogenesis in 3T3-L1 adipocytes. In order to better understand the role of Rab18 in the regulation of lipid metabolism in adipocytes, we evaluated the effects of age, fat location, metabolic status, and hormonal milieu on Rab18 expression in rodent white adipose tissue (WAT). Rab18 mRNA was undetectable at postnatal day 15 (P15), but reached adult levels by P45, in both male and female rats. In adult rats, Rab18 immunolocalized around LDs, as well as within the cytoplasm of mature adipocytes. A weak Rab18 signal was also detected in the stromal-vascular fraction of WAT. In mice, fasting significantly increased, though with a distinct time-course pattern, Rab18 mRNA and protein levels in visceral and subcutaneous WAT. The expression of Rab18 was also increased in visceral and subcutaneous WAT of obese mice (diet-induced, ob/ob, and New Zealand obese mice) compared with lean controls. Rab18 expression in rats was unaltered by castration, adrenalectomy, or GH deficiency but was increased by hypophysectomy, as well as hypothyroidism. When viewed together, our results suggest the participation of Rab18 in the regulation of lipid processing in adipose tissue under both normal and pathological conditions. PMID- 23093556 TI - Sex Differences in Attentional Performance in a Clinical Sample With ADHD of the Combined Subtype. AB - OBJECTIVE: The goal of the present study was to assess whether girls with ADHD express similar deficits in various attention tasks to those described in boys. METHOD: A total of 175 children with the combined subtype of ADHD (89 females) and 132 normal controls (60 females) aged 8 to 14 years participated. Five different tests were conducted: alertness, sustained attention, focused attention, divided attention, and a set-shifting task. RESULTS: The children with ADHD performed worse on all aspects of attention compared with healthy control participants. Several overall general sex differences could be detected, with boys exhibiting faster reaction times and greater response variability. Controlling for ADHD symptom severity and psychiatric comorbidities, no Sex * Diagnosis interaction was found, suggesting that males and females with ADHD experience comparable attentional deficits. CONCLUSION: These results indicate that deficits in various attentional domains are a robust component of ADHD in males and females. PMID- 23093559 TI - Arterial thromboembolism in cancer patients treated with cisplatin: a systematic review and meta-analysis. AB - Cisplatin has been associated with an increased risk of arterial thromboembolic events (ATEs). However, because this association is mostly based on case reports and retrospective studies, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of ATEs associated with cisplatin. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based vs non-cisplatin-based chemotherapy in patients with solid tumors, which were identified from PubMed articles published between 1990 and 2010. Incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using a random effects model. A total of 8216 patients from 38 trials were included. Among patients treated with cisplatin based chemotherapy, the summary incidence of ATEs was 0.67% (95% CI = 0.40% to 0.95%), and the RR of ATEs was 1.36 (95% CI = 0.86 to 2.17; P = .19). No increase in ATEs was detected in any prespecified subgroup. PMID- 23093561 TI - Impact of community wealth on use of cardiac-resynchronization therapy with defibrillators for heart failure patients. AB - BACKGROUND: Disparities in cardiovascular disease treatment are a major health policy concern. A complex interplay of patient, provider, and social contextual factors affect inequities in care. METHODS AND RESULTS: We used data regarding 22 205 patient stays in the National Cardiovascular Data Registry to explore the effect of hospital resources on receipt of a heart failure therapy, cardiac resynchronization therapy with defibrillation (CRT-D). When added to patient level variables, hospital ownership, cardiac patient volume, cardiac procedure availability, CRT-D, implantable cardioverter-defibrillator implantation volumes, and hospital financial characteristics were individually predictive of CRT-D receipt. In the full hierarchical model, average median household income (P<0.0001) and implantable cardioverter-defibrillator implantation volume (P<0.001) remained significant predictors of CRT-D receipt. Patients treated at hospitals in affluent communities were more likely to receive CRT-D than patients treated in poor communities, despite accounting for other patient and hospital characteristics, including insurance status. CONCLUSIONS: These findings suggest that the likelihood of receiving CRT-D is mediated by community wealth and hospital resources, and that health policy targeting insurance coverage alone may be ineffective in resolving inequities in care. PMID- 23093560 TI - Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3. AB - BACKGROUND: Persistent infections with carcinogenic human papillomavirus (HPV) types are the necessary cause of cervical cancer. We recently demonstrated that the HPV16 genome is strongly methylated in cervical precancer compared with transient infections. However, the extent of methylation in other HPV types and its role in progression to cancer is poorly understood. METHODS: We analyzed whole-genome methylation patterns of the three next most carcinogenic HPV genotypes: HPV31 (closely related to HPV16), and two other closely related types, HPV18 and HPV45. DNA was extracted from cervical cytology specimens from 92 women with precancer and 96 women infected with HPV31, HPV18, or HPV45, but who had no cytological or histological abnormalities. After bisulfite modification, genome wide pyrosequencing was performed covering 80-106 sites. We calculated differences in median methylation, odds ratios, areas under the curve, and Spearman rank correlation coefficients for methylation levels between different sites. All statistical tests were two-sided. RESULTS: For all three HPV types, we observed strongly elevated methylation levels at multiple CpG sites in the E2, L2, and L1 regions among women with cervical intraepithelial neoplasia grade 3 compared with women with transient infections. We observed high correlation of methylation patterns between phylogenetically related types. The highest areas under the curve were 0.81 for HPV31, 0.85 for HPV18, and 0.98 for HPV45. Differential methylation patterns in cervical intraepithelial neoplasia grade 3 patients with multiple infections suggest that methylation can clarify which of the infections is causal. CONCLUSIONS: Carcinogenic HPV DNA methylation indicates transforming HPV infections. Our findings show that methylation of carcinogenic HPV types is a general phenomenon that warrants development of diagnostic assays. PMID- 23093562 TI - Evaluating the impact of public health notification: Duke clopidogrel experience. AB - BACKGROUND: Provider and public health interventions in the late 2006 sought to change the duration of clopidogrel use after drug-eluting stent (DES) implantation. We evaluated whether public health interventions were associated with changes in patient-reported clopidogrel use among DES patients. METHODS AND RESULTS: We used interrupted time analyses to evaluate trends in duration of patient-reported clopidogrel use before, during, and after public and provider interventions. We included patients with significant coronary artery disease receiving an intracoronary stent between April 2004 and December 2007 at a single tertiary care center. The center supplemented national and regulatory messaging regarding the role of clopidogrel after DES implantation with direct-to-patient and to-their-provider notifications in December 2006. The combination of public and provider direct notification was associated with significant changes in the percent of DES patients reporting clopidogrel use at 6 months (16.55% increase, P=0.010) and 12 months (15.33% increase, P=0.004), but no change at 24-month follow-up (4.64, P=0.295). During the same period, there was no change in the percent of bare-metal stent patients reporting clopidogrel use at 6-month ( 3.73%, 0.654), 12-month (-5.98%, P=0.389), and 24-month follow-up (-5.16, P=0.708). Although mortality rates through 24 months seemed to decrease between the pre- and postintervention periods, these changes were not significant (DES, P=0.086; bare-metal stent, P=0.296). CONCLUSIONS: The combination of national scientific and regulatory messaging supplemented by local, personal communications to DES patients and their primary healthcare providers was associated with a significant increase in patient-reported clopidogrel use. PMID- 23093563 TI - Origins of medical innovation: the case of coronary artery stents. AB - BACKGROUND: Innovative medical devices make major contributions to patient welfare, and coronary stents have been among the most important device developments of recent decades. However, the origins of such breakthrough medical technologies remain poorly understood. METHODS AND RESULTS: Using a comprehensive database of patents, we identified all individuals and institutions that developed intellectual property related to stent technology early in its development process. The patents were categorized and described using a predetermined qualitative coding strategy. We found 245 granted patents related to bare metal coronary artery stents from 1984 (when the first patent issued in this field) to 1994 (after the first stents were approved). Each year showed an increase in the number of patent filings: from 1 in 1984 to 97 in 1994. The largest fraction of patents was issued to private entities (44.9% of the total). Public companies, individual inventors, and nonprofit institutions represented 31.4%, 18.0%, and 5.7%, respectively. The top 10 most-cited patents in the field were dominated by 2 private entities, Expandable Grafts Partnership and Cook Inc, organizations created by or dependent on the work of independent academic physician-inventors. CONCLUSIONS: Coronary artery stent technology first arose from individual physician-inventors within academic medical centers and their associated private companies. After these initial innovations were in place, the field became dominated by large public companies. This history suggests that policies aimed at encouraging transformative medical device development would have their greatest effect if focused on individual inventors and scientists performing the early stages of technology development. PMID- 23093564 TI - Petroleum jelly-induced penile paraffinoma with inguinal lymphadenitis mimicking incarcerated inguinal hernia. AB - Chronic granulomatous inflammation may develop after injecting foreign oily substances into the penis. The disorder affects mainly the site of administration, but regional lymphadenopathy or even systemic disease can occur. We present a 39-year-old man with petroleum jelly-induced penile lesion and unilateral inguinal lymphadenitis mimicking incarcerated inguinal hernia. At hernioplasty no hernial sac was found, but enlarged lymph nodes suspicious for malignancy were identified. The histopathologic findings of these nodes were consistent with mineral oil granuloma. Paraffinoma of the male genitalia can cause various clinical features posing a differential diagnostic dilemma. Regional lymphadenitis may be the main clinical characteristic. Patient's history, physical and histopathological examination are required to establish the diagnosis. PMID- 23093566 TI - Adult intrarenal neuroblastoma presenting as renal cell carcinoma. PMID- 23093565 TI - Renal angiomyoadenomatous tumour: Imaging features. AB - Renal angiomyoadenomatous tumour is a rare, recently described neoplasm with a distinctive histological appearance. Although reported in the pathology literature, to our knowledge, no prior reports have described its imaging appearance. We describe the computed tomography and magnetic resonance imaging features of an incidentally detected renal angiomyoadenomatous tumour that appeared as a well-marginated, solid T2-hypointense enhancing mass, in a 50-year old woman. It is indistinguishable from a variety of benign and malignant renal neoplasms. PMID- 23093567 TI - A rare case of metastatic lung cancer to the bladder. AB - Cancer metastasis to the bladder from non-contiguous sites is very rare. Lung metastasis to the bladder is even more uncommon, with an extensive literature search identifying only four documented cases in the past 20 years. Of these four cases, only one was from lung adenocarcinoma. In this report, we present the case of a 66-year-old male with known lung adenocarcinoma found to have the incidental finding of a bladder mass upon computed tomography imaging. Histochemical staining of samples from the bladder confirmed metastatic dissemination from the primary lung malignancy. PMID- 23093568 TI - Pediatric renal inflammatory myofibroblastic tumours: A case report and review of the etiology and management options. AB - Inflammatory myofibroblastic tumours (IMTs) have been described in lung, bladder, spleen, breast, pancreas, liver, colon, spermatic cord, prostate, peripheral nerves, orbit and kidney. Traditionally believed as having a reactive pathogenesis, IMTs are now viewed more as a neoplasm. This report describes a case of a renal IMT in a 14-year-old girl with spina bifida associated neurogenic bladder and a history of recurrent urinary tract infections. This represents a unique case as pediatric renal IMTs are very rare in the literature. We discuss how this patient was managed and how she presented compared to other reported cases. PMID- 23093569 TI - Technique de York-Mason dans le traitement des fistules prostato-rectales (a propos de trois cas) : Technique et synthese de la litterature. PMID- 23093570 TI - Simultaneous bilateral tubeless percutaneous nephrolithotomy: A report of 2 cases and review of the literature. AB - Percutaneous nephrolithotomy (PCNL) is currently the standard of care to remove large renal calculi. Traditionally, a large-bore nephrostomy tube is placed postoperatively. However, the necessity of this practice has been recently challenged. Theoretically, bilateral tubeless PCNL offers advantages of lower postoperative discomfort, shorter hospital stay and thus lower cost. We review the literature and present two cases of simultaneous bilateral tubeless PCNL from two patients who were referred to a tertiary stone centre from remote areas. PMID- 23093571 TI - Dual-point competition association assay: a fast and high-throughput kinetic screening method for assessing ligand-receptor binding kinetics. AB - The concept of ligand-receptor binding kinetics is emerging as an important parameter in the early phase of drug discovery. Since the currently used kinetic assays are laborious and low throughput, we developed a method that enables fast and large format screening. It is a so-called dual-point competition association assay, which measures radioligand binding at two different time points in the absence or presence of unlabeled competitors. Specifically, this assay yields the kinetic rate index (KRI), which is a measure for the binding kinetics of the unlabeled ligands screened. As a prototypical drug target, the adenosine A(1) receptor (A(1)R) was chosen for assay validation and optimization. A screen with 35 high-affinity A(1)R antagonists yielded seven compounds with a KRI value above 1.0, which indicated a relatively slow dissociation from the target. All other compounds had a KRI value below or equal to 1.0, predicting a relatively fast dissociation rate. Several compounds were selected for follow-up kinetic quantifications in classical kinetic assays and were shown to have kinetic rates that corresponded to their KRI values. The dual-point assay and KRI value may have general applicability at other G-protein-coupled receptors, as well as at drug targets from other protein families. PMID- 23093572 TI - Barriers to the diagnosis and treatment of venous thromboembolism in advanced cancer patients: a qualitative study. AB - BACKGROUND: Venous thromboembolism is common in patients with cancer and the risk increases with advanced disease. Evidence-based treatment is administration of low-molecular-weight heparin daily by subcutaneous injection. Clinical uncertainty exists as to whether treating venous thromboembolism in advanced disease is in the patient's best interests. AIM: To explore the barriers faced by doctors when diagnosing and treating patients with cancer-associated thrombosis. DESIGN: Qualitative, in-depth interview study using framework analysis. PARTICIPANTS: Forty-five UK doctors across urban and rural settings, from three specialties, oncology, palliative medicine and general practice, with a mixture of senior and junior staff. RESULTS: Organisational constraints served to act as barriers to the diagnosis and treatment of this patient group. Issues were identified around access to diagnostic testing. A cancer-associated thrombosis patient having to wait for a scan as an inpatient was sometimes deemed unnecessary. Patient ambulance transport (especially transportation of hospice patients) was often viewed as inflexible and bureaucratic. Low-molecular-weight heparin prescribing had sometimes led to tension between the acute, community and hospice sectors about whose prescribing responsibility this was, with different areas having divergent 'rules' and practices. Finally, the doctors interviewed discussed the role of nurses. CONCLUSIONS: Multiple logistical barriers are hindering best patient care for people with cancer-associated thrombosis. There is scope for some of these barriers to be reduced to improve service delivery and ultimately patient care. The research team proposes practical recommendations, which could yield direct benefit for patients and the health services. PMID- 23093574 TI - Smooth muscle cells: to be or not to be? Response to Nguyen et Al. PMID- 23093573 TI - Smooth muscle cell plasticity: fact or fiction? PMID- 23093575 TI - The Mad1-Mad2 balancing act--a damaged spindle checkpoint in chromosome instability and cancer. AB - Cancer cells are commonly aneuploid. The spindle checkpoint ensures accurate chromosome segregation by controlling cell cycle progression in response to aberrant microtubule-kinetochore attachment. Damage to the checkpoint, which is a partial loss or gain of checkpoint function, leads to aneuploidy during tumorigenesis. One form of damage is a change in levels of the checkpoint proteins mitotic arrest deficient 1 and 2 (Mad1 and Mad2), or in the Mad1:Mad2 ratio. Changes in Mad1 and Mad2 levels occur in human cancers, where their expression is regulated by the tumor suppressors p53 and retinoblastoma 1 (RB1). By employing a standard assay, namely the addition of a mitotic poison at mitotic entry, it has been shown that checkpoint function is normal in many cancer cells. However, in several experimental systems, it has been observed that this standard assay does not always reveal checkpoint aberrations induced by changes in Mad1 or Mad2, where excess Mad1 relative to Mad2 can lead to premature anaphase entry, and excess Mad2 can lead to a delay in entering anaphase. This Commentary highlights how changes in the levels of Mad1 and Mad2 result in a damaged spindle checkpoint, and explores how these changes cause chromosome instability that can lead to aneuploidy during tumorigenesis. PMID- 23093576 TI - Cell surface dynamics - how Rho GTPases orchestrate the interplay between the plasma membrane and the cortical cytoskeleton. AB - Small GTPases are known to regulate hundreds of cell functions. In particular, Rho family GTPases are master regulators of the cytoskeleton. By regulating actin nucleation complexes, Rho GTPases control changes in cell shape, including the extension and/or retraction of surface protrusions and invaginations. Protrusion and invagination of the plasma membrane also involves the interaction between the plasma membrane and the cortical cytoskeleton. This interplay between membranes and the cytoskeleton can lead to an increase or decrease in the plasma membrane surface area and its tension as a result of the fusion (exocytosis) or internalization (endocytosis) of membranous compartments, respectively. For a long time, the cytoskeleton and plasma membrane dynamics were investigated separately. However, studies from many laboratories have now revealed that Rho GTPases, their modulation of the cytoskeleton, and membrane traffic are closely connected during the dynamic remodeling of the cell surface. Arf- and Rab dependent exocytosis of specific vesicles contributes to the targeting of Rho GTPases and their regulatory factors to discrete sites of the plasma membrane. Rho GTPases regulate the tethering of exocytic vesicles and modulate their subsequent fusion. They also have crucial roles in the different forms of endocytosis, where they participate in the sorting of membrane domains as well as the sculpting and sealing of membrane flasks and cups. Here, we discuss how cell surface dynamics depend on the orchestration of the cytoskeleton and the plasma membrane by Rho GTPases. PMID- 23093577 TI - Female sexual abusers' cognition: a systematic review. AB - Until recently, the sexual offending literature focused on male perpetrators and neglected to examine the characteristics of female perpetrators. As a result, treatment provision for female sexual abusers has been either nonexistent or inappropriately adapted from programs designed for males. What we do know is that male and female sexual abusers share similarities; however, there remain distinct differences that warrant empirical and theoretical study. The current review systematically examines the literature on offense-supportive cognition in female sexual abusers. The aim of this systematic review is to aid clinical practitioners who work with female sexual abusers by providing an evaluation of current available research regarding implicit theories, rape myth acceptance, violence-supportive cognition, gender stereotypes, beliefs about sex, and empathy. We conclude that further research examining the offense-supportive cognition of female sexual abusers is needed in order to facilitate more effective empirically driven clinical practice. PMID- 23093578 TI - Pediatric drug labeling: still an unfinished need. PMID- 23093579 TI - Are our children all right? PMID- 23093580 TI - Testing cardiac reserve: then and now. 1923. PMID- 23093581 TI - PRO: physician-performed ultrasound: the time has come for routine use in acute care medicine. PMID- 23093582 TI - CON: physician-performed ultrasound: the time has come for routine use in acute care medicine. PMID- 23093583 TI - Aspects of the use of ultrasound in vascular cannulation. PMID- 23093584 TI - Practice guidelines for ultrasound-guided subclavian vein catheterization: analyzing the evidence. PMID- 23093585 TI - Long QT syndrome, amiodarone use, and the mechanism underlying lidocaine toxicity. PMID- 23093586 TI - Rescue reversal: an addendum. PMID- 23093587 TI - A nutrient-wide association study on blood pressure. AB - BACKGROUND: A nutrient-wide approach may be useful to comprehensively test and validate associations between nutrients (derived from foods and supplements) and blood pressure (BP) in an unbiased manner. METHODS AND RESULTS: Data from 4680 participants aged 40 to 59 years in the cross-sectional International Study of Macro/Micronutrients and Blood Pressure (INTERMAP) were stratified randomly into training and testing sets. US National Health and Nutrition Examination Survey (NHANES) four cross-sectional cohorts (1999-2000, 2001-2002, 2003-2004, 2005 2006) were used for external validation. We performed multiple linear regression analyses associating each of 82 nutrients and 3 urine electrolytes with systolic and diastolic BP in the INTERMAP training set. Significant findings were validated in the INTERMAP testing set and further in the NHANES cohorts (false discovery rate <5% in training, P<0.05 for internal and external validation). Among the validated nutrients, alcohol and urinary sodium-to-potassium ratio were directly associated with systolic BP, and dietary phosphorus, magnesium, iron, thiamin, folacin, and riboflavin were inversely associated with systolic BP. In addition, dietary folacin and riboflavin were inversely associated with diastolic BP. The absolute effect sizes in the validation data (NHANES) ranged from 0.97 mm Hg lower systolic BP (phosphorus) to 0.39 mm Hg lower systolic BP (thiamin) per 1 SD difference in nutrient variable. Inclusion of nutrient intake from supplements in addition to foods gave similar results for some nutrients, though it attenuated the associations of folacin, thiamin, and riboflavin intake with BP. CONCLUSIONS: We identified significant inverse associations between B vitamins and BP, relationships hitherto poorly investigated. Our analyses represent a systematic unbiased approach to the evaluation and validation of nutrient-BP associations. PMID- 23093588 TI - Nutrient-wide association studies: another road to the same destination. PMID- 23093589 TI - ValidNESs: a database of validated leucine-rich nuclear export signals. AB - ValidNESs (http://validness.ym.edu.tw/) is a new database for experimentally validated leucine-rich nuclear export signal (NES)-containing proteins. The therapeutic potential of the chromosomal region maintenance 1 (CRM1)-mediated nuclear export pathway and disease relevance of its cargo proteins has gained recognition in recent years. Unfortunately, only about one-third of known CRM1 cargo proteins are accessible in a single database since the last compilation in 2003. CRM1 cargo proteins are often recognized by a classical NES (leucine-rich NES), but this signal is notoriously difficult to predict from sequence alone. Fortunately, a recently developed prediction method, NESsential, is able to identify good candidates in some cases, enabling valuable hints to be gained by in silico prediction, but until now it has not been available through a web interface. We present ValidNESs, an integrated, up-to-date database holding 221 NES-containing proteins, combined with a web interface to prediction by NESsential. PMID- 23093590 TI - X-inactivation: quantitative predictions of protein interactions in the Xist network. AB - The transcriptional silencing of one of the female X-chromosomes is a finely regulated process that requires accumulation in cis of the long non-coding RNA X inactive-specific transcript (Xist) followed by a series of epigenetic modifications. Little is known about the molecular machinery regulating initiation and maintenance of chromosomal silencing. Here, we introduce a new version of our algorithm catRAPID to investigate Xist associations with a number of proteins involved in epigenetic regulation, nuclear scaffolding, transcription and splicing processes. Our method correctly identifies binding regions and affinities of protein interactions, providing a powerful theoretical framework for the study of X-chromosome inactivation and other events mediated by ribonucleoprotein associations. PMID- 23093591 TI - MuMoD: a Bayesian approach to detect multiple modes of protein-DNA binding from genome-wide ChIP data. AB - High-throughput chromatin immunoprecipitation has become the method of choice for identifying genomic regions bound by a protein. Such regions are then investigated for overrepresented sequence motifs, the assumption being that they must correspond to the binding specificity of the profiled protein. However this approach often fails: many bound regions do not contain the 'expected' motif. This is because binding DNA directly at its recognition site is not the only way the protein can cause the region to immunoprecipitate. Its binding specificity can change through association with different co-factors, it can bind DNA indirectly, through intermediaries, or even enforce its function through long range chromosomal interactions. Conventional motif discovery methods, though largely capable of identifying overrepresented motifs from bound regions, lack the ability to characterize such diverse modes of protein-DNA binding and binding specificities. We present a novel Bayesian method that identifies distinct protein-DNA binding mechanisms without relying on any motif database. The method successfully identifies co-factors of proteins that do not bind DNA directly, such as mediator and p300. It also predicts literature-supported enhancer promoter interactions. Even for well-studied direct-binding proteins, this method provides compelling evidence for previously uncharacterized dependencies within positions of binding sites, long-range chromosomal interactions and dimerization. PMID- 23093592 TI - A minimal bacterial RNase J-based degradosome is associated with translating ribosomes. AB - Protein complexes directing messenger RNA (mRNA) degradation are present in all kingdoms of life. In Escherichia coli, mRNA degradation is performed by an RNA degradosome organized by the major ribonuclease RNase E. In bacteria lacking RNase E, the existence of a functional RNA degradosome is still an open question. Here, we report that in the bacterial pathogen Helicobacter pylori, RNA degradation is directed by a minimal RNA degradosome consisting of Hp-RNase J and the only DExD-box RNA helicase of H. pylori, RhpA. We show that the protein complex promotes faster degradation of double-stranded RNA in vitro in comparison with Hp-RNase J alone. The ATPase activity of RhpA is stimulated in the presence of Hp-RNase J, demonstrating that the catalytic capacity of both partners is enhanced upon interaction. Remarkably, both proteins are associated with translating ribosomes and not with individual 30S and 50S subunits. Moreover, Hp RNase J is not recruited to ribosomes to perform rRNA maturation. Together, our findings imply that in H. pylori, the mRNA-degrading machinery is associated with the translation apparatus, a situation till now thought to be restricted to eukaryotes and archaea. PMID- 23093593 TI - The Papillomavirus Episteme: a central resource for papillomavirus sequence data and analysis. AB - The goal of the Papillomavirus Episteme (PaVE) is to provide an integrated resource for the analysis of papillomavirus (PV) genome sequences and related information. The PaVE is a freely accessible, web-based tool (http://pave.niaid.nih.gov) created around a relational database, which enables storage, analysis and exchange of sequence information. From a design perspective, the PaVE adopts an Open Source software approach and stresses the integration and reuse of existing tools. Reference PV genome sequences have been extracted from publicly available databases and reannotated using a custom created tool. To date, the PaVE contains 241 annotated PV genomes, 2245 genes and regions, 2004 protein sequences and 47 protein structures, which users can explore, analyze or download. The PaVE provides scientists with the data and tools needed to accelerate scientific progress for the study and treatment of diseases caused by PVs. PMID- 23093594 TI - Dissociation and re-association of RNA polymerase with DNA during osmotic stress response in Escherichia coli. AB - The thermodynamic association of RNA polymerase (RNAP) with DNA is sensitive to salt concentration in vitro. Paradoxically, previous studies of changes in osmolarity during steady-state cell growth found no dependence between the association of RNAP to DNA and K(+) concentration in Escherichia coli. We reevaluated this issue by following the interaction of RNAP and genomic DNA in time-course experiments during the hyper-osmotic response. Our results show that the interaction is temporally controlled by the same physical chemistry principle in the cell as in vitro. RNAP rapidly dissociates from the genome during the initial response when the cytoplasmic K(+) accumulates transiently, and concurrently the nucleoid becomes hyper-condensed. The freed RNAP re-associates with the genome during a subsequent osmoadaptation phase when organic osmoprotectants accumulate as K(+) levels decrease. RNAP first surrounds the hyper-condensed nucleoid forming a sphere of RNAP before it progressively moves in to the center of the nucleoid. Our findings reinterpret the dynamic protein DNA interactions during osmotic stress response. We discuss the implications of the dissociation/association of RNAP for osmotic protection and nucleoid structure. PMID- 23093595 TI - Exploring Ty1 retrotransposon RNA structure within virus-like particles. AB - Ty1, a long terminal repeat retrotransposon of Saccharomyces, is structurally and functionally related to retroviruses. However, a differentiating aspect between these retroelements is the diversity of the replication strategies used by long terminal repeat retrotransposons. To understand the structural organization of cis-acting elements present on Ty1 genomic RNA from the GAG region that control reverse transcription, we applied chemoenzymatic probing to RNA/tRNA complexes assembled in vitro and to the RNA in virus-like particles. By comparing different RNA states, our analyses provide a comprehensive structure of the primer-binding site, a novel pseudoknot adjacent to the primer-binding sites, three regions containing palindromic sequences that may be involved in RNA dimerization or packaging and candidate protein interaction sites. In addition, we determined the impact of a novel form of transposon control based on Ty1 antisense transcripts that associate with virus-like particles. Our results support the idea that antisense RNAs inhibit retrotransposition by targeting Ty1 protein function rather than annealing with the RNA genome. PMID- 23093596 TI - The RNA-binding domain of influenzavirus non-structural protein-1 cooperatively binds to virus-specific RNA sequences in a structure-dependent manner. AB - Influenzavirus non-structural protein NS1 is involved in several steps of the virus replication cycle. It counteracts the interferon response, and also exhibits other activities towards viral and cellular RNAs. NS1 is known to bind non-specifically to double-stranded RNA (dsRNA) as well as to viral and cellular RNAs. We set out to search whether NS1 could preferentially bind sequence specific RNA patterns, and performed an in vitro selection (SELEX) to isolate NS1 specific aptamers from a pool of 80-nucleotide(nt)-long RNAs. Among the 63 aptamers characterized, two families were found to harbour a sequence that is strictly conserved at the 5' terminus of all positive-strand RNAs of influenzaviruses A. We found a second virus-specific motif, a 9 nucleotide sequence located 15 nucleotides downstream from NS1's stop codon. In addition, a majority of aptamers had one or two symmetrically positioned copies of the 5' GUAAC / 3'-CUUAG double-stranded motif, which closely resembles the canonical 5' splice site. Through an in-depth analysis of the interaction combining fluorimetry and gel-shift assays, we showed that NS1's RNA-binding domain (RBD) specifically recognizes sequence patterns in a structure-dependent manner, resulting in an intimate interaction with high affinity (low nanomolar to subnanomolar K(D) values) that leads to oligomerization of the RBD on its RNA ligands. PMID- 23093597 TI - Quadruplex formation as a molecular switch to turn on intrinsically fluorescent nucleotide analogs. AB - Quadruplexes are involved in the regulation of gene expression and are part of telomeres at the ends of chromosomes. In addition, they are useful in therapeutic and biotechnological applications, including nucleic acid diagnostics. In the presence of K(+) ions, two 15-mer sequences d(GGTTGGTGTGGTTGG) (thrombin binding aptamer) and d(GGGTGGGTGGGTGGG) (G3T) fold into antiparallel and parallel quadruplexes, respectively. In the present study, we measured the fluorescence intensity of one or more 2-aminopurine or 6-methylisoxanthopterin base analogs incorporated at loop-positions of quadruplex forming sequences to develop a detection method for DNA sequences in solution. Before quadruplex formation, the fluorescence is efficiently quenched in all cases. Remarkably, G3T quadruplex formation results in emission of fluorescence equal to that of a free base in all three positions. In the case of thrombin binding aptamer, the emission intensity depends on the location of the fluorescent nucleotides. Circular dichroism studies demonstrate that the modifications do not change the overall secondary structure, whereas thermal unfolding experiments revealed that fluorescent analogs significantly destabilize the quadruplexes. Overall, these studies suggest that quadruplexes containing fluorescent nucleotide analogs are useful tools in the development of novel DNA detection methodologies. PMID- 23093598 TI - The common ancestral core of vertebrate and fungal telomerase RNAs. AB - Telomerase is a ribonucleoprotein with an intrinsic telomerase RNA (TER) component. Within yeasts, TER is remarkably large and presents little similarity in secondary structure to vertebrate or ciliate TERs. To better understand the evolution of fungal telomerase, we identified 74 TERs from Pezizomycotina and Taphrinomycotina subphyla, sister clades to budding yeasts. We initially identified TER from Neurospora crassa using a novel deep-sequencing-based approach, and homologous TER sequences from available fungal genome databases by computational searches. Remarkably, TERs from these non-yeast fungi have many attributes in common with vertebrate TERs. Comparative phylogenetic analysis of highly conserved regions within Pezizomycotina TERs revealed two core domains nearly identical in secondary structure to the pseudoknot and CR4/5 within vertebrate TERs. We then analyzed N. crassa and Schizosaccharomyces pombe telomerase reconstituted in vitro, and showed that the two RNA core domains in both systems can reconstitute activity in trans as two separate RNA fragments. Furthermore, the primer-extension pulse-chase analysis affirmed that the reconstituted N. crassa telomerase synthesizes TTAGGG repeats with high processivity, a common attribute of vertebrate telomerase. Overall, this study reveals the common ancestral cores of vertebrate and fungal TERs, and provides insights into the molecular evolution of fungal TER structure and function. PMID- 23093599 TI - Targeting the DNA-binding activity of the human ERG transcription factor using new heterocyclic dithiophene diamidines. AB - Direct modulation of gene expression by targeting oncogenic transcription factors is a new area of research for cancer treatment. ERG, an ETS-family transcription factor, is commonly over-expressed or translocated in leukaemia and prostate carcinoma. In this work, we selected the di-(thiophene-phenyl-amidine) compound DB1255 as an ERG/DNA binding inhibitor using a screening test of synthetic inhibitors of the ERG/DNA interaction followed by electrophoretic mobility shift assays (EMSA) validation. Spectrometry, footprint and biosensor-surface plasmon resonance analyses of the DB1255/DNA interaction evidenced sequence selectivity and groove binding as dimer. Additional EMSA evidenced the precise DNA-binding sequence required for optimal DB1255/DNA binding and thus for an efficient ERG/DNA complex inhibition. We further highlighted the structure activity relationships from comparison with derivatives. In cellulo luciferase assay confirmed this modulation both with the constructed optimal sequences and the Osteopontin promoter known to be regulated by ERG and which ERG-binding site was protected from DNaseI digestion on binding of DB1255. These data showed for the first time the ERG/DNA complex modulation, both in vitro and in cells, by a heterocyclic diamidine that specifically targets a portion of the ERG DNA recognition site. PMID- 23093600 TI - The Comparative Toxicogenomics Database: update 2013. AB - The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) provides information about interactions between environmental chemicals and gene products and their relationships to diseases. Chemical-gene, chemical-disease and gene disease interactions manually curated from the literature are integrated to generate expanded networks and predict many novel associations between different data types. CTD now contains over 15 million toxicogenomic relationships. To navigate this sea of data, we added several new features, including DiseaseComps (which finds comparable diseases that share toxicogenomic profiles), statistical scoring for inferred gene-disease and pathway-chemical relationships, filtering options for several tools to refine user analysis and our new Gene Set Enricher (which provides biological annotations that are enriched for gene sets). To improve data visualization, we added a Cytoscape Web view to our ChemComps feature, included color-coded interactions and created a 'slim list' for our MEDIC disease vocabulary (allowing diseases to be grouped for meta-analysis, visualization and better data management). CTD continues to promote interoperability with external databases by providing content and cross-links to their sites. Together, this wealth of expanded chemical-gene-disease data, combined with novel ways to analyze and view content, continues to help users generate testable hypotheses about the molecular mechanisms of environmental diseases. PMID- 23093601 TI - DoriC 5.0: an updated database of oriC regions in both bacterial and archaeal genomes. AB - Replication of chromosomes is one of the central events in the cell cycle. Chromosome replication begins at specific sites, called origins of replication (oriCs), for all three domains of life. However, the origins of replication still remain unknown in a considerably large number of bacterial and archaeal genomes completely sequenced so far. The availability of increasing complete bacterial and archaeal genomes has created challenges and opportunities for identification of their oriCs in silico, as well as in vivo. Based on the Z-curve theory, we have developed a web-based system Ori-Finder to predict oriCs in bacterial genomes with high accuracy and reliability by taking advantage of comparative genomics, and the predicted oriC regions have been organized into an online database DoriC, which is publicly available at http://tubic.tju.edu.cn/doric/ since 2007. Five years after we constructed DoriC, the database has significant advances over the number of bacterial genomes, increasing about 4-fold. Additionally, oriC regions in archaeal genomes identified by in vivo experiments, as well as in silico analyses, have also been added to the database. Consequently, the latest release of DoriC contains oriCs for >1500 bacterial genomes and 81 archaeal genomes, respectively. PMID- 23093602 TI - Rationally designed bidirectional promoter improves the evolutionary stability of synthetic genetic circuits. AB - One problem with synthetic genes in genetically engineered organisms is that these foreign DNAs will eventually lose their functions over evolutionary time in absence of selective pressures. This general limitation can restrain the long term study and industrial application of synthetic genetic circuits. Previous studies have shown that because of their crucial regulatory functions, prokaryotic promoters in synthetic genetic circuits are especially vulnerable to mutations. In this study, we rationally designed robust bidirectional promoters (BDPs), which are self-protected through the complementarity of their overlapping forward and backward promoter sequences on DNA duplex. When the transcription of a target non-essential gene (e.g. green fluorescent protein) was coupled to the transcription of an essential gene (e.g. antibiotic resistance gene) through the BDP, the evolutionary half-time of the gene of interest increases 4-10 times, depending on the strain and experimental conditions used. This design of using BDPs to increase the mutational stability of genetic circuits can be potentially applied to synthetic biology applications in general. PMID- 23093603 TI - The Online Protein Processing Resource (TOPPR): a database and analysis platform for protein processing events. AB - We here present The Online Protein Processing Resource (TOPPR; http://iomics.ugent.be/toppr/), an online database that contains thousands of published proteolytically processed sites in human and mouse proteins. These cleavage events were identified with COmbinded FRActional DIagonal Chromatography proteomics technologies, and the resulting database is provided with full data provenance. Indeed, TOPPR provides an interactive visual display of the actual fragmentation mass spectrum that led to each identification of a reported processed site, complete with fragment ion annotations and search engine scores. Apart from warehousing and disseminating these data in an intuitive manner, TOPPR also provides an online analysis platform, including methods to analyze protease specificity and substrate-centric analyses. Concretely, TOPPR supports three ways to retrieve data: (i) the retrieval of all substrates for one or more cellular stimuli or assays; (ii) a substrate search by UniProtKB/Swiss-Prot accession number, entry name or description; and (iii) a motif search that retrieves substrates matching a user-defined protease specificity profile. The analysis of the substrates is supported through the presence of a variety of annotations, including predicted secondary structure, known domains and experimentally obtained 3D structure where available. Across substrates, substrate orthologs and conserved sequence stretches can also be shown, with iceLogo visualization provided for the latter. PMID- 23093604 TI - RNA polymerase III mutants in TFIIFalpha-like C37 that cause terminator readthrough with no decrease in transcription output. AB - How eukaryotic RNA polymerases switch from elongation to termination is unknown. Pol III subunits Rpc53 and Rpc37 (C53/37) form a heterodimer homologous to TFIIFbeta/alpha. C53/37 promotes efficient termination and together with C11 also mediates pol III recycling in vitro. We previously developed Schizosaccharomyces pombe strains that report on two pol III termination activities: RNA oligo(U) 3' end cleavage, and terminator readthrough. We randomly mutagenized C53 and C37 and isolated many C37 mutants with terminator readthrough but no comparable C53 mutants. The majority of C37 mutants have strong phenotypes with up to 40% readthrough and map to a C-terminal tract previously localized near Rpc2p in the pol III active center while a minority represent a distinct class with weaker phenotype, less readthrough and 3'-oligo(U) lengthening. Nascent pre-tRNAs released from a terminator by C37 mutants have shorter 3'-oligo(U) tracts than in cleavage-deficient C11 double mutants indicating RNA 3'-end cleavage during termination. We asked whether termination deficiency affects transcription output in the mutants in vivo both by monitoring intron-containing nascent transcript levels and (14)C-uridine incorporation. Surprisingly, multiple termination mutants have no decrease in transcript output relative to controls. These data are discussed in context of current models of pol III transcription. PMID- 23093605 TI - Comparison of mRNA features affecting translation initiation and reinitiation. AB - Regulation of gene expression at the level of translation accounts for up to three orders of magnitude in its efficiency. We systematically compared the impact of several mRNA features on translation initiation at the first gene in an operon with those for the second gene. Experiments were done in a system with internal control based on dual cerulean and red (CER/RFP) fluorescent proteins. We demonstrated significant differences in the efficiency of Shine Dalgarno sequences acting at the leading gene and at the following genes in an operon. The majority of frequent intercistronic arrangements possess medium SD dependence, medium dependence on the preceding cistron translation and efficient stimulation by A/U-rich sequences. The second cistron starting immediately after preceding cistron stop codon displays unusually high dependence on the SD sequence. PMID- 23093606 TI - Translational fidelity maintenance preventing Ser mis-incorporation at Thr codon in protein from eukaryote. AB - Aminoacyl-tRNA synthetase (aaRS) catalyzes the first step of protein synthesis, producing aminoacyl-tRNAs as building blocks. Eukaryotic aaRS differs from its prokaryotic counterpart in terminal extension or insertion. Moreover, the editing function of aaRSs is an indispensable checkpoint excluding non-cognate amino acids at a given codon and ensuring overall translational fidelity. We found higher eukaryotes encode two cytoplasmic threonyl-tRNA synthetases (ThrRSs) with difference in N-terminus. The longer isoform is more closely related to the ThrRSs of higher eukaryotes than to those of lower eukaryotes. A yeast strain was generated to include deletion of the thrS gene encoding ThrRS. Combining in vitro biochemical and in vivo genetic data, ThrRSs from eukaryotic cytoplasm were systematically analyzed, and role of the eukaryotic cytoplasmic ThrRS-specific N terminal extension was elucidated. Furthermore, the mechanisms of aminoacylation and editing activity mediated by Saccharomyces cerevisiae ThrRS (ScThrRS) were clarified. Interestingly, yeast cells were tolerant of variation at the editing active sites of ScThrRS without significant Thr-to-Ser conversion in the proteome even under significant environmental stress, implying checkpoints downstream of aminoacylation to provide a further quality control mechanism for the yeast translation system. This study has provided the first comprehensive elucidation of the translational fidelity control mechanism of eukaryotic ThrRS. PMID- 23093608 TI - Discovering chimeric transcripts in paired-end RNA-seq data by using EricScript. AB - MOTIVATION: The discovery of novel gene fusions can lead to a better comprehension of cancer progression and development. The emergence of deep sequencing of trancriptome, known as RNA-seq, has opened many opportunities for the identification of this class of genomic alterations, leading to the discovery of novel chimeric transcripts in melanomas, breast cancers and lymphomas. Nowadays, few computational approaches have been developed for the detection of chimeric transcripts. Although all of these computational methods show good sensitivity, much work remains to reduce the huge number of false-positive calls that arises from this analysis. RESULTS: We proposed a novel computational framework, named chimEric tranScript detection algorithm (EricScript), for the identification of gene fusion products in paired-end RNA-seq data. Our simulation study on synthetic data demonstrates that EricScript enables to achieve higher sensitivity and specificity than existing methods with noticeably lower running times. We also applied our method to publicly available RNA-seq tumour datasets, and we showed its capability in rediscovering known gene fusions. PMID- 23093609 TI - Fast protein structure alignment using Gaussian overlap scoring of backbone peptide fragment similarity. AB - MOTIVATION: Aligning and comparing protein structures is important for understanding their evolutionary and functional relationships. With the rapid growth of protein structure databases in recent years, the need to align, superpose and compare protein structures rapidly and accurately has never been greater. Many structural alignment algorithms have been described in the past 20 years. However, achieving an algorithm that is both accurate and fast remains a considerable challenge. RESULTS: We have developed a novel protein structure alignment algorithm called 'Kpax', which exploits the highly predictable covalent geometry of C(alpha) atoms to define multiple local coordinate frames in which backbone peptide fragments may be oriented and compared using sensitive Gaussian overlap scoring functions. A global alignment and hence a structural superposition may then be found rapidly using dynamic programming with secondary structure-specific gap penalties. When superposing pairs of structures, Kpax tends to give tighter secondary structure overlays than several popular structure alignment algorithms. When searching the CATH database, Kpax is faster and more accurate than the very efficient Yakusa algorithm, and it gives almost the same high level of fold recognition as TM-Align while being more than 100 times faster. PMID- 23093607 TI - Chromatin acetylation at transcription start sites and vitamin D receptor binding regions relates to effects of 1alpha,25-dihydroxyvitamin D3 and histone deacetylase inhibitors on gene expression. AB - The nuclear hormone 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3) or 1,25D) regulates its target genes via activation of the transcription factor vitamin D receptor (VDR) far more specifically than the chromatin modifier trichostatin A (TsA) via its inhibitory action on histone deacetylases. We selected the thrombomodulin gene locus with its complex pattern of five VDR binding sites and multiple histone acetylation and open chromatin regions as an example to investigate together with a number of reference genes, the primary transcriptional responses to 1alpha,25(OH)(2)D(3) and TsA. Transcriptome-wide, 18.4% of all expressed genes are either up-or down-regulated already after a 90 min TsA treatment; their response pattern to 1alpha,25(OH)(2)D(3) and TsA sorts them into at least six classes. TsA stimulates a far higher number of genes than 1alpha,25(OH)(2)D(3) and dominates the outcome of combined treatments. However, 200 TsA target genes can be modulated by 1alpha,25(OH)(2)D(3) and more than 1000 genes respond only when treated with both compounds. The genomic view on the genes suggests that the degree of acetylation at transcription start sites and VDR binding regions may determine the effect of TsA on mRNA expression and its interference with 1alpha,25(OH)(2)D(3). Our findings hold true also for other HDAC inhibitors and may have implications on dual therapies using chromatin modifiers and nuclear receptor ligands. PMID- 23093610 TI - Genotype calling and phasing using next-generation sequencing reads and a haplotype scaffold. AB - MOTIVATION: Given the current costs of next-generation sequencing, large studies carry out low-coverage sequencing followed by application of methods that leverage linkage disequilibrium to infer genotypes. We propose a novel method that assumes study samples are sequenced at low coverage and genotyped on a genome-wide microarray, as in the 1000 Genomes Project (1KGP). We assume polymorphic sites have been detected from the sequencing data and that genotype likelihoods are available at these sites. We also assume that the microarray genotypes have been phased to construct a haplotype scaffold. We then phase each polymorphic site using an MCMC algorithm that iteratively updates the unobserved alleles based on the genotype likelihoods at that site and local haplotype information. We use a multivariate normal model to capture both allele frequency and linkage disequilibrium information around each site. When sequencing data are available from trios, Mendelian transmission constraints are easily accommodated into the updates. The method is highly parallelizable, as it analyses one position at a time. RESULTS: We illustrate the performance of the method compared with other methods using data from Phase 1 of the 1KGP in terms of genotype accuracy, phasing accuracy and downstream imputation performance. We show that the haplotype panel we infer in African samples, which was based on a trio-phased scaffold, increases downstream imputation accuracy for rare variants (R2 increases by >0.05 for minor allele frequency <1%), and this will translate into a boost in power to detect associations. These results highlight the value of incorporating microarray genotypes when calling variants from next-generation sequence data. AVAILABILITY: The method (called MVNcall) is implemented in a C++ program and is available from http://www.stats.ox.ac.uk/~marchini/#software. PMID- 23093612 TI - Letter by Arsava and Topcuoglu regarding article, "Ischemic brain injury following intracerebral hemorrhage--a critical review". PMID- 23093611 TI - A method for integrative structure determination of protein-protein complexes. AB - MOTIVATION: Structural characterization of protein interactions is necessary for understanding and modulating biological processes. On one hand, X-ray crystallography or NMR spectroscopy provide atomic resolution structures but the data collection process is typically long and the success rate is low. On the other hand, computational methods for modeling assembly structures from individual components frequently suffer from high false-positive rate, rarely resulting in a unique solution. RESULTS: Here, we present a combined approach that computationally integrates data from a variety of fast and accessible experimental techniques for rapid and accurate structure determination of protein protein complexes. The integrative method uses atomistic models of two interacting proteins and one or more datasets from five accessible experimental techniques: a small-angle X-ray scattering (SAXS) profile, 2D class average images from negative-stain electron microscopy micrographs (EM), a 3D density map from single-particle negative-stain EM, residue type content of the protein protein interface from NMR spectroscopy and chemical cross-linking detected by mass spectrometry. The method is tested on a docking benchmark consisting of 176 known complex structures and simulated experimental data. The near-native model is the top scoring one for up to 61% of benchmark cases depending on the included experimental datasets; in comparison to 10% for standard computational docking. We also collected SAXS, 2D class average images and 3D density map from negative stain EM to model the PCSK9 antigen-J16 Fab antibody complex, followed by validation of the model by a subsequently available X-ray crystallographic structure. PMID- 23093614 TI - Evidence-based community stroke rehabilitation. PMID- 23093613 TI - Reperfusion therapy in unclear-onset stroke based on MRI evaluation (RESTORE): a prospective multicenter study. AB - BACKGROUND AND PURPOSE: Unclear-onset strokes are generally excluded from time based thrombolytic therapy. We examined the safety and feasibility of magnetic resonance imaging-based reperfusion therapy in unclear-onset stroke. METHODS: This prospective, multicenter, single-arm study screened consecutive unclear onset stroke patients within 6 hours of symptom detection. Patients with perfusion-diffusion mismatch>20% and negative or subtle fluid-attenuated inversion recovery changes were treated with intravenous tissue plasminogen activator, intra-arterial therapy, or a combination. The safety outcome was symptomatic intracranial hemorrhage within 48 hours after treatment. The primary efficacy outcome was a 3-month modified Rankin Scale score of 0 to 2. Controls were untreated unclear-onset stroke patients prospectively captured in stroke registries. RESULTS: Of 430 unclear-onset stroke patients, 83 (19.3%) received reperfusion therapy (mean age, 67.5+/-10.4 years; males, 66.3%; median baseline National Institutes of Health Stroke Scale, 14). Symptomatic intracranial hemorrhage with any neurological decline developed in 5 patients (6.0%). Symptomatic intracranial hemorrhage with National Institutes of Health Stroke Scale worsening >=4 developed in 3 patients (3.6%). Thirty-seven patients (44.6%) achieved modified Rankin Scale score of 0 to 2, and 24 (28.9%) had modified Rankin Scale score of 0 to 1. Female, baseline National Institutes of Health Stroke Scale score, no immediate or early recanalization, and more white blood cells were independent predictors of poor outcome. Compared with untreated controls, the treated group was significantly associated with good outcomes of modified Rankin Scale score of 0 to 2 after adjusting for age, sex, and baseline National Institutes of Health Stroke Scale in logistic regression analysis (odds ratio, 2.25; 95% CI, 1.14-4.49). CONCLUSIONS: In unclear-onset stroke patients, magnetic resonance imaging-based reperfusion therapy was feasible and safe. Randomized controlled trials are warranted to confirm the benefit of reperfusion therapy for unclear-onset stroke. PMID- 23093615 TI - B vitamins and magnetic resonance imaging-detected ischemic brain lesions in patients with recent transient ischemic attack or stroke: the VITAmins TO Prevent Stroke (VITATOPS) MRI-substudy. AB - BACKGROUND AND PURPOSE: Elevated concentrations of homocysteine are associated with cerebral small vessel disease (CSVD). B-vitamin supplementation with folate and vitamins B12 and B6 reduces homocysteine concentrations. In a substudy of the VITAmins TO Prevent Stroke (VITATOPS) trial, we assessed the hypothesis that the addition of once-daily supplements of B vitamins would reduce the progression of CSVD-related brain lesions. METHODS: A total of 359 patients with recent stroke or transient ischemic attack, who were randomly allocated to double-blind treatment with placebo or b vitamins, underwent brain MRI at randomization and after 2 years of B-vitamin supplementation. MR images were analyzed blinded to treatment allocation. Outcomes related to the prespecified hypothesis were progression of white matter hyperintensities and incident lacunes. We also explored the effect of B-vitamin supplementation on the incidence of other ischemic abnormalities. RESULTS: After 2 years of treatment with b vitamins or placebo, there was no significant difference in white matter hyperintensities volume change (0.08 vs 0.13 cm3; P=0.419) and incidence of lacunes (8.0% vs 5.9%, P=0.434; odds ratio=1.38). In a subanalysis of patients with MRI evidence of severe CSVD at baseline, b-vitamin supplementation was associated with a significant reduction in white matter hyperintensities volume change (0.3 vs 1.7 cm3; P=0.039). CONCLUSIONS: Daily B-vitamin supplementation for 2 years did not significantly reduce the progression of brain lesions resulting from presumed CSVD in all patients with recent stroke or transient ischemic attack but may do so in the subgroup of patients with recent stroke or transient ischemic attack and severe CSVD. CLINICAL TRIAL REGISTRATION: http://vitatops.highway1.com.au/. Unique identifier: NCT00097669 and ISRCTN74743444. PMID- 23093616 TI - Comparing ticagrelor versus clopidogrel in patients with a history of cerebrovascular disease: a net clinical harm? PMID- 23093617 TI - Evaluation of choroidal thickness in retinitis pigmentosa using enhanced depth imaging optical coherence tomography. AB - OBJECTIVE: To describe the choroidal characteristics of patients with retinitis pigmentosa (RP) using enhanced depth imaging (EDI) and spectral domain (SD) optical coherence tomography (OCT). PURPOSE: To investigate the spectral-domain ocular coherence tomography features of the choroid in patients with RP using EDI. METHODS: A prospective, case-control study of 21 patients from the Cole Eye Institute with RP imaged using the Spectralis OCT and an EDI protocol. Submacular choroidal thickness measurements were obtained beneath the fovea and at 500 um intervals for 2.5 mm nasal and temporal to the centre of the fovea. These measurements were compared to choroidal thickness measurements from 25 healthy age-matched controls with similar refractive error range and no clinical evidence of retinal or glaucomatous disease. Statistical analysis was performed to compare choroidal thickness at each location between the two groups and to correlate choroidal thickness with best-corrected visual acuity and central retinal thickness. RESULTS: Mean ages were 40.6 years for control patients and 45.1 years for RP patients (p>0.05). Mean choroidal thickness measurements were 245.6+/-103 um in RP patients and 337.8.2+/-109 um in controls (p<0.0001). There was no correlation between subfoveal choroidal thickness and visual acuity or retinal thickness in the RP patients when compared to the control group. CONCLUSIONS: Submacular choroidal thickness, as measured by SD-OCT EDI, is significantly reduced in patients with RP, but did not correlate with visual acuity or retinal thickness in RP patients. Further research is needed to understand better the pathophysiological significance of the choroidal alterations present in RP. PMID- 23093618 TI - Regulation of multiple DNA repair pathways by the Fanconi anemia protein SLX4. AB - SLX4, the newly identified Fanconi anemia protein, FANCP, is implicated in repairing DNA damage induced by DNA interstrand cross-linking (ICL) agents, topoisomerase I (TOP1) inhibitors, and in Holliday junction resolution. It interacts with and enhances the activity of XPF-ERCC1, MUS81-EME1, and SLX1 nucleases, but the requirement for the specific nucleases in SLX4 function is unclear. Here, by complementing a null FA-P Fanconi anemia cell line with SLX4 mutants that specifically lack the interaction with each of the nucleases, we show that the SLX4-dependent XPF-ERCC1 activity is essential for ICL repair but is dispensable for repairing TOP1 inhibitor-induced DNA lesions. Conversely, MUS81-SLX4 interaction is critical for resistance to TOP1 inhibitors but is less important for ICL repair. Mutation of SLX4 that abrogates interaction with SLX1 results in partial resistance to both cross-linking agents and TOP1 inhibitors. These results demonstrate that SLX4 modulates multiple DNA repair pathways by regulating appropriate nucleases. PMID- 23093619 TI - Intraperitoneal influx of neutrophils in response to IL-33 is mast cell dependent. AB - IL-33 is a recently discovered cytokine involved in induction of Th2 responses and functions as an alarmin. Despite numerous recent studies targeting IL-33, its role in vivo is incompletely understood. Here we investigated inflammatory responses to intraperitoneal IL-33 injections in wild-type and mast cell deficient mice. We found that wild-type mice, but not mast cell-deficient W(sh)/W(sh) mice, respond to IL-33 treatment with neutrophil infiltration to the peritoneum, whereas other investigated cell types remained unchanged. In W(sh)/W(sh) mice, the IL-33-induced innate neutrophil response could be rescued by local reconstitution with wild-type but not with T1/ST2(-/-) mast cells, demonstrating a mast cell-dependent mechanism. Furthermore, we found this mechanism to be partially dependent on mast cell-derived TNF, as we observed reduced neutrophil infiltration in W(sh)/W(sh) mice reconstituted with TNF(-/-) bone marrow-derived mast cells compared with those reconstituted with wild-type bone marrow-derived mast cells. In agreement with our in vivo findings, we demonstrate that human neutrophils migrate toward the supernatant of IL-33 treated human mast cells. Taken together, our findings reveal that IL-33 activates mast cells in vivo to recruit neutrophils, a mechanism dependent on IL 33R expression on peritoneal mast cells. Mast cells activated in vivo by IL-33 probably play an important role in inflammatory reactions. PMID- 23093620 TI - Fcgamma receptor antigen targeting potentiates cross-presentation by human blood and lymphoid tissue BDCA-3+ dendritic cells. AB - The reactivation of human cytomegalovirus (HCMV) poses a serious health threat to immune compromised individuals. As a treatment strategy, dendritic cell (DC) vaccination trials are ongoing. Recent work suggests that BDCA-3(+) (CD141(+)) subset DCs may be particularly effective in DC vaccination trials. BDCA-3(+) DCs had however been mostly characterized for their ability to cross-present antigen from necrotic cells. We here describe our study of human BDCA-3(+) DCs in elicitation of HCMV-specific CD8(+) T-cell clones. We show that Fcgamma-receptor (FcgammaR) antigen targeting facilitates antigen cross-presentation in several DC subsets, including BDCA-3(+) DCs. FcgammaR antigen targeting stimulates antigen uptake by BDCA-1(+) rather than BDCA-3(+) DCs. Conversely, BDCA-3(+) DCs and not BDCA-1(+) DCs show improved cross-presentation by FcgammaR targeting, as measured by induced release of IFNgamma and TNF by antigen-specific CD8(+) T cells. FcgammaR-facilitated cross-presentation requires antigen processing in both an acidic endosomal compartment and by the proteasome, and did not induce substantial DC maturation. FcgammaRII is the most abundantly expressed FcgammaR on both BDCA-1(+) and BDCA-3(+) DCs. Furthermore we show that BDCA-3(+) DCs express relatively more stimulatory FcgammaRIIa than inhibitory FcgammaRIIb in comparison with BDCA-1(+) DCs. These studies support the exploration of FcgammaR antigen targeting to BDCA-3(+) DCs for human vaccination purposes. PMID- 23093621 TI - Unwinding the von Willebrand factor strings puzzle. AB - von Willebrand factor (VWF) is amongst others synthesized by endothelial cells and stored as ultra-large (UL) VWF multimers in Weibel-Palade bodies. Although UL VWF is proteolysed by ADAMTS13 (a disintegrin-like and metalloprotease domain with thrombospondin type-1 motif, number 13) on secretion from endothelial cells, in vitro experiments in the absence of ADAMTS13 have demonstrated that a proportion of these UL-VWF multimers remain anchored to the activated endothelium. These multimers unravel, bind platelets, and wave in the direction of the flow. These so-called VWF "strings" have also been visualized in vivo, lining the lumen of activated mesenteric veins of Adamts13(-/-) mice. Various studies have demonstrated the extraordinary length of these VWF strings, the availability of their platelet binding and ADAMTS13 cleavage sites, and the possible nature of their endothelial attachment. VWF strings are also capable of tethering leukocytes and parasite-infected red blood cells. However, the majority of studies have been performed in the absence of ADAMTS13, a condition only experienced in thrombotic thrombocytopenic purpura. A normal functional role of VWF strings in healthy persons or in other disease pathologies remains unclear. In this review, we discuss some of the puzzling characteristics of VWF strings, and we debate whether the properties of VWF strings in the absence of ADAMTS13 might be relevant for understanding (patho)physiologic mechanisms. PMID- 23093622 TI - Biosimilars: what clinicians should know. AB - Biosimilar medicinal products (biosimilars) have become a reality in the European Union and will soon be available in the United States. Despite an established legal pathway for biosimilars in the European Union since 2005 and increasing and detailed regulatory guidance on data requirements for their development and licensing, many clinicians, particularly oncologists, are reluctant to consider biosimilars as a treatment option for their patients. Major concerns voiced about biosimilars relate to their pharmaceutical quality, safety (especially immunogenicity), efficacy (particularly in extrapolated indications), and interchangeability with the originator product. In this article, the members and experts of the Working Party on Similar Biologic Medicinal Products of the European Medicines Agency (EMA) address these issues. A clear understanding of the scientific principles of the biosimilar concept and access to unbiased information on licensed biosimilars are important for physicians to make informed and appropriate treatment choices for their patients. This will become even more important with the advent of biosimilar monoclonal antibodies. The issues also highlight the need for improved communication between physicians, learned societies, and regulators. PMID- 23093623 TI - Connecting with prostate cancer survivors. PMID- 23093625 TI - L'AUC - etendre sa portee. PMID- 23093624 TI - Se rapprocher avec les survivants de la cancer de la prostate. PMID- 23093626 TI - The CUA extending its reach. PMID- 23093628 TI - A unique case of an alpha-fetoprotein-producing lung cancer with testicular metastasis. AB - Alpha-fetoprotein (AFP)-producing primary lung tumours are rare; we present the first case of an AFP-producing lung tumour with metastasis to testes. The patient, a 72-year-old man, presented with a history of flu-like symptoms and abdominal pain. On examination he had a hard, tender left scrotal mass. Imaging showed a 4.4-cm right lower lobe lung mass and the serum-AFP was raised (1189 ng/mL). Left orchidectomy excised a necrotic tumour. Microscopy showed complete hemorrhagic infarction and immunohistochemistry showed a lack of staining for AFP. Serum-AFP rose 3 days post-orchidectomy to 1466 ng/mL. The patient subsequently developed melaena and died. Autopsy revealed a 9 * 5-cm necrotic right lower lobe lung tumour. Immunohistochemistry showed the tumour cells reacted with a pan-cytokeratin antibody and less than 5% expressed AFP. Bilateral adrenal tumour deposits were also identified in addition to those in the bowel and spleen. The expression of AFP solely in the lung lesion and lack of expression in both testes, together with a rise in serum-AFP post-orchidectomy and the bilateral adrenal metastases, is overwhelming evidence for the reversal of the usual situation: a poorly differentiated AFP-secreting metastatic lung adenocarcinoma. PMID- 23093627 TI - 2012 update: guidelines for adult urinary incontinence collaborative consensus document for the canadian urological association. PMID- 23093629 TI - Challenging the 10-year rule: The accuracy of patient life expectancy predictions by physicians in relation to prostate cancer management. AB - INTRODUCTION: : We assess physicians' ability to accurately predict life expectancies. In prostate cancer this prediction is especially important as it affects screening decisions. No previous studies have examined accuracy in the context of real cases and concrete end points. METHODS: : Seven clinical scenarios were summarized from charts of deceased patients. We recruited 100 medical professionals to review these scenarios and estimate each patient's life expectancy. Responses were analyzed with respect to the patients' actual survival end points, then stratified based on the demographic information provided. RESULTS: : Respondent factors, such as sex, level of training, location of work or specialty, made no significant difference on prediction accuracy. Furthermore, respondents were typically pessimistic in their estimations with a negative linear trend between estimated life expectancy and actual survival. Overall, respondents were within 1 year of actual life expectancy only 15.9% of the time; on average, respondents were 67.4% inaccurate in relation to actual survival. If framed in terms of correctly identifying which patients would live more than or less than 10 years (dichotomous accuracy), physicians were correct 68.3% of the time. CONCLUSIONS: : Physicians do poorly at predicting life expectancy and tend to underestimate how long patients have left to live. This overall inaccuracy raises the question of whether physicians should refine screening and treatment criteria, find a better proxy or dispose of the criteria altogether. PMID- 23093630 TI - Life expectancy estimation in prostate cancer patients. PMID- 23093631 TI - Should peritoneal dialysis catheters be removed at the time of kidney transplantation? AB - BACKGROUND: : Delayed graft function (DGF) following transplantation necessitates support in the form of hemodialyis (HD) or peritoneal dialysis (PD). However, post-transplant PD-related complication and failure rates are unknown. METHODS: : We studies patients who were on PD at the time of kidney transplantation over a 4 year period at two separate institutions. RESULTS: : Of the 137 PD patients, 19 had their catheters removed at the time of transplant. Of the remaining 118 patients, 89% had immediate graft function. PD-related complications in this group included peritonitis (n=5), catheter-related infections (n=2) and emergency laparotomy (n=1). Of the 15 patients requiring post-transplant PD, 33% developed peritonitis and 20% had fluid-leaks necessitating HD. Overall, leaving a PD catheter in situ post- transplantation is associated with 7% rate of peritonitis versus 0% if removed (p < 0.05). CONCLUSIONS: : PD catheter removal should be considered at the time of renal transplantation, as postoperative PD-related failure/complication rates are high. PMID- 23093632 TI - The PD catheter dilemma. PMID- 23093633 TI - Evolving therapeutic strategies for premature ejaculation: The search for on demand treatment - topical versus systemic. AB - Premature ejaculation (PE) is a common sexual dysfunction affecting 20% to 30% of men worldwide. Definitions of PE vary, but it is typically characterized by short intravaginal ejaculatory latency time (IELT) with concomitant sexual dissatisfaction and distress. PE may be lifelong or acquired, but its etiology remains unclear. Treatment of PE typically involves pharmacotherapy, particularly when lifelong. Although there are numerous reports on the off-label use of selective serotonin reuptake inhibitors (SSRIs) and other compounds, only 2 treatments have been evaluated in randomized controlled phase 3 clinical trials: PSD502 and dapoxetine (SSRI). Both significantly improved IELT and patient reported outcome domains of ejaculatory control, sexual satisfaction, and distress as measured by the index of premature ejaculation (IPE), compared with placebo. They constitute the focus of this review. Evidence demonstrated that PSD502, dapoxetine and other SSRIs all significantly improve the symptoms of PE. Systemic use of SSRIs presents risks associated with the known pharmacology of this class. PSD502 allows for topical on-demand treatment applied applied immediately before intercourse, and is not associated with systemic adverse events. PMID- 23093635 TI - The management of high-risk, locally advanced, prostate cancer radiation therapy. PMID- 23093634 TI - Spontaneous fracture of indwelling polyurethane ureteral stents: A case series and review of literature. AB - Polyurethane, due to its low cost, high versatility and availability, it commonly used for ureteral stents. Spontaneous fracture of these stents is rare, and the most dreaded complication. We present four cases of spontaneous fracture of indwelling polyurethane ureteral stents and review the literature to identify potential factors and preventive strategies. PMID- 23093636 TI - Radical prostatectomy is the most cost-effective primary treatment modality for men diagnosed with high-risk prostate cancer. PMID- 23093641 TI - Metastatic urothelial carcinoma to pericardia manifested by dyspnea from cardiac tamponade during systemic chemotherapy: Case report and literature review. AB - A 53-year-old man presented for further evaluation due to microscopic hematuria and left lumbar pain. Computed tomography revealed a large tumour in the left renal pelvis with multiple metastases. Despite effective systemic chemotherapy, he developed dyspnea, and was diagnosed with cardiac tamponade. Pericardial involvement in an advanced malignancy is common, but symptomatic cardiac metastasis from urothelial carcinoma is rare. Of the reports of symptomatic cardiac metastasis from urothelial carcinoma, only 3 cases presented as cardiac tamponade. We report here a rare case of cardiac tamponade caused by a renal pelvic carcinoma with positive cytodiagnosis of pericardial effusion. We also summarize and discuss the symptoms, treatment, and prognosis of the pathological condition, and present a brief review of previously published reports. PMID- 23093642 TI - Primary adrenocortical sarcomatoid carcinoma: Report of a case. AB - We report the case of a 72-year-old man with a right adrenocortical mass who had undergone complete tumour excision with the adrenal gland and around adipose tissue. Pathologic examination led to a final diagnosis of primary sarcomatoid carcinoma of the right adrenal gland. The patient was without recurrence at the one year follow-up. To our knowledge, this is the first case in China and the second reported case in English published studies. PMID- 23093643 TI - Acute urinary retention due to cystic echinococcosis: A case report. AB - Urinary hydatidosis is very rare and represents 2% to 4% of all cases of cystic echinococcosis. We present a case of a 21-year-old man with symptoms of frequency, urinary retention and reduced force in urinary stream due to cystic echinococcosis. Anti-Echinococcus granulosus antibodies were determined by echinococcosis western blotting, and pelvic computed tomography revealed a 11 * 14 * 10-cm retrovesical homogeneous cystic mass. The patient underwent surgical intervention; the cystic mass and retrovesical cavity were removed. After a 3 year follow-up period, there was no episode of lower urinary tract symptoms. This case illustrates that cystic echinococcosis should be considered in every case of cystic mass, especially in endemic countries, such as Turkey. PMID- 23093644 TI - Essential role of using virtual pyeloscopy in the diagnosis of small satellite renal pelvic tumour in solitary kidney patient. AB - Virtual pyeloscopy (VP) plays an important role in the organ-sparing nephroscopic tumour resection and traditional pole resection, especially when a fibreoptic ureteroscopic examination cannot be performed. A 67-year-old man developed macroscopic hematuria. Abdominal computed tomography (CT) and cystoscopy revealed a lower calix renal stone and a 20-mm lower pyelon mass suggesting transitional cell cancer. An additional small satellite lesion in the pelvico-ureteral junction was supposedly present. Three-phase MultiDetector CT with VP showed a solitary 3 to 4-mm renal pelvic lesion beyond the known calix stone and lower pole mass. In our case, VP played an important role in the organ-sparing nephroscopic tumour resection and traditional pole resection. PMID- 23093646 TI - Spontaneous regression of biopsy proven primary renal cell carcinoma: A case study. AB - Spontaneous regression of renal cell carcinoma (RCC) is a well-recognized and interesting phenomenon that is poorly understood and rarely documented. There are very few reported cases of spontaneously regressed primary RCC. We present a 63 year-old male with a biopsy-proven RCC that regressed with complete resolution of symptoms. PMID- 23093645 TI - Buried penis: An unrecognized risk factor in the development of invasive penile cancer. AB - One of the documented benefits of neonatal circumcision is protection against invasive penile cancer. To date there have been a handful of published cases of invasive penile cancer in men circumcised as neonates. We report a case of a 73 year-old man, with a history of neonatal circumcision with no evidence of previous human papillomavirus exposure, who developed a buried penis secondary to obesity. He was diagnosed with Grade 2, pT3N0 squamous cell carcinoma of the penis. This report suggests that buried penis may pose a risk factor for the development of penile cancer despite the protective effects of neonatal circumcision. Thus periodic examination of a buried penis is warranted even in patients with no risk factors for penile cancer. A review of the literature is provided. PMID- 23093647 TI - Incidentally detected bilaterally symmetrical seminal and vas calcification in young infertile male: a case report, literature review and algorithm for diagnosis. AB - Bilateral seminal and vas calcification is not common, especially in young age. Association with many disease conditions has been described, with diabetes mellitus being the most common association. A 34-year-old man presented with primary infertility and right upper ureteric calculus. His evaluation revealed extensive, bilateral seminal and vas calcification with normal semen analysis and first-time detected diabetes mellitus. His female partner was evaluated and found to have bilateral fallopian tubes blockage. We reviewed the literature and present here the algorithm for diagnosis of such patients, along with details of this particular patient. PMID- 23093648 TI - Metastases of renal cell carcinoma to the larynx and thyroid: Two case reports on metastasis developing years after nephrectomy. AB - Renal cell carcinoma (RCC) has a high metastatic potential due to its hematogen and vascular features. It metastasizes frequently to the lungs, the bones, the liver, the lymph nodes and the brain. Metastasis of RCC to the head and neck region is quite rare. In this case report, two RCC patients with head and neck metastases are presented: one occurring after 5 years and the other occurring 17 years after diagnosis. PMID- 23093649 TI - Proteolytic activity in cowshed dust extracts induces C5a release in murine bronchoalveolar lavage fluids which may account for its protective properties in allergic airway inflammation. AB - OBJECTIVE: Intranasal application of cowshed dust extract (CDE) during sensitisation in a murine model of experimental asthma leads to a significant alleviation of the clinical parameters of the allergic immune response. However, neither the immunological mechanisms underlying this protective effect nor all of the protective substances included in CDE have yet been described. Recently, complement factor 5a (C5a) receptor signalling has been identified to play a regulatory role in allergic airway disease. Thus we investigated whether CDE can activate the complement system to release biologically active C5a in the lung. METHODS: Proteins included in CDE were identified by mass spectrometry. Complement cleaving activity of a serine protease identified in CDE was validated with the purified enzyme, and the biological activity of the released C5a was determined. C5a was applied in a murine model of allergy to prove its protective impact on allergic airway disease. RESULTS: CDE induced the release of C5a in murine bronchoalveolar lavages (BAL). We identified a serine protease from the midgut of tenebrio molitor larvae in CDEs which was able to induce the release of biologically active C5a in murine BAL. We applied C5a in different doses to female Balb/c mice during the sensitisation phase and during the first antigen challenge and showed that C5a has the ability to dampen important parameters of allergic airway inflammation, such as infiltration of proinflammatory cells into lung tissue or Th2 cytokine secretion by lung cells. CONCLUSIONS: We conclude that the C5a generating enzyme included in CDE might account for some of the allergy protective effects of CDE by generation of C5a in murine lungs. PMID- 23093650 TI - Novel insights into immune and inflammatory responses to respiratory viruses. AB - Viral lower respiratory tract infection (LRTI) can lead to severe disease at all ages, but with the exception of influenza vaccination, prevention is not available for most respiratory viruses, hence, effective, disease-limiting therapy is urgently required. To enable the development of novel effective therapeutic approaches, we need to improve understanding of the pathological mechanisms of viral LRTI. Here, we will discuss recently gained new insight into early, innate immune and inflammatory responses to respiratory viruses by airway epithelial cells and mucosal immune cells. Following virus recognition, these cells generate a range of mediators, including innate interferons, proinflammatory cytokines, and growth and differentiation factors which have pivotal roles in effective virus control, and the development of inflammation and disease in viral LRTI. PMID- 23093651 TI - Airway inflammation in patients with chronic non-asthmatic cough. AB - INTRODUCTION: Chronic non-asthmatic cough (CC) is a clinical challenge and underlying pathophysiological mechanisms remain still not completely understood. One of the most common comorbidities in CC is gastro-oesophageal reflux disease (GORD). Airway epithelium damage can contribute to airway inflammation in CC. AIMS: We studied airway inflammation in patients with CC compared to healthy controls. Patients with GORD were treated with proton pump inhibitors (PPI) and cough response to PPI was evaluated. PATIENTS AND METHODS: Sputum was induced in 41 adults with CC and 20 healthy non-smokers who were age and sex matched. We compared sputum differential cell count by cytospin and cytokine and chemokine production at the mRNA and/or protein levels by real-time (RT)-PCR and cytokine bead array (CBA), between patients with CC and healthy subjects. Furthermore we studied airway inflammation in patients with different comorbidities. RESULTS: No differences in sputum differential cell counts were observed between patients with CC and healthy subjects. Sputum monocyte chemoattractant protein-1 (MCP-1) protein levels were significantly higher in patients when compared to controls. Thymic stromal lymphopoietin (TSLP) mRNA was significantly more often expressed in sputum of patients with CC than from healthy controls. Sputum transforming growth factor (TGF)-beta levels did not differ between patients and controls, but were significantly lower in the PPI responders compared to the non-responders; p=0.047. There is no evidence for impaired T helper cell (Th)1/Th2/Th17 balance in CC. Patients with reflux oesophagitis (RO) have significantly more sputum eosinophils than patients without RO. CONCLUSIONS: CC is a condition presenting with different disease phenotypes. High sputum MCP-1 levels are present in a large group of patients with CC and a majority of these patients with CC have increased sputum TSLP levels, most likely produced by damaged airway epithelial cells. PMID- 23093652 TI - IL-25 drives remodelling in allergic airways disease induced by house dust mite. AB - BACKGROUND: Overexpression of the transforming growth factor beta family signalling molecule smad2 in the airway epithelium provokes enhanced allergen induced airway remodelling in mice, concomitant with elevated levels of interleukin (IL)-25. OBJECTIVE: We investigated whether IL-25 plays an active role in driving this airway remodelling. METHODS: Anti-IL-25 antibody was given to mice exposed to either inhaled house dust mite (HDM) alone, or in conjunction with an adenoviral smad2 vector which promotes an enhanced remodelling phenotype. RESULTS: Blocking IL-25 in allergen-exposed mice resulted in a moderate reduction in pulmonary eosinophilia and levels of T helper type 2 associated cytokines, IL 5 and IL-13. In addition, IL-25 neutralisation abrogated peribronchial collagen deposition, airway smooth muscle hyperplasia and airway hyperreactivity in control mice exposed to HDM and smad2-overexpressing mice. IL-25 was shown to act directly on human fibroblasts to induce collagen secretion. Recruitment of endothelial progenitor cells to the lung and subsequent neovascularisation was also IL-25 dependent, demonstrating a direct role for IL-25 during angiogenesis in vivo. Moreover, the secretion of innate epithelial derived cytokines IL-33 and thymic stromal lymphopoietin (TSLP) was completely ablated. CONCLUSIONS: In addition to modulating acute inflammation, we now demonstrate a role for IL-25 in orchestrating airway remodelling. IL-25 also drives IL-33 and TSLP production in the lung. These data delineate a wider role for IL-25 in mediating structural changes to the lung following allergen exposure and implicate IL-25 as a novel therapeutic target for the treatment of airway remodelling in asthma. PMID- 23093653 TI - Understanding the elusive mechanism of action of TCF7L2 in metabolism. PMID- 23093654 TI - Seeing is believing: dietary fatty acids hurry up from the stomach to the heart of patients with impaired glucose tolerance. PMID- 23093655 TI - Muscle perfusion: its measurement and role in metabolic regulation. PMID- 23093656 TI - 31P-magnetization transfer magnetic resonance spectroscopy measurements of in vivo metabolism. AB - Magnetic resonance spectroscopy offers a broad range of noninvasive analytical methods for investigating metabolism in vivo. Of these, the magnetization transfer (MT) techniques permit the estimation of the unidirectional fluxes associated with metabolic exchange reactions. Phosphorus (31P) MT measurements can be used to examine the bioenergetic reactions of the creatine-kinase system and the ATP synthesis/hydrolysis cycle. Observations from our group and others suggest that the inorganic phosphate (P(i)) -> ATP flux in skeletal muscle may be modulated by certain conditions, including aging, insulin resistance, and diabetes, and may reflect inherent alterations in mitochondrial metabolism. However, such effects on the P(i) -> ATP flux are not universally observed under conditions in which mitochondrial function, assessed by other techniques, is impaired, and recent articles have raised concerns about the absolute magnitude of the measured reaction rates. As the application of 31P-MT techniques becomes more widespread, this article reviews the methodology and outlines our experience with its implementation in a variety of models in vivo. Also discussed are potential limitations of the technique, complementary methods for assessing oxidative metabolism, and whether the P(i) -> ATP flux is a viable biomarker of metabolic function in vivo. PMID- 23093657 TI - Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. AB - Impaired cardiac systolic and diastolic function has been observed in preclinical models and in subjects with type 2 diabetes. Using a recently validated positron emission tomography (PET) imaging method with 14(R,S)-[(18F]-fluoro-6-thia heptadecanoic acid to quantify organ-specific dietary fatty acid partitioning, we demonstrate in this study that overweight and obese subjects with impaired glucose tolerance (IGT+) display significant increase in fractional myocardial dietary fatty acid uptake over the first 6 h postprandial compared with control individuals (IGT-). Measured by [11C]acetate with PET, IGT+ subjects have a significant increase in myocardial oxidative index. IGT+ subjects have significantly reduced left ventricular stroke volume and ejection fraction (LVEF) and tend to display impaired diastolic function, as assessed by PET ventriculography. We demonstrate an inverse relationship between increased myocardial dietary fatty acid partitioning and LVEF. Fractional dietary fatty acid uptake is reduced in subcutaneous abdominal and visceral adipose tissues in IGT+ directly associated with central obesity. Fractional dietary fatty acid uptake in skeletal muscles or liver is, however, similar in IGT+ versus IGT-. The current study demonstrates, for the first time, that excessive myocardial partitioning of dietary fatty acids occurs in prediabetic individuals and is associated with early impairment of left ventricular function and increased myocardial oxidative metabolism. PMID- 23093658 TI - Vegfa protects the glomerular microvasculature in diabetes. AB - Vascular endothelial growth factor A (VEGFA) expression is increased in glomeruli in the context of diabetes. Here, we tested the hypothesis that this upregulation of VEGFA protects the glomerular microvasculature in diabetes and that therefore inhibition of VEGFA will accelerate nephropathy. To determine the role of glomerular Vegfa in the development and progression of diabetic nephropathy, we used an inducible Cre-loxP gene-targeting system that enabled genetic deletion of Vegfa selectively from glomerular podocytes of wild-type or diabetic mice. Type 1 diabetes was induced in mice using streptozotocin (STZ). We then assessed the extent of glomerular dysfunction by measuring proteinuria, glomerular pathology, and glomerular cell apoptosis. Vegfa expression increased in podocytes in the STZ model of diabetes. After 7 weeks of diabetes, diabetic mice lacking Vegfa in podocytes exhibited significantly greater proteinuria with profound glomerular scarring and increased apoptosis compared with control mice with diabetes or Vegfa deletion without diabetes. Reduced local production of glomerular Vegfa in a mouse model of type 1 diabetes promotes endothelial injury accelerating the progression of glomerular injury. These results suggest that upregulation of VEGFA in diabetic kidneys protects the microvasculature from injury and that reduction of VEGFA in diabetes may be harmful. PMID- 23093662 TI - Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy. AB - OBJECTIVE: The aim of this study was to evaluate the association of urinary cystatin C, a tubular damage marker, with the progression of type 2 diabetic nephropathy. RESERCH DESIGN AND METHODS: The baseline values of serum and urinary cystatin C were measured as primary parameters and those of urinary nonalbumin protein (NAP) were measured as secondary parameters. In this prospective observational study, a total of 237 type 2 diabetic patients were followed up for 29 months (13-44 months). RESULTS: Both the urinary cystatin C-to-creatinine ratio (CCR) and NAP-to-creatinine ratio (NAPCR) were significantly different according to the degree of albuminuria. Both markers had strongly positive correlations at baseline. After adjusting for several clinical factors, both urinary CCR and NAPCR had significant associations with the decline of the estimated glomerular filtration rate (eGFR) (r = 0.160, P = 0.021; r = 0.412, P < 0.001, respectively). Urinary CCR had positive correlations with the decline of eGFR in the subpopulation of patients with eGFR >=60 mL/min/1.73 m(2). In patients with eGFR >=60 mL/min/1.73 m(2) and normoalbuminuria, only urinary NAPCR showed a significant association with the decline of eGFR; urinary CCR did not. In multivariate regression analysis, the number of patients who progressed to chronic kidney disease stage 3 or greater was higher in those in the upper tertiles of both the urinary levels of cystatin C and NAP than in those in the lower tertiles. CONCLUSIONS: The results of this study suggest that urinary cystatin C and NAP may be predictors of the progression of type 2 diabetic nephropathy. PMID- 23093661 TI - Comparison of BMI and physical activity between old order Amish children and non Amish children. AB - OBJECTIVE: The Old Order Amish (OOA) is a conservative Christian sect of European origin living in Pennsylvania. Diabetes is rare in adult OOA despite a mean BMI rivaling that in the general U.S. non-Hispanic white population. The current study examines childhood factors that may contribute to the low prevalence of diabetes in the OOA by comparing OOA children aged 8-19 years with National Health and Nutrition Examination Survey (NHANES) data and children from Maryland's Eastern Shore (ES), a nearby, non-Amish, rural community. We hypothesized that pediatric overweight is less common in OOA children, that physical activity (PA) and BMI are inversely correlated, and that OOA children are more physically active than ES children. RESEARCH DESIGN AND METHODS: We obtained anthropometric data in 270 OOA children and 229 ES children (166 non Hispanic white, 60 non-Hispanic black, 3 Hispanic). PA was measured by hip-worn accelerometers in all ES children and in 198 OOA children. Instrumentation in 43 OOA children was identical to ES children. RESULTS: OOA children were approximately 3.3 times less likely than non-Hispanic white ES children and NHANES estimates to be overweight (BMI >=85th percentile, Centers for Disease Control and Prevention). Time spent in moderate/vigorous PA (MVPA) was inversely correlated to BMI z-score (r = -0.24, P = 0.0006). PA levels did not differ by ethnicity within the ES group, but OOA children spent an additional 34 min/day in light activity (442 +/- 56 vs. 408 +/- 75, P = 0.005) and, impressively, an additional 53 min/day in MVPA (106 +/- 54 vs. 53 +/- 32, P < 0.0001) compared with ES children. In both groups, boys were more active than girls but OOA girls were easily more active than ES boys. CONCLUSIONS: We confirmed all three hypotheses. Together with our previous data, the study implies that the OOA tend to gain their excess weight relatively late in life and that OOA children are very physically active, both of which may provide some long-term protection against diabetes. PMID- 23093663 TI - Metabolic syndrome risk profiles among African American adolescents: national health and nutrition examination survey, 2003-2010. AB - OBJECTIVE: Although African American adolescents have the highest prevalence of obesity, they have the lowest prevalence of metabolic syndrome across all definitions used in previous research. To address this paradox, we sought to develop a model of the metabolic syndrome specific to African American adolescents. RESEARCH DESIGN AND METHODS: Data from the National Health and Nutrition Examination Survey (2003-2010) of 822 nonpregnant, nondiabetic, African American adolescents (45% girls; aged 12 to 17 years) who underwent physical examinations and fasted at least 8 h were analyzed. We conducted a confirmatory factor analysis to model metabolic syndrome and then used latent profile analysis to identify metabolic syndrome risk groups among African American adolescents. We compared the risk groups on probability of prediabetes. RESULTS: The best-fitting metabolic syndrome model consisted of waist circumference, fasting insulin, HDL, and systolic blood pressure. We identified three metabolic syndrome risk groups: low, moderate, and high risk (19% boys; 16% girls). Thirty-five percent of both boys and girls in the high-risk groups had prediabetes, a significantly higher prevalence compared with boys and girls in the low-risk groups. Among adolescents with BMI higher than the 85th percentile, 48 and 36% of boys and girls, respectively, were in the high-risk group. CONCLUSIONS: Our findings provide a plausible model of the metabolic syndrome specific to African American adolescents. Based on this model, approximately 19 and 16% of African American boys and girls, respectively, are at high risk for having the metabolic syndrome. PMID- 23093664 TI - Plasma exposure to insulin glargine and its metabolites M1 and M2 after subcutaneous injection of therapeutic and supratherapeutic doses of glargine in subjects with type 1 diabetes. AB - OBJECTIVE: In vivo, after subcutaneous injection, insulin glargine (21(A)-Gly 31(B)-Arg-32(B)-Arg-human insulin) is enzymatically processed into 21(A)-Gly human insulin (metabolite 1 [M1]). 21(A)-Gly-des-30(B)-Thr-human insulin (metabolite 2 [M2]) is also found. In vitro, glargine exhibits slightly higher affinity, whereas M1 and M2 exhibit lower affinity for IGF-1 receptor, as well as mitogenic properties, versus human insulin. The aim of the study was to quantitate plasma concentrations of glargine, M1, and M2 after subcutaneous injection of glargine in male type 1 diabetic subjects. RESEARCH DESIGN AND METHODS: Glargine, M1, and M2 were determined in blood samples obtained from 12, 11, and 11 type 1 diabetic subjects who received single subcutaneous doses of 0.3, 0.6, or 1.2 units . kg(-1) glargine in a euglycemic clamp study. Glargine, M1, and M2 were extracted using immunoaffinity columns and quantified by a specific liquid chromatography-tandem mass spectrometry assay. Lower limit of quantification was 0.2 ng . mL(-1) (33 pmol . L(-1)) per analyte. RESULTS: Plasma M1 concentration increased with increasing dose; geometric mean (percent coefficient of variation) M1-area under the curve between time of dosing and 30 h after dosing (AUC(0-30h)) was 1,261 (66), 2,867 (35), and 4,693 (22) pmol . h . L(-1) at doses of 0.3, 0.6, and 1.2 units . kg(-1), respectively, and correlated with metabolic effect assessed as pharmacodynamics-AUC(0-30h) of the glucose infusion rate following glargine administration (r = 0.74; P < 0.01). Glargine and M2 were detectable in only one-third of subjects and at a few time points. CONCLUSIONS: After subcutaneous injection of glargine in male subjects with type 1 diabetes, exposure to glargine is marginal, if any, even at supratherapeutic doses. Glargine is rapidly and nearly completely processed to M1 (21(A)-Gly-human insulin), which mediates the metabolic effect of injected glargine. PMID- 23093665 TI - Methane generation during experimental serpentinization of olivine. PMID- 23093666 TI - Arrow poisons in the Palaeolithic? PMID- 23093668 TI - Early Solar System hydrothermal activity in chondritic asteroids on 1-10-year timescales. AB - Chondritic meteorites are considered the most primitive remnants of planetesimals from the early Solar System. As undifferentiated objects, they also display widespread evidence of water-rock interaction on the parent body. Understanding this history has implications for the formation of planetary bodies, the delivery of water to the inner Solar System, and the formation of prebiotic molecules. The timescales of water-rock reactions in these early objects, however, are largely unknown. Here, we report evidence for short-lived water-rock reactions in the highly metamorphosed ordinary chondrite breccia Villalbeto de la Pena (L6). An exotic clast (d = 2cm) has coexisting variations in feldspar composition and oxygen isotope ratios that can only result from hydrothermal conditions. The profiles were modeled at T = 800 degrees C and P(H(2)O) = 1 bar using modified grain-boundary diffusion parameters for oxygen self-diffusion and reaction rates of NaSiCa(-1)Al(-1) exchange in a fumarole. The geochemical data are consistent with hydrothermal activity on the parent body lasting only 1-10 y. This result has wide-ranging implications for the geological history of chondritic asteroids. PMID- 23093667 TI - Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. AB - Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M. tuberculosis infection of Atg5(fl/fl) LysM-Cre(+) mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophil infiltration and IL-17 response with increased IL-1alpha levels. Macrophages from uninfected Atg5(fl/fl) LysM-Cre(+) mice displayed a cell-autonomous IL-1alpha hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation. PMID- 23093669 TI - Hyperactive self-inactivating piggyBac for transposase-enhanced pronuclear microinjection transgenesis. AB - We have developed a unique method for mouse transgenesis. The transposase enhanced pronuclear microinjection (PNI) technique described herein uses the hyperactive piggyBac transposase to insert a large transgene into the mouse genome. This procedure increased transgene integration efficiency by fivefold compared with conventional PNI or intracytoplasmic sperm injection-mediated transgenesis. Our data indicate that the transposase-enhanced PNI technique additionally requires fewer embryos to be microinjected than traditional methods to obtain transgenic animals. This transposase-mediated approach is also very efficient for single-cell embryo cytoplasmic injections, offering an easy-to implement transgenesis method to the scientific community. PMID- 23093670 TI - Phase competition in trisected superconducting dome. AB - A detailed phenomenology of low energy excitations is a crucial starting point for microscopic understanding of complex materials, such as the cuprate high temperature superconductors. Because of its unique momentum-space discrimination, angle-resolved photoemission spectroscopy (ARPES) is ideally suited for this task in the cuprates, where emergent phases, particularly superconductivity and the pseudogap, have anisotropic gap structure in momentum space. We present a comprehensive doping- and temperature-dependence ARPES study of spectral gaps in Bi(2)Sr(2)CaCu(2)O(8+delta), covering much of the superconducting portion of the phase diagram. In the ground state, abrupt changes in near-nodal gap phenomenology give spectroscopic evidence for two potential quantum critical points, p = 0.19 for the pseudogap phase and p = 0.076 for another competing phase. Temperature dependence reveals that the pseudogap is not static below T(c) and exists p > 0.19 at higher temperatures. Our data imply a revised phase diagram that reconciles conflicting reports about the endpoint of the pseudogap in the literature, incorporates phase competition between the superconducting gap and pseudogap, and highlights distinct physics at the edge of the superconducting dome. PMID- 23093671 TI - Mechanism of oxygen detoxification by the surprisingly oxygen-tolerant hyperthermophilic archaeon, Pyrococcus furiosus. AB - The anaerobic archaeon Pyrococcus furiosus grows by fermenting carbohydrates producing H(2), CO(2), and acetate. We show here that it is surprisingly tolerant to oxygen, growing well in the presence of 8% (vol/vol) O(2). Although cell growth and acetate production were not significantly affected by O(2), H(2) production was reduced by 50% (using 8% O(2)). The amount of H(2) produced decreased in a linear manner with increasing concentrations of O(2) over the range 2-12% (vol/vol), and for each mole of O(2) consumed, the amount of H(2) produced decreased by approximately 2 mol. The recycling of H(2) by the two cytoplasmic hydrogenases appeared not to play a role in O(2) resistance because a mutant strain lacking both enzymes was not more sensitive to O(2) than the parent strain. Decreased H(2) production was also not due to inactivation of the H(2) producing, ferredoxin-dependent membrane-bound hydrogenase because its activity was unaffected by O(2) exposure. Electrons from carbohydrate oxidation must therefore be diverted to relieve O(2) stress at the level of reduced ferredoxin before H(2) production. Deletion strains lacking superoxide reductase (SOR) and putative flavodiiron protein A showed increased sensitivity to O(2), indicating that these enzymes play primary roles in resisting O(2). However, a mutant strain lacking the proposed electron donor to SOR, rubredoxin, was unaffected in response to O(2). Hence, electrons from sugar oxidation normally used to produce H(2) are diverted to O(2) detoxification by SOR and putative flavodiiron protein A, but the electron flow pathway from ferredoxin does not necessarily involve rubredoxin.| PMID- 23093672 TI - Coordinated repression of cell cycle genes by KDM5A and E2F4 during differentiation. AB - Epigenetic regulation underlies the robust changes in gene expression that occur during development. How precisely epigenetic enzymes contribute to development and differentiation processes is largely unclear. Here we show that one of the enzymes that removes the activating epigenetic mark of trimethylated lysine 4 on histone H3, lysine (K)-specific demethylase 5A (KDM5A), reinforces the effects of the retinoblastoma (RB) family of transcriptional repressors on differentiation. Global location analysis showed that KDM5A cooccupies a substantial portion of target genes with the E2F4 transcription factor. During ES cell differentiation, knockout of KDM5A resulted in derepression of multiple genomic loci that are targets of KDM5A, denoting a direct regulatory function. In terminally differentiated cells, common KDM5A and E2F4 gene targets were bound by the pRB related protein p130, a DREAM complex component. KDM5A was recruited to the transcription start site regions independently of E2F4; however, it cooperated with E2F4 to promote a state of deepened repression at cell cycle genes during differentiation. These findings reveal a critical role of H3K4 demethylation by KDM5A in the transcriptional silencing of genes that are suppressed by RB family members in differentiated cells. PMID- 23093673 TI - C1q limits dendritic cell differentiation and activation by engaging LAIR-1. AB - C1q, the first component of complement, and leukocyte-associated Ig-like receptor 1 (LAIR-1; CD305), an inhibitory receptor expressed on hematopoietic cells, have both been associated with arrest of monocyte-derived dendritic cell (DC) differentiation and inhibition of Toll-like receptor activity in plasmacytoid DCs. Defects in both molecules have been implicated in susceptibility to, and progression of, systemic lupus erythematosus. Inhibitory signaling partners for C1q on monocytes and DCs remain undefined. Because C1q contains collagen-like motifs and LAIR-1 is a universal collagen receptor, we hypothesized that C1q is a functional ligand for LAIR-1. Binding analyses in cell-free systems and on the cell membrane demonstrate that C1q and its collagen tail associate with LAIR-1 and LAIR-2 (CD306), a soluble inhibitor of LAIR-1. Both C1q and its collagen tail trigger phosphorylation of LAIR-1 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in monocytes. Functional analyses show that C1q-mediated inhibition of monocyte-DC differentiation and C1q-mediated inhibition of IFN-alpha production by plasmacytoid DCs were both reversed by LAIR-2. Moreover, C1q-mediated inhibition of DC differentiation was reversed by LAIR-1 siRNA. Thus, C1q is a functional ligand for LAIR-1 restricting immune cell differentiation and activation. The discovery of C1q interactions with LAIR-1 and LAIR-2 lends much needed insight into molecular mechanisms operating to prevent the loss of tolerance, particularly in systemic lupus erythematosus. PMID- 23093674 TI - Next-generation antibody discovery platforms. PMID- 23093675 TI - Fibroblast growth factor 10 gene regulation in the second heart field by Tbx1, Nkx2-5, and Islet1 reveals a genetic switch for down-regulation in the myocardium. AB - During cardiogenesis, Fibroblast Growth Factor (Fgf10) is expressed in the anterior second heart field. Together with Fibroblast growth factor 8 (Fgf8), Fgf10 promotes the proliferation of these cardiac progenitor cells that form the arterial pole of the heart. We have identified a 1.7-kb region in the first intron of Fgf10 that is necessary and sufficient to direct transgene expression in this cardiac context. The 1.7-kb sequence is directly controlled by T-box transcription factor 1 (Tbx1) in anterior second heart field cells that contribute to the outflow tract. It also responds to both NK2 transcription factor related, locus 5 (Nkx2-5) and ISL1 transcription factor, LIM/homeodomain (Islet1), acting through overlapping sites. Mutation of these sites reduces transgene expression in the anterior second heart field where the Fgf10 regulatory element is activated by Islet1 via direct binding in vivo. Analysis of the response to Nkx2-5 loss- and Isl1 gain-of-function genetic backgrounds indicates that the observed up-regulation of its activity in Nkx2-5 mutant hearts, reflecting that of Fgf10, is due to the absence of Nkx2-5 repression and to up-regulation of Isl1, normally repressed in the myocardium by Nkx2-5. ChIP experiments show strong binding of Nkx2-5 in differentiated myocardium. Molecular and genetic analysis of the Fgf10 cardiac element therefore reveals how key cardiac transcription factors orchestrate gene expression in the anterior second heart field and how genes, such as Fgf10, normally expressed in the progenitor cell population, are repressed when these cells enter the heart and differentiate into myocardium. Our findings provide a paradigm for transcriptional mechanisms that underlie the changes in regulatory networks during the transition from progenitor state to that of the differentiated tissue. PMID- 23093676 TI - HIV-1 Nef interferes with T-lymphocyte circulation through confined environments in vivo. AB - HIV-1 negative factor (Nef) elevates virus replication and contributes to immune evasion in vivo. As one of its established in vitro activities, Nef interferes with T-lymphocyte chemotaxis by reducing host cell actin dynamics. To explore Nef's influence on in vivo recirculation of T lymphocytes, we assessed lymph-node homing of Nef-expressing primary murine lymphocytes and found a drastic impairment in homing to peripheral lymph nodes. Intravital imaging and 3D immunofluorescence reconstruction of lymph nodes revealed that Nef potently impaired T-lymphocyte extravasation through high endothelial venules and reduced subsequent parenchymal motility. Ex vivo analyses of transendothelial migration revealed that Nef disrupted T-lymphocyte polarization and interfered with diapedesis and migration in the narrow subendothelial space. Consistently, Nef specifically affected T-lymphocyte motility modes used in dense environments that pose high physical barriers to migration. Mechanistically, inhibition of lymph node homing, subendothelial migration and cell polarization, but not diapedesis, depended on Nef's ability to inhibit host cell actin remodeling. Nef-mediated interference with in vivo recirculation of T lymphocytes may compromise T-cell help and thus represents an important mechanism for its function as a HIV pathogenicity factor. PMID- 23093677 TI - Intrinsic reaction-cycle time scale of Na+,K+-ATPase manifests itself in the lipid-protein interactions of nonequilibrium membranes. AB - Interaction between integral membrane proteins and the lipid-bilayer component of biological membranes is expected to mutually influence the proteins and the membrane. We present quantitative evidence of a manifestation of the lipid protein interactions in liposomal membranes, reconstituted with actively pumping Na(+),K(+)-ATPase, in terms of nonequilibrium shape fluctuations that contain a relaxation time, tau, which is robust and independent of the specific fluctuation modes of the membrane. In the case of pumping Na(+)-ions, analysis of the flicker noise temporal correlation spectrum of the liposomes leads to tau ~/= 0.5 s, comparing favorably with an intrinsic reaction-cycle time of about 0.4 s from enzymology. PMID- 23093678 TI - Transient receptor potential channel promiscuity frustrates constellation pharmacology. PMID- 23093679 TI - Investigation of American Association of Physicists in Medicine Report 204 size specific dose estimates for pediatric CT implementation. AB - PURPOSE: To compare five methodologies the American Association of Physicists in Medicine Report 204 used to calculate size-specific dose estimates (SSDEs) for pediatric computed tomography (CT). MATERIALS AND METHODS: The institutional review board waived consent for this HIPAA-compliant retrospective study. The five SSDE methodologies were investigated for calculation variation based on volumetric CT dose index (CTDI), or CTDI(vol), of chest, abdominal, and pelvic CT. SSDE calculations were derived from a predominantly pediatric population of 186 patients retrospectively and consecutively analyzed from June through November 2011. Eighty (43%) of the 186 patients were female, and 106 (57%) were male. Mean patient age was 8.6 years +/- 6.3 (standard deviation), the age range was 1 month to 28 years, and mean weight was 37.7 kg +/- 33.1, with a range of 3.4-146.6 kg. SSDE conversion factors were derived from anteroposterior (AP) and lateral dimensions measured on the patient's CT radiograph. The measurements were either used independently, or as a summation, or to calculate the patient's effective diameter; additionally, SSDE was derived on the basis of the patient's age (International Commission on Radiation Units Report 74 data). SSDE conversion factors were applied to CTDI(vol) data that corrected for both 16- and 32-cm diameter CTDI phantom measurements. SSDE data were summarized by using the patient's originally prescribed weight-based CT scanning protocols. Data were summarized by using descriptive statistics. RESULTS: SSDEs derived from individual measurements varied 2%-12%. The combination of measurements (sum or effective diameter) varied 0.9%-2%. The age approach varied by an average of 2% (in the younger population [0-13 years]), but up to 44%, with an average of 18% (in the older population [14-18 years]). No SSDE correction was required for patients of varying size who weighed 36 kg or less when CTDI(vol) was measured by using a 16-cm CTDI phantom or for patients weighing 100-140 kg when CTDI(vol) was measured by using a 32-cm phantom. CTDI(vol) measured by using a 32-cm phantom in patients weighing between 36 and 100 kg and patients weighing more than 140 kg differed from SSDE by an average of 35%. An average difference of 1% was found between male and female SSDE-corrected values when the two sexes were compared within the same CT weight scanning categories. CONCLUSION: The combination of AP and lateral measurements should be used to determine SSDE correction factors when possible. For pediatric patients, CTDI(vol) calculated with a 32-cm phantom requires SSDE conversion to more accurately estimate patient dose; CTDI(vol) calculated with a 16-cm phantom for pediatric patients weighing 36 kg or less does not require SSDE conversion. PMID- 23093680 TI - Methods for calculating sensitivity and specificity of clustered data: a tutorial. AB - The performance of a diagnostic test is often expressed in terms of sensitivity and specificity compared with the reference standard. Calculations of sensitivity and specificity commonly involve multiple observations per patient, which implies that the data are clustered. Whether analysis of sensitivity and specificity per patient or using multiple observations per patient is preferable depends on the clinical context and consequences. The purpose of this article was to discuss and illustrate the most common statistical methods that calculate sensitivity and specificity of clustered data, adjusting for the possible correlation between observations within each patient. This tutorial presents and illustrates the following methods: (a) analysis at different levels ignoring correlation, (b) variance adjustment, (c) logistic random-effects models, and (d) generalized estimating equations. The choice of method and the level of reporting should correspond with the clinical decision problem. If multiple observations per patient are relevant to the clinical decision problem, the potential correlation between observations should be explored and taken into account in the statistical analysis. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12120509/-/DC1. PMID- 23093681 TI - Differentiation of an intrapancreatic accessory spleen from a small (<3-cm) solid pancreatic tumor: value of diffusion-weighted MR imaging. AB - PURPOSE: To evaluate the value of diffusion-weighted (DW) imaging in differentiation of an intrapancreatic accessory spleen (IPAS) from a small (<3 cm) solid pancreatic tumor. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Twenty patients with IPAS and 22 patients with small solid pancreatic tumors were included. All patients underwent abdominal magnetic resonance (MR) imaging with DW and gadoxetic acid-enhanced imaging. Qualitative (signal intensity) and quantitative (signal intensity and apparent diffusion coefficient [ADC]) evaluations were performed by two observers. Fisher exact test and Mann-Whitney U test were used for comparing groups. RESULTS: Compared with the spleen, the IPAS showed isointensity more frequently than did small pancreatic tumors on T2 weighted images (95% [19 of 20] vs 41% [nine of 22]), arterial phase images (100% [20 of 20] vs 18% [four of 22]), portal phase images (100% [20 of 20] vs 23% [five of 22]), late phase images (100% [20 of 20] vs 41% [nine of 22]), and DW images with b value of 0 sec/mm(2) (100% [20 of 20] vs 9% [two of 22]), b value of 100 sec/mm(2) (95% [19 of 20] vs 27% [six of 22]), and b value of 800 sec/mm(2) (100% [20 of 20] vs 27% [six of 22]), with significant differences (P < .01). The means of the absolute value of relative signal intensity and ADC ratio on DW images of IPAS were significantly lower and closer to zero than those of pancreatic tumors (P < .05). Visual assessment of the similarity between pancreatic lesion and spleen on DW images for diagnosis of IPAS yielded diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of 95% (40 of 42), 100% (20 of 20), 91% (20 of 22), 91% (20 of 22), and 100% (20 of 20), respectively, for observer 1 and 90% (38 of 42), 95% (19 of 20), 86% (19 of 22), 86% (19 of 22), and 95% (19of 20), respectively, for observer 2. CONCLUSION: In addition to conventional morphologic MR imaging, DW imaging can be used as a tool for differentiating IPAS from solid pancreatic tumors. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12112765/-/DC1. PMID- 23093683 TI - Closed-loop systems: diversity and natural selection. PMID- 23093684 TI - Rate and determinants of association between advanced retinopathy and chronic kidney disease in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. AB - OBJECTIVE: To evaluate the rate and determinants of concordance between advanced diabetic retinopathy (DR) and chronic kidney disease (CKD), as assessed by both albuminuria and estimated glomerular filtration rate (eGFR), in the large cohort of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 15,773) visiting consecutively 19 hospital-based diabetes clinics in years 2007 and 2008 were examined. DR was assessed by dilated fundoscopy. CKD was defined based on albuminuria and eGFR. RESULTS: CKD was present in 58.64% of subjects with advanced DR, whereas advanced DR was detectable only in 15.28% of individuals with any CKD and correlated with the albuminuric CKD phenotypes more than with the nonalbuminuric phenotype. Age, male sex, diabetes duration, hemoglobin A(1c), hypertension, triglycerides, previous cardiovascular disease, and, inversely, HDL cholesterol correlated independently with the presence of any CKD in individuals with advanced DR; correlates differed according to the presence of albuminuria, reduced eGFR, or both. Conversely, factors associated with the presence of advanced DR in subjects with any CKD were diabetes treatment, previous cardiovascular disease, albuminuria, and, inversely, smoking, eGFR, and age at diagnosis. CONCLUSIONS: Concordance of CKD with advanced DR is low in subjects with type 2 diabetes, and CKD without advanced DR is more frequent than isolated advanced DR, at variance with type 1 diabetes. Factors independently associated with the presence of any CKD in individuals with advanced DR differ, at least in part, from those correlating with the presence of advanced DR in subjects with any CKD and by CKD phenotype. PMID- 23093685 TI - Metabolic syndrome and risk of cancer: a systematic review and meta-analysis. AB - OBJECTIVE: Available evidence supports the emerging hypothesis that metabolic syndrome may be associated with the risk of some common cancers. We did a systematic review and meta-analysis to assess the association between metabolic syndrome and risk of cancer at different sites. RESEARCH DESIGN AND METHODS: We conducted an electronic search for articles published through October 2011 without restrictions and by reviewing reference lists from retrieved articles. Every included study was to report risk estimates with 95% CIs for the association between metabolic syndrome and cancer. RESULTS: We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001). CONCLUSIONS: Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome. PMID- 23093687 TI - Incretin effect of glucagon-like peptide 1 receptor agonist is preserved in presence of ABCC8/SUR1 mutation in beta-cell. PMID- 23093688 TI - Incidence of type 1 diabetes in Mexico: data from an institutional register 2000 2010. PMID- 23093689 TI - Glucose derangements in very young children with cystic fibrosis and pancreatic insufficiency. PMID- 23093690 TI - Comment on: Fraser et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo-controlled trial. Diabetes Care 2012;35:1095-1097. PMID- 23093692 TI - Review: little evidence that PUFA supplementation improves symptoms in ADHD. PMID- 23093694 TI - Review: non-steroidal anti-inflammatory drugs may reduce schizophrenia symptom severity in the short term when added to antipsychotics. PMID- 23093693 TI - Review: social skills groups may improve social competence in children and adolescents with autism spectrum disorder. PMID- 23093695 TI - How to use Helicobacter pylori testing in paediatric practice. AB - The current reference standard for investigating H. pylori associated disease in children remains upper intestinal endoscopy and biopsies for histology and culture or RUT. Non-invasive tests should be used to confirm H. pylori eradication following treatment. Currently there is insufficient evidence to recommend them over invasive tests in symptomatic children, because they cannot be used reliably in children to diagnose or distinguish H. pylori-associated diseases from conditions that are not H. pylori related. Recent evidence-based guidelines recommend treatment in children with confirmed H. pylori-related diseases. However, with further knowledge of the measurable health risks for H. pylori-infected children, or with the availability of vaccination or future treatment options, the risk-benefit relationship and recommendations regarding non-invasive testing may change. PMID- 23093696 TI - Thyroid diseases cause mismatch between MIBI scan and neck ultrasound in the diagnosis of hyperfunctioning parathyroids: usefulness of FNA-PTH assay. AB - DESIGN: To evaluate the efficacy of the main tools in the diagnostic localization of hyperfunctioning parathyroids (HP) in primary hyperparathyroidism (pHPT) with concomitant thyroid diseases. METHODS: Forty-three patients with pHPT associated with nodular goiter (NG, n=32) and/or autoimmune thyroid diseases (AITDs, n=11) for a total of 63 neck lesions were considered. Sixteen patients displaying HP (16 lesions), unequivocally localized by sestaMIBI scintigraphy (MIBI) and neck ultrasound (US) (group I), were compared with 27 patients (47 neck lesions) displaying equivocal parathyroid localization (group II). In all cases, neck US, MIBI scan, cytology, and parathyroid hormone assay in fine-needle aspiration washout fluid (FNA-PTH) were performed. All patients finally underwent surgery. RESULTS: According to histological examination, high FNA-PTH values (>103 pg/ml) correctly identified all HP in both groups of patients (100% of sensitivity and specificity). Both MIBI and US correctly identified all HP only in group I patients; in contrast, four patterns of mismatch between these techniques were observed in group II patients, leading to low diagnostic performances of neck US (71.4% sensitivity and 78.9% specificity) and of MIBI scan (35.7% sensitivity and 42.1% specificity). The latter was due to both false-negative (mainly in AITD) and false-positive (mainly in NG) scan images. CONCLUSIONS: Coexistent thyroid diseases are responsible for mismatch between MIBI and US images resulting in equivocal HP localization. In these cases, FNA-PTH resulted in the most accurate tool to identify HP. However, although safe, it should be advised only to patients with uncertain HP localization. PMID- 23093697 TI - Thyroid function and the metabolic syndrome in older persons: a population-based study. AB - BACKGROUND: Studies suggest an association between a high TSH and (individual components of) the metabolic syndrome. Only a few studies have been performed in the general older population. OBJECTIVE: This study investigates the association between serum TSH and the metabolic syndrome in a representative sample of older persons in The Netherlands. DESIGN AND PATIENTS: Data of the Longitudinal Aging Study Amsterdam were used, which is an ongoing cohort study in a representative sample of Dutch older persons. A total of 1187 subjects (590 men and 597 women) between the ages of 65 and 88 years participated in the study. MEASUREMENTS: Metabolic syndrome (US National Cholesterol Education Program definition) and its individual components were assessed, as well as serum TSH levels. RESULTS: Among the participants, the prevalence of the metabolic syndrome was 34.2%. The mean serum TSH was 1.9 mU/l. Subjects in the upper quartile with a serum TSH level above 2.28 mU/l (odds ratio (OR)=1.68; 95% confidence interval (CI) 1.19-2.37) had a significantly increased prevalence of metabolic syndrome compared with subjects in the lowest quartile with a serum TSH below 1.04 mU/l. After adjustment for confounders, age, sex, alcohol use, total physical activity, and smoking, the OR was 1.62 (95% CI 1.15-2.32). CONCLUSIONS: Subjects with a serum TSH in the upper quartile have a higher prevalence of metabolic syndrome as compared with subjects with a serum TSH in the lowest quartile. PMID- 23093698 TI - Early changes in carcinoembryonic antigen but not in calcitonin levels are correlated with the progression-free survival in medullary thyroid carcinoma patients treated with cytotoxic chemotherapy. AB - INTRODUCTION: The prognostic value of serum calcitonin (CT) and carcinoembryonic antigen (CEA) doubling time has been recently demonstrated in medullary thyroid carcinoma (MTC) patients. No study has yet validated the surrogate role of these markers for survival during treatment. The aim of this study was to evaluate, in patients with advanced MTC treated with cytotoxic chemotherapy, the relationship between early changes of serum CT or CEA levels and progression-free survival (PFS). PATIENTS AND METHODS: The files of 28 consecutive metastatic MTC patients with progressive disease, treated with cytotoxic chemotherapy in a single tertiary referral center between 2000 and 2010, were retrospectively reviewed. Serum CT and CEA measurements and radiological Response Evaluation Criteria in Solid Tumors (RECIST) evaluations were collected every 3 months. The relationship between changes in serum CT and CEA levels at 3 months, defined by an increase or a decrease of at least 20%, and PFS according to RECIST 1.0, was estimated using Kaplan-Meier curves and log-rank test. RESULTS: The median follow-up for the 28 patients was 68 months. According to RECIST, a partial response, a stabilization or a progression was observed in 14, 43, and 43% of cases respectively. Median PFS from the initiation of cytotoxic chemotherapy was 4.5 months. Median PFS among patients with and without significant CT increase at 3 months was 4.6 and 3.3 months respectively (P=0.75). Median PFS among patients with a significant CEA increase at 3 months was 2.7 months, whereas it was 19.1 months in patients in whom CEA did not increase (P=0.02). CONCLUSION: At 3 months, an increase of serum CEA but not of CT levels appears as a valuable surrogate marker of short PFS in MTC patients treated with cytotoxic chemotherapy. A prospective validation is expected. PMID- 23093699 TI - MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism. AB - OBJECTIVE: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases. DESIGN AND METHODS: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27(Kip1), beta-catenin and Ki-67 was conducted by immunohistochemistry. RESULTS: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours. CONCLUSIONS: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours. PMID- 23093700 TI - The pubertal transition in 179 healthy Danish children: associations between pubarche, adrenarche, gonadarche, and body composition. AB - BACKGROUND: Pubertal onset is usually defined by breast development in girls and testicular growth in boys. Pubarche is defined as the attainment of pubic hair and is considered as a sign of pubertal transition. Pubarche is preceded by a gradual increase in production of adrenal androgens, DHEA and Delta4 androstenedione (Adione), a process termed adrenarche. OBJECTIVE: To study the natural course of pubertal transition and the associations with adrenarche, body fat, and linear growth. DESIGN AND METHODS: A longitudinal study of 179 healthy children (89 girls) with higher socioeconomic background examined every 6 months for 5 years. Pubic hair stage, breast stage, genital stage, testicular volume (TV), height, weight, and four skinfolds were measured. RESULTS: In girls, median age (25th and 75th percentiles) at thelarche (B2+) was 10.1 years (9.3-10.9). In boys, median age at attaining a TV >3 ml was 11.5 years (10.9-12.0). Median age at pubarche (PH2+) was 10.9 years (10.3-11.4) in girls and 11.6 years (10.8-12.4) in boys. Only 6.8% (4/59) of the girls and 24.6% (15/61) of the boys developed pubic hair as the first isolated sign of puberty. Serum DHEAS and Adione increased with age, although the increase in Adione was most pronounced in girls. No associations between early age at thelarche/testicular growth and increased body fat (BMI and sum of four skinfolds) were observed. CONCLUSION: Danish children rarely experience pubarche as the first sign of puberty. No associations between age at pubertal onset and body composition were found. Circulating levels of Adione, but not DHEAS, increased with the onset of puberty, although with large interindividual variability. PMID- 23093701 TI - Proteomic biomarkers of type 2 diabetes mellitus risk in women with polycystic ovary syndrome. AB - Women with polycystic ovary syndrome (PCOS) are at increased risk of developing insulin resistance and type 2 diabetes mellitus (T2DM). In this study, we attempted to list the proteomic biomarkers of PCOS and T2DM that have been published in the literature so far. We identified eight common biomarkers that were differentially expressed in both women with PCOS and T2DM when compared with healthy controls. These include pyruvate kinase M1/M2, apolipoprotein A-I, albumin, peroxiredoxin 2, annexin A2, alpha-1-B-glycoprotein, flotillin-1 and haptoglobin. These biomarkers could help improve our understanding of the links between PCOS and T2DM and could be potentially used to identify subgroups of women with PCOS at increased risk of T2DM. More studies are required to further evaluate the role these biomarkers play in women with PCOS and T2DM. PMID- 23093703 TI - Sp1 and Sp3 transcription factors mediate leptin-induced collagen alpha1(I) gene expression in primary culture of male rat hepatic stellate cells. AB - Mechanisms by which leptin stimulates collagen alpha(1)(I) [Col1a(I)] gene expression are unclear. The purposes of this study were to identify the trans acting factors and cis-acting elements in Col1a(I) promoter involved in this effect as well as the pathways that are implicated. In primary cultures of rat hepatic stellate cells (HSCs), we measured the effects of leptin on Col1a(I) gene and protein expression and on the binding of nuclear proteins to the Col1a(I) promoter. We found that leptin increased Col1a(I) gene and protein expression in activated HSCs. Transient transfections showed that leptin exerted its effects through elements located between -220 and -112 bp of the Col1a(I) promoter. Gel retardation assays demonstrated that leptin induced the binding of transcription factors specific protein (Sp)-1 and Sp3 to two elements located between -161 and 110 bp of the Col1a(I) promoter. Leptin-induced Sp1/Sp3 phosphorylation, but this effect was suppressed by inhibiting or silencing Janus kinase-2, phosphatidylinositol-3-kinase, nonphagocytic adenine dinucleotide phosphate (NADPH) oxidase, or ERK1/2, by the use of antioxidants or catalase, or by preventing protein-aldehyde adduct formation. Leptin provoked oxidative stress, aldehyde-protein adduct formation, and increased gene expression of some components of the NADPH oxidase complex. In conclusion, in HSCs, leptin up regulates Col1a(I) gene expression after activating NADPH oxidase, inducing oxidative stress, aldehyde-protein adduct formation, and ERK1/2 phosphorylation, which in turn activates Sp1/Sp3 and provokes the binding of these two factors to regulatory elements located between -161 and -110 bp of the Col1a(I) promoter. These findings may contribute to a better understanding of mechanisms involved in the leptin-induced liver fibrosis. PMID- 23093702 TI - Additive effects of nicotine and high-fat diet on hepatic steatosis in male mice. AB - Smoking is a major risk factor for diabetes and cardiovascular disease and may contribute to nonalcoholic fatty liver disease. We hypothesize that in the presence of nicotine, high-fat diet (HFD) causes more severe hepatic steatosis in obese mice. Adult C57BL6 male mice were fed a normal chow diet or HFD and received twice daily injections of nicotine (0.75 mg/kg body weight, ip) or saline for 10 wk. Light microscopic image analysis revealed significantly higher lipid accumulation in livers from mice on HFD plus nicotine (190 +/- 19 MUm(2)), compared with mice on HFD alone (28 +/- 1.2 MUm(2)). A significant reduction in the percent volume of endoplasmic reticulum (67.8%) and glycogen (49.2%) was also noted in hepatocytes from mice on HFD plus nicotine, compared with mice on HFD alone. The additive effects of nicotine on the severity of HFD-induced hepatic steatosis was associated with significantly greater oxidative stress, increased hepatic triglyceride levels, higher incidence of hepatocellular apoptosis, inactivation (dephosphorylation) of AMP-activated protein kinase, and activation of its downstream target acetyl-coenzyme A-carboxylase. Treatment with acipimox, an inhibitor of lipolysis, significantly reduced nicotine plus HFD-induced hepatic lipid accumulation. We conclude that: 1) greater oxidative stress coupled with inactivation of AMP-activated protein kinase mediate the additive effects of nicotine and HFD on hepatic steatosis in obese mice and 2) increased lipolysis is an important contributor to hepatic steatosis. We surmise that nicotine exposure is likely to exacerbate the metabolic abnormalities induced by high-fat intake in obese patients. PMID- 23093704 TI - Science to practice: Can hyperpolarized water be used to enhance MR angiography and flow measurement? AB - The method described by Lingwood et al is a continuously flowing system rather than the discrete batch approach of the dissolution dynamic nuclear polarization method, which means the hyperpolarized molecule can be continuously available for injection on demand. PMID- 23093705 TI - Avoiding testocracy. PMID- 23093709 TI - Case 187: De Garengeot hernia. PMID- 23093710 TI - Diffusion kurtosis and diffusion-tensor MR imaging in Parkinson disease. PMID- 23093711 TI - Measurement of muscle stiffness in children with spastic cerebral palsy. PMID- 23093707 TI - Musculoskeletal tumors: how to use anatomic, functional, and metabolic MR techniques. AB - Although the function of magnetic resonance (MR) imaging in the evaluation of musculoskeletal tumors has traditionally been to help identify the extent of disease prior to treatment, its role continues to evolve as new techniques emerge. Conventional pulse sequences remain heavily used and useful, but with the advent of chemical shift imaging, diffusion-weighted imaging, perfusion imaging and MR spectroscopy, additional quantitative metrics have become available that may help expand the role of MR imaging to include detection, characterization, and reliable assessment of treatment response. This review discusses a multiparametric approach to the evaluation of musculoskeletal tumors, with a focus on the utility and potential added value of various pulse sequences in helping establish a diagnosis, assess pretreatment extent, and evaluate a tumor in the posttreatment setting for recurrence and treatment response. PMID- 23093712 TI - Supraacetabular fossa. PMID- 23093714 TI - Socioeconomic and regional aspects in the use of specialized psychiatric care--a Finnish nationwide follow-up study. AB - BACKGROUND: Mental health problems in childhood and adolescence are an important public health concern. The general aim of Finnish health policy is to offer equal services for all inhabitants according to need, irrespective of socio-economic background or place of residence. Here, we assess equity in access to psychiatric care in a long-term nationwide follow-up study from birth to early adulthood. METHODS: All 60 069 children born in Finland in 1987 were followed up through health registers from 1987 to 2008. The cohort members' use of specialized psychiatric outpatient and inpatient care was assessed and linked to their socio economic status and residential area. RESULTS: Altogether, 14.4% of the cohort members had received specialized psychiatric care during the follow-up. Females used significantly more specialized psychiatric outpatient care than males. In addition, the use of specialized psychiatric care was more common among young people with a poor socio-economic background and those living in urban areas. CONCLUSIONS: A notable number of the young adults born in Finland in 1987 used specialized psychiatric care during their childhood and adolescence. Use was clearly defined by sex and residential area, as well as by parental socio economic status and education. The data indicate that equity in access to mental health services should be highlighted in health policies, as contemporary outpatient mental health care has not been equally available for people living within and outside urban areas. PMID- 23093715 TI - Intimate partner violence and sexual health outcomes: a population-based study among 16-44-year-old women in Estonia. AB - BACKGROUND: Violence against women as a public issue and health burden has only recently been acknowledged in Estonia. The aim of this study was to outline the prevalence and to explore the associations of intimate partner violence (IPV) and selected sexual health outcomes. METHODS: Data from the population based cross sectional survey among representative sample of 16-44-year-old non-pregnant women (n = 1966) were analysed using multivariate logistic regression. RESULTS: Of 1966 respondents, 362 (18.4%) reported IPV during 12 months preceding the survey. Physical IPV was reported by 339 (17.2%), sexual by 80 (4.1%) and both physical and sexual by 35 (1.8%) of respondents. After controlling for significant confounding socio-demographic factors, exposure to IPV was found to be associated with contraception non-use [adjusted odds ratio (AOR) = 2.02, 95% confidence interval (CI) 1.44-2.82] or the use of unreliable contraceptive methods (AOR = 1.54, CI 1.16-2.04) during the most recent sexual intercourse, having never used a condom (AOR = 1.53, CI 1.12-2.10), repeat induced abortion (AOR = 1.72, CI 1.24 2.37), lifetime sexually transmitted infections (AOR = 2.05, CI 1.56-2.68) and dyspareunia (AOR = 2.14, CI 1.65-2.77). CONCLUSION: The exposure of IPV was an important contributor to sexual risk behaviour and adverse sexual health outcomes among women of reproductive age in Estonia. Any strategy to promote sexual health should include prevention of IPV and other forms of violence against women with the strengthening of women's sexual and reproductive rights. PMID- 23093716 TI - Impact of economic crisis and other demographic and socio-economic factors on self-rated health in Greece. AB - BACKGROUND: Financial crisis and worsened socio-economic conditions are associated with greater morbidity, less utilization of health services and deteriorated population's health status. The aim of the present study was to investigate the determinants of self-rated health in Greece. METHODS: Two national cross-sectional surveys conducted in 2006 and 2011 were combined, and their data were pooled giving information for 10 572 individuals. The sample in both studies was random and stratified by gender, age, degree of urbanization and geographic region. Logistic regression analysis was used to determine the impact of several factors on self-rated health. RESULTS: Poor self-rated health was most common in older people, unemployed, pensioners, housewives and those suffering from chronic disease. Men, individuals with higher education and those with higher income have higher probability to report better self-rated health. Furthermore, the probability of reporting poor self-rated health is higher at times of economic crisis. CONCLUSION: Our findings confirm the association of self-rated health with economic crisis and certain demographic and socio-economic factors. Given that the economic recession in Greece deepens, immediate and effective actions targeting health inequalities and improvements in health status are deemed necessary. PMID- 23093717 TI - Investigating cervical, oesophageal and colon cancer risk and survival among migrants in The Netherlands. AB - BACKGROUND: Studies on cancer in migrants can shed light on grey areas in cancer aetiology and can help assessing the effectiveness of prevention measures. In this study, we aimed to determine the impact of migration and different ethnic backgrounds on cervical, colon and oesophageal cancer risk and survival. METHODS: Cancers diagnosed in 1996-2009 were selected from The Netherlands Cancer Registry. Besides standardized incidence ratios, differences in survival were explored using Cox regression and relative survival analysis. RESULTS: All migrant women had increased risks for cervical cancer when compared with Dutch native women, ranging from standardized incidence ratio = 1.8 (95% confidence interval 1.6-2.2) in Surinamese women to 1.2 (0.9-1.5) in Turkish women. Relative survival was better among Moroccan, Surinamese and Antillean migrants [5-year relative survival rates (RSR) range: 71-73%] compared with that of native Dutch (66%); however, it was poorer in Indonesians (51%). Although oesophageal cancer risk was lower in all migrants with Standardized incidence ratios ranging from 0.1 to 0.6, survival was slightly lower relative to Dutch natives (1-year RSR: 21 32% compared with 37%; Turkish: 42%). Colon cancer was less common among migrants, particularly among Moroccans and Turkish. Five-year RSR from colon cancer was equal or better in all migrants (range: 48% in Indonesians to 62% in Turkish) compared with Dutch natives (48%). CONCLUSION: Risk of cervical, oesophageal and colon cancer in migrants mainly reflects the risks in their countries of origin. Almost similar cancer survival rates in migrants and native Dutch individuals points towards successful and comprehensive health care in The Netherlands. Primary cancer prevention should target high-risk groups and involve migration-sensitive approaches. PMID- 23093718 TI - Socio-economic position early in life, cognitive development and cognitive change from young adulthood to middle age. AB - BACKGROUND: We examine the influence of social circumstances early in life on changes in cognitive function from young adulthood to middle age, and we explore the impact of birth characteristics, childhood activities, education and adult social class on the expected relationship. METHODS: A cohort of 11 532 men born in Copenhagen, Denmark in 1953-7906, 10 246 and 2483 participants-had completed assessments of cognitive function at ages 12, 18 and 57 years, respectively. Linear regression was used to investigate the association of early-life characteristics with cognitive test scores at these ages and with score changes from early to mid-adulthood. RESULTS: The cognitive scores at age 57 years had high correlations with scores at ages 12 (r = 0.67) and 18 years (r = 0.70), and these two scores also showed bivariate correlation (r = 0.69). Having a father from the working class at birth was associated with lower cognitive function at ages 12, 18 and 57 years. The latter relation was attenuated when educational status at age 18 years and adult social class were adjusted for, while birth characteristics and childhood activities had minor influence. Having an unskilled father at birth, low education, few intellectual and many social activities in childhood as well as low adult social class were associated with decline in cognitive function. CONCLUSION: Adverse social circumstances early in life were associated with lower cognitive function at ages 12, 18 and 57 years, as well as with a decline between these ages. Educational status at age 18 years and adult social class seemed to account for most of the associations, whereas childhood activities were independent predictors that did not explain the social inequality. PMID- 23093719 TI - Seven goals for public health training in the 21st century. PMID- 23093720 TI - Modeling kinetic rate variation in third generation DNA sequencing data to detect putative modifications to DNA bases. AB - Current generation DNA sequencing instruments are moving closer to seamlessly sequencing genomes of entire populations as a routine part of scientific investigation. However, while significant inroads have been made identifying small nucleotide variation and structural variations in DNA that impact phenotypes of interest, progress has not been as dramatic regarding epigenetic changes and base-level damage to DNA, largely due to technological limitations in assaying all known and unknown types of modifications at genome scale. Recently, single-molecule real time (SMRT) sequencing has been reported to identify kinetic variation (KV) events that have been demonstrated to reflect epigenetic changes of every known type, providing a path forward for detecting base modifications as a routine part of sequencing. However, to date no statistical framework has been proposed to enhance the power to detect these events while also controlling for false-positive events. By modeling enzyme kinetics in the neighborhood of an arbitrary location in a genomic region of interest as a conditional random field, we provide a statistical framework for incorporating kinetic information at a test position of interest as well as at neighboring sites that help enhance the power to detect KV events. The performance of this and related models is explored, with the best-performing model applied to plasmid DNA isolated from Escherichia coli and mitochondrial DNA isolated from human brain tissue. We highlight widespread kinetic variation events, some of which strongly associate with known modification events, while others represent putative chemically modified sites of unknown types. PMID- 23093721 TI - Who are the patients with early arthritis with worse than death scores on the EQ 5D? Results from the ESPOIR cohort. AB - OBJECTIVES: The EQ-5D is a five-dimension multi-attribute questionnaire widely used to calculate quality-adjusted life-year scores. We aimed to describe patients with early arthritis (EA) and EQ-5D < 0, a state worse than death, at baseline and over 2 years and determine aspects of EA associated with a negative score. METHODS: EQ-5D scores for 813 patients were longitudinally assessed over 24 months. Characteristics and health status of patients with EQ-5D < 0 were analysed. Multivariate logistic regression was used to determine aspects of EA associated with a negative score. RESULTS: At baseline, 90 (11%) patients had a negative EQ-5D score (median EQ-5D -0.052; range -0.530 to -0.011). Almost all patients had extreme pain/discomfort and at least moderate problems in anxiety/depression domain. These patients had lower educational level, greater disease activity, higher HAQ score (greater functional disability), greater pain and fatigue, lower Short Form 36 (SF-36) mental component scores and higher CRP levels than patients with EQ-5D >= 0 (all P < 0.001). In the logistic regression model, worse HAQ and SF-36 mental component scores were associated with EQ-5D < 0. Results were similar at 6, 12 and 24 months, with 25, 23 and 24 patients, respectively, in a state worse than death. CONCLUSION: Pain or discomfort, often severe, is a key domain of the EQ-5D for patients with EA in a health state worse than death, and poor HAQ and SF-36 mental component scores were always independently associated with a state worse than death. EA patients may have specific needs necessitating better management of pain and psychological state. PMID- 23093722 TI - Exploring ankylosing spondylitis-associated ERAP1, IL23R and IL12B gene polymorphisms in subphenotypes of psoriatic arthritis. AB - OBJECTIVE: To ascertain whether AS-associated polymorphisms of ERAP1, IL23R and IL12B genes associate with subphenotypes of PsA, particularly axial radiographic disease once stratified by HLA-B27 and HLA-Cw*0602 status. METHODS: rs30187 (ERAP1 gene), rs6887695 (IL12B gene), rs11209026 and rs7530511 (IL23R gene) single nucleotide polymorphisms were genotyped in 263 PsA cases from a prospective cohort and compared with data from healthy controls (n = 3266-5422). ERAP1 results were stratified according to HLA-B27 and HLA-Cw*0602 status. Investigation of association with age at onset of psoriasis/PsA, arthritic joint count, axial radiographic disease, peripheral radiographic erosions, Psoriasis Area Severity Index, nail score and HAQ was made. RESULTS: There was a strong association between rs6887595 (IL12B) and PsA, with homozygosity for the major allele being more frequent in PsA than controls (odds ratio 1.70; 95% CI 1.3, 2.2; P < 0.001). A trend was demonstrated for the minor allele of rs11209026 (IL23R) to be less frequent in patients with erosive joint disease than in those without erosions or controls (7%, 14% and 12%, respectively). None of the polymorphisms associated with the presence of axial radiographic disease or other clinical parameters. CONCLUSION: We have confirmed a strong association between rs6887595 (IL12B) and PsA. A trend has been demonstrated between an IL23R variant and peripheral erosive disease. ERAP1 was not associated with axial radiographic disease in PsA. Spinal involvement in PsA may be genetically different from that in AS, which is in keeping with previous observations that the clinical and radiographic pattern of axial disease also differs. PMID- 23093723 TI - Impact of self-reported comorbidity on physical and mental health status in early symptomatic osteoarthritis: the CHECK (Cohort Hip and Cohort Knee) study. AB - OBJECTIVE: To describe the relationship between comorbidity (absolute number as well as the presence of specific comorbidities) and pain, physical functioning and mental health status of participants with early symptomatic OA of the hip or knee. METHODS: In the Netherlands, a prospective 10-year follow-up study was initiated by the Dutch Arthritis Association in participants with early symptomatic OA of the hip or knee: CHECK (Cohort Hip and Cohort Knee), which consists of 1002 individuals. At baseline, linear regression analysis was used to determine the influence of comorbidity on the outcome variables: Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, WOMAC physical functioning, Medical Outcomes Study Short Form 36 (SF-36) Physical Component Summary and Mental Component Summary. RESULTS: Of 979 subjects, 67% reported one or more comorbidities. After controlling for age, gender, social status and severity of radiographic OA (Kellgren and Lawrence score), back disorders have the largest effect on WOMAC pain and physical functioning, and one of the largest effects on physical status of SF-36, besides obesity. Mental status was negatively influenced by the additional presence of duodenal ulcer, thyroid disease, and migraine or chronic headache. CONCLUSION: In early stage of OA, the presence of additional problems in the musculoskeletal system and of obesity have a negative effect on pain and physical health status. Also mental status is affected in early symptomatic OA by the presence of specific comorbidities. Comorbidity should be assessed and treated to improve the burden of illness in patients with early symptomatic OA. PMID- 23093724 TI - Kinetic analysis of pre-ribosome structure in vivo. AB - Pre-ribosomal particles undergo numerous structural changes during maturation, but their high complexity and short lifetimes make these changes very difficult to follow in vivo. In consequence, pre-ribosome structure and composition have largely been inferred from purified particles and analyzed in vitro. Here we describe techniques for kinetic analyses of the changes in pre-ribosome structure in living cells of Saccharomyces cerevisiae. To allow this, in vivo structure probing by DMS modification was combined with affinity purification of newly synthesized 20S pre-rRNA over a time course of metabolic labeling with 4 thiouracil. To demonstrate that this approach is generally applicable, we initially analyzed the accessibility of the region surrounding cleavage site D site at the 3' end of the mature 18S rRNA region of the pre-rRNA. This revealed a remarkably flexible structure throughout 40S subunit biogenesis, with little stable RNA-protein interaction apparent. Analysis of folding in the region of the 18S central pseudoknot was consistent with previous data showing U3 snoRNA-18S rRNA interactions. Dynamic changes in the structure of the hinge between helix 28 (H28) and H44 of pre-18S rRNA were consistent with recently reported interactions with the 3' guide region of U3 snoRNA. Finally, analysis of the H18 region indicates that the RNA structure matures early, but additional protection appears subsequently, presumably reflecting protein binding. The structural analyses described here were performed on total, affinity-purified, newly synthesized RNA, so many classes of RNA and RNA-protein complex are potentially amenable to this approach. PMID- 23093725 TI - Diagnosis of acetabular labral tears: comparison of three-dimensional intermediate-weighted fast spin-echo MR arthrography with two-dimensional MR arthrography at 3.0 T. AB - BACKGROUND: Magnetic resonance (MR) arthrography is the ideal imaging modality for the acetabular labrum. Three-dimensional (3D) fast spin-echo (FSE) sequences have similar diagnostic performance as two-dimensional (2D) conventional MR imaging for ligaments, menisci, or bone marrow edema in the knee. PURPOSE: To compare the diagnostic accuracy and inter-observer reliability of 3D intermediate weighted FSE sequence and 2D FSE sequences for the diagnosis of acetabular labral tears. MATERIAL AND METHODS: Institutional review board approval was obtained and informed consent was waived for 45 patients (47 hips) who underwent 3D and 2D MR arthrography and subsequent arthroscopic surgery. The 3D sequences were performed using volumetric intermediate-weighted fast spin-echo imaging with fat suppression (voxel size, 0.6 * 0.6 * 1.2 mm; imaging time, 6 min 38 s). Labral tear was retrospectively and independently evaluated by two radiologists in four areas of the labrum (anterosuperior, posterosuperior, anteroinferior, and posteroinferior) on 3D and 2D FSE sequences. Statistical differences between the sensitivity and specificity of the methods were analyzed with the McNemar test, using arthroscopic findings as the reference standard. Inter-observer agreement was calculated using kappa statistics. RESULTS: Arthroscopic findings confirmed labral tears at 40 anterosuperior, 23 posterosuperior, 0 anteroinferior, and 2 posteroinferior quadrants. Sensitivity and specificity were 74% and 89% for 2D FSE sequences, and 78% and 92% for 3D FSE sequences, respectively. Sensitivities and specificities for the methods were not different statistically (P > 0.05). Inter-observer agreement for labral tear was substantial for 2D FSE sequences (kappa = 0.774) and almost perfect for 3D FSE sequences (kappa = 0.842). CONCLUSION: 3D intermediate-weighted FSE MR arthrography is excellent for diagnosing acetabular labral tears. Sensitivity, specificity, and inter-observer reliability were similar to conventional 2D MR arthrography. For evaluation of the labrum, 3D FSE MR arthrography is more time-efficient than 2D FSE MR arthrography. PMID- 23093726 TI - The "bridging sign": a MR finding for combined full-thickness tears of the subscapularis tendon and the supraspinatus tendon. AB - BACKGROUND: In daily practice, we discovered one of the secondary magnetic resonance (MR) findings of the subscapularis (SSC) tendon tear, the "bridging sign", which has not been previously described. PURPOSE: To describe the "bridging sign" on shoulder MR imaging and its radiological and clinical significance in patients with SSC tendon tear. MATERIAL AND METHODS: Twenty-nine patients who had undergone shoulder arthroscopy and had full-thickness tear of the subscapularis tendon were enrolled. The medical records of the 29 patients were retrospectively reviewed for the duration of shoulder pain, rotator cuff tears, and associated arthroscopic findings: biceps tendon abnormality and superior glenoid labral tear. Then, preoperative shoulder MR images were retrospectively reviewed for the presence or absence of the "bridging sign" and associated MR findings: periarticular fluid and fatty atrophy of the supraspinatus and subscapularis muscles. The type of rotator cuff tear associated with the "bridging sign" was assessed and the sensitivity, specificity, and accuracy of the "bridging sign" for the diagnosis of a certain type of rotator cuff tear were calculated. Associated arthroscopic and MR findings and mean duration of the shoulder pain between the patients with and without the "bridging sign" were compared. RESULTS: The "bridging sign" was seen in 17 of 29 patients and corresponded to a complex of the torn and superomedially retracted subscapularis tendon, coracohumeral ligament, and superior glenohumeral ligament, adhered to the anterior margin of the torn supraspinatus (SSP) tendon on arthroscopy. All patients with the "bridging sign" had combined full-thickness tear (FTT) of the cranial 1/2 portion of the subscapularis tendon and anterior 1/2 portion of the SSP tendon. The sensitivity, specificity, and accuracy of the "bridging sign" for the diagnosis of combined FTTs of the SSC tendon and anterior portion of the SSP tendon were 81.0%, 100%, and 86.2%, respectively. The patients with the "bridging sign" had longer duration of shoulder pain and more frequent associated arthroscopic and MR findings than the patients without the "bridging sign". CONCLUSION: The "bridging sign" is a highly specific finding for combined full-thickness tears of the subscapularis tendon and anterior portion of the supraspinatus tendon, associated with more chronic shoulder pain and more sever rotator cuff tear. PMID- 23093727 TI - Sociocultural challenges of beta-thalassaemia major birth in carriers of beta thalassaemia in Iran. AB - OBJECTIVE: Despite premarital screening, prenatal diagnosis and the option for voluntary termination of pregnancy, some Iranian couples continue a pregnancy with a fetus affected with beta-thalassaemia major (beta-TM). We examined the reasons for this decision, to evaluate the sociocultural challenges these couples face. METHODS: A retrospective evaluation of medical records of all fetuses aborted was conducted to identify those with beta-TM, to determine the frequency of beta-TM births and to establish the number of couples with beta-thalassaemia who declined prenatal diagnosis or a termination of pregnancy in this period. We investigated the reasons for declining these options. RESULTS: The birth prevalence of beta-TM decreased from 39.38 to 2.68 in 100,000 live births from 2005 to 2010. Terminations of pregnancy for affected fetuses increased from 67 in 2005 to 135 in 2010. We identified eight couples as beta-thalassaemia carriers who declined prenatal diagnosis or a termination of pregnancy. All but one couple already had a child with beta-TM. The reasons for declining prenatal diagnosis were strong religious beliefs, superstition and faith in a supernatural solution in six couples. Economic and cultural factors, and previous termination of pregnancy were also mentioned as reasons by the other two couples. CONCLUSION: Although most of the couples had a beta-TM child and related socioeconomic problems, their reasons for refusing prenatal diagnosis or termination remain a challenge for the healthcare system in Iran. Couple screening and educational programmes have effectively decreased the rates of refusal in at-risk couples in recent years. PMID- 23093728 TI - Three peaks in the polymerase chain reaction fragile X analysis. AB - OBJECTIVE: To report and discuss the observation of three fragments on polymerase chain reaction (PCR) in routine carrier screening for fragile X. METHODS: From 2005 through 2010, 34,500 women underwent prenatal screening for fragile X. PCR was carried out to amplify the repeat segment. The resulting fragments were scanned by a genetic analyser. RESULTS: Three PCR peaks representing three different-sized fragments were found in 25 of the 34,500 women (1:1380 or 0.072%). Karyotype analysis was performed in 16 subjects. Full triple X was found in three women, while two had triple X mosaicism. Of the 16 karyotyped women, five (31%) had a finding of XXX (full or mosaic). CONCLUSIONS: Triple X (full or mosaic) is the most frequently encountered mechanism responsible for three peaks on fragile X PCR testing. PMID- 23093729 TI - Screening for haemoglobinopathies on cord blood: laboratory and clinical experience. AB - OBJECTIVES: Blood from the umbilical cord (cord blood) is screened for haemoglobinopathies in several neonatal screening programmes, as well as before banking as a source of stem cells. We investigated the pre-analytical and analytical aspects of neonatal screening for haemoglobinopathies on liquid cord blood using the Sebia Haemoglobin kit. We give an interpretation of the results as well as a proposed scheme for reporting of the results. METHODS: A neonatal screening programme on liquid cord blood has been performed in all labour wards in Brussels since 1994. Using that material, the screening methods of isoelectric focusing and capillary zone electrophoresis were compared using 962 cord blood samples. From December 2008 to December 2010, 47,388 neonatal samples were analysed by capillary electrophoresis as the first-line method for neonatal screening. High-performance liquid chromatography was used as the second-line method. RESULTS: Capillary zone electrophoresis on liquid cord blood enabled the detection of all clinically significant haemoglobin variants, significant levels of Hb Bart's, and beta-thalassaemia major. Among the 47,388 neonatal samples tested, 362 (0.7%) were suspected to be contaminated with maternal blood, but no diagnostic error was reported retrospectively for a major haemoglobinopathy. Recommendations for the interpretation and reporting of results of neonatal screening for haemoglobinopathies using the Sebia Haemoglobin kit are proposed. CONCLUSIONS: A routine capillary electrophoresis kit adapted to neonatal screening and liquid cord blood is reliable for screening for haemoglobinopathies. It enables early detection and reporting of all major haemoglobinopathies and most minor ones. It also enables use of a simple scheme to report the results. PMID- 23093730 TI - Dramatic increase in cervical cancer registrations in young women in 2009 in England unlikely to be due to the new policy not to screen women aged 20-24. AB - OBJECTIVE: To explore whether the 17% increase in cervical cancer in England in 2009 was due to the change in cervical screening policy. METHODS: Trends in incidence of cervical cancer and of cervical intraepithelial neoplasia grade 3 (CIN3) were analysed for England, Wales and Scotland. Invasive cervical cancer data on 4079 cancers in women aged 20-39 diagnosed between April 2007 and August 2011 in England were analysed by single year of age. RESULTS: In England there was a 38% (95% confidence intervals [CI] 18-62%) increase in cervical cancer incidence rates in women aged 25-29 in 2009 relative to 2008, and a 30% (11-51%) increase in women aged 35-39. Compared rates in 2010 are similar to those in 2008. The average increase between 2000 and 2010 in women aged 25-29 was no greater in England than in Scotland and Wales (relative risk 0.98, 95% CI 0.69 1.39). In England there has been a gradual increase in CIN3 (particularly for ages 25-29) since 2003, with a more dramatic increase in 2009, but a fall in 2010. Audit data showed an increase in cancers diagnosed at age 25 in 2009/2010 and 2010/2011 (P <= 0.0004). No increase was observed at age 26. For ages 27-29 an increase in cancer was observed for 2008/2009-2009/2010 when compared with 2007/2008-2010/2011 (P < 0.00001), but linear trends were not significant. CONCLUSIONS: The increase in cervical cancer in England in 2009 cannot be attributed to the lack of screening of women aged 20-24, or to a general decrease in the coverage or quality of cervical screening. PMID- 23093731 TI - Efficacy versus effectiveness study design within the European screening trial for prostate cancer: consequences for cancer incidence, overall mortality and cancer-specific mortality. AB - OBJECTIVE: To assess the impact of different study designs on outcome data within the European Randomized Study of Screening for Prostate Cancer (ERSPC). METHODS: Observed data from the Gothenburg centre (effectiveness trial with upfront randomization before informed consent) and the Rotterdam centre (efficacy trial with randomization after informed consent) were compared with expected data, which were retrieved from national cancer registries and life tables. Endpoints were 11-year cumulative prostate cancer (PC) incidence, overall mortality and PC specific mortality. RESULTS: In Gothenburg, the 11-year PC incidence was higher than predicted (5.8%) in both the intervention (12.4%) and control arms (7.3%). The observed overall mortality was higher than predicted (15.9%) in both the intervention (17.8%) and control arms (18.5%). The observed PC-specific mortality in the intervention arm was 0.56% versus 0.83% in the control arm, while the expected mortality was 0.83%. In Rotterdam, the observed PC incidence in the intervention arm (10.4%) was higher than expected (4.4%). The incidence in the control arm was 4.6%. The observed overall mortality was lower than expected: 13.6% in the intervention arm and 14.0% in the control arm versus an expected mortality of 16.1%. The observed PC-specific mortality was lower than expected (0.65%) in both the intervention (0.27%) and control arms (0.41%). CONCLUSIONS: Our results suggest that an efficacy trial with informed consent prior to randomization may have introduced a 'healthy screenee bias'. Therefore, an effectiveness trial with consent after randomization may more accurately estimate the PC-specific mortality reduction if population-based screening is introduced. PMID- 23093732 TI - Evaluating the evidence: direct-to-consumer screening tests advertised online. AB - OBJECTIVES: Unsupervised online direct-to-consumer (DTC) access to medical services has rapidly expanded to medical screening tests, which have not been critically evaluated for their evidence basis. The objective of this study is to identify the scope of online-advertised DTC screening tests, outline the evidence for use of available DTC testing and suggest regulatory reform to address the relevant issues. METHODS: An observational study of website advertisements, testing services and counselling/follow-up services for DTC testing was conducted. Data were collected from websites between 4 April and 1 June 2011. Each website was assessed for tests offered, advertised indications and availability of counselling/follow-up services. Advertised testing indications were compared with US Preventive Services Task Force recommendations and/or specialty guidelines and categorized as Supported, Against, Insufficient Evidence or No Guidance. RESULTS: Of 20 companies identified as offering DTC screening tests, 95% (19/20) do not clearly offer pretest counselling, post-test counselling and/or test follow-up. One hundred and twenty-seven different tests were identified. Only 19/127 (15%) could be Supported for screening in a target group selected for testing; 38/127 (30%) were given recommendations to avoid use in specific target group(s) selected for testing ('Against recommendations'); 29/127 (23%) had Insufficient Evidence of value, and for 64/127 (50%) No Guidance could be given. Only 4/127 (3%) tests were Supported for general screening use. CONCLUSIONS: Virtually all identified medical tests advertised and offered DTC are not recommended for use in screening by evidence-based guidelines. Limited oversight may lead to inaccurate self-diagnosis, treatment and wasted health resources. PMID- 23093733 TI - Newborn screening for alpha-thalassaemia by a capillary electrophoresis method. PMID- 23093735 TI - Comparison of self-obtained penile-meatal swabs to urine for the detection of C. trachomatis, N. gonorrhoeae and T. vaginalis. AB - BACKGROUND: Self-obtained penile-meatal swabs and urine specimens have been used for Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) for outreach screening in men. OBJECTIVE: To compare the sensitivity of self-collected male penile-meatal swabs and urine for the detection of CT, NG and TV. METHODS: Matching penile-meatal swabs and urines were collected at home after recruitment to the study; via the internet programme, http://www.iwantthekit.org. The instructions directed the participant to place the tip of a Copan flocked swab at the meatal opening of the urethra to collect the penile-meatal sample. Two ml of urine was collected after the swab onto a Copan sponge-on-a-shaft collection device. Both swab and urine were placed into individual Aptima transport media tubes and mailed to the laboratory for testing. All specimens were tested for CT and NG using the GenProbe Aptima Combo2 Assay and for TV using GenProbe Aptima Analyte Specific Reagents with TV oligonucleotides. RESULTS: Of 634 men, 86 (13.6%) were positive for CT, 9 (1.4%) were positive for NG and 56 (9.3%) positive for TV. For CT, swab sensitivity was 81/86 (94.2%), and urine sensitivity was 66/86 (76.7%). For NG, swab sensitivity was 9/9 (100%) and urine sensitivity was 8/9 (88.9%). For TV, swab sensitivity was 45/56 (80.4%) and urine sensitivity was 22/56 (39.3%). CONCLUSIONS: Self obtained penile-meatal swabs provided for the detection of more CT, NG and TV, than urine specimens. PMID- 23093736 TI - Point-of-care tests for the diagnosis of Neisseria gonorrhoeae infection: a systematic review of operational and performance characteristics. AB - OBJECTIVES: Systematic review of the performance and operational characteristics of point-of-care (POC) tests for the diagnosis of Neisseria gonorrhoeae. METHODS: We searched PubMed and Embase until August 2010 using variations of the terms: 'rapid test', 'Neisseria gonorrhoeae' and 'evaluation'. RESULTS: We identified 100 papers, 14 studies were included; nine evaluated leucocyte esterase (LE) dipsticks and three immunochromatographic strips, and two clinical audits of microscopy were identified. Of the field evaluations the gold standard was nucleic acid amplification technology in six studies and bacterial culture in the other six. In four studies, 50% or more of the patients were symptomatic. The median sensitivity of LE dipsticks was 71% (range 23-85%), median specificity was 70% (33-99%), median positive predictive value (PPV) was 19% (5-40%) and median negative predictive value (NPV) was 95% (56-99%). One LE study found a sensitivity of 23% overall, increasing to 75% in symptomatic women. LE dipsticks mostly involved three steps and took under 2 min. The median sensitivity of immunochromatographic tests (ICT) was 70% (60-94%), median specificity was 96% (89-97%), median PPV was 56% (55-97%) and median NPV was 93% (92-99%). Immunochromatic strips involved five to seven steps and took 15-30 min. Specificity of microscopy ranged from 38% to 89%. CONCLUSIONS: ICT and LE tests had similar sensitivities, but sensitivity results may be overestimated as largely symptomatic patients were included in some studies. ICT had a higher specificity in women than LE tests. The findings highlight the need for improved POC tests for diagnosis of N gonorrhoeae and more standardised evaluations. PMID- 23093738 TI - Condoms, bloody condoms; yet more problems. PMID- 23093739 TI - Community pharmacy and cash reward: a winning combination for chlamydia screening? AB - OBJECTIVES: To date, the uptake of chlamydia screening in community pharmacies has been limited. The objective of this cross-sectional study was to determine if a cash reward, offered to both the provider and the consumer of chlamydia screening, increased the uptake of screening in community pharmacies. METHODS: During 4 weeks in 2011, chlamydia screening and education were offered in four city and two suburban pharmacies to people aged 16-30 years. Those who provided a urine sample for testing, contact details, and completed a brief questionnaire were rewarded with $A10. Positive participants, and their nominated contacts, were offered treatment. RESULTS: Over a period of 751.5 h, 979 testing kits were requested, and 900 (93%) urine samples returned. Using probabilistic linkage methods, we determined that 671/900 (75%) urine samples were from unique individuals. 0.9 unique samples were obtained/hour of screening, 63% of which were provided by men. 19/671 (2.8%; 95% CI 1.7% to 4.4%) people tested positive, 5.2% (95% CI 2.8% to 8.8%) of women, and 1.4% (1.4 0.5 to 3.1) of men. 11/19 (58%) people were contacted and treated-two for suspected pelvic inflammatory disease. CONCLUSIONS: Providing a cash reward to encourage chlamydia screening in community pharmacies resulted in greater participation rates than previously reported pharmacy-based studies, particularly among men. Easily implemented mechanisms to reduce inappropriate repeat screening, incorrect contact details and effects on pharmacy work flow may enhance the efficiency of this approach. PMID- 23093740 TI - Mainstreaming HIV services for men who have sex with men: the role of general practitioners. PMID- 23093741 TI - International Workshop on Improving Data Quality and Quantity for XAFS Experiments (Q2XAFS 2011). PMID- 23093742 TI - A step toward standardization: development of accurate measurements of X-ray absorption and fluorescence. AB - This paper explains how to take the counting precision available for XAFS (X-ray absorption fine structure) and attenuation measurements, of perhaps one part in 10(6) in special cases, to produce a local variance below 0.01% and an accuracy of attenuation of the order 0.01%, with an XAFS accuracy at a similar level leading to the determination of dynamical bond lengths to an accuracy similar to that obtained by standard and experienced crystallographic measurements. This includes the necessary corrections for the detector response to be linear, including a correction for dark current and air-path energy dependencies; a proper interpretation of the range of sample thicknesses for absorption experiments; developments of methods to measure and correct for harmonic contamination, especially at lower energies without mirrors; the significance of correcting for the actual bandwidth of the beam on target after monochromation, especially for the portability of results and edge structure from one beamline to another; definitions of precision, accuracy and XAFS accuracy suitable for theoretical model analysis; the role of additional and alternative high-accuracy procedures; and discusses some principles regarding data formats for XAFS and for the deposition of data sets with manuscripts or to a database. Increasingly, the insight of X-ray absorption and the standard of accuracy needed requires data with high intrinsic precision and therefore with allowance for a range of small but significant systematic effects. This is always crucial for absolute measurements of absorption, and is of equal importance but traditionally difficult for (usually relative) measurements of fluorescence XAFS or even absorption XAFS. Robust error analysis is crucial so that the significance of conclusions can be tested within the uncertainties of the measurements. Errors should not just include precision uncertainty but should attempt to include estimation of the most significant systematic error contributions to the results. This is essential if the results are to be subject to deposition in a central accessible reference database; it is also crucial for specifying a standard data format for portability and ease of use by depositors and users. In particular this will allow development of theoretical formulations to better serve the world wide XAFS community, and a higher and more easily comparable standard of manuscripts. PMID- 23093743 TI - XAFS data collection: an integrated approach to delivering good data. AB - Energy scale calibration and reliable intensity measurement are the main issues related to the collection of good spectroscopy data. The accurate determination of the energy scale is often established by using foils of optimum thickness to calibrate the monochromator. However, mechanical issues with the monochromator, movement of the source, or even the resolution of the spectrometer can have an effect on the measured energy scale. For the issue of accurate intensity measurements, calibrated detectors are necessary to ensure a reliable measurement of the spectroscopic signal, both in transmission and fluorescence detection modes. In this paper a review of the most common techniques used for energy calibration and for collecting X-ray absorption spectroscopy data is given, together with a brief description of the factors that have an impact on the intensity of the measured signal. A brief description of the versatile X-ray absorption spectroscopy beamline, I20, at Diamond Light Source is also presented, giving particular emphasis on how the beamline design has been undertaken to tackle these key issues. In particular, the use of a four-bounce monochromator will be discussed, highlighting the advantages of the device for the measurement of spectroscopy data. PMID- 23093744 TI - Towards data format standardization for X-ray absorption spectroscopy. AB - A working group on data format standardization for X-ray absorption spectroscopy (XAS) has recently formed under the auspices of the International X-ray Absorption Society and the XAFS Commission of the International Union of Crystallography. This group of beamline scientists and XAS practitioners has been tasked to propose data format standards to meet the needs of the world-wide XAS community. In this report, concepts for addressing three XAS data storage needs are presented: a single spectrum interchange format, a hierarchical format for multispectral X-ray experiment, and a relational database format for XAS data libraries. PMID- 23093746 TI - X-ray absorption spectroscopy at a protein crystallography facility: the Canadian Light Source beamline 08B1-1. AB - It is now possible to perform X-ray absorption spectroscopy (XAS) on metalloprotein crystals at the Canadian Macromolecular Crystallography Facility bend magnet (CMCF-BM) beamline (08B1-1) at the Canadian Light Source. The recent addition of a four-element fluorescence detector allows users to acquire data suitable for X-ray absorption near-edge structure and extended X-ray absorption fine-structure based studies by monitoring fluorescence. CMCF beamline users who wish to supplement their diffraction data with XAS can do so with virtually no additional sample preparation. XAS data collection is integrated with the established Mx Data Collector software package used to collect diffraction data. Mainstream XAS data-processing software packages are available for the users; assistance with data processing and interpretation by staff is also available upon request. PMID- 23093747 TI - IR and X-ray time-resolved simultaneous experiments: an opportunity to investigate the dynamics of complex systems and non-equilibrium phenomena using third-generation synchrotron radiation sources. AB - Third-generation storage rings are modern facilities working with high currents and designed to host powerful radiation sources, like undulators and wigglers, and to deliver high-brilliance beams to users. Many experiments at high spatial resolution, such as spectromicroscopy at the nanometre scale and with high temporal resolution to investigate kinetics down to the picosecond regime, are now possible. The next frontier is certainly the combination of different methods in a unique set-up with the ultimate available spatial and temporal resolutions. In the last decade much synchrotron-based research has exploited the advantage of complementary information provided by time-resolved X-ray techniques and optical methods in the UV/Vis and IR domains. New time-resolved and concurrent approaches are necessary to characterize complex systems where physical-chemical phenomena occur under the same experimental conditions, for example to detect kinetic intermediates via complementary but independent observations. In this contribution we present scientific cases from original works and literature reviews to support the proposed IR/X-ray simultaneous approach, with both probes exploiting synchrotron radiation sources. In addition, simple experimental layouts that may take advantage of the high brilliance and the wide spectral distribution of the synchrotron radiation emission will be given for specific researches or applications to investigate dynamic processes and non-equilibrium phenomena occurring in many condensed matter and biological systems, of great interest for both fundamental research and technological applications. PMID- 23093745 TI - X-ray-induced photo-chemistry and X-ray absorption spectroscopy of biological samples. AB - As synchrotron light sources and optics deliver greater photon flux on samples, X ray-induced photo-chemistry is increasingly encountered in X-ray absorption spectroscopy (XAS) experiments. The resulting problems are particularly pronounced for biological XAS experiments. This is because biological samples are very often quite dilute and therefore require signal averaging to achieve adequate signal-to-noise ratios, with correspondingly greater exposures to the X ray beam. This paper reviews the origins of photo-reduction and photo-oxidation, the impact that they can have on active site structure, and the methods that can be used to provide relief from X-ray-induced photo-chemical artifacts. PMID- 23093748 TI - Design considerations for a new beamline for standard EXAFS at a high-energy low emittance storage ring. AB - P65 is a new EXAFS beamline to be built at the PETRA III storage ring at DESY in Hamburg. It will mainly be used for standard EXAFS applications with a relatively large beam and moderate flux density. While the beamline optics will be similar to many other standard EXAFS beamlines, the insertion device at such a large high energy storage ring with low emittance like PETRA III will need special attention. This paper discusses the main design considerations for the construction of such a beamline at a 6 GeV storage ring with an emittance of 1 nm rad. PMID- 23093749 TI - A tool to plan photon-in/photon-out experiments: count rates, dips and self absorption. AB - A program that helps to plan experiments where the emitted X-rays are detected is presented. The tool is based on the standard formula for fluorescence-detected X ray absorption spectroscopy and uses tabulated parameters to estimate count rates. The objective is to evaluate the feasibility of an experiment, estimate the influence of self-absorption on the spectral shape and investigate the possibility of range-extended EXAFS. The occurrence of 'negative' edges, i.e. a decrease in the detected signal, is discussed. PMID- 23093750 TI - T-REX: new software for advanced QEXAFS data analysis. AB - New approaches to analyze the data generated by modern time-resolved X-ray absorption spectroscopy instrumentation are presented as part of a new analysis software to handle files containing typically a few thousand EXAFS spectra. Various filter techniques to remove high-frequency noise and run-away values are discussed as well as advanced analysis tools like linear combination fitting, EXAFS fitting, principal component analysis and phase-sensitive detection. These techniques were implemented in a user-friendly graphical user interface to analyse huge data files where it is not possible to treat each spectrum separately. New ideas to exploit existent tools more efficiently for time resolved EXAFS data analysis are discussed theoretically as well as applied to real measurements, especially in situ catalytic experiments and surface-sensitive reflection-mode X-ray absorption studies of thin film growth. PMID- 23093751 TI - Performance and status of beamline BL8 at SLRI for X-ray absorption spectroscopy. AB - Beamline BL8 of the Synchrotron Light Research Institute (Thailand) is routinely operated for X-ray absorption spectroscopy (XAS) in an intermediate photon energy range (1.25-10 keV). The photon energy is scanned by using a double-crystal monochromator, the crystal pair of which can be interchanged among KTP(011), InSb(111), Si(111) and Ge(220). The experimental set-up conveniently facilitates XAS measurements in transmission and fluorescence-yield modes at several K-edges of elements ranging from magnesium to zinc. Instrumentation and specification of the beamline and the XAS station are described, together with the determination of the available photon flux [0.1-6 * 10(10) photon s(-1) (100 mA)(-1)], energy resolution (1-5 * 10(-4)) and stability of photon energy calibration (0.07 eV), representing the beamline performance. Data quality and accuracy of XANES and EXAFS measured at BL8 are compared with those of other well established beamlines. A noted distinction of BL8 is its relatively high sensitivity for studying phosphorous, sulfur and chlorine in diluted systems and its maximum beam size of 14 mm (width) * 1 mm (height), which is suitable for bulk characterization. PMID- 23093752 TI - Time-resolved XAS (Bonn-SUT-SLRI) beamline at SLRI. AB - An energy-dispersive X-ray absorption spectroscopy beamline has been constructed at the Synchrotron Light Research Institute, Thailand. The beamline was designed to utilize the synchrotron radiation with photon energies between 2400 and 8000 eV. The horizontal focusing of the bent crystal in the energy-dispersive monochromator offers a small polychromatic focal spot of 1 mm at the sample position. By employing an energy-dispersive scheme, the whole X-ray absorption near-edge structure (XANES) can be obtained simultaneously using a position sensitive detector with a fastest readout speed of 25 ms. The short data collection time opens a new opportunity for time-resolved X-ray absorption spectroscopy (XAS) experiments such as studies of changes of the electronic structures or the local coordination environments of an atom during a change in thermodynamic conditions. For this purpose, an in situ cell was designed and fabricated for the beamline. Thermal oxidation of TiO(2) was chosen as an in situ experiment example. The structural change of TiO(2) as a function of temperatures was monitored from the change in the measured XAS spectra. The obtained Ti K-edge XANES spectra clearly show the formation of an anatase phase when the temperature was raised to 673 K. PMID- 23093753 TI - Complete polarization analysis of an APPLE II undulator using a soft X-ray polarimeter. AB - Two APPLE II undulators installed on the Diamond I10 beamline have all four magnet arrays shiftable and thus can generate linear polarization at any arbitrary angle from 0 degrees to 180 degrees , as well as all other states of elliptical polarization. To characterize the emitted radiation polarization state from one APPLE II undulator, the complete polarization measurement was performed using a multilayer-based soft X-ray polarimeter. The measurement results appear to show that the linear polarization angle offset is about 6 degrees compared with other measurements at 712 eV, equivalent to an undulator jaw phase offset of 1.1 mm. In addition, the polarization states of various ellipticities have also been measured as a function of the undulator row phase. PMID- 23093754 TI - A variable ultra-short-pathlength solution cell for XAFS transmission spectroscopy of light elements. AB - An X-ray absorption fine-structure spectroscopy (XAFS) cell that is suitable for solution-phase studies of the light elements in the series from Na(+) and Ca(2+) is described. This cell has an ultra-short pathlength that can be remotely adjusted using a miniature stepper-motor drive and thereby readily provides transmission pathlengths in the range from submicrometer to several hundred micrometers. The flexibility to vary the pathlength enables acquisition of high quality XAFS spectra and also allows one to check for potential distortions in the spectra from thickness effects. The primary components are mostly commercially available optical parts. The performance of this device is demonstrated at the Cl K-edge (2.8 keV) for several different aqueous Cl(-) solutions. PMID- 23093755 TI - Single-exposure dual-energy-subtraction X-ray imaging using a synchrotron source. AB - Projection radiography of the chest has long been plagued by the presence of bony anatomy obscuring visibility of the lungs and heart. Dual-energy subtraction is a well known method for differentiating bone and soft tissue, but existing techniques are not ideally suited to dynamic imaging. Herein a new technique to address this problem is presented. The harmonic content of a monochromated X-ray beam is exploited, and two in-line detectors are used to perform single-exposure dual-energy imaging. Images of a phantom demonstrate the ability to both separate and quantitatively measure the thickness of constituent materials, whilst images of a mouse thorax demonstrate the ability to separate bone and soft tissue in a biological specimen. The technique is expected to improve the performance of dynamic lung imaging. PMID- 23093756 TI - In situ beamline analysis and correction of active optics. AB - At the Diamond Light Source, pencil-beam measurements have enabled long wavelength slope errors on X-ray mirror surfaces to be examined under ultra-high vacuum and beamline mounting without the need to remove the mirror from the beamline. For an active mirror an automated procedure has been implemented to calculate the actuator settings that optimize its figure. More recently, this in situ pencil-beam method has been applied to additional uses for which ex situ measurements would be inconvenient or simply impossible. First, it has been used to check the stability of the slope errors of several bimorph mirrors at intervals of several weeks or months. Then, it also proved useful for the adjustment of bender and sag compensation actuators on mechanically bent mirrors. Fits to the bending of ideal beams have been performed on the slope errors of a mechanically bent mirror in order to distinguish curvatures introduced by the bending actuators from gravitational distortion. Application of the optimization procedure to another mechanically bent mirror led to an improvement of its sag compensation mechanism. PMID- 23093757 TI - QXAFS system of the BL14W1 XAFS beamline at the Shanghai Synchrotron Radiation Facility. AB - The quick-scanning XAFS (QXAFS) method is achieved at the BL14W1 XAFS beamline at the Shanghai Synchrotron Radiation Facility based on the EPICS and LabVIEW systems. This is realised by the unprecedented use of LabVIEW's data logging and supervisory control module for communication with EPICS in synchrotron radiation facilities. A fine QXAFS spectrum with an energy range of 1.2 keV at the Cu K edge has been collected in 2 s with stable beam position and the data quality is comparable with that of the step-mode XAFS spectrum. Analog-to-digital converter and double-crystal monochromator set-ups have been optimized in order to acquire optimal parameters for the QXAFS experiments. Signal-to-noise ratios of these spectra have been calculated in order to estimate the importance of these parameters. PMID- 23093758 TI - Accurate dosimetry in scanning transmission X-ray microscopes via the cross linking threshold dose of poly(methyl methacrylate). AB - The sensitivity of various polymers to radiation damage by soft X-rays has been measured previously with scanning transmission X-ray microscopes. However, the critical dose values reported by different groups for the same material differ by more than 100%. Possible sources of this variability are investigated here for poly(methyl methacrylate) (PMMA) using controlled exposure to monochromatic soft X-rays at 300 eV. Radiation sensitivity, judged by several different criteria, was evaluated as a function of dose rate, pre-exposure thermal treatments and X ray polarization. Both the measured critical dose and the dose required to initiate negative mode (cross-linking) were observed to depend only on dose, not the other factors explored. A method of determining detector efficiency from the dose required to initiate negative mode in PMMA is outlined. This method was applied to many of the soft X-ray STXMs presently operating to derive the efficiencies of their transmitted X-ray detectors in the C 1s absorption-edge region. PMID- 23093759 TI - X-ray photon correlation spectroscopy using a fast pixel array detector with a grid mask resolution enhancer. AB - The performance of a fast pixel array detector with a grid mask resolution enhancer has been demonstrated for X-ray photon correlation spectroscopy (XPCS) measurements to investigate fast dynamics on a microscopic scale. A detecting system, in which each pixel of a single-photon-counting pixel array detector, PILATUS, is covered by grid mask apertures, was constructed for XPCS measurements of silica nanoparticles in polymer melts. The experimental results are confirmed to be consistent by comparison with other independent experiments. By applying this method, XPCS measurements can be carried out by customizing the hole size of the grid mask to suit the experimental conditions, such as beam size, detector size and sample-to-detector distance. PMID- 23093760 TI - Accounting for low-frequency synchrotron X-ray beam position fluctuations for dynamic visualizations. AB - Synchrotron X-ray radiography on beamline 05B1-1 at the Canadian Light Source Inc. was employed to study dynamic liquid water transport in the porous electrode materials of polymer electrolyte membrane fuel cells. Dynamic liquid water distributions were quantified for each radiograph in a sequence, and non-physical liquid water measurements were obtained. It was determined that the position of the beam oscillated vertically with an amplitude of ~25 um at the sample and a frequency of ~50 mHz. In addition, the mean beam position moved linearly in the vertical direction at a rate of 0.74 um s(-1). No evidence of horizontal oscillations was detected. In this work a technique is presented to account for the temporal and spatial dependence of synchrotron beam intensity, which resulted in a significant reduction in false water thickness. This work provides valuable insight into the treatment of radiographic time-series for capturing dynamic processes from synchrotron radiation. PMID- 23093761 TI - Capturing dynamics with Eiger, a fast-framing X-ray detector. AB - Eiger is the next-generation single-photon-counting pixel detector following the widely used Pilatus detector. Its smaller pixel size of 75 um * 75 um, higher frame rate of up to 22 kHz, and practically zero dead-time (~4 us) between exposures will further various measurement methods at synchrotron sources. In this article Eiger's suitability for X-ray photon correlation spectroscopy (XPCS) is demonstrated. By exploiting its high frame rate, complementary small-angle X ray scattering (SAXS) and XPCS data are collected in parallel to determine both the structure factor and collective diffusion coefficient of a nano-colloid suspension. For the first time, correlation times on the submillisecond time scale are accessible with a large-area pixel detector. PMID- 23093762 TI - The point-spread function of fiber-coupled area detectors. AB - The point-spread function (PSF) of a fiber-optic taper-coupled CCD area detector was measured over five decades of intensity using a 20 um X-ray beam and ~2000 fold averaging. The 'tails' of the PSF clearly revealed that it is neither Gaussian nor Lorentzian, but instead resembles the solid angle subtended by a pixel at a point source of light held a small distance (~27 um) above the pixel plane. This converges to an inverse cube law far from the beam impact point. Further analysis revealed that the tails are dominated by the fiber-optic taper, with negligible contribution from the phosphor, suggesting that the PSF of all fiber-coupled CCD-type detectors is best described as a Moffat function. PMID- 23093763 TI - A proof-of-principle experiment of a novel harmonics separation optics for synchrotron facilities. AB - A proof-of-principle experiment of a novel harmonics separation optics for synchrotron facilities is presented. The harmonic separator is a Si crystal cut in an inclined geometry in which the impinging beam undergoes a diffractive refractive effect owing to the dispersive nature of X-ray refraction. A polychromatic beam containing higher-order energies is spatially separated behind the separator into individual monochromatic diffraction spots. A synchrotron experiment at a bending-magnet beamline with 7 keV fundamental energy is presented. The spot of the third-order harmonic of 21 keV is deviated from the fundamental by 0.35 mm at a distance 1 m behind the device. PMID- 23093764 TI - X-ray beam monitor made by thin-film CVD single-crystal diamond. AB - A novel beam position monitor, operated at zero bias voltage, based on high quality chemical-vapor-deposition single-crystal Schottky diamond for use under intense synchrotron X-ray beams was fabricated and tested. The total thickness of the diamond thin-film beam monitor is about 60 um. The diamond beam monitor was inserted in the B16 beamline of the Diamond Light Source synchrotron in Harwell (UK). The device was characterized under monochromatic high-flux X-ray beams from 6 to 20 keV and a micro-focused 10 keV beam with a spot size of approximately 2 um * 3 um square. Time response, linearity and position sensitivity were investigated. Device response uniformity was measured by a raster scan of the diamond surface with the micro-focused beam. Transmissivity and spectral responsivity versus beam energy were also measured, showing excellent performance of the new thin-film single-crystal diamond beam monitor. PMID- 23093765 TI - A 30 nm-resolution hard X-ray microscope with X-ray fluorescence mapping capability at BSRF. AB - A full-field transmission X-ray microscope (TXM) operating continuously from 5 keV to 12 keV with fluorescence mapping capability has been designed and constructed at the Beijing Synchrotron Radiation Facility, a first-generation synchrotron radiation facility operating at 2.5 GeV. Spatial resolution better than 30 nm has been demonstrated using a Siemens star pattern in both absorption mode and Zernike phase-contrast mode. A scanning-probe mode fluorescence mapping capability integrated with the TXM has been shown to provide 50 p.p.m. sensitivity for trace elements with a spatial resolution (limited by probing beam spot size) of 20 um. The optics design, testing of spatial resolution and fluorescence sensitivity are presented here, including performance measurement results. PMID- 23093766 TI - Regridding reconstruction algorithm for real-time tomographic imaging. AB - Sub-second temporal-resolution tomographic microscopy is becoming a reality at third-generation synchrotron sources. Efficient data handling and post-processing is, however, difficult when the data rates are close to 10 GB s(-1). This bottleneck still hinders exploitation of the full potential inherent in the ultrafast acquisition speed. In this paper the fast reconstruction algorithm gridrec, highly optimized for conventional CPU technology, is presented. It is shown that gridrec is a valuable alternative to standard filtered back-projection routines, despite being based on the Fourier transform method. In fact, the regridding procedure used for resampling the Fourier space from polar to Cartesian coordinates couples excellent performance with negligible accuracy degradation. The stronger dependence of the observed signal-to-noise ratio for gridrec reconstructions on the number of angular views makes the presented algorithm even superior to filtered back-projection when the tomographic problem is well sampled. Gridrec not only guarantees high-quality results but it provides up to 20-fold performance increase, making real-time monitoring of the sub-second acquisition process a reality. PMID- 23093767 TI - Diffraction-enhanced X-ray imaging under low-temperature conditions: non destructive observations of clathrate gas hydrates. AB - Diffraction-enhanced imaging (DEI) is a phase-contrast X-ray imaging technique suitable for visualizing light-element materials. The method also enables observations of sample-containing regions with large density gradients. In this study a cryogenic imaging technique was developed for DEI-enabled measurements at low temperature from 193 K up to room temperature with a deviation of 1 K. Structure-II air hydrate and structure-I carbon dioxide (CO(2)) hydrate were examined to assess the performance of this cryogenic DEI technique. It was shown that this DEI technique could image gas hydrate coexisting with ice and gas bubbles with a density resolution of about 0.01 g cm(-3) and a wide dynamic density range of about 1.60 g cm(-3). In addition, this method may be a way to make temperature-dependent measurements of physical properties such as density. PMID- 23093768 TI - Coupling transmission electron microscopy with synchrotron radiation X-ray fluorescence microscopy to image vascular copper. AB - Recently, using synchrotron radiation X-ray fluorescence microscopy (SRXRF), the copper accumulation in rat aortic elastin and copper topography in human THP-1 cell monolayer have been described. However, it is necessary to locate more accurately cellular copper in the vascular cells and tissues. In the current study, SRXRF coupling with transmission electron microscopy (TEM) was used to image copper in sections of human THP-1 cells and mouse aorta. The results showed that sections of 1 um thickness are required for SRXRF producing a correlative image with TEM between copper topography and cellular ultrastructure. As compared with SRXRF alone, coupling TEM with SRXRF can clearly identify the location of copper in the nucleus and nucleolus in non-dividing THP-1 cell sections, and can differentiate the copper location at elastic laminae from collagen in mouse aortic sections. Thus, these results revealed new information about the copper topography in vascular cells and tissues and highlighted the potential of TEM SRXRF to investigate the role of copper in macrophage and aortic homeostasis. PMID- 23093769 TI - X-ray velocimetry within the ex vivo carotid artery. AB - X-ray velocimetry offers a non-invasive method by which blood flow, blood velocity and wall shear stress can be measured in arteries prone to atherosclerosis. Analytical tools for measuring haemodynamics in artificial arteries have previously been developed and here the first quantification of haemodynamics using X-ray velocimetry in a living mammalian artery under physiologically relevant conditions is demonstrated. Whole blood seeded with a clinically used ultrasound contrast agent was pumped with a steady flow through live carotid arterial tissue from a rat, which was kept alive in a physiological salt solution. Pharmacological agents were then used to produce vascular relaxation. Velocity measurements were acquired with a spatial resolution of 14 um * 14 um and at a rate of 5000 acquisitions per second. Subtle velocity changes that occur are readily measurable, demonstrating the ability of X-ray velocimetry to sensitively and accurately measure haemodynamics ex vivo. Future applications and possible limitations of the technique are discussed, which allows for detailed living tissue investigations to be carried out for various disease models, including atherosclerosis and diabetic vasculopathy. PMID- 23093770 TI - A hard X-ray nanoprobe beamline for nanoscale microscopy. AB - The Hard X-ray Nanoprobe Beamline (or Nanoprobe Beamline) is an X-ray microscopy facility incorporating diffraction, fluorescence and full-field imaging capabilities designed and operated by the Center for Nanoscale Materials and the Advanced Photon Source at Sector 26 of the Advanced Photon Source at Argonne National Laboratory. This facility was constructed to probe the nanoscale structure of biological, environmental and material sciences samples. The beamline provides intense focused X-rays to the Hard X-ray Nanoprobe (or Nanoprobe) which incorporates Fresnel zone plate optics and a precision laser sensing and control system. The beamline operates over X-ray energies from 3 to 30 keV, enabling studies of most elements in the periodic table, with a particular emphasis on imaging transition metals. PMID- 23093771 TI - Dame Louise Napier Johnson (1940-2012). PMID- 23093773 TI - Targeted deletion of Vegfa in adult mice induces vision loss. AB - Current therapies directed at controlling vascular abnormalities in cancers and neovascular eye diseases target VEGF and can slow the progression of these diseases. While the critical role of VEGF in development has been well described, the function of locally synthesized VEGF in the adult eye is incompletely understood. Here, we show that conditionally knocking out Vegfa in adult mouse retinal pigmented epithelial (RPE) cells, which regulate retinal homeostasis, rapidly leads to vision loss and ablation of the choriocapillaris, the major blood supply for the outer retina and photoreceptor cells. This deletion also caused rapid dysfunction of cone photoreceptors, the cells responsible for fine visual acuity and color vision. Furthermore, Vegfa deletion showed significant downregulation of multiple angiogenic genes in both physiological and pathological states, whereas the deletion of the upstream regulatory transcriptional factors HIFs did not affect the physiological expressions of angiogenic genes. These results suggest that endogenous VEGF provides critical trophic support necessary for retinal function. Targeting factors upstream of VEGF, such as HIFs, may be therapeutically advantageous compared with more potent and selective VEGF antagonists, which may have more off-target inhibitory trophic effects. PMID- 23093774 TI - Obesity-programmed mice are rescued by early genetic intervention. AB - Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity. PMID- 23093775 TI - Hypoxic pulmonary vasoconstriction requires connexin 40-mediated endothelial signal conduction. AB - Hypoxic pulmonary vasoconstriction (HPV) is a physiological mechanism by which pulmonary arteries constrict in hypoxic lung areas in order to redirect blood flow to areas with greater oxygen supply. Both oxygen sensing and the contractile response are thought to be intrinsic to pulmonary arterial smooth muscle cells. Here we speculated that the ideal site for oxygen sensing might instead be at the alveolocapillary level, with subsequent retrograde propagation to upstream arterioles via connexin 40 (Cx40) endothelial gap junctions. HPV was largely attenuated by Cx40-specific and nonspecific gap junction uncouplers in the lungs of wild-type mice and in lungs from mice lacking Cx40 (Cx40-/-). In vivo, hypoxemia was more severe in Cx40-/- mice than in wild-type mice. Real-time fluorescence imaging revealed that hypoxia caused endothelial membrane depolarization in alveolar capillaries that propagated to upstream arterioles in wild-type, but not Cx40-/-, mice. Transformation of endothelial depolarization into vasoconstriction involved endothelial voltage-dependent alpha1G subtype Ca2+ channels, cytosolic phospholipase A2, and epoxyeicosatrienoic acids. Based on these data, we propose that HPV originates at the alveolocapillary level, from which the hypoxic signal is propagated as endothelial membrane depolarization to upstream arterioles in a Cx40-dependent manner. PMID- 23093776 TI - A misplaced lncRNA causes brachydactyly in humans. AB - Translocations are chromosomal rearrangements that are frequently associated with a variety of disease states and developmental disorders. We identified 2 families with brachydactyly type E (BDE) resulting from different translocations affecting chromosome 12p. Both translocations caused downregulation of the parathyroid hormone-like hormone (PTHLH) gene by disrupting the cis-regulatory landscape. Using chromosome conformation capturing, we identified a regulator on chromosome 12q that interacts in cis with PTHLH over a 24.4-megabase distance and in trans with the sex-determining region Y-box 9 (SOX9) gene on chromosome 17q. The element also harbored a long noncoding RNA (lncRNA). Silencing of the lncRNA, PTHLH, or SOX9 revealed a feedback mechanism involving an expression-dependent network in humans. In the BDE patients, the human lncRNA was upregulated by the disrupted chromosomal association. Moreover, the lncRNA occupancy at the PTHLH locus was reduced. Our results document what we believe to be a novel in cis- and in trans-acting DNA and lncRNA regulatory feedback element that is reciprocally regulated by coding genes. Furthermore, our findings provide a systematic and combinatorial view of how enhancers encoding lncRNAs may affect gene expression in normal development. PMID- 23093777 TI - HELLP babies link a novel lincRNA to the trophoblast cell cycle. AB - The HELLP syndrome is a pregnancy-associated disease inducing hemolysis, elevated liver enzymes, and low platelets in the mother. Although the HELLP symptoms occur in the third trimester in the mother, the origin of the disease can be found in the first trimester fetal placenta. A locus for the HELLP syndrome is present on chromosome 12q23 near PAH. Here, by multipoint nonparametric linkage, pedigree structure allele sharing, and haplotype association analysis of affected sisters and cousins, we demonstrate that the HELLP locus is in an intergenic region on 12q23.2 between PMCH and IGF1. We identified a novel long intergenic noncoding RNA (lincRNA) transcript of 205,012 bases with (peri)nuclear expression in the extravillous trophoblast using strand-specific RT-PCR complemented with RACE and FISH. siRNA-mediated knockdown followed by RNA-sequencing, revealed that the HELLP lincRNA activated a large set of genes that are involved in the cell cycle. Furthermore, blocking potential mutation sites identified in HELLP families decreased the invasion capacity of extravillous trophoblasts. This is the first large noncoding gene to be linked to a Mendelian disorder with autosomal recessive inheritance. PMID- 23093778 TI - Attenuated adenosine-to-inosine editing of microRNA-376a* promotes invasiveness of glioblastoma cells. AB - In the human brain, microRNAs (miRNAs) from the microRNA-376 (miR-376) cluster undergo programmed "seed" sequence modifications by adenosine-to-inosine (A-to-I) editing. Emerging evidence suggests a link between impaired A-to-I editing and cancer, particularly in high-grade gliomas. We hypothesized that disruption of A to-I editing alters expression of genes regulating glioma tumor phenotypes. By sequencing the miR-376 cluster, we show that the overall miRNA editing frequencies were reduced in human gliomas. Specifically in high-grade gliomas, miR-376a* accumulated entirely in an unedited form. Clinically, a significant correlation was found between accumulation of unedited miR-376a* and the extent of invasive tumor spread as measured by magnetic resonance imaging of patient brains. Using both in vitro and orthotopic xenograft mouse models, we demonstrated that the unedited miR-376a* promoted glioma cell migration and invasion, while the edited miR-376a* suppressed these features. The effects of the unedited miR-376a* were mediated by its sequence-dependent ability to target RAP2A and concomitant inability to target AMFR. Thus, the tumor-dependent introduction of a single base difference in the miR-376a* sequence dramatically alters the selection of its target genes and redirects its function from inhibiting to promoting glioma cell invasion. These findings uncover a new mechanism of miRNA deregulation and identify unedited miR-376a* as a potential therapeutic target in glioblastoma cells. PMID- 23093779 TI - Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism. AB - Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton. PMID- 23093780 TI - PPARbeta/delta affects pancreatic beta cell mass and insulin secretion in mice. AB - PPARbeta/delta protects against obesity by reducing dyslipidemia and insulin resistance via effects in muscle, adipose tissue, and liver. However, its function in pancreas remains ill defined. To gain insight into its hypothesized role in beta cell function, we specifically deleted Pparb/d in the epithelial compartment of the mouse pancreas. Mutant animals presented increased numbers of islets and, more importantly, enhanced insulin secretion, causing hyperinsulinemia. Gene expression profiling of pancreatic beta cells indicated a broad repressive function of PPARbeta/delta affecting the vesicular and granular compartment as well as the actin cytoskeleton. Analyses of insulin release from isolated PPARbeta/delta-deficient islets revealed an accelerated second phase of glucose-stimulated insulin secretion. These effects in PPARbeta/delta-deficient islets correlated with increased filamentous actin (F-actin) disassembly and an elevation in protein kinase D activity that altered Golgi organization. Taken together, these results provide evidence for a repressive role for PPARbeta/delta in beta cell mass and insulin exocytosis, and shed a new light on PPARbeta/delta metabolic action. PMID- 23093781 TI - Dendritic cells tolerized with adenosine A2AR agonist attenuate acute kidney injury. AB - DC-mediated NKT cell activation is critical in initiating the immune response following kidney ischemia/reperfusion injury (IRI), which mimics human acute kidney injury (AKI). Adenosine is an important antiinflammatory molecule in tissue inflammation, and adenosine 2A receptor (A2AR) agonists protect kidneys from IRI through their actions on leukocytes. In this study, we showed that mice with A2AR-deficient DCs are more susceptible to kidney IRI and are not protected from injury by A2AR agonists. In addition, administration of DCs treated ex vivo with an A2AR agonist protected the kidneys of WT mice from IRI by suppressing NKT production of IFN-gamma and by regulating DC costimulatory molecules that are important for NKT cell activation. A2AR agonists had no effect on DC antigen presentation or on Tregs. We conclude that ex vivo A2AR-induced tolerized DCs suppress NKT cell activation in vivo and provide a unique and potent cell-based strategy to attenuate organ IRI. PMID- 23093782 TI - Nanog signaling in cancer promotes stem-like phenotype and immune evasion. AB - Adaptation of tumor cells to the host is a major cause of cancer progression, failure of therapy, and ultimately death. Immune selection drives this adaptation in human cancer by enriching tumor cells with a cancer stem cell-like (CSC-like) phenotype that makes them resistant to CTL-mediated apoptosis; however, the mechanisms that mediate CSC maintenance and proliferation are largely unknown. Here, we report that CTL-mediated immune selection drives the evolution of tumor cells toward a CSC-like phenotype and that the CSC-like phenotype arises through the Akt signaling pathway via transcriptional induction of Tcl1a by Nanog. Furthermore, we found that hyperactivation of the Nanog/Tcl1a/Akt signaling axis was conserved across multiple types of human cancer. Inhibition of Nanog in a murine model of colon cancer rendered tumor cells susceptible to immune-mediated clearance and led to successful, long-term control of the disease. Our findings establish a firm link among immune selection, disease progression, and the development of a stem-like tumor phenotype in human cancer and implicate the Nanog/Tcl1a/Akt pathway as a central molecular target in this process. PMID- 23093783 TI - New mechanisms of glucocorticoid-induced insulin resistance: make no bones about it. AB - Glucocorticoids are a powerful tool used to treat a range of human illnesses, including autoimmune diseases and cancer, and to prevent rejection following organ transplantation. While lifesaving for many, they come with a steep price, often leading to obesity, insulin resistance, diabetes, and osteoporosis. In this issue of the JCI, Brennan-Speranza and colleagues provide evidence that the osteoblast-derived peptide osteocalcin is one of the drivers of the metabolic derangements associated with glucocorticoid therapy. This novel mechanism could open up new avenues for the treatment of these disorders. PMID- 23093784 TI - Lung capillaries raise the hypoxia alarm. AB - When ventilation is blocked, the lung can protect against the loss of blood oxygenation by activating localized arterial vasoconstriction, reducing blood flow to underventilated regions, and redirecting flow to better-ventilated alveoli. This phenomenon, hypoxic pulmonary vasoconstriction (HPV), preserves the overall efficiency of blood oxygenation, but the mechanism by which the hypoxic signal is transmitted to the smooth muscle that contracts the arterioles has remained largely a mystery. In this issue of the JCI, Wang et al. reveal that the endothelial lining of the hypoxic alveoli plays a key role in sensing hypoxia and transmitting the signal to initiate HPV. PMID- 23093785 TI - Turning a blind eye to anti-VEGF toxicities. AB - Excessive blood vessel growth is a key feature of many retinal diseases, and recently, anti-VEGF therapy has been successfully applied to treat neovascular age-related macular degeneration (AMD), diabetic macular edema, and retinal vein occlusion. In this issue of the JCI, Kurihara et al. reveal an essential role of Vegfa in maintaining choroid vasculature and cone photoreceptors, critical for central and color vision. Their findings suggest that therapeutic approaches to blocking VEGF signaling in retinal diseases might have unexpected detrimental side effects and that the development of alternative strategies might be necessary. PMID- 23093786 TI - Micro-editing mistake translates into a devastating brain tumor. AB - RNA modifications are increasingly being recognized as critical players in cancer. While adenosine-to-inosine RNA editing is consistently deregulated in cancer, we are still unable to draw a straight line connecting transcript specific editing and carcinogenesis. The findings by Choudhury et al. in this issue of the JCI bridge this gap by mechanistically implicating underediting of miR-376a* in promoting glioma invasiveness through redirection of its mRNA targets. Moreover, RAP2A and AMFR convincingly emerge as key regulators of glioma migration and invasion affected by deregulated microRNA editing. Being inherently malleable, epigenetic mechanisms may provide feasible targets for therapeutic benefit. PMID- 23093787 TI - The promise of immune cell therapy for acute kidney injury. AB - Acute kidney injury (AKI) often results from ischemia reperfusion, sepsis, or exposure to nephrotoxins and is associated with a high rate of mortality and morbidity. Advances in understanding the pathophysiology of AKI may lead to the development of specific therapies. Although there is evidence of an important role for immune cells in AKI, the specific relevant populations and the mechanisms of their actions are unclear. In this issue of the JCI, Li et al. demonstrate that adenosine manipulates DC responses to kidney injury, raising hope that immunotherapy could be a tangible approach to AKI. PMID- 23093788 TI - Tipping the scales early: probing the long-term effects of obesity. AB - Obesity has reached epidemic proportions in the United States, and obesity related illnesses have become a leading preventable cause of death. Childhood obesity is also growing in frequency, and the impact of a lifetime spent in the overweight state is only beginning to emerge in the literature. In this issue of the JCI, Bumaschny et al. used a genetic mouse model to investigate the self perpetuating nature of obesity and shed some light on why it can become increasingly difficult to lose weight over time. PMID- 23093789 TI - Genetic "lnc"-age of noncoding RNAs to human disease. AB - The list of functions of long noncoding RNAs (lncRNAs) in human tissues is rapidly growing. To further underscore their critical role in human health, two reports in this issue of JCI associate altered expression of novel lncRNAs with the heritable syndromes HELLP and brachydactyly type E. PMID- 23093791 TI - Retrospective multicenter survey on food-related symptoms suggestive of cow's milk allergy in NICU neonates. AB - BACKGROUND: Cow's milk allergy (CMA) is one of the causes of gastrointestinal symptoms in neonates. A relationship between non-immunoglobulin (Ig) E mediated allergic reactions and CMA in early infancy has been proposed, but the clinical features and pathogenesis have not been established. The objective of this study is to determine the clinical characteristics of the neonates found in the earlier study to have food-related symptoms that suggested CMA. METHODS: A second questionnaire was sent to 53 NICUs, as a follow-up to the earlier study, to collect information on the background, onset age, clinical features, and results of clinical examinations. RESULTS: The median birth weight was 2614g and the median gestational age was 36.9 weeks. Symptoms developed within 6 days after birth in 40% of cases. Gastrointestinal symptoms were seen in 90% of cases and were mainly vomiting, bloody stool and abdominal distention. A specific IgE test, a lymphocyte stimulation test, and a fecal eosinophil test were conducted in 88%, 23% and 55% of cases, respectively, and the positive rates were 30%, 84%, and 75%, respectively. An oral food challenge (OFC) test was performed in 26% for confirmation of the diagnosis. CONCLUSIONS: We confirmed that the clinical manifestations of food-related symptoms suggestive of CMA in neonates were distinctly different from those of common immediate type food allergy and were largely affected by underlying factors such as prematurity and gastroenterological surgery. Further OFC-based prospective accumulation of cases of CMA in neonates will be particularly important to reveal the full clinical features of this disease. PMID- 23093792 TI - Efficacy of budesonide in combination with formoterol in patients with inadequately controlled asthma on fluticasone in combination with salmeterol. PMID- 23093793 TI - Asthma control can be maintained after fixed-dose, budesonide/ formoterol combination inhaler therapy is stepped down from medium to low dose. AB - BACKGROUND: In cases using a budesonide/formoterol combination inhaler, many patients are started on fixed-dose treatment at 640/18MUg (4 puffs) daily, but there are no guidelines yet regarding the step-down method when control has been maintained. METHODS: Patients with moderate asthma treated with either budesonide 400MUg and salmeterol 100MUg (GINA step3 group) or salmeterol/fluticasone 250 at 2 puffs (GINA step4 group) were enrolled and started on therapy of budesonide/formoterol 4 puffs. Thereafter, step-down to 2 puffs was performed if either of the following criteria was met at 8-week intervals: fractional exhaled nitric oxide (FeNO) <= 28 ppb plus asthma control test (ACT) score >= 22, or ACT score >= 24 at 3 consecutive visits regardless of FeNO level. Thereafter, changes in ACT score, the number of acute exacerbations and reliever use, and FeNO level were monitored through 48th week. RESULTS: Fifty-one patients, 27 in step3 group and 24 in step4 group, underwent step-down. ACT scores and the number of reliever use remained stable in both groups even after step-down. In contrast, FeNO levels increased gradually in step4 group, whereas in the step3 group they increased immediately after step-down. Step-down was considered to be safely performed because the numbers of reliever use and those of moderate or more severe exacerbations during the 48-week period has not changed significantly compared to before step-down. CONCLUSIONS: If complete control of asthma, not only of clinical symptoms but also airway inflammation, is achieved by 3-6 months of fixed-dose budesonide/formoterol 4 puffs/day, it should be possible to safely perform step-down to 2 puffs/day. PMID- 23093794 TI - Guideline for hereditary angioedema (HAE) 2010 by the Japanese Association for Complement Research - secondary publication. AB - This guideline was provided by the Japanese Association for Complement Research targeting clinicians for making an accurate diagnosis of hereditary angioedema (HAE), and for prompt treatment of the HAE patient in Japan. This is a 2010 year version and will be updated according to any pertinent medical advancements. PMID- 23093795 TI - Pathogenesis of cholinergic urticaria in relation to sweating. AB - Cholinergic urticaria (CU) has clinically characteristic features, and has been frequently described in the literature. However, despite its comparatively old history, the pathogenesis and classification remains to be clarified. CU patients are occasionally complicated by anhidrosis and/or hypohidrosis. This reduced sweat type should be included in the classification because the therapeutic approaches are different from the ordinary CU. It is also well-known that autologous sweat is involved in the occurrence of CU. More than half of CU patients may have sweat hypersensitivity. We attempt to classify CU and address the underlying mechanisms of CU based on the published data and our findings. The first step for classification of CU seems to discriminate the presence or absence of hypersensitivity to autologous sweat. The second step is proposed to determine whether the patients can sweat normally or not. With these data, the patients could be categorized into three subtypes: (1) CU with sweat hypersensitivity; (2) CU with acquired anhidrosis and/or hypohidrosis; (3) idiopathic CU. The pathogenesis of each subtype is also discussed in this review. PMID- 23093796 TI - Wheat-dependent exercise-induced anaphylaxis sensitized with hydrolyzed wheat protein in soap. AB - Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a specific form of wheat allergy typically induced by exercise after ingestion of wheat products. Wheat omega-5 gliadin is a major allergen associated with conventional WDEIA, and detection of serum immunoglobulin E (IgE) specific to recombinant omega-5 gliadin is a reliable method for its diagnosis. Recently, an increased incidence of a new subtype of WDEIA, which is likely to be sensitized via a percutaneous and/or rhinoconjunctival route to hydrolyzed wheat protein (HWP), has been observed. All of the patients with this new subtype had used the same brand of soap, which contained HWP. Approximately half of these patients developed contact allergy several months later and subsequently developed WDEIA. In each of these patients, contact allergy with soap exposure preceded food ingestion-induced reactions. Other patients directly developed generalized symptoms upon ingestion of wheat products. The predominant observed symptom of the new WDEIA subtype was angioedema of the eyelids; a number of patients developed anaphylaxis. This new subtype of WDEIA has little serum omega-5 gliadin-specific serum IgE. PMID- 23093797 TI - Japanese guidelines for diagnosis and treatment of urticaria in comparison with other countries. AB - Several guidelines for urticaria and angioedema have been published in Europe and United States since 1997. General principles for diagnosis and treatments of them are similar. However, each guideline has its own characteristics and shows differences in areas such as the coverage of urticaria subtypes, nomenclatures, and hierarchy of the medications. In Japan, the Japanese Dermatological Association (JDA) published its first guideline for urticaria and angioedema in 2005. It established a new classification of urticaria and angioedema together with the definition of each subtype. It emphasized the importance of discriminating idiopathic urticaria, consisting of acute urticaria and chronic urticaria from inducible urticaria, such as allergic urticaria, physical urticaria and cholinergic urticaria. It contains several unique algorithms for diagnosis and treatment of urticaria from a view point of clinical practices, and was further enforced by a style of EBM in 2011. Nevertheless, these guidelines have not been recognized outside of Japan, because of a language barrier. In this article, the outline of the newest guidelines by JDA are introduced and compared with the guidelines in other countries published in English. PMID- 23093798 TI - Separate mechanisms act concurrently to shed and release the prion protein from the cell. AB - The cellular prion protein (PrP (C) ) is attached to the cell membrane via its glycosylphosphatidylinositol (GPI)-anchor and is constitutively shed into the extracellular space. Here, three different mechanisms are presented that concurrently shed PrP (C) from the cell. The fast alpha-cleavage released a N terminal fragment (N1) into the medium and the extreme C-terminal cleavage shed soluble full-length (FL-S) PrP and C-terminally cleaved (C1-S) fragments outside the cell. Also, a slow exosomal release of full-length (FL) and C1-fragment (C1) was demonstrated. The three separate mechanisms acting simultaneously, but with different kinetics, have to be taken into consideration when elucidating functional roles of PrP (C) and also when processing of PrP (C) is considered as a target for intervention in prion diseases. Further, in this study it was shown that metalloprotease inhibitors affected the extreme C-terminal cleavage and shedding of PrP (C) . The metalloprotease inhibitors did not influence the alpha-cleavage or the exosomal release. Taken together, these results are important for understanding the different mechanisms acting in parallel in the shedding and cleavage of PrP (C) . PMID- 23093799 TI - Protective role of MyD88-independent innate immune responses against prion infection. AB - Despite recent progress in the understanding of prion diseases, little is known about the host-defense mechanisms against prion. Although it has long been thought that type I interferon (IFN-I) has no protective effect on prion infection, certain key molecules in innate immunity such as toll-like receptor (TLR) 4 seemed to be involved in the host response. For this reason we decided to focus on TLRs and investigate the role of a transcription factor, interferon regulatory factor 3 (IRF3), because the absence of MyD88, a major adaptor signaling molecule of TLRs, has no effect on the survival of prion infected mice. Intriguingly, survival periods of prion inoculated IRF3-knockout mice became significantly shorter than those of wild-type mice. In addition, IRF3 stimulation inhibited PrP (Sc) replication in prion persistently-infected cells, and a de novo prion infection assay revealed that IRF3-overexpression could make host cells resistant to prion infection. Our work suggests that IRF3 may play a key role in innate immune responses against invasion of prion pathogens. Activated IRF3 could upregulate several anti-pathogen factors, including IFN-I, and induce sequential responses. Although the mechanism for the anti-prion effects mediated by IRF3 has yet to be clarified, certain interferon responsive genes might be involved in the anti-prion host-defense mechanism. PMID- 23093801 TI - Grey matter lesions in MS: from histology to clinical implications. AB - Although multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the white matter (WM) of the central nervous system, several pathological and magnetic resonance imaging (MRI) studies have shown that a large amount of lesions are located in the cortical and deep gray matter. The histopathological and immunological characteristics of cortical lesions differ significantly from those located in the WM, which suggests a location-dependent expression of the MS immunopathological process. More recently, the availability of not-conventional MRI sequences having higher sensitivity for the gray matter has allowed to depict in vivo a portion of such lesions. The available MRI data obtained on large cohorts of patients, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment, and with the evolution of the disease toward the secondary progressive phase. This review provides a summary of the main histopathological and MRI findings of cortical lesions in MS and discusses their possible clinical implications. PMID- 23093800 TI - Astrocyte signaling and neurodegeneration: new insights into CNS disorders. AB - Growing evidence indicates that astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival, but rather they are involved in a striking number of active functions that are critical to the performance of the central nervous system (CNS). As a consequence, it is becoming more and more evident that the peculiar properties of these cells can actively contribute to the extraordinary functional complexity of the brain and spinal cord. This new perception of the functioning of the CNS opens up a wide range of new possibilities to interpret various physiological and pathological events, and moves the focus beyond the neuronal compartment toward astrocyte neuron interactions. With this in mind, here we provide a synopsis of the activities astrocytes perform in normal conditions, and we try to discuss what goes wrong with these cells in specific pathological conditions, such as Alzheimer Disease, prion diseases and amyotrophic lateral sclerosis. PMID- 23093802 TI - The toxin-antitoxin system tisB-istR1: Expression, regulation, and biological role in persister phenotypes. AB - Chromosomally encoded toxin-antitoxin (TA) systems are abundantly present in bacteria and archaea. They have become a hot topic in recent years, because-after many frustrating years of searching for biological functions-some are now known to play roles in persister formation. Persister cells represent a subset of a bacterial population that enters a dormant state and thus becomes refractory to the action of antibiotics. TA modules come in several different flavors, regarding the nature of their gene products, their molecular mechanisms of regulation, their cellular targets, and probably their role in physiology. This review will primarily focus on the SOS-associated tisB/istR1 system in Escherichia coli and discuss its nuts and bolts as well as its effect in promoting a subpopulation phenotype that likely benefits long-term survival of a stressed population. PMID- 23093804 TI - Characterization and evaluation of a new oncolytic vaccinia virus strain LIVP6.1.1 for canine cancer therapy. AB - Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is one novel approach for canine cancer therapy. In this study we described for the first time the characterization and the use of new VACV strain LIVP6.1.1 as an oncolytic agent against canine cancer in a panel of four canine cancer cell lines including: soft tissue sarcoma (STSA-1), melanoma (CHAS), osteosarcoma (D-17) and prostate carcinoma (DT08/40). Cell culture data demonstrated that LIVP6.1.1 efficiently infected and destroyed all four tested canine cancer cell lines. In two different xenograft models on the basis of the canine soft tissue sarcoma STSA-1 and the prostate carcinoma DT08/40 cell lines, a systemic administration of the LIVP6.1.1 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. In summary, the pre-clinical evaluation has demonstrated the efficacy of LIVP6.1.1 for canine cancer therapy. Furthermore, a clinical trial with canine cancer patients has already been started. PMID- 23093803 TI - RNA helicases: diverse roles in prokaryotic response to abiotic stress. AB - Similar to proteins, RNA molecules must fold into the correct conformation and associate with protein complexes in order to be functional within a cell. RNA helicases rearrange RNA secondary structure and RNA-protein interactions in an ATP-dependent reaction, performing crucial functions in all aspects of RNA metabolism. In prokaryotes, RNA helicase activity is associated with roles in housekeeping functions including RNA turnover, ribosome biogenesis, translation and small RNA metabolism. In addition, RNA helicase expression and/or activity are frequently altered during cellular response to abiotic stress, implying they perform defined roles during cellular adaptation to changes in the growth environment. Specifically, RNA helicases contribute to the formation of cold adapted ribosomes and RNA degradosomes, implying a role in alleviation of RNA secondary structure stabilization at low temperature. A common emerging theme involves RNA helicases acting as scaffolds for protein-protein interaction and functioning as molecular clamps, holding RNA-protein complexes in specific conformations. This review highlights recent advances in DEAD-box RNA helicase association with cellular response to abiotic stress in prokaryotes. PMID- 23093805 TI - Bioengineered protein phosphatase 2A: update on need. AB - Harmful algal blooms caused by phytoplankton can occur in all aquatic environments. Some of the algae present in these blooms are capable of producing extremely potent toxins. Due to climate change and eutrophication, harmful algal blooms are increasing on a global scale. One kind of toxin producing algae are those that produce okadaic acid, its derivatives (dinophysistoxin-1 and 2), and microcystins. These toxins are potent inhibitors of protein phosphatase 2A, so this protein is used to detect the mentioned toxins in natural samples. Originally protein phosphatase 2A purified from animal tissues was used, but enzyme activity and stability fluctuations prevented the use of the enzyme in detection kits. Expression of the enzyme as a recombinant protein provided a solution to this problem. For this purpose, several strategies have been followed. We evaluated the activity, specificity and stability of the human protein phosphatase 2A catalytic subunit alpha expressed in insect larvae and showed that this expression system can be a reliable source of high quantities of stable enzyme. PMID- 23093807 TI - Ultra-high cooling rate utilizing thin film evaporation. AB - This research introduces a cell cryopreservation method, which utilizes thin film evaporation and provides an ultra-high cooling rate. The microstructured surface forming the thin film evaporation was fabricated from copper microparticles with an average diameter of 50 MUm. Experimental results showed that a cooling rate of approximately 5[Formula: see text]10(4) degrees C/min was achieved in a temperature range from 10 degrees C to -187 degrees C. The current investigation will give birth to a cell cryopreservation method through vitrification with relatively low concentrations of cryoprotectants. PMID- 23093808 TI - Formation and cell translocation of carbon nanotube-fibrinogen protein corona. AB - The binding of plasma fibrinogen with both single-walled and multi-walled carbon nanotubes (SWNTs and MWNTs) has been examined. Specifically, our absorbance study indicated that MWNTs were coated with multi-layers of fibrinogen to render a "hard protein corona," while SWNTs were adsorbed with thin layers of the protein to precipitate out of the aqueous phase. In addition, static quenching as a result of energy transfer from fluorescently labeled fibrinogen to their nanotube substrates was revealed by Stern-Volmer analysis. When exposed to HT-29 cells, the nanotubes and fibrinogen could readily dissociate, possibly stemming from their differential affinities for the amphiphilic membrane bilayer. PMID- 23093806 TI - A computational systems analysis of factors regulating alpha cell glucagon secretion. AB - Glucagon, a peptide hormone secreted from the alpha-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of glucagon secretion to better understand these processes. The mathematical model of alpha-cell metabolic parameters is based on our previous model for pancreatic beta-cells. We also formulated an ionic model for action potentials that incorporates Ca ( 2+) , K (+) , Na (+) and Cl (-) currents. Metabolic and ionic models are coupled to the equations describing Ca ( 2+) homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca ( 2+) channels. Paracrine and endocrine regulations were analyzed with an emphasis on their effects on a hyperpolarization of membrane potential. This general model simulates and gives insight into the mechanisms of regulation of glucagon secretion under a wide range of experimental conditions. We also reviewed and analyzed dysfunctional mechanisms in alpha-cells to determine key pharmacological targets for modulating glucagon secretion in type 1 and 2 diabetes. PMID- 23093809 TI - The importance of cantilever dynamics in the interpretation of Kelvin probe force microscopy. AB - A realistic interpretation of the measured contact potential difference (CPD) in Kelvin probe force microscopy (KPFM) is crucial in order to extract meaningful information about the sample. Central to this interpretation is a method to include contributions from the macroscopic cantilever arm, as well as the cone and sharp tip of a KPFM probe. Here, three models of the electrostatic interaction between a KPFM probe and a sample are tested through an electrostatic simulation and compared with experiment. In contrast with previous studies that treat the KPFM cantilever as a rigid object, we allow the cantilever to bend and rotate; accounting for cantilever bending provides the closest agreement between theory and experiment. We demonstrate that cantilever dynamics play a major role in CPD measurements and provide a simulation technique to explore this phenomenon. PMID- 23093811 TI - Immediate revision in patients with bilateral recurrent laryngeal nerve palsy after thyroid and parathyroid surgery. How worthy is it? AB - The aim of the present study was to determine whether immediate revision surgery has benefits for patients with iatrogenic bilateral recurrent laryngeal nerve (RLN) palsy. From January 1, 2004 to January 30, 2011, 29 consecutive patients underwent immediate revision after total thyroidectomy. The cohort comprised 29 patients, 2 males and 27 females, aged 23 to 76 years (median 52 years). Identification of the type and extent of injury of each branch was reported in the protocol, and reconstruction was performed whenever possible. A complete transection of the nerve or one of its branches was found in 14 and 5 nerves, respectively. In three patients, the nerve was completely or partially transected on both sides. Seven anatomically intact nerves were injured by loaded ligature, in one case there was a sign of thermal damage and four nerves showed signs of excessive manipulation (thinning of the nerve trunk). Primary end-to-end anastomosis was performed in seven completely transected RLN and four transected anterior branches of RLN. None of the reconstructed nerve trunks or its branches regained function, although good muscle tone was observed. 23 of 38 intact nerves (61%) regained function, and normal vocalcord mobility on both sides was restored in only four patients. In all cases with regained vocal-cord mobility, functional recovery occurred within 3 months after primary surgery. In conclusion, immediate revision after thyroidectomy may help to indicate the type of RLN damage, which is a predictor of functional recovery and one of major factors influencing future therapeutic management. PMID- 23093810 TI - Propranolol is an effective treatment for airway haemangiomas: a critical analysis and meta-analysis of published interventional studies. AB - Haemangiomas represent the most common benign tumours in infancy, affecting 1-2% of newborns. The present meta-analysis aimed to critically review the current evidence on the efficacy of propranolol in the management of airway haemangiomas, and explore potential adverse events and treatment failures. A literature review was performed in Medline and other available database sources, along with critical analysis of pooled data. Seventeen studies were included in the analysis. No study represented Level I evidence. The total number of treated patients was 61; 14 patients received propranolol as single-treatment. The comparative effectiveness of propranolol vs. systemic steroids was documented in 35 children, and showed superior outcome in the vast majority (94%, p < 0.001). The mean obstruction before propranolol administration was 72%, and after intervention was 20% (p < 0.001). The mean referral-age for children with airway haemangiomas was 2.4 months, the mean starting-age of propranolol treatment was 5.1 months and the mean follow-up period was 8.4 months. Four children failed to respond (6.5%), and in seven the haemangioma relapsed after discontinuation of treatment (11.5%). The results of the present study suggest that propranolol can be recommended for the treatment of airway haemangiomas, as it was found to be effective and outperformed the previously-considered gold standard treatment methods, with fewer side-effects. Immediate treatment with propranolol should be initiated once a diagnosis of symptomatic airway haemangioma is confirmed, and cardiovascular assessment has been performed. Children should remain on propranolol until the haemangioma enters the phase of involution. Active parental monitoring is essential to ensure treatment safety. PMID- 23093812 TI - Transoral laser surgery for recurrent glottic cancer after radiotherapy: oncologic and functional outcomes. AB - Primary radiotherapy (RT) has been successfully employed for treatment of early glottic cancer for the past half century. However, local recurrences still occur in 5-35% of patients. Salvage options for persistent/recurrent glottic cancer include total laryngectomy, open neck partial laryngectomies (ONPLs) and transoral laser surgery (TLS). We performed a retrospective chart review of 35 patients with glottic squamous cell carcinoma previously submitted to RT and managed by TLS at the Department of Otorhinolaryngology - Head and Neck Surgery of the University of Brescia, Italy, from 1995 to 2009. Oncologic outcomes were estimated using the Kaplan-Meier method, and separately calculated for the entire cohort of patients (n = 35) and for patients with true persistent/recurrent disease (n = 30), thus excluding the second primary tumours (n = 5). Hospitalization time and complications were obtained by chart review. Functional outcomes of a subgroup of 10 patients in terms of speech and swallowing were analyzed by the Voice Handicap Index (VHI), GRBAS scale, Multi Dimensional Voice Program (MDVP), M.D. Anderson Dysphagia Inventory (MDADI) questionnaire, videoendoscopy (VEES), and videofluoroscopy (VFS) of swallowing (both graded according to Donzelli's scale), and compared to a cohort of 10 patients matched for age, gender and pT category, treated by the same team of surgeons by TLS as a primary treatment. The types of resection used were: 18 Type III, 1 Type IV, and 16 Type V cordectomies. Postoperative staging was 16 rpT1a, 17 rpT2, and 2 rpT3. The 5-year overall survival for the entire series was 91%. Five-year disease specific survival, local control with laser alone, and organ preservation rates were 94%, 84% and 87%, respectively. Among the variables tested by univariate analysis, for the entire cohort of patients the pT category had a statistically significant impact on local control with laser alone. Anterior transcommissural extension had a borderline statistical impact on disease-specific survival, while it was clearly significant on overall survival. The status of surgical margins and presence of recurrence after TLS statistically influenced both organ preservation and local control with laser alone. The mean values of VHI, MDADI, and MDVP did not show any statistically significant difference between irradiated and non-irradiated patients. The same was true for GRBAS, VEES, and VFS. This series confirms that TLS after RT failure can be considered a successful surgical option in selected early recurrences, with functional outcomes comparable to those observed after TLS as a primary treatment, and much better than those classically described after ONPLs. PMID- 23093813 TI - Bilateral transverse sinus stenosis in patients with tinnitus. AB - Tinnitus is a frequent complaint in patients affected by intracranial hypertension (IH). Recently, some studies have reported an association between idiopathic intracranial hypertension (IIH) and bilateral transverse sinus stenosis (BTSS). We investigated the relationship between BTSS and monosymptomatic tinnitus, regardless of its clinical characteristics, in subjects without clinical evidence of IH. We selected 78 subjects (all women, mean age 49.5 +/- 10.36) affected by tinnitus, without clinical history of audiological and otological pathologies, enrolled among outpatients of the Institute of Audiology and Phoniatrics in Catanzaro, Italy, over a 2 year period. All subjects underwent psychometric evaluation, psychoacoustic assessment, neurological and ophthalmological examination, cerebral magnetic resonance venography (MRV) and brain magnetic resonance imaging (MRI). MRV identified BTSS in 17.9% (14 patients). In the BTSS group, tinnitus was bilateral/central in 21%, and monolateral in the remaining patients (50% left; 29% right ear). It was more frequently pulsating in the BTSS group, but 64.9% of BTSS subjects described their tinnitus as stable. No features of tinnitus showed statistical significance in association with BTSS. In BTSS subjects, we found values suggesting IH by lumbar puncture (LP) in 40% of cases. In these patients, LP gave immediate improvement of tinnitus. The association between BTSS and tinnitus, regardless of its features, must be considered when other causes of tinnitus are excluded. PMID- 23093814 TI - Multiparametric statistical correlations between paranasal sinus anatomic variations and chronic rhinosinusitis. AB - Improvements in functional endoscopic sinus surgery (FESS) and computed tomography (CT) have concurrently increased interest in the anatomy of the paranasal region. Common anatomical variations are not rare in patients with chronic paranasal sinusitis. The aim of this retrospective study was to analyze the incidence of anatomic variations of the lateral nasal wall in a series of 200 patients with persistent symptoms of rhinosinusitis, after failure of medical therapies, and their correlation with paranasal sinus disease. A detailed analysis of CT scans showed that 140 of 200 (70%) patients had anatomic variations. In particular, 122 patients (87%) were affected by common anatomic variations, and 18 patients (13%) with uncommon variations. There were 85 (60.7%) male and 55 (39.3%) females with ages ranging from 13 to 77 years (mean 45.5 years). The maxillary sinus was most commonly involved, followed by the anterior ethmoid, frontal sinus, posterior ethmoid and sphenoid sinus. Statistically significant association was found between the presence of common anatomic variations - septal deviation, bilateral concha bullosa, medial deviation of uncinate process, Haller cell, ethmoidal bulla hypertrophic, agger nasi cell - and the presence of sinus mucosal disease (p < 0.05). There was no significant correlation between other common and uncommon anatomic variations and mucosal pathologies. The associations were evaluated using the Fisher's exact test, and compared with those reported in the literature. Considering the results obtained, we believe that some anatomic variations may increase the risk of sinus mucosal disease. We therefore emphasize the importance of a careful evaluation of CT study in patients with persistent symptoms and recurrent chronic rhinosinusitis in order to identify those with anatomical variations that may have an increased risk of developing rhinosinusitis. PMID- 23093815 TI - Database application for patients with obstructive sleep apnoea syndrome. AB - Obstructive sleep apnoea syndrome (OSAS) results from upper airway collapse during sleep. It represents an increasingly recognized pathology associated with many diseases. Herein, we describe a database for patients with OSAS. This has different goals: to facilitate good uniformity in clinical assessment, to allow the use of the application even by non-ENT specialists, to evaluate the results of medical and/or surgical treatments and to enable a statistical meta-analysis derived from the data collected in many OSAS medical centres. PMID- 23093816 TI - Evidence-based review of treatment options for patients with glottic cancer. PMID- 23093817 TI - Long-term outcomes after transcanalicular laser dacryocystorhinostomy. AB - The main objective of the present study was to prospectively evaluate long-term surgical success and safety in patients with nasolacrimal duct obstruction treated with a multidiode transcanalicular laser and bicanalicular silicone intubation stenting. 42 patients treated with transcanalicular laser dacryocystorhinostomy for nasolacrimal duct obstruction were prospectively enrolled. In all cases, silicone stents were inserted. Subjective outcome measure was resolution or improvement of epiphora. Objective outcome measures were patency of the lacrimal system tested with fluorescein and persistence of the nasolacrimal window visualized by nasal endoscopy. The lacrimal system was functional in 95.2% of the patients. The endocanalicular laser DCR failed in two of the 42 (4.8%) cases. External dacryocystorhinostomy was performed successfully on the failed cases. Lacrimal pump syndrome was not seen in any patient. In conclusion, endocanalicular laser dacryocystorhinostomy using a multidiode laser appears to be an effective technique in patients unresponsive to medical therapy. PMID- 23093818 TI - Metastasis to the right stellate ganglion and vagal nerve: pathological alterations causing sudden death. A case report. AB - Sudden death in a 66-year-old woman with squamous cell carcinoma of the oral cavity and exclusive metastatic involvement of the right stellate ganglion and right nerve vagus is reported. The patient also suffered from paroxysmal atrial fibrillation treated with quinidine. An autopsy showed exclusive metastases to the right stellate ganglion and vagus nerve, along with decreased nerve fibre density in the ventricular myocardium suggesting that Wallerian axon degeneration of cardiac fibres was responsible for sudden death. PMID- 23093819 TI - Carotidynia: new aspects of a controversial entity. AB - Idiopathic carotidynia or Fay syndrome is a little known pathology, which in the past was the subject of much controversy. Even though carotydinia was removed as a pathological entity from the second International Headache Society classification in 2004, recent reports seem to confirm that the disease demonstrates unusual radiological findings. The presence of a typical amorphous enhancing soft tissue surrounding the carotid artery by MRI, CT and ultrasonography in patients with carotidynia has reopened discussion on the hypothesis that carotidynia may represent a distinctive inflammatory process. The aetiology of carotidynia is unknown. We report a case of carotidynia that developed after an upper airway infection, wherein MR studies demonstrated typical enhanced tissue surrounding the common carotid artery in contiguity with pathological enhancement in laryngeal tissue. PMID- 23093820 TI - Anti-inflammatory effects of concentrated ethanol extracts of Edelweiss (Leontopodium alpinum Cass.) callus cultures towards human keratinocytes and endothelial cells. AB - Edelweiss (Leontopodium alpinum Cass.) is traditionally employed in folk medicine as an anti-inflammatory remedy. In nature, the plant is sparsely available and protected; therefore production of callus cultures was established. A concentrated ethanolic extract of culture homogenate, with leontopodic acid representing 55 +/- 2% of the total phenolic fraction (ECC55), was characterized for anti-inflammatory properties in primary human keratinocytes (PHKs) and endotheliocytes (HUVECs). Inflammatory responses were induced by UVA+UVB, lipopolysaccharide (LPS), oxidized low-density lipoprotein (oxLDL), and a mixture of proinflammatory cytokines. Trichostatin A, a sirtuin inhibitor, was used to induce keratinocyte inflammatory senescence. ECC55 (10-50 MUg/mL) protected PHK from solar UV-driven damage, by enhancing early intracellular levels of nitric oxide, although not affecting UV-induced expression of inflammatory genes. Comparison of the dose-dependent inhibition of chemokine (IL-8, IP-10, MCP-1) and growth factor (GM-CSF) release from PHK activated by TNFalpha + IFNgamma showed that leontopodic acid was mainly responsible for the inhibitory effects of ECC55. Sirtuin-inhibited cell cycle, proliferation, and apoptosis markers were restored by ECC55. The extract inhibited LPS-induced IL-6 and VCAM1 genes in HUVEC, as well as oxLDL-induced selective VCAM1 overexpression. Conclusion. Edelweiss cell cultures could be a valuable source of anti-inflammatory substances potentially applicable for chronic inflammatory skin diseases and bacterial and atherogenic inflammation. PMID- 23093821 TI - CXCL1-triggered interaction of LFA1 and ICAM1 control glucose-induced leukocyte recruitment during inflammation in vivo. AB - It is well acknowledged that proinflammatory stimulation during acute hyperglycemia is able to aggravate inflammatory diseases. However, the mechanisms of proinflammatory effects of glucose are controversially discussed. We investigated leukocyte recruitment after intravenous injection of glucose in different inflammatory models using intravital microscopy. Flow chamber experiments, expression analysis, functional depletion, and knockout of key adhesion molecules gave mechanistic insight in involved pathways. We demonstrated that a single injection of glucose rapidly increased blood glucose levels in a dose-dependent manner. Notably, during tumor necrosis factor (TNF) alpha-induced inflammation leukocyte recruitment was not further enhanced by glucose administration, whereas glucose injection profoundly augmented leukocyte adhesion and transmigration into inflamed tissue in the trauma model, indicating that proinflammatory properties of glucose are stimulus dependent. Experiments with functional or genetic inhibition of the chemokine receptor CXCR2, intercellular adhesion molecule 1 (ICAM1), and lymphocyte function antigen 1 (LFA1) suggest that keratino-derived-chemokine CXCL1-triggered interactions of ICAM1 and LFA1 are crucially involved in the trauma model of inflammation. The lacking effect of glucose on beta(2) integrin expression and on leukocyte adhesion in dynamic flow chamber experiments argues against leukocyte-driven underlying mechanisms and favours an endothelial pathway since endothelial ICAM1 expression was significantly upregulated in response to glucose. PMID- 23093822 TI - Palliative care beyond oncology! PMID- 23093824 TI - Nonpain Symptoms of New and Follow-up Cancer Patients Attending a Palliative Care Outpatient Clinic in Saudi Arabia. AB - BACKGROUND: Epidemiology of cancer-related nonpain symptoms receives less attention in literature as compared with cancer pain. OBJECTIVE: This paper aims at exploring the prevalence and severity of nonpain symptoms in cancer patients attending a palliative care (PC) outpatient clinic. MATERIALS AND METHODS: Over a 5 months period, consecutive adult cancer patients attending PC outpatient clinic at a tertiary hospital were evaluated for the presence and severity of 10 nonpain symptoms. Patients were grouped to new or follow-up cases and were also grouped according to performance status and cancer type. Prevalence and severity of symptoms were compared between groups using t test or analysis of variance as appropriate. RESULTS: Fifty-one males and 73 females were interviewed. The most common cancer is female breast (27.4%) followed by head and neck (15.3%). Majority of patients (67%) were new to PC clinic. Patients had 5.1 nonpain symptoms on average, with most common symptoms being tiredness (79.8%), loss of appetite (71.8%), dry mouth (69.4%), anxiety (60.5%), and depression (50.8%). The least common symptoms were confusion and nausea (22.6% each). The median scores of severity were highest for tiredness, loss of appetite, dry mouth, and insomnia (5 points each). Symptoms were fewer among patients with good performance status (P = 0.002), whereas age, gender, cancer type, and encounter type were not associated with difference in symptom prevalence. Younger patients, females and those with poor performance status have shown a tendency toward higher severity scores for several symptoms. CONCLUSION: The significant prevalence and severity of nonpain symptoms among new and follow-up cancer patients seen in a PC outpatient clinic emphasizes the need for comprehensive assessment and routinely audited symptom management plans. PMID- 23093823 TI - A comprehensive review of head and neck cancer rehabilitation: physical therapy perspectives. AB - Rehabilitation in relation to cancer can be preventative, restorative, supportive, and palliative. It is recognized that patients may have rehabilitation needs throughout their care pathway. The role of physiotherapy in the cancer rehabilitation is less understood and particularly in the head and neck cancer (HNC) patients. This results in various residual deformities and dysfunctions for the patients with HNC. The objective of this review is to provide detailed information regarding the problems faced after the cancer treatments and rehabilitation of patients who suffered with HNC. The fact that cancer patients are facing several months of chemotherapy and/or radiotherapy and usually major surgery, as well as the direct effect of immobility due to pain, means that muscle wasting, joint stiffness, as well as de-conditioning and fatigue are inevitable. The absence of physiotherapy intervention would be detrimental to patient care and the ability of the patient/family to cope with the effects of the disease or its treatment on their functional capacity and quality of life. Following any treatment for HNC, physical therapy may play an essential role in preventing various complications and helping patients to mitigate impairments, and restoring function of the shoulder joint, neck, and face. PMID- 23093825 TI - Health-related Quality of Life and Existential Concerns Among Patients with End stage Renal Disease. AB - BACKGROUND: Health-Related Quality Of Life (HRQOL) among patients with End-Stage Renal Disease (ESRD) is significantly impacted by virtue of varied disease or treatment-related factors, and its evaluation along with existential concerns is required for providing comprehensive care to the patient. AIM: The aim of this study was to describe the various dimensions of HRQOL and existential concerns and to examine the relationship between the two among patients with ESRD. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted among 54 patients with ESRD undergoing maintenance hemodialysis in a teaching hospital. A semi-structured questionnaire was used to assess socio-demographic characteristics and existential concerns of the respondents. The HRQOL was evaluated using a standardized scale of Kidney Disease Quality of Life-Short Form (KDQOL-SFTM) questionnaire. Data were presented as frequencies, mean +/- Standard Deviation (SD) for baseline characteristics and scores. Pearson correlation was used to study the association between various domains of quality of life and existential concerns. RESULTS: Among HRQOL, the worst results obtained were in the domain of burden of kidney disease (33.45 +/- 13.53), work status (49.07 +/- 24.75), quality of social interaction (62.22 +/-11.80), general health (43.06 +/- 13.01), and physical functioning (47.50 +/- 18.88). Disrupted personal integrity (12.80 +/- 2.81) and loss of continuity (5.37 +/- 1.17) were most bothersome existential concerns. A co-relational model behaves distinctly eliciting weak to strong association among various domains of HRQOL and existential concerns. CONCLUSION: Patients with ESRD reported impaired HRQOL in most of the domains. Existential concerns are distinguished as important dimensions of HRQOL. Association between HRQOL and existential concerns showed that these dimensions are distinct, and there is a need for assessing and attending these entities through a multidisciplinary approach to alleviate the suffering and achieving a sense of overall wellbeing among patients. PMID- 23093826 TI - Fatigue in breast cancer patients on adjuvant treatment: course and prevalence. AB - INTRODUCTION: Fatigue is a major complain in breast cancer patients and survivors. Patterns and degree varies with schedule and type of the treatment. Different co-factors may aggravate fatigue. Multimodal approach is helpful in managing fatigue. AIM: To quantify prevalence, course and degree of fatigue in breast cancer patients on adjuvant treatment and effectiveness of different management approach. MATERIALS AND METHODS: One Hundred and ten post-mastectomy breast cancer patients (Stage I to Stage III) were assessed. Patients on chemotherapy were assessed one week before, day after chemotherapy and two weeks later in every cycle. Patients on External Beam Radiation Therapy (EBRT) were assessed one week before and every week during radiation. Assessment was continued on second and fourth week of follow up. Functional Assessment of Chronic Illness Therapy - Fatigue subscale (FACIT-F) was used for assessment. Significant cofactors were also searched for. RESULTS: Eighty four percent patients experienced fatigue. Fatigue was more prevalent during chemotherapy (91%) than EBRT (77%). Patients on Chemotherapy exhibit peak fatigue day after Chemotherapy and decreased level until the next cycle. Significant increase of fatigue was seen only in first cycle. Patient on EBRT had gradually increased fatigue during the course of treatment. Lower degree of fatigue was present in post treatment period. Anemia was a significant cofactor causing fatigue (P < 0.05). Blood Transfusion improved fatigue scores. CONCLUSION: Fatigue increases during chemotherapy and or EBRT. Different intervention strategies are needed to address the issue. PMID- 23093827 TI - When Palliative Treatment Achieves More Than Palliation: Instances of Long-term Survival after Palliative Radiotherapy. AB - CONTEXT: Palliative radiotherapy aims at symptom alleviation and improvement of quality of life. It may be effective in conferring a reasonable quantum of local control, as well as possibly prolonging survival on the short term. However, there can be rare instances where long-term survival, or even cure, results from palliative radiotherapy, which mostly uses sub-therapeutic doses. AIM: To categorize and characterize the patients with long-term survival and/or cure after palliative radiotherapy. MATERIALS AND METHODS: This study is a retrospective analysis of hospital records of patients treated with palliative radiotherapy from 2001 to 2006 at the Regional Cancer Centre, Shimla. RESULTS: Of the analyzed 963 patients who received palliative radiotherapy, 2.4% (n = 23) survived at least 5 years, with a large majority of these surviving patients (73.9%, n = 17) being free of disease. CONCLUSIONS: In addition to providing valuable symptom relief, palliative radiotherapy utilizing sub-therapeutic doses may, in a small proportion of patients, bestow long-term survival, and possibly cure. Rationally, such a favorable, but rare outcome cannot be expected with supportive care alone. PMID- 23093828 TI - Study of Nurses' Knowledge about Palliative Care: A Quantitative Cross-sectional Survey. AB - CONTEXT: Studies have documented that nurses and other health care professionals are inadequately prepared to care for patients in palliative care. Several reasons have been identified including inadequacies in nursing education, absence of curriculum content related to pain management, and knowledge related to pain and palliative care. AIMS: The objective of this paper was to assess the knowledge about palliative care amongst nursing professionals using the palliative care knowledge test (PCKT). SETTINGS AND DESIGN: Cross-sectional survey of 363 nurses in a multispecialty hospital. MATERIALS AND METHODS: The study utilized a self-report questionnaire- PCKT developed by Nakazawa et al., which had 20 items (statements about palliative care) for each of which the person had to indicate 'correct', 'incorrect', or 'unsure.' The PCKT had 5 subscales (philosophy- 2 items, pain- 6 items, dyspnea- 4 items, psychiatric problems- 4 items, and gastro-intestinal problems- 4 items). STATISTICAL ANALYSIS USED: Comparison across individual and professional variables for both dimensions were done using one-way ANOVA, and correlations were done using Karl-Pearson's co efficient using SPSS version 16.0 for Windows. RESULTS: The overall total score of PCKT was 7.16 +/- 2.69 (35.8%). The philosophy score was 73 +/- .65 (36.5%), pain score was 2.09 +/- 1.19 (34.83%), dyspnea score was 1.13 +/- .95 (28.25%), psychiatric problems score was 1.83 +/- 1.02 (45.75%), and gastro-intestinal problems score was 1.36 +/- .97 (34%). (P = .00). The female nurses scored higher than their male counterparts, but the difference was not significant (P > .05). CONCLUSIONS: Overall level of knowledge about palliative care was poor, and nurses had a greater knowledge about psychiatric problems and philosophy than the other aspects indicated in PCKT. PMID- 23093829 TI - Dyspnea management in palliative home care: a case series in malaysia. AB - Managing dyspnea at home is a challenging task. Although a competent palliative home care team can assist a patient to live at home with better pain control, dyspnea is usually not as well managed. In the Asian context, there are few research studies in dyspnea management in palliative home care. This paper aims to illustrate the cultural context that has an impact on dyspnea management at home and the assessment and management of dyspnea in a community palliative care setting in Malaysia. This paper reports on a study of 5 dyspneic patients suffering from both cancer-related and non-cancer-related dyspnea. Its focus is on a unique Asian cultural belief system that affects communication about prognosis and the role of family in palliative home care. In addition, this paper also describes dyspnea assessment, the barriers to morphine use, benzodiazepine prescription, oxygen therapy, and nonpharmacologic intervention in this center. PMID- 23093830 TI - Palliative and end of life care issues of carcinoma thyroid patient. AB - Malignancies of the thyroid gland has steadily increased over the last few decades, out of which mostly are differentiated carcinomas of the papillary or of follicular type, have a good prognosis and highest cure rate if treatment commences early. Here, we report a case of an 18-years-old boy with a huge multinodular goiter, which compromised the airway and lung metastasis, presented at advance stage of disease in tertiary care center. Factors prevent early diagnosis and treatment, distressing symptoms patient can develop, palliation of those symptoms, and effort to be made to prevent the delay are highlighted. PMID- 23093831 TI - Gabapentin in the treatment of persistent hiccups in advanced malignancy. AB - Hiccups are a distressing symptom in advanced malignancies in the setting of palliative care. A case of persistent hiccups treated with oral Gabapentin is presented to highlight the clinical and ethical dilemmas in patients with advanced malignancy. A 70-year-old male with non-small cell cancer of the lung with widespread metastases presented with persistent hiccups. The patient and family sought only symptom relief from home, without hospitalization or further investigations. The hiccups were dramatically relieved by oral Gabapentin, highlighting the recent reports that mention this molecule as being useful for hiccups. Gabapentin is a simple tool that may be utilized by palliative care physicians to relieve hiccups in advanced malignancies. PMID- 23093832 TI - Ampullary neuroendocrine tumor presenting with biliary obstruction and gastric outlet obstruction. AB - Neuroendocrine tumors of the ampulla of Vater are extremely rare cause of extrahepatic biliary obstruction and further rarer cause of duodenal obstruction, and only a few cases have been reported in the literature. Herein we report a case of ampullary neuroendocrine tumor in a 75-year-old woman who presented with biliary obstruction and gastric outlet obstruction palliated with metal biliary and duodenal stenting with relief of jaundice and vomiting at 1 month of follow up. PMID- 23093833 TI - Consensus of the present and prospects on endoscopic diagnosis and treatment in East asian countries. AB - Background and Aim. New diagnostic or therapeutic methods in endoscopy have been used. Current clinical application of these procedures is not well known. The aim of this study is to investigate the present situation on endoscopic diagnosis and treatment of gastrointestinal disorders in East Asian countries. Method. A representative member from the International Gastrointestinal Consensus Symposium Committee provided a questionnaire to physicians in China, Indonesia, Japan, Korea, the Philippines, and Thailand. Results. In total, 514 physicians including gastroenterologists, surgeons, and general practitioners enrolled. The most frequently occurring disorder as the origin of upper gastrointestinal bleeding is gastric ulcer. Capsule endoscopy is selected as the first choice for the diagnosis of small intestine bleeding. The second choice was double-balloon endoscopy or angiography. For patients with gastric adenoma, the number of physicians who choose endoscopic mucosal resection is larger than those selecting endoscopic submucosal dissection (ESD) in China, Indonesia, the Philippines, and Thailand. ESD is chosen first in Japan and Korea. Conclusion. New instruments or techniques on endoscopy have not come into wide use yet, and there is diversity in the situation on it in Asian countries. We should unify the endoscopic diagnostic criteria or treated strategy in patients with GI disease. PMID- 23093834 TI - Bone marrow microenvironment in multiple myeloma progression. AB - Substantial advances have been made in understanding the biology of multiple myeloma (MM) through the study of the bone marrow (BM) microenvironment. Indeed, the BM niche appears to play an important role in differentiation, migration, proliferation, survival, and drug resistance of the malignant plasma cells. The BM niche is composed of a cellular compartment (stromal cells, osteoblasts, osteoclasts, endothelial cells, and immune cells) and a noncellular compartment including the extracellular matrix (ECM) and the liquid milieu (cytokines, growth factors, and chemokines). In this paper we discuss how the interaction between the malignant plasma cell and the BM microenvironment allowed myeloma progression through cell homing and the new concept of premetastatic niche. PMID- 23093836 TI - Antilithiasic and hypolipidaemic effects of Raphanus sativus L. var. niger on mice fed with a lithogenic diet. AB - In Mexico, Raphanus sativus L. var. niger (black radish) has uses for the treatment of gallstones and for decreasing lipids serum levels. We evaluate the effect of juice squeezed from black radish root in cholesterol gallstones and serum lipids of mice. The toxicity of juice was analyzed according to the OECD guidelines. We used female C57BL/6 mice fed with a lithogenic diet. We performed histopathological studies of gallbladder and liver, and measured concentrations of cholesterol, HDL cholesterol and triglycerides. The juice can be considered bioactive and non-toxic; the lithogenic diet significantly induced cholesterol gallstones; increased cholesterol and triglycerides levels, and decreased HDL levels; gallbladder wall thickness increased markedly, showing epithelial hyperplasia and increased liver weight. After treatment with juice for 6 days, cholesterol gallstones were eradicated significantly in the gallbladder of mice; cholesterol and triglycerides levels decreased too, and there was also an increase in levels of HDL (P < 0.05). Gallbladder tissue continued to show epithelial hyperplasia and granulocyte infiltration; liver tissue showed vacuolar degeneration. The juice of black radish root has properties for treatment of cholesterol gallstones and for decreasing serum lipids levels; therefore, we confirm in a preclinical study the utility that people give it in traditional medicine. PMID- 23093835 TI - Stable plastid transformation for high-level recombinant protein expression: promises and challenges. AB - Plants are a promising expression system for the production of recombinant proteins. However, low protein productivity remains a major obstacle that limits extensive commercialization of whole plant and plant cell bioproduction platform. Plastid genetic engineering offers several advantages, including high levels of transgenic expression, transgenic containment via maternal inheritance, and multigene expression in a single transformation event. In recent years, the development of optimized expression strategies has given a huge boost to the exploitation of plastids in molecular farming. The driving forces behind the high expression level of plastid bioreactors include codon optimization, promoters and UTRs, genotypic modifications, endogenous enhancer and regulatory elements, posttranslational modification, and proteolysis. Exciting progress of the high expression level has been made with the plastid-based production of two particularly important classes of pharmaceuticals: vaccine antigens, therapeutic proteins, and antibiotics and enzymes. Approaches to overcome and solve the associated challenges of this culture system that include low transformation frequencies, the formation of inclusion bodies, and purification of recombinant proteins will also be discussed. PMID- 23093837 TI - Mechanism of growth inhibition of prostate cancer xenografts by valproic acid. AB - Valproic Acid (VPA), a histone deacetylase inhibitor, has been demonstrated to cause a marked decrease in proliferation of prostate cancer (PCa) cells in vitro and a significant reduction in tumor volume in vivo. The goal of this study is to better understand the VPA-induced growth inhibition in vivo, by studying expression of various markers in PCa xenografts. METHODS: For in vitro experiments, PCa cells were treated with 0, 0.6, and 1.2 mM VPA for 14 days. For in vivo models, experimental animals received 0.4% VPA in drinking water for 35 days. Tissue microarray was generated using cell pellets and excised xenografts. RESULTS: VPA treatment causes cell cycle arrest in PCa cells in vivo, as determined by increase in p21 and p27 and decrease in cyclin D1 expression. Increased expression of cytokeratin18 was also seen in xenografts. LNCaP xenografts in treated animals had reduced androgen receptor (AR) expression. While decreased proliferation was found in vitro, increase in apoptosis was found to be the reason for decreased tumor growth in vivo. Also, an anti-angiogenic effect was observed after VPA treatment. CONCLUSION: VPA inhibits tumor growth by multiple mechanisms including cell cycle arrest, induction of differentiation, and inhibition of growth of tumor vasculature. PMID- 23093838 TI - Protegrin-1 inhibits dengue NS2B-NS3 serine protease and viral replication in MK2 cells. AB - Dengue diseases have an economic as well as social burden worldwide. In this study, the antiviral activity of protegrin-1 (PG-1, RGGRLCYCRRRFCVCVGR) peptide towards dengue NS2B-NS3pro and viral replication in Rhesus monkey kidney (MK2) cells was investigated. The peptide PG-1 was synthesized by solid-phase peptide synthesis, and disulphide bonds formation followed by peptide purification was confirmed by LC-MS and RPHPLC. Dengue NS2B-NS3pro was produced as a single-chain recombinant protein in E. coli. The NS2B-NS3pro assay was carried out by measuring the florescence emission of catalyzed substrate. Real-time PCR was used to evaluate the inhibition potential of PG-1 towards dengue serotype-2 (DENV-2) replication in MK2 cells. The results showed that PG-1 inhibited dengue NS2B NS3pro at IC(50) of 11.7 MUM. The graded concentrations of PG-1 at nontoxic range were able to reduce viral replication significantly (P < 0.001) at 24, 48, and 72 hrs after viral infection. However, the percentage of inhibition was significantly (P < 0.01) higher at 24 hrs compared to 48 and 72 hrs. These data show promising therapeutic potential of PG-1 against dengue infection, hence it warrants further analysis and improvement of the peptide features as a prospective starting point for consideration in designing attractive dengue virus inhibitors. PMID- 23093839 TI - Toxicity of citrate-capped silver nanoparticles in common carp (Cyprinus carpio). AB - Juvenile common carp (Cyprinus carpio) were used as a model to investigate acute toxicity and oxidative stress caused by silver nanoparticles (Ag-NPs). The fish were exposed to different concentrations of Ag-NPs for 48 h and 96 h. After exposure, antioxidant enzyme levels were measured, including glutathione-S transferase (GST), superoxidase dismutase, and catalase (CAT). Other biochemical parameters and histological abnormalities in different tissues (i.e., the liver, gills, and brain) were also examined. The results showed that Ag-NPs agglomerated in freshwater used during the exposure experiments, with particle size remaining <100 nm. Ag-NPs had no lethal effect on fish after 4 days of exposure. Biochemical analysis showed that enzymatic activities in the brain of the fish exposed to 200 MUg/L of Ag-NPs were significantly reduced. Varied antioxidant enzyme activity was recorded in the liver and gills. Varied antioxidant enzyme activity was recorded for CAT in the liver and GST in the gills of the fish. However, the recovery rate of fish exposed to 200 MUg/L of Ag-NPs was slower than when lower particle concentrations were used. Other biochemical indices showed no significant difference, except for NH(3) and blood urea nitrogen concentrations in fish exposed to 50 MUg/L of Ag-NPs. This study provides new evidence about the effects of nanoparticles on aquatic organisms. PMID- 23093840 TI - Identification of women for referral to colposcopy by neural networks: a preliminary study based on LBC and molecular biomarkers. AB - Objective of this study is to investigate the potential of the learning vector quantizer neural network (LVQ-NN) classifier on various diagnostic variables used in the modern cytopathology laboratory and to build an algorithm that may facilitate the classification of individual cases. From all women included in the study, a liquid-based cytology sample was obtained; this was tested via HPV DNA test, E6/E7 HPV mRNA test, and p16 immunostaining. The data were classified by the LVQ-NN into two groups: CIN-2 or worse and CIN-1 or less. Half of the cases were used to train the LVQ-NN; the remaining cases (test set) were used for validation. Out of the 1258 cases, cytology identified correctly 72.90% of the CIN-2 or worst cases and 97.37% of the CIN-1 or less cases, with overall accuracy 94.36%. The application of the LVQ-NN on the test set allowed correct classification for 84.62% of the cases with CIN-2 or worse and 97.64% of the cases with CIN-1 or less, with overall accuracy of 96.03%. The use of the LVQ-NN with cytology and the proposed biomarkers improves significantly the correct classification of cervical precancerous lesions and/or cancer and may facilitate diagnosis and patient management. PMID- 23093842 TI - Evaluation of DNA single and double strand breaks in women with cervical neoplasia based on alkaline and neutral comet assay techniques. AB - A hospital-based unmatched case-control study was performed in order to determine the relation of DNA single (ssb) and double (dsb) strand breaks in women with and without cervical neoplasia. Cervical epithelial cells of 30 women: 10 with low grade squamous intraepithelial lesions (LG-SIL), 10 with high-grade SIL (HG-SIL), and 10 without cervical lesions were evaluated using alkaline and neutral comet assays. A significant increase in global DNA damage (ssb + dsb) and dsb was observed in patients with HG-SIL (48.90 +/- 12.87 and 23.50 +/- 13.91), patients with LG-SIL (33.60 +/- 14.96 and 11.20 +/- 5.71), and controls (21.70 +/- 11.87 and 5.30 +/- 5.38; resp.). Pearson correlation coefficient reveled a strong relation between the levels ssb and dsb (r(2) = 0.99, P = 0.03, and r(2) = 0.94, P = 0.16, resp.) and progression of neoplasia. The increase of dsb damage in patients with HG-SIL was confirmed by DNA breakage detection-FISH (DBD-FISH) on neutral comets. Our results argue in favor of a real genomic instability in women with cervical neoplasia, which was strengthened by our finding of a higher proportion of DNA dsb. PMID- 23093841 TI - Induction of apoptosis and cell cycle arrest in human colorectal carcinoma by Litchi seed extract. AB - The Litchi (Litchi chinensis) fruit products possess rich amounts of flavanoids and proanthocyanidins. Its pericarp has been shown to inhibit breast and liver cancer cell growth. However, the anticolorectal cancer effect of Litchi seed extract has not yet been reported. In this study, the effects of polyphenol-rich Litchi seed ethanol extract (LCSP) on the proliferation, cell cycle, and apoptosis of two colorectal cancer cell lines Colo320DM and SW480 were examined. The results demonstrated that LCSP significantly induced apoptotic cell death in a dose-dependent manner and arrested cell cycle in G2/M in colorectal carcinoma cells. LCSP also suppressed cyclins and elevated the Bax : Bcl-2 ratio and caspase 3 activity. This study provides in vitro evidence that LCSP serves as a potential chemopreventive agent for colorectal cancer. PMID- 23093843 TI - Comparison of acute recoil between bioabsorbable poly-L-lactic acid XINSORB stent and metallic stent in porcine model. AB - OBJECTIVE: To investigate acute recoil of bioabsorbable poly-L-lactic acid (PLLA) stent. BACKGROUND: As newly developed coronary stent, bioabsorbable PLLA stent still encountered concern of acute stent recoil. METHODS: Sixteen minipigs were enrolled in our study. Eight PLLA XINSORB stents (Weite Biotechnology Co., Ltd., China) and eight metallic stents (EXCEL, Jiwei Co., Ltd. China) were implanted into coronary arteries. Upon quantitative coronary angiography analysis, acute absolute recoil was defined as the difference between mean diameter of inflated balloon (X) and mean lumen diameter of stent immediately after deployment (Y), while acute percent recoil was defined as (X-Y)/X and expressed as a percentage. Intravascular ultrasound (IVUS) was performed immediately after implantation and 24 hours later to compare cross-sectional area (CSA) between two groups and detect stent malapposition or collapse. RESULTS: Acute absolute recoil in XINSORB and EXCEL was 0.02 +/- 0.13 mm and -0.08 +/- 0.08 mm respectively (P = 0.19). Acute percent recoil in XINSORB and EXCEL was 0.66 +/- 4.32% and -1.40 +/- 3.83%, respectively (P = 0.45). CSA of XINSORB was similar to that of EXCEL immediately after implantation, so was CSA of XINSORB at 24-hours followup. Within XINSORB group, no difference existed between CSA after implantation and CSA at 24-hours followup. No sign of acute stent malapposition was detected by IVUS. CONCLUSIONS: The acute stent recoil of XINSORB is similar to that of EXCEL. No acute stent malapposition or collapse appeared in both kinds of stent. This preclinical study was designed to provide preliminary data for future studies of long-term efficacy and safety of XINSORB stent. PMID- 23093845 TI - Overexpression of runt-related transcription factor-2 is associated with advanced tumor progression and poor prognosis in epithelial ovarian cancer. AB - AIM: To investigate clinical significance of runt-related transcription factor (RUNX)-2 in epithelial ovarian cancer (EOC). METHODS: RUNX2 protein expression and its subcellular localization were detected by immunohistochemistry in 116 patients with EOC. RESULTS: RUNX2 protein was predominantly expressed in cell nucleus of EOC tissues. The expression level of RUNX2 in EOC tissues was significantly higher than that in normal ovarian tissues (P < 0.001). In addition, the nuclear labeling index (LI) of RUNX2 in tumor cells was significantly associated with the advanced clinical stage of EOC tissues (P = 0.001). Moreover, EOC patients with high RUNX2 LI had significantly shorter overall (P < 0.001) and progression-free (P = 0.002) survival than those with low RUNX2 LI. Especially, subgroup analysis revealed that EOC patients with high clinical stages (III~IV) in high RUNX2 expression group demonstrated a significantly worse clinical outcome than those in low RUNX2 expression group, but patients with low clinical stages (I~II) had no significantly different prognosis between high and low RUNX2 expression groups. CONCLUSIONS: Our data suggest for the first time that RUNX2 overexpression is associated with advanced tumor progression and poor clinical outcome of EOC patients. RUNX2 might be a novel prognostic marker of EOC. PMID- 23093844 TI - Lysine acetylation: elucidating the components of an emerging global signaling pathway in trypanosomes. AB - In the past ten years the number of acetylated proteins reported in literature grew exponentially. Several authors have proposed that acetylation might be a key component in most eukaryotic signaling pathways, as important as phosphorylation. The enzymes involved in this process are starting to emerge; acetyltransferases and deacetylases are found inside and outside the nuclear compartment and have different regulatory functions. In trypanosomatids several of these enzymes have been described and are postulated to be novel antiparasitic targets for the rational design of drugs. In this paper we overview the most important known acetylated proteins and the advances made in the identification of new acetylated proteins using high-resolution mass spectrometry. Also, we summarize what is known so far about the acetyltransferases and deacetylases in eukaryotes, focusing on trypanosomes and their potential use as chemotherapeutic targets. PMID- 23093846 TI - Validation of a new animal model of vulnerable plaques by intravascular optical coherence tomography in vivo. AB - We aimed to establish a rabbit model of vulnerable plaques (VPs) with the morphology and component characteristics of human VPs and to evaluate the microstructural features of VPs in vivo using intravascular optical coherence tomography (OCT). Twelve rabbits underwent endothelial denudation of the carotid artery and consumed a 1% high-cholesterol diet (HCD). They were equally divided into two groups: group A (modified needle injury) and group B (balloon injury). OCT was undertaken thrice before injury as well as 1 h and 12 weeks after injury. The degree of acute artery injury after endothelial denudation was detected by OCT. Twelve weeks after injury, OCT showed that both groups generated VPs which had thin fibrous caps and a large lipid core, whereas plaques in group A had smaller lipid arcs (P < 0.0001). Histological findings demonstrated that a larger eccentricity index (EI) (P < 0.05) and greater infiltration of macrophages (P < 0.05) in group A than in group B. Qualitative and morphometric analyses of plaques showed a significant correlation between histological and OCT measurements. A combination of modified endothelial denudation and an HCD in rabbits produced more eccentric lesions similar to those seen in humans. These data suggest that OCT could be a useful tool for evaluation of the degree of injury and VPs in vivo. PMID- 23093848 TI - Effects of norepinephrine and acetylcholine on the development of cultured Leydig cells in mice. AB - Few data have suggested how norepinephrine (NE) and acetylcholine (Ach) regulate the development of Leydig cells in mice at prepuberty, except for data indicating endocrine effects. The present study aims to elucidate the roles of NE and Ach on the differentiation and proliferation of Leydig cells. Firstly, the expression of adrenergic receptors and muscarinic acetylcholine receptors in Leydig cells was investigated. It was found that adrenergic receptors (beta1AR, beta2AR, and alpha1D) and muscarinic acetylcholine receptors (M1 and M3) mRNA are expressed in adult Leydig cells. Then, the effects of NE and Ach on the differentiation and proliferation of Leydig cells were analyzed. The results showed that NE and Ach at 10 MUM significantly increased the number of 3beta-hydroxysteroid dehydrogenase- (3beta-HSD-) positive Leydig cells and improved the expression of proliferating cell nuclear antigen (PCNA) in Leydig cells on postnatal day (PD) 15 (P < 0.05). NE and Ach at 10 MUM had no impact on the expression of PCNA mRNA (P > 0.05), but reduced the expression of 3beta-HSD mRNA in adult Leydig cells and a murine Leydig tumor cell line (MLTC-1) (P < 0.05). Therefore, a conclusion may be reached that NE and Ach participated in stimulating the development of Leydig cells in mice from prepuberty to adult stage. PMID- 23093847 TI - Protein palmitoylation and pathogenesis in apicomplexan parasites. AB - Apicomplexan parasites comprise a broad variety of protozoan parasites, including Toxoplasma gondii, Plasmodium, Eimeria, and Cryptosporidium species. Being intracellular parasites, the success in establishing pathogenesis relies in their ability to infect a host-cell and replicate within it. Protein palmitoylation is known to affect many aspects of cell biology. Furthermore, palmitoylation has recently been shown to affect important processes in T. gondii such as replication, invasion, and gliding. Thus, this paper focuses on the importance of protein palmitoylation in the pathogenesis of apicomplexan parasites. PMID- 23093849 TI - The effect of bradykinin B2 receptor polymorphisms on the susceptibility and severity of osteoarthritis in a Chinese cohort. AB - BACKGROUND: The B2-bradykinin receptor (BDKRB2) has been reported to associate with onset and development of Osteoarthritis (OA); however, the role of BDKRB2 genetic polymorphisms in OA remains unknown. METHOD: A total of 245 patients with primary knee OA and 264 healthy volunteer were recruited. BDKRB2 gene polymorphisms, -58T/C and +9/-9 bp polymorphisms, were genotyped. RESULTS: The genotype distributions and allele frequencies of +9/-9 bp polymorphisms significantly differed between OA and control subjects. Logistic regression analysis showed carriers with -9/-9 genotype had a significantly increased risk for knee OA compared with the +9/+9 genotype (adjusted OR = 2.356, P < 0.001). The OR for -9 allele carriage was significantly higher than +9 allele carriage (adjusted OR = 1.52, P < 0.001). The +9/-9 bp polymorphisms also determined the OA radiographic severity. The presence of -9 bp was associated with severer OA. The -58T/C polymorphisms did not affect OA risk and severity. CONCLUSION: The +9/ 9 bp polymorphisms of BDKRB2 gene may be used as a genetic marker for the susceptibility and severity of OA. PMID- 23093851 TI - Optimization of fermentation medium for the production of atrazine degrading strain Acinetobacter sp. DNS(32) by statistical analysis system. AB - Statistical experimental designs provided by statistical analysis system (SAS) software were applied to optimize the fermentation medium composition for the production of atrazine-degrading Acinetobacter sp. DNS(32) in shake-flask cultures. A "Plackett-Burman Design" was employed to evaluate the effects of different components in the medium. The concentrations of corn flour, soybean flour, and K(2)HPO(4) were found to significantly influence Acinetobacter sp. DNS(32) production. The steepest ascent method was employed to determine the optimal regions of these three significant factors. Then, these three factors were optimized using central composite design of "response surface methodology." The optimized fermentation medium composition was composed as follows (g/L): corn flour 39.49, soybean flour 25.64, CaCO(3) 3, K(2)HPO(4) 3.27, MgSO(4).7H(2)O 0.2, and NaCl 0.2. The predicted and verifiable values in the medium with optimized concentration of components in shake flasks experiments were 7.079 * 10(8) CFU/mL and 7.194 * 10(8) CFU/mL, respectively. The validated model can precisely predict the growth of atrazine-degraing bacterium, Acinetobacter sp. DNS(32). PMID- 23093850 TI - Strategies for enhancing vaccine-induced CTL antitumor immune responses. AB - Vaccine-induced cytotoxic T lymphocytes (CTLs) play a critical role in adaptive immunity against cancers. An important goal of current vaccine research is to induce durable and long-lasting functional CTLs that can mediate cytotoxic effects on tumor cells. To attain this goal, there are four distinct steps that must be achieved. To initiate a vaccine-induced CTL antitumor immune response, dendritic cells (DCs) must capture antigens derived from exogenous tumor vaccines in vivo or autologous DCs directly loaded in vitro with tumor antigens must be injected. Next, tumor-antigen-loaded DCs must activate CTLs in lymphoid organs. Subsequently, activated CTLs must enter the tumor microenvironment to perform their functions, at which point a variety of negative regulatory signals suppress the immune response. Finally, CTL-mediated cytotoxic effects must overcome the tolerance induced by tumor cells. Each step is a complex process that may be impeded in many ways. However, if these steps happen under appropriate regulation, the vaccine-induced CTL antitumor immune response will be more successful. For this reason, we should gain a better understanding of the basic mechanisms that govern the immune response. This paper, based on the steps necessary to induce an immune response, discusses current strategies for enhancing vaccine-induced CTL antitumor immune responses. PMID- 23093852 TI - Actinobacillus succinogenes ATCC 55618 fermentation medium optimization for the production of succinic acid by response surface methodology. AB - As a potential intermediary feedstock, succinic acid takes an important place in bulk chemical productions. For the first time, a method combining Plackett-Burman design (PBD), steepest ascent method (SA), and Box-Behnken design (BBD) was developed to optimize Actinobacillus succinogenes ATCC 55618 fermentation medium. First, glucose, yeast extract, and MgCO(3) were identified to be key medium components by PBD. Second, preliminary optimization was run by SA method to access the optimal region of the key medium components. Finally, the responses, that is, the production of succinic acid, were optimized simultaneously by using BBD, and the optimal concentration was located to be 84.6 g L(-1) of glucose, 14.5 g L(-1) of yeast extract, and 64.7 g L(-1) of MgCO(3). Verification experiment indicated that the maximal succinic acid production of 52.7 +/- 0.8 g L(-1) was obtained under the identified optimal conditions. The result agreed with the predicted value well. Compared with that of the basic medium, the production of succinic acid and yield of succinic acid against glucose were enhanced by 67.3% and 111.1%, respectively. The results obtained in this study may be useful for the industrial commercial production of succinic acid. PMID- 23093853 TI - Cloning of acyl-ACP thioesterase FatA from Arachis hypogaea L. and its expression in Escherichia coli. AB - In this study, a full-length cDNA of the acyl-ACP thioesterase, AhFatA, was cloned from developing seeds of Arachis hypogaea L. by 3'-RACE. Sequence analysis showed that the open reading frame encodes a peptide of 372 amino acids and has 50-70% identity with FatA from other plants. Real-time quantitative PCR analysis revealed that AhFatA was expressed in all tissues of A. hypogaea L., but most strongly in the immature seeds harvested at 60 days after pegging. Heterologous expression of AhFatA in Escherichia coli affected bacterial growth and changed the fatty acid profiles of the membrane lipid, resulting in directed accumulation towards palmitoleic acid and oleic acid. These results indicate that AhFatA is at least partially responsible for determining the high palmitoleic acid and oleic acid composition of E. coli. PMID- 23093854 TI - Structure and functional characteristics of rat's left ventricle cardiomyocytes under antiorthostatic suspension of various duration and subsequent reloading. AB - The goal of the research was to identify the structural and functional characteristics of the rat's left ventricle under antiorthostatic suspension within 1, 3, 7 and 14 days, and subsequent 3 and 7-day reloading after a 14-day suspension. The transversal stiffness of the cardiomyocyte has been determined by the atomic force microscopy, cell respiration--by polarography and proteins content--by Western blotting. Stiffness of the cortical cytoskeleton increases as soon as one day after the suspension and increases up to the 14th day, and starts decreasing during reloading, reaching the control level after 7 days. The stiffness of the contractile apparatus and the intensity of cell respiration also increases. The content of non-muscle isoforms of actin in the cytoplasmic fraction of proteins does not change during the whole experiment, as does not the beta-actin content in the membrane fraction. The content of gamma-actin in the membrane fraction correlates with the change in the transversal stiffness of the cortical cytoskeleton. Increased content of alpha-actinin-1 and alpha-actinin-4 in the membrane fraction of proteins during the suspension is consistent with increased gamma-actin content there. The opposite direction of change of alpha actinin-1 and alpha-actinin-4 content suggests their involvement into the signal pathways. PMID- 23093855 TI - Profiling of age-related changes in the tibialis anterior muscle proteome of the mdx mouse model of dystrophinopathy. AB - X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdx tibialis anterior muscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdx tibialis anterior muscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy. PMID- 23093856 TI - Simulating radiotherapy effect in high-grade glioma by using diffusive modeling and brain atlases. AB - Applying diffusive models for simulating the spatiotemporal change of concentration of tumour cells is a modern application of predictive oncology. Diffusive models are used for modelling glioblastoma, the most aggressive type of glioma. This paper presents the results of applying a linear quadratic model for simulating the effects of radiotherapy on an advanced diffusive glioma model. This diffusive model takes into consideration the heterogeneous velocity of glioma in gray and white matter and the anisotropic migration of tumor cells, which is facilitated along white fibers. This work uses normal brain atlases for extracting the proportions of white and gray matter and the diffusion tensors used for anisotropy. The paper also presents the results of applying this glioma model on real clinical datasets. PMID- 23093857 TI - Codon preference optimization increases prokaryotic cystatin C expression. AB - Gene expression is closely related to optimal vector-host system pairing in many prokaryotes. Redesign of the human cystatin C (cysC) gene using the preferred codons of the prokaryotic system may significantly increase cysC expression in Escherichia coli (E. coli). Specifically, cysC expression may be increased by removing unstable sequences and optimizing GC content. According to E. coli expression system codon preferences, the gene sequence was optimized while the amino acid sequence was maintained. The codon-optimized cysC (co-cysC) and wild type cysC (wt-cysC) were expressed by cloning the genes into a pET-30a plasmid, thus transforming the recombinant plasmid into E. coli BL21. Before and after the optimization process, the prokaryotic expression vector and host bacteria were examined for protein expression and biological activation of CysC. The recombinant proteins in the lysate of the transformed bacteria were purified using Ni(2+)-NTA resin. Recombinant protein expression increased from 10% to 46% based on total protein expression after codon optimization. Recombinant CysC purity was above 95%. The significant increase in cysC expression in E. coli expression produced by codon optimization techniques may be applicable to commercial production systems. PMID- 23093858 TI - Desipramine pretreatment improves sympathetic remodeling and ventricular fibrillation threshold after myocardial ischemia. AB - Abnormal increase in sympathetic nerve sprouting was responsible for the ventricular arrhythmogenesis after myocardial infarction. This study investigated whether the norepinephrine transporter inhibitor, desipramine, can modulate sympathetic remodeling and ventricular fibrillation threshold (VFT) after myocardial ischemia-reperfusion. Rats were administered desipramine (0.8 mg/kg, i.v.) before or after myocardial ischemia. VFT, infarct size, tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43)-positive nerve fibers were measured after one week. The VFT of preischemic treatment group was 11.0 +/- 2.65 V and significantly higher than that of control ischemic group (7.2 +/- 1.30 V, P < 0.05). Infarct size in the preischemic treatment group (23.3 +/- 2.4%) was significantly lower than that in the control ischemic group (30.8 +/- 1.3%, P < 0.05) and the delayed application group (27.1 +/- 2.6%, P < 0.05). The density of TH and GAP43-positive nerve fibers in the control ischemic group was significantly higher than that in the other three groups (P < 0.05). The density of nerve fibers improved after desipramine treatment. Moreover, there was a negative correlation between the VFT and both TH and GAP43-positive nerve fiber density in the infarct border zone (P < 0.05). Desipramine treatment before acute myocardial ischemia can decrease infarct size, improve sympathetic remodeling, and increase VFT and electrical stability of ischemic hearts. Desipramine appears to cause myocardial ischemic preconditioning. PMID- 23093859 TI - Animal experimental study of the fully biodegradable atrial septal defect (ASD) occluder. AB - This study was conducted to evaluate the feasibility, safety, biocompatibility, and degradation features of a fully biodegradable occluder for closure of atrial septal defect (ASD) in an acute canine model. The ASD was created in 20 healthy mongrel dogs by the brockenbrough needle, and the fully biodegradable occluders were implanted by self-made delivery system. The success rate and complications were observed. Acute ASD models were successfully created in 18 dogs, and 16 occluders were successfully implanted in the ASD models. Animals were sacrificed at different times after procedure. The cardiac gross anatomy showed that all occluders were stable in the interatrial septum, no vegetation or thrombus formation was observed on the surface of all occluders. They were embedded into endogenous host tissue gradually at 12-week follow-up. Different periods of pathological observations suggested that the occluders degraded gradually over about 24 weeks and essentially became an integral part of the septum. Transcatheter closure of ASD in acute canine model using the fully biodegradable ASD occluder has the potential of a high successful rate of technique, excellent biocompatibility, and fewer complications with adequate, immediate, and short term results. PMID- 23093860 TI - A laccase with antiproliferative and HIV-I reverse transcriptase inhibitory activities from the mycorrhizal fungus Agaricus placomyces. AB - A novel 68 kDa laccase was purified from the mycorrhizal fungus Agaricus placomyces by utilizing a procedure that comprised three successive steps of ion exchange chromatography and gel filtration as the final step. The monomeric enzyme exhibited the N-terminal amino acid sequence of DVIGPQAQVTLANQD, which showed only a low extent of homology to sequences of other fungal laccases. The optimal temperature for A. placomyces laccase was 30 degrees C, and optimal pH values for laccase activity towards the substrates 2,7'-azinobis[3 ethylbenzothiazolone-6-sulfonic acid] diammonium salt (ABTS) and hydroquinone were 5.2 and 6.8, respectively. The laccase displayed, at 30 degrees C and pH 5.2, K(m) values of 0.392 mM towards hydroquinone and 0.775 mM towards ABTS. It potently suppressed proliferation of MCF 7 human breast cancer cells and Hep G2 hepatoma cells and inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity with an IC(50) of 1.8 MUM, 1.7 MUM, and 1.25 MUM, respectively, signifying that it is an antipathogenic protein. PMID- 23093861 TI - Gecko crude peptides induce apoptosis in human liver carcinoma cells in vitro and exert antitumor activity in a mouse ascites H22 xenograft model. AB - AIM: To investigate the anti-tumor effects and mechanisms of gecko crude peptides (GCPs) in vitro and in vivo. METHODS: 3-(4,5)-Dimethylthiahiazo (-z-y1)-3,5-di phenytetrazoliumromide (MTT) assay was applied to measure the effects of GCPs on the HepG2 cell viability. Fluorescence morphology was used to identify apoptotic cells. A xenograft H22 liver cancer model was established in Kunming mice. The tumor-bearing mice were treated with daily intraperitoneal injections of normal saline (NS group) or GCPs (80, 40 or 20 mg/kg) for 10 days, or once per two days with 2 mg/kg doxorubicin (ADR group; n = 10 each). Serum tumor necrosis factor (TNF-alpha) and interleukin (IL)-6 were quantified using ELISA assay. RESULTS: GCPs significantly inhibited the growth of HepG2 cells and induced typical apoptotic morphological features through increasing bcl-2/bax ratio in a dose- and time-dependent manner in vitro. The tumor weights of the ADR group, GCPs (H) group, GCPs (M) group, GCPs (L) group were smaller compared to the NS group. While the white blood cell count, thymus index, spleen index were higher in the high dose GCPs group than the NS group (P < 0.05), the VEGF expression in tumor tissue and serum TNF-alpha and IL-6 levels in the GCPs groups were lower than the NS group (P < 0.05). PMID- 23093862 TI - Acanthus ebracteatus Vahl. ethanol extract enhancement of the efficacy of the collagen scaffold in wound closure: a study in a full-thickness-wound mouse model. AB - Acanthus ebracteatus Vahl. is a Thai herb that is effective in wound healing. We sought to quantitatively determine whether or not the combined application of Acanthus ebracteatus Vahl. and a collagen scaffold will increase wound closure and angiogenesis. Balb/c mice (body weight: 22-25 g) were anesthetized with sodium thiopental. The dorsal skin incision measuring 1.5 * 1.5 cm was made and then deepened using scissors to produce a full-thickness incision down to the level of the panniculus carnosus. The size of the wound was approximately 10% of the total body surface area. The collagen sheet was implanted onto the wound. Animals were divided into 4 major groups as follows: wound with normal saline (W NSS), wound treated with 0.3 g/kg BW of Acanthus ebracteatus Vahl. extract (W-AE (0.3 g/kg.bw)), wound implanted with collagen scaffold (W-Coll), and wound implanted with collagen scaffold and treated with 0.3 g/kg BW of Acanthus ebracteatus Vahl. (W-Coll-AE combination). On day 14, the W-Coll-AE group showed decreased wound areas and increased capillary vascularity (CV) when compared to the other 3 groups, W-NSS, W-AE0.3, and W-Coll. In the present study, the combination of AE0.3 with collagen showed the best effect on skin angiogenesis and promoted wound closure with less neutrophil infiltration. PMID- 23093863 TI - Umbilical cord-derived mesenchymal stem cells for hematopoietic stem cell transplantation. AB - Hematopoietic stem cell transplantation (HSCT) is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs) can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs) are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted. PMID- 23093864 TI - Intrabone transplant of cord blood stem cells establishes a local engraftment store: a functional PET/FDG study. AB - BACKGROUND: Despite advancements in comprehension of molecular mechanisms governing bone marrow (BM) homing of hematopoietic stem cells, cord blood transplant (CBT) suffers from a slow rate of hematopoietic recovery. Intrabone (i.b.) injection has been proposed as a method able to improve speed of BM engraftment with respect to conventional i.v. protocols. However, the mechanisms underlying this benefit are largely unknown. AIM: To verify whether i.b.-CBT determines a local engraftment able to predict the reconstitution of recipient hematopoiesis. DESIGN AND METHODS: Twenty-one patients with hematologic malignancies received i.b. injection into both iliac crests of 3.2 +/- 0.68 * 107/kg cord blood cells. One month following i.b.-CBT, PET-CT imaging was performed. Maximal standardized uptake values (SUVs) were assessed in BM of both iliac crests and in all lumbar vertebrae. RESULTS: Maximal SUV within iliac crests was higher than in lumbar vertebrae (4.1 +/- 1.7 versus 3.2 +/- 0.7, resp., P = 0.01). However, metabolic activity in these two different BM districts was significantly correlated (r = 0.7, P < 0.001). Moreover, FDG uptake values within the injection site closely predicted platelet recovery 100 days after i.b. CBT (r = 0.72, P < 0.01). CONCLUSIONS: The metabolic activity of injected BM predicts the subsequent rate of hematopoietic recovery after i.b.-CBT, suggesting a pivotal role of the local engraftment in the reconstitution of recipient hematopoiesis. PMID- 23093865 TI - Evaluation of mammary cancer in 7,12-dimethylbenz(a)anthracene-induced Wister rats by asymmetrical temperature distribution analysis using thermography: a comparison with serum CEA levels and histopathology. AB - Animal surface temperature profile captured using infrared camera is helpful for the assessment of physiological responses associated with the regulation of body temperature. Diagnosing breast cancer in early stage itself has a greater effect on the prognosis. In this work, asymmetrical temperature distribution analysis of chemical carcinogen 7,12-dimethyl benz(a)anthracene-induced in the lower right flank region of Wistar rats (n = 6) was carried out to test the potential of thermography in diagnosing mammary cancer and tumor growth over a period of nine weeks in comparison with histopathology results as standard. Temperature difference between the tumor induced lower right and left side of flank region was significant (with P value <0.001), whereas in the abdomen and shoulder there was no significant difference in temperature between right and left sides. Percentage of asymmetrical temperature difference in the tumor induced lower flank region was 0.5 to 2%, whereas in the other regions it was <0.5%. Green pixel distribution in RGB color histogram was asymmetrical in the tumor induced lower flank region. Temperature reduction was observed in the tumor induced region after the seventh day of carcinogen induction. Asymmetrical thermogram analysis is the best method of diagnosing mammary cancer and for studying tumor development. PMID- 23093867 TI - Expression of neural markers by undifferentiated rat mesenchymal stem cells. AB - The spontaneous expression of neural markers by mesenchymal stem cells (MSCs) has been considered to be a demonstration of MSCs' predisposition to differentiate towards neural lineages. In view of their application in cell therapy for neurodegenerative diseases, it is very important to deepen the knowledge about this distinctive biological property of MSCs. In this study, we evaluated the expression of neuronal and glial markers in undifferentiated rat MSCs (rMSCs) at different culture passages (from early to late). rMSCs spontaneously expressed neural markers depending on culture passage, and they were coexpressed or not with the neural progenitor marker nestin. In contrast, the number of rMSCs expressing mesengenic differentiation markers was very low or even completely absent. Moreover, rMSCs at late culture passages were not senescent cells and maintained the MSC immunophenotype. However, their differentiation capabilities were altered. In conclusion, our results support the concept of MSCs as multidifferentiated cells and suggest the existence of immature and mature neurally fated rMSC subpopulations. A possible correlation between specific MSC subpopulations and specific neural lineages could optimize the use of MSCs in cell transplantation therapy for the treatment of neurological diseases. PMID- 23093869 TI - Mapping the pharmaceutical situation in your country: First things first... PMID- 23093868 TI - Altered polarization, morphology, and impaired innate immunity germane to resident peritoneal macrophages in mice with long-term type 2 diabetes. AB - Type 2 diabetes (T2D) is associated with perturbed innate immunity. Macrophages, bridging innate immunity and metabolic disturbances, play important roles in controlling immune homeostasis. However, the effect of long-term diabetic milieu (DM) on the functions and phenotypes of macrophages is still not clear. In this study, we used resident peritoneal macrophages (RPMs) from 5-month-old db/db mice to investigate the changes of macrophages. It was found that RPMs in db/db mice significantly reduced phagocytosis and adhesion capacity. After standardization with body weight, the number of F4/80(+) RPMs markedly reduced in db/db mice, and, furthermore, the macrophages skewed to M2-polarizated macrophages. The results of morphology found that the RPMs shape of db/db mice was nearly round, but the RPMs shape of control mice was spindle-shaped and irregular. In this study, we found the cell numbers, morphology, and innate immunity functions of RPMs in 5-month-old type 2 diabetic mice (db/db mice) obtained by abdominal cavity lavage were significantly altered. Importantly, we also found the remarkably increased M2-RPMs in diabetic mice for the first time. PMID- 23093870 TI - Evaluation of drug promotional materials in a hospital setting in Nepal. AB - OBJECTIVES: Unethical drug promotion is a common problem worldwide. In, Nepal, there is limited vigilance on the quality of information supplied by the drug companies to the doctors. The objectives of this study were to analyze the promotional materials provided by the drug companies as per WHO ethical criteria for medicinal drug promotion. METHODS: Promotional materials present in the Drug Information Center (DIC) during the period from September to December 2007 were collected. The collected promotional materials of different pharmaceutical companies were compared with WHO's Ethical Criteria for Medicinal Drug Promotion. RESULTS: The name of active constituent(s) was mentioned in 87.87% (n=29) of promotional items. Therapeutic indication was mentioned in 87.88% (n=29) of promotional material but information on side effects [33.33% (n=11)], drug interactions [9.09% (n=3)] and use in pregnancy and lactation [12.12% (n=4)] were lacking in the majority of promotional materials. CONCLUSION: In a country like Nepal with limited drug information resources, the promotional materials provided by the manufacturers can largely influence the prescription behavior of the clinicians. Our findings suggest the need for interventions to improve the content of the promotional materials provided by the drug companies. PMID- 23093871 TI - Starting a pharmacovigilance program within a teaching hospital: Challenges and experiences from Lalitpur, Nepal. AB - Pharmacovigilance plays an important role in the rational use of medicines by providing information about adverse drug reactions (ADRs) in the general population. Knowledge of ADRs caused by drugs is important for effective treatment. KIST Medical College has recently joined the national pharmacovigilance program as a regional center. Clinicians, pharmacists, house officers, nurses and other staff are encouraged to report ADRs to the center. The center started functioning from mid-July 2008. The objective of this study was to report the various ADRs presented to the center in its first seven months of operation. Doctors and other health care professionals were briefed regarding the ADR reporting system. An ADR reporting form was designed and circulated to all the departments in the hospital. The reported reactions were analyzed for causality, severity and preventability using different scales. To date, thirty six ADRs have been reported. The majority of the reports (23) were from the Department of Medicine. Other departments like Pediatrics, Obstetrics-Gynecology and Radiology have also reported ADRs. As per the causality assessment, 21 (58.3%) reports were found to be "possible" and 15 (41.6%) were found to be probably associated with the named medication. With respect to severity, 17 (47.2%) reports were mild and 19 (52.7%) were moderate. As per the preventability scale, 8 (22.2%) ADRs were definitely preventable while 28 (77.7%) were not preventable. The ADRs are reported to the Uppsala Monitoring Center through Vigiflow via the Department of Drug Administration. PMID- 23093872 TI - Community pharmacy practice in India: past, present and future. AB - Today, community pharmacists play an important role in any country as they take responsibility for patient's medicine related needs for access to healthcare. However, in India only the supply of medicines remains the core activity of the community pharmacist. Most community pharmacists in the country still hardly offer patient-oriented service. The role of the pharmacists in the community, and with it their medicine management, may change in the wake of the rapid growth of domestic medicine output and national healthcare expenditure. This article seeks to discuss the genesis of Indian community pharmacy, the majority of which are privately owned, and sketches its education, training and future prospects. PMID- 23093873 TI - Pharmacy in the United arab emirates. PMID- 23093874 TI - Traditional and complementary medicines: Quality assessment strategies and safe usage. PMID- 23093875 TI - Evidence based pharmaceutical policy research: Is it all talk or does it contribute to improving health in developing countries? PMID- 23093876 TI - A bibliometric study of publication patterns in access to medicines research in developing countries. AB - OBJECTIVES: Developing countries face considerable problems in both accessing and properly utilizing essential medicines. One challenge to achieving these goals in resource-poor settings is a limited knowledge base as to what works to improve the selection, access and use of essential medicines including; ways to ensure affordable prices, increase sustainable financing, and strengthen reliable supply systems that are relevant to these settings. The objective of this study was to search the existing evidence base on access to medicine issues in developing countries and to assess publication patterns regarding the nature of topics studied, areas where gaps of information exist and the general trends in publications in this area. METHODS: A PubMed search was conducted to retrieve publications on access to medicines in developing countries between 1999-2008. Our search strategy builds and expands on a search strategy developed for a Cochrane review to include a wider range of topics related to access to medicines and pharmaceutical policy. Retrieved articles were categorized by research topics, year of publication, study area, and country of residence of corresponding author to establish patterns in publications with respect to these categories over the past 10 years. RESULTS: Medicine selection, intellectual property rights, and monitoring and quality assurance were among the top topics studied over the last 10 years. Corresponding authors residing in high-income countries represented around 50% of all publications relative to low-income (18%) and middle-income countries (32%). Although an increasing trend in the number of publications per year was found, the increase was relatively small and variable over a 10-year period. CONCLUSIONS: There are few peer-reviewed publications on access to medicines in developing countries with an average of only 76 publications per year over the past 10 years. Increasing the local evidence base as to what works to improve access to medicines in resource poor countries, particularly to the poor, is of the utmost priority to accelerating the achievement of global medicine goals. PMID- 23093877 TI - Community pharmacy based research activity in India: A bibliometric study of the past ten years. AB - OBJECTIVES: The objective of this study was to analyze and record the published evidence regarding community pharmacy practice in India during the past decade (1998-2008). METHODS: A bibliometric review analysis of the original papers was undertaken to assess the different aspects of community pharmacy practice in India. The MEDLINE, Index Copernicus, IndMed, DOAJ databases and the journals such as Indian Journal of Pharmaceutical Sciences and Indian Journal of Hospital Pharmacy were used as data sources. Type of papers, type of journals, category of papers, production indicators and impact factor of the journals were analyzed. RESULTS: Thirty papers were included in the study. The papers were published in 13 different journals, 33.3% of them being in the Indian Journal of Hospital Pharmacy. The average number of authors per paper was 2.73 (SD=1.41). Impact factor was available for only three journals. CONCLUSIONS: There are limited studies being published in India which cover the community pharmacy related activities in India. The key indicators which emerge from the literature review present some fundamental challenges to the development of the role of the community pharmacist in India. PMID- 23093878 TI - Medicines information in medical journal advertising in Australia, Malaysia and the United States: A comparative cross-sectional study. AB - OBJECTIVE: The aim of this study was to compare the provision of medicines information in medical journal advertising in Australia, Malaysia and the United States. METHODS: A consecutive sample of 85 unique advertisements from each country was selected from the advertisements published between January 2004 to December 2006 in three widely circulated medical journals and one prescribing reference manual. The availability of brand name and generic name, indication, contraindications, dosage, side-effects, warnings, interactions and precautions was compared between the three countries. RESULTS: We examined 255 distinct advertisements for 136 pharmaceutical products. Journal advertising in Australia, Malaysia and the US usually provided brand names and generic names (range 96 100%). Information on dosage was significantly less likely to be mentioned (32%) in the US than in Australia (92%) and Malaysia (48%) (P < 0.001). Warning information was significantly less likely to be provided in Australia (5%) than in the US (81%) and Malaysia (9%) (P < 0.001). Apart from information on brand name, generic name, warnings and dosage, other product information significantly less likely to be provided in journal advertising in Malaysia than in Australia and the US (P < 0.001). Similar trends in the provision of product information for the same medicines published in these countries were noted. Brand name and generic name were always provided in the three countries (100%). However, information on the negative effects of medicines was less frequently provided in Malaysia than in Australia and the US. CONCLUSIONS: Journal advertising in Australia, Malaysia and the US failed to provide complete product information. Low quality of information provided in Malaysia indicates the need for effective regulation of provision of medicines information in journal advertising. Different standards of medicines information provided in these three countries suggest that pharmaceutical promotion needs to be better controlled at the international level. PMID- 23093879 TI - Antimicrobial use in a country with insufficient enforcement of pharmaceutical regulations: A survey of consumption and retail sales in Ulaanbaatar, Mongolia. AB - OBJECTIVE: To examine the inappropriate use of antimicrobials by investigating (1) actual utilization pattern and retail sales and (2) antimicrobial resistant information provided by health professionals in Ulaanbaatar, Mongolia. METHODS: We investigated antimicrobial use in Ulaanbaatar, Mongolia by surveying 619 consenting customers who attended 250 randomly chosen pharmacies in December 2006. Pharmacy staff were also interviewed about antimicrobials purchased. In January 2007, we surveyed 117 consenting Ulaanbaatar medical doctors from seven local hospitals about their perceptions of treatment failure due to antimicrobial resistance. RESULTS: Among 619 pharmacy customers, 48% of them had bought at least one type of antimicrobial medicine and, of these, 42% had a prescription to purchase antimicrobials. On average, 67% of the customers reported that a pharmacy worker had given them information regarding the dose and timing at which the medicine should be used but only 9% reported that they had been given information regarding possible adverse effects. The survey of medical doctors suggested that some antibiotics had become less effective clinically between 2001 and 2006. CONCLUSION: The study shows that less than half of all customers who purchased an antibiotic at a pharmacy had a prescription. This shows that antimicrobials can be readily purchased without a prescription despite the existence of laws making such practices illegal. There is a need to establish a vigilant drug regulatory authority to promote enforcement and regulation of medicines in Mongolia. To create awareness regarding the dangers of antimicrobial resistance, educational campaigns for consumers are also necessary. PMID- 23093881 TI - A student reflects on the rest of the world through Southern Med Review. PMID- 23093880 TI - Assessing different perspectives on the value of a pharmaceutical innovation. AB - Numerous pharmaceutical products are launched each year for the treatment of various medical conditions. The prescriber is in a difficult position to determine which the optimal product is for a specific patient, when he has available immediate release as well as sustained action capsules and tablets, chewable tablets and liquid dosage forms. Some have activity within 15 minutes while others take longer. Some are more costly but have never been implicated with gastric distress; some are very widely prescribed and others are not well known. Some are promoted as enhancing compliance and others for schedule simplicity.In order to make sense of the array of diverse product attributes and to determine the value associated with different dosage form features, separate panels of practicing physicians, practicing pharmacists and patients were asked to ascribe value to a list of 10 drug product features that were mentioned in drug product advertisements in medical journals, by indicating what percentage price increase that feature might merit over a basic product without that feature. In addition, the respondents were asked to rank order the mentioned product features.In all three panels, efficacy and safety were accorded the highest status. Pharmacists and patients appeared to be most welcoming of some of the listed features. This pilot study demonstrates that there appears to be a recognized value assigned to some product features and it may differ by audience. PMID- 23093882 TI - The Trans-Pacific Partnership Agreement: a threat to affordable medicines and public health. PMID- 23093883 TI - Local production of medical technologies and its effect on access in low and middle income countries: a systematic review of the literature. AB - OBJECTIVES: The objective of this study was to assess the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products. Our preliminary hypothesis is that studies showing a robust relationship between local production and access to medical products are sparse, at best. METHODS: An extensive literature search was conducted using a wide variety of databases and search terms intending to capture as many different aspects of this issue as possible. The results of the search were reviewed and categorized according to their relevance to the research question. The literature was also reviewed to determine the rigor used to examine the effects of local production and what implications these experiences hold for other developing countries. RESULTS: Literature addressing the benefits of local production and the link between it and access to medical products is sparse, mainly descriptive and lacking empirical evidence. Of the literature we reviewed that addressed comparative economics and strategic planning of multinational and domestic firms, there are few dealing with emerging markets and lower-middle income countries and even fewer that compare local biomedical producers with multinational corporations in terms of a reasonable metric. What comparisons exist mainly relate to prices of local versus foreign/multinational produced medicines. CONCLUSIONS: An assessment of the existing theoretical and empirical literature examining the link between "local production" of pharmaceuticals and medical devices and increased local access to these products reveals a paucity of literature explicitly dealing with this issue. Of the literature that does exist, methods used to date are insufficient to prove a robust relationship between local production of medical products and access to these products. There are mixed messages from various studies, and although the studies may correctly depict specific situations in specific countries with reference to specific products, such evidence cannot be generalized. Our review strongly supports the need for further research in understanding the dynamic link between local production and access to medical products. PMID- 23093884 TI - Essential medicines for reproductive health: developing evidence based interagency list. AB - OBJECTIVES: Although poor reproductive health constitutes a significant proportion of the disease burden in developing countries, essential medicines for reproductive health are often not available to the population. The objective was to analyze the guiding principles for developing national Essential Medicines Lists (EML). The second objective was to compare the reproductive health medicines included on these EMLs to the 2002 WHO/UNFPA list of essential drugs and commodities for reproductive health. Another objective was to compare the medicines included in existing international lists of medicines for reproductive health. METHODS: The authors calculated the average number of medicines per clinical groups included in 112 national EMLs and compared these average numbers with the number of medicines per clinical group included on the WHO/UNFPA List. Additionally, they compared the content of the lists of medicines for reproductive health developed by various international agencies. RESULTS: In 2003, the review of the 112 EMLs highlighted that medicines for reproductive health were not consistently included. The review of the international lists identified inconsistencies in their recommendations. The reviews' outcomes became the catalyst for collaboration among international agencies in the development of the first harmonized Interagency List of Essential Medicines for Reproductive Health. Additionally, WHO, UNFPA and PATH published guidelines to support the inclusion of essential medicines for reproductive health in national medicine policies and EMLs. The Interagency List became a key advocacy tool for countries to review their EMLs.In 2009, a UNFPA/WHO assessment on access to reproductive health medicines in six countries demonstrated that the major challenge was that the Interagency List had not been updated recently and was inconsistently used. CONCLUSION: The addition of cost-effective medicines for reproductive health to EMLs can result in enhanced equity in access to and cost containment of these medicines, and improve quality of care. Action is required to ensure their inclusion in national budget lines, supply chains, policies and programmatic guidance. PMID- 23093886 TI - Analyzing readability of medicines information material in Slovenia. AB - OBJECTIVE: Readability has been claimed to be an important factor for understanding texts describing health symptoms and medications. Such texts may be a factor which indirectly affects the health of the population. Despite the expertise of physicians, the readability of information sources may be important for acquiring essential treatment information. The aim of this study was to measure the readability level of medicines promotion material in Slovenia. METHODS: The Flesch readability formula was modified to comply with Slovene texts. On the basis of determining the Slovene readability algorithm, the readability ease related to the readability grade level of different Slovene texts was established. In order to estimate an adjustment of the texts to the recommended readability grade level of the targeted population, readability values of English texts were set. One sample t-test and standard deviations from the arithmetic mean values were used as statistical tests. RESULTS: The results of the research showed low readability scores of the Slovene texts. Difficult readability values were seen in different types of examined texts: in patient information leaflets, in the summaries of product characteristics, in promotional materials, while describing over-the-counter medications and in the materials for creating disease awareness. Especially low readability values were found within the texts belonging to promotional materials intended for the physicians. None of researched items, not even for the general public, were close to primary school grade readability levels and therefore could not be described as easily readable. CONCLUSION: This study provides an understanding of the level of readability of selected Slovene medicines information material. It was concluded that health related texts were not compliant with general public or with healthcare professional needs. PMID- 23093885 TI - Pharmaceutical policies in European countries in response to the global financial crisis. AB - OBJECTIVE: The objective of this paper is to analyze which pharmaceutical policies European countries applied during the global financial crisis. METHODS: We undertook a survey with officials from public authorities for pharmaceutical pricing and reimbursement of 33 European countries represented in the PPRI (Pharmaceutical Pricing and Reimbursement Information) network based on a questionnaire. The survey was launched in September 2010 and repeated in February 2011 to obtain updated information. RESULTS: During the survey period from January 2010 to February 2011, 89 measures were identified in 23 of the 33 countries surveyed which were implemented to contain public medicines expenditure. Price reductions, changes in the co-payments, in the VAT rates on medicines and in the distribution margins were among the most common measures. More than a dozen countries reported measures under discussion or planned, for the remaining year 2011 and beyond. The largest number of measures were implemented in Iceland, the Baltic states (Estonia, Latvia, Lithuania), Greece, Spain and Portugal, which were hit by the crisis at different times. CONCLUSIONS: Cost-containment has been an issue for high-income countries in Europe - no matter if hit by the crisis or not. In recent months, changes in pharmaceutical policies were reported from 23 European countries. Measures which can be implemented rather swiftly (e.g. price cuts, changes in co-payments and VAT rates on medicines) were among the most frequent measures. While the "crisis countries" (e.g. Baltic states, Greece, Spain) reacted with a bundle of measures, reforms in other countries (e.g. Poland, Germany) were not directly linked to the crisis, but also aimed at containing public spending. Since further reforms are under way, we recommend that the monitoring exercise is continued. PMID- 23093887 TI - Pharmacy practice in the Republic of Macedonia. AB - As part of wider reforms within the pharmaceutical sector, the pharmaceutical care concept has been introduced in the Republic of Macedonia. This article provides discussion on current opportunities and challenges which pharmacy practice face in Macedonia. The emphasis is on three prerequisites for the implementation of pharmaceutical care including: organization of pharmaceutical services, legislation, and professional training. The author argues that Macedonia possesses a favorable pharmacy workforce, solid legal basis and supportive structures of healthcare services in order to implement pharmaceutical care. Implementing pharmaceutical care has not been without its challenges, such as: lack of clinical skills, inadequate continuing education and the current remuneration structure for pharmacy services. While Good Pharmacy Practice (GPP) Guidelines have been developed, wider professional debate and practical steps have not been undertaken to promote the concept of pharmaceutical care nationally. Therefore, an integrated national approach to develop strategy, standards and tools for patient-oriented pharmaceutical practice has to be formulated. In addition, there is a need to undertake more comprehensive analysis of current pharmacy practice, to explore the awareness and willingness of the pharmacists to embrace pharmaceutical care practices, and to identify the opportunities and barriers for implementation of pharmacy practice. PMID- 23093888 TI - Pharmacy practice in Qatar: challenges and opportunities. AB - The State of Qatar is a small oil and gas-rich Gulf country that is experiencing rapid development in health care services, including pharmaceutical services. To date, there is no autonomous professional pharmacy association or society that regulates or promotes the practice of pharmacy in Qatar, and the challenges that face the profession of pharmacy in Qatar mirror the challenges facing the profession in all other Middle Eastern countries. However, a set of initiatives and projects that include pioneering educational initiatives, close alignment of practice with the educational providers, stronger leadership from a National Health Strategy, and the development of pharmacy leadership groups at the practice level all contribute in the fast development of the practice of pharmacy in this country. In this commentary, we provide a snapshot of the pharmaceutical scene in Qatar, and in doing so, we shall discuss the challenges that face the practice, and the main landmarks and initiatives that are destined to move pharmacy forward in Qatar. PMID- 23093889 TI - What determines the duration of patient medication compliance in patients with chronic disease: are we looking in the wrong place? AB - OBJECTIVES: The objective of this study was to do a pilot inquiry, to determine whether physicians with similar practices in the same neighborhood demonstrated any difference in the duration of compliance among their patients. METHODS: Through a cooperating urban community pharmacy, patients with prescriptions for hypertension and type II diabetes were identified for this pilot study. Patients refill medication records were searched to determine the average number of months of drug regimen compliance. The patient data of the four local physicians were separated and compared. RESULTS: One physician was able to generate refill durations nearly double that of the average duration of medication refills seen in the patients consulting the several other nearby physicians. CONCLUSION: In this pilot study, it was determined that there are differences in the compliance behavior of patients attending different physicians. We can conclude that some communication or personality characteristics of some physicians appear to be more successful in achieving higher compliance. Subsequent studies should identify those which may be at least partially responsible for this finding. PMID- 23093890 TI - Impact of pharmacist recruitment on ADR reporting: Malaysian experience. PMID- 23093891 TI - BigPharma and unethical marketing of medicinal products. PMID- 23093892 TI - Pharmacy practice: Is the gap between the North and South widening? PMID- 23093893 TI - Should the C in CME Stand for Commercial? PMID- 23093894 TI - The burden of adverse events during treatment of drug-resistant tuberculosis in Namibia. AB - OBJECTIVE: Namibia faces a dual burden of HIV/AIDS and tuberculosis (TB). In 2010, HIV prevalence was 18.8%, the TB case notification rate was 634 cases per 100,000 population and the TB/HIV co-infection rate was 58%. There were 372 cases of drug-resistant TB (DR-TB) in 2009. The objective of this study was to assess the prevalence, profile and outcome of adverse events (AEs) associated with treatment of DR-TB and to explore possible influences of HIV disease on the occurrence of adverse events. METHODS: This was a cross-sectional descriptive study. After ethical approval, data were collected from treatment records of all patients treated for DR-TB at the study facility between January 2008 and February 2010 using a structured data collection form. RESULTS: A total of 141 adverse events of varying severity were experienced in 90% (53/59) of patients.The TB/HIV co-infection rate was 53% (n=31). The prevalence of gastrointestinal tract adverse events (abdominal pains, constipation, diarrhea, nausea and vomiting) was 64%, tinnitus 45%, joint pain 28%and decreased hearing 25%. Abdominal pains, rash, nausea, decreased hearing and joint pain were more common in HIV infected than in HIV uninfected patients. CONCLUSIONS: Adverse events of varying severity are common during treatment of DR-TB, particularly in the intensive phase of therapy. Some adverse events were more prevalent in DR-TB patients co-infected with HIV. The study concludes that the characteristics and risk factors of serious adverse events should be further examined. PMID- 23093895 TI - The Vanuatu medical supply system - documenting opportunities and challenges to meet the Millennium Development Goals. AB - OBJECTIVES: Limited human resources are widely recognised as a barrier to achieve health-related Millennium Development Goals. Availability of medical supplies and suitably trained health personnel are crucial to ensuring a well-functioning medical supply system. The objective of this paper is to identify the factors which influence the availability of medical supplies within the health facilities of Vanuatu. METHODS: A qualitative triangulated strategy using semi-structured interviews, observational workplace surveys and semi-structured focus groups was developed. This research was approved by the Human Ethics Committee of the University of Canberra and was funded through a direct grant from the United Nations Population Fund Suva, Pacific sub regional office. RESULTS: During two weeks of data collection, 21 interviews were conducted, observational workplace surveys were completed in 19 facilities and 22 personnel participated in three focus groups across three provinces. The interviewees had a wide range of primary professional groupings and were representative of the Vanuatu health workforce. A complex array of medical supply issues are described from within the three tiered structure of the medical supply system. CONCLUSION: The results of this research have further informed our understanding of the competencies required by healthcare personnel to conduct medical supply management activities effectively in Pacific Island countries. As a result of this research, a platform is provided for the government of Vanuatu to engage development partners to work toward a sustainable medical supply system. PMID- 23093897 TI - Impact of regulatory requirements on medicine registration in African countries - perceptions and experiences of pharmaceutical companies in South Africa. AB - OBJECTIVE: Access to medicines has long been and remains a challenge in African countries. The impact of medicines registration policies in these countries poses a challenge for pharmaceutical companies wanting to register medicines in these countries. The recent AMRHI (African Medicines Registration Harmonisation Initiative) has increased the focus on the need for harmonisation. Medicines registration regulations differ across African countries. Anecdotal evidence, based on the experience of pharmaceutical companies on progress towards harmonisation is somewhat different, i.e. that country specific requirements were a barrier to the registration of medicines. The objective of this study was therefore to determine the nature and extent of regulatory hurdles experienced by pharmaceutical companies who wish to register and supply medicines to African countries. METHODS: This cross-sectional descriptive pilot study was conducted across pharmaceutical companies, both local and multinational. These companies were based in South Africa and were also members of Pharmaceutical Industry Association of South Africa (PIASA). The pharmaceutical companies supply both the private and public sectors. An online survey was developed using Survey Monkey. Survey questions focused on the following strands: nature and level of current supply of medicines to African countries by companies, general regulatory requirements, region specific questions and country specific questions across four regional economic communities in Africa, namely; Southern African Development Community (SADC), East African Community (EAC), Economic Community of the West African States (ECOWAS) and Economic Community of Central African States (ECCAS). RESULTS: A total of 33 responses were received to the questionnaire of which 26 respondents were from the PIASA Regulatory working group and 7 were from the PIASA Export working group.It was noted that since most of the regulatory authorities in Africa are resource-constrained, harmonisation of medicine registration policies will contribute positively to ensuring the safety, quality and efficacy of medicines. The experience of pharmaceutical companies indicated that country specific regulatory requirements are a barrier to registering and supplying medicines to African countries. In particular, GMP inspections, GMP inspection fees and country specific labeling were cited as key problems. CONCLUSION: Pharmaceutical companies operating in African markets are experiencing difficulties in complying with the technical requirements of individual African countries. Further research is required to provide a balanced perspective on the country specific regulatory requirements vs. the African Regulatory Harmonisation Initiative (AMRHI). PMID- 23093896 TI - Perception and attitude of general practitioners regarding generic medicines in Karachi, Pakistan: A questionnaire based study. AB - OBJECTIVES: In developing countries out-of-pocket payments (OOP) are as high as 80% of healthcare spending. Generic medicines can be instrumental in reducing this expenditure. The current study is aimed to explore the knowledge, perception, and attitude of general practitioners towards generic medicines in Karachi, Pakistan. METHODS: This exploratory, descriptive study was conducted on a sample of 289 randomly selected general practitioners who were dispensing at their private clinics in Karachi, Pakistan. The questionnaires were distributed and collected by hand. Data was entered to SPSS version 17. Fischer's exact test was applied to see the association between variables. RESULTS: A total of 206 questionnaires were included in the study. A response rate of 71.3% was achieved. Out of 206 respondents, 139 (67.5%) were male while 67 (32.5%) respondents were female. Close to three quaters of the respondents (n= 148; 71.8%) showed correct knowledge about generic medicines being a 'copy of the brand name medicines' and 'interchangeable with brand name medicines' (n= 148; 71.8%). In terms of safety, the majority of respondents (n=85; 41.26%) incorrectly understood that the generic medicines are less safe than brand name medicines. The total percentage of correct responses was seen in 53% of the respondents. More than half of the respondents agreed that locally manufactured medicines are of the same effectiveness as brand name medicines (n=114; 55.4%). Male practitioners with practice experience of 11-15 years showed positive perception towards the quality of multinational products. The Majority of respondents believed that their prescribing decision is influenced by medical representatives (n=117; 56.8%). More than three-quarters of the respondents expressed their wish to prescribe low cost medicines in their practice (n=157; 76.2%). More than one third of the respondents expressed their uneasiness to prescribe products from all local manufacturers (n=72; 35%). CONCLUSION: There were gaps identified in the knowledge of respondents. Although good perception and attitude were noted among the respondents, dissemination of information regarding generic medicines may perhaps strengthen generic prescribing. There is a need to introduce 'Quality by Design' concept in local manufacturing units. This, in turn, can inculcate confidence in prescribers towards locally manufactured generic medicines. PMID- 23093898 TI - Discounts and rebates granted to public payers for medicines in European countries. AB - OBJECTIVE: The objective of this study was to provide an overview about the existence and types of discounts and rebates granted to public payers by the pharmaceutical industry in European countries. METHODS: Data were collected via a questionnaire in spring 2011. Officials from public authorities for pharmaceutical pricing and reimbursement represented in the PPRI (Pharmaceutical Pricing and Reimbursement Information) network provided the information and reviewed the compilation. RESULTS: Information is available from 31 European countries. Discounts and rebates granted to public payers by pharmaceutical industry were reported for 25 European countries. Such discounts exist both in the in- and out-patient sectors in 21 countries and in the in-patient sector only in four countries. Six countries reported not having any regulations or agreements regarding the discounts and rebates granted by industry. The most common discounts and rebates are price reductions and refunds linked to sales volume but types such as in-kind support, price-volume and risk-sharing agreements are also in place. A mix of various types of discounts and rebates is common. Many of these arrangements are confidential. Differences regarding types, the organizational and legal framework, validity and frequency of updates and the amount of the discounts and rebates granted exist among the surveyed countries. CONCLUSIONS: In Europe, discounts and rebates on medicines granted by pharmaceutical industry to public payers are common tools to contain public pharmaceutical expenditure. They appear to be used as a complimentary measure when price regulation does not achieve the desired results and in the few European countries with no or limited price regulation. The confidential character of many of these arrangements impedes transparency and may lead to a distortion of medicines prices. An analysis of the impact on these measures is recommended. PMID- 23093899 TI - Disease related knowledge and quality of life: a descriptive study focusing on hypertensive population in Pakistan. AB - OBJECTIVE: This study aims to evaluate association between Health related quality of lifeand disease state knowledge among hypertensive population of Pakistan. METHODS: A cross sectional descriptive study was undertaken with a representative cohort of hypertension patients. Using prevalence based sampling technique, a total of 385 hypertensive patients were selected from two public hospitals of Quetta city, Pakistan. Hypertension Fact Questionnaire (HFQ) and European Quality of Life scale (EQ-5D) were used for data collection. Statistical Package for the Social Sciences 16.0 was used to compute descriptive analysis of patients' demographic and disease related information. Categorical variables were described as percentages while continuous variables were expressed as mean +/- standard deviation (SD). Spearman's rho correlation was used to identify the association between study variables. RESULTS: The mean (SD) age of the patients was 39.02 (6.59), with 68.8% males (n=265). The mean (SD) duration of hypertension was 3.01 (0.93) years. Forty percent (n=154) had bachelor degree with 34.8% (n=134) working in private sector. Almost forty one percent (n=140) had monthly income of more than 15000 Pakistan rupees per month with 75.1% (n=289) having urban residency. The mean EQ-5D descriptive score (0.46+/-0.28) and EQ-VAS score (63.97+/-6.62) indicated lower HRQoL in our study participants. Mean knowledge score was 8.03 +/- 0.42. Correlation coefficient between HRQoL and knowledge was 0.208 (p< 0.001), indicating a week positive association. CONCLUSION: Results of this study highlight hypertension knowledge to be weakly associated with HRQoL suggesting that imparting knowledge to patients do not necessarily improve HRQoL. More attention should be given to identify individualized factors affecting HRQoL. PMID- 23093900 TI - The effect of implementing "medicines zero mark-up policy" in Beijing community health facilities. PMID- 23093902 TI - Lactosylated liposomes for targeted delivery of doxorubicin to hepatocellular carcinoma. AB - BACKGROUND: N-lactosyl-dioleoylphosphatidylethanolamine (Lac-DOPE) was synthesized and evaluated as a liver-specific targeting ligand via asialoglycoprotein receptors for liposomal delivery of doxorubicin. METHODS: Lactosylated liposomes encapsulating calcein (Lac-L-calcein) or doxorubicin (Lac L-DOX) composed of egg phosphatidylcholine, cholesterol, monomethoxy polyethylene glycol 2000-distearoyl phosphatidylethanolamine, and Lac-DOPE at 50:35:5:10 (mol/mol) were prepared by polycarbonate membrane extrusion and evaluated in human hepatocellular carcinoma HepG2 cells. Cellular uptake of Lac-L-calcein was monitored by confocal microscopy and by flow cytometry. The cytotoxicity of Lac-L DOX was evaluated by MTT assay. The pharmacokinetic properties of Lac-L-DOX were studied in normal mice, and its biodistribution and antitumor activity were studied in nude mice with HepG2 xenografts. RESULTS: The size of Lac-L-DOX was less than 100 nm and the liposomes demonstrated excellent colloidal stability. In vitro uptake of Lac-L-calcein by HepG2 cells was four times greater than that of non-targeted L-calcein. In the presence of 20 mM lactose, the uptake of Lac-L calcein was inhibited, suggesting that asialoglycoprotein receptors mediated the observed cellular uptake. Lac-L-DOX exhibited enhanced in vivo cytotoxicity compared with the nontargeted liposomal doxorubicin (L-DOX), and its pharmacokinetic parameters indicate that Lac-L-DOX has a long blood circulation time (t(1/2) 8.73 hours). Tissue distribution and therapeutic efficacy studies in nude mice bearing HepG2 xenografts show that Lac-L-DOX had significantly stronger tumor inhibitory activity compared with L-DOX and free doxorubicin, along with a higher accumulation of drug within the tumor site and greater cellular uptake by tumor cells. CONCLUSION: These data suggest that lactosylated liposomes are promising drug delivery vehicles for hepatocellular carcinoma. PMID- 23093901 TI - Beyond FEV1 in COPD: a review of patient-reported outcomes and their measurement. AB - Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms and pathological consequences. Although primarily viewed as a respiratory disease, COPD has both pulmonary and extrapulmonary effects, which have an impact on many aspects of physical, emotional, and mental well-being. Traditional assessment of COPD relies heavily on measuring lung function, specifically forced expiratory volume in 1 second (FEV(1)). However, the evidence suggests that FEV(1) is a relatively poor correlate of symptoms such as breathlessness and the impact of COPD on daily life. Furthermore, many consequences of the disease, including anxiety and depression and the ability to perform daily activities, can only be described and reported reliably by the patient. Thus, in order to provide a comprehensive view of the effects of interventions in clinical trials, it is essential that spirometry is accompanied by assessments using patient-reported outcome (PRO) instruments. We provide an overview of patient-reported outcome concepts in COPD, such as breathlessness, physical functioning, and health status, and evaluate the tools used for measuring these concepts. Particular attention is given to the newly developed instruments emerging in response to recent regulatory guidelines for the development and use of PROs in clinical trials. We conclude that although data from the development and validation of these new PRO instruments are emerging, to build the body of evidence that supports the use of a new instrument takes many years. Furthermore, new instruments do not necessarily have better discriminative or evaluative properties than older instruments. The development of new PRO tools, however, is crucial, not only to ensure that key COPD concepts are being reliably measured but also that the relevant treatment effects are being captured in clinical trials. In turn, this will help us to understand better the patient's experience of the disease. PMID- 23093903 TI - New inhalation-optimized itraconazole nanoparticle-based dry powders for the treatment of invasive pulmonary aspergillosis. AB - PURPOSE: Itraconazole (ITZ) dry powders for inhalation (DPI) composed of nanoparticles (NP) embedded in carrier microparticles were prepared and characterized. METHODS: DPIs were initially produced by reducing the ITZ particle size to the nanometer range using high-pressure homogenization with tocopherol polyethylene 1000 succinate (TPGS, 10% w/w ITZ) as a stabilizer. The optimized nanosuspension and the initial microsuspension were then spray-dried with different proportions of or in the absence of mannitol and/or sodium taurocholate. DPI characterization was performed using scanning electron microscopy for morphology, laser diffraction to evaluate the size-reduction process, and the size of the dried NP when reconstituted in aqueous media, impaction studies using a multistage liquid impactor to determine the aerodynamic performance and fine-particle fraction that is theoretically able to reach the lung, and dissolution studies to determine the solubility of ITZ. RESULTS: Scanning electron microscopy micrographs showed that the DPI particles were composed of mannitol microparticles with embedded nano- or micro-ITZ crystals. The formulations prepared from the nanosuspension exhibited good flow properties and better fine-particle fractions, ranging from 46.2% +/- 0.5% to 63.2% +/- 1.7% compared to the 23.1% +/- 0.3% that was observed with the formulation produced from the initial microsuspension. Spray-drying affected the NP size by inducing irreversible aggregation, which was able to be minimized by the addition of mannitol and sodium taurocholate before the drying procedure. The ITZ NP-based DPI considerably increased the ITZ solubility (58 +/- 2 increased to 96 +/- 1 ng/mL) compared with that of raw ITZ or an ITZ microparticle-based DPI (<10 ng/mL). CONCLUSION: Embedding ITZ NP in inhalable microparticles is a very effective method to produce DPI formulations with optimal aerodynamic properties and enhanced ITZ solubility. These formulations could be applied to other poorly water-soluble drugs and could be a very effective alternative for treating invasive pulmonary aspergillosis. PMID- 23093904 TI - Development of novel cationic chitosan-and anionic alginate-coated poly(D,L lactide-co-glycolide) nanoparticles for controlled release and light protection of resveratrol. AB - BACKGROUND: Resveratrol, like other natural polyphenols, is an extremely photosensitive compound with low chemical stability, which limits the therapeutic application of its beneficial effects. The development of innovative formulation strategies, able to overcome physicochemical and pharmacokinetic limitations of this compound, may be achieved via suitable carriers able to associate controlled release and protection. In this context, nanotechnology is proving to be a powerful strategy. In this study, we developed novel cationic chitosan (CS)- and anionic alginate (Alg)-coated poly(d,l-lactide-co-glycolide) nanoparticles (NPs) loaded with the bioactive polyphenolic trans-(E)-resveratrol (RSV) for biomedical applications. METHODS: NPs were prepared by the nanoprecipitation method and characterized in terms of morphology, size and zeta potential, encapsulation efficiency, Raman spectroscopy, swelling properties, differential scanning calorimetry, and in vitro release studies. The protective effect of the nanosystems under the light-stressed RSV and long-term stability were investigated. RESULTS: NPs turned out to be spherical in shape, with size ranging from 135 to about 580 nm, depending on the composition and the amount of polyelectrolytes, while the encapsulation efficiencies increased from 8% of uncoated poly(d,l-lactide-co-glycolide) (PLGA) to 23% and 32% of Alg- and CS coated PLGA NPs, respectively. All nanocarriers are characterized by a biphasic release pattern, and more effective controlled release rates are obtained for NPs formulated with higher polyelectrolyte concentrations. Stability studies revealed that encapsulation provides significant protection against light-exposure degradation, by reducing the trans-cis photoisomerization reaction. Moreover, the nanosystems are able to prevent the degradation of trans isoform and the leakage of RSV from the carrier for a period of 6 months. CONCLUSION: Our findings indicated that the newly developed CS- and Alg-coated PLGA NPs are suitable to be used for the delivery of bioactive RSV. The encapsulation of RSV into optimized polymeric NPs provides improved drug loading, effective controlled release, and protection against light-exposure degradation, thus opening new perspectives for the delivery of bioactive related phytochemicals to be used for (nano)chemoprevention/chemotherapy. PMID- 23093906 TI - Multidisciplinary treatment for peripheral arterial occlusive disease and the role of eHealth and mHealth. AB - Increasingly unaffordable health care costs are forcing care providers to develop economically viable and efficient health care plans. Currently, only a minority of all newly diagnosed peripheral arterial occlusive disease (PAOD) patients receive efficient and structured conservative treatment for their disease. The aim of this article is to introduce an innovative effective treatment model termed ClaudicatioNet. This concept was launched in The Netherlands as a means to combat treatment shortcomings and stimulate cohesion and collaboration between stakeholders. The overall goal of ClaudicatioNet is to stimulate quality and transparency of PAOD treatment by optimizing multidisciplinary health care chains on a national level. Improved quality is based on stimulating both a theoretical and practical knowledge base, while eHealth and mHealth technologies are used to create clear insights of provided care to enhance quality control management, in addition these technologies can be used to increase patient empowerment, thereby increasing efficacy of PAOD treatment. This online community consists of a web portal with public and personal information supplemented with a mobile application. By connecting to these tools, a social community is created where patients can meet and keep in touch with fellow patients, while useful information for supervising health care professionals is provided. The ClaudicatioNet concept will likely create more efficient and cost-effective PAOD treatment by improving the quality of supervised training programs, extending possibilities and stimulating patient empowerment by using eHealth and mHealth solutions. A free market principle is introduced by introducing transparency to provided care by using objective and subjective outcome parameters. Cost effectiveness can be achieved using supervised training programs, which may substitute for or postpone expensive invasive vascular interventions. PMID- 23093905 TI - New developments in the treatment of partial-onset epilepsy. AB - Although most people presenting with partial-onset seizures will achieve control with antiepileptic medication, a considerable minority will have difficult-to treat epilepsy that is resistant to existing medication. Over the last few years, a large number of new antiepileptic drugs have been developed. Some of these have a novel mode of action. Many of the older antiepileptic drugs act through sodium channels or by enhancement of gamma amino butyric acid (GABA). Lamotrigine has sodium-channel blocking properties but also has other important modes of action, indicated by efficacy in treating not only partial-onset but also generalized seizures. Vigabatrin and tiagabine both increase GABA activity, by inhibiting GABA transaminase and limiting GABA reuptake, respectively. The main mode of action of gabapentin and pregabalin is not via GABA but through a selective inhibitory effect on voltage-gated calcium channels containing the alpha(2)delta 1 subunit. Levetiracetam inhibits the recycling of SV2A (synaptic vesicle protein 2A) neurotransmitter vesicles but also has other effects, including inhibition of voltage-dependent calcium channels. Some drugs, eg, felbamate, zonisamide, and topiramate, have multiple modes of action. In many cases, although the main mode of action may have been identified, other modes of action also play a role. Two recently developed antiepileptic drugs appear to have completely novel primary modes of action; retigabine (ezogabine) and perampanel act on the potassium channel and on AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors, respectively. The hope is that antiepileptic drugs with a novel mode of action will be effective where previous drugs have failed and will not have unacceptable adverse effects. However, experience with these medications is too limited to allow any conclusions to be drawn at present. PMID- 23093907 TI - Mentoring in biostatistics: some suggestions for reform. AB - Mentoring is routinely used as a tool to facilitate acquisition of skills by new professionals in fields like medicine, nursing, surgery, and business. While mentoring has been proposed as an effective strategy for knowledge and skills transfer in biostatistics and related fields, there is still much to be done to facilitate adoption by stakeholders, including academia and employers of biostatisticians. This is especially troubling given that biostatisticians play a key role in the success or otherwise of clinical research conducted for evidence based decisions. In this paper, we offer suggestions on how mentoring can be applied in practice to advance the statistical training of future biostatisticians. In particular, we propose steps that academic statistics departments, professional statistical societies, and statistics organizations can take to advance the mentoring of young biostatisticians. Our suggestions also cover what mentors and mentees can do to facilitate a successful mentoring relationship. PMID- 23093908 TI - Bid-overexpression regulates proliferation and phosphorylation of Akt and MAPKs in response to etoposide-induced DNA damage in hepatocellular carcinoma cells. AB - BACKGROUND: Growing evidence supports BH3-interacting domain death agonist (Bid) playing a dual role in DNA damage response. However, the effects of Bid on hepatocellular carcinoma (HCC) cell proliferation in response to etoposide induced DNA damage have not been sufficiently investigated. METHODS: Using a stable Bid-overexpression HCC cell line, Bid/PLC/PRF/5, overexpression of Bid promoted loss of viability in response to etoposide-induced DNA damage. MTT [3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]- and BrdU (5'-bromo 2'-deoxyuridine)-labeling assays revealed that etoposide-inhibited HCC cells grew in concentration-and time-dependent manners. The phosphorylations of Akt and mitogen-activated protein kinases (MAPKs) in response to etoposide-induced DNA damage were analyzed by Western blotting. RESULTS: The survival rates of 100 MUM etoposide on the cells with control vector and Bid/PLC/PRF/5 at 48 hours amounted to 71% +/- 0.75% and 59% +/- 0.60% with MTT assay, and similar results of 85% +/- 0.08% and 63% +/- 0.14% with BrdU-labeling assay respectively. Moreover, overexpression of Bid sensitized the cells to apoptosis at a high dose of etoposide (causing irreparable damage). However, it had little effect on the proliferation at a low dose of etoposide (repairable damage). Furthermore, the phosphorylation status of Akt and MAPKs were investigated. Overexpression of Bid suppressed the activation of Akt with respect to etoposide-induced DNA damage. Similar to Akt, the levels of phosphorylated p38 and phosphorylated c-Jun were attenuated by Bid-overexpression. On the contrary, the level of phosphorylated ERK1/2 was sustained at a high level, especially in Bid/PLC/PRF/5 cells. CONCLUSION: Taken together, these results suggest that overexpression of Bid suppressed the activation of Akt, p38, and c-Jun, and promoted the activation of ERK1/2 induced by etoposide, suggesting that the promotion of ERK1/2 activation may have a negative effect on Bid-mediated HCC DNA damage induced by etoposide. PMID- 23093909 TI - Prevalence of extended-spectrum beta-lactamase-producing bacteria in food. AB - Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae with Cefotaximase-Munchen (CTX-M) enzymes are rapidly increasing worldwide and pose a threat to health care. ESBLs with CTX-M enzymes have been isolated from animals and different food products, but it is unknown if food imported from the Mediterranean area may be a possible reservoir of these bacteria. During 2007 2008, swab samples from food across different retail outlets (mostly food from the Mediterranean countries and Swedish chicken) were collected. Escherichia coli strains from Swedish meat and E. coli isolates from unspecified food from a Swedish food testing laboratory were also examined. In 349 of the 419 swab samples, growth of Enterobacteriaceae was found. In most of the samples, there was also growth of Gram-negative environmental bacteria. Air dry-cured products contained significantly less Enterobacteriaceae isolates compared to lettuces; however, none of the examined Enterobacteriaceae harbored ESBLs. This study did not support the theory that imported food from the Mediterranean area or Swedish domestic food might constitute an important vehicle for the dissemination of ESBL producing Enterobacteriaceae; however, a spread from food to humans may have occurred after 2008. PMID- 23093910 TI - Polypodium leucotomos Extract use to prevent and reduce the risk of infectious diseases in high performance athletes. AB - OBJECTIVE: Many components of the immune system undergo adverse changes during intense physical activity in athletes, leading to a heightened risk of respiratory tract infections. This study evaluated the reduction in infectious processes in athletes due to intensive training with anapsos. METHODS: The study compared athletes who took 480 mg Polypodium leucotomos Extract (Armaya fuerte; Centrum laboratories, Alicante, Spain) twice daily for 3 months (n = 50) with a control group (n = 50) in the evaluation of the onset of infectious processes and relapses during an 8-month period (June 2010 to January 2011). RESULTS: The onset of infectious processes in the Polypodium leucotomos Extract group was lower when compared to the control group (14% versus 56%). Relapse in the Polypodium leucotomos Extract group was seen in just one athlete (14.2%) compared to ten athletes (37.5%) in the control group. CONCLUSION: Polypodium leucotomos Extract has been shown to be useful in the prevention of infectious processes, as well as reducing recurring episodes in athletes. PMID- 23093912 TI - A novel image encryption algorithm based on DNA subsequence operation. AB - We present a novel image encryption algorithm based on DNA subsequence operation. Different from the traditional DNA encryption methods, our algorithm does not use complex biological operation but just uses the idea of DNA subsequence operations (such as elongation operation, truncation operation, deletion operation, etc.) combining with the logistic chaotic map to scramble the location and the value of pixel points from the image. The experimental results and security analysis show that the proposed algorithm is easy to be implemented, can get good encryption effect, has a wide secret key's space, strong sensitivity to secret key, and has the abilities of resisting exhaustive attack and statistic attack. PMID- 23093911 TI - Critical evaluation of the role of acarbose in the treatment of diabetes: patient considerations. AB - The alpha-glucosidase inhibitor acarbose has been used for more than 20 years in the management of hyperglycemia. Owing to its unique mode of action in the gastrointestinal tract, its properties are very different from other antidiabetic medications. Patients on long-term treatment to control a chronic disease are not only interested in good treatment efficacy, but are also even more interested in the safety and side effects of their medications. Significant aspects of acarbose predominantly regarding safety and tolerability in the management of type 2 diabetes and prediabetes are reviewed. It is concluded that acarbose is a convenient long-term treatment option, with benefits for both type 2 diabetics and patients in a prediabetic state. PMID- 23093913 TI - Strategies to fight stigma toward people with mental disorders: perspectives from different stakeholders. AB - This study aims to provide a more complete and exhaustive perspective on the whole range of potential strategies to fight stigma by considering the perspectives of different stakeholders. Delegates to a Canadian conference were invited to participate in a survey that focused on stigma, from which the responses to the following question were analyzed: tell us briefly what you do to reduce prejudice and stigma toward people with a diagnosis of mental disorder? From 253 participants, 15 categories of strategies to fight stigma were identified from the verbatim (e.g., sharing/encouraging disclosure). These categories fell under six main themes: education, contact, protestation, person centered, working on recovery and social inclusion, and reflexive consciousness. The occurrence of these themes was different among stakeholders (clinical, organizational, and experiential knowledge). For example, people with mental disorders (experiential knowledge) often mentioned contact and person centered strategies, while mental health professionals (clinical knowledge) preferred education and working on recovery and social inclusion strategies. The results from this study highlight the need to pay more attention to the concept of disclosure of mental disorders in the process for de-stigmatization. Future studies are needed to assess the impact of the emerging strategies to fight stigma in the community. PMID- 23093914 TI - Comparative gastric morphometry of Muong indigenous and Vietnamese wild pigs. AB - It is hypothesized that despite sharing a similar habitat, the Muong indigenous and Vietnamese wild pigs may reveal different gastric morphology. Due to the protective nature of procuring these pigs, a total of 12 Muong indigenous pigs and nine Vietnamese wild pigs stomach collected post mortem were analysed for selected biometric parameters and histology. The result indicated that the stomach of the Vietnamese wild pig is broader with a bigger capacity and greater proportion of proper gastric glands. Interestingly, the stomach mass correlated well with live body weight in both breeds apart from possessing similar histomorphometry of the gastric gland regions. On the other hand, the thicker (P < 0.05) submucosa in the Vietnamese wild pig is attributed to the presence of numerous loose connective tissues, abundant blood vessels, adipose tissues and nerve plexus. The appearance of lymphoid follicles underneath the tubular gastric glands in the Vietnamese wild pig exceeded that of Muong indigenous pigs. This finding suggested that the difference in feeding behavior as well as immunity. In conclusion, adaptations found in the Vietnamese wild pig indicated that this breed is equipped with a bigger and effectively functional stomach to suit its digestive physiology and immunity in the wild. PMID- 23093917 TI - Evaluating the adequacy of gravity models as a description of human mobility for epidemic modelling. AB - Gravity models have a long history of use in describing and forecasting the movements of people as well as goods and services, making them a natural basis for disease transmission rates over distance. In agent-based micro-simulations, gravity models can be directly used to represent movement of individuals and hence disease. In this paper, we consider a range of gravity models as fits to movement data from the UK and the US. We examine the ability of synthetic networks generated from fitted models to match those from the data in terms of epidemic behaviour; in particular, times to first infection. For both datasets, best fits are obtained with a two-piece 'matched' power law distance distribution. Epidemics on synthetic UK networks match well those on data networks across all but the smallest nodes for a range of aggregation levels. We derive an expression for time to infection between nodes in terms of epidemiological and network parameters which illuminates the influence of network clustering in spread across networks and suggests an approximate relationship between the log-likelihood deviance of model fit and the match times to infection between synthetic and data networks. On synthetic US networks, the match in epidemic behaviour is initially poor and sensitive to the initially infected node. Analysis of times to infection indicates a failure of models to capture infrequent long-range contact between large nodes. An assortative model based on node population size captures this heterogeneity, considerably improving the epidemiological match between synthetic and data networks. PMID- 23093916 TI - Multiple spike time patterns occur at bifurcation points of membrane potential dynamics. AB - The response of a neuron to repeated somatic fluctuating current injections in vitro can elicit a reliable and precisely timed sequence of action potentials. The set of responses obtained across trials can also be interpreted as the response of an ensemble of similar neurons receiving the same input, with the precise spike times representing synchronous volleys that would be effective in driving postsynaptic neurons. To study the reproducibility of the output spike times for different conditions that might occur in vivo, we somatically injected aperiodic current waveforms into cortical neurons in vitro and systematically varied the amplitude and DC offset of the fluctuations. As the amplitude of the fluctuations was increased, reliability increased and the spike times remained stable over a wide range of values. However, at specific values called bifurcation points, large shifts in the spike times were obtained in response to small changes in the stimulus, resulting in multiple spike patterns that were revealed using an unsupervised classification method. Increasing the DC offset, which mimicked an overall increase in network background activity, also revealed bifurcation points and increased the reliability. Furthermore, the spike times shifted earlier with increasing offset. Although the reliability was reduced at bifurcation points, a theoretical analysis showed that the information about the stimulus time course was increased because each of the spike time patterns contained different information about the input. PMID- 23093918 TI - Osteoprotegerin in bone metastases: mathematical solution to the puzzle. AB - Bone is a common site for cancer metastasis. To create space for their growth, cancer cells stimulate bone resorbing osteoclasts. Cytokine RANKL is a key osteoclast activator, while osteoprotegerin (OPG) is a RANKL decoy receptor and an inhibitor of osteoclastogenesis. Consistently, systemic application of OPG decreases metastatic tumor burden in bone. However, OPG produced locally by cancer cells was shown to enhance osteolysis and tumor growth. We propose that OPG produced by cancer cells causes a local reduction in RANKL levels, inducing a steeper RANKL gradient away from the tumor and towards the bone tissue, resulting in faster resorption and tumor expansion. We tested this hypothesis using a mathematical model of nonlinear partial differential equations describing the spatial dynamics of OPG, RANKL, PTHrP, osteoclasts, tumor and bone mass. We demonstrate that at lower expression rates, tumor-derived OPG enhances the chemotactic RANKL gradient and osteolysis, whereas at higher expression rates OPG broadly inhibits RANKL and decreases osteolysis and tumor burden. Moreover, tumor expression of a soluble mediator inducing RANKL in the host tissue, such as PTHrP, is important for correct orientation of the RANKL gradient. A meta analysis of OPG, RANKL and PTHrP expression in normal prostate, carcinoma and metastatic tissues demonstrated an increase in expression of OPG, but not RANKL, in metastatic prostate cancer, and positive correlation between OPG and PTHrP in metastatic prostate cancer. The proposed mechanism highlights the importance of the spatial distribution of receptors, decoys and ligands, and can be applied to other systems involving regulation of spatially anisotropic processes. PMID- 23093919 TI - CAVER 3.0: a tool for the analysis of transport pathways in dynamic protein structures. AB - Tunnels and channels facilitate the transport of small molecules, ions and water solvent in a large variety of proteins. Characteristics of individual transport pathways, including their geometry, physico-chemical properties and dynamics are instrumental for understanding of structure-function relationships of these proteins, for the design of new inhibitors and construction of improved biocatalysts. CAVER is a software tool widely used for the identification and characterization of transport pathways in static macromolecular structures. Herein we present a new version of CAVER enabling automatic analysis of tunnels and channels in large ensembles of protein conformations. CAVER 3.0 implements new algorithms for the calculation and clustering of pathways. A trajectory from a molecular dynamics simulation serves as the typical input, while detailed characteristics and summary statistics of the time evolution of individual pathways are provided in the outputs. To illustrate the capabilities of CAVER 3.0, the tool was applied for the analysis of molecular dynamics simulation of the microbial enzyme haloalkane dehalogenase DhaA. CAVER 3.0 safely identified and reliably estimated the importance of all previously published DhaA tunnels, including the tunnels closed in DhaA crystal structures. Obtained results clearly demonstrate that analysis of molecular dynamics simulation is essential for the estimation of pathway characteristics and elucidation of the structural basis of the tunnel gating. CAVER 3.0 paves the way for the study of important biochemical phenomena in the area of molecular transport, molecular recognition and enzymatic catalysis. The software is freely available as a multiplatform command-line application at http://www.caver.cz. PMID- 23093920 TI - Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels. AB - Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3',5'-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding domain. Based on previously determined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the second ligand obstructed channel opening similar to the empty channel. Analysis of the net probability fluxes in terms of the transition path theory revealed pronounced hysteresis for channel activation and deactivation. These results provide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function. PMID- 23093921 TI - Spatially pooled contrast responses predict neural and perceptual similarity of naturalistic image categories. AB - The visual world is complex and continuously changing. Yet, our brain transforms patterns of light falling on our retina into a coherent percept within a few hundred milliseconds. Possibly, low-level neural responses already carry substantial information to facilitate rapid characterization of the visual input. Here, we computationally estimated low-level contrast responses to computer generated naturalistic images, and tested whether spatial pooling of these responses could predict image similarity at the neural and behavioral level. Using EEG, we show that statistics derived from pooled responses explain a large amount of variance between single-image evoked potentials (ERPs) in individual subjects. Dissimilarity analysis on multi-electrode ERPs demonstrated that large differences between images in pooled response statistics are predictive of more dissimilar patterns of evoked activity, whereas images with little difference in statistics give rise to highly similar evoked activity patterns. In a separate behavioral experiment, images with large differences in statistics were judged as different categories, whereas images with little differences were confused. These findings suggest that statistics derived from low-level contrast responses can be extracted in early visual processing and can be relevant for rapid judgment of visual similarity. We compared our results with two other, well- known contrast statistics: Fourier power spectra and higher-order properties of contrast distributions (skewness and kurtosis). Interestingly, whereas these statistics allow for accurate image categorization, they do not predict ERP response patterns or behavioral categorization confusions. These converging computational, neural and behavioral results suggest that statistics of pooled contrast responses contain information that corresponds with perceived visual similarity in a rapid, low-level categorization task. PMID- 23093922 TI - The dynamics of naturally acquired immunity to Plasmodium falciparum infection. AB - Severe malaria occurs predominantly in young children and immunity to clinical disease is associated with cumulative exposure in holoendemic settings. The relative contribution of immunity against various stages of the parasite life cycle that results in controlling infection and limiting disease is not well understood. Here we analyse the dynamics of Plasmodium falciparum malaria infection after treatment in a cohort of 197 healthy study participants of different ages in order to model naturally acquired immunity. We find that both delayed time-to-infection and reductions in asymptomatic parasitaemias in older age groups can be explained by immunity that reduces the growth of blood stage as opposed to liver stage parasites. We found that this mechanism would require at least two components - a rapidly acting strain-specific component, as well as a slowly acquired cross-reactive or general immunity to all strains. Analysis and modelling of malaria infection dynamics and naturally acquired immunity with age provides important insights into what mechanisms of immune control may be harnessed by malaria vaccine strategists. PMID- 23093923 TI - Estimating the hidden burden of bovine tuberculosis in Great Britain. AB - The number of cattle herds placed under movement restrictions in Great Britain (GB) due to the suspected presence of bovine tuberculosis (bTB) has progressively increased over the past 25 years despite an intensive and costly test-and slaughter control program. Around 38% of herds that clear movement restrictions experience a recurrent incident (breakdown) within 24 months, suggesting that infection may be persisting within herds. Reactivity to tuberculin, the basis of diagnostic testing, is dependent on the time from infection. Thus, testing efficiency varies between outbreaks, depending on weight of transmission and cannot be directly estimated. In this paper, we use Approximate Bayesian Computation (ABC) to parameterize two within-herd transmission models within a rigorous inferential framework. Previous within-herd models of bTB have relied on ad-hoc methods of parameterization and used a single model structure (SORI) where animals are assumed to become detectable by testing before they become infectious. We study such a conventional within-herd model of bTB and an alternative model, motivated by recent animal challenge studies, where there is no period of epidemiological latency before animals become infectious (SOR). Under both models we estimate that cattle-to-cattle transmission rates are non linearly density dependent. The basic reproductive ratio for our conventional within-herd model, estimated for scenarios with no statutory controls, increases from 1.5 (0.26-4.9; 95% CI) in a herd of 30 cattle up to 4.9 (0.99-14.0) in a herd of 400. Under this model we estimate that 50% (33-67) of recurrent breakdowns in Britain can be attributed to infection missed by tuberculin testing. However this figure falls to 24% (11-42) of recurrent breakdowns under our alternative model. Under both models the estimated extrinsic force of infection increases with the burden of missed infection. Hence, improved herd level testing is unlikely to reduce recurrence unless this extrinsic infectious pressure is simultaneously addressed. PMID- 23093924 TI - Linkers of cell polarity and cell cycle regulation in the fission yeast protein interaction network. AB - The study of gene and protein interaction networks has improved our understanding of the multiple, systemic levels of regulation found in eukaryotic and prokaryotic organisms. Here we carry out a large-scale analysis of the protein protein interaction (PPI) network of fission yeast (Schizosaccharomyces pombe) and establish a method to identify 'linker' proteins that bridge diverse cellular processes - integrating Gene Ontology and PPI data with network theory measures. We test the method on a highly characterized subset of the genome consisting of proteins controlling the cell cycle, cell polarity and cytokinesis and identify proteins likely to play a key role in controlling the temporal changes in the localization of the polarity machinery. Experimental inspection of one such factor, the polarity-regulating RNB protein Sts5, confirms the prediction that it has a cell cycle dependent regulation. Detailed bibliographic inspection of other predicted 'linkers' also confirms the predictive power of the method. As the method is robust to network perturbations and can successfully predict linker proteins, it provides a powerful tool to study the interplay between different cellular processes. PMID- 23093925 TI - The laminar cortex model: a new continuum cortex model incorporating laminar architecture. AB - Local field potentials (LFPs) are widely used to study the function of local networks in the brain. They are also closely correlated with the blood-oxygen level-dependent signal, the predominant contrast mechanism in functional magnetic resonance imaging. We developed a new laminar cortex model (LCM) to simulate the amplitude and frequency of LFPs. Our model combines the laminar architecture of the cerebral cortex and multiple continuum models to simulate the collective activity of cortical neurons. The five cortical layers (layer I, II/III, IV, V, and VI) are simulated as separate continuum models between which there are synaptic connections. The LCM was used to simulate the dynamics of the visual cortex under different conditions of visual stimulation. LFPs are reported for two kinds of visual stimulation: general visual stimulation and intermittent light stimulation. The power spectra of LFPs were calculated and compared with existing empirical data. The LCM was able to produce spontaneous LFPs exhibiting frequency-inverse (1/f) power spectrum behaviour. Laminar profiles of current source density showed similarities to experimental data. General stimulation enhanced the oscillation of LFPs corresponding to gamma frequencies. During simulated intermittent light stimulation, the LCM captured the fundamental as well as high order harmonics as previously reported. The power spectrum expected with a reduction in layer IV neurons, often observed with focal cortical dysplasias associated with epilepsy was also simulated. PMID- 23093926 TI - Regulatory network structure as a dominant determinant of transcription factor evolutionary rate. AB - The evolution of transcriptional regulatory networks has thus far mostly been studied at the level of cis-regulatory elements. To gain a complete understanding of regulatory network evolution we must also study the evolutionary role of trans factors, such as transcription factors (TFs). Here, we systematically assess genomic and network-level determinants of TF evolutionary rate in yeast, and how they compare to those of generic proteins, while carefully controlling for differences of the TF protein set, such as expression level. We found significantly distinct trends relating TF evolutionary rate to mRNA expression level, codon adaptation index, the evolutionary rate of physical interaction partners, and, confirming previous reports, to protein-protein interaction degree and regulatory in-degree. We discovered that for TFs, the dominant determinants of evolutionary rate lie in the structure of the regulatory network, such as the median evolutionary rate of target genes and the fraction of species-specific target genes. Decomposing the regulatory network by edge sign, we found that this modular evolution of TFs and their targets is limited to activating regulatory relationships. We show that fast evolving TFs tend to regulate other TFs and niche-specific processes and that their targets show larger evolutionary expression changes than targets of other TFs. We also show that the positive trend relating TF regulatory in-degree and evolutionary rate is likely related to the species-specificity of the transcriptional regulation modules. Finally, we discuss likely causes for TFs' different evolutionary relationship to the physical interaction network, such as the prevalence of transient interactions in the TF subnetwork. This work suggests that positive and negative regulatory networks follow very different evolutionary rules, and that transcription factor evolution is best understood at a network- or systems-level. PMID- 23093927 TI - Membrane-elasticity model of Coatless vesicle budding induced by ESCRT complexes. AB - The formation of vesicles is essential for many biological processes, in particular for the trafficking of membrane proteins within cells. The Endosomal Sorting Complex Required for Transport (ESCRT) directs membrane budding away from the cytosol. Unlike other vesicle formation pathways, the ESCRT-mediated budding occurs without a protein coat. Here, we propose a minimal model of ESCRT-induced vesicle budding. Our model is based on recent experimental observations from direct fluorescence microscopy imaging that show ESCRT proteins colocalized only in the neck region of membrane buds. The model, cast in the framework of membrane elasticity theory, reproduces the experimentally observed vesicle morphologies with physically meaningful parameters. In this parameter range, the minimum energy configurations of the membrane are coatless buds with ESCRTs localized in the bud neck, consistent with experiment. The minimum energy configurations agree with those seen in the fluorescence images, with respect to both bud shapes and ESCRT protein localization. On the basis of our model, we identify distinct mechanistic pathways for the ESCRT-mediated budding process. The bud size is determined by membrane material parameters, explaining the narrow yet different bud size distributions in vitro and in vivo. Our membrane elasticity model thus sheds light on the energetics and possible mechanisms of ESCRT-induced membrane budding. PMID- 23093928 TI - A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins. AB - Gauging the systemic effects of non-synonymous single nucleotide polymorphisms (nsSNPs) is an important topic in the pursuit of personalized medicine. However, it is a non-trivial task to understand how a change at the protein structure level eventually affects a cell's behavior. This is because complex information at both the protein and pathway level has to be integrated. Given that the idea of integrating both protein and pathway dynamics to estimate the systemic impact of missense mutations in proteins remains predominantly unexplored, we investigate the practicality of such an approach by formulating mathematical models and comparing them with experimental data to study missense mutations. We present two case studies: (1) interpreting systemic perturbation for mutations within the cell cycle control mechanisms (G2 to mitosis transition) for yeast; (2) phenotypic classification of neuron-related human diseases associated with mutations within the mitogen-activated protein kinase (MAPK) pathway. We show that the application of simplified mathematical models is feasible for understanding the effects of small sequence changes on cellular behavior. Furthermore, we show that the systemic impact of missense mutations can be effectively quantified as a combination of protein stability change and pathway perturbation. PMID- 23093929 TI - Phasic firing in vasopressin cells: understanding its functional significance through computational models. AB - Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing. PMID- 23093930 TI - Determining host metabolic limitations on viral replication via integrated modeling and experimental perturbation. AB - Viral replication relies on host metabolic machinery and precursors to produce large numbers of progeny - often very rapidly. A fundamental example is the infection of Escherichia coli by bacteriophage T7. The resource draw imposed by viral replication represents a significant and complex perturbation to the extensive and interconnected network of host metabolic pathways. To better understand this system, we have integrated a set of structured ordinary differential equations quantifying T7 replication and an E. coli flux balance analysis metabolic model. Further, we present here an integrated simulation algorithm enforcing mutual constraint by the models across the entire duration of phage replication. This method enables quantitative dynamic prediction of virion production given only specification of host nutritional environment, and predictions compare favorably to experimental measurements of phage replication in multiple environments. The level of detail of our computational predictions facilitates exploration of the dynamic changes in host metabolic fluxes that result from viral resource consumption, as well as analysis of the limiting processes dictating maximum viral progeny production. For example, although it is commonly assumed that viral infection dynamics are predominantly limited by the amount of protein synthesis machinery in the host, our results suggest that in many cases metabolic limitation is at least as strict. Taken together, these results emphasize the importance of considering viral infections in the context of host metabolism. PMID- 23093932 TI - Norovirus immunity and the great escape. PMID- 23093933 TI - Transgenic expression of the Helicobacter pylori virulence factor CagA promotes apoptosis or tumorigenesis through JNK activation in Drosophila. AB - Gastric cancer development is strongly correlated with infection by Helicobacter pylori possessing the effector protein CagA. Using a transgenic Drosophila melanogaster model, we show that CagA expression in the simple model epithelium of the larval wing imaginal disc causes dramatic tissue perturbations and apoptosis when CagA-expressing and non-expressing cells are juxtaposed. This cell death phenotype occurs through activation of JNK signaling and is enhanced by loss of the neoplastic tumor suppressors in CagA-expressing cells or loss of the TNF homolog Eiger in wild type neighboring cells. We further explored the effects of CagA-mediated JNK pathway activation on an epithelium in the context of oncogenic Ras activation, using a Drosophila model of metastasis. In this model, CagA expression in epithelial cells enhances the growth and invasion of tumors in a JNK-dependent manner. These data suggest a potential role for CagA-mediated JNK pathway activation in promoting gastric cancer progression. PMID- 23093934 TI - Identification of FAM111A as an SV40 host range restriction and adenovirus helper factor. AB - The small genome of polyomaviruses encodes a limited number of proteins that are highly dependent on interactions with host cell proteins for efficient viral replication. The SV40 large T antigen (LT) contains several discrete functional domains including the LXCXE or RB-binding motif, the DNA binding and helicase domains that contribute to the viral life cycle. In addition, the LT C-terminal region contains the host range and adenovirus helper functions required for lytic infection in certain restrictive cell types. To understand how LT affects the host cell to facilitate viral replication, we expressed full-length or functional domains of LT in cells, identified interacting host proteins and carried out expression profiling. LT perturbed the expression of p53 target genes and subsets of cell-cycle dependent genes regulated by the DREAM and the B-Myb-MuvB complexes. Affinity purification of LT followed by mass spectrometry revealed a specific interaction between the LT C-terminal region and FAM111A, a previously uncharacterized protein. Depletion of FAM111A recapitulated the effects of heterologous expression of the LT C-terminal region, including increased viral gene expression and lytic infection of SV40 host range mutants and adenovirus replication in restrictive cells. FAM111A functions as a host range restriction factor that is specifically targeted by SV40 LT. PMID- 23093935 TI - Plasmodium falciparum gametocyte development 1 (Pfgdv1) and gametocytogenesis early gene identification and commitment to sexual development. AB - Malaria transmission requires the production of male and female gametocytes in the human host followed by fertilization and sporogonic development in the mosquito midgut. Although essential for the spread of malaria through the population, little is known about the initiation of gametocytogenesis in vitro or in vivo. Using a gametocyte-defective parasite line and genetic complementation, we show that Plasmodium falciparumgametocyte development 1 gene (Pfgdv1), encoding a peri-nuclear protein, is critical for early sexual differentiation. Transcriptional analysis of Pfgdv1 negative and positive parasite lines identified a set of gametocytogenesis early genes (Pfge) that were significantly down-regulated (>10 fold) in the absence of Pfgdv1 and expression was restored after Pfgdv1 complementation. Progressive accumulation of Pfge transcripts during successive rounds of asexual replication in synchronized cultures suggests that gametocytes are induced continuously during asexual growth. Comparison of Pfge gene transcriptional profiles in patient samples divided the genes into two groups differing in their expression in mature circulating gametocytes and providing candidates to evaluate gametocyte induction and maturation separately in vivo. The expression profile of one of the early gametocyte specific genes, Pfge1, correlated significantly with asexual parasitemia, which is consistent with the ongoing induction of gametocytogenesis during asexual growth observed in vitro and reinforces the need for sustained transmission-blocking strategies to eliminate malaria. PMID- 23093936 TI - Regulation of anti-Plasmodium immunity by a LITAF-like transcription factor in the malaria vector Anopheles gambiae. AB - The mosquito is the obligate vector for malaria transmission. To complete its development within the mosquito, the malaria parasite Plasmodium must overcome the protective action of the mosquito innate immune system. Here we report on the involvement of the Anopheles gambiae orthologue of a conserved component of the vertebrate immune system, LPS-induced TNFalpha transcription factor (LITAF), and its role in mosquito anti-Plasmodium immunity. An. gambiae LITAF-like 3 (LL3) expression is up-regulated in response to midgut invasion by both rodent and human malaria parasites. Silencing of LL3 expression greatly increases parasite survival, indicating that LL3 is part of an anti-Plasmodium defense mechanism. Electrophoretic mobility shift assays identified specific LL3 DNA-binding motifs within the promoter of SRPN6, a gene that also mediates mosquito defense against Plasmodium. Further experiments indicated that these motifs play a direct role in LL3 regulation of SRPN6 expression. We conclude that LL3 is a transcription factor capable of modulating SRPN6 expression as part of the mosquito anti Plasmodium immune response. PMID- 23093937 TI - Immunity to intracellular Salmonella depends on surface-associated antigens. AB - Invasive Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and changing Salmonella serovar spectrum. Novel vaccines with broad serovar coverage are needed, but suitable protective antigens remain largely unknown. Here, we tested 37 broadly conserved Salmonella antigens in a mouse typhoid fever model, and identified antigen candidates that conferred partial protection against lethal disease. Antigen properties such as high in vivo abundance or immunodominance in convalescent individuals were not required for protectivity, but all promising antigen candidates were associated with the Salmonella surface. Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens. Confocal microscopy of infected tissues revealed that many live Salmonella resided alone in infected host macrophages with no damaged Salmonella releasing internal antigens in their vicinity. In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella. In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens. PMID- 23093938 TI - Phosphorylation of the chromatin binding domain of KSHV LANA. AB - The Kaposi sarcoma associated herpesvirus (KSHV) latency associated nuclear antigen (LANA) is expressed in all KSHV associated malignancies and is essential for maintenance of KSHV genomes in infected cells. To identify kinases that are potentially capable of modifying LANA, in vitro phosphorylation assays were performed using an Epstein Barr virus plus LANA protein microarray and 268 human kinases purified in active form from yeast. Interestingly, of the Epstein-Barr virus proteins on the array, the EBNA1 protein had the most similar kinase profile to LANA. We focused on nuclear kinases and on the N-terminus of LANA (amino acids 1-329) that contains the LANA chromatin binding domain. Sixty-three nuclear kinases phosphorylated the LANA N-terminus. Twenty-four nuclear kinases phosphorylated a peptide covering the LANA chromatin binding domain (amino acids 3-21). Alanine mutations of serine 10 and threonine 14 abolish or severely diminish chromatin and histone binding by LANA. However, conversion of these residues to the phosphomimetic glutamic acid restored histone binding suggesting that phosphorylation of serine 10 and threonine 14 may modulate LANA function. Serine 10 and threonine 14 were validated as substrates of casein kinase 1, PIM1, GSK-3 and RSK3 kinases. Short-term treatment of transfected cells with inhibitors of these kinases found that only RSK inhibition reduced LANA interaction with endogenous histone H2B. Extended treatment of PEL cell cultures with RSK inhibitor caused a decrease in LANA protein levels associated with p21 induction and a loss of PEL cell viability. The data indicate that RSK phosphorylation affects both LANA accumulation and function. PMID- 23093939 TI - Coevolution and hierarchical interactions of Tomato mosaic virus and the resistance gene Tm-1. AB - During antagonistic coevolution between viruses and their hosts, viruses have a major advantage by evolving more rapidly. Nevertheless, viruses and their hosts coexist and have coevolved, although the processes remain largely unknown. We previously identified Tm-1 that confers resistance to Tomato mosaic virus (ToMV), and revealed that it encodes a protein that binds ToMV replication proteins and inhibits RNA replication. Tm-1 was introgressed from a wild tomato species Solanum habrochaites into the cultivated tomato species Solanum lycopersicum. In this study, we analyzed Tm-1 alleles in S. habrochaites. Although most part of this gene was under purifying selection, a cluster of nonsynonymous substitutions in a small region important for inhibitory activity was identified, suggesting that the region is under positive selection. We then examined the resistance of S. habrochaites plants to ToMV. Approximately 60% of 149 individuals from 24 accessions were resistant to ToMV, while the others accumulated detectable levels of coat protein after inoculation. Unexpectedly, many S. habrochaites plants were observed in which even multiplication of the Tm-1-resistance-breaking ToMV mutant LT1 was inhibited. An amino acid change in the positively selected region of the Tm-1 protein was responsible for the inhibition of LT1 multiplication. This amino acid change allowed Tm-1 to bind LT1 replication proteins without losing the ability to bind replication proteins of wild-type ToMV. The antiviral spectra and biochemical properties suggest that Tm-1 has evolved by changing the strengths of its inhibitory activity rather than diversifying the recognition spectra. In the LT1-resistant S. habrochaites plants inoculated with LT1, mutant viruses emerged whose multiplication was not inhibited by the Tm-1 allele that confers resistance to LT1. However, the resistance-breaking mutants were less competitive than the parental strains in the absence of Tm-1. Based on these results, we discuss possible coevolutionary processes of ToMV and Tm-1. PMID- 23093940 TI - The respiratory syncytial virus polymerase has multiple RNA synthesis activities at the promoter. AB - Respiratory syncytial virus (RSV) is an RNA virus in the Family Paramyxoviridae. Here, the activities performed by the RSV polymerase when it encounters the viral antigenomic promoter were examined. RSV RNA synthesis was reconstituted in vitro using recombinant, isolated polymerase and an RNA oligonucleotide template representing nucleotides 1-25 of the trailer complement (TrC) promoter. The RSV polymerase was found to have two RNA synthesis activities, initiating RNA synthesis from the +3 site on the promoter, and adding a specific sequence of nucleotides to the 3' end of the TrC RNA using a back-priming mechanism. Examination of viral RNA isolated from RSV infected cells identified RNAs initiated at the +3 site on the TrC promoter, in addition to the expected +1 site, and showed that a significant proportion of antigenome RNAs contained specific nucleotide additions at the 3' end, demonstrating that the observations made in vitro reflected events that occur during RSV infection. Analysis of the impact of the 3' terminal extension on promoter activity indicated that it can inhibit RNA synthesis initiation. These findings indicate that RSV polymerase promoter interactions are more complex than previously thought and suggest that there might be sophisticated mechanisms for regulating promoter activity during infection. PMID- 23093941 TI - MOV10 RNA helicase is a potent inhibitor of retrotransposition in cells. AB - MOV10 protein, a putative RNA helicase and component of the RNA-induced silencing complex (RISC), inhibits retrovirus replication. We show that MOV10 also severely restricts human LINE1 (L1), Alu, and SVA retrotransposons. MOV10 associates with the L1 ribonucleoprotein particle, along with other RNA helicases including DDX5, DHX9, DDX17, DDX21, and DDX39A. However, unlike MOV10, these other helicases do not strongly inhibit retrotransposition, an activity dependent upon intact helicase domains. MOV10 association with retrotransposons is further supported by its colocalization with L1 ORF1 protein in stress granules, by cytoplasmic structures associated with RNA silencing, and by the ability of MOV10 to reduce endogenous and ectopic L1 expression. The majority of the human genome is repetitive DNA, most of which is the detritus of millions of years of accumulated retrotransposition. Retrotransposons remain active mutagens, and their insertion can disrupt gene function. Therefore, the host has evolved defense mechanisms to protect against retrotransposition, an arsenal we are only beginning to understand. With homologs in other vertebrates, insects, and plants, MOV10 may represent an ancient and innate form of immunity against both infective viruses and endogenous retroelements. PMID- 23093942 TI - Recovery of arrested replication forks by homologous recombination is error prone. AB - Homologous recombination is a universal mechanism that allows repair of DNA and provides support for DNA replication. Homologous recombination is therefore a major pathway that suppresses non-homology-mediated genome instability. Here, we report that recovery of impeded replication forks by homologous recombination is error-prone. Using a fork-arrest-based assay in fission yeast, we demonstrate that a single collapsed fork can cause mutations and large-scale genomic changes, including deletions and translocations. Fork-arrest-induced gross chromosomal rearrangements are mediated by inappropriate ectopic recombination events at the site of collapsed forks. Inverted repeats near the site of fork collapse stimulate large-scale genomic changes up to 1,500 times over spontaneous events. We also show that the high accuracy of DNA replication during S-phase is impaired by impediments to fork progression, since fork-arrest-induced mutation is due to erroneous DNA synthesis during recovery of replication forks. The mutations caused are small insertions/duplications between short tandem repeats (micro homology) indicative of replication slippage. Our data establish that collapsed forks, but not stalled forks, recovered by homologous recombination are prone to replication slippage. The inaccuracy of DNA synthesis does not rely on PCNA ubiquitination or trans-lesion-synthesis DNA polymerases, and it is not counteracted by mismatch repair. We propose that deletions/insertions, mediated by micro-homology, leading to copy number variations during replication stress may arise by progression of error-prone replication forks restarted by homologous recombination. PMID- 23093943 TI - Cytokinesis-based constraints on polarized cell growth in fission yeast. AB - The rod-shaped fission yeast Schizosaccharomyces pombe, which undergoes cycles of monopolar-to-bipolar tip growth, is an attractive organism for studying cell cycle regulation of polarity establishment. While previous research has described factors mediating this process from interphase cell tips, we found that division site signaling also impacts the re-establishment of bipolar cell growth in the ensuing cell cycle. Complete loss or targeted disruption of the non-essential cytokinesis protein Fic1 at the division site, but not at interphase cell tips, resulted in many cells failing to grow at new ends created by cell division. This appeared due to faulty disassembly and abnormal persistence of the cell division machinery at new ends of fic1Delta cells. Moreover, additional mutants defective in the final stages of cytokinesis exhibited analogous growth polarity defects, supporting that robust completion of cell division contributes to new end-growth competency. To test this model, we genetically manipulated S. pombe cells to undergo new end take-off immediately after cell division. Intriguingly, such cells elongated constitutively at new ends unless cytokinesis was perturbed. Thus, cell division imposes constraints that partially override positive controls on growth. We posit that such constraints facilitate invasive fungal growth, as cytokinesis mutants displaying bipolar growth defects formed numerous pseudohyphae. Collectively, these data highlight a role for previous cell cycles in defining a cell's capacity to polarize at specific sites, and they additionally provide insight into how a unicellular yeast can transition into a quasi-multicellular state. PMID- 23093944 TI - Mining the unknown: a systems approach to metabolite identification combining genetic and metabolic information. AB - Recent genome-wide association studies (GWAS) with metabolomics data linked genetic variation in the human genome to differences in individual metabolite levels. A strong relevance of this metabolic individuality for biomedical and pharmaceutical research has been reported. However, a considerable amount of the molecules currently quantified by modern metabolomics techniques are chemically unidentified. The identification of these "unknown metabolites" is still a demanding and intricate task, limiting their usability as functional markers of metabolic processes. As a consequence, previous GWAS largely ignored unknown metabolites as metabolic traits for the analysis. Here we present a systems-level approach that combines genome-wide association analysis and Gaussian graphical modeling with metabolomics to predict the identity of the unknown metabolites. We apply our method to original data of 517 metabolic traits, of which 225 are unknowns, and genotyping information on 655,658 genetic variants, measured in 1,768 human blood samples. We report previously undescribed genotype-metabotype associations for six distinct gene loci (SLC22A2, COMT, CYP3A5, CYP2C18, GBA3, UGT3A1) and one locus not related to any known gene (rs12413935). Overlaying the inferred genetic associations, metabolic networks, and knowledge-based pathway information, we derive testable hypotheses on the biochemical identities of 106 unknown metabolites. As a proof of principle, we experimentally confirm nine concrete predictions. We demonstrate the benefit of our method for the functional interpretation of previous metabolomics biomarker studies on liver detoxification, hypertension, and insulin resistance. Our approach is generic in nature and can be directly transferred to metabolomics data from different experimental platforms. PMID- 23093945 TI - Regulation of ATG4B stability by RNF5 limits basal levels of autophagy and influences susceptibility to bacterial infection. AB - Autophagy is the mechanism by which cytoplasmic components and organelles are degraded by the lysosomal machinery in response to diverse stimuli including nutrient deprivation, intracellular pathogens, and multiple forms of cellular stress. Here, we show that the membrane-associated E3 ligase RNF5 regulates basal levels of autophagy by controlling the stability of a select pool of the cysteine protease ATG4B. RNF5 controls the membranal fraction of ATG4B and limits LC3 (ATG8) processing, which is required for phagophore and autophagosome formation. The association of ATG4B with-and regulation of its ubiquitination and stability by-RNF5 is seen primarily under normal growth conditions. Processing of LC3 forms, appearance of LC3-positive puncta, and p62 expression are higher in RNF5( /-) MEF. RNF5 mutant, which retains its E3 ligase activity but does not associate with ATG4B, no longer affects LC3 puncta. Further, increased puncta seen in RNF5( /-) using WT but not LC3 mutant, which bypasses ATG4B processing, substantiates the role of RNF5 in early phases of LC3 processing and autophagy. Similarly, RNF 5 inactivation in Caenorhabditis elegans increases the level of LGG-1/LC3::GFP puncta. RNF5(-/-) mice are more resistant to group A Streptococcus infection, associated with increased autophagosomes and more efficient bacterial clearance by RNF5(-/-) macrophages. Collectively, the RNF5-mediated control of membranalATG4B reveals a novel layer in the regulation of LC3 processing and autophagy. PMID- 23093947 TI - Release of Full-Length PrP(C) from Cultured Neurons Following Neurotoxic Challenges. AB - The susceptibility of the normal cellular prion protein isoform, cellular prion protein (PrP(C)), to proteolytic digestion has been well documented. In addition, a link between PrP(C) and the cytosolic protease, calpain, has been reported although the specifics of the interaction remain unclear. We performed in vitro and in cell-based studies to examine this relationship. We observed that human recombinant PrP (HrPrP) was readily cleaved by calpain-1 and -2, and we have identified and defined the targeted cleavage sites. In contrast, HrPrP was resistant to caspase-3 digestion. Unexpectedly, when brain lysates from PrP(C) expressing mice were treated with calpain, no appreciable loss of the intact PrP(C), nor the appearance of PrP(C) breakdown products (BDPs) were observed, even though alpha II-spectrin was converted to its signature calpain-induced BDPs. In addition, when rat cerebrocortical neuronal cultures (RtCNC) were subjected to the two neurotoxins at subacute levels, maitotoxin (MTX) and N methyl-d-aspartate (NMDA), PrP(C)-BDPs were also not detectable. However, a novel finding from these cell-based studies is that apparently full-length, mature PrP(C) is released into culture media from RtCNC challenged with subacute doses of MTX and NMDA. Calpain inhibitor SNJ-1945 and caspase inhibitor IDN-6556 did not attenuate the release of PrP(C). Similarly, the lysosomal protease inhibitor, NH(4)Cl, and the proteasome inhibitor, lactacystin, did not significantly alter the integrity of PrP(C) or its release from the RtCNC. In conclusion, rat neuronal PrP(C) is not a significant target for proteolytic modifications during MTX and NMDA neurotoxic challenges. However, the robust neurotoxin-mediated release of full-length PrP(C) into the cell culture media suggests an unidentified neuroprotective mechanism for PrP(C). PMID- 23093946 TI - Specific missense alleles of the arabidopsis jasmonic acid co-receptor COI1 regulate innate immune receptor accumulation and function. AB - Plants utilize proteins containing nucleotide binding site (NB) and leucine-rich repeat (LRR) domains as intracellular innate immune receptors to recognize pathogens and initiate defense responses. Since mis-activation of defense responses can lead to tissue damage and even developmental arrest, proper regulation of NB-LRR protein signaling is critical. RAR1, SGT1, and HSP90 act as regulatory chaperones of pre-activation NB-LRR steady-state proteins. We extended our analysis of mutants derived from a rar1 suppressor screen and present two allelic rar1 suppressor (rsp) mutations of Arabidopsis COI1. Like all other coi1 mutations, coi1(rsp) missense mutations impair Jasmonic Acid (JA) signaling resulting in JA-insensitivity. However, unlike previously identified coi1 alleles, both coi1(rsp) alleles lack a male sterile phenotype. The coi1(rsp) mutants express two sets of disease resistance phenotypes. The first, also observed in coi1-1 null allele, includes enhanced basal defense against the virulent bacterial pathogen Pto DC3000 and enhanced effector-triggered immunity (ETI) mediated by the NB-LRR RPM1 protein in both rar1 and wild-type backgrounds. These enhanced disease resistance phenotypes depend on the JA signaling function of COI1. Additionally, the coi1(rsp) mutants showed a unique inability to properly regulate RPM1 accumulation and HR, exhibited increased RPM1 levels in rar1, and weakened RPM1-mediated HR in RAR1. Importantly, there was no change in the steady-state levels or HR function of RPM1 in coi1-1. These results suggest that the coi1(rsp) proteins regulate NB-LRR protein accumulation independent of JA signaling. Based on the phenotypic similarities and genetic interactions among coi1(rsp), sgt1b, and hsp90.2(rsp) mutants, our data suggest that COI1 affects NB LRR accumulation via two NB-LRR co-chaperones, SGT1b and HSP90. Together, our data demonstrate a role for COI1 in disease resistance independent of JA signaling and provide a molecular link between the JA and NB-LRR signaling pathways. PMID- 23093948 TI - What does galvanic vestibular stimulation actually activate: response. PMID- 23093950 TI - Bias, accuracy, and impact of indirect genetic effects in infectious diseases. AB - Selection for improved host response to infectious disease offers a desirable alternative to chemical treatment but has proven difficult in practice, due to low heritability estimates of disease traits. Disease data from field studies is often binary, indicating whether an individual has become infected or not following exposure to an infectious disease. Numerous studies have shown that from this data one can infer genetic variation in individuals' underlying susceptibility. In a previous study, we showed that with an indirect genetic effect (IGE) model it is possible to capture some genetic variation in infectivity, if present, as well as in susceptibility. Infectivity is the propensity of transmitting infection upon contact with a susceptible individual. It is an important factor determining the severity of an epidemic. However, there are severe shortcomings with the Standard IGE models as they do not accommodate the dynamic nature of disease data. Here we adjust the Standard IGE model to (1) make expression of infectivity dependent on the individuals' disease status (Case Model) and (2) to include timing of infection (Case-ordered Model). The models are evaluated by comparing impact of selection, bias, and accuracy of each model using simulated binary disease data. These were generated for populations with known variation in susceptibility and infectivity thus allowing comparisons between estimated and true breeding values. Overall the Case Model provided better estimates for host genetic susceptibility and infectivity compared to the Standard Model in terms of bias, impact, and accuracy. Furthermore, these estimates were strongly influenced by epidemiological characteristics. However, surprisingly, the Case-Ordered model performed considerably worse than the Standard and the Case Models, pointing toward limitations in incorporating disease dynamics into conventional variance component estimation methodology and software used in animal breeding. PMID- 23093951 TI - Automated lobe-based airway labeling. AB - Regional quantitative analysis of airway morphological abnormalities is of great interest in lung disease investigation. Considering that pulmonary lobes are relatively independent functional unit, we develop and test a novel and efficient computerized scheme in this study to automatically and robustly classify the airways into different categories in terms of pulmonary lobe. Given an airway tree, which could be obtained using any available airway segmentation scheme, the developed approach consists of four basic steps: (1) airway skeletonization or centerline extraction, (2) individual airway branch identification, (3) initial rule-based airway classification/labeling, and (4) self-correction of labeling errors. In order to assess the performance of this approach, we applied it to a dataset consisting of 300 chest CT examinations in a batch manner and asked an image analyst to subjectively examine the labeled results. Our preliminary experiment showed that the labeling accuracy for the right upper lobe, the right middle lobe, the right lower lobe, the left upper lobe, and the left lower lobe is 100%, 99.3%, 99.3%, 100%, and 100%, respectively. Among these, only two cases are incorrectly labeled due to the failures in airway detection. It takes around 2 minutes to label an airway tree using this algorithm. PMID- 23093949 TI - Pro-Resolving Lipid Mediators (SPMs) and Their Actions in Regulating miRNA in Novel Resolution Circuits in Inflammation. AB - Unresolved inflammation is associated with several widely occurring diseases such as arthritis, periodontal diseases, cancer, and atherosclerosis. Endogenous mechanisms that curtail excessive inflammation and prompt its timely resolution are of considerable interest. In recent years, previously unrecognized chemical mediators derived from polyunsaturated fatty acids were identified that control the acute inflammatory response by activating local resolution programs. Among these are the so-called specialized pro-resolving lipid mediators (SPMs) that include lipoxins (LX), resolvins (Rv), protectins (PD), and maresins (MaR), because they are enzymatically biosynthesized during resolution of self-limited inflammation. They each possess distinct chemical structures and regulate cellular pathways by their ability to activate pro-resolving G-protein coupled receptors (GPCRs) in a stereospecific manner. For instance, RvD1 controls several miRNAs of interest in self-limited acute inflammation that counter-regulate the mediators and proteins that are involved in inflammation. Here, we overview some of the biosynthesis and mechanisms of SPM actions with focus on the recently reported miR involved in their pro-resolving responses that underscore their beneficial actions in the regulation of acute inflammation and its timely resolution. The elucidation of these mechanisms operating in vivo to keep acute inflammation within physiologic boundaries as well as stimulate resolution have opened resolution pharmacology and many new opportunities to target inflammation related human pathologies via activating resolution mechanisms. PMID- 23093952 TI - Transcriptional Activity of PGC-1alpha and NT-PGC-1alpha Is Differentially Regulated by Twist-1 in Brown Fat Metabolism. AB - Brown fat expresses two PGC-1alpha isoforms (PGC-1alpha and NT-PGC-1alpha) and both play a central role in the regulation of cellular energy metabolism and adaptive thermogenesis by interacting with a wide range of transcription factors including PPARgamma, PPARalpha, ERRalpha, and NRF1. PGC-1alpha consists of 797 amino acids, whereas alternative splicing of the PGC-1alpha gene produces a shorter protein called NT-PGC-1alpha (aa 1-270). We report in this paper that transcriptional activity of PGC-1alpha and NT-PGC-1alpha is differently affected by the transcriptional regulator, Twist-1. Twist-1 suppresses PGC-1alpha but not NT-PGC-1alpha. The inhibition of PGC-1alpha activity by Twist-1 is mediated by direct interaction through the C-terminal region of PGC-1alpha (aa 353-797). Thus, the absence of the corresponding C-terminal domain in NT-PGC-1alpha allows NT-PGC-1alpha to be free from Twist-1-mediated inhibition. Overexpression of Twist-1 in brown adipocytes suppresses transcription of a subset of PGC-1alpha target genes involved in mitochondrial fatty acid oxidation and uncoupling (CPT1beta, UCP1, and ERRalpha). In contrast, NT-PGC-1alpha-mediated induction of these genes is unaffected by Twist-1. These findings show that differences in inhibitory protein-protein interactions of PGC-1alpha and NT-PGC-1alpha with Twist-1 lead to differential regulation of their function by Twist-1. PMID- 23093953 TI - Aspects of inflammation and oxidative stress in pediatric obesity and type 1 diabetes: an overview of ten years of studies. AB - Obesity and type 1 diabetes (T1DM) are the two most common conditions of altered metabolism in children and adolescents. In both, similar long-term cardiovascular complications are known to occur, mediated in large part by underlying inflammatory and oxidative processes whose biochemical details remain relatively unclear. Through a series of experiments in these patient populations, over the last decade our laboratory has clarified a number of key issues in this field. Interestingly, while obese and type 1 diabetic children often differed in the specific type and magnitude of molecular alterations, in both groups a clear exaggeration of inflammatory and oxidative activation was detected when compared to healthy, age-matched controls. Our main findings include definition of resting and exercise-induced cytokine patterns and leukocyte profiles, patterns of activation of immune cells in vitro, and correlation of the magnitude of observed alterations with severity of obesity and quality of glycemic control. Further, we have identified a series of alterations in growth factor profiles during exercise that parallel inflammatory changes in obese children. This paper offers a concise overview of the salient results from this decade-long research effort. PMID- 23093955 TI - Local assemblies of paired-end reduced representation libraries sequenced with the illumina genome analyzer in maize. AB - The use of next-generation DNA sequencing technologies has greatly facilitated reference-guided variant detection in complex plant genomes. However, complications may arise when regions adjacent to a read of interest are used for marker assay development, or when reference sequences are incomplete, as short reads alone may not be long enough to ascertain their uniqueness. Here, the possibility of generating longer sequences in discrete regions of the large and complex genome of maize is demonstrated, using a modified version of a paired-end RAD library construction strategy. Reads are generated from DNA fragments first digested with a methylation-sensitive restriction endonuclease, sheared, enriched with biotin and a selective PCR amplification step, and then sequenced at both ends. Sequences are locally assembled into contigs by subgrouping pairs based on the identity of the read anchored by the restriction site. This strategy applied to two maize inbred lines (B14 and B73) generated 183,609 and 129,018 contigs, respectively, out of which at least 76% were >200 bps in length. A subset of putative single nucleotide polymorphisms from contigs aligning to the B73 reference genome with at least one mismatch was resequenced, and 90% of those in B14 were confirmed, indicating that this method is a potent approach for variant detection and marker development in species with complex genomes or lacking extensive reference sequences. PMID- 23093956 TI - Delayed gel indurations as an adverse effect of polyacrylamide filler and its easy treatment. AB - Background. The more increasing use of permanent soft tissue fillers such as polyacrylamide hydrogel (PAAG) for aesthetic purposes, the more adverse events resulting from them are reported. Occasionally, nonserious complications and misdiagnosis result in unnecessary surgeries and sequels. Objective. To introduce delayed gel indurations (DGIs) as a late onset complication of PAAG and its easy treatment. Patient and Methods. Twenty patients (17 females and 3 males) referred to us with subcutaneous mass at injected site of PAAG. We diagnosed DGI based on clinical and sonography findings and treatment was performed with a hole by 16 gauge needle and squeezing. Results. From 20 patients with 21 cases of DGI, 5 (23.8%), 5 (23.8%), and 5 (23.8%) cases in cheeks, glabella, and lips were seen, respectively. The time range between PAAG injection and presentation of patients was 10-28 months (mean = 17.5%). All of the patients responded very well to treatment without recurrence and any complications. Conclusion. DGI is a nonserious, late onset, and easily treated complication of PAAG that is probably induced due to water exchange between gel and surrounding tissue and modest host immune reaction to gel. PMID- 23093954 TI - Impact of insulin resistance on silent and ongoing myocardial damage in normal subjects: the Takahata study. AB - BACKGROUND: Insulin resistance (IR) is part of the metabolic syndrome (Mets) that develops after lifestyle changes and obesity. Although the association between Mets and myocardial injury is well known, the effect of IR on myocardial damage remains unclear. METHODS AND RESULTS: We studied 2200 normal subjects who participated in a community-based health check in the town of Takahata in northern Japan. The presence of IR was assessed by homeostasis model assessment ratio, and the serum level of heart-type fatty acid binding protein (H-FABP) was measured as a maker of silent and ongoing myocardial damage. H-FABP levels were significantly higher in subjects with IR and Mets than in those without metabolic disorder regardless of gender. Multivariate logistic analysis showed that the presence of IR was independently associated with latent myocardial damage (odds ratio: 1.574, 95% confidence interval 1.1-2.3) similar to the presence of Mets. CONCLUSIONS: In a screening of healthy subjects, IR and Mets were similarly related to higher H-FABP levels, suggesting that there may be an asymptomatic population in the early stages of metabolic disorder that is exposed to myocardial damage and might be susceptible to silent heart failure. PMID- 23093957 TI - The role of portal vein thrombosis in the clinical course of inflammatory bowel diseases: report on three cases and review of the literature. AB - Inflammatory bowel diseases are associated with an increased risk of vascular complications. The most important are arterial and venous thromboembolisms, which are considered as specific extraintestinal manifestations of inflammatory bowel diseases. Among venous thromboembolism events, portal vein thrombosis has been described in inflammatory bowel diseases. We report three cases of portal vein thrombosis occurring in patients with active inflammatory bowel disease. In two of them, hepatic abscess was present. Furthermore, we performed a systematic review based on the clinical literature published on this topic. PMID- 23093958 TI - Specific and Rapid Detection of Mycobacterium tuberculosis Complex in Clinical Samples by Polymerase Chain Reaction. AB - Background. Tuberculosis, a global health problem and highly prevalent in India, has always been a serious problem with respect to definitive diagnosis. Polymerase chain reaction (PCR) techniques are now widely used for early detection and species differentiation of mycobacteria, but mostly with their own limitations. We aim to detect and differentiate Mycobacterium tuberculosis (Mtb) infections by choosing appropriate target sequences, ideally present in all mycobacterial species (MTB complex) and absent in others. Methods. Amplification of three target sequences from unrelated genes, namely, hsp 65 (165 bp), dnaJ (365 bp), and insertion element IS 6110 (541 bp) by PCR was carried out in clinical samples from suspected cases of tuberculosis/ mycobacterioses and healthy controls. Results. The sensitivity of this method ranged from 73.33% to 84.61%, and the specificity was 80%. The PCR method was significantly better (P = 0.03 and P = 0.009) than both smear and culture methods. Conclusion. Our trimarker-based PCR method could specifically detect M. tuberculosis and MTB complex infection from that of major pathogenic NTM and nonpathogenic mycobacteria. This method, by well distinguishing between MTB complex and NTM, presented a fast and accurate method to detect and diagnose mycobacterial infections more efficiently and could thereby help in better patient management particularly considering the increase in mycobacterial infections due to emergence of NTM over the past decades. PMID- 23093959 TI - Role of Inhaled Steroids in Vascular Airway Remodelling in Asthma and COPD. AB - In chronic obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), changes in bronchial microvasculature are present in response to inflammatory stimuli. Vascular changes may significantly contribute to airway wall remodelling. Angiogenesis and vascular leakage are prevalent in asthma, while vasodilation and vascular leakage dominate in COPD. An endothelial dysfunction may be present both in asthma and in COPD. Vascular changes may occur simultaneously with the thickening of the airway wall and the narrowing of the bronchial lumen. Consequently, pharmacological control of bronchial vascular remodelling may be crucial for symptom control in asthma and COPD. In asthmatic airways, inhaled steroids can downregulate vascular remodelling by acting on proangiogenic factors. Additionally, studies on combination therapy with long acting beta2-agonists and inhaled steroids have provided evidence of a possible synergistic action on components of vascular remodelling in asthma. In COPD, there is less experimental evidence on the effect of inhaled steroids on airway microvascular changes. Importantly, vascular endothelial growth factor (VEGF), the most specific growth factor for vascular endothelium, is crucially involved in the pathophysiology of airway vascular remodelling, both in asthma and COPD. The inhibition of VEGF and its receptor may be useful in the treatment of the vascular changes in the airway wall. PMID- 23093961 TI - Challenges of the oral cancer burden in India. AB - Oral cancer ranks in the top three of all cancers in India, which accounts for over thirty per cent of all cancers reported in the country and oral cancer control is quickly becoming a global health priority. This paper provides a synopsis of the incidence of oral cancer in India by focusing on its measurement in cancer registries across the country. Based on the International Classification of Disease case definition adopted by the World Health Organisation, and the International Agency for Research on Cancer, this review systematically examines primary and secondary data where the incidence or prevalence of oral cancer is known to be directly reported. Variability in age adjusted incidence with crude incidence is projected to increase by 2030. Challenges focus on measurement of disease incidence and disease-specific risk behavior, predominantly, alcohol, and tobacco use. Future research should be aimed at improving quality of data for early detection and prevention of oral cancer. PMID- 23093960 TI - Folate and colorectal cancer in rodents: a model of DNA repair deficiency. AB - Fortification of grains has resulted in a positive public health outcome vis-a vis reduced incidence of neural tube defects. Whether folate has a correspondingly beneficial effect on other disease outcomes is less clear. A role for dietary folate in the prevention of colorectal cancer has been established through epidemiological data. Experimental data aiming to further elucidate this relationship has been somewhat equivocal. Studies report that folate depletion increases DNA damage, mutagenesis, and chromosomal instability, all suggesting inhibited DNA repair. While these data connecting folate depletion and inhibition of DNA repair are convincing, we also present data demonstrating that genetic inhibition of DNA repair is protective in the development of preneoplastic colon lesions, both when folate is depleted and when it is not. The purpose of this paper is to (1) give an overview of the data demonstrating a DNA repair defect in response to folate depletion, and (2) critically compare and contrast the experimental designs utilized in folate/colorectal cancer research and the corresponding impact on tissue folate status and critical colorectal cancer endpoints. Our analysis suggests that there is still an important need for a comprehensive evaluation of the impact of differential dietary prescriptions on blood and tissue folate status. PMID- 23093962 TI - Effects of surface charges on dental implants: past, present, and future. AB - Osseointegration is a major factor influencing the success of dental implantation. To achieve rapid and strong, durable osseointegration, biomaterial researchers have investigated various surface treatment methods for dental subgingival titanium (Ti) implants. This paper focuses on surface-charge modification on the surface of titanium dental implants, which is a relatively new and very promising methodology for improving the implants' osseointegration properties. We give an overview on both theoretical explanations on how surface charge affects the implants' osseointegration, as well as a potential surface charge modification method using sandblasting. Additionally, we discuss insights on the important factors affecting effectiveness of surface-charge modification methods and point out several interesting directions for future investigations on this topic. PMID- 23093963 TI - Diversity across Seasons of Culturable Pseudomonas from a Desiccation Lagoon in Cuatro Cienegas, Mexico. AB - Cuatro Cienegas basin (CCB) is a biodiversity reservoir within the Chihuahuan desert that includes several water systems subject to marked seasonality. While several studies have focused on biodiversity inventories, this is the first study that describes seasonal changes in diversity within the basin. We sampled Pseudomonas populations from a seasonally variable water system at four different sampling dates (August 2003, January 2004, January 2005, and August 2005). A total of 70 Pseudomonas isolates across seasons were obtained, genotyped by fingerprinting (BOX-PCR), and taxonomically characterized by 16S rDNA sequencing. We found 35 unique genotypes, and two numerically dominant lineages (16S rDNA sequences) that made up 64% of the sample: P. cuatrocienegasensis and P. otitidis. We did not recover genotypes across seasons, but lineages reoccurred across seasons; P. cuatrocienegasensis was isolated exclusively in winter, while P. otitidis was only recovered in summer. We statistically show that taxonomic identity of isolates is not independent of the sampling season, and that winter and summer populations are different. In addition to the genetic description of populations, we show exploratory measures of growth rates at different temperatures, suggesting physiological differences between populations. Altogether, the results indicate seasonal changes in diversity of free-living aquatic Pseudomonas populations from CCB. PMID- 23093965 TI - Single-Stage BAHA and Mastoid Obliteration. AB - A single-stage fitting of a bone-anchored hearing aid (BAHA) implant and abutment with mastoid obliteration both obviates the need for two separate procedures and utilises the BAHA soft tissue reduction in the mastoid obliteration. Such a procedure has good outcomes in terms of osseointegration and achieving a dry ear. We present a 6-patient case series report highlighting the technique of combined BAHA insertion and mastoid obliteration in six patients. All patients at twelve month followup have a good degree of sound localisation and hearing thresholds with their BAHA and are free from the social stigma associated with a foul smelling discharging ear. PMID- 23093964 TI - Clinical use of aided cortical auditory evoked potentials as a measure of physiological detection or physiological discrimination. AB - The clinical usefulness of aided cortical auditory evoked potentials (CAEPs) remains unclear despite several decades of research. One major contributor to this ambiguity is the wide range of variability across published studies and across individuals within a given study; some results demonstrate expected amplification effects, while others demonstrate limited or no amplification effects. Recent evidence indicates that some of the variability in amplification effects may be explained by distinguishing between experiments that focused on physiological detection of a stimulus versus those that differentiate responses to two audible signals, or physiological discrimination. Herein, we ask if either of these approaches is clinically feasible given the inherent challenges with aided CAEPs. N1 and P2 waves were elicited from 12 noise-masked normal-hearing individuals using hearing-aid-processed 1000-Hz pure tones. Stimulus levels were varied to study the effect of hearing-aid-signal/hearing-aid-noise audibility relative to the noise-masked thresholds. Results demonstrate that clinical use of aided CAEPs may be justified when determining whether audible stimuli are physiologically detectable relative to inaudible signals. However, differentiating aided CAEPs elicited from two suprathreshold stimuli (i.e., physiological discrimination) is problematic and should not be used for clinical decision making until a better understanding of the interaction between hearing aid-processed stimuli and CAEPs can be established. PMID- 23093966 TI - Endometriosis in adolescence. AB - Endometriosis is a common cause of pelvic pain and infertility. The majority of women report symptoms since adolescence, and there are rare cases of endometriosis in premenarchal age patients. Symptoms in adolescence are similar to those in adulthood. Treatment usually consists of oral contraceptives and nonsteroidal anti-inflammatory drugs. In cases where this treatment is not successful, laparoscopy and biopsy of the lesions are necessary for diagnosis. However, emerging new technologies provide new options, in particular the use of serological markers. PMID- 23093967 TI - Incidental rickets in the emergency department setting. AB - Vitamin D deficiency rickets is a childhood osteomalacia, with impaired skeletal development and potentially skeletal deformities. The radiographic findings of rickets are many but include widening, fraying, and cupping of the metaphysis. Developmental delay and related complications of seizure and tetany have also been reported. This medical entity is often thought of as a classic medical disease of the past. However, it persists, and the recognition of rickets is on the rise. The reemergence of rickets correlates with the increase in the number of children exclusively breastfed and with the frequent use of sun block in the pediatric population. We present two cases of rickets, diagnosed through a visit to the Emergency Department made for unrelated symptoms. These two cases illustrate the importance of diagnosing rickets as an "incidental" finding. With early detection, dietary supplementation can be initiated potentially sparing the patient symptomatic disease. PMID- 23093968 TI - Venous small bowel infarction: intraoperative laser Doppler flowmetry discriminates critical blood supply and spares bowel length. AB - Introduction. In mesenteric infarction due to arterial occlusion, laser Doppler flowmetry and spectrometry are known reliable noninvasive methods for measuring microvascular blood flow and oxygen utilisation. Case Presentation. As an innovation we used these methods in a patient with acute extensive mesenteric infarction due to venous occlusion, occurring after radical right hemicolectomy. Aiming to avoid short bowel syndrome, we spared additional 110 cm of small bowel, instead of leaving only 80 centimetres of clinically viable small bowel in situ. The pathological examination showed only 5 mm of vital mucosa to be left distal to the dissection margin. No further interventions were necessary. Conclusion. Laser doppler flowmetry and spectrometry are potentially powerful methods to assist the surgeon's decision-making in critical venous mesenteric perfusion, thus having an important impact on clinical outcome. PMID- 23093969 TI - Thrombocytopenia in the setting of hemodialysis using biocompatible membranes. AB - Thrombocytopenia is a known potential side effect of hemodialysis, however, it is rarely seen in patients who undergo hemodialysis using biocompatible membranes. This case demonstrates hemodialysis-associated thrombocytopenia with use of biocompatible dialysis membranes that expose blood directly to polysulfone. The thrombocytopenia resolved in this patient when the dialysis membrane was changed to a biocompatible model with a polyethylene glycol barrier layer preventing direct interaction between patient blood and polysulfone. The calculated Naranjo ADR score of 9 indicates a highly probable adverse reaction. PMID- 23093970 TI - A Case of Multiple Endocrine Neoplasia Type 2B and Gangliomatosis of Gastrointestinal Tract. AB - Multiple endocrine neoplasia type 2 (MEN2) is a rare familial syndrome caused by mutations in the RET protooncogene and it is transmitted as an autosomal dominant trait. The underlying problem for all the MEN syndromes is failure of a tumour suppressor gene. The genetic defect in MEN2 is on chromosome 10 (10q11.2) and has also been identified both for MEN2A and MEN2B. The reported patient is an 18-year old girl presented with long-term diarrhea and enterocutaneous fistula. Her thyroid nodules, marfanoid habitus and bumpy lips, were also highly suggestive for MEN2B. PMID- 23093971 TI - QT Prolongation Complicated with Torsades de Pointes in Prosthetic Mitral Valve Endocarditis: A Case Report. AB - We present the case of a 49-year-old male patient with prosthetic mitral valve endocarditis associated with QT prolongation and torsades de pointes. He was asymptomatic until the end of January 2012, when he was admitted to our hospital emergency unit because of syncope, fever, and suspicion of endocarditis. Cardiologic evaluation was requested and the transthoracic (TTE) and transesophageal (TEE) echocardiograms revealed vegetations on the prosthetic mitral valve. All cultures were positive for methicillin-sensitive Staphylococcus aureus. The corrected QT (QTc) interval was markedly prolonged upon admission (QTc 540 ms). He experienced torsades de pointes (TdP) several times and he was recovered after bystander cardiopulmonary resuscitation. The clinical course and the long QTc interval with deep inverted T wave were completely normalized 4 weeks after. He continued on triple antibiotic therapy for 45 days with a good revolution. The clinical features and the possible mechanisms of QT prolongation (inflammation, infection) of this patient are discussed. PMID- 23093972 TI - Clonality assessment in a case of multifocal adamantinoma and a review of the literature. AB - Adamantinoma is a low-grade, malignant biphasic bone tumour predominantly located in the tibia. In up to 50% of all cases this is combined with one or more lesions in the ipsilateral fibula. Whether these lesions represent regional metastases or arise de novo is not yet exactly known. In order to address this question, we extracted DNA from the respective fresh frozen tumour tissues in a case of a young woman with a multifocal adamantinoma of both the tibia and ipsilateral fibula. Afterwards the X inactivation pattern was studied by means of methylation sensitive polymerase chain reaction and primers that target the polymorphic CGG trinucleotide repeat of FMR1 gene and the polymorphic CAG repeat, on exon 1 of the human androgen receptor gene (AR). The analysis of the AR was homozygous and not informative. Studying the FMR1 gene, we detected a 100% skewing of the X inactivation pattern of both locations and found that the same allele was methylated. Even if the fibula lesion arose de novo there would have been a 50 : 50 chance that the same allele was methylated. As this methylation pattern was found we cannot provide a valid explanation for the origin of the fibula lesion. Analysis of X inactivation patterns in future cases of polyfocal adamantinoma might provide further evidence for one of the two theories. PMID- 23093973 TI - Adrenal cortex-sparing surgery for bilateral multiple pheochromocytomas in a patient with von hippel-lindau disease. AB - Pheochromocytomas can be a part of familial neoplastic syndromes, in which case they tend to be multiple and involve both adrenal glands. Therefore, sparing adrenocortical function represents a major concern while dealing with these hereditary lesions. Herein, we describe the clinical characteristics and the management strategy of a patient with von Hippel-Lindau (VHL) disease who had multiple, bilateral pheochromocytomas as well as bilateral renal masses, pancreatic masses, and a paracaval mass. Only a portion of the left adrenal gland has remained in situ after two consecutive open surgeries and a percutaneous radiofrequency ablation which have been performed to treat the various components of this syndrome. No adrenal or extra-adrenal pheochromocytoma recurrences have been detected during a follow-up period of more than 2 years. Pancreatic and adrenal functions were normal throughout the postoperative period and never necessitated any replacement therapy. Adrenal cortex-sparing surgery is a valid option for VHL disease patients who present with synchronous bilateral adrenal pheochromocytomas. PMID- 23093974 TI - Foreign body aspiration of a dental bridge in the left main stem bronchus. AB - Aspiration of tracheobronchial foreign bodies is a life-threatening event that occurs mainly in children. Occurrence in adults is rare and usually has a subtle presentation as most adults are unaware of aspiration of any foreign material. Decreased levels of consciousness, sedation, and neuromuscular diseases are major risk factors for foreign body aspiration in adults. Prompt diagnosis and intervention through foreign body retrieval are critical to prevent significant morbidity and mortality. Retrieval procedure is risky, and sudden decompensation of the patient can occur anytime. We are presenting an adult who accidentally aspirated his dental prosthesis during sleep and underwent successful retrieval of the dental bridge using flexible bronchoscopy. PMID- 23093975 TI - Recurrent posterior reversible encephalopathy syndrome potentially related to AIDS and end-stage renal disease: a case report and review of the literature. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome that is characterized by clinical features including headache, altered mental status, cortical blindness, seizures, and other focal neurological signs as well as subcortical edema without infarction on neuroimaging. Under the umbrella of hypertensive encephalopathy, PRES is defined by reversible cerebral edema due to dysfunction of the cerebrovascular blood-brain barrier unit. The pathophysiology of PRES is thought to result from abnormalities in the transmembrane flow of intravascular fluid and proteins caused by two phenomena: one, cerebral autoregulatory failure and two, loss of integrity of the blood brain barrier. PRES is not a common disease in patients with human immunodeficiency virus (HIV) and AIDS with only three previously reported cases. Both the HIV and end-stage renal disease appear to further compromise the blood brain barrier. Although uncommon, PRES recurrence has been described. To the best of our knowledge, this is the first report demonstrating recurrent PRES in a HIV patient on hemodialysis for end-stage renal disease. PMID- 23093976 TI - Paroxysmal autonomic instability with dystonia after pneumococcal meningoencephalitis. AB - Streptococcus pneumoniae is a common cause of bacterial meningitis, frequently resulting in severe neurological impairment. A seven-month-old child presenting with Streptococcus pneumoniae meningoencephalitis developed right basal ganglia and hypothalamic infarctions. Daily episodes of agitation, hypertension, tachycardia, diaphoresis, hyperthermia, and decerebrate posturing were observed. The diagnosis of paroxysmal autonomic instability with dystonia was established. The patient responded to clonidine, baclofen, and benzodiazepines. Although this entity has been reported in association with traumatic brain injury, and as a sequel to some nervous system infections, this is the first case, to our knowledge, associated with pneumococcal meningoencephalitis. PMID- 23093977 TI - Neural crest stem cells from dental tissues: a new hope for dental and neural regeneration. AB - Several stem cell sources persist in the adult human body, which opens the doors to both allogeneic and autologous cell therapies. Tooth tissues have proven to be a surprisingly rich and accessible source of neural crest-derived ectomesenchymal stem cells (EMSCs), which may be employed to repair disease-affected oral tissues in advanced regenerative dentistry. Additionally, one area of medicine that demands intensive research on new sources of stem cells is nervous system regeneration, since this constitutes a therapeutic hope for patients affected by highly invalidating conditions such as spinal cord injury, stroke, or neurodegenerative diseases. However, endogenous adult sources of neural stem cells present major drawbacks, such as their scarcity and complicated obtention. In this context, EMSCs from dental tissues emerge as good alternative candidates, since they are preserved in adult human individuals, and retain both high proliferation ability and a neural-like phenotype in vitro. In this paper, we discuss some important aspects of tissue regeneration by cell therapy and point out some advantages that EMSCs provide for dental and neural regeneration. We will finally review some of the latest research featuring experimental approaches and benefits of dental stem cell therapy. PMID- 23093979 TI - Growth factors released from gelatin hydrogel microspheres increase new neurons in the adult mouse brain. AB - Recent studies have shown that new neurons are continuously generated by endogenous neural stem cells in the subventricular zone (SVZ) of the adult mammalian brain. Some of these new neurons migrate to injured brain tissues and differentiate into mature neurons, suggesting that such new neurons may be able to replace neurons lost to degenerative disease or injury and improve or repair neurological deficits. Here, we tested whether delivering growth factors via gelatin hydrogel microspheres would support neurogenesis in the SVZ. Insulin-like growth factor-1 (IGF-1)-containing microspheres increased the number of new neurons in the SVZ. Hepatocyte growth factor (HGF)-containing microspheres increased the number of new neurons migrating from the SVZ towards the injured striatum in a stroke model in mouse. These results suggest that the strategy of using gelatin hydrogel microspheres to achieve the sustained release of growth factors holds promise for the clinical regeneration of damaged brain tissues from endogenous neural stem cells in the adult SVZ. PMID- 23093980 TI - Novel therapeutic/integrative approaches for celiac disease and dermatitis herpetiformis. AB - Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. Gluten is a protein component in wheat and other cereals like rye and barley. At present, the only available treatment is a strict gluten-free diet. Recent advances have increased our understanding of the molecular basis for this disorder. Last decade has seen new scientific developments in this disease and led to the formulation of new concepts of pathophysiology that offer possible targets for new treatments or interventions integrative to the gluten-free diet. PMID- 23093978 TI - Applications of amniotic membrane and fluid in stem cell biology and regenerative medicine. AB - The amniotic membrane (AM) and amniotic fluid (AF) have a long history of use in surgical and prenatal diagnostic applications, respectively. In addition, the discovery of cell populations in AM and AF which are widely accessible, nontumorigenic and capable of differentiating into a variety of cell types has stimulated a flurry of research aimed at characterizing the cells and evaluating their potential utility in regenerative medicine. While a major focus of research has been the use of amniotic membrane and fluid in tissue engineering and cell replacement, AM- and AF-derived cells may also have capabilities in protecting and stimulating the repair of injured tissues via paracrine actions, and acting as vectors for biodelivery of exogenous factors to treat injury and diseases. Much progress has been made since the discovery of AM and AF cells with stem cell characteristics nearly a decade ago, but there remain a number of problematic issues stemming from the inherent heterogeneity of these cells as well as inconsistencies in isolation and culturing methods which must be addressed to advance the field towards the development of cell-based therapies. Here, we provide an overview of the recent progress and future perspectives in the use of AM- and AF-derived cells for therapeutic applications. PMID- 23093981 TI - Bojesodok-eum, a Herbal Prescription, Ameliorates Acute Inflammation in Association with the Inhibition of NF-kappaB-Mediated Nitric Oxide and ProInflammatory Cytokine Production. AB - Bojesodok-eum (BSE) is a herbal prescription consisting of Coptidis Rhizoma and Scutellariae Radix as main components. This paper investigated the effects of BSE on the induction of nitric oxide (NO), prostaglandin E(2) (PGE(2)), and proinflammatory cytokines that are caused by lipopolysaccharide (LPS) in murine macrophage cell line and on the paw edema formation in animals. Administration of BSE (0.3 g/kg and 1 g/kg) in rats significantly inhibited carrageenan-induced paw edema formation, as did dexamethasone, an anti-inflammatory positive control drug. In cell model, treatment of BSE decreased the production of NO and PGE(2) in RAW264.7 cells stimulated by LPS. BSE also inhibited the expression of iNOS and COX-2 protein as well as COX activity in a concentration-dependent manner. Consistently, BSE suppressed the ability of LPS to produce TNF-alpha, interleukin 1beta, and interleukin-6. LPS treatment induced nuclear NF-kappaB level and I kappaBalpha phosphorylation, which were inhibited subsequent treatment of BSE, suggesting its repression of LPS-inducible NF-kappaB activation. BSE abrogated the induction of NO, PGE(2), and proinflammatory cytokines, as well as iNOS and COX-2 protein expression in RAW264.7 cells stimulated by LPS as mediated with NF kappaB inhibition. PMID- 23093983 TI - Salidroside decreases atherosclerotic plaque formation in low-density lipoprotein receptor-deficient mice. AB - Salidroside is isolated from Rhodiola rosea and is one of the main active components in Rhodiola species. The present study was designed to evaluate the effects of Salidroside on atherosclerotic plaque formation in high-fat diet-(HFD ) fed female LDL receptor knockout (LDLr(-/-)) mice. LDLr(-/-) mice fed an atherogenic HFD for 12 weeks were divided into two groups. One group was administered Salidroside (50 mg/kg/oral gavage) daily for 8 weeks, while the control group was administered saline. Salidroside treatment reduced serum lipids levels and the plaque area through the arch to the abdominal aorta. Furthermore, Salidroside improved macrophage content and enhanced collagen and smooth muscle cells contents in the aortic sinus. These changes were associated with reduced MCP-1, VCAM-1, and VCAM-1 protein expression in atherosclerotic aortas. All these results suggest that Salidroside decreases atherosclerotic plaques formation via effects on lipid lowering and anti-inflammation in HFD-fed LDLr(-/-) mice. PMID- 23093982 TI - Utilization of and Attitudes towards Traditional Chinese Medicine Therapies in a Chinese Cancer Hospital: A Survey of Patients and Physicians. AB - Background. In China, the use of traditional Chinese medicine (TCM) is very popular, but little is known about how it is integrated with conventional cancer care. We conducted parallel surveys of patients and physicians on TCM utilization. Methods. Two hundred forty-five patients and 72 allopathic physicians at the Fudan University Shanghai Cancer Center completed questions on their use of and attitude towards TCM. Results. Patient mean age was 51, with 60% female. Eighty-three percent of patients had used TCM. Use was greatest for Chinese herbal medicine (CHM; 55.8%). Only 1.3% of patients used acupuncture and 6.8% Qi Gong or Tai Qi. Sixty-three percent of patients notified their oncologist about TCM use. The most common reason for use was to improve immune function. CHM was often used with a goal of treating cancer (66.4%), a use that 57% of physicians agreed with. Physicians were most concerned with interference with treatment, lack of evidence, and safety. Ninety percent of physicians have prescribed herbs and 87.5% have used TCM themselves. Conclusion. The use of TCM by Chinese cancer patients is exceptionally high, and physicians are generally well informed and supportive of patients' use. Botanical agents are much more commonly used than acupuncture or movement-based therapies. PMID- 23093984 TI - Changing academic medicine: strategies used by academic leaders of integrative medicine-a qualitative study. AB - In Western countries, complementary and alternative medicine (CAM) is more and more provided by practitioners and family doctors. To base this reality of health care provision on an evidence-base, academic medicine needs to be included in the development. In the study we aimed to gain information on a structured approach to include CAM in academic health centers. We conducted a semistructured interview study with leading experts of integrative medicine to analyze strategies of existing academic institutions of integrative medicine. The study sample consisted of a purposive sample of ten leaders that have successfully integrated CAM into medical schools in the USA, Great Britain, and Germany and the Director of the National Center for Alternative and Complementary Medicine. Analysis was based on content analysis. The prerequisite to foster change in academic medicine was a strong educational and professional background in academic medicine and research methodologies. With such a skill set, the interviewees identified a series of strategies to align themselves with colleagues from conventional medicine, such as creating common goals, networking, and establishing well-functioning research teams. In addition, there must be a vision of what should be needed to be at the center of all efforts in order to implement successful change. PMID- 23093985 TI - Toona sinensis Leaf Aqueous Extract Improves the Functions of Sperm and Testes via Regulating Testicular Proteins in Rats under Oxidative Stress. AB - Toona sinensis leaf (TSL) is commonly used as a vegetable and in spice in Asia. In this study, feeding with aqueous extract of TSL (TSL-A) alleviated oxidative stress and recovered the motility and functions of sperm in rats under oxidative stress. Protein expressions in testes identified by proteomic analysis and verified by Western blot demonstrated that TSL-A not only downregulated the level of glutathione transferase mu6 (antioxidant system), heat shock protein 90 kDa beta (protein misfolding repairing system), cofilin 2 (spermatogenesis), and cyclophilin A (apoptosis) but also upregulated crease3-hydroxy-3-methylglutaryl coenzyme A synthase 2 (steroidogenesis), heat shock glycoprotein 96, and pancreatic trypsin 1 (sperm-oocyte interaction). These results indicate that TSL A promotes the functions of sperm and testes via regulating multiple testicular proteins in rats under oxidative stress, suggesting that TSL-A is a valuable functional food supplement to improve functions of sperm and testes for males under oxidative stress. PMID- 23093986 TI - Prescription patterns of chinese herbal products for osteoporosis in taiwan: a population-based study. AB - Background. Traditional Chinese medicine (TCM) includes Chinese herbal products (CHPs), acupuncture, and traumatology manipulative therapies. TCM physicians often prescribe CHP to treat patients with osteoporosis; however, the drugs used and their patterns of prescriptions have yet to be characterized. This study, therefore, aimed to evaluate the CHP used for the treatment of osteoporosis in Taiwan and their prescription patterns. Methods. A cohort of one million randomly sampled cases from the National Health Insurance Research Database (NHIRD) was analyzed to evaluate the frequencies and percentages of herbal formula and single herb prescriptions for osteoporosis. Association rules were then applied to evaluate the CHP coprescription patterns and the prevalence of osteoporosis. Results. The osteoporosis cohort included 16 544 patients, of whom more than 70% had used TCM on one or more occasion. Of these patients, 4 292 (25.9%) had been hospitalized at least once because of fracture. Du-Huo-Ji-Sheng-Tang and Du Zhong (Cortex Eucommiae) were the most frequently prescribed herbal formula and single herb, respectively, for the treatment of osteoporosis. Conclusion. This study identified patterns of CHP use for the treatment of osteoporosis. However, further research is required to fully elucidate the efficacy and safety of these CHP. PMID- 23093987 TI - Advance directives in nursing homes: prevalence, validity, significance, and nursing staff adherence. AB - BACKGROUND: The German Advance Directives Act of 2009 confirms that advance directives (ADs) are binding. Little is known, however, about their prevalence in nursing homes, their quality, and whether they are honored. METHODS: In 2007, we carried out a cross-sectional survey in all 11 nursing homes of a German city in the state of North Rhine-Westphalia (total nursing home population, 1089 residents). The ADs were formally analyzed and assessed by 3 raters with respect to 5 clinical decision-making scenarios. The specifications of the ADs were compared with what the nurses reported that they would do in each scenario. RESULTS: 11% of the nursing home residents had a personal AD, and a further 1.4% an AD by proxy. 52% of the 119 ADs that we analyzed contained no documentation of the patient's decision-making capacity and/or voluntariness, and only 3% contained documentation of a medical consultation. Most ADs failed to state what should be done in case the patient acutely became incapable of consenting to treatment (inter-rater agreement [IRA] >83%). For the case of permanent decisional incapacity, many ADs contained ambiguous information (IRA<43%). 23 directives stated that the patient should not have cardiopulmonary resuscitation in case an arrest occurred in the patient's current clinical condition, but the nurses reported a corresponding do-not-resuscitate agreement for only 9 of these 23 patients. CONCLUSION: In 2007, ADs were rare in these German nursing homes, and most of the existing ones were invalid, of little meaning, and/or disregarded by the nursing staff. There is little reason to believe that the Advance Directives Act of 2009 will bring about any major change in this miserable status quo. Advance care planning, a system-oriented concept still uncommon in Germany, could give new impulses to promote a cultural change in this respect. PMID- 23093988 TI - The therapeutic potential of intraocular depot steroid systems: developments aimed at prolonging duration of efficacy. AB - BACKGROUND: Corticosteroids play a major role in the treatment of many diseases of the posterior ocular segment. Systemically or topically administered steroids usually do not attain therapeutic concentrations in the retina, as they must first cross the blood-retina barrier. Intravitreal application is a useful alternative means of achieving therapeutic concentrations in the posterior segment but must be repeated every few weeks, because drugs given in this way have a short half-life. Intraocular sustained-release implants have been now developed in order to prolong the effect of intravitreal drugs and to lessen the need for repeated application. Macular edema is a typical indication for intravitreal steroid treatment. METHODS: Selective review of the literature. RESULTS: Various intravitreal corticosteroid implants have been evaluated in prospective, randomized clinical trials in recent years, and some have been approved for clinical use. Implants are either longer-acting and non-resorbable (fluocinolone acetonide implants) or shorter-acting and resorbable (dexamethasone implants). Major adverse effects of intravitreal corticosteroids include the induction or worsening of cataracts and elevated intraocular pressure. The likelihood of a complication varies from implant to implant and depends on the duration of action of the particular one used. CONCLUSION: Intravitreal corticosteroid implants are a new option in the treatment of diseases of the posterior ocular segment. Long-term results are not yet available. The optimal treatment for these diseases will need to be the focus of further clinical research. PMID- 23093989 TI - In-flight medical emergencies. AB - BACKGROUND: One in every 10 000 to 40 000 passengers on commercial aircraft will have a medical incident while on board. Many physicians are unaware of the special features of the cabin atmosphere, the medical equipment available on airplanes, and the resulting opportunities for medical intervention. METHODS: A selective literature search was performed and supplemented with international recommendations and guidelines and with data from the Lufthansa registry. RESULTS: Data on in-flight medical emergencies have been collected in various ways, with varying results; it is generally agreed, however, that the more common incidents include gastrointestinal conditions (diarrhea, nausea, vomiting), circulatory collapse, hypertension, stroke, and headache (including migraine). Data from the Lufthansa registry for the years 2010 and 2011 reveal the rarity of cardiopulmonary resuscitation (mean: 8 cases per year), death (12 cases per year), childbirth (1 case per year), and psychiatric incidents (81 cases per year). If one assumes that one medical incident arises for every 10 000 passengers, and that there are 400 passengers on board each flight, then one can calculate that the probability of experiencing at least one medical incident reaches 95% after 24 intercontinental flights. CONCLUSION: An in-flight medical emergency is an exceptional event for the physician and all other persons involved. Physician passengers can act more effectively if they are aware of the framework conditions, the available medical equipment, and the commonly encountered medical conditions. PMID- 23093990 TI - Intrauterine surgery--choices and limitations. AB - BACKGROUND: The past decade has seen much progress in intrauterine surgery. Randomized trials have documented the benefit of some procedures of this type for the unborn child. METHOD: Selective literature review RESULTS: Randomized trials have demonstrated the benefit of fetoscopic laser coagulation of placental anastomoses in twin-to-twin transfusion syndrome (TTTS) and of intrauterine surgery via hysterotomy for the repair of spina bifida. Other fetoscopic procedures have yielded promising initial results but are not yet supported by findings from randomized trials. Some intrauterine surgical procedures must still be considered experimental in view of the lack of randomized trials and the rarity of the conditions they are designed to treat. Fetoscopic laser coagulation for TTTS is by far the most common procedure in fetal surgery; TTTS arises in roughly 1 in 2500 pregnancies. The other procedures discussed in this article are performed much less often and for rarer indications. In general, intrauterine surgery is indicated only to treat conditions that would otherwise lead to intrauterine death or irreversible prenatal damage. CONCLUSION: Intrauterine surgery is a rapidly developing field. Prenatal intervention by laser coagulation is indicated to treat severe TTTS, as its benefit has been shown in a randomized trial. Not enough evidence is yet available for the possible benefit of intrauterine surgery to treat myelomeningocele and congenital diaphragmatic hernia. Other indications are experimental. When an indication for intrauterine surgery exists, the parents should be informed and, depending on their wishes, referred to a center where it can be performed. PMID- 23093991 TI - Medication errors in pediatric emergencies: a systematic analysis. AB - BACKGROUND: Errors in drug administration are among the commonest medical errors. Children are particularly at risk for such errors because of the need to calculate doses individually. Doses that are ten times the correct amount (1000% of the correct dose) are occasionally given and can be life-threatening. In a simulated resuscitation in a pediatric emergency room, an error of this type occurred for one of the 32 medications that were ordered. The highest error rates are to be expected in prehospital emergency medicine. In this review, we analyze the process of ordering medications and describe the potential interventions for lowering error rates that have been evaluated to date. METHOD: Systematic literature review RESULTS: We found 32 original publications that concerned the evaluation of interventions for lowering error rates in the ordering of medications for children. Error rates can be lowered by interventions that improve prescribers' knowledge of pediatric pharmacotherapy (courses, immediately accessible sources of information) and by aids to the cognitive process of ordering medication (calculators, computer programs, tables of doses by weight). They can also be lowered by raising awareness of the problem of erroneous medication ordering and by monitoring medication orders, as well as by structured communication and standardized, unambiguously labeled drug preparations. In the hospital setting, computer programs for medication orders with a built-in pediatric pharmacological database are highly recommended. In the prehospital setting, the "pediatric emergency ruler" enables accurate estimation of the patient's weight, provides age-appropriate dosage recommendations, and directly indicates the steps needed for calculation of the correct dose. CONCLUSION: Children in medical emergency situations are at significant risk for medication errors. The measures described here can markedly lower the rate of dangerous errors. PMID- 23093992 TI - Urinary diversion--approaches and consequences. AB - BACKGROUND: Bladder cancer is not a rare disease: In 2010, there were more than 70 000 affected patients in the United States. Radical cystectomy for the treatment of muscle invasive bladder cancer necessitates urinary diversion. METHODS: We present the current options for urinary diversion and their different indications on the basis of a selective search for pertinent literature in PubMed and our own clinical experience. RESULTS: When bladder cancer is treated with curative intent, continence-preserving orthotopic urinary bladder replacement is preferred. For heterotopic urinary bladder replacement, a reservoir is fashioned from an ileal or ileocecal segment. Urine is diverted to the rectum by way of the sigmoid colon. When bladder cancer is treated with palliative intent, non continence-preserving cutaneous urinary diversion is usually performed: The creation either of a renal-cutaneous fistula or a self-retaining ureteral stent is a purely palliative procedure. In these interventions, the resorptive surface of the bowel segment used can no longer play its original physiological role in the gastrointestinal tract, even though its absorptive and secretory functions are still intact. This has metabolic consequences, because the diverted urine here comes into contact with a large area of bowel epithelium. Early preventive treatment must be provided against potentially serious complications such as metabolic acidosis and loss of bone density. The resection of ileal segments can also lead to malabsorption. The risk of secondary malignancy is elevated after either continence-preserving anal urinary diversion (>2%) or bladder augmentation (>1%). CONCLUSION: There are four options for urinary diversion after cystectomy that can be performed when surgery is performed with either curative or palliative intent. There are also a number of purely palliative interventions. PMID- 23093993 TI - CT angiography in the diagnosis of brain death. PMID- 23093994 TI - Technical aids in the diagnosis of brain death: a comparison of SEP, AEP, EEG, TCD and CT angiography. AB - BACKGROUND: The use of technical aids to confirm brain death is a controversial matter. Angiography with the intra-arterial administration of contrast medium is the international gold standard, but it is not allowed in Germany except in cases where it provides a potential mode of treatment. The currently approved tests in Germany are recordings of somatosensory evoked potentials (SSEP), brain perfusion scintigraphy, transcranial Doppler ultrasonography (TCD), and electroencephalography (EEG). CT angiography (CTA), a promising new alternative, is being increasingly used as well. METHODS: In a prospective, single-center study that was carried out from 2008 to 2011, 71 consecutive patients in whom brain death was diagnosed on clinical grounds underwent recording of auditory evoked potentials (AEP) and SSEP as well as EEG, TCD and CTA. RESULTS: The validity of CTA for the confirmation of brain death was 94%; the validity of the other tests was: 94% for EEG, 92% for TCD, 82% for SSEP, and 2% for AEP. In 61 of the 71 patients (86%), the EEG, TCD and CTA findings all accorded with the clinical diagnosis. The diagnosis of brain death was established beyond doubt in all patients. CONCLUSION: In this study, the technical aids yielded discordant results in 14% of cases, necessitating interpretation by an expert examiner. The perfusion tests, in particular, can give false-positive results in patients with large cranial defects, skull fractures, or cerebrospinal fluid drainage. In such cases, electrophysiologic tests or a repeated clinical examination should be performed instead. CTA is a promising, highly reliable new method for demonstrating absent intracranial blood flow. In our view, it should be incorporated into the German guidelines for the diagnosis of brain death. PMID- 23093996 TI - Digital photo documentation of forensically relevant injuries as part of the clinical first response protocol. AB - BACKGROUND: A problem encountered by medical examiners is that they have to assess injuries that have already been medically treated. Thus, they have to base their reports on clinical forensic examinations performed hours or days after an injury was sustained, or even base their assessment solely on information gleaned from medical files. In both scenarios, the forensic examiner has to rely heavily on the first responder's documentation of the original injury pattern. Medical priority will be to immediately treat a patient's injuries, and the first responder may, in addition, initially be unaware of a possibly criminal origin of an injury. As a result, the documentation of injuries is frequently of limited value for forensic purposes. This situation could be improved if photographic records were briefly made of injuries before they were treated. METHODS: German language medicolegal, criminal, and photography journals and books were selectively searched with the help of PubMed and other databases. In addition, the authors' experiences in creating and evaluating photographic records for clinical forensic use were assessed. RESULTS: This paper is an aid to creating photographic records of sufficient quality for forensic purposes. The options provided by digital photography in particular make this endeavor feasible even in a clinical setting. In addition, our paper illuminates some technical aspects of creating and archiving photographic records for forensic use, and addresses possible error sources. CONCLUSION: With the requisite technical background knowledge, injuries can be photographically recorded to forensic standards during patient care. PMID- 23093995 TI - Surgical resection of urological tumor metastases following medical treatment. AB - BACKGROUND: The rate of systemic metastases is about 20% in testicular germ cell tumors, 25% to 30% in prostate cancer, 30% in urothelial carcinoma with muscle invasion, and 50% in renal-cell carcinoma. This article is a critical review of current data on the resection of metastases of urological tumors after systemic drug treatment. METHODS: Review of pertinent publications retrieved by a selective literature search. RESULTS: No pertinent prospective, randomized trials, meta-analyses, or Cochrane reviews have been published. The publications available for review include guidelines and retrospective studies with evidence levels ranging from IIB to III. For non-seminomatous germ cell tumors with tumor markers that are negative or have reached a plateau after chemotherapy, resection of retroperitoneal, intra-abdominal, and intrathoracic metastases with curative intent is now the treatment of choice at clinical reference centers. For urothelial carcinoma that has gone into partial remission after systemic chemotherapy, with full resectability, the resection of metastases prolongs survival from about 13 months to 31-41 months. For prostatic carcinoma with solitary, intrapelvic lymph-node metastases and PSA less than 4 ng/mL, the resection of metastases prolongs 5-year progression-free survival in 40% to 50% of cases. There is, however, no indication for the resection of retro-peritoneal, visceral, or bony metastases. In renal-cell carcinoma, the resection of pulmonary or hepatic metastases is associated with a 5-year survival rate of 40% to 50% or 62%, respectively, and should thus be made a component of the treatment plan for this disease. The indication for resecting metastases of urological cancers should always be established by an interdisciplinary tumor board in the light of the existing scientific evidence. CONCLUSION: The resection of metastases of some types of urological cancer after chemotherapy can prolong progression-free and overall survival. This form of treatment deserves consideration as a component of individual care and of the interdisciplinary treatment plan for urological cancers. PMID- 23093997 TI - Correspondence (letter to the editor): Two further aspects. PMID- 23094000 TI - Surgical intervention for pulmonary metastases. AB - INTRODUCTION: Autopsy studies of persons who died of cancer have shown the lungs to be the sole site of metastasis in about 20% of cases. The resection of pulmonary metastases is indicated for palliative purposes if they contain a large volume of necrotic tumor, infiltrate the thoracic wall to produce pain, or cause hemoptysis or retention pneumonia. Metastasectomy with curative intent may be indicated for carefully selected patients. METHODS: This review is based on a selective search of the PubMed database for articles that were published from 2006 to 2011 and contained the keywords "pulmonary metastasectomy," "lung resection of metastasis," and "lung metastasectomy." RESULTS: No prospective comparative trials have been performed to date that might provide evidence for prolongation of survival by pulmonary metastasectomy; nor have there been any randiomized, controlled trials yielding evidence that would assist in the decision whether to treat pulmonary metastases with surgery, radiotherapy, or chemotherapy (or some combination of these). The indication for surgery is a function of the histology of the primary tumor, the number and location of metastases, the lung capacity that is expected to remain after surgery, and the opportunity for an R0 resection. Favorable prognostic factors include a long disease-free interval between the treatment of the primary tumor and the discovery of pulmonary metastases, the absence of thoracic lymph node metastases, and a small number of pulmonary metastases. The reported 5-year survival rates after pulmonary metastasectomy, depending on the primary tumor, are 35.5% to 47% for renal-cell carcinoma, 39.1% to 67.8% for colorectal cancer, 29% to 52% for soft-tissue sarcoma, 38% to 49.7% for osteosarcoma, and 79% to 94% for non seminomatous germ-cell tumors. For the latter two types of tumor, chemotherapy is the most beneficial form of treatment for long-term survival. CONCLUSION: When there is no good clinical alternative, the resection of pulmonary metastases can give some patients long-lasting freedom from malignant disease. Patients should be carefully selected on the basis of clinical staging with defined prognostic indicators. PMID- 23094001 TI - Acute lymphoblastic leukemia in children: treatment planning via minimal residual disease assessment. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common type of cancer in children and adolescents, accounting for 30% of all cases of malignancy in this age group. The cure rate of ALL is now above 80%. The clinical and biological characteristics of ALL that have been studied to date are of limited use in predicting the individual response. Newly developed methods for the assessment of minimal residual disease (MRD) are more helpful in this regard. METHODS: Review of pertinent literature retrieved by a selective search in Medline. RESULTS: MRD assessment has gradually been incorporated into ALL treatment planning over the past two decades. In the largest study to date of the use of MRD for this purpose, which included 3648 children with ALL, the MRD status on days 33 and 78 after the start of treatment was found to be the most important prognostic factor. The study group included 3184 patients with B precursor ALL (leukemia consisting of immature B-lymphocytes), of whom a large subgroup (standard risk profile, 42%) had a seven-year event-free survival rate (7Y-EFS) of 91.1%; for the 6% of B-ALL patients with a high-risk profile, the cumulative rate of recurrence was 38.5 %.The remaining 464 patients had T-ALL (leukemia consisting of T-lymphocytes). The leukemia cells were eliminated more slowly overall in these patients than in those with B-ALL. Nonetheless, the T-ALL patients with a standard risk profile (16% of all T-ALL patients) had an excellent 7Y-EFS rate (91.1%), while the high-risk group (21% of all T-ALL patients) had an MRD recurrence rate of 37.7%. These findings are representative of current data from around the world on children and adults with ALL. CONCLUSION: MRD analysis enables more accurate prediction of ALL patients' response to treatment. Risk-group stratification by MRD assessment has already brought about considerable improvement in individualized treatment planning. PMID- 23094002 TI - Current status of epibulbar anti-glaucoma drainage devices in glaucoma surgery. AB - BACKGROUND: The term "glaucoma" covers a heterogeneous group of progressive optic neuropathies that are accompanied by characteristic visual-field defects. Primary open-angle glaucoma, the most common type, progresses insidiously and causes blindness if untreated. All current forms of treatment aim at lowering the intraocular pressure (IOP) in patients whose IOP is elevated. The implantation of anti-glaucoma drainage systems is one of the available options for surgical treatment. METHODS: This review is based on pertinent literature retrieved by a selective search, including glaucoma treatment guidelines from Germany and abroad. RESULTS: A paradigm shift is currently underway regarding the indications for the implantation of anti-glaucoma drainage systems. Trabeculectomy (a "fistulating" operation in which the aqueous humor is led out of the eye under the conjunctiva) is still considered the surgical gold standard, but drainage systems have been implanted with increasing frequency in recent years. Studies have shown that these systems are more likely to be beneficial the earlier they are implanted in the course of the patient's disease. Five-year follow-up data from the randomized, multicenter Tube Versus Trabeculectomy (TVT) study have now revealed that anti-glaucoma drainage systems are equivalent to trabeculectomy with respect to long-term IOP reduction, complication rates, and absolute and relative clinical success rates. CONCLUSION: Glaucoma is a major clinical and socio-economic problem whose surgical treatment increasingly involves the implantation of anti-glaucoma drainage systems. PMID- 23094003 TI - Complex medical ethical problems. PMID- 23094004 TI - The facts are incomplete. PMID- 23094014 TI - Recent emergence of Staphylococcus aureus clonal complex 398 in human blood cultures. AB - BACKGROUND: Recently, a clone of MRSA with clonal complex 398 (CC398) has emerged that is related to an extensive reservoir in animals, especially pigs and veal calves. It has been reported previously that methicillin-susceptible variants of CC398 circulate among humans at low frequency, and these have been isolated in a few cases of bloodstream infections (BSI). The purpose of this study was to determine the prevalence of S. aureus CC398 in blood cultures taken from patients in a geographic area with a high density of pigs. METHODOLOGY/PRINCIPAL FINDINGS: In total, 612 consecutive episodes of S. aureus BSI diagnosed before and during the emergence of CC398 were included. Three strains (2 MSSA and 1 MRSA) that were isolated from bacteremic patients between 2010-2011 were positive in a CC398 specific PCR. There was a marked increase in prevalence of S. aureus CC398 BSI isolated between 2010-2011 compared to the combined collections that were isolated between 1996-1998 and 2002-2005 (3/157, 1.9% vs. 0/455, 0.0%; p = 0.017). CONCLUSIONS/SIGNIFICANCE: In conclusion, in an area with a relative high density of pigs, S. aureus CC398 was found as a cause of BSI in humans only recently. This indicates that S. aureus CC398 is able to cause invasive infections in humans and that the prevalence is rising. Careful monitoring of the evolution and epidemiology of S. aureus CC398 in animals and humans is therefore important. PMID- 23094015 TI - How early can the seeding dates of spring wheat be under current and future climate in Saskatchewan, Canada? AB - BACKGROUND: Shorter growing season and water stress near wheat maturity are the main factors that presumably limit the yield potential of spring wheat due to late seeding in Saskatchewan, Canada. Advancing seeding dates can be a strategy to help producers mitigate the impact of climate change on spring wheat. It is unknown, however, how early farmers can seed while minimizing the risk of spring frost damage and the soil and machinery constraints. METHODOLOGY/PRINCIPAL FINDINGS: This paper explores early seeding dates of spring wheat on the Canadian Prairies under current and projected future climate. To achieve this, (i) weather records from 1961 to 1990 were gathered at three sites with different soil and climate conditions in Saskatchewan, Canada; (ii) four climate databases that included a baseline (treated as historic weather climate during the period of 1961-1990) and three climate change scenarios (2040-2069) developed by the Canadian global climate model (GCM) with the forcing of three greenhouse gas (GHG) emission scenarios (A2, A1B and B1); (iii) seeding dates of spring wheat (Triticum aestivum L.) under baseline and projected future climate were predicted. Compared with the historical record of seeding dates, the predicted seeding dates were advanced under baseline climate for all sites using our seeding date model. Driven by the predicted temperature increase of the scenarios compared with baseline climate, all climate change scenarios projected significantly earlier seeding dates than those currently used. Compared to the baseline conditions, there is no reduction in grain yield because precipitation increases during sensitive growth stages of wheat, suggesting that there is potential to shift seeding to an earlier date. The average advancement of seeding dates varied among sites and chosen scenarios. The Swift Current (south-west) site has the highest potential for earlier seeding (7 to 11 days) whereas such advancement was small in the Melfort (north-east, 2 to 4 days) region. CONCLUSIONS/SIGNIFICANCE: The extent of projected climate change in Saskatchewan indicates that growers in this region have the potential of earlier seeding. The results obtained in this study may be used for adaptation assessments of seeding dates under possible climate change to mitigate the impact of potential warming. PMID- 23094016 TI - Protection of retinal ganglion cells and retinal vasculature by Lycium barbarum polysaccharides in a mouse model of acute ocular hypertension. AB - Acute ocular hypertension (AOH) is a condition found in acute glaucoma. The purpose of this study is to investigate the protective effect of Lycium barbarum polysaccharides (LBP) and its protective mechanisms in the AOH insult. LBP has been shown to exhibit neuroprotective effect in the chronic ocular hypertension (COH) experiments. AOH mouse model was induced in unilateral eye for one hour by introducing 90 mmHg ocular pressure. The animal was fed with LBP solution (1 mg/kg) or vehicle daily from 7 days before the AOH insult till sacrifice at either day 4 or day 7 post insult. The neuroprotective effects of LBP on retinal ganglion cells (RGCs) and blood-retinal-barrier (BRB) were evaluated. In control AOH retina, loss of RGCs, thinning of IRL thickness, increased IgG leakage, broken tight junctions, and decreased density of retinal blood vessels were observed. However, in LBP-treated AOH retina, there was less loss of RGCs with thinning of IRL thickness, IgG leakage, more continued structure of tight junctions associated with higher level of occludin protein and the recovery of the blood vessel density when compared with vehicle-treated AOH retina. Moreover, we found that LBP provides neuroprotection by down-regulating RAGE, ET-1, Abeta and AGE in the retina, as well as their related signaling pathways, which was related to inhibiting vascular damages and the neuronal degeneration in AOH insults. The present study suggests that LBP could prevent damage to RGCs from AOH-induced ischemic injury; furthermore, through its effects on blood vessel protection, LBP would also be a potential treatment for vascular-related retinopathy. PMID- 23094017 TI - No evidence for a second evolutionary stratum during the early evolution of mammalian sex chromosomes. AB - Mammalian sex chromosomes originated from a pair of autosomes, and homologous genes on the sex chromosomes (gametologs) differentiated through recombination arrest between the chromosomes. It was hypothesized that this differentiation in eutherians took place in a stepwise fashion and left a footprint on the X chromosome termed "evolutionary strata." The evolutionary stratum hypothesis claims that strata 1 and 2 (which correspond to the first two steps of chromosomal differentiation) were generated in the stem lineage of Theria or before the divergence between eutherians and marsupials. However, this prediction relied solely on the molecular clock hypothesis between pairs of human gametologs, and molecular evolution of marsupial sex chromosomal genes has not yet been investigated. In this study, we analyzed the following 7 pairs of marsupial gametologs, together with their eutherian orthologs that reside in stratum 1 or 2: SOX3/SRY, RBMX/Y, RPS4X/Y, HSFX/Y, XKRX/Y, SMCX/Y (KDM5C/D, JARID1C/D), and UBE1X/Y (UBA1/UBA1Y). Phylogenetic analyses and estimated divergence time of these gametologs reveal that they all differentiated at the same time in the therian ancestor. We have also provided strong evidence for gene conversion that occurred in the 3' region of the eutherian stratum 2 genes (SMCX/Y and UBE1X/Y). The results of the present study show that (1) there is no compelling evidence for the second stratum in the stem lineage of Theria; (2) gene conversion, which may have occurred between SMCX/Y and UBE1X/Y in the eutherian lineage, potentially accounts for their apparently lower degree of overall divergence. PMID- 23094018 TI - Humanized mouse model of skin inflammation is characterized by disturbed keratinocyte differentiation and influx of IL-17A producing T cells. AB - Humanized mouse models offer a challenging possibility to study human cell function in vivo. In the huPBL-SCID-huSkin allograft model human skin is transplanted onto immunodeficient mice and allowed to heal. Thereafter allogeneic human peripheral blood mononuclear cells are infused intra peritoneally to induce T cell mediated inflammation and microvessel destruction of the human skin. This model has great potential for in vivo study of human immune cells in (skin) inflammatory processes and for preclinical screening of systemically administered immunomodulating agents. Here we studied the inflammatory skin response of human keratinocytes and human T cells and the concomitant systemic human T cell response.As new findings in the inflamed human skin of the huPBL-SCID-huSkin model we here identified: 1. Parameters of dermal pathology that enable precise quantification of the local skin inflammatory response exemplified by acanthosis, increased expression of human beta-defensin-2, Elafin, K16, Ki67 and reduced expression of K10 by microscopy and immunohistochemistry. 2. Induction of human cytokines and chemokines using quantitative real-time PCR. 3. Influx of inflammation associated IL-17A-producing human CD4+ and CD8+ T cells as well as immunoregulatory CD4+Foxp3+ cells using immunohistochemistry and -fluorescence, suggesting that active immune regulation is taking place locally in the inflamed skin. 4. Systemic responses that revealed activated and proliferating human CD4+ and CD8+ T cells that acquired homing marker expression of CD62L and CLA. Finally, we demonstrated the value of the newly identified parameters by showing significant changes upon systemic treatment with the T cell inhibitory agents cyclosporine-A and rapamycin. In summary, here we equipped the huPBL-SCID-huSkin humanized mouse model with relevant tools not only to quantify the inflammatory dermal response, but also to monitor the peripheral immune status. This combined approach will gain our understanding of the dermal immunopathology in humans and benefit the development of novel therapeutics for controlling inflammatory skin diseases. PMID- 23094020 TI - The free energy barrier for arginine gating charge translation is altered by mutations in the voltage sensor domain. AB - The gating of voltage-gated ion channels is controlled by the arginine-rich S4 helix of the voltage-sensor domain moving in response to an external potential. Recent studies have suggested that S4 moves in three to four steps to open the conducting pore, thus visiting several intermediate conformations during gating. However, the exact conformational changes are not known in detail. For instance, it has been suggested that there is a local rotation in the helix corresponding to short segments of a 3(10)-helix moving along S4 during opening and closing. Here, we have explored the energetics of the transition between the fully open state (based on the X-ray structure) and the first intermediate state towards channel closing (C1), modeled from experimental constraints. We show that conformations within 3 A of the X-ray structure are obtained in simulations starting from the C1 model, and directly observe the previously suggested sliding 3(10)-helix region in S4. Through systematic free energy calculations, we show that the C1 state is a stable intermediate conformation and determine free energy profiles for moving between the states without constraints. Mutations indicate several residues in a narrow hydrophobic band in the voltage sensor contribute to the barrier between the open and C1 states, with F233 in the S2 helix having the largest influence. Substitution for smaller amino acids reduces the transition cost, while introduction of a larger ring increases it, largely confirming experimental activation shift results. There is a systematic correlation between the local aromatic ring rotation, the arginine barrier crossing, and the corresponding relative free energy. In particular, it appears to be more advantageous for the F233 side chain to rotate towards the extracellular side when arginines cross the hydrophobic region. PMID- 23094019 TI - The cellular protein MCM3AP is required for inhibition of cellular DNA synthesis by the IE86 protein of human cytomegalovirus. AB - Like all DNA viruses, human cytomegalovirus (HCMV) infection is known to result in profound effects on host cell cycle. Infection of fibroblasts with HCMV is known to induce an advance in cell cycle through the G(0)-G(1) phase and then a subsequent arrest of cell cycle in early S-phase, presumably resulting in a cellular environment optimum for high levels of viral DNA replication whilst precluding replication of cellular DNA. Although the exact mechanisms used to arrest cell cycle by HCMV are unclear, they likely involve a number of viral gene products and evidence points to the ability of the virus to prevent licensing of cellular DNA synthesis. One viral protein known to profoundly alter cell cycle is the viral immediate early 86 (IE86) protein--an established function of which is to initially drive cells into early S phase but then inhibit cellular DNA synthesis. Here we show that, although IE86 interacts with the cellular licensing factor Cdt1, it does not inhibit licensing of cellular origins. Instead, IE86 mediated inhibition of cellular DNA synthesis requires mini-chromosome maintenance 3 (MCM3) associated protein (MCM3AP), which can cause subsequent inhibition of initiation of cellular DNA synthesis in a licensing-independent manner. PMID- 23094021 TI - Implicit learning of recursive context-free grammars. AB - Context-free grammars are fundamental for the description of linguistic syntax. However, most artificial grammar learning experiments have explored learning of simpler finite-state grammars, while studies exploring context-free grammars have not assessed awareness and implicitness. This paper explores the implicit learning of context-free grammars employing features of hierarchical organization, recursive embedding and long-distance dependencies. The grammars also featured the distinction between left- and right-branching structures, as well as between centre- and tail-embedding, both distinctions found in natural languages. People acquired unconscious knowledge of relations between grammatical classes even for dependencies over long distances, in ways that went beyond learning simpler relations (e.g. n-grams) between individual words. The structural distinctions drawn from linguistics also proved important as performance was greater for tail-embedding than centre-embedding structures. The results suggest the plausibility of implicit learning of complex context-free structures, which model some features of natural languages. They support the relevance of artificial grammar learning for probing mechanisms of language learning and challenge existing theories and computational models of implicit learning. PMID- 23094022 TI - A spiroligomer alpha-helix mimic that binds HDM2, penetrates human cells and stabilizes HDM2 in cell culture. AB - We demonstrate functionalized spiroligomers that mimic the HDM2-bound conformation of the p53 activation domain. Spiroligomers are stereochemically defined, functionalized, spirocyclic monomers coupled through pairs of amide bonds to create spiro-ladder oligomers. Two series of spiroligomers were synthesized, one of structural analogs and one of stereochemical analogs, from which we identified compound 1, that binds HDM2 with a Kd value of 400 nM. The spiroligomer 1 penetrates human liver cancer cells through passive diffusion and in a dose-dependent and time-dependent manner increases the levels of HDM2 more than 30-fold in Huh7 cells in which the p53/HDM2 negative feed-back loop is inoperative. This is a biological effect that is not seen with the HDM2 ligand nutlin-3a. We propose that compound 1 modulates the levels of HDM2 by stabilizing it to proteolysis, allowing it to accumulate in the absence of a p53/HDM2 feedback loop. PMID- 23094023 TI - Inhibition of hepatitis B virus and induction of hepatoma cell apoptosis by ASGPR directed delivery of shRNAs. AB - Hepatitis B virus (HBV) infection is a worldwide liver disease and nearly 25% of chronic HBV infections terminate in hepatocellular carcinoma (HCC). Currently, there is no effective therapy to inhibit HBV replication and to eliminate hepatoma cells, making it highly desired to develop novel therapies for these two stages of the HBV-caused detrimental disease. Recently, short hairpin RNA (shRNA) has emerged as a potential therapy for virus-infected disease and cancer. Here, we have generated a shRNA, pGenesil-siHBV4, which effectively inhibits HBV replication in the human hepatoma cell line HepG2.2.15. The inhibitory effects of pGenesil-siHBV4 are manifested by the decrease of both the HBV mRNA level and the protein levels of the secreted HBV surface antigen (HBsAg) and HBV e antigen (HBeAg), and by the reduction of secreted HBV DNA. Using mouse hydrodynamic tail vein injection, we demonstrate that pGenesil-siHBV4 is effective in inhibiting HBV replication in vivo. Because survivin plays a key role in cancer cell escape from apoptosis, we further generated pGenesil-siSurvivin, a survivin-silencing shRNA, and showed its effect of triggering apoptosis of HBV-containing hepatoma cells. To develop targeted shRNA therapy, we have identified that as a specific binder of the asialoglycoprotein receptor (ASGPR), jetPEI-Hepatocyte delivers pGenesil-siHBV4 and pGenesil-siSurvivin specifically to hepatocytes, not other types of cells. Finally, co-transfection of pGenesil-siHBV4 and pGenesil siSurvivin exerts synergistic effects in inducing hepatoma cell apoptosis, a novel approach to eliminate hepatoma by downregulating survivin via multiple mechanisms. The application of these novel shRNAs with the jetPEI-Hepatocyte targeting strategy demonstrates the proof-of-principle for a promising approach to inhibit HBV replication and eliminate hepatoma cells with high specificity. PMID- 23094024 TI - Comparative genomic hybridization analysis shows different epidemiology of chromosomal and plasmid-borne cpe-carrying Clostridium perfringens type A. AB - Clostridium perfringens, one of the most common causes of food poisonings, can carry the enterotoxin gene, cpe, in its chromosome or on a plasmid. C. perfringens food poisonings are more frequently caused by the chromosomal cpe carrying strains, while the plasmid-borne cpe-positive genotypes are more commonly found in the human feces and environmental samples. Different tolerance to food processing conditions by the plasmid-borne and chromosomal cpe-carrying strains has been reported, but the reservoirs and contamination routes of enterotoxin-producing C. perfringens remain unknown. A comparative genomic hybridization (CGH) analysis with a DNA microarray based on three C. perfringens type A genomes was conducted to shed light on the epidemiology of C. perfringens food poisonings caused by plasmid-borne and chromosomal cpe-carrying strains by comparing chromosomal and plasmid-borne cpe-positive and cpe-negative C. perfringens isolates from human, animal, environmental, and food samples. The chromosomal and plasmid-borne cpe-positive C. perfringens genotypes formed two distinct clusters. Variable genes were involved with myo-inositol, ethanolamine and cellobiose metabolism, suggesting a new epidemiological model for C. perfringens food poisonings. The CGH results were complemented with growth studies, which demonstrated different myo-inositol, ethanolamine, and cellobiose metabolism between the chromosomal and plasmid-borne cpe-carrying strains. These findings support a ubiquitous occurrence of the plasmid-borne cpe-positive strains and their adaptation to the mammalian intestine, whereas the chromosomal cpe-positive strains appear to have a narrow niche in environments containing degrading plant material. Thus the epidemiology of the food poisonings caused by two populations appears different, the plasmid-borne cpe-positive strains probably contaminating foods via humans and the chromosomal strains being connected to plant material. PMID- 23094025 TI - Periodontal disease and risk of chronic obstructive pulmonary disease: a meta analysis of observational studies. AB - BACKGROUND: Many epidemiological studies have found a positive association between periodontal disease (PD) and risk of chronic obstructive pulmonary disease (COPD), but this association is varied and even contradictory among studies. We performed a meta-analysis to ascertain the relationship between PD and COPD. METHODS: PubMed and Embase database were searched up to January 10, 2012, for relevant observational studies on the association between PD and risk of COPD. Data from the studies selected were extracted and analyzed independently by two authors. The meta-analysis was performed using the Comprehensive Meta Analysis software. RESULTS: Fourteen observational studies (one nested case control, eight case-control, and five cross-sectional) involving 3,988 COPD patients were yielded. Based on random-effects meta-analysis, a significant association between PD and COPD was identified (odds ratio = 2.08, 95% confidence interval = 1.48-2.91; P<0.001), with sensitivity analysis showing that the result was robust. Subgroups analyses according to study design, ethnicity, assessment of PD/COPD, and adjusted/unadjusted odds ratios also revealed a significant association. Publication bias was detected. CONCLUSIONS: Based on current evidence, PD is a significant and independent risk factor of COPD. However, whether a causal relationships exists remains unclear. Morever, we suggest performing randomized controlled trails to explore whether periodontal interventions are beneficial in regulating COPD pathogenesis and progression. PMID- 23094026 TI - Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by gamma-secretase inhibitor IX. AB - Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the gamma secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells. PMID- 23094027 TI - Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. AB - BACKGROUND: Cell viability and motility comprise ubiquitous mechanisms involved in a variety of (patho)biological processes including cancer. We report a technical comparative analysis of the novel impedance-based xCELLigence Real-Time Cell Analysis detection platform, with conventional label-based endpoint methods, hereby indicating performance characteristics and correlating dynamic observations of cell proliferation, cytotoxicity, migration and invasion on cancer cells in highly standardized experimental conditions. METHODOLOGY/PRINCIPAL FINDINGS: Dynamic high-resolution assessments of proliferation, cytotoxicity and migration were performed using xCELLigence technology on the MDA-MB-231 (breast cancer) and A549 (lung cancer) cell lines. Proliferation kinetics were compared with the Sulforhodamine B (SRB) assay in a series of four cell concentrations, yielding fair to good correlations (Spearman's Rho 0.688 to 0.964). Cytotoxic action by paclitaxel (0-100 nM) correlated well with SRB (Rho>0.95) with similar IC(50) values. Reference cell migration experiments were performed using Transwell plates and correlated by pixel area calculation of crystal violet-stained membranes (Rho 0.90) and optical density (OD) measurement of extracted dye (Rho>0.95). Invasion was observed on MDA-MB-231 cells alone using Matrigel-coated Transwells as standard reference method and correlated by OD reading for two Matrigel densities (Rho>0.95). Variance component analysis revealed increased variances associated with impedance-based detection of migration and invasion, potentially caused by the sensitive nature of this method. CONCLUSIONS/SIGNIFICANCE: The xCELLigence RTCA technology provides an accurate platform for non-invasive detection of cell viability and motility. The strong correlations with conventional methods imply a similar observation of cell behavior and interchangeability with other systems, illustrated by the highly correlating kinetic invasion profiles on different platforms applying only adapted matrix surface densities. The increased sensitivity however implies standardized experimental conditions to minimize technical-induced variance. PMID- 23094028 TI - Genetic association analysis of complex diseases incorporating intermediate phenotype information. AB - Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA) studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24-25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs--rs1800469, rs1982072, and rs2241714--in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46*10(-5), 1.18*10(-5), and 6.57*10(-6), respectively). The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex disease association analysis and the modified meta-analysis method is robust to incorporate intermediate phenotype or other quantitative risk factor in the analysis. PMID- 23094029 TI - Colonoscopic findings in Peruvian patients with chronic diarrhea. AB - OBJECTIVE: To report the colonoscopic and pathological findings in patients with chronic diarrhea from a gastroenterology unit during approximately 3 years in a general teaching hospital located in Lima-Peru. MATERIALS AND METHODS: Patients with chronic diarrhea as the motive for colonoscopy from March 2008 to December 2010 were selected from the colonoscopy report computerized database. Colonoscopic findings were registered. Biopsies taken during the procedure were prospectively reviewed. RESULTS: 226 patients were included, of which 162 (71.7%) had a colon biopsy available. The average age of the patients was 53.6+/-16.36. 85.8% of patients were reported to have a normal colon. 14.8% of patients were found to have a normal colonic mucosa or mucosal edema, 35.8% of patients had lymphocytic colitis and 28.4% had paucicelular colitis. CONCLUSIONS: The majority of colonoscopies were reported with unremarkable macroscopic findings. Lymphocytic colitis was unusually frequent compared to previous reports. PMID- 23094030 TI - Protein-protein interaction analysis highlights additional loci of interest for multiple sclerosis. AB - Genetic factors play an important role in determining the risk of multiple sclerosis (MS). The strongest genetic association in MS is located within the major histocompatibility complex class II region (MHC), but more than 50 MS loci of modest effect located outside the MHC have now been identified. However, the relative candidate genes that underlie these associations and their functions are largely unknown. We conducted a protein-protein interaction (PPI) analysis of gene products coded in loci recently reported to be MS associated at the genome wide significance level and in loci suggestive of MS association. Our aim was to identify which suggestive regions are more likely to be truly associated, which genes are mostly implicated in the PPI network and their expression profile. From three recent independent association studies, SNPs were considered and divided into significant and suggestive depending on the strength of the statistical association. Using the Disease Association Protein-Protein Link Evaluator tool we found that direct interactions among genetic products were significantly higher than expected by chance when considering both significant regions alone (p<0.0002) and significant plus suggestive (p<0.007). The number of genes involved in the network was 43. Of these, 23 were located within suggestive regions and many of them directly interacted with proteins coded within significant regions. These included genes such as SYK, IL-6, CSF2RB, FCLR3, EIF4EBP2 and CHST12. Using the gene portal BioGPS, we tested the expression of these genes in 24 different tissues and found the highest values among immune related cells as compared to non-immune tissues (p<0.001). A gene ontology analysis confirmed the immune-related functions of these genes. In conclusion, loci currently suggestive of MS association interact with and have similar expression profiles and function as those significantly associated, highlighting the fact that more common variants remain to be found to be associated to MS. PMID- 23094031 TI - In-car nocturnal blue light exposure improves motorway driving: a randomized controlled trial. AB - Prolonged wakefulness greatly decreases nocturnal driving performance. The development of in-car countermeasures is a future challenge to prevent sleep related accidents. The aim of this study is to determine whether continuous exposure to monochromatic light in the short wavelengths (blue light), placed on the dashboard, improves night-time driving performance. In this randomized, double-blind, placebo-controlled, cross-over study, 48 healthy male participants (aged 20-50 years) drove 400 km (250 miles) on motorway during night-time. They randomly and consecutively received either continuous blue light exposure (GOLite, Philips, 468 nm) during driving or 2*200 mg of caffeine or placebo of caffeine before and during the break. Treatments were separated by at least 1 week. The outcomes were number of inappropriate line crossings (ILC) and mean standard deviation of the lateral position (SDLP). Eight participants (17%) complained about dazzle during blue light exposure and were removed from the analysis. Results from the 40 remaining participants (mean age +/- SD: 32.9+/ 11.1) showed that countermeasures reduced the number of inappropriate line crossings (ILC) (F(2,91.11) = 6.64; p<0.05). Indeed, ILC were lower with coffee (12.51 [95% CI, 5.86 to 19.66], p = 0.001) and blue light (14.58 [CI, 8.75 to 22.58], p = 0.003) than with placebo (26.42 [CI, 19.90 to 33.71]). Similar results were found for SDLP. Treatments did not modify the quality, quantity and timing of 3 subsequent nocturnal sleep episodes. Despite a lesser tolerance, a non-inferior efficacy of continuous nocturnal blue light exposure compared with caffeine suggests that this in-car countermeasure, used occasionally, could be used to fight nocturnal sleepiness at the wheel in blue light-tolerant drivers, whatever their age. More studies are needed to determine the reproducibility of data and to verify if it can be generalized to women. TRIAL REGISTRATION: ClinicalTrials.gov NCT01070004. PMID- 23094032 TI - Obesity-susceptibility loci and their influence on adiposity-related traits in transition from adolescence to adulthood--the HUNT study. AB - INTRODUCTION: Obesity-susceptibility loci have been related to adiposity traits in adults and may affect body fat estimates in adolescence. There are indications that different sets of obesity-susceptibility loci influence level of and change in obesity-related traits from adolescence to adulthood. OBJECTIVES: To investigate whether previously reported obesity-susceptible loci in adults influence adiposity traits in adolescence and change in BMI and waist circumference (WC) from adolescence into young adulthood. We also examined whether physical activity modifies the effects of these genetic loci on adiposity related traits. METHODS: Nine obesity-susceptibility variants were genotyped in 1 643 adolescents (13-19 years old) from the HUNT study, Norway, who were followed up into young adulthood. Lifestyle was assessed using questionnaires and anthropometric measurements were taken. The effects of genetic variants individually and combined in a genetic predisposition score (GPS) on obesity related traits were studied cross-sectionally and longitudinally. A modifying effect of physical activity was tested. RESULTS: The GPS was significantly associated to BMI (B: 0.046 SD/allele [0.020, 0.073], p = 0.001) in adolescence and in young adulthood (B: 0.041 SD/allele [0.015, 0.067], p = 0.002) as it was to waist circumference (WC). The GPS was not associated to change in BMI (p = 0.762) or WC (p = 0.726). We found no significant interaction effect between the GPS and physical activity. CONCLUSIONS: Our observations suggest that obesity susceptibility loci established in adults affect BMI and WC already in adolescence. However, an association with change in adiposity-related traits from adolescence to adulthood could not be verified for these loci. Neither could an attenuating effect of physical activity on the association between the obesity susceptibility genes and body fat estimates be revealed. PMID- 23094033 TI - Early initiation of smoking and alcohol drinking as a predictor of lower forearm bone mineral density in late adolescence: a cohort study in girls. AB - BACKGROUND: Adolescence is a critical stage for bone accrual. It is also decisive for the establishment of behaviors such as smoking and alcohol drinking. OBJECTIVE: To quantify the short- and long-term associations between smoking and drinking initiation and bone mineral density in adolescent girls. METHODS: We used prospective data from 731 girls identified in public and private schools in Porto, Portugal. Evaluations were conducted when participants were 13 and 17 years old. Bone mineral density (BMD) was measured at the forearm by dual-energy X-ray absorptiometry and weight, height and fat-free mass were measured. Pubertal development status was estimated using menarche age. Self-administered questionnaires were used to collect data on smoking and alcohol drinking, physical exercise and calcium and vitamin D intakes. BMD in early and late adolescence was analyzed as a continuous or dichotomous (Z-score cutoff: -1.0) variable. Associations were calculated using linear or logistic regression. RESULTS: Over one quarter of these girls had tried smoking by 13, while 59% had drunk alcoholic beverages and 20% had experienced both behaviors by that age. Lower mean BMD at 17 years of age was observed in girls who had ever smoked by 13, as well as in those who reported drinking at that age. There were no significant cross-sectional associations between experience and frequency of smoking or drinking and BMD at 13 years of age. However, we observed significant associations between BMD z-score<-1 in late adolescence and having ever smoked by 13, after adjustment for menarche age and sports practice, (OR = 1.92; 95% CI: 1.21, 3.05) and with ever smoking and drinking in the same period (OR = 2.33; 95% CI: 1.36, 4.00). CONCLUSION: Our study adds prospective evidence to the role of early initiation of smoking and alcohol drinking as relevant markers of lower bone mineral density in late adolescence. PMID- 23094034 TI - A booklet on participants' rights to improve consent for clinical research: a randomized trial. AB - OBJECTIVE: Information on the rights of subjects in clinical trials has become increasingly complex and difficult to understand. This study evaluates whether a simple booklet which is relevant to all research studies improves the understanding of rights needed for subjects to provide informed consent. METHODS: 21 currently used informed consent forms (ICF) from international clinical trials were separated into information related to the specific research study, and general information on participants' rights. A booklet designed to provide information on participants' rights which used simple language was developed to replace this information in current ICF's Readability of each component of ICF's and the booklet was then assessed using the Flesch-Kincaid Reading ease score (FK). To further evaluate the booklet 282 hospital inpatients were randomised to one of three ways to present research information; a standard ICF, the booklet combined with a short ICF, or the booklet combined with a simplified ICF. Comprehension of information related to the research proposal and to participant's rights was assessed by questionnaire. RESULTS: Information related to participants' rights contributed an average of 44% of the words in standard ICFs, and was harder to read than information describing the clinical trial (FK 25 versus (vs.) 41 respectively, p = 0.0003). The booklet reduced the number of words and improved FK from 25 to 42. The simplified ICF had a slightly higher FK score than the standard ICF (50 vs. 42). Comprehension assessed in inpatients was better for the booklet and short ICF 62%, (95% confidence interval (CI) 56 to 67) correct, or simplified ICF 62% (CI 58 to 68) correct compared to 52%, (CI 47 to 57) correct for the standard ICF, p = 0.009. This was due to better understanding of questions on rights (62% vs. 49% correct, p = 0.0008). Comprehension of study related information was similar for the simplified and standard ICF (60% vs. 64% correct, p = 0.68). CONCLUSIONS: A booklet provides a simple consistent approach to providing information on participant rights which is relevant to all research studies, and improves comprehension of patients who typically participate in clinical trials. PMID- 23094035 TI - Isolation of osteoprogenitors from human jaw periosteal cells: a comparison of two magnetic separation methods. AB - Human jaw periosteum tissue contains osteoprogenitors that have potential for tissue engineering applications in oral and maxillofacial surgeries. To isolate osteoprogenitor cells from heterogeneous cell populations, we used the specific mesenchymal stem cell antigen-1 (MSCA-1) antibody and compared two magnetic separation methods. We analyzed the obtained MSCA-1(+) and MSCA-1(-) fractions in terms of purity, yield of positive/negative cells and proliferative and mineralization potentials. The analysis of cell viability after separation revealed that the EasySep method yielded higher viability rates, whereas the flow cytometry results showed a higher purity for the MACS-separated cell fractions. The mineralization capacity of the osteogenic induced MSCA-1(+) cells compared with the MSCA-1(-) controls using MACS was 5-fold higher, whereas the same comparison after EasySep showed no significant differences between both fractions. By analyzing cell proliferation, we detected a significant difference between the proliferative potential of the osteogenic cells versus untreated cells after the MACS and EasySep separations. The differentiated cells after MACS separation adjusted their proliferative capacity, whereas the EasySep-separated cells failed to do so. The protein expression analysis showed small differences between the two separation methods. Our findings suggest that MACS is a more suitable separation method to isolate osteoprogenitors from the entire jaw periosteal cell population. PMID- 23094037 TI - Factors influencing collaborative activities between non-professional disaster volunteers and victims of earthquake disasters. AB - BACKGROUND: Assistance from non-professional disaster volunteers (hereinafter, volunteers) is essential for disaster victims to recover physically and rebuild their lives; however, disaster victims in some areas are reluctant to accept assistance from volunteers. This study explored factors that may influence collaborative activities between volunteers and victims of earthquake disasters. METHODS: From July to September 2008, a self-reporting questionnaire survey was conducted with all 302 leaders of neighborhood associations in a city within Niigata Prefecture at the time of the Niigataken Chuetsu-oki Earthquake in 2007. Each factor was determined based on the Health Belief Model. Multiple regression analysis was conducted, using collaborative activities as the objective variable. RESULTS: From 261 valid responses received (response rate 86.4%), 41.3% of leaders collaborated with volunteers, and 60.2% of associations had residents who collaborated with volunteers. Collaboration with volunteers was significantly and positively related to perceived severity of an earthquake disaster (standardized partial regression coefficient beta = 0.224, p<0.001) and neighborhood association activities during the earthquake disaster (beta = 0.539, p<0.001). A positive and marginally significant relation was found between such collaboration and sense of coherence within a community (beta = 0.137, p = 0.06), social capital (beta = 0.119, p = 0.08), and perceived benefits (beta = 0.116, p = 0.09). CONCLUSION: Collaboration between disaster victims and volunteers during the response to an earthquake may require the preemptive estimation of damage by residents during normal times and the enhancement of neighborhood association activities during a disaster. For residents to have such estimation abilities, public institutions should provide information related to anticipated disaster damage and appropriate disaster prevention training and education. In addition, residents should create a disaster prevention map with other residents. Lastly, promoting neighborhood association activities may require the participation of many residents in disaster drills and education as well as a preemptive discussion of neighborhood activities during a disaster. PMID- 23094038 TI - The outcome of the oxidations of unusual enediamide motifs is governed by the stabilities of the intermediate iminium ions. AB - We compare the results from the oxidation of two unusual "enediamide" motifs (3,4 dihydropyrazin-2(1H)-ones), where a double bond is flanked by two amides. In one case the oxidation led to a ring-opened product arising from the cleavage of the double bond, and in the other a rare cis-dioxygenated compound was obtained. Both products have been characterized by X-ray crystallography. The outcomes of the key reactions are rationalized based on calculated free energies of intermediates. PMID- 23094036 TI - Cognition in males and females with autism: similarities and differences. AB - The male bias in autism spectrum conditions (ASC) has led to females with ASC being under-researched. This lack of attention to females could hide variability due to sex that may explain some of the heterogeneity within ASC. In this study we investigate four key cognitive domains (mentalizing and emotion perception, executive function, perceptual attention to detail, and motor function) in ASC, to test for similarities and differences between males and females with and without ASC (n = 128 adults; n = 32 per group). In the mentalizing and facial emotion perception domain, males and females with ASC showed similar deficits compared to neurotypical controls. However, in attention to detail and dexterity involving executive function, although males with ASC showed poorer performance relative to neurotypical males, females with ASC performed comparably to neurotypical females. We conclude that performance in the social-cognitive domain is equally impaired in male and female adults with ASC. However, in specific non social cognitive domains, performance within ASC depends on sex. This suggests that in specific domains, cognitive profiles in ASC are modulated by sex. PMID- 23094039 TI - Improved eIF4E binding peptides by phage display guided design: plasticity of interacting surfaces yield collective effects. AB - Eukaryotic initiation factor (eIF)4E is over-expressed in many types of cancer such as breast, head and neck, and lung. A consequence of increased levels of eIF4E is the preferential translation of pro-tumorigenic proteins (e.g. c-Myc and vascular endothelial growth factor) and as a result is regarded as a potential therapeutic target. In this work a novel phage display peptide has been isolated against eIF4E. From the phage sequence two amino acids were delineated which improved binding when substituted into the eIF4G1 sequence. Neither of these substitutions were involved in direct interactions with eIF4E and acted either via optimization of the helical capping motif or restricting the conformational flexibility of the peptide. In contrast, substitutions of the remaining phage derived amino acids into the eIF4G1 sequence disrupted binding of the peptide to eIF4E. Interestingly when some of these disruptive substitutions were combined with key mutations from the phage peptide, they lead to improved affinities. Atomistic computer simulations revealed that the phage and the eIF4G1 derivative peptide sequences differ subtly in their interaction sites on eIF4E. This raises the issue, especially in the context of planar interaction sites such as those exhibited by eIF4E, that given the intricate plasticity of protein surfaces, the construction of structure-activity relationships should account for the possibility of significant movement in the spatial positioning of the peptide binding interface, including significant librational motions of the peptide. PMID- 23094040 TI - Parapapillary atrophy: histological gamma zone and delta zone. AB - BACKGROUND: To examine histomorphometrically the parapapillary region in human eyes. METHODOLOGY/PRINCIPAL FINDINGS: The histomorphometric study included 65 human globes (axial length:21-37 mm). On anterior-posterior histological sections, we measured the distance Bruch's membrane end (BME)-optic nerve margin ("Gamma zone"), BME-retinal pigment epithelium (RPE) ("Beta zone"), BME-beginning of non-occluded choriocapillaris, and BME-beginning of photoreceptor layer. "Delta zone" was defined as part of gamma zone in which blood vessels of at least 50 um diameter were not present over a length of >300 um. Beta zone (mean length:0.35+/-0.52 mm) was significantly (P = 0.01) larger in the glaucoma group than in the non-glaucomatous group. It was not significantly (P = 0.28) associated with axial length. Beta zone was significantly (P = 0.004) larger than the region with occluded choriocapillaris. Gamma zone (mean length:0.63+/-1.25 mm) was associated with axial length (P<0.001;r(2) = 0.73) with an increase starting at an axial length of 26.5 mm. It was not significantly (P = 0.24) associated with glaucomatous optic neuropathy. Delta zone (present only in eyes with axial length of >=27 mm) was associated with axial length (P = 0.001) and scleral flange length (P<0.001) but not with glaucoma (P = 0.73). CONCLUSIONS/SIGNIFICANCE: Parapapillary gamma zone (peripapillary sclera without overlying choroid, Bruch's membrane and deep retinal layers) was related with axial globe elongation and was independent of glaucoma. Delta zone (no blood vessels >50 um diameter within gamma zone) was present only in highly axially elongated globes and was not related with glaucoma. Beta zone (Bruch's membrane without RPE) was correlated with glaucoma but not with globe elongation. Since the region with occluded choriocapillaris was smaller than beta zone, complete loss of RPE may have occurred before complete choriocapillaris closure. PMID- 23094041 TI - Altered hypothalamic protein expression in a rat model of Huntington's disease. AB - Huntington's disease (HD) is a neurodegenerative disorder, which is characterized by progressive motor impairment and cognitive alterations. Changes in energy metabolism, neuroendocrine function, body weight, euglycemia, appetite function, and circadian rhythm can also occur. It is likely that the locus of these alterations is the hypothalamus. We used the HD transgenic (tg) rat model bearing 51 CAG repeats, which exhibits similar HD symptomology as HD patients to investigate hypothalamic function. We conducted detailed hypothalamic proteome analyses and also measured circulating levels of various metabolic hormones and lipids in pre-symptomatic and symptomatic animals. Our results demonstrate that there are significant alterations in HD rat hypothalamic protein expression such as glial fibrillary acidic protein (GFAP), heat shock protein-70, the oxidative damage protein glutathione peroxidase (Gpx4), glycogen synthase1 (Gys1) and the lipid synthesis enzyme acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1). In addition, there are significant alterations in various circulating metabolic hormones and lipids in pre-symptomatic animals including, insulin, leptin, triglycerides and HDL, before any motor or cognitive alterations are apparent. These early metabolic and lipid alterations are likely prodromal signs of hypothalamic dysfunction. Gaining a greater understanding of the hypothalamic and metabolic alterations that occur in HD, could lead to the development of novel therapeutics for early interventional treatment of HD. PMID- 23094042 TI - Reinforcement learning of targeted movement in a spiking neuronal model of motor cortex. AB - Sensorimotor control has traditionally been considered from a control theory perspective, without relation to neurobiology. In contrast, here we utilized a spiking-neuron model of motor cortex and trained it to perform a simple movement task, which consisted of rotating a single-joint "forearm" to a target. Learning was based on a reinforcement mechanism analogous to that of the dopamine system. This provided a global reward or punishment signal in response to decreasing or increasing distance from hand to target, respectively. Output was partially driven by Poisson motor babbling, creating stochastic movements that could then be shaped by learning. The virtual forearm consisted of a single segment rotated around an elbow joint, controlled by flexor and extensor muscles. The model consisted of 144 excitatory and 64 inhibitory event-based neurons, each with AMPA, NMDA, and GABA synapses. Proprioceptive cell input to this model encoded the 2 muscle lengths. Plasticity was only enabled in feedforward connections between input and output excitatory units, using spike-timing-dependent eligibility traces for synaptic credit or blame assignment. Learning resulted from a global 3-valued signal: reward (+1), no learning (0), or punishment (-1), corresponding to phasic increases, lack of change, or phasic decreases of dopaminergic cell firing, respectively. Successful learning only occurred when both reward and punishment were enabled. In this case, 5 target angles were learned successfully within 180 s of simulation time, with a median error of 8 degrees. Motor babbling allowed exploratory learning, but decreased the stability of the learned behavior, since the hand continued moving after reaching the target. Our model demonstrated that a global reinforcement signal, coupled with eligibility traces for synaptic plasticity, can train a spiking sensorimotor network to perform goal-directed motor behavior. PMID- 23094044 TI - A network analysis of countries' export flows: firm grounds for the building blocks of the economy. AB - In this paper we analyze the bipartite network of countries and products from UN data on country production. We define the country-country and product-product projected networks and introduce a novel method of filtering information based on elements' similarity. As a result we find that country clustering reveals unexpected socio-geographic links among the most competing countries. On the same footings the products clustering can be efficiently used for a bottom-up classification of produced goods. Furthermore we mathematically reformulate the "reflections method" introduced by Hidalgo and Hausmann as a fixpoint problem; such formulation highlights some conceptual weaknesses of the approach. To overcome such an issue, we introduce an alternative methodology (based on biased Markov chains) that allows to rank countries in a conceptually consistent way. Our analysis uncovers a strong non-linear interaction between the diversification of a country and the ubiquity of its products, thus suggesting the possible need of moving towards more efficient and direct non-linear fixpoint algorithms to rank countries and products in the global market. PMID- 23094043 TI - Proliferative regeneration of zebrafish lateral line hair cells after different ototoxic insults. AB - Sensory hair cells in the zebrafish lateral line regenerate rapidly and completely after damage. Previous studies have used a variety of ototoxins to kill lateral line hair cells to study different phenomena including mechanisms of hair cell death and regeneration. We sought to directly compare these ototoxins to determine if they differentially affected the rate and amount of hair cell replacement. In addition, previous studies have found evidence of proliferative hair cell regeneration in zebrafish, but both proliferation and non-mitotic direct transdifferentiation have been observed during hair cell regeneration in the sensory epithelia of birds and amphibians. We sought to test whether a similar combination of regenerative mechanisms exist in the fish. We analyzed the time course of regeneration after treatment with different ototoxic compounds and also labeled dividing hair cell progenitors. Certain treatments, including cisplatin and higher concentrations of dissolved copper, significantly delayed regeneration by one or more days. However, cisplatin did not block all regeneration as observed previously in the chick basilar papilla. The particular ototoxin did not appear to affect the mechanism of regeneration, as we observed evidence of recent proliferation in the majority of new hair cells in all cases. Inhibiting proliferation with flubendazole blocked the production of new hair cells and prevented the accumulation of additional precursors, indicating that proliferation has a dominant role during regeneration of lateral line hair cells. PMID- 23094045 TI - Hospital recorded morbidity and breast cancer incidence: a nationwide population based case-control study. AB - INTRODUCTION: Chronic diseases and their complications may increase breast cancer risk through known or still unknown mechanisms, or by shared causes. The association between morbidities and breast cancer risk has not been studied in depth. METHODS: Data on all Danish women aged 45 to 85 years, diagnosed with breast cancer between 1994 and 2008 and data on preceding morbidities were retrieved from nationwide medical registries. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using conditional logistic regression associating the Charlson comorbidity score (measured using both the original and an updated Charlson Comorbidity Index (CCI)) with incident breast cancer. Furthermore, we estimated associations between 202 morbidity categories and incident breast cancer, adjusting for multiple comparisons using empirical Bayes (EB) methods. RESULTS: The study included 46,324 cases and 463,240 population controls. Increasing CCI score, up to a score of six, was associated with slightly increased breast cancer risk. Among the Charlson diseases, preceding moderate to severe renal disease (OR = 1.25, 95% CI: 1.06, 1.48), any tumor (OR = 1.17, 95% CI: 1.10, 1.25), moderate to severe liver disease (OR = 1.86, 95% CI: 1.32, 2.62), and metastatic solid tumors (OR = 1.49, 95% CI: 1.17, 1.89), were most strongly associated with subsequent breast cancer. Preceding myocardial infarction (OR = 0.89, 95% CI: 0.81, 0.99), connective tissue disease (OR = 0.87, 95% CI: 0.80, 0.94), and ulcer disease (OR = 0.91, 95% CI: 0.83, 0.99) were most strongly inversely associated with subsequent breast cancer. A history of breast disorders was associated with breast cancer after EB adjustment. Anemias were inversely associated with breast cancer, but the association was near null after EB adjustment. CONCLUSIONS: There was no substantial association between morbidity measured with the CCI and breast cancer risk. PMID- 23094046 TI - Hybrid molecular mechanics/coarse-grained simulations for structural prediction of G-protein coupled receptor/ligand complexes. AB - Understanding how ligands bind to G-protein coupled receptors (GPCRs) provides insights into a myriad of cell processes and is crucial for drug development. Here we extend a hybrid molecular mechanics/coarse-grained (MM/CG) approach applied previously to enzymes to GPCR/ligand complexes. The accuracy of this method for structural predictions is established by comparison with recent atomistic molecular dynamics simulations on the human beta2 adrenergic receptor, a member of the GPCRs superfamily. The results obtained with the MM/CG methodology show a good agreement with previous all-atom classical dynamics simulations, in particular in the structural description of the ligand binding site. This approach could be used for high-throughput predictions of ligand poses in a variety of GPCRs. PMID- 23094047 TI - Chemical alarm cues are conserved within the coral reef fish family Pomacentridae. AB - Fishes are known to use chemical alarm cues from both conspecifics and heterospecifics to assess local predation risks and enhance predator detection. Yet it is unknown how recognition of heterospecific cues arises for coral reef fishes. Here, we test if naive juvenile fish have an innate recognition of heterospecific alarm cues. We also examine if there is a relationship between the intensity of the antipredator response to these cues and the degree to which species are related to each other. Naive juvenile anemone fish, Amphiprion percula, were tested to see if they displayed antipredator responses to chemical alarm cues from four closely related heterospecific species (family Pomacentridae), a distantly related sympatric species (Asterropteryx semipunctatus) and a saltwater (control). Juveniles displayed significant reductions in foraging rate when exposed to all four confamilial heterospecific species but they did not respond to the distantly related sympatric species or the saltwater control. There was also a strong relationship between the intensity of the antipredator response and the extent to which species were related, with responses weakening as species became more distantly related. These findings demonstrate that chemical alarm cues are conserved within the pomacentrid family, providing juveniles with an innate recognition of heterospecific alarm cues as predicted by the phylogenetic relatedness hypothesis. PMID- 23094048 TI - Genome analysis of Legionella pneumophila strains using a mixed-genome microarray. AB - BACKGROUND: Legionella, the causative agent for Legionnaires' disease, is ubiquitous in both natural and man-made aquatic environments. The distribution of Legionella genotypes within clinical strains is significantly different from that found in environmental strains. Developing novel genotypic methods that offer the ability to distinguish clinical from environmental strains could help to focus on more relevant (virulent) Legionella species in control efforts. Mixed-genome microarray data can be used to perform a comparative-genome analysis of strain collections, and advanced statistical approaches, such as the Random Forest algorithm are available to process these data. METHODS: Microarray analysis was performed on a collection of 222 Legionella pneumophila strains, which included patient-derived strains from notified cases in The Netherlands in the period 2002 2006 and the environmental strains that were collected during the source investigation for those patients within the Dutch National Legionella Outbreak Detection Programme. The Random Forest algorithm combined with a logistic regression model was used to select predictive markers and to construct a predictive model that could discriminate between strains from different origin: clinical or environmental. RESULTS: Four genetic markers were selected that correctly predicted 96% of the clinical strains and 66% of the environmental strains collected within the Dutch National Legionella Outbreak Detection Programme. CONCLUSIONS: The Random Forest algorithm is well suited for the development of prediction models that use mixed-genome microarray data to discriminate between Legionella strains from different origin. The identification of these predictive genetic markers could offer the possibility to identify virulence factors within the Legionella genome, which in the future may be implemented in the daily practice of controlling Legionella in the public health environment. PMID- 23094049 TI - Sustained beta-cell dysfunction but normalized islet mass in aged thrombospondin 1 deficient mice. AB - Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10-12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10-12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10-12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ~15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life. PMID- 23094050 TI - APE1/Ref-1 regulates STAT3 transcriptional activity and APE1/Ref-1-STAT3 dual targeting effectively inhibits pancreatic cancer cell survival. AB - Pancreatic cancer is a largely incurable disease, and increasing evidence supports strategies targeting multiple molecular mediators of critical functions of pancreatic ductal adenocarcinoma cells. Intracellular redox state modulates the activity of various signal transduction pathways and biological processes, including cell survival, drug resistance and responsiveness to microenvironmental factors. Recently, it has been shown that the transcription factor STAT3 is under redox control, but the mechanisms involved in its regulation are unknown. Here, we demonstrate for the first time that STAT3 DNA binding and transcriptional activity is directly regulated by the redox function of the APE1/Ref-1 endonuclease, using overexpression and redox-specific mutational strategies, and gene knockdown. Also, pharmacological blockade of APE1/Ref-1 by the redox selective inhibitor E3330 abrogates STAT3 DNA binding. Since APE1/Ref-1 also exerts redox control on other cancer-associated transcription factors, we assessed the impact of dual-targeting of STAT3 signaling and APE1/Ref-1 redox on pancreatic cancer cell functions. We observed that disruption of APE1/Ref-1 redox activity synergizes with STAT3 blockade to potently inhibit the proliferation and viability of human PDAC cells. Mechanistically, we show that STAT3-APE1/Ref-1 dual targeting promotes marked tumor cell apoptosis, with engagement of caspase-3 signaling, which are significantly increased in comparison to the effects triggered by single target blockade. Also, we show that STAT3-APE1/Ref-1 dual blockade results in significant inhibition of tumor cell migration. Overall, this work demonstrates that the transcriptional activity of STAT3 is directly regulated by the redox function of APE1/Ref-1, and that concurrent blockade of STAT3 and APE1/Ref-1 redox synergize effectively inhibit critical PDAC cell functions. PMID- 23094051 TI - Characterization of ectonucleotidases in human medulloblastoma cell lines: ecto 5'NT/CD73 in metastasis as potential prognostic factor. AB - Medulloblastoma (MB) is the most common malignant brain tumor in children and occurs mainly in the cerebellum. Important intracellular signaling molecules, such those present in the Sonic Hedgehog and Wnt pathways, are involved in its development and can also be employed to determine tumor grade and prognosis. Ectonucleotidases, particularly ecto-5'NT/CD73, are important enzymes in the malignant process of different tumor types regulating extracellular ATP and adenosine levels. Here, we investigated the activity of ectonucleotidases in three malignant human cell lines: Daoy and ONS76, being representative of primary MB, and the D283 cell line, derived from a metastatic MB. All cell lines secreted ATP into the extracellular medium while hydrolyze poorly this nucleotide, which is in agreement with the low expression and activity of pyrophosphate/phosphodiesterase, NTPDases and alkaline phosphatase. The analysis of AMP hydrolysis showed that Daoy and ONS76 completely hydrolyzed AMP, with parallel adenosine production (Daoy) and inosine accumulation (ONS76). On the other hand, D283 cell line did not hydrolyze AMP. Moreover, primary MB tumor cells, Daoy and ONS76 express the ecto-5'NT/CD73 while D283 representative of a metastatic tumor, revealed poor expression of this enzyme, while the ecto adenosine deaminase showed higher expression in D283 compared to Daoy and ONS76 cells. Nuclear beta-catenin has been suggested as a marker for MB prognosis. Further it can promotes expression of ecto-5'NT/CD73 and suppression of adenosine deaminase. It was observed that Daoy and ONS76 showed greater nuclear beta catenin immunoreactivity than D283, which presented mainly cytoplasmic immunoreactivity. In summary, the absence of ecto-5'NT/CD73 in the D283 cell line, a metastatic MB phenotype, suggests that high expression levels of this ectonucleotidase could be correlated with a poor prognosis in patients with MB. PMID- 23094052 TI - A multi-analyte assay for the non-invasive detection of bladder cancer. AB - Accurate urinary assays for bladder cancer (BCa) detection would benefit both patients and healthcare systems. Through genomic and proteomic profiling of urine components, we have previously identified a panel of biomarkers that can outperform current urine-based biomarkers for the non-invasive detection of BCa. Herein, we report the diagnostic utility of various multivariate combinations of these biomarkers. We performed a case-controlled validation study in which voided urines from 127 patients (64 tumor bearing subjects) were analyzed. The urinary concentrations of 14 biomarkers (IL-8, MMP-9, MMP-10, SDC1, CCL18, PAI-1, CD44, VEGF, ANG, CA9, A1AT, OPN, PTX3, and APOE) were assessed by enzyme-linked immunosorbent assay (ELISA). Diagnostic performance of each biomarker and multivariate models were compared using receiver operating characteristic curves and the chi-square test. An 8-biomarker model achieved the most accurate BCa diagnosis (sensitivity 92%, specificity 97%), but a combination of 3 of the 8 biomarkers (IL-8, VEGF, and APOE) was also highly accurate (sensitivity 90%, specificity 97%). For comparison, the commercial BTA-Trak ELISA test achieved a sensitivity of 79% and a specificity of 83%, and voided urine cytology detected only 33% of BCa cases in the same cohort. These data show that a multivariate urine-based assay can markedly improve the accuracy of non-invasive BCa detection. Further validation studies are under way to investigate the clinical utility of this panel of biomarkers for BCa diagnosis and disease monitoring. PMID- 23094053 TI - Association between proton magnetic resonance spectroscopy measurements and CAG repeat number in patients with spinocerebellar ataxias 2, 3, or 6. AB - The aim of this study was to correlate magnetic resonance spectroscopy (MRS) measurements, including that for the N-acetyl aspartate (NAA)/creatine (Cr) ratio in the vermis (denoted V-NAA), right cerebellar hemisphere (R-NAA), and left (L NAA) cerebellar hemisphere, with the clinical scale for the assessment and rating of ataxia (SARA) score for patients with spinocerebellar ataxia (SCA) types 2, 3, and 6. A total of 24 patients with SCA2, 48 with SCA3, and 16 with SCA6 were recruited; 12 patients with SCA2, 43 with SCA3, and 8 with SCA6 underwent detailed magnetic resonance neuroimaging. Forty-four healthy, age-matched individuals without history of neurologic disease served as control subjects. V NAA and patient age were used to calculate the predicted age at which a patient with SCA2 or SCA3 would reach an onset V-NAA value. Results showed the following: the NAA/Cr ratio decreased with increasing age in patients with SCA but not in control subjects; the SARA score increased progressively with age and duration of illness; V-NAA showed a better correlation with SARA score than R-NAA in patients with SCA2 or SCA3; the ratio of age to V-NAA correlated well with CAG repeat number; the retrospectively predicted age of onset for SCA2 and SCA3 was consistent with patient-reported age of onset; R-NAA showed a better correlation with SARA score than V-NAA in patients with SCA6; V-NAA and R-NAA correlated with clinical severity (SARA score) in patients with SCA. The correlation between CAG repeat number and age could be expressed as a simple linear function, which might explain previous observations claiming that the greater the CAG repeat number, the earlier the onset of illness and the faster the disease progression. These findings support the use of MRS values to predict age of disease onset and to retrospectively evaluate the actual age of disease onset in SCA. PMID- 23094054 TI - Exosomal lipids impact notch signaling and induce death of human pancreatic tumoral SOJ-6 cells. AB - Exosomes are of increasing interest as alternative mode of cell-to-cell communication. We previously reported that exosomes secreted by human SOJ-6 pancreatic tumor cells induce (glyco)protein ligand-independent cell death and inhibit Notch-1 pathway, this latter being particularly active during carcinogenesis and in cancer stem cells. Therefore, we asked whether exosomal lipids were key-elements for cell death and hypothesized that cholesterol-rich membrane microdomains were privileged sites of exosome interactions with tumor cells. To address these questions and based on the lipid composition of exosomes from SOJ-6 cells (Ristorcelli et al. (2008) FASEB J. 22; 3358-3369) enriched in cholesterol and sphingomyelin (lipids forming liquid-ordered phase, Lo) and depleted in phospholipids (lipids forming liquid-disordered phase, Ld), we designed Synthetic Exosome-Like Nanoparticles (SELN) with ratios Lo/Ld from 3.0 to 6.0 framing that of SOJ-6 cell exosomes. SELN decreased tumor cell survival, the higher the Lo/Ld ratio, the lower the cell survival. This decreased survival was due to activation of cell death with inhibition of Notch pathway. FRET analyses indicated fusions/exchanges of SELN with cell membranes. Fluorescent SELN co-localized with the ganglioside GM1 then with Rab5A, markers of lipid microdomains and of early endosomes, respectively. These interactions occurred at lipid microdomains of plasma and/or endosome membranes where the Notch-1 pathway matures. We thus demonstrated a major role for lipids in interactions between SELN and tumor cells, and in the ensued cell death. To our knowledge this is the first report on such effects of lipidic nanoparticles on tumor cell behavior. This may have implications in tumor progression. PMID- 23094055 TI - VS411 reduced immune activation and HIV-1 RNA levels in 28 days: randomized proof of-concept study for antiviral-hyperactivation limiting therapeutics. AB - BACKGROUND: A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4(+) T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. METHODS: Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naive HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. RESULTS: VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4(+) T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: -1.47 log(10) copies/mL; CD4(+) T cell count: +135 cells/mm(3)) and fewest adverse events. CONCLUSIONS: VS411 successfully established the Proof-of-Concept that AV HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. TRIAL REGISTRATION: ITEudraCT 2007-002460-98. PMID- 23094056 TI - Adequacy of maternal iron status protects against behavioral, neuroanatomical, and growth deficits in fetal alcohol spectrum disorders. AB - Fetal alcohol spectrum disorders (FASD) are the leading non-genetic cause of neurodevelopmental disability in children. Although alcohol is clearly teratogenic, environmental factors such as gravidity and socioeconomic status significantly modify individual FASD risk despite equivalent alcohol intake. An explanation for this variability could inform FASD prevention. Here we show that the most common nutritional deficiency of pregnancy, iron deficiency without anemia (ID), is a potent and synergistic modifier of FASD risk. Using an established rat model of third trimester-equivalent binge drinking, we show that ID significantly interacts with alcohol to impair postnatal somatic growth, associative learning, and white matter formation, as compared with either insult separately. For the associative learning and myelination deficits, the ID-alcohol interaction was synergistic and the deficits persisted even after the offsprings' iron status had normalized. Importantly, the observed deficits in the ID-alcohol animals comprise key diagnostic criteria of FASD. Other neurobehaviors were normal, showing the ID-alcohol interaction was selective and did not reflect a generalized malnutrition. Importantly ID worsened FASD outcome even though the mothers lacked overt anemia; thus diagnostics that emphasize hematological markers will not identify pregnancies at-risk. This is the first direct demonstration that, as suggested by clinical studies, maternal iron status has a unique influence upon FASD outcome. While alcohol is unquestionably teratogenic, this ID-alcohol interaction likely represents a significant portion of FASD diagnoses because ID is more common in alcohol-abusing pregnancies than generally appreciated. Iron status may also underlie the associations between FASD and parity or socioeconomic status. We propose that increased attention to normalizing maternal iron status will substantially improve FASD outcome, even if maternal alcohol abuse continues. These findings offer novel insights into how alcohol damages the developing brain. PMID- 23094057 TI - Differences in soil fungal communities between European beech (Fagus sylvatica L.) dominated forests are related to soil and understory vegetation. AB - Fungi are important members of soil microbial communities with a crucial role in biogeochemical processes. Although soil fungi are known to be highly diverse, little is known about factors influencing variations in their diversity and community structure among forests dominated by the same tree species but spread over different regions and under different managements. We analyzed the soil fungal diversity and community composition of managed and unmanaged European beech dominated forests located in three German regions, the Schwabische Alb in Southwestern, the Hainich-Dun in Central and the Schorfheide Chorin in the Northeastern Germany, using internal transcribed spacer (ITS) rDNA pyrotag sequencing. Multiple sequence quality filtering followed by sequence data normalization revealed 1655 fungal operational taxonomic units. Further analysis based on 722 abundant fungal OTUs revealed the phylum Basidiomycota to be dominant (54%) and its community to comprise 71.4% of ectomycorrhizal taxa. Fungal community structure differed significantly (p<=0.001) among the three regions and was characterized by non-random fungal OTUs co-occurrence. Soil parameters, herbaceous understory vegetation, and litter cover affected fungal community structure. However, within each study region we found no difference in fungal community structure between management types. Our results also showed region specific significant correlation patterns between the dominant ectomycorrhizal fungal genera. This suggests that soil fungal communities are region-specific but nevertheless composed of functionally diverse and complementary taxa. PMID- 23094058 TI - Quercetin inhibits angiogenesis mediated human prostate tumor growth by targeting VEGFR- 2 regulated AKT/mTOR/P70S6K signaling pathways. AB - Angiogenesis is a crucial step in the growth and metastasis of cancers, since it enables the growing tumor to receive oxygen and nutrients. Cancer prevention using natural products has become an integral part of cancer control. We studied the antiangiogenic activity of quercetin using ex vivo, in vivo and in vitro models. Rat aortic ring assay showed that quercetin at non-toxic concentrations significantly inhibited microvessel sprouting and exhibited a significant inhibition in the proliferation, migration, invasion and tube formation of endothelial cells, which are key events in the process of angiogenesis. Most importantly, quercetin treatment inhibited ex vivo angiogenesis as revealed by chicken egg chorioallantoic membrane assay (CAM) and matrigel plug assay. Western blot analysis showed that quercetin suppressed VEGF induced phosphorylation of VEGF receptor 2 and their downstream protein kinases AKT, mTOR, and ribosomal protein S6 kinase in HUVECs. Quercetin (20 mg/kg/d) significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model, indicating that quercetin inhibited tumorigenesis by targeting angiogenesis. Furthermore, quercetin reduced the cell viability and induced apoptosis in prostate cancer cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Collectively the findings in the present study suggest that quercetin inhibits tumor growth and angiogenesis by targeting VEGF-R2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy. PMID- 23094059 TI - Causes of death on antiretroviral therapy: a post-mortem study from South Africa. AB - BACKGROUND: Mortality in the first months of antiretroviral therapy (ART) is a significant clinical problem in sub-Saharan Africa. To date, no post-mortem study has investigated the causes of mortality in these patients. METHODS: HIV-positive adults who died as in-patients at a Johannesburg academic hospital underwent chart-review and ultrasound-guided needle autopsy for histological and microbiological examination of lung, liver, spleen, kidney, bone marrow, lymph node, skin and cerebrospinal fluid. A clinico-pathologic committee considered all available data and adjudicated immediate and contributing causes of death. RESULTS: Thirty-nine adults were enrolled: 14 pre-ART, 15 early-ART (7-90 days), and 10 late-ART (>90 days). Needle sampling yielded adequate specimen in 100% of kidney, skin, heart and cerebrospinal fluid samples, 97% of livers and lungs, 92% of bone marrows, 87% of spleens and 68% of lymph nodes. Mycobacterial infections were implicated in 69% of deaths (26 of 27 of these due to M. tuberculosis), bacterial infections in 33%, fungal infections in 21%, neoplasm in 26%, and non infectious organ failure in 26%. Immune reconstitution inflammatory syndrome (IRIS) was implicated in 73% of early-ART deaths. Post-mortem investigations revealed previously undiagnosed causes of death in 49% of cases. Multiple pathologies were common with 62% of subjects with mycobacterial infection also having at least one other infectious or neoplastic cause of death. CONCLUSIONS: Needle biopsy was efficient and yielded excellent pathology. The large majority of deaths in all three groups were caused by M. tuberculosis suggesting an urgent need for improved diagnosis and expedited treatment prior to and throughout the course of antiretroviral therapy. Complex, unrecognized co-morbidities pose an additional challenge. PMID- 23094060 TI - Serum neutralizing activities from a Beijing homosexual male cohort infected with different subtypes of HIV-1 in China. AB - Protective antibodies play a critical role in an effective HIV vaccine; however, eliciting antibodies to block infection by viruses from diverse genetic subtypes remains a major challenge. As the world's most populous country, China has been under the threat of at least three major subtypes of circulating HIV-1 viruses. Understanding the cross reactivity and specificities of serum antibody responses that mediate broad neutralization of the virus in HIV-1 infected Chinese patients will provide valuable information for the design of vaccines to prevent HIV-1 transmission in China. Sera from a cohort of homosexual men, who have been managed by a major HIV clinical center in Beijing, China, were analyzed for cross sectional neutralizing activities against pseudotyped viruses expressing Env antigens of the major subtype viruses (AE, BC and B subtypes) circulating in China. Neutralizing activities in infected patients' blood were most capable of neutralizing viruses in the homologous subtype; however, a subset of blood samples was able to achieve broad neutralizing activities across different subtypes. Such cross neutralizing activity took 1-2 years to develop and CD4 binding site antibodies were critical components in these blood samples. Our study confirmed the presence of broadly neutralizing sera in China's HIV-1 patient population. Understanding the specificity and breadth of these neutralizing activities can guide efforts for the development of HIV vaccines against major HIV-1 viruses in China. PMID- 23094061 TI - Extracellular glutathione decreases the ability of Burkholderia cenocepacia to penetrate into epithelial cells and to induce an inflammatory response. AB - BACKGROUND: The airway surface liquid (ASL) of Cystic Fibrosis (CF) patients contains a lower concentration of reduced glutathione (GSH) with respect to healthy people. It is not known whether this defect may favor lung colonization by opportunistic pathogens. PRINCIPAL FINDINGS: We have analyzed the effects of extracellular GSH on the ability of Burkholderia cenocepacia to penetrate and multiply in epithelial respiratory cells. Extracellular GSH proved to be able to drastically reduce the pathogen ability to adhere and invade airway epithelial cells. This effect is correlated to a GSH-dependent increase in the number of free thiols on the surface of epithelial cells, suggestive of a change in the oxidoreductive status of membrane proteins involved in B. cenocepacia recognition. Moreover, treatments with GSH led to a consistent reduction of the expression of IL-8, TNF-alpha and IL-1beta in response to B. cenocepacia infection. CONCLUSIONS AND SIGNIFICANCE: Extracellular GSH modulates the interaction between B. cenocepacia and epithelial respiratory cells and inhibits the bacterial invasion into these cells. This suggests that therapies aimed at restoring normal levels of GSH in the ASL might be beneficial to control CF lung infections. PMID- 23094062 TI - Adapting to a changing world: unraveling the role of man-made habitats as alternative feeding areas for slender-billed gull (Chroicocephalus genei). AB - Current rates of wildlife habitat loss have placed increasing demands on managers to develop, validate and implement tools aimed at improving our ability to evaluate such impacts on wildlife. Here, we present a case study conducted at the Natural Area of Donana (SW Spain) where remote sensing and stable isotope (delta(13)C, delta(15)N) analyses of individuals were combined to unravel (1) the effect of variations in availability of natural food resources (i.e. from natural marshes) on reproductive performance of a Slender-billed Gull (Chroicocephalus genei) population, and (2) the role of two adjacent, artificial systems (a fish farm and saltmines) as alternate anthropogenic feeding areas. Based on long-term (1983-2004) remote-sensing, we inferred the average extent of flooded area at the marshland (a proxy to natural resource availability) annually. Estimated flooded areas (ranging from extreme drought [ca. 151 ha, 1995] to high moisture [15,049 ha, 2004]) were positively related to reproductive success of gulls (estimated for the 1993-2004 period, and ranging from ca. 0 to 1.7 fledglings per breeding pairs), suggesting that habitat availability played a role in determining their reproductive performance. Based on blood delta(13)C and delta(15)N values of fledglings, 2001-2004, and a Bayesian isotopic mixing model, we conclude that saltmines acted as the main alternative foraging habitat for gulls, with relative contributions increasing as the extent of marshland decreased. Although adjacent, anthropogenic systems have been established as the preferred breeding sites for this gull population, dietary switches towards exploitation of alternative (anthropogenic) food resources negatively affected the reproductive output of this species, thus challenging the perception that these man-made systems are necessarily a reliable buffer against loss of natural feeding habitats. The methodology and results derived from this study could be extended to a large suite of threatened natural communities worldwide, thus providing a useful framework for management and conservation. PMID- 23094063 TI - Knowledge, attitudes, practices and emotional reactions among residents of avian influenza (H5N1) hit communities in Vietnam. AB - BACKGROUND: Awareness of individuals' knowledge and predicting their behavior and emotional reactions is crucial when evaluating clinical preparedness for influenza pandemics with a highly pathogenic virus. Knowledge, attitude, and practice (KAP) relating to avian influenza (H5N1) virus infection among residents in communities where H5N1 patients occurred in Vietnam has not been reported. METHODS AND PRINCIPAL FINDINGS: Face-to-face interviews including KAP survey were conducted in Bac Kan province, located in the northeast mountainous region of Vietnam. Participants were residents who lived in a community where H5N1 cases have ever been reported (event group, n = 322) or one where cases have not been reported (non-event group, n = 221). Data on emotional reactions of participants and healthcare-seeking behavior after the event in neighboring areas were collected as well as information on demographics and environmental measures, information sources, and KAP regarding H5N1. These data were compared between two groups. Higher environmental risk of H5N1 and improper poultry-handling behaviors were identified in the event group. At the time of the event, over 50% of the event group sought healthcare for flu-like symptoms or because they were scared. Awareness of the event influenced KAP scores. Healthcare-seeking behavior and attention to H5N1 poultry outbreaks diminished in the event group as time passed after the outbreak compared with the non-event group. Factors that motivated participants to seek healthcare sooner were knowledge of early access to healthcare and the risk of eating sick/dead poultry, and perception of the threat of H5N1. CONCLUSIONS: Awareness of H5N1 patients in neighboring areas can provoke panic in residents and influence their healthcare-seeking behavior. Periodic education to share experiences on the occurrence of H5N1 patients and provide accurate information may help prevent panic and infection and reduce mortality. Local conditions should be taken into account when emphasizing the need for early access to healthcare. PMID- 23094064 TI - Positive and negative relationship between anxiety and depression of patients in pain: a bifactor model analysis. AB - BACKGROUND: The relationship between anxiety and depression in pain patients has not been clarified comprehensively. Previous research has identified a common factor in anxiety and depression, which may explain why depression and anxiety are strongly correlated. However, the specific clinical features of anxiety and depression seem to pull in opposite directions. OBJECTIVE: The purpose of this study is to develop a statistical model of depression and anxiety, based on data from pain patients using Hospital Anxiety and Depression Scale (HADS). This model should account for the positive correlation between depression and anxiety in terms of a general factor and also demonstrate a latent negative correlation between the specific factors underlying depression and anxiety. METHODS: The anxiety and depression symptoms of pain patients were evaluated using the HADS and the severity of their pain was assessed with the visual analogue scale (VAS). We developed a hierarchical model of the data using an IRT method called bifactor analysis. In addition, we tested this hierarchical model with model fit comparisons with unidimensional, bidimensional, and tridimensional models. The correlations among anxiety, depression, and pain severity were compared, based on both the bidimensional model and our hierarchical model. RESULTS: The bidimensional model analysis found that there was a large positive correlation between anxiety and depression (r = 0.638), and both scores were significantly positively correlated with pain severity. After extracting general factor of distress using bifactor analysis, the specific factors underlying anxiety and depression were weakly but significantly negatively correlated (r = -0.245) and only the general factor was significantly correlated with pain severity. Compared with the three first-order models, the bifactor hierarchical model had the best model fit. CONCLUSION: Our results support the hypothesis that apart from distress, anxiety and depression are inversely correlated. This finding has not been convincingly demonstrated in previous research. PMID- 23094065 TI - Evidence of late-summer mating readiness and early sexual maturation in migratory tree-roosting bats found dead at wind turbines. AB - Understanding animal mating systems is an important component of their conservation, yet the precise mating times for many species of bats are unknown. The aim of this study was to better understand the details and timing of reproductive events in species of bats that die most frequently at wind turbines in North America, because such information can help inform conservation strategies. We examined the reproductive anatomy of hoary bats (Lasiurus cinereus), eastern red bats (L. borealis), and silver-haired bats (Lasionycteris noctivagans) found dead beneath industrial-scale wind turbines to learn more about when they mate. We evaluated 103 L. cinereus, 18 L. borealis, and 47 Ln. noctivagans from wind energy facilities in the United States and Canada. Histological analysis revealed that most male L. cinereus and L. borealis, as well as over half the Ln. noctivagans examined had sperm in the caudae epididymides by late August, indicating readiness to mate. Testes regression in male hoary bats coincided with enlargement of seminal vesicles and apparent growth of keratinized spines on the glans penis. Seasonality of these processes also suggests that mating could occur during August in L. cinereus. Spermatozoa were found in the uterus of an adult female hoary bat collected in September, but not in any other females. Ovaries of all females sampled had growing secondary or tertiary follicles, indicating sexual maturity even in first-year females. Lasiurus cinereus, L. borealis, and Ln. noctivagans are the only North American temperate bats in which most first-year young of both sexes are known to sexually mature in their first autumn. Our findings provide the first detailed information published on the seasonal timing of mating readiness in these species most affected by wind turbines. PMID- 23094066 TI - The structural dynamics of the flavivirus fusion peptide-membrane interaction. AB - Membrane fusion is a crucial step in flavivirus infections and a potential target for antiviral strategies. Lipids and proteins play cooperative roles in the fusion process, which is triggered by the acidic pH inside the endosome. This acidic environment induces many changes in glycoprotein conformation and allows the action of a highly conserved hydrophobic sequence, the fusion peptide (FP). Despite the large volume of information available on the virus-triggered fusion process, little is known regarding the mechanisms behind flavivirus-cell membrane fusion. Here, we evaluated the contribution of a natural single amino acid difference on two flavivirus FPs, FLA(G) ((98)DRGWGNGCGLFGK(110)) and FLA(H) ((98)DRGWGNHCGLFGK(110)), and investigated the role of the charge of the target membrane on the fusion process. We used an in silico approach to simulate the interaction of the FPs with a lipid bilayer in a complementary way and used spectroscopic approaches to collect conformation information. We found that both peptides interact with neutral and anionic micelles, and molecular dynamics (MD) simulations showed the interaction of the FPs with the lipid bilayer. The participation of the indole ring of Trp appeared to be important for the anchoring of both peptides in the membrane model, as indicated by MD simulations and spectroscopic analyses. Mild differences between FLA(G) and FLA(H) were observed according to the pH and the charge of the target membrane model. The MD simulations of the membrane showed that both peptides adopted a bend structure, and an interaction between the aromatic residues was strongly suggested, which was also observed by circular dichroism in the presence of micelles. As the FPs of viral fusion proteins play a key role in the mechanism of viral fusion, understanding the interactions between peptides and membranes is crucial for medical science and biology and may contribute to the design of new antiviral drugs. PMID- 23094067 TI - Hyperglycaemia exacerbates choroidal neovascularisation in mice via the oxidative stress-induced activation of STAT3 signalling in RPE cells. AB - Choroidal neovascularisation (CNV) that occurs as a result of age-related macular degeneration (AMD) causes severe vision loss among elderly patients. The relationship between diabetes and CNV remains controversial. However, oxidative stress plays a critical role in the pathogenesis of both AMD and diabetes. In the present study, we investigated the influence of diabetes on experimentally induced CNV and on the underlying molecular mechanisms of CNV. CNV was induced via photocoagulation in the ocular fundi of mice with streptozotocin-induced diabetes. The effect of diabetes on the severity of CNV was measured. An immunofluorescence technique was used to determine the levels of oxidative DNA damage by anti-8-hydroxy-2-deoxyguanosine (8-OHdG) antibody, the protein expression of phosphorylated signal transducer and activator of transcription 3 (p-STAT3) and vascular endothelial growth factor (VEGF), in mice with CNV. The production of reactive oxygen species (ROS) in retinal pigment epithelial (RPE) cells that had been cultured under high glucose was quantitated using the 2',7' dichlorofluorescein diacetate (DCFH-DA) method. p-STAT3 expression was examined using Western blot analysis. RT-PCR and ELISA processes were used to detect VEGF expression. Hyperglycaemia exacerbated the development of CNV in mice. Oxidative stress levels and the expression of p-STAT3 and VEGF were highly elevated both in mice and in cultured RPE cells. Treatment with the antioxidant compound N-acetyl cysteine (NAC) rescued the severity of CNV in diabetic mice. NAC also inhibited the overexpression of p-STAT3 and VEGF in CNV and in RPE cells. The JAK-2/STAT3 pathway inhibitor AG490 blocked VEGF expression but had no effect on the production of ROS in vitro. These results suggest that hyperglycaemia promotes the development of CNV by inducing oxidative stress, which in turn activates STAT3 signalling in RPE cells. Antioxidant supplementation helped attenuate the development of CNV. Thus, our results reveal a potential strategy for the treatment and prevention of diseases involving CNV. PMID- 23094068 TI - Characterization of Culex pipiens complex (Diptera: Culicidae) populations in Colorado, USA using microsatellites. AB - Mosquitoes such as those in the Culex pipiens complex are important vectors of disease. This study was conducted to genetically characterize Cx. pipiens complex populations in the state of Colorado, USA, and to determine the number of genetic clusters represented by the data. Thirteen populations located among four major river basins were sampled (n = 597 individuals) using a panel of 14 microsatellites. The lowest-elevation sites had the highest Expected Heterozygosity (H(E)) values (range 0.54-0.65). AMOVA results indicated the presence of statistically significant amounts of variation within each level when populations were analyzed as one group or when they were grouped either by river basin or by their position on the east or west side of the Rocky Mountains. Most pairwise F(ST) values were significant via permutation test (range 0-0.10), with the highest values from comparisons with Lamar, in southeast CO. A neighbor joining tree based on Cavalli-Sforza and Edwards's chord distances was consistent with the geographic locations of populations, as well as with the AMOVA results. There was a significant isolation by distance effect, and the cluster analysis resolved five groups. Individuals were also assayed with an additional microsatellite marker, Cxpq78, proposed to be monomorphic in Cx. pipiens but polymorphic in the closely related but biologically distinct species Cx. quinquefasciatus. Low frequencies (<=3%) of Cx. quinquefasciatus alleles for this marker were noted, and mostly confined to populations along the Interstate 25 corridor. Pueblo was distinct in that it had 10% Cx. quinquefasciatus alleles, mostly of one allele size. The degree of population genetic structure observed in this study is in contrast with that of Cx. tarsalis, the other major vector of WNV in the western U.S., and likely reflects the two species' different dispersal strategies. PMID- 23094069 TI - Criterion and concurrent validity of the activPALTM professional physical activity monitor in adolescent females. AB - BACKGROUND: The activPAL has been identified as an accurate and reliable measure of sedentary behaviour. However, only limited information is available on the accuracy of the activPAL activity count function as a measure of physical activity, while no unit calibration of the activPAL has been completed to date. This study aimed to investigate the criterion validity of the activPAL, examine the concurrent validity of the activPAL, and perform and validate a value calibration of the activPAL in an adolescent female population. The performance of the activPAL in estimating posture was also compared with sedentary thresholds used with the ActiGraph accelerometer. METHODOLOGIES: Thirty adolescent females (15 developmental; 15 cross-validation) aged 15-18 years performed 5 activities while wearing the activPAL, ActiGraph GT3X, and the Cosmed K4B2. A random coefficient statistics model examined the relationship between metabolic equivalent (MET) values and activPAL counts. Receiver operating characteristic analysis was used to determine activity thresholds and for cross-validation. The random coefficient statistics model showed a concordance correlation coefficient of 0.93 (standard error of the estimate = 1.13). An optimal moderate threshold of 2997 was determined using mixed regression, while an optimal vigorous threshold of 8229 was determined using receiver operating statistics. The activPAL count function demonstrated very high concurrent validity (r = 0.96, p<0.01) with the ActiGraph count function. Levels of agreement for sitting, standing, and stepping between direct observation and the activPAL and ActiGraph were 100%, 98.1%, 99.2% and 100%, 0%, 100%, respectively. CONCLUSIONS: These findings suggest that the activPAL is a valid, objective measurement tool that can be used for both the measurement of physical activity and sedentary behaviours in an adolescent female population. PMID- 23094070 TI - Amino acid uptake in arbuscular mycorrhizal plants. AB - We examined the extent to which arbuscular mycorrhizal (AM) fungi root improved the acquisition of simple organic nitrogen (ON) compounds by their host plants. In a greenhouse-based study, we used quantum dots (fluorescent nanoparticles) to assess uptake of each of the 20 proteinaceous amino acids by AM-colonized versus uncolonized plants. We found that AM colonization increased uptake of phenylalanine, lysine, asparagine, arginine, histidine, methionine, tryptophan, and cysteine; and reduced uptake of aspartic acid. Arbuscular mycorrhizal colonization had the greatest effect on uptake of amino acids that are relatively rare in proteins. In addition, AM fungi facilitated uptake of neutral and positively-charged amino acids more than negatively-charged amino acids. Overall, the AM fungi used in this study appeared to improve access by plants to a number of amino acids, but not necessarily those that are common or negatively-charged. PMID- 23094071 TI - Mating behaviour and vibratory signalling in non-hearing cave crickets reflect primitive communication of Ensifera. AB - In Ensifera, the lack of well-supported phylogeny and the focus on acoustic communication of the terminal taxa hinders understanding of the evolutionary history of their signalling behaviour and the related sensory structures. For Rhaphidophoridae, the most relic of ensiferans following morphology-based phylogenies, the signalling modes are still unknown. Together with a detailed description of their mating process, we provide evidence on vibratory signalling for the sympatric European species Troglophilus neglectus and T. cavicola. Despite their temporal shift in reproduction, the species' behaviours differ significantly. Signalling by abdominal vibration constitutes an obligatory part of courtship in T. neglectus, while it is absent in T. cavicola. Whole-body vibration is expressed after copulation in both species. While courtship signalling appears to stimulate females for mating, the function of post copulation signals remains unclear. Mating and signalling of both species were found to take place in most cases on bark, and less frequently on other available substrates, like moss and rock. The signals' frequency spectra were substrate dependent, but with the dominant peak always expressed below 120 Hz. On rock, the intensity of T. neglectus courtship signals was below the species' physiological detection range, presumably constraining the evolution of such signalling in caves. The species' behavioural divergence appears to reflect their divergent mating habitats, in and outside caves. We propose that short-range tremulation signalling in courtship, such as is expressed by T. neglectus, represents the primitive mode and context of mechanical signalling in Ensifera. The absence of high-frequency components in the signals may be related to the absence of the crista acoustica homologue (CAH) in the vibratory tibial organ of Rhaphidophoridae. This indirectly supports the hypothesis proposing that the CAH, as an evolutionary precursor of the ear, evolved in Ensifera along the (more) complex vibratory communication, also associated with signals of higher carrier frequency. PMID- 23094072 TI - Association of common genetic variants in the MAP4K4 locus with prediabetic traits in humans. AB - Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) is expressed in all diabetes-relevant tissues and mediates cytokine-induced insulin resistance. We investigated whether common single nucleotide polymorphisms (SNPs) in the MAP4K4 locus associate with glucose intolerance, insulin resistance, impaired insulin release, or elevated plasma cytokines. The best hit was tested for association with type 2 diabetes. Subjects (N = 1,769) were recruited from the Tubingen Family (TUF) study for type 2 diabetes and genotyped for tagging SNPs. In a subgroup, cytokines were measured. Association with type 2 diabetes was tested in a prospective case-cohort study (N = 2,971) derived from the EPIC Potsdam study. Three SNPs (rs6543087, rs17801985, rs1003376) revealed nominal and two SNPs (rs11674694, rs11678405) significant associations with 2-hour glucose levels. SNPs rs6543087 and rs11674694 were also nominally associated with decreased insulin sensitivity. Another two SNPs (rs2236936, rs2236935) showed associations with reduced insulin release, driven by effects in lean subjects only. Three SNPs (rs11674694, rs13003883, rs2236936) revealed nominal associations with IL-6 levels. SNP rs11674694 was significantly associated with type 2 diabetes. In conclusion, common variation in MAP4K4 is associated with insulin resistance and beta-cell dysfunction, possibly via this gene's role in inflammatory signalling. This variation's impact on insulin sensitivity may be more important since its effect on insulin release vanishes with increasing BMI. PMID- 23094073 TI - WNT10A plays an oncogenic role in renal cell carcinoma by activating WNT/beta catenin pathway. AB - Renal cell carcinoma (RCC) is a malignancy with poor prognosis. WNT/beta-catenin signaling dysregulation, especially beta-catenin overactivation and WNT antagonist silencing, is associated with RCC carcinogenesis and progression. However, the role of WNT ligands in RCC has not yet been determined. We screened 19 WNT ligands from normal kidney and RCC cell lines and tissues and found that WNT10A was significantly increased in RCC cell lines and tissues as compared to that in normal controls. The clinical significance of increase in WNT10A was evaluated by performing an immunohistochemical association study in a 19-year follow-up cohort comprising 284 RCC and 267 benign renal disease (BRD) patients. The results of this study showed that WNT10A was dramatically upregulated in RCC tissues as compared to that in BRD tissues. This result suggests that WNT10A, nuclear beta-catenin, and nuclear cyclin D1 act as independent risk factors for RCC carcinogenesis and progression, with accumulative risk effects. Molecular validation of cell line models with gain- or loss-of-function designs showed that forced WNT10A expression induced RCC cell proliferation and aggressiveness, including higher chemoresistance, cell migration, invasiveness, and cell transformation, due to the activation of beta-catenin-dependent signaling. Conversely, WNT10A siRNA knockdown decreased cell proliferation and aggressiveness of RCC cells. In conclusion, we showed that WNT10A acts as an autocrine oncogene both in RCC carcinogenesis and progression by activating WNT/beta-catenin signaling. PMID- 23094075 TI - Long-term effects of irrigation with waste water on soil AM fungi diversity and microbial activities: the implications for agro-ecosystem resilience. AB - The effects of irrigation with treated urban wastewater (WW) on the arbuscular mycorrhizal fungi (AMF) diversity and soil microbial activities were assayed on a long-term basis in a semiarid orange-tree orchard. After 43 years, the soil irrigated with fresh water (FW) had higher AMF diversity than soils irrigated with WW. Microbial activities were significantly higher in the soils irrigated with WW than in those irrigated with FW. Therefore, as no negative effects were observed on crop vitality and productivity, it seems that the ecosystem resilience gave rise to the selection of AMF species better able to thrive in soils with higher microbial activity and, thus, to higher soil fertility. PMID- 23094076 TI - Sex-biased dispersal of a frog (Odorrana schmackeri) is affected by patch isolation and resource limitation in a fragmented landscape. AB - Sex-biased dispersal is widespread in the animal kingdom and is affected by numerous factors including mating system, social factors and environmental conditions. Unlike birds and mammals, there is no common trend in amphibians and explaining the direction and degree of sex-biased dispersal in species-specific cases is difficult. We conducted a study on dispersal of the Chinese piebald odorous frog (Odorrana schmackeri) in a fragmented landscape associated with dam construction. Ten microsatellite loci were used to analyze 382 samples sourced from 14 fragmented 'islands'. Assignment tests indicated a significant pattern of female-biased dispersal on one island with inconsistencies in the strength and direction of this pattern between nearby islands. The effects of four island attributes and two potential impact factors on the pattern of sex-biased dispersal were examined. We found that the extent of isolation from the mainland and the number of breeding sites both showed a negative correlation with female biased dispersal, such that the closer an island is to the mainland the more likely it is to display female biased dispersal, and the more breeding sites on an island the more male immigrants. Based on these results, we conclude that geographic isolation and limited breeding resources are the most likely explanation for the patterns of dispersal observed in this fragmented population of amphibians. PMID- 23094074 TI - Association of the IL-10 gene family locus on chromosome 1 with juvenile idiopathic arthritis (JIA). AB - BACKGROUND: The cytokine IL-10 and its family members have been implicated in autoimmune diseases and we have previously reported that genetic variants in IL 10 were associated with a rare group of diseases called juvenile idiopathic arthritis (JIA). The aim of this study was to fine map genetic variants within the IL-10 cytokine family cluster on chromosome 1 using linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (tSNPs) approach with imputation and conditional analysis to test for disease associations. METHODOLOGY/PRINCIPAL FINDINGS: Fifty-three tSNPs were tested for association between Caucasian paediatric cohorts [219 systemic JIA (sJIA), 187 persistent oligoarticular JIA (pOJIA), and 139 extended OJIA (eOJIA) patients], and controls (Wellcome Trust control cohort, WTCCC2). Significant association with sJIA was detected at rs1400986 in the promoter of IL-20 (odds ratio 1.53; 95% CI 1.21-1.93; p = 0.0004), but in no other subtypes. Imputation analysis identified additional associated SNPs for pOJIA at IL-20 and IL-24, including a rare, functional, missense variant at IL-24 with a p = 0.0002. Penalised logistic regression analysis with HyperLasso and conditional analysis identified several further associations with JIA subtypes. In particular, haplotype analysis refined the sJIA association, with a joint effect at rs1400986 and rs4129024 in intron 1 of MAPKAPK2 (p = 3.2E-5). For pOJIA, a 3-SNP haplotype including rs1878672 in intron 3 of IL-10 showed evidence for association (p = 0.0018). In eOJIA, rs10863962 (3'UTR of FCAMR) and rs12409577 (intron of IL-19) haplotype showed some evidence of association (p = 0.0003). CONCLUSIONS: This study supports previous association of IL-20 with sJIA. Haplotype analyses provided stronger association signals than single point analyses, while a penalised logistic regression approach also suggested multiple independent association signals. Replication studies are required to confirm or refute these findings. The results indicate that combined effects with unknown/rare variants remain to be characterised in JIA, and represent a possible example of synthetic association in this region. PMID- 23094077 TI - The roles of gene duplication, gene conversion and positive selection in rodent Esp and Mup pheromone gene families with comparison to the Abp family. AB - Three proteinaceous pheromone families, the androgen-binding proteins (ABPs), the exocrine-gland secreting peptides (ESPs) and the major urinary proteins (MUPs) are encoded by large gene families in the genomes of Mus musculus and Rattus norvegicus. We studied the evolutionary histories of the Mup and Esp genes and compared them with what is known about the Abp genes. Apparently gene conversion has played little if any role in the expansion of the mouse Class A and Class B Mup genes and pseudogenes, and the rat Mups. By contrast, we found evidence of extensive gene conversion in many Esp genes although not in all of them. Our studies of selection identified at least two amino acid sites in beta-sheets as having evolved under positive selection in the mouse Class A and Class B MUPs and in rat MUPs. We show that selection may have acted on the ESPs by determining K(a)/K(s) for Exon 3 sequences with and without the converted sequence segment. While it appears that purifying selection acted on the ESP signal peptides, the secreted portions of the ESPs probably have undergone much more rapid evolution. When the inner gene converted fragment sequences were removed, eleven Esp paralogs were present in two or more pairs with K(a)/K(s) >1.0 and thus we propose that positive selection is detectable by this means in at least some mouse Esp paralogs. We compare and contrast the evolutionary histories of all three mouse pheromone gene families in light of their proposed functions in mouse communication. PMID- 23094078 TI - Repositioning antimicrobial agent pentamidine as a disruptor of the lateral interactions of transmembrane domain 5 of EBV latent membrane protein 1. AB - The lateral transmembrane protein-protein interactions (PPI) have been regarded as "undruggable" despite their importance in many essential biological processes. The homo-trimerization of transmembrane domain 5 (TMD-5) of latent membrane protein 1 (LMP-1) is critical for the constitutive oncogenic activation of the Epstein-Barr virus (EBV). Herein we repurpose the antimicrobial agent pentamidine as a regulator of LMP-1 TMD-5 lateral interactions. The results of ToxR assay, tryptophan fluorescence assay, courmarin fluorescence dequenching assay, and Bis Tris sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) consistently show pentamidine disrupts LMP-1 TMD-5 lateral interactions. Furthermore, pentamidine inhibits LMP-1 signaling, inducing cellular apoptosis and suppressing cell proliferation in the EBV infected B cells. In contrast, EBV negative cells are less susceptible to pentamidine. This study provides a novel non-peptide small molecule agent for regulating LMP-1 TMD-5 lateral interactions. PMID- 23094079 TI - Mechanisms of peptide-induced pore formation in lipid bilayers investigated by oriented 31P solid-state NMR spectroscopy. AB - There is a considerable interest in understanding the function of antimicrobial peptides (AMPs), but the details of their mode of action is not fully understood. This motivates extensive efforts in determining structural and mechanistic parameters for AMP's interaction with lipid membranes. In this study we show that oriented-sample (31)P solid-state NMR spectroscopy can be used to probe the membrane perturbations and disruption by AMPs. For two AMPs, alamethicin and novicidin, we observe that the majority of the lipids remain in a planar bilayer conformation but that a number of lipids are involved in the peptide anchoring. These lipids display reduced dynamics. Our study supports previous studies showing that alamethicin adopts a transmembrane arrangement without significant disturbance of the surrounding lipids, while novicidin forms toroidal pores at high concentrations leading to more extensive membrane disturbance. PMID- 23094080 TI - Evaluation of the prevalence of urinary tract infection in rural Panamanian women. AB - OBJECTIVE: Urinary tract infection (UTI) is the most common non-intestinal infection worldwide. In the developed world, incidence and prevalence of UTI would be similar owing to the relatively short duration of illness experienced by women with ready access to healthcare services. We hypothesize that, in the developing world, factors limiting access to care and those which may increase the likelihood of developing UTI, result in increased morbidity. This difference is reflected in an increased prevalence of UTI in regions where women suffer the effects of UTI for extended periods of time. METHODS: This study represents a cross sectional analysis of UTI prevalence in rural western Panama conducted over the course of a 3-day medical mission. All women 18-45 years of age reporting to the medical brigade clinic were tested for UTI by dipstick urinalysis and a brief history regardless of whether they themselves were presenting with a complaint. RESULTS: UTI was diagnosed clinically by providers in 29.8% of the women tested although only 21.15% of these same women met the evidence-based study criteria. This prevalence of 21.15% is seven times greater than reported by the Panamanian Ministry of Health. When comparing the effectiveness of clinical diagnosis relative to urinalysis by dipstick, a Kappa coefficient revealed only low moderate agreement (0.42; SE 0.0955). CONCLUSIONS: The prevalence of UTI in rural western Panama is greater than would be expected based on prevalence data from either the US or Panamanian Ministry of Health and may represent an opportunity for targeted interventions, including educational programming about UTI prevention. PMID- 23094081 TI - The carboxyl-terminus of human immunodeficiency virus type 2 circulating recombinant form 01_AB capsid protein affects sensitivity to human TRIM5alpha. AB - Human immunodeficiency virus (HIV) type 2 shows limited geographical distribution compared with HIV type 1. Although 8 genetic groups of HIV type 2 (HIV-2) have been described, recombinant viruses between these groups are rarely observed. Recently, three HIV-2 patients in Japan were described with rapidly progressive, acquired immunodeficiency. These patients were infected with an A/B inter-group recombinant designated CRF01_AB. Here, we characterize the capsid protein (CA) encoded by the viruses from these patients. HIV-2 CRF01_AB CA showed unique amino acid sequence almost equally distinct from group A and group B viruses. Notably, HIV-2 CRF01_AB CA showed potent resistance to human TRIM5alpha. In addition to the previously identified amino acid position 119 in the N-terminal domain of CA, we found that HIV-2 CRF01_AB-specific amino acid substitutions in the C-terminal domain also were necessary for resistance to human TRIM5alpha. These results indicate that retroviruses can evade TRIM5alpha by substitution at residues within the C-terminal domain of CA. PMID- 23094082 TI - Variation of intragenic tandem repeat tract of tolA modulates Escherichia coli stress tolerance. AB - In recent work we discovered that the intragenic tandem repeat (TR) region of the tolA gene is highly variable among different Escherichia coli strains. The aim of this study was therefore to investigate the biological function and dynamics of TR variation in E. coli tolA. The biological impact of TR variation was examined by comparing the ability of a set of synthetic tolA variants with in frame repeat copies varying from 2 to 39 to rescue the altered susceptibility of an E. coli DeltatolA mutant to deoxycholic acid, sodium dodecyl sulfate, hyperosmolarity, and infection with filamentous bacteriophage. Interestingly, although each of the TolA variants was able to at least partly rescue the DeltatolA mutant, the extent was clearly dependent on both the repeat number and the type of stress imposed, indicating the existence of opposing selective forces with regard to the optimal TR copy number. Subsequently, TR dynamics in a clonal population were assayed, and we could demonstrate that TR contractions are RecA dependent and enhanced in a DNA repair deficient uvrD background, and can occur at a frequency of 6.9*10( 5). PMID- 23094083 TI - Effects of easy-to-use protein-rich energy bar on energy balance, physical activity and performance during 8 days of sustained physical exertion. AB - BACKGROUND: Previous military studies have shown an energy deficit during a strenuous field training course (TC). This study aimed to determine the effects of energy bar supplementation on energy balance, physical activity (PA), physical performance and well-being and to evaluate ad libitum fluid intake during wintertime 8-day strenuous TC. METHODS: Twenty-six men (age 20+/-1 yr.) were randomly divided into two groups: The control group (n = 12) had traditional field rations and the experimental (Ebar) group (n = 14) field rations plus energy bars of 4.1 MJ*day(-1). Energy (EI) and water intake was recorded. Fat free mass and water loss were measured with deuterium dilution and elimination, respectively. The energy expenditure was calculated using the intake/balance method and energy availability as (EI/estimated basal metabolic rate). PA was monitored using an accelerometer. Physical performance was measured and questionnaires of upper respiratory tract infections (URTI), hunger and mood state were recorded before, during and after TC. RESULTS: Ebar had a higher EI and energy availability than the controls. However, decreases in body mass and fat mass were similar in both groups representing an energy deficit. No differences were observed between the groups in PA, water balance, URTI symptoms and changes in physical performance and fat-free mass. Ebar felt less hunger after TC than the controls and they had improved positive mood state during the latter part of TC while controls did not. Water deficit associated to higher PA. Furthermore, URTI symptoms and negative mood state associated negatively with energy availability and PA. CONCLUSION: An easy-to-use protein-rich energy bars did not prevent energy deficit nor influence PA during an 8-day TC. The high content of protein in the bars might have induced satiation decreasing energy intake from field rations. PA and energy intake seems to be primarily affected by other factors than energy supplementation such as mood state. PMID- 23094084 TI - A circadian clock in the olfactory bulb anticipates feeding during food anticipatory activity. AB - Rabbit pups ingest food, in this case milk, once a day with circadian periodicity and are a natural model of food anticipatory activity. During nursing, several sensory systems receive information about properties of the food, one of them being the olfactory system, which has received little attention in relation to synchronization by food. In addition, the olfactory bulb has a circadian pacemaker that exhibits rhythms independently of the suprachiasmatic nucleus, but the biological functions of these rhythms are largely unknown. In the present contribution, we hypothesized that circadian suckling of milk synchronizes rhythms in the olfactory bulb. To this aim we explored by immunohistochemistry, rhythms of FOS and PER1 proteins, as indicators of activation and reporter of oscillations, respectively, through a complete 24-h cycle in periglomerular, mitral and granular cell layers of both the main and the accessory olfactory bulb. Subjects were 7-day-old rabbit pups scheduled to nurse during the night (02:00 h) or day (10:00 h), and also fasted subjects, to explore the possible persistence of oscillations. In the three layers of the main olfactory bulb, FOS was high at time of nursing, then further increased 1.5 h afterward, and then decreased to increase again in advance of the next nursing bout. This pattern persisted, without the postprandial increase, in fasted subjects with a shift in subjects nursed at 02:00. PER1 was increased 2-8 h after nursing and this increase persisted in most cell layers, with a shift, in fasted subjects. In the accessory olfactory bulb we only observed a consistent pattern of FOS expression in the mitral cell layer of nursed subjects, similar to that of the main olfactory bulb. We conclude that the main olfactory bulb is synchronized during milk ingestion, but during fasting its oscillations perhaps are modulated by the suprachiasmatic nucleus, as proposed for rodents. PMID- 23094086 TI - miRandola: extracellular circulating microRNAs database. AB - MicroRNAs are small noncoding RNAs that play an important role in the regulation of various biological processes through their interaction with cellular messenger RNAs. They are frequently dysregulated in cancer and have shown great potential as tissue-based markers for cancer classification and prognostication. microRNAs are also present in extracellular human body fluids such as serum, plasma, saliva, and urine. Most of circulating microRNAs are present in human plasma and serum cofractionate with the Argonaute2 (Ago2) protein. However, circulating microRNAs have been also found in membrane-bound vesicles such as exosomes. Since microRNAs circulate in the bloodstream in a highly stable, extracellular form, they may be used as blood-based biomarkers for cancer and other diseases. A knowledge base of extracellular circulating miRNAs is a fundamental tool for biomedical research. In this work, we present miRandola, a comprehensive manually curated classification of extracellular circulating miRNAs. miRandola is connected to miRo, the miRNA knowledge base, allowing users to infer the potential biological functions of circulating miRNAs and their connections with phenotypes. The miRandola database contains 2132 entries, with 581 unique mature miRNAs and 21 types of samples. miRNAs are classified into four categories, based on their extracellular form: miRNA-Ago2 (173 entries), miRNA-exosome (856 entries), miRNA-HDL (20 entries) and miRNA-circulating (1083 entries). miRandola is available online at: http://atlas.dmi.unict.it/mirandola/index.html. PMID- 23094085 TI - GWA analysis for milk production traits in dairy sheep and genetic support for a QTN influencing milk protein percentage in the LALBA gene. AB - In this study, we used the Illumina OvineSNP50 BeadChip to conduct a genome-wide association (GWA) analysis for milk production traits in dairy sheep by analyzing a commercial population of Spanish Churra sheep. The studied population consisted of a total of 1,681 Churra ewes belonging to 16 half-sib families with available records for milk yield (MY), milk protein and fat yields (PY and FY) and milk protein and fat contents (PP and FP). The most significant association identified reached experiment-wise significance for PP and FP and was located on chromosome 3 (OAR3). These results confirm the population-level segregation of a previously reported QTL affecting PP and suggest that this QTL has a significant pleiotropic effect on FP. Further associations were detected at the chromosome-wise significance level on 14 other chromosomal regions. The marker on OAR3 showing the highest significant association was located at the third intron of the alpha lactalbumin (LALBA) gene, which is a functional and positional candidate underlying this association. Sequencing this gene in the 16 Churra rams of the studied resource population identified additional polymorphisms. One out of the 31 polymorphisms identified was located within the coding gene sequence (LALBA_g.242T>C) and was predicted to cause an amino acid change in the protein (Val27Ala). Different approaches, including GWA analysis, a combined linkage and linkage disequilibrium study and a concordance test with the QTL segregating status of the sires, were utilized to assess the role of this mutation as a putative QTN for the genetic effects detected on OAR3. Our results strongly support the polymorphism LALBA_g.242T>C as the most likely causal mutation of the studied OAR3 QTL affecting PP and FP, although we cannot rule out the possibility that this SNP is in perfect linkage disequilibrium with the true causal polymorphism. PMID- 23094087 TI - Global protein conjugation by ubiquitin-like-modifiers during ischemic stress is regulated by microRNAs and confers robust tolerance to ischemia. AB - Hibernation torpor provides an excellent model of natural tolerance to ischemia. We have previously shown that massive global SUMOylation occurs during hibernation torpor in ground squirrels. We have also shown that overexpression of Ubc9, SUMO-1, or SUMO-2/3 provides protection against ischemic damage in cell lines and cortical neurons exposed to oxygen/glucose deprivation, and in mice exposed to middle cerebral artery occlusion. We have now extended our study to other Ubiquitin-Like-Modifiers (ULMs), which have multiple cellular functions during stress, in order to assess the possibility that they also have roles in tolerance to ischemia. We found that not only SUMO conjugation, but also global protein conjugation by other ULMs including NEDD8, ISG15, UFM1 and FUB1 were significantly increased in the brains of hibernating ground squirrels during torpor. By means of miRNA microarrays of ground squirrel brain samples (from active and torpor phase) we found that the miR-200 family (miR-200a,b,c/miR 141/miR-429) and the miR-182 family (miR-182/miR-183/miR-96) were among the most consistently depressed miRNAs in the brain during the torpor phase as compared to active animals. In addition, we showed that these miRNAs are involved in the expression of various ULM proteins and their global conjugation to proteins. We observed that inhibition of the miR-200 family and/or miR-182 family miRNA activities in SHSY5Y cells increases global protein conjugation by the above ULMs and makes these cells more tolerant to OGD-induced cell death. This is the first report to describe that the natural tolerance to brain ischemia in hibernators is linked to regulation by microRNAs of a broad range of ubiquitin-like modifiers. PMID- 23094088 TI - "SP-G", a putative new surfactant protein--tissue localization and 3D structure. AB - Surfactant proteins (SP) are well known from human lung. These proteins assist the formation of a monolayer of surface-active phospholipids at the liquid-air interface of the alveolar lining, play a major role in lowering the surface tension of interfaces, and have functions in innate and adaptive immune defense. During recent years it became obvious that SPs are also part of other tissues and fluids such as tear fluid, gingiva, saliva, the nasolacrimal system, and kidney. Recently, a putative new surfactant protein (SFTA2 or SP-G) was identified, which has no sequence or structural identity to the already know surfactant proteins. In this work, computational chemistry and molecular-biological methods were combined to localize and characterize SP-G. With the help of a protein structure model, specific antibodies were obtained which allowed the detection of SP-G not only on mRNA but also on protein level. The localization of this protein in different human tissues, sequence based prediction tools for posttranslational modifications and molecular dynamic simulations reveal that SP-G has physicochemical properties similar to the already known surfactant proteins B and C. This includes also the possibility of interactions with lipid systems and with that, a potential surface-regulatory feature of SP-G. In conclusion, the results indicate SP-G as a new surfactant protein which represents an until now unknown surfactant protein class. PMID- 23094090 TI - DNA methyltransferase 3b is dispensable for mouse neural crest development. AB - The neural crest is a population of multipotent cells that migrates extensively throughout vertebrate embryos to form diverse structures. Mice mutant for the de novo DNA methyltransferase DNMT3b exhibit defects in two neural crest derivatives, the craniofacial skeleton and cardiac ventricular septum, suggesting that DNMT3b activity is necessary for neural crest development. Nevertheless, the requirement for DNMT3b specifically in neural crest cells, as opposed to interacting cell types, has not been determined. Using a conditional DNMT3b allele crossed to the neural crest cre drivers Wnt1-cre and Sox10-cre, neural crest DNMT3b mutants were generated. In both neural crest-specific and fully DNMT3b-mutant embryos, cranial neural crest cells exhibited only subtle migration defects, with increased numbers of dispersed cells trailing organized streams in the head. In spite of this, the resulting cranial ganglia, craniofacial skeleton, and heart developed normally when neural crest cells lacked DNMT3b. This indicates that DNTM3b is not necessary in cranial neural crest cells for their development. We conclude that defects in neural crest derivatives in DNMT3b mutant mice reflect a requirement for DNMT3b in lineages such as the branchial arch mesendoderm or the cardiac mesoderm that interact with neural crest cells during formation of these structures. PMID- 23094089 TI - Distinct and overlapping roles of Nipah virus P gene products in modulating the human endothelial cell antiviral response. AB - Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that causes fatal encephalitis in up to 75% of infected humans. Like other paramyxoviruses, NiV employs co-transcriptional mRNA editing during transcription of the phosphoprotein (P) gene to generate additional mRNAs encoding the V and W proteins. The C protein is translated from the P mRNA, but in an alternative reading frame. There is evidence from both in vitro and in vivo studies to show that the P gene products play a role in NiV pathogenesis. We have developed a reverse genetic system to dissect the individual roles of the NiV P gene products in limiting the antiviral response in primary human microvascular lung endothelial cells, which represent important targets in human NiV infection. By characterizing growth curves and early antiviral responses against a number of recombinant NiVs with genetic modifications altering expression of the proteins encoded by the P gene, we observed that multiple elements encoded by the P gene have both distinct and overlapping roles in modulating virus replication as well as in limiting expression of antiviral mediators such as IFN-beta, CXCL10, and CCL5. Our findings corroborate observations from in vivo hamster infection studies, and provide molecular insights into the attenuation and the histopathology observed in hamsters infected with C, V, and W-deficient NiVs. The results of this study also provide an opportunity to verify the results of earlier artificial plasmid expression studies in the context of authentic viral infection. PMID- 23094091 TI - Co-operative additive effects between HLA alleles in control of HIV-1. AB - BACKGROUND: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles- irrespective of linkage disequilibrium--function co-operatively. METHODOLOGY/PRINCIPAL FINDINGS: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate 'co-operative additive' effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel 'sharing score' to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). CONCLUSIONS/SIGNIFICANCE: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect. PMID- 23094092 TI - Long-term effect of antibodies against infused alpha-galactosidase A in Fabry disease on plasma and urinary (lyso)Gb3 reduction and treatment outcome. AB - INTRODUCTION: Enzyme replacement therapy (ERT) with alpha-Galactosidase A (aGal A) may cause antibody (AB) formation against aGal A in males with Fabry disease (FD). Anti agalsidase ABs negatively influence globotriaosylceramide (Gb3) reduction. We investigated the impact of agalsidase AB on Gb3 and lysoGb3 and clinical outcome in Fabry patients on ERT. METHODS: Adult male and female patients on ERT for at least one year were included. Urinary Gb3 was measured by HPLC, plasma lysoGb3 by LC-ESI-MS/MS and AB with a neutralization assay. RESULTS: Of the 59 patients evaluable patients, 0/30 females and 17/29 males developed anti-agalsidase antibodies (AB+). Only 3/17 males had transient (low) titers (tolerized). All AB+ patients developed antibodies during the first year of treatment. Change of agalsidase preparation (or dose) did not induce antibody formation. AB+ males had significant less decline in plasma lysoGb3 compared to AB- males (p = 0.04). Urinary Gb3 levels decreased markedly in AB- but remained comparable to baseline in AB+ males (p<0.01). (Lyso)Gb3 reduction in plasma and urine on ERT was correlated with LVmass reduction in females and development white matter lesions and stroke. CONCLUSION: In male patients antibodies against aGal A remained present up to 10 years of ERT. The presence of these antibodies is associated with a less robust decrease in plasma lysoGb3 and a profound negative effect on urinary Gb3 reduction, which may reflect worse treatment outcome. PMID- 23094093 TI - Inorganic phosphate accelerates the migration of vascular smooth muscle cells: evidence for the involvement of miR-223. AB - BACKGROUND: An elevated serum inorganic phosphate (Pi) level is a major risk factor for kidney disease and downstream vascular complications. We focused on the effect of Pi levels on human aortic vascular smooth muscle cells (VSMCs), with an emphasis on the role of microRNAs (miRNAs). METHODOLOGY/PRINCIPAL FINDINGS: Exposure of human primary VSMCs in vitro to pathological levels of Pi increased calcification, migration rate and concomitantly reduced cell proliferation and the amount of the actin cytoskeleton. These changes were evidenced by significant downregulation of miRNA-143 (miR-143) and miR-145 and concomitant upregulation of their targets and key markers in synthetic VSMCs, such as Kruppel-like factors-4 and -5 and versican. Interestingly, we also found that miR-223 (a marker of muscle damage and a key factor in osteoclast differentiation) is expressed in VSMCs and is significantly upregulated in Pi treated cells. Over-expressing miR-223 in VSMCs increased proliferation and markedly enhanced VSMC migration. Additionally, we found that the expression of two of the known miR-223 targets, Mef2c and RhoB, was highly reduced in Pi treated as well as miR-223 over-expressing VSMCs. To complement these in vitro findings, we also observed significant downregulation of miR-143 and miR-145 and upregulation of miR-223 in aorta samples collected from ApoE knock-out mice, which display vascular calcification. CONCLUSIONS/SIGNIFICANCE: Our results suggest that (i) high levels of Pi increase VSMC migration and calcification, (ii) altered expression levels of miR-223 could play a part in this process and (iii) miR-223 is a potential new biomarker of VSMC damage. PMID- 23094094 TI - Effectiveness of HBV vaccination in infants and prediction of HBV prevalence trend under new vaccination plan: findings of a large-scale investigation. AB - BACKGROUND: Hepatitis B virus (HBV) infection remains a severe public health problem. Investigating its prevalence and trends is essential to prevention. METHODS: To evaluate the effectiveness of HBV vaccination under the 1992 Intervention Program for infants and predicted HBV prevalence trends under the 2011 Program for all ages. We conducted a community-based investigation of 761,544 residents of 12 counties in Zhejiang Province selected according to their location, population density, and economic development. The HBV prevalence trends were predicted by a time-shifting approach. HBV surface antigen (HBsAg) and alanine amino transferase (ALT) were determined. RESULTS: Of the 761,544 persons screened for HBsAg, 54,132 were positive (adjusted carrier rate 6.13%); 9,455 had both elevated ALT and a positive HBsAg test (standardized rate 1.18%). The standardized HBsAg carrier rate for persons aged <=20 years was 1.51%. Key factors influencing HBV infection were sex, age, family history, drinking, smoking, employment as a migrant worker, and occupation. With the vaccination program implemented in 2011, we predict that by 2020, the HBsAg carrier rate will be 5.27% and that for individuals aged <=34 years will reach the 2% upper limit of low prevalence according to the WHO criteria, with a standardized rate of 1.86%. CONCLUSIONS: The national HBV vaccination program for infants implemented in 1992 has greatly reduced the prevalence of HBV infection. The 2011 program is likely to reduce HBV infection in Zhejiang Province to a low moderate prevalence, and perinatal transmission is expected to be controlled by 2020. PMID- 23094095 TI - Does facial resemblance enhance cooperation? AB - Facial self-resemblance has been proposed to serve as a kinship cue that facilitates cooperation between kin. In the present study, facial resemblance was manipulated by morphing stimulus faces with the participants' own faces or control faces (resulting in self-resemblant or other-resemblant composite faces). A norming study showed that the perceived degree of kinship was higher for the participants and the self-resemblant composite faces than for actual first-degree relatives. Effects of facial self-resemblance on trust and cooperation were tested in a paradigm that has proven to be sensitive to facial trustworthiness, facial likability, and facial expression. First, participants played a cooperation game in which the composite faces were shown. Then, likability ratings were assessed. In a source memory test, participants were required to identify old and new faces, and were asked to remember whether the faces belonged to cooperators or cheaters in the cooperation game. Old-new recognition was enhanced for self-resemblant faces in comparison to other-resemblant faces. However, facial self-resemblance had no effects on the degree of cooperation in the cooperation game, on the emotional evaluation of the faces as reflected in the likability judgments, and on the expectation that a face belonged to a cooperator rather than to a cheater. Therefore, the present results are clearly inconsistent with the assumption of an evolved kin recognition module built into the human face recognition system. PMID- 23094096 TI - Phylogenetic analysis and molecular evolution patterns in the MIR482-MIR1448 polycistron of Populus L. AB - The microRNAs (miRNAs) miR482 and miR1448 are disease resistance-related miRNAs; the former is ubiquitously distributed in seed plants whereas the latter has only been reported in Populus trichocarpa. The precursor and mature sequences of poplar miR1448 are highly homologous to those of poplar miR482, and these two miRNAs are located in one transcript as a polycistron. Therefore, we hypothesized that the MIR1448 gene may have evolved from the MIR482 gene in poplar. However, the molecular evolution patterns of this process remain unclear. In this study, utilizing cloning and Blast analysis in NCBI ESTs and whole-genome shotgun contigs (WGS) dataset, we determined that the MIR482-MIR1448 polycistron is a family-specific clustered miRNA in Salicaceae. Moreover, phylogenetic analysis illustrated that MIR1448 is the product of a tandem duplication event from MIR482. Nucleotide substitution analysis revealed that both MIR482 and MIR1448 have more rapid evolution ratios than ribosomal DNA (rDNA) genes, and that compensatory mutations that occurred in the stem region of the secondary structure were the main mechanisms that drove the evolution of these MIRNA genes. Furthermore, by comparing the substitution patterns in the miRNA-target complexes of miR482 and miR1448, we inferred that co-evolution between miRNAs and their targets was the major force that drove the "duplicated MIR482" evolve to MIR1448. We propose a novel miRNA-target pairing pattern called the "frameshift targeted mechanism" to explain the gain of target genes by miR1448. The results also imply that the major role of miR482 was in resistance to disease or other stresses via NBS-LRR proteins, whereas the biological functions of miR1448 are more diverse. PMID- 23094097 TI - beta-Adrenergic cAMP signals are predominantly regulated by phosphodiesterase type 4 in cultured adult rat aortic smooth muscle cells. AB - BACKGROUND: We investigated the role of cyclic nucleotide phosphodiesterases (PDEs) in the spatiotemporal control of intracellular cAMP concentrations in rat aortic smooth muscle cells (RASMCs). METHODOLOGY/PRINCIPAL FINDINGS: The rank order of PDE families contributing to global cAMP-PDE activity was PDE4> PDE3 = PDE1. PDE7 mRNA expression but not activity was confirmed. The Fluorescence Resonance Energy Transfer (FRET)-based cAMP sensor, Epac1-camps, was used to monitor the time course of cytosolic cAMP changes. A pulse application of the beta-adrenoceptor (beta-AR) agonist isoproterenol (Iso) induced a transient FRET signal. Both beta(1)- and beta(2)-AR antagonists decreased the signal amplitude without affecting its kinetics. The non-selective PDE inhibitor (IBMX) dramatically increased the amplitude and delayed the recovery phase of Iso response, in agreement with a role of PDEs in degrading cAMP produced by Iso. Whereas PDE1, PDE3 and PDE7 blockades [with MIMX, cilostamide (Cil) and BRL 50481 (BRL), respectively] had no or minor effect on Iso response, PDE4 inhibition [with Ro-20-1724 (Ro)] strongly increased its amplitude and delayed its recovery. When Ro was applied concomitantly with MIMX or Cil (but not with BRL), the Iso response was drastically further prolonged. PDE4 inhibition similarly prolonged both beta(1)- and beta(2)-AR-mediated responses. When a membrane-targeted FRET sensor was used, PDE3 and PDE4 acted in a synergistic manner to hydrolyze the submembrane cAMP produced either at baseline or after beta-AR stimulation. CONCLUSION/SIGNIFICANCE: Our study underlines the importance of cAMP-PDEs in the dynamic control of intracellular cAMP signals in RASMCs, and demonstrates the prominent role of PDE4 in limiting beta-AR responses. PDE4 inhibition unmasks an effect of PDE1 and PDE3 on cytosolic cAMP hydrolyzis, and acts synergistically with PDE3 inhibition at the submembrane compartment. This suggests that mixed PDE4/PDE1 or PDE4/PDE3 inhibitors would be attractive to potentiate cAMP-related functions in vascular cells. PMID- 23094098 TI - Alterations in white matter microstructure in neurofibromatosis-1. AB - Neurofibromatosis (NF1) represents the most common single gene cause of learning disabilities. NF1 patients have impairments in frontal lobe based cognitive functions such as attention, working memory, and inhibition. Due to its well characterized genetic etiology, investigations of NF1 may shed light on neural mechanisms underlying such difficulties in the general population or other patient groups. Prior neuroimaging findings indicate global brain volume increases, consistent with neural over-proliferation. However, little is known about alterations in white matter microstructure in NF1. We performed diffusion tensor imaging (DTI) analyses using tract-based spatial statistics (TBSS) in 14 young adult NF1 patients and 12 healthy controls. We also examined brain volumetric measures in the same subjects. Consistent with prior studies, we found significantly increased overall gray and white matter volume in NF1 patients. Relative to healthy controls, NF1 patients showed widespread reductions in white matter integrity across the entire brain as reflected by decreased fractional anisotropy (FA) and significantly increased absolute diffusion (ADC). When radial and axial diffusion were examined we found pronounced differences in radial diffusion in NF1 patients, indicative of either decreased myelination or increased space between axons. Secondary analyses revealed that FA and radial diffusion effects were of greatest magnitude in the frontal lobe. Such alterations of white matter tracts connecting frontal regions could contribute to the observed cognitive deficits. Furthermore, although the cellular basis of these white matter microstructural alterations remains to be determined, our findings of disproportionately increased radial diffusion against a background of increased white matter volume suggest the novel hypothesis that one potential alteration contributing to increased cortical white matter in NF1 may be looser packing of axons, with or without myelination changes. Further, this indicates that axial and radial diffusivity can uniquely contribute as markers of NF1 associated brain pathology in conjunction with the typically investigated measures. PMID- 23094099 TI - Achieving adequate margins in ameloblastoma resection: the role for intra operative specimen imaging. Clinical report and systematic review. AB - BACKGROUND: Ameloblastoma is a locally aggressive odontogenic neoplasm. With local recurrence rates reaching 90%, only completeness of excision can facilitate cure. Surgical clearance has widely been based on pre-operative imaging to guide operative excision margins, however use of intra-operative specimen x-ray or frozen-section has been sought to improve clearance rates, and advanced imaging technologies in this role have been proposed. This manuscript aims to quantify the evidence for evaluating intra-operative resection margins and present the current standard in this role. METHOD: The current study comprises the first reported comparison of imaging modalities for assessing ameloblastoma margins. A case is presented in which margins are assessed with each of clinical assessment based on preoperative imaging, intra-operative specimen x-ray, intra-operative specimen computed tomography (CT) and definitive histology. Each modality is compared quantitatively. These results are compared to the literature through means of systematic review of current evidence. RESULTS: A comparative study highlights the role for CT imaging over plain radiography. With no other comparative studies and a paucity of high level evidence establishing a role for intra-operative margin assessment in ameloblastoma in the literature, only level 4 evidence supporting the use of frozen section and specimen x-ray, and only one level 4 study assesses intra-operative CT. CONCLUSION: The current study suggests that intra-operative specimen CT offers an improvement over existing techniques in this role. While establishing a gold-standard will require higher level comparative studies, the use of intra-operative CT can facilitate accurate single stage resection. PMID- 23094100 TI - Allosteric modulation of the activity of the glucagon-like peptide-1 (GLP-1) metabolite GLP-1 9-36 amide at the GLP-1 receptor. AB - Glucagon-like peptide-1 (GLP-1) released from intestinal L cells in response to nutrients has many physiological effects but particularly enhances glucose dependent insulin release through the GLP-1 receptor (GLP-1R). GLP-1 7-36 amide, the predominant circulating active form of GLP-1, is rapidly truncated by dipeptidyl peptidase-4 to GLP-1 9-36 amide, which is generally considered inactive. Given its physiological roles, the GLP-1R is targeted for treatment of type 2 diabetes. Recently 'compound 2' has been described as both an agonist and positive allosteric modulator of GLP-1 7-36 amide affinity, but not potency, at the GLP-1R. Importantly, we demonstrated previously that exendin 9-39, generally considered a GLP-1R antagonist, enhances compound 2 efficacy (or vice versa) at the GLP-1R. Given that GLP-1 9-36 amide is the major circulating form of GLP-1 post-prandially and is a low affinity weak partial agonist or antagonist at the GLP-1R, we investigated interaction between this metabolite and compound 2 in a cell line with recombinant expression of the human GLP-1R and the rat insulinoma cell line, INS-1E, with native expression of the GLP-1R. We show compound 2 markedly enhances efficacy and potency of GLP-1 9-36 amide for key cellular responses including AMP generation, Ca(2+) signaling and extracellular signal regulated kinase. Thus, metabolites of peptide hormones including GLP-1 that are often considered inactive may provide a means of manipulating key aspects of receptor function and a novel therapeutic strategy. PMID- 23094101 TI - TTX-resistant NMDA receptor-mediated membrane potential oscillations in neonatal mouse Hb9 interneurons. AB - Conditional neuronal membrane potential oscillations have been identified as a potential mechanism to help support or generate rhythmogenesis in neural circuits. A genetically identified population of ventromedial interneurons, called Hb9, in the mouse spinal cord has been shown to generate TTX-resistant membrane potential oscillations in the presence of NMDA, serotonin and dopamine, but these oscillatory properties are not well characterized. Hb9 interneurons are rhythmically active during fictive locomotor-like behavior. In this study, we report that exogenous N-Methyl-D-Aspartic acid (NMDA) application is sufficient to produce membrane potential oscillations in Hb9 interneurons. In contrast, exogenous serotonin and dopamine application, alone or in combination, are not sufficient. The properties of NMDA-induced oscillations vary among the Hb9 interneuron population; their frequency and amplitude increase with increasing NMDA concentration. NMDA does not modulate the T-type calcium current (I(Ca(T))), which is thought to be important in generating locomotor-like activity, in Hb9 neurons. These results suggest that NMDA receptor activation is sufficient for the generation of TTX-resistant NMDA-induced membrane potential oscillations in Hb9 interneurons. PMID- 23094102 TI - Alveolar macrophages play a key role in cockroach-induced allergic inflammation via TNF-alpha pathway. AB - The activity of the serine protease in the German cockroach allergen is important to the development of allergic disease. The protease-activated receptor (PAR)-2, which is expressed in numerous cell types in lung tissue, is known to mediate the cellular events caused by inhaled serine protease. Alveolar macrophages express PAR-2 and produce considerable amounts of tumor necrosis factor (TNF)-alpha. We determined whether the serine protease in German cockroach extract (GCE) enhances TNF-alpha production by alveolar macrophages through the PAR-2 pathway and whether the TNF-alpha production affects GCE-induced pulmonary inflammation. Effects of GCE on alveolar macrophages and TNF-alpha production were evaluated using in vitro MH-S and RAW264.6 cells and in vivo GCE-induced asthma models of BALB/c mice. GCE contained a large amount of serine protease. In the MH-S and RAW264.7 cells, GCE activated PAR-2 and thereby produced TNF-alpha. In the GCE induced asthma model, intranasal administration of GCE increased airway hyperresponsiveness (AHR), inflammatory cell infiltration, productions of serum immunoglobulin E, interleukin (IL)-5, IL-13 and TNF-alpha production in alveolar macrophages. Blockade of serine proteases prevented the development of GCE induced allergic pathologies. TNF-alpha blockade also prevented the development of such asthma-like lesions. Depletion of alveolar macrophages reduced AHR and intracellular TNF-alpha level in pulmonary cell populations in the GCE-induced asthma model. These results suggest that serine protease from GCE affects asthma through an alveolar macrophage and TNF-alpha dependent manner, reflecting the close relation of innate and adaptive immune response in allergic asthma model. PMID- 23094103 TI - Trauma activation patients: evidence for routine alcohol and illicit drug screening. AB - BACKGROUND: Statistics from the National Trauma Data Bank imply that discretionary blood alcohol and urine drug testing is common. However, there is little evidence to determine which patients are appropriate for routine testing, based on information available at trauma center arrival. In 2002, Langdorf reported alcohol and illicit drug rates in Trauma Activation Patients. METHODOLOGY/PRINCIPAL FINDINGS: This is a retrospective investigation of alcohol and illicit drug rates in consecutive St. Elizabeth Health Center (SEHC) trauma patients. SEHC Trauma Activation Patients are compared with the Langdorf Activation Patients and with the SEHC Trauma Nonactivation Patients. Minimum Rates are positive tests divided by total patients (tested and not tested). Activation patients: The minimum alcohol rates were: SEHC 23.1%, Langdorf 28.2%, combined 24.8%. The minimum illicit drug rates were: SEHC 15.7%, Langdorf 23.5, combined 18.3%. The minimum alcohol and/or illicit drug rates were: SEHC 33.4%, Langdorf 41.8%, combined 36.2%. Nonactivation patients: The SEHC minimum alcohol rate was 4.7% and the minimum illicit drug rate was 6.0%. CONCLUSIONS: Alcohol and illicit drug rates were significantly greater for Trauma Activation Patients, when compared to Nonactivation Patients. At minimum, Trauma Activation Patients are likely to have a 1-in-3 positive test for alcohol and/or an illicit drug. This substantial rate suggests that Trauma Activation Patients, a readily discernible group at trauma center arrival, are appropriate for routine alcohol and illicit drug testing. However, discretionary testing is more reasonable for Trauma Nonactivation Patients, because minimum rates are low. PMID- 23094104 TI - Relative importance of modularity and other morphological attributes on different types of lithic point weapons: assessing functional variations. AB - The specific using of different prehistoric weapons is mainly determined by its physical properties, which provide a relative advantage or disadvantage to perform a given, particular function. Since these physical properties are integrated to accomplish that function, examining design variables and their pattern of integration or modularity is of interest to estimate the past function of a point. Here we analyze a composite sample of lithic points from southern Patagonia likely formed by arrows, thrown spears and hand-held points to test if they can be viewed as a two-module system formed by the blade and the stem, and to evaluate the degree in which shape, size, asymmetry, blade: stem length ratio, and tip angle explain the observed variance and differentiation among points supposedly aimed to accomplish different functions. To do so we performed a geometric morphometric analysis on 118 lithic points, departing from 24 two dimensional landmark and semi landmarks placed on the point's contour. Klingenberg's covariational modularity tests were used to evaluate different modularity hypotheses, and a composite PCA including shape, size, asymmetry, blade: stem length ratio, and tip angle was used to estimate the importance of each attribute to explaining variation patterns. Results show that the blade and the stem can be seen as "near decomposable units" in the points integrating the studied sample. However, this modular pattern changes after removing the effects of reduction. Indeed, a resharpened point tends to show a tip/rest of the point modular pattern. The composite PCA analyses evidenced three different patterns of morphometric attributes compatible with arrows, thrown spears, and hand-held tools. Interestingly, when analyzed independently, these groups show differences in their modular organization. Our results indicate that stone tools can be approached as flexible designs, characterized by a composite set of interacting morphometric attributes, and evolving on a modular way. PMID- 23094105 TI - In vivo imaging of brain ischemia using an oxygen-dependent degradative fusion protein probe. AB - Within the ischemic penumbra, blood flow is sufficiently reduced that it results in hypoxia severe enough to arrest physiological function. Nevertheless, it has been shown that cells present within this region can be rescued and resuscitated by restoring perfusion and through other protective therapies. Thus, the early detection of the ischemic penumbra can be exploited to improve outcomes after focal ischemia. Hypoxia-inducible factor (HIF)-1 is a transcription factor induced by a reduction in molecular oxygen levels. Although the role of HIF-1 in the ischemic penumbra remains unknown, there is a strong correlation between areas with HIF-1 activity and the ischemic penumbra. We recently developed a near infrared fluorescently labeled-fusion protein, POH-N, with an oxygen-dependent degradation property identical to the alpha subunit of HIF-1. Here, we conduct in vivo imaging of HIF-active regions using POH-N in ischemic brains after transient focal cerebral ischemia induced using the intraluminal middle cerebral artery occlusion technique in mice. The results demonstrate that POH-N enables the in vivo monitoring and ex vivo detection of HIF-1-active regions after ischemic brain injury and suggest its potential in imaging and drug delivery to HIF-1 active areas in ischemic brains. PMID- 23094106 TI - How peroxisomes affect aflatoxin biosynthesis in Aspergillus flavus. AB - In filamentous fungi, peroxisomes are crucial for the primary metabolism and play a pivotal role in the formation of some secondary metabolites. Further, peroxisomes are important site for fatty acids beta-oxidation, the formation of reactive oxygen species and for their scavenging through a complex of antioxidant activities. Oxidative stress is involved in different metabolic events in all organisms and it occurs during oxidative processes within the cell, including peroxisomal beta-oxidation of fatty acids. In Aspergillus flavus, an unbalance towards an hyper-oxidant status into the cell is a prerequisite for the onset of aflatoxin biosynthesis. In our preliminary results, the use of bezafibrate, inducer of both peroxisomal beta-oxidation and peroxisome proliferation in mammals, significantly enhanced the expression of pex11 and foxA and stimulated aflatoxin synthesis in A. flavus. This suggests the existence of a correlation among peroxisome proliferation, fatty acids beta-oxidation and aflatoxin biosynthesis. To investigate this correlation, A. flavus was transformed with a vector containing P33, a gene from Cymbidium ringspot virus able to induce peroxisome proliferation, under the control of the promoter of the Cu,Zn-sod gene of A. flavus. This transcriptional control closely relates the onset of the antioxidant response to ROS increase, with the proliferation of peroxisomes in A. flavus. The AfP33 transformant strain show an up-regulation of lipid metabolism and an higher content of both intracellular ROS and some oxylipins. The combined presence of a higher amount of substrates (fatty acids-derived), an hyper-oxidant cell environment and of hormone-like signals (oxylipins) enhances the synthesis of aflatoxins in the AfP33 strain. The results obtained demonstrated a close link between peroxisome metabolism and aflatoxin synthesis. PMID- 23094107 TI - Characterization of chicken spleen transcriptome after infection with Salmonella enterica serovar Enteritidis. AB - In this study we were interested in identification of new markers of chicken response to Salmonella Enteritidis infection. To reach this aim, gene expression in the spleens of naive chickens and those intravenously infected with S. Enteritidis with or without previous oral vaccination was determined by 454 pyrosequencing of splenic mRNA/cDNA. Forty genes with increased expression at the level of transcription were identified. The most inducible genes encoded avidin (AVD), extracellular fatty acid binding protein (EXFABP), immune responsive gene 1 (IRG1), chemokine ah221 (AH221), trappin-6-like protein (TRAP6) and serum amyloid A (SAA). Using cDNA from sorted splenic B-lymphocytes, macrophages, CD4, CD8 and gammadelta T-lymphocytes, we found that the above mentioned genes were preferentially expressed in macrophages. AVD, EXFABP, IRG1, AH221, TRAP6 and SAA were induced also in the cecum of chickens orally infected with S. Enteritidis on day 1 of life or day 42 of life. Unusual results were obtained for the immunoglobulin encoding transcripts. Prior to the infection, transcripts coding for the constant parts of IgM, IgY, IgA and Ig light chain were detected in B lymphocytes. However, after the infection, immunoglobulin encoding transcripts were expressed also by T-lymphocytes and macrophages. Expression of AVD, EXFABP, IRG1, AH221, TRAP6, SAA and all immunoglobulin genes can be therefore used for the characterization of the course of S. Enteritidis infection in chickens. PMID- 23094108 TI - Genomic expression analyses reveal lysosomal, innate immunity proteins, as disease correlates in murine models of a lysosomal storage disorder. AB - Niemann-Pick Type C (NPC) disease is a rare, genetic, lysosomal disorder with progressive neurodegeneration. Poor understanding of the pathophysiology and a lack of blood-based diagnostic markers are major hurdles in the treatment and management of NPC and several additional, neurological lysosomal disorders. To identify disease severity correlates, we undertook whole genome expression profiling of sentinel organs, brain, liver, and spleen of Balb/c Npc1(-/-) mice relative to Npc1(+/-) at an asymptomatic stage, as well as early- and late symptomatic stages. Unexpectedly, we found prominent up regulation of innate immunity genes with age-dependent change in their expression, in all three organs. We shortlisted a set of 12 secretory genes whose expression steadily increased with age in both brain and liver, as potential plasma correlates of neurological and/or liver disease. Ten were innate immune genes with eight ascribed to lysosomes. Several are known to be elevated in diseased organs of murine models of other lysosomal diseases including Gaucher's disease, Sandhoff disease and MPSIIIB. We validated the top candidate lysozyme, in the plasma of Npc1(-/-) as well as Balb/c Npc1(nmf164) mice (bearing a point mutation closer to human disease mutants) and show its reduction in response to an emerging therapeutic. We further established elevation of innate immunity in Npc1(-/-) mice through multiple functional assays including inhibition of bacterial infection as well as cellular analysis and immunohistochemistry. These data revealed neutrophil elevation in the Npc1(-/-) spleen and liver (where large foci were detected proximal to damaged tissue). Together our results yield a set of lysosomal, secretory innate immunity genes that have potential to be developed as pan or specific plasma markers for neurological diseases associated with lysosomal storage and where diagnosis is a major problem. Further, the accumulation of neutrophils in diseased organs (hitherto not associated with NPC) suggests their role in pathophysiology and disease exacerbation. PMID- 23094115 TI - Trypanosome diversity in wildlife species from the serengeti and Luangwa Valley ecosystems. AB - BACKGROUND: The importance of wildlife as reservoirs of African trypanosomes pathogenic to man and livestock is well recognised. While new species of trypanosomes and their variants have been identified in tsetse populations, our knowledge of trypanosome species that are circulating in wildlife populations and their genetic diversity is limited. METHODOLOGY/PRINCIPAL FINDINGS: molecular phylogenetic methods were used to examine the genetic diversity and species composition of trypanosomes circulating in wildlife from two ecosystems that exhibit high host species diversity: the Serengeti in Tanzania and the Luangwa Valley in Zambia. Phylogenetic relationships were assessed by alignment of partial 18S, 5.8S and 28S trypanosomal nuclear ribosomal DNA array sequences within the Trypanosomatidae and using ITS1, 5.8S and ITS2 for more detailed analysis of the T. vivax clade. In addition to Trypanosoma brucei, T. congolense, T. simiae, T. simiae (Tsavo), T. godfreyi and T. theileri, three variants of T. vivax were identified from three different wildlife species within one ecosystem, including sequences from trypanosomes from a giraffe and a waterbuck that differed from all published sequences and from each other, and did not amplify with conventional primers for T. vivax. CONCLUSIONS/SIGNIFICANCE: Wildlife carries a wide range of trypanosome species. The failure of the diverse T. vivax in this study to amplify with conventional primers suggests that T. vivax may have been under-diagnosed in Tanzania. Since conventional species-specific primers may not amplify all trypanosomes of interest, the use of ITS PCR primers followed by sequencing is a valuable approach to investigate diversity of trypanosome infections in wildlife; amplification of sequences outside the T. brucei clade raises concerns regarding ITS primer specificity for wildlife samples if sequence confirmation is not also undertaken. PMID- 23094116 TI - Hantavirus pulmonary syndrome in Santa Cruz, Bolivia: outbreak investigation and antibody prevalence study. AB - We report the results of an investigation of a small outbreak of hantavirus pulmonary syndrome in 2002 in the Department of Santa Cruz, Bolivia, where the disease had not previously been reported. Two cases were initially reported. The first case was a physician infected with Laguna Negra virus during a weekend visit to his ranch. Four other persons living on the ranch were IgM antibody positive, two of whom were symptomatic for mild hantavirus pulmonary syndrome. The second case was a migrant sugarcane worker. Although no sample remained to determine the specific infecting hantavirus, a virus 90% homologous with Rio Mamore virus was previously found in small-eared pygmy rice rats (Oligoryzomys microtis) trapped in the area. An antibody prevalence study conducted in the region as part of the outbreak investigation showed 45 (9.1%) of 494 persons to be IgG positive, illustrating that hantavirus infection is common in Santa Cruz Department. Precipitation in the months preceding the outbreak was particularly heavy in comparison to other years, suggesting a possible climatic or ecological influence on rodent populations and risk of hantavirus transmission to humans. Hantavirus infection appears to be common in the Santa Cruz Department, but more comprehensive surveillance and field studies are needed to fully understand the epidemiology and risk to humans. PMID- 23094117 TI - Leishmania donovani argininosuccinate synthase is an active enzyme associated with parasite pathogenesis. AB - BACKGROUND: Gene expression analysis in Leishmania donovani (Ld) identified an orthologue of the urea cycle enzyme, argininosuccinate synthase (LdASS), that was more abundantly expressed in amastigotes than in promastigotes. In order to characterize in detail this newly identified protein in Leishmania, we determined its enzymatic activity, subcellular localization in the parasite and affect on virulence in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Two parasite cell lines either over expressing wild type LdASS or a mutant form (G128S) associated with severe cases of citrullinemia in humans were developed. In addition we also produced bacterially expressed recombinant forms of the same proteins. Our results demonstrated that LdASS has argininosuccinate synthase enzymatic activity that is abolished using an ASS specific inhibitor (MDLA: methyl-D-L-Aspartic acid). However, the mutant form of the protein is inactive. We demonstrate that though LdASS has a glycosomal targeting signal that binds the targeting apparatus in vitro, only a small proportion of the total cellular ASS is localized in a vesicle, as indicated by protection from protease digestion of the crude organelle fraction. The majority of LdASS was found to be in the cytosolic fraction that may include large cytosolic complexes as indicated by the punctate distribution in IFA. Surprisingly, comparison to known glycosomal proteins by IFA revealed that LdASS was located in a structure different from the known glycosomal vesicles. Significantly, parasites expressing a mutant form of LdASS associated with a loss of in vitro activity had reduced virulence in vivo in BALB/c mice as demonstrated by a significant reduction in the parasite load in spleen and liver. CONCLUSION/SIGNIFICANCE: Our study suggests that LdASS is an active enzyme, with unique localization and essential for parasite survival and growth in the mammalian host. Based on these observations LdASS could be further explored as a potential drug target. PMID- 23094118 TI - Added value of antigen ELISA in the diagnosis of neurocysticercosis in resource poor settings. AB - BACKGROUND: Neurocysticercosis (NCC) is the most common cause of acquired epilepsy in Taenia solium endemic areas, primarily situated in low-income countries. Diagnosis is largely based upon the "Del Brutto diagnostic criteria" using the definitive/probable/no NCC diagnosis approach. Neuroimaging and specific T. solium cysticercosis antibody detection results are at the mainstay of this diagnosis, while antigen detection in serum has never been included. This study aimed at evaluating the addition of antigen detection as a major diagnostic criterion, especially in areas where neuroimaging is absent. METHODS: The B158/B60 monoclonal antibody-based enzyme-linked immunosorbent assay (ELISA) for the detection of circulating cysticercus antigen was carried out retrospectively on serum samples collected during a hospital-based study from 83 people with epilepsy (PWE) in an endemic area. RESULTS: The addition of antigen results as a major criterion allowed the correct diagnosis of definitive NCC in 10 out of 17 patients as opposed to 0/17 without antigen results in the absence of neuroimaging. A sensitivity of 100% and a specificity of 84% were determined for the diagnosis of active NCC using antigen ELISA. While the use of a higher cutoff improves the specificity of the test to 96%, it decreases its sensitivity to 83%. CONCLUSIONS: In areas where neuroimaging is absent, NCC diagnosis according to the existing criteria is problematic. Taking into account its limitations for diagnosis of inactive NCC, antigen detection can be of added value for diagnosing NCC in PWE by supporting diagnostic and treatment decisions. Therefore, we recommend a revision of the "Del Brutto diagnostic criteria" for use in resource poor areas and suggest the inclusion of serum antigen detection as a major criterion. PMID- 23094119 TI - Leishmania mexicana induces limited recruitment and activation of monocytes and monocyte-derived dendritic cells early during infection. AB - While C57BL/6 mice infected in the ear with L. major mount a vigorous Th1 response and resolve their lesions, the Th1 response in C57BL/6 mice infected with L. mexicana is more limited, resulting in chronic, non-healing lesions. The aim of this study was to determine if the limited immune response following infection with L. mexicana is related to a deficiency in the ability of monocyte derived dendritic cells (mo-DCs) to prime a sufficient Th1 response. To address this issue we compared the early immune response following L. mexicana infection with that seen in L. major infected mice. Our data show that fewer monocytes are recruited to the lesions of L. mexicana infected mice as compared to mice infected with L. major. Moreover, monocytes that differentiate into mo-DCs in L. mexicana lesions produced less iNOS and migrated less efficiently to the draining lymph node as compared to those from L. major infected mice. Treatment of L. mexicana infected mice with alpha-IL-10R antibody resulted in increased recruitment of monocytes to the lesion along with greater production of IFN-gamma and iNOS. Additionally, injection of DCs into the ear at the time of infection with L. mexicana also led to a more robust Th1 response. Taken together, these data suggest that during L. mexicana infection reduced recruitment, activation and subsequent migration of monocytes and mo-DCs to the draining lymph nodes may result in the insufficient priming of a Th1 response. PMID- 23094120 TI - Performance and safety of praziquantel for treatment of intestinal schistosomiasis in infants and preschool children. AB - BACKGROUND: In 2012 the WHO formally recognised that infants and preschool children are at significant risk of schistosomiasis and qualify for treatment with praziquantel (PZQ). Targeted surveys determining both the performance and safety of this drug are now needed in endemic areas. We have formally assessed parasitological cure and putative side-effects in a prospective cohort of Schistosoma mansoni-infected children (aged 5 months-7 years old) in lakeshore settings of Uganda. METHODOLOGY/PRINCIPAL FINDINGS: From a total of 369 children found to be egg-patent for intestinal schistosomiasis, 305 were followed-up three to four weeks after PZQ treatment and infection status re-assessed. Separately, a previously tested side-effect questionnaire was employed before and 24 hours after PZQ treatment to assess incidence and amelioration of symptoms in young children and their mothers. While the overall observed parasitological cure was 56.4%, a significant difference was found between a sub-set of children who had a history of multiple PZQ treatments (between one and four in an 18 month period), where cure rate was 41.7%, and those who had never received treatment (cure rate was 77.6%). PZQ proved to be safe, with only mild reported side effects which cleared within a month after treatment. Prevalence of reported symptoms was significantly lower in children than in mothers, and fewer side-effects were reported upon subsequent rounds of PZQ treatment. CONCLUSION/SIGNIFICANCE: Our findings show that PZQ treatment of young children resulted in satisfactory cure rates, and marked reduction in egg-output, with only mild and transient reported side-effects. However, the cure rate is clearly lower in younger children and those with history of previous treatment. Cure rate, but not egg reduction rate, was also lower in children with heavier pre-intervention infection intensity. With chemotherapy now recommended as a long-term strategy for disease control in young children, research into optimising the periodicity of targeted treatment strategies is now crucial. PMID- 23094122 TI - Optimal therapy for IB2 and IIA2 cervical cancer: surgery or chemoradiotherapy? PMID- 23094121 TI - First discovery of two polyketide synthase genes for mitorubrinic acid and mitorubrinol yellow pigment biosynthesis and implications in virulence of Penicillium marneffei. AB - BACKGROUND: The genome of P. marneffei, the most important thermal dimorphic fungus causing respiratory, skin and systemic mycosis in China and Southeast Asia, possesses 23 polyketide synthase (PKS) genes and 2 polyketide synthase nonribosomal peptide synthase hybrid (PKS-NRPS) genes, which is of high diversity compared to other thermal dimorphic pathogenic fungi. We hypothesized that the yellow pigment in the mold form of P. marneffei could also be synthesized by one or more PKS genes. METHODOLOGY/PRINCIPAL FINDINGS: All 23 PKS and 2 PKS-NRPS genes of P. marneffei were systematically knocked down. A loss of the yellow pigment was observed in the mold form of the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants. Sequence analysis showed that PKS11 and PKS12 are fungal non-reducing PKSs. Ultra high performance liquid chromatography photodiode array detector/electrospray ionization-quadruple time of flight-mass spectrometry (MS) and MS/MS analysis of the culture filtrates of wild type P. marneffei and the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants showed that the yellow pigment is composed of mitorubrinic acid and mitorubrinol. The survival of mice challenged with the pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants was significantly better than those challenged with wild type P. marneffei (P<0.05). There was also statistically significant decrease in survival of pks11 knockdown, pks12 knockdown and pks11pks12 double knockdown mutants compared to wild type P. marneffei in both J774 and THP1 macrophages (P<0.05). CONCLUSIONS/SIGNIFICANCE: The yellow pigment of the mold form of P. marneffei is composed of mitorubrinol and mitorubrinic acid. This represents the first discovery of PKS genes responsible for mitorubrinol and mitorubrinic acid biosynthesis. pks12 and pks11 are probably responsible for sequential use in the biosynthesis of mitorubrinol and mitorubrinic acid. Mitorubrinol and mitorubrinic acid are virulence factors of P. marneffei by improving its intracellular survival in macrophages. PMID- 23094123 TI - Emerging concept of tailored lymphadenectomy in endometrial cancer. PMID- 23094124 TI - Early human papillomavirus testing predicts residual/recurrent disease after LEEP. AB - OBJECTIVE: The purpose of this study was to determine the predictive factors for residual/recurrent disease and to analyze the timing for Pap smears and human papillomavirus (HPV) testing during follow-up after loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN) 2 or worse. METHODS: We retrospectively analyzed 183 patients (mean age, 39.3 years) with CIN 2/3 who were treated with LEEP. Post-LEEP follow-up was performed by Pap smear and HPV hybrid capture2 (HC2) testing. The definition of persistent/recurrent disease was biopsy-proven CIN 2 or worse. RESULTS: Among 183 patients, punch biopsies were CIN 2 in 31 (16.9%) and CIN 3 in 152 (83.1%). HPV HC2 tests before LEEP were positive in 170 (95.5%) of 178 patients. During follow-up, 12 patients (6.6%) had residual/recurrent CIN 2+. LEEP margin status was a significant predictive factor for persistent/recurrent disease. Other factors such as age, HPV HC2 viral load (>=100 relative light units), and HPV typing (type 16/18 vs. other types) did not predict recurrence. Early HPV HC2 testing at 3 months after LEEP detected all cases of residual/recurrent disease. The sensitivity and negative predictive value of the HPV HC2 test for residual/recurrent disease were both 100% at 3 and 6 months. CONCLUSION: Margin involvement in conization specimens was a significant factor predicting residual/recurrent disease after LEEP. HPV test results at 3 and 6 months after treatment were comparable. Early 3 month follow-up testing after LEEP can offer timely information about residual/recurrent disease and alleviate patient anxiety early about treatment failure. PMID- 23094125 TI - Comparison of outcomes between radical hysterectomy followed by tailored adjuvant therapy versus primary chemoradiation therapy in IB2 and IIA2 cervical cancer. AB - OBJECTIVE: To compare survival outcomes and treatment-related morbidities between radical hysterectomy (RH) and primary chemoradiation therapy (CRT) in patients with bulky early-stage cervical cancer. METHODS: We selected 215 patients with stage IB2 and IIA2 cervical cancer (tumor diameter > 4 cm on magnetic resonance imaging) who underwent RH followed by tailored adjuvant therapy (n=147) or primary CRT (n=68) at two tertiary referral centers between 2001 and 2010. RESULTS: About twenty nine percent of patients were cured by RH alone and these patients experienced the best survival outcomes with the lowest morbidity rates. After the median follow-up times of 40 months, 27 RH (18.4%) and 20 CRT (29.4%) patients had recurrence (p=0.068) and 23 (15.6%) and 17 (25%) patients died of disease (p=0.101). The 5-year progression-free survival were 77% and 66% (p=0.047), and the 5-year overall survival were 78% and 67% (p=0.048) after RH and primary CRT, respectively. In multivariate analysis, patients who received primary CRT was at higher risk for tumor recurrence (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.24 to 4.14; p=0.008) and death (OR, 3.02; 95% CI, 1.53 to 5.98; p=0.001) than those who received RH. Grade 3-4, early (17% vs. 30.9%, p=0.021) and late (1.4% vs. 8.8%, p=0.007) complications were significantly less frequent after RH than primary CRT. CONCLUSION: Thirty percent of patients were cured by RH alone. A treatment outcome was better in this retrospective study in terms of morbidity and survival. Randomized trials are needed to confirm this result. PMID- 23094126 TI - Comparison of concurrent chemoradiation therapy with weekly cisplatin versus monthly fluorouracil plus cisplatin in FIGO stage IIB-IVA cervical cancer. AB - OBJECTIVE: Concurrent chemoradiation therapy (CCRT) is the standard treatment for locally advanced cervical cancer. Although the optimal chemotherapeutic regimen is not yet defined, previous randomized trials have demonstrated that 5 fluorouracil (5-FU) plus cisplatin every 3 weeks and weekly cisplatin are the most popular regimens. The purpose of this study was to compare the outcomes of weekly CCRT with cisplatin and monthly CCRT with 5-FU plus cisplatin for locally advanced cervical cancer. METHODS: We retrospectively reviewed data from 255 patients with FIGO stage IIB-IVA cervical cancer. Patients were classified into two CCRT groups according to the concurrent chemotherapy: weekly CCRT group, consisted of CCRT with weekly cisplatin for six cycles; and monthly CCRT group, consisted of CCRT with cisplatin and 5-FU every 4 weeks for two cycles followed by additional consolidation chemotherapy for two cycles with the same regimen. RESULTS: Of 255 patients, 152 (59.6%) patients received weekly CCRT and 103 (40.4%) received monthly CCRT. The mean follow-up period was 39 months (range, 1 to 186 months). Planned CCRT was given to 130 (85.5%) patients in weekly CCRT group and 84 (81.6%) patients in monthly CCRT group, respectively. Severe adverse effects were more common in the monthly CCRT group than in the weekly CCRT group. There were no statistically significant differences in progression-free survival and overall survival between the two groups (p=0.715 and p=0.237). CONCLUSION: Both weekly CCRT and monthly CCRT seem to have similar efficacy for patients with locally advanced cervical cancer, but the weekly cisplatin is better tolerated. PMID- 23094127 TI - Pelvic exenteration for recurrent cervical cancer: ten-year experience at National Cancer Center in Korea. AB - OBJECTIVE: To evaluate survival and morbidity after pelvic exenteration (PE) for the curative management of recurrent cervical cancer. METHODS: We retrospectively evaluated patients with recurrent cervical cancer who underwent PE from January 2001 to April 2011. Patients were identified from the registry of our institution. The clinical status and demographic information was obtained by reviewing the medical records. RESULTS: Sixty-one recurrent cervical cancer patients underwent PE. Patients who received radiotherapy, operation, chemotherapy before PE were 98%, 41%, and 23%, respectively. The total morbidity rate was 44%; 10 (16%) patients had early complications (30 days or less after PE), whereas 22 (36%) patients had late complications. Wound problems were common early complications (7/18), and bowel fistulas were common late complications (9/30). The five-year overall survival and five-year disease-free survival were 56% and 49%, respectively. Median follow-up was 22 months (range, 1.8 to 60 months). Affecting factors for overall survival were resection margin status, pelvic wall and rectal involvement. CONCLUSION: Our overall 5-year survival is encouraging. Although the morbidity rate is still high, PE is a potentially curative opportunity in gynecological malignancies with no other treatment options. The most important factors for overall survival after PE are the resection margin status, pelvic wall involvement and rectal involvement. PMID- 23094128 TI - How low is low enough? Evaluation of various risk-assessment models for lymph node metastasis in endometrial cancer: a Korean multicenter study. AB - OBJECTIVE: The aim of this study was to identify a standard for the evaluation of future models for prediction of lymph node metastasis in endometrial cancer through estimation of performance of well-known surgicopathological models. METHODS: Using the medical records of 947 patients with endometrial cancer who underwent surgical management with lymphadenectomy, we retrospectively assessed the predictive performances of nodal metastasis of currently available models. RESULTS: WE EVALUATED THREE MODELS INCLUDED: 1) a model modified from the Gynecologic Oncology Group (GOG) pilot study; 2) one from the GOG-33 data; and 3) one from Mayo Clinic data. The three models showed similar negative predictive values ranging from 97.1% to 97.4%. Using Bayes' theorem, this can be translated into 2% of negative post-test probability when 10% of prevalence of lymph node metastasis was assumed. In addition, although the negative predictive value was similar among these models, the proportion that was classified as low-risk was significantly different between the studies (56.4%, 44.8%, and 30.5%, respectively; p<0.001). CONCLUSION: The current study suggests that a false negativity of 2% or less should be a goal for determining clinical usefulness of preoperative or intraoperative prediction models for low-risk of nodal metastasis. PMID- 23094129 TI - Risk factors for recurrence amongst high intermediate risk patients with endometrioid adenocarcinoma. AB - OBJECTIVE: To determine risk factors associated with recurrence in patients with high intermediate risk (HIR) endometrioid adenocarcinoma. METHODS: A retrospective analysis of patients with HIR endometrioid adenocarcinoma who underwent hysterectomy, bilateral salpingo-oophorectomy, with or without pelvic/para-aortic lymphadenectomy at the University of Pennsylvania between 1990 and 2009 was performed. RESULTS: A total of 103 women with HIR endometrial cancer were identified. Multivariable analysis revealed that >=2/3 myometrial invasion (HR, 4.79; p=0.010) and grade 3 disease (HR, 3.04; p=0.045) were independently predictive of distant metastases. The 5-year distant metastases free survival (DMFS) for patients with neither or one of these risk factors was 89%, and the 5 year DMFS for patients with both risk factors was 48% (p<0.001). CONCLUSION: Patients with both grade 3 disease and deep third myometrial invasion have a high risk of distant metastases. Identifying these patients may be important in rationally selecting patients for systemic therapy. PMID- 23094130 TI - Platelet to lymphocyte ratio as a prognostic factor for epithelial ovarian cancer. AB - OBJECTIVE: To determine whether preoperative platelets to lymphocyte ratio (PLR) could predict disease stage, surgical outcome, and survival in patients with epithelial ovarian cancer (EOC). METHODS: Medical records of EOC patients who had surgery between January 2004 and December 2010 were reviewed. Clinicopathological and complete blood count data were collected. The optimal predictive value of PLR to predict advanced stage, suboptimal surgery, and survival was determined and compared with those of thrombocytosis (>=400,000 cells/mm(3)) and neutrophil to lymphocyte ratio (NLR) >=2.6. RESULTS: A total of 166 EOC patients were included in the study. PLR of 200 yielded better predictive values than those of thrombocytosis and NLR >=2.6. The area under curve (AUC), sensitivity, specificity, positive and negative predictive values, and accuracy of PLR to predict advanced stage were: 0.66, 59.0%, 72.7%, 65.7%, 66.7%, and 66.3%, respectively. The corresponding values to predict suboptimal surgery were: 0.70, 70.0%, 69.8%, 50.0%, 84.4%, and 69.9%. The patients who had PLR>=200 had significantly shorter progression-free and overall survivals than those with PLR<200. Stage, grade, surgical outcome, thrombocytosis, and PLR were significant prognostic factors for survivals by univariable analyses while only stage remained significant by multivariable analysis. CONCLUSION: PLR had potential clinical value in predicting advanced stage disease or suboptimal surgery. PLR was a better prognostic indicator for survivals of EOC patients compared to thrombocytosis or NLR>2.6. PMID- 23094131 TI - Overexpression of CD73 in epithelial ovarian carcinoma is associated with better prognosis, lower stage, better differentiation and lower regulatory T cell infiltration. AB - OBJECTIVE: The purpose of the current study was to evaluate survival outcome according to the expression status of CD73 in patients with epithelial ovarian cancer. METHODS: A total of 167 patients with epithelial ovarian cancer were enrolled in the current study. For each patient, a retrospective review of medical records was conducted. Immunohistochemical staining for CD73, CD8, FoxP3, and CD68 was performed using tissue microarray made with paraffin embedded tissue block. RESULTS: Among the enrolled patients, 29.9% of patients (n=50) showed negative expression for CD73, whereas 70.1% of patients (n=117) showed positive expression for CD73. The CD73 positive group showed better prognosis compared to the CD73 negative group (5-year overall survival of CD73 positive group, 73.0%; that of CD73 negative group, 50.1%; p=0.023). CD73 was more frequently expressed in mucinous adenocarcinoma and clear cell carcinoma compared to serous or endometrioid adenocarcinoma. In addition, CD73 overexpressions were more frequently detected in patients with known good prognostic factors, i.e., low stage, well/moderate differentiation, negative peritoneal cytology, no lymphovascular involvement, and no macroscopic residual tumor after debulking surgery. There was significantly more infiltration of regulatory T cells in the CD73 negative group compared to the CD73 positive group. CONCLUSION: Good prognosis in patients with overexpression of CD73 may be due to that overexpression of CD73 was more frequently observed in epithelial ovarian cancer patients with known good prognostic factors. Therefore, this result means that favorable differentiation and stage have more influence on survival outcome than adverse effect of CD73 per se. PMID- 23094132 TI - New insights into cervical cancer screening. AB - Worldwide, cervical cancer is a leading cause of cancer related morbidity and mortality. For over 50 years, cervical cytology has been the gold standard for cervical cancer screening. Because of its profound effect on cervical cancer mortality in nations that have adopted screening programs, the Pap smear is widely accepted as the model screening test. Since its introduction, many studies have analyzed the Pap smear and found that it is not without its shortcomings including low sensitivity for detection of cervical intraepithelial neoplasia 2/3. Additionally, the discovery of infection with the human papillomavirus (HPV) as a necessary step in the development of cervical cancer has led to the development of HPV testing as an adjunct to cytology screening. More recently, researchers have compared HPV testing and cytology in the primary screening of cervical cancer. In this review, we will discuss cytologic testing limitations, the role of HPV DNA testing as an alternative screening tool, the impact of the HPV vaccine on screening, and future directions in cervical cancer screening. PMID- 23094133 TI - Sweet's syndrome: a cutaneous harbinger of ovarian carcinoma. AB - Sweet's syndrome, or acute febrile neutrophilic dermatosis, is a condition characterized by fever, neutrophilia, erythematous skin lesions, and a dermal infiltrate consisting predominantly of mature neutrophils on histology. Sweet's syndrome is a reactive phenomenon and should be considered a cutaneous marker of systemic disease, including underlying malignancy. We present a case of a 56-year old woman who presented with vague abdominal symptoms and a tender, erythematous rash on her extremities. Biopsy of her skin lesions revealed Sweet's syndrome. A work-up for malignancy eventually demonstrated a pelvic mass and carcinomatosis, and a diagnosis of advanced-stage papillary serous ovarian carcinoma was subsequently made. In postmenopausal women who present with Sweet's syndrome, a comprehensive evaluation for malignancy is indicated. In women with a known diagnosis of cancer, Sweet's syndrome may manifest in the detection of persistent or recurrent disease. PMID- 23094136 TI - Protease-catalysed direct asymmetric Mannich reaction in organic solvent. AB - We reported the first enzyme-catalysed, direct, three-component asymmetric Mannich reaction using protease type XIV from Streptomyces griseus (SGP) in acetonitrile. Yields of up to 92% with enantioselectivities of up to 88% e.e. and diastereoselectivities of up to 92:8 (syn:anti) were achieved under the optimised conditions. This enzyme's catalytic promiscuity expands the application of this biocatalyst and provides a potential alternative method for asymmetric Mannich reactions. PMID- 23094135 TI - Microbial diversity in long-term water-flooded oil reservoirs with different in situ temperatures in China. AB - Water-flooded oil reservoirs have specific ecological environments due to continual water injection and oil production and water recycling. Using 16S rRNA gene clone library analysis, the microbial communities present in injected waters and produced waters from four typical water-flooded oil reservoirs with different in situ temperatures of 25 degrees C, 40 degrees C, 55 degrees C and 70 degrees C were examined. The results obtained showed that the higher the in situ temperatures of the oil reservoirs is, the less the effects of microorganisms in the injected waters on microbial community compositions in the produced waters is. In addition, microbes inhabiting in the produced waters of the four water flooded oil reservoirs were varied but all dominated by Proteobacteria. Moreover, most of the detected microbes were not identified as indigenous. The objective of this study was to expand the pictures of the microbial ecosystem of water-flooded oil reservoirs. PMID- 23094137 TI - Conserved and divergent elements in Torso RTK activation in Drosophila development. AB - The repeated use of signalling pathways is a common phenomenon but little is known about how they become co-opted in different contexts. Here we examined this issue by analysing the activation of Drosophila Torso receptor in embryogenesis and in pupariation. While its putative ligand differs in each case, we show that Torso-like, but not other proteins required for Torso activation in embryogenesis, is also required for Torso activation in pupariation. In addition, we demonstrate that distinct enhancers control torso-like expression in both scenarios. We conclude that repeated Torso activation is linked to a duplication and differential expression of a ligand-encoding gene, the acquisition of distinct enhancers in the torso-like promoter and the recruitment of proteins independently required for embryogenesis. A combination of these mechanisms is likely to allow the repeated activation of a single receptor in different contexts. PMID- 23094138 TI - Differential expression of HIV-1 interfering factors in monocyte-derived macrophages stimulated with polarizing cytokines or interferons. AB - HIV-1 replication in macrophages can be regulated by cytokines and infection is restricted in macrophages activated by type I interferons and polarizing cytokines. Here, we observed that the expression levels of the cellular factors Trim5alpha, CypA, APOBEC3G, SAMHD-1, Trim22, tetherin and TREX-1, and the anti HIV miRNAs miR-28, miR-150, miR-223 and miR-382 was upregulated by IFN-alpha and IFN-beta in macrophages, which may account for the inhibiting effect on viral replication and the antiviral state of these cells. Expression of these factors was also increased by IFN-gamma +/- TNF-alpha, albeit to a lesser extent; yet, HIV-1 replication in these cells was not restricted at the level of proviral synthesis, indicating that these cellular factors only partially contribute to the observed restriction. IL-4, IL-10 or IL-32 polarization did not affect the expression of cellular factors and miRNAs, suggesting only a limited role for these cellular factors in restricting HIV-1 replication in macrophages. PMID- 23094139 TI - Artificial specific binders directly recovered from chemically modified nucleic acid libraries. AB - Specific binders comprised of nucleic acids, that is, RNA/DNA aptamers, are attractive functional biopolymers owing to their potential broad application in medicine, food hygiene, environmental analysis, and biological research. Despite the large number of reports on selection of natural DNA/RNA aptamers, there are not many examples of direct screening of chemically modified nucleic acid aptamers. This is because of (i) the inferior efficiency and accuracy of polymerase reactions involving transcription/reverse-transcription of modified nucleotides compared with those of natural nucleotides, (ii) technical difficulties and additional time and effort required when using modified nucleic acid libraries, and (iii) ambiguous efficacies of chemical modifications in binding properties until recently; in contrast, the effects of chemical modifications on biostability are well studied using various nucleotide analogs. Although reports on the direct screening of a modified nucleic acid library remain in the minority, chemical modifications would be essential when further functional expansion of nucleic acid aptamers, in particular for medical and biological uses, is considered. This paper focuses on enzymatic production of chemically modified nucleic acids and their application to random screenings. In addition, recent advances and possible future research are also described. PMID- 23094140 TI - Nucleic-Acid-binding chromophores as efficient indicators of aptamer-target interactions. AB - The binding affinity and specificity of nucleic acid aptamers have made them valuable candidates for use as sensors in diagnostic applications. In particular, chromophore-functionalized aptamers offer a relatively simple format for detection and quantification of target molecules. We describe the use of nucleic acid-staining reagents as an effective tool for detecting and signaling aptamer target interactions. Aptamers varying in size and structure and targeting a range of molecules have been used in conjunction with commercially available chromophores to indicate and quantify the presence of cognate targets with high sensitivity and selectivity. Our assay precludes the covalent modification of nucleic acids and relies on the differential fluorescence signal of chromophores when complexed with aptamers with or without their cognate target. We also evaluate factors that are critical for the stability of the complex between the aptamer and chromophore in presence or absence of target molecules. Our results indicate the possibility of controlling those factors to enhance the sensitivity of target detection by the aptamers used in such assays. PMID- 23094141 TI - Functional Annotation of Small Noncoding RNAs Target Genes Provides Evidence for a Deregulated Ubiquitin-Proteasome Pathway in Spinocerebellar Ataxia Type 1. AB - Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder caused by the expansion of CAG repeats in the ataxin 1 (ATXN1) gene. In affected cerebellar neurons of patients, mutant ATXN1 accumulates in ubiquitin-positive nuclear inclusions, indicating that protein misfolding is involved in SCA1 pathogenesis. In this study, we functionally annotated the target genes of the small noncoding RNAs (ncRNAs) that were selectively activated in the affected brain compartments. The primary targets of these RNAs, which exhibited a significant enrichment in the cerebellum and cortex of SCA1 patients, were members of the ubiquitin proteasome system. Thus, we identified and functionally annotated a plausible regulatory pathway that may serve as a potential target to modulate the outcome of neurodegenerative diseases. PMID- 23094142 TI - Potential of peptides as inhibitors and mimotopes: selection of carbohydrate mimetic peptides from phage display libraries. AB - Glycoconjugates play various roles in biological processes. In particular, oligosaccharides on the surface of animal cells are involved in virus infection and cell-cell communication. Inhibitors of carbohydrate-protein interactions are potential antiviral drugs. Several anti-influenza drugs such as oseltamivir and zanamivir are derivatives of sialic acid, which inhibits neuraminidase. However, it is very difficult to prepare a diverse range of sugar derivatives by chemical synthesis or by the isolation of natural products. In addition, the pathogenic capsular polysaccharides of bacteria are carbohydrate antigens, for which a safe and efficacious method of vaccination is required. Phage-display technology has been improved to enable the identification of peptides that bind to carbohydrate binding proteins, such as lectins and antibodies, from a large repertoire of peptide sequences. These peptides are known as "carbohydrate-mimetic peptides (CMPs)" because they mimic carbohydrate structures. Compared to carbohydrate derivatives, it is easy to prepare mono- and multivalent peptides and then to modify them to create various derivatives. Such mimetic peptides are available as peptide inhibitors of carbohydrate-protein interactions and peptide mimotopes that are conjugated with adjuvant for vaccination. PMID- 23094143 TI - Effects of metformin on the regulation of free Fatty acids in insulin resistance: a double-blind, placebo-controlled study. AB - Introduction. Impaired free fatty acid (FFA) metabolism is closely linked to insulin resistance. Our aim was to evaluate plasma FFA changes in insulin resistance in a physiological situation after improvement of insulin sensitivity by metformin. Methods. A double-blind, placebo-controlled intervention with metformin was carried out in patients with insulin resistance. Nineteen patients were randomized to receive metformin 850 mg b.i.d. during 6 weeks or placebo. Participants underwent a mental stress test and an oral glucose tolerance test (OGTT) before and after treatment. Results. Fasting plasma glucose, FFA, and HOMA IR tended to decrease after metformin, suggesting improved insulin sensitivity. FFA concentrations during the mental stress test showed a similar pattern after metformin, albeit lower at all time points, in contrast to the placebo group. The decrease in fasting plasma FFAs was positively associated to the decrease in HbA1c (r = 0.70; P = 0.03) and in fasting glucose (r = 0.74; P = 0.01). The suppression of plasma FFAs during OGTT did not change by metformin or placebo. Conclusion. Metformin in insulin resistance did not lead to improved FFA dynamics despite a trend of improved insulin sensitivity. Metformin most likely decreases plasma FFAs mainly by suppressing fasting FFA concentrations and not by suppression of acute stress-induced lipolysis. PMID- 23094144 TI - Flaxseed lignan complex administration in older human type 2 diabetics manages central obesity and prothrombosis-an invitation to further investigation into polypharmacy reduction. AB - Aim. Animal and human study evidence supports the hypothesis that flaxseed lignan complex (FLC) at a dose of 600 mg secoisolariciresinol diglucoside (SDG)/day for three months would combat hyperglycaemia, dyslipidemia, blood pressure, central obesity, prothrombotic state, inflammation, and low density lipoprotein (LDL) oxidation. Methods. Sixteen type 2 diabetic patients completed this double-blind, randomised crossover placebo-controlled study. A univariate repeated measures analysis of covariance (significance P < 0.05) was followed by a mixed linear model effects analysis corrected for multiple comparisons (MCC). Results. Prior to MCC, FLC caused decreased fasting plasma glucose, A1c, inflammation (c reactive protein (CRP) and interleukin-6 (IL-6)), and increased bleeding time. After correction for multiple comparisons, FLC induced a statistically significant increase in bleeding time and smaller waist circumference gain. No treatment effect occurred in the other variables before or after adjustment. Conclusions. It is concluded that FLC significantly increased bleeding time thus reducing the prothrombotic state, reduced central obesity gain as measured by waist circumference, and did not affect significantly the other dependent variables measured after adjustment for multiple comparisons. These findings, not yet published in human type 2 diabetes, suggest that this FLC dose over at least three months, may, subject to further investigation, reduce polypharmacy. PMID- 23094145 TI - A measure of depression in a modern asian community: singapore. AB - The construct validity of two depression measures, Zung's Self-rating Depression Scale (SDS) and the Asian Adolescents Depression Scale (AADS), was investigated. Three studies were conducted using two samples collected in two stages, and the results were used to construct the Asian Depression Scale (ADS). Participants responded to the SDS and AADS in random order of presentation during stage 1; two months later, validation variables were collected. Study 1 found that the SDS is a reliable and valid measure of depression for Singaporean Chinese, but it does not cover the interpersonal dimension found in the AADS. Study 2 combined the two measures and found six factors. One of these factors, negative social self, which was a unique Asian depressive symptom cluster, consisted only of AADS items, while the affective manifestation and psychosomatic symptoms factor primarily consisted of items from the SDS. Study 3 selected high-loading items from the identified factors to construct the ADS, which showed excellent internal reliability, and good convergent and discriminant validity. Incremental predictive validity found on criterion data collected in stage 2, supported the nonspuriousness of the Asian Depression Scale. PMID- 23094147 TI - Use and indications of human acellular dermis in ventral hernia repair at a community hospital. AB - Background. To evaluate the use, indications, and short-term outcomes for human acellular dermis. Methods. We retrospectively reviewed patients having human acellular dermis placed for ventral hernia repair from January 2008 through October 2009. Demographic information, operative details, and outcomes of patients with and without recurrences were compared; a P value <0.05 was considered significant. Results. 115 patients met inclusion criteria. The average age was 60 years (range, 24-89). The technique of repair included primary repair with overlay of mesh in 76%, bridge repair in 13%, and underlay in 11%. Average cost of mesh per operation was $3,709 (range $191-10,630). Open repairs were performed in 90% of patients with addition of component separation in 12%. At an average of 13 months, 58 patients were available for followup (50%), with a 47% recurrence rate. The morbidity rate was 48% and the mortality rate was 2%. Technique of repair was the only significant risk factor for recurrence with bridge repairs associated with a higher rate of recurrence (P < 0.05). Conclusions. The use of biologic grafts for ventral hernia repair is becoming more popular especially in clean cases. Although followup is limited, there remains a high recurrence rate associated with the use of human acellular dermis. PMID- 23094146 TI - Hepatitis C virus: a critical appraisal of new approaches to therapy. AB - The HCV council 2011 convened 11 leading clinicians and researchers in hepatitis C virus from academic medical centers in the United States to provide a forum for the practical and comprehensive evaluation of current data regarding best practices for integrating new direct-acting antiviral agents into existing treatment paradigms. The council investigated 10 clinical practice statements related to HCV treatment that reflect key topical areas. Faculty members reviewed and discussed the data related to each statement, and voted on the nature of the evidence and their level of support for each statement. In this new era of DAAs, a comprehensive and critical analysis of the literature is needed to equip clinicians with the knowledge necessary to design, monitor, and modify treatment regimens in order to optimize patient outcomes. PMID- 23094148 TI - Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. AB - Estrogen and growth factors play a major role in uterine leiomyoma (UtLM) growth possibly through interactions of receptor tyrosine kinases (RTKs) and estrogen receptor-alpha (ERalpha) signaling. We determined the genomic and nongenomic effects of 17beta-estradiol (E(2)) on IGF-IR/MAPKp44/42 signaling and gene expression in human UtLM cells with intact or silenced IGF-IR. Analysis by RT(2) Profiler PCR-array showed genes involved in IGF-IR/MAPK signaling were upregulated in UtLM cells by E(2) including cyclin D kinases, MAPKs, and MAPK kinases; RTK signaling mediator, GRB2; transcriptional factors ELK1 and E2F1; CCNB2 involved in cell cycle progression, proliferation, and survival; and COL1A1 associated with collagen synthesis. Silencing (si)IGF-IR attenuated the above effects and resulted in upregulation of different genes, such as transcriptional factor ETS2; the tyrosine kinase receptor, EGFR; and DLK1 involved in fibrosis. E(2) rapidly activated IGF-IR/MAPKp44/42 signaling nongenomically and induced phosphorylation of ERalpha at ser118 in cells with a functional IGF-IR versus those without. E(2) also upregulated IGF-I gene and protein expression through a prolonged genomic event. These results suggest a pivotal role of IGF-IR and possibly other RTKs in mediating genomic and nongenomic hormone receptor interactions and signaling in fibroids and provide novel genes and targets for future intervention and prevention strategies. PMID- 23094150 TI - Stereotactic body radiotherapy for metastatic lung cancer as oligo-recurrence: an analysis of 42 cases. AB - Purpose. To investigate the outcome and toxicity of stereotactic body radiotherapy (SBRT) in patients with oligo-recurrence cancer in the lung (ORCL). Methods and Materials. A retrospective review of 42 patients with ORCL who underwent SBRT in our two hospitals was conducted. We evaluated the outcome and adverse effects after SBRT for ORCL. Results. All patients finished their SBRT course without interruptions of toxicity reasons. The median follow-up period was 20 months (range, 1-90 months). The 2-year local control rate and overall survival were 87% (95% CI, 75-99%) and 65% (95% CI, 48-82%). As for prognostic factor, the OS of patients with a short disease-free interval (DFI) <31.9 months, between the initial therapy and SBRT for ORCL, was significantly worse than the OS of long DFI ?31.9 months (P < 0.05). The most commonly observed late effect was radiation pneumonitis. One patient had grade 4 gastrointestinal toxicity (perforation of gastric tube). No other ? grade 3 acute and late adverse events occurred. There were no treatment-related deaths during this study. Conclusions. In patients with ORCL, radical treatment with SBRT is safe and provides a chance for long-term survival by offering favorable local control. PMID- 23094149 TI - The immune response and its therapeutic modulation in bronchiectasis. AB - Bronchiectasis (BC) is a chronic pulmonary disease with tremendous morbidity and significant mortality. As pathogen infection has been advocated as a triggering insult in the development of BC, a central role for the immune response in this process seems obvious. Inflammatory cells are present in both the airways as well as the lung parenchyma, and multiple mediators of immune cells including proteases and cytokines or their humoral products are increased locally or in the periphery. Interestingly, a defect in the immune system or suppression of immune response during conditions such as immunodeficiency may well predispose one to the devastating effects of BC. Thus, the outcome of an active immune response as detrimental or protective in the pathogenesis of BC may be dependent on the state of the patient's immunity, the severity of infection, and the magnitude of immune response. Here we reassess the function of the innate and acquired immunity in BC, the major sites of immune response, and the nature of the bioactive mediators. Furthermore, the potential link(s) between an ongoing immune response and structural alterations accompanying the disease and the success of therapies that can modulate the nature and extent of immune response in BC are elaborated upon. PMID- 23094151 TI - Positive pressure for obesity hypoventilation syndrome. AB - Obesity is increasing world-wide; obesity hypoventilation syndrome (OHS), formerly Pickwickian syndrome, has increased in parallel. Despite its prevalence, OHS has not been studied well, but there is abundant evidence that it is tightly linked with sleep-disordered breathing, most commonly obstructive sleep apnea. This article reviews the pathophysiology of OHS as well as the literature regarding the benefits of treating this disorder with positive airway pressure. We also emphasize that while positive pressure treatments may temporize cardiopulmonary disease progression, simultaneous pursuit of weight reduction is central to long-term management of this condition. PMID- 23094152 TI - Effects of Heliox in Stable COPD Patients at Rest and during Exercise. AB - Heliox has been administered to stable chronic obstructive pulmonary disease (COPD) patients at rest and during exercise on the assumption that this low density mixture would have reduced work of breathing, dynamic hyperinflation, and, consequently, dyspnea sensation. Contrary to these expectations, beneficial effects of heliox in these patients at rest have been reported only sporadically, and the majority of the studies performed until now suggests that heliox is not a therapeutic option in spontaneously breathing resting COPD patients. On the other hand, when it is administered to COPD patients exercising at a constant work rate, heliox systematically decreases dyspnea sensation, and, often but not always, increases exercise tolerance. For these reasons, heliox has been evaluated as a non pharmacological tool to power rehabilitation programs. The conflicting results provided by the published trials probably point at a substantial heterogeneity of the COPD patients population in terms of respiratory mechanics and gas exchange. Therefore, further studies, aimed to the identification of mechanisms conditioning the response of exercising COPD patients to heliox, are warranted, before heliox administration, which is costly and cumbersome, can be routinely used in rehabilitation programs. PMID- 23094154 TI - The influence of effective energy on computed tomography number depends on tissue characteristics in monoenergetic cardiac imaging. AB - Purpose. To evaluate the influence of effective energy on computed tomography (CT) number in monoenergetic images (MEIs). Methods. Three bottle phantoms filled with water, oil, and a contrast agent were scanned at 100 and 140 kVp tube energy with a dual-source CT scanner. Cardiac dual-energy CT data was collected from 17 patients. CT numbers were measured in the 3 phantom materials and in the left ventricular cavity, myocardium, pericardial fat, and vertebral bone in MEIs from 40 to 190 keV. Results. In the phantoms, the mean CT number increased in oil whereas it decreased in the contrast agent as the energy level increased (P < 0.001). In clinical subjects, the mean CT numbers for the left ventricular cavity, myocardium, and vertebral bone were highest in the 40 keV images (P < 0.001) and decreased as the energy level increased. In contrast, the CT number for pericardial fat was lowest in the 40 keV images (P < 0.001) and increased with increasing energy. Conclusions. The influence of effective energy on CT number varies with material and tissue type in monoenergetic cardiac imaging, which could evaluate tissue characteristics through assessment of the changes in CT number associated with effective energies. PMID- 23094153 TI - Pulmonary hypertension in parenchymal lung disease. AB - Idiopathic pulmonary arterial hypertension (IPAH) has been extensively investigated, although it represents a less common form of the pulmonary hypertension (PH) family, as shown by international registries. Interestingly, in types of PH that are encountered in parenchymal lung diseases such as interstitial lung diseases (ILDs), chronic obstructive pulmonary disease (COPD), and many other diffuse parenchymal lung diseases, some of which are very common, the available data is limited. In this paper, we try to browse in the latest available data regarding the occurrence, pathogenesis, and treatment of PH in chronic parenchymal lung diseases. PMID- 23094155 TI - Epigenetic Methylation of Parathyroid CaR and VDR Promoters in Experimental Secondary Hyperparathyroidism. AB - Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we examined changes in methylation levels of parathyroid CaR and VDR promoters in vivo and in vitro. Methods. Uremia was induced by 5/6 nephrectomy. Melting temperature profiling of CaR and VDR PCR products after bisulfite treatment of genomic DNA from rat parathyroids was performed. Real-time PCR measured expression of PTH, CaR, VDR, and klotho genes in vitro. Results. Parathyroids from uremic rats had similar low levels of methylation in vivo and in vitro. In culture, a significant downregulation of CaR, VDR, and klotho within two hours of incubation was observed, while housekeeping genes remained stable for 24 hours. Conclusion. In uremic s-HPT and in vitro, no overall changes in methylation levels in the promoter regions of parathyroid CaR and VDR genes were found. Thus, epigenetic methylation of these promoters does not explain decreased parathyroid expression of CaR and VDR genes in uremic s-HPT. PMID- 23094156 TI - Urotensin-II: More Than a Mediator for Kidney. AB - Human urotensin-II (hU-II) is one of the most potent vasoconstrictors in mammals. Although both hU-II and its receptor, GPR14, are detected in several tissues, kidney is a major source of U-II in humans. Recent studies suggest that U-II may have a possible autocrine/paracrine functions in kidney and may be an important target molecule in studying renal pathophysiology. It has several effects on tubular transport and probably has active role in renal hemodynamics. Although it is an important peptide in renal physiology, certain diseases, such as hypertension and glomerulonephritis, may alter the expression of U-II. As might be expected, oxidative stress, mediators, and inflammation are like a devil's triangle in kidney diseases, mostly they induce each other. Since there is a complex relationship between U-II and oxidative stress, and other mediators, such as transforming growth factor beta1 and angiotensin II, U-II is more than a mediator in glomerular diseases. Although it is an ancient peptide, known for 31 years, it looks like that U-II will continue to give new messages as well as raising more questions as research on it increases. In this paper, we mainly discuss the possible role of U-II on renal physiology and its effect on kidney diseases. PMID- 23094157 TI - Renal function in patients with hypertension associated congestive cardiac failure seen in a tertiary hospital. AB - Background. Chronic kidney disease is frequently seen in patients with congestive cardiac failure and is an independent risk factor for morbidity and mortality. The aim of this study was to determine the prevalence of chronic kidney disease in patients with hypertension associated congestive cardiac failure. Method. One hundred and fifty patients with hypertension associated congestive cardiac failure were recruited consecutively from the medical outpatient department and the medical wards of the Nnamdi Azikiwe University Teaching Hospital Nnewi over a one year period, January to December 2010. Patients' biodata and medical history were obtained, detailed physical examination done and each patient had a chest X ray, 12 lead ECG, urinalysis, serum urea and creatinine assay done. Ethical clearance was obtained from the Ethical Review Board of our institution and data analysed using SPSS-version 16. Results. There were 86 males and 64 females with mean age 62.7 +/- 12.5 years. The mean blood pressures were systolic 152.8 +/- 28.5 mmHg and diastolic 94.3 +/- 18 mmHg. 84.7% had blood pressure >=140/90 mmHg on presentation. The mean GFR was 70.1 +/- 31.3 mls/min. 76% of subjects had GFR <90 mls/min and no statistical significant difference between males and females, P = 0.344. The mean serum urea was 7.2 +/- 51 mmol/L while the mean serum creatinine was 194 +/- 416.2 mmol/L. Conclusions. This study has demonstrated that majority of patients presenting with hypertension associated congestive cardiac failure have some degree of chronic kidney disease. PMID- 23094158 TI - Ready-to-Eat Cereal Consumption Patterns: The Relationship to Nutrient Intake, Whole Grain Intake, and Body Mass Index in an Older American Population. AB - Objective. To investigate the relationship between ready-to-eat (RTE) breakfast cereal consumption patterns and body mass index (BMI), nutrient intake, and whole grain intake in an older American population. Design. A cross-sectional survey of US households, collected by the NPD Group via the National Eating Trends (NET) survey. Main outcome measures include BMI, nutrient intake, and whole grain intake. Subjects/Setting. The sample included 1759 participants age 55 and older, which was divided into approximate quartiles based on intake of RTE breakfast cereal for the 2-week period (0 servings, 1-3 servings, 4-7 servings, and >=8 servings). Results. In the multivariate linear regression analysis adjusted for energy and age; intake of dietary fiber, whole grains, and the majority of micronutrients examined were found to be positively associated with frequent RTE cereal consumption. The proportion of participants consuming less than the Estimated Average Requirement (EAR) was lower for the highest quartile of RTE cereal consumers compared to nonconsumers, for the majority of vitamins and minerals examined. Significant differences in BMI between RTE breakfast cereal intake groups were found for men. Conclusion. Results suggest that ready-to-eat breakfast cereals may contribute to the nutritional quality of the diets of older Americans. Prospective studies and experimental trials are needed to better evaluate the role of RTE cereal consumption in energy balance. PMID- 23094160 TI - Evaluation of strength and irradiated movement pattern resulting from trunk motions of the proprioceptive neuromuscular facilitation. AB - Introduction. The proprioceptive neuromuscular facilitation (PNF) is a physiotherapeutic concept based on muscle and joint proprioceptive stimulation. Among its principles, the irradiation is the reaction of the distinct regional muscle contractions to the position of the application of the motions. Objective. To investigate the presence of irradiated dorsiflexion and plantar flexion and the existing strength generated by them during application of PNF trunk motions. Methods. The study was conducted with 30 sedentary and female volunteers, the PNF motions of trunk flexion, and extension with the foot (right and left) positioned in a developed equipment coupled to the load cell, which measured the strength irradiated in Newton. Results. Most of the volunteers irradiated dorsal flexion in the performance of the flexion and plantar flexion during the extension motion, both presenting an average force of 8.942 N and 10.193 N, respectively. Conclusion. The distal irradiation in lower limbs became evident, reinforcing the therapeutic actions to the PNF indirect muscular activation. PMID- 23094159 TI - The long and short of it: the role of telomeres in fetal origins of adult disease. AB - Placental insufficiency, maternal malnutrition, and other causes of intrauterine growth restriction (IUGR) can significantly affect short-term growth and long term health. Following IUGR, there is an increased risk for cardiovascular disease and Type 2 Diabetes. The etiology of these diseases is beginning to be elucidated, and premature aging or cellular senescence through increased oxidative stress and DNA damage to telomeric ends may be initiators of these disease processes. This paper will explore the areas where telomere and telomerase biology can have significant effects on various tissues in the body in IUGR outcomes. PMID- 23094161 TI - New trends in dermoscopy to minimize the risk of missing melanoma. AB - During the last decades, induction of dermoscopy in the clinical setting resulted in significant modifications in the management of melanocytic lesions. Indeed, the dermatoscope reveals a fascinating world of morphologic structures invisible to the naked eye, adding valuable information to a clinician evaluating a mole. However, since the technique counts only a couple of decades, new research data are continuously gathering and modify the "optimal" management of melanocytic lesions. In the present paper, we summarize the latest trends in dermoscopy concerning early melanoma diagnosis, management of nodular lesions, diagnosis of mucosal melanoma, and digital followup. PMID- 23094163 TI - Sensory deprivation and brain plasticity. PMID- 23094164 TI - Spinal anaesthesia for emergency caesarean section in a morbid obese woman with severe preeclampsia. AB - Background. Morbid obesity in a pregnancy is a great challenge to medical practice especially when the patient requires caesarean section. Case Summary. A 38-year-old unbooked gravida 3 Para 2(+0) weight 195 kg, height 1.7 m with a blood pressure of 210/160 mmhg had spinal anaesthesia for emergency caesarean section which was technically difficult for severe preeclampsia at 32-week gestation. She had poor wound healing and spent 18 days postoperatively on hospital admission. Conclusion. Morbid obesity is a challenge to both obstetric and anaesthetic practice. Antenatal care is necessary in reducing both maternal morbidity and mortality. PMID- 23094162 TI - Regulation of signal transduction by glutathione transferases. AB - Glutathione transferases (GST) are essentially known as enzymes that catalyse the conjugation of glutathione to various electrophilic compounds such as chemical carcinogens, environmental pollutants, and antitumor agents. However, this protein family is also involved in the metabolism of endogenous compounds which play critical roles in the regulation of signaling pathways. For example, the lipid peroxidation product 4-hydroxynonenal (4-HNE) and the prostaglandin 15 deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) are metabolized by GSTs and these compounds are known to influence the activity of transcription factors and protein kinases involved in stress response, proliferation, differentiation, or apoptosis. Furthermore, several studies have demonstrated that GSTs are able to interact with different protein partners such as mitogen activated protein kinases (i.e., c-jun N-terminal kinase (JNK) and apoptosis signal-regulating kinase 1 (ASK1)) which are also involved in cell signaling. New functions of GSTs, including S-glutathionylation of proteins by GSTs and ability to be a nitric oxide (NO) carrier have also been described. Taken together, these observations strongly suggest that GST might play a crucial role during normal or cancer cells proliferation or apoptosis. PMID- 23094165 TI - Cardiomyopathy associated with celiac disease in childhood. AB - Celiac disease is predominantly a disease of the small intestine characterized by chronic malabsorption in genetically susceptible individuals who ingest grains containing gluten, such as wheat, barley, and rye. Although previously believed to be uncommon, celiac disease may be present in up to 1% of the adult and children population. Celiac disease is associated frequently with iron-deficiency anemia, dermatitis herpetiformis, selective IgA deficiency, thyroid disorders, diabetes mellitus, and various connective tissue disorders but is rarely associated with cardiomyopathy. PMID- 23094166 TI - Whistle from afar: a case of endotracheal metastasis in papillary thyroid cancer. AB - Endotracheal metastasis is a rare situation, usually associated with malignancies of breast and gastrointestinal tract, specially colon. Papillary carcinoma of thyroid commonly disseminates through lymphatic channels and tracheal involvement through vascular route is rarely reported. Here, we report a case of tracheal metastasis from papillary carcinoma of thyroid. The patient responded to external beam radiation therapy with cobalt 60 beams in a dose of 44 Gy followed by a 16 Gy boost. The patient is under followup and is presently asymptomatic. This paper adds to the repertoire of evidence in treatment of endotracheal metastasis. PMID- 23094167 TI - Bevacizumab-induced reversible thrombocytopenia in a patient with adenocarcinoma of colon: rare adverse effect of bevacizumab. AB - We report a case of bevacizumab- (BEV-) induced thrombocytopenia in a 59-year-old man with adenocarcinoma of colon. After colectomy, the patient was treated with twelve cycles of FOLFOX-4 (folinic acid, 5-fluorouracil, and oxaliplatin) regimen. On relapse, he was treated with FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) regimen along with BEV 10 mg/kg for 6 cycles. After that, BEV was continued for maintenance as a single agent at an interval of three weeks. After the13th cycle of BEV, the patient developed melena with epistaxis and thrombocytopenia, from which he recovered on withdrawal of BEV. On rechallenge with half the initial dose, there was once again a reversible drop in platelet count. The proposed mechanism of thrombocytopenia may be immune-mediated peripheral destruction of platelets. PMID- 23094168 TI - Solitary extramedullary plasmacytoma of the thyroid gland. AB - Solitary extramedullary plasmacytoma of the thyroid gland is an uncommon condition. Up to date, its clinical pathological features are not fully understood. We present a case of an extramedullary nonmucosal plasmacytoma of the thyroid gland which is the first case with regional metastatic lymph nodes. This condition requires a scrupulous survey to rule out a metastatic multiple myeloma. Although localized forms management is still controversial, authors require combined approach for regional metastatic forms. The prognosis is favorable compared to solitary bone plasmacytomas or multiple myeloma. PMID- 23094169 TI - Thyroid tissue connected to normally located thyroid gland: ectopic or exophytic? AB - Ectopic thyroid tissue is seen rarely. It is often seen in cervical midline, and rarely in other areas such as submandibular area. Diagnosis is made histopathologically by fine needle biopsy after the elimination of malignancy. In the treatment of ectopic thyroid tissue, surgical excision is mostly applied. According to our knowledge, there is no exophytic thyroid tissue reported in the literature. In this paper, a 32-year-old woman who presented with a swelling under the right jaw and found a thyroid tissue attached to the normally located thyroid gland with a fibrous band in the neck was discussed. PMID- 23094170 TI - Chlamydia trachomatis tonsillopharyngitis. AB - Reports about the extragenital spread of Chlamydia trachomatis (CT) to oropharynx are limited. We report a male patient with progressive tonsillopharyngitis resistant to amoxicillin/clavulanic acid therapy. The patient presented 9 days after an orogenital and oroanal sexual intercourse with a female sex worker. The microimmunofluorescence revealed CT tonsillopharyngitis, and after completing a one-week course of doxycycline, the patient recovered completely. More cases of CT tonsillopharyngitis may be revealed if attention is paid to an association of sexual activity with enduring tonsillopharyngitis. PMID- 23094171 TI - Liesegang-like rings in lactational changes in the breast. AB - Liesagang-like rings (LR) are periodic structures with equally spaced radial striations formed by a process that involves diffusion, nucleation, flocculation or precipitation, and supersaturation. Being more common in vitro, on rare occasions also reported in vivo in association with inflammatory or cystic lesions and confused with parasites or calcification on needle aspirates. The current paper documents that LRs may be seen in noncystic and noninflammatory changes of the breast. PMID- 23094172 TI - Ectopic functioning adrenocortical oncocytic adenoma (oncocytoma) with myelolipoma causing virilization. AB - Functioning adrenal adenomas are well-described entities that can rarely occur outside the adrenal gland in the ectopic adrenal tissue. Similarly, myelolipoma is an another benign lesion of the adrenal tissue which can rarely occur outside the adrenal gland. We report the first case of a testosterone producing an extra adrenal adrenocortical oncocytoma accompanied by a myelolipoma. The patient presented with virilization and elevated androgen levels. Imaging revealed a retroperitoneal mass, which histologically consisted of oncocytes and intermingled myelolipoma. Postoperative androgen levels decreased to normal. The tumor cells were strongly positive for inhibin and Melan-A, supporting the adrenal origin. This case demonstrates a diagnostic challenge in which correlation with histology, immunohistochemistry, and serum endocrine studies led to the final diagnosis. PMID- 23094173 TI - Embryologic Association of Tornwaldt's Cyst with Cerebral Artery Abnormalities and Infarction: A Case Report. AB - Background and Purpose. Tornwaldt's cysts are rare nasopharyngeal lesions that develop from remnants of the embryonic notochord. Summary of Case. We reported a twelve-year-old female stroke patient with Tornwaldt's cysts, whose father also suffered a stroke at age fifty two with the presence of an abdominal aortic aneurysm, suggesting a genetic influence in this case. Conclusions. This paper suggests an etiologic connection between Tornwaldt's cysts and cerebral vasculature abnormalities by way of notochordal dysfunction during development, likely the result of perturbation of notochord-derived molecular cues during development or biogenesis. PMID- 23094175 TI - Symptomatic early congenital syphilis: a common but forgotten disease. AB - Congenital syphilis is a severe, disabling infection often with grave consequences seen in infants. It occurs due to the transmission of the disease from an infected mother to the unborn infant through the placenta. This long forgotten disease continues to affect pregnant women resulting in perinatal morbidity and mortality. The continuing prevalence of this disease reveals the failure of control measures established for its prevention. We put forth a case of symptomatic congenital syphilis presenting with skeletal manifestations at birth, a rare finding in literature. The report stresses upon the importance of implementing the World Health Organization's recommendation that all pregnant women should be screened for syphilis in the first antenatal visit in the first trimester and again in the late pregnancy. PMID- 23094174 TI - Nonconvulsive status epilepticus on electroencephalography: an atypical presentation of subacute sclerosing panencephalitis in two children. AB - Subacute sclerosing panencephalitis is a neurodegenerative disease secondary to measles infection that usually has a typical presentation with progressive myoclonia, cognitive decline, and periodic slow-wave complexes on electroencephalography. We report two pediatric cases who presented with periodic myoclonic jerks and cognitive decline. In both cases, the electroencephalogram showed continuous nonconvulsive status epilepticus activity. Both had elevated measles antibodies in cerebrospinal fluid and blood. Pediatricians need to be aware of this atypical presentation of subacute sclerosing panencephalitis. PMID- 23094176 TI - Congenital midline cervical cleft: diagnosis, pathologic findings, and early stage treatment. AB - Congenital midline cervical cleft is a very uncommon malformation of the anterior neck, with less than 100 cases reported in medical literature. Herein we present a case of a female neonate with this anomaly. A detailed description of the macroscopic and microscopic characteristics is performed. As it is derived from the natural history of the lesion, prompt clinical diagnosis, and operative treatment during early infancy predispose to a better aesthetic and functional prognosis. PMID- 23094177 TI - Rehabilitation of executive functions in a real-life setting: goal management training applied to a person with schizophrenia. AB - The aim was to assess the efficacy of a modified version of Goal Management Training (GMT) in a person with schizophrenia who had difficulties in attaining the final goal for new and multitasking daily-life situations. GMT is designed to improve abilities in establishing goal-directed plans and carrying them out effectively. Beneficial effects of GMT were measured for several clinical questionnaires, laboratory tasks, and three real-life situations: meal preparation (trained, familiar); washing (nontrained, familiar); meeting preparation (nontrained, unfamiliar). The results revealed improvement in planning and on trained laboratory and meal preparation tasks and a generalization of GMT effects on nontrained laboratory and everyday tasks. Self esteem also improved. Finally, a two-year followup indicated the durability of the beneficial effects. PMID- 23094178 TI - Agomelatine augmentation of escitalopram therapy in treatment-resistant obsessive compulsive disorder: a case report. AB - Obsessive-compulsive disorder (OCD) is a chronic condition characterized by obsessions or compulsions that cause distress or interfere with functioning. Selective serotonin reuptake inhibitors are the first-line strategy in the treatment of OCD, but approximately 40% to 60% of patients with OCD fail to respond to them. Several augmentation strategies have been proposed, including the use of atypical antipsychotics and antidepressant combinations. In the present paper we describe the case of a young female patient suffering from severe treatment-resistant OCD who remitted as a result of agomelatine augmentation of escitalopram therapy. PMID- 23094179 TI - Proximal dissection and rupture of a popliteal cyst: a case report. AB - Popliteal cysts are swellings in the popliteal fossa due to enlargement of the gastrocnemius semimembranous bursa. These cysts might burst, and they usually rupture posteriorly and inferiorly with severe pain in the calf. We describe a patient with popliteal cyst that dissected proximally and ruptured in the soft tissue of the thigh. PMID- 23094180 TI - "Heart appearance" infarction of the pons: a case report. AB - "Heart appearance" on magnetic resonance imaging (MRI) is a unique presentation of bilateral medial medullary infarction. In contrast, "heart appearance" infarction of the pons has rarely been featured in the medical literature. In this paper, we present a case of "heart appearance" infarction of the pons with its MRI and magnetic resonance angiography (MRA) findings. The patient was an 87 year-old male who manifested with weakness in the four extremities. Later, bulbar palsy and tetraplegia became apparent, and he eventually was trapped in locked-in syndrome. Brain MRI disclosed a "heart appearance" lesion in the pons, which was high on diffusion-weighted image MRI and low on apparent diffusion coefficient map MRI. Brain MRA demonstrated that the basilar artery remained intact. A diagnosis of fresh, bilateral pontine infarction with a "heart appearance" was made. After the treatment he was transferred to another hospital for long-term care. This case suggests that bilateral ischemic involvement of the pons is possible even in the context of an intact basilar artery. PMID- 23094181 TI - Remission achieved in refractory advanced takayasu arteritis using rituximab. AB - A 25-year-old patient was referred due to subclavian stenosis, identified on echocardiography. She presented with exertional dizziness and dyspnoea. Questioning revealed bilateral arm claudication. Examination demonstrated an absent right ulnar pulse and asymmetrical brachial blood pressure. Bruits were evident over both common carotid arteries. Doppler ultrasound and MRI angiograms revealed occlusion or stenosis in multiple large arteries. Takayasu arteritis (TA) was diagnosed and induction therapy commenced: 1 mg/kg oral prednisolone and 500 mg/m(2) intravenous cyclophosphamide (CYC). Attempts to reduce prednisolone below 15 mg/d proved impossible due to recurring disease activity. Adjuvant azathioprine 100 mg/d was subsequently added. Several weeks later, the patient was admitted with a left homonymous hemianopia. The culprit lesion in the right carotid artery was surgically managed and the patient discharged on azathioprine 150 mg/d and prednisolone 30 mg/d. Despite this, deteriorating exertional dyspnoea and angina pectoris were reported. Reimaging confirmed new stenosis in the right pulmonary artery. Surgical treatment proved infeasible. Given evidence of refractory disease activity on maximal standard therapy, we initiated rituximab, based on recently reported B-cell activity in TA. PMID- 23094182 TI - Primary malignant melanoma of the gallbladder: a case report and review of the literature. AB - Malignant melanoma is characterized by the ability of diffuse metastases. Since the first report of an isolated malignant melanoma case of the gallbladder, it is already controversial whether isolated cases are metastatic or primary tumors. A 49-year-old woman appealed to the emergency unit because of abdominal pain. Ultrasonography revealed increased thickness of the gallbladder wall and a lesion with surrounding fluid sized 12 mm without acoustic shadow, which arose from the gallbladder wall and was consistent with a polyp. Histopathologic evaluation of the surgical specimen after laparoscopic cholecystectomy revealed malign epithelial tumor consisting of atypical cells with large eosinophilic cytoplasm and dense melanin pigment within the cytoplasm of the tumor cells. As no other focus was identified as a result of the evaluation, the patient was diagnosed with primary malignant melanoma of the gallbladder. In this paper, we aimed to define our treatment modality for a case with isolated malignant melanoma of the gallbladder. PMID- 23094183 TI - Entrapment of a dormia basket in the cystic duct: case report. AB - Nowadays endoscopic treatment of common bile duct stones is considered the treatment of choice for all common bile duct stones. Although this procedure is related to a good success rate, in rare cases serious complications can happen, especially if you use a Dormia basket. Here we describe the clinical case of a patient affected by hepatolithiasis, cholelithiasis, and common bile duct lithiasis with entrapment of a Dormia basket in the cystic duct. It was necessary to perform a surgical choledochotomy to deal with this rare complication. PMID- 23094184 TI - Unusual Case of Metastatic Gastrointestinal Adenocarcinoma to the Cervical Spine without a Detectable Primary Source in a Patient with Acquired Immunodeficiency Syndrome: A Case Report. AB - The authors report a case of metastatic gastrointestinal adenocarcinoma to the cervical spine in a patient with acquired immunodeficiency syndrome (AIDS) being treated with antiretroviral therapy. The source of this tumor could not be identified despite a thorough evaluation. A 49-year-old male being treated for AIDS presents with worsening neck pain and left distal arm weakness. MRI demonstrated an erosive mass within the cervical four vertebral body extending through the pedicle on the left side. Patient underwent needle biopsy followed by combined anterior and posterior fusion procedures. Pathology demonstrated metastatic gastrointestinal adenocarcinoma without known primary origin. He is currently undergoing palliative radiotherapy. This is an unusual case of metastatic gastrointestinal adenocarcinoma to the cervical spine. This should be included on the differential diagnosis of spinal lesions in this patient population and may represent a unique tumor in patients with HIV/AIDS who are on immunosuppressive therapy. PMID- 23094185 TI - Fluoroscopy-guided resolution of ingested thrombus leading to functional disturbance of a continuous-flow left ventricular assist device. AB - The third generation of left ventricular assist devices (LVADs) has been shown to improve outcome and quality of life in patients suffering from acute and chronic heart failure. However, VAD-associated complications are still a challenge in the clinical practice. Here we report the resolution of a mobile thrombus formation in the proximity of the inflow cannula of a third generation of LVADs (HVAD Pump, HeartWare, Inc.) in a patient with chronic heart failure 4 months after implantation. PMID- 23094186 TI - Feasibility of robotic-assisted laparoscopic nephroureterectomy in left ventricular assist device patient. AB - Left ventricular assist devices (LVADs) have revolutionized management options for patients with advanced heart failure. It is not uncommon for patients treated with these devices to present with noncardiac surgical conditions including urologic problems. Maintaining perioperative hemodynamic and hematologic stability is a special challenge. The minimally invasive surgery provides well documented advantages over the open approach including a less operative blood loss and faster convalescence. In carefully selected patients, robotic-assisted surgery can be utilized in the management of patients with complex urologic diseases in a dire need for these benefits. We present the first case of robotic assisted laparoscopic nephroureterectomy (RANU) with retroperitoneal lymph node dissection for upper tract transitional cell carcinoma (TCC) in a patient treated with LVAD. PMID- 23094187 TI - Epidermal inclusion cyst presenting as a palpable scrotal mass. AB - We report a scrotal epidermal inclusion cyst located outside the median raphe which a rare entity in the absence of trauma and few cases have been reported. 47 year old male presents with a complaint of right sided testicular swelling and discomfort. On examination a 3 cm mass was palpated between the scrotum and the medial thigh on the subcutaneous tissue with a positive slip sign. Complete surgical excision of the cyst was performed. Histopathology confirmed epidermal inclusion cyst with no evidence of malignancy. PMID- 23094188 TI - Crossed Renal Ectopia without Fusion-An Unusual Cause of Acute Abdominal Pain: A Case Report. AB - Introduction. Crossed renal ectopia is a congenital anomaly which usually goes unnoticed as most cases are asymptomatic. The majority, 90% of these are fused. Case Presentation. We report an unusual presentation of a case of crossed renal ectopia without fusion. Our patient is a 16-year-old adolescent male, previously fit and healthy, who presented with acute onset of abdominal pain. The clinical suspicion was that of an abdominal aortic aneurysm. Computed tomography with intravenous contrast revealed nonfused crossed renal ectopia. Conclusion. Although renal ectopia is an uncommon cause of acute abdominal pain, there should be an index of clinical suspicion in previously healthy individuals presenting with acute abdominal pain. PMID- 23094189 TI - IgG4 Inflammatory Pseudotumor of the Kidney. AB - Hyper-IgG4 disease is a rare systemic disorder that usually affects middle age males. It is characterized by elevated serum IgG4 levels and infiltration of organs by IgG4 positive plasma cells associated with fibrosis. Patients usually present with mass or masses in the involved organ that mimic neoplasia. While initially described in the pancreas, IgG4-related inflammatory tumors have been now described in many organs. We describe an unusual case of an IgG4-related pseudotumor of the kidney. PMID- 23094190 TI - Carcinoid tumor in a mature thymic teratoma: a rare type of extra cardiac mass. AB - We describe the case of a young female affected by a thymus teratoma coexisting with carcinoid tumor. PMID- 23094191 TI - Ovarian mass causing paradoxical MI and leg ischaemia. AB - Paradoxical embolus through a patent foramen ovale is a well-reported phenomenon. Clinical consequences include stroke, intestinal infarction, lower limb ischaemia, and even acute myocardial infarction (MI), via embolisation to the coronary arteries. We present a case of acute MI, cardiogenic shock, and cardiac arrest caused not by this mechanism, but by embolisation of thrombotic material to the aortic root with transient complete occlusion of the left main stem (LMS) coronary artery. During percutaneous coronary intervention to treat this occlusion the thrombus became lodged at the aortic bifurcation causing lower limb ischaemia. Despite successful treatment of this via bilateral groin exploration and thromboembolectomy the patient became increasingly acidotic and an abdominal and pelvic CT scan was performed. This revealed the source of the thrombus to be the patient's congested and compressed pelvic veins which were the result of a large, previously undiagnosed ovarian malignancy with metastatic spread. Although very unusual we feel this case highlights an important differential in the diagnosis of anterolateral MI and images similar to those presented here are previously unreported in the literature. PMID- 23094192 TI - Variant branching pattern of axillary artery: a case report. AB - During routine dissection of an approximately 50-year-old male cadaver for the undergraduate medical students at Melaka Manipal Medical College, Manipal University, Manipal, we came across a variation in branching pattern of right axillary artery. The second part of axillary artery gave rise to a common trunk which divided into the subscapular and lateral thoracic arteries. The third part of right axillary artery gave rise to anterior and posterior circumflex humeral arteries. Variations in the branching pattern of axillary artery are important for the surgeons performing interventional or diagnostic procedures in cardiovascular diseases. PMID- 23094193 TI - "Register and Roll": A Novel Initiative to Improve First Door-to-Balloon Time in ST Elevation Myocardial Infarction. AB - Objective. We examined the cause of transfer delay in patients with an acute ST segment myocardial infarction (STEMI) from non percutaneous coronary intervention (PCI) capable to PCI capable hospitals. We then implemented a novel, simple, and reliable initiative to improve the transfer process. Background. Guidelines established by the ACC/AHA call for door-to-balloon times of <=90 minutes for patients with STEMI. When hospital transfer is necessary, this is only met in 8.6% of cases. Methods. All patients presenting with STEMI to a non-PCI capable hospital from April 2006 to February 2009 were analyzed retrospectively. After identifying causes of transfer delay the "Register and Roll" initiative was developed. An analysis of effect was conducted from March 2009 to July 2011. Results. 144 patients were included, 74 pre-initiative and 70 post- initiative. Time to EMS activation was a major delay in patient transfer. After implementation, the EMS activation time has significantly decreased and time to reperfusion approaches recommended goal (Median 114 min versus 90 min, P < 0.001), with 55% in <90 minutes. Conclusion. "Register and Roll" streamlines the triage process and improves hospital transfer times. This initiative is easily instituted and reliable in a community hospital setting where resources are limited. PMID- 23094195 TI - Drosophila melanogaster Selection for Survival of Bacillus cereus Infection: Life History Trait Indirect Responses. AB - To study evolved resistance/tolerance in an insect model, we carried out an experimental evolution study using D. melanogaster and the opportunistic pathogen B. cereus as the agent of selection. The selected lines evolved a 3.0- to 3.3-log increase in the concentration of spores required for 50% mortality after 18-24 generations of selection. In the absence of any treatment, selected lines evolved an increase in egg production and delayed development time. The latter response could be interpreted as a cost of evolution. Alternatively, delayed development might have been a target of selection resulting in increased adult fat body function including production of antimicrobial peptides, and, incidentally, yolk production for oocytes and eggs. When treated with autoclaved spores, the egg production difference between selected and control lines was abolished, and this response was consistent with the hypothesis of a cost of an induced immune response. Treatment with autoclaved spores also reduced life span in some cases and elicited early-age mortality in the selected and wound-control lines both of which were consistent with the hypothesis of a cost associated with induction of immune responses. In general, assays on egg production yielded key outcomes including the negative effect of autoclaved spores on egg production. PMID- 23094194 TI - Elevated angiopoietin-1 serum levels in patients with Alzheimer's disease. AB - Background. Alzheimer's disease (AD) is the most common cause of dementia in the elderly. AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles and by massive neuronal loss in the brain. There is epidemiologic and pathologic evidence that AD is associated with vascular risk factors and vascular diseases, contributing to cerebral hypoperfusion with consecutive stimulation of angiogenesis and upregulation of proangiogenic factors such as Angiopoietin-1 (Ang-1). Methods. In the present study, we measured Ang-1 serum levels in 42 patients with AD, 20 patients with mild cognitive impairment (MCI), and in 40 healthy elderly controls by ELISA. Results. We found significantly increased Ang-1 serum levels in patients with AD compared to control subjects (P = 0.003). There was no significant difference between MCI patients and healthy controls (P = 0.553) or between AD and MCI patients (P = 0.054). The degree of cognitive impairment as measured by the mini-mental status examination (MMSE) score was significantly correlated with the Ang-1 serum levels in all patients and healthy controls. Conclusions. We found significantly increased Ang-1 serum levels in AD patients. We could also show an association between Ang-1 serum levels and the cognitive status in all patients and healthy controls. Thus, serum Ang-1 could be a potential candidate for a biomarker panel for AD diagnosis. PMID- 23094196 TI - Rapamycin Augments the NMDA-Mediated TNF Suppression of MRSA-Stimulated RAW264.7 Murine Macrophages. AB - Background. Methicillin-resistant Staphylococcus aureus (MRSA) can stimulate massive cytokine release. Ketamine suppresses tumor necrosis factor (TNF) secretion by MRSA-stimulated RAW264.7 macrophages, and the mechanism likely involves N-methyl-D-aspartic acid (NMDA) receptor antagonism. The downstream effects of NMDA-mediated TNF suppression, specifically the PI3K/Akt and mTOR modulation, have not been described. Methods. RAW264.7 cells were stimulated for 18 hrs with 10(5) to 10(7) CFU/mL inocula of either of two prototypical community acquired- (CA-) MRSA isolates, USA300 strain LAC and USA400 strain MW2. Then we added the NMDA inhibitors ketamine or 2R-amino-5-phosphonopentanoate (AP5), NMDA substrate, LY294002, and rapamycin in various combinations. Results. NMDA inhibition suppressed TNF secretion by almost a third compared to the no-ketamine control. When NMDA substrate was added, the TNF secretion increased by 10%. Addition of LY294002 suppressed TNF production by macrophages by 20%. Rapamycin exhibited a concentration-dependent TNF induction-suppression response: induction at doses of 0.1 and 1 ng/mL and suppression at 10 and 100 ng/mL. Induction of TNF was abolished when LY294002 was added and the suppression became uniform. Ketamine-induced suppression of TNF secretion was intensified 10-15% when rapamycin was added, but not when LY294002 was added. Conclusion. These findings suggest that NMDA-induced TNF suppression can be augmented by concurrent mTOR inhibition. PMID- 23094197 TI - Effects of kalsis, a dietary supplement, on bone metabolism in the ovariectomized rats. AB - We studied the ability of Kalsis, a food supplement that contains selenium, citric acid, and vitamin E, to prevent the effects of ovariectomy on bone loss. Six-month-old, Wistar female rats were studied. Groups (n = 12): SHAM: sham operated rats; OVX: ovariectomized rats, treated with vehicle; OVX + Kalsis: ovariectomized rats treated with Kalsis (25 mg/kg/day) for 3 months. Bone mineral density (BMD) was determined by DXA in lumbar spine and femur. Computerized microtomography (MUCT) in femur and serum osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), beta-isomer of carboxyterminal telopeptide of collagen I (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase (TRAP) were performed. Treatment with Kalsis prevented BMD loss in OVX group. MUCT showed a decrease in BV/TV, and trabecular number, and an increase in trabecular separation in OVX rats. Kalsis administration attenuated partially bone loss observed by MUCT due to ovariectomy. BGP, PINP, and the resorption index (CTX/TRAP) were increased in OVX group. Treatment with Kalsis maintained this increase. The mechanism of action of this supplement is not through a decrease in bone remodelling rate. The antioxidant action of this food supplement, due to the synergism of all its components, as a cause of its beneficial effect is suggested. PMID- 23094198 TI - The prognostic value of lymph node cross-sectional cancer area in node-positive breast cancer: a comparison with N stage and lymph node ratio. AB - The number of positive axillary lymph nodes (LNs) is the only node-related factor for prognostic evaluation of breast cancer recognized by AJCC (TNM staging). However, N staging may not completely reflect LN tumor involvement due to the erroneous count of LNs in the presence of matted LNs and different tumor volume in LNs. Additionally, the positive/total LN ratio (LNR) has been shown to outperform N staging in survival prediction. In our study, to better quantify the tumor involvement of axillary LNs, we measured the cross-sectional cancer area (CSCA) of the positive LNs in 292 breast cancer patients diagnosed between 1998 and 2000 in our institution and compared its prognostic value to that of number of positive LNs (metLN)/N stage and LNR. Statistical analyses of these three LN related factors were performed by Kaplan-Meier method and multivariate Cox's regression model. Patients were divided into three groups based on the different LN CSCA (<50, 50-500, and >500 mm(2)), or LNR (<0.1, 0.1-0.65, and >0.65), or N stage (N1-N3). Multivariate analysis demonstrated LNR was the most significant LN related survival predictor with hazard ratio (HR) 25.0 (P = 0.001), compared to the metLN (HR 0.09, P = 0.052) and CSCA (HR 2.24, P = 0.323). PMID- 23094199 TI - Immunohistochemical expression of platelet-derived growth factor receptors in ovarian cancer patients with long-term follow-up. AB - Introduction. The well-documented role of the PDGF system in tumor growth and angiogenesis has prompted the development of new biological agents targeting the PDGF system. The aim of the present study was to analyze the expression of the PDGF-receptors in ovarian cancer and to investigate its relation to histopathological parameters and long-term overall survival. Methods. The immunohistochemical expression of PDGFR-alpha and PDGFR-beta was investigated in tumor and stromal cells in 170 patients with histologically verified epithelial ovarian cancer. Results. Almost half of the tumor specimens showed high expression of PDGFR-alpha and PDGFR-beta in tumor cells (43% and 41%) and in stromal compartments (32% and 44%). There was a significant association between high expression of PDGFR-alpha and high expression of PDGFR-beta in both tumor and stromal cells. Coexpression of PDGFR-alpha and PDGFR-beta in stromal cells was seen more often in serous adenocarcinomas than in nonserous adenocarcinomas. No clear correlation between PDGFR expression and longterm overall survival or clinical parameters was found. Conclusions. PDGFR-alpha and PDGFR-beta were expressed in a subset of ovarian carcinomas but did not show significant prognostic importance in this material. PMID- 23094200 TI - SenseWear Armband and Stroke: Validity of Energy Expenditure and Step Count Measurement during Walking. AB - The purpose of this study was to test the validity of the SenseWear Pro Armband (SWA) for the measurement of energy expenditure (EE) and step count against a criterion in persons with stroke. Twelve participants with chronic stroke (mean age 64.2 +/- 10.4 years; mean gait speed 0.67 +/- 0.25 m/sec) completed two trials of a six-minute walk test, while wearing a SenseWear Armband (SWA) on each arm and being continuously monitored using a portable metabolic cart. Agreement between estimates of energy expenditure from the SWA and the metabolic cart was fair for the armband on the hemiplegic arm (intraclass correlation cefficient (ICC) = 0.586) and good for the armband on the unaffected arm (ICC = 0.702). Agreement between the SWA estimate of step count, and step count as measured by the Step Activity Monitor was poor (ICC < 0.352), with significant underestimation by the SWA. Our results show that, for these moderately impaired persons with stroke, the SWA should be used with caution for the measurement of energy expenditure and should not be used to measure step count. PMID- 23094202 TI - Prostate stem cell antigen gene is expressed in islets of pancreas. AB - Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface antigen with an organ-dependent expression pattern in cancers; e.g., up regulated in prostate cancer and down-regulated in gastric cancer. Previously it was reported that PSCA is not expressed in the normal pancreas but aberrantly expressed in pancreatic cancer. In this present study, we identified PSCA expression in islets of the pancreas by immunohistochemistry, which was co localized with four islet-cell markers: insulin, glucagon, somatostatin and pancreatic polypeptide. In our investigation of the transcription start site of PSCA, we found a non-coding splicing variant of PSCA as well as authentic PSCA transcripts in mRNA samples from a normal pancreas. Both the transcripts were also identified in several pancreatic cancer cell lines. We previously reported that PSCA expression is correlated to the methylation status of the enhancer region in gastric and gallbladder cancer cell lines but not in pancreatic cancer cell lines, suggesting that PSCA expression is regulated in a diff erent mode in pancreatic cancer from that in gastric and gallbladder cancers. PMID- 23094201 TI - Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages. AB - Experimental autoimmune encephalomyelitis (EAE) in Lewis rats is an acute monophasic paralytic central nervous system disease, in which most rats spontaneously recover from paralysis. EAE in Lewis rats is induced by encephalitogenic antigens, including myelin basic protein. EAE is mediated by CD4(+) Th1 cells, which secrete pro-inflammatory mediators, and spontaneous recovery is mediated by regulatory T cells. Recently, it was established that classically activated macrophages (M1 phenotype) play an important role in the initiation of EAE, while alternatively activated macrophages (M2 phenotype) contribute to spontaneous recovery from rat EAE. This review will summarize the neuroimmunological aspects of active monophasic EAE, which manifests as neuroinflammation followed by neuroimmunomodulation and/or neuroprotection, with a focus on the role of alternatively activated macrophages. PMID- 23094203 TI - TonEBP and SMIT expression in human placenta. AB - Tonicity-responsive enhancer binding protein (TonEBP) is a signal transcription factor of transporters such as sodium-myo-inositol cotransporter (SMIT), aldose reductase. TonEBP has a variety of functions such as control of intracellular osmolytes and immunomodulating. It is known that TonEBP is abundant in the placenta, but location and function aren't known. The aim of this study is to describe the localization of TonEBP in the placenta. We assayed the immunohistochemistry of TonEBP and performed in situ hybridization of SMIT in normal human full term placenta. In normal human full term placenta, TonEBP was in villous trophoblasts, extravillous trophoblasts and some endothelial cells. The result of the in situ hybridization of SMIT was similar to that of immunohistochemistry of TonEBP. Neither TonEBP nor SMIT was present in TonEBP knockout mouse placenta. This shows TonEBP is a key factor in SMIT transcription. TonEBP may play an important role in transporting of inositol to fetus in placenta. PMID- 23094204 TI - Expression of Bis in the mouse gastrointestinal system. AB - The Bcl-2 interacting death suppressor (Bis) protein is known to be involved in a variety of pathophysiological conditions. We recently generated bis-deficient mice, which exhibited early lethality with typical nutritional deprivation status. To further investigate the molecular basis for the malnutrition phenotype of bis deficient mice, we explored Bis expression in the digestive system of normal mice. Western blot analysis and quantitative real time reverse transcription polymerase chain reaction analysis indicated that Bis expression is highest in the esophagus, followed by the stomach, colon, jejunum and ileum. Immunohistochemical data indicated that Bis expression is restricted to the stratified squamous epitheliums in the esophagus and forestomach, and was not notable in the columnar epitheliums in the stomach, small intestine and colon. In addition, strong Bis immunoreactivity was detected in the striated muscles surrounding the esophagus and smooth muscles at a lesser intensity throughout the gastrointestinal (GI) tract. Ganglionated plexuses, located in submucous layers, as well as intermuscular layers, were specifically immunoreactive for Bis. Immunofluorescence studies revealed that Bis is co-localized in glial fibrillary acidic protein-expressing enteric glial cells. Immunostaining with neuron specific esterase antibodies indicate that Bis is also present in the cell bodies of ganglions in the enteric nervous system (ENS). Our findings indicate that Bis plays a role in regulating GI functions, such as motility and absorption, through modulating signal transmission between the ENS and smooth muscles or the intestinal epitheliums. PMID- 23094205 TI - Aloe vera gel and thyroid hormone cream may improve wound healing in Wistar rats. AB - Therapeutic effects of various treatment options in wound healing have been one of the most controversial issues in surgical science. The present study was carried out to examine and compare the effects of Aloe vera gel, thyroid hormone cream and silver sulfadiazine cream onsutured incisions in Wistar rats. In a randomized controlled trial, thirty-six Wistar male rats, 250 to 300 g, received surgical incisions followed by topical application of Aloe vera gel, thyroid hormone cream and silver sulfadiazine 1%. To assess the efficacy of each treatment technique, a histological approach was used to evaluate the mean number of fibroblasts, macrophages, neutrophils, blood vessel sections and thickness of the regenerating epithelium and dermis on days 4, 7 and 14. Re-epithelialization and angiogenesis were significantly improved in Aloe vera gel group compared with the other treatments while thyroid hormone cream had positive effects on day 4 (P<=0.05). Topical administration of Aloe vera gel is recommended as the treatment of choice for surgical incisions. PMID- 23094206 TI - Effects of high-fat diet on the numerical density and number of neuronal cells and the volume of the mouse hypothalamus: a stereological study. AB - It has been demonstrated that the type of diet affects the brain structure and function. Consumption of fat-rich food is one of the most important factors that lead to increase in the prevalence of cardiovascular and neurological diseases. High-fat diet may change the volume and neuronal number or density in the hypothalamus, which is the center of energy control. Therefore, this study was designed to study the effect of high-fat diet on the density and number of neurons, and also the volume of hypothalamus in adult male mice. Forty male mice were divided into the control and experimental groups. The control group were fed with standard and the experimental groups, with high-fat diet for 4 (short-term) or 8 (long-term) weeks. The animals were perfused and brains were immediately removed, post-fixed and cut coronally and serially using cryostat at 30-um thickness. Every 6th sections were stained by cresyl violet. The numerical density and number of neuron and the volume of hypothalamus were estimated by using unbiased stereological methods. Data analysis showed that both short and long time consumption of high-fat diet decreased the neuronal cell density of the hypothalamus. Interestingly, despite a decrease in the neuronal cell density, long time consumption of high-fat diet could significantly increase the volume of hypothalamus (P<0.05). High fat diet decreased the neuronal cell density and increased the volume of the hypothalamus, but it did not significantly change its total neurons. These changes might be due to an increase in the extracellular space through inflammation or gliosis in the hypothalamus. PMID- 23094207 TI - Initial stage of fetal development of the pharyngotympanic tube cartilage with special reference to muscle attachments to the tube. AB - Fetal development of the cartilage of the pharyngotympanic tube (PTT) is characterized by its late start. We examined semiserial histological sections of 20 human fetuses at 14-18 weeks of gestation. As controls, we also observed sections of 5 large fetuses at around 30 weeks. At and around 14 weeks, the tubal cartilage first appeared in the posterior side of the pharyngeal opening of the PTT. The levator veli palatini muscle used a mucosal fold containing the initial cartilage for its downward path to the palate. Moreover, the cartilage is a limited hard attachment for the muscle. Therefore, the PTT and its cartilage seemed to play a critical role in early development of levator veli muscle. In contrast, the cartilage developed so that it extended laterally, along a fascia like structure that connected with the tensor tympani muscle. This muscle appeared to exert mechanical stress on the initial cartilage. The internal carotid artery was exposed to a loose tissue facing the tubal cartilage. In large fetuses, this loose tissue was occupied by an inferior extension of the temporal bone to cover the artery. This later-developing anterior wall of the carotid canal provided the final bony origin of the levator veli palatini muscle. The tubal cartilage seemed to determine the anterior and inferior margins of the canal. Consequently, the tubal cartilage development seemed to be accelerated by a surrounding muscle, and conversely, the cartilage was likely to determine the other muscular and bony structures. PMID- 23094208 TI - Col1a1-cre mediated activation of beta-catenin leads to aberrant dento-alveolar complex formation. AB - Wnt/beta-catenin signaling plays a critical role in bone formation and regeneration. Dentin and cementum share many similarities with bone in their biochemical compositions and biomechanical properties. Whether Wnt/beta-catenin signaling is involved in the dento-alveolar complex formation is unknown. To understand the roles of Wnt/beta-catenin signaling in the dento-alveolar complex formation, we generated conditional beta-catenin activation mice through intercross of Catnb(+/lox(ex3)) mice with Col1a1-cre mice. In mutant mice, tooth formation and eruption was disturbed. Lower incisors and molars did not erupt. Bone formation was increased in the mandible but tooth formation was severely disturbed. Hypomineralized dentin was deposited in the crown but roots of molars were extremely short and distorted. In the odontoblasts of mutant molars, expression of dentin matrix proteins was obviously downregulated following the activation of beta-catenin whereas that of mineralization inhibitor was increased. Cementum and periodontal ligament were hypoplastic but periodontal space was narrow due to increased alveolar bone formation. While cementum matrix proteins were decreased, bone matrix proteins were increased in the cementum and alveolar bone of mutant mice. These results indicate that local activation of beta-catenin in the osteoblasts and odontoblasts leads to aberrant dento-alveolar complex formation. Therefore, appropriate inhibition of Wnt/beta-catenin signaling is important for the dento-alveolar complex formation. PMID- 23094209 TI - Study on branching pattern of aortic arch in Indian. AB - Knowledge of the branching pattern of aortic arch is important during supra aortic angiography, aortic instrumentation, thoracic and neck surgery. The purpose of this study is to describe different branching pattern of arch of aorta in Indian subjects, in order to offer useful data to anatomists, radiologists, vascular surgeons while relating it to the embryological basis. Seventy five arches of adult Indian cadavers were exposed and their branches examined during cadaveric dissection in the Department of Anatomy, Government Medical College, Nagpur. The usual three-branched aortic arch was found in 58 cadavers (77.3%); the 11 (14.66%) remaining aortic arch showed only two branches, out of which one was a common trunk, which incorporated the brachiocephalic trunk and left common carotid and other left subclavian artery and 6 (8%) aortic arches showed direct arch origin of the left vertebral artery. Although the variations are usually asymptomatic, they may cause dyspnoea, dysphasia, intermittent claudication, misinterpretation of radiological examinations and complications during neck and thorax surgery. Knowledge of different patterns of arch of aorta is critical when invading the arch of aorta and its branches by instruments, as all these areas are delicate. PMID- 23094210 TI - Bilateral absence of musculocutaneous nerve with unusual branching pattern of lateral cord and median nerve of brachial plexus. AB - A 43-year-old female cadaver showed a complete bilateral absence of the musculocutaneous nerve. The anterior compartment muscles of both arms were supplied by median nerve excepting the coracobrachialis which was innervated by a direct branch from the lateral cord of brachial plexus. The median nerve, after supplying the biceps and brachialis muscles, gave onto the lateral cutaneous nerve of the forearm. The median nerve also showed variation on the left side where it was formed by two lateral roots and one medial root. Variations of the brachial plexus are of great interest to anatomists, clinicians and surgeons, in that they may be incorporated in their day to day practice. Our present case may be noted for its clinical and surgical significance in the variations of brachial plexus which can be useful for diagnostic purposes. PMID- 23094212 TI - Applied aspects of humane anatomy with advanced technologies. PMID- 23094211 TI - Variant insertion of the teres major muscle. AB - The teres major (TerMa) muscle has a clinical significance for tendon transfer procedures in patients with massive rotator cuff tears. Individually, it originates from the dorsum of the inferior angle of scapula and inserts into the medial lip of bicepital groove of the humerus. Functionally, TerMa in cooperation with latissimus dorsi (LD) adducts arm, medially rotates arm, and assists in arm extension. The variation of TerMa insertion is very rare. In the shoulder and axillary regions of a 33-year-old Thai male cadaver, the variant insertion of the right TerMa was found. The muscle fibers of TerMa are directly attached at the supero-medial border of LD tendon. Notably, there was no terminal tendon of TerMa. To explain an unusual movement of the arm, this rare variation of the TerMa insertion is necessary to be recognized. This case report is very important for surgeons to preoperatively consider using the terminal tendon of TerMa for tendon transfer in treating patients with irreparable cuff tears. PMID- 23094213 TI - From patch to repair. PMID- 23094214 TI - Clinical and functional anatomy of the urethral sphincter. AB - Continence and micturition involve urethral closure. Especially, insufficient strength of the pelvic floor muscles including the urethral sphincter muscles causes urinary incontinence (UI). Thus, it is most important to understand the main mechanism causing UI and the relationship of UI with the urethral sphincter. Functionally and anatomically, the urethral sphincter is made up of the internal and the external sphincter. We highlight the basic and clinical anatomy of the internal and the external sphincter and their clinical meaning. Understanding these relationships may provide a novel view in identifying the main mechanism causing UI and surgical techniques for UI. PMID- 23094216 TI - Noninvasive urodynamic evaluation. AB - The longevity of the world's population is increasing, and among male patients, complaints of lower urinary tract symptoms (LUTS) are growing. Testing to diagnose LUTS and to differentiate between the various causes should be quick, easy, cheap, specific, not too bothersome for the patient, and noninvasive or minimally so. Urodynamic evaluation is the gold standard for diagnosing bladder outlet obstruction (BOO) but presents some inconveniences such as embarrassment, pain, and dysuria; furthermore, 19% of cases experience urinary retention, macroscopic hematuria, or urinary tract infection. A greater number of resources in the diagnostic armamentarium could increase the opportunity for selecting less invasive tests. A number of groups have risen to this challenge and have formulated and developed ideas and technologies to improve noninvasive methods to diagnosis BOO. These techniques start with flowmetry, an increase in the interest of ultrasound, and finally the performance of urodynamic evaluation without a urethral catheter. Flowmetry is not sufficient for confirming a diagnosis of BOO. Ultrasound of the prostate and the bladder can help to assess BOO noninvasively in all men and can be useful for evaluating the value of BOO at assessment and during treatment of benign prostatic hyperplasia patients in the future. The great advantages of noninvasive urodynamics are as follows: minimal discomfort, minimal risk of urinary tract infection, and low cost. This method can be repeated many times, permitting the evaluation of obstruction during clinical treatment. A urethral connector should be used to diagnose BOO, in evaluation for surgery, and in screening for treatment. In the future, noninvasive urodynamics can be used to identify patients with BOO to initiate early medical treatment and evaluate the results. This approach permits the possibility of performing surgery before detrusor damage occurs. PMID- 23094215 TI - Characterization of bladder selectivity of antimuscarinic agents on the basis of in vivo drug-receptor binding. AB - The in vivo muscarinic receptor binding of antimuscarinic agents (oxybutynin, solifenacin, tolterodine, and imidafenacin) used to treat urinary dysfunction in patients with overactive bladder is reviewed. Transdermal administration of oxybutynin in rats leads to significant binding of muscarinic receptors in the bladder without long-term binding in the submaxillary gland and the abolishment of salivation evoked by oral oxybutynin. Oral solifenacin shows significant and long-lasting binding to muscarinic receptors in mouse tissues expressing the M(3) subtype. Oral tolterodine binds more selectively to muscarinic receptors in the bladder than in the submaxillary gland in mice. The muscarinic receptor binding of oral imidafenacin in rats is more selective and longer-lasting in the bladder than in other tissues such as the submaxillary gland, heart, colon, lung, and brain, suggesting preferential muscarinic receptor binding in the bladder. In vivo quantitative autoradiography with (+)N-[(11)C]methyl-3-piperidyl benzilate in rats shows significant occupancy of brain muscarinic receptors with the intravenous injection of oxybutynin, solifenacin, and tolterodine. The estimated in vivo selectivity in brain is significantly greater for solifenacin and tolterodine than for oxybutynin. Imidafenacin occupies few brain muscarinic receptors. Similar findings for oral oxybutynin were observed with positron emission tomography in conscious rhesus monkeys with a significant disturbance of short-term memory. The newer generation of antimuscarinic agents may be advantageous in terms of bladder selectivity after systemic administration. PMID- 23094217 TI - Effect of anti-siglec-f antibody and reactive oxygen species blocking on histamine release in urinary bladder of ovalbumin-treated mice. AB - PURPOSE: Sialic acid-binding Ig-like lectin (Siglec) is an immune inhibitory receptor that plays a role in the negative regulation of the activation of immune cells. This study aimed to evaluate the effects of anti-Siglec-F on plasma and urinary histamine levels in ovalbumin (OVA)-challenged urinary bladder in mice. METHODS: Thirty BALB/c mice were used. In group I (control group, n=5), mice were sensitized with OVA and challenged with saline. In group II (OVA challenge group, n=5), OVA was used for intraperitoneal sensitization and intravesical challenge. The challenged mice in group III (control immunoglobulin G [IgG] group, n=5) and those in group IV (anti-Siglec-F group, n=5) were intraperitoneally pretreated with rabbit control IgG or anti-Siglec-F antibody, respectively. In groups V (N acetylcysteine [NAC] in OVA challenge group, n=5) and VI (control NAC only, n=5), mice were pretreated with NAC. RESULTS: Urinary histamine concentrations were significantly higher 7 days after intravesical OVA challenge (P<0.01), whereas plasma histamine levels were not. Pretreatment with anti-Siglec-F antibody significantly prevented the increase in urinary histamine release (P<0.05), whereas pretreatment with the IgG antibody control did not. Also, pretreatment of the OVA challenge group with NAC did not affect the histamine concentration in either urine or plasma. CONCLUSIONS: Systemic anti-Siglec-F treatment showed anti allergic effects at least on local histamine release, particularly in the lower urinary bladder. PMID- 23094218 TI - Relationship between Body Mass Index and Overactive Bladder in Women and Correlations with Urodynamic Evaluation. AB - PURPOSE: Overactive bladder (OAB) is a common condition. In women, studies have shown that the prevalence of OAB is positively related to increasing body mass index (BMI). Our objective was to define a relationship between BMI and OAB through correlation with urodynamic study (UDS). METHODS: A prospective study was conducted. Ambulatory women aged 18 years or older who had symptoms of OAB for at least 3 months were enrolled. Patients answered a questionnaire, had their weight and height recorded, and underwent UDS. Patients were categorized into 3 groups as follows: group 1, BMI<25; group 2, BMI 25 to 29.9; and group 3, BMI>=30. RESULTS: A total of 113 patients were examined (group 1, n=32; group 2, n=40; group 3, n=41). The patients' mean ages were 50, 55, and 59 years for groups 1, 2, and 3, respectively (P<0.05). Group 3 showed a significant increase in the incidence of subjective mixed leakage and the number of pads used compared with groups 1 and 2. No significant differences were seen among the groups in duration of symptoms, OAB V-8 score, or the incidence of subjective urgency or stress leakage. The UDS parameters of groups 1, 2, and 3 showed no statistically significant differences for most variables. Group 3 showed a significant increase in the incidence of urge leakage by UDS compared with group 2 only. CONCLUSIONS: Increasing BMI was age related. A BMI>=30 showed a higher incidence of subjective urinary mixed leakage and pad use. UDS showed no significant correlation between OAB and any BMI category for most UDS parameters. PMID- 23094219 TI - Impact of lower urinary tract symptoms and depression on health-related quality of life in older adults. AB - PURPOSE: We aimed primarily to investigate the level of health-related quality of life (HRQoL), lower urinary tract symptoms (LUTS), and depression in older adults and secondly to identify the impact of LUTS and depression on HRQoL. METHODS: A community-based cross-sectional study was conducted from April to November 2010. Participants were recruited from five community senior centers serving community dwelling older adults in Jeju city. Data analysis was based on 171 respondents. A structured questionnaire was used to guide interviews; the data were collected including demographic characteristics, body mass index, adherence to regular exercise, comorbidities (hypertension, diabetes mellitus, and osteoarthritis), depression, urinary incontinence, LUTS (measured via the International Prostate Symptom Score [IPSS]), and HRQoL as assessed by use of the EQ-5D Index. Stepwise multiple regression analysis was used to test predictors of HRQoL. RESULTS: Eighteen percent (18.6%) of the respondents reported depressive symptoms. The mean LUTS score was 8.9 (IPSS range, 0 to 35). The severity of LUTS, was reported to be mild (score, 0 to 7) by 53% of the respondents, moderate (score, 8 to 19) by 34.5%, and severe (score, 20 to 35) by 12.5%. HRQoL was significantly predicted by depression (Partial R(2)=0.193, P<0.01) and LUTS (Partial R(2)=0.048, P=0.0047), and 24% of the variance in HRQoL was explained. CONCLUSIONS: LUTS and depression were the principal predictors of HRQoL in older adults. PMID- 23094220 TI - Botulinum toxin in neurogenic detrusor overactivity. AB - PURPOSE: To evaluate the effects of botulinum toxin on urodynamic parameters and quality of life in patients with neurogenic detrusor overactivity. METHODS: Thirty four adult patients with spinal cord injury and detrusor overactivity were selected. The patients received 300 units of botulinum toxin type A. The endpoints evaluated with the episodes of urinary incontinence and measured the maximum cystometric capacity, maximum amplitude of detrusor pressure and bladder compliance at the beginning and end of the study (24 weeks) and evaluated the quality of life by applying the Qualiveen questionnaire. RESULTS: A significant decrease in the episodes of urinary incontinence was observed. All urodynamic parameters presented a significant improvement. The same was observed in the quality of life index and the specific impact of urinary problems scores from the Qualiveen questionnaire. Six patients did not complete the study, two due to incomplete follow-up, and four violated protocol and were excluded from the analyses. No systemic adverse events of botulinum toxin type A were reported. CONCLUSIONS: A botulinum toxin type A showed a significantly improved response in urodynamics parameters and specific and general quality of life. PMID- 23094221 TI - Transvaginal cystocele repair by purse-string technique reinforced with three simple sutures: surgical technique and results. AB - PURPOSE: Different techniques for cystocele repair including the conventional anterior colporrhaphy and mesh technique are known. Our goal was to evaluate the anatomical success and safety of our method of transvaginal anterior vaginal wall repair by the purse-string technique reinforced with three simple additional sutures in the repair of cystocele over a 4-year follow-up period. METHODS: This was a retrospective review of 69 consecutive patients (grades 2 to 4) who underwent the above operations between 2001 and 2011, including their success rates as assessed by use of the Baden-Walker halfway classification system. RESULTS: Of the patients, 62 patients (98%) were completely cured of cystocele and 1 patient showed grade 2 cystocele recurrence that required no further treatment. Two patients with grade 4 cystocele were completely cured. There was no vaginal erosion related to the cystocele repair. CONCLUSIONS: Transvaginal anterior colporrhaphy by a purse-string technique reinforced with simple additive sutures appears to be a simple, safe, and easily performed approach in cystocele repair. There is no need for other material for reinforcement, even in high-grade cystocele, which is an advantage of our technique. PMID- 23094222 TI - Posterior urethral valve: delayed presentation in adolescence. AB - Posterior urethral valves (PUV) are now commonly suspected on antenatal ultrasound, but can present with a broad spectrum of severity postnatally. Rarely, the diagnosis is missed until adolescence or adulthood when the patient usually presents with lower urinary tract symptoms. We describe an even rarer case of PUV in a late adolescent who first presented with preserved renal function and urinary incontinence. We review the literature on presentation, natural history and outcomes of both early and late presenting PUV cases. PMID- 23094223 TI - An Organic Intravesical Foreign Body Caused by Penetrating Trauma that was Missed during Initial Management. AB - We report a case of an intravesical foreign body that was incompletely removed endoscopically and that defied diagnosis with current diagnostic tools. A 65-year old man visited Korea University Anam Hospital complaining of dysuria and a sensation of residual urine. His medical history included an intravesical foreign body caused by penetrating trauma, and he had undergone endoscopic removal of foreign bodies 1 year previously. After additional remnant intravesical foreign bodies were found, he had undergone additional endoscopic removal and his urinary symptoms subsided. After 2 years, however, he again presented to the clinic complaining of dysuria and gross hematuria. Cystoscopy and computed tomography for intravesical foreign bodies were performed, but no evidence of a remnant foreign body was found. Open exploration revealed a remnant foreign body penetrating the bladder. A partial cystectomy including the foreign body was performed. We suggest that cases of penetrating injury with a radiolucent object may warrant primary open exploration and foreign body removal owing to the inherent difficulties in diagnosis and endoscopic treatment of such objects. PMID- 23094224 TI - Intracorporeal anastomosis in laparoscopic gastric cancer surgery. AB - Laparoscopic gastrectomy has become widely used as a minimally invasive technique for the treatment of gastric cancer. When it was first introduced, most surgeons preferred a laparoscopic-assisted approach with a minilaparotomy rather than a totally laparoscopic procedure because of the technical challenges of achieving an intracorporeal anastomosis. Recently, with improved skills and instruments, several surgeons have reported the safety and feasibility of a totally laparoscopic gastrectomy with intracorporeal anastomosis. This review describes the recent technical advances in intracorporeal anastomoses using circular and linear staplers that allow for totally laparoscopic distal, total, and proximal gastrectomies. Data that demonstrate advantages in early surgical outcomes of a total laparoscopic method compared to laparoscopic-assisted operations are also discussed. PMID- 23094225 TI - Expression of intercellular adhesion molecule-1 and e-selectin in gastric cancer and their clinical significance. AB - PURPOSE: Among cell adhesion molecules, serum levels of intercellular adhesion molecule-1 and E-selectin are known to be correlated with the metastatic potential of gastric cancer. In the present study, the authors investigated the expression of intercellular adhesion molecule-1 and E-selectin in gastric cancer tissues and cultured gastric cancer cells, and examined their clinical value in gastric cancer. MATERIALS AND METHODS: The protein was extracted from gastric cancer tissues and cultured gastric cancer cells (MKN-28 and Kato-III) and the expression of intercellular adhesion molecule-1 and E-selectin was examined by western blotting. The clinical significance of intercellular adhesion molecule-1 and E-selectin was explored, using immunohistochemical staining of specimens from 157 gastric cancer patients. RESULTS: In western blot analysis, the expressions of intercellular adhesion molecule-1 in gastric cancer tissues and cultured gastric cancer cells were increased, however, E-selectin in gastric cancer tissues and cells were not increased. Among 157 gastric cancer patients, 79 patients (50%) were intercellular adhesion molecule-1 positive and had larger tumor size, an increased depth of tumor invasion, lymph node metastasis and perineural invasion. The intercellular adhesion molecule-1 positive group showed a higher incidence of tumor recurrence (40.5%), and a poorer 3-year survival than the negative group (54.9 vs. 85.9%, respectively). CONCLUSIONS: Intercellular adhesion molecule-1 is overexpressed in gastric cancer tissues and cultured gastric cancer cells, whereas E-selectin is not overexpressed. Increased expression of intercellular adhesion molecule-1 in gastric cancer could be related to the aggressive nature of the tumor, and has a poor prognostic effect on gastric cancer. PMID- 23094226 TI - Risk stratification for serosal invasion using preoperative predictors in patients with advanced gastric cancer. AB - PURPOSE: Although serosal invasion is a critical predisposing factor for peritoneal dissemination in advanced gastric cancer, the accuracy of preoperative assessment using routine imaging studies is unsatisfactory. This study was conducted to identify high-risk group for serosal invasion using preoperative factors in patients with advanced gastric cancer. MATERIALS AND METHODS: We retrospectively analyzed clinicopathological features of 3,529 advanced gastric cancer patients with Borrmann type I/II/III who underwent gastrectomy at Korea Cancer Center Hospital between 1991 and 2005. We stratified patients into low- (<=40%), intermediate- (40~70%), and high-risk (>70%) groups, according to the probability of serosal invasion. RESULTS: Borrmann type, size, longitudinal and circumferential location, and histology of tumors were independent risk factors for serosal invasion. Most tumors of whole stomach location or encircling type had serosal invasion, so they belonged to high-risk group. Patients were subdivided into 12 subgroups in combination of Borrmann type, size, and histology. A subgroup with Borrmann type II, large size (>=7 cm), and undifferentiated histology and 2 subgroups with Borrmann type III, large size, and regardless of histology belonged to high-risk group and corresponded to 25% of eligible patients. CONCLUSIONS: This study have documented high-risk group for serosal invasion using preoperative predictors. And risk stratification for serosal invasion through the combination with imaging studies may collaboratively improve the accuracy of preoperative assessment, reduce the number of eligible patients for further staging laparoscopy, and optimize therapeutic strategy for each individual patient prior to surgery. PMID- 23094227 TI - Comparison of Surgical Outcomes between Robotic and Laparoscopic Gastrectomy for Gastric Cancer: The Learning Curve of Robotic Surgery. AB - PURPOSE: Laparoscopic gastrectomy is a widely accepted surgical technique. Recently, robotic gastrectomy has been developed, as an alternative minimally invasive surgical technique. This study aimed to evaluate the question of whether robotic gastrectomy is feasible and safe for the treatment of gastric cancer, due to its learning curve. MATERIALS AND METHODS: We retrospectively reviewed the prospectively collected data of 100 consecutive robotic gastrectomy patients, from November 2008 to March 2011, and compared them to 282 conventional laparoscopy patients during the same period. The robotic gastrectomy patients were divided into 20 initial cases; and all subsequent cases; and we compared the clinicopathological features, operating times, and surgical outcomes between the three groups. RESULTS: The initial 20 robotic gastrectomy cases were defined as the initial group, due to the learning curve. The initial group had a longer average operating time (242.25+/-74.54 minutes vs. 192.56+/-39.56 minutes, P>0.001), and hospital stay (14.40+/-24.93 days vs. 8.66+/-5.39 days, P=0.001) than the experienced group. The length of hospital stay was no different between the experienced group, and the laproscopic gastrectomy group (8.66+/-5.39 days vs. 8.11+/-4.10 days, P=0.001). The average blood loss was significantly less for the robotic gastrectomy groups, than for the laparoscopic gastrectomy group (93.25+/-84.59 ml vs. 173.45+/-145.19 ml, P<0.001), but the complication rates were no different. CONCLUSIONS: Our study shows that robotic gastrectomy is a safe and feasible procedure, especially after the 20 initial cases, and provides a satisfactory postoperative outcome. PMID- 23094228 TI - Tumor size as a prognostic factor in gastric cancer patient. AB - PURPOSE: The purpose of this study is to investigate the prognostic significance of tumor size for 5-year survival rate in patients with gastric cancer. MATERIALS AND METHODS: A total of 1,697 patients with gastric cancer, who underwent potentially curative gastrectomy, were evaluated. Patients were divided into 4 groups as follows, according to the median size of early and advanced gastric cancer, respectively: small early gastric cancer (tumor size <=3 cm), large early gastric cancer (tumor size >3 cm), small advanced gastric cancer (tumor size <=6 cm), and large advanced gastric cancer (tumor size >6 cm). The prognostic value of tumor size for 5-year survival rate was investigated. RESULTS: In a univariate analysis, tumor size is a significant prognostic factor in advanced gastric cancer, but not in early gastric cancer. Multivariate analysis showed that tumor size is an independent prognostic factor for 5-year survival rate in advanced gastric cancer (P=0.003, hazard ratio=1.372, 95% confidence interval=1.115~1.690). When advanced gastric cancer is subdivided into 2 groups, according to serosa invasion: Group 1; serosa negative (T2 and T3, 7th AJCC), and Group 2; serosa positive (T4a and T4b, 7th AJCC), tumor size is an independent prognostic factor in Group 1 (P=0.011, hazard ratio=1.810, 95% confidence interval=1.149~2.852) and in Group 2 (P=0.033, hazard ratio=1.288, 95% confidence interval=1.020~1.627), respectively. CONCLUSIONS: Tumor size is an independent prognostic factor in advanced gastric cancer irrespective of the serosa invasion, but not in early gastric cancer. PMID- 23094229 TI - Transumbilical single-incision laparoscopic wedge resection for gastric submucosal tumors: technical challenges encountered in initial experience. AB - PURPOSE: To report the initial clinical experience with single-incision laparoscopic gastric wedge resection for submucosal tumors. MATERIALS AND METHODS: The medical records of 10 patients who underwent single-incision laparoscopic gastric wedge resection between July 2009 and March 2011 were reviewed retrospectively. The demographic data, clinicopathologic and surgical outcomes were assessed. RESULTS: The mean tumor size was 2.5 cm (range, 1.2~5.0 cm), and the tumors were mostly located on the anterior wall (4/10) or along the greater curvature (4/10), of the stomach. Nine of ten procedures were performed successfully, without the use of additional trocars, or conversion to laparotomy. One patient underwent conversion to multiport laparoscopic surgery, to get simultaneous cholecystectomy safely. The mean operating time was 66.5 minutes (range, 24~132 minutes), and the mean postoperative hospital stay was 5 days (range, 4~7 days). No serious perioperative complications were observed. Of the 10 submucosal tumors, the final pathologic report revealed 5 gastrointestinal stromal tumors, 4 schwannomas, and 1 heterotopic pancreas. CONCLUSIONS: Single incision laparoscopic gastric wedge resection for gastric submucosal tumors is feasible and safe, when performed by experienced laparoscopic surgeons. This technique provides favorable cosmetic results, and also short hospital stay and low morbidity, in carefully selected candidates. PMID- 23094230 TI - 18F-2-Deoxy-2-Fluoro-D-Glucose Positron Emission Tomography: Computed Tomography for Preoperative Staging in Gastric Cancer Patients. AB - PURPOSE: The use of 18F-2-deoxy-2-fluoro-D-glucose positron emission tomography computed tomography as a routine preoperative modality is increasing for gastric cancer despite controversy with its usefulness in preoperative staging. In this study we aimed to determine the usefulness of preoperative positron emission tomography-computed tomography scans for staging of gastric cancer. MATERIALS AND METHODS: We retrospectively analyzed 396 patients' positron emission tomography computed tomography scans acquired for preoperative staging from January to December 2009. RESULTS: The sensitivity of positron emission tomography-computed tomography for detecting early gastric cancer was 20.7% and it was 74.2% for advanced gastric cancer. The size of the primary tumor was correlated with sensitivity, and there was a positive correlation between T stage and sensitivity. For regional lymph node metastasis, the sensitivity and specificity of the positron emission tomography-computed tomography were 30.7% and 94.7%, respectively. There was no correlation between T stage and maximum standardized uptake value or between tumor markers and maximum standardized uptake value. Fluorodeoxyglucose uptake was detected by positron emission tomography-computed tomography in 24 lesions other than the primary tumors. Among them, nine cases were found to be malignant, including double primary cancers and metastatic cancers. Only two cases were detected purely by positron emission tomography computed tomography. CONCLUSIONS: Positron emission tomography-computed tomography could be useful in detecting metastasis or another primary cancer for preoperative staging in gastric cancer patients, but not for T or N staging. More prospective studies are needed to determine whether positron emission tomography computed tomography scans should be considered a routine preoperative imaging modality. PMID- 23094231 TI - Consideration of cardia preserving proximal gastrectomy in early gastric cancer of upper body for prevention of gastroesophageal reflux disease and stenosis of anastomosis site. AB - PURPOSE: The aim of this study is to evaluate the feasibility and safety of cardia preserving proximal gastrectomy, in early gastric cancer of the upper third. MATERIALS AND METHODS: A total of 10 patients were diagnosed with early gastric cancer of the upper third through endoscopic biopsy. The operation time, length of resection free margin, number of resected lymph nodes and postoperative complications, gastrointestinal symptoms, nutritional status, anastomotic stricture, and recurrence were examined. RESULTS: There were 5 males and 5 females. The mean age was 56.5+/-0.5 years. The mean operation time was 188.5+/ 0.5 minutes (laparoscopic operation was 270 minutes). Nine patients were T1 stage (T2 : 1), and N stage was all N0. The mean number of resected lymph nodes was 25.2+/-0.5. The length of proximal resection free margin was 3.1+/-0.1 cm and distal was 3.7+/-0.1 cm. Early complications were surgical site infection (1), bleeding (1), and gastro-esophageal reflux disease (1) (this symptom was improved with medication). Late complications were dyspepsia (3) (this symptom was improved without any treatment), and others were nonspecific results of endoscopy or symptom. CONCLUSIONS: Cardia preserving proximal gastrectomy was feasible for early gastric cancer of the upper third. Further evaluation and prospective research will be required. PMID- 23094232 TI - Changes of quality of life after gastric cancer surgery. AB - PURPOSE: The aim of this study was to evaluate chronological change of quality of life after surgery in patients with gastric cancer during one year postoperatively. MATERIALS AND METHODS: Quality of life data were obtained from 272 gastric cancer patients who underwent curative gastrectomy between September 2008 and February 2011 at the Kyungpook National University Hospital. The Korean versions of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core (QLQ) 30 with gastric cancer-specific module, the EORTC QLQ-STO22 were used to assess quality of life. All patients had no evidence of recurrence or metastasis during the first postoperative year. Patients were asked to complete the questionnaire, by themselves preoperatively, 3-, 6-, 9-, and 12-months postoperatively. RESULTS: Physical functioning score and role functioning score significantly decreased at first 3 months after surgery and the significant differences were noticed until 12 months after surgery. Emotional functioning score started with the lowest score before surgery and significant improvement was shown 6 months after surgery. Most symptom scores and STO-22 scores were highest at 3 months after surgery and gradually decreased, thereafter. Eating restriction, anxiety, taste, body image scores was highest at 3 months after surgery without significant decrease afterwards. CONCLUSIONS: Most scales worsened after surgery and gradually recovered afterwards with some differences in rate of recovery. However the scales did not fully recover by 1 year period. Further follow-up after 1 year would be helpful in determining which scales are permanently damaged and which are just taking longer time to recover. PMID- 23094233 TI - Gastroduodenal intussusception resulting from large hyperplastic polyp. AB - Gastroduodenal intussusception is an infrequent cause of gastrointestinal obstructive disease. Benign neoplasms, gastrointestinal stromal tumors and pedunculated adenocarcinomas of less than 5 cm have been reported to cause gastroduodenal intussusception. We report a case of 76-year-old woman who was presented with a 3-day history of nausea and vomiting due to upper gastrointestinal obstruction. Computed tomography revealed gastroduodenal intussusception with the transpyloric herniation of alarge gastric hyperplastic polyp. The patient underwent laparoscopic wedge resection with the eversion method. PMID- 23094235 TI - Harnessing the power of transposon mutagenesis for antibacterial target identification and evaluation. AB - Determining the mechanism of action of bacterial growth inhibitors can be a formidable challenge in the progression of small molecules into antibacterial therapies. To help address this bottleneck, we have developed a robust transposon mutagenesis system using a suite of outward facing promoters in order to generate a comprehensive range of expression genotypes in Staphylococcus aureus from which to select defined compound-resistant transposon insertion mutants. Resistance stemming from either gene or operon over/under-expression, in addition to deletion, provides insight into multiple factors that contribute to a compound's observed activity, including means of cell envelope penetration and susceptibility to efflux. By profiling the entire resistome, the suitability of an antibacterial target itself is also evaluated, sometimes with unanticipated results. We herein show that for the staphylococcal signal peptidase (SpsB) inhibitors, modulating expression of lipoteichoic acid synthase (LtaS) confers up to a 100-fold increase in the minimal inhibitory concentration. As similarly efficient transposition systems are or will become established in other bacteria and cell types, we discuss the utility, limitations and future promise of Tnp mutagenesis for determining both a compound's mechanism of action and in the evaluation of novel targets. PMID- 23094234 TI - Cytokinesis in Drosophila male meiosis. AB - Cytokinesis separates the cytoplasm and the duplicated genome into two daughter cells at the end of cell division. This process must be finely regulated to maintain ploidy and prevent tumor formation. Drosophila male meiosis provides an excellent cell system for investigating cytokinesis. Mutants affecting this process can be easily identified and spermatocytes are large cells particularly suitable for cytological analysis of cytokinetic structures. Over the past decade, the powerful tools of Drosophila genetics and the unique characteristics of this cell system have led researchers to identify molecular players of the cell cleavage machinery and to address important open questions. Although spermatocyte cytokinesis is incomplete, resulting in formation of stable intercellular bridges, the molecular mechanisms are largely conserved in somatic cells. Thus, studies of Drosophila male meiosis will shed new light on the complex cell circuits regulating furrow ingression and substantially further our knowledge of cancer and other human diseases. PMID- 23094236 TI - How Should Authors Address Copyright Issues before Submission of Manuscripts? PMID- 23094237 TI - Augmentation mammaplasty using implants: a review. AB - One of the techniques for augmentation mammaplasty is the procedure using implants. Even though this technique has been used for many years, there are still several controversial issues to be discussed and overcome for patient safety. In this review article, capsular contracture, leak or rupture of the implants, possible systemic disease, relation with breast cancer, and recent problems with Poly Implant Prothese implants are described and discussed. PMID- 23094238 TI - The effect of phosphatidylcholine and deoxycholate compound injections to the localized adipose tissue: an experimental study with a murine model. AB - BACKGROUND: Phosphatidylcholine (PPC) and deoxycholate (DCA) compound has been recently used for the purpose of partial lipolysis and is valued for its efficacy and lower invasiveness compared to liposuction and dermolipectomy used previously. In this article, the authors discuss the efficacy of the PPC dissolved in DCA via an experimental rat study model, along with suggesting a useful animal experimental model for the study of adipose tissue and lipolysis. METHODS: Bilateral inguinal fat pads of an experimental rat were elevated with the deep inferior epigastric vessel as the sole vascular pedicle. Normal saline was injected on one side as a control group and a PPC and DCA compound was injected on the other side. After 4 days, the rats were euthanized for microscopic tissue examination. The pathology was scored by a semiquantitative system in 4 categories: normal fat amount, fat necrosis, inflammatory activity, and stage of fibrosis. A Wilcoxon signed-rank test powered by SPSS packet program was used for statistical analysis and to determine significance. RESULTS: Microscopic examination was performed on the obtained samples, and the experimental data of all four categories showed significant histologic differences compared to the control group. All of the data also showed statistical significance by the Wilcoxon signedrank test (P<0.01). CONCLUSIONS: In the inguinal fat pad rat model, the control group and the experimental group had a differed significantly in the amount of normal fat tissue, inflammation, necrosis, and fibrosis. We recommend the rat inguinal fat pad model used in this study, as it is likely to be useful in related research. PMID- 23094239 TI - A skin fixation method for decreasing the influence of wound contraction on wound healing in a rat model. AB - BACKGROUND: The elasticity of the back skin of the rat reduced the tension around wounds during the wound healing process in that region, and thus activates wound contraction. The authors proposed two skin fixation methods using readily available materials to decrease the influence of wound contraction on wound healing and designed an experiment to determine their effects. METHODS: The authors made 36 skin wounds on the backs of 18 rats, and they divided them into three groups. Each group was treated with three different kinds of dressing materials, each with different skin fixing characteristics. Group A was a control group. Group B and group C were dressed by the first and the second skin fixation method. We measured the areas of the wounds post-surgically and calculated the wound area reduction rates. RESULTS: The two skin fixation methods both reduced the effect of wound contraction compared to the control group. Each of the two methods had different outcomes in reducing wound contraction. CONCLUSIONS: The experiment demonstrated significant differences among the wound areas and the wound area reduction rates of the three groups as a result of differences in the degree of wound contraction. To obtain accurate results from wound healing experiments, appropriate skin fixation methods must be adopted. PMID- 23094240 TI - Prognosis of full-thickness skin defects in premature infants. AB - BACKGROUND: In the extremities of premature infants, the skin and subcutaneous tissue are very pliable due to immaturity and have a greater degree of skin laxity and mobility. Thus, we can expect wounds to heal rapidly by wound contraction. This study investigates wound healing of full-thickness defects in premature infant extremities. METHODS: The study consisted of 13 premature infants who had a total of 14 cases of full-thickness skin defects of the extremities due to extravasation after total parenteral nutrition. The wound was managed with intensive moist dressings with antibiotic and anti-inflammatory agents. After wound closure, moisturization and mild compression were performed. RESULTS: Most of the full-thickness defects in the premature infants were closed by wound contraction without granulation tissue formation on the wound bed. The defects resulted in 3 pinpoint scars, 9 linear scars, and 2 round hypertrophic scars. The wounds with less granulation tissue were healed by contraction and resulted in linear scars parallel to the relaxed skin tension line. The wounds with more granulation tissue resulted in round scars. There was mild contracture without functional abnormality in 3 cases with a defect over two thirds of the longitudinal length of the dorsum of the hand or foot. The patients' parents were satisfied with the outcomes in 12 of 14 cases. CONCLUSIONS: Full-thickness skin defects in premature infants typically heal by wound contraction with minimal granulation tissue and scar formation probably due to excellent skin mobility. PMID- 23094241 TI - Surgical correction of whistle deformity using cross-muscle flap in secondary cleft lip. AB - BACKGROUND: The whistle deformity is one of the common sequelae of secondary cleft lip deformities. Santos reported using a crossed-denuded flap for primary cleft lip repair to prevent a vermilion notching. The authors modified this technique to correct the whistle deformity, calling their version the cross muscle flap. METHODS: From May 2005 to January 2011, 14 secondary unilateral cleft lip patients were treated. All suffered from a whistle deformity, which is characterized by the deficiency of the central tubercle, notching in the upper lip, and bulging on the lateral segment. The mean age of the patients was 13.8 years and the mean follow-up period was 21.8 weeks. After elevation from the lateral vermilion and medial tubercle, two muscle flaps were crossed and turned over. The authors measured the three vertical heights and compared the two height ratios before and after surgery for evaluation of the postoperative results. RESULTS: None of the patients had any notable complications and the whistle deformity was corrected in all cases. The vertical height ratios at the midline on the upper lip and the affected Cupid's bow point were increased (P<0.05). The motion of the upper lip was acceptable. CONCLUSIONS: A cross muscle flap is simple and it leaves a minimal scar on the lip. We were able to reconstruct the whistle deformity in secondary unilateral cleft lip patients with a single state procedure using a cross-muscle flap. PMID- 23094242 TI - Influence of the Alveolar Cleft Type on Preoperative Estimation Using 3D CT Assessment for Alveolar Cleft. AB - BACKGROUND: The bone graft for the alveolar cleft has been accepted as one of the essential treatments for cleft lip patients. Precise preoperative measurement of the architecture and size of the bone defect in alveolar cleft has been considered helpful for increasing the success rate of bone grafting because those features may vary with the cleft type. Recently, some studies have reported on the usefulness of three-dimensional (3D) computed tomography (CT) assessment of alveolar bone defect; however, no study on the possible implication of the cleft type on the difference between the presumed and actual value has been conducted yet. We aimed to evaluate the clinical predictability of such measurement using 3D CT assessment according to the cleft type. METHODS: The study consisted of 47 pediatric patients. The subjects were divided according to the cleft type. CT was performed before the graft operation and assessed using image analysis software. The statistical significance of the difference between the preoperative estimation and intraoperative measurement was analyzed. RESULTS: The difference between the preoperative and intraoperative values were -0.1+/-0.3 cm(3) (P=0.084). There was no significant intergroup difference, but the groups with a cleft palate showed a significant difference of -0.2+/-0.3 cm(3) (P<0.05). CONCLUSIONS: Assessment of the alveolar cleft volume using 3D CT scan data and image analysis software can help in selecting the optimal graft procedure and extracting the correct volume of cancellous bone for grafting. Considering the cleft type, it would be helpful to extract an additional volume of 0.2 cm(3) in the presence of a cleft palate. PMID- 23094243 TI - Algorithm for Primary Full-thickness Skin Grafting in Pediatric Hand Burns. AB - BACKGROUND: Pediatric hand burns are a difficult problem because they lead to serious hand deformities with functional impairment due to rapid growth during childhood. Therefore, adequate management is required beginning in the acute stage. Our study aims to establish surgical guidelines for a primary full thickness skin graft (FTSG) in pediatric hand burns, based on long-term observation periods and existing studies. METHODS: From January 2000 to May 2011, 210 patients underwent primary FTSG. We retrospectively studied the clinical course and treatment outcomes based on the patients' medical records. The patients' demographics, age, sex, injury site of the fingers, presence of web space involvement, the incidence of postoperative late deformities, and the duration of revision were critically analyzed. RESULTS: The mean age of the patients was 24.4 months (range, 8 to 94 months), consisting of 141 males and 69 females. The overall observation period was 6.9 years (range, 1 to 11 years) on average. At the time of the burn, 56 cases were to a single finger, 73 to two fingers, 45 to three fingers, and 22 to more than three. Among these cases, 70 were burns that included a web space (33.3%). During the observation, 25 cases underwent corrective operations with an average period of 40.6 months. CONCLUSIONS: In the volar area, primary full-thickness skin grafting can be a good indication for an isolated injured finger, excluding the web spaces, and injuries of less than three fingers including the web spaces. Also, in the dorsal area, full-thickness skin grafting can be a good indication. However, if the donor site is insufficient and the wound is large, split-thickness skin grafting can be considered. PMID- 23094244 TI - Usefulness of Oncoplastic Volume Replacement Techniques after Breast Conserving Surgery in Small to Moderate-sized Breasts. AB - BACKGROUND: In Korean women, many of whom have small to moderate-sized breasts, it is difficult to cover a partial breast defect using oncoplastic volume displacement techniques after removal of an adequate volume of tissue during oncologic surgery. In such cases, oncoplastic volume replacement techniques are more useful. METHODS: From January 2007 to December 2011, 104 women underwent a total of 107 breast-conserving surgeries with various kinds of oncoplastic volume replacement techniques. We used latissimus dorsi (LD) myocutaneous flap for cases in which the resection mass was greater than 150 g. In case with a resection mass less than 150 g, we used regional flaps such as a lateral thoracodorsal flap, a thoracoepigastric flap, or perforator flaps such as an intercostal artery perforator (ICAP) flap or a thoracodorsal artery perforator (TDAP) flap. RESULTS: The mean age was 46.1 years, and the average follow-up interval was 10.3 months. The patients underwent oncoplastic volume replacement techniques with a lateral thoracodorsal flap (n=9), thoracoepigastric flap (n=7), ICAP flap (n=25), TDAP flap (n=12), and LD flap (n=54). There was one case of congestion in an LD flap, and two cases of fat necrosis in an ICAP flap. Most of the patients were satisfied with the cosmetic results. CONCLUSIONS: Oncoplastic volume replacement techniques can be reliable and useful for the correction of breast deformity after breast-conserving surgery, especially in patients with small to moderate sized breasts. PMID- 23094245 TI - Reliability of reconstructed breast flap after chemotherapy and radiotherapy in immediate breast reconstruction. AB - BACKGROUND: Postmastectomy adjuvant therapy is used to prevent locoregional recurrence and improve overall breast cancer specific survival rates. However, it can adversely affect the cosmetic results of reconstruction. Therefore, the authors examined flap stability and patients' satisfaction with immediate breast reconstruction after adjuvant therapy. METHODS: We retrospectively reviewed the medical records of 204 patients from January 2006 to November 2011. For complication rates, the authors categorized the patients who underwent the immediate breast reconstruction into 4 groups: adjuvant chemotherapy and radiotherapy group, adjuvant chemotherapy only group, adjuvant radiotherapy only group, and the group that did not undergo adjuvant therapy. For comparison of patients' satisfaction, the study was performed with an additional 16 patients who had undergone delayed breast reconstruction. RESULTS: Regarding complication rates, the group that had undergone adjuvant therapy showed no significant difference compared to the group that did not undergo adjuvant therapy. In evaluating the patients' satisfaction, there was no significant difference. CONCLUSIONS: Even after adjuvant therapy, immediate breast reconstruction showed good results with respect to flap stability and patients' satisfaction. Immediate breast reconstruction and adjuvant therapy is a safe and useful option for breast cancer patients. PMID- 23094246 TI - Does fibrin sealant reduce seroma after immediate breast reconstruction utilizing a latissimus dorsi myocutaneous flap? AB - BACKGROUND: The most common complication of latissimus dorsi myocutaneous flap in breast reconstruction is seroma formation in the back. Many clinical studies have shown that fibrin sealant reduces seroma formation. We investigated any statistically significant differences in postoperative drainage and seroma formation when utilizing the fibrin sealant on the site of the latissimus dorsi myocutaneous flap harvested for immediate breast reconstruction after skin sparing partial mastectomy. METHODS: A total of 46 patients underwent immediate breast reconstruction utilizing a latissimus dorsi myocutaneous island flap. Of those, 23 patients underwent the procedure without fibrin sealant and the other 23 were administered the fibrin sealant. All flaps were elevated with manual dissection by the same surgeon and were analyzed to evaluate the potential benefits of the fibrin sealant. The correlation analysis and Mann-Whitney U test were used for analyzing the drainage volume according to age, weight of the breast specimen, and body mass index. RESULTS: Although not statistically significant, the cumulative drainage fluid volume was higher in the control group until postoperative day 2 (530.1 mL compared to 502.3 mL), but the fibrin sealant group showed more drainage beginning on postoperative day 3. The donor site comparisons showed the fibrin sealant group had more drainage beginning on postoperative day 3 and the drain was removed 1 day earlier in the control group. CONCLUSIONS: The use of fibrin sealant resulted in no reduction of seroma formation. Because the benefits of the fibrin sealant are not clear, the use of fibrin sealant must be fully discussed with patients before its use as a part of informed consent. PMID- 23094247 TI - Efficacy of quilting sutures and fibrin sealant together for prevention of seroma in extended latissimus dorsi flap donor sites. AB - BACKGROUND: The extended latissimus dorsi flap is important for breast reconstruction. Unfortunately, donor site seroma is the most common complication of extended latissimus dorsi flap for breast reconstruction. Although using fibrin sealant in the donor site reduces the rate of seroma formation, donor site seroma remains a troublesome complication. The purpose of this study was to analyze the effectiveness of the combination of quilting sutures and fibrin sealant in the latissimus dorsi donor site for the prevention of seroma. METHODS: Forty-six patients who underwent breast reconstruction with extended latissimus flap were enrolled in the study. The patients received either fibrin sealant (group 1, n=25) or a combination of fibrin sealant and quilting sutures (group 2, n=21) in the extended latissimus dorsi donor site. Outcome measures were obtained from the incidence, volume of postoperative seroma, total drainage amount, indwelling period of drainage, and duration of hospital stay. RESULTS: The incidence of seroma was 76% in group 1 and 42.9% in group 2 (P=0.022). We also found significant reductions in seroma volume (P=0.043), total drainage amount (P=0.002), indwelling period of drainage (P=0.01), and frequency of aspiration (P=0.043). The quilting sutures did not affect the rate of drainage, tube reinsertion, or hospital stay. CONCLUSIONS: The use of quilting sutures combined with fibrin sealant on the latissimus dorsi flap donor site is helpful for reducing the overall seroma volume, frequency of aspiration, and total drainage amount. PMID- 23094248 TI - Effects of preoperative biopsies on recurrence in head and neck skin cancer. AB - BACKGROUND: Skin cancer is the most common malignant tumor in humans. Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are the two most common types of skin cancers. When skin cancer is clinically suspected, preoperative biopsies are recommended for a definite diagnosis. However, despite a concern over potential increased risk of metastasis associated with mechanical manipulation, there have been few investigations into whether a preoperative biopsy affected the recurrence of BCC and SCC. METHODS: Primary BCC or SCC patients who underwent standard surgical excision from 1991 to 2010 were reviewed and a retrospective analysis was performed. Ultimately, 45 BCC patients and 54 SCC patients, who did not meet the exclusion criteria, were analyzed. To identify whether a preoperative biopsy affected the recurrence of BCC and SCC, the recurrence rates of each with and without biopsy were compared. RESULTS: Preoperative biopsy had no statistically significant effect on recurrence (BCC, P=0.8680; SCC, P=0.7520). Also, there was no statistical significance between the interval from initial biopsy to first operation and recurrence (BCC, P=0.2329; SCC, P=0.7140). Even though there was no statistical significance, the mean interval from the biopsy to the operation among the BCC patients who underwent preoperative biopsy was 9.2 months in those who had recurrence and 2.0 months in those who had no recurrence. CONCLUSIONS: There was no statistically significant relationship between preoperative biopsy and recurrence of BCC and SCC. However, there was a tendency toward recurrence in patients with a longer interval between the biopsy and the corrective operation in BCC. PMID- 23094249 TI - Analysis of 120 pectoralis major flaps for head and neck reconstruction. AB - BACKGROUND: A pectoralis major flap is one of the standard tools for the reconstruction of defects of the head and neck. Despite the technical advancement in free tissue transfer in head and neck reconstruction, the benefits of a pectoralis major flap should not be overlooked. The purpose of this study is to evaluate our 17 years of experience in reconstructing defects of the head and neck region using the pectoralis major flap. METHODS: We retrospectively reviewed the medical records of 112 patients (120 cases) who underwent pectoralis major flap operations for head and neck reconstruction during a period ranging from 1994 to 2010. RESULTS: In our series, no total necrosis of the flap occurred. Of the total cases, 30.8% presented with flap-related complications. Major complications occurred in 20% of all of the cases but were then all successfully treated. The male sex was correlated with the occurrence of overall complications (P=0.020) and major complications (P=0.007). Preoperative albumin levels of <3.8 g/dL were correlated with the formation of fistula (P=0.030). Defects of the hypopharynx were correlated with the occurrence of major complications (P=0.019) and the formation of fistula (P=0.012). Secondary reconstructions were correlated with the occurrence of overall complications (P=0.013) and the formation of fistula (P=0.030). CONCLUSIONS: A pectoralis major flap is still considered to be a safe, versatile one-stage reconstruction procedure in the management of the defects of head and neck and the protection of the carotid artery. PMID- 23094250 TI - Thickness of rectus abdominis muscle and abdominal subcutaneous fat tissue in adult women: correlation with age, pregnancy, laparotomy, and body mass index. AB - BACKGROUND: Rectus abdominis muscle and abdominal subcutaneous fat tissue are useful for reconstruction of the chest wall, and abdominal, vaginal, and perianal defects. Thus, preoperative evaluation of rectus abdominis muscle and abdominal subcutaneous fat tissue is important. This is a retrospective study that measured the thickness of rectus abdominis muscle and abdominal subcutaneous fat tissue using computed tomography (CT) and analyzed the correlation with the patients' age, gestational history, history of laparotomy, and body mass index (BMI). METHODS: A total of 545 adult women were studied. Rectus abdominis muscle and abdominal subcutaneous fat thicknesses were measured with abdominopelvic CT. The results were analyzed to determine if the thickness of the rectus abdominis muscle or subcutaneous fat tissue was significantly correlated with age, number of pregnancies, history of laparotomy, and BMI. RESULTS: Rectus abdominis muscle thicknesses were 9.58 mm (right) and 9.73 mm (left) at the xiphoid level and 10.26 mm (right) and 10.26 mm (left) at the umbilicus level. Subcutaneous fat thicknesses were 24.31 mm (right) and 23.39 mm (left). Rectus abdominismuscle thickness decreased with age and pregnancy. History of laparotomy had a significant negative correlation with rectus abdominis muscle thickness at the xiphoid level. Abdominal subcutaneous fat thickness had no correlation with age, number of pregnancies, or history of laparotomy. CONCLUSIONS: Age, gestational history, and history of laparotomy influenced rectus abdominis muscle thickness but did not influence abdominal subcutaneous fat thickness. These results are clinically valuable for planning a rectus abdominis muscle flap and safe elevation of muscle flap. PMID- 23094251 TI - Facial Soft Tissue Augmentation using Autologous Fat Mixed with Stromal Vascular Fraction. AB - BACKGROUND: Autologous fat grafting evolved over the twentieth century to become a quick, safe, and reliable method for restoring volume. However, autologous fat grafts have some problems including uncertain viability of the grafted fat and a low rate of graft survival. To overcome the problems associated with autologous fat grafts, we used uncultured adipose tissue-derived stromal cell (stromal vascular fraction, SVF) assisted autologous fat grafting. Thus, the purpose of this study was to evaluate the effect of SVF in a clinical trial. METHODS: SVF cells were freshly isolated from half of the aspirated fat and were used in combination with the other half of the aspirated fat during the procedure. Between March 2007 and February 2008, a total of 9 SVF-assisted fat grafts were performed in 9 patients. The patients were followed for 12 weeks after treatment. Data collected at each follow-up visit included clinical examination of the graft site(s), photographs for historical comparison, and information from a patient questionnaire that measured the outcomes from the patient perspective. The photographs were evaluated by medical professionals. RESULTS: Scores of the left facial area grafted with adipose tissue mixed with SVF cells were significantly higher compared with those of the right facial area grafted with adipose tissue without SVF cells. There was no significant adverse effect. CONCLUSIONS: The subjective patient satisfaction survey and surgeon survey showed that SVF assisted fat grafting was a surgical procedure with superior results. PMID- 23094252 TI - Usefulness of Intravenous Anesthesia Using a Target-controlled Infusion System with Local Anesthesia in Submuscular Breast Augmentation Surgery. AB - BACKGROUND: Patients have anxiety and fear of complications due to general anesthesia. Through new instruments and local anesthetic drugs, a variety of anesthetic methods have been introduced. These methods keep hospital costs down and save time for patients. In particular, the target-controlled infusion (TCI) system maintains a relatively accurate level of plasma concentration, so the depth of anesthesia can be adjusted more easily. We conducted this study to examine whether intravenous anesthesia using the TCI system with propofol and remifentanil would be an effective method of anesthesia in breast augmentation. METHODS: This study recruited 100 patients who underwent breast augmentation surgery from February to August 2011. Intravenous anesthesia was performed with 10 mg/mL propofol and 50 ug/mL remifentanil simultaneously administered using two separate modules of a continuous computer-assisted TCI system. The average target concentration was set at 2 ug/mL and 2 ng/mL for propofol and remifentanil, respectively, and titrated against clinical effect and vital signs. Oxygen saturation, electrocardiography, and respiratory status were continuously measured during surgery. Blood pressure was measured at 5-minute intervals. Information collected includes total duration of surgery, dose of drugs administered during surgery, memory about surgery, and side effects. RESULTS: Intraoperatively, there was transient hypotension in two cases and hypoxia in three cases. However, there were no serious complications due to anesthesia such as respiratory difficulty, deep vein thrombosis, or malignant hypertension, for which an endotracheal intubation or reversal agent would have been needed. All the patients were discharged on the day of surgery and able to ambulate normally. CONCLUSIONS: Our results indicate that anesthetic methods, where the TCI of propofol and remifentanil is used, might replace general anesthesia with endotracheal intubation in breast augmentation surgery. PMID- 23094253 TI - Fingertip reconstruction using free toe tissue transfer without venous anastomosis. AB - BACKGROUND: This study was designed to introduce the feasibility of toe tissue transfer without venous outflow for fingertip reconstruction. METHODS: Five cases of fingertip defects were treated successfully with this method. Four cases were traumatic fingertip defects, and one case was a hook-nail deformity. The lateral pulp of a great toe or medioinferior portion of a second toe was used as the donor site. An arterial pedicle was dissected only within the digit and anastomosis was performed within 2 cm around the defect margin. The digital nerve was repaired simultaneously. No additional dissection of the dorsal or volar pulp vein was performed in either the donor or recipient sites. Other surgical procedures were performed following conventional techniques. Postoperative venous congestion was monitored with pulp temperature, color, and degree of tissue oxygen saturation. Venous congestion was decompressed with a needle-puncture method intermittently, but did not require continuous external bleeding for salvage. RESULTS: Venous congestion was observed in all the flaps, but improved within 3 or 4 days postoperatively. The flap size was from 1.5*1.5 cm(2) to 2.0*3.0 cm(2). The mean surgical time was 2 hours and 20 minutes. A needle puncture was carried out every 2 hours during the first postoperative day, and then every 4 hours thereafter. The amount of blood loss during each puncture procedure was less than 0.2 mL. In the long-term follow-up, no flap atrophy was observed. CONCLUSIONS: When used properly, the free toe tissue transfer without venous anastomosis method can be a treatment option for small defects on the fingertip area. PMID- 23094254 TI - Application of Mini-abdominoplasty after Conservative Excision of Extensive Cesarean Scar Endometriosis. AB - Endometriosis is defined as the presence of functioning endometrial tissue outside the uterine cavity, and the standard treatment is extensive surgical excision. Cesarean scar endometriosis is a type of cutaneous endometriosis arising on or near a Cesarean section scar. A 44-year-old woman presented with a 9*6 cm sized dark-brown, stony-hard, irregular, lower abdominal mass of four years duration. The patient had a history of two Cesarean deliveries, 14 and 16 years ago. Suspecting endometriosis, we excised the tumor conservatively rather than extensively to prevent incisional hernia considering the benign nature of the tumor and the low possibility of recurrence because the patient's age was near menopause, along with simultaneous bilateral salpingo-oophorectomy that was performed in this case. On reconstruction, mini-abdominoplasty was adopted to avoid possible wound complications and cosmetic deformities. The patient was satisfied with the cosmetic results, and neither recurrence nor functional problems occurred during the 1-year follow-up period. Plastic surgeons should keep in mind the possibility of cutaneous endometriosis in an abdominal mass of a female of reproductive age with a previous history of pelvic or intra-abdominal surgery. An optimal result from oncological, functional, and cosmetic standpoints can be achieved with conservative excision followed by mini-abdominoplasty of extensive Cesarean scar endometriosis. PMID- 23094255 TI - Reduction of Zygomatic Fractures Using the Carroll-Girard T-bar Screw. AB - Zygomatic fractures are the second most common facial bone fractures encountered and treated by plastic surgeons. Stable fixation of fractured fragments after adequate exposure is critical for ensuring three-dimensional anatomic reduction. Between January 2008 and December 2010, 17 patients with zygomatic fractures were admitted to our hospital; there were 15 male and 2 female patients. The average age of the patients was 41 years (range, 19 to 75 years). We exposed the inferior orbital rim and zygomatic complex through a lateral brow, intraoral, and subciliary incisions, which allowed for visualization of the bone, and then the fractured parts were corrected using the Carroll-Girard T-bar screw. Postoperative complications such as malar asymmetry, diplopia, enophthalmos, and postoperative infection were not observed. Lower eyelid retraction and temporary ectropion occurred in 1 of the 17 patients. Functional and cosmetic results were excellent in nearly all of the cases. In this report, we describe using the Carroll-Girard T-bar screw for the reduction of zygomatic fractures. Because this instrument is easy to use and can rotate to any direction and vector, it can be used to correct displaced zygomatic bone more accurately and safely than other devices, without leaving facial scars. PMID- 23094256 TI - The efficacy of bioabsorbable mesh as an internal splint in primary septoplasty. AB - Nasal bone fractures are often accompanied by septal fractures or deformity. Posttraumatic nasal deformity is usually caused by septal fractures. Submucosal resection and septoplasty are commonly used surgical techniques for the correction of septal deviation. However, septal perforation or saddle nose deformity is a known complication of submucosal resection. Hence, we chose to perform septoplasty, which is a less invasive procedure, as the primary treatment for nasal bone fractures accompanied by septal fractures. During septoplasty, we used a bioabsorbable mesh as an internal splint. We used the endonasal approach and inserted the mesh bilaterally between the mucoperichondrial flap and the septal cartilage. The treatment outcomes were evaluated by computed tomography (CT) and the nasal obstruction symptom evaluation (NOSE) scale. The CT scans demonstrated a significant improvement in the septal deviation postoperatively. The symptomatic improvement rated by the NOSE scale was greater at 1 month and 6 months after surgery compared to the preoperative status. There were no cases of extrusion or infection of the implant. In cases of moderate or severe septal deviation without dislocation from the vomerine groove on the CT scan, our technique should be considered one of the treatments of choice. PMID- 23094257 TI - Management of malignant melanoma. PMID- 23094258 TI - Regraft from Amputated Forehead Tissue of a 4*7 cm Skin Defect Containing Bony Defects. PMID- 23094259 TI - Primary adenocarcinoma of the lacrimal gland. PMID- 23094260 TI - High mobility group B1 levels in sepsis and Disseminated Intravascular Coagulation. AB - Cytokines trigger coagulant and fibrinolytic systems in sepsis to result in Disseminated Intravascular Coagulation (DIC) that is an important complication and leads to disseminated hemorrhages and multi-organ failure. High Mobility Group B1 DNA Binding (HMGB1) protein is a cytokine taking part in systemic inflammatory response. The objective of this study was to investigate HMGB1 levels in groups of septic patients with and without DIC.Twenty-one septic patients without DIC and 12 septic patients with DIC from the Intensive Care Unit (ICU) were included in the study. In addition, 20 patients admitted to the ICU without sepsis or DIC and 20 healthy volunteers served as controls. Levels of HMGB1, prothrombin time, activated partial thromboplastin time, fibrinogen, D dimer, protein C, protein S, anti-thrombin III (ATIII), platelet (thrombocyte) and leukocyte count were determined. Levels of fibrinogen, protein C, ATIII and platelet count were significantly lower and D-dimer was significantly higher in the group with sepsis plus DIC compared to the group with sepsis without DIC. Levels of HMGB1 were higher in the group with sepsis and DIC compared to the group with sepsis; however, the difference was not statistically significant and the levels of HGMB1 of both groups were significantly higher compared to ICU and healthy control groups. HMGB1 levels were not significantly different in survivor and non survivor patients. HMGB1 levels did not differ in lower respiratory tract infection (LRTI) and urinary tract infection (UTI) in regard to the etiology of sepsis. PMID- 23094261 TI - Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P. AB - Multidrug resistance has for many years attracted attention of numerous investigators. Attempts have also been made to increase efficiency of anti neoplastic therapy. For this reason, most of efforts have been devoted to analysing proteins engaged in the mechanism of multidrug resistance such as the N glycosylated membrane protein glycoprotein P. Interestingly, glycosylation probably plays a significant role in the intracellular location and activity of modified proteins. Inhibitors of glycosylation have been demonstrated to alter the activity of glycoprotein P in various ways, depending on the cell line examined. These inhibitors markedly reduce multidrug resistance of cancer cells, thus promoting success of anti-neoplastic therapy. Here, we review the basic knowledge on N-glycosylation inhibitors, their effect on glycoprotein P and their therapeutic potential. PMID- 23094262 TI - Dexamethasone inhibits U937 cell adhesion via the down-regulation of ROCK1 activity. AB - OBJECTIVE: To explore the effect of dexamethasone (DEX) on monocyte adhesion function and its underlying mechanism. METHODS: The effects of DEX and fasudil on adhesion of cultured U937 monocytes to human umbilical vein endothelial cells (HUVEC) following stimulation with phorbol myristate acetate (PMA) were studied; Changes in the Rho-associated coiled-coil protein kinase 1 (ROCK1) protein content and activity were evaluated. RESULTS: DEX and fasudil significantly inhibited U937 cell adhesion rates under PMA stimulation and inhibited ROCK1 activity. Mifepristone (RU-486) and cycloheximide (CHX) did not alter these effects of DEX. CONCLUSIONS: DEX interferes with the adhesion function of U937 cells through the inhibition of ROCK1 activity. PMID- 23094263 TI - Psychosocial distress and periodontitis in adolescents. AB - PURPOSE: To assess whether adolescents with periodontitis presented with higher scores for non-psychotic psychosocial disorders than control subjects without periodontitis. MATERIALS AND METHODS: A case control study (n = 160) nested in a well-defined adolescent population (n = 9,163) was performed using the 28-item Spanish version of the General Health Questionnaire. The inclusion criterion for being a case was a clinical attachment level of >= 3 mm in at least two teeth. Multiple logistic regression analyses were used to assess the association between periodontitis and psychosocial distress. RESULTS: The response rate was high and 94% of the participants answered all the items of the questionnaire. Similarly, the internal consistency of the instrument was high (Cronbach's = 0.91). The results of multiple logistic regression analyses, adjusted for age and gender, suggested an association between case status and higher total scoring for psychosocial distress (OR = 1.69). Among the four subdomains of the General Health Questionnaire, the dimensions 'somatic symptoms' and 'severe depression' appeared positively associated with periodontal case status, albeit not significantly. CONCLUSION: The findings of this study suggest that the association between periodontitis and dimensions of psychosocial distress can be documented early in life. This calls for awareness on the part of healthcare providers attending adolescents. PMID- 23094264 TI - Clinical evaluation of the plaque-removing ability of four different toothbrushes in visually impaired children. AB - PURPOSE: To evaluate the efficacy of plaque removal of four different toothbrushes in visually disabled children. Three manual toothbrushes with different bristle designs (Oral-B CrossAction 40-regular, Oral-B ShinyClean 40 soft, Oral-B Advantage 40-soft) were compared with an electric toothbrush with an oscillating rotating head (Colgate Motion). MATERIALS AND METHODS: Forty visually impaired children in a professional education center participated in the study and were divided into 4 groups of 10 participants each. To obtain a plaque-free condition at baseline, professional toothcleaning was performed on each participant. After instructions on how to use the toothbrushes, each group started the experiment using a differently designed toothbrush. After 1 week of application, the Quigley Hein plaque index (QHI) was used to assess the oral hygiene status of each participant. Student's t-test was chosen for comparing brushes. P < 0.01 was considered as the significance level. Results were presented as mean +/- standard deviation. RESULTS: The QHI values obtained with the electric Colgate Motion brush were the lowest (0.088 +/- 0.051) and Advantage (0.801 +/- 0.132) the highest. Although the QHI values with the manual Oral-B CrossAction (0.439 +/- 0.094) were lower than those with the Oral-B shiny clean (0.503 +/- 0.098), there was no statistical difference between the two. CONCLUSION: The electric toothbrushes are still the most effective in the visually disabled group. However, because of cheaper cost, easier availability and use, the Oral-B CrossAction toothbrush with criss-cross bristles could be a suitable alternative. PMID- 23094265 TI - The acidogenic potential of different milk formulas on dental plaque pH. AB - PURPOSE: To investigate the effect of different milk formulas on dental plaque pH. MATERIALS AND METHODS: Six commercial infant milk formulas were selected, with 10% sucrose solution as the positive and deionised water as the negative control, and tested among ten children aged 7-10 years. The plaque pH changes were recorded by using a combination electrode. RESULTS: Mouth rinsing with all infant formulas significantly reduced the plaque pH (Tukey's multiple comparison test, P < 0.05) to levels below the pre-rinse pH value for sucrose solution and also below the pH obtained after rinsing with water. Each milk formula had a significant but variable buffering effect or tendency to decrease the pH. The formula with the least buffering effect was Nestogen (9.21%) followed by Nan (11.92%), and the highest buffering effect was shown by Lactodex (20.13%). The pH drop ranged from 0.72 for Farex to 0.98 for Nan. CONCLUSION: The results of this study underscore the need for parents and clinicians to be fully aware of the potential harm of various infant formulas and their major role in the etiology of ECC. These findings may help in creating a new generation of foods which, if not 'friendly to teeth', may be thought of as 'friendlier' than their predecessors. PMID- 23094266 TI - Association between obesity, dental caries and socioeconomic status in 6- and 13 year-old school children. AB - PURPOSE: To investigate the association between dental caries, obesity and socioeconomic status (SES) in 6-and 13-yearold school children in Davangere city, Karnataka, India. MATERIALS AND METHODS: Data were obtained from a cohort of 1,550 children. Dental caries detection was performed according to the World Health Organization criteria and the medical evaluation assessed the body mass index (BMI). With appropriate sample weighting, relationships between dmft/DMFT, obesity and socioeconomic status were assessed using the Kruskal-Wallis H test and multivariate logistic regression. RESULTS: The prevalence of dental caries was 28.9%. The mean dmft and DMFT scores for 6-year-olds were 2.1 +/- 3.75 and 0.16 +/- 0.59, respectively, and corresponding values for 13-year-olds were 0.03 +/- 0.19 and 0.91 +/- 2.04. Of the total sample, the mean BMI was 16.56 +/- 2.8. Approximately 63.4% of the children were classified as normal weight, 18.1% as overweight and 7.5% as obese. When adjusted for covariates, the logistic regression model showed that there was a significant association between overweight children (P < 0.001), obese children (P < 0.05) and caries prevalence. CONCLUSION: This study demonstrated a significant association between caries frequency and obesity in school children. In future preventive programmes, the importance of obesity should not only be emphasised with respect to general diseases but also with regard to carious lesions. PMID- 23094267 TI - Relationship of smoking and smokeless tobacco use to tooth loss in a central Indian population. AB - PURPOSE: The present study was conducted to determine the patterns of tooth loss among subjects with different tobacco- related habits and compare it with non users of tobacco. MATERIALS AND METHODS: A total of 1075 patients over the age of 14 years attending the Department of Periodontics, People's College of Dental Sciences and Research Centre, Bhopal, India from May to September 2009 were included in the study. Besides name, age and gender, information regarding tobacco habits was recorded through interviews. Based on the tobacco habits, the patients were grouped into 4 categories: group 1 (non-users of tobacco), group 2 (smokers only), group 3 (smokeless tobacco users only) and group 4 (users of both smoking and smokeless tobacco). Tooth loss was determined by clinical examination of all permanent teeth excluding the third molars. Tooth loss included missing or extracted teeth as well as teeth indicated for extraction due to periodontal disease, dental caries or wasting diseases. Prevalence and mean tooth loss for whole dentition, maxillary and mandibular arches were compared between the 4 groups. The chi-square test and one-way ANOVA were used for comparing the prevalence and mean tooth loss, respectively, between different groups. RESULTS: The overall prevalence and mean tooth loss, respectively, for different groups were as follows: group 1: 28.3% and 0.85; group 2: 56.1% and 1.97; group 3: 58.7% and 2.38; group 4: 56.7% and 2.48 (P < 0.001 for both prevalence and mean tooth loss). The prevalence and mean tooth loss, respectively, for the maxillary arch for the different groups were: group 1: 15.3% and 0.32; group 2: 43% and 1.24; group 3: 34.3% and 0.91; group 4: 45.4% and 1.26 (P < 0.001 for both prevalence and mean tooth loss). The prevalence and mean tooth loss, respectively, for the mandibular arch for the different groups were: group 1: 22.3% and 0.52; group 2: 33.6% and 0.73; group 3: 50.9% and 1.48; group 4: 48.5% and 1.23 (P < 0.001 for both prevalence and mean tooth loss). CONCLUSION: When compared to non-users of tobacco, tooth loss was greater among subjects who consumed tobacco. In India, where consumption of tobacco in different forms is very common, public health programmes need to be implemented to increase public awareness regarding the adverse effects of tobacco on oral health. PMID- 23094268 TI - Evaluation of elementary school teachers' knowledge and attitudes about immediate emergency management of traumatic dental injuries. AB - PURPOSE: To investigate teachers' knowledge and attitudes about emergency management of traumatic dental injuries (TDIs) in children. MATERIALS AND METHODS: A total of 764 teachers from 13 elementary schools were included in the study. Data were collected using a self-reporting questionnaire in which teachers were asked about demographic information, previous experience with dental trauma, first-aid training, knowledge of emergency management and how they would respond to two hypothetical TDI cases. RESULTS: Of the 764 participants, 550 (71.4%) returned the questionnaire; of these, 309 (56.2%) were female and 241 (43.8%) were male. While 297 teachers reported having had first-aid training, only 13 (4.4%) of them reported emergency management of TDIs being covered in this training. Less than half of respondents (47.5%, n = 261) correctly answered the question on the appropriate response to a TDI involving a fractured tooth and only one-quarter of respondents (25.4%, n=140) correctly answered the question on the appropriate response to a TDI involving an avulsed tooth. CONCLUSION: The results of this study demonstrated teachers' low level of knowledge about the emergency treatment of TDIs in schoolchildren, suggesting that educational programmes are needed to improve proper emergency management of TDIs by teachers. PMID- 23094269 TI - Submergence of vital roots for the preservation of residual ridge: a clinical study. AB - PURPOSE: To test the value of submerging vital roots for the preservation of the residual ridge. MATERIALS AND METHODS: The study sample consisted of 10 patients whose bone height on both submerged and control sites was measured with the help of OPG tracings and the use of grids, from the immediate post-operative period to 3 months, 6 months and 9 months post-operatively. Statistical analysis was performed using the t-test and one-way ANOVA. RESULTS: The amount of bone loss was significantly greater in the control area in comparison to the submerged area from the immediate post-operative period to 3 months, 6 months and 9 months post operatively. CONCLUSION: Although the retained roots do not prevent the resorption of residual ridge, they aid in decreasing the resorptive pattern, thereby preserving the residual ridge to some extent. This may be an expedient and inexpensive way to preserve residual ridge, requiring minimal specialised training. PMID- 23094270 TI - Prevalence and pattern of dental caries among a sample of nigerian public primary school children. AB - PURPOSE: To determine the prevalence and pattern of dental caries among public primary school children in Lagos State, Nigeria. MATERIALS AND METHODS: A cross sectional survey of pupils in randomly selected public primary schools in Lagos State Nigeria was conducted. Dental examinations were carried out on 2835 children and caries diagnosis was based on the WHO diagnostic criteria (1999). RESULTS: Overall caries prevalence in the study population was 13.1% with the highest caries prevalence recorded among eight-year-old children (17.7%), boys (13.5%) and those of the Hausa tribe (15.0%). The DMFT score ranged between 0 and 11 with a mean score and standard deviation of 0.344 +/- 0.937. Children aged 5 10 years had slightly higher caries prevalence (14.8%) than those aged 11-16 years (10.6%). The first molars were the worst affected teeth in both the deciduous and permanent dentitions. The mandibular left first molar had the highest caries prevalence (4.7%) in the deciduous dentition, while the right mandibular first molar had the highest tooth-specific caries prevalence (3.5%) in the permanent dentition. The restorative index for the study population was 0.3% while the treatment index was 5.7%. CONCLUSION: While the caries prevalence in the study population is very low, the treatment and restorative indices are unacceptably low. There is a need for early preventive strategies and treatment services in terms of restorative care for this important age group. PMID- 23094271 TI - Evaluation of human enamel surfaces treated with theobromine: a pilot study. AB - PURPOSE: The objectives of this in-vitro study were to investigate the effect of theobromine, which is the principle xanthine species in Theobroma cacao, at two concentrations on the surface hardness and topography of human enamel. MATERIALS AND METHODS: Twenty-four freshly extracted human third molars were collected and stored in distilled water with 0.1% thymol solution at room temperature prior to the experiments. The enamel specimens were treated with one coat of theobromine at two concentrations (100 mg/l or 200 mg/l in distilled water) for 5 min. Enamel surfaces in the control group received no theobromine. They were then kept in distilled water for 1 week and subjected to SEM analysis. The specimens were demineralised by storing them in acidic hydroxyethylcellulose for three days. After baseline microhardness measurements, they were incubated either in 100 or 200 mg/l theobromine for 5 min. The control group was kept in distilled water. After washing the specimens under distilled water, they were kept in a remineralising solution for 18 h. Microhardness of the enamel surface was initially determined for each specimen before artificial demineralisation. After demineralisation, the experimental groups were incubated in 100 mg or 200 mg theobromine and control-group specimens were placed in remineralising solution. RESULTS: Enamel surfaces of the untreated control group presented a generally smooth and slightly hummocky surface with small lines of pits. Specimens treated with theobromine showed differences between the two concentrations. The group treated with 200 mg/l solution for 5 min showed a greater quantity of globules on enamel than did specimens treated with 100 mg/l solution. CONCLUSION: As shown by the microhardness values, a consistent and remarkable protection of the enamel surface was found with the application of theobromine. PMID- 23094272 TI - Feeding habits and oral hygiene practices as determinants of early childhood caries in 3- to 5-year-old children of Belgaum City, India. AB - PURPOSE: To investigate whether feeding and oral hygiene practices of preschool children are associated with the risk and prevalence of Early Childhood Caries (EC). MATERIALS AND METHODS: A cross-sectional study comprising 1250 children aged 3 to 5 years from Belgaum was designed. On the first day, validated questionnaires along with parental informed consent forms were distributed to the children and were collected after a week. Validated questionnaires consisted of 20 close-ended questions pertaining to feeding and oral hygiene practices. Consent was obtained from parents of the 1116 children who were examined for EC. Data analysis included correlation coefficients and logistic regressions. RESULTS: Among the children studied, 97.3% were breastfed, of which 41.25% were breastfed until 2 years of age. Seventy- five percent of children who were breastfed beyond 2 years were affected by EC. Exclusive bottle feeding was practiced in 46.15%; 64.85% of them suffered from EC. Burping was not practiced in 25.18%, and 68.68% of these were affected by EC. EC was more prevalent in 89% of children who were weaned later than 12 months of age. Parental assistance for oral hygiene was not seen in 37.27% and 67.22% of these suffered from EC. Overall, 63.17% of the children were affected by EC. CONCLUSION: Prolonged breastfeeding, absence of burping the child, delay in starting oral hygiene practices and lack of parental assistance with the same were shown to be significant determining factors for EC. Health education and proper guidelines on feeding and oral hygiene practices can substantially reduce the risk and prevalence of EC. PMID- 23094273 TI - Efficacy of chlorhexidine mouthrinses with and without alcohol - a clinical study. AB - PURPOSE: To compare the efficacy of alcohol-free chlorhexidine mouthrinse to chlorhexidine with alcohol and a placebo (water) in controlling plaque and reducing gingival inflammation in patients with gingivitis. MATERIALS AND METHODS: This was a single-blind, parallel-group study with 30 gingivitis patients in whom the plaque index (Silness and Loe) and gingival index (Loe and Silness) were recorded prior to treatment with 0.2% chlorhexidine mouthrinse with alcohol (group I, n = 10; CHX-A), 0.2% chlorhexidine mouthrinse without alcohol (group II, n = 10; CHXNA) or a placebo (water) (group II, n = 10; P). The plaque and gingival indices were recorded again at days 14 and 28 after the start of treatment. RESULTS: There were significant differences in plaque and gingival indices with both chlorhexidine rinses compared to the placebo. The gingival index showed a greater clinical change in group II (CHX-NA) than in group I (CHX A). CONCLUSION: The alcohol-free rinse was as effective as the one containing alcohol in controlling plaque and reducing gingival inflammation. Therefore, its use can be recommended in all periodontal patients, but especially in those for whom the use of alcohol may lead to side effects. PMID- 23094274 TI - Apical periodontitis in association with the quality of root fillings and coronal restorations: a 14-year investigation in young Greek adults. AB - PURPOSE: To examine the possible association between the presence of apical periodontitis (AP) and the quality of endodontic treatment and coronal restoration over a time period of 14 years. MATERIALS AND METHODS: 1781 panoramic radiographs of freshmen cadets, taken between the years 1995-2008 were included in this study. The periapical status was evaluated using the Periapical Index (PAI) scoring system. The chisquare test and logistic regression analysis were used to examine associations between apical disease and the quality of both the root filling and the coronal restoration. RESULTS: 62.3% of the examined teeth demonstrated AP. The number of root-filled teeth and the prevalence of AP were found to be higher in OPGs taken between 1995 and 2001 than those taken between 2002 and 2008. Both the quality of the coronal restoration and the quality of the root filling (length and lateral seal) were found to be correlated with the presence of AP, but the factor most significantly associated seemed to be the coronal restoration (OR = 0.404, 95% CI: 0.174-0.940). CONCLUSION: The quality of the endodontic treatment in young Greek adults was poor but improved over the years. Both the quality of the endodontic treatment and coronal restoration appeared to affect the periapical status of the treated teeth. The factor that probably most determined the periapical health was the quality of the coronal restoration. PMID- 23094275 TI - [The effect of probiotics in ulcerative colitis]. PMID- 23094276 TI - Both PAX6 and MITF are required for pigment epithelium development in vivo. PMID- 23094277 TI - [Image of the month. Gastritis cystica polyposa treated with endoscopic submucosal dissection]. PMID- 23094278 TI - [The laser in dermatology]. PMID- 23094279 TI - [Coercive measures in Iceland: history of a remarkable exception]. PMID- 23094280 TI - [Not Available]. PMID- 23094281 TI - [Not Available]. PMID- 23094282 TI - [Not Available]. PMID- 23094283 TI - [Breastfeeding increases the risk of childhood eczema]. PMID- 23094284 TI - [Remember there are grants for smoking cessation drugs]. PMID- 23094285 TI - [No evidence for population-based screening for type 2-diabetes]. PMID- 23094286 TI - Biomarkers in the clinic: a cautionary tale. PMID- 23094288 TI - Mental health-related risk factors for violence: using the evidence to guide mental health triage decision making. AB - Mental health clinicians working in emergency crisis assessment teams or mental health triage roles are required to make rapid and accurate risk assessments. The assessment of violence risk at triage is particularly pertinent to the early identification and prevention of patient violence, and to enhancing the safety of clinical staff and the general public. To date, the evidence base for mental health triage violence risk assessment has been minimal. This study aimed to address this evidence gap by identifying best available evidence for mental health-related risk factors for patient-initiated violence. We conducted a systematic review based on the National Health and Medical Research Council of Australia's methodology for systematic reviews. A total of 6847 studies were retrieved, of which 326 studies met the study inclusion criteria. Of these studies, 277 met inclusion criteria but failed the quality appraisal process, thus a total of 49 studies were included in the final review. The risk factors that achieved the highest evidence grading were predominantly related to dynamic clinical factors immediately observable in the patient's general appearance, behaviour and speech. These factors included hostility/anger, agitation, thought disturbance, positive symptoms of schizophrenia, suspiciousness and irritability. PMID- 23094291 TI - [Clinical issues on prescribing psychotropics for elderly patients]. AB - Psychopharmaologic intervention for elderly patients requires careful considerations for physical characteristics, comorbid medical illness, and interaction between drugs for psychotropic and somatic diseases drugs. Elderly patients often suffer from depression, delirium, and dementia, which occasionally coexist with each other. Antidepressants, antipsychotics, anxiolytics and hypnotics are prescribed according to the targeted psychiatric symptoms. Drug effect tens to be strengthened and prolonged pharmacodynamically in elderly patients because of decline of drug clearance in liver and kidney, prolongation of elimination half life of lipophilic drug resulted from reduced muscle tissue, and elevated free serum drug level induced by low albuminemia. Elderly patients pharmacokinetically develop adverse effects in relatively lower serum drug level. Lower initial dose and slow titration should be strongly recommended. Cerebrovascular disease and neurodegerative disease are frequently observed among elderly patients. Significant number of patients with cerebrovascular disease are complicated with depression, delirium, and in lower prevalence, dementia. Although drugs used in acute phase stroke have no pharmacodynamic interaction with psychotropics, many patients be carefully titrated with continuous monitoring of PT-INR during concurrent use of tricyclic antidepressants and selective serotonin reuptake inhibitors. Alzheimer's disease and Parkinson's disease are highly prevalent and clinically important neurodegerative disease in elderly population. Patients with Alzheimer's disease frequently exhibit delirium soon after hospitalization, which necessitates appropriate pharmacotherapy with psychotropics. After Food and Drug Foundation warned against antipsychotic use for patients with dementia, this off-label use are considered to be avoided but disease frequently coincide with depression and receive antidepressant treatment. If selegiline id prescribed, antidepressants cannot be initiated without discontinuation of selegiline. When delirium develops in patients with Parkinson's disease, second generation antipsychotics such as quetiapine are firstly administered with caution for deterioration of motor symptoms. PMID- 23094292 TI - [Treatment strategy of a patient with multiple cerebral aneurysms and subarachnoid hemorrhage: a case with both coil embolization suitable aneurysm and the unsuitable one]. PMID- 23094293 TI - [Dose adjustment of multiple drugs administration for schizophrenia and QOL]. PMID- 23094294 TI - [Clinical usage of Yi-gan san-schizophrenia, borderline personality disorder, dyskinesia etc-]. AB - Yi-gan san (YGS, yokukan-san in Japanese) was developed in 1555 by Xue Kai as a remedy for restlessness and agitation in children. Prompted by the increasing life expectancy of the Japanese population, geriatricians have begun to use this traditional regimen for behavioral and psychological symptoms of dementia in the elderly. Moreover, we reported that YGS therapy is a well-tolerated and effective remedy that improves the symptoms of schizophrenia., borderline personality disorder, Charles Bonnet Syndrome, pervasive developmental disorder. Asperger's disorder, neuroleptics induced tardive dyskinesia, and restless legs syndrome. In a pilot investigation, we administered YGS as an open-label adjunct to antipsychotic medication to patients with treatment-resistant shizophrenia, borderline personality disorder, Charles Bonnet Syndrome, pervasive developmental disorder, Asperger's disorder, neuroleptics induced tardive dyskinesia. The present lecture summarizes the available data based on the above our data. In addition, we extend our discussion to the potential applications of YGS for combining this treatment with cellular and molecular therapy. PMID- 23094295 TI - [Psychiatric emergency services and forensic psychiatry]. PMID- 23094296 TI - Maternal, newborn and child health in Nepal. PMID- 23094297 TI - Professional misconduct (Med10/145P). PMID- 23094298 TI - He skillfully walked the line. PMID- 23094299 TI - Our moral obligation to skin care: calling for inclusivity. PMID- 23094301 TI - Guiding lights: peer navigators help others after finding their own way. PMID- 23094300 TI - A clinical view: a trio of HIV specialists offer their take on HIV--then, now, and in the future. Interview by Heidi M Nass. PMID- 23094302 TI - Piecing the puzzle together. PMID- 23094303 TI - Breaking the silence: the insidious effects of trauma and PTSD. PMID- 23094304 TI - Simply Rob: advocate and artist, a man of words uses them to spread truth. PMID- 23094305 TI - The psoriasis plot thickens. PMID- 23094306 TI - What is your diagnosis? Folliculocentric tinea versicolor. PMID- 23094307 TI - Varicella-zoster virus in children immunized with the varicella vaccine. AB - We present the case of a 4-year-old immunocompetent girl with varicella-zoster virus (VZV) that occurred 45 months after a single dose of the varicella vaccine. Varicella-zoster virus is rare in children, particularly those who have received the varicella vaccine. Our case illustrates the need for a continued high index of suspicion, even among vaccinated children with herpetiform rashes, for varicella reactivation or reinfection. PMID- 23094308 TI - Dermatopathology diagnosis. Primary systemic amyloidosis. PMID- 23094309 TI - Severe psoriasis with positive tuberculosis test and treatment with biologic therapy: a case report. AB - Psoriasis and tuberculosis (TB) are 2 conditions with high prevalence in the general population, often present simultaneously in the same patient. The crucial cytokine involved in the pathogenesis of psoriasis, tumor necrosis factor alpha (TNF-alpha), also is important in defending against mycobacteria. Therefore, it is important to screen patients for a latent TB infection (LTBI) while they are undergoing treatment with TNF-alpha antagonists. We present a case of a patient with psoriasis and LTBI who underwent treatment with etanercept. PMID- 23094310 TI - Irritant contact dermatitis due to the use of a continuous positive airway pressure nasal mask: 2 case reports and review of the literature. AB - Nasal continuous positive airway pressure (CPAP) is commonly used to treat various respiratory conditions including obstructive sleep apnea (OSA). Several side effects related to the use of nasal CPAP are described in the literature. The side effects can cause patients to discontinue this effective therapy. We report 2 patients who used nasal CPAP for several years for the treatment of OSA and developed irritant contact dermatitis (ICD) from a CPAP nasal mask. PMID- 23094311 TI - Cutaneous manifestations of Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a multisystemic genetic disease associated with structural, behavioral, and intellectual disorders. The clinical appearance of PWS includes dysmorphic facial features with almond-shaped eyes, a narrow bifrontal diameter, and a thin upper lip; short stature; central obesity; and small hands and feet. We present a case of a 27-year-old woman with PWS and describe the typical clinical features and cutaneous manifestations of PWS. PMID- 23094312 TI - Generalized pustular psoriasis of Zambusch: case report of successful disease control with cyclosporine and etanercept. AB - Generalized pustular psoriasis of Zambusch is a unique and challenging skin condition to successfully manage. Patients often encounter potentially high recurrence rates of pustular eruptions despite multidrug treatment regimens with high morbidity as a consequence. We report a case of generalized pustular psoriasis of Zambusch in a patient whose disease initially flared following early treatment with the anti-tumor necrosis factor alpha (anti-TNF-alpha) inhibitor etanercept but was later successfully managed with cyclosporine and reintroduction of etanercept. We also discuss therapeutic management options for generalized pustular psoriasis. PMID- 23094313 TI - Coma blisters sans coma. AB - Coma blisters (CBs) are self-limited lesions that occur in regions of pressure during unconscious states classically induced by barbiturates. We report a case of CBs sans coma that were histologically confirmed in a 41-year-old woman who developed multiple tense abdominal bullae with surrounding erythema following a transatlantic flight. Interestingly, the patient was fully conscious and denied medication use or history of medical conditions. A clinical diagnosis of CBs was confirmed by histopathologic findings of eccrine gland necrosis, a hallmark of these bulIous lesions. PMID- 23094314 TI - Preliminary study of the efficacy and tolerability of combination therapy with calcipotriene ointment 0.005% and tacrolimus ointment 0.1% in the treatment of stable plaque psoriasis. AB - Calcipotriene ointment is widely used in the topical treatment of psoriasis, with tacrolimus ointment as an effective alternative in controlling stable plaque psoriasis. The efficacy of the combination of both products on stable plaque psoriasis has not been assessed in the literature consulted. We evaluated the efficacy of calcipotriene ointment 0.005% applied twice daily, tacrolimus ointment 0.1% applied twice daily, or a morning application of calcipotriene and an evening application of tacrolimus in 27 participants with stable plaque psoriasis over an 8-week treatment period. The mean reduction in the sum of the scores between baseline and week 8 was significant (P = .001) for calcipotriene alone (39.5%), tacrolimus alone (38.2%), and the combination of calcipotriene and tacrolimus (60.7%). Combination therapy was statistically more effective than tacrolimus alone (P = .043) but not statistically superior to calcipotriene alone (P=.056). Most adverse events (AEs) were related to skin irritation and pruritus; however, no AEs were evident in participants given the combination therapy. PMID- 23094315 TI - Neurofibromatosis associated with plaque-type psoriasis: coincidental occurrence or causal association? PMID- 23094316 TI - Therapeutic modalities for localized psoriasis: 308-nm UVB excimer laser versus nontargeted phototherapy. AB - UVB phototherapy is an effective treatment modality for psoriasis. For patients with localized plaque-type lesions, 308-nm excimer laser phototherapy offers rapidly delivered, targeted, high UVB doses, while sparing adjacent healthy skin. We aimed to compare the advantages and disadvantages of the 308-nm xenon chloride (XeCI) UVB excimer laser with nontargeted broadband UVB (BB-UVB), narrowband UVB (NB-UVB), and psoralen plus UVA (PUVA) phototherapies. A PubMed search for studies evaluating the efficacy and safety of the laser versus nontargeted phototherapeutic modalities was conducted. Three prospective nonrandomized studies compared NB-UVB with excimer laser phototherapy. No head-to-head studies were found for BB-UVB or PUVA compared to excimer laser. Both the 308-nm excimer laser and nontargeted phototherapies were found to effectively clear localized psoriasis. Although it is proposed that excimer laser exclusively treats diseased skin with better response rates, split-body trials revealed no differences. Long term studies are necessary to compare the effects of high-dose excimer laser regimens with nontargeted phototherapies. PMID- 23094317 TI - Language universals and misidentification: a two-way street. AB - Certain ill-formed phonological structures are systematically under-represented across languages and misidentified by human listeners. It is currently unclear whether this results from grammatical phonological knowledge that actively recodes ill-formed structures, or from difficulty with their phonetic encoding. To examine this question, we gauge the effect of two types of tasks on the identification of onset clusters that are unattested in an individual's language. One type calls attention to global phonological structure by eliciting a syllable count (e.g., does medifinclude one syllable or two?). A second set of tasks promotes attention to local phonetic detail by requiring the detection of specific segments (e.g., does medifinclude an e?). Results from five experiments show that, when participants attend to global phonological structure, ill-formed onsets are misidentified (e.g., mdif-->medif) relative to better-formed ones (e.g., mlif). In contrast, when people attend to local phonetic detail, they identify ill-formed onsets as well as better-formed ones, and they are highly sensitive to non-distinctive phonetic cues. These findings suggest that misidentifications reflect active recoding based on broad phonological knowledge, rather than passive failures to extract acoustic surface forms. Although the perceptual interface could shape such knowledge, the relationship between language and misidentification is a two-way street. PMID- 23094318 TI - On the prosodic expression of pragmatic prominence: the case of pitch register lowering in Akan. AB - This article presents data from three production experiments investigating the prosodic means of encoding information structure in Akan, a tone language that belongs to the Kwa branch of the Niger-Congo family, spoken in Ghana. Information structure was elicited via context questions that put target words either in wide, informational, or corrective focus, or in one of the experiments also in pre-focal or post-focal position rendering it as given. The prosodic parameters F0 and duration were measured on the target words. Duration is not consistently affected by information structure, but contrary to the prediction that High (H) and Low (L) tones are raised in ex situ (fronted) focus constructions we found a significantly lower realization of both H and L tones under corrective focus in ex situ and in situ focus constructions. Givenness does not seem to be marked prosodically. The data suggest that pragmatic prominence is expressed prosodically by means of a deviation from an unmarked prosodic structure. Results are thus contradicting the view of the effort code that predicts a positive correlation of more effort resulting in higher F0 targets. PMID- 23094320 TI - The relationship between the perception and production of coarticulation during a sound change in progress. AB - The present study is concerned with lax /u/-fronting in Standard British English and in particular with whether this sound change in progress can be attributed to a waning of the perceptual compensation for the coarticulatory effects of context. Younger and older speakers produced various monosyllables in which /u/ occurred in different symmetrical consonantal contexts. The same speakers participated in a forced-choice perception experiment in which they categorized a synthetic /I-u/ continuum embedded in fronting /s_t/ and non-fronting /w_l/ contexts. /u/ was shown to be fronted for the younger age group in both production and perception. Although there was no conclusive evidence that younger listeners compensated less for coarticulation than did older listeners, the size of the coarticulatory influence of consonantal context on /u/ in perception was found to be smaller than in production for the younger than for the older group. The findings are consistent with a model of sound change in which the perceptual compensation for coarticulation wanes ahead of changes that take place to coarticulatory relationships in speech production. As a result, the perception and production of coarticulation may be unusually misaligned with respect to each other for some speaker-listeners participating in a sound change in progress. PMID- 23094319 TI - (De-)accentuation and the process of information status: evidence from event related brain potentials. AB - The paper reports on a perception experiment in German that investigated the neuro-cognitive processing of information structural concepts and their prosodic marking using event-related brain potentials (ERPs). Experimental conditions controlled the information status (given vs. new) of referring and non-referring target expressions (nouns vs. adjectives) and were elicited via context sentences, which did not - unlike most previous ERP studies in the field--trigger an explicit focus expectation. Target utterances displayed prosodic realizations of the critical words which differed in accent position and accent type. Electrophysiological results showed an effect of information status, maximally distributed over posterior sites, displaying a biphasic N400--Late Positivity pattern for new information. We claim that this pattern reflects increased processing demands associated with new information, with the N400 indicating enhanced costs from linking information with the previous discourse and the Late Positivity indicating the listener's effort to update his/her discourse model. The prosodic manipulation registered more pronounced effects over anterior regions and revealed an enhanced negativity followed by a Late Positivity for deaccentuation, probably also reflecting costs from discourse linking and updating respectively. The data further lend indirect support for the idea that givenness applies not only to referents but also to non-referential expressions ('lexical givenness'). PMID- 23094321 TI - Kinematic signatures of telic and atelic events in ASL predicates. AB - This article presents an experimental investigation of kinematics of verb sign production in American Sign Language (ASL) using motion capture data. The results confirm that event structure differences in the meaning of the verbs are reflected in the kinematic formation: for example, in the telic verbs (THROW, HIT), the end-point of the event is marked in the verb sign movement by significantly greater deceleration, as compared to atelic verbs (SWIM, TRAVEL). This end-point marker is highly robust regardless of position of the verb in the sentence (medial vs. final), although other prominent kinematic measures, including sign duration and peak speed of dominant hand motion within the sign, are affected by prosodic processes such as Phrase Final Lengthening. The study provides the first kinematic confirmation that event structure is expressed in movement profiles of ASL verbs, up to now only supported by apparent perceptual distinctions. The findings raise further questions about the psychology of event representation both in human languages and in the human mind. PMID- 23094322 TI - Say it like you mean it: mothers' use of prosody to convey word meaning. AB - Prosody plays a variety of roles in infants' communicative development, aiding in attention modulation, speech segmentation, and syntax acquisition. This study investigates the extent to which parents also spontaneously modulate prosodic aspects of infant directed speech in ways that distinguish semantic aspects of language. Fourteen mothers of two-year-old children read a picture book to their children in which they labeled pictures using dimensional adjectives (e.g., big, small, hot, cold). Recordings of the mothers' input to their children were analyzed acoustically and antonyms within each dimension were compared. Mothers modulated aspects of their prosody including amplitude and duration of target words and sentences to distinguish dimensional adjectives. Mothers appear to recruit prosody in the service of word learning. PMID- 23094323 TI - The similarity of plural endings and linking elements in regional speech variants of Dutch. AB - The plural suffix -en (noot+en, 'nuts') is pronounced differently by speakers coming from different regions of the Netherlands. In this study, we compared the pronunciation of the plural suffix -en in phrases (noot+en kraken, 'to crack nuts') with linking en in compounds (noot+en+kroker, 'nutcracker'), because some claim that both are similar (Schreuder, Neijt, van der Weide, & Baayen, 1998), whereas others claim that they are not (Verkuyl, 2007). The pronunciations of 109 participants coming from five regions of the Netherlands were therefore compared in a picture naming task. A systematic relation between the pronunciations of plural -en and linking en was detected: Speakers from the Northern and Eastern regions produced [(upside-down e)n] most often for both the linking elements and plural endings, while speakers from the Middle and Western regions produced [upside-down e] most often for both. For speakers from the Southern region, we found no preference to pronounce either [upside-down e] or [upside-down e n] in compounds or phrases. It is concluded that Dutch speakers often do not distinguish plural -en from linking en in their speech production. Possibly, speakers of Dutch consider linking en and plural -en as the same morpheme. PMID- 23094324 TI - Robert Hooke, 1635-1703. AB - Robert Hooke was a polymath whose expertise during the 17th century spanned many different scientific areas. As a schoolboy on the Isle of Wight he was obsessed with the possibility of human flight and later became equally absorbed in cosmology and planetary motion. His skills as an artist were put to good use both as an architect following the Great Fire of London and before that in Micrographia. Although that book is best known for demonstrating the power of Hooke's microscope, Micrographia describes distant planetary bodies, the wave theory of light, the organic origin of fossils, and various other philosophical and scientific interests of its author The following thumbnail sketches of Hooke reveal him to be a man of enormous energy and imagination whose ideas were often pirated or under-rated. PMID- 23094325 TI - Overview of current additive manufacturing technologies and selected applications. AB - Three-dimensional printing or rapid prototyping are processes by which components are fabricated directly from computer models by selectively curing, depositing or consolidating materials in successive layers. These technologies have traditionally been limited to the fabrication of models suitable for product visualization but, over the past decade, have quickly developed into a new paradigm called additive manufacturing. We are now beginning to see additive manufacturing used for the fabrication of a range of functional end use components. In this review, we briefly discuss the evolution of additive manufacturing from its roots in accelerating product development to its proliferation into a variety of fields. Here, we focus on some of the key technologies that are advancing additive manufacturing and present some state of the art applications. PMID- 23094326 TI - Development of lithium-ion batteries from micro-structured to nanostructured materials: its issues and challenges. AB - Lithium-ion batteries are the systems of choice, offering high energy density, flexibility, lightness in weight, design and longer lifespan than comparable battery technologies. A brief historical review is given of the development of Li ion rechargeable batteries, highlighting the ongoing research strategies, and highlighting the challenges regarding synthesis, characterization, electrochemical performance and safety of these systems. This work is primarily focused on development of Li-ion batteries from micro-structured to nanostructured materials and some of the critical issues namely, electrode preparation, synthesis, and electrochemical characterization. The purpose of this review is to act as a reference for future work in this area. PMID- 23094327 TI - The repertoire of DNA-binding transcription factors in prokaryotes: functional and evolutionary lessons. AB - The capabilities of organisms to contend with environmental changes depend on their genes and their ability to regulate their expression. DNA-binding transcription factors (TFs) play a central role in this process, because they regulate gene expression positively and/or negatively, depending on the operator context and ligand-binding status. In this review, we summarise recent findings regarding the function and evolution of TFs in prokaryotes. We consider the abundance of TFs in bacteria and archaea, the role of DNA-binding domains and their partner domains, and the effects of duplication events in the evolution of regulatory networks. Finally, a comprehensive picture for how regulatory networks have evolved in prokaryotes is provided. PMID- 23094328 TI - Biochar, and its potential contribution to improving soil quality and carbon capture. PMID- 23094329 TI - Mucosal vaccination--an old but still vital strategy. AB - The basic premise of vaccinology is to achieve strong protective immunity against defined infectious agents by a vaccine mimicking the effects of natural primary exposure to a pathogen. Because an exposure of humans and animals to microbes occurs mostly through mucosal surfaces, targeting the mucosa seems a rational and efficient vaccination strategy. Many experimental and clinical data confirmed that mucosal immunization offers many advantages over widely used in human and veterinary medicine subcutaneous or intramuscular immunization. In the present article selected aspects regarding mucosal vaccination are discussed. The structure and function of mucosa-associated lymphoid tissue (MALT), comprised of four main mucosal compartments forming a structural and functional unity as well as pivotal cellular MALT components (dendritic and M cells) were briefly characterized. Particular attention was focused on the mode of simple but efficacious delivery of vaccine antigens to mucosal surfaces. A few trials to generate potential mucosal vaccines against toxoplasmosis introduced by nasal or oral routes to experimental animals are also presented. PMID- 23094330 TI - Nematodes of the large intestine of the European bison of the Bialowieza National Park. AB - The present study was conducted on 31 males and females of the European bison, eliminated during the winter seasons 2007-2011 in the Bialowieza Primeval Forest, Poland. The caeca of 14 free-ranging bison, aged from 3 months up to 16 years, the most favorable infection site for the large intestine nematodes, were investigated during the winter of 2007/2008. The parasitological autopsies of the large intestines of 9 free-ranging bison aged from 5 months up to 10 years as well as 9 bison kept in the close reserves aged from one up to 20 years were done during the winter seasons of 2008-2011 to determine localization of nematodes in large intestine and the total intensity of parasite infection. Five species of nematodes (i.e., Trichuris ovis, Oesophagostomum venulosum, O. radiatum, Ashworthius sidemi, Nematodirus helvetianus) were found in dissected caecum of bison culled during the winter of 2007/2008. During the seasons of 2008-2010, 6 species of nematodes were found in the large intestine of bison (i.e., T. ovis, O. venulosum, O. radiatum, A. sidemi, N. roscidus and Bunostomum trigonocephalum). We did not find any nematodes in the lumen of the large intestine of captive bison culled during the seasons of 2010/2011. The results of the present study indicate that the intensity of infection by the large intestine nematodes of the European bison in the Bialowieza Primeval Forest has stayed at the comparable level throughout the last 20 years; however the number of nematode species has increased. The observed level of parasitic infection is typical of subclinical parasitoses. PMID- 23094331 TI - First record of Spinturnix bechsteini (Acari: Mesostigmata: Spinturnicidae) from Poland with remarks on the diagnostic value of some characters. AB - Spinturnix bechsteini Deunff et al., 2004 (Acari: Spinturnicidae) associated with Myotis bechsteinii (Kuhl, 1817) (Chiroptera: Vespertilionidae) is reported for the first time from Poland. The usefulness of some morphological features for differentiating S. bechsteini from other spinturnicid mites belonging to the myoti group was studied. The mite fauna occurring on M. bechsteinii, the only host of S. bechsteini, are very poorly known. In Poland only five species have been found. PMID- 23094332 TI - New for the fauna of Poland species of Psorergates spp. with the data of occurrence of mites from Psorergatidae family (Acari, Prostigmata) in native mammals. AB - Five species of skin mites from Psorergatidae family have been found in four rodent species (Apodemus flavicollis, A. sylvaticus, Mus musculus, Myodes glareolus) coming from northern part of Poland. Three species (Psorergates microti, P. musculinus, P. simplex) appeared to be new ones for the fauna of Poland. Moreover A. sylvaticus and M. glareolus are a new hosts for P. apodemi, P. muricola, P. microti and P. musculinus from Poland. All developmental stages with immature stages predominance were found within particular species. The mites were found in skin fragments from different body areas, however they preferred head skin. The paper presents the list of species observed so far in Poland taking into consideration their hosts--currently the Psorergatidae fauna in Poland includes 10 species noted in eleven mammals species among rodents, bats and insectivores. PMID- 23094333 TI - Parasites of captive fallow deer (Dama dama L.) from southern Poland with special emphasis on Ashworthius sidemi. AB - Fallow deer in Poland is an alien species, with an ambiguous legal status. It is considered both, a game and a farm animal, which introductions in recent years led to a substantial increase of its population. As a representative of cervids, it shares with other free-ranging and domestic ruminants many of gastrointestinal helminths, among them an alien Ashworthius sidemi, the nematode of a high pathogenicity. Until now, the parasite was observed in Poland at two foci of the wild (i.e., Bialowieza and Bieszczady forests), but not yet in fallow deer. The present study was intended to recognize the infection level, and helminth species composition, in fallow deer living in captivity. Alimentary tracts of four animals, hunted in enclosure situated in Dulowa Primeval Forest, were dissected. Nematodes belonging to seven species: Spiculopteragia spiculoptera, S. mathevossiani, S. asymmetrica, Nematodirus filicollis, Aonchotheca bovis, Oesophagostomum radiatum and Ashworthius sidemi were recovered, with the latest helminth being predominat. In the present study, the origin of A. sidemi infection, its impact on the host and abomasum nematode communities, as well as the potential parasite spread on other ruminants, were investigated. PMID- 23094334 TI - Secretion of hydrolytic enzymes by fungal strains, isolated from patients with malignant tumors of head and neck, before, during and after radiotherapy. AB - One method of treatment used in cancer therapy is radiotherapy which can injure the oral, pharynx or larynx mucosa and predisposes tissue to the development of fungal infections. The aim of the study paper was the mycological examinations of swabs from the oral cavity and pharynx of patients obtained prior to, in week 3, on the last day of and 3 weeks after radiotherapy, as well as isolation of fungi and identification of the selected parameter of strains pathogenecity, i.e. hydrolytic enzyme release. Forty-three patients with oral cavity, pharynx or larynx carcinoma were examined at four points during a course of radiotherapy: before treatment, in week 3 of treatment, on the last day of treatment and 3 weeks afterwards. The mycological examination was conducted based on a procedure introduced in the Department of Biology and Medical Parasitology, Medical University of Lodz. The activity of the hydrolytic enzymes was evaluated with a bioMerieux API ZYM test kit. More than 2/3 of the patients (68.2%) were found to have a fungal infection in the first examination, 4/5 (80%) in the second, about 3/5 (57.1%) in the third and all (100%) in the last examination. The release of enzymes varied, and on different stages show different inactive enzymes: at the start, alpha-chymotrypsin and alpha-mannosidase; at 3 weeks, beta-glucuronidase and alpha-mannosidase; at the end, alpha-chymotrypsin; at 3 weeks after the end, trypsin, alpha-chymotrypsin, alpha-galaktosidase and alpha-fucosidase. The most frequent species isolated from the patients treated by radiotherapy is Candida albicans and C. glabrata. The latter is characterized by resistance to the majority of antimycotic medications. The isolated strains are characterized by the highest activity of leucine arylamidase, acid phosphatase and naphthol--AS-BI phosphohydrolase. Considering the enzymes produced, most of the strains can be included to biotypes D3, C6 and A. PMID- 23094335 TI - The morphology of juvenile stages of Bubophilus aluconis Nattress and Skoracki, 2009 (Acari: Syringophilidae) with a description of a male. AB - The morphology of juvenile and adult stages of the quill mite Bubophilus aluconis Nattress and Skoracki, 2009 parasitizing the Long-eared Owl Asio otus (Linnaeus) (Aves: Strigiformes) in Poland is described and illustrated. Poland is a new location and A. otus is a new host species for B. aluconis. A description of the male is presented for the first time for this quill mite species. PMID- 23094336 TI - Occurrence of Encephalitozoon intestinalis in the Red ruffed lemur (Varecia rubra) and the Ring-tailed lemur (Lemur catta) housed in the Poznan Zoological Garden, Poland. AB - Encephalitozoon intestinalis is one of the most common microsporidial species found in humans worldwide but it has rarely been identified in animals. The presence of this pathogen has been detected in a few species of domestic, captive and wild mammals as well as in three species of birds. The aim of the present study was to examine fecal samples obtained from mammals housed in the Poznan Zoological Garden, Poland, for the presence of potentially human-infectious microsporidia. A total of 339 fresh fecal samples collected from 75 species of mammals belonging to 27 families and 8 orders were examined for the presence of microsporidian spores. Microsporidian spores were identified in 3 out of 339 (0.9%) examined fecal samples. All samples identified as positive by chromotrope 2R and calcofluor white M2R were also positive by the FISH assay. Using multiplex FISH in all 3 fecal samples, only spores of E. intestinalis were identified in 2 out of 14 Ring-tailed lemurs (Lemur catta) and in one out of 17 Red ruffed lemurs (Varecia variegata rubra). To our knowledge this is the first diagnosis of E. intestinalis in Ring-tailed and Red ruffed lemurs. It should be mentioned that both lemur species are listed by the IUCN Red List of Threatened Species. Although the lemurs were asymptomatically infected, the possibility of widespread infection or death of these animals remains in the event of an elevated stress or a decrease in their immunological functions. PMID- 23094337 TI - The other side of the needle. PMID- 23094338 TI - We can do better: with patient-centered care. PMID- 23094339 TI - The many faces of minimal change nephrotic syndrome: an overview and case study. AB - Idiopathic nephrotic syndrome is the most common form of nephrotic syndrome in the pediatric population. Three major histopathological findings have been identified. The most common is that of minimal change nephrotic syndrome. Most of these cases respond well to oral steroids and achieve long-term remission. For those that become steroid dependent, the clinical course can be quite difficult. The case study included demonstrates some of the difficulties that can be encountered and questions that still exist with management of this diagnosis. PMID- 23094340 TI - Acceptability of motivational interviewing among hemodialysis clinic staff: a pilot study. AB - OBJECTIVE: This pilot study investigated the acceptability of motivational interviewing among a group of dialysis clinic staff. DESIGN: A non-experimental, posttest-only design was used for this pilot study. SAMPLE/SETTING: Dialysis clinic staff (N = 8) were recruited from a Midwestern non-profit, freestanding hemodialysis clinic. METHODS: Staff received three three-hour training sessions in motivational interviewing and monthly individual coaching sessions with a motivational interviewing expert for three months. Staff then completed anonymous questionnaires and participated in a focus group discussion. RESULTS: Staff reported liking the motivational interviewing skills they learned and finding them useful; however, staff reported disagreement with statements indicating they used motivational interviewing skills effectively on a regular basis, that their work environments were supportive of motivational interviewing, and that motivational interviewing was consistent with their natural patient care approach. CONCLUSIONS: Results indicate that staff are receptive to motivational interviewing skills, and with sufficient training and feedback to enhance confidence, dialysis staff will develop further motivational interviewing competence and comfort for long-term use. PMID- 23094341 TI - The need for a comprehensive foot care model. AB - There is a prevalence of lower extremity amputations in patients with diabetes mellitus who are receiving hemodialysis; the frequency occurs because diabetes affects sensation, circulation, and the healing process, which predisposes patients with diabetes to skin damage and increases the risk for infections and foot ulcers. In a lifetime, about 15% of patients with diabetes will develop foot ulcers requiring an amputation. Previous research demonstrates that proper foot care and adequate footwear with frequent inspections of the feet will prevent foot ulcers. This article proposes the use of a comprehensive foot care model. PMID- 23094342 TI - Calciphylaxis: a case study. AB - Caring for J.D. was a stressful experience. The extent of her wounds, pain, and limited options for treatment was very frustrating for the nursing staff. Although she did not survive, patient outcomes were met to some degree. Her pain was controlled to a greater extent, and there was less infection present in her wounds. The nurses worked with J.D. closely to improve her pain control and facilitate less painful dressing changes. They were vigilant in assessing the progress of her wound healing and communicating any increased signs of infections from her wounds. They sang with her to help distract her from the pain she was experiencing and to help her cope with her lengthy 8-month hospitalization. Providing care for J.D. was also a very important learning experience for nurses in terms of appropriate pain management for patients with CUA, wound care, and the need to sustain adequate nutrition to promote wound healing. CUA is a rare but potentially fatal disease that occurs in patients with end stage renal disease (ESRD). Early diagnosis and treatment are essential to prevent the devastating effects of this disease. Nephrology nurses need to reinforce the importance of keeping calcium, phosphorous, and parathyroid levels within normal ranges for their patients on dialysis. They also need to be vigilant in monitoring for potential CUA skin lesions to prevent and treat it early. To date, treatment options are mostly based on findings from case reports. Treatment requires a multidisciplinary approach with input from nephrologists, nurses, pain specialists, infectious disease specialists, and surgeons. The major goals of treatment are controlling risk factors, controlling pain, and preventing wound infection and possible sepsis. More studies need to be conducted to test interventions that may help treat CUA. PMID- 23094343 TI - Does the direct application of povidone-lodine hasten hemostasis of the cannulation site after the removal of hemodialysis needles? AB - Historically, povidone-iodine has had multiple uses in the care of patients receiving hemodialysis and peritoneal dialysis due to its broad antimicrobial properties. Anecdotally, nephrology nurses and technicians have used preparation pads impregnated with povidone-iodine at hemodialysis cannulation sites after removing the needle post-treatment to hasten the clotting time at the site. This article explores the literature related to the use of povidone-iodine in the process of hemostasis after the removal of hemodialysis cannulation needles and also discusses the potential risks of using povidone-iodine in the patient population with renal failure. PMID- 23094344 TI - Making the case for cookbook care. PMID- 23094345 TI - Forging a new future. PMID- 23094346 TI - If it takes the young to survive, who exactly is that? PMID- 23094347 TI - NOEP grant funded to build oncology certified nurse workforce. PMID- 23094348 TI - Going with a new flow. PMID- 23094349 TI - Start me up. PMID- 23094350 TI - Social pro. Interview by Elizabeth Gardner. PMID- 23094351 TI - A kick in the pants. PMID- 23094353 TI - Transforming a culture for safety and quality. PMID- 23094352 TI - We care, we vote. AB - Election day is fast approaching and the debate over the federal deficit is heating up. No one can do a better job of explaining the challenges in health care than you. PMID- 23094354 TI - Bad connection. Rural areas still not wired for digital health care. PMID- 23094355 TI - Rewarding performance. Big busines and value-based payments. PMID- 23094356 TI - Scalpel or an axe? Cutting costs with a gentler touch. PMID- 23094357 TI - A teaching moment. Goodbye best practice, hello lean. PMID- 23094358 TI - Building a quality care model. PMID- 23094359 TI - Health care's costliest 1%. AB - Patients at the top of the utilization pyramid consume a bigger share of resources each year. Who are they, and how can providers and communities better treat them? PMID- 23094360 TI - Forecasting a budget deal. Interview by Bob Kehoe. PMID- 23094361 TI - Focus on the C-suite: strategist-in-chief. PMID- 23094362 TI - Better blood management could be a boon for hospitals. AB - Surgery without transfusions saves money, improves patient outcomes, proponents say. So what's holding you back? PMID- 23094363 TI - American Hospital Association Environmental Scan 2013. PMID- 23094364 TI - Court held police had no liability for attack on RN. Ginapp v. City of Bellvue, 282 Neb. 1027 S-11-193 N.W. 2d (1/6/2012)-NE. PMID- 23094365 TI - Court affirmed trial court's judgment for defendant on jury verdict. Case on point: Perry v. Gilotra-Mallik, A11A2099 GACA (3/13/2012)-GA. PMID- 23094366 TI - MO: City employee failed to follow protocols: act negated application of sovereign immunity. Richardson v. Burrow, ED97002 MOCAE (2/21/2012)-MO. PMID- 23094367 TI - NY: Patient sues for negligent IV infiltrations: hospital's motion for summary judgment denied. Kalstein v. County of Nassau, 2012-30569 NYMISC(2/27/2012)-NY. PMID- 23094368 TI - Staffing agency liable for death due to failure to monitor B/P. Case on point: Medical Staffing Network Inc. v. Connors, A11A1927 GACA (1/24/2012)-GA. PMID- 23094369 TI - Asynchronous changes in phenology of migrating Broad-tailed Hummingbirds and their early-season nectar resources. AB - Phenological advancements driven by climate change are especially pronounced at higher latitudes, so that migrants from lower latitudes may increasingly arrive at breeding grounds after the appearance of seasonal resources. To explore this possibility, we compared dates of first arrival of Broad-tailed Hummingbirds (Selasphorus platycercus) to dates of flowering of plants they visit for nectar. Near the southern limit of the breeding range, neither hummingbird arrival nor first flowering dates have changed significantly over the past few decades. At a nearby migration stopover site, first flowering of a major food plant has advanced, but peak flowering has not. Near the northern limit of the breeding range, first and peak flowering of early-season food plants have shifted to earlier dates, resulting in a shorter interval between appearance of first hummingbirds and first flowers. If phenological shifts continue at current rates, hummingbirds will eventually arrive at northern breeding grounds after flowering begins, which could reduce their nesting success. These results support the prediction that migratory species may experience the greatest phenological mismatches at the poleward limits of their migration. A novel hypothesis based on these results posits that the poleward limit for some species may contract toward lower latitudes under continued warming. PMID- 23094370 TI - Niche engineering reveals complementary resource use. AB - Greater resource use by diverse communities might result from species occupying complementary niches. Demonstrating niche complementarity among species is challenging, however, due to the difficulty in relating differences between species in particular traits to their use of complementary resources. Here, we overcame this obstacle by exploiting plastic foraging behavior in a community of predatory insects common on Brassica oleracea plants in Washington, USA. These predators complemented one another by partitioning foraging space, with some species foraging primarily along leaf edges and others at leaf centers. We hypothesized that emergent biodiversity effects would occur when predators partitioned foraging space on leaves, but not when spatial complementarity was dampened. Indeed, on intact leaves, edge- and center-foraging predators combined to kill more prey than any single predator species could by itself. These emergent diversity effects, however, disappeared on plants damaged by the caterpillar Plutella xylostella. Caterpillar chew-holes brought edge habitats to the center of leaves, so that all predator species could attack aphids anywhere on plants. With spatial niche differences diminished, there were no benefits of predator diversity; the most voracious single predator species killed the most aphids. Thus, caterpillar herbivory determined whether multi-predator-species effects reflected complementarity or species' individual impacts. Our study provides direct evidence for a causative relationship between niche differentiation and increased resource consumption by diverse communities, as revealed by ecological engineers that homogenize the foraging environment. PMID- 23094371 TI - Conserving and promoting evenness: organic farming and fire-based wildland management as case studies. AB - Healthy ecosystems include many species (high richness) with similar abundances (high evenness). Thus, both aspects of biodiversity are worthy of conservation. Simultaneously conserving richness and evenness might be difficult, however, if, for example, the restoration of previously absent species to low densities brings a cost in reduced evenness. Using meta-analysis, we searched for benefits to biodiversity following adoption of two common land-management schemes: the implementation of organic practices by farmers and of controlled burning by natural-land managers. We used rarefaction to eliminate sampling bias in all of our estimates of richness and evenness. Both conservation practices significantly increased evenness and overall abundance across taxonomic classifications (arthropods, birds, non-bird vertebrates, plants, soil organisms). Evenness and richness varied independently, leading to no richness-evenness correlation and no significant overall change in richness. Demonstrating the importance of rarefaction, analyses of raw data that did not receive rarefaction indicated misleadingly strong benefits of organic agriculture and burning for richness while underestimating true gains in evenness. Both organic farming and burning favored species that were not numerically dominant, re-balancing communities as uncommon species gained individuals. Our results support the assertion that richness and evenness capture separate facets of biodiversity, each needing individual attention during conservation. PMID- 23094372 TI - Avoiding unintentional eviction from integral projection models. AB - Integral projection models (IPMs) are increasingly being applied to study size structured populations. Here we call attention to a potential problem in their construction that can have important consequences for model results. IPMs are implemented using an approximating matrix and bounded size range. Individuals near the size limits can be unknowingly "evicted" from the model because their predicted future size is outside the range. We provide simple measures for the magnitude of eviction and the sensitivity of the population growth rate (lambda) to eviction, allowing modelers to assess the severity of the problem in their IPM. For IPMs of three plant species, we found that eviction occurred in all cases and caused underestimation of the population growth rate (lambda) relative to eviction-free models; it is likely that other models are similarly affected. Models with frequent eviction should be modified because eviction is only possible when size transitions are badly mis-specified. We offer several solutions to eviction problems, but we emphasize that the modeler must choose the most appropriate solution based on an understanding of why eviction occurs in the first place. We recommend testing IPMs for eviction problems and resolving them, so that population dynamics are modeled more accurately. PMID- 23094373 TI - Revisiting competition in a classic model system using formal links between theory and data. AB - Formal links between theory and data are a critical goal for ecology. However, while our current understanding of competition provides the foundation for solving many derived ecological problems, this understanding is fractured because competition theory and data are rarely unified. Conclusions from seminal studies in space-limited benthic marine systems, in particular, have been very influential for our general understanding of competition, but rely on traditional empirical methods with limited inferential power and compatibility with theory. Here we explicitly link mathematical theory with experimental field data to provide a more sophisticated understanding of competition in this classic model system. In contrast to predictions from conceptual models, our estimates of competition coefficients show that a dominant space competitor can be equally affected by interspecific competition with a poor competitor (traditionally defined) as it is by intraspecific competition. More generally, the often-invoked competitive hierarchies and intransitivities in this system might be usefully revisited using more sophisticated empirical and analytical approaches. PMID- 23094374 TI - Testing the importance of plant strategies on facilitation using congeners in a coastal community. AB - Much is known about how environmental stress mediates the strength of facilitation, but less is known about how different plant traits affect facilitation. We examined interactions between the shrub Tamarix chinensis and two congeneric forbs (Suaeda salsa and S. glauca) on the Chinese coast. Although S. salsa and S. glauca are both annuals, morphologically similar, and have synchronous phenologies, they have contrasting adaptive strategies. S. glauca is salt intolerant but competitively superior, and S. salsa is salt tolerant but competitively inferior. Field surveys showed that S. glauca was associated with T. chinensis canopies while S. salsa was more abundant in open areas. A T. chinensis removal experiment showed that S. glauca cover was lower and soil salinity higher after two years in removal than in control plots. Transplant experiments showed that S. salsa performance under T. chinensis canopies was reduced by competition from S. glauca and T. chinensis, while in open areas S. glauca was not affected by S. salsa competition. Thus, contrasting competitive abilities and stress tolerances of S. glauca and S. salsa underlie their facilitative and competitive interactions with T. chinensis, suggesting that plant strategies are critical to the outcome of species interactions. PMID- 23094375 TI - Soil carbon sequestration in prairie grasslands increased by chronic nitrogen addition. AB - Human-induced increases in nitrogen (N) deposition are common across many terrestrial ecosystems worldwide. Greater N availability not only reduces biological diversity, but also affects the biogeochemical coupling of carbon (C) and N cycles in soil ecosystems. Soils are the largest active terrestrial C pool and N deposition effects on soil C sequestration or release could have global importance. Here, we show that 27 years of chronic N additions to prairie grasslands increased C sequestration in mineral soils and that a potential mechanism responsible for this C accrual was an N-induced increase in root mass. Greater soil C sequestration followed a dramatic shift in plant community composition from native-species-rich C4 grasslands to naturalized-species-rich C3 grasslands, which, despite lower soil C gains per unit of N added, still acted as soil C sinks. Since both high plant diversity and elevated N deposition may increase soil C sequestration, but N deposition also decreases plant diversity, more research is needed to address the long-term implications for soil C storage of these two factors. Finally, because exotic C3 grasses often come to dominate N enriched grasslands, it is important to determine if such N-dependent soil C sequestration occurs across C3 grasslands in other regions worldwide. PMID- 23094376 TI - Proposing a resolution to debates on diversity partitioning. AB - There have been intense debates about the decomposition of regional diversity (gamma) into its within-community component (alpha) and between-community component (beta). Although a recent Ecology Forum achieved consensus in the use of "numbers equivalents" (Hill numbers) as the proper choice of diversity measure, three related major issues were still left unresolved. (1) What is the precise meaning of the "independence" or "statistical independence" of alpha diversity and beta diversity? (2) Which partitioning (additive vs. multiplicative) should be used for a given application? (3) What is the proper formula for alpha diversity, as there are two formulas in the literature? This paper proposes a possible resolution to each of these issues. For the first issue, we clarify the definitions of "independence" and "statistical independence" from two perspectives so that confusion about this issue can be cleared up. We also discuss the causes of dependence, so that the dependence relationship between any two diversity components in both partitioning schemes can be rigorously justified by theory and also intuitively understood by simulation. For the second issue, both multiplicative and additive beta diversities based on Hill numbers are useful measures and quantify different aspects of communities. However, neither can be directly applied to compare relative compositional similarity or differentiation across multiple regions with different numbers of communities because multiplicative beta diversity depends on the number of communities, and additive beta diversity additionally depends on alpha (equivalently, on gamma). Such dependences should be removed. We propose transformations to remove these dependences, and we show that the transformed multiplicative beta and additive beta both lead to the same classes of measures, which are always in a range of [0, 1] and thus can be used to compare relative similarity or differentiation among communities across multiple regions. These similarity measures include multiple-community generalizations of the Sorenson, Jaccard, Horn, and Morisita-Horn measures. For the third issue, we present some observations including a finding about which alpha formula produces independent alpha and beta components. These may help to resolve the choice of a proper formula for alpha diversity. Some related issues are also briefly discussed. PMID- 23094377 TI - Caught in a fire trap: recurring fire creates stable size equilibria in woody resprouters. AB - Globally, fire maintains many mesic habitats in an open canopy state by killing woody plants while reducing the size of those able to resprout. Where fire is frequent, tree saplings are often suppressed by a "fire trap" of repeated topkill (death of aerial biomoass) and resprouting, preventing them from reaching adult size. The ability to tolerate repeated topkill is an essential life-history trait that allows a sapling to persist until it experiences a long fire-free interval, during which it can escape the fire trap. We hypothesized that persistence in the fire trap results from a curvilinear relationship between pre-burn size and resprout size, which causes a plant to approach an equilibrial size in which post fire biomass recovery is equal to fire-induced biomass loss. We also predicted that the equilibrial stem size is positively related to resource availability. To test these hypotheses, we collected data on pre-burn and resprout size of five woody plant species at wetland ecotones in longleaf pine savanna subjected to frequent burning. As expected, all species exhibited similar curvilinear relationships between pre-burn size and resprout size. The calculated equilibrial sizes were strong predictors of mean plant size across species and growing conditions, supporting the persistence equilibrium model. An alternative approach using matrix models yielded similar results. Resprouting was less vigorous in dry sites than at wet sites, resulting in smaller equilibrial stem sizes in drier sites; extrapolating these results provides an explanation for the absence of these species in xeric uplands. This new framework offers a straightforward approach to guide data collection for experimental, comparative, and modeling studies of plant persistence and community dynamics in frequently burned habitats. PMID- 23094378 TI - Intra- and interspecific tree growth across a long altitudinal gradient in the Peruvian Andes. AB - Tree growth response across environmental gradients is fundamental to understanding species distributional ecology and forest ecosystem ecology and to predict future ecosystem services. Cross-sectional patterns of ecosystem properties with respect to climatic gradients are often used to predict ecosystem responses to global change. Across sites in the tropics, primary productivity increases with temperature, suggesting that forest ecosystems will become more productive as temperature rises. However, this trend is confounded with a shift in species composition and so may not reflect the response of in situ forests to warming. In this study, we simultaneously studied tree diameter growth across the altitudinal ranges of species within a single genus across a geographically compact temperature gradient, to separate the direct effect of temperature on tree growth from that of species compositional turnover. Using a Bayesian state space modeling framework we combined data from repeated diameter censuses and dendrometer measurements from across a 1700-m altitudinal gradient collected over six years on over 2400 trees in Weinmannia, a dominant and widespread genus of cloud forest trees in the Andes. Within species, growth showed no consistent trend with altitude, but higher-elevation species had lower growth rates than lower-elevation species, suggesting that species turnover is largely responsible for the positive correlation between productivity and temperature in tropical forests. Our results may indicate a significant difference in how low- and high latitude forests will respond to climate change, since temperate and boreal tree species are consistently observed to have a positive relationship between growth and temperature. If our results hold for other tropical species, a positive response in ecosystem productivity to increasing temperatures in the Andes will depend on the altitudinal migration of tree species. The rapid pace of climate change, and slow observed rates of migration, suggest a slow, or even initially negative response of ecosystem productivity to warming. Finally, this study shows how the observed scale of biological organization can affect conclusions drawn from studies of ecological phenomena across environmental gradients, and calls into question the common practice in tropical ecology of lumping species at higher taxonomic levels. PMID- 23094379 TI - Coexistence in tropical forests through asynchronous variation in annual seed production. AB - The storage effect is a mechanism that can facilitate the coexistence of competing species through temporal fluctuations in reproductive output. Numerous natural systems have the prerequisites for the storage effect, yet it has rarely been quantitatively assessed. Here, we investigate the possible importance of the storage effect in explaining the coexistence of tree species in the diverse tropical forest on Barro Colorado Island, Panama. This tropical forest has been monitored for more than 20 years, and annual seed production is asynchronous among species, a primary requirement for the storage effect. We constructed a model of forest regeneration that includes species-specific recruitment through seed, sapling, and adult stages, and we parameterized the model using data for 28 species for which information is known about seedling germination and survival. Simulations of the model demonstrated that the storage effect alone can be a strong mechanism allowing long-term persistence of species. We also developed a metric to quantify the strength of the storage effect in a way comparable to classical resource partitioning. Applying this metric to seed production data from 108 species, the storage effect reduces the strength of pairwise interspecific competition to 11-43% of the strength of intraspecific competition, thereby demonstrating strong potential to facilitate coexistence. Finally, for a subset of 51 species whose phylogenetic relationships are known, we compared the strength of the storage effect between pairs of species to their phylogenetic similarity. The strength of the storage effect between closely related species was on average no different from distantly related species, implying that the storage effect can be important in promoting the coexistence of even closely related species. PMID- 23094380 TI - Belowground herbivory increases vulnerability of New England salt marshes to die off. AB - Belowground herbivory is commonly overlooked as a mechanism of top-down control in vegetated habitats, particularly in aquatic ecosystems. Recent research has revealed that increased densities of the herbivorous crab Sesarma reticulatum have led to runaway herbivory and widespread salt marsh die-off on Cape Cod, Massachusetts, USA. Aboveground herbivory is a major driver of this cordgrass habitat loss, but the role of belowground grazing is poorly understood. Sesarma live in communal burrows typically consisting of 1-2 openings and containing 2-3 crabs. However, at die-off sites, burrow complexes can cover > 90% of the low marsh zone, with crab densities as high as 50 crabs/m2 and burrow opening densities of 170 openings/m2. The magnitude of belowground Sesarma activity in association with salt marsh die-off provides an excellent opportunity to extend our knowledge of belowground herbivory impacts in coastal wetlands. Since Sesarma burrows allow access to cordgrass roots and rhizomes, and Sesarma are frequently restricted to burrows by thermal stress and predation, we hypothesized that belowground herbivory would be widespread in die-off areas. We experimentally demonstrate that Sesarma readily eat belowground roots and rhizomes in addition to aboveground cordgrass leaves. We then partitioned above- and belowground herbivory with field manipulations and found that belowground grazing is not only common, but can cause total plant mortality. Additional experiments revealed that plants remain vulnerable to belowground herbivory even after reaching a size refuge from aboveground grazing. This suggests that belowground herbivory contributes to salt marsh die-offs and adds to growing evidence that belowground herbivory is a widespread structuring force in plant communities that can limit habitat persistence. PMID- 23094381 TI - Large herbivores maintain termite-caused differences in herbaceous species diversity patterns. AB - Termites and large herbivores affect African savanna plant communities. Both functional groups are also important for nutrient redistribution across the landscape. We conducted an experiment to study how termites and large herbivores, alone and in combination, affect herbaceous species diversity patterns in an African savanna. Herbaceous vegetation on large vegetated Macrotermes mounds (with and without large herbivores) and on adjacent savanna areas (with and without large herbivores) was monitored over three years in Lake Mburo National Park, Uganda. We found substantial differences in species richness, alpha diversity, evenness, and stability between termite mound herbaceous vegetation and adjacent savanna vegetation. Within months of fencing, levels of species richness, evenness, and stability were no longer significantly different between savanna and mounds. However, fencing reduced the cumulative number of species, particularly for forbs, of which 48% of the species were lost. Fencing increased the beta diversity (dissimilarity among plots) on the resource-poor (in terms of both nutrients and soil moisture) savanna areas, while it did not significantly affect beta diversity on the resource-rich termite mounds. While termites cause substantial heterogeneity in savanna vegetation, large herbivores further amplify these differences by reducing beta diversity on the savanna areas. Large herbivores are, however, responsible for the maintenance of a large number of forbs at the landscape level. These findings suggest that the mechanisms underlying the effects of termites and large herbivores on savanna plant communities scale up to shape community structure and dynamics at a landscape level. PMID- 23094382 TI - Temporal variability in California grasslands: soil type and species functional traits mediate response to precipitation. AB - Plant communities on infertile soils may be relatively resistant to climatic variation if species in these communities have "stress-tolerant" functional traits that limit their ability to respond to climate. Alternatively, such communities may be more sensitive to climatic variation if their relatively sparse vegetative cover exposes species to more extreme changes in factors such as temperature or wind. We compared temporal variability in species richness and composition over 10 years between grasslands on infertile serpentine and "normal" sedimentary soils. Variability in species richness and species composition tracked mean annual precipitation on both soils, but variability was lower in serpentine grasslands. Communities on serpentine had lower functional diversity and had species with more "stress-tolerant" traits than non-serpentine communities (i.e., shorter stature, lower specific leaf area, and lower leaf area). Within and between soils, variability in species richness and temporal turnover were lower in communities scoring as more stress tolerant on a multivariate index of these traits; however, community variability was unrelated to functional diversity. Within 41 species found commonly on both soils, variability in occurrence and cover were also lower on serpentine soils, even though intraspecific trait differences between soils were minimal; this suggests a direct effect of soil type on species variability in addition to the indirect, trait-mediated effect. Communities with higher biomass had higher annual variability in species occurrence and cover. Our results suggest that infertile soils reduce compositional variability indirectly by selecting for stress tolerant traits and directly by limiting productivity. We conclude that communities on infertile soils may respond more conservatively to predicted changes in precipitation, including increased variability, than communities on soils of normal fertility. PMID- 23094383 TI - Unraveling plant-animal diversity relationships: a meta-regression analysis. AB - In the face of unprecedented loss of biodiversity, cross-taxon correlates have been proposed as a means of obtaining quantitative estimates of biodiversity for identifying habitats of important conservation value. Habitat type, animal trophic level, and the spatial extent of studies would be expected to influence the strength of such correlations. We investigated these effects by carrying out a meta-analysis of 320 case studies of correlations between plant and animal species richnesses. The diversity of arthropods, herps, birds, and mammals significantly increased with plant diversity regardless of species habitat. However, correlations were stronger when plant and animal species richnesses were compared between habitats (gamma diversity) than within single habitats (alpha diversity). For arthropods, both the coefficient of correlation and the slope of the regression line were also greater for primary than for secondary consumers. These findings substantiate the use of plant species richness as an indicator of the diversity of animal taxa over space. PMID- 23094385 TI - Outpatient treatment of adults with cystic fibrosis by primary care physicians. AB - Primary care physicians now see adult patients with Cystic Fibrosis (CF) who have multi organ consequences of the disease that present a complex management dilemma. Early diagnosis and treatment of these problems is important to limit morbidity. In this article we will review common problems experienced by these patients and present approaches to their management. PMID- 23094384 TI - Public school parents' perspectives of the Mississippi Healthy Students Act of 2007: findings from 2009-2011. AB - Annual evaluations of the Mississippi Healthy Students Act of 2007 (MHSA) were conducted from 2009-2011 among four stakeholder groups: (1) parents of public school students; (2) adolescents; (3) school officials (e.g., superintendents); (4) state-level policymakers (e.g., legislators). We examine results from the first state-wide study among a randomized sample of parents (N>3,600 per year) on childhood obesity as it related to MHSA. Parents were surveyed to determine: (1) knowledge/attitudes towards MHSA; (2) knowledge/attitudes/behaviors (KAB) that influence children's health; and (3) perceived overweight/obesity of self and child versus BMI-determined overweight/obesity. Across all three years, parents were very supportive of MHSA across a number of variables, while parents greatly underestimated obesity among self and child when compared to their BMI data. Results highlight complexities of parents' KAB that potentially influence children's health, including the MHSA. Policy implications are discussed. PMID- 23094386 TI - A common, but unexpected, suspect. PMID- 23094387 TI - Twelve doses for tuberculosis prevention--review of a new evidenced based regimen. PMID- 23094388 TI - MSMA cosponsors first-ever Mississippi Rx Drug Summit. PMID- 23094389 TI - Raising the bar, but failing to meet the goal: a young physician reflects on Match Day and Mississippi's primary care workforce. PMID- 23094390 TI - My view from second year: reflections of a Mississippi medical student. PMID- 23094391 TI - Top 10 facts you should know about diabetes. PMID- 23094392 TI - An interview with Charles D. "Buddy" Daughdrill, executive director of the Mississippi Public Health Association. Interview by Richard D deShazo. PMID- 23094393 TI - [We want to care for our veterans]. PMID- 23094394 TI - [European guidelines for lipid treatment are tailored according to risk level]. PMID- 23094395 TI - [Researching physicians provide better care]. PMID- 23094396 TI - [Interns continue researching after licensure. Research-internship seems to be a merit when applying for clinical service, shows Gothenburg Study]. PMID- 23094397 TI - [HAS-BLED shows bleeding risk in ischemic stroke and atrial fibrillation. But adjustments are needed for safer assessment, according to quality study]. PMID- 23094398 TI - [Congestive heart failure, part 1: investigation]. PMID- 23094399 TI - [Immunosuppression may mask severe infection. Septic arthritis in tocilizumab treatment yielded only modest acute-phase reaction]. PMID- 23094400 TI - [Diffuse symptoms in young women may indicate venous thromboembolism. Important to ask about the use of combined hormonal contraception]. PMID- 23094401 TI - [About the structure and beneficial effects of the apology]. PMID- 23094403 TI - Longing for the lounge. PMID- 23094402 TI - [How MS was discovered in Sweden]. PMID- 23094404 TI - Yes, let's trust the experts. PMID- 23094405 TI - Stories remind: there's no greater satisfaction. PMID- 23094406 TI - Well-being takes center stage. PMID- 23094407 TI - Greeking out. PMID- 23094408 TI - Policing the profession. PMID- 23094409 TI - Break out of your box: 15 ways to promote collegiality among physicians. PMID- 23094410 TI - On mentoring. PMID- 23094411 TI - Work group proposes governance changes. PMID- 23094412 TI - The 15 percent. Helping physicians find common ground in a complex world. PMID- 23094413 TI - Reflections. PMID- 23094414 TI - Was there ever a "golden age" of medicine? PMID- 23094415 TI - Which is feared more: harm to the ego or financial peril? A survey of anesthesiologists' attitudes about medical malpractice. AB - This article reports the results of a study of anesthesiologists to assess their concerns regarding medical malpractice liability risk. Specifically, it explored whether their fears stem more from being named as a party to a suit or from the financial impact of damage awards. According to the respondents, their reputation among patients and colleagues is of greater concern than the financial impact of a malpractice suit. Forty-six percent of the 149 respondents reported a constant fear of malpractice risk; 43% were concerned about their reputation among colleagues and 57% feared their reputation would be compromised among patients. A large majority voiced concern about potential inclusion in the National Practitioner Data Bank (83%) and their rankings on online physician-grading sites (85%). Forty-one percent said financial consequences were a concern, and 54% indicated that obtaining affordable liability coverage was an issue. PMID- 23094416 TI - Creating our future together. PMID- 23094417 TI - Kidney donation and chronic kidney disease. PMID- 23094418 TI - Voter restrictions in Florida (and elsewhere in the United States). PMID- 23094419 TI - The University of Rhode Island College of Pharmacy. PMID- 23094420 TI - The role of comparative effectiveness research in medicine and health. PMID- 23094421 TI - Pharmacists as diabetes educators and diabetes disease managers. PMID- 23094423 TI - A ten-year experience of a pharmacist consulting team for statewide bioterrorism and emergency preparedness. PMID- 23094422 TI - Rhode Island's interprofessional education initiatives. PMID- 23094424 TI - Medication therapy management in community pharmacy practice. PMID- 23094425 TI - Pharmacy research at URI: mining red maple (Acer rubrum) trees for novel therapeutics to manage diabetes. PMID- 23094426 TI - Pharmacy research at URI: bile acids and bile salt export pump: physiology and pathology. PMID- 23094427 TI - Going deep for drug discovery: an ocean to bedside approach to explore sub seafloor microbes for the next generation of antibiotics. PMID- 23094428 TI - Nanoparticles for cancer treatment. PMID- 23094429 TI - Seasonal influenza vaccination among pregnant women in Rhode Island, 2002-2011. PMID- 23094430 TI - Thyroid lymphoma. PMID- 23094431 TI - [Sensitivity for antibiotics among the E. coli strains isolated from patients with different clinical stage of infection]. AB - Enteric rods are the microorganisms most commonly isolated from blood of hospitalized patients. Bloodstream infections caused by them are associated with significant patient mortality. The aim of the study was analysis of clinical course and evaluation of clinical response on bloodstream infection caused by Escherichia coli. Microorganisms were evaluated for sensibility for antibacterial drugs. For that reason MIC (Minimal Inhibitory Concentration) of antibiotics from different groups was determined for E. coli strains isolated from patients with different clinical stage of infection. No significant differences were shown in sensitivity for antibiotics and MIC among the E. coli strains in correlation with clinical condition of studied patients. PMID- 23094432 TI - [Metrological analysis of stabilization material damages in AO treatment method]. AB - The aim of the study was the assessment of the material damages within the AO plates, used in fractures stabilization. Both the fixation material that became fractured and the fixation material removed without essential macroscopic damages were taken into consideration. There were 40 randomly chosen patients in the studied group (20 women and 20 men), who underwent stabilization of the fracture with the use of AO method in Second Department of Surgery of the Jagiellonian University Medical College between 2000-2009, followed by the removal of the fixation material and its metrological analysis. The mean age of patients in the studied group was 38 years. The mean follow-up was 4,3 years (2-11 y.). Complete bone union was achieved in 37 patients after the stabilization. Loosening and fracure of the fixation matierial was observed in 3 patients. Another stabilization surgery was necessary in these cases. After metrological analysis of the fixation material noticeable surface damages were found in 6 patients and damages within the holes in 20 plates, including 3 fractures. Damages of the fixation material were taking place mostly in patients with the femoral bone fractures. CONCLUSIONS: 1) There are two typical damages of the stabilization plates: the surface damage and the damage within the screw holes. 2) Damage and loosening of the plates are mainly caused by its re-modelling and traumatisation during the surgery. 3) No essential surface changes were observed within most of the AO plates and the changes within the screw holes are observed in half of the cases. PMID- 23094433 TI - [Prospective assessment of circulatory sufficiency of the patients after 3F equine pericardial stentless bioprosthesis replacement]. AB - INTRODUCTION: During years more and more advanced Technologies are used for treatment of severe aortic stenosis. One of them is equine pericardial stentless bioprothesis. AIM OF THE STUDY: the aim of the study was prospective assessment of circulatory sufficiency of the patients after 3F equine pericardial stentless bioprothesis replacement (ATS-Medtronic, Inc, Minneapolis, USA). PATIENTS AND METHODS: Patients qualified to valve replacement were qualified to the study. The procedures were performed in general anesthesia and medial thoracothomy. The New York Heart Association (NYHA) scale was analyzed to estimate clinical results of the procedures. RESULTS: 45 patients (10 women and 35 men) aged 23-78 (mean 54 (+/- SD 12.7) were included into the study. Patients were observed during one year follow up (FU). At the baseline three pts had NYHA II stage, 35 - III and 7 IV. There was no pts in NYHA I stage. After 3-6 months FU 34 pts were at NYHA I stage (79%) and 9 at NYHA II. After 11-14 FU 33 pts were at NYHA I (80.4%) and 8 NYHA II (19.5%). There was no pts at NYHA IV during 12 months FU (differences between observational periods statistically significant p < 0.001). CONCLUSIONS: During one-year FU after equine pericardial stentless bioprothesis implantation the improvement of NYHA grade was observed. PMID- 23094434 TI - [Clinical evaluation of complications after implantation of stentless biological equine pericardial bioprothesis]. AB - Stentless bio-protheses are more and more frequently used in patients with severe aortic stenosis, due to good hemo-dynamic parameters and durability after aortic valve replacement (AVR). Aim of the study was the clinical evaluation of complications after surgical AVR using the 3F equine pericardial stentless bioprothesis (ATS Medtronic, Inc, Minneapolis, USA). PATIENTS AND METHODS: 45 patients (10 women, 35 men), aged from 23 to 78 had implanted the bioprothesis. RESULTS: Two patients died in perioperative period, but the bioprotehsis function was correct. In two patients gastrointestinal (GE) bleeding was observed due to anticoagulation therapy. In remaining 41 patients during one year follow-up no complications were noted. CONCLUSIONS: After implantation 3F bioprotehesis two unrelated deaths and 2 GE bleeding complications were observed. Other 41 patients had no complications during 1 year follow-up. PMID- 23094435 TI - [Intravenous thrombolysis patients with acute ischemic stroke: the analysis of the 100 cases. Part I. Characteristic of the patients and effectiveness of treatment]. AB - BACKGROUND: Intravenous thrombolytic therapy with recombinant tissue activator (rt-PA) in treating acute ischemic stroke is effective and safe in the time window 4.5 hours after symptom onset. MATERIAL AND METHODS: In the study group of patients demographic and logistic data and vascular risk factors were analysed. We also analysed status of the patients at the moment of admission, after 24 hours, one month and 3 months after symptom onset according to National Institutes of Health Stroke Scale (NIHSS) and results of treatment after 3 months according to modified Rankin Score (mRS). We compared the selective variables with data from the register SITS. RESULTS: Between September 2006 and April 2009 in the stroke unit in Sandomierz 807 patients with ischemic stroke were treated, including 100 patients (aged 42-88, mean 69.74 +/- 9.85; 55% of men) treated with rt-PA (12.39%). In 22% of patients treated rt-PA large and medium vessel disease, in 47%--cardiogenic embolism, in 4%--small vessel disease, in 3%-- other unusual causes and in 24%--infarct multiple etiology were diagnosed. The average time from the onset of the disease to the beginning of the treatment was 148.25 +/- 38.77 min. (in SITS centers--145 min.). At the moment of admission the average neurological conditions in NIHSS 12.03 +/- 4.94 (SITS--12); after 24 hours--8.51 +/- 6.09; after 7 days--6.51 +/- 6.38; after one month--4.27 +/- 5.15 and after 3 months--2.95 +/- 3.36 were evaluated. The results according to mRS were respectively: after 7 days--2.80 +/- 1.77; after 1 month--2.37 +/- 2.00 and after 3 months 2.16 +/- 2.16(SITS--2.5). After 3 months 53% of patients were functionally independent (SITS--53%), 29%--had moderate or severe disability ( 32%) and 18%--died (-15%). CONCLUSIONS: In analysed time in stroke unit in Sandomierz the percentage of patients with acute ischemic stroke treated with rt PA was high. The presentation of results of intravenous thrombolysis in patients with acute ischemic stroke performed in different centers makes the important aspect of evaluation of the effectiveness and safety of this therapy. PMID- 23094436 TI - [Intravenous thrombolysis patients with acute ischemic stroke--the analysis of the 100 cases. Part II. Neuroimaging, the analysis of hemorrhagic complications and deaths]. AB - INTRODUCTION: Computed tomography (CT) remains the basic diagnostic examination in patients with ischaemic stroke. The main purpose of CT examination is distinguishing between hemorrhagic and ischemic stroke, exclusion of other diseases and revealing early ischemic radiological changes. MATERIAL AND METHODS: The results of baseline CT scans and CT performed on 2nd and 7th days after symptom onset, in terms of patients' long-term outcome, presence of serious adverse events and deaths within 3 months were analyzed. RESULTS: The analysis included 100 patients treated with rt-PA in stroke unit from September 2006 to April 2009. More than one third of patients had normal baseline CT, in one third- old ischemic changes and in one third--early ischemic changes were revealed. After 3 months the patients who had early changes in baseline CT, and those who had extensive ischemic changes in the area of MCA (middle cerebral artery) or ICA (internal carotid artery) had the worst clinical status. In this group deaths appeared most often (in a subgroup with ischemic signs in the whole territory of MCA, p < 0.01 and in a group of patients with stroke in the ICA territory, p < 0.001), similarly to a group of patients with old changes in baseline CT (34.3% died; p < 0.001) and a group with cerebral edema in control CT (32.4%; p < 0.01). Hemorrhagic transformation appeared in 18% of patients. In this group of patients we found higher risk of death within 3 months after stroke onset(p < 0.001). CONCLUSIONS: The imaging examinations are very important in process of qualification of patients for thrombolytic treatment. Safety of intravenous thrombolysis in patients with ischemic stroke depends on the detailed analyses of the CT scans. PMID- 23094437 TI - [Comparison of self-estimation of disuric disorders gauged IPSS scale and qualities of lives QoL with self-estimation of sexual life gauged by IIEF-5 scale]. AB - Evaluation of men with a point scale is a simple method that can be used both in primary care and specialist in-patient treatment. Although its use is not widespread. International scoring system for evaluation of symptoms of the prostate is common in Poland (IPSS). Responses to the questionnaire are the basis of IPSS scale. Quality of life form (QoL) is in addition to the scale of IPSS. It defines subjective assessment of patient well-being in case of symptoms of lower urinary tract at the same level as at the time of the study. 5-point questionnaire IIEF-5 has been used in Poland since 1999 to assess men's sexual life. The aim of the study is to compare the assessment of disuric disorders measured using the International Prostate System Score (IPSS) and Quality of Life scale versus scale of men's sexual self-esteem IIEF-5 in men at the age of 50-70. The study included 1746 randomly selected residents of the district Cracow Downtown, at the age of 50-70. Medical interview was carried out (including complaints of lower urinary tract symptoms (IPSS), quality of life (QoL) and sexual dysfunction (IIEF-5); physical examination with assessment of individual systems with particular emphasis on genitourinary system, physical examination of the prostate (DRE), PSA level in total and free fractions, a biopsy of the prostate under ultrasound control if necessary. For the analysis qualified 1746 men. The men were divided into groups called groups of disease: a suspicion of prostate cancer, can not rule out prostate cancer, prostate cancer confirmed, probable benign prostatic hyperplasia (BPH), no lesions. The largest was the group with probable benign prostatic hyperplasia 64.89% of the total respondents, followed by a group of men without lesions, 26.29%, a group of probable prostate cancer was 6.41% of the respondents, a group with whom you can not rule out prostate cancer was 1.89%, the smallest was the group with confirmed prostate cancer, 0.52% of all male respondents. The age groups were: 498 respondents aged 50-54 years and 391 aged 55-59, 397 aged 60-64 and 460 aged 65-70. Mean age was 59.24 years. Ppicked up data were processed and analized by STATA- 5,0. Differences between groups relative to answers for the questions of scales: IPSS, QoL and IIEEF5 questionnaire were analized by Mann-Whitney, Kruskal- Wallis, Scheffe's and chi2 tests. Homogeneity of the IPSS were analised by a Cronbach coefficient test. Accordance of each questions of the scale to whole scale were analised by correlation and line regression tests. Based on the analysis of the total scale score by IPSS and QoL scale and quality of life questionnaire IIEF-5 showed that in the process of aging in the population more frequently in older than in younger men, there are complaints from the urinary tract and deteriorating quality of life of self-esteem and quality of life of sexual self esteem. After analyzing the result of scale: IPSS, QoL, and IIEF-5 in the disease groups, it was found that the total score of IPSS differentiates men in the group with probable benign prostatic hyperplasia, from a group of men without lesions and men with suspected prostate cancer. Statistically significant reduction in quality of life (QoL) in patients with confirmed prostate cancer and in the group with probable benign prostatic hyperplasia compared with men without lesions. The highest self-esteem sex life (IIEF-5) was found in men without lesions and the lowest in the group with known prostate cancer. The scale of quality of life (QoL) was significantly positively correlated with the results of IPSS scale, as well as with each of its questions. Deterioration in the quality of life occurred as a crescendo pain of lower respiratory tract. With the increase in the incidence and severity of each symptom on a scale IPSS worsening of self-esteem was examined using a scale IIEF-5. U of men with the deterioration of the quality of life measured by the scale of QoL, worsening their sexual self-esteem scale IIEF-5. In the process of aging are growing complaints from the lower urinary tract, self-esteem deteriorates the quality of life, including sexual life, which is especially marked in men with enlarged prostate. The scale of quality of life (QoL) is significantly positively correlated with the results of IPSS scale. With the increase in the incidence and severity of symptoms on a scale IPSS had decreased self-test using the IIEF-5 scale. The deterioration of quality of life measured with QoL was associated with decreased sexual self-esteem scale IIEF-5. PMID- 23094438 TI - [Quality of life in health and disease--what is it, how and why evaluate it]. AB - The concept of quality of life has many meanings, is variously defined, understood and tested. There is no universal, generally accepted definition of quality of life, but all of the ways to understand this construct have common features--quality of life is subjective, it is associated with health but its meaning is much broader and multidimensional by involving multiple clinical, functional and social variables. In the last decade, followed by redefining the concept of health as a positive resource it is recommended to perceive the quality of life holistically, including both--satisfaction with life in general and satisfaction with its particular domains. The study is an attempt to present the matter of quality of life in the most synthetic way possible, to the extent allowed by its complexity. PMID- 23094439 TI - [Psychological factors affecting medical conditions--contemporary conception of psychosomatic syndrome]. AB - While analyzing the character of relationship between soma and psyche throughout the centuries one can perceive its alternate changes triggered of many different reasons. XX century was a period in which researchers described psychosomatic dependences unambiguously however different explorers had understood it somewhat differently. These transformations throughout the centuries were the bases to create in XXI century a new system free from controversial and difficult to accept on the ground of medicine foundations. Prepared to introduce together with from DSM-V, the study of Psychological Factors Affecting Medical Conditions seems to be free from mistakes and helpful in treatment of ills. PMID- 23094440 TI - [PARP inhibitors and their role in the therapy of triple-negative metastatic breast cancer]. AB - Breast cancer is the most common neoplasm among women. The risk of disease increases with age, particularly in postmenopausal period. The method of treatment depends on the stage of disease, state of receptors and molecular subtype. Depending on indications there are few options: surgical treatment, radiotherapy, hormonotherapy, chemotherapy and targeted therapy. Systemic treatment of metastatic triple-negative breast cancer is not satisfying. Hopes are laid upon poly(ADP-ribose) polymerase inhibitors. Studies over these substances in both: in connection with the standard chemotherapy and as monotherapy bring promising results. The article presents the molecular basics of polymerase poly(ADP-ribose) function as well as the possibilities of using its inhibitors in treatment of triple-negative breast cancer. PMID- 23094441 TI - [Moral and religious issues in health care]. AB - The paper summarises the moral and spiritual factors important in care for sick people. Medical care is one of the ancient forms of our activity as humans, expounding care for other people's well-being. The moral aspect of medical care is deeply rooted in constant daily interaction between the patient and the doctor aiming at easing symptoms, support, help, prevention and defense. Such teleological orientation of medicine is, according to John Paul II, made possible not so much by technology but by physician's conscience, wisdom and unlimited honesty. This is where ethics is needed to regulate that particular relation. This ethics stems from Christian morality, which raises our role as humans to that of guardians of dignity of another human being. Man is indeed the measure of all things, and this becomes the context for all relations including man's relation to God, but also relation of God to man. Thus, human dignity assumes the status of unconditional natural rule, inherently forestalling all legal arrangements. The morality of health care requires holistic approach, including care for body, mind, social interaction and spiritual needs. Only then, as explained by dr Ewa Kucharska, is it possible to answer patient's all needs. The moral side of the therapeutic contract bounds the doctor and the patient, alike. From this point of view, it is immoral not to cooperate with physicians in their strife for the preservation of health and life itself. Self negligence or active self harm (drugs, alcohol abuse, HIV/AIDS) are the utmost examples of such dishonesty. Finally, the imperative to bring hope and faith to the suffering, vests special importance in hospital chaplains, who bring good word, but most importantly the sacrament to those in need. The prayer in turn may evoke strong hope for cure, capable of supporting both soul and body. The suffering of man cannot be understood on rational grounds. It requires acceptance, and, above all, it requires faith. And this understanding is reached only by faith and participation in Christ's sufferings. PMID- 23094442 TI - Navigating ICD-10: how one organization prepares for implementation. PMID- 23094443 TI - Revenue cycle? More like a revenue rhythm. PMID- 23094444 TI - Tips for revenue cycle improvement. PMID- 23094445 TI - Supporting family and colleagues can help nurses manage their grief. PMID- 23094446 TI - When your patients die: living with cumulative grief. PMID- 23094447 TI - What makes for a good death instead of a bad death? PMID- 23094448 TI - To retain oncology nurses, offer grief resolution. PMID- 23094449 TI - How do you cope with patients' death? PMID- 23094451 TI - How does CMS affect oncology nursing practice? PMID- 23094450 TI - The case of the vexing vesicant. PMID- 23094452 TI - Researchers uncover new evidence for stem cells. PMID- 23094453 TI - Cultural issues in nondisclosure require sensitivity. PMID- 23094454 TI - Complexity of images: experimental and computational estimates compared. AB - We tested whether visual complexity can be modeled through the use of parameters relevant to known mechanisms of visual processing. In psychophysical experiments observers ranked the complexity of two groups of stimuli: 15 unfamiliar Chinese hieroglyphs and 24 outline images of well-known common objects. To predict image complexity, we considered: (i) spatial characteristics of the images, (ii) spatial-frequency characteristics, (iii) a combination of spatial and Fourier properties, and (iv) the size of the image encoded as a JPEG file. For hieroglyphs the highest correlation was obtained when complexity was calculated as the product of the squared spatial-frequency median and the image area. This measure accounts for the larger number of lines, strokes, and local periodic patterns in the hieroglyphs. For outline objects the best predictor of the experimental data was complexity estimated as the number of turns in the image, as Attneave (1957 Journal of Experimental Psychology 53 221-227) obtained for his abstract outlined images. Other predictors of complexity gave significant but lower correlations with the experimental ranking. We conclude that our modeling measures can be used to estimate the complexity of visual images but for different classes of images different measures of complexity may be required. PMID- 23094455 TI - Effects of luminance on dynamic random-dot correlogram evoked visual potentials. AB - Although dynamic random-dot correlogram evoked visual potentials (DRDC-VEPs) are a three-decade-old method to detect the cortical binocularity in humans and animals, our knowledge of the influence of fundamental stimulus parameters and the underlying cerebral processing mechanisms has remained limited. The purpose of this study was to evaluate the effect of luminance on DRDC-VEPs in adults. The variability and detectability of DRDC-VEPs were investigated under different stimulus luminance conditions with neutral density filters. Our results have demonstrated that DRDC-VEPs can be evoked in a wide luminance range, and the response amplitude was practically independent of luminance between 4.75 cd m(-2) and 0.015 cd m(-2), while DRDC-VEP latencies showed a strong linear correlation with log luminance. There is, however, a limit (0.06 cd m(-2)) below which DRDC VEPs are not reliably recordable. Luminance reduction-induced delays in DRDC-VEP latencies cannot be explained simply by retinal mechanisms, since their regression slope does not follow the course of electroretinogram and cortical evoked potential latencies. Luminance independence of DRDC-VEP amplitude suggests that binocular correlation-processing cortical neurons receive input predominantly from the magnocellular visual pathway. PMID- 23094456 TI - Mapping the "forbidden zone" near and away from the fixation point. AB - Burt and Julesz modified the classical view of Panum's fusional area by incorporating the concept of the disparity gradient. They found that an area of double vision, described as the forbidden zone for single vision, is present when the angular separation between two objects is small. However, Krol and van de Grind argued that Burt and Julesz's finding could be explained by the classical theories (specifically Ogle, 1932 JOSA 22 664-728) in which the probability for fusion is a function of peripheral angle and disparity magnitude. We examined whether a forbidden zone can be specified within Ogle's experimental space. We found forbidden zones (a) when fixation was placed on one of the two objects and (b) when fixation was placed away from both objects. Krol and van de Grind's arguments do not easily explain the results in (b). The size of the forbidden zones was less than the predicted disparity gradient of unity that Burt and Julesz found in their experiment. PMID- 23094457 TI - Consistency of likeability of objects across views and time. AB - Subjective impressions of face images (eg personality trait judgments) are consistent across exposure durations and viewpoints. In this study, we investigated whether subjective likeability of common non-face objects would also be consistent. Participants rated the likeability of 32 common objects (eg chair, car, and kettle). Although the rated likeability scores were generally higher for objects shown in three-quarter views than for the same objects shown in full frontal views, object-wise correlations across the views were significant (experiment 1). The likeability ratings based on brief exposure duration (eg 100 ms) also significantly correlated with those based on unlimited exposure duration (experiment 2). Even when the duration was brief, the consistency across the views was replicated. The findings confirmed that the subjective likeability of common objects is consistent and the process underlying it is efficient, similar to those of faces. However, the mean rated likeability was higher for longer exposure durations, suggesting a negative bias for briefly observed objects. Since this bias is contrary to previously reported findings for faces, the mechanisms for determining subjective likeability of common objects may be partially different from those of faces. PMID- 23094458 TI - Perceptions of dominance following glimpses of faces and bodies. AB - Dominance is one of the most ecologically important social traits that humans express and perceive. Here, we examined perceivers' capacity to judge dominance under physical and temporal constraints. In study 1, dominant, neutral, and submissive poses of otherwise non-expressive faces and impoverished facial outlines were judged after exposure for 27 ms, 40 ms, 94 ms, or at a self-paced rate (approximately 2000 ms). Perceivers' judgments of dominance were significantly more accurate than chance guessing for exposures of 40 ms and greater, with no significant increase in accuracy given additional viewing time. In study 2, we replaced faces with bodies and figural outlines of bodies. Perceivers' judgments were again better than chance for exposures of 40 ms and greater, but significant increases in accuracy were observed for durations of 94 ms and at a self-paced rate. Finally, in study 3, we combined studies 1 and 2 to allow comparisons across stimuli. Results showed that judgments of dominance from the faces were significantly more accurate than were those of the bodies, and judgments of full stimuli were more accurate than were those of outlines. These data extend our knowledge of the efficient and accurate perception of social cues from nonverbal behavior. PMID- 23094459 TI - The composite-face effect survives asymmetric face distortions. AB - In two experiments, we investigated whether adults use holistic processing even for faces that are grossly distorted because their eyes have been moved asymmetrically to violate the common layout of a face (distorting its first-order relations). To this end we used a compelling demonstration that faces are processed as wholes, the composite-face effect. Specifically, adults judged the similarity of sequentially presented top halves of normal (original condition) and distorted faces with one eye (one-eye condition) or two eyes (two-eyes condition) shifted up by an abnormal amount. Trials were either blocked by type of distortion (experiment 1) or intermixed within the experiment (experiment 2). In both experiments, participants demonstrated a composite-face effect of the same magnitude in the three conditions, a pattern suggesting that they processed holistically even faces whose first-order relations were violated. PMID- 23094460 TI - Effects of band-pass spatial frequency filtering of face and object images on the amplitude of N170. AB - Previous studies have suggested that physiological responses are greatest and face recognition performance is best when a band of middle relative spatial frequencies (SFs) is included in stimuli. Conversely, behavioural data suggest that object recognition performance shows comparatively little effect of SF variations. Here, we examine the effects of SF filtering on the amplitude of the N170 ERP component when participants are shown images of faces and objects. Our findings show that with face stimuli the amplitude of N170 exhibits a band-pass modulation function, with responses to middle SFs (around 11 cycles per face) being statistically indistinguishable from responses to full-band faces. In contrast to faces, object stimuli elicited a relatively flat function across much of the spectrum. However, for both faces and objects, middle spatial frequencies were sufficient to elicit the same N170 magnitude as full-band images. Our results with face stimuli are in accordance with previous work examining single cell and MEG responses. Our results with objects are compatible with previous behavioural work showing a relative robustness of object recognition to SF manipulations. Our findings are novel in showing that the middle band elicits the same N170 as full-band images in both faces and objects. PMID- 23094461 TI - Studies of the angular function of a Duncker-type induced motion illusion. AB - Duncker (1929/1955, Source Book of Gestalt Psychology, pp 161-172) demonstrated a laboratory version of induced motion. He showed that, when a stationary spot of light in a dark laboratory is enclosed in an oscillating rectangular frame, the frame is perceived as stationary and the dot appears to move in the direction opposite the true motion of the frame. Zivotofsky (2004, Investigative Ophthalmology & Visual Science 45 2867-2872) studied a more complex variant of the Duncker illusion, in which both the inducing and the test stimuli moved: a single red test dot moved horizontally left or right while a dense background set of black dots on a white background moved vertically up or down. When the background inducing dots moved up (down), the truly horizontally translating test dot appeared to drift at an angle down (up) from the horizontal. In experiment 1, we used two methods to measure the complete angular function of the Zivotofsky effect and found it to peak with an inducer-test direction separation of approximately 30 degrees, similar to the inducing angle that has been found to maximise other direction illusions. Experiment 2 tested and confirmed predictions regarding the effects of relative test and inducer speeds based on the vectorial subtraction of the inducing velocity from the test velocity. PMID- 23094462 TI - A comparison of self-reported and measured autostereogram skills with clinical indicators of vergence and accommodative function. AB - Failure to perceive the disparity-defined form in autostereograms by those with clinically normal stereoacuity can occur when achieving or maintaining the precise vergence angle required to place the intended left and right images on corresponding areas of the two retinas is difficult. Since vergence and accommodation must be maintained at different depth planes to permit sensory fusion of an autostereogram, poor autostereogram skill has been suggested by different investigators to be related either to the presence of a binocular vision anomaly (ie a poorly tuned binocular system) or to a binocular system that is well-coordinated. The purpose of this study was to clarify the relationship between binocular visual performance and autostereogram skill. PMID- 23094463 TI - Assessment of changes in confidence, attitude, and knowledge of non-psychiatric physicians undergoing a depression training program in Taiwan. AB - OBJECTIVE: To assess whether non-psychiatric physicians would benefit from a national depression training program and explore associated factors. METHOD: Attending physicians were asked to complete survey questionnaires of confidence, attitude, knowledge, and their willingness to implement new strategies to improve care, before and after training. Paired t-test and multiple regression analysis were used to determine the differences and explore factors associated with the domains of confidence, attitude, and knowledge. McNemar's test was used to compare the difference between the physicians' intention to change depression management before and after training. RESULTS: Of 524 eligible physicians, 307 (59%) completed the pre- and post-program assessments. These physicians showed significantly increased knowledge score and willingness to implement new treatment strategies, as well as more positive attitude toward and confidence in treating depression. The lower corresponding baseline score was associated with greater improvement in domains ofknowledge, confidence, and attitude. Completion of the training was associated with an improvement in knowledge and becoming less helpless and avoidant attitude. Other factors including non-family-medicine physicians, post-graduate education, and female gender are associated with greater improvements in various domains. CONCLUSIONS: Our study shows that even a brief educational program can positively influence the physicians' knowledge, attitudes, and confidence in treating depression. Further work is needed to monitor whether the effects of training are long-term, and can be translated into behavioral change in practice. PMID- 23094464 TI - A cross-sectional study of body shape and eating attitude among Indian female healthcare students. AB - OBJECTIVE: The current study aimed at assessing eating attitude and body shape concerns among Indian female healthcare students who had received some teaching/training in Psychiatry. METHOD: The study was conducted at government medical and nursing college. All the undergraduate healthcare students enrolled with institute at the time of study constituted the sampling frame for the study. Survey-based methodology was used for data collection. Study scales included semi structured proforma, Eating Attitudes Test-26 (EAT-26) (including the three sub scales), and Body Shape Questionnaire (BSQ). Data were analyzed using Pearson's and Spearman's correlation statistics and ANOVA with post hoc analysis. RESULTS: A total of 498 students returned the completed study questionnaire. There was significant correlation between Body Mass Index (BMI) and EAT-26 scores) including the sub-scales score of EAT-26). Similarly, BMI and BSQ scores were also significantly correlated. DISCUSSION: The findings from current study help understand the body shape and eating attitudes of Indian female healthcare students who had received some teaching/training in Psychiatry. PMID- 23094465 TI - A study of postpartum depression in a fast developing country: prevalence and related factors. AB - BACKGROUND: Depression is a common and disabling complication of postpartum women. There is a paucity of research on postpartum depressive disorders and their predictors in women from Arab countries. AIM: The aim of this study was to determine the prevalence and identify risk factors of postpartum depression among Arab women in Qatar using Edinburgh Postnatal Depression Scale Score (EPDS). DESIGN: This is a prospective cross-sectional study conducted during the period from January 2010 to May 2011. SETTING: Primary healthcare centers of the Supreme Council of Health, State of Qatar. SUBJECTS: A representative sample of 1669 mothers within 6 months after delivery were approached and 1379 (82.6%) mothers participated in this study. METHODS: The study was based on a face-to-face interview with a designed diagnostic screening questionnaire. Occurrence of postpartum depressive symptoms was assessed by the EPDS. Also, socio-demographic characteristics, medical and family history, and obstetric variables of patients were collected through a designed questionnaire. The diagnostic screening questionnaire was reviewed and calculated the final score which identified the risk cases. RESULTS: The prevalence of postpartum depression among the study sample was 17.6%. Mothers of age above 35 years (49.9% vs. 39.2%; p < 0 .001), low education below intermediate level (51% vs. 35.8%; p < 0.001), housewives (38.7% vs. 29%; p = 0.03), with low monthly income (QR 5000-9999) (43.2% vs. 32.2%; p < 0.001) were significantly at high risk for postpartum depression. Maternal complications (38.7% vs. 26.1%; p < 0.001) and caesarean section (36.2% vs. 28.8%; p = 0.022) were significantly higher among depressed mothers compared to non-depressed women. Financial difficulties (OR = 2.04; p < 0.001), prematurity (OR = 1.64; p = 0.025), poor family support (OR = 1.52; p = 0.016), dissatisfaction in marital life (OR = 1.26; p = 0.005), poor marital relationship (OR = 1.13; p = 0.05) were the main predictors of postpartum depression. CONCLUSION: This prevalence of postpartum depression in women living in Qatar was comparable to previous epidemiological research done in developing countries. Financial difficulties, prematurity, lack of family support, and poor marital relationships have been identified as main risk factors for developing postpartum depression. PMID- 23094466 TI - Impact of co-morbid mental illness on the diagnosis and management of patients hospitalized for medical conditions in a general hospital. AB - AIMS: Comorbidities including hyperglycemia, diabetes, and hypertension are frequently observed in psychiatric patients. Nevertheless, this population has higher rates of morbidity and mortality from medical illnesses compared to non psychiatric patients. The present study evaluated the diagnosis and management of general medical hospitalized patients with and without mental illness. METHODS: The study group consisted of 200 hospitalized subjects including 100 subjects who met the DSM-IV criteria for schizophrenia or bipolar disorder and 100 age-matched controls. All patients were evaluated for a comorbid condition, concomitant medication, biochemical parameters. Comorbid conditions were defined using the National Cholesterol Education Program risk factors categories: diabetes (fasting plasma glucose level > or = 126 mg/dl and/or pharmacological treatment); hypertension (systolic blood pressure > or =140 mm Hg and/or diastolic BP > or = 90 mm Hg and/or pharmacological treatment); dyslipidemia (hypertriglyceridemia (> or = 150 mg/dl); and/or pharmacological treatment and/or low HDL cholesterol level (< 40 mg/dl in men and < 50 mg/dl in women). RESULTS: The two groups were similar in terms of age, sex, mean blood pressure, glucose, and lipids. Patients with a history of psychiatric illness were less frequently diagnosed with medical conditions such as hypertension, dyslipidemia, and diabetes compared to the non psychiatric population, though according NCEP criteria, these conditions did not significantly differ between the two groups. Significantly fewer psychiatric than non-psychiatric patients received aspirin, statins, anti-hypertensive and anti diabetic medications. Although more obesity was diagnosed in psychiatric patients, significantly fewer diet consults were performed during hospitalization. While significantly more smokers and more pulmonary hospitalizations were observed in the psychiatric group, fewer subjects in this group received instruction for smoking cessation compared to the non-psychiatric population. CONCLUSIONS: Comorbid medical conditions such as diabetes, hypertension, dyslipidemia, and obesity are under-diagnosed and under-treated in hospitalized psychiatric patients compared with the non-psychiatric population. Patients with mental illness have significantly less preventive intervention during hospitalization. PMID- 23094467 TI - The cardiac anxiety questionnaire: cross-validation among cardiac inpatients. AB - OBJECTIVE: General anxiety symptoms are common in patients with cardiac disease and considered to have an adverse effect on cardiac prognosis. The role of specific cardiac anxiety, however, is still unknown. The aim of this study is to examine the factor structure, reliability, and validity of the Dutch version of the Cardiac Anxiety Questionnaire (CAQ), which was specifically designed to assess heart focused anxiety. METHODS: Two hundred thirty-seven patients admitted for an acute coronary syndrome (ACS) and a control group of 49 patients admitted for an exacerbation of rheumatoid arthritis (RA) completed the CAQ, the Agoraphobic Cognitions Questionnaire, Mobility Inventory, Beck Depression Inventory, Beck Anxiety Inventory, and the State-Trait Anxiety Inventory. RESULTS: Although the original three-factor solution (fear, avoidance, and attention) was acceptable (model fit parameters: CFI = 0.89 and TLI = 0.87), our data were best explained by a four-factor model including safety seeking behaviors. Internal consistency and test-retest reliability were good. The CAQ had moderate correlations with the other anxiety and depression questionnaires. Recently admitted ACS patients had significantly higher scores than RA patients, even after controlling for general anxiety and depressive symptoms (p < 0.001). CONCLUSION: The CAQ is a reliable and valid instrument to assess cardiac anxiety in patients hospitalized with ACS. These results enable longitudinal studies to examine the relationship of heart-focused anxiety with cardiac prognosis and to evaluate interventions specifically targeted at anxiety in cardiac patients. PMID- 23094468 TI - Premenstrual dysphoric disorder in East Asia: a review of the literature. AB - OBJECTIVE: Fluctuations in ovarian steroids during specific phases of the reproductive cycle, such as pre-menstruation, have been hypothesized to contribute to women's increased vulnerability to depression. This current study's goal is to summarize the literature regarding Premenstrual Dysphoric Disorder (PMDD) in the East Asian countries of Taiwan, China (including Hong Kong and Macau), Japan, and Korea. METHOD: A Pubmed and Chinese Electronic Periodical Service (CEPS) literature review was conducted using the key words "Premenstrual Dysphoric Disorder" along with "Japan," rea," "Taiwan," "Hong Kong," and "Macau." Using these criteria, 17 articles were found. Three articles were excluded because they did not involve PMDD in the aforementioned countries. In addition to this search, an article found in a review of the research on reproductive mental health disorders in China was utilized. That review contained one article regarding PMDD with an English language abstract, which was utilized in this current article. RESULTS: The rates of PMDD in East Asia (1.3-2.8%) appear to be lower than that seen in the Western literature (3-8%). Many of the risk factors for PMDD were the same in the Eastern and Western literature, although some key differences were found. The few studies on treatment of PMDD in East Asia have shown positive results. CONCLUSIONS: The rates of PMDD appear to be lower in East Asia, though reasons for this result are discussed. Few studies have been conducted examining the efficacy of psychotropic medications commonly used to treat PMDD in this population. PMID- 23094469 TI - Suicidality and its associated factors in cancer patients: results of a multi center study in Korea. AB - OBJECTIVE: The current study examined the prevalence and associated factors of suicidality among Korean cancer patients. Moreover, the association of multiple psychological morbidities with suicidality was investigated among cancer patients. METHODS: A cross-sectional, multi-center survey of 400 cancer patients was administered in five cancer-treatment hospitals throughout South Korea. Study variables were assessed using standardized measures including the Mini International Neuropsychiatric Interview suicidality module, the Hospital Anxiety and Depression Scale, and the Impact of Event Scale-Revised. RESULTS: 20.1% (80/399) of patients were positive cases of suicidality. Having no religion (p = .010), poor performance status (p = .000), and psychological comorbidity (p = .021) were significantly associated with the experience of suicidality in the multivariate analysis. Compared to "fully active" patients, patients who were capable of self-care but unable to perform any work activities had about a six times higher risk of suicidality (p = .000). Compared to patients with no psychological morbidity, the risk of suicidality was significantly higher among patients with comorbid anxiety and depression (p = .024), those experiencing comorbid depression and post-traumatic stress disorder (PTSD) (p = 0.051), and those experiencing comorbid anxiety, depression and PTSD (p = .001). CONCLUSIONS: This study found that having no religion, impaired levels of overall functioning, and "multiple psychological morbidities" were associated with suicidality in Korean cancer patients. These findings suggest a need for careful monitoring of these factors and enhanced comprehensive care addressing both the physical and psychosocial functioning of patients with cancer in suicide prevention efforts. PMID- 23094470 TI - Sexual arousal difficulties in women treated with antidepressants: a comparison between escitalopram and fluoxetine. AB - OBJECTIVE: To compare the risk of sexual arousal difficulties between two groups of depressed female patients in remission who were treated with either escitalopram or fluoxetine. Associated factors were also examined. METHODS: This was a cross-sectional study involving 112 female patients attending the psychiatric clinic, University Kebangsaan Malaysia Medical Centre (UKMMC) with depressive disorders as assessed by using the Structured Clinical Interview for DSM-IV (SCID), who had been in remission for the previous 2 months as defined by a score of < or = 10 from an assessment using the Montgomery-Asberg Depression Rating Scale (MADRS) and were treated with either fluoxetine or escitalopram. Sexual arousal difficulties were assessed using the arousal subscale of Malay Version of the Female Sexual Function Index (MVFSFI). RESULTS: The rate of sexual arousal difficulties was 41.1% for all subjects. Sexual arousal difficulties occurred in 50.0% of subjects treated with fluoxetine and 32.1% with escitalopram. However, this difference was not statistically significant (p = 0.055). Multivariate logistic regression analysis showed that higher dose of antidepressant (adjusted OR = 4.08, 95 CI = 1.70-9.81) was significantly associated with female sexual arousal difficulties. CONCLUSION: The risk of sexual arousal difficulties was higher in female patients who were treated with higher doses of either fluoxetine or escitalopram. PMID- 23094471 TI - Goal orientation and work role performance: predicting adaptive and proactive work role performance through self-leadership strategies. AB - This article explores the relationship between goal orientation, self-leadership dimensions, and adaptive and proactive work role performances. The authors hypothesize that learning orientation, in contrast to performance orientation, positively predicts proactive and adaptive work role performances and that this relationship is mediated by self-leadership behavior-focused strategies. It is posited that self-leadership natural reward strategies and thought pattern strategies are expected to moderate this relationship. Workers (N = 108) from a software company participated in this study. As expected, learning orientation did predict adaptive and proactive work role performance. Moreover, in the relationship between learning orientation and proactive work role performance through self-leadership behavior-focused strategies, a moderated mediation effect was found for self-leadership natural reward and thought pattern strategies. In the end, the authors discuss the results and implications are discussed and future research directions are proposed. PMID- 23094472 TI - Company norms affect which traits are preferred in job candidates and may cause employment discrimination. AB - This study investigated a possible mechanism behind employment discrimination. Participants completed a recruitment task where emphasis on cohesion (employees should "fit in") versus fairness (everybody should be treated equally) was manipulated by describing the norms of a fictitious company differently. There was a comparatively stronger preference in the cohesion condition for traits and interview questions related to social competence (e.g., friendliness, gregariousness, empathy). Furthermore, participants in the cohesion condition primarily pictured socially competent employees, whereas those in the fairness condition primarily pictured employees possessing productivity-related characteristics (e.g., education, experience, and talent). The norm effect was moderated by participants' awareness of the applicants' ethnicity. When expecting applicants with foreign backgrounds, participants in the cohesion condition showed increased preference for selection methods related to social competence. Implications for recruitment practices are discussed. PMID- 23094473 TI - Processes through which adolescents believe romantic relationships influence friendship quality. AB - Little is known about how romantic relationships influence adolescents' friendships. The purpose of this exploratory study was to identify behaviors through which adolescents believe romantic relationships influence friendship quality. Intimate exchange, co-rumination, encouragement, and conflict resolution were identified as processes through which romantic relationships influence friendship quality. Associations between these variables and friendship quality were investigated with 340 adolescents. Adolescents believed these processes occurred frequently within friendship. Gender differences suggest girls may be more sensitive to the influence of romantic partners on their friendships than are boys. Hierarchical regression analyses revealed that greater intimacy, encouragement, compromise, and less co-rumination were associated with more positive beliefs about friendship quality when one friend has a girlfriend or boyfriend. Greater co-rumination and less encouragement were predictive of negative friendship quality. Thus, these processes may represent avenues through which romantic relationships positively and negatively influence friendship quality. Findings highlight the need to understand friendships as part of a complex social network that includes romantic ties. PMID- 23094475 TI - 5S: the unsung hero of operational and safety excellence. PMID- 23094476 TI - Controlling facility noise with curtain walls. AB - High noise levels in the workplace are a significant health hazard to employees. Dealing with high noise levels can be a difficult and expensive undertaking, but it is also necessary. Insulated curtain walls represent a cost-effective and flexible alternative to classic methods used for noise abatement and bring their own value in other ways to an industrial environment. From employee safety to employee comfort resulting in higher productivity, the benefits of keeping noise levels under control are real and obvious. PMID- 23094474 TI - Relative importance and utility of positive worker states: a review and empirical examination. AB - Our purpose was to identity the unique contribution, relative importance, and utility of positive worker states. Using Luthans et al.'s (2007) five positive organizational behavior criteria, a variety of positive worker states were reviewed and then empirically tested to establish if they met these criteria. Data were collected from 724 restaurant employees. Positive worker states included: job involvement, perceived organizational support, engagement, and vigor. Criteria were self-reported performance, customer service, turnover intention, satisfaction, and quality of life. Our review indicated consistency between predictor adequacy of meeting the criteria and their empirical relationship with key outcomes. This research found the positive worker states to be independent constructs that had differential effects depending on the focused outcome. Regression and relative weights analyses showed involvement was a weak predictor of outcomes, while perceived organizational support was the most consistent predictor. Vigor was most useful when predicting job performance. Quality of life was poorly explained. PMID- 23094477 TI - Radiation sources in natural gas well activities. PMID- 23094478 TI - IAQ complaints: survival techniques for the safety professional. PMID- 23094479 TI - Steering clear of driving program pitfalls. PMID- 23094480 TI - Educate, train, and visualize. PMID- 23094482 TI - Get in the game: applying gamification to on-the-job safety. PMID- 23094481 TI - The winding staircase to setting up a safety incentive program. PMID- 23094483 TI - Safety in action: a practical application. PMID- 23094485 TI - Step into safety right. PMID- 23094484 TI - Dispelling hearing protection myths. PMID- 23094486 TI - Higher calling. PMID- 23094487 TI - Mining the value of computer-based training. PMID- 23094488 TI - Five changing trends in managing workplace ergonomics. PMID- 23094489 TI - Three things every industrial hygienist should know about gas monitoring. PMID- 23094490 TI - Gas monitoring success stories. PMID- 23094492 TI - The business case for workplace alcohol prevention. PMID- 23094491 TI - Plan ahead to prevent slips and falls. PMID- 23094493 TI - Drug testing promotes workplace safety. PMID- 23094494 TI - Choosing the perfect work access lift. PMID- 23094495 TI - Better together. PMID- 23094496 TI - Measuring safety excellence. PMID- 23094497 TI - Leading habits. PMID- 23094498 TI - Avoidance of dairy products: implications for nutrient adequacy and health. PMID- 23094499 TI - Caesareans by request. AB - PURPOSE: To describe the attitudes of nulliparas (women who have never given birth) about caesarean delivery on maternal request, and to examine their characteristics, perceptions and fears related to vaginal birth and caesarean delivery. DESIGN: Cross-sectional survey. PARTICIPANTS: Canadian nulliparas, 18 to 24 years of age, attending an educational institution. METHODS: A previously developed questionnaire was adapted, evaluated for validity and pretested. The questionnaire was presented in class by a research assistant. Participants placed questionnaires in a box to maintain confidentiality. The main outcome measure was participants' attitudes toward caesarean delivery on request. Descriptive, bivariate and multivariate regression statistical analyses were done. RESULTS: Of 260 women invited, 140 (53.8%) participated. Participants' mean age was 20.4 years, and 95 per cent were born in Quebec. The majority (63.3%) had heard about caesarean delivery on maternal request, but only 28.6 per cent had a favourable attitude toward it. Having fears about vaginal birth (p < 0.001), thinking that caesarean delivery was less stressful than vaginal birth (p = 0.042) and that vaginal birth had more negative consequences for the mother (p = 0.014) and a positive attitude of peers (p = 0.013) were four factors associated with a favourable attitude. For this group of respondents, these four factors would successfully predict attitudes to caesarean section upon maternal request 66.5 per cent of the time. PMID- 23094500 TI - Baby-friendly designation: honouring a commitment to best practice. PMID- 23094501 TI - Building strength and engagement. PMID- 23094502 TI - Prescribing in Alberta's influenza assessment centres. PMID- 23094503 TI - Juicy news. PMID- 23094504 TI - Energy at work. PMID- 23094505 TI - B.C.'s research brokers. PMID- 23094506 TI - Rethinking the meaning of literacy. PMID- 23094507 TI - Optimistic about new directions in mental health. PMID- 23094508 TI - Primary health care leads to better health. PMID- 23094509 TI - Detailed observation of arterial healing after stent implantation in swine arteries by using optical coherence tomography. AB - BACKGROUND: Histopathological examination is not suitable for sequential in vivo analysis of arterial healing after stenting because it can be performed only after the animals are killed. Optical coherence tomography (OCT) provides higher resolution than intravascular ultrasound (IVUS). The aim of this study was to compare arterial healing images after stenting on the basis of the findings of histopathological examination, IVUS, and OCT. METHODS: We examined 12 vessels; 12 bare-metal stents were implanted in 6 miniature swine. Histopathological examination, IVUS, and OCT imaging were performed at 1 and 4 weeks after stenting. For quantitative analysis of IVUS and OCT images, we examined cross sectional frames at 1-mm intervals. For neointimal coverage analysis, the neointimal coverage score was classified into 1 of the 4 categories. A fully covered strut was scored as 3, a partially covered strut was scored as 1 or 2, and an uncovered strut was scored as 0. RESULTS: In IVUS and OCT analyses, the average neointimal thickness increased between 1 and 4 weeks (p < 0.0001). OCT revealed higher scores at 1 and 4 weeks than IVUS did (at week 1, p < 0.0001; at week 4, p < 0.0001). OCT analysis evaluated the neointimal coverage similarly to histopathological examination. CONCLUSIONS: On assessment of arterial healing after stenting, we found that the results of the histological examination were more similar to those of the OCT analysis than to those of the IVUS. An OCT imaging device can be used to precisely and sequentially analyze the arterial healing process after stenting. PMID- 23094510 TI - AGR2 as a potential biomarker of human lung adenocarcinoma. AB - BACKGROUND: The present study aimed to identify useful candidate biomarkers of lung adenocarcinoma for clinical diagnosis and treatment using proteomics technology. METHODS: We assessed frequently highly overexpressed proteins in 12 cases of lung adenocarcinoma compared with adjacent normal tissue samples by liquid chromatography tandem mass spectrometry (LC-MS/MS) coupled with isobaric tags for relative and absolute quantitation (iTRAQ) technology, and validated the expression of target proteins by immunohistochemistry in 268 lung adenocarcinoma cases. Protein expression and clinicopathological variables were compared statistically for the evaluation of novel biomarkers. RESULTS: One hundred seventy-seven proteins displaying significant quantitative changes compared with adjacent normal-appearing lung tissue were identified in more than 9 out of 12 lung adenocarcinoma patients. Based on the results of liquid chromatography tandem mass spectrometry, Ingenuity Pathway, and immunohistochemical analyses, anterior gradient homolog 2 (AGR2) (upregulated 9.9-fold) was selected as a potential biomarker of human lung adenocarcinoma. AGR2 was positive in 94% of lung adenocarcinoma patients. Negative AGR2 expression was associated with poor survival (p = 0.007). CONCLUSIONS: AGR2 is likely to become a biomarker for clinical applications. PMID- 23094511 TI - Comparison of adverse events of erlotinib with those of gefitinib in patients with non-small cell lung cancer: a case-control study in a Japanese population. AB - BACKGROUND: Rash, liver dysfunction, and diarrhea are known as adverse events of erlotinib and gefitinib. However, clinical trials with gefitinib have reported different adverse events compared to those with erlotinib. In an in vitro study, cytochrome P450 (CYP) 2D6 was shown to be involved in the metabolism of gefitinib and not of erlotinib. It has been hypothesized that gefitinib therapy results in different adverse events compared to erlotinib therapy. METHODS: The frequency of each adverse event was evaluated in a case-control study on Japanese patients who were treated with gefitinib or erlotinib. The CYP2D6 phenotype was categorized into 2 groups according to functional or reduced metabolic levels. In addition, we evaluated the odds ratio (OR) of adverse events with each factor, including CYP2D6 activities as well as treatment types. RESULTS: A total of 112 patients received gefitinib therapy, 74 patients received erlotinib therapy, and 17 patients received erlotinib and gefitinib sequentially. The OR of developing rash with gefitinib versus erlotinib treatment was 0.38 (95% confidence interval [CI], 0.15-0.86). The OR of developing diarrhea with gefitinib versus erlotinib treatment was 0.46 (95% CI, 0.22-0.94). The OR of developing liver dysfunction with gefitinib versus erlotinib treatment was 3.30 (95% CI, 1.59-7.22). Reduced function of CYP2D6 was not associated with an increased risk of any adverse events in both gefitinib and erlotinib cohorts. CONCLUSIONS: Erlotinib had higher rate of rash and diarrhea than gefitinib. Liver dysfunction occurred significantly more often in the gefitinib group than in the erlotinib group. PMID- 23094512 TI - Thrice-weekly insulin injection with nurse's support for diabetic hemodialysis patients having difficulty with self injection. AB - Although poor glycemic control is known as an independent predictor of mortality in diabetic hemodialysis patients, it is often difficult for some patients to perform standard self injection insulin therapy. Some practical methods are needed for such patients. We evaluated the usefulness of a new regimen of insulin therapy, namely thrice-weekly insulin injection with nurse's support (TWINS) using insulin NPH or glargine at the end of each hemodialysis sessions in 5 outpatients on hemodialysis with type 2 diabetes mellitus showing HbAlc levels > or = 8.0% (JDS). HbA1c levels were successfully decreased in all patients from 9.3 +/- 1.1% to 6.9 +/- 0.7% (mean +/- SD) in six months without hypoglycemia symptoms. These preliminary results suggest that this regimen can be one of the practical choices in poor-controlled diabetes patients on regular hemodialysis who have difficulty in self injection of insulin. PMID- 23094513 TI - Two cases of transthoracic pericardial fenestration for pericardial effusion. AB - Pericardial effusion and cardiac tamponade are often refractory and difficult to manage. The transthoracic pericardial fenestration which create a window is the conventional procedure for releasing pericardial effusion to the thoracic cavity. We experienced two cases of pericardial fenestration. The first case was a patient with hypertrophic cardiomyopathy with pericardial effusion. She had a thoracic compression fracture, which indicated pericardial fenestration before an orthopedic surgery. The second case was a patient with recurrent cardiac tamponade caused by postpericardiotomy syndrome after off-pump coronary artery bypass grafting. In both cases, the patients underwent left anterior thoracotomy of about 10 cm at the level of the 5th intercostal space. The pericardium was incised within a radius of about 20 mm; furthermore, the fenestrated window was opened to the left thoracic cavity. In this paper, we present our experience of pericardial fenestration and discuss a review of the literature. PMID- 23094514 TI - Aorto-renal bypass surgery normalized blood pressure without antihypertensive medications in a young female patient with renal artery occlusion. AB - We described a 19 year old female case with renovascular hypertension, whose blood pressure was high taking antihypertensive medications. The right renal artery was completely occluded at its ostium, and percutaneous transluminal renal angioplasty was unsuccessful. After aortorenal bypass surgery, blood pressure was normalized without administration of antihypertensive medication. PMID- 23094515 TI - [Oral dietary supplements with copper, magnesium, manganese and zinc-based new complexes]. AB - Oligoelements such as copper, magnesium, manganese and zinc are involved in several metabolic, enzymatic and immunological processes. They are also important for the integral tissue proteins and could be involved in gene expression regulation. The deficiency of these essential elements hampers the appropriate function of the body and may cause various diseases. Therefore, it is important to guarantee the incorporation of these trace elements in the diet, but the quantity provided is not always adequate for the optimum body performance. Currently, conventional nutritional supplements have two major problems. The first one is attributed to the association of inorganic salts with metals which might cause low absorption and gastric intolerance. The second problem is caused when several metals are present in a formulation which could lead to possible antagonistic interactions. For this reason, this study explores the development of cations (i.e., copper, zinc, magnesium and manganese) and amino acids (i.e., glycine and asparagine) new complexes formulated into compacts for oral administration. In each reaction, ligands were linked to non-antagonistic cation pairs. The complex formation was characterized by infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis and powder X-ray diffraction analyses. Compact disintegration and in-vitro dissolution tests for these complexes were also determined. PMID- 23094516 TI - [Proposal for the harmonization of the values of reference for nutritional labeling in Latin America (NVR-LA)]. AB - The values of recommendation of intake of nutrients, important for nutritional labeling, present variations among the countries of Latin America. The aim of the NVR project is to establish consensually harmonized nutritional labeling values to be adopted among the Latin American countries. From the search and analysis of the different values of recommendations used in the countries of Latin America, was defined by consensus a proposal to a total of 36 nutrient values. The expectation of everyone involved with the project is to take its accessible results and encourage the countries of the region to adopt the proposal, with the support of scientific organizations, Governments and Academia. Thus labeling will be simpler, easy understanding and help the consumer a better selection of products. PMID- 23094517 TI - [Classification of Colombian children with malnutrition according to NCHS reference or WHO standard]. AB - A descriptive study was conducted to evaluate the concordance of National Center for Health Statistics reference (NCHS) used to classify undernourished children from Colombia with the WHO Child Growth Standards. We used data from children aged 6 to 59 months with acute malnutrition (Z <-2) and severe (Z <-3) who were admitted to the "Unidad Vida Infantil" nutrition program in Colombia. Indicators height-for-age, weight for-height were analyzed when they were admitted to the hospital and weight for-height leaving the hospital. A statistical method used to compare means was T-student. Correlation coefficient intraclass (CCI) and Kappa index evaluated the concordance between NCHS and OMS; McNemar method evaluated the changes on the nutritional classification for children according to growth devices used. Of the total number of children classified as normal by NCHS, 10.4% were classified as stunted by WHO. 64% of the children admitted to the hospital presented acute malnutrition according to NCHS, of these 44,8% presented severe emaciation according to OMS, indeed severe emaciation increased of 36,0% to 63,3% using OMS. 5% of children leaving the hospital could need to stay more days if they had been evaluated with OMS. Growth devices shown high concordance in height for-age (CCI = 0,988; k= 0,866) and weight for-height (CCI = 0,901; k = 0,578). Concluded that OMS growth standards classified more malnourished children and more severe states, in addition more malnourished children could be hospitalized and they could stay more days. PMID- 23094518 TI - Public intervention in food and nutrition in Brazil. AB - In the last twenty years, the Brazilian government has created a number of income transfer programs for the poorest portion of the population to promote food and nutrition security and eradicate extreme poverty, hunger and malnutrition. These programs have achieved satisfactory results, which cannot, however, be attributed solely to the transference of income, as they involve other governmental public policies in health, education and basic sanitation, Combined, the aim of such public policies is to break patterns of the poverty across generations, thereby contributing to human development in the country. PMID- 23094519 TI - [Somatophysiologycal and nutritional characterization of teen immigrants in Spain. Variation by gender and origin]. AB - The 13 and 14 years of human life cycle are very sensitive to environment, so that migration and changes in living conditions related may influence further. The aim of this study is to characterize the nutritional and somatic status of the immigrant adolescent population of Madrid with the objectivity of bioanthropometric assessment. 519 adolescent students not born in Spain were evaluated. The sample was taken in the public schools of the Community of Madrid and conducted the following groups: Spanish control sample (38.9%), Latin America (50.9%), Magreb (4.5%), Asia (3.8%) and Eastern Europe (1.9%). The situation is Normal weight for the total sample, except in boys of Eastern Europe (Overweight). The pattern reflected a daily dietary intake of 3.73 +/- 0.91, being the dinner the most represented food. The diet quality as measured by KidMed showed that 10.2% followed a low quality diet, 58.6% have a better diet and 31.2% optimal. Higher scores were found in the Magreb group and lowest in Asia. In all groups showed a trend towards increased consumption of fruit and vegetables in Spain. PMID- 23094520 TI - [Evolution of nutritional status in hemodialysis patients during 4 years of follow]. AB - Protein-calorie malnutrition as well as systemic inflammation and metabolic disorders are common among patients with chronic renal failure undergoing renal replacement therapy (hemodialysis), which contributes to their morbidity and mortality. This work has followed 90 patients of both sexes with chronic kidney disease who were treated with hemodialysis periodically in our unit for four years. All patients were performed quarterly measurements of plasma albumina (A1b), total cholesterol (TC), total protein (TP) and monthly transferrin (Tr), Anthropometric measurements of height and weight were taken on all patients by using a balance/stadiometer (Perperson 113481); weight was measured in kilograms and height in centimetres. BMI was calculated with this formula: weight/height2 and classified according to the WHO criteria: BMI < 18.50: Underweight; from 18.50 to 24.99: Normal range; from 25.00 to 29.99: Overweight; and BMI > or =30.00: Obese. The aim of this work was evaluate the nutritional status of these patients through the assessment of biochemical parameters and anthropometric parameters and determine if these patients suffer alterations suggesting nutritional deterioration directly related to the time on dialysis. During the 4 years all patients showed a significant decline of biochemical parameters, on the other hand the BMI did not significant changes in relation to malnutrition. Malnutrition in patients on dialysis is therefore evident, the BMI does not correspond with the biochemical parameters observed, so nutritional deterioration of these patients is mainly manifested by biochemical parameters studied. PMID- 23094521 TI - Parents perception of weight status of Mexican preschool children using different tools. AB - The aim of this study was to evaluate the ability of parents to estimate the weight status of preschool children attending the Instituto Mexicano del Seguro Social (IMSS) day-care centers using three different tools. A total of 100 parent child pairs attending to all the existing IMSS day-care centers in Ensenada (n = 9) completed a questionnaire on the perception of children's weight status using verbal description, sketches, and pictures. Chi squared test and univariate logistic regression was applied to assess the difference in perception between the tools used, the factors associated with the weight status perception and to identify predictors of parental underestimation of their child's weight. The sample size was estimated for a significance level of 0.05 with statistical power of 80%. No significant differences were found in the perception of weight status using different tools. The parents' underestimation of the child's weight status ranged from 51 to 59%, this percentage jumps to 79 to 84% in overweight children and 82 to 91% in obese children. Being a young mother and having a daughter increased the risk of underestimation. Higher odds of underestimation were found in > 2BMI z-score. The high underestimation found in this study shows that the ability of parents in signaling an alert to prevent childhood obesity might be highly reduced and preventive health programs should include increasing the weight status perception. PMID- 23094522 TI - [Evaluation of the maternal perception of her child's weight and body mass index heritability in mestizas dyads in Southeastern Mexico]. AB - Descriptive correlational study. The objectives were the following: 1) evaluate maternal perception of her child's weight through two test, Word-perception (WVP) test and the Body mass index (BMI) of the child as perceived by the mother (Body weight index perception [BWIP]); 2)evaluate the sensitivity and specificity of the tests, and 3) quantify BMI heritability (h2) in 173 mother-child dyads. WP was assessed by asking the question, How do you think your child is? For assessing BWIP, the mother referred the child's eight and height, and we calculated the child's BMI as perceived by the mother. The weight and height of the mothers and their children were measured. We found that 10.3% of mothers of children with Overweight (OW) and 1.8% of mothers of children with Obesity (OB) perceived their children adequately by means of WP; by means of the BWIP test, 38.5 and 67.3% of mothers of children with OW and OB, respectively, exhibited adequate perception. BWIP sensitivity was 55.3% and specificity was 54.4%. BWI h2 was 15%. We was concluded that mothers did not perceive the OW-OB of their children, and that asking the mother for the weight and height of the child (BMIP) will aids her to perceive the OW-OB of her child. The BWI h2 indicate that the lifestyle factors of this population contribute to OW-OB. Given the broad socioeconomic and cultural diversity, these results of the southeastern Mexican state of Campeche should be evaluated with similar study designs. PMID- 23094523 TI - [Nutritional knowledge and its association with overweight and obesity in Mexican women with low socioeconomic level]. AB - The objective of this study was to identify the association between knowledge about nutrition with the presence of obesity or overweight in women with low income in Mexico City. Data was obtained with the Urban Food and Nutrition Survey 2002 in the Metropolitan Area of Mexico City (ENURBAL 2002), a stratified multistage and clustered design survey. An ordinal logistic regression model was used in order to estimate the probability to present obesity and overweight or obesity, in relation to nutritional knowledge, age, education, employment, socioeconomic status, and total fat consumption. The variables that were related to overweight or obesity: correct or regular nutrition knowledge (OR = 2,00; CI95% = 1,13-3,54) and (OR = 1,54; CI 95%= 1,03-2,30), respectively; age 30 years (OR = 3,00; CI 95% = 1,94-4,64), belonging to a medium- low socioeconomic status (OR = 2,04; CI 95% = 1,33-3,15), and high fat consumption (OR = 1,65; CI 95% = 1,07-2,55). For obesity was age 30 years (OR = 2,42; IC 95% = 1,48-3,94) and high fat consumption (OR = 1,67; IC 95% = 1,05-2,66). Our results helped to identify associated factors in women with obesity and overweight from low income households, mainly those concerning with nutrition knowledge. This emphasizes the importance of improving knowledge about nutrition, in planning the strategy for interventions aimed to prevent overweight and obesity. PMID- 23094524 TI - [Evaluation of a nutrition education and physical activity intervention in Chilean low socioeconomic women]. AB - The objective of the study was to assess a nutrition education and physical activity intervention to decrease obesity changing food habits and increasing physical activity in low socioeconomic women. Four groups were selected and followed-up during six months: one was intervened with food education and physical activity (group A); another with food education (group B); a third with physical activity (group C), and a control group. Three nutrition education workshops were carried out with community leaders and nutritionists, and three times per week physical activity sessions were performed. Anthropometric measurements and food and physical activity surveys were carried out before and after the intervention. Obesity increased in group A, but decreased 10% in the other two intervened groups (B and C), and total fatty mass decreased in group B. In the control group, obesity did not change but total fatty mass increased. Attendance to physical activity sessions was poor, with negative results in the nutritional impact in the physical activity intervened groups (B and C). We conclude that obesity was reduced in 10% in groups B and C; total fatty mass was reduced in group B and increased in the control group. Healthy diet and physical activity habits improved in the three intervened groups. With these results, an intervention program in nutrition education and physical activity can be available for future community interventions in low socioeconomic women. PMID- 23094525 TI - [Viability and efects of the probiotic lactobacillus aracaseissp aracasei in Chilean low-fat Gauda cheese]. AB - The objective of this study is to infer the survival of the probiotic Lactobacillus paracasei ssp paracasei added during the processing of low-fat Gouda cheese, during the maturation (21 days) and the commercialization (14 days), in order to see the influence that this organism has on the quality of the product. The treatments were: TI (control): Gouda with normal fat content; T2: Low fat Gouda cheese (QGS) T3: QGS, with additional probiotic added with the initial culture; T4: QGS, with the probiotic added in the cooking of the curd. For the count of the probiotic, the methodology was used set forth by the American Public Health Association, (APHA), proteolysis by the method of soluble tyrosine in trichloroacetic acid (TCA), and the physical and chemical analysis using the methods standardized by the International Dairy Federation, and Chilean normative. The counts obtained were from 10(8) ufc/g y 10(7) ufc/g in the cheeses that had the probiotic additive (T3 and T4, respectively) close to the level of innocuous (10(8) ufc/g) during the study period of 35 days. The proteolysis incremented normally, and was the same in all of the treatments during the 35 days studied. The treatments with fat-reduction presented approximately, 31% less fat than the control treatment, and also higher moistness. Within the treatments, there was no evidence of taste and general feel; in turn the cheeses with the reduction of fat resulted firmer, less cohesive, than the control, and with similar elasticity. PMID- 23094526 TI - [Health properties and sensory quality of apple snack destined for school feeding]. AB - An apple snack has been developed with the purpose of introducing foods derived from fruit to reduce obesity in school children of Santiago, Chile. Apple slices of the 'Fuji' variety were dehydrated, with skin included, at 60 degrees C for 4 h obtaining a product with 4.6 g/100 g of humidity and water activity (Aw) of 0.56. The apple snack presented 24.8 +/- 0.3 g/100 g b.s. of dietary fiber and 550.16 +/- 5.89 mgGAE/100 g b.s of polyphenols which converts into a healthy food, it also presents high antioxidant capacity measured by FRAP, with 0.59 mmolFe/100g. The sensory analysis done in school children between the ages of 8 and 12 years old indicates that the product presents high acceptability, is a crispy product, of a crunchy texture, with bittersweet flavor, so it is an alternative for school snacks. PMID- 23094527 TI - Soapstone utensils may improve iron status in adult women. A preliminary study. AB - Soapstone is among the first heat-resistant materials to have been used by man for the manufacture of culinary utensils, but its impact on human nutrition has merited little attention. Here, we present a preliminary evaluation of the impact of soapstone pans on the iron status in humans. Five nuns (37.6 +/- 6.31 y) replaced the soapstone for their traditional aluminum cookware, without any alteration of the diet itself. Comparison of the hematological data, determined before and 10 weeks after switching the pans, revealed that hemoglobin rose from 13.26 to 14.0 mg x dL(-1) (p = 0.0048), and hematocrit increased from 38.14 to 40.71% (p = 0.0002), while the transferrin saturation index went from 28.04 to 28.96% (p = 0.0147) and ferritin, from 31.5 to 34.74 microg x gL(-1) (p = 0.0681). By simply replacing the soapstone for the traditional aluminum cookware, substantially improved the iron status in all subjects in a relatively short period of time. PMID- 23094529 TI - The seasonal variations of respiratory syncytial virus infections in Turkey: a 2 year epidemiological study. AB - Respiratory syncytial virus (RSV) infections may cause severe respiratory diseases, particularly in infants and young children. In order to determine the timing of prophylaxis, the seasonal variations of RSV had to be determined. We report the climate-related results of an epidemiological study conducted in 32 hospitals of Turkey between May 2008 and September 2010, on children < 2 years of age hospitalized with lower respiratory tract infection. Information on socio demographics, medical history, risk factors for RSV, diagnosis and severity of RSV, and hospitalization was recorded. RSV Respi-strip test kits were used to detect RSV. The meteorological data, including average monthly temperature, relative humidity (RH) and rainfalls of all cities were obtained, and the correlations between meteorological variables and RSV positivity were determined. Informed consents were obtained before the study. Overall, 3,464 children (61.9% boys), with a mean age of 6.4 months, were evaluated. RSV positivity was 16.9%. RSV peaked in January and March, in the first and second RSV seasons, respectively. When Turkey was evaluated as a whole, RSV was positively correlated with RH (p < 0.001, R = 0.627) and rainfalls (p = 0.001, R = 0.572), and was negatively correlated with temperature (p < 0.001, R = -0.778). However, when the regions were evaluated separately, the rainfalls had a negative correlation with RSV activity in the Black Sea and East Anatolian regions. The current study shows the seasonal variation of RSV infections in Turkey in two consecutive RSV seasons. Country-specific viral surveillance systems are required to detect respiratory virus activities and to implement health care strategies. PMID- 23094528 TI - Fetal and neonatal effects of anticoagulants used in pregnancy: a review. AB - There are several relative (promising regarding a reduction in placenta-mediated complications such as preeclampsia) and absolute (e.g. a recurrent or recent thromboembolic event, mechanical heart valves) reasons for use of anticoagulant drugs during pregnancy. Warfarin readily crosses the placenta because of its low molecular weight, and is associated with a distinctive embryopathy known as fetal warfarin syndrome when exposure occurs between the sixth and twelfth weeks of gestation. Warfarin embryopathy may be avoided by stopping warfarin and switching to heparin when pregnancy is achieved or as soon as possible after conception. Heparins, unfractionated heparin and low molecular weight heparin are the preferred agents for anticoagulation in pregnancy because they show no transplacental passage due to their high molecular weights. Both heparins and warfarin are safe for the infant during breastfeeding. Aspirin is prescribed with increasing frequency to reduce the risk of miscarriage and poor pregnancy outcome. Although aspirin crosses the placenta, it is safe in low doses. However, the safety of higher doses of aspirin during the first pregnancy is uncertain. PMID- 23094530 TI - Screening for retinopathy of prematurity (ROP) in the middle Black Sea region of Turkey. AB - This study was designed to determine the frequency of retinopathy of prematurity (ROP) and the effectiveness of the screening protocol in preterm infants for our country. With these objectives, the charts of 1000 preterm infants were reviewed in Ondokuz Mayis University, Department of Ophthalmology. ROP frequency, the effect of gestational age (GA) and birth weight (BW) and the effectiveness of the screening protocol were evaluated. In this study, ROP was observed in 30.8% of infants and not observed in 69.2% of infants. Threshold ROP was detected in 7.0%. The frequency of threshold ROP was 43.5%, 20.0%, 12.6%, and 8.8% in the infants with GA of < or = 26, 26-28, 29-30, and 31-32 weeks, respectively. Threshold ROP was not observed in babies born after 34 weeks. Treatment was required for 11% of the infants. ROP treatment requirement (11%) was limited to babies with GA of < 34 weeks of gestation. Incidence of ROP was inversely proportional with GA and BW. Treatment was not required when GA was > 34 weeks. A new ROP screening protocol is proposed for Turkey, which is: screening of preterm babies with GA of < 34 weeks and BW of < 1800 g. PMID- 23094531 TI - Rubella vaccination during the preconception period or in pregnancy and perinatal and fetal outcomes. AB - The rubella vaccine is contraindicated in pregnancy. Between July and August 2009, the Turkish Republic Ministry of Health implemented a vaccine program to eradicate rubella in women in the reproductive period. In this program, many pregnant women were also vaccinated inadvertently. In this study, 62 pregnant women applied to our clinic who were vaccinated either during pregnancy or within one month before the last menstrual period. Seventeen of them were followed until the end of the pregnancy by fetal echocardiography and detailed ultrasonography. Rubella immunoglobulin (Ig) M and IgG antibodies were studied in the cord blood obtained at birth. All fetuses were examined by a pediatrician, an ophthalmologist and a pediatric cardiologist. A hearing test was also performed on all neonates. No signs of congenital rubella syndrome could be found. PMID- 23094532 TI - Mannose-binding lectin gene codon 54 polymorphism susceptible to brucellosis in Turkish children. AB - Genetic factors are as important as environmental factors in susceptibility to brucellosis. Among these genetic factors, mannose-binding lectin (MBL) deficiency contributes to susceptibility to animal brucellosis. The aim of the study is to determine the influence of codon 54 polymorphisms in the MBL gene on susceptibility to brucellosis. Forty-three patients diagnosed with brucellosis and 106 healthy children were admitted in the study. In the patient group, 19 (44.2%) subjects had AA, 22 (51.1%) subjects had AB and 2 (4.6%) subjects had BB genotypes for codon 54 polymorphism. Eighty-two (77.4%) of the healthy children had AA genotype, while 24 (22.6%) had AB genotype. Our results revealed that genotype frequencies carrying MBL variant allele at codon 54 among the patients were significantly higher compared to those found in the control group (55.8% and 22.6%, respectively; p = 0.0001, odds ratio [OR] = 4.316, 95% confidence interval [CI]: 2.030-9.177). Our data suggest that children with MBL codon 54 AB or BB genotype are more susceptible to brucellosis. PMID- 23094533 TI - Surfactant therapy in late preterm infants: respiratory distress syndrome and beyond. AB - A significant ratio of late preterm infants receives surfactant therapy (ST) for respiratory distress syndrome (RDS) and for other neonatal lung diseases characterized by surfactant inactivation or dysfunction. We aimed to investigate the clinical and therapeutic characteristics and outcomes of late preterm infants who received ST in the last 10 years in our neonatal intensive care unit. During the 10-year period, 77 late preterm infants received ST. The underlying lung diseases were RDS in 51 (66.2%), congenital pneumonia in 15 (19.5%), congenital diaphragmatic hernia in 4 (5.2%), pulmonary edema due to hydrops fetalis in 4 (5.2%), and acute respiratory distress syndrome (ARDS) in 3 (3.9%) infants. Pulmonary hypertension was a significant predictive factor for mortality. Although RDS was the main cause of respiratory failure in late preterm infants, other lung diseases leading to surfactant dysfunction were not rare; therefore, ST should be considered as a life-saving treatment. PMID- 23094534 TI - Celiac disease prevalence in epileptic children from Serbia. AB - Celiac disease (CD) is a genetically determined autoimmune enteropathy, induced by gluten ingestion. To date, different prevalences of CD in children with epilepsy have been reported. The aim of this study was to determine CD prevalence in our patients with epilepsy, using anti-tissue transglutaminase (tTG) antibodies as a screening test. One hundred twenty-five children (72 girls, 53 boys; age range: 2-18 years, mean age: 10.51 +/- 3.53) with idiopathic epilepsy from South East Serbia were tested for immunoglobulin (IgA) tTG antibodies. All positive patients were offered endoscopic small bowel biopsy. Biopsies were examined histopathologically in order to confirm the CD diagnosis. The control group consisted of 150 healthy children. Three patients with epilepsy were positive for IgA tTG antibodies. In all of them, small bowel biopsy was performed, and only one was proven to have CD by histopathology (Marsh IIIa grade). The prevalence of biopsy-proven CD in children with epilepsy was not significantly higher in the study group compared to controls (0.8% vs.0.6%, p > 0.05). The results of this study indicate that children with idiopathic epilepsy from our region should not be routinely tested for CD. PMID- 23094535 TI - Thirty-three-year experience on childhood poisoning. AB - By comparing our data for the period 1985-2008 with findings from a previous report covering the period 1975-1984, we aimed to share our experience with poisoning cases in order to contribute toward its prevention, diagnosis and treatment. The records of patients admitted to the Pediatric Intensive Care Unit with acute poisoning between November 1985 and October 2008 were evaluated retrospectively. The records of 2251 patients with acute poisoning could be retrieved. Poisoning mostly occurred in the home (92%), via the oral route (92.5%) and by a single intoxicant (81.3%). Two distinct peaks were observed: in boys between 1-5 years of age and in girls between 13-16 years of age. It was noted that 67.4% of poisoning cases were accidental, whereas 25.9% were suicidal and 6.7% were a result of a therapeutic error. Nearly two-thirds (64%) of cases were drug-related, while 36% were non-drug-related. Analgesics-antipyretics ranked first among the drug-related cases, whereas ingestion of a corrosive substance was most common among cases with non-drug poisoning. Colchicine was associated with the highest fatality, while among the causes of non-drug poisoning, carbon monoxide was the deadliest. The overall mortality rate in this study was 1.9%. Mortality from non-drug poisoning was higher than from drug related causes (3.9% vs. 1.3%). Almost all cases of poisoning below the age of 6 years are potentially preventable. The results of this study highlight the need for reforms in industrial and health policies, with the aim of increasing awareness regarding potential toxins, appropriate storage of potential toxins, and general precautions to promote safety in the home. PMID- 23094536 TI - Family and infant characteristics in relation to age at walking in Turkey. AB - The purpose of this study was to assess the onset of independent ambulation relative to possible relationships with maternal and infant characteristics. In a cross-sectional study, the health files of 1,553 Turkish children aged 12-23 months were selected by the multistage sampling method in the Nomenclature of Territorial Units for Statistics (NUTS) regions coded as low, medium and high malnutrition levels in Turkey. Children were selected from health centers by systematic sampling technique in each region. Kaplan-Meier analysis and estimated mean values were used for data description; log-rank test and the Cox multivariable regression analysis were applied for data analysis. Maternal education level, occupation, region of residence, gestational iron supplementation, child's gender, child's nutritional status, and presence of anemia in the infant during the survey period demonstrated significant relationships with walking unassisted in the univariate analysis. However, multivariable analysis showed that high maternal education, absence of parental consanguinity and appropriate weight-for-age Z score were positively associated with earlier age of walking. These findings showed the importance of improvement in girls' education, prevention of postnatal growth retardation and improvement in diet quality for children's gross motor development. In addition, counseling programs should be given to decrease the rate of parental consanguinity. PMID- 23094537 TI - Analysis of idiopathic ventricular tachycardia in childhood. AB - Idiopathic ventricular tachycardia (VT) is a relatively benign and rare form of VT. It is seen in young people without demonstrable cardiac pathology. The aim of our study was to review the clinical picture of idiopathic VT, before evaluating the indications for antiarrhythmic treatment and the efficacy of radiofrequency ablation (RFA). The notes of patients diagnosed with idiopathic VT in the last 13 years (n: 22) were included in the study. The median age of onset was 11 years (1 month-16 years). We evaluated the findings regarding the diagnosis, treatment and prognosis of these patients. The most common initial symptom was palpitation, in 15 cases. Five children with idiopathic VT were symptom-free. VT was of right ventricular origin in 10 patients and left ventricular origin in 8 patients. Beta blockers were the mainstay of medical treatment in right VT and calcium channel blockers (Ca-channel blocker) were mostly used in left VT cases. The success rate of RFA was 57% in right VT and 100% in left VT. The median follow-up was 41 months (9 months-60 months), and all patients are alive currently with no symptoms. VT without demonstrable cardiac pathology is associated with a good prognosis. Treatment is unnecessary for asymptomatic non-sustained VT. RFA is useful in patients with symptomatic drug-refractory idiopathic VT arising from the left or right ventricle. PMID- 23094538 TI - Marriage characteristics and reproductive health of adolescents in Turkey: findings from Demographic and Health Surveys 1998 and 2008. AB - Adolescent marriage is an important issue given its social and medical consequences. This study focuses on the recent trends in adolescent marriage and reproductive health in Turkey to provide insights for action. Data from the Demographic and Health Surveys of 1998 and 2008 were used. Adolescent marriage and reproductive health indicators were assessed for urban-rural residences, demographic regions and educational levels. Logistic regression was used to predict marriage and birth in adolescence. Despite the decrease in the proportion of married adolescents from 1998 to 2008, the findings suggest no improvement in some marriage characteristics. In both surveys, over 60% of ever-married adolescents had been pregnant at least once. There is an increase in contraceptive use and antenatal care. Our findings showed that in Turkey, women living in rural areas, from poor households, with more traditional parental families, with less education, and who are not working are more likely to get married in their adolescent ages. PMID- 23094539 TI - Toxicological evaluation of two children diagnosed as Munchausen syndrome by proxy. AB - Munchausen syndrome by proxy is a kind of child abuse in which affected children are often hospitalized for long periods and endure repetitive, painful and expensive diagnostic attempts. We present herein two toxicologically confirmed cases of Munchausen syndrome by proxy. Case 1 is a 16-month-old male who had fever, peripheral cyanosis, tremor, and reported cardiac arrest. Symptoms recurred in the hospital when the mother administered fluids. Toxicology detected 3.5 ng/ml mercury (Hg) in the fluid and 9.4 microg Hg/g creatinine in the urine. Case 2 is a 14-year-old female who had irregular blood findings and multiple hospitalizations. Serum analysis detected warfarin. Both mothers were transferred to psychiatric care. Munchausen syndrome by proxy should be suspected when clinical/laboratory findings are negative, illness descriptions are inconsistent, and frequent hospitalization yields no diagnosis. Psychiatric evaluation and toxicological analysis are recommended. PMID- 23094540 TI - A unique case of magnet ingestion with respect to presentation and management. AB - Magnet ingestion may lead to serious complications with delay in diagnosis and treatment. The forceful attraction between magnets, with gastric and/or intestinal wall entrapped between them, can cause injury through pressure necrosis. The radiological appearance of more than one magnet on X-ray can be easily misinterpreted as belonging to only one rod-like radiopaque foreign body, even if the magnets are located in different parts of the gastrointestinal tract, thus delaying the management up to the onset of emergent surgical complications. A 17-month-old female with ingestion of a pair of magnets is presented, together with introduction of the clinical picture and therapeutic approach, which differed from the other previously reported cases. The ovoid shape of the magnets, their localization in the gastrointestinal tract (leading to entrapped gastric and intestinal wall between them), absence of any complication, and the therapeutic approach of endoscopic retrieval are the main distinguishing features of this case from those previously reported. PMID- 23094541 TI - Percutaneous retrieval of a chronic catheter fragment from the left ventricle in a child. AB - Embolization of a catheter fragment is a very rarely seen complication, and few cases have been reported in children. Catheter fragments must be urgently extracted due to life-threatening complications. Most catheter fragments are removed very soon after being lost in the cardiovascular system, including the venous system and right side of the heart. In our report, we describe a child with catheter fragment, which was removed from the left ventricle 32 days after embolization. This catheter fragment was successfully retrieved percutaneously using a gooseneck snare catheter through the femoral artery. PMID- 23094542 TI - Catheter fragment embolization: a rare yet serious complication of catheter use in pediatric oncology. AB - Embolization is a rare but serious complication of venous central catheters in pediatric oncology. The reported cases in the literature are due in common to catheter ruptures. The most common cause is constant compression of the costoclavicular arch, known as "pinch-off" syndrome. We report a seven-year-old boy in whom embolization occurred as a late complication. Difficulty in the dissection of dense collagen periportal fibrosis was the main problem during the extraction session. The embolization occurred 10 months later. In an elective setting, percutaneous retrieval techniques were used successfully to extract the catheter fragments, and full recovery was achieved. PMID- 23094543 TI - Mediastinal Hodgkin lymphoma arising from cystic lymphangioma: case report in a child. AB - Mediastinal disease is a frequent clinical presentation in children with Hodgkin lymphoma. It is usually due to mediastinal lymphadenopathy or involvement of the thymus gland. Cystic lymphangiomas are benign tumors of the lymphatic system, and less than 1% present as a solitary mediastinal mass. To our knowledge, there has been no report in the literature describing Hodgkin lymphoma arising from cystic lymphangioma. In this report, we describe a patient with mediastinal cystic lymphangioma, from which Hodgkin lymphoma was determined to have arisen. PMID- 23094544 TI - Esophagitis and almost complete esophageal occlusion in a girl with epidermolysis bullosa. AB - Epidermolysis bullosa is a genetically transmitted skin disorder that typically manifests with trauma-induced skin blistering, scarring and in some cases mucosal involvement. Esophageal webs, strictures or stenosis can be found in about a third of the patients with the recessive dystrophic type of this disease. We report a six-year-old girl with recessive dystrophic epidermolysis bullosa and progressive dysphagia. Almost complete esophageal occlusion was found on barium swallow and esophagoscopy (endoscopic signs of esophagitis were also seen). She was treated successfully with fluoroscopically guided balloon dilatation and esomeprazole. Fluoroscopically guided balloon dilatation and postdilatation use of esomeprazole is a safe and effective therapy for recessive dystrophic epidermolysis bullosa patients with almost complete esophageal occlusion and esophagitis. PMID- 23094545 TI - Multiple axillary-infraclavicular lymph node metastasis from malignant rhabdoid tumor of unknown primary site. AB - Malignant rhabdoid tumors (MRT) mostly originate from the kidney and central nervous system. However, they may also originate from retroperitoneal and paravertebral regions, mediastinum, liver, chest wall, extremity, and neck, as well as from the soft tissues. The most important method in the differential diagnosis is the analysis of cytogenetic alterations in the INI1 gene. A six month-old girl presented with multiple conglomerated lymphadenopathies located in the anterior axillary line. MRT diagnosis was confirmed by loss of INI1 expression in the tumor tissue. This is the first case in the literature with unknown primary focus diagnosed from lymph node metastasis. PMID- 23094546 TI - Insulin edema in a child with diabetes mellitus type 1. AB - Despite the essential role of insulin in the management of patients with diabetes mellitus type 1, insulin use can cause a variety of adverse effects, such as hypoglycemia and weight gain. Herein, we describe an adolescent girl with type 1 diabetes mellitus diagnosed one year ago, who presented with edema of the lower extremities approximately two weeks after an increase in the insulin dose; other causes of edema were excluded. Spontaneous recovery was observed in the patient. PMID- 23094547 TI - Why gastric perforation occurs in patients with isolated esophageal atresia: more vulnerable stomach? AB - Gastric perforation (GP) in patients with isolated esophageal atresia (EA) is seen more than expected. The etiology of the perforation may be vulnerability of these immature stomachs. Gastrostomy operation should be performed by gentle handling. The volume of gastrostomy feedings should be increased incrementally. The early diagnosis of perforation is only possible with a high index of suspicion. The stomach should be visualized by gastrography with soluble contrast material as soon as the perforation is suspected. PMID- 23094548 TI - Congenital distal esophageal obstruction caused by intraluminal mucosal web. AB - Here, we report a case with intraluminal membrane (web) located in the lower esophagus causing complete obstruction. Esophagogram revealed complete obstruction near the esophagogastric junction. Surgical excision of the esophageal membrane was performed. To our knowledge, only a few cases with membranous esophageal atresia have been reported. It must be remembered in neonates who cannot tolerate feeding. PMID- 23094549 TI - The diagnostic criteria of benign monomelic amyotrophy. PMID- 23094550 TI - A few comments on Tayan-Reimann-Prasad syndrome. PMID- 23094551 TI - What about egology. PMID- 23094552 TI - "The effects of miniscrew with class III traction in growing patients with maxillary deficiency". PMID- 23094553 TI - Intrusion and uprighting teeth for fixed prosthesis with temporary anchorage device. AB - The mandibular first permanent molar is usually first to erupt around the age of six. Therefore, if the oral hygiene is not impeccable, it is usually also the first permanent tooth decayed in a child's mouth. A plethora of circumstances may lead to pulpal involvement, periapical pathosis, and endodontic treatment and in unfortunate situations, removal of this tooth. If this tooth is not replaced, or the extraction space is not retained for a considerable amount of time, the posterior occlusion will collapse. The most common occurrence is tipping of teeth in juxtaposition to the extraction site and extrusion of at least one opposing tooth. This article will describe efficient uprighting and intrusion of offending teeth prior to placement of fixed prosthesis. The author will explain the procedure step by step, first on acrylic models and then on the actual patient. PMID- 23094554 TI - The orthodontist and the obstructive sleep apnea patient. AB - Obstructive sleep apnea is a common breathing disorder with serious effects on a patient's health and quality of life. Orthodontists should be aware of the disease and competent at recognizing common signs and symptoms in their patients. Due to their expertise and familiarity with growth and development as well as orthopedic and surgical correction of the jaws, orthodontists are ideally suited to treat OSA patients. The goal of this article is to provide an overview to orthodontists on the important role they can play in the treatment of this serious and often under-diagnosed disease. PMID- 23094555 TI - Clinical implications of early loss of a lower deciduous canine. AB - In crowded dental arches, the permanent lateral incisors often erupt and resorb the mesial portion of the root of deciduous canines, causing their premature loss. Therefore, knowledge on clinical aspects related to etiologic factors is necessary to pediatric orthodontists and clinical dentists for diagnosis and treatment with regard to incisor crowding and adjustment. The aim of the present study was to describe a clinical case characterized by the unilateral loss of a lower deciduous canine, offering clinical considerations on this issue and discussing the various procedures implemented to prevent potential problems. A patient, 8 years of age, had the lower right deciduous canine prematurely lost, resulting in a deviation from the midline to the same side of the loss caused by the migration of the permanent incisors. The antimeric canine was removed and a fixed apparatus was attached to the lower arch associated to a spring to correct the midline. Next, a lip bumper device was employed to promote the vestibular conduction of the lower incisors to accommodate the permanent canines in the arch. Although early loss of deciduous canines occurs frequently, treatment possibilities are controversial and further studies on the subject are necessary Orthodontic evaluation should be always considered to minimize the need to extract permanent teeth and/or future orthodontic treatment. PMID- 23094556 TI - A comparative study between lip bumper and headgear as maxillary molar retainers following distalization. AB - Abstract: There are many appliances that can be used to correct molar relationship, achieving upper molar distalization, in Class II malocclusion. This research aimed to study the dental effects promoted by lip bumper to retain maxillary molars that had previously been distalized using a Cetlin appliance in conjunction with headgear. PMID- 23094557 TI - Treatment of Class III malocclusion in a young adult patient: a case report. AB - This article describes the treatment of a young adult male with a concave profile, skeletal class III malocclusion because of a prognathic mandible and proclined upper incisors. The therapy included stages: 1. Pre-surgical orthodontics involving leveling and aligning of upper and lower arches, protraction of lower molars and retraction of upper incisors; 2. Surgical phase involving BSSO with mandibular setback and 3. Post-surgical orthodontics for finishing and detailing. The treatment lasted 23 months and improved facial esthetics significantly The treatment resulted in a functional occlusion with a lack of lateral cuspid guidance that could be accepted considering the difficulty of the case. Over jet and overbite are within norms. PMID- 23094558 TI - Orthodontic correction of Class III malocclusion in a young patient with the use of a simple fixed appliance. AB - Anterior crossbites are one of the most common orthodontic problems we observe in growing children. The first step in treating an anterior crossbite is to determine whether the crossbite is dental or skeletal in nature. To determine a precise diagnosis, a thorough clinical, radiographic and model analysis is required. This article shows the treatment of Class III malocclusion by correcting anterior dental crossbite with the use of a simple fixed appliance. PMID- 23094559 TI - A comparision of Twin-block and Forsus (FRD) functional appliance--a cephalometric study. AB - The aim was to compare the effects of Twin-block & Forsus (FRD) functional appliances in the correction of Angles Class II division 1 malocclusions. MATERIALS AND METHODS: Pre- and post-treatment lateral cephalograms of 25 patients who underwent treatment with twin block for the correction of class II div 1 were compared with 25 patients who underwent treatment with Forsus appliance. These were again compared with the pre follow up and post follow up lateral cephalograms of 25 patients who have not undergone any treatment during this period. All the 3 group patients were compared for skeletal, dental and soft tissue parameters. RESULTS: Cephalometric analysis revealed that both Twin-block & Forsus Fatigue Resistant Device (FRD) appliances stimulated mandibular growth. Statistically significant differences between the two groups were found. Twin block patients showed statistically very high significant (p < 0.001) increase in mandibular length (6.02 mm) whereas Forsus appliance patients showed significant (p < 0.05) increase in mandibular length (1.6 mm) when compared with control group (0.3 mm). No significant restriction of maxillary growth was found in either of the two experimental groups when compared to control group. Significant increase in lower anterior facial height & posterior facial height was observed in both experimental groups in relation to control group. Significant reduction of overjet and overbite was observed in both experimental groups. Class I molar relationship and improvement in the soft tissue profile were achieved in both treatment groups compared with control group. CONCLUSIONS: Both Twin Block and Forsus were effective in the treatment of Class II Div 1 malocclusion. Class II correction with Twin-block is more due to mandibular skeletal and dentoalveolar changes whereas in Forsus, it is more due to dentoalveolar changes and less skeletal changes. PMID- 23094560 TI - Modified transpalatal arch for molar intrusion. AB - We have modified transpalatal arch (TPA) to intrude the extruded molar. The appliance is fabricated from 0.036 inch stainless steel wire which has a palatal and buccal arm. The appliance is activated by stretching an elastomeric chain from the palatal to the buccal arm such that the stretched chain lies across the occlusal surface of extruded second molar with an intensive force of 50 grams. The advantages of this appliance include reduced chair side time, patient comfort and cost effectiveness. PMID- 23094561 TI - The cervical vertebrae maturation stage method. AB - Determining growth stage for effective implementation of certain orthopedic treatment modalities is paramount; further determining if there is residual growth in a prospective patient is of equal importance. Surprisingly, many orthodontic clinicians lack sufficient knowledge in this area to confidently implement certain aspects of orthodontic treatment, consequently carrying out many treatment modalities in an untimely and ineffective manner. Age, dental development, sexual maturation or increases in height are all means that have been used to determine stages of skeletal development. However, a more predictable and reliable method for helping establish skeletal maturity is the CVMS (Cervical Vertebrae Maturation Stage) Method. This article will try to help determine the stage of skeletal maturity using the CVMS method since using it may also help determine the best timing for maxillo-mandibular orthopedic treatment. PMID- 23094562 TI - A new look at an old bite splint. AB - The purpose of this article is to explain a broader rationale for the use of the classic "bite splint" in general dental, orthodontic and other specialty practices. The author's motivation for writing comes from over 50 years of diagnosing the indications for a splint, and developing variations in the design, fabrication, delivery and adjustments to it. Techniques for diagnosis and patients' feedback are included. PMID- 23094563 TI - A way to find anchorage when missing molar teeth. PMID- 23094564 TI - The impact of a positive work atmosphere. PMID- 23094565 TI - The return of the inlay/ onlay? PMID- 23094566 TI - Mandatory influenza vaccination. PMID- 23094567 TI - First impressions count. AB - The art and craft of recording intra-oral anatomy successfully with dental impressions relies on the interaction of three critical factors--the 'golden triangle of impression-taking': an appreciation of the anatomical features to be recorded, the material used to take the impression and the clinical handling/operative technique applied. This paper aims to discuss the three factors and their inter-relationships, detailing clinical tips for successful, reproducible and consistent outcomes. CLINICAL RELEVANCE: Obtaining accurate dental impressions is the key to success in a wide range of clinical restorative procedures. This paper offers clinical advice to practitioners to plan and then take predictable, good quality impressions for their restorative cases. PMID- 23094568 TI - Ethical marketing in 'aesthetic' ('esthetic') or'cosmetic dentistry'. Part 3. AB - This, the third and final article in this series on ethical marketing, makes it clear that cosmetic dentistry is not a guaranteed one-way ticket to happiness for either patients or dentists, but it can be for lawyers. In fact, this area of dentistry is fraught with many dangers for the unwary patient and even for the enthusiastic or experienced dentist. In general, it is not at all wise to raise patient expectations beyond that which is definitely going to be easily achievable in his/her particular case. CLINICAL RELEVANCE: If things go wrong with extensive cosmetic dentistry, or are judged as being suboptimal, or unacceptable, by the patient, then that dentist may become liable for all the remakes of that elective cosmetic dentistry for the lifetime of the patient, together with all the associated general and specific damages. This is because, if the elective cosmetic dentistry had not been done, the patient would not have needed to have the remakes. Informed consent is a major issue with cosmetic dentistry, as is avoiding any possible claims for breach of contract, which could be verbal, implied or written. PMID- 23094569 TI - Impacted maxillary canines--a perennial problem. AB - Ectopic eruption with impaction of maxillary permanent canine teeth is a frequently encountered clinical problem. Surgical exposure and attachment of a gold chain to impacted maxillary canines is often required in order to bring them into the dental arch and to allow good alignment. The principle of radiographic parallax is employed to determine whether the impacted canine is placed buccal or palatal to adjacent teeth. Good flap design allows adequate access to the impacted tooth. Bone removal should be adequate to free the impacted crown to its greatest circumference. An orthodontic eyelet with a gold chain is then bonded to the crown of the impacted tooth. Use of a good bonding technique will minimize chances of bond failure necessitating a second surgical procedure. A traumatic surgical procedure will allow minimal postoperative complications and a rapid recovery. CLINICAL RELEVANCE: This article describes a surgical technique to expose impacted maxillary canines and attach gold chains, to facilitate orthodontic alignment into the dental arch. The principle of radiographic parallax to determine the bucco-palatal position of impacted canines is also discussed. PMID- 23094570 TI - Dentinogenesis imperfecta: full-mouth rehabilitation using implants and sinus grafts--a case report. AB - This case report outlines one possible treatment modality to manage the developmental abnormality dentinogenesis imperfecta (DI). In this case, the patient's dentition is restored using a combination of full-coverage crowns for the remaining teeth and implant-supported crowns to replace missing teeth in a re organized occlusal scheme. The case also demonstrates the effective use of the sinus graft procedure with simultaneous placement of dental implants. This paper also aims to make the reader aware of the current thinking behind treatment delivered to this group of patients, focusing on full-mouth rehabilitation using a combination of implant-supported and conventional metal ceramic crowns. CLINICAL RELEVANCE: For the general dental practitioner this case outlines the prevalence and cause of DI. It demonstrates how early diagnosis and appropriate referral has an impact on future treatment. PMID- 23094571 TI - Follow the leader: Part 2 - Leadership pillar 1--developing the vision. PMID- 23094572 TI - Dental local anaesthetics and latex: advice for the dental practitioner. AB - Natural rubber latex (NRL) is present in many medical products, including disposable gloves, adhesive tape and bungs in medicine vials. People sensitized to NRL are at risk of developing allergic reactions, which can present with delayed symptoms such as a localized red itchy rash, or with immediate symptoms such as itching of the skin and eyes, sneezing, bronchospasm or anaphylactic shock. People sensitized to NRL should avoid contact with all products that contain it, either in the product itself, in the packaging or introduced during the manufacturing process or storage. This paper highlights the implications of latex allergy in patients for dental healthcare staff, and provides a list of local anaesthetic preparations used in dentistry in the UK which are latex free. CLINICAL RELEVANCE: All dental staff need to be aware of latex allergy and know where to find information on latex content of dental local anaesthetics. PMID- 23094573 TI - Oral medicine: 1. Ulcers: aphthous and other common ulcers. PMID- 23094574 TI - Technique tips--management of a de-bonded, fixed-fixed, resin-bonded bridge. PMID- 23094575 TI - Physical signs for the general dental practitioner. Case 97. Cushing's syndrome. PMID- 23094576 TI - [Current treatment of rheumatic patients]. PMID- 23094577 TI - [Janus kinase inhibitors as a new therapeutic principle]. PMID- 23094578 TI - [Vaccinations in patients with autoimmune inflammatory rheumatic diseases--EULAR recommendations for pediatric and adult patients]. AB - Since patients with autoimmune inflammatory rheumatic diseases are prone to infectious complications--on one hand due to the rheumatic disease itself, on the other hand due to the immunosuppressive therapy--vaccination is an essential tool to prevent these infectious complications. Although there exist several recommendations for the vaccination of immunocompromised patients, many questions still remain for the distinct clinical situations of patients with autoimmune inflammatory rheumatic diseases. In addition, there are several questions concerning the safety and efficacy of various vaccinations, especially with regard to live-attenuated vaccines. Therefore, EULAR (European League Against Rheumatism) assembled two expert panels to clarify as much of these clinical problems as possible. After extensive literature review and evidence grading, the expert panels published recommendations for the vaccination of adult and pediatric patients, which are outlined in this review article. PMID- 23094579 TI - [Revival of selected well-tried antibiotics. Special features of the antiinfective agents penicillin G, fosfomycin, aztreonam and colistin]. AB - Although a worldwide increasing incidence of bacterial infections with panresistant pathogens may need innovative antiinfective agents, no breakthrough developments can be expected in the near future. As a consequence, well-tried antibiotics like aztreonam, fosfomycin and colistin, are experiencing a clinical revival, particularly if they are used in an improved manner. Even penicillin G with its narrow spectrum of antimicrobial activity remains an important considerable agent of first choice in special indications compared to broad spectrum antiinfectives. PMID- 23094580 TI - Analysis of energy generation and glycolysis pathway in diminazene aceturate resistant Babesia gibsoni isolate in vitro. AB - In our previous study, the level of parasitemia of the diminazene aceturate (DA) resistant B. gibsoni isolate was continuously lower than that of the wild-type, indicating the possible alteration of energy metabolism in that isolate. Therefore, in the present study, the concentrations of ATP, glucose, lactate, and pyruvate, and the activities of lactate dehydrogenase and pyruvate kinase in the wild-type and DA-resistant isolate of B. gibsoni were measured and compared to investigate the amount of energy generation and the activity of the glycolysis pathway. As a result, the intracellular ATP and glucose concentrations in the DA resistant B. gibsoni isolate were significantly higher than those in the wild type. Meanwhile, the concentrations of lactate and pyruvate and the activities of lactate dehydrogenase and pyruvate kinase in the DA-resistant B. gibsoni isolate were not different from those in the wild-type. These results indicated that the DA-resistant B. gibsoni isolate contained a higher ATP concentration than the wild-type, but the activity of the glycolysis pathway was not altered in the DA resistant B. gibsoni isolate. However, we could not determine the mechanism of the high energy production of the DA-resistant B. gibsoni isolate. Further studies on the energy metabolism of B. gibsoni are necessary to clarify the mechanism of the high energy production in the DA-resistant B. gibsoni isolate. PMID- 23094581 TI - Effects of interferon-tau on cattle persistently infected with bovine viral diarrhea virus. AB - In this study, the antiviral effects of bovine interferon-tau (boIFN-tau) on bovine viral diarrhea virus (BVDV) were examined in vitro and in vivo. In the in vitro experiments, the replication of cytopathic and non-cytopathic BVDV was inhibited in the bovine cells treated with boIFN-tau. The replication of BVDV was completely suppressed by boIFN-tau at a concentration higher than 10(2) U/ml. In order to examine the effect of boIFN-tau on virus propagation in cattle persistently infected (PI) with non-cytopathic BVDV, boIFN-tau was subcutaneously administered to PI cattle at 10(5) U/kg or 10(6) U/kg body weight 5 times per week for 2 weeks. No physical abnormality such as depression was observed in the cattle during the experiment. The mean BVDV titers in the serum of the PI cattle decreased slightly during the boIFN-tau administration period with the dose of 10(6) U/kg. However, the BVDV titers in the serum returned to the pre administration level after the final boIFN-tau administration. These results suggest that boIFN-tau demonstrates an anti-BVDV effect, reducing the BVDV level in serum transiently when injected into PI cattle. PMID- 23094582 TI - Inhibitory effects of an M2-specific monoclonal antibody on different strains of influenza A virus. AB - New approaches to the treatment of influenza have been designed based on the highly conserved antigenicity of the M2 envelope protein among influenza A virus strains. The present study examined the anti-viral activities of an anti-M2 ectodomain (M2e) monoclonal antibody (clone rM2ss23), which binds to the M2 proteins of the influenza A virus strains A/ Aichi/2/68 (H3N2) (Aichi) and A/PJR/8/34 (H1N1) (PR8). The results showed that rM2ss23 bound to both Aichi and PR8 M2 proteins expressed on the cell surface. While the antibody did not prevent virus entry into cells, it significantly inhibited plaque formation by the Aichi strain in a dose-dependent manner when infected cells were cultured in the presence of the antibody. By contrast, the growth of PR8 (H1N1) was not affected by the antibody. A reverse genetics approach revealed that the inhibitory effect of rM2ss23 on the Aichi virus was abolished by replacing the genes encoding the HA and/or M proteins with those of the PR8 strain. These results suggest that rM2ss23 prevents virus release from infected cells and further suggest that the mechanisms underlying the virus budding mediates by HA and M2 proteins might differ between the Aichi and PR8 strains. PMID- 23094583 TI - Development and evaluation of indirect enzyme-linked immunosorbent assay for a screening test to detect antibodies against classical swine fever virus. AB - An indirect enzyme-linked immunosorbent assay (ELISA) was developed for a screening test to detect antibodies against classical swine fever virus (CSFV). Viral glycoproteins, which were purified from swine kidney cells infected with CSFV ALD/A76 strain by the immunoaffinity purification using monoclonal antibody against E2 protein, were adsorbed on a microtiter plate as the antigen for the antibody detection. Each antibody titer of serum sample was expressed as a sample per positive value calculated with optical absorbance of each sample and that of a positive control. The advantage of this ELISA is its higher sensitivity: most sera containing more than 4 neutralization titers were determined to be positive. This ELISA is unable to discriminate between antibodies against CSFV and those against other ruminant pestiviruses, therefore positive sera in this ELISA should be evaluated by a cross-neutralization test using CSFV, bovine viral diarrhea virus, and border disease virus. Taken together, the indirect ELISA developed in this study is useful screening tool to detect antibodies against CSFV for the large-scale monitoring of classical swine fever. PMID- 23094584 TI - The chicken 2'-5' oligoadenylate synthetase A inhibits the replication of West Nile virus. AB - West Nile virus (WNV) is a pathogen to cause West Nile encephalitis when the infection occurs in the brain. Previous studies in mice identified the 2'-5' oligoadenylate synthetase 1b (Oas1b) gene as a determining factor for resistance to WNV infection. In addition, it has been suggested that human OAS1 and OASL are associated with the resistance to the WNV infection. WNV is maintained in nature through a complex life cycle involving wildbirds and mosquitoes. Birds are not only susceptible to the WNV, but also act as reservoir hosts, thus participating in the spread of the disease. It has previously been reported that chicken OASL possesses the oligoadenylate synthetase activity. However, until now the antiviral activity of chicken OASL has not been determined. In this study, we investigated the putative antiviral activity of chicken OASL by ectopic expression of this enzyme in mammalian cells and then infecting these cells with WNV replicon. We demonstrate that chicken OASL has an antiviral activity against the WNV. This is the first report to show that chicken OASL is associated with the resistance to the WNV infection. PMID- 23094585 TI - Plasmodium circumflexum in a Shikra (Accipiter badius): phylogeny and ultra structure of the haematozoa. AB - A wild-caught, juvenile Shikra (Accipiter badius) was evaluated for rehabilitation at the Kasetsart University Raptor Rehabilitation Unit (KURRU) with a history of weakness. Plasmodium sp. was observed by both light and electron microscopy in blood obtained on day 1 of evaluation. Based on the appearance of erythrocytic meronts and gametocytes, the parasites were defined as Plasmodium (Giovannolaia) circumflexum. The sequence analysis of the mitochondrial cytochrome b gene from the plasmodia was closely related to parasites found in the Grey-headed woodpecker from Myanmar and the Brown hawk-owl from Singapore. Transmission electron microscopic examination revealed organelles in the haematozoa and heterophils that ingested the plasmodia. This is the first recorded case of Plasmodium circumflexum in a wild Shikra. This note emphasises the molecular characterisation and ultra-structure of the haematozoa. PMID- 23094586 TI - Bovine viral diarrhea virus infection in a dairy herd with high prevalence of persistently infected calves. AB - A dairy herd including approximately 50 milking cows and 40 heifers and calves was investigated. This herd was detected with high prevalence of calves persistently infected (PI) with bovine viral diarrhea virus (BVDV). Nine PI animals including a milking cow and 8 newborn calves were detected in the herd within 4 months. Prevalence of PI animals in this herd was estimated 7.0% which was very high compared to that estimated in previous reports. All newborn PI calves were strongly suspected to have a single origin of infection as estimated from the homology of the virus genes. The cause of high prevalence could not be clarified. Removal of PI animals and continuous examination of newborn calves were important for the elimination of BVDV from the herd. PMID- 23094587 TI - Explaining differences in the environmental performance of countries: a comparative study. AB - What influences countries' environmental performance? Do structural differences alone affect the level of air pollution? Do economic conditions determine water quality? Might society's dominant ideology and values impact national environmental performance? Are different kinds of environmental-performance indicators affected by the same variables? This paper employs comparative empirical analyses of EPI data to address these questions. Doing so enables us to contribute the following five insights to the research literature. First, we propose a conceptual categorization of EP following their health, ecological and global aspects. Second, we demonstrate that social policy, a previously underexplored factor, affects environmental policy and performance. Third, we provide evidence for the role of international engagement in explaining global related environmental performance. Fourth, our research extends the sample studied beyond the traditional OECD sample to 68 countries with diverse development status. Finally, we demonstrate that the multiple regression models we employed provide high levels of explanatory power (up to 89%). Collectively, the results demonstrate the important role of social policy in explaining differences in the environmental performance of countries. In addition, the differences in the influence of the explanatory variables on each of the proposed category support our theoretical arguments for differentiating between various categories of environmental performance. PMID- 23094588 TI - Effect of helix stability on the formation of loop-loop complexes. AB - Kissing loop complexes are loop-loop complexes where two RNA hairpins interact through their complementary loops. In this work, we have investigated the role of the helical stems on the ability of hairpins derived from the ColE1 plasmid to associate as kissing loop complexes in the presence and absence of divalent cations. Our results show that although kissing loop complexes form more readily in the presence of Mg(2+), they are able to form in the presence of 850 mM NaCl, as long as their stems contain at least six base-pairs. Formation of the Na(+) loop-loop complexes is facilitated by changing the sequence at the stem-loop interface to include less stable AU base pairs. We suggest that the conformation at the stem-loop interface is critical in the formation of kissing loop complexes and that in the absence of Mg(2+) the conformation at the stem-loop interface is packed more loosely than with Mg(2+), to allow for a lower charge density. Consistent with this hypothesis, shortening the stems to five base pairs results in unfolding of the hairpins and formation of an extended duplex rather than a kissing loop complex because the short stems are not stable enough to tolerate the necessary conformation at the stem-loop interface to allow the formation of a kissing loop complex. PMID- 23094589 TI - Design, synthesis, and evaluation of inhibitors of pyruvate phosphate dikinase. AB - Pyruvate phosphate dikinase (PPDK) catalyzes the phosphorylation reaction of pyruvate that forms phosphoenolpyruvate (PEP) via two partial reactions: PPDK + ATP + P(i) -> PPDK-P + AMP + PP(i) and PPDK-P + pyruvate -> PEP + PPDK. Based on its role in the metabolism of microbial human pathogens, PPDK is a potential drug target. A screen of substances that bind to the PPDK ATP-grasp domain active site revealed that flavone analogues are potent inhibitors of the Clostridium symbiosum PPDK. In silico modeling studies suggested that placement of a 3-6 carbon-tethered ammonium substituent at the 3'- or 4'-positions of 5,7 dihydroxyflavones would result in favorable electrostatic interactions with the PPDK Mg-ATP binding site. As a result, polymethylene-tethered amine derivatives of 5,7-dihydroxyflavones were prepared. Steady-state kinetic analysis of these substances demonstrates that the 4'-aminohexyl-5,7-dyhydroxyflavone 10 is a potent competitive PPDK inhibitor (K(i) = 1.6 +/- 0.1 MUM). Single turnover experiments were conducted using 4'-aminopropyl-5,7-dihydroxyflavone 7 to show that this flavone specifically targets the ATP binding site and inhibits catalysis of only the PPDK + ATP + P(i) -> PPDK-P + AMP PP(i) partial reaction. Finally, the 4'-aminopbutyl-5,7-dihydroxyflavone 8 displays selectivity for inhibition of PPDK versus other enzymes that utilize ATP and NAD. PMID- 23094590 TI - GLP-1 agonists for type 2 diabetes: pharmacokinetic and toxicological considerations. AB - INTRODUCTION: Within recent years, glucagon-like peptide 1 receptor agonists (GLP 1-RA) have emerged as a new treatment option for type 2 diabetes. The GLP-1-RA are administered subcutaneously and differ substantially in pharmacokinetic profiles. AREAS COVERED: This review describes the pharmacokinetics and safety aspects of the currently available GLP-1 receptor agonists, liraglutide (based on the structure of native GLP-1), exenatide twice daily and exenatide once weekly (based on exendin-4) in relation to the kinetics and toxicology of native GLP-1. The review is based on electronic literature searches and legal documents in the form of assessment reports from the European Medicines Agency and the United States Food and Drug Administration. EXPERT OPINION: GLP-1-based therapy combines several unique mechanisms of action and have the potential to gain widespread use in the fight against diabetes and obesity. The difference in chemical structure have strong implications for key pharmacokinetic parameters such as absorption and clearance, and eventually the safety and efficacy of the individual GLP-1-RA. The main safety concerns are pancreatitis and neoplasms, for which there are no identifiable differences in risk between the available agents. Antibody formation and injection site reactions are more frequent with the exendin-4-based compounds. The efficacy with regard to Hb(A1c) reduction is superior with the longer-acting agonists, whereas the shorter-acting GLP-1-RA seems to provide greater postprandial glucose control and lower tolerability as a possible consequence of less induction of tachyphylaxis. The future place of these agents will depend on the added safety and efficacy data in the several ongoing cardiovascular outcome trials. PMID- 23094592 TI - Prospect theory does not describe the feedback-related negativity value function. AB - Humans handle uncertainty poorly. Prospect theory accounts for this with a value function in which possible losses are overweighted compared to possible gains, and the marginal utility of rewards decreases with size. fMRI studies have explored the neural basis of this value function. A separate body of research claims that prediction errors are calculated by midbrain dopamine neurons. We investigated whether the prospect theoretic effects shown in behavioral and fMRI studies were present in midbrain prediction error coding by using the feedback related negativity, an ERP component believed to reflect midbrain prediction errors. Participants' stated satisfaction with outcomes followed prospect theory but their feedback-related negativity did not, instead showing no effect of marginal utility and greater sensitivity to potential gains than losses. PMID- 23094591 TI - A time-saving strategy for MAS NMR spectroscopy by combining nonuniform sampling and paramagnetic relaxation assisted condensed data collection. AB - We present a time-saving strategy for acquiring 3D magic angle spinning NMR spectra for chemical shift assignments in proteins and protein assemblies in the solid state. By simultaneous application of nonuniform sampling (NUS) and paramagnetic-relaxation-assisted condensed data collection (PACC), we can attain 16-fold time reduction in the 3D experiments without sacrificing the signal-to noise ratio or the resolution. We demonstrate that with appropriate concentration of paramagnetic dopant introduced into the sample the overwhelming majority of chemical shifts are not perturbed, with the exception of a limited number of shifts corresponding to residues located at the surface of the protein, which exhibit small perturbations. This approach enables multidimensional MAS spectroscopy in samples of intrinsically low sensitivity and/or high spectral congestion where traditional experiments fail, and is especially beneficial for structural and dynamics studies of large proteins and protein assemblies. PMID- 23094593 TI - Cutaneous mastocytosis extending beyond a radiotherapy site: a form of radiodermatitis or a neoplastic phenomenon? AB - Ionising radiation is often used as an adjuvant in the management of breast cancer. Acute and chronic skin changes are well recognised complications associated with its use. We demonstrate a rare clinical presentation of cutaneous mastocytosis that occurred at the site of radiotherapy and then extended beyond this boundary, and ask whether this can be treated as a localised side effect of radiotherapy or whether the potential for systemic mastocytosis needs to be excluded. PMID- 23094594 TI - Treatment of chronic headache of cervical origin with lipostructure: an observational study. AB - OBJECTIVE: To test feasibility, safety, and efficacy of local transplant of stromal fraction of adipose tissue in the treatment of chronic headaches of cervical origin. BACKGROUND: Chronic headaches of cervical origin (chronic cervicogenic headache and occipital neuralgia) are characterized by persistent pain due to the involvement of the great occipital nerve, with concurrent myofascial spasm and the consequent nerve entrapment within the trapezoid tunnel. METHODS: Tolerability and effectiveness of treatment of chronic cervicogenic headaches refractory to conventional therapies were evaluated in 24 patients. The visual analog scale of pain and the medication use diary were used in the 3 months preceding treatment; moreover, in order to verify the quality of life, patients are required to fill before surgery the neck pain disability index, the headache disability index, migraine disability assessment scale questionnaire, and the short-form 12 standard v1 questionnaire. Follow-up examination was performed at 3 and 6 months. RESULTS: In 19 cases (79.2%), a good clinical response was recorded. At 6-month follow-up analysis, recurrence of occipital pain was recorded in 7 cases (29.2%); there is a significant reduction in disability and pain scores, and also a significant reduction of need for pharmacologic treatment and a fast return to previous work capacities. CONCLUSIONS: The key point of our therapeutic strategy might be the regenerative role of stromal fraction of adipose tissue transplanted in the area of the occipital nerve entrapment; the results of the present study are encouraging both in terms of reduction of pain scores and in terms of quality of life improvement. The technique is minimally invasive, and no complications were recorded; indeed, the procedure seems to be safe and effective, and thus, a randomized study with larger follow-up and in a large series will be started. PMID- 23094595 TI - Segmental spinal cord hypoplasia in a Holstein Friesian calf. AB - An 8-day-old female Holstein Friesian calf was examined because of congenital spastic paresis of the hind limbs. Myelography revealed deviation and thinning of subarachnoid contrast medium columns in the lumbar segment. Upon magnetic resonance imaging, the 'hour-glass' subdural compression appeared as a T1 hypointense, T2-hyperintense ovoidal area suggestive of cerebral spinal fluid collection, compatible with hydrosyringomyelia. The calf was euthanized and the necropsy confirmed the diagnosis of segmental spinal cord hypoplasia of the lumbar tract associated to hydromyelic and syringomyelic cavities. PMID- 23094596 TI - Improving the quality of polymer-coated urea with recycled plastic, proper additives, and large tablets. AB - Polymer-coated urea (PCU) has great potential for increasing crop production and enhancing nitrogen (N) fertilizer use efficiency, benefiting the ecosystem. However, current PCUs are used only in a limited market, and the main obstacle to the wider use of PCUs is high cost compared to that of conventional N fertilizers. In this study, the low cost PCU and large tablet polymer-coated urea (LTPCU) were prepared by using recycling polystyrene foam and various sealants as the coating materials. The structural and chemical characteristics of the coating shells of the coated fertilizers were examined. The N release characteristics of coated fertilizers were determined in 25 degrees C water under laboratory conditions. The relationship between the N release longevity and the amount of coating material and the percentage of different sealants were evaluated. The results indicated that recycling polystyrene foam was the ideal coating material of the controlled release fertilizer. The polyurethane that was synthesized by the reaction of castor oil and isocyanate was better than the wax as the additive to delay the N release rate of coated urea. The coating material used for LTPCU was 70-80% less than those used for commercial PCUs under the same N release longevity. The cost of the recycling polystyrene foam used for coating one ton of pure N of the LTPCU was about one-seventh to one-eighth of the cost of the traditional polymer used for the commercial PCU. The experimental data showed that the LTPCU with good controlled-release capacities, being economical and eco friendly, could be promising for wide use in agriculture and horticulture. PMID- 23094598 TI - Pd-catalyzed imine cyclization: synthesis of antimalarial natural products Aplidiopsamine A, Marinoquinoline A, and their potential hybrid NCLite-M1. AB - Palladium-catalyzed cyclization of imines has been developed to construct the extremely rare 3H-pyrrolo[2,3-c]quinoline ring system for diversity oriented first total synthesis of antimalarial marine natural product Aplidiopsamine A as well as synthesis of Marinoquinoline A and potential natural product hybrid NCLite-M1. PMID- 23094597 TI - Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial. AB - AIMS: This 52-week, randomized, multinational, open-label, parallel-group, non inferiority trial investigated the efficacy and safety of basal-bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in combination with insulin aspart, in subjects aged 2-16 years with Type 1 diabetes mellitus. METHODS: Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight were followed over 52 weeks. RESULTS: After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA(1c) [mean difference insulin detemir-NPH: 1.30 mmol/mol, 95% CI -1.32 to 3.92 (0.12%, 95% CI -0.12 to 0.36) in the full analysis set and 1.41 mmol/mol, 95% CI -1.26 to 4.08 (0.13%, 95% CI -0.12 to 0.37) in the per protocol analysis set]. Hypoglycaemic events per subject-year of exposure of 24-h and nocturnal hypoglycaemia were significantly lower with insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60-0.97, P = 0.028 and 0.62, 95% CI 0.47-0.84, P = 0.002, respectively). Weight standard deviation (sd) scores (body weight standardized by age and gender) decreased with insulin detemir, but increased slightly with NPH insulin (change: -0.12 vs. 0.04, P < 0.001). At end of the trial, median insulin doses were similar in both treatment groups. CONCLUSIONS: Insulin detemir was non-inferior to NPH insulin after 52 weeks' treatment of children and adolescents aged 2-16 years, and was associated with a significantly lower risk of hypoglycaemia, together with significantly lower weight sd score when compared with NPH insulin. PMID- 23094599 TI - Silicon surface functionalization targeting Si-N linkages. AB - Silicon substrates have been a fascinating topic of fundamental and applied research for well over 50 years. They have attracted even more attention over the last couple of decades with advances in chemical functionalization that made oxide-free silicon surfaces a reality. Fundamentally new electronic properties and chemical reactivity became available, and the focus of chemical research turned more toward targeting specific chemical bonds and functionalities on silicon. Although thermodynamics clearly drives most processes under ambient conditions toward the formation of an oxide layer, kinetic control of the oxidation processes and thermodynamic tricks based on gaining stability of surface monolayers with high-density assembly have allowed for the formation of stable Si-C bonds and Si-O-C linkages on oxide-free silicon crystals. This feature article targets recent advances in making Si-N linkages on the same oxide free single crystals. It covers the range of chemical approaches to achieving this goal and offers possible chemistry that can take advantage of the systems produced. The present status of the field and the future directions of its development will be considered. PMID- 23094600 TI - European phylogeography of the epiphytic lichen fungus Lobaria pulmonaria and its green algal symbiont. AB - In lichen symbiosis, fungal and algal partners form close associations, often codispersed by vegetative propagules. Due to the particular interdependence, processes such as colonization, dispersal or genetic drift are expected to result in congruent patterns of genetic structure in the symbionts. To study the population structure of an obligate symbiotic system in Europe, we genotyped the fungal and algal symbionts of the epiphytic lichen Lobaria pulmonaria at eight and seven microsatellite loci, respectively, and analysed about 4300 L. pulmonaria thalli from 142 populations from the species' European distribution range. Based on a centroid approach, which localizes centres of genetic differentiation with a high frequency of geographically restricted alleles, we identified the South Italy-Balkan region as the primary glacial refugial area of the lichen symbiosis. Procrustean rotation analysis and a distance congruence test between the fungal and algal population graphs indicated general concordance between the phylogeographies of the symbionts. The incongruent patterns found in areas of postglacial recolonization may show the presence of an additional refugial area for the fungal symbiont, and the impact that horizontal photobiont transmission and different mutation rates of the symbionts have on their genotypic associations at a continental scale. PMID- 23094601 TI - Fracture resistance of bone samples filled with fibre-reinforced composite posts: an ex vivo model. AB - AIM: To evaluate the strengthening effect of two different types of fibre reinforced composite (FRC) posts in an ex vivo experimental model. METHODOLOGY: Compact and hollow bone samples from bovine femurs were used as standardized samples. A total of 80 hollow samples were divided into two groups and filled either with a prefabricated FRC post or with individually adapted FRC posts. For each group, half of the samples were subjected to thermocycling (5-55 degrees C, 5000*). The remaining samples were kept for 24 h at 37 degrees C at 100% relative humidity. All samples were loaded diametrically until fracture. The null hypothesis tested was that the fracture resistance of standardized bone samples is not influenced by the type of FRC post, independently of the exposure to thermocycling. Results were evaluated by anova, and subsequent multiple comparisons were performed. RESULTS: The samples filled with the individually adapted FRC posts were more resistant to fracture than the prefabricated ones (P < 0.001), but this difference was not apparent in the thermocycled groups. Detachment of the posts upon fracture was highest after thermocycling for both groups, amounting to 55% and 95% for the individual adapted posts and the prefabricated posts, respectively. CONCLUSIONS: Initially, the samples filled with the individually adapted FRC posts were more resistant to fracture than those filled with the prefabricated ones. However, after ageing of the samples, both types of posts had similar strengthening effects. PMID- 23094602 TI - Vaginal infections update. AB - Vaginal symptoms are one of the leading reasons that women visit their health care providers. Women often self-diagnose and may treat themselves inappropriately. This article describes the etiology, risk factors, symptoms, diagnosis, and treatment of the 3 most common vaginal infections: bacterial vaginosis, trichomoniasis, and vulvovaginal candidiasis. PMID- 23094603 TI - A type VI secretion system regulated by OmpR in Yersinia pseudotuberculosis functions to maintain intracellular pH homeostasis. AB - Type VI secretion systems (T6SSs) which widely distributed in Gram-negative bacteria have been primarily studied in the context of cell interactions with eukaryotic hosts or other bacteria. We have recently identified a thermoregulated T6SS4 in the enteric pathogen Yersinia pseudotuberculosis. Here we report that OmpR directly binds to the promoter of T6SS4 operon and regulates its expression. Further, we observed that the OmpR-regulated T6SS4 is essential for bacterial survival under acidic conditions and that its expression is induced by low pH. Moreover, we showed that T6SS4 plays a role in pumping H(+) out of the cell to maintain intracellular pH homeostasis. The acid tolerance phenotype of T6SS4 is dependent on the ATPase activity of ClpV4, one of the components of T6SS4. These results not only uncover a novel strategy utilized by Y. pseudotuberculosis for acid resistance, but also reveal that T6SS, a bacteria secretion system known to be functional in protein transportation has an unexpected function in H(+) extrusion under acid conditions. PMID- 23094604 TI - Distinguishing sluggish cognitive tempo from ADHD in children and adolescents: executive functioning, impairment, and comorbidity. AB - Controversy continues as to whether sluggish cognitive tempo (SCT) is a subtype of attention-deficit/hyperactivity disorder (ADHD) or a distinct disorder. This study examined differences between these disorders in demographics, executive functioning (EF), impairment, and prior professional diagnoses to address the issue. There were 1,800 children 6 to 17 years of age of both sexes from various U.S. ethnic backgrounds who were divided into four groups: (a) high SCT but not ADHD (N = 41), (b) high ADHD but not SCT (N = 95), (c) high in both SCT and ADHD (N = 61), and (d) the control group (N = 1,603). Besides providing demographics, parents completed scales assessing ADHD and SCT symptoms, EF deficits, and psychosocial impairment and reported their child's history of professional diagnoses. SCT symptoms formed two distinct but interrelated factors separate from those for ADHD. SCT differed from ADHD in demographics (age, sex ratio, parental education, income). ADHD was associated with more severe and pervasive EF deficits than SCT, whereas SCT was chiefly associated with mild deficits in Self-Organization. ADHD contributed far more variance to EF deficits than did SCT. Both disorders were impairing, but ADHD was more severely and pervasively so than SCT, especially in Home-School domains; SCT was most impairing in Community Leisure domains. Different patterns of comorbidity were evident between SCT and ADHD. SCT showed less comorbidity and was particularly associated with depression. SCT may comprise a distinct disorder from ADHD but both may coexist in 39% to 59% of cases each. PMID- 23094605 TI - Two faces of microbiota in inflammatory and autoimmune diseases: triggers and drugs. AB - The prevalence of chronic autoimmune and inflammatory diseases, such as inflammatory bowel disease, allergies, or rheumatic diseases, is steadily increasing in developed countries. This increase is probably accelerated by environmental factors, such as decrease in infectious burden or changes in food processing. These lifestyle changes then strongly influence the strongest stimulus for the immune system - commensal microbiota. Despite the differences in the affected organ, the immune-mediated diseases have one or more factors in common - microbe either as a trigger or as a protector, mucosal barrier dysfunction, and dysregulation of the immune system. The core questions, which microbes are involved and how these diseases can be cured or even prevented still remain unsolved. Powered by the recent progress in technology, by new insights into the function of immune system, by advances in microbiome research, and extended use of gnotobiological techniques, these mechanisms are now being unravelled and new therapeutic possibilities are emerging. To secure their niche, the microbes devised many ingenious ways, how to dampen the inflammation. Nonpathogenic microorganisms or microbial components isolated from probiotic, commensal or even pathogenic microbes could be, therefore, used to interfere with the pathogenetic mechanisms of immune-mediated diseases. PMID- 23094606 TI - Prevalence and prognostic impact of comorbidities in amyotrophic lateral sclerosis. AB - BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is characterized by rapidly progressive paralysis of striated muscles due to the loss of upper and lower motor neurons. The disease leads to death within 2-5 years, mainly due to respiratory failure. The pathogenesis of ALS is still unexplained for the most part. In this study, we aimed to determine the prevalence of different cardiovascular, metabolic, and neuropsychiatric comorbidities in a large ALS cohort and to evaluate their influence on the disease course. METHODS: A cohort of 514 patients with ALS of our ALS outpatient clinic was investigated retrospectively with reference to known prognostic factors and comorbidities. The prevalence of concomitant diseases was compared with the data from the German general population. Uni- and multivariate survival analyses were performed using the Cox proportional hazards model and Kaplan-Meier analysis. RESULTS: The prevalence of cardiovascular diseases and cardiovascular risk factors was significantly lower in patients with ALS compared to the German general population, whilst the prevalence of dementia, parkinsonism, and depressive symptoms was significantly higher in the ALS cohort. None of the investigated comorbidities had an influence on the disease course or on the survival of patients. CONCLUSIONS: Persons with cardiovascular diseases or risk factors seem to be at lower risk of ALS. Although these diseases are apparently somehow protective regarding ALS susceptibility, their presence did not modify disease progression and survival in patients with ALS. Our study further confirms the well-known continuum between ALS and dementia. It also suggests a link with other neurodegenerative diseases such as Parkinson's disease. PMID- 23094608 TI - Synthesis and characterization of polyurethane-urea microcapsules containing galangal essential oil: statistical analysis of encapsulation. AB - Galangal essential oil (GEO) is known to possess antimicrobial activity (e.g. against Staphylococcus aureus). A way to increase oil lifetime in plants is encapsulation in polyurethane-urea (PUU) microcapsules. In this study, PUU microcapsules with GEO were synthesized by interfacial polymerization at oil water interface in oil-water emulsion. A statistical analysis of the microcapsule size was successfully applied for characterization of the encapsulation process. Using the model of reversible aggregation, it was shown that the process of encapsulation takes place in the conditions of thermodynamic control. The polymerization conditions (agitation rate in the range 2000-10 000 rpm/min) are the key factors that affect the mean microcapsule size of primary capsules formed during encapsulation. Two complementary processes were determined the mean capsule size during a transformation of these primary microcapsules: break-up and coalescence of oil droplets in the oil-in-water emulsion. The agitation rate does not influence the coalescence of the oil droplets, but the threshold value of agitation speed (in this system 4000 rpm/min) does exist and that is what strongly increases break-up of oil droplets. The higher agitation rate resulted in smaller size of microcapsules (mean diameter decreasing from 5.6 to 4.9 um for primary capsules and from 13.8 to 9.8 um for secondary capsules) and with a narrower size distribution. The last mode of encapsulation allows the more effective use the shell material for encapsulating of larger amount of oil. PMID- 23094607 TI - Physical therapy and psychological intervention normalize cortisol levels and improve vitality in women with endometriosis. AB - There is as yet no effective treatment for endometriosis. The objective of this study was to evaluate the effectiveness of submitting women with endometriosis and chronic pelvic pain to a therapeutic protocol involving physical and psychological therapy. Twenty-six female volunteers were submitted to a treatment protocol consisting of 2.5-h sessions, once a week for 10 weeks. We applied a Visual Analogue Scale, the Perceived Stress Questionnaire (PSQ), and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Morning, afternoon, and evening levels of cortisol were determined in saliva samples. The PSQ scores were significantly lower after treatment, whereas the scores for the SF-36 vitality and physical functioning domains were significantly higher. Salivary cortisol levels were higher after treatment in the samples collected in the morning, but not in those collected in the afternoon or evening. The post-treatment cortisol levels were similar to those reported for healthy women. There were positive correlations between vitality, role emotional, social functioning, and mental health, and negative correlations to perceived stress. In conclusion, the physical and psychological intervention protocol applied in this study to women suffering of endometriosis was effective in reducing perceived stress, normalizing cortisol levels, increasing vitality and improving physical functioning. PMID- 23094609 TI - Effect of antioxidants on the stability of ONO-1301, a novel long-acting prostacyclin agonist, loaded in PLGA microspheres. AB - The purpose of this study was to investigate the physicochemical stability of ONO 1301 in poly(lactide-co-glycolide) microspheres (PLGA MS) under storage for 28 days in the absence or presence of butylated hydroxytoluene (BHT) or alpha tocopherol as antioxidant. First, we observed the hydrolysed product: (i) in acidic solution and oxidized product and (ii) in PLGA MS under storage in HPLC study, each structure was determined by liquid chromatography-nuclear magnetic resonance/mass spectrometry. Second, ONO-1301-loaded PLGA MS containing 10% BHT was shown to be superior to ONO-1301-loaded PLGA MS without BHT, in the standpoint of the stability under storage or in vitro drug-release test, and AUC(0-28) following subcutaneous injection in rats. Finally, ONO-1301-loaded PLGA MS with 10% BHT were demonstrated to be significantly more effective than ONO 1301-loaded PLGA MS without BHT in a murine sponge model of angiogenesis. In conclusion, BHT is an effective antioxidant on the stability of ONO-1301 in PLGA MS under storage. PMID- 23094610 TI - Measuring spirituality in health care research. PMID- 23094611 TI - Understanding of the word "spirituality" by theologians compared to lay people: an empirical study from a secular region. AB - Although widely used, we know very little of the meaning of the word spirituality in secular, non-English speaking societies, and different understandings might lead to misunderstandings and unclear communication. This empirical study compares a theologian and a lay group on their understandings of the term spirituality by analysis of a questionnaire consisting of 115 possible associations of the word spirituality. Analysis compares six understandings of spirituality: 1) positive dimensions in human life and well-being; 2) new Age ideology; 3) integrated part of established religious life; 4) vague striving, opposed to religion; 5) selfishness; and 6) ordinary inspiration in human activities. Results show the theologians understand spirituality more as part of established religious life than the lay group, whereas the lay group understands spirituality more as a striving toward something transcendent, vaguely defined. In conclusion, it is suggested never to use the term spirituality without a notion or some keywords framing the meaning of the word in the specific context. PMID- 23094612 TI - Using spirituality after an adult CF diagnosis: cognitive reframing and adherence motivation. AB - Chronic illness is a significant stressor; the majority of Americans cope utilizing spirituality. Numerous studies demonstrate links between spiritual coping and health outcomes. The purpose of this study was to determine whether persons diagnosed with cystic fibrosis (CF) as adults use spirituality to cope and influence disease management. Semi-structured interviews were completed and analyzed using grounded theory. Data saturation was reached following twelve interviews (83% female); representing 100% participation of those approached and 48% of eligible adults. Persons with late-life CF diagnoses used spirituality to make meaning, understanding themselves in a collaborative partnership with their pulmonologist and God. Supporting themes were: (a) God's intervention depended on treatment adherence and (b) spiritual meaning was constructed through positively reframing their experience. The constructed meaning differed from that of adult parents of children with CF. Late-life diagnosed adults focused on personal responsibility for health. Clinical and research implications for chaplains are presented. PMID- 23094613 TI - An interprofessional educational approach to teaching spiritual assessment. AB - Spirituality is an essential aspect of a patient's health that can and should be integrated into routine health care. Despite recommendations of accrediting organizations such as the Association of American Medical Colleges, the National Association of Social Workers, and the Association of Professional Chaplains, there is little well defined curriculum focusing on interprofessional spiritual assessment. This article explores one program's use of an interprofessional approach in teaching spiritual assessment to students from medicine, social work, and chaplaincy. Learning objectives were adapted from the Association of American Medical Colleges Medical School Objectives Project. Workshop evaluations show that students can learn key concepts of spirituality and the basics of spiritual assessment while developing an understanding and respect for the role of chaplains, social workers, and physicians. PMID- 23094614 TI - The chaplain profession from the employer perspective: an analysis of hospice chaplain job advertisements. AB - Hospitals and hospice organizations who are hiring chaplains to provide spiritual care for terminally ill patients post online job advertisements with specific qualifications and communication skills that applicants should possess. An examination of job advertisements can uncover trends in credentials and responsibilities expected of hospice chaplains. Results of a framework analysis of 71 hospice chaplain job advertisements indicated that 44% of chaplain job advertisements did not require chaplain applicants to have completed clinical pastoral education (CPE) and 41% did not required ordination and/or endorsement from a recognized denomination. Only 37% of hiring organizations required or preferred professional certification. Furthermore, patient support (70%), ambassadorship (54%), team collaboration (52%), and interfaith proficiency (46%) were the communication skills that advertisements tended to emphasize. This article focuses on how the study findings reflect ongoing challenges for the chaplain occupational group on its path to professionalization. PMID- 23094615 TI - Bearing the burden: deployment stress among army national guard chaplains. AB - Military Chaplains are a critical component of behavioral health and spiritual support in combat operations. Support of combat operations has taken a toll on these caregivers. The purpose of this study was to explore the impact of deployment on the psychosocial and health characteristics and reintegration of Army National Guard (ARNG) chaplains. Seventy-four ARNG chaplains participated in an anonymous, online survey. Results were categorized into two mutually exclusive groups, combat deployed and non-combat deployed. Although both groups tended to present similar results, Combat deployed group chaplains were significantly more likely to be of higher rank, have served in a pastoral role in the ARNG longer, and present with higher scores for combat exposure, resilience, and alcohol use. Further, five and seven participants, respectively, the majority of whom were from the combat deployed group, endorsed "frequently" or "a great deal" to negative religious coping. These endorsements of abandonment may relate back to Reserve component specific deployment concerns. PMID- 23094618 TI - Art in children's hospitals. PMID- 23094619 TI - Art at The Children's Hospital at Westmead. PMID- 23094620 TI - Image of the month. PMID- 23094621 TI - Probiotics may prevent upper respiratory tract infections, but should we recommend them? PMID- 23094622 TI - Leukotriene antagonists in asthma. PMID- 23094623 TI - Is malodorous urine associated with urinary tract infection in children? PMID- 23094624 TI - New malaria vaccine reduces malaria by half in African children. PMID- 23094625 TI - Imaging after a first febrile UTI in infants and children: less is more? PMID- 23094626 TI - Putting bed-sharing findings into perspective. PMID- 23094627 TI - The triple risk model for shared sleeping. PMID- 23094628 TI - Pheochromocytoma presenting as pyrexia of unknown origin. PMID- 23094629 TI - Clinical phenotypes associated with type II collagen mutations. PMID- 23094631 TI - Taronga zoo paediatrics. PMID- 23094632 TI - Hitchhiker's guide to the literature. PMID- 23094633 TI - Restrictions on infant formulas. PMID- 23094634 TI - Continuous positive pressure non-invasive ventilation for the management of obstructive sleep apnoea in a 15-year-old girl with polycystic ovary syndrome. PMID- 23094635 TI - Study of three families with Hb Agrinio [alpha29(B10)Leu->Pro, CTG>CCG (alpha2)] in the Spanish population: three homozygous cases. AB - Most alpha-thalassemia (alpha-thal) mechanisms are deletions of one or both alpha globin genes and less than 5.0-10.0% are point mutations. Hb Agrinio [alpha29(B10)Leu->Pro, CTG>CCG (alpha2)] is a hyperunstable alpha chain structural variant in which the thalassemic phenotype is determined by a post translational precipitation of the structurally anomalous chain in erythroid precursors. This study involved 14 cases with Hb Agrinio from three families. Selective sequencing of the alpha2 gene showed a CTG(Leu)>CCG(Pro) mutation at codon 29. The mutation was found in a heterozygous state in 11 cases and in a homozygous state in three cases. These are the first cases with Hb Agrinio described in Spain. In all cases where a leucine is exchanged for a proline, an unstable hemoglobin (Hb) will occur both in the alpha and the beta chain. Some of these are as unstable as Hb Agrinio and their presence is difficult to detect except by DNA sequencing. PMID- 23094636 TI - Influence of BCL11A, HBS1L-MYB, HBBP1 single nucleotide polymorphisms and the HBG2 XmnI polymorphism On Hb F levels. AB - In search of genetic alterations responsible for high fetal hemoglobin (Hb F) phenotypes in the population of eastern India, 91 probands were screened for four polymorphisms by sequencing and/or restriction fragment length polymorphism (RFLP) analysis. These are the A>G allele on the rs4895441 locus in the intergenic region between HBS1L and MYB on chromosome 6, the G>A allele on the rs4671393 locus on chromosome 2 (BCL11A gene), the A>C allele on the rs2071348 (HBBP1 gene) and the XmnI polymorphism (rs7482144, -158 position of HBG2) on chromosome 11. We found a significant association (p = 0.002 and 0.0013) of Hb F levels with rs2071348 and rs4895441, respectively. However, the polymorphism rs4671393 gene did not show significant association with Hb F levels (p = 0.0655). As is well known, the XmnI polymorphism (p <0.0001) showed the strongest association. PMID- 23094637 TI - Two assays to evaluate potential genotoxic effects of hydroxyurea in sickle cell disease patients. AB - Hydroxycarbamide, well known in clinical settings as hydroxyurea (HU), is an antineoplastic agent inhibiting the ribonucleotide reductase enzyme, and thus, the conversion of ribonucleotides into deoxyribonucleotides. A concern about long term side effects of HU treatment in sickle cell disease patients, particularly genotoxicity, has often been evoked. The present study assessed two suitable methods to evaluate oxidative DNA damage associated with HU: the comet assay on blood lymphocytes and the quantification of urinary excretion of 8 oxodeoxyguanosine (8-oxodG). Both methods were applied in a preliminary study including seven sickle cell disease patients treated with HU, seven untreated sickle cell disease patients and five healthy volunteers. Concerning DNA damage, the comet assay and the 8-oxodG assay did not reveal any significant differences among the three groups. Methodologies used in this pilot study could be suitable to carry out further research in this area including a larger size sample setting. PMID- 23094638 TI - The effects of telmisartan and amlodipine in treatment-naive and previously treated hypertensive patients: a subanalysis from a 4 * 4 factorial design study. AB - The subanalysis of a 4 * 4 factorial, 8-week study to evaluate the efficacy and tolerability of telmisartan (T) 40-80 mg/amlodipine (A) 5-10 mg used in treatment naive patients (n = 231) and patients previously treated with antihypertensive agents (n = 880). Similar blood pressure (BP) reductions were achieved with T + A, regardless of their pretreatment status. Highest reductions were achieved with T80 + A10 (treatment-naive -26.5/-18.2 mm Hg and previously treated -25.6/-19.9 mm Hg). Most patients (treatment-naive 72.4% and previously treated 77.6%), including those with added risk, achieved BP goal (<140/90 mm Hg) with T80 + A10. Tolerability was comparable in both groups. PMID- 23094639 TI - Pharmacokinetics of new oral hepatitis C antiviral drugs. AB - INTRODUCTION: Approximately 175 million people worldwide are chronically infected with the hepatitis C virus (HCV), representing 3% of the total world population. Until recently, the only available therapeutic option for these patients was the combination of pegylated IFN-alpha plus ribavirin that overall resulted in HCV eradication in less than a half of cases. The development of new therapies with greater efficacy has been eagerly awaited but new challenges have emerged, with drug interactions being among the most challenging. AREAS COVERED: This review updates the main pharmacokinetic and pharmacodynamic characteristics of the most promising new oral direct-acting antivirals (DAA) for hepatitis C. Given that a large proportion of chronic hepatitis C patients receive other medications, drug interactions are further discussed. EXPERT OPINION: The recent approval of the first HCV genotype 1 protease inhibitors is a landmark step in the fight against the HCV pandemic. The benefit of higher rates of response along with shorter duration of treatment is counterbalanced by significant drug interactions and unprecedented complexities in the use of these drugs and management of their side effects. The knowledge of key pharmacologic parameters of distinct DAA is important for care providers in charge of chronic hepatitis C patients as it will avoid the danger of unexpected drug interactions. This concern must be particularly emphasized in special group populations, such as in HIV-HCV coinfected individuals and transplant patients, in whom interactions between DAA and antiretrovirals or immunosuppressants, respectively, are frequent. PMID- 23094640 TI - Evaluation of drug-induced injury and human response in precision-cut tissue slices. AB - 1.Drug induced organ injury is multifaceted, encompassing a spectrum of cell types and numerous networks reflecting cell-cell and cell-matrix interactions. Characterization of drug induced side effects and human response can be addressed in organ slice models. 2.The application of human tissue to various organ slice models including liver, intestine, kidney, liver-blood co-cultures and thyroid enhances our ability to focus on the clinical relevance of side effects identified in animal studies for human, and to evaluate potential biomarkers of the side effects. Dose-response relationships can help discern drug concentrations which alter organ function or affect morphology, to identify drug concentrationswhich could pose a risk for humans. 3.Insight into pathways of organ injury, by incorporating gene and protein expression profiling, with functional measurements and morphology, aid to define species differences and sensitivity. 4.Human organ slice studies are valuable for bridging the extrapolation of animal derived data and for identifying mechanisms relevant for humans, thereby expanding the scope of translational research for drug safety assessment. PMID- 23094641 TI - Stress among healthcare students--a cross disciplinary perspective. AB - BACKGROUND AND PURPOSES: Perceived stress (PS) among healthcare students worldwide is a recognized problem. To address the paucity of data about the actual degree of PS, this study aimed to: 1) evaluate and compare PS across three healthcare programs (Physical Therapy [PT], Communication Disorders [CD], and Nutrition Sciences [NS]) in one university; 2) evaluate changes in PS across study years; 3) identify the contribution of academic- and socio-demographic related variables to PS; and 4) determine whether the Israeli students' PS levels differ from those of their peers in other countries. METHODS: A cross-sectional survey was performed among all undergraduate PT, CD, and NS students from one university. Data were collected using anonymous questionnaires. Instruments included the Perceived Stress Scale 10 (PSS) and the Undergraduate Sources of Stress (USOS). ANOVA was used to evaluate the differences between the three programs, and regression analysis to evaluate the contribution of socio demographic factors to PS and USOS. RESULTS: A total of 312 students (PT--154; CD -92; NS--66) participated in the study. Mean PSS (range: 13.5-13.6) was similar in the three programs. The USOS academic factor was the most reported source of stress in all programs. Most socio-demographic variables were not related to either PS or USOS. CONCLUSIONS: Students from PT, CD, and NS programs perceived similar levels of stress. The academic factor was perceived as the most important source of stress by students from the three departments, despite differences in the academic educational programs. Further studies are needed to generalize these results and enable a comparison between healthcare students and other students' stress perceptions. PMID- 23094642 TI - Changing conceptions of teaching in medical faculty. AB - BACKGROUND: The Association of American Medical Colleges and Howard Hughes Medical Institute have urged medical faculty to develop in themselves, and in their students, habits of critical professional inquiry, while stressing the importance of integrating formal learning with hands-on, practical experience. AIMS: This study describes the impact of a year-long faculty development program on conceptions of teaching held by 16 faculty in a medical school affiliated with a large private Midwestern research university. METHOD: Using pre and post semi structured interviews, researchers identified three conceptions of teaching - transmission, acquisition, and engagement - found in participants, comparing how participants' conceptions changed by the end of the program. RESULTS: Researchers found that 13 out of 16 (81%) faculty developed or maintained a more complex understanding of teaching by the end of the program. CONCLUSIONS: This study recommends that faculty developers (1) encourage their faculty to reflect substantially on what it means to teach - with the goal of assisting faculty to move beyond the idea of teaching as transmission or even as acquisition, to conceiving it as helping their students ask deep questions and make conceptual connections for themselves; (2) help faculty understand that developing a more complex understanding of teaching is as crucial to their professional development as developing their research and clinical skills; and (3) provide substantial opportunities for participants to explore teaching and learning as an evidence based practice with colleagues and students. PMID- 23094643 TI - My first biliary colic patient. PMID- 23094645 TI - Role of the electric field affected zone (EFAZ) on the electrophoretic deposition of TiO2 nanoparticles under symmetric low-frequency AC electric fields. AB - In the present study, electrophoretic deposition (EPD) of TiO(2) nanoparticles under the application of symmetric AC fields was investigated. In the first step, EPD of TiO(2) nanoparticles under a DC field at 50 V resulted in the particles' deposition on one electrode, consistent with conventional EPD principles. However, no deposits were formed on any of the electrode surfaces for symmetric sinusoidal waves at 1 Hz. In this case, enhancing the electric field strength through the application of higher potentials was considered to extend the electric field affected zone (EFAZ) in front of the electrode, increasing the particles' opportunity to deposit. A kinetic model was then derived based on the Hamaker approach to calculate the deposited mass under an AC electric field. Although this model was found to be in agreement with experimental results at 1 Hz above 200 V, some deviation was detected at lower voltages. This trend shows that there is a threshold field strength below which EFAZ is not wide enough to let particles deposit under an AC electric field. PMID- 23094644 TI - Dss1 release activates DNA binding potential in Brh2. AB - Dss1 is an intrinsically unstructured polypeptide that partners with the much larger Brh2 protein, the BRCA2 ortholog in Ustilago maydis, to form a tight complex. Mutants lacking Dss1 have essentially the same phenotype as mutants defective in Brh2, implying that through physical interaction Dss1 serves as a positive activator of Brh2. Dss1 associates with Brh2 through an interaction surface in the carboxy-terminal region. Certain derivatives of Brh2 lacking this interaction surface remain highly competent in DNA repair as long as a DNA binding domain is present. However, the Dss1-independent activity raises the question of what function might be met in the native protein by having Brh2 under Dss1 control. Using a set of Brh2 fusions and truncated derivatives, we show here that Dss1 is capable of exerting control when there is a cognate Dss1-interacting surface present. We find that association of Dss1 attenuates the DNA binding potential of Brh2 and that the amino-terminal domain of Brh2 helps evict Dss1 from its carboxy-terminal interaction surface. The findings presented here add to the notion that Dss1 serves in a regulatory capacity to dictate order in association of Brh2's amino-terminal and carboxy-terminal domains with DNA. PMID- 23094647 TI - Discovery of spin glass behavior in Ln2Fe4Sb5 (Ln = La-Nd and Sm). AB - Single crystals of Ln(2)Fe(4)Sb(5) (Ln = La-Nd and Sm) were grown from an inert Bi flux. Measurements of the single crystal X-ray diffraction revealed that these compounds crystallize in the tetragonal space group I4/mmm with lattice parameters of a ~ 4 A, c ~ 26 A, V ~ 500 A(3), and Z = 2. This crystal structure consists of alternating LnSb(8) square antiprisms and Fe-sublattices composed of nearly equilateral triangles of bonded Fe atoms. These compounds are metallic and display spin glass behavior, which originates from the magnetic interactions within the Fe-sublattice. Specific heat measurements are void of any sharp features that can be interpreted as contributions from phase transitions as is typical for spin glass systems. A large, approximately linear in temperature, contribution to the specific heat of La(2)Fe(4)Sb(5) is observed at low temperatures that we interpret as having a magnetic origin. Herein, we report the synthesis, structure, and physical properties of Ln(2)Fe(4)Sb(5) (Ln = La-Nd and Sm). PMID- 23094646 TI - Total synthesis of alotaketal A. AB - The total synthesis of the cAMP signaling pathway activator (-)-alotaketal A is reported. A convergent approach to the unusual alotane sesterterpenoid skeleton was employed, exploiting a remarkable LiDBB-mediated coupling of an (R)-carvone derived delta-lactone with an allyl bromide side chain, followed by spiroacetalization. PMID- 23094648 TI - On the suitability of steady RANS CFD for forced mixing ventilation at transitional slot Reynolds numbers. AB - Accurate prediction of ventilation flow is of primary importance for designing a healthy, comfortable, and energy-efficient indoor environment. Since the 1970s, the use of computational fluid dynamics (CFD) has increased tremendously, and nowadays, it is one of the primary methods to assess ventilation flow in buildings. The most commonly used numerical approach consists of solving the steady Reynolds-averaged Navier-Stokes (RANS) equations with a turbulence model to provide closure. This article presents a detailed validation study of steady RANS for isothermal forced mixing ventilation of a cubical enclosure driven by a transitional wall jet. The validation is performed using particle image velocimetry (PIV) measurements for slot Reynolds numbers of 1000 and 2500. Results obtained with the renormalization group (RNG) k-epsilon model, a low Reynolds k-epsilon model, the shear stress transport (SST) k-omega model, and a Reynolds stress model (RSM) are compared with detailed experimental data. In general, the RNG k-epsilon model shows the weakest performance, whereas the low Re k-epsilon model shows the best agreement with the measurements. In addition, the influence of the turbulence model on the predicted air exchange efficiency in the cubical enclosure is analyzed, indicating differences up to 44% for this particular case. PRACTICAL IMPLICATIONS: This article presents a detailed numerical study of isothermal forced mixing ventilation driven by a low-velocity (transitional) wall jet using steady computational fluid dynamics (CFD) simulations. It is shown that the numerically obtained room airflow patterns are highly dependent on the chosen turbulence model and large differences with experimentally obtained velocity fields can be present. The renormalization group (RNG) k-epsilon model, which is commonly used for room airflow modeling, shows the largest deviations from the measured velocities, indicating the care that must be taken when selecting a turbulence model for room airflow prediction. As a result of the different predictions of the flow pattern in the room, large differences are present between the predicted air exchange efficiency obtained with the four tested turbulence models, which can be as high as 44%. PMID- 23094649 TI - Mood, anxiety, and substance-use disorders and suicide risk in a military population cohort. AB - There are meager prospective data from nonclinical samples on the link between anxiety disorders and suicide or the extent to which the association varies over time. We examined these issues in a cohort of 309,861 U.S. Air Force service members, with 227 suicides over follow-up. Mental disorder diagnoses including anxiety, mood, and substance-use disorders (SUD) were based on treatment encounters. Risk for suicide associated with anxiety disorders were lower compared with mood disorders and similar to SUD. Moreover, the associations between mood and anxiety disorders with suicide were greatest within a year of treatment presentation. PMID- 23094650 TI - Model-based analysis of skin conductance responses: Towards causal models in psychophysiology. AB - The empirical investigation of unobservable psychological processes usually rests on operational definitions. As an alternative, we propose the use of explicit causal models. This is particularly useful in psychophysiology, where formal models can be expressed mathematically, exploiting biophysical constraints, and inverted to yield estimates of unobservable processes. In psychophysiology, recent advances have been made in causal modeling for skin conductance responses, which we discuss to exemplify the development of such models. Empirical evidence suggests that these methods have a greater validity compared to operational approaches. This review concludes by considering the theoretical implications for the field of psychophysiology and benefits for practical data analysis. PMID- 23094651 TI - Improving the selectivity of antimicrobial peptides from anuran skin. AB - Anuran skin is known to be a rich source of antimicrobial peptides although their therapeutic potential is often limited due to their toxicity against mammalian cells. The analysis of structure-activity relationships among anuran antimicrobial peptides provided the parameters to construct the "Mutator" tool for improving their selectivity for bacterial cells, by suggesting appropriate point substitutions. Double substitution analogues [K2, K16] of the Xenopus tropicalis peptide XT-7 and [I2, K19] of the Ascaphus truei peptide ascaphin-8 were predicted by this tool to have an increased 'therapeutic index' (TI = HC(50)/MIC for erythrocytes with respect to bacteria) > 80. The mutated peptides were synthesized and respectively found to have experimental TI values > 130 for S. aureus or E. coli, a considerable improvement with respect to TI < 37 for the parent compounds. Circular dichroism studies of the mutated peptides suggested this may in part be due to variations in the alpha-helical structure. For P. aeruginosa, which is more resistant to XT-7, the TI increased in the mutated peptide from 5 to >270, also due to a significant improvement in minimal inhibitory concentration. We have shown that the Mutator tool is capable of suggesting limited variations in natural anuran peptides capable of increasing peptide selectivity, by decreasing toxicity against mammalian erythrocytes, in general without compromising antibacterial activity. The tool is freely available on the Mutator Web server at http://split4.pmfst.hr/mutator/. PMID- 23094652 TI - Ultrasound imaging of embedded shrapnel facilitates diagnosis and management of myofascial pain syndrome. AB - Trigger points can result from a variety of inciting events including muscle overuse, trauma, mechanical overload, and psychological stress. When the myofascial trigger points occur in cervical musculature, they have been known to cause headaches. Ultrasound imaging is being increasingly used for the diagnosis and interventional management of various painful conditions. A veteran was referred to the pain clinic for management of his severe headache following a gunshot wound to the neck with shrapnel embedded in the neck muscles a few years prior to presentation. He had no other comorbid conditions. Physical examination revealed a taut band in the neck. An ultrasound imaging of the neck over the taut band revealed the deformed shrapnel located within the levator scapulae muscle along with an associated trigger point in the same muscle. Ultrasound guided trigger point injection, followed by physical therapy resolved his symptoms. This is a unique report of embedded shrapnel and coexisting myofascial pain syndrome revealed by ultrasound imaging. The association between shrapnel and myofascial pain syndrome requires further investigation. PMID- 23094653 TI - The relationship between variable host grouping and functional responses among parasitoids of Antispila nysaefoliella (Lepidoptera: Heliozelidae). AB - Our study investigated the importance of variability in the parasitoid community as a source of selection on host group size using a field population of the tupelo leafminer, Antispila nysaefoliella Clemens, which specializes on tupelo, Nyssa sylvatica Marsh. Larvae were collected from leaves with variable numbers of larvae and screened for parasitism using polymerase chain reaction of mitochondrial cytochrome oxidase I using markers designed specifically for amplifying parasitoid DNA while excluding host DNA. This method of selective PCR was effective for detecting the presence and identifying species of immature stages of three hymenopteran superfamilies: Chalcidoidea, Ichneumonoidea and Platygastroidea, which represented 83.4%, 16.0% and 0.6% of the total detectable parasitism, respectively. Our resulting sequences were then calibrated with sequences from identified adult parasitoids that had been either reared or field captured. A cluster analysis revealed 10 distinct clades that showed differences in attack patterns with respect to host traits and season. Total parasitism followed an inverse density-dependent or density-independent pattern with respect to host density (number per leaf). However, when parasitoid taxa were considered separately, one clade, which could be a cryptic species of Pnigalio maculipes Crawford (Chalcidoidea: Eulophidae), was found to increase its per leaf attack rate with host density. Our results suggest that parasitoid community composition and differences among species in their attack strategies can play a large role in determining the adaptive advantage of host grouping. PMID- 23094654 TI - The use of radiography and the apex locator in endodontic treatment within the UK: a comparison between endodontic specialists and general dental practitioners. AB - AIM: To investigate the attitudes of general dental practitioners (GDPs) and specialist endodontists working in the UK in the use of radiography and apex locators during root canal treatment and to see if use was related to respondent's age and the year of graduation. METHODOLOGY: A postal questionnaire was sent to 857 randomly selected GDPs and all endodontic specialists working in the UK (170). Non-responders were sent a further two mailings. Chi-squared tests were used to compare both groups at the P < 0.05 level of significance. For nonparametric data, the Mann-Whitney U test was employed. RESULTS: The overall response rate was 73%. There were significant differences between endodontic specialists and GDPs in the prescription of the preoperative, the cone-fit and the postoperative radiograph. A total of 114 (86.4%) endodontic specialists and 321 (53.2%) GDPs reported using an apex locator (P < 0.001). Eighty-eight (66.7%) endodontists and 217 (36%) GDPs used an apex locator and a radiograph to determine the working length for a single-rooted tooth (P < 0.001). For multi rooted teeth, 91 (68.9%) endodontists and 229 (38%) GDPs used a combined approach of an electronic apex locator and a working-length radiograph (P < 0.001). One millimetre short of the radiographic apex was employed by 56.2% of respondents as the apical limit. There were significant differences (P < 0.001) between the two groups with regard to routine radiographic follow-up. CONCLUSIONS: Both endodontists and GDPs were found to be observing national guidelines when performing root canal treatment. Greater use of apex locators was found amongst endodontists who tended to use a combined approach of an apex locator and periapical radiography. PMID- 23094655 TI - Flow-directed assembly of block copolymer vesicles in the lab-on-a-chip. AB - We demonstrate a microfluidic approach to the production of block copolymer vesicles via flow-directed self-assembly in a segmented gas-liquid device. Chemical conditions that favor spherical micelles in the bulk are found to yield a nearly pure population of vesicles on a chip-a transformation of two full morphological steps-because of a coalescence mechanism enabled by high shear. The production of polymeric vesicles via top-down control in a microfluidic device enables new processing routes to applications including drug delivery formulations in the lab-on-a-chip. PMID- 23094658 TI - Export of cyst wall material and Golgi organelle neogenesis in Giardia lamblia depend on endoplasmic reticulum exit sites. AB - Giardia lamblia parasitism accounts for the majority of cases of parasitic diarrheal disease, making this flagellated eukaryote the most successful intestinal parasite worldwide. This organism has undergone secondary reduction/elimination of entire organelle systems such as mitochondria and Golgi. However, trophozoite to cyst differentiation (encystation) requires neogenesis of Golgi-like secretory organelles named encystation-specific vesicles (ESVs), which traffic, modify and partition cyst wall proteins produced exclusively during encystation. In this work we ask whether neogenesis of Golgi-related ESVs during G. lamblia differentiation, similarly to Golgi biogenesis in more complex eukaryotes, requires the maintenance of distinct COPII-associated endoplasmic reticulum (ER) subdomains in the form of ER exit sites (ERES) and whether ERES are also present in non-differentiating trophozoites. To address this question, we identified conserved COPII components in G. lamblia cells and determined their localization, quantity and dynamics at distinct ERES domains in vegetative and differentiating trophozoites. Analogous to ERES and Golgi biogenesis, these domains were closely associated to early stages of newly generated ESV. Ectopic expression of non-functional Sar1 GTPase variants caused ERES collapse and, consequently, ESV ablation, leading to impaired parasite differentiation. Thus, our data show how ERES domains remain conserved in G. lamblia despite elimination of steady-state Golgi. Furthermore, the fundamental eukaryotic principle of ERES to Golgi/Golgi-like compartment correspondence holds true in differentiating Giardia presenting streamlined machinery for secretory organelle biogenesis and protein trafficking. However, in the Golgi-less trophozoites ERES exist as stable ER subdomains, likely as the sole sorting centres for secretory traffic. PMID- 23094659 TI - The protective effects of 6-CySeCD with GPx activity against UVB-induced injury in HaCaT cells. AB - BACKGROUND: The generation of harmful reactive oxygen species (ROS) induced by UVB irradiation could induce cell apoptosis and change the cell cycle. 6A,6A' dicyclohexylamine-6B,6B'-diselenide-bis-beta-cyclodextrin (6-CySeCD) is a novel glutathione peroxidase (GPx; EC 1.11.1.9) mimic. The aim of this study was to investigate the anti-oxidative effects of 6-CySeCD in cultured immortalised human keratinocyte cells (HaCaT). METHODS: HaCaT cells were treated with 30 mJ/cm(2) UVB to establish a damage model. The cultured HaCaT cells were randomly assigned to the control, UVB and treatment groups. The treatment group was incubated with 20 MUmol/L of GPx mimics before UVB irradiation. Cell viability was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the level of lipid peroxidation was determined by the formation of malondialdehyde (MDA), DNA fragmentation was observed using agarose gel electrophoresis and the levels of intracellular ROS and cell cycle progression were measured by flow cytometry. RESULTS: The levels of cytotoxicity, intracellular ROS, lipid peroxidation and oxidative DNA damage significantly increased after UVB irradiation in the HaCaT cells. UVB irradiation caused pre-G1 -phase arrest in HaCaT cells and significantly reduced the number of HaCaT cells in the S phase. The GPx mimics 6 CySeCD and 2-phenyl-l,2-benzisoselenazol-3(2H)-one (ebselen) significantly blocked UVB-induced apoptosis and changed the cell cycle of the HaCaT cells. The blocked effect of pretreatment 6-CySeCD in UVB-irradiated HaCaT cells was better than that of pretreatment with ebselen. CONCLUSION: 6-CySeCD can relieve the damage induced by UVB irradiation in HaCaT cells. PMID- 23094660 TI - Transition metal photoredox catalysis of radical thiol-ene reactions. AB - We describe the anti-Markovnikov hydrothiolation of olefins using visible-light absorbing transition metal photocatalysts. The key thiyl radical intermediates are generated upon quenching of photoexcited Ru*(bpz)3(2) with a variety of thiols. The adducts of a wide variety of olefins and thiols are formed in excellent yield (73-99%). PMID- 23094662 TI - Supraorbital neuralgia caused by nerve entrapment visualized on ultrasonography. PMID- 23094661 TI - Reduction of intestinal mucosal immune function in heat-stressed rats and bacterial translocation. AB - PURPOSE: The aim of this study was to further understand the effects and mechanism of heat stress on the intestinal mucosal immune system of the rat, including changes in the intestinal mucosal barrier and immune function and their effects on bacterial translocation. MATERIALS AND METHODS: Sprague Dawley (SD) rats were randomly divided into control and heat-stress groups. Both groups were housed in a 25 degrees C environment of 60% relative humidity. The heat-stress group was subjected to 40 degrees C for 2 h daily over 3 days. RESULTS: Compared with the control group villi length in the small intestines of the heat-stress group was shortened. Jejunal mucosa were seriously damaged and the number of goblet cells in the epithelia of the duodenum and jejunum was significantly reduced. Electron microscopy revealed intestinal mucosal disorder, a large number of exudates of inflammatory fibrous material, fuzzy tight junction structure between epithelial cells, and cell gap increases in the heat-stress group. Transcription of IFN-gamma, IL-2, IL-4, and IL-10, was significantly reduced, as was that of the intestinal mucosal immune-related proteins TLR2, TLR4, and IgA. The number of CD3(+) T cells and CD3(+)CD4(+)CD8(-) T cells in the mesenteric lymph nodes (MLNs) was significantly lower, while the number of CD3(+)CD4( )CD8(+) T cells was significantly increased. The bacteria isolated from the MLNs were Escherichia coli. CONCLUSIONS: Heat stress damages rat intestinal mechanical and mucosal immune barriers, and reduces immune function of the intestinal mucosa and mesenteric lymphoid tissues, leading to bacterial translocation. PMID- 23094663 TI - The search for in vitro systems. (preface). PMID- 23094664 TI - Analysis of retinal ganglion cell complex thickness after Brilliant Blue-assisted vitrectomy for idiopathic macular holes. AB - PURPOSE: The purpose of this study was to evaluate retinal ganglion cell complex (GCC) thickness changes in eyes undergoing Brilliant Blue-assisted macular hole surgery (MHS) using Fourier-domain optical coherence tomography (FD-OCT). MATERIALS AND METHODS: This is a prospective, comparative, and observational case series of 70 eyes in 70 consecutive patients with idiopathic macular holes who underwent vitrectomy between December 2010 and October 2011. The study group consisted of 44 eyes in 44 patients, who underwent MHS with Brilliant Blue assisted internal limiting membrane (ILM) peeling; 26 eyes in 26 patients, who underwent MHS without ILM peeling, constituted the control group. In both groups, complete ophthalmologic examinations and quantitative analysis of the GCC and retinal nerve fiber layer (RNFL) thicknesses were performed before and after the procedures using OCT. The findings from both groups were compared. RESULTS: Six months after surgery, the rate of closure of macular holes evaluated by OCT was 80.7% in the control group and 97% in the study group. There was no significant difference between preoperative and postoperative GCC and RNFL thickness values in both groups. CONCLUSIONS: No significant decrease was observed in the thickness values of the retinal GCC and RNFL after Brilliant Blue-assisted ILM peeling for MHS. Therefore, this surgical procedure can be performed safely for the treatment of macular holes. PMID- 23094668 TI - Individual differences in the encoding processes of egocentric and allocentric survey knowledge. AB - This study examined how different components of working memory are involved in the acquisition of egocentric and allocentric survey knowledge by people with a good and poor sense of direction (SOD). We employed a dual-task method and asked participants to learn routes from videos with verbal, visual, and spatial interference tasks and without any interference. Results showed that people with a good SOD encoded and integrated knowledge about landmarks and routes into egocentric survey knowledge in verbal and spatial working memory, which is then transformed into allocentric survey knowledge with the support of all three components, distances being processed in verbal and spatial working memory and directions in visual and spatial working memory. In contrast, people with a poor SOD relied on verbal working memory and lacked spatial processing, thus failing to acquire accurate survey knowledge. Based on the results, a possible model for explaining individual differences in spatial knowledge acquisition is proposed. PMID- 23094667 TI - Voronoff to virion: 1920s testis transplantation and AIDS. AB - BACKGROUND: We address accusations linking AIDS with testis transplantation performed by a French surgeon, Serge Voronoff (1866-1951), and their implications in the future of animal-to-human organ transplantation. METHODS: Biographical literature on Voronoff and scientific literature on xenotransplantation and the origin of HIV were reviewed. RESULTS: IN the 1920s, Serge Voronoff transplanted testes from primates into humans to revitalize them sexually and physically, making him one of the first surgeons to perform xenotransplantation-transplanting live tissues between species. In recent years, some have postulated that Voronoff's transplants may have caused or contributed to the AIDS epidemic. However, consensus among virologists holds that HIV most likely originated from a chimpanzee virus known as simian immunodeficiency viruses (SIV) which many agree was transmitted to humans during the hunting of primates in the early 1900s. As these accusations have never been addressed, evidence is reviewed which refutes the claims. HIV isolate studies are summarized, which show that SIV was most likely transferred to humans from a chimpanzee species different from those used by Voronoff. Furthermore, literature suggests that Voronoff's experiments were performed in Europe and the United States, not central Africa. CONCLUSIONS: Over 100,000 people await organ transplants, making the prospect of using animal organs to meet demand increasingly favorable. The accusations against Voronoff and others have led to increased concern over cross-species disease transfer. The evidence presented refutes those claims and is used to explain the need for further research into xenotransplantation. PMID- 23094669 TI - From 1D chain to 3D framework uranyl diphosphonates: syntheses, crystal structures, and selective ion exchange. AB - In this work, we demonstrate a family of new inorganic-organic hybrid uranyl diphosphonates based on 1-hydroxyethylidenediphosphonic acid (H(4)L) linker by using hydrothermal method. These compounds, (Hbpi)[(UO(2))(H(2)O)(HL)].H(2)O (UP 1), represents 1D structure, (Hbpi)[(UO(2))(H(2)O)(HL)] (UP-2), (H(2)dib)(0.5)[(UO(2))(H(2)O)(HL)] (UP-3), and [(UO(2))(H(2)O)(H(2)L)].2H(2)O (UP 4) feature 2D architectures, (H(2)bipy){[(UO(2))(H(2)O)](2)[(UO(2))(H(2)O)(2)](L)(2)}.2H(2)O (UP-5), and (H(3)O)(2){[(UO(2))(H(2)O)](3)(L)(2)}.2H(2)O (UP-6) adopt 3D networks (bpi: 1 (biphenyl-4-yl)-1H-imidazole, dib: 1,4-di(1H-imidazol-1-yl)benzene, bipy: 2,2' bipyridine). Among them, UP-1, UP-2, UP-3, and UP-4 possess the same structural building unit but with different structures. UP-5 and UP-6 feature the same UO(2)/L ratio of 3:2 but a different structural building unit. Photoluminescence studies reveal that UP-5 displays characteristic emissions of uranyl cations. Ion exchange experiments demonstrate that the H(3)O(+) in UP-6 can be easily and selectively exchanged by monovalent cations including Na(+), K(+), Cs(+), and Ag(+) cations, whereas the framework retains identical as confirmed by single crystal X-ray diffractions. PMID- 23094670 TI - The van der Waals interactions in sphere-shell and cone-shell configurations. AB - This work introduces two expressions for the integration of the van der Waals interactions in geometries that are relevant to determining oil solubilization in micelles and the interaction among surfactants in micelles. The first integral applies to the interaction between a sphere and a spherical shell that surrounds the sphere. The second integral calculates the interaction between a truncated cone and the rest of a spherical shell that contains the cone. The new sphere shell integration method was validated via a comparison between fully predicted and experimental surface tensions of alkanes at room temperature and reproduced the near zero surface tension values that are obtained close to the critical point. The cone-shell integration method was validated, in association with the sphere-shell expression, using a comparison between predicted and experimental cohesive energies for alkanes. PMID- 23094672 TI - Planar chirality change in dediazoniation reactions of paracyclophanes and mechanistic implication. AB - Dediazoniation reactions of (S(p))-4-bromo-13-[2.2]paracyclophanyldiazonium fluoborate 2a through a heterolytic cleavage process gave products with partial racemization. In contrast, dediazoniation reactions of (S(p))-2a undergoing a nonheterolytic cleavage process afforded products with retention of configuration. A key intermediate, the bromonium cation B, caused the racemization. The unexpected racemization allowed the mechanisms of the dediazoniation reaction to be probed. PMID- 23094671 TI - Computed tomography-guided transgluteal percutaneous nephrolithotripsy in an ectopic pelvic kidney: novel technique. AB - BACKGROUND AND PURPOSE: Management of stones in the ectopic pelvic kidney can be very challenging. Treatment of each patient should be individualized. We describe a new approach that is CT-guided transgluteal percutaneous nephrolithotripsy (PCNL). CASE AND TECHNIQUE: A 19-year-old male presented with symptomatic right ectopic pelvic kidney stones. He was treated with CT-guided transgluteal PCNL. The patient was stone free at postoperative day 1. No major complications were observed, and the patient was discharged home on postoperative day 2. CONCLUSION: CT-guided transgluteal PCNL is a safe and effective option for selected patients with ectopic pelvic kidney stones. PMID- 23094673 TI - Abstracts of the XXXI Congress of the European Academy of Allergy and Clinical Immunology. Geneva, Switzerland. June 16-20, 2012. PMID- 23094674 TI - High gene flow on a continental scale in the polyandrous Kentish plover Charadrius alexandrinus. AB - Gene flow promotes genetic homogeneity of species in time and space. Gene flow can be modulated by sex-biased dispersal that links population genetics to mating systems. We investigated the phylogeography of the widely distributed Kentish plover Charadrius alexandrinus. This small shorebird has a large breeding range spanning from Western Europe to Japan and exhibits an unusually flexible mating system with high female breeding dispersal. We analysed genetic structure and gene flow using a 427-bp fragment of the mitochondrial (mtDNA) control region, 21 autosomal microsatellite markers and a Z microsatellite marker in 397 unrelated individuals from 21 locations. We found no structure or isolation-by-distance over the continental range. However, island populations had low genetic diversity and were moderately differentiated from mainland locations. Genetic differentiation based on autosomal markers was positively correlated with distance between mainland and each island. Comparisons of uniparentally and biparentally inherited markers were consistent with female-biased gene flow. Maternally inherited mtDNA was less structured, whereas the Z-chromosomal marker was more structured than autosomal microsatellites. Adult males were more related than females within genetic clusters. Taken together, our results suggest a prominent role for polyandrous females in maintaining genetic homogeneity across large geographic distances. PMID- 23094676 TI - Simvastatin induces osteogenic differentiation in human amniotic fluid mesenchymal stem cells (AFMSC). AB - Amniotic fluid is a complex mixture composed of water, salts and different cells types derived from embryo exfoliation. Some of these cells present similar characteristics to mesenchymal stem cells as adherent properties, typical surface antigens and differentiation capacity. These cells are called amniotic fluid derived mesenchymal stem cells (AFMSCs) and are easily obtained by amniocentesis, propagated in culture and differentiated in several cell types with specific inductions. In this study, we observe the ability of simvastatin, a 3-HMG-CoA reductase inhibitor, to induce AFSMCs osteogenic differentiation. When AFSMCs were incubated with medium containing simvastatin, it was observed morphological changes, calcium deposits formation confirmed by Alizarin Red stain. Differentiated cells also expressed typical osteogenic genes, as osteopontin and osteocalcin. In conclusion, simvastatin could be used as an optional osteogenic induction agent for amniotic fluid-derived mesenchymal stem cells. PMID- 23094675 TI - Patient satisfaction in an academic chronic pain clinic. AB - OBJECTIVES: Patient perception of healthcare quality is of growing interest. It has been shown that patient satisfaction is associated with compliance with medical advice and clinical outcome. The 3-fold purpose of this study was to identify which attributes of the patient-physician interaction most strongly correlated with patients' perceptions of provider quality of care, to identify key drivers that move patients' perception of overall provider quality from "very good" to "excellent," and to identify features of the pain clinic experience that were most important to patients but were simultaneously perceived as lacking. METHODS: Randomized patient satisfaction survey conducted via telephone approximately 3 weeks after the patient's pain clinic visit. RESULTS: A total of 999 patients participated in the survey over 5 years (estimated response rate 60.2%). Thoroughness, listening, and time spent with the provider were the 3 attributes most strongly associated with the patients' perceptions of provider quality of care, while thoroughness, listening, punctuality, and clear instructions were the drivers of "very good" vs. "excellent" patient perceived overall provider quality. Areas identified for clinic improvement include thoroughness, providing adequate explanations and instructions, and including patient preferences in decision making. CONCLUSIONS: These results may guide pain clinic physicians as they seek to improve patient perceptions of their care and ultimately patient outcomes. PMID- 23094679 TI - Dissociation of membrane-anchored heterotrimeric G-protein induced by G(alpha) subunit binding to GTP. AB - Heterotrimeric G-proteins' activation on the intracellular side of the cell membrane is initiated by stimulation of the G-Protein Coupled Receptors (GPCRs) extra-cellular part. This two-step activation mechanism includes (1) an exchange between GDP and GTP molecules in the G(alpha) subunit and (2) a dissociation of the whole G(alphabetagamma) complex into two membrane-anchored blocks, namely the isolated G(alpha) and G(betagamma) subunits. Although X-ray data are available for both inactive G(alphabetagamma):GDP and active G(alpha):GTP complexes, intermediate steps involved in the molecular mechanism of the dissociation have not yet been addressed at the molecular level. In this study, we first built a membrane-anchored intermediate G(ialphabetagamma):GTP complex. This model was then equilibrated by molecular dynamics simulations before the Targeted Molecular Dynamics (TMD) technique was used to force the G(alpha) subunit to evolve from its inactive (GDP-bound) to its active (GTP-bound) conformations, as described by available X-ray data. The TMD constraint was applied only to the G(alpha) subunit so that the resulting global rearrangements acting on the whole G(alphabetagamma):GTP heterotrimer could be analyzed. We showed how these mainly local conformational changes of G(alpha) could initiate large domain:domain motions of the whole complex, the G(betagamma) behaving as an almost quasi-rigid block. This separation of the two G(alpha):GTP and G(betagamma) subunits required the loss of several interactions at the G(alpha):G(betagamma) interface that were reported. This study provided an atomistic view of the crucial intermediate step of the G-proteins activation, e.g., the dissociation, that could hardly be elucidated by the experiment. PMID- 23094678 TI - Effect of predictive cuing on response inhibition in children with heavy prenatal alcohol exposure. AB - BACKGROUND: Heavy prenatal exposure to alcohol leads to widespread cognitive deficits, including problems with attention and response inhibition. This study examined blood oxygen level-dependent response in children with and without histories of heavy prenatal alcohol exposure during a task of response inhibition consisting of cued and noncued trials. METHODS: Children and adolescents (ages 8 to 18 years) with (alcohol-exposed [AE] = 20) and without (control [CON] = 15) histories of heavy prenatal exposure to alcohol underwent functional magnetic resonance imaging while performing a go/no-go task. Unbeknownst to subjects, a predictive cue preceded the no-go stimulus in 87% of trials. RESULTS: Groups were matched on demographic variables and did not differ on most measures of task performance. However, following cued stimuli, the AE group demonstrated a lower hit rate to go stimuli and more conservative response bias than the CON group. AE participants demonstrated more activation during no-go trials (inhibition) relative to go trials in the left precuneus, cingulate gyrus, anterior cingulate, and right medial frontal gyrus. During cue-dependent response inhibition, the AE group demonstrated less activation in the left precentral and postcentral gyrus compared to the CON group. CONCLUSIONS: Consistent with previous studies of response inhibition, the AE group demonstrated greater frontal and parietal activation when attempting to inhibit prepotent responses than the CON group, despite similar rates of commission errors. This study further demonstrated that the AE group had impaired behavioral performance on cued trials and demonstrated less activation in precentral and postcentral gyri relative to the CON group on these trials. This investigation provides evidence of impaired behavioral and neural processing of sequential information in fetal alcohol spectrum disorders, which can help improve inhibition in typical populations. PMID- 23094680 TI - Imaging diagnosis-multicentric lymphoma of granular lymphocytes imaged with FDG PET/CT in a dog. AB - A 5-year-old female spayed bulldog was referred for mild dyspnea, decreased activity and appetite, occasional nonproductive cough, polydipsia, and polyuria. A 2-deoxy-2-[(18) F]fluoro-D-glucose (FDG) positron emission tomography/computed tomography (PET/CT) scan revealed unexpected activity in the heart, lungs, and mild generalized lymphadenopathy that led to the diagnosis of lymphoma of granular lymphocytes after nonspecific findings on imaging with standard modalities of echocardiography, thoracic radiography, and abdominal ultrasound. PET/CT scanning is a useful whole body imaging modality with high sensitivity for changes associated with canine lymphoma. PMID- 23094681 TI - A Raney-cobalt-mediated tandem reductive cyclization route to the 1,5 methanoazocino[4,3-b]indole framework of the uleine and Strychnos alkaloids. AB - The readily accessible enones 8, 17, and 18 undergo 2-fold reductive cyclization reactions upon exposure to hydrogen in the presence of Raney-cobalt and thereby afford compounds 11 (72%), 19 (47%), and 20 (84%), respectively. These products embody the ABCD-ring system associated with the title alkaloids, and compound 11 can be converted, over four steps and in 33% yield, into congener 24 incorporating the ABCDE-ring system of the Strychnos alkaloids. PMID- 23094682 TI - Social support and trait personality are independently associated with resting cardiovascular function in women. AB - OBJECTIVES: Social support is thought to positively influence appraisals of stressors and coping resources, thereby attenuating the harmful effects of stress. Notably, perceived available support (rather than actually received support) is believed to benefit well-being independent of the sense of obligation or threats to self-esteem that receiving support may entail. This study examined whether perceived support levels were associated with reduced cardiovascular levels, an important predictor of cardiovascular disease risk, independent of broad trait personality variables frequently reported to overlap with perceived support. In doing so, we sought to determine whether the effects of perceived support are independent of links between personality and social support. DESIGN: A cross-sectional design was employed. METHODS: Resting cardiovascular levels were measured using a Finometer in a sample of healthy women (N = 145). The Short Form Social Support Questionnaire and the Revised Eysenck's Personality Questionnaire were used to assess support levels and personality. Regression was used to compare associations with psychometric indices of support (namely, perceived network size and perceived satisfaction with support) and personality (psychoticism, extraversion and neuroticism). RESULTS: Support independently predicted systolic blood pressure (SBP; p = .03) and HR (p = .02) when personality was controlled for, while personality also predicted SBP (p = .01) and DBP (p = .02). Support effects were not mediated by personality. CONCLUSIONS: The findings corroborate previous research indicating links between support and resting cardiovascular levels and additionally demonstrate these to be independent of associations between support and personality. PMID- 23094683 TI - Structural and functional neuroimaging in migraine: insights from 3 decades of research. AB - Modern imaging methods provide unprecedented insights into brain structure, perfusion, metabolism, and neurochemistry, both during and between migraine attacks. Neuroimaging investigations conducted in recent decades bring us closer to uncovering migraine as a multifaceted, primarily central nervous system disorder. Three main categories of structural and functional brain changes are described in this review, corresponding to the migrainous aura, ictal headache, and interictal states. These changes greatly advance our understanding of multiple pathophysiologic underpinnings of migraine, from central "migraine generating" loci, to cortical spreading depression, intimate mechanisms underlying activation of neuronal pain pathways in vulnerable patients, central sensitization, and chronification. Structural imaging begins to explain the complex connections between migraine and cerebral vascular events, white matter lesions, grey matter density alterations, iron deposition, and microstructural brain damage. Selected structural and functional alterations of brain structures, as identified with imaging methods, may represent the foundation of new diagnostic strategies and serve as markers of therapeutic efficacy. PMID- 23094684 TI - Rheumatoid neutrophilic dermatosis with tense blister formation: a case report and review of the literature. AB - We report a 78-year-old woman with rheumatoid neutrophilic dermatosis (RND) presenting with tense blisters; an extremely rare manifestation of this condition. Systemic corticosteroid was of limited efficacy, while dapsone was effective. A literature review of four similar cases showed that tense blisters in this type of RND tended to appear on the lower extremities of aged, female rheumatoid arthritis patients. Of note, half of the cases were resistant to corticosteroids, as anti-neutrophil agents are reported to be effective. Accordingly, it is important to recognise this unusual manifestation for the timely initiation of appropriate therapy. PMID- 23094685 TI - Dry powder inhalation exposures of the endotracheally intubated rat lung, ex vivo and in vivo: the pulmonary pharmacokinetics of fluticasone furoate. AB - BACKGROUND: The isolated perfused rat lung (IPL) is a suitable model for studying lung-specific pharmacokinetics (PK) of inhaled drugs. So far, little has been known, however, whether the PK measured in the ex vivo organ corresponds to the PK measured in similarly exposed animals in vivo, in particular the endotracheally intubated rat (EIR). The purpose of the current research was to compare the PK of inhaled corticosteroid fluticasone furoate (FF) in the IPL and the EIR. METHOD: Aerosols of FF with mass median aerodynamic diameters ranging from 2.2 to 3.2 MUm were generated with the DustGun aerosol generator. The IPL, perfused in the single-pass mode, was exposed via inhalation to 5.6 and 46 MUg of FF. Following inhalation, the perfusate was repeatedly sampled for 100 min, after which the lungs were recovered for quantitation of remaining FF. Two groups of EIR were also exposed via inhalation to 7 MUg of FF. One group was immediately euthanized for determination of the initial deposition of FF in the lungs. From the second group, four venous blood samples were drawn up to 4 hr after exposure. The animals were then sacrificed for determination of FF remaining in the lungs. RESULTS: Following inhalation, FF was slowly disappearing from both the IPL and the lungs of the EIR, with a half-life of pulmonary retention of 4.3-4.9 hr for all three exposure series. For the low exposure levels, the concentration curve of FF in the IPL perfusate was similar in shape to that in venous blood of the EIR, with a Cmax of 1.0 and 0.8 nM for the IPL and the EIR, respectively. CONCLUSIONS: The results indicate that the IPL and the EIR, when used jointly in PK studies, can provide a detailed characterization of inhaled drugs or toxicants. PMID- 23094686 TI - Comparative in vitro performance of three small-volume valved holding chambers with beclomethasone/formoterol pressurized metered dose inhaler. AB - BACKGROUND: The use of valved holding chambers (VHCs) with pressurized metered dose inhalers (pMDIs) is reported to reduce the oral deposition of inhaled drugs and to facilitate the handling of these devices by patients, especially children. Although the number of commercially available VHCs is increasing, the correct choice of VHC in clinical practice is important, because VHCs are not equally effective regarding medication delivery. Hence, we aimed to evaluate the use of three small-volume VHCs-Vortex((r)), AeroChamber((r)) Plus (ACP), and Able SpacerTM (AS)-along with a commercial pMDI containing a combination of beclomethasone and formoterol (Innovair((r))) frequently used by asthma patients. METHODS: Evaluation of the delivered dose of both drugs and analysis of particle size distribution of aerosols emitted for the inhaler were performed using the Next Generation Impactor with and without the tested VHCs. RESULTS: The VHCs retained significant quantities of both drugs and dramatically reduced the quantity of drugs deposited in the throat of the impactor, indicating that particles with large size were preferably retained in the VHCs. Interestingly, although the delivered dose of both drugs was reduced by the use of VHCs, the use of the Vortex and the ACP resulted in comparable fine particle doses (FPDs) to that obtained when the pMDI was used alone, whereas the AS VHC significantly reduced the FPDs of both drugs. This may be due to the fact that, unlike the AS VHC, the Vortex and the ACP VHCs are made of antistatic materials that minimize the electrostatic interaction with emitted aerosols, enhancing medication delivery. CONCLUSION: The Vortex and the ACP VHCs present interesting advantages over the AS VHC to be used with Innovair pMDI. However, these results are based on an in vitro evaluation and need to be validated in an in vivo study in order to clinically assess the performance of these VHCs. PMID- 23094688 TI - Single molecular recognition force spectroscopy study of a luteinizing hormone releasing hormone analogue as a carcinoma target drug. AB - The luteinizing hormone-releasing hormone- Pseudomonas aeruginosa exotoxin 40 (LHRH-PE40), is a candidate target drug associated with elevated LHRH receptor (LHRH-R) expression in malignant tumor tissue. The capability of LHRH-PE40 to recognize LHRH-Rs on a living cell membrane was studied with single molecular recognition force spectroscopy (SMFS) based on atomic force microscopy (AFM). The recognition force of LHRH-PE40/LHRH-R was compared with that of LHRH/LHRH-R by dynamic force spectroscopy. Meanwhile, cell growth inhibition assay and fluorescence imaging were presented as complementary characterization. The results show that LHRH moiety keeps its capability to recognize LHRH-R specifically, which implies that recombinant protein LHRH-PE40 can be a promising target drug. PMID- 23094687 TI - In vitro investigation of the effect of ambient humidity on regional delivered dose with solution and suspension MDIs. AB - BACKGROUND: Existing literature has shown that high relative humidity (RH) affects in vitro aerosol drug delivery of nebulizer and pressurized metered dose inhaler (pMDI) formulations. The aim of this study is to investigate in vitro mouth-throat deposition and lung delivery of selected solution and suspension pMDI formulations, under a range of RH, temperature, and flow rate conditions. METHODS: The Alberta Idealized Throat was connected to a collection filter and placed in an environmental control chamber. The formulations selected were beclomethasone dipropionate (BDP) in 13% w/w ethanol/1.3% w/w glycerol and HFA 134a propellant solution ("BDP HFA134a"), BDP in 13% w/w ethanol and HFA-227 propellant solution ("BDP HFA227"), and Flixotide Evohaler (fluticasone propionate 250 MUg/dose in HFA-134a suspension). Each of these pMDI formulations was dispersed into the mouth-throat and filter assembly in triplicate, according to an experimental matrix consisting of the following conditions: air flow rates of 28.3, 60, and 90 L/min; 0%, 35%, and 80% RH; operating temperatures of 20 degrees C and 40 degrees C. RESULTS: There was a general increase in mouth-throat deposition and corresponding decrease in filter deposition (representing lung dose fraction), with increasing RH for both BDP HFA134a and Flixotide pMDIs. Increasing temperature from 20 degrees C to 40 degrees C resulted in decreased mouth-throat deposition and increased lung dose fraction for the solution pMDIs, but generally no effect for the suspension pMDI. CONCLUSIONS: Not only is the dose delivery of pMDI formulations affected by environmental conditions (in some cases causing up to 50% reduction in lung delivery), but solution and suspension formulations also behave differently in response to these conditions. These results have implications during dosage form design, testing, and for usage patient use. PMID- 23094690 TI - Synthesis of indenes via Bronsted acid catalyzed cyclization of diaryl- and alkyl aryl-1,3-dienes. AB - Substituted indenes can be synthesized via the Bronsted acid catalyzed cyclization of diaryl- and alkyl aryl-1,3-dienes. In this approach, treatment of symmetric or unsymmetric diaryl- and alkyl aryl-1,3-dienes with a catalytic amount of trifluoromethanesulfonic acid gives a variety of indene derivatives in good to excellent yields under mild conditions. PMID- 23094689 TI - IgE, but not IgG4, antibodies to Ara h 2 distinguish peanut allergy from asymptomatic peanut sensitization. AB - BACKGROUND: There are no available clinical tests that can accurately predict peanut allergy (PA) and/or anaphylaxis. This study is aimed at evaluating whether the component-resolved diagnostic (CRD) IgE and IgG4 tests can (i) distinguish PA from asymptomatic peanut sensitization (PS) and (ii) differentiate anaphylactic from nonanaphylactic PA. METHODS: This study included 20 nonatopic controls, 58 asymptomatically peanut-sensitized children, 55 nonanaphylactic, and 53 anaphylactic PA cases from the Chicago Food Allergy Study. IgE and IgG4 to 103 allergens were measured using the ImmunoCAP ISAC technology and were compared among each group of children. The random forest test was applied to estimate each allergen's ability to predict PA and/or peanut anaphylaxis. RESULTS: Peanut allergy cases (with or without anaphylaxis) had significantly higher IgE reactivity to Ara h 1-3 (peanut allergens) and Gly m 5-6 (soy allergens) than asymptomatically sensitized children (P < 0.00001). Similar but more modest relationships were found for IgG4 to Ara h 2 (P < 0.01). IgE to Ara h 2 was the major contributor to accurate discrimination between PA and asymptomatic sensitization. With an optimal cutoff point of 0.65 ISU-E, it conferred 99.1% sensitivity, 98.3% specificity, and a 1.2% misclassification rate in the prediction of PA, which represented a higher discriminative accuracy than IgE to whole peanut extract (P = 0.008). However, none of the IgE and/or IgG4 tests could significantly differentiate peanut anaphylaxis from nonanaphylactic PA. CONCLUSIONS: IgE to Ara h 2 can efficiently differentiate clinical PA from asymptomatic PS, which may represent a major step forward in the diagnosis of PA. PMID- 23094691 TI - Synthesis and antimalarial activity of urenyl Bis-chalcone in vitro and in vivo. AB - Some novel derivatives of Bis-chalcone were synthesized and characterized by their physical and spectral data. All the synthesized compounds were subsequently screened for in vitro globin hydrolysis, beta-hematin formation, and murine Plasmodium berghei, using chloroquine as the reference drug. Most of the synthesized compounds exhibited mild to moderate susceptibilities toward the parasite in comparison with the standard. The most active antimalarial compound was 1,1-Bis-[(3',4'-N-(urenylphenyl)-3-(3",4",5"-trimethoxyphenyl)]-2-propen-1 one 5, with a percentage of inhibition of heme polymerization of 87.05 +/- 0.77, and this compound increased the survival time after infection, reduce the parasitemia and delay the progression of malaria. PMID- 23094692 TI - A guide to writing a scientific paper: a focus on high school through graduate level student research. AB - This article presents a detailed guide for high school through graduate level instructors that leads students to write effective and well-organized scientific papers. Interesting research emerges from the ability to ask questions, define problems, design experiments, analyze and interpret data, and make critical connections. This process is incomplete, unless new results are communicated to others because science fundamentally requires peer review and criticism to validate or discard proposed new knowledge. Thus, a concise and clearly written research paper is a critical step in the scientific process and is important for young researchers as they are mastering how to express scientific concepts and understanding. Moreover, learning to write a research paper provides a tool to improve science literacy as indicated in the National Research Council's National Science Education Standards (1996), and A Framework for K-12 Science Education (2011), the underlying foundation for the Next Generation Science Standards currently being developed. Background information explains the importance of peer review and communicating results, along with details of each critical component, the Abstract, Introduction, Methods, Results, and Discussion. Specific steps essential to helping students write clear and coherent research papers that follow a logical format, use effective communication, and develop scientific inquiry are described. PMID- 23094693 TI - The effects of carbaryl on the development of zebrafish (Danio rerio) embryos. AB - In the United States, Sevin(TM) brand insecticide is one of the most commonly used insecticides. The active ingredient in Sevin(TM), carbaryl (1-napthyl-N methylcarbamate), is a known acetylcholinesterase (AChE) inhibitor that prevents the breakdown of acetylcholine to acetate and choline at the synapse. While carbaryl successfully causes the death of insects by paralysis, it has also been shown to have negative effects on the development of several nontarget species. To study the effects of carbaryl on nontarget species, zebrafish (Danio rerio) were used, as they are a good model for both toxicology and development studies. Our study suggests that carbaryl induces changes in morphology, specifically in embryo size and shape. Additionally, carbaryl causes defects in heart formation that is characterized by a decrease in heart rate and a developmental delay/defect in cardiac looping. A significant decrease in the number of spinal cord neurons present was also observed. Further investigation showed that there was an increase in cell death in carbaryl-treated embryos. The results indicate that carbaryl may have a greater environmental impact than initially intended. Our study, which was conducted solely by undergraduates at a liberal arts college, indicates that carbaryl may be detrimental to the development of nontarget species. PMID- 23094694 TI - Restricted distribution and limited gene flow in the model ciliate Tetrahymena thermophila. AB - The biogeography of microbial eukaryotes has long been debated, but few phylogeographic data have been available to assess whether protists tend to have ubiquitous or endemic distributions. We addressed this issue in the ciliate Tetrahymena thermophila, a highly successful model system in cell and molecular biology. We found that this species has a distribution that is restricted to the Eastern United States, with high diversity in the northeast and low diversity across the rest of its distribution. We find high levels of population subdivision, low rates of migration and significant isolation by distance, supporting the moderate endemicity model of protist biogeography. This restricted gene flow may be a result of small population size, which would reduce the probability of migration events, or the inability to establish after migration. This work lays the foundation for T. thermophila to become a valuable model system for studying population biology. PMID- 23094695 TI - Guanine nucleobase adducts formed by [Pt(di-(2-picolyl)amine)Cl]Cl: evidence that a tridentate ligand with only in-plane bulk can slow guanine base rotation. AB - Pt(II) complexes bind preferentially at N7 of G residues of DNA, causing DNA structural distortions associated with anticancer activity. Some distortions induced by difunctional cisplatin are also found for monofunctional Pt(II) complexes with carrier ligands having bulk projecting toward the guanine base. This ligand bulk can be correlated with impeded rotation about the Pt-N7(guanine) bond. Pt(N(H)dpa)(G) adducts (N(H)dpa = di-(2-picolyl)amine, G = 5'-GMP, 5'-GDP, 5'-GTP, guanosine, 9-EtG, and 5'-IMP) were used to assess whether a tridentate carrier ligand having bulk concentrated in the coordination plane can impede guanine nucleobase rotation. Because the Pt(N(H)dpa) moiety contains a mirror plane but is unsymmetrical with respect to the coordination plane, Pt(N(H)dpa)(G) adducts can form anti or syn rotamers with the guanine O6 and the central N-H of N(H)dpa on the opposite or the same side of the coordination plane, respectively. The observation of two sharp, comparably intense guanine H8 NMR signals provided evidence that these Pt(N(H)dpa)(G) adducts exist as mixtures of syn and anti rotamers, that rotational interchange is impeded by N(H)dpa, and that the key interactions involves steric repulsions between the pyridyl and guanine rings. The relative proximity of the guanine H8 to the anisotropic pyridyl rings allowed us to conclude that the syn rotamer was usually more abundant. However, the anti rotamer was more abundant for the Pt(N(H)dpa)(5'-GTP) adduct, in which a hydrogen bond between the 5'-GTP gamma-phosphate group and the N(H)dpa central N-H is geometrically possible. In all previous examples of the influence of hydrogen bond formation on rotamer abundance in Pt(II) guanine adducts, these hydrogen bonding interactions occurred between ligand groups in cis positions. Thus, the role of a trans ligand group in influencing rotamer abundance, as found here, is unusual. PMID- 23094696 TI - Does grammatical aspect affect motion event cognition? A cross-linguistic comparison of English and Swedish speakers. AB - In this article, we explore whether cross-linguistic differences in grammatical aspect encoding may give rise to differences in memory and cognition. We compared native speakers of two languages that encode aspect differently (English and Swedish) in four tasks that examined verbal descriptions of stimuli, online triads matching, and memory-based triads matching with and without verbal interference. Results showed between-group differences in verbal descriptions and in memory-based triads matching. However, no differences were found in online triads matching and in memory-based triads matching with verbal interference. These findings need to be interpreted in the context of the overall pattern of performance, which indicated that both groups based their similarity judgments on common perceptual characteristics of motion events. These results show for the first time a cross-linguistic difference in memory as a function of differences in grammatical aspect encoding, but they also contribute to the emerging view that language fine tunes rather than shapes perceptual processes that are likely to be universal and unchanging. PMID- 23094698 TI - Quantification and structure elucidation of in vivo bevacizumab modification in rabbit vitreous humor after intravitreal injection. AB - Off-label and intravitreal use of bevacizumab, a recombinant immunoglobulin against VEGF, has been practiced widely for ophthalmic treatments. However, longitudinal data of its intravitreal status is unavailable due to a lack of reliable methods for bevacizumab determination. Thus its pharmacokinetics and pharmacodynamics are uncertain. We developed and validated a high performance liquid chromatographic method to determine bevacizumab in vitreous humor and utilized a novel strategy to assess in vivo temporal binding changes by affinity chromatography. Mass spectrometry and tandem mass spectrometry detection were used for structural evaluation. The coefficient of variation (CV) for intrabatch imprecision varied from 0.5 to 14.3% and for interbatch imprecision from 1.9 to 11.6%. The linearity was over 0.9982, lower limit of quantification 1.95 MUg, recoveries over 95%, and accuracy between 90 and 112% over the range of 1.95-250 MUg of bevacizumab in 100 MUL of vitreous humor. Blank vitreous humor showed no interference peak. It was stable at room temperature for 5 h. Bevacizumab elimination in the vitreous followed first order kinetics with half-life as 5.7 days and elimination rate as 0.1221 day(-1). Peptide mapping and tandem mass spectrometry revealed structural modifications of the in vivo bevacizumab mainly on the heavy chain in both variable and constant regions 7 days after intravitreal injection. Minor changes were also discovered on the light chain. Affinity chromatography showed significant affinity changes in samples 21 days after intravitreal injection. The changes were consistent with structural modifications as found in endothelial cell migration assays results. In conclusion, we have established a robust chromatographic method for determination of bevacizumab and strategies with affinity chromatography and molecular mass detection that revealed bevacizumab structural and possible functional changes in vitreous. PMID- 23094697 TI - IL-1R signalling is critical for regulation of multi-walled carbon nanotubes induced acute lung inflammation in C57Bl/6 mice. AB - Exposure to certain engineered nanomaterials has been associated with pathological changes in animal models raising concerns about potential human health effects. MWCNT have been reported to activate the NLRP3 inflammasome in vitro, correlating with lung inflammation and pathology, in vivo. In this study, we investigated the role of IL-1 signalling in pulmonary inflammatory responses in WT and IL-1R-/- mice after exposure to MWCNT. The results suggest that MWCNT were effective in inducing acute pulmonary inflammation. Additionally, WT mice demonstrated significant increased airway resistance 24 h post exposure to MWCNT, which was also blocked in the IL-1R-/- mice. In contrast, by 28 days post exposure to MWCNT, the inflammatory response that was initially absent in IL-1R-/ mice was elevated in comparison to the WT mice. These data suggest that IL-1R signalling plays a crucial role in the regulation of MWCNT-induced pulmonary inflammation. PMID- 23094699 TI - Risk stratification for hepatitis B virus related hepatocellular carcinoma. AB - Hepatitis B virus (HBV) infection is the major cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC) worldwide, especially in the Asia Pacific region. Several hepatitis B viral factors predictive of clinical outcomes in HBV carriers have been identified. The Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-HBV (REVEAL-HBV) study from Taiwan illustrated the strong association between HBV-DNA level at study entry and risk of HCC over time. In this community-based cohort study, male gender, older age, high serum alanine aminotransferase level, positive hepatitis B e antigen, higher HBV-DNA level, HBV genotype C infection, and core promoter mutation are independently associated with a higher risk of HCC. Another large hospital-based Elucidation of Risk Factors for Disease Control or Advancement in Taiwanese Hepatitis B Carriers cohort of Taiwanese patients further validated the findings of REVEAL-HBV. The risk of HCC started to increase when HBV-DNA level was higher than 2000 IU/mL. Both HBV-DNA and HBsAg levels were shown to be associated with HCC development. While HBV-DNA level had better predictive accuracy than HBsAg level, when investigating the overall cohort in patients with HBV-DNA level < 2000 IU/mL, HBsAg level >= 1000 IU/mL was identified as a new independent risk factor for HCC. With the results from REVEAL-HBV, a risk calculation for predicting HCC in non-cirrhotic patients has been developed and validated by independent cohorts (Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B).Taken together, ample evidence indicates that HBsAg level can complement HBV-DNA level in predicting HCC development, especially in HBV carriers with low viral load. In conclusion, HBV treatment guidelines should include the risk stratification of HCC to individualize the management of HBV carriers with different levels of HCC risk. PMID- 23094700 TI - Imaging diagnosis-cholangiocellular adenoma: contrast-enhanced ultrasonographic findings of a benign tumor mimicking malignant neoplasia in a dog. AB - A 9-year-old Giant Schnauzer was referred for polyuria and polydipsia. On abdominal ultrasound, a hyperechoic mass with low color Doppler signal was detected in the medial right hepatic lobe. Contrast-enhanced ultrasound (CEUS) demonstrated increased enhancement of the mass during the arterial phase, and contrast washout during portal and late phases with decreased enhancement relative to the liver. These findings were consistent with primary liver malignancy or liver metastasis. A final diagnosis of cholangiocellular adenoma was made based on histopathology. To our knowledge, this is the first description of a benign hepatic neoplasm exhibiting malignant CEUS characteristics in a dog. PMID- 23094701 TI - Triple red blood cell alloantibody formation after bone-allograft transplantation. AB - In this case report, we provide evidence for the possibility of red blood cell alloimmunization after bone-allograft transplantation. Here, we present a 13-year old boy who received a bone allograft due to impending hip-luxation. Five months later he was shown to have developed three different alloantibodies: anti-D, anti C and anti-E, which were induced by the bone allograft. Red blood cell alloimmunization is a possible adverse event when a patient is exposed to allogenic red blood cells. These antibodies may cause transfusion reactions when incompatible blood is administered. More importantly, these antibodies may cause severe, or even fatal, hemolytic disease of the fetus or newborn, stretching the importance of preventing antibody formation, especially in young women. This case demonstrates the importance of selecting rhesus phenotype compatible bone allografts. PMID- 23094702 TI - Cross-evaluation of facial hyperpigmented lesions based on fluorescence color image and cross-polarized color image. AB - BACKGROUND/PURPOSE: Hyperpigmentation is a common skin problem that looks darker than normal skin regions. Accurate evaluation of a hyperpigmented lesion (HPL) is of clinical importance because proper choice of treatment can be dependent on it. This study aimed to differentiate between epidermal and dermal HPLs. METHODS: Cross-polarized color images (CPCIs) and fluorescence color images (FCIs) were acquired from the same facial regions. Contrast-limited adaptive histogram equalization (CLAHE) was employed to enhance the image contrast and a fuzzy c means algorithm was implemented to extract the HPLs. The HPLs were superimposed to investigate the difference between CPCI and FCI. RESULTS: The HPL was successfully extracted by applying both CLAHE and fuzzy c-means algorithms. CPCI and FCI resulted in a slightly different HPL, even from the same facial region, indicating a greater percentage area of HPL in FCI than CPCI. CONCLUSION: CPCI and FCI may be utilized to differentiate HPLs that exist in different skin layers. Thus, this approach may contribute to the effective treatment of HPLs. PMID- 23094703 TI - Cooperative titanocene and phosphine catalysis: accelerated C-X activation for the generation of reactive organometallics. AB - The study presented herein describes a reductive transmetalation approach toward the generation of Grignard and organozinc reagents mediated by a titanocene catalyst. This method enables the metalation of functionalized substrates without loss of functional group compatibility. Allyl zinc reagents and allyl, vinyl, and alkyl Grignard reagents were generated in situ and used in the addition to carbonyl substrates to provide the corresponding carbinols in yields up to 99%. It was discovered that phosphine ligands effectively accelerate the reductive transmetalation event to enable the metalation of C-X bonds at temperatures as low as -40 degrees C. Performing the reactions in the presence of chiral diamines and amino alcohols led to the enantioselective allylation of aldehydes. PMID- 23094704 TI - Pharmacokinetics of anti-tuberculosis drugs in Venezuelan children younger than 16 years of age: supportive evidence for the implementation of revised WHO dosing recommendations. AB - OBJECTIVES: The World Health Organization (WHO) recently issued revised first line antituberculosis (anti-TB) drug dose recommendations for children, with dose increases proposed for each drug. No pharmacokinetic data are available from South American children. We examined the need for implementation of these revised guidelines in Venezuela. METHODS: Plasma isoniazid, rifampicin, pyrazinamide and ethambutol concentrations were assessed prior to and at 2, 4 and 8 h after intake of TB drugs by 30 TB patients aged 1-15 years. The effects of dose in mg/kg, age, sex, body weight, malnutrition and acetylator phenotype on maximum plasma drug concentrations (Cmax) and exposure (AUC0-24) were determined. RESULTS: 25 patients (83%) had an isoniazid Cmax below 3 mg/l and 23 patients (77%) had a rifampicin Cmax below 8 mg/l. One patient (3%) had a pyrazinamide Cmax below 20 mg/l. The low number of patients on ethambutol (n = 5) precluded firm conclusions. Cmax and AUC0-24 of all four drugs were significantly and positively correlated with age and body weight. Patients aged 1-4 years had significantly lower Cmax and AUC0-24 values for isoniazid and rifampicin and a trend to lower values for pyrazinamide compared to those aged 5-15 years. The geometric mean AUC0-24 for isoniazid was much lower in fast acetylators than in slow acetylators (5.2 vs. 12.0, P < 0.01). CONCLUSION: We provide supportive evidence for the implementation of the revised WHO pediatric TB drug dose recommendations in Venezuela. Follow-up studies are needed to describe the corresponding plasma levels that are achieved by the recommended increased doses of TB drugs. PMID- 23094705 TI - Clusters of actinides with oxide, peroxide, or hydroxide bridges. PMID- 23094706 TI - Quantitative attachment and detachment of bacterial spores from fine wires through continuous and pulsed DC electrophoretic deposition. AB - We demonstrate the uniform attachment of bacterial spores electrophoretically onto fine wires in liquids and subsequently quantitatively detached back into suspension. It was found that the use of a pulsed voltage method resulted in a uniform coverage of spores and prevented visible bubble formation resulting from water electrolysis which tended to dislodge the spores from the wires. By monitoring the electrophoretically derived current, this method could also be used to quantitatively measure the surface charges on spores and the deposition rate. The method is generic and should be applicable to the deposition of any charged biological material (e.g., spores, bacteria, viruses) onto metal surfaces. PMID- 23094707 TI - In medication-overuse headache, fMRI shows long-lasting dysfunction in midbrain areas. AB - OBJECTIVE: The primary aim of our study was to evaluate if a group of medication overuse headache (MOH) patients present dysfunctions in the mesocorticolimbic dopamine circuit. The secondary aim was to disentangle the role of the medication overuse and of the acute/chronic headache in determining these alterations and to investigate their persistence. BACKGROUND: Several researches have suggested that MOH may belong to the spectrum of addictive behavior. Preclinical models and neuroimaging studies have consistently demonstrated that in addiction, critical long-lasting alterations occur in the mesocorticolimbic dopamine circuit. If MOH shares some neurophysiological features with addiction, long-lasting functional alterations of the mesocorticolimbic dopamine system related to medication overuse should be present. METHODS: We collected functional magnetic resonance imaging data during the execution of a decision-making under risk paradigm in 8 MOH patients immediately after beginning medication withdrawal, in 8 detoxified MOH patients at 6 months after beginning medication withdrawal, in 8 chronic migraine patients, and in 8 control subjects. RESULTS: Our results revealed that MOH patients present: (1) reduced task-related activity in the substantia nigra/ventral tegmental area complex and increased activity in the ventromedial prefrontal cortex, when compared with controls; (2) reduced activity in the substantia nigra/ventral tegmental area complex, when compared with chronic migraine patients; (3) increased activity in the ventromedial prefrontal cortex, when compared with detoxified MOH patients. CONCLUSION: Our study showed that MOH patients present dysfunctions in the mesocorticolimbic dopamine circuit, in particular in the ventromedial prefrontal cortex and in the substantia nigra/ventral tegmental area complex. The ventromedial prefrontal cortex dysfunctions seem to be reversible and attributable to the acute/chronic headache, whereas the substantia nigra/ventral tegmental area complex dysfunctions are persistent and possibly related to medication overuse. These dysfunctions might be the expression of long-lasting neuroadaptations related to the overuse of medications and/or a pre-existing neurophysiological condition leading to vulnerability to medication overuse. The observed persistent dysfunctions in the midbrain dopamine suggest that MOH may share some neurophysiological features with addiction. PMID- 23094708 TI - Evaluation of bedoradrine sulfate (MN-221), a novel, highly selective beta2 adrenergic receptor agonist for the treatment of asthma via intravenous infusion. AB - BACKGROUND: The number of hospitalizations or deaths due to asthma, most of which result from acute exacerbations of asthma, has remained the same for the past 20 years. MN-221 (bedoradrine sulfate) is a novel, highly selective beta2- (beta2-) adrenergic agonist administered via intravenous (IV) infusion in development for the treatment for acute exacerbation of asthma. OBJECTIVES: Trial MN-221-CL-004 assessed the safety profile and preliminary efficacy of MN-221 in escalating doses in patients with stable mild-to-moderate asthma. Study MN-221-CL-005 assessed the safety profile and preliminary efficacy of MN-221 in patients with stable moderate-to-severe asthma when given as a fixed dose over 1- or 2- hr infusion. METHODS: Two randomized, placebo-controlled clinical trials (n = 40) were performed to evaluate the pharmacokinetic (PK) and clinical effects of a novel, highly selective beta2-agonist, MN-221, via IV infusion. Safety evaluations included vital signs, adverse events (AEs), clinical laboratory parameters, and electrocardiogram results. Efficacy evaluation included measurement of forced expiratory volume in 1 second (FEV) a1nd PK parameters were additionally monitored. The study was reviewed and approved by the Institutional Review Board at each site. RESULTS: Adverse effects were mild or moderate and there were no serious AEs or deaths during the studies. The most frequently reported AEs were tremor, hypokalemia, and headache. There were no consistent dose-dependent effects of MN-221 on any safety parameters, with the exception of heart rate, which was not considered to be clinically significant and did not require any treatment. Moderate hypokalemia occurred once in one subject in the MN-221-CL-004 study and twice in one subject in the MN-221-CL-005 study and were transient and returned to normal range following single oral potassium chloride treatments. PK assessments indicated a linear response in MN-221 plasma concentrations for the doses evaluated. Dose escalation results showed that mean changes in FEV1 from pre-infusion were significantly greater than placebo and an overall dose response was statistically significant (p < .0001). Post-infusion FEV1 improvements appeared to plateau at the 30 MUg/min dose level despite a higher peak plasma concentration at 60 MUg/min. Dose-rate escalation results demonstrated greater mean increases in change in FEV1 compared to the placebo group with the largest increase associated with the higher MN-221 dose rate and peak plasma concentration. CONCLUSIONS: The safety profile of MN-221 and evidence of dose- and plasma-concentration-related bronchodilation supports further clinical development and suggests the potential for clinical benefit without increased clinical risk, particularly for patients where inhaled or nebulized therapy is not adequate or possible. Trial registry name and registration number:Name: MN-221-CL-005Number: NCT00679263. PMID- 23094709 TI - Associations of VEGF/VEGF-receptor and HGF/c-Met promoter polymorphisms with progression/regression of retinopathy of prematurity. AB - PURPOSE: To determine the effect(s) of vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), hepatocyte growth factor (HGF), and HGF receptor (c Met) polymorphisms on progression/regression of retinopathy of prematurity (ROP) in premature infants. MATERIALS AND METHODS: This study comprised both a prospective analysis and a clinically relevant laboratory investigation. Enrolled were 123 Turkish preterm infants--gestational age (GA), <=34 weeks; birth weight (BW), <=1500 g--from a single tertiary care center. Infants were grouped as those who had undergone laser therapy (Group 1, n = 42), those with spontaneously regressed ROP (Group 2, n = 50), and those with no ROP (controls) (Group 3, n = 31). VEGF (-634) C and VEGF (-460) C polymorphisms were analyzed using the PCR restriction fragment length polymorphism (RFLP) (PCR-RFLP) technique. VEGFR-2, HGF, and c-Met gene promoter polymorphisms were determined by direct sequencing. RESULTS: Mean GAs and BWs of infants in Groups 1 and 2 were statistically significantly lower than those of Group 3 (p = 0.001). Frequencies of VEGF (-634) C and VEGF (-460) C polymorphisms were similar for all groups. We found a +32G->A single-nucleotide polymorphism (SNP) in the promoter region of the VEGFR-2 gene. HGF and c-Met gene promoter polymorphisms were not found in any group. CONCLUSIONS: Our results indicate that there is no association between the carrier states of gene promoter polymorphisms VEGF (-634) C, VEGF (-460) C, and VEGFR-2, and progression or spontaneous regression of ROP in preterm infants. The absence of HGF and c-Met polymorphisms in our study groups suggests that polymorphisms in the minimal promoters of these genes are not involved in the pathogenesis of ROP. PMID- 23094710 TI - Elucidating the mechanism of reversible oxiranations via magnetization transfer spectroscopy. AB - The reversible [2 + 1] cycloadditions between an N,N'-diamidocarbene (DAC) and eight aldehydes were examined using NMR spectroscopy. Variable temperature magnetization transfer experiments revealed higher exchange rates and lower activation barriers when electron-deficient aldehydes were employed. Likewise, competitive equilibrium studies indicated a thermodynamic preference for electron deficient aryl and sterically unhindered alkyl aldehydes compared to more electron-rich or bulkier substrates. Collectively, these and other data collected were consistent with the oxiranation process proceeding in an asynchronous manner. PMID- 23094711 TI - Systemic nocardiosis in a Mediterranean population of cultured meagre, Argyrosomus regius Asso (Perciformes: Sciaenidae). AB - Marine cultured meagre, Argyrosomus regius Asso, in central and western Greece were affected by an outbreak of systemic granulomatous disease subsequently demonstrated to be nocardiosis. The fish were originally imported as juveniles from hatcheries in France and Italy and on-grown in Greece, the latter also providing broodstock for a small number of local Greek hatcheries for the production of second-generation juveniles. The disease in cage reared fish had been present throughout the year, particularly in the 1+ and 2+ year old fish with a low to variable morbidity and 1-4% total mortality. Multiple lesions were visible externally on the skin of affected fish, with severe ulcerations and necrosis. Internally, multifocal yellowish-white nodules, 0.1-0.5 cm in diameter, were visible on the surface of several internal organs. Histopathology revealed systemic granulomatous inflammation. Fite-Faraco staining clearly demonstrated the presence of Nocardia-like organisms which were Gram-positive, long, rod to beaded filamentous bacteria. Nocardia genus-specific 16s RNA primers NG1 and NG2 were used to generate a 600 bp fragment recovered from affected tissue, confirming the diagnosis of Nocardia spp. To our knowledge, this is the first report of nocardiosis in meagre. PMID- 23094712 TI - Retinal vasculopathy in autosomal dominant dyskeratosis congenita due to TINF2 mutation. PMID- 23094713 TI - Biomechanical comparison of glycomer 631 and glycomer 631 knotless for use in canine incisional gastropexy. AB - OBJECTIVE: To compare the load to failure of incisional gastropexy performed with standard glycomer 631 (G) and with knotless glycomer 631 (GV) in ex vivo model of gastropexy. STUDY DESIGN: Cadaveric study. SAMPLE POPULATION: Cadaveric canine stomach and body wall (n = 24). METHODS: Specimens were divided into 4 groups based on suture type (G, GV) and size (3 metric, 2 metric). An incisional gastropexy was performed on all samples, and load to failure evaluated. RESULTS: Gastropexy with GV had significantly higher load to failure than gastropexy performed with G (P = .0006). Suture size had no significant effect on maximum load to failure (P = .36). The interaction between size of the suture and suture materials had a significant effect on the load to failure of the gastropexy (P = .0474). Knotless glycomer 631, 3 metric had significantly greater load to failure than G 3 metric (P = .0016) and G 2 metric (P = .0107). CONCLUSION: A knotless suture appears to have comparable, if not greater load to failure than a standard suture of similar composition when used in canine incisional gastropexy in an acute ex vivo model. PMID- 23094714 TI - The adaptive potential of Populus balsamifera L. to phenology requirements in a warmer global climate. AB - The manner in which organisms adapt to climate change informs a broader understanding of the evolution of biodiversity as well as conservation and mitigation plans. We apply common garden and association mapping approaches to quantify genetic variance and identify loci affecting bud flush and bud set, traits that define a tree's season for height growth, in the boreal forest tree Populus balsamifera L. (balsam poplar). Using data from 478 genotypes grown in each of two common gardens, one near the southern edge and another near the northern edge of P. balsamifera's range, we found that broad-sense heritability for bud flush and bud set was generally high (H(2) > 0.5 in most cases), suggesting that abundant genetic variation exists for phenological response to changes in the length of the growing season. To identify the molecular genetic basis of this variation, we genotyped trees for 346 candidate single nucleotide polymorphisms (SNPs) from 27 candidate genes for the CO/FT pathway in poplar. Mixed-model analyses of variance identified SNPs in 10 genes to be associated with variation in either bud flush or bud set. Multiple SNPs within FRIGIDA were associated with bud flush, whereas multiple SNPs in LEAFY and GIGANTEA 5 were associated with bud set. Although there was strong population structure in stem phenology, the geographic distribution of multilocus association SNP genotypes was widespread except at the most northern populations, indicating that geographic regions may harbour sufficient diversity in functional genes to facilitate adaption to future climatic conditions in many sites. PMID- 23094715 TI - Current pharmacotherapy for cholestatic liver disease. AB - IMPORTANCE OF THE FIELD: The cholestatic liver diseases comprise a heterogeneous group of disorders which, left untreated, usually progresses to cirrhosis and liver failure. Most are recognized before the onset of advanced fibrosis, thereby affording an opportunity for disease modifying therapy. AREAS COVERED: This review will cover the current pharmacologic management of the most common causes of cholestatic liver disease in adults, including primary biliary cirrhosis, primary biliary cirrhosis-autoimmune hepatitis overlap syndrome, primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, intestinal failure associated liver disease, and immunoglobulin G4-associated cholangitis. Pharmacologic management of complications of cholestasis will also be reviewed. EXPERT OPINION: Effective therapy for most cholestatic liver disease is lacking. Ursodeoxycholic acid (UDCA) slows the progression of primary biliary cirrhosis but the majority of patients do not have a full response. Even in those with a complete response, UDCA does not cure the disease. There is currently no effective medical therapy for primary sclerosing cholangitis. Symptoms and serum liver biochemistry values in intrahepatic cholestasis of pregnancy are improved with UDCA, but it is not certain if this alters the course of disease. Immunoglobulin G4-associated cholangitis is responsive to steroids but may relapse. The farnesoid X receptor agonists are a promising new class of drugs currently being tested in cholestatic liver disease. PMID- 23094716 TI - Synthesis and biological activity of organoantimony(III)-containing heteropolytungstates. AB - Three discrete organoantimony(III)-containing heteropolytungstates [(PhSb(III))(4)(A-alpha-Ge(IV)W(9)O(34))(2)](12-) (1), [(PhSb(III))(4)(A-alpha P(V)W(9)O(34))(2)](10-) (2), and [{2-(Me(2)NCH(2)C(6)H(4))Sb(III)}(3)(B-alpha As(III)W(9)O(33))](3-) (3) have been synthesized in one-pot reactions in aqueous medium using the appropriate lacunary heteropolyanion precursor and organoantimony(III) source. Polyanions 1-3 were isolated as hydrated salts, (NH(4))(12)[(PhSb(III))(4)(A-alpha-Ge(IV)W(9)O(34))(2)].20H(2)O (1a), Rb(9)Na[(PhSb(III))(4)(A-alpha-P(V)W(9)O(34))(2)].20H(2)O (2a), and Rb(3)[{2 (Me(2)NCH(2)C(6)H(4))Sb(III)}(3)(B-alpha-As(III)W(9)O(33))].7H(2)O (3a). The compounds 1a-3a were fully characterized in the solid state using infrared (IR) spectroscopy, single-crystal XRD, and thermogravimetric and elemental analyses. The stability of 1-3 in aqueous solution was confirmed by multinuclear NMR ((1)H, (13)C, (31)P, and (183)W) spectroscopy. Preliminary studies on the biological activity of 1-3 showed that all three compounds might act as potent antimicrobial agents. PMID- 23094717 TI - Rh-catalyzed addition of arylboroxines to cyclic N-(isopropanesulfinyl)ketimines. AB - Arylboroxines, which are easily accessed by drying commercially available arylboronic acids, are added to N-(isopropanesulfinyl)ketimines derived from cyclohexanone, N-Boc-piperidin-4-one, and tetrahydropyran-4-one in high yields and with excellent functional group compatibility via rhodium catalysis. These results contrast with additions to the corresponding ketimines incorporating the larger N-tert-butanesulfinyl group, which give considerably lower yields. Efficient two-step preparation of racemic isopropanesulfinamide from inexpensive isopropyl disulfide and recycling of the isopropanesulfinyl group from the addition products are also described. PMID- 23094718 TI - Spreading activation in an attractor network with latching dynamics: automatic semantic priming revisited. AB - Localist models of spreading activation (SA) and models assuming distributed representations offer very different takes on semantic priming, a widely investigated paradigm in word recognition and semantic memory research. In this study, we implemented SA in an attractor neural network model with distributed representations and created a unified framework for the two approaches. Our models assume a synaptic depression mechanism leading to autonomous transitions between encoded memory patterns (latching dynamics), which account for the major characteristics of automatic semantic priming in humans. Using computer simulations, we demonstrated how findings that challenged attractor-based networks in the past, such as mediated and asymmetric priming, are a natural consequence of our present model's dynamics. Puzzling results regarding backward priming were also given a straightforward explanation. In addition, the current model addresses some of the differences between semantic and associative relatedness and explains how these differences interact with stimulus onset asynchrony in priming experiments. PMID- 23094719 TI - Why doctors prescribe opioids to known opioid abusers. PMID- 23094720 TI - Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. AB - BACKGROUND: There are limited data comparing radiofrequency catheter ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation. METHODS: We randomly assigned 294 patients with paroxysmal atrial fibrillation and no history of antiarrhythmic drug use to an initial treatment strategy of either radiofrequency catheter ablation (146 patients) or therapy with class IC or class III antiarrhythmic agents (148 patients). Follow-up included 7-day Holter-monitor recording at 3, 6, 12, 18, and 24 months. Primary end points were the cumulative and per-visit burden of atrial fibrillation (i.e., percentage of time in atrial fibrillation on Holter-monitor recordings). Analyses were performed on an intention-to-treat basis. RESULTS: There was no significant difference between the ablation and drug-therapy groups in the cumulative burden of atrial fibrillation (90th percentile of arrhythmia burden, 13% and 19%, respectively; P=0.10) or the burden at 3, 6, 12, or 18 months. At 24 months, the burden of atrial fibrillation was significantly lower in the ablation group than in the drug-therapy group (90th percentile, 9% vs. 18%; P=0.007), and more patients in the ablation group were free from any atrial fibrillation (85% vs. 71%, P=0.004) and from symptomatic atrial fibrillation (93% vs. 84%, P=0.01). One death in the ablation group was due to a procedure-related stroke; there were three cases of cardiac tamponade in the ablation group. In the drug-therapy group, 54 patients (36%) underwent supplementary ablation. CONCLUSIONS: In comparing radiofrequency ablation with antiarrhythmic drug therapy as first-line treatment in patients with paroxysmal atrial fibrillation, we found no significant difference between the treatment groups in the cumulative burden of atrial fibrillation over a period of 2 years. (Funded by the Danish Heart Foundation and others; MANTRA-PAF ClinicalTrials.gov number, NCT00133211.). PMID- 23094721 TI - Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. AB - BACKGROUND: Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers. METHODS: We obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1. RESULTS: Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction). CONCLUSIONS: Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.). PMID- 23094724 TI - Peripheral mechanisms in irritable bowel syndrome. PMID- 23094722 TI - Association of neighborhood characteristics with bystander-initiated CPR. AB - BACKGROUND: For persons who have an out-of-hospital cardiac arrest, the probability of receiving bystander-initiated cardiopulmonary resuscitation (CPR) may be influenced by neighborhood characteristics. METHODS: We analyzed surveillance data prospectively submitted from 29 U.S. sites to the Cardiac Arrest Registry to Enhance Survival between October 1, 2005, and December 31, 2009. The neighborhood in which each cardiac arrest occurred was determined from census-tract data. We classified neighborhoods as high-income or low-income on the basis of a median household income threshold of $40,000 and as white or black if more than 80% of the census tract was predominantly of one race. Neighborhoods without a predominant racial composition were classified as integrated. We analyzed the relationship between the median income and racial composition of a neighborhood and the performance of bystander-initiated CPR. RESULTS: Among 14,225 patients with cardiac arrest, bystander-initiated CPR was provided to 4068 (28.6%). As compared with patients who had a cardiac arrest in high-income white neighborhoods, those in low-income black neighborhoods were less likely to receive bystander-initiated CPR (odds ratio, 0.49; 95% confidence interval [CI], 0.41 to 0.58). The same was true of patients with cardiac arrest in neighborhoods characterized as low-income white (odds ratio, 0.65; 95% CI, 0.51 to 0.82), low income integrated (odds ratio, 0.62; 95% CI, 0.56 to 0.70), and high-income black (odds ratio, 0.77; 95% CI, 0.68 to 0.86). The odds ratio for bystander-initiated CPR in high-income integrated neighborhoods (1.03; 95% CI, 0.64 to 1.65) was similar to that for high-income white neighborhoods. CONCLUSIONS: In a large cohort study, we found that patients who had an out-of-hospital cardiac arrest in low-income black neighborhoods were less likely to receive bystander-initiated CPR than those in high-income white neighborhoods. (Funded by the Centers for Disease Control and Prevention and others.). PMID- 23094723 TI - Patients' expectations about effects of chemotherapy for advanced cancer. AB - BACKGROUND: Chemotherapy for metastatic lung or colorectal cancer can prolong life by weeks or months and may provide palliation, but it is not curative. METHODS: We studied 1193 patients participating in the Cancer Care Outcomes Research and Surveillance (CanCORS) study (a national, prospective, observational cohort study) who were alive 4 months after diagnosis and received chemotherapy for newly diagnosed metastatic (stage IV) lung or colorectal cancer. We sought to characterize the prevalence of the expectation that chemotherapy might be curative and to identify the clinical, sociodemographic, and health-system factors associated with this expectation. Data were obtained from a patient survey by professional interviewers in addition to a comprehensive review of medical records. RESULTS: Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer did not report understanding that chemotherapy was not at all likely to cure their cancer. In multivariable logistic regression, the risk of reporting inaccurate beliefs about chemotherapy was higher among patients with colorectal cancer, as compared with those with lung cancer (odds ratio, 1.75; 95% confidence interval [CI], 1.29 to 2.37); among nonwhite and Hispanic patients, as compared with non-Hispanic white patients (odds ratio for Hispanic patients, 2.82; 95% CI, 1.51 to 5.27; odds ratio for black patients, 2.93; 95% CI, 1.80 to 4.78); and among patients who rated their communication with their physician very favorably, as compared with less favorably (odds ratio for highest third vs. lowest third, 1.90; 95% CI, 1.33 to 2.72). Educational level, functional status, and the patient's role in decision making were not associated with such inaccurate beliefs about chemotherapy. CONCLUSIONS: Many patients receiving chemotherapy for incurable cancers may not understand that chemotherapy is unlikely to be curative, which could compromise their ability to make informed treatment decisions that are consonant with their preferences. Physicians may be able to improve patients' understanding, but this may come at the cost of patients' satisfaction with them. (Funded by the National Cancer Institute and others.). PMID- 23094725 TI - Images in clinical medicine. Hibernoma of the neck. PMID- 23094726 TI - Case records of the Massachusetts General Hospital. Case 33-2012. A 34-year-old woman with episodic paresthesias and altered mental status after childbirth. PMID- 23094727 TI - Catheter ablation for paroxysmal atrial fibrillation. PMID- 23094728 TI - Aspirin--from prevention to targeted therapy. PMID- 23094729 TI - Talking with patients about dying. PMID- 23094730 TI - Strip searches in the Supreme Court--prisons and public health. PMID- 23094732 TI - Anastrozole and fulvestrant in metastatic breast cancer. PMID- 23094733 TI - Anastrozole and fulvestrant in metastatic breast cancer. PMID- 23094734 TI - Anastrozole and fulvestrant in metastatic breast cancer. PMID- 23094736 TI - Coronary CT angiography for acute chest pain. PMID- 23094737 TI - Coronary CT angiography for acute chest pain. PMID- 23094739 TI - Blockade of chemotaxis in graft-versus-host disease. PMID- 23094741 TI - Benign prostatic hyperplasia and lower urinary tract symptoms. PMID- 23094743 TI - Shock-wave lithotripsy for renal calculi. PMID- 23094745 TI - Case 23-2012: A man with abdominal pain and weight loss. PMID- 23094746 TI - Case 23-2012: A man with abdominal pain and weight loss. PMID- 23094751 TI - Images in clinical medicine. Selective intraarterial thrombolysis for cardioembolic stroke. PMID- 23094752 TI - Clinical decisions. Prostate cancer screening--polling results. PMID- 23094753 TI - Fluorescence correlation spectroscopy directly monitors coalescence during nanoparticle preparation. AB - Dual color fluorescence cross-correlation spectroscopy (DC FCCS) experiments were conducted to study the coalescence and aggregation during the formation of nanoparticles. To assess the generality of the method, three completely different processes were selected to prepare the nanoparticles. Polymeric nanoparticles were formed either by solvent evaporation from emulsion nanodroplets of polymer solutions or by miniemulsion polymerization. Inorganic nanocapsules were formed by polycondensation of alkoxysilanes at the interface of nanodroplets. In all cases, DC FCCS provided fast and unambiguous information about the occurrence of coalescence and thus a deeper insight into the mechanism of nanoparticle formation. In particular, it was found that coalescence played a minor role for the emulsion-solvent evaporation process and the miniemulsion polymerization, whereas substantial coalescence was detected during the formation of the inorganic nanocapsules. These findings demonstrate that DC FCCS is a powerful tool for monitoring nanoparticles genesis. PMID- 23094754 TI - Diabetic retinopathy and atherosclerosis: is there a link? AB - Diabetic retinopathy (DR) is the leading cause of blindness amongst the working age population, and diabetes accelerated cardiovascular disease (CVD) the commonest cause of death in diabetic patients. Although, there is evidence suggesting a close association between DR and CVD, particularly in patients with Type 2 diabetes, the pathophysiology underlying the link is unclear. Here we review common risk factors and pathogenic mechanisms linking DR and CVD, and aim to highlight the need for a more holistic view of the management of diabetes and its complications. The understanding of the link between the two complications could eventually lead to refined management strategies and improved patient outcomes in the expanding diabetes epidemic. PMID- 23094755 TI - Nonalcoholic fatty liver disease in Asia: a story of growth. AB - Ten years ago, few if any researchers in Asia showed interest in nonalcoholic fatty liver disease (NAFLD). Today, NAFLD is increasingly recognized as a major chronic liver disease not only in Western countries but also in Asia. Its importance is exemplified by its high prevalence, disease progression, and association with major medical disorders. In Asia, 15-30% of the general adult population suffers from NAFLD. In patients with diabetes and metabolic syndrome, the reported prevalence is typically over 50%. Patients with the active form of NAFLD, namely steatohepatitis (NASH), may have fibrosis progression and eventually develop cirrhosis. Patients with NASH-related cirrhosis have similar mortality to those with other causes of cirrhosis, and they have a high risk of developing hepatocellular carcinoma up to 2-3% per year. In addition, NAFLD patients have a high prevalence of cardiovascular disease and colorectal neoplasm. One major challenge for practicing clinicians is how to identify patients with significant liver disease among many who are found to have NAFLD. While liver biopsy is traditionally considered the gold standard for disease staging, it is invasive and unpleasant, and is an impractical tool for a disease that affects a quarter of the general population. To this end, new developments in transient elastography and biomarkers such as cytokeratin-18 fragments can help exclude significant liver fibrosis and NASH, respectively. This article summarizes a young researcher's journey through this exciting area of research and what he has learned from amazing people all around the world. PMID- 23094756 TI - Radiographic liver size in Pekingese dogs versus other dog breeds. AB - Differential diagnoses for canine liver disease are commonly based on radiographic estimates of liver size, however little has been published on breed variations. Aims of this study were to describe normal radiographic liver size in Pekingese dogs and to compare normal measurements for this breed with other dog breeds and Pekingese dogs with liver disease. Liver measurements were compared for clinically normal Pekingese (n = 61), normal non-Pekingese brachycephalic (n = 45), normal nonbrachycephalic (n = 71), and Pekingese breed dogs with liver disease (n = 22). For each dog, body weight, liver length, T11 vertebral length, thoracic depth, and thoracic width were measured on right lateral and ventrodorsal abdominal radiographs. Liver volume was calculated using a formula and ratios of liver length/T11 vertebral length and liver volume/body weight ratio were determined. Normal Pekingese dogs had a significantly smaller liver volume/body weight ratio (16.73 +/- 5.67, P < 0.05) than normal non-Pekingese brachycephalic breed dogs (19.54 +/- 5.03) and normal nonbrachycephalic breed dogs (18.72 +/- 6.52). The liver length/T11 vertebral length ratio in normal Pekingese (4.64 +/- 0.65) was significantly smaller than normal non-Pekingese brachycephalic breed dogs (5.16 +/- 0.74) and normal nonbrachycephalic breed dogs (5.40 +/- 0.74). Ratios of liver volume/body weight and liver length/T11 vertebral length in normal Pekingese were significantly different from Pekingese with liver diseases (P < 0.05). Findings supported our hypothesis that Pekingese dogs have a smaller normal radiographic liver size than other breeds. We recommend using 4.64* the length of the T11 vertebra as a radiographic criterion for normal liver length in Pekingese dogs. PMID- 23094757 TI - Re: Comparison of mortality outcomes after radical prostatectomy versus radiotherapy in patients with localized prostate cancer: a population-based analysis. PMID- 23094758 TI - Serological survey of HIV and syphilis in pregnant women in Madagascar. AB - OBJECTIVES: Peripartal transmission of human immunodeficiency virus (HIV) and Treponema pallidum, the causative agent of syphilis, leads to severe consequences for newborns. Preventive measures require awareness of the maternal infection. Although HIV and syphilis testing in Madagascar could be theoretically carried out within the framework of the national pregnancy follow-up scheme, the required test kits are rarely available at peripheral health centres. In this study, we screened blood samples of pregnant Madagascan women for HIV and syphilis seroprevalence to estimate the demand for systemic screening in pregnancy. METHODS: Retrospective anonymous serological analysis for HIV and syphilis was performed in plasma samples from 1232 pregnant women that were taken between May and July 2010 in Ambositra, Ifanadiana, Manakara, Mananjary, Moramanga and Tsiroanomandidy (Madagascar) during pregnancy follow-up. Screening was based on Treponema pallidum haemagglutination tests for syphilis and rapid tests for HIV, with confirmation of positive screening results on line assays. RESULTS: Out of 1232 pregnant women, none were seropositive for HIV and 37 (3%) were seropositive for Treponema pallidum. CONCLUSIONS: Our findings are in line with previous studies that describe considerable syphilis prevalence in the rural Madagascan population. The results suggest a need for screening to prevent peripartal Treponema pallidum transmission, while HIV is still rare. If they are known, Treponema pallidum infections can be easily, safely and inexpensively treated even in pregnancy to reduce the risk of transmission. PMID- 23094759 TI - Transmission of angiosarcomas from a common multiorgan donor to four transplant recipients. AB - We describe the donor tumor transmission of metastatic angiosarcomas to four transplant recipients through transplantation of deceased-donor organs, i.e. kidneys, lung and liver, from an apparently unaffected common female multiorgan donor. Fluorescent in situ hybridization of angiosarcoma cells confirmed that the tumor was of female donor's origin in male kidney recipients. Recent literature associated increased urokinase-plasminogen-activator-receptor (uPAR) and plasma soluble urokinase-plasminogen-activator-receptor (suPAR) levels with metastatic malignancies. Now we found that, compared to baseline levels, both deceased-donor kidney recipients showed increased uPAR transcripts in mononuclear cells as well as increased plasma suPAR levels after the diagnosis of metastatic angiosarcomas, i.e. 4 months after donor tumor transmission. These results show an association of uPAR/suPAR in donor tumor transmission of metastatic angiosarcomas in humans. PMID- 23094760 TI - A 3-month analysis of disability, quality of life, and disease course in patients with migraine. AB - OBJECTIVE: To describe a short-term "real-life" longitudinal evolution of migraine course, quality of life, and disability in a sample of patients attending to a specialty center and to evaluate the association between the changes in patient-reported outcomes, number of reported headaches, their severity, and treatment consumption. BACKGROUND: Clinical trials demonstrated that symptomatic and preventive therapies reduce migraine headache frequency and severity, thus improving quality of life and reducing disability. However, the longitudinal trajectory of health outcomes of patients under specific treatments but out of the setting of a clinical trial is almost unexplored. DESIGN: Longitudinal observational study with a 3-month follow-up. METHODS: Adult patients suffering from migraine, both with and without aura, were consecutively enrolled and administered the Migraine Disability Assessment, World Health Organization Disability Assessment Schedule, second version, and the Medical Outcome Survey 36-Item Short-Form Health Survey. Analysis of variance for repeated measures was used to assess longitudinal differences between baseline and the 3-month follow-up at employed assessments, number of days with headache in the previous 3 months and average judgment on attacks' severity, number of triptans and anti-inflammatory drugs consumed for acute treatment of attacks; effect size was used to determine magnitude of change. Baseline differences between completers and non-completers was evaluated with the independent-sample t test. Pearson's correlation was used to cross-sectionally assess the association between total number of headache in the previous 6 months, average headache severity, total number of triptans and anti-inflammatory drugs taken, and the scores observed at follow-up for the 3 assessment instruments. The independent sample t-test was used to assess cross-sectional differences between subjects taking preventive therapy and those taking only acute ones for total number of headaches, their severity, and total number of triptans and anti-inflammatory taken, considering scores referred to the 3-month follow-up evaluation. RESULTS: One hundred and two patients were enrolled (85.3% females; mean age 43.5) and 85 patients (85.9% females; mean age 44.3) completed the 3-month follow-up; no relevant differences between completers and non-completers were observed. Small changes (effect size <0.50) were observed in longitudinal analysis, in particular for World Health Organization Disability Assessment Schedule scales, while frequency and severity of headaches were substantially stable. Few significant correlations were observed, in particular between the total number of days with headache and Migraine Disability Assessment score (0.54; P < .01), and between the total number of days with headache and the total number of triptans taken (0.46; P < .01). Compared with patients taking acute medication only, those on preventive therapy reported worse general health (mean 50.3, standard deviation [SD] 21.0 compared with mean 63.8, SD 16.5; t = 3.31, P = .001) and consumed less anti-inflammatory drugs (mean 3.5, SD 5.6 compared with mean 7.5, SD 9.1; t = 2.25, P = .014). CONCLUSIONS: In this study, migraine frequency and intensity were almost stable over 3 months, and an evident trend toward improvement was found in disability and in some health-related quality of life aspects, particularly in the social activity domain. Our results clearly indicate that continuity of care has a positive impact on patients' health status and functioning, also in stable patients already on anti-migraine therapy, and that the use of patient-oriented outcome measures is a viable way to capture such improvements. PMID- 23094761 TI - Interaction of celecoxib with membranes: the role of membrane biophysics on its therapeutic and toxic effects. AB - The present work provides a biophysical characterization of the interaction of celecoxib, a cyclo-oxigenase-2 selective nonsteroidal anti-inflammatory drug, with membranes using liposomes, constituted by phosphatidylcholines, as membrane model systems. In order to mimic biological conditions, the experiments were performed at physiological pH (7.4); at an acidic pH to mimic the conditions of the inflamed cells (5.0); and at different membrane physical states (gel, ripple, and fluid phase). Important information regarding the celecoxib-membrane interactions was gathered by the complementary biophysical techniques: derivative spectrophotometry was used to determine liposome/water partition coefficient of celecoxib; dynamic light scattering (DLS) measurements were performed to study the influence of celecoxib on lipid main phase transition temperature; fluorescence binding measurements were made to assess the location of celecoxib within the membrane; and small-angle and wide-angle X-ray scattering (SAXS and WAXS) were used to assess the changes in the structure and order of phosphatidylcholine bilayers caused by the presence of celecoxib. The overall results obtained indicate that celecoxib greatly interacts with membranes. Briefly, celecoxib exhibits a high liposome/water partition coefficient that is non-pH-dependent, but the location of celecoxib within the membrane is pH dependent. In fact, celecoxib is more deeply located inside the membrane at pH 5.0, while it locates closer to the surface at pH 7.4. DLS, SAXS, and WAXS results have shown a high membrane fluidization in the presence of celecoxib, especially at pH 7.4. Overall, the current study can contribute to a biophysical characterization of the celecoxib-membrane interaction. The relevance of the gathered results will be discussed in terms of the reported celecoxib therapeutic and toxic effects. PMID- 23094763 TI - Correlation of activated clotting times and standard laboratory coagulation tests in paediatric non-cardiac surgery. AB - The activated clotting time (ACT) was invented as a whole blood test to detect coagulopathy, but nowadays is almost exclusively used to guide heparin anticoagulation. Although the ACT provides a fairly reliable and fast bedside test of the coagulation status, only a few studies have focused on its use to monitor pre- or intraoperative coagulation status as an early marker of impaired haemostasis or increased bleeding tendency. The aim of this study was to compare intraoperative i-STAT((r)) ACT values with commonly used thresholds of standard coagulation tests for the diagnosis of coagulopathy during paediatric non-cardiac surgery. We performed a prospective, observational study in a University Children's hospital and included 50 paediatric patients who underwent major elective, non-cardiac, surgery. The i-STAT((r)) kaolin ACT test was obtained intraoperatively and compared to the commonly used threshold of standard coagulation tests (PT/INR, aPTT, and plasma fibrinogen level). A total of 181 blood samples were taken from 50 pediatric patients. Moderate correlation was found between ACT and aPTT (r = 0.694; p < 0.001), and all other coagulation tests. The median ACT values remained within the normal range throughout the entire surgical phase, while standard coagulation tests were mostly abnormal during surgery. Intraoperative measurement of ACT did not provide comparable thresholds of normal haemostasis as compared to standard coagulation testing. PMID- 23094762 TI - Human monocyte responses to lipopolysaccharide and 9-cis retinoic acid after laparoscopic surgery for colon cancer. AB - Surgery, even modern minimal invasive laparoscopic surgery, induces an initial inflammatory and acute phase response which is followed by a period of immunosuppression rendering surgical patients more susceptible to infection. Here, we aimed to study changes in monocyte inflammatory responses and inflammatory modulation mechanisms following laparoscopic colorectal surgery for colon cancer. Blood samples were collected from 19 colon cancer patients before, directly after and daily for 3 days following surgery. Blood cells were exposed ex vivo to bacterial lipopolysaccharide (LPS) or the inflammatory modulator 9-cis retinoic acid (9cisRA). In blood samples taken prior to surgery, we found significant pro-inflammatory responses to LPS, indicating classical monocyte activation. Directly after surgery, LPS induced significantly less early pro inflammatory cytokines and monocyte/granulocyte-attracting chemokines. The LPS mediated release of interleukin (IL)-1beta was still significantly attenuated 3 days after surgery. In patient monocytes collected after surgery, we found increased levels of suppressors of cytokine signaling (SOCS)1 and SOCS3 mRNA, reported to be associated with polarization towards resolving macrophages. The retinoic acid isomer 9cisRA, reported to attenuate LPS-mediated inflammatory responses and alter chemokine responses in cultured monocytes, had a similar effect in patient blood. Three days after surgery, 9cisRA still attenuated pro inflammatory responses, but the induction of monocyte chemoattractive protein (MCP)-1/CCL2 mRNA in monocytes was reduced. This study indicates changes in monocyte responses that last for at least 3 days after laparoscopic surgery. PMID- 23094764 TI - [The rational preoperative diagnosis of ovarian tumors - imaging techniques and tumor biomarkers (review)]. AB - The majority of patients who suffer from an early-stage or advanced-stage of ovarian cancer complain about symptoms, mainly gastrointestinal ones. The pelvic examination in ovarian cancer detection is limited by the adnexal position in the pelvis and frequent extraovarian spread of disease. Recently, any reliable tumor biomarker (CA 125 and/or HE4), which can be used in differential diagnosis between benign and malignant ovarian tumors, does not exist. According the results of the largest multicenter International Ovarian Trial Analysis (IOTA), ultrasound if performed by an experienced sonologist is an ideal diagnostic method in differential diagnosis between benign and malignant ovarian tumors. The experienced examiner is also able to detect extraovarian tumor spread and to assess tumor operability. Magnetic resonance imaging (MRI) is used only to complement ultrasound in cases when high tissue resolution is needed. Computed tomography (CT) is a useful method for detection of extraovarian spread, especially in cases when an ultrasound examiner experienced in abdominal scanning is not available. Similarly, fusion of positron emission tomography with CT (PET/CT) is a highly accurate method for the detection of abdominal and extraabdominal tumor spread, but its use is limited by cost and the low availability of this method. On the other hand, PET/CT is not recommended for primary ovarian cancer detection because of its lower sensitivity in comparison to ultrasound and its high false positive rates as well. PMID- 23094765 TI - [Review of current classification and terminology of vulvar disorders]. AB - OBJECTIVE: To summarize current terminology and classification of vulvar disorders. DESIGN: Review article. SETTING: Gynecologic oncology center, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Medical School of Charles University, Prague. METHODS AND RESULTS: Vulvar disorders include wide spectrum of different diagnoses. Multidisciplinary collaboration is frequently needed in diagnostical and therapeutical process. It is essential to use unified terminology using standard dermatological terms, and unified classification for comprehensible communication between different medical professions. Current classification, which is based on Clinical-pathological criteria, was established by International Society for the Study of Vulvovaginal Disease. Recently, there was introduced Clinical classification, which groups disorders according to main morphological finding. CONCLUSIONS: Adequate and unified classification and terminology are necessary for effective communication during the diagnostical process. PMID- 23094766 TI - [Ultrasound in urogynecology]. AB - OBJECTIVE OF THE STUDY: The objective of the study is to display the role and importance of ultrasound examination in urogynecology. DESIGN: Literature review. SETTINGS: Department of Gynecology and Obstetrics, First Medical Faculty, Charles University, General Teaching Hospital, Prague. MATERIAL AND METHODS: Presentation of the standards in use of ultrasound imaging in urogynecology and presentation of our practical skills in ultrasound diagnoses in the management of lower urinary tract dysfunctions and in monitoring of the effect of surgical treatment and its complications. CONCLUSIONS: Ultrasound is an excellent method for the investigation of the lower urinary tract, not only as a diagnostic tool but also for the monitoring of the effect of surgical procedures. PMID- 23094767 TI - [The vaginal tension-free tape procedure solving stress urinary incontinence in woman]. AB - The objective of our work was to summarize tape anti-incontinence operation procedures addressing the stress type of incontinence in women; to evaluate their therapeutic effect and possible peri- or post-operation complications for individual operation procedures. Upon comparison of the selected anti incontinence operation procedures, to recommend which procedure is preferred under what circumstances. PMID- 23094768 TI - [Vaginal prolapse and levator ani avulsion injury]. AB - Levator ani avulsion injury is one of the main factors associated with vaginal prolapse of all compartments. Levator avulsion is the main link between vaginal delivery and subsequent vaginal prolapse - cause and sequel. The risk for prolapse is doubled in women with levator injury (RR = 1,9). The risk for prolapse is mainly expressed for anterior and central compartment. In retrospective analysis of women after vaginal repair without use of implants the recurrence rate was 29%. In subanalysis of only of women with recurrence the avulsion injury was detected in 85%. The risk of recurrence of prolapse after native tissue repair is four times higher if the avulsion is present to those where not. Levator avulsion injury is main etiological and risk factor associated with uterine and vaginal prolapse as the sequel of delivery trauma. This injury also increases significantly the risk of prolapse recurrence after native tissue vaginal repair. PMID- 23094769 TI - [Office hysteroscopy - management and results]. AB - OBJECTIVE: Sum up the knowledge about office hysteroscopy. TYPE OF STUDY: Review of literature and our own experience. SETTING: Department of Gynaecology and Obstetrics, First Faculty of Medicine, Charles University Prague and General Teaching Hospital Prague. METHODS: Data from scientific literature and 10 years of our own experience with office hysteroscopy. CONCLUSIONS: Hysteroscopy provides optical evaluation of uterine cavity. Most of the benign intrauterine organics pathologies could be managed in a outpatient setting with a vaginoscopic approach without any anaesthesia and analgesia. Using that approach we can recommend to perform endometrial target biopsy, resection of endometrial polyps up to 1.5 cm and pedunculated submucous myomas up to 1 cm as well as resection of filmy intrauterine adhesions. Method is comfortable for well managed patients and practically complication-free. PMID- 23094770 TI - [Endometriosis]. AB - OBJECTIVE: To summarize current knowledge of pathogenesis, diagnostics and treatment of endometriosis. DESIGN: Review article. SETTING: Centre for diagnostics and treatment of endometriosis, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Faculty of Medicine of Charles University, Prague. METHODS AND RESULTS: Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflammatory reaction. The condition is predominantly found in women of reproductive age, from all ethnic and social groups. The associated symptoms - pain, infertility - can impact on general physical, mental and social well being. Treatment must be individualised, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multi disciplinary approach involving a pain clinic and counselling should be considered early in the treatment plan. CONCLUSION: Endometriosis is a medical condition with high recurrence rate and especially those patients with deep infiltrating endometriosis should be centralized to the centres experienced in diagnostics, complicated surgical treatment and providing multi-disciplinary approach with adequate postoperative care. PMID- 23094771 TI - [Laparoscopic lymph-node dissection in gynecological surgery]. AB - OBJECTIVE: To analyze our experience with transperitoneal laparoscopic dissection of lymphatic nodes in women with gynecologic malignancies. STUDY DESIGN: Retrospective clinical study. SETTING: Center of gynecologic endoscopy and minimally invasive surgery; Department of Obstetrics and Gynecology, General Faculty Hospital and 1st Medical Faculty in Prague. METHODS: Analysis of data from our laparoscopic procedures in the years 2006-2011. The following procedures have been included: systematic pelvic lymphadenectomy (PLN), paraaortic lymphadenectomy (PALN), pelvic sentinel node excision, focused dissection of bulky lymphatic nodes from pelvis or paraaortic area. RESULTS: We performed 177 primarily laparoscopic procedures pointed at dissection of pelvic and/or paraaortic lymph-nodes. The mean operating time and the mean number of lymph nodes was 82 minutes and 26.5 nodes in patients with PLN, and 75 minutes and 12.5 nodes in patients with PALN. The overall rate of laparo-conversions was 4.5%; the incidence of major complications was 6.8% and of serious bleeding 5.6%. Laparoscopic lymphadenectomy could not be performed or completed in 2.3% of cases. Complications were more frequently associated with PALN than with PLN. SUMMARY: Laparoscopic approach to PLN and PALN is feasible in vast majority of patients. It provides adequate earnings of the lymphatic nodes, tolerable operative time, and relatively low complication rate. The highly experienced operation team for especially high infrarenal PALN is necessary. PMID- 23094772 TI - [Laparoscopic uterus sparing treatment of uterine fibroids]. AB - OBJECTIVE: To report up-to date knowledge on laparoscopic, uterine sparing treatment of uterine fibroids. STUDY DESIGN: Review. SETTING: Uterine Fibroids Center, Department of Obstetrics and Gynecology, Charles University, Prague. METHODS: Analysis of our clinical experience and available literature resources. RESULTS: The management of uterine fibroids depends on the symptoms, location, and size of fibroids and on the reproductive plans of the patient. The surgical treatment has changed from laparotomy to minimally invasive surgery. In general, laparoscopic myomectomy (LM) is considered the best option in symptomatic patients with pregnancy plans. The laparoscopic approach is associated with lower postoperative morbidity as well as lower incidence of massive postoperative adhesion formation compared to laparotomy. The limitation of laparoscopic myomectomy is the size and the number of fibroids but also the location and the accessibility for the laparoscopic suturing. Laparoscopic uterine artery occlusion (LUAO) represents one of the alternatives to LM in patients with multiple small myomas or in patients with fibroids in unfavorable location. LUAO may be advantageously used prior to LM in order to reduce peroperative blood loss or to prevent the persisting fibroids from growing. However there is no universal treatment of uterine fibroids in fertile patients and in each single patient the indication and surgical method should be thoroughly considered. . PMID- 23094773 TI - Detection of fetal major structural anomalies at the 11-14 ultrasound scan in an unselected population. AB - OBJECTIVE: The aim of the study was to determine the efficacy of the 11-14 week scan in detecting fetuses with structural anomalies. STUDY DESIGN AND METHODS: Prospective interventional study in an unselected population of pregnant women in a 5-year period (2003-2008) in a single ultrasound unit. 8889 fetuses with median CRL 65mm (45-84mm) were examined. Continuing pregnancies were rescanned at 20-22 weeks. Actual structural anomalies among newborns from the studied group were obtained from our computerized database. RESULTS: The median maternal age was 30 years (14-50 years). The incidence of anomalies was 16.08 per 1000 (143/8889). Of these, 99 of the 143 were detected with prenatal sonography. 46.9% (67/143) of all anomalies were detected at the 11-14 week scan. Later in pregnancy, another 22.3% (32/143) of structural anomalies were detected. CONCLUSIONS: 67.7% of all antenatally detected malformations by ultrasound were recognized in the 11 14 week scan. Obviously, the second trimester scan cannot be abandoned, as it provides effective detection of other anomalies. PMID- 23094774 TI - [In vitro fertilization - analysis of data in Czech National Assisted Reproduction Register from years 2007-2011]. AB - OBJECTIVE: Analysis of IVF cycles (excluding donor oocytes programs) in Czech National Assisted Reproduction Register (NRAR). DESIGN: Retrospective study. METHODS: We analyzed NRAR data from 1. 1. 2007 to 31. 12. 2011 (107 529 cycles) concerning IVF cycles, according standards of European IVF monitoring - European Society of Human Reproduction and Embryology (EIM ESHRE). RESULTS: Yearly in Czech Republic there is 10 000-14 000 initiated IVF cycles. In agreement with common experience, IVF results differ depending the age of woman. The completeness of data in NRAR decreases significantly during the cycle course; data concerning the delivery after the cycle are missing in more than 50% of cycles in some years. So, parameters of cycle effectiveness are not possible to evaluate yet. CONCLUSION: Number of IVF centers in Czech Republic is still growing. Number of IVF cycles (and similarly frozen embryo transfer cycles) in Czech Republic is in general yearly very similar. In the subgroup of the age under 34, the number of cycles slightly diminishes, in the age group 34-40 increases. Number of cycles in Oocyte donation cycles and in Oocyte reception cycles is increasing. The effectiveness of IVF treatments is not possible to evaluate due to an important part of cycles with missing data concerning pregnancies and deliveries. It is necessary to stimulate centers to send missing data, but also to create the interconnection with the Deliveries register and the Abortions register, to reach data in cases, where it is really difficult to reach them by centers. PMID- 23094775 TI - [Acute or expectant management in premature labour with preterm premature rupture of the membranes?]. AB - OBJECTIVE: To evaluate current knowledge about the management of preterm premature rupture of the membranes (PPROM). DESIGN: Review article. SETTING: Perinatological center, Department of Gynecology and Obstetrics, General Faculty Hospital and 1st Medical School of Charles University, Prague. METHODS AND RESULTS: Expectant management in case of PPROM increases the incidence of infection/ inflammation but does not statistically increase mortality and serious morbidity of the infants. The incidence of infants morbidity corresponds with gestational age. The most serious complications occur in the lower gestational age. It is necessary to take an individual approach. The acute management increases the number of operative deliveries and respiratory distress syndrome (RDS) in the infants. The combination of RDS, extremely prematurity and hypoxia during the labour decreases the infants survival rate. CONCLUSIONS: The prolongation of the latency period in pregnancies above 28th week does not deteriorate the neonatal mortality or morbidity. PMID- 23094776 TI - [Childbirth analgesia and anesthesia in the Czech Republic in 2012. The 20th anniversary of post-graduate education]. AB - The aim of this study was to ascertain the current status of analgesia and anesthesia used during childbirth in the Czech Republic. Using data from questionnaires, an overview of individual labor-related anesthetic procedures and methods and frequency of their use was obtained. A positive trend in the increase of neuroaxial methods used in maternity wards over the last twenty years has been the result of a systematic program of interdisciplinary post-gradual education for doctors and birth attendants in the Czech Republic. PMID- 23094777 TI - [Comparison of short term results of TVT-O and TVT-S in the surgical treatment of stress urinary incontinence]. AB - OBJECTIVE OF THE STUDY: To compare short term results of tension free vaginal tape - obturator (TVT-O) and the tension free vaginal tape Seccure in the treatment of urodynamic stress urinary incontinence (USI). DESIGN: Randomize trial. SETTINGS: Department of Gynecology and Obstetrics, First Medical Faculty, Charles University; General Teaching Hospital, Prague. MATERIAL AND METHODS: This single-centre randomized three-arm trial compared the objective and subjective efficacy and early failure rate of the TVT-O and TVT-S H and U approach by objective criteria (cough test) and subjective criteria using the International Consultation on Incontinence Questionnaire-Short form (ICIQ-UI SF). The objective efficacy rate was defined as the number of patients with a negative cough stress test. Subjective cure was defined by no stress leakage of urine after surgery based on evaluation of ICIQ - UI SH (when patients ticked "Never" / "Urine does not leak" in answer to Question 6: When does urine leak?). RESULTS: 197 women with proved SUI were randomized into three groups - TVT-O (68), TVT-S H (64) and TVT-S U (65). Each patient allocated to a treatment group received the planned surgery. There were no differences in each group in pre-operative characteristics. Three months after surgery were analyzed 65 women in TVT-O group, 61 in TVT-S H and 60 in TVT-S U. 95.4% subjects in the TVT-O group, 82% in the TVT-S H group and 76.7% in the TVT-S U group had stress test negative (p=0.006). 90.8% subjects in the TVT-O group, 82% in the TVT-S H group and 78.3% in the TVT-S U group were subjectively continent (NS). CONCLUSIONS: Our study demonstrated a significantly lower objective cure rate in the single incision TVT S group compared to the TVT-O group three months after surgery. PMID- 23094778 TI - [Atypical pain in the uterine rupture]. AB - OBJECTIVE: To give attention to the rare complication of pregnancy. DESIGN: Case report. SETTINGS: Dept. of Obstetric and Gynecology, 1st Faculty of Medicine, Charles University and General Faculty Hospital Prague. METHODS: Description of acute abdominal pain which imitated the appendicitis in case of the uterine rupture. CONCLUSION: The uterine rupture is the rare and very dangerous complication of pregnancy. In the time of increasing number of the cesarean section and the operation on the uterine wall, we must thing on the uterine rupture. PMID- 23094779 TI - [Epidemiology of genital warts in female population of Czech Republic]. AB - OBJECTIVE: The aim of study was to evaluate prevalence of genital warts in Czech Republic. SUBJECT: Multicentric prospective observation study. SETTING: HPV College. METHODS: During 6 month (February 2010 - July 2010) 20 private gynaecological centers in all Czech Republic were counting up the number of genital warts cases. Risk factors, therapy and knowledges about genital warts were evaluated. RESULTS: There were 637 patients with genital warts in cohort of 70 980 patients. The prevalence of genital warts was 0.89%. The most frequent risk factor was cigarette smoking in 37%. Main strategy for treatment were podophyllin local application and cold knife excision. CONCLUSION: The prevalence of genital warts in our study has shown importance for its prevention by rules of safety sex and HPV vaccination against HPV type 6 and 11. PMID- 23094780 TI - [Validity of the oncological cytodiagnostics and colposcopy examination versus biopsy in cervical carcinoma prevention]. AB - THE AIM OF THE STUDY: The basic praebioptic methods detecting the precancerous lesions of the uterine cervix are oncologic cytology (PAP smears) and colposcopy. However in the Czech Republic the incidence of the invasive carcinomas during the last 10 years did not considerably decrease. Therefore the goal of our study is to estimate the validity of the prebioptic methods and compare the results of praebioptic methods (procedures) versus biopsy. TYPE OF THE STUDY: Analysis of the results of the oncologic cervical cytology comparing with the results of cervical biopsies performed during the years 2002-2003 were compared to those of the year 2009. THE SUBJECT AND METHODS OF THE STUDY: evaluation of the prebioptic methods (cytology, colposcopy) versus biopsy prior and during the start of the National Screening in the Czech Republic. SETTING: 1. Centre for Gynaecological Oncological prevention, 1st Faculty of Medicine, Charles University Prague, Department of Gynaecology and Obstetrics. 2. Institute of Physiology, Department of cybernetics, 1st Faculty of Medicine, Charles University, Prague. 3. Institute of Pathology, University of Ostrava. 4. Institue for Mother and Child Care, Prague. SUMMARY: We screened the documentation related to the treatment of 423 women with cervical lesions, examined at the Oncological prevention centre of the Obstetrical and Gynaecological Department of the 1st Faculty of Medicine Charles University Prague and the General Teaching Hospital in Prague 2. Results of the oncologic cytology, colposcopy and biopsy were compared. The comparison revealed differences related to the time of examinations. During the years 2002 and 2003 the agreement between cytologic diagnosis and biopsies in the group of HSIL was 40 %. In the year 2009 the agreement between HSIL and CIN was 68% the colposcopic diagnosis of precancerous lesions with those of bioptic specimens, during the years 2002 and 2003 was 90% while in the year 2009, during the National Screening, the agreement reached 98%. PMID- 23094782 TI - Vemurafenib for the treatment of melanoma. AB - INTRODUCTION: Metastatic melanoma is an aggressive disease resistant to chemotherapy. Recent clinical trials have reported improved survival for two novel agents; ipilimumab, a humanized, IgG1 monoclonal antibody that blocks cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and vemurafenib , a BRAF (v raf murine sarcoma viral oncogene homolog B1) inhibitor targeting an activating mutation in the serine-threonine-protein kinase BRAF gene. AREAS COVERED: The authors reviewed preclinical and clinical data examining the safety of vemurafenib in melanoma. MEDLINE and EMBASE were searched using the medical subject heading 'vemurafenib' and the following text terms: melanoma, BRAF inhibition, vemurafenib. This review provides the reader with an overview of current data examining the efficacy and safety of vemurafenib in metastatic melanoma. EXPERT OPINION: Vemurafenib is an oral agent licensed for patients with BRAF V600E mutation-positive inoperable and metastatic melanoma. The most common adverse effects observed in Phase III clinical trials were dermatological events, arthralgia and fatigue. Specific dermatological toxicities included development of cutaneous squamous cell cancers and keratoacanthomas. Prolongation of the QT interval was also reported. Regular dermatological assessments and electrocardiograms are recommended. Ongoing trials are examining vemurafenib in both the adjuvant setting and metastatic setting in combination with ipilimumab and MEK inhibitors (mitogen-activated protein kinase/extracellular signal regulated kinase). Understanding and overcoming mechanisms of resistance to BRAF inhibitors is the focus of ongoing research. PMID- 23094783 TI - Abnormal serum free light chain ratio predicts poor overall survival in mantle cell lymphoma. AB - Serum free light Chain (sFLC) ratios have been correlated with survival outcomes in Hodgkin and non-Hodgkin lymphoma subtypes. This study was undertaken to investigate the prognostic impact of abnormal sFLC ratios in mantle cell lymphoma (MCL). two patient cohorts were analysed for sFLC parameters: a preliminary retrospective cohort and a uniformly treated cohort of 20 relapsed/refractory MCL patients, enrolled in a phase II clinical trial of single agent lenalidomide treatment. 52% of patients had an abnormality of one or more sFLC parameter (71% of the first cohort and 40% of the second cohort). In cohort two, a high baseline SFLC ratio correlated with poorer overall survival (OS) compared to a low/normal ratio (median OS: 1.4 months vs. 19 months respectively; P = 0.001). For patients presenting with an elevated sFLC ratio at trial entry a rise of >35% in the sFLC ratio correlated with disease progression and a sFLC ratio of >2* normal at trial entry correlated with aggressive disease. These data are the first to show a clear clinical correlation between sFLC ratios and survival outcomes in a uniformly treated cohort of MCL patients. We suggest that these markers may be useful in managing patients with MCL in the future. PMID- 23094785 TI - The structure of MLn(hfbc)4 and a key to high circularly polarized luminescence. AB - The heterobimetallic complex CsEu[(+)-hfbc](4) (hfbc = 3-heptafluorobutyryl camphorate), prepared by Kaizaki and co-workers, displays the highest ratio of polarization versus total luminescence (measured by the g(lum) factor), i.e., ~85% of the emitted photons at 595 nm are left-circularly polarized. We present a detailed structural analysis in solution, based on paramagnetic nuclear magnetic resonance (NMR), and discuss the possible dynamic processes, where its analogues are involved. We demonstrate that the first coordination sphere is very close to the achiral regular square antiprism (SAPR) with D(4d) symmetry, which rules out the intrinsic dissymmetry of the Eu environment for rationalizing the g(lum). In contrast, the dynamic coupling between the f-f transitions, responsible for the emission, to the ligand-centered pi-pi* transition at 310 nm displays almost ideal geometry to justify g(lum) and discloses a key to high circularly polarized emission. PMID- 23094781 TI - Defining evolutionary boundaries across parapatric ecomorphs of Black Salamanders (Aneides flavipunctatus) with conservation implications. AB - The accurate delimitation of evolutionary population units represents an important component in phylogeographic and conservation genetic studies. Here, we used a combined population assignment and historical demographic approach to study a complex of ecomorphologically distinctive populations of Black Salamanders (Aneides flavipunctatus) that are parapatrically distributed and meet at a three-way contact zone in north-western California. We used mitochondrial tree-based and multilocus clustering methods to evaluate a priori two- (Northern and Southern) and three (Northern, Coast and Inland) population hypotheses derived from previous studies. Mitochondrial results were consistent with the two and three-population hypotheses, while the nDNA clustering results supported only the two-population hypothesis. Historical demographic analyses and mtDNA gene divergence estimates revealed that the Northern and Southern populations split during the Pliocene (2-5 Ma). Subdivision of the Southern population into Coast and Inland populations was estimated to be late Pleistocene (0.24 Ma), although our mtDNA results suggested a Pliocene divergence. Effective gene flow estimates (2N(e)m) suggest that either the two- or three-population hypotheses remain valid. However, our results unexpectedly revealed that the Northern population might instead represent two parapatric populations that separated nearly 4 Ma. These results are surprising because the Pliocene divergence between these ecomorphologically conservative forms is similar or older than for the ecomorphologically divergent Coast and Inland sister populations. We conclude that Black Salamanders in north-western California belong to at least three or four populations or species, and these all meet criteria for being Evolutionary Significant Units or 'ESUs' and therefore warrant conservation consideration. PMID- 23094784 TI - Nanoblade delivery and incorporation of quantum dot conjugates into tubulin networks in live cells. AB - Quantum dots (QDs) have not been used to label cytoskeleton structure of live cells owing to limitations in delivery strategies, and QDs conjugation methods and issues with nonspecific binding. We conjugated tubulin to QDs and applied the emerging method of photothermal nanoblade to deliver QD-tubulin conjugates into live Hela cells. This method will open new opportunities for cytosolic targeting of QDs in live cells. PMID- 23094786 TI - Effect of ursodeoxycholic acid and endoscopic sphincterotomy in long-term stenting for common bile duct stones. AB - BACKGROUND AND AIM: We investigated the patency rate of a biliary stent and the effects of ursodeoxycholic acid (UDCA) therapy and endoscopic sphincterotomy (EST) for difficult-to-remove common bile duct stones. METHOD: A total of 63 endoscopic retrograde cholangiopancreatographies (ERCPs) were performed in 36 patients (mean age, 86.0 years; male-female, 17:19) for stenting. Among the 63 subjects, 28 were further treated with EST; 20, with UDCA therapy; and 43, without UDCA therapy. RESULTS: The mean patency time was significantly longer in the UDCA treatment group (1,012 days) than in the "stent without UDCA" group (354 days; P = 0.0002; hazard ratio, 0.253). The mean patency time was significantly longer in the patients who had stent placement with EST (1074 days) than in those who had stent placement without EST (279 days; P = 0.001; hazard ratio, 0.439). The mean patency time was significantly longer in the patients who had stent placement with UDCA therapy and EST (1211 days) than in the patients who had stent placement with either UDCA therapy or EST (425 days; P = 0.031; hazard ratio, 0.3292). The mean patency time was significantly longer in the patients who had stent placement with either UDCA therapy or EST than in those who had stent placement without UDCA therapy or EST (263 days; P = 0.0465; hazard ratio, 0.5124). CONCLUSION: Biliary stenting combined with UDCA therapy and EST may be considered as an effective treatment method for cases of common bile duct stones in elderly patients that are difficult to remove. PMID- 23094787 TI - Dose reduction of antiretrovirals: a feasible and testable approach to expand HIV treatment in developing countries. PMID- 23094789 TI - Approach to hypohidrosis. AB - Hypohidrosis refers to diminished sweating in response to appropriate stimuli. This can cause hyperthermia, heat exhaustion and death. The aetiology of hypohidrosis can be divided into exogenous, dermatological and neurological causes. Exogenous causes act either by systemic neurohormonal inhibition of sweating or localised damage to the skin and sweat glands. Dermatological disorders can result from congenital disorders, wherein other ectodermal tissues may also be affected, or acquired disorders in which manifestations of the primary disease predominate. Neurological disorders should be classified based on an upper motor neuron or lower motor neuron pattern of disease. In the former, there is spasticity and hyperactive reflexes whereas in the latter, flaccidity and hypoactive reflexes predominate. Acquired idiopathic generalised anhidrois refers to isolated anhidrosis with no other detectable abnormalities. When approaching a patient with hypohidrois, exogenous causes should first be excluded. Physical examination, paying attention to mucocutaneous manifestations and neurological signs, will dichotomise if the lesion is dermatological or neurological. In the former, a skin biopsy is the investigation of choice. In the latter, one should consider magnetic resonance imaging of the brain and spinal cord for upper motor neuron lesions, nerve conduction tests for lower motor neuron lesions and autonomic nerve function tests for autonomic dysfunction. Finally, if a diagnosis of acquired idiopathic generalised anhidrosis is suspected, a quantitative sudomotor axon reflex test and serum immunoglobulin-E levels may be performed. Treatment involves addressing the underlying condition and avoidance of aggravating factors. Acquired idiopathic generalised anhidrosis responds well to high dose systemic corticosteroids. PMID- 23094788 TI - Comparison of de novo cancer incidence in Australian liver, heart and lung transplant recipients. AB - Population-based evidence on the relative risk of de novo cancer in liver and cardiothoracic transplant recipients is limited. A cohort study was conducted in Australia using population-based liver (n = 1926) and cardiothoracic (n = 2718) registries (1984-2006). Standardized incidence ratios (SIRs) were computed by cancer type, transplanted organ and recipient age. Cox regression models were used to compare cancer incidence by transplanted organ. During a median 5-year follow-up, the risk of any cancer in liver and cardiothoracic recipients was significantly elevated compared to the general population (n = 499; SIR = 2.62, 95%CI 2.40-2.86). An excess risk was observed for 16 cancer types, predominantly cancers with a viral etiology. The pattern of risk by cancer type was broadly similar for heart, lung and liver recipients, except for Merkel cell carcinoma (cardiothoracic only). Seventeen cancers (10 non-Hodgkin lymphomas), were observed in 415 pediatric recipients (SIR = 23.8, 95%CI 13.8-38.0). The adjusted hazard ratio for any cancer in all recipients was higher in heart compared to liver (1.29, 95%CI 1.03-1.63) and lung compared to liver (1.65, 95%CI 1.26-2.16). Understanding the factors responsible for the higher cancer incidence in cardiothoracic compared to liver recipients has the potential to lead to targeted cancer prevention strategies in this high-risk population. PMID- 23094791 TI - Multi-scale simulation of the simian immunodeficiency virus fusion peptide. AB - Fusion peptides of type I fusion glycoproteins are structural elements of several enveloped viruses which enable the fusion between host and virus membranes. It is generally suggested that these peptides can promote the early fusion steps by inducing membrane curvature and that they adopt a tilted helical conformation in membranes. Although this property has been the subject of several experimental and in silico studies, an extensive sampling of the membrane peptide interaction has not yet been done. In this study, we performed coarse-grained molecular dynamic simulations in which the lipid bilayer self-assembles around the peptide. The simulations indicate that the SIV fusion peptide can adopt two different orientations in a DPPC bilayer, a major population which adopts a tilted interfacial orientation and a minor population which is perpendicular to the bilayer. The simulations also indicate that for the SIV mutant that does not induce fusion in vitro the tilt is abolished. PMID- 23094790 TI - Trade-off in the effect of the APOE gene on the ages at onset of cardiocascular disease and cancer across ages, gender, and human generations. AB - Decades of studies of candidate genes show their complex role in aging-related traits. We focus on apolipoprotein E e2/3/4 polymorphism and ages at onset of cardiovascular diseases (CVD) and cancer in the parental and offspring generations of the Framingham Heart Study participants to gain insights on the role of age and gender across generations in genetic trade-offs. The analyses show that the apolipoprotein E e4 allele carriers live longer lives without cancer than the non-e4 allele carriers in each generation. The role of the e4 allele in onset of CVD is age- and generation-specific, constituting two modes of sexually dimorphic genetic trade-offs. In offspring, the e4 allele confers risk of CVD primarily in women and can protect against cancer primarily in men of the same age. In the parental generation, genetic trade-off is seen in different age groups, with a protective role of the e4 allele against cancer in older men and its detrimental role in CVD in younger women. The puzzling complexity of genetic mechanisms working in different genders, ages, and environments calls for more detail and systemic analyses beyond those adapted in current large-scale genetic association studies. PMID- 23094792 TI - Imaging diagnosis-bilateral abnormal ossification of the supraglenoid tubercle and cranial glenoid cavity in an English Setter. AB - An 8-month-old intact male English Setter was presented with bilateral shoulder lameness. Radiographic and CT examinations demonstrated bilateral irregular margination and separation of the supraglenoid tubercle from the scapula, with involvement of the cranial articular surface of the glenoid cavity. After 30 days of cage rest, complete fusion of proximal portions of both supraglenoid tubercles and persistent un-united cranial portions of both glenoid cavities were evident. Histopathologic findings from biopsies of glenoid cavity defects were consistent with osteochondrosis or focal chondrodysplasia. PMID- 23094793 TI - Commentary: Early father-infant interaction and externalizing behaviors--a response to Ramchandani et al. (2013). AB - Many researchers have attempted to uncover the precise contribution of fathers to childrearing in relation to both young and older children's development during the past five decades (Lamb, 1975), including during the infancy period (Parke & O'Leary. S, 1975). However, few have been able to isolate precise mechanisms by which specific types of paternal childrearing practices may be linked to specific types of prosocial and problem behavior. The current paper by Ramchandani et al. (2013) breaks new ground in identifying a precise dimension of paternal parenting during early infancy--engagement--and linking it to maternal reports of infant externalizing problem behavior. Importantly, this association was found after accounting for the influence of several child, paternal, and maternal characteristics, including observed maternal sensitivity. Specifically, the authors found that fathers observed to be less engaging with their 3-month olds were reported by mothers to show fewer disruptive problems 9 months later. PMID- 23094794 TI - Lack of drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and warfarin in healthy volunteers. AB - AIM: To investigate potential drug-drug interactions between empagliflozin and warfarin. METHODS: Healthy subjects (n = 18) received empagliflozin 25 mg qd for 5 days (treatment A), followed by empagliflozin 25 mg qd for 7 days (days 6-12) with a single 25 mg dose of warfarin on day 6 (treatment B), and a single 25 mg dose of warfarin alone (treatment C), in an open-label, crossover study. Subjects received treatments in sequence AB_C or C_AB with a washout period of >=14 days between AB and C or C and AB. RESULTS: Warfarin had no effect on empagliflozin area under concentration-time curve or maximum plasma concentration at steady state (AUC(tau,ss) or C(max,ss)): geometric mean ratios (GMRs) (90% confidence intervals [CI]) were 100.89% (96.86, 105.10) and 100.64% (89.79, 112.80), respectively. Empagliflozin had no effect on AUC from 0 h to infinity (AUC(0 infinity)) or C(max) for R- or S-warfarin (GMRs [90% CI] for AUC(0-infinity): 98.49% [95.29, 101.80] and 95.88% [93.40, 98.43], respectively; C(max): 97.89% [91.12, 105.15] and 98.88% [91.84, 106.47], respectively). Empagliflozin had no clinically relevant effects on warfarin's anticoagulant activity (international normalised ratio [INR]) (GMR [95% CI] for peak INR: 0.87 [0.73, 1.04]; area under the effect-time curve from 0 to 168 h: 0.88 [0.79, 0.98]. No drug-related adverse events were reported for empagliflozin after monotherapy or combined administration. The combination of empagliflozin and warfarin was well tolerated. CONCLUSIONS: No drug-drug interactions were observed between empagliflozin and warfarin, indicating that empagliflozin and warfarin can be co-administered without dosage adjustments of either drug. PMID- 23094795 TI - Cytotoxic effects of Jay Amin hydroxamic acid (JAHA), a ferrocene-based class I histone deacetylase inhibitor, on triple-negative MDA-MB231 breast cancer cells. AB - The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [ Spencer , et al. ( 2011 ) ACS Med. Chem. Lett. 2 , 358 - 362 ]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC(50) of 8.45 MUM at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G(2)/M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short- (5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of "aggressive" breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity. PMID- 23094796 TI - Effect of an obesogenic diet during the juvenile period on growth pattern, fatness and metabolic, cardiovascular and reproductive features of Swine with obesity/leptin resistance. AB - The objective of this study was to determine, in a female swine model of leptin resistance (Iberian pig), the effect of an obesogenic diet, with high saturated fat content, during the juvenile period, on the appearance of early obesity and its possible effects on metabolic syndrome-related parameters and reproductive features (puberty attainment). Thus, from 130 to 245 days-old, seven Iberian gilts had ad libitum access to food enriched with saturated fat whilst six females acted as controls and had ad libitum access to a commercial maintenance diet. Results showed that a high fat intake-level during the juvenile period induces early obesity with lower body weight and size but a higher body fat content. Such obesity was related with impairments of glucose regulation predisposing for insulin resistance, but also with an earlier onset of puberty. However, there were no signs of hypertriglyceridemia and hypertension; the gilts diminish their intake level and modify their metabolic features by increasing insulin secretion. In conclusion, Iberian gilts freely eating saturated fat diets during the juvenile period have the prodrome of metabolic syndrome but, during their juvenile period, are still able to develop an adaptive response to the diet. PMID- 23094797 TI - Reversible visual loss caused by combination therapy of alfuzosin and finasteride in a patient with uveitic glaucoma. AB - PURPOSE: To report a case of ischemic optic neuropathy caused by medication for benign prostatic hyperplasia (BPH). METHODS: The medical record of a patient who experienced gradual visual loss during the BPH medication was retrospectively reviewed. OBSERVATIONS: A 60-year-old man who had uveitic glaucoma, presented with gradual decrease of visual acuity in the left eye over 3 months. There were no signs of increased intraocular pressure or recurrence of uveitis; however, the best-corrected visual acuity of the left eye had decreased from 20/20 to 20/70. Decreased color vision and a relative afferent pupillary defect were present in the left eye. The patient had been taking a combination regimen of alfuzosin and finasteride for the past 6 months to treat BPH. He reported experiencing frequent episodes of dizziness after starting the BPH medication. Under the impression that he had ischemic optic neuropathy due to systemic hypotension caused by the medication, we switched his regimen to a monotherapy of tamsulosin. After 1 month, the visual acuity and color vision of the left eye was recovered. CONCLUSIONS: Optic nerves affected by glaucoma may be more vulnerable to systemic hypotension, resulting in an increased risk of further ischemic injury. Drugs that can induce systemic hypotension should be prescribed with caution to glaucoma patients. PMID- 23094798 TI - Hydrogen gas acts as a novel bioactive molecule in enhancing plant tolerance to paraquat-induced oxidative stress via the modulation of heme oxygenase-1 signalling system. AB - Hydrogen gas (H2) was recently proposed as a novel antioxidant and signalling molecule in animals. However, the physiological roles of H2 in plants are less clear. Here, we showed that exposure of alfalfa seedlings to paraquat stress increased endogenous H2 production. When supplied with exogenous H2 or the heme oxygenase-1 (HO-1)-inducer hemin, alfalfa plants displayed enhanced tolerance to oxidative stress induced by paraquat. This was evidenced by alleviation of the inhibition of root growth, reduced lipid peroxidation and the decreased hydrogen peroxide and superoxide anion radical levels. The activities and transcripts of representative antioxidant enzymes were induced after exposure to either H2 or hemin. Further results showed that H2 pretreatment could dramatically increase levels of the MsHO-1 transcript, levels of the protein it encodes and HO-1 activity. The previously mentioned H2-mediated responses were specific for HO-1, given that the potent HO-1-inhibitor counteracted the effects of H2. The effects of H2 were reversed after the addition of an aqueous solution of 50% carbon monoxide (CO). We also discovered enhanced tolerance of multiple environmental stresses after plants were pretreated with H2 . Together, these results suggested that H2 might function as an important gaseous molecule that alleviates oxidative stress via HO-1 signalling. PMID- 23094799 TI - Mosaic structure of native ant supercolonies. AB - According to the inclusive fitness theory, some degree of positive relatedness is required for the evolution and maintenance of altruism. However, ant colonies are sometimes large interconnected networks of nests, which are genetically homogenous entities, causing a putative problem for the theory. We studied spatial structure and genetic relatedness in two supercolonies of the ant Formica exsecta, using nuclear and mitochondrial markers. We show that there may be multiple pathways to supercolonial social organization leading to different spatial genetic structures. One supercolony formed a genetically homogenous population dominated by a single mtDNA haplotype, as expected if founded by a small number of colonizers, followed by nest propagation by budding and domination of the habitat patch. The other supercolony had several haplotypes, and the spatial genetic structure was a mosaic of nuclear and mitochondrial clusters. Genetic diversity probably originated from long-range dispersal, and the mosaic population structure is likely a result of stochastic short-range dispersal of individuals. Such a mosaic spatial structure is apparently discordant with the current knowledge about the integrity of ant colonies. Relatedness was low in both populations when estimated among nestmates, but increased significantly when estimated among individuals sharing the same genetic cluster or haplogroup. The latter association indicates the important historical role of queen dispersal in the determination of the spatial genetic structure. PMID- 23094800 TI - Cosmetic reconstruction of a nasal plane and rostral nasal skin defect using a modified nasal rotation flap in a dog. AB - OBJECTIVE: To report reconstruction of a defect of the nasal plane and the rostral dorsum of the nose in a dog using a nasal rotation flap with Burow's triangles. STUDY DESIGN: Clinical report. ANIMALS: Mixed-breed dog (1.5 years, 8.6 kg). METHODS: A nasal defect caused by chronic granulomatous inflammation and involving the lateral nasal plane and adjacent rostral nasal dorsum in a dog was reconstructed and closed using a unilateral nasal rotation flap incorporating dorsal nasal plane tissue, with excision of Burow's triangles. RESULTS: The modified unilateral nasal rotation flap was effective in closing a defect of the rostral nasal dorsum. Incorporation of dorsal nasal plane tissue in the flap allowed for a cosmetic reconstruction of the lateral nasal plane defect (wing of nostril). CONCLUSIONS: Skin defects on the rostral dorsum of the nose and defects of the nasal plane in dogs can be closed and/or reconstructed using nasal rotation flaps incorporating nasal plane tissue. PMID- 23094802 TI - Influence of the metal (Al, Cr, and Co) and the substituents of the porphyrin in controlling the reactions involved in the copolymerization of propylene oxide and carbon dioxide by porphyrin metal(III) complexes. 2. Chromium chemistry. AB - The reactivities of chromium(III) complexes LCrX, where L = 5,10,15,20 tetraphenylporphyrin (TPP), 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TFPP), and 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP) and X = Cl or OH, have been studied with respect to their ability to homopolymerize propylene oxide (PO) and copolymerize PO and CO(2) to yield polypropylene oxide (PPO) and polypropylene carbonate (PPC) or propylene carbonate (PC), respectively, with and without the presence of a cocatalyst, namely, 4-dimethylaminopyridine (DMAP) or PPN(+)Cl(-) (bis(triphenylphosphine)iminium chloride). The homopolymerization is notably faster (TOF ~ 2000 h(-1) at room temperature) than copolymerization, which commonly leads to ether-rich polymers. Studies of kinetics reveal that for TPPCr(OH) with DMAP (1 equiv) the propagation reaction rate is first order in [Cr] with excess PO. With PPN(+)Cl(-) as a cocatalyst the reaction order in [Cr] and [Cl(-)] is complicated by the presence of two growing chains, and the presence of excess [Cl(-)] facilitates the formation of PC by two different backbiting mechanisms. The fixation of CO(2) is promoted by [Cl(-)] but is not greatly influenced by CO(2) pressure (1-50 bar). The reactions and polymers have been monitored by UV-visible spectroscopy, react-IR, GPC, ESI, and MALDI TOF, and NMR ((1)H, (13)C{(1)H}) spectroscopy. Notable differences are seen in these reactions when compared with earlier studies by Darensbourg et al. with salen chromium(III) systems and related aluminum(III) porphyrins. PMID- 23094801 TI - Exploring the efficacy and safety of single-agent sorafenib in a cohort of Italian patients with hepatocellular carcinoma. AB - This study investigates the effectiveness and safety of sorafenib in a heterogeneous cohort of Child-Pugh A, B and C patients with advanced hepatocellular carcinoma in a clinical-practice scenario. Adult patients with hepatocellular carcinoma and treated with sorafenib 800 mg/day were eligible for this multicentric retrospective observational study. Safety analyses were performed and the effectiveness of sorafenib was assessed in terms of time to progression (TTP) and overall survival (OS). In total, 93 patients were enrolled: 14 were Child-Pugh A, 70 were Child-Pugh B and nine were Child-Pugh C. No differences in the frequency of grade 3 adverse events among different Child-Pugh classes were reported. In the overall cohort, median OS was 12 months (95% CI: 11.7-12.8 months) and TTP was 3 months (95% CI: 2.5-3.4 months). The Child-Pugh score had a statistically significant effect on TTP: 6.6 months in Child-Pugh A, 2.8 months in Child-Pugh B and 2.0 months in Child-Pugh C patients (p = 0.012). To our knowledge, this study includes the largest cohort of Caucasian Child-Pugh B and C patients ever treated with sorafenib. Although the retrospective design of this study does not allow reaching any definite conclusion, the results could lend some preliminary support to the safety and the effectiveness of sorafenib monotherapy in patients with Child-Pugh B and Child-Pugh C liver function. PMID- 23094803 TI - Enhanced ultraviolet emission from poly(vinyl alcohol) ZnO nanoparticles using a SiO2-Au core/shell structure. AB - Enhanced near band gap edge (NBE) emissions of PVA-ZnO nanoparticles were achieved by employing SiO(2)-Au core/shell nanostructures whereas the defect level emission (DLE) is greatly suppressed. A maximum enhancement of nearly 400% was observed using SiO(2)-Au for the emission with optical resonance at 554 nm. SiO(2)-Au core/shell nanostructures also show a superior tunability of resonance energy as compared to that of the pure metal nanoparticles. The enhancement of the NBE emission and suppressed DLE is ascribed to the transfer of the energetic electrons excited by surface plasmon from metal nanoparticles to the conduction band of ZnO nanoparticles. PMID- 23094805 TI - How we decide when a neonate needs a transfusion. AB - The decision to transfuse a neonate can be approached by addressing a series of questions that cover the cause of anaemia, alternatives to transfusion, the need for transfusion and the risks. Recent clinical trials of red cell transfusions have started to inform evidence-based transfusion practice, but have raised uncertainties about neurological outcomes when policies advocating use of fewer red cell transfusions at lower haemoglobin concentration (Hb) thresholds were tested. Red cell transfusions should be considered when the Hb <120 g/l for premature neonates requiring mechanical ventilation support, with lower thresholds applying for oxygen-dependent neonates not requiring ventilation or for late anaemia (Hb <70-100 g/l, depending on gestational and post-natal age). There is no recent high quality evidence to inform thresholds for prophylactic platelet transfusions in stable non-bleeding premature neonates with platelet count levels of 50 * 10(9) /l, although common practice has become more restrictive, using lower safe thresholds for platelet transfusion between 20 and 30 * 10(9) /l. A more appropriate transfusion strategy for fresh frozen plasma (FFP) in neonates is one that emphasizes the therapeutic use of FFP in the face of bleeding, rather than prophylactic use in stable non-bleeding neonates who often have mild to moderate apparent abnormalities of standard coagulation tests, after allowing for appropriate reference ranges. PMID- 23094804 TI - The effect of environmental enrichment on substantia nigra gene expression after traumatic brain injury in rats. AB - Experimental investigations into the effects of traumatic brain injury (TBI) have demonstrated significant alterations in dopaminergic systems. Dopaminergic fibers originating within the substantia nigra and ventral tegmental area (VTA) are important for reward learning, addiction, movement, and behavior. However, little is known about the effect of TBI on substantia nigra and VTA function. Environmental enrichment (EE) has been shown to improve functional outcome after TBI, and a number of studies suggest that it may exert some benefits via dopaminergic signaling. To better understand the role of dopamine in chronic TBI pathophysiology and the effect of EE, we examined the mRNA expression profile within the substantia nigra and VTA at 4 weeks post-injury. Specifically, three comparisons were made: 1) TBI versus sham, 2) sham+EE versus sham+standard (STD) housing, and 3) TBI+EE versus TBI+STD. There were differential expressions of 25, 4, and 40 genes in these comparisons, respectively. Chronic alterations in genes post-injury within the substantia nigra and VTA included genes important for cellular membrane homeostasis and transcription. EE-induced gene alterations after TBI included genes important for signal transduction, in particular calcium signaling pathways, membrane homeostasis, and metabolism. Elucidation of these alterations in gene expression within the substantia nigra and VTA provides new insights into chronic changes in dopamine signaling post-TBI, and the potential role of EE in TBI rehabilitation. PMID- 23094806 TI - 'You don't get told anything, they don't do anything and nothing changes'. Medicine as a resource and constraint in progressive ataxia. AB - BACKGROUND: Progressive ataxias are neurological disorders affecting balance, co ordination of movement and speech. OBJECTIVE: A qualitative study was undertaken to discover patients' experiences of ataxia and its symptoms. PARTICIPANTS: Thirty-eight people with ataxia recruited from patient support groups and two hospital outpatients departments. DESIGN: Cross-sectional qualitative study with thematic analysis. RESULTS: These accounts highlight the limits of medicine in the context of a rare, incurable and disabling disorder, and the embodied uncertainties brought by slowly progressive diseases that lie at the boundaries of mainstream medical knowledge. The existential crises faced by people with ataxia are seemingly magnified by sometimes idiopathic aetiologies and the limited number of inherited conditions identifiable by the available genetic tests. Interviewees were drawn into a medical system that was focused mainly on the diagnosis process, with widely varying results. However, when asked, most had rather valued the provision of disability aids and physical therapies. Only one informant reported overcoming the myriad uncertainties of progressive ataxia, and their account supported the notion of 'biographical repair' in chronic illness. CONCLUSIONS: Clinical uncertainties in ataxia constrained people's attempts to deal with their condition. The construction of the proactive, informed, medical consumer who is assumed to be a partner in care is problematic in the context of a rare and difficult-to-diagnose disease for which there is usually no cure. Service providers should be mindful of the need to manage patient expectations in relation to diagnosis and cure. More focus might usefully be placed on the provision of physical therapies and disability aids. PMID- 23094807 TI - [A comparison of two methods of long-term external ECG telemonitoring in patients after ablation for atrial fibrillation]. AB - AIM: The aim of the study was to compare two methods of long-term ECG monitoring after atrial fibrillation (AF) ablation. METHODS: The study included 279 patients with paroxysmal (n = 163) or persistent (n = 116) AF, who were followed up for 1 year after the first catheter ablation for AF. All patients were provided with episodic ECG recorder for 1 year and instructed to send at least 2 random ECG recordings per day and whenever they sensed symptoms. They were also provided with external loop recorder for 2-3 weeks at 6 and 12 months to enable more continuous ECG monitoring. RESULTS: At the end of 39 +/- 12 (12-60) month follow up, 143 (88%) patients with paroxysmal AF, and 105 (91%) patients with persistent AF, respectively, remained in stable sinus rhythm. The efficacy of episodic recorder expressed as a ratio of patients with identified AF/atrial tachycardia (AT) out of all patients with a documented episode of AF/AT was superior to the efficacy of loop recorder. No AF/AT episode was recorded with the loop recorder that was not also documented by the episodic recorder. Of the patients with the AF/AT recurrence detected by the episodic recorder, the arrhythmia was also revealed by the loop recorder in 70% of the patients after paroxysmal AF ablation (p < 0.001), and in 52% of the patients after persistent AF ablation (p = 0.006). Asymptomatic AF/AT was present in 42 (26%) of patients with paroxysmal AF, and in 28 (24%) patients with persistent AF (p = 0.810). From conventional follow-up unexpected and clinically significant episode of AF/AT that required change in therapy was detected in 9 (5.5%) patients after ablation for paroxysmal AF, and in 4 (3.4%) patients after ablation for persistent FS. CONCLUSION: More episodes of AF/AT after ablation were detected by 1-year daily ECG monitoring using episodic recorder as compared to periodic ECG monitoring with loop recorder. Identification of clinically significant episodes of AF/AT unrecognized from conventional follow-up was low. PMID- 23094808 TI - [Regular exercise training decreases asymmetric dimethylarginine after kidney transplantation]. AB - BACKGROUND: Levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine are elevated in patients undergoing kidney transplantation and may contribute to vascular complications. In this study we tested the hypothesis that elevated asymmetric dimethylarginine can be reduced in patients after kidney transplantation by early regular physical exercise. Selected cytokines and metabolic parameters were also analysed. METHODS: Plasma samples for analysis of asymmetric dimethylarginine, adiponectin, leptin, soluble leptin receptor, resistin, visfatin, CRP, TNFalpha and selected metabolic parameters were obtained from randomly selected sixty eight patients after kidney transplantation who agreed to participate in a supervised aerobic exercise program for six months. Samples were collected before the training began (one month after surgery with stabilized graft function) and at six months after initiation. Sixty transplant patients matched for age, sex, HLA typing, duration of previous dialysis, history of cardiovascular disease and immunosupression regimen who did not exercise regularly and did not participate in the training program were examined as controls. RESULTS: There were no differences in elevated asymmetric dimethylarginine levels between both groups before the training program began. After six months of exercise, asymmetric dimethylarginine concentration in the exercising group I significantly decreased (3.5 +/- 0.45 vs 2.11 +/- 0.35 umol/L, P < 0.01) and was also significantly lower comparing to non-exercising group II (2.11 +/- 0.23 vs 3.25 +/- 0.34 umol/L, P < 0.01). We found significant changes in exercising group I: adiponectin (15.4 +/- 6.6 vs 22.3 +/- 6.2 mg/mL, P < 0.01), leptin (51.3 +/- 11.2 vs 20.3 +/- 9.2 ng/L, P < 0.01), soluble leptin receptor (24.6 +/- 8.4 vs 46.1 +/- 11.4 U/mL, P < 0.01), resistin (20.8 +/- 10.1 vs 14.6 +/- 6.4 mg/mL, P < 0.025) and visfatin (1.8 +/- 0.2 vs 1.2 +/- 0.01 ng/mL, P < 0.05). Blood lipids, HbA1c, CRP and TNFalpha were also affected by the training program. CONCLUSIONS: Elevated asymmetric dimethylarginine level, selected adipocytokines and proinflammatory cytokines in patients after kidney transplantation were significantly influenced by early regular exercise. This regimen may decrease cardiovascular risk in patients after kidney transplantation. PMID- 23094809 TI - [Superficial thrombophlebitis, unjustly underestimated disease - has the time come to change our view?]. AB - Superficial thrombophlebites represent a very heterogeneous group of diseases which is caused by the difference between two basic forms of ST - varicophlebitis and thrombophlebitis of a "healthy" vein, as well as by other factors - the ratio of thrombotic and inflammatory process, the location and extent of thrombosis in superficial venous system, the distance from deep venous system, the stage of venous insufficiency and the general thrombotic risk of a patient. ST shares many common features with deep vein thrombosis (clinical risk factors, thrombophilic disorders), both diseases often coincide or follow one another. Some authors suggest considering ST as a part of venous thromboembolism in a broader sense. There are ensuing unresolved questions regarding ST management. So far, no evidence-based treatment has been clearly defined. Anticoagulation is recommended in more serious cases but no consensus about dosing and duration has been reached. The CALISTO trial confirmed a benefit of fondaparinux in prophylactic dose in the therapy of isolated ST and the results have been reflected in recent guidelines of expert groups. Further studies to improve our knowledge of ST and to earn more evidence about its management are definitely needed. PMID- 23094810 TI - [Drug compliance - a pitfall of therapy of rheumatoid arthritis?]. AB - Drug compliance is one of the conditions for effective treatment of various chronic diseases, including rheumatoid arthritis as well. This disease is characterized by a variable course, remissions and relapses, and also by specific treatment. The character of this illness and used medications may represent a risk in terms of non-compliance. As in other chronic diseases, scientists engage in identifying of the compliance rate for many years and the aim of this work is to summarize the state of knowledge in the field of drug compliance in rheumatoid arthritis. PMID- 23094811 TI - [Peripartal life-threatening hemorrhage - interdisciplinary consensus opinion]. AB - 22 experts from the fields of gynecology and obstetrics, anesthesiology and resuscitation, intensive care, hematology and transfusion medicine has developed recommendations for diagnosis and procedure for life-threatening peripartum haemorrhage, which is still one of the most common causes of maternal mortality in childbirth. This guidelines, which is valid for the Czech Republic, supported by a total of 10 professional medical societies. There are based on new knowledge applicable at this time and is focused mainly on eliminating the most common causes of bleeding during delivery and prevention of haemorrhagic shock. PMID- 23094812 TI - [Warning about risk of invasive infections in splenectomized patients. Experiences from University Hospital Brno, Czech Republic, in 2011]. AB - Syndrome of fulminant sepsis in splenectomized (overwhelming postsplenectomy infection - OPSI) is feared and often fatal infectious complication in patients after splenectomy. The risk of syndrome of fulminant sepsis in splenectomized in these persons persists lifelong and doesn't diminish during the time. Etiologically, encapsulated bacterias like Streptococcus pneumoniae, Haemophilus influenzae group b and Neisseria meningitidis are involved. As the mortality of syndrome of fulminant sepsis in splenectomized is very high, it is indispensable to educate and vaccinate persons in risk. The authors present case reports of three splenectomized patients who were hospitalized for invasive pneumococcal infection in the University Hospital Brno, Czech Republic, in 2011. PMID- 23094813 TI - [Morbus Weil - a case study and principles]. AB - We present a case of a 66 years old man without significant medical history who was admitted to a geriatric department of a local hospital for a critical clinical state with severe icterus (billirubin 368 umol/l), acute renal failure (urea 48 mmol/l, creatinine 714 umol/l) and severe thrombocytopaenia. When the patients son completed his personal history on the 4th day of hospitalization reporting that the patient had worked in a pub flooded during local floods, we also considered leptospirosis as a potential cause of his current state. Parenteral penicillin antibiotics (amoxicillin + clavulanate) were prescribed and comprehensive infusion rehydration, corrective and haemostyptic treatments were continued. Despite transient worsening of thrombocytopaenia to 8 * 103/ul, we did not observe any severe bleeding, thrombocytopaenia gradually improved and thrombocyte levels were in the reference range from the 7th day of hospitalization. Acute renal failure (ARF) did not involve oliguria and an intensive conservative treatment provided gradual improvement of the clinical status as well as laboratory parameters with creatinine levels at discharge of 121.3 umol/l. Heamodialysis was not used. Billirubin levels also gradually declined to 25 umol/l at discharge. Leptospiral antibodies in the urine and serum were suggestive of leptospirosis. The diagnosis was confirmed with follow up investigations 13 days after discharge. The condition was caused by Leptospira icterohaemorrhagiae. The patients condition was complicated with deterioration of pre-existing hearing impairment. We also expect a contribution of leptospirosis to its anamnesis. Antibiotic treatment continued for 16 day, 7 of which with parenteral administration. Haemodynamically stable, normotensive, afebrile, self sufficient patient was discharged on 37th day of hospitalization to primary care. PMID- 23094814 TI - [Heart tumor manifesting as a sudden cardiac death]. AB - Cardiac tumors are rare. They can be divided into primary and secondary. Primary tumors are benign or malignant. The diagnostics is based on imaging techniques. Therapy is surgical on the first place, followed by chemotherapy and radiotherapy in case of malignant tumors. Prognosis of benign tumors is favourable. We present a case report of a patient dying suddenly after hospital admission on for malignant ventricular arrhythmia. Gradually we revealed a nehodgkin lymphoma infiltration of the heart as the structural fundamental of this arrhythmia. PMID- 23094815 TI - [Our experience in treatment of multicentric plasma-cell Castleman disease associated with vasculitis manifestations - case report and literature review]. AB - Castleman disease is a rare idiopathic non-neoplastic lymphoproliferative disorder with 2 clinical (unicentric and multicentric) and 3 histomorphological (hyaline-vascular, plasma-cell and mixed) forms identified. The case report given here describes the 3-year experience with therapy in a patient, male born 1961, diagnosed with multicentric plasma-cell Castleman disease (HIV and HHV-8 negative) with the finding of generalized lymphadenopathy and splenomegaly. During first line treatment (R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, 3 cycles in total, 12/2008-2/2009) the development of bilateral upper and lower limb edemas with clinical manifestation of vasculitis occurred and a restaging computed tomography (CT) examination revealed a stable finding of the lymphadenomegaly. Greater success was achieved with thalidomide regimen (CTD: cyclophosphamide, thalidomide, dexamethasone, 10 cycles, 3/2009 1/2010) leading to reduction in the size of the hypervascularized lymph nodes (almost by 50%) as well as their radiopharmaceutical (fluorodeoxyglucose) uptake as seen on a combined positron emission tomography and computed tomography (PET/CT) scan imaging. Thalidomide was given daily at doses between 100 and 200 mg. We returned to the CTD regimen again in April 2010 after a short period of monoclonal antibody tocilizumab treatment (400 mg intravenous in 2-week intervals with 50% dose reduction due to a limited supply of the drug, 5 doses in total) during which edemas reoccurred with a CT scan finding of stable lymphadenomegaly. However, the renewed regimen with thalidomide was stopped after 2.5 cycles due to adverse effects of thalidomide (neuropathy) and corticoids (Cushing syndrome). In September 2010, after enrollment in the Celgenes Compassionate Use Program we were able to start treating the patient with the derivative of thalidomide, lenalidomide, at a dosage of 25 mg on days 1-21 in a 28-day cycle, 15 cycles in total (10/2010-12/2011). The monotherapy with lenalidomide was very well tolerated by the patient without any effects of myelotoxicity, thromboembolism or relapses of edemas and vasculitis, additionally now with apparent improvement of fatic disorder and the patients motor abilities. Thus, lenalidomide represents an attractive alternative agent for patients with Castleman disease after rituximab and cytostatics failures. It has a favourable safety profile and could be therefore considered for administering in first line treatment. PMID- 23094816 TI - [Hyperventilation echocardiography in vasospastic angina pectoris diagnosing]. AB - Hyperventilation echocardiography is an established diagnostic test in patients with suspected variant angina pectoris. It has got sufficient sensitivity (60 80%) and specificity (85-100%). Positive hyperventilation test is rarely found, which relates to low prevalence of variant angina. The diagnostic yield of the test depends on the population selected for testing: positive result can be expected in patients with a history of typical burning chest pain, ST segment elevation/depression and/or inversions of U wave during the chest pain episode, arrhythmias related to the chest pain, coronary artery stenosis less than 50% of artery diameter, multi-vessel disease, high activity of illness at the time of hyperventilation test. We present a case of 37 years old man with typical angina pectoris at rest and non-Q myocardial infarction, in whom the coronary angiography was negative. Variant angina pectoris was diagnosed by hyperventilation echocardiography. The ECG tracings showing typical ischemic patterns during the hyperventilation test are included. PMID- 23094817 TI - On the role of histamine receptors in regulating pigmentary responses in Oreochromis mossambicus melanophores. AB - PURPOSE: The present work was carried out to reveal the involvement of histamine receptors at the neuro-melanophore junction of teleost, Oreochromis mossambicus. METHODS: The isolated scale melanophores were assayed using the mean melanophore size index and their responses were recorded in presence of various concentrations of histamine along with H(1) and H(2) receptor specific agonists and antagonist and potentiator compound 48/80. RESULTS: Melanophores showed high sensitivity to histamine and its specific agonists. Histamine caused a dose dependent pigment aggregation, whereas 2-(2-Pyridyl) ethylamine (PEA), a specific H(1)R agonist also caused aggregation in a similar manner. Conversely, amthamine, a specific H(2)R agonist resulted in pigment dispersion. The effects were antagonized by mepyramine; specific H(1)R antagonist and ranitidine a specific H(2)R antagonist. CONCLUSION: It is concluded that O. mossambicus melanophores have both H(1) and H(2) receptors which mediate melanophore aggregation and dispersion respectively. Compound 48/80 augmented the melanin-aggregating and dispersing effects of PEA and amthamine. It is suggested that the effect of histamine is directly mediated through H1 and H2 receptors, whereas H1Rs may be predominantly involved in the aggregatory responses. PMID- 23094818 TI - Medical outcomes in African American live kidney donors: a matched cohort study. AB - It is uncertain if live kidney donation increases future risk of hypertension and kidney disease in African Americans. We conducted a cohort study across two transplant centers enrolling African Americans who donated between 1993 and 2006. A comparison group of African American nondonors were selected from healthy participants in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective cohort study. A total of 103 donors and 235 matched nondonors were assessed at mean ( +/- SD) of 6.8 +/- 2.3 and 6.4 +/- 2.2 years after donation or cohort entry, respectively. The primary outcome was risk of hypertension in donors at follow-up. The secondary outcomes were proportion of donors with eGFR <60 mL/min/1.73 m2 and microalbuminuria. Hypertension risk was higher in donors compared to nondonors (42/103 [40.8%] vs. 42/235 [17.9%]), absolute risk difference 22.9% (95% confidence interval 12.2-33.6%) and relative risk 2.4 (95% confidence interval 1.7-3.4). Of the 42 donors with hypertension, 22 (52.4%) were untreated. Sixteen donors (15.5%) had an eGFR <60 mL/min/1.73 m(2) , 6 (5.8%) had microalbuminuria and none were on dialysis. Our retrospective study shows that live kidney donation is associated with increased risk of hypertension in African Americans and emphasizes the importance of donor follow-up. PMID- 23094819 TI - Identification of microbiota present on the surface of Taleggio cheese using PCR DGGE and RAPD-PCR. AB - Microbial DNA from 9 batches of Taleggio PDO cheese sampled at various times during ripening, brines, swabs of wooden shelves used for cheese dry-salting, and 13 commercial cheeses were analyzed by denaturing gradient gel electrophoresis (PCR-DGGE) and/or random amplification of polymorphic DNA (RAPD-PCR). Sequencing allowed the detection of 12 genera, 27 species, and 2 unclassified bacteria. Molecular analysis allowed for the detection of microorganisms not previously associated with Taleggio such as Lactobacillus paracasei, Carnobacterium maltaromaticum, Bacillus licheniformis, Corynebacterium variabile, Psychrobacter cibarius, and Staphylococcus carnosus. For the first time Massilia spp. was detected in a dairy ecosystem. PRACTICAL APPLICATION: Indigenous species and strains of bacteria identified by this study could be used for the selection of dairy cultures to be employed routinely by manufacturers to control the Taleggio cheese production. The new cultures may give the bases for driving dairy processes and, consequently, control the typical flavor resulting from metabolic actions of environmental microorganisms. PMID- 23094820 TI - Effectiveness and safety of protease inhibitor-based regimens in HIV-infected Thai children failing first-line treatment. AB - OBJECTIVES: Virological failure on first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based treatment regimens has become a problem in HIV-infected children on long-term antiretroviral therapy (ART). Protease inhibitor (PI)-based regimens are therefore often given to children failing NNRTI-based regimens. The aim of the study was to assess the 48-week effectiveness, safety and predictive factors for viral suppression of PI-based regimens in HIV-infected Thai children who had failed NNRTI-based regimens. METHODS: This study assessed 41 HIV-infected children who had failed first-line NNRTI-based regimens and were switched to PI based regimens for at least 48 weeks. We assessed their CD4 cell counts, plasma HIV RNA levels, weight-for-age and height-for-age z-scores, and adverse events. RESULTS: The children's median age was 9.5 years (range 1.5-15.8 years). At baseline, their median CD4 cell count was 276 cells/MUL [interquartile range (IQR) 160-749 cells/MUL], and their median plasma HIV RNA level was 4.5 log10 HIV 1 RNA copies/mL (IQR 3.9-4.8 log10 copies/mL). After 48 weeks of PI-based therapy, their CD4 cell counts increased to a median of 572 cells/MUL (IQR 343 845 cells/MUL) and in 73.2% plasma HIV RNA levels decreased to < 50 copies/mL. Their median weight-for-age and height-for-age z-scores were stable over the period of the study. Diarrhoea occurred in 29.3% of patients. Triglyceride levels were significantly higher at weeks 24 and 48 in comparison to baseline measurements. CONCLUSIONS: PI-based regimens are safe and effective for HIV infected Thai children who have failed first-line NNRTI-based regimens. However, long-term follow-up is warranted in order to ascertain the feasibility and sustainability of these new regimens. PMID- 23094821 TI - Fano-like resonances arising from long-lived molecule-plasmon interactions in colloidal nanoantennas. AB - We examine ultrafast dynamics in a coupled molecule-plasmon system. Using a new ultrafast Raman technique called surface enhanced-femtosecond stimulated Raman spectroscopy (SE-FSRS), we prove that plasmonic nanoparticles and adsorbed molecules are coupled by the appearance of Fano-like lineshapes, which arise from the interaction of narrowband vibrational coherences and the broadband plasmon resonance. We probe the effect of plasmon energy on the vibrational lineshapes and observe changes in the phase of the line shape dispersion. Finally, we examine the effect of plasmon-molecule coupling on the molecular vibrational coherence lifetime. Surprisingly, coupling of the molecular vibration to the plasmon does not significantly shorten the vibrational coherence dephasing time. Better understanding of the ultrafast dynamics of excited vibrational states and vibrational coherences in coupled molecular-plasmonic systems should assist in developing a mechanism-based view of plasmonically enhanced photovoltaic and photocatalytic systems. PMID- 23094822 TI - Histone deacetylase inhibitors: a patent review (2009 - 2011). AB - INTRODUCTION: Given the involvement of histone deacetylases (HDACs) in regulation of gene expression, they are believed to be 'master regulators' of many diseases. Thus, HDAC inhibitors (HDACis) are able to modulate transcriptional activity. These molecules can induce cell cycle arrest, differentiation and apoptosis of tumor cells in culture and in animal models and therefore are emerging as an exciting new class of potential anti-cancer agents for the treatment of solid and hematological malignancies. AREAS COVERED: The aim of this review is to provide an overview of current knowledge and molecular mechanisms of HDACis, and the most recent patents existing in the field of HDACis from 2009 until 2011. EXPERT OPINION: In recent years, an increasing number of structurally diverse HDACis have been identified. In addition, non-cancer diseases, including neurodegeneration, metabolic, inflammatory and autoimmune disorders, infectious and cardiovascular diseases have also been proposed for an HDACi treatment. The growing body of evidence of the potential benefits of disease treatment based on the use of HDACis has led to a large number of patent applications throughout the world. PMID- 23094824 TI - Lymphoma and other lymphoproliferative disorders in inflammatory bowel disease: a review. AB - The lymphoproliferative disorders (LDs) are a heterogeneous group of at least 70 conditions that result from the clonal proliferation of B, T, and NK cells. Inflammatory bowel disease (IBD)-associated lymphomas are typically B-cell LD, while T-cell or Hodgkin's lymphomas are rare. In IBD patients not on immunosuppression, the risk of LD seems to be similar or slightly higher than the background population risk. Thiopurine therapy is associated with an increased risk: the relative risk is increased four- to sixfold and the absolute risk varies between 1 in 4000-5000 for those aged 20-29 to 1 in 300-400 in those over 70. It is difficult to quantify the risk of anti- tumor necrosis factor (TNF) therapy alone; however, it appears to be less than for thiopurines alone. There is particular concern regarding the development of post-transplant-like LD in those with latent epstein-barr virus (EBV) infection exposed to immunosuppressives, the occurrence of hepatosplenic T cell lymphoma in patients treated with combination anti-TNF and thiopurine therapy, and the development of hemophagocytic lymphohistiocytosis in those who acquire a primary EBV or other infections while on immunosuppressive medication. There are currently no guidelines for monitoring EBV (or other virus) status in patients on immunosuppression, although it could be used to monitor those who have a prior history of lymphoma and are about to start a thiopurine or anti-TNF agent. In discussing the risks of lymphoproliferative disorders associated with agents used for the treatment of IBD, patients can often be reassured that the benefits of such therapy still outweigh the small, but real, risks. PMID- 23094823 TI - In vitro modelling of rat mucosal mast cell function in Trichinella spiralis infection. AB - Intestinal infection with the parasitic nematode, Trichinella spiralis, provides a robust context for the study of mucosal mast cell function. In rats, mucosal mast cells are exposed to parasites during the earliest stage of infection, affording an opportunity for mast cells to contribute to an innate response to infection. During secondary infection, degranulation of rat mucosal mast cells coincides with expulsion of challenge larvae from the intestine. The goal of this study was to evaluate the rat bone marrow-derived mast cells (BMMC) and the rat basophilic leukaemia cell line (RBL-2H3) as models for mucosal mast cells, using parasite glycoproteins and antibody reagents that have been tested extensively in rats in vivo. We found that BMMC displayed a more robust mucosal phenotype. Although T. spiralis glycoproteins bound to mast cell surfaces in the absence of antibodies, they did not stimulate degranulation, nor did they inhibit degranulation triggered by immune complexes. Parasite glycoproteins complexed with specific monoclonal IgGs provoked release of rat mast cell protease II (RMCPII) and beta-hexosaminidase from both cell types in a manner that replicated results observed previously in passively immunized rats. Our results document that RBL-2H3 cells and BMMC model rat mucosal mast cells in the contexts of innate and adaptive responses to T. spiralis. PMID- 23094825 TI - Radiographic features of primary and concomitant flexor enthesopathy in the canine elbow. AB - Primary flexor enthesopathy is a recently recognized elbow disorder and should be considered in the differential diagnosis of elbow lameness. For treatment planning purposes, it is important to make a distinction between primary and concomitant forms of the disease. The purpose of this prospective study was to compare radiographic findings for dogs with primary flexor enthesopathy (n = 17), concomitant flexor enthesopathy (n = 24), elbow dysplasia (n = 13), and normal dogs (n = 7). All dogs underwent a complete radiographic examination and each radiographic image was evaluated for the presence or absence of following characteristics: irregular medial humeral epicondyle, spur and calcified body. Additionally, the presence or absence of other elbow disorders (medial coronoid process disease, osteochondritis dissecans, ununited anconeal process, incongruity, subtrochlear sclerosis, and osteoarthritis) was recorded. Radiographic characteristics of flexor enthesopathy were found in 86% of painful joints in the primary flexor enthesopathy group and in 100% of painful joints in the concomitant flexor enthesopathy group. Radiographic characteristics of flexor enthesopathy were not found in sound elbow and elbow dysplasia groups. Frequencies and details of individual radiographic characteristics did not differ between primary and concomitant flexor enthesopathy groups. Findings support the use of radiography as a first screening method for detection of flexor enthesopathy, but not as a technique for distinguishing primary vs. concomitant forms. PMID- 23094826 TI - Editorial: vasoactive intestinal peptide (vip): historic perspective and future potential. AB - Numerous studies, since the late 1970s, have highlighted the role of vasoactive intestinal peptide (VIP) in the immune system of mammals. Importantly, these studies have show that VIP has an inhibitory effect on the production and action of many different inflammatory mediators and many studies have now shown the therapeutic potential of VIP in animal models of human disease. This review will briefly discuss the effects of VIP on immune cell function and discuss the therapeutic potential for VIP in inflammatory diseases of humans. The review will also introduce some areas of research which are discussed by contributing authors within this special edition of EMIDDT. PMID- 23094827 TI - VIP as a potential therapeutic agent in gram negative sepsis. AB - Gram negative sepsis remains a high cause of mortality and places a great burden on public health finance in both the developed and developing world. Treatment of sepsis, using antibiotics, is often ineffective since pathology associated with the disease occurs due to dysregulation of the immune system (failure to return to steady state conditions) which continues after the bacteria, which induced the immune response, have been cleared. Immune modulation is therefore a rational approach to the treatment of sepsis but to date no drug has been developed which is highly effective, cheap and completely safe to use. One potential therapeutic agent is VIP, which is a natural peptide and is highly homologous in all vertebrates. In this review we will discuss the effect of VIP on components of the immune system, relevant to gram negative sepsis, and present data from animal models. Furthermore we will hypothesise on how these studies could be improved in future and speculate on the possible different ways in which VIP could be used in clinical medicine. PMID- 23094828 TI - VIP in inflammatory bowel disease: state of the art. AB - The pathogenesis of inflammatory bowel syndrome (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC) is poorly understood. However, an inflammatory component is a common hallmark. It has been suggested that CD principally involves Th1 and/or Th17 cells, while UC is considered to be more Th2 driven. Because vasoactive intestinal peptide (VIP) has emerged in the last decade as a putative candidate for the treatment of inflammatory diseases with a Th1 component, it may as well serve as a therapeutic target in CD. In addition, experiments using mice deficient in VIP or its receptors have revealed that the endogenously-produced VIP may participate in the regulation of immunity. The aim of the present review is to summarize the quite considerable array of data which suggests that the VIP-receptor system plays a key role in modulating multiple molecular and cellular players involved in IBD. PMID- 23094830 TI - Potential applications of vasoactive intestinal Peptide-based therapies on transplantation. AB - Vasoactive intestinal peptide (VIP) is a well-known immunoregulatory neuropeptide produced by the immune system in response to inflammation, autoimmunity or alloantigens as a natural endogenous mechanism of induction of tolerance. VIP has been proven therapeutically effective in various experimental models of autoimmune disorders and recently in human sarcoidosis. Numerous studies clearly show that VIP exerts its immunomodulatory effects by downregulating both inflammatory and Th1 responses. Recent evidences suggest that new actors enter in scene to play a role in this scenario of tolerance. By inducing antigen-specific regulatory T cells and tolerogenic dendritic cells, VIP seems to reinforce/reinstall immune tolerance, especially under autoimmune conditions. Transplantation is also a condition where VIP-related therapies emerge as promising tools for clinical application. Induction of alloantigen-specific tolerance is critical to achieve organ transplant tolerance and to avoid graft versus-host responses following allogeneic hematopoietic transplantation. This review will focus on describing the capacity of VIP to induce suppressive/regulatory immune cells and how we can manage this cell-based therapeutic strategy to induce transplant tolerance in subjects free of immunosuppressive drugs. PMID- 23094829 TI - VIP in neurological diseases: more than a neuropeptide. AB - A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation or abnormal neural development. PMID- 23094831 TI - Clinical potential of VIP by modified pharmaco-kinetics and delivery mechanisms. AB - Vasoactive intestinal peptide (VIP) conveys various physiological effects in the digestive tract, nervous and cardiovascular system, airways, reproductive system, endocrine system, and more. A family of specific membrane bound receptors, termed VPAC1, VPAC2, and PAC1, bind VIP and trigger the effects. Many of them are of clinical interest. To date more than two thousand publications suggest the use of VIP in diseases like asthma, erectile dysfunction, blood pressure regulation, inflammation, endocrinology, tumours, etc. Despite this considerable potential, the peptide is not regularly used in clinical settings. A key problem is the short half life of inhaled or systemically administered VIP due to rapid enzymatic degradation. This shortcomings could be overcome with stable derivates or improved pharmacokinetics. A promising strategy is to use biocompatible and degradable depots, to protect the peptide from early degradation and allow for controlled release. This review focuses on aspects of clinical applications of VIP and the idea to use formulations based on biodegradable particles, to constitute a dispersible VIP-depot. Smart particle systems protect the peptide from early degradation, and assist the sustainable cell targeting with VIP for therapeutic or imaging purposes. PMID- 23094832 TI - Why e-return services fail: a psychological contract violation approach. AB - This study elucidates why and how e-return services (e-RS) fail, representing a preliminary attempt to explain the critical role of psychological contract violation (PCV) and explore its antecedents and outcomes in e-RS research. Based on marketing, psychology, and information systems-related studies, a theoretical framework is developed to correlate perceived fairness (PF), causal attribution (CA), and magnitude of negative outcome (MNO) with customers' PCV. Additionally, based on trust (TR), exactly how PCV further influences customers' stickiness intention (SI) is examined as well. Analysis results indicate that PF, CA, and MNO influence customers during both the evaluation stage and the customer receipt of e-RS, subsequently deriving PCV. These factors contribute to the subsequent success of e-RS, especially, customers' TR and SI. Furthermore, recommendations are made on how firms should evaluate PCV and its influencing factors to prevent e-RS failure. PMID- 23094834 TI - Gemcitabine-loaded biocompatible nanocapsules for the effective treatment of human cancer. AB - AIM: To encapsulate the nucleoside gemcitabine (GEM) in novel PEGylated polymeric nanocapsules (NanoGEM). MATERIALS & METHODS: The biological activity of NanoGEM was tested both in vitro and in vivo in comparison with the free drug. The NanoGEM was made of polylactic acid and allowed the entrapment of a great amount of GEM. RESULTS & DISCUSSION: The NanoGEM showed mean sizes of approximately 200 nm, a polydispersity index of approximately 0.1 and a zeta-potential of -30 mV. It exerted a stronger, quicker effect on the reduction of HEK293 cell growth in vitro in comparison with free GEM and had an in vivo antitumoral effect on the proliferation of xenograft tumors at a drug dosage tenfold less than its saline solution. The employment of nanocapsules increased the plasmatic half-life of the drug and allowed a great accumulation of GEM inside the tumors. CONCLUSION: NanoGEM represents a promising new tool for the treatment of cancer. PMID- 23094835 TI - Electrochemical and spectroscopic study of Ce(III) coordination in the 1-butyl-3 methylpyrrolidinium bis(trifluoromethylsulfonyl)imide ionic liquid containing chloride ion. AB - Cyclic staircase voltammetry, controlled potential coulometry, and electronic absorption spectroscopy were used to probe the coordination and accessible oxidation states of Ce(3+) dissolved in the ionic liquid 1-butyl-1 methylpyrrolidinium bis(trifluoromethylsulfonyl)imide (BuMePyroTf(2)N) before and after the addition of chloride ion as BuMePyroCl. Controlled potential coulometry indicated that the oxidation of Ce metal in this ionic liquid produces only Ce(3+). Spectroscopic examination of the resulting solutions indicated that Ce(3+) was weakly solvated by Tf(2)N(-) ions as [Ce(Tf(2)N)(x)]((x-3)-), x >= 3. This species can be reduced at negative potentials, probably to a related Ce(2+) species, but the latter is unstable and quickly disproportionates to Ce(3+) and Ce(0); the latter appears to react with the ionic liquid. The addition of Cl(-) to solutions of [Ce(Tf(2)N)(x)]((x-3)-) causes the precipitation of CeCl(3)(s), providing a convenient route to the nondestructive recovery of Ce(3+) from the ionic liquid. However, as the Cl(-) concentration is further increased, the CeCl(3)(s) redissolves as the octahedral complex, [CeCl(6)](3-), and the voltammetric and spectroscopic signature for [Ce(Tf(2)N)(x)]((x-3)-) disappears. Absorption spectroscopy indicated that the bulk controlled potential oxidation of solutions containing [CeCl(6)](3-) produces [CeCl(6)](2-). Although stable on the time scale of voltammetry, this species slowly reacts with the ionic liquid and is converted back to [CeCl(6)](3-). PMID- 23094836 TI - Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3beta signaling pathway. AB - Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6 hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3beta) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3beta activity caused by 6 OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3beta phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6 OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3beta signaling. PMID- 23094837 TI - Palaeodontological analysis of an Iron Age dental sample from a cave burial site near Gornji Vakuf, Bosnia and Herzegovina. AB - This article presents the results of a palaeocultural and palaeodontological research of Cave No. 5 near the villages of Bistrica and Krupa in the municipality of Gornji Vakuf, southwest Bosnia. This cave is located on the west slope of Mt Vranica. inside the cave, several artefacts and skeletal remains of about 20 persons have been found. Radiocarbon 14C analysis of one bone sample showed that people whose remains were found in the cave lived 2765+/-75 years ago. Palaeodontological examinations on a total sample of 36 human teeth included tooth status, occlusal tooth wear, presence of developmental enamel defects, and odontometric analysis. PMID- 23094838 TI - [The first state-owned pharmacy in Serbia]. AB - The first state-owned pharmacy in Serbia dates back to 1836. At first its title was Dvorska i voena apoteka (Court and Military Pharmacy), which later changed to Pravitelstvena apoteka (Government Pharmacy). The pharmacy moved from Kragujevac to Belgrade on two occasions along with the government seat, to finally settle in Belgrade on 8 december 1841 Pravitelstvena Apoteka fostered the development of the pharmaceutical science in the country and acted as a public healthcare institution. It had a state-of-the-art laboratory, equipped for chemical analysis of mineral water and for toxicological and biochemical analysis of water containers. It is the cradle of the applied chemistry in serbia and it operated as a controlling centre for other pharmacies. In 1853, Pravitelstvena Apoteka opened a branch Filijala Pravitelstvene Apoteke, which was run by the Central Pharmacy in Belgrade and the appointed administrator Dorde Bogdanovic, MPharm. On 10 June 1859, both pharmacies were privatised by the decree of the Prince of Serbia, Duke Milos Obrenovic. PMID- 23094839 TI - Dr Franz Tripold (1865-1956), one of the most important pioneer physicians in Opatija/Abbazia. AB - Dr Tripold was one of the first Austrian physicians to practice in Opatija. He graduated from Karl-Franzens University in Graz in 1889 and moved to Opatija in 1891. Along with his medical practice, Tripold was the head physician of the volunteer Fire Brigade and Rescue Society of Opatija and meteorological observer. In 1906, he published a climatological study entitled das Klima von Abbazia (The Climate of Opatija), which was based on his own 8-year observations of the weather conditions and the 12-year observations done by his predecessor, E. Krainz. In 1908, he was appointed Imperial Counsellor by the Austrian emperor. For his medical practice in Opatija, Dr Tripold received several foreign awards, and the Viennese Volunteer Rescue Society appointed him its honorary member. The Tripolds moved to Turin in 1947. He was buried there at Cimitero monumentale. Opatija, Town-Museum of Central Europe, a project designed to identify and reunite old friends, has honoured the memory of Dr Tripold by including him in a poster of the ten most famous citizens of Opatija, and the fire station in Opatija placed a plaque on the wall in his honour. PMID- 23094840 TI - Renaissance plays as a useful source for the comparison between English and Croatian early modern medicine. AB - This paper evaluates the differences between English and Croatian views of early modern medicine through the respective Renaissance plays. As Renaissance made no particular distinction between arts and sciences, plays of that time provide a very common source of medical narrative. During Renaissance both languages produced high literary achievements, which makes them exemplars among their Germanic and Slavic counterparts, and justifies this comparison, regardless of their significant differences. One should bear in mind that while England was a unified kingdom, with London as the major cultural centre, Croatia's division among the neighbouring powers produced several prominent cultural centres such as Zadar, Sibenik, Split, Hvar, Korcula, and the most important one, Dubrovnik. One should also bear in mind that the golden age of Croatian Renaissance plays had finished as early as 1567 with the death of Marin DrZic, before it even started in England with the foundation of the first permanent theatrical companies in 1576. Along these lines, this paper compares their early modern attitudes toward medicine in general and men and women practitioners in particular. In this respect, it evaluates the influences of the origin, patronage, and religion of their authors. Special attention is given to William Shakespeare (1564-1616) and Marin DrZic (1508-1567) as the exemplars of English and Croatian Renaissance literature. PMID- 23094841 TI - [Malaria in Pula in the seventies of the 19th century and the epidemic in 1879]. AB - Malaria played a leading role in the complex Istrian sanitary history. From the beginning of the 18th century, wars, famine, and epidemics depopulated large areas and favoured the spread of the diseases. Socioeconomic structures were also affected, generating a drop in cultivation of the fields, end of drainage works, and later, abandonment of farmed land because of the formation of palustrine stagnant water and decay of traditional sanitary regulations. The dissolution of Benedictine monasteries also played an important role in the spread of malaria. Working on tillage, drainage and cultivation, the Benedictines not only radically changed the Istrian landscape, reducing the impact and spread of infectious diseases but, through a wise land administration, they also succeeded in creating food supplies for famine periods, which were so frequent in the region. Southern Istria and the town of Pula in particular, were the most affected by the disease. Owing to severe famine that hit Istria in 1879, malaria assumed epidemic proportions, causing widespread malnutrition and physiological weakness on the population, which favoured the propagation of infectious agents. PMID- 23094842 TI - Cardiopulmonary resuscitation: a historical perspective leading up to the end of the 19th century. AB - Social laws and religious beliefs throughout history underscore the leaps and bounds that the science of resuscitation has achieved from ancient times until today. The effort to resuscitate victims goes back to ancient history, where death was considered a special form of sleep or an act of God. Biblical accounts of resuscitation attempts are numerous. Resuscitation in the Middle Ages was forbidden, but later during Renaissance, any prohibition against performing cardiopulmonary resuscitation (CPR) was challenged, which finally led to the Enlightenment, where scholars attempted to scientifically solve the problem of sudden death. It was then that the various components of CPR (ventilation, circulation, electricity, and organization of emergency medical services) began to take shape. The 19th century gave way to hallmarks both in the ventilatory support (intubation innovations and the artificial respirator) and the open-and closed chest circulatory support. Meanwhile, novel defibrillation techniques had been employed and ventricular fibrillation described. The groundbreaking discoveries of the 20th century finally led to the scientific framework of CPR. In 1960, mouth-to-mouth resuscitation was eventually combined with chest compression and defibrillation to become CPR as we now know it. This review presents the scientific milestones behind one of medicine's most widely used fields. PMID- 23094833 TI - A coupled phylogeographical and species distribution modelling approach recovers the demographical history of a Neotropical seasonally dry forest tree species. AB - We investigated here the demographical history of Tabebuia impetiginosa (Bignoniaceae) to understand the dynamics of the disjunct geographical distribution of South American seasonally dry forests (SDFs), based on coupling an ensemble approach encompassing hindcasting species distribution modelling and statistical phylogeographical analysis. We sampled 17 populations (280 individuals) in central Brazil and analysed the polymorphisms at chloroplast (trnS-trnG, psbA-trnH, and ycf6-trnC intergenic spacers) and nuclear (ITS nrDNA) genomes. Phylogenetic analyses based on median-joining network showed no haplotype sharing among population but strong evidence of incomplete lineage sorting. Coalescent analyses showed historical constant populations size, negligible gene flow among populations, and an ancient time to most recent common ancestor dated from ~4.7 +/- 1.1 Myr BP. Most divergences dated from the Lower Pleistocene, and no signal of important population size reduction was found in coalescent tree and tests of demographical expansion. Demographical scenarios were built based on past geographical range dynamic models, using two a priori biogeographical hypotheses ('Pleistocene Arc' and 'Amazonian SDF expansion') and on two additional hypotheses suggested by the palaeodistribution modelling built with several algorithms for distribution modelling and palaeoclimatic data. The simulation of these demographical scenarios showed that the pattern of diversity found so far for T. impetiginosa is in consonance with a palaeodistribution expansion during the last glacial maximum (LGM, 21 kyr BP), strongly suggesting that the current disjunct distribution of T. impetiginosa in SDFs may represent a climatic relict of a once more wide distribution. PMID- 23094843 TI - Eating habits in the turn of the 19th and 20th century: exhibition of menu cards at the Sarajevo City Museum. AB - Through a selection of menu cards exhibited at the Sarajevo City Museum, this article looks into the eating habits in Bosnia and Herzegovina in the second half of the 19th and the first half of the 20th century (period before the World War I). These menu cards offer a specific overview of eating habits of all ranks of society in Bosnia and Herzegovina, where there are no essential differences between dinner tables of prelates and ordinary people. The paper gives a short comparison of traditional eating habits in Bosnia and Herzegovina with nowadays eating habits, especially concerning the problem of obesity. PMID- 23094844 TI - [The attempts of Bishop Ivan Sintic (1792-1837) to treat snake and other animal bites: from intuition to scientific dispute]. AB - This manuscript describes an attempt to treat snake and other animal bites using an ointment made of a plant Aster atticus (sternkraut, of the family Aster). The recipe for this ointment had passed from an Istrian Bernardo Alessandri to bishop Ivan Anton Sintic at the end of the 18th century. At the request by the Austrian administration of the Province of Zadar, Sintic published a booklet on how to prepare the plant and use it, and the administration distributed the booklet to local practitioners. Encouraged by the new therapy, physician Srecko Randic of Bakar, took it for the subject of his doctoral dissertation, an published it in Vienna in 1840. However, the efficiency of this therapy was disputed by the new island of Krk physician Ivan Krstitelj Kubic after years of follow up and investigation. PMID- 23094845 TI - Mummified saints of the Northern Croatian Littoral. AB - The Istrian town of Vodnjan hosts a collection of mummified bodies and relics. Three mummies are completely preserved and belong to Blessed Leon Bembo, St Giovanni Olini, and St Nicolosa Bursa, while the other three are mummified remains of St Barbara, St Sebastian, and St Mary of Egypt. This article gives an overview of the three completely preserved bodies, including their external condition, hagiographic data, statements and hypotheses that need verification by future targeted scientific research. Although local populations attribute divine properties to the remains and treat their continued preservation as a mystery, their origin is probably similar to that of other mummified saints. A scientific study performed on the mummies will probably help to reveal the true origin and type of mummification of the bodies. Additional paleopathological research could also determine the cause of death, if the saints died by natural causes, or attest to any mutilation or sign of torture suffered in life and confirm them as the cause of death. Proper bioarchaeological research could bring useful osteobiographical updates to the existing records about these saints. PMID- 23094846 TI - [Traces of health culture in the 1427 code of Grbalj]. AB - The Code of Grbalj regulated a number of legal issues in this area and marked the passage from common to statutory law. It brings several curiosities related to the health culture of the time, such as that a barber was not liable for patient's death due to surgery. In fact, surgery was preceded by a symbolic act in which the barber would hand a razor to the patient, and the patient would hand it back. The intention of this provision was to protect the surgeon from blood feud. As for the corpse, the Code provided that it should be kept at home overnight and buried in the morning. Punitive provisions include stoning of the engaged couple in case of pregnancy, as engagement commanded absolute virtue. The punishment for striking parents was to cut off the hand that hit them; the ear was cut off or the nose scarred to permanently mark an adulteress or a woman who stole from the husband's house and sold the stolen property to fill up her belly. Children who stole from the house and sold the property were punished by flogging with a chibouk. PMID- 23094847 TI - [No one writes about the colonel. In memoriam: Lovro Mirosevic, M.D., M.Sc., D.Sc. (1927-2009)]. AB - If it is possible to speak about the goals of an essay at all, this essay aims at reminding of a life story of a very prolific scientist and professor of Rijeka Faculty of Medicine, the gynecologist-obstetrician Lovro Mirosevic, born in 1927 in Blato (the island of Korcula) and died in 2009 in Opatija. The author of the present essay had the privilege of knowing dr. Mirosevic very well: the portrait thus is devoid of the pretension of objectivity. PMID- 23094848 TI - Ventricular response during lungeing exercise in horses with lone atrial fibrillation. AB - REASONS FOR PERFORMING THE STUDY: Atrial fibrillation (AF) is the most important dysrhythmia affecting performance in horses and has been associated with incoordination, collapse and sudden death. Limited information is available on ventricular response during exercise in horses with lone AF. OBJECTIVES: To investigate ventricular response in horses with lone AF during a standardised lungeing exercise test. METHODS: A modified base-apex electrocardiogram was recorded at rest and during a standardised lungeing exercise test from 43 horses diagnosed with lone AF. During the test horses walked for 7 min, trotted for 10 min, cantered for 4 min, galloped for 1 min and recovered for 7 min. RESULTS: Individual average heart rate during walk ranged from 42 to 175 beats/min, during trot from 89 to 207 beats/min, during canter from 141 to 269 beats/min, and during gallop from 191 to 311 beats/min. Individual beat-to-beat maximal heart rate ranged from 248 to 492 beats/min. Ventricular premature depolarisations were present in 81% of the horses: at rest (16%), during exercise (69%), and during recovery (2%). In 33% of the horses, broad QRS complexes with R-on-T morphology were found. CONCLUSIONS: Exercising horses with lone AF frequently develop disproportionate tachycardia. In addition, QRS broadening and even R-on-T morphology is frequently found. QRS broadening may originate from ventricular ectopic foci or from aberrant intraventricular conduction, for example due to bundle branch block. This might explain the high number of complexes currently classified as ventricular premature depolarisations. POTENTIAL RELEVANCE: Prevalence of QRS broadening and especially R-on-T was very high in horses with AF and was found at low levels of exercise. These dysrhythmias are considered risk factors for the development of ventricular tachycardia and fibrillation and they might explain signs of weakness, collapse or sudden death that have been reported in horses with AF. PMID- 23094849 TI - Inheritance of the chronic myeloproliferative neoplasms. A systematic review. AB - This systematic review investigated the inheritance of the classical chronic myeloproliferative neoplasms (MPNs) including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) and chronic myelogenous leukemia (CML). Sixty-one articles were included and provided 135 families with a total of 341 participants distributed to various subtypes of MPN: 50% PV, 23% ET, 14% PMF, 10% CML and 3% non-MPN hematological disorder. Women developed the disease earlier than men (43.1 years vs 47.3 years; p = 0.074), while the general average age of onset was 46 years, notably younger than sporadic cases. The clinical phenotype of the families showed a homogenous (67%) and a heterogeneous (33%) pattern, with the majority being PV-PV pairs (36%) and PV-PMF pairs (17%), respectively. This observation suggests that the susceptibility gene (or genes) is not restricted to one subtype supporting the hypothesis of a mutation in an early multipotent stem cell. Furthermore, a major subgroup of families provided evidence of an autosomal dominant (AD) inheritance with reduced penetrance. This study suggests that the origin of MPNs may occur in at least three different settings: (i) a sporadic, (ii) genetic heterogeneity with polygenetic and environmental impact and (iii) a familial phenotype following an AD inheritance. PMID- 23094850 TI - Premature rupture of membranes before 34 weeks managed expectantly: maternal and perinatal outcomes in singletons. AB - OBJECTIVES: To ascertain the risk factors for imminent delivery and infection in pregnant women with premature rupture of membranes (PPROM) before 34 weeks of gestation, evaluate maternal and fetal outcomes and identify obstetric factors for determining which patients meet the criteria for home follow-up. METHODS: Medical charts of all women with PPROM admitted to the Vall d'Hebron Hospital (HVH) between January 2006 and December 2010 were retrospectively reviewed. RESULTS: During the study period, 216 women were admitted with a diagnosis of PPROM <34 weeks of gestation with a singleton, live, structurally-normal fetus. Mean gestational age at delivery was 31 weeks. Sixty-two patients (28.7%) delivered before 28 weeks and 76 of the infants (35.2%) had birth weight <1,500 g. Overall, 202 infants (93.5%) survived to be discharged home. On stratifying by gestational age at PPROM diagnosis, prognosis was better when PPROM occurred near to term. Gestational age at delivery was increased in pregnant women with no oligohydramnios, no shortened cervix and with negative endocervical and vaginal cultures at PPROM diagnosis (33 weeks of gestation) vs. pregnant women with positive cultures at admission (27 weeks), oligohydramnios at admission (28 weeks) and shortened cervix (26 weeks). This difference was statistically significant (p = 0.005). CONCLUSIONS: Protective factors for PPROM could be normal AFI, cervical length >25 mm and negative cultures at PPROM diagnosis. These factors could permit home follow-up of this group of patients. PMID- 23094852 TI - [60]Fulleropyrrolidines bearing pi-conjugated moiety for polymer solar cells: contribution of the chromophoric substituent on C60 to the photocurrent. AB - Two fullerene-terthiophene dyads without hexyl chains (3T-C60) and with hexyl chains (3TH-C60) on the terthiophene substituent are synthesized by 1,3-dipolar cycloaddition of corresponding azomethine ylides to C60. The cyclic voltammetry studies indicate no apparent electronic communication between the terthiophene pendent group and the fulleropyrrolidine core in the ground state. However, a significant florescence quenching is observed for 3T-C60 and 3TH-C60, compared to their fluorescent terthiophene (3T) and 3TH precursors, respectively, suggesting the occurrence of strong intramolecular electron/energy transfers in the photoexcited state. Furthermore, these new fulleropyrrolidine derivatives are applied as electron acceptors to fabricate poly(3-hexylthiophene) (P3HT) based bulk heterojunction solar cells. The incident photon-to-current efficiency (IPCE) value of the P3HT/3T-C60 device is significantly higher than that of the P3HT/PCBM cell in wavelengths of 350-420 nm. This finding provides direct evidence for the contribution of 3T excitons to the photocurrent. Replacing 3T C60 with 3TH-C60 effectively improves the morphology of the photoactive layer and widens the window of optimal D/A ratios, raising the power conversion efficiency (PCE) from 2.14% to 2.54%. Importantly, these devices exhibit superior stability of PCE against high-temperature aging. PMID- 23094853 TI - Is rosuvastatin effective for non-alcoholic steatohepatitis with dyslipidemia? PMID- 23094851 TI - Effects of cocaine and withdrawal on the mouse nucleus accumbens transcriptome. AB - Genetic association studies, pharmacological investigations and analysis of mice lacking individual genes have made it clear that Cocaine administration and Withdrawal have a profound impact on multiple neurotransmitter systems. The GABAergic medium spiny neurons of the nucleus accumbens (NAc) exhibit changes in the expression of genes encoding receptors for glutamate and in the signaling pathways triggered by dopamine binding to G-protein-coupled dopamine receptors. Deep sequence analysis provides a sensitive, quantitative and global analysis of the effects of Cocaine on the NAc transcriptome. RNA prepared from the NAc of adult male mice receiving daily injections of Saline or Cocaine, or Cocaine followed by a period of Withdrawal, was used for high-throughput sequence analysis. Changes were validated by quantitative polymerase chain reaction or Western blot. On the basis of pathway analysis, a preponderance of the genes affected by Cocaine and Withdrawal was involved in the cadherin, heterotrimeric G protein and Wnt signaling pathways. Distinct subsets of cadherins and protocadherins exhibited a sustained increase or decrease in expression. Sustained down-regulation of several heterotrimeric G-protein beta- and gamma subunits was observed. In addition to altered expression of receptors for small molecule neurotransmitters, neuropeptides and endocannabinoids, changes in the expression of plasma membrane transporters and vesicular neurotransmitter transporters were also observed. The effects of chronic Cocaine and Withdrawal on the expression of genes essential to cholinergic, glutamatergic, GABAergic, peptidergic and endocannabinoid signaling are as profound as their effects on dopaminergic transmission. Simultaneous targeting of multiple Withdrawal-specific changes in gene expression may facilitate development of new therapeutic approaches that are better able to prevent relapse. PMID- 23094854 TI - Combined hepatocellular carcinoma and neuroendocrine carcinoma with sarcomatous change of the liver after transarterial chemoembolization. AB - Primary hepatic neuroendocrine carcinoma is rare and its origin is not clearly understood. An admixture of hepatocellular carcinoma (HCC) and neuroendocrine carcinoma is particularly rare. Here, we report a patient with an extremely rare combination of HCC and neuroendocrine carcinoma of the liver. To our knowledge, this is the first reported case in which the carcinoma showed sarcomatous change. The patient was a 76-year-old man who had received outpatient treatment for chronic hepatitis C. On abdominal computed tomography (CT), the hepatic tumor was enhanced in the arterial phase but its density was lower than that of normal liver in the portal phases. His serum alpha-fetoprotein (AFP) level was very high. Therefore, transarterial chemoembolization (TACE) was performed based on the diagnosis of HCC. Ten months after TACE, his serum AFP level had increased to the level measured before TACE. Partial hepatectomy was performed because CT revealed poor enhancement of the recurrent tumor. Histopathologically, the tumor consisted of two distinct components: moderately differentiated HCC was intermingled with a neuroendocrine carcinoma, which was accompanied by sarcomatous changes. Immunohistochemically, the neuroendocrine carcinoma cells were positive for CD56, chromogranin A and neuron-specific enolase, and negative for AFP. The sarcomatous area was positive for AE1/3 and CD56, consistent with sarcomatous change of neuroendocrine carcinoma. The neuroendocrine carcinoma and/or sarcomatous change may have been due to phenotypic changes and/or dedifferentiation of HCC induced by TACE. Six months after surgery, the patient was diagnosed with metastasis of the neuroendocrine carcinoma to sacral bone. He died 7 months after surgery. PMID- 23094855 TI - Icteric acute hepatitis E with no response of immunoglobulin M class anti hepatitis E virus antibody. AB - A 68-year-old Japanese man developed icteric acute hepatitis during periodic care after undergoing gastrectomy due to early gastric cancer. The routine serological markers for hepatitis A, B and C viruses were all negative. Although the liver enzymes spontaneously recovered without any specific therapy, cholestasis was relatively prolonged and successfully treated with prednisolone. Determination of serum hepatitis E virus (HEV) RNA revealed the transient infection of HEV, and both immunoglobulin (Ig)A and IgG class anti-HEV antibodies were detected after the disease onset, whereas those were negative when measured 3 weeks prior to the onset. In addition, the titer of serum IgA class antibody was associated with the clinical signs of hepatitis. In contrast, no IgM class antibody was detected throughout the course. This case suggests that screening only with IgM class antibody is not sufficient to detect acute HEV infection. PMID- 23094856 TI - Interpretation of molecular results in segmental uniparental disomy. PMID- 23094858 TI - Factor XIII Val34Leu mutation and liver fibrosis rate in viral hepatitis. PMID- 23094857 TI - Reply from the authors. PMID- 23094859 TI - Reply from the authors. PMID- 23094861 TI - Ankle dynamic in stroke patients: agonist vs. antagonist muscle relations. AB - INTRODUCTION: Atypical ankle patterns of muscle activity during gait are commonly reported in patients with stroke. These findings can be due to changes between tibialis anterior (TA) and soleus (SOL) coactivation mechanisms. OBJECTIVE: To compare the electromyographic activity (EMGa) of SOL and TA muscles and antagonist coactivation (C) level in the contralateral (CONTRA) and ipsilateral (IPSI) limbs to the side of the stroke lesion during the stance phase of the gait cycle. METHODS: Twelve subjects with a stroke episode participated in this study. The electromyographic signal of TA and SOL and ground reaction forces were acquired while subjects walked at their self-selected speed. Values of ground reaction forces were used to divide the stance phase of gait into initial contact, midstance, and terminal stance. In each sub-phase, the magnitude of TA and SOL was calculated as well as the level of the antagonist C. RESULTS: Although no statistical differences were found, mean values of SOL EMGa were lower in the IPSI limb in all stance phases in relation to the CONTRA limb, and the opposite was observed in the TA EMGa. Moreover, higher mean levels of antagonist C were only found during the initial contact sub-phase in the CONTRA limb and in the other sub-phases in the IPSI limb. Besides, statistical differences were observed only during midstance. CONCLUSION: In stroke subjects, the antagonist C level during midstance of gait may reflect the dysfunction of the neuronal system over the IPSI limb. PMID- 23094860 TI - The anti-viral effect of sorafenib in hepatitis C-related hepatocellular carcinoma. AB - BACKGROUND: Sorafenib is currently the only approved systemic therapy shown to have efficacy in the treatment of advanced hepatocellular carcinoma (HCC). Recent studies suggest that hepatitis C (HCV)-related HCC patients derive more clinical benefit from sorafenib than other subgroups, but the mechanism for this effect is unknown. In vitro data suggest that sorafenib may exert anti-viral properties, and thus our aim in this study was to evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. AIM: To evaluate potential anti-viral activity of sorafenib in patients with HCV-related HCC. METHODS: We prospectively enrolled patients with HCV-related HCC treated with sorafenib for up to 6 months. Baseline clinical, viral and oncologic data were collected. Patients' HCV viral loads were obtained at various time points, and compared with their baseline viral levels. No patients received any known anti-viral therapy during this time. RESULTS: Thirty-three patients were identified with baseline and subsequent HCV levels available for analysis. Six patients completed 6 months of full dose sorafenib, and comparisons of their HCV viral loads showed no significant change at week 24 (difference of means = 0.3500, CI: -0.1799-0.8799, P = 0.150), or the interim time points. Similarly, the HCV viral loads of all patients who received sorafenib and the viral loads of those patients who had tumour response to sorafenib showed no significant changes at any time point. CONCLUSION: Despite preclinical data and previous subgroup analyses suggesting that sorafenib has an anti-viral effect against HCV, this study suggests that sorafenib lacks significant anti-viral activity in HCV patients with HCC. PMID- 23094862 TI - Dermatoscopy of facial non-pigmented actinic keratosis regarding to grades of the lesions. PMID- 23094863 TI - Overflow microfluidic networks: application to the biochemical analysis of brain cell interactions in complex neuroinflammatory scenarios. AB - Neuroinflammation plays a central role in neurodegenerative diseases and involves a large number of interactions between different brain cell types. Unraveling the complexity of cell-cell interaction in neuroinflammation is crucial for both clarifying the molecular mechanisms involved and increasing efficacy in drug development. Here, we provide a versatile analytical method for specifically addressing cell-to-cell communication, using primary brain cells, a microfluidic device, and a multiparametric readout approach. Different cell types are plated in separate chambers of a microfluidic network so that culturing conditions can be independently controlled and single cell types can be selectively primed with different stimuli. When chambers are microfluidically connected, the specific contribution of each cell type can be finely monitored by analyzing morphology, vitality, calcium dynamics, and electrophysiology parameters. We exemplify this approach by examining the role of astrocytes derived from two different brain regions (cortex and hippocampus) on neuronal viability in two types of neuroinflammatory insults, namely, metabolic stress and exposure to amyloid beta fibrils, and demonstrate regional differences in glial control of neuronal physiopathology. In particular, we show that during metabolic stress, cortical but not hippocampal astrocytes play a neuroprotective role; also, in an exacerbated inflammatory scenario consisting in the exposure to Abeta + IL-1beta, hippocampal but not cortical astrocytes play a detrimental role on neurons. Aside from bringing novel insights into the glial role in neuroinflammation, the method presented here represents a promising tool for addressing a wide range of biological and biochemical phenomena, characterized by a complex interaction of multiple cell types. PMID- 23094864 TI - Tanshinone derivatives: a patent review (January 2006 - September 2012). AB - INTRODUCTION: Tanshinone IIA (TSIIA), cryptotanshinone and tanshinone I are major bioactive constituents of Danshen, a Chinese herbal medicine. Sodium tanshinone IIA sulfonate (STS) is a water-soluble derivative of TSIIA and it is currently used for treating cardiovascular diseases in China. AREAS COVERED: The article presents a review of the anti-atherosclerosis, cardioprotective effects, neuroprotection and anti-tumor activities of TSIIA and a review of patents on tanshinone derivatives from January 2006 to September 2012. EXPERT OPINION: Mechanistic studies have discovered that TSIIA modulates ion channels, kinases, hormone receptors, apoptosis proteins, growth factors, cytokines, microRNA, tumor suppressor and many other targets, revealing an intricate biological network modulated by TSIIA. Many patents have attempted to overcome the low water solubility of TSIIA and tanshinone I by attaching a polar substituent or by a prodrug strategy. However, biological activities of these tanshinone derivatives need to be further evaluated. Given the extensive in vitro and in vivo biological activities of TSIIA, this compound is a promising candidate to be further developed as a novel therapeutics for treating atherosclerosis, cardiovascular diseases, neurodegenerative diseases and cancer. PMID- 23094865 TI - Editorial: a swan song. PMID- 23094866 TI - Automated phosphopeptide identification using multiple MS/MS fragmentation modes. AB - Phosphopeptide identification is still a challenging task because fragmentation spectra obtained by mass spectrometry do not necessarily contain sufficient fragment ions to establish with certainty the underlying amino acid sequence and the precise phosphosite. To improve upon this, it has been suggested to acquire pairs of spectra from every phosphorylated precursor ion using different fragmentation modes, for example CID, ETD, and/or HCD. The development of automated tools for the interpretation of these paired spectra has however, until now, lagged behind. Using phosphopeptide samples analyzed by an LTQ-Orbitrap instrument, we here assess an approach in which, on each selected precursor, a pair of CID spectra, with or without multistage activation (MSA or MS2, respectively), are acquired in the linear ion trap. We applied this approach on phosphopeptide samples of variable proteomic complexity obtained from Arabidopsis thaliana . We present a straightforward computational approach to reconcile sequence and phosphosite identifications provided by the database search engine Mascot on the spectrum pairs, using two simple filtering rules, at the amino acid sequence and phosphosite localization levels. If multiple sequences and/or phosphosites are likely, they are reported in the consensus sequence. Using our program FragMixer, we could assess that on samples of moderate complexity, it was worth combining the two fragmentation schemes on every precursor ion to help efficiently identify amino acid sequences and precisely localize phosphosites. FragMixer can be flexibly configured, independently of the Mascot search parameters, and can be applied to various spectrum pairs, such as MSA/ETD and ETD/HCD, to automatically compare and combine the information provided by these more differing fragmentation modes. The software is openly accessible and can be downloaded from our Web site at http://proteomics.fr/FragMixer. PMID- 23094867 TI - In vitro release of ketoprofen from hydrophilic matrix tablets containing cellulose polymer mixtures. AB - The effect of cellulose ether polymer mixtures, containing both hydroxypropylcellulose (HPC) and hydroxypropylmethylcellulose (HPMC K15M or K100M), on ketoprofen (KTP) release from matrix tablets was investigated. In order to evaluate the compatibility between the matrix components, Raman spectroscopy, scanning electron microscopy (SEM), and X-ray powder diffraction (XRPD) experiments were performed. The results evidence the absence of significant intermolecular interactions that could eventually lead to an incompatibility between the drug and the different excipients. Formulations containing mixtures of polymers with both low and high viscosity grades were prepared by a direct compression method, by varying the polymer/polymer (w/w) ratio while keeping the drug amount incorporated in the solid dispersion constant (200 mg). The hardness values of different matrices were found within the range 113.8 to 154.9 N. HPLC analysis showed a drug content recovery between 99.3 and 102.1%, indicating that no KTP degradation occurred during the preparation process. All formulations attained a high hydration degree after the first hour, which is essential to allow the gel layer formation prior to tablet dissolution. Independent-model dissolution parameters such as t(10%) and t(50%) dissolution times, dissolution efficiency (DE), mean dissolution time (MDT), and area under curve (AUC) were calculated for all formulations. Zero-order, first-order, Higuchi, and Korsmeyer-Peppas kinetic models were employed to interpret the dissolution profiles: a predominantly Fickian diffusion release mechanism was obtained - with Korsmeyer-Peppas exponent values ranging from 0.216 to 0.555. The incorporation of HPC was thus found to play an essential role as a release modifier from HPMC containing tablets. PMID- 23094869 TI - Fast and efficient photodetection in nanoscale quantum-dot junctions. AB - We report on a photodetector in which colloidal quantum dots directly bridge nanometer-spaced electrodes. Unlike in conventional quantum-dot thin film photodetectors, charge mobility no longer plays a role in our quantum-dot junctions as charge extraction requires only two individual tunnel events. We find an efficient photoconductive gain mechanism with external quantum efficiencies of 38 electrons-per-photon in combination with response times faster than 300 ns. This compact device-architecture may open up new routes for improved photodetector performance in which efficiency and bandwidth do not go at the cost of one another. PMID- 23094868 TI - Transcriptomics of coping strategies in free-swimming Lepeophtheirus salmonis (Copepoda) larvae responding to abiotic stress. AB - The salmon louse Lepeophtheirus salmonis is a marine ectoparasite of wild and farmed salmon in the Northern Hemisphere. Infections of farmed salmon are of economic and ecological concern. Nauplius and copepodid salmon lice larvae are free-swimming and disperse in the water column until they encounter a host. In this study, we characterized the sublethal stress responses of L. salmonis copepodid larvae by applying a 38K oligonucleotide microarray to profile transcriptomes following 24 h exposures to suboptimal salinity (30-10 parts per thousand (0/00)) or temperature (16-4 degrees C) environments. Hyposalinity exposure resulted in large-scale gene expression changes relative to those elicited by a thermal gradient. Subsequently, transcriptome responses to a more finely resolved salinity gradient between 30 0/00 and 25 0/00 were profiled. Minimal changes occurred at 29 0/00 or 28 0/00, a threshold of response was identified at 27 0/00, and the largest response was at 25 0/00. Differentially expressed genes were clustered by pattern of expression, and clusters were characterized by functional enrichment analysis. Results indicate larval copepods adopt two distinct coping strategies in response to short-term hyposaline stress: a primary response using molecular chaperones and catabolic processes at 27 0/00; and a secondary response up-regulating ion pumps, transporters, a different suite of chaperones and apoptosis-related transcripts at 26 0/00 and 25 0/00. The results further our understanding of the tolerances of L. salmonis copepodids to salinity and temperature gradients and may assist in the development of salmon louse management strategies. PMID- 23094871 TI - Assessment of neurogenic dysphagia using bulbar electromyography. PMID- 23094870 TI - The National Children's Study and its importance for perinatal nurses. PMID- 23094872 TI - Total phenolics, carotenoids, ascorbic acid, and antioxidant properties of fresh cut mango (Mangifera indica L., cv. Tommy Atkin) as affected by infrared heat treatment. AB - Mango (Mangifera indica L.) is a major tropical fruit that has not been exploited for fresh-cut or minimally processed products on a scale similar to apples, pineapples, or melons. The objective of this study was to investigate the effect of infrared (IR) treatment on total phenolics, carotenoids, ascorbic acid, and antioxidant properties of fresh-cut cubes from 'Tommy Atkin' mangoes. Mango cubes were IR treated (5, 10, 15 min) and evaluated at 4-d intervals during 16-d storage at 4 +/- 1 degrees C. Total phenolics, carotenoids, and ascorbic acid content in fresh-cut control mango cubes were 43.33, 1.37, and 15.97 mg/100 g FW, respectively. IR treatments increased total phenolics (59.23 to 71.16 mg/100 g FW) and decreased ascorbic acid (12.14 to 15.38 mg/100 g, FW). Total carotenoids showed a mixed trend (1.13 to 1.66 mg/100 g, FW). The IR treatment showed a significant positive impact on antioxidant properties (MUM TE/100 g, FW) of mango cubes, as assayed by ABTS (261.5 compared with 338.0 to 416.4), DPPH (270.5 compared with 289.4 to 360.5), and ORAC (6686 compared with 8450 to 12230). Total phenolics, carotenoids, ascorbic acid, and antioxidant capacity decreased over 16 d storage. However, IR treated samples had consistently higher ABTS, DPPH, and total phenolics during storage. It was demonstrated that IR treatment can be effectively used in improving antioxidant properties of fresh-cut mangoes with minimal effect on the visual appearance. PRACTICAL APPLICATION: Various methods/treatments are in use for extending the quality of fresh-cut fruits, including mild heat treatment. This study explored the application of infrared (IR) heat for processing fresh-cut mango cubes and evaluated its effect on vitamin C and antioxidant capacity during 16-d storage. This is the first study reporting on the use of IR heat in fresh-cut fruits. IR treatment was shown to be effective in retaining antioxidant properties of fresh-cut mango cubes with minimal effect on the visual appearance. PMID- 23094873 TI - Elevated expression of brain-derived neurotrophic factor facilitates visual imprinting in chicks. AB - With the aim of elucidating the neural mechanisms of early learning, we studied the role of brain-derived neurotrophic factor (BDNF) in visual imprinting in birds. The telencephalic neural circuit connecting the visual Wulst and intermediate medial mesopallium is critical for imprinting, and the core region of the hyperpallium densocellulare (HDCo), situated at the center of this circuit, has a key role in regulating the activity of the circuit. We found that the number of BDNF mRNA-positive cells in the HDCo was elevated during the critical period, particularly at its onset, on the day of hatching (P0). After imprinting training on P1, BDNF mRNA-positive cells in the HDCo increased in number, and tyrosine phosphorylation of TrkB was observed. BDNF infusion into the HDCo at P1 induced imprinting, even with a weak training protocol that does not normally induce imprinting. In contrast, K252a, an antagonist of Trk, inhibited imprinting. Injection of BDNF at P7, after the critical period, did not elicit imprinting. These results suggest that BDNF promotes the induction of imprinting through TrkB exclusively during the critical period. PMID- 23094874 TI - Client perceptions of a work rehabilitation programme for women: the Redesigning Daily Occupations (ReDO) project. AB - AIM: The Redesigning Daily Occupations programme (ReDO) is a Swedish work rehabilitation programme for women on sick leave due to stress-related disorders. The aim of the study was to investigate the participants' perceptions of taking part in the work rehabilitation programme. METHODS: Seven of the 38 women who completed ReDO were interviewed during and after the programme. The interviews were analysed by manifest and latent content analysis. RESULTS: The informants were satisfied with the content of the programme and the support they received in the programme and when returning to work. The women thought they had become more aware of what they did during a day and how they performed their daily activities, which helped them to change their ways of performing them. The result highlighted different parts of their rehabilitation process which constituted four sub-themes: "Perceptions of the ReDO", "The intrinsic process", "Person related changes", and "Perceptions of returning to work", and formed the core theme "Critical parts of the rehabilitation process". CONCLUSIONS: The findings may not be generalized to other settings and future research should further investigate work rehabilitation for the target group. PMID- 23094875 TI - Magnetocardiography for the diagnosis of coronary artery disease: a systematic review and meta-analysis. AB - BACKGROUND: Coronary artery disease (CAD) has a significant disease burden making early diagnosis and management imperative. Magnetocardiography (MCG) is a relatively new noninvasive technique that allows diagnosis of CAD by recording the magnetic fields generated by the electrical activity of the heart. METHODS: We searched MEDLINE and the Cochrane Central Register of Controlled Trials for prospective studies that evaluated the test characteristics (e.g., sensitivity, specificity, likelihood ratios) of MCG for detection of CAD. Studies were included if they evaluated either patients with stable CAD documented by angiogram or patients presenting initially with acute coronary syndrome and subsequently diagnosed with CAD. The quality of included studies was assessed using an adaptation of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) tool. We performed meta-analyses of sensitivity, specificity and positive and negative likelihood ratios using Meta-DiSc software. RESULTS: Screening of titles and abstracts followed by full-text review yielded seven studies that met our inclusion criteria. Meta-analyses yielded a pooled sensitivity of 83% (95% confidence interval [CI] 80% to 86%) and a specificity of 77% (95% CI 73% to 81%). The pooled positive likelihood ratio was 3.92 (95% CI 2.30 to 6.66) and negative likelihood ratio was 0.20 (95% CI 0.12 to 0.35). Significant heterogeneity was present in all meta-analyses. CONCLUSIONS: The pooled test characteristics for MCG are similar to those of existing noninvasive modalities for diagnosing CAD. Our results suggest that MCG is a potential complementary or alternative tool for noninvasive detection of CAD. PMID- 23094876 TI - Brugada phenocopy: new terminology and proposed classification. AB - Brugada syndrome is a channelopathy characterized on ECG by coved ST-segment elevation (>=2 mm) in the right precordial leads and is associated with an increased risk of malignant ventricular arrhythmias. The term Brugada phenocopy is proposed to describe conditions that induce Brugada-like ECG manifestations in patients without true Brugada syndrome. An extensive review of the literature identified case reports that were classified according to their suspected etiological mechanism. Future directions to learn more about these intriguing cases is discussed. PMID- 23094877 TI - Patients with tombstoning pattern on the admission electrocardiography who have undergone primary percutaneous coronary intervention for anterior wall ST elevation myocardial infarction: in-hospital and midterm clinical outcomes. AB - BACKGROUND: A tombstoning pattern (T-pattern) is associated with in-hospital poor outcomes patients with ST-segment elevation myocardial infarction (STEMI), but no data are available for midterm follow-up. We sought to determine the prognostic value of a T-pattern on admission electrocardiography (ECG) for in-hospital and midterm mortality in patients with anterior wall STEMI treated with primary percutaneous coronary intervention (PCI). METHODS: After exclusion, 169 consecutive patients with anterior wall STEMI (mean age: 55 +/- 12.9 years; 145 men) undergoing primary PCI were prospectively enrolled in this study. Patients were classified as a T-pattern (n = 32) or non-T-pattern (n = 137) based upon the admission ECG. Follow-up to 6 months was performed. RESULTS: In-hospital mortality tended to be higher in the T-pattern group compared with non-T-pattern group (9.3% vs 2.1% respectively, P = 0.05). All-cause mortality was higher in the T-pattern group than non-T-pattern group for 6 month (P = 0.004). After adjusting the baseline characteristics, the T-pattern remained an independent predictor of 6-month all-cause mortality (odds ratio: 5.18; 95% confidence interval: 1.25-21.47, P = 0.02). CONCLUSION: A T-pattern is a strong independent predictor of 6-month all-cause mortality in anterior STEMI treated with primary PCI. Therefore, it may be an indicator of high risk among patients with anterior wall STEMI. PMID- 23094879 TI - Natural history of early repolarization in the inferior leads. AB - AIMS: Though early repolarization (ER) in the inferior leads has been associated with increased cardiovascular risk, its natural history is uncertain. We aimed to study the serial electrocardiographic behavior of inferior ER and understand factors associated with that behavior. METHODS: We selected electrocardiograms (ECGs) from patients with the greatest amplitude of ER in AVF from ECGs of 29,281 ambulatory patients recorded between 1987 and 1999 at the Palo Alto Veterans Affairs Hospital. Starting from the highest amplitude, we reviewed the ECGs and medical records from the first 85%. From this convenience sample, 36 were excluded for abnormal patterns similar to ER. The remaining 257 patients were searched for another ECG at least 5 months later, of whom, 136 satisfied this criteria. These ECGs were paired for comparison and coded by four interpreters. RESULTS: The average time between the first and second ECGs was 10 years. Of the 136 subjects, 47% retained ER while 53% no longer fulfilled the amplitude criteria. While no significant differences were found in initial heart rate (HR) or time interval between ECGs, those who lost the ER pattern had a greater difference in HR between the ECGs. There was no significant difference in the incidence of cardiovascular events or deaths. CONCLUSIONS: In conclusion, the ECG pattern of ER was lost over 10 years in over half of the cohort. The loss of ER was partially explained by changes in HR, but not higher incidence of cardiovascular events or death, suggesting the entity is a benign finding. PMID- 23094878 TI - Measure of the QT-RR dynamic coupling in patients with the long QT syndrome. AB - BACKGROUND: The patients with the long QT syndrome type-1 (LQT-1) have an impaired adaptation of the QT interval to heart rate changes. Yet, the description of the dynamic QT-RR coupling in genotyped LQT-1 has never been thoroughly investigated. METHOD: We propose a method to model the dynamic QT-RR coupling by defining a transfer function characterizing the relationship between a QT interval and its previous RR intervals measured from ambulatory Holter recordings. Three parameters are used to characterize the QT-RR coupling: a fast gain (Gain(F) ), a slow gain (Gain(L) ), and a time constant (tau). We investigated the values of these parameters across genders, and in genotyped LQT 1 patients with normal QTc interval duration (QTc < 470 ms). RESULTS: The QT-RR dynamic profiles are significantly different between LQT-1 patients (97) and controls (154): LQT-1 have longer QTc interval (453 +/- 35 vs. 384 +/- 26 ms, P < 0.0001), and an increased dependency of the QT interval to previous RR changes revealed by a larger Gain(L) (0.22 +/- 0.06 vs. 0.18 +/- 0.07, P < 0.0001) and Gain(F) (0.05 +/- 0.02 vs. 0.03 +/- 0.01, P < 0.0001). Importantly, LQT-1 patients have a faster QT dynamic response to previous RR changes described by tau: 122 +/- 44 vs. 172 +/- 92 beats (P < 0.0001). This faster QT dynamic response of the QT-RR dynamic coupling remained in LQT-1 patients with QTc in a normal range (<430 ms). CONCLUSIONS: The measurement of QT-RR dynamic coupling could be used in patients suspected to carry a concealed form of the LQT-1 syndrome, or to provide insights into the types of arrhythmogenic triggers a patient may be prone to. PMID- 23094880 TI - QT interval and long-term mortality risk in the Framingham Heart Study. AB - BACKGROUND: The association between QT interval and mortality has been demonstrated in large, prospective population-based studies, but the strength of the association varies considerably based on the method of heart rate correction. We examined the QT-mortality relationship in the Framingham Heart Study (FHS). METHODS: Participants in the first (original cohort, n = 2,365) and second generation (offspring cohort, n = 4,530) cohorts were included in this study with a mean follow up of 27.5 years. QT interval measurements were obtained manually using a reproducible digital caliper technique. RESULTS: Using Cox proportional hazards regression adjusting for age and sex, a 20 millisecond increase in QTc (using Bazett's correction; QT/RR(1/2) interval) was associated with a modest increase in risk of all-cause mortality (HR 1.14, 95% CI 1.10-1.18, P < 0.0001), coronary heart disease (CHD) mortality (HR 1.15, 95% CI 1.05-1.26, P = 0.003), and sudden cardiac death (SCD, HR 1.19, 95% CI 1.03-1.37, P = 0.02). However, adjustment for heart rate using RR interval in linear regression attenuated this association. The association of QT interval with all-cause mortality persisted after adjustment for cardiovascular risk factors, but associations with CHD mortality and SCD were no longer significant. CONCLUSION: In FHS, there is evidence of a graded relation between QTc and all-cause mortality, CHD death, and SCD; however, this association is attenuated by adjustment for RR interval. These data confirm that using Bazett's heart rate correction, QTc, overestimates the association with mortality. An association with all-cause mortality persists despite a more complete adjustment for heart rate and known cardiovascular risk factors. PMID- 23094881 TI - Recovery of heart rate variability and ventricular repolarization indices following exercise. AB - BACKGROUND: There is a heightened risk of sudden cardiac death related to exercise and the postexercise recovery period, but the precise mechanism is unknown. We have demonstrated that sympathoexcitation persists for >=45 minutes after exercise in normals and subjects with coronary artery disease (CAD). The purpose of this study is to determine whether this persistent sympathoexcitation is associated with persistent heart rate variability (HRV) and ventricular repolarization changes in the postexercise recovery period. METHODS AND RESULTS: Twenty control subjects (age 50.7 +/- 1.4 years), 68 subjects (age 58.2 +/- 1.5 years) with CAD and preserved left ventricular ejection fraction (LVEF), and 18 subjects (age 57.6 +/- 2.4 years) with CAD and depressed LVEF underwent a 16 minute submaximal bicycle exercise protocol with continuous ECG monitoring. QT and RR intervals were measured in recovery to calculate the time dependent corrected QT intervals (QTc), the QT-RR relationship, and HRV. QTc was dependent on the choice of rate correction formula. There were no differences in QT-RR slopes among the three groups in early recovery. HRV recovered quickly in controls, more slowly in those with CAD-preserved LVEF, and to a lesser extent in those with CAD-depressed LVEF. CONCLUSION: Despite persistent sympathoexcitation for the 45-minute recovery period, ventricular repolarization changes do not persist for that long and HRV changes differ by group. Additional understanding of the dynamic changes in cardiac parameters after exercise is needed to explore the mechanism of increased sudden cardiac death risk at this time. PMID- 23094882 TI - Development and validation of a prognostic index for risk stratification of patients with early repolarization. AB - BACKGROUND: Early repolarization (ER) is associated with increased mortality in the general population. We sought to develop and validate a prognostic index (PI) of mortality in patients with ER. METHODS: We identified 852 consecutive patients (mean age 49 +/- 12 years) with ER (J-point elevation >=0.1 mV in inferior or lateral leads), from the VA electronic electrocardiogram (ECG) database. A random sample of age-matched patients with normal ECG was used as control (n = 257). The initial cohort was randomly split into a derivation and a validation cohort (2/3 and 1/3 of patients, respectively). A PI was derived from the weighed sum of the regression coefficients of each independent risk factor in the final model using Cox regression analysis. RESULTS: During a median follow-up of 6.4 years, 170 patients died. ER was associated with increased mortality compared to control (HR 1.49, 95% CI 1.05-2.12; P = 0.03). Older age, lower body mass index, non-African American race, current use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers or sulfonyureas, prolonged corrected QT (QTc), and higher ER amplitude independently predicted all-cause mortality. Annualized mortality rates were 1.3%, 2.2%, and 3.7% in the low, intermediate, and high-risk groups, respectively, in the derivation cohort (log rank P < 0.0001) and 0.8%, 1.9%, and 4.1% in the low, intermediate, and high-risk groups, respectively, in the validation cohort (log rank P < 0.0001). Model discrimination was very good (c-statistic = 0.85 and 0.80 for derivation and validation cohort, respectively). CONCLUSIONS: A PI derived from simple clinical and ECG characteristics predicts mortality in patients with ER and may be used clinically for risk stratification. PMID- 23094883 TI - Electrocardiographic abnormalities in centenarians and octogenarians: a case matched study. AB - BACKGROUND: Centenarians have been proposed as a model of successful aging but recent studies suggest a high prevalence of cardiovascular diseases. Some findings on their electrocardiograms (ECGs) are simply age-related and others mirror underlying diseases. We aimed to identify ECG features truly associated with extreme age. METHODS: Retrospective analysis of 55 centenarians hospitalized between January 2000 and June 2010. Each centenarian was matched with three octogenarians according to gender, presence of hypertension, aortic stenosis, heart failure, and ischemic heart disease. RESULTS: A history of hypertension was present in 32 (58%) centenarians, aortic stenosis in 6 (11%), heart failure in 8 (15%), and ischemic heart disease in 6 (11%). Centenarians had a higher heart rate than octogenarians (81 +/- 15 bpm vs. 72 +/- 15 bpm, respectively, P < 0.001) but were less frequently on beta-blockers (7% vs. 36%, respectively, P < 0.001). Centenarians displayed more frequently atrial premature beats than octogenarians (18% vs. 3%, respectively, P < 0.001) but tended to have less atrial fibrillation (15% vs. 22% respectively, P = 0.21). Centenarians had more frequently left QRS axis deviation (48% vs. 28%, P = 0.009) and Q waves (14% vs. 1%, P = 0.02). QT interval was more prolonged in centenarians (446 +/- 42 ms vs. 429 +/- 39 ms, P = 0.008). Two centenarians (4%) and 24 (15%) octogenarians had a strictly normal ECG (P = 0.02). CONCLUSIONS: Abnormal ECG is a common finding in centenarians, with different characteristics than in younger elderly individuals. These differences are unrelated to the presence of cardiac diseases. PMID- 23094884 TI - Predictive value of heart rate recovery after exercise testing in addition to brain natriuretic peptide levels in ambulatory patients with nonischemic dilated cardiomyopathy. AB - BACKGROUND: Heart rate recovery (HRR) is related to autonomic function and is a prognostic marker in cardiovascular disease. We sought to investigate the clinical utility of HRR in addition to BNP levels in ambulatory outpatients with nonischemic dilated cardiomyopathy (NICM). METHODS: Seventy-nine NICM outpatients were followed for a mean of 19 months. HRR was defined as the difference in heart rate between peak exercise and 1 minute later. On the basis of the lower tertile value, we allocated the patients to two groups: with HRR >12 bpm (n = 48; normal) and with HRR <=12 bpm (n = 31, abnormal). RESULTS: The probability of cardiac event-free survival was significantly lower in the abnormal HRR group than in the normal HRR group (P = 0.002). Stepwise multivariate analysis revealed that plasma BNP and HRR were independent predictors of cardiac events. Patients with both HRR <=12 bpm and BNP >=200 pg/mL had significantly higher rates of cardiac events than those in whom only one, or neither, of these variables was abnormal. CONCLUSIONS: HRR after exercise testing, in addition to plasma BNP level, might be a useful indicator as a predictor for admission due to worsening heart failure and its combination is able to provide additive prognostic information in ambulatory outpatients with NICM. PMID- 23094885 TI - A family with recurrent sudden death and no clinical clue. AB - BACKGROUND: Sudden cardiac death of a child is a devastating event for the family and an enormous challenge for the attending physician. METHODS AND RESULTS: We report a family with repeat events of sudden cardiac death and recurrent ventricular fibrillation in a teenage girl, where autopsy data and clinical investigations were inconclusive. The diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT) was established only following finding a gene mutation in the cardiac ryanodine receptor. CONCLUSIONS: Interpretation of autopsy data, provocation testing and genetic testing in victims of sudden death and family members are discussed to correctly identify the cause and properly manage asymptomatic carriers in such families. PMID- 23094886 TI - Elimination of fatal arrhythmias through ablation of triggering premature ventricular contraction in type 3 long QT syndrome. AB - Congenital long QT syndrome (LQTS) is the most common inherited arrhythmia, fatal arrhythmias are the main causes of sudden death, and often induced by the premature ventricular contractions (PVCs). Ablation of the triggering PVCs may eliminate the fatal arrhythmias and prevent the sudden death in patients with LQTS. We report a 19-year-old boy diagnosed with type 3 LQTS, frequent fatal arrhythmias induced by PVCs with the identical QRS morphology. Successful ablation of the triggering PVCs was done and a single-chamber implantable cardioverter defibrillator (ICD) was implanted. There was no fatal arrhythmia events recorded by ICD during 29-month follow-up. Catheter ablation was the effective method to eliminate the fatal arrhythmias through ablation of the triggering PVCs in the present LQT3 patient. PMID- 23094887 TI - Incidentally found situs inversus with dextrocardia: inferior myocardial infarction in an 86-year-old woman. AB - Situs inversus with dextrocardia is a rare condition. Yet, the incidence of atheroclerosis and myocardial infarction in patients with dextrocardia is similar to that in general population. The diagnosis of acute myocardial infarction is somewhat tricky and difficult if the dextrocardia is not recognized. We present the electrocardiogram, coronary angiograms, and chest radiogram of a patient with incidentally found situs inversus with dextrocardia. PMID- 23094888 TI - Complete absence of precordial R waves due to absence of left-sided pericardium. AB - Poor R-wave progression (PRWP) in the precordial leads on random ECG is relatively frequent in the general population and includes a broad differential diagnosis. Here, we present for the first time a case of complete absence of precordial R waves associated with a prominent R wave in aVR due to the absence of the left-sided pericardium in a 44-year-old woman who experienced sudden cardiac death. PMID- 23094889 TI - Bidirectional ventricular tachycardia due to coronary allograft vasculopathy a unique presentation. AB - Bidirectional ventricular tachycardia (BVT) is an uncommon type of polymorphic ventricular tachycardia (PVT) with alternating polarity of the QRS complex most commonly described digitalis toxicity. Recent data has demonstrated the possible molecular basis of this electrocardiographic phenomenon. To our knowledge this is the first reported case of BVT in a patient with orthotopic cardiac transplantation and coronary allograft vasculopathy. PMID- 23094890 TI - Regulating drug information in Europe: a pyrrhic victory for pharmaceutical industry critics? AB - Informed by recent sociological debates on pharmaceuticalisation, this article examines the evolution of the current EU legal proposal on prescription drug information to patients, as well as the surrounding controversies. In 2008 the European Commission proposed the relaxation of the existing rules governing drug information provision to patients by the pharmaceutical industry. Critics of the industry's influence over health policy and markets, including consumer organisations, industry-independent patient organisations and health professionals, rejected the Commission's proposal, claiming that the industry cannot be considered a reliable source of patient information due to inherent financial conflicts of interest. Since these critics were at least partially successful in rallying opinion against the Commission proposal, they functioned as countervailing forces to promotion-driven pharmaceuticalisation. Even so, as a watered-down version of the proposal moved through the European Parliament it was further modified to ultimately resemble the Swedish system that was held up as a high-quality example of industry-based information provision. Yet this article contends that the Swedish system displays evidence of corporate bias. Significantly, basing EU policy on a drug information system not resistant to corporate bias risks creating practices that violate the legally mandated mission of EU drug regulation, which is to 'promote and protect public health'. PMID- 23094891 TI - Pt-Mo and Pt-W mixed-metal clusters with chelating or bridging diphosphine short bite ligands (Ph2P)2NH and (Ph2P)2N(CH2)9CH3: a combined synthetic and theoretical study. AB - The reactivity of the complexes [PtCl(2){Ph(2)PN(R)PPh(2)-P,P}] (R = -H, 3; R = (CH(2))(9)CH(3), 8) toward group 6 carbonylmetalates Na[MCp(CO)(3)] (M = W or Mo, Cp = cyclopentadienyl) was explored. When R = H, the triangular clusters [PtM(2)Cp(2)(CO)(5)(MU-dppa)] (M = W, 4; M = Mo, 5), in which the diphosphane ligand bridges a Pt-M bond, were obtained as the only products. When R = (CH(2))(9)CH(3), isomeric mixtures of the triangular clusters [PtM(2)Cp(2)(CO)(5){Ph(2)PN(R)PPh(2)-P,P}], in which the diphosphane ligand chelates the Pt center (M = W, 11; M = Mo, 13) or bridges a Pt-M bond (M = W, 12; M = Mo, 14), were obtained. Irrespective of the M/Pt ratio used when R = (CH(2))(9)CH(3), the reaction of [PtCl(2){Ph(2)PN(R)PPh(2)-P,P}] with Na[MCp(CO)(3)] in acetonitrile stopped at the monosubstitution stage with the formation of [PtCl{MCp(CO)(3)}{Ph(2)PN(R)PPh(2)-P,P}] (R = -(CH(2))(9)CH(3), M = W, 9; M = Mo, 10), which are the precursors to the trinuclear clusters formed in THF when excess carbonylmetalate was used. The dynamic behavior of the dppa derivatives 4 and 5 in solution as well as that of their carbonylation products 6 and 7, respectively, is discussed. Density functional calculations were performed to study the thermodynamics of formation of 4 and 5 and 11-14, to evaluate the relative stabilities of the chelated and bridged forms and to trace a possible pathway for the formation of the trinuclear clusters. PMID- 23094893 TI - Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate. AB - Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or flexible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fibrous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fibrosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39). PMID- 23094892 TI - His26 protonation in cytochrome c triggers microsecond beta-sheet formation and heme exposure: implications for apoptosis. AB - Cytochrome c unfolds locally and reversibly upon heating at pH 3. UV resonance Raman (UVRR) spectra reveal that instead of producing unordered structure, unfolding converts turns and some helical elements to beta-sheet. It also disrupts the Met80-heme bond, and has been previously shown to induce peroxidase activity. Aromatic residues that are H-bonded to a heme propionate (Trp59 and Tyr48) alter their orientation, indicating heme displacement. T-jump/UVRR measurements give time constants of 0.2, 3.9, and 67 MUs for successive phases of beta-sheet formation and concomitant reorientation of Trp59. UVRR spectra reveal protonation of histidines, and specifically of His26, whose H-bond to Pro44 anchors the 40s Omega loop; this loop is known to be the least stable 'foldon' in the protein. His26 protonation is proposed to disrupt its H-bond with Pro44, triggering the extension of a short beta-sheet segment at the 'neck' of the 40s Omega loop into the loop itself and back into the 60s and 70s helices. The secondary structure change displaces the heme via H-bonds from residues in the growing beta-sheet, thereby exposing it to exogenous ligands, and inducing peroxidase activity. This unfolding mechanism may play a role in cardiolipin peroxidation by cyt c during apoptosis. PMID- 23094894 TI - Effect of streptozotocin induced diabetes on rat hippocampus. AB - OBJECTIVE: The present study was designed to evaluate the diabetes induced neuronal damage in the hippocampus of the rat brain. BACKGROUND: Diabetes mellitus is an endocrine metabolic disorder of impaired carbohydrate, fat and protein metabolisms characterized by chronic hyperglycemia. The neurological consequences of diabetes mellitus in the brain have gained attention most recently. MATERIALS AND METHODS: Male albino rats of Wistar strain, aged 30 days were used. The rats were divided into (A) Normal Control (B) Vehicle Control (C) 15 days of Streptozotocin (STZ), (D) 30 days of STZ, (E) 45 days of STZ, (F) 60 days of STZ diabetic groups (n = 6 in each group). Blood glucose levels and body weight were measured before STZ injection, 2 days after STZ injection and on the day of sacrifice. At the end of the experimental period rats were scarified and brains were processed for cresyl violet staining and the number of survived neurons in the hippocampus was quantified. RESULTS: Microscopic examination of cresyl violet stained sections of diabetic rat hippocampus showed significant and reliable changes. There was a significant difference in the number of survived neurons especially in 30 days of STZ, 45 days of STZ and 60 days of STZ diabetic groups compared to normal control group. CONCLUSION: The results of our study indicated that diabetic complications can cause rapid damage to the neurons in the hippocampus (Fig. 12, Ref. 22). PMID- 23094895 TI - Impact of nitric oxide precursor L-arginine on oxidative stress against typhoid. AB - OBJECTIVES: Typhoid fever is a global health problem caused by Salmonella. Salmonellae are gram-negative, flagellate, nonsporulating, facultative anaerobic bacilli that ferment glucose, reduce nitrate to nitrite, and synthesize peritrichous flagella when motile. Nowadays, most of the drugs are resistant, the fact of which compels the search for formulated drugs. Nitric oxide (NO) and its congeners react with different compounds or radicals probably mediating the broad spectrum antimicrobial activity of reactive nitrogen species (RNS) as well as reactive oxygen species (ROS) against diverse microorganisms. Exogenous administration of L-arginine results in increased NO production. The formulation of NO precursors, (i.e. of L -arginine and ciprofloxacin) is used against experimentally induced salmonellosis. Lipid hydroperoxide can be decomposed to produce alkoxy and peroxy radicals which eventually yield numerous carbonyl products such as malondialdehyde (MDA). MATERIAL AND METHODS: Estimation of lipid peroxidation (LPO) was done by modified method of Utley et al (1967). RESULTS AND DISCUSSION: Infection with S. typhimurium significantly induced lipid peroxidation on days 8 and 11 as indicated by enhancement of MDA levels compared to the control mice (20 % and 9.52 %) (Tab. 1, Fig. 2, Ref. 20). PMID- 23094896 TI - The effect of acute swimming exercise on plasma leptin in rats. AB - Exercise is known to increase free fatty acid and glucose metabolism. In consideration of such physiological effects of leptin such as reducing food intake and increasing energy consumption, many researchers have studied the relation between leptin and exercise. Despite the inconsistency between results, it is generally accepted that physical activity causes changes in leptin secretion. The present study aims to determine the changes that occur in plasma leptin levels of the rats subjected to acute swimming exercise, immediately after exercise, and in the 24th and 48th hours following exercise.Forty adult male rats of Spraque Dawley species were equally allocated to 4 groups. Group 1: General Control Group. Group 2: Swimming Group, the group that was decapitated just after 30-minutes of acute swimming exercise. Group 3: Swimming Group, the group that was decapitated 24 hours after 30-minutes of acute swimming exercise. Group 4: Swimming Group, the group that was decapitated 48 hours after 30-minutes of acute swimming exercise. Plasma leptin levels of the experimental animals were determined according to RIA method in the blood samples collected by decapitation method. Comparison of plasma leptin levels between groups revealed that the Group 3 had the highest plasma leptin levels (p <0.01). Plasma leptin levels in the Group 1 (control) and 4 were not different and the Group 2 had the lowest plasma leptin levels (p <0.01). Results of the present study show that an acute swimming exercise and/or stress factors associated with an acute exercise inhibit leptin secretion from the adipose tissue (Tab. 1, Ref. 21). PMID- 23094897 TI - Population genetic study of diabetes and diabetic retinopathy among Egyptians. AB - OBJECTIVES: To clarify the population genetic background of diabetes mellitus among Egyptians and its effect on developing diabetic retinopathy (DR). BACKGROUND: Genes play an important role in the development of diabetes mellitus. METHODS: A statistical study was carried on 214 patients with diabetes mellitus after clinical genetic evaluation including medical and family history, family pedigree analysis, and determination of blood sugar, cholesterol and triglycerides levels. Ophthalmic examination was done to detect diabetic retinopathy. RESULTS: Family history of diabetes was higher in type I while parental consanguinity was higher in type II. Type I diabetics had positive familial aggregation with sharp falling in frequency of affection from the first to the second to the third degree relatives. Type II diabetes is generally a disease of multifactorial inheritance and AD inheritance in part of pedigrees; however AR inheritance could not be excluded. Family history of DR was higher among diabetic patients with DR than in patients without retinopathy (p < 0.05). Female gender, type I diabetes, duration of diabetes, triglycerides and positive family history of diabetic retinopathy were predictive risk factors for DR. CONCLUSION: Genetic factors play an important role in various forms of DM, however the inheritance is complex. Although most cases of DM are multifactorial disorders, monogenic forms have been also identified. Family history is an important risk factor for the development of DR. Molecular studies are recommended to detect which of the implicated genes are responsible for the development of DR among diabetic Egyptians (Tab. 4, Fig. 1, Ref. 18). PMID- 23094898 TI - Association of smoking frequency and cigarette consumption with obesity in Korean adolescents. AB - The purpose of this study was to examine whether smoking frequency and cigarette consumption were related with obesity in Korean adolescents. A total of 72,399 adolescents from 1st grade middle-school to 3rd grade high-school participated in the 5th Korea Youth Risk Behavior Web-based Survey (KYRBWS) project in 2009. The relationship between the body mass index (BMI), smoking frequency, and cigarette consumption was assessed using multivariate logistic regression analysis after adjusting for covariate variables like age, frequency of alcohol consumption and severe alcohol intoxication, amount of alcohol consumed, parents' education level, economic status, sedentary activities during the week, mental stress, sleep duration, frequency of vigorous and moderate physical activities, and muscular strength exercises during the week. We concluded that both smoking frequency and cigarette consumption had positive effects with regard to weight loss in adolescents. However, because smoking has negative side effects on general health, including an increase in abdominal fat and morbidity rates of obesity-related diseases, we recommend that adolescents should not smoke (Tab. 3, Ref. 26). PMID- 23094899 TI - Is a routine preoperative rectosigmoidoscopy necessary in patients with bilateral inguinal hernia? AB - OBJECTIVES: The purpose of this prospective study was to evaluate the association between bilateral inguinal hernias and colorectal cancers. PURPOSE: Inguinal hernias are one of the most common subjects in surgical practice and have been known to be associated with some other pathologies since 1831. Although there are some series in literature reporting the association of colorectal cancers with inguinal hernias, it is still controversial to perform colorectal diagnostic tools in hernia patients. Colorectal cancers are particularly accused to be in association with synchronous bilateral hernias as they increase the intra abdominal pressure. METHODS: Rectosigmoidoscopy was performed in 110 consecutive bilateral hernia patients and the results were recorded prospectively. Patients having colorectal diseases were excluded. RESULTS: There were no pathologies in 87 (%79,1) rectosigmoidoscopies, while benign pathologies (hemorrhoids, polyps and diverticulitis) were diagnosed in 23 (%20,9). CONCLUSIONS: It has not been proved yet that colorectal cancers increase the incidence of bilateral inguinal hernias. The incidence of benign pathologies in our series was similar to that of same age population without hernia. As a conclusion of this study we believe that rectosigmoidoscopy is not necessary for synchronous bilateral hernias unless the patient has any complaints or risk factors. Colorectal screening tools are performed when the clinical findings or the story of the patient support colorectal cancers) (Tab. 1, Ref. 25). PMID- 23094900 TI - Adding magnesium to levobupivacaine for axillary brachial plexus block in arteriovenous fistule surgery. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effect of adding magnesium to levobupivacaine on sensory and motor block onset and duration for axillary brachial plexus block in chronic renal failure (CRF) patients scheduled for arteriovenous fistule surgery (AVFS). METHODS: 80 patients, ASA III, aged 30 to 70 years, randomized and divided into 4 groups: Group I (n = 20) received total 41 ml of levobupivacaine 0.5 % + 1 ml NaCl 0.9 % mixture; Group II (n = 20) received 41 ml of levobupivacaine 0.5 % + 1 ml magnesium sulfate (150 mg) mixture; Group III (n = 20) received total 41 ml of levobupivacaine 0.25 % + 1 ml NaCl 0.9 % mixture; and Group IV (n = 20) received total 41 ml of levobupivacaine 0.25 % + 1 ml magnesium sulfate (150 mg) mixture by perineural axillary brachial plexus block. All patients were evaluated with regard to motor and sensory blocks. Motor and sensory block ending times were recorded. RESULTS: Motor and sensory block onset times were statistically decreased in Group II when compared with Goup I, and also the motor and sensory block durations were increased in Group II when compared with Goup I (p < 0.05). Sensory block onset times were statistically decreased in Group IV when compared with Goup III (p < 0.05). CONCLUSIONS: We conclude that by its decreasing effect on local anesthetic dose, magnesium may reduce the side effects due to high local anesthetic doses in patients with CRF (Tab. 1, Ref. 11). PMID- 23094901 TI - Is there an association between serum 25-hydroxyvitamin D concentrations and disease activity in rheumatoid arthritis? AB - BACKGROUND: Recently, it has been recognized that vitamin D not only is important for calcium metabolism and maintenance of bone healthy, but also plays an important role in reducing risk of many chronic diseases including rheumatoid arthritis (RA), systemic lupus erythematosus, insulin-dependent diabetes mellitus, multiple sclerosis, several cancers, heart and infectious diseases. In RA, the role of vitamin D is undefined. METHODS: The objective of this present study was to determine serum 25-hydroxyvitamin D (25(OH)D) concentrations in patients with RA and to establish its correlation with disease activity. This study was performed on fifty-five consecutive patients RA fulfilling the American Collage of Rheumatology (ACR) criteria for the classification of RA and forty five healthy subjects. Serum 25(OH)D levels were measured using Elecsys 25(OH)D reactive kit. Disease activity was assessed according to DAS28, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The association between serum levels of 25(OH)D and age, gender, disease duration and disease activity parameters were established. RESULTS: The mean serum 25(OH)D levels were significantly decreased in RA patients compared to healthy controls (p < 0.01) and were associated with higher levels of parathyroid hormone. Vitamin D deficiency (i.e. < 30 ng/ml) was found in 50 patients (90.9 %). Serum levels of vitamin D lower than 20 ng/ml were found in 72 % of patients. We did not find the correlation between serum 25(OH)D levels and disease activity parameters. CONCLUSIONS: Our findings have demonstrated that serum 25(OH)D levels is highly prevalent in patient with RA. We believe that it will be helpful to investigate the vitamin D levels in order to determine the osteomalacia risk of RA patients (Tab. 2, Ref. 11). PMID- 23094902 TI - Ischemia-modified albumin (IMA) in differential diagnosis of transient myocardial ischemia from non ischemic chest pain. AB - BACKGROUND: Early diagnosis of acute coronary syndrome (ACS) is an important factor in reducing mortality of this disease. Cardiac troponins are not elevated within first hours. So there is a need to optimize the clinical applicability and accuracy of novel ACS markers, particularly with regard to utilizing this technique in combination with other diagnostic methods. METHODS: In this prospective study, we examined 226 patients between July 2009 and March 2010, admitted with chest pain to emergency room (ER). The study groups constisted of 120 subjects presenting with chest pain whose initial and subsequent diagnosis was unstable angina (UA), and 106 subjects whose initial diagnosis was unstable angina but subsequent diagnosis was non ischemic chest pain(NICP). For each patient electrocardiogram (ECG), cardiac troponins (cTnT), creatinine phosphokinase (CPK), IMA levels were measured. We used McNemar's test for correlated proportions and logistic regression and ROC curve for achieving better result. RESULTS: In this study median IMA values were definitely higher in patients with ACS compared with non ischemic chest pain (NICP) (p < 0.0001) (83.5 to 49.6). An IMA cut-off threshold derived from the receiver operating characteristics curve (ROC) was 85U/ml and gives 54 % (95%CI 51 to 56) sensitivity and 87 % (95%CI 83 to 92) specificity in our population. Negative predictive value was 62 % (95%CI 59 to 66). When IMA and ECG and cTnT were considered together sensitivity was 97.5 % and specificity was 63 %, respectively. CONCLUSION: Ischemia-modified albumin did not provide superior sensitivity or specificity compared with other diagnostic tests (Tab. 1, Fig. 2, Ref. 25). PMID- 23094903 TI - Euglycemic state reduces the incidence of critical illness polyneuropathy and duration of ventilator dependency in medical intensive care unit. AB - OBJECTIVE: To examine the effect of euglycemic blood glucose control with normal insulin therapy on the incidence of critical illness polyneuropathy and duration of mechanical ventilation compared to that of conventional insulin therapy in a medical ICU. BACKGROUND: Despite the criticism over increased risk of hypoglycemia, the prevention of hyperglycemia through intensive insulin therapy has recently been confirmed to reduce the critical illness polyneuropathy (CIP). METHODS: In a single blind randomized clinical trial, forty adult patients admitted to the medical ICU were randomized to either euglycemic control (80-140 mg/dL) (Group N) or conventional approach (180-200 mg/dL, Group C). Duration of mechanical ventilation and the presence of CIP were investigated. RESULTS: The mean blood glucose levels were 131.76 +/- 40.15 mg/dL in group N and 169.87 +/- 50.66 mg/dL in group C (p < 0.001). Patients in group N were on mechanical ventilation for significantly less time than those in group C (p = 0.04). The diagnosis of CIP was significantly more frequent in group C than in group N (p = 0.01). CONCLUSIONS: Glucose control at levels 80-140 mg/dL with normal insulin administration is likely to be associated with both reduced incidence of CIP and duration of ventilator dependency in medical ICU (Tab. 3, Ref. 24). PMID- 23094904 TI - Unexpected malignant pericardial mesothelioma presenting as pericardial constriction. AB - Pericardial mesothelioma is a rare and highly aggressive and lethal cardiac tumour. A 25-year-old male patient who was complaining of fever, night sweats, shortness of breath and palpitations after an upper respiratory system infection was admitted in May 2008. He had a history of 12 years exposure to asbestos. When the patient was referred to our hospital in June 2008, his complaints of palpitations and shortness of breath were continuing. He had oedema of legs and a venous swelling on his neck. The echocardiography showed pericardial effusion and pericardial thickening which were also found on the CT. Through median sternotomy a pericardectomy and tumor resection were performed. Histological and immunohistochemical findings lead to the diagnosis of malignant pericardial mesothelioma. In conclusion, there is still not a radical therapy for primary pericardial mesothelioma. Surgery is done to prevent cardiac tamponade and relieves constriction (Fig. 1, Ref. 12). PMID- 23094905 TI - Fibroepithelioma of Pinkus. AB - Basal cell carcinoma (BCC) is recently the most common cancer in humans characterized by several histopathological subtypes. Fibroepithelioma of Pinkus (FEP) is traditionally classified as a very rare variant of BCC, however, it manifests clinical and morphological differences that distinguish it from most other types BCCs. This study was performed to evaluate the incidence of FEP and clinical-pathological characteristics of patients diagnosed with this tumor. Four cases of primary FEP (3 females, 1 male, mean age 53.4 y) were analyzed retrospectively. The prevalence of FEP was 0.7 % of all diagnosed BCCs. Topographically, tumors were localized on the right brachium, right gluteal region, left mesogastrium, and right side of the abdomen. Histological examination showed typical anastomosing cords of basaloid cells extending from the overlying epidermis into the loose fibrous stroma in the dermis. Mitotic activity or significant cellular atypia, as well as sign of solar dermatosis were absent. Mean horizontal and vertical diameter of the lesions were 7.7 and 2.8 mm, retrospectively. We did not observe infiltration of deeper skin structures. All lesions were removed completely and classified as pathological stage pT1. Three cases manifested typical picture of a "pure" FEP, one lesion had partially a feature of nodular type BCC, too. Although FEP is conventionally considered as indolent BCC variant with a favorable clinical outcome, recent evidences also favors its classification as a form of trichoblastoma. This is appropriate example how some types of cutaneous tumors can overlap in terms of dignity and clinical-morphological characteristics. This should be taken into account in differential diagnosis and in predicting of biological behaviour of the individual tumors of the skin (Tab. 2, Fig. 3, Ref. 26). PMID- 23094906 TI - Malignant peripheral nerve sheath tumour (malignant epithelioid Schwannoma) of the parotid gland. AB - PROBLEMS/OBJECTIVES: Malignant peripheral nerve sheath tumours are uncommon soft tissue tumours originating from Schwann cells or nerve sheath cells. Malignant epithelioid schwannoma is an aggressive variant of malignant peripheral nerve sheath tumour, and unfortunately is related with a high rate of recurrence and poor prognosis. METHODOLOGY: In this study we present a rare case of malignant epithelioid schwannoma of the parotid gland and we discuss its origin, unusual presentation, and possible treatments options. RESULTS: Patient underwent total parotidectomy without neck dissection. Postoperative radiotherapy and chemotherapy management were not necessary. CONCLUSION: Patients with malignant epithelioid schwannomas typically present with pain and/or rapid enlargement of a pre-existing lesion but the diagnosis of these tumours remains difficult as it is based primarily on clinical suspicion. There is no recognized management for this tumour yet while the prognosis seems to correlate best with the extent of surgical resection (Fig. 4, Ref. 16). PMID- 23094907 TI - Protein arginine methylation in Saccharomyces cerevisiae. AB - Recent research has implicated arginine methylation as a major regulator of cellular processes, including transcription, translation, nucleocytoplasmic transport, signalling, DNA repair, RNA processing and splicing. Arginine methylation is evolutionarily conserved, and it is now thought that it may rival other post-translational modifications such as phosphorylation in terms of its occurrence in the proteome. In addition, multiple recent examples demonstrate an exciting new theme: the interplay between methylation and other post translational modifications such as phosphorylation. In this review, we summarize our current understanding of arginine methylation and the recent advances made, with a focus on the lower eukaryote Saccharomyces cerevisiae. We cover the types of methylated proteins, their responsible methyltransferases, where and how the effects of arginine methylation are seen in the cell, and, finally, discuss the conservation of the biological function of methylarginines between S. cerevisiae and mammals. PMID- 23094908 TI - Efficacy of epidural lidocaine combined with tramadol or neostigmine on perineal analgesia in the horse. AB - REASONS FOR PERFORMING STUDY: Short duration of analgesia is among the limitations of a single epidural injection with lidocaine in horses. OBJECTIVES: To evaluate the effectiveness and safety of epidural lidocaine in combination with either tramadol or neostigmine for perineal analgesia in horses. METHODS: Epidural catheters were placed in 6 saddle horses that then were given 3 treatments: 2% lidocaine (0.2 mg/kg bwt) alone, 2% lidocaine (0.2 mg/kg bwt) plus tramadol (0.5 mg/kg bwt), and 2% lidocaine (0.2 mg/kg bwt) plus neostigmine (1.0 MUg/kg bwt). The order of treatments was randomised. Haemodynamic variables, respiratory rate, rectal temperature, analgesia, motor block and behaviour scores were compared among the 3 treatments. These parameters were determined before drug administration (baseline), at 5, 10, 15, 30, 45, 60, 75 and 90 min, and every 30 min thereafter until loss of analgesia. RESULTS: Duration of analgesia was longer with lidocaine plus tramadol (210 +/- 12 min) compared with lidocaine plus neostigmine (150 +/- 35 min) or lidocaine alone (70 +/- 12 min; P<0.05). All treatments produced mild or moderate motor block without behavioural changes. Other adverse effects were not observed in any of the horses. CONCLUSION AND POTENTIAL RELEVANCE: Further studies are required to demonstrate whether tramadol or neostigmine have a role in the management of post operative pain when coadministered with lidocaine. PMID- 23094909 TI - Combined texture feature analysis of segmentation and classification of benign and malignant tumour CT slices. AB - A computer software system is designed for the segmentation and classification of benign from malignant tumour slices in brain computed tomography (CT) images. This paper presents a method to find and select both the dominant run length and co-occurrence texture features of region of interest (ROI) of the tumour region of each slice to be segmented by Fuzzy c means clustering (FCM) and evaluate the performance of support vector machine (SVM)-based classifiers in classifying benign and malignant tumour slices. Two hundred and six tumour confirmed CT slices are considered in this study. A total of 17 texture features are extracted by a feature extraction procedure, and six features are selected using Principal Component Analysis (PCA). This study constructed the SVM-based classifier with the selected features and by comparing the segmentation results with the experienced radiologist labelled ground truth (target). Quantitative analysis between ground truth and segmented tumour is presented in terms of segmentation accuracy, segmentation error and overlap similarity measures such as the Jaccard index. The classification performance of the SVM-based classifier with the same selected features is also evaluated using a 10-fold cross-validation method. The proposed system provides some newly found texture features have an important contribution in classifying benign and malignant tumour slices efficiently and accurately with less computational time. The experimental results showed that the proposed system is able to achieve the highest segmentation and classification accuracy effectiveness as measured by jaccard index and sensitivity and specificity. PMID- 23094910 TI - OsNAC5 overexpression enlarges root diameter in rice plants leading to enhanced drought tolerance and increased grain yield in the field. AB - Drought conditions are among the most serious challenges to crop production worldwide. Here, we report the results of field evaluations of transgenic rice plants overexpressing OsNAC5, under the control of either the root-specific (RCc3) or constitutive (GOS2) promoters. Field evaluations over three growing seasons revealed that the grain yield of the RCc3:OsNAC5 and GOS2:OsNAC5 plants were increased by 9%-23% and 9%-26% under normal conditions, respectively. Under drought conditions, however, RCc3:OsNAC5 plants showed a significantly higher grain yield of 22%-63%, whilst the GOS2:OsNAC5 plants showed a reduced or similar yield to the nontransgenic (NT) controls. Both the RCc3:OsNAC5 and GOS2:OsNAC5 plants were found to have larger roots due to an enlarged stele and aerenchyma at flowering stage. Cell numbers per cortex layer and stele of developing roots were higher in both transgenic plants than NT controls, contributing to the increase in root diameter. The root diameter was enlarged to a greater extent in the RCc3:OsNAC5, suggesting the importance of this phenotype for enhanced drought tolerance. Microarray experiments identified 25 up-regulated genes by more than three-fold (P < 0.01) in the roots of both transgenic lines. Also identified were 19 and 18 up-regulated genes that are specific to the RCc3:OsNAC5 and GOS2:OsNAC5 roots, respectively. Of the genes specifically up-regulated in the RCc3:OsNAC5 roots, GLP, PDX, MERI5 and O-methyltransferase were implicated in root growth and development. Our present findings demonstrate that the root-specific overexpression of OsNAC5 enlarges roots significantly and thereby enhances drought tolerance and grain yield under field conditions. PMID- 23094911 TI - Type II kinase inhibitors: an opportunity in cancer for rational design. AB - With the advent of the Type II kinase inhibitor imatinib (Gleevec) for treatment against cancer, rational design of tailored molecules has brought a revolution in medicinal chemistry for treating tumours caused by kinase malfunctioning. Among different types of kinase inhibitors, the design of Type II inhibitors has been rationalized for maximizing the benefits and reducing drawbacks. Here we highlight the development made in Type II inhibitors, discussing the advantages and disadvantages of these types of molecules. Furthermore, we present the strategies for designing druggable molecules that either selectively inhibit target kinases or overcome drug resistance. PMID- 23094912 TI - N6-isopentenyladenosine and its analogue N6-benzyladenosine induce cell cycle arrest and apoptosis in bladder carcinoma T24 cells. AB - Cytokinins are phytohormones critically involved in the regulation of plant growth and development. They also affect the proliferation and differentiation of animal cells, thus representing new tools to treat diseases that involve dysfunctional cell growth and/or differentiation. Recently, by performing structure-function studies on human cells, we found that only N6 isopentenyladenosine and its benzyl analogue N6-benzyladenosine suppress the clonogenic activity and the growth of different neoplastic cells. We here broaden our studies on bladder carcinoma T24 cells, because, due to the high recurrence rate of bladder cancer, new active molecules are sought to contrast the growth of this tumor. Early events induced by N6-isopentenyladenosine and N6 benzyladenosine are the alteration of T24 cell morphology and the disorganization of the actin cytoskeleton. After 24 h N6-isopentenyladenosine and N6 benzyladenosine inhibit growth by arresting the cells in the G0/G1 phase of the cell cycle. We also show that the two compounds induce apoptosis, an event linked to the activation of caspase 3. Since DNA damage is a prime factor resulting in cell cycle arrest and apoptosis, it is noteworthy that we do not detect any genotoxic effect upon treatment of T24 cells with N6-isopentenyladenosine and N6- benzyladenosine. Because the disruption of actin filaments leads to G1 arrest and is also implicated in apoptosis, we hypothesize that cytoskeletal rearrangement might be responsible for triggering the antiproliferative and proapotpotic effects of N6-isopentenyladenosine and N6- benzyladenosine in T24 cells. PMID- 23094913 TI - SJSZ glycoprotein (38 kDa) inhibits cell cycle and oxidative stress in N-methyl N'-nitro-N-nitrosoguanidine-induced ICR mice. AB - The initiation stage of liver cancer is closely related to abnormal cell proliferation as observed for other types of carcinogenesis. Recently, we isolated a glycoprotein from Styrax japonica Siebold et al Zuccarini (SJSZ glycoprotein), which consists of a carbohydrate moiety (52.64%) and a protein moiety (47.36%). In this study, the antitumoric mechanism of SJSZ glycoprotein during the initiation stage in N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG; 40 mg/kg, BW)-induced ICR was investigated. First, we evaluated the activities of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), thiobarbituric acid reactive substances (TBARS), and activities of antioxidative enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT)] in mouse liver tissue and serum. The alpha-fetoprotein (AFP), cell cycle-related factors [cyclin D1/ cyclin dependent kinase (CDK) 4], cell cycle inhibitors (CKIs; p53, p21, and p27), and proliferating cell nuclear antigen (PCNA) were then assessed using Western Blot analysis. The results of this analysis showed that the SJSZ glycoprotein (10 mg/kg, BW) decreased the levels of LDH, ALT, TBARS, and the expression of AFP but it increased the activity of hepatic anti-oxidant enzymes (SOD, GPx and CAT). In addition, the SJSZ glycoprotein (10 mg/kg, BW)was shown to decrease the expression of cyclin D1/CDK4 and PCNA and increase the expression of CKIs (p53, p21, and p27). The results in this study indicate that the SJSZ glycoprotein displays anti-oxidative stress and anti-cell proliferation activity in MNNG induced ICR. PMID- 23094915 TI - Recombinant snake venom cystatin inhibits tumor angiogenesis in vitro and in vivo associated with downregulation of VEGF-A165, Flt-1 and bFGF. AB - Previous studies have shown that recombinant snake venom cystatin (sv-cystatin) inhibits the invasion and metastasis of tumor cells in vitro and in vivo. The purpose of this study was to investigate the ability of recombinant sv-cystatin to inhibit tumor angiogenesis in vitro and in vivo, and the mechanisms underlying this effect. Recombinant sv-cystatin inhibited proliferation of human umbilical vein endothelial cells (HUVECs) at 100 and 200 MUg/mL after 72, 96 and 120 h. Recombinant sv-cystatin also inhibited tumor-endothelial cell adhesion at 25, 50, 100 and 200 MUg/mL. Recombinant sv-cystatin inhibited capillary-like tube formation by HUVECs at 10, 25, 50, 100 and 200 MUg/mL following 12, 24 and 36 h incubation. Furthermore, recombinant sv-cystatin significantly suppressed microvessel density (MVD) of lung tumor colonies in C57BL/6 mice inoculated in the lateral tail vein with B16F10 melanoma cells. Administration of recombinant sv-cystatin significantly decreased MVD of primary tumor tissues in nude mice implanted subcutaneously with human hepatocellular carcinoma cells (MHCC97H). Exposure of B16F10 and MHCC97H cells to increasing doses of recombinant sv cystatin suppressed secretion of vascular endothelial growth factor (VEGF)-A165 and basic fibroblast growth factor (bFGF) into the surrounding medium (P < 0.05). The expression of fms-related tyrosine kinase 1 (Flt-1) protein in HUVECs was decreased by 25, 50, 100 and 200 MUg/mL recombinant sv-cystatin (P < 0.05). This study demonstrates that recombinant sv-cystatin inhibits tumor angiogenesis associated with downregulation of VEGF-A165, Flt-1 and bFGF. This suggests that recombinant sv-cystatin may have potential pharmaceutical applications as an antiangiogenic and antimetastatic therapeutic agent. PMID- 23094914 TI - Pomegranate extracts and cancer prevention: molecular and cellular activities. AB - There is increased appreciation by the scientific community that dietary phytochemicals can be potential weapons in the fight against cancer. Emerging data has provided new insights into the molecular and cellular framework needed to establish novel mechanism-based strategies for cancer prevention by selective bioactive food components. The unique chemical composition of the pomegranate fruit, rich in antioxidant tannins and flavonoids has drawn the attention of many investigators. Polyphenol rich fractions derived from the pomegranate fruit have been studied for their potential chemopreventive and/or cancer therapeutic effects in several animal models. Although data from in vitro and in vivo studies look convincing, well designed clinical trials in humans are needed to ascertain whether pomegranate can become part of our armamentarium against cancer. This review summarizes the available literature on the effects of pomegranate against various cancers. PMID- 23094916 TI - Safety issues of vitamin D supplementation. AB - Vitamin D deficiency is a re-emerging global health problem, which is primarily due to inadequate vitamin D synthesis in the skin. Supplement use is an effective measure to improve vitamin D status. However, some safety issues have to be considered, which are highlighted in this review article: The concept of vitamin D safety consists of two models, the safe tolerable upper intake level (UL) method, and the idea of adequate circulating 25-hydroxyvitamin D (25[OH]D) levels. Oral vitamin D intakes up to 250 MUg/d have not been associated with harm. Hypercalcemia, the hallmark of vitamin D intoxication, may only occur if circulating 25(OH)D levels are consistently above 375-500 nmol/l. However, some observational studies indicate that already circulating 25(OH)D levels > 125 nmol/l are related to an increased morbidity and mortality risk. Therefore, the Institute of Medicine has set the UL for adults at 100 MUg/d, and the adequate circulating 25(OH)D level at 50 to 125 nmol/l. In clinical practice, oral vitamin D dosing has to consider that the increment in circulating 25(OH)D depends on baseline 25(OH)D levels and the person's body weight. It is reasonable to assess 25(OH)D before and 3-6 months after initiation of oral vitamin D administration and to adjust the dose, if necessary. In future, two issues have to be clarified: First, would it be more appropriate to define instead of a fixed UL a variable UL, based on the individual's body weight? Second, what are the underlying mechanisms, if any, for potentially harmful vitamin D effects at circulating 25(OH)D levels between 125 and 375 nmol/l. PMID- 23094917 TI - Epidemiology of vitamin D and colorectal cancer. AB - Garland and Garland first hypothesized that better vitamin D status lowered risk of colorectal cancer in 1980. Subsequently, the relation between vitamin D status and colorectal cancer risk has been investigated in epidemiologic studies. Various approaches have been used to estimate vitamin D status, including direct measures of circulating 25(OH)vitamin D levels, surrogates or determinants of vitamin D (including region of residence, intake, and sun exposure estimates, or a combination of these). These measures of vitamin D status have been studied in relation to colorectal adenoma, precursors of cancer, and colorectal cancer incidence and mortality. In general, all lines of inquiry from observational studies indicate that better vitamin D status is associated with lower colorectal cancer risk. While most of the studies have examined vitamin D status in relation to risk of incident colorectal cancer, some evidence suggests that vitamin D may be additionally important for colorectal cancer progression and mortality. Although the influence of confounding factors cannot be entirely excluded, the consistency of the association using various approaches to measure vitamin D, for diverse endpoints and in diverse populations shows high consistency and is strongly suggestive of a causal association. Thus, improving vitamin D status could be potentially beneficial against colorectal cancer incidence and mortality. PMID- 23094919 TI - Supplementation, optimal status, and analytical determination of vitamin D: where are we standing in 2012? AB - There is a growing interest for vitamin D in the medical and scientific community as well as in the public medias as illustrated by a huge number of publications. Most experts claim that vitamin D deficiency/insufficiency is widespread with potential important public health consequences. It may seem surprising for many persons that a deficiency in a vitamin may be so frequent in countries where food is so diversified and easily available. In fact, vitamin D is not a vitamin stricto sensu as it is mainly synthesized in the skin under the action of UVB rays, while its food sources are scarce. Furthermore, UVB rays are absent during a marked part of the year at latitudes greater than 35-40?, while pollution and cloud cover reduce the number of UVB reaching the earth, and many factors such as age, skin pigmentation, covering clothes, sun creams reduce the capacity of the skin to synthesize vitamin D3. Vitamin D must be hydroxylated to form 1,25dihydroxyvitamin D (1,25OH2D), the active metabolite. As 1,25OH2D is released into the bloodstream and binds to a receptor present in several distant tissues, it may be considered as a hormone, vitamin D being thus a pre-prohormone. In the present article, we review briefly the metabolism and various effects of vitamin D as well as the vitamin D assays and vitamin D treatments. We define vitamin D deficiency/insufficiency considering separately the population and the patient level and propose our opinion about which patients may benefit from vitamin D testing. PMID- 23094920 TI - Vitamin D, sunlight, and the epidemiology of prostate cancer. AB - The hypothesis that vitamin D deficiency increases the risk of clinical prostate cancer has stimulated an extensive body of research. Ecologic studies have shown that mortality rates from prostate cancer are inversely correlated with levels of ultraviolet radiation, the principal source of vitamin D. Human prostate cells express receptors for 1,25-Dihydroxyvitamin D which exerts pleitropic anticancer effects on these cells in vitro and in animal models. Moreover, normal prostate cells synthesize 1,25-Dihydroxyvitamin D from circulating levels of 25-OHD, whose levels are dependent on exposure to ultraviolet light. Analytic epidemiologic studies of vitamin D and prostate cancer have focused on polymorphisms in the vitamin D receptor (VDR), on serum vitamin D levels, and on solar exposure. A role for VDR polymorphisms in prostate cancer risk and progression is established. Prospective studies of serum 25(OH)D do not support a protective role for higher levels of 25(OH)D on prostate cancer risk overall, but a role for vitamin D deficiency is supported by several studies. Conversely, a growing body of evidence implicates low levels of 25-OHD with an increased risk of fatal prostate cancer. The results of most epidemiologic studies of sunlight exposure are consistent with a protective effect of exposure to ultraviolet radiation. The discrepancy between the results of studies of solar exposure and studies of serum 25-OHD may be related to methodological differences and to uncertainties regarding the critical period for vitamin D exposure. Additionally, both high dietary intake of calcium and high levels of calcium in serum are positively associated with prostate cancer risk. The relationship between serum 25(OH)D levels and risk of prostate cancer may differ by calcium intake. PMID- 23094921 TI - Relevance of vitamin D in bone and muscle health of cancer patients. AB - Cancer patients with advanced disease frequently feel weak and fatigued, and have an increased risk of fracture. At the same time several reports describe the high prevalence of vitamin D deficiency in these patients. This review will summarize the impact of vitamin D deficiency on muscle weakness and fracture risk. While larger clinical trials of vitamin D supplementation are lacking in cancer patients, the evidence from clinical trials among older adults of the general population support a significant benefit of vitamin D on muscle strength, and fall and fracture reduction. Mechanistic evidence regarding the presence of the specific vitamin D receptor in muscle tissue and muscle biopsy abnormalities observed with deficiency will be reviewed, as well as molecular and non-molecular effects of vitamin D in muscle tissue. At the clinical level, the evidence from randomized controlled trials of vitamin D supplementation on functional improvement and fall reduction will be summarized. Finally, trial and epidemiological data will be reviewed to assess desirable serum 25-hydroxyvitamin D levels for optimal muscle health. PMID- 23094922 TI - Shedding light on serum vitamin D concentrations and the risk of rarer cancers. AB - Cancer is a broad term for many disparate diseases with different etiologies, commonly classified by affected organ site. This review summarizes the published evidence from prospective cohort studies examining the associations between vitamin D, measured as serum 25-hydroxyvitamin D (25OHD) concentrations, and the risk of rarer cancer sites including pancreatic, non-Hodgkin lymphoma, ovarian, endometrial, kidney, gastric and esophageal cancer. Overall, evidence from prospective cohort studies provides little support for a protective association between adequate or higher serum 25OHD concentrations and risk of these rarer cancer sites. Additionally, controversy persists concerning a potential increased risk of pancreatic cancer associated with serum 25OHD levels > 100 nmol/L due to conflicting results reported by two large prospective pooling projects. PMID- 23094923 TI - Vitamin D, sunlight and cancer connection. AB - It has been more than 100 years when it was first appreciated that increased sun exposure reduced risk of dying of cancer. The most beneficial effect of sun exposure is the production of vitamin D in the skin. Recent evidence suggests that most cells in the body not only have a vitamin D receptor but also have the capacity to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Once formed 1,25-dihydroxyvitamin D can inhibit cellular proliferation, induce cellular maturation, inhibit angiogenesis and ultimately cause apoptosis to prevent malignancy. A multitude of studies have associated improved vitamin D status with decreased risk for developing several deadly cancers including colon, breast, pancreatic and ovarian cancers. Patients with cancer are at high risk for vitamin D deficiency. Sensible sun exposure, vitamin D fortification and vitamin D supplementation should be encouraged to improve the vitamin D status of children and adults not only for bone health but for reducing risk of developing and dying of cancer. The goal is to achieve a blood level of 25-hydroxyvitamin D of 40-60 ng/mL. This can be accomplished by children taking 600-1000 and adults 1500-2000 international units (IU) vitamin D daily from diet and supplements along with sensible sun exposure when the sun is capable of producing vitamin D in the skin. PMID- 23094924 TI - Sunlight vitamin D and skin cancer. AB - Today, there is a controversial debate in many scientific and public communities on how much sunlight is appropriate to balance between the positive and negative effects of solar UV-exposure. UV exposure undoubtedly causes DNA damage of skin cells and is a major environmental risk factor for all types of skin cancers. In geographic terms, living in parts of the world with increased erythemal UV or high average annual bright sun results in increased risks of skin cancers, with the greatest increased risk for squamous cell carcinoma, followed by basal cell carcinoma and then melanoma. On the other hand, sunlight exerts positive effects on human health, that are mediated in part via UV-B-mediated cutaneous photosynthesis of vitamin D. It has been estimated that at present, approximately 1 billion people worldwide are vitamin D-deficient or -insufficient. This epidemic causes serious health problems that are still widely under-recognized. Vitamin D deficiency leads to well documented problems for bone and muscle function. There are also associations between vitamin D-deficiency and increased incidence of and/or unfavourable outcome for a broad variety of independent diseases, including various types of malignancies (e.g. colon-, skin-, and breast cancer), autoimmune diseases, infectious diseases, and cardiovascular diseases. In this review, the present literature is analyzed to summarize our present knowledge about the important relationship of sunlight, vitamin D and skin cancer. PMID- 23094918 TI - Role of calcium, vitamin D, and the extrarenal vitamin D hydroxylases in carcinogenesis. AB - Vitamin D deficiency and low calcium intake are considered risk factors for several cancers. Vitamin D, synthesized in the skin or ingested through the diet, is transformed through two hydroxylation steps to the active metabolite, 1alpha,25-dihydroxyvitamin D3 (1,25-D3). 25-hydroxylases in the liver are responsible for the first hydroxylation step. The ultimate activation is performed by the renal 25-hydroxyvitamin D 1alpha-hydroxylase (CYP27B1), while the 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1) in the kidneys degrades the active metabolite. These two renal vitamin D hydroxylases control the endocrine serum 1,25-D3 levels, and are responsible for maintaining mineral homeostasis. In addition, the active vitamin D hormone 1,25-D3 regulates cellular proliferation, differentiation, and apoptosis in multiple tissues in a paracrine/autocrine manner. Interestingly, it is the low serum level of the precursor 25- hydroxyvitamin D3 (25-D3) that predisposes to numerous cancers and other chronic diseases, and not the serum concentration of the active vitamin D hormone. The extra-renal autocrine/paracrine vitamin D system is able to synthesize and degrade locally the active 1,25- D3 necessary to maintain normal cell growth and to counteract mitogenic stimuli. Thus, vitamin D hydroxylases play a prominent role in this process. The present review describes the role of the vitamin D hydroxylases in cancer pathogenesis and the cross-talk between the extra-renal autocrine/paracrine vitamin D system and calcium in cancer prevention. PMID- 23094925 TI - Vitamin D and breast cancer incidence and outcome. AB - Based on preclinical studies and early clinical observations, an association between vitamin D status and breast cancer incidence and outcome has been proposed. Against this background, information on vitamin D and breast cancer was reviewed with focused attention on emerging clinical studies in this area. Prospective cohort studies do not associate 25-hydroxyvitamin D levels with breast cancer incidence. While case-control studies of this question are positive, they may be confounded by reverse causality as 25- hydroxyvitamin D levels are influenced by breast cancer presence and stage. Studies of 25 hydroxyvitamin D and subsequent breast cancer recurrence provide mixed results but strongest associations were seen in analyses uncontrolled for prognostic variables, cancer therapy, BMI and physical activity. The one full-scale randomized, placebo-controlled trial evaluating calcium (1000 mg elemental calcium per day) and vitamin D supplementation (400 IU D3 per day) with 36,282 participants failed to demonstrate a supplement effect on lowering breast cancer incidence. Breast cancer patients not uncommonly have vitamin D deficiency but limited control populations in available reports preclude precise prevalence estimates. As breast cancer patients are at risk for bone loss and musculoskeletal complaints from cancer or associated therapies, monitoring 25 hydroxyvitamin D levels and vitamin D3 supplementation in moderate dose (1,000- 1,500 IU D3 per day) can be recommended with expectation of mainly bone benefit. In women with breast cancer, future vitamin D supplementation studies need to be appropriately designed and powered to provide definitive assessments. However, a full-scale randomized trial evaluating the influence of vitamin D supplementation on breast cancer recurrence is likely not feasible. PMID- 23094926 TI - The anti-cancer actions of vitamin D. AB - Vitamin D3 is biologically inert. To become active, it requires two successive hydroxylation steps catalyzed by two cytochrome P450 enzymes, first to synthesize the pro-hormone 25-hydroxyvitamin D3 [25(OH)D3] and then the active hormone 1alpha,25- dihydroxyvitamin D3 [1alpha,25(OH)2D3]. 1alpha,25(OH)2D3 has high affinity for the vitamin D receptor (VDR), a transcription factor and a member of the steroid receptor superfamily. Through VDR, 1alpha,25(OH)2D3 regulates more than 200 genes in mammals, including those involved in the calcium and phosphorus homeostasis, immune function, reproduction, cardiovascular, central nerve system, inflammation, angiogenesis, and cellular proliferation, differentiation and apoptosis. Due to its versatile roles in maintaining and regulating normal cellular phenotypes and functions, 1alpha,25(OH)2D3 has been implicated as an anti-cancer agent. In fact, ecological and epidemiologic data have linked vitamin D deficiency with the incidence and mortality of many types of cancer. More importantly, in vitro and in vivo animal model studies have clearly demonstrated the anti-tumor effects of vitamin D. In this review, we describe the anticancer actions of vitamin D, with special emphasis on different pathways underlying the VDR-mediated genomic as well as less-defined non-genomic actions of vitamin D. PMID- 23094927 TI - Update on evidence that support a role of solar ultraviolet-B irradiance in reducing cancer risk. AB - The ultraviolet-B (UVB)-vitamin D-cancer hypothesis was proposed in 1980 yet has not been fully accepted. Ecological studies based on geographical variations of cancer rates with respect to solar UVB doses have supported the hypothesis for about 20 cancers. This paper reviews the evidence from studies of personal or group UVB irradiance. Studies have associated personal UVB irradiance with reduced risk for breast, colon, endometrial, prostate, and renal cancer, as well as non-Hodgkin's lymphoma (NHL). However, some studies have also found increased risk of NHL from UV irradiance, probably due to immunosuppression by UVA near 370 nm. Several related approaches have also been used to study the hypothesis. Studies in Norway and the UK found that diagnosis in summer or fall is associated with increased survival rates for breast, colon, lung, and prostate cancer, as well as Hodgkin's lymphoma. Diagnosis of nonmelanoma skin cancer is associated with reduced risk of several cancers in sunny countries, but not often in highlatitude countries. Living at higher surface elevation is associated with reduced risk of some cancers. In a recent analyzed study of cancer rates for 54 occupations in Nordic countries, a UVB index based on standardized incidence ratios of lip cancer less those for lung cancer was inversely correlated with 15 types of cancer for males, but only four types for females. This ecological study provides additional evidence that UVB doses at high latitudes are adequate to reduce the risk of cancer, but requires considerable time outside to produce sufficient vitamin D. Because only vitamin D production has been proposed to explain the UVB-cancer link, studies reviewed in this paper should be considered strong evidence for the hypothesis. PMID- 23094928 TI - Vitamin D and cancer mortality: systematic review of prospective epidemiological studies. AB - Accumulating evidence from experimental and epidemiological studies suggests that vitamin D deficiency might be a causal risk factor for cancer and therewith associated mortality. We performed a systematic review in Medline up to February 2012 to identify prospective studies on 25-hydroxyvitamin D (25[OH]D) and cancer mortality as well as on 25(OH)D and survival in cancer patients. Our search retrieved 13 studies on cancer-specific mortality and 20 studies on overall mortality in cancer patients. Data on 25(OH)D and cancer mortality were mainly derived from general populations. The results were inconsistent and yielded either no, inverse or positive associations. By contrast, the majority of studies in cancer patients showed that patients with higher 25(OH)D levels had a decreased risk of mortality. This relationship was particularly evident in cohorts of colorectal cancer patients. In contrast, there was no indication for increased mortality risk with higher vitamin D levels in any cancer cohort. In conclusion, the relationship of vitamin D status and cancerspecific mortality is still unclear and warrants further studies. Our results provide a strong rationale to perform prospective randomized controlled studies to document a potential effect of vitamin D supplementation on survival in cancer patients. PMID- 23094929 TI - Vitamin D supplementation and cancer: review of randomized controlled trials. AB - Data from experimental studies suggest that vitamin D receptor activation exerts anti-cancer effects on virtually all steps of carcinogenesis. Epidemiological data support an inverse association of vitamin D serum levels and vitamin D receptor polymorphisms with cancer incidence and mortality. Based on this promising rationale for use of vitamin D and its analogues in cancer prevention and treatment, several interventional studies have been initiated and partially published. Trials with vitamin D were mainly organized for the prevention of fracture in elderly people, usually in association with calcium supplements. Prevention studies with vitamin D have rarely been done in the context of vitamin D to evaluate a protective effect on cancer. Findings from prospective cohort studies on colorectal cancer risk and on mortality constitute pieces of evidence strong enough to consider that previous randomized controlled trials (RCTs) of vitamin D use and cancer may not have correctly addressed the question, and that new randomized trials should be organized. The reasons are due to several unsolved issues including selection of the effective dose, varying baseline levels of subjects before randomization, compliance with the intervention, contamination of the placebo group (i.e., intake of vitamin D supplements by subjects allocated to the placebo group) and unknown effective lag time between start of the intervention and disease onset. The present review summarizes the existing knowledge on vitamin D RCTs and cancer. In addition we also briefly describe the design of some ongoing trials on vitamin D supplementation and cancer. PMID- 23094930 TI - Vitamin D and cancer: current evidence and future perspective. PMID- 23094931 TI - Long-pulsed 1064 nm Nd:YAG laser improves hypertrophic port-wine stains. AB - BACKGROUND: Hypertrophic port-wine stains (PWS) usually respond poorly to pulsed dye laser treatment. The long-pulsed 1064 nm Nd:YAG laser can target deeper situated vessels and may therefore be more effective. OBJECTIVE: To evaluate the efficacy and safety of the Nd:YAG laser for the treatment of hypertrophic PWS. METHODS: In a retrospective cohort study, all hypertrophic PWS patients treated with the Nd:YAG laser between 2005 and 2011 were invited for follow-up. Clinical improvement was assessed using Physician Global Assessment (PhGA) and Patient Global Assessment (PGA). RESULTS: Assessment was obtained in 32 of 44 eligible patients (mean age 51.4 years), after a mean of 2.8 (SD +/- 2.1) Nd:YAG laser treatments. Good or excellent improvement of hypertrophy was found in a majority of patients, both by PhGA (91%) and PGA (93%). Good or excellent improvement of colour was found in 63% of patients by PhGA, and in 87% by PGA. Recurrence of hypertrophy was seen in three patients. All but two patients would recommend Nd:YAG treatment to other patients. Mild to moderate scars were seen in seven patients, hypopigmentation in 14 patients. CONCLUSION: The 1064 nm Nd:YAG laser is highly effective in the treatment of hypertrophic PWS with only a few treatments needed. Mostly mild side effects were seen in half of all patients. Hypertrophy seems to respond better than colour. To further improve colour, a combination with pulsed dye laser treatment is advisory. Observation of immediate clinical endpoints is important when using the Nd:YAG laser, to optimize outcomes and reduce side effects. PMID- 23094932 TI - Effects on gastrointestinal transit and antroduodenojejunal manometry after gut directed hypnotherapy in irritable bowel syndrome (IBS). AB - BACKGROUND: Gut-directed hypnotherapy is an effective treatment in irritable bowel syndrome (IBS) but little is known about the mechanisms of action. In this study we aimed to investigate the effects on gastrointestinal motility when treating IBS with gut-directed hypnotherapy. METHODS: We randomized 90 patients with IBS, refractory to standard management to receive gut-directed hypnotherapy 1 h/week for 12 weeks or supportive treatment for the same time period. Eighty one subjects (40 hypnotherapy, 41 controls) could be evaluated by one or more of the following investigations, both before and after the intervention: gastric emptying time, small bowel transit time, colonic transit time, and antroduodenojejunal manometry. RESULTS: No significant differences in gastric emptying time, small bowel transit time, or colonic transit time was found when comparing the baseline and post-intervention measurements in the hypnotherapy group or in the control group. The same was true concerning the results of the antroduodenojejunal manometry. However, there was a numerical trend toward a higher number of migrating motor complexes at manometry and an accelerated gastric emptying time after hypnotherapy that did not reach statistical significance. CONCLUSIONS: In this study, we were not able to find evidence for long-standing effects on gastrointestinal motility as a mediator of the effects on IBS when treating the condition with gut-directed hypnotherapy. Further research to understand the mechanism of action is needed. PMID- 23094933 TI - Investigation of adaptation after liver transplantation using Roy's Adaptation Model. AB - In this study we explored the adaptation of transplant recipients in Turkey using the Roy Adaptation Model. A descriptive qualitative design was used with data collected from liver transplant recipients in either individual or group interviews between May 2009 and February 2010. Using deductive content analysis, four themes were identified in the data: physiological mode, self-concept mode, role function mode, and interdependence mode. Each theme included both adaptive and ineffective behaviors of liver transplant recipients. The findings of this study indicate that liver transplant recipients need information and support about their ineffective behaviors in all modes of the Roy Adaptation Model. The findings also support the use of a nursing model in the delivery of nursing care for liver transplantation recipients. PMID- 23094934 TI - Body mass index patterns following dysvascular lower extremity amputation. AB - PURPOSE: Using preliminary data, we examined: (i) patterns of body mass index (BMI) over the year following amputation by amputation level and (ii) the association between BMI and mobility and prosthetic device use. METHOD: Patients from three medical centers undergoing dysvascular amputation (N = 87; M age = 62) participated in interviews pre-surgically and at 6 weeks, 4 months, and 12 months following amputation. The main outcome was self-reported BMI, adjusting for limb weight lost due to amputation. Additional outcomes were mobility and time spent using and walking in a prosthetic device. RESULTS: Adjusted BMI slightly decreased at 6 weeks (pre-surgery M = 31.2; 6 weeks M = 30.3) and 4 months (M = 30.7) but exceeded baseline levels by 12 months (M = 31.7). There were no significant BMI differences by amputation level. In multivariable analyses, higher pre-surgical BMI was associated with fewer hours of prosthetic device walking at month 4 (beta = -0.49) and poorer overall mobility at month 12 (beta = -0.22). CONCLUSIONS: BMI increased at one year following amputation surgery. Higher pre-surgical BMI was associated with poorer mobility and prosthetic device use. Interventions are needed to prevent excess weight gain in the year following amputation. IMPLICATIONS FOR REHABILITATION: * People undergoing lower-extremity amputation have high rates of overweight and obesity and continue to gain weight in the year following amputation. * Objective assessment of body mass index (both with and without a prosthetic device) and waist circumference would help future research efforts. * Targeting weight loss post-amputation could improve the health of people with lower-extremity amputations. PMID- 23094935 TI - Improved momentum-transfer theory for ion mobility. 1. Derivation of the fundamental equation. AB - For the first time the fundamental ion mobility equation is derived by a bottom up procedure, with N real atomic ion-atomic neutral collisions replaced by N repetitions of an average collision. Ion drift velocity is identified as the average of all pre- and postcollision velocities in the field direction. To facilitate velocity averaging, collisions are sorted into classes that "cool" and "heat" the ion. Averaging over scattering angles establishes mass-dependent relationships between pre- and postcollision velocities for the cooling and heating classes, and a combined expression for drift velocity is obtained by weighted addition according to relative frequencies of the cooling and heating encounters. At zero field this expression becomes identical to the fundamental low-field ion mobility equation. The bottom-up derivation identifies the low field drift velocity as 3/4 of the average precollision ion velocity in the field direction and associates the passage from low-field to high-field conditions with the increasing dominance of "cooling" collisions over "heating" collisions. Most significantly, the analysis provides a direct path for generalization to fields of arbitrary strength. PMID- 23094936 TI - Spatial and temporal patterns of genetic variation in the widespread antitropical deep-sea coral Paragorgia arborea. AB - Numerous deep-sea species have apparent widespread and discontinuous distributions. Many of these are important foundation species, structuring hard bottom benthic ecosystems. Theoretically, differences in the genetic composition of their populations vary geographically and with depth. Previous studies have examined the genetic diversity of some of these taxa in a regional context, suggesting that genetic differentiation does not occur at scales of discrete features such as seamounts or canyons, but at larger scales (e.g. ocean basins). However, to date, few studies have evaluated such diversity throughout the known distribution of a putative deep-sea species. We utilized sequences from seven mitochondrial gene regions and nuclear genetic variants of the deep-sea coral Paragorgia arborea in a phylogeographic context to examine the global patterns of genetic variation and their possible correlation with the spatial variables of geographic position and depth. We also examined the compatibility of this morphospecies with the genealogical-phylospecies concept by examining specimens collected worldwide. We show that the morphospecies P. arborea can be defined as a genealogical-phylospecies, in contrast to the hypothesis that P. arborea represents a cryptic species complex. Genetic variation is correlated with geographic location at the basin-scale level, but not with depth. Additionally, we present a phylogeographic hypothesis in which P. arborea originates from the North Pacific, followed by colonization of the Southern Hemisphere prior to migration to the North Atlantic. This hypothesis is consistent with the latest ocean circulation model for the Miocene. PMID- 23094937 TI - Advancing the science of environmental exposures during pregnancy and the gene environment through the National Children's Study. AB - In this article we provide nurses with information on the importance of studying environmental exposures during fetal, infant, and childhood development in the National Children's Study. Nurses should be aware of this study to aid in mitigating the complex health problems that arise from environment-health interactions. Nurses may help to educate the public, patients, and caregivers and are in an ideal position to be strong advocates for policy change and regulatory monitoring and enforcement. PMID- 23094940 TI - Biomechanical and neurophysiological mechanisms related to postural control and efficiency of movement: a review. AB - Understanding postural control requires considering various mechanisms underlying a person's ability to stand, to walk, and to interact with the environment safely and efficiently. The purpose of this paper is to summarize the functional relation between biomechanical and neurophysiological perspectives related to postural control in both standing and walking based on movement efficiency. Evidence related to the biomechanical and neurophysiological mechanisms is explored as well as the role of proprioceptive input on postural and movement control. PMID- 23094939 TI - Accurate assessment of drooling severity with the 5-minute drooling quotient in children with developmental disabilities. AB - AIM: The aims of this study were to examine whether objective measurements of the 10-minute drooling quotient (DQ10) and the 5-minute drooling quotient (DQ5) are interchangeable; to assess agreement between the measurements and their accuracy in classifying drooling severity; and to develop a time-efficient clinical assessment. METHOD: The study cohort included 162 children (61 females, 101 males; mean age 11 y 6 mo, SD 4 y 5 mo, range 3 y 9 mo-22 y 1 mo) suffering from moderate to profuse drooling. One hundred and twenty-four had cerebral palsy and 38 had other developmental disabilities. Seventy-four of the participants were ambulant and 88 non-ambulant. The original DQ10 was recalculated into a 5-minute score (DQ5). Assessments were undertaken while the participants were in a rest situation (DQ(R)) and while they were active (DQ(A)). Agreement in scores was quantified using intraclass correlations and Bland-Altman plots. To classify drooling, area under the receiver operating characteristic curve analysis was used to compare accuracy of the DQ10 and DQ5 at rest and during activity. RESULTS: Agreement between DQ10A, and DQ5(A), and between DQ10(R) and DQ5(R) was high (intraclass correlation coefficient >0.90). Moderate agreement existed between DQ(A) and DQ(R). DQ(A) scores were more accurate in classifying children's drooling behaviour. For DQ5(A), a cut-off point of 18 or more (drooling episodes/observation time) might indicate 'constant drooling'. INTERPRETATION: The DQ10 and DQ5 can be used interchangeably. DQ(A) is most discriminative for drooling severity. For evaluating treatment efficiency the cut off point can be used. For clinical and research purposes, the DQ5 is time efficient and cost saving while validity, and intrarater and interrater reliability are preserved. PMID- 23094938 TI - Cerebral stimulation for the affective component of neuropathic pain. AB - OBJECTIVES: To review the current state of cerebral stimulation for neuropathic pain and to propose that cerebral stimulation should aim also at the affective sphere of chronic pain rather than solely focusing on the primary sensory discriminative sphere. METHODS: The past and current goals of cerebral stimulation are reviewed as well as its limitations. A novel deep brain stimulation approach is proposed to evaluate this conceptual shift from somatosensory to affective sphere of pain targeting. APPROACH: Thalamic and other central pain syndromes are typically intractable to current treatment methods, including cerebral neuromodulation of somatosensory pathways, leading to long term distress and disability. Our modern understanding of chronic pain pathophysiology is based largely on the neuromatrix theory, where cognitive, affective, and sensory-discriminative spheres contribute equally to the overall pain experience. During the last decade, the safety and feasibility of chronic stimulation of neural pathways related to mood and affect has been explored with promising results. Here, we propose a novel approach to modulate the affective sphere of chronic pain by targeting similar networks in patients with treatment refractory central pain. Our primary goal is not to produce (or measure) analgesia, but rather to modulate the affective burden of chronic pain. DISCUSSION: Cerebral neuromodulation for neuropathic pain has had limited efficacy thus far. Shifting our aim to neural networks related to the affective sphere of pain may allow us to reduce pain conditioning and pain-related disability. Our ultimate goal is to promote rehabilitation from chronic pain social and occupational. PMID- 23094941 TI - Comparison of quercetin pharmacokinetics following oral supplementation in humans. AB - The objective of the study was to investigate the absorption of quercetin aglycone in 18 healthy human subjects administered via the following oral carrier systems: suspension of quercetin (quercetin QU995 powder in Tang((r)) and spring water), nutritional bars (First StrikeTM), and chews (RealFXTM Q-PlusTM). Subjects were divided into 3 groups of 6 individuals each receiving 500 mg quercetin in one of the aforementioned formulations. Blood levels were monitored immediately pre- and for 32 h postadministration. The concentration of total quercetin in blood samples was determined by solid phase extraction followed by high-performance liquid chromatography analysis. Pharmacokinetic parameters were determined by noncompartmental modeling using Kinetica software. The C(max) of quercetin was highest with RealFXTM Q-PlusTM Chews (1051.9 +/- 393.1 MUg/L) achieved within 3.3 h as compared to that for First StrikeTM Bars (698.1 +/- 189.5 MUg/L in 2.3 h) and Tang((r)) suspension (354.4 +/- 87.6 MUg/L in 4.7 h). The results showed no statistically significant difference in quercetin absorption among groups due to high variability within groups receiving quercetin from same dosage form. This study represents the first comprehensive evaluation of quercetin absorption from quercetin fortified oral food products at doses commonly used for quercetin supplementation. PRACTICAL APPLICATION: The current study describes for the first time, comprehensive evaluation of quercetin PK in humans from quercetin fortified oral food products at doses commonly used for quercetin supplementation. Owing to quercetin's potent antioxidant and anti inflammatory actions, quercetin is widely being used as a nutritional supplement. In order to maximize the bioavailability of quercetin for its use in efficacy studies, it is important to determine its ideal oral carrier system and route for its delivery. The current research unveils vital information about quercetin supplementation to the international community, especially to soldiers, athletes, and the dietary supplement industry. PMID- 23094942 TI - Rare-earth metal tris(trimethylsilylmethyl) anionic complexes bearing one 1 phenyl-2,3,4,5-tetrapropylcyclopentadienyl ligand: synthesis, structural characterization, and application. AB - Synthesis and structural characterization of half-sandwich rare-earth metal tris(trimethylsilylmethyl) anionic complexes bearing one 1-phenyl-2,3,4,5 tetrapropylcyclopentadienyl ligand are achieved. These soluble anionic compounds show good reactivity in the stoichiometric reaction with dibenzoylmethane (DBM) to give the salt-free half-sandwich complex bearing two chelate DBM ligands. More importantly, they can serve as excellent and general catalyst precursors for the addition of different types of amines including primary aromatic amines (ArNH(2)), acyclic (RR'NH, ArRNH, and ArAr'NH; R, R' = Alkyl group, Ar, Ar' = Aromatic group), or cyclic secondary aliphatic amines to carbodiimides yielding efficiently guanidines. Acyclic secondary amines of the general formula ArAr'NH and ArRNH cannot be achieved efficiently by the previous rare-earth catalysts because of their weak nucleophilicity and steric hindrance. Our results show clearly the reactivities of anionic trialkyl precursors are comparable with the corresponding neutral alkyl complex in the stoichimetric reaction but exhibit better catalytic activity than the known catalysts. PMID- 23094943 TI - Rosuvastatin and diabetes: when the evidences talk. AB - Diabetes increases the risk of cardiovascular disease; however, this risk is further increased as a result of other factors. This observation is particularly relevant with regard to lipid abnormalities. Although diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL-cholesterol, and small dense LDL particles, the main determinant of the role of dyslipidemia in the prognosis of diabetics is LDL cholesterol. In recent years, LDL cholesterol targets have become progressively lower, and most current recommendations establish an LDL cholesterol target of <70 mg/dL for diabetics. This target can only be achieved using potent statins at adequate doses. Although it has been suggested that statins may interfere with glycemic metabolism, the benefits of reducing LDL cholesterol by statins are much greater than this possible deleterious effect. Rosuvastatin is one of the most potent statins available. Several studies have shown that it effectively reduces LDL cholesterol to recommended targets in diabetics. Moreover, rosuvastatin modestly increases HDL cholesterol and decreases triglycerides. The risk of side effects is low, as is the risk of interactions with other drugs. In this manuscript, the efficacy and safety profile of rosuvastatin in diabetic population is reviewed. PMID- 23094944 TI - The superstable 25 kDa monolayer protected silver nanoparticle: measurements and interpretation as an icosahedral Ag152(SCH2CH2Ph)60 cluster. AB - A cluster obtained in high yield from the reduction of a silver-thiolate precursor, Ag-SCH(2)CH(2)Ph, exhibited a single sharp peak near 25 kDa in the matrix-assisted laser desorption mass spectrum (MALDI MS) and a well-defined metal core of ~2 nm measured with transmission electron microscopy (TEM). The cluster yields a single fraction in high-performance liquid chromatography (HPLC). Increased laser fluence fragments the cluster until a new peak near 19 kDa predominates, suggesting that the parent cluster-Ag(152)(SCH(2)CH(2)Ph)(60) evolves into a stable inorganic core-Ag(152)S(60). Exploiting combined insights from investigations of clusters and surface science, a core-shell structure model was developed, with a 92-atom silver core having icosahedral-dodecahedral symmetry and an encapsulating protective shell containing 60 Ag atoms and 60 thiolates arranged in a network of six-membered rings resembling the geometry found in self-assembled monolayers on Ag(111). The structure is in agreement with small-angle X-ray scattering (SAXS) data. The protective layer encapsulating this silver cluster may be the smallest known three-dimensional self-assembled monolayer. First-principles electronic structure calculations show, for the geometry-optimized structure, the development of a ~0.4 eV energy gap between the highest-occupied and lowest-unoccupied states, originating from a superatom 90 electron shell-closure and conferring stability to the cluster. The optical absorption spectrum of the cluster resembles that of plasmonic silver nanoparticles with a broad single feature peaking at 460 nm, but the luminescence spectrum shows two maxima with one attributed to the ligated shell and the other to the core. PMID- 23094945 TI - Ageing with telecare: care or coercion in austerity? AB - In recent years images of independence, active ageing and staying at home have come to characterise a successful old age in western societies. 'Telecare' technologies are heavily promoted to assist ageing-in-place and a nexus of demographic ageing, shrinking healthcare and social care budgets and technological ambition has come to promote the 'telehome' as the solution to the problem of the 'age dependency ratio'. Through the adoption of a range of monitoring and telecare devices, it seems that the normative vision of independence will also be achieved. But with falling incomes and pressure for economies of scale, what kind of independence is experienced in the telehome? In this article we engage with the concepts of 'technogenarians' and 'shared work' to illuminate our analysis of telecare in use. Drawing on European-funded research we argue that home-monitoring based telecare has the potential to coerce older people unless we are able to recognise and respect a range of responses including non-use and 'misuse' in daily practice. We propose that re-imagining the aims of telecare and redesigning systems to allow for creative engagement with technologies and the co-production of care relations would help to avoid the application of coercive forms of care technology in times of austerity. PMID- 23094946 TI - Gene targeting in maize by somatic ectopic recombination. AB - Low transformation efficiency and high background of non-targeted events are major constraints to gene targeting in plants. We demonstrate here applicability in maize of a system that reduces the constraint from transformation efficiency. The system requires regenerable transformants in which all of the following elements are stably integrated in the genome: (i) donor DNA with the gene of interest adjacent to sequence for repair of a defective selectable marker, (ii) sequence encoding a rare-cutting endonuclease such as I-SceI, (iii) a target locus (TL) comprising the defective selectable marker and I-SceI cleavage site. Typically, this requires additional markers for the integration of the donor and target sequences, which may be assembled through cross-pollination of separate transformants. Inducible expression of I-SceI then cleaves the TL and facilitates homologous recombination, which is assayed by selection for the repaired marker. We used bar and gfp markers to identify assembled transformants, a dexamethasone inducible I-SceI::GR protein, and selection for recombination events that restored an intact nptII. Applying this strategy to callus permitted the selection of recombination into the TL at a frequency of 0.085% per extracted immature embryo (29% of recombinants). Our results also indicate that excision of the donor locus (DL) through the use of flanking I-SceI cleavage sites may be unnecessary, and a source of unwanted repair events at the DL. The system allows production, from each assembled transformant, of many cells that subsequently can be treated to induce gene targeting. This may facilitate gene targeting in plant species for which transformation efficiencies are otherwise limiting. PMID- 23094947 TI - Toe modifications in hind feet shoes optimise hoof-unrollment in sound Warmblood horses at trot. AB - REASONS FOR PERFORMING STUDY: It was shown that rolled-toe shoes smooth hoof unrollment and thereby reduce peak loading of forelimbs in trotting Warmblood horses. Shoe design and shoeing technique for hind feet have been modified over recent decades from fully fitted, toe-clipped shoes to set-back, side-clipped shoes. OBJECTIVES: To study the effects of different shoe modifications on loading and movement of the hind hoof. METHODS: Ten clinically sound Warmblood horses were shod with 3 types of hind shoe: first, fully fitted, toe-clipped shoes, followed randomly by side-clipped shoes without a rolled toe that were set back by half the thickness of the hoof wall in the plantar direction and identical side-clipped shoes with a rolled toe, with 2 days between shoeing sessions to adapt to the shoes. Then horses were trotted in a straight line over a pressure-force plate combination. Hoof dynamics were compared statistically with the fully fitted shoe condition using a general linear model repeated measures test (P<0.05). RESULTS: There were no significant differences in the characteristics of limb timing, such as stance time and breakover duration nor the peak vertical and horizontal ground reaction force. By setting back the hind shoes, the centre of pressure at toe-off was positioned less dorsally. The rolled toe resulted in a smoother shift of the centre of pressure and thus more fluent hoof-unrollment. Both alternative types of shoe allowed a more lateral orientation of the centre of pressure at toe-off. CONCLUSIONS AND POTENTIAL RELEVANCE: Toe modifications of hind shoes can influence hindlimb kinematics positively. Setting the hind shoe back and rolling the toe leads to smoother hoof unrollment, which enables the horse to coordinate movement correctly without loss of propulsion. Thus, shoe modifications might facilitate movement and thereby help prevent overload injuries. PMID- 23094948 TI - Chromogranin A is a sensitive marker of progression or regression in ileo-cecal neuroendocrine tumors. AB - OBJECTIVE: The correlation between plasma Chromogranin A concentrations and changes in tumor size evaluated by computed tomography (CT) - as a gold standard was evaluated. MATERIAL AND METHODS: One hundred and sixteen patients with CgA producing ileo-cecal neuroendocrine tumors were evaluated by events, which were recorded when a CT was followed by another CT 1 - 12 months later. Change in tumor size was defined as regression, progression, or stable disease using RECIST criteria 1.1. Of 426 events, there were 97 with progression, 279 with stable disease, and 50 with regression. Based on the ROC curves a cutoff value of 25% change was selected to discriminate between increased, decreased, or unchanged CgA concentrations in plasma, using a sensitive radioimmunoassay with well defined epitope specificity. RESULTS: In the 97 events showing tumor progression diagnostic sensitivity and specificity of an increased CgA concentration were 86% and 86%, respectively. The positive and negative predictive values were 64% and 85%, respectively. In the 279 events with unchanged tumor size the diagnostic sensitivity and specificity of an unchanged CgA concentration were 73% and 86%, and the positive and negative predictive values were 91% and 63%, respectively. In the 50 events showing tumor regression, diagnostic sensitivity and specificity of a decrease in CgA concentration were 78% and 91%, the positive and negative predictive values being 55% and 97%. CONCLUSIONS: CgA concentrations in plasma have a high diagnostic accuracy in monitoring patients with ileo-cecal neuroendocrine tumors. In particular, an increase in plasma CgA concentration was useful to indicate tumor progression. PMID- 23094949 TI - Metabonomics of newborn screening dried blood spot samples: a novel approach in the screening and diagnostics of inborn errors of metabolism. AB - A novel, single stage high resolution mass spectrometry-based method is presented for the population level screening of inborn errors of metabolism. The approach proposed here extends traditional electrospray tandem mass spectrometry screening by introducing nanospray ionization and high resolution mass spectrometry, allowing the selective detection of more than 400 individual metabolic constituents of blood including acylcarnitines, amino acids, organic acids, fatty acids, carbohydrates, bile acids, and complex lipids. Dried blood spots were extracted using a methanolic solution of isotope labeled internal standards, and filtered extracts were electrosprayed using a fully automated chip-based nanospray ion source in both positive and negative ion mode. Ions were analyzed using an Orbitrap Fourier transformation mass spectrometer at nominal mass resolution of 100,000. Individual metabolic constituents were quantified using standard isotope dilution methods. Concentration threshold (cutoff) level-based analysis allows the identification of newborns with metabolic diseases, similarly to the traditional electrospray tandem mass spectrometry (ESI-MS/MS) method; however, the detection of additional known biomarkers (e.g., organic acids) results in improved sensitivity and selectivity. The broad range of detected analytes allowed the untargeted multivariate statistical analysis of spectra and identification of additional diseased states, therapeutic artifacts, and damaged samples, besides the metabolic disease panel. PMID- 23094950 TI - A tripyrrolylmethane-based macrobicyclic triazacryptand: X-ray structure, size selective anion binding, and fluoride-ion-mediated proton-deuterium exchange studies. AB - A new class of tripyrrolylmethane-based triazacryptand with bridgehead carbons and acyclic molecules were synthesized by the Mannich reaction of tripyrrolylmethane with primary or secondary amine hydrochloride and formaldehyde, respectively. The structure of the triazacryptand was determined by X-ray diffraction (XRD) method. The anion binding properties of both the bicyclic and acyclic receptors were studied by (1)H NMR titration method. The binding studies showed that both receptors exhibit very high affinity and bind strongly with the F(-) ion in DMSO-d(6). However, the binding constant of azacryptand with F(-) is much higher than that of the acyclic receptor. This is attributed to the preorganization of the azacryptand having a specific cavity size, and the strength and the number of hydrogen bonds formed by the F(-) ion. This is supported by the crystal structures of F(-), Cl(-), and Br(-) ion complexes of the bicyclic receptor and by DFT calculations. The X-ray structures showed that the azacryptand receptor forms an inclusion complex with only the F(-) ion; other anions bind in the clefts of the macrobicycle, thus supporting a size-selective anion binding behavior. The high affinity and the selectivity of the macrobicycle as a neutral receptor of the F(-) ion in the presence of other competitive anions in DMSO-d(6) were confirmed by (1)H NMR spectroscopy. Furthermore, the F(-)-ion mediated hydrogen-deuterium exchanges were monitored by (19)F NMR spectroscopy, showing multiplets based on the formation of all possible deuterium-exchanged fluoride complexes in solution. PMID- 23094951 TI - Resting beta hypersynchrony in secondary dystonia and its suppression during pallidal deep brain stimulation in DYT3+ Lubag dystonia. AB - OBJECTIVES: 1) To characterize patterns of globus pallidus interna neural synchrony in patients with secondary dystonia; 2) to determine whether neural hypersynchrony in the globus pallidus externa (GPe) and interna (GPi) is attenuated during high frequency deep brain stimulation (HF DBS) in a patient with DYT3+ dystonia and in a patient with secondary dystonia due to childhood encephalitis. MATERIALS AND METHODS: We recorded local field potentials from the DBS lead in the GPi of four patients (seven hemispheres) with secondary dystonia and from one patient (two hemispheres) with primary DYT3+ dystonia. In two patients, we also recorded pallidal local field potentials during the administration of 10 sec epochs of HF DBS. RESULTS: Power spectral densities during rest demonstrated visible peaks in the beta band in seven out of nine cases. In DYT3+ dystonia, power in the alpha and beta bands, but not theta band, was attenuated during HF DBS in the GPe and in GPi, and attenuation was most prominent in the high beta band. This patient demonstrated an early and maintained improvement in dystonia. There was no beta peak and the power spectrum was not attenuated during HF DBS in a patient with secondary dystonia due to childhood encephalitis. CONCLUSIONS: These results suggest that beta hypersynchrony, demonstrated now in both primary and secondary dystonia, may play a pathophysiological role in pathological hyperkinesis. Further investigation is needed in a larger cohort of well-characterized primary and secondary dystonia patients. PMID- 23094952 TI - Maternal psychosocial determinants of fetal and infant health and the National Children's Study. AB - The purpose of this article is to inform perinatal nurses about the longitudinal National Children's Study (NCS), which was mandated by Congress. The NCS was designed to follow infants from before birth to age 21, and researchers propose to study 100,000 children. This complex and extensive study will provide especially relevant information to perinatal nurses in practice, teaching, and research. PMID- 23094953 TI - Facilitating medical withdrawal from opiates in rural Ontario. AB - CONTEXT: The abuse of oxycodone in Northwestern Ontario, Canada, has escalated at alarming rates raising concerns that opiate use has reached epidemic proportions, particularly among the First Nations communities. The authors were involved in establishing Ontario's first rural inpatient medical withdrawal unit to serve patients seeking abstinence. ISSUES: The development of the medical withdrawal support services (MWSS) required creative and adaptive strategies to respond to the geographical, cultural and institutional circumstances. LESSONS LEARNED: Key factors to support program efficacy and successful outcomes for clients during the inaugural eight months of operation are interprofessional and collaborative approaches with a cultural awareness.Key words: addiction, Canada, First Nation, medical withdrawal. PMID- 23094954 TI - Acceptability and preferences of six different routes of drug application for acute breathlessness: a comparison study between the United Kingdom and Germany. AB - BACKGROUND: Opioids are the drugs of choice for management of breathlessness in advanced disease, but acute episodic breathlessness remains difficult to manage. New routes of opioid applications with quicker onset of action seem attractive for the management of episodic breathlessness. OBJECTIVE: This study aimed to determine the acceptability and preference of different routes of opioid applications in patients suffering from breathlessness due to advanced disease. DESIGN: The study consisted of structured face-to-face interviews with patients suffering from breathlessness due to lung cancer (LC), chronic obstructive pulmonary disease (COPD), chronic heart failure (CHF), and motor neurone disease (MND). Images and explanation were used to illustrate six application forms (oral, inhaled, sublingual, intranasal, buccal, transmucosal). RESULTS: Participants numbered 119 (UK n=48, Germany n=71), 60% male, mean age 67.7 years (SD 9.9); 50% suffered from COPD. Inhaled was the most accepted (87%) and preferred (68%) route of application, followed by sublingual (45%/13%) and intranasal (42%/8%). The oral was least accepted (24%) and least preferred (9%) although nearly all participants had previous experiences with it (97%). Ratings were similar in both countries but different for preferences of sublingual (UK>Germany) and intranasal (Germany>UK). In general, participants from the UK rated more often "yes" for acceptability of all routes compared to Germany. CONCLUSION: Inhaled was the most accepted and preferred route of application, but no route seemed to be acceptable to all patients. Therefore, individual patient preferences should be explored before drug prescription to enhance compliance and convenience. PMID- 23094956 TI - The high prevalence of testosterone deficiency in population of Polish men over 65 years with erectile dysfunctions. AB - OBJECTIVES: Erectile dysfunctions (EDs) are in part caused by hormonal causes; but in men over 65 years of age, testosterone deficiency seems to play an important role. However, in population of Polish men over 65 years of age with relative poor health status, the prevalence of testosterone deficiency in patients with ED is unknown. MATERIAL AND METHODS: 286 men over 65 years of age with EDs were invited to complete an erectile function questionnaire (IIEF-5), as a diagnostic tool for EDs. Serum total testosterone (TT) levels were measured. Linear regression model was used to analyze the factors that are associated with testosterone deficiency. RESULTS: The prevalence of testosterone deficiency was 17, 33, 42 and 57% for testosterone levels of less than 200, 250, 300 and 350 ng/dL, respectively. Only 47% patients had testosterone levels in the normal range (>350 ng/dL). The degree of ED was significantly higher in men with lowest testosterone levels (p < 0,002), and it was mild in 39.5% of cases, mild-to moderate in 26.2%, moderate in 18.2% and severe in 16%. There was significant inverse relationship between age and TT (r = -0.3328, p < 0.05), IIEF-5 score and TT (r = -0.3149, p < 0.05) and IIEF-5 score and age (r = -0.3463, p < 0.05). The most common metabolic disorders were: obesity (68% in men with TT levels >350 ng/dL and 91% in men with TT levels <350 ng/dL) and dyslipidemia (54 and 95%, respectively). Obesity, age and hyperlipidemia all correlated with significantly decreased testosterone levels. Impaired fasting glucose did not affect the testosterone levels. CONCLUSIONS: Testosterone deficiency was very common in population of Polish men presenting with EDs and correlated negatively with age, obesity and dyslipidemia. These results can be associated with relative poor health status of Polish population. PMID- 23094957 TI - Anti-angiogenic therapies in prostate cancer. AB - Prostate cancer (PCa) is the second most common type of cancer among men in Western societies. Once in the castrate-resistant metastatic setting therapeutic options are limited. The importance of angiogenesis in the progression of PCa has been widely reported providing a rationale to test anti-angiogenic compounds for PCa treatment in clinical trials (CTs). However, in spite of the promising results shown in preclinical models and some anti-tumor activity observed in CTs, to date, no angiogenic inhibitor has been approved for use in PCa. This editorial outlines the latest clinical evidence regarding anti-angiogenic therapies in PCa treatment. PMID- 23094955 TI - How lizards survived blizzards: phylogeography of the Liolaemus lineomaculatus group (Liolaemidae) reveals multiple breaks and refugia in southern Patagonia and their concordance with other codistributed taxa. AB - Patagonia was shaped by a complex geological history, including the Miocene uplift of the Andes, followed by volcanism, marine introgressions, and extreme climatic oscillations during Pliocene-Pleistocene glaciation-deglaciation cycles. The distributional patterns and phylogenetic relationships of southern patagonian animals and plants were affected in different ways, and those imprints are reflected in the seven phylogeographic breaks and eight refugia that have been previously proposed. In this study, we estimated time-calibrated phylogenetic/phylogeographic patterns in lizards of the Liolaemus lineomaculatus group and relate them to historical Miocene-to-Pleistocene events of Patagonia and the previously proposed phylogeographic patterns. Individuals from 51 localities were sequenced for the mitochondrial marker (cyt-b) and a subsample of individuals from each mitochondrial lineage was sequenced for one nuclear (LDA12D) and one slow evolving mitochondrial gene (12S). Our analyses revealed strong phylogeographic structure among lineages and, in most cases, no signal of demographic changes through time. The lineomaculatus group is composed of three strongly supported clades (lineomaculatus, hatcheri and kolengh + silvanae), and divergence estimates suggested their origins associated with the oldest known Patagonian glaciation (7-5 Ma); subsequent diversification within the lineomaculatus clade coincided with the large Pliocene glaciations (~3.5 Ma). The lineomaculatus clade includes nine strongly genetically and geographically structured lineages, five of which are interpreted as candidate species. Our findings suggest that some Liolaemus lineages have persisted in situ, each of them in a different refugium, through several glaciation-deglaciation cycles without demographic fluctuations. We also summarize and update qualitative evidence of some shared phylogeographic breaks and refugia among plants, rodents and lizards. PMID- 23094958 TI - Production of trans-free margarine with stearidonic acid soybean and high stearate soybean oils-based structured lipid. AB - Omega-3 fatty acids (n-3 FAs) have been positively associated with prevention and treatment of chronic diseases. Intake of high amounts of trans fatty acids (TFAs) is correlated with increased risk of coronary heart disease, inflammation, and cancer. Structured lipid (SL) was synthesized using stearidonic acid (SDA) soybean oil and high-stearate soybean oil catalyzed by Lipozyme((r)) TLIM lipase. The SL was compared to extracted fat (EF) from a commercial brand for FA profile, sn-2 positional FAs, triacylglycerol (TAG) profile, polymorphism, thermal behavior, oxidative stability, and solid fat content (SFC). Both SL and EF had similar saturated FA (about 31 mol%) and unsaturated FA (about 68 mol%), but SL had a much lower n-6/n-3 ratio (1.1) than EF (5.8). SL had 10.5 mol% SDA. After short-path distillation, a loss of 53.9% was observed in the total tocopherol content of SL. The tocopherols were lost as free tocopherols. SL and EF had similar melting profile, beta' polymorph, and oxidative stability. Margarine was formulated using SL (SLM) and EF (RCM, reformulated commercial margarine). No sensory difference was observed between the 2 margarines. The SL synthesized in this study contained no TFA and possessed desirable polymorphism, thermal properties, and SFC for formulation of soft margarine. The margarine produced with this SL was trans-free and SDA-enriched. PRACTICAL APPLICATION: The current research increases the food applications of stearidonic acid (SDA) soybean oil. trans-Free SDA containing SL was synthesized with desirable polymorph, thermal properties, and SFC for formulation of soft margarine. The margarine produced with this SL had no trans fat and had a low n-6/n-3 ratio. This may help in reducing trans fat intake in our diet while increasing n-3 FA intake. PMID- 23094959 TI - Pyrazole-substituted near-infrared cyanine dyes exhibit pH-dependent fluorescence lifetime properties. AB - Near-infrared heptamethine cyanine dye is functionalized with pyrazole derivatives at the meso-position to induce pH-dependent photophysical properties. The presence of pyrazole unsubstituted at (1) N-position is essential to induce pH-dependent fluorescence intensity and lifetime changes in these dyes. Replacement of meso-chloro group of cyanine dye IR820 with (1) N-unsubstituted pyrazole resulted in the pH-dependent fluorescence lifetime changes from 0.93 ns in neutral media to 1.27 ns in acidic media in DMSO. Time-resolved emission spectra (TRES) revealed that at lower pH, the pyrazole consists of fluorophores with two distinct lifetimes, which cor-responds to pH-sensitive and non-pH sensitive species. In contrast, (1) N-substituted pyrazoles do not exhibit pH response, suggesting excited state electron transfer as the mechanism of pH dependent fluorescence lifetime sensitivity for this class of compounds. PMID- 23094960 TI - Involvement of transcription factor Ets-1 in the expression of the alpha3 integrin subunit gene. AB - The alpha3beta1 integrin is an adhesion receptor for extracellular matrix proteins, and plays crucial roles in cell motility, proliferation, and differentiation. The aberrant expression of this adhesion molecule on tumor cells is frequently associated with their malignant behaviors. We previously reported that the Ets transcription factor-binding consensus sequence 133 bp upstream of the mouse alpha3 integrin gene is an important element for its expression in various tumor cell lines. In the present study, we attempted to identify a transcription factor bound to the Ets-consensus sequence, and found that Ets-1 bound to this sequence in an electrophoretic mobility shift assay, chromatin immunoprecipitation assay, and pull-down assay with a tandem repeat of the sequence as adsorbent. We next examined the role of Ets-1 in alpha3 integrin gene expression by use of a luciferase assay with a reporter plasmid containing the 5' flanking region of the alpha3 integrin gene. Cotransfection of HEK293T cells with an Ets-1 expression construct and the reporter plasmid increased luciferase activity. By contrast, transfection of HT1080 cells (high alpha3 integrin expresser) with a dominant-negative mutant of Ets-1 decreased luciferase activity. Overexpression of Ets-1 in HepG2 hepatocellular carcinoma cells (low alpha3 integrin expresser) upregulated alpha3 integrin expression as assessed by immunoprecipitation. Finally, the induction of alpha3 integrin gene expression in HepG2 cells after transforming growth factor-beta1 treatment was abrogated by the dominant-negative mutant of Ets-1. These results suggest that Ets-1 is involved in transcriptional activation of the alpha3 integrin gene through its binding to the Ets-consensus sequence at -133 bp. PMID- 23094961 TI - Association of asthma symptoms with cigarette smoking and alcohol consumption in Korean adolescents. AB - The association of asthma symptoms with cigarette smoking and alcohol consumption in Korean adolescents was investigated in this study using the data of Korean Youth Risk Behavior Survey. Associated risk factors for experiencing asthma symptoms were explored in 3432 adolescents. In the symptomatic group, 21.7% were current smokers, compared to 10.9% in the asymptomatic group. Current smokers in the symptomatic group also smoked more cigarettes than those in the asymptomatic group. In the symptomatic group, 27.4% were current drinkers, compared to 17.9% in the asymptomatic group. Current drinkers in the symptomatic group were more likely to drink alcohol and to have experienced severe intoxication than those in the asymptomatic group. Participants who had been diagnosed within one year (odds ratio = 5.19, 95% confidence interval = 4.17-6.44) and those who had smoked over 20 days during the past 30 days (odds ratio = 1.77, 95% confidence interval = 1.26-2.49) were more likely to experience asthma symptoms. Healthcare providers should identify the risk behaviors of adolescents with asthma and counsel them and their parents simultaneously. PMID- 23094962 TI - Involvement of Tyr108 in the enzyme mechanism of the small laccase from Streptomyces coelicolor. AB - The enzyme mechanism of the multicopper oxidase (MCO) SLAC from Streptomyces coelicolor was investigated by structural (XRD), spectroscopic (optical, EPR), and kinetics (stopped-flow) experiments on variants in which residue Tyr108 had been replaced by Phe or Ala through site-directed mutagenesis. Contrary to the more common three-domain MCOs, a tyrosine in the two-domain SLAC is found to participate in the enzyme mechanism by providing an electron during oxygen reduction, giving rise to the temporary appearance of a tyrosyl radical. The relatively low k(cat)/K(M) of SLAC and the involvement of Y108 in the enzyme mechanism may reflect an adaptation to a milieu in which there is an imbalance between the available reducing and oxidizing co-substrates. The purported evolutionary relationship between the two-domain MCOs and human ceruloplasmin appears to extend not only to the 3D structure and the mode of binding of the Cu's in the trinuclear center, as noted before, but also to the enzyme mechanism. PMID- 23094963 TI - Assessment of the upper limb in cerebral palsy: validity and reliability of the revised VOAA-DDD. PMID- 23094964 TI - Theory of three-dimensional nanocrescent light harvesters. AB - The optical properties of three-dimensional crescent-shaped gold nanoparticles are studied using a transformation optics methodology. The polarization insensitive, highly efficient, and tunable light harvesting ability of singular nanocrescents is demonstrated. We extend our approach to more realistic blunt nanostructures, showing the robustness of their plasmonic performance against geometric imperfections. Finally, we provide analytical and numerical insights into the sensitivity of the device to radiative losses and nonlocal effects. Our theoretical findings reveal an underlying relation between structural bluntness and spatial dispersion in this particular nanoparticle configuration. PMID- 23094965 TI - Brain talk: power and negotiation in children's discourse about self, brain and behaviour. AB - This article examines children's discourse about self, brain and behaviour, focusing on the dynamics of power, knowledge and responsibility articulated by children. The empirical data discussed in this article are drawn from the study of Voices on Identity, Childhood, Ethics and Stimulants, which included interviews with 151 US and UK children, a subset of whom had a diagnosis of attention deficit/hyperactivity disorder. Despite their contact with psychiatric explanations and psychotropic drugs for their behaviour, children's discursive engagements with the brain show significant evidence of agency and negotiated responsibility. These engagements suggest the limitations of current concepts that describe a collapse of the self into the brain in an age of neurocentrism. Empirical investigation is needed in order to develop agent-centred conceptual and theoretical frameworks that describe and evaluate the harms and benefits of treating children with psychotropic drugs and other brain-based technologies. PMID- 23094966 TI - Bariatric surgery, bone loss, obesity and possible mechanisms. AB - Bariatric surgery remains the most effective treatment for severely obese patients. However, the potential long-term effects of bariatric surgical procedures on health, including bone health, are only partially understood. The goal of this review was to present data on the impact of bariatric surgery on bone metabolism and to analyse possible reasons for the loss of bone mass that frequently occurs after bariatric surgery. Such factors include nutritional deficiencies, rapid weight loss per se, effects of fat-derived adipokines and gut derived appetite-regulatory hormones. However, the relative roles of these factors in skeletal regulation and the mechanisms by which they work are not yet fully defined. Our review was focussed on the complex relationship between body weight, fat mass and bone mass, as well as peripheral and central mediators potentially involved in the dual regulation of both energy and bone homeostasis. We also review the data on the inverse relationship between central obesity, bone marrow fat and osteoporosis. As the number of bariatric operations increases, it is imperative to recognize mechanisms responsible for bariatric surgery-induced bone loss, with careful monitoring of bone health including long-term fracture incidence in patients undergoing these procedures. PMID- 23094968 TI - Secondary ion mass spectrometry: characterizing complex samples in two and three dimensions. PMID- 23094967 TI - Pneumocephalus in five horses. AB - Pneumocephalus is occasionally encountered in horses but poorly described in the literature. The study aimed to describe historical, clinical and diagnostic imaging findings and outcome in horses to increase the awareness and recognition of the condition amongst equine practitioners, allowing appropriate management of these cases. Cases of pneumocephalus from 4 participating institutions were identified and case details extracted from the medical records. Five cases of pneumocephalus were identified. Head trauma with suspected or confirmed fractures of the sinuses was the underlying cause in 4 cases, while the remaining horse was thought to have developed pneumocephalus secondary to sinusitis or trauma. Diagnosis was established radiographically in 4 cases and by computed tomography in a fifth. Gas was noted between the cranial vault and the brain, in the lateral ventricles, in the brain parenchyma and within the cranial cervical canal. The gas accumulation resolved gradually in all horses and did not appear independently to result in neurological compromise. Long-term outcome was available for 3 cases, 2 of which were ultimately subjected to euthanasia due to neurological deficits. Pneumocephalus is a possible consequence of head trauma or sinusitis in horses; although the finding is frequently incidental, it has the potential to develop into a life-threatening complication. Imaging the complete skull and cranial cervical spine is important to allow identification and appropriate management of these cases. The use of computed tomography enables easier identification and localisation of the gas accumulation within the central nervous system. PMID- 23094969 TI - F-wave suppression induced by suprathreshold high-frequency repetitive trascranial magnetic stimulation in poststroke patients with increased spasticity. AB - OBJECTIVE: High-intensity and high-frequency repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex was carried out in poststroke patients with increased spasticity, and the changes in F-wave parameters in comparison with M-wave parameters induced by rTMS were examined. METHODS: Ten hertz rTMS pulses were delivered to the primary motor cortex of the lesion side at 110% intensity of the resting motor threshold, and F-waves were obtained from the first dorsal interosseous muscle. F-waves were recorded before (pre-stim) and immediately after the end of rTMS (post-stim) in poststroke patients. RESULTS: F wave persistence and F/M Amp.Ratio increased significantly in patients with lesions in upper motor tract as compared with healthy subjects (Wilcoxon rank sum test, p = 0.00023 and p = 0.0073, respectively). After the rTMS application, both F-wave persistence and F/M Amp.Ratio decreased significantly (paired t-test, p = 0.0095 and p = 0.037, respectively). However, the F-wave amplitude did not show a statistically significant variance in poststroke patients. CONCLUSIONS: High frequency suprathreshold rTMS may suppress the F-waves by enhancing the inhibitory effect on spinal excitability through the corticospinal tract, and F wave persistence and F/M Amp.Ratio can be used to determine the effect of rTMS on patients with increased spasticity. PMID- 23094970 TI - Usefulness index in nonspecific abdominal pain--an aid in the diagnosis? AB - OBJECTIVE: In 1990, Lavelle and Kanagaratnam introduced Usefulness Index (UI) test for assessment of usefulness of clinical observations. Although, nonspecific abdominal pain (NSAP) is the most common diagnosis among secondary care patients with acute abdominal pain, the efficiency of UI test is rarely considered in NSAP. METHODS: In an extension of the World Organisation of Gastro-Enterology Research Committee (OMGE) acute abdominal pain study, 1333 patients presenting with acute abdominal pain were included in the study. The clinical signs (n = 14) and tests (n = 3) in each patient were recorded in detail, using a predefined structured data collection sheet, and the collected data were compared with the final diagnoses of the patients. RESULTS: The most significant clinical tests and signs of NSAP in univariate analysis were (UI = Usefulness Index and RR = risk ratio): rigidity (UI = 0.36, RR = 32.2), rebound (UI = 0.33, RR = 6.3), guarding (UI = 0.25, RR = 4.9), Murphy's positive (UI = 0.13, 8.9), bowel sounds (UI = 0.12, RR = 3.3), and renal tenderness (UI = 0.12, RR = 2.2). The sensitivity of the doctors' initial decision in detecting NSAP was 0.70 with a specificity of 0.83 and with the UI = 0.37 and RR = 11.4. CONCLUSION: The patients with negative test results in rigidity, rebound, guarding, Murphy's, and bowel sounds tended to be at risk for NSAP and in these patients the UI test could be an aid for clinician to differentiate NSAP from other causes of acute abdominal pain. PMID- 23094971 TI - Structural determinants in protein folding: a single conserved hydrophobic residue determines folding of EGF domains. AB - The epidermal growth factor (EGF) domain is evolutionarily conserved despite hypervariability in amino acid sequences. They fold into a three-looped conformation with a disulfide pairing of C(1)-C(3), C(2)-C(4) ,and C(5)-C(6). To elucidate the structural determinants that dictate the EGF fold, we selected the fourth and fifth EGF domains of thrombomodulin (TM) as models; the former domain folds into the canonical conformation, while the latter domain folds with alternate disulfide pairing of C(1)-C(2), C(3)-C(4), and C(5)-C(6). Since their third disulfide (C(5)-C(6)) is conserved, we examined the folding tendencies of synthetic peptides corresponding to truncated domain four (t-TMEGF4) and five (t TMEGF5), encompassing the segment C(1) to C(4). These peptides fold into their respective disulfide isoforms indicating that they contain all the required structural determinants. On the basis of the folding tendencies of these peptides in the absence and presence of 6 M Gn.HCl or 0.5 M NaCl, we determined that hydrophobic interactions are needed for the canonical EGF fold but not for the noncanonical fold. Sequence alignment of extant EGF domains and examination of their three-dimensional structures allowed us to identify a highly conserved hydrophobic residue in intercysteine loop 3 as the key contributor, which nucleates the hydrophobic core and acts as the lynch pin. When this hydrophobic residue (Tyr25) was substituted with a more hydrophilic Thr, the hydrophobic interactions were disrupted, and t-TMEGF4-Y25T folds similar to t-TMEGF5. Taken together, our results for the first time demonstrate that a single conserved hydrophobic residue acts as the key determinant in the folding of EGF domains. PMID- 23094972 TI - Effects of a heavy atom on molecular order and morphology in conjugated polymer:fullerene photovoltaic blend thin films and devices. AB - We study the molecular order and morphology in poly(3-hexylthiophene) (P3HT) and poly(3-hexylselenophene) (P3HS) thin films and their blends with [6,6]-phenyl C(61)-butyric acid methyl ester (PCBM). We find that substitution of the sulfur atoms in the thiophene rings of P3HT by heavy selenium atoms increases the tendency of the molecules to form better ordered phase; interestingly, their overall fraction of ordered phase is much lower than that of P3HT-based films. The higher tendency of P3HS molecules to order (aggregate) is consistent with more planar chain conformation simulated. The lower fraction of ordered phase (or the higher fraction of disordered phase) in P3HS-based films is clearly identified by in-plane skeleton Raman modes under resonant excitation conditions, such as a smaller ratio of the C?C modes associated with the ordered (~1422 cm( 1)) and disordered (~1446 cm(-1)) phases (I(1422 cm(-1))/I(1446 cm(-1)) = 1.4 for P3HS and 0.6 for P3HS:PCBM), compared with P3HT-based films (I(1449 cm( 1))/I(1470 cm(-1)) = 2.5 for P3HT and 1.0 for P3HT:PCBM) and a larger Raman dispersion of the C?C mode: P3HS (17 cm(-1)) versus P3HT (6 cm(-1)) and P3HS:PCBM (36 cm(-1)) versus P3HT:PCBM films (23 cm(-1)). The higher fraction of disordered phase in P3HS prevents the formation of micrometer-sized PCBM aggregates in blend films during thermal annealing. Importantly, this lower fraction but better quality of ordered phase in P3HS molecules strongly influences P3HS:PCBM photovoltaic performance, producing smaller short-circuit current (J(sc)) in pristine devices, but significantly larger increase in J(sc) after annealing compared to P3HT:PCBM devices. Our results clarify the effects of heavy atom substitution in low band gap polymers and their impact on blend morphology and device performance. Furthermore, our study clearly demonstrates resonant Raman spectroscopy as a simple, but powerful, structural probe which provides important information about "fraction/quantity of ordered phase" of molecules, not easily accessible using traditional X-ray-based techniques. PMID- 23094973 TI - Mavrilimumab, a human monoclonal GM-CSF receptor-alpha antibody for the management of rheumatoid arthritis: a novel approach to therapy. AB - INTRODUCTION: Mavrilimumab , formerly known as CAM-3001, a GM-CSF receptor-alpha antibody, is the first human monoclonal antibody to be used in Phase II studies (2011) to modulate the innate immunity pathway targeting GM-CSF signaling in moderate rheumatoid arthritis (RA). AREAS COVERED: Analysis of available clinical trial data on GM-CSF receptor-alpha antibody and medical literature search using MEDLINE for molecular mechanisms of pathogenesis of RA and its treatment forms the basis of this expert opinion review. The mavrilimumab Phase II double blind, randomized, placebo-controlled ascending dose trial demonstrated statistically significant achievement of primary and secondary end points in patients with moderate RA. The trial demonstrated significant clinical benefit in the 100 mg mavrilimumab cohort compared to the placebo group. EXPERT OPINION: The novel molecular targeting mechanism of mavrilimumab together with its demonstrated clinical efficacy, tolerability and safety profile in Phase II clinical trials in moderate RA, suggests significant potential utility for this drug to induce clinical remission, reduce flares and improve morbidity and mortality in patients with RA. PMID- 23094975 TI - Vertical partitioning between sister species of Rhizopogon fungi on mesic and xeric sites in an interior Douglas-fir forest. AB - Understanding ectomycorrhizal fungal (EMF) community structure is limited by a lack of taxonomic resolution and autecological information. Rhizopogon vesiculosus and Rhizopogon vinicolor (Basidiomycota) are morphologically and genetically related species. They are dominant members of interior Douglas-fir (Pseudotsuga menziesii var. glauca) EMF communities, but mechanisms leading to their coexistence are unknown. We investigated the microsite associations and foraging strategy of individual R. vesiculosus and R. vinicolor genets. Mycelia spatial patterns, pervasiveness and root colonization patterns of fungal genets were compared between Rhizopogon species and between xeric and mesic soil moisture regimes. Rhizopogon spp. mycelia were systematically excavated from the soil and identified using microsatellite DNA markers. Rhizopogon vesiculosus mycelia occurred at greater depth, were more spatially pervasive, and colonized more tree roots than R. vinicolor mycelia. Both species were frequently encountered in organic layers and between the interface of organic and mineral horizons. They were particularly abundant within microsites associated with soil moisture retention. The occurrence of R. vesiculosus shifted in the presence of R. vinicolor towards mineral soil horizons, where R. vinicolor was mostly absent. This suggests that competition and foraging strategy may contribute towards the vertical partitioning observed between these species. Rhizopogon vesiculosus and R. vinicolor mycelia systems occurred at greater mean depths and were more pervasive in mesic plots compared with xeric plots. The spatial continuity and number of trees colonized by genets of each species did not significantly differ between soil moisture regimes. PMID- 23094974 TI - Overcoming aspirin treatment failure in diabetes. AB - People with diabetes have an increased risk of life-threatening cardiovascular disease compared to the general population. Furthermore, people with diabetes are at greatly increased risk of not responding to standard anti-platelet therapy, such as aspirin, for the prevention of atherothrombotic events. This phenomenon is often referred to as treatment failure. Those who are at increased risk of such events despite aspirin therapy can be prospectively identified by a variety of laboratory measures of residual on-treatment platelet function, known as aspirin resistance. However, there is little agreement among laboratories on the approaches to these measurements, and insufficient data to guide the clinical management of people with diabetes-associated aspirin resistance if it is prospectively identified. This review provides a critical appraisal of the different approaches to the detection and evidence of mechanisms which contribute to this phenomenon, as well evidence for the potential effectiveness of different clinical approaches to overcoming aspirin treatment failure in diabetes. Potential mechanisms of aspirin resistance in diabetes include elevated platelet turnover that results in an immature platelet fraction able to synthesise the uninhibited therapeutic target of aspirin, cyclooxygenase-1 (COX-1); residual thromboxane production by both COX-1-dependent and COX-1-independent pathways; up regulation of aspirin-insensitive pathways of platelet function, such as adenosine diphosphate signalling; and increased underlying atherosclerotic disease burden that results in elevated underlying platelet hyper-reactivity. High on-aspirin platelet reactivity in diabetes may be related to glycemic control. Potential approaches to treatment include controlling modifiable risk factors to achieve effective glycemic control, guided increases in aspirin dose or frequency of administration, or the use of additional antiplatelet therapies. While evidence suggests that altering antiplatelet therapy, particularly by increasing frequency of aspirin administration, can overcome incomplete inhibition of thromboxane synthesis, no clinical studies to date have assessed the effectiveness of these in preventing breakthrough atherothrombosis. While some clinicians currently alter therapy on the basis of theoretical potential benefit of these strategies following identification of aspirin resistance in the laboratory, this is not yet supported by clinical evidence of a benefit, and clear clinical guidelines for the management of aspirin resistance are lacking. PMID- 23094976 TI - Research nurses collaborate with clinical nurses for success in the National Children's Study. AB - The National Children's Study is a longitudinal, prospective, observational study designed to enroll more than 100,000 children from more than 100 communities across the United States. In this article, research nurses share their experiences as members of one Vanguard Study Center in the planning, development, and implementation of tailored research protocols. Collaboration among research and clinical nurses and use of the RN birth team model were critical for success. PMID- 23094977 TI - Solvent-dependent fluorescence lifetimes of estrone, 17beta-estradiol and 17alpha ethinylestradiol. AB - The fluorescence lifetimes of the estrogens, estrone, 17beta-estradiol and 17alpha-ethinylestradiol, were studied in various solvents. The fluorescence lifetimes of 17beta-estradiol and 17alpha-ethinylestradiol decreased from 4.7 to 0.9 ns as the solvent hydrogen bond accepting ability increased, in good agreement with other phenolic molecules. Estrone's two fluorescence bands had distinct lifetimes, with the 304 nm band having a lifetime shorter than 200 ps, reflecting efficient energy transfer to the carbonyl group, which had lifetimes ranging from 4.4 to 4.9 ns depending on the solvent. Solvent effects on the (1) pipi*, (1) pisigma* and (1) npi* states that are relevant to estrogen photophysics can adequately explain these trends. The solvent dependence on the excited states of these potent endocrine disruptors has significant implications for their photochemistry. PMID- 23094978 TI - TB questions, East Kwaio answers: community-based participatory research in a remote area of Solomon Islands. AB - INTRODUCTION: East Kwaio is a remote region on the island of Malaita, Solomon Islands. Atoifi Adventist Hospital (the Hospital) is the only hospital and tuberculosis (TB) services provider in the region. If people come to the Hospital with TB, they are usually admitted for the two-month intensive phase of treatment as there are no community-based TB services. Most people walk or travel by canoe to the Hospital as there are no roads. East Kwaio is known to have high rates of TB; however, it has a low case detection rate and low treatment completion. The aims of this study were to explore why people with TB, especially from the mountain areas, present to the Hospital so late in their illness or do not present at all. The study was part of a larger project to strengthen the research capacity of local health workers and community leaders, supported by visiting researchers from Australia. METHODS: Semi-structured interviews with TB patients, a focus group of key informants and direct interaction with a community with a history of TB were used to explore reasons why people present to the Hospital late in their TB illness. RESULTS: Four interviews and a focus group of 12 key informants were conducted and a mountain hamlet with a history of TB was visited. The results represent the data from the interviews and the focus group. The time delay in presenting to the Hospital from when participants first became unwell ranged between two and three years. In the mountain hamlet, two additional people with probable TB were seen who had not presented to the Hospital during illnesses of five and nine months. Reasons for delays included: seeking care from traditional healers; the challenge of accessing health services due to distance, cost and cultural issues different from the Hospital's worldview; social isolation when in hospital; and being old so not having long to live. Delays in diagnosis of people with TB will increase the risk of transmission to family and through hamlets and villages. This study has led to plans being developed to build a more culturally appropriate TB ward and community treatment program. CONCLUSIONS: The study has identified TB questions that need East Kwaio answers. It has shown that a small project can inform the development of important changes to TB services, such as the redevelopment and relocation of the TB ward. To enable TB control, the local health services need to develop an understanding of, and appropriately engage with, traditional beliefs that influence how people interact with Hospital TB treatment and management. This is the case even if the beliefs are based on a worldview different than that of the health service providers. Ongoing operational research is required into TB diagnosis and treatment services and the many factors that contribute to the high TB burden in this remote area. PMID- 23094979 TI - Lipoproteins in bacteria: structures and biosynthetic pathways. AB - Bacterial lipoproteins are characterized by the presence of a conserved N terminal lipid-modified cysteine residue that allows the hydrophilic protein to anchor onto bacterial cell membranes. These proteins play important roles in a wide variety of bacterial physiological processes, including virulence, and induce innate immune reactions by functioning as ligands of the mammalian Toll like receptor 2. We review recent advances in our understanding of bacterial lipoprotein structure, biosynthesis and structure-function relationships between bacterial lipoproteins and Toll-like receptor 2. Notably, 40 years after the first report of the triacyl structure of Braun's lipoprotein in Escherichia coli, recent intensive MS-based analyses have led to the discovery of three new lipidated structures of lipoproteins in monoderm bacteria: the lyso, N-acetyl and peptidyl forms. Moreover, the bacterial lipoprotein structure is considered to be constant in each bacterium; however, lipoprotein structures in Staphylococcus aureus vary between the diacyl and triacyl forms depending on the environmental conditions. Thus, the lipidation state of bacterial lipoproteins, particularly in monoderm bacteria, is more complex than previously assumed. PMID- 23094980 TI - Porosity and water activity effects on stability of crystalline beta-carotene in freeze-dried solids. AB - Stability of entrapped crystalline beta-carotene as affected by water activity, solids microstructure, and composition of freeze-dried systems was investigated. Aliquots (1000 mm(3) , 20% w/w solids) of solutions of maltodextrins of various dextrose equivalents (M040:DE6, M100:DE11, and M250:DE25.5), M100-sugars (1:1 glucose, fructose and sucrose), and agar for gelation with dispersed beta carotene were frozen at -20, -40, or -80 degrees C and freeze-dried. Glass transition and alpha-relaxation temperatures were determined with differential scanning calorimetry and dynamic mechanical analysis, respectively. beta-Carotene contents were monitored spectrophotometrically. In the glassy solids, pore microstructure had a major effect on beta-carotene stability. Small pores with thin walls and large surface area allowed beta-carotene exposure to oxygen which led to a higher loss, whereas structural collapse enhanced stability of beta carotene by decreasing exposure to oxygen. As water plasticized matrices, an increase in molecular mobility in the matrix enhanced beta-carotene degradation. Stability of dispersed beta-carotene was highest at around 0.2 a(w) , but decreasing structural relaxation times above the glass transition correlated well with the rate of beta-carotene degradation at higher a(w) . Microstructure, a(w) , and component mobility are important factors in the control of stability of beta-carotene in freeze-dried solids. PRACTICAL APPLICATION: beta-Carotene expresses various nutritional benefits; however, it is sensitive to oxygen and the degradation contributes to loss of nutritional values as well as product color. To increase stability of beta-carotene in freeze-dried foods, the amount of oxygen penetration need to be limited. The modification of freeze-dried food structures, for example, porosity and structural collapse, components, and humidity effectively enhance the stability of dispersed beta-carotene in freeze dried solids. PMID- 23094981 TI - Experience of using electromyography of the genioglossus in the investigation of paediatric dysphagia. AB - AIM: The aim of the study was to assess, retrospectively, the utility of genioglossus electromyography (gEMG) in evaluating children with suspected neurogenic feeding and swallowing difficulties. METHOD: Children who were evaluated using gEMG at a tertiary paediatric neurology dysphagia service were reviewed. Data were analysed by the presence/absence of neurogenic changes on gEMG and the method of feeding at their most recent follow-up. RESULTS: The study group comprised 59 individuals (36 males, 23 females; median age 20 mo; range 1 mo-15 y). The study cohort included individuals with heterogeneous neurological phenotypes (n=40), craniofacial syndrome (n=10), and congenital bulbar palsy (n=9). gEMG identified 35 out of 59 (60%) with neurogenic changes. At follow-up, 24 individuals were on oral feeds and 35 were on alternative methods of feeding (nasogastric /gastrostomy). Eight out of 24 children on oral feeds showed neurogenic changes compared with 27 out of 35 on alternative feeds. chi(2) analysis of feeding method at follow-up and the presence or absence of neurogenic change on EMG was highly significant (p<=0.002). When confounding factors for alternative feeds were accounted for on univariate analysis, the neurogenic changes, severe gastro-oesophageal reflux disease, and respiratory comorbidities were statistically significant in predicting the alternative feeding, whereas growth failure and behavioural difficulties were not significant confounders. Moreover, multiple logistic regression analysis revealed that the neurogenic changes were independently predictive of an alternative method of feeding after adjusting for other confounders with an odds ratio of 29.6 (95% confidence interval 3.97-220; p<0.007). CONCLUSION: gEMG is a valuable complementary tool in the evaluation of children with neurogenic dysphagia as the degree of severity is independently correlated with long-term feeding outcomes. PMID- 23094982 TI - Maintenance of perioperative antiplatelet and anticoagulant therapy for vitreoretinal surgery. AB - BACKGROUND: The objective of this study was to prospectively assess the risk of bleeding from vitreoretinal surgery in a continuous unbiased cohort of patients taking unsuspended antiplatelet or anticoagulant therapy. DESIGN: Prospective hospital-based study. PARTICIPANTS: Eighty-five patients taking unsuspended aspirin, clopidogrel and/or warfarin therapy undergoing all forms of vitreoretinal surgery at The Mater Misericordiae University and The Mater Private Hospital, Dublin, Ireland. METHODS: Consecutive patients undergoing vitreoretinal surgery taking unsuspended antiplatelet or anticoagulant therapy over a 1-year period were included in this prospective study to evaluate the intraoperative and postoperative bleeding complications. MAIN OUTCOME MEASURES: The intraoperative and postoperative bleeding rates. RESULTS: One hundred and seven vitreoretinal procedures were performed on 85 patients taking unsuspended antiplatelet or anticoagulant therapy. The intraoperative bleeding rate was 23%, the majority of which consisted of mild bleeding into the vitreous cavity during vitrectomy. The postoperative bleeding rate was 22%, consisting of 3.7% anterior chamber haemorrhage, 11% dispersed vitreous cavity haemorrhage, 4.7% dense vitreous cavity haemorrhage, 0.9% subretinal haemorrhage and 1.9% localized choroidal haemorrhage. The single greatest significant independent predictor of intraoperative bleeding was proliferative diabetic retinopathy and of postoperative bleeding was the presence of diabetes mellitus. CONCLUSIONS: There were no cases of uncontrolled intraoperative haemorrhage or serious postoperative choroidal haemorrhage. Mild haemorrhagic oozing during vitrectomy and dispersed vitreous cavity haemorrhage postoperatively were common. For the majority of patients taking antiplatelet or anticoagulant medication, these agents can be safely continued in the vitreoretinal surgical perioperative period. PMID- 23094983 TI - Splitting bodies/selves: women's concepts of embodiment at the moment of birth. AB - Little sociological research has focused specifically on the moment of birth. In this article we draw upon interview data with women who had very recently given birth for the first time to explore the ways in which they described both their own embodiment and that of their infants at this time. We use the term 'the body being-born' to describe the liminality and fragmentation of the foetal/infant body as women experience it when giving birth. The study found that mode of birth was integral to the process of coming to terms with this body during and following birth. The women who gave birth vaginally without anaesthesia experienced an intense physicality as they felt their bodies painfully opening as the 'body-being-born' forced its way out. In contrast the women who had had a Caesarean section tended to experience both their own bodies and those of their infants as absent and alienated. Most of the women took some time to come to terms with the infant once it was born, conceptualising it as strange and unknown, but those who delivered by Caesarean section had to work even harder in coming to terms with the experience. PMID- 23094984 TI - Discovery of novel integrin ligands from combinatorial libraries using a multiplex "beads on a bead" approach. AB - The development of screening approaches to identify novel affinity ligands has paved the way for a new generation of molecular targeted nanomedicines. Conventional methods typically bias the display of the target protein to ligands during the screening process. We have developed an unbiased multiplex "beads on a bead" strategy to isolate, characterize, and validate high affinity ligands from OBOC libraries. Novel non-RGD peptides that target alpha(v)beta(3) integrin were discovered that do not affect cancer or endothelial cell biology. The peptides identified here represent novel integrin-targeted agents that can be used to develop targeted nanomedicines without the risk of increased tumor invasion and metastasis. PMID- 23094985 TI - On the energetic dependence of charge separation in low-band-gap polymer/fullerene blends. AB - The energetic driving force required to drive charge separation across donor/acceptor heterojunctions is a key consideration for organic optoelectronic devices. Herein we report a series of transient absorption and photocurrent experiments as a function of excitation wavelength and temperature for two low band-gap polymer/fullerene blends to study the mechanism of charge separation at the donor/acceptor interface. For the blend that exhibits the smallest donor/acceptor LUMO energy level offset, the photocurrent quantum yield falls as the photon excitation energy is reduced toward the band gap, but the yield of bound, interfacial charge transfer states rises. This interplay between bound and free charge generation as a function of initial exciton energy provides key evidence for the role of excess energy in driving charge separation of direct relevance to the development of low-band-gap polymers for enhanced solar light harvesting. PMID- 23094986 TI - Interleukin-6 receptor gene 48892 A/C polymorphism is associated with metabolic syndrome in female Taiwanese adolescents. AB - BACKGROUND: This study was to evaluate the relationship between the interleukin-6 receptor (IL-6R) 48892 A/C single-nucleotide polymorphism (SNP) (rs8192284) and the metabolic syndrome (MetS) and its components among young adolescents in Taiwan. METHODS: We enrolled 925 adolescents (451 boys and 474 girls). Modified National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) criteria were applied to define MetS (with age- and gender-specific 90th percentile cutoff point of variables). Subjects had three or more of the following cardiometabolic abnormalities that occur in MetS: high blood pressure, high fasting glucose, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), and obesity. The characteristics of the MetS components associated with different alleles and genotypes of the IL-6R rs8192284 SNP were compared. RESULTS: Frequencies of alleles and genotypes of the IL-6R 48892 polymorphism were similar in both sexes. Boys with C-alleles had borderline lower TG levels than A-allele carriers (66.0+/-30.1 vs. 70.3+/-34.6 mg/dL, p=0.07). However, girls with C-alleles had higher waist circumference (WC) (68.0+/-7.9 vs. 67.0+/-7.7 cm) and lower HDL-C levels (50.7+/-11.1 vs. 52.2+/-11.7 g/dL) than A allele carriers (p=0.05). The prevalence of MetS and its components, high WC and low HDL-C level, were higher in female C-allele carriers (all p<0.05) but not in boys. The odds ratios for high WC, low HDL-C levels, and MetS for female C-allele carriers were 1.54 (95% confidence interval [CI]: 1.01-2.34), 1.49 (95% CI: 1.01 2.18), and 2.19-2.39 (95% CI: 1.15-4.51), respectively, when compared with A allele carriers. CONCLUSIONS: The IL-6R 48892 A/C polymorphism is associated with high TG and WC, and low HDL-C levels in adolescents. Additionally, there is a gender difference in the incidence of MetS, indicating a possible gene-gender interaction of the IL-6R 48892 A/C polymorphism in MetS among Taiwanese adolescents. PMID- 23094987 TI - MTRR 66A>G polymorphism as maternal risk factor for Down syndrome: a meta analysis. AB - Down syndrome (DS) is the most common cause of mental retardation. Recent reports have investigated possible genetic factors that may increase maternal risk for DS. Methionine synthase reductase (5-methyltetrahydrofolate-homocysteine methyltransferase reductase MTRR) plays an important role in folic acid pathway and a common polymorphism (c.66A>G) has been associated with DS but results were controversial. This meta-analysis summarizes the available data concerning this association. Online major databases were searched to identify case-control studies regarding MTRR 66A>G polymorphism and DS. Crude odds ratios (OR) and 95% confidence intervals (CI) were calculated for maternal risk to have a DS child both using fixed and random effects (RE) models. Eleven articles from six populations were identified, including 1226 DS mothers and 1533 control mothers. Heterogeneity among studies was significant (Q=29.7, DF=10, p=0.001; I(2)=66.3%). The pooled OR in a RE model showed an increase in the risk of having a DS child associated with the G allele (OR 1.23, 95% CI 1.02-1.49). The fixed effect pooled OR was 1.19 (95% CI 1.08-1.31). This meta-analysis indicates that maternal MTRR 66A>G polymorphism is associated with an increased risk of having a DS child. PMID- 23094988 TI - Chronic disease risk among adults with cerebral palsy: the role of premature sarcopoenia, obesity and sedentary behaviour. AB - Premature declines in function among adults with cerebral palsy (CP) are generally attributed to weakness, spasticity and orthopaedic abnormalities, as well as chronic pain and fatigue. Very little research or clinical attention has been devoted to the confluence and consequences of early muscle wasting and obesity as mediators of secondary comorbidity in this population, and perhaps more importantly, to the role of lifestyle to potentiate these outcomes. At present, there are no national surveillance programmes that monitor chronic health in adults with CP; however, mortality records have demonstrated a greater prevalence of coronary heart disease as compared with the general population. Although by definition, CP is a 'non-progressive' condition, secondary factors such as habitual sedentary behaviour, obesity, and premature sarcoepenia may increase the severity of functional impairment throughout adulthood, and lead to cardiometabolic disease, fragility and/or early mortality. Herein we describe the heightened health risk represented in adults with CP, and discuss the hallmark phenotypic features that coincide with ageing, obesity and cardiometabolic disorders. Moreover, we provide discussion regarding the protective role of habitual physical activity to stimulate anti-inflammatory pathways and to ameliorate global risk. Although physical therapeutic modalities are already widely acknowledged as a vital component to improve movement quality in CP, the purpose of this review was to present a compelling case for the value of lifelong physical activity participation for both function and cardiometabolic health preservation. PMID- 23094989 TI - Does chronic atrial fibrillation induce cardiac remodeling? AB - AIM: The aim of this study was to compare cardiac structure and function in patients with chronic atrial fibrillation (CAF), as opposed to patients with paroxysmal atrial fibrillation (PAF), and normal control subjects. METHODS AND RESULTS: This study included 83 patients, divided into 3 groups: group A, 32 patients with CAF for >=6 months; group B, 29 patients in sinus rhythm with a documented history of PAF; and group C, 22 patients without history of atrial fibrillation. Patients with CAF were older (71 years vs. 64 in group B, and 64 in group C). Apart from age, groups were clinically similar. After careful clinical evaluation, comprehensive echocardiography studies were performed including cardiac chambers' size, systolic and diastolic left ventricular function. Left atrium (LA) volume index was significantly larger in CAF than PAF and control patients: 39 +/- 13 versus 34 +/- 9 versus 25 +/- 8 (P < 0.003). Left ventricular ejection fraction was lower in CAF: 53.8 +/- 7 versus 61.6 +/- 6.7 versus 58.4 +/ 5.2% (P < 0.001). Isovolumic relaxation time was shorter in CAF, 65 +/- 16 versus 82 +/- 21 versus 81 +/- 13 msec (P < 0.001). E/Vp was significantly greater in CAF 2.6 +/- 0.8 versus 1.7 +/- 0.4 versus 1.7 +/- 0.5 (P < 0.001). Additional diastolic parameters were also significantly different. CONCLUSION: These findings demonstrate that in patients with CAF structural and functional cardiac changes occur. Patients with CAF as opposed to both normal subjects and patients with PAF have larger left atria and reduced systolic and diastolic left ventricular function. PMID- 23094990 TI - On-demand control system for deep brain stimulation for treatment of intention tremor. AB - OBJECTIVES: Intention tremor becomes evident only when patients intend to move their body and is characterized by dysmetria. We have developed an on-demand control system that triggers the switching on/off of deep brain stimulation (DBS) instantly for the control of intention tremor. MATERIAL AND METHODS: We used surface electrodes for the recording of electromyographic (EMG) activity, and the power of EMG activity was analyzed instantly employing the fast Fourier transform. The on-demand control system switched on DBS when only the power of tremor frequency exceeded the on-trigger threshold, and the system switched off DBS when the total power of EMG activity decreased below the off-trigger threshold. RESULTS: The on-demand control system triggered the switching on/off of DBS accurately, and controlled intention tremor completely. Our on-demand control system is small and portable, and suitable for clinical use. CONCLUSIONS: The on-demand control system for DBS is useful for controlling intention tremor and may decrease the incidence of tolerance to DBS and may be a powerful tool for various applications of neuromodulation therapy. PMID- 23094992 TI - New adamantane phenylalkylamines with sigma-receptor binding affinity and anticancer activity, associated with putative antagonism of neuropathic pain. AB - The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The sigma(1), sigma(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound. PMID- 23094993 TI - Laser trapping chemistry: from polymer assembly to amino acid crystallization. AB - Laser trapping has served as a useful tool in physics and biology, but, before our work, chemists had not paid much attention to this technique because molecules are too small to be trapped in solution at room temperature. In late 1980s, we demonstrated laser trapping of micrometer-sized particles, developed various methodologies for their manipulation, ablation, and patterning in solution, and elucidated their dynamics and mechanism. In the 1990s, we started laser trapping studies on polymers, micelles, dendrimers, and gold, as well as polymer nanoparticles. Many groups also reported laser trapping studies of nanoclusters, DNA, colloidal suspensions, etc. Following these research streams, we have explored new molecular phenomena induced by laser trapping. Gradient force leading to trapping, mass transfer by local heating, and molecular reorientation following laser polarization are intimately coupled with molecular cluster and aggregate formation due to their intermolecular interactions, which depend on whether the trapping position is at the interface/surface or in solution. In this Account, we summarize our systematic studies on laser trapping chemistry and present some new advances and our future perspectives. We describe the laser trapping of nanoparticles, polymers, and amino acid clusters in solution by focusing a continuous wave 1064 nm laser beam on the molecules of interest and consider their dynamics and mechanism. In dilute solution, nanoparticles with weak mutual interactions are individually trapped at the focal point, while laser trapping of nanoparticles in concentrated solution assembles and confines numerous particles at the focal spot. The assembly of polymers during their laser trapping extends out from the focal point because of the interpolymer interactions, heat transfer, and solvent flow. When the trapping laser is focused at an interface between a thin heavy water solution film of glycine and a glass substrate, the assembled molecules nucleate and evolve to a liquid-liquid phase separation, or they will crystallize if the trapping laser is focused on the solution surface. Laser trapping can induce spatiotemporally the liquid and solid nucleation of glycine, and the dense liquid droplet or crystal formed can grow to a bulk scale. We can control the polymorph of the formed glycine crystal selectively by tuning trapping laser polarization and power. These results provide a new approach to elucidate dynamics and mechanism of crystallization and are the fundamental basis for studying not only enantioselective crystallization but also confined polymerization, trapping dynamics by ultrashort laser pulses, and resonance effect in laser trapping. PMID- 23094991 TI - Challenges for stem cells to functionally repair the damaged auditory nerve. AB - INTRODUCTION: In the auditory system, a specialized subset of sensory neurons are responsible for correctly relaying precise pitch and temporal cues to the brain. In individuals with severe-to-profound sensorineural hearing impairment these sensory auditory neurons can be directly stimulated by a cochlear implant, which restores sound input to the brainstem after the loss of hair cells. This neural prosthesis therefore depends on a residual population of functional neurons in order to function effectively. AREAS COVERED: In severe cases of sensorineural hearing loss where the numbers of auditory neurons are significantly depleted, the benefits derived from a cochlear implant may be minimal. One way in which to restore function to the auditory nerve is to replace these lost neurons using differentiated stem cells, thus re-establishing the neural circuit required for cochlear implant function. Such a therapy relies on producing an appropriate population of electrophysiologically functional neurons from stem cells, and on these cells integrating and reconnecting in an appropriate manner in the deaf cochlea. EXPERT OPINION: Here we review progress in the field to date, including some of the key functional features that stem cell-derived neurons would need to possess and how these might be enhanced using electrical stimulation from a cochlear implant. PMID- 23094994 TI - Environmental margin and island evolution in Middle Eastern populations of the Egyptian fruit bat. AB - Here, we present a study of the population genetic architecture and microevolution of the Egyptian fruit bat (Rousettus aegyptiacus) at the environmental margins in the Middle East using mitochondrial sequences and nuclear microsatellites. In contrast to the rather homogenous population structure typical of cave-dwelling bats in climax tropical ecosystems, a relatively pronounced isolation by distance and population diversification was observed. The evolution of this pattern could be ascribed to the complicated demographic history at higher latitudes related to the range margin fragmentation and complex geomorphology of the studied area. Lineages from East Africa and Arabia show divergent positions. Within the northwestern unit, the most marked pattern of the microsatellite data set is connected with insularity, as demonstrated by the separate status of populations from Saharan oases and Cyprus. These demes also exhibit a reduction in genetic variability, which is presumably connected with founder effects, drift and other potential factors related to island evolution as site-specific selection. Genetic clustering indicates a semipermeability of the desert barriers in the Sahara and Arabian Peninsula and a corridor role of the Nile Valley. The results emphasize the role of the island environment in restricting the gene flow in megabats, which is also corroborated by biogeographic patterns within the family, and suggests the possibility of nascent island speciation on Cyprus. Demographic analyses suggest that the colonization of the region was connected to the spread of agricultural plants; therefore, the peripatric processes described above might be because of or strengthened by anthropogenic changes in the environment. PMID- 23094995 TI - Do low testosterone levels contribute to ill-health during male ageing? AB - Testosterone regulates male sexual development and body composition. In adult men, testosterone levels exhibit a gradual decline with increasing age. Whether it is age per se or health and behaviour related factors that are responsible for this decline, and the implications thereof for subsequent health remain controversial. Observational studies report associations of lower testosterone levels with poorer health outcomes in ageing men, including frailty, reduced sexual activity, insulin resistance and cardiovascular events and mortality. However, outcome data from randomised clinical trials of testosterone are limited, and are lacking for major endpoints such as cardiovascular events. The risks and benefits of testosterone intervention in older men require further clarification. This article will review the role of testosterone in men, discuss epidemiological and interventional data illuminating its potential role to preserve health during male ageing, consider the limitations of the evidence base and implications for clinical practice, and explore future directions for research in this topical area. PMID- 23094996 TI - The placenta as a research biospecimen. AB - The placenta provides a unique opportunity to study the prenatal environment of the fetus to better understand subsequent infant and child health and illness. In this article we describe the role of the placenta as a research biospecimen, including placental morphology and cytokine biomarkers. Because of the role of the placenta in contemporary research, members of the perinatal health care team involved in birth have an important role in advancing science. PMID- 23094997 TI - Structural basis for dual inhibitory role of tamarind Kunitz inhibitor (TKI) against factor Xa and trypsin. AB - A Kunitz type dual inhibitor (TKI) of factor Xa (FXa) and trypsin was found in tamarind. It also shows prolongation of blood coagulation time. The deduced 185 amino acid sequence of TKI by cDNA cloning and sequence analysis revealed that it belongs to the Kunitz type soybean trypsin inhibitor (STI) family; however, it has a distorted Kunitz signature sequence due to insertion of Asn15 in the motif. TKI exhibited a competitive inhibitory activity against both FXa (K(i) = 220 nm) and porcine pancreatic trypsin (K(i) = 3.2 nm). The crystal structure of TKI shows a beta-trefoil fold similar to Kunitz STI inhibitors; however, a distinct mobile reactive site, an inserted residue and loop beta7beta8 make it distinct from classical Kunitz inhibitors. The crystal structure of TKI-trypsin and a 3D model of TKI-FXa complex revealed that the distinct reactive site loop probably plays a role in dual inhibition. The reactive site of TKI interacts with an active site and two exosites (36 loop and autolysis loop) of FXa. Apart from Arg66 (P1), Arg64 (P3) is one of the most important residues responsible for the specificity of TKI towards FXa. Along with the reactive site loop (beta4beta5), loops beta1 and beta7beta8 also interact with FXa and could further confer selectivity for FXa. We also present the role of inserted Asn15 in the stabilization of complexes. To the best of our knowledge, this is the first structure of FXa inhibitor belonging to the Kunitz type inhibitor family and its unique structural and sequence features make TKI a novel potent inhibitor. DATABASE: The complete nucleotide of TKI was deposited in the NCBI gene databank with accession no. HQ385502. The atomic coordinates and structure factor files for the structure of TKI and TKI:PPT complex have been deposited in the Protein Data Bank with accession numbers 4AN6 and 4AN7, respectively STRUCTURED DIGITAL ABSTRACT: TKI and TKI bind by x-ray crystallography (View interaction) TKI and PPT bind by x-ray crystallography (View interaction). PMID- 23094998 TI - Clinical and mycological features of onychomycosis in central Tunisia: a 22 years retrospective study (1986-2007). AB - Onychomycosis is the most frequently encountered nail disease and may be difficult to diagnose and treat. The objective of this study was to determine the prevalence, the clinical and mycological characteristics of onychomycosis in central Tunisia. It is a retrospective study performed over a 22-year period (1986-2007). It included 7151 patients (4709 women and 2442 men) with suspected fingernails and/or toenails onychomycosis. The patients were referred to the Mycology-Parasitology Laboratory of Farhat Hached hospital in Sousse for mycological examination. Both direct microscopy and culture of the nail material were performed to diagnose and identify the causative fungal species. Onychomycosis was confirmed in 78.6% of investigated patients (5624/7151). The positivity rate was higher in women as compared with men. In both men and women, fingernails were most frequently involved than toenails. No significant relation was found between gender and toenails onychomycosis, whereas fingernails were frequently involved in women. As far as aetiological agents are considered, dermatophytes, yeast and moulds were responsible for 49.9%, 47.4% and 2.7% of onyxis cases respectively. In fingernail infections, yeast were the most frequent fungi (83.6%), Candida albicans being the leading species (51.6%). In contrast, in toenail infections, dermatophytes were more frequent (74.1%). Trichophyton rubrum was by far the dominant species (88.1%). Yeast were observed more frequently in women whereas dermatophytes were more common in men. Moulds were involved in 4.2% of cases. The most frequent species were Aspergillus sp. and Chrysosporium sp. Onychomycosis is a frequent disease in central Tunisia. T. rubrum is the predominant agent in toenails infection and yeast, mainly C. albicans, in fingernails onychomycosis. PMID- 23094999 TI - The ability of cyanobacterial cells to restore UV-B radiation induced damage to Photosystem II is influenced by photolyase dependent DNA repair. AB - Damage of DNA and Photosystem-II are among the most significant effects of UV-B irradiation in photosynthetic organisms. Both damaged DNA and Photosystem-II can be repaired, which represent important defense mechanisms against detrimental UV B effects. Correlation of Photosystem-II damage and repair with the concurrent DNA damage and repair was investigated in the cyanobacterium Synechocystis PCC6803 using its wild type and a photolyase deficient mutant, which is unable to repair UV-B induced DNA damages. A significant amount of damaged DNA accumulated during UV-B exposure in the photolyase mutant concomitant with decreased Photosystem-II activity and D1 protein amount. The transcript level of psbA3, which is a UV-responsive copy of the psbA gene family encoding the D1 subunit of the Photosystem-II reaction center, is also decreased in the photolyase mutant. The wild-type cells, however, did not accumulate damaged DNA during UV-B exposure, suffered smaller losses of Photosystem-II activity and D1 protein, and maintained higher level of psbA3 transcripts than the photolyase mutant. It is concluded that the repair capacity of Photosystem-II depends on the ability of cells to repair UV-B-damaged DNA through maintaining the transcription of genes, which are essential for protein synthesis-dependent repair of the Photosystem-II reaction center. PMID- 23095001 TI - Structure and thermodynamics of Drug-RNA aptamer interactions. AB - This mini-review will provide an overview on the recent studies of structure and thermodynamics of RNA aptamers that target drug molecules. These aptamers are studied to provide insight into RNA drug interactions. This interaction is important due to the many roles RNA plays in cell biology. PMID- 23095000 TI - Interactions of curcumin and its derivatives with nucleic acids and their implications. AB - Curcumin (diferuloylmethane) is a yellow polyphenol found in the rhizome of the annual herb turmeric (Curcuma longa) belonging to the family Zingiberaceae. Its interaction with a huge number of molecular targets like cytokines, growth factors, transcription factors, receptors, pro-inflammatory enzymes, protein kinases and adhesion molecules has been studied extensively. Interaction of curcumin with nucleic acids has been the focus of extensive research in recent years. Curcumin is observed to be genotoxic and antigenotoxic agent in time and concentration dependent manner. Curcumin and its derivatives either alone or as metal complexes have been reported to bind directly to DNA. The interactions are mainly as DNA minor groove binding or as DNA intercalating agents. The similarity in the shape of curcumin to DNA minor groove binding drugs is the motivation for exploring its binding to DNA minor grooves. Thus curcumin is a "double edged sword": having therapeutic potential as a minor groove binder but at the same time it may cause DNA damage in the cell at high concentration. The purpose of this review is to summarize the current information related to interaction of curcumin metal complexes and its derivatives with nucleic acids and the implication such interaction can have on therapeutics. PMID- 23095002 TI - From Blatter radical to 7-substituted 1,3-diphenyl-1,4 dihydrothiazolo[5',4':4,5]benzo[1,2-e][1,2,4]triazin-4-yls: toward multifunctional materials. AB - A Blatter radical is oxidized to benzotriazin-7(H)-one which after amination and subsequent acyl- and aroylation gives N-(benzotriazin-6-yl)carboxamides that undergo ring closure with P(2)S(5) to afford the corresponding thiazolo[5',4':4,5]benzo[1,2-e][1,2,4]triazin-4-yls. These highly delocalized radicals are air stable and show good reversible electrochemical behavior. PMID- 23095003 TI - How did international agencies perceive the avian influenza problem? The adoption and manufacture of the 'One World, One Health' framework. AB - Over the past few years, a 'One World, One Health' (OWOH) policy framework has become the guiding principle for international responses to avian influenza and other zoonotic infectious diseases. Several specialised inter-governmental agencies, including the World Health Organization, the Food and Agricultural Organization and World Organization for Animal Health, jointly endorsed and promoted this framework. This article attempts to explain why international agencies advocated OWOH despite its vagueness. By examining how these international agencies gradually reframed avian flu problems, this article illustrates the crucial roles of international agencies in constructing disease knowledge and relevant policy responses. It shows that the three agencies adopted an all-inclusive approach to reduce conflicts, defend their legitimacy, and facilitate commitment for collaboration. Not only has this new framework reduced tensions between agencies, it has also reshaped the interests and interactions of other global actors. The case thus illustrates how these organisational actors actively manufacture new cognitive frames and policy regimes that advance their own legitimacy and influence. PMID- 23095004 TI - Factors affecting electronic health information needs in primary care patients. AB - BACKGROUND: Electronic health information is a new concept in the Lithuanian healthcare system. It gives the possibility of obtaining accurate medical information online by quick, convenient, and private access and presents to the patients the opportunity for better-informed decisions on their own health and greater participation in healthcare processes. The aim of this study is to assess the availability of health information for patients and to assess the factors affecting a patient's health-related information needs on the Internet. SUBJECTS AND METHODS: A cross-sectional study design was used. Self-perceived needs for health-related information and health-related information on the Internet were evaluated by means of a questionnaire. The questionnaires were distributed to the patients during on-site visits to primary care physician. Cumulative numbers of health information searches were calculated. RESULTS: The Internet was used by 63.2% of the respondents. Electronic health information search indicated 47.3% were Internet users. Internet users were statistically significantly more satisfied and informed about available electronic health services: registration for physician services (p<0.001), health information portal (p<0.001), electronic health record (p<0.001), clinical investigations (p=0.001), medical consultations (p=0.009), patient health education services (p=0.019), and patient self-help groups. A higher frequency of health information searches on the Internet was more associated with female patients (odds ratio [OR], 3.1; p=0.012), patients having chronic disease (p=0.013), living in couples (OR, 14.8; p=0.031), having e health service experience (OR, 7.0; p<0.001), daily Internet user (OR, 6.7; p=0.054), and longer duration of Internet use per day (OR, 1.3; p=0.046). CONCLUSIONS: The Internet is an important source of health information. Internet users are more satisfied with available health information. Female patients, those having chronic disease, living as couples, and having e-health service experience, and daily Internet users are the most frequent users of health information on the Internet. PMID- 23095005 TI - New mothers' interest in web-based health promotion: association with healthcare barriers, risk status, and user characteristics. AB - OBJECTIVE: Our first aim was to assess the contributions of health-related risks, barriers to healthcare, and user characteristics to new mothers' interest in two Web-based health programs: postpartum weight loss or parenting advice. Our second aim was to determine if the preceding proximal variables diminished associations of income level with interest in Web-based health programs. SUBJECTS AND METHODS: A mail survey of a stratified random sample was conducted with a resulting analytic sample that included 121 white/Anglo, African American, or Hispanic women of higher and lower income. Weight risk (being overweight or obese) and psychosocial/behavioral risk (alcohol use, depression, smoking) were the predictors of interest in a weight loss program and parenting advice, respectively. Financial, structural, and function factors served as barriers to care. Frequency of Internet use assessed user characteristics. Hierarchical logistic regression analysis was used to evaluate predictors. RESULTS: Being overweight (adjusted odds ratio [OR], 5.55; 95% confidence interval [CI], 2.18, 14.11) was the only variable to affect likelihood of interest in an Internet based weight loss program; income level was not a significant predictor. Having two or more psychosocial/behavioral risks (adjusted OR, 0.22; 95% CI, 0.50, 0.92) was the only predictor of interest in Internet-based parenting advice; income level was not a significant predictor after adjusting for other variables (OR, 0.55; 95% CI, 0.19, 1.55). CONCLUSIONS: The type of risk and program topic decreased or increased likelihood of interest in Internet-based programming. Weight risks increased interest in weight loss programming, but psychosocial/behavioral risks deceased interest in parenting advice. PMID- 23095006 TI - Effects of a comprehensive intervention program, including hot bathing, on overweight adults: a randomized controlled trial. AB - AIM: The objective of this study was to evaluate the effects of a comprehensive overweight intervention program, which utilizes hot bathing, on overweight, community-dwelling middle-aged and older adults in a randomized controlled trial. METHODS: The program was carried out in a hot bath facility and included 66 community-dwelling middle-aged and older Japanese adults (mean age 61.6 years, SD 7.5, 77.3% were women). The participants were randomly assigned to an exercise, diet and hot bathing intervention group (group A), exercise and diet intervention group (group B), a hot-bathing intervention group (group C) and a control group (group D). The participants in groups A and B participated in a comprehensive intervention program (including exercise and diet classes) twice a week for 3 months, and groups A and C had hot bathing. RESULTS: After 3 months, the participants in group A showed a reduction in weight, abdominal circumference, body mass index and body fat percentage compared with the other intervention groups. And the lower extremity function (i.e. walking speed) had greater improvement in the participants in groups A and B compared with groups C and D. In group C, in which only hot bathing was the intervention, there were no significant improvements in measurement items. CONCLUSIONS: Our study provides preliminary evidence that a comprehensive intervention program, including hot bathing, is useful for community residents with a tendency toward overweight. PMID- 23095007 TI - Effect of estrogen and testosterone replacement therapy on cognitive fatigue. AB - Both estrogen and testosterone insufficiency has been associated with reduced psychological well-being including fatigue. However, hormonal replacement studies on fatigue are rare. Therefore, we wanted to study the effect of testosterone and estrogen replacement therapy on cognitive fatigue and the relation between sex hormone levels and cognitive fatigue in oophorectomized women. Fifty women with surgically induced menopause (mean age: 54.0 +/- 2.9 years) were randomly assigned to treatment with estradiol valerate in combination with testosterone undecanoate or placebo for 24 weeks in a double-blind cross-over study. Neuropsychological tests and questionnaires were used to assess cognitive fatigue and psychological well-being. Cognitive fatigue was significantly associated to poor self-rated health and higher body mass index but not to general psychological well-being or sex hormone levels. Treatment with testosterone + estrogen had no significant effect on cognitive fatigue but the results indicated a curvilinear relation for hormonal levels. The estrogen/testosterone ratio was more related to functions rather than high or low hormone levels per se. We found that cognitive fatigue is frequent in oophorectomized women and negatively associated to self-perceived health and positively associated to BMI. A well balanced ratio between estrogen and testosterone levels may be important for cognitive fatigue. PMID- 23095011 TI - Discovery and therapeutic potential of kinin receptor antagonists. AB - INTRODUCTION: Kinins are bioactive peptide hormones that exert biological effects by activating two types of G protein-coupled receptors namely, B(1) (B(1)R) and B(2) (B(2)R). These modulate normal physiological cellular functions, inflammatory disorders and carcinogenesis. New and novel kinin receptor antagonists have been synthesized and their efficacy evaluated. AREAS COVERED: The authors provide a comprehensive review on the cellular and molecular biology of kinins and their receptors is delineated along with evolution and discovery of selective peptide and non-peptide antagonists. The authors describe the in vitro and in vivo methods used to understand the relative functional roles of B(1)R and B(2)R in physiology and pathohysiology. Furthermore, the authors translate the evaluation of kinin antagonists in selected preclinical models and associated clinical indications. Literature was surveyed from original publications, standard sources, SciFinder, patent applications and clinical trials. EXPERT OPINION: The authors suggest that several key areas of functional biology need consideration, namely: re-evaluation, particularly in vivo, of the mechanism of action and relative functional roles of the B(1)R and B(2)R in physiology and acute and chronic disease in animals and man; need for improved animal models with increased use of humanized and human systems; development of fluorescent probes for use in vivo in animals and man using advanced imaging techniques; combination of kinin receptor antagonists and traditional chemotherapy for various cancers. PMID- 23095012 TI - Multiple repeat caesarean section in the UK: incidence and consequences to mother and child. A national, prospective, cohort study. AB - OBJECTIVE: To estimate the incidence of multiple repeat caesarean section (MRCS) (five or more) in the UK and to describe the outcomes for women and their babies relative to women having fewer repeat caesarean sections. DESIGN: A national population-based prospective cohort study using the UK Obstetric Surveillance System (UKOSS). SETTING: All UK hospitals with consultant-led maternity units. POPULATION: Ninety-four women having their fifth or greater MRCS between January 2009 and December 2009, and 175 comparison women having their second to fourth caesarean section. METHODS: Prospective cohort and comparison identification through the UKOSS monthly mailing system. MAIN OUTCOME MEASURES: Incidence, maternal and neonatal complications. Relative risk, unadjusted (OR) and adjusted (aOR) odds ratio estimates. RESULTS: The estimated UK incidence of MRCS was 1.20 per 10 000 maternities [95% confidence interval (CI), 0.97-1.47]. Women with MRCS had significantly more major obstetric haemorrhages (>1500 ml) (aOR, 18.6; 95% CI, 3.89-88.8), visceral damage (aOR, 17.6; 95% CI, 1.85-167.1) and critical care admissions (aOR, 15.5; 95% CI, 3.16-76.0), than women with lower order repeat caesarean sections. These risks were greatest in the 18% of women with MRCS who also had placenta praevia or accreta. Neonates of mothers having MRCS were significantly more likely to be born prior to 37 weeks of gestation (OR, 6.15; 95% CI, 2.56-15.78) and therefore had higher rates of complications and admissions. CONCLUSIONS: MRCS is associated with greater maternal and neonatal morbidity than fewer caesarean sections. The associated maternal morbidity is largely secondary to placenta praevia and accreta, whereas higher rates of preterm delivery are most likely a response to antepartum haemorrhage. PMID- 23095008 TI - Identification of small-molecule enhancers of arginine methylation catalyzed by coactivator-associated arginine methyltransferase 1. AB - Arginine methylation is a common post-translational modification that is crucial in modulating gene expression at multiple critical levels. The arginine methyltransferases (PRMTs) are envisaged as promising druggable targets, but their role in physiological and pathological pathways is far from being clear due to the limited number of modulators reported to date. In this effort, enzyme activators can be invaluable tools useful as gain-of-function reagents to interrogate the biological roles in cells and in vivo of PRMTs. Yet the identification of such molecules is rarely pursued. Herein we describe a series of aryl ureido acetamido indole carboxylates (dubbed "uracandolates"), able to increase the methylation of histone (H3) or nonhistone (polyadenylate-binding protein 1, PABP1) substrates induced by coactivator-associated arginine methyltransferase 1 (CARM1), both in in vitro and cellular settings. To the best of our knowledge, this is the first report of compounds acting as CARM1 activators. PMID- 23095013 TI - Efficacy of botulinum toxin A in children with cerebral palsy in Gross Motor Function Classification System levels IV and V: a systematic review. AB - AIM: Previous studies have shown the efficacy of botulinum toxin type A (BoNT-A) in the management of ambulant individuals with cerebral palsy (CP). There is little evidence on its use in non-ambulant children with CP. This review aimed to investigate indications and efficacy for BoNT-A use in managing pain, care, and comfort, and improving function in children with CP in Gross Motor Function Classification System (GMFCS) levels IV and V. METHOD: Electronic databases were searched from the earliest available date to June 2012 using a combination of subject headings and free text. Inclusion criteria consisted of studies with (1) participants aged 18 or under, (2) participants with CP in GMFCS levels IV and V, (3) participants receiving BoNT-A treatment, and (4) studies published in English language peer-reviewed journals. RESULTS: The search resulted in a total of 814 studies, of which 19 met the inclusion criteria. Eighteen studies provided level IV or V evidence and one level I evidence according to the American Academy for Cerebral Palsy and Developmental Medicine guidelines for the development of systematic reviews. Most of the studies were of weak to moderate methodological quality. INTERPRETATION: The evidence that BoNT-A is effective in reducing postoperative pain in children with CP in GMCFS levels IV and V is limited, with only one level I study identified. Remaining indications were general pain reduction, maintaining hip integrity, achieving functional changes, and goal attainment. A high percentage of participants in the studies showed positive changes in these areas. With the poor level of evidence of the included studies, no definite conclusion could be drawn on the indications for BoNT-A use in children with CP in GMCFS levels IV and V. Further investigation by rigorous studies is required. PMID- 23095015 TI - Matrix metalloproteinase-2 and -9 levels in patients with dilated ascending aorta and bicuspid aortic valve. AB - BACKGROUND: Predictors of aortic dilatation are not well-described in patients with bicuspid aortic valve (BAV). Changes in extracellular matrix composition in the aortic wall may play an important role. Our study aimed to examine the relationship between ascending aortic dilatation and biochemical markers for collagen metabolism, such as matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) levels in patients with BAV. METHODS: All patients underwent cardiac echocardiography using a standard protocol, and aortic measurements were made in end-diastole. One hundred twelve BAV patients with no or mild valvular impairment were recruited and grouped according to the aortic dimensions corrected for body surface area (BSA) and age. There were 54 patients with dilated ascending aorta (Group 1) and 58 patients with nondilated ascending aorta (group 2). The plasma levels of MMP-2 and MMP-9 were determined by ELISA. RESULTS: The mean ascending aorta diameter was 4.49 +/- 0.49 mm in group 1 and 3.51 +/- 0.46 mm in group 2 (P < 0.001). There were no significant difference in gender, BSA, presence of hypertension, diabetes mellitus, hyperlipidemia, and smoking between the 2 groups. Nevertheless, no significant difference was observed in the levels of MMP-2 and MMP-9 between the 2 groups. The ascending aorta diameter correlated significantly with age (r = 0.438 P < 0.001). No significant correlation was observed between plasma MMP-2 and MMP-9 concentration and ascending aorta diameter, respectively (r = -0.005 P = 0.58, r = -0.106 P = 0.07). Multivariate analysis showed that age was independent predictor of aortic dilatation (P <= 0.001). CONCLUSION: Age was an independent predictor of aortic dilatation in patients with BAV, whereas MMP-2 and 9 levels were not relevant by aortic dilatation. PMID- 23095014 TI - Effects of high-pressure processing on inactivation of Salmonella Typhimurium, eating quality, and microstructure of raw chicken breast fillets. AB - High-pressure inactivation of Salmonella Typhimurium DMST 28913, eating quality, and microstructure of pressurized raw chicken breast meat was determined. The inoculated samples (approximately 7 log CFU/g initial load) were processed at 300 and 400 MPa, using pressurized medium of 25 to 35 degrees C during pressurization. Weibull model was well fitted to the survival curves with tailing. Least severe conditions with acceptable inactivation levels were 300 MPa, 35 degrees C, 1 min (approximately 2 log reduction) and 400 MPa, 30 degrees C, 1 min (approximately 4 log reduction). Based on these 2 conditions, the 400 MPa treatment yielded the raw chicken meat with higher L* value, greater cooking loss, and lower water holding capacity. Cooked chicken breast meat prepared from the pressurized samples had firmer texture than the control. Scanning electron microscopic images showed that higher pressure resulted in increasing extent of protein coagulation and the contraction of the muscle bundles. PRACTICAL APPLICATION: For raw chicken breast fillet, 300 MPa, 35 degrees C, 1 min was the condition that reasonably reduced the load of Salmonella Typhimurium. However, the pressurized samples had greater cooking loss. Marination with brine containing sodium chloride and phosphate prior to pressurization might help improve this eating quality. PMID- 23095016 TI - How to facilitate introduction of delivery system in transaortic transcatheter aortic valve implantation. AB - A new method to facilitate both introduction and handling of the delivery system in transcatheter valve implantation via the direct transaortic access (TAo-TAVI) is presented. An additional upper 2-cm incision facilitates the coaxiality between the delivery system and the aortic root. PMID- 23095018 TI - Exploring and exploiting polar-pi interactions with fluorinated aromatic amino acids. AB - Fluorination has become an increasingly attractive strategy in protein engineering for both basic research and biomedical applications. Thus researchers would like to understand the consequences of fluorination to the structure, stability, and function of target proteins. Although a substantial amount of work has focused on understanding the properties of fluorinated aliphatic amino acids, much less is known about fluorinated aromatic residues. In addition, polar-pi interactions, often referred to as aromatic interactions, may play a significant role in protein folding and protein-protein interactions. Fluorination of aromatic residues presents an ideal strategy for probing polar-pi interactions in proteins. This Account summarizes the recent studies of the incorporation of fluorinated aromatic amino acids into proteins. Herein we discuss the effects of fluorinating aromatic residues and rationalize them in the context of polar-pi interactions. The results strongly support the proposal that polar-pi interactions are energetically significant to protein folding and function. For example, an edge-face interaction of a pair of phenylalanines contributes as much as -1 kcal/mol to protein stability, while cation-pi interactions can be much stronger. Furthermore, this new knowledge provides guidelines for protein engineering with fluorination. Importantly, incorporating perfluorinated aromatic residues into proteins enables novel mechanisms of molecular recognition that do not exist in native proteins, such as arene-perfluoroarene stacking. Such novel mechanisms can be used for programming protein folding specificity and engineering peptide-based materials. PMID- 23095017 TI - Bright core-shell semiconductor quantum wires. AB - Colloidal CdTe quantum wires are reported having ensemble photoluminescence efficiencies as high as 25% under low excitation-power densities. High photoluminescence efficiencies are achieved by formation of a monolayer CdS shell on the CdTe quantum wires. Like other semiconductor nanowires, the CdTe quantum wires may contain frequent wurtzite-zinc-blende structural alternations along their lengths. The present results demonstrate that the optical properties, emission-peak shape and photoluminescence efficiencies, are independent of the presence or absence of such structural alternations. PMID- 23095019 TI - Time-of-flight secondary ion mass spectrometry with principal component analysis of titania-blood plasma interfaces. AB - Treatment of osseoimplant surfaces with autologous platelet-rich plasma prepared according to the plasma rich in growth factors (PRGF-Endoret) protocol prior to implantation yields promising results in the clinic. Our objective is to understand the organization of complex interfaces between blood plasma preparations of various compositions and model titania surfaces. Here we present the results of the morphological and chemical characterization of TiO(2) surfaces incubated with four types of blood plasma preparations devoid of leukocytes and red blood cells: either enriched in platelets (PRGF-Endoret) or platelet depleted, and either activated with CaCl(2) to induce clotting, or not. Chemical characterization was done by time-of-flight secondary ion mass spectrometry with principal component analysis (ToF-SIMS/PCA). The interface morphology was studied with scanning electron and atomic force microscopy. Immunofluorescence microscopy was used to identify platelets and infer their activation state. We observe clear differences among the four types of interfaces by ToF-SIMS/PCA. Some of these could be straightforwardly related to the differences in the sample morphology and known effects of platelet activation, but others are more subtle. Strikingly, it was possible to differentiate between these samples by ToF-SIMS/PCA of the protein species alone. This clearly indicates that the composition, orientation, and/or conformation of the proteins in these specimens depend both on the platelets' presence and on their activation. The ToF-SIMS imaging functionality furthermore provides unique insight into the distribution of phospholipid species in these samples. PMID- 23095020 TI - Active site analysis of yeast flavohemoglobin based on its structure with a small ligand or econazole. AB - Flavohemoglobins (flavoHbs) serve various microorganisms as the major protective enzymes against NO-mediated toxicity. FlavoHbs dominantly function as an NO dioxygenase (O2+ NO-> NO3 -), the required electron being shuttled from NAD(P)H via FAD to the heme iron. The X-ray structures of the flavoHb from Saccharomyces cerevisae presented in complex with an unknown small ligand (Yhb) and with econazole (Yhb(E) ) at 2.1 and 3.0 A resolutions, respectively, reveal a high architectural accordance between prokaryotic and eukaryotic family members. The active site is characterized by a proximal heme side with a strictly conserved histidine, glutamate and tyrosine triad and a highly variable distal heme side with helix shifts up to 10 A mainly dependent on the presence/absence and size of the bound ligand. In yeast flavoHb, the small heme iron ligand adjusts a catalytically productive active site geometry that reliably suggests the NO and O(2) binding site. O(2) is activated by its ligation to an electron-rich heme iron and a hydrogen bond to Tyr29 and Gln53. High active site similarities between eukaryotic Yhb and bacterial single-domain globins argue for identical biochemical reactions. Binding of the bulky econazole implies a large-scale induced-fit process concerning, in particular, an outwards shift of helices B and E to increase the active site pocket. Yeast Yhb and Ralstonia eutropha flavoHb both structurally studied in complex with econazole indicate conformational differences between the inhibitors and the polypeptide primarily caused by stable binding of a phospholipid to the latter and by distinct loop D structures. DATABASE: Structural data and final coordinates of Yhb and Yhb-econazole are available in the Protein Data Bank under the accession numbers 4G1V and 4G1B. PMID- 23095022 TI - Palladium-catalyzed C-H functionalization using guanidine as a directing group: ortho arylation and olefination of arylguanidines. AB - Palladium-catalyzed C-H functionalization using guanidine as the directing group was achieved under mild reaction conditions. Various guanidine derivatives were produced in moderate to good yields by using simple unactivated arenes or ethyl acrylate as the source of arylation or olefination, respectively. PMID- 23095021 TI - Incomplete lineage sorting or secondary admixture: disentangling historical divergence from recent gene flow in the Vinous-throated parrotbill (Paradoxornis webbianus). AB - Although Pleistocene glaciations had a major impact on the population genetic patterns of many species in North America and Europe, it remains unclear how these climatic fluctuations contributed to species diversification in East Asia. One reason for this is the difficulty of distinguishing genetic admixture following secondary contact from incomplete lineage sorting, both of which can generate similar patterns of genetic variation. Using a combination of multilocus analyses and coalescent simulation, we explore how these two processes occurred in the Pleistocene evolutionary history of a widespread East Asian bird, the Vinous-throated parrotbill, Paradoxornis webbianus. Maximum likelihood (ML) tree identified two major mitochondrial lineages, which are geographically separated in most parts of its range, but are sympatric at a few sampling sites. NJ tree and Structure analysis of microsatellite data set revealed an extensive level of admixture and little population structure, suggesting recent admixture between two formerly separated groups. Networks from nuclear DNA data sets, however, did not indicate any geographically isolated groups but rather a panmictic population, thus support incomplete lineage sorting. By using coalescent simulation approaches, we show that both processes did occur, although at different temporal scales. During the Pleistocene glaciations, probably around 0.1-0.5 Ma (the Marine Isotope Stage 6, MIS6), P. webbianus contracted into two separate refugia, and subsequently accumulated genetic divergence. During the interglacial MIS5, the species expanded into previously glaciated areas allowing the once separated groups to come into contact and become admixed. Taken together, our results indicate the current genetic variation within P. webbianus is a combination pattern of widespread distribution in pre-Pleistocene, then contraction and fragmentation into separated refugia during glacial advance, followed by recently postglacial expansion and admixture. PMID- 23095023 TI - Synthesis and structural elucidation of diversely functionalized 5,10 diaza[5]helicenes. AB - Diversely functionalized diaza[5]helicenes have been synthesized starting from 6,9-dichloro-5,10-diaza[5]helicene, which was prepared from a readily available quinoline building block via Wittig reaction followed by photochemical electrocyclization. The helicene skeleton was substituted by a variety of O-, S-, N-, and C-centered nucleophiles using nucleophilic aromatic substitution reactions and palladium-catalyzed reactions like Suzuki coupling and Buchwald Hartwig aminations. We have determined, using X-ray single-crystal diffraction, the crystal structures of the chloro- and methoxy-substituted diaza[5]helicenes. A resolution strategy based on diastereomeric separation by substitution of the dichloro derivative with a chiral amine has been shown. PMID- 23095024 TI - Sibling composition and children's anthropometric indicators of nutritional status: evidence from native Amazonians in Bolivia. AB - BACKGROUND: Siblings compete for parental resources. Little is known about how sibling composition (older sisters, older brothers, younger sisters, younger brothers) might affect child anthropometric indicators of nutritional status. AIM: This study evaluates the associations between sibling composition and child anthropometry using panel data from a native Amazonian society (Tsimane'). METHODS: Anthropometry of ~168 girls and 169 boys aged 2-9 years were measured annually during 2002-2007 (2360 observations). Children's weight-for-height Z score (WHZ), mid-upper arm circumference (MUAC), mid-upper arm muscle area (AMA) and triceps skin-fold thickness (TST) were regressed separately against all of the sibling composition variables while controlling for child's age and survey year. Multivariate panel linear regressions were used with individual, village, survey year and village-year fixed-effects, clustering by household. RESULTS: Among girls, an additional older brother was associated with a 1.4% decrease in MUAC (p < 0.01) and a 4.3% decrease in AMA (p < 0.01); an additional younger sister was associated with a 6.3% decrease in TST (p < 0.01). The association between sibling composition and arm anthropometry was robust to various model specifications. CONCLUSION: Older brothers and younger sisters were negatively associated with arm measures in girls. This finding may help improve policy interventions that aim to address children's nutritional health and long-term well-being. PMID- 23095025 TI - Impact of consultant operative supervision and surgical mortality in Australia. AB - BACKGROUND: In this study, the Australian and New Zealand Audit of Surgical Mortality evaluated the effect of operative supervision on certain post-operative outcomes in the surgical death subset. METHODS: This retrospective cohort study was based upon mortality data collected in 2009 which included 1673 patients who died and had surgery within 30 days of death or during the last admission. Cases were divided into three groups: consultant not supervising (group NS), consultant supervising (group S) and consultant performing the operation (group C). A comparison was done nationally and between participating states in Australia. Certain post-operative outcomes were compared between the three groups as well as between elective and emergency operations. RESULTS: There were significant variations in the levels of operative supervision among states in Australia. Group NS (n = 468) generally had more favourable post-operative outcomes than group S (n = 147) and group C (n = 1058), with post-operative complication rates of 24.8%, 37.4% and 40.9% for groups NS, S and C, respectively. The level of operative supervision in emergency operations was half that of elective operations. Nevertheless, the post-operative complications rate was significantly lower in emergency operations (30.6%) compared with elective operations (64.4%). The same trend was seen with clinical management deficiencies and unplanned return to theatre. CONCLUSION: Operative supervision in emergency setting within Australian hospitals appears to be potentially inadequate. However, the available data suggest that unsupervised surgery did not result in worse post-operative outcomes. In appropriately selected cases, the data support surgical registrars performing surgery without consultant supervision. PMID- 23095027 TI - West Nile virus: the production of a public health pandemic. AB - The West Nile virus (WNV), as it was presented in the texts and discourses on the Public Health Agency of Canada's (PHAC) website during its initial emergence, was an effect of the kinds of knowledge, techniques of power and disciplinary apparatuses that operate on that website and in society. With reference to Michel Foucault's relations of power, this article offers an approach for translating theories of power into techniques and technologies of power that can be used to conduct a social construction discourse analysis, and gives examples from the use of surveillance, normalisation, exclusion and regulation in PHAC's responses to the WNV epidemic in Canada. This study concludes with the assertion that shifting the ways in which social and political relations of power contour public health theories and practice is crucial. The present moment requires the development of global health responses to pandemics that are rooted less in the proliferation of apparatuses of control and more in epidemiological innovations and integrated, multi-perspectival research approaches to infectious diseases research, and in the governance of pandemic control and prevention initiatives. PMID- 23095026 TI - Synthesis and kinetic evaluation of cyclophostin and cyclipostins phosphonate analogs as selective and potent inhibitors of microbial lipases. AB - A new series of customizable diastereomeric cis- and trans-monocyclic enol phosphonate analogs to Cyclophostin and Cyclipostins were synthesized. Their potencies and mechanisms of inhibition toward six representative lipolytic enzymes belonging to distinct lipase families were examined. With mammalian gastric and pancreatic lipases no inhibition occurred with any of the compounds tested. Conversely, Fusarium solani Cutinase and lipases from Mycobacterium tuberculosis (Rv0183 and LipY) were all fully inactivated. The best inhibitors displayed a cis conformation (H and OMe) and exhibited higher inhibitory activities than the lipase inhibitor Orlistat toward the same enzymes. Our results have revealed that chemical group at the gamma-carbon of the phosphonate ring strongly impacts the inhibitory efficiency, leading to a significant improvement in selectivity toward a target lipase over another. The powerful and selective inhibition of microbial (fungal and mycobacterial) lipases suggests that these seven-membered monocyclic enol-phosphonates should provide useful leads for the development of novel and highly selective antimicrobial agents. PMID- 23095028 TI - Recently patented and widely used valves for transcatheter aortic valve implantation. AB - Aortic stenosis (AS) is a serious condition in the aging US and European populations. Management of a stenotic valve is crucial as it can become symptomatic quickly leading to ventricular deterioration and overall poor quality of life. Considering that AS is a disease of the elderly patient population, surgical intervention may not be well tolerated by some patients. Transcatheter aortic valve implantation (TAVI) has emerged as an alternative approach for patients who are unsuitable surgical candidates. Since the first balloon expandable Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) was implanted by Dr. Cribier, many other valves have been introduced into clinical practice. Self-expanding valves such as the CoreValve ReValving system (Medtronic, Minneapolis, MN) for retrograde implantation and Symetis TX for antegrade and transapical implantation are the most frequently used self-expanding valves. The SAPIEN valve, on the other hand can be implanted both antegrade as well as retrograde. Overall, the most widely used valves are the Edwards SAPIEN and the CoreValve, which have been implanted in more than 40,000 patients worldwide. The Symetis valve has shown promising results in small series in Europe and may be introduced to the US market in the near future. This manuscript will review these 3 recently patented valves and discuss some of the clinical results that are available. PMID- 23095029 TI - Overview of recent drug discovery approaches for new generation leukotriene A4 hydrolase inhibitors. AB - INTRODUCTION: LTA(4)H is a bifunctional enzyme with hydrolase and aminopeptidase activities. The hydrolase function of this enzyme specifically catalyzes the rate limiting step in the conversion of LTA(4) to LTB(4), one of the most potent chemoattractant and activator of neutrophils. The wealth of in vitro and in vivo data favors in support of LTA(4)H as an appealing target for the discovery and development of anti-inflammatory drugs. AREAS COVERED: The authors provide an overview of the recent advances on LTA(4)H inhibitors since 2000. The review details the medicinal chemistry efforts leading to the generation of novel inhibitor chemotypes with desirable drug-like properties as well as the advantages and disadvantages of LTA(4)H as a desirable therapeutic target. EXPERT OPINION: Most of the LTA(4)H inhibitors block pro-inflammatory LTB(4) biosynthesis by concomitant inhibition of both the hydrolase and aminopeptidase activities of LTA(4)H. However, the degradation of another endogenous chemoattractant substrate (PGP) by aminopeptidase function of LTA(4)H was shown, introducing a new anti-inflammatory mission for this pro-inflammatory enzyme. LTA(4)H inhibitors were also shown to maintain anti-inflammatory lipoxin formation. Hence, the data on new LTA(4)H inhibitors should be cautiously interpreted with regard to potential repercussions of preventing PGP degradation as well as for the clinical benefits of concomitant lipoxin formation. PMID- 23095030 TI - Rifaximin in the treatment of recurrent Clostridium difficile infection. AB - BACKGROUND: Clostridium difficile can cause severe antibiotic-associated colitis. Conventional treatments with metronidazole and vancomycin improve symptoms, but after discontinuation of treatment, C. difficile infection (CDI) recurs in a number of patients. Rifaximin is a rifamycin-based non-systemic antibiotic that has effect against C. difficile. AIM: To assess the effectiveness of rifaximin in recurrent C. difficile infection. METHODS: We retrospectively evaluated the records of 32 patients who were treated with rifaximin for recurrent C. difficile infection. The symptoms were evaluated 12 weeks after the start of treatment and patient records were followed up until 1 year after treatment. RESULTS: The mean age of the patients was 55 years (median 64, range: 19-84 years). Before the initiation of rifaximin therapy, the patients had undergone, on the average, 4.4 (range: 2-12) antimicrobial courses for C. difficile infection. C. difficile strain typing was performed in 27 patients. Eight (30%) patients had a strain with a DNA profile compatible with the BI/NAP1/027 ribotype. Antibiotic susceptibilities were determined of isolates from 22 patients. Most isolates (68%) had very low MIC-values for rifampin (<0.002 MUg/mL) and the highest MIC value was 3.0 MUg/mL. Isolates with a DNA profile compatible with the BI/NAP1/027 ribotype had, on the average, higher MICs of rifampin. After 12 weeks 17 (53%) patients had no relapse. The MIC value of rifampin seemed to predict the response to rifaximin treatment. CONCLUSIONS: Rifaximin is a safe treatment for C. difficile infection. It has a reasonable effect in C. difficile infection and it can be considered as an optional treatment for recurrent C. difficile infection. PMID- 23095031 TI - Left ventricular pseudoaneurysm following myocardial infarction. PMID- 23095032 TI - Assessment of upper-limb capacity, performance, and developmental disregard in children with cerebral palsy: validity and reliability of the revised Video Observation Aarts and Aarts module: Determine Developmental Disregard (VOAA-DDD R). AB - AIM: To investigate the validity and reliability of the revised Video-Observation Aarts and Aarts module: Determine Developmental Disregard (VOAA-DDD-R). METHOD: Upper-limb capacity and performance were assessed in children with unilateral spastic cerebral palsy (CP) by measuring overall duration of affected upper-limb use and the frequency of specific behaviours during a task in which bimanual activity was demanded ('stringing beads') and stimulated ('decorating a muffin'). Developmental disregard was defined as the difference in duration of affected upper-limb use between both tasks. Raters were two occupational and one physical therapist who received 3 hours of training. Construct validity was determined by comparing children with CP with typically developing children. Intrarater, interrater, and test-retest reliability were determined using the intraclass correlation coefficient. Standard errors of measurement and smallest detectable differences were also calculated. RESULTS: Twenty-five children with CP (15 females, 10 males; mean age 4 y 9 mo [SD 1 y 7 mo], range 2 y 9 mo-8 y; Manual Ability Classification System levels I-III) scored lower on capacity (p=0.052) and performance (p<0.001), and higher on developmental disregard (p<0.001) than 46 age- and sex-matched typically developing children (23 males; mean age 5 y 3 mo [SD 1 y 5 mo], range 2 y 6 mo-8 y). The intraclass correlation coefficients (0.79-1.00) indicated good reliability. Absolute agreement was high, standard errors of measurement ranged from 4.5 to 6.8%, and smallest detectable differences ranged from 12.5 to 19.0%. INTERPRETATION: The VOAA-DDD-R can be reliably and validly used by occupational and physical therapists to assess upper limb capacity, performance, and developmental disregard in children (2 y 6 mo-8 y) with CP. PMID- 23095034 TI - Applying different methods to evaluate the freshness of large yellow croacker (Pseudosciaena crocea) fillets during chilled storage. AB - The freshness of large yellow croaker ( Pseudosciaena crocea ) fillets was evaluated over 20 days of chilled storage under vacuum packaging. The physicochemical properties [pH, K value, thiobarbituric acid (TBA), texture profile analyses (TPA), color], microbiological properties [total viable count (TVC)], sensory attributes, transcriptomics (levels of transcripts coding for cathepsin L), and functional properties of proteins [emulsion activity (EA) and emulsion stability (ES)] were assessed at 0, 5, 10, 15, and 20 days of storage. This study also investigated the effect of the storage time on fish muscle proteome in large yellow croaker using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS). The parameters that were the most sensitive to storage duration were color (C*(ab)), TPA (springiness, chewiness, and resilience), pH, K value, TVC, levels of transcripts coding for cathepsin L, EA, ES, and sensory attributes. The three altered proteins were successfully identified. Therefore, these parameters might be considered suitable indicators for evaluating the freshness of large yellow croaker fillets during chilled storage under vacuum packaging. PMID- 23095035 TI - Unsymmetrical squaraines incorporating quinoline for near infrared responsive dye sensitized solar cells. AB - Two new unsymmetrical squaraines (WCH-SQ10 and WCH-SQ11), wherein the electron rich 3,4-ethylenedioxy-thiophene conjugated fragment was linked unconventionally to the squaraine core and triphenyl amine donor, and carboxylic acid substituted quinoline was used as an acceptor, were prepared. WCH-SQ10 and WCH-SQ11 dyes in ethanol have the lambda(max) of 686 and 673 nm, respectively. The corresponding photovoltaic devices exhibit an attractively panchromatic response over 1000 nm, suggesting that quinoline benefits the low energetic electron injection. PMID- 23095033 TI - Vascular binding of a pathogen under shear force through mechanistically distinct sequential interactions with host macromolecules. AB - Systemic dissemination of microbial pathogens permits microbes to spread from the initial site of infection to secondary target tissues and is responsible for most mortality due to bacterial infections. Dissemination is a critical stage of disease progression by the Lyme spirochaete, Borrelia burgdorferi. However, many mechanistic features of the process are not yet understood. A key step is adhesion of circulating microbes to vascular surfaces in the face of the shear forces present in flowing blood. Using real-time microscopic imaging of the Lyme spirochaete in living mice we previously identified the first bacterial protein (B. burgdorferi BBK32) shown to mediate vascular adhesion in vivo. Vascular adhesion is also dependent on host fibronectin (Fn) and glycosaminoglycans (GAGs). In the present study, we investigated the mechanisms of BBK32-dependent vascular adhesion in vivo. We determined that BBK32-Fn interactions (tethering) function as a molecular braking mechanism that permits the formation of more stable BBK32-GAG interactions (dragging) between circulating bacteria and vascular surfaces. Since BBK32-like proteins are expressed in a variety of pathogens we believe that the vascular adhesion mechanisms we have deciphered here may be critical for understanding the dissemination mechanisms of other bacterial pathogens. PMID- 23095036 TI - Early response and local control of stage I non-small-cell lung cancer after stereotactic radiotherapy: difference by histology. AB - To investigate the possible influences of various factors on tumor response to radiation, regression speeds and long-term local control rates of primary adenocarcinoma and squamous cell carcinoma of the lung after stereotactic body radiotherapy were evaluated. Ninety-one patients (65 men and 26 women) with a median age of 76 years were serially examined using computed tomography at 2, 4 and 6 months after treatment. Tumor histology was adenocarcinoma in 62 patients and squamous cell carcinoma in 29 patients. The prescribed dose was 48 Gy in four fractions given twice a week for T1 tumors (<= 3 cm) and 52 Gy in four fractions given twice a week for T2 tumors (3-5 cm). Tumor shrinkage speed and 3-year local control rates were similar between T1 and T2 tumors and between patients with normal pulmonary function and those with impaired function. Squamous cell carcinomas shrank faster than adenocarcinomas at 2 and 4 months after radiation, but mean relative tumor size at 6 months and local control rates at 3 years did not differ significantly between the two histologies. Tumors in patients with a higher hemoglobin level tended to shrink faster but the control rates were not different. It is concluded that, although squamous cell carcinoma shrinks faster than adenocarcinoma, the two types of lung cancer are of similar radiosensitivity in terms of long-term control rates. Radiosensitivity should not be evaluated by early tumor response. PMID- 23095037 TI - A fluorogenic probe for the catalyst-free detection of azide-tagged molecules. AB - Fluorogenic reactions in which non- or weakly fluorescent reagents produce highly fluorescent products can be exploited to detect a broad range of compounds including biomolecules and materials. We describe a modified dibenzocyclooctyne that under catalyst-free conditions undergoes fast strain-promoted cycloadditions with azides to yield strongly fluorescent triazoles. The cycloaddition products are more than 1000-fold brighter compared to the starting cyclooctyne, exhibit large Stokes shift, and can be excited above 350 nm, which is required for many applications. Quantum mechanical calculations indicate that the fluorescence increase upon triazole formation is due to large differences in oscillator strengths of the S(0) <-> S(1) transitions in the planar C(2v)-symmetric starting material compared to the symmetry-broken and nonplanar cycloaddition products. The new fluorogenic probe was successfully employed for labeling of proteins modified by an azide moiety. PMID- 23095038 TI - Associations between dispositions to rash action and internalizing and externalizing symptoms in children. AB - Impulsivity is not a unitary construct; instead, dispositions to rash action can be divided into five moderately-correlated dimensions. However, the associations between these dimensions and symptoms of psychopathology among youth remain unclear. The goal of this study was to examine associations between different dispositions to rash action and psychopathology in a community sample of middle school youth. One hundred forty-four youth (M age = 11.9; 65% Hispanic, 30% African American; 50% male; 81% qualifying for free school lunches) participated in this study. Self-reported questionnaire measures of dispositions to rash action (lack of planning, lack of perseverance, sensation seeking, negative urgency, and positive urgency) and psychopathology symptoms (conduct disorder [CD], alcohol use, depression, overall anxiety, panic, generalized anxiety, social anxiety, and separation anxiety, as well as teacher reports of attention deficit/hyperactivity disorder [ADHD] inattentive and hyperactive symptoms) were used. Negative and positive urgency were positively associated with all symptom types examined except certain anxiety subtypes (and positive urgency was not associated with ADHD symptoms). Lack of planning was positively associated with externalizing and depressive symptoms. Lack of perseverance was positively associated with CD. Sensation seeking was positively associated with both CD and alcohol use. When other dispositions were adjusted for, negative urgency remained a positive predictor of CD, whereas positive urgency remained a positive predictor of depressive and panic symptoms. Sensation seeking was negatively associated with separation anxiety. Psychopathology symptoms are differentially related to dispositions to rash action in children; emotion-based dispositions to rash action may be particularly important targets for future research. PMID- 23095039 TI - Surgical management in patients with pancreatic cancer: a Queensland perspective. AB - BACKGROUND: Little has been published regarding presenting symptoms, investigations and outcomes for patients with pancreatic cancer in Australia. Data from a series of patients undergoing attempted resection in Queensland, Australia, are presented with the aim of assisting development of consistent strategies in disease management. METHODS: We reviewed the medical records of 121 patients who underwent attempted surgical resection and who took part in a case control study between 2007 and 2009. Information relating to symptoms, investigations, surgical procedures and outcomes was captured. RESULTS: The mean age was 63 years and 60% were men. The most common presenting symptoms were jaundice (64%) and pain (63%). Over 80% of patients had multiple imaging investigations or laparoscopy prior to surgery. Seventy-eight patients (64%) had a completed resection and 23% of these had involved margins. The presence of metastases and/or involvement of vessels or adjacent structures precluded resection in the remaining patients. The 1-year survival for patients whose resections were completed was 77% compared with 51% for those whose tumours were not resectable (P = 0.004). There was no 30-day mortality and 68% of patients were alive 1 year after diagnosis. Resections were performed in 11 different hospitals but over 90% of patients underwent their surgery in one of five high volume centres. CONCLUSION: The Queensland experience is consistent with that reported internationally. A significant proportion of attempted resections was not completed because preoperative staging underestimated disease extent. Most patients with potentially resectable disease are being treated in high-volume centres. PMID- 23095040 TI - Dentine sialoprotein expression in gingival crevicular fluid during trauma induced root resorption. AB - AIM: To detect and quantify dentine sialoprotein (DSP) in the gingival crevicular fluid (GCF) of luxated teeth. METHODOLOGY: Eighteen subjects were enroled and distributed as follows. Group I (n = 6, positive control): subjects with primary second molar teeth undergoing physiological root resorption. Group II (n = 6, negative control): subjects with permanent mature maxillary central incisors. Subjects with a recent history (<1 week) of luxation injury were included in group III (n = 6, test group) and standardized digital radiographs with a superimposed mesh gauge were exposed at various time intervals. Percentage of radiographic root resorption (%RRR) was calculated. GCF was collected using microcapillary pipettes. DSP in the GCF was quantified using enzyme-linked immunosorbant assay. Group III was subjected to Spearman's rank test to establish the correlation between the concentration of DSP and %RRR at 6 weeks, 3 and 6 months. RESULTS: Quantifiable amounts of DSP were released in the GCF of subjects in Group I and III. However, the protein was not detected in Group II. Detectable quantities of DSP were observed in the GCF of luxated teeth before any radiographic evidence of root resorption (base line radiograph). A positive correlation was established at 6 weeks (r = 0.795), 3 (r = 0.755) and 6 month (r = 0.837) between the release of DSP and %RRR (P < 0.05). CONCLUSION: Dentine sialoprotein was released in the GCF of luxated teeth and its concentration correlated with the active and remission phases of this pathological process. Further investigation is required to establish a potentially noninvasive aid for diagnosing and monitoring root resorption. PMID- 23095042 TI - Photoswitching-enabled novel optical imaging: innovative solutions for real-world challenges in fluorescence detections. AB - Because of its ultrasensitivity, fluorescence offers a noninvasive means to investigate biomolecular mechanisms, pathways, and regulations in living cells, tissues, and animals. However, real-world applications of fluorescence technologies encounter many practical challenges. For example, the intrinsic heterogeneity of biological samples always generates optical interferences. High background such as autofluorescence can often obscure the desired signals. Finally, the wave properties of light limit the spatial resolution of optical microscopy. The key to solving these problems involves using chemical structures that can modulate the fluorescence output. Photoswitchable fluorescent molecules that alternate their emissions between two colors or between bright-and-dark states in response to external light stimulation form the core of these technologies. For example, molecular fluorescence modulation can switch fluorophores on and off. This feature supports super-resolution, which enhances resolution by an order of magnitude greater than the longstanding diffraction limit barrier. The reversible modulation of such probes at a particular frequency significantly amplifies the frequency-bearing target signal while suppressing interferences and autofluorescence. In this Account, we outline the fundamental connection between constant excitation and oscillating fluorescence. To create molecules that will convert a constant excitation into oscillating emission, we have synthesized photoswitchable probes and demonstrated them as proofs of concept in super-resolution imaging and frequency-domain imaging. First, we introduce the design of molecules that can convert constant excitation into oscillating emission, the key step in fluorescence modulation. Then we discuss various technologies that use fluorescence modulation: super-resolution imaging, dual-color imaging, phase-sensitive lock-in detection, and frequency-domain imaging. Finally, we present two biological applications to demonstrate the power of photoswitching-enabled fluorescence imaging. Because synthetic photoswitchable probes can be much smaller, more versatile, and more efficient at high performance modulation experiments, they provide a complement to photoswitchable fluorescent proteins. Although new challenges remain, we foresee a bright future for photoswitching-enabled imaging and detection. PMID- 23095041 TI - Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit. AB - The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains. PMID- 23095044 TI - Comparison of procedure cost for thrombectomy of arteriovenous fistulas and grafts. AB - Expenditures on dialysis vascular access now exceed $2.5 Billion annually in the US. Studies suggest that significant savings could be achieved by increasing arteriovenous fistula (AVF) prevalence to >65%. It is common but unsubstantiated opinion that AVF have lower maintenance costs than arteriovenous grafts (AVG). This manuscript tests this hypothesis by direct comparison. Equipment utilization time and supply utilization on 110 thrombectomy procedures on AVF and 258 on AVG were compared. Procedures techniques were standardized within one facility and procedures performed by a multiple but limited number of operators. There were no significant differences in demographic variables and comorbid factors between groups. Time to complete AVF thrombectomy was 1.7 times that for AVG. In addition, major supplies used such as wires and balloons were also significantly greater. Interventionists who took longer than average to thrombectomize AVF took longer than average to thrombectomize AVG. The prevalence of arterial inflow lesions was 1.5 greater in thrombosed AVF versus Thrombosed AVG. Procedure costs when analyzed in terms of procedure time, room utilization, staff, and equipment are significantly greater for thrombosed AVF than thrombosed AVG. PMID- 23095046 TI - Housing adaptations from the perspectives of Swedish occupational therapists. AB - AIM: The aim of this study was to investigate how occupational therapists in Sweden administer housing adaptation cases, how they perceive the housing adaptation process, and which improvements they consider necessary. METHODS: A total of 1 679 occupational therapists employed by the county councils or the local authorities (and involved in housing adaptations) participated in a web based survey. The survey targeted issues related to referral and needs identification, assessment, certification, case progress feedback, and evaluation. RESULTS: Less than half of the occupational therapists systematized the assessment prior to intervention and very few conducted any evaluation afterwards. Feedback from workmen or grant managers to the occupational therapists on each case's adaptation progress was often asked for but rarely given. The majority of the participants were satisfied with the housing adaptation process in general, while at the same time they indicated a need for further improvements in the process. Differences between occupational therapists related to employer and year of graduation were found on the majority of the targeted issues. CONCLUSIONS: To conclude, to a very large extent housing adaptations seem to be based on non-standardized procedures for assessment, and only a few of them are evaluated systematically. PMID- 23095043 TI - Selective cross-coupling of organic halides with allylic acetates. AB - A general protocol for the coupling of haloarenes with a variety of allylic acetates is presented. Strengths of the method are a tolerance for electrophilic (ketone, aldehyde) and acidic (sulfonamide, trifluoroacetamide) substrates and the ability to couple with a variety of substituted allylic acetates. Secondary alkyl bromides can also be allylated under slightly modified conditions, demonstrating the generality of the approach. Finally, the coupling of a reactive vinyl halide could be achieved by the use of a very hindered ligand and more reactive, branched allylic acetates. PMID- 23095045 TI - The transcription factor AtDOF4.2 regulates shoot branching and seed coat formation in Arabidopsis. AB - Plant-specific DOF (DNA-binding with one finger)-type transcription factors regulate various biological processes. In the present study we characterized a silique-abundant gene AtDOF (Arabidopsis thaliana DOF) 4.2 for its functions in Arabidopsis. AtDOF4.2 is localized in the nuclear region and has transcriptional activation activity in both yeast and plant protoplast assays. The T-M-D motif in AtDOF4.2 is essential for its activation. AtDOF4.2-overexpressing plants exhibit an increased branching phenotype and mutation of the T-M-D motif in AtDOF4.2 significantly reduces branching in transgenic plants. AtDOF4.2 may achieve this function through the up-regulation of three branching-related genes, AtSTM (A. thaliana SHOOT MERISTEMLESS), AtTFL1 (A. thaliana TERMINAL FLOWER1) and AtCYP83B1 (A. thaliana CYTOCHROME P450 83B1). The seeds of an AtDOF4.2-overexpressing plant show a collapse-like morphology in the epidermal cells of the seed coat. The mucilage contents and the concentration and composition of mucilage monosaccharides are significantly changed in the seed coat of transgenic plants. AtDOF4.2 may exert its effects on the seed epidermis through the direct binding and activation of the cell wall loosening-related gene AtEXPA9 (A. thaliana EXPANSIN-A9). The dof4.2 mutant did not exhibit changes in branching or its seed coat; however, the silique length and seed yield were increased. AtDOF4.4, which is a close homologue of AtDOF4.2, also promotes shoot branching and affects silique size and seed yield. Manipulation of these genes should have a practical use in the improvement of agronomic traits in important crops. PMID- 23095047 TI - Velocity vector imaging of longitudinal mechanical properties of upstream and downstream shoulders and fibrous cap tops of human carotid atherosclerotic plaque. AB - AIMS: Atherosclerotic plaque rupture is closely related to high regional mechanical stress in the plaque itself. We aimed to explore the longitudinal mechanical properties of upstream and downstream shoulders and fibrous cap tops of human atherosclerotic plaques in vivo by velocity vector imaging (VVI) combined with acoustic densitometry (AD) imaging. METHODS AND RESULTS: We included 135 patients with carotid atherosclerotic plaque. VVI and AD were used to examine 3 regions of carotid plaque along the longitudinal-axis view. A total of 405 regions were classified with low or high AD values by corrected averages image intensity (AIIc%) < or >=50, respectively. Peak systolic strain, strain rate (SR), and velocity were significantly greater for upstream than downstream shoulders and fibrous cap tops of carotid plaque (P < 0.05 for both). AIIc% was significantly lower for upstream than downstream plaque shoulders (P < 0.05). Peak systolic SR of the plaque regions was negatively correlated with corresponding AIIc% (R(2) = 0.499, P < 0.05). CONCLUSIONS: The longitudinal strain of human carotid atherosclerotic plaques as derived by VVI is associated with its corresponding AD but also in part with the internal position of the strain, with values greater for upstream than downstream shoulders and fibrous cap tops. PMID- 23095048 TI - Neuropsychological profile in adults with neurofibromatosis type 1 compared to a control group. AB - BACKGROUND: Neurofibromatosis type 1 (NF1) is a common inherited autosomal dominant condition, characterised by multiple cafe-au-lait macules, axillary and/or inguinal freckling, iris Lisch nodules and tumours of the nervous system such as neurofibromas and optic pathway gliomas. At the same time, NF1 is frequently associated with intellectual disabilities across several neuropsychological domains. Existing neuropsychological data in NF1 adults are limited and sometimes contradictory. Moreover, most studies use a non-IQ controlled norm group for comparison. This study sought to investigate specific neuropsychological characteristics in intellectual abilities unrelated to the global intellectual capacity. METHOD: Twenty NF1 adults and an IQ-, age- and gender-matched control group completed a comprehensive neuropsychological test battery composed of specific cognitive tests investigating visual-spatial abilities and memory, auditory memory, selective and sustained attention and executive functioning. A short version of the Wechsler Adult Intelligence Scale - III was also administered to both groups. RESULTS: Norm comparison showed that both groups perform poorly on most neuropsychological functions, except for sustained attention. However, comparison with the IQ-matched control group showed significantly lower scores on visual-spatial abilities and memory, on auditory working memory and on tests for cognitive flexibility in NF1 adults. Nevertheless, as the significant difference in average estimated IQ score between the NF1 group and the selected control group almost reaches the 5% significance level, further analysis is needed to include IQ as a covariate. Eventually, problems in visual-spatial skills and auditory long-term memory seem to be specific NF1-related deficits, while problems in attention and executive functioning are particularly related to their general lowered intellectual abilities. CONCLUSION: Taking into account that primary visual perception problems could be part of a more general central coherence deficit while interpreting auditory memory problems as possibly related to deficits in language use and comprehension, this idea also fits with the observation of several problems in social information processing and functioning of NF1 persons. PMID- 23095049 TI - Analysis of HLA-A, -B, -C, -DR, -DQ polymorphisms in the South Tunisian population and a comparison with other populations. AB - BACKGROUND: The Human Leucocyte Antigen (HLA) system is often used as a genetic marker for analysing populations. HLA antigen distribution among the Tunisian population is not well defined because of the lack of a general population study. AIM: The aim of the present study was to investigate the polymorphism of HLA-A, B, -C, -DR and -DQ loci in the South Tunisian population. SUBJECTS AND METHODS: This study has investigated HLA-A, -B, -C, -DR and -DQ polymorphisms in 123 unrelated healthy individuals originating from the south of Tunisia. HLA class I was studied by serology and completed by polymerase chain reaction-sequence specific primer (PCR-SSP). HLA class II was performed using PCR-SSP. RESULTS: The most common alleles were A-2 (0.2154), B-44 (0.1179), C7 (0.2114), DR4 (0.1626) and DQ2 (0.313). A1-B-8-C7-DR3-DQ2 (2.84%) was the predominant haplotype in this population. Comparisons with data of other worldwide populations based on phylogenetic tree and multidimensional scaling analysis were done. This study suggests that both HLA class I and class II polymorphism specificities demonstrate a high diversity in this South Tunisian population, which reflects ancient and recent admixture with neighbouring populations. CONCLUSION: The results provide useful information for further studies of Tunisian population evolution, anthropology and for resolving HLA frequencies when searching for HLA compatible donors in transplantation and for the analysis of disease associations. PMID- 23095050 TI - Lipid rearrangement in DSPC/DMPC bilayers: a neutron reflectometry study. AB - Lipid translocation in membranes is still far from being understood and well characterized for natural cell membranes as well as for simpler bilayer model systems. Several discrepancies with respect to its occurrence and its characteristic time scale are present in the literature. In the current work, the structural changes induced by lipid rearrangement in a distearoyl-/dimyristoyl phosphocholine binary lipid system have been addressed by means of neutron reflectivity. It has been shown that a fast, spontaneous compositional reorganization with lipid transfer between the two leaflets of the bilayer takes place only when the lipid species are both in the fluid phase. This process has been identified as the so-called lipid flip-flop. Moreover, the influence of the preparation protocol on the structural properties of the system has been investigated. PMID- 23095051 TI - Clinical association of intrathecal and mirrored oligoclonal bands in paediatric neurology. AB - AIM: Biomarkers such as autoantibodies, neopterin, and oligoclonal bands (OCBs) are increasingly used for the diagnosis of treatable inflammatory central nervous system (CNS) disorders. We investigated the correlation between the results of OCB testing and clinical diagnoses in a large contemporary cohort of children with a broad range of neurological conditions. METHOD: Cerebrospinal fluid (CSF) and serum from 200 children (94 females, 106 males; age range 2 mo-15 y 10 mo, mean age 6 y 9 mo, SD +/-4.9) who underwent CSF investigation for their neurological condition were tested for OCBs using isoelectric focusing. RESULTS: The patients were divided into those with inflammatory (n=58) and non inflammatory (n=142) CNS disorders. Intrathecal OCBs (OCBs restricted to the CSF) were found in 11 out of 58 (19%) of those with inflammatory CNS disorders compared with none of the 142 patients with non-inflammatory CNS disorders (p<0.001). Diseases associated with intrathecal OCB were multiple sclerosis, Rasmussen encephalitis, N-methyl-d-aspartate receptor (NMDAR) encephalitis, voltage-gated potassium channel (VGKC) encephalopathy, herpes (HSV) encephalitis, 'other' encephalitides, acute cerebellar ataxia, and aseptic meningitis. Mirrored OCBs (identical OCBs in the serum and CSF) were less specific but were still found in 14 out of 58 (24%) children with inflammatory CNS disorders compared with only 6 out of 142 (4%) children with non-inflammatory CNS disorders (p<0.001). Diseases associated with mirrored OCBs included acute disseminated encephalomyelitis (ADEM), VGKC encephalopathy, West syndrome, NMDAR encephalitis, 'other' encephalitides, polio-like illness, Rasmussen encephalitis, cerebral vasculitis, metachromatic leukodystrophy, and bacterial meningitis. Intrathecal OCBs and mirrored OCBs had a positive predictive value for inflammatory CNS disease of 1 (95% confidence interval [CI] 0.68-1) and 0.7 (95% CI 0.46-0.87) respectively. CONCLUSION: Intrathecal OCBs were restricted to patients with inflammatory CNS disorders. They are a useful, but non-specific, biomarker of CNS inflammation of multiple causes. Mirrored OCBs are less specific, but still support a possible inflammatory CNS disorder. The presence of either intrathecal or mirrored OCBs should raise suspicion of an inflammatory CNS disorder. PMID- 23095052 TI - Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report. AB - WHAT IS KNOWN AND OBJECTIVE: Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC. CASE SUMMARY: This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. WHAT IS NEW AND CONCLUSION: CBD can be effective for the treatment of cannabis withdrawal syndrome. PMID- 23095053 TI - The S100A6 calcium-binding protein regulates endothelial cell-cycle progression and senescence. AB - Endothelial cells regulate many aspects of vascular physiology, including vasculogenesis and angiogenesis. The S100 family of calcium-binding proteins regulates many aspects of cell function but their roles in vascular physiology are less well understood. Herein, we investigated the expression and function of S100-related family members in endothelial cells. Analysis of total endothelial mRNAs using a human gene chip array revealed significant gene expression of the S100 calcium-binding protein family members S100A6, S100A10, S100A11 and S100A13. We then examined the expression and functional properties of the major S100 family member, S100A6, in vascular endothelial cells. Comparison of primary and transformed human cells revealed significant differences in S100A6 protein levels in these cells. In primary human endothelial cells, S100A6 was present in both the nucleus and the cytoplasm. To assess the function of endothelial S100A6, we depleted protein levels using RNA interference and this caused increased cell cycle arrest in the G2/M phase under different conditions. S100A6 depletion caused a decrease in both cyclin-dependent kinase 1 (CDK1) and phospho-CDK1 levels, which are essential for eukaryote cell-cycle progression. S100A6 depletion also decreased expression of CDK1, cyclin A1 (CCNA1) and cyclin B (CCNB1) genes with effects on cell-cycle progression. Depletion of endothelial S100A6 levels also elevated beta-galactosidase expression, which is an important hallmark of cellular senescence and exit from the mammalian cell cycle. We thus propose that S100A6 has an important role in regulating endothelial commitment to, and progression through, the cell cycle. PMID- 23095054 TI - Linking epigenetics to lipid metabolism: focus on histone deacetylases. AB - A number of recent studies revealed that epigenetic modifications play a central role in the regulation of lipid and of other metabolic pathways such as cholesterol homeostasis, bile acid synthesis, glucose and energy metabolism. Epigenetics refers to aspects of genome functions regulated in a DNA sequence independent fashion. Chromatin structure is controlled by epigenetic mechanisms through DNA methylation and histone modifications. The main modifications are histone acetylation and deacetylation on specific lysine residues operated by two different classes of enzymes: Histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. The interaction between these enzymes and histones can activate or repress gene transcription: Histone acetylation opens and activates chromatin, while deacetylation of histones and DNA methylation compact chromatin making it transcriptionally silent. The new evidences on the importance of HDACs in the regulation of lipid and other metabolic pathways will open new perspectives in the comprehension of the pathophysiology of metabolic disorders. PMID- 23095055 TI - Jahn-Teller dynamics in a series of high-symmetry Co(II) chelates determine paramagnetic relaxation enhancements. AB - NMR paramagnetic relaxation enhancements (PREs) of a series of structurally characterized, trigonal bis-trispyrazolylborate (Tp) chelates of high-spin Co(II), spanning 100-850 MHz in field, are reported. Prior knowledge of the metal nucleus distances allows numerical extraction of position-dependent electron spin relaxation rates (tau(c)(-1)) from direct measurement of the individual PREs of the four symmetry distinct protons in Co(Tp)(2), using available closed-form expressions. The data for this electronically complex system where spin-orbit coupling defines the ground state electronic structure are analyzed in terms of the Solomon-Bloembergen-Morgan (SBM) relations, as well as available zero-field splitting limit theories. A simple angular correction is shown to be sufficient to reconcile the individual tau(c)(T) data for the four classes of protons. The data identify a previously unrecognized dynamic Jahn-Teller effect in these historically important complexes, with a barrier of ~230 cm(-1), pointing to a level of dynamics in trispyrazolylborate chemistry that has not been described before, and further show that it is the Jahn-Teller that is responsible for the PREs in fluid solution. A field-dependent component is also identified for the two protons nearest g(//), which is suggested to arise due to Zeeman mixing of excited state character into the ground level. PMID- 23095056 TI - Epigenetics and chromatin dynamics: a review and a paradigm for functional disorders. AB - BACKGROUND: Motility and functional gastrointestinal disorders have high prevalence in the community, cause significant morbidity, and represent a major health care burden. Despite major advances in our understanding of the cellular and molecular basis of gastrointestinal neuromuscular functions, many of these diseases still defy mechanistic explanations. The biopsychosocial model underlying the current classification of functional gastrointestinal disorders recognizes and integrates the pathogenetic role of genetic, environmental, and psychosocial factors but has not been associated with specific molecular mechanisms. PURPOSE: Here, we propose that this integrative function is encoded in the chromatin, composed of the DNA and associated histone and non-histone proteins and non-coding RNA. By establishing epigenetically heritable 'molecular memories' of past stimuli including environmental challenges, the chromatin determines an individual's responses to future insults and translates them into high-order outputs such as symptoms and illness behavior. Thus, surveying epigenetic signatures throughout the genome of affected cells in individual patients may make it possible to better understand and ultimately control the phenomena described by the biopsychosocial model. In this review, we provide a high-level but comprehensive description of the concepts and mechanisms underlying epigenetics and chromatin dynamics, describe the mechanisms whereby the environment can alter the epigenome and identify aspects of functional gastrointestinal and motility disorders where epigenetic mechanisms are most likely to play important roles. PMID- 23095058 TI - Efficacy of lasers as an adjunct to chemo-mechanical disinfection of infected root canals: a systematic review. AB - The aim was to evaluate the efficacy of various types of lasers used as an adjunct to chemo-mechanical disinfection of infected root canals with the outcome measures 'normal periapical condition' or 'reduction of microbial load'. PubMed, CENTRAL and ISI Web of Knowledge literature searches with specific indexing terms and a subsequent hand search were made with stated limits and criteria. Relevant publications were retrieved, followed by interpretation. The quality of each included publication was assessed as high, moderate or low. The initial search process yielded 234 publications. All abstracts of these publications were read, and the reference lists of relevant publications were hand-searched. Ten articles were read in full text and interpreted according to a data extraction form. Five were included in the systematic review and were assessed. A meta-analysis was impossible to perform because the included studies were heterogeneous with regard to study design, treatment and outcome measures. Positive effects were reported; however, no concluding evidence grade could be made because each included study was judged to have low quality, primarily due to lack of a power analysis, blinding and reproducibility. The evidence grade for whether lasers can be recommended as an adjunct to chemo-mechanical disinfection of infected root canals was insufficient. This does not necessarily imply that laser should not be used as an adjunct to root canal treatment but instead underscores the need for future high-quality studies. PMID- 23095057 TI - Effect of surfactant hydrophobicity on the pathway for unfolding of ubiquitin. AB - This paper describes the interaction between ubiquitin (UBI) and three sodium n alkyl sulfates (SC(n)S) that have the same charge (Z = -1) but different hydrophobicity (n = 10, 12, or 14). Increasing the hydrophobicity of the n-alkyl sulfate resulted in (i) an increase in the number of distinct intermediates (that is, complexes of UBI and surfactant) that form along the pathway of unfolding, (ii) a decrease in the minimum concentrations of surfactant at which intermediates begin to form (i.e., a more negative DeltaG(binding) of surfactant for UBI), and (iii) an increase in the number of surfactant molecules bound to UBI in each intermediate or complex. These results demonstrate that small changes in the hydrophobicity of a surfactant can significantly alter the binding interactions with a folded or unfolded cytosolic protein. PMID- 23095059 TI - Griseusins F and G, spiro-naphthoquinones from a tin mine tailings-derived alkalophilic Nocardiopsis species. AB - Griseusins F (1) and G (2), two 2a-hydro-8a-(2-oxopropyl)-substituted spiro naphthoquinones with a previously undescribed C23 polyketide skeleton, were isolated from a Yunnan tin mine tailings-derived alkalophilic actinomycete, Nocardiopsis sp. YIM DT266. Their complete structure assignments with the absolute stereochemistry were elucidated by spectroscopic data, X-ray crystal diffraction, calculation of optical rotation, and CD spectroscopic analysis. Compounds 1 and 2 exhibited strong cytotoxicity (IC50 0.37-0.82 MUM) and antibacterial activity (MIC 0.80-1.65 MUg/mL) against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) in vitro. PMID- 23095061 TI - Intramolecular Pd(0)-catalyzed reactions of (2-iodoanilino)-aldehydes: a joint experimental-computational study. AB - An extensive joint experimental-computational density functional theory (DFT) study has been carried out to gain insight into the factors that control the chemoselectivity (i.e., acylation vs alpha-arylation reaction) of palladium catalyzed cyclizations of (2-iodoanilino)-aldehydes. To this end, the nature of the tethers joining the aniline nitrogen and the aldehyde moiety, different palladium precatalysts and reaction conditions (base and temperature), as well as different additives (mono- and bidendate ligands) has been explored. The adequate selection of these variables allows for the control of the selectivity of the process. Thus, (2-iodoanilino)-aldehydes generally lead to the formation of nucleophilic addition derived products when Cs(2)CO(3)/Et(3)N is used as base. In contrast, the use of stronger bases like K(t)OBu (in the presence of PhOH) mainly forms alpha-arylation reaction products. The different reaction pathways leading to the experimentally observed reaction products have been studied by means of computational tools. PMID- 23095062 TI - Mouse models of laminopathies. AB - The A- and B-type lamins are nuclear intermediate filament proteins in eukaryotic cells with a broad range of functions, including the organization of nuclear architecture and interaction with proteins in many cellular functions. Over 180 disease-causing mutations, termed 'laminopathies,' have been mapped throughout LMNA, the gene for A-type lamins in humans. Laminopathies can range from muscular dystrophies, cardiomyopathy, to Hutchinson-Gilford progeria syndrome. A number of mouse lines carrying some of the same mutations as those resulting in human diseases have been established. These LMNA-related mouse models have provided valuable insights into the functions of lamin A biogenesis and the roles of individual A-type lamins during tissue development. This review groups these LMNA related mouse models into three categories: null mutants, point mutants, and progeroid mutants. We compare their phenotypes and discuss their potential implications in laminopathies and aging. PMID- 23095063 TI - Challenges and prospects of lithium-sulfur batteries. AB - Electrical energy storage is one of the most critical needs of 21st century society. Applications that depend on electrical energy storage include portable electronics, electric vehicles, and devices for renewable energy storage from solar and wind. Lithium-ion (Li-ion) batteries have the highest energy density among the rechargeable battery chemistries. As a result, Li-ion batteries have proven successful in the portable electronics market and will play a significant role in large-scale energy storage. Over the past two decades, Li-ion batteries based on insertion cathodes have reached a cathode capacity of ~250 mA h g(-1) and an energy density of ~800 W h kg(-1), which do not meet the requirement of ~500 km between charges for all-electric vehicles. With a goal of increasing energy density, researchers are pursuing alternative cathode materials such as sulfur and O2 that can offer capacities that exceed those of conventional insertion cathodes, such as LiCoO2 and LiMn2O4, by an order of magnitude (>1500 mA h g(-1)). Sulfur, one of the most abundant elements on earth, is an electrochemically active material that can accept up to two electrons per atom at ~2.1 V vs Li/Li(+). As a result, sulfur cathode materials have a high theoretical capacity of 1675 mA h g(-1), and lithium-sulfur (Li-S) batteries have a theoretical energy density of ~2600 W h kg(-1). Unlike conventional insertion cathode materials, sulfur undergoes a series of compositional and structural changes during cycling, which involve soluble polysulfides and insoluble sulfides. As a result, researchers have struggled with the maintenance of a stable electrode structure, full utilization of the active material, and sufficient cycle life with good system efficiency. Although researchers have made significant progress on rechargeable Li-S batteries in the last decade, these cycle life and efficiency problems prevent their use in commercial cells. To overcome these persistent problems, researchers will need new sulfur composite cathodes with favorable properties and performance and new Li-S cell configurations. In this Account, we first focus on the development of novel composite cathode materials including sulfur-carbon and sulfur-polymer composites, describing the design principles, structure and properties, and electrochemical performances of these new materials. We then cover new cell configurations with carbon interlayers and Li/dissolved polysulfide cells, emphasizing the potential of these approaches to advance capacity retention and system efficiency. Finally, we provide a brief survey of efficient electrolytes. The Account summarizes improvements that could bring Li-S technology closer to mass commercialization. PMID- 23095064 TI - Transitions--a method of growth and development. PMID- 23095065 TI - Improving dental visits for individuals with autism spectrum disorders through an understanding of sensory processing. AB - The increasing prevalence of autism spectrum disorder (ASD) suggests that dental practices will be seeing patients with this diagnosis more frequently. Although patients with ASD have similar dental needs to other patients, the symptoms of the disorder may influence the ability of dental practitioners to provide necessary care. Dental professionals may be unaware of the difficulties with sensory processing common to patients with ASD. However, awareness of sensory processing issues and knowledge of strategies to improve the sensory experience for individuals with ASD may improve dental visits for these patients and allow for enhanced dental care provision. PMID- 23095067 TI - Improving residents' oral health through staff education in nursing homes. AB - This study assessed the efficacy of oral care education among nursing home staff members to improve the oral health of residents. Nursing home support staff members (NHSSMs) in the study group received oral care education at baseline between a pretest and posttest. NHSSMs' oral care knowledge was measured using a 20-item knowledge test at baseline, posteducation, and at a 6-month follow-up. Residents' oral health was assessed at baseline and again at a 6-month follow-up using the Modified Plaque Index (PI) and Modified Gingival Index (GI). Among staff members who received the oral care education (n = 32), posttest knowledge statistically significantly increased from the pretest level (p < .05). Thirty nine control residents of the nursing homes and 41 study residents participated. Among residents in the study group, PI decreased at 6 months compared to baseline (p < .05), but there was no statistically significant difference in their GI measurements between baseline and 6-month follow-up (p= .07). PMID- 23095066 TI - Prevalence of oral health problems in U.S. adults, NHANES 1999-2004: exploring differences by age, education, and race/ethnicity. AB - Using the National Health and Nutrition Examination Surveys (NHANES) 1999-2004, the authors examined age patterns in oral health indicators by race/ethnicity and socioeconomic status related to edentulism, presence of root caries, and periodontal disease. Our analysis included subjects who were non-Hispanic White, Mexican American, and African American over the age of 20, and who participated in the NHANES oral health examination. African Americans experienced more oral health problems at younger ages; as age increased, so did racial disparities in oral health problems. Lower educational attainment was strongly associated with more oral health problems at all ages. These results may indicate a faster progression of oral health problems with age among African Americans, thus suggesting that the "earlier aging" of members of racial/ethnic minorities which has been reported in prior research may also be found in oral health. PMID- 23095068 TI - Iowa dentists' involvement in care for patients who are homebound. AB - This study investigated the frequency of Iowa dentists' provision of in-office and out-of-office dental care for people who are homebound, as well as comparing the practice and educational characteristics among dentists who did and did not provide care for patients who were homebound. The authors mailed a survey form to all licensed dentists on the Iowa State Health Professional license database (n = 1,168), excluding pediatric dentists and orthodontists. A second mailing was sent to all nonrespondents four months later, resulting in 638 returned forms for a 54.6% response rate. The questionnaire included two outcome responses associated with the treatment in the dentist's office or in the patient's home for patients who are homebound. About 40% of Iowa dentists reported providing care in the office to patients who are homebound, but care outside of the office was provided by fewer dentists (6%) who had more years of practice experience. These results suggest an increased sense of professional or community responsibility among these older Iowa dentists. Education efforts may increase homebound care and more involvement of younger dentists. PMID- 23095069 TI - The effects of professional oral health care on patients in the subacute stage of emergent neurosurgical disorders. AB - This study evaluated the effectiveness of professional oral health care (POHC) on patients who were in the subacute stage of neurosurgical disorders. Forty subjects (26 male, 14 female) with acute cerebrovascular disorders or neurotrauma were randomly divided into two groups. The intervention group (n = 21) received POHC treatment by dental hygienists, and the control group (n = 19) did not. To evaluate the change in oral health status of the subjects, an oral examination was carried out at baseline and four weeks later. For the subjects in the intervention group, periodontal condition, oral hygiene status, and oral function improved statistically significantly. The detection rate for methicillin resistant Staphylococcus aureus (MRSA) was statistically significantly lower in the intervention group than in the control group. These results suggest that POHC performed by dental hygienists in collaboration with nurses plays an important role in the promotion not only of oral health but also of general health. PMID- 23095070 TI - Interdisciplinary approach to the management of Ewing sarcoma: a case report. AB - Ewing sarcoma is a common primary bone malignancy occurring in childhood and adolescence. This case report describes a 4-year-old female patient who had Ewing sarcoma in the left clavicular region. The patient underwent total excision of the left clavicle and subsequently developed periodontitis and multiple carious lesions after chemotherapy. Caries risk and salivary flow rate tests were performed, followed by periodontal treatment, topical fluoride application, restoration of caries, and oral hygiene instruction. The care of this patient demonstrates that an interdisciplinary approach is essential to eliminate all foci of infection, minimize morbidity, and improve the patient's general health before, during, and after oncological treatment. PMID- 23095071 TI - An innovative approach to cessation of thumb-sucking in a child with epilepsy: a case report. AB - The thumb-sucking habit is acquired in infancy, but if it persists beyond preschool age, it can have deleterious effects on facial growth, oral function, occlusal relationship, and aesthetics, leading to dental and skeletal deformities. This paper presents a clinical case history of using nonpunitive reminder therapy to intercept the thumb-sucking habits of an 8-year-old child with epilepsy. A modified Bluegrass appliance was used along with the positive reinforcement. The modified Bluegrass appliance utilized an acrylic roller and was very comfortable for the patient; it was also successful in eliminating the habit within a short period of time. PMID- 23095073 TI - Three-dimensional quantification of pretorqued nickel-titanium wires in edgewise and prescription brackets. AB - OBJECTIVE: To quantify the three-dimensional moments and forces produced by pretorqued nickel-titanium (NiTi) rectangular archwires fully engaged in 0.018- and 0.022-inch slots of central incisor and molar edgewise and prescription brackets. MATERIALS AND METHODS: Ten identical acrylic dental models with retroclined maxillary incisors were fabricated for bonding with various bracket wire combinations. Edgewise, Roth, and MBT brackets with 0.018- and 0.022-inch slots were bonded in a simulated 2 * 4 clinical scenario. The left central incisor and molar were sectioned and attached to load cells. Correspondingly sized straight and pretorqued NiTi archwires were ligated to the brackets using 0.010-inch ligatures. Each load cell simultaneously measured three force (Fx, Fy, Fz) and three moment (Mx, My, Mz) components. The faciolingual, mesiodistal, and inciso-occluso/apical axes of the teeth corresponded to the x, y, and z axes of the load cells, respectively. Each wire was removed and retested seven times. Three-way analysis of variance (ANOVA) examined the effects of wire type, wire size, and bracket type on the measured orthodontic load systems. Interactions among the three effects were examined and pair-wise comparisons between significant combinations were performed. RESULTS: The force and moment components on each tooth were quantified according to their local coordinate axes. The three way ANOVA interaction terms were significant for all force and moment measurements (P < .05), except for Fy (P > .05). CONCLUSION: The pretorqued wire generates a significantly larger incisor facial crown torquing moment in the MBT prescription compared to Roth, edgewise, and the straight NiTi wire. PMID- 23095075 TI - Inventory of callous-unemotional traits in a community sample of preschoolers. AB - The purpose of this study was to test the factor structure of the Inventory of Callous-Unemotional Traits (ICU; Frick, 2004 ) and to study the relation between the derived dimensions and external variables in a community sample of preschool children. A total of 622 children 3 and 4 years of age were assessed with a semistructured diagnostic interview, the ICU, and other questionnaires on psychopathology, temperament, and executive functioning, completed by parents and teachers. Confirmatory factor analysis derived from teachers' ICU responses yielded three dimensions: Callousness, Uncaring, and Unemotional. Callousness and Uncaring subscale scores correlated with the specific scales related to aggressive behavior, temperament, executive functioning, and conduct problems. The ICU scale scores discriminated cross-sectionally oppositional defiant disorder (ODD) and conduct disorder (CD) diagnoses, aggressive and nonaggressive symptoms of CD, use of services, and ODD/CD-related family burden. Longitudinally, Callousness subscale score at age 3 predicted ODD or CD diagnosis at age 4. Unemotional was not associated with aggressive measures, but it was linked to anxiety disorders cross-sectionally and longitudinally. Callous Unemotional traits contributed significantly to predicting disruptive behavior disorders controlling for sex, temperament, and executive functioning (predictive accuracy between 3 and 5%). The ICU is a promising questionnaire for identifying early Callous and Uncaring traits in preschool years that may help in the identification of a subset of preschool children who might have severe behavioral problems. PMID- 23095074 TI - Concept and health-related properties of nonextractable polyphenols: the missing dietary polyphenols. AB - Most research studies in the field of dietary polyphenols or phenolic compounds use a chemical approach focusing exclusively on polyphenols extracted from plant foods with organic solvents. However, an appreciable part of polyphenols are not extracted with organic solvents and thus are ignored in biological, nutritional, and epidemiological studies. Recent studies have shown that these nonextractable polyphenols (NEPP) are a major part of total dietary polyphenols and that they exhibit a significant biological activity. A physiological approach is proposed on the basis that the bioavailability and health-related properties of polyphenols depend on their solubility in intestinal fluids, which is different from their solubility in organic solvents. This paper tries to clarify the concept of NEPP, distinguishing between chemical and physiological approaches and pointing out the main qualitative and quantitative differences between them. It is stressed that the literature and databases refer to only extractable polyphenols. Greater attention to NEPP may fill the current gap in the field of dietary polyphenols. PMID- 23095076 TI - Single-molecule lactonization of octadecylrhodamine B at a liquid-liquid interface. AB - The total internal reflection laser fluorescence microscope method was used to observe the lateral diffusion of a single octadecylrhodamine B (C(18)RB) molecule at the toluene-water interface. The interfacial diffusion constant of single fluorescent cation C(18)RB(+) was obtained from the maximum residence time in a small observation area with pH <2. For pH >3, the maximum residence time was remarkably shortened, indicating that single fluorescent zwitterion C(18)RB(+/-) rapidly converted to the nonfluorescent lactone at the interface. The lactonization rate was completed within 0.13 ms at the toluene-water interface but slowed to 67 ms at an interface saturated with dimyristoylphosphatidylcholine. PMID- 23095077 TI - Understanding diversity-stability relationships: towards a unified model of portfolio effects. AB - A major ecosystem effect of biodiversity is to stabilise assemblages that perform particular functions. However, diversity-stability relationships (DSRs) are analysed using a variety of different population and community properties, most of which are adopted from theory that makes several restrictive assumptions that are unlikely to be reflected in nature. Here, we construct a simple synthesis and generalisation of previous theory for the DSR. We show that community stability is a product of two quantities: the synchrony of population fluctuations, and an average species-level population stability that is weighted by relative abundance. Weighted average population stability can be decomposed to consider effects of the mean-variance scaling of abundance, changes in mean abundance with diversity and differences in species' mean abundance in monoculture. Our framework makes explicit how unevenness in the abundances of species in real communities influences the DSR, which occurs both through effects on community synchrony, and effects on weighted average population variability. This theory provides a more robust framework for analysing the results of empirical studies of the DSR, and facilitates the integration of findings from real and model communities. PMID- 23095078 TI - The use of Talking Mats to support people with dementia and their carers to make decisions together. AB - Policy guidelines insist that people with dementia should be involved in decisions about key life choices and transitions. However, as dementia affects both cognitive and communication difficulties, it becomes increasingly difficult to do this, and innovative and effective ways to support people with dementia and their carers to interact with each other are needed. This project, funded by Joseph Rowntree Foundation, examined if Talking Mats, a low-tech communication framework, could support family carers and people with dementia to discuss issues around daily living with each other. The fieldwork phase took place from September 2008 to May 2009. Eighteen couples (person with dementia and their family carer) from Scotland and the North of England were involved. The couples were visited in their own homes and asked to discuss together four topics (Personal Care; Getting Around; Housework; Activities) under two different conditions: (i) using the Talking Mats framework and (ii) using their usual communication methods (UCMs). After the interviews, each participant was asked separately to complete a short questionnaire (Involvement Measure), which included five questions to evaluate how involved s/he felt in each type of discussion and a final question to measure satisfaction with the overall discussion. The findings show that both people with dementia and their carers feel more involved in discussions about how they are managing their daily living when using the Talking Mats framework, compared with their UCM. They also feel more satisfied with the outcome of those discussions. The use of Talking Mats could result in increased well-being and positive adjustment to accepting increasing levels of care for people with dementia. In addition, it could improve the relationship between the person with dementia and family carers, if all involved feel that the views of the person with dementia and the family carer have truly been acknowledged. PMID- 23095079 TI - Rehabilitation of the geriatric dialysis patient. AB - Dialysis is offered to patients with end-stage renal disease as a life-sustaining therapy. However, studies have shown that elderly patients experience high rates of functional disability, hospitalization, institutionalization, and mortality on chronic dialysis therapy, and that the initiation of dialysis is in fact associated with an acceleration in functional decline. These findings have sparked debate about the utility of dialysis for elderly renal patients. In this article, it is proposed that geriatric rehabilitation can prevent, reverse or delay the onset of functional disability and associated adverse outcomes in older dialysis patients, and thus should be incorporated routinely into standard geriatric dialysis care. We outline the causes of disability in elderly dialysis patients, and demonstrate the potential impact of rehabilitation using a case scenario. Models of rehabilitation that have been shown to be effective in improving outcomes for elderly renal and nonrenal populations, including inpatient rehabilitation, exercise training, falls prevention, and home-based models, are reviewed. PMID- 23095080 TI - The challenges of everyday technology in the workplace for persons with acquired brain injury. AB - PURPOSE: To explore and describe how persons with an acquired brain injury (ABI) managed the everyday technology (ET) that they needed to use in their workplace and how this use influences their opportunities to work. METHODS: Nine persons with an ABI were interviewed and observed when managing ET in their workplace. The data were analysed qualitatively with a constant comparative method. RESULTS: The main category, "The challenge of managing ET in the workplace", consisted of three categories, all of which reflected different kinds of discrepancies between the participants' ability to manage ET and the demands that ET imposes on them in work: "Struggling with ET to be able to continue to work; "Depending on strategies to cope with ET to continue in a particular profession", and "Managing ET at work but concerned about keeping up with the changes". CONCLUSIONS: The result revealed discrepancies between the abilities of the persons with ABI to manage ET in relation to the demands that technology imposed on them in their work setting. This indicated that professionals need to consider the role of ET when designing interventions supporting a person's return to work after an ABI. PMID- 23095081 TI - Rapid construction of the ABC ring system in the Daphniphyllum alkaloid daphniyunnine C. AB - An efficient and scalable synthesis of the ABC ring system common to the calyciphylline A-type alkaloids has been developed. The tricyclic core of the alkaloids features a bowl-shaped [6-6-5] skeleton with five stereogenic centers including an all-carbon quaternary center. It was constructed rapidly from a readily available carvone derivative through a seven-step sequence involving an aza-Michael addition and Pd-catalyzed enolate alpha-vinylation as key steps. PMID- 23095082 TI - Incidence of and risk factors for symptomatic benign prostatic hyperplasia in kidney transplant recipients: a cohort study. AB - OBJECTIVE: The purpose of this study was to investigate the effect of immunosuppressants on the incidence of and risk factors for symptomatic benign prostatic hyperplasia (BPH) in relative-donor kidney transplant recipients. MATERIAL AND METHODS: A retrospective cohort study was performed to determine the incidence of symptomatic BPH in kidney transplant recipients according to standard diagnostic criteria, the expression levels of keratinocyte growth factor, transforming growth factor-beta (TGF-beta) and serum testosterone, and the CD4/CD8 ratio in T lymphocytes. Results. The incidence of symptomatic BPH (50 59-year-old group, p = 0.010; 60-69-year-old group, p = 0.004; >= 70-year-old group, p = 0.032), testosterone level (50-59-year-old group, p = 0.045; 60-69 year-old group, p = 0.035; >= 70-year-old group, p = 0.041) and the CD4/CD8 ratio (50-59-year-old group, p = 0.013; 60-69-year-old group, p = 0.010; >= 70-year-old group, p = 0.015) of kidney transplant recipients with long-term calcineurin inhibitor (CNI) and prednisone use were all lower than those values in a normal group that had not received transplants. The TGF-beta (p < 0.001) expression level was higher in kidney transplant recipients than in the non-transplant group, and the keratinocyte growth factor expression level was not statistically different between the kidney transplant recipients and the non-transplant group. CONCLUSIONS: Kidney transplant recipients with long-term CNI and prednisone use may have a low incidence of symptomatic BPH, which may be related to TGF-beta and keratinocyte growth factor expression, testosterone levels and lymphocyte infiltration. Further high-quality prospective studies are needed to confirm these conclusions. PMID- 23095083 TI - Comparison of adhesion, invasion, motility, and toxin production of Campylobacter strains and their resistant mutants. AB - The objectives of this study were to compare the in vitro adhesion and invasion of human epithelial cells, motility, and toxin production characteristics of Campylobacter-susceptible strains and their fluoroquinolone- or macrolide resistant mutants. Susceptible strains and resistant mutants demonstrated similar adhesion capacities to epithelial cells. For Campylobacter coli, fluoroquinolone resistant mutants with Thr86Ile or Asp90Asn substitutions showed a higher rate of invasion of Caco-2 cells than their isogenic parental strain. Fluoroquinolone resistance did not impact C. coli motility. Mutants harboring Asp90Asn had greater cytotoxic activity than the parental strain. Macrolide resistance had no impact on the studied characteristics of C. coli. For Campylobacter jejuni, fluoroquinolone-resistant mutants had slightly different invasiveness levels and significantly lower motility than the isogenic parental strain. C. jejuni macrolide-resistant mutants with A2074G substitution in the 23S rRNA gene had a higher invasiveness level than its parental strain, but mutants with A2074C in 23S rRNA and G221A in rplD showed reduced motility and similar invasion levels to the susceptible strains. Neither fluoroquinolone nor macrolide resistance appears to affect C. jejuni cytotoxicity. In conclusion, mutations that are frequently encountered in Campylobacter-resistant strains can enhance the invasiveness in Caco-2 cells. PMID- 23095084 TI - The activity of silver nanoparticles (axonnite) on clinical and environmental strains of Enterococcus spp. AB - AIMS: The spread of bacterial antibiotic resistance among clinical strains is a growing problem nowadays. Resistance in Enterococcus spp. strains has merited special concern of late, as they have become significant nosocomial pathogens. Hence, the use of compounds such as silver nanoparticles (AgNPs), displaying various mechanisms of action, is a growing new approach against virulent, drug resistant infections. Therefore, the activity of AgNPs obtained by a physical method (microexplosion method) was tested against 30 clinical and environmental Enterococcus spp. strains presenting diverse virulence and resistance patterns. RESULTS: The minimal inhibitory concentration for all the species ranged from 0.39 to 3.125 MUg/ml. No statistical differences (p=0.26) were found between resistance to AgNPs and resistance to antibiotics, suggesting high activity of AgNPs even against multidrug-resistant strains. CONCLUSIONS: AgNPs obtained by this method seem to be a promising alternative to chemotherapeutics in the treatment or prevention of enterococcal infections. PMID- 23095085 TI - Emergence of a multidrug-resistant Haemophilus influenzae strain causing chronic pneumonia in a patient with common variable immunodeficiency. AB - We report the emergence of a multidrug-resistant Haemophilus influenzae strain in a patient with common variable immunodeficiency suffering from recurrent bronchopneumonia caused by H. influenzae. After the patient had received several antibiotic therapies, a strain was isolated showing resistance to ampicillin, ampicillin/sulbactam, cefazolin, cefuroxime, ciprofloxacin, and clarithromycin. Polymerase chain reaction analyses and sequencing revealed the presence of the beta-lactamase gene bla(TEM-1), two mutations (A502T and R517H) in the ftsI gene encoding the transpeptidase region of the penicillin-binding protein 3, and one mutation in the ribosomal protein gene L4 (G65D) conferring resistance to beta lactams and macrolides, respectively. Additionally, the plasmid-encoded aac(6') Ib-cr gene mediating slightly reduced susceptibility to quinolones and two mutations in the DNA gyrase gene gyrA and one mutation in the topoisomerase IV gene parC were identified leading to a high-level fluoroquinolone-resistant phenotype. In conclusion, the treatment of H. influenzae infections accompanied by high bacterial loads such as bronchopneumonia can be complicated by the selection of multidrug-resistant strains. Moreover, the emergence of aac(6')-Ib cr in H. influenzae causing low fluoroquinolone resistance levels might have contributed to the selection of DNA gyrase and topoisomerase IV mutants. PMID- 23095086 TI - Structure and function of the PorB porin from disseminating Neisseria gonorrhoeae. AB - The outer membrane of Gram-negative bacteria contains a large number of channel forming proteins, porins, for the uptake of small nutrient molecules. Neisseria gonorrhoeae PorBIA (PorB of serotype A) are associated with disseminating diseases and mediate a rapid bacterial invasion into host cells in a phosphate sensitive manner. To gain insights into this structure-function relationship we analysed PorBIA by X-ray crystallography in the presence of phosphate and ATP. The structure of PorBIA in the complex solved at a resolution of 3.3 A (1 A=0.1 nm) displays a surplus of positive charges inside the channel. ATP ligand-binding in the channel is co-ordinated by the positively charged residues of the channel interior. These residues ligate the aromatic, sugar and pyrophosphate moieties of the ligand. Two phosphate ions were observed in the structure, one of which clamped by two arginine residues (Arg92 and Arg124) localized at the extraplasmic channel exit. A short beta-bulge in beta2-strand together with the long L3 loop narrow the barrel diameter significantly and further support substrate specificity through hydrogen bond interactions. Interestingly the structure also comprised a small peptide as a remnant of a periplasmic protein which physically links porin molecules to the peptidoglycan network. To test the importance of Arg92 on bacterial invasion the residue was mutated. In vivo assays of bacteria carrying a R92S mutation confirmed the importance of this residue for host-cell invasion. Furthermore systematic sequence and structure comparisons of PorBIA from Neisseriaceae indicated Arg92 to be unique in disseminating N. gonorrhoeae thereby possibly distinguishing invasion-promoting porins from other neisserial porins. PMID- 23095088 TI - Production of cytotoxic glidobactins/luminmycins by Photorhabdus asymbiotica in liquid media and live crickets. AB - Photorhabdus asymbiotica engages in a two-part life cycle that requires adaptation to both symbiotic and pathogenic phases. The genome of P. asymbiotica contains several gene clusters, which are predicted to be involved in the biosynthesis of unique secondary metabolites that are hypothesized to enhance the bacterium's pathogenic capabilities. However, recent reports on Photorhabdus secondary metabolite production have indicated that many of its genes are silent under laboratory culture conditions. Using a circumscribed panel of media and alternative fermentation conditions, we have successfully achieved the production of a series of new and known glidobactin/luminmycin derivatives from P. asymbiotica including glidobactin A (1), luminmycin A (2), and luminmycin D (3). These compounds were also obtained upon infection of live crickets with the bacterium. Luminmycin D showed cytotoxicity against human pancreatic cells (IC50 of 0.11 MUM), as well as proteasome inhibition (IC50 of 0.38 MUM). PMID- 23095087 TI - Migraine and psychiatric comorbidities among sub-saharan african adults. AB - BACKGROUND: Despite being a highly prevalent disorder and substantial cause of disability, migraine is understudied in Africa. Moreover, no previous study has investigated the effects of stress and unipolar psychiatric comorbidities on migraine in a sub-Saharan African cohort. OBJECTIVE: To evaluate the prevalence of migraine and its association with stress and unipolar psychiatric comorbidities among a cohort of African adults. METHODS: This was a cross sectional epidemiologic study evaluating 2151 employed adults in sub-Saharan Africa. A standardized questionnaire was used to identify sociodemographic, headache, and lifestyle characteristics of participants. Migraine classification was based on the International Classification of Headache Disorders-2 diagnostic criteria. Depressive, anxiety, and stress symptoms were ascertained with the Patient Health Questionnaire and the Depression Anxiety Stress Scale, respectively. Multivariable logistic regression models were used to estimate adjusted odds ratio (OR) and 95% confidence intervals (CIs). RESULTS: A total of 9.8% (n=212) of study participants fulfilled criteria for migraine (9.8%, 95% CI 8.6-11.1) with a higher frequency among women (14.3%, 95% CI 11.9-16.6) than men (6.9%, 95% CI 5.5-8.3). Similar to predominantly Caucasian migraine cohorts, sub Saharan African migraineurs were more likely to be younger, have a lower education, and more likely to report a poor health status than non-migraineurs. However, in contrast with historical reports in predominantly Caucasian migraine cohorts, sub-Saharan African migraineurs were less likely to report smoking than non-migraineurs. Participants with moderately severe depressive symptoms had over a 3-fold increased odds of migraine (OR=3.36, 95% CI 1.30-8.70) compared with those classified as having minimal or no depressive symptoms, and the odds of migraine increased with increasing severity of depressive symptoms (P trend<0.001). Similarly, those with mild, moderate, and severe anxiety symptoms had increased odds of migraine (OR=2.28, 95% CI 1.24-4.21; OR=1.77, 95% CI 0.93 3.35; and OR=5.39, 95% CI 2.19-13.24, respectively). Finally, those with severe stress had a 3.57-fold increased odds of migraine (OR=3.57, 95% CI 1.35-9.46). CONCLUSION: Although historically it has been reported that migraine prevalence is greater in Caucasians than African Americans, our study demonstrates a high migraine prevalence among urban-dwelling Ethiopian adults (9.9%) that is comparable with what is typically reported in predominantly Caucasian cohorts. Further, among employed sub-Saharan African adults and similar to predominantly Caucasian populations, migraine is strongly associated with stress and unipolar psychiatric symptoms. The high burden of migraine and its association with stress and unipolar psychiatric symptoms in our study of well-educated and urban dwelling African adults has important clinical and public health implications pending confirmation in other African populations. PMID- 23095089 TI - A fluorescent sensor for GABA and synthetic GABA(B) receptor ligands. AB - While gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter, suitable tools to measure its concentration in living cells with high spatiotemporal resolution are missing. Herein, we describe the first ratiometric fluorescent sensor for GABA, dubbed GABA-Snifit, which senses GABA with high specificity and spatiotemporal resolution on the surface of living mammalian cells. GABA-Snifit is a semisynthetic fusion protein containing the GABA(B) receptor, SNAP- and CLIP-tag, a synthetic fluorophore and a fluorescent GABA(B) receptor antagonist. When assembled on cell surfaces, GABA-Snifit displays a GABA dependent fluorescence emission spectrum in the range of 500-700 nm that permits sensing micromolar to millimolar GABA concentrations. The ratiometric change of the sensor on living cells is 1.8. Furthermore, GABA-Snifit can be utilized to quantify the relative binding affinities of GABA(B) receptor agonists, antagonists and the effect of allosteric modulators. These properties make GABA Snifit a valuable tool to investigate the role of GABA and GABA(B) in biological systems. PMID- 23095090 TI - Dihydrogen catalysis: a degradation mechanism for N2-fixation intermediates. AB - Molecular hydrogen plays multiple roles in activation of nitrogen. Among others, it inhibits the overall process of N(2)-reduction catalyzed by nitrogenase enzyme. The H(2)-assisted dehydrogenation and the H-atom transfer reactions (called dihydrogen catalysis, DHC) are suggested as possible mechanisms for the degradation and removal of potential intermediates formed during the reduction of nitrogen. Several iron-organic model reactions associated with the core stereospecific reaction (cis-N(2)H(2) + H(2) -> N(2) + H(2) + H(2)) are examined using a comprehensive density functional theory and ab initio analysis of the corresponding potential energy surfaces. A variety of energetically feasible decomposition pathways are identified for the DHC-oxidation of iron-bound [N(x)H(y)]-species. A liberated diazene intermediate (HN?NH) is suggested to interact in situ with two proximal hydridic H-atoms of an activated (hydrided) Fe catalyst to produce N(2) and H(2) with a low or even no activation barrier. The majority of identified pathways are shown to be highly sensitive to the electronic environment and spin configuration of metallocomplexes. The H(2) assisted transport of a single H-atom from a bound [N(x)H(y)] moiety to either the proximal or distal (Fe, S or N) active centers of a catalyst provides an alternative degradation (interconversion) mechanism for the relevant intermediates. The two types of molecular hydrogen-assisted reactions highlighted above, namely, the H(2)-assisted dehydrogenation and the transport of H-atoms, suggest theoretical interpretations for the observed H(2)-inhibition of N(2) activation and HD formation (in the presence of D(2)). The DHC reactions of various [N(x)H(y)] moieties are expected to play significant roles in the industrial high-pressure hydrodenitrification and other catalytic processes involving the metabolism of molecular hydrogen. PMID- 23095092 TI - Antimicrobial effects of root canal medicaments against Enterococcus faecalis and Streptococcus mutans. AB - AIM: To compare the antimicrobial activities of Activ Point (Roeko, Langenau, Germany), Calcium Hydroxide Plus Point (Roeko, Langenau, Germany), calcium hydroxide, 1% chlorhexidine gel and bioactive glass (S53P4) against Enterococcus faecalis and Streptococcus mutans. METHODOLOGY: One hundred and twenty extracted single-rooted human teeth were used. After removing the crowns, root canals were prepared by using the Protaper rotary system. Following autoclave sterilization, root canals were incubated at 37 degrees C with E. faecalis ATCC 29212 and S. mutans RSHM 676 for 1 week. The specimens, which were divided into five treatment groups for each microorganism according to the intracanal medicament used, were tested in 10 experimental runs. In each experimental run, 10 roots were included as treatment, one root as positive control and one root as sterility control. Sterile paper points were utilized to take samples from root canals after the incubation of teeth in thioglycollate medium at 37 degrees C for 1 week. Samples taken from teeth by sterile paper points were inoculated onto sheep blood agar, and following an overnight incubation, the colonies grown on sheep blood agar were counted and interpreted as colony-forming units. Results were tested statistically by using Kruskal-Wallis and Conover's nonparametric multiple comparison tests. RESULTS: CHX gel (P < 0.001 and P < 0.001), Activ Point (P = 0.003 and P = 0.002) and Ca(OH)2 (P = 0.010 and P = 0.005) were significantly more effective against E. faecalis than that of Ca(OH)2 Plus Point and bioactive glass, respectively. On the other hand, compared with Ca(OH)2 , CHX gel (P < 0.001), and Activ Point (P < 0.001), bioactive glass (P = 0.014) produced significantly lower colony counts of S. mutans. When compared with the positive control, treatment with Ca(OH)2 Plus Point (P = 0.085 and P = 0.066) did not produce significantly lower colony counts of E. faecalis and S. mutans, respectively. CONCLUSIONS: Compared with the medicaments having an antimicrobial effect because of their alkaline pH, the medicaments containing chlorhexidine were effective against both E. faecalis and S. mutans. PMID- 23095093 TI - Primary cardiac lymphoma: echocardiography and F-18-fluorodeoxyglucose positron emission tomography in selection of a biopsy site. AB - A 63-year-old man was referred to our hospital because of a cardiac tumor. Transthoracic echocardiography revealed a rough, mobile tumor in the dilated right atrium, and transesophageal echocardiography showed that the tumor consisted of small, botryoidal masses. Catheter-based biopsy carried a high risk of embolism. Therefore, we used F-18-fluorodeoxyglucose positron emission tomography (FDG-PET), which revealed an abnormal accumulation in the right cervical lymph nodes, as well as in the heart. We safely performed biopsy of the lymph nodes and diagnosed the patient with primary cardiac lymphoma. We concluded that echocardiography and FDG-PET are useful for selecting an appropriate biopsy site in primary cardiac lymphoma. PMID- 23095091 TI - Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1 , 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery is very effective in reducing excess body weight and improving glucose homeostasis in obese subjects. Changes in the pattern of gut hormone secretion are thought to play a major role, but the mechanisms leading to both changed hormone secretion and beneficial effects remain unclear. Specifically, it is not clear whether changes in the number of hormone-secreting enteroendocrine cells, or changes in the releasing stimuli, or both, are important. METHODS: We estimated numbers of enteroendocrine cells after immunohistochemical staining in fixed tissue samples from rats at 10-11 months after RYGB. KEY RESULTS: Numbers of glucagon-like peptide-1 (GLP-1) (L-cells, co expressing peptide YY (PYY)), cholecystokinin (CCK), neurotensin, and 5-HT immunoreactive cells were significantly increased in the Roux and common limbs, but not the biliopancreatic limb in RYGB rats compared with sham-operated, obese rats fed high-fat diet, and chow-fed controls. This increase was mostly accounted for by general hyperplasia of all intestinal wall layers of the nutrient-perfused Roux and common limbs, and less to increased density of expression. The number of ghrelin cells in the bypassed stomach was not different among the three groups. CONCLUSIONS & INFERENCES: The findings suggest that the number of enteroendocrine cells increases passively as the gut adapts, and that the increased total number of L- and I-cells is likely to contribute to the higher circulating levels of GLP 1, PYY, and CCK, potentially leading to suppression of food intake and stimulation of insulin secretion. Whether changes in releasing stimuli also contribute to altered circulating levels will have to be determined in future studies. PMID- 23095094 TI - The effects of cerebral white matter changes on cardiovascular responses to cognitive and physical activity in a stroke population. AB - Autonomic nervous system (ANS) control may be disrupted by cerebrovascular disease. We investigated the relationship between alterations in white matter integrity and regulation of the ANS in 23 participants who sustained a stroke within 5 years. These participants underwent diffusion tensor imaging, and fractional anisotropy values were calculated (DTI-FA) for each hemisphere and lobe. Cognitive and physical exertion tasks were performed while recording an electrocardiogram. Respiratory sinus arrhythmia (RSA) decreased more during a verbal fluency task with lower left hemisphere DTI-FA. Further, the physical stressor yielded decreases in RSA with lower frontal DTI-FA and higher temporal lobe DTI-FA, p < .05 (perhaps a release effect on the central autonomic network). Decrements in ANS regulation may have functional consequences that alter behavior, as well as potentially increasing the risk for further vascular disease. PMID- 23095095 TI - A pilot study exploring quality of life experienced by patients undergoing negative-pressure wound therapy as part of their wound care treatment compared to patients receiving standard wound care. AB - The use of negative pressure wound therapy (NPWT) has been widely documented as a technique to help heal complex wounds. This article presents the findings of a preliminary study which aimed to explore quality of life (QoL) experienced by patients undergoing NPWT as part of their wound care treatment in comparison to that of patients with a wound using traditional (standard) wound care therapies. A quasi-experimental study was undertaken, with patients treated in wound care/vascular clinics with chronic/acute wounds. QoL impact was measured using the Cardiff Wound Impact Schedule and administered post-consent at timed intervals. Our results identified that there were no real differences in QoL scores recorded by patients over the 12-week period. Although there was no overall interaction between the therapies used for wound healing, NPWT did have an effect on social life: during the first 2 weeks of the application of therapy, patients in the NPWT group reported an increase in the social life domain. The authors conclude that true QoL can only be elicited if an accurate baseline is established or if data is collected over a long enough period to allow comparison of scores over time. PMID- 23095096 TI - Primordial oil slick and the formation of hydrophobic tetrapyrrole macrocycles. AB - The functional end products of the extant biosynthesis of tetrapyrrole macrocycles in photosynthetic organisms are hydrophobic: chlorophylls and bacteriochlorophylls. A model for the possible prebiogenesis of hydrophobic analogues of nature's photosynthetic pigments was investigated by reaction of acyclic reactants in five media: aqueous solution (pH 7, 60 degrees C, 24 h); aqueous solution containing 0.1 M decanoic acid (which forms a turbid suspension of vesicles); or aqueous solution accompanied by dodecane, mesitylene, or a five component organic mixture (each of which forms a phase-separated organic layer). The organic mixture was composed of equimolar quantities of decanoic acid, dodecane, mesitylene, naphthalene, and pentyl acetate. The reaction of 1,5 dimethoxy-3-methylpentan-2,4-dione and 1-aminobutan-2-one to give etioporphyrinogens was enhanced in the presence of decanoic acid, affording (following chemical oxidation) etioporphyrins (tetraethyltetramethylporphyrins) in yields of 1.4-10.8% across the concentration range of 3.75-120 mM. The yield of etioporphyrins was greater in the presence of the five-component organic mixture (6.6% at 120 mM) versus that with dodecane or mesitylene (2.1% or 2.9%, respectively). The reaction in aqueous solution with no added oil-slick constituents resulted in phase separation-where the organic reactants themselves form an upper organic layer-and the yield of etioporphyrins was 0.5-2.6%. Analogous reactions leading to uroporphyrins (hydrophilic, eight carboxylic acids) or coproporphyrins (four carboxylic acids) were unaffected by the presence of decanoic acid or dodecane, and all yields were at most ~2% or ~8%, respectively. Taken together, the results indicate a facile means for the formation of highly hydrophobic constituents of potential value for prebiotic photosynthesis. PMID- 23095098 TI - Experimentally determined standard thermodynamic properties of synthetic MgSO(4).4H(2)O (Starkeyite) and MgSO(4).3H(2)O: a revised internally consistent thermodynamic data set for magnesium sulfate hydrates. AB - The enthalpies of formation of synthetic MgSO(4).4H(2)O (starkeyite) and MgSO(4).3H(2)O were obtained by solution calorimetry at T=298.15 K. The resulting enthalpies of formation from the elements are [Formula: see text] (starkeyite)= 2498.7+/-1.1 kJ.mol(-1) and [Formula: see text] (MgSO(4).3H(2)O)=-2210.3+/-1.3 kJ.mol(-1). The standard entropy of starkeyite was derived from low-temperature heat capacity measurements acquired with a physical property measurement system (PPMS) in the temperature range 5 K 25 mmHg, hyperglycaemia and pneumonia predicted a worse outcome. CONCLUSIONS: Deviations from the TBI treatment protocol were frequent. Pneumonia was the most frequent extracranial complication. Age, GCS score, pupil dilation, ISS, high ICP, hyperglycaemia and pneumonia predicted a worse outcome. PMID- 23095139 TI - Definitions of infertility and recurrent pregnancy loss: a committee opinion. AB - This document contains the definitions of infertility and recurrent pregnancy loss as defined by the Practice Committee of the American Society for Reproductive Medicine. It replaces the document titled, "Definitions of Infertility and Recurrent Pregnancy Loss," last published in 2008, Fertil Steril 2008;90(Suppl 3):S60. PMID- 23095140 TI - Criteria for number of embryos to transfer: a committee opinion. AB - Based on American Society for Reproductive Medicine (ASRM) and Society for Assisted Reproductive Technology data available for 2010, ASRM's guidelines for the number of embryos to be transferred in in vitro fertilization cycles have been further refined in continuing efforts to reduce the number of higher-order multiple pregnancies. This version replaces the document titled Guidelines on number of embryos transferred that was published most recently in August of 2009, Fertil Steril 2009;92:1518-9. PMID- 23095141 TI - Testing and interpreting measures of ovarian reserve: a committee opinion. AB - Currently, there is no uniformly accepted definition of decreased ovarian reserve (DOR), as the term may refer to three related but distinctly different outcomes: oocyte quality, oocyte quantity, or reproductive potential. Available evidence concerning the performance of ovarian reserve tests is limited by small sample sizes, heterogeneity among study design, analyses and outcomes, and the lack of validated outcome measures. PMID- 23095143 TI - Prostatic sarcoma after conservative treatment with brachytherapy for low-risk prostate cancer. PMID- 23095142 TI - Recommendations for gamete and embryo donation: a committee opinion. AB - This document provides the latest recommendations for evaluation of potential sperm, oocyte, and embryo donors, incorporating recent information about optimal screening and testing for sexually transmitted infections, genetic diseases, and psychological assessments. This revised document incorporates recent information from the U.S. Centers for Disease Control and Prevention, the US Food and Drug Administration, and the American Association of Tissue Banks, with which all programs offering gamete and embryo donation services must be thoroughly familiar, and replaces the document titled, "2008 Guidelines for Gamete and Embryo Donation: A Practice Committee Report," last published in Fertil Steril 2008;90:S30-44. PMID- 23095144 TI - Chest wall reconstruction with acellular dermal matrix (Strattice(TM)) and a TRAM flap. PMID- 23095147 TI - Bulk, surface, and gas-phase limited water transport in aerosol. AB - The influence of solute species on mass transfer to and from aqueous aerosol droplets is investigated using an electrodynamic balance coupled with light scattering techniques. In particular, we explore the limitations imposed on water evaporation by slow bulk phase diffusion and by the formation of surface organic films. Measurements of evaporation from ionic salt solutions, specifically sodium chloride and ammonium sulfate, are compared with predictions from an analytical model framework, highlighting the uncertainties associated with quantifying gas diffusional transport. The influence of low solubility organic acids on mass transfer is reported and compared to both model predictions and previous work. The limiting value of the evaporation coefficient that can be resolved by this approach, when uncertainties in key thermophysical quantities are accounted for, is estimated. The limitation of slow bulk phase diffusion on the evaporation rate is investigated for gel and glass states formed during the evaporation of magnesium sulfate and sucrose droplets, respectively. Finally, the effect of surfactants on evaporation has been probed, with soluble surfactants (such as sodium dodecyl sulfate) leading to little or no retardation of evaporation through slowing of surface layer kinetics. PMID- 23095145 TI - Terminal vs bridging hydrides of diiron dithiolates: protonation of Fe2(dithiolate)(CO)2(PMe3)4. AB - This investigation examines the protonation of diiron dithiolates, exploiting the new family of exceptionally electron-rich complexes Fe(2)(xdt)(CO)(2)(PMe(3))(4), where xdt is edt (ethanedithiolate, 1), pdt (propanedithiolate, 2), and adt (2 aza-1,3-propanedithiolate, 3), prepared by the photochemical substitution of the corresponding hexacarbonyls. Compounds 1-3 oxidize near -950 mV vs Fc(+/0). Crystallographic analyses confirm that 1 and 2 adopt C(2)-symmetric structures (Fe-Fe = 2.616 and 2.625 A, respectively). Low-temperature protonation of 1 afforded exclusively [MU-H1](+), establishing the non-intermediacy of the terminal hydride ([t-H1](+)). At higher temperatures, protonation afforded mainly [t-H1](+). The temperature dependence of the ratio [t-H1](+)/[MU-H1](+) indicates that the barriers for the two protonation pathways differ by ~4 kcal/mol. Low temperature (31)P{(1)H} NMR measurements indicate that the protonation of 2 proceeds by an intermediate, proposed to be the S-protonated dithiolate [Fe(2)(Hpdt)(CO)(2)(PMe(3))(4)](+) ([S-H2](+)). This intermediate converts to [t H2](+) and [MU-H2](+) by first-order and second-order processes, respectively. DFT calculations support transient protonation at sulfur and the proposal that the S-protonated species (e.g., [S-H2](+)) rearranges to the terminal hydride intramolecularly via a low-energy pathway. Protonation of 3 affords exclusively terminal hydrides, regardless of the acid or conditions, to give [t-H3](+), which isomerizes to [t-H3'](+), wherein all PMe(3) ligands are basal. PMID- 23095146 TI - Make a lasting impression: the neural consequences of re-encountering people who emote inappropriately. AB - We can learn about the affective content of the environment by observing the behavior of others; their responses to stimuli tend to be appropriate to the context. To investigate the impact of observing such appropriate, compared with inappropriate, behaviors, we developed a novel behavioral task where participants observed different faces reacting to emotional scenes. We found that affective categorization of a scene was facilitated when it was presented alongside an appropriate facial expression (Experiment 1). Further, we observed that several brain areas in the right hemisphere-the putamen, insula, orbitofrontal cortex, and dorsal anterior cingulate cortex-were more activate when viewing faces that were previously observed emoting inappropriately (Experiment 2). We contend that these areas form a network that codes for the retrieval of affective conflict information generated by observing individuals producing inappropriate emotions. PMID- 23095148 TI - Diabetic foot wounds in haemodialysis patients: 2-year outcome after percutaneous transluminal angioplasty and minor amputation. AB - Critical limb ischaemia (CLI) is known to be associated with high mortality. In some patients, surgery cannot be performed due to high risk of perioperative death and complications. In other cases, there is only pain at rest but no wound. Therefore, it is difficult to accurately predict the prognosis of individual patients. We examined the prognosis of CLI cases in which therapeutic footwear was made for ambulation after wounds healed. The subjects were 31 haemodialysis patients with diabetic foot wounds, which were treated with percutaneous transluminal angioplasty and minor amputation. The subjects were 22 men and 9 women. Female patients were significantly older than male patients (P = 0.046). Two-year postoperative outcomes were survival in 19 patients and death in 12 patients. Eight of twelve deceased patients had a history of coronary intervention. There were 8 deaths among 13 patients with such history, indicating a marginally significant increase in the mortality rate (P = 0.060). Re amputation was performed in 6 of 19 patients who survived. Two years postoperatively, 41.9% of patients overall survived without re-amputation. It is important to increase the number of cases for further study to improve the well being of CLI patients and to examine medical economics. PMID- 23095149 TI - Current research issues in occupational and environmental exposure in Portugal and Europe. PMID- 23095150 TI - On the assessment of exposure to airborne ultrafine particles in urban environments. AB - The aim of this study was to contribute to the assessment of exposure levels of ultrafine particles in the urban environment of Lisbon, Portugal, due to automobile traffic, by monitoring lung deposited alveolar surface area (resulting from exposure to ultrafine particles) in a major avenue leading to the town center during late spring, as well as in indoor buildings facing it. Data revealed differentiated patterns for week days and weekends, consistent with PM(2.5) and PM10 patterns currently monitored by air quality stations in Lisbon. The observed ultrafine particulate levels may be directly correlated with fluxes in automobile traffic. During a typical week, amounts of ultrafine particles per alveolar deposited surface area varied between 35 and 89.2 MUm2/cm3, which are comparable with levels reported for other towns in Germany and the United States. The measured values allowed for determination of the number of ultrafine particles per cubic centimeter, which are comparable to levels reported for Madrid and Brisbane. In what concerns outdoor/indoor levels, we observed higher levels (32 to 63%) outdoors, which is somewhat lower than levels observed in houses in Ontario. PMID- 23095151 TI - Occupational exposure to aflatoxin (AFB1) in poultry production. AB - Aflatoxin B1 (AFB1) has been recognized to produce cancer in human liver. In addition, epidemiological and laboratory studies demonstrated that the respiratory system was a target for AFB1. Exposure occurs predominantly through the food chain, but inhalation represents an additional route of exposure. The present study aimed to examine AFB1 exposure among poultry workers in Portugal. Blood samples were collected from a total of 31 poultry workers from six poultry farms. In addition, a control group (n = 30) was included comprised of workers who undertook administrative tasks. Measurement of AFB1 in serum was performed by enzyme-linked immunosorbent assay (ELISA). For examining fungi contamination, air samples were collected through an impaction method. Air sampling was obtained in pavilion interior and outside the premises, since this was the place regarded as the reference location. Using molecular methods, toxicogenic strains (aflatoxin producing) were investigated within the group of species belonging to Aspergillus flavus complex. Eighteen poultry workers (59%) had detectable levels of AFB1 with values ranging from <1 ng/ml to 4.23 ng/ml and with a mean value of 2 +/- 0.98 ng/ml. AFB1 was not detected in the serum sampled from any of the controls. Aspergillus flavus was the fungal species third most frequently found in the indoor air samples analyzed (7.2%) and was the most frequently isolated species in air samples containing only Aspergillus genus (74.5%). The presence of aflatoxigenic strains was only confirmed in outdoor air samples from one of the units, indicating the presence of a source inside the building in at least one case. Data indicate that AFB1 inhalation represents an additional risk in this occupational setting that needs to be recognized, assessed, and prevented. PMID- 23095152 TI - Fungal contamination of poultry litter: a public health problem. AB - Although numerous studies have been conducted on microbial contaminants associated with various stages related to poultry and meat products processing, only a few reported on fungal contamination of poultry litter. The goals of this study were to (1) characterize litter fungal contamination and (2) report the incidence of keratinophilic and toxigenic fungi presence. Seven fresh and 14 aged litter samples were collected from 7 poultry farms. In addition, 27 air samples of 25 litters were also collected through impaction method, and after laboratory processing and incubation of collected samples, quantitative colony-forming units (CFU/m3) and qualitative results were obtained. Twelve different fungal species were detected in fresh litter and Penicillium was the most frequent genus found (59.9%), followed by Alternaria (17.8%), Cladosporium (7.1%), and Aspergillus (5.7%). With respect to aged litter, 19 different fungal species were detected, with Penicillium sp. the most frequently isolated (42.3%), followed by Scopulariopsis sp. (38.3%), Trichosporon sp. (8.8%), and Aspergillus sp. (5.5%). A significant positive correlation was found between litter fungal contamination (CFU/g) and air fungal contamination (CFU/m3). Litter fungal quantification and species identification have important implications in the evaluation of potential adverse health risks to exposed workers and animals. Spreading of poultry litter in agricultural fields is a potential public health concern, since keratinophilic (Scopulariopsis and Fusarium genus) as well as toxigenic fungi (Aspergillus, Fusarium, and Penicillium genus) were isolated. PMID- 23095153 TI - Occurrence of Cryptosporidium in a wastewater treatment plant in North Germany. AB - Cryptosporidium parvum is one of the most common human parasitic protozoa and is responsible for many waterborne outbreaks in several industrialized countries. The oocyst, which is the infective form, is known to be highly resistant to wastewater treatment procedures and represents a potential hazard to human populations through contaminated raw or treated wastewater. In this investigation, the occurrence of Cryptosporidium in wastewater samples was monitored and removal efficiency was assessed. Treated (effluent) and untreated (influent) wastewater samples were collected seasonally over a period of 2 years. Oocysts were repeatedly detected in influent and effluent samples collected from the treatment plant during all sampling seasons, with a mean concentration of 782 oocysts/L. The seasonal distribution showed that oocysts are predominant during autumn and winter. Molecular analyses via the small (18S) subunit of rRNA amplification and subsequent sequencing with an objective of characterizing the oocysts revealed that Cryptosporidium parvum was the dominant Cryptosporidium parasite present in wastewater. PMID- 23095154 TI - Indoor air quality in Portuguese archives: a snapshot on exposure levels. AB - Indoor air quality recently entered legislation in Portugal. Several parameters must be evaluated and kept within limits in order to obtain a certification for air quality and energy consumption. Certification parameters were analyzed in two Portuguese archives in order to assess indoor air quality both for people attending or working on these premises and for maintenance of a written heritage that must be retained for future generations. Carbon monoxide (CO) and carbon dioxide (CO2), formaldehyde, and fungal counts were kept within stipulated limits. Relative humidity (RH), volatile organic compounds (VOC), particulate matter (PM10), and ozone (O3) showed values above legislated levels and justified the implementation of corrective measures. In terms of conservation, studies on the limit values are still needed, but according to the available international guidelines, some of the analyzed parameters such as PM10, O3, and RH were also above desirable values. Corrective measures were proposed to these institutions. Although this study was only of a short duration, it proved valuable in assessing potential eventual problems and constitutes the first Portuguese indoor air quality assessment taking into consideration both aspects of an archive such as human health and heritage safekeeping. PMID- 23095155 TI - Could houseplants improve indoor air quality in schools? AB - Previous studies performed by the National Aeronautics Space Administration (NASA) indicated that plants and associated soil microorganisms may be used to reduce indoor pollutant levels. This study investigated the ability of plants to improve indoor air quality in schools. A 9-wk intensive monitoring campaign of indoor and outdoor air pollution was carried out in 2011 in a primary school of Aveiro, Portugal. Measurements included temperature, carbon dioxide (CO2), carbon monoxide (CO), concentrations of volatile organic compounds (VOC), carbonyls, and particulate matter (PM10) without and with plants in a classroom. PM10 samples were analyzed for the water-soluble inorganic ions, as well for carbonaceous fractions. After 6 potted plants were hung from the ceiling, the mean CO2 concentration decreased from 2004 to 1121 ppm. The total VOC average concentrations in the indoor air during periods of occupancy without and with the presence of potted plants were, respectively, 933 and 249 MUg/m3. The daily PM10 levels in the classroom during the occupancy periods were always higher than those outdoors. The presence of potted plants likely favored a decrease of approximately 30% in PM10 concentrations. Our findings corroborate the results of NASA studies suggesting that plants might improve indoor air and make interior breathing spaces healthier. PMID- 23095156 TI - Occupational exposure to Aspergillus by swine and poultry farm workers in Portugal. AB - Aspergillus is among a growing list of allergens that aggravate asthmatic responses. Significant pulmonary pathology is associated with Aspergillus-induced allergic and asthmatic lung disease. Environments with high levels of exposure to fungi are found in animal production facilities such as for swine and poultry, and farmers working with these are at increased risk for occupational respiratory diseases. Seven Portuguese poultry and seven swine farms were analyzed in order to estimate the prevalence, amount, and distribution of Aspergillus species, as well as to determine the presence of clinical symptoms associated with asthma and other allergy diseases in these highly contaminated settings. From the collected fungal isolates (699), an average incidence of 22% Aspergillus was detected in poultry farms, while the prevalence at swine farms was 14%. The most frequently isolated Aspergillus species were A. versicolor, A. flavus, and A. fumigatus. In poultry farms, A. flavus presented the highest level of airborne spores (>2000 CFU/m3), whereas in swine farms the highest was A. versicolor, with an incidence fourfold greater higher than the other mentioned species. Eighty workers in these settings were analyzed, ranging in age from 17 to 93 yr. The potentially hazardous exposure of poultry workers to mold allergens using sensitization markers was evaluated. Although no significant positive association was found between fungal contamination and sensitization to fungal antigens, a high incidence of respiratory symptoms in professionals without asthma was observed, namely, wheezing associated with dyspnea (23.8%) and dyspnea after strenuous activities (12.3%), suggesting underdiagnosed respiratory disturbances. Further, 32.5% of all exposed workers noted an improvement of respiratory ability during resting and holidays. From all the analyzed workers, seven were previously diagnosed with asthma and four reported the first attack after the age of 40 yr, which may be associated with their occupational exposure. Some of the fungi, namely, the Aspergillus species detected in this study, are known to induce hypersensitivity reactions in humans. This study confirmed the presence and distribution of Aspergillus in Portuguese poultry and swine farms, suggesting a possible occupational health problem and raising the need for preventive and protective measures to apply to avoid exposure in both occupational settings. PMID- 23095157 TI - Integration of biomonitoring and instrumental techniques to assess the air quality in an industrial area located in the coastal of central Asturias, Spain. AB - Throughout the world, epidemiological studies were established to examine the relationship between air pollution and mortality rates and adverse respiratory health effects. However, despite the years of discussion the correlation between adverse health effects and atmospheric pollution remains controversial, partly because these studies are frequently restricted to small and well-monitored areas. Monitoring air pollution is complex due to the large spatial and temporal variations of pollution phenomena, the high costs of recording instruments, and the low sampling density of a purely instrumental approach. Therefore, together with the traditional instrumental monitoring, bioindication techniques allow for the mapping of pollution effects over wide areas with a high sampling density. In this study, instrumental and biomonitoring techniques were integrated to support an epidemiological study that will be developed in an industrial area located in Gijon in the coastal of central Asturias, Spain. Three main objectives were proposed to (i) analyze temporal patterns of PM10 concentrations in order to apportion emissions sources, (ii) investigate spatial patterns of lichen conductivity to identify the impact of the studied industrial area in air quality, and (iii) establish relationships amongst lichen conductivity with some site-specific characteristics. Samples of the epiphytic lichen Parmelia sulcata were transplanted in a grid of 18 by 20 km with an industrial area in the center. Lichens were exposed for a 5-mo period starting in April 2010. After exposure, lichen samples were soaked in 18-MOmega water aimed at determination of water electrical conductivity and, consequently, lichen vitality and cell damage. A marked decreasing gradient of lichens conductivity relative to distance from the emitting sources was observed. Transplants from a sampling site proximal to the industrial area reached values 10-fold higher than levels far from it. This finding showed that lichens reacted physiologically in the polluted industrial area as evidenced by increased conductivity correlated to contamination level. The integration of temporal PM10 measurements and analysis of wind direction corroborated the importance of this industrialized region for air quality measurements and identified the relevance of traffic for the urban area. PMID- 23095158 TI - Incidence of aflatoxin M1 in human and animal milk in Jordan. AB - This study was undertaken to determine the presence of aflatoxin M1 (AFM1) in animal milk. In addition, exposure of infants to aflatoxin M1 (AFM1) and lactating mothers to aflatoxin B1 (AFB1) was examined using AFM1 in breast milk as a biomarker for exposure to AFB1. In total, 100 samples of fresh animal milk and fermented milk (buttermilk) and 80 samples of human breast milk were collected during the period 2011-2012. An enzyme-linked immunosorbent assay (ELISA) was used for the analysis of milk samples. AFM1 was detected in all animal fresh and fermented milk samples. The concentrations of AFM1 in 70 samples of fresh and fermented milk were higher than the maximum tolerance limit accepted by the European Union and the United States of 50 ng/kg. In human milk samples the average concentration of AFM1 was higher than the maximum tolerance limit accepted by the European Union and the United States of 25 ng/kg. Logistic regression analysis failed to show a correlation between AFM1 and type and amount of dairy consumption, vegetables, fruits, and meat. However, an association between AFM1 and cereal consumption was detected. This study is the first to report on the occurrence of AFM1 in milk consumed by the Jordanian population. PMID- 23095159 TI - Fungal and microbial volatile organic compounds exposure assessment in a waste sorting plant. AB - In the management of solid waste, pollutants over a wide range are released with different routes of exposure for workers. The potential for synergism among the pollutants raises concerns about potential adverse health effects, and there are still many uncertainties involved in exposure assessment. In this study, conventional (culture-based) and molecular real-time polymerase chain reaction (RTPCR) methodologies were used to assess fungal air contamination in a waste sorting plant which focused on the presence of three potential pathogenic/toxigenic fungal species: Aspergillus flavus, A. fumigatus, and Stachybotrys chartarum. In addition, microbial volatile organic compounds (MVOC) were measured by photoionization detection. For all analysis, samplings were performed at five different workstations inside the facilities and also outdoors as a reference. Penicillium sp. were the most common species found at all plant locations. Pathogenic/toxigenic species (A. fumigatus and S. chartarum) were detected at two different workstations by RTPCR but not by culture-based techniques. MVOC concentration indoors ranged between 0 and 8.9 ppm (average 5.3 +/- 3.16 ppm). Our results illustrated the advantage of combining both conventional and molecular methodologies in fungal exposure assessment. Together with MVOC analyses in indoor air, data obtained allow for a more precise evaluation of potential health risks associated with bioaerosol exposure. Consequently, with this knowledge, strategies may be developed for effective protection of the workers. PMID- 23095160 TI - Cobalt-induced changes in the spleen of mice from different stages of development. AB - Cobalt(II) accumulates in organs such as spleen, kidneys, heart, and liver. The aim of the present study was to investigate the effects of cobalt ethylenediamine tetraacetic acid (Co-EDTA) on spleen of developing mice. Pregnant BALB/c mice in late gestation were subjected to Co-EDTA treatment at daily doses of 75 or 125 mg/kg in drinking water, which continued until d 90 of the newborn pups. The newborn pups were sacrificed on d 18, 25, 30, 45, 60, and 90, which correspond to different stages of development. Spleens were excised, weighed, and processed for histological analysis. Spleen index (SI) was calculated as a ratio of spleen weight to body weight. Cobalt(II) bioaccumulation in spleen was determined using flame atomic absorption spectrometry (FAAS). Preliminary results showed that chronic treatment of mice with low- or high-dose Co-EDTA disturbed extramedullary hematopoiesis in the spleen. The number of megakaryocytes was reduced compared to controls. SI was also reduced in d 18 mice treated with low- or high-dose Co EDTA. However, exposure to 75 mg/kg led to an increase of SI in all other experimental groups. FAAS analysis revealed significant cobalt(II) accumulation in spleen of treated mice. The Co(II) levels in spleens of d 18 mice were highest compared to other experimental groups, indicating that at this period mice are more sensitive to treatment. Exposure to cobalt-EDTA resulted in accumulation of Co(II) in spleen, altered SI, and hematopoiesis. Immature mice appear to be more sensitive to chronic treatment than adults. PMID- 23095161 TI - Levels and indoor-outdoor relationships of size-specific particulate matter in naturally ventilated Portuguese schools. AB - Indoor exposure to particulate matter (PM) has received great interest due to the epidemiological evidence of its health impact, particularly in susceptible populations such as children. The present study investigated indoor concentrations of three PM size fractions in 11 naturally ventilated schools with static heating systems, and the relationship between indoor and outdoor PM concentrations. The study was performed in Porto, Portugal, during winter and included school buildings and individual classrooms with walk-through surveys, as well as indoor and outdoor air monitoring. Mean 12-h indoor daytime concentrations PM10, PM(2.5), and PM1 were 140, 95, and 91 MUg/m3, respectively. During the day, PM(2.5) and PM1 concentrations were lower indoors than outdoors (indoor/outdoor ratios of 0.83 and 0.8, respectively), whereas PM10 showed the opposite trend. Concentrations decreased significantly during the night, 49% for PM10 and 27% for PM(2.5) and PM1. These findings reflect the significant contribution from the activities of occupants inside classrooms to higher indoor levels of PM10 levels, whereas the fine fraction of PM(2.5) and PM1 is primarily influenced by outdoor concentrations. This study provides a link between size specific PM in Portuguese schools with contribution of outdoor versus indoor air. Our results suggest that exposure to PM is high and highlights the need for strategies that provide healthier school environments. PMID- 23095162 TI - Environmental risk assessment of arsenic and fluoride in the Chaco Province, Argentina: research advances. AB - The arsenic (As) and fluoride (F-) concentration in groundwater and potential adverse human health risk was investigated in the Central-West Region of the Chaco Province, northern Argentina. The mean concentration of As in shallow groundwater was 95 MUg/L, where 76% of samples exceeded the World Health Organization (WHO) guideline value of 10 MUg/L, while in deep groundwater it was 90 MUg/L, where 63% samples exceeded 10 MUg/L. For As health risk assessment, the average daily dose, hazard quotient (HQ), and cancer risk were calculated. The values of HQ were found to be >1 in 77% of samples. This level of contamination is considered to constitute a high chronic risk compared with U.S. Environmental Protection Agency (EPA) guidelines. Further, a significant portion of the population has lifetime carcinogenic risk >10-4 and may suffer from cancer. A positive correlation was observed between As and F- in groundwater. The Codigo Alimentario Argentino (CAA) suggested a limit of F- in drinking water as low as 0.8 mg/L under tropical environmental conditions; however, in shallow (39%) and deep groundwater (32%), samples exceeded these values. Exposure to F- was calculated and compared with the adequate intake of minimal safe level exposure dose of 0.05 mg/kg/d and it was noted that 42% of population may be at high risk of fluorosis. Chronic exposure to high As and F- levels in this population represents a concern due to possible adverse health effects attributed to these elements. PMID- 23095163 TI - Laryngeal rhabdomyoma in a dog. AB - A 3-year-old, female spayed Australian Shepherd dog was presented to Veterinary Healthcare Associates in Winter Haven, FL with a history of respiratory stridor, difficulty swallowing, and a change in bark for approximately 3 months. Radiographs revealed a soft tissue mass caudal to the epiglottis. Oral and computerized tomographic (CT) examinations were performed under general anesthesia and revealed a small firm mass in the caudal larynx on the right side. Cytologic evaluation of a fine-needle aspirate of the mass revealed cells consistent with a rhabdomyoma, oncocytoma, or granular cell tumor. Histopathologic interpretation was rhabdomyoma or oncocytoma. Histochemical staining with periodic acid-Schiff was mostly negative with a low number of weakly positive cells and with phosphotungstic acid-hematoxylin was strongly positive with visible cross striations. Tumor cells did not express pancytokeratin AE1/AE3, were strongly immunoreactive for myoglobin and muscle specific actin, and did not express vimentin except for a low number of weakly immunoreactive cells. These findings confirmed a diagnosis of rhabdomyoma. Primary neoplasia of the larynx is rare, and widely varying types of neoplasms have been documented in this location. Due to the cytologic and histologic similarities between rhabdomyoma, oncocytoma, and granular cell tumor, these neoplasms should be differentiated using histochemical staining and immunohistochemical analysis. PMID- 23095164 TI - Immunological detection of enzymes for sulfate reduction in anaerobic methane oxidizing consortia. AB - Anaerobic oxidation of methane (AOM) coupled to sulfate reduction (SR) at marine gas seeps is performed by archaeal-bacterial consortia that have so far not been cultivated in axenic binary or pure cultures. Knowledge about possible biochemical reactions in AOM consortia is based on metagenomic retrieval of genes related to those in archaeal methanogenesis and bacterial sulfate reduction, and identification of a few catabolic enzymes in protein extracts. Whereas the possible enzyme for methane activation (a variant of methyl-coenzyme M reductase, Mcr) was shown to be harboured by the archaea, enzymes for sulfate activation and reduction have not been localized so far. We adopted a novel approach of fluorescent immunolabelling on semi-thin (0.3-0.5 MUm) cryosections to localize two enzymes of the SR pathway, adenylyl : sulfate transferase (Sat; ATP sulfurylase) and dissimilatory sulfite reductase (Dsr) in microbial consortia from Black Sea methane seeps. Both Sat and Dsr were exclusively found in an abundant microbial morphotype (c. 50% of all cells), which was tentatively identified as Desulfosarcina/Desulfococcus-related bacteria. These results show that ANME-2 archaea in the Black Sea AOM consortia did not express bacterial enzymes of the canonical sulfate reduction pathway and thus, in contrast to previous suggestions, most likely cannot perform canonical sulfate reduction. Moreover, our results show that fluorescent immunolabelling on semi-thin cryosections which to our knowledge has been so far only applied on cell tissues, is a powerful tool for intracellular protein detection in natural microbial associations. PMID- 23095165 TI - Cohort profile: The Isle of Man Birth Cohort Study. AB - The Isle of Man is a self-governing British Crown Dependency situated equidistantly from England, Scotland and Ireland. In 1991, its population of ~75,000 comprised ~50% indigenous Manx and 50% immigrants, mainly from the surrounding countries. It was invited to join the European Longitudinal Study of Pregnancy and Childhood. The aim of the study was to enrol all pregnant women resident on the Island with an expected date of delivery in the 18-month period of January 1991-June 1992. A total of 1314 livebirths formed the eligible cohort. Questionnaires were completed by mothers and their partners during pregnancy and subsequently at 6 weeks, 6 months, 18 months, 3, 5, 7 and 15/16 years. Hands-on examination of the children occurred at age 7 years, when biological samples were collected. Teachers completed questionnaires at 7 and 15 years; medical records were extracted for the obstetric and childhood periods. Response rates varied from >80% from teachers and children at 15 years to only 23% from partners when their children were aged 7 years. Selected data sets are available to collaborators, although many of the data need funds for further collaboration. PMID- 23095166 TI - An unusual case of left atrial myxoma and papillary fibroelastoma. PMID- 23095168 TI - Negative symptoms: another differential. AB - OBJECTIVE: The aim of this article is to describe a complex case of apparent flat affect in a particular workplace. CONCLUSION: Mafia operatives display apparent flat affect during working hours. PMID- 23095169 TI - Abstracts of the 2012 Sino-American Symposium on Clinical and Translational Medicine (SAS-CTM). Shanghai, China. June 27-29, 2012. PMID- 23095167 TI - Kainate receptor signaling in pain pathways. AB - Receptors and channels that underlie nociceptive signaling constitute potential sites of intervention for treatment of chronic pain states. The kainate receptor family of glutamate-gated ion channels represents one such candidate set of molecules. They have a prominent role in modulation of excitatory signaling between sensory and spinal cord neurons. Kainate receptors are also expressed throughout central pain neuraxis, where their functional contributions to neural integration are less clearly defined. Pharmacological inhibition or genetic ablation of kainate receptor activity reduces pain behaviors in a number of animal models of chronic pain, and small clinical trials have been conducted using several orthosteric antagonists. This review will cover kainate receptor function and participation in pain signaling as well as the pharmacological studies supporting further consideration as potential targets for therapeutic development. PMID- 23095172 TI - Supratentorial primitive neuroectodermal tumor in an adult: a case report and review of the literature. AB - INTRODUCTION: Supratentorial primitive neuroectodermal tumors predominantly occur in children, and are rare in the adult population. Less than 100 cases of supratentorial primitive neuroectodermal tumor have been reported in adults internationally. Our case study reports this rare incident. CASE PRESENTATION: A 22-year-old Hispanic man presented with headaches, blurry vision, diplopia, intermittent vomiting, and grossly decreased vision. A magnetic resonance image showed a left posterior parietal heterogeneously enhancing mass measuring 4.2cm * 7.2cm * 7.0cm. After craniotomy for resection and decompression, the mass was histologically revealed to be a supratentorial primitive neuroectodermal tumor. Standardized immunohistochemical studies for this mass were carried out. CONCLUSION: We have concluded that immunohistochemical and genetic workup should be included in the standardized pathological workup for primitive neuroectodermal tumors in order to provide more prognostic information. Based on our current literature review, we propose an immunohistochemical panel. PMID- 23095171 TI - A unique gender difference in early onset melanoma implies that in addition to ultraviolet light exposure other causative factors are important. AB - Using US SEER17 Registry data, age-specific melanoma incidence rates were calculated and comparisons were made between males and females. Relative Risk (RR) for males and females in each age group was computed and compared with that from Nordic Cancer Registry data set and to that for non-melanoma skin cancer (NMSC). For age groups 44 and younger, females showed higher incidence rates, with a peak difference at age 20-24 (RR = 2.01, 95% CI = 1.21-3.33). Males exhibited higher incidence rates after age 44. The same bimodal gender difference was confirmed by the Nordic Cancer Registry data set, but it was not observed for NMSC, which is known to be strongly associated with cumulative exposure to solar UV radiation. We conclude that exposure to solar ultraviolet (UV) radiation is the major causative factor for melanoma at older age (>44 yr), but that other factors may play a role in early onset melanomas, particularly in females. PMID- 23095170 TI - High yield derivation of enriched glutamatergic neurons from suspension-cultured mouse ESCs for neurotoxicology research. AB - BACKGROUND: Recently, there has been a strong emphasis on identifying an in vitro model for neurotoxicity research that combines the biological relevance of primary neurons with the scalability, reproducibility and genetic tractability of continuous cell lines. Derived neurons should be homotypic, exhibit neuron specific gene expression and morphology, form functioning synapses and consistently respond to neurotoxins in a fashion indistinguishable from primary neurons. However, efficient methods to produce neuronal populations that are suitable alternatives to primary neurons have not been available. METHODS: With the objective of developing a more facile, robust and efficient method to generate enriched glutamatergic neuronal cultures, we evaluated the neurogenic capacity of three mouse embryonic stem cell (ESC) lines (R1, C57BL/6 and D3) adapted to feeder-independent suspension culture. Neurogenesis and neuronal maturation were characterized as a function of time in culture using immunological, genomic, morphological and functional metrics. The functional responses of ESNs to neurotropic toxins with distinctly different targets and mechanisms of toxicity, such as glutamate, alpha-latrotoxin (LTX), and botulinum neurotoxin (BoNT), were also evaluated. RESULTS: Suspension-adapted ESCs expressed markers of pluripotency through at least 30 passages, and differentiation produced 97*106 neural progenitor cells (NPCs) per 10-cm dish. Greater than 99% of embryonic stem cell-derived neurons (ESNs) expressed neuron specific markers by 96 h after plating and rapidly developed complex axodendritic arbors and appropriate compartmentalization of neurotypic proteins. Expression profiling demonstrated the presence of transcripts necessary for neuronal function and confirmed that ESN populations were predominantly glutamatergic. Furthermore, ESNs were functionally receptive to all toxins with sensitivities and responses consistent with primary neurons. CONCLUSIONS: These findings demonstrate a cost-effective, scalable and flexible method to produce a highly enriched glutamatergic neuron population. The functional characterization of pathophysiological responses to neurotropic toxins and the compatibility with multi-well plating formats were used to demonstrate the suitability of ESNs as a discovery platform for molecular mechanisms of action, moderate-throughput analytical approaches and diagnostic screening. Furthermore, for the first time we demonstrate a cell-based model that is sensitive to all seven BoNT serotypes with EC50 values comparable to those reported in primary neuron populations. These data providing compelling evidence that ESNs offer a neuromimetic platform suitable for the evaluation of molecular mechanisms of neurotoxicity. PMID- 23095173 TI - Possible relation between maternal consumption of added sugar and sugar-sweetened beverages and birth weight--time trends in a population. AB - BACKGROUND: High birth weight (BW) is a risk factor for later obesity. In Norway, mean BW and proportion of large newborns increased from 1989 to 2000 and subsequently decreased to the 1989 level by 2010. The purpose of the study was to explore causes of this temporary increase. METHODS: From a regional prospective database pregnancy and newborn data were extracted for all 33088 singleton pregnancies resulting in live infants born at term without malformations during 1989-2010. Trends in BW, ponderal index and proportion of large newborns were related to individual prenatal exposures, including pre-pregnancy body mass index (PP-BMI) and gestational weight gain (GWG) for the years 2001-2010, and thereafter related ecologically to national population data on consumption of nutrients and physical activity. RESULTS: For the regional cohort mean (standard deviation) BW increased from 3580 (453) grams in 1989/90 to 3633 (493) grams in 2001/02 (p<0.001), and decreased to 3583 (481) grams in 2009/10 (p<0.001). The proportion with BW>4500 grams increased from 2.6% to 4.8% (p<0.001) and subsequently decreased to 3.3% (p=0.002). The trends remained after adjustment for relevant exposures. For the years 2001/02 to 2009/10 (n= 15240) mean (SD) PP BMI increased from 24.36 (4.44) to 24.85 (5.02) kg/m2 (p<0.001) while GWG decreased from 14.79 (5.85) to 13.86 (5.79) kg (p<0.001). The estimated net effect of changes in PP-BMI, GWG and other known exposures was a 6 grams reduction in BW from 2001/02 to 2009/10, leaving 44 grams reduction unexplained. National consumption of major nutrients did not change, but consumption of sucrose, in large part as sugar-sweetened beverages (SSB) changed in parallel to the BW trends. CONCLUSION: The temporary increase in BW and large babies in the regional cohort was identical to that reported for Norway. Individual level data on known pregnancy related predictors for BW could not explain these changes, but the parallel time trend in national consumption of sucrose, in particular as SSB, may lend support to a hypothesis that intake of sugar may have a direct effect on BW and infant body proportions independent of effects through PP-BMI and GWG. PMID- 23095174 TI - Neuroprotective effects of Alpinia katsumadai against experimental ischemic damage via control of oxidative stress. AB - CONTEXT: Alpinia katsumadai (Zingiberaceae) has been identified by the National Plant Quarantine Service in Korea. The extract of Alpinia katsumadai seed (EAKS) has antioxidant activities. OBJECTIVE: We investigated the neuroprotective effects of EAKS on ischemic damage in the gerbil hippocampal CA1 region after transient cerebral ischemia. MATERIALS AND METHODS: The ethanol extract of EAKS was obtained by organic solvent, collected in Kangwon province (South Korea) and orally administered using a feeding needle once a day for one week before transient cerebral ischemia in gerbils. RESULT: We adapted oral administration of 25 and 50 mg/kg EAKS because there are no data about the absorption and metabolism of EKAS. We found a significant neuroprotection in the 50 mg/kg EAKS treated ischemia group, not in the 25 mg/kg EAKS-treated ischemia group, at 4 days ischemia-reperfusion (I-R). In the 50 mg/kg EAKS-treated ischemia group, about 68% of pyramidal neurons in the CA1 region were immunostained with neuronal nuclei (NeuN) 4 days after I-R, compared to the vehicle-treated ischemia group. 8 Hydroxy-2'-deoxyguanosine (a marker for DNA damage) and 4-hydroxy-2-nonenal (a marker for lipid peroxidation) immunoreactivity in the CA1 region of the EAKS treated ischemia group were not markedly changed compared to the vehicle-treated ischemia group. In addition, Cu,Zn- and Mn-SOD immunoreactivity in the CA1 region of the EAKS-treated ischemia group were increased compared to the vehicle-treated ischemia group. DISCUSSION: Repeated supplements of EAKS could protect neurons against ischemic damage, showing that DNA damage and lipid peroxidation are attenuated and SODs are increased in the ischemic CA1 region. PMID- 23095175 TI - Intracoronary monocyte chemoattractant protein 1 and vascular endothelial growth factor levels are associated with necrotic core, calcium and fibrous tissue atherosclerotic plaque components: an intracoronary ultrasound radiofrequency study. AB - AIMS: To investigate the relationship between various serum biomarkers and coronary atherosclerotic plaque composition obtained by intravascular ultrasound virtual histology (IVUS-VH). METHODS: Using ELISA, we measured the serum levels of CD40 ligand, C-reactive protein, monocyte chemoattractant protein 1 (MCP-1), metalloproteinase 9, P-selectin and vascular endothelial growth factor (VEGF) in 40 patients with manifested coronary artery disease. RESULTS: Correlation analysis between biomarkers levels, IVUS grayscale parameters and VH-defined necrotic core (NC), calcium, fibrous and fibrofatty components was performed. MCP 1 and VEGF levels correlated with the severity of area stenosis (r = 0.35, p = 0.03 and r = 0.38, p = 0.017, respectively) and inversely correlated with the remodeling index (r = -0.35, p = 0.03 and r = 0.35, p = 0.02, respectively). Higher levels of MCP-1 were associated with increased calcium (r = 0.47, p = 0.004), NC (r = 0.38, p = 0.02) and less fibrous tissue components (r = -0.34, p = 0.03), whereas VEGF had an inverse correlation with both calcium components (r = -0.37, p = 0.02) and NC (r = -0.34, p = 0.036) but was strongly associated with increased fibrous components (r = 0.47, p = 0.003). No significant correlation was noted for any of the other biomarkers. CONCLUSIONS: MCP-1 and VEGF serum levels in patients with ischemic heart disease are correlated with coronary artery plaque burden and composition. PMID- 23095176 TI - A report of two novel NR5A1 mutation families: possible clinical phenotype of psychiatric symptoms of anxiety and/or depression. AB - OBJECTIVE: NR5A1 or steroidogenic factor 1 is a nuclear receptor that plays important roles in the hypothalamus-pituitary-steroidogenic axis. The clinical phenotype of most 46,XY mutation carriers includes disorders of sex development (DSD) without adrenal insufficiency, whereas 46,XX mutation carriers have phenotypes ranging from no symptoms to ovarian insufficiency. Although genetically engineered ventromedial hypothalamus-specific Nr5a1 knockout mice show anxiety behaviour, no psychiatric symptoms have been reported in human NR5A1 mutation carriers. We report clinical and molecular findings for individuals (from two families) with NR5A1 mutations, showing psychiatric symptoms. DESIGN AND METHODS: We screened for NR5A1 mutations in a cohort of 34 patients with 46,XY DSD using PCR-based sequencing. Psychiatric symptoms were assessed using mental health assessment tools and structured clinical interviews. Functional properties of detected mutant NR5A1s were studied in silico and in vitro, including three-dimensional (3D) mutation models, subcellular NR5A1 protein localization and transactivation assays. RESULTS: We found 2 (46,XY) patients with NR5A1 heterozygous novel mutations (p.D257fs and p.V424del), which were transmitted from their respective mothers. The patients' clinical findings indicated DSD without adrenal insufficiency. Both mothers showed psychiatric symptoms, including excessive anxiety and/or depression. The mother and grandmother of one patient had premature ovarian insufficiency. Functional studies showed altered 3D models of p.V424del and normal subcellular NR5A1 localization and impaired transcriptional activation without dominant-negative effects in both mutations. CONCLUSIONS: We found 2 (46,XX) NR5A1 mutation carriers with excessive anxiety and/or depression. These results suggest that excessive anxiety and/or depression are possible clinical phenotypes of 46,XX NR5A1 mutations. PMID- 23095177 TI - Chronic postconcussion symptoms and functional outcomes in OEF/OIF veterans with self-report of blast exposure. AB - Postconcussion symptoms (PCS) and functional outcomes were evaluated in 91 OEF/OIF outpatient veterans with reported histories of blast-exposure, with the goal of evaluating (1) the association between these outcomes and a clinical diagnosis of mild traumatic brain injury (mTBI) with or without loss of consciousness (LOC); and (2) the influence of post-traumatic stress disorder (PTSD) and depression on PCS reporting and perceived functional limitations. Individuals who reported mTBI with LOC had greater PCS complaints than individuals who reported mTBI without LOC or individuals without mTBI. However, after adjusting for severity of PTSD and depression symptoms, this group difference disappeared. Functional limitations were particularly prominent in the psychosocial domain. Again, PTSD was significantly associated with functional outcomes, but the mTBI with LOC group had greater psychosocial limitations than the other two groups, even when PTSD and depression symptoms were taken into account. These findings highlight the role of mental health in both outcomes, but additionally point to the impact of mTBI with LOC on long-term psychosocial adjustment. PMID- 23095179 TI - Special vulnerability of children to environmental exposures. AB - Fetal life and childhood are the periods most vulnerable to the harmful effects of exposure to environmental insults. This is because, during these periods, there is rapid cell division,organs are being formed, and growth is rapid. Thus, disruption of these processes may result in life-long abnormalities.Of particular concern are exposures that alter cognitive function and behavior, but exposures that alter growth, development,and reproductive and immune system function and that may increase risk of development of diseases like cancer later in life are also especially important. Exposure to environmental chemicals as well as infectious agents occurs via air, food,water, and absorption through the skin. Therefore, the environment in which fetal and childhood development occurs is very important. Unfortunately, poverty is a major risk factor for both exposures and childhood and later-life disease resulting from exposures to both environmental chemicals and infectious agents. It is very important to protect children because they are the future generation. PMID- 23095178 TI - Cancer module genes ranking using kernelized score functions. AB - BACKGROUND: Co-expression based Cancer Modules (CMs) are sets of genes that act in concert to carry out specific functions in different cancer types, and are constructed by exploiting gene expression profiles related to specific clinical conditions or expression signatures associated to specific processes altered in cancer. Unfortunately, genes involved in cancer are not always detectable using only expression signatures or co-expressed sets of genes, and in principle other types of functional interactions should be exploited to obtain a comprehensive picture of the molecular mechanisms underlying the onset and progression of cancer. RESULTS: We propose a novel semi-supervised method to rank genes with respect to CMs using networks constructed from different sources of functional information, not limited to gene expression data. It exploits on the one hand local learning strategies through score functions that extend the guilt-by association approach, and on the other hand global learning strategies through graph kernels embedded in the score functions, able to take into account the overall topology of the network. The proposed kernelized score functions compare favorably with other state-of-the-art semi-supervised machine learning methods for gene ranking in biological networks and scales well with the number of genes, thus allowing fast processing of very large gene networks. CONCLUSIONS: The modular nature of kernelized score functions provides an algorithmic scheme from which different gene ranking algorithms can be derived, and the results show that using integrated functional networks we can successfully predict CMs defined mainly through expression signatures obtained from gene expression data profiling. A preliminary analysis of top ranked "false positive" genes shows that our approach could be in perspective applied to discover novel genes involved in the onset and progression of tumors related to specific CMs. PMID- 23095180 TI - Nature's cure for cleanup of contaminated environment- a review of bioremediation strategies. AB - Population explosion, to the tune of -7.2 billion, along with excessive use of natural resources and a variety of anthropogenic activities, has resulted in large-scale contamination of the environment, especially the soil and groundwater.Contamination in the environment is an ever-increasing phenomenon, and often, regulatory systems and cleaning operations are not commensurate with waste generation. It is therefore necessary to search for effective and low-cost methods, especially following and stimulating the mechanisms of nature's cure. Bioremediation technologies resting upon the vast potential of biodiversity for the monitoring and abatement of environmental pollution have been briefly reviewed. PMID- 23095181 TI - A framework for assessing and predicting the environmental health impact of infectious diseases: a case study of leptospirosis. AB - This article demonstrates the practical application of an integrated environmental health impact assessment (IEHIA)methodology to investigate an infectious disease (leptospirosis)and the value of using such an approach to estimate future health impact. The assessment described the current health impact (using leptospirosis seroprevalence as a proxy measure)and estimated the future health impact based on scenarios that included indicators of different risk factors. The application of an IEHIA methodology to assess the health impact of an infectious disease was shown to enhance the ability to quantify associations between a disease agent and its health impact by taking into account the environmental drivers of transmission, human behaviour, socio economic factors, and the multiple pathways through which exposure and infection could occur. PMID- 23095182 TI - Improving access to adequate water and basic sanitation services in Indonesia. AB - A wide range of water problems faces nations and individuals around the world. These problems include international and regional disputes over water, water scarcity and contamination,unsustainable use of groundwater, ecological degradation,and the threat of climate change. At the heart of the world's water problems, however, is the failure to provide even the most basic water services for billions of people and the devastating human health problems associated with that failure. In 2000, the World Health Organization reported about regularly monitoring access to water and sanitation of 89%of the world's population, in which about 1.1 billion people lacked access to "improved water supply" and more than 2.4 billion lacked access to "improved sanitation". The development of water and basic sanitation services in Indonesia does not indicate any significant progress in the last two decades.The prevalence of water-borne diseases tends to increase yearly, which poses a risk for a population of over a million people. Therefore, it is not realistic to achieve the Millennium Development Goals target by 2015. Redefining approaches like providing integrated programs and action in water and sanitation services must be a priority to protect human health in Indonesia. PMID- 23095184 TI - Vegan carriage of group B streptococcus: a questionnaire study utilising social media. PMID- 23095185 TI - Does docosahexaenoic acid (DHA) status in pregnancy have any impact on postnatal growth? Six-year follow-up of a prospective randomized double-blind monocenter study on low-dose DHA supplements. AB - Fetuses and breastfed children depend on the maternal docosahexaenoic acid (DHA) supply, which might have long-lasting consequences. We studied the growth of 6 year-old children whose mothers received supplemental DHA from midpregnancy to 3 months after delivery. One hundred and forty-four pregnant women had been randomized to receive one of three vitamin-mineral supplements, one supplying an additional 200 mg/day DHA. Of the original sample, 120 children were measured at age 6 years with standardized methods. As one objective of the follow-up was to investigate the DHA influence on normal growth, the DHA group was compared with the pooled controls after exclusion of five premature infants. The weight, length, body mass index (BMI), head circumference, and skin-fold thickness at 6 years were similar in the 41 children of the DHA group and the 74 controls. Longitudinally, the BMI z-scores of the DHA group increased up at a later age than that of the controls. We found a highly significant negative correlation between height at 6 years and the increase in red blood cell DHA concentration of mothers from 22 to 37 weeks of pregnancy. We conclude that DHA supplements during midpregnancy corrected a low maternal DHA status (which correlated with children's height) and was favorable in regard to the BMI development up to 6 years. PMID- 23095186 TI - Perinatal risks after IVF and ICSI. AB - Pregnancies that occur after infertility treatment, particularly after assisted reproduction, constitute high-risk pregnancies. Occurrences of conditions such as high blood pressure, preeclampsia, growth retardations and bleeding are higher in comparison with the norm of spontaneously entered pregnancies. The rate of premature births and the frequency of intrauterine deaths are much higher than the average for all pregnancies. Furthermore, pregnancies resulting from in - vitro fertilisation (IVF) have significantly higher rates of requiring induced labour or caesarean section. However, it is to be assumed that these complications and unfortunate developments are not caused by extracorporeal fertilisation itself, but rather are due to the frequency of multiples and to the risk factors of the women involved. These women are, on average, older and there are often more problems with cycle irregularities, uterine anomalies and obesity than in the total collective of all pregnancies. The methods of modern reproductive medicine often bring a higher rate of multiple pregnancies. The clinical problem of multiple pregnancies is, above all, the raised rate of premature births and intrauterine growth retardations that contribute to the significantly higher rate of morbidity and mortality for these children. The slightly higher rate of congenital defects after IVF and intracytoplasmic sperm injection (ICSI) are also attributed more to the risk profile of the parents and less to the techniques themselves. The most important and easy-to-avoid complication is the multiple pregnancy, and it should be our goal to lower this rate even further. PMID- 23095187 TI - How safe is preterm operative vaginal delivery and which is the instrument of choice? AB - OBJECTIVE: The objective of this study was to determine neonatal outcomes in preterm operative vaginal delivery given the current paucity of data available to guide clinicians. STUDY DESIGN: A retrospective review of 64 cases was conducted, and neonatal outcomes were compared to spontaneous vaginal deliveries in similar gestations. The primary outcomes studied were death and occurrence of intraventricular haemorrhage. Secondary outcomes included admission to NICU, Apgar < 3 at 5 min, ventilation requirement, jaundice requiring treatment, culture-proven sepsis and necrotising enterocolitis. The study was conducted in a stand-alone maternity unit of approximately 9000 deliveries per year. RESULTS AND CONCLUSIONS: We concluded that although vacuum delivery is avoided in preterm infants, outcomes were similar to forceps deliveries of similar gestations. PMID- 23095188 TI - Induction of labor after a prior cesarean delivery: lessons from a population based study. AB - OBJECTIVES: The aims of this study were (1) to determine the success rate of induction of labor (IOL) in women with a prior cesarean section (CS) and (2) to compare the perinatal outcome of a trial of labor (TOL) in women with one prior CS who had an IOL, spontaneous onset of labor, or an elective repeated CS (ERCS). MATERIAL AND METHODS: This study population was divided into three groups: women who had (1) ERCS (n = 1916), (2) spontaneous TOL (n = 4263), and (3) IOL (n = 1576). RESULTS: (1) The rate of IOL in the study cohort was 20.3%; of these, 67.4% had a successful vaginal birth after cesarean (VBAC). (2) Patients in the spontaneous TOL group had a higher VBAC rate than did those who had IOL (P < 0.001). (3) The rate of uterine rupture was comparable among all study groups. And (4) a prior vaginal birth increased the likelihood of having a successful induction and a VBAC by 50%. CONCLUSION: IOL in patients with a previous CS is successful in about two-thirds of the cases. Induction is a safe and useful tool that can serve as an alternative for ERCS and assist to reduce the rate of ERCS. PMID- 23095189 TI - Polymorphism 1936A > G in the AKAP10 gene (encoding A-kinase-anchoring protein 10) is associated with higher cholesterol cord blood concentration in Polish full term newsborns. AB - AIMS: A-Kinase anchoring proteins (AKAPs) coordinate the specificity of protein kinase A signaling by localizing the kinase to subcellular sites. The 1936G (V646) AKAP10 allele has been associated with adults with low cholinergic/vagus nerve sensitivity and with newborns with increased blood pressure. Decreased activity of the parasympathetic system is associated with risk of metabolic syndrome. The aim of this study was to answer the question of whether 1936A > G AKAP10 polymorphism is associated with metabolic changes in full-term newborns that are predictive factors for the metabolic phenotype in adulthood. METHODS: The study included 114 consecutive healthy Polish newborns born after the end of the 37 th week of gestation to healthy women with uncomplicated pregnancies. At birth, cord blood of neonates was obtained for isolation of genomic DNA and cholesterol as well as triglyceride concentration. RESULTS: The cholesterol level in homozygotes GG was significantly higher than that in 1936A variant carriers (AG + AA, recessive mode of inheritance). CONCLUSIONS: Our results demonstrate a possible association between the 1936G AKAP10 variant and the total cholesterol level in the cord blood of the Polish newborn population. PMID- 23095190 TI - Guttus, tiralatte and teterelle: a history of breast pumps. AB - Breast pumps have been used since antiquity, and their form has changed with the available material. The ancient Greeks used the ceramic guttus type, both to empty the breast and feed the infant. The Romans invented glass milk-extractors, sucked by the mother herself to elevate retracted nipples. Devices in the form of a smoking pipe were in widespread use when corsets had caused an epidemic of flat nipples in the 17th century. In the 19th century, vessels to be sucked both by mother and infant were developed to facilitate breastfeeding for preterm infants. When from 1870 the role of pathogenic bacteria became known, easy and thorough cleaning became an important feature of breast pumps. The 20th century sexualized the female breast to such a degree that its nourishing function was threatened. Electric pumps, developed at the beginning of the 20th century for hospital use, found a large private market when breast feeding in public was no longer tolerated. Today, breast pumps are mainly used to enable breastfeeding mothers to return to work. PMID- 23095191 TI - Pregnancy and neonatal outcome following an antenatal diagnosis of cleft lip and palate. AB - AIM: To identify the significance of associated antenatal ultrasound findings on long-term prognosis following the antenatal diagnosis of cleft lip/palate [CL(P)]. PATIENTS AND METHODS: Retrospective case note analysis of patients seen at a single tertiary referral centre with a diagnosis of CL(P). The patients were classified as those with unilateral or bilateral clefts and then further subdivided according to the presence of associated anomalies, and these were related to pregnancy and neonatal outcome. RESULTS: A total of 125 singleton pregnancies were seen at the antenatal diagnostic unit, 14 of which were subsequently lost to follow-up. Eighty-two (65.6%) had a diagnosis of unilateral CL(P) and 43 (34.4%) a bilateral CL(P). Seventy-five foetuses (67.5%) had no other anomalies detected on antenatal ultrasound. Seventeen patients (15%) underwent a termination of pregnancy. A normal postnatal outcome was seen in 79% of liveborn infants overall. Only 50% of foetuses diagnosed with a single minor anomaly and 4% of the foetuses in whom more than two minor anomalies or one major anomaly had been detected on ultrasound had a normal postnatal outcome. Infants with bilateral CL(P) had a significantly reduced incidence of a normal postnatal course (60% vs. 87.5%, P<0.01). CONCLUSION: In cases of CL(P), there is a high incidence of associated anomalies detected on antenatal ultrasound and these significantly increase the risk of poor neonatal outcome. PMID- 23095192 TI - Placental transfer of clarithromycin in human pregnancies with preterm premature rupture of membranes. AB - AIM: The aim of this study was to evaluate the transplacental transfer of clarithromycin, which was used in the treatment of preterm premature rupture of membranes (PPROM) in human pregnancies, by comparing umbilical cord and maternal serum clarithromycin concentrations. METHODS: Singleton pregnant women with PPROM (<34 weeks) were prospectively enrolled between April 2009 and January 2011. The diagnosis of PPROM was made with vaginal pooling, leakage, nitrazine, and Amnisure tests. The women were managed expectantly with bed rest, corticosteroids, and a triple antibiotic combination including ceftriaxone, clindamycin, and clarithromycin. Amniocentesis was offered, and culture for aerobe/anaerobe and mycoplasma was performed. After delivery, blood was drawn from the mother's antecubital and umbilical cord veins. Clarithromycin concentrations were measured using liquid chromatography-tandem mass spectrometry. The percentage and correlation between cord and maternal serum clarithromycin concentrations were calculated. Logistic regression analysis was performed to investigate the factors related to the cord and maternal serum clarithromycin concentration percentage. RESULTS: A total of 34 cord-maternal serum pairs were included in the final analysis. The mean cord-maternal serum clarithromycin concentration percentage was 7.93+/-0.9%. There was a good correlation between cord serum and maternal serum clarithromycin concentration (r=0.795, P<0.001). The cord-maternal serum clarithromycin concentration percentage significantly increased according to advancing gestation (P<0.001). CONCLUSIONS: Our data showed that the mean placental transfer of clarithromycin is approximately 8% and dependent on gestational age. PMID- 23095193 TI - Stepwise sequential screening for Down's syndrome (combined test associated with modified genetic sonography) in pregnant women with low risk for chromosomal disorders. AB - OBJECTIVE: To assess the sensitivity (Sen) and false positive ratio (FPR) of stepwise sequential screening [1st step: combined test (CT), 2nd step: modified genetic sonography (major malformation and nuchal fold, MGS)] as a screening method for Down's syndrome (DS) in the general population of pregnant women. METHODS: Prospective study. During a 5-year study period (July 2005 to June 2010), 17,911 pregnant women were screened for DS using a stepwise sequential screening method (CT+MGS). We evaluated the Sen and FPR (95% CI) of the two chromosomal disorder screening methods for DS: CT and CT+MGS. RESULTS: Seventeen thousand nine hundred and eleven cases were analysed, including 67 with chromosome abnormalities and 45 with DS. The Sen of CT for DS was 80% (95% CI; 68.3-91.7) (36/45) with a FPR of 4.2% (95% CI; 3.9-4.5) (752/17, 866). The Sen of CT+MSG for DS was 93.3 (95% CI; 85.9-99) (42/45) with a FPR of 4.8% (95% CI; 4.5 5.1) (860/17, 866). CONCLUSIONS: MGS coupled with CT increases the Sen of DS diagnosis by 13.3% (95% CI; 2.7-25.9), with an increase in FPR of 0.6% (95% CI; 0.5-0.7). PMID- 23095194 TI - Clinical evaluation of soluble intercellular adhesion molecule-1 and insulin like growth factor-binding protein-1-based rapid immunoassays for the diagnosis of prelabor rupture of membranes. AB - AIMS: To evaluate the clinical value of two rapid tests, based on soluble intercellular adhesion molecule-1 (Leakection) and insulinlike growth factor binding protein-1 (Amnioquick), for the diagnosis of prelabor rupture of membranes. METHODS: A total of 200 pregnant women were recruited in this study: 100 pregnant women with membrane rupture and 100 healthy pregnant women as controls. Patients and controls were randomly divided into Leakection and Amnioquick groups, respectively. Sensitivity and specificity were calculated on the basis of the detection results. RESULTS: For the 100 women tested with Leakection, the sensitivity and specificity was 94% and 96%, respectively; the total accuracy was 95%. For the 100 women tested with Amnioquick, the sensitivity and specificity was 80% and 100%, respectively; the total accuracy was 90%. CONCLUSIONS: Both Leakection and Amnioquick are noninvasive and inexpensive rapid tests for the diagnosis of premature or prelabor rupture of membranes with high sensitivity and specificity. These tests could greatly help the timely diagnosis of premature or prelabor rupture of membranes in clinical practice. PMID- 23095195 TI - A curriculum to teach and evaluate resident skills in the management of postpartum hemorrhage. AB - AIM: The aim of this study was the development of a curriculum for the management of postpartum hemorrhage and an objective assessment of technical skills (OSATS) for uterine compression sutures. METHOD: Twenty-two residents participated in the study. Evaluations included the global rating scale, task-specific checklist, and pass/fail rating for the OSATS and task-specific checklist for the hemorrhage drill. The reliability and validity of the evaluation tools were calculated. RESULTS: The inter-rater reliability was 0.98 for the hemorrhage drill checklist, 0.77 for the global rating scale, and 0.93 for the uterine suture checklist. Construct validity evaluation revealed senior residents performed superiorly to junior residents on the global rating scale (P=0.006) and on the uterine suture checklist (P=0.04). There was an improvement in performance on the post-test in comparison to the pretest (P=0.001). CONCLUSION: We present an inexpensive, reliable, and valid curriculum to teach and evaluate the medical and surgical management of postpartum hemorrhage. PMID- 23095196 TI - Testing volume is not synonymous of cost, value and efficacy in laboratory diagnostics. PMID- 23095197 TI - Investigation of a slope discontinuity in a patients' results distribution for D dimer. PMID- 23095198 TI - An unusual interference in CK MB assay caused by a macro enzyme creatine phosphokinase (CK) type 2 in HIV-infected patients. PMID- 23095199 TI - Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain. AB - BACKGROUND: Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. METHODS: Sixty consecutive patients with >= 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. RESULTS: No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. CONCLUSIONS: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation. PMID- 23095200 TI - Cut-off values of serum growth hormone (GH) in pharmacological stimulation tests (PhT) evaluated in short-statured children using a chemiluminescent immunometric assay (ICMA) calibrated with the International Recombinant Human GH Standard 98/574. PMID- 23095201 TI - Serum homocysteine concentrations in Chinese children with autism. PMID- 23095202 TI - Plasma choline and betaine correlate with serum folate, plasma S-adenosyl methionine and S-adenosyl-homocysteine in healthy volunteers. AB - BACKGROUND: Choline is essential for mammalian cell function. It plays a critical role in cell membrane integrity, neurotransmission, cell signaling and lipid metabolism. Moreover, choline is involved in methylation in two ways: a) its synthesis requires methyl groups donated by S-adenosyl-methionine (AdoMet); and b) choline oxidation product betaine methylates homocysteine (Hcy) to methionine (Met) and produces dimethylglycine. This later donates one carbon units to tetrahydrofolate (THF). METHODS: To evaluate the correlations of choline and betaine with folate, AdoMet, S-anenosyl-homocysteine (AdoHcy), total homocysteine (tHcy), and DNA methylation, choline, betaine and dimethylglycine were measured by LC-MS/MS in plasma of 109 healthy volunteers, in whom folate, AdoMet, AdoHcy, tHcy, and DNA methylation have previously been reported. RESULTS: Using a bivariate model, choline and betaine showed strong positive correlations with folate (r = 0.346 and r = 0.226), AdoHcy (r = 0.468 and r = 0.296), and correlated negatively with AdoMet/AdoHcy ratio (r = - 0.246 and r = - 0.379). Only choline was positively correlated with AdoMet (r = 0.453). Using a multivariate linear regression model, choline correlated strongly with folate ( beta = 17.416), AdoMet ( beta = 61.272), and AdoHcy ( beta = 9.215). Betaine correlated positively with folate ( beta = 0.133) and negatively with tHcy ( beta = - 0.194) ratio. Choline is an integral part of folate and methylation pathways. CONCLUSIONS: Our data highlight the importance of integrating choline in studies concerning addressing pathological conditions related to folate, homocysteine and methylation metabolism. PMID- 23095203 TI - Evaluation of the BRAHMS Kryptor((r)) thyroglobulin minirecovery test in patients with differentiated thyroid carcinoma. AB - BACKGROUND: The present study was undertaken to evaluate a new sensitive thyroglobulin (Tg) mini-recovery test (Tg-mrec) for the detection of potential interferences in sera from patients with differentiated thyroid carcinoma (DTC) and low Tg levels. METHODS: 167 DTC patients with serum Tg <2 MUg/L were enrolled. Both TgAb and Tg-mrec measurements were performed on the automated Kryptor((r)) platform. Serum pretreatment in proprietory blocking tubes was perfomed to screen for heterophile antibody interferences. The concordance rates between tests were evaluated. RESULTS: One case of over-recovery occurred in a patient with discordant Tg results in different immunoassays. The prevalences of a positive TgAb test and a reduced recovery rate were 15%-12%, respectively. Serum TgAb and Tg-mrec tests were both positive in 16 patients, both negative in 138 patients and discordant in 13 patients, respectively. The concordance rate between the Tg-mrec test and the TgAb assay was 92% (Cohens' kappa 0.894; 95% confidence interval: 0.82-0.93, p<0.001). In all, among seven clinically relevant interferences, three were found by TgAb, five by Tg-mrec and six by using both tests. CONCLUSIONS: The automated Kryptor((r)) Tg-mrec test has a complimentary value to TgAb immunoassay testing in the detection of potential interferences in Tg measurements in patients with DTC and low Tg values (i.e., <2 MUg/L). Tg-mrec may detect interferences from TgAb not measured directly by an individual TgAb assay or from other interfering substances, such as heterophile antibodies. PMID- 23095204 TI - Genetics and molecular biology in laboratory medicine, 1963-2013. AB - The past 50 years have seen many changes in laboratory medicine, either as causes or consequences of increases in productivity and expansion of the range of information which can be provided. The drivers and facilitators of change in relation to clinical applications of molecular biology included the need for diagnostic tools for genetic diseases and technical advances such as PCR and sequencing. However, molecular biology techniques have proved to have far wider applications, from detection of infectious agents to molecular characterization of tumors. Journals such as Clinical Chemistry and Laboratory Medicine play an important role in communication of these advances to the laboratory medicine community and in publishing evaluations of their practical value. PMID- 23095205 TI - Validation of a fast and reliable liquid chromatography-tandem mass spectrometry (LC-MS/MS) with atmospheric pressure chemical ionization method for simultaneous quantitation of voriconazole, itraconazole and its active metabolite hydroxyitraconazole in human plasma. AB - BACKGROUND: Voriconazole and itraconazole are two broad-spectrum antifungal triazole derivates administered for the prevention and in the treatment of invasive fungal infections. Their broad inter- and intra-individual pharmacokinetic variability and the high probability of drug-drug interactions justify therapeutic drug monitoring. METHODS: After liquid-liquid extraction with tert-butyl methyl ether, chromatographic separation was achieved on a Zorbax Eclipse XDB-C18 column using gradient elution with 10 mM ammonium formate and acetonitrile. Detection was performed by a tandem mass spectrometer coupled to LC via an atmospheric pressure chemical ionization (APCI) and quantification was performed using selected reaction monitoring (SRM) transitions RESULTS: Total run time was 4.5 min. The method was validated for concentrations ranging from 0.05 to 10 MUg/mL for voriconazole and from 0.025 to 5 MUg/mL for itraconazole and hydroxyitraconazole, respectively. The intra- and inter-day correlation coefficients of variation were <7.7%-<9.2%, respectively. The accuracy ranged from 92.6% to 109%. CONCLUSIONS: A rapid and simple liquid chromatography atmospheric pressure chemical ionization-tandem mass spectrometry (LC-APCI-MS/MS) method has been developed and validated to measure voriconazole itraconazole and hydroxyitraconazole in human plasma. This method is successfully applied to samples from patients receiving antifungal treatment. PMID- 23095206 TI - Laboratory hematology in the history of Clinical Chemistry and Laboratory Medicine. AB - BACKGROUND: For the occasion of the 50th anniversary of the journal Clinical Chemistry and Laboratory Medicine (CCLM), an historic overview of papers that the journal has published in the field of laboratory hematology (LH) is presented. METHODS: All past volumes of CCLM were screened for papers on LH and these were categorized. Bibliographic data of these papers were also analyzed. RESULTS: CCLM published in total 387 LH papers. The absolute number of LH papers published annually showed a significant increase over the years since 1985. Also the share of LH papers demonstrated a steady increase (overall mean 5%, but mean 8% over the past 4 years). The most frequent category was coagulation and fibrinolysis (23.5%). Authors from Germany contributed the most LH papers to the journal (22.7%), followed by the Netherlands and Italy (16.3 and 13.2%, respectively). Recent citation data indicated that other publications cited LH review papers much more frequently than other types of papers. CONCLUSIONS: The history of the journal reflects the emergence and development of laboratory hematology as a separate discipline of laboratory medicine. PMID- 23095207 TI - Activated CD4+ T cells target mesangial antigens and initiate glomerulonephritis. AB - AIMS: The role of kidney infiltrating T cells in the pathology of lupus nephritis is unclear. This study was undertaken to investigate whether CD4+ T cell responses to a surrogate mesangial antigen can initiate glomerulonephritis. METHODS: Ovalbumin (OVA) was deposited in the glomerular mesangium of C57BL/6 (B6) mice using anti-alpha8-integrin immunoliposomes (alpha8ILs). This was followed by injection of activated OVA-reactive CD4+ transgenic OT2 T cells. Trafficking of antigen-specific OT2 T cells to kidneys and lymph nodes was studied by flow cytometry. Glomerular pathology and immune cell infiltration was characterized by immunostaining. Role of CCR2 deficiency on T cell-mediated glomerulonephritis was investigated using B6.ccr2(-/-) mice. RESULTS: alpha8ILs delivered OVA specifically to the renal glomeruli. Adoptively transferred OT2 T cells preferentially accumulated in renal lymph nodes and in the renal cortex. Kidneys showed glomerular inflammation with recruitment of endogenous T cells, dendritic cells and macrophages. T cell-mediated inflammation induced mesangial cell activation and an increase in glomerular MCP1 and fibronectin. The formation of inflammatory foci was driven by Ly6C monocytes and was CCR2 dependent. CONCLUSIONS: The findings from this study show that T cells reactive with antigens in the mesangium are sufficient to initiate glomerular pathology. Antigen-specific CD4 T cells act by inducing glomerular MCP1 production which mediates recruitment of inflammatory monocytes resulting in glomerulonephritis. Thus, down-modulation of T cell responses within the kidneys of lupus patients will be a beneficial therapeutic approach. PMID- 23095208 TI - Elevated glucose level at 30 minutes during an oral glucose tolerance test in obese adolescents: a new disorder of glucose tolerance. AB - We observed glucose levels >140 mg/dL measured at 30 minutes (min) during an oral glucose tolerance test (OGTT) in some obese patients. We aimed to investigate the significance of this finding by comparing lipid profiles, insulin resistance indices, and systemic inflammatory mediators between obese adolescents with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and elevated glucose levels at 30 min. The study involved 80 obese (body mass index >95(th) percentile for age and sex) adolescents (48 female, 32 male) between 11 and 16 years of age. Depending on OGTT results, patients were divided into NGT and IGT groups. The third group was recruited from the NGT group as having glucose levels > 140 mg/dL at 30 minutes. Lipid profiles, [interleukin-6 (IL-6)], neopterin, and lipoprotein associated phospholipase A2 (Lp-PLA2)] were assessed. Neopterin and Lp-PLA2 levels were significantly higher in obese adolescents with elevated glucose levels at 30 min. compared with those in both NGT and IGT groups (p=0.013, and 0.004, respectively). In these adolescents, IL-6 levels were significantly higher only than the NGT group (p=0.01). In logistic regression analysis, IL-6, neopterin and Lp-PLA2 levels were detected to be related to high blood glucose levels at 30 min (OR 1.11, p=0.01; OR 9.03, p=0.013; OR 1.01, p=0.004 respectively). Obese adolescents with elevated glucose levels at 30 min. demonstrated higher inflammatory mediators levels, which were atherosclerotic indicators, than obese adolescents with NGT and IGT. These results suggest that glucose levels >140 mg/dL measured at 30 min during an OGTT may be a new disorder of glucose tolerance in obesity. PMID- 23095209 TI - Neuromuscular symptoms in a patient with familial pseudohypoparathyroidism type Ib diagnosed by methylation-specific multiplex ligation-dependent probe amplification. AB - Pseudohypoparathyroidism type Ib (PHP-Ib) is a rare genetic disorder characterized by hypocalcemia and hyperphosphatemia due to imprinting defects in the maternally derived GNAS allele. Patients with PHP-Ib are usually identified by tetany, convulsions, and/or muscle cramps, whereas a substantial fraction of patients remain asymptomatic and are identified by familial studies. Although previous studies on patients with primary hypoparathyroidism have indicated that hypocalcemia can be associated with various neuromuscular abnormalities, such clinical features have been rarely described in patients with PHP-Ib. Here, we report a 12-year-old male patient with familial PHP-Ib and unique neuromuscular symptoms. The patient presented with general fatigue, steppage gait, and myalgia. Physical examinations revealed muscular weakness and atrophies in the lower legs, a shortening of the bilateral Achilles' tendons and absence of deep tendon reflexes. Laboratory tests showed hypocalcemia, hyperphosphatemia, elevated serum intact PTH level, and impaired responses of urinary phosphate and cyclic AMP in an Ellsworth-Howard test, in addition to an elevated serum creatine kinase level. Clinical features of the patient were significantly improved after 1 month of treatment with alfacalcidol and calcium. Methylation-specific multiplex ligation dependent probe amplification (MS-MLPA) and subsequent PCR analyses identified a methylation defect at exon A/B of GNAS and a microdeletion involving exons 4-6 of the GNAS neighboring gene STX16 in the patient and in his asymptomatic brother. The results suggest that various neuromuscular features probably associated with hypocalcemia can be the first symptoms of PHP-Ib, and that MS-MLPA serves as a powerful tool for screening of GNAS abnormalities in patients with atypical manifestations. PMID- 23095210 TI - OSR1-sensitive renal tubular phosphate reabsorption. AB - BACKGROUND: The oxidative stress-responsive kinase 1 (OSR1) participates in the WNK-(with no K) kinase dependent regulation of renal salt excretion and blood pressure. Little is known, however, about the role of OSR1 in the regulation of further renal transport systems. The present study analyzed the effect of OSR1 on NaPiIIa, the major renal tubular phosphate transporter. METHODS: Immunohistochemistry and confocal microscopy were employed to determine renal localization of OSR1 and NaPiIIa. To elucidate the effect of OSR on NaPiIIa activity, cRNA encoding NaPiIIa was injected into Xenopus oocytes with or without additional injection of cRNA encoding OSR1, and phosphate transport was estimated from phosphateinduced currents determined with dual electrode voltage clamp. To elucidate the in vivo significance of OSR1 serum phosphate and hormone concentrations as well as urinary phosphate output of mice carrying one allele of WNK-resistant OSR1 (osr1tg/(+)) were compared to the respective values of wild type mice (osr1(+/+)). RESULTS: NaPiIIa and OSR1 were both expressed in proximal renal tubule cells. Coexpression of OSR1 significantly up-regulated phosphate induced currents in NaPiIIa-expressing Xenopus oocytes. Despite decreased serum phosphate concentration urinary phosphate excretion was significantly increased and NaPiIIa protein abundance in the brush border membrane significantly reduced in osr1tg/(+) mice as compared to osr1(+/+) mice. Serum PTH and calcitriol levels were similar in osr1tg/(+) mice and in osr1(+/+) mice, serum FGF23 concentration was, however, significantly higher in osr1tg/(+) mice than in osr1(+/+) mice. CONCLUSIONS: OSR1 is expressed in proximal renal tubules and participates in the regulation of FGF23 release and renal tubular phosphate transport. PMID- 23095211 TI - Pseudorejection and true rejection after kidney transplantation: classification and clinical significance. AB - OBJECTIVES: Multiple factors may result in an elevation in serum creatinine level after kidney transplantation, mimicking rejection. It is crucial to differentiate between a true rejection and other conditions inducing a 'pseudorejection', in order to avoid overtreatment, or worse, mistreatment. Our goal was to review and classify true rejections and pseudorejections and their clinical significance. MATERIAL AND METHODS: This was a retrospective review of articles published in the USA and Europe, from 1976 to the present. The sites from which information was retrieved included PubMed, Clinical Imaging, Histopathology, Archives of Surgery, JACS, the American Urological Association, Medline and Springer Link. The importance of the resistive index will also be emphasized. RESULTS: We reviewed 61 articles regarding the causes of renal graft dysfunction, which may be classified into true rejections and pseudorejections, the latter including the following 6 factors: hyperglycemia, ureteral obstruction, lymphocele, arterial stenosis, infection and recurrence of primary pathology. CONCLUSIONS: 'Pseudorejection' has been described only once, for the first time in 1976 in the USA, and there have been no other reports since then. Multiple factors, mainly hyperglycemia, may induce a pseudorejection, presenting with an elevation of serum creatinine level and leading the clinician to an erroneous diagnosis of true rejection initially, resulting in inappropriate management. PMID- 23095212 TI - Quantitative myocardial perfusion in mice based on the signal intensity of flow sensitized CMR. AB - BACKGROUND: In the conventional approach to arterial spin labeling in the rodent heart, the relative difference in the apparent T(1) relaxation times corresponding to selective and non-selective inversion is related to perfusion via a two compartment model of tissue. But accurate determination of T(1) in small animal hearts is difficult and prone to errors due to long scan times and high heart rates. In this study we introduce the theoretical frame work for an alternative method (SI-method) based purely on the signal intensity of slice select and non-select inversion recovery images at a single inversion time at short repetition time. METHODS: A modified Bloch equation was solved to derive perfusion as a function of signal intensity of flow sensitized segmented gradient echo acquisitions. A two compartment fast exchanging model of tissue was assumed. To test the new technique first it was implemented on a flow phantom and then it was compared with the conventional T(1) method in an in vivo study of healthy C57BL/6 mice (n=12). Finally the SI-method was used in comparison to a Late Gadolinium Enhanced (LGE) method to qualitatively and quantitatively assess perfusion deficits in an ischemia-reperfusion mouse model (n=4). RESULTS: The myocardial perfusion of healthy mice obtained by the SI-method, 5.6 +/- 0.5 ml/g/min, (mean +/- standard deviation) was similar (p=0.38) to that obtained by the conventional method, 5.6 +/- 0.3 ml/g/min. The variance in perfusion within the left ventricle was less for the SI-method than that for the conventional method (p<0.0001). The mean percentage standard deviation among repeated measures was 3.6%. The LGE regions of the ischemia reperfusion model were matched with regions of hypo-perfusion in the perfusion map. The average perfusion in the hypo perfused region among all four IR mice was 1.2 +/- 0.9 ml/g/min and that of the remote region was 4.4 +/- 1.2 ml/g/min. CONCLUSIONS: The proposed signal intensity based ASL method with a segmented acquisition scheme allows accurate high resolution perfusion mapping in small animals. It's short scan time, high reproducibility and ease of post process makes it a robust alternative to the conventional ASL technique that relies on T(1) measurements. PMID- 23095213 TI - Effect of drug use and influence of abstinence on sexual functioning in a Spanish male drug-dependent sample: a multisite study. AB - INTRODUCTION: To date, it has been difficult to address the issue of sexual functioning and drug use, and many approaches to it have basic problems and methodological errors. AIM: The present cross-sectional study compared the sexual functioning scores of a group of drug users with those of a group of nondrug users. It explored the relationship between drug abstinence and sexual functioning. MAIN OUTCOME MEASURES: A sample of 905 males participated in this study (549 met the substance dependence criteria and 356 were controls). All of them were assessed with the Changes in Sexual Functioning Questionnaire-Drugs version. METHOD: The assessment was conducted from September 2009 to January 2011. The clinical sample was evaluated in nine different substance abuse treatment facilities. RESULTS: Results show that, overall, all dimensions (pleasure, desire, arousal, and orgasm) were moderately impaired. Yet, differences regarding preferred substance were observed. Pleasure and orgasm were the two areas most significantly impaired. In these areas, all drugs seemed to negatively affect sexual functioning. However, desire and arousal were not affected by all the substances. In addition, at least after 2 weeks of drug abstinence, no relationship was found between drug abstinence and improvement in sexual functioning. The sample studied had an average of 1 year of drug abstinence and was found to have poorer sexual functioning than the control group. CONCLUSIONS: Therefore, these results seem to contradict those that argue that drug use only impairs sexual functioning temporarily. Moreover, they suggest that sexual functioning does not improve just by stopping drug use. PMID- 23095214 TI - Emerging molecular targets in melanoma invasion and metastasis. AB - Metastatic cutaneous melanoma accounts for the majority of skin cancer deaths due to its aggressiveness and high resistance to current therapies. To efficiently metastasize, invasive melanoma cells need to change their cytoskeletal organization and alter contacts with the extracellular matrix and the surrounding stromal cells. Melanoma cells can use different migratory strategies depending on varying environments to exit the primary tumour mass and invade surrounding and later distant tissues. In this review, we have focused on tumour cell plasticity or the interconvertibility that melanoma cells have as one of the factors that contribute to melanoma metastasis. This has been an area of very intense research in the last 5 yr yielding a vast number of findings. We have therefore reviewed all the possible clinical opportunities that this new knowledge offers to both stratify and treat cutaneous malignant melanoma patients. PMID- 23095215 TI - Twice recurrent gallstone ileus: a case report. AB - INTRODUCTION: Gallstone ileus is a rare cause of bowel obstruction and results from the passage of gallstones into the bowel. CASE PRESENTATION: We present the case of an 83-year-old Caucasian woman who had three episodes of gallstone ileus, each of which was managed with simple enterotomy. This sequence is one of the first reported in the medical literature and may be seen to challenge the traditional surgical approach of enterotomy alone. CONCLUSIONS: The available evidence comparing enterotomy alone with combined enterotomy, cholecystectomy, and fistula closure in the management of gallstone ileus is reviewed. Neither approach is clearly identified as superior, but available series suggest that simple enterotomy may be safer than a combined approach and does not result in a higher rate of recurrent biliary disease. PMID- 23095217 TI - De novo myeloid sarcoma in a 4-month-old infant: a case report and review of the literature. AB - Myeloid sarcoma is a rare tumor of immature myeloid cells in an extramedullary site. Myeloid sarcoma may present in a variety of locations; skin is one of the common sites. It may precede or occur concurrently with acute myeloid leukemia, chronic myeloid leukemia, other forms of myeloproliferative disorders/myelodysplastic syndrome or de novo. We report a case of a 4-month-old female who presented with cutaneous lesions without evidence of leukemia, determined to be de novo myeloid sarcoma. She had erythematous nodules in multiple skin sites. Biopsy revealed a diffuse atypical mononuclear cell infiltrate involving the entire dermis and extending to the subcutis. The infiltrate was diffusely positive for lysozyme, CD43, CD15, CD33, CD68 and CD117 and was negative for CD3, CD20, CD34, CD56, CD79a, CD99, myeloperoxidase, desmin, chromogranin and synaptophysin, supporting a diagnosis of myeloid sarcoma. No leukemic involvement was found on evaluation of peripheral blood or bone marrow aspiration. Chromosomal abnormalities were found at chromosomes 7, 10 and 11. The skin lesions resolved following multiple chemotherapy courses, then recurred requiring additional treatment. De novo myeloid sarcoma involving skin without evidence of leukemia can occur in an infant and may present a diagnostic challenge. PMID- 23095216 TI - Evaluation of cell proliferation, apoptosis, and DNA-repair genes as potential biomarkers for ethanol-induced CNS alterations. AB - BACKGROUND: Alcohol use disorders (AUDs) lead to alterations in central nervous system (CNS) architecture along with impaired learning and memory. Previous work from our group and that of others suggests that one mechanism underlying these changes is alteration of cell proliferation, apoptosis, and DNA-repair in neural stem cells (NSCs) produced as a consequence of ethanol-induced effects on the expression of genes related to p53-signaling. This study tests the hypothesis that changes in the expression of p53-signaling genes represent biomarkers of ethanol abuse which can be identified in the peripheral blood of rat drinking models and human AUD subjects and posits that specific changes may be correlated with differences in neuropsychological measures and CNS structure. RESULTS: Remarkably, microarray analysis of 350 genes related to p53-signaling in peripheral blood leukocytes (PBLs) of binge-drinking rats revealed 190 genes that were significantly altered after correcting for multiple testing. Moreover, 40 of these genes overlapped with those that we had previously observed to be changed in ethanol-exposed mouse NSCs. Expression changes in nine of these genes were tested for independent confirmation by a custom QuantiGene Plex (QGP) assay for a subset of p53-signaling genes, where a consistent trend for decreased expression of mitosis-related genes was observed. One mitosis-related gene (Pttg1) was also changed in human lymphoblasts cultured with ethanol. In PBLs of human AUD subjects seven p53-signaling genes were changed compared with non-drinking controls. Correlation and principal components analysis were then used to identify significant relationships between the expression of these seven genes and a set of medical, demographic, neuropsychological and neuroimaging measures that distinguished AUD and control subjects. Two genes (Ercc1 and Mcm5) showed a highly significant correlation with AUD-induced decreases in the volume of the left parietal supramarginal gyrus and neuropsychological measures. CONCLUSIONS: These results demonstrate that alcohol-induced changes in genes related to proliferation, apoptosis, and DNA-repair are observable in the peripheral blood and may serve as a useful biomarker for CNS structural damage and functional performance deficits in human AUD subjects. PMID- 23095218 TI - Identification of mild cognitive impairment in ACTIVE: algorithmic classification and stability. AB - Rates of mild cognitive impairment (MCI) have varied substantially, depending on the criteria used and the samples surveyed. The present investigation used a psychometric algorithm for identifying MCI and its stability to determine if low cognitive functioning was related to poorer longitudinal outcomes. The Advanced Cognitive Training of Independent and Vital Elders (ACTIVE) study is a multi-site longitudinal investigation of long-term effects of cognitive training with older adults. ACTIVE exclusion criteria eliminated participants at highest risk for dementia (i.e., Mini-Mental State Examination < 23). Using composite normative for sample- and training-corrected psychometric data, 8.07% of the sample had amnestic impairment, while 25.09% had a non-amnestic impairment at baseline. Poorer baseline functional scores were observed in those with impairment at the first visit, including a higher rate of attrition, depressive symptoms, and self reported physical functioning. Participants were then classified based upon the stability of their classification. Those who were stably impaired over the 5-year interval had the worst functional outcomes (e.g., Instrumental Activities of Daily Living performance), and inconsistency in classification over time also appeared to be associated increased risk. These findings suggest that there is prognostic value in assessing and tracking cognition to assist in identifying the critical baseline features associated with poorer outcomes. PMID- 23095220 TI - An educational program to assist clinicians in identifying elder investment fraud and financial exploitation. AB - Due to age-related factors and illnesses, older adults may become vulnerable to elder investment fraud and financial exploitation (EIFFE). The authors describe the development and preliminary evaluation of an educational program to raise awareness and assist clinicians in identifying older adults at risk. Participants (n = 127) gave high ratings for the program, which includes a presentation, clinician pocket guide, and patient education brochure. Thirty-five respondents returned a completed questionnaire at the 6-month follow-up, with 69% (n = 24) of those indicating use of the program materials in practice and also reporting having identified 25 patients they felt were vulnerable to EIFFE. These findings demonstrate the value of providing education and practical tools to enhance clinic-based screening of this underappreciated but prevalent problem. PMID- 23095219 TI - Engaged scholarship and gerontological program relevance: opportunities and challenges. AB - Engaged scholarship promotes contribution to the academic body of knowledge through equal partnership between academic scholars and community representatives in education, research, and public service or intervention. Such partnerships can expand our notions of service learning and applied research. In this article, the authors discuss the potential contribution of engaged scholarship to the relevance of gerontological education and research programs. The authors discuss the role of engaged scholarship in the philosophy of education, in the promotion of social justice, and its relevance for the civic responsibility and accountability of educational institutions. Finally, the authors describe benefits and barriers to participation in engaged scholarship and challenges in the recruitment of engaged scholars. PMID- 23095221 TI - An evaluation of an online postgraduate dementia studies program. AB - Education is key to addressing the challenges of providing high-quality care to the ever growing number of people with dementia. Although dementia education is required for multiple professions and disciplines working with people with dementia and their families and friends, there is a gap in knowledge of students' views about university-level online dementia education. This article reports on an evaluation, via an online questionnaire, of student views of the delivery modes and learning impact for the first online postgraduate program in Dementia Studies worldwide. The majority of our respondents (65%) reported their participation in the Dementia Studies program as broadening their thinking, with 61% reporting that it broadened their practice. Students also reported on the utility of initial face-to-face teaching and the extent to which they are able to apply their learning to practice. The article concludes by suggesting that a blended learning approach, comprising online and face-to-face teaching with an emphasis on reflexivity has the potential to meet the global demand for skilled dementia care practitioners and to create leaders in the dementia care field. PMID- 23095222 TI - Training of home health aides and nurse aides: findings from national data. AB - Training and satisfaction with training were examined using data from nationally representative samples of 2,897 certified nursing assistants (CNAs) from the National Nursing Assistant Survey and 3,377 home health aides (HHAs) from the National Home Health Aide Survey conducted in 2004 and 2007, respectively. This article focuses on the commonalities and differences in the perceptions of CNAs and HHAs regarding the initial and continuing education they received to prepare them for their job. More than 80% of HHAs and all CNAs received some initial training. Of these, significantly more HHAs compared to CNAs felt that training had prepared them "very well" for their jobs. The two groups also differed in their assessments of the content of the initial training; for example, more CNAs believed that their training was "excellent" in helping them address patients' limitations in activities of daily living compared to HHAs. The vast majority of HHAs and CNAs received continuing education, and about three fourths in each group assessed this training as being "very useful." In light of the increasing demands for HHAs and CNAs with the aging of America, findings from these national studies could be used to inform educational and training initiatives for this critical workforce. PMID- 23095223 TI - Communicating with patients who have advanced dementia: training nurse aide students. AB - The increase of dementia in older adults is changing how medical care is delivered. Recognizing symptoms of pain, managing behaviors, and providing quality of life for people who have advanced dementia requires a new skill set for caregivers. Researchers in this study targeted nurse aide students to test an educational module's effect on students' perceptions of dementia and their ability to care for patients with dementia. The results indicated the training was effective regarding nurse aides' understanding of residual cognitive abilities and need for meaningful contact among patients with advanced dementia; however, the training was not successful in terms of nurse aides' comfort level or perceived skills in working with this population of patients. The findings suggest a need to transform how caregivers are trained in communication techniques. Incorporating this training into nurse aide education has the potential to increase quality of life for people with dementia. PMID- 23095226 TI - Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA. AB - BACKGROUND: Hospitals nowadays have to serve numerous patients with limited medical staff and equipment while maintaining healthcare quality. Clinical pathway informatics is regarded as an efficient way to solve a series of hospital challenges. To date, conventional research lacks a mathematical model to describe clinical pathways. Existing vague descriptions cannot fully capture the complexities accurately in clinical pathways and hinders the effective management and further optimization of clinical pathways. METHOD: Given this motivation, this paper presents a clinical pathway management platform, the Imperial Clinical Pathway Analyzer (ICPA). By extending the stochastic model performance evaluation process algebra (PEPA), ICPA introduces a clinical-pathway-specific model: clinical pathway PEPA (CPP). ICPA can simulate stochastic behaviours of a clinical pathway by extracting information from public clinical databases and other related documents using CPP. Thus, the performance of this clinical pathway, including its throughput, resource utilisation and passage time can be quantitatively analysed. RESULTS: A typical clinical pathway on stroke extracted from a UK hospital is used to illustrate the effectiveness of ICPA. Three application scenarios are tested using ICPA: 1) redundant resources are identified and removed, thus the number of patients being served is maintained with less cost; 2) the patient passage time is estimated, providing the likelihood that patients can leave hospital within a specific period; 3) the maximum number of input patients are found, helping hospitals to decide whether they can serve more patients with the existing resource allocation. CONCLUSIONS: ICPA is an effective platform for clinical pathway management: 1) ICPA can describe a variety of components (state, activity, resource and constraints) in a clinical pathway, thus facilitating the proper understanding of complexities involved in it; 2) ICPA supports the performance analysis of clinical pathway, thereby assisting hospitals to effectively manage time and resources in clinical pathway. PMID- 23095227 TI - Clinical implication of adenosine test at repeat atrial fibrillation ablation procedure: the importance of detecting dormant thoracic vein conduction. AB - BACKGROUND: Pulmonary vein reconnection after electrical isolation is commonly observed in the context of atrial fibrillation ablation and is associated with recurrent atrial tachyarrhythmias. Adenosine test was been performed to identify acute dormant conduction immediately after pulmonary vein isolation at index procedure. However, the utility of adenosine test at repeat procedure has not been reported. METHODS AND RESULTS: We report 5 paroxysmal atrial fibrillation cases without any structural heart disease in which dormant thoracic vein conduction was associated with recurrent atrial tachyarrhythmias. All patients had undergone circumferential ipsilateral pulmonary vein isolation at the index procedure. Superior vena cava isolation was performed if superior vena cava triggered atrial fibrillation was identified. At the index procedure, adenosine test did not provoke venous reconduction. At the repeat procedure, adenosine provoked clinical arrhythmia in 4 out of 5 cases after transient reconnection between culprit thoracic vein and atrium despite absence of reconnection at the start of the procedure. After the elimination of the dormant conduction gaps, all patients were free from recurrent arrhythmia. CONCLUSIONS: Adenosine provokes dormant thoracic vein conduction associated with the late recurrence of atrial tachyarrhythmias after previous thoracic vein isolation. Thus, adenosine provocation test can specifically help identify and target the cause of recurrent atrial arrhythmia. PMID- 23095228 TI - Atrial fibrillation-associated remodeling does not promote atrial thrombus formation in canine models. AB - BACKGROUND: The most important complication of atrial fibrillation (AF) is thromboembolic stroke. Although AF-related remodeling is considered important in atrial thrombogenesis, its role never has been directly tested. This study assessed effects of AF-related remodeling on the atrial thrombogenic milieu by using radiofrequency ablation (RFA) to create a quantifiable prothrombotic nidus. METHODS AND RESULTS: We studied normal control dogs (control, n=16) and 3 canine AF-models: (1) atrial tachycardia remodeling (ATR; n=16) induced by atrial tachypacing (400 bpm for 1 week, with atrioventricular block and ventricular pacing at 80 bpm); (2) congestive heart failure (CHF; n=14) attributable to ventricular tachypacing (240 bpm for 2 weeks); and (3) chronic AF (CAF; n=8) induced by atrial tachypacing (35+/-3 days) without atrioventricular block. CAF dogs had AF for 13+/-1 days until euthanization. After remodeling was established, RFA lesions were created in both atria. Half the ATR and CHF dogs were subjected to atrial tachypacing during 7-day post-RFA follow-up. Electrophysiological and echocardiographic studies were performed before RFA and 7 days after RFA, and then hearts were removed and atrial thrombi were quantified by histomorphometry. Burst-pacing-induced AF duration was significantly greater in ATR, CHF, and CAF groups versus control group. The atrial effective refractory period shortened in ATR and CAF groups. Left atrial diameter was significantly larger with CHF, but not with ATR. Neither total thrombus volume nor thrombus volume per lesion differed significantly among groups. Table.Properties of Ablation Lesions and Atrial Thrombi Experimental GroupControl (n=16)ATR (n=16)CHF (n=14)CAF (n=8)N of ablation lesions per dog6.9+/-0.36.6+/-0.27.2+/-0.26.9+/ 0.4Ablation lesion area, mm(2)53.1+/-3.558.3+/-4.857.7+/-4.944.3+/-3.7Ablation lesion depth, mm5.2+/-0.25.1+/-0.35.3+/-0.25.2+/-0.2Ablation lesion volume, mm(3)205.2+/-17.8211.6+/-17.6231.5+/-29.0176.8+/-22.2N of thrombi per dog5.4+/ 0.44.7+/-0.35.6+/-0.46.5+/-0.4Presence of thrombus, %80+/-572+/-577+/-695+/-3Mean thrombus volume in both atria, mm(3)20.8+/-3.414.9+/-2.212.2+/-2.622.5+/-5.6Mean thrombus volume in left atria, mm(3)8.2+/-1.54.0+/-0.95.5+/-1.68.1+/-3.3Mean thrombus volume in right atria, mm(3)30.1+/-5.422.7+/-4.317.9+/-4.132.8+/ 8.3Total thrombus volume in both atria, mm(3)140.5+/-21.399.7+/-16.886.1+/ 17.5131.1+/-22.7Total thrombus volume in left atria, mm(3)22.8+/-5.311.8+/ 3.317.0+/-3.723.3+/-6.4Total thrombus volume in right atria, mm(3)117.7+/ 21.587.8+/-17.269.1+/-16.1107.8+/-23.3Thrombus volume normalized to ablation lesion area in both atria, mm(3)/mm(2)0.5+/-0.10.4+/-0.11.5+/-1.10.8+/ 0.3Thrombus volume normalized to ablation lesion volume in both atria0.2+/ 0.10.1+/-0.00.5+/-0.40.3+/-0.1 ATR indicates atrial tachycardia remodeling; CAF, chronic atrial fibrillation; and CHF, congestive heart failure. There were no statistically significant differences for any groups vs control group for any of these variables studied. CONCLUSIONS: None of the AF substrates tested, including sustained atrial tachycardia/AF itself, enhanced post-RFA atrial thrombus formation. Indices of electrical and structural remodeling did not predict post RFA thrombogenic potential. Contrary to widely held but previously untested notions, we were unable to demonstrate prothrombotic effects of AF-related remodeling. PMID- 23095229 TI - Red blood cell distribution width as a biomarker for need for coronary artery bypass graft surgery and its clinical outcome. PMID- 23095230 TI - Relationship of glioblastoma multiforme to the subventricular zone is associated with survival. AB - The subventricular zone (SVZ) lines the lateral ventricles and represents the origin of neural and some cancer stem cells. Tumors contacting the SVZ may be more invasive with higher potential to recruit migratory progenitor cells. Our specific aim was to determine whether SVZ involvement in glioblastoma multiforme (GBM) is associated with a higher recurrence rate and shorter overall survival. MR imaging and clinical data from 91 patients with GBM treated at our institution were retrospectively reviewed. Tumors were classified as type I if the contrast enhancing lesion contacted both the SVZ and cortex on pre-operative MRI, type II if only the SVZ was involved, type III if only cortex was involved, and type IV if the lesion did not contact either the SVZ or cortex. Progression-free survival (PFS) and overall survival were estimated based on Kaplan-Meier calculations. When comparing type I tumors with types II-IV, only 39% of patients with type I tumors were free of recurrence and alive at 6 months, significantly fewer than for all other types combined (67%; P = .01). PFS at 6 months was also less, at only 47% among patients with SVZ-positive tumors, compared with 69% in the SVZ negative group (P = .002). Patients with SVZ involvement also demonstrated a more rapid time to progression, compared with those not involving the SVZ (P = .003). Patients with GBM involving the SVZ have decreased overall survival and PFS, which may have prognostic and therapeutic implications. PMID- 23095231 TI - BSAC standardized disc susceptibility testing method (version 11). AB - This article highlights key amendments incorporated into version 11 of the BSAC standardized disc susceptibility testing method, available as Supplementary data at JAC Online (http://jac.oxfordjournals.org/) and on the BSAC web site (http://bsac.org.uk/susceptibility/guidelines-standardized-disc-susceptibility testing-method/). The basic disc susceptibility testing method remains unchanged, but there have been a number of alterations to the interpretive criteria for certain organism/drug combinations due to continuing harmonization with the EUCAST MIC breakpoints and constant efforts to improve the reliability and clinical applicability of the guidance. PMID- 23095232 TI - Bone marrow plasma cell separation - validation of separation algorithm. PMID- 23095234 TI - Early imaging of macular hole closure: a diagnostic technique and its quality for gas-filled eyes with spectral domain optical coherence tomography. AB - BACKGROUND/AIMS: This study was conducted to establish a reliable method to determine macular hole (MH) closure of gas-filled eyes. METHOD: 21 consecutive eyes with MH underwent vitrectomy with gas tamponade, and spectral domain optical coherence tomography (SD-OCT) was performed using our diagnostic technique. The quality of OCT images was rated as signal strength (SS) and evaluated by masked observers. RESULTS: The quality to determine MH closure (SS >=4) was sufficient in all eyes. In addition, SD-OCT images (SS >=6) obtained from 16/21 eyes showed detailed retinal structures including the inner segment/outer segment line. The next day after surgery, MH closure was confirmed in 12/21 eyes, and residual MH was observed in 9/21 eyes. Among these 9 eyes, 7 eyes were closed within 2 weeks. CONCLUSION: The present method provided clear SD-OCT images from gas-filled eyes, which is not only essential for the diagnosis of MH closure but also for establishing proper protocols and for studying the pathology of gas-filled eyes. PMID- 23095233 TI - A novel mouse model of podocyte depletion. AB - AIM: The goal of this study was to examine the capacity for glomerular repair after a podocyte-depleting injury. METHODS: We created transgenic (TG) mice expressing the yeast enzyme cytosine deaminase specifically in glomerular podocytes. In these TG animals, the prodrug 5-flucytosine (5-FC) is converted to 5-fluorouracil and promotes cell death. RESULTS: Treatment with increasing dosages of 5-FC caused graded increases in proteinuria 1-2 weeks after treatment, which returned to control levels by the 10-week time point. Light microscopic examination revealed minimal pathology at the 2-week time point, but electron microscopy revealed found foot process effacement as well as focal areas of glomerular basement membrane duplication, and immunohistochemical studies detected podocyte apoptosis and a decrease in the number of Wilms' tumor protein 1 (WT1)-positive cells. By the 10-week time point, however, the number of WT1 positive cells was similar to controls and a few mice had developed focal areas of glomerulosclerosis. Consistent with the effects of 5-FC on podocyte number, expression of the podocyte mRNAs for nephrin, podocin, synaptopodin and podocalyxin were altered in a similar temporal fashion. CONCLUSION: The glomerulus has a significant capacity for repair after a podocyte-depleting injury. PMID- 23095235 TI - Epidemiological trends in zoophilic and geophilic fungi in Iran. AB - BACKGROUND: Dermatophytes can be divided into geophilic (soil), zoophilic (animals) and anthropophilic (human) strains, depending on the source of the keratin. The predominant organisms vary within a given geographical region during different periods, which is influenced by a number of factors, such as population movements, socioeconomic circumstances and level of surveillance. Thus, the incidence is very variable. AIM: To determine the epidemiology of superficial fungal infections due to zoophilic and geophilic fungi in patients referred to the Pasteur Institute of Iran. METHODS: The clinical presentation of zoophilic and geophilic dermatophyte-related infections was reviewed retrospectively from the medical records of all subjects referred to our laboratory for assessment of cutaneous fungal infection. Mycological examination consisted of culturing of pathological material followed by direct microscopy. Diagnosis was based on the macroscopic and microscopic characteristics of the colonies. RESULTS: Of the 3976 clinically suspected cases of dermatophytosis, 239 (39.6%) were zoophilic dermatophytosis, confirmed by direct examination and culture. They occurred in 93 (39%) female patients and 146 (61%) male patients (median age 27.4 years, range 1.5-75). The commonest zoophilic fungi isolated were Trichophyton mentagrophytes var. mentagrophytes (28%), followed by Trichophyton verrucosum (9.3%) and Microsporum canis (2.2%). The geophilic fungus Microsporum gypseum was isolated from 0.33% of patients. CONCLUSION: This study identifies the epidemiological trends and the predominant organisms causing zoophilic dermatophytosis in humans in Tehran. Consideration of the current epidemiological trends in the incidence of cutaneous zoophilic fungal pathogens is essential for investigation, diagnosis and treatment. PMID- 23095236 TI - The neuroprotective effect of losartan through inhibiting AT1/ASK1/MKK4/JNK3 pathway following cerebral I/R in rat hippocampal CA1 region. AB - AIMS: It has been well documented that angiotensin II type 1 (AT(1) ) receptor blockers (ARBs) are known to attenuate neural damage and the c-Jun N-terminal protein kinase 3 (JNK3) pathway and caspase-3 signal are involved in neuronal cell death following cerebral ischemia/reperfusion (I/R). In this study, we first showed that losartan could protect neurons against cerebral I/R-induced injury. METHODS: Cerebral ischemia model was induced by four-vessel occlusion. Antisense oligodeoxynucleotides (ODNs) against AT1 receptor and losartan were used to detect whether the AT1 receptor implicated in cerebral I/R. Immunoprecipitation (IP) and immunoblotting (IB) were used to detect the interactions between beta arrestin-2 and AT1/apoptosis signal-regulating kinase 1 (ASK1)/MAP kinase kinase 4 (MKK4) signaling module following cerebral I/R. RESULTS: First, losartan decreased cerebral I/R-induced neuronal death. Second, losartan depressed the beta-arrestin-2-assembled AT1/ASK1/MKK4 signaling module. Third, losartan depressed the activation of c-jun, JNK3, Bcl-2, caspase-3 and the release of cytochrome c from mitochondria to cytoplasm. CONCLUSION: Taken together, losartan could attenuate neural damage following the cerebral I/R via inhibiting the beta arrestin-2-assembled AT1/ASK1/MKK4 signaling module and depressing the activation of c-jun, JNK3, and caspase-3 and the release of cytochrome c. PMID- 23095237 TI - Egocentric and allocentric spatial representations in Williams syndrome. AB - Williams syndrome (WS) is a neurodevelopmental disorder characterized by severe visuospatial deficits, particularly affecting spatial navigation and wayfinding. Creating egocentric (viewer-dependent) and allocentric (viewer-independent) representations of space is essential for the development of these abilities. However, it remains unclear whether egocentric and allocentric representations are impaired in WS. In this study, we investigate egocentric and allocentric frames of reference in this disorder. A WS group (n = 18), as well as a chronological age-matched control group (n = 20), a non-verbal mental age-matched control group (n = 20) and a control group with intellectual disability (n = 17), was tested with a computerized and a 3D spatial judgment task. The results showed that WS participants are impaired when performing both egocentric and allocentric spatial judgments even when compared with mental age-matched control participants. This indicates that a substantial deficit affecting both spatial representations is present in WS. The egocentric impairment is in line with the dorsal visual pathway deficit previously reported in WS. Interestingly, the difficulties found in performing allocentric spatial judgments give important cues to better understand the ventral visual functioning in WS. PMID- 23095238 TI - Mitral annular calcification is associated with pulse wave velocity but not with augmentation index. AB - OBJECTIVE: To investigate the possible relationship between mitral annular calcification (MAC) and arterial stiffness. SUBJECTS AND METHODS: Forty-two patients (mean age 68 +/- 6 years) with MAC and an age-matched control group of 41 individuals (mean age 66 +/- 6 years) were studied. Arterial stiffness and wave reflections of the study population were evaluated by using applanation tonometry (SphygmoCor). Aortic pulse wave velocity (PWV) was measured as an index of aortic stiffness. The heart rate-corrected augmentation index (AIx@75) was estimated as a composite marker of wave reflections and arterial stiffness. RESULTS: Aortic PWV was significantly higher in patients with MAC (12.2 +/- 2.3 m/s) than in controls (10.1 +/- 1.3 m/s, p = 0.0001). However, AIx@75 was similar between the groups (28 +/- 10 vs. 29 +/- 10%, p = 0.59). Multivariate analysis involving the whole population revealed that brachial diastolic blood pressure (beta = 1.87, p = 0.04) and MAC (beta = 0.41, p = 0.0001) were independent determinants of aortic PWV. CONCLUSION: The data showed that MAC was significantly associated with increased arterial stiffness and that it was an independent determinant of aortic PWV. PMID- 23095239 TI - Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis. AB - Cardiovascular disease is increased in patients with chronic kidney disease (CKD) and is the principle cause of morbidity and mortality in these patients. In patients with stage 5 CKD, structural changes in the myocardium have been implicated as the principle cardiovascular processes leading to this increase in morbidity and mortality, while atherosclerotic events including acute myocardial infarction and strokes are responsible for approximately 10-15% of cardiovascular deaths. Dyslipidemia is common in CKD patients and is usually not characterized by elevated cholesterol levels, except in patients with marked proteinuria. Increased triglyceride levels in conjunction with decreased high-density lipoprotein levels are the commonest qualitative abnormality. Characteristically, abnormalities in the metabolism of apolipoprotein (apo) B-containing lipoproteins have been described, including both gut derived (apoB-48) as well as those produced by hepatic synthesis (apoB-100). A decrease in enzymatic delipidation as well as reduced receptor removal of these lipoproteins both contribute to the increased levels of these apo-B-containing particles and their remnants (which are believed to be highly atherogenic). Abnormalities in the metabolism of apoA containing lipoproteins are also present and these changes contribute to the lower levels of HDL seen. Qualitative abnormalities of these HDL particles may be associated with cellular oxidative injury and contribute to a pro-inflammatory, pro-thrombotic milieu that is frequently present in CKD patients. PMID- 23095240 TI - Effect of statin therapy on the progression of common carotid artery intima-media thickness: an updated systematic review and meta-analysis of randomized controlled trials. AB - AIM: To evaluate the effect of statin therapy on the decrease of common carotid artery intima-media thickness (CCA-IMT) compared to placebo or usual care. METHODS: A systematic search of electronic databases (MEDLINE, EMBASE, and Cochrane Center Register) up to December 2011 was performed. Two reviewers independently determined the eligibility of randomized controlled trials (RCTs) comparing statin therapy with a placebo or usual care with a minimum follow-up of 6 months. RESULTS: Twenty-one RCTs involving 6317 individuals were included in this review. The pooled weighted mean difference (WMD) between statin therapy and placebo or usual care on CCA-IMT was -0.029 mm (95%CI: -0.045, -0.013). Subgroup analyses showed significant effects of lovastatin (WMD: -0.077; 95%CI: -0.082, 0.073) and simvastatin (WMD: -0.069; 95%CI: -0.094, -0.045), followed by pravastatin and rosuvastatin, but no significant benefits of atorvastatin, fluvastatin, or cerivastatin. A greater decrease in mean CCA-IMT was observed in the setting of secondary prevention versus primary prevention (WMD: -0.045 vs. 0.004), in younger patients versus older patients (WMD: -0.057 vs. -0.041), and in studies where the patient proportion was males >= females (-0.044 vs. -0.008). Meta-regression analysis showed a significant association between changes in mean CCA-IMT with decreasing triglyceride levels. A similar, but not statistically significant trend was also found between CCA-IMT decrease and the decrease in LDL C levels or increase in HDL-C levels. CONCLUSION: Statin therapy is associated with a favorable decrease in CCA-IMT, an effect that seems to be mainly driven by the CCA-IMT at baseline and the extent of lipid decrease, specifically triglycerides. PMID- 23095241 TI - Multicenter study to determine the diagnosis criteria of heterozygous familial hypercholesterolemia in Japan. AB - AIM: Heterozygous patients of familial hypercholesterolemia (FH) are known to have a high risk of coronary artery disease (CAD). Early diagnosis and prompt treatment are necessary to prevent their CAD. In this study we tried to amend the Japanese diagnostic criteria of FH for general practitioners by examining each component of the current criteria. METHODS: A multicenter study was performed, which included 1356 dyslipidemic patients at 6 centers. Pretreatment demographic information including LDL-cholesterol (LDL-C), Achilles tendon thickness (ATT), family history of FH and premature CAD and the result of genetic analysis were analyzed. RESULTS: Of 1356 patients, 419 were diagnosed with FH by criteria in 1988, which were used as a golden standard. We tried to define FH according to 3 conventional major items, i.e., 1) LDL-C, 2) ATT and/or cutaneous nodular xanthomas (CX), 3) family history of FH and/or family history of premature CAD. We then determined the cutoff of LDL-C using the new criteria. When we used 180 mg/dL as the cutoff of LDL-C, 94.3% of FH patients and 0.85% of non-FH satisfied 2 or more criteria. When we used 190 mg/dL, 92.1% of FH and 0.85% of non-FH satisfied 2 or more criteria; therefore, we chose 180 mg/dL for the cutoff of LDL C in the new criteria and proposed that the diagnosis of definite FH can be made if 2 or more criteria are satisfied. CONCLUSIONS: We examined each component for the diagnosis of heterozygous FH in a multicenter study in Japan. PMID- 23095242 TI - Guidelines for the management of familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is a highly prevalent autosomal dominant hereditary disease, generally characterized by three major signs, hyper-low density-lipoprotein (LDL) cholesterolemia, tendon/skin xanthomas and premature coronary artery disease (CAD). Because the risk of CAD is very high in these patients, they should be identified at an early stage of their lives and started on intensive treatment to control LDL-cholesterol. We here introduce a new guideline for the management of FH patients in Japan intending to achieve better control to prevent CAD. Diagnostic criteria for heterozygous FH are 2 or more of 1) LDL-cholesterol >=180 mg/dL, 2) tendon/skin xanthoma(s), and 3) family history of FH or premature CAD within second degree relatives, for adults; and to have both 1) LDL-cholesterol >=140 mg/dL and 2) family history of FH or premature CAD within second degree relatives, for children. For the treatment of adult heterozygous FH, intensive lipid control with statins and other drugs is necessary. Other risks of CAD, such as smoking, diabetes mellitus, hypertension etc., should also be controlled strictly. Atherosclerosis in coronary, carotid, or peripheral arteries, the aorta and aortic valve should be screened periodically. FH in children, pregnant women, and women who wish to bear a child should be referred to specialists. For homozygotes and severe heterozygotes resistant to drug therapies, LDL apheresis should be performed. The treatment cost of homozygous FH is authorized to be covered under the program of Research on Measures against Intractable Diseases by the Japanese Ministry of Health, Labour, and Welfare. PMID- 23095243 TI - Directed evolution of bright mutants of an oxygen-independent flavin-binding fluorescent protein from Pseudomonas putida. AB - BACKGROUND: Fluorescent reporter proteins have revolutionized our understanding of cellular bioprocesses by enabling live cell imaging with exquisite spatio temporal resolution. Existing fluorescent proteins are predominantly based on the green fluorescent protein (GFP) and related analogs. However, GFP-family proteins strictly require molecular oxygen for maturation of fluorescence, which precludes their application for investigating biological processes in low-oxygen environments. A new class of oxygen-independent fluorescent reporter proteins was recently reported based on flavin-binding photosensors from Bacillus subtilis and Pseudomonas putida. However, flavin-binding fluorescent proteins show very limited brightness, which restricts their utility as biological imaging probes. RESULTS: In this work, we report the discovery of bright mutants of a flavin binding fluorescent protein from P. putida using directed evolution by site saturation mutagenesis. We discovered two mutations at a chromophore-proximal amino acid (F37S and F37T) that confer a twofold enhancement in brightness relative to the wild type fluorescent protein through improvements in quantum yield and holoprotein fraction. In addition, we observed that substitution with other aromatic amino acids at this residue (F37Y and F37W) severely diminishes fluorescence emission. Therefore, we identify F37 as a key amino acid residue in determining fluorescence. CONCLUSIONS: To increase the scope and utility of flavin-binding fluorescent proteins as practical fluorescent reporters, there is a strong need for improved variants of the wild type protein. Our work reports on the application of site saturation mutagenesis to isolate brighter variants of a flavin-binding fluorescent protein, which is a first-of-its-kind approach. Overall, we anticipate that the improved variants will find pervasive use as fluorescent reporters for biological studies in low-oxygen environments. PMID- 23095244 TI - Subacute effects of ecstasy on mood: an exploration of associated risk factors. AB - Ecstasy use may result in lowered mood, anxiety or aggression in the days following use. Yet, few studies have investigated what factors increase the risk of experiencing such symptoms. Ecstasy users (at least once in the last 12 months) who subsequently took ecstasy (n=35) over the period of one week, were compared on measures of mood, sleep, stress and drug use, with those who abstained from ecstasy (n=21) that week. Measures were administered the week prior to ecstasy use and one and three days following use, or the equivalent day for abstainers. Mood symptoms were assessed using the Kessler-10 self-report psychological distress scale, a subjective mood rating (1-10), and using the depression, anxiety and hostility items from the clinician-rated Brief Psychiatric Rating Scale. Timeline Followback methods were used to collect information on drug use and life stress in the past month. Self-reported sleep quality was also assessed. Ecstasy use was not associated with subacute depressive, anxiety or aggressive symptoms. Rather, lowered mood and increased psychological distress were associated with self-reported hours and quality of sleep obtained during the three-day follow-up. These findings highlight the importance of considering sleep disruption in understanding the short-term mood effects of ecstasy use. PMID- 23095245 TI - Differential effects of antipsychotic agents on obsessive-compulsive symptoms in schizophrenia: a longitudinal study. AB - Indirect evidence supports the assumption that antiserotonergic second-generation antipsychotics (SGA) induce and aggravate obsessive-compulsive symptoms (OCS) in schizophrenia. However, multimodal studies assessing the long-term interaction of pharmacotherapy and psychopathology are missing. Over 12 months, we followed-up 75 schizophrenia patients who were classified into two groups according to antipsychotic treatment: clozapine or olanzapine (group I) versus aripiprazole or amisulpride (group II). We applied the Yale Brown Obsessive Compulsive Scale (YBOCS) and investigated between-group changes over time as the primary endpoint. Group I showed markedly higher YBOCS scores at both time points. Repeated measure analyses of variance (ANOVAs) revealed significant interaction effects of group and time (per protocol sample (PP): p=0.006). This was due to persistently high OCS severity within group I, and decreasing YBOCS scores within group II. OCS severity correlated significantly with the negative and general psychopathology subscales of the Positive and Negative Syndrome Scale (PANSS), as well as with depressive symptoms. The progressive differences in OCS severity between our groups support the assumption of differential pharmacodynamic effects on comorbid OCS in schizophrenia. Further studies should address the pathogenetic mechanism, define patients at risk and facilitate early detection as well as therapeutic interventions. PMID- 23095247 TI - Elevated red blood cell distribution width is associated with higher recourse to coronary artery bypass graft. AB - BACKGROUND: Red blood cell distribution width (RDW) is a measure of heterogeneity in erythrocyte size used in the differential diagnosis of anemia. High levels are associated with elevated cardiovascular biomarkers and increased mortality. The hypothesis of this study is that high RDW levels on admission are associated with higher recourse to coronary artery bypass graft (CABG) in unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) patients. METHODS: An observational, cross-sectional study of all adult patients undergoing coronary angiography admitted to an urban tertiary care center in 2007 with UA or NSTEMI was conducted. Data was gathered by review of inpatient charts. RDW was considered 'high' if it exceeded the 95th percentile (16.3%). RESULTS: Among the 503 subjects included in the analysis, high RDW was independently associated with higher recourse to CABG versus a nonsurgical approach [OR = 2.39 (1.04-5.50); p = 0.041] but not with conservative management [OR = 0.97 (0.51-1.84); p = 0.922] or percutaneous coronary intervention [OR = 0.67 (0.36-1.25); p = 0.208]. CONCLUSIONS: This study of patients with UA or NSTEMI demonstrated an independent association of elevated RDW with higher recourse to CABG. RDW should be considered in the stratification of patients presenting with UA or NSTEMI. PMID- 23095248 TI - Effectiveness of photoactivated disinfection (PAD) to kill enterococcus faecalis in planktonic solution and in an infected tooth model. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of photoactivated disinfection (PAD) in killing Enterococcus faecalis (EF) in planktonic solution and in an infected tooth model. METHODS: One hundred and thirty-two glass tubes of EF samples with concentration of 10(14) colony forming units (CFU)/mL and photosensitizer were prepared. Sixteen groups were set up and subjected to diode laser, and then received a radiation energy dose ranging from 0.5 to 5.5 J. The bactericidal effect was measured by the mean CFU of viable EF after irradiation. Sixty single-rooted teeth were selected and contaminated with EF, and then given PAD therapy; 5.25% NaOCl irrigation and saline solution were used to disinfect the root canals. Microbial samples were taken before and after disinfection, and after 72 h recovery, and then the CFU were counted. RESULTS: The bactericidal effect increased linearly with the irradiation energy dose in planktonic solution. For the same irradiation energy dose, the bactericidal effect was greater in group receiving 100 mW than in that receiving 50 mW and exposed to doubled irradiation time (p<0.05). No bacterium was detected after irrigation in the NaOCl group in the root canal model, but the recovery of bacteria after 72 h was detected in 11 samples. Bacteria were detected in all the other groups, and PAD was significantly more effective than saline solution in reducing the number of bacterial cells within the root canals (p<0.05). CONCLUSIONS: PAD was shown to have bactericidal effect on EF, and the bactericidal effect increased linearly with the irradiation energy dose and was superior using higher output power. PAD could decrease EF in root canals effectively, but was no more effective than 5.25% NaOCl, and PAD is more effective in planktonic solution than in root canals. PMID- 23095249 TI - Strategy for eliciting antigen-specific CD8+ T cell-mediated immune response against a cryptic CTL epitope of merkel cell polyomavirus large T antigen. AB - BACKGROUND: Merkel cell carcinoma (MCC) is a relatively new addition to the expanding category of oncovirus-induced cancers. Although still comparably rare, the number of cases has risen dramatically in recent years. Further complicating this trend is that MCC is an extremely aggressive neoplasm with poor patient prognosis and limited treatment options for advanced disease. The causative agent of MCC has been identified as the merkel cell polyomavirus (MCPyV). The MCPyV encoded large T (LT) antigen is an oncoprotein that is theorized to be essential for virus-mediated tumorigenesis and is therefore, an excellent MCC antigen for the generation of antitumor immune responses. As a foreign antigen, the LT oncoprotein avoids the obstacle of immune tolerance, which normally impedes the development of antitumor immunity. Ergo, it is an excellent target for anti-MCC immunotherapy. Since tumor-specific CD8+ T cells lead to better prognosis for MCC and numerous other cancers, we have generated a DNA vaccine that is capable of eliciting LT-specific CD8+ T cells. The DNA vaccine (pcDNA3-CRT/LT) encodes the LT antigen linked to a damage-associated molecular pattern, calreticulin (CRT), as it has been demonstrated that the linkage of CRT to antigens promotes the induction of antigen-specific CD8+ T cells. RESULTS: The present study shows that DNA vaccine-induced generation of LT-specific CD8+ T cells is augmented by linking CRT to the LT antigen. This is relevant since the therapeutic effects of the pcDNA3-CRT/LT DNA vaccine is mediated by LT-specific CD8+ T cells. Mice vaccinated with the DNA vaccine produced demonstrably more LT-specific CD8+ T cells. The DNA vaccine was also able to confer LT-specific CD8+ T cell-mediated protective and therapeutic effects to prolong the survival of mice with LT expressing tumors. In the interest of determining the LT epitope which most MCC specific CD8+ T cells recognize, we identified the amino acid sequence of the immunodominant LT epitope as aa19-27 (IAPNCYGNI) and found that it is H-2kb restricted. CONCLUSION: The results of this study can facilitate the development of other modes of MCC treatment such as peptide-based vaccines and adoptive transfer of LT-specific CD8+ T cells. Likewise, the MCC DNA vaccine has great potential for clinical translation as the immunologic specificity is high and the treatment strategy can be exported to address other virus-induced tumors. PMID- 23095250 TI - An ergonomic study of single-port versus multi-port laparoscopic mesh insertion for ventral hernia repair. AB - PURPOSE: To assess the mental effort and physical discomfort of placement of a prosthetic mesh into the abdominal cavity with single-incision laparoscopic surgery (SILS) or multi-port laparoscopic access for incisional ventral hernia repair. METHODS: A total of 10 surgeons with previous experience in conventional laparoscopic surgery performed four surgical tasks through a multi-port laparoscopic access and a SILS access in a porcine model during a first 4-hour working session and a second 2-hour working session. These tasks included (a) introduction of a prosthetic mesh for abdominal wall surgery, (b) manipulation of the mesh inside the abdomen, (c) manipulation of the laparoscopic instruments and (d) mesh insertion to the intraperitoneal abdominal wall and fixation with tackers. The level of mental effort was assessed with the Subjective Mental Effort Questionnaire (SMEQ) and physical discomfort with the Local Experienced Discomfort Scale (LED). RESULTS: Seventy percent were men, with a mean age of 45 years and a mean of 18 years of experience in practicing surgery. The SMEQ questionnaire showed a median physical effort of 24.4 (range 9-36.1) points for the multi-port laparoscopic access and 107.4 (range 74.7-128.4) for SILS (p < 0.01). Statistically significant differences between multi-port laparoscopic surgery and SILS were consistently demonstrated in all tasks as well as in both the 4-hour and 2-hour working sessions. The median (interquartile range) score of the LED scale was 12.5 (2-34.5) for tasks during multi-port laparoscopic surgery and 53.5 (29-89.2) for SILS (p < 0.001). All individual tasks were associated with a significantly higher physical effort for SILS than for conventional laparoscopic access, which were also independent of being performed during the 4 hour or 2-hour working periods. CONCLUSIONS: Placement and manipulation of a prosthetic mesh for incisional ventral hernia repair is more difficult with SILS than using multi-port laparoscopic access, independently of previous experience with standard laparoscopic techniques. This greater difficulty was observed both in terms of mental effort and physical discomfort. More experimental and clinical studies are needed to define specific training aspects and clinical advantages of incisional ventral hernia repair through SILS. PMID- 23095251 TI - Determination of ELISA reproducibility to detect protein markers in exhaled breath condensate. AB - Exhaled breath condensate (EBC) is a representative sample from the lungs that may be used to detect different markers, but the reproducibility of these determinations is unknown over time. The aim of this paper is to assess the reproducibility of protein marker determination in EBC using samples collected at two different time points. EBC and blood were collected from 16 healthy subjects, smokers and non-smokers by using the ECoScreen device. EBC was collected on two separate occasions within ten days. Enzyme-linked immunosorbent assay (ELISA) was performed to measure angiogenesis and hypoxia markers. Blood and EBC samples were analyzed by ELISA to detect angiogenesis markers: vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin. A hypoxia marker, the anhydrase IX, was also determined. Biomarker concentration was higher in plasma samples compared to EBC. bFGF determination was higher in women (39.47 +/- 3.914 versus 27.15 +/- 3.145; p < 0.05). There were no significant differences among the averages of detection for any of the markers. The Bland Altman method showed that the average of the differences or biases in EBC for every biomarker was close to zero, indicating a good reproducibility of the measurements. Nevertheless, the VEGF showed wide limits of agreement. EBC is suitable to detect biomarkers by ELISA and the measurements are reproducible over time. Nevertheless, some factors such as sex should be taken into account when analyzing the results. PMID- 23095253 TI - The effect of magnetic field on the impurity binding energy of shallow donor impurities in a Ga1-xInxNyAs1-y/GaAs quantum well. AB - Using a variational approach, we have investigated the effects of the magnetic field, the impurity position, and the nitrogen and indium concentrations on impurity binding energy in a Ga1-xInxNyAs1-y/GaAs quantum well. Our calculations have revealed the dependence of impurity binding on the applied magnetic field, the impurity position, and the nitrogen and indium concentrations. PMID- 23095252 TI - Correlation of bacterial type and antibiotic sensitivity with maternal antibiotic exposure in early-onset neonatal sepsis. AB - BACKGROUND: Antibiotic administration during pregnancy as group B Streptococcus prophylaxis or as treatment of maternal conditions has become widespread. OBJECTIVE: To assess whether bacterial type and antibiotic resistance in early onset neonatal sepsis are associated with maternal antibiotic use. METHODS: All positive blood and/or cerebrospinal fluid cultures (case-only study) and respective antibiotic sensitivities from newborns delivered in Shaare Zedek Medical Center, Jerusalem, Israel, between 01/01/1997 and 31/01/2007, taken during the first 72 h of life, were studied. Clinical and demographic data were obtained from the medical records of the infant/mother dyads. Three groups were defined by type of maternal antibiotic exposure: (1) no exposure, (2) intrapartum antibiotic prophylaxis (IAP), (3) antepartum antibiotic exposure during the month prior to delivery and extending into delivery or with subsequent IAP (AAE). Factors potentially associated with Gram-negative bacteremia and resistance to ampicillin were analyzed using multivariate logistic regression. RESULTS: Ninety seven different organisms grew from 94 infants (1.03 per 1,000 live births). By univariate analysis, AAE, gestational age <= 32 weeks, chorioamnionitis and rupture of membranes >= 18 h, were significantly associated with both Gram negative sepsis and antibiotic resistance. By multivariate analysis, AAE was significantly associated with both outcomes, while gestational age <=32 weeks was only associated with antibiotic resistance. CONCLUSIONS: AAE for more than 24 h is associated with an increased proportion of Gram-negative organisms and ampicillin resistance in early-onset neonatal sepsis. Antepartum antibiotic therapy and its ramifications need to be continuously monitored and prospectively studied. PMID- 23095255 TI - Exposure of pregnant rats to cigarette-smoke condensate causes glomerular abnormalities in offspring. AB - BACKGROUND: Higher blood pressure and albuminuria are found in offspring of mothers who smoke during pregnancy. Whether or not kidney development is affected by maternal smoking is unknown. METHODS: Sprague-Dawley rats were randomly allocated to twice-daily cigarette smoke and nicotine condensate (1 mg/kg) or vehicle at day 10 of pregnancy until delivery. RESULTS: Exposed offspring did not differ from control offspring with respect to body weight, kidney weight, albuminuria, and creatinine clearance. Both male and female offspring had higher tail-plethysmographic blood pressures and lower mean glomerular volume, podocyte, mesangial-cell, and endothelial-cell number, compared to control offspring. CONCLUSIONS: The data document that prenatal exposure to cigarette-smoke condensate containing nicotine influences normal kidney development and could predispose to higher blood pressures later in life. PMID- 23095254 TI - Hepatic STAMP2 decreases hepatitis B virus X protein-associated metabolic deregulation. AB - Six transmembrane protein of prostate 2 (STAMP2) plays a key role in linking inflammatory and diet-derived signals to systemic metabolism. STAMP2 is induced by nutrients/feeding as well as by cytokines such as TNFalpha, IL-1beta, and IL 6. Here, we demonstrated that STAMP2 protein physically interacts with and decreases the stability of hepatitis B virus X protein (HBx), thereby counteracting HBx-induced hepatic lipid accumulation and insulin resistance. STAMP2 suppressed the HBx-mediated transcription of lipogenic and adipogenic genes. Furthermore, STAMP2 prevented HBx-induced degradation of IRS1 protein, which mediates hepatic insulin signaling, as well as restored insulin-mediated inhibition of gluconeogenic enzyme expression, which are gluconeogenic genes. We also demonstrated reciprocal expression of HBx and STAMP2 in HBx transgenic mice. These results suggest that hepatic STAMP2 antagonizes HBx-mediated hepatocyte dysfunction, thereby protecting hepatocytes from HBV gene expression. PMID- 23095256 TI - Pharmacophore-based drug design and biological evaluation of novel ABCB1 inhibitors. AB - Overexpression of ABCB1 is one of major barriers for multidrug resistance in chemotherapy and limits drug oral bioavailability. Inhibition of ABCB1 would sensitize multidrug resistance in clinical cancer chemotherapy. With this aim, a 3D pharmacophore model was created based on known ABCB1 inhibitors with correlation coefficient of 0.94, comprising three hydrophobic features and one hydrogen bond acceptor. It was further validated and used to search our in-house 3D database for potential ABCB1 inhibitors. The inhibitory activities of the best hits were evaluated by several biological assays, such as rhodamine 123 accumulation assay, chemosensitization assay, multidrug resistance 1-Madin-Darby canine kidney cells/Madin-Darby canine kidney cells permeability assay. Finally, compounds YZ-3 and YZ-16 were identified as potential leads to be developed in the designing of novel potent ABCB1 inhibitors. PMID- 23095257 TI - IBDsite: a Galaxy-interacting, integrative database for supporting inflammatory bowel disease high throughput data analysis. AB - BACKGROUND: Inflammatory bowel diseases (IBD) refer to a group of inflammatory conditions concerning colon and small intestine, which cause socially uncomfortable symptoms and often are associated with an increased risk of colon cancer. IBD are complex disorders, which rely on genetic susceptibility, environmental factors, deregulation of the immune system, and host relationship with commensal microbiota. The complexity of these pathologies makes difficult to clearly understand the mechanisms of their onset. Therefore, the study of IBD must be faced exploiting an integrated and multilevel approach, ranging from genes, transcripts and proteins to pathways altered in affected tissues, and carefully considering their regulatory mechanisms, which may intervene in the pathology onset. It is also crucial to have a knowledge base about the symbiotic bacteria that are hosted in the human gut. To date, much data exist regarding IBD and human commensal bacteria, but this information is sparse in literature and no free resource provides a homogeneously and rationally integrated view of biomolecular data related to these pathologies. METHODS: Human genes altered in IBD have been collected from literature, paying particular interest for the immune system alterations prompted by the interaction with the gut microbiome. This process has been performed manually to assure the reliability of collected data. Heterogeneous metadata from different sources have been automatically formatted and integrated in order to enrich information about these altered genes. A user-friendly web interface has been created for easy access to structured data. Tools such as gene clustering coefficients, all-pairs shortest paths and pathway lengths calculation have been developed to provide data analysis support. Moreover, the implemented resource is compliant to the Galaxy framework, allowing the collected data to be exploited in the context of high throughput bioinformatics analysis. RESULTS: To fill the lack of a reference resource for 'omics' science analysis in the context of IBD, we developed the IBDsite (available at http://www.itb.cnr.it/ibd), a disease-oriented platform, which collects data related to biomolecular mechanisms involved in the IBD onset. The resource provides a section devoted to human genes identified as altered in IBD, which can be queried at different biomolecular levels and visualised in gene centred report pages. Furthermore, the system presents information related to the gut microbiota involved in IBD affected patients. The IBDsite is compliant with all Galaxy installations (in particular, it can be accessed from our custom version of Galaxy, http://www.itb.cnr.it/galaxy), in order to facilitate high throughput data integration and to enable evaluations of the genomic basis of these diseases, complementing the tools embedded in the IBDsite. CONCLUSIONS: Lots of sparse data exist concerning IBD studies, but no on-line resource homogeneously and rationally integrate and collect them. The IBDsite is an attempt to group available information regarding human genes and microbial aspects related to IBD, by means of a multilevel mining tool. Moreover, it constitutes a knowledge base to filter, annotate and understand new experimental data in order to formulate new scientific hypotheses, thanks to the possibility of integrating genomics aspects by employing the Galaxy framework. Discussed use cases demonstrate that the developed system is useful to infer not trivial knowledge from the existing widespread data or from novel experiments. PMID- 23095259 TI - Long-term treatment of Lewis-Sumner syndrome with subcutaneous immunoglobulin infusions. AB - Lewis-Sumner syndrome (LSS, synonymous multifocal acquired demyelinating sensory and motor neuropathy, MADSAM) is a dysimmune peripheral neuropathy responding to corticosteroids and intravenous immunoglobulins (IVIG) in the majority of patients. We report on the long term treatment (37 and 46months respectively) of two LSS patients, who had initially responded to IVIG, with subcutaneous immunoglobulins (SCIg). Both were switched to SCIg since stabilization by IVIG could only be achieved with short treatment intervals, and one of them also suffered from recurrent transient ischemic attacks (TIAs) following IVIG related increased blood viscosity. Long-term use of SCIg was safe and well tolerated. Both patients were clinically stable with only mild to moderate fluctuations requiring SCIg dosage adaptions. No further ischemic events occurred, when the patient was switched to SCIg. PMID- 23095258 TI - Voltage-gated sodium channel expression and action potential generation in differentiated NG108-15 cells. AB - BACKGROUND: The generation of action potential is required for stimulus-evoked neurotransmitter release in most neurons. Although various voltage-gated ion channels are involved in action potential production, the initiation of the action potential is mainly mediated by voltage-gated Na+ channels. In the present study, differentiation-induced changes of mRNA and protein expression of Na+ channels, Na+ currents, and cell membrane excitability were investigated in NG108 15 cells. RESULTS: Whole-cell patch-clamp results showed that differentiation (9 days) didn't change cell membrane excitability, compared to undifferentiated state. But differentiation (21 days) induced the action potential generation in 45.5% of NG108-15 cells (25/55 cells). In 9-day-differentiated cells, Na+ currents were mildly increased, which was also found in 21-day differentiated cells without action potential. In 21-day differentiated cells with action potential, Na+ currents were significantly enhanced. Western blot data showed that the expression of Na+ channels was increased with differentiated-time dependent manner. Single-cell real-time PCR data demonstrated that the expression of Na+ channel mRNA was increased by 21 days of differentiation in NG108-15 cells. More importantly, the mRNA level of Na+ channels in cells with action potential was higher than that in cells without action potential. CONCLUSION: Differentiation induces expression of voltage-gated Na+ channels and action potential generation in NG108-15 cells. A high level of the Na+ channel density is required for differentiation-triggered action potential generation. PMID- 23095260 TI - Unusual cases of adult intersexuality in the European eel Anguilla anguilla. AB - Two cases of intersexuality are reported for the first time in European eel, Anguilla anguilla (at the beginning of the silver eel stage), within 140 fish caught as glass eels in the south-west of France and reared in tanks at 17 degrees C. Cysts containing spermatozoa were observed in ovaries with pre vitellogenic oocytes. This feature is very uncommon, especially owing to the fact that male cells do not normally reach this stage in captivity, and an environmentally controlled transdifferentation process may not be excluded. Besides, the expression of the gonadal aromatase gene (cyp19a1a) was found to be higher in these 2 intersexual fish compared to normal females, although these results must be considered with caution since only 2 intersexual fish were available. A possible feminizing effect of this 'abnormal' upregulation of aromatase is discussed. PMID- 23095261 TI - Neuroendoscopic transnasal surgery for skull base tumors: basic approaches, avoidance of pitfalls, and recent innovations. AB - Since the introduction of endoscopic technology in the neurosurgical field, the role of transnasal surgery has been dramatically enlarged. With this technique, we can approach the anterior cranial base, parasellar region, clivus, cavernous sinus, and craniovertebral junction, less invasively than with conventional microsurgery. This review describes the two major approach methods in endoscopic skull base surgery, the endonasal approach and the transseptal approach. The endonasal approach uses two nostrils without nasal specula and the mucosa on the sphenoid rostrum and the posterior margin of the nasal septum are removed. In the transseptal approach, only a single nostril is available, but using the nasal speculum, sufficient surgical field can be obtained with only a small incision on the septum. In either approach method, it is very important to avoid excessive mucosal damage and to select the appropriate approach for each patient. The endoscopic skull base approach is one of the least invasive surgical procedures, which is a very promising therapeutic choice with potential for further advances. For better surgical outcomes and further progress, cooperation with rhinolaryngologists who have much more knowledge and experience about nasal surgery than neurosurgeons is essential. We believe this article will contribute to the development of safe and effective surgical procedures, and to the benefit of the patients suffering with intractable skull base lesions. PMID- 23095262 TI - Therapeutic strategy and long-term outcome of meningiomas located in the posterior cranial fossa. AB - The clinical and surgical findings of 41 consecutive cases of posterior cranial fossa meningiomas operated on between January 1987 and December 2011 at Saitama Medical Center/Saitama Medical University were reviewed. The 31 female and 10 male patients were aged from 19 to 74 years (mean 54 years). The tumors were located in the petroclival (N=15), craniovertebral junction (N=6), lateral tentorial (N=12), and cerebellopontine angle (N=8) regions. Mean tumor equivalent diameter was 4.3 cm (range 2-9 cm). Head pain (46.3%) and gait disturbance (26.8%) were the most common presenting symptoms, and cranial neuropathies were the most common neurological signs on admission. Mean preoperative performance status (Karnofsky scale) was 83% (range 40-100%). Surgical approaches to these tumors included presigmoidal transpetrosal, retrosigmoidal, transcondylar, and combined approaches. In 4 cases, a staged procedure was performed. Gross total resection was achieved in 85.4% of patients, and subtotal/partial resection in 12.2%. Surgical mortality was 2.4% and complications were encountered in 11 patients (26.8%) including temporary neurological deficits in 4 patients. The mean follow-up period was 8.2 years, ranging from 1 to 24 years, and the mean performance status of patients at 12 months after the last surgery was 92% (range 0-100%). Recurrence or progression of disease was found in 9.8% of cases. Postoperative adjuvant therapy was performed in 6 cases. My experience suggests that although posterior cranial fossa meningiomas represent a continuing challenge for contemporary neurosurgeons, such tumors may be completely or subtotally removed with low rate of mortality and acceptable morbidity, allowing most of these patients to achieve good outcome in long-term follow up. PMID- 23095263 TI - Gamma knife radiosurgery for benign cavernous sinus tumors: treatment concept and outcomes in 120 cases. AB - Availability of modern computer-aided robotized devices, such as the Automatic Positioning System (APSTM; Elekta Instruments AB, Stockholm, Sweden) and PerfexionTM (Elekta Instruments AB), allowed us to develop the original concept of robotic gamma knife microradiosurgery, which is based on the very precise irradiation of the lesion with regard to conformity and selectivity; intentional avoidance of the excessive irradiation of functionally-important anatomical structures, particularly cranial nerves, located both within and in the vicinity of the target; and delivery of sufficient irradiation energy to the tumor with the intention to attain lesion shrinkage, while keeping the marginal dose sufficiently low for prevention of possible complications. The results of such treatment strategy were evaluated retrospectively in 120 patients with benign cavernous sinus neoplasms (pituitary adenomas, meningiomas, schwannomas, and hemangiomas), who were followed up from 24 to 78 months (mean 47 months) after radiosurgery. Tumor growth control and shrinkage rates were 98% and 68%, respectively. More than 50% volume reduction was noted in 25% of lesions. The most prominent volumetric tumor response was observed in hemangiomas, followed by schwannomas, pituitary adenomas, and meningiomas. Treatment-related complications were marked in 7% of cases, and were mainly related to transient isolated cranial neuropathy appearing within several months after radiosurgery. Major morbidity was limited to one patient (0.8%). Application of microradiosurgical treatment principles provides effective and safe management of benign cavernous sinus tumors and is associated with high probability of lesion shrinkage and minimal risk of complications. PMID- 23095264 TI - Aspiration versus excision: a single center experience of forty-seven patients with brain abscess over 10 years. AB - The efficacies of two different surgical approaches, aspiration and excision, were investigated for the management of large solitary encapsulated pyogenic brain abscess located in superficial non-eloquent areas, and the impact on length of hospital stay, duration of postoperative antibiotic use, improvement in neurological status, and morbidity and mortality were compared. This retrospective study at Sher-i-Kashmir Institute of Medical Sciences included 47 patients with pyogenic brain abscess from a total of 114 patients evaluated in the Department of Neurosurgery over a period of 10 years from October 2001 to October 2011. Comparisons were made between aspiration and excision in terms of duration of antibiotic use, length of hospital stay, and overall treatment cost. Aspiration was performed in 29 patients (61.7%), of whom 7 patients needed second aspiration, and 18 patients underwent excision (38.3%) of the abscess capsule. The mean duration of antibiotic use in the excision group was significantly shorter at 2.7 weeks (standard deviation [SD]+/-1.1) compared to the aspiration group at 3.8 weeks (SD+/-1.3) (p=0.006). Similarly, mean length of hospital stay was significantly shorter in the excision group at 18.1 days (SD+/-7.7) compared to the aspiration group at 24.9 days (SD+/-6.6) (p=0.002). In addition, significantly earlier improvement in neurological function (p=0.025) and significantly lower rate of re-surgery (p=0.0238) were found in the excision group compared to the aspiration group. Excision is better than aspiration as far as duration of antibiotic use, length of hospital stay, and overall cost of treatment is concerned, with no significant difference in morbidity and mortality. PMID- 23095265 TI - Bumping phenomenon during continuous coagulation with bipolar forceps. AB - During continuous bipolar coagulation, the coagulum sometimes ruptures suddenly and audibly, leading to hemostasis failure and damage to the surrounding tissues. Such coagulum rupture is a phenomenon that is similar to microwave bumping, which occurs because of unequal heat distribution as a result of sudden elevation in temperature. The present study investigated the conditions under which bumping can occur during bipolar coagulation using samples of whole blood. Two types of bipolar forceps were assessed: forceps with gold-plated tips and IsoCoolTM forceps. The time until the bumping phenomenon occurred was measured, and the occurrence rate of bumping was calculated. Thermal characteristics were then assayed using a thermographic camera. As the output of the bipolar coagulator increased, the time until bumping decreased whereas the occurrence rate of bumping during coagulation increased. At lower outputs, the occurrence rate of bumping was significantly lower using IsoCoolTM forceps than that using forceps with gold-plated tips (p<0.0001). Furthermore, bumping during coagulation could be prevented if the tips of the forceps at the coagulation site were repeatedly opened and closed. The bumping phenomenon is influenced by various factors such as heat, electrical power, equipment, and coagulation technique. Neurosurgeons should understand the technical certain aspects of these surgical tools and develop appropriate advanced techniques for temperature control. PMID- 23095266 TI - Combined transmastoid/middle fossa approach for intracranial extension of middle ear cholesteatoma. AB - A retrospective review was performed of patients treated for middle ear cholesteatoma with bone defects of the skull base via a combined transmastoid/middle fossa approach at the University of Tsukuba Hospital from 2006 through 2011 to determine the safety and effectiveness of a combined transmastoid/middle fossa approach for the treatment of cholesteatoma involving the middle cranial fossa. The bone defects of the skull base were reconstructed with a galeal flap pedicled with a parietal branch of the superficial temporal artery and an autologous bone flap. The clinical and radiological data were analyzed. This series included 8 patients (6 men and 2 women) with a mean age of 46.3 years (range 10-67 years). One of the patients preoperatively exhibited meningoencephalocele of the middle fossa skull base, and in the remaining 7 patients, petrous bone involvement such as involvement of the supralabyrinthine cells was observed. The cholesteatoma lesion was totally removed and inner ear function preserved in all the patients. Cerebrospinal fluid leakage was observed in 1 patient during and after the surgery. Neither meningitis nor recurrence was observed in any patient during the follow-up periods (mean 29.4 months, range 6 64 months). The combined transmastoid/middle fossa approach allowed complete removal of cholesteatoma with middle cranial fossa involvement while preserving hearing and preventing postoperative cerebrospinal fluid leakage and meningitis. PMID- 23095267 TI - Spontaneous hemorrhage from orbital cavernous hemangioma resulting in sudden onset of ophthalmopathy in an adult--case report. AB - A 61-year-old woman presented with a very rare case of spontaneous bleeding from an orbital cavernous hemangioma manifesting as sudden onset of ophthalmic pain, proptosis, diplopia, and nausea. Magnetic resonance (MR) imaging and computed tomography (CT) revealed an intraconal, well-demarcated cystic mass with hemorrhage. The mass was immediately removed through a transcranial approach. Histological examination showed that the mass was a cavernous hemangioma. Ophthalmopathy was resolved by surgery. Orbital cavernous hemangioma is very common in adults, but spontaneous bleeding is extremely rare relative to intracranial cavernous hemangiomas. This rare case emphasizes the importance of careful neuroimaging evaluation with MR imaging and CT for diagnosing orbital cavernous hemangioma associated with spontaneous bleeding. PMID- 23095268 TI - Hemophilic pseudotumor of the temporal bone with conductive hearing loss--case report. AB - A 46-year-old man with factor VIII deficiency presented with a rare case of hemophilic pseudotumor in the temporal bone manifesting as severe conductive hearing loss and external ear bleeding. The pseudotumor expanded and destroyed the temporal bone and skin of the external ear over the course of 8 years. The pseudotumor was surgically excised, and the patient's symptoms improved. Histological examination of a specimen collected from inside the pseudotumor demonstrated blood products in various stages of evolution and showed that the outer membrane consisted of a collagen layer. Hemophilic pseudotumors are rare complications occurring in 1-2% of patients with mild or severe hemophilia. Pseudotumors are chronic, slowly expanding, encapsulated cystic masses, and most are located in the long bones and pelvis. The present case suggests that cranial pseudotumor should be considered in the differential diagnosis of cranial lesion in a patient with hemophilia. PMID- 23095269 TI - Mesenchymal chondrosarcoma of the orbit--case report. AB - A 20-year-old woman presented with a rare case of intraorbital mesenchymal chondrosarcoma manifesting as a 6-month history of progressive ptosis and exophthalmos of her left eye. Computed tomography and magnetic resonance imaging revealed a partially calcified round mass occupying the postbulbar space. Partial removal of the tumor via a left fronto-orbital approach was performed. The histological diagnosis was mesenchymal chondrosarcoma, and additional intraorbital exenteration was performed. Neither chemotherapy nor radiotherapy was performed. She was free from tumor recurrence at the 6-year follow-up examination. Radical resection, including exenteration if possible, is recommended for intraorbital mesenchymal chondrosarcoma. PMID- 23095270 TI - Clivus metastasis from gastric signet ring cell carcinoma after a 10-year disease free interval--case report. AB - A 64-year-old male presented with an extremely unusual case of solitary clivus metastasis from gastric cancer manifesting as mild headache and diplopia 10 years after radical excision of the primary tumor. The patient underwent surgical resection using an endoscopic transsphenoidal approach. Histological examination revealed typical signet ring cell carcinoma (SRC) which was identical to that of the previous gastric cancer. Why the late recurrence occurred such a long time after the first surgery and how it spread to the clivus remain unclear. The characteristics of SRC and the process of "tumor dormancy" may have been involved in the mechanism underlying late metastasis. PMID- 23095271 TI - Intracranial germinoma manifesting as cavernous sinus syndrome--case report. AB - An 11-year-old girl presented with a rare case of neurohypophyseal germinoma manifesting as cavernous sinus syndrome with left abducens nerve palsy. Magnetic resonance (MR) imaging showed a mass located in the left cavernous sinus. Biopsy revealed an inflammatory reaction with lymphocytic infiltration. Postoperative MR imaging showed regression of the mass. Her eye movements were also restored. However, after 5 months, she developed right oculomotor and abducens nerve palsy, and MR imaging showed a large suprasellar mass invading the bilateral cavernous sinuses. The transcranial biopsy sample showed positive staining for placental alkaline phosphatase and c-kit, and the diagnosis of germinoma was confirmed. Chemotherapy and radiotherapy were administered, and the patient has been in complete remission for over 4 years. PMID- 23095272 TI - Cavernous sinus thrombophlebitis related to dental infection--two case reports. AB - Two cases of cavernous sinus thrombophlebitis (CST) caused by dental infection are described. A 64-year-old woman presented with palsies of the left oculomotor and trochlear nerves after tooth extraction for dental caries in the left maxilla. A 54-year-old man presented with palsy of the left trochlear nerve, sensory disturbance in the ophthalmic and maxillary divisions of the left trigeminal nerve, ptosis, proptosis, and chemosis after dental treatment for caries and periodontitis in the left maxilla. In both patients, computed tomography and magnetic resonance imaging with contrast medium showed non enhanced lesions within the left cavernous sinus and dilation of the superior ophthalmic veins, which indicated CST. These conditions were resolved by administration of broad-spectrum antibiotics. CST is rare but lethal, so prompt diagnosis is crucial, and immediate appropriate treatment is essential. PMID- 23095273 TI - Fulminant tuberculous meningitis--autopsy case report. AB - A 56-year-old Japanese male presented with tuberculous meningitis (TBM) manifesting as irrational behavior. He underwent lumbar puncture, which showed inflammatory cerebrospinal fluid (CSF) findings. Administration of anti tuberculosis (TB) agents was started on the day after admission (Day 1) because delayed treatment of TBM might be fatal. On Day 4, magnetic resonance (MR) imaging and MR angiography showed fresh infarctions, hydrocephalus, and stenoses of arteries. CSF drainage and biopsy of brain tissue were performed, but the pathological findings were non-specific. Frequent CSF examinations, cultures, and polymerase chain reaction were performed, but no positive finding of TB was obtained. He died on Day 14. Brain autopsy showed Langerhans giant cells and Ziehl-Neelsen-positive TB bodies. Unfortunately, our patient suffered very poor outcome irrespective of early anti-TB treatment starting Day 1, suggesting the probability of delayed admission or drug-resistant TB. TB infection including TBM has become rare in developed countries, and diagnosis remains difficult. Corticosteroid therapy may be effective for TBM, but may be restricted and ameliorate mortality but not morbidity. Further study is required to establish second line treatment if TBM is resistant to anti-TB agents and corticosteroid administration. PMID- 23095274 TI - Usefulness of L-[methyl-11c]methionine positron emission tomography in the treatment of idiopathic hypertrophic cranial pachymeningitis--case report. AB - A 53-year-old man suffered from pulsating headache for 2 months. Magnetic resonance imaging with gadolinium revealed a linear or nodular mass along the left fronto-parietal convexity. Positron emission tomography (PET) with L-[methyl 11C]methionine (11C-MET) demonstrated increased uptake in the enhanced lesion. Biopsy, obtained by craniotomy, demonstrated granulation with lymphocyte and plasma cell infiltration, suggesting inflammatory changes, and a diagnosis of idiopathic hypertrophic cranial pachymeningitis (IHCP) was made. Steroid therapy resulted in improvement of the clinical symptoms and shrinkage of the enhanced lesion in a week. Follow-up 11C-MET PET study, after 18 months of steroid therapy, demonstrated significantly decreased uptake in the lesion, so the steroid therapy was discontinued. Neither clinical nor radiological recurrence was observed one year after discontinuation of the steroid therapy. This case of IHCP with increased 11C-MET uptake, which then decreased after steroid therapy suggests that 11C-MET PET is a useful monitoring modality for therapeutic efficacy against IHCP, and can indicate the appropriate timing of therapy discontinuation. PMID- 23095275 TI - Neuromyelitis optica spectrum disorder: 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography findings--case report. AB - A 51-year-old female with a history of rheumatoid arthritis rapidly developed anterior neck pain and paresis in the left upper and lower extremities and right lower extremity, sensory disturbance in the left upper and lower extremities, and bladder and rectal disorder. Adduction of the left eye and abduction of the right eye were also disturbed. Spinal magnetic resonance imaging demonstrated severe edema in the C1-T5 levels, which then deteriorated rapidly over 3 days, and lesions enhanced with gadolinium in the C1-C3 and C5-T3 levels. 2-Deoxy-2 [18F]fluoro-D-glucose positron emission tomography study demonstrated the inflammatory sites as segmental enhanced accumulation in the C1-C3, C5-C6, and T1 levels. The serum anti-aquaporin 4 antibody level was positive and she was diagnosed with neuromyelitis optica spectrum disorder. Marked improvement in the neurological conditions, concomitant with reduced spinal cord edema, was obtained by steroid pulse therapy. PMID- 23095276 TI - Neurocognitive late effects of pediatric brain tumors of the posterior fossa: a quantitative review. AB - Deficits in neurocognitive functioning are an important area of late effects in survivors of pediatric brain tumors; however, a quantitative analysis of the magnitude of these deficits in survivors of brain tumors of the posterior fossa has not been conducted. Despite tumor locations in the posterior regions of the brain, individual studies have documented deficits in a variety of domains, reflective of impairment in other brain regions. The current study provides a comprehensive meta-analysis of literature on neurocognitive late effects found in survivors of posterior fossa tumors. Results indicated significant deficits in both specific and broad indices of neurocognitive functioning, and the overall magnitude of effects across domains ranged from medium to large (g = -0.62 to 1.69) with a large mean overall effect size (g = -1.03). Moderator analyses indicated significantly greater effects for survivors diagnosed at a younger age and those who received radiation therapy. These findings underscore the importance of monitoring neurocognitive late effects in survivors of pediatric brain tumors of the posterior fossa, as well as the need for more consistent consideration of demographic, diagnostic, and treatment-related variables to allow for examination of factors that moderate these deficits. PMID- 23095277 TI - Combination therapy for manic phases: a critical review of a common practice. AB - All relevant guidelines recommend monotherapy as the initial treatment for manic phases of bipolar disorder (BD), with combination therapy reserved for severe cases or as a subsequent choice. However, in routine practice, monotherapy is often not sufficiently effective for acute and/or maintenance therapy. As a consequence, most patients are given combination therapies. An extensive search concerning combination treatment for manic episodes was conducted for relevant international randomized controlled studies, treatment guidelines and comprehensive reviews published since 1980. The scientific literature is sufficiently rich to validate the superiority of combination therapy over monotherapy in the manic phase in terms of efficacy and prevention of relapse; its safety profile is acceptable. Side effects are more frequent with combination therapy as a whole than with monotherapy, and discontinuation rates due to adverse events are higher. Continued administration of antipsychotics after a manic phase is controversial: drug classification, the course of the disease and the predominant polarity should all be considered before treatment is continued. Combinations including olanzapine and asenapine and to a lesser extent risperidone are associated with weight gain, those including quetiapine, haloperidol and asenapine with sedation, and those including aripiprazole with akathisia. This review of literature leads us to suggest that combination therapy including an atypical antipsychotic with lithium or valproate may be considered as a first-line approach. An appropriate algorithm for making decisions about combination treatment needs to be developed and included in future guidelines. PMID- 23095279 TI - Patients with good collateralization may profit from cilostazol. PMID- 23095278 TI - Paradigmatic status of an endo- and exoglucanase and its effect on crystalline cellulose degradation. AB - BACKGROUND: Microorganisms employ a multiplicity of enzymes to efficiently degrade the composite structure of plant cell wall cellulosic polysaccharides. These remarkable enzyme systems include glycoside hydrolases (cellulases, hemicellulases), polysaccharide lyases, and the carbohydrate esterases. To accomplish this challenging task, several strategies are commonly observed either separately or in combination. These include free enzyme systems, multifunctional enzymes, and multi-enzyme self-assembled designer cellulosome complexes. RESULTS: In order to compare these different paradigms, we employed a synthetic biology approach to convert two different cellulases from the free enzymatic system of the well-studied bacterium, Thermobifida fusca, into bifunctional enzymes with different modular architectures. We then examined their performance compared to those of the combined parental free-enzyme and equivalent designer-cellulosome systems. The results showed that the cellulolytic activity displayed by the different architectures of the bifunctional enzymes was somewhat inferior to that of the wild-type free enzyme system. CONCLUSIONS: The activity exhibited by the designer cellulosome system was equal or superior to that of the free system, presumably reflecting the combined proximity of the enzymes and high flexibility of the designer cellulosome components, thus enabling efficient enzymatic activity of the catalytic modules. PMID- 23095281 TI - Subclinical vasculitis as a potential mechanism to explain the heightened cardiovascular risk in rheumatoid arthritis. PMID- 23095280 TI - Myosin light chain phosphorylation is critical for adaptation to cardiac stress. AB - BACKGROUND: Cardiac hypertrophy is a common response to circulatory or neurohumoral stressors as a mechanism to augment contractility. When the heart is under sustained stress, the hypertrophic response can evolve into decompensated heart failure, although the mechanism(s) underlying this transition remain largely unknown. Because phosphorylation of cardiac myosin light chain 2 (MLC2v), bound to myosin at the head-rod junction, facilitates actin-myosin interactions and enhances contractility, we hypothesized that phosphorylation of MLC2v plays a role in the adaptation of the heart to stress. We previously identified an enzyme that predominantly phosphorylates MLC2v in cardiomyocytes, cardiac myosin light chain kinase (cMLCK), yet the role(s) played by cMLCK in regulating cardiac function in health and disease remain to be determined. METHODS AND RESULTS: We found that pressure overload induced by transaortic constriction in wild-type mice reduced phosphorylated MLC2v levels by ~40% and cMLCK levels by ~85%. To examine how a reduction in cMLCK and the corresponding reduction in phosphorylated MLC2v affect function, we generated Mylk3 gene-targeted mice and transgenic mice overexpressing cMLCK specifically in cardiomyocytes. Pressure overload led to severe heart failure in cMLCK knockout mice but not in mice with cMLCK overexpression in which cMLCK protein synthesis exceeded degradation. The reduction in cMLCK protein during pressure overload was attenuated by inhibition of ubiquitin-proteasome protein degradation systems. CONCLUSIONS: Our results suggest the novel idea that accelerated cMLCK protein turnover by the ubiquitin proteasome system underlies the transition from compensated hypertrophy to decompensated heart failure as a result of reduced phosphorylation of MLC2v. PMID- 23095282 TI - Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is a systemic inflammatory condition associated with increased cardiovascular risk. This is not fully explained by traditional risk factors, but direct vascular inflammation and aortic stiffening may play a role. We hypothesized that patients with RA exhibit aortic inflammation, which can be reversed with anti-tumor necrosis factor-alpha therapy and correlates with aortic stiffness reduction. METHODS AND RESULTS: Aortic inflammation was quantified in 17 patients with RA, before and after 8 weeks of anti-tumor necrosis factor-alpha therapy by using (18)F-fluorodeoxyglucose positron emission tomography with computed tomography coregistration. Concomitantly, 34 patients with stable cardiovascular disease were imaged as positive controls at baseline. Aortic fluorodeoxyglucose target-to-background ratios (TBRs) and aortic pulse wave velocity were assessed. RA patients had higher baseline aortic TBRs in comparison with patients who have cardiovascular disease (2.02+/-0.22 versus 1.74+/-0.22, P=0.0001). Following therapy, aortic TBR fell to 1.90+/-0.29, P=0.03, and the proportion of inflamed aortic slices (defined as TBR >2.0) decreased from 50+/-33% to 33+/-27%, P=0.03. Also, TBR in the most diseased segment of the aorta fell from 2.51+/-0.33 to 2.05+/-0.29, P<0.0001. Treatment also reduced aortic pulse wave velocity significantly (from 9.09+/-1.77 to 8.63+/-1.42 m/s, P=0.04), which correlated with the reduction of aortic TBR (R=0.60, P=0.01). CONCLUSIONS: This study demonstrates that RA patients have increased aortic (18)F-fluorodeoxyglucose uptake in comparison with patients who have stable cardiovascular disease. Anti-tumor necrosis factor-alpha therapy reduces aortic inflammation in patients with RA, and this effect correlates with the decrease in aortic stiffness. These results suggest that RA patients exhibit a subclinical vasculitis, which provides a mechanism for the increased cardiovascular disease risk seen in RA. PMID- 23095283 TI - A historic cohort study on accelerated advancement of enteral feeding volumes in very premature infants. AB - BACKGROUND: The optimal rate of enteral feeding (EF) advancement in very low birth weight infants is under debate. OBJECTIVES: To evaluate the effects of accelerated EF advancement on the time to full enteral feeds, on early postnatal growth as well as on the frequency of necrotizing enterocolitis (NEC) and focal intestinal perforation (FIP) in very premature infants. METHODS: In a retrospective single-center historic cohort study, infants with a gestational age <32 weeks at birth and birth weight <1,500 g, born between January 1, 2006, and December 31, 2007 (n = 136), were compared with infants born between January 1, 2010, and December 31, 2010 (n = 88). In 2006/2007, enteral feeds were initiated on day 1 with 10-15 ml/kg/day and advanced by 15-20 ml/kg/day. In 2010, enteral feeds were initiated with 20 ml/kg/day on day 1 and advanced by 25-30 ml/kg/day. Full enteral feeds were defined as >= 140 ml/kg/day. Data are presented as median (P25-P75). RESULTS: The time to establish full enteral feeds was shorter in 2010: 8 (7-11) days in 2006/2007 versus 6 (5-9) days in 2010. The incidences of NEC and FIP were 2.7 and 4.1% in 2006/2007 and 3.3 and 2.2% in 2010, respectively. Weight gain was not affected by the rate of EF advancement. Higher parenteral protein intake during week 1 in 2006/2007 was associated with better head circumference growth. CONCLUSIONS: The new approach was associated with a significantly shorter period to establish full enteral feeds. No difference in the incidence of FIP or NEC was observed; however, the study was underpowered to detect small but possibly important differences. PMID- 23095284 TI - FT-IR study of the polysaccharides isolated from the skin juice, gel juice, and flower of Aloe vera tissues affected by fertilizer treatment. AB - BACKGROUND: This experiment was conducted to evaluate the effect of different amounts of fertilizers on the polysaccharides of Aloe vera plant. There were four different treatments, viz. T1 = 150% N, T2 = 150% P, T3 = 150% K, and T4 = 150% NPK (50% N + 50% P + 50% K) soil. Crude water-soluble polysaccharides were isolated from the gel juice, skin juice, and flowers of A. vera planted in these soils. RESULTS: Result indicates that skin juice contained 2.4 times the level of polysaccharides in gel juice from one plant, suggesting the potential industrial application of A. vera skin rather than discarding it. After anion-exchange chromatography, neutral polysaccharides accounted for 58.1% and 78.5% of the total recovered neutral and acidic polysaccharide preparations from the gel juice and skin juice, respectively, whereas the crude flower polysaccharides were largely composed of weakly acidic polysaccharides (84.2%). Sugar analysis of the polysaccharides after gel permeation chromatography revealed that glucose and galactose were the most abundant monosaccharide in the neutral polysaccharides from the gel juice and skin juice, respectively. The acidic polysaccharides from the two juices consisted of glucuronic acid, galactose, glucose, mannose, and xylose with variable proportions. CONCLUSIONS: Except glucuronic acid (15.4%) in flower acidic polysaccharide, the flower neutral and acidic polysaccharides contained galactose, glucose, and mannose as the main sugar components. Glucuronic acid was the major uronic acid in all acidic polysaccharides from different tissues. PMID- 23095285 TI - INNULs: A novel design amplification strategy for retrotransposable elements for studying population variation. AB - OBJECTIVES: Retrotransposable elements (REs), consisting of long interspersed nuclear elements (LINEs) and short interspersed nuclear elements (SINEs), are a group of markers that can be useful for human identity testing. Until now, however, due to the inherent size difference (up to 6 kb in some instances) associated with insertion and null alleles (or INNULs), the use of REs for facilitated population studies has not been sought or practical. The size of the insertion elements (from a few hundred to several thousand bp) has proven to limit their utility as a marker because of the inefficient amplicon yield with PCR. A novel primer design now facilitates INNUL marker testing. A preliminary panel of single-locus markers was developed to evaluate the potential of typing these insertion elements. Nine INNULs (5 Alu and 4 LINEs) were typed in three major North American populations and analyzed for population genetic features. In addition, the variation of each marker among the sample populations provides insight of its potential use as individual identification or ancestral marker. METHODS: INNUL markers were developed into fluorescently labeled single-loci PCR. Nine markers were developed with amplicons that were less than 180 bp in length, and, depending on the locus amplicons of the INNULs, alleles varied in size from 50 to 1 bp. This allele size is noteworthy because the insertion alleles of the 9 loci range in size from 297 to 6,195 bp. The allele distribution of the INNULs was assessed and analyzed in three major North American populations. RESULTS: Upon observation of the distribution of the alleles in three major North American populations, the markers generally met Hardy-Weinberg expectations, and there was little evidence of detectable levels of linkage disequilibrium. Due to varying distributions of the alleles in the major population groups tested, some of the markers might be better suited for use as an individual identification marker, while others are better suited for bio-ancestral studies. CONCLUSIONS: Using the primer design strategy described in our work, SINEs and (for the first time, to our knowledge) LINEs can be utilized as markers for studying population genetic variation that is more amenable to the limitations of the PCR technique. This study lays the foundation for future work of developing a multiplex panel of INNUL markers that can be used as a single-tube assay for human identity testing utilizing small amplicons (<180 bp), which could be useful for ancient or degraded forensic DNA samples. PMID- 23095286 TI - Picosecond carrier dynamics induced by coupling of wavefunctions in a Si-nanodisk array fabricated by neutral beam etching using bio-nano-templates. AB - The picosecond carrier dynamics in a closely packed Si-nanodisk (Si-ND) array with ultrathin potential barrier fabricated by neutral beam etching using bio nano-templates was investigated by time-resolved photoluminescence (PL). The PL decay curves were analyzed as a function of photon energy by the global fitting method. We show three spectral components with different decay times, where the systematic energy differences of the spectral peaks are clarified: 2.03 eV for the fastest decaying component with a decay time tau = 40 ps, 2.02 eV for tau = 300 ps, and 2.00 eV for tau = 1.6 ns. These energy separations ranging from 10 to 30 meV among the emissive states can be attributed to the coupling of wavefunctions of carriers between neighboring NDs. PMID- 23095287 TI - 12S-hydroxyeicosatetraenoic acid levels link to coronary artery disease in Type 2 diabetic patients. AB - BACKGROUND: 12(S)-Hydroxyeicosatetraenoic acid (12(S)-HETE) is a metabolite of arachidonic acid. 12(S)-HETE is involved in the pathogenesis of atherosclerosis and diabetes. However, the correlation between 12(S)-HETE and coronary artery disease (CAD) in the diabetic patient is unclear. AIMS: The study investigated the relationship between 12(S)-HETE and CAD in Type 2 diabetes (T2D). METHODS: Plasma 12(S)- HETE levels were detected by enzyme-linked immunosorbent assay in 103 healthy controls (control), 109 diabetic patients without CAD (diabetic), and 152 diabetic patients with CAD (diabetic-CAD). RESULTS: 12(S)-HETE levels were higher in both diabetic and diabetic-CAD groups compared to control and in the diabetic-CAD group compared to the diabetic group. In the multiple linear stepwise regression analysis, 12(S)-HETE levels correlated independently with CAD, systolic blood pressure, and glycated hemoglobin. CONCLUSIONS: These results indicate that 12(S)-HETE levels are increased in diabetic patients with CAD, suggesting a role for atherosclerosis in T2D. PMID- 23095289 TI - Can the ABILHAND handle manual ability in MS? AB - BACKGROUND: Hand dysfunction is common in multiple sclerosis (MS). Recent interest has focused on incorporating patient-reported outcome (PRO) instruments into clinical trials. Nevertheless, examinations are rare in MS of existing manual ability measures. OBJECTIVES: The objective of this paper is to evaluate the 23-item ABILHAND, developed for use after stroke, in people with MS, comparing the findings from two psychometric approaches. METHODS: We analysed ABILHAND data from 300 people with MS using: 1) traditional psychometric methods (data completeness, scaling assumptions, reliability, internal and external construct validity); and 2) Rasch measurement methods (including targeting, item response category ordering, data fit to the Rasch model, spread of item locations, item scoring bias, item stability, reliability, person response validity). RESULTS: Traditional psychometric methods implied ABILHAND was reliable and valid in this sample. Rasch measurement methods supported this finding. The three-category scoring function worked as intended and item fit to Rasch model expectations was acceptable. The 23 items (location range -3.16 to +2.73 logits) mapped a continuum of manual ability. Reliability was high (Person Separation Index (PSI) = 0.95). CONCLUSION: Both psychometric evaluations supported ABILHAND as a robust manual ability PRO measure for MS. Rasch measurement methods were more informative and, consistent with its role of detecting anomalies, identified ways of advancing further ABILHAND's measurement performance to reduce any potential for type II errors in clinical trials. PMID- 23095288 TI - Dynamic change of heme environment in soluble guanylate cyclase and complexation of NO-independent drug agents with H-NOX domain. AB - Soluble guanylate cyclase is a heterodimer receptor that functions in several signal transduction pathways. Conversion of guanosine 5'-triphosphate to 3',5' cyclic monophosphate second messenger at the catalytic domain is regulated by the changes at heme nitric oxide/oxygen domain of the beta-subunit. To better understand conformational changes at heme site that may impact on activities of catalytic domain, three soluble guanylate cyclase homolog proteins with heme at Fe-His state were investigated, and their dynamic behaviors were monitored in both unliganded (apo) and complex with heme. As a result of dynamic conformational changes, Lys110, Asp45, Arg135, and Glu41 were found interacting with the site gate, which may interfere with transportation of small molecules in and out of the heme site. An alternative binding site adjacent to that of heme was identified. Binding affinity of several nitric oxide-independent activators and heme-dependent stimulators was examined, and their binding modes in the heme site and in the alternative binding site in the human soluble guanylate cyclase enzyme were computationally simulated. The calculated binding energies were used as criteria to filter results of virtual high-throughput screenings based on FlexX ligand-docking algorithm and absorption, distribution, metabolism, excretion, and toxicity properties on databases of available drugs. The identified drugs from virtual high-throughput screening have been suggested for experimental investigations, based on which they may either be directly repurposed or require structural modifications for better physico-chemical and pharmacological properties. PMID- 23095290 TI - Effects of betel nut on cardiovascular risk factors in a rat model. AB - BACKGROUND: Areca nut (commonly known as betel nut) chewing has been shown to be associated with metabolic syndrome and cardiovascular disease (CVD). The mechanism by which betel nut ingestion could lead to development of CVD is not precisely known; however, dyslipidemia, hyperhomocysteinemia, hypertriglyceridemia and inflammation could be some of the potential risk factors. This study was undertaken to investigate the effects of two dosages of betel nut on homocysteinemia, inflammation and some of the components of metabolic syndrome, such as hypertriglyceridemia, low HDL-cholesterol, obesity and fasting hyperglycemia in a rat model. METHODS: Thirty-six adult female Sprague Dawley rats, aged 10-12 weeks were divided into three equal groups. Group 1 served as the control group (n = 12) and received water, whereas groups 2 and 3 were given water suspension of betel nut orally in two dosages, 30 mg and 60 mg, respectively for a period of 5 weeks. At the end of the fifth week, the animals were weighed and sacrificed, blood was collected and liver, kidney, spleen and stomach were removed for histological examination.Plasma/serum was analyzed for glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, homocysteine, folate, vitamin B12 and N-acetyl-beta-D-glucosaminidase (NAG) - a marker of inflammation. RESULTS: When the mean concentration values of 3 groups were compared using one way ANOVA followed by Tukey's HSD-test, there was a significant increase in the concentration of total cholesterol (p = 0.04) in the group receiving 30 mg/day betel nut compared to the control group. However, administration of a higher dose of betel nut (60 mg/day) had no significant effect on the serum concentrations of glucose, total cholesterol, HDL cholesterol, LDL-cholesterol, and NAG. Histological examination of spleen revealed a dose-dependent extramedullary hematopoiesis. No other remarkable change in the tissues (liver, kidney and stomach) was observed.Mean serum/plasma levels of folate, vitamin B12 and homocysteine were not found to be significantly different in all the groups. Betel nut ingestion had no effect on the mean body weights of rats. CONCLUSIONS: Low dosage of betel nut is found to be associated with hypercholesterolemia. However, betel nut ingestion is not associated with hyperhomocysteinemia, hypertriglyceridemia, hyperglycemia, inflammation and increase in body weight in a rat model. PMID- 23095291 TI - Filtering capacity of Daphnia magna on sludge particles in treated wastewater. AB - A great challenge in water reuse is the reduction of suspended particle concentration in wastewater. In particular the reduction of the presence of small particles in suspension which cause a cloudy appearance in the water and, which also make disinfection difficult. The present study evaluates the filtering capacity of a population of Cladodera (Daphnia magna) in secondary effluents from a wastewater plant. The study was performed in both a mesocosm and the laboratory, in an effort to compare the grazing on sludge particles by Daphnia versus the settling rate of those sludge particles. The particle volume concentration of small particles (with a diameter below 30 MUm) was used to evaluate the efficiency of the proposed biotreatment system for small particles. Both laboratory and mesocosm results showed that the suspended particle volume concentration decreased with time due to the Daphnia filtration, with the highest reduction in experiments carried out with the highest Daphnia concentration. In the mesocosm experiments, the Daphnia diameter was also found to play an important role, with an allometric relationship between the filtering rate of Daphnia and the Daphnia nondimensional diameter. In laboratory experiments, the effect of D. magna in the suspended concentration of small particles was in the range of 10.1-29.4%, according to the range of Daphnia concentration of 10-50 ind/l. For laboratory experiments, sedimentation was responsible for 62.2% of the suspended particle concentration reduction. For the mesocosm experiments, the reduction in the particle concentration attributed to the Daphnia filtration ranged between 2.5 and 39%, corresponding to Daphnia concentrations of between 5 and 100 ind/l (i.e. biovolumes of 8-60 ind/l). PMID- 23095292 TI - Role of cellular L-arginine uptake and nitric oxide production on renal blood flow and arterial pressure regulation. AB - PURPOSE OF REVIEW: L-Arginine (L-Arg) is the substrate for nitric oxide (NO) formation. Reduced NO bioavailability, particularly within the renal circulation, has been identified as a key factor in the pathogenesis of hypertension. This review focuses on the pathogenic role of abnormal L-Arg transport, particularly within the kidney, in hypertension. RECENT FINDINGS: Most recent studies have attempted to restore NO bioavailability in cardiovascular diseases with the use of antioxidants to reduce NO inactivation, but this approach has failed to provide beneficial effects in the clinical setting. We argue that this may be due to reduced NO formation in hypertension, which has largely been overlooked as a means of restoring NO bioavailability in cardiovascular diseases. Recent data indicate that renal L-Arg transport plays an important role in regulating both renal perfusion and function and the long-term set point of arterial pressure in health. Perturbations in the renal L-Arg transport system can give rise to abnormal renal perfusion and function, initiating hypertension and related renal damage. SUMMARY: Accordingly, we propose that L-Arg transporters are a new treatment target in hypertension and in disease states where renal NO bioavailability is disturbed. PMID- 23095293 TI - A case of simultaneous transvaginal NOTES gastrectomy and vaginal hysterectomy in a patient with gastric submucosal tumor and uterine prolapse. AB - A 5-cm gastric submucosal tumor was incidentally found through abdominal CT as a preoperative work-up for hysterectomy in a 62-year-old woman with uterine prolapse. NOTES using a flexible gastrointestinal endoscope via the transvaginal route was indicated to accomplish concomitant partial gastrectomy and hysterectomy. Perigastric dissection was performed, followed by stapled partial gastrectomy using transvaginal NOTES technique with two transabdominal ports. The specimen was delivered transvaginally by enlarging the initial vaginal entry site. Vaginal hysterectomy was then accomplished by utilizing the enlarged vaginal wound. The patient showed rapid and uneventful postoperative recovery without any narcotic need. No complication was noted, her cosmetic result was satisfactory, and there was complete resolution of preoperative gynecological symptoms. Female patients with concomitant gastrointestinal and gynecological conditions requiring large specimen retrieval would potentially be suitable candidates for the transvaginal NOTES approach. PMID- 23095294 TI - Single-incision laparoscopic surgery for small bowel resection with an intraumbilical arcuate incision in children. AB - Single-incision laparoscopic surgery (SILS) has been performed on children for various procedures. However, few reports are available about SILS for small bowel resection, particularly involving conventional instruments in the pediatric population. Herein, we report four cases of small bowel resection with single umbilical incision and a three-trocar approach. From October 2010 to September 2011, we performed small bowel resection with SILS on four cases, including a boy with an intestinal duplication cyst and three children with Meckel's diverticulum. An intraumbilical arcuate incision was made to expose the abdominal wall fascia, and one 5-mm and two 3.5-mm trocars were inserted. It was not necessary to extend the initial incision to exteriorize the lesion except in one case in which we applied the so-called Y-V closure plasty. All procedures were successful and did not require conversion, and all patients recovered smoothly without any complications. Small bowel resection using the SILS approach is suitable for these diseases. PMID- 23095295 TI - Thoracoscopic resection for a pulmonary nodule with the infiltrate of IgG4 positive plasma cells. AB - This report describes a rare case of IgG4-related lung disease that was difficult to distinguish from lung cancer. CT revealed a well-demarcated round tumor in S10 of the right lung of a 56-year-old man suspected of having lung cancer. PET revealed high fluorodeoxyglucose uptake with a maximum standardized uptake value of 14.0. Because primary lung cancer was strongly suspected, lower lobectomy was performed via the thoracoscopic approach without mini-thoracotomy. Histopathology showed lymphoplasmacytic infiltration. Immunostaining revealed numerous IgG4 positive plasma cells diffusely infiltrating the tumor. Serum IgG4 levels increased, thereby confirming the diagnosis of IgG4-related lung disease. PMID- 23095296 TI - Ovarian vein thrombosis following total laparoscopic hysterectomy. AB - Ovarian vein thrombosis usually occurs in pregnant patients, especially during the postpartum period. However, it is a rare complication following laparoscopic surgery in gynecology. The risk of a thromboembolic event is not well defined, and evidence-based guidelines regarding deep vein thrombosis prophylaxis in gynecological laparoscopic surgery are still lacking. Herein we report a rare case of ovarian vein thrombosis following total laparoscopic hysterectomy in a 35 year-old woman who developed a fever of unknown origin on postoperative day 3. A complete fever work-up was done. Her urine, vaginal stump and blood culture were all negative, and her white blood cell count was normal. CT revealed left ovarian vein thrombosis. The patient responded well to anticoagulation in conjunction with antibiotic therapy. PMID- 23095297 TI - Minimally invasive and simultaneous removal of herniated intracanal and extracanal lumbar nucleus pulposus with a percutaneous spinal endoscope. AB - Herniated nucleus pulposus (HNP) in the lumbar spine is usually found in the neural canal (in the intracanal space) and occasionally in the extracanal space, where it is known as a lateral HNP. HNP is rarely found simultaneously in both spaces. However, we experienced such a case in a 48-year-old man who presented with right leg pain and lower back pain that had lasted for more than a year. MRI revealed HNP in both the right intracanal and extracanal spaces at L2-L3. A transforaminal approach was used to complete a percutaneous endoscopic discectomy. An 8-mm incision was made with the patient under local anesthesia, and the percutaneous endoscope was inserted at the affected disc space. First, the HNP fragments in the intracanal space were removed, and then the cannula and endoscope were extracted to the extracanal space where the extracanal fragments were removed. Two hours after the surgery, the patient stood and walked. Right leg pain and lower back pain had disappeared. Unlike other techniques such as Love's procedure and the microendoscopic discectomy technique, the use of a transforaminal approach with the percutaneous endoscopic technique enables the HNP fragments in the intracanal and extracanal spaces to be removed at the same time with a single approach. PMID- 23095298 TI - Arantius' ligament approach for the left extrahepatic Glissonean pedicle in pure laparoscopic left hemihepatectomy. AB - INTRODUCTION: Laparoscopic hemihepatectomy has not yet become widely accepted because of the technical difficulties in controlling each Glissonean pedicle laparoscopically. MATERIALS AND SURGICAL TECHNIQUE: The subjects in the present study included 12 patients who underwent laparoscopic left hemihepatectomy between August 2007 and June 2011. Arantius' ligament was divided. Retracting the caudal stump of the ligament revealed a space between the left Glissonean pedicle and the liver parenchyma. The left Glissonean pedicle could be easily encircled by using an Endo Retract Maxi. No Glissonean injuries, including bleeding or biliary leakage, occurred in any of the 12 patients. DISCUSSION: Therefore, the Arantius' ligament approach for the left extrahepatic Glissonean pedicle appears to be feasible and safe for successfully performing pure laparoscopic left hemihepatectomy. PMID- 23095299 TI - Pancreaticojejunostomy with closure of the pancreatic stump by endoscopic linear stapler in laparoscopic pancreaticoduodenectomy: a reliable technique and benefits for pancreatic resection. AB - INTRODUCTION: We introduce a technique for pancreaticojejunostomy with closure of the pancreatic stump by endoscopic linear stapler as a reliable intervention with benefits for pancreatic resection in laparoscopic pancreaticoduodenectomy (Lap PD). MATERIALS AND SURGICAL TECHNIQUE: Following laparoscopic resection, we perform pancreaticojejunostomy under direct visualization. We employ the same method as in open surgery and enter via a 4-5-cm incision, the minimum size feasible for easy removal of resected material from the body, positioned directly above the stump of the distal pancreas. In January 2011, we began using endoscopic linear stapler when cutting the pancreas during Lap-PD in order to reduce the leakage of pancreatic juice, which may contain tumor cells from the neoplastic lesion. Since then, we have used this procedure in 12 subjects undergoing Lap-PD and 5 subjects undergoing laparoscopic central pancreatectomy. We have observed postoperative complication in only one of the laparoscopic central pancreatectomy cases, involving grade B/C pancreatic fistula, and in none of the Lap-PD cases. DISCUSSION: Our pancreaticojejunostomy with closure of the pancreatic stump by endoscopic linear stapler is a feasible procedure in Lap-PD and has produced positive results over a short time frame. PMID- 23095300 TI - Single-incision laparoscopic distal pancreatectomy with or without splenic preservation: how we do it. AB - INTRODUCTION: Recent interest in improving cosmetic outcomes has led to single incision laparoscopic surgery (SILS) being performed in a variety of organs. However, this innovative technique has rarely been introduced in pancreatic surgery, as it is considered to be a challenging procedure. We report herein our technique of single-incision laparoscopic distal pancreatectomy with or without splenic preservation. MATERIALS AND SURGICAL TECHNIQUE: A 2.5-cm intraumbilical mini-laparotomy was made for the placement of a SILS Port as a single access site. The overall procedures were similar to those performed in the standard laparoscopic distal pancreatectomy with multiple trocars. To obtain better exposure of the operative field, we made technical refinements by employing gastric suspension with sutures, the tug-exposure technique, a balloon retractor, and gravity by changing the patient's position. The pancreas was transected with a linear stapler, and the specimen was extracted through the umbilical wound. DISCUSSION: Patients were discharged without any complications. The umbilical wounds were almost invisible 1 month after surgery. We believe that SILS, with some technical refinements, can be safely applied for distal pancreatectomy. Although the cosmetic benefits of single-incision laparoscopic distal pancreatectomy are obvious, several issues such as the extent of invasiveness, cost, indications, and learning curve need to be investigated. PMID- 23095301 TI - Percutaneous endoscopic translaminar approach for herniated nucleus pulposus in the hidden zone of the lumbar spine. AB - INTRODUCTION: Percutaneous endoscopic discectomy (PED) is the least invasive surgery for lumbar herniated nucleus pulposus (HNP). Most HNP can be removed through traditional PED approaches, but the challenging case is an HNP that has migrated into the hidden zone. We have established a percutaneous endoscopic translaminar approach (PETA) using the PED system to address such cases. MATERIALS AND SURGICAL TECHNIQUE: Under fluoroscopy, an 8-mm skin incision is made 5 mm lateral to the midline. The PED cannula is placed on the lamina percutaneously. With a specially made high-speed drill with a diameter of 3.2 mm, a 4-mm bone hole is made. Through the bone hole, an HNP in the hidden zone can be detected. With a rongeur for PED, the HNP can be removed and then the decompressed nerve root is verified. We have treated nine cases of hidden-zone HNP. In all cases, the HNP was successfully removed, as confirmed by postoperative MRI. Clinical outcomes were acceptable: five showed excellent recovery and the remaining four were good. DISCUSSION: We have introduced the PETA technique to safely access the hidden zone with the PED system. This approach is the least invasive technique for managing hidden-zone HNP. PMID- 23095302 TI - Usefulness of the novel evolutional anvil grasper for laparoendoscopic surgery for intracorporeal circular stapled anastomosis during laparoscopic colorectal surgery. AB - Traditional anvil graspers cannot delicately handle the anvil head as a result of their unique jaw shape that enhances grip force, and they are not suitable for confined pelvic space. With a manufacturing company, we developed a novel anvil grasper, the evolutional anvil grasper for laparoendoscopic surgery (EAGLE), to ensure more precise and safer anastomosis procedures. The EAGLE has curved blades that create a 6-mm grasping surface that is the same diameter as the anvil stem and is covered with tungsten carbide tips. When using the EAGLE, a surgeon grasps the anvil stem slightly and easily, handles the anvil head and proximal colon, and smoothly sets the anvil to the center rod of the circular stapler. A surgeon can also securely grasp the stem of the anvil, push it into the center rod of the circular stapler and then perform a sequence of actions in anastomosis procedures smoothly and safely. PMID- 23095303 TI - Multisensory integration weightings underlying haptic feedback in laparoscopic surgery. PMID- 23095305 TI - Factors affecting auditory performance of postlinguistically deaf adults using cochlear implants: an update with 2251 patients. AB - OBJECTIVE: To update a 15-year-old study of 800 postlinguistically deaf adult patients showing how duration of severe to profound hearing loss, age at cochlear implantation (CI), age at onset of severe to profound hearing loss, etiology and CI experience affected CI outcome. STUDY DESIGN: Retrospective multicenter study. METHODS: Data from 2251 adult patients implanted since 2003 in 15 international centers were collected and speech scores in quiet were converted to percentile ranks to remove differences between centers. RESULTS: The negative effect of long duration of severe to profound hearing loss was less important in the new data than in 1996; the effects of age at CI and age at onset of severe to profound hearing loss were delayed until older ages; etiology had a smaller effect, and the effect of CI experience was greater with a steeper learning curve. Patients with longer durations of severe to profound hearing loss were less likely to improve with CI experience than patients with shorter duration of severe to profound hearing loss. CONCLUSIONS: The factors that were relevant in 1996 were still relevant in 2011, although their relative importance had changed. Relaxed patient selection criteria, improved clinical management of hearing loss, modifications of surgical practice, and improved devices may explain the differences. PMID- 23095304 TI - Prospective memory and antiretroviral medication non-adherence in HIV: an analysis of ongoing task delay length using the memory for intentions screening test. AB - Using multi-process framework by McDaniel and Einstein (2000), the current study examined whether the length of prospective memory (PM) delay intervals as measured by the 2- and 15-min subscales of the Memory for Intentions Screening Test (MIST) have differential predictive value for antiretroviral (ARV) adherence. Participants included 74 HIV-infected individuals whose ARV adherence was tracked with an electronic monitoring system. Participants were classified as "adherent" (n = 49) or "non-adherent" (n = 25) based on recorded pill bottle openings of >=90% of prescribed doses over 30 days. An adherence group by MIST delay interval interaction was observed, such that non-adherent participants had worse performance on the 15-min, but not 2-min delay PM MIST subscales. The observed MIST 15-min delay effects were significantly more pronounced on time- versus event-cued PM trials. Long-delay time-based PM was predictive of non adherence independent of demographics, mood state, self-reported adherence, and general cognitive functioning. Findings from this clinical study indicate that ARV non-adherence may be particularly associated with deficits in strategic cue monitoring over longer PM delays, which may inform interventions to improve adherence among persons living with HIV infection. PMID- 23095308 TI - Lymphocyte-derived catecholamines induce a shift of Th1/Th2 balance toward Th2 polarization. AB - AIMS: Our previous work has shown that lymphocytes synthesize and secrete catecholamines (CAs), which regulate lymphocyte proliferation and apoptosis. In the present study, we explored the effect of the lymphocyte-derived CAs on differentiation and function of T helper (Th) cells. METHODS: Lymphocytes were separated from the mesenteric lymph nodes of mice and stimulated by concanavalin A (Con A). These cells were treated with alpha-methyl-p- tyrosine (alpha-MT), an inhibitor of tyrosine hydroxylase (TH) that is a rate-limiting enzyme for synthesis of CAs, and pargyline, an inhibitor of monoamine oxidase that degrades CAs. RESULTS: Treatment of Con A-stimulated lymphocytes with alpha-MT (10(-6) M) reduced CAs both in the cultured lymphocytes and in the culture supernatants. Simultaneously, alpha-MT upregulated expression of mRNAs and proteins of T-box expressed in T cells (T-bet) and interferon-gamma (IFN-gamma) but downregulated expression of mRNAs and proteins of GATA binding protein 3 (GATA-3) and interleukin-4 (IL-4) in Con A-activated lymphocytes. In contrast, pargyline (10( 6) M) increased intracellular and supernatant CA contents in Con A-activated lymphocytes. Meanwhile, the treatment with pargyline downregulated expression of T-bet and IFN-gamma but upregulated expression of GATA-3 and IL-4 in these lymphocytes. CONCLUSION: CAs synthesized and secreted by lymphocytes regulate differentiation and function of Th cells, with an effect facilitating the shift of Th1/Th2 balance toward Th2 polarization. PMID- 23095307 TI - Double-blind, placebo-controlled randomized trial with adalimumab for treatment of juvenile onset ankylosing spondylitis (JoAS): significant short term improvement. AB - INTRODUCTION: While adalimumab is licensed for ankylosing spondylitis (AS), open uncontrolled studies suggest therapeutic efficacy of TNF-inhibitors in juvenile onset AS (JoAS). METHODS: A total of 32 patients aged 12 to 17 years with severe, active and refractory JoAS were enrolled in a multicenter, randomized, double blind, placebo-controlled parallel study of 12 weeks, followed by open-label adalimumab until week 24 for all patients. ASAS40 was used as the primary, and ASAS20, PedACR and single items were used as the secondary outcome measures for the intention to treat population. RESULTS: A total of 17 patients were randomized to receive adalimumab 40 mg/2 weeks and 15 patients received placebo. Two patients (one of each group) discontinued prematurely due to insufficient efficacy and were labeled as non-responders. In the double-blind part, more patients on adalimumab achieved an ASAS40 at week 4 (41%), week 8 (53%) and week 12 (53%) than on placebo (20%, 33%, 33%), while differences at week 8 only reached borderline significance (P = 0.05). Also, at 4, 8 and 12 weeks ASAS20/PedACR30/70 response rates were higher in the adalimumab group (53%/53%/29%; 59%/76%/41%; 53%/65%/53%) compared to placebo (27%/27%/7%; 27%/33%/13%; 33%/40%/27%). In the adalimumab group a significant decrease of all disease activity parameters was noted at week 12 and was even more pronounced at week 24. At week 12 the Bath Ankylosing Spondylitis Disease activity spinal inflammation score decreased by 65% (P <0.001), the back pain score decreased by 50% (P <0.005), the Bath AS Functional Index (BASFI) score decreased by 47% (P <0.02), while the Childhood Health Assessment Questionnaire-Disability Index (CHAQ-DI) score improved by 65% (P <0.005). ANCOVA analysis demonstrated superiority of adalimumab over placebo for the physician global assessment of disease activity, parents' global assessment of subject's overall well-being, active joint count (all P <0.05) and erythrocyte sedimentation rate (ESR) (P <0.01). CONCLUSIONS: Adalimumab was well tolerated and highly effective in a double-blind randomized trial in patients with JoAS. Treatment effects rapidly occurred and persisted for at least 24 weeks of treatment. TRIAL REGISTRATION: EudraCT 2007-003358-27. PMID- 23095309 TI - A young adult presenting with granulomatous hepatitis and nephrotic syndrome: A case report. AB - Amyloidosis is a rare disease characterised by the deposition of insoluble extracellular fibrillar proteins in various tissues of the body. The pattern of manifestation is organ dependent and also on whether the disease is localised or systemic, primary or secondary. Primary systemic amyloidosis is a disease of adulthood. In reported cases, the mean patient age of onset is 65 years. We report a case of a young adult who presented with jaundice and leg oedema which ultimately found to have granulomatous hepatitis and nephrotic syndrome secondary to systemic amyloidosis. The purpose of this case report is to reiterate the importance of a high index of suspicion in considering amyloidosis in such presentations regardless of the presenting age. PMID- 23095310 TI - Synthesis of esters of androgens with unsaturated fatty acids for androgen requiring therapy. AB - Androgens' metabolism and activity are gaining a more and more important role in human physiology particularly referring to aging and to neurodegenerative diseases. Androgen treatment is often required for long-lasting disorders. In order to improve their duration and effects, androgens can be administered as esters of carboxylic acids. The novelty of our research is the use of esters of androgens with specific unsaturated fatty acids, in order to reduce possible side effects particularly related to chronic pathologies with altered lipid homeostasis such as X-linked adrenoleukodystrophy and cardiovascular disorders. Thus the esters of the main androgenic substances testosterone, dihydrotestosterone (DHT) and their metabolite 5alpha-androstan-3alpha,17beta diol were chemically obtained by coupling with different unsaturated fatty acids. To this aim, fatty acids with various degree of unsaturation and belonging to different series were selected. Specifically, oleic acid (18:1, n-9), linoleic acid (18:2, n-6), and the n-3 fatty acids, alpha-linolenic acid (18:3), eicosapentaenoic acid (EPA, 20:5), and docosahexaenoic acid (DHA, 22:6) were used obtaining corresponding esters with acceptable yields and good degree of purity. All the synthesized compounds were tested for their cytotoxic activities in mouse NIH3T3 and human astrocyte cell lines. The esters demonstrated good tolerability and no in vitro cytotoxic effect in both cell cultures. After these promising preliminary results, the esters will be suitable for in vivo studies in order to ascertain their pharmacokinetic characteristics and their biological effects. PMID- 23095311 TI - Factors related to discontinued clinic attendance by patients with podoconiosis in southern Ethiopia: a qualitative study. AB - BACKGROUND: Podoconiosis is a lymphoedema of non-infectious cause which results in long-term ill health in affected individuals. Simple, effective treatment is available in certain parts of Ethiopia, but evidence indicates that not all patients continue collecting treatment supplies from clinic sites once started. We used qualitative techniques to explore factors related to discontinued attendance at outreach clinics of a non-government organization in southern Ethiopia. METHODS: A cross-sectional qualitative study was conducted in four clinic sites through unstructured in-depth interviews, key informant interviews and focus group discussions with the involvement of 88 study subjects. RESULTS: Discontinuation of clinic visits is common among podoconiosis patients. The reasons were: remoteness from the clinic sites, unrealistic expectation of 'special' aid, worry about increasing stigma, illness and misconceptions about treatment. CONCLUSIONS: Several of these factors are remediable through community and individual information and education. Appropriate routes to deliver this information must be identified. Certain factors (such as distance to clinic sites and stigma) require substantial expansion of services or liaison with village level government health services. PMID- 23095312 TI - Concordance between HIV-2 genotypic coreceptor tropism predictions based on plasma RNA and proviral DNA. AB - In this study, assessing HIV-2 tropism among 43 paired plasma/peripheral blood mononuclear cell specimens, the concordance between proviral DNA and plasma RNA genotypic tropism prediction was 74%. All the discordances were attributable to the prediction of R5 in RNA and X4/dual-mixed in DNA. HIV-2 genotypic tropism test based on proviral DNA is a suitable tool for tropism determination in HIV-2 infected patients with low or undetectable viral load. PMID- 23095314 TI - An internationally generalizable risk index for mortality after one year of antiretroviral therapy. AB - OBJECTIVE: Despite the success of antiretroviral therapy (ART), excess mortality continues for those with HIV infection. A comprehensive approach to risk assessment, addressing multiorgan system injury on ART, is needed. We sought to develop and validate a practical and generalizable mortality risk index for HIV infected individuals on ART. DESIGN AND METHODS: The Veterans Aging Cohort Study (VACS) was used to develop the VACS Index, based on age, CD4 cell count, HIV-1 RNA, hemoglobin, aspartate and alanine transaminase, platelets, creatinine and hepatitis C status, and a Restricted Index based on age, CD4 cell count and HIV-1 RNA with an outcome of death up to 6 years after ART initiation. Validation was in six independent cohorts participating in the ART Cohort Collaboration (ART CC). RESULTS: In both the development (4932 patients, 656 deaths) and validation cohorts (3146 patients, 86 deaths) the VACS Index had better discrimination than the Restricted Index (c-statistics 0.78 and 0.72 in VACS, 0.82 and 0.78 in ART CC). The VACS Index also demonstrated better discrimination than the Restricted Index for HIV deaths and non-HIV deaths, in men and women, those younger and older than 50 years, with and without detectable HIV-1 RNA, and with or without HCV coinfection. CONCLUSIONS: Among HIV-infected patients treated with ART, the VACS Index more accurately discriminates mortality risk than traditional HIV markers and age alone. By accounting for multiorgan system injury, the VACS Index may prove a useful tool in clinical care and research. PMID- 23095316 TI - Vitamin D insufficiency may impair CD4 recovery among Women's Interagency HIV Study participants with advanced disease on HAART. AB - BACKGROUND: Recent studies in HIV-infected men report an association between low vitamin D (25OH-D) and CD4 recovery on HAART. We sought to test this relationship in the Women's Interagency HIV Study (WIHS). METHODS: We examined 204 HIV infected women with advanced disease, who started HAART after enrollment in the WIHS. We measured vitamin D (25OH-D) levels about 6 months prior to HAART initiation. The relationship between CD4 recovery (defined as increases of >=50, 100, and 200 cells at 6, 12, and 24 months) and exposure variables was examined using logistic regression models at 6, 12 and 24 months post-HAART initiation in unadjusted and adjusted analyses, and using multivariable longitudinal Generalized Estimating Equations (GEE). Vitamin D insufficiency was defined as 25OH-D levels at least 30 ng/ml. RESULTS: The majority were non-Hispanic black (60%) and had insufficient vitamin D levels (89%). In adjusted analyses, at 24 months after HAART, insufficient vitamin D level (OR 0.20, 95% CI 0.05-0.83) was associated with decreased odds of CD4 recovery. The undetectable viral load (OR 11.38, 95% CI 4.31-30.05) was associated with CD4 recovery. The multivariable GEE model found that average immune reconstitution attenuated significantly (P < 0.01) over time among those with insufficient vitamin D levels compared with those with sufficient vitamin D levels. CONCLUSION: Vitamin D insufficiency is associated with diminished late CD4 recovery after HAART initiation among US women living with advanced HIV. The mechanism of this association on late CD4 recovery may be late vitamin D-associated production of naive CD4 cells during immune reconstitution. PMID- 23095317 TI - Anisakis simplex hypersensitivity is associated with chronic urticaria in endemic areas. AB - BACKGROUND: Chronic urticaria (CU) may affect up to 1% of the general population. Anisakis simplex hypersensitivity is frequent in areas where raw fish is consumed and A. simplex allergy represents a relevant cause of acute urticaria. We assessed the possible association between CU and A. simplex sensitization in an area where marinated fish is very frequently eaten. METHODS: A thorough history of CU was sought in 919 adults seen at the Allergy Center, Bari. CU patients and 187 controls underwent skin-prick testing with a commercial extract of A. simplex, and reactors were recommended a 6-month raw-fish-free diet regimen. Responders were followed after a further 3 months. RESULTS: Of 919 subjects, 213 (23%) met the criteria for CU and 106/213 (49.7%) were sensitized to A. simplex with a significant difference between patients aged >65 or <65 years (56 vs. 41%, respectively; p < 0.05). All patients hypersensitive to A. simplex were regular consumers of marinated fish. In a control population without CU, the prevalence of A. simplex sensitization was 16% (p < 0.001). The 6-month diet regimen led to the disappearance of urticaria in 82/106 cases (77%) versus 1/42 (2%) subjects who did not change their dietary habits (p < 0.001). All nonresponders were sensitized to house-dust mites. Of 75 responders who were followed-up after 3 months, CU relapsed in 88% of those who had reintroduced raw fish versus 14% of those who were still on the diet (p < 0.001). CONCLUSION: In areas where raw or marinated fish is frequently eaten, A. simplex hypersensitivity is a frequent cause of CU. PMID- 23095318 TI - Cardioprotection: chances and challenges of its translation to the clinic. AB - Myocardial infarct size is a major determinant of prognosis. Ischaemic preconditioning with brief coronary occlusion and reperfusion before a sustained period of coronary occlusion with reperfusion delays infarct development. Ischaemic postconditioning uses repetitive brief coronary occlusion during early reperfusion of myocardial infarction and reduces infarct size. Remote ischaemic preconditioning uses brief ischaemia and reperfusion of a distant organ to protect the myocardium. These conditioning protocols recruit a complex signal cascade of sarcolemmal receptor activation, intracellular enzyme activation, and ultimately mitochondrial stabilisation and inhibition of death signalling. Conditioning protocols have been successfully used in patients undergoing elective coronary revascularisation and reperfusion after acute myocardial infarction. Pharmacological recruitment of cardioprotective signalling has also been used to reduce infarct size, but so far without prognostic benefit. Outcomes of cardioprotection are affected by age, sex, comorbidities, and drugs, but also by technical issues related to determination of infarct size and revascularisation procedure. PMID- 23095319 TI - The nature of progress in nanopatterning. PMID- 23095315 TI - Longitudinal analysis of an HLA-B*51-restricted epitope in integrase reveals immune escape in early HIV-1 infection. AB - OBJECTIVE: To fully define cytotoxic T-lymphocyte (CTL) escape variants of an HLA B*51-restricted integrase epitope in early HIV-1 infection. DESIGN: Ninety-four longitudinally sampled acute/early HIV-1 subtype B-infected participants were assessed to determine HLA-B*51-restricted LPPVVAKEI (LI9) escape variants. METHODS: LI9 was sequenced at baseline and subsequent time points. Interferon gamma (IFNgamma) ELISpot assays were performed using serial log dilutions of variant LI9 peptides to determine the cellular response and functional avidity. RESULTS: There is a significant association between HLA-B*51 expression and an evolving LI9 sequence from baseline to year 1 (P < 0.0001). We detected that the V32I and P30X polymorphisms emerged within HLA-B*51 participants over time. Reversion of the P30S polymorphism was observed by year 1 in one HLA-B*51 participant. LPPIIAKEI and LPSIVAKEI had significantly lower functional avidity compared with LPPVVAKEI and so may be less well recognized by LI9-specific CTLs; a positive IFNgamma response to IPSVVAKEI was rarely seen. Functional avidity to wild-type LI9 inversely correlated with viral load (R = 0.448, P = 0.0485). CONCLUSION: Our results provide support for the role of HLA-B*51-restricted CTLs and functional avidity in the control of early HIV-1 infection. PMID- 23095320 TI - Omega-3 fatty acids ameliorate proteinuria but not renal function in IgA nephropathy: a meta-analysis of randomized controlled trials. AB - BACKGROUND/AIM: The effects of omega-3 fatty acids (O3FAs) on renal function and proteinuria in immunoglobulin A nephropathy (IgAN) are not fully understood. Thus, we conducted an up-to-date meta-analysis of the currently available randomized controlled trials (RCTs) to validate the effects of O3FA in IgAN. METHODS: A literature search was performed in PubMed, Medline, Embase and the Cochrane Central Registry of Controlled Trials using an extended search strategy to identify RCTs that assessed the treatment efficacy of O3FA in IgAN. The dose effect relationships of O3FA on renal function and proteinuria were also determined. RESULTS: Five RCTs with a total of 233 patients were included in our analysis. Our results demonstrated that while O3FA does not have any beneficial effects in preserving renal function in IgAN, proteinuria was significantly reduced. Furthermore, patients who received a high dose of O3FA (>3 g/day) did not differ from those who received a low dose of O3FA (<=3 g/day) in renal function or proteinuria. CONCLUSION: The currently available evidence suggests that O3FA has no benefit in preserving renal function, but can ameliorate proteinuria in IgAN. However, the effects of O3FA on proteinuria are not dose dependent. PMID- 23095321 TI - Confident methods for the evaluation of the hydrogen content in nanoporous carbon microfibers. AB - : Nanoporous carbon microfibers were grown by chemical vapor deposition in the vapor-liquid solid mode using different fluid hydrocarbons as precursors in different proportions. The as-grown samples were further treated in argon and hydrogen atmospheres at different pressure conditions and annealed at several temperatures in order to deduce the best conditions for the incorporation and re incorporation of hydrogen into the microfibers through the nanopores. Since there are some discrepancies in the results on the hydrogen content obtained under vacuum conditions, in this work, we have measured the hydrogen content in the microfibers using several analytical methods in ambient conditions: surface tension, mass density, and Raman measurements. A discussion on the validity of the results obtained through the correlation between them is the purpose of the present work. PMID- 23095322 TI - Subclinical cardiomyopathy and long QT syndrome: an echocardiographic observation. AB - OBJECTIVE: Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to syncope and sudden death secondary to LQT-triggered ventricular arrhythmias. Long QT syndrome has been regarded as a purely electrical disease. Recent reports have shown by echocardiography that LQTS patients have contraction abnormalities that are associated with cardiac arrhythmias. The purpose of this study was to determine the spectrum and prevalence of echocardiographic anomalies in a large cohort of patients diagnosed genetically and/or clinically with LQTS. OUTCOME MEASURES: Two-dimensional and Doppler echocardiographic studies performed during medical evaluation in Mayo's LQTS Clinic were reviewed for 216 LQTS patients. Echocardiograms were evaluated for morphologic abnormalities and atrial and ventricular size and function. Left atrial volume was indexed by body mass. Arrhythmic events were defined as a history of aborted cardiac arrest, documented ventricular tachycardia or fibrillation, and syncope. RESULTS: While 75% of patients had normal standard echocardiograms, 54 patients (25%) had at least one abnormal echocardiographic finding. Most common were subclinical cardiomyopathic changes, including increased left atrial volume index (n = 25), left or right ventricular enlargement (n = 7), and grade I-II diastolic dysfunction (n = 7). Left atrial volume index was higher in LQTS patients with arrhythmic events compared with those without (24.4 +/- 5.5 mL/m(2) vs. 22.3 +/- 6.1 mL/m(2) , P =.02). Corrected QT intervals and left atrial volume index correlated significantly albeit weakly (r(2) = 0.04, P <.01). Concomitant congenital heart disease was found in two patients. CONCLUSIONS: Subclinical cardiomyopathic changes were found in nearly 20% of LQTS patients. Left atrial enlargement was the most common finding and was associated with prolonged corrected QT and arrhythmic events. These changes may stem from underlying contraction abnormalities caused by ion channel dysfunction. PMID- 23095323 TI - The activation of MAPK in melanoma cells resistant to BRAF inhibition promotes PD L1 expression that is reversible by MEK and PI3K inhibition. AB - PURPOSE: Selective BRAF inhibition (BRAFi) provides a paradigm shift for melanoma treatment. The duration of benefit is typically limited before resistance develops. Interest remains in combining targeted and immune therapies to overcome resistance and improve durability of clinical benefit. One mechanism of evading immune destruction is programmed death-1-ligand 1 (PD-L1) expression by tumors that results in potent antitumor immune suppression. EXPERIMENTAL DESIGN: BRAFi resistant melanoma cells were examined for changes in PD-L1 expression by immunoblot and flow cytometry. Signaling pathways involved in altering PD-L1 expression were examined. Strategies to maximize the effect of the BRAFi therapy were studied including MEKi, MEKi combinations, and additional pathways including phosphoinositide-3 kinase (PI3K). RESULTS: Melanoma cells resistant to BRAFi exhibit increased MAPK signaling and promotion of PD-L1 expression. PD-L1 expression is transcriptionally modulated by c-Jun and augmented by STAT3. MEK inhibition (MEKi) regains downregulation of MAPK signaling and suppresses the production of PD-L1. MEKi in melanoma cells shows dual therapeutic effects with simultaneous suppression of PD-L1 expression and induction of apoptosis. By combining MEKi with BRAFi, an additive effect on the inhibition of PD-L1 expression results. CONCLUSIONS: We report a novel mechanism that suppresses preexisting immune responses in patients with melanoma receiving BRAFi therapy. BRAFi resistance leads to increased expression of PD-L1 in melanoma cells, mediated by c-Jun and STAT3. MEKi may be feasible to counteract BRAFi resistance of MAPK reactivation and also for the additive effect of PD-L1 suppression. Potential therapeutic benefits of combining targeted inhibitors and immune modulation to improve patient outcomes should be investigated. PMID- 23095325 TI - Fitting parametric random effects models in very large data sets with application to VHA national data. AB - BACKGROUND: With the current focus on personalized medicine, patient/subject level inference is often of key interest in translational research. As a result, random effects models (REM) are becoming popular for patient level inference. However, for very large data sets that are characterized by large sample size, it can be difficult to fit REM using commonly available statistical software such as SAS since they require inordinate amounts of computer time and memory allocations beyond what are available preventing model convergence. For example, in a retrospective cohort study of over 800,000 Veterans with type 2 diabetes with longitudinal data over 5 years, fitting REM via generalized linear mixed modeling using currently available standard procedures in SAS (e.g. PROC GLIMMIX) was very difficult and same problems exist in Stata's gllamm or R's lme packages. Thus, this study proposes and assesses the performance of a meta regression approach and makes comparison with methods based on sampling of the full data. DATA: We use both simulated and real data from a national cohort of Veterans with type 2 diabetes (n=890,394) which was created by linking multiple patient and administrative files resulting in a cohort with longitudinal data collected over 5 years. METHODS AND RESULTS: The outcome of interest was mean annual HbA1c measured over a 5 years period. Using this outcome, we compared parameter estimates from the proposed random effects meta regression (REMR) with estimates based on simple random sampling and VISN (Veterans Integrated Service Networks) based stratified sampling of the full data. Our results indicate that REMR provides parameter estimates that are less likely to be biased with tighter confidence intervals when the VISN level estimates are homogenous. CONCLUSION: When the interest is to fit REM in repeated measures data with very large sample size, REMR can be used as a good alternative. It leads to reasonable inference for both Gaussian and non-Gaussian responses if parameter estimates are homogeneous across VISNs. PMID- 23095324 TI - Molecular imaging reveals a role for AKT in resistance to cisplatin for ovarian endometrioid adenocarcinoma. AB - PURPOSE: Ovarian cancer is the fifth leading cause of cancer-related deaths among American women. Platinum-based chemotherapy, such as cisplatin, represents the standard-of-care for ovarian cancer. However, toxicity and acquired resistance to cisplatin have proven challenging in the treatment of patients with ovarian cancer. EXPERIMENTAL DESIGN: Using a genetically engineered mouse model of ovarian endometrioid adenocarcinoma (OEA) in combination with molecular-imaging technologies, we studied the activation of the AKT serine/threonine kinase in response to long-term cisplatin therapy. RESULTS: Treatment of cells in culture and tumor-bearing animals with cisplatin resulted in activation of AKT, a key mediator of cell survival. On the basis of these results, we investigated the therapeutic use of AKT inhibition in combination with cisplatin, which resulted in enhanced and prolonged induction of apoptosis and in significantly improved tumor control as compared with either agent alone. CONCLUSION: These results provide an impetus for clinical trials using combination therapy. To facilitate these trials, we also show the use of diffusion-weighted MRI as an imaging biomarker for evaluation of therapeutic efficacy in OEA. PMID- 23095326 TI - Association between serotonin transporter-linked polymorphic region and escitalopram antidepressant treatment response in Korean patients with major depressive disorder. AB - OBJECTIVE: Various studies have shown that short (s)/long (l) polymorphisms of the serotonin transporter-linked polymorphic region (5-HTTLPR) might predict treatment outcome to selective serotonin reuptake inhibitors. The purpose of this study was to evaluate the association between 5-HTTLPR and clinical response to escitalopram treatment in Korean subjects with major depressive disorder. METHODS: One hundred and fifteen Korean patients diagnosed with major depressive disorder were evaluated during 8 weeks of escitalopram treatment at a dose of 5 20 mg/day. Patients were genotyped for 5-HTTLPR using polymerase chain reaction. Clinical symptoms were evaluated by the 21-item Hamilton Depression Rating (HAMD 21) scale during the 8 weeks of treatment. RESULTS: Therapeutic response to antidepressant escitalopram was better in s allele carriers (ss, sl) than in l allele homozygotes (ll) at 8 weeks of treatment (OR = 6.24, p = 0.026). The proportion of s allele carriers in responders was higher than that in non responders (96.6 vs. 85.7%). The percentile decline in HAMD-21 in s allele carriers (59.86 +/- 3.23%) was larger than that in HAMD-21 in l allele homozygotes (43.13 +/- 11.49%; p = 0.029). However, 5-HTTLPR genotypes were not significantly associated with remission (p > 0.05). CONCLUSIONS: Our results show that treatment response to escitalopram at 8 weeks was moderated by 5-HTTLPR, with better response rates for s allele carriers than for l allele homozygotes. Although the role of 5-HTTLPR as a definite predictor of selective serotonin reuptake inhibitor treatment response cannot be confirmed from current results, they do suggest a trend for better response in s allele carriers. PMID- 23095327 TI - Perceived mastery of work among shift workers in the Norwegian offshore petroleum industry. AB - This study investigated associations between individual and work-related factors and perceived mastery of work among offshore shift workers. 2,406 employees of a Norwegian petroleum company were invited to participate. A web-based survey was used and 1336 completed questionnaires were returned (56%). Mastery of work was assessed using QPS Nordic Mastery Scale and the results were compared with a sample from the QPS Nordic study. Individual factors adjusted for were age, gender, marital status and personality. The following work-related factors were included: demands, control, support, night work and shift work home interference. Female offshore shift workers reported higher levels of perceived mastery of work compared with women in the comparison sample. The following variables were independently associated with perceived mastery of work: female gender (beta=0.10, p=0.008), decisional demands (beta=0.13, p<0.001), control (beta=0.05, p=0.009), social support (beta=0.07, p<0.001), shift-work locus of control (beta=0.04, p=0.005) and neuroticism (beta=-0.29, p<0.001). Post hoc analyses showed no sex differences in perceived mastery in two separate work positions on the platforms. Work-related variables and personality explained 55% and 45% respectively of the total variance (R(2)=0.22) explained by the final model. Female petroleum offshore workers reported somewhat higher levels of mastery of work than their male colleagues, however, this may be due to different work positions. Work-related factors accounted for about half of the explained variance and decisional demands, control and support remained statistically significant after controlling for personality. PMID- 23095328 TI - Dismissals - a major concern, but only one among others? AB - The Finnish forest industry has undergone extensive transition in recent years. This study investigates the effect of restructuring on the well-being of blue collar employees who continued working in the organization after the changes. All six factories selected for the study were in the process of restructuring between baseline and the follow-up survey. The factories were grouped according to personnel reduction (dismissals): Change group 1 - no dismissals; and Change group 2 - dismissals. The majority of the analyses were carried out using longitudinal data (n=382). The associations between the changes in personnel and functional and psychological well-being were analysed using ANCOVA (adjusted for age, gender, education, and outcome at baseline). In both change groups the level of functional well-being improved after restructuring, but the level of psychological well-being decreased. The content of the changes, regardless of whether they involved personnel dismissals, did not affect the magnitude of the decrease in psychological well-being. It seems that the effect of restructuring on the psychological well-being of employees working in the restructuring organization is considerable, even when no dismissals are involved. The impact of change on functional well-being seems to be different. PMID- 23095329 TI - Recurrence of sickness absence due to depression after returning to work at a Japanese IT company. AB - There have been few epidemiological studies on recurrent sickness absence due to depression after returning to work (RTW). The objective of this study was to investigate the prognosis of workers who are RTW with depression in a Japanese company. This study employed a descriptive epidemiology study design. Subjects of this study were 540 employees who worked full-time and were registered in the Health Data System and returned to work from April 2002 to March 2008 after their first leave of absence due to depression. We investigated the recurrence of sickness absence due to depression after returning to work using the Kaplan-Meier survival curve method. During the 8.5 yr follow-up period, almost half of the RTW employees experienced recurrent sickness absence. There was a steep increase in recurrent rates the first two years after RTW, and 85.2% of total recurrence of sickness absence had occurred within three years after the index episode. PMID- 23095330 TI - HealthTwiSt: the Berlin Twin Registry for health research. AB - The Berlin Twin Registry has its focus on health research. It is operated as a private company, making twin studies available to academic institutions as well as commercial partners in the area of biotechnology and nutrition. Recruitment is based on invitation in the context of mass media coverage of scientific results. Phenotyping in the unselected twin subjects is directed toward intermediate phenotypes that can bear on common diseases. These phenotypes include proteomic approaches and gene expression. Some results are briefly described to give an impression of the range of research topics and related opportunities for retrospective and prospective collaborative research. PMID- 23095331 TI - Usutu virus in blackbirds (Turdus merula), Czech Republic, 2011-2012. AB - The central European lineage of Usutu virus was isolated from a blackbird (Turdus merula), which was found dead in the city of Brno, Czech Republic, in 2011. The virus RNA was detected in two other dead blackbirds in Brno during 2012. PMID- 23095333 TI - Development of auditory localization accuracy and auditory spatial discrimination in children and adolescents. AB - The present study investigated the development of two parameters of spatial acoustic perception in children and adolescents with normal hearing, aged 6-18 years. Auditory localization accuracy was quantified by means of a sound source identification task and auditory spatial discrimination acuity by measuring minimum audible angles (MAA). Both low- and high-frequency noise bursts were employed in the tests, thereby separately addressing auditory processing based on interaural time and intensity differences. Setup consisted of 47 loudspeakers mounted in the frontal azimuthal hemifield, ranging from 90 degrees left to 90 degrees right (-90 degrees , +90 degrees ). Target signals were presented from 8 loudspeaker positions in the left and right hemifields (+/-4 degrees , +/-30 degrees , +/-60 degrees and +/-90 degrees ). Localization accuracy and spatial discrimination acuity showed different developmental courses. Localization accuracy remained stable from the age of 6 onwards. In contrast, MAA thresholds and interindividual variability of spatial discrimination decreased significantly with increasing age. Across all age groups, localization was most accurate and MAA thresholds were lower for frontal than for lateral sound sources, and for low frequency compared to high-frequency noise bursts. The study also shows better performance in spatial hearing based on interaural time differences rather than on intensity differences throughout development. These findings confirm that specific aspects of central auditory processing show continuous development during childhood up to adolescence. PMID- 23095332 TI - Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults. AB - BACKGROUND: Transcription of the cathelicidin antimicrobial peptide (CAMP) gene is induced by binding of the bioactive form of vitamin D, 1,25-dihydroxyvitamin D, to the vitamin D receptor. Significant levels of the protein hCAP18/LL-37 are found in the blood and may protect against infection and/or sepsis. We hypothesized that serum vitamin D levels may modulate the circulating levels of hCAP18. Only three studies have shown a positive correlation between circulating 25-hydroxyvitamin D and hCAP18 levels. Here we provide additional evidence for such a correlation in healthy, middle-aged adults. FINDINGS: Serum levels of 25 hydroxyvitamin D [25(OH)D] and plasma levels of hCAP18 were determined in 19 healthy middle-aged (mean of 50.1 years) adult men and women. Plasma hCAP18 concentrations correlated with serum 25(OH)D concentrations in subjects with 25(OH)D levels <= 32 ng/ml (r = 0.81, p < 0.005) but not in subjects with concentrations > 32 ng/ml (r = 0.19, p = 0.63). CONCLUSIONS: We conclude that plasma hCAP18 levels correlate with serum 25(OH)D levels in subjects with concentrations of 25(OH)D <= 32 ng/ml as opposed to those with concentrations > 32 ng/ml and that vitamin D status may regulate systemic levels of hCAP18/LL-37. PMID- 23095334 TI - Metabolic syndrome components and risk factors for pancreatic adenocarcinoma: a case-control study in China. AB - BACKGROUND: Metabolic syndrome is a complex collection of interrelated conditions. Recent data have shown that metabolic syndrome may play a role in several cancers. Pancreatic adenocarcinoma is the fourth most common cause of death from cancer in the United States and the fifth in Europe. Despite the increasing numbers of published studies, the etiology of pancreatic adenocarcinoma is incompletely defined. Therefore, this paper aims to evaluate the risk factors for pancreatic adenocarcinoma. METHODS: This was a case-control study of pancreatic adenocarcinoma patients who were referred to the Peking Union Medical College Hospital. Controls were randomly selected from an existing database of healthy individuals at the Health Screening Center. Data on metabolic syndrome, pancreatic diseases, liver diseases, and a history of diabetes and history of hypertension were collected either by conducting a retrospective review of the patients' records and health examination reports or by interview. RESULTS: A history of smoking (OR = 2.981), diabetes (OR = 2.421), cholecystolithiasis (OR = 5.453), or chronic pancreatitis (OR = 28.264) as well as the levels of fasting blood glucose (OR = 4.241), total cholesterol (OR = 1.793), and apolipoprotein A (OR = 36.065) were significantly related to pancreatic adenocarcinoma. CONCLUSIONS: Cholelithiasis, chronic pancreatitis, and certain metabolic syndrome components are potential risk factors for the development of pancreatic adenocarcinoma. PMID- 23095335 TI - Development of a community commitment scale with cross-sectional survey validation for preventing social isolation in older Japanese people. AB - BACKGROUND: Elderly social isolation could be prevented by facilitating communication or mutual helping at the neighborhood level. The helping of elderly neighbors by local volunteers may relate to their community commitment (CC), but ways to measure CC have not been identified. The aim of the present study was to develop a Community Commitment Scale (CCS) to measure psychological sense of belonging and socializing in the community among local volunteers, for research in prevention of elderly social isolation. We also tested the CCS in a general population of the elderly. METHODS: A pilot test of 266 Japanese urban residents was conducted to examine face validity for 24 identified items, of which 12 items were selected for the CCS, based on a 4-point Likert-type scale. The CCS was developed via self-report questionnaires to 859 local volunteers in two suburban cities and to 3484 randomly sampled general residents aged 55 years or older living in one of the cities. To assess concurrent validity, data were collected using the Brief Sense of Community Scale (Peterson; 2008) and two types of single questions on self-efficacy for helping elderly neighbors. RESULTS: Item analysis and factor analysis identified 8 items, which were classified between two datasets under the domains of "belonging" and "socializing" in the local volunteers and the general residents. Cronbach's alpha (which conveyed the internal consistency of the CCS) was 0.75 in local volunteers and 0.78 in general residents. The correlation coefficients between the scores of the CCS and BSCS were 0.54 for local volunteers and 0.62 for general residents. ANOVA comparing the CCS between the confidence levels of the two types of single question of self efficacy on helping elderly neighbors showed a strong relationship in the volunteers and residents. CONCLUSIONS: These results demonstrate acceptable internal consistency and concurrent validity for the CCS, with the two dimensions "belonging" and "socializing", among the local volunteers and general residents in urban Japanese areas. Community commitment measured by the CCS was related to the degree of confidence for self-efficacy in helping elderly neighbors to prevent elderly social isolation. PMID- 23095337 TI - "Occult" melanocytes in nail matrix melanoma. PMID- 23095336 TI - Plasma leptin and energy expenditure during prolonged, moderate intensity, treadmill exercise. AB - BACKGROUND: Current literature shows conflicting results regarding the possible direct role of exercise on leptin concentrations, mainly because of a non homogeneous level of energy expenditure (EE) and the lack of standardization of energy balance. AIM: The aim of the study was to evaluate the effect of exercise duration and its corresponding EE on leptin levels, during prolonged treadmill exercise, in a well-controlled laboratory setting. MATERIALS AND METHODS: Seven young trained males underwent a 4-h treadmill exercise. The starting intensity was set at 65% of maximal oxygen consumption. At the start of the test and throughout the exercise, venous blood samples were drawn for the assays of leptin, glucose, free fatty acids (FFA), cortisol, epinephrine (E) and norepinephrine (NE). Hourly and total EE was monitored with gas analysis. RESULTS: Plasma leptin levels decreased from 1.10+/-0.15 to 0.85+/-0.26 MUg/l (p<0.01) at the end of the exercise, reaching a significant reduction already after the second hour. FFA and cortisol showed a progressive significant increase, while glucose did not significantly change throughout the test. Plasma E and NE significantly increased at all sampling times compared to basal values (48.1+/-30.3 to 352.3+/-187.7 pg/ml, p<0.001 and 238.1+/-118.9 to 1798.7+/-413.5 pg/ml, p<0.001). The random-effects model for panel data analysis showed negative correlation between leptin, NE and the values of progressive EE (r2=0.745, p<0.05). CONCLUSIONS: Our data demonstrate that, during a prolonged moderate intensity exercise, leptin decrease is significantly related to the total EE. Further, NE concentrations seem to play an important role in the inhibition of leptin secretion. PMID- 23095338 TI - Significance of cyclooxygenase 2, EZH-2 polycomb group and p53 expression in actinic keratosis and squamous cell carcinomas of the skin. AB - The development and progression of squamous cell carcinoma (SCC) of the skin is characterized by an accumulation of molecular changes. The aim of this study was to investigate the association of the immunohistochemical expression of cyclooxygenase-2 (COX-2), enhancer of zeste homolog 2 (EZH-2), and p53 in actinic keratosis (AK) and SCC and detect any differences between invasive and preinvasive squamous epidermal lesions. Forty-three cases with AK, 38 with SCC, and 9 with SCC arising on AK (SCC/AK) were studied. For COX-2 immunostaining, weak or no reaction was associated with AK (58.10% of cases), whereas moderate or strong reaction with SCCs (34.2% and 39.5%, respectively). Furthermore, 88.9% of the "mixed" SCC/AK specimens demonstrated moderate reaction (chi2 = 29.924, P < 0.0001). For EZH-2 immunostaining, a weak or no reaction was observed in 62.8% of AK cases, whereas a moderate reaction was observed in 42.1% of SCCs and 77.8% of "mixed" SCC/AK cases (chi2 = 18.91, P = 0.001). Weak immunoreactivity of p53 was associated with AK (58.1%), moderate with SCC (44.7%), and strong with SCC/AK lesions (66.7%) (chi2 = 15.999, P = 0.003). COX-2, p53, but mainly EZH-2 immune expression seems to be strongly associated with the biological potential of squamous epidermal cells and seems to be differentiating SCC by comparison to AK of the skin. The value of the combined expression of these markers is worth being further investigated as an additional tool for diagnostic, prognostic, and possibly, therapeutic use. PMID- 23095339 TI - Cutaneous nodules as a diagnostic clue in multiple myeloma. AB - Cutaneous plasmacytomas are monoclonal proliferations of plasma cells which can be classified into primary (with no other concomitant bony or extramedullary disease) or secondary (generally associated with multiple myeloma (MM), extramedullary plasmacytoma, or plasma cell leukemia). Cutaneous plasmacytomas can appear in some patients with MM and, rarely, the skin lesions suppose the first clinical manifestation of the disease. Their development is considered as a poor prognostic sign, associated with a life expectancy of less than 12 months after diagnosis. An unusual case of MM is described, in which the histopathological study of a skin nodule provided invaluable information for diagnosis. PMID- 23095340 TI - A rare case of granuloma annulare in a 5-year-old child with type 1 diabetes and autoimmune thyroiditis. AB - Granuloma annulare (GA) has rarely been reported in childhood, and its etiology still remains unclear. Its association with type 1 diabetes (T1D) and other chronic systemic diseases such as autoimmune thyroiditis (AT) or rheumatoid arthritis has been reported. There is no description in the literature of pediatric cases and the simultaneous association of GA and multiple autoimmune diseases in the same subject. We report the case of a 5-year-old girl who presented onset signs and symptoms of T1D. The diagnosis of T1D was confirmed by the presence of autoimmune T1D antibodies. Moreover, AT was also diagnosed by autoantibodies and positive ultrasound. One month later, coin-size erythematous lesions appeared initially on the trunk but soon spread over the body. Once dermatophytosis had been excluded, a skin biopsy confirmed a diagnosis of GA. Although a clear mechanism remains still unknown, clinicians must take into consideration an association of GA in patients with T1D or AT to avoid unnecessary medical investigations and/or inadequate pharmacological treatment. PMID- 23095341 TI - Malignant chondroid syringoma of the face with bone invasion. AB - Malignant chondroid syringoma is a very rare type of malignant sweat gland tumor. Diagnosis is based on pathologic features but is complicated by the low frequency of this tumor. The authors report a new case of malignant chondroid syringoma, initially misdiagnosed as basal cell carcinoma, that exhibited very aggressive local behavior and was located on the face, a rare site for this tumor. The authors describe its histopathologic appearance and highlight the importance of including adenoid cystic carcinoma in the differential diagnosis. PMID- 23095342 TI - A real-life study on acquired skills from using an adrenaline autoinjector. AB - BACKGROUND: Training programs performed by allergists have increased the ability of patients' recognition and management of anaphylaxis. We aim to investigate the permanence of effect of an anaphylaxis training program and to determine the factors affecting it beyond training given by allergists. METHODS: Children and/or their caregivers who had been prescribed an adrenaline autoinjector at least 1 year before were invited to take part in the study. The knowledge about anaphylaxis was assessed using a questionnaire and the skills were practically tested. RESULTS: Sixty-four (50 caregivers/14 children >12 years of age) of 80 patients who accepted the invitation were included in the study. Fifty-nine patients obtained the autoinjector after initial prescription. Among them, 42 (71%) still had the device at the time of the study. The most common reason for not having the autoinjector was no longer feeling it was necessary (54.6%). Of the cases, 39.4% were competent in autoinjector use. There was a significant relation between adrenaline autoinjector competency and regular allergy visits (p = 0.010), believing that it is necessary (p = 0.04), having an adrenaline autoinjector (p = 0.003), and previous history of severe anaphylaxis (p = 0.010). Autoinjector competency score decreased as time elapsed from the last visit (rho = -0.382; p = 0.002) and the first instruction (rho = -0.317; p = 0.01). Regular visits (p = 0.009) and history of severe anaphylaxis (p = 0.007) were found as independent factors having an effect on adrenaline autoinjector competency. CONCLUSIONS: Training of patients/caregivers by allergists does not guarantee the permanence of acquired skills on anaphylaxis in the long run. Regular follow-up visits should be fostered. PMID- 23095344 TI - Synthesis of PEGylated gold nanostars and bipyramids for intracellular uptake. AB - A great number of works have focused their research on the synthesis, design and optical properties of gold nanoparticles for potential biological applications (bioimaging, biosensing). For this kind of application, sharp gold nanostructures appear to exhibit the more interesting features since their surface plasmon bands are very sensitive to the surrounding medium. In this paper, a complete study of PEGylated gold nanostars and PEGylated bipyramidal-like nanostructures is presented. The nanoparticles are prepared in high yield and their surfaces are covered with a biocompatible polymer. The photophysical properties of gold bipyramids and nanostars, in suspension, are correlated with the optical response of single and isolated objects. The resulting spectra of isolated gold nanoparticles are subsequently correlated to their geometrical structure by transmission electron microscopy. Finally, the PEGylated gold nanoparticles were incubated with melanoma B16-F10 cells. Dark-field microscopy showed that the biocompatible gold nanoparticles were easily internalized and most of them localized within the cells. PMID- 23095343 TI - Polymorphisms in hormone metabolism and growth factor genes and mammographic density in Norwegian postmenopausal hormone therapy users and non-users. AB - INTRODUCTION: Mammographic density (MD) is one of the strongest known breast cancer risk factors. Estrogen and progestin therapy (EPT) has been associated with increases in MD. Dense breast tissue is characterized by increased stromal tissue and (to a lesser degree) increased numbers of breast epithelial cells. It is possible that genetic factors modify the association between EPT and MD, and that certain genetic variants are particularly important in determining MD in hormone users. We evaluated the association between MD and 340 tagging single nucleotide polymorphisms (SNPs) from about 30 candidate genes in hormone metabolism/growth factor pathways among women who participated in the Norwegian Breast Cancer Screening Program (NBCSP) in 2004. METHODS: We assessed MD on 2,036 postmenopausal women aged 50 to 69 years using a computer-assisted method (Madena, University of Southern California) in a cross-sectional study. We used linear regression to determine the association between each SNP and MD, adjusting for potential confounders. The postmenopausal women were stratified into HT users (EPT and estrogen-only) and non-users (never HT). RESULTS: For current EPT users, there was an association between a variant in the prolactin gene (PRL; rs10946545) and MD (dominant model, Bonferroni-adjusted P (Pb) = 0.0144). This association remained statistically significant among current users of norethisterone acetate (NETA)-based EPT, a regimen common in Nordic countries. Among current estrogen-only users (ET), there was an association between rs4670813 in the cytochrome P450 gene (CYP1B1) and MD (dominant model, Pb = 0.0396). In never HT users, rs769177 in the tumor necrosis factor (TNF) gene and rs1968752 in the region of the sulfotransferase gene (SULT1A1/SULT1A2), were significantly associated with MD (Pb = 0.0202; Pb = 0.0349). CONCLUSIONS: We found some evidence that variants in the PRL gene were associated with MD in current EPT and NETA users. In never HT users, variants in the TNF and SULT1A1/SULT1A2 genes were significantly associated with MD. These findings may suggest that several genes in the hormone metabolism and growth factor pathways are implicated in determining MD. PMID- 23095345 TI - Quantitative study of GaAs nanowires catalyzed by Au film of different thicknesses. AB - In this letter, we quantitatively investigated epitaxial GaAs nanowires catalyzed by thin Au films of different thicknesses on GaAs (111)B substrates in a metal-organic chemical vapor deposition reactor. Prior to nanowire growth, the de-wetting of Au thin films to form Au nanoparticles on GaAs (111)B in AsH3 ambient at different temperatures is investigated. It is found that with increasing film thickness, the size of the Au nanoparticles increases while the density of the nanoparticles reduces. Furthermore, higher annealing temperature produces larger Au nanoparticles for a fixed film thickness. As expected, the diameters and densities of the as-grown GaAs nanowires catalyzed by these thin Au films reflect these trends. PMID- 23095346 TI - Factors associated with chronic kidney disease progression in Australian nephrology practices. AB - BACKGROUND/AIMS: Chronic kidney disease (CKD) is a major health issue worldwide. The aim of this study was to explore factors associated with CKD progression in Australian nephrology practices. METHODS: This was a retrospective study utilising an electronic medical record (EMR), Audit4 (Software for Specialists, Australia). The baseline visit was defined as the first entry into the EMR. The primary outcome was the rate of change in estimated glomerular filtration rate (eGFR). RESULTS: 1,328 patients were included with a mean eGFR at baseline of 37.4 +/- 0.7 ml/min/1.73 m(2), a mean follow-up of 17.7 months and a mean annual rate of change in eGFR of -0.84 +/- 0.26 ml/min/1.73 m(2). Univariate analysis demonstrated that women, smokers, and patients prescribed erythropoiesis stimulating agents (ESA) had a significantly more rapid decline in eGFR (p = 0.007, 0.033, and 0.003, respectively). On multivariate analysis: gender, age, prescription of ESA and phosphate binders, and baseline eGFR were significantly associated with CKD progression (p = 0.003, 0.004, <0.001, 0.029, and <0.001, respectively). CONCLUSIONS: This study identifies potential factors associated with CKD progression in a population referred to nephrologists, but current data quality may result in bias. Implementation of changes in the format of data collection is required so that busy clinicians record essential information to enable this to become a more accurate and reliable research tool. PMID- 23095347 TI - Effect of the adjunct of carbon dioxide during cardiopulmonary bypass on cerebral oxygenation. AB - INTRODUCTION: Over the last few years, near-infrared spectroscopy (NIRS) has been introduced to study cerebral haemodynamics and oxygenation. This paper points out how the use of an external source of CO2 effects on the absolute value of cerebral NIRS during cardiac surgery on cardiopulmonary bypass. PATIENTS AND METHODS: Between January 2010 and September 2011, 368 patients underwent congenital heart disease correction on cardiopulmonary bypass (CPB). Nineteen patients, with a mean age of 26 days (range 6-120 days), required an external source of CO2 to correct hypocarbia during cardiopulmonary bypass. Different parameters were monitored: NIRS value, oxygen saturation, oxygen partial pressure, CO2 partial pressure, haematocrit, mean arterial pressure and pH. They were analyzed during different phases of the surgical procedure: before, during and after CO2 infusion. RESULTS: There were no deaths during the hospital stay. The NIRS value increased significantly (p<0.05) after the addition of CO2, from a starting value of 52.9 to a final value of 63.4. PaCO2 was found to increase too: from 31.3 mmHg to 40.6 mmHg. On the other hand, both values decreased when the CO2 was removed, to respective final values of 55.8 and 34.4 mmHg. Mean arterial pressure, haematocrit and PaO2 didn't modify significantly during this period. CONCLUSIONS: Nowadays, NIRS is usually used in cardiac surgery to reduce possible risks of neurological damage. The importance of the role of pCO2 in the cerebral vascular resistance and in cerebral blood flow has already been proven. This research demonstrates a relationship between pCO2 and the NIRS value. This paper could introduce an important correcting tool when an inadequate NIRS value occurs although the level of oxygenation, haematocrit and mean arterial pressure are acceptable and the arterial line is accurately positioned. PMID- 23095348 TI - Insensible water loss from the Hilite 2400LT oxygenator: an in vitro study. AB - BACKGROUND: Neonatal extracorporeal membrane oxygenation (ECMO) patients are particularly vulnerable to the effects of uncompensated insensible water loss resulting in hypernatraemia. There exists a long-standing relationship between hypernatraemia and varying degrees of cerebral dysfunction. The aim of this study is to explore the degree to which free water loss occurs across a commonly used ECMO oxygenator, the polymethylpentene (PMP) membrane Hilite 2400LT (Medos, Medizintechnik AG, Stolberg, Germany). The secondary aim is to assess to what extent the addition of heat and/or humidity ameliorates this water loss. METHODS: An ECMO circuit consisting of a centrifugal pump and a Hilite 2400LT oxygenator was primed with crystalloid and albumin. Each experimental trial was carried out in triplicate, with gas flow rates of 1, 3 and 4.8 L/min being investigated. Fluid loss was assessed at six time points over a 24-hour period. RESULTS: Water loss increased significantly from 1 to 3 L/min gas flow (p=0.05) and from 3 to 4.8 L/min gas flow (p=0.025). The mean water loss differences between the differing gas flow trials per L/min gas flow were non-significant (72.4 +/-3.9 ml/24 hrs). The effect of heating the gas to 37 degrees C did not significantly alter water loss, whereas heat and humidity reduced water loss significantly (p=0.009). CONCLUSIONS: Insensible water loss from a Hilite 2400LT oxygenator is approximately 72 ml/day per L/min gas flow over 24 hrs. Heating and humidifying the gas reduces the fluid loss significantly to approximately 8 ml/L/min gas flow over 24 hrs (p=0.009). PMID- 23095349 TI - Do imports of rainbow trout carcasses risk introducing viral haemorrhagic septicaemia virus into England and Wales? AB - A qualitative import risk assessment was undertaken to assess the likelihood of introduction and establishment of viral haemorrhagic septicaemia virus (VHSV) genotype 1a in England and Wales (E&W), via the processing of imported rainbow trout (Oncorhynchus mykiss) carcasses from continental Europe. The likelihood was estimated for one import from an infected farm. Four main routes by which susceptible populations could be exposed to VHSV via processing waste were considered: (i) run-off from solid waste to watercourses, (ii) contamination of birds or rodents with VHSV by scavenging solid waste, (iii) discharge of liquid waste to mains drainage, and (iv) discharge of liquid waste directly to watercourses. Data on the biophysical characteristics of VHSV, its epidemiology, fish processing practices and waste management were collected. Likelihoods for each step of the four pathways were estimated. Pathway 4 (discharge of liquid waste to a watercourse) was judged as the most likely to result in infection of susceptible individuals. Levels of virus entering the aquatic environment via pathways 1-3 were judged to be many times lower than pathway 4 due mainly to the treatment of solid waste (pathways 1 and 2) and high levels of dilution (pathways 1, 2 and 3). Thirty-four trout farms process fish, of which seven have imported carcasses for processing. Compared with other processing facilities, on-farm processing results in a higher likelihood of VHSV exposure and establishment via all four pathways. Data availability was an issue; the analysis was particularly constrained by a lack of data on the prevalence of VHSV in Europe, volume of trade of carcasses into the UK and processing practices in E&W. It was concluded that the threat of VHSV introduction into E&W could be reduced by treatment of liquid effluent from processing plants and by sourcing carcasses for on-farm processing only from approved VHSV free areas. PMID- 23095350 TI - The acute salivary ghrelin response to a psychosocial stress is enhanced in symptomatic patients with bulimia nervosa: a pilot study. AB - BACKGROUND: Stress is a precipitating factor for both binge eating and bulimia nervosa (BN); however, the biological mechanisms through which it may trigger binge eating are poorly understood. There is evidence that the adrenal hormone cortisol and the gastric peptide ghrelin might be involved in stress-induced food ingestion. We hypothesized that symptomatic patients with BN might disclose deranged responses of ghrelin and/or cortisol to stressors and that this could be related to their binge-eating behaviour. METHODS: Here we investigated salivary cortisol and ghrelin responses to the Trier Social Stress Test (TSST) in 10 women with acute BN and 10 age-matched healthy females. Eating-related psychopathology and behaviours were assessed by self-report measures. RESULTS: No significant differences emerged between bulimic patients and healthy controls in the pre stress salivary levels of both cortisol and ghrelin. The BN patients displayed normal cortisol but enhanced ghrelin responses to TSST. No significant correlations emerged between stress-induced salivary hormone changes and self report measures of binge eating. CONCLUSION: To our knowledge, this is the first study showing deranged salivary ghrelin reactivity to a psychosocial stressor in symptomatic patients with BN. The extent to which this could contribute to the binge-eating behaviour of BN subjects awaits clarification. PMID- 23095351 TI - Cost-effectiveness of acupuncture for irritable bowel syndrome: findings from an economic evaluation conducted alongside a pragmatic randomised controlled trial in primary care. AB - BACKGROUND: There is insufficient evidence to determine whether acupuncture is a cost-effective treatment for irritable bowel syndrome. The objective of this study is to assess the cost-effectiveness of acupuncture as an adjunct to usual care versus usual care alone for the treatment of Irritable Bowel Syndrome (IBS). METHODS: Cost-utility analysis conducted alongside a pragmatic, multicentre, randomised controlled trial. 233 patients with irritable bowel syndrome were randomly allocated to either acupuncture plus usual care, or usual care alone. Cost-effectiveness outcomes are expressed in terms of incremental cost per quality adjusted life year (QALY) at one year after randomisation. Costs were estimated from the UK National Health Service perspective for a time horizon of one year. Cost-utility ratios were estimated based on complete case analysis for the base case analysis, where only patients with available EQ-5D and cost data were included. Sensitivity analyses comprised a multiple imputation approach for missing data and a subgroup analysis for the more severe cases of IBS. RESULTS: The base case analysis showed acupuncture to be marginally more effective than usual care (gain of 0.0035 QALYs, 95% CI: -0.00395 to 0.0465) and more expensive (incremental cost of L218 per patient (95% CI: 55.87 to 492.87) resulting in an incremental cost-effectiveness ratio of approximately L62,500. Sensitivity analysis using multiple imputation for missing data resulted in acupuncture appearing less effective and more costly than usual care, so usual care is dominant. Subgroup analysis selecting the most severe cases of IBS (Symptom Severity Score of over 300) suggested that acupuncture may be a cost-effective treatment option for this group, with a cost-per-QALY of L6,500. CONCLUSIONS: Acupuncture as an adjunct to usual care is not a cost-effective option for the whole IBS population; however it may be cost-effective for those with more severe irritable bowel syndrome. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905. PMID- 23095352 TI - Mothers' beliefs and barriers about childhood diarrhea and its management in Morang district, Nepal. AB - BACKGROUND: In developing countries, mothers usually manage diarrhea at home with the pattern of management depending on perceived disease severity and beliefs. The study was carried out with the objective of determining mothers' beliefs and barriers about diarrhea and its management. METHODS: Qualitative methods involving two focus group discussions and eight in-depth interviews were used to collect the data. The study was conducted at the following places: Tankisinuwari, Kanchanbari and Pokhariya of Morang district, Nepal during the months of February and March 2010. Purposive sampling method was adopted to recruit twenty mothers based on the inclusion criteria. A semi-structured interview guide was used to conduct the interviews. Written informed consent was obtained from all of the participants before conducting the interviews. The interviews were moderated by the main researcher with the support of an expert observer from Nobel Medical College. The interviews were recorded with the permission of the participants and notes were written by a pre trained note-taker. The recordings were transcribed verbatim. All the transcribed data was categorized and analyzed using thematic content analysis. RESULTS: Twenty mothers participated in the interviews and most (80%) of them were not educated. About 75% of the mothers had a monthly income of up to 5000 Nepalese rupees (US$ 60.92). Although a majority of mothers believed diarrhea to be due to natural causes, there were also beliefs about supernatural origin of diarrhea. Thin watery diarrhea was considered as the most serious. There was diversity in mothers' beliefs about foods/fluids and diarrhea management approaches. Similarly, several barriers were noted regarding diarrhea prevention and/or management such as financial weakness, lack of awareness, absence of education, distance from healthcare facilities and senior family members at home. The elderly compelled the mothers to visit traditional healers. CONCLUSIONS: There were varied beliefs among the mothers about the types, causes and severity of diarrhea, classification of foods/fluids and beliefs and barriers about preventing or treating diarrhea. PMID- 23095354 TI - [Current status of cadmium exposure among Japanese, especially regarding the safety standard for cadmium concentration in rice and adverse effects on proximal renal tubular function observed in farmers exposed to cadmium through consumption of self-grown rice]. AB - Because the staple food in Japan is rice, which absorbs cadmium (Cd) from the soil efficiently, rice is the main source of exposure to Cd in the Japanese population. In addition, there have been many Cd-contaminated farming areas in Japan. Therefore, a safety standard for the Cd concentration in rice was set as 0.4 ppm by the Japanese government. This safety standard has been followed for decades without any appropriate scientific or legal basis. However, recent epidemiological studies of female Japanese farmers exposed to Cd through self grown rice, that is, a series of Japanese Multi-centered Environmental Toxicant Study (JMETS), showed evidence that the safety standard is appropriate. Therefore, general Japanese consumers are unlikely exposed to Cd excessively with the application of this safety standard, considering the trend of decreasing amount of rice consumed among the Japanese population. On the other hand, Japanese farmers were found to be at risk of Cd exposure through the consumption of self-grown rice with a high Cd concentration. Actually, the JMETS showed that female farmers at 70 years of age or older had a decreased proximal renal tubular function due to the high renal accumulation of Cd. On the basis of these findings, "medical examinations for Cd exposure" have recently been implemented for farmers residing in Cd-polluted areas in northern Japan. Because it has been estimated that such Cd-polluted areas are actually larger, it is necessary to implement medical examinations of more farmers there, particularly the elderly. PMID- 23095355 TI - [Itai-itai disease: cadmium-induced renal tubular osteomalacia]. AB - Cadmium (Cd) is one of the most toxic elements to which humans could be exposed at work or in the environment. The outbreak of itai-itai disease, which is the most severe stage of chronic Cd poisoning, occurred in the Cd-polluted Jinzu River basin in Toyama. In this area, the river was contaminated by slag from a mine upstream; as a consequence, the soil in rice paddies was polluted with heavy metals including Cd through irrigation water from around 1910 to the 1960s. The government of Toyama prefecture carried out an extensive survey on Cd concentration in rice and soil of the paddy fields and declared that the upper layer of a total of 1500 ha of paddy fields should be replaced by nonpolluted soil. Then, an intervention program of soil replacement in the polluted paddy fields was continually carried out from 1980 to 2011. As a result, Cd concentration in rice markedly decreased. The kidney is the organ critically affected after long-term exposure to Cd. Proximal tubular dysfunction (RTD) has been found among the inhabitants of the Jinzu River basin. The very recent report by the Environmental Agency in Japan in 2009 has disclosed that b2 microglobulinuria with RTD is still found at a high prevalence among the inhabitants of the Jinzu River basin of both sexes. Twenty patients with itai itai disease (1 male and 19 females), who attended our hospital and received medical examination during 2000 to 2008, had applied for recognition as itai-itai disease patients to the government of Toyama prefecture. In this paper, the recent epidemiological and clinical features of itai-itai disease are discussed on the basis of a review of the cases of these 19 female patients. PMID- 23095356 TI - [Fibroblast growth factor 23 mediates the phosphaturic actions of cadmium]. AB - Phosphaturia has been documented following cadmium (Cd) exposure in both humans and experimental animals. Fibroblast growth factor 23 (FGF23) serves as an essential phosphate homeostasis pathway in the bone-kidney axis. In the present study, we investigated the effects of Cd on phosphate (Pi) homeostasis in mice. Following Cd injection into C57BL/6J mice, plasma FGF23 concentration significantly increased. The urinary Pi excretion level was significantly higher in the Cd-injected C57BL/6J mice than in the control group. Plasma Pi concentration decreased only slightly in the Cd-injected mice compared with the control group. No changes were observed in the concentration of the plasma parathyroid hormone and 1,25-dihydroxy vitamin D(3) in both groups of mice. We observed a decrease in phosphate transport activity and also a decrease in the expression level of renal phosphate transporter Npt2c, but not that of Npt2a. Furthermore, we examined the effect of Cd on Npt2c in Npt2a-knockout (KO) mice, which expresses Npt2c as a major NaPi cotransporter. Injecting Cd to Npt2aKO mice induced a significant increase in plasma FGF23 concentration and urinary Pi excretion level. Furthermore, we observed decreases in phosphate transport activity and renal Npt2c expression level in the Cd-injected Npt2a KO mice. The present study suggests that hypophosphatemia induced by Cd may be closely associated with FGF23. PMID- 23095357 TI - [Cadmium induces p53-dependent apoptosis through the inhibition of Ube2d family gene expression]. AB - Cadmium (Cd), a harmful metal, exerts severe toxic effects on various tissues such as those in the kidney, liver, lung, and bone. In particular, renal toxicity with damage to proximal tubule cells is caused by chronic exposure to Cd. However, the molecular mechanism underlying chronic Cd renal toxicity remains to be understood. In this review, we present our recent findings since we examined to search for the target molecules involved in the renal toxicity of Cd using toxicogenomics. In NRK-52E rat renal tubular epithelial cells, we found using DNA microarrays that Cd suppressed the expression of the gene encoding Ube2d4, a member of the Ube2d family. The Ube2d family consists of selective ubiquitin conjugating enzymes associated with p53 degradation. Moreover, Cd suppressed the expressions of genes encoding all Ube2d family members (Ube2d1/2/3/4) prior to the appearance of cytotoxicity in NRK-52E cells. Cd markedly increased p53 protein level and induced p53 phosphorylation and apoptosis in the cells. In vivo studies showed that chronic Cd exposure also suppressed Ube2d family gene expression and induced p53 accumulation and apoptosis in the renal tubules of the mouse kidney. These findings suggest that Cd causes p53-dependent apoptosis due to the inhibition of p53 degradation through the down-regulation of Ube2d family genes in NRK-52E cells and mouse kidney. Thus, the Ube2d family genes may be one of the key targets of renal toxicity caused by Cd. PMID- 23095358 TI - [Reducing cadmium content of rice grains by means of flooding and a few problems]. AB - The effects of water management in rice paddies on the levels of cadmium (Cd) and arsenic (As) in Japanese rice grains were tested. In order to reduce the Cd concentration in rice grains, flooding for 3 weeks before and after heading was most effective, but this treatment increased As concentration considerably. Aerobic treatment was effective in reducing As concentration in rice grains, but increased Cd concentration markedly. In the pot experiment, flooding treatment after heading was more effective than flooding treatment before heading in reducing both Cd and As concentrations in rice grains. The concentration of dimethylarsinic acid (DMA) in rice grains was very low under aerobic conditions, but increased in the continuous-flooding treatment. In the field experiment, the grain As concentration in the case of flooding for 3 weeks before and after heading was higher than that in the case of intermittent irrigation. The ratios of DMA to the total As concentration were 3-52% in the pot experiment and 7-13% in the field experiment. PMID- 23095359 TI - [Re-evaluation of the fundamentals of trace elements]. AB - The roles of trace elements have been extensively studied for decades. However, recent advances in both molecular and epidemiological studies on trace elements have provided new information and concepts on the actions of trace elements. Some of our fundamental knowledge on the roles of trace elements based on classical data should be replaced by new concept based on new findings. This series of "Re evaluation of the Fundamentals of Trace Elements" aims to provide new fundamentals on trace elements by reviewing rapidly advancing knowledge in this study area. The first article is a critical review on the role of chromium in human nutrition. PMID- 23095360 TI - [Is chromium an essential trace element in human nutrition?]. AB - It has been recognized that chromium is an essential trace element associated with carbohydrate metabolism, and chromium deficiency causes an impaired glucose tolerance. Recently, however, Vincent et al. have reported that chromium is not an essential trace element. In the present report, the author evaluated the nutritional essentiality of chromium by reviewing several previous reports. In almost all previous reports, the chromium concentration in the animal feed used was higher than 0.1 MUg/g, and it is difficult to consider that the experimental animals were in a low-chromium state. In addition, the amount of chromium administered to the animals for the improvement of glucose tolerance was at a pharmacological level, and corresponded to a level that far exceeded the human daily chromium intake (20 to 80 MUg/day). On the other hand, recent research has clearly shown that feeding with a severely low-chromium diet (0.016 MUg/g) does not impair glucose tolerance. The amount of chromium absorbed in humans estimated from chromium intake (20 to 80 MUg/day), chromium absorption rate (1%), and urinary chromium excretion (<1 MUg/day) is less than 1 MUg/day, which is much lower than those of other essential trace elements. In addition, because there is an inconsistency between the chromium concentration in food and chromium intake, chromium intake seems to be dependent on chromium contamination during food processing and cooking. It is concluded that there is a high possibility that chromium is not an essential trace element. PMID- 23095361 TI - [Association between sleep quality and life function among elderly community residents]. AB - OBJECTIVE: To investigate the association between sleep quality and life function in an elderly Japanese population. METHODS: A total of 563 residents of a village in Kumamoto Prefecture aged >=65 years were asked to fill out a self-administered questionnaire survey from June to July 2010. Sleep quality and life function were respectively evaluated using the Pittsburgh Sleep Quality Index (PSQI) and Basics Check List, which is used to screen elderly individuals at high risk of needing long-term care in the future. As adjustment factors, age, sex, economic situation, residency status, medical history, depression status, and cognitive function were assessed. We examined the relationship between sleep quality and life function using multiple logistic regression analysis, with life function as a dependent variable. Subjects already receiving care or with psychiatric disorders or severe cognitive disturbance were excluded from analysis. RESULTS: Among the subjects (n=395), a significant relationship was found between poor sleep quality and impaired life function in all models. The odds ratio was 1.82 (95% confidence interval: 1.03-3.23) in the final model controlling for all adjustment factors. CONCLUSIONS: Our findings here suggest a significant relationship between poor sleep quality and impaired life function among elderly community residents. Given these findings, intervention to improve sleep may help delay or prevent the need for long-term care among elderly individuals. PMID- 23095362 TI - [Effect of large-scale repair work on indoor formaldehyde levels upon and subjective symptoms in, medical students during gross anatomy dissection course]. AB - OBJECTIVES: To examine the effect of large-scale repair work on indoor formaldehyde (FA) levels and subjective symptoms in medical students during a gross anatomy dissection course. METHODS: We measured the indoor FA levels, room air temperature, and room humidity during a gross anatomy dissection course. In addition, the prevalence of subjective symptoms, keeping allergy state, and wearing personal protective equipment were surveyed in two groups of students using a self-administered questionnaire. RESULTS: The mean indoor FA levels before and after repair work were 1.22 ppm and 0.14 ppm, respectively. The mean indoor FA level significantly decreased after repair work. The prevalences of most subjective symptoms before the anatomy practice were similar before and after the repair work. However, the prevalences of most subjective symptoms during the anatomy practice were lower after the repair work. CONCLUSIONS: The mean indoor FA levels and prevalences of subjective symptoms decreased after the repair work. We have to continuously monitor indoor FA levels, carry out private countermeasures to minimize exposure to FA, and maintain equipment for ventilation to be able to conduct practice in a comfortable environment. PMID- 23095363 TI - [Acute mild hypoxia impairment of dynamic cerebral autoregulation assessed by spectral analysis and thigh-cuff deflation]. AB - OBJECTIVES: Acute hypoxia may impair dynamic cerebral autoregulation. However, previous studies have been controversial. The difference in methods of estimation of dynamic cerebral autoregulation is reported to be responsible for conflicting reports. We, therefore, conducted this study using two representative methods of estimation of dynamic cerebral autoregulation to test our hypothesis that dynamic cerebral autoregulation is impaired during acute exposure to mild hypoxia. METHODS: Eleven healthy men were exposed to 15% oxygen concentration for two hours. They were examined under normoxia (21% O(2)) and hypoxia (15% O(2)). The mean arterial pressure (MAP) in the radial artery was measured by tonometry, and cerebral blood flow velocity (CBFv) in the middle cerebral artery was measured by transcranial Doppler ultrasonography. Dynamic cerebral autoregulation was assessed by spectral and transfer function analyses of beat-by-beat changes in MAP and CBFv. Moreover, the dynamic rate of regulation and percentage restoration of CBFv were estimated when a temporal decrease in arterial pressure was induced by thigh-cuff deflation. RESULTS: Arterial oxygen saturation decreased significantly during hypoxia (97+/-0% to 88+/-1%), whereas respiratory rate was unchanged, as was steady-state CBFv. With 15% O(2), the very-low-frequency power of CBFv variability increased significantly. Transfer function coherence (0.40+/ 0.02 to 0.53+/-0.05) and gain (0.51+/-0.07 cm/s/mmHg to 0.79+/-0.11 cm/s/mmHg) in the very-low-frequency range increased significantly. Moreover, the percentage restoration of CBF velocity determined by thigh-cuff deflation decreased significantly during hypoxia (125+/-25% to 65+/-8%). CONCLUSIONS: Taken together, these results obtained using two representative methods consistently indicate that mild hypoxia impairs dynamic cerebral autoregulation. PMID- 23095364 TI - [Perspective on the nuclear power plant accident caused by the great east Japan earthquake and tsunami: health impairment risks due to pollution by radioactive materials from the damaged plant as recognized by experts and by the general population and role of the experts]. AB - INTRODUCTION: Large amounts of radioactive materials were leaked into the environment from the Fukushima Daiichi Nuclear Power Plant (FDNPP) of the Tokyo Electric Power Company damaged by the 2011 Great East Japan Earthquake and accompanying tsunami. Increased health impairment risks due to the leaked radioactive materials are of concern over a long period of time and over a wide geographical area. From the results of epidemiologic studies conducted after the Chernobyl accident, the health risks are not anticipated to be very marked. The purpose of the present study is to examine (i) the elevated health risks as viewed by the general population, (ii) tolerance to the risks that the general population suffer from their viewpoint, and (iii) the overall picture as seen by researchers and experts in specialized areas of study after the accident. METHOD: Information was obtained from articles in print and on the Internet and by interviewing a psychologist and tens of employees of several corporations. RESULTS AND DISCUSSION: Epidemiologic studies conducted after the severe accident of the nuclear power plant in Chernobyl revealed an elevated risk of thyroid cancer in children due to (131)I while elevated risks due to radioactive materials other than (131)I were not detected. The amount of radioactive materials leaked into the environment from the FDNPP was less than that in Chernobyl. Therefore, it is possible to estimate that health impairment risks due to the leaked radioactive materials from the FDNPP are low. However, it is impossible to conclude a zero risk. It is likely that the general population does not fully understand the health impairment risks due to the leaked radioactive materials from the FDNPP. Although no increased incidences of diseases other than thyroid cancer of children were scientifically shown en masse from studies in Chernobyl, individual risks and results in the future caused by the severe accident of FDNPP cannot be denied. Much of the general population is apt to demand the security of a zero risk from human-generated disasters such as the severe accident of FDNPP. Many are very intolerant of the health impairment risks factors and wish to avoid any risk altogether. The viewpoint of the general population differs considerably from that of epidemiologists and other research experts. Researchers and experts are often well versed in their own specialized areas but ignorant of other areas. Thus, it is difficult to grasp the complete view of an event under consideration. This so-called 'takotsubo' situation is dangerous in human society. Researchers and experts must make effort to understand areas other than their own specialized areas. Scientific researchers usually possess a great deal of conviction from the results of their own studies. They are apt to ignore criticism of their study results from individuals working in other research areas even when the results of their studies are inadequate. When the conditions of their studies are changed somewhat and insufficient information is obtained, the results may not be accurate. Researchers and experts should take full cognizance of this possibility, view with strong skepticism about the results of studies even in their own areas, and listen with humility to criticisms from those working in fields of discipline other than their own. CONCLUSIONS: It should be fully recognized that the viewpoint of the general population is considerably different from that of researchers and experts regarding health risks due to the severe accident of FDNPP. Researchers and experts must make effort to understand the opinions of those working in areas other than their own in order to grasp a true and complete view of an event under consideration. PMID- 23095365 TI - Neonatal sepsis at Muhimbili National Hospital, Dar es Salaam, Tanzania; aetiology, antimicrobial sensitivity pattern and clinical outcome. AB - BACKGROUND: Neonatal sepsis contributes significantly to morbidity and mortality among young infants. The aetiological agents as well as their susceptibility to antimicrobial agents are dynamic. This study determined aetiology, antimicrobial susceptibility and clinical outcome of neonatal sepsis at Muhimbili National Hospital. METHODS: Three hundred and thirty neonates admitted at the Muhimbili National Hospital neonatal ward between October, 2009 and January, 2010 were recruited. Standardized questionnaires were used to obtain demographic and clinical information. Blood and pus samples were cultured on MacConkey, blood and chocolate agars and bacteria were identified based on characteristic morphology, gram stain appearance and standard commercially prepared biochemical tests. Antimicrobial sensitivity testing was performed for ampicillin, cloxacillin, gentamicin, amikacin, cefuroxime and ceftriaxone on Mueller Hinton agar using the Kirby Bauer diffusion method. RESULTS: Culture proven sepsis was noted in 24% (74/330) of the study participants. Isolated bacterial pathogens were predominantly Staphylococcus aureus, Klebsiella spp and Escherichia coli. Klebsiella spp 32.7% (17/52) was the predominant blood culture isolate in neonates aged below seven days while Staphylococcus aureus 54.5% (12/22) was commonest among those aged above seven days. Staphylococcus aureus was the predominant pus swabs isolate for both neonates aged 0-6 days 42.2% (98/232) and 7-28 days 52.3% (34/65). Resistance of blood culture isolates was high to ampicillin 81.1% (60/74) and cloxacillin 78.4% (58/74), moderate to ceftriaxone 14.9% (11/74) and cefuroxime 18.9% (14/74), and low to amikacin 1.3% (1/74). Isolates from swabs had high resistance to ampicillin 89.9% (267/297) and cloxacillin 85.2 (253/297), moderate resistance to ceftriaxone 38.0% (113/297) and cefuroxime 36.0% (107/297), and low resistance to amikacin 4.7% (14/297). Sepsis was higher in neonates with fever and hypothermia (p=0.02), skin pustules (p<0.001), umbilical pus discharge and abdominal wall hyperemia (p=0.04). Presence of skin pustules was an independent predictor of sepsis OR 0.26, 95% CI (0.10-0.66) p=0.004. The overall death rate was 13.9% (46/330), being higher in neonates with sepsis 24.3% (18/74) than those without 10.9% (28/256), p=0.003. CONCLUSIONS: Staphylococcus aureus was predominant isolate followed by Klebsiella and Escherichia coli. There was high resistance to ampicillin and cloxacillin. Mortality rate due to neonatal sepsis was high in our setting. Routine antimicrobial surveillance should guide the choice of antibiotics for empirical treatment of neonatal sepsis. PMID- 23095366 TI - Now that we've got the map, where are we going? Moving from gene candidate lists to function in studies of brain evolution. PMID- 23095367 TI - Programmable self-assembly of carbon nanotubes assisted by reversible denaturation of a protein. AB - Self-assembly of pristine multi-walled carbon nanotubes (CNTs) in aqueous dispersion using a protein, bovine serum albumin (BSA), has been demonstrated. Step-wise conformational changes in BSA as a function of temperature have been deployed to direct the assembly of nanotubes. More specifically, CNTs distributed randomly in native BSA at 35 degrees C as well as completely denatured BSA solution at 80 degrees C self-assemble in the intermediate temperature range of 45-65 degrees C, as evident from scanning and transmission electron microscopy. Fourier transform infrared (FTIR) and fluorescence studies indicate significant changes in the alpha-helical content of the protein with respect to the amide I and II bands and tryptophan emission intensity, respectively. The stability of CNT dispersion in BSA solution has been attributed to the hydrophobic interaction between nanotubes and the protein molecule by adding sodium cholate to the dispersion. Moreover, a mechanism based on electrostatic repulsion between BSA bound CNTs has been proposed for the thermally reversible assembly of CNTs in BSA solution based on evidence from zeta potential measurements and FTIR spectroscopy. Thus the present report demonstrates bio-mimetic self-assembly of as-synthesized CNTs using changes in surface charge and conformation of an unfolding protein for biomedical applications and nanobiotechnology. PMID- 23095368 TI - Acoustic rhinometry and aspirin nasal challenge in the diagnosis of aspirin intolerant asthma: clinical finding and safety aspects. AB - BACKGROUND: The safety and utility of nasal provocation tests with lysine-aspirin (L-ASA) in the diagnosis of aspirin-intolerant asthma (AIA) have previously been described in a short series of patients. OBJECTIVES: To describe the clinical features and safety of an L-ASA challenge test in patients with AIA. METHODS: We evaluated 72 patients (79% women), with a mean +/- SD age of 47.9 +/- 14.5 years. All patients were submitted to an L-ASA nasal provocation test (29 mg in each nostril) under acoustic rhinometry (AcR) control. Symptom score (0-3), visual analogical scale and nitric oxide determinations were performed at baseline and at 15, 30, 60 and 90 min. A decrease in nasal volume of at least 25% was considered a positive test. Nasal nitric oxide (nNO) and forced expiratory volume in 1 s were measured. RESULTS: Nasal congestion and rhinorrhea represented 51 and 32%, respectively, of total symptoms. According to AcR data, the L-ASA challenge test was positive in 20% of patients at 15 min, an additional 36% were positive at 30 min, 18% at 60 min, and the remaining 26% at 90 min. nNO nasal values decreased but did not reach statistical significance. No pulmonary or systemic reactions were observed. CONCLUSIONS: Symptoms of nasal congestion associated with the reduction in nasal volume measured by AcR are the most useful parameters for establishing the diagnosis of AIA using the L-ASA nasal challenge. The method is very well tolerated and can be safely used even in patients with severe asthma. PMID- 23095369 TI - Efficacy of different gonadotropin combinations to support ovulation induction in WHO type I anovulation infertility: clinical evidences of human recombinant FSH/human recombinant LH in a 2:1 ratio and highly purified human menopausal gonadotropin stimulation protocols. AB - BACKGROUND: The World Helath Organization (WHO) Group I anovulation, or hypogonadotropic hypogonadism (HH), is characterized by reduced hypothalamic/pituitary activity which results in abnormally low serum FSH and LH levels and negligible estrogen activity. AIM: To compare the efficacy of human recombinant FSH (r-hFSH) plus human recombinant LH (r-hLH) in a 2:1 ratio with highly purified human menopausal gonadotropin (hMG-HP) urinary extract, containing LH-like activity, in women with HH. SUBJECTS AND METHODS: This two-arm randomized open-label study included 35 HH women (aged 25-36 yr) attending our Center. Eighteen patients received 150 IU hMG-HP (150 IU FSH + 150 IU LH-like activity) and seventeen received 150IU r-hFSH/75IU rhLH daily for a maximum of 16 days. Ovulation was induced by a single administration of hCG on the day after the last hMG-HP or r-hFSH/r-hLH. RESULTS: The primary efficacy endpoint was ovulation induction as measured by follicle >=17 mm, pre-ovulatory estradiol (E 2 ) >=400 pmol/l and mid-luteal phase progesterone (P 4 ) >=25 nmol/l. Secondary efficacy endpoints included E 2 levels/follicle at mid-cycle, number of follicles at mid-cycle and pregnancy rate (PR). Following a total of 70 cycles, 70% of r hFSH/r-hLH treated patients met the primary endpoint vs 88% in hMG-HP group (p=0.11). However, PR in r-hFSH/r-hLH group was 55.6% compared to 23.3% in hMG-HP group (p=0.01). CONCLUSIONS: The primary endpoint achievement did not correlate with PR. This study has shown the superiority of LH compared to hCG in supporting FSH-induced follicular development in HH women. PMID- 23095371 TI - The synthesis of nitrogen/sulfur co-doped TiO2 nanocrystals with a high specific surface area and a high percentage of {001} facets and their enhanced visible light photocatalytic performance. AB - Nitrogen/sulfur co-doped anatase TiO2 nanocrystals with a high specific surface area and a high percentage of {001} facets were synthesized by a solvent-thermal process followed by the calcination with thiourea at an optimum heat treatment temperature. Under current experimental conditions, the optimum heat treatment temperature was found at 300 degrees C, which successfully introduced nitrogen and sulfur dopants into the anatase lattice to replace a small portion of oxygen atoms while preserving the geometry of these anatase TiO2 nanocrystals to maintain a high percentage of {001} facets. These nitrogen/sulfur co-doped anatase TiO2 nanocrystals demonstrated a largely enhanced light absorption in the whole visible-light range and exhibited much higher photocatalytic performance than both P25 TiO2 nanoparticles and anatase TiO2 nanocrystals with a high percentage of {001} facets under visible-light illumination. PMID- 23095370 TI - Optimal Mode of clearance in critically ill patients with Acute Kidney Injury (OMAKI)--a pilot randomized controlled trial of hemofiltration versus hemodialysis: a Canadian Critical Care Trials Group project. AB - INTRODUCTION: Among critically ill patients with acute kidney injury (AKI) needing continuous renal replacement therapy (CRRT), the effect of convective (via continuous venovenous hemofiltration [CVVH]) versus diffusive (via continuous venovenous hemodialysis [CVVHD]) solute clearance on clinical outcomes is unclear. Our objective was to evaluate the feasibility of comparing these two modes in a randomized trial. METHODS: This was a multicenter open-label parallel group pilot randomized trial of CVVH versus CVVHD. Using concealed allocation, we randomized critically ill adults with AKI and hemodynamic instability to CVVH or CVVHD, with a prescribed small solute clearance of 35 mL/kg/hour in both arms. The primary outcome was trial feasibility, defined by randomization of >25% of eligible patients, delivery of >75% of the prescribed CRRT dose, and follow-up of >95% of patients to 60 days. A secondary analysis using a mixed-effects model examined the impact of therapy on illness severity, defined by sequential organ failure assessment (SOFA) score, over the first week. RESULTS: We randomized 78 patients (mean age 61.5 years; 39% women; 23% with chronic kidney disease; 82% with sepsis). Baseline SOFA scores (mean 15.9, SD 3.2) were similar between groups. We recruited 55% of eligible patients, delivered >80% of the prescribed dose in each arm, and achieved 100% follow-up. SOFA tended to decline more over the first week in CVVH recipients (-0.8, 95% CI -2.1, +0.5) driven by a reduction in vasopressor requirements. Mortality (54% CVVH; 55% CVVHD) and dialysis dependence in survivors (24% CVVH; 19% CVVHD) at 60 days were similar. CONCLUSIONS: Our results suggest that a large trial comparing CVVH to CVVHD would be feasible. There is a trend toward improved vasopressor requirements among CVVH treated patients over the first week of treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00675818. PMID- 23095372 TI - Oxidative stress, macrophage infiltration and CD163 expression are determinants of long-term renal outcome in macrohematuria-induced acute kidney injury of IgA nephropathy. AB - BACKGROUND: Macroscopic hematuria (MH) may cause acute kidney injury (AKI) in IgA nephropathy. Up to 25% of patients with MH-associated AKI do not recover baseline renal function. Our objective was to identify subjects at high risk for an adverse renal function. METHODS: We examined macrophages, oxidative stress markers (NADPH-p22 and HO-1) and the hemoglobin scavenger receptor (CD163) in renal biopsy specimens from 33 MH-AKI patients with complete recovery (CR, n = 17) or incomplete recovery (IR, n = 16) of renal function after 6.72 (range 0.5 21.5) years of follow-up. RESULTS: CD163-expressing macrophages, HO-1 and NADPH p22 expression were located in areas surrounding tubules with iron deposits and filled with erythrocyte casts. CD163-positive macrophages score and HO-1- and p22 positive staining correlated positively with percentage of tubules with erythrocyte casts and tubular necrosis. Macrophage infiltration, CD163-positive macrophage score, NADPH-p22- and HO-1-positive staining areas were significantly greater in IR patients when compared with CR patients. The CD163-positive macrophage score and oxidative stress markers (p22 and HO-1) were negatively correlated with renal function outcome, as determined by estimated glomerular filtration rate (eGFR) and proteinuria, at the end of the follow-up period. In multivariate analysis, the CD163-positive macrophage score remained significantly associated with final eGFR and proteinuria after adjustment by age, gender, duration of MH, initial eGFR and proteinuria. CONCLUSIONS: Increased macrophage infiltration, CD163 expression and oxidative stress are significant prognostic factors for an IR of renal function in patients with MH-associated AKI. These molecular pathways may be involved in the renal response to injury and could be useful to improve diagnosis and therapeutics. PMID- 23095373 TI - Clinical characteristics of patients with Mycoplasma pneumoniae-related acute hepatitis. AB - BACKGROUND/AIMS: Although the hepatobiliary manifestations of Mycoplasma pneumoniae infection have been described in several previous studies, controversies still remain. The aim of this study was to evaluate the clinical characteristics of patients with M. pneumoniae-related hepatitis and compare to those with M. pneumoniae infection but not hepatitis. METHODS: We reviewed the medical chart of patients diagnosed with M. pneumoniae infection serologically. RESULTS: Among the 117 patients with M. pneumoniae infection enrolled in the study, 25 showed acute hepatitis without any evidence of another cause. Patients with hepatitis presented with prodromal symptoms more frequently and also had a higher body temperature and C-reactive protein (CRP) levels than patients without hepatitis. Frequencies of respiratory tract involvement were not different between two groups. Clinical signs recovered within three weeks in both groups following the institution of antibiotic therapy. Multivariate analysis revealed that male sex, age <40 years, and high CRP levels were significantly linked to M. pneumoniae-related hepatitis. CONCLUSIONS: We found that acute hepatitis associated with M. pneumoniae occurred in about 21% of all M. pneumoniae infections, and gender, age, and CRP levels were factors related to the occurrence of M. pneumoniae-related hepatitis. PMID- 23095374 TI - Complex motor sequence skills profit from sleep. AB - Simple motor memory has been shown to benefit from sleep; however, more complex motor skills have rarely been investigated so far. We investigated complex motor learning using a dance mat and choreographies in 36 healthy, young male subjects. Subjects performed one song and two new songs in three sessions distributed over 24 h to test sequence-specific learning and skill transfer. Each song had a unique choreography. One group learned the main song in the evening and was retested 12 and 24 h later on the main song and each one new song (PM-AM-PM). The second group underwent the same procedure; however, the first session was in the morning (AM-PM-AM). Thus, one group slept before the first retest (PM-AM-PM) while the other group slept between the first and the second retest (AM-PM-AM). Regarding sequence-specific learning, sleep induced a significant difference between the groups, which disappeared after both groups had slept. A significant transfer effect occurred independent of sleep. During both new songs, no difference between the groups was seen; however, the second and third songs were learned significantly faster than the first song. This study could show that complex motor sequence learning benefits from sleep while skill transfer seems to occur independently of sleep. PMID- 23095375 TI - Joint action European partnership for action against cancer. AB - Cancer is a major European public health issue and represents the second most important cause of death and morbidity in Europe. Moreover, as a result of constant advances in medicine, medical technology and other sciences, and due to improvements in economic circumstances, cancer survival rates are increasing in Europe and prevalent cases (i.e. number of subjects who have experienced cancer) represent a growing proportion of the population. In order to tackle cancer efficiently throughout the European Member states, the European Commission launched the Joint Action (JA) 'European Partnership for Action Against Cancer' (EPAAC) facilitated by the Community Health Programme, in September 2009. EPAAC is designed to fill a gap in cooperation, collaboration and shared experiences for countries with similar needs and diverse experience in the area of their national cancer control policies. Activities and studies are tackling the main challenges of cancer control in Europe as a whole and in the Member states, including the provision of services and health system responses, human resources and research. In contrast with previous European actions in the field of cancer, EPAAC joins different partners and stakeholders at various levels ranging from Member states (including Iceland and Norway) and Regions to patient representatives. PMID- 23095376 TI - Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial. AB - BACKGROUND: Acupuncture is used by patients as a treatment for irritable bowel syndrome (IBS) but the evidence on effectiveness is limited. The purpose of the study was to evaluate the effectiveness of acupuncture for irritable bowel syndrome in primary care when provided as an adjunct to usual care. METHODS: DESIGN: A two-arm pragmatic randomised controlled trial. SETTING: Primary care in the United Kingdom. PATIENTS: 233 patients had irritable bowel syndrome with average duration of 13 years and score of at least 100 on the IBS Symptom Severity Score (SSS). INTERVENTIONS: 116 patients were offered 10 weekly individualised acupuncture sessions plus usual care, 117 patients continued with usual care alone. MEASUREMENTS: Primary outcome was the IBS SSS at three months, with outcome data collected every three months to 12 months. RESULTS: There was a statistically significant difference between groups at three months favouring acupuncture with a reduction in IBS Symptom Severity Score of -27.43 (95% CI: 48.66 to -6.21, p=0.012). The number needed to treat for successful treatment (>=50 point reduction in the IBS SSS) was six (95% CI: 3 to 17), based on 49% success in the acupuncture group vs. 31% in the control group, a difference between groups of 18% (95% CI: 6% to 31%). This benefit largely persisted at 6, 9 and 12 months. CONCLUSIONS: Acupuncture for irritable bowel syndrome provided an additional benefit over usual care alone. The magnitude of the effect was sustained over the longer term. Acupuncture should be considered as a treatment option to be offered in primary care alongside other evidenced based treatments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905. PMID- 23095377 TI - ENU-induced phenovariance in mice: inferences from 587 mutations. AB - BACKGROUND: We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. FINDINGS: In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. CONCLUSIONS: Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice. PMID- 23095379 TI - Clinicians learn less and less about more and more until they know nothing about everything; researchers learn more and more about less and less until they know everything about nothing: discuss. AB - A number of recent developments in our understanding of the biology of heritability question commonly held views on the immutability of genetic factors. These have numerous potential implications for improving understanding and practice in pre- and postconceptional care and for infant and child mental health, and they carry a cautionary message against overgeneralization. PMID- 23095378 TI - Behavior genetics and postgenomics. AB - The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology. PMID- 23095380 TI - Is behavioral genetics 'too-big-to-know' science? AB - Several new molecular findings and concepts furnish evidence in support of gene environment interdependence, challenging some of the current tenets and basic statistics of behavioral genetics. I, however, argue that (1) some of the expectations evoked by "neogenomics" are contradicted by findings; and (2) while epigenetic and gene expression effects are complex, they can to some extent be incorporated into "classical" behavioral genetics modeling. PMID- 23095381 TI - Twin and family studies are actually more important than ever. AB - Charney argues that the presence of inherited epigenetic effects makes twin, family, and adoption studies obsolete. This argument relies on both a faulty characterization of these studies and indirect comparisons of DNA and "neogenetic" factors. I argue that twin and family studies will in fact serve a necessary and vital role in the study of epigenetic and neogenetic processes. PMID- 23095382 TI - Heritability estimates in behavior genetics: wasn't that station passed long ago? AB - Charney describes several mechanisms that will bias estimates of heritability in unpredictable directions. In addition, the mechanisms described by Charney explain the puzzling fact that research in human-behavior genetics routinely reports higher heritabilities than animal studies do. However, I argue that the concept of heritability has no real place in human research anyway. PMID- 23095383 TI - Postgenomics and genetic essentialism. AB - Traditional lay perceptions of genetics are plagued with essentialist biases leading to some unfortunate consequences. Changes in the scientific understanding of heredity in general, and in genotype-phenotype relationships more specifically, provide a vital basis for shifting public understanding of genetics. Facilitating postgenomic literacy among the public has the potential to have translational implications in diminishing deleterious attitudes, beliefs, and behaviors. PMID- 23095384 TI - Non-Mendelian etiologic factors in neuropsychiatric illness: pleiotropy, epigenetics, and convergence. AB - The target article by Charney on behavior genetics/genomics discusses how numerous molecular factors can inform heritability estimations and genetic association studies. These factors find application in the search for genes for behavioral phenotypes, including neuropsychiatric disorders. We elaborate upon how single causal factors can generate multiple phenotypes, and discuss how multiple causal factors may converge on common neurodevelopmental mechanisms. PMID- 23095385 TI - Is genomics bad for you? AB - The plasticity of the genome complicates genetic causation but should be investigated from a functional perspective. Specific adaptive hypotheses are referenced in the target article, but it is also necessary to explain how the integrity of the genome is maintained despite processes that tend towards its diversification and degradation. These include the accumulation of deleterious changes and intragenomic conflict. PMID- 23095386 TI - Preventing a paradigm shift: a plea for the computational genome. AB - Against the opinion that DNA as program is not sufficiently explanatory, we maintain that the cellular machinery is entirely computational, and we identify the crucial notion of the interpreter that expresses the gene with the minimal gene set. Epigenetics research does not so much need paradigm shifts as the unraveling of an exceedingly complex computational machine. PMID- 23095387 TI - Biology trumps statistics in the postgenomic era. AB - Charney discusses the growing realization in the postgenomic era that genomic biology deviates from Mendelian assumptions at the heart of genetic heritability and association studies. Given the complexity of genomic biology, how are we to identify meaningful genetic factors that contribute to behavioral? One response is to make genetic variants the focus of biological rather than statistical analyses of behavior. PMID- 23095388 TI - Affirmation of a developmental systems approach to genetics. AB - More than 40 years ago, Gilbert Gottlieb and like-minded scholars argued for the philosophical necessity of approaching genetic contributions to development through a multilevel, bidirectional systems perspective. Charney's target article builds on this heritage in significant ways, offering more recent examples of the interactions of biology and context, as well as the diversity of developmental mechanisms, and reaffirming a way forward for genetic research. PMID- 23095389 TI - Genetic sensitivity to the environment, across lifetime. AB - The target article by Charney convincingly argues that genomic plasticity perinatally induced by the environment creates a complication in determining which parts of behavior are attributed to nature and which to nurture. I argue that real life is even more complex because (1) genotype influences sensitivity to environmental stimuli, and (2) the genome continues to be modified throughout life. PMID- 23095390 TI - A call for an expanded synthesis of developmental and evolutionary paradigms. AB - Charney's target article continues a critique of genetic blueprint models of development that suggests reconsideration of concepts of adaptation, inheritance, and environment, which can be well illustrated in current research on infant attachment. The concepts of development and adaptation are so heavily based on the model of genetics and inheritance forged in the modern synthesis that they will require reconsideration to accommodate epigenetic inheritance. PMID- 23095391 TI - From gene activity to behavior (and back again). AB - Documenting the bidirectional traffic from gene action to the external environment and its effects on behavior remains a major conceptual, empirical, and analytical challenge for developmental science. Charney has provided an instructive snapshot of where we are in meeting this challenge and, in so doing, exposes the considerable shortcomings of the traditional genomic model employed by behavior genetics. PMID- 23095392 TI - The fate of heritability in the postgenomic era. AB - This commentary argues that age changes in heritability are incompatible with Charney's theory. The new genetics must be tempered by the findings that many epigenetic phenomena are random and are linked to pathology, thus making them peripheral to the design of complex adaptations. Behavior-genetic findings are compatible with strong maternal effects; G * E correlations likely underestimate environmental effects; and G * E interactions are unlikely to be an important aspect of normal development. PMID- 23095393 TI - A developmental science commentary on Charney's "Behavior genetics and postgenomics". AB - Charney's target article convincingly demonstrates the need for the discipline of quantitative human behavior genetics to discard its false assumptions and to employ the techniques, assumptions, and research program characteristic of modern developmental psychobiology. PMID- 23095394 TI - Assumptions in studies of heritability and genotype-phenotype association. AB - Charney's dismissal of well-established methods in behavioral genetic research is misguided. He claims that studies of heritability and genetic association depend for their validity on six assumptions, but he cites no sources to support this claim. We explain why none of the six assumptions is strictly necessary for the utility of either method of genetic analysis. PMID- 23095395 TI - Estimating the actual subject-specific genetic correlations in behavior genetics. AB - Generalization of the standard behavior longitudinal genetic factor model for the analysis of interindividual phenotypic variation to a genetic state space model for the analysis of intraindividual variation enables the possibility to estimate subject-specific heritabilities. PMID- 23095396 TI - Gene-independent heritability of behavioural traits: don't we also need to rethink the "environment"? AB - Behavioural phenotypes have been explained by genetic and environmental factors (E) and their interaction. Here we suggest a rethinking of the E factor. Passively incurred environmental influences (E pass) and actively copied information and behaviour (E act) may be distinguished at shared and non-shared level. We argue that E act underlies mutation and selection and is the base of gene-independent heritability. PMID- 23095397 TI - Relational developmental systems: a paradigm for developmental science in the postgenomic era. AB - This commentary argues that the anomalies suffered by the population behavior genetics paradigm are more widespread than suggested by Charney, including many made in the field of developmental science. Further, it is argued that, according to the criteria established by Kuhn, there is and has been available an alternative scientific paradigm that provides the formative context for Charney's postgenomic view. This is the relational developmental systems paradigm. PMID- 23095398 TI - The history of the nature/nurture issue. AB - It is worthy to supplement Charney with two historical issues: (1) There were two rival trends in the rebirth of genetic thought in the 1960s: the universal and the variation related. This traditional duality suggested that heredity cannot be equated with genetic determinism. (2) The classical debates and reinterpretation of adoption/twin studies in the 1980s regarding intelligence suggested that the environment had a more active role in unfolding the genetic program. PMID- 23095399 TI - Epigenetic regulation of brain-derived neurotrophic factor: implications in neurodevelopment and behavior. AB - Several recent research findings have implicated brain-derived neurotrophic factor (BDNF) as a mediator of neuronal plasticity. The BDNF gene is under extensive epigenetic regulation, which modulates how much or how little environmental experiences become encoded within neurons and neural circuits. Future scientific progress within the postgenomic paradigm requires elucidation of the functional trajectory in neogenetic and environment interactions. PMID- 23095400 TI - Parental brain and socioeconomic epigenetic effects in human development. AB - Critically significant parental effects in behavioral genetics may be partly understood as a consequence of maternal brain structure and function of caregiving systems recently studied in humans as well as rodents. Key parental brain areas regulate emotions, motivation/reward, and decision making, as well as more complex social-cognitive circuits. Additional key environmental factors must include socioeconomic status and paternal brain physiology. These have implications for developmental and evolutionary biology as well as public policy. PMID- 23095401 TI - Neogenomic events challenge current models of heritability, neuronal plasticity dynamics, and machine learning. AB - We address current needs for neogenomics-based theoretical and computational approaches for several neuroscience research fields, from investigations of heritability properties, passing by investigations of spatiotemporal dynamics in the neuromodulatory microcircuits involved in perceptual learning and attentional shifts, to the application of genetic algorithms to create robots exhibiting ongoing emergence. PMID- 23095402 TI - A straw man's neogenome. AB - The neogenome has indeed changed how to understand the relationship between genotype and phenotype. However, this does not imply a paradigm shift, but simply a normal development of a young science. Charney creates a straw man out of the myth of an immutable genetics, and conveys the wrong idea that heritability studies and gene association studies are no longer valid. PMID- 23095403 TI - Reintegration of child soldiers in Burundi: a tracer study. AB - BACKGROUND: Substantial attention and resources are aimed at the reintegration of child soldiers, yet rigorous evaluations are rare. METHODS: This tracer study was conducted among former child soldiers (N=452) and never-recruited peers (N=191) who participated in an economic support program in Burundi. Socio-economic outcome indicators were measured retrospectively for the period before receiving support (T1; 2005-06); immediately afterwards (T2; 2006-07); and at present (T3; 2010). Participants also rated present functional impairment and mental health indicators. RESULTS: Participants reported improvement on all indicators, especially economic opportunity and social integration. At present no difference existed between both groups on any of the outcome indicators. Socio-economic functioning was negatively related with depression- and, health complaints and positively with intervention satisfaction. CONCLUSION: The present study demonstrates promising reintegration trajectories of former child soldiers after participating in a support program. PMID- 23095405 TI - Emerging trends in renal replacement therapy for acute kidney injury. Preface. PMID- 23095406 TI - Sensors and hybrid therapies: a new approach with automated citrate anticoagulation. AB - BACKGROUND: Hybrid therapies use intermittent hemodialysis (IHD) machines adapted to provide prolonged intermittent or continuous renal replacement therapy in the intensive care unit (ICU). Despite the low cost, hybrid therapy use is limited warranting a novel approach. METHODS: The literature was reviewed for limitations of hybrid protocols, use of regional citrate anticoagulation (RCA) on hybrid systems and sensors for IHD and hybrid therapy. The novel hybrid program in the authors' institution is presented as a plausible future direction for the modality. RESULTS: Hybrid therapies are limited by access flow and clotting alarms. Technology limitations render many IHD sensors inoperable at low dialysate flow. A synergy with RCA allows a novel, safe approach with low blood flows and high dialysate flows with alarm- and clotting-free operation and all commercial IHD sensors functional. CONCLUSION: The low cost, ease of use, safety and efficacy of hybrid therapy with near-automated RCA may lead to rapid expansion of this form of ICU renal support. PMID- 23095407 TI - Advances in continuous renal replacement therapy: citrate anticoagulation update. AB - Because of the potential side effects of heparin, methods of regional citrate anticoagulation (RCA) for continuous renal replacement therapy (CRRT) have been gaining wider acceptance with the development of simplified and safer protocols. Advantages of RCA include the avoidance of systemic anticoagulation and heparin induced thrombocytopenia. The disadvantage is that citrate can add complexity and labor intensity to CRRT. Frequent monitoring of electrolytes, ionized calcium, and acid-base status is required, due to the potential for hypernatremia, metabolic alkalosis, and systemic ionized hypocalcemia. If properly monitored, complications associated with RCA are uncommon. A variety of methods of delivering RCA are described in the literature. Overall, studies of RCA, as compared to unfractionated heparin, report better filter survival times and less bleeding. In this section, we summarize the characteristics of citrate as an anticoagulant and provide an update of citrate use in CRRT. PMID- 23095408 TI - Extracorporeal carbon dioxide removal: the future of lung support lies in the history. AB - Extracorporeal organ support in patients with dysfunction of vital organs like the kidney, heart, and liver has proven helpful in bridging the patients to recovery or more definitive therapy. Mechanical ventilation in patients with respiratory failure, although indispensable, has been associated with worsening injury to the lungs, termed ventilator-induced lung injury. Application of lung protective ventilation strategies are limited by inevitable hypercapnia and hypercapnic acidosis. Various alternative extracorporeal strategies, proposed more than 30 years ago, to combat hypercapnia are now more readily available. In particular, the venovenous approach to effective carbon dioxide removal, which involves minimal invasiveness comparable to renal replacement therapy, appears to be very promising. The clinical applications of these extracorporeal carbon dioxide removal therapies may extend beyond just lung protection in ventilated patients. This article summarizes the rationale, technology and clinical application of various extracorporeal lung assist techniques available for clinical use, and some of the future perspectives in the field. PMID- 23095409 TI - Advances in peritoneal dialysis in acute kidney injury. AB - Peritoneal dialysis (PD) is a simple, safe, cheap, and efficient renal replacement therapy method. It can correct metabolic disorders and fluid overload in acute kidney injury (AKI) patients both in and out of the intensive care unit. Use of PD in AKI is enhanced by placement of a Tenckhoff catheter, which can be safely accomplished at the bedside. Some PD modalities, such as high-volume PD and continuous-flow PD, can provide dialysis doses and efficiency comparable to extracorporeal blood purification methods. PD is particularly suitable for neonates, children, and patients with refractory heart failure or who are otherwise hemodynamically unstable. PD should be considered in situations where systemic anticoagulation and/or vascular access are problematic. PD is limited by a lower efficiency that may produce inadequate renal replacement in larger and/or severely hypercatabolic patients. Fluid removal can be unpredictable, there is a risk of infection, and possible issues with mechanical ventilation. In this article, we discuss the use of PD in AKI, with emphasis on recent advances. PMID- 23095410 TI - Cell-based strategies for the treatment of kidney dysfunction: a review. AB - Conventional treatment of acute and chronic renal diseases has focused on solute removal. Novel strategies aim to treat the multifactorial disease states of acute kidney injury and chronic kidney disease by mitigating inflammation. Cell-based technologies for the treatment of kidney dysfunction fall under two broad categories: cell therapy and cell processing. Cell therapy utilizes cells that are isolated, cultured outside of the body, and reintroduced as therapy, leveraging beneficial metabolic and synthetic functions. For example, renal tubule cells have been used to provide gluconeogenesis, ammoniagenesis, metabolism of glutathione, catabolism of important peptide hormones, growth factors, and cytokines critical to multiorgan homeostasis and immunomodulation to treat renal dysfunction. Cell processing focuses on altering the characteristics of cell populations inside the body to provide therapy. The selective cytopheretic device is an example of this novel therapeutic strategy that aims to modulate the innate immune response during organ dysfunction, additional organ injury, by binding and deactivating leukocytes. In this review, both cell therapy and cell processing approaches will be discussed in the context of acute kidney injury and chronic renal disease. PMID- 23095411 TI - Tailored therapy: matching the method to the patient. AB - Clinicians frequently have to decide when dialysis should be initiated and which modality should be used to support kidney function in critically ill patients with acute kidney injury. In most instances, these decisions are made based on the consideration of a variety of factors including patient condition, available resources and prevailing local practice experience. There is a wide variation worldwide in how these factors influence the timing of initiation and the utilization of various modalities. In this article, we review the therapeutic goals of renal support and the relative advantages and shortcomings of different dialysis techniques. We describe strategies for matching the timing of initiation to the choice of modality to individualize renal support in intensive care unit patients. PMID- 23095412 TI - Renal replacement therapy in the end-stage renal disease patient with critical illness. AB - Dialysis patients account for 1-9% of all intensive care unit (ICU) admissions. As a result of the increasing prevalence of patients with end-stage renal disease (ESRD) and the changing demographics of this population, the number of dialysis patients requiring hospitalization and ICU support is expected to increase. Critically ill ESRD patients have more comorbidity and higher severity of illness than the general population resulting in higher ICU and in-hospital mortality rates. ESRD patients have been excluded from trials evaluating renal replacement therapy in the ICU, therefore little information is available about the optimal management of renal replacement therapy for dialysis patients in this setting. This review focuses on the epidemiology of chronic dialysis patients admitted to the ICU and discusses an approach to providing renal replacement therapy for critically ill patients with ESRD. PMID- 23095414 TI - Ultrafiltration therapy for cardiorenal syndrome: physiologic basis and contemporary options. AB - BACKGROUND: Heart failure (HF) has a high readmission rate in part due to conventional and recently developed therapeutic options having suboptimal results. Extracorporeal and peritoneal ultrafiltration have been advocated as more beneficial methods for fluid removal in decompensated or refractory HF, respectively. METHODS: Traditional and emerging concepts explaining the pathophysiology of HF and the cardiorenal syndrome are reviewed. Extracorporeal and peritoneal ultrafiltration clinical trials are then discussed in terms of potential physiologic benefits, feasibility and their effects on both cardiac and renal function. RESULTS: Ultrafiltration therapy can efficiently correct volume overload in the acute setting, improve cardiac functional and quality of life parameters, and is associated with long-lasting benefits such as reduced HF related readmissions. Although excessive fluid removal can adversely affect the kidneys, there is evidence that careful protocols can restore diuretic sensitivity and maintain stable renal function; crafting safe parameters has yet to be studied. CONCLUSION: While extracorporeal ultrafiltration is an appealing therapeutic option for patients with acute decompensated HF, determining the optimal fluid removal rate and the impact on renal function need further investigation. Peritoneal dialysis may be an appropriate alternative in the setting of chronic refractory HF, but controlled studies are needed. Further trials are warranted to determine the long-term outcomes from both ultrafiltration modalities in HF. PMID- 23095413 TI - Pediatric renal replacement therapy in the intensive care unit. AB - Renal replacement therapy (RRT) is used in a wide variety of pediatric populations. In this article, we will review the advantages and disadvantages of the different RRT modalities and the technical aspects of providing pediatric RRT. In addition, we will review the use of RRT with extracorporeal membrane oxygenation, the use of continuous RRT in the critically ill child with acute kidney injury and fluid overload, and the use of RRT for the removal of toxins and treatment of inborn errors of metabolism. PMID- 23095415 TI - Extracorporeal liver support. AB - Mortality of patients with liver failure remains unacceptably high. As the liver has an enormous potential to regenerate, extracorporeal liver support devices may allow patients with liver failure to be bridged to recovery. Alternatively, liver assist may allow patients with advanced liver disease to be managed until a suitable organ for transplant is available. Current approaches to liver support include the use of biological devices that contain hepatocytes and those that function as detoxification devices, and artificial liver support systems. This review describes the current state of the art and existing data on the use of these devices to treat patients with liver failure. PMID- 23095416 TI - Continuous hemodiafiltration with a cytokine-adsorbing hemofilter for sepsis. AB - Since the introduction of the new pathophysiological concept of pathogen associated molecular patterns (PAMPS) and alarmins, endotoxin has been recognized as only one of the PAMPS. It is widely accepted that hypercytokinemia plays a pivotal role in the pathophysiology of sepsis. Many kinds of blood purification modalities have been proposed as a therapeutic tool against sepsis, including high-volume continuous hemofiltration whose efficacy has recently been questioned. We report that continuous hemodiafiltration (CHDF) with a cytokine adsorbing hemofilter (CAH), such as polymethyl methacrylate hemofilter and AN69ST hemofilter (CAH-CHDF), can remove many kinds of cytokines and has been very effective in the treatment of severe sepsis and septic shock. Based on the understanding of the recent pathophysiology, we suggest that CAH-CHDF is an alternate therapy to direct hemoperfusion with endotoxin-adsorbing column in the treatment of sepsis. PMID- 23095417 TI - Predicting and managing complications of renal replacement therapy in the critically ill. AB - Renal replacement therapy (RRT) remains associated with a significant risk of serious complications, and critically ill patients requiring RRT continue to manifest particularly poor overall survival rates. These poor outcomes persist despite improvements in the modalities employed as well as an enhanced understanding of the effects of the extracorporeal circuit, anticoagulation, treatment doses, fluid replacement and dialysis membrane. More recently, there has been an emerging appreciation that intermittent RRT (in the chronic maintenance haemodialysis setting) is capable of generating sufficient circulatory stress to propagate additional widespread end-organ injury. The mitigation of this plethora of risks by the correct identification of complications, targeting of therapy refinements and prediction, whilst problems still remain occult, is desirable and becoming increasingly possible in the pursuit of improved outcomes in this high-mortality therapeutic field. PMID- 23095418 TI - Handling continuous renal replacement therapy-related adverse effects in intensive care unit patients: the dialytrauma concept. AB - Continuous renal replacement therapy (CRRT) is increasingly used for the management of critically ill patients. As a consequence, the incidence of complications that accompany CRRT is also rising. However, a standardized approach for preventing or minimizing these adverse events is lacking. Dialytrauma is a newly proposed concept that encompasses all harmful adverse events related to CRRT while providing a framework for prevention or, at the least, early recognition of these events in order to attenuate the consequences. A mainstay of this approach is the utilization of a dedicated checklist for improving CRRT quality and patient safety. In this context, we discuss the most important adverse effects of CRRT and review current strategies to minimize them. PMID- 23095419 TI - Acid-base and electrolyte abnormalities during renal support for acute kidney injury: recognition and management. AB - Acute kidney injury (AKI) is associated with electrolyte and acid-base disturbances such as hyperkalemia, metabolic acidosis, hypocalcemia and hyperphosphatemia. The initiation of dialysis in AKI can efficiently treat these complications. The choice of dialysis modality can be made based on their operational characteristics to tailor the therapy according to the clinical scenario. Each dialysis modality can also trigger significant electrolyte and acid-base disorders, such as hypokalemia, hypophosphatemia and metabolic alkalosis, which may direct changes in fluid delivery and composition. Continuous techniques may be particularly useful in these situations as they allow more time for correction and to maintain balance. This review provides an overview of the electrolyte and acid-base disturbances occurring in AKI and after the initiation of dialysis and discusses therapeutic options in this setting. PMID- 23095420 TI - Prevention and management of dialysis catheter complications in the intensive care unit. AB - Dialysis dependence at hospital discharge after acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the intensive care unit (ICU) is found in 10-15% of survivors. In case of severe AKI in the ICU, it is necessary to reconcile two objectives: the creation of an adequate temporary angioaccess for RRT and the preservation of the patient's vascular network in case of evolution to end-stage renal disease. A central venous catheter (CVC) is the best option for RRT in the ICU setting. Most catheter-related hazards can be prevented by following best clinical practices for insertion and handling of the CVC, and by knowing the advantages and disadvantages of the different types of catheters, the sites and techniques of insertion, the types of RRT modality for choosing the best CVC option, and the prophylactic and therapeutic measures to prevent and to manage the complications. We review here some important aspects of the CVC for the treatment of AKI in the ICU. PMID- 23095422 TI - Combination therapy patterns and predictors of ADHD in commercially insured and Medicaid populations. AB - OBJECTIVES: Several stimulant and nonstimulant medications are used alone or in combination to treat attention-deficit/hyperactivity disorder (ADHD). Little is known about the current prevalence and predictors of combination therapy. This analysis describes ADHD medication use focusing on combination versus monotherapy. METHODS: Health insurance claims from the Truven Health MarketScan(r) Commercial Database and Multi-State Medicaid Database were analyzed for patients with an ADHD diagnosis (International Classification of Diseases, Ninth Revision codes 314.0x). Patients included were aged >= 6 years as of January 2010, continuously enrolled from July 2009 through December 2010, and had a claim for an ADHD medication in 2010. Medication use was measured in treatment months during 2010. Baseline demographic and clinical predictors of combination therapy (> 1 ADHD medication class in the same month) involving atomoxetine, long acting stimulants, and alpha2-adrenergic agonists were explored using logistic regression, with generalized estimating equations to account for within-patient correlation between months. RESULTS: Commercially insured patients with ADHD (N = 211 226) were primarily aged 6 to 17 years (58.4%) and male (61.5%). Attention deficit/hyperactivity disorder with hyperactivity was present in 15.8% of these patients. Combination therapy was used in 10.3% of 1 125 119 treatment months. Short-acting stimulants and alpha2-adrenergic agonists had the highest combination use (45.3% and 54.0%, respectively). Patients with ADHD insured through Medicaid (N = 125 104) were primarily aged 6 to 17 years (94.4%) and male (69.5%). Hyperactivity was present in 39.7% of these patients. Combination therapy was used in 24.0% of 721 986 treatment months. Short-acting stimulants, alpha2-adrenergic agonists, and intermediate-acting stimulants had the highest combination use (70.0%, 63.8%, and 51.8%, respectively). In multivariate models for both data sources, female patients were less likely to use combination therapy. Patients with hyperactivity were more likely to use combination therapy. Tics/Tourette's syndrome was associated with combination therapy for atomoxetine and long-acting stimulants. CONCLUSION: In commercially insured and Medicaid ADHD populations, combination therapy rates differed by medication class, as did the demographic and clinical characteristics statistically significantly associated with combination therapy. This suggests that these medications may be used differently in clinical practice. PMID- 23095423 TI - Discontinuity in the transition from pediatric to adult health care for patients with attention-deficit/hyperactivity disorder. AB - BACKGROUND: Although attention-deficit/hyperactivity disorder (ADHD) is a chronic disorder, treatment declines dramatically in adolescence and into early adulthood. This premature termination of care is likely compounded by the difficulty many patients have switching from a pediatric to an adult provider. OBJECTIVE: To review, from the adult primary care provider perspective, the barriers to continuity of care and their implications for patients with ADHD who transition from pediatric to adult health care. DESIGN: Literature review. APPROACH: Relevant articles were identified by searches of the PubMed and EMBASE databases and by reviewing the reference lists of articles obtained from these searches. RESULTS: Health care transition for adolescents and young adults with ADHD remains a crucial area of research. The current literature reveals a number of barriers to the continuity of care, including disparities and inadequacies in ADHD education in primary care and internal medicine residencies, prohibitive prescribing practices with respect to stimulants, inadequate clinic staffing, lack of support in the college health care system, inadequate health insurance coverage, and failure to conduct transitional planning. Without improved continuity of care and adherence to medication, adolescents and young adults with ADHD are at greater risk of academic, social, and vocational difficulties, as well as behavioral problems, including substance abuse, unsafe driving, and criminal activity. CONCLUSION: If we are to adequately address the health care needs of adolescents and young adults with ADHD, we need to educate primary care providers and support additional research. PMID- 23095424 TI - The effects of methylphenidate on cognitive function in children with attention deficit/hyperactivity disorder. AB - Focusing on behavioral criteria for attention-deficit/hyperactivity disorder (ADHD) diagnosis leads to considerable neuropsychological profile heterogeneity among diagnosed children, as well as variable response to methylphenidate (MPH) treatment. Documenting "cold" executive working memory (EWM) or "hot" self regulation (SR) neuropsychological impairments could aid in the differential diagnosis of ADHD subtypes and may help to determine the optimal MPH treatment dose. In this study, children with ADHD inattentive type (n = 19), combined type (n = 33), and hyperactive-impulse type (n = 4) underwent randomized controlled MPH trials; neuropsychological, behavioral, and observational data were collected to evaluate the children's responses. Those with moderate or significant baseline EWM/SR impairment showed robust MPH response, whereas response for those with lower baseline impairment was equivocal. Implications for medication use and titration, academic achievement, and long-term treatment efficacy are examined. PMID- 23095425 TI - The novel use of objective laboratory school tasks to measure stress responses in children with ADHD. AB - OBJECTIVE: To pilot the novel use of 2 existing laboratory school measures--the Permanent Product Measure of Performance (PERMP) and the Grammar Task--as provoking stimuli of stress, and to observe the effects of medication and stress on children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Children received individually determined optimal doses of an oral methylphenidate stimulant medication on 1 of 2 consecutive modified laboratory school days, which is a setting that is known for being a reliable measure of the exact timing of treatment effects. Blood pressure and heart rate measurements collected after administration of the PERMP, an ability-adjusted math test, were presumed to be stress related when compared with baseline data. In addition, children ranked their stress levels on a stress rating scale and completed the Grammar Task as a measure of academic performance. RESULTS: Seven subjects enrolled in and completed the study. The results suggest that children with ADHD demonstrate a decreased stress response when medicated, as measured by blood pressure, heart rate, and academic performance. CONCLUSION: Completion of a more difficult PERMP was associated with an increased stress response. This study supports an expanded use of both the PERMP and Grammar Task. Future controlled studies should include larger samples and other indicants of stress responses, particularly peripherally circulating catecholamine levels. PMID- 23095426 TI - Management strategies for attention-deficit/hyperactivity disorder: a regional deliberation on the evidence. AB - Parents, clinicians, and policymakers require the latest evidence to help inform treatment decisions. The New England Comparative Effectiveness Public Advisory Council (CEPAC) leverages existing federally produced comparative effectiveness research supplemented with additional clinical and economic analyses to deliberate on the latest evidence. At its June 2012 meeting, the CEPAC voted on the evidence for the treatment of attention-deficit/hyperactivity disorder (ADHD) in preschoolers and school-aged children. The CEPAC voted unanimously that parent behavior training was better than usual care (eg, wait-list control) for the preschool population. They also judged it to be of "reasonable value" compared with usual care. The CEPAC also stipulated unanimously that medications are better than usual care (eg, services provided at individual practitioner discretion) for school-aged children in regards to long-term effectiveness and safety. The CEPAC members and clinical experts recommended the increased use of parent behavior training as first-line therapy for preschoolers and emphasized the importance of proper monitoring of and dosing for all children who receive medication for their ADHD symptoms. The ADHD CEPAC meeting demonstrated the important role that a public, transparent deliberation on the latest medical evidence can have in supporting informed decision making and efficient use of health care resources. PMID- 23095427 TI - Evaluation of the 9-item Patient Health Questionnaire (PHQ-9) as an assessment instrument for symptoms of depression in patients with multiple sclerosis. AB - BACKGROUND: Patients with multiple sclerosis (MS) have a high prevalence of depression, but there are concerns regarding assessment of possible depression status using rating scales, such as the 9-item Patient Health Questionnaire (PHQ 9). The idea has been proposed that PHQ-9 scores are contaminated by the MS symptoms of fatigue and impaired concentration, decreasing the validity of measurement. OBJECTIVES: To determine the extent to which scores on the PHQ-9 are contaminated by patients reporting symptoms attributable to MS. METHODS: Baseline PHQ-9 scores from an ongoing prospective cohort study of depression in patients with MS (N = 173) were compared with those of a general population sample (N = 3304). Depression prevalence estimates for the MS and general population samples were calculated using conventional algorithm and cutoff point scoring methods, as well as modified scoring methods, excluding fatigue and concentration deficits. Correlations between scores on adjusted scoring methods were analyzed. The proportion that each item contributed to total PHQ-9 scores was also calculated. A logistic regression model evaluated the relationship between symptom severity and MS status corrected for age, sex, and other depressive symptoms. RESULTS: Conventional PHQ-9 algorithm and cutoff point scoring yielded 2-week prevalence estimates of 9.8% and 21.4%, respectively, in patients with MS, and 3.3% and 8.4%, respectively, in the general population. In both samples, conventional and modified scoring methods were strongly correlated (Spearman rank correlation coefficient > 0.9). The proportion of total scores contributed by fatigue and concentration items was not different between samples. With adjustment for other depressive symptoms, the MS sample had greater odds of endorsement for guilt (odds ratio, 2.17; P = 0.025) and fatigue (odds ratio, 1.51; P = 0.046). CONCLUSION: Inclusion or exclusion of fatigue and concentration items on the PHQ 9 scale does not substantially alter the performance of the scale. With use of the PHQ-9 in MS populations, we find no evidence to suggest that modified approaches to scoring are necessary. PMID- 23095428 TI - The use of stimulant medication to treat neurocognitive deficits in patients with pediatric cancer, traumatic brain injury, and sickle cell disease: a review. AB - Several chronic health conditions of childhood, including pediatric cancers, traumatic brain injury (TBI), and sickle cell disease (SCD) are associated with significant neurocognitive impairments that can compromise educational attainment and future vocational opportunities. The prominence of attentional deficits as part of the neurocognitive sequelae associated with each of these conditions has led some researchers to draw parallels with another chronic condition that manifests in childhood, specifically the inattentive subtype of attention deficit/hyperactivity disorder (ADHD). Because ADHD shares similar neurocognitive and symptomatological features with pediatric cancer, TBI, and SCD, stimulant medications may be indicated to treat associated deficits in each condition. However, relatively few studies have investigated the safety and effectiveness of stimulant medications in treating neurocognitive sequelae in children with cancer, TBI, or SCD. Thus, clinicians have received little guidance regarding a potentially useful treatment modality for ameliorating the neurocognitive deficits that can profoundly impact the educational, psychosocial, and vocational development of youth with these chronic health conditions. We provide a review of the literature and synthesize current developments in research regarding treatment with stimulant medication for children with cancer, TBI, and SCD, as well as discuss special considerations for each condition. PMID- 23095429 TI - Vascular cognitive impairment and dementia expenditures: 7-year inpatient cost description in community dwellers. AB - BACKGROUND: Vascular cognitive impairment (VCI) and vascular dementia (VaD) are prevalent conditions with a growing impact on health care expenses. Few studies have addressed expenditures on cognitive vascular disease. We quantify the expenses of tertiary-care inpatients with VCI and VaD and provide the first report on the specific cost of care in community-dwelling patients with small- and large-vessel ischemic cognitive disease. METHODS: This is a cost-description study of inpatient expenditures from the Spanish National Health Institute and regional government perspectives. We retrospectively analyzed the expenses in a prospective cohort of 122 community dwellers with VCI who developed small-vessel disease with ischemic white matter disease (Binswanger's disease) (n = 60), lacunar state (n = 26), or large-vessel disease (n = 36). Admissions with a primary or secondary diagnosis of transient ischemic attack or stroke, cognitive impairment or dementia, and other diagnoses related to cerebrovascular disease were assessed. RESULTS: The average cost per patient was $33 740. The costs per VCI admission were similar across groups (~$9545). The average number of admissions increased during the progression of the disease (VCI, 1.2; VaD, 2.5) and contributed to higher expenses per patient during the VaD stage (~$22 631) compared with the VCI stage (~$11 110). Half of patients (n = 61; 50%) progressed without ischemic events during the VCI stage. These patients incurred lower per patient costs during the VCI stage ($9750 vs $12 464), and costs increased during the post-VaD diagnosis stage ($28 528 vs $16 734). CONCLUSION: Large- and small vessel cerebrovascular diseases are common and costly conditions. Vascular cognitive impairment presenting with stroke may incur greater expenses than VCI onset without stroke. Thus, patients with large-vessel disease incurred higher costs during the VCI stage. Care became more onerous at an advanced VaD stage in all groups. During the VaD stage, the expenditures of patients with Binswanger's disease were significantly higher and eventually counterbalanced the initially lower costs seen during the VCI stage. PMID- 23095430 TI - The implications of tamper-resistant formulations for opioid rotation. AB - Because rates of both opioid prescribing and opioid abuse have increased, drug companies have responded by considering strategies to make opioid formulations less attractive for abuse without compromising safety or efficacy for patients with legitimate pain management needs. The emergence of tamper-resistant opioid formulations is intended to deter abuse by creating obstacles to crushing or dissolving opioid tablets and capsules. At present, 2 long-acting and 1 immediate release (IR) opioids are available in tamper-resistant formulations. Oxycodone controlled-release and oxymorphone extended-release tablets have each been reformulated with a hardened matrix that resists crushing or dissolution in liquids, making them difficult to prepare for nasal insufflation or intravenous use. Oxycodone IR has been reformulated with aversive ingredients that create nasal discomfort if the tablet is crushed and insufflated. Tamper-resistant opioid formulations are likely to be selected for patients who are identified as being at risk for abuse. However, patients vary in their response to individual opioids and may require rotation to a series of alternative opioids before finding one that is effective and sufficiently well tolerated. With only a few tamper-resistant opioid formulations currently available, switching and rotation may become difficult. As a result, patients who do not respond to a tamper resistant opioid formulation or experience intolerable adverse events may require rotation to a formulation without tampering safeguards. Prescribers will need to be on guard for patients who may make false claims of poor response or adverse events to avoid tamper-resistant opioid formulations. Moreover, prescribers need to be aware of any tamper-resistance mechanisms that may affect efficacy or tolerability in patients with legitimate pain management needs compared with formulations without tampering safeguards. PMID- 23095431 TI - Empowering people with diabetes: improving perceptions and outcomes with technical advances in insulin pens. AB - For people with diabetes treated with insulin, the development of insulin pens has led to important advantages compared with the use of vials and syringes. Insulin pens are associated with improved ease of use, user confidence, treatment satisfaction, and quality of life compared with vials and syringes. Continual improvements to insulin pen designs to further enhance usability and improve patient perceptions may help to lower patients' resistance to initiating insulin therapy and further improve treatment adherence. This article reviews recent developments in prefilled insulin pens that may assist health care professionals when considering insulin-delivery devices to recommend to their patients. PMID- 23095432 TI - Focusing on cardiovascular disease in type 2 diabetes mellitus: an introduction to bromocriptine QR. AB - Cardiovascular risk reduction is a key priority in patients with diabetes. The relationship between glycemic control and macrovascular outcomes, such as the benefit of intensive glucose control and the importance of postprandial or fasting blood glucose, is still under debate. A number of pharmacologic options are available to treat type 2 diabetes mellitus and these options have differing evidence for their cardiovascular safety. In this article, the novel agent bromocriptine quick release is discussed. Recently approved, this once-daily treatment provides glycemic control as monotherapy or in combination with other antihyperglycemic medications and has been shown in a prospective phase 3 safety study to not increase cardiovascular risk. Therefore, bromocriptine quick release increases the range of options available to treat patients with type 2 diabetes mellitus without increasing cardiovascular risk. PMID- 23095433 TI - Predisease conditions and serum vitamin D levels in healthy Mexican American adults. AB - AIMS: To elucidate the relationship between low circulating serum vitamin D levels and predisease conditions (ie, prediabetes and prehypertension) in healthy Mexican American adults. METHODS: Analyses were conducted using data from the United States National Health and Nutrition Examination Survey (NHANES) from 2001 through 2006. Free-living (ie, community-dwelling, nonimprisoned) adult Mexican American subjects (N = 788; men, n = 443; women, n = 345) who had provided written informed consent and had no history of diabetes, hypertension, dyslipidemia, metabolic syndrome, and/or cardiovascular disease were included in this report. Participants were not ingesting any prescription medications, nor did they exhibit any evidence of malabsorption. Participants were determined to be disease free. RESULTS: The mean serum vitamin D level for Mexican American adults (N = 788) of 50.5 nmol/L was significantly higher (P < 0.0001) than the mean of 35.9 nmol/L for non-Hispanic black adults (n = 621), and significantly lower (P < 0.0001) than the mean of 65.0 nmol/L for non-Hispanic white adults (n = 1711). Although age, sex, and body mass index were all significantly associated with prehypertension and prediabetes, no such association was found for serum vitamin D levels. CONCLUSION: A successive, incremental shift of approximately 15 nmol/L in vitamin D distribution was seen in the transition from the dark-skinned non-Hispanic black population to the brown-skinned Mexican American population, and from the brown-skinned Mexican American population to the non-Hispanic white population. In contrast to the non-Hispanic black and non-Hispanic white populations, wherein previous studies found that serum vitamin D levels below the 75th percentile were associated with prediabetes and prehypertension, no such association was detected among the Mexican American population. The reason for this lack of association among the Mexican American population is unclear. PMID- 23095434 TI - Family medicine and sports medicine students' perceptions of their educational environment at a primary health care center in Germany: using the DREEM questionnaire. AB - The medical learning environment is changing progressively due to its crucial importance in clinical learning and educational performance. The purpose of this study was to investigate student perceptions of the medical learning environment at a primary health care center outside of a university hospital using the Dundee Ready Educational Environment Measure (DREEM) questionnaire. Various aspects of the environment were compared between family medicine (FM) and sports medicine (SM) students to assess the role of these different rotations and their effect on student perceptions. The DREEM questionnaire, a validated tool for measuring perceptions of educational environments in medical educational environments, was completed by 110 students who were enrolled in FM and SM rotations at Wuppertal Primary Health Care and Research Center in Wuppertal, Germany. Other than 9 of the 50 items, there were no statistically significant differences in DREEM questionnaire scores between these 2 groups, indicating that students' perceptions of the educational environment were not remarkably affected by their rotations. Scores across the sample were fairly high (FM students, 139.45/200; SM students, 140.05/200; overall total score, 139.85/200). These high scores suggest that students enrolled in FM and SM health science programs generally hold positive perceptions of their course environment outside of the university hospital. The positive perception of the educational environment at this primary health care center is hopefully indicative of similar rotations' perceptions internationally. While future studies are needed to confirm this, the current findings offer a chance to identify and explore the areas that received low scores in greater detail. PMID- 23095435 TI - New perspectives on the management of gout, a common primary care disorder. PMID- 23095436 TI - What can epigenomics do for you? PMID- 23095437 TI - Clinical features of children with venom allergy and risk factors for severe systemic reactions. AB - BACKGROUND: Severe systemic reactions (SRs) to insect venom are rare in childhood and there are few data on this study population. The aim of our study is to analyze the clinical features and to document the risk factors for severe SRs in children with insect venom allergy. METHODS: Children with SRs after Hymenoptera sting were analyzed. The diagnosis was based on medical history, skin tests and/or specific IgE testing. RESULTS: Seventy-six children were included [57 boys (75%), mean age 9.8 +/- 3.4 years]. The mean age of children at the time of SR was 8.3 +/- 3.4 years. Reactions were accounted for Vespula (wasp) venom in 58 (76%) and Apis mellifera (bee) venom in 18 (24%) patients. Twenty-six percent of patients had aeroallergen sensitization and 33% had atopic disease, whereas 66% had experienced previous stings. The upper limb was the most frequent area of sting (43%), and the cutaneous system (99%) was the most frequent involved system. SRs occurred in 59% of patients. Multivariate logistic regression analysis revealed eosinophilia (>5%) [odds ratio (OR) 12.6; confidence interval (CI) 1.5-109.7; p = 0.022], female sex (OR 6.4; CI 1.5-26.9; p = 0.011) and accompanying atopic disease (OR 3.4; CI 1.2-12.3; p = 0.016) as significant risk factors for severe SRs. Ninety-seven percent of patients were admitted to the emergency department; however, epinephrine was used in only 46% of patients. CONCLUSIONS: There was a high frequency of hypersensitivity to wasp venom among the study population, and severe reactions were related to mild eosinophilia, female sex and concomitant atopic diseases. A better understanding of the risk factors may lead to effective utilization of health care sources in the future. PMID- 23095438 TI - Efficient removal of serum bilirubin by a novel artificial liver support system using albumin convection: a pilot study. AB - BACKGROUND/AIMS: To compare the efficacy of a new artificial liver support system, fractionated plasma separation and adsorption integrated with hemofiltration, with the old system, plasma adsorption. METHODS: Sixteen patients with acute liver failure each received a first session of treatment using the old system, in which plasma was perfused through an adsorber. They then received a second session using the new system, in which albumin-rich plasma separated using a fraction plasma separator was ultrafiltrated using a hemofilter and perfused through an adsorber before being returned to blood. RESULTS: The new system had a higher clearance of bilirubin and slower decline of clearance over time. There was a lower reduction ratio of bilirubin, bile acid, urea, and creatinine; longer prolongation of coagulation parameters; and greater decline in albumin level using the old system compared with the new one. CONCLUSIONS: Use of the novel system results in more efficient removal of toxins and fewer deterious effects than the old system. PMID- 23095440 TI - Immunosuppression. PMID- 23095439 TI - Factors associated with dietary adherence in celiac disease: a nationwide study. AB - AIMS: Diagnostics and follow-up of celiac disease have gradually shifted from tertiary centers to secondary and primary health care. In order to establish whether this has affected the success of treatment, and to identify predictors for dietary non-adherence, we carried out a study in a nationwide cohort of treated celiac patients. PATIENTS AND METHODS: 843 biopsy-proven patients, 94 children and 749 adults, were enrolled and interviewed. Adherence to a gluten free diet was determined by means of an interview and serological testing. RESULTS: Altogether, 88% were on a strict gluten-free diet; the rest had occasional dietary transgressions. Younger age at diagnosis, being currently a teenager, and current symptoms were associated with non-adherence. There was no association between non-adherence and place of diagnosis, gender, disease phenotype or severity of symptoms before diagnosis, presence of comorbidities, family history of celiac disease, smoking, duration of diet, use of oats, self efficacy for the diet or lack of follow-up. CONCLUSIONS: Good dietary adherence can be achieved also in patients diagnosed and followed in primary health care. In a country with a high prevalence and good general knowledge of celiac disease, only age at diagnosis and age at present would appear to be major determinants for adherence. PMID- 23095441 TI - Abdominal pathology in patients with diabetes ketoacidosis. AB - INTRODUCTION: The objective is to describe the incidence and nature of significant abdominal pathologies in patients with diabetes ketoacidosis (DKA) and abdominal pain. METHODS: Retrospective chart review (N = 86) of patients with DKA from January 1, 2005, to January 31, 2010, was performed. Data included demographics, co-morbidities, compliance, chief complaints and physical findings, blood count, metabolic profile, lactic acid, glycosylated hemoglobin (HbAlC), amylase, lipase, anion gap, arterial gases, imaging and final diagnosis. Continuous variables were described as mean +/- standard deviation and compared with the Student's t test. Categorical variables were expressed as percentages (%) and compared with the Mantel-Haenszel chi test. Univariate analysis was conducted among patients with and without significant abdominal pain and also with and without significant abdominal pathology. Two lipase strata were created at 400 U. Multivariate model to identify limits (confidence interval) of the estimated risk imposed by the predictor found significant in univariate analysis. A P value of <= 0.05 was considered significant. Stat View 5.0 (SAS Institute, Cary, NC) was used for the statistical analysis. RESULTS: In patients with abdominal pain, 17% had significant abdominal pathology mainly acute pancreatitis (AP). Serum amylase and lipase level were found to be an indicator of significant underlying pathology (both P values <=0.001). The logistic model created showed that patients with lipase level >=400 U have a 7% increased risk of having AP with confidence interval of 0.01 to 0.6. CONCLUSION: Patients with DKA and abdominal pain with lipase >400 U have an increased risk of significant underlying abdominal pathology (AP). PMID- 23095442 TI - Rare cutaneous metastases from gastric cancer. PMID- 23095443 TI - Thymoma presenting as chest pain. PMID- 23095444 TI - A case of pulmonary cholesterol granuloma: an (18)F-fluorodeoxyglucose positron emission tomography image. AB - A 77-year-old woman with Sjogren's syndrome has been followed for mild interstitial pneumonia. A 2-cm pulmonary nodule was incidentally found in the left lower lobe, and positron emission tomography-computed tomography showed (18)F-fluorodeoxyglucose uptake with a maximum standardized uptake value of 8.78 in this nodule. Although this suggested a malignant disease, transbronchial biopsy of the nodule revealed that it was cholesterol granuloma. It is known that some benign inflammatory diseases show an increased uptake of (18)F fluorodeoxyglucose, particularly granulomatous lesions like tuberculosis. To our knowledge, this is the first report of (18)F-fluorodeoxyglucose-positron emission tomography findings for cholesterol granuloma. We speculate that increased (18)F fluorodeoxyglucose uptake with cholesterol granuloma occurs through cellular infiltration and macrophage proliferation, resulting in the activation of glycolysis-like tuberculosis. PMID- 23095445 TI - What remains to be done to allow quantitative X-ray microanalysis performed with EDS to become a true characterization technique? AB - This article reviews different methods used to perform quantitative X-ray microanalysis in the electron microscope and also demonstrates the urgency of measuring the fundamental parameters of X-ray generation for the development of accurate standardless quantitative methods. Using ratios of characteristic lines acquired on the same X-ray spectrum, it is shown that the Cliff and Lorimer K A-B factor can be used in a general correction method that is appropriate for all types of specimens and electron microscopes, providing that appropriate corrections are made for X-ray absorption, fluorescence, and indirect generation. Since the fundamental parameters appear in the K A-B factor, only the ratio of the ionization cross sections needs to be known, not their absolute values. In this regard, the measurement of ratios of the K A-B factor (or intensities at different beam energies of the same material with no change of beam spreading in the material) permits the validation for the best models to compute the ratio of ionization cross sections. It is shown, using this method, that the nonrelativistic Bethe equation, to compute ionization cross section, is very close to the equation of E. Casnati et al. (J Phys B 15, 155-167, 1982) and also to the equations proposed by D. Bote and F. Salvat (Phys Rev A 77, 042701, 2008) for the computation of the ratio of ionization cross sections. The method is extended to show that it could be used to determine the values of the Coster Kronig transitions factors, an important fundamental parameter for the generation of L and M lines that is mostly known with poor accuracy. The detector efficiency can be measured with specimens where their intensities were measured with an energy dispersive spectrometer detector, the efficiency of which has been measured in an X-ray synchrotron (M. Alvisi et al., Microsc Microanal 12, 406 415, 2006). The spatial resolution should always be computed when performing quantitative X-ray microanalysis and the equations of R. Gauvin (Microsc Microanal 13(5), 354-357, 2007) for bulk materials and the one presented in this article for thin films should be used. The effects of X-rays generated by fast secondary electrons and by Auger electrons are reviewed, and their effect can be detrimental for the spatial resolution of materials involving low-energy X-ray lines, in certain specific conditions. Finally, quantitative X-ray microanalysis of heterogeneous materials is briefly reviewed. PMID- 23095446 TI - Atom probe tomography simulations and density functional theory calculations of bonding energies in Cu3Au. AB - In this article the Cu-Au binding energy in Cu3Au is determined by comparing experimental atom probe tomography (APT) results to simulations. The resulting bonding energy is supported by density functional theory calculations. The APT simulations are based on the Muller-Schottky equation, which is modified to include different atomic neighborhoods and their characteristic bonds. The local environment is considered up to the fifth next nearest neighbors. To compare the experimental with simulated APT data, the AtomVicinity algorithm, which provides statistical information about the positions of the neighboring atoms, is applied. The quality of this information is influenced by the field evaporation behavior of the different species, which is connected to the bonding energies. PMID- 23095447 TI - Microscopy and microanalysis of hematological parameters in common carp, Cyprinus carpio, inhabiting a polluted lake in North East India. AB - Optical and scanning electron microscopy (SEM) of red blood cells (RBCs) of common carp, Cyprinus carpio, inhabiting a polluted lake in Northeast India revealed a number of abnormalities. About 7% of the RBC showed the presence of a micronucleus, besides the presence of some bi-nucleated and abnormally shaped nuclei. RBCs, white blood cells, and hemoglobin content were found to be reduced significantly as compared to the control. SEM showed the presence of spherocytes, early stages of echinocytes, cytoplasmic blebbing, erythrocytes with contraction from one side, abnormal shape of erythrocytes (hexagonal/pentagonal/tetragonal), development of lobopodial projections, cell rupture, membrane internalization, and formation of ring-shaped RBC. Energy dispersive X-ray spectroscopy (EDS) showed the presence of a considerable percentage of silicon and lead in erythrocytes of the fish collected from the polluted lake, in contrast to a negligible concentration of the two elements in control fish. Significance of the study in relation to fish health in a polluted body of water and the importance of SEM, EDS, and light microscopy in utilizing hematological parameters as pollution indicators are discussed. PMID- 23095448 TI - Micro energy-dispersive X-ray fluoresence mapping of enamel and dental materials after chemical erosion. AB - Energy-dispersive X-ray fluorescence was employed to test the hypothesis that beverage consumption or mouthwash utilization will change the chemical properties of dental materials and enamel mineral content. Bovine enamel samples (n = 45) each received two cavity preparations (n = 90), each pair filled with one of three dental materials (R: nanofilled composite resin; GIC: glass-ionomer cement; RMGIC: resin-modified GIC). Furthermore, they were treated with three different solutions (S: saliva; E: erosion/Pepsi Twist(r); or EM: erosion+mouthwash/Colgate Plax(r)). It was found that mineral loss in enamel was greater in GICE samples than in RE > RMGICE > RMGICEM > REM > GICEM. An increased percentage of Zr was found in REM indicating organic matrix degradation. Dental materials tested (R, GIC, and RMGIC) were not able to protect adjacent enamel from acid erosion by the soft drink tested. The use of mouthwash promoted protection of enamel after erosion by the soft drink. To avoid chemical dissolution by mouthwashes, protection by resin composites with surface sealants is recommended. PMID- 23095449 TI - Disassembling glancing angle deposited films for high-throughput, single-post growth scaling measurements. AB - With growing interest in nanostructured thin films produced by glancing angle deposition (GLAD), it becomes increasingly important to understand their overall growth mechanics and nanocolumn structure. We present a new method of isolating the individual nanocolumns of GLAD films, facilitating automated measurement of their broadening profiles. Data collected for alpha = 81 degrees TiO2 vertical nanocolumns deposited across a range of substrate rotation rates demonstrates that these rates influence growth scaling parameters. Further, individual posts were found in each case that violate predicted Kardar-Parisi-Zhang growth scaling limits. The technique's current iteration is comparable to existing techniques in speed: though data were studied from 10,756 individual objects, the majority could not be confidently used in subsequent analysis. Further refinement may allow high-throughput automated film characterization and permit close examination of subtle growth trends, potentially enhancing control over GLAD film broadening and morphology. PMID- 23095450 TI - Microstructural characterization of consolidant products for historical renders: an innovative nanostructured lime dispersion and a more traditional ethyl silicate limewater solution. AB - The conservation and durability of historical renders must be carried out through compatible techniques and materials. An important operation is the restitution of historical renders cohesion, turned friable by the loss of binder, usually due to physical and/or chemical actions. Surface consolidation is based on the use of materials with aggregating properties. This operation is reached usually through the application of organic or mineral consolidants, but inorganic consolidants are becoming preferred due to better compatibility and durability. In this article two mineral compatible consolidation products were studied: a commercial suspension of calcium hydroxide nanoparticles in propanol and a limewater dispersion of ethyl silicate. Microscopy (optical and scanning electron microscopy) and X-ray microanalyses of the consolidation products and of the consolidated mortar specimens were carried out. To assess the mechanical properties and product's efficacy, analyses of the compression, flexural strength, and superficial hardness were performed. Microscopy results show that limewater dispersion of ethyl silicate forms platelike silica gels, which can interfere in product penetration. Otherwise, nanolime particles permit homogeneous distribution and optimum penetration on the treated substrate, improving cementing action and the agglomeration process. PMID- 23095451 TI - Transmission electron microscope observation of organic-inorganic hybrid thin active layers of light-emitting diodes. AB - We performed transmission electron microscope (TEM) observation of organic inorganic hybrid thin films fabricated by the sol-gel reaction and used as the active layers of organic light-emitting diodes. The cross-sectional TEM images show that the films consist of a triple-layer structure. To evaluate the composition of these layers, the distribution of atoms in them was measured by energy-dispersive X-ray fluorescence spectroscopy. As a result, most of the organic emissive material, poly(9,9-dioctyl-fluorene-co-N-4-butylphenyl diphenylamine (TFB), was found to be distributed in the middle layer sandwiched by SiO and SiO2 layers. The surface SiO layer was fabricated due to the lack of oxygen. This means that the best sol-gel condition was changed due to the TFB doping; thus, the novel best condition should be found. PMID- 23095452 TI - Exploiting protein flexibility to predict the location of allosteric sites. AB - BACKGROUND: Allostery is one of the most powerful and common ways of regulation of protein activity. However, for most allosteric proteins identified to date the mechanistic details of allosteric modulation are not yet well understood. Uncovering common mechanistic patterns underlying allostery would allow not only a better academic understanding of the phenomena, but it would also streamline the design of novel therapeutic solutions. This relatively unexplored therapeutic potential and the putative advantages of allosteric drugs over classical active site inhibitors fuel the attention allosteric-drug research is receiving at present. A first step to harness the regulatory potential and versatility of allosteric sites, in the context of drug-discovery and design, would be to detect or predict their presence and location. In this article, we describe a simple computational approach, based on the effect allosteric ligands exert on protein flexibility upon binding, to predict the existence and position of allosteric sites on a given protein structure. RESULTS: By querying the literature and a recently available database of allosteric sites, we gathered 213 allosteric proteins with structural information that we further filtered into a non redundant set of 91 proteins. We performed normal-mode analysis and observed significant changes in protein flexibility upon allosteric-ligand binding in 70% of the cases. These results agree with the current view that allosteric mechanisms are in many cases governed by changes in protein dynamics caused by ligand binding. Furthermore, we implemented an approach that achieves 65% positive predictive value in identifying allosteric sites within the set of predicted cavities of a protein (stricter parameters set, 0.22 sensitivity), by combining the current analysis on dynamics with previous results on structural conservation of allosteric sites. We also analyzed four biological examples in detail, revealing that this simple coarse-grained methodology is able to capture the effects triggered by allosteric ligands already described in the literature. CONCLUSIONS: We introduce a simple computational approach to predict the presence and position of allosteric sites in a protein based on the analysis of changes in protein normal modes upon the binding of a coarse-grained ligand at predicted cavities. Its performance has been demonstrated using a newly curated non redundant set of 91 proteins with reported allosteric properties. The software developed in this work is available upon request from the authors. PMID- 23095453 TI - Encephalocystocele - uncommon diagnosis in prenatal medicine. AB - Encephalocystocele is a developmental malformation characterized by brain herniation accompanied with extracranial cystic protrusion of the ventricular system. This nosological unit is often overlooked and insufficiently classified merely as encephalocele. Herein, two exceptionally clear cases of the parieto occipital cranioschisis with encephalocystocele and congenital hydrocephalus of the lateral ventricles are documented with 2-dimensional/3-dimensional sonographic images and the corresponding MRI findings. In both cases, prenatal diagnosis was confirmed by autopsy. PMID- 23095454 TI - Establishment of transgene-free induced pluripotent stem cells reprogrammed from human stem cells of apical papilla for neural differentiation. AB - INTRODUCTION: Induced pluripotent stem cells (iPSCs) are a potent cell source for neurogenesis. Previously we have generated iPSCs from human dental stem cells carrying transgene vectors. These exogenous transgenes may affect iPSC behaviors and limit their clinical applications. The purpose of this study was to establish transgene-free iPSCs (TF-iPSCs) reprogrammed from human stem cells of apical papilla (SCAP) and determine their neurogenic potential. METHODS: A single lentiviral 'stem cell cassette' flanked by the loxP site (hSTEMCCA-loxP), encoding four human reprogramming factors, OCT4, SOX2, KLF4, and c-MYC, was used to reprogram human SCAP into iPSCs. Generated iPSCs were transfected with plasmid pHAGE2-EF1alpha-Cre-IRES-PuroR and selected with puromycin for the TF-iPSC subclones. PCR was performed to confirm the excision of hSTEMCCA. TF-iPSC clones did not resist to puromycin treatment indicating no pHAGE2-EF1alpha-Cre-IRES PuroR integration into the genome. In vitro and in vivo analyses of their pluripotency were performed. Embryoid body-mediated neural differentiation was undertaken to verify their neurogenic potential. RESULTS: TF-SCAP iPSCs were generated via a hSTEMCCA-loxP/Cre system. PCR of genomic DNA confirmed transgene excision and puromycin treatment verified the lack of pHAGE2-EF1alpha-Cre-IRES PuroR integration. Transplantation of the TF-iPSCs into immunodeficient mice gave rise to teratomas containing tissues representing the three germ layers -- ectoderm (neural rosettes), mesoderm (cartilage and bone tissues) and endoderm (glandular epithelial tissues). Embryonic stem cell-associated markers TRA-1-60, TRA-2-49 and OCT4 remained positive after transgene excision. After neurogenic differentiation, cells showed neural-like morphology expressing neural markers nestin, betaIII-tubulin, NFM, NSE, NeuN, GRM1, NR1 and CNPase. CONCLUSIONS: TF SCAP iPSCs reprogrammed from SCAP can be generated and they may be a good cell source for neurogenesis. PMID- 23095455 TI - Four decades of chronic haemodialysis: lessons from the past and implications for the future. AB - BACKGROUND: There have been substantial changes in the provision of chronic haemodialysis (HD) therapy over time, yet data regarding the impact of these differences on clinical outcomes are limited. AIM: To identify factors which have significantly changed over the last 40 years in relation to patients receiving maintenance HD therapy. METHODS: All 2,647 patients who were established on the chronic HD programme in Northern Ireland between 1970 and 2010 were included. Clinical data and survival outcomes were obtained from a prospectively recorded database. The study period was divided into four decades in order to assess the temporal changes. RESULTS: The total number of patients receiving HD therapy has risen, and the mean age of the HD population has increased significantly (39.0 years in the 1970s vs. 66.8 years in the 2000s, p < 0.001). Diabetic nephropathy has emerged as the commonest aetiology for ESRD (0% in the 1970s to 20.3% in the 2000s, p < 0.001). The median survival of patients on HD has improved significantly over time from 5.2 months (95% CI 2.6-15.5) in the 1970s to 41.7 months (95% CI 38-45.2) in the 2000s (p < 0.0001). Factors that remained significant in determining survival were age, primary renal diagnosis, and decade of commencement of dialysis. CONCLUSIONS: Survival on HD has significantly improved despite older patients with multiple co-morbidities being accepted for treatment reflecting both increased dialysis frequency and better management of cardiovascular risk factors. The increasing age of HD patients and their improved survival have implications for future planning and delivery of dialysis. PMID- 23095456 TI - Improved awareness and appropriate use of non-occupational post-exposure prophylaxis (nPEP) for HIV prevention following a multi-modal communication strategy. AB - BACKGROUND: In May 2005, the Western Australian Department of Health (WA Health) developed a communication strategy to improve the awareness and appropriate use of non-occupational post-exposure prophylaxis (nPEP) in WA. The communication strategy included the development of an nPEP information pamphlet, the establishment of a 24 hour nPEP phone line and the distribution of the WA Health nPEP guidelines to health professionals. The communication strategy was aimed at gay men, people in sero-discordant relationships, people living with HIV, injecting drug users and health care providers with patients from these populations. This evaluation aimed to assess the awareness and appropriate use of nPEP in WA before and after the commencement of the nPEP communication strategy. METHODS: A program logic method was used to identify the immediate (short-term) and ultimate (long-term) outcomes of the communication strategy. The achievement of these outcomes was evaluated using data from website statistics, a survey of 'sexuality sensitive' doctors, statistics published in Perth Gay Community Periodic Surveys (PGCPS) and data from the WA nPEP database. A chi(2) test for trend was conducted to identify any significant changes in the ultimate outcome indicators pre- and post-strategy. RESULTS: nPEP awareness among gay men in the PGCPS initially increased from 17.2% in 2002 to 54.9% in 2008, then decreased to 39.9% in 2010. After the commencement of the communication strategy, the proportion of nPEP prescriptions meeting the eligibility criteria for nPEP significantly increased (61.2% in 2002-2005 to 90.0% in 2008-2010 (p < .001)). The proportion of nPEP recipients who completed the prescribed course of nPEP (46.6% in 2002-2005 to 66.9% in 2008-2010 (p = .003)) and the proportion who received a post-nPEP HIV test three to four months after the first visit for nPEP (38.8% in 2002-2005 to 51.9% in 2008-2010 (p = .023)) also increased. CONCLUSIONS: Since the introduction of the nPEP communication strategy, the delivery and appropriate use of nPEP have significantly improved in WA. In the 2008-2010 period, an improvement in HIV testing of nPEP recipients at three month follow-up was reported for the first time in WA. However, there is a need for ongoing activities to raise nPEP awareness among gay men. PMID- 23095457 TI - Tuning the magnetic anisotropy of Co-Ni nanowires: comparison between single nanowires and nanowire arrays in hard-anodic aluminum oxide membranes. AB - Co(x)Ni(1-x) alloy nanowires with varying Co content (0 <= x <= 0.95), having a diameter of 130 nm and length of around 20 MUm, are synthesized by template assisted electrodeposition into the nanopores of SiO(2) conformal coated hard anodic aluminum oxide membranes. The magneto-structural properties of both single isolated nanowires and hexagonally ordered nanowire arrays of Co-Ni alloys are systematically studied by means of magneto-optical Kerr effect magnetometry and vibrating sample magnetometry, respectively, allowing us to compare different alloy compositions and to distinguish between the magnetostatic and magnetocrystalline contributions to the effective magnetic anisotropy for each system. The excellent tunable soft magnetic properties and magnetic bistability exhibited by low Co content Co-Ni nanowires indicate that they might become the material of choice for the development of nanostructured magnetic systems and devices as an alternative to Fe-Ni alloy based systems, being chemically more robust. Furthermore, Co contents higher than 51 at.% allow us to modify the magnetic behavior of Co-rich nanowires by developing well controlled magnetocrystalline anisotropy, which is desirable for data storage applications. PMID- 23095458 TI - Comparison of superoxide dismutase, glutathione peroxidase and adenosine deaminase activities between respiratory and nocturnal subtypes of patients with panic disorder. AB - OBJECTIVE: There is mounting evidence indicating that oxidative and inflammatory processes may have an important role in the pathogenesis of panic disorder (PD). PD is a heterogeneous disease, and panic attacks are divided according to the different symptom clusters as respiratory, nocturnal, non-fearful, cognitive, or vestibular subtypes. The aim of this study was to compare whole-blood and serum superoxide dismutase (SOD), glutathione peroxidase and adenosine deaminase activities in PD patients with/without nocturnal, respiratory subtypes and healthy subjects. METHODS: The study was conducted including 60 patients with PD and 30 healthy control subjects. The Panic Attack Symptom Checklist, Panic and Agoraphobia Scale, Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale were administered to the patients. Biochemical analyses were performed after all the blood samples were collected. RESULTS: We found that whole-blood SOD and glutathione peroxidase activities of patients were significantly lower and adenosine deaminase activities of patients were higher than those of healthy controls. There were no statistically significant differences between respiratory and nocturnal subtypes. In addition, there were no marked relationships between the duration of illness and panic-agoraphobia scores of patients with nocturnal subtypes. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale scores of patients with the nocturnal subtype were markedly higher than those of patients without the nocturnal subtype. CONCLUSION: The results suggest that oxidative and inflammatory processes may play a role in the pathophysiology of PD. These findings may support the idea that both nocturnal and respiratory subtypes of PD have different symptom clusters of the same disease. PMID- 23095459 TI - High prevalence of thyroid dysfunction in pregnant women. AB - BACKGROUND/AIM: Maternal thyroid dysfunction during pregnancy has been associated with adverse obstetric and neonatal outcomes. This prospective study evaluates the prevalence of these disorders in pregnant women. SUBJECTS AND METHODS: Serum levels of TSH, free T4 (fT4), and thyroperoxidase antibodies (TPO-Ab) were measured in 951 women at different gestational ages of pregnancy. Trimester specific reference ranges for TSH were used to classify pregnant women into five groups: 1) Overt hypothyroidism (OH); 2) Subclinical hypothyroidism (SCH); 3) Isolated hypothyroxinemia (IH); 4) Low TSH (isolated or associated with high fT4); and 5) Normal. A classification was made also according to the lower and upper ranges provided by the manufacturer for thyroid hormones. Pregnant women who were at a high risk of developing thyroid disease were identified. RESULTS: Altogether, 117 women (12.3%) had hypothyroidism and 25 (2.6%) had low TSH. The prevalence of both OH and SCH was higher in the high-risk group than in the low risk group, but 17.9% of women with hypothyroidism were classified at low-risk. A family history of thyroid disorders and TPO-Ab positivity increased the risk of SCH. Using non-pregnant reference range for TSH, 10.6% of women were misclassificated. CONCLUSIONS: The high prevalence of hypothyroidism observed in this study suggests that accurate thyroid screening with trimester specific reference ranges should be warranted, particularly in areas with mild to moderate iodine deficiencies. PMID- 23095460 TI - Long-term outcome of patients after a single interruption of antiretroviral therapy: a cohort study. AB - BACKGROUND: To describe the long term outcome of patients who interrupted highly active antiretroviral therapy (HAART) once, identify the variables associated with earlier need to re-start HAART, and the response when therapy was resumed. A retrospective observational cohort of 66 adult patients with HIV-1 infection who interrupted HAART with a CD4+cell count >= 350 cells/MUL and undetectable viral load (VL) was performed. The pre-established CD4+ cell count for restarting therapy was 300cells/MUL. Cox regression was used to analyse the variables associated with earlier HAART reinitiation. RESULTS: The median follow-up was 209 weeks (range, 64-395). Rates of HIV-related or possible HIV-related events were 0.37 (one case of acute retroviral syndrome) and 1.49 per 100 patient-years, respectively. Two patients died after re-starting therapy and having reached undetectable VL. Three patients suffered a sexually transmitted disease while off therapy. Fifty patients (76%) resumed therapy after a median of 97 weeks (range, 17-267). Age, a nadir of CD4+ <250 cells/MUL, and a mean VL during interruption of >10,000 copies/ml were independent predictors for earlier re-start. The intention-to-treat success rate of the first HAART resumed regimen was 85.4%. There were no differences by regimen used, nor between regimens that were the same as or different from the one that had been interrupted. CONCLUSIONS: Our data suggest highly active antiretroviral therapy may be interrupted in selected patients because in these patients, when the HAART is restarted, the viral and clinical response may be achieved. PMID- 23095461 TI - Does the variable-stiffness colonoscope makes colonoscopy easier? A meta-analysis of the efficacy of the variable stiffness colonoscope compared with the standard adult colonoscope. AB - BACKGROUND: The variable-stiffness colonoscope (VSC) appears to have advantages over the standard adult colonoscope (SAC), although data are conflicting. To provide a comprehensive up-to-date review, we conducted a meta-analysis to compare the efficacies of the VSC and SAC. METHODS: Electronic databases, including PubMed, EMBASE, the Cochrane library and the Science Citation Index, were searched to retrieve relevant trials. In addition, meeting abstracts and the reference lists of retrieved articles were reviewed for further relevant studies. RESULTS: Eight randomized controlled trials (RCTs), enrolling a total of 2033 patients, were included in the meta-analysis. There was no significant heterogeneity among these studies. The cecal intubation rate was higher with the use of VSC (RR = 1.03, 95% CI 1.01 to 1.06, 8 RCTs). The VSC was also associated with fewer position changes made during colonoscopy. Time to cecal intubation was similar with VSC and SAC (WMD -0.54, 95% CI -1.40 to 0.32) but shorter in subgroup analysis with the use of VSC (WMD = -1.36, 95% CI -2.29 to -0.43). Sedation dose used with the two types of instruments showed no evidence of differences either. For all trials, only patients were blinded because of the nature of the interventions. CONCLUSION: Use of the VSC significantly improved the cecal intubation rate and reduced ancillary maneuvers made during the procedure. Cecal intubation time was similar for the two colonoscope types over all trials, whereas a shortened time with the use of the adult VSC was seen in subgroup analysis. PMID- 23095464 TI - Relating the progeny production curve to the speed of an epidemic. AB - The dependence of the initial infection rate, r, on the basic reproductive number, R(0), and the temporal moments of the progeny production curve are examined. A solution to the linearized Kermack-McKendrick equation is presented and used to analyze a variety of theoretical models of pathogen reproduction. The solution yields a relation between r and the basic reproductive number, R(0); the mean time between pathogen generations, MU; and the standard deviation about this mean, sigma. A transformation using the dimensionless variables rMU and rsigma is introduced, which maps the solution onto a one-dimensional curve. An approximation for the value of r in terms of R(0) and the first four temporal moments of the reproductive curve is derived. This allows direct comparison of epidemics resulting from theoretical models with those generated using experimentally obtained reproduction curves. For epidemics characterized by a value of rMU < 5, the value of r is well determined (<2%) by this fourth-order expansion regardless of the functional form of the reproduction curve. PMID- 23095463 TI - New anticoagulants for treatment of venous thromboembolism. AB - Venous thromboembolism (VTE) is a major cause of morbidity and mortality and anticoagulation is the cornerstone of treatment. Although effective, traditional anticoagulants (i.e., heparins and vitamin K antagonists) have significant limitations and there are several unmet needs. Therefore, new drugs have been developed, including direct factor Xa inhibitors (e.g., rivaroxaban, apixaban and edoxaban) and thrombin inhibitors (e.g., dabigatran etexilate). The characteristics of these agents and the main results of published clinical studies dealing with VTE treatment are critically summarized in this article. PMID- 23095462 TI - Role of TRPC1 and TRPC3 channels in contraction and relaxation of mouse thoracic aorta. AB - BACKGROUND/AIMS: Canonical transient receptor potential (TRPC) channels modulate membrane potential and intracellular Ca(2+). We examined the role of TRPC1 and TRPC3 channels in vasocontraction and relaxation in mouse aorta. METHODS: Vasocontraction and relaxation of aorta from wild-type (WT), TRPC1 KO and TRPC3 knockout (KO) mice were measured for phenylephrine (Phe) and carbachol (CCh). Intracellular Ca(2+) was measured in primary aorta endothelial cells (EC) and whole cell K(+) current in freshly isolated smooth muscle cells (SMC). RESULTS AND CONCLUSION: TRPC1 KO aorta showed increased vasocontraction to Phe compared to WT and TRPC3 KO aorta due to diminished role of BK(Ca) channels. BK(Ca) mRNA (aorta) and whole cell current (SMC) were reduced versus WT. Contraction in WT aorta was increased to TRPC1 KO level by BK(Ca) channel inhibition. Relaxation to CCh was reduced in TRPC1 KO and TRPC3 KO aortas with concomitant reduction in EC Ca(2+) response. Pyr3 (TRPC3 blocker) reduced the Ca(2+) response to CCh in EC from WT, but not TRPC3 KO mice. In summary, TRPC1 attenuates receptor-mediated contraction through activation and/or expression of SMC BK(Ca) channels while TRPC3 does not contribute to receptor-mediated constriction. Both TRPC1 and TRPC3 participate in EC Ca(2+) influx and vasorelaxation of aorta. PMID- 23095465 TI - Strong genetic differentiation between North American and European populations of Phytophthora alni subsp. uniformis. AB - Alder decline caused by Phytophthora alni has been one of the most important diseases of natural ecosystems in Europe during the last 20 years. The emergence of P. alni subsp. alni -the pathogen responsible for the epidemic-is linked to an interspecific hybridization event between two parental species: P. alni subsp. multiformis and P. alni subsp. uniformis. One of the parental species, P. alni subsp. uniformis, has been isolated in several European countries and, recently, in North America. The objective of this work was to assess the level of genetic diversity, the population genetic structure, and the putative reproduction mode and mating system of P. alni subsp. uniformis. Five new polymorphic microsatellite markers were used to contrast both geographical populations. The study comprised 71 isolates of P. alni subsp. uniformis collected from eight European countries and 10 locations in North America. Our results revealed strong differences between continental populations (Fst = 0.88; Rst = 0.74), with no evidence for gene flow. European isolates showed extremely low genetic diversity compared with the North American collection. Selfing appears to be the predominant mating system in both continental collections. The results suggest that the European P. alni subsp. uniformis population is most likely alien and derives from the introduction of a few individuals, whereas the North American population probably is an indigenous population. PMID- 23095466 TI - Combined use of two biocontrol agents with different biocontrol mechanisms most likely results in less than expected efficacy in controlling foliar pathogens under fluctuating conditions: a modeling study. AB - Effective use of biocontrol agents (BCAs) is a potentially important component of sustainable agriculture; recently, there has been a trend for combined use of several BCAs, with an expectation of synergistic interactions among them. A previous numerical study suggested that, under homogenous conditions in which two BCAs occupied the same host tissue as the pathogen, combined use of two BCAs with different biocontrol mechanisms resulted, in most cases, in efficacies similar to using the more efficacious one alone; this result is consistent with published experimental results. The present study investigates whether combined use of a mycoparasitic and a competitive BCA leads to greater efficacy than that expected when the model is modified to allow for fluctuating temperature regimes and the effects of temperature on the pathogen and BCAs. Within the range of parameter values considered, combined use of two BCAs is shown to be less effective than that expected under the assumption of Bliss independence, and to result in a level of efficacy similar to that achieved by the more efficacious component used alone, indicating antagonistic interactions between the two BCAs. Nevertheless, combined use of two BCAs resulted in a slightly longer delay in epidemic development than did individual use of BCAs. Stochastic variability in simulated hourly temperatures did not result in a high level of variability in efficacy among replicates; nevertheless, the among-replicate variability appeared to be greater for the combined use of BCAs than for individual BCAs used alone. In contrast, there were greater effects of varying BCA-temperature relationships and application time (reflected in the temperature profile) on efficacy, suggesting the importance of characterizing the relationship between BCA activity and environmental conditions in future research. PMID- 23095467 TI - Purification of protein AP-toxin from Arthrinium phaeospermum causing blight in Bambusa pervariabilis * Dendrocalamopisis grandis and its metabolic effects on four bamboo varieties. AB - Bambusa pervariabilis * Dendrocalamopisis grandis blight is caused by a toxin produced by the fungus Arthrinium phaeospermum. In this study, a toxin fraction (P1-2-2) with an estimated molecular mass of 31 kDa was purified from a culture filtrate of this fungus by ammonium sulfate precipitation, Sephadex G-50 gel chromatography, Q Sepharose Fast Flow anion exchange resin, and Sephadex G-75 chromatography. The N-terminal amino acid sequence (i.e., H(2)N-Gln-Val-Arg-Asp Arg-Leu-Glu-Ser-Thr) determined by Edman degradation showed homology to known serine alkaline proteases. The purified protein was named AP-toxin. Effects of the purified protein toxin on total phenol, flavonoid, total nucleic acid, DNA, RNA, soluble protein, and soluble sugar content, as well as DNase and RNase activities and disease index, were analyzed in different bamboo varieties by the impregnation method. The toxin had a significant effect on each parameter tested. In addition, a significant correlation was observed among the metabolic index, treatment time, bamboo resistance, and disease index. These data suggest that AP toxin plays an important role in mediating the phytotoxic activities of A. phaeospermum. This study also indicates that metabolic indices could reflect the resistance indices of hybrid bamboo to blight. PMID- 23095468 TI - microRNAs in asthma: potential therapeutic targets. AB - PURPOSE OF REVIEW: Asthma is a global disease affecting millions of people. Current treatments are largely symptomatic and, although often effective, can be associated with various side effects. microRNAs (miRNAs/miRs) are regulatory RNAs that affect protein synthesis. They represent new therapeutic targets, and medicines that target specific miRNAs may have potential in the treatment of asthma. RECENT FINDINGS: There have been a number of studies in the field of miRNA that implicate specific miRNAs in the pathophysiology of asthma. For example, studies using mouse models have identified miRNAs that are altered in response to allergen challenge. Certain miRNAs that are involved in the regulation of interleukin-13 and the TH2 response, key components of the asthmatic response, have been shown to be amenable to modulation by premiRs and antimiRs. Other studies have identified miRNAs that are implicated in bronchial smooth muscle hyperresponsiveness and proliferation. Single-nucleotide polymorphisms in miRNA responsive elements within asthma susceptibility genes, and also in miRNAs themselves, can also contribute to the asthma phenotype. SUMMARY: Developing miRNA-based medicines to treat the pulmonary manifestations of asthma could yield therapeutics with new properties that have the potential to treat both the inflammation and hyperresponsivesness associated with this disease. PMID- 23095469 TI - Epidemic myalgia in adults associated with human parechovirus type 3 infection, Yamagata, Japan, 2008. AB - Human parechovirus has rarely been shown to cause clinical disease in adults. During June-August 2008, a total of 22 adults sought treatment at Yonezawa City Hospital in Yamagata, Japan, for muscle pain and weakness of all limbs; most also had fever and sore throat. All patients received a clinical diagnosis of epidemic myalgia; clinical laboratory findings suggested an acute inflammatory process. Laboratory confirmation of infection with human parechovirus type 3 (HPeV3) was made for 14 patients; we isolated HPeV3 from 7 patients, detected HPeV3 genome in 11, and observed serologic confirmation of infection in 11. Although HPeV3 is typically associated with disease in young children, our results suggest that this outbreak of myalgia among adults was associated with HPeV3 infection. Clinical consideration should be given to HPeV3 not only in young children but also in adults when an outbreak occurs in the community. PMID- 23095470 TI - Health surveillance of deployed military personnel occasionally leads to unexpected findings. AB - Post-traumatic stress disorder (PTSD) can be caused by life threatening illness, such as cancer and coronary events. The study by Forbes et al. made the unexpected finding that military personnel evacuation with medical illness have similar rates of PTSD to those evacuated with combat injuries. It may be that the illness acts as a nonspecific stressor that interacts with combat exposures to increase the risk of PTSD. Conversely, the inflammatory consequence of systemic illness may augment the effects to traumatic stress and facilitate the immunological abnormalities that are now being associated with PTSD and depression. The impact of the stress on cytokine systems and their role in the onset of PTSD demands further investigation. Military personnel evacuated due to physical illness require similar screening and monitoring for the risk of PTSD to those injured who are already known to be at high risk. PMID- 23095471 TI - Hierarchical Naive Bayes for genetic association studies. AB - BACKGROUND: Genome Wide Association Studies represent powerful approaches that aim at disentangling the genetic and molecular mechanisms underlying complex traits. The usual "one-SNP-at-the-time" testing strategy cannot capture the multi factorial nature of this kind of disorders. We propose a Hierarchical Naive Bayes classification model for taking into account associations in SNPs data characterized by Linkage Disequilibrium. Validation shows that our model reaches classification performances superior to those obtained by the standard Naive Bayes classifier for simulated and real datasets. METHODS: In the Hierarchical Naive Bayes implemented, the SNPs mapping to the same region of Linkage Disequilibrium are considered as "details" or "replicates" of the locus, each contributing to the overall effect of the region on the phenotype. A latent variable for each block, which models the "population" of correlated SNPs, can be then used to summarize the available information. The classification is thus performed relying on the latent variables conditional probability distributions and on the SNPs data available. RESULTS: The developed methodology has been tested on simulated datasets, each composed by 300 cases, 300 controls and a variable number of SNPs. Our approach has been also applied to two real datasets on the genetic bases of Type 1 Diabetes and Type 2 Diabetes generated by the Wellcome Trust Case Control Consortium. CONCLUSIONS: The approach proposed in this paper, called Hierarchical Naive Bayes, allows dealing with classification of examples for which genetic information of structurally correlated SNPs are available. It improves the Naive Bayes performances by properly handling the within-loci variability. PMID- 23095472 TI - Clinical Bioinformatics: challenges and opportunities. AB - BACKGROUND: Network Tools and Applications in Biology (NETTAB) Workshops are a series of meetings focused on the most promising and innovative ICT tools and to their usefulness in Bioinformatics. The NETTAB 2011 workshop, held in Pavia, Italy, in October 2011 was aimed at presenting some of the most relevant methods, tools and infrastructures that are nowadays available for Clinical Bioinformatics (CBI), the research field that deals with clinical applications of bioinformatics. METHODS: In this editorial, the viewpoints and opinions of three world CBI leaders, who have been invited to participate in a panel discussion of the NETTAB workshop on the next challenges and future opportunities of this field, are reported. These include the development of data warehouses and ICT infrastructures for data sharing, the definition of standards for sharing phenotypic data and the implementation of novel tools to implement efficient search computing solutions. RESULTS: Some of the most important design features of a CBI-ICT infrastructure are presented, including data warehousing, modularity and flexibility, open-source development, semantic interoperability, integrated search and retrieval of -omics information. CONCLUSIONS: Clinical Bioinformatics goals are ambitious. Many factors, including the availability of high-throughput "-omics" technologies and equipment, the widespread availability of clinical data warehouses and the noteworthy increase in data storage and computational power of the most recent ICT systems, justify research and efforts in this domain, which promises to be a crucial leveraging factor for biomedical research. PMID- 23095473 TI - Acute human immunodeficiency virus infection. AB - The clinical spectrum of acute human immunodeficiency virus (HIV) infection, a common clinical syndrome, may range from asymptomatic to a severe illness. The purpose of this review is to increase awareness of this syndrome, which is rarely suspected and often missed in clinical care settings, and provide an informative reference for primary care providers. The diagnosis of acute HIV infection is important for both patient care and public health concerns. In this article, the epidemiology, pathophysiology, clinical presentation, diagnosis and treatment of acute HIV infection are reviewed. PMID- 23095475 TI - Clarithromycin stops lung function decline in airway-centered interstitial fibrosis. AB - Airway-centered interstitial fibrosis (ACIF) is a distinct type of lung interstitial fibrosis characterized by lesions centered on the airways. Several cases reported in the literature showed little to no effect of corticosteroids and a high mortality rate in the absence of lung transplantation. No other efficient approach is described for the treatment of this type of fibrosis. We report for the first time the case of a 44-year-old patient diagnosed with ACIF on surgical lung biopsy and stabilized with clarithromycin after failure of systemic corticosteroids. We need to confirm this benefit in other patients to ascertain the anti-inflammatory effect of macrolides, which are far less harmful compared to corticosteroids or immunosuppressant drugs. PMID- 23095476 TI - The Hawaiian Freshwater Algal Database (HfwADB): a laboratory LIMS and online biodiversity resource. AB - BACKGROUND: Biodiversity databases serve the important role of highlighting species-level diversity from defined geographical regions. Databases that are specially designed to accommodate the types of data gathered during regional surveys are valuable in allowing full data access and display to researchers not directly involved with the project, while serving as a Laboratory Information Management System (LIMS). The Hawaiian Freshwater Algal Database, or HfwADB, was modified from the Hawaiian Algal Database to showcase non-marine algal specimens collected from the Hawaiian Archipelago by accommodating the additional level of organization required for samples including multiple species. DESCRIPTION: The Hawaiian Freshwater Algal Database is a comprehensive and searchable database containing photographs and micrographs of samples and collection sites, geo referenced collecting information, taxonomic data and standardized DNA sequence data. All data for individual samples are linked through unique 10-digit accession numbers ("Isolate Accession"), the first five of which correspond to the collection site ("Environmental Accession"). Users can search online for sample information by accession number, various levels of taxonomy, habitat or collection site. HfwADB is hosted at the University of Hawaii, and was made publicly accessible in October 2011. At the present time the database houses data for over 2,825 samples of non-marine algae from 1,786 collection sites from the Hawaiian Archipelago. These samples include cyanobacteria, red and green algae and diatoms, as well as lesser representation from some other algal lineages. CONCLUSIONS: HfwADB is a digital repository that acts as a Laboratory Information Management System for Hawaiian non-marine algal data. Users can interact with the repository through the web to view relevant habitat data (including geo referenced collection locations) and download images of collection sites, specimen photographs and micrographs, and DNA sequences. It is publicly available at http://algae.manoa.hawaii.edu/hfwadb/. PMID- 23095477 TI - [A woman with an ulcer of the leg]. AB - A 47-year-old woman with a history of ulcerative colitis and rheumatoid arthritis presented with a large ulcer with an erythematous halo of the right lower leg. The clinical course and the histopathological results were indicative of pyoderma gangrenosum. PMID- 23095478 TI - [A jaundiced patient with acute kidney injury]. AB - A 56-year-old man with obstructive icterus due to pancreas cysts presented with acute kidney insufficiency and bilirubin casts in the urinary sediment as a sign of bilirubin-associated acute kidney injury. PMID- 23095480 TI - [Acute obstructive colon carcinoma and liver metastases: how to treat?]. AB - BACKGROUND: The incidence of patients who present with acute obstructive colon carcinoma and synchronous liver metastases is increasing. CASE DESCRIPTION: Two men aged 70 and 71 both had acute obstructive colon carcinoma with synchronous liver metastases. Both patients underwent successful stent placement that solved the colonic obstruction. Five weeks later the first patient underwent an elective surgical procedure at which both the colon carcinoma and the liver metastases were resected. The second patient had more widespread metastases and first received chemotherapy. After six courses of chemotherapy the liver metastases became resectable and he underwent a two-stage liver resection with a left-sided hemicolectomy. CONCLUSION: These cases illustrate that placing a stent can be an alternative to an acute operation, and thus can save the patient from an emergency laparotomy with creation of a stoma that needs closure afterwards. In addition stent placement is a good starting point for an intended curative treatment trajectory, also in the setting of synchronous liver metastases accompanying the acute obstructive carcinoma. PMID- 23095481 TI - [Premature pubarche is not always an innocent phenomenon]. AB - Premature pubarche is defined as growth of pubic hair before the age of 8 years in girls and 9 years in boys. In most cases, it is caused by premature adrenarche, which is a premature increased synthesis of androgens in the adrenal gland and is considered to be relatively harmless. Premature pubarche can also result from severe pathology, which makes it necessary to find the cause of premature exposition to androgens. We present 3 girls, aged 5-8 years, with premature pubarche. They were eventually diagnosed with 'premature adrenarche', 'non-classical congenital adrenal hyperplasia' and 'adrenal adenoma', respectively. No treatment is indicated for premature adrenarche. The patient with non-classical congenital adrenal hyperplasia was treated with hydrocortisone; in the patient with an adrenal adenoma - a rare but severe condition - the adenoma was resected. The diagnoses were established based on progression of growth, bone age and serum levels of dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone and 17-hydroxyprogesterone. Fast progression of pubarche, accelerated growth velocity and advanced bone age should be considered alarm symptoms in patients with premature pubarche. PMID- 23095482 TI - [Mumps makes a comeback]. AB - After vaccination of Dutch children against mumps started in 1987 through the National Immunisation Programme the incidence of mumps decreased greatly. However, outbreaks of mumps have been occurring since the end of 2009, especially among students. We describe a vaccinated 20-year-old woman with uncomplicated mumps, a vaccinated 20-year-old student with mumps orchitis, and an unvaccinated 14-year-old boy who developed one-sided permanent deafness as a complication of mumps. Mumps outbreaks are likely caused by factors including incomplete protection following vaccination, waning of immunity, and intensive crowding. Mumps currently affects mainly people who were vaccinated more than 10 years ago. Outbreak response concentrates on surveillance, outbreak investigations, disease awareness, and provision of catch up vaccination to unvaccinated or incompletely vaccinated students. Adequate surveillance, important for building evidence for possible changes in mumps vaccination recommendations, depends on recognizing mumps and its complications. PMID- 23095483 TI - [The role of family members in healthcare: what mental healthcare can learn from other healthcare sectors]. AB - In mental health care, a good relationship between healthcare professionals and family members of the patient is frustrated by the strong emphasis on patient autonomy. A comparison with other healthcare sectors (oncology and nursing home care) shows that this need not be the case. An improved relationship between healthcare professionals and family members is important for all parties involved; healthcare professionals can use the knowledge of family members, family members are better equipped to perform their care tasks, and patients can receive better care since formal and informal care are better aligned to each other. PMID- 23095484 TI - [Iron-deficiency anaemia in patients in their 80s]. AB - Iron-deficiency anaemia in very old patients is a frequent finding; this often poses a diagnostic dilemma for the physician. For example, should additional testing take place? And if so, what kind of tests? Is prescribing iron supplement therapy and adopting an expectative course sufficient? The two cases in this article illustrate different treatment strategies. If doubts about which strategy to choose arise, it is recommended that iron first be supplied and the effect of this treatment checked after three weeks. The haemoglobin level should have risen at least 0.7 mmol/l. If there has been no effect, supplemental (endoscopic) examinations may be considered, provided they meet a therapeutic goal. PMID- 23095485 TI - [Role of metformin in diabetes treatment--is metformin falling from grace?]. AB - Two recent meta-analyses focused on the risk-benefit ratio of metformin in the treatment of type 2 diabetes mellitus. Both studies conclude that the risk benefit ratio of metformin monotherapy or combined with insulin is uncertain. In our opinion, the interpretation of the known literature in these meta-analyses could be flawed. To ascertain the effects of metformin on cardiovascular end points, a follow-up period of at least 8 years proved necessary. However, these meta-analyses included a number of studies with a limited follow-up period, thus impairing the possibility to make a proper comparison of the long-term effects of metformin. In addition, one meta-analysis based the weight of included studies on the number of events in all studies, including two safety studies, as opposed to the number of studied patients. PMID- 23095486 TI - Tissue damage in kidney, adrenal glands and diaphragm following extracorporeal shock wave lithotripsy. AB - This study was designed to investigate whether exposure to short-term extracorporeal shock wave lithotripsy (ESWL) produces histologic changes or induces apoptosis in the kidney, adrenal glands or diaphragm muscle in rats. The effect of shock waves on the kidney of male Wistar rats (n = 12) was investigated in an experimental setting using a special ESWL device. Animals were killed at 72 h after the last ESWL, and the tissues were stained with an in situ Cell Death Detection Kit, Fluorescein. Microscopic examination was performed by fluorescent microscopy. Apoptotic cell deaths in the renal tissue were not observed in the control group under fluorescent microscopy. In the ESWL group, local apoptotic changes were observed in the kidney in the area where the shock wave was focused. The apoptotic cell deaths observed in the adrenal gland of the control group were similar to those observed in the ESWL groups, and apoptosis was occasionally observed around the capsular structure. Apoptotic cell deaths in the diaphragm muscle were infrequently observed in the control group. Apoptosis in the ESWL group was limited to the mesothelial cells. This study demonstrated that serious kidney, adrenal gland and diaphragm muscles damage occurred following ESWL, which necessitated the removal of the organ in the rat model. It is recognized that the ESWL complications related to the kidney, adrenal gland and diaphragm muscles are rare and may be managed conservatively. PMID- 23095487 TI - Melatonin attenuates oxidative stress, liver damage and hepatocyte apoptosis after bile-duct ligation in rats. AB - The goal of this study was to evaluate the possible protective effects of melatonin against cholestatic oxidative stress, liver damage and hepatocyte apoptosis in the common rats with bile duct ligation (BDL). A total of 24 male Wistar albino rats were divided into three groups: control, BDL and BDL + received melatonin; each group contains eight animals. Melatonin-treated BDL rats received daily melatonin 100 mg/kg/day via intraperitoneal injection. The application of BDL clearly increased the malondialdehyde (MDA) levels and decreased the superoxide dismutase (SOD) and glutathione (GSH) activities. Melatonin treatment significantly decreased the elevated tissue MDA levels and increased the reduced SOD and GSH enzyme levels in the tissues. The changes demonstrate that the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, mononuclear cells and neutrophil infiltration into the widened portal areas as observed in the BDL group. The data indicate that melatonin attenuates BDL-induced cholestatic liver injury, bile duct proliferation and fibrosis. The alpha-smooth muscle actin (alpha-SMA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the BDL were observed to be reduced with the melatonin treatment. These results suggest that administration of melatonin is a potentially beneficial agent to reduce liver damage in BDL by decreasing oxidative stress. PMID- 23095488 TI - Antioxidant activity via DPPH, gram-positive and gram-negative antimicrobial potential in edible mushrooms. AB - Edible mushrooms (EMs) are nutritionally rich source of proteins and essential amino acids. In the present study, the antioxidant activity via 1,1-diphenyl-2 picrylhydrazyl (DPPH) and antimicrobial potential in EMs (Pleurotus ostreatus, Morchella esculenta, P. ostreatus (Black), P. ostreatus (Yellow) and Pleurotus sajor-caju) were investigated. The DPPH radical scavenging activity revealed that the significantly higher activity (66.47%) was observed in Morchella esculenta at a maximum concentration. Similarly, the dose-dependent concentrations (200, 400, 600, 800 and 1000 ug) were also used for other four EMs. Pleurotus ostreatus exhibited 36.13% activity, P. ostreatus (Black (B)) exhibited 30.64%, P. ostreatus (Yellow (Y)) exhibited 40.75% and Pleurotus sajor-caju exhibited 47.39% activity at higher concentrations. Furthermore, the antimicrobial potential were investigated for its toxicity against gram-negative bacterial strains (Escherichia coli, Pseudomonas aeroginosa, Salmonella typhi, Klebsiella pneumonia, Erwinia carotovora and Agrobacterium tumifaciens), gram-positive bacterial strains (Bacillus subtilis, Bacillus atrophaeus and Staphylococcus aureus) and a fungal strain (Candida albicans) in comparison with standard antibiotics. Antimicrobial screening revealed that the ethanol extract of P. ostreatus was active against all microorganism tested except E. coli. Maximum zone of inhibition (13 mm) was observed against fungus and A. tumifaciens. P. sajor-caju showed best activities (12.5 mm) against B. subtilis, B. atrophaeus and K. pneumonia. P. ostreatus (Y) showed best activities against P. aeroginosa (21.83 mm), B. atrophaeus (20 mm) and C. albicans (21 mm). P. ostreatus (B) exhibited best activities against C. albicans (16 mm) and slightly lower activities against all other microbes except S. typhi. M. esculenta possess maximum activities in terms of inhibition zone against all microorganisms tested except S. typhi. PMID- 23095489 TI - The impact of high-frequency repetitive transcranial magnetic stimulation on fine motor functions in medication-resistant major depression. AB - OBJECTIVES: Although high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the left dorsolateral prefrontal cortex (DLPFC) has been reported to improve mood symptoms in major depressive disorder (MDD), research on its impact on psychomotor symptoms is scarce. This study assessed the psychomotor effects of 1 and 10 sessions, respectively, of HF-rTMS over the left DLPFC. METHODS: Ten HF-rTMS sessions were applied in 21 medication-free MDD patients over a 2-week period. At the beginning, one placebo (sham)-controlled rTMS session was also applied in a cross-over, single-blind design. Psychomotor variables were digitally recorded during completion of a Fitts' task, at baseline, after the first and second real/sham session and at the end point. RESULTS: The total 10-session treatment period resulted in a decrease of depression severity. One HF-rTMS session resulted in improvements on the Fitts' task, without a difference between active and sham stimulation, however. No further improvements occurred from session 2 to session 10. CONCLUSIONS: No evidence was provided to link the observed psychomotor improvements to HF-rTMS stimulation, as a practice effect could have impacted the significant psychomotor outcomes. PMID- 23095490 TI - Dynamics of carbon nanotube alignment by electric fields. AB - The dynamics of multiwall carbon nanotube (MWCNT) alignment inside viscous media using electric fields is investigated. Electrical current measurements were performed in situ during the application of an electric field to liquid solutions of deionized water or dissolved polymer containing MWCNTs. The variation of electrical current over time was associated to the dynamics of the MWCNT network formation. The influence of the electric field magnitude and frequency on the MWCNT network formation was studied. MWCNT migration towards the negative electrode was observed when a direct current electric field was applied, whereas formation of an aligned MWCNT network was achieved for an alternating current electric field. The increase of the electric field frequency promotes a faster formation of an aligned MWCNT network and thinner MWCNT bundles. A higher viscosity of the liquid medium yields slower MWCNT alignment evidenced by a slower change of electrical current through the viscous system. An analytical model based on the dielectrophoresis-induced torque, which considers the viscosity of the medium, is also proposed to explain the dynamics of MWCNT alignment. Furthermore, aligned MWCNT/polysulfone solid composites were fabricated and electrically characterized. The solid composites presented anisotropic electrical conductivity, which was more evident for low MWCNT concentrations (0.1-0.2 wt%). PMID- 23095491 TI - Analysis of the clinical relevance of antimitochondrial antibodies to the beta- and gamma-subunits of the F1F0-ATPase in patients with primary biliary cirrhosis. AB - BACKGROUND: In a recent study we showed that in patients with primary biliary cirrhosis (PBC) being positive or negative for anti-M2 antibodies reacting with the 2-oxoacid-dehydrogenase complex (ODC) also antibodies to the beta- and gamma subunits of F1F0-ATPase (anti-beta, anti-gamma) occur. This is a mitochondrial enzyme but parts are also expressed on plasma membranes of endothelial cells. Here we wanted to analyse in more detail their clinical relevance. METHODS: Fifty nine untreated and histologically defined PBC patients who had been followed for at least five years were included into the study (51 anti-M2 positive, 8 anti-M2 negative). Twenty-three of them were treated in the follow up with ursodeoxycholic acid (UDCA), eight received during a trial methotrexate (MTX). In 13 patients orthotopic liver transplantation (OLT) had to be performed. Serum samples before and during therapy were available. Patients were analysed with respect to laboratory parameters, disease activity and histological stages.Patients' sera were tested by ELISA for IgG- and IgM-antibodies against the beta- and gamma-subunits which had been recombinant expressed in E.coli and highly purified by electro-elution from SDS-gels after electrophoresis. RESULTS: Fifty-nine percent of the anti-M2 positive and 50% of the anti-M2 negative PBC patients had anti-beta- and/or anti-gamma-antibodies. There were no differences between anti-beta- and/or anti-gamma-antibody positive or negative patients with respect to biochemical parameters, immunoglobulins, histological stages or disease activity. Antibody reactivity significantly decreased during UDCA and MTX treatment and also after OLT. CONCLUSIONS: Antibodies to the beta- and gamma subunits of F1F0-ATPase occur in anti-M2 positive and -negative PBC but do not have any relevance with respect to clinical activity or prognosis. However, in contrast to the anti-M2 antibodies they decrease during UDCA and immunosuppressive therapy. PMID- 23095492 TI - Good knowledge about hypertension is linked to better control of hypertension; a multicentre cross sectional study in Karachi, Pakistan. AB - BACKGROUND: According to the National Health survey only 3% of the population has controlled hypertension. This study was designed to elucidate the knowledge about hypertension in hypertensive patients at three tertiary care centers in Karachi. Secondly we sought to compare the knowledge of those with uncontrolled hypertension and controlled hypertension. METHODS: It was a cross-sectional study conducted at The Aga Khan University hospital (AKUH), Ziauddin Hospital (ZH) and Civil hospital, Karachi (CHK. All diagnosed Hypertensive patients (both inpatients and outpatients) coming to a tertiary care hospital in Pakistan aged > 18 years were included. Patients were categorized into 2 groups: controlled and uncontrolled hypertension based on their initial BP readings on presentation Uncontrolled Hypertension was defined as average BP >= 140/90 mm Hg in patients on treatment. Controlled Hypertension (HTN) was defined as average BP <140/90 mm Hg in patients on treatment. Standardized methods were used to record BP in the sitting position. Knowledge was recorded as a15 item question. Primary outcome was knowledge about hypertension. RESULTS: A total of 650 participants were approached and consented 447 were found eligible. 284(63.5%) were from Aga Khan University, 101(22.6) from Dow University of health sciences and 62(13.9) were from Ziauddin University. Mean (SD) age of participants was 57.7(12) years, 50.1(224) were men. Controlled hypertension was present in 323(72.3) and uncontrolled hypertension was present in 124(27.4). The total mean (SD) Knowledge score was 20.97(4.93) out of a maximum score of 38. On comparison of questions related to knowledge between uncontrolled and controlled hypertension, there was statistically significant different in; meaning of hypertension (p <0.001), target SBP(p0.001), target DBP(p 0.001), importance of SBP versus DBP, improvement of health with lowering of blood pressure (p 0.002), high blood pressure being asymptomatic (p <0.001), changing lifestyle improves blood pressure(p 0.003),hypertension being a lifelong disease (<0.001), lifelong treatment with antihypertensives(<0.001) and high blood pressure being part of aging(<0.001). On comparison of knowledge as a composite score between uncontrolled and controlled hypertensive; Mean (SD) score was 21.85(4.74) v18.67 (4.70) (p value: < 0.001). On multivariate analysis; gender beta (95% CI) 1.67(0.75, 2.59) p <0.001, uncontrolled blood pressure; -2.70(-3.76,-1.67) p <0.001, Sindhi ethnicity; -1.79(-3.25,-3.27) p 0.01 and pukhtoon ethnicity; 2.72(-4.13,-1.32) p <0.001 were significantly associated with knowledge score. CONCLUSION: Knowledge about hypertension in hypertensive patients is not adequate and is alarmingly poor in patients with uncontrolled hypertension. More emphasis needs to be made on target blood pressure and need for taking antihypertensives for life to patients by physicians. PMID- 23095495 TI - Temperament and childhood obesity risk: a review of the literature. AB - OBJECTIVE: Temperament, or individual differences in behavioral styles, could explain why many individuals are susceptible to childhood obesity in the current environment while others are not. The objective of this article is to review the growing body of literature linking weight outcomes with 2 aspects of temperament, negativity and self-regulation. METHOD: Studies conducted through 2011 and assessing at least 1 weight outcome and 1 aspect of early negativity or self regulation in normally developing infants and young children were included. RESULTS: Most studies suggest that greater levels of negative reactivity in early life may increase the risk of obesity, and greater self-regulation may be protective. While temperaments of individuals tend to be relatively stable over time, there is evidence that links between early temperament and weight outcomes are malleable. CONCLUSIONS: Relationships between temperament and weight outcomes are becoming well established. More research is needed to confirm the longitudinal nature of these relationships and to shed light on the mediators and moderators of these relationships and their implications for obesity interventions. PMID- 23095493 TI - FBXW7 is involved in Aurora B degradation. AB - FBXW7, a component of E3 ubiquitin ligase, plays an important role in mitotic checkpoint, but its role remains unclear. Aurora B is a mitotic checkpoint kinase that plays a pivotal role in mitosis by ensuring correct chromosome segregation and normal progression through mitosis. Whether Aurora B and FBXW7 are coordinately regulated during mitosis is not known. Here, we show that FBXW7 is a negative regulator for Aurora B. Ectopic expression of FBXW7 can suppress the expression of Aurora B. Accordingly, FBXW7 deficiency leads to Aurora B elevation. Mechanistic studies show that all FBXW7 isoforms are negative regulators of Aurora B expression through ubiquitination-mediated protein degradation. Aurora B interacts with R465 and R505 residues of WD 40 domain of FBXW7. Significantly, inverse correlation between FBXW7 and Aurora B elevation is translated into the deregulation of mitosis. FBWX7 expression mitigates Aurora B mediated cell growth and mitotic deregulation. In addition, FBXW7 reduces the percentage of multinucleated cells caused by Aurora B overexpression. These data suggest that FBXW7 is an important negative regulator of Aurora B, and that the loss or mutation of FBXW7 as seen in many types of cancer could lead to an abnormal elevation of Aurora B and result in deregulated mitosis, which accelerates cancer cell growth. PMID- 23095496 TI - Determinants of appointment absenteeism at an outpatient pediatric autism clinic. AB - OBJECTIVE: Two widely discussed yet highly understudied factors that obstruct timely diagnosis and intervention among children with an autism spectrum disorder (ASD) are missed scheduled appointments and wait time for outpatient services. Research surrounding outpatient appointment no-show and cancellation rates as well as predictors of such would shed light on the barriers to community-based clinical care. METHODS: In this study, data from 8049 children and adolescents (mean = 6.97 years, SD = 4.81) with scheduled appointments at a multidisciplinary pediatric outpatient autism center were examined. A total of 43,504 appointments, scheduled between June 2003 and April 2012, were analyzed. Random and fixed effects multinomial logistic regression models were employed to explore the child , clinician-, and appointment-related determinants of no-show and cancellation for initial and follow-up appointments. RESULTS: A no-show rate of 9% and 15%, and a cancellation rate of 11% and 10% was observed for initial (n = 8049) and follow-up (n = 35,455) appointments, respectively. Different predictors were found for both no-show and cancellation at the initial and follow-up appointments. In the multivariate analyses, the most consistent and robust predictors of no-show were African-American child race, medical assistance, provider type and appointment type, and evening appointments. For cancellation, these included increased wait time and provider type. Importantly, cancellation and no-show at the initial evaluation increased the risk for these same outcomes at follow-up. CONCLUSION: As ASD prevalence figures continue to increase in the United States, findings surrounding wait time, appointment absenteeism, and clinical models of care are important to improving public health. PMID- 23095497 TI - Estradiol modulates tumor necrosis factor-induced endothelial inflammation: role of tumor necrosis factor receptor 2. AB - The sex hormone estradiol (E(2)) appears to mediate both anti-atherogenic and pro inflammatory effects in premenopausal women, suggesting a complex immunomodulatory role. Tumor necrosis factor (TNF) is a key pro-inflammatory cytokine involved in the pathogenesis of atherosclerosis and other inflammatory diseases. Alterations at the TNF receptors (TNFRs) and their downstream signaling/transcriptional pathways can affect inflammatory responses. Given this background, we hypothesized that chronic E(2) exposure would alter endothelial inflammatory response involving modulation at the levels of TNFRs and signaling pathways. HUVECs were used as the model system. Pre-treatment with E(2) did not significantly alter TNF-induced upregulation of pro-inflammatory molecules ICAM-1 (3-6 times) and VCAM-1 (5-7 times). However, pharmacological inhibition of transcriptional pathways suggested a partial shift from NF-KB (from 97 to 64%) towards the JNK/AP-1 pathway in ICAM-1 upregulation on E(2) treatment. In contrast, VCAM-1 expression remained NF-KB dependent in both control (~96%) and E(2) treated (~85%) cells. The pro-inflammatory TNF effects were mediated by TNFR1. Interestingly, E(2) pre-treatment increased TNFR2 levels in these cells. Concomitant TNFR2 activation (but not TNFR1 activation alone) led to the shift towards JNK/AP-1-mediated ICAM-1 upregulation in E(2)-treated cells, suggesting the effects of chronic E(2) to be dependent on TNFR2 signaling. PMID- 23095498 TI - The human "magnesome": detecting magnesium binding sites on human proteins. AB - BACKGROUND: Magnesium research is increasing in molecular medicine due to the relevance of this ion in several important biological processes and associated molecular pathogeneses. It is still difficult to predict from the protein covalent structure whether a human chain is or not involved in magnesium binding. This is mainly due to little information on the structural characteristics of magnesium binding sites in proteins and protein complexes. Magnesium binding features, differently from those of other divalent cations such as calcium and zinc, are elusive. Here we address a question that is relevant in protein annotation: how many human proteins can bind Mg2+? Our analysis is performed taking advantage of the recently implemented Bologna Annotation Resource (BAR PLUS), a non hierarchical clustering method that relies on the pair wise sequence comparison of about 14 millions proteins from over 300.000 species and their grouping into clusters where annotation can safely be inherited after statistical validation. RESULTS: After cluster assignment of the latest version of the human proteome, the total number of human proteins for which we can assign putative Mg binding sites is 3,751. Among these proteins, 2,688 inherit annotation directly from human templates and 1,063 inherit annotation from templates of other organisms. Protein structures are highly conserved inside a given cluster. Transfer of structural properties is possible after alignment of a given sequence with the protein structures that characterise a given cluster as obtained with a Hidden Markov Model (HMM) based procedure. Interestingly a set of 370 human sequences inherit Mg2+ binding sites from templates sharing less than 30% sequence identity with the template. CONCLUSION: We describe and deliver the "human magnesome", a set of proteins of the human proteome that inherit putative binding of magnesium ions. With our BAR-hMG, 251 clusters including 1,341 magnesium binding protein structures corresponding to 387 sequences are sufficient to annotate some 13,689 residues in 3,751 human sequences as "magnesium binding". Protein structures act therefore as three dimensional seeds for structural and functional annotation of human sequences. The data base collects specifically all the human proteins that can be annotated according to our procedure as "magnesium binding", the corresponding structures and BAR+ clusters from where they derive the annotation (http://bar.biocomp.unibo.it/mg). PMID- 23095499 TI - Central corneal thickness measurements with different imaging devices and ultrasound pachymetry. AB - PURPOSE: The aim of this study was to compare 4 methods of central corneal thickness (CCT) measurements in terms of their agreement, repeatability, and measurement time. METHODS: CCT was measured in 184 eyes of 92 healthy subjects by the same examiner. The methods used were as follows: noncontact specular microscopy (SM; Topcon SP-3000P; Topcon Corporation, Tokyo, Japan), Pentacam rotating Scheimpflug photography system (Oculus Inc, Wetzlar, Germany), optical low-coherence reflectometry (OLCR; LenStar LS900; Haag-Streit AG, Koeniz, Switzerland), and ultrasound pachymetry (UP; PachPen; Accutome Inc, Malvern, PA). The duration for each examination was measured by an independent observer. RESULTS: The mean age (+/-SD) of the subjects was 54.3 (+/- 15.3) years. The mean CCTs (+/- SD) for SM, Pentacam, OLCR, and UP were 507.8 (+/- 30.2), 538.4 (+/- 31.7), 531.8 (+/- 31.4), and 528.3 (+/- 32.9) MUm, respectively. The Bland-Altman plots showed closest agreement for OLCR-UP, followed by OLCR-Pentacam and Pentacam-UP. SM had the poorest agreement with the other methods. CCTs measured by SM were on average 20 to 30 MUm thinner than those of the other methods. The coefficient of repeatability for SM, Pentacam, OLCR, and UP were 3.14%, 4.23%, 1.51%, and 3.46%, respectively. The mean measurement times (+/- SD) were 13.5 (+/ 5.7), 45.7 (+/- 12.3), 18.5 (+/- 7.1), and 5.6 (+/- 1.0) seconds, respectively. CONCLUSIONS: CCT measurements between OLCR-UP and OLCR-Pentacam are comparable and can be used interchangeably in clinical practice. However, SM underestimates CCT compared with the other methods, whereas Pentacam was found to be the least repeatable and took the longest time. PMID- 23095500 TI - Evaluation of tear osmolarity in non-Sjogren and Sjogren Syndrome dry eye patients with the TearLab system. PMID- 23095501 TI - Angiogenesis inhibition: quo vadis? PMID- 23095502 TI - Imputation reliability on DNA biallelic markers for drug metabolism studies. AB - BACKGROUND: Imputation is a statistical process used to predict genotypes of loci not directly assayed in a sample of individuals. Our goal is to measure the performance of imputation in predicting the genotype of the best known gene polymorphisms involved in drug metabolism using a common SNP array genotyping platform generally exploited in genome wide association studies. METHODS: Thirty nine (39) individuals were genotyped with both Affymetrix Genome Wide Human SNP 6.0 (AFFY) and Affymetrix DMET Plus (DMET) platforms. AFFY and DMET contain nearly 900000 and 1931 markers respectively. We used a 1000 Genomes Pilot + HapMap 3 reference panel. Imputation was performed using the computer program Impute, version 2. SNPs contained in DMET, but not imputed, were analysed studying markers around their chromosome regions. The efficacy of the imputation was measured evaluating the number of successfully imputed SNPs (SSNPs). RESULTS: The imputation predicted the genotypes of 654 SNPs not present in the AFFY array, but contained in the DMET array. Approximately 1000 SNPs were not annotated in the reference panel and therefore they could not be directly imputed. After testing three different imputed genotype calling threshold (IGCT), we observed that imputation performs at its best for IGCT value equal to 50%, with rate of SSNPs (MAF > 0.05) equal to 85%. CONCLUSIONS: Most of the genes involved in drug metabolism can be imputed with high efficacy using standard genome-wide genotyping platforms and imputing procedures. PMID- 23095503 TI - Desmoplastic malignant melanoma: a study of ten cases and status of BRAF mutation. AB - BACKGROUND: Desmoplastic malignant melanoma (DM) is a rare variant of melanoma. BRAF gene mutations have been poorly explored in this entity. OBJECTIVE: To detect BRAF gene mutation in a series of DM. METHODS: This is a single-center retrospective study of ten patients with DM, with a biomolecular analysis of BRAF mutation. RESULTS: The male:female ratio was 2.3:1, with a mean patient age of 66.5 years. Melanoma arose in the head and neck region in 3 cases. The mean tumor thickness was 7.97 mm, Clark level was IV or V in all cases. Six melanomas were of the pure DM variant. Three patients had at least one local recurrence, two had regional node metastases, and two experienced systemic metastases which they died of (average follow-up 34.1 months). A V600E BRAF mutation was detected in only one patient. CONCLUSION: BRAF mutation seems to be a rare event in DM contrary to other melanoma variants. PMID- 23095504 TI - Tumor islands in resected early-stage lung adenocarcinomas are associated with unique clinicopathologic and molecular characteristics and worse prognosis. AB - Tumor islands-large collections of tumor cells isolated within alveolar spaces can be seen in lung adenocarcinomas. Recently we observed by 3-dimensional reconstruction that these structures were connected with each other and with the main tumor in different tissue planes, raising the possibility of tumor islands being a means of extension. However, the clinical and prognostic significance of tumor islands remains unknown. In this study, we compared clinicopathologic and molecular characteristics and prognosis of stages I to II lung adenocarcinomas with tumor islands (n=58) and those without (n=203). Lung adenocarcinomas with tumor islands were more likely to occur in smokers, exhibit higher nuclear grade and a solid or micropapillary pattern of growth, and harbor KRAS mutations. In contrast, lung adenocarcinomas without tumor islands were more likely to present as minimally invasive adenocarcinoma, show a lepidic pattern of growth, and harbor EGFR mutations. Although there was no difference in stage, the prognosis of lung adenocarcinomas with tumor islands was significantly worse than those without. The 5-year recurrence-free survival for patients with tumor islands and those without was 44.6% and 74.4%, respectively (log rank P=0.010). The survival difference remained significant (P <0.020) by multivariate analysis, and the presence of tumor islands was associated with almost 2-fold increase in the risk of recurrence. Even in the stage IA cohort, more than half of the patients with tumor islands experienced recurrence within 5 years. Thus, aggressive surveillance and/or further intervention may be indicated for patients whose tumors exhibit tumor islands. PMID- 23095505 TI - CD137 ligand is expressed in primary and secondary lymphoid follicles and in B cell lymphomas: diagnostic and therapeutic implications. AB - CD137 ligand (4-1BB ligand, TNFSF9, CD137L) is a member of the tumor necrosis factor family whose binding to its receptor, CD137 (4-1BB, TNFRSF9), mediates costimulatory and prosurvival signals necessary for T-cell activation and regulation of humoral immune responses. Recent studies have shown that anti-CD137 immunotherapy has promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. Here, we define the tissue expression profile of CD137L, which has not been previously explored. We characterized the expression of CD137L in normal and neoplastic human hematopoietic and nonhematopoietic tissue and found that CD137L is preferentially expressed in B cells of the primary follicles, mantle zones of the secondary follicles, germinal centers, and in normal endothelial cells. Double immunofluorescence labeling in tissue sections and flow cytometry analysis further showed that CD137L is a potential new marker of memory B cells. Evaluation of over 700 human hematopoietic tumors revealed that the majority of B-cell lymphomas expressed CD137L, which include mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In contrast, CD137L expression was lacking in Hodgkin lymphoma and T-cell lymphoma. Our findings suggest that CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas and raise the possibility that its expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and other malignancies. PMID- 23095506 TI - Partial sampling of radical prostatectomy specimens: detection of positive margins and extraprostatic extension. AB - Currently there is no global agreement as to how extensively a radical prostatectomy specimen should be sectioned and histologically examined. We analyzed the ability of different methods of partial sampling in detecting positive margin (PM) and extraprostatic extension (EPE)-2 pathologic features of prostate cancer that are most easily missed by partial sampling of the prostate. Radical prostatectomy specimens from 617 patients treated with open radical prostatectomy between 1992 and 2011 were analyzed. Examination of the entirely submitted prostate detected only PM in 370 (60%), only EPE in 100 (16%), and both in 147 (24%) specimens. We determined whether these pathologic features would have been diagnosed had the examination of the specimen been limited only to alternate sections (method 1), alternate sections representing the posterior aspect of the gland in addition to one of the mid-anterior aspects (method 2), and every section representing the posterior aspect of the gland in addition to one of the mid-anterior aspects, supplemented by the remaining ipsilateral anterior sections if a sizeable tumor is seen (method 3). Methods 1 and 2 missed 13% and 21% of PMs and 28% and 47% of EPEs, respectively. Method 3 demonstrated better results missing only 5% of PMs and 7% of EPEs. Partial sampling techniques missed slightly more PMs and EPEs in patients with low-risk to intermediate-risk prostate cancer, although even in high-risk cases none of the methods detected all of the studied aggressive pathologic features. PMID- 23095507 TI - Human papillomavirus-related carcinomas of the sinonasal tract. AB - High-risk human papillomavirus (HPV) is an established cause of head and neck carcinomas arising in the oropharynx. The presence of HPV has also been reported in some carcinomas arising in the sinonasal tract, but little is known about their overall incidence or their clinicopathologic profile. The surgical pathology archives of The Johns Hopkins Hospital were searched for all carcinomas arising in the sinonasal tract from 1995 to 2011, and tissue microarrays were constructed. p16 immunohistochemical analysis and DNA in situ hybridization for high-risk types of HPV were performed. Demographic and clinical outcome data were extracted from patient medical records. Of 161 sinonasal carcinomas, 34 (21%) were positive for high-risk HPV DNA, including type 16 (82%), type 31/33 (12%), and type 18 (6%). HPV-positive carcinomas consisted of 28 squamous cell carcinomas and variants (15 nonkeratinizing or partially keratinizing, 4 papillary, 5 adenosquamous, 4 basaloid), 1 small cell carcinoma, 1 sinonasal undifferentiated carcinoma, and 4 carcinomas that were difficult to classify but exhibited adenoid cystic carcinoma-like features. Immunohistochemistry for p16 was positive in 59/161 (37%) cases, and p16 expression strongly correlated with the presence of HPV DNA: 33 of 34 (97%) HPV-positive tumors exhibited high p16 expression, whereas only 26 of 127 (20%) HPV-negative tumors were p16 positive (P<0.0001). The HPV-related carcinomas occurred in 19 men and 15 women ranging in age from 33 to 87 years (mean, 54 y). A trend toward improved survival was observed in the HPV-positive group (hazard ratio=0.58, 95% confidence interval [0.26, 1.28]). The presence of high-risk HPV in 21% of sinonasal carcinomas confirms HPV as an important oncologic agent of carcinomas arising in the sinonasal tract. Although nonkeratinizing squamous cell carcinoma is the most common histologic type, there is a wide morphologic spectrum of HPV-related disease that includes a variant that resembles adenoid cystic carcinoma. The distinctiveness of these HPV-related carcinomas of the sinonasal tract with respect to risk factors, clinical behavior, and response to therapy remains to be clarified. PMID- 23095508 TI - Clear cell nodular hidradenoma involving the lymphatic system: a tumor of uncertain malignant potential or a novel example of "metastasizing" benign tumor? AB - Exceedingly rare cases of neoplasms with clear-cut histopathologic features of benignity can show locoregional or even distant spread. Such cases can become putative examples of "benign metastasis" when a completely favorable clinical outcome is documented after an adequately long follow-up. We report 8 cases of morphologically benign clear cell nodular hidradenoma (CCNH) with lymphatic involvement. In 5 cases the cutaneous tumor showed small foci of intravascular deposits of neoplastic cells; in 2 cases the cutaneous tumor presented with a synchronous tumor in a regional node; in 1 case a nodal location CCNH was found with no evidence of any primary in the skin. All the cases were treated with conservative surgery and none of them showed disease progression during a follow up period ranging from 2 to 11 years. These data suggest that in the absence of other histopathologic features of malignancy, lymphatic spread in CCNH can still carry an excellent prognosis and can be therefore considered as an example of "benign metastasis." As the latter concept can be set forth only after an uneventful long-term follow-up, in routine practice, cases of morphologically benign CCNH with lymphatic involvement are best labeled "atypical CCNH," or "CCNH like tumor of uncertain malignant potential." PMID- 23095509 TI - Syphilitic and lymphogranuloma venereum (LGV) proctocolitis: clues to a frequently missed diagnosis. AB - A rising incidence of syphilis and lymphogranuloma venereum (LGV) underscores the importance of recognizing these sexually transmitted infections (STI) in routine anocolonic biopsies. To increase awareness of their morphologic manifestations, we undertook a clinicopathologic study of our experience: syphilis (7 patients, 7 specimens), LGV (2 patients, 4 specimens), and syphilis/LGV (1 patient, 3 specimens). The diagnoses of all study specimens were confirmed with pertinent clinical studies. All study patients were human immunodeficiency virus positive, and all 9 with available history were men who have sex with men. The majority presented with bleeding (9), pain (6), and tenesmus (4). Ulcerations were the most common endoscopic abnormality (7), whereas mass lesions were confined to the syphilis group (4). None of the initial impressions included LGV, and syphilis was prospectively suggested only by pathologists (6 of 8) without the knowledge of clinical information and on the basis of morphology. Alternative impressions included condyloma acuminatum (3), inflammatory bowel disease (3), and malignancy (2), among others. All study specimens shared the following histologic core features: an intense lymphohistiocytic infiltrate with prominent plasma cells and lymphoid aggregates, only mild to moderate acute inflammation, minimal basal plasmacytosis and crypt distortion, and only rare granulomas and Paneth cell metaplasia. The spirochetes were focally demonstrated on a Treponema pallidum immunohistochemical stain (1) but not on silver stains (3). All patients with available follow-up data showed resolution of symptoms and imaging abnormalities after STI therapy (6). In summary, we report a unique pattern of STI proctocolitis consistently identified in patients with serologically confirmed syphilis and/or LGV infection; pertinent STI therapy leads to resolution of clinical abnormalities. This histologic pattern is important to recognize for timely treatment, for prevention of onward STI transmission, and to avoid the diagnostic pitfalls of inflammatory bowel disease or malignancy. PMID- 23095510 TI - Gastrointestinal surgery and related complications in patients with Ehlers-Danlos syndrome: a systematic review. AB - INTRODUCTION: Ehlers-Danlos syndrome (EDS) is a rare inherited group of connective tissue diseases characterized by joint hypermobility, skin hyperextensibility and bruising tendency. Common features of patients with EDS include vascular and gastrointestinal perforations. The purpose of this systematic review is to address gastrointestinal diseases and the complications associated with surgical treatment of diseases relating to the gastrointestinal system in patients with EDS. METHODS: PubMed search including the Medical Subject Heading (MeSH) terms 'Ehlers-Danlos Syndrome' and 'Gastrointestinal Diseases', and an Embase search including the Map Term to Subject Heading 'Ehlers-Danlos Syndrome' with 'AND' function of the keyword 'Gastrointestinal'. RESULTS: The literature search resulted in inclusion of 53 articles after application of eligibility criteria. The primary results drawn from the literature was that spontaneous ruptures of vessels and spontaneous perforations of the sigmoid colon occur in patients with EDS. CONCLUSION: Surgery in patients with EDS is associated with a high risk of complications, which is why preoperative indications should be considered. Optimal therapy for these patients includes the awareness that EDS is a systemic disease involving fragility, bleeding and spontaneous perforations from almost all organ systems. Often, a nonsurgical approach can be the best choice for these patients, depending on the condition. PMID- 23095513 TI - Open Access, the Creative Commons Attribution Licence, and the Nutrition Society journals. PMID- 23095512 TI - Effects of curcumin on stem-like cells in human esophageal squamous carcinoma cell lines. AB - BACKGROUND: Many cancers contain cell subpopulations that display characteristics of stem cells. Because these cancer stem cells (CSCs) appear to provide resistance to chemo-radiation therapy, development of therapeutic agents that target CSCs is essential. Curcumin is a phytochemical agent that is currently used in clinical trials to test its effectiveness against cancer. However, the effect of curcumin on CSCs is not well established. The current study evaluated curcumin-induced cell death in six cancer cell lines derived from human esophageal squamous cell carcinomas. Moreover, these cell lines and the ones established from cells that survived curcumin treatments were characterized. METHODS: Cell loss was assayed after TE-1, TE-8, KY-5, KY-10, YES-1, and YES-2 cells were exposed to 20-80 MUM curcumin for 30 hrs. Cell lines surviving 40 or 60 MUM curcumin were established from these six original lines. The stem cell markers aldehyde dehydrogenase-1A1 (ALDH1A1) and CD44 as well as NF-kappaB were used to compare CSC-like subpopulations within and among the original lines as well as the curcumin-surviving lines. YES-2 was tested for tumorsphere-forming capabilities. Finally, the surviving lines were treated with 40 and 60 MUM curcumin to determine whether their sensitivity was different from the original lines. RESULTS: The cell loss after curcumin treatment increased in a dose dependent manner in all cell lines. The percentage of cells remaining after 60 MUM curcumin treatment varied from 10.9% to 36.3% across the six lines. The cell lines were heterogeneous with respect to ALDH1A1, NF-kappaB and CD44 expression. KY-5 and YES-1 were the least sensitive and had the highest number of stem-like cells whereas TE-1 had the lowest. The curcumin-surviving lines showed a significant loss in the high staining ALDH1A1 and CD44 cell populations. Tumorspheres formed from YES-2 but were small and rare in the YES-2 surviving line. The curcumin-surviving lines showed a small but significant decrease in sensitivity to curcumin when compared with the original lines. CONCLUSION: Our results suggest that curcumin not only eliminates cancer cells but also targets CSCs. Therefore, curcumin may be an effective compound for treating esophageal and possibly other cancers in which CSCs can cause tumor recurrence. PMID- 23095514 TI - Antiphospholipid antibodies, brain infarcts, and cognitive and motor decline in aging (ABICMA): design of a community-based, longitudinal, clinical-pathological study. AB - The overall goal of the Antiphospholipid Antibodies, Brain Infarcts, and Cognitive and Motor Decline in Aging study is to test the hypothesis that antiphospholipid antibodies (aPL) are associated with an increased risk of pathologically proven brain infarcts and are related to cognitive and motor decline in aging. Putative biologic mechanisms underlying the association of aPL with infarcts and the relation of aPL with clinical outcomes of cognitive and motor impairment, including vascular and other processes, will be examined. The design of this longitudinal, clinical-pathologic study involves quantifying four aPL assays, and relating these to brain infarcts, and to cognitive and motor decline. Vascular mechanisms assessed using antemortem magnetic resonance neuroimaging and postmortem neuropathology, as well as nonvascular mechanisms of inflammation and blood-brain barrier permeability alterations will be examined as plausible mediators of the relation of aPL to cognitive and motor impairment. We will take advantage of antemortem biological specimens (longitudinally collected sera and plasma from which aPL, annexins, C-reactive protein, and matrix metalloproteinases will be quantified), and clinical, neuroimaging, and postmortem neuropathologic data from about 800 elderly, community-dwelling women and men who have agreed to brain autopsy at the time of death, participating in one of two ongoing studies of aging: the Religious Orders Study and the Memory and Aging Project. PMID- 23095515 TI - Presence of a temperature gradient among genital tract portions and the thermal changes within these portions over the estrous cycle in beef cows. AB - The aim of the present study was to describe the temperature of the different portions of the female genital tract and their relation to rectal temperature and to investigate the effect of steroid hormones profiles on these variables over the estrous cycle in cattle. Four nonpregnant Japanese Black cows were investigated daily over two successive estrous cycles using a digital thermometer with a long probe and rounded-end sensor to record the temperature of the rectum (RT), vagina (VT), cervix (CT), uterine body (UBT) and uterine horns (UHT). Blood samples were collected immediately before temperature recording to assay peripheral levels of progesterone (P(4)) and estradiol-17beta (E(2)). Moreover, transrectal ultrasonography was carried out after temperature recording to monitor the ovulatory follicle and track ovulation. During the experiment, the ambient temperature and relative humidity were recorded for further calculation of the temperature humidity index (THI). The temperature within the genital tracts in these cows progressively increased towards the uterine horns from the vagina. The VT, CT, UBT and UHTs were significantly higher in association with peripheral P(4) concentrations greater than 4 ng/ml (mid-luteal phase) when compared with lower peripheral P(4) concentrations. The VT was more significantly (P<0.01) correlated to the CT, UBT and UHTs than RT. In conclusion, a temperature gradient was present among the vagina, cervix and uterus over the estrous cycle, and changes in peripheral P(4) concentrations were associated with the thermal variations within these portions. The VT could be more beneficial than RT in monitoring temperature of deeper portions of the female genital tract in bovine. PMID- 23095516 TI - The activity and localization of 3beta-hydroxysteroid dehydrogenase/Delta(5) Delta(4) isomerase and release of androstenedione and progesterone by uterine tissues during early pregnancy and the estrous cycle in pigs. AB - Steroid hormones are produced by the porcine uterus. We hypothesized that the uterus in pigs possesses active 3beta-hydroxysteroid dehydrogenase/Delta(5) Delta(4) isomerase (3beta-HSD) responsible for progesterone and androstenedione production, that uterine steroids may supplement the amount of steroid hormones produced by embryos and corpus luteum and that these steroids are necessary for maintenance of pregnancy. In this study, we examined 1) endometrial and myometrial expression of 3beta-HSD mRNA, 2) uterine 3beta-HSD protein activity and 3) in vitro production of A(4) and P(4) by uterine slices harvested from pigs on days 10 to 11, 12 to 13 and 15 to 16 of pregnancy and the estrous cycle. The expression of 3beta-HSD and the presence and activity of 3beta-HSD protein were different in the endometrium and the myometrium during the examined periods of pregnancy and the estrous cycle. Production of A(4) by the endometrium and myometrium was highest on days 12 to 13 of pregnancy and the estrous cycle. Endometrial secretion of P(4) did not differ in the course of early pregnancy and on the respective days of the estrous cycle. The gravid myometrium was the highest source of P(4) in pregnant pigs on days 12 to 13. The release of P(4) by the cyclic myometrium rose during the examined days of the estrous cycle. The steroidogenic activity of the uterus, as described in this study, may support early pregnancy or the luteal phase of the estrous cycle in pigs. PMID- 23095518 TI - Functional annotation and ENU. AB - Functional annotation of every gene in the mouse genome is a herculean task that requires a multifaceted approach. Many large-scale initiatives are contributing to this undertaking. The International Knockout Mouse Consortium (IKMC) plans to mutate every protein-coding gene, using a combination of gene trapping and gene targeting in embryonic stem cells. Many other groups are performing using the chemical mutagen ethylnitrosourea (ENU) or transpon-based systems to induce mutations, screening offspring for phenovariants and identifying the causative mutations. A recent paper in BMC Research Notes by Arnold et al. presents data from an ENU-based mutagenesis project that provides not only some of the first phenotype-genotype information for a large number of genes, but also a trove of information, all publicly available, that demonstrates the specificity and efficiency of ENU mutagenesis. PMID- 23095517 TI - Changes in serum and cerebrospinal fluid cytokines in response to non neurological surgery: an observational study. AB - BACKGROUND: Surgery launches an inflammatory reaction in the body, as seen through increased peripheral levels of cytokines and cortisol. However, less is known about perioperative inflammatory changes in the central nervous system (CNS).Our aim was to compare inflammatory markers in serum and cerebrospinal fluid (CSF) before and after surgery and evaluate their association with measures of blood-brain barrier (BBB) integrity. METHODS: Thirty-five patients undergoing knee arthroplastic surgery with spinal anesthesia had CSF and serum samples drawn before, after and on the morning following surgery. Cytokines and albumin in serum and CSF and cortisol in CSF were assessed at all three points. RESULTS: Cytokines and cortisol were significantly increased in serum and CSF after surgery (Ps <0.01) and CSF increases were greater than in serum. Ten individuals had an increased cytokine response and significantly higher CSF/serum albumin ratios (Ps <0.01), five of whom had albumin ratios in the pathological range (>11.8). Serum and CSF levels of cytokines were unrelated, but there were strong correlations between CSF IL-2, IL-10 and IL-13, and albumin ratios (Ps <0.05) following surgery. CONCLUSION: Cytokine increases in the CNS were substantially greater than in serum, indicating that the CNS inflammatory system is activated during peripheral surgery and may be regulated separately from that in the peripheral body. CSF cytokine increase may indicate sensitivity to trauma and is linked to BBB macromolecular permeability. PMID- 23095519 TI - Microvascular dilatation after haemodialysis is determined by the volume of fluid removed and fall in mean arterial pressure. AB - BACKGROUND/AIMS: The effects of haemodialysis on the microcirculation are poorly understood. This study examined the changes in small vessel calibre. METHODS: 24 patients (including 12 males, median age 62.5 years, range 30-87) underwent digital retinal photography immediately before and after routine haemodialysis. Arteriolar and venular calibres were measured from the images by a trained grader using a highly reproducible, computer-assisted method. RESULTS: Patients had an average 2.0 +/- 0.3 litres of fluid removed with dialysis, and their mean arterial blood pressure fell by 6.8 mm Hg (CI 13.8-0.2, p = 0.06). Retinal arteriole calibre did not change (mean difference 2.3 um, CI -1.1 to 5.7, p = 0.17) but the venules dilated (mean difference 12.7 um, CI 7.3-18.3, p < 0.001). Calibre returned to baseline by 2 h. Venules dilated less in diabetics than non diabetics (mean difference -6.2 um, CI -9.6 to -2.9, p < 0.01). Retinal venular dilatation correlated positively with the volume of fluid removed per kilogramme body weight (5.9, CI 0.2-11.5, p = 0.04), and negatively with the fall in mean arterial pressure (-0.36, CI -0.72 to -0.01, p < 0.05) after adjusting for age, gender, diabetes and dyslipidaemia. CONCLUSION: Haemodialysis is associated with systemic venular dilatation. PMID- 23095520 TI - A case of life-threatening Staphylococcus aureus endocarditis involving percutaneous transcatheter prosthetic pulmonary valve. AB - While right ventricle to pulmonary artery homograft is the surgical procedure of choice for relieving right ventricle outflow tract obstruction; it is limited by the need for multiple surgical replacements owing to progressive conduit obstruction, valve dysfunction, or patient growth. Since January 2010, percutaneous transcatheter placement of prosthetic pulmonary valve (Melody valve) has emerged as an attractive alternative to surgical replacement of dysfunctional right ventricle to pulmonary artery homograft in the United States. We report a case of 19-year-old girl born with truncus arteriosus who underwent transcatheter placement of prosthetic pulmonary valve due to homograft insufficiency. She presented after 4 months with a febrile episode and was found to have Staphylococcus aureus endocarditis of her prosthetic valve. The infection caused multi-organ dysfunction despite bacteriological clearance and led to severe dysfunction of the valve which ultimately required surgical removal. The case highlights a rare but serious complication of percutaneous prosthetic pulmonary valves. PMID- 23095521 TI - Matching health information seekers' queries to medical terms. AB - BACKGROUND: The Internet is a major source of health information but most seekers are not familiar with medical vocabularies. Hence, their searches fail due to bad query formulation. Several methods have been proposed to improve information retrieval: query expansion, syntactic and semantic techniques or knowledge-based methods. However, it would be useful to clean those queries which are misspelled. In this paper, we propose a simple yet efficient method in order to correct misspellings of queries submitted by health information seekers to a medical online search tool. METHODS: In addition to query normalizations and exact phonetic term matching, we tested two approximate string comparators: the similarity score function of Stoilos and the normalized Levenshtein edit distance. We propose here to combine them to increase the number of matched medical terms in French. We first took a sample of query logs to determine the thresholds and processing times. In the second run, at a greater scale we tested different combinations of query normalizations before or after misspelling correction with the retained thresholds in the first run. RESULTS: According to the total number of suggestions (around 163, the number of the first sample of queries), at a threshold comparator score of 0.3, the normalized Levenshtein edit distance gave the highest F-Measure (88.15%) and at a threshold comparator score of 0.7, the Stoilos function gave the highest F-Measure (84.31%). By combining Levenshtein and Stoilos, the highest F-Measure (80.28%) is obtained with 0.2 and 0.7 thresholds respectively. However, queries are composed by several terms that may be combination of medical terms. The process of query normalization and segmentation is thus required. The highest F-Measure (64.18%) is obtained when this process is realized before spelling-correction. CONCLUSIONS: Despite the widely known high performance of the normalized edit distance of Levenshtein, we show in this paper that its combination with the Stoilos algorithm improved the results for misspelling correction of user queries. Accuracy is improved by combining spelling, phoneme-based information and string normalizations and segmentations into medical terms. These encouraging results have enabled the integration of this method into two projects funded by the French National Research Agency-Technologies for Health Care. The first aims to facilitate the coding process of clinical free texts contained in Electronic Health Records and discharge summaries, whereas the second aims at improving information retrieval through Electronic Health Records. PMID- 23095522 TI - Erlotinib antagonizes ABC transporters in acute myeloid leukemia. AB - Erlotinib was originally developed as an epidermal growth factor receptor (EGFR) specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated. Conversely, in preclinical settings, erlotinib has been shown to inhibit the constitutive activation of SRC kinases and mTOR, as well as to synergize with the DNA methyltransferase inhibitor azacytidine (a reference therapeutic for a subset of leukemia patients) by promoting its intracellular accumulation. Here, we show that both erlotinib and gefitinib (another EGFR inhibitor) inhibit transmembrane transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), also in acute myeloid leukemia (AML) cells that do not overexpress these pumps. Thus, inhibition of drug efflux by erlotinib and gefitinib selectively exacerbated (in a synergistic or additive fashion) the cytotoxic response of KG-1 cells to chemotherapeutic agents that are normally extruded by ABC transporters (e.g., doxorubicin and etoposide). Erlotinib limited drug export via ABC transporters by multiple mechanisms, including the downregulation of surface-exposed pumps and the modulation of their ATPase activity. The effects of erlotinib on drug efflux and its chemosensitization profile persisted in patient-derived CD34+ cells, suggesting that erlotinib might be particularly efficient in antagonizing leukemic (stem cell) subpopulations, irrespective of whether they exhibit or not increased drug efflux via ABC transporters. PMID- 23095524 TI - GapFiller: a de novo assembly approach to fill the gap within paired reads. AB - BACKGROUND: Next Generation Sequencing technologies are able to provide high genome coverages at a relatively low cost. However, due to limited reads' length (from 30 bp up to 200 bp), specific bioinformatics problems have become even more difficult to solve. De novo assembly with short reads, for example, is more complicated at least for two reasons: first, the overall amount of "noisy" data to cope with increased and, second, as the reads' length decreases the number of unsolvable repeats grows. Our work's aim is to go at the root of the problem by providing a pre-processing tool capable to produce (in-silico) longer and highly accurate sequences from a collection of Next Generation Sequencing reads. RESULTS: In this paper a seed-and-extend local assembler is presented. The kernel algorithm is a loop that, starting from a read used as seed, keeps extending it using heuristics whose main goal is to produce a collection of error-free and longer sequences. In particular, GapFiller carefully detects reliable overlaps and operates clustering similar reads in order to reconstruct the missing part between the two ends of the same insert. Our tool's output has been validated on 24 experiments using both simulated and real paired reads datasets. The output sequences are declared correct when the seed-mate is found. In the experiments performed, GapFiller was able to extend high percentages of the processed seeds and find their mates, with a false positives rate that turned out to be nearly negligible. CONCLUSIONS: GapFiller, starting from a sufficiently high short reads coverage, is able to produce high coverages of accurate longer sequences (from 300 bp up to 3500 bp). The procedure to perform safe extensions, together with the mate-found check, turned out to be a powerful criterion to guarantee contigs' correctness. GapFiller has further potential, as it could be applied in a number of different scenarios, including the post-processing validation of insertions/deletions detection pipelines, pre-processing routines on datasets for de novo assembly pipelines, or in any hierarchical approach designed to assemble, analyse or validate pools of sequences. PMID- 23095523 TI - The PERK-eIF2alpha phosphorylation arm is a pro-survival pathway of BCR-ABL signaling and confers resistance to imatinib treatment in chronic myeloid leukemia cells. AB - Activation of adaptive mechanisms plays a crucial role in cancer progression and drug resistance by allowing cell survival under stressful conditions. Therefore, inhibition of the adaptive response is considered as a prospective therapeutic strategy. The PERK-eIF2alpha phosphorylation pathway is an important arm of the unfolded protein response (UPR), which is induced under conditions of endoplasmic reticulum (ER) stress. Our previous work showed that ER stress is induced in chronic myeloid leukemia (CML) cells. Herein, we demonstrate that the PERK eIF2alpha phosphorylation pathway is upregulated in CML cell lines and CD34+ cells from CML patients and is associated with CML progression and imatinib resistance. We also show that induction of apoptosis by imatinib results in the downregulation of the PERK-eIF2alpha phosphorylation arm. Furthermore, we demonstrate that inactivation of the PERK-eIF2alpha phosphorylation arm decreases the clonogenic and proliferative capacities of CML cells and sensitizes them to death by imatinib. These findings provide evidence for a pro-survival role of PERK-eIF2alpha phosphorylation arm that contributes to CML progression and development of imatinib resistance. Thus, the PERK-eIF2alpha phosphorylation arm may represent a suitable target for therapeutic intervention for CML disease. PMID- 23095525 TI - Toxic shock syndrome of a probable gynecologic source in an adolescent: a case report and review of the literature. AB - BACKGROUND: Toxic shock syndrome (TSS) is an acute toxin-mediated infectious syndrome characterized by fever, hypotension, desquamation, and multiorgan involvement. It is a rare condition (incidence of 0.79/100,000 women), particularly in the adolescent population, and it may be menstrual (mTSS) or non menstrual (nmTSS) in origin. CASE: A 15-year-old girl developed symptoms of nausea, vomiting, and diarrhea that worsened over a 3-day period. At initial presentation, she was hypotensive, febrile, and tachycardic. Her condition deteriorated and within 36 hours she required intubation, vasopressor treatment, and antibiotic therapy. Multiple sites were cultured but only the vaginal culture, which grew Staphylococcus aureus, was positive. Recent menses with tampon use was reported. She responded to aggressive therapy and was discharged home 3 weeks after initial presentation. SUMMARY AND CONCLUSION: We describe a rare case of TSS of a probable gynecologic source in a 15-year-old female who successfully responded to aggressive intensive care treatment. mTSS should be considered in the differential diagnosis of an adolescent presenting with signs of septic shock, particularly if there is a recent history of tampon use. Early intervention is critical to improving survival. PMID- 23095526 TI - Gynecologic concerns in pubertal females with blood disorders. AB - PURPOSE OF REVIEW: The incidence and prevalence of blood disorders varies depending on the underlying etiology, age, ethnicity, family history, and presence of comorbid medical conditions. Gynecologic problems occurring around puberty may cause stress to families and patients, as well as management challenges to providers. RECENT FINDINGS: Management strategies in the setting of bleeding disorders include hormonal and non-hormonal options to address problems occurring around puberty. Management strategies in the setting of clotting disorders allow providers to address common problems occurring in adolescence, while minimizing risk of venous thromboembolism. SUMMARY: Preparedness is important at this time of life, not only to prevent unwanted gynecologic complications or hospitalizations related to specific blood conditions, but also to identify problems related to reproductive care that may be exacerbated or complicated by an underlying blood disorder. PMID- 23095527 TI - Isolated unilateral amazia: an exceptional breast anomaly. AB - BACKGROUND: Amazia is a rare breast anomaly. It consists of the absence of the mammary gland, with normal nipple-areola complex. It usually presents associated with a syndrome and it can be diagnosed during infancy or at the beginning of puberty. CASE: Here we report a case of a 13-year-old female with a late diagnosis of unilateral amazia. No distinctive body or anatomic abnormalities were found. She was referred for surgical reconstruction. COMMENTS: Amazia is an uncommon entity with a lack of incidence information in the literature. Early diagnosis and proper treatment are essential to avoid body image complications, especially among adolescent women. PMID- 23095528 TI - Ovarian torsion in a patient with mullerian agenesis: increased risk? AB - BACKGROUND: Patients with mullerian agenesis may be at an increased risk of ovarian torsion due to the absence of the utero-ovarian ligament and the fact that the ovary is not tethered to a fixed and relatively non-mobile structure, the uterus. CASE: We report a case of a 14-year-old female with abdominal pain who had a physical examination suggestive of mullerian agenesis. Imaging was non diagnostic and demonstrated an abdominal mass. Emergent surgery revealed ovarian torsion. SUMMARY AND CONCLUSION: We present this case of ovarian torsion and mullerian agenesis, in order to highlight the association and to review potential risk factors. PMID- 23095529 TI - Does motherhood affect the quality of life of adolescents? AB - STUDY OBJECTIVE: Assess the quality of life (QOL) of female adolescents with children compared to those without children. DESIGN: Cross-sectional. SETTING: Public university-affiliated family planning clinic, Sao Paulo, Brazil. PARTICIPANTS: 91 female adolescents (16-19 years) of low socio-economic status with and without children. INTERVENTIONS: The Portuguese version of the WHOQOL BREF questionnaire was used. OUTCOME MEASURES: Mean scores of the 4 main domains were compared between adolescents with and without children. RESULTS: Both mothers (N = 40) and nonmothers (N = 51) had low mean scores (<75%) in most of the QOL domains. Compared to adolescents without children, adolescent mothers scored significantly lower in the physical (52.1 vs 59.4, P = .0137) and social (66.9 vs 77.3, P = .0182) domains. CONCLUSION: Adolescent mothers have a significantly lower quality of life in the physical and in the social relationships domains than nonmothers. PMID- 23095530 TI - Large mesonephric cyst with acute adnexal torsion in a teenage girl. AB - BACKGROUND: Mesonephric duct remnants usually do not present any clinical dilemma. However, if the cellular lining remains active, it may lead to cystic lesions that may cause pain or torsion of the adnexa. CASE: This is a 13-year-old female who presented because of severe pelvic pain. Ultrasound and CT scan revealed a large cystic mass in the pelvis. Mini-laparotomy confirmed torsion of the left adnexa due to the mass. The adnexa was untwisted. The cyst and the left tube were removed and the ovary regained its blood flow and was saved. SUMMARY AND CONCLUSION: Mesonephric duct cyst should be considered in the diagnosis of pelvic masses in adolescent girls. PMID- 23095531 TI - Baby boom or bust ... is 64 the new 57? PMID- 23095532 TI - United States anesthesiologists over 50: retirement decision making and workforce implications. AB - BACKGROUND: Anesthesiology is among the medical specialties expected to have physician shortage. With little known about older anesthesiologists' work effort and retirement decision making, the American Society of Anesthesiologists participated in a 2006 national survey of physicians aged 50-79 yr. METHODS: Samples of anesthesiologists and other specialists completed a survey of work activities, professional satisfaction, self-defined health and financial status, retirement plans and perspectives, and demographics. A complex survey design enabled adjustments for sampling and response-rate biases so that respondents' characteristics resembled those in the American Medical Association Physician Masterfile. Retirement decision making was modeled with multivariable ordinal logistic regression. Life-table analysis provided a forecast of likely clinical workforce trends over an ensuing 30 yr. RESULTS: Anesthesiologists (N = 3,222; response rate = 37%) reported a mean work week of 49.4 h and a mean retirement age of 62.7 yr, both values similar to those of other older physicians. Work week decreased with age, and part-time work increased. Women worked a shorter work week (mean, 47.9 vs. 49.7 h, P = 0.024), partly due to greater part-time work (20.2 vs. 13.1%, P value less than 0.001). Relative importance of factors reported among those leaving patient care differed by age cohort, subspecialty, and work status. Poor health was cited by 64% of anesthesiologists retiring in their 50s as compared with 43% of those retiring later (P = 0.039). CONCLUSIONS: This survey lends support for greater attention to potentially modifiable factors, such as workplace wellness and professional satisfaction, to prevent premature retirement. The growing trend in part-time work deserves further study. PMID- 23095537 TI - Respect your elders. PMID- 23095538 TI - Anesthesiologist age and litigation: what is the association? PMID- 23095539 TI - Take away some of the keys. PMID- 23095540 TI - Maybe it isn't aging. PMID- 23095543 TI - Unresponsiveness versus unconsciousness. PMID- 23095545 TI - Use of risperidone in cardiac surgery patients with subsyndromal delirium. PMID- 23095547 TI - Hemorrhagic shock and acute kidney injury model. PMID- 23095549 TI - Physostigmine and restless legs syndrome. PMID- 23095554 TI - Challenges in defining 'palliative care' for the purposes of clinical trials. AB - PURPOSE OF REVIEW: Palliative care has become part of mainstream medicine with increasing evidence about the effectiveness of specialist palliative care (SPC) on patient and family outcomes. Comparison of studies testing SPC interventions is challenging as types of interventions and reporting of components of the intervention vary. In consequence, study results are difficult to interpret. RECENT FINDINGS: There is a continuous lack of clarity in palliative care definitions. For clinical trials, multidisciplinary care, supportive care documentation, symptom assessment and symptom management are suggested as key domains. In recent studies testing palliative care as an intervention SPC physicians and palliative care nurses were core members of multiprofessional teams, but integration of other team members varied. Management of symptoms and psychosocial issues were central to SPC with various other areas described. Services were delivered by hospital and community support teams, in palliative care units, outpatient clinics and hospital. Cost information was only provided by a few studies. SUMMARY: Due to the lack of an agreed definition of palliative care and heterogeneity in reporting of components of an SPC intervention comparison of studies remains challenging. Key aspects of palliative care interventions are incurable disease, multidisciplinary approach, focus on symptom management including standardized assessment, psychosocial and family support, and (advance) care planning. Detailed information about all aspects of the intervention should be provided. PMID- 23095555 TI - The importance and pitfalls of correlational science in palliative care research. AB - PURPOSE OF REVIEW: Correlational science discovers associations between patient characteristics, symptoms and biomarkers. Correlational science using data from cross-sectional studies is the most frequently applied study design in palliative care research. The purpose of this review is to address the importance and potential pitfalls in correlational science. RECENT FINDINGS: Associations observed in correlational science studies can be the basis for generating hypotheses that can be tested in experimental studies and are the basic data needed to develop classification systems that can predict patient outcomes. Major pitfalls in correlational science are that associations do not equate with causality and that statistical significance does not necessarily equal a correlation that is of clinical interest. Researchers should be aware of the end points that are clinically relevant, that end-points should be defined before the start of the analyses, and that studies with several end-points should account for multiplicity. SUMMARY: Correlational science in palliative care research can identify related clinical factors and biomarkers. Interpretation of identified associations should be done with careful consideration of the limitations underlying correlational analyses. PMID- 23095556 TI - The urokinase plasminogen activating system in thyroid cancer: clinical implications. AB - The urokinase plasminogen activator (uPA) system (uPAS) comprises the uPA, its cell membrane receptor (uPAR) and two specific inhibitors, the plasminogen activator inhibitor 1 (PAI-1) and 2 (PAI-2). The uPA converts the plasminogen in the serine protease plasmin, involved in a number of physiopathological processes requiring basement membrane (BM) or extracellular matrix (ECM) remodelling, including tumor progression and metastasis. The tumor-promoting role of PAS is not limited to the degradation of ECM and BM required for local diffusion and spread to distant sites of malignant cells, but widens to tumor cell proliferation, adhesion and migration, intravasation, growth at the metastatic site and neoangiogenesis. The relevance of uPAS in cancer progression has been confirmed by several studies which documented an increased expression of uPA, uPAR and PAI-1 in different human malignancies, and a positive correlation between the levels of one or more of them and a poor prognosis. For these reasons, the uPAS components have aroused considerable interest as suitable targets for anticancer therapy, and several pharmacological approaches aimed at inhibiting the uPA and/or uPAR expression or function in preclinical and clinical settings have been described. In the present manuscript, we will first glance at uPAS biological functions in human cancer progression and its clinical significance in terms of prognosis and therapy. We will then review the main findings regarding expression and function of uPAS components in thyroid cancer tissues along with the experimental and clinical evidence suggesting its potential value as molecular prognostic marker and therapeutic target in thyroid cancer patients. PMID- 23095557 TI - Aortic valve replacement through the upper ministernotomy: preliminary experience with modified technique. AB - Minimally invasive approach for aortic valve surgery has been developed since 1995, reducing the complications related to the full sternotomy. We have introduced a new method for central cannulation that reduces the length of surgical incision for the aortic valve replacement through upper mini-sternotomy. To improve the surgical view without enlargement of the incision, two small additional incisions are performed for both arterial and atrial cannulation. We have used the modified technique in 60 patients without sternal infection or other surgical complications and with good cosmetic results. PMID- 23095558 TI - Minimally invasive video-assisted thyroid surgery: how can we improve the learning curve? AB - OBJECTIVE: Minimally invasive video-assisted thyroidectomy (MIVAT) is a technically demanding procedure and requires a surgical team skilled in both endocrine and endoscopic surgery. A time consuming learning and training period is mandatory at the beginning of the experience. The aim of our report is to focus some aspects of the learning curve of the surgeon who practices video assisted thyroid procedures for the first time, through the analysis of our preliminary series of 36 cases. PATIENTS AND METHODS: From September 2004 to April 2005 we selected 36 patients for minimally invasive video-assisted surgery of the thyroid. The patients were considered eligible if they presented with a nodule not exceeding 35 mm in maximum diameter; total thyroid volume within normal range; absence of biochemical and echographic signs of thyroiditis. We analyzed surgical results, conversion rate, operating time, post-operative complications, hospital stay, cosmetic outcome of the series. RESULTS: We performed 36 total thyroidectomy. The procedure was successfully carried out in 33/36 cases. Post-operative complications included 3 transient recurrent nerve palsies and 2 transient hypocalcemias; no definitive hypoparathyroidism was registered. All patients were discharged 2 days after operation. The cosmetic result was considered excellent by most patients. CONCLUSIONS: Advances in skills and technology have enabled surgeons to reproduce most open surgical techniques with video-assistance or laparoscopically. Training is essential to acquire any new surgical technique and it should be organized in detail to exploit it completely. PMID- 23095559 TI - Surgical treatment of thymoma: personal experience. AB - INTRODUCTION: Thymomas (THs) are rare epithelial tumors of the thymus gland. In this study we report our personal experience in the management and surgical treatment of THs. CASE REPORTS: We report two clinical cases treated with combined therapy (surgery followed by adjuvant therapy). RESULTS: Total transternal thymectomy was performed in both patients. The post-operative course was uneventful. The patients received adjuvant radiotherapy and chemotherapy. No relapse has been observed during follow-up. DISCUSSION: THs are usually slowly growing tumors with similar incidence in both sexes. They occur through a wide age range, with a peak in the fifth and sixth decades. Distinctive features reminiscent of the normal thymus make the pathologic diagnosis of THs easy in most cases. Malignant behaviour is indicated by microscopic or macroscopic invasion of the tumor capsule or surrounding organs or by the presence of metastases. Although there is no standardized staging system for thymoma, the one proposed by Masaoka is commonly employed. Total thymectomy is the procedure of choice, even for encapsulated tumors, with carefully exploration of the mediastinum for evidence of ectopic thymic tissue or local invasion. CONCLUSIONS: Despite an indolent course and a cytologically bland appearance, all thymic tumors can manifest a malignant behavior. Surgery continues to be the mainstay of treatment, and the ability to achieve complete resection seems to be the most important prognostic factor. Multimodality treatment involving postoperative chemotherapy and radiotherapy appears to increase the rate of complete resection and improves survival in advanced THs. PMID- 23095560 TI - Simultaneous volvulus of the transverse and sigmoid colon: case report. AB - INTRODUCTION: Volvulus of transverse colon is rare when compared to cecal and sigmoid volvulus. Cases involving simultaneous volvulus of the transverse colon and another colonic segment are extremely rare. CASE REPORT: We report a rare case of simultaneous sigmoid and transverse colon volvulus in a 82-year-old Caucasian female. CONCLUSION: Volvulus is a well recognized cause of large bowel obstruction. The development of transverse and sigmoid volvulus in the same patient is extremely rare. Though rare this possibility must always be considered in the differential diagnosis, when dealing with recurrent intermittent abdominal pain or acute intestinal obstruction. PMID- 23095561 TI - Giant condyloma acuminatum quickly growing: case report. AB - BACKGROUND: Giant Condyloma Acuminatum (GCA) is a rare, slow growing, large cauliflower tumor of the penile foreskin and perianal region with benign histologic appearance but high propensity for local invasion and recurrences. GCA is associated with Human Papilloma Virus (HPV) types 6 and 11 and it also has considerable risk of neoplastic transformation into fully invasive squamous cell carcinoma into about 5 years. OBJECTIVE: Because of the rarity of perianal GCA, to date there is no general agreement on the best method for treatment. We wanted to know if surgical approach only was a good method to treat our case. CASE REPORT: A 28 years old man, HIV-negative, with a 4 years history of perianal GCA quickly growing underwent full tickness local excision at least 0,7 cm margin of normal tissue with skin grafting taken from the thighs. Fecal contamination was avoided by diet and loperamide per os. At two years follow-up no recurrence was detected. CONCLUSION: Surgical approach with full tickness excision and immediate skin-grafting and regular follow-up demonstrated effective to treat GCA and to minimize disease recurrence. PMID- 23095562 TI - Clinical manifestations due to pharmacological interactions in pediatric ophthalmic surgery: topical drugs and general anaesthesia. AB - INTRODUCTION: The authors consider the type and the incidence of the adverse effects due to the interaction between ophthalmic drugs and general anaesthesia in pediatric ophthalmic surgery. PATIENTS AND METHODS: The experience included 176 general anaesthesia in 100 children aged between 9,2 months and 11,4 years (mean age 4,9 years). RESULTS: In the 100 patients we reported: 4 cases (2.7% general anaesthesias) of sinus tachycardia with heart rhythm varying between 170 and 180 beats per minute (3.6%); 5 cases of sinus bradycardia, varying between 60 and 70 beats per minute (3.3%); 3 cases of bronchospasm (2%); 2 cases of psychomotor agitation/disturbances in pre-convulsive state after anaesthesia (1.3%); 3 cases of arterial hypotension (60-70 mmHg) (2%); 7 cases of skin rush around neck and chest (4.6%); 1 case of prolonged apnoea (0.6%). CONCLUSIONS: The clinical manifestations, principally on the cardio-circulatory and nervous system are subjected to critical revision, to foresee the pharmacological interferences and therefore to prepare the necessary measure of medical treatment. PMID- 23095563 TI - Risk factors in reoperative thyroid surgery for recurrent goitre: our experience. AB - AIM: Reoperative thyroid surgery is an uncommon operation associated with a higher complication rate; we reviewed our series of patients on whom reoperative thyroid surgery was performed. METHOD: 106 patients had a thyroid reoperation for recurrent multinodular goiter (93 patients), recurrent thyrotoxicosis (3) or suspected malignancy (10); bilateral completion thyroidectomy was performed in 68 cases, lobectomy in 36, removal of a mediastinal recurrence and of a pyramidal remnant in 1 patient respectively. RESULTS: Temporary hypoparathyroidism occurred in 41 patients (38.67%), definitive in 7 (6.6%), transient recurrent laryngeal nerve palsy in 5 (4.71%), permanent nerve palsy in 1 (0.94%); in 3 cases (2.83%) surgical revision of haemostasis was necessary for postoperative haemorrhage. After monolateral surgery we had 13 cases of transient hypoparathyroidism (34.21%), 2 of definitive (5.26%) and 1 transient recurrent laryngeal nerve palsy (2.63%); after bilateral surgery we had 29 cases of transient hypoparathyroidism (42.64%), 5 of definitive (7.35%), 4 of transient recurrent laryngeal nerve palsy (5.88%), 1 of definitive (1.47%) and 3 of postoperative bleeding (4.41%). CONCLUSIONS: Reoperative thyroid surgery is a technical challenge with a high incidence of complications. Scarring, edema and friability of the tissues together with distortion of the landmarks make reoperative surgery hazardous. A higher risk of complications is described when previous surgery has been performed on both sides. Total thyroidectomy should be considered the procedure of choice for benign multinodular goiter eliminating the potential of a reoperation. Whenever necessary, reoperative thyroidectomy may be performed safely with little morbidity in experienced hands. PMID- 23095564 TI - Surgical treatment of papillary thyroid carcinoma without lymph nodal involvement. AB - BACKGROUND: In the treatment of differentiated thyroid cancer (DTC), in absence of enlarged lymph nodes, the role of routine central lymph node dissection (RCLD) remains controversial. The aim of this study is to analyze data resulting from total thyroidectomy (TT) not combined with RCLD in the treatment of DTC. METHODS: We retrospectively evaluated the clinical records of 80 patients treated between January 1996 and December 2003 with TT without RCLND, in absence of suspected enlarged lymph nodes at preoperative ultrasonography and intraoperatively during neck exploration. In this series, 75 patients (93.7%) underwent radioiodine (RAI) ablation, followed by Thyroid Stimulating Hormone (TSH) suppression therapy. In case of locoregional lymph nodal recurrence, a central (VI) and ipsilateral (III IV) selective lymph node dissection was performed. RESULTS: Incidence of permanent hypoparathyroidism (iPTH < 10 pg/ml) and unilateral temporary vocal fold paralysis were respectively 2.55% and 2.55%. Locoregional recurrence, with positive cervical lymph nodes, after a 10.3 +/- 4.7 years mean follow-up was observed in 3 patients (3.75%). They were submitted to a central (VI) and ipsilateral (III-IV) selective neck dissection without significant complications. CONCLUSIONS: In our series, TT not combined with RCLD was associated to a low locoregional recurrence rate, even if the lack of a control group treated with RCLD does not allow any generalized assumption. RCLD may be indicated in high risk patients, in whom lymph nodal recurrence is more frequent. More prospective randomized studies are needed to better define the role of RCLD and postoperative radioiodine ablation. PMID- 23095565 TI - Is there a role of percutaneous drainage in non-parasitic splenic cysts? Case report. AB - Pathogenesis, classification and treatment of non-parasitic splenic cysts (NPSCs) are controversial. The utility of percutaneous aspiration of the cyst is not well understood. We report a case of a 32 year-old woman with a symptomatic giant epidermoid cyst of the spleen treated with laparoscopic splenectomy. A percutaneous transcatheter drainage was performed under ultrasound guidance before surgical procedure in order to classify the type of cyst and to choose the best treatment. PMID- 23095566 TI - Stapled haemorrhoidopexy vs. Milligan-Morgan haemorrhoidectomy for grade III haemorrhoids: a randomized clinical trial. AB - The aim of this double blind randomized clinical trial was to compare the short term and long-term outcomes of stapled haemorrhoidopexy (SH group) performed using a circular stapler with that of the Milligan-Morgan haemorrhoidectomy (MMH group). A total of 79 consecutive patients with grade III haemorrhoids were randomized into two groups treated with SH (n. 39) and MMH (n. 40). The outcomes of the procedures were evaluated postoperatively and over a follow-up period of minimum 2 years. Patients undergoing the SH procedure showed greater short term advantages than MMH group with reduced pain, shorter length of hospital stay, earlier return to work and high patient satisfaction. Long-term follow-up has indicated more favourable results in MMH group in terms of resumption of symptoms with absence of residual prolapse and risk of recurrence of prolapse. At two years follow-up recurrent prolapse was confirmed in six patients of SH group (13%) whereas in none of the MMH group. At six months follow-up there weren't significant difference in the mean satisfaction score for the two groups. At two years the mean satisfaction score was higher in the MMH group vs SH group. Seven patients in the SH group needed a reoperation whereas none in MMH group. From January 2009, in our Surgery Unit the patients are always informed about a higher recurrence rate of SH and we perform this technique only when the patient choices to accept this risk to take advantage of the short-term benefits of this procedure. PMID- 23095567 TI - Benefits of laparoscopic colorectal surgery in the geriatric patient. AB - BACKGROUND: Our aim is the retrospective valuation of results in over 75 year-old patients, with colorectal cancer, treated with laparoscopic and laparotomic surgery, considering how laparoscopic surgery has improved these patients' outcome. PATIENTS AND METHODS: We took all over 75 year-old patients, affected by colorectal cancer, treated with colectomy. Patients has been divided into two groups: laparotomy group and laparoscopy group. Data concerning patients, i.e., age, sex, BMI, ASA, comorbidities, were collected with data concerning the operation (surgical time, conversion percentage). Postoperative outcomes - i.e., gas evacuation, bowel movements, solid and liquid feeding, need to ICU, complications, re-surgery, hospitalization and type of discharge, mortality - were evaluated. RESULTS: A total of 145 patients are included: laparotomy 80 and laparoscopy 51. Two groups are homogeneous for age, sex, BMI, ASA, comorbidities. Surgical times are the same. Need to Intesive Care Unit (ICU) is lower in laparoscopy. Gas evacuation and bowel movements are earlier in laparoscopy. Liquid and solid diet is earlier in laparoscopy. Hospitalization was earlier after laparoscopy. Discharge at home is more frequent in laparoscopy. Major and minor complications are lower in laparoscopy. Post-operative mortality is lower in laparoscopy. CONCLUSIONS: Laparoscopy improves over 75 year-old patients' outcomes, after elective surgery for colorectal cancer. Surgery trauma, anaesthesia, nutritional and hemodynamic alterations, are factors that break the old patients' fragile physiologic balance. Less traumatic surgery improves old patients' outcomes. PMID- 23095568 TI - Evaluation of negative pressure vacuum-assisted system in acute and chronic wounds closure: our experience. AB - Negative-pressure therapy or vacuum-assisted closure (VAC) has been used in clinical applications since the 1940's and has increased in popularity over the past decade. This dressing technique consists of an open cell foam dressing put into the wound cavity, a vacuum pump produces a negative pressure and an adhesive drape. A controlled sub atmospheric pressure from 75 to 150 mmHg is applied. The vacuum-assisted closure has been applied by many clinicians to chronic wounds in humans; however it cannot be used as a replacement for surgical debridement. The initial treatment for every contaminated wound should be the necrosectomy. The VAC therapy has a complementary function and the range of its indications includes pressure sores, stasis ulcers, chronic wounds such as diabetic foot ulcers, post traumatic and post operative wounds, infected wounds such as necrotizing fasciitis or sternal wounds, soft-tissue injuries, bone exposed injuries, abdominal open wounds and for securing a skin graft. We describe our experience with the VAC dressing used to manage acute and chronic wounds in a series of 135 patients, with excellent results together with satisfaction of the patients. PMID- 23095569 TI - Constructing a question bank based on script concordance approach as a novel assessment methodology in surgical education. AB - BACKGROUND: Script Concordance Test (SCT) is a new assessment tool that reliably assesses clinical reasoning skills. Previous descriptions of developing SCT question banks were merely subjective. This study addresses two gaps in the literature: 1) conducting the first phase of a multistep validation process of SCT in Plastic Surgery, and 2) providing an objective methodology to construct a question bank based on SCT. METHODS: After developing a test blueprint, 52 test items were written. Five validation questions were developed and a validation survey was established online. Seven reviewers were asked to answer this survey. They were recruited from two countries, Saudi Arabia and Canada, to improve the test's external validity. Their ratings were transformed into percentages. Analysis was performed to compare reviewers' ratings by looking at correlations, ranges, means, medians, and overall scores. RESULTS: Scores of reviewers' ratings were between 76% and 95% (mean 86% +/- 5). We found poor correlations between reviewers (Pearson's: +0.38 to -0.22). Ratings of individual validation questions ranged between 0 and 4 (on a scale 1-5). Means and medians of these ranges were computed for each test item (mean: 0.8 to 2.4; median: 1 to 3). A subset of test items comprising 27 items was generated based on a set of inclusion and exclusion criteria. CONCLUSION: This study proposes an objective methodology for validation of SCT-question bank. Analysis of validation survey is done from all angles, i.e., reviewers, validation questions, and test items. Finally, a subset of test items is generated based on a set of criteria. PMID- 23095570 TI - Exploration of the association between quality of life, assessed by the EQ-5D and ICECAP-O, and falls risk, cognitive function and daily function, in older adults with mobility impairments. AB - BACKGROUND: Our research sought to understand how falls risk, cognitive function, and daily function are associated with health related quality of life (using the EuroQol-5D) and quality of life (using the ICECAP-O) among older adults with mobility impairments. METHODS: The EQ-5D and ICECAP-O were administered at 12 months post first clinic attendance at the Vancouver Falls Prevention Clinic. We report descriptive statistics for all baseline characteristics collected at first clinic visit and primary outcomes of interest. Using multivariate stepwise linear regression, we assessed the construct validity of the EQ-5D and ICECAP-O using three dependent measures that are recognized indicators of "impaired mobility" - physiological falls risk, general balance and mobility, and cognitive status among older adults. RESULTS: We report data on 215 seniors who attended the Vancouver Falls Prevention Clinic and received their first clinic assessment. Patients had a mean age of 79.3 (6.2) years. After accounting for known covariates (i.e., age and sex), the ICECAP-O domains explained a greater amount of variation in each of the three dependent measures compared with the EQ-5D domains. CONCLUSION: Both the EQ-5D and ICECAP-O demonstrate associations with falls risk and general balance and mobility; however, only the ICECAP-O was associated with cognitive status among older adults with mobility impairments. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022866. PMID- 23095571 TI - The utility of administrative data for surveillance of comorbidity in multiple sclerosis: a validation study. AB - BACKGROUND: Although comorbidity is important in multiple sclerosis (MS), few validated methods for its assessment exist. We validated and applied administrative case definitions for several comorbidities in MS. METHODS: Using provincial administrative data we identified persons with MS and a matched general population cohort. Case definitions for chronic lung disease (CLD), epilepsy, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and migraine were developed using administrative data, and validated against medical records. We applied these definitions to estimate the age-standardized prevalence of these comorbidities in the MS and matched cohorts. RESULTS: Versus medical records, administrative case definitions showed moderate agreement for CLD (K = 0.41), migraine (K = 0.51), and epilepsy (K = 0.44), fair agreement for IBS (K = 0.36) and could not be calculated for IBD (small sample size). The 2005 prevalence of CLD was similar in the MS (15.6%) and general populations (14.4%). The prevalence of the remaining comorbidities was higher in the MS than the general populations: epilepsy (4.12 vs. 1.12%), IBD (0.78 vs. 0.65%), IBS (12.2 vs. 6.80%) and migraine (23.0 vs. 16.5%). CONCLUSIONS: Administrative data are valid for tracking CLD, epilepsy, and migraine in MS. The prevalence of epilepsy, IBD, IBS and migraine is increased in MS versus the general population. PMID- 23095572 TI - Endothelial nitric oxide synthase in dorsal root ganglia during chronic inflammatory nociception. AB - Nitric oxide (NO) is a gaseous molecule implicated both in vascular tone and nociceptive transmission. The capillary blood supply to the dorsal root ganglia (DRG) is unique because it is highly permeable to several low and high molecular weight compounds. This anatomical situation leads to a potential role of endothelial nitric oxide synthase (eNOS) in inflammatory nociception, which is not well established. Therefore, we examined the role of eNOS in DRG in a murine chronic inflammatory pain model induced by complete Freund's adjuvant using L N(5)-(1-iminoethyl)ornithine (L-NIO), a potent inhibitor of eNOS activity. Pain state was examined using a behavioral test. The expression of eNOS, platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF) was examined by immunofluorescence. In control animals, CD31 was detected in vessels; VEGF was localized both in vessels and neurons while a weak eNOS immunopositivity was detected in both vessels and in neurons. Under inflammatory pain conditions, eNOS, CD31 and VEGF immunopositivity increased. Administration of L-NIO significantly attenuated thermal hyperalgesia by 24 h and decreased eNOS activity and CD31 immunopositivity by 7 days. VEGF was unaffected. Our results show that eNOS plays a nociceptive role in the early phases of inflammation while in the later phases it may be involved in neurotrophic support. PMID- 23095573 TI - Rescue from acute neuroinflammation by pharmacological chemokine-mediated deviation of leukocytes. AB - BACKGROUND: Neutrophil influx is an important sign of hyperacute neuroinflammation, whereas the entry of activated lymphocytes into the brain parenchyma is a hallmark of chronic inflammatory processes, as observed in multiple sclerosis (MS) and its animal models of experimental autoimmune encephalomyelitis (EAE). Clinically approved or experimental therapies for neuroinflammation act by blocking leukocyte penetration of the blood brain barrier. However, in view of unsatisfactory results and severe side effects, complementary therapies are needed. We have examined the effect of chlorite oxidized oxyamylose (COAM), a potent antiviral polycarboxylic acid on EAE. METHODS: EAE was induced in SJL/J mice by immunization with spinal cord homogenate (SCH) or in IFN-gamma-deficient BALB/c (KO) mice with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Mice were treated intraperitoneally (i.p.) with COAM or saline at different time points after immunization. Clinical disease and histopathology were compared between both groups. IFN expression was analyzed in COAM-treated MEF cell cultures and in sera and peritoneal fluids of COAM-treated animals by quantitative PCR, ELISA and a bioassay on L929 cells. Populations of immune cell subsets in the periphery and the central nervous system (CNS) were quantified at different stages of disease development by flow cytometry and differential cell count analysis. Expression levels of selected chemokine genes in the CNS were determined by quantitative PCR. RESULTS: We discovered that COAM (2 mg i.p. per mouse on days 0 and 7) protects significantly against hyperacute SCH-induced EAE in SJL/J mice and MOG35 55-induced EAE in IFN-gamma KO mice. COAM deviated leukocyte trafficking from the CNS into the periphery. In the CNS, COAM reduced four-fold the expression levels of the neutrophil CXC chemokines KC/CXCL1 and MIP-2/CXCL2. Whereas the effects of COAM on circulating blood and splenic leukocytes were limited, significant alterations were observed at the COAM injection site. CONCLUSIONS: These results demonstrate novel actions of COAM as an anti-inflammatory agent with beneficial effects on EAE through cell deviation. Sequestration of leukocytes in the non-CNS periphery or draining of leukocytes out of the CNS with the use of the chemokine system may thus complement existing treatment options for acute and chronic neuroinflammatory diseases. PMID- 23095574 TI - Impact of solute carrier family 29 member 1 (SLC29A1) single nucleotide polymorphisms on mRNA expression in peripheral blood mononuclear cells. AB - The effects of solute carrier family 29 member 1 (SLC29A1) single nucleotide polymorphism (SNP), rs6932345 and rs747199, on SLC29A1 mRNA expression were examined. The expression levels of SLC29A1 mRNA in peripheral blood mononuclear cells (PBMCs) isolated from 46 healthy subjects (28 males and 18 females) was compared between wild-type and mutant carriers. The mRNA levels in the rs6932345 wild-type (AA genotype) was 1.71 times that in the mutation carriers (AC/CC genotype) (p<0.05). Similar results were observed for rs747199, because rs747199 was linked with rs6932345 at a frequency of 84.8%. It was confirmed that wild type for rs6932345 and rs747199 showed higher SLC29A1 mRNA expression in PBMCs. PMID- 23095575 TI - Bacterial and fungal chitinase chiJ orthologs evolve under different selective constraints following horizontal gene transfer. AB - BACKGROUND: Certain bacteria from the genus Streptomyces are currently used as biological control agents against plant pathogenic fungi. Hydrolytic enzymes that degrade fungal cell wall components, such as chitinases, are suggested as one possible mechanism in biocontrol interactions. Adaptive evolution of chitinases are previously reported for plant chitinases involved in defence against fungal pathogens, and in fungal chitinases involved in fungal-fungal interactions. In this study we investigated the molecular evolution of chitinase chiJ in the bacterial genus Streptomyces. In addition, as chiJ orthologs are previously reported in certain fungal species as a result from horizontal gene transfer, we conducted a comparative study of differences in evolutionary patterns between bacterial and fungal taxa. FINDINGS: ChiJ contained three sites evolving under strong positive selection and four groups of co-evolving sites. Regions of high amino acid diversity were predicted to be surface-exposed and associated with coil regions that connect certain alpha-helices and beta-strands in the family 18 chitinase TIM barrel structure, but not associated with the catalytic cleft. The comparative study with fungal ChiJ orthologs identified three regions that display signs of type 1 functional divergence, where unique adaptations in the bacterial and fungal taxa are driven by positive selection. CONCLUSIONS: The identified surface-exposed regions of chitinase ChiJ where sequence diversification is driven by positive selection may putatively be related to functional divergence between bacterial and fungal orthologs. These results show that ChiJ orthologs have evolved under different selective constraints following the horizontal gene transfer event. PMID- 23095576 TI - Simple cystatin C formula compared to serum creatinine-based formulas for estimation of glomerular filtration rate in patients with mildly to moderately impaired kidney function. AB - BACKGROUND: Serum cystatin C (SCC)-based formulas and the newer creatinine formula (the Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI)) were proposed as improved glomerular filtration rate (GFR) markers. The aim of our study was to compare serum creatinine (SCr)-based and SCC-based equations against (51)Cr-EDTA clearance in patients with mildly to moderately impaired kidney function. METHODS: 255 adult Caucasian patients with chronic kidney disease (GFR 89-30 ml/min/1.73 m(2)) were enrolled. In each patient, (51)Cr-EDTA clearance, SCr and SCC were determined. GFR was calculated using the Cockcroft Gault (C&G), Modification of Diet in Renal Disease (MDRD), CKD-EPI formulas and simple cystatin C formula (SCCF) (100/SCC). RESULTS: The receiver-operating characteristic curve analysis (cut-off for GFR 60 ml/min/1.73 m(2)) showed that the SCCF had a higher diagnostic accuracy than C&G but not than MDRD or CKD-EPI formulas. The Bland-Altman analysis for the same cut-off value showed that creatinine formulas underestimated and SCCF overestimated the measured GFR. Analysis of ability to correctly predict a patient's GFR <60 or >60 ml/min/1.73 m(2) showed the higher ability for the SCCF compared to all creatinine-based formulas. CONCLUSION: Our results indicate that the SCCF is a reliable marker of GFR and comparable to creatinine formulas including the CKD-EPI formula. PMID- 23095577 TI - Types of marriages, population structure and genetic disease. AB - A high occurrence rate of consanguineous marriages may favour the onset and increased frequency of autosomal recessive diseases in a population. The population of Monte Santo, Bahia, Brazil, has a high frequency of rare genetic diseases such as mucopolysaccharidosis type VI, whose observed frequency in this population is 1:5000, while the incidence of this disease recorded in other regions of the world varies from 1:43,261 in Turkey to 1:1,505,160 in Switzerland. To verify the influence of consanguineous marriage on the increased frequency of observed genetic diseases in this population, the population structure and frequency of different types of marriage during different time periods were evaluated. A total of 9765 marriages were found in an analysis of parish marriage records from the city. Over three periods, 1860-1895, 1950-1961 and 1975-2010, the inbreeding rates were 37.1%, 13.2% and 4.2% respectively. Although there was a high rate of inbreeding, endogamic marriages were the dominant marriage type in all three periods. In the most recent period, there was an increase in the number of exogamous marriages and those among immigrants, but most of these occurred among individuals from cities that neighbour Monte Santo. The low rate of migration and high frequency of endogamic and consanguineous marriages show that growth of this population is predominantly internal and could explain the occurrence, and increase in frequency, of recessive genetic diseases in the city. PMID- 23095578 TI - Anomalous left coronary artery from the pulmonary artery with a large patent ductus arteriosus: aversion of a catastrophe. AB - We present an infant who had an anomalous left coronary artery arising from the pulmonary artery (ALCAPA) and a large patent ductus arteriosus (PDA), who was diagnosed before a potentially catastrophic closure of PDA. In the presence of normal left ventricular function and the absence of coronary artery collaterals, it is difficult to diagnose ALCAPA. A disproportionate degree of left ventricular dilation and severity of mitral valve regurgitation relative to the degree of PDA shunt, and echogenic papillary muscles on an echocardiogram should raise a suspicion of coronary artery anomalies. The infant underwent surgical ligation of PDA with translocation of coronary arteries and had an uneventful recovery. PMID- 23095579 TI - [Specific treatments of the psychiatric community and thrombogenesis]. AB - BACKGROUND: The causes of venous thrombosis (DVT) are multifactorial. Psychiatric patients present several etiologic features. AIM: Our objective was to determine the role of specific treatments of the psychiatric community on thrombogenesis. METHODS: STUDY POPULATION: retrospective, descriptive and analytical study of 20 cases of DVT in psychiatric patients. LITERATURE REVIEW: We searched MEDLINE (PubMed) between 1959 and 2009. We reviewed article titles and abstracts and full text of selected studies of psychiatric patients with venous thromboembolism (VTE) disease. We identified 31 studies that investigated the association between psychiatric disease and venous thromboembolic events. RESULTS: Our population was young, with an average age of 44.8 years. Lower limb VT is predominant (16 cases). The most common psychiatric disorders are: anxiety-depression (12 cases), unclassifiable psychotic disorders (seven cases) and major depressive disorder (five cases). Their average duration was of 6.4 years. Seventy percent of our patients were taking first generation neuroleptics (NLP), of short half-life (13/14 cases) and at high doses (11/14 patients). Our sample is characterized by the frequency of thrombophilia (45%) and detention in a psychiatric community (35%). Our results are relatively consistent with aggregate data from the literature, underlining a facilitating and pejorative role of the psychiatric community with regard to venous thromboembolic disease. In the psychiatric community, venous thromboembolic disease is conditioned by a combination of several thromboembolism risk factors: linked in part to the psychiatric illness itself; but above all to the specific therapeutic methods in the psychiatric community (antipsychotics, restraint...) which are easily preventable. The relationship between antipsychotic medication and VTE was first suggested about four decades ago, only a few years after the introduction of phenothiazines and reserpine. An association between atypical antipsychotic agents and VTE has been previously suggested for clozapine among young adults with psychiatric disorders. More recently, an increased risk of VTE was suspected for olanzapine or risperidone. The risk for VTE seems to be highest during the initial months of treatment with antipsychotics. Several biological mechanisms of action have been proposed to explain this relationship. One plausible mechanism derives from research suggesting that conventional antipsychotic drugs are associated with enhanced platelet aggregation. A second possible explanation stems from the presence of anticardiolipin antibodies, which increase the risk of venous or arterial thrombosis, as well as in some patients prescribed chloropromazine. A third hypothesis is that venous stasis exacerbated by sedation, commonly found in patients treated with low-potency antipsychotic drugs, may contribute to processes that increase the risk of thrombosis. CONCLUSION: Other than the medical aspect, the psychiatric community itself is characterized by a large number of variables, providing a particularly encouraging and derogatory hypothesis on the advent and development of VTE. PMID- 23095580 TI - [Results of the French cohort of the European observational study FINDER: quality of life of patients treated with antidepressants]. AB - OBJECTIVES: To describe health-related quality of life (HRQoL), pain, clinical outcomes and treatment patterns in French patients with depression treated by general practitioners and psychiatrists. METHODS: Factors Influencing Depression Endpoints Research (FINDER) is a European longitudinal observational, naturalistic, multicentre study to determine the HRQoL (SF-36 and EQ-5D) and to assess outcomes of depression and anxiety (Hospital Anxiety and Depression Scale [HADS]), and pain (VAS) in a population of depressed patients initiating antidepressant treatment. Clinical diagnosis of depression was based on physician's clinical judgment. Physicians decided at their own discretion and clinical practice to initiate pharmacological treatment for depression. Adult patients with a first or new episode of depression were enrolled between May 2004 and September 2005, and followed up for 6 months. Across Europe, 437 physicians observed 3468 patients. RESULTS: In France, 606 patients (approximately 17% of the whole sample) were enrolled by 57 psychiatrists and 46 general practitioners. These patients were (mean +/- SD) 45.6 +/- 13.0 years old, 69% female and 39% having had a previous depressive episode in the last 2 years. According to the patient-rated HADS score greater or equal to 11, most patients (75%) were classified as cases of depression as well as cases of anxiety (84%); 51% of patients rated their overall pain severity (based on VAS cut-off of 30 mm) as moderate/severe, with 65% of these patients reporting no medical explanation for their pain. The majority (81%) of the patients were prescribed selective serotonin reuptake inhibitors (SSRI). During the 6-month follow-up, the majority of the patients (73%) remained on the same antidepressant at the same dose during the course of treatment. Between baseline and 6-month endpoint, French patients improved their mean scores (SD) on the SF-36 physical score by+3.5 (9.0) (P<0.001) and mental score by+20.6 (14.2) (P<0.001); on the EQ-5D Health State Index by+0.37 (0.32) (P<0.001) and the EQ-5D VAS by+32.3 (25.0) (P<0.001); on the HADS depression score by-8.1 (6.0) (P<0.001) and HADS anxiety score by-6.9 (5.0) (P<0.001). Patients with moderate/severe pain at baseline improved their overall pain on a mean VAS score by-34.1 (28.7) (P<0.001). CONCLUSIONS: More than half of the French patients enrolled in the study experienced pain associated with depression. During follow-up, patients improved all of their outcome measurements (physical and mental SF-36 scores, depression and anxiety HADS scores, pain VAS, EQ-5D Health State Index and VAS) and most patients remained on the same antidepressant at the same dose. PMID- 23095581 TI - [Anatomical contents in the Rorschach test: comparison between a population of nurses and a control group]. AB - INTRODUCTION: The study of answer contents to a Rorschach test leads to numerous debates and controversies. From a pragmatic point of view, the recurrent question is to understand the meaning of a content (or its repetition) in a protocol. From a discursive and perceptive point of view, it is hazardous to give an interpretation other than descriptive and contextual. Indeed, no single interpretative theory or analysis method is able to determine with certainty and rigor a strict correlation between people's psychological functioning and the contents they perceive. METHODS: In this empirical context, we studied the "anatomy" answers (frequencies and formal qualities) in a population of nurses (n=38) matched with a control group (non-medical subjects, n=38). The Rorschach test was administrated according to the recommendations of the Integrated System. RESULTS: The average of An+Xy answers was clearly and significantly higher in the nurse population (3.58) than in the control group (0.89) and than in the three comparative norms that we selected (from 0.96 to 1.83). Concerning the formal quality, the repeated-measures analysis of variance showed a significant interaction effect: although subjects in the control group gave a similar number of ordinary, unusual and minus forms for An+Xy answers, the nurses gave more erroneous (minus) forms (1.79) than unusual forms (1.21) and finally than ordinary forms (0.58). DISCUSSION: Two hypotheses may be suggested in order to explain our findings. On one hand, it is highly probable that our results are linked to the everyday body confrontation in a nurse's job. On the other hand, we suggest that by giving An+Xy answers, nurses tend to reveal some idiosyncratic characteristics in order to show their own identity. Indeed, our nurse subjects were selected because of their job, and so they complied with the social identity that was implicitly expected. This is congruent with the complex functioning in social reality: in a social group, people will not verbalize all of their perceptions; they will preferentially verbalize perceptions that define their social identity. Conversely, if some perceptions do not comply with the subject's identity, these perceptions will be less frequently verbalized, despite the fact that they were perceived. Concerning the second main finding, the inadequate formal quality of answers given by nurses emphasizes a visual misrepresentation conditioning due to one's job. This effect is interesting from a psychological point of view because it suggests that this tendency to perceive more anatomical contents arises to the detriment of the "reality". Finally, our findings allowed us to suggest the hypothesis of the role of identity in answer contents to a Rorschach test according to the context, and to formulate some recommendations about the content use in the Rorschach interpretation. PMID- 23095582 TI - [Factors related to suicide attempts in a Tunisian sample of patients with schizophrenia]. AB - INTRODUCTION: The mortality rate in schizophrenia is 4.5 times higher than in the general population. Suicide is one of the main causes of premature death in this affection. Life time prevalence of this behavior ranges from 10 to 15%, which represents a risk 20 to 50 times higher than in the general population. In addition, 40 to 93% of patients who committed suicide had attempted suicide previously. Thus, assessment of correlated variables with suicide attempts is a fundamental issue for developing preventive and therapeutic strategies in suicidal behavior. To the best of our knowledge, no systematic study has yet investigated suicide attempts in an Arabic Muslim population with schizophrenia, although many authors have demonstrated cultural differences in socio-demographic and clinical variables related to suicide attempts within many geographic areas around the world. OBJECTIVES: The objectives of this study were to assess the frequency and characteristics of lifetime suicide attempts in Tunisian schizophrenic outpatients and to determine the correlated socio-demographic, clinical and therapeutic variables. METHODS: A total of 134 patients with a DSM IV diagnosis of schizophrenia who attended the outpatient department of the university psychiatric hospital of Tunis were included. The main demographic and lifetime clinical variables considered were: gender, marital status, family history of psychiatric disorders and suicide attempts, age at time of recruitment, age at onset of illness, duration of untreated psychosis defined as the interval between the onset of the illness and the first antipsychotic treatment, the type and dose of current treatment, dose of antipsychotic drugs converted to chlorpromazine equivalents, extrapyramidal side effects assessed with the Simpson Angus rating scale, number of hospitalizations, comorbid substance abuse, cigarette smoking, severity of psychopathology measured with the Positive And Negative Syndrome Scale (PANSS), and history of at least one suicide attempt. A suicide attempt was defined as a self-destructive act carried out with at least some intent to end one's life. We also assessed the number, the used methods and the causes of suicide attempts. We subdivided the sample into two sub samples according to the presence or absence of suicidal attempts. We analyzed and compared the demographic, clinical and therapeutic variables. RESULTS: Out of the 134 patients, 45 (32%) had attempted suicide at least once. Half of them (49%) had attempted suicide more than once. The number of suicide attempts varied from one to five with an average of 1.8. The most used methods were medication overdose (n=18, 23.4%), followed by organophosphate poisoning (n=11, 14.3%), defenestration (n=9, 11.7%) and hanging or using sharp objects (n=7, 9.1% for each of them). The main reported reasons of suicide attempts were depressive symptoms (n=46, 60%) including depressed mood and hopelessness, stressful life events (bereavement, divorce, separation) (n=35, 46%) and presence of delusions and/or auditory hallucinations (n=25, 32.5%). No differences were found between the two groups regarding the different socio-demographic variables. Significant differences were found with respect to a duration of untreated psychosis equal to or more than one year (P<0.001), smoking in men (P=0.03), positive symptoms score on the PANSS (P<0.001), scores of Simpson-Angus scale (P=0.029) and poor medication compliance (P=0.02). CONCLUSION: Demographic variables as suggested by other studies are less valuable predictors of suicide attempts in patients with schizophrenia. Interventions for reducing such behavior should focus on clinical variables and integrate an early diagnosis of the disease, reduce positive psychotic symptoms and tobacco consumption, correct extrapyramidal signs and improve medication compliance. PMID- 23095583 TI - [Promoting family-professional partnership in institutions for children with autism]. AB - OBJECTIVE: The present study aims to evaluate the impact of the Family Professional Partnership Model on parents' perception of being enabled and empowered in the treatment of their autistic children. In the context of treatment for children with autism, the Family-Professional Partnership Model strives to create an egalitarian relationship between parents and mental health professionals and it encourages parents to actively participate in their child's treatment. To evaluate the effectiveness of the Family-Professional Partnership Model at enabling and empowering parents of autistic children at the IME, parents of autistic children (n=18) completed the EPS and the PES. METHOD: For the purposes of this study, the EPS and the PES were translated into French. Eighteen parent couples of autistic children (ages 4-13 years) receiving treatment at the IME for 1 to 2 years agreed to participate. Participants' responses to the EPS were correlated with their responses to the PES. RESULTS: Parent scores on the EPS significantly correlated with their scores on the PES. Father scores on the two measurements correlated significantly, whereas the correlation between mother scores on these measurements remained insignificant. CONCLUSION: The findings of this study are limited by the small sample size (n=18) but they suggest that the Family-Professional Partnership Model had a positive impact on parent enablement and empowerment in taking care of their autistic children. Future studies should evaluate enablement and empowerment in a larger sample of subjects. They should also evaluate specific factors in the Family-Professional Partnership that lead to parent empowerment. PMID- 23095584 TI - [Epidemiology of anorexia nervosa: a review]. AB - A critical review of the literature was conducted to provide answers to three questions: firstly, are we facing a national and/or international epidemic of anorexia nervosa (AN) as claimed in the media by certain professionals? Secondly, is AN simply an ordinary crisis of adolescence? Thirdly, is it a pathology that solely affects the higher socio-professional categories? METHOD: A Medline search was conducted and backed up by a manual search to find all the studies or literature reviews published on prevalence, incidence rates, outcomes, morbidity and mortality in AN and its links with social class, covering the period 2000 2011. RESULTS: The differing methodologies of the studies on these themes have a considerable impact on the interpretation of results. For each indicator retained, the results observed in the different studies are detailed and commented in the light of these differences. The prevalence of AN in women aged 11 to 65 in non-clinical population ranges from 0 to 2.2 %. It varies in particular with the age of the studied subjects, the measurements used, and the definition criteria for AN. Among men, the lifetime prevalence is around 0.3%. The marked disparities in incidence rates observed are related to the nature of the samples considered: subjects consulting in hospital, whether in a specialised department or in any department, those consulting general practitioners (GPs), or subjects from general population samples recruited in different surveys (girls in schools for example). The incidence of female cases is low in general medicine or specialised consultation in town (whatever the speciality): from 4.2 and 8.3/100,000 individuals per year. It is much higher in the general population, ranging from 109 to 270/100,000 individuals per year. In fact, the studies reporting variations in the incidence of AN were conducted on samples from clinical populations in certain countries (United States and United Kingdom). They are probably more a reflection of variations in detection rates and use of healthcare, than of variations in the incidence in the general population. The mean duration of AN appears shorter in the general population than in clinical populations. On average, 47% of the individuals treated for AN recovered, 34% improved, 21% had a chronic eating disorder, and 5% died. The outcome is better for subjects treated during adolescence. Mortality is frequently expressed in crude mortality rate (CMR), which is not very informative on account of the heterogeneous natures of the cohorts followed; only the studies reporting standardised mortality rate (SMR) are informative. AN appears as having one of the highest mortality rates among psychiatric pathologies. Mortality varies according to the population considered. Rates observed are 6.2 to 10.6 times greater than that observed in the general population for a follow-up duration ranging respectively from 13 to 10 years. It is lower for longer follow-up periods, only 3.7 times more frequent than in the general population for follow up periods of 20 to 40 years. It appears lower for subjects treated before the age of 20. The main causes of death are eating disorder complications, suicide and cancer. One review of the literature concluded in the absence of any significant link between this pathology and social class. DISCUSSION: There is nothing in the incidence and prevalence data to back up the notion of a recent "epidemic" of AN. AN is not simply a crisis of adolescence: morbidity and mortality are considerable in this pathology. The relationship between AN and social class is not established. PMID- 23095585 TI - [Bipolar disorders and comorbid anxiety: prognostic impact and therapeutic challenges]. AB - INTRODUCTION: Anxiety disorders are among the main psychiatric conditions co occuring with bipolar disorders. Many clinical and epidemiological studies have found much higher prevalence rates of generalized anxiety disorder, social phobia, obsessive-compulsive disorder, panic disorder and post-traumatic stress disorder in bipolar patients than in the general population, regardless of age. In the National Comorbidity Survey for instance, the diagnosis of at least one anxiety disorder was made for nearly 90% of bipolar subjects. Several issues arise from this high comorbidity, such as the way anxiety disorders alter the course and prognosis of the mood disorder, and challenge typical therapeutic strategies. This article reviews data on clinical and therapeutical significance of such comorbidity. LITERATURE FINDINGS: Many studies point out the poorer outcome for bipolar patients with co-occurring anxiety symptoms: apart from the alarming increase of suicidal ideas and suicide attempts, authors have found a shorter duration of euthymia, more comorbid addictions, mixed states and rapid cycling, and lower response to treatments. This is the reason why monitoring the suicidal risk in those bipolar patients with co-occurring anxiety disorders is of critical importance. From a physiopathological standpoint, the precise links between both pathologies remains unclear. The frequency of this comorbidity and its significance on long term prognosis stands in sharp contrast with the very few therapeutic studies conducted in this indication so far. Pharmacological approaches are strongly limited by the risk of mood switching under antidepressants and drug dependence on anxiolytics such as benzodiazepines. Nevertheless, there is emerging evidence of the interest of atypical antipsychotics such as olanzapine and mood stabilisers such as lamotrigine to control anxiety symptoms in bipolar patients. There is weaker evidence for other molecules. Taking into account other therapeutic approaches than the pharmacological approach appears accurate. Psychosocial interventions such as cognitive-behavioral therapies or psychoeducation appear essential to improve in a correct way the global functioning and quality of life of these patients. PMID- 23095586 TI - [Treating specific childhood phobia in a single session? A systematic review of the literature]. AB - OBJECTIVE: The essential feature of specific phobia is a persistent fear of clearly discernable, circumscribed objects or situations. The DSM-IV distinguishes four subtypes: animal, natural environment, blood-injection-injury, and situational. Specific phobias frequently co-occur. Specific phobia is one of the most common psychiatric disorders with a lifetime prevalence of 12.5% and is about twice as common in women as in men. Most phobias have a childhood onset except for the situational subtype which usually occurs during patients' twenties. It is well known that childhood anxiety increases the risk of psychiatric disorders such as depression and anxiety in later life, as well as the risk of suicide attempts and psychiatric hospitalization. Nonetheless, there are few studies on the psychobiology and pharmacotherapy of specific phobias. Neuroimaging studies have shown that specific phobia seems to be associated with amygdala (more specifically the right amygdala) and anterior cingulate cortex hyperactivation that is reduced after exposure therapy. The aim of this study is to propose the first systematic review of specific phobia treatment among children. METHOD: The review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines. Two databases (Medline and Web of Science) were searched combining the search terms: specific phobia and treatment. English and French language were imposed. There were no publication date or publication status limitations. Seventy-four studies met the inclusion criteria and 36 were included. RESULTS: The goal of treatment is to achieve habituation and eventual extinction of the phobic reaction. Treatments for children's anxiety have been suggested to work through diverse processes such as counter-conditioning, extinction, habituation, change in catastrophic cognitions, development of coping skills, increased self-efficacy, emotional processing, and changes in expectancies and perceptions of dangerousness. Most phobias respond robustly to in vivo exposure, but this approach is associated with high dropout rates and low treatment acceptance. One Session Treatment, a variant of cognitive behavioral therapy, combines graduated in vivo exposure, participant modeling, reinforcement, psychoeducation, cognitive challenges, and skills training in an intensive treatment model. The limited data available on medication shows little promise. Finally, relapse is a common phenomenon, and little is known on the long term outcome of the illness. PMID- 23095588 TI - [Infants and toddlers behavioral and functional disorders: characteristics, mother-child interactions, alliance and outcome after a brief parents-child psychotherapy. A pilot study]. AB - OBJECTIVES: Functional and behavioral disorders are the most frequent reasons for consultation in infant psychiatry, but there are still few studies about the efficacy of parents-child psychotherapies. Functional disorders appear to be easier to treat than behavioral disorders. The aim of this study was: (1) to assess outcome after a brief psychotherapy in a population of 49 infants aged 3 to 30 months, presenting functional or behavioral disorders; (2) to compare characteristics before therapy and outcomes for children with functional disorders and with behavioral disorders, to have a better understanding of the worse outcome of children with behavioral disorders. METHODS: Two assessments were performed, one before treatment and the second a month after the end of the therapy including the infant's symptoms (Symptom Check-list), parents' anxious and depressive symptoms (Hospital Anxiety and Depression scale) and mother-infant interactions (Crittenden Experimental Index of adult-infant relationship). The therapeutic alliance was assessed by the therapist and the parents after the first consultation (Working Alliance Inventory). RESULTS: The assessments after therapy show complete or partial improvement in the child's symptoms, in the mother's anxious and depressive symptoms and in the father's anxious symptoms. During interaction, the mothers become more sensible, the number of controlling and of unresponsive mothers decrease, while the children become more cooperative and less passive. Initial characteristics and outcome are however different according to the type of the child's disorder. The children with behavioral disorders are older and present an association of several symptoms. The disorder onset is later. Their mothers are, before therapy, more anxious and depressive. The therapeutic alliance is weaker. After therapy, despite the fact that their mothers' affective state and that interactive behavior improves, the mothers are more anxious and less sensible, while the children no longer differ from the group without behavioral disorder from the point of view of opposition (assessed during mother-child interaction). CONCLUSION: Although this study is limited by the lack of a control group and the sample size, it underlines some particularities of infants and toddlers presenting behavioral disorders and the difficulties involved in their treatment. One can wonder if these characteristics are specific of the behavioral disorders or if they are the result of an older dysfunction, complicated by the developmental evolution of the child and the duration of the difficulties. The small number of cases, among the children with behavioral disorders, presenting a preexistent functional disorder, the absence of difference in the duration of the disorders, and the different disorder's onset plead in favor of the first hypothesis. The behavioral disorders often associate child psychopathology, dysfunctional parents-child-relationships and environmental factors difficult to modify with a brief therapy focused on the relationship. It would appear necessary to develop specific treatments for this population. PMID- 23095587 TI - [Prolonged corticosteroid-therapy and anxiety-depressive disorders, longitudinal study over 12 months]. AB - To date, there is little data in the literature describing the anxiety and depressive disorders iatrogenic to corticosteroids. These disorders are common, underestimated, with potentially serious consequences that may jeopardize the patient's prognosis; their management is not consensual. OBJECTIVES: The objective of our work is to determine the prevalence of anxiety and depressive disorders induced by corticosteroids, assessing their accountability to the corticosteroids and studying their risk factors. METHODS: We conducted a prospective longitudinal study over 12months evaluating the prevalence of anxiety and depressive disorders in patients followed for chronic skin diseases treated with prolonged corticosteroid-therapy. Our patients were assessed using standardized instruments: the Mini International Neuropsychiatric Interview (MINI), the Hamilton Anxiety Scale (HAS) and the Beck Depression Inventory (BDI). RESULTS: Of 54 patients included, our study showed a high prevalence of anxiety and depressive disorders estimated at 27%. These disorders were divided into depressive disorder in 16% of cases, and anxiety disorder in 11% of cases. The early onset of these disorders was found during the first weeks of treatment. According to the Beck Depression Inventory (BDI), depression was moderate in 67% of cases; severe with suicide attempts in 22% of cases, and mild in 11% of cases. According to the Hamilton Anxiety Scale (HAS), anxiety was mild in 33% of cases and moderate in 67% of cases. The disorders observed were mainly distributed into: 33% deep pemphigus, 27% lupus, 13% bullous pemphigoid and 13% dermatomyositis. In this study the statistically significant risk factors are dose of corticosteroids and personal psychiatric history of the patient; in addition, there is a high prevalence of disorders in patients whose age exceeds 40 years, female gender, and patients treated for deep pemphigus. The evolution after pharmacological treatment and supportive psychotherapy was favorable in most patients. CONCLUSION: The psychiatric examination prior to prescription of long-term corticosteroid-therapy use should be standard practice to identify patients at risk, discuss the treatment modalities, and provide comprehensive care. PMID- 23095589 TI - ["It was me or them!": the no exit escape of a future author of psychotic double parricide]. AB - CASE-REPORT: H. had perceived his father as an evil persecutor ever since his adolescence. He developed paranoid schizophrenia of persecution in which his father occupied the main role. Little by little, in his desperate resistance against his father, perceived as his enemy, he acquired such a feeling of prejudice, of violation of his personality, and of impotence that the only way out was to escape in order to survive. At the age of 18, he decides to run away from home and from France to stop suffering. He goes to Canada and later to the USA where he would stay 9 years, during which his madness does not stop. Wherever he goes, he always feels the presence of his father in his head: "He orders me, he criticizes me from a distance, he steals all my thoughts, he is in charge of my actions, he takes away the bread from my mouth to humiliate me and kill me..." Thanks to his marginal lifestyle, he maintains a relative adaptation, a fragile equilibrium in his existential bubble in which he doesn't tolerate any breaking and entering. His delusion of prejudices and persecution, of which the main character had always been his father, extends to include society in general, cornering and leading the subject to commit an offense as a reaction of irrepressible pathological self-defense. He is questioned by the police, taken to prison and later taken to an American psychiatric hospital, after shooting at those whom he thinks are "CIA agents" (who are actually people forcing him to move the boat in which he lives). After being deported back to France, he returns to his parent's home, the source of all his madness. During the following months, he lives locked up in his room afraid of being near his father and tormented by his delirious ideas. In order to stop his suffering, he decides to buy a fire-arm to kill himself. One day, his father, accompanied by his mother, break into his room. He takes the rifle hidden under the mattress, and kills his father at point blank. "I thought that I had instantly killed my father, because he fell face down on the ground. On the other hand, my mother remained standing while my sister, screaming, escaped through the window of the living room. My mother, injured on her right side, moved back to the living room. Seeing that my mother hadn't fallen to the ground and not wanting to make her suffer, I reloaded my rifle. I took out the cartridge, and reloaded the rifle with a cartridge of buckshot. It seemed to me that she was still standing in front of the couch. I fired the gun a second time without looking and at that moment she falls on the couch... dead... She is the enemy because she is my father's wife". DISCUSSION: The recounting and analysis of this double psychotic parricide case illustrate the psychopathologic constants and criminal dynamic that are most often present in this type of crime. The constants are the following: the perpetrator of the post-adolescence or adult parricide is often a psychotic young man; he/she lives a long, delusional story in which one or both parents have an important role; this insane delusion leads to suffering and/or to identifiable behavioral problems that together can constitute a criminal psychic state; The homicidal reaction takes place right after one or a group of factors (such as an argument, brawl, a fit of delusion, interruption of the therapeutic treatment...) that are set off in the criminal pathological state. These psychopathological constants, if they conjoin, are also the factors and indicators of danger. They should be considered as a warning sign to take preventive and remedial measures. PMID- 23095590 TI - [Cyber-bullying in adolescents: associated psychosocial problems and comparison with school bullying]. AB - AIM: The aim of this study was to determine the prevalence of adolescents engaged in cyber-bullying and then to identify whether students involved in cyber- and school bullying present the same characteristics of internalizing problems (insomnia, perceived social disintegration, psychological distress) and externalizing problems (general aggressiveness, antisocial behavior). METHOD: Semi-structured interviews were conducted with 738 adolescents from a high-school and a middle-school (mean age=14.8 +/- 2.7). The Electronic Bullying Questionnaire and the Olweus Bully/Victim Questionnaire were used to identify profiles of cyber-bullying (cyber-victim, cyber-bully, cyber-bully/victim and cyber-neutral) and school bullying (victim, bully, bully/victim and neutral). Internalizing problems were investigated using the Athens Insomnia Scale, a Perceived Social Disintegration Scale and a Psychological Distress Scale. Externalizing problems were assessed using a General Aggressiveness Scale and an Antisocial Behavior Scale. RESULTS: Almost one student in four was involved in cyber-bullying (16.4% as cyber-victim, 4.9% as cyber-bully and 5.6% as cyber bully/victim); 14% of our sample was engaged in school bullying as a victim, 7.2% as a bully and 2.8% as a bully/victim. The majority of adolescents involved in cyber-bullying were not involved in school bullying. With regard to the problems associated with school bullying, internalizing problems were more prevalent in victims and bully/victims, whereas externalizing problems were more common in bullies and bully/victims. A similar pattern was found in cyber-bullying where internalizing problems were characteristic of cyber-victims and cyber bully/victims. Insomnia was elevated in the cyber-bully group which is specific to cyberbullying. General aggressiveness and antisocial behavior were more prevalent in cyber-bullies and cyber-bully/victims. Looking at the differences between types of bullying, victims of "school only" and "school and cyber" bullying had higher scores for insomnia and perceived social disintegration than victims of "cyber only" bullying or students "non-involved". Higher general aggressiveness scores were observed for "school only" bullies and "school and cyber" bullies than for bullies in "cyber only" bullying or students "non involved". Regarding antisocial behavior, "school only" bullies, "cyber only" bullies, "school and cyber" bullies had higher scores than students "non involved". DISCUSSION: This study highlights the importance of investigating both school and cyber-bullying as many psychosocial problems are linked to these two specific and highly prevalent forms of bullying. PMID- 23095591 TI - [Evaluation of the risks of relapse: an inescapable evolution in practices]. PMID- 23095592 TI - [Mental issues of clinical research interviews in an intercultural context]. AB - INTRODUCTION: The interview is an intersubjective meeting in which the stakes are complex. This frequently used method in social and human sciences research brings to the foreground various mental processes. Despite its clear distinction from the therapeutic interview, due to its purpose and the origin of the request, the research interview generates for both the participant and the researcher unconscious phenomena and contributes to the epistemological reflection inherent to the clinical approach. AIM OF THE PAPER: The aim of this article is to demonstrate that the mental processes mobilized in the participants and in the researcher, who belong to the same culture of origin during the research interview, may be analyzed in four dimensions: intrapsychique, intersubjective, projective and group. METHODS: So as to illustrate the various mental processes that are engaged, a research conducted in clinical intercultural psychology regarding the adaptive processes and the identity strategies of Korean mothers living in France or in Quebec is used. In order to offer maximum freedom of expression to the participants, the interviews were conducted in Korean, and then translated into French. The intrapsychic dimension is illustrated by an example from the interview with a 44-year-old Korean woman met in Paris. Following the Rogerian theory (1952, 1961), we understand that the participant comes to a coherent reorganization of her own conception throughout the interview, allowing her to speak and to think about her autobiography. From the interaction between two subjectivities, the thought and the discourse are involved in the co construction of meaning. The understanding of the intersubjective dimension is supported by the theory of Winnicott (1971), developed for the transitional space. Like the mother-child relationship in the game device, the mental permeability available to the researcher is supposed to guarantee the development of the interviewee's confidence. The example of the interview conducted with another 39-year-old Korean woman living in Paris illustrates this intersubjective dimension. The analysis of the relationship between the researcher and his object of research will argue the projective dimension. In the quoted research, the researcher is facing a situation in which the participant's problems remind him of his own questionings. The work of analysis, with hindsight and in the after fact, on the position of the researcher and his subjective implication, is necessary to avoid the possible risk of subjectivation. The group dimension has several levels: institutional, national, international or even worldwide. Thus, the intercultural aspect is particularly highlighted in an attempt to present the complexity of the process. DISCUSSION: The idea of the interculturality awareness at several levels was highlighted in particular by taking the institutional transference/counter-transference movement into consideration. The transfer mezo level revealed itself as one of the analyzers of the group dimension, such as the motivation for accepting the participation in our investigation. In other words, it requires understanding both the relationship conducted by each individual with the institution, and that conducted by two subjects met within the institution. In the current world marked by globalization, "the geohistory of the clinical encounter" (Derivois, 2010) becomes an interesting tool to understand the complexity of the encounter issues arising from the clinical consultation. PMID- 23095593 TI - [On the dynamics of psychological functioning through speech analysing]. AB - OBJECTIVE: The aim of this study is to focus on the clinical aspects of four linguistic indicators that emerge from automatic speech analysis. BACKGROUND: From a theoretical point of view, the number of proposals deals with cognitive activity, the number of modelizations with emotional activity, the number of connections with judgment activity and the number of action verbs can refer to behavioral activity. METHODS: To test these hypotheses we have studied two protocols of Thematic Aperception Test (TAT) randomized from non-clinical groups for the former and from a group of schizophrenic patients for the latter. RESULTS: The outcomes regarding the non-clinical protocols lead to the conclusion that the four indicators are coherent (alpha=0.93) and correlated; this confirms the clinical data on the cohesive personality of this young lady. The absence of correlations within the schizophrenic protocols reflects the dissociative syndrome of this patient. CONCLUSION: Finally, the study of the dynamics of this protocol, using our four linguistic criteria, confirms both the affective indifference and the increase of behavioral activity of this patient when the mentalization fails. After discussion and despite its capacity to describe clinical cases, the validity of this method needs to be completed (by relating the language indicators to production time stories) in further explorations, even if its reliability is good (alpha=0.93). PMID- 23095594 TI - [Acute catatonia: Questions, diagnosis and prognostics, and the place of atypical antipsychotics]. AB - INTRODUCTION: Acute catatonia is a non-specific, relatively frequent syndrome, which manifests itself through characteristic motor signs that enables its diagnosis. It occurs in association with mood disorders, psychotic disorders and several somatic or toxic diseases. Its short-term prognosis is of paramount importance. Without effective treatment, it is associated with high mortality. Despite the vital risk inherent in this disorder, it is not recognized as an independent diagnostic category by international rankings, which makes its diagnostic detection difficult and consequently does not allow adequate therapeutic care. However, if benzodiazepines and electroconvulsive therapy have proved effective in the treatment of acute catatonia, the role of atypical antipsychotics remains controversial. In fact, despite the progress made by the DSM-IV-TR and CIM 10 by the recognition of the etiologic diversity of catatonia, we deplore the absence to date of a consensus on clinical management and therapy of catatonia, which constitutes a source of confusion for practitioners in their approach to catatonic patients. To illustrate the difficulty in supporting these patients, we report here a clinical vignette. CLINICAL FEATURES: Mr. M. aged 21, without psychiatric history, has shown a functional acute psychotic episode involving a delirious and hallucinatory syndrome associated with a marked catatonic dimension. Olanzapine was initiated at a dose of 10mg/d on the nineth day of hospitalization; the clinical picture was complicated by a malignant catatonia justifying the halt of olanzapine and the institution, in intensive units, of 15mg per day of lorazepam. After 72hours, the patient has not responded to this treatment. ECT was expected, but the patient died on the 12th day. DISCUSSION: This case raises a threefold question: the crucial issue of immediate vital prognosis, that of the truthfulness of the positive diagnosis of this psychotic table and finally the issue of therapeutic care, primarily the well founded or otherwise use of an atypical antipsychotic for the treatment of this type of psychotic disorder. For Mr. M., the clinical diagnosis that he has shown, according to the DSM IV-TR, is brief psychotic disorder "temporary diagnosis". This diagnosis - brief psychotic disorder - does not actually allow for a specific clinical approach to this type of psychotic table. The immediate vital prognosis inherent in the catatonic dimension may not be properly evaluated and the therapeutic conduct may miss the application of the specific treatment of the catatonic syndrome. The proper diagnosis for this type of psychotic disorder would be "catatonia" as proposed by Taylor and Fink, instead of "brief psychotic disorder" if the international rankings have included this disorder as a separate and independent diagnosis. The identification by international rankings of the catatonic syndrome as an independent diagnostic category seems essential for clinicians to allow: its clinical detection, the establishment of a syndromic diagnosis of catatonic disorder, appropriate prognostic evaluation and finally, the application of a suitable therapeutic strategy. Conventional treatment, benzodiazepine- and/or ECT-based, can solve the catatonic episode in a few days, irrespective of its etiology and its severity. Moreover, while all authors agree that conventional antipsychotics may induce a catatonic state or worsen a preexisting catatonia into a malignant catatonia and should thus be avoided for catatonic patients or with prior catatonic episodes, recent data from the literature emphasize the frequent and successful use of atypical antipsychotics, including olanzapine, in various clinical forms of benign catatonia. However, our patient did not respond to treatment with olanzapine and got even more complicated. Was the malignant catatonia that this patient has shown induced by olanzapine ? The answer to this question seems difficult since some authors report the efficacy of olanzapine in malignant catatonia. We wonder if we should have kept olanzapine and strengthen its dosage like Cassidy et al. in 2001 and Suzuki et al. in 2010 for the treatment of the malignant form constituted in this patient rather than having stopped it and used lorazepam as indicated by Taylor and Fink in 2003. IN CONCLUSION: The non-recognition of catatonia as an independent entity, the lack of a therapeutic consensus and the pending issue on the safety and efficacy of atypical antipsychotics in the treatment of catatonia are at the origin of the difficulties of therapeutic support of catatonic patients. PMID- 23095595 TI - [Blood-injection-injury phobia: Physochophysiological and therapeutical specificities]. AB - INTRODUCTION: Seventy-five percent of patients with blood-injection-injury phobia (BII-phobia) report a history of fainting in response to phobic stimuli. This specificity may lead to medical conditions remaining undiagnosed and untreated, incurring considerable cost for the individual and society. The psychophysiology of BII-phobia remains poorly understood and the literature on effective treatments has been fairly sparse. Aims of the systematic review: to synthesize the psychophysiology of BII-phobia and to propose a systematic review of the literature on effectiveness of different treatments evaluated in this indication. RESULTS: Firstly, the most distinct feature of the psychophysiology of BII-phobia is its culmination in a vasovagal syncope, which has been described as biphasic. The initial phase involves a sympathetic activation as is typically expected from fear responses of the fight-flight type. The second phase is characterized by a parasympathetic activation leading to fainting, which is associated with disgust. Subjects with syncope related to BII-phobia have an underlying autonomic dysregulation predisposing them to neurally mediated syncope, even in the absence of any blood or injury stimulus. Many studies report that BII-phobic individuals have a higher level of disgust sensitivity than individuals without any phobia. Secondly, behavioral psychotherapy techniques such as exposure only, applied relaxation, applied tension, and tension only, have demonstrated efficacy with no significant difference between all these techniques. The disgust induction has not improved effectiveness of exposure. CONCLUSION: We have explained the psychophysiology of BII-phobia, the understanding of which is required to study and validate specific techniques, in order to improve the prognosis of this disorder, which is a public health issue. PMID- 23095596 TI - [Premenstrual symptomatology, somatization and physical anhedonia]. AB - INTRODUCTION: Physical (headache, abdominal pain, e.g.), emotional (irritability, diminution of self-esteem, e.g.) and/or behavioral disturbances (fatigue, decrease of libido, e.g.) appear frequently during the premenstrual phase of menstrual cycles. Of moderate to severe intensity, these varied symptoms sometimes hinder the usual personal, social and/or professional functioning by generating significant suffering. Thus, premenstrual syndrome (PS) and premenstrual dysphoric disorder (PDD) are closely related to depressive disorders in many prior studies. In spite of solid links associating depression with premenstrual disorders in the literature, the psychological dimension of the premenstrual symptomatology still remains underestimated. OBJECTIVE: The objective of this study is to examine the nature of possible relationships between a moderate premenstrual symptomatology and different modes of information processing with physical and emotional stimuli, such as somatization and physical anhedonia, well-known symptoms of depressive disorders. METHOD: One hundred and five students in psychology from the Francois Rabelais university (France), aged between 18 to 50 years old (M=20.98, SD=3.43), were invited to fill in French versions of the Menstrual Distress Questionnaire [25] (Moos, 1991), the somatization subscale of the Symptom Check-List 90 [26] (Derogatis & Cleary, 1977), and the Physical Anhedonia Scale [28] (Chapman et al., 1976). Pearson correlation coefficients were calculated and a multiple regression analysis was conducted with Statistica software. RESULTS: Main results reveal that premenstrual symptomatology is positively related to somatization (r=0.58; P<0.001) and negatively to physical anhedonia (r=-0.27; P<0.05). Physical anhedonia (beta=-0.20; P<0.05) and somatization (beta=0.55; P<0.001) may take part in the appearance of a premenstrual symptomatology. CONCLUSION: These results allow us to enrich our knowledge on the origin and the nature of the premenstrual symptomatology, which would be physiological, psychological and social, in order to adapt and widen the therapeutic options by proposing, in parallel with the specific medical treatments, psychological interventions based on cognitive and behavioral techniques aiming a decentralization and a restructuration of the physical symptoms. PMID- 23095597 TI - [Minor neurological and physical anomalies in patients with first-episode psychosis]. AB - INTRODUCTION: Over the last several decades, there has been an increasing number of neuroanatomical, neuroimaging, neurophysiological, and neuropsychological studies in search of structural, functional, and cognitive correlates of brain insult(s) that could ultimately lead to unravelling the pathophysiology of schizophrenia. A direct, easily administered, and inexpensive way of investigating brain dysfunction in schizophrenia is the study of neurological soft signs and minor physical anomalies, two putative indices of developmental abnormality. The study of these neurodevelopmental markers in the first-episode psychosis allows the detection of the neurodevelopmental abnormalities at the onset of psychosis. AIMS OF THE STUDY: The objectives of our study were to determinate the prevalence, the scores, and the nature of neurological soft signs (NSS) and minor physical anomalies (MPA) in patients with first-episode psychosis and to explore the correlations between these neurodevelopmental markers and the demographic, clinical and therapeutic features. METHOD: A cross-sectional study was carried-out on 61 patients (mean age: 28.9+/-9.4years; 86.9% were males), hospitalized for first-episode psychosis (DSM-IV-TR diagnosis of schizophrenia, schizophreniform disorder, brief psychotic disorder, delusional disorder, and psychotic disorder not otherwise specified). The evaluation procedure consisted of a retrospective assessment of the premorbid functioning by the Premorbid Functioning Scale (PAS) and the following clinical scales: Positive and Negative Symptoms Scale (PANSS), Clinical Global Impression (CGI) and Global Assessment of Functioning (GAF), the NSS scale of Krebs et al. (23 items exploring motor coordination, motor integrative function, sensory integration, involuntary movements or posture, quality of lateralization) and the MPA scale of Gourion et al. (41 items, exploring anomalies of face, eyes, ears, mouth, hands and feet). RESULTS: The prevalence of NSS was 83.6% (cut-off point=9.5), with a mean total score of 15.3+/-6.7. The highest score was for the motor coordination. The prevalence of MPA was 62.7% (cut-off point=5), with a mean total score of 5.8+/ 3.2. The most common MPA were the fine hair (50.8%), adherent earlobes (49.2%) and clinodactyly (31.1%). Correlations were found between the NSS total score and the Poor Premorbid Functioning (r=0.32, P=0.04), the PANSS total score (r=0.36, P=0.005), and the negative (r=0.45, P<0.001) and disorganization sub-scores (r=0.41, P=0.001), the CGI-severity of (r=0.30, P=0.02), the impairment functioning in the GAF (r=-0.26, P=0.04) and with extrapyramidal symptoms (r=0.52, P<0.001). However, no correlation was found between the NSS total scores, age, gender, the PANSS positive sub-score, the daily dosage of antipsychotics, the CGI-improvement score and the MPA total score. There was no correlation between MPA total score and demographic, clinical and therapeutic features of patients. Moreover, there was no correlation between the NSS or MPA scores and the short-term evolution (6months to 1year) towards schizophrenia. CONCLUSION: These results confirm the data in the literature relating high NSS and MPA scores in patients with a first-episode psychosis. The NSS appear to characterize severe psychotic disorders with more negative and disorganization symptoms and poor social functioning and may be a prognostic indicator. PMID- 23095598 TI - [The role of inhibition in obsessional-compulsive disorders]. AB - INTRODUCTION: The nature of neuropsychological mechanisms underlying the clinical picture of obsessions and compulsions has not been clearly determined. A number of studies has emphasized the role of cognitive deficits, but diversity of methodology and overlapping of clinical sub-groups have not established a specific cognitive functioning of these patients. The studies carried out on executive functions have, however, helped to identify the important role that both inhibition and cognitive flexibility play in obsessive-compulsive (OC) symptoms. Most of them have found that a deficit of inhibition and alteration of cognitive flexibility could explain inflexibility and repetitive thoughts and actions typical of all types of OC disorders. The aim of the paper is to present the published data supporting the hypothesis of a specific role played by a deficit of inhibition and cognitive inflexibility. In the first, theoretical part, we present the neuropsychological approach emphasizing inhibition and lack of flexibility as a promising explanation of the functioning of OC disorders. In the second part, we will present studies using various measurements of inhibition and the results of which, therefore, support this hypothesis. ARGUMENTS AND DISCUSSION: On the theoretical level, it is the model of attention that was used in explaining the OCD hypothesis. In the model of attention control of action, described by Norman, Shallice and Burgess, three systems were emphasized: one that takes care of routine actions, and the second that takes over the first in situations where automatic activities must stop in order to establish an attention control and therefore inhibit automatic responses. When selection of everyday and automatic activities is not sufficient to accomplish a task, it is the third system, that of cognitive control, which takes over. This supervisory attentional system operates in non-routine and ambiguous activities. The cognitive control is charged with detecting potential or emitted cognitive errors and resolving ambiguous situations. Neurocognitive studies show that cingular anterior cortex and prefrontal lateral cortex are engaged in ambiguous and conflicting situations. These two regions are considered essential for inhibition of routine actions, adjustment to change and, more generally, for an efficient and flexible behaviour. Repetitive nature of verification rituals in OCD could be explained in terms of lack of relationship between two systems, leaving in action the one that regulates automatic activities. Therefore, the rituals are considered to be under particular influence of the system which, being in charge of automatic actions, has a deficit in disengagement. Another model of attention, described by Posner, gives a further explanation of OCD. Mental inhibition has the capacity to treat information, either by applying strategies to control it (i.e. trying not to remember an unpleasant event) or leaving it to automatic control (i.e. incapacity to experience an emotion in relation to a particular event). In this way, the effort to suppress an intrusive thought is considered as controlled and deliberate cognitive treatment of emotionally charged information. In OCD, in the context of heightened anxiety, the assumed negative valence of information would influence habitual suppression of thought during controlled treatment. As a result, controlled efforts to suppress obsessions in emotionally stressful situations, would lead to the production of repetitive thoughts, as controlled treatment of information has failed in this action. On a clinical and experimental level, these studies have led to a better understanding and conceptualization of OCD. In spite of some conflicting results, there are concordant data in favour of hypotheses of the role of sub-cortical and frontal regions and their function in inhibition/desinhibition implied in the onset and maintenance of OCD. Functional neuroimagery anomalies are also in favour of the role of sub-cortical-frontal region in clinical manifestations of OCD. They are often associated with low performance in cognitive tasks, especially those implying frontal functions, which are, in turn, dependent on a necessary level of attention in order to guide or inhibit motor and cognitive programs. PMID- 23095599 TI - [Prevalence of pathological gambling in Lebanese students]. AB - INTRODUCTION: Pathological gambling is a behavioral dependency on hazard games that is classified, in the DSM-IV, among impulse control disorders. According to many studies, the international prevalence of pathological ranges between 2 and 6%. This disorder is often accompanied by a considerable impact on patients' life as well as on the life of people surrounding them. Adolescents and young adults are considered to be a population at risk to develop this kind of behavioral dependency. The problem of pathological gambling is one of the major problems from which the Lebanese population of university students in Lebanese society suffers. The prevalence of pathological gambling in the Lebanese population of university students is lacking from the contemporary medical literature. MATERIALS AND METHODS: In our study, five of the biggest private universities in Lebanon (Notre-Dame University of Louaize [NDU], Lebanese American University [LAU], American University of Beirut [AUB], Saint-Joseph University [USJ] and Holy Spirit University of Kaslik [USEK]) were surveyed. Each questionnaire was based essentially on the South Oaks Gambling Screen (SOGS). RESULTS: Four hundred and seventy-seven questionnaires were completed in these universities. Among the 477 students that completed the questionnaire, 5.87% appeared to be suffering from pathological gambling; 25.15% of responding students presented some problems related to gambling while the rest of them, corresponding to 68.92%, had no problems related to gambling. CONCLUSION: This is the first study of its kind conducted in the Lebanon. Its interest lies in that it offers an important evaluation of the prevalence of pathological gambling in the Lebanese population of university students. According to this study, the prevalence of pathological gambling in Lebanese university students is high. Prevention programs and sensitization strategies are needed in order to prevent the occurrence of this disorder in the Lebanese young. More studies are needed in this domain in order to evaluate precisely the prevalence of pathological gambling in Lebanese university students. PMID- 23095600 TI - [Toxoplasma gondii: a potential role in the genesis of psychiatric disorders]. AB - INTRODUCTION: Toxoplasma gondii is the most common protozoan parasite in developed nations. Up to 43% of the French population may be infected, depending on eating habits and exposure to cats, and almost one third of the world human's population may be infected. Two types of infection have been described: a congenital form and an acquired form. Although the medical profession treats these latent cases as asymptomatic and clinically unimportant, results of animal studies and recent studies of personality profiles, behavior, and psychomotor performance have led to reconsider this assumption. PRECLINICAL DATA: Among rats: parasite cysts are more abundant in amygdalar structures than those found in other regions of the brain. Infection does not influence locomotion, anxiety, hippocampal-dependent learning, fear conditioning (or its extinction) and neophobia in rats. Rats' natural predator is the cat, which is also T. gondii's reservoir. Naturally, rats have an aversion to cat urine, but the parasite suppresses this aversion in rats, thus influencing the infection cycle. Tachyzoites may invade different types of nervous cells, such as neurons, astrocytes and microglial cells in the brain, and Purkinje cells in cerebellum. Intracellular tachyzoites manipulate several signs for transduction mechanisms involved in apoptosis, antimicrobial effectors functions, and immune cell maturation. Dopamine levels are 14% higher in mice with chronic infections. These neurochemical changes may be factors contributing to mental and motor abnormalities that accompany or follow toxoplasmosis in rodents and possibly in humans. Moreover, the antipsychotic haloperidol and the mood stabilizer valproic acid most effectively inhibit Toxoplasma growth in vitro with synergistic activity. CLINICAL DATA: The effects of the parasite are not due to the manipulation in an evolutionary sense but merely due to neuropathological or neuroimmunological effects of the parasite's presence. Toxoplasmosis and schizophrenia: epidemiological studies point to a role for toxoplasmosis in schizophrenia's etiology, probably during pregnancy and early life, this association being congruent with studies in animal models indicating that animal exposures of the developing brain to infectious agents or immune modulating agents can be associated with behavioral changes that do not appear until the animal reaches full maturity. Psychiatric patients have increased rates of toxoplasmic antibodies, the differences between cases and controls being greatest in individuals who are assayed near the time of the onset of their symptoms. The increase of dopamine in the brain of infected subjects can represent the missing link between toxoplasmosis and schizophrenia. Toxoplasmosis and Obsessive Compulsive Disorder (OCD): the seropositivity rate for anti-T. gondii IgG antibodies among OCD patients is found to be significantly higher than the rate in healthy volunteers. Infection of basal ganglia may be implicated in the pathogenesis of OCD among Toxoplasma seropositive subjects. Toxoplasmosis and personality: infected men appear to be more dogmatic, less confident, more jealous, more cautious, less impulsive and more orderly than others. Conversely, infected women seem warmest, more conscientious, more insecure, more sanctimonious and more persistent than others. It is possible that differences in the level of testosterone may be responsible for the observed behavioral differences between Toxoplasma-infected and Toxoplasma-free subjects. CONCLUSION: In the future two major avenues for research seem essential. On one hand, prospective studies and research efforts must still be carried out to understand the mechanisms by which the parasite induces these psychiatric disorders. On the other hand, it has not yet been demonstrated that patients with positive toxoplasmic serology may better respond to haloperidol's or valproic acid's antiparasitic activity. These results may appear as a major issue in the drug's prescribing choices and explain variability in response to the treatment of patients with schizophrenia that is not explained by the genetic polymorphism. PMID- 23095601 TI - [The traumatic passage of migrant children at school]. AB - INTRODUCTION: At school, the migrant child has to face an intense symbolization that articulates the experience of migration, the family past and the availability of the school environment to accommodate beyond its primary mission of education. Migration is a potential source of trauma. This article aims to show the complexity of the processes involved in the psyche of the child and discusses aspects of latency as well as intercultural issues. METHOD: The study was conducted on the psychological examination of a 7-year old migrant child that we met at school. The meetings took place because of difficulties for the child, highlighted by the school. The data are from interviews with the child's teacher and the mother of the child, as well as the projective methods available to the child, the Rorschach test and the game Play Mobile. Both tools have been used as a method of investigation and as a support for mediation. RESULTS: Media and projective interviews reveal the mother's lack of understanding of behavioral problems of children. The mother appeared to be emotionally unavailable for her son. She had a lot of difficulty in containing him. As for the child, he tried to maintain the presence of an absent father, portrayed the story of his immigration and his growing awareness of the processes involved. The child invested the clinical relationship and expressed every effort to symbolize the experience of pre-migration and migration times. DISCUSSION: The analysis reveals different types of passages: family passage, institutional passage, and projective passage that requires a mental reorganization of previous experiences. It appears that the environment is very important in the psychological construction of the child. The difficulty of investing school knowledge comes from a lack of evidence of his personal history. The discussion raises some issues of migration latency period as well as some problems with changing cultural context. To symbolize and build an intercultural Me, the migrant child needs to rely on stable environments. PMID- 23095602 TI - [Assessing beliefs and attitudes of relatives of patients with schizophrenia: a study in a Tunisian sample]. AB - INTRODUCTION: Investigating and understanding family member's causal beliefs and attitudes about schizophrenia is an important step in the management of the illness. They likely influence the family's help-seeking decisions and affect both adherence with biomedical interventions and social integration of the patients. The aim of this study was to describe Tunisian families' beliefs about the causes, the symptoms and the treatments of schizophrenia. METHODS: We led a transversal study including 91 relatives of patients with schizophrenia or schizoaffective disorder (DSM-IV). We excluded patients with mental retardation or neurological diseases. For family members, we excluded participants with a history of mental disorders or cognitive impairments. We collected basic socio demographic data for both patients and relatives. We asked relatives to respond by "yes/no/I am not certain" to a three-part questionnaire including 27 items dealing with causal explanations, symptoms and optimal cures for schizophrenia. RESULTS: The mean age of the relatives was 49.8 (+/-13.7) years; 54.9% were men; 49.4% were parents, 8.8% spouses, 39.6% brothers or sisters; 25.3% had not attended school, 24.2% had attended primary school, 37.4% junior high school or high school and 13.2% had a university degree; 63.7% lived in an urban area; 33% had low economic status and 41.8% reported having another family member with mental disorder. Only 46.2% of participants had asked psychiatrists about the diagnosis of their sick relatives and only 16.5% were able to label the term "schizophrenia". Among the cited etiologies of schizophrenia, religious causes were found in 76.9% of cases, they first cited God's will or fate and secondly God's punishment. Magical explanations such as witchcraft and possession by "djinns" were found in 47.3% of cases. The biological causes were cited by 59.3% of participants. The majority of participants (95.6%) proved the need for drugs and 81.3% the utility of psychotherapies. However, 30.8% believed in non-medical practices such as reading Holy Koran verses, charity and exorcism. Significant correlations were found between relatives' low level of education, low economic status, living in a rural area and supernatural beliefs, traditional practices, stigma and the use of the term 'madness'. Significant correlations were also found between family history of mental disorders and beliefs on family and hereditary causes. CONCLUSION: In this study, opinions and attitudes regarding schizophrenia were related to education level, economic status and geographic origin. Few persons recognized the term "schizophrenia" despite a long contact with the mental health system. This fact points out the need to improve the psychoeducation of family members of persons with schizophrenia. PMID- 23095603 TI - [Validation of the French version of the Maternal Self-report Inventory (short form)]. AB - BACKGROUND: Self-esteem is defined as the opinion of one's self that one establishes and maintains during the lifetime. Self-esteem is considered to be based on general as well as specific elements that define the individual's identity. Whereas overall self-esteem evolves over the lifespan, specific elements change regularly and thus have an impact on these specific types of self esteem. Maternity is a central defining element of a woman's life, and it is believed that a woman can develop a specific self-esteem based on her experience of motherhood. Many studies have shown how overall self-esteem is affected during the perinatal period, and the relationship between self-esteem and other variables, notably post-partum depression. OBJECTIVES: The objective of this study was to translate, evaluate, and validate the short version of the Maternal Self-Esteem Inventory (MSI, Shea & Tronick in 1988) for use in French populations. The MSI short form is a 26-item questionnaire using a Likert response format in five points. METHOD: The sample was composed of 251 French female participants (mean age 30; SD=4.52) who had given birth two days earlier. Participants completed the MSI and the Edinburgh Post-natal Depression Scale (EDPS). RESULTS: The results of a factorial analysis showed five factors which partially correspond to the original English version of the MSI short form. These five factors were negatively correlated to the EPDS. The five factors showed good to excellent internal consistency. CONCLUSIONS: The current study provides a translated and validated version of the MSI short form in French. It provides a specific indicator of self-esteem with regards to motherhood and the experience of maternity. The MSI can provide useful data that can help identify women at risk for negative feelings about themselves, which can lead later to manifestations of perinatal psychopathology (e.g, post-partum depression). PMID- 23095604 TI - [Personality and personality disorders in the elderly: diagnostic, course and management]. AB - OBJECTIVE: Little is known about personality and personality disorders in the elderly. This paper summarizes the literature in these fields. METHODS: Articles were selected using a Medline and Google Scholar search. The keywords were personality, personality disorder, aging and elderly. RESULTS: Personality is not fixed and can change across the life-time including in the elderly. Personality disorders are frequent with a prevalence estimated between 10 and 20%. These rates are essentially equivalent to that of younger groups. Clinical presentation of these disorders may change over time. Longitudinal observations generally support that the "immature" personality disorders (cluster B), show improvement over time, while the more "mature" (clusters A and C) are characterized by a more chronic course. Many patients with late onset schizophrenia or delusional disorder have a premorbid cluster A personality. Patients with cluster C personality are also stable, and exposed, like all other personality disorders, to depression. Studies suggest that personality disorders may attenuate, re emerge or appear de novo according to the cluster and the social context. Diagnosing personality disorders in the elderly is a complex undertaking, largely because of the difficulty encountered in distinguishing functional impairments related to personality from those related to physiological and environmental aspects of aging. Tools for assessing personality disorders exist, but there is no ideal assessment instrument for geriatric personality disorders. Psychiatric history and biographical elements have to be collected accurately. Personality disorders may seriously complicate mental and physical health and quality of life. Indeed, a greater risk of depression, suicide, dementia and social isolation is shown in this population. Different types of caring and treatment exist including psychotherapy and pharmacotherapy. Pharmacological strategies should consider augmentation with psychotherapeutic strategies. Interventions should target the predominant presenting problems. Indeed, personality disordered elderly people are a heterogeneous group with frequent axis I comorbidities. Care should be taken on how to administer pharmacological treatment (risk of noncompliance or abuse), pharmacokinetics, pharmacodynamics and finally interaction with age-specific comorbidities. Psychotherapy has shown its effectiveness notably in the management of depression. In institutions, clinical identification of a personality disorder would inform and advise staff regarding the approach to be adopted, and also avoid negative countertransference, emphasizing the pathological aspect of the subject's personality and his/her suffering. CONCLUSION: Future research should develop adapted and specific diagnosis tools (dimensional and categorical mixed approach), prevention and caring in the elder population. Those studies would be able to determine the link between normal and pathological personality, mortality, depression and dementia. PMID- 23095605 TI - Modelling osteomyelitis. AB - BACKGROUND: This work focuses on the computational modelling of osteomyelitis, a bone pathology caused by bacteria infection (mostly Staphylococcus aureus). The infection alters the RANK/RANKL/OPG signalling dynamics that regulates osteoblasts and osteoclasts behaviour in bone remodelling, i.e. the resorption and mineralization activity. The infection rapidly leads to severe bone loss, necrosis of the affected portion, and it may even spread to other parts of the body. On the other hand, osteoporosis is not a bacterial infection but similarly is a defective bone pathology arising due to imbalances in the RANK/RANKL/OPG molecular pathway, and due to the progressive weakening of bone structure. RESULTS: Since both osteoporosis and osteomyelitis cause loss of bone mass, we focused on comparing the dynamics of these diseases by means of computational models. Firstly, we performed meta-analysis on a gene expression data of normal, osteoporotic and osteomyelitis bone conditions. We mainly focused on RANKL/OPG signalling, the TNF and TNF receptor superfamilies and the NF-kB pathway. Using information from the gene expression data we estimated parameters for a novel model of osteoporosis and of osteomyelitis. Our models could be seen as a hybrid ODE and probabilistic verification modelling framework which aims at investigating the dynamics of the effects of the infection in bone remodelling. Finally we discuss different diagnostic estimators defined by formal verification techniques, in order to assess different bone pathologies (osteopenia, osteoporosis and osteomyelitis) in an effective way. CONCLUSIONS: We present a modeling framework able to reproduce aspects of the different bone remodeling defective dynamics of osteomyelitis and osteoporosis. We report that the verification-based estimators are meaningful in the light of a feed forward between computational medicine and clinical bioinformatics. PMID- 23095606 TI - Liquefaction versus torsional IP: a comparative study on endothelial cells, corneal edema and corneal sensitivity. AB - BACKGROUND/AIMS: To compare the impact of liquefaction and torsional IP cataract extraction methods on endothelial cell count (ECC), central corneal edema, and central corneal sensitivity (CCS) in a sample of cataract patients. METHODS: The liquefaction (LG) and torsional IP (TG) group consisted of 47 and 48 grade 2 cataract eyes, respectively. Uncorrected and best spectacle-corrected visual acuity, ECC, central corneal thickness (CCT), and CCS were measured 1 day prior to surgery, 10 days, 1 and 3 months postoperatively. RESULTS: Significant difficulties in the nucleus fragmentation were encountered in 2 LG eyes, and they were excluded from the study. Both techniques provided excellent refractive outcomes (LG, p < 0.001; TG, p = 0.02). Nonsignificant differences were detected in CCT values at the final postoperative examination; however, TG patients presented higher CCT on the first postoperative day (p = 0.04). Both groups presented comparable significant reductions in ECC (LG, p < 0.001; TG, p < 0.001) and CCS (LG, p = 0.02; TG, p = 0.02). CONCLUSION: Both methods provide excellent refractive outcomes, with comparable impact on ECC and CCS. Liquefaction seems to provide less corneal edema; however, difficulties in nucleus fragmentation may be encountered even in grade 2 cataracts. PMID- 23095607 TI - Bladder outlet procedures in the setting of anticoagulation therapy. AB - PURPOSE OF REVIEW: To assess the safety and bleeding risk in men on chronic oral anticoagulation, including antiplatelet therapies, undergoing bladder outlet procedures for the treatment of benign prostatic hyperplasia (BPH). RECENT FINDINGS: There are conflicting findings; however, most recent series show that when treating bladder outlet obstruction from BPH in patients on chronic anticoagulants, there is an increased risk of hemorrhagic complications for these men. There is also an increased risk of cardiovascular and cerebrovascular complications, especially when antithrombotic therapy is used for secondary prevention and is withdrawn perioperatively. Some have found bipolar electrosurgical vaporization of the prostate, laser vaporization, and enucleation of the prostate to provide superior hemostatic outcomes compared to classic monopolar transurethral resection of the prostate. SUMMARY: Extra caution should always be given to patients on chronic anticoagulation undergoing surgical procedures, given increased risk of bleeding and cardiovascular and cerebrovascular complications. For men with BPH undergoing bladder outlet procedures, photoselective vaporization of the prostate, Holmium laser enucleation of the prostate, and vaporization of the prostate with bipolar electrosurgical instruments may result in less bleeding complications. Further prospective randomized studies are needed to elucidate which methods provide better hemostasis and lower postoperative bleeding to best manage men with BPH on chronic antithrombotic therapy, especially when the anticoagulation therapy cannot be discontinued prior to therapy. PMID- 23095608 TI - Surgery in the Internet era. PMID- 23095609 TI - Ultrasonic dissection versus conventional dissection techniques in pancreatic surgery: a randomized multicentre study. AB - OBJECTIVE: : This prospective randomized multicenter trial was performed to assess the potential benefits of ultrasonic energy dissection compared with conventional dissection techniques in pancreatic surgery. BACKGROUND: : Surgical procedures for tumors of the pancreatic head involve time-consuming manual dissection. The primary hypothesis was that use of ultrasonic tissue and vessel dissection would lead to substantial saving in operative time during pancreatic resection. METHODS: : Patients eligible for pancreaticoduodenectomy (PD) or pylorus-preserving PD (PPPD) were randomized to group A (dissection with ultrasonic device) or group B (conventional dissection) from March 2009 to May 2011. The primary endpoint was overall duration of operation time. Secondary endpoints were time to end of resection phase, intraoperative blood loss, number of transfused units of blood, and postoperative morbidity. RESULTS: : Analysis of primary and secondary endpoints included 101 patients, who received either PD or PPPD. Demographical characteristics and clinical parameters were similar in both groups. The use of an ultrasonic dissection device did not significantly reduce overall operation time (median 316 minutes in group A and 319 minutes in group B, P = 0.95) and did not significantly increase the costs of surgery. Analysis of secondary endpoints revealed no difference in postoperative course. CONCLUSIONS: : Tissue dissection and vessel closure using an ultrasonic device is equivalent to dissection with conventional techniques in pancreatic surgery. PMID- 23095610 TI - Blood transfusions and prognosis in colorectal cancer: long-term results of a randomized controlled trial. AB - OBJECTIVE: Perioperative blood transfusions may adversely affect survival in patients with colorectal malignancy, although definite proof of a causal relationship has never been reported. BACKGROUND: We report the long-term outcomes of a randomized controlled trial performed between 1986 and 1991 to compare the effects of allogeneic blood transfusions and an autologous blood transfusion program in colorectal cancer patients. METHODS: All 475 randomized patients operated upon for colorectal cancer were tracked via a national computerized record-linkage system to investigate survival and cause of death. Kaplan-Meier survival curves were constructed and multivariate Cox regression analysis was performed to study 20 years' overall survival. Colorectal cancer specific survival was analyzed over the 10-year time period after surgery. RESULTS: The overall survival percentage at 20 years after surgery was worse in the autologous group (21%) compared to the allogeneic group (28%) (P = 0.041; log rank test). Cox regression, allowing for tumor stage, age, and sex, resulted in a hazard ratio (autologous vs allogeneic group) for overall mortality of 1.24 (95% confidence interval 1.00-1.54; P = 0.051). Colorectal cancer-specific survival at 10 years for the whole study group was 48% and 60% for the autologous and allogeneic group, respectively (P = 0.020; log-rank test). The adjusted hazard ratio was 1.39 (95 confidence interval 1.05-1.83; P = 0.045). CONCLUSIONS: At long-term follow-up colorectal cancer patients did not benefit from autologous transfusion compared with standard allogeneic transfusion. On the contrary, the overall and colorectal cancer-specific survival rates were worse in the patients in the autologous transfusion group. PMID- 23095611 TI - Complete replacement of open repair for ruptured abdominal aortic aneurysms by endovascular aneurysm repair: a two-center 14-year experience. AB - OBJECTIVE: To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. BACKGROUND: Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. METHODS: We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Orebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. RESULTS: Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Orebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). CONCLUSIONS: The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA. PMID- 23095612 TI - Incidence and risks of liver resection: an all-inclusive French nationwide study. AB - OBJECTIVE: To evaluate at a national level the incidence of liver resection, postoperative mortality, and variables that predict this outcome. BACKGROUND: Data on indications of and results of liver resection are mainly derived from high-volume centers. Nationwide data are lacking. METHODS: French health care databases were screened to identify all patients who had undergone elective hepatectomy between 2007 and 2010. The patients' age, address, associated conditions, indication and extent of hepatic (or extrahepatic) surgery and the hospital type, location, and hepatectomy caseload were retrieved. Logistic regression was used to measure the influence of these parameters on in-hospital and 90-day mortality rates. The model, created using patients operated on in 2007 and 2009, was tested in those operated on in 2008 and 2010. RESULTS: Overall, 28,708 hepatectomies were performed. The annual incidence (13.2 per 10 adult inhabitants) varied between regions, but the extremal quotient was limited to 2.2 because 15% of the operations took place outside the patients' home region. Hospitals performed a median of 4 resections per year but 53% of all resections were performed in institutions with a volume of more than 50 per year. Treatment for primary tumors and major resections correlated with hepatectomy caseload. In hospital and 90-day mortality were 3.4% and 5.8%, respectively. The area under the receiver operating characteristic curve of the prognostic model was 0.78/0.77 in the training and validation sample. CONCLUSIONS: There were significant disparities in practice. In-hospital mortality underestimated true, postoperative mortality by more than 50%. The model created may be useful for more efficient regionalization of care and patient counseling. PMID- 23095613 TI - Value of transient elastography measured with FibroScan in predicting the outcome of hepatic resection for hepatocellular carcinoma. AB - OBJECTIVE: : To evaluate the efficacy of preoperative liver stiffness (LS) measurement in predicting postoperative liver failure (PLF) after hepatectomy for hepatocellular carcinoma (HCC). BACKGROUND: : Hepatectomy for HCC in cirrhosis is affected by the risk of PLF, which is not completely predictable with common biochemical tests. Transient elastography with FibroScan is used to calculate the degree of LS, and it may be applicable to patients scheduled for hepatectomy to estimate perioperative complications. METHODS: : Ninety-two patients undergoing hepatectomy for HCC were prospectively evaluated with preoperative FibroScan. Accuracy of LS measurement in predicting PLF, the presence of cirrhosis, and the presence of clinical signs of portal hypertension (PH) were assessed using receiver operating characteristic (ROC) analysis. RESULTS: : In 2 patients, LS measurement could not be performed because of obesity; consequently, 90 patients were suitable for the study. Perioperative mortality was 2.2% (2 patients); PLF occurred in 28.9% of patients (26 patients). ROC analysis identified patients with LS value higher than or equal to 15.7 kPa as being at higher risk of PLF [area under the curve (AUC) = 0.865, 95% confidence interval: 0.776-0.928; sensitivity = 96.1%; specificity = 68.7%; positive predictive value = 55.6%; negative predictive value = 97.8%; positive likelihood ratio = 3.08; negative likelihood ratio = 0.056; P < 0.001]. Patients with LS value lower than 14.8 kPa had no PLF. LS value higher than 12.6 kPa and higher than 19.6 kPa was correlated with the presence of cirrhosis (AUC = 0.880; P < 0.001), and of PH (AUC = 0.786; P < 0.001), respectively. Multivariate analysis showed that low preoperative serum sodium levels (P = 0.012), histological cirrhosis (P = 0.024), and elevated LS (P = 0.005) were independent predictors of PLF. CONCLUSIONS: : LS measured with FibroScan is a valid tool for prediction of PLF in patients undergoing hepatectomy for HCC. PMID- 23095614 TI - Prospective, long-term comparison of quality of life in laparoscopic versus open ventral hernia repair. AB - OBJECTIVES: To compare laparoscopic ventral hernia repair (LVHR) versus open ventral hernia repair (OVHR) for quality of life (QOL), complications, and recurrence in a large, prospective, multinational study. INTRODUCTION: As recurrence rates have decreased for LVHR and OVHR, QOL has become an extremely important differentiating outcomes measure. METHODS: A prospective, international database was queried from September 2007 to July 2011 for LVHR and OVHR. Carolinas Comfort Scale (CCS) was utilized to quantify QOL (pain, movement limitation, and mesh sensation) preoperatively and at 1, 6, and 12 months postoperatively. RESULTS: A total of 710 repairs included 402 OVHR and 308 LVHR. Demographics were mean age 57.1 +/- 13.3 years, 49.6% male, 21.7% recurrent hernias, mean body mass index of 30.3 +/- 6.6, and mean defect size of 89.4 +/- 130.8. Preoperatively, 56.9% had pain, and 53.2% experienced movement limitation. At 1-month follow-up, 587 (82.7%) patients were provided CCS scores; more LVHR patients experienced pain (P < 0.001) and movement limitations (P < 0.001). At 6 and 12 months, there were no differences in QOL with 466 (65.6%) and 478 (67.3%) patients responding, respectively. After controlling for confounding variables, LVHR was independently associated with more frequent discomfort [odds ratio (OR) = 1.9, confidence interval (CI): 1.2-3.1], movement limitation (OR = 1.6, CI: 1.0 2.7), and overall symptoms (OR = 1.6, CI: 1.0-2.6) at 1 month. LVHR resulted in a shorter length of stay (LOS) (P < 0.001) and fewer infections (P = 0.004), but overall complication rates were equal. Recurrence rates were also equal (P = 0.66). CONCLUSION: In the largest, prospective QOL study comparing LVHR and OVHR, LVHR is associated with a decrease in QOL in the short term. LOS and infection rates are decreased in LVHR, but overall complication and recurrence rates are equal. PMID- 23095615 TI - Age as a long-term prognostic factor in bariatric surgery. AB - OBJECTIVE: : To analyze the potential effects of preoperative age on postoperative weight loss in patients who underwent Roux-en-Y gastric bypass (RYGBP) with long-term follow-up data. BACKGROUND: : The reasons for individual differences in surgically induced weight loss are not completely understood. To date, there are no available studies specifically aimed at analyzing the effects of age on weight loss in patients undergoing the same operation and with long term follow-up data. METHODS: : Retrospective analysis of prospectively collected data for all patients who underwent RYGBP between 2006 and 2010. To evaluate weight loss, we used preoperative and follow-up body mass index (BMI), analyzed by the mixed-effects linear model for repeated measures. To evaluate age effects, patients were classified in quartiles (<=35 years, 36-42 years, 43-51 years, >=52 years). RESULTS: : A total of 489 patients entered the study; preoperatively, the younger group showed a significantly higher BMI (mean BMI: 48.2 in patients aged <=35 years, 46.9 in 36-42 years, 45.5 in 43-51 years, 45.7 in >=52 years, P = 0.014) and a higher percentage of super-obesity (41.6% among patients aged <=35 years, 28.1% among 36-42 years, 27.6% among 43-51 years, 28.3% among >= 52 years, P = 0.047). In spite of this, younger patients experienced a significantly greater and prolonged BMI decrease during the entire follow-up period and the BMI trend over time resulted significantly modified according to age quartiles (P = 0.036). CONCLUSIONS: : This study provides a new prognostic factor in bariatric surgery: patient age. Because advanced age represents a risk factor for complications and mortality, and given that bariatric surgery may not be as effective in older patients compared to younger subjects, we believe that surgical indications in patients older than 50 years should be carefully weighed up. PMID- 23095616 TI - New insight into hyperthermic intraperitoneal chemotherapy: induction of oxidative stress dramatically enhanced tumor killing in in vitro and in vivo models. AB - BACKGROUND: The aim of hyperthermic intraperitoneal chemotherapy (HIPEC) is to eradicate microscopic residual tumor after radical surgical tumor excision in patients with peritoneal carcinomatosis. The common use of antineoplastic agents such as mitomycin C, doxorubicin, or oxaliplatin with hyperthermia fails to eradicate tumors in a significant subset of patients, and alternative approaches to target chemoresistant cells are needed. The induction of reactive oxygen species (ROS) by inhibiting the critical detoxification enzyme superoxide dismutase (SOD) during hyperthermia is an appealing approach to induce death of residual cancer cells. METHODS: Human and murine colon cancer cell lines were subjected to mild hyperthermia (40-42 degrees C), and treated with chemotherapy, similar to clinical protocols. ROS were induced by the SOD inhibitor diethyldithiocarbamate (DDC), a metabolite of the drug disulfiram. In mice, peritoneal carcinomatosis use C57Bl/6 was induced in C57Bl/6 by intraperitoneal injection of syngenic tumor cells (MC38). RESULTS: Hyperthermia alone failed to kill cells but induced intracellular ROS and activated protective mechanisms. Chemotherapy conferred inconsistent cytotoxicity depending on the cell line and dose. In contrast, induction of ROS by DDC consistently activated apoptotic pathways, with increased cell death in combination with mild hyperthermia. In vivo, combined treatment with DDC and hyperthermia significantly delayed tumor progression in tumor-bearing mice. In addition, hyperthermic combined treatment with chemotherapy and DDC significantly improved animal survival compared with chemotherapy alone. CONCLUSIONS: Addition of DDC improves the efficacy of existing HIPEC protocols in a safe way and may open the door to a more effective, multimodal HIPEC. PMID- 23095617 TI - Segmental reversal of the small bowel can end permanent parenteral nutrition dependency: an experience of 38 adults with short bowel syndrome. AB - OBJECTIVE: This study aimed to assess the results of segmental reversal of the small bowel (SRSB) in patients with short bowel syndrome (SBS) who were "permanently" dependent on parenteral nutrition (PN) and to identify possible prognostic factors for weaning. SUMMARY BACKGROUND DATA: SRSB is a nontransplant surgical option for patients with SBS who require long-term PN. Few studies have reported outcomes in humans. METHODS: : All patients who were permanently dependent on PN and underwent a SRSB between 1985 and 2010 for SBS were included. The data were retrospectively retrieved. RESULTS: Thirty-eight patients underwent SRSB. The median age was 55.5 years (range, 18-76). The median length of the small bowel remnant was 49 cm (20-140), including a reversed segment of 10 cm (6 15). The median follow-up was 57.7 months (1-304). At the 5-year follow-up, 17 patients had been weaned from PN (45%). In the remaining patients, PN dependency had decreased from 7 +/- 1 to 4 +/- 1 days per week. The survival rate was 84%. The prognostic factors for weaning were a short time between subtotal enterectomy and SRSB (P = 0.036), a longer than typical stay in the nutrition unit (P = 0.035), and an SRSB longer than 10 cm (P = 0.024). CONCLUSIONS: SRSB has a role as a conservative alternative to small bowel transplantation in patients with SBS permanently dependent on PN. With a segmental reversal of 10 to 12 cm, almost half of the patients can be expected to be weaned from PN. PMID- 23095618 TI - Reappraisal of the risks and benefits of major liver resection in patients with initially unresectable colorectal liver metastases. AB - OBJECTIVES: To determine short- and long-term outcomes of major hepatectomy in patients with downstaged colorectal liver metastases considered initially unresectable (IU). BACKGROUND: Improvements in both surgical technique and efficacy of chemotherapy have increased the rate of resection for IU colorectal liver metastases. The outcome of these patients needs to be reassessed. PATIENTS AND METHODS: From 2000 to 2011, 257 patients underwent major hepatectomy for colorectal liver metastases. Of these, 87 (34%) IU patients required portal vein occlusion after chemotherapy downstaging. Patients requiring less than 12 cycles and 12 or more cycles of chemotherapy before resection were defined as fast responders and slow responders, respectively. RESULTS: Compared with fast responders, slow responders had increased mortality (0% vs 19%, P = 0.003) and major morbidity rates (20% vs 55%, P < 0.001) despite almost identical tumor characteristics and similar procedures. In multivariate analysis, the only factor associated with increased major morbidity was the existence of a number of chemotherapy cycles of 12 or more (hazard ratio [HR]: 5.32, confidence interval [CI]: 1.69-16.7, P = 0.004). One-, 3-, and 5-year disease-free survival rates for the entire population were 48%, 17.5%, and 13%, respectively. Multivariate analysis found that slow responders (HR: 2.89, CI: 1.67-5.04, P < 0.001) and patients without adjuvant chemotherapy (HR: 2.38, CI: 1.33-4.35, P = 0.004) had a significantly decreased disease-free survival. All slow responders postoperatively recurred within 3 years. CONCLUSIONS: Liver resection in slow responders, that is, IU patients requiring 12 or more chemotherapy cycles and portal vein occlusion to achieve resectability, is associated with poor short- and long-term outcomes. These patients would probably benefit from more conservative strategies. PMID- 23095619 TI - Volumetric analysis of remnant liver regeneration after major hepatectomy in bevacizumab-treated patients: a case-matched study in 82 patients. AB - BACKGROUND: The objective was to determine the liver regeneration capacity and morbidity and mortality rates after major hepatectomy for colorectal metastases in patients having undergone bevacizumab-based chemotherapy (bev+). PATIENTS AND METHODS: Between 2006 and 2011, 41 patients underwent major hepatectomy within 3 months of bevacizumab and were matched with 41 patients operated on following systemic chemotherapy without bevacizumab (bev-). The matching criteria were the following: number of courses of chemotherapy, chemotherapy-free interval, age, and type of hepatectomy. After measurements of remnant liver volume (RLV) preoperatively and at 1 month (RLV1M), volumetric gain was calculated as absolute (RLV1M-RLV) or relative regeneration [(RLV1M-RLV/RLV)]. Ninety-day morbidity was rated according to the Clavien-Dindo classification. RESULTS: There were 21 right, 9 extended right, and 11 left hepatectomies in each group. Groups were comparable in terms of matching criteria, body mass index, American Society of Anesthesiologists score, and RLV. No mortalities were observed. There were no intergroup differences in overall morbidity (56% in bev+ vs 34.1%; P = 0.075) or postoperative liver failure. A severe complication occurred in 5 bev+ (4 eviscerations) and 4 bev- (bile leakages) (P = 0.95). The median hospital stay was similar in both groups as were the degrees of absolute and relative liver regeneration (143% in bev+ vs 114%; P = 0.20). Liver regeneration was not influenced by the type of hepatectomy, the number of courses of chemotherapy, or age more than 65 years. CONCLUSIONS: In a methodologically robust trial in the largest cohort reported up to date, bevacizumab did not impair liver regeneration after major hepatectomy-even in elderly patients or those with high exposure to chemotherapy. PMID- 23095620 TI - Integrative marker analysis allows risk assessment for metastasis in stage II colon cancer. AB - OBJECTIVES: Individualized risk assessment in patients with UICC stage II colon cancer based on a panel of molecular genetic alterations. BACKGROUND: Risk assessment in patients with colon cancer and localized disease (UICC stage II) is not sufficiently reliable. Development of metachronous metastasis is assumed to be governed largely by individual tumor genetics. METHODS: Fresh frozen tissue from 232 patients (T3-4, N0, M0) with complete tumor resection and a median follow-up of 97 months was analyzed for microsatellite stability, KRAS exon 2, and BRAF exon 15 mutations. Gene expression of the WNT-pathway surrogate marker osteopontin and the metastasis-associated genes SASH1 and MACC1 was determined for 179 patients. The results were correlated with metachronous distant metastasis risk (n = 22 patients). RESULTS: Mutations of KRAS were detected in 30% patients, mutations of BRAF in 15% patients, and microsatellite instability in 26% patients. Risk of recurrence was associated with KRAS mutation (P = 0.033), microsatellite stable tumors (P = 0.015), decreased expression of SASH1 (P = 0.049), and increased expression of MACC1 (P < 0.001). MACC1 was the only independent parameter for recurrence prediction (hazard ratio: 6.2; 95% confidence interval: 2.4-16; P < 0.001). Integrative 2-step cluster analysis allocated patients into 4 groups, according to their tumor genetics. KRAS mutation, BRAF wild type, microsatellite stability, and high MACC1 expression defined the group with the highest risk of recurrence (16%, 7 of 43), whereas BRAF wild type, microsatellite instability, and low MACC1 expression defined the group with the lowest risk (4%, 1 of 26). CONCLUSIONS: MACC1 expression predicts development of metastases, outperforming microsatellite stability status, as well as KRAS/BRAF mutation status. PMID- 23095621 TI - A survival analysis of the liver-first reversed management of advanced simultaneous colorectal liver metastases: a LiverMetSurvey-based study. AB - BACKGROUND: Liver-first reversed management (RM) for the treatment of patients with simultaneous colorectal liver metastases (CRLM) includes liver-directed chemotherapy, the resection of the CRLM, and the subsequent resection of the primary cancer. Retrospective data have shown that up to 80% of patients can successfully undergo a complete RM, whereas less than 30% of those undergoing classical management (CM) do so. This registry-based study compared the 2 approaches. METHODS: The study was based on the LiverMetSurvey (January 1, 2000 to December 31, 2010) and included patients with 2 or more metastases. All patients had irinotecan and/or oxaliplatin-based chemotherapy before liver surgery. Patients undergoing simultaneous liver and colorectal surgery were excluded. RESULTS: A total of 787 patients were included: 729 in the CM group and 58 in the RM group. Patients in the 2 groups had similar numbers of metastases (4.20 vs 4.80 for RM and CM, P = 0.231) and Fong scores of 3 or more (79% vs 87%, P = 0.164). Rectal cancer, neoadjuvant rectal radiotherapy, and the use of combined irinotecan/oxaliplatin chemotherapy were more frequent in the RM group (P < 0.001), whereas colorectal lymph node involvement was more frequent in the CM group (P < 0.001). Overall survival and disease-free survival were similar in the RM and CM groups (48% vs 46% at 5 years, P = 0.965 and 30% vs 26%, P = 0.992). CONCLUSIONS: Classical and reversed managements of metastatic liver disease in colorectal cancer are associated with similar survival when successfully completed. PMID- 23095622 TI - Evolution of pancreas transplantation: long-term results and perspectives from a high-volume center. AB - OBJECTIVE: To describe the evolution of pancreas transplantation from 1979 to 2011. The aim was to examine factors influencing long-term patient and graft survival, surgical methods, and risk factors influencing organ performance after transplantation. BACKGROUND: Pancreas transplantation has become the therapy of choice for patients suffering insulin-dependent diabetes and end stage renal failure. METHODS: Retrospective analysis of 509 consecutive pancreas transplants (442 simultaneous pancreas and kidney [SPK], 20 pancreas transplanted alone [PTA], and 47 pancreas transplanted after kidney [PAK]), performed at the University Hospital Innsbruck. The data were statistically analyzed using the Kaplan-Meier method and log-rank test. RESULTS: After overcoming initial immunological and technical problems between 1979 and 1988 (5-year pancreas graft survival rate, 29.7%), pancreas transplantation evolved during the second decade (1989-1996; 5-year pancreas graft survival rate, 42.2%). Technical changes, optimized immunosuppression, careful pretransplant evaluation, and improved graft monitoring have become standard in the last decade and result in excellent 5-year patient (94.3%), kidney (89.4%), and pancreas (81.5%) graft survival. Five-year graft survival was superior in SPK (68.8%) compared with PAK (62.5%) and PTA (16.4%). SPK retransplantation can be carried out safely with 5-year patient (87.5%) and pancreas graft (75.0%) survival. Overall 5-year patient survival after loss of the first pancreas graft is significantly better in patients who underwent retransplantation (89.4% vs. 67.9%, P = 0.001). Long-term pancreas graft survival is independent of donor body mass index, sex, and cause of death, anastomosis time and the number of human leukocyte antigen (HLA) mismatches, recipient age, body mass index, sex, current panel reactive antibodies, and waiting time. Significant risk factors for reduced graft survival are cold ischemia time and donor age. CONCLUSIONS: During the last 32 years, many problems in pancreas transplantation have been overcome and it may currently represent the therapeutic gold standard for some patients with diabetes and end stage renal failure. PMID- 23095624 TI - Job satisfaction among young board-certified surgeons at academic centers in Europe and North America. AB - OBJECTIVES: To identify independent factors influencing job satisfaction of academic surgeons within their first 10 years after board certification. BACKGROUND DATA: Job satisfaction is increasingly recognized as a crucial factor for high performance of individuals and teams in most organizations. Sophisticated tools are now available to assess job satisfaction in medicine. METHODS: A survey among 439 faculty surgeons from 16 European countries, United States, and Canada was conducted in 2011. Satisfaction at work was analyzed using the validated Global Job Satisfaction (GJS) instrument (score range, -36 to +36), modified to an extended version (eGJS) (score range, -87 to +87) covering additional personal and environmental factors. Independent factors were identified with multiple logistic regression analysis. RESULTS: Response rate was high at 59% (439/744). Median age of responders was 39 years, with 17% women. North American surgeons scored higher on the eGJS when compared with Europeans (median: 21 vs. 33, respectively, P < 0.001). The surgical specialty with the highest median eGJS score was colorectal, whereas general surgery scored lowest (median: 33 vs 7, respectively, P = 0.002). On multivariate analysis, independent factors of high job satisfaction included protected time for research (odds ratio [OR]: 9), good team relationship (OR: 7), female sex (OR: 5), having a partner (OR: 4), feeling enthusiastic about work (OR: 4), being pleased with life accomplishments (OR: 4), having the standard of living one deserves (OR: 3), and clinical autonomy (OR: 3). In contrast, independent predictors of poor job satisfaction were feeling frustrated by work (ie, a burnout item) (OR: 37), worrying about personal life at work (OR: 3), and having to work too many weekends (OR: 3). CONCLUSIONS: Satisfaction in young faculty members mostly relates to research opportunities, clinical autonomy, burnout, and lifestyle. Understanding satisfaction factors may improve productivity and competence. PMID- 23095623 TI - Barrett's esophagus and adenocarcinoma risk: the experience of the North-Eastern Italian Registry (EBRA). AB - OBJECTIVE: To establish the incidence and risk factors for progression to high grade intraepithelial neoplasia (HG-IEN) or Barrett's esophageal adenocarcinoma (BAc) in a prospective cohort of patients with esophageal intestinal metaplasia [(BE)]. BACKGROUND: BE is associated with an increased risk of BAc unless cases are detected early by surveillance. No consistent data are available on the prevalence of BE-related cancer, the ideal surveillance schedule, or the risk factors for cancer. METHODS: In 2003, a regional registry of BE patients was created in north-east Italy, establishing the related diagnostic criteria (endoscopic landmarks, biopsy protocol, histological classification) and timing of follow-up (tailored to histology) and recording patient outcomes. Thirteen centers were involved and audited yearly. The probability of progression to HG IEN/BAc was calculated using the Kaplan-Meier method; the Cox regression model was used to calculate the risk of progression. RESULTS: HG-IEN (10 cases) and EAc (7 cases) detected at the index endoscopy or in the first year of follow-up were considered to be cases of preexisting disease and excluded; 841 patients with at least 2 endoscopies {median, 3 [interquartile range (IQR): 2-4); median follow-up = 44.6 [IQR: 24.7-60.5] months; total 3083 patient-years} formed the study group [male/female = 646/195; median age, 60 (IQR: 51-68) years]. Twenty-two patients progressed to HG-IEN or BAc (incidence: 0.72 per 100 patient-years) after a median of 40.2 (26.9-50.4) months. At multivariate analysis, endoscopic abnormalities, that is, ulceration or nodularity (P = 0.0002; relative risk [RR] = 7.6; 95% confidence interval, 2.63-21.9), LG-IEN (P = 0.02, RR = 3.7; 95% confidence interval, 1.22-11.43), and BE length (P = 0.01; RR = 1.16; 95% confidence interval, 1.03-1.30) were associated with BE progression. Among the LG IEN patients, the incidence of HG-IEN/EAc was 3.17 patient-years, that is, 6 times higher than in BE patients without LG-IEN. CONCLUSIONS: These results suggest that in the absence of intraepithelial neoplastic changes, BE carries a low risk of progression to HG-IEN/BAc, and strict surveillance (or ablative therapy) is advisable in cases with endoscopic abnormalities, LG-IEN or long BE segments. PMID- 23095625 TI - Redo coloanal anastomosis: a retrospective study of 66 patients. AB - INTRODUCTION: Low colorectal (LCRA) and coloanal anastomoses (CAA) are associated with high leakage rate. After such complication, around 17% of patients remain with their stoma. Treatment of failed LCRA and CAA is not frequently proposed. The aim of this study was to evaluate the results of redo surgery in such patients. METHODS: Patients who underwent redo surgery between 2000 and 2010 were retrospectively included. Success was defined as a functional anastomosis without diverting stoma. Quality of life and continence were assessed with health survey scoring (SF-12) and Wexner scores. RESULTS: Sixty-six patients were included, 44 had an LCRA, and 22 had a CAA. Reasons for redo surgery were chronic pelvic abscess (n = 21), rectovaginal fistula (n = 19), strictures (n = 10), prior Hartmann procedures (n = 13), or colovesical fistulas (n = 3). Redo surgery was impossible in 3 patients. Soave's procedure was performed in 27 patients. There were 20 transmesenteric (30.8%) and 5 Deloyers' (7.7%) maneuvers. All patients were diverted. There was no operative mortality. Morbidity rate was 32.3%, 9 patients had to be reoperated. After a median delay of 2.2 months (0.8-121.6), stoma was closed in 56 patients. Forty-six patients were recontacted. Using the SF-12 score, with a median physical health composite scale (PCS) of 48 (28-65) and a median mental health composite scale (MCS) of 52.5 (21-66), quality of life was not altered. Median Wexner score was 8 (0-17); 28% of patients had never experienced incontinence and 60% had fragmentation. With a median follow-up of 35.7 months [range: 0-122.4, 47.9 (+/-37.8)], 52 patients were cured (78.8%). CONCLUSIONS: After failed LCRA or CAA, redo anastomosis has a high success rate and acceptable morbidity and function. PMID- 23095626 TI - Tumor progression after preoperative portal vein embolization. AB - OBJECTIVE: To evaluate tumor growth in a series of patients undergoing liver resection after portal vein embolization (PVE). BACKGROUND: The regenerative response after PVE leading to compensatory hypertrophy of the nonembolized liver segments potentially enhances tumor growth. METHODS: Portal vein embolization was performed in 28 patients diagnosed with colorectal metastases between 2004 and 2011. Tumor volume was measured by computed tomography (CT) volumetry before and after PVE. Tumor growth rate (TGR) was measured by CT volumetry and compared with that of a non-PVE control group with colorectal metastases of whom 30 had 2 CT scans preoperatively. Also, newly diagnosed tumors in the future remnant liver (FRL) after PVE and after resection were analyzed. RESULTS: The median TGR of PVE patients was 0.53 mL/d (interquartile range [IQR], 0.02-1.88) versus 0.09 mL/d (IQR, -0.04 to 0.40; P = 0.03) in non-PVE patients. The TGR was 0.15 (IQR, -0.52 to 0.66) mL/d before PVE and 0.85 (IQR, -0.10 to 1.62) mL/d after PVE in the same patients (P = 0.03). Seven patients (25%) showed new tumor lesions in the FRL after PVE, of whom 3 patients (11%) were not resectable. Patients (8 of 19; 42%) after PVE also showed a higher rate of recurrent metastases in the remnant liver at follow-up than non-PVE patients (1 of 28; 4%). Survival was significantly better for non-PVE patients, with a 3-year survival rate of 77% versus 26% in patients undergoing PVE. CONCLUSIONS: Portal vein embolization is associated with increased TGR and new tumor in the FRL and recurrent tumor after resection. Short intervals and interval chemotherapy between PVE and resection are, therefore, advised. PMID- 23095627 TI - A multicenter randomized clinical trial of primary anastomosis or Hartmann's procedure for perforated left colonic diverticulitis with purulent or fecal peritonitis. AB - OBJECTIVES: To evaluate the outcome after Hartmann's procedure (HP) versus primary anastomosis (PA) with diverting ileostomy for perforated left-sided diverticulitis. BACKGROUND: The surgical management of left-sided colonic perforation with purulent or fecal peritonitis remains controversial. PA with ileostomy seems to be superior to HP; however, results in the literature are affected by a significant selection bias. No randomized clinical trial has yet compared the 2 procedures. METHODS: Sixty-two patients with acute left-sided colonic perforation (Hinchey III and IV) from 4 centers were randomized to HP (n = 30) and to PA (with diverting ileostomy, n = 32), with a planned stoma reversal operation after 3 months in both groups. Data were analyzed on an intention-to treat basis. The primary end point was the overall complication rate. The study was discontinued following an interim analysis that found significant differences of relevant secondary end points as well as a decreasing accrual rate (NCT01233713). RESULTS: Patient demographics were equally distributed in both groups (Hinchey III: 76% vs 75% and Hinchey IV: 24% vs 25%, for HP vs PA, respectively). The overall complication rate for both resection and stoma reversal operations was comparable (80% vs 84%, P = 0.813). Although the outcome after the initial colon resection did not show any significant differences (mortality 13% vs 9% and morbidity 67% vs 75% in HP vs PA), the stoma reversal rate after PA with diverting ileostomy was higher (90% vs 57%, P = 0.005) and serious complications (Grades IIIb-IV: 0% vs 20%, P = 0.046), operating time (73 minutes vs 183 minutes, P < 0.001), hospital stay (6 days vs 9 days, P = 0.016), and lower in-hospital costs (US $16,717 vs US $24,014) were significantly reduced in the PA group. CONCLUSIONS: This is the first randomized clinical trial favoring PA with diverting ileostomy over HP in patients with perforated diverticulitis. PMID- 23095629 TI - Protection of pharmacological postconditioning in liver surgery: results of a prospective randomized controlled trial. AB - OBJECTIVES: : To elucidate the possible organ-protective effect of pharmacological postconditioning in patients undergoing liver resection with inflow occlusion. BACKGROUND: : Inflow occlusion reduces blood loss during liver transection in selected patients but is potentially harmful due to ischemia reperfusion injury. Preventive strategies include the use of repetitive short periods of ischemia interrupted by a reperfusion phase (intermittent clamping), application of a short period of ischemia before transection (ischemic preconditioning), or pharmacological preconditioning before transection. Whether intervention after resection (postconditioning) may confer protection is unknown. METHODS: : A 3 arm, prospective, randomized trial was designed for patients undergoing liver resection with inflow occlusion to compare the effects of pharmacological postconditioning with the volatile anesthetic agent sevoflurane (n = 48), intermittent clamping (n = 50), or no protective intervention (continuous inflow occlusion, n = 17). Endpoints included peak serum aspartate transaminase level, postoperative complications, and hospital stay. All patients were intravenously anesthetized with propofol. In patients with postconditioning, propofol infusion was stopped upon reperfusion and replaced with sevoflurane for 10 minutes. RESULTS: : Compared with the control group, both postconditioning (P = 0.044) and intermittent clamping (P = 0.015) significantly reduced aspartate transaminase levels. The risk of complications was significantly decreased by postconditioning, odds ratio, 0.08 [95% confidence interval (CI), 0.02-0.36; P = 0.001]) and intermittent clamping, odds ratio, 0.50 [95% CI, 0.26-0.96; P = 0.038], compared with controls. Both interventions reduced length of hospital stay, postconditioning -4 days [95% CI, -6 to -1; P = 0.009], and intermittent clamping -2 days, [95% CI, -4 to 0; P = 0.019]. CONCLUSIONS: : Pharmacological postconditioning reduces organ injury and postoperative complications. This easily applicable strategy should be used in patients with prolonged continuous inflow occlusion. PMID- 23095630 TI - A randomized trial of hemithyroidectomy versus Dunhill for the surgical management of asymmetrical multinodular goiter. AB - OBJECTIVE: To assess the immediate and long-term clinical results of 2 different surgical procedures for the treatment of asymmetrical multinodular goiter (AMG). BACKGROUND: Half of the patients presenting with a single benign thyroid nodule have contralateral subclinical disease. There is a controversy whether these patients should be treated with hemithyroidectomy (HMT) or with a more extensive procedure. METHODS: Adult patients with a benign unilateral dominant nodule and contralateral nodule(s) with a diameter of less than 10 mm detected on neck ultrasonography were randomized to HMT or Dunhill (DUN). Rates of complications, remnant growth, incidental carcinoma, and reoperation were assessed. RESULTS: A total of 118 patients (F/M:110/8, mean age 43 years) were included and randomized: 65 to HMT and 53 to DUN. After randomization, 28 patients were excluded leaving 47 HMT and 43 DUN long-term (55 +/- 35 months) evaluable patients. Mean nodule size was 38 and 6 mm for the dominant and contralateral nodules, respectively. No differences were found in operative time, accidental parathyroidectomy, parathyroid autotransplantation, or wound complications. Transient hypocalcemia was more common in DUN (30% vs 8%; P < 0.001). No permanent complications were observed. At the last follow-up visit, thyroid stimulating hormone was similar in both groups. Remnant growth (20 vs 0%; P < 0.001), appearance of new nodules (55 vs 14%; P < 0.001), and overall reoperation rate (9.2 vs 1.8%, P = 0.2) were more common in HMT, mostly because of undiagnosed cancer requiring completion thyroidectomy. Thirty percent of HMTs developed hypothyroidism and required long-term T4 supplementation. CONCLUSIONS: DUN appears superior to HMT for the treatment of AMG in terms of early reoperation for missed carcinomas and disease progression. Both procedures have a similarly uneventful postoperative course. PMID- 23095628 TI - HAnd Suture Versus STApling for Closure of Loop Ileostomy (HASTA Trial): results of a multicenter randomized trial (DRKS00000040). AB - OBJECTIVES: The objective of the HASTA trial was to compare hand suture versus stapling loop ileostomy closure in a randomized controlled trial. BACKGROUND: Bowel obstruction is one of the main and the clinically and economically most relevant complication following closure of loop ileostomy after low anterior resection. The best surgical technique for closure of loop ileostomy has not been defined yet. METHODS: HASTA trial is a multicenter pragmatic randomized controlled surgical trial with 2 parallel groups to compare hand suture versus stapling for closure of loop ileostomy. The primary endpoint was the rate of bowel obstruction within 30 days after ileostomy closure. RESULTS: A total of 337 randomized patients undergoing closure of loop ileostomy after low anterior resection because of rectal cancer in 27 centers were included. The overall rate of postoperative ileus after ileostomy closure was 13.4%. Seventeen of 165 (10.3%) patients in the stapler group and 27 of 163 (16.6%) in the hand suture group developed bowel obstruction within 30 days postoperatively [odds ratio (OR) = 1.72; 95% confidence interval (CI): 0.89-3.31 = 0.10]. Duration of surgical intervention was significantly shorter in the stapler group (15 minutes; P < 0.001). Multivariable analysis of potential risk factors did not reveal any significant correlation with development of postoperative ileus. Rate of anastomotic leakage (stapler: 3.0%, hand suture: 1.8%, P = 0.48) did not differ significantly as well as all other secondary endpoints. CONCLUSIONS: Hand-sewn anastomosis versus stapler ileo-ileostomy for ileostomy closure are equally effective in terms of postoperative bowel obstruction, with stapler anastomosis leading to a shorter operation time. Postoperative ileus after ileostomy reversal remains a relevant complication. PMID- 23095631 TI - Efficacy of an absorbable fibrin sealant patch (TachoSil) after distal pancreatectomy: a multicenter, randomized, controlled trial. AB - OBJECTIVE: To evaluate the role of an absorbable fibrin sealant patch (TachoSil) in reducing postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). BACKGROUND: POPF remains the main complication after DP. METHODS: This was a prospective, open, randomized, study in which patients undergoing elective DP were randomized to standard surgical suturing or stapling with or without TachoSil. The primary end point was the incidence of POPF according to International Study Group on Pancreatic Fistula criteria. Amylase level in drainage fluid, number of days until removal of drain, and duration of hospital stay were secondary end points. RESULTS: A total of 275 patients were enrolled at 19 centers over a 2-year period (TachoSil, n = 145; standard, n = 130). Twenty percent of procedures were laparoscopic and 21% were spleen-preserving resections. The incidence of POPF was not significantly different between groups (TachoSil, 62%; standard 68%; P = 0.267). Grade A fistula rate was similar in both groups (TachoSil 54%; standard 55%), whereas the grade B + C fistula rate was 8% with TachoSil versus 14% without (P = 0.139). Amylase drainage level on postoperative day 1 was significantly reduced with TachoSil (P = 0.025). Median number of days until drainage removal and length of hospital stay were similar in both groups (7 and 10 days, respectively). CONCLUSIONS: The POPF rate was higher than expected when International Study Group on Pancreatic Fistula criteria were strictly applied, although the majority were biochemical fistulas. TachoSil had no significant effect on the rate of POPF, although there was a significant reduction of amylase level in drainage fluid on postoperative day 1. PMID- 23095632 TI - The use of fatty liver grafts in modern allocation systems: risk assessment by the balance of risk (BAR) score. AB - OBJECTIVE: To integrate the amount of hepatic steatosis in modern liver allocation models. BACKGROUND: The aim of this study was to combine the 2 largest liver transplant databases (United States and Europe) in 1 comprehensive model to predict outcome after liver transplantation, with a novel focus on the impact of the presence of steatosis in the graft. METHODS: We adjusted the balance of risk (BAR) score for its application to the European Liver Transplant Registry (ELTR) database containing 11,942 patients. All liver transplants from ELTR and United Network for Organ Sharing with recorded liver biopsies were then combined in one survival analysis in relation to the presence of graft micro- (n = 9,677) and macrosteatosis (n = 11,516). RESULTS: Microsteatosis, regardless of the amount, was associated with a similar relationship between mortality and BAR score as nonsteatotic livers. Low-grade macrosteatotic liver grafts (<=30% macrosteatosis) resulted in 5-year graft-survival rates of 60% or more up to BAR 18, comparable to nonsteatotic grafts. However, use of moderate or severely steatotic liver grafts (>30% macrosteatosis) resulted in acceptable outcome only if the cumulative risk at transplant was low, that is, BAR score of 9 or less. CONCLUSIONS: Microsteatotic or 30% or less macrosteatotic liver grafts can be used safely up to BAR score of 18 or less, but liver grafts with more than 30% macrosteatotis should be used with risk adjustment, that is, up to BAR score of 9 or less. PMID- 23095633 TI - The pregnant motor vehicle accident casualty: adherence to basic workup and admission guidelines. Letter to the editor. PMID- 23095634 TI - Glutaminolysis feeds mTORC1. PMID- 23095635 TI - Alteration/deficiency in activation-3 (Ada3) plays a critical role in maintaining genomic stability. AB - Cell cycle regulation and DNA repair following damage are essential for maintaining genome integrity. DNA damage activates checkpoints in order to repair damaged DNA prior to exit to the next phase of cell cycle. Recently, we have shown the role of Ada3, a component of various histone acetyltransferase complexes, in cell cycle regulation, and loss of Ada3 results in mouse embryonic lethality. Here, we used adenovirus-Cre-mediated Ada3 deletion in Ada3(fl/fl) mouse embryonic fibroblasts (MEFs) to assess the role of Ada3 in DNA damage response following exposure to ionizing radiation (IR). We report that Ada3 depletion was associated with increased levels of phospho-ATM (pATM), gammaH2AX, phospho-53BP1 (p53BP1) and phospho-RAD51 (pRAD51) in untreated cells; however, radiation response was intact in Ada3(-/-) cells. Notably, Ada3(-/-) cells exhibited a significant delay in disappearance of DNA damage foci for several critical proteins involved in the DNA repair process. Significantly, loss of Ada3 led to enhanced chromosomal aberrations, such as chromosome breaks, fragments, deletions and translocations, which further increased upon DNA damage. Notably, the total numbers of aberrations were more clearly observed in S-phase, as compared with G1 or G2 phases of cell cycle with IR. Lastly, comparison of DNA damage in Ada3(fl/fl) and Ada3(-/-) cells confirmed higher residual DNA damage in Ada3(-/-) cells, underscoring a critical role of Ada3 in the DNA repair process. Taken together, these findings provide evidence for a novel role for Ada3 in maintenance of the DNA repair process and genomic stability. PMID- 23095636 TI - Controversial aspects of oncogene-induced senescence. AB - Oncogene-induced senescence (OIS) is a fail-safe mechanism that is developed to suppress cell proliferation caused by aberrant activation of oncoproteins in normal cells. Most of the available literature considers senescence to be caused by activated RAS or RAF proteins. In the current review, we will discuss some of the controversial aspects of RAS- or RAF-induced senescence in different types of normal cells: are tumor suppressors important for OIS? What is the role of DNA damage in OIS? Are there different types of OIS? PMID- 23095637 TI - RECQ1 is required for cellular resistance to replication stress and catalyzes strand exchange on stalled replication fork structures. AB - RECQ1 is the most abundant of the five human RecQ helicases, but little is known about its biological significance. Recent studies indicate that RECQ1 is associated with origins of replication, suggesting a possible role in DNA replication. However, the functional role of RECQ1 at damaged or stalled replication forks is still unknown. Here, for the first time, we show that RECQ1 promotes strand exchange on synthetic stalled replication fork-mimicking structures and comparatively analyze RECQ1 with the other human RecQ helicases. RECQ1 actively unwinds the leading strand of the fork, similar to WRN, while RECQ4 and RECQ5beta can only unwind the lagging strand of the replication fork. Human replication protein A modulates the strand exchange activity of RECQ1 and shifts the equilibrium more to the unwinding mode, an effect also observed for WRN. Stable depletion of RECQ1 affects cell proliferation and renders human cells sensitive to various DNA damaging agents that directly or indirectly block DNA replication fork progression. Consequently, loss of RECQ1 activates DNA damage response signaling, leads to hyper-phosphorylation of RPA32 and activation of CHK1, indicating replication stress. Furthermore, depletion of RECQ1 leads to chromosomal condensation defects and accumulation of under-condensed chromosomes. Collectively, our observations provide a new insight into the role of RECQ1 in replication fork stabilization and its role in the DNA damage response to maintain genomic stability. PMID- 23095638 TI - Ser2481-autophosphorylated mTOR colocalizes with chromosomal passenger proteins during mammalian cell cytokinesis. AB - Energy- and nutrient-sensing proteins such as AMPK, mTOR and S6K1 are now recognized as novel regulators of mitotic completion in proliferating cells. We investigated the cellular distribution of the Ser2481 autophosphorylation of mTOR, which directly monitors mTORC-specific catalytic activity, during mammalian cell mitosis and cytokinesis. Automated immunofluorescence experiments in human carcinoma cell lines revealed that phospho-mTOR (Ser2481) exhibited profound spatial and temporal dynamics during cell division. Phospho-mTOR (Ser2481) was strikingly enriched in mitotic cells, and in prophase, bright phospho-mTOR (Ser2481) staining could be clearly observed among condensed chromosomes. Phospho-mTOR (Ser2481) then redistributes from diffuse cytosolic staining that partially colocalizes with the mitotic spindle during the early phases of mitosis to the furrow at the onset of cytokinesis. Like the bona fide chromosomal passenger proteins (CPPs) INCENP and Aurora B, phospho-mTOR (Ser2481) displayed noteworthy accumulation in the central spindle midzone and the midbody regions, which persisted during the furrowing process. Accordingly, double-staining experiments confirmed that phospho-mTOR (Ser2481) largely colocalized with CCPs in the midbodies. The CPP-like mitotic localization of phospho-mTOR (Ser2481) was fully prevented by the microtubule-depolymerizing drug nocodazole; mitotic traveling of phospho-mTOR (Ser2481) to the midbody during telophase and cytokinesis, where it appears to be integrated into the CPP-driven cytokinetic machinery, may therefore require dynamic microtubules. Although the Ser2448 phosphorylated form of mTOR was also found at high levels during M-phase in human cancer cells, we failed to observe a significant association of phospho-mTOR (Ser2448) with CCP-positive mitotic and cytokinetic structures. Our findings add phospho-mTOR (Ser2481) to the growing list of phospho-active forms of proteins belonging to the AMPK/mTOR/S6K1 signaling axis that reside at the mitotic and cytokinetic apparatus. Future studies should elucidate how the specific ability of phospho-mTOR (Ser2481) to spatially and temporally couple to the cleavage furrow and midbody region as a CPP-like protein can signal to or from adjacent signaling complexes and/or with the basic machinery of cell abscission. PMID- 23095639 TI - The role of D-GADD45 in oxidative, thermal and genotoxic stress resistance. AB - There is a relationship between various cellular stress factors and aging. In earlier studies, we demonstrated that overexpression of the D-GADD45 gene increases the life span of Drosophila melanogaster. In this study, we investigate the relationship between D-GADD45 activity and resistance to oxidative, genotoxic and thermal stresses as well as starvation. In most cases, flies with constitutive and conditional D-GADD45 overexpression in the nervous system were more stress-resistant than ones without overexpression. At the same time, most of the studied stress factors increased D-GADD45 expression in the wild-type strain. The lifespan-extending effect of D-GADD45 overexpression was also retained after exposure to chronic and acute gamma-irradiation, with doses of 40 sGy and 30 Gy, respectively. However, knocking out D-GADD45 resulted in a significant reduction in lifespan, lack of radiation hormesis and radioadaptive response. A dramatic decrease in the spontaneous level of D-GADD45 expression was observed in the nervous system as age progressed, which may be one of the causes of the age related deterioration of organismal stress resistance. Thus, D-GADD45 expression is activated by most of the studied stress factors, and D-GADD45 overexpression resulted in an increase of stress resistance. PMID- 23095640 TI - Mesenchymal traits are selected along with stem features in breast cancer cells grown as mammospheres. AB - Increasing evidence indicates that invasive properties of breast cancers rely on gain of mesenchymal and stem features, which has suggested that the dual targeting of these phenotypes may represent an appealing therapeutic strategy. It is known that the fraction of stem cells can be enriched by culturing breast cancer cells as mammospheres (MS), but whether these pro-stem conditions favor also the expansion of cells provided of mesenchymal features is still undefined. In the attempt to shed light on this issue, we compared the phenotypes of a panel of 10 breast cancer cell lines representative of distinct subtypes (luminal, HER2 positive, basal-like and claudin-low), grown in adherent conditions and as mammospheres. Under MS-proficient conditions, the increment in the fraction of stem-like cells was associated to upregulation of the mesenchymal marker Vimentin and downregulation of the epithelial markers expressed by luminal cells (E cadherin, KRT18, KRT19, ESR1). Luminal cells tended also to upregulate the myoepithelial marker CD10. Taken together, our data indicate that MS-proficient conditions do favor mesenchymal/myoepithelial features, and indicate that the use of mammospheres as an in vitro tumor model may efficiently allow the exploitation of therapeutic approaches aimed at targeting aggressive tumors that have undergone epithelial-to-mesenchymal transition PMID- 23095641 TI - GHRH antagonist when combined with cytotoxic agents induces S-phase arrest and additive growth inhibition of human colon cancer. AB - Treatment of colon cancer with an antagonist of growth hormone-releasing hormone (GHRH), JMR-132, results in a cell cycle arrest in S-phase of the tumor cells. Thus, we investigated the effect of JMR-132 in combination with S-phase-specific cytotoxic agents, 5-FU, irinotecan and cisplatin on the in vitro and in vivo growth of HT-29, HCT-116 and HCT-15 human colon cancer cell lines. In vitro, every compound inhibited proliferation of HCT-116 cells in a dose-dependent manner. Treatment with JMR-132 (5 MUM) combined with 5-FU (1.25 MUM), irinotecan (1.25 MUM) or cisplatin (1.25 MUM) resulted in an additive growth inhibition of HCT-116 cells in vitro as shown by MTS assay. Cell cycle analyses revealed that treatment of HCT-116 cells with JMR-132 was accompanied by a cell cycle arrest in S-phase. Combination treatment using JMR-132 plus a cytotoxic drug led to a significant increase of the sub-G 1 fraction, suggesting apoptosis. In vivo, daily treatment with GHRH antagonist JMR-132 decreased the tumor volume by 40-55% (p < 0.001) of HT-29, HCT-116 and HCT-15 tumors xenografted into athymic nude mice. Combined treatment with JMR-132 plus chemotherapeutic agents 5-FU, irinotecan or cisplatin resulted in an additive tumor growth suppression of HT 29, HCT-116 and HCT-15 xenografts to 56-85%. Our observations indicate that JMR 132 enhances the antiproliferative effect of S-phase-specific cytotoxic drugs by causing accumulation of tumor cells in S-phase. PMID- 23095643 TI - Acute bacterial prostatitis in humans: current microbiological spectrum, sensitivity to antibiotics and clinical findings. AB - OBJECTIVE: To assess the current microbiological profile and sensitivity to antibiotics in patients with acute bacterial prostatitis (ABP). PATIENTS AND METHODS: In the period 2003-2010, we treated 192 ABP patients, aged from 18 to 85 years (average 56.3 years). We performed a biochemical examination including a microbiological urine examination. After admission, we immediately began the empirical antibacterial treatment. RESULTS: The clinical picture was dominated by pain, prostate enlargement and failure of micturition in 185 (96.4%) patients; 14 (7.3%) patients had acute urinary retention where epicystostomy was necessary. Fever occurred in 177 (92.2%) patients and Escherichia coli was the most frequent etiological agent detected in 103 (53.7%) patients followed by Pseudomonas aeruginosa and Klebsiella species. In 16 (8.3%) patients we found 2 bacteriological strains. Sterile urine was found in 65 (33.8%) patients. Fluoroquinolones, aminoglycosides and cephalosporins were used most frequently. 147 (76.6%) patients were treated according to the microbiological results. Overview of resistance shows an increase in resistance to fluoroquinolones. In 14 (7.3%) patients there was progression to urosepsis. CONCLUSION: Clinicians should consider local drug-resistance patterns when choosing antibiotics and should adjust the therapy on the basis of bacterial cultures and local sensitivity to antibiotics. PMID- 23095642 TI - HER2-Akt signaling in regulating COP9 signalsome subunit 6 and p53. AB - HER2/neu oncogene is frequently overexpressed in various types of cancer, and the (PI3K)-Akt signaling pathway is often activated in HER2-overexpressing cancer cells. CSN6, subunit 6 of the COP9 signalosome complex, is pivotal in regulating MDM2 to destabilize p53, but its upstream regulators remain unclear. Here we show that the HER2-Akt axis is linked to CSN6 regulation, and that Akt is a positive regulator of CSN6. Ectopic expression of Akt can increase the expression of CSN6; accordingly, Akt inhibition leads to CSN6 destabilization. Mechanistic studies show that Akt causes CSN6 phosphorylation at Ser 60, which, in turn, reduces ubiquitin-mediated protein degradation of CSN6. Significantly, Akt's positive impact on CSN6 elevation translates into p53 degradation, potentiating transformational activity and increasing DNA damage. Akt inhibition can attenuate these defects caused by CSN6. These data suggest that Akt is an important positive regulator of CSN6, and that activation of Akt in many types of cancer could lead to abnormal elevation of CSN6 and result in downregulated p53 and increased DNA damage, which promotes cancer cell growth. PMID- 23095644 TI - Reactions to caregiving during an intervention targeting frailty in community living older people. AB - BACKGROUND: The demands and consequences of caregiving are considerable. However, such outcomes are not commonly investigated in the evaluation of interventions targeting frailty. This study aims to explore family carers' reactions to caregiving during an intervention targeting frailty in community living older people. METHOD: A study of carers (n=119) embedded in a 12 month randomised controlled intervention targeting frailty in people 70 years or older, compared to usual care. Reactions to caregiving were measured in the domains of health, finance, self-esteem, family support and daily schedule. Anxiety and depression levels were also evaluated. Carer outcomes were measured at baseline, 6 months and 12 months and at 3 months post frailty intervention. RESULTS: Carers of frail older people in the intervention group showed a sustained improvement in health scores during the intervention targeting frailty, while health scores for carers of the frail older people in the control group, decreased and therefore their health worsened (F=2.956, p=0.034). The carers of the frail older people in the intervention group reported overall better health (F=5.303, p=0.023) and self esteem (F=4.158, p=0.044), and co-resident carers reported higher self-esteem (F=4.088, p=0.046). Anxiety levels increased for carers in both intervention and control groups (F=2.819, p=0.04). CONCLUSION: The inclusion of carers in trials targeting frail older people may assist in the identification of at-risk carers and facilitate the provision of information and support that will assist them to continue providing care. Further research that explores the features of frailty interventions that impact on the caregiving experience is recommended. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12608000565347. PMID- 23095647 TI - [Palliative procedures in malignant dysphagia]. PMID- 23095645 TI - Comparison of predicted susceptibility between genotype and virtual phenotype HIV drug resistance interpretation systems among treatment-naive HIV-infected patients in Asia: TASER-M cohort analysis. AB - BACKGROUND: Accurate interpretation of HIV drug resistance (HIVDR) testing is challenging, yet important for patient care. We compared genotyping interpretation, based on the Stanford University HIV Drug Resistance Database (Stanford HIVdb), and virtual phenotyping, based on the Janssen Diagnostics BVBA's vircoTYPETM HIV-1, and investigated their level of agreement in antiretroviral (ARV) naive patients in Asia, where non-B subtypes predominate. METHODS: Sequences from 1301 ARV-naive patients enrolled in the TREAT Asia Studies to Evaluate Resistance - Monitoring Study (TASER-M) were analysed by both interpreting systems. Interpretations from both Stanford HIVdb and vircoTYPETM HIV-1 were initially grouped into 2 levels: susceptible and non-susceptible. Discrepancy was defined as a discordant result between the susceptible and non susceptible interpretations from the two systems for the same ARV. Further analysis was performed when interpretations from both systems were categorised into 3 levels: susceptible, intermediate and resistant; whereby discrepancies could be categorised as major discrepancies and minor discrepancies. Major discrepancy was defined as having a susceptible result from one system and resistant from the other. Minor discrepancy corresponded to having an intermediate interpretation in one system, with a susceptible or resistant result in the other. The level of agreement was analysed using the prevalence adjusted bias adjusted kappa (PABAK). RESULTS: Overall, the agreement was high, with each ARV being in "almost perfect agreement", using Landis and Koch's categorisation. Highest discordance was observed for efavirenz (75/1301, 5.8%), all arising from susceptible Stanford HIVdb versus non-susceptible vircoTYPETM HIV-1 predictions. Protease Inhibitors had highest level of concordance with PABAKs all above 0.99, followed by Nucleoside Reverse Transcriptase Inhibitors with PABAKs above 0.97 and non-NRTIs with the lowest PABAK of 0.88. The 68/75 patients with discordant efavirenz results harboured the V179D/E mutations compared to 7/1226 with no efavirenz discrepancy (p-value <0.001). In the 3-level comparison, all but one of the discrepancies was minor. CONCLUSIONS: The two systems agreed well with lowest concordance observed for efavirenz. When interpreting HIVDR, especially in non-B subtypes, clinical correlation is crucial, in particular when efavirenz resistance is interpreted based on V179D/E. PMID- 23095646 TI - In vivo modification of tyrosine residues in recombinant mussel adhesive protein by tyrosinase co-expression in Escherichia coli. AB - BACKGROUND: In nature, mussel adhesive proteins (MAPs) show remarkable adhesive properties, biocompatibility, and biodegradability. Thus, they have been considered promising adhesive biomaterials for various biomedical and industrial applications. However, limited production of natural MAPs has hampered their practical applications. Recombinant production in bacterial cells could be one alternative to obtain useable amounts of MAPs, although additional post translational modification of tyrosine residues into 3,4-dihydroxyphenyl-alanine (Dopa) and Dopaquinone is required. The superior properties of MAPs are mainly attributed to the introduction of quinone-derived intermolecular cross-links. To solve this problem, we utilized a co-expression strategy of recombinant MAP and tyrosinase in Escherichia coli to successfully modify tyrosine residues in vivo. RESULTS: A recombinant hybrid MAP, fp-151, was used as a target for in vivo modification, and a dual vector system of pET and pACYC-Duet provided co expression of fp-151 and tyrosinase. As a result, fp-151 was over-expressed and mainly obtained from the soluble fraction in the co-expression system. Without tyrosinase co-expression, fp-151 was over-expressed in an insoluble form in inclusion bodies. The modification of tyrosine residues in the soluble-expressed fp-151 was clearly observed from nitroblue tetrazolium staining and liquid chromatography-mass/mass spectrometry analyses. The purified, in vivo modified, fp-151 from the co-expression system showed approximately 4-fold higher bulk scale adhesive strength compared to in vitro tyrosinase-treated fp-151. CONCLUSION: Here, we reported a co-expression system to obtain in vivo modified MAP; additional in vitro tyrosinase modification was not needed to obtain adhesive properties and the in vivo modified MAP showed superior adhesive strength compared to in vitro modified protein. It is expected that this co expression strategy will accelerate the use of functional MAPs in practical applications and can be successfully applied to prepare other Dopa/Dopaquinone based biomaterials. PMID- 23095648 TI - [Loop diuretics improves diuresis, but not renal function in the intensive care patient with acute renal failure]. PMID- 23095649 TI - [No evidence for renal protective effect of loop diuretics for patients having oliguria]. AB - In many intensive care units, loop diuretics are used more or less routinely to achieve a urinary output above 1 ml/kg/h in critically ill patients. We do not in the literature find any basis of this strategy. In contrast, this practice may cause a risk of circulatory instability in the critically ill patient due to large diuresis and volume depletion. There is no evidence so far that the use of loop diuretics has a renal protective effect or any other beneficial impact on the renal function. The use of loop diuretics in oliguric critically ill patients may be harmful. Consequently an individual assessment is required. PMID- 23095650 TI - [Transcatheter aortic valve implantation in patients with severe aortic stenosis]. AB - In the late 1980's, Denmark was the birthplace for the concept of transcatheter valve implantation. In 2002, the first successful transcatheter aortic valve implantation (TAVI) was performed in humans. TAVI has matured beyond the learning curve period with a high overall procedural success rate and relatively few serious associated complications. TAVI is now an established treatment for severe aortic stenosis in patients who have prohibitive or high surgical risk; and the treatment has proven to yield symptomatic and prognostic benefits. Innovations and advances continue in this field. PMID- 23095651 TI - [Research training is inadequate among future medical doctors]. AB - This questionnaire survey investigated interest and activity in pregraduate research among 643 medical students at the Faculty of Health and Medical Sciences at the University of Copenhagen. We find, that although the students show great interest and motivation for research, very few have actual research experience. The students described suboptimal research training, lack of tutoring and facilitation as well as of career counselling. Also, conditions for pregraduate research activities are unequal among the faculties of health sciences in Denmark. PMID- 23095652 TI - [Polyneuropathy associated with monoclonal gammopathy of undetermined significance]. AB - The prevalence of polyneuropathy in patients with monoclonal gammopathy of undetermined significance (MGUS) has been reported to be 10-50%. The majority of patients have a chronic, slowly progressive, distal, symmetric and predominantly sensory polyneuropathy. A caused relationship between polyneuropathy and immunoglobulin (Ig)M MGUS is better established than the relationship between polyneuropathy and IgG/IgA MGUS because of the observed binding of IgM to myelin sheaths and widening of myelin lamellae. In randomized controlled trials plasma exchange, immunosuppressive, rituximab and intravenous Ig have been found to have a clinical meaningful effect. PMID- 23095653 TI - [A syndrome of chronic ataxic polyneuropathy, ophtalmoplegia, IgM paraprotein, cold agglutinins and anti-disialosyl antibodies can cause diplopia in patients with chronic sensory polyneuropathy]. AB - CANOMAD is a rare syndrome of chronic ataxic polyneuropathy, ophtalmoplegia, IgM paraprotein, cold agglutinins and anti-disialosyl antibodies. We present a case of a 65-year-old woman with clinical and electrophysiological features of chronic sensory polyneuropathy and diplopia. Serum samples from the patient contained IgM paraprotein and anti-GM2-antibodies. Treatment with intravenous immunoglobulins resulted in an improvement of the patient's diplopia and polyneuropathy. The case shows the importance of considering CANOMAD as a cause of diplopia in patients with chronic sensory polyneuropathy. PMID- 23095654 TI - [Primary adenocarcinoma of the male urethra]. AB - We present a case of a 43-year-old man treated for urethral stricture. Cystoscopy showed unusual tissue in the posterior urethra. Biopsies showed adenocarcinoma which was positive for cytokeratins 7 and 20 and negative for prostate specific antigen. Immunohistochemistry in this case was important for the diagnosis, primary urethral adenocarcinoma. PMID- 23095655 TI - [Kleine-Levin syndrome is a diagnostic challenge]. AB - Kleine-Levin syndrome (KLS) is a rare disorder characterized by recurrent episodes of hypersomnia, disturbed behaviour, and cognitive function; it may by accompanied by hyperphagia/hypersexuality. KLS is often seen after a minor infection in young men but the aetiology is unknown. This case rapport illustrates how a 16-year-old boy with ADHD presented with a range of the above mentioned symptoms and was assessed by neurologists, internal medicine doctors and psychiatrists. After two new episodes he was finally diagnosed with KLS. The understanding of this disorder is intriguing. PMID- 23095656 TI - [Calcified amorpheus tumour of the heart as the cause of near syncope]. AB - Calcified amorphoeus tumour of the heart (cardiac CAT) is a rare non-neoplastic tumour of the heart. To the best of our knowledge, this is the first case report of cardiac CAT in Scandinavia. The patient was a 55-year-old woman with obesity, hypertension, hyperlipidaemia, a history of smoking, and a family history of ischaemic heart disease. She presented with dyspnoea and near syncope. The tumour was resected, and cytopathology was preformed on its content. Based on the cytopathology, the pathologist concluded that the tumour most likely was cardiac CAT, though a calcified myxoma could not be excluded with certainty. PMID- 23095657 TI - [Swimming pool granuloma]. PMID- 23095658 TI - Age of onset: can we rely on essential tremor patients to report this? Data from a prospective, longitudinal study. AB - BACKGROUND: Essential tremor (ET) is among the most prevalent neurological diseases. Age of onset, a key variable in neuroepidemiological and genetic research, is chiefly assessed by self-report rather than medical record review; the latter may be of little use. As a researcher, one wonders about the quality of this self-report. Is age of onset something which can be reproducibly self reported by patients? There are few published data to aid researchers. METHODS: Age of onset was self-reported at two time points (baseline and follow-up) in 86 ET cases in a longitudinal epidemiological study in New York. RESULTS: The mean follow-up interval was 5.7 +/- 2.5 (maximum = 14) years. Overall, agreement between the baseline and follow-up reports was high (rho = 0.85, p < 0.001). Yet the difference (age of onset (baseline) - age of onset (follow-up)) ranged widely (from -47 to 32 years), and in one fifth of cases was >= 10 years. Greater agreement was associated with several clinical factors including age, medication use, embarrassment, depressive symptoms, cognitive test score and disease duration. CONCLUSIONS: Differences in reported age of onset in ET may vary widely, and in up to one fifth of patients may be substantial. Investigators should approach these self-reports with caution. PMID- 23095659 TI - Diastolic flow parameters are not sensitive in predicting necrotizing enterocolitis in patients undergoing hybrid procedure. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a significant cause of morbidity and mortality in neonates with complex single-ventricle anatomy undergoing stage I palliation. Hybrid approach is another option for initial single-ventricle palliation. The goal of this study was to determine if there were differences in echocardiographic indices between patients undergoing the hybrid procedure who developed NEC vs. those that did not develop NEC. METHODS: Retrospective chart review was performed on patients who underwent the hybrid procedure. Patients were included if an echocardiogram with adequate Doppler tracings through the patent ductus arteriosus stent was available. Echocardiographic indices measured included antegrade velocity-time integral (VTI), retrograde VTI, effective VTI, VTI regurgitant fraction, VTI retrograde/VTI antegrade ratio, calculated cardiac output, peak antegrade velocity through the ductal stent, retrograde/antegrade time ratio, and percent regurgitant time. Indices were compared in patients who developed NEC (NEC Group) and those who did not develop NEC (No NEC Group). NEC was defined as a Bell Stage >=2. RESULTS: Sixty-nine patients met inclusion criteria. Eight of the 69 patients developed NEC. There was no significant difference between the NEC and No NEC Group for antegrade VTI (10.4 +/- 3.2 cm vs. 12.7 +/- 4.4 cm), retrograde VTI (5.3 +/- 1.5 cm vs. 6.1 +/- 2.2 cm), effective VTI (5.1 +/- 2.9 cm vs. 6.6 +/- 3.3 cm), VTI regurgitant fraction (53.6 +/- 14.7% vs. 49.7 +/- 13.6%), and VTI retrograde/VTI antegrade ratio (0.54 +/- 0.15 vs.0.50 +/- 0.14). Cardiac output (4.2 +/- 1.4 L/min/m(2) vs. 4.8 +/- 1.8 L/min/m(2) ) and peak velocity (117.5 +/- 28.9 cm/s and 142.4 +/- 42.6 cm/s) were also not different between the NEC and No NEC Groups. Furthermore, retrograde/antegrade time ratios (1.6 +/- 0.2 vs. 1.7 +/- 0.3) and percent retrograde time (60.6 +/- 3.0% vs. 62.0 +/- 4.0%) were not different between the NEC and No NEC Groups. CONCLUSION: Echocardiographic indices were not sensitive in determining the development of NEC in patients undergoing the hybrid procedure. Larger studies with more sensitive imaging techniques are required to help risk stratify NEC in this complex patient population. PMID- 23095661 TI - Prevalence of dyslipidemia among HIV-infected patients using first-line highly active antiretroviral therapy in Southern Ethiopia: a cross-sectional comparative group study. AB - BACKGROUND: Data on lipid profile abnormalities among patients receiving highly active antiretroviral treatment in Ethiopia are very limited. The aim of this study was to determine the prevalence of dyslipidemia and characteristics of lipid profiles among patients living with human immunodeficiency virus (HIV) using first-line highly active antiretroviral therapy (HAART) in Southern Ethiopia. METHODS: This cross sectional comparative group study was conducted between March and May 2012, and included 113 HIV infected patients treated for a minimum of one year with first-line HAART regimens that included Efavirenz and Nevirapine (HAART group) and others 113 who had never received HAART (pre-HAART group). Serum lipid profiles were determined after overnight fasting and dyslipidemia was assessed according to the United State National Cholesterol Education program-III guideline. For statistical analysis Chi-square, student's t test, and logistic regression were used using Statistical Package for Social Sciences (SPSS) Version 20. RESULT: Ninety-three (82.3%) of HAART and 87 (76.9%) pre-HAART patients had at least one laboratory abnormality, which is compatible with a diagnosis of dyslipidemia. Total cholesterol >= 200 mg/dl occurred in 43.4% of HAART and 15.9% pre-HAART patients (p=<0.0001), whereas HDL-cholesterol below 40 mg/dl occurred in 43.4% and in 63.7% respectively, (p=0.002). The LDL cholesterol >= 130 mg/dl occurred in 33.6% of HAART and 15% pre-HAART patients (p=0.001), while triglycerides >= 150 mg/dl occurred in 55.8% and 31.0% respectively, (p=0.001). Receiving of HAART was significantly and positively associated with raised total cholesterol, LDL-cholesterol, and triglycerides. The adjusted odds ratio (95% CI) of HAART-treated vs. pre-HAART was 3.80 (1.34-6.55) for total cholesterol >= 200 mg/dl; 2.64 (1.31-5.32) for LDL- cholesterol >= 130 mg/dl and 2.50 (1.41-4.42) for triglycerides >=150 mg/dl. CONCLUSION: Use of first-line antiretroviral therapy regimens that contain Efavirenz and Nevirapine were associated with raised total cholesterol, LDL-cholesterol, and triglycerides, an established atherogenic lipid profiles. Lipid profiles should be performed at baseline before commencement of antiretroviral therapy and then periodically through treatment follow-up to monitor any rising trends. PMID- 23095660 TI - EVA: Exome Variation Analyzer, an efficient and versatile tool for filtering strategies in medical genomics. AB - BACKGROUND: Whole exome sequencing (WES) has become the strategy of choice to identify a coding allelic variant for a rare human monogenic disorder. This approach is a revolution in medical genetics history, impacting both fundamental research, and diagnostic methods leading to personalized medicine. A plethora of efficient algorithms has been developed to ensure the variant discovery. They generally lead to ~20,000 variations that have to be narrow down to find the potential pathogenic allelic variant(s) and the affected gene(s). For this purpose, commonly adopted procedures which implicate various filtering strategies have emerged: exclusion of common variations, type of the allelics variants, pathogenicity effect prediction, modes of inheritance and multiple individuals for exome comparison. To deal with the expansion of WES in medical genomics individual laboratories, new convivial and versatile software tools have to implement these filtering steps. Non-programmer biologists have to be autonomous combining themselves different filtering criteria and conduct a personal strategy depending on their assumptions and study design. RESULTS: We describe EVA (Exome Variation Analyzer), a user-friendly web-interfaced software dedicated to the filtering strategies for medical WES. Thanks to different modules, EVA (i) integrates and stores annotated exome variation data as strictly confidential to the project owner, (ii) allows to combine the main filters dealing with common variations, molecular types, inheritance mode and multiple samples, (iii) offers the browsing of annotated data and filtered results in various interactive tables, graphical visualizations and statistical charts, (iv) and finally offers export files and cross-links to external useful databases and softwares for further prioritization of the small subset of sorted candidate variations and genes. We report a demonstrative case study that allowed to identify a new candidate gene related to a rare form of Alzheimer disease. CONCLUSIONS: EVA is developed to be a user-friendly, versatile, and efficient-filtering assisting software for WES. It constitutes a platform for data storage and for drastic screening of clinical relevant genetics variations by non-programmer geneticists. Thereby, it provides a response to new needs at the expanding era of medical genomics investigated by WES for both fundamental research and clinical diagnostics. PMID- 23095662 TI - Helminth parasite communities of allopatric populations of the frog Leptodactylus podicipinus from Pantanal, Brazil. AB - Several factors may influence the structure of parasite communities in amphibian hosts. In this study, we describe the helminth parasites of three allopatric populations of the frog Leptodactylus podicipinus and test whether host size and sex were determinants of the structure and composition of the helminth communities. One hundred and twenty-three anurans were collected from three different study sites within the Pantanal wetlands and surveyed for helminth parasites. We found 14 helminth taxa: 7 species of nematodes, 4 species of trematodes, 1 species of cestodes, 1 species of acanthocephalan and one unidentified cyst. Host sex and size did not cause significant differences in helminth abundance or richness. The structure of helminth communities from the three study sites varied in terms of species composition, abundance and diversity. Six out of 14 helminth taxa were found in the three localities. Among those, the nematodes Cosmocerca podicipinus and Rhabdias sp., the trematode Catadiscus propinquus and the helminth cyst showed significant differences in mean abundances. We suggest that such differences found among the three component communities are driven by biotic and abiotic factors operating locally. Moreover, these differences stress the importance of local conditions, such as hydrologic characteristics and landscape composition, on helminth community structure. PMID- 23095663 TI - High-Throughput parallel blind Virtual Screening using BINDSURF. AB - BACKGROUND: Virtual Screening (VS) methods can considerably aid clinical research, predicting how ligands interact with drug targets. Most VS methods suppose a unique binding site for the target, usually derived from the interpretation of the protein crystal structure. However, it has been demonstrated that in many cases, diverse ligands interact with unrelated parts of the target and many VS methods do not take into account this relevant fact. RESULTS: We present BINDSURF, a novel VS methodology that scans the whole protein surface in order to find new hotspots, where ligands might potentially interact with, and which is implemented in last generation massively parallel GPU hardware, allowing fast processing of large ligand databases. CONCLUSIONS: BINDSURF is an efficient and fast blind methodology for the determination of protein binding sites depending on the ligand, that uses the massively parallel architecture of GPUs for fast pre-screening of large ligand databases. Its results can also guide posterior application of more detailed VS methods in concrete binding sites of proteins, and its utilization can aid in drug discovery, design, repurposing and therefore help considerably in clinical research. PMID- 23095664 TI - Inadequate treatment of ventilator-associated and hospital-acquired pneumonia: risk factors and impact on outcomes. AB - BACKGROUND: Initial antimicrobial therapy (AB) is an important determinant of clinical outcome in patients with severe infections as pneumonia, however well conducted studies regarding prognostic impact of inadequate initial AB in patients who are not undergoing mechanical ventilation (MV) are lacking. In this study we aimed to identify the risk factors for inadequate initial AB and to determine its subsequent impact on outcomes in both ventilator associated pneumonia (VAP) and hospital acquired pneumonia (HAP). METHODS: We retrospectively studied the accuracy of initial AB in patients with pneumonia in a university hospital in Turkey. A total of 218 patients with HAP and 130 patients with VAP were included. For each patient clinical, radiological and microbiological data were collected. Stepwise multivariate logistic regression analysis was used for risk factor analysis. Survival analysis was performed by using Kaplan-Meier method with Log-rank test. RESULTS: Sixty six percent of patients in VAP group and 41.3% of patients in HAP group received inadequate initial AB. Multiple logistic regression analysis revealed that the risk factors for inadequate initial AB in HAP patients were; late-onset HAP (OR = 2.35 (95% CI, 1.05-5.22; p = 0.037) and APACHE II score at onset of HAP (OR = 1.06 (95% CI, 1.01-1.12); p = 0.018). In VAP patients; antibiotic usage in the previous three months (OR = 3.16 (95% CI, 1.27-7.81); p = 0.013) and admission to a surgical unit (OR = 2.9 (95% CI, 1.17-7.19); p = 0.022) were found to be independent risk factors for inadequate initial AB. No statistically significant difference in crude hospital mortality and 28-day mortality was observed between the treatment groups in both VAP and HAP. However we showed a significant increase in length of hospital stay, duration of mechanical ventilation and a prolonged clinical resolution in the inadequate AB group in both VAP and HAP. CONCLUSION: Our data suggests that the risk factors for inadequate initial AB are indirectly associated with the acquisition of resistant bacteria for both VAP and HAP. Although we could not find a positive correlation between adequate initial AB and survival; empirical AB with a broad spectrum should be initiated promptly to improve secondary outcomes. PMID- 23095665 TI - Cyclosporine A impairs norepinephrine-induced vascular contractility. AB - Usage of cyclosporine A (CsA) after kidney transplantation may be associated with development of nephrotoxicity and vasculopathy, but the mechanisms by which CsA causes vascular dysfunction are still under scrutiny. We established a transplantation model and investigated the effect of CsA on vascular contractility with the aid of a pressurized myograph in comparison with control and unilaterally nephrectomized rats. Results were correlated with mRNA expression studies of alpha- and beta-adrenoreceptors, in mesenteric resistance arteries versus the thoracic aorta. Consequences of everolimus on functional properties as well as adrenoreceptor expression were also studied. CsA significantly downregulated expression of mesenteric adrenoreceptors, whereas no effect on aortic adrenoreceptors was seen. Administration of everolimus had no influence on mRNA adrenoreceptor expression in mesenteric resistance arteries. Furthermore, contractile responses of mesenteric resistance arteries to norepinephrine were markedly reduced after treatment with CsA, while there was no difference in contraction by endothelin. Everolimus did not alter the contractility response at all. In summary, norepinephrine-induced, but not endothelin-induced, contractile responses of mesenteric resistance arteries are blunted in CsA-treated rats. This finding was accompanied by a marked downregulation of adrenoreceptors in mesenteric resistance arteries and was limited to the usage of CsA. PMID- 23095666 TI - Very early development of nucleus taeniae of the amygdala. AB - The avian nucleus taeniae of the amygdala (TnA) corresponds to part of the mammalian medial amygdala. Like its mammalian counterpart, it has been shown to be involved in the control of social function. According to behavioral observations, such control is already necessary early in the ontogenetic development of a bird. If so, TnA should be one of the earliest differentiating brain structures of the telencephalon. Our anatomical study shows that TnA can already be delineated at posthatching day one. The volume of TnA exhibits a growth spurt between days 1 and 8 posthatch, developing at a faster rate than the entire telencephalon. Our results suggest that between days 1 and 8 the growth of neuropil exceeds the enhancement of neuron number (leading to a decrease of cell density), and an addition at the same pace of new neurons and neuropil thereafter. A plateau is reached at posthatch day 30. The development of TnA precedes that of the song control nuclei and is similar to the early growth of thalamic and telencephalic sensory areas. This adds to the idea that this structure may already be involved in social control at the time of hatching. A proximate cause of the early development of TnA might be the direct afference from the olfactory bulb. PMID- 23095667 TI - A comparison of clinical registry versus administrative claims data for reporting of 30-day surgical complications. AB - OBJECTIVES: To compare the recording of 30-day postoperative complications between a national clinical registry and Medicare inpatient claims data and to determine whether the addition of outpatient claims data improves concordance with the clinical registry. BACKGROUND: Policymakers are increasingly discussing use of postoperative complication rates for value-based purchasing. There is debate regarding the optimal data source for such measures. METHODS: Patient records (2005-2008) from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) were linked to Medicare inpatient and outpatient claims data sets. We assessed the ability of (1) Medicare inpatient claims and (2) Medicare inpatient and outpatient claims to detect a core set of ACS-NSQIP 30-day postoperative complications: superficial surgical site infection (SSI), deep/organ-space SSI, any SSI (superficial and/or deep/organ-space), urinary tract infection, pneumonia, sepsis, deep venous thrombosis (DVT), pulmonary embolism, venous thromboembolism (DVT and/or pulmonary embolism), and myocardial infarction. Agreement of patient-level complications by ACS-NSQIP versus Medicare was assessed by kappa statistics. RESULTS: A total of 117,752 patients from more than 200 hospitals were studied. The sensitivity of inpatient claims data for detecting ACS-NSQIP complications ranged from 0.27 to 0.78; the percentage of false-positives ranged from 48% to 84%. Addition of outpatient claims data improved sensitivity slightly but also greatly increased the percentage of false-positives. Agreement was routinely poor between clinical and claims data for patient-level complications. CONCLUSIONS: This analysis demonstrates important differences between ACS-NSQIP and Medicare claims data sets for measuring surgical complications. Poor accuracy potentially makes claims data suboptimal for evaluating surgical complications. These findings have meaningful implications for performance measures currently being considered. PMID- 23095668 TI - Developing standards for malaria microscopy: external competency assessment for malaria microscopists in the Asia-Pacific. AB - BACKGROUND: Malaria diagnosis has received renewed interest in recent years, associated with the increasing accessibility of accurate diagnosis through the introduction of rapid diagnostic tests and new World Health Organization guidelines recommending parasite-based diagnosis prior to anti-malarial therapy. However, light microscopy, established over 100 years ago and frequently considered the reference standard for clinical diagnosis, has been neglected in control programmes and in the malaria literature and evidence suggests field standards are commonly poor. Microscopy remains the most accessible method for parasite quantitation, for drug efficacy monitoring, and as a reference of assessing other diagnostic tools. This mismatch between quality and need highlights the importance of the establishment of reliable standards and procedures for assessing and assuring quality. This paper describes the development, function and impact of a multi-country microscopy external quality assurance network set up for this purpose in Asia. METHODS: Surveys were used for key informants and past participants for feedback on the quality assurance programme. Competency scores for each country from 14 participating countries were compiled for analyses using paired sample t-tests. In-depth interviews were conducted with key informants including the programme facilitators and national level microscopists. RESULTS: External assessments and limited retraining through a formalized programme based on a reference slide bank has demonstrated an increase in standards of competence of senior microscopists over a relatively short period of time, at a potentially sustainable cost. The network involved in the programme now exceeds 14 countries in the Asia-Pacific, and the methods are extended to other regions. CONCLUSIONS: While the impact on national programmes varies, it has translated in some instances into a strengthening of national microscopy standards and offers a possibility both for supporting revival of national microcopy programmes, and for the development of globally recognized standards of competency needed both for patient management and field research. PMID- 23095669 TI - The role of the host defense system in the development of cerebral vasospasm: analogies between atherosclerosis and subarachnoid hemorrhage. AB - Similar to atherosclerosis, platelet-derived growth factor (PDGF)-BB, a major growth factor for vascular smooth muscle cells, is produced in arterial walls to repair arteries after subarachnoid hemorrhage (SAH). On review of a series of research articles that focus on defensive host responses to SAH, PDGF-BB is identified as a spasmogen, based on the following findings: (1) foreign substances injected into the subarachnoid space cause persistent constriction of cerebral arteries with a time course and histological features almost identical to those seen after SAH; (2) persistent constriction induced by SAH or a foreign substance is dependent on the complement system; (3) the complement system, which stimulates platelets, macrophages and endothelial cells to secrete PDGF-BB, is activated in both the cerebrospinal fluid (CSF) and plasma immediately after SAH; (4) PDGF-BB levels in the CSF are significantly elevated in patients with delayed cerebral ischemia; (5) the immunodensity of PDGF-BB in the arterial walls correlates well with the severity of cerebral vasospasm; (6) intracisternal injection of PDGF-BB induces persistent constriction of cerebral arteries in a dose-dependent manner; (7) prolonged contact with blood clots promotes the contractile response of cerebral arteries to PDGF-BB, and (8) administration of an antagonist of PDGF-BB function suppresses the development of cerebral vasospasm. PMID- 23095670 TI - Normalization of tumor vasculature by R-Ras. PMID- 23095671 TI - Transactivation by low and high levels of human p53 reveals new physical rules of engagement and novel super-transactivation sequences. PMID- 23095672 TI - Transformer proteins. PMID- 23095674 TI - PARty promoters: hormone-dependent gene regulation requires CDK2 activation of PARP1. AB - Comment on: Wright RH, et al. Genes Dev 2012; 26:1972-83. PMID- 23095673 TI - Barrett esophagus: what a mouse model can teach us about human disease. AB - The incidence of esophageal adenocarcinoma (EAC) is rapidly rising in the western world and accounts for 2% of all cancer-related deaths. The precursor lesion for EAC is Barrett esophagus (BE), which is strongly associated with gastresophageal reflux disease. A major limitation to the study of EAC has been the absence of tractable and genetically modifiable preclinical models of BE. A mouse model of BE and EAC that resembles human disease could provide novel insights into the origins and molecular pathogenesis of BE. In addition, validated animal models could help stratify BE patients given the limited predictive power of current standard endoscopic measures and clinical assessment. Here, we review the findings from recently developed mouse models of BE and EAC and their impact on clinical decision making, surveillance programs and therapeutic options. The data, taken together, suggest potential origins of BE from the gastric cardia, a role of bile acid and hypergatrinemia for carcinogenesis, a growing importance for columnar-like epithelium and a critical role for Notch signaling. PMID- 23095675 TI - Regulatory circuitry governing morphogenesis in Saccharomyces cerevisiae and Candida albicans. PMID- 23095676 TI - 'When did my tremor start?': can essential tremor patients pinpoint their disease onset?. PMID- 23095677 TI - Propofol increases angiotensin-converting enzyme 2 expression in human pulmonary artery endothelial cells. AB - BACKGROUND/AIMS: Propofol, a widely used sedative-hypnotic agent for induction/maintenance of anesthesia and sedation of critically ill patients, reportedly has therapeutic potential for hypertension. Angiotensin-converting enzyme 2 (ACE2) is a promising therapeutic target for pulmonary arterial hypertension. In the present study, we explored the effect of propofol on ACE2 expression in human pulmonary artery endothelial cells (HPAECs). METHODS: HPAECs were treated with propofol in different concentrations (1, 10, 20, 40 or 50 umol/l) for different lengths of time (6, 12, 18, 24 or 30 h) with or without transcription inhibitor actinomycin D or phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002. RESULTS: Propofol increased the ACE2 mRNA level in a dose- and time-dependent manner within 24 h. Propofol treatment dose-dependently increased the ACE2 protein level and the cell membrane ACE2 activity. Transcription inhibitor actinomycin D and PI3K inhibitor LY294002 abrogated the augmenting effect of propofol on the mRNA level of ACE2 in HPAECs. CONCLUSION: Propofol enhances the ACE2 expression in HPAECs by increasing the transcription of ACE2 via a PI3K-dependent mechanism, which leads to increased ACE2 activity on the cell membrane. This study provides new insights into propofol's vascular protective effects as well as its therapeutic potential for pulmonary arterial hypertension. PMID- 23095678 TI - Nursing home characteristics associated with methicillin-resistant Staphylococcus aureus (MRSA) Burden and Transmission. AB - BACKGROUND: MRSA prevalence in nursing homes often exceeds that in hospitals, but reasons for this are not well understood. We sought to measure MRSA burden in a large number of nursing homes and identify facility characteristics associated with high MRSA burden. METHODS: We performed nasal swabs of residents from 26 nursing homes to measure MRSA importation and point prevalence, and estimate transmission. Using nursing home administrative data, we identified facility characteristics associated with MRSA point prevalence and estimated transmission risk in multivariate models. RESULTS: We obtained 1,649 admission and 2,111 point prevalence swabs. Mean MRSA point prevalence was 24%, significantly higher than mean MRSA admission prevalence, 16%, (paired t-test, p<0.001), with a mean estimated MRSA transmission risk of 16%.In multivariate models, higher MRSA point prevalence was associated with higher admission prevalence (p=0.005) and higher proportions of residents with indwelling devices (p=0.01). Higher estimated MRSA transmission risk was associated with higher proportions of residents with diabetes (p=0.01) and lower levels of social engagement (p=0.03). CONCLUSIONS: MRSA importation was a strong predictor of MRSA prevalence, but MRSA burden and transmission were also associated with nursing homes caring for more residents with chronic illnesses or indwelling devices. Frequent social interaction among residents appeared to be protective of MRSA transmission, suggesting that residents healthy enough to engage in group activities do not incur substantial risks of MRSA from social contact. Identifying characteristics of nursing homes at risk for high MRSA burden and transmission may allow facilities to tailor infection control policies and interventions to mitigate MRSA spread. PMID- 23095681 TI - Abstracts of Challenges in Malaria Research. Basel, Switzerland. October 10-12, 2012. PMID- 23095679 TI - The burden of neglected tropical diseases in Ethiopia, and opportunities for integrated control and elimination. AB - BACKGROUND: Neglected tropical diseases (NTDs) are a group of chronic parasitic diseases and related conditions that are the most common diseases among the 2.7 billion people globally living on less than US$2 per day. In response to the growing challenge of NTDs, Ethiopia is preparing to launch a NTD Master Plan. The purpose of this review is to underscore the burden of NTDs in Ethiopia, highlight the state of current interventions, and suggest ways forward. RESULTS: This review indicates that NTDs are significant public health problems in Ethiopia. From the analysis reported here, Ethiopia stands out for having the largest number of NTD cases following Nigeria and the Democratic Republic of Congo. Ethiopia is estimated to have the highest burden of trachoma, podoconiosis and cutaneous leishmaniasis in sub-Saharan Africa (SSA), the second highest burden in terms of ascariasis, leprosy and visceral leishmaniasis, and the third highest burden of hookworm. Infections such as schistosomiasis, trichuriasis, lymphatic filariasis and rabies are also common. A third of Ethiopians are infected with ascariasis, one quarter is infected with trichuriasis and one in eight Ethiopians lives with hookworm or is infected with trachoma. However, despite these high burdens of infection, the control of most NTDs in Ethiopia is in its infancy. In terms of NTD control achievements, Ethiopia reached the leprosy elimination target of 1 case/10,000 population in 1999. No cases of human African trypanosomiasis have been reported since 1984. Guinea worm eradication is in its final phase. The Onchocerciasis Control Program has been making steady progress since 2001. A national blindness survey was conducted in 2006 and the trachoma program has kicked off in some regions. Lymphatic Filariasis, podoconiosis and rabies mapping are underway. CONCLUSION: Ethiopia bears a significant burden of NTDs compared to other SSA countries. To achieve success in integrated control of NTDs, integrated mapping, rapid scale up of interventions and operational research into co implementation of intervention packages will be crucial. PMID- 23095680 TI - Naturally occurring mutations to HCV protease inhibitors in treatment-naive patients. AB - BACKGROUND: Protease inhibitors (PIs) to treat hepatitis C (HCV) virus infection have been approved and others are under development. RESULTS: The aims of this study were to illustrate natural polymorphisms in the HCV protease and measure the frequency of PI resistance mutations in different HCV genotypes from PI-naive patients.Direct sequencing of HCV NS3/4A protease was performed in 156 HCV patients naive to PIs who were infected with genotype 1a (n = 31), 1b (n = 39), 2 (n = 30), 3 (n = 33) and 4 (n = 23).Amino acid (aa) substitutions associated with HCV PI resistance were found in 17/156 (10.8%) sequences. Mutations V36L, T54S, V55A/I, and Q80K/L were observed in 29% of patients with genotype 1a, and V55F, Q80L/N and M175L in 10% of patients with genotype 1b. The mutation V158M was found in 3% of patients with genotype 2, D168Q was present in 100% of patients with genotype 3 and D168E was observed in 13% of patients with genotype 4. In addition, multiple aa polymorphisms not associated with PI resistance were detected in patients with genotypes 1a, 1b and 4. CONCLUSIONS: Although major PI resistance mutations were not detected, other resistance mutations conferring low level resistance to PIs together with a number of natural polymorphisms were observed in proteases of PI naive HCV patients. A more extensive analysis is needed to better evaluate the impact of baseline resistance and compensatory mutations in the efficacy of HCV PI treatment. PMID- 23095682 TI - Two cases of psoriasis responding to erlotinib: time to revisiting inhibition of epidermal growth factor receptor in psoriasis therapy?. AB - Erlotinib inhibits the tyrosine kinase of epidermal growth factor receptor (EGFR) and is successfully used in lung cancer treatment. EGFR is essential in skin development and function and may have a role in the pathogenesis of psoriasis. Cutaneous side effects are very common in patients treated with erlotinib, and therapeutic use of erlotinib in dermatological disorders has therefore not been considered. We report two cases of patients with lung cancer and concomitant psoriasis treated with erlotinib with complete resolution of the skin problems. We present a review of the current literature on the topic. PMID- 23095684 TI - Predictors of left ventricular reverse remodeling and subsequent outcome in nonischemic dilated cardiomyopathy. AB - BACKGROUND: Optimal medical therapy can lead to left ventricular (LV) reverse remodeling (LVRR) in nonischemic dilated cardiomyopathy (NIDCM). However, because the clinical variables associated with LVRR are poorly defined, we sought to identify them and their prognostic role, and to evaluate the role of initial and midterm levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the long-term follow-up of patients with NIDCM. METHODS AND RESULTS: We evaluated 329 consecutive hospitalized patients with NIDCM by reviewing the records in the institutional heart failure database. Clinical and echocardiographic data were available for 253 (77%) patients at the midterm follow-up (16 +/- 7 months). The patients were followed thereafter until the combined endpoint of cardiovascular death, heart transplantation, or hospitalization for heart failure. LVRR was noted in 97 (38%) of 253 patients at midterm. The baseline predictors of LVRR were higher systolic blood pressure, QRS duration <120 ms, use of a beta-blocker, and a small indexed LV end-systolic dimension. In landmark survival analysis from the midterm evaluation, LVRR, low midterm NT-proBNP level, and continuous use of a beta-blocker were independently related to good long-term results. CONCLUSIONS: Monitoring of patients with NIDCM using both cardiac imaging of the LV structure and by assessing neurohormonal status (NT-proBNP level) at the midterm follow-up might be clinically useful for predicting the long-term clinical prognosis of NIDCM. PMID- 23095685 TI - Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review. AB - Cardiovascular diseases, especially coronary artery disease (CAD), are the leading causes of death in patients with chronic obstructive pulmonary disease (COPD). There is a high prevalence of common risk factors in the COPD/CAD patient population including smoking, sedentary lifestyle and low socio-economic status. However, various studies have shown that airflow limitation is an independent risk factor for cardiovascular diseases. Chronic low-grade systemic inflammation, oxidative stress and increased platelet activation have been widely reported to be pathophysiological links between COPD and atherosclerosis. Statins and inhaled corticosteroids have been investigated as potential therapeutic interventions in COPD that may lower cardiovascular risk. The goals of this review are to examine the evidence for increased cardiovascular risk in COPD patients, the possible mechanisms linking these two chronic conditions, to discuss possible predictors or markers of poor outcomes among patients diagnosed with both COPD and CAD, and the therapeutic options aimed at reducing cardiovascular risks associated with COPD. PMID- 23095683 TI - 3D-FISH analysis of embryonic nuclei in mouse highlights several abrupt changes of nuclear organization during preimplantation development. AB - BACKGROUND: Embryonic development proceeds through finely tuned reprogramming of the parental genomes to form a totipotent embryo. Cells within this embryo will then differentiate and give rise to all the tissues of a new individual. Early embryonic development thus offers a particularly interesting system in which to analyze functional nuclear organization. When the organization of higher-order chromatin structures, such as pericentromeric heterochromatin, was first analyzed in mouse embryos, specific nuclear rearrangements were observed that correlated with embryonic genome activation at the 2-cell stage. However, most existing analyses have been conducted by visual observation of fluorescent images, in two dimensions or on z-stack sections/projections, but only rarely in three dimensions (3D). RESULTS: In the present study, we used DNA fluorescent in situ hybridization (FISH) to localize centromeric (minor satellites), pericentromeric (major satellites), and telomeric genomic sequences throughout the preimplantation period in naturally fertilized mouse embryos (from the 1-cell to blastocyst stage). Their distribution was then analyzed in 3D on confocal image stacks, focusing on the nucleolar precursor bodies and nucleoli known to evolve rapidly throughout the first developmental stages. We used computational imaging to quantify various nuclear parameters in the 3D-FISH images, to analyze the organization of compartments of interest, and to measure physical distances between these compartments. CONCLUSIONS: The results highlight differences in nuclear organization between the two parental inherited genomes at the 1-cell stage, i.e. just after fertilization. We also found that the reprogramming of the embryonic genome, which starts at the 2-cell stage, undergoes other remarkable changes during preimplantation development, particularly at the 4-cell stage. PMID- 23095686 TI - Early systolic blood pressure changes in incident hemodialysis patients are associated with mortality in the first year. AB - BACKGROUND: In incident hemodialysis (HD) patients, the relationship between early systolic blood pressure (SBP) dynamics and mortality is unknown. METHODS: Baseline SBP levels were stratified into 5 categories ranging from <120 and >=180 mm Hg. Early pre-HD SBP change was defined as the slope of pre-HD SBP from week 1 to 12 and categorized in quartiles (Q1, lowest slope). SBP slopes were computed for each patient by simple linear regression. RESULTS: In 3,446 incident HD patients (42% females, 44% black, age 62 +/- 15 years), the median pre-HD SBP slope was -1.7 (Q1) to +2.3 (Q4) mm Hg/week. In an adjusted multivariate Cox regression analysis, patients with declining SBP (slope Q1) had higher mortality compared to patients with increasing pre-HD SBP (slope Q4) at 12 months (hazard ratio 2.01, 95% confidence interval 1.35-3.01). In addition, patients with baseline pre-HD SBP <120 mm Hg showed higher mortality compared to the reference group (SBP >=180 mm Hg) at 12 months (hazard ratio 1.89, 95% confidence interval 1.03-3.45). CONCLUSION: Baseline pre-HD SBP and early SBP dynamics are associated with mortality in the first year of dialysis. Patients who had low (pre-HD SBP <120 mm Hg) or declining SBP had the highest mortality rates. Particular attention is warranted in incident HD patients with low or declining SBP. PMID- 23095689 TI - Do mentors know who they are mentoring? PMID- 23095687 TI - Use of mobile and cordless phones and survival of patients with glioma. AB - BACKGROUND: We analysed the survival of patients after glioma diagnosis in relation to the use of wireless phones. METHODS: All cases diagnosed between 1997 and 2003 with a malignant brain tumour (n = 1,251) in our case-control studies were included and followed from the date of diagnosis to the date of death or until May 30, 2012. RESULTS: For glioma, the use of wireless phones (mobile and cordless phones) gave a hazard ratio (HR) = 1.1 (95% confidence interval, CI = 0.9-1.2), with > 10-year latency HR = 1.2 (95% CI = 1.002-1.5, p trend = 0.02). For astrocytoma grade I-II (low-grade), the results were, HR = 0.5 (95% CI = 0.3 0.9) and for astrocytoma grade IV (glioblastoma), HR = 1.1 (95% CI = 0.95-1.4), with > 10 year latency HR = 1.3 (95% CI = 1.03-1.7). In the highest tertile (> 426 h) of cumulative use, HR = 1.2 (95% CI = 0.95-1.5) was found for glioblastoma. The results were similar for mobile and cordless phones. CONCLUSIONS: Decreased survival of glioma cases with long-term and high cumulative use of wireless phones was found. A survival disadvantage for astrocytoma grade IV, but a survival benefit for astrocytoma grade I-II was observed which could be due to exposure-related tumour symptoms leading to earlier diagnosis and surgery in that patient group. PMID- 23095690 TI - 50 years ago in the Journal of Pediatrics: Pulmonary Pneumocystis carinii infection. PMID- 23095691 TI - 50 years ago in the Journal of Pediatrics: the use of hypothermia in pediatric emergencies. PMID- 23095692 TI - 50 years ago in the Journal of Pediatrics: Acute renal failure in infancy and childhood. PMID- 23095693 TI - 50 years ago in the Journal of Pediatrics: Photogenic and self-induced epilepsy. PMID- 23095694 TI - Improving drug formulations for neonates: making a big difference in our smallest patients. PMID- 23095695 TI - A computerized self-help intervention is as effective as face-to-face counseling for adolescents seeking help for depression. PMID- 23095696 TI - Adding prednisolone to standard immunoglobulin therapy is beneficial for patients with severe Kawasaki disease. PMID- 23095697 TI - Whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy reduces mortality into childhood. PMID- 23095698 TI - Combination of sumatriptan/naproxen effectively treats migraine headaches in adolescents. PMID- 23095699 TI - Neuromuscular training program reduces knee injuries among adolescent female soccer players. PMID- 23095700 TI - Amphotericin B deoxycholate and fluconazole are most effective treatments for invasive candidiasis in infants. PMID- 23095708 TI - The parasite fauna of the Patagonian toothfish Dissostichus eleginoides off the Falkland Islands. AB - The parasite fauna of juvenile Dissostichus eleginoides, while they inhabit the Falkland's shelf, was examined, giving new detailed information on spatial, ontogenic and seasonal variations. A total of 24,943 parasites from 15 different taxa were found in the stomach of 502 individual fish. Parasite species composition and abundance allowed separation of toothfish by area between the north-west and south-east of the Falklands. The digenean, Elytrophalloides oatesi, and the nematodes, Hysterothylacium spp. and Anisakis spp., were the most common, all with a prevalence >20%. For some seasons ontogenic changes in abundance were significant in these three parasite taxa, and this is discussed in terms of ontogenic and seasonal changes in diet. Elytrophalloides oatesi and Hysterothylacium spp. showed spatial and seasonal differences in abundance with greater numbers in the warmer waters of the north-west and during the summer months. Differences in abundance of E. oatesi between the Falklands and other regions indicate its potential for use as a biological tag to study toothfish movements and population structure; however, more seasonal data would be required before this technique could be used. PMID- 23095709 TI - Modelling non-homogeneous stochastic reaction-diffusion systems: the case study of gemcitabine-treated non-small cell lung cancer growth. AB - BACKGROUND: Reaction-diffusion based models have been widely used in the literature for modeling the growth of solid tumors. Many of the current models treat both diffusion/consumption of nutrients and cell proliferation. The majority of these models use classical transport/mass conservation equations for describing the distribution of molecular species in tumor spheroids, and the Fick's law for describing the flux of uncharged molecules (i.e oxygen, glucose). Commonly, the equations for the cell movement and proliferation are first order differential equations describing the rate of change of the velocity of the cells with respect to the spatial coordinates as a function of the nutrient's gradient. Several modifications of these equations have been developed in the last decade to explicitly indicate that the tumor includes cells, interstitial fluids and extracellular matrix: these variants provided a model of tumor as a multiphase material with these as the different phases. Most of the current reaction diffusion tumor models are deterministic and do not model the diffusion as a local state-dependent process in a non-homogeneous medium at the micro- and meso scale of the intra- and inter-cellular processes, respectively. Furthermore, a stochastic reaction-diffusion model in which diffusive transport of the molecular species of nutrients and chemotherapy drugs as well as the interactions of the tumor cells with these species is a novel approach. The application of this approach to he scase of non-small cell lung cancer treated with gemcitabine is also novel. METHODS: We present a stochastic reaction-diffusion model of non small cell lung cancer growth in the specification formalism of the tool Redi, we recently developed for simulating reaction-diffusion systems. We also describe how a spatial gradient of nutrients and oncological drugs affects the tumor progression. Our model is based on a generalization of the Fick's first diffusion law that allows to model diffusive transport in non-homogeneous media. The diffusion coefficient is explicitly expressed as a function depending on the local conditions of the medium, such as the concentration of molecular species, the viscosity of the medium and the temperature. We incorporated this generalized law in a reaction-based stochastic simulation framework implementing an efficient version of Gillespie algorithm for modeling the dynamics of the interactions between tumor cell, nutrients and gemcitabine in a spatial domain expressing a nutrient and drug concentration gradient. RESULTS: Using the mathematical framework of model we simulated the spatial growth of a 2D spheroidal tumor model in response to a treatment with gemcitabine and a dynamic gradient of oxygen and glucose. The parameters of the model have been taken from recet literature and also inferred from real tumor shrinkage curves measured in patients suffering from non-small cell lung cancer. The simulations qualitatively reproduce the time evolution of the morphologies of these tumors as well as the morphological patterns follow the growth curves observed in patients. CONCLUSIONS: s This model is able to reproduce the observed increment/decrement of tumor size in response to the pharmacological treatment with gemcitabine. The formal specification of the model in Redi can be easily extended in an incremental way to include other relevant biophysical processes, such as local extracellular matrix remodelling, active cell migration and traction, and reshaping of host tissue vasculature, in order to be even more relevant to support the experimental investigation of cancer. PMID- 23095710 TI - Effects of different loading doses of dexmedetomidine on bispectral index under stepwise propofol target-controlled infusion. AB - BACKGROUND AND PURPOSE: Stepwise propofol target-controlled infusion (TCI) can achieve a less disturbed condition of hemodynamics and respiration. Its combination with dexmedetomidine may have some advantages for patients. We studied the effects of different loading doses of dexmedetomidine on the bispectral index (BIS) under stepwise propofol TCI. METHODS: Forty patients were randomly assigned into groups D(1.0), D(0.5), D(0.25) and D(0), in which dexmedetomidine at 1.0, 0.5, 0.25 or 0 ug*kg(-1) was infused over 10 min followed by 0.5 ug*kg(-1)*h(-1) and stepwise propofol TCI, which was administered with target effect site concentration (Ce) at 0.5 ug*ml(-1), and increased until 2.5 ug*ml(-1) by 1.0 ug*ml(-1) after 5 min reaching target Ce. BIS, heart rate, MAP, pulse oxygen saturation, RR and end-tidal carbon dioxide pressure were recorded before loading dose (T(0)), at 5 min (T(5 min)) and 10 min (T(10 min)) after starting infusion, after 5 min reaching Ce of 0.5, 1.5 and 2.5 ug*ml(-1) (T(p0.5), T(p1.5) and T(p2.5)). RESULTS: BIS values in group D(1.0) were significantly lower compared with those in group D(0) since T(10 min) and those in groups D(0.5) and D(0.25) since T(p0.5). In group D(1.0), heart rate decreased significantly at T(5 min) and T(10 min), heart rate at T(10 min) was significantly lower compared with that in group D(0). MAP remained stable during the loading dose infusion and decreased to some degree after propofol infusion in all groups. Changes in pulse oxygen saturation, RR and end-tidal carbon dioxide pressurewere similar among the groups without respiration depression. CONCLUSION: A loading dose of dexmedetomidine of 1.0 ug*kg(-1), not 0.5 ug*kg(-1) or less, over 10 min followed by 0.5 ug*kg(-1)*h(-1) can definitely decrease the BIS under stepwise propofol TCI with clinically stable blood pressure and without respiration depression, while attention should be paid to decreased heart rate. PMID- 23095711 TI - Ca(2+) influx versus efflux during eryptosis in uremic erythrocytes. PMID- 23095712 TI - Associations of dietary indices with biomarkers of dietary exposure and cardiovascular status among adolescents in Germany. AB - BACKGROUND: Adolescence is an important life stage for the development of dietary preferences and health behaviour. Longitudinal studies indicated that cardiovascular status in adolescence predicts cardiovascular risk marker values in adulthood. Several diet quality indices for adolescents have been developed in the past, but literature concerning associations between indices and biomarkers of dietary exposure and cardiovascular status is rather sparse. Hence, the aim of this study was to analyse associations of dietary indices with biomarkers of dietary exposure and cardiovascular status. METHODS: For the present analysis, data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS 2003-2006) were used. The analysis included 5,198 adolescents, aged 12 to 17 years. The Healthy Food Diversity Index (HFD), the Healthy Nutrition Score for Kids and Youth (HuSKY), the Indicator Food Index (IFI) and a simple fruit/vegetable intake index were derived from food frequency questionnaire information to indicate a healthy diet. Adjusted mean values for homocysteine, uric acid, CRP, total cholesterol, HDL-C, ferritin, HbA1c, folate, vitamin B12 and BMI were calculated using complex-samples general linear models for quintiles of the different indices. Furthermore, the agreement in ranking between the different indices was calculated by weighted kappa. All statistical analyses were conducted for boys and girls separately, and were adjusted for potential confounders. RESULTS: Folate was positively associated with the HFD, the HuSKY, and fruit/vegetable intake for both boys and girls and with IFI for boys. Among girls, positive associations were seen between vitamin B12 and the IFI and between diastolic blood pressure and the IFI as well as fruit/vegetable intake. A negative association was found between homocysteine and the HFD, the HuSKY, and the IFI for both boys and girls and with fruit/vegetable intake for boys. Among boys, uric acid and HbA1c were negatively and prevalence of obesity positively associated with the IFI. CONCLUSIONS: Overall, the indices, even the simpler ones, seem to have a similar general capability in predicting biomarkers of dietary exposure. To predict risk of cardiovascular disease dietary indices may have to be more specific. PMID- 23095713 TI - Construction of a two-parameter empirical model of left ventricle wall motion using cardiac tagged magnetic resonance imaging data. AB - BACKGROUND: A one-parameter model was previously proposed to characterize the short axis motion of the LV wall at the mid-ventricle level. The single parameter of this model was associated with the radial contraction of myocardium, but more comprehensive model was needed to account for the rotation at the apex and base levels. The current study developed such model and demonstrated its merits and limitations with examples. MATERIALS AND METHODS: The hearts of five healthy individuals were visualized using cardiac tagged magnetic resonance imaging (tMRI) covering the contraction and relaxation phases. Based on the characteristics of the overall dynamics of the LV wall, its motion was represented by a combination of two components - radial and rotational. Each component was represented by a transformation matrix with a time-dependent variable alpha or beta.Image preprocessing step and model fitting algorithm were described and applied to estimate the temporal profiles of alpha and beta within a cardiac cycle at the apex, mid-ventricle and base levels. During this process, the tagged lines of the acquired images served as landmark reference for comparing against the model prediction of the motion. Qualitative and quantitative analyses were performed for testing the performance of the model and thus its validation. RESULTS: The alpha and beta estimates exhibited similarities in values and temporal trends once they were scaled by the radius of the epicardium (r(epi))and plotted against the time scaled by the period of the cardiac cycle (T(cardiac)) of each heart measured during the data acquisition. alpha/repi peaked at about Deltat/T(cardiac)=0.4 and with values 0.34, 0.4 and 0.3 for the apex, mid-ventricle and base level, respectively. beta/r(epi) similarly maximized in amplitude at about Deltat/T(cardiac)=0.4, but read 0.2 for the apex and - 0.08 for the base level. The difference indicated that the apex twisted more than the base. CONCLUSION: It is feasible to empirically model the spatial and temporal evolution of the LV wall motion using a two-parameter formulation in conjunction with tMRI-based visualization of the LV wall in the transverse planes of the apex, mid-ventricle and base. In healthy hearts, the analytical model will potentially allow deriving biomechanical entities, such as strain, strain rate or torsion, which are typically used as diagnostic, prognostic or predictive markers of cardiovascular diseases including diabetes. PMID- 23095714 TI - Different pattern of clinical deficits in stroke mimics treated with intravenous thrombolysis. AB - BACKGROUND: Guidelines recommend intravenous thrombolysis (IVT) to be applied as early as possible in ischemic stroke (IS), while clinical presentation is often assessed by using the National Institutes of Health Stroke Scale (NIHSS). However, diagnostic workup under time pressure bears the risk of misdiagnosis. Little is known about whether NIHSS could help to differentiate between IS and stroke mimics (SM) in patients being evaluated for IVT. METHODS: Prospectively collected data of 326 consecutive patients treated with IVT were analyzed. Baseline characteristics and NIHSS subscores were compared between SM and IS. RESULTS: Among 326 patients, 23 (7%) had a final diagnosis other than IS. Age and vascular risk factors were comparable in both groups. Patients with SM less often had oculomotor disturbance (0 vs. 37%, p < 0.001), dysarthria (9 vs. 51%, p < 0.001), hemineglect (0 vs. 30%, p < 0.01), hemianopia (0 vs. 22%, p < 0.01) and facial palsy (33 vs. 70%, p < 0.01). On the other hand, global aphasia without hemiparesis was more prevalent in SM patients (43 vs. 6%, p < 0.001). CONCLUSION: Our study suggests that patients with SM undergoing IVT present with a different pattern of clinical deficits than patients with IS. PMID- 23095715 TI - Cell type-dependent requirement of autophagy in HSV-1 antiviral defense. AB - Type I interferons (IFNs) are induced during most viral infections and are considered to be the primary and universal means of innate viral control. However, several other innate mechanisms, including autophagy, have recently been shown to play an important role in antiviral defense. In our recent study, we utilized a herpes simplex virus 1 (HSV-1) infection model to investigate the relationship between cell type and innate antiviral immune mechanisms. Our study demonstrates that dorsal root ganglion (DRG) neurons undergo an innate antiviral response to HSV-1 that differs from the antiviral program induced in mitotic cells in three distinct ways. First, DRG neurons produce less type I IFN and undergo a less effective IFN antiviral program vs. mitotic cells in response to HSV-1 infection. Second, the type I IFN program initiated in DRG neurons induces less cell death than in mitotic cells. Third, in the absence of a robust type I IFN response, DRG neurons, but not mitotic cells, rely on autophagy in HSV-1 defense. Our findings reveal a cell type-specific requirement for autophagy in defense against HSV-1, and offer insight into the cell-appropriate antiviral defense mechanism employed by neurons. PMID- 23095716 TI - Historically low mitochondrial DNA diversity in koalas (Phascolarctos cinereus). AB - BACKGROUND: The koala (Phascolarctos cinereus) is an arboreal marsupial that was historically widespread across eastern Australia until the end of the 19th century when it suffered a steep population decline. Hunting for the fur trade, habitat conversion, and disease contributed to a precipitous reduction in koala population size during the late 1800s and early 1900s. To examine the effects of these reductions in population size on koala genetic diversity, we sequenced part of the hypervariable region of mitochondrial DNA (mtDNA) in koala museum specimens collected in the 19th and 20th centuries, hypothesizing that the historical samples would exhibit greater genetic diversity. RESULTS: The mtDNA haplotypes present in historical museum samples were identical to haplotypes found in modern koala populations, and no novel haplotypes were detected. Rarefaction analyses suggested that the mtDNA genetic diversity present in the museum samples was similar to that of modern koalas. CONCLUSIONS: Low mtDNA diversity may have been present in koala populations prior to recent population declines. When considering management strategies, low genetic diversity of the mtDNA hypervariable region may not indicate recent inbreeding or founder events but may reflect an older historical pattern for koalas. PMID- 23095717 TI - Polymorphisms in the p63 and p73 genes are associated with ovarian cancer risk and clinicopathological variables. AB - OBJECTIVE: p73 and p63 are two structural and functional homologs of p53, and their biological functions in cancer progression have attracted attention due to the presence of variants generated by genetic polymorphisms. Recently, three single nucleotide polymorphisms (SNPs) in the p63 and p73 genes have been associated with female reproduction. In the present study, we aimed to evaluate the relationship between these SNPs and ovarian cancer susceptibility and clinical pathology. METHODS: We genotyped the p63 (rs873330 [Genbank, refSNP ID] T > C [T: original base, C: mutant base]) and p73 (rs4648551 G > A and rs6695978 G > A) SNPs in ovarian cancers and healthy controls and analyzed the distributions of genotype frequencies to evaluate the association of the genotypes with the risk of ovarian cancer and the clinicopathological characteristics. Logistic regression models were applied in statistical analyses. RESULTS: Our research revealed that p73 rs6695978 G > A was significantly associated with ovarian cancer patients. Women with the A allele were at increased risk of ovarian cancer compared to carriers of the G allele (OR = 1.55; 95% CI:1.07-2.19; P = 0.003). Meanwhile, the at-risk A allele was positively related with the occurrence of mucinous ovarian cancer (OR = 3.48; 95% CI:1.15 6.83; P = 0.001), low degree of differentiation (OR = 1.87; 95% CI:1.03-3.47; P = 0.003), lymph node metastasis (OR = 1.69; 95% CI: 1.14-2.75; P = 0.010) and estrogen receptor positive (OR = 2.72; 95% CI: 1.38-4.81; P = 0.002). However, we were unable to find any associations of the polymorphisms in another two SNPs (rs4648551 G > A, rs873330 T > C) with ovarian cancer risk and clinicopathological parameters. CONCLUSIONS: The p73 rs6695978 G > A polymorphism will serve as a modifier of ovarian cancer susceptibility and prognosis. Further investigations with large sample sizes and of the mechanistic relevance of p73 polymorphism will be warranted. PMID- 23095718 TI - Hyperemesis gravidarum in the Medical Birth Registry of Norway - a validity study. AB - BACKGROUND: Valid registration of medical information is essential for the quality of registry-based research. Hyperemesis gravidarum (HG) is characterized by severe nausea and vomiting, weight loss and electrolyte imbalance starting before 22nd gestational week. Given the fact that HG is a generally understudied disease which might have short- and long- term health consequences for mother and child, it is of importance to know whether potential misclassification bias influences the results of future studies. We therefore assessed the validity of the HG-registration in the in Medical Birth Registry of Norway (MBRN) using hospital records. METHODS: The sample comprised all women registered in MBRN with HG and who delivered at Ulleval and Akershus hospitals in 1.1.-31.3.1970, 1.4. 30.6.1986, 1.7.-30.9.1997 and 1.10.-31.12.2001. A random sample of 10 women per HG case, without HG according to MBRN, but who delivered during the same time periods at the same hospitals was also collected. The final sample included 551 women. Sensitivity, specificity, positive and negative predictive values (PPV and NPV) were estimated using strict and less strict diagnostic criteria of HG, indicating severe and mild HG, respectively. Hospital journals were used as gold standard. RESULTS: Using less strict diagnostic criteria of HG, sensitivity, specificity, PPV and NPV were 83.9% (95% CI: 67.4-92.9), 96.0% (95% CI: 93.9 97.3), 55.3% (95% CI: 41.2-68.6) and 99.0% (95% CI: 97.7-99.6), respectively. For strict diagnostic criteria, being hospitalised due to HG the corresponding values were 64% (95% CI: 38.8-87.2), 92% (95% CI: 90.2-94.6), 18.6% (95% CI: 10.2-31.9) and 99.0% (95% CI: 97.7-99.6). CONCLUSIONS: The results from our study are comparable to previous research on disease registration in MBRN, and show that MBRN can be considered valid for mild HG but not for severe HG. PMID- 23095719 TI - No harmful effect of dialysis-induced hypotension on the myocardium in patients who have normal ejection fraction and a negative exercise test. AB - BACKGROUND: We investigated the effects of dialysis-induced hypotension (DIH) on the myocardium of patients who have a normal ejection fraction and normal treadmill stress tests. METHODS: This study included 26 end-stage renal disease (ESRD) patients with DIH, 30 ESRD patients without DIH (non-DIH), and 30 control subjects. Mitral-myocardial systolic velocity (MSV), the mitral E'/A' ratio, the left ventricle filling pressure index (E/E' ratio), tricuspid-MSV, and the tricuspid E'/A' ratio were calculated. RESULTS: Biventricular systolic and diastolic functions were impaired in dialysis patients. The mitral and tricuspid MSV were similar between DIH and non-DIH patients (8.03 +/- 0.90 cm/s vs. 8.31 +/ 1.68 cm/s, p = 0.896, and 13.27 +/- 2.97 cm/s vs. 13.15 +/- 2.37 cm/s, p = 0.980). Mitral and tricuspid E'/A' were similar between DIH and non-DIH patients. (1.30 +/- 0.53 vs. 1.16 +/- 0.56, p = 0.695, and 0.70 +/- 0.24 vs. 0.68 +/- 0.33, p = 0.976). Likewise, the E/E' ratio was similar between DIH and non-DIH patients (8.20 +/- 2.83 vs. 8.28 +/- 2.53, p = 0.990). CONCLUSION: Although biventricular systolic and diastolic function is impaired in dialysis patients compared to controls, DIH episodes did not have an adverse effect on the myocardial functions. PMID- 23095720 TI - Online machine translation use with nursing literature: evaluation method and usability. AB - Japanese nurses are now being required to use research in clinical practice. As a result, they increasingly need to read nursing research literature written in English. Online machine translation is a convenient tool that may address any existing language barrier. The quality of machine translation has been evaluated using various methods; however, its reliability for nursing literature is unknown. In this study, existing methods for evaluating online machine translation quality were examined for structural accuracy and intelligibility of translations of nursing literature, and the usability of machine translations is discussed. In total, 297 English sentences from nursing study abstracts were evaluated for accuracy and intelligibility; 75 word items were identified as specific terms. Interrater reliability of the evaluation method was measured using two raters. The results showed the strong reliability of the existing evaluation method. Also, a possibly usable online machine translation system being offered in Japan was identified. Specific terms seemed to influence the extent of the intelligibility of the translations. Future studies need to include more samples of the nursing population to examine general perceptions of the usability of online machine translation systems for reading English nursing literature among the Japanese nursing population. PMID- 23095722 TI - Role of epicardial adipose tissue in atrial fibrillation. PMID- 23095721 TI - Association between physical activity and risk of stroke subtypes: the atherosclerosis risk in communities study. AB - BACKGROUND: The relationship between stroke subtypes and physical activity is unclear. METHODS: Using data from 13,069 men and women aged 45-64 years who participated in the Atherosclerosis Risk in Communities Study, physical activity was assessed by self-report using the Baecke questionnaire at baseline (1987 1989). The American Heart Association's ideal cardiovascular health guidelines served as a basis for the calculation of three physical activity categories: poor, intermediate, and ideal. Stroke and its subtypes were ascertained from physician review of medical records. Multivariable adjusted hazard ratios (HR) and 95% confidence intervals (CI) were calculated using Cox regression models. RESULTS: During a median follow-up of 18.8 years, a total of 648 incident ischemic strokes occurred. Significant inverse associations were found between physical activity categories and total, total ischemic, and nonlacunar stroke in adjusted models (age, sex, race-center, education, cigarette-years). Compared with poor physical activity, the adjusted HR (95% CI) for ideal physical activity were 0.78 (0.62-0.97) for total, 0.76 (0.59-0.96) for total ischemic, 0.85 (0.51 1.40) for lacunar, 0.77 (0.47-1.27) for cardioembolic, and 0.71 (0.51-0.99) for nonlacunar stroke. Additional adjustments for waist-to-hip ratio, systolic blood pressure, antihypertensive medication, diabetes, left ventricular hypertrophy and laboratory parameters attenuated the HR. Further sex- and race-specific analyses revealed that the association was predominantly observed among males and among African-Americans. CONCLUSION: These data suggest a tendency toward a reduced risk of total, total ischemic, and nonlacunar stroke with higher levels of physical activity. PMID- 23095723 TI - Age-related changes in listening effort for various types of masker noises. AB - OBJECTIVE: The purpose of the present study was to evaluate the relationship between cognitive function, listening effort, and speech recognition for a group of younger and older adults with normal hearing and a group of older adults with hearing impairment in various types of background maskers. The authors hypothesize that, as the masker condition becomes more difficult listening effort will increase, but the increase will be greater for older participants than for younger participants. DESIGN: A dual-task paradigm was used to objectively evaluate listening effort. The primary task required participants to repeat sentences presented in three different background-masker conditions: (1) two talker (TT), (2) six-talker, and (3) speech-shaped noise (SSN). The secondary task was a Digital Visual Pursuit Rotor Tracking test, for which participants were instructed to use a computer mouse to track a moving target around an ellipse that was displayed on a computer screen. Each of the two tasks was separately and concurrently presented at a fixed overall speech-recognition performance level of 76% correct. In addition, participants subjectively rated how easy it was to listen to the sentences in each masker condition on a scale from 0 (i.e., very difficult) to 100 (i.e., very easy). Last, participants completed a battery of cognitive tests that measured working memory (Reading Span Test), processing speed (Digit Symbol Substitution Test), and selective attention (Stroop Test) ability. RESULTS: Results revealed that participants' working memory and processing speed abilities were significantly related to their speech recognition performance in noise in all three background-masker conditions. Participants rated the TT condition to be the most difficult listening condition and the SSN condition to be the easiest listening condition. Both groups of older participants expended significantly more listening effort than younger participants did in the SSN and TT masker conditions. For each group of participants, there were no significant differences in listening effort measured across the masker conditions, with the exception of the younger participants, who expended more effort listening in the six-talker masker condition compared with the SSN condition. Participants' listening effort expended on the TT and SSN masker conditions was significantly correlated with their working memory and processing speed performance. CONCLUSIONS: Findings from the present study indicate that older adults require more cognitive resources than younger adults to understand speech in background noise. PMID- 23095724 TI - An environmental assessment of the parasite fauna of the reef-associated grouper Epinephelus areolatus from Indonesian waters. AB - Sixty Epinephelus areolatus were examined for metazoan fish parasites in Indonesia, off Segara Anakan lagoon, Java and in Balinese waters. The study revealed 21 different parasite species, and 14 new host and locality records. The anisakid nematodes Anisakis typica and, for the first time in Indonesia, Anisakis sp. HC-2005 were identified by using molecular methods. Ecological parameters were calculated for both sites off the anthropogenically influenced Segara Anakan lagoon and the relatively undisturbed reference site at the southern Balinese coast. The fish from Segara Anakan demonstrated a significantly higher enzymatic activity (Hepatosomatic index) and a significantly reduced number of heteroxenous gut helminths (e.g. the digenean Didymodiclinus sp., the nematode Raphidascaris sp. and the acanthocephalan Serrasentis sagittifer). Other regional differences for E. areolatus included ecto-/endoparasite ratio, endoparasite diversity, the parasite species composition and prevalence of infection of the respective parasite species. We applied the stargraph method to visualize observed regional differences using grouper parasites as biological indicators for the sampled coastal ecosystems at both sampling sites. PMID- 23095725 TI - Significance of Gleason grading of low-grade carcinoma of the prostate with therapeutic option of active surveillance. AB - INTRODUCTION: Active surveillance needs a precise grading diagnosis of a low grade carcinoma of the prostate (Gleason score (GS) 6) within a small organ confined tumor. However, how accurate is the gold standard of GS 6 in predicting a small pT2 carcinoma? To answer this question, we have analyzed grading systems in this study. METHODS: Prostatic carcinomas in biopsy and corresponding radical prostatectomy (RP) specimens of 960 patients were graded by the Gleason system in which glandular fusions and nucleolar stage (prominence and location) were considered. RESULTS: Using the modified Gleason grading, a high upgrading rate from the biopsy to RP specimens (GS 6-7) and in even 30% a non-organ-confined growth pattern (pT3) of GS 6 carcinoma in RP was found. When considering glandular fusion and the incorporation of the state of nucleoli within the Gleason grading, the agreement of score 6 between biopsy and RP specimens as well as the prediction of a pT2a tumor increased from about 80 to 90%. CONCLUSION: The combination of Gleason grading and grading of the nuclear and nucleolar features may help to identify patients eligible for active surveillance. PMID- 23095726 TI - Enhanced depth imaging optical coherence tomography of the choroid in Vogt Koyanagi-Harada disease. AB - PURPOSE: Optical coherence tomography (OCT) using enhanced depth imaging (EDI) allows evaluation of choroidal thickness. Our objective was to analyze subfoveal choroidal thickness by EDI-OCT before and after the initiation of high-dose corticosteroid treatment in 8 patients (16 eyes) with new-onset acute Vogt Koyanagi-Harada (VKH) disease. METHODS: Retrospective review of clinical records. RESULTS: The outer border of the choroid was not evident by EDI-OCT in any patients at presentation. Subfoveal choroidal thickness was measurable by 1 week after the initiation of treatment (mean, 578 MUm) and decreased thereafter (mean at 1 month, 397 MUm; 3 months, 392 MUm; 6 months, 384 MUm; 12 months, 332 MUm). Rebound of choroidal thickening was observed in three patients (five eyes) during corticosteroid tapering in the absence of other evidence of increased inflammation. Peripapillary atrophy was present at 12 months in 6 of 6 eyes that had a choroidal thickness >550 MUm at 1 week after initiating treatment, in contrast to none of the 8 eyes with a choroidal thickness <=550 MUm (P = 0.0003). CONCLUSION: Enhanced depth imaging-optical coherence tomography revealed decreasing choroidal thickness with high-dose corticosteroid treatment in our patients. Choroidal thickness as measured by EDI-OCT may serve as a marker for degree of choroidal inflammation in acute VKH disease. PMID- 23095727 TI - Visual outcome correlates with inner macular volume in eyes with surgically closed macular hole. AB - PURPOSE: To determine the macular morphologic features that correlate best with visual outcome in eyes with surgically closed idiopathic macular hole. METHODS: Transversal observational case series of 24 eyes (22 subjects) imaged postoperatively using high-resolution Fourier domain optical coherence tomography (FD-OCT). Total and inner macular volume for central 3 mm area, central foveal thickness, and size of foveal inner segment-outer segment junction abnormality were correlated with best-corrected visual acuity. Microperimetry (MP-1) test was performed in a subset of 18 eyes. RESULTS: Mean postoperative best-corrected visual acuity was 20/36 (range, 20/25-20/70). Postoperative follow-up mean was 32.97 +/- 24.68 months (range, 5-96 months). Eighteen eyes underwent internal limiting membrane (ILM) peeling. Among FD-OCT parameters, logarithm of the minimum angle of resolution best-corrected visual acuity and mean total microperimetry-1 sensitivity correlated best with inner macular volume in all eyes and ILM-peeled eyes (P < 0.05). Macular surface irregularities were noted in 12 eyes (66.7%) with ILM peeling but in none of the non-ILM-peeled eyes (P = 0.02). No significant correlation was found between microperimetry-1 sensitivity and other FD-OCT parameters. CONCLUSION: Because inner macular volume strongly correlated with visual outcome in eyes with surgically closed macular hole, the possible effect of ILM peeling on visual outcome needs to be further investigated. PMID- 23095729 TI - Deep anterior lamellar corneal dissection to improve visualization during vitreoretinal surgery. PMID- 23095728 TI - Proteomic analysis of vitreous biopsy techniques. AB - PURPOSE: To compare vitreous biopsy methods using analysis platforms used in proteomics biomarker discovery. METHODS: Vitreous biopsies from 10 eyes were collected sequentially using a 23-gauge needle and a 23-gauge vitreous cutter instrument. Paired specimens were evaluated by UV absorbance spectroscopy, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and liquid chromatography tandem mass spectrometry (LC-MS/MS). RESULTS: The total protein concentration obtained with a needle and vitrectomy instrument biopsy averaged 1.10 mg/mL (standard error of the mean = 0.35) and 1.13 mg/mL (standard error of the mean = 0.25), respectively. In eight eyes with low or medium viscidity, there was a very high correlation (R = 0.934) between the biopsy methods. When data from 2 eyes with high viscidity vitreous were included, the correlation was reduced (R = 0.704). The molecular weight protein sodium dodecyl sulfate-polyacrylamide gel electrophoresis profiles of paired needle and vitreous cutter samples were similar, except for a minority of pairs with single band intensity variance. Using LC-MS/MS, equivalent peptides were identified with similar frequencies (R >= 0.90) in paired samples. CONCLUSION: Proteins and peptides collected from vitreous needle biopsies are nearly equivalent to those obtained from a vitreous cutter instrument. This study suggests both techniques may be used for most proteomic and biomarker discovery studies of vitreoretinal diseases, although a minority of proteins and peptides may differ in concentration. PMID- 23095730 TI - High prevalence of sleep disordered breathing in patients with diabetic macular edema. PMID- 23095732 TI - Measurement of brain edema by noninvasive cerebral electrical impedance in patients with massive hemispheric cerebral infarction. AB - BACKGROUND: Malignant cerebral infarction often occurs in patients with massive cerebral infarction. Monitoring brain edema is therefore helpful to make correct clinical decisions. Our previous studies have confirmed that cerebral electrical impedance (CEI) can sensitively reflect the brain edema after stroke. METHODS: The CEI was measured consecutively by a noninvasive brain edema monitor in 69 patients with massive hemispheric cerebral infarction (MHCI). The results of the CEI were converted into the perturbation index (PI). The characteristics of dynamic changes of the CEI after MHCI were analyzed. Receiver-operating characteristics analysis was used to calculate predictive values for PI and other known parameters including NIHSS score and infarct volume. RESULTS: (1) The overall rate of positive CEI was 88.4% (61/69) in all patients with MHCI. (2) The PI on the infarct side increased significantly within 24 h after stroke onset and reached a peak level 3-5 days after stroke onset (p < 0.01). (3) Age, NIHSS score at admission, infarct volume, and the PI at 24 h after stroke onset were significantly different between the malignant and nonmalignant groups. The best predictor of a malignant MHCI was the PI at 24 h after stroke onset with a cut off value of 10.02 (90.9% sensitivity, 87.2% specificity, 76.9% positive predictive value, 95.3% negative predictive value). CONCLUSIONS: The noninvasive CEI can sensitively reflect the brain edema in patients with MHCI. Monitoring the CEI may help to predict malignant MHCI and guide treatment decisions. PMID- 23095733 TI - Dimensions of gender relations and reproductive health inequity perceived by female undergraduate students in the Mekong Delta of Vietnam: a qualitative exploration. AB - INTRODUCTION: Increasing evidence indicates that gender equity has a significant influence on women's health; yet few culturally specific indicators of gender relations exist which are applicable to health. This study explores dimensions of gender relations perceived by female undergraduate students in southern Vietnamese culture, and qualitatively examines how this perceived gender inequity may influence females' sexual or reproductive health. METHODS: Sixty-two female undergraduate students from two universities participated in eight focus group discussions to talk about their perspectives regarding national and local gender equity issues. RESULTS: Although overall gender gaps in the Mekong Delta were perceived to have decreased in comparison to previous times, several specific dimensions of gender relations were emergent in students' discussions. Perceived dimensions of gender relations were comparable to theoretical structures of the Theory of Gender and Power, and to findings from several reports describing the actual inferiority of women. Allocation of housework and social paid work represented salient dimensions of labor. The most salient dimension of power related to women in positions of authority. Salient dimensions of cathexis related to son preference, women's vulnerability to blame or criticism, and double standards or expectations. Findings also suggested that gender inequity potentially influenced women's sexual and reproductive health as regards to health information seeking, gynecological care access, contraceptive use responsibility, and child bearing. CONCLUSION: Further investigations of the associations between gender relations and different women's sexual and reproductive health outcomes in this region are needed. It may be important to address gender relations as a distal determinant in health interventions in order to promote gender-based equity in sexual and reproductive health. PMID- 23095734 TI - Analgesic effects of tramadol in combination with adjuvant drugs: an experimental study in rats. AB - BACKGROUND: Tramadol is often coadministered subcutaneously with adjuvants to treat pain, nausea/vomiting, dyspnea and delirium in cancer patients. The aim of the study was to investigate analgesia of tramadol coadministered with adjuvants in rats. MATERIALS AND METHODS: Male rats (Wistar race) received a single tramadol dose separately (0.45 mg/kg) or tramadol with haloperidol (0.45 mg/kg), midazolam (0.3 mg/kg), levomepromazine (0.35 mg/kg), metoclopramide (1.0 mg/kg), hyoscine butylbromide (1.7 mg/kg) or ketamine (0.3 mg/kg) as a single subcutaneous injection. Analgesia was measured by a tail flick test after 15, 30, 60 and 90 min of drug administration. RESULTS: Tramadol analgesia was enhanced with haloperidol (30, 60 and 90 min) and with midazolam (60 and 90 min). Tramadol with levomepromazine (30, 60 and 90 min) and tramadol with metoclopramide (30 and 90 min) attenuated tramadol analgesia. Tramadol with hyoscine butylbromide and tramadol with ketamine did not change tramadol analgesia. CONCLUSIONS: Significant changes in tramadol analgesia after the administration of different adjuvants could be demonstrated in this experimental single-dose study. Future clinical trials have to further explore the benefits of these drug combinations. PMID- 23095735 TI - Secondary hyperparathyroidism in chronic dialysis patients. PMID- 23095736 TI - Cells of visceral smooth muscles. PMID- 23095737 TI - Evaluation of adaptive relaxation of the rat stomach using an orally inserted balloon instead of surgical intervention by demonstrating the effects of capsaicin and Nomega-nitro-L-arginine methylester. AB - Gastric functions such as adaptive relaxation have usually been monitored in rats using a surgically inserted barostat's balloon. However, surgery causes physiological damage to the rat stomach. This study is an investigation of adaptive relaxation of the rat stomach using a slightly modified balloon, which is introduced into the stomach through the mouth of anesthetized rats without the need for balloon surgery, attached to a brostat. In this case, the balloon was placed between the fore-stomach and the fundus, but towards the fore-stomach. The balloon volume increased gradually just after an increment in the balloon pressure, and reached a plateau within 1 min. This increased volume just after the increment of the balloon pressure was defined as adaptive relaxation. Adaptive relaxation increased with pressure increases in a pressure dependent manner. Pre-treatment with Nomega-nitro-L-arginine methylester (30 mg/kg, i.v.) caused this adaptive relaxation to be significantly inhibited as compared with the control. On the contrary, adaptive relaxation was significantly enhanced by pre-treatment with capsaicin (0.5 mg/kg, p.o.). These findings show that this method is both useful for investigating the physiology of adaptive relaxation of the stomach without surgery and to show that nitric oxide plays an important role in the adaptive relaxation of the stomach as reported previously. PMID- 23095738 TI - Simultaneous measurement of gastric emptying and gastrocecal transit times in conscious rats using a breath test after ingestion of [1-13C] acetic acid and lactose-[13C] ureide. AB - This study reports a method for the evaluation of both gastric emptying and gastrocecal transit times in rats simultaneously by using the same breath testing system measuring equipment. Male rats were used after fasting. Gastric emptying and gastrocecal transit time were evaluated by using [1-13C] acetic acid (8 mg/kg) and lactose-[13C] ureide (60 mg/kg), respectively. A mixture of both 13C labelled compounds dissolved in Racol (liquid nutrient formula) was administered orally. The level of 13CO2 in the expired air was measured using an infrared spectrometer at appropriate intervals for a period of 420 min. The level of 13CO2 in the expired air from [1-13C] acetic acid increased with time and peaked at about 30 min before decreasing, while that from lactose-[13C] ureide increased after about 180 min. The time taken to reach the maximum value of gastric emptying (Tmax) was 27.5+/-0.9 min. Gastrocecal transit time was 180+/-11.5 min, which was calculated as the time before the 13CO2 value increased again. These results accorded with the results of gastric emptying and gastrocecal transit time evaluated by using each 13C-labelled compound separately. These results demonstrate that this method is useful for the simultaneous evaluation of gastric emptying and gastrocecal transit times in rats. PMID- 23095739 TI - Genetically similar strains of Escherichia coli O157:H7 isolated from sheep, cattle and human patients. AB - BACKGROUND: Comparatively little is known about the prevalence or the molecular characteristics of the zoonotic pathogen E. coli O157:H7 in the sheep reservoir. To investigate this and determine the host specificity of subclones of the bacterium, we have conducted a slaughterhouse prevalence study in sheep and compared the collected isolates to O157:H7 previously isolated from cattle and human patients. RESULTS: Verotoxin-producing O157:H7 was found in 11/597 (1.8%) of samples from sheep in Swedish slaughterhouses, 9/492 faecal (1.8%) and 2/105 ear samples (1.9%). All positive sheep were < 6 months old. Pulsed field gel electrophoresis typing revealed exact matches between isolates from the sheep prevalence study and human patients as well as between isolates from sheep and cattle. In one case, matching isolates were found in sheep, cattle, and a human patient in the same municipality. Identical PFGE profiles generally corresponded to similar but non-identical multi-locus VNTR profiles. In one sheep sample, SNP typing found the highly virulent clade 8 variant of O157:H7. The virulence gene profiles of sheep isolates from the prevalence study and three sheep farms linked to cases of human illness were investigated by PCR detection (eaeA, hlyA, cdtV-B, vtx1), and partial sequencing of vtx2. The observed profiles were similar to those of cattle strains investigated previously. CONCLUSIONS: The same pathogenic subtypes of VTEC O157:H7, including the highly virulent clade 8, appear to be present in both sheep and cattle in Sweden, suggesting strains can circulate freely between ruminant reservoirs. PMID- 23095740 TI - A modified Larson's method of posterolateral corner reconstruction of the knee reproducing the physiological tensioning pattern of the lateral collateral and popliteofibular ligaments. AB - BACKGROUND: Consensus has been lacking as to how to reconstruct the posterolateral corner (PLC) of the knee in patients with posterolateral instability. We describe a new reconstructive technique for PLC based on Larson's method, which reflects the physiological load-sharing pattern of the lateral collateral ligament (LCL) and popliteofibular ligament (PFL). FINDINGS: Semitendinosus graft is harvested, and one limb of the graft comprises PFL and the other comprises LCL. Femoral bone tunnels for the LCL and popliteus tendon are made at their anatomical insertions. Fibular bone tunnel is prepared from the anatomical insertion of the LCL to the proximal posteromedial portion of the fibular head, which corresponds to the insertion of the PFL. The graft end for popliteus tendon is delivered into the femoral bone tunnel and secured on the medial femoral condyle. The other end for LCL is passed through the fibular tunnel from posterior to anterior. While the knee is held in 90 of flexion, the graft is secured in the fibular tunnel using a 5 mm interference screw. Then, the LCL end is passed into the femoral bone tunnel and secured at the knee in extension. CONCLUSIONS: Differential tension patterns between LCL and PFL is critical when securing these graft limbs. Intrafibular fixation of the graft using a small interference screw allows us to secure these two graft limbs independently with intended tension at the intended flexion angle of the knee. PMID- 23095741 TI - Dual role for motif 1 residues of human lysyl-tRNA synthetase in dimerization and packaging into HIV-1. AB - The primer for reverse transcription in human immunodeficiency virus type 1, human tRNA(Lys,3), is selectively packaged into the virion along with tRNA(Lys1,2). Human lysyl-tRNA synthetase (hLysRS), the only cellular factor known to interact specifically with all three tRNA(Lys) isoacceptors, is also selectively packaged into HIV-1. We have previously defined a tRNA(Lys) packaging complex that includes the tRNA(Lys) isoacceptors, LysRS, HIV-1 Gag, GagPol, and viral RNA. Numerous studies support the hypothesis that during tRNA(Lys) packaging, a Gag.GagPol complex interacts with a tRNA(Lys).LysRS complex, with Gag interacting specifically with the catalytic domain of LysRS, and GagPol interacting with both Gag and tRNA(Lys). In this work, we have identified residues along one face of the motif 1 dimerization helix (H7) of hLysRS that are critical for packaging of the synthetase into virions. Mutation of these residues affects binding to Gag in vitro, as well as the oligomerization state and aminoacylation activity of the synthetase. Taken together, these data suggest that H7 of LysRS has a dual function. In its canonical role it maintains the synthetase dimer interface, whereas in its function in tRNA primer recruitment, it bridges interactions with HIV-1 Gag. PMID- 23095742 TI - Human SMC2 protein, a core subunit of human condensin complex, is a novel transcriptional target of the WNT signaling pathway and a new therapeutic target. AB - Human SMC2 is part of the condensin complex, which is responsible for tightly packaging replicated genomic DNA prior to segregation into daughter cells. Engagement of the WNT signaling pathway is known to have a mitogenic effect on cells, but relatively little is known about WNT interaction with mitotic structural organizer proteins. In this work, we described the novel transcriptional regulation of SMC2 protein by direct binding of the beta catenin.TCF4 transcription factor to the SMC2 promoter. Furthermore, we identified the precise region in the SMC2 promoter that is required for beta catenin-mediated promoter activation. Finally, we explored the functional significance of down-regulating SMC2 protein in vivo. Treatment of WNT-activated intestinal tumor cells with SMC2 siRNA significantly reduced cell proliferation in nude mice, compared with untreated controls (p = 0.02). Therefore, we propose that WNT signaling can directly activate SMC2 transcription as a key player in the mitotic cell division machinery. Furthermore, SMC2 represents a new target for oncological therapeutic intervention. PMID- 23095743 TI - Artemin stimulates radio- and chemo-resistance by promoting TWIST1-BCL-2 dependent cancer stem cell-like behavior in mammary carcinoma cells. AB - Artemin (ARTN) has been reported to promote a TWIST1-dependent epithelial to mesenchymal transition of estrogen receptor negative mammary carcinoma (ER-MC) cells associated with metastasis and poor survival outcome. We therefore examined a potential role of ARTN in the promotion of the cancer stem cell (CSC)-like phenotype in mammary carcinoma cells. Acquired resistance of ER-MC cells to either ionizing radiation (IR) or paclitaxel was accompanied by increased ARTN expression. Small interfering RNA (siRNA)-mediated depletion of ARTN in either IR or paclitaxel-resistant ER-MC cells restored cell sensitivity to IR or paclitaxel. Expression of ARTN was enriched in ER-MC cells grown in mammospheric compared with monolayer culture and was also enriched along with BMI1, TWIST1, and DVL1 in mammospheric and ALDH1+ populations. ARTN promoted mammospheric growth and self-renewal of ER-MC cells and increased the ALDH1+ population, whereas siRNA-mediated depletion of ARTN diminished these CSC-like cell behaviors. Furthermore, increased ARTN expression was significantly correlated with ALDH1 expression in a cohort of ER-MC patients. Forced expression of ARTN also dramatically enhanced tumor initiating capacity of ER-MC cells in xenograft models at low inoculum. ARTN promotion of the CSC-like cell phenotype was mediated by TWIST1 regulation of BCL-2 expression. ARTN also enhanced mammosphere formation and the ALDH1+ population in estrogen receptor-positive mammary carcinoma (ER+MC) cells. Increased expression of ARTN and the functional consequences thereof may be one common adaptive mechanism used by mammary carcinoma cells to promote cell survival and renewal in hostile tumor microenvironments. PMID- 23095744 TI - Distinct characteristics of two 2-Cys peroxiredoxins of Vibrio vulnificus suggesting differential roles in detoxifying oxidative stress. AB - Peroxiredoxins (Prxs) are ubiquitous antioxidant enzymes reducing toxic peroxides. Two distinct 2-Cys Prxs, Prx1 and Prx2, were identified in Vibrio vulnificus, a facultative aerobic pathogen. Both Prxs have two conserved catalytic cysteines, C(P) and C(R), but Prx2 is more homologous in amino acid sequences to eukaryotic Prx than to Prx1. Prx2 utilized thioredoxin A as a reductant, whereas Prx1 required AhpF. Prx2 contained GGIG and FL motifs similar to the motifs conserved in sensitive Prxs and exhibited sensitivity to overoxidation. MS analysis and C(P)-SO(3)H specific immunoblotting demonstrated overoxidation of C(P) to C(P)-SO(2)H (or C(P)-SO(3)H) in vitro and in vivo, respectively. In contrast, Prx1 was robust and C(P) was not overoxidized. Discrete expression of the Prxs implied that Prx2 is induced by trace amounts of H(2)O(2) and thereby residential in cells grown aerobically. In contrast, Prx1 was occasionally expressed only in cells exposed to high levels of H(2)O(2). A mutagenesis study indicated that lack of Prx2 accumulated sufficient H(2)O(2) to induce Prx1. Kinetic properties indicated that Prx2 effectively scavenges low levels of peroxides because of its high affinity to H(2)O(2), whereas Prx1 quickly degrades higher levels of peroxides because of its high turnover rate and more efficient reactivation. This study revealed that the two Prxs are differentially optimized for detoxifying distinct ranges of H(2)O(2), and proposed that Prx2 is a residential scavenger of peroxides endogenously generated, whereas Prx1 is an occasional scavenger of peroxides exogenously encountered. Furthermore, genome sequence database search predicted widespread coexistence of the two Prxs among bacteria. PMID- 23095745 TI - The tRNA recognition mechanism of folate/FAD-dependent tRNA methyltransferase (TrmFO). AB - The conserved U54 in tRNA is often modified to 5-methyluridine (m(5)U) and forms a reverse Hoogsteen base pair with A58 that stabilizes the L-shaped tRNA structure. In Gram-positive and some Gram-negative eubacteria, m(5)U54 is produced by folate/FAD-dependent tRNA (m(5)U54) methyltransferase (TrmFO). TrmFO utilizes N(5),N(10)-methylenetetrahydrofolate (CH(2)THF) as a methyl donor. We previously reported an in vitro TrmFO assay system, in which unstable [(14)C]CH(2)THF was supplied from [(14)C]serine and tetrahydrofolate by serine hydroxymethyltransferase. In the current study, we have improved the TrmFO assay system by optimization of enzyme and substrate concentrations and introduction of a filter assay system. Using this assay, we have focused on the tRNA recognition mechanism of TrmFO. 42 tRNA mutant variants were prepared, and experiments with truncated tRNA and microhelix RNAs revealed that the minimum requirement of TrmFO exists in the T-arm structure. The positive determinants for TrmFO were found to be the U54U55C56 sequence and G53-C61 base pair. The gel mobility shift assay and fluorescence quenching showed that the affinity of TrmFO for tRNA in the initial binding process is weak. The inhibition experiments showed that the methylated tRNA is released before the structural change process. Furthermore, we found that A38 prevents incorrect methylation of U32 in the anticodon loop. Moreover, the m(1)A58 modification clearly accelerates the TrmFO reaction, suggesting a synergistic effect of the m(5)U54, m(1)A58, and s(2)U54 modifications on m(5)s(2)U54 formation in Thermus thermophilus cells. The docking model of TrmFO and the T-arm showed that the G53-C61 base pair is not able to directly contact the enzyme. PMID- 23095746 TI - Regulator of G-protein signaling-21 (RGS21) is an inhibitor of bitter gustatory signaling found in lingual and airway epithelia. AB - The gustatory system detects tastants and transmits signals to the brain regarding ingested substances and nutrients. Although tastant receptors and taste signaling pathways have been identified, little is known about their regulation. Because bitter, sweet, and umami taste receptors are G protein-coupled receptors (GPCRs), we hypothesized that regulators of G protein signaling (RGS) proteins may be involved. The recent cloning of RGS21 from taste bud cells has implicated this protein in the regulation of taste signaling; however, the exact role of RGS21 has not been precisely defined. Here, we sought to determine the role of RGS21 in tastant responsiveness. Biochemical analyses confirmed in silico predictions that RGS21 acts as a GTPase-accelerating protein (GAP) for multiple G protein alpha subunits, including adenylyl cyclase-inhibitory (Galpha(i)) subunits and those thought to be involved in tastant signal transduction. Using a combination of in situ hybridization, RT-PCR, immunohistochemistry, and immunofluorescence, we demonstrate that RGS21 is not only endogenously expressed in mouse taste buds but also in lung airway epithelial cells, which have previously been shown to express components of the taste signaling cascade. Furthermore, as shown by reverse transcription-PCR, the immortalized human airway cell line 16HBE was found to express transcripts for tastant receptors, RGS21, and downstream taste signaling components. Over- and underexpression of RGS21 in 16HBE cells confirmed that RGS21 acts to oppose bitter tastant signaling to cAMP and calcium second messenger changes. Our data collectively suggests that RGS21 modulates bitter taste signal transduction. PMID- 23095747 TI - Insights into ectodomain shedding and processing of protein-tyrosine pseudokinase 7 (PTK7). AB - The membrane PTK7 pseudokinase, a component of both the canonical and noncanonical/planar cell polarity Wnt pathways, modulates cell polarity and motility in biological processes as diverse as embryo development and cancer cell invasion. To determine the individual proteolytic events and biological significance of the ectodomain shedding in the PTK7 function, we used highly invasive fibrosarcoma HT1080 cells as a model system. Current evidence suggested a likely link between PTK7 shedding and cell invasion in our HT1080 cell model system. We also demonstrated that in HT1080 cells the cleavage of the PTK7 ectodomain by an ADAM proteinase was coupled with the membrane type-1 matrix metalloproteinase (MT1-MMP) cleavage of the PKP(621)?LI site in the seventh Ig like domain of PTK7. Proteolytic cleavages led to the generation of two soluble, N-terminal and two matching C-terminal, cell-associated fragments of PTK7. This proteolysis was a prerequisite for the intramembrane cleavage of the C-terminal fragments of PTK7 by gamma-secretase. gamma-Secretase cleavage was predominantly followed by the efficient decay of the resulting C-terminal PTK7 fragment via the proteasome. In contrast, in HT1080 cells, which overexpressed the C-terminal PTK7 fragment, the latter readily entered the nucleus. Our data imply that therapeutic inhibition of PTK7 shedding may be used to slow cancer progression. PMID- 23095748 TI - Parkin and mitofusins reciprocally regulate mitophagy and mitochondrial spheroid formation. AB - Mitochondrial homeostasis via mitochondrial dynamics and quality control is crucial to normal cellular functions. Mitophagy (mitochondria removed by autophagy) stimulated by a mitochondrial uncoupler, carbonyl cyanide m chlorophenylhydrazone (CCCP), requires Parkin, but it is not clear why Parkin is crucial to this process. We found that in the absence of Parkin, carbonyl cyanide m-chlorophenylhydrazone induced the formation of mitochondrial spheroids. Mitochondrial spheroid formation is also induced in vivo in the liver by acetaminophen overdose, a condition causing severe oxidative mitochondrial damages and liver injury. Mitochondrial spheroids could undergo a maturation process by interactions with acidic compartments. The formation of this new structure required reactive oxygen species and mitofusins. Parkin suppressed these mitochondrial dynamics by promoting mitofusin degradation. Consistently, genetic deletion of mitofusins without concomitant expression of Parkin was sufficient to prevent mitochondrial spheroid formation and resumed mitophagy. Mitochondrial spheroid formation and mitophagy could represent different strategies of mitochondrial homeostatic response to oxidative stress and are reciprocally regulated by mitofusins and Parkin. PMID- 23095749 TI - Motor neuron-specific disruption of proteasomes, but not autophagy, replicates amyotrophic lateral sclerosis. AB - Evidence suggests that protein misfolding is crucially involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, controversy still exists regarding the involvement of proteasomes or autophagy in ALS due to previous conflicting results. Here, we show that impairment of the ubiquitin proteasome system, but not the autophagy-lysosome system in motor neurons replicates ALS in mice. Conditional knock-out mice of the proteasome subunit Rpt3 in a motor neuron-specific manner (Rpt3-CKO) showed locomotor dysfunction accompanied by progressive motor neuron loss and gliosis. Moreover, diverse ALS linked proteins, including TAR DNA-binding protein 43 kDa (TDP-43), fused in sarcoma (FUS), ubiquilin 2, and optineurin were mislocalized or accumulated in motor neurons, together with other typical ALS hallmarks such as basophilic inclusion bodies. On the other hand, motor neuron-specific knock-out of Atg7, a crucial component for the induction of autophagy (Atg7-CKO), only resulted in cytosolic accumulation of ubiquitin and p62, and no TDP-43 or FUS pathologies or motor dysfunction was observed. These results strongly suggest that proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role. Enhancement of proteasome activity may be a promising strategy for the treatment of ALS. PMID- 23095750 TI - Light-dependent structural change of chicken retinal Cryptochrome4. AB - Animals have several classes of cryptochromes (CRYs), some of which function as core elements of circadian clockwork, circadian photoreceptors, and/or light dependent magnetoreceptors. In addition to the circadian clock genes Cry1 and Cry2, nonmammalian vertebrates have the Cry4 gene, the molecular function of which remains unknown. Here we analyzed chicken CRY4 (cCRY4) expression in the retina with in situ hybridization and found that cCRY4 was likely transcribed in the visual pigment cells, cells in the inner nuclear layer, and retinal ganglion cells. We further developed several monoclonal antibodies to the carboxyl terminal extension of cCRY4 and localized cCRY4 protein with immunohistochemistry. Consistent with the results of in situ hybridization, cCRY4 immunoreactivity was found in visual pigment cells and cells located at the inner nuclear layer and the retinal ganglion cell layer. Among the antibodies, one termed C1-mAb had its epitope within the carboxyl-terminal 14-amino acid sequence (QLTRDDADDPMEMK) and associated with cCRY4 in the retinal soluble fraction more strongly in the dark than under blue light conditions. Immunoprecipitation experiments under various light conditions indicated that cCRY4 from the immunocomplex formed in the dark dissociated from C1-mAb during blue light illumination as weak as 25 MUW/cm(2) and that the release occurred with not only blue but also near UV light. These results suggest that cCRY4 reversibly changes its structure within the carboxyl-terminal region in a light-dependent manner and operates as a photoreceptor or magnetoreceptor with short wavelength sensitivity in the retina. PMID- 23095751 TI - The soy isoflavone equol may increase cancer malignancy via up-regulation of eukaryotic protein synthesis initiation factor eIF4G. AB - Dietary soy is thought to be cancer-preventive; however, the beneficial effects of soy on established breast cancer is controversial. We recently demonstrated that dietary daidzein or combined soy isoflavones (genistein, daidzein, and glycitein) increased primary mammary tumor growth and metastasis. Cancer promoting molecules, including eukaryotic protein synthesis initiation factors (eIF) eIF4G and eIF4E, were up-regulated in mammary tumors from mice that received dietary daidzein. Herein, we show that increased eIF expression in tumor extracts of mice after daidzein diets is associated with protein expression of mRNAs with internal ribosome entry sites (IRES) that are sensitive to eIF4E and eIF4G levels. Results with metastatic cancer cell lines show that some of the effects of daidzein in vivo can be recapitulated by the daidzein metabolite equol. In vitro, equol, but not daidzein, up-regulated eIF4G without affecting eIF4E or its regulator, 4E-binding protein (4E-BP), levels. Equol also increased metastatic cancer cell viability. Equol specifically increased the protein expression of IRES containing cell survival and proliferation-promoting molecules and up-regulated gene and protein expression of the transcription factor c-Myc. Moreover, equol increased the polysomal association of mRNAs for p 120 catenin and eIF4G. The elevated eIF4G in response to equol was not associated with eIF4E or 4E-binding protein in 5' cap co-capture assays or co-immunoprecipitations. In dual luciferase assays, IRES-dependent protein synthesis was increased by equol. Therefore, up-regulation of eIF4G by equol may result in increased translation of pro-cancer mRNAs with IRESs and, thus, promote cancer malignancy. PMID- 23095752 TI - IL-36gamma/IL-1F9, an innate T-bet target in myeloid cells. AB - By concerted action in dendritic (DC) and T cells, T-box expressed in T cells (T bet, Tbx21) is pivotal for initiation and perpetuation of Th1 immunity. Identification of novel T-bet-regulated genes is crucial for further understanding the biology of this transcription factor. By combining siRNA technology with genome-wide mRNA expression analysis, we sought to identify new T bet-regulated genes in predendritic KG1 cells activated by IL-18. One gene robustly dependent on T-bet was IL-36gamma, a recently described novel IL-1 family member. Promoter analysis revealed a T-bet binding site that, along with a kappaB site, enables efficient IL-36gamma induction. Using knock-out animals, IL 36gamma reliance on T-bet was extended to murine DC. IL-36gamma expression by human myeloid cells was confirmed using monocyte-derived DC and M1 macrophages. The latter model was employed to substantiate dependence of IL-36gamma on endogenous T-bet in human primary cells. Ectopic expression of T-bet likewise mediated IL-36gamma production in HaCaT keratinocytes that otherwise lack this transcription factor. Additional experiments furthermore revealed that mature IL 36gamma has the capability to establish an inflammatory gene expression profile in human primary keratinocytes that displays enhanced mRNA levels for TNFalpha, CCL20, S100A7, inducible NOS, and IL-36gamma itself. Data presented herein shed further light on involvement of T-bet in innate immunity and suggest that IL 36gamma, besides IFNgamma, may contribute to functions of this transcription factor in immunopathology. PMID- 23095753 TI - Transient activation of the PI3K-AKT pathway by hepatitis C virus to enhance viral entry. AB - The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Here we report that hepatitis C virus (HCV) transiently activates the PI3K-AKT pathway. This activation was observed as early as 15 min postinfection, peaked by 30 min, and became undetectable at 24 h postinfection. The activation of AKT could also be mediated by UV-inactivated HCV, HCV pseudoparticle, and the ectodomain of the HCV E2 envelope protein. Because antibodies directed against CD81 and claudin-1, but not antibodies directed against scavenger receptor class B type I or occludin, could also activate AKT, the interaction between HCV E2 and its two co-receptors CD81 and claudin-1 probably triggered the activation of AKT. This activation of AKT by HCV was important for HCV infectivity, because the silencing of AKT by siRNA or the treatment of cells with its inhibitors or with the inhibitor of its upstream regulator PI3K significantly inhibited HCV infection, whereas the expression of constitutively active AKT enhanced HCV infection. The PI3K-AKT pathway is probably involved in HCV entry, because the inhibition of this pathway could inhibit the entry of HCV pseudoparticle but not the VSV pseudoparticle into cells. Furthermore, the treatment of cells with the AKT inhibitor AKT-V prior to HCV infection inhibited HCV infection, whereas the treatment after HCV infection had no obvious effect. Taken together, our studies indicated that HCV transiently activates the PI3K-AKT pathway to facilitate its entry. These results provide important information for understanding HCV replication and pathogenesis and raised the possibility of targeting this cellular pathway to treat HCV patients. PMID- 23095754 TI - Mechanism for targeting the A-kinase anchoring protein AKAP18delta to the membrane. AB - A-kinase anchoring proteins (AKAPs) are a family of scaffolding proteins that target PKA and other signaling molecules to cellular compartments and thereby spatiotemporally define cellular signaling events. The AKAP18 family comprises AKAP18alpha, AKAP18beta, AKAP18gamma, and AKAP18delta. The delta isoform targets PKA and phosphodiesterase PDE4D to AQP2 (aquaporin-2)-bearing vesicles to orchestrate the acute regulation of body water balance. Therefore, AKAP18delta must adopt a membrane localization that seems at odds with (i) its lack of palmitoylation or myristoylation sites that tailor its isoforms AKAP18alpha and AKAP18beta to membrane compartments and (ii) the high sequence identity to the preferentially cytoplasmic AKAP18gamma. Here, we show that the electrostatic attraction of the positively charged amino acids of AKAP18delta to negatively charged lipids explains its membrane targeting. As revealed by fluorescence correlation spectroscopy, the binding constant of purified AKAP18delta fragments to large unilamellar vesicles correlates (i) with the fraction of net negatively charged lipids in the bilayer and (ii) with the total amount of basic residues in the protein. Although distantly located on the sequence, these positively charged residues concentrate in the tertiary structure and form a clear binding surface. Thus, specific recruitment of the AKAP18delta-based signaling module to membranes such as those of AQP2-bearing vesicles must be achieved by additional mechanisms, most likely compartment-specific protein-protein interactions. PMID- 23095755 TI - Mouse sperm membrane potential hyperpolarization is necessary and sufficient to prepare sperm for the acrosome reaction. AB - Mammalian sperm are unable to fertilize the egg immediately after ejaculation; they acquire this capacity during migration in the female reproductive tract. This maturational process is called capacitation and in mouse sperm it involves a plasma membrane reorganization, extensive changes in the state of protein phosphorylation, increases in intracellular pH (pH(i)) and Ca(2+) ([Ca(2+)](i)), and the appearance of hyperactivated motility. In addition, mouse sperm capacitation is associated with the hyperpolarization of the cell membrane potential. However, the functional role of this process is not known. In this work, to dissect the role of this membrane potential change, hyperpolarization was induced in noncapacitated sperm using either the ENaC inhibitor amiloride, the CFTR agonist genistein or the K(+) ionophore valinomycin. In this experimental setting, other capacitation-associated processes such as activation of a cAMP-dependent pathway and the consequent increase in protein tyrosine phosphorylation were not observed. However, hyperpolarization was sufficient to prepare sperm for the acrosome reaction induced either by depolarization with high K(+) or by addition of solubilized zona pellucida (sZP). Moreover, K(+) and sZP were also able to increase [Ca(2+)](i) in non-capacitated sperm treated with these hyperpolarizing agents but not in untreated cells. On the other hand, in conditions that support capacitation-associated processes blocking hyperpolarization by adding valinomycin and increasing K(+) concentrations inhibited the agonist-induced acrosome reaction as well as the increase in [Ca(2+)](i). Altogether, these results suggest that sperm hyperpolarization by itself is key to enabling mice sperm to undergo the acrosome reaction. PMID- 23095756 TI - Human exonuclease 5 is a novel sliding exonuclease required for genome stability. AB - Previously, we characterized Saccharomyces cerevisiae exonuclease 5 (EXO5), which is required for mitochondrial genome maintenance. Here, we identify the human homolog (C1orf176; EXO5) that functions in the repair of nuclear DNA damage. Human EXO5 (hEXO5) contains an iron-sulfur cluster. It is a single-stranded DNA (ssDNA)-specific bidirectional exonuclease with a strong preference for 5'-ends. After loading at an ssDNA end, hEXO5 slides extensively along the ssDNA prior to cutting, hence the designation sliding exonuclease. However, the single-stranded binding protein human replication protein A (hRPA) restricts sliding and enforces a unique, species-specific 5'-directionality onto hEXO5. This specificity is lost with a mutant form of hRPA (hRPA-t11) that fails to interact with hEXO5. hEXO5 localizes to nuclear repair foci in response to DNA damage, and its depletion in human cells leads to an increased sensitivity to DNA-damaging agents, in particular interstrand cross-linking-inducing agents. Depletion of hEXO5 also results in an increase in spontaneous and damage-induced chromosome abnormalities including the frequency of triradial chromosomes, suggesting an additional defect in the resolution of stalled DNA replication forks in hEXO5-depleted cells. PMID- 23095757 TI - Sumoylation of SAE2 C terminus regulates SAE nuclear localization. AB - SUMOylation occurs predominantly in the nucleus, but non-nuclear proteins can also be SUMOylated. It is unclear how intracellular trafficking of the SUMOylation enzymes is regulated to catalyze SUMOylation in different cellular compartments. Here we report that the SAE2 subunit of human SUMO activation enzyme (SAE) underwent rapid nucleocytoplasmic shuttling and its nuclear accumulation depended on SUMO modification at the C terminus. The SUMOylation sites included three Lys residues on the bipartite nuclear localization sequence (NLS) and two Lys residues outside of but adjacent to the NLS, and their SUMOylation was catalyzed by Ubc9. Because SAE2 forms a tight heterodimer with SAE1 and it controls the trafficking of the heterodimer, this study has identified the mechanism used to localize SAE to the nucleus. Similar mechanisms are likely to exist for other proteins that depend on SUMOylation for nuclear localization. PMID- 23095758 TI - Crystal structure of a voltage-gated K+ channel pore module in a closed state in lipid membranes. AB - Voltage-gated K(+) channels underlie the electrical excitability of cells. Each subunit of the functional tetramer consists of the tandem fusion of two modules, an N-terminal voltage-sensor and a C-terminal pore. To investigate how sensor coupling to the pore generates voltage-dependent channel opening, we solved the crystal structure and characterized the function of a voltage-gated K(+) channel pore in a lipid membrane. The structure of a functional channel in a membrane environment at 3.1 A resolution establishes an unprecedented connection between channel structure and function. The structure is unique in delineating an ion occupied ready to conduct selectivity filter, a confined aqueous cavity, and a closed activation gate, embodying a dynamic entity trapped in an unstable closed state. PMID- 23095759 TI - Enhanced apoptotic death of erythrocytes induced by the mycotoxin ochratoxin A. AB - BACKGROUND: The mycotoxin ochratoxin A, an agent responsible for endemic Balkan nephropathy is known to trigger apoptosis and thus being toxic to several organs including the kidney. The mechanisms involved in ochratoxin A induced apoptosis include oxidative stress. Sequelae of ochratoxin intoxication include anemia. Similar to apoptosis of nucleated cells, erythrocytes may undergo suicidal cell death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling resulting in phosphatidylserine-exposure at the cell surface. Eryptosis could be triggered by Ca2+ -entry through oxidant sensitive unspecificcation channels increasing cytosolic Ca2+ activity ([Ca2+]i). The Ca2+ sensitivity of cell membrane scrambling could be enhanced and eryptosis thus triggered by ceramide. The removal of suicidal erythrocytes may lead to anemia. Moreover, eryptotic erythrocytes could adhere to the vascular wall thus impeding microcirculation. The present study explored, whether ochratoxin A stimulates eryptosis. METHODS: Fluo3-fluorescence was utilized to determine [Ca2+]i, forward scatter to estimate cell volume, annexin-V-binding to identify phosphatidylserine exposing cells, fluorescent antibodies to detect ceramide formation and hemoglobin release to quantify hemolysis. Moreover, adhesion to human vascular endothelial cells (HUVEC) was determined utilizing a flow chamber. RESULTS: A 48 h exposure to ochratoxin A was followed by significant increase of Fluo3 fluorescencei (>= 2.5 uM), increase of ceramide abundance (10 uM), decrease of forward scatter (>= 5 uM) and increase of annexin-V-binding (>= 2.5 uM). Ochratoxin A exposure slightly but significantly enhanced hemolysis (10 uM). Ochratoxin (10 uM) enhanced erythrocyte adhesion to HUVEC. Removal of extracellular Ca2+ significantly blunted, but did not abrogate ochratoxin A induced annexin V binding. CONCLUSIONS: Ochratoxin A triggers suicidal erythrocyte death or eryptosis, an effect partially but not fully due to stimulation of Ca2+ -entry. PMID- 23095760 TI - Relationship between inappropriate left ventricular hypertrophy and ejection fraction independent of absolute or indexed mass in a community sample of black African ancestry. AB - AIM: We determined whether left ventricular hypertrophy (LVH) which exceeds that predicted from workload [inappropriate LV mass (LVM(inappr))] is associated with reduced left ventricle (LV) systolic chamber function independent of and more closely than absolute or indexed left ventricular mass (LVM). METHODS: In 626 randomly selected adult participants from a community sample of black Africans, using echocardiography we assessed absolute LVM, LVM indexed to height(2.7) (LVMI), LVM(inappr), LV wall stress, ejection fraction, and midwall fractional shortening (FSmid). LVM(inappr) was determined as percentage of observed/predicted LVM. Predicted LVM was calculated from a previously validated formula that incorporates stroke work. LVMI(inappr) more than 150% was considered to be inappropriate LVH. This threshold was identified from the upper 95% confidence interval for LVMI(inappr) determined in 140 healthy participants. RESULTS: A total of 21.7% of participants had LVH (LVMI > 51 g/m(2.7)) and 18.5% had inappropriate LVH. With adjustments for LV stress and other confounders there was a strong inverse relationship between LVM(inappr) and ejection fraction (partial r = -0.41, P < 0.0001), whereas only modest inverse relations between LVM or LVMI and ejection fraction were noted (partial r = -0.07 to -0.09, P < 0.05-0.09) (P < 0.0001, comparison of partial r values). The independent relationship between LVM(inappr) and ejection fraction persisted with further adjustments for LVM or LVMI (partial r = -0.52, P < 0.0001). LVM(inappr) and FSmid were similarly inversely related (P < 0.0001) and these relations were also stronger and independent of LVM or LVMI. CONCLUSION: Inappropriate LVH is strongly and inversely related to variations in ejection fraction independent of and more closely than LVM or LVMI in a community sample of black African ancestry. These data suggest that LVH is a compensatory response to workload, but when exceeding that predicted by workload, is associated with LV systolic chamber decompensation. PMID- 23095761 TI - Analysis of composition-based metagenomic classification. AB - BACKGROUND: An essential step of a metagenomic study is the taxonomic classification, that is, the identification of the taxonomic lineage of the organisms in a given sample. The taxonomic classification process involves a series of decisions. Currently, in the context of metagenomics, such decisions are usually based on empirical studies that consider one specific type of classifier. In this study we propose a general framework for analyzing the impact that several decisions can have on the classification problem. Instead of focusing on any specific classifier, we define a generic score function that provides a measure of the difficulty of the classification task. Using this framework, we analyze the impact of the following parameters on the taxonomic classification problem: (i) the length of n-mers used to encode the metagenomic sequences, (ii) the similarity measure used to compare sequences, and (iii) the type of taxonomic classification, which can be conventional or hierarchical, depending on whether the classification process occurs in a single shot or in several steps according to the taxonomic tree. RESULTS: We defined a score function that measures the degree of separability of the taxonomic classes under a given configuration induced by the parameters above. We conducted an extensive computational experiment and found out that reasonable values for the parameters of interest could be (i) intermediate values of n, the length of the n-mers; (ii) any similarity measure, because all of them resulted in similar scores; and (iii) the hierarchical strategy, which performed better in all of the cases. CONCLUSIONS: As expected, short n-mers generate lower configuration scores because they give rise to frequency vectors that represent distinct sequences in a similar way. On the other hand, large values for n result in sparse frequency vectors that represent differently metagenomic fragments that are in fact similar, also leading to low configuration scores. Regarding the similarity measure, in contrast to our expectations, the variation of the measures did not change the configuration scores significantly. Finally, the hierarchical strategy was more effective than the conventional strategy, which suggests that, instead of using a single classifier, one should adopt multiple classifiers organized as a hierarchy. PMID- 23095763 TI - Highlighting a need to distinguish cell cycle signatures from cellular responses to chemotherapeutics in SR-FTIR spectroscopy. AB - Previous research has seen difficulties in establishing clear discrimination by principal component analysis (PCA) between drug-treated cells analysed by single point SR-FTIR spectroscopy, relative to multisampling cell monolayers by conventional FTIR. It is suggested that the issue arises due to signal mixing between cellular-response signatures and cell cycle phase contributions in individual cells. Consequently, chemometric distinction of cell spectra treated with multiple drugs is difficult even with supervised methods. In an effort to separate cell cycle chemistry from cellular response chemistry in the spectra, renal carcinoma cells were stained with propidium iodide and fluorescent activated cell sorted (FACS) after exposure to a number of chemotherapeutic compounds; 5-fluorouracil (5FU) and a set of novel gold-based experimental compounds. The cell spectra were analysed separately by PCA in G(1), S or G(2)/M phase. The mode of action of established drug 5FU, known to disrupt S phase, was confirmed by FACS analysis. The chemical signature of 5FU-treated cells discriminated against both the control and gold-compound (KF0101)-treated cell spectra, suggesting a different mode of action due to a difference in cellular response. PMID- 23095762 TI - miR-17-5p targets the p300/CBP-associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells. AB - BACKGROUND: Androgen receptor (AR) signalling is critical to the initiation and progression of prostate cancer (PCa). Transcriptional activity of AR involves chromatin recruitment of co-activators, including the p300/CBP-associated factor (PCAF). Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease. Whether miRNAs regulate PCAF expression in PCa cells to regulate AR transcriptional activity is still unclear. METHODS: Expression of PCAF was investigated in several PCa cell lines by qRT-PCR, Western blot, and immunocytochemistry. The effects of PCAF expression on AR-regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation, reporter gene construct analysis, and MTS assay. Targeting of PCAF by miR-17-5p was evaluated using the luciferase reporter assay. RESULTS: PCAF was upregulated in several PCa cell lines. Upregulation of PCAF promoted AR transcriptional activation and cell growth in cultured PCa cells. Expression of PCAF in PCa cells was associated with the downregulation of miR-17-5p. Targeting of the 3'-untranslated region of PCAF mRNA by miR-17-5p caused translational suppression and RNA degradation, and, consequently, modulation of AR transcriptional activity in PCa cells. CONCLUSIONS: PCAF is upregulated in cultured PCa cells, and upregulation of PCAF is associated with the downregulation of miR-17-5p. Targeting of PCAF by miR-17 5p modulates AR transcriptional activity and cell growth in cultured PCa cells. PMID- 23095765 TI - Unexpected manganese(III) acetate-mediated reactions of beta-enamino carbonyl compounds with 1-(pyridin-2-yl)-enones under mechanical milling conditions. AB - The solvent-free reactions of beta-enamino carbonyl compounds with 1-(pyridin-2 yl)-enones in the presence of manganese(iii) acetate dihydrate unexpectedly afforded 2-acyl-3-aryl-6,7-dihydro-4(5H)-benzofuran derivatives under mechanical milling conditions. PMID- 23095764 TI - Impact of genetic risk assessment on nutrition-related lifestyle behaviours. AB - Genetic susceptibility testing for common complex disease is a practice that is currently in clinical use. There are two types of gene mutations, and therefore, two varieties of genotype testing: deterministic and susceptibility. As the term suggests, deterministic genes determine whether or not a person will develop a given trait in mendelian fashion, such as Huntington's disease. Genotype screening for such deterministic mutations has existed for decades, and is commonly used in routine medical practice. In recent years, the sequencing of the human genome has identified several 'susceptibility genes' or genes with incomplete penetrance. Mutations in these genes may increase disease susceptibility, but are not causative for disease. Genetic susceptibility testing allows unaffected individuals to obtain risk information for a variety of common complex diseases and health conditions including Alzheimer's disease (AD), CVD, cancer and diabetes. The availability of genetic susceptibility testing has increased over the past decade, and several studies are now focusing on the impact that genetic testing has on health and other lifestyle behaviours related to nutrition. The aim of this paper is to review the literature and evaluate what, if any, impact genetic risk assessment has on behaviours related to nutrition and physical activity. This paper summarises seven clinical studies that evaluated the impact of disclosing genetic risk information for disease on nutrition-related health behaviour changes. Of these seven studies, only three studies reported that health behaviour change was influenced by genotype disclosure. PMID- 23095766 TI - Photodynamic therapy for chronic central serous chorioretinopathy: a 4-year follow-up study. AB - PURPOSE: To evaluate the efficacy and safety of standard photodynamic therapy with verteporfin at 48 months in patients with chronic central serous chorioretinopathy. METHODS: A retrospective, multicenter, interventional case series analysis in patients with chronic central serous chorioretinopathy, treated with standard photodynamic therapy, and with >=4 years of follow-up. Evaluations were performed every 3 months in the first year, every 6 months in the second year, and thereafter annually. Optical coherence tomography was performed in all visits. Fluorescein angiography and indocyanine green angiography were performed at baseline and thereafter as necessary. Retinal thickness on optical coherence tomography was measured manually, evaluating central macular thickness and neural retina thickness. Main outcomes included the evolution of best-corrected visual acuity, the resolution of subretinal fluid, documented with optical coherence tomography, the number of treatments, and the evaluation of neural retina thickness during the 48 months of follow-up. RESULTS: The study included 46 eyes of 42 patients, 38 men (90.4%) and 4 women (9.5%), with mean age of 49.19 +/- 9.9 years (range, 32-70 years), and the minimal follow up period was 48 months (mean, 56.8 +/-10.3 months). Subretinal fluid was observed in all the included eyes at baseline, and 10 eyes (21.7%) had intraretinal diffuse or cystoid fluid. Concerning the mean best-corrected visual acuity, a statistically significant improvement (P < 0.01, Student t-test) was registered from 58.8 +/- 18.3 letters at baseline to 66.9 +/- 18.6 letters at 48th month. A complete resolution of subretinal fluid was achieved in 93.4%, and resolution of intraretinal fluid occurred in all 10 cases at 48 months. Neural retina thickness remained stable during the 48 months of follow-up (163.8 +/- 47 MUm at baseline and 163.8 +/- 46 MUm at 48 months). The mean number of treatments was 1.08 +/- 0.3. No systemic or ocular side effects were registered. CONCLUSION: Standard photodynamic therapy with verteporfin was effective and safe in chronic central serous chorioretinopathy treatment with a significant improvement in the long term, both anatomic and visual, without inducing additional retinal atrophy or systemic adverse effects. PMID- 23095767 TI - The effect of air tamponade on the ingress of ocular surface pathogens in sutureless transconjunctival microincisional vitrectomy. AB - PURPOSE: To assess the effect of air versus fluid tamponade on the intraocular migration of india ink particles through nonsutured transconjunctival 23-gauge sclerotomies in living porcine eyes. METHODS: Both eyes (n = 20) underwent 3 port, transconjunctival, 23-gauge vitrectomy. An angled trocar insertion technique was used in all cases. In each animal, one eye underwent a partial fluid-air exchange at the conclusion of the vitrectomy, yielding an air fill of approximately 80% (n = 10), whereas the other was left fluid filled (n = 10). After removal of the instruments and trocar cannulae, india ink was applied to the ocular surface. Animals were allowed to partially recover from anesthesia and resume normal blinking behavior. Animals were then reanesthetized, euthanized, and enucleated. Histopathologic examination was performed in a masked fashion. The presence and location of ink was noted for each identified sclerotomy. RESULTS: Ink was identified on the ocular surface in 18 of 20 eyes. Sclerotomy wounds were identified in 16 of 20 eyes. Ink penetration was seen in 2 of 16 sclerotomy wounds, 1 in an air-filled globe and 1 in a fluid-filled globe. In both eyes, the ink was identified along the outer one third of the wound. There was no penetration of ink along the inner two thirds of the sclerotomy wound or in the posterior segment of any eyes. CONCLUSION: In an experimental, in vivo, porcine model, india ink migration into angled transconjunctival sclerotomy incisions was minimal, regardless of the use of an 80% fluid-air exchange at the conclusion of the case. PMID- 23095768 TI - Diagnostic and therapeutic challenges. PMID- 23095769 TI - Effects of soluble CD14 and cytokine levels on diabetic macular edema and visual acuity. AB - PURPOSE: The pathogenesis of diabetic retinopathy has been suggested to be associated with ocular inflammation. Macrophages and monocytes that infiltrate the eye are known to express CD14. After shedding from the membrane-bound CD14, soluble CD14 (sCD14) is released, which could potentially activate inflammatory signaling. In this study, the authors investigated ocular fluid and serum levels of vascular endothelial growth factor (VEGF), sCD14, and other inflammatory cytokines in patients with diabetic macular edema (DME). Furthermore, the authors determined any potential correlation between these factors and visual acuity. METHODS: Vitreous fluid, aqueous humor, and serum samples from 14 eyes with DME and 24 control eyes were investigated. Soluble CD14, interleukin 8, interferon inducible protein 10, monocyte chemotactic protein 1, monokine induced by interferon gamma, and VEGF were measured simultaneously by FACSCalibur flow cytometer. Visual acuity was measured in all patients with DME before surgery, with the assessors being blinded to the patients' diagnoses. RESULTS: All factors were significantly elevated in vitreous fluid of DME eyes. Soluble CD14 and VEGF levels in vitreous fluid and aqueous humor were significantly higher in patients with DME than in nondiabetic controls (P < 0.05). In patients with DME, vitreous and aqueous humor concentrations of sCD14 correlated significantly. In these patients, vitreous fluid concentration of sCD14 correlated significantly with that of VEGF or interleukin 8 or monocyte chemotactic protein 1. In addition, there was a significant positive correlation between preoperative visual acuity and intraocular sCD14 concentrations. CONCLUSION: Soluble CD14 may act as key regulator of VEGF production and contribute to the pathogenesis of diabetic retinopathy. PMID- 23095771 TI - Letter from editor November 2012. PMID- 23095772 TI - The prognostic and predictive value of combined HE4 and CA-125 in ovarian cancer patients. AB - OBJECTIVE: A risk-of-ovarian-malignancy algorithm (ROMA) based on human epididymis protein 4 (HE4) and CA-125 has been reported to categorize women with a pelvic mass into high or low risk of ovarian malignancy. Originally, the ROMA score was developed for diagnostic purposes and the clinical application of HE4 for other purposes such as a predictor of survival or platinum resistance has not been extensively investigated. The objective of the present study was to evaluate the prognostic importance of prechemotherapy combined levels of HE4 and CA-125 and prediction of platinum resistance. Furthermore, we wanted to investigate the dynamics of the markers during treatment. MATERIALS AND METHODS: Serum from 137 patients with newly diagnosed serous ovarian cancer was analyzed for CA-125 and HE4 using ELISAs in a training data set. Patients with high levels (upper third percentiles) of both HE4 and CA-125 were classified as high-risk patients. Data were validated in an independent data set of an additional 94 patients. HE4 and CA-125 were also analyzed at all cycles of subsequent chemotherapy. RESULTS: The combined score of HE4 and CA-125 was highly predictive of both progression-free and overall survival in univariate as well as multivariate survival analysis. Values in the upper third percentiles (66th) were significantly associated with decreased progression-free and overall survival in both the training and in the validation set (P < 0.05 in all analyses).The positive predictive value in relation to platinum resistance was higher for the combination of markers than for the markers individually. The positive predictive values were 64.3% and 60.7% for combined CA-125/HE4 in the training and validation sets, respectively. CONCLUSIONS: The combination of HE4 and CA-125 levels at baseline just before initiation of chemotherapy was significantly associated with decreased progression-free and overall survival and to some extent with platinum resistance. PMID- 23095770 TI - Cognition and incident dementia hospitalization: results from the atherosclerosis risk in communities study. AB - BACKGROUND/AIMS: Cognitive decline is a defining feature of dementia. We sought to determine if a single baseline cognitive test score or change in test score over time is more strongly associated with risk of dementia hospitalization. We also sought to compare short- and long-term dementia risk. METHODS: Prospective cohort study of 9,399 individuals from the Atherosclerosis Risk in Communities Study (median 10 years of follow-up). Cognition was assessed at two time points (6 years apart) using three tests: Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test. Dementia hospitalizations were determined using ICD-9 codes. RESULTS: Baseline cognitive test scores were associated with both short-term and long-term risk of dementia. The association of 6-year change in cognitive test score with dementia risk was stronger than that of individual test scores at a single visit [change from highest to lowest tertile, DWRT: hazard ratio = 6.45 (95% confidence interval = 1.80-23.08); DSST: hazard ratio = 10.94 (95% confidence interval = 3.07-38.97)]. CONCLUSIONS: In this community-based population, 6-year changes in cognitive scores were more strongly associated with risk of incident dementia hospitalization than baseline scores, although single DWRT and DSST scores were predictive. Our findings support the contention that cognitive changes may precede clinical dementia by a decade or more. PMID- 23095773 TI - Prognostic impact of the cancer stem cell-related marker NANOG in ovarian serous carcinoma. AB - OBJECTIVE: The objective of this study was to evaluate the prognostic significance of NANOG expression in ovarian serous carcinoma. METHODS: The expression of NANOG was evaluated in 6 ovarian carcinoma cell lines, paclitaxel resistant SKOV3 cells, and SKOV3 spheroid cells with semiquantitative reverse transcription-polymerase chain reaction and Western blotting. NANOG expression was also measured immunohistochemically in a tissue microarray containing ovarian tissues from 74 patients with ovarian serous carcinoma and 24 with ovarian serous cystadenoma. Each sample was scored based on signal intensity and proportion, and a score greater than 4 was considered "positive." RESULTS: NANOG mRNA expression was variable in different ovarian cancer cell lines. The mRNA level of NANOG was increased in the paclitaxel-resistant SKOV3 cells and SKOV3 spheroid cells compared with that in the SKOV3 cells. NANOG expression was positive in 21.6% of 74 ovarian serous carcinoma tissues, but none of the ovarian serous cystadenoma tissues were positive. Positive NANOG expression was associated with residual tumor size after surgery (P = 0.032). The overall survival of the patients with positive NANOG expression was poorer than that of the patients with negative NANOG expression (P = 0.020). In patients with stage I and II disease, positive NANOG expression was independently associated with shorter overall survival compared with negative NANOG expression (40 vs 120 months, respectively; P = 0.031). CONCLUSIONS: Positive NANOG expression is associated with poor prognosis of ovarian serous carcinoma. NANOG has potential as a predictor of survival for patients with ovarian carcinomas and may be involved in the mechanism of chemoresistance. PMID- 23095774 TI - Aberrant expression of long noncoding RNAs in cervical intraepithelial neoplasia. AB - OBJECTIVE: Long noncoding RNAs (lncRNAs) are a unique class of messenger RNA-like transcripts of at least 200 nucleotides in length with no significant protein coding capacity. Aberrant lncRNA expression is emerging as a major component of the cancer transcriptome. Here, we sought to determine if differential lncRNA expression is a feature of the human cervical intraepithelial neoplasia (CIN) transcriptome. METHODS: Sequence data were derived from 16 long serial analyses of gene expression (L-SAGE) libraries constructed from cervical specimens representing mild (CIN1), moderate (CIN2), and severe (CIN3) histopathologic grades of CIN. A novel lncRNA discovery pipeline was developed to query the expression of lncRNAs within the SAGE data sets. RESULTS: A total of 2,230,370 sequence tags were delineated from the 16 SAGE libraries, representing the expression of 367,482 unique tags at varying abundance. Using a novel stepwise filtering strategy, we analyzed the cervical SAGE libraries and identified the expression profiles of 1056 lncRNAs in the human cervix. We present the first lncRNA expression profile derived from nonneoplastic cervical tissue and establish that changes in lncRNA expression do occur in cervical intraepithelial lesions. Our analysis also shows statistically significant aberrant expression of lncRNAs in the 3 CIN grades, suggesting that these unique noncoding RNA transcripts may contribute to the development and progression of precursor lesions. CONCLUSIONS: Through the analysis of L-SAGE libraries constructed from cervical specimens, we provide the first lncRNA expression profile of the cervix and demonstrate aberrant expression in early-stage neoplasia. PMID- 23095775 TI - Altered claudin-4 expression in progesterone-treated endometrial adenocarcinoma cell line Ishikawa. AB - OBJECTIVE: To detect the expression change of claudin-4 in Ishikawa endometrial adenocarcinoma cell line in response to progesterone. To determine whether claudin-4 is involved in the anticancer effect of progesterone. METHODS: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to determine the 50% inhibitory concentration (IC50) of megestrol acetate (MA) in treating Ishikawa cells. After the Ishikawa cells were treated with MA at IC50, cell apoptosis was examined by flow cytometry and transmission electron microscopy. The messenger RNA and protein expression levels of claudin-4 were further quantified by real-time polymerase chain reaction and Western blot. The localization of claudin-4 was examined by immunofluorescent staining. RESULTS: The IC50 of MA on Ishikawa cells was 15 mg/L incubated for 72 hours. Apoptosis percentage was elevated from 0.07% +/- 0.02% to 3.93% +/- 0.81% after MA treatment. The expression of claudin-4 at both protein and messenger RNA levels was significantly decreased after the treatment of MA (P < 0.05). The localization of claudin-4 transferred from cytomembrane to cytoplasm and nucleus. CONCLUSION: Megestrol acetate can inhibit the growth of Ishikawa cells. It may work through decreasing claudin-4 expression and cell apoptosis. The localization change of claudin-4 may also be involved in the anticancer effect of progesterone. PMID- 23095776 TI - Advanced cytoreductive surgery workshop report. AB - The Advanced Course in Cytoreductive Surgery for Ovarian Cancer and Gynecologic Peritoneal Surface Malignancies was held at the University of California Irvine Medical Center on November 4-5, 2011. The course director was Dr Robert E. Bristow, the Philip J. DiSaia Chair and Division Director of Gynecologic Oncology. Meeting information was distributed via e-mail blasts by the International Gynecologic Cancer Society. The workshop was comprised of didactic modules, a cadaver laboratory, and heated intraperitoneal chemotherapy demonstration. This was a not-for-profit workshop, and registration fees were used to support course faculty travel to UC Irvine and pay for the cadavers. PMID- 23095777 TI - Vaginal vault dehiscence and increased use of vaginal vault brachytherapy: what are the implications? AB - Literature reports describe the potential for increased incidence of vaginal vault dehiscence after minimally invasive surgery, and incidental reports of vaginal vault dehiscence with vaginal vault brachytherapy. This review explores the risk of increased vaginal complications in a setting of greater use of both minimally invasive surgical techniques and adjuvant vaginal vault brachytherapy in early endometrial cancer. The impact of associated patient-related and tumor related risk factors on clinical decision making is evaluated in selecting therapy that provides optimal tumor control while minimizing treatment adverse effects. PMID- 23095779 TI - American Society of Clinical Oncology 2012 Annual Meeting: highlights from the gynecologic oncology track. AB - The 2012 Annual Meeting of the American Society of Clinical Oncology (ASCO) was held in Chicago, June 1-5, 2011, and brought together more than 25,000 oncology professionals from a broad range of specialties to explore the theme, "Collaborating to Conquer Cancer". The Gynecologic Oncology Track had a strong international presence, with important clinical trials being presented from Japan, Germany, Norway, the United States, and others. This meeting report will highlight several phase 3 and phase 2 clinical trials as well as notable translational research endeavors and other selected abstracts. PMID- 23095778 TI - Sexual function of patients with endometrial cancer enrolled in the Gynecologic Oncology Group LAP2 Study. AB - OBJECTIVES: To present responses to sexual function items contained within the quality of life (QOL) survey of the Gynecologic Oncology Group LAP2 study, to investigate associations between sexual function and other factors (such as relationship quality and body image), and to explore patterns of response in patients with endometrial cancer. METHODS: Participants enrolled in the LAP2 QOL study arm completed a self-report QOL survey, which contained sexual function items, before surgery, and at 1, 3, and 6 weeks and 6 months after surgery. Responses to sexual function questions were classified into 3 patterns-responder, intermittent responder, and nonresponder-based on whether the sexual function items were answered when the QOL survey was completed. RESULTS: Of 752 patients who completed the QOL survey, 225 completed the sexual function items within the QOL survey, 224 responded intermittently, and 303 did not respond at all. No significant differences of sexual function were found between the patients randomized to laparoscopy compared to laparotomy. Among those who responded completely or intermittently, sexual function scores declined after surgery and recovered to presurgery levels at 6 months. Sexual function was positively associated with better quality of relationship (P < 0.001), body image (P < 0.001), and QOL (P < 0.001), and negatively associated with fear of sex (P < 0.001). CONCLUSION: Our findings suggest that younger patients, those who were married, and those who had quality relationships were more likely to answer the sexual function items and have better quality of sexual function. Factors such as age, relationship quality, body image, and pain may place women with endometrial cancer at risk for sexual difficulties in the immediate recovery period; however, sexual function improved by 6 months postoperatively in our cohort of patients with early-stage endometrial cancer. PMID- 23095780 TI - Nanoparticle biofabrication using English ivy (Hedera helix). AB - BACKGROUND: English ivy (Hedera helix) is well known for its adhesive properties and climbing ability. Essential to its ability to adhere to vertical surfaces is the secretion of a nanocomposite adhesive containing spherical nanoparticles, 60 85 nm in diameter, produced exclusively by root hairs present on adventitious roots. These organic nanoparticles have shown promise in biomedical and cosmetic applications, and represent a safer alternative to metal oxide nanoparticles currently available. RESULTS: It was discovered that the maximum adventitious root production was achieved by a 4 h application of 1 mg/ml indole-3 butyric acid (IBA) to juvenile English ivy shoot segments cultured in custom vessels. After incubation of the shoots under continuous light at 83 MUmol/m2 s at 20 degrees C for 2 weeks, the adventitious roots were harvested from the culture system and it was possible to isolate 90 mg of dry weight nanoparticles per 12 g of roots. The nanoparticle morphology was characterized by atomic force microscopy, and found to be similar to previous studies. CONCLUSIONS: An enhanced system for the production of English ivy adventitious roots and their nanoparticles by modifying GA7 Magenta boxes and identifying the optimal concentration of IBA for adventitious root growth was developed. This system is the first such platform for growing and harvesting organic nanoparticles from plants, and represents an important step in the development of plant-based nanomanufacturing. It is a significant improvement on the exploitation of plant systems for the formation of metallic nanoparticles, and represents a pathway for the generation of bulk ivy nanoparticles for translation into biomedical applications. PMID- 23095781 TI - Bubble chamber clotting during continuous renal replacement therapy: vertical versus horizontal blood flow entry. AB - BACKGROUND: The continuous renal replacement therapy (CRRT) bubble trap chamber is a frequent site of clotting. AIMS: To assess clot formation when comparing our standard 'vertical' blood entry chamber (BEC) with a new 'horizontal' BEC. METHODS: Adult ICU patients requiring CRRT were treated with the vertical BEC and then a similar subsequent cohort with the horizontal BEC in continuous veno venous haemofiltration mode. RESULTS: 40 chambers were assessed for each design. Circuit life was 13.9 +/- 9.5 h for the vertical and 17.7 +/- 15.9 h for the horizontal BEC (p = 0.33). APTT, however, was higher for the horizontal BEC (55.7 +/- 34.7 vs. 37.4 +/- 9.0, p < 0.002) and no difference in circuit life was found after multivariable analysis. A clotting score >=3 was observed in 85% of all chambers. There was no difference in chamber clotting score (vertical 3.6 +/- 1.03 vs. horizontal 3.8 +/- 1.0, p = 0.5). In addition, no difference was found when scores were divided into two groups using a 'likelihood' to clot analysis (p = 1.0). CONCLUSION: CRRT horizontal BEC were not associated with less clotting compared to our standard vertical BEC. PMID- 23095782 TI - Cognitive effects of subthalamic nucleus stimulation in Parkinson's disease: a controlled study. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN-DBS) improves motor function in selected patients with Parkinson's disease (PD) but can be associated with variable changes in cognitive functions. METHODS: We studied 21 patients selected for STN-DBS and compared 6-month clinical and neuropsychological outcomes between those who underwent surgery (n = 9) and those who voluntarily refused it (n = 12). RESULTS: Motor and quality of life outcomes were markedly superior in the STN-DBS group versus controls. A wide neuropsychological battery was administered, and the whole sample showed a statistically significant worsening in phonemic verbal fluency, time to perform the Trail Making Test part B, Digit Symbol score of WAIS-III and color-naming score of the Stroop Test. In comparison to controls, a trend to a slightly worse deterioration in phonemic verbal fluency was observed in the STN-DBS patients and was significantly correlated with reductions in the L-dopa-equivalent daily dose (r = 0.850, p = 0.007). CONCLUSION: Our study confirms the safety of STN-DBS from a cognitive standpoint; a reduction in verbal fluency at 6 months after surgery can also be related to PD progression and medication reduction. PMID- 23095783 TI - Phylloid pattern of hypomelanosis closely related to chromosomal abnormalities in the 13q detected by SNP array analysis. AB - Phylloid hypomelanosis is a distinct type of pigmentary mosaicism characterized by congenital hypochromic macules resembling a floral ornament with various elements such as round or oval patches, asymmetrical macules similar to begonia leaves, or oblong lesions. It has been found to be predominantly associated with abnormalities in chromosome 13 and sometimes as-sociated with different extracutaneous abnormalities. Here, we report 2 new cases of phylloid hypomelanosis due to mosaicism involving chromosome 13. The first one is a mosaicism for a supernumerary marker belonging to chromosome 13 and the second one is the first report of phylloid hypomelanosis associated with a mosaic deletion of 13q. Because of the extremely low level of mosaicism in these 2 cases, SNP array analysis on skin fibroblasts was carried out, showing a 13q21.33 q34 duplication (71,024,411-115,103,529) and a 13q13.3-q34 (38,368,012 115,103,529) deletion. Both cases underline on the one hand the strict connection between phylloid hypomelanosis and anomalies of chromosome 13, and on the other hand the relevance of the SNP array analysis on skin fibroblasts in the detection of low-level mosaicism. PMID- 23095785 TI - Pure sensory syndromes and post-stroke pain secondary to bilateral thalamic lacunar infarcts: a case report. AB - INTRODUCTION: Patients often complain about sensory symptoms that appear to the doctor as harmless, and reassurances are often given. Sensory strokes may easily be ignored. CASE PRESENTATION: A 48-year-old Caucasian woman with insulin dependent diabetes and hyperlipidemia experienced symptoms that progressed within hours to a complete left-sided hemisensory syndrome. This was caused by a lacunar infarct in the ventral posterior tier nuclei of the right thalamus. A few days later she gradually developed an almost identical, but incomplete hemisensory syndrome on the opposite side caused by a corresponding lacune in the left thalamus. Severe persistent and paroxysmal pain on both sides of the body became disabling. CONCLUSION: Small strokes only affecting the somatosensory system should not be underestimated. Neuropathic pain may result. Probably unique in the present case is the demonstration of bilateral thalamic pain secondary to two almost identical thalamic infarcts. Small vessel disease (microatheroma or lipohyalinosis) was the most likely cause of the lacunes. One can only speculate if there was an occlusion in two separate thalamic perforators, or in a single dominant artery supplying the bilateral thalami. PMID- 23095786 TI - Analysis of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells associated with cardiac myogenesis in mouse embryo. AB - Caspase activation is associated with skeletal muscle differentiation in mouse embryos. We examined the relationship between cardiac myogenesis and cell death using mice hearts at embryonic days (E) 11.5-15.5 and fetal rat heart H9C2 cells. The number of TdT-mediated dUTP nick end labeling (TUNEL)-positive cells increased with fetal age and was much higher than that of single-stranded DNA (ssDNA)- and active caspase-3 (aCasp3)-positive cells. TUNEL and aCasp3 double staining resulted in 3 types of positive cells: TUNEL(+)/aCasp3(+), TUNEL(+)/aCasp3(-) and TUNEL(-)/aCasp3(+). TUNEL(+)/aCasp3(-) cells were the most common but lacked morphological features of apoptosis, such as nuclear condensation or fragmentation. The expression of anti-apoptotic factors increased during E11.5-15.5. Furthermore, TUNEL-positive H9C2 cells without nuclear condensation or fragmentation were observed only in myotubes later in the culture period. In this study, the dynamics of TUNEL-positive cardiomyocyte was inconsistent with the activation of apoptosis cascade, and their morphological feature was clearly different from representative apoptosis. From these findings, we concluded that the increased number of TUNEL-positive cardiomyocyte, having the DNA strand breaks, would be associated with the progression of cardiac myogenesis. PMID- 23095787 TI - Genetic identification of Iberian rodent species using both mitochondrial and nuclear loci: application to noninvasive sampling. AB - Species identification through noninvasive sampling is increasingly used in animal conservation genetics, given that it obviates the need to handle free living individuals. Noninvasive sampling is particularly valuable for elusive and small species such as rodents. Although rodents are not usually assumed to be the most obvious target for conservation, of the 21 species or near-species present in Iberia, three are considered endangered and declining, while several others are poorly studied. Here, we develop a genetic tool for identifying all rodent species in Iberia by noninvasive genetic sampling. To achieve this purpose, we selected one mitochondrial gene [cytochrome b (cyt-b)] and one nuclear gene [interphotoreceptor retinoid-binding protein (IRBP)], which we first sequenced using tissue samples. Both genes allow for the phylogenetic distinction of all species except the sibling species Microtus lusitanicus and Microtus duodecimcostatus. Overall, cyt-b showed higher resolution than IRBP, revealing a clear barcoding gap. To allow these markers to be applied to noninvasive samples, we selected a short highly diagnostic fragment from each gene, which we used to obtain sequences from faeces and bones from owl pellets. Amplification success for the cyt-b and IRBP fragment was 85% and 43% in faecal and 88% and 64% in owl pellet DNA extractions, respectively. The method allows the unambiguous identification of the great majority of Iberian rodent species from noninvasive samples, with application in studies of distribution, spatial ecology and population dynamics, and for conservation. PMID- 23095788 TI - Targeting the HER2 receptor in metastatic breast cancer. AB - The advent of targeted therapies has revolutionized the treatment of certain types of cancer. Identification of molecular targets on cancer cells has led to the design of novel drugs, which either used as single agents or in combination with chemotherapy, has prolonged survival in metastatic disease, or contributed to curative treatment in the adjuvant setting. A literature review was conducted to identify and present current knowledge on the molecular function of the HER2 receptor, its role in the pathogenesis of breast cancer and anti-HER2 targeted drugs in use or under development. Many molecular targets have been identified in breast cancer, with the HER family of receptors being the ones most extensively studied. Trastuzumab and lapatinib target the HER2 receptor and are approved drugs for the treatment of metastatic breast cancer. Several other targeted agents, including T-DM1, pertuzumab, neratinib, afatinib and ertumaxomab, are currently being tested in vivo as well as in clinical studies. The use of targeted therapies in metastatic breast cancer has improved prognosis, increased survival and dramatically changed the way we treat breast cancer patients today. PMID- 23095789 TI - Mechanism of paroxysmal nocturnal hemoglobinuria clonal dominance: possible roles of different apoptosis and CD8+ lymphocytes in the selection of paroxysmal nocturnal hemoglobinuria clones. AB - BACKGROUND AND OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic stem cell disorder, manifests when the PNH clone populates in the hematopoietic compartment. We explored the roles of different apoptosis of GPI+ and GPI- (glycosylphosphatidylinositol) cells and CD8+ lymphocytes in a selection of PNH clones. PATIENTS AND METHODS: Granulocytes from PNH patients and normal controls were subjected to an apoptosis assay using annexin V. Hematopoietic cell in semisolid media were cultured with or without CD8+ lymphocytes. RESULTS: In PNH, CD59+ granulocytes exhibited more apoptosis than their CD59- counterparts, after 0 or 4 hours in liquid growth culture system (mean [standard error of mean]: 2.1 (0.5) vs 1.2 (0.2), P=.01 at 0 hour and 3.4 [0.7] vs 1.8 [0.3], P=.03 at 4 hour, respectively). The presence of mononuclear cells (MNCs) rendered a greater difference in apoptosis. The percentages of apoptotic CD59+ granulocytes measured at 4 hours with or without MNC fraction were correlated with the sizes of PNH clones (r=0.633, P=.011; and r=0.648, P=.009; respectively). The autologous CD8+ lymphocytes inhibited CFU-GM and BFU-E colony formation in PNH patients when compared with normal controls (mean [SEM] of percentages of inhibition: 61.7 (10.4) vs 11.9 (2.0), P=.008 for CFU-GM and 26.1 (6.9) vs 4.9 (1.0), P=.037 for BFU-E). CONCLUSIONS: Increased apoptosis of GPI+ blood cells is likely to be responsible in selection and expansion of PNH clones. MNCs or possibly CD8+ lymphocytes may play a role in this phenomenon. PMID- 23095790 TI - Clinical outcome of docetaxel in advanced or metastatic endometrial cancer. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy, safety and toxicity of docetaxel as first-line chemotherapy or in previously treated patients (one regimen) with recurrent or metastatic endometrial cancer. DESIGN AND SETTING: Prospective phase II study in patients referred to the Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Egypt. PATIENTS AND METHODS: Fifty patients with advanced or metastatic endometrial cancer were enrolled to receive docetaxel 70 mg/m(2) administered intravenously on day 1 of a 3-week cycle. If patients responded well to docetaxel, additional cycles were administered until progressive disease or unacceptable toxicity occurred. Therapy response was evaluated every 6 weeks. RESULTS: Of 50 patients with a median age of 60 years (range, 40-70 years) who entered the study, 17 patients (34%) had received one prior chemotherapy regimen. All patients were evaluable for efficacy, yielding an overall response rate of 34% (95% confidence interval, 14.8%-55.6%); complete response and partial response (PR) were 4% and 30%, respectively. Of 17 pretreated patients, 5 (29%) had a PR. The median duration of response was 2 months. The median time-to progression was 4 months and the median survival time was 18 months. The predominant toxicity was grade 3-4 neutropenia, occurring in 92% of the patients, although febrile neutropenia arose in 10% of the patients. Edema was mild and infrequent. CONCLUSION: The study clearly demonstrated that docetaxel is active in the treatment of endometrial cancer. Toxicity was manageable and predominantly hematologic. PMID- 23095791 TI - Addition of amifostine to the CHOP regimen in elderly patients with aggressive non-Hodgkin lymphoma: a phase II trial showing reduction in toxicity without altering long-term survival. AB - BACKGROUND AND OBJECTIVES: We report the 8-year follow-up of 34 patients aged >=69 years old with NHL included in a phase IIb open-label randomized parallel groups study to evaluate the effectiveness of amifostine in preventing the toxicity of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP regime) . PATIENTS AND METHODS: Patients were randomized to receive classical CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2) [maximum 2 mg] on day 1 and prednisone 100 mg/day for 5 days) or CHOP plus amifostine (6 cycles of amifostine 910 mg/m(2) on day 1). Efficacy (time to progression, TTP; disease-free survival, DFS; overall survival, OS) and toxicity endpoints were evaluated. RESULTS: Thirty-four patients were randomized to A-CHOP (n=18) or CHOP (n=16). Patients with A-CHOP vs CHOP had significantly lower toxicity; neutropenia grade 4 ocurred in 13/92 (13%) vs 23/85 (27%, P=0.007) cycles, febrile neutropenia in 3/92 A-CHOP (3%) vs 8/85 (10%, P=.056) CHOP cycles, hospitalization for toxicity in 4/92 (4%) A-CHOP vs 11/85 (13%, P=.05) CHOP cycles. Median hospitalization stay for toxicity was 5 days with A-CHOP vs 8 days with CHOP (P=.05). There were no significant differences at 8 years in TTP (A-CHOP, 48.9% vs CHOP, 36.3%; P=.65), DFS (A-CHOP, 72.9% vs CHOP 55.6%; P=.50) and OS (A-CHOP, 44.3% vs CHOP, 54.4%). There was no long-term toxicity of clinical interest. The only prognostic factor identified to 8 years was the International Prognostic Index (IPI low/low intermediate risk vs high intermediate/high risk; HR=2.98; CI 95%:1.01-8.77; P=.048). CONCLUSION: These results show that amifostine can be added to the standard CHOP treatment schedule with less acute toxicity and without influencing the outcome. PMID- 23095792 TI - The effect of low altitude on blood count parameters. AB - BACKGROUND AND OBJECTIVES: High altitude has an effect on blood count parameters, but low altitude (especially below sea level) has not been studied. DESIGN AND SETTING: A cross-sectional study of aymptomatic subjects aged between 18 to 35 years of age who had reported to the blood bank at the King Abdullah University Hospital (KAUH)/Irbid and Ministry of Health, Jordan, during the period between January 2010 to June 2011 for blood donation. METHODS: Hematological values were compared in healthy adult blood donors living in areas 200 to 300 meters below sea level and areas 500 to 1500 meters above sea level. The study population consisted of 800 females and 666 males aged between 18 to 35 years. RESULTS: The mean values for hemoglobin level, mean corpuscular volume and leukocyte counts were significantly higher in people living above sea level than in people living below sea level (P < .0001), whereas platelet count and red cell distribution width were significantly higher in people living below sea level than in people living above sea level (P < .0001). CONCLUSION: We found a significant difference in hematological parameters in healthy adults living above and below sea level. The hematological values presented here are from a large, representative population sample and the first report of people living below sea level. PMID- 23095793 TI - A new hint to clonal dominance in PNH. PMID- 23095794 TI - Allogeneic stem cell transplantation for acute myeloid leukemia with del(7q) following untreated chronic lymphocytic leukemia. AB - The development of hematologic malignancy in the presence of chronic lymphocytic leukemia (CLL) is rare. We present a case of acute myeloid leukemia (AML) with del(7q) occurring in a patient with a 4-year history of untreated CLL. Application of flow cytometry and immunohistochemistry allowed for characterization of two distinct coexisting malignant cell populations. After undergoing induction and consolidation chemotherapy, the patient achieved complete remission of AML with the persistence of CLL. Allogeneic transplantation was pursued given his unfavorable cytogenetics. Subsequent matched unrelated donor allogeneic stem cell transplantation resulted in full engraftment and complete remission, with no evidence of AML or CLL. Due to a scarcity of reported cases, insight into treatment and prognosis in cases of concurrent AML and CLL is limited. However, prognosis seems dependent on the chemosensitivity of AML. CLL did not have a detrimental effect on treatment or transplant outcome in our case. This is the first reported case of concomitant de novo AML and CLL to undergo allogeneic transplantation. The patient remained in complete hematologic and cytogenetic remission of both malignancies over a year after transplantation. PMID- 23095795 TI - The t(9;11) confers good prognosis in AML patients treated with stem cell transplantation as compared to non-t(9;11) and other adverse-risk abnormalities. PMID- 23095796 TI - Oral chemotherapy in cancers: what about adherence? PMID- 23095797 TI - Extramedullary plasmacytoma of the liver. PMID- 23095798 TI - Cell cycle: Order in the pericentriolar material. PMID- 23095799 TI - Effects of carvedilol as third-line add-on therapy on blood pressure and glucose metabolism in type 2 diabetic patients with chronic renal disease stage 3 and above. AB - BACKGROUND: We evaluated the effect of coadministration of beta-blocker (carvedilol) as the third agent with angiotensin II receptor blockers (ARB) and calcium channel blockers (CCB) on blood pressure (BP) regulation and glucose metabolism. METHODS: Diabetic patients who did not achieve the therapeutic BP goal (140/90 mmHg) by ARB and CCB combination therapy were recruited. This study was designed to compare the BP regulating effects by adding carvedilol (10 mg/day, n=30) and by doubling the dose of either ARB (n=34) or CCB (n=31). Serum glucose metabolism was examined. RESULTS: The carvedilol group showed a decrease (P<0.01) in BP from 166+/-11/90+/-8 to 156+/-9/84+/-7 mmHg at 12 weeks. In the ARB and CCB groups, BP also decreased (P<0.01) from 164+/-11/87+/-8 to 153+/ 10/83+/-8 and 163+/-7/87+/-8 to 153+/-8/84+/-9 mmHg at 12 weeks. The rates of achieving therapeutic goal at 12 weeks were 36.7% in the carvedilol, 38.2% in the ARB and 41.9% in the CCB group. Serum glucose metabolism did not change in all groups. CONCLUSIONS: These results suggest that adding carvedilol decreased BP as safely as increasing the dose of ARB or CCB in patients with diabetic nephropathy. PMID- 23095802 TI - Reducing interruptions to improve medication safety. AB - In the fast-paced environment of a cardiac and thoracic surgery telemetry unit, nurses are interrupted hundreds of times per day. These interruptions can have a detrimental effect on patient safety during medication administration. This article describes a bundle of safety interventions that reduced the average number of interruptions during medication administration by 2.11 interruptions per encounter and decreased reported medication errors by a total of 28 incidents over a 3-month period. PMID- 23095803 TI - NR1I2 polymorphisms are related to tacrolimus dose-adjusted exposure and BK viremia in adult kidney transplantation. AB - BACKGROUND: Pregnane X, encoded by the gene NR112, is a nuclear receptor whose primary role is to promote the detoxification and clearance of drugs and other foreign compounds from the body. AIM: The aim of this study was to analyze associations between NR1I2 polymorphisms, immunosuppressant drug exposure, and clinical outcomes in adult kidney transplant recipients. METHODS: Exposures to tacrolimus, mycophenolic acid, and total and free prednisolone were estimated at month 1 posttransplant using validated multiple regression-derived limited sampling strategies. RESULTS: In the 158 subjects studied, median (interquartile range) dose-adjusted exposure to tacrolimus was significantly higher in individuals carrying the NR1I2 8055T variant allele, when compared with exposure in wild-type individuals [20 (14, 22) MUg.h/L/mg versus 15 (9, 24) MUg.h/L/mg; P =0.0007]. Using multivariable logistic regression, NR1I2 8055T carrier status was independently predictive of higher dose-adjusted tacrolimus exposure (P=0.0005). Moreover, BK viremia was seen significantly more frequently in NR1I2 8055T allele carriers compared with wild-type individuals (38% vs 18%, P=0.005) and possession of the NR1I2 8055T allele imposed significantly higher odds of BK viremia (adjusted odds ratio, 2.76 [95% confidence interval, 1.33-7.73]; P=0.006). No significant difference in geometric mean peak BK viral replication titer was observed between 8055T carriers and noncarriers. No NR1I2 SNP or haplotype was significantly, independently associated with total or free prednisolone or MPA exposure. CONCLUSIONS: These data demonstrate an impact of pregnane X receptor polymorphisms on tacrolimus pharmacokinetics. Association of the 8055T allele with BK viremia suggests clinically significant "overimmunosuppression" in individuals with this genotype. PMID- 23095804 TI - Early eczema and the risk of childhood asthma: a prospective, population-based study. AB - BACKGROUND: Severe eczema in young children is associated with an increased risk of developing asthma and rhino-conjunctivitis. In the general population, however, most cases of eczema are mild to moderate. In an unselected cohort, we studied the risk of current asthma and the co-existence of allergy-related diseases at 6 years of age among children with and without eczema at 2 years of age. METHODS: Questionnaires assessing various environmental exposures and health variables were administered at 2 years of age. An identical health questionnaire was completed at 6 years of age. The clinical investigation of a random subsample ascertained eczema diagnoses, and missing data were handled by multiple imputation analyses. RESULTS: The estimate for the association between eczema at 2 years and current asthma at 6 years was OR=1.80 (95% CI 1.10-2.96). Four of ten children with eczema at 6 years had the onset of eczema after the age of 2 years, but the co-existence of different allergy-related diseases at 6 years was higher among those with the onset of eczema before 2 years of age. CONCLUSIONS: Although most cases of eczema in the general population were mild to moderate, early eczema was associated with an increased risk of developing childhood asthma. These findings support the hypothesis of an atopic march in the general population. TRIAL REGISTRATION: The Prevention of Allergy among Children in Trondheim study has been identified as ISRCTN28090297 in the international Current Controlled Trials database. PMID- 23095805 TI - Comparing the reconstruction of regulatory pathways with distinct Bayesian networks inference methods. AB - BACKGROUND: Inference of biological networks has become an important tool in Systems Biology. Nowadays it is becoming clearer that the complexity of organisms is more related with the organization of its components in networks rather than with the individual behaviour of the components. Among various approaches for inferring networks, Bayesian Networks are very attractive due to their probabilistic nature and flexibility to incorporate interventions and extra sources of information. Recently various attempts to infer networks with different Bayesian Networks approaches were pursued. The specific interest in this paper is to compare the performance of three different inference approaches: Bayesian Networks without any modification; Bayesian Networks modified to take into account specific interventions produced during data collection; and a probabilistic hierarchical model that allows the inclusion of extra knowledge in the inference of Bayesian Networks. The inference is performed in three different types of data: (i) synthetic data obtained from a Gaussian distribution, (ii) synthetic data simulated with Netbuilder and (iii) Real data obtained in flow cytometry experiments. RESULTS: Bayesian Networks with interventions and Bayesian Networks with inclusion of extra knowledge outperform simple Bayesian Networks in all data sets when considering the reconstruction accuracy and taking the edge directions into account. In the Real data the increase in accuracy is also observed when not taking the edge directions into account. CONCLUSIONS: Although it comes with a small extra computational cost the use of more refined Bayesian network models is justified. Both the inclusion of extra knowledge and the use of interventions have outperformed the simple Bayesian network model in simulated and Real data sets. Also, if the source of extra knowledge used in the inference is not reliable the inferred network is not deteriorated. If the extra knowledge has a good agreement with the data there is no significant difference in using the Bayesian networks with interventions or Bayesian networks with the extra knowledge. PMID- 23095806 TI - Slow extended nocturnal home hemodialysis shows superior adequacy compared to in center dialysis: a mathematical analysis. AB - Extended nocturnal home hemodialysis has gained renewed interest. However, no removal data for single/double needle (lumen) (SL and DL, respectively) or for low/high blood flow in extended dialysis are available. Therefore, we studied dialysis adequacy in different nocturnal home hemodialysis strategies. Coupling a kinetic with a dialyzer model, we calculated a reduction ratio from pre- to post dialysis (RR) and total solute removal (TSR) of urea, methylguanidine (MG), beta2 microglobulin, and phosphate. Simulations were done for dialysis with blood flow Qb350 ml/min (DL-4h), extended DL high flow with Qb350 (DL-HF-8h) and low flow with Qb175 (DL-LF-8h), and SL with Qb273 (SL-8h). Compared to DL-4h, TSR was 28 59% larger for DL-HF-8h. TSR was most increased for beta2-microglobulin (18%) with DL-LF-8h, and for MG (35%) with SL-8h. Furthermore, RRs were equal (DL-LF 8h), higher (SL-8h), and even more increased (DL-HF-8h) for all studied solutes. In the home setting, DL-LF-8h and SL-8h are safe and promising strategies. PMID- 23095807 TI - Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields. AB - Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. PMID- 23095808 TI - Cross-sectional association between polyfluoroalkyl chemicals and cognitive limitation in the National Health and Nutrition Examination Survey. AB - BACKGROUND/AIMS: Our limited understanding of how polyfluoroalkyl chemicals (PFCs) may impact on human health suggests the potential for a protective impact on brain health. This study was designed to explore the association between PFCs and cognitive ability in older adults. METHODS: We assessed the association between four PFCs, perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonic acid (PFHxS), and self-reported limitation due to difficulty remembering or periods of confusion using data from participants aged 60-85 years from the 1999-2000 and 2003-2008 National Health and Nutrition Examination Surveys. We also considered whether diabetic status or diabetic medication use modifies this association in light of in vitro evidence that PFCs may act on the same receptors as some diabetic medications. RESULTS: In multivariable adjusted models, point estimates suggest a protective association between PFCs and self-reported cognitive limitation (odds ratio, OR; 95% confidence interval, CI) for a doubling in PFC concentration: PFOS (OR, 0.90; 95% CI, 0.78, 1.03), PFOA (OR, 0.92; 95% CI, 0.78, 1.09), PFNA (OR, 0.91; 95% CI, 0.79, 1.04) and PFHxS (OR, 0.93; 95% CI, 0.82, 1.06). The protective association was concentrated in diabetics, with strong, significant protective associations in nonmedicated diabetics. CONCLUSIONS: This cross-sectional study suggests that there may be a protective association between exposure to PFCs and cognition in older adults, particularly diabetics. PMID- 23095810 TI - 'Man-in-the-barrel' syndrome with bilateral 6th cranial nerve palsy. PMID- 23095809 TI - Involvement of the P2X7 purinergic receptor and c-Jun N-terminal and extracellular signal-regulated kinases in cyclooxygenase-2 and prostaglandin E2 induction by LL-37. AB - Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E(2) (PGE(2)) production. We previously demonstrated that human beta-defensin-3 induces COX-2 and PGE(2) in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE(2) synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE(2) in cell free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X(7) purinergic receptor significantly abrogated COX-2 induction and PGE(2) production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE(2) synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1beta did so via nuclear factor-KB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE(2) synthesis via the P2X(7) receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease. PMID- 23095811 TI - Animal models for human polycystic kidney disease. AB - Polycystic kidney disease (PKD) is a hereditary disorder with abnormal cellular proliferation, fluid accumulation in numerous cysts, remodeling of extracellular matrix, inflammation, and fibrosis in the kidney and liver. The two major types of PKD show autosomal dominant (ADPKD) or autosomal recessive inheritance (ARPKD). ADPKD is one of the most common genetic diseases, with an incidence of 1:500-1,000. Approximately 50% of patients with ADPKD develop end-stage renal disease (ESRD) by the age of 60. On the other hand, ARPKD is relatively rare, with an incidence of approximately 1:20,000-40,000. ARPKD is diagnosed early in life, often prenatally. The gene products responsible for ADPKD and ARPKD distribute in primary cilia and are thought to control intercellular Ca(2+). Two types of animal model of PKD have been established: spontaneous hereditary models identified by the typical manifestations of PKD and gene-engineered models established by modification of human orthologous genes. Both types of animal models are used to study the mechanism of cystogenesis and efficacy of medical treatments. In PKD progression, critical roles of signaling pathways including MAPK, mTOR, and PPAR-gamma have been discovered with these models. Therefore, experimental animal models are indispensable for investigating molecular mechanisms of PKD onset and progression as well as potential therapeutic treatments. PMID- 23095812 TI - PITT: pronuclear injection-based targeted transgenesis, a reliable transgene expression method in mice. AB - Transgenic (Tg) mice have been extensively used as valuable tools for analyses of gene function and have also served as models for many human diseases. Typically, a transgenic mouse is created by microinjection of DNA into pronuclei in which the DNA gets integrated at random locations in the genome. Frequently however, the random integration of multiple copies of a transgene results in transgene silencing, probably because of a positional effect and/or repeat-induced gene silencing. The transgene silencing issue has been overcome by single-copy transgene integration into a predetermined locus through ES cell-mediated transgenesis, despite it being expensive and more time-consuming compared with pronuclear injection (PI)-mediated transgenesis. Recently, several groups have reported novel approaches that employ PI for targeted transgenesis. They are based on site-specific recombination catalyzed by a recombinase or an integrase or homologous recombination enhanced by a zinc-finger nuclease via PI. These next generation transgenesis methods, which we termed as PI-based Targeted Transgenesis (PITT), are more convenient and faster than ES cell-based transgenesis. Furthermore, the Tg mice generated by these newer methods contain a single-copy transgene and exhibit reliable expression of the transgene. The objective of this review is to present the recent progress in mouse targeted transgenesis. PMID- 23095813 TI - Genomic mixing to elucidate the genetic system of complex traits. AB - Understanding the genetic basis of complex traits has become one of the major issues in genetics, but recent advances in this field are still faced with a difficulty, the so-called "missing heritability." It is speculated that missing heritability mainly stems from a large number of variants of small effect that are poorly detected by currently available methods. In order to overcome this problem, many recent genetic studies of complex traits have actively used outbred stocks of mice. However, most of the available outbred stocks have a limited amount of genetic variation, because many stocks originate from Swiss mouse colonies. We have repeatedly shown that wild-derived strains are a useful mouse resource since there is a large genetic diversity among these strains. Here, we give an overview of mouse resources produced by crossing different founder mice. Finally, we propose an advantage of new attempts to conduct selective breeding using heterogeneous stocks created by mixing genomes of wild-derived inbred strains of mice when studying complex traits. PMID- 23095814 TI - Effect of moderate treadmill exercise on some physiological parameters in untrained Beagle dogs. AB - The aim of the present study was to evaluate the modifications of some physiological parameters during moderate treadmill exercise in seven healthy Beagle dogs. All animals were submitted to treadmill exercise consisting of walking (15 min), trotting (20 min) and walking (10 min). At every step, rectal temperature (RT) was measured, and the mean heart rate (HR) was assessed. Venous blood samples were collected immediately before starting the treadmill exercise session (at rest), after the end of walking (15 min), trotting (20 min) and walking (10 min), and after 30 min of passive recovery. For immediate assessment of lactate and glucose concentration, blood was analyzed with portable blood lactate and blood glucose analyzers, respectively. Blood was also transferred into sterile glass tubes containing K(3)-ethylenediaminetetraacetic acid (K(3) EDTA) for evaluation of red blood cells (RBC), white blood cells (WBC), platelets (PLT), hemoglobin (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC). One-way repeated measures analysis of variance (ANOVA) showed a significant effect of treadmill exercise (P<0.05) on RT, HR, lactate, glucose, RBC and Hct. Considering these significant variations, the knowledge of RT, HR, glucose and lactate concentrations, RBC, and Hct, the most suitable and sensitive indicators of response to treadmill exercise in untrained dogs, is essential in order to evidence the individual levels of exercise tolerance, to investigate exercise-related problems and to design specific and individual treadmill protocols. PMID- 23095815 TI - Male Hatano high-avoidance rats show high avoidance and high anxiety-like behaviors as compared with male low-avoidance rats. AB - Our prime objective was to establish an optimal model animal for studying avoidance learning and memory in rodents. The two-way rat inbred strains of Hatano high- (HAA) and low-avoidance (LAA) animals were originally selected and bred in accordance with their high or low performance respectively in the shuttle box active avoidance task. Previous studies demonstrated that they have clear strain differences in endocrine stress response, which is related to acquisition of aversive learning and emotional reactivity. To evaluate the effect of selection by the shuttle-box task on avoidance performance and emotional reactivity, male Hatano rats underwent passive avoidance, open field and elevated plus maze tests. The present results show that the avoidance performance in the passive task was significantly greater in HAA rats than in LAA rats. Furthermore, HAA rats showed high anxiety-like behaviors compared with LAA rats in open field and elevated plus maze tests. Taken together, this study demonstrated that 1) selection and breeding of Hatano HAA and LAA strain rats by shuttle-box task had been properly carried out with the criterion of high and low avoidance performance respectively and that 2) HAA rats were predisposed to high anxiety compared with LAA rats. These results indicated that Hatano HAA and LAA rats can be useful models for studying avoidance learning and memory. PMID- 23095816 TI - Distinct distribution of the tensin family in the mouse kidney and small intestine. AB - Tensin family members are cytoplasmic proteins that are localized to the integrin mediated cell-basement membrane junctions and implicated in cytoskeletal organization, cell migration, and proliferation. The mammalian genome contains four paralogs, Tns1, Tns2, Tns3, and Tns4. Murine mutations in the Tns1 and Tns2 genes cause polycystic kidney disease and glomerular sclerosis, respectively, and Tns3-null mice exhibit an impaired intestinal epithelial development. However, the knowledge concerning the localization of each tensin is still fragmentary. In this study, the cellular and subcellular distributions of tensin members were defined and compared with each other. RT-PCR analysis indicated that Tns2 and Tns3 were more abundant in isolated glomeruli and that Tns1 was highly expressed in areas other than the glomeruli, but no Tns4 expression was observed in the kidney. All tensin members were detected in the small intestine. Immunohistochemical staining revealed that Tns1 was predominantly localized to the mesangium of glomeruli and renal tubules. In contrast, Tns2 and Tns3 were highly expressed in the podocytes and the partial collecting system. In the small intestine, Tns2 and Tns3 were highly expressed in crypt and villous epithelial cells. Furthermore, we found that Tns3 was colocalized with TJ protein ZO-1 in renal tubules. These results indicate distinct differences in the cellular expression of Tns1, Tns2, and Tns3, and suggest that they may be able to function independently of each other in the kidney and the small intestine. PMID- 23095817 TI - A study on optimizing the cryopreservation methods for Bama miniature pig semen. AB - In this study, the cryopreservation methods for Bama miniature pig semen were investigated and optimized. First, using an orthogonal experimental design, the semen freezing-thawing procedure for Bama miniature boars was optimized based on analysis of the effects of concentrations of LDL (LC, parameter A), trehalose (TC, parameter B) and glycerol (GC, parameter C), the equilibration time at 15 degrees C (ET, parameter D), and the thawing method (TM, parameter E) on sperm motility. The results showed that the effects of the parameters could be arranged as A>C>B>D>E. The LDL concentration and final glycerol concentration had exceedingly significant effects on the motility of thawed spermatozoa (P<0.01), and the effects of the trehalose concentration, equilibration time at 15 degrees C, and the thawing method were not significant (P>0.05). Scheme 2 (A(3)B(4)C(2)D(3)E(1)) gave a motility of 52.26% after thawing. Then, using sperm motility, acrosome integrity, plasma membrane integrity, and DNA injury rate as indicators, four combinations, on the basis of scheme 2, were designed to analyze the protective effects of different combinations of LDL, glycerol, and trehalose; the results showed that combination of 9% LDL, 200 mM trehalose, and 2% glycerol (i.e., combination 4) demonstrated significantly better protective effects than the other combinations (P<0.05), further verifying that scheme 2 was the best for cryopreservation of Bama miniature boar semen. In this way, a method with favorable performance was established for cryopreservation of semen of Bama miniature boars. PMID- 23095818 TI - Effects of cyclic heat stress or vitamin C supplementation during cyclic heat stress on HSP70, inflammatory cytokines, and the antioxidant defense system in Sprague Dawley rats. AB - A total of 21 male SD rats were divided into three groups to investigate the effects of consecutive cyclic heat stress or vitamin C under heat stress on heat shock protein (HSP) 70, inflammatory cytokines, and antioxidant systems. The heat stress (HS) and vitamin C supplementation during heat stress (HS+VC) groups were exposed to cyclic heat stress (23 to 38 to 23 degrees C) for 2 h on each of seven consecutive days. The HS+VC group had free access to water containing 0.5% vitamin C throughout the experiment. Hepatic HSP70 mRNA in the HS group was significantly (P<0.05) higher than that in the control (CON) or HS+VC group. The mRNA levels of tumor necrosis factor (TNF)-alpha and inducible nitric oxide synthase (iNOS) in the HS group were greater (P<0.05) than those in the CON group. The HS+VC group showed significantly (P<0.05) lower mRNA levels of hepatic interleukin-6 and TNF-alpha than the HS group. However, thymic HSP70 and inflammatory cytokines were unaffected by treatments. In the hepatic antioxidant system, the mRNA and activity of glutathione peroxidase (GPX) were greater (P<0.05) in the HS than in the CON group, whereas the HS+VC group showed markedly (P<0.05) lower GPX mRNA and activity than the HS group. However, superoxide dismutase, glutathione S-transferase, and malondialdehyde were unaffected by treatments. In conclusion, cyclic heat stress activated hepatic HSP70, TNF-alpha, iNOS, and GPX genes, whereas vitamin C during heat stress ameliorated heat stress induced cellular responses in rats. PMID- 23095819 TI - Effect of dietary protein levels on sex hormones in growing male rats kept under constant darkness. AB - The purpose of this experiment was to clarify the effects of dietary protein levels on the gonadal development and sex hormones in male rats kept under constant darkness as a model of disturbed daily rhythm. Four-week-old male rats (Fischer 344 strain) were kept under constant darkness or normal lighting (12-h light/dark cycle). Two kinds of experimental diet were prepared, one with low dietary protein levels (9% casein) and one with normal levels (18% casein). Harper mineral mixture and Panvitan were used as mineral and vitamin sources, respectively. After 4 weeks, gonadal weight, serum testosterone, and other hormone contents were evaluated. The gonadal weight in the constant darkness groups (D-groups) was lower than that in the normal lighting groups (N-groups). Although the low-protein diet in the D-groups significantly reduced gonadal weight, the normal-protein diet mitigated the reduction of gonadal weight in rats kept under constant darkness. Serum testosterone and androstenedione concentrations were lower in D-group rats fed the low-protein diet. There were no effects of lighting condition or protein levels on serum luteinizing hormone (LH), follicle- stimulating hormone (FSH), or progesterone concentrations. These results indicate that the suppression of gonadal development in D-group rats fed the low-protein diet was caused by low testosterone, which we attribute to the inhibition of synthesized androstenedione, a precursor of testosterone. The present study showed that constant darkness and the low- protein diet inhibited the synthetic pathway from progesterone to androstenedione. PMID- 23095821 TI - A simplified electrospray ionization source based on electrostatic field induction for mass spectrometric analysis of droplet samples. AB - A simplified electrospray ionization source based on electrostatic field induction is introduced in this paper. The electrostatic field induced spray ionization, termed EFISI, is easily performed using a needle electrode and a capillary, and it does not require heat, gas, a syringe pump or any other equipment. A high voltage is applied to a needle electrode which does not contact the sample. The capillary is used as a sample spray emitter without any electrical contact or tip modification. As only a 1 MUL sample droplet is needed for analysis with no or little pretreatment, the EFISI source is particularly suitable for the mass spectrometric analysis of microlitre volume samples. The change of charge distribution in the droplet solution, by the induction of an external electrostatic field from the needle electrode, is proposed to be the main cause of ion formation. We demonstrate its feasibility for the characterization of a wide range of organic compounds and biomolecules in pure solutions or complex matrices. The influence of sample capillary length and droplet solvent composition on the ionization process are also discussed. PMID- 23095822 TI - Solvent-free chemoselective oxidation of thioethers and thiophenes by mechanical milling. AB - Organosulphur compounds can be easily and selectively oxidized to sulfones using a small excess of Oxone((r)) (1.6 eq.) under solventless mechanical milling conditions. This green procedure has been efficiently applied to a series of model compounds and to the desulphurization of medium/high sulphur content paraffins (up to 3000 mg kg(-1)). PMID- 23095823 TI - Interleukin 10 polymorphisms and cervical cancer risk: a meta-analysis. AB - BACKGROUND: A debate exists about whether interleukin 10 (IL-10) polymorphisms (IL-10-1082G/A and IL-10-592C/A) confer additional risk for cervical cancer. To derive a more precise estimation of the relationship between IL-10 polymorphisms and cervical cancer risk, we conducted a meta-analysis of all available studies relating the -1082G/A and -592C/A polymorphisms of the IL-10 gene to the risk of developing cervical cancer. METHODS: Eight studies were eligible for IL-10 1082G/A (1498 cases and 1608 controls), and 5 studies were eligible for IL-10 592C/A (2396 cases and 1388 controls). Pooled odds ratios (ORs) were appropriately derived from fixed-effects or random-effects models. Subgroup analyses were performed by ethnicity and Hardy-Weinberg equilibrium in the controls. RESULTS: In the overall analysis, no significant association between the IL-10-1082G/A polymorphism and the risk of cervical cancer was observed. In the subgroup analysis by ethnicity, IL-10 -1082A allele was associated with decreased cervical cancer susceptibility among whites (A vs G: OR, 0.39; 95% confidence interval [CI], 0.32-0.47). Studies with controls deviated from Hardy Weinberg equilibrium showed an evident association in dominant model (GA/AA vs GG: OR, 1.73 [95% CI, 1.04-2.89]). On the other hand, with respect to -592C/A polymorphism, significantly elevated cervical cancer risk was found in the overall analysis (A vs C: OR, 1.16 [95% CI, 1.04-1.31]; AA vs CC: OR, 1.36 [95% CI, 1.00-1.84]; CA/AA vs CC: OR, 1.18 [95% CI, 1.01-1.39]; AA vs CC/CA: OR, 1.25 [95% CI, 1.01-1.55]). Stratified analysis indicated that significantly increased risks were also found among Asians in the allelic model (A vs C: OR, 1.23 [95% CI, 1.01-1.49]). CONCLUSIONS: Interleukin 10-1082 G/A polymorphism showed no effect on cervical cancer risk in the overall analysis. The genetic polymorphism in IL-10-592C/A is a risk factor for developing cervical cancer, especially for Asians. PMID- 23095824 TI - Editor's note. PMID- 23095825 TI - Personalized care in neuro-oncology coming of age: why we need MGMT and 1p/19q testing for malignant glioma patients in clinical practice. AB - Histological subtyping and grading by malignancy are the cornerstones of the World Health Organization (WHO) classification of tumors of the central nervous system. They shall provide clinicians with guidance as to the course of disease to be expected and the choices of treatment to be made. Nonetheless, patients with histologically identical tumors may have very different outcomes, notably in patients with astrocytic and oligodendroglial gliomas of WHO grades II and III. In gliomas of adulthood, 3 molecular markers have undergone extensive studies in recent years: 1p/19q chromosomal codeletion, O(6)-methylguanine methyltransferase (MGMT) promoter methylation, and mutations of isocitrate dehydrogenase (IDH) 1 and 2. However, the assessment of these molecular markers has so far not been implemented in clinical routine because of the lack of therapeutic implications. In fact, these markers were considered to be prognostic irrespective of whether patients were receiving radiotherapy (RT), chemotherapy, or both (1p/19q, IDH1/2), or of limited value because testing is too complex and no chemotherapy alternative to temozolomide was available (MGMT). In 2012, this situation has changed: long-term follow-up of the Radiation Therapy Oncology Group 9402 and European Organisation for Research and Treatment of Cancer 26951 trials demonstrated an overall survival benefit from the addition to RT of chemotherapy with procarbazine/CCNU/vincristine confined to patients with anaplastic oligodendroglial tumors with (vs without) 1p/19q codeletion. Furthermore, in elderly glioblastoma patients, the NOA-08 and the Nordic trial of RT alone versus temozolomide alone demonstrated a profound impact of MGMT promoter methylation on outcome by therapy and thus established MGMT as a predictive biomarker in this patient population. These recent results call for the routine implementation of 1p/19q and MGMT testing at least in subpopulations of malignant glioma patients and represent an encouraging step toward the development of personalized therapeutic approaches in neuro-oncology. PMID- 23095826 TI - Neurocognitive functioning in adult WHO grade II gliomas: impact of old and new treatment modalities. AB - In the treatment of patients with low-grade glioma, there still is controversy on how surgical intervention, radiation therapy, and chemotherapy contribute to an ameliorated progression-free survival, overall survival, and treatment-related neurotoxicity. With the ongoing changes in treatment options for these patients, neurocognitive functioning is an increasingly important outcome measure, because neurocognitive impairments can have a large impact on self-care, social and professional functioning, and consequently, health-related quality of life. Many factors contribute to neurocognitive outcome, such as direct and indirect tumor effects, seizures, medication, and oncological treatment. Although the role of radiotherapy has been studied extensively, the adverse effects on neurocognitive function of other treatment-related factors remain elusive. This holds for both resective surgery, in which the use of intraoperative stimulation mapping has a high potential benefit concerning survival and patient functioning, and the use of chemotherapy that might have some interesting new applications, such as the facilitation of total resection for initially primary or recurrent diffuse low grade glioma tumors. This article will discuss these treatment options in patients with low-grade glioma and their potential effects on neurocognitive functioning. PMID- 23095827 TI - Cerebral white matter integrity and executive function in adult survivors of childhood medulloblastoma. AB - Survivors of pediatric medulloblastoma are at risk for neurocognitive dysfunction. Reduced white matter integrity has been correlated with lower intelligence in child survivors, yet associations between specific cognitive processes and white matter have not been examined in long-term adult survivors. Twenty adult survivors of medulloblastoma were randomly recruited from a larger institutional cohort of adult survivors of childhood cancer. Survivors underwent comprehensive neurocognitive evaluations and MRI. Data on brain volume and cortical thickness and diffusion tensor imaging were acquired, including measures of fractional anisotropy, apparent diffusion coefficient, and axial and radial diffusivity. Observed neurocognitive scores were compared with population norms and correlated to MRI indices. Survivors were, on average, 29 years of age and 18 years postdiagnosis. Mean full-scale intelligence quotient was nearly 1 SD below the normative mean (86.3 vs 100, P = .004). Seventy-five percent of survivors were impaired on at least one measure of executive function. Radial diffusivity in the frontal lobe of both hemispheres was correlated with shifting attention (left: r(s) = -0.67, P = .001; right: r(s) = -0.64, P = .002) and cognitive flexibility (left: r(s) = -0.56, P = .01; right: r(s) = -0.54, P = .01). Volume and cortical thickness were not correlated with neurocognitive function. Neurocognitive impairment was common and involved many domains. Reduced white matter integrity in multiple brain regions correlated with poorer performance on tasks of executive function. Future research integrating diffusion tensor imaging should be a priority to more rigorously evaluate long-term consequences of cancer treatment and to inform cognitive intervention trials in this high-risk population. PMID- 23095828 TI - Neuro-oncology and palliative care: a challenging interface. PMID- 23095829 TI - Radiation-induced cognitive impairment--from bench to bedside. AB - Approximately 100,000 patients per year in the United States with primary and metastatic brain tumor survive long enough (>6 months) to develop radiation induced brain injury. Before 1970, the human brain was thought to be radioresistant; the acute central nervous system (CNS) syndrome occurs after single doses of >= 30 Gy, and white matter necrosis can occur at fractionated doses of >= 60 Gy. Although white matter necrosis is uncommon with modern radiation therapy techniques, functional deficits, including progressive impairments in memory, attention, and executive function have become increasingly important, having profound effects on quality of life. Preclinical studies have provided valuable insights into the pathogenic mechanisms involved in radiation induced cognitive impairment. Although reductions in hippocampal neurogenesis and hippocampal-dependent cognitive function have been observed in rodent models, it is important to recognize that other brain regions are affected; non-hippocampal dependent reductions in cognitive function occur. Neuroinflammation is viewed as playing a major role in radiation-induced cognitive impairment. During the past 5 years, several preclinical studies have demonstrated that interventional therapies aimed at modulating neuroinflammation can prevent/ameliorate radiation induced cognitive impairment independent of changes in neurogenesis. Translating these exciting preclinical findings to the clinic offers the promise of improving the quality of life in patients with brain tumors who receive radiation therapy. PMID- 23095830 TI - Peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. AB - Peripheral neuropathies induced by chemotherapy (CIPN) are an increasingly frequent problem. Contrary to hematologic adverse effects, which can be treated with hematopoetic growth factors, neither prophylaxis nor specific treatment is available, and only symptomatic treatment can be offered. Neurotoxic drugs are becoming a major dose-limiting factor. The epidemiology is still unclear. Several drug-dependent pathogenetic mechanisms exist. CIPN are predominately sensory, length-dependent neuropathies that develop after a typical cumulative dose. Usually, the appearance of CIPN is dose dependent, although in at least 2 drugs (oxaliplatin and taxanes), immediate toxic effects occur. The most frequent substances causing CIPN are platin compounds, vinka alkaloids, taxanes, and bortezomib and thalidomide. The role of synergistic neurotoxicity caused by previously given chemo-therapies and concomitant chemotherapies and the role pre existent neuropathy on the development of a CIPN is not clear. As the number of long-term cancer survivors increases and a new focus on long-term effects of chemotherapy-induced neuropathies emerge, concepts of rehabilitation need to be implemented to improve the patients' functions and quality of life. PMID- 23095832 TI - Practical strategies for management of fatigue and sleep disorders in people with brain tumors. PMID- 23095831 TI - Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. AB - Seizures represent a common symptom in low-grade gliomas; when uncontrolled, they significantly contribute to patient morbidity and negatively impact quality of life. Tumor location and histology influence the risk for epilepsy. The pathogenesis of tumor-related epilepsy is multifactorial and may differ among tumor histologies (glioneuronal tumors vs diffuse grade II gliomas). Gross total resection is the strongest predictor of seizure freedom in addition to clinical factors, such as preoperative seizure duration, type, and control with antiepileptic drugs (AEDs). Epilepsy surgery may improve seizure control. Radiotherapy and chemotherapy with alkylating agents (procarbazine + CCNU+ vincristine, temozolomide) are effective in reducing the frequency of seizures in patients with pharmacoresistant epilepsy. Newer AEDs (levetiracetam, topiramate, lacosamide) seem to be better tolerated than the old AEDs (phenobarbital, phenytoin, carbamazepine), but there is lack of evidence regarding their superiority in terms of efficacy. PMID- 23095833 TI - Thromboembolic disease in patients with high-grade glioma. AB - Venous thromboembolism (VTE) is common throughout the course of disease in high grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets. PMID- 23095834 TI - Factors influencing quality of life in adult patients with primary brain tumors. AB - We performed a literature review with respect to factors influencing health related quality of life (QOL) in adults with primary brain tumors. A comprehensive, peer-reviewed literature search was performed including studies examining QOL in adults with high-grade gliomas and low-grade gliomas and in routine neuro-oncology practice. The interpretation and implication of QOL domain scores may be different in high-grade, low-grade, and benign brain tumors. Several patient-related, treatment-related, and sociocultural factors influence QOL scores. Pretreatment baseline QOL domain scores have been shown to be a predictive parameter for survival function. Implementation of QOL scores in routine clinical practice is underused. QOL is an important outcome measure in the treatment of patients with brain tumors and should be incorporated as a surrogate end point along with traditional end points, such as disease-free and overall survival in most current trials. PMID- 23095835 TI - Working memory and the identification of facial expression in patients with left frontal glioma. AB - Patients with brain tumors may have cognitive dysfunctions including memory deterioration, such as working memory, that affect quality of life. This study was to explore the presence of defects in working memory and the identification of facial expressions in patients with left frontal glioma. This case-control study recruited 11 matched pairs of patients and healthy control subjects (mean age +/- standard deviation, 37.00 +/- 10.96 years vs 36.73 +/- 11.20 years; 7 male and 4 female) from March through December 2011. The psychological tests contained tests that estimate verbal/visual-spatial working memory, executive function, and the identification of facial expressions. According to the paired samples analysis, there were no differences in the anxiety and depression scores or in the intelligence quotients between the 2 groups (P > .05). All indices of the Digit Span Test were significantly worse in patients than in control subjects (P < .05), but the Tapping Test scores did not differ between patient and control groups. Of all 7 Wisconsin Card Sorting Test (WCST) indexes, only the Preservative Response was significantly different between patients and control subjects (P < .05). Patients were significantly less accurate in detecting angry facial expressions than were control subjects (30.3% vs 57.6%; P < .05) but showed no deficits in the identification of other expressions. The backward indexes of the Digit Span Test were associated with emotion scores and tumor size and grade (P < .05). Patients with left frontal glioma had deficits in verbal working memory and the ability to identify anger. These may have resulted from damage to functional frontal cortex regions, in which roles in these 2 capabilities have not been confirmed. However, verbal working memory performance might be affected by emotional and tumor-related factors. PMID- 23095836 TI - Molecular markers in pediatric neuro-oncology. AB - Pediatric molecular neuro-oncology is a fast developing field. A multitude of molecular profiling studies in recent years has unveiled a number of genetic abnormalities unique to pediatric brain tumors. It has now become clear that brain tumors that arise in children have distinct pathogenesis and biology, compared with their adult counterparts, even for those with indistinguishable histopathology. Some of the molecular features are so specific to a particular type of tumors, such as the presence of the KIAA1549-BRAF fusion gene for pilocytic astrocytomas or SMARCB1 mutations for atypical teratoid/rhabdoid tumors, that they could practically serve as a diagnostic marker on their own. Expression profiling has resolved the existence of 4 molecular subgroups in medulloblastomas, which positively translated into improved prognostication for the patients. The currently available molecular markers, however, do not cover all tumors even within a single tumor entity. The molecular pathogenesis of a large number of pediatric brain tumors is still unaccounted for, and the hierarchy of tumors is likely to be more complex and intricate than currently acknowledged. One of the main tasks of future molecular analyses in pediatric neuro-oncology, including the ongoing genome sequencing efforts, is to elucidate the biological basis of those orphan tumors. The ultimate goal of molecular diagnostics is to accurately predict the clinical and biological behavior of any tumor by means of their molecular characteristics, which is hoped to eventually pave the way for individualized treatment. PMID- 23095837 TI - Neurotransmission: Anxious interactions. PMID- 23095838 TI - Neurotransmission: GABA calls stop in the striatum. PMID- 23095839 TI - Smoking Cessation Related to Improved Patient-Reported Pain Scores Following Spinal Care. AB - BACKGROUND: Smoking is associated with low back pain, intervertebral disc disease, inferior patient outcomes following surgical interventions, and increased rates of postoperative complications. The purpose of the present study was to examine the effect of smoking and smoking cessation on pain and disability in patients with painful spinal disorders. METHODS: We examined a prospectively maintained database of records for 5333 patients with axial or radicular pain from a spinal disorder with regard to smoking history and the patient assessment of pain on four visual analog scales during the course of care. Confounding factors, including secondary gain, sex, age, and body mass index, were also examined. The mean duration of follow-up was eight months. Multivariate statistical analysis was performed with variables including smoking status, secondary gain status, sex, depression, and age as predictors of pain and disability. RESULTS: Compared with patients who had never smoked, patients who were current smokers reported significantly greater pain in all visual analog scale pain ratings (p < 0.001). The mean improvement in reported pain over the course of care was significantly different between nonsmokers and current smokers (p <0.001). Compared with patients who had continued to smoke, those who had quit smoking during the course of care reported significantly greater improvement in pain in visual analog scale pain ratings for worst (p = 0.013), current (p < 0.05), and average weekly pain (p = 0.024). The mean improvement in the visual analog scale pain ratings was clinically important in patients in all three groups of nonsmokers. As a group, those who had continued smoking during treatment had no clinically important improvement in reported pain. CONCLUSIONS: Given a strong association between improved patient-reported pain and smoking cessation, this study supports the need for smoking cessation programs for patients with a painful spinal disorder. PMID- 23095840 TI - A UML profile for the OBO relation ontology. AB - BACKGROUND: Ontologies have increasingly been used in the biomedical domain, which has prompted the emergence of different initiatives to facilitate their development and integration. The Open Biological and Biomedical Ontologies (OBO) Foundry consortium provides a repository of life-science ontologies, which are developed according to a set of shared principles. This consortium has developed an ontology called OBO Relation Ontology aiming at standardizing the different types of biological entity classes and associated relationships. Since ontologies are primarily intended to be used by humans, the use of graphical notations for ontology development facilitates the capture, comprehension and communication of knowledge between its users. However, OBO Foundry ontologies are captured and represented basically using text-based notations. The Unified Modeling Language (UML) provides a standard and widely-used graphical notation for modeling computer systems. UML provides a well-defined set of modeling elements, which can be extended using a built-in extension mechanism named Profile. Thus, this work aims at developing a UML profile for the OBO Relation Ontology to provide a domain-specific set of modeling elements that can be used to create standard UML based ontologies in the biomedical domain. PMID- 23095841 TI - Prevalence of and factors associated with chronic kidney disease (CKD) in Japanese subjects without notable chronic diseases, undergoing an annual health checkup. AB - BACKGROUND: The prevalence of chronic kidney disease (CKD) is increasing dramatically. The aim of the present study is to explore the prevalence of and the factors associated with CKD in subjects without notable chronic disease. METHODS: In a cross-sectional study, we analyzed the annual health checkup data of 39,211 residents (11,636 males and 27,575 females) aged 40-74 years (58.6 +/- 8.6 years) without notable chronic diseases, who underwent a health checkup at the Public Health Centers of Osaka city. CKD was defined as those with an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m2 and/or urinary protein of (+) or more. RESULTS: The overall prevalence of CKD was 20.5%, and increased remarkably with age. Multivariate logistic regression analysis demonstrated that male gender (OR: 0.83, p<0.0001), age of 50-59 years (2.92, p<0.0001), age of 60-74 years (4.92, p<0.0001), the presence of diabetes (0.80, p=0.0307), dyslipidemia (1.21, p=0.0138), obesity (1.23, p<0.0001), hyperuricemia (2.63, p<0.0001) and a history of cardiovascular disease (1.26, p=0.0135) were significant factors that were independently associated with CKD. CONCLUSIONS: In urban subjects without notable chronic disease, the prevalence of CKD was 20.5%. Several metabolic abnormalities, i.e., dyslipidemia and hyperuricemia, were significantly associated with CKD. PMID- 23095842 TI - [Social environmental risk factors and mental disorders: insights into underlying neural mechanisms drawing on the example of urbanicity]. AB - The importance of social environmental factors for mental disorders is well known; nonetheless explanations of the underlying associations are still incomplete. For example this holds true for the schizophrenia risk factor urban upbringing (early urbanicity), which puzzled researchers for a long time. This article reports on recently identified neural correlates of this factor in the context of social stress processing. Drawing on this example, it is demonstrated how the identification of such correlates can contribute to the etiological understanding of mental disorders. While including genetic risk mechanisms and gene-environment interactions, a theoretical model is specified that postulates changes in the perigenual anterior cingulate cortex (pACC) and a heightened sensitivity towards social stressors as the relevant link between risk of schizophrenia and early urbanicity. PMID- 23095846 TI - Endoneurial fibroblast-like cells. AB - Endoneurial fibroblast-like cells (EFLCs) have been described for more than 60 years, but the embryology, functions, and pathology of these cells are not well defined. Several hypotheses of their origin have been proposed. A previous study suggesting that they were of neural crest origin is supported by our data in humans. This lineage might account for EFLCs having multiple biologic functions and involvement in pathological processes. Here, we review what is known about the origin; functions in collagen synthesis, phagocytosis, inflammatory responses, and immune surveillance; and the pathological alterations of EFLCs based on the literature and on our personal observations. PMID- 23095843 TI - [Depression and neurological diseases]. AB - In many neurological diseases a depressive syndrome is a characteristic sign of the primary disease or is an important comorbidity. Post-stroke depression, for example, is a common and relevant complication following ischemic brain infarction. Approximately 4 out of every 10 stroke patients develop depressive disorders in the course of the disease which have a disadvantageous effect on the course and the prognosis. On the other hand depression is also a risk factor for certain neurological diseases as was recently demonstrated in a meta-analysis of prospective cohort studies which revealed a much higher stroke risk for depressive patients. Furthermore, depression plays an important role in other neurological diseases with respect to the course and quality of life, such as Parkinson's disease, multiple sclerosis and epilepsy. This article gives a review of the most important epidemiological, pathophysiological and therapeutic aspects of depressive disorders as a comorbidity of neurological diseases and as a risk factor for neurological diseases. PMID- 23095847 TI - Differential effects of FK506 on structural and functional axonal deficits after diffuse brain injury in the immature rat. AB - Diffuse axonal injury is a major component of traumatic brain injury in children and correlates with long-term cognitive impairment. Traumatic brain injury in adult rodents has been linked to a decrease in compound action potential (CAP) in the corpus callosum, but information on trauma-associated diffuse axonal injury in immature rodents is limited. We investigated the effects of closed head injury on CAP in the corpus callosum of 17-day-old rats. The injury resulted in CAP deficits of both myelinated and unmyelinated fibers in the corpus callosum between 1 and 14 days postinjury (dpi). These deficits were accompanied by intra axonal dephosphorylation of the 200-kDa neurofilament subunit (NF200) at 1 and 3 dpi, a decrease in total NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi. Although total phosphatase activity decreased at 1 dpi, calcineurin activity was unchanged. The calcineurin inhibitor, FK506, significantly attenuated the injury induced NF200 dephosphorylation of NF200 at 3 dpi and axonal degeneration at 3 and 7 dpi but did not affect the decrease in NF200 protein levels or impaired axonal transport. FK506 had no effect on CAP deficits at 3 dpi but exacerbated the deficit in only the myelinated fibers at 7 dpi. Thus, in contrast to adult animals, FK506 treatment did not improve axonal function in brain-injured immature animals, suggesting that calcineurin may not contribute to impaired axonal function. PMID- 23095848 TI - Reducing available soluble beta-amyloid prevents progression of cerebral amyloid angiopathy in transgenic mice. AB - Cerebral amyloid angiopathy (CAA), the accumulation of beta-amyloid (Abeta) in the walls of leptomeningeal and cortical blood vessels of the brain, is a major cause of intracerebral hemorrhage and cognitive impairment and is commonly associated with Alzheimer disease. The progression of CAA, as measured in transgenic mice by longitudinal imaging with multiphoton microscopy, occurs in a predictable linear manner. The dynamics of Abeta deposition in and clearance from vascular walls and their relationship to the concentration of Abeta in the brain are poorly understood. We manipulated Abeta levels in the brain using 2 approaches: peripheral clearance via administration of the amyloid binding "peripheral sink" protein gelsolin and direct inhibition of its formation via administration of LY-411575, a small-molecule gamma-secretase inhibitor. We found that gelsolin and LY-411575 both reduced the rate of CAA progression in Tg2576 mice from untreated rates of 0.58% +/- 0.15% and 0.52% +/- 0.09% to 0.11% +/- 0.18% (p = 0.04) and -0.17% +/- 0.09% (p < 0.001) of affected vessel per day, respectively, in the absence of an immune response. The progression of CAA was also halted when gelsolin was combined with LY-411575 (-0.004% +/- 0.10%, p < 0.003). These data suggest that CAA progression can be prevented with non-immune approaches that may reduce the availability of soluble Abeta but without evidence of substantial amyloid clearance from vessels. PMID- 23095851 TI - Stroke and transient ischemic attack incidence rate in Spain: the IBERICTUS study. AB - BACKGROUND: In Spain, stroke is a major public health concern, but large population-based studies are scarce and date from the 1990s. We estimated the incidence and in-hospital mortality of stroke through a multicentered population based stroke register in 5 geographical areas of Spain, i.e. Lugo, Almeria, Segovia, Talavera de la Reina and Mallorca, representing north, south, central (*2) and Mediterranean areas of Spain, respectively, the aim and novelty being that all methodologies were standardized, and diagnoses were verified by a neurologist using neuroimaging techniques. METHODS: The register identified subjects >17 years of age who suffered a first-ever stroke or transient ischemic attack (TIA) between 1 January and 31 December 2006. Stroke and TIA were defined according to the WHO criteria. The Lausanne Stroke Registry definitions were used to classify ischemic stroke subtypes, as follows: (1) large-artery atherosclerosis (LAA); (2) cardioembolism (CE); (3) lacunar stroke or small artery occlusion (SAO); (4) stroke of other infrequent cause (SIC), and (5) stroke of undetermined cause (UND). We used several complementary data sources such as hospital discharge registers, emergency room registers and primary care surveillance systems. RESULTS: In the 1-year study period, we identified 2,700 first-ever cerebrovascular episodes (53% men; 2,257 strokes + 443 TIA episodes). Brain CT in the acute stage was performed in 99% of cases. Of a total of 2,257 stroke patients, 1,817 (81%) had cerebral infarction, 350 (16%) had intracerebral hemorrhage, 59 (3%) had subarachnoid hemorrhage (SAH) and 31 (1%) had unclassifiable stroke. The overall unadjusted annual incidence for all cerebrovascular events was 187 per 100,000 [95% confidence interval (CI) 180-194; incidence for men: 202, 95% CI 189-210; incidence for women: 187, 95% CI 180 194]. The subtype of ischemic stroke could be determined in 1,779 patients and was classified as LAA in 624 (35%), CE in 352 (20%), SAO in 316 (18%), SIC in 56 (3%) and UND in 431 (24%). The incidence rates per 100,000 (95% CI) standardized to the 2006 European population were as follows: all cerebrovascular events, 176 (169-182); all stroke (non-TIA), 147 (140-153); TIA, 29 (26-32); ischemic stroke, 118 (112-123); intracerebral hemorrhage, 23 (21-26), and SAH, 4.2 (3.1-5.2). Incidence rates clearly increased with age in both genders, with a peak at or above 85 years of age. The in-hospital mortality was 14%. CONCLUSIONS: Our results show that the incidence of stroke and TIA in Spain is moderate compared to other Western and European countries. However, it is expected that these figures will change due to progressively aging populations. PMID- 23095849 TI - Hippocampal proNGF signaling pathways and beta-amyloid levels in mild cognitive impairment and Alzheimer disease. AB - Hippocampal precursor of nerve growth factor (proNGF)/NGF signaling occurs in conjunction with beta-amyloid (Abeta) accumulations in Alzheimer disease (AD). To assess the involvement of this pathway in AD progression, we quantified these proteins and their downstream pathway activators in postmortem tissues from the brains of subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD using immunoblotting and ELISA. Hippocampal proNGF was significantly greater in AD cases compared with those in NCI and MCI cases. TrkA was significantly reduced in MCI compared with those in NCI and AD, whereas p75 neurotrophin receptor, sortilin, and neurotrophin receptor homolog 2 remained stable. Akt decreased from NCI to MCI to AD, whereas phospho-Akt and phospho-Akt to-Akt ratio were elevated in AD compared with those in MCI and NCI. No differences were found in phospho-Erk, Erk, or their ratio across groups. Although c-jun kinase (JNK) remained stable across groups, phospho-JNK and the phospho-JNK-to-JNK ratio increased significantly in AD compared with those in NCI and MCI. Expression levels of Abeta(1-40), Abeta(1-42), and Abeta(40/42) ratio were stable. Statistical analysis revealed a strong positive correlation between proNGF and phospho-JNK, although only proNGF was negatively correlated with cognitive function and only TrkA was negatively associated with pathologic criteria. These findings suggest that alterations in the hippocampal NGF signaling pathway in MCI and AD favor proNGF-mediated proapoptotic pathways, and that this is independent of Abeta accumulation during AD progression. PMID- 23095852 TI - Utility of capture-recapture methodology to assess completeness of amyotrophic lateral sclerosis case ascertainment. AB - BACKGROUND: With the establishment of a national amyotrophic lateral sclerosis (ALS) registry in the United States, methods are needed to ascertain the completeness of case ascertainment, especially in view of the proposal to rely largely on existing data sources. METHODS: Data about ALS patients residing in the 5-county metropolitan Atlanta area (within the State of Georgia) from 2001 to 2005 were categorized according to their source--ALS Association, clinical (Emory Healthcare, community neurologist, Veterans Health Administration, Veterans Benefits Administration), Medicare and death certificates. ALS diagnoses were verified using chart review. Capture-recapture analyses were carried out using log-linear modeling, stratified by age and race. RESULTS: The final model (based on 798 cases), which included the 4 main sources and 3 two-way interaction terms, yielded an estimated total population of 880 (95% CI 816-965), indicating that the combination of case-finding methods identified about 90.7% of cases. The estimated 5-year period prevalence is 38.5/100,000 (95% CI 35.66-42.19). CONCLUSION: This study highlights gaps in data based on existing data sources and illustrates a method for combining data from multiple sources to help facilitate the successful establishment of a US national ALS registry. PMID- 23095854 TI - Effects of physical activity on the quality of life in taiwanese lung cancer patients receiving active treatment or off treatment. AB - BACKGROUND: Lung cancer is the leading cause of cancer deaths in the world. Physical activity can enhance the quality of life (QOL) of cancer patients. However, the best timing according to cancer therapy to implement physical activities for lung cancer patients is not yet clear. OBJECTIVE: The purpose of our study was to examine the relationship between physical activity and QOL in different cancer-treatment periods among lung cancer patients. METHODS: This study used a cross-sectional design. Instruments included the Functional Assessment of Cancer Therapy-Lung Cancer and the Godin Leisure-Time Exercise Questionnaire. RESULTS: In total, 185 patients participated in this study, and results showed that only 25% of participants achieved recommended physical activity guidelines. Of all patients, 50.3% engaged in light physical activity, such as walking. During active-treatment periods, lung cancer patients who engaged in light or moderate activity had significantly higher scores for the overall QOL than did those who were completely sedentary. However, during off treatment periods, there were no significant differences in the overall QOL with different activity levels. CONCLUSIONS: The QOL may be improved by engaging in light or moderate physical activity during active-treatment periods among lung cancer patients. IMPLICATIONS FOR PRACTICE: It is important for healthcare providers to consider promoting physical activity based on different cancer treatments to improve the QOL of Taiwanese lung cancer patients. PMID- 23095853 TI - Connexin mimetic peptides inhibit Cx43 hemichannel opening triggered by voltage and intracellular Ca2+ elevation. AB - Connexin mimetic peptides (CxMPs), such as Gap26 and Gap27, are known as inhibitors of gap junction channels but evidence is accruing that these peptides also inhibit unapposed/non-junctional hemichannels (HCs) residing in the plasma membrane. We used voltage clamp studies to investigate the effect of Gap26/27 at the single channel level. Such an approach allows unequivocal identification of HC currents by their single channel conductance that is typically ~220 pS for Cx43. In HeLa cells stably transfected with Cx43 (HeLa-Cx43), Gap26/27 peptides inhibited Cx43 HC unitary currents over minutes and increased the voltage threshold for HC opening. By contrast, an elevation of intracellular calcium ([Ca(2+)](i)) to 200-500 nM potentiated the unitary HC current activity and lowered the voltage threshold for HC opening. Interestingly, Gap26/27 inhibited the Ca(2+)-potentiated HC currents and prevented lowering of the voltage threshold for HC opening. Experiments on isolated pig ventricular cardiomyocytes, which display strong endogenous Cx43 expression, demonstrated voltage-activated unitary currents with biophysical properties of Cx43 HCs that were inhibited by small interfering RNA targeting Cx43. As observed in HeLa-Cx43 cells, HC current activity in ventricular cardiomyocytes was potentiated by [Ca(2+)](i) elevation to 500 nM and was inhibited by Gap26/27. Our results indicate that under pathological conditions, when [Ca(2+)](i) is elevated, Cx43 HC opening is promoted in cardiomyocytes and CxMPs counteract this effect. PMID- 23095855 TI - Mediating effects of sense of coherence on family caregivers' depressive distress while caring for terminally ill cancer patients. AB - BACKGROUND: The stress and coping theory suggests that the impact of caregiving on caregivers' life depends more on personal psychological resources (ie, sense of coherence [SOC]) than on objective caregiving demands or social resources. However, SOC's mediation roles in helping caregivers cope with the challenges of end-of-life care have never been explored. OBJECTIVE: The objective of this study was to evaluate the mediation effects of SOC on caregivers' depressive distress while providing end-of-life care. METHODS: The Center for Epidemiological Studies Depression Scale scores from a convenience sample of 621 family caregivers were analyzed using structural equation modeling. We used the Sobel test to verify the significance of SOC's mediation effects on the relationships between identified stressors (objective caregiving demands, patient symptom distress), appraisals (confidence in caregiving, subjective caregiving burden), and caregivers' depressive distress. RESULTS: Sense of coherence mediated effects on relationships between Center for Epidemiological Studies-Depression Scale scores and subjective caregiving burden (P = .000), confidence in caregiving (P = .014), and objective caregiving demands (P = .000). Although the strength of SOC did not attenuate the impact of caregivers' perceived patient symptom distress on caregiver depressive distress, SOC mediated this effect secondarily through appraisals of subjective caregiving burden and confidence in caregiving. CONCLUSION: Personal psychological resources, as indicated by the strength of personal SOC, significantly mediated the effects of caregiving stressors, appraisals of caregiving confidence, and subjective caregiving burden on depressive distress of family caregivers while providing end-of-life care. IMPLICATIONS FOR PRACTICE: Nursing interventions to enhance caregivers' SOC may decrease their depressive distress through increasing their confidence in providing end-of-life care and lightening their perceived caregiving burden. PMID- 23095856 TI - Clinical presentation and ischemic zone on MRI in cancer patients with acute ischemic stroke. AB - AIMS: This study was conducted to evaluate the clinical and MRI profiles in acute cancer strokes, and to demonstrate our experience with thrombolytic therapy in cancer stroke patients. METHODS: We prospectively studied active cancer patients with acute ischemic stroke who underwent MRI within 48 h of the onset of symptoms. Patients were grouped based on the presence of conventional stroke mechanisms (CSM). Clinical characteristics and MRI profiles were evaluated. RESULTS: A total of 70 patients were finally included in this study. Patients without CSM were more frequently presented with encephalopathy than those with CSM (29.4 vs. 2.8%, p = 0.002). The diffusion-perfusion mismatch pattern was more prevalent in patients with CSM (21 patients, 58.3%) than in patients without CSM (8 patients, 23.5%). Patients who had a higher tertiles of D-dimer level were significantly less likely to have the diffusion-perfusion mismatch pattern (p = 0.015). Among patients who presented within 6 h of the onset of stroke, revascularization therapy was performed in 4 of 16 (25%) patients with CSM, but none of the patients without CSM. CONCLUSION: Based on the stroke mechanisms, the optimal strategy of thrombolytic therapy should be considered differently in cancer patients with acute ischemic stroke. PMID- 23095858 TI - Cor triatriatum sinister with an atrial septal defect: an unusual cause of Lutembacher physiology. PMID- 23095857 TI - Assessment of systematic effects of methodological characteristics on candidate genetic associations. AB - Candidate genetic association studies have been found to have a low replication rate in the past. Here, we aimed to assess whether aspects of reported methodological characteristics in genetic association studies may be related to the magnitude of effects observed. An observational, literature-based investigation of 511 case-control studies of genetic association studies indexed in 2007, was undertaken. Meta-regression analyses were used to assess the relationship between 23 reported methodological characteristics and the magnitude of genetic associations. The 511 studies had been conducted in 52 countries and were published in 220 journals (median impact factor 5.1). The multivariate meta regression model of methodological characteristics plus disease category accounted for 17.2 % of the between-study variance in the magnitude of the reported genetic associations. Our findings are consistent with the view that better conducted and better reported genetic association research may lead to less inflated results. PMID- 23095859 TI - MUMAL: multivariate analysis in shotgun proteomics using machine learning techniques. AB - BACKGROUND: The shotgun strategy (liquid chromatography coupled with tandem mass spectrometry) is widely applied for identification of proteins in complex mixtures. This method gives rise to thousands of spectra in a single run, which are interpreted by computational tools. Such tools normally use a protein database from which peptide sequences are extracted for matching with experimentally derived mass spectral data. After the database search, the correctness of obtained peptide-spectrum matches (PSMs) needs to be evaluated also by algorithms, as a manual curation of these huge datasets would be impractical. The target-decoy database strategy is largely used to perform spectrum evaluation. Nonetheless, this method has been applied without considering sensitivity, i.e., only error estimation is taken into account. A recently proposed method termed MUDE treats the target-decoy analysis as an optimization problem, where sensitivity is maximized. This method demonstrates a significant increase in the retrieved number of PSMs for a fixed error rate. However, the MUDE model is constructed in such a way that linear decision boundaries are established to separate correct from incorrect PSMs. Besides, the described heuristic for solving the optimization problem has to be executed many times to achieve a significant augmentation in sensitivity. RESULTS: Here, we propose a new method, termed MUMAL, for PSM assessment that is based on machine learning techniques. Our method can establish nonlinear decision boundaries, leading to a higher chance to retrieve more true positives. Furthermore, we need few iterations to achieve high sensitivities, strikingly shortening the running time of the whole process. Experiments show that our method achieves a considerably higher number of PSMs compared with standard tools such as MUDE, PeptideProphet, and typical target-decoy approaches. CONCLUSION: Our approach not only enhances the computational performance, and thus the turn around time of MS based experiments in proteomics, but also improves the information content with benefits of a higher proteome coverage. This improvement, for instance, increases the chance to identify important drug targets or biomarkers for drug development or molecular diagnostics. PMID- 23095860 TI - Metal-organic framework templated synthesis of Co3O4 nanoparticles for direct glucose and H2O2 detection. AB - Co(3)O(4) nanoparticles (NPs) with an average diameter of about 20 nm were synthesized by using MOFs as a template. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed to characterize the as prepared Co(3)O(4) NPs. Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) were used to confirm the structure of the Co(3)O(4) NPs. Then the Co(3)O(4) NPs were modified on a glassy carbon electrode (GCE) to obtain a non-enzymatic glucose and H(2)O(2) sensor. The NPs show electrocatalytic activity toward oxidation of glucose and H(2)O(2) in alkaline medium. For glucose detection, the developed sensor shows a short response time (less than 6 s), a high sensitivity of 520.7 MUA mM(-1) cm(-2), a detection limit of 0.13 MUM (S/N = 3), and good selectivity. The high concentration of NaCl does not poison the electrode. Its application for the detection of glucose in a human blood serum sample shows good agreement with the results obtained from the hospital. Furthermore, the proposed sensor was used for the detection of H(2)O(2). The results indicate that the detection limit and sensitivity for H(2)O(2) are 0.81 MUM and 107.4 MUA mM(-1) cm(-2), respectively. Determination of H(2)O(2) concentration in a disinfectant sample by the proposed biosensor also showed satisfactory result. The high sensitivity and low detection limit can be attributed to the excellent electrocatalytic performance of the as-prepared Co(3)O(4) NPs. These results demonstrate that the as-prepared Co(3)O(4) NPs have great potential applications in the development of sensors for enzyme-free detection of glucose and H(2)O(2). PMID- 23095862 TI - Standardization of dynamic contrast-enhanced ultrasound for the evaluation of antiangiogenic therapies: the French multicenter Support for Innovative and Expensive Techniques Study. AB - OBJECTIVES: The objectives of this study are to describe the standardization and dissemination of dynamic contrast-enhanced ultrasound (DCE-US) for the evaluation of antiangiogenic treatments in solid tumors across 19 oncology centers in France and to define a quality score to account for the variability of the evaluation criteria used to collect DCE-US data. MATERIALS AND METHODS: This prospective Soutien aux Techniques Innovantes Couteuses (Support for Innovative and Expensive Techniques) DCE-US study included patients with metastatic breast cancer, melanoma, colon cancer, gastrointestinal stromal tumors, renal cell carcinoma and patients with primary hepatocellular carcinoma tumors treated with antiangiogenic therapy. The DCE-US method was made available across 19 oncology centers in France. Overall, 2339 DCE-US examinations were performed by 65 radiologists in 539 patients.One target site per patient was studied. Standardized DCE-US examinations were performed before treatment (day 0) and at days 7, 15, 30, and 60. Dynamic contrast-enhanced ultrasound data were transferred from the different sites to the main study center at the Institut Gustave-Roussy for analysis. Quantitative analyses were performed with a mathematical model to determine 7 DCE US functional parameters using raw linear data. Radiologists had to evaluate 6 criteria that were potentially linked to the precision of the evaluation of these parameters: lesion size, target motion, loss of target, clear borders, total acquisition of wash-in, and vascular recognition imaging window adapted to the lesion size.Eighteen DCE-US examinations were randomly selected from the Soutien aux Techniques Innovantes Couteuses (Support for Innovative and Expensive Techniques) database. Each examination was quantified twice by 8 engineers/radiologists trained to evaluate the perfusion parameters. The intraobserver variability was estimated on the basis of differences between examinations performed by the same radiologist. The mean coefficient of variability associated with each quality criterion was estimated. The final quality score, ranging from 0 to 5, was defined according to the value of coefficient of variability for each criterion. RESULTS: A total of 2062 examinations were stored with raw linear data. Five criteria were found to have a major impact on quality: lesion size, motion, loss of target, borders, and total acquisition of wash-in. Only 3% of the examinations were of poor quality (quality of 0); quality was correlated with the radiologists' experience, such that it was significantly higher for radiologists who had performed more than 60 DCE-US examinations (P < 0.0001). CONCLUSIONS: The DCE-US methodology has been successfully provided to several centers across France together with strict rules for quality assessment. Only 3% of examinations carried out at these centers were considered not interpretable. PMID- 23095864 TI - Teaching tolerance: New approaches to enzyme replacement therapy for Pompe disease. AB - Babies born with Pompe disease require life-long treatment with enzyme replacement therapy (ERT). Despite the human origin of the therapy, recombinant human lysosomal acid alpha glucosidase (GAA, rhGAA), ERT unfortunately leads to the development of high titers of anti-rhGAA antibody, decreased effectiveness of ERT, and a fatal outcome for a significant number of children who have Pompe disease. The severity of disease, anti-drug antibody (ADA) development, and the consequences thereof are directly related to the degree of the enzyme deficiency. Babies born with a complete deficiency GAA are said to have cross-reactive immunologic material (CRIM)-negative Pompe disease and are highly likely to develop GAA ADA. Less frequently, GAA ADA develop in CRIM-positive individuals. Currently, GAA-ADA sero-positive babies are treated with a combination of immunosuppressive drugs to induce immunological tolerance to ERT, but the long term effect of these regimens is unknown. Alternative approaches that might redirect the immune response toward antigen-specific tolerance without immunosuppressive agents are needed. Methods leading to the induction of antigen specific regulatory T cells (Tregs), using peptides such as Tregitopes (T regulatory cell epitopes) are under consideration for the future treatment of CRIM-negative Pompe disease. Tregitopes are natural T cell epitopes derived from immunoglobulin G (IgG) that cause the expansion and activation of regulatory T cells (Treg). Teaching the immune system to tolerate GAA by co-delivering GAA with Tregitope peptides might dramatically improve the lives of CRIM-negative babies and could be applied to other enzyme replacement therapies to which ADA have been induced. PMID- 23095865 TI - Phacilitate Immunotherapy Leaders' Forum: How to tap into dilutive and non dilutive funding sources for immunotherapy projects--Barcelona, May 9-11, 2012. AB - How to tap into dilutive and non-dilutive funding sources for immunotherapy projects. PMID- 23095863 TI - Novel developments in the mechanisms of immune tolerance to allergens. AB - Allergy is the result of a disbalanced immune response to environmental innocuous antigens. Despite of accumulating data to define the pathomechanisms that take place in case of allergic diseases a detailed understanding of sequence of events that lead to the "normal" scenario of tolerance development are still under debate. Allergen-specific immunotherapy is the only causal treatment of allergic diseases. It modifies the immune response to a particular antigen to achieve tolerance against the symptom-causing allergen. This process is considered to mirror physiological peripheral tolerance induction. A number of immunological changes have been described to occur under allergen immunotherapy, including the generation of allergen-specific regulatory T cells, the induction of allergen specific IgG4, an increase in the Th1/Th2 cytokine ratio and decreased activation and function of effector cells such as mast cells, basophils and eosinophils. PMID- 23095866 TI - Maturation and upregulation of functions of murine dendritic cells (DCs) under the influence of purified aromatic-turmerone (AR). AB - The aim of this work is to evaluate the effects of purified aromatic-turmerone (ar-turmerione, AR) on murine dendritic cells (DCs). These impacts of AR on DCs from bone marrow derived DCs(BMDCs) were assessed with use of conventional scanning electron microscopy (SEM), fluorescence activated cell sorting (FACS), transmission electron microscopy (TEM), cytochemistry assay, FITC-dextran, bio assay and enzyme linked immunosorbent assay (ELISA). We found that AR induced phenotypic maturation as evidenced by increased expression of CD86, CD40, CD83, CD80 and major histocompatibility complex II (MHC II). The functional tests showed the activity of acidic phosphatase (ACP) inside the DCs were downregulated after treatment with AR (which occurs when phagocytosis of DCs were decreased). Finally, we proved that AR increased the production of IL-12 and tumor necrosis factor alpha (TNF-alpha). These data suggested that AR could promote phenotypic and functional maturation of DCs and this adjuvant-like activity may have potential therapeutic value. It is therefore concluded that AR could exert positive modulation on murine DCs. PMID- 23095867 TI - Cost-effectiveness of polysaccharide pneumococcal vaccination in people aged 65 and above in Poland. AB - INTRODUCTION: Invasive pneumococcal disease is associated with substantial morbidity, mortality and cost implications, which could be reduced by vaccination. AIM: To assess the cost-effectiveness of a 23-valent pneumococcal vaccine in the elderly (65 and older) in Poland. METHODS: A Markov model with a 1 year cycle length was developed, allowing up to 10 cohorts to enter the model over the lifetime horizon (35 years). In the base case, costs and benefits were assessed using the public health care payer (NFZ) perspective. The analysis included routine vaccination of all elderly and high-risk (HR) elderly versus no vaccination. The analysis assumed that the government would reimburse 50% of the vaccine price. Costs and benefits were discounted 5%, with costs expressed in 2009 Polish Zloty (PLN). Extensive sensitivity analyses were carried out. RESULTS: PPV23 vaccination targeting all elderly and HR elderly in Poland would avoid 8,935 pneumococcal infections, 2,542 hospitalisations, 671 deaths and 5,886 infections, 1,673 hospitalisations and 441 deaths respectively. The incremental cost per QALY gained would be PLN 3,382 in all elderly and PLN2,148 in HR elderly. CONCLUSION: Vaccinating adults 65 and older regardless of risk status with a 23-valent pneumococcal vaccine, is cost-effective, resulting in clinical and economic benefits including a non-negligible reduction of ambulatory doctor visits, hospitalizations and, deaths in Poland. PMID- 23095868 TI - Focusing on flu: Parent perspectives on school-located immunization programs for influenza vaccine. AB - School-located immunization programs (SLIP) will only be successful if parents consent to their children's participation. It is critical to understand parent perspectives regarding the factors that make them more or less likely to provide that consent. Organizations creating SLIPs will be able to capitalize on the aspects of SLIPs that parents appreciate, and address and correct issues that may give rise to parent concerns. This study involved five focus groups among the parents of school students in a large, urban school district. Findings highlight the broad range of concepts important to parents when considering participation in a SLIP. The safety and trust issues regarding vaccines in general that are so important to parents are also important to parents when considering participation in a SLIP. Effective communication strategies that include assurances regarding tracking of information and the competence and experience of immunizers will be helpful when addressing parents regarding SLIPs. In addition, parents were very cognizant of and positive regarding the public health benefits associated with SLIPs. Further study among larger populations of parents will further refine these ideas and aid in the development of successful influenza vaccine SLIPs that directly address and communicate with parents about the issues most important to them. PMID- 23095869 TI - HIV-1 Tat B-cell epitope vaccination was ineffectual in preventing viral rebound after ART cessation: HIV rebound with current ART appears to be due to infection with new endogenous founder virus and not to resurgence of pre-existing Tat dependent viremia. AB - CD4 T cell activation, essential for productive HIV infection, is provided initially in acute HIV infection by innate immune system secretion of activating cytokines. This cytokine response wanes with time and long-term activation of CD4 cells is maintained by HIV Tat protein secreted by HIV infected cells. Structured treatment interruption (STI) in well-controlled antiretroviral-treated (ART) subjects was explored a decade ago with a consensus finding that, in most subjects, HIV levels rebounded within four weeks to pre-ART levels. Based on these observations we initiated a randomized placebo-controlled study of a universal anti-Tat epitope vaccine, TUTI-16, to determine if immunological blockade of Tat would prevent HIV rebound after ART cessation. TUTI-16 immunization was safe, with predominantly mild local and systemic injection related adverse reactions. TUTI-16 was also immunogenic, with high levels of anti Tat antibodies compared with levels previously shown to reduce HIV replication in vivo. Of 21 subjects analyzed, 13 (62%) had HIV rebounds vs. 8 (38%) that remained aviremia, but this distribution was not vaccine-related (p = 0.61 log rank (Mantel-Cox) test), nullifying our hypothesis that anti-Tat antibodies would block rebound of Tat-dependent set-point HIV viremia after ART cessation. Our present findings are consistent with recent molecular findings that rebounding virus following STI is homogeneous and unrelated to previous circulating HIV, suggesting that rebounding HIV represents new founder virus, akin to the original acute HIV infection. We propose, therefore, that STI may have potential as a practical and economical approach to testing the safety and efficacy of candidate prophylactic HIV vaccines. PMID- 23095870 TI - Allergen immunotherapy for allergic respiratory diseases. AB - Allergen specific immunotherapy involves the repeated administration of allergen products in order to induce clinical and immunologic tolerance to the offending allergen. Immunotherapy is the only etiology-based treatment that has the potential for disease modification, as reflected by longterm remission following its discontinuation and possibly prevention of disease progression and onset of new allergic sensitizations. Whereas subcutaneous immunotherapy is of proven value in allergic rhinitis and asthma there is a risk of untoward side effects including rarely anaphylaxis. Recently the sublingual route has emerged as an effective and safer alternative. Whereas the efficacy of SLIT in seasonal allergy is now well-documented in adults and children, the available data for perennial allergies and asthma is less reliable and particularly lacking in children. This review evaluates the efficacy, safety and longterm benefits of SCIT and SLIT and highlights new findings regarding mechanisms, potential biomarkers and recent novel approaches for allergen immunotherapy. PMID- 23095871 TI - Vaccine for the mind: Immunity against self at the choroid plexus for erasing biochemical consequences of stressful episodes. AB - Stressful episodes or chronic stress can shape our brain, leaving behind their biochemical signature on the neural tissue parenchyma. Mitigating such detrimental effects on the central nervous system (CNS) would be advantageous for coping with stress. While the underlying mechanisms that facilitate this response are still a mystery, recent studies demonstrate that boosting specific components of circulating immunity can potentially enhance our ability to deal with stressors. Yet, the fact that the adaptive arm of the immune system is largely excluded from directly interacting with the healthy CNS raises a key question as to how these cells exert their beneficial effects. Boosting immunity against self by active immunization with CNS-derived peptides was shown to reduce anxiety levels and to modulate hippocampal plasticity. These effects correlate with increased immune surveillance at the borders of the brain; specifically, at the choroid plexus (CP), an epithelial layer that resides at the junction between the blood circulation, and the brain and plays a key role in maintaining and restoring brain homeostasis, regulating cerebrospinal-fluid (CSF) production and neurotropic factors composition. Here, we suggest that immunomodulation of this site by active immunization could protect against stressful episodes, thereby providing a therapeutic, as well as preventive, vaccine for the mind against stress and depression. PMID- 23095872 TI - Adjuvants for allergy vaccines. AB - Allergen-specific immunotherapy is currently performed via either the subcutaneous or sublingual routes as a treatment for type I (IgE dependent) allergies. Aluminum hydroxide or calcium phosphate are broadly used as adjuvants for subcutaneous allergy vaccines, whereas commercial sublingual vaccines rely upon high doses of aqueous allergen extracts in the absence of any immunopotentiator. Adjuvants to be included in the future in products for allergen specific immunotherapy should ideally enhance Th1 and CD4+ regulatory T cell responses. Imunomodulators impacting dendritic or T cell functions to induce IL10, IL12 and IFNgamma production are being investigated in preclinical allergy models. Such candidate adjuvants encompass synthetic or biological immunopotentiators such as glucocorticoids, 1,25-dihydroxy vitamin D3, selected probiotic strains (e.g., Lactobacillus and Bifidobacterium species) as well as TLR2 (Pam3CSK4), TLR4 (monophosphoryl lipid A, synthetic lipid A analogs) or TLR9 (CpGs) ligands. Furthermore, the use of vector systems such as mucoadhesive particules, virus-like particles or liposomes are being considered to enhance allergen uptake by tolerogenic antigen presenting cells present in mucosal tissues. PMID- 23095874 TI - Recombinant allergens: the present and the future. AB - Allergen specific immunotherapy (SIT) is the only known causative treatment of allergic diseases. Recombinant allergen-based vaccination strategies arose from a strong need to both to improve safety and enhance efficacy of SIT. In addition, new vaccines can be effective in allergies including food allergy or atopic dermatitis, which poorly respond to the current treatment with allergen extracts. A number of successful clinical studies with both wild-type and hypoallergenic derivatives of recombinant allergens vaccines have been reported for the last decade. They showed high efficacy and safety profile as well as very strong modulation of T and B cell responses to specific allergens. PMID- 23095873 TI - New routes for allergen immunotherapy. AB - IgE-mediated allergy is a highly prevalent disease in the industrialized world. Allergen-specific immunotherapy (SIT) should be the preferred treatment, as it has long lasting protective effects and can stop the progression of the disease. However, few allergic patients choose to undergo SIT, due to the long treatment time and potential allergic adverse events. Since the beneficial effects of SIT are mediated by antigen presenting cells inducing Th1, Treg and antibody responses, whereas the adverse events are caused by mast cells and basophils, the therapeutic window of SIT may be widened by targeting tissues rich in antigen presenting cells. Lymph nodes and the epidermis contain high density of dendritic cells and low numbers of mast cells and basophils. The epidermis has the added benefit of not being vascularised thereby reducing the chances of anaphylactic shock due to leakage of allergen. Hence, both these tissues represent highly promising routes for SIT and are the focus of discussion in this review. PMID- 23095875 TI - Specific immunotherapy in grass pollen allergy. AB - Since its description by noon in 1911, desensitization, or allergen specific immunotherapy (SIT), has been largely used in respiratory allergic diseases treatment. It remains the only etiologic treatment for allergic diseases. The development of the sublingual route and new forms of medication, as an alternative to subcutaneous injection, has led to large scale clinical trials. Many of them had been performed with allergen tablets, particularly in the field of pollen allergy. These studies have confirmed that SIT is efficient in reducing all respiratory allergic symptoms. Data on long-term benefits and sustained efficacy after stopping treatment have also been published. These show an impact on natural history of allergic disease, in particular, a reduction in the risk of asthma in desensitized rhinitic subjects and in the acquisition of new sensitivities. The basic mechanisms of immunotherapy are becoming better understood and allow us to envisage improvements in this therapeutic method in the future. The sublingual route appears to be safer with a better safety profile. This may lead to an extension of allergen specific immunotherapy indications in patients with respiratory allergic diseases. PMID- 23095878 TI - Association between carotenoids and outcome of cervical intraepithelial neoplasia: a prospective cohort study. AB - BACKGROUND: It has been suggested that micronutrients such as alpha-tocopherol, retinol, lutein, cryptoxanthin, lycopene, and alpha- and beta-carotene may help in the prevention of cervical cancer. Our aim was to investigate whether serum concentrations and/or dietary intake of micronutrients influence the regression or progression of low-grade cervical abnormalities. METHODS: In a prospective cohort study of 391 patients with cervical intraepithelial neoplasia (CIN) grade 1-2 lesions, we measured serum micronutrient concentrations in addition to a self administered questionnaire about dietary intake. We evaluated the hazard ratio (HR) adjusted for CIN grade, human papillomavirus genotype, total energy intake and smoking status. RESULTS: In non-smoking regression subjects, regression was significantly associated with serum levels of zeaxanthin/lutein (HR 1.25, 0.78 2.01, p = 0.024). This benefit was abolished in current smokers. Regression was inhibited by high serum levels of alpha-tocopherol in smokers (p = 0.042). In progression subjects, a significant protective effect against progression to CIN3 was observed in individuals with a medium level of serum beta-carotene [HR 0.28, 95 % confidence interval (CI) 0.11-0.71, p = 0.007), although any protective effect from a higher level of serum beta-carotene was weaker or abolished (HR 0.52, 95 % CI 0.24-1.13, p = 0.098). Increasing beta-carotene intake did not show a protective effect (HR 2.30, 95 % CI 0.97-5.42, p = 0.058). CONCLUSIONS: Measurements of serum levels of carotenoids suggest that regression is modulated by smoking status. Maintaining a medium serum level of beta-carotene has a protective effect for progression; however, carotene intake is not correlated with serum levels of carotenoids. PMID- 23095879 TI - Combination of irinotecan (CPT-11) and nedaplatin (NDP) for recurrent patients with uterine cervical cancer. AB - BACKGROUND: The clinical activity of combination of irinotecan (CPT-11) and nedaplatin (NDP) for recurrent patients with uterine cervical cancer was evaluated retrospectively. METHODS: Intravenous CPT-11 was given at 60 mg/m(2) (days 1, 8, 15), followed by NDP 80 mg/m(2) (day 1), every 4 weeks. RESULTS: According to the medical records, 29 cases have received this regimen since 2000. Median age was 57 years (range, 29-80), and performance status (PS) of the patients was 18 cases with PS 0, 10 cases with PS 1, and 1 case with PS 2, respectively. Clinical stage was as follows: 3 cases of stage Ib1, 2 cases of Ib2, 2 cases of IIa, 10 cases of IIb, 8 cases of IIIb, and 4 cases of IVb. There were 27 cases of squamous cell carcinoma and 2 cases of adenocarcinoma. Concerning hematological toxicity of grade 3 or more, neutropenia, leukopenia, and febrile neutropenia were observed in 79.3 %, 96.6 %, and 13.8 % of cases, respectively. For nonhematological toxicity, nausea, anorexia, joint pain, and confusion were observed in only 1 case, respectively, and as a result, in 7 cases chemotherapy was not completed. Among 26 cases with clinically evaluable lesions, there were 7 complete responses, 3 partial responses, 7 stable disease, and 9 progressive disease; the clinical response rate was 38.5 %. Median progression free survival was 7 months (range, 0-38 months). CONCLUSION: The combination of CPT-11 and NDP seems to be active for patients with recurrent uterine cervical cancer. PMID- 23095880 TI - Early or continued osteoporosis treatment during nonvertebral fracture-healing: no harm done commentary on an article by Silvano Adami, MD, PhD, et al.: ''denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing. results from the FREEDOM trial''. PMID- 23095881 TI - CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. PMID- 23095882 TI - WNT4 and RSPO1 together are required for cell proliferation in the early mouse gonad. AB - The gonad arises from the thickening of the coelomic epithelium and then commits into the sex determination process. Testis differentiation is activated by the expression of the Y-linked gene Sry, which promotes cell proliferation and differentiation of Sertoli cells, the supporting cells of the testis. In absence of Sry (XX individuals), activation of WNT/CTNNB1 signalling, via the upregulation of Rspo1 and Wnt4, promotes ovarian differentiation. However, Rspo1 and Wnt4 are expressed in the early undifferentiated gonad of both sexes, and Axin2-lacZ, a reporter of canonical WNT/CTNNB1 signalling, is expressed in the coelomic region of the E11.5 gonadal primordium, suggesting a role of these factors in early gonadal development. Here, we show that simultaneous ablation of Rspo1 and Wnt4 impairs proliferation of the cells of the coelomic epithelium, reducing the number of progenitors of Sertoli cells in XY mutant gonads. As a consequence, in XY Wnt4(-/-); Rspo1(-/-) foetuses, this leads to the differentiation of a reduced number of Sertoli cells and the formation of a hypoplastic testis exhibiting few seminiferous tubules. Hence, this study identifies Rspo1 and Wnt4 as two new regulators of cell proliferation in the early gonad regardless of its sex, in addition to the specific role of these genes in ovarian differentiation. PMID- 23095883 TI - Retinoic acid signaling in Sertoli cells regulates organization of the blood testis barrier through cyclical changes in gene expression. AB - Mammalian spermatogenesis contributes a constant production of large numbers of spermatozoa, which is achieved by a cyclically regulated program known as the seminiferous epithelial cycle. Sertoli cells, functionally unique somatic cells, create a microenvironment to support the continuous differentiation of germ cells especially through the formation of a blood-testis barrier (BTB). The BTB is essential for maintaining homeostasis in seminiferous tubules and opens transiently at stages VII-VIII to ensure constant differentiation of spermatogenic cells. However, it is poorly understood how the dynamic organization of BTB is regulated. In our current study, we find that the overexpression of a dominant-negative form of RARalpha (dnRARalpha) in Sertoli cells disrupts the BTB at stages VII-XII and causes the large-scale apoptosis of differentiating germ cells. These abnormal events are found to be associated with cyclical gene expression changes in Sertoli cells, which can be represented by abnormal activation and repression of genes showing peaks of expression during stages I-VI and VII-XII, respectively. We find that one such gene, Ocln, encoding a tight junction component, partly contributes to the BTB disruption caused by dnRARalpha. Taken together, our data suggest that the cyclical activation of RA signaling in Sertoli cells during stages VII-XII contributes to a periodic organization of the BTB through changes in stage-dependent gene expression. PMID- 23095884 TI - A conserved function for Strabismus in establishing planar cell polarity in the ciliated ectoderm during cnidarian larval development. AB - Functional and morphological planar cell polarity (PCP) oriented along the oral aboral body axis is clearly evident in the ectoderm of torpedo-shaped planula larvae of hydrozoan cnidarians such as Clytia hemisphaerica. Ectodermal epithelial cells bear a single motile cilium the beating of which is coordinated between cells, causing directional swimming towards the blunt, aboral pole. We have characterised PCP during Clytia larval development and addressed its molecular basis. PCP is first detectable in ectodermal cells during gastrulation as coordinated basal body positioning, the ciliary root becoming consistently positioned on the oral side of the apical surface of the cell. At later stages, more pronounced structural polarity develops around the base of each cilium in relation to the cilia beating direction, including a characteristic asymmetric cortical actin organisation. Morpholino antisense oligonucleotide and mRNA injection studies showed that PCP development requires the Clytia orthologues of the core Fz-PCP pathway components Strabismus (CheStbm), Frizzled (CheFz1) and Dishevelled (CheDsh). Morpholinos targeting any of these components prevented ectodermal PCP, disrupted ciliogenesis and inhibited embryo elongation during gastrulation, which involves cell intercalation. We show that YFP-tagged CheStbm adopts a polarised intracellular distribution, localising preferentially to the aboral boundary of each cell, as has been demonstrated in Drosophila and some vertebrate PCP studies. Our findings in a cnidarian strongly suggest that the Fz PCP pathway is a highly conserved and evolutionary ancient metazoan feature that is probably widely responsible for oriented swimming and/or feeding in relation to body axis in the many ciliated larval types found throughout the animal kingdom. PMID- 23095885 TI - Cell cycle regulates cell type in the Arabidopsis sepal. AB - The formation of cellular patterns during development requires the coordination of cell division with cell identity specification. This coordination is essential in patterning the highly elongated giant cells, which are interspersed between small cells, in the outer epidermis of the Arabidopsis thaliana sepal. Giant cells undergo endocycles, replicating their DNA without dividing, whereas small cells divide mitotically. We show that distinct enhancers are expressed in giant cells and small cells, indicating that these cell types have different identities as well as different sizes. We find that members of the epidermal specification pathway, DEFECTIVE KERNEL1 (DEK1), MERISTEM LAYER1 (ATML1), Arabidopsis CRINKLY4 (ACR4) and HOMEODOMAIN GLABROUS11 (HDG11), control the identity of giant cells. Giant cell identity is established upstream of cell cycle regulation. Conversely, endoreduplication represses small cell identity. These results show not only that cell type affects cell cycle regulation, but also that changes in the cell cycle can regulate cell type. PMID- 23095886 TI - A segmentation clock operating in blastoderm and germband stages of Tribolium development. AB - In Drosophila, all segments form in the blastoderm where morphogen gradients spanning the entire anterior-posterior axis of the embryo provide positional information. However, in the beetle Tribolium castaneum and most other arthropods, a number of anterior segments form in the blastoderm, and the remaining segments form sequentially from a posterior growth zone during germband elongation. Recently, the cyclic nature of the pair-rule gene Tc-odd-skipped was demonstrated in the growth zone of Tribolium, indicating that a vertebrate-like segmentation clock is employed in the germband stage of its development. This suggests that two mechanisms might function in the same organism: a Drosophila like mechanism in the blastoderm, and a vertebrate-like mechanism in the germband. Here, we show that segmentation at both blastoderm and germband stages of Tribolium is based on a segmentation clock. Specifically, we show that the Tribolium primary pair-rule gene, Tc-even-skipped (Tc-eve), is expressed in waves propagating from the posterior pole and progressively slowing until they freeze into stripes; such dynamics are a hallmark of clock-based segmentation. Phase shifts between Tc-eve transcripts and protein confirm that these waves are due to expression dynamics. Moreover, by tracking cells in live embryos and by analyzing mitotic profiles, we found that neither cell movement nor oriented cell division could explain the observed wave dynamics of Tc-eve. These results pose intriguing evolutionary questions, as Drosophila and Tribolium segment their blastoderms using the same genes but different mechanisms. PMID- 23095887 TI - Twist1 mediates repression of chondrogenesis by beta-catenin to promote cranial bone progenitor specification. AB - The bones of the mammalian skull vault form through intramembranous ossification. Skull bones ossify directly, in a process regulated by beta-catenin, instead of passing through a cartilage intermediate. We tested whether beta-catenin is necessary for fate selection of intramembranous bone progenitors in the skull. Here, we show in mice that removal of beta-catenin from skull bone progenitors results in the near complete transformation of the skull bones to cartilage, whereas constitutive beta-catenin activation inhibits skull bone fate selection. beta-catenin directly activated Twist1 expression in skull progenitors, conditional Twist1 deletion partially phenocopied the absence of beta-catenin, and Twist1 deletion partially restored bone formation in the presence of constitutive beta-catenin activation. Finally, Twist1 bound robustly to the 3'UTR of Sox9, the central initiator of chondrogenesis, suggesting that Twist1 might directly repress cartilage formation through Sox9. These findings provide insight into how beta-catenin signaling via Twist1 actively suppresses the formation of cartilage and promotes intramembranous ossification in the skull. PMID- 23095888 TI - Frizzled 2 and frizzled 7 function redundantly in convergent extension and closure of the ventricular septum and palate: evidence for a network of interacting genes. AB - Frizzled (Fz) 2 and Fz7, together with Fz1, form a distinct subfamily within the Frizzled family of Wnt receptors. Using targeted gene deletion, we show that: Fz7(-/-) mice exhibit tail truncation and kinking with 100% penetrance and ventricular septal defects (VSDs) with ~15% penetrance; Fz2(+/-);Fz7(-/-) mice exhibit VSDs with ~50% penetrance and cleft palate with less than 10% penetrance; and Fz2(-/-);Fz7(-/-) mice exhibit convergent extension defects and mid gestational lethality with 100% penetrance. When Fz2 and/or Fz7 mutations are combined with mutations in Vangl2, Dvl3, Wnt3a, Wnt5a or Wnt11, an increased frequency of VSDs is observed with Dvl3, Wnt3a and Wnt11; an increased frequency of palate closure defects is observed with Vangl2; and early lethality and enhanced tail shortening are observed with Wnt5a. To assess the signaling pathways that underlie these and other Frizzled-mediated genetic interactions, we used transfected mammalian cells to analyze (1) canonical Wnt signaling induced by all pairwise combinations of the ten mouse Frizzleds and the 19 mouse Wnts and (2) localization of each Frizzled at cell-cell junctional complexes formed by mouse Celsr1, a likely indicator of competence for planar cell polarity signaling. These in vitro experiments indicate that Fz2 and Fz7 are competent to signal via the canonical pathway. Taken together, the data suggest that genetic interactions between Fz2, Fz7 and Vangl2, Dvl3 and Wnt genes reflect interactions among different signaling pathways in developmental processes that are highly sensitive to perturbations in Frizzled signaling. PMID- 23095889 TI - HIF1alpha is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. AB - Collagen production is fundamental for the ontogeny and the phylogeny of all multicellular organisms. It depends on hydroxylation of proline residues, a reaction that uses molecular oxygen as a substrate. This dependency is expected to limit collagen production to oxygenated cells. However, during embryogenesis, cells in different tissues that develop under low oxygen levels must produce this essential protein. In this study, using the growth plate of developing bones as a model system, we identify the transcription factor hypoxia-inducible factor 1 alpha (HIF1alpha) as a central component in a mechanism that underlies collagen hydroxylation and secretion by hypoxic cells. We show that Hif1a loss of function in growth plate chondrocytes arrests the secretion of extracellular matrix proteins, including collagen type II. Reduced collagen hydroxylation and endoplasmic reticulum stress induction in Hif1a-depleted cells suggests that HIF1alpha regulates collagen secretion by mediating its hydroxylation and consequently its folding. We demonstrate in vivo the ability of Hif1alpha to drive the transcription of collagen prolyl 4-hydroxylase, which catalyzes collagen hydroxylation. We also show that, concurrently, HIF1alpha maintains cellular levels of oxygen, most likely by controlling the expression of pyruvate dehydrogenase kinase 1, an inhibitor of the tricarboxylic acid cycle. Through this two-armed mechanism, HIF1alpha acts as a central regulator of collagen production that allows chondrocytes to maintain their function as professional secretory cells in the hypoxic growth plate. As hypoxic conditions occur also during pathological conditions such as cancer, our findings may promote the understanding not only of embryogenesis, but also of pathological processes. PMID- 23095890 TI - Autotaxin/Lpar3 signaling regulates Kupffer's vesicle formation and left-right asymmetry in zebrafish. AB - Left-right (L-R) patterning is essential for proper organ morphogenesis and function. Calcium fluxes in dorsal forerunner cells (DFCs) are known to regulate the formation of Kupffer's vesicle (KV), a central organ for establishing L-R asymmetry in zebrafish. Here, we identify the lipid mediator lysophosphatidic acid (LPA) as a regulator of L-R asymmetry in zebrafish embryos. LPA is produced by Autotaxin (Atx), a secreted lysophospholipase D, and triggers various cellular responses through activation of specific G protein-coupled receptors (Lpar1-6). Knockdown of Atx or LPA receptor 3 (Lpar3) by morpholino oligonucleotides perturbed asymmetric gene expression in lateral plate mesoderm and disrupted organ L-R asymmetries, whereas overexpression of lpar3 partially rescued those defects in both atx and lpar3 morphants. Similar defects were observed in embryos treated with the Atx inhibitor HA130 and the Lpar1-3 inhibitor Ki16425. Knockdown of either Atx or Lpar3 impaired calcium fluxes in DFCs during mid-epiboly stage and compromised DFC cohesive migration, KV formation and ciliogenesis. Application of LPA to DFCs rescued the calcium signal and laterality defects in atx morphants. This LPA-dependent L-R asymmetry is mediated via Wnt signaling, as shown by the accumulation of beta-catenin in nuclei at the dorsal side of both atx and lpar3 morphants. Our results suggest a major role for the Atx/Lpar3 signaling axis in regulating KV formation, ciliogenesis and L-R asymmetry via a Wnt-dependent pathway. PMID- 23095892 TI - A novel antibacterial compound from Siegesbeckia glabrescens. AB - The crude methanol extract of the dried aerial parts of Siegesbeckia glabrescens (Compositae) showed antibacterial activity against the foodborne pathogen Staphylococcus aureus. Bioactivity-guided separation led to the isolation of 3 (dodecanoyloxy)-2-(isobutyryloxy)-4-methylpentanoic acid from nature for the first time. The structure was determined by spectroscopic data analysis (UV, MS, and NMR). The minimal inhibitory concentration (MIC) of 3-(dodecanoyloxy)-2 (isobutyryloxy)-4-methylpentanoic acid against S. aureus was found to be 3.12 μg/mL. In addition, in a further antimicrobial activity assay against Gram positive (B. subtilis, E. faecalis, P. acnes, S. epidermidis, S. schleiferi subsp. coagulans, S. agalactiae and S. pyrogens), and Gram-negative bacteria (E. coli and P. aeruginosa), and yeast strains (C. alibicans and F. neoformans), the antimicrobial activity of the compound was found to be specific for Gram-positive bacteria. The MIC values of the compound for Gram-positive bacteria ranged from 3.12 to 25 mg/mL. Furthermore, it was found that the 2-(isobutyryloxy)-4 methylpentanoic acid substituent may operate as a key factor in the antibacterial activity of the compound, together with the laurate group. PMID- 23095893 TI - Development of new drugs for an old target: the penicillin binding proteins. AB - The widespread use of β-lactam antibiotics has led to the worldwide appearance of drug-resistant strains. Bacteria have developed resistance to β-lactams by two main mechanisms: the production of β-lactamases, sometimes accompanied by a decrease of outer membrane permeability, and the production of low-affinity, drug resistant Penicillin Binding Proteins (PBPs). PBPs remain attractive targets for developing new antibiotic agents because they catalyse the last steps of the biosynthesis of peptidoglycan, which is unique to bacteria, and lies outside the cytoplasmic membrane. Here we summarize the “current state of the art” of non-β-lactam inhibitors of PBPs, which have being developed in an attempt to counter the emergence of β lactam resistance. These molecules are not susceptible to hydrolysis by β lactamases and thus present a real alternative to β-lactams. We present transition state analogs such as boronic acids, which can covalently bind to the active serine residue in the catalytic site. Molecules containing ring structures different from the β-lactam-ring like lactivicin are able to acylate the active serine residue. High throughput screening methods, in combination with virtual screening methods and structure based design, have allowed the development of new molecules. Some of these novel inhibitors are active against major pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and thus open avenues new for the discovery of novel antibiotics. PMID- 23095891 TI - Endothelial deletion of murine Jag1 leads to valve calcification and congenital heart defects associated with Alagille syndrome. AB - The Notch signaling pathway is an important contributor to the development and homeostasis of the cardiovascular system. Not surprisingly, mutations in Notch receptors and ligands have been linked to a variety of hereditary diseases that impact both the heart and the vasculature. In particular, mutations in the gene encoding the human Notch ligand jagged 1 result in a multisystem autosomal dominant disorder called Alagille syndrome, which includes tetralogy of Fallot among its more severe cardiac pathologies. Jagged 1 is expressed throughout the developing embryo, particularly in endothelial cells. Here, we demonstrate that endothelial-specific deletion of Jag1 leads to cardiovascular defects in both embryonic and adult mice that are reminiscent of those in Alagille syndrome. Mutant mice display right ventricular hypertrophy, overriding aorta, ventricular septal defects, coronary vessel abnormalities and valve defects. Examination of mid-gestational embryos revealed that the loss of Jag1, similar to the loss of Notch1, disrupts endothelial-to-mesenchymal transition during endocardial cushion formation. Furthermore, adult mutant mice exhibit cardiac valve calcifications associated with abnormal matrix remodeling and induction of bone morphogenesis. This work shows that the endothelium is responsible for the wide spectrum of cardiac phenotypes displayed in Alagille Syndrome and it demonstrates a crucial role for Jag1 in valve morphogenesis. PMID- 23095894 TI - Aqueous synthesis of 1-H-2-substituted benzimidazoles via transition-metal-free intramolecular amination of aryl iodides. AB - A straightforward method has been developed for the synthesis of the benzimidazole ring system through a carbon-nitrogen cross-coupling reaction. In the presence of 2.0 equiv. of K(2)CO(3) in water at 100 °C for 30 h, the intramolecular cyclization of N-(2-iodoaryl)benzamidine provides benzimidazole derivatives in moderate to high yields. Remarkably, the procedure occurs exclusively in water and doesn’t require the use of any additional reagent/catalyst, rendering the methodology highly valuable from both environmental and economical points of view. PMID- 23095895 TI - Antioxidant, lipoxygenase and histone deacetylase inhibitory activities of Acridocarbus orientalis from Al Ain and Oman. AB - Acridocarpus orientalis (AO) is a traditional medicinal plant used for treatment of inflammatory diseases that may have potential in cancer treatment. In the present study, the aqueous ethanolic crude extract of Acridocarpus aerial parts obtained from Al Ain and Oman were evaluated for their antioxidant capability, polyphenolic content, anti-lipoxygenase and anti-histone deacetylase (HDAC) properties. The total antioxidant capacity was estimated by the FRAP, DPPH, ABTS and b-carotene bleaching assays. Acridocarpus-Al Ain exhibited the highest polyphenolic content (184.24 mg gallic acid/g) and the best antioxidant activity (1.1, 1.04, 1.14 mmol ascorbic acid equivalent/g in the FRAP, ABTS and DPPH assays, respectively). Additionally, the same extract showed significant anti inflammatory properties via lipoxygenase (LOX) inhibitory activity (IC(50) = 50.58 µg/mL). Acridocarpus-Al Ain also showed the strongest histone deacetylase (HDACs) inhibitory activity (IC(50) = 93.28 µg/mL). The results reported here suggest that there was a significant influence of location and the plant may be considered a good source of compounds with antioxidant, anti-LOX and HDAC properties for therapeutic, nutraceutical and functional food applications. PMID- 23095896 TI - Chemical synthesis, backbone cyclization and oxidative folding of cystine-knot peptides: promising scaffolds for applications in drug design. AB - Cystine-knot peptides display exceptional structural, thermal, and biological stability. Their eponymous motif consists of six cysteine residues that form three disulfide bonds, resulting in a notably rigid structural core. Since they highly tolerate either rational or combinatorial changes in their primary structure, cystine knots are considered to be promising frameworks for the development of peptide-based pharmaceuticals. Despite their relatively small size (two to three dozens amino acid residues), the chemical synthesis route is challenging since it involves critical steps such as head-to-tail cyclization and oxidative folding towards the respective bioactive isomer. Herein we describe the topology of cystine-knot peptides, their synthetic availability and briefly discuss potential applications of engineered variants in diagnostics and therapy. PMID- 23095897 TI - A minor dihydropyran apocarotenoid from mated cultures of Blakeslea trispora. AB - The heterocyclic C15 apocarotenoid 1 was isolated from mated cultures of the strains F986 (+) and F921 (−) of Blakeslea trispora. This new compound formed during sexual interaction is a minor constituent of the culture media and its structure was elucidated by spectroscopic data, including 2D-NMR. A plausible biosynthetic pathway involving a double degradation of β-carotene, followed by several oxidations of the resulting monocyclofarnesane C15 fragment is proposed. PMID- 23095898 TI - Antioxidant Activity and phytochemical composition of the leaves of Solanum guaraniticum A. St.-Hil. AB - Solanum guaraniticum is a shrub belonging to the Solanaceae family popularly known in Brazil as jurubeba or false-jurubeba. The aim of this study was to evaluate the antioxidant activity of crude extract and chloroform, ethyl acetate and n-butanol fractions from its leaves, verifying the ability to remove reactive species and identify and quantify phenolic compounds. The ethyl acetate fraction showed the highest amount of total polyphenols (546.57 +/- 2.35 mg gallic acid equivalent/g) and the lowest IC(50) (9.11 +/- 0.75 ug/mL) by the DPPH method. Furthermore, the chloroform fraction presented the highest content of flavonoids (75.73 +/- 0.34 mg rutin equivalents/g), tannins (56.03 +/- 0.68 mg catechin equivalents/g) and alkaloids (10.79 +/- 0.06 mg/g). This fraction was effective in the scavenging of reactive species by 2',7'-dichlorofluorescein diacetate assay, in addition to completely reducing protein carbonyl content and reducing lipid peroxidation at basal levels even at low concentrations. Chlorogenic, caffeic and rosmarinic acids were identified and quantified by HPLC/DAD. These results show that S. guaraniticum is rich in phenolic compounds and has potential as an antioxidant. PMID- 23095899 TI - Improving the fermentation production of the individual key triterpene ganoderic acid me by the medicinal fungus Ganoderma lucidum in submerged culture. AB - Enhanced ganoderic acid Me (GA-Me, an important anti-tumor triterpene) yield was attained with the medicinal fungus Ganoderma lucidum using response surface methodology (RSM). Interactions were studied with three variables, viz. glucose, peptone and culture time using a Central Composite Design (CCD). The CCD contains a total of 20 experiments with the first 14 experiments organized in a fractional factorial design, with the experimental trails from 15 to 20 involving the replications of the central points. A polynomial model, describing the relationships between the yield of GA-Me and the three factors in a second-order equation, was developed. The model predicted the maximum GA-Me yield of 11.9 mg·L−1 for glucose, peptone, culture time values of 44.4 g·L−1, 5.0 g·L−1, 437.1 h, respectively, and a maximum GA Me yield of 12.4 mg·L−1 was obtained in the validation experiment, which represented a 129.6% increase in titre compared to that of the non optimized conditions. In addition, 11.4 mg·L−1 of GA-Me was obtained in a 30-L agitated fermenter under the optimized conditions, suggesting the submerged culture conditions optimized in the present study were also suitable for GA-Me production on a large scale. PMID- 23095901 TI - Oxidation of dibenzothiophene catalyzed by [C8H17N(CH3)3]3H3V10O28 using molecular oxygen as oxidant. AB - An isopolyoxovanadate catalyst [C(8)H(17)N(CH(3))(3)](3)H(3)V(10)O(28) shows high catalytic activity in oxidation of dibenzothiophene (DBT) to its corresponding sulfone using molecular oxygen as oxidant under mild reaction conditions. This is potentially a promising approach to achieve ultradeep desulfurization of fuels (e.g. diesel) because the sulfones can be more conveniently removed from the fuels by either extraction or selective adsorption. PMID- 23095900 TI - Purinergic signaling, dyslipidemia and inflammatory disease. AB - Metabolic syndrome is a compound obesity disorder, wherein the abnormal metabolism of glucose and lipid is associated with the development of chronic inflammatory diseases. The prevalence of this disease is increasing in the developed world, but the causative linkage between these metabolic disorders has remained obscure. Metabolic disease may be associated with chronic nucleotide secretion, purinergic signaling and activation of inflammatory pathways. Purinergic signaling has been implicated in impaired glucose metabolism and inflammatory disease and may contribute to dyslipidemia. Our research shows that purinergic signaling disrupts hepatic lipoprotein metabolism by blocking insulin receptor signaling and by activating cellular autophagic pathways. Chronic stimulation of purinergic signaling may therefore be causative to glucose and lipid metabolic disorders and associated with the development of cardiovascular disease. PMID- 23095902 TI - Action imagery combined with action observation activates more corticomotor regions than action observation alone. AB - BACKGROUND AND PURPOSE: Both action observation (AO) and action imagery have been proposed as therapeutic options for stroke rehabilitation. Currently, it is not clear to what extent their underlying neuronal mechanisms differ from each other and whether one of these therapeutic options might be preferable for this purpose. METHODS: Twenty-six neurologically healthy subjects were investigated using functional magnetic resonance imaging during AO alone and during AO with additional action imagery of video clips showing simple, object-related hand actions. RESULTS: The blood oxygenation level dependent (BOLD) signal induced by AO increased in a bihemispheric, symmetrical network of areas including the occipital, superior, and inferior parietal cortex, dorsal and ventral premotor regions, and the prefrontal cortex. The addition of imagery to the AO elicited additional activation in both cerebellar hemispheres, caudate nucleus, ventral and dorsal premotor cortex, inferior parietal cortex, and the supplementary motor area. DISCUSSION AND CONCLUSION: These data reveal more profound activations of the motor system during AO in conjunction with imagery than during AO alone. These results may have important implications for neurorehabilitation and motor learning. PMID- 23095903 TI - Deficits in intersegmental trunk coordination during walking are related to clinical balance and gait function in chronic stroke. AB - BACKGROUND AND PURPOSE: Decreased walking speed after stroke may be related to changes in temporal and distance gait factors, endurance, and balance. Functional gait deficits may also be related to changes in coordination, specifically between transverse (yaw) plane trunk movements. Our aim was to determine the relationship between intersegmental coordination during gait and functional gait and balance deficits in individuals with stroke. METHODS: Eleven individuals with chronic stroke and 11 age-matched subjects without disability participated in 2 sessions. In Session 1, clinical evaluations of trunk/limb impairment (Chedoke McMaster Stroke Assessment), functional gait (Functional Gait Assessment), and balance (BesTest) were performed. In Session 2, gait kinematics during eight 30 second walking trials on a self-paced treadmill at 2 speeds (comfortable and equivalent) were recorded. Equivalence of walking speeds was obtained by asking subjects without disability to walk approximately 20% slower and subjects with stroke to walk approximately 20% faster than their comfortable speed. Thorax and pelvis 3-dimensional angular ranges of motion (ROMs) and intersegmental coordination using the continuous relative phase were analyzed. RESULTS: Comfortable walking speed was slower in subjects with stroke (0.78 m/s) than in subjects without disability (1.22 m/s), despite matched cadences. At both comfortable and equivalent walking speeds (0.97-0.98 m/s), participants with stroke used more thoracic ROM than pelvic transverse ROM in comparison with subjects without disability. Transverse thorax-pelvis coordination was similar between groups when walking speeds were equivalent, but there was more in-phase coordination in participants with stroke walking at their comfortable, slower speed. In subjects with stroke, thoracic ROM and continuous relative phase were correlated with several clinical functional gait and balance measures. DISCUSSION AND CONCLUSION: Changes in segmental transverse ROM and coordination were associated with poor gait and with balance abilities in individuals with stroke. Interventions focusing on recovery of these movement characteristics may lead to better clinical outcomes. PMID- 23095905 TI - Comparison of 454 pyrosequencing methods for characterizing the major histocompatibility complex of nonmodel species and the advantages of ultra deep coverage. AB - Characterization and population genetic analysis of multilocus genes, such as those found in the major histocompatibility complex (MHC) is challenging in nonmodel vertebrates. The traditional method of extensive cloning and Sanger sequencing is costly and time-intensive and indirect methods of assessment often underestimate total variation. Here, we explored the suitability of 454 pyrosequencing for characterizing multilocus genes for use in population genetic studies. We compared two sample tagging protocols and two bioinformatic procedures for 454 sequencing through characterization of a 185-bp fragment of MHC DRB exon 2 in wolverines (Gulo gulo) and further compared the results with those from cloning and Sanger sequencing. We found 10 putative DRB alleles in the 88 individuals screened with between two and four alleles per individual, suggesting amplification of a duplicated DRB gene. In addition to the putative alleles, all individuals possessed an easily identifiable pseudogene. In our system, sequence variants with a frequency below 6% in an individual sample were usually artefacts. However, we found that sample preparation and data processing procedures can greatly affect variant frequencies in addition to the complexity of the multilocus system. Therefore, we recommend determining a per-amplicon variant frequency threshold for each unique system. The extremely deep coverage obtained in our study (approximately 5000*) coupled with the semi-quantitative nature of pyrosequencing enabled us to assign all putative alleles to the two DRB loci, which is generally not possible using traditional methods. Our method of obtaining locus-specific MHC genotypes will enhance population genetic analyses and studies on disease susceptibility in nonmodel wildlife species. PMID- 23095906 TI - On proposing special issues for the Journal of Youth and Adolescence. PMID- 23095907 TI - Examining associations between race, urbanicity, and patterns of bullying involvement. AB - Research on the role of race and urbanicity in bullying involvement has been limited. The present study examined bullying involvement subgroups that relate to race, urbanicity, and the perceived reason for the bullying. Self-report data were collected from 10,254 middle school youth (49.8 % female; 62.4 % Caucasian, 19.0 % African American, and 5.6 % Hispanic) and latent class analyses were used to identify three subtypes of bullying involvement: low involvement (50 %), victim (31.3 %), and bully-victim (18.7 %). Irrespective of urbanicity (urban vs. non-urban), African American youth were more likely to be members of either the victim or bully-victim classes than the low involvement class. Further exploration of the community context suggested that urbanicity was associated with the increased likelihood of having been racially bullied. Urban bully victims were also more likely to have been bullied about money than non-urban bully-victims. Findings underscore the importance of addressing both race and urbanicity for culturally sensitive prevention programming. PMID- 23095908 TI - Bacterial contamination of amniotic membrane in a tissue bank from Iran. AB - Human Amniotic Membrane (AM) transplantation can promote tissue healing and reduce inflammation, tissue scarring and neovascularization. Homa Peyvand Tamin (HPT) tissue bank has focused on manufacturing human cell and tissue based products including AM. The purpose of this study is to evaluate and identify bacterial contamination of AMs that is produced by HPT for several ophthalmic applications. From July 2006 to April 2011, 122 placentas from cesarean sections were retrieved by HPT after obtaining informed consent from the donors. Besides testing donor's blood sample for viral markers, microbiological evaluation was performed pre and post processing. During tissue processing, decontamination was performed by an antibiotic cocktail including; Gentamicin, Ceftriaxone and Cloxacillin. Of 271 cesarean section AM donors who were screened as potential donors, 122 were accepted for processing and assessed for microbiological contamination. Donors' age were between 21 and 41 years (Mean = 27.61 +/- 0.24). More than 92% of mothers were in their first or second gravidity with full term pregnancies. The most prevalent organisms were Staphylococci species (72.53%). After processing, contamination rates markedly decreased by 84.62% (p value = 0.013). According to our results, most of bacterial contaminations were related to donation process and the contamination pattern suggests procurement team as a source. Therefore we recommend that regular training programs should be implemented by tissue banks for procurement staff. These programs should focus on improved donor screening and proper aseptic technique for tissue retrieval. We also suggest that tissue banks should periodically check the rate and types of tissue contaminations. These data help them to find system faults and to update processing methods. PMID- 23095909 TI - History of primary immunodeficiency diseases. AB - PURPOSE OF REVIEW: This issue of Current Opinion in Allergy and Clinical Immunology is focused on primary immunodeficiency diseases (PIDs). Like every disorder, PID has its own specific history, starting with the discovery of agammaglobulinemia in 1952 and still expanding at a rapid pace, covering, at the time of this publication, more than 180 genetically determined disorders. However, as this report attempts to demonstrate, the history of PID is intertwined with the development of modern medicine and is the direct result of the innovative thinking of physician scientists who introduced new concepts in pathology, microbiology, biochemistry, and immunology, based on carefully designed experiments. As a consequence of the novel ideas put forth in the late 19th century, progress in public health, the discovery of antimicrobials, and the utilization of biologic products led to the recognition of genetically determined defects of Immunity and the design of effective treatment strategies. RECENT FINDINGS: The discovery of the structure of DNA, its replication, and the mapping of the human genome has transformed the field of PID into a predictable science of cutting edge therapies and diagnostic concepts. SUMMARY: This review illustrates the historic events that led to the discovery, classification, and molecular definition of PID. PMID- 23095910 TI - Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies. AB - PURPOSE OF REVIEW: This review discusses the strengths and challenges of using whole genome sequencing (WGS)/whole exome sequencing (WES) for identifying novel genetic causes of primary immunodeficiencies. RECENT FINDINGS: WGS permits comprehensive sequencing of introns and exons, whereas WES allows deeper sequencing of exonic regions at a lower cost. Due to the large number of genetic variants found in each genome, it is necessary to use filtering approaches to distinguish deleterious from benign variants. WES has been used successfully to identify novel genetic causes of primary immunodeficiency. Complex structural variations and non-Mendelian disorders remain challenges for WGS/WES. SUMMARY: WGS/WES is a powerful screening tool with great potential to identify genetic causes of primary immunodeficiencies for research and clinical applications. To use WGS/WES effectively, it is necessary to understand how to filter the sequencing data and to realize its limitations as well as its strengths. PMID- 23095911 TI - Immunotherapy for allergic fungal sinusitis. AB - PURPOSE OF REVIEW: Allergic fungal sinusitis (AFS) results from an immunoglobulin E (IgE)-mediated, eosinophil-predominant hypersensitivity reaction to extramucosal fungi within the paranasal sinuses. Although the pathogenesis of this noninvasive process is still not fully understood, there is new information. Recently, the use of allergen immunotherapy with fungal antigens as an adjunct in treatment of AFS has been evaluated. In this review, we summarize the experience in the published literature on the topic. RECENT FINDINGS: There is evidence to suggest that allergen immunotherapy to fungal allergens may be effective in the treatment of symptoms of AFS and may decrease the rate of postoperative exacerbations and further operations. There is no evidence that this therapy induces immune complex disease. These studies pave the way for controlled trials of immunotherapy in patients with AFS. SUMMARY: Allergen immunotherapy to fungi shows promise as a treatment to decrease the recurrence of AFS and should be considered a part of the treatment regimen. However, because the number of patients treated has been small and one study suggested that fungal immunotherapy administered before removal of fungal contents from the sinuses could worsen sinusitis, controlled studies are essential to moving forward. PMID- 23095912 TI - Application of polymeric nanoparticles in immunotherapy. AB - PURPOSE OF REVIEW: The purpose of the present review is to underline the importance of nanoparticulate carriers, such as polymeric nanoparticles, in the future development of safe and effective formulation in the field of immunotherapy against infectious diseases and cancer. RECENT FINDINGS: Polymeric nanoparticles can modulate the immune response, that is, by targeting antigens to dendritic cells that possess a crucial role in initiating immune responses, and might be potentially useful in immunotherapy. SUMMARY: In the last decades, significant progress in research and clinics has been made to offer possible innovative therapeutics for the management of infectious diseases and cancer. Polymeric nanoparticles are particularly adept at facilitating immunotherapeutic approaches because they can be engineered to have different physical properties, encapsulated agents, and surface ligands. Moreover, these systems are administrable for all routes, are capable of being actively taken up by dendritic cells and have shown promising potential in systemic and mucosal immunotherapy. Here, some recent findings on these systems, in their potential applications for infectious and cancer immunotherapy, are reported. PMID- 23095913 TI - Current world literature. PMID- 23095915 TI - Combined analysis of genome-wide expression and copy number profiles to identify key altered genomic regions in cancer. AB - BACKGROUND: Analysis of DNA copy number alterations and gene expression changes in human samples have been used to find potential target genes in complex diseases. Recent studies have combined these two types of data using different strategies, but focusing on finding gene-based relationships. However, it has been proposed that these data can be used to identify key genomic regions, which may enclose causal genes under the assumption that disease-associated gene expression changes are caused by genomic alterations. PMID- 23095916 TI - 2p or not 2p: tuppence-based SERS for the detection of illicit materials. AB - Deposition of silver onto British 2p coins has been demonstrated as an efficient and cost effective approach to producing substrates capable of promoting surface enhanced Raman scattering (SERS). Silver application to the copper coins is undemanding taking just 20 s, and results in the formation of multiple hierarchial dendritic structures. To demonstrate that the silver deposition sites were capable of SERS the highly fluorescent Rhodamine 6G (R6G) probe was used. Analyses indicated that Raman enhancement only occurs at the silver deposition sites and not from the roughened copper surface. The robustness of the substrate in the identification and discrimination of illegal and legal drugs of abuse was then explored. Application of the drugs to the substrates was carried out using spotting and soaking methodologies. Whilst little or no SERS spectra of the drugs were generated upon spotting, soaking of the substrate in a methanolic solution of the drugs yielded a vast amount of spectral information. Excellent reproducibility of the SERS method and classification of three of the drugs, 4 methylmethcathinone (mephedrone), 5,6-methylenedioxy-2-aminoindane (MDAI) and 3,4 methylenedioxy-N-methylamphetamine (MDMA) were demonstrated using principal components analysis and partial least squares. PMID- 23095917 TI - The development, implementation, and assessment of an innovative faculty mentoring leadership program. AB - Effective mentoring is an important component of academic success. Few programs exist to both improve the effectiveness of established mentors and cultivate a multispecialty mentoring community. In 2008, in response to a faculty survey on mentoring, leaders at Brigham and Women's Hospital developed the Faculty Mentoring Leadership Program as a peer learning experience for midcareer and senior faculty physician and scientist mentors to enhance their skills and leadership in mentoring and create a supportive community of mentors. A planning group representing key administrative, educational, clinical, and research mentorship constituencies designed the nine-month course.Participants met monthly for an hour and a half during lunchtime. Two cofacilitators engaged the diverse group of 16 participants in interactive discussions about cases based on the participants' experiences. While the cofacilitators discussed with the participants the dyadic mentor-mentee relationship, they specifically emphasized the value of engaging multiple mentors and establishing mentoring networks. In response to postsession and postcourse (both immediately and after six months) self-assessments, participants reported substantive gains in their mentoring confidence and effectiveness, experienced a renewed sense of enthusiasm for mentoring, and took initial steps to build a diverse network of mentoring relationships.In this article, the authors describe the rationale, design, implementation, assessment, and ongoing impact of this innovative faculty mentoring leadership program. They also share lessons learned for other institutions that are contemplating developing a similar faculty mentoring program. PMID- 23095918 TI - Perspective: follow the money: the implications of medical schools' funds flow models. AB - Medical schools conduct research, provide clinical care, and educate future physicians and scientists. Each school has its own unique mix of revenue sources and expense sharing among the medical school, faculty practice plan(s), parent university, and affiliated hospital(s). Despite these differences, revenues from clinical care subsidize the money-losing research and education missions at every medical school.In this perspective, the authors discuss the flow of funds among a medical school, its faculty practice plan(s), parent university, and affiliated hospital(s). They summarize where medical school revenues come from, how revenues and expenses flow within a medical school and between a medical school and its partners, and why understanding this process is crucial to leading and managing such an enterprise. They conclude with recommendations for medical schools to consider in developing funds flow models that meet their individual needs and circumstances: (1) understand economic drivers, (2) reward desired behaviors, (3) enable every unit to generate a positive margin, (4) communicate budget priorities, financial performance, and the use of institutional resources, and (5) establish principles for sharing resources and allocating expenses among entities within the institution.Medical schools should develop funds flow models that are transparent, aligned with their strategic priorities, and reward the behaviors necessary to produce effective collaboration within and across mission areas. PMID- 23095919 TI - The nature of excellent clinicians at an academic health science center: a qualitative study. AB - PURPOSE: To understand the nature of excellent clinicians at an academic health science center by exploring how and why excellent clinicians achieve high performance. METHOD: From 2008 to 2010, the authors conducted a qualitative study using a grounded theory approach. Members of the Clinical Advisory Committee in the Department of Pediatrics at the University of Toronto nominated peers whom they saw as excellent clinicians. The authors then conducted in-depth interviews with the most frequently nominated clinicians. They audio-recorded and transcribed the interviews and coded the transcripts to identify emergent themes. RESULTS: From interviews with 13 peer-nominated, excellent clinicians, a model emerged. Dominant themes fell into three categories: (1) core philosophy, (2) deliberate activities, and (3) everyday practice. Excellent clinicians are driven by a core philosophy defined by high intrinsic motivation and passion for patient care and humility. They refine their clinical skills through two deliberate activities-reflective clinical practice and scholarship. Their high performance in everyday practice is characterized by clinical skills and cognitive ability, people skills, engagement, and adaptability. CONCLUSIONS: A rich theory emerged explaining how excellent clinicians, driven by a core philosophy and engaged in deliberate activities, achieve high performance in everyday practice. This theory of the nature of excellent clinicians provides a holistic perspective of individual performance, informs medical education, supports faculty career development, and promotes clinical excellence in the culture of academic medicine. PMID- 23095920 TI - Florida State University College of Medicine: from ideas to outcomes. AB - The Florida State University College of Medicine (FSU COM) was established in 2000, the first new MD-granting medical school in the United States in over 25 years. In its brief history, the FSU COM has developed rapidly in accordance with its founding mission to meet the need for primary care physicians, especially those caring for the elderly and the underserved. The school recently received a full continuation of accreditation for the maximum period, eight years, from the Liaison Committee on Medical Education.The authors describe FSU COM's new, innovative educational program using community-based clinical training on six statewide regional campuses and two rural sites. Third- and fourth-year students are assigned to community physicians in a one-on-one clinical training model in all of the settings where physicians practice. Over 70% of student clinical training is in such settings. The authors describe how the model operates, including curricular oversight (which ensures quality and equivalence of the educational experience at all sites), the regional campus structure, administration, education program delivery during core clerkships, and assessment of students' performance. Ongoing required faculty development for all clerkship faculty is an essential feature of the training program, as is tracking of all individual student contacts through an online clinical data collection system used for evaluation of the clerkship experiences as well as research.The authors demonstrate that the school has been highly successful in implementing its mission, and that the challenge ahead is to sustain its approach to the training of future physicians. PMID- 23095921 TI - Perspective: the education community must develop best practices informed by evidence-based research to remediate lapses of professionalism. AB - In July 2011, the Alpha Omega Alpha Honor Medical Society sponsored a think tank of experts in the field of medical professionalism to focus on interventions and remediation strategies for those-medical students, residents, faculty, and practicing physicians-who demonstrate lapses in professional performance, particularly if the lapses are repeated. Several participants have produced scholarly work on the assessment of professionalism. However, assessment has a limited purpose unless it leads to improvements at both the organizational and individual levels. The field of professionalism has matured enough to recognize that one of the contemporary issues within the self-regulation framework is the task of remediation. Yet there is a paucity of evidence to inform best practices to help those who have lapses. Ultimately, the most effective response to an individual's lapse in professionalism may not be simply to gather knowledge about remedial practices but also to understand organizational responses to the information about such practices already possessed by the institution.The authors report the think tank participants' recommendations on (1) how to use existing data on professionalism remediation and (2) what new evidence is needed to advance approaches to remediation of professional performance. Participants also recommended that the education community can focus on interventions and remediation by (1) performing studies about improving medical professionalism when lapses occur, (2) identifying best evidence-based remediation practices, (3) widely disseminating those practices, and (4) moving over time from a best practices approach to remediation (which does not yet exist) to a best-evidence model. PMID- 23095922 TI - The comprehensive geriatric assessment guide: an exploratory analysis of a medical trainee performance evaluation tool. AB - PURPOSE: Few opportunities exist for medical students and residents to receive feedback on specific geriatric skills because they are frequently unsupervised when assessing elderly patients. Patients and caregivers are currently an untapped source of clinical content feedback. The purpose of this study was to determine whether patients/caregivers could accurately complete a postassessment evaluation of trainees' clinical performance. METHOD: The authors developed the Comprehensive Geriatric Assessment Guide (CGAG) consisting of 36 yes/no/don't remember questions that prompt the patient/caregiver to indicate what topics the trainee discussed during clinical assessment. In 2010, two raters independently listened to audio recordings of 10 trainee-administered clinical assessments, scoring them using the CGAG to determine interrater reliability. Next, 32 patients/caregivers completed a CGAG after a trainee-administered clinical assessment. Then, the authors compared the results with a "gold standard" CGAG of the encounter. RESULTS: Interrater reliability for the CGAG was high (90.4% agreement), indicating that the patients/caregivers were able to accurately complete the postassessment CGAG. Of 36 CGAG questions, 30 had patient/caregiver and gold standard agreement of over 80%; the remaining 6 had low agreement. CONCLUSIONS: Patients and caregivers were able to recall sufficient clinical assessment detail to potentially provide constructive feedback to medical trainees on their assessment skills via the CGAG. Six questions with low agreement will be reworded to improve clarity on future versions of the CGAG. Future investigations will help determine whether use of the CGAG during medical education may help trainees improve assessment performance and allow educators to track progress in geriatric competencies. PMID- 23095923 TI - Preparing students to be academicians: a national student-led summer program in teaching, leadership, scholarship, and academic medical career-building. AB - Medical schools have the responsibility of producing future leaders in academic medicine, yet few students choose academic medicine as a career. In 2009, the American Medical Student Association (AMSA) and the George Washington University School of Medicine and Health Sciences joined forces to provide students with a comprehensive introduction to careers in academic medicine through the redesign of an existing annual summer program for medical students. Since 2004, AMSA had hosted the Medical Education Leadership Institute, a weeklong program that attracted medical students from across the country who were interested in gaining teaching skills. In the redesigned sixth annual program, the authors expanded the curriculum to include principles of leadership, of medical education scholarship (or project development), and of academic medicine career-building. The purpose of this article is to describe the features of this comprehensive program and to share the lessons learned from its development and implementation. The authors also describe the multifaceted approach they used to evaluate the program, which featured a rubric they derived from social cognitive career theory. PMID- 23095924 TI - The road to an academic medicine career: a national cohort study of male and female U.S. medical graduates. AB - PURPOSE: To explore the relationship between gender and full-time faculty appointment in a national cohort of contemporary U.S. medical school graduates. METHOD: The authors analyzed deidentified, individual records for the 1998-2004 national cohort of U.S. medical graduates using multivariate logistic regression to identify predictors of full-time faculty appointment through July 2009. They reported adjusted odds ratios (aOR) significant at P < .05. RESULTS: Of 66,889 graduates, 12,038 (18.0%) had held full-time faculty appointments. Among all graduates, women (aOR = 1.21) were more likely than men to have held faculty appointments. Among only male graduates, those who participated in research during college (aOR = 1.08), who entered medical school with greater planned career involvement in research (aOR = 1.08), and who authored/coauthored a research paper during medical school (aOR = 1.12) were more likely, and those with higher debt were less likely (aOR = 0.96), to have held faculty appointments. Among only faculty appointees, higher proportions of men than women had participated in medical school research electives (63.5% [3,899/6,138] versus 54.2% [3,197/5,900]; P < .001) and authored/coauthored research papers during medical school (44.1% [2,707/6,138] versus 33.6% [1,981/5,900]; P < .001); female faculty had reported higher debt at medical school graduation than had male faculty (P = .014). CONCLUSIONS: In this national cohort of U.S. medical graduates, women were more likely than men to have held full-time faculty appointments. However, male and female faculty appointees entered academic medicine with different research experiences and debt, possibly impacting their academic medicine career trajectories. PMID- 23095925 TI - The College of Human Medicine at Michigan State University: expansion and reinvention. AB - The College of Human Medicine (CHM) at Michigan State University, which graduated its first class in 1972, was one of the first community-based medical schools in the country. It was established as a state-funded medical school with specific legislative directives to educate primary care physicians who would serve the needs of the state, particularly those of underserved areas. However, the model has proved challenging to sustain with the many changes to the health care system and the economic climate of Michigan. In 2006, a two-phase expansion plan was implemented, and in 2010, CHM permanently expanded the matriculating class from 106 to 200 students with the establishment of a second four-year site for medical education in Grand Rapids. This article describes what school leaders and faculty have learned as they look back at the opportunity provided by expansion as well as the growing pains and lessons learned. The community-based model met many of the mission-related goals for CHM's graduates, who represent a diverse group of practitioners whose values resonate with the school's mission. Expansion has offered an opportunity to explore new research and clinical opportunities as well as to more fully realize the potential of community partners to meet local health care needs and reinvent a robust future for community-integrated medical education. PMID- 23095926 TI - Perspective: a business school view of medical interprofessional rounds: transforming rounding groups into rounding teams. AB - An effective interprofessional medical team can efficiently coordinate health care providers to achieve the collective outcome of improving each patient's health. To determine how current teams function, four groups of business students independently observed interprofessional work rounds on four different internal medicine services in a typical academic hospital and also interviewed the participants. In all instances, caregivers had formed working groups rather than working teams. Participants consistently exhibited parallel interdependence (individuals working alone and assuming their work would be coordinated with other caregivers) rather than reciprocal interdependence (individuals working together to actively coordinate patient care), the hallmark of effective teams. With one exception, the organization was hierarchical, with the senior attending physician possessing the authority. The interns exclusively communicated with the attending physician in one-on-one conversations that excluded all other members of the team. Although nurses and pharmacists were often present, they never contributed their ideas and rarely spoke.The authors draw on these observations to form recommendations for enhancing interprofessional rounding teams. These are to include the bedside nurse, pharmacist, and case manager as team members, begin with a formal team launch that encourages active participation by all team members, use succinct communication protocols, conduct work rounds in a quiet, distraction-free environment, have teams remain together for longer durations, and receive teamwork training and periodic coaching. High-performing businesses have effectively used teams for decades to achieve their goals, and health care professionals should follow this example. PMID- 23095927 TI - Conflicting messages: examining the dynamics of leadership on interprofessional teams. AB - PURPOSE: Despite the importance of leadership in interprofessional health care teams, little is understood about how it is enacted. The literature emphasizes a collaborative approach of shared leadership, but this may be challenging for clinicians working within the traditionally hierarchical health care system. METHOD: Using case study methodology, the authors collected observation and interview data from five interprofessional health care teams working at teaching hospitals in urban Ontario, Canada. They interviewed 46 health care providers and conducted 139 hours of observation from January 2008 through June 2009. RESULTS: Although the members of the interprofessional teams agreed about the importance of collaborative leadership and discussed ways in which their teams tried to achieve it, evidence indicated that the actual enactment of collaborative leadership was a challenge. The participating physicians indicated a belief that their teams functioned nonhierarchically, but reports from the nonphysician clinicians and the authors' observation data revealed that hierarchical behaviors persisted, even from those who most vehemently denied the presence of hierarchies on their teams. CONCLUSIONS: A collaborative approach to leadership may be challenging for interprofessional teams embedded in traditional health care, education, and medical-legal systems that reinforce the idea that physicians sit at the top of the hierarchy. By openly recognizing and discussing the tensions between traditional and interprofessional discourses of collaborative leadership, it may be possible to help interprofessional teams, physicians and clinicians alike, work together more effectively. PMID- 23095928 TI - Are central institutional review boards the solution? The National Heart, Lung, and Blood Institute Working Group's report on optimizing the IRB process. AB - The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB. PMID- 23095929 TI - Teaching health centers: a new paradigm in graduate medical education. AB - The Patient Protection and Affordable Care Act of 2010 created the Teaching Health Center Graduate Medical Education (THCGME) program to provide graduate medical education (GME) funding directly to community-based health centers that expand or establish new primary care residency programs. The THCGME program was the legislation's only new investment in GME, and it represents a significant departure from the Medicare GME funding system. It provides payments to ambulatory care centers for both direct and indirect GME expenses, and mandates a level of reporting from recipients that is not required for Medicare GME support. This initial look at the 11 inaugural teaching health centers (THCs) shows that they are training primary care residents in relevant delivery models (e.g., interprofessional teams, patient-centered medical homes), developing educational initiatives that address primary care practice in underserved areas, and transforming organizational and funding structures to support community-based training. The THCs plan to evaluate and report resident performance, patient quality of care, and graduate outcomes. The work of the first THCs has implications for primary care training, the GME system, and future policies and legislation aimed at strengthening the health care workforce. PMID- 23095930 TI - Multisource feedback in evaluating the performance of doctors: the example of the UK General Medical Council patient and colleague questionnaires. AB - PURPOSE: Internationally, there is increasing interest in monitoring and evaluating doctors' professional practice. Multisource feedback (MSF) offers one way of collecting information about doctors' performance. The authors investigated the psychometric properties of two questionnaires developed for this purpose and explored the biases that may exist within data collected via such instruments. METHOD: A cross-sectional study was conducted in 11 UK health care organizations during 2008-2011. Patients (n = 30,333) and colleagues (n = 17,012) rated the professional performance of 1,065 practicing doctors, using the General Medical Council Patient Questionnaire (PQ) and Colleague Questionnaire (CQ). The psychometric properties of the questionnaires were assessed, and regression modeling was used to explore factors that influenced patient and colleague responses on the core questionnaire items. RESULTS: Although the questionnaires demonstrated satisfactory internal consistency, test-retest reliability, and convergent validity, patient and colleague ratings were highly skewed toward favorable impressions of doctor performance. At least 34 PQs and 15 CQs were required to achieve acceptable reliability (G > 0.70). Item ratings were influenced by characteristics of the patient and colleague respondents and the context in which their feedback was provided. CONCLUSIONS: The PQ and CQ are acceptable for the provision of formative feedback on a doctor's professional practice within an appraisal process. However, biases identified in the questionnaire data suggest that caution is required when interpreting and acting on this type of information. MSF derived from these questionnaires should not be used in isolation to inform decisions about a doctor's fitness to practice medicine. PMID- 23095931 TI - The prevalence and effects of environmental tobacco smoke exposure among inner city children: lessons for pediatric residents. AB - PURPOSE: To determine the prevalence of environmental tobacco smoke (ETS) exposure, to explore the relationship between ETS exposure and the use of health services, and to examine the degree to which pediatric residents document ETS exposure status and counsel parents. METHOD: In 2006, the authors recruited dyads of children (0-12 years old) and their mothers from an inner-city pediatric group practice clinic. Mothers completed a survey, and the authors searched the children's medical charts. The authors compared ETS-exposed children with nonexposed children using chi-square, t test, and ANOVA analyses. They also ran logistic regression analyses to examine the relationship between the use of health services and selected child and maternal variables. RESULTS: More than 60% (142/232) of children were exposed to ETS, and more than 69% (99/142) of those children had a mother who smoked. ETS exposure significantly predicted the overall number of sick visits, even after controlling for sociodemographic confounders (odds ratio = 7.44; 95% confidence internal = 1.21-44.55). About 80% (187/232) of mothers reported that their child's pediatrician had counseled them on the dangers of ETS exposure. Less than half (105/232) of the children's charts included their ETS exposure status. CONCLUSIONS: Although pediatric residents often counsel parents on the dangers of ETS exposure, educators should teach residents to regard ETS exposure status as a fifth vital sign. By screening for and documenting ETS exposure status, residents can identify at-risk children and parents, who could benefit from counseling. PMID- 23095932 TI - "It depends": results of a qualitative study investigating how practicing internists approach professional dilemmas. AB - PURPOSE: Context has a critical influence on individuals' behaviors and is essential to understanding lapses in professionalism, yet little is known about contextual factors relevant to practicing physicians. This study used standardized professionalism dilemmas, or challenges, to explore practicing internists' reasoning in their handling of typical challenges. METHOD: In spring 2011, the authors created several professional challenges relevant to physicians in practice and conducted five focus groups with practicing internists (n = 40). Each group discussed five or six of the challenges, and the facilitators specifically asked what the participants would do and why. The authors used constructivist grounded theory to analyze the transcripts. RESULTS: The scenarios were effective in eliciting discussion and debate. Analysis revealed many guiding principles (e.g., patient welfare, keeping patients happy) that influenced physicians in their approach to professionalism challenges, but these principles were highly context-dependent. The authors found individuals' responses to be malleable and subject to much modification depending on input from peers. Responses often shifted in an iterative and complex manner, depending on factors such as the "type" of patients (including the physician's personal feelings toward them), the nature of the illness or diagnosis, and the physician's relationships with others. CONCLUSIONS: Despite recognizing and articulating basic guiding principles of professionalism, physicians' approaches to professional challenges were subject to multiple, interdependent, idiosyncratic forces unique to each situation. A deeper understanding of these factors and how they interact is critical for the development of strategies to teach and evaluate professionalism in practice. PMID- 23095933 TI - Transcriptional regulation of RKIP expression by androgen in prostate cells. AB - BACKGROUND/AIMS: Raf kinase inhibitory protein (RKIP) is a scaffolding molecule in the PEBP family that sequesters certain signaling molecules away from their pathways, thereby abrogating intracellular growth signals. RKIP has been assigned multiple functions and is associated with an increasing number of diseases through its involvement with signal transduction pathways. We previously demonstrated that RKIP is highly expressed in human normal prostate epithelial cells and plays a pivotal role during prostate cancer (PCa) progression. Whether RKIP is subject to endocrine regulation has not been reported. METHODS: The effect of dihydrotestosterone (DHT) on RKIP expression in normal prostate epithelial cells was determined by real-time RT-PCR and Western blot. Report assay was performed to determine whether the regulation of RKIP by androgens is at the transcriptional level. The binding of androgen receptor (AR) to the RKIP promoter was determined by EMSA and Chromatin Immunoprecipitation (ChIP) assays. To determine whether RKIP was regulated by androgen in vivo, we examined RKIP expression level in response to castration in 6-8 week old C57BL/6 male mice. RESULTS: Here we report that DHT positively regulates the transcription of RKIP in the normal prostate epithelial cells. The anti-androgen bicalutamide blocked androgen-mediated regulation of RKIP, which indicates that this regulation is mediated through AR. Transfection of the cells with a RKIP promoter-driven luciferase reporter vector showed that DHT increased RKIP promoter activity in parallel with changes in expression. EMSA demonstrates that AR binds to a putative ARE in the RKIP promoter, which was further validated by ChIP assay. Importantly, these data are further supported by our in vivo experiment where castrated mice had less RKIP expression in their prostate glands than sham operated mice. CONCLUSIONS: Collectively, the results establish RKIP as a novel androgen target gene. Androgens induce RKIP expression through AR-mediated transcriptional modulation of the RKIP promoter in the prostate. This is the first demonstration of endocrine regulation of the metastasis suppressor gene RKIP. PMID- 23095934 TI - Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial. AB - BACKGROUND: MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing. METHODS: HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876). RESULTS: Approximately 8% of patients screened as having R5 virus by OTA were classified as having non R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar. CONCLUSIONS: The exclusion of ~8% of patients with CXCR4 using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response. PMID- 23095935 TI - An electronic medical record-based model to predict 30-day risk of readmission and death among HIV-infected inpatients. AB - BACKGROUND: Readmission after hospitalization is costly, time-consuming, and remains common among HIV-infected individuals. We sought to use data from the Electronic Medical Record (EMR) to create a clinical, robust, multivariable model for predicting readmission risk in hospitalized HIV-infected patients. METHODS: We extracted clinical and nonclinical data from the EMR of HIV-infected patients admitted to a large urban hospital between March 2006 and November 2008. These data were used to build automated predictive models for 30-day risk of readmission and death. RESULTS: We identified 2476 index admissions among HIV infected inpatients who were 73% males, 57% African American, with a mean age of 43 years. One-quarter were readmitted, and 3% died within 30 days of discharge. Those with a primary diagnosis during the index admission of HIV/AIDS accounted for the largest proportion of readmissions (41%), followed by those initially admitted for other infections (10%) or for oncologic (6%), pulmonary (5%), gastrointestinal (4%), and renal (3%) causes. Factors associated with readmission risk include: AIDS defining illness, CD4 <= 92, laboratory abnormalities, insurance status, homelessness, distance from the hospital, and prior emergency department visits and hospitalizations (c = 0.72; 95% confidence interval: 0.70 to 0.75). The multivariable predictors of death were CD4 < 132, abnormal liver function tests, creatinine >1.66, and hematocrit <30.8 (c = 0.79; 95% confidence interval: 0.74 to 0.84) for death. CONCLUSIONS: Readmission rates among HIV infected patients were high. An automated model composed of factors accessible from the EMR in the first 48 hours of admission performed well in predicting the 30-day risk of readmission among HIV patients. Such a model could be used in real time to identify HIV patients at highest risk so readmission prevention resources could be targeted most efficiently. PMID- 23095936 TI - Safe coadministration of raltegravir-based HAART in HIV-infected patients with HCV-cirrhosis receiving triple therapy with telaprevir or boceprevir. PMID- 23095937 TI - The balancing act of the inflammatory cascade after bilateral total knee arthroplasty commentary on an article by Kethy M. Jules-Elysee, MD, et al.: ''steroid modulation of cytokine release and desmosine levels in bilateral total knee replacement. a prospective, double-blind, randomized controlled trial''. PMID- 23095938 TI - mRNA expression levels among cell regulatory and DNA damage genes in benzene exposed workers in China. AB - OBJECTIVE: We investigated how cells respond to the induction of DNA damage, focusing specifically on mRNA expression levels of cell regulatory and DNA repair genes under exposure to benzene. METHOD: The study sample was classified into three groups: direct exposure to benzene (A), indirect exposure to benzene (B), and non-exposed (C). Concentrations of benzene in the air of workplaces were monitored. Further blood biochemical parameters, cell cycle-regulated and DNA damage-related genes expression were analyzed. RESULTS: The mRNA expression levels of Apel, Rad51, Bcl-2, Bax, Xpa, and Xpc genes were significantly down regulated in groups A and B, with a dramatic up-regulation of p21 gene in group A accompanied by significantly lower counts of white blood cells, hemoglobin, platelets and lymphocyte subsets of CD8+, CD4+, T and B cells. CONCLUSION: The results indicated that exposure to benzene had significantly altered mRNA expression of some critical cell regulatory and DNA repair genes. PMID- 23095940 TI - Imaging acidosis in tumors using a pH-activated near-infrared fluorescence probe. AB - A novel pH activatable near-infrared fluorescence probe was developed, which successfully visualized acidosis in tumors. This probe holds promise to non invasively predict the tumor metastasis potential and evaluate the therapeutic response. PMID- 23095941 TI - Enhancement of carotenoid biosynthesis in the green microalga Dunaliella salina with light-emitting diodes and adaptive laboratory evolution. AB - There is a particularly high interest to derive carotenoids such as beta-carotene and lutein from higher plants and algae for the global market. It is well known that beta-carotene can be overproduced in the green microalga Dunaliella salina in response to stressful light conditions. However, little is known about the effects of light quality on carotenoid metabolism, e.g., narrow spectrum red light. In this study, we present UPLC-UV-MS data from D. salina consistent with the pathway proposed for carotenoid metabolism in the green microalga Chlamydomonas reinhardtii. We have studied the effect of red light-emitting diode (LED) lighting on growth rate and biomass yield and identified the optimal photon flux for D. salina growth. We found that the major carotenoids changed in parallel to the chlorophyll b content and that red light photon stress alone at high level was not capable of upregulating carotenoid accumulation presumably due to serious photodamage. We have found that combining red LED (75 %) with blue LED (25 %) allowed growth at a higher total photon flux. Additional blue light instead of red light led to increased beta-carotene and lutein accumulation, and the application of long-term iterative stress (adaptive laboratory evolution) yielded strains of D. salina with increased accumulation of carotenoids under combined blue and red light. PMID- 23095942 TI - Design, expression, and characterization of a novel targeted plectasin against methicillin-resistant Staphylococcus aureus. AB - A novel specifically targeted antimicrobial peptide (STAMP) that was especially effective against methicillin-resistant Staphylococcus aureus (MRSA) was designed by fusing the AgrD1 pheromone to the N-terminal end of plectasin. This STAMP was named Agplectasin, and its gene was synthesized and expressed in Pichia pastoris X-33 via pPICZalphaA. The highest amount of total secreted protein reached 1,285.5 mg/l at 108 h during the 120-h induction. The recombinant Agplectasin (rAgP) was purified by cation exchange chromatography and hydrophobic exchange chromatography; its yield reached 150 mg/l with 94 % purity. The rAgP exhibited strong bactericidal activity against S. aureus but not Staphylococcus epidermidis or other types of tested bacteria. A bactericidal kinetics assay showed that the rAgP killed over 99.9 % of tested S. aureus (ATCC 25923 and ATCC 43300) in both Mueller-Hinton medium and human blood within 10 h when treated with 4* minimal inhibitory concentration. The rAgP caused only approximately 1 % hemolysis of human blood cells, even when the concentration reached 512 MUg/ml, making it potentially feasible as a clinical injection agent. In addition, it maintained a high activity over a wide range of pH values (2.0-10.0) and demonstrated a high thermal stability at 100 degrees C for 1 h. These results suggested that this STAMP has the potential to eliminate MRSA strains without disrupting the normal flora. PMID- 23095939 TI - DNA barcoding in a biodiversity hot spot: potential value for the identification of Malagasy Euphorbia L. listed in CITES Appendices I and II. AB - The island of Madagascar is a key hot spot for the genus Euphorbia, with at least 170 native species, almost all endemic. Threatened by habitat loss and illegal collection of wild plants, nearly all Malagasy Euphorbia are listed in CITES Appendices I and II. The absence of a reliable taxonomic revision makes it particularly difficult to identify these plants, even when fertile, and thereby compromises the application of CITES regulations. DNA barcoding, which can facilitate species-level identification irrespective of developmental stage and the presence of flowers or fruits, may be a promising tool for monitoring and controlling trade involving threatened species. In this study, we test the potential value of barcoding on 41 Euphorbia species representative of the genus in Madagascar, using the two widely adopted core barcode markers (matK and rbcL), along with two additional DNA regions, nuclear internal transcribed spacer (ITS) and the chloroplastic intergenic spacer psbA-trnH. For each marker and for selected marker combinations, inter- and intraspecific distance estimates and species discrimination rates are calculated. Results using just the 'official' barcoding markers yield overlapping inter- and intraspecific ranges and species discrimination rates below 60%. When ITS is used, whether alone or in combination with the core markers, species discrimination increases to nearly 100%, whereas the addition of psbA-trnH produces less satisfactory results. This study, the first ever to test barcoding on the large, commercially important genus Euphorbia shows that this method could be developed into a powerful identification tool and thereby contribute to more effective application of CITES regulations. PMID- 23095943 TI - Harvest site influences the growth properties of adipose derived stem cells. AB - The therapeutic potential of adult stem cells may become a relevant option in clinical care in the future. In hand and plastic surgery, cell therapy might be used to enhance nerve regeneration and help surgeons and clinicians to repair debilitating nerve injuries. Adipose-derived stem cells (ASCs) are found in abundant quantities and can be harvested with a low morbidity. In order to define the optimal fat harvest location and detect any potential differences in ASC proliferation properties, we compared biopsies from different anatomical sites (inguinal, flank, pericardiac, omentum, neck) in Sprague-Dawley rats. ASCs were expanded from each biopsy and a proliferation assay using different mitogenic factors, basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) was performed. Our results show that when compared with the pericardiac region, cells isolated from the inguinal, flank, omental and neck regions grow significantly better in growth medium alone. bFGF significantly enhanced the growth rate of ASCs isolated from all regions except the omentum. PDGF had minimal effect on ASC proliferation rate but increases the growth of ASCs from the neck region. Analysis of all the data suggests that ASCs from the neck region may be the ideal stem cell sources for tissue engineering approaches for the regeneration of nervous tissue. PMID- 23095944 TI - Galangin and its emerging anti-neoplastic effects. PMID- 23095945 TI - Rates and predictors of postpartum depression by race and ethnicity: results from the 2004 to 2007 New York City PRAMS survey (Pregnancy Risk Assessment Monitoring System). AB - The objective of this study was to examine racial/ethnic disparities in the diagnosis of postpartum depression (PPD) by: (1) identifying predictors that account for prevalence rate differences across groups, and (2) comparing the strength of predictors across groups. 3,732 White, African American, Hispanic, and Asian/Pacific Islander women from the New York City area completed the Pregnancy Risk Assessment Monitoring System from 2004 to 2007, a population-based survey that assessed sociodemographic risk factors, maternal stressors, psycho education provided regarding depression, and prenatal and postpartum depression diagnoses. Sociodemographic and maternal stressors accounted for increased rates in PPD among Blacks and Hispanics compared to Whites, whereas Asian/Pacific Islander women were still 3.2 times more likely to receive a diagnosis after controlling for these variables. Asian/Pacific Islanders were more likely to receive a diagnosis after their providers talked to them about depressed mood, but were less likely than other groups to have had this conversation. Prenatal depression diagnoses increased the likelihood for PPD diagnoses for women across groups. Gestational diabetes decreased the likelihood for a PPD diagnosis for African Americans; a trend was observed in the association between having given birth to a female infant and increased rates of PPD diagnosis for Asian/Pacific Islanders and Whites. The risk factors that account for prevalence rate differences in postpartum diagnoses depend on the race/ethnic groups being compared. Prenatal depression is confirmed to be a major predictor for postpartum depression diagnosis for all groups studied; however, the associations between other postpartum depression risk factors and diagnosis vary by race/ethnic group. PMID- 23095946 TI - The impact of mental health on chronic rhinosinusitis symptom scores. AB - We aimed to assess whether anxiety and depression influence a patient's subjective symptom scores in chronic rhinosinusitis (CRS). Fifty-seven consecutive patients referred with CRS were asked to complete Sinonasal Outcome Test-22 (SNOT22) and Hospital Anxiety and Depression Score (HADS) questionnaires. Spearman's rank correlation was used to test association between SNOT22 and HADS. Linear regression was used to simultaneously analyse SNOT, HADS, patient age and gender. Mean anxiety score was 7.9 (range 0-19) with 32 % scoring over 11 (A score of >= 11 for either anxiety or depression is suggestive). Mean depression score was 5.0 (range 0-17), with 11 % scoring over 11. Five patients scored over 11 for both domains in the HADS questionnaire. Total SNOT22 and both anxiety (Spearman's rho = 0.48, p = 0.0002) and depression scores (rho = 0.44, p = 0.0007) revealed a strong association. We also identified a very strong association between psychological symptoms (questions 11-20) in SNOT22 and anxiety (rho = 0.60, p = 0.0001) and depression scores (rho = 0.341, p = 0.002). However, there was no association between nose-specific symptoms in SNOT22 and anxiety score in HADS (rho = 0.18, p = 0.1775), but there was a strong association between nose-specific symptoms of SNOT22 and depression score in HADS (rho = 0.32, p = 0.02). There is a strong association between total SNOT 22 and HADS score, but this appears to be due to the impact on generic quality of life items rather than disease-specific symptoms. This supports inclusion of global items in the SNOT22, but also use of two separate subscales when interpreting data. PMID- 23095947 TI - Physiology of the ageing gut. AB - PURPOSE OF REVIEW: This article will review the recent publications (over the last 1-2 years) concerning the effects of ageing on gastrointestinal function, with an emphasis on the motor and sensory function of the gut. RECENT FINDINGS: Recent publications support earlier observations of an age-related selective decline in the number of cholinergic neurons in the enteric nervous system, but also reveal a progressive loss of interstitial cells of Cajal in the stomach and colon throughout adult life. These changes appear to have surprisingly little effect on gastrointestinal motor function in healthy ageing, although gut sensation is impaired and older individuals have an increased susceptibility to gastrointestinal complications of comorbid illnesses. SUMMARY: Alterations in gut function with ageing have particular implications in the oesophagus, colon, and anorectum. Dysphagia, gastro-oesophageal reflux disease, constipation, and faecal incontinence are the most prevalent clinical manifestations. Older individuals are also susceptible to postprandial hypotension, in which altered cardiovascular responses to intestinal nutrient exposure are pivotal. Dysphagia, delayed gastric emptying, and constipation are increasingly being recognized as early features of Parkinson's disease, and frequently precede the neurological manifestations. PMID- 23095948 TI - [Long-term results for subcutaneous Detour(r) prosthesis for ureteral obstruction: experiences of implantation, aftercare and management of complications]. AB - BACKGROUND: We present the long-term results of implementation of the Detour(r) prosthesis as an alternative to established methods of surgical, percutaneous or internal urinary diversion. PATIENTS AND METHODS: Between 2004 and 2012 a total of 40 prostheses were implanted in 31 patients (mean age 65 years) with ureteral strictures of various origins. In the follow-up the patients underwent examinations and completed questionnaires. RESULTS: The average follow-up was 23 months (range 1-92 months). Sonographic examinations showed no urinary retention in 38 out of 40 implanted systems. The retention values were stable in 19 patients, improved in 7 and worse in 3. The quality of life (QoL) was high (EORTC QLQ-C30 90%). Intraoperative complications were 2 intestinal lesions and 3 bleeding of the renal-pelvic system. Postoperative urinary tract infections and wound complications were encountered. In the long-term course three infected hydronephroses occurred which were treated and cured with antibiotics and temporary nephrostomy and 4 systems were explanted, including 2 exchanges. CONCLUSIONS: The system may be considered for patients with ureteral strictures with palliative and curative intent. There were no significant disadvantages in comparison with established methods. There were fewer risks in implantation and complications were manageable. The quality of life was significantly improved. PMID- 23095949 TI - Using the compensated heat pulse method to monitor trends in stem water content in standing trees. AB - Studying the dynamics of stem water content (theta) in living trees has an outstanding physiological interest but all the available techniques to measure theta exhibit major drawbacks. In this work, we present a new methodology to estimate variations in theta along with sap velocity using the compensated heat pulse (CHP) technique. One lab experiment was performed on several wooden blocks obtained from three different tree species. Samples were slowly dried and their moisture loss was monitored by both gravimetric approaches and time-domain reflectometry (TDR) or CHP probes in order to contrast the validity of our methodology (volumetric specific heat (VSH)-CHP) over a range of water contents. In addition, a field experiment was conducted to monitor theta fluctuations in standing olive trees (Olea europaea L. cv. 'Arbequina') growing under three different irrigation regimes. In the lab test, the actual theta values deduced gravimetrically differed from the estimates yielded by the VSH-CHP method. However, it could successfully track relative changes in the water stored for the range of theta expected in living wood. Furthermore, the field experiment showed a seasonal change in theta, which was similar in shape and magnitude to those reported in the literature for olive and other Mediterranean tree species. On the other hand, differences in the seasonal patterns of theta between irrigation treatments strongly corresponded with those of sap flow and some leaf water potential measurements. The results of this work suggest that the CHP technique could be employed to monitor the dynamics of both theta and sap flow simultaneously in standing trees and evidence that seasonal changes in theta might be used as a long-term water status indicator. PMID- 23095950 TI - The trans-sphincteric posterior sagittal repair of recto-urinary and recto vaginal fistulae using SurgisisTM mesh and fibrin sealant. AB - Recto-urinary, recto-vaginal and ileo-anal pouch-associated fistulae are rare yet a significant clinical problem due to their profound impact on patients' quality of life and are a challenge to repair. In this report, we describe repair of these complex fistulae using a modified trans-sphincteric posterior sagittal approach with SurgisisTM mesh and fibrin sealant and review our repair outcomes. PMID- 23095951 TI - The Corynebacterium pseudotuberculosis in silico predicted pan-exoproteome. AB - BACKGROUND: Pan-genomic studies aim, for instance, at defining the core, dispensable and unique genes within a species. A pan-genomics study for vaccine design tries to assess the best candidates for a vaccine against a specific pathogen. In this context, rather than studying genes predicted to be exported in a single genome, with pan-genomics it is possible to study genes present in different strains within the same species, such as virulence factors. The target organism of this pan-genomic work here presented is Corynebacterium pseudotuberculosis, the etiologic agent of caseous lymphadenitis (CLA) in goat and sheep, which causes significant economic losses in those herds around the world. Currently, only a few antigens against CLA are known as being the basis of commercial and still ineffective vaccines. In this regard, the here presented work analyses, in silico, five C. pseudotuberculosis genomes and gathers data to predict common exported proteins in all five genomes. These candidates were also compared to two recent C. pseudotuberculosis in vitro exoproteome results. RESULTS: The complete genome of five C. pseudotuberculosis strains (1002, C231, I19, FRC41 and PAT10) were submitted to pan-genomics analysis, yielding 306, 59 and 12 gene sets, respectively, representing the core, dispensable and unique in silico predicted exported pan-genomes. These sets bear 150 genes classified as secreted (SEC) and 227 as potentially surface exposed (PSE). Our findings suggest that the main C. pseudotuberculosis in vitro exoproteome could be greater, appended by a fraction of the 35 proteins formerly predicted as making part of the variant in vitro exoproteome. These genomes were manually curated for correct methionine initiation and redeposited with a total of 1885 homogenized genes. CONCLUSIONS: The in silico prediction of exported proteins has allowed to define a list of putative vaccine candidate genes present in all five complete C. pseudotuberculosis genomes. Moreover, it has also been possible to define the in silico predicted dispensable and unique C. pseudotuberculosis exported proteins. These results provide in silico evidence to further guide experiments in the areas of vaccines, diagnosis and drugs. The work here presented is the first whole C. pseudotuberculosis in silico predicted pan-exoproteome completed till today. PMID- 23095953 TI - Newborn screening for critical congenital heart disease: potential roles of birth defects surveillance programs--United States, 2010-2011. AB - In September 2011, the Secretary of the U.S. Department of Health and Human Services (HHS) approved the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) 2010 recommendation that all newborns be screened for critical congenital heart disease (CCHD) using pulse oximetry, a noninvasive test of blood oxygenation, to prevent mortality and morbidity. CDC partnered with the National Birth Defects Prevention Network (NBDPN) to conduct a survey designed to assess state birth defect surveillance programs' potential roles, capabilities, and readiness to assist with newborn screening activities for CCHD. States were surveyed in November 2010, after the initial SACHDNC recommendation, and again in November 2011, after the Secretary's approval. From 2010 to 2011, the number of birth defects surveillance programs involved in CCHD screening increased from one to 10. Barriers exist, such as the lack of legislative authority, staffing, funding, and informatics infrastructure. Sixty seven percent of programs take an average of more than 12 months to collect complete data on birth defect cases, including congenital heart defects. An assessment of state birth defects programs' existing data and capability to lead the evaluation of screening for CCHD is warranted. PMID- 23095952 TI - Screening reactive metabolites bioactivated by multiple enzyme pathways using a multiplexed microfluidic system. AB - A multiplexed, microfluidic platform to detect reactive metabolites is described, and its performance is illustrated for compounds metabolized by oxidative and bioconjugation enzymes in multi-enzyme pathways to mimic natural human drug metabolism. The device features four 8-electrode screen printed carbon arrays coated with thin films of DNA, a ruthenium-polyvinylpyridine (RuPVP) catalyst, and multiple enzyme sources including human liver microsomes (HLM), cytochrome P450 (cyt P450) 1B1 supersomes, microsomal epoxide hydrolase (EH), human S9 liver fractions (Hs9) and N-acetyltransferase (NAT). Arrays are arranged in parallel to facilitate multiple compound screening, enabling up to 32 enzyme reactions and measurements in 20-30 min. In the first step of the assay, metabolic reactions are achieved under constant flow of oxygenated reactant solutions by electrode driven natural catalytic cycles of cyt P450s and cofactor-supported bioconjugation enzymes. Reactive metabolites formed in the enzyme reactions can react with DNA. Relative DNA damage is measured in the second assay step using square wave voltammetry (SWV) with RuPVP as catalyst. Studies were done on chemicals known to require metabolic activation to induce genotoxicity, and results reproduced known features of metabolite DNA-reactivity for the test compounds. Metabolism of benzo[a]pyrene (B[a]P) by cyt P450s and epoxide hydrolase showed an enhanced relative DNA damage rate for DNA compared to cyt P450s alone. DNA damage rates for arylamines by pathways featuring both oxidative and conjugative enzymes at pH 7.4 gave better correlation with rodent genotoxicity metric TD(50). Results illustrate the broad utility of the reactive metabolite screening device. PMID- 23095954 TI - Progress toward global eradication of dracunculiasis--January 2011-June 2012. AB - Dracunculiasis (Guinea worm disease) is caused by Dracunculus medinensis, a parasitic worm. Approximately 1 year after initial infection from contaminated drinking water, the worm emerges through the skin of the infected person, usually on the lower limb. Pain and secondary bacterial wound infection can cause temporary or permanent disability that disrupts work and schooling for the entire family. In 1986, the World Health Assembly (WHA) called for dracunculiasis elimination and the Guinea Worm Eradication Program, supported by The Carter Center, World Health Organization (WHO), United Nations Children's Fund (UNICEF), CDC, and other partners, was coalesced to assist ministries of health of endemic countries in meeting this goal. At that time, an estimated 3.5 million cases occurred annually in 20 countries in Africa and Asia. This report updates published and previously unpublished surveillance data reported by ministries of health and describes progress toward global dracunculiasis eradication. In 2011, a total of 1,058 cases were reported. As of 2012, dracunculiasis remained endemic in only four countries. Through June 2012, worldwide reductions in reported cases continued, compared with the first 6 months of 2011. Failures in surveillance and containment, lack of clean drinking water, and insecurity in Mali and parts of South Sudan continue to challenge dracunculiasis eradication efforts. PMID- 23095955 TI - Progress toward poliomyelitis eradication--Chad, January 2011-August 2012. AB - In 1988, the World Health Assembly launched the Global Polio Eradication Initiative (GPEI) to interrupt transmission of wild poliovirus (WPV). By January 2012, indigenous WPV transmission had been interrupted in all countries except Afghanistan, Pakistan, and Nigeria. However, importation of WPV caused outbreaks in 29 and reestablished transmission in four, previously polio-free African countries during 2003-2011. Transmission after WPV importation is considered reestablished when it continues for >= 12 months; in Chad, transmissions of WPV type 3 (WPV3) and WPV type 1 (WPV1) were reestablished. WPV3 was imported from Nigeria in 2007 and continued to circulate; the latest reported WPV3 case occurred on March 10, 2011. Transmission of WPV1 continued after a WPV1 case was imported from Nigeria in September 2010; the latest reported WPV1 occurred on June 14, 2012. This report updates previous reports and describes polio eradication activities and progress in Chad during January 2011-August 2012, as of October 2, 2012. Five WPV1 cases were reported during January-August 2012, compared with 111 WPV1 cases and three WPV3 cases reported during the same period in 2011. Five circulating type 2 vaccine-derived poliovirus (cVDPV2) cases occurred during July-August 2012. Current progress suggests that Chad could interrupt reestablished WPV transmission in 2012, although limitations in surveillance hamper the ability to detect ongoing transmission. Furthermore, with ongoing endemic WPV transmission in Nigeria, Chad remains at risk for new WPV importations. Efforts to strengthen surveillance and enhance routine and campaign immunization performance will need to continue in Chad to ensure interruption of reestablished WPV transmission, limit circulation after any WPV importation, and interrupt transmission of cVDPV. PMID- 23095957 TI - Pharmacology of procedural sedation. PMID- 23095959 TI - Reviving the advanced practice column: a clinically and academically relevant endeavor. PMID- 23095960 TI - A model of authentic leadership to support a healthy work environment. PMID- 23095961 TI - Improving glycemic control with the adjunct use of a data management software program. AB - BACKGROUND: Published studies have supported the implementation of tight glucose control (TGC) programs to improve patient outcomes and reduce mortality rates. However, measuring a program's efficiency is challenging, because of a lack of systems that capture data, allow access to data, and support analysis and interpretation in a near prospective time frame. We hypothesized that providing clinicians access to real-time blood glucose (BG) results reports could improve the efficacy of our TGC program. METHODS: We performed a retrospective review of BG data during a 12-month period in a surgical trauma intensive care unit at a level I trauma center. A unit-specific insulin algorithm was used throughout the study. We compared BG values before and after the implementation of a data management software program that allowed clinicians access to real-time BG results reports. Reports were run daily and weekly to monitor the unit's TGC program. RESULTS: A total of 70 616 BG values from 1044 patients were analyzed. An overall decrease was observed in the BG level mean, from 121 mg/dL to 112 mg/dL (P < .001), as well as a decrease in the aggregated mean across patients, from 132 mg/dL to 119 mg/dL (P < .001), after implementation of the software. The percentage of values within the target range of 80 to 110 mg/dL increased from 38.9% to 50.4% (P < .001). The percentage of BG values less than 70 increased from 2.7% to 3.4% (P < .001). However, the percentage of severe hypoglyce-mic episodes (<= 40 mg/dL) remained unchanged. CONCLUSIONS: Access to real-time aggregated BG data reports through the use of a data management software program improved the efficacy of our TGC program. PMID- 23095962 TI - High-frequency percussive ventilation using the VDR-4 ventilator: an effective strategy for patients with refractory hypoxemia. AB - High-frequency percussive ventilation (HFPV) has been used for patients with severe respiratory compromise refractory to conventional mechanical ventilation. It frequently results in equivalent or improved oxygenation and ventilation at lower peak pressures than conventional ventilation, thus minimizing secondary ventilator-associated lung injury. The only ventilator currently available that delivers HFPV is the volume diffusive respirator (VDR-4; Percussionaire Corp, Sandpoint, Idaho). High-frequency percussive ventilation is delivered via a pneumatically powered, pressure-limited, time-cycled, high-frequency flow interrupter and provides small tidal volumes with 300 to 700 oscillations per minute. Following transition to HFPV, respiratory status often stabilizes or improves within a few hours. The unique gas flow mobilizes significant volumes of pulmonary secretions, further facilitating gas exchange. This article reviews the operating principles of HFPV, the functional components of the VDR-4, and the special nursing care considerations to include sedation, hemodynamic assessment, skin and oral care, nutrition, and weaning from ventilation. PMID- 23095963 TI - Islam, brain death, and transplantation: culture, faith, and jurisprudence. AB - A significant gap exists between availability of organs for transplant and patients with end-stage organ failure for whom organ transplantation is the last treatment option. Reasons for this mismatch include inadequate approach to potential donor families and donor loss as a result of refractory cardiopulmonary instability during and after brainstem herniation. Other reasons include inadequate cultural competence and sensitivity when communicating with potential donor families. Clinicians may not have an understanding of the cultural and religious perspectives of Muslim families of critically ill patients who may be approached about brain death and organ donation. This review analyzes Islamic cultural and religious perspectives on organ donation, transplantation, and brain death, including faith-based directives from Islamic religious authorities, definitions of death in Islam, and communication strategies when discussing brain death and organ donation with Muslim families. Optimal family care and communication are highlighted using case studies and backgrounds illustrating barriers and approaches with Muslim families in the United States and in the Kingdom of Saudi Arabia that can improve cultural competence and family care as well as increase organ availability within the Muslim population and beyond. PMID- 23095964 TI - Pharmacotherapy for pediatric acute and critical care. PMID- 23095965 TI - Pharmacotherapy of pediatric advanced life support and toxicological emergencies. AB - Guidelines for pediatric advanced life support have been available for nearly a quarter of a century. Recommendations for the pharmacological management of pediatric cardiac arrest have changed over these years. Several important differences have been observed between adult advanced cardiac life support and pediatric advanced life support that must be recognized when children require resuscitation, such as the cause of the arrest, age-specific monitoring parameters, weight-based medication dosing, and obstacles in obtaining venous access. To make matters more complicated, differences also exist across neonatal and pediatric age spectrums. In addition, some toxicological emergencies commonly occurring in children require pharmacological management with agents that have a unique mechanism of action for cardiac support. PMID- 23095967 TI - Sedation and analgesia in critically ill children. AB - The interplay of pain, discomfort, and fear can cause agitation in critically ill children. Therefore, sedation and analgesia are essential components in the intensive care unit setting and are best managed with a multidisciplinary team approach. No one standard approach exists to assess and manage pain and anxiety. Many tools are available for the assessment of pain and sedation, but each tool has its advantages and disadvantages. Clinicians should consider adopting a validated tool for routine continuous assessment. Multiple pharmacological therapies are available to manage pain, anxiety, fear, and agitation. Dosing of these agents can be influenced by age-related pharmacokinetic and pharmacodynamic changes. Agents should be selected on the basis of the child's disease state, desired level of sedation, and cardiac and respiratory status. PMID- 23095971 TI - Neonatal and pediatric parenteral nutrition. AB - Parenteral nutrition is one of the most important therapeutic modalities invented in the last several decades. Since its introduction in the 1960s, this modality has saved thousands of lives by providing nutrients parenterally to sustain growth in premature neonates with severe intestinal immaturity and other pediatric patients with intestinal failure, such as a gastrointestinal fistula or short bowel syndrome. Although parenteral nutrition can be a lifesaving treatment, it is not benign. Many complications can result from either short- or long-term usage. This review discusses the nutritional requirements, common complications, medication additives, and special considerations for pediatric patients requiring parenteral nutrition. PMID- 23095969 TI - Pharmacological management of pediatric patients with sepsis. AB - With an overall mortality rate of 4.2%, sepsis is one of the most common causes of death in children worldwide. The Surviving Sepsis Campaign outlines rapid initiation of volume resuscitation with crystalloids and timely administration of broad-spectrum antibiotics as the backbone of sepsis treatment. Initial antibiotics should be broad enough to cover the most likely pathogens, but antibiotic therapy should be de-escalated when culture results become available. Therapy with a vasopressor and/or an inotrope is often necessary in patients with sepsis to improve blood pressure and cardiac output. Adjunctive therapy with hydrocortisone is sometimes beneficial in the setting of catecholamine resistance and/or adrenal insufficiency. Insulin may also be needed in some patients for the treatment of hyperglycemia. Current guidelines have improved the treatment of sepsis, but more research is needed. This article reviews sepsis pathophysiology, treatment, and supportive care specifically as they relate to pediatric patients. PMID- 23095974 TI - Engaging research partners to advance clinical inquiry. PMID- 23095975 TI - Phagocytic NADPH oxidase links ARNO-Arf6 signaling pathway in glucose-stimulated insulin secretion from the pancreatic beta-cell. AB - BACKGROUND: Recent findings from our laboratory have demonstrated that glucose stimulated insulin secretion (GSIS) involves interplay between a variety of small G proteins belonging to the Rho (e.g., Cdc42 and Rac1) and ADP-ribosylation factor (e.g., Arf6) subfamilies. Using immunological, pharmacological and molecular biological approaches, we have also identified guanine nucleotide exchange factors (GEFs) for Rac1 (e.g., Tiam1) and Arf6 (e.g., ARNO) in clonal INS-1 832/13 cells, normal rat islets and human islets. As a logical extension to these studies, we investigated, herein, potential downstream signaling steps involved in Arf6/ARNO-mediated GSIS. METHODS: Using a selective pharmacological inhibitor of ARNO/Arf6 signaling axis (e.g., secinH3) we assessed regulatory roles for Arf6/ARNO in promoting phospholipase D (PLD), phagocytic NADPH oxidase (Nox2), reactive oxygen species (ROS), extracellular-regulated kinases (ERK 1/2) and cofilin (actin-severing protein] signaling steps in clonal INS-1 832/13 cells. RESULTS: Our data suggested a marked inhibition by secinH3 of glucose induced PLD activation, ERK1/2 phosphorylation and dephosphorylation of cofilin, suggesting that Arf6/ ARNO signaling mediates PLD, ERK1/2 and cofilin activation in beta-cells. In addition, secinH3 blocked glucose-induced Nox2 activation and associated ROS generation, thus placing Nox downstream to Arf6/ARNO signaling step. Lastly, we also demonstrate a significantly higher cofilin phosphorylation (inactive) in islets derived from type 2 diabetic human donors as well as the Zucker Diabetic Fatty (ZDF) rat, a model for type 2 diabetes. CONCLUSION: Together, our current findings identify signaling steps downstream to ARNO/Arf6 axis leading to insulin secretion. PMID- 23095976 TI - Caffeine improves the ability of serotonin-deficient (Pet-1-/-) mice to survive episodic asphyxia. AB - BACKGROUND: In neonatal rodents, serotonin (5-HT) neurons are critical for successful autoresuscitation. We hypothesized that caffeine, a respiratory stimulant, would hasten the onset of gasping and improve autoresuscitation in 5 HT-deficient, Pet-1(-/-) mice. METHODS: Using a head-out system and electrocardiogram, we measured respiratory and heart rate (HR) responses of Pet 1(-/-) rodents and their littermates during episodic asphyxia at postnatal days 8 9 (P8-9). After a baseline recording, we injected either vehicle or caffeine (i.p.) at doses of 1, 5, or 10 mg/kg. We then induced 10 brief (~30 s) episodes of asphyxia, each interspersed with 5 min of room air to allow autoresuscitation. In addition to measuring survival, we measured the duration of hypoxic apnea (time to initiate gasping) and time to recover eupnea and HR. RESULTS: Caffeine had a dose-dependent effect of hastening the onset of gasping, recovery of breathing, and restoration of HR in Pet-1(-/-) (but not in wild-type) rodents, thereby improving survival across asphyxic episodes. Increased survival was strongly correlated with hastened onset of gasping. CONCLUSION: Our data suggest that caffeine reduces mortality relating to asphyxia and 5-HT deficiency. These findings may be relevant for efforts to reduce the incidence of sudden infant death syndrome (SIDS), given that SIDS is associated with failed autoresuscitation and reduced brainstem 5-HT. PMID- 23095977 TI - Effect of balloon atrial septostomy on cerebral oxygenation in neonates with transposition of the great arteries. AB - BACKGROUND: The aim of this study was to determine the effect of balloon atrial septostomy (BAS) on cerebral oxygenation in neonates with transposition of the great arteries (TGA). METHODS: In term neonates with TGA, regional cerebral tissue oxygen saturation (r(c)SO(2)) was measured using near-infrared spectroscopy (NIRS) for a period of 2 h, before BAS, after BAS, and 24 h after BAS. In neonates who did not require BAS on clinical grounds, r(c)SO(2) was measured within 24 h of admission and 24 h later. RESULTS: BAS was performed in 12 of 21 neonates. r(c)SO(2) increased from a median of 42% (before) to 48% at 2 h after BAS (P < 0.05), as did transcutaneous arterial oxygen saturation (spO(2)) (from 72% to 85%, P < 0.01). r(c)SO(2) increased further during the next 24 h (from 48% to 64%, P < 0.05), whereas spO(2) remained stable. Although beginning from a lower baseline (42 vs. 51%, P < 0.01), r(c)SO(2) was higher in neonates treated with BAS, as compared with neonates not treated with BAS, 24 h after the procedure (64 vs. 58%, P < 0.05); spO(2) was, however, similar between the two groups. CONCLUSION: BAS improves cerebral oxygen saturation in neonates with TGA. Complete recovery of cerebral oxygen saturation occurred only 24 h after BAS. PMID- 23095978 TI - Longitudinal infusion of a complex of insulin-like growth factor-I and IGF binding protein-3 in five preterm infants: pharmacokinetics and short-term safety. AB - BACKGROUND: In preterm infants, low levels of insulin-like growth factor-I (IGF I) and IGF binding protein 3 (IGFBP-3) are associated with impaired brain growth and retinopathy of prematurity (ROP). Treatment with IGF-I/IGFBP-3 may be beneficial for brain development and may decrease the prevalence of ROP. METHODS: In a phase II pharmacokinetics and safety study, five infants (three girls) with a median (range) gestational age (GA) of 26 wk + 6 d (26 wk + 0 d to 27 wk + 2 d) and birth weight of 990 (900-1,212) g received continuous intravenous infusion of recombinant human (rh)IGF-I/rhIGFBP-3. Treatment was initiated during the first postnatal day and continued for a median (range) duration of 168 (47-168) h in dosages between 21 and 111 ug/kg/24 h. RESULTS: Treatment with rhIGF-I/rhIGFBP-3 was associated with higher serum IGF-I and IGFBP-3 concentrations (P < 0.001) than model-predicted endogenous levels. Of 74 IGF-I samples measured during study drug infusion, 37 (50%) were within the target range, 4 (5%) were above, and 33 (45%) were below. The predicted dose of rhIGF-I/rhIGFBP-3 required to establish circulating levels of IGF-I within the intrauterine range in a 1,000 g infant was 75-100 ug/kg/24 h. No hypoglycemia or other adverse effects were recorded. CONCLUSION: In this study, continuous intravenous infusion of rhIGF-I/rhIGFBP-3 was effective in increasing serum concentrations of IGF-I and IGFBP-3, and was found to be safe. PMID- 23095979 TI - Plasma cytokines and markers of endothelial activation increase after packed red blood cell transfusion in the preterm infant. AB - BACKGROUND: Transfusion of packed red blood cells (PRBCs) saves lives in the neonatal critical care setting and is one of the most common interventions in the preterm infant. The number and volume of PRBC transfusions are associated with several major neonatal morbidities, although a direct causal link between transfusion and major neonatal morbidity is still to be proven. Transfusion related immunomodulation (TRIM) may underlie these adverse outcomes, yet it has received little attention in the high-risk preterm infant. METHODS: One transfusion event was studied in infants <=28 wk gestation between 2 and 6 wk postnatal age (n = 28). Plasma inflammatory cytokines and markers of endothelial activation were measured in the infants before and 2-4 h after transfusion, as well as in the donor pack. RESULTS: Median (range) age at transfusion was 18 (14 39) days with the pretransfusion hemoglobin level at 9.8 (7.4-10.2) g/dl. Interleukin (IL)-1beta (P = 0.01), IL-8 (P = <0.001), tumor necrosis factor-alpha (P = 0.008), and monocyte chemoattractant protein (P = 0.01) were increased after transfusion. A similar elevation in markers of endothelial activation was seen after transfusion with increased plasma macrophage inhibitory factor (P = 0.005) and soluble intracellular adhesion molecule-1 (P = <0.001). CONCLUSION: Production of inflammatory cytokines and immunoactivation of the endothelium observed after the transfusion of PRBCs in the preterm infant may be a manifestation of TRIM. The implications of this emerging phenomenon within the preterm neonatal population warrant further investigation. PMID- 23095981 TI - Relationship between lower limb muscle strength and 6-minute walk test performance in stroke patients. AB - OBJECTIVE: The aim of this study was to determine if lower limb muscle strength and/or spasticity are related to performance in the 6-min walk test (6MWT) in stroke patients. METHODS: A total of 24 patients (12 males and 12 females) participated in the study. Muscle strength (Medical Research Council (MRC) scale) and spasticity (modified Ashworth scale) were assessed prior to the 6MWT. Heart rate was recorded at rest and during the 6MWT. Subjects were divided into two groups: (i) those with a high MRC sum score, and (ii) those with a low MRC sum score. The relationship between the 6MWT distance and the other parameters was analysed using a Spearman's rank correlation coefficient. RESULTS: There was a significant and positive relationship between 6MWT distance and lower limb muscle strength (p = 0.001), whereas no significant correlations were found between the 6MWT distance and spasticity, resting heart rate and heart rate during the 6MWT. CONCLUSION: The 6MWT distance may be a good indicator of lower limb muscle strength, and lower limb strengthening may improve gait capacity in stroke patients. PMID- 23095980 TI - Iron supplementation dose for perinatal iron deficiency differentially alters the neurochemistry of the frontal cortex and hippocampus in adult rats. AB - BACKGROUND: Long-term prefrontal cortex (PFC)- and hippocampus-based cognitive deficits are the sequelae of perinatal iron deficiency, despite iron supplementation starting in the newborn period. Whether high-dose iron supplementation prevents these deficits is yet to be determined. METHODS: Perinatal iron deficiency was induced in rat pups using a low-iron (3 mg/kg diet) diet during gestation until postnatal day (P)8. Iron was supplemented using a standard (40 mg/kg diet) or a 10-fold higher (400 mg/kg diet) iron-containing diet until P21. PFC and hippocampal neurochemistry was determined using in vivo (1)H nuclear magnetic resonance (NMR) spectroscopy at 9.4 Tesla on P90. RESULTS: Both standard and 10-fold higher iron supplementation doses corrected anemia and brain iron deficiency by P21. The neurochemical profile of the PFC in both supplementation groups was comparable with the control group. In the hippocampus, standard-dose iron supplementation resulted in lower concentrations of N acetylaspartate (NAA) and phosphoethanolamine (PE) and higher concentrations of N acetylaspartylglutamate (NAAG) and glycerophosphocholine + phosphocholine (GPC + PC). High-dose iron supplementation resulted in lower PE and higher GPC + PC concentrations. CONCLUSION: The iron supplementation dose for perinatal iron deficiency differentially alters the neurochemical profile of the PFC and hippocampus in adults. The neurochemical changes suggest altered glutamatergic neurotransmission, hypomyelination, and abnormal phospholipid metabolism in the formerly iron-deficient (FID) hippocampus. PMID- 23095982 TI - Gene-expression-based cancer subtypes prediction through feature selection and transductive SVM. AB - With the advancement of microarray technology, gene expression profiling has shown great potential in outcome prediction for different types of cancers. Microarray cancer data, organized as samples versus genes fashion, are being exploited for the classification of tissue samples into benign and malignant or their subtypes. They are also useful for identifying potential gene markers for each cancer subtype, which helps in successful diagnosis of particular cancer type. Nevertheless, small sample size remains a bottleneck to design suitable classifiers. Traditional supervised classifiers can only work with labeled data. On the other hand, a large number of microarray data that do not have adequate follow-up information are disregarded. A novel approach to combine feature (gene) selection and transductive support vector machine (TSVM) is proposed. We demonstrated that 1) potential gene markers could be identified and 2) TSVMs improved prediction accuracy as compared to the standard inductive SVMs (ISVMs). A forward greedy search algorithm based on consistency and a statistic called signal-to-noise ratio were employed to obtain the potential gene markers. The selected genes of the microarray data were then exploited to design the TSVM. Experimental results confirm the effectiveness of the proposed technique compared to the ISVM and low-density separation method in the area of semisupervised cancer classification as well as gene-marker identification. PMID- 23095983 TI - Giant left ventricular aneurysm as a late complication of inferior myocardial infarction. PMID- 23095984 TI - Predicting survival in heart failure: a risk score based on 39 372 patients from 30 studies. AB - AIMS: Using a large international database from multiple cohort studies, the aim is to create a generalizable easily used risk score for mortality in patients with heart failure (HF). METHODS AND RESULTS: The MAGGIC meta-analysis includes individual data on 39 372 patients with HF, both reduced and preserved left ventricular ejection fraction (EF), from 30 cohort studies, six of which were clinical trials. 40.2% of patients died during a median follow-up of 2.5 years. Using multivariable piecewise Poisson regression methods with stepwise variable selection, a final model included 13 highly significant independent predictors of mortality in the following order of predictive strength: age, lower EF, NYHA class, serum creatinine, diabetes, not prescribed beta-blocker, lower systolic BP, lower body mass, time since diagnosis, current smoker, chronic obstructive pulmonary disease, male gender, and not prescribed ACE-inhibitor or angiotensin receptor blockers. In preserved EF, age was more predictive and systolic BP was less predictive of mortality than in reduced EF. Conversion into an easy-to-use integer risk score identified a very marked gradient in risk, with 3-year mortality rates of 10 and 70% in the bottom quintile and top decile of risk, respectively. CONCLUSION: In patients with HF of both reduced and preserved EF, the influences of readily available predictors of mortality can be quantified in an integer score accessible by an easy-to-use website www.heartfailurerisk.org. The score has the potential for widespread implementation in a clinical setting. PMID- 23095985 TI - First reported case of septal artery rupture after endo-myocardial biopsies. PMID- 23095986 TI - Simple aspiration in acute myocardial infarction: too simple to be true? PMID- 23095987 TI - The relationship of depression, anxiety and stress with low bone mineral density in post-menopausal women. AB - The goal of the present study was to examine the relationships of depression, anxiety and stress with bone mineral density (BMD). We hypothesized negative relations between those mood variables and BMD in three assessed areas. The study showed association between depression and decreased BMD. The hypothesis regarding anxiety and stress was partially confirmed. INTRODUCTION: In the last decade, the relationship of osteoporosis to psychological variables has been increasingly studied. The accumulating evidence from these studies supports the conclusion that depression is related to decreased BMD. Nevertheless, several studies found no support for this relationship. Moreover, only a small number of studies examined the association between anxiety or stress and decreased BMD. The goal of the present study was to examine the relationships of depression, anxiety and stress with BMD by means of adequate measuring instruments, while controlling for background factors known to be related to BMD decrease (e.g., body mass index, family history). METHOD: The study included 135 post-menopausal female participants, who arrived for BMD screening, between the years 2006 and 2009. Several days prior to the examination, participants completed a series of questionnaires assessing depression and anxiety. BMD was measured using DXA, in spine, right and left hip. RESULTS: The study showed negative associations between depression and BMD variables in the three assessed areas. There were negative correlations between anxiety, stress and spine BMD, as well as a tendency towards negative relations in the right and left hip BMD. Concurrent hierarchical regressions showed that the addition of the three psychological variables increased the explained variance by 6-8 %. In addition, depression was found to have a unique significant contribution to the explained variance in right and left hip BMD. CONCLUSIONS: The findings provide supporting evidence for the existence of associations between mood variables and decreased BMD. Further research is required for gaining deeper insight into these relationships. PMID- 23095989 TI - Prevention of haloperidol-induced alterations in brain acetylcholinesterase activity by vitamins B co-administration in a rodent model of tardive dyskinesia. AB - Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1 mg/kg i.p. daily administration during 21 days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6 mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect. PMID- 23095988 TI - CENP-A: the key player behind centromere identity, propagation, and kinetochore assembly. AB - Chromosome segregation is the one of the great problems in biology with complexities spanning from biophysics and polymer dynamics to epigenetics. Here, we summarize the current knowledge and highlight gaps in understanding of the mechanisms controlling epigenetic regulation of chromosome segregation. PMID- 23095990 TI - A validated bowel-preparation tolerability questionnaire and assessment of three commonly used bowel-cleansing agents. AB - BACKGROUND AND STUDY AIMS: Bowel-cleansing studies are frequently underpowered, poorly designed, and with subjective assessments. Consensus on tolerability of the bowel-cleansing agents is thus lacking. This study developed and validated a bowel-preparation tolerability questionnaire and used it to assess the tolerability of three bowel-cleansing agents, sodium phosphate (NaP), polyethylene glycol (PEG), and sodium picosulphate (Pico), in a prospective randomized single-blinded trial of ambulatory patients. PATIENTS AND METHODS: The bowel-preparation tolerability questionnaire was validated in 125 consecutive patients and then bowel-preparation agent tolerability was assessed in 634 patients in a prospective randomized single-blinded trial. RESULTS: The questionnaire's internal consistency was satisfactory with good to excellent "test-retest" reliability for aggregate tolerability and visual analogue scores. Validity assessment confirmed it as reliable and accurate. Of 634 patients, 97.8 % took >75 % of the allocated preparation and 98.9 % completed the questionnaire. Overall, Pico was better tolerated than PEG (p < 0.001) and NaP (p < 0.001). NaP was better tolerated than PEG (p < 0.001). Regardless of the bowel-preparation agent used, males tolerated them better than females (p = 0.009) as did patients having their procedure in the AM. Older patients, however, tolerated all preparations better than younger patients (p = 0.006). CONCLUSIONS: This study used the first validated bowel-preparation tolerability questionnaire and identified that age, sex, and procedure time all impacted tolerability. Overall, Pico was best tolerated, but PEG's tolerability in patients >=60 years was equal to that of Pico and NaP, suggesting that PEG can be recommended for older patients to avoid the electrolyte disturbances associated with the osmotic preparations. PMID- 23095992 TI - Heterosis: emerging ideas about hybrid vigour. AB - Perceived by Charles Darwin in many vegetable plants and rediscovered by George H Shull and Edward M East in maize, heterosis or hybrid vigour is one of the most widely utilized phenomena, not only in agriculture but also in animal breeding. Although, numerous studies have been carried out to understand its genetic and/or molecular basis in the past 100 years, our knowledge of the underlying molecular processes that results in hybrid vigour can best be defined as superficial. Even after century long deliberations, there is no consensus on the relative/individual contribution of the genetic/epigenetic factors in the manifestation of heterosis. However, with the recent advancements in functional genomics, transcriptomics, proteomics, and metabolomics-related technologies, the riddle of heterosis is being reinvestigated by adopting systems-level approaches to understand the underlying molecular mechanisms. A number of intriguing hypotheses are converging towards the idea of a cumulative positive effect of the differential expression of a variety of genes, on one or several yield-affecting metabolic pathways or overall energy-use efficiency, as the underlying mechanism for the manifestation of heterosis. Presented here is a brief account of clues gathered from various investigative approaches targeted towards better scientific understanding of this process. PMID- 23095991 TI - CD34+ hematopoietic stem cells mobilization, paralleled with multiple cytokines elevated in patients with HBV-related acute-on-chronic liver failure. AB - BACKGROUND: Recent studies indicate that bone marrow (BM)-derived stem cells contribute to liver regeneration. But limited information is available on the dynamic and mechanisms of mobilization of BM-derived hematopoietic stem cells (HSCs) after acute-on-chronic liver failure (ACLF). AIMS: The purpose of this study was to assess the mobilization of BM-derived CD34+ HSCs in ACLF patients, and elucidate the association of stress-induced cytokines in HSCs mobilization and/or liver repair in ACLF patients. METHODS: Thirty patients with HBV-related ACLF, 30 patients undergoing chronic hepatitis B, and 20 healthy controls were enrolled. The percentages of peripheral blood CD34+ cells were determined by two color flow cytometry. The hepatic commitment of mobilized CD34+ cells was investigated by RT-PCR. The serum levels of stress-induced cytokines were determined by enzyme-linked immunosorbent assays. RESULTS: A significant increase of circulating CD34+ cells was observed in ACLF patients. RT-PCR analyses showed that the mobilized CD34+ cells expressed both CD34 mRNA and liver-specific markers including cytokeratin 19 and alpha-fetoprotein. In parallel with mobilization of BM-derived CD34+ cells, elevated serum levels of hepatocyte growth factor, interleukin-6, stem cell factor, granulocyte colony-stimulating factor and matrix metalloproteinase 9 were observed in ACLF patients. CONCLUSION: We demonstrated that ACLF led to mobilization of CD34+ cells, which had a hepatic differentiation potential. PMID- 23095993 TI - Ethylene-responsive transcription factors interact with promoters of ADH and PDC involved in persimmon (Diospyros kaki) fruit de-astringency. AB - The persimmon fruit is a particularly good model for studying fruit response to hypoxia, in particular, the hypoxia-response ERF (HRE) genes. An anaerobic environment reduces fruit astringency by converting soluble condensed tannins (SCTs) into an insoluble form. Although the physiology of de-astringency has been widely studied, its molecular control is poorly understood. Both CO(2) and ethylene treatments efficiently removed the astringency from 'Mopan' persimmon fruit, as indicated by a decrease in SCTs. Acetaldehyde, the putative agent for causing de-astringency, accumulated during these treatments, as did activities of the key enzymes of acetaldehyde synthesis, alcohol dehydrogenase (ADH), and pyruvate decarboxylase (PDC). Eight DkADH and DkPDC genes were isolated, and three candidates for a role in de-astringency, DkADH1, DkPDC1, and DkPDC2, were characterized by transcriptional analysis in different tissues. The significance of these specific isoforms was confirmed by principal component analysis. Transient expression in leaf tissue showed that DkPDC2 decreased SCTs. Interactions of six hypoxia-responsive ERF genes and target promoters were tested in transient assays. The results indicated that two hypoxia-responsive ERF genes, DkERF9 and DkERF10, were involved in separately regulating the DkPDC2 and DkADH1 promoters. It is proposed that a DkERF-DkADH/DkPDC cascade is involved in regulating persimmon de-astringency. PMID- 23095994 TI - Microbial recognition and evasion of host immunity. AB - Plants are able to detect microbes by pattern recognition receptors in the host cells that, upon recognition of the enemy, activate effective immune responses in the invaded tissue. Recognition of microbes occurs by common conserved structures called microbe-associated molecular patterns (MAMPs). Plant pathogens and beneficial soil-borne microbes live in close contact with their host. Hence, prevention of the host's defence programme is essential for their survival. Active suppression of host defences by microbial effector proteins is a well known strategy employed by many successful plant-associated microbes. Evasion of host immune recognition is less well studied but is emerging as another important strategy. Escape from recognition by the host's immune system can be caused by alterations in the structure of the recognized MAMPs, or by active intervention of ligand-receptor recognition. This paper reviews the structure and recognition of common MAMPs and the ways that plant-associated microbes have evolved to prevent detection by their host. PMID- 23095995 TI - Pinot blanc and Pinot gris arose as independent somatic mutations of Pinot noir. AB - Somatic mutation is a natural mechanism which allows plant growers to develop new cultivars. As a source of variation within a uniform genetic background, it also represents an ideal tool for studying the genetic make-up of important traits and for establishing gene functions. Layer-specific molecular characterization of the Pinot family of grape cultivars was conducted to provide an evolutionary explanation for the somatic mutations that have affected the locus of berry colour. Through the study of the structural dynamics along chromosome 2, a very large deletion present in a single Pinot gris cell layer was identified and characterized. This mutation reveals that Pinot gris and Pinot blanc arose independently from the ancestral Pinot noir, suggesting a novel parallel evolutionary model. This proposed 'Pinot-model' represents a breakthrough towards the full understanding of the mechanisms behind the formation of white, grey, red, and pink grape cultivars, and eventually of their specific enological aptitude. PMID- 23095996 TI - Cyanobacterial-based approaches to improving photosynthesis in plants. AB - Plants rely on the Calvin-Benson (CB) cycle for CO(2) fixation. The key carboxylase of the CB cycle is ribulose-1,5-bisphosphate carboxylase/oxygenase (RubisCO). Efforts to enhance carbon fixation in plants have traditionally focused on RubisCO or on approaches that can help to remedy RubisCO's undesirable traits: its low catalytic efficiency and photorespiration. Towards reaching the goal of improving plant photosynthesis, cyanobacteria may be instrumental. Because of their evolutionary relationship to chloroplasts, they represent ideal model organisms for photosynthesis research. Furthermore, the molecular understanding of cyanobacterial carbon fixation provides a rich source of strategies that can be exploited for the bioengineering of chloroplasts. These strategies include the cyanobacterial carbon concentrating mechanism (CCM), which consists of active and passive transporter systems for inorganic carbon and a specialized organelle, the carboxysome. The carboxysome encapsulates RubisCO together with carbonic anhydrase in a protein shell, resulting in an elevated CO(2) concentration around RubisCO. Moreover, cyanobacteria differ from plants in the isoenzymes involved in the CB cycle and the photorespiratory pathways as well as in mechanisms that can affect the activity of RubisCO. In addition, newly available cyanobacterial genome sequence data from the CyanoGEBA project, which has more than doubled the amount of genomic information available for cyanobacteria, increases our knowledge on the CCM and the occurrence and distribution of genes of interest. PMID- 23095997 TI - Cooperation of three WRKY-domain transcription factors WRKY18, WRKY40, and WRKY60 in repressing two ABA-responsive genes ABI4 and ABI5 in Arabidopsis. AB - Three evolutionarily closely related WRKY-domain transcription factors WRKY18, WRKY40, and WRKY60 in Arabidopsis were previously identified as negative abscisic acid (ABA) signalling regulators, of which WRKY40 regulates ABI4 and ABI5 expression, but it remains unclear whether and how the three transcription factors cooperate to regulate expression of ABI4 and ABI5. In the present experiments, it was shown that WRKY18 and WRKY60, like WRKY40, interact with the W-box in the promoters of ABI4 and ABI5 genes, though the three WRKYs have their own preferential binding domains in the two promoters. WRKY18 and WRKY60, together with WRKY40, inhibit expression of the ABI5 and/or ABI4 genes, which is consistent with their negative roles in ABA signalling. Further, genetic evidence is provided that mutations of ABI4 and ABI5 genes suppress ABA-hypersensitive phenotypes of the null mutant alleles of WRKY18 and WRKY60 genes, demonstrating that ABI4 and ABI5 function downstream of these two WRKY transcription factors in ABA signalling. A working model of cooperation of the three WRKYs in repressing ABI4 and ABI5 expression is proposed, in which the three WRKYs antagonize or aid each other in a highly complex manner. These findings help to understand the complex mechanisms of WRKY-mediated ABA signal transduction. PMID- 23095998 TI - Role of a respiratory burst oxidase of Lepidium sativum (cress) seedlings in root development and auxin signalling. AB - Reactive oxygen species are increasingly perceived as players in plant development and plant hormone signalling pathways. One of these species, superoxide, is produced in the apoplast by respiratory burst oxidase homologues (rbohs), a family of proteins that is conserved throughout the plant kingdom. Because of the availability of mutants, the focus of research into plant rbohs has been on Arabidopsis thaliana, mainly on AtrbohD and AtrbohF. This study investigates: (i) a different member of the Atrboh family, AtrbohB, and (ii) several rbohs from the close relative of A. thaliana, Lepidium sativum ('cress'). Five cress rbohs (Lesarbohs) were sequenced and it was found that their expression patterns were similar to their Arabidopsis orthologues throughout the life cycle. Cress plants in which LesarbohB expression was knocked down showed a strong seedling root phenotype that resembles phenotypes associated with defective auxin-related genes. These transgenic plants further displayed altered expression of auxin marker genes including those encoding the auxin responsive proteins 14 and 5 (IAA14 and IAA5), and LBD16 (LATERAL ORGAN BOUNDARIES DOMAIN16), an auxin-responsive protein implicated in lateral root initiation. It is speculated that ROS produced by rbohs play a role in root development via auxin signalling. PMID- 23095999 TI - Phenotypic and developmental plasticity of xylem in hybrid poplar saplings subjected to experimental drought, nitrogen fertilization, and shading. AB - Variation in xylem structure and function has been extensively studied across different species with a wide taxonomic, geographical, and ecological coverage. In contrast, our understanding of how xylem of a single species can adjust to different growing condition remains limited. Here phenotypic and developmental plasticity in xylem traits of hybrid poplar (Populus trichocarpa*deltoides) was studied. Clonally propagated saplings were grown under experimental drought, nitrogen fertilization, and shade for >30 d. Xylem hydraulic and anatomical traits were subsequently examined in stem segments taken from two different vertical positions along the plant's main axis. The experimental treatments affected growth and development and induced changes in xylem phenotype. Across all treatments, the amount of leaf area supported by stem segments (A(L)) scaled linearly with stem native hydraulic conductivity (K (native)), suggesting that the area of assimilating leaves is constrained by the xylem transport capacity. In turn, K (native) was mainly driven by the size of xylem cross-sectional area (A(X)). Moreover, the structural and functional properties of xylem varied significantly. Vulnerability to cavitation, measured as the xylem pressure inducing 50% loss of conductivity (P50), ranged from -1.71 MPa to -0.15 MPa in saplings subjected to drought and nitrogen fertilization, respectively. Across all treatments and stem segment positions, P50 was tightly correlated with wood density. In contrast, no relationship between P50 and xylem-specific conductivity (K (S)) was observed. The results of this study enhance our knowledge of plant hydraulic acclimation and provide insights into common trade-offs that exist in xylem structure and function. PMID- 23096000 TI - Modification of tomato growth by expression of truncated ERECTA protein from Arabidopsis thaliana. AB - ERECTA family genes encode leucine-rich repeat receptor-like kinases that control multiple aspects of plant development such as elongation of aboveground organs, leaf initiation, development of flowers, and epidermis differentiation. These receptors have also been implicated in responses to biotic and abiotic stress, probably as a consequence of their involvement in regulation of plant architecture. Here, ERECTA signalling in tomatoes (Solanum lycopersicum) was manipulated by expressing truncated ERECTA protein (AtDeltaKinase) from Arabidopsis using two different promoters. In Arabidopsis, this protein functions in a dominant-negative manner, disrupting signalling of the whole ERECTA gene family. Expression of AtDeltaKinase under a constitutive 35S promoter dramatically reduced vegetative growth and led to the formation of fruits with a reduced seed set. Similarly, expression of AtDeltaKinase under its own promoter resulted in transgenic tomato plants with diminished growth, a reduced number of leaves, changed flowering time, and slightly increased stomata density. The transgenic plants also exhibited increased tolerance to water deficit stress, at least partially due to their diminished surface area. These phenotypes of the transgenic plants were the result of ERECTA signalling disruption at the protein level, as the expression of two endogenous tomato ERECTA family genes was not suppressed. These results demonstrate the significance of ERECTA family genes for development and stress responses in tomato and suggest that truncated ERECTA can be used to manipulate the growth of crop species. PMID- 23096001 TI - New insights into the reduction systems of plastidial thioredoxins point out the unique properties of thioredoxin z from Arabidopsis. AB - In plants, thioredoxins (TRX) constitute a large protein disulphide oxidoreductase family comprising 10 plastidial members in Arabidopsis thaliana and subdivided in five types. The f- and m-types regulate enzymes involved mainly in carbon metabolism whereas the x, y, and z types have an antioxidant function. The reduction of TRXm and f in chloroplasts is performed in the light by ferredoxin:thioredoxin reductase (FTR) that uses photosynthetically reduced ferredoxin (Fd) as a reductant. The reduction system of Arabidopsis TRXx, y, and z has never been demonstrated. Recently, a gene encoding an atypical plastidial NADPH-dependent TRX reductase (NTRC) was found. In the present study, gene expression analysis revealed that both reductases are expressed in all organs of Arabidopsis and could potentially serve as electron donors to plastidial TRX. This ability was tested in vitro either with purified NTRC in presence of NADPH or with a light-driven reconstituted system comprising thylakoids and purified Fd and FTR. The results demonstrate that FTR reduces the x and y TRX isoforms but not the recently identified TRXz. Moreover, the results show that NTRC cannot be an efficient alternative reducing system, neither for TRXz nor for the other plastidial TRX. The data reveal that TRXf, m, x, and y, known as redox regulators in the chloroplast, have also the ability to reduce TRXz in vitro. Overall, the present study points out the unique properties of TRXz among plastidial TRX. PMID- 23096002 TI - Prediction of back-scatter radiations to a beam monitor chamber of medical linear accelerators by use of the digitized target-current-pulse analysis method. AB - In small-field irradiation, the back-scattered radiation (BSR) affects the counts measured with a beam monitor chamber (BMC). In general, the effect of the BSR depends on the opened-jaw size. The effect is significantly large in small-field irradiation. Our purpose in this study was to predict the effect of BSR on LINAC output accurately with an improved target-current-pulse (TCP) technique. The pulse signals were measured with a system consisting of a personal computer and a digitizer. The pulse signals were analyzed with in-house software. The measured parameters were the number of pulses, the change in the waveform and the integrated signal values of the TCPs. The TCPs were measured for various field sizes with four linear accelerators. For comparison, Yu's method in which a universal counter was used was re-examined. The results showed that the variance of the measurements by the new method was reduced to approximately 1/10 of the variance by the previous method. There was no significant variation in the number of pulses due to a change in the field size in the Varian Clinac series. However, a change in the integrated signal value was observed. This tendency was different from the result of other investigations in the past. Our prediction method is able to define the cutoff voltage for the TCP acquired by digitizer. This functionality provides the capability of clearly classifying TCPs into signals and noise. In conclusion, our TCP analysis method can predict the effect of BSR on the BMC even for small-field irradiations. PMID- 23096003 TI - Identification of genomic regions involved in resistance against Sclerotinia sclerotiorum from wild Brassica oleracea. AB - The lack of resistant source has greatly restrained resistance breeding of rapeseed (Brassica napus, AACC) against Sclerotinia sclerotiorum which causes severe yield losses in rapeseed production all over the world. Recently, several wild Brassica oleracea accessions (CC) with high level of resistance have been identified (Mei et al. in Euphytica 177:393-400, 2011), bringing a new hope to improve Sclerotinia resistance of rapeseed. To map quantitative trait loci (QTL) for Sclerotinia resistance from wild B. oleracea, an F2 population consisting of 149 genotypes, with several clones of each genotypes, was developed from one F1 individual derived from the cross between a resistant accession of wild B. oleracea (B. incana) and a susceptible accession of cultivated B. oleracea var. alboglabra. The F2 population was evaluated for Sclerotinia reaction in 2009 and 2010 under controlled condition. Significant differences among genotypes and high heritability for leaf and stem reaction indicated that genetic components accounted for a large portion of the phenotypic variance. A total of 12 QTL for leaf resistance and six QTL for stem resistance were identified in 2 years, each explaining 2.2-28.4 % of the phenotypic variation. The combined effect of alleles from wild B. oleracea reduced the relative susceptibility by 22.5 % in leaves and 15 % in stems on average over 2 years. A 12.8-cM genetic region on chromosome C09 of B. oleracea consisting of two major QTL intervals for both leaf and stem resistance was assigned into a 2.7-Mb genomic region on chromosome A09 of B. rapa, harboring about 30 putative resistance-related genes. Significant negative corrections were found between flowering time and relative susceptibility of leaf and stem. The association of flowering time with Sclerotinia resistance is discussed. PMID- 23096004 TI - Jews and Arabs in the same region in Israel exhibit major differences in dietary patterns. AB - The Jewish majority and Arab minority populations in Israel exhibit disparities in nutrition-related chronic diseases, but comparative, population-based dietary studies are lacking. We evaluated ethnic differences in dietary patterns in a population-based, cross-sectional study of Arab and Jewish urban adults (n = 1104; age 25-74 y). Dietary intake was assessed with an interviewer-administered, quantified FFQ. We used principal-component analysis to identify 4 major dietary patterns: Ethnic, Healthy, Fish and Meat Dishes, and Middle Eastern Snacks and Fast Food. The Ethnic and Healthy patterns exhibited major ethnic differences. Participants in the top Ethnic intake tertile (97% Arab) had modified Mediterranean-style Arabic dietary habits, whereas those in the bottom Ethnic tertile (98% Jewish) had central/northern European-style dietary habits. The Arab participants with less strongly ethnicity-associated dietary habits were younger [OR for 10-y decrease = 1.42 (95% CI: 1.21-1.68)] and male [OR = 2.23 (95% CI: 1.53-3.25)]. Jews with less strongly ethnicity-associated dietary habits were less recent immigrants [OR = 8.97 (95% CI: 5.05-15.92)], older [OR for 10-y decrease = 0.80 (95% CI: 0.69-0.92)], had post-secondary education [OR = 2.04 (95% CI: 1.06-3.94)], and reported other healthy lifestyle behaviors. In relation to the Healthy pattern, Arabs were less likely than Jews to be in the top intake tertile, but the magnitude of the difference was less in diabetic participants. Participants reporting other healthy lifestyle behaviors were more likely to have a high intake of the Healthy pattern. Substantial differences were found between Arabs and Jews in dietary patterns and suggest a need for culturally congruent dietary interventions to address nutrition-related chronic disease disparities. PMID- 23096006 TI - Mode of action: moving toward a more relevant and efficient assessment paradigm. AB - To advance the utility and predictability of safety evaluation, an integrated approach that relies on all existing knowledge to understand how agents perturb normal biological function or structure is needed to progress more focused evaluation strategies. The mode of action (MOA)-human relevance framework developed by the International Program for Chemical Safety and The International Life Sciences Institute provides a useful analytical approach where different lines of evidence (e.g., in vitro, in vivo) can be organized, linked, and integrated at different levels of biological organization into a more efficient, hypothesis-driven approach to safety evaluation. This framework provides a weight of-evidence approach based on considerations for causality (as originally articulated by Bradford Hill), including dose response and temporal concordance, consistency, specificity, and biological plausibility and coherence. Once an animal MOA and its key events are established, qualitative and quantitative comparisons between experimental animals and humans are made based on the key events. This comparison enables a conclusion as to whether the MOA is likely operative in humans and, if so, whether it can result in a more refined hazard and dose-response assessment. This framework provides an important tool to promote and formalize the use of MOA data in safety evaluation regardless of whether the information comes from traditional or novel approaches, such as those recommended by the NRC in its 2007 report "Toxicity Testing in the 21st Century," which recommends moving away from traditional approaches of measuring adverse endpoints by using newer technologies to identify ways agents may considerably perturb cellular pathways to produce their toxicity. PMID- 23096007 TI - Establishment of true niacin deficiency in quinolinic acid phosphoribosyltransferase knockout mice. AB - Pyridine nucleotide coenzymes are involved in >500 enzyme reactions and are biosynthesized from the amino acid L-tryptophan (L-Trp) as well as the vitamin niacin. Hence, "true" niacin-deficient animals cannot be "created" using nutritional techniques. We wanted to establish a truly niacin-deficient model animal using a protocol that did not involve manipulating dietary L-Trp. We generated mice that are missing the quinolinic acid (QA) phosphoribosyltransferase (QPRT) gene. QPRT activity was not detected in qprt(-/ )mice. The qprt(+/+), qprt(+/-), or qprt(-/-) mice (8 wk old) were fed a complete diet containing 30 mg nicotinic acid (NiA) and 2.3 g L-Trp/kg diet or an NiA-free diet containing 2.3 g L-Trp/kg diet for 23 d. When qprt(-/-)mice were fed a complete diet, food intake and body weight gain did not differ from those of the qprt(+/+) and qprt(+/-) mice. On the contrary, in the qprt(-/-) mice fed the NiA free diet, food intake and body weight were reduced to 60% (P < 0.01) and 70% (P < 0.05) of the corresponding values for the qprt(-/-) mice fed the complete diet at d 23, respectively. The nutritional levels of niacin, such as blood and liver NAD concentrations, were also lower in the qprt(-/-) mice than in the qprt(+/+) and the qprt(+/-) mice. Urinary excretion of QA was greater in the qprt(-/-) mice than in the qprt(+/+) and qprt(+/-) mice (P < 0.01). These data suggest that we generated truly niacin-deficient mice. PMID- 23096005 TI - A higher adherence to a Mediterranean-style diet is inversely associated with the development of frailty in community-dwelling elderly men and women. AB - Adherence to a Mediterranean-style diet is associated with a lower risk for mortality, cognitive decline, and dementia. Whether adherence to a Mediterranean style diet protects against age-related frailty is unclear. Therefore, our objective was to examine the association between a Mediterranean-style diet with the risk of frailty in community-dwelling older persons. We conducted longitudinal analyses using data from 690 community-living persons (>=65 y) who were randomly selected from a population registry in Tuscany, Italy. Participants of the Invecchiare in Chianti study of aging completed the baseline examination in 1998-2000 and were re-examined at least once over 6 y. Adherence to a Mediterranean-style diet (scored 0-9, modeled categorically as <=3, 4-5, and >=6) was computed from the European Prospective Investigation into Cancer and nutrition FFQ previously validated in this cohort. Frailty was defined as having at least 2 of the following criteria: poor muscle strength, feeling of exhaustion, low walking speed, and low physical activity. After a 6-y follow-up, higher adherence (score >=6) to a Mediterranean-style diet was associated with lower odds of developing frailty [OR = 0.30 (95% CI: 0.14, 0.66)] compared with those with lower adherence (score <=3). A higher adherence to a Mediterranean style diet at baseline was also associated with a lower risk of low physical activity (OR = 0.62; 95% CI: 0.40, 0.96) and low walking speed [OR = 0.48 (95% CI: 0.27, 0.86)] but not with feelings of exhaustion and poor muscle strength. In community-dwelling older adults, higher adherence to a Mediterranean-style diet was inversely associated with the development of frailty. PMID- 23096008 TI - Kinetics of L-theanine uptake and metabolism in healthy participants are comparable after ingestion of L-theanine via capsules and green tea. AB - L-Theanine, an amino acid in green tea, is suggested to improve cognition and mood. Therefore, L-theanine is available as a supplement and is now used as an ingredient in functional drinks. Because data on the metabolic fate of L-theanine from human studies are lacking, we investigated the kinetics of L-theanine uptake and its metabolites, ethylamine and glutamic acid, in healthy participants. Within a randomized crossover study, 12 participants ingested a bolus of 100 mg L theanine via capsules or green tea. On further occasions, 3 participants received 50 and 200 mg L-theanine via capsules. Blood and urine were collected before and up to 24 h postconsumption to determine the concentrations of L-theanine, proteinogenic amino acids, and ethylamine in plasma, erythrocytes, and urine by HPLC. L-Theanine increased in plasma, erythrocytes, and urine with comparable results after both treatments. The maximum plasma concentration of L-theanine occurred 0.8 h after intake of 100 mg L-theanine via capsules (24.3 +/- 5.7 MUmol/L) and tea (26.5 +/- 5.2 MUmol/L), respectively. The AUC of L-theanine in plasma increased dose dependently after intake of 50, 100, and 200 mg L-theanine via capsules. Moreover, ethylamine and glutamic acid increased in plasma and were excreted by urine after intake of capsules and tea. In conclusion, L-theanine is rapidly absorbed and seems to be hydrolyzed to ethylamine and glutamic acid. A minor part of L-theanine is retained in erythrocytes. Kinetics and urinary excretion of L-theanine, ethylamine, and glutamic acid are comparable after both treatments. Thus, functional effects of L-theanine intake may result from L theanine, ethylamine, or glutamic acid. PMID- 23096009 TI - A proposal for an upper limit of leucine safe intake in healthy adults. AB - Based on recent research, an upper limit of safe intake (ULSI) for leucine is proposed for healthy adults: 0.53 g/(kg.d). Because leucine has been used as a dietary supplement for many years in people practicing exercise and sport, further study with long-term exposure to leucine in this specific subpopulation should be performed to eventually adjust the ULSI. PMID- 23096010 TI - Cooking enhances but the degree of ripeness does not affect provitamin A carotenoid bioavailability from bananas in Mongolian gerbils. AB - Banana is a staple crop in many regions where vitamin A deficiency is prevalent, making it a target for provitamin A biofortification. However, matrix effects may limit provitamin A bioavailability from bananas. The retinol bioefficacies of unripe and ripe bananas (study 1A), unripe high-provitamin A bananas (study 1B), and raw and cooked bananas (study 2) were determined in retinol-depleted Mongolian gerbils (n = 97/study) using positive and negative controls. After feeding a retinol-deficient diet for 6 and 4 wk in studies 1 and 2, respectively, customized diets containing 60, 30, or 15% banana were fed for 17 and 13 d, respectively. In study 1A, the hepatic retinol of the 60% ripe Cavendish group (0.52 +/- 0.13 MUmol retinol/liver) differed from baseline (0.65 +/- 0.15 MUmol retinol/liver) and was higher than the negative control group (0.39 +/- 0.16 MUmol retinol/liver; P < 0.0065). In study 1B, no groups differed from baseline (0.65 +/- 0.15 MUmol retinol/liver; P = 0.20). In study 2, the 60% raw Butobe group (0.68 +/- 0.17 MUmol retinol/liver) differed from the 60% cooked Butobe group (0.87 +/- 0.24 MUmol retinol/liver); neither group differed from baseline (0.80 +/- 0.27 MUmol retinol/liver; P < 0.0001). Total liver retinol was higher in the groups fed cooked bananas than in those fed raw (P = 0.0027). Body weights did not differ even though gerbils ate more green, ripe, and raw bananas than cooked, suggesting a greater indigestible component. In conclusion, thermal processing, but not ripening, improves the retinol bioefficacy of bananas. Food matrix modification affects carotenoid bioavailability from provitamin A biofortification targets. PMID- 23096011 TI - Quantitation of whole-blood total folate within defined MTHFR C677T genotype groups by isotope dilution-liquid chromatography-tandem mass spectrometry differs from microbiologic assay. AB - Standardization of folate measurement is needed for accurate assessment of folate status. We compared the measurement of whole-blood folate by isotope dilution liquid chromatography-tandem MS (ID-LC-MS/MS) with the historical gold standard microbiological assay (MA) using 3 common calibrators within the frame of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. Seventy-three whole-blood samples with an even distribution of MTHFR C677T genotypes (24 CC, 24 CT, 24 TT) were prepared, and total folate was determined by ID-LC-MS/MS and MA using the following calibrators: 5-methyltetrahydrofolate (5-methylTHF) (Merck), folic acid (FA) (Merck), and FA (Sigma). To compare the methods, 5 formyltetrahydrofolate (5-formylTHF) was excluded in the ID-LC-MS/MS summation of total folate, because it is likely that the majority of 5-formylTHF detected is a pyrazino-s-triazine oxidation product of 5-methylTHF. MA whole-blood folate measured by using the FA calibrators was consistently higher than with the 5 methylTHF calibrator. Differences between dilutions and analysis of spiked whole blood samples showed a nonlinear response, with overrecovery of 5-methylTHF by ~23% toward the higher end of the MA calibration range. Significant proportional biases between ID-LC-MS/MS and MA were found in all comparisons except when the MA was calibrated with 5-methylTHF and a higher sample dilution of 1:1600 (regression slope: 1.05; P = 0.31; intercept-21, P = 0.16). Calibration bias and matrix effects in the MA underscore the need for a formally accepted whole-blood folate reference method. ID-LC-MS/MS procedures have the potential to offer a high degree of accuracy; however, further work is needed to determine the origin of the pyrazino-s-triazine derivative. PMID- 23096013 TI - Novel soybean oils differing in fatty acid composition alter immune functions of moderately hypercholesterolemic older adults. AB - Linoleic acid (LA) and alpha-linolenic acid (ALA) are essential fatty acids that play an important role in modulation of T cell proliferation. The effects of consuming novel soybean oils varying in LA:ALA ratios on T cell proliferation and inflammatory responses were assessed in older adults. Eighteen participants (>50 y old) with elevated cholesterol concentrations (3.37-4.14 mmol/L LDL cholesterol) consumed 5 experimental diets in random order for periods of 35 d. Each diet contained 30% of energy as fat, two-thirds of which was high-oleic acid soybean oil (HiOleic-SO), soybean oil (SO), low-SFA soybean oil (LoSFA-SO), hydrogenated soybean oil (Hydrog-SO), or low-ALA soybean oil (LoALA-SO), resulting in LA:ALA ratios of 2.98, 8.70, 9.69, 15.2, and 18.3, respectively. Participants had higher proliferative responses to phytohemagglutinin (PHA) compared with baseline following consumption of SO (26%; P < 0.05), LoSFA-SO (22%; P < 0.05), or HiOleic-SO (24%; P < 0.05) diets. Proliferative response was similar to the baseline after participants consumed diets with an LA:ALA ratio >10 (Hydrog-SO and LoALA-SO). Post-diet intervention, LA:ALA ratios correlated with proliferative responses to PHA (r = -0.87; P = 0.05). An optimal proliferative response was observed at an LA:ALA ratio of 8.70, with an inverse correlation between proliferative response and LA:ALA ratios >8.70. These effects were independent of changes in the production of PGE(2), inflammatory cytokines, or cytokines involved in growth of lymphocytes. These data suggest that the LA:ALA ratio modulates the proliferative ability of T lymphocytes, which may be due to subtle changes in fatty acid composition of the phospholipids in immune cells. PMID- 23096015 TI - Total parenteral nutrition induces a shift in the Firmicutes to Bacteroidetes ratio in association with Paneth cell activation in rats. AB - The use of total parenteral nutrition (TPN) in the treatment of critically ill patients has been the subject of debate because it has been associated with disturbances in intestinal homeostasis. Important factors in maintaining intestinal homeostasis are the intestinal microbiota and Paneth cells, which exist in a mutually amendable relationship. We hypothesized that the disturbed intestinal homeostasis in TPN-fed individuals results from an interplay between a shift in microbiota composition and alterations in Paneth cells. We studied the microbiota composition and expression of Paneth cell antimicrobial proteins in rats receiving TPN or a control diet for 3, 7, or 14 d. qPCR analysis of DNA extracts from small intestinal luminal contents of TPN-fed rats showed a shift in the Firmicutes:Bacteroidetes ratio in favor of Bacteroidetes after 14 d (P < 0.05) compared with the control group. This finding coincided with greater staining intensity for lysozyme and significantly greater mRNA expression of the Paneth cell antimicrobial proteins lysozyme (P < 0.05), rat alpha-defensin 5 (P < 0.01), and rat alpha-defensin 8 (P < 0.01). Finally, 14 d of TPN resulted in greater circulating ileal lipid-binding protein concentrations (P < 0.05) and greater leakage of horseradish peroxidase (P < 0.01), which is indicative of enterocyte damage and a breached intestinal barrier. Our findings show a shift in intestinal microbiota in TPN-fed rats that correlated with changes in Paneth cell lysozyme expression (r(s) = -0.75, P < 0.01). Further studies that include interventions with microbiota or nutrients that modulate them may yield information on the involvement of the microbiota and Paneth cells in TPN associated intestinal compromise. PMID- 23096016 TI - Neutrophil gelatinase-associated lipocalin (NGAL): the clinician's perspective. PMID- 23096017 TI - Protein S and protein C measurements should not be undertaken during vitamin K antagonist therapy. PMID- 23096014 TI - Dietary zinc reduction, pyruvate supplementation, or zinc transporter 5 knockout attenuates beta-cell death in nonobese diabetic mice, islets, and insulinoma cells. AB - Pancreatic zinc (Zn(2+)) concentrations are linked to diabetes and pancreatic dysfunction, but Zn(2+) is also required for insulin processing and packaging. Zn(2+) released with insulin increases beta-cell pancreatic death after streptozotocin toxin exposure in vitro and in vivo. Triosephosphate accumulation, caused by NAD(+) loss and glycolytic enzyme dysfunction, occur in type-1 diabetics (T1DM) and animal models. We previously showed these mechanisms are also involved in Zn(2+) neurotoxicity and are attenuated by nicotinamide- or pyruvate-induced restoration of NAD(+) concentrations, Zn(2+) restriction, or inhibition of Sir2 proteins. We tested the hypothesis that similar Zn(2+)- and NAD(+)-mediated mechanisms are involved in beta-cell toxicity in models of ongoing T1DM using mouse insulinoma cells, islets, and nonobese diabetic (NOD) mice. Zn(2+), streptozotocin, and cytokines caused NAD(+) loss and death in insulinoma cells and islets, which were attenuated by Zn(2+) restriction, pyruvate, nicotinamide, NAD(+), and inhibitors of Sir2 proteins. We measured diabetes incidence and mortality in NOD mice and demonstrated that pyruvate supplementation, or genetic or dietary Zn(2+) reduction, attenuated these measures. T-lymphocyte infiltration, punctate Zn(2+) staining, and beta-cell loss increased with time in islets of NOD mice. Dietary Zn(2+) restriction or Zn(2+) transporter 5 knockout reduced pancreatic Zn(2+) staining and increased beta-cell mass, glucose homeostasis, and survival in NOD mice, whereas Zn(2+) supplementation had the opposite effects. Pancreatic Zn(2+) reduction or NAD(+) restoration (pyruvate or nicotinamide supplementation) are suggested as novel targets for attenuating T1DM. PMID- 23096018 TI - Interchangeability of venous and capillary HbA(1c) results is affected by oxidative stress. PMID- 23096019 TI - Suitability of POC lactate methods for fetal and perinatal lactate testing: considerations for accuracy, specificity and decision making criteria. AB - BACKGROUND: Point of care (POC) testing for fetal scalp blood lactate is a more user friendly and more successful approach compared to scalp pH for intrapartum fetal monitoring. The aim of this study was to assess the analytical specificity and clinical reliability of three POC lactate methods. METHODS: The analytical performance of three POC lactate methods was compared to Cobas 6000 (Roche Diagnostics) laboratory reference method: Lactate Pro from Arkray, GEM 4000 from Instrumentation Laboratory and StatStrip Lactate from Nova Biomedical. The clinical performance and influences on accuracy and decision making criteria for the three POC methods was assessed with umbilical cord samples and compared to the laboratory reference method. The influence of varying ranges of hemoglobin, pH and partial oxygen pressure (pO(2)) on the accuracy of results was assessed. RESULTS: Although all three POC methods showed good correlation with the reference method for the umbilical cord sample population (r=0.989, 0.973 and 0.980, respectively), Lactate Pro and Gem 4000 showed a significant negative bias compared to the reference method. The degree of bias meant a significant readjustment of decision making criteria was required for fetal lactate use. The accuracy of the Lactate Pro results was affected by hemoglobin and to a lesser extent pH. CONCLUSIONS: The three electrochemical POC devices can measure fetal lactate reliably. StatStrip Lactate showed a closer correlation and concordance to our laboratory reference method. The results of this study indicate the requirement for predetermining the reliability of POC lactate methods before use present in fetal and perinatal settings. PMID- 23096020 TI - Distributions and ranges of values of blood and urinary biomarker of inflammation and oxidative stress in the workers engaged in office machine manufactures: evaluation of reference values. AB - BACKGROUND: Interleukins, interferons and oxidative DNA products are important biomarkers assessing the inflammations and tissue damages caused by toxic materials in the body. We tried to evaluate distributions, reference values and age related changes of blood levels of inflammatory cytokines, C-reactive protein (CRP), IgE and urine levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG) among workers in a cohort study evaluating the health influences of toner particles. METHODS: A total of 1366 male workers under age 50 years (age 19-49 years; 718 exposed and 648 not exposed to toner particles) in a cross sectional study of 1614 (categorized as 809 exposed and 805 not exposed, age 19-59 years) workers in a photocopier company has been followed prospectively as the cohort. Blood levels of interleukin (IL)-4, IL-6, IL-8, interferon-gamma (IFN-gamma), CRP, IgE and urine 8-OHdG were measured annually for 5 years. RESULTS: Reference values of the biomarkers are; CRP: 0.01-0.63*10(-2) g/L, IgE: 6-1480 IU/mL, IL-4: 2.6-76.1 pg/mL, IL-6: 0.4-4.9 pg/mL and 8-OHdG: 1.5-8.2 ng/mgCr. We could not evaluate reference values for IL-8 and IFN- gamma because most of the values were below the sensitivity limits (2.0 pg/mL and 0.1 IU/mL, respectively). There were no differences of the biomarker levels between the toner exposed and the control workers. We observed a statistically significant age related decrease of serum IL 4 levels. CONCLUSIONS: This is the first report assessing the distributions and reference values of inflammatory biomarker levels in a large scaled cohort. We observed age related changes of some of the biomarkers. We could not detect any differences of the studied biomarker values between the toner exposed and the control workers. PMID- 23096021 TI - Molecular analysis of reticulocyte binding protein-2 gene in Plasmodium vivax isolates from India. AB - BACKGROUND: Plasmodium vivax reticulocyte binding protein-2 (PvRBP-2) is a promising candidate for development of vaccine against parasite. DNA sequence polymorphism in pvrbp-2 which may hamper the vaccine development program has been identified in laboratory strains. Therefore, unraveling genetic polymorphism in pvrbp-2 from field isolates is a prerequisite for success in vaccine development. This study was designed with a primary aim to uncover genetic polymorphism in pvrbp-2 among P. vivax field isolates. RESULTS: Using virtual restriction mapping of pvrbp-2 sequences, two restriction enzymes (AluI and ApoI) were selected for the development of pvrbp-2 as a PCR-RFLP marker. Restriction fragment length polymorphism (RFLP) analysis revealed a high degree of genetic polymorphism in the pvrbp-2 gene among field isolates of P. vivax. ApoI-RFLP was found to be more efficient in identifying the extent of genetic polymorphism in pvrbp-2 compared to AluI-RFLP. Combined genotyping/haplotyping of RFLP pattern revealed a total of 36 distinct RFLP patterns among 83 P. vivax isolates analyzed. DNA sequence analysis also supports high degree of genetic polymorphism among field isolates of P. vivax. Pvrbp-2 PCR-RFLP method is able to distinguish multiple infection up to 16.86% and it revealed a low level of shared genetic pool between more than two populations. CONCLUSION: The study suggests that pvrbp-2 is highly polymorphic genetic marker which can be used for population genetic analyses. RFLP analysis suggests presence of nearly similar proportion of Sal-1 and Belem alleles in Indian P. vivax populations. The larger extent of genetic polymorphism identified from limited samples advocates to screen genetic polymorphism in pvrbp 2 from malaria endemic geographical regions and countries for designing pvrbp-2 based anti-malarial control measures. PMID- 23096022 TI - Evaluation of serological tests for diagnosis of Chlamydophila pneumoniae pneumonia in patients with nursing and healthcare-associated pneumonia. AB - Nursing and healthcare-associated pneumonia (NHCAP) is a new category that is distinct from community-acquired pneumonia that has been documented in the 2011 Japanese Respiratory Society (JRS) guidelines. We aimed to evaluate an ELNAS Plate test for detecting anti-Chlamydophila pneumoniae-specific immunoglobulin M (IgM) antibodies in patients with NHCAP, by comparing the results of the ELNAS test with those of the Hitazyme enzyme-linked immunosorbent assay (Hitazyme ELISA) and those of immunoblotting and microimmunofluorescence (MIF) tests. During the study period, we enrolled 739 patients with pneumonia in a university hospital and 812 patients with pneumonia in a community hospital; of these, 250 (34 %) and 349 (43 %), respectively, were classified as having NHCAP. C. pneumoniae pneumonia was detected in five cases by the MIF test and ELNAS test. All five cases demonstrated significant IgG antibody seroconversion, while one case was IgM-positive. Sixty-seven of the total of 599 patients (11 %) were C. pneumoniae IgM-positive on the Hitazyme-ELISA. One of the IgM-positive cases was confirmed by other methods and was shown to be a true positive. In the remaining cases, however, three other tests-the ELNAS test, the MIF test, and immunoblotting analysis-did not reveal any positive cases. The ELNAS, Hitazyme ELISA, and MIF tests did not detect any significant increases in IgG or IgA antibody titers between paired sera. The results of the newly available ELNAS test for detecting anti-C. pneumoniae-specific IgM antibody correlated well with the results of the other established serological tests. To increase the diagnostic rate in patients with NHCAP, physicians should measure IgG antibody rather than IgM antibody using paired sera. PMID- 23096023 TI - Probing the conformational behavior of a monoclonal antibody with surfactant affinity capillary electrophoresis (SurfACE). AB - Multiple peaks are observed for a monoclonal antibody (mAb) when analyzed by "protein MEKC" (micellar electrokinetic capillary chromatography) using SDS containing run buffers. We present our efforts to understand the mechanism of peak formation and the factors that affect the distribution of the mAb between these peaks. We used "intrinsic" charge ladders of the mAb to determine that peak to-peak differences in the amount of bound surfactant are comparable to the aggregation numbers of protein-bound micelles. This suggests that the peaks represent sequential unfolding intermediates formed after collisions with micelles. Since this mechanism differs from that of small-molecule MEKC, we prefer to view this technique as a variant of affinity capillary electrophoresis and call it "SurfACE." We also find that the peak distribution is highly sensitive to pH. Lower pH favors the formation of more highly bound complexes, probably through an electrostatic effect on the kinetics. If the run buffer pH is high enough, the peak distribution appears to be set during the post-injection mixing process, as the mAb encounters surfactant during its transition from the lower-pH sample environment. Analysts who wish to interpret "protein MEKC" electropherograms should take note of these effects. PMID- 23096024 TI - Tetraphenylethene modified perylene bisimide: effect of the number of substituents on AIE performance. AB - Perylene bisimide derivatives substituted with one and two tetraphenylethene moieties at 1 and 1,7-postions show distinct optical properties. The former displays characteristic emission features of perylene bisimides in solution and red emission in the aggregate state, while the latter is nonemissive in solution but highly red-emissive in the aggregate state. PMID- 23096027 TI - [A specific phobia of amyotrophic lateral sclerosis (ALS phobia)]. AB - A specific phobia of amyotrophic lateral sclerosis (ALS phobia) was not previously described in the literature. We examined 21 patients, 11 men and 10 women, aged 28-72 years, with symptoms of this phobia. Only 23% of patients had a history of the psychiatric disorder in the past. The duration of phobia symptoms was significantly higher in patients with moderate and severe phobia than in mild cases (1.5+/-0.6 and 5.0+/-1.1 months respectively; r<0.05). The severity of ALS phobia was correlated with its duration (r= -0.5; p=0.004). The primary character of phobia was established in 52.4% of patients basing on the regression of phobia symptoms assessed by the Hamilton anxiety scale after psychotherapy and pharmacotherapy (17+/-4 and 3+/-1 scores before and 3 months after treatment, respectively; p<0.05). PMID- 23096028 TI - [Dynamics of neurocognitive functioning in patients in early stages of schizophrenia and schizophrenia spectrum disorders]. AB - The purpose of the study was to assess the dynamics of neurocognitive functioning in patients with the first episode of schizophrenia and schizophrenia spectrum disorders at baseline and in 5-year follow-up. The total number of patients was 67. The severity of symptoms was measured with the PANSS. Cognitive functioning was assessed with the Cognitive Processes Assessment Scale which is based on the methodological approaches developed by A.R. Luria. The liability of cognitive impairment with a tendency to decrease in severity was found in patients with a single psychosis or a history of few psychoses (n=25). In patients with more severe progression of disease (n=33), some labiality of cognitive impairment was observed as well, but, as opposed to the first group, its severity was increasing during the whole 5-year follow-up period. The most severely ill patients with early onset and the most progressive course of the disease (n=9) demonstrated the most severe cognitive impairment, which remained stable along the follow-up. In conclusion, the data obtained present the neurocognitive deficit in schizophrenia and schizophrenia spectrum disorders as not an unchangeable phenomenon, with its dynamics corresponding to regularities of the disease course and its progression. PMID- 23096030 TI - [Inbred disgust propensity in the aspect of the development of pathological personality]. AB - Correlations between inborn (constituional) disgust propensity, dynamics of personality disorders and development of contamination fear in obsessive compulsive disorder (OCD) were studied in 54 patients with milder forms of mysophobia. Three types of contamination fear characterized by different combinations of disgust propensity and personality traits were singled out. Clinical features of OCD were shown to correspond to premorbid personality while denotative characteristics of OCD were correlated with constituional phenomenon of disgust propensity. The results suggest that disgust propensity is a stable personality dimension contributing to the development of contamination fear. PMID- 23096033 TI - [Efficacy of cytoflavin in patients with hypertonic encephalopathy and constitutional venous insufficiency]. AB - We examined 60 patients with constitutional venous insufficiency, suffering from hypertensive encephalopathy of I and II stages, mean age 43,4+/- 6,3 years. Patients of the main group (n=30) received Cytoflavin (2 tablets twice a day) and standard therapy (acetylsalicylic acid and antihypertensive drugs). Thirty patients of the parallel group received only standard therapy. At the 25th day of the study, there were the decrease in the number of complaints, including specific "venous complaints", the reduction of cephalalgia syndrome, asthenic and autonomic disorders; the improvement of quality of life and better cerebral hemodynamics on all structural and functional levels. PMID- 23096035 TI - [Side-effects of the treatment with disease modifying drugs in patients with multiple sclerosis: an analysis of register data in the Yaroslavl region]. AB - Authors have followed up 230 patients with multiple sclerosis treated with disease modifying drugs (DMD) using the data of the Multiple sclerosis register of the Yaroslavl oblast during 2009-2011. Original drugs and their generics registered in Russia are used. Patients received interferon-beta 1a for intramuscular introduction (avonex - 3.0%), interferon-beta 1a for hypodermic injection (rebif - 19.2%, genfakson - 8.5%), interferon-beta 1b (betaferon - 16.5%, extavia - 18.2%, ronbetal - 18.0%), glatimer acetate (copaxone - 16.7%). Adverse effects were recorded and subjective tolerability of the drug by the patient was assessed. Statistically significant differences in the safety profile between some bioanalogues and original DMD were identified. This finding suggests that effects of different DMD should be studied in depth in clinical and post marketing trials. PMID- 23096037 TI - [Mexidol in the complex treatment of patients in the acute period of tick borne encephalitis]. AB - Therapeutical action of mexidol as compared to piracetam was evaluated in groups of patients with tick borne encephalitis in the acute period of disease. Mexidol was administered as add-on to antiviral treatment in 72 patients while 89 patients received piracetam. The drugs were introduced intravenously during the first 10 days and then were given as tablets during 2 months. Based on these results, we can recommend the inclusion of mexidol in the pathogenetic treatment (fever symptoms) of tick born encephalitis. The use of mexidol as compared to piracetam led to more pronounced positive changes, higher percentage of favorable outcomes and lower frequency of residual signs. PMID- 23096039 TI - [Mental and autonomic disorders in children and adolescents with diabetes mellitus type I and their correction using color and rhythm therapy]. AB - The objective of the study was to work out a method of color and rhythm therapy (CRT) for correction of mental and autonomic disorders in children with diabetes mellitus type I. The elaboration of the method was based on the results of examination of 62 patients, aged 7-16 years. In addition, a psychometric assessment of anxiety (the Spielberger-Khanin test), stress resistance and communicative abilities (the Luscher color test), depression (the scale of Saint Petersburg Bekhterev's Psychoneurological Research Institute) and autonomic dysfunctions (the Vein's questionnaire) was performed. CRT was conducted with the apparatus"Color-rhythm" that allows to perform stimulation with the light of specified length. The high effectiveness of CRT in the correction of mental and autonomic disorders depending on the character of disorders and effects of separate photic stimuli (red or yellow, green and blue), sequence and rhythm of their presentation is demonstrated. The choice of automatic working regime of the apparatus is proved to be optimal. PMID- 23096041 TI - [Attention deficit hyperactivity disorder with comorbid anxiety disorders: pharmacotherapy options]. AB - Comorbid anxiety disorders are observed in many patients with attention deficit hyperactivity disorder (ADHD): 25-33% compared to 6-10% in pediatric population. Therapeutic effects of Adaptol have been studied, indicated for children and adolescents with ADHD as monotherapy, in dosages of 25-35 mg/kg for 1-3 months. The positive influence of Adaptol on the core symptoms of ADHD was confirmed: reduction of hyperactivity and impulsivity was registered after 1st month, while clinical manifestations of the attention deficit were decreased on the 2nd-3rd months of the treatment. Anxiolytic activity became apparent from the 1st month and continued to increase on the 2nd-3rd months of the treatment. Simultaneously significant reduction of the oppositional-defiant disorder manifestations were observed. PMID- 23096043 TI - [Neurophysiological characteristics of treatment efficacy in late onset depression]. AB - To reveal neurophysiological correlates of treatment efficacy of late onset depression, EEG spectral power, peak latencies of the "late" components of auditory cognitive evoked potentials, and sensorimotor reaction time have been analyzed in two groups of elderly patients, aged 53-72 years, with prolonged psychogenic depressive reaction (F43.21 by ICD-10) and with endogenous depression (F33.1 and F31.3 by ICD-10) during the treatment with antidepressants. Baseline depression severity has been associated with the EEG signs of the decreased functional state of anterior areas of the left hemisphere, and of the increased activation of the right hemisphere (especially, of its temporal regions). The pronounced improvement of clinical condition of patients after psychopharmacotherapy with antidepressants led to the decrease of peak latencies of the "late" components (R2, N2 i R3) of auditory cognitive evoked potentials, and to the acceleration of sensorimotor reaction time that have been associated with the EEG signs of the improvement of the functional state of posterior brain areas, and of the facilitation of inhibitory processes in the right hemisphere (especially, in its frontal, central and temporal regions), and of the more pronounced activation of frontal areas of the left hemisphere. The results are in line with the views on systemic character of brain functioning impairment in depression, as well as on the preferential role of the left hemisphere in the control of positive emotions, and of the right hemisphere role in the control of negative emotions as well as in the pathogenesis of depression. PMID- 23096045 TI - [Depressive disorders in elderly patients: an attempt of psychometric assessment with the Montgomery-Asberg Depression Rating Scale]. AB - The objectives of this paper were to choose a psychometric scale that meets requirements for "comparison standard" in elaboration of new methods for psychometric assessment of late depression and to evaluate distortion of results for standard scale used in elderly patients. Based on the literature analysis, authors chosed the Montgomery-Asberg Depression Rating Scale (MADRS) as an etalon. The comparative analysis of MADRS scores and results of psychopathological evaluation revealed distortions of MADRS scores related to elder age. Qualitative and quantitative distortions were assessed for every MADRS item and for the total score. The analysis of separate components revealed that 7 out of 10 MADRS items were significantly changed and correlated with the age of patients while the total score did not change. This allows to use MADRS total score in further studies without any corrections. Application of the MADRS as a comparative scale in the symptomatic analysis of late depression needs the use of correction coefficients. PMID- 23096047 TI - [The role of the 5-HTTLPR polymorphism of the serotonin transporter gene in the development of depression in patients with coronary heart disease]. AB - Depression is commonly present in patients with coronary heart disease (CHD). Identification of early predictors of depression in CHD patients is an important direction of current research in the field of psychosomatic medicine. Serotonin transporter gene polymorphism (5-HTTLPR) was earlier reported to contribute to the development of depression comorbid to CHD. The present study aimed at investigating the role of the 5-HTTLPR polymorphism, stress factors and personality traits in the prediction of depressive symptoms in patients with CHD. The study included 169 male patients, aged from 31 to 84 years, mean age 59+/-8.8 years. Depression was diagnosed in 135 (79.9%) patients; in 71 (42%) patients it was related to the presence of CHD (nosogenic factor). Severity of depressive symptoms as defined by HAM-D-21 was associated with the interaction between the 5 HTTLPR polymorphism, nosogenic factor and trait anxiety. Risk of depression was 7.0 times higher in carriers of an S allele in the presence of the nosogenic factor. In other combinations of a 5-HTTLPR variant with the presence or absence of the nosogenic factor, trait anxiety contributed significantly to the variance of depressive symptoms. Patients with higher scores on the Spilberger STAI had 5 and 7 times higher risk of moderate and marked depression compared to those with moderate and low anxiety scores. The approach suggested in the study may be useful for the prediction of depression and its severity in patients with CHD. PMID- 23096048 TI - [Becker myotonia with pes eauinus: a case report]. PMID- 23096049 TI - [The complex treatment of the pain syndrome in diabetic distal polyneuropathy using intraosteal blockades]. PMID- 23096050 TI - [Drug-induced parkinsonism]. PMID- 23096051 TI - [Spine osteochondrosis and its complications]. PMID- 23096053 TI - Incidence and etiology of late preterm admissions to the neonatal intensive care unit and its associated respiratory morbidities when compared to term infants. AB - OBJECTIVE: To determine etiology of neonatal intensive care unit (NICU) admission and acute morbidities in late preterm (LPT) neonates. METHODS: Neonates admitted at New York University Langone Medical Center's NICU were grouped as follows: period 1: all LPT neonates with gestational age between 34(0)/(7) and 36(6)/(7) weeks and born between January 2006 and June 2007; period 2: all term neonates born between January 2007 and June 2008. Neonatal and maternal data were collected from both the groups and compared. RESULTS: Thirty-three percent of LPT births were admitted to the NICU, compared with 7% of term births (p < 0.05). LPT neonates had an increased incidence of low birth weight, hypoglycemia, hypothermia, and hyperbilirubinemia as an admission diagnosis (p < 0.001). The overall incidence of respiratory distress syndrome (RDS) was 9%, 4%, 3%, 0.7%, 0.2% and 0% in 34-week, 35-week, 36-week, 37-week, 38- to 39-week, and 40-week gestational age neonates (p < 0. 001).There was an increased incidence of RDS and persistent pulmonary hypertension, along with an increased need for surfactant replacement therapy, continuous positive airway pressure, and ventilator support in the LPT group when compared with the term neonates (p < 0.001). CONCLUSIONS: LPT neonates are at increased risk for hypothermia, hypoglycemia, hyperbilirubinemia, and respiratory morbidity requiring increased respiratory support when compared with term neonates. PMID- 23096052 TI - Metformin compared with insulin in the treatment of pregnant women with overt diabetes: a randomized controlled trial. AB - OBJECTIVE: To compare the safety and tolerability of metformin to insulin for glycemic control among women with preexisting type 2 and early A2 gestational diabetes. STUDY DESIGN: Women with preexisting type 2 diabetes and those diagnosed with gestational diabetes who required medical management prior to 20 weeks were randomly assigned to metformin or insulin. Glycemic control, defined as >50% capillary blood glucose within target range, was compared between groups. Other outcomes included patient tolerance, neonatal and obstetric complications, maternal weight gain, neonatal cord blood C-peptide, and patient satisfaction with therapy. RESULTS: Twenty-eight women completed the study, with 14 in each group. Of the 15 women assigned to metformin, 100% continued to receive metformin until delivery, although 43% required supplemental insulin to achieve glycemic control. Glucose measures did not differ between the groups, and the proportion who met fasting and postprandial glycemic target values did not differ between the groups. Women treated with metformin had significantly fewer subjective episodes of hypoglycemia compared with those using insulin (0% versus 36%; p = 0.04) as well as reported glucose values < 60 mg/dL (7.1% versus 50%; p = 0.03). CONCLUSION: Metformin should be considered for treatment of overt diabetes and early A2 gestational diabetes in pregnancy. PMID- 23096054 TI - Perinatal complications in twin pregnancies after 34 weeks: effects of gestational age at delivery and chorionicity. AB - OBJECTIVE: To evaluate the perinatal outcome of twins approaching term in relation to chorionicity and gestational age at delivery. STUDY DESIGN: We accessed data pertaining to a cohort of 471 twin pregnancies with certain chorionicity delivered at > 34.0 weeks' gestation. Twin gestation per se, estimated fetal weight below the 10th percentile, or any intertwin discordance was not an indication for delivery before 40.0 weeks. Predictors of adverse perinatal outcome were identified using logistic regression analysis. RESULTS: There were no stillbirths. Adverse neonatal outcome occurred in 27% of monochorionic versus 16% of dichorionic gestations. At multivariate analysis, lower gestational age at delivery (odds ratio [OR] 0.70, 95% confidence interval [CI] 0.57 to 0.87), monochorionicity (OR 2.06, 95% CI 1.16-3.63), and either twin being growth-restricted (OR 2.35, 95% CI 1.22 to 4.54) were independent predictors of adverse neonatal outcome. Analysis of adverse neonatal outcome stratified by gestational age and chorionicity identified 36 to 37 weeks as optimal timing for delivery of monochorionic twins, and dichorionic twin pregnancies should be allowed to continue until term. CONCLUSION: Among twin gestations delivered after 34 weeks with appropriate fetal growth, reassuring fetal status at weekly assessment, and absence of obstetric complications, delivery after 36 weeks for monochorionic twins and at term for dichorionic twins minimizes the risk of stillbirths and neonatal morbidity. PMID- 23096056 TI - Fast joint detection-estimation of evoked brain activity in event-related FMRI using a variational approach. AB - In standard within-subject analyses of event-related functional magnetic resonance imaging (fMRI) data, two steps are usually performed separately: detection of brain activity and estimation of the hemodynamic response. Because these two steps are inherently linked, we adopt the so-called region-based joint detection-estimation (JDE) framework that addresses this joint issue using a multivariate inference for detection and estimation. JDE is built by making use of a regional bilinear generative model of the BOLD response and constraining the parameter estimation by physiological priors using temporal and spatial information in a Markovian model. In contrast to previous works that use Markov Chain Monte Carlo (MCMC) techniques to sample the resulting intractable posterior distribution, we recast the JDE into a missing data framework and derive a variational expectation-maximization (VEM) algorithm for its inference. A variational approximation is used to approximate the Markovian model in the unsupervised spatially adaptive JDE inference, which allows automatic fine-tuning of spatial regularization parameters. It provides a new algorithm that exhibits interesting properties in terms of estimation error and computational cost compared to the previously used MCMC-based approach. Experiments on artificial and real data show that VEM-JDE is robust to model misspecification and provides computational gain while maintaining good performance in terms of activation detection and hemodynamic shape recovery. PMID- 23096057 TI - Medical director responsibilities for outpatient cardiac rehabilitation/secondary prevention programs: 2012 update: a statement for health care professionals from the American Association for Cardiovascular and Pulmonary Rehabilitation and the American Heart Association. AB - Medical directors of cardiac rehabilitation/secondary prevention (CR/SP) programs are responsible for the safe and effective delivery of high-quality CR/SP services to eligible patients. Yet, the training and resources for CR/SP medical directors are limited. As a result, there appears to be considerable variability throughout CR/SP programs in the United States in the roles, responsibilities, and engagement of CR/SP medical directors. Since the publication of the 2005 scientific statement from the American Heart Association and American Association of Cardiovascular and Pulmonary Rehabilitation regarding medical director responsibilities for outpatient CR/SP programs, significant changes have occurred. This statement updates the responsibilities of CR/SP medical directors, in view of changes in federal legislation and regulations and changes in health care delivery and clinical practice that impact the roles and responsibilities of CR/SP medical directors. PMID- 23096058 TI - Relationship between cognitive and motor performance in physically well-recovered men with traumatic brain injury. AB - OBJECTIVE: To explore the relationship between cognitive and motor performance in physically well-recovered men with traumatic brain injury. DESIGN: Cross sectional explorative study in a national neurorehabilitation centre. SUBJECTS: Men with post-acute traumatic brain injury (n = 34; aged 19-55 years) who had recovered well physically. METHODS: Cognitive performance (attention, information processing, cognitive flexibility, motor regulation, praxis of the upper limbs) and motor performance (postural balance, agility, rhythm-co-ordination) were assessed. Partial rank correlation coefficients and analyses of covariance were used to assess the associations between these tests. RESULTS: Associations were found between the time taken in both Trail Making tests and performance time in the agility test (r = 0.57). The score on the Digit Symbol test correlated with time in the agility test (r = -0.52). Patients with normal performance in verbal fluency performed the tests of dynamic balance and agility 26% more quickly than those with abnormal performance. Moreover, patients with normal performance in the reproduction of rhythmic structures were 20% faster in the dynamic balance test. Motor functions of the hands associated with all the motor-performance test results. CONCLUSION: Measures of information processing, attention and executive functioning may be associated with motor performance. Apart from the theoretical relevance, the finding of an association between cognitive and motor performance may have clinical relevance with regard to rehabilitation. PMID- 23096060 TI - Cobalt-catalysed synthesis of highly substituted styrene derivatives via arylzincation of alkynes. AB - A new two-step procedure was developed by carbozincation of internal and terminal alkynes to synthesise highly functionalised vinylzinc bromides. Various tri and tetrasubstituted alkenes were prepared in moderate to good yields under mild reaction conditions in a stereo-selective manner. This methodology represents an interesting alternative to previously known methods. PMID- 23096059 TI - Tensile strength after closure of mesenteric gaps in laparoscopic gastric bypass: three techniques tested in a porcine model. AB - BACKGROUND: Internal hernias occur frequently after laparoscopic gastric bypass. We have found no data on the relative strength of the various techniques available for closing these defects. The present study was performed to obtain such data to form a theoretical basis for clinical studies. METHODS: Six piglets were operated laparoscopically and four loops of small bowel created in each. These mesenteric gaps were closed over a distance of 40 mm using (1) running 2-0 Ethibond(r) suture, (2) Endo Hernia stapler, (3) fibrin glue (Tisseel(r)) and (4) controls, where the mesenteric surfaces were rubbed with a sponge and approximated without further intervention. After 6 weeks, the different segments of the mesentery were excised. The tensile strength was measured using continuously increased traction until the closure ruptured. The ordinary mesentery served as the control. The breaking tension and total amount of energy transferred to the tissue were registered. RESULTS: Control areas with rubbed areas developed no adhesions. Suture and staple lines contracted by 30 % in length, whereas the fibrin glued lines were even shorter. Median tensile strength was greatest for the sutured lines (14,293 mN) and stapled lines (10,798 mN). Fibrin glued lines were significantly weaker (6,780 mN, p = 0.013 and p = 0.026), but as strong as ordinary mesentery (4,165 mN). CONCLUSIONS: If ongoing controlled randomized trials show closure to be beneficial, further studies should include staples as one of the options for the closure of mesenteric defects. The role of fibrin glue needs to be further investigated. PMID- 23096061 TI - An adequate interset rest period for strength recovery during a common isokinetic test. AB - Isokinetic testing is used in rehabilitation settings on a regular basis; yet, there is a lack of consistency in rest period usage among protocols. Furthermore, the allotment of rest periods has been arbitrary (e.g., 30, 60, 90 seconds or more). This investigation examines the work:rest ratio as an effective method of standardizing rest periods in isokinetic testing. The purpose of this study was to establish an adequate rest period that would allow reproducibility of strength during a common isokinetic strength test. Twenty-seven healthy college-aged men (age, 23 +/- 3.8 years; body weight, 79.54 +/- 11.09 kg) were tested on 5 separate occasions: 2 familiarization sessions and 3 experimental sessions. Each subject performed a knee extension/flexion isokinetic strength protocol (Cybex NORM; Lumex, Inc., Ronkonkoma, NY, USA) to determine peak torque by performing 5 maximal reciprocal repetitions at each ascending velocity of 60, 180, and 300 degrees .s. Work:rest ratios of 1:3, 1:8, and 1:12 were counterbalanced between sets. A 3 * 3 repeated measures analysis of variance was used to analyze the data. A significance level of alpha <= 0.05 was used for all tests. There was no significant difference in either knee extension or knee flexion peak torque when comparing work:rest ratios. These findings suggest that a 1:3 work:rest ratio is sufficient during a common isokinetic strength test. PMID- 23096062 TI - Effects of body position and loading modality on muscle activity and strength in shoulder presses. AB - Little is known about the effect of performing upper-body resistance exercises with dumbbells versus barbells and standing versus seated. Therefore, this study sought to compare electromyogram activity (EMG) and one-repetition maximum (1-RM) in barbell and dumbbell shoulder presses performed seated and standing. Fifteen healthy men volunteered for 1-RM and EMG testing with a load corresponding to 80% of the 1-RM. Electromyogram activity was measured in the anterior, medial, and posterior deltoids and biceps and triceps brachii. The following EMG differences or trends were observed: For deltoid anterior: ~11% lower for seated barbell versus dumbbell (p = 0.038), ~15% lower in standing barbell versus dumbbell (p < 0.001), ~8% lower for seated versus standing dumbbells (p = 0.070); For medial deltoid, ~7% lower for standing barbell versus dumbbells (p = 0.050), ~7% lower for seated versus standing barbell (p = 0.062), 15% lower for seated versus standing dumbbell (p = 0.008); For posterior deltoid: ~25% lower for seated versus standing barbell (p < 0.001), ~24% lower for seated versus standing dumbbells (p = 0.002); For biceps, ~33% greater for seated barbell versus dumbbells (p = 0.002), 16% greater for standing barbell versus dumbbell (p = 0.074), ~23% lower for seated versus standing dumbbells (p < 0.001); For triceps, ~39% greater for standing barbell versus dumbbells (p < 0.001), ~20% lower for seated versus standing barbell (p = 0.094). 1-RM strength for standing dumbbells was ~7% lower than standing barbell (p = 0.002) and ~10% lower than seated dumbbells (p < 0.001). In conclusion, the exercise with the greatest stability requirement (standing and dumbbells) demonstrated the highest neuromuscular activity of the deltoid muscles, although this was the exercise with the lowest 1 RM strength. PMID- 23096063 TI - The effects of lower extremity muscle activation and passive range of motion on single leg squat performance. AB - Knee valgus is a potential risk factor for lower extremity (LE) injuries. Clinical movement screenings and passive range of motion (PROM) measurements may help identify neuromuscular patterns, which contribute to knee valgus. The purpose of this study was to compare LE muscle activation and PROM between subjects who display visual medial knee displacement (MKD) during a single leg squat (SLS) and those who do not. We hypothesized that muscular activation and PROM would differ between the groups. Forty physically active adults (20 controls, 20 MKDs) participated in this study. Subjects completed 10 LE PROM assessments and performed 5 SLS trials while electromyography (EMG) data were collected from 8 LE muscles. Three separate multivariate analysis of variance were used to identify group differences in EMG data, muscle coactivation, and PROM. Results during the SLS indicated hip coactivation ratios revealed smaller gluteus medius to hip adductor (GMed:Hip Add) (p = 0.028) and gluteus maximus to hip adductor (GMax:Hip Add) coactivation ratios (p = 0.007) compared with the control group. Also, the MKD group displayed significantly less passive ankle dorsiflexion with the knee extended (p = 0.047) and flexed (p = 0.034), and greater talar glide motion (p = 0.012). The findings of this study indicate that MKD during a SLS seems to be influenced by decreased coactivation of the gluteal to the hip adductor muscles and restricted dorsiflexion. Therefore, conditioning, rehabilitation, and injury prevention programs should focus on decreasing hip adductor activity, increasing hip abductor and external rotator activity, and increasing ankle dorsiflexion in hopes to decrease the incidence of these injuries. PMID- 23096064 TI - Effects of different amplitudes (high vs. low) of whole-body vibration training in active adults. AB - The aim of this study was to evaluate the effects of two different amplitudes of whole-body vibrations on the development of strength, mechanical power of the lower limb, and body composition. Thirty-eight recreationally active participants took part in the study. Participants were divided in two experimental groups (low amplitude group [GL] = 2 mm; high amplitude group [GH] = 4 mm) and a control group. The experimental groups performed an incremental vibratory training, 2 days per week during 6 weeks. The frequency of vibration (50 Hz), time of work (60 seconds), and time of rest (60 seconds) were constant for GL and GH groups. All the participants were on the platform in a static semi-squat position. Maximum isokinetic strength, body composition, and performance in vertical jumps (squat and countermovement jumps) were evaluated at the beginning and at the end of the training cycle. A significant increase of isokinetic strength was observed in GL and GH at angular velocities of 60 degrees .s(-1), 180 degrees .s(-1) and 270 degrees .s(-1). Total lean mass was significantly increased in GH (0.9 +/- 1.0 kg). There were no significant changes in the total fat mass in any of the groups. Significant changes were not observed in different variables (height, peak power, and rate of force development) derived from the vertical jumps for any of the groups submitted to study. The vibration training, whatever the amplitude, produced significant improvements in isokinetic strength. However, high vibration amplitude training presents better adaptations for hypertrophy than the training with low vibration amplitude. In this sense, GH would be a better training if the practitioners want to develop both strength and hypertrophy of the lower limbs. PMID- 23096065 TI - Association of weekly strength exercise frequency and academic performance among students at a large university in the United States. AB - The study aimed to examine (a) the association between weekly strength exercise frequency and grade point average (GPA), and (b) the demographic characteristics of weekly strength exercise frequency among undergraduate students at a large southern state university in the United States. Health behavior data (N = 1125) collected by the American College Health Association at the university in 2008 were analyzed. Analysis of variance was used to investigate weekly strength exercise frequency differences in GPA, sex, ethnicity, and year in university. The results revealed that those who more frequently engaged in strength exercise had significantly higher GPA. There was a significant difference in weekly strength exercise frequency by sex and ethnicity. Findings suggest that regular engagement in strength exercise may not only have physical health benefits but is also associated with academic achievement in high education. There is a need to further investigate the mechanism of strength exercise on GPA among university students. PMID- 23096066 TI - Dopaminergic-induced paraphilias associated with impulse control and related disorders in patients with Parkinson disease. PMID- 23096067 TI - Association of early post-procedure hemodynamic management with the outcomes of subarachnoid hemorrhage patients. AB - Post-procedure hemodynamic management for aneurysmal subarachnoid hemorrhage is controversial because of the paucity of studied patients. Using a Japanese administrative database, we tested whether increased albumin, catecholamine, and volumes of fluid administered between the procedure and the 4th post-procedure day would be associated with outcomes of mortality, consciousness deterioration at discharge and re-intubation between the 5th and 14th post-procedure days. Across 550 hospitals, 5,400 patients were identified who received clipping, wrapping and endovascular coiling within 48 h after admission in 2010. Patient characteristics and the administration of albumin, catecholamine, and volume of fluid normalized by body weight were analyzed among the groups and categorized according to the presence of albumin and catecholamine administered between the procedure and the 4th post-procedure day. The association of early hemodynamic management with outcomes was measured using logistic regression models, through controlling for the preference of early administration of albumin and catecholamine. For the patients, 9.3 % received albumin only, 14.4 % catecholamine only, and 4.9 % both between the procedure and the 4th post procedure day, while 16.5 % received albumin or catecholamine on other days. Variation in albumin and catecholamine administration was observed. Higher normalized fluid volume, commenced before the 4th post-procedure day, was associated with increased mortality and re-intubation (although with decreased complications), and vice versa between the 4th and 14th post-procedure days. Catecholamine administration was associated with worsened outcomes. Hypervolemic and hypertensive therapies commenced before the 4th post-procedure day require further research to determine whether their associations with outcomes in this administrative data base are causal or not. PMID- 23096068 TI - Decreased serum vitamin D in idiopathic benign paroxysmal positional vertigo. AB - Previous studies have demonstrated an association of osteopenia/osteoporosis with idiopathic benign paroxysmal positional vertigo (BPPV). Since vitamin D takes part in the regulation of calcium and phosphorus found in the body and plays an important role in maintaining proper bone structure, decreased bone mineral density in patients with BPPV may be related to decreased serum vitamin D. We measured the serum levels of 25-hydroxyvitamin D in 100 patients (63 women and 37 men, mean age +/- SD = 61.8 +/- 11.6) with idiopathic BPPV and compared the data with those of 192 controls (101 women and 91 men, mean age +/- SD = 60.3 +/- 11.3) who had lived in the same community without dizziness or imbalance during the preceding year. The selection of the controls and acquisition of clinical information were done using the data from the Fourth Korean National Health and Nutrition Examination Survey, 2008. The serum level of 25-hydroxyvitamin D was lower in the patients with BPPV than in the controls (mean +/- SD = 14.4 +/- 8.4 versus 19.1 +/- 6.8 ng/ml, p = 0.001). Furthermore, patients with BPPV showed a higher prevalence of decreased serum vitamin D (<20 ng/ml, 80.0 vs. 60.1 %, p < 0.001) than the controls. Multiple logistic regression analyses adjusted for age, sex, body mass index, hypertension, diabetes, proteinuria, regular exercise and the existence of decreased bone mineral density demonstrated that vitamin D insufficiency (10-20 ng/ml) and deficiency (<10 ng/ml) were associated with BPPV with the odds ratios of 3.8 (95 % confidence interval = 1.51-9.38, p = 0.004) and 23.0 (95 % confidence interval = 6.88-77.05, p < 0.001). Our study demonstrated an association between idiopathic BPPV and decreased serum vitamin D. Decreased serum vitamin D may be a risk factor of BPPV. PMID- 23096069 TI - Psoriasis during natalizumab treatment for multiple sclerosis. AB - Beta-interferon therapy is known to trigger psoriasis, but this effect has not been previously reported for other multiple sclerosis treatments, such as natalizumab. The following is a case report. A 31-year-old woman affected by psoriasis and relapsing-remitting multiple sclerosis suffered a severe worsening of psoriasis symptoms during natalizumab treatment and acquired a drug-resistant course. This case suggests that aggravation of psoriasis might be a rare side effect of natalizumab, and that clinicians should be aware of the possibility of paradoxical activation of autoimmune diseases during its treatment. PMID- 23096070 TI - Affective saliency modifies visual tracking behavior in disorders of consciousness: a quantitative analysis. PMID- 23096071 TI - Modified electroconvulsive therapy for the treatment of refractory schizophrenia like psychosis associated with Huntington's disease. PMID- 23096072 TI - Hemoglobin decline in cancer patients receiving chemotherapy without an erythropoiesis-stimulating agent. AB - PURPOSE: The aim of this study was to examine the rate and timing of hemoglobin decline from <10 g/dL to <9 g/dL in cancer patients receiving chemotherapy. METHODS: Pooled data from the placebo arms of six randomized, controlled trials (RCTs) of darbepoetin alfa and data from an aggregated US community oncology clinic electronic medical records (EMR) database were analyzed. Patients had baseline hemoglobin >=10 g/dL (RCTs) or baseline hemoglobin between >=10 g/dL and <11 g/dL (EMR episodes) that declined to <10 g/dL at least once during the study period. The proportion of patients/episodes with hemoglobin decline to <9 g/dL by 3, 6, and 9 weeks without erythropoiesis-stimulating agents was estimated from data in each of the data sources, as was the rate of transfusions in the RCTs. RESULTS: Data from 411 patients receiving placebo in the RCTs and 10,523 patients (10,942 episodes) in the EMR database were analyzed. Forty percent and 35 % of RCT patients and EMR episodes, respectively, had a hemoglobin decline from <10 g/dL to <9 g/dL at week 3, 54 % and 43 % at week 6, and 58 % and 46 % at week 9. Of patients in the RCTs, 43 % required an RBC transfusion. CONCLUSIONS: Hemoglobin can rapidly decline in cancer patients receiving chemotherapy with hemoglobin levels around 10 g/dL, particularly in patients >=65 years of age. The rapid rate of hemoglobin decline in these patients should be considered for optimal anemia management. PMID- 23096073 TI - Takagi-Sugeno fuzzy models in the framework of orthonormal basis functions. AB - An approach to obtain Takagi-Sugeno (TS) fuzzy models of nonlinear dynamic systems using the framework of orthonormal basis functions (OBFs) is presented in this paper. This approach is based on an architecture in which local linear models with ladder-structured generalized OBFs (GOBFs) constitute the fuzzy rule consequents and the outputs of the corresponding GOBF filters are input variables for the rule antecedents. The resulting GOBF-TS model is characterized by having only real-valued parameters that do not depend on any user specification about particular types of functions to be used in the orthonormal basis. The fuzzy rules of the model are initially obtained by means of a well-known technique based on fuzzy clustering and least squares. Those rules are then simplified, and the model parameters (GOBF poles, GOBF expansion coefficients, and fuzzy membership functions) are subsequently adjusted by using a nonlinear optimization algorithm. The exact gradients of an error functional with respect to the parameters to be optimized are computed analytically. Those gradients provide exact search directions for the optimization process, which relies solely on input-output data measured from the system to be modeled. An example is presented to illustrate the performance of this approach in the modeling of a complex nonlinear dynamic system. PMID- 23096074 TI - A cluster-based differential evolution algorithm with external archive for optimization in dynamic environments. AB - This paper presents a Cluster-based Dynamic Differential Evolution with external Archive (CDDE_Ar) for global optimization in dynamic fitness landscape. The algorithm uses a multipopulation method where the entire population is partitioned into several clusters according to the spatial locations of the trial solutions. The clusters are evolved separately using a standard differential evolution algorithm. The number of clusters is an adaptive parameter, and its value is updated after a certain number of iterations. Accordingly, the total population is redistributed into a new number of clusters. In this way, a certain sharing of information occurs periodically during the optimization process. The performance of CDDE_Ar is compared with six state-of-the-art dynamic optimizers over the moving peaks benchmark problems and dynamic optimization problem (DOP) benchmarks generated with the generalized-dynamic-benchmark-generator system for the competition and special session on dynamic optimization held under the 2009 IEEE Congress on Evolutionary Computation. Experimental results indicate that CDDE_Ar can enjoy a statistically superior performance on a wide range of DOPs in comparison to some of the best known dynamic evolutionary optimizers. PMID- 23096075 TI - Online modeling with tunable RBF network. AB - In this paper, we propose a novel online modeling algorithm for nonlinear and nonstationary systems using a radial basis function (RBF) neural network with a fixed number of hidden nodes. Each of the RBF basis functions has a tunable center vector and an adjustable diagonal covariance matrix. A multi-innovation recursive least square (MRLS) algorithm is applied to update the weights of RBF online, while the modeling performance is monitored. When the modeling residual of the RBF network becomes large in spite of the weight adaptation, a node identified as insignificant is replaced with a new node, for which the tunable center vector and diagonal covariance matrix are optimized using the quantum particle swarm optimization (QPSO) algorithm. The major contribution is to combine the MRLS weight adaptation and QPSO node structure optimization in an innovative way so that it can track well the local characteristic in the nonstationary system with a very sparse model. Simulation results show that the proposed algorithm has significantly better performance than existing approaches. PMID- 23096076 TI - Towards a snowdrift game optimization to vertex cover of networks. AB - To solve the vertex cover problem in an agent-based and distributed networking systems utilizing local information, we treat each vertex as an intelligent rational agent rather than an inanimate one and provide a spatial-snowdrift-game based optimization framework to vertex cover of networks. We analyze the inherent relation between the snowdrift game and the vertex cover: Strict Nash equilibriums of the spatial snowdrift game are the intermediate states between vertex-covered and minimal-vertex-covered states. Such equilibriums are obtained by employing the memory-based best response update rule. We also find that a better approximate solution in terms of the minimal vertex cover will be achieved by increasing the individuals' memory length, because such a process optimizes the individuals' strategies and helps them convert from bad equilibriums into better ones. Our findings pave a new way to solve the vertex cover problem from the perspective of agent-based self-organized optimization. PMID- 23096077 TI - Auditory perspective taking. AB - Effective communication with a mobile robot using speech is a difficult problem even when you can control the auditory scene. Robot self-noise or ego noise, echoes and reverberation, and human interference are all common sources of decreased intelligibility. Moreover, in real-world settings, these problems are routinely aggravated by a variety of sources of background noise. Military scenarios can be punctuated by high decibel noise from materiel and weaponry that would easily overwhelm a robot's normal speaking volume. Moreover, in nonmilitary settings, fans, computers, alarms, and transportation noise can cause enough interference to make a traditional speech interface unusable. This work presents and evaluates a prototype robotic interface that uses perspective taking to estimate the effectiveness of its own speech presentation and takes steps to improve intelligibility for human listeners. PMID- 23096078 TI - Myocardial 123I-MIBG scintigraphy predicts an impairment in myocardial functional reserve during dobutamine stress in patients with idiopathic dilated cardiomyopathy. AB - PURPOSE: We investigated whether myocardial (123)I-metaiodobenzylguanidine ((123)I-MIBG) scintigraphy predicts impairment of myocardial functional reserve in response to dobutamine stress in patients with idiopathic dilated cardiomyopathy (DCM). METHODS: Forty DCM patients (LVEF 39 +/- 12 %) underwent myocardial (123)I-MIBG scintigraphy, echocardiography, and cardiac catheterization. Myocardial (123)I-MIBG uptake was quantified as the delayed heart to mediastinum (H/M) ratio and washout rate (WR). Local denervation was evaluated on polar map images. LV dP/dt (max) and T(1/2) were determined from left ventricular pressure curves at baseline and during dobutamine infusion (15 MUg/kg /min). Patients were classified into two groups as follows: group A comprised 21 patients showing a delayed H/M ratio of <1.9 (median value); group B comprised 19 patients showing a delayed H/M ratio of >= 1.9. RESULTS: The percentage change in heart rate (%HR), LV dP/dt (max) (%LV dP/dt (max)), and T (1/2) (%T (1/2)) from baseline to dobutamine stress were significantly more reduced in group A than in group B (39.3 +/- 20.2 %, 55.2 +/- 24.1 %, p < 0.01; 102.3 +/- 46.3 %, 152.0 +/- 72.3 %, p < 0.05; 38.7 +/- 15.3 %, 46.9 +/- 15.4 %, p < 0.05, respectively). No significant differences between the two groups were observed in the echocardiographic parameters or baseline cardiac catheterization parameters. Significant correlations were found between delayed H/M ratio and %HR (r = 0.35, p < 0.05), %LV dP/dt (max) (r = 0.45, p < 0.05) and %T (1/2) (r = 0.34, p < 0.05). Significant inverse correlations were also found between WR and %HR (r = -0.37, p < 0.05), %LV dP/dt (max) (r = -0.60, p < 0.0001), and %T (1/2) (r = -0.34, p < 0.05). SPECT images revealed enhanced denervation from the inferoposterior to anterior wall in accordance with the advancement of global denervation. CONCLUSION: Reduced (123)I-MIBG uptake and increased washout were related to impairment in adrenergic myocardial functional reserve in idiopathic DCM. PMID- 23096079 TI - In vivo characterization of 68Ga-NOTA-VEGF 121 for the imaging of VEGF receptor expression in U87MG tumor xenograft models. AB - PURPOSE: Vascular endothelial growth factor receptors (VEGFRs) are associated with tumor growth and induction of tumor angiogenesis and are known to be overexpressed in various human tumors. In the present study, we prepared and evaluated (68)Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-benzyl (NOTA) VEGF(121) as a positron emission tomography (PET) radioligand for the in vivo imaging of VEGFR expression. METHODS: (68)Ga-NOTA-VEGF(121) was prepared by conjugation of VEGF(121) and p-SCN-NOTA, followed by radiolabeling with (68)GaCl(3) and then purification using a PD-10 column. Human aortic endothelial cell (HAEC) binding of (68)Ga-NOTA-VEGF(121) was measured as a function of time. MicroPET and biodistribution studies of U87MG tumor xenografted mice were performed at 1, 2, and 4 h after injection of (68)Ga-NOTA-VEGF(121). The tumor tissues were then sectioned and subjected to immunostaining. RESULTS: The decay corrected radiochemical yield of (68)Ga-NOTA-VEGF(121) was 40 +/- 4.5 % and specific activity was 243.1 +/- 104.6 GBq/MUmol (8.6 +/- 3.7 GBq/mg). (68)Ga-NOTA VEGF(121) was avidly taken up by HAECs in a time-dependent manner, and the uptake was blocked either by 32 % with VEGF(121) or by 49 % with VEGFR2 antibody at 4 h post-incubation. In microPET images of U87MG tumor xenografted mice, radioactivity was accumulated in tumors (2.73+/-0.32 %ID/g at 2 h), and the uptake was blocked by 40 % in the presence of VEGF(121). In biodistribution studies, tumor uptake (1.84+/-0.14 %ID/g at 2 h) was blocked with VEGF(121) at a similar level (52 %) to that of microPET images. Immunostaining analysis of U87MG tumor tissues obtained after the microPET imaging showed high levels of VEGFR2 expression. CONCLUSION: These results demonstrate that (68)Ga-NOTA-VEGF(121) has potential for the in vivo imaging of VEGFR expression. In addition, our results also suggest that the in vivo characteristics of radiolabeled VEGF depend on the properties of the radioisotope and the chelator used. PMID- 23096080 TI - The diagnostic value of 18F-FDG PET and MRI in paediatric histiocytosis. AB - PURPOSE: To analyse the diagnostic value of (18)F-FDG PET and MRI for the evaluation of active lesions in paediatric Langerhans cell histiocytosis. METHODS: We compared 21 (18)F-FDG PET scans with 21 MRI scans (mean time interval 17 days) in 15 patients (11 male, 4 female, age range 4 months to 19 years) with biopsy-proven histiocytosis. Primary criteria for the lesion-based analysis were signs of vital histiocyte infiltrates (bone marrow oedema and contrast enhancement for MRI; SUV greater than the mean SUV of the right liver lobe for PET). PET and MR images were analysed separately and side-by-side. The results were validated by biopsy or follow-up scans after more than 6 months. RESULTS: Of 53 lesions evaluated, 13 were confirmed by histology and 40 on follow-up investigations. The sensitivity and specificity of PET were 67 % and 76 % and of MRI were 81 % and 47 %, respectively. MRI showed seven false-positive bone lesions after successful chemotherapy. PET showed five false-negative small bone lesions, one false-negative lesion of the skull and three false-negative findings for intracerebral involvement. PET showed one false-positive lesion in the lymphoid tissue of the head and neck region and two false-positive bone lesions after treatment. Combined PET/MR analysis decreased the number of false-negative findings on primary staging, whereas no advantage over PET alone was seen in terms of false-positive or false-negative results on follow-up. CONCLUSION: Our retrospective analysis suggests a pivotal role of (18)F-FDG PET in lesion follow up due to a lower number of false-positive findings after chemotherapy. MRI showed a higher sensitivity and is indispensable for primary staging, evaluation of brain involvement and biopsy planning. Combined MRI/PET analysis improved sensitivity by decreasing the false-negative rate during primary staging indicating a future role of simultaneous whole-body PET/MRI for primary investigation of paediatric histiocytosis. PMID- 23096081 TI - Toxic effects of the ingestion of water-soluble elements found in soil under the atmospheric influence of an industrial complex. AB - In this study, we investigated the toxic effects of water-soluble elements from a contaminated soil via gavage in a single dose, simulating a geophagy event. The contaminated soil was collected in a field located in an industrial complex, and the control soil was collected in a reference area. Metabolic and behavioral parameters in Wistar male rats were measured after 24 and 96 h of gavage. After 96 h, the major organs were weighed, blood was collected to check hematological parameters, the bone marrow was taken for the micronucleus test, and the liver was used for evaluating the total antioxidant capacity, lipoperoxidation and protein carbonylation. Animals exposed to contaminated soil presented a few significant alterations by comparison with control animals: TBARS and protein carbonyl levels increased, the relative weight of the kidneys increased, metabolic parameters (body weight gain, food intake, water consumption, urine and feces production) depressed and there was behavioral alteration. These findings suggest that soils impacted by atmospheric contaminants can affect the organism physiological status jeopardizing the health of populations living in industrial areas. Finally, this study reassures that ingestion of potentially contaminated soils, even for short periods of time, can cause health risks. PMID- 23096082 TI - Minor allele of the APOA4 gene T347S polymorphism predisposes to obesity in postmenopausal Turkish women. AB - The aim of this study was to examine the relationship between APOA4 gene T347S polymorphism with obesity measures and serum lipids in Turkish adults. Randomly selected sample of 1,554 adults (754 men, mean age 50.4 +/- 11.9 years and 800 women, mean age 49.6 +/- 11.8 years) were included in the study. 346 Women (43.2 %) were postmenopausal. Genotyping was performed by using hybridization probes in real-time PCR. Not men but postmenopausal women, carrying the S347 allele, were associated with 1.5 kg/m(2) higher BMI (P = 0.016) and 3.6 cm wider waist circumference (P = 0.005) than postmenopausal T347 homozygotes, controlled for covariates. Logistic regression analyses of this polymorphism, adjusted for age, fasting triglyceride, smoking status, alcohol consumption and physical activity disclosed the rare allele to be associated with obesity in postmenopausal women at an odds of 1.80 (95 % CI 1.09-2.97; P = 0.021). Serum apoB level was lower in S347 allele carriers (110.9 +/- 2.9 mg/dL) than in T347 homozygotes (119.0 +/- 2.4 mg/dL; P = 0.035) in men but not women. APOA4 T347S polymorphism was unrelated to lipids and other lipoproteins in either gender. The APOA4 S347 allele predisposes to obesity and high waist circumference in Turkish postmenopausal women. ApoB levels are lower only in men in S347 allele carriers. PMID- 23096083 TI - A functional polymorphism in XRCC1 is associated with glioma risk: evidence from a meta-analysis. AB - Previous studies show that X-ray cross-complementing group 1 (XRCC 1) Arg399Gln may result in variations in repair efficiency of DNA damage, and this repair deficit may eventually cause individual susceptibility to glioma. However, published data regarding the association between XRCC 1 Arg399Gln polymorphism and glioma risk was contradictory. The aim of this study was to derive a more precise estimation of the association of XRCC 1 Arg399Gln polymorphism with glioma risk by performing a meta-analysis of eligible studies. Odds ratios (ORs) and 95 % confidence intervals (95 %CIs) were used to assess the strength of the association. We performed a meta-analysis of eleven published studies that included 2,808 glioma cases and 3,114 controls. Overall, there was a significant association between XRCC1 Arg399Gln polymorphism and glioma risk in two genetic models (for ArgGln vs ArgArg: OR = 1.30, 95 % CI 1.01-1.68; for GlnGln/ArgGln vs ArgArg: OR = 1.28, 95 % CI 1.01-1.62). In the stratified analysis by ethnicity, the XRCC1 Arg399Gln polymorphism had a higher risk of glioma development among Asians (for Gln vs Arg: OR = 1.34, 95 % CI 1.12-1.61; for GlnGln vs ArgArg: OR = 1.72, 95 % CI 1.18-2.51; for ArgGln vs ArgArg: OR = 1.31, 95 % CI 1.01-1.71; for GlnGln/ArgGln vs ArgArg: OR = 1.41, 95 % CI 1.10-1.80; for GlnGln vs ArgArg/ArgGln: OR = 1.48, 95 % CI 1.05-2.09)., but not among Caucasians. In conclusion, the results suggest that the XRCC 1 Arg399Gln polymorphism may contribute to the susceptibility of glioma in Asians. PMID- 23096084 TI - Molecular cloning and expression of 17beta-hydroxysteroid dehydrogenase type 2 gene in Hu sheep. AB - 17beta-Hydroxysteroid dehydrogenase type 2 (17beta-HSD2) catalyzes the NADP+ dependent oxidation of the most potent estrogen 17beta-estradiol into the weak estrogen estrone, and the conversion of testosterone to androstenedione. It has been reported that 17beta-HSD2 was expressed in many tissues in human, rats, however, the full-length sequence of 17beta-HSD2 gene and its expression in ewe were still unknown. In this study, we cloned the full-length cDNA sequence and investigated mRNA differential expression in 28 tissues of 12 adult Hu-Sheep which were fed with high- and low- dietary intake. The 1,317 bp full-length cDNA sequence was first cloned. The coding region was 1,167 bp in length, and the monomer was estimated to contain 389 amino acid residues. It shares high AA sequence identity with that of bos Taurus (96.13 %), sus scrofa (77.06 %), canis lupus familiaris (70.44 %), Callithrix jacchus (65.72 %), Nomascus leucogenys (65.46 %), pan troglodytes (65.21 %), human (64.69 %), mus musculus (58.35 %), and a comparatively lower identity to danio rerio (37.85 %). 17beta-HSD2 gene was high expressed in gastrointestinal (GI) tract, liver, but weakly expressed in other tissues. No detected expression was examined in lung. 17beta-HSD2 gene expression was significantly difference in rumen, omasum, duodenum, cecum, hypophysis after high- and low- dietary intake. Results from the present study suggested that 17beta-HSD2 plays a crucial role in almost all tissues protecting against excessive levels of active steroid hormone, and GI tract maybe an important steroid hormone metabolizing organ in Hu-Sheep. This present study is the first to provide the primary foundation for further insight into this ovine gene. PMID- 23096085 TI - Molecular cloning and recombinant expression of cytochrome P450 CYP6B6 from Helicoverpa armigera in Escherichia coli. AB - The cytochrome P450 s play a significant role in the detoxification of plant allelochemicals and synthetic insecticides in Lepidoptera. In the cotton bollworm Helicoverpa armigera, 2-tridecanone and quercetin can induce P450-dependent monooxygenase activity increased, to further the characterization of P450, the CYP6B6 of cotton bollworm (H. armigera) was cloned, sequenced and expressed in pMAL-p2x vector and expressed in Escherichia coli. The deduced amino acid sequences of cytochrome P450 in the midgut and fat body of H. armigera showed 98.23 and 97.84 % similarity with CYP6B6, respectively. According to nomenclature of P450 s, the P450 genes we got belong to CYP6B. Purification of recombinant protein based on the affinity of MBP for maltose was achieved by Mal-Tag magnetic beads. The purified protein was used to raise polyclonal antibody according to classical procedure. SDS-PAGE and Western blot results indicated that MBP-CYP6B6 had been successfully expressed. The ethoxycoumarin-O-deethylase activity of the purified recombinant protein was 36.5 +/- 8.12 pmol of 7-hydroxycoumarin/min/mg protein, which showed the fusion MBP-CYP6B6 had the ability to o-deethylase of 7 ethoxycoumarin. PMID- 23096086 TI - Molecular characterization, expression analysis and association study with meat quality traits of porcine TTID gene. AB - Titin immunoglobulin domain protein (TTID) is localized to the Z-line and binds to alpha-actinin, gamma-filamin. It plays an indispensable role in stabilization and anchorage of thin filaments. In this study, the full-length cDNA sequence was isolated by the reverse transcription-polymerase chain reaction (RT-PCR) and the rapid amplification of cDNA ends (RACE). The TTID sequence was deposited into the Genbank under the accession no. DQ157551. The deduced protein of 499 amino acids showed 93 % identity to the corresponding human and rat sequence. Semi quantitative RT-PCR revealed porcine TTID gene was expressed highest level in skeletal muscle, at second-highest level in the heart, but only low expression in the fat was detected. Bioinformatics analysis shows the molecular weight of the TTID protein is 55.747 kD with a PI of 9.26. It contains the protein function site of two potential Ig-like domain profiles, six N-myristoylation sites, six potential Casein kinase II phosphorylation sites, eight protein kinase C phosphorylation sites, three N-glycosylation sites, a tyrosine kinase phosphorylation site and a cell attachment sequence site. No putative base substitution was detected in the coding region by comparing sequences of Large White, Landrace and Meishan pig breeds. A T978C single nucleotide polymorphism in the intron 6 of porcine TTID gene was detected by a HinfI PCR-restriction fragment length polymorphism. Study showed allele frequency differences among four purebreds. Association of the genotypes with meat quality traits showed that different genotypes of porcine TTID gene were significantly associated with meat pH (m.Biceps Femoris) (P < 0.05), meat color value (m.longissimus Dorsi) (P < 0.05) and Water Moisture (m.longissimus Dorsi) (P < 0.05). PMID- 23096087 TI - Isolation and characterization of a gene from Medicago sativa L., encoding a bZIP transcription factor. AB - A full-length cDNA of 1,537 nucleotides was cloned from Medicago sativa L. cv. "Zhongmu No. 1" by rapid amplification of cDNA ends. It was designated as MsZIP, encoding a protein of 340 amino acids. The protein molecular weight was 36.43 kDa, and the theoretical isoelectric point was 5.72. The MsZIP preferentially localized in nucleus and have signal peptide. Blast analysis revealed that MsZIP shared the highest homology with some bZIP proteins of M. truncatula. The transcript of MsZIP was strongly enriched in leaf compared with root and stem of mature alfalfa plants. MsZIP was strongly induced by 15 % PEG6000 (polyethylene glycol), 50 MUM abscisic acid, 200 mM NaCl, 70 MUM gibberellic acid, 5 mM salicylic acid and 200 MUM methyl jasmonate. Physiological resistance parameters were measured in the transgenic tobacco. Malondialdehyde content, relative water content, soluble sugar content, soluble protein content and proline content in transgenic tobacco increased compared with non-transgenic tobacco under salt stress or drought stress. The results showed that accumulation of the MsZIP protein in the vegetative tissues of transgenic plants enhanced their tolerance to osmotic pressure stress. These results demonstrate a role for the MsZIP protein in stress protection and suggest the potential of the MsZIP gene for genetic engineering of salt tolerance and drought tolerance. PMID- 23096088 TI - Characterization of the NADP-malic enzymes in the woody plant Populus trichocarpa. AB - Plant NADP-malic enzyme (NADP-ME, EC 1.1.1.40) participates in a large number of metabolic pathways, but little is known about the NADP-ME family in woody plants or trees. Here, we characterized the tree Populus trichocarpa NADP-ME (PtNADP-ME) family and the properties of the family members. Five NADP-ME genes (PtNADP-ME1 PtNADP-ME5) were found in the genome of Populus. Semi-quantitative RT-PCR analysis show that the transcription levels of PtNADP-ME1 in lignified stems and roots are clearly higher than in other tissues, and PtNADP-ME2, PtNADP-ME3, PtNADP-ME4 and PtNADP-ME5 are broadly expressed in various tissues. PtNADP-ME gene expression was found to respond to salt and osmotic stresses, and NaCl salts upregulated the transcripts of putative plastidic ones (PtNADP-ME4 and PtNADP ME5) significantly. Further, the NADP-ME activities of Populus seedlings increased at least two-fold under NaCl, mannitol and PEG treatments. Also, the expression of PtNADP-ME2 and PtNADP-ME3 increased during the course of leaf wounding. Each recombinant PtNADP-ME proteins were expressed and purified from Escherichia coli, respectively. Coomassie brilliant blue and NADP-ME activity staining on native polyacrylamide gels showed different oligomeric states of the recombinant PtNADP-MEs in vitro. Noticeably, the cytosolic PtNADP-ME2 aggregates as octamers and hexadecamers while the plastidic PtNADP-ME4 resembles hexamers and octamers. The four PtNADP-ME proteins except for PtNADP-ME1 have high activities on native polyacrylamide gels including different forms for PtNADP-ME2 (octamers and hexadecamers) or for PtNADP-ME4 (hexamers and octamers). High concentrations of NADP substrate decreased the activities of all PtNADP-MEs slightly, while the malate had no effect on them. The kinetic parameters (V (max), K (m), K (cat), and K (cat)/K (m)) of each isoforms were summarized. Our data show the different effects of metabolites (influx into tricarboxylic acid cycle or Calvin cycle) on the activity of the individual PtNADP-ME in vitro. According to phylogenetic analysis, five PtNADP-MEs are clustered into cytosolic dicot, plastidic dicot, and monocot and dicot cytosolic groups in a phylogenetic tree. These results suggest that woody Populus NADP-ME family have diverse properties, and possible roles are discussed. PMID- 23096089 TI - Prior peritoneal lavage with hot 0.9 % saline induces HSP70 expression and protects against cerulein-induced acute pancreatitis in rats. AB - Recent studies have indicated that pre-induction of heat shock protein 70 (HSP70) expression in the pancreas protects against secretagogue-induced pancreatitis. In those studies, the HSP70 was mostly induced by unfeasible conditions. The aim of this current study was to investigate the effect of peritoneal lavage with hot 0.9 % saline (42 degrees C) on the pancreatic expression of HSP70 and its protective effect on cerulein-induced acute pancreatitis in rats. Male Wistar rats were peritoneally lavaged with 0.9 % saline at 42 degrees C for 30 min. HSP70 expression was evaluated by western blotting analysis. Prior peritoneal lavages with hot and warm saline were performed. Acute pancreatitis was induced by administration of intraperitoneal injection of cerulein (20 MUg/kg) four times, and its severity was assessed by measuring serum amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and trypsinogen activation peptide (TAP) levels. Pancreatic sections were stained with hematoxylin and eosin for histological evaluation. Peritoneal lavage with hot 0.9 % saline increased intrapancreatic HSP70 expression and ameliorated the cerulein-induced pancreatitis in rats, judged by the significantly reduced serum amylase, TNF alpha, and IL-6 concentrations; histopathological scores, and serum TAP levels. Peritoneal lavage with hot 0.9 % saline can induce HSP70 expression and prevent cerulein-induced acute pancreatitis in rats. The results suggest that HSP70 protects against cerulein-induced pancreatitis by preventing proinflammatory cytokine synthesis and trypsinogen activation during acute pancreatitis. PMID- 23096090 TI - Amerindians show no association of PPAR-gamma2 gene Ala12 allele and obesity: an "unthrifty" variant population genetics. AB - Obesity is for many scholars the most important starting status that gives rise to Metabolic Syndrome (MS) and Type 2 Diabetes (T2D). In the present paper, a genetically homogeneous Amerindian population, as defined by HLA genes, has been genotyped for one of the MS and T2D predisposing genes: PPAR-gamma Ala12 and Pro 12 variants. Ala12 has been negatively associated with obesity, but other authors do not find such an association. Notwithstanding, a meta-analysis that used many subjects clearly demonstrated that PPAR-gamma Ala12 bearing ones had a reduced risk for T2D. Our results show that Amerindians do not have association of PPAR gamma2 Ala12 and obesity; the latter was measured by waist circumference values after taken specific Amerindian normal waist parameters. Also, a population genetics study indicates that Pro12 allele was the wild allele, which must have occurred before modern humans left Africa. Ala12 may have appeared in Caucasoids later on, according to our comparisons. Negroids tend to show low or null Ala 12 allele frequencies, while most other populations have a significant frequency, particularly European Caucasoids. This may suggest that appearance of Ala12 allele occurred after populations adapted to an agricultural feeding. PMID- 23096091 TI - Association between IL10, IL10RA, and IL10RB SNPs and ischemic stroke with hypertension in Korean population. AB - The pathogenesis of stroke is associated with the immune and inflammatory responses. Cytokines, such as interleukin 10 (IL10), play an important role in the process of inflammation. To investigate whether IL10, IL10RA, and IL10RB polymorphisms are associated with the risk of ischemic stroke (IS), selected two IL10 SNPs (rs1518111 and rs1554286), three IL10RA SNPs (rs2256111, rs4252243, and rs2228054), and two IL10RB SNPs (rs999788 and rs2834167) were analyzed in 120 patients with IS and 285 control subjects. All IS patients were classified into the clinical subgroups, according to the levels of blood pressure (hypertension, present and absent), fasting plasma glucose (diabetes mellitus, present and absent), and lipids (dyslipidemia, present and absent). SNPStats and SPSS 18.0 program were used to obtain the odds ratios, 95 % confidence intervals, and P values. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive models) were performed to analyze the genetic data. Seven polymorphisms were not associated with the IS, but showed significant associations with hypertension, in the risk of IS. These results suggest that the IL10, IL10RA, and IL10RB genes may be contributed to the hypertension in the risk of IS in the Korean population. PMID- 23096092 TI - The l58Val/Met polymorphism of catechol-O-methyl transferase gene and prostate cancer risk: a meta-analysis. AB - The association between COMT Val158Met polymorphism and prostate cancer has been evaluated. However, the results of these studies on the association remain conflicting. To derive a more precise estimation of the relationship, a meta analysis was performed. A comprehensive search was conducted to identify the eligible studies of COMT Val158Met polymorphism and prostate cancer risk. Summary odds ratios (OR) and 95 % confidence interval (CI) for COMT Val158Met polymorphism and prostate cancer were calculated. Statistical analysis was performed with the software program Review Manage (Version 5.0) and Stata (Version 12.0). Six case-control studies, totally 4,118 persons including 2,143 cases and 1,975 controls, met the included criteria and thus were selected. Our analysis suggested that Val158Met polymorphism was associated with prostate cancer risk in overall population. Collectively, the results of the present study suggest that significant associations of COMT Val158Met polymorphisms with prostate cancer were observed (for additive model: OR = 1.068, 95 % CI = 1.002 1.138, P (heterogeneity) = 0.363, P = 0.043; for dominant model: OR = 1.266, 95 % CI = 1.057-1.517, P (heterogeneity) = 0.000, P = 0.011; for recessive model: OR = 1.050, 95 % CI = 0.961-1.146, P (heterogeneity) = 0.558, P = 0.279; and Val allele versus Met allele OR = 0.932, 95 % CI = 0.894-0.971, P (heterogeneity) = 0.272, P = 0.001). In the subgroup analysis, we detected no significant association between the COMT 158 Val/Met genotype and prostate cancer risk in Caucasian and Asian populations, while the contrary result for additive model (OR = 2.43, 95 % CI = 1.08-5.43, P (heterogeneity) = 0.04, P = 0.03) in Asian populations. The result of this meta-analysis suggests that COMT l58Val/Met polymorphism might be contributed to the overall prostate cancer risk. PMID- 23096093 TI - Analysis of the polymorphisms in the caprine Gli3 gene and their associations with production traits in goats. AB - Gli3 is a zinc finger transcription factor which plays a critical role in regulating animal development, metabolism and energy partitioning and thus has the potential to influence economical important traits in farm animals. In this study, we screened the complete exons of the caprine Gli3 gene using PCR-SSCP methods in 430 individuals from three goat breeds to identify sequence variants that might be associated with growth traits. Six novel mutations (GU363952:g.739C>G, 749A>T, 1636C>A, 1982delT, 1983T>C, 2856T>C) were identified. Significant associations were observed between the mutations GU363952:g.739C>G and g.749A>T with body height, chest circumference and canon circumference. Individuals with genotype G4-CC/AA and G4-CG/AT were significantly higher than individuals with genotype G4-GG/TT in body height, chest circumference and canon circumference. The results of this study suggested that the Gli3-gene-specific SNP could be a useful marker for growth traits in future marker-assisted selection programs in goat. PMID- 23096095 TI - Worse glycaemic control in LADA patients than in those with type 2 diabetes, despite a longer time on insulin therapy. AB - AIMS/HYPOTHESIS: Our aim was to study whether glycaemic control differs between individuals with latent autoimmune diabetes in adults (LADA) and patients with type 2 diabetes, and whether it is influenced by time on insulin therapy. METHODS: We performed a retrospective study of 372 patients with LADA (205 men and 167 women; median age 54 years, range 35-80 years) from Swedish cohorts from Skane (n = 272) and Vasterbotten (n = 100). Age- and sex-matched patients with type 2 diabetes were included as controls. Data on the use of oral hypoglycaemic agents (OHAs), insulin and insulin-OHA combination therapy was retrieved from the medical records. Poor glycaemic control was defined as HbA(1c) >=7.0% (>=53 mmol/mol) at follow-up. RESULTS: The individuals with LADA and with type 2 diabetes were followed for an average of 107 months. LADA patients were leaner than type 2 diabetes patients at diagnosis (BMI 27.7 vs 31.0 kg/m(2); p < 0.001) and follow-up (BMI 27.9 vs 30.2 kg/m(2); p < 0.001). Patients with LADA had been treated with insulin for longer than those with type 2 diabetes (53.3 vs 28.8 months; p < 0.001). There was no significant difference between the patient groups with regard to poor glycaemic control at diagnosis, but more patients with LADA (67.8%) than type 2 diabetes patients (53.0%; p < 0.001) had poor glycaemic control at follow-up. Patients with LADA had worse glycaemic control at follow-up compared with participants with type 2 diabetes (OR = 1.8, 95% CI 1.2, 2.7), adjusted for age at diagnosis, HbA(1c), BMI at diagnosis, follow-up time and duration of insulin treatment. CONCLUSIONS/INTERPRETATION: Individuals with LADA have worse glycaemic control than patients with type 2 diabetes despite a longer time on insulin therapy. PMID- 23096094 TI - Noradrenergic control of neuronal firing in cerebellar nuclei: modulation of GABA responses. AB - The effects of noradrenaline (NA) on inhibitory responses to gamma aminobutyric acid (GABA) in neurones of the deep cerebellar nuclei were studied in vivo in rats, using extracellular single-unit recordings and microiontophoretic drug application. NA application altered GABA-evoked responses in 95 % of the neurones tested, but the effects differed between nuclei. Application of NA depressed GABA responses in the medial (MN) and posterior interpositus (PIN) nuclei, but enhanced GABA responses in the anterior interpositus nucleus (AIN). Comparable proportions of enhancing (57 %) and depressive (43 %) effects were found in the lateral nucleus (LN). The alpha2 noradrenergic receptor agonist clonidine mimicked the depressive effect of NA on GABA responses in MN and PIN and its enhancing effects in AIN and LN, while the alpha2 antagonist yohimbine partially blocked these effects. The beta-adrenergic agonist isoproterenol and antagonist timolol respectively induced and partially blocked enhancements of GABA responses in all nuclei except for LN, where isoproterenol had a weak depressive effect. It is concluded that NA modulates GABA responses by acting on both alpha2 and beta receptors. Activation of these receptors appears to be synergistic in the AIN and opposite in the remaining deep nuclei. These results support the hypothesis that the noradrenergic system participates in all the regulatory functions involving the cerebellum in a specific and differential manner, and suggest that any change in NA content, as commonly observed in ageing or stress, could influence cerebellar activity. PMID- 23096096 TI - Upregulation of VEGF expression is associated with accumulation of HIF-1alpha in the skin of naive scleroderma patients. AB - Systemic sclerosis is a disease hallmarked by microangiopathy; the enlargement and leakage of skin capillaries in active stages develops into extensive avascular areas, clinically associated with severe tissue hypoxia and the formation of digital ulcers. Vascular endothelial growth factor (VEGF) is upregulated in all stages of the disease, with little effect on efficient neovascularization. The oxygen-regulated alpha-subunit of hypoxia-inducible transcription factor-1 (HIF-1alpha) represents a key mechanism involved in the transcriptional regulation of VEGF. The aim of this study is to investigate expression of the oxygen-regulated alpha-subunit of HIF-1 and VEGF in naive scleroderma patients. For this purpose, skin biopsies (dorsal hand surface) from scleroderma patients were analyzed and compared with control skin biopsies. Immunoreactivity for VEGF was enhanced in scleroderma patients, in contrast to restricted positive immunostaining in suprabasal keratinocytes observed in normal skin. In a similar fashion, all skin biopsies from scleroderma patients were strongly HIF-1alpha reactive, compared with rare immunoreactivity observed in normal skin. The pattern was similar in all stages of scleroderma. These observations for the first time directly connect constitutive hypoxia with VEGF upregulation in scleroderma patients. The sequence of events needs to be precisely mapped, and the pro- and antiangiogenic switches which may interfere with efficient tissue neovascularization identified, in order to provide meaningful therapeutic strategies. PMID- 23096097 TI - Preterm Birth Genome Project (PGP) -- validation of resources for preterm birth genome-wide studies. AB - We determined a series of quality control (QC) analyses to assess the usability of DNA collected and processed from different countries utilizing different DNA extraction techniques prior to genome-wide association studies (GWAS). The quality of DNA collected utilizing four different DNA extraction techniques and the impact of shipping DNA at different temperatures on array performance were evaluated. Fifteen maternal-fetal pairs were used from four countries. DNA was extracted using four approaches: whole blood, blood spots with whole genome amplification (WGA), saliva and buccal swab. Samples were sent to a genotyping facility, either on dry ice or at room temperature and genotyped using Affymetrix SNP array 6.0. QC measured included extraction techniques, effect of shipping temperatures, accuracy and Mendelian concordance. Significantly fewer (50 % ) single nucleotide polymorphisms (SNPs) passed QC metrics for buccal swab DNA (P < 0.0001) due to missing genotype data (P < 0.0001). Whole blood or saliva DNA had the highest call rates (99.2 0.4 % and 99.3 0.2 % , respectively) and Mendelian concordance. Shipment temperature had no effect. DNA from blood or saliva had the highest call rate accuracy, and buccal swabs had the lowest. DNA extracted from blood, saliva and blood spots were found suitable for GWAS in our study. PMID- 23096098 TI - Perinatal prevention of bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD), defined as oxygen dependency for at least 28 days after birth, is a common adverse outcome of very premature birth. Affected children require frequent readmissions to hospital in the fi rst 2 years, and although lung growth and remodelling results in progressive improvement in lung function, airflow abnormalities may remain. Indeed, the most severely affected experience troublesome respiratory symptoms as adolescents and young adults. As a consequence, many potential preventative strategies have been investigated, and some have resulted in a reduction in BPD but with a negative risk/benefit ratio, for example, postnatal corticosteroids. Others therapies, namely antenatal corticosteroids and postnatal surfactant, have resulted in significant benefits to infants, including reductions in respiratory distress syndrome, necrotising enterocolitis, intraventricular haemorrhage and neonatal death, but have not impacted favourably on the incidence of BPD, perhaps due to the increased survival of very immature infants. In one major trial, it has been shown that BPD can be reduced without adverse effects by caffeine administration. Avoidance of high oxygen concentrations at resuscitation is also a promising approach to reduce BPD. PMID- 23096099 TI - Correlation between an absence of cervical gland area on transvaginal sonography and cervical mucus hyaluronic acid levels in women with threatened preterm delivery. AB - PURPOSE: Transvaginal sonographic findings of an absent cervical gland area (CGA) and a short cervical length (CL) are frequently observed in patients with threatened preterm delivery. The present study aimed to clarify whether sonographic findings are due to active production of hyaluronic acid (HA)in the cervix. METHODS: Possible relationships between sonographic findings of the presence or absence of the CGA and/or a short CL and cervical mucus HA concentration were investigated in 68 women with threatened preterm delivery at 22 - 31 weeks' gestation and 136 women without threatened preterm delivery as controls. RESULTS: HA levels were higher in women with threatened preterm delivery (68.0 ng/mL) than in controls (39.0 ng/mL; P = 0.001). Similarly, HA levels were higher in women with preterm labor showing an absent CGA and a short CL than in women with threatened preterm delivery without such findings (P < 0.01). Stepwise multivariate logistic regression identified an absent CGA and threatened preterm delivery as independent predictors of high HA levels (P = 0.04). HA concentration was not predictive for preterm delivery. CONCLUSION: A sonographic finding of an absent CGA reflects high HA levels in the cervix with threatened preterm delivery. PMID- 23096100 TI - Defining hypoxic ischemic encephalopathy in newborn infants: benchmarking in a South African population. AB - OBJECTIVES: There are few population-based studies of hypoxic ischemic encephalopathy (HIE) in sub-Saharan Africa, and the published criteria that are used to define and grade HIE are too variable for meaningful comparisons between studies and populations. Our objectives were (1) to investigate how the incidence of HIE in our region varies with different criteria for intrapartum hypoxia and (2) to determine how encephalopathy severity varies with different grading systems. METHOD: We reviewed the records of infants with a diagnosis of HIE born between September 2008 and March 2009 in public facilities in the Southern Cape Peninsula, South Africa.The incidence of HIE was calculated according to four definitions of intrapartum hypoxia and graded according to three methods. RESULTS: Depending on which defining criteria were applied,the incidence of HIE varied from 2.3 to 4.3 per 1000 live births, of mild HIE ranged from 0.4 to 1.3 per 1000 live births, and of moderate-severe HIE ranged from 1.5 to 3.7 per 1000 livebirths. Ninety-seven of the 110 (88%) infants reviewed had at least one intrapartum-related abnormality. Only 62 (56%) infants had a blood gas performed in the fi rst hour of life. CONCLUSION: The incidence and grade of HIE can vary more than 2-fold in the same population, depending on which defining criteria are used. Consensus definitions are needed for benchmarking. PMID- 23096101 TI - Emotional modulation of the synapse. AB - Acute stress and emotional arousal can enhance the consolidation of long-term memories in a manner that is dependent on beta -adrenoceptor activation in the basolateral complex of the amygdala (BLA). The BLA interacts with multiple memory systems in the brain to modulate a variety of classes of memory. However, the synaptic mechanisms of this interaction remain unresolved. This review describes the evidence of modulation of memory and synaptic plasticity produced by emotional arousal,stress hormones, and pharmacological or electrophysiological stimulation of the amygdala. The amygdala modulation of local translation and/or degradation of the synaptic plasticity-related proteins, activity-regulated cytoskeletal-associated protein and calcium/calmodulin dependent protein kinase II alpha , is offered as a potential mechanism for the rapid memory consolidation that is associated with emotionally arousing events. This model shares features with synaptic tagging and the emotional tagging hypotheses. PMID- 23096103 TI - PKMzeta inhibition prevents the metaplastic change induced by conditioned taste aversion on insular cortex long-term potentiation in vivo. AB - The activity history of a given neuron or pathway has been suggested to influence its future responses to synaptic inputs. In particular, training in several learning tasks produces a metaplastic change, that is, a change in the ability to induce subsequent synaptic plasticity. Experimental evidence shows that the maintenance of long term memory and long-term potentiation (LTP) requires the persistent action of the atypical protein kinase Cisoform, protein kinase M zeta (PKM zeta ). Recent work has demonstrated that the inactivation of PKM zeta in the insular cortex (IC) abolishes conditioned taste aversion (CTA) long term memory. Our previous studies in the IC have demonstrated that the induction of LTP in the basolateral amygdaloid nucleus (Bla)-IC projection previous to CTA training enhances the retention of this task. Moreover, recently, we have observed that CTA training blocks the subsequent induction of LTP in the Bla-IC projection. The aim of the present study was to investigate the participation of PKM zetaon the CTA-dependent modification of the ability to induce subsequent LTP in the Bla-IC projection in vivo . Thus, we have delivered high-frequency stimulation in the Bla-IC projection in order to induce in vivo IC-LTP in the rats that underwent or did not have an impairment of CTA retention due to the intracortical administration of the selective PKM zeta pseudosubstrate inhibitory peptide, ZIP. Our results show that the microinfusion of ZIP into the IC of the behaving rats impairs long-term memory of CTA and prevents its effects on IC-LTP. These results indicate that PKM zeta is a key component of the cellular mechanisms necessary for the persistence of lasting memory traces as well as for those underlying metaplastic changes in neocortex, contributing to the persistence of aversive memories. PMID- 23096104 TI - Estrogen, cognitive functions and emotion: an overview on humans, non-human primates and rodents in reproductive years. AB - Accumulating evidence has highlighted a number of important, global issues regarding the influence of estrogen on emotion and cognitive functions,including learning and memory processes, both in animal models and humans. The influence of estrogen on cognition and emotion can be explained by taking into account its modulator role on several neurotransmitter systems, acetylcholine in particular, but also catecholamines,serotonin and GABA in rodents, primates and humans. Another reason may lie in the wide spread presence of the two classes (a and~) of estrogen receptors in many brain regions involved in emotion and cognition, including the hippocampal formation, amygdala and cerebral cortex. The present review reports on research conducted in our laboratory and others with the objective of identifying the action of estrogens on cognition and emotion in rodents, monkeys and humans in youth. In particular, the first section,focused on the mechanisms of estrogens action in the brain, illustrates the involvement of estrogen receptors and neurotransmitters in the cognitive and emotional processes; the second section deals with the estrogen effects on cognitive and emotional mechanisms, with particular emphasis on memory and the involvement of estrogen in emotion and cognition across the estrous/menstrual cycle. PMID- 23096105 TI - Identification of a novel in-frame deletion in BRCA2 and analysis of variants of BRCA1/2 in Italian patients affected with hereditary breast and ovarian cancer. AB - BACKGROUND: An estimated 5 % - 10 % of all breast cancers are due to an inherited predisposition and, out of these, about 30 % are caused by germline mutations of the BRCA1 and BRCA2 genes. The prevalence of germline mutations in theBRCA1 and BRCA2 genes varies among ethnic groups. The aims of this study are to evaluate deleterious mutations and genomic rearrangements in BRCA1/2 genes and the CHEK21100delC mutation in a cohort of Italian women affected with hereditary breast and/or ovarian cancer. In addition we clarify the effect of the novel variants identified in BRCA2 gene bymRNA analysis and prediction software. METHODS: We enrolled 103 consecutive Italian patients affected with hereditary breast and/or ovarian cancer, aged23 - 69 years. RESULTS: We found BRCA1/2 mutations in 15/103 probands(14.6 % ). Among these, a BRCA2 gene mutation has not been described previously. In addition, we identified five novel BRCA2 variants (S1341, IVS1-59t > c, IVS11-74insA, IVS12 + 74c > g and I1167V). No genomic BRCA1/2re arrangements or CHEK2 1100delC mutation was found in our patients. The novel BRCA2 mutation NS1742del(p.N1742_S1743del) was an in-frame 6 bp deletion that results in loss of two amino acids. CONCLUSIONS: In silico analysis conducted for S1341, IVS1-59t > c, IVS11-74insA and IVS12 + 74c > g of BRCA2 predicted the variants as neutral and benign, whereas the results for I1167V was inconclusive. mRNA analysis for the novel BRCA2 intronic variant IVS11-74insA and the already published BRCA1 variant C197 shows that they have no effect on the splicing. These results are in agreement with in silico analysis. PMID- 23096102 TI - Molecular brake pad hypothesis: pulling off the brakes for emotional memory. AB - Under basal conditions histone deacetylases(HDACs) and their associated co repressor complexes serve as molecular 'brake pads' to prevent the gene expression required for long-term memory formation. Following a learning event, HDACs and their co-repressor complexes are removed from a subset of specific gene promoters, allowing the histone acetylation and active gene expression required for long-term memory formation.Inhibition of HDACs increases histone acetylation,extends gene expression profiles, and allows for the formation of persistent long-term memories for training events that are otherwise forgotten. We propose that emotionally salient experiences have utilized this system to form strong and persistent memories for behaviorally significant events. Consequently, the presence or absence of HDACs at a selection of specific gene promoters could serve as a critical barrier for permitting the formation of long-term memories. PMID- 23096106 TI - Minor improvement of venous blood specimen collection practices in primary health care after a large-scale educational intervention. AB - BACKGROUND: Venous blood specimen collection is a common health care practice that has to follow strict guidelines, non-compliance among sampling staff may compromise patient safety. We evaluated a large-scale 2 h educational intervention that emphasised guideline adherence to assess possible improvements of venous blood specimen collection practices. METHODS: Blood specimen haemolysis is usually caused by inadequate venous blood specimen collection and handling, reflecting overall pre-analytical handling. We monitored haemolysis of serum samples with haemolysis index corresponding to >= 150 mg/L of free haemoglobin for specimens sent from 11 primary health care centres and analysed on a Vitros 5,1 clinical chemistry analyser before (2008, n = 6652 samples) and after (2010, n = 6121 samples) the intervention. RESULTS: The total percentage of haemolysed specimens was 11.8 % compared to 10.5 % (p = 0.022) before the intervention. As groups, rural primary health care centres demonstrated a significant reduction [Odds ratios (OR) = 0.744] of haemolysed specimens after intervention, whereas urban primary health care centres demonstrated a significant increase (OR = 1.451) of haemolysis. CONCLUSIONS: A large-scale 2 h educational intervention to make venous blood specimen collection staff comply with guideline practices had minor effects on collection practices. Educational interventions may be effective in wards/care centres demonstrating venous blood specimen collection practices with larger deviations from guidelines. PMID- 23096107 TI - Performance evaluation of three different immunoassays for detection of antibodies to hepatitis B core. PMID- 23096108 TI - Contribution of procoagulant phospholipids, thrombomodulin activity and thrombin generation assays as prognostic factors in intensive care patients with septic and non-septic organ failure. AB - BACKGROUND: Multiple organ dysfunction syndrome (MODS) observed in patients with sepsis and in nonseptic patients organ failure (OF) is associated with a high mortality rate. We investigated whether new coagulation assays [quantification of procoagulant phospholipids (PPL) activity, functional assays measuring the activity of thrombomodulin (TMa) or tissue factor (TFa) and thrombin generation using calibrated automated thrombography (CAT)] could constitute new tools to better understand the physiopathology of MODS and have any prognostic value. METHODS: We measured TMa, TFa, PPL and CAT in 32 healthy controls, 24 patients with sepsis and 26 patients with non-septic OF. We compared these parameters with usual coagulation assays [prothrombin time, activated partial thromboplastin time, protein C (PC), protein S, D-Dimers (D-Di), soluble thrombomodulin (sTM)] and markers of inflammation (IL-6, CRP). Samples were collected within 24 h of the diagnosis. RESULTS: TMa, TFa, PPL, the lag time and time to thrombin peak levels were increased in both groups of patients. For both groups D-Di, IL-6, CRP and endogenous thrombin potential (ETP) were higher in non-survivors than in survivors, while PC and PPL were lower in non-survivors than in survivors. TMa increase was more marked in non-survivors patients with OF, while the ratio TMa/sTM was low in non-survivors with sepsis. Received operating characteristic (ROC) curve analysis indicated that thrombin peak and ETP were the more powerful discriminating factors in patients with sepsis or non-septic OF, respectively. CONCLUSIONS: PPL, TMa and CAT assays could represent promising tools to identify patients with increased risk of mortality in MODS and could procure insights into pathogenesis of MODS. PMID- 23096109 TI - Serum kallikrein-8 correlates with skin activity, but not psoriatic arthritis, in patients with psoriatic disease. AB - BACKGROUND: About 30% of cutaneous psoriasis (PsC) patients develop psoriatic arthritis (PsA) in the joint, which is under-recognized by dermatologists. Biomarkers for PsA are needed so that early referral to a rheumatologist is made. Kallikreins (KLKs) are secreted serine proteases implicated in skin desquamation and inflammation. This study examined KLK potential as serum biomarkers of PsA in cutaneous psoriasis patients. METHODS: KLKs were measured by ELISAs in synovial fluids of three PsA patients and three control early osteoarthritis (OA) patients, as well as in a cohort of 152 serum samples collected from age- and sex matched PsC patients, with (n=76) or without PsA (n=76). KLK expression in psoriatic plaques was examined by immunohistochemistry. Univariate and multivariate logistic regression analyses were conducted to analyze the association between serum KLK levels and disease class (PsC, PsA). Serum KLKs that associated with PsA were correlated with clinical parameters of skin and joint activity. RESULTS: Among the seven KLKs tested, KLK6 and KLK8 were elevated in both PsA synovial fluids and psoriatic plaques, but only serum KLK8 levels were associated with psoriatic disease (odds ratio=2.56, p=0.03). Although significantly elevated in PsC and PsA sera compared to healthy controls, KLK8 did not discriminate PsA from PsC patients. KLK8 correlated positively with the psoriasis area and severity index (PASI) (r=0.43, p=0.001) independent of age, sex and psoriasis duration ( beta=1.153, p=0.0003) and exhibited no correlations with tender or swollen joint counts. CONCLUSIONS: Increased KLK8 serum level in PsA patients reflects disease activity in the skin but not in the joints. Serum KLK levels are not useful for screening psoriasis patients for PsA. PMID- 23096110 TI - Brazilian laboratory indicators program. AB - BACKGROUND: This paper describes the evolution, structure, operation and some outcomes of the Brazilian Laboratory Indicators Program created by the Brazilian Society of Clinical Pathology/Laboratory Medicine (Sociedade Brasileira de Patologia Clinica/Medicina Laboratorial, or SBPC/ML), in partnership with ControlLab, a Brazilian Company that provides services for proficiency testing, internal control, calibration, and training indicators for clinical laboratories. METHODS: This web-based program is confidential for all participants. It contains 61 indicators categorized into three groups. Program operation and data analysis methods are described and indicators are reported in box plot format, with grouping varying in accordance with the profiles of the participating laboratories. Three indicators were selected as examples of program effectiveness in 2011: hemolysis, blood re-collection and productivity. RESULTS: Participants profile, examples of three indicators for the year 2011 (hemolysis, blood re collection and productivity) and exploratory research conducted in 2012 on the implementation of the program are presented. Data related to laboratories participating in the program from 2006 to 2011 were collected and graphically represented. CONCLUSIONS: The Brazilian Laboratory Indicators Program brings important benefits for participants, contributing to the improvement of existing health systems in Brazil. PMID- 23096111 TI - B-Vitamin dependent methionine metabolism and alcoholic liver disease. AB - Convincing evidence links aberrant B-vitamin dependent hepatic methionine metabolism to the pathogenesis of alcoholic liver disease (ALD). This review focuses on the essential roles of folate and vitamins B6 and B12 in hepatic methionine metabolism, the causes of their deficiencies among chronic alcoholic persons, and how their deficiencies together with chronic alcohol exposure impact on aberrant methionine metabolism in the pathogenesis of ALD. Folate is the dietary transmethylation donor for the production of S-adenosylmethionine (SAM), which is the substrate for all methyltransferases that regulate gene expressions in pathways of liver injury, as well as a regulator of the transsulfuration pathway that is essential for production of glutathione (GSH), the principal antioxidant for defense against oxidative liver injury. Vitamin B12 regulates transmethylation reactions for SAM production and vitamin B6 regulates transsulfuration reactions for GSH production. Folate deficiency accelerates the experimental development of ALD in ethanol-fed animals while reducing liver SAM levels with resultant abnormal gene expression and decreased production of antioxidant GSH. Through its effects on folate metabolism, reduced SAM also impairs nucleotide balance with resultant increased DNA strand breaks, oxidation, hepatocellular apoptosis, and risk of carcinogenesis. The review encompasses referenced studies on mechanisms for perturbations of methionine metabolism in ALD, evidence for altered gene expressions and their epigenetic regulation in the pathogenesis of ALD, and clinical studies on potential prevention and treatment of ALD by correction of methionine metabolism with SAM. PMID- 23096112 TI - Consent and the use of the bodies of the dead. AB - Gametes, tissue, and organs can be taken from the dying or dead for reproduction, transplantation, and research. Whole bodies as well as parts can be used for teaching anatomy. While these uses are diverse, they have an ethical consideration in common: the claims of the people whose bodies are used. Is some use permissible only when people have consented to the use, actually wanted the use, would have wanted the use, not opposed the use, or what? The aim of this article is to make progress in answering these questions. Initially I assume knowledge of people's desires in order to test whether consent is directly required by their rights without worrying about mistaken uses against their wishes. I claim consent is not directly required by people's rights. If we know people wanted or would want a use, their rights permit the use, but if we know they wanted or would want not to be used, their rights do not permit the use. The knowledge assumption is then dropped and the question becomes how to decide what to do when the wishes of rightholders are not known. I suggest working out what to do when wishes are known and then adjusting, on the basis of whatever evidence there is, for probability and strength of desire. There are other considerations too, for instance about default rules. The key general comment here is that, in setting rules, the costs to rightholders in not getting what they want needs to be taken into account. The final section tries to show that, in setting these rules, mistaken uses are not to be taken as worse than mistaken failure to use. PMID- 23096113 TI - Bortezomib, melphalan, and prednisone in elderly patients with relapsed/refractory multiple myeloma: a multicenter, open label phase 1/2 study. AB - BACKGROUND: In elderly patients with newly diagnosed multiple myeloma (MM), the addition of bortezomib to standard, combined oral melphalan and prednisone (MP) significantly increases the response rate and event-free survival compared with MP alone. METHODS: In this phase 1/2 trial, the authors assessed the dosing, efficacy, and safety of a lower dose-intensity MP schedule plus weekly bortezomib as salvage treatment for elderly patients with MM. To assess the maximum tolerated dose, 19 patients who had relapsed/refractory MM after 1 or 2 lines of treatment entered the first phase of the study. They received melphalan at a dose of 24 mg for 28 days; bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22; and prednisone at a dose of 50 mg every other day of a 28-day cycle for a total of 9 cycles. At the end of the first phase, based on the good efficacy and acceptable toxicity of this combination, an additional 23 patients were enrolled. RESULTS: After a median follow-up of 21 months, of 42 patients who relapsed, 24 (57%) obtained at least a partial response, 4 had stable disease, and 11 had progressive disease. The median time to progression was 18 months, and the median overall survival was 30 months. Grade 3 and 4 toxicity was observed in 16 of 42 patients (38%) and was more frequent during the early cycles. CONCLUSIONS: A weekly infusion of bortezomib associated with lower dose-intensity MP induced a high proportion of responses and was well tolerated in elderly patients with relapsed/refractory MM. PMID- 23096114 TI - The microRNA-26a target E2F7 sustains cell proliferation and inhibits monocytic differentiation of acute myeloid leukemia cells. AB - Blocks in genetic programs required for terminal myeloid differentiation and aberrant proliferation characterize acute myeloid leukemia (AML) cells. 1,25 Dihydroxy-vitamin D3 (VitD3) arrests proliferation of AML cells and induces their differentiation into mature monocytes. In a previous study, we showed that miR 26a was induced upon VitD3-mediated monocytic differentiation. Here, we identify E2F7 as a novel target of miR-26a. We show that E2F7 significantly promotes cell cycle progression and inhibits monocytic differentiation of AML cells. We also demonstrate that E2F7 binds the cyclin-dependent kinase inhibitor p21(CIP1/WAF1) (cyclin-dependent kinase inhibitor 1A) promoter repressing its expression. Moreover, interfering with E2F7 expression results in inhibition of c-Myc (v-myc myelocytomatosis viral oncogene homolog) transcriptional activity. This leads to the downregulation of c-Myc transcriptional target miR-17-92 cluster, whose expression has a well-defined role in contributing to block monocytic differentiation and sustain AML cell proliferation. Finally, we show that the expression of E2F7 is upregulated in primary blasts from AML patients. Thus, these findings indicate that the newly identified miR-26a target E2F7 might have an important role in monocytic differentiation and leukemogenesis. PMID- 23096115 TI - The adaptor protein FADD and the initiator caspase-8 mediate activation of NF kappaB by TRAIL. AB - Besides inducing apoptosis, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) activates NF-kappaB. The apoptosis signaling pathway of TRAIL is well characterized involving TRAIL receptors, Fas-associated protein with death domain (FADD) and caspase-8. In contrast, the molecular mechanism of TRAIL signaling to NF-kappaB remains controversial. Here, we characterized the receptor proximal mediators of NF-kappaB activation by TRAIL. Deletion of the DD of TRAIL receptors 1 and 2 revealed that it is essential in NF-kappaB signaling. Because FADD interacts with the TRAIL receptor DD, FADD was tested. RNAi-mediated knockdown of FADD or FADD deficiency in JURKAT T-cell leukemia cells decreased or disabled NF-kappaB signaling by TRAIL. In contrast, TRAIL-induced activation of NF-kappaB was maintained upon loss of receptor interacting protein 1 (RIP1) or knockdown of FLICE-like inhibitory protein (FLIP). Exogenous expression of FADD rescued TRAIL-induced NF-kappaB signaling. Loss-of-function mutations of FADD within the RHDLL motif of the death effector domain, which is required for TRAIL induced apoptosis, abrogated FADD's ability to recruit caspase-8 and mediate NF kappaB activation. Accordingly, deficiency of caspase-8 inhibited TRAIL-induced activation of NF-kappaB, which was rescued by wild-type caspase-8, but not by a catalytically inactive caspase-8 mutant. These data establish the mechanism of TRAIL-induced NF-kappaB activation involving the TRAIL receptor DD, FADD and caspase-8, but not RIP1 or FLIP. Our results show that signaling of TRAIL-induced apoptosis and NF-kappaB bifurcates downstream of caspase-8. PMID- 23096116 TI - Intrinsic caspase-8 activation mediates sensitization of erlotinib-resistant tumor cells to erlotinib/cell-cycle inhibitors combination treatment. AB - Inhibitors of the tyrosine kinase activity of epidermal growth factor receptor, as erlotinib, have an established role in treating several cancer types. However, resistance to erlotinib, particularly in breast cancer cell lines, and erlotinib treatment-associated disorders have also been described. Also, methods and combination therapies that could reverse resistance and ameliorate non-desirable effects represent a clinical challenge. Here, we show that the ATP non competitive CDK2/cyclin A inhibitor NBI1 sensitizes erlotinib-resistant tumor cells to the combination treatment (co-treatment) for apoptosis-mediated cell death. Furthermore, in erlotinib-sensitive cells, the effective dose of erlotinib was lower in the presence of NBI1. The analysis in the breast cancer MDA-MB-468 erlotinib-resistant and in lung cancer A549 cell lines of the molecular mechanism underlying the apoptosis induced by co-treatment highlighted that the accumulation of DNA defects and depletion of cIAP and XIAP activates the ripoptosome that ultimately activates caspases-8 and -10 and apoptosis. This finding could have significant implications for future treatment strategies in clinical settings. PMID- 23096117 TI - Novel transglutaminase 1 mutations in patients affected by lamellar ichthyosis. AB - Lamellar Ichthyosis (LI) is a form of congenital ichthyosis that is caused by mutations in the TGM1 gene that encodes for the transglutaminase 1 (TG1) enzyme. Functional inactivation of TG1 could be due to mutations, deletion or insertions. In this study, we have screened 16 patients affected by LI and found six new mutations: two transition/transversion (R37G, V112A), two nonsense mutations and two putative splice site both leading to a premature stop codon. The mutations are localized in exons 2 (N-terminal domain), 5, 11 (central catalytic domain), and none is located in the two beta-barrel C-terminal domains. In conclusion, this study expands the current knowledge on TGM1 mutation spectrum, increasing the characterization of mutations would provide more accurate prenatal genetic counselling for parents at-risk individuals. PMID- 23096118 TI - Quantifying anti-gravity torques for the design of a powered exoskeleton. AB - Designing an upper extremity exoskeleton for people with arm weakness requires knowledge of the joint torques due to gravity and joint stiffness, as well as, active residual force capabilities of users. The objective of this research paper is to describe the characteristics of the upper limb of children with upper limb impairment. This paper describes the experimental measurements of the torque on the upper limb due to gravity and joint stiffness of three groups of subjects: able-bodied adults, able-bodied children, and children with neuromuscular disabilities. The experiment involves moving the arm to various positions in the sagittal plane and measuring the resultant force at the forearm. This force is then converted to torques at the elbow and shoulder. These data are compared to a two-link lumped mass model based on anthropomorphic data. Results show that the torques based on anthropometry deviate from experimentally measured torques as the arm goes through the range. Subjects with disabilities also maximally pushed and pulled against the force sensor to measure maximum strength as a function of arm orientation. For all subjects, the maximum voluntary applied torque at the shoulder and elbow in the sagittal plane was found to be lower than gravity torques throughout the disabled subjects' range of motion. This experiment informs designers of upper limb orthoses on the contribution of passive human joint torques due to gravity and joint stiffness and the strength capability of targeted users. PMID- 23096119 TI - Developing a multi-joint upper limb exoskeleton robot for diagnosis, therapy, and outcome evaluation in neurorehabilitation. AB - Arm impairments in patients post stroke involve the shoulder, elbow and wrist simultaneously. It is not very clear how patients develop spasticity and reduced range of motion (ROM) at the multiple joints and the abnormal couplings among the multiple joints and the multiple degrees-of-freedom (DOF) during passive movement. It is also not clear how they lose independent control of individual joints/DOFs and coordination among the joints/DOFs during voluntary movement. An upper limb exoskeleton robot, the IntelliArm, which can control the shoulder, elbow, and wrist, was developed, aiming to support clinicians and patients with the following integrated capabilities: 1) quantitative, objective, and comprehensive multi-joint neuromechanical pre-evaluation capabilities aiding multi-joint/DOF diagnosis for individual patients; 2) strenuous and safe passive stretching of hypertonic/deformed arm for loosening up muscles/joints based on the robot-aided diagnosis; 3) (assistive/resistive) active reaching training after passive stretching for regaining/improving motor control ability; and 4) quantitative, objective, and comprehensive neuromechanical outcome evaluation at the level of individual joints/DOFs, multiple joints, and whole arm. Feasibility of the integrated capabilities was demonstrated through experiments with stroke survivors and healthy subjects. PMID- 23096120 TI - Control of stair ascent and descent with a powered transfemoral prosthesis. AB - This paper presents a finite state-based control system for a powered transfemoral prosthesis that provides stair ascent and descent capability. The control system was implemented on a powered prosthesis and evaluated by a unilateral, transfemoral amputee subject. The ability of the powered prosthesis to provide stair ascent and descent capability was assessed by comparing the gait kinematics, as recorded by a motion capture system, with the kinematics provided by a passive prosthesis, in addition to those recorded from a set of healthy subjects. The results indicate that the powered prosthesis provides gait kinematics that are considerably more representative of healthy gait, relative to the passive prosthesis, for both stair ascent and descent. PMID- 23096125 TI - Self reporting RNA probes as an alternative to cleavable small molecule mass tags. AB - The large size of biological molecules such as proteins and oligonucleotides makes them inherently problematic to analyse and quantify directly by mass spectrometry. For these molecules, electrospray ionisation produces multiply charged species and associated alkali metal adducts which can reduce sensitivity and complicate quantification. Whereas time-of-flight mass analysers, often coupled to matrix-assisted laser desorption/ionisation, can have insufficient mass resolution to resolve these large molecules in the higher m/z range. This has led to the development of cleavable small molecule mass tag approaches for the indirect analysis of biomolecules such as proteins and oligonucleotides. Existing methodologies require the design and synthesis of a cleavable linker to join the biomolecule and the mass tag. Here, an alternative approach to small molecule mass tags is presented, which exploits the properties of the RNA molecule to afford self-reporting probes which can be easily synthesised using automated phosphoramidite chemistry. The sugar-phosphate backbone of RNA was used as a built-in enzyme cleavable linker and through the use of RNase digestion of bromine labelled oligonucleotides the observation of a range of small molecule mass tags by mass spectrometry is demonstrated. This study provides a proof-of concept that RNase digestion can be used to produce labelled small molecule mass tags from oligonucleotide probes, thus eliminating the need for custom design and synthesis of a cleavable linker. PMID- 23096123 TI - Five-year incidence of angle closure among glaucoma health examination participants. AB - BACKGROUND AND AIM: To investigate incidence of angle closure (AC) and its associated factors through a community-based longitudinal study over a 5-year period. METHODS: Japanese residents aged 40 years or over who underwent two glaucoma health examinations held in 2005 and 2010 were enrolled. Of the participants of the first glaucoma health examination (first examination), those who satisfied exclusion criteria such as having eyes with angle closure, glaucoma, incisional ocular surgery, or other conditions that could influence the results were eliminated from the second glaucoma health examination (second examination). In addition to routine ophthalmic examination, a scanning peripheral anterior chamber depth analyzer (SPAC) was employed to investigate the anterior chamber configuration. The incidence of angle closure over the 5-year period and its associated factors were investigated. RESULTS: Of the 754 participants of the first examination, 569 participants were invited for the second examination and 331 participants (87 males and 244 females, age: 62.6 +/- 12.7 years), or 619 eyes, were analyzed after eliminating eyes matching exclusion criteria. In the 5-year period, the incidence of AC was 5.4 % (95 % CI: 3.5-8.4 %) of participants or 5.5 % (95 % CI: 4.0-7.6 %) of eyes, including eight eyes (1.3 %) with primary angle-closure glaucoma. Eyes that developed AC had a much smaller SPAC grade at the first examination and a greater decrease in SPAC grade than those that did not develop AC, whereas age and sex were not associated. CONCLUSIONS: AC was developed by 5.4 % of senior Japanese residents over the 5 year period. The shallow anterior chamber and the marked decrease in anterior chamber depth were associated with AC development. PMID- 23096124 TI - Subjective pain, visual recovery and visual quality after LASIK, EpiLASIK (flap off) and APRK - a consecutive, non-randomized study. AB - INTRODUCTION: Laser in situ keratomileusis (LASIK) is superior to surface ablation techniques (SAT) such as alcohol photorefractive keratectomy (APRK) or Epi-LASIK (EpiK) in terms of visual recovery and postoperative pain. This study compares subjective symptoms and visual recovery of two different SATs with LASIK. MATERIALS AND METHODS: One hundred and twenty seven patients were operated using one of the three techniques. Patients filled out a questionnaire describing symptoms assessing subjective visual recovery on a linear scale from 'not functioning' to 'full visual function' and pain on a linear scale from 'no pain' to 'severe daily pain'. Subjective symptoms such as halos, double vision, low night vision, reduced contrast and dry eyes were also evaluated. RESULTS: Visual recovery was faster and discomfort symptoms less pronounced with the LASIK than with surface ablation procedures. More pain was reported after APRK than after EpiK (flap-off technique) in the early postoperative period, with a maximum of pain on postoperative days 3-4. Subjective visual recovery showed no statistically significant difference between the two surface ablation procedures. Halos, double vision, low night vision, reduced contrast and dry eyes were more extensively reported by the EpiK than the APRK group and were less pronounced in the LASIK than in the SAT group. DISCUSSION AND CONCLUSIONS: Our study does not uniformly support the previously published favourable results of EpiK compared to APRK with regard to subjective recovery of vision and postoperative pain. PMID- 23096127 TI - Sagging posterior layer thoracolumbar fascia: can it be the cause or result of adjacent segment diseases? AB - STUDY DESIGN: A retrospective study. OBJECTIVE: Thoracolumbar fascia (TLF) is an important anatomic structure that plays a role in integrating back muscles and maintaining the stability of lower back. Functional failure of TLF can be one of the factors in the vicious cycle of progressive spinal instability. The purpose of this study is to assess the TLF and correlate it with spinal stability in the instrumented lumbar surgery patients. MATERIALS AND METHODS: From January 2008 to March 2009, 68 consecutive postoperative lumbar or thoracolumbar spine magnetic resonance images were retrospectively reviewed to evaluate the morphologic changes of TLF. It was considered as "sagging posterior layer TLF" when it showed abrupt bulging appearance on parasagittal planes. To determine the spinal stability, flexion and extension lumbar lateral films were also reviewed. The correlation between sagging TLF and adjacent segment disease (ASD) were analyzed. RESULT: Fifty patients (19 males and 31 females, mean age 52.4 y) showed sagging posterior layer TLF, and 32 of them developed >=1 junctional problems, such as retrolistheses (n=25), compression fractures (n=5), spondylolistheses (n=4), progressive scoliosis (n=4), and segmental instability with bone marrow change (n=2). There was statistically significant correlation between the instrumented surgery and sagging TLF (P-value <0.001). And there was also significant correlation between the sagging TLF and ASD (P-value <0.001). CONCLUSIONS: Morphologic changes of the TLF in postoperative magnetic resonance imaging can be the earliest and predictable findings in the progressive development of the ASD. PMID- 23096126 TI - Isoflurane inhibits neutrophil recruitment in the cutaneous Arthus reaction model. AB - PURPOSE: Neutrophil recruitment to the inflammatory sites is regulated by a variety of adhesion molecules including beta2 integrins. The dependency of neutrophil recruitment on beta2 integrins is variable in different tissues, but has not yet been verified in the cutaneous passive reverse Arthus reaction. We examined this question and also evaluated the impact of isoflurane on neutrophil recruitment to the skin because we previously showed in vitro that isoflurane binds and inhibits beta2 integrins. METHODS: The dependency on beta2 integrins in neutrophil recruitment to the skin in the Arthus reaction was examined using alphaL, alphaM and beta2 knockout mice. Then, we evaluated the effect of isoflurane on neutrophil recruitment to the skin. In addition, the effects of isoflurane on neutrophil binding to intercellular adhesion molecule-1 (ICAM-1), one of the beta2 integrin ligands, were studied in vitro using cell adhesion assays. RESULTS: Neutrophil recruitment to the skin in the Arthus reaction model was totally dependent on beta2 integrins, as beta2 knockout mice completely abolished it. However, the defect of only one of the beta2 integrins was not sufficient to abolish neutrophil recruitment. Isoflurane reduced neutrophil recruitment to the skin by approximately 90 %. Also, isoflurane inhibited neutrophil adhesion to beta2 integrin ligand ICAM-1. CONCLUSIONS: We demonstrated that (1) neutrophil recruitment to the skin was totally dependent on beta2 integrins, and (2) isoflurane significantly impaired neutrophil recruitment. Based on the previous studies on the contribution of other adhesion molecules in neutrophil recruitment, it is likely that isoflurane at least partially affects on beta2 integrins in this model. PMID- 23096128 TI - In Vivo Study of Hydroxyapatite-coated Hat Type Cervical Intervertebral Fusion Cage Combined With IGF-I and TGF-beta1 in the Goat Model. AB - STUDY DESIGN: An in vivo animal experimental study. OBJECTIVE: To investigate the hydroxyapatite (HA) coating in a modified fusion cage in improving the results of cervical intervertebral fusion and the role of combination of IGF-I and TGF-beta1 treatment in a goat cervical spine interbody fusion model. MATERIALS AND METHODS: Thirty-two goats were divided into 4 groups (n=8 for each) and underwent C3-4 discectomy and intervertebral fusion by the following methods: group 1, autologous tricortical iliac crest bone graft; group 2, cage only; group 3, cage coated with HA; group 4, cage coated with HA+IGF-I and TGF-beta1. Radiography was performed preoperatively, postoperatively, and after 1, 2, 4, 8, and 12 weeks. At the same time points, disk space height, intervertebral angle, and lordosis angle were measured. At 12 weeks postoperatively, the goats were killed and fused segments were harvested. Biomechanical study was performed in flexion, extension, axial rotation, and lateral bending with a nondestructive stiffness method to determine the range of motion and stiffness. All cervical fusion specimens underwent histomorphologic studies. RESULTS: All 3 cage-treated groups showed significantly higher values for disk space height, intervertebral angle, and lordosis angle compared with the autologous tricortical iliac group at 1, 2, 4, 8, and 12 weeks after surgery (P<0.05). The stiffness of hat-shaped cervical intervertebral fusion cage coated with HA+IGF-I and TGF-beta1 in flexion, extension, and lateral bending was significantly greater than that of the other groups (P<0.05), and the stiffness of hat-shaped cervical intervertebral fusion cage coated with HA in extension, axial rotation, and lateral bending was significantly greater than that of fusion with the bone graft and cage-only groups (P<0.05). Histomorphologic evaluation showed better fusion in 3 cage groups than in the bone graft group. In group 4 of the cage coated with HA+IGF-I and TGF-beta1, a slightly more advanced bone matrix formation was shown than in groups without coating. CONCLUSIONS: HA coating can improve the fusion effect of the cervical intervertebral cage, and IGF-I and TGF-beta1 can enhance bone fusion. PMID- 23096129 TI - Prospective evaluation of quality of life in adolescent idiopathic scoliosis before and after surgery. AB - STUDY DESIGN: Prospective observational study. OBJECTIVE: To assess patient quality of life before and after surgical treatment of adolescent idiopathic scoliosis (AIS) and determine whether an association exists between quality of life and curve magnitude, curve correction, and type of instrumentation. SUMMARY OF BACKGROUND DATA: Assessment of AIS surgery outcomes has always been based on analysis of radiographic measurements and postoperative curve correction. However, there is a current trend toward greater emphasis on patient-centered outcomes. Assessment of treatment success on the basis of these outcomes requires prospective use of quality-of-life surveys before and after AIS treatment. METHODS: Prospective study of 33 patients undergoing surgical treatment of AIS. Mean age was 15.6 years and mean Cobb angle was 70.5 degrees. Patients were randomly allocated into one of 2 instrumentation groups (hybrid and pedicle screws alone), and the Scoliosis Research Society-30 questionnaire (SRS-30) and Short Form-36 Health Survey (SF-36) questionnaires were administered preoperatively and at 3-, 6-, and 12-month follow-up. Statistical testing was performed to determine whether survey scores correlated with Cobb angle, curve correction, or type of instrumentation. RESULTS: SRS-30 and SF-36 scores improved significantly. The greatest changes occurred in the self-image and satisfaction with management domains of the SRS-30 survey. SRS-30 and SF-36 scores showed worsening pain and decreased function at 3-month follow-up, but significant improvement from baseline at 12 months. Total SRS-30 scores were significantly improved at 6- and 12-month follow-up, as were subscores in the general health, vitality, and social functioning domains of SF-36. Curve magnitude, percent curve correction, and type of instrumentation had no significant influence on final SRS 30 and SF-36 scores. CONCLUSIONS: Surgical treatment of AIS improved patient quality of life, as shown by significant improvement on all SRS-30 and SF-36 domains. Questionnaire scores did not correlate with Cobb angle, curve correction, or type of instrumentation. PMID- 23096131 TI - MS2DB+: a software for determination of disulfide bonds using multi-ion analysis. AB - MS2DB+ is an open-source platform-independent web application for determining, in polynomial time, the disulfide linkages in proteins using tandem mass spectrometry (MS/MS) data. It utilizes an efficient approximation algorithm which allows the consideration of multiple ion-types (a, a(o), a*, b, b(o), b*, c, x, y, y(o), y*, and z) in the analysis. Once putative disulfide bonds are identified, a graph optimization approach is used to obtain the most likely global disulfide connectivity pattern. PMID- 23096130 TI - Whole-genome methylation analysis of benign and malignant colorectal tumours. AB - Changes in DNA methylation, whether hypo- or hypermethylation, have been shown to be associated with the progression of colorectal cancer. Methylation changes substantially in the progression from normal mucosa to adenoma and to carcinoma. This phenomenon has not been studied extensively and studies have been restricted to individual CpG islands, rather than taking a whole-genome approach. We aimed to study genome-wide methylation changes in colorectal cancer. We obtained 10 fresh-frozen normal tissue-cancer sample pairs, and five fresh-frozen adenoma samples. These were run on the lllumina HumanMethylation27 whole-genome methylation analysis system. Differential methylation between normal tissue, adenoma and carcinoma was analysed using Bayesian regression modelling, gene set enrichment analysis (GSEA) and hierarchical clustering (HC). The highest-rated individual gene for differential methylation in carcinomas versus normal tissue and adenomas versus normal tissue was GRASP (padjusted = 1.59 * 10(-5) , BF = 12.62, padjusted = 1.68 * 10(-6) , BF = 14.53). The highest-rated gene when comparing carcinomas versus adenomas was ATM (padjusted = 2.0 * 10(-4) , BF = 10.17). Hierarchical clustering demonstrated poor clustering by the CIMP criteria for methylation. GSEA demonstrated methylation changes in the Netrin-DCC and SLIT ROBO pathways. Widespread changes in DNA methylation are seen in the transition from adenoma to carcinoma. The finding that GRASP, which encodes the general receptor for phosphoinositide 1-associated scaffold protein, was differentially methylated in colorectal cancer is interesting. This may be a potential biomarker for colorectal cancer. PMID- 23096132 TI - The role of STAT3 activation in modulating the immune microenvironment of GBM. AB - Glioblastoma multiforme (GBM) modulates the immune system to engance its malignant potential. Signal transducer and activator of transcription 3 (STAT3) activation is a regulatory node in modulating the immune microenvironment in several human tumors, including GBM. To investigate whether STAT3 inhibition might enhance anti-tumor responses, we inhibited STAT3 signaling using small interfering RNA against STAT3. We tested the human GBM cell lines U87, U251, and HS683, which are known to constitutively express high levels of phospho-STAT3. STAT3 inhibition resulted in enhanced expression of several pro-inflammatory cytokines and chemokines and supernatants from STAT3-silenced human GBM cell lines increased lipopolysaccharide-induced dendritic cell activation in vitro. We obtained comparable results when STAT3 activity was suppressed with specific small molecule inhibitors. Our results support the hypothesis that activated STAT3 contributes to the immunosuppressive microenvironment in GBM and support previous studies implicating STAT3 as a potential target for immunotherapy. PMID- 23096134 TI - Frequency of brain metastases from prostate cancer: an 18-year single-institution experience. AB - It has recently been reported that the incidence of brain metastases (BMs) from prostate cancer (PC) has increased in comparison with historical series. The aim of this study was to compare the incidence of BMs in the pre- and post-docetaxel era in a single institution in which all oncological patients are referred to one Radiotherapy and one Medical Oncology Department. We searched the electronic databases of these departments for all males with BMs entered from 1994 to 2011. The year of the introduction of docetaxel into clinical practice (2002) divided the observation period into two 9-year periods: period 1 (P1) from 1994 until 2002 (P1), and period 2 (P2) after 2002. The number of patients with BMs was constant: 241 patients in P1 and 249 in P2. The greatest changes in frequency between P1 and P2 involved colorectal cancer (+75.9 %), renal cancer (+141.9 %), and PC (+238.7 %). The total number of patients with BMs from PC was nine: two in P1 (0.8 %) and seven in P2 (2.8 %). All but two of these patients developed BMs after becoming castration-resistant. Median BM-free survival was 36 months, whereas median BM survival was 8 weeks. As the appearance of BMs in the natural history of PC is usually related to the late phase of the disease, and mortality due to PC remained constant, it seems that there really has been an increase in the frequency of BMs from PC that may reflect a gain in survival. PMID- 23096133 TI - Anaplastic PXA in adults: case series with clinicopathologic and molecular features. AB - Pleomorphic xanthoastrocytomas with anaplastic features (PXA-As) are rare tumors about which little is known regarding clinicopathologic and molecular features. Several studies have identified BRAF V600E mutations in PXA-As, but the percentage with mutation may differ between adult and pediatric examples, and limited information exists about immunohistochemistry for isocitrate dehydrogenase 1 (IDH1). Ten cases of adult PXA-As seen at our institution since 2000 were assessed for BRAF V600E mutation by polymerase chain reaction testing (PCR) and IDH1 by immunohistochemistry. Patients ranged in age from 18-68 years; four PXA-As affected temporal lobe and two were cystic. Four patients underwent gross total resection and 9 of 10 patients received cranial irradiation and/or adjuvant chemotherapy. Five survived less than 5 years, although 2 of 5 patients died from non-tumor causes. Four long-term survivors are alive at 7.5, 9.8, 11.4, and 11.9 years post-diagnosis. Two of four long term survivors had BRAF V600E mutation: patients were ages 18 and 28 years. A 48-year-old male without BRAF mutation survives at 9.8 years, even with thalamic location; conversely a 68-year old female with temporal lobe tumor and BRAF mutation survived 1.9 years after diagnosis. All tumors were IDH1 immunonegative. This case series details clinicopathologic features of a subset of rare PXA-As in adults. BRAF V600E mutation was identified in 50 % of these cases. PMID- 23096135 TI - Assessment of Lateral Compression type 1 pelvic ring injuries by intraoperative manipulation: which fracture pattern is unstable? AB - PURPOSE: We performed a prospective study to document, by intra-operative manipulation under anaesthesia (MUA) of the pelvic ring, the stability of lateral compression type 1 injuries that were managed in a Level-I Trauma Centre. The documentation of the short-term outcome of the management of these injuries was our secondary aim. METHODS: A total of 63 patients were included in the study. Thirty-five patients (group A) were treated surgically whereas 28 (group B) were managed nonoperatively. Intraoperative rotational instability, evident by more than two centimetres of translation during the manipulation manoeuvre, was combined with a complete sacral fracture in all cases. RESULTS: A statistically significant difference was present between the length of hospital stay, the time to independent pain-free mobilisation, post-manipulation pain levels and opioid requirements between the two groups, with group A demonstrating significantly decreased values in all these four variables (p < 0.05). There was also a significant difference between the pre- and 72-hour post-manipulation visual analogue scale and analgesic requirements of the group A patients, whereas the patients in group B did not demonstrate such a difference. CONCLUSION: LC-1 injuries with a complete posterior sacral injury are inheritably rotationally unstable and patients presenting with these fracture patterns definitely gain benefit from surgical stabilisation. PMID- 23096136 TI - Expansion of alien gammarids in the Vistula Lagoon and the Vistula Delta (Poland). AB - Amphipod crustaceans belong to the most successful invaders of aquatic environments. The work provides information concerning the spatial and temporal scales of expansion of four alien gammarid amphipods (three of them of Ponto Caspian and one of North American origin): Pontogammarus robustoides (G.O. Sars, 1894), Obesogammarus crassus (G.O. Sars, 1894), Dikerogammarus haemobaphes (Eichwald, 1841), and Gammarus tigrinus Sexton, 1939 in the Vistula Lagoon (VL) and the Vistula Delta (VD) in 2008-2010. The mean abundance of these gammarids in nearshore zones was 382 ind m(-2) in VL and 89 ind m(-2) in VD. Their mean biomasses were likewise greater in VL (0.91 g m(-2)) than in VD (0.49 g m(-2)). G. tigrinus was the most dominant species in both nearshore zones of VL and VD and attained the highest frequency in these areas. The study gives evidence of total extinction of native gammarid species. PMID- 23096137 TI - Comparison of different methods for extraction of polycyclic aromatic hydrocarbons (PAHs) from Sicilian (Italy) coastal area sediments. AB - This paper describes a work aimed at improving the conditions of an extraction method, coupling GC-MS determination, for the analysis without cleanup phase, of polycyclic aromatic hydrocarbons (PAHs) from sediment samples. The automatic Soxhlet extraction in warm mode (using Extraction System B-811 Standard, Buchi) has demonstrated advantages for automation, reduced extraction time, and lower solvent use than for conventional Soxhlet extraction. Under these conditions, the recoveries are very good as they resulted greater than 85% and, in most of the cases, near 100%. The repeatability is also satisfactory (relative standard deviation less than 15%). The detection limits are also acceptable and ranged from 0.001 to0.01 MUg/kg dry weight. Fifty-four sediment samples were collected. The total concentration of the 17 compounds investigated, in samples of sediments collected from three Sicilian coastal areas, expressed as the sum of concentrations, varies from 99 to 11,557 MUg/kg of dry matrix; concentrations of total PAHs in the sediments of Cala are two to three times higher than the other stations. PMID- 23096138 TI - Monitoring spatiotemporal variations of diel radon concentrations in peatland and forest ecosystems based on neural network and regression models. AB - Concentrations of outdoor radon-222 ((222)Rn) in temperate grazed peatland and deciduous forest in northwestern Turkey were measured, compared, and modeled using artificial neural networks (ANNs) and multiple nonlinear regression (MNLR) models. The best-performing multilayer perceptron model selected out of 28 ANNs considerably enhanced accuracy metrics in emulating (222)Rn concentrations relative to the MNLR model. The two ecosystems had similar diel patterns with the lowest (222)Rn concentrations in the afternoon and the highest ones near dawn. Mean level (5.1 + 2.5 Bq m(-3) h(-1)) of (222)Rn in the forest was three times smaller than that (15.8 + 9.7 Bq m(-3)) of (222)Rn in the peatland. Mean (222)Rn level had negative and positive relationships with air temperature and relative humidity, respectively. PMID- 23096139 TI - The Lady Windermere syndrome. PMID- 23096140 TI - Selection for inpatient rehabilitation after severe stroke: what factors influence rehabilitation assessor decision-making? AB - OBJECTIVES: This study aimed to identify factors that assessors considered important in decision-making regarding suitability for inpatient rehabilitation after acute severe stroke. DESIGN: Multi-site prospective observational cohort study. SUBJECTS: Consecutive acute, severe stroke patients and their assessors for inpatient rehabilitation. METHODS: Rehabilitation assessors completed a questionnaire, rating the importance (10 point visual analogue scale) and direction (positive, negative or neutral) of 15 patient related and 2 organisational items potentially affecting their decision regarding patients' acceptance to rehabilitation. RESULTS: Of the 75 patients referred to rehabilitation and included in this study 61 (81.3%) were accepted for inpatient rehabilitation. The items considered to be most important in the decision to accept the patient for rehabilitation were pre-morbid cognition, pre-morbid mobility and pre-morbid communication. For those not accepted the most important items were current mobility, social support and current cognition. Factor analysis revealed 3 underlying factors, interpreted as post-stroke status, pre morbid status, and social attributes, accounting for 61.8% of the total variance. All were independently associated with acceptance for rehabilitation (p < 0.05). CONCLUSIONS: This study highlights the importance of pre-morbid function and social factors in addition to post-stroke function in the decision making process for acceptance to rehabilitation following severe stroke. Future models for selection for rehabilitation should consider inclusion of these factors. PMID- 23096141 TI - [Pedriatric ophthalmology and new strategies of strabismus therapy]. PMID- 23096142 TI - [Effectivity of an occlusion-supporting PC-based visual training programme by horizontal drifting sinus gratings in children with amblyopia]. AB - BACKGROUND: The studies of Kampf et al. suggested an efficiency of a computer based stimulation therapy by drifting sinus gratings in patients with anisometropic and/or strabismic amblyopia but provided no clear evidence. This is the first trial with amblyopic patients without previous treatment at the beginning of amblyopia therapy. METHODS: A prospective, randomised, single blinded, placebo-controlled study of n = 15 patients with anisometropic and/or strabismic amblyopia without previous treatment was performed. Age of the patients was between 4 and 10 years, mean 6.3 years (+/- 2.0), all after full correction of refraction errors and refractive adaptation. Stimulation therapy was performed 5 times a week over 4 weeks, respectively 2 * 20 min, a drifting sinus grating of constant spatial and temporal frequency was combined with computer games (n = 8). Control group had only computer games with a neutral background (n = 7). In both groups patching was only done in stimulation times. RESULTS: Stimulation and control group did not differ due to age, gender, and cause of amblyopie, baseline visual acuity, and time of wearing glasses. There was no significant difference in the development of visual acuity over the stimulation period between stimulation and control groups. CONCLUSIONS: Stimulation therapy with drifting sinus gratings did not improve the development of visual acuity in the first phase of amblyopia treatment combined with minimal occlusion therapy. Accordingly, the stimulation therapy is not adequate to replace sufficient occlusion therapy. Whether this therapy could support patching therapy and improve acuity development in later therapy phases cannot be assumed from this trial. PMID- 23096143 TI - [Bilateral medial rectus recession with posterior fixation suture for large infantile esotropia]. AB - BACKGROUND: Surgery for infantile large angle esotropia is not uniform. Bilateral medial rectus recession (BMR), combined recess-resect procedure, also combined with simultaneous contralateral medial rectus recession or secondary other procedures are common. Alternatively, bilateral medial rectus recession with posterior fixation suture (BMRF) has been used. We analysed the effect of BMRF for this specific indication. PATIENTS AND METHODS: We undertook a retrospective evaluation of squint angles in simultaneous (S) and alternating (A) prism cover test before and 3 months after BMRF with and without additional oblique muscle surgery as primary surgery for esotropia >= 20 degrees performed at our department between 1997 and 2009, as well as the rate of second procedures. RESULTS: Sixty-one children (0.5 % of all patients who received eye muscle surgery during the same time interval) were included. Medians (10 % and 90 % quantiles) were: age at surgery 48.4 months (23.6; 76.0), refraction (spherical equivalent)2.25 dpt (0.25; 5.50), posterior fixation 5.5 mm + 13.0 mm (12.5; 13.0) from limbus, recession 5.0 mm (4.0; 5.0), inferior oblique recession in 29 children (27 bilateral), preoperative squint angles at 5 m S/A 29 degrees (20; 40), at 0.3 m S/A 35 degrees (24; 45), postoperative at 5 m S 0 degrees (-6; 10), A 2 degrees (-6; 11), at 0.3 m S 1 degrees (-5; 12), A 3.5 degrees (-5; 13), S <= 5 degrees in 70.2 % at 5 m and 60.3 % at 0.3 m, consecutive exotropia 6-10 degrees and > 10 degrees in 7.0 and 3.5 % at 5 m and 8.6 and 1.7 % at 0.3 m, residual esotropia 6-10 degrees and > 10 degrees in 10.5 and 8.8 % at 5 m and 13.8 and 15.5 % at 0.3 m. Seven children (11.5 %) were re-operated for esotropia, four for exotropia (6.6 %). CONCLUSION: Bilateral medial rectus recession with retroequatorial myopexy (Cuppers procedure) is an effective one step procedure for large infantile esotropia. In roughly two-thirds of the cases, the squint angle was corrected within +/- 5 degrees with one surgery, which is similar to reported success rates of BMR. PMID- 23096144 TI - [Traumatic III nerve palsy]. AB - Ptosis, anisocoria, loss of accommodation, incomitant exotropia, vertical and torsional disorders are the obstacles for binocularity after a traumatic III nerve palsy when a usable fusion field of vision with a more or less level head is to be acheived. To accept monocular vision may be the best choice in many cases. Therapeutic efforts to restore binocularity must deal with all aspects of the palsy. Strongly contraindicated are uncritical ptosis operations or simple repositioning interventions on the fellow eye to merely reduce the angle. Those who have a good knowledge of the entire spectrum of ocular muscle surgery, have experienced contact lens specialists at hand, and are proficient in all procedures of refractive lens surgery may, after comprehensive patient counselling, attempt to treat these patients and can in isolated cases achieve functionally useful results. PMID- 23096145 TI - [Autosomal recessive bestrophinopathy (ARB): a clinical and molecular description of two patients at childhood]. AB - BACKGROUND: Autosomal recessive bestrophinopathy (ARB) is associated with mutations in BEST1. ARB is rarely diagnosed compared to BEST1-associated autosomal dominant (a. d.) juvenile vitelliform macular degeneration (Morbus Best, VMD). This is not only due to its low prevalence, but also to the phenotypic appearance. This paper describes typical features in two patients and discusses novel findings using improved ophthalmological diagnostic tools. MATERIAL AND METHODS: Two unrelated boys with reduced visual acuity as well as five further relatives underwent a comprehensive ophthalmological examination including electroretinography (ERG) and electrooculography (EOG) according to ISCEV standard, fundus autofluorescence (FAF) and spectral-domain optic coherence tomography (SD-OCT). BEST1 was screened for mutations based on the clinical diagnosis. RESULTS: Visual acuity ranged between 0.2 and 0.5 in the patients. Multifocal yellowish paramacular and peripheral lesions were visible in the fundus correlating with spots of increased FAF. The lesions correlated with thickening of the RPE layer. Especially in the inner nuclear layer hyporeflective areas were visible, reminiscent of retinoschisis but without changes of FAF. In both patients the ganzfeld ERG was within the normal range and the mfERG presented obvious reductions of amplitudes in the central area. The EOG did not show a light peak. Goldmann perimetry was normal for isopters III/4e and I/4e. The fundus controlled perimetry revealed a central sensitivity loss. Molecular genetic analysis identified four (two novel) mutations in BEST1, in the compound heterozygous state in both patients. The screened relatives carried one of the mutations in the heterozygous state and were ophthalmologically unremarkable apart from age-related changes. CONCLUSION: ARB is a rare disease, presenting with obvious differences to a.d. Mobus Best. The phenotype can easily be identified by the extramacular multifocal yellowish lesions with increased FAF and accompanied by early loss of visual acuity. Specific diagnostic tests like OCT, FAF recordings and electrophysiology support the diagnosis. Molecular genetic screening confirms the diagnosis and the autosomal recessive inheritance. PMID- 23096146 TI - [Vitreomacular interface and posterior vitreomacular adhesion in exudative age related macular degeneration (AMD): an OCT-based comparative study]. AB - PURPOSE: The aim of this study was to evaluate posterior vitreomacular adhesion as a risk factor for choroidal neovascularisation (CNV) in age-related macular degeneration (AMD). The vitreoretinal interface was examined using spectralis optical coherence tomography (Spectralis-OCT, Heidelberg Engineering). PATIENTS AND METHODS: In a retrospective observational case series 375 consecutive eyes of 375 patients (age 51-90 years) were examined with spectralis OCT and fluorescein angiography (Spectralis-HRA, Heidelberg Engineering). Vitreomacular adhesion was defined when a posterior hyaloid line attached to the inner retinal surface was seen in OCT. In 202 patients with exudative AMD the incidence of posterior vitreomacular adhesion was compared to 173 control eyes (72 with non-exudative AMD and 101 eyes without retinal alterations). RESULTS: We found posterior vitreomacular adhesions in 151 patients (40.27 %). In the control group 53 patients (30.6 %) showed vitreomacular adhesions compared to 98 patients (48.5 %) with exudative AMD. The difference was statistically significant (p = 0.001). The location of vitreomacular adhesion was observed over the area of the CNV in 87 patients (88 %) with exudative AMD. CONCLUSIONS: Spectralis OCT allows a detailed examination of the vitreomacular interface. The frequency of posterior vitreomacular adhesion is significantly increased in eyes with CNV in AMD. Chronic vitreomacular traction may be a risk factor for the development of exudative AMD. PMID- 23096147 TI - [Letter from a reader]. AB - OBJECTIVE: Whether the treatment of benign ampullary tumors should be performed as transduodenal surgical excision or endoscopic ampullectomy depends on the size and spread of the tumor. In this videopaper we report technical hints on the surgical resection. INDICATIONS: Surgical resection is indicated for benign ampullary lesions if endoscopic resection is not possible. In addition, local resection can be performed in cases with high risk of malignancy or in a palliative intention. PROCEDURE: The duodenum is mobilized by the Kocher maneuver. It is recommendable to perform a cholecystectomy to introduce a flexible catheter antegrade into the common bile duct through the cystic duct for identification of the papilla of Vater by digital palpation. An anterolateral oblique duodenotomy is made and thereby the tumor of the papilla is exposed, followed by a submucosal injection of epinephrine to elevate the tumor. Afterwards a 5-10 mm margin is scored circumferentially in the mucosa around the adenoma. The extent of the excision is based on the preoperative and intraoperative assessment; a submucosal or full thickness (for transmural lesions) excision can be performed. After submucosal excision the mucosa of the ampulla is approximated to the mucosa of the duodenum. In cases with full thickness ampullectomy the borders of the pancreatic and bile duct are approximated and then the entire complex is sutured to the full wall of the duodenum. Furthermore in some cases with extensive resection a separate reconstruction of the pancreatic and bile duct may be required. A terminal assessment of the ductal patency is imperative. The duodenectomy is closed and a paraduodenal drain is placed. CONCLUSION: Transduodenal resection of periampullary tumors can be technically demanding, but provides a stage-adapted treatment modality for benign and premalignant lesions of the papilla of Vater. PMID- 23096149 TI - Histological and mucin histochemical study of the small intestine of the Persian squirrel (Sciurus anomalus). AB - This article describes the histological and mucin histochemical properties of the small intestine of the Persian squirrel (Sciurus anomalus). This species is widely distributed in the Middle East and can be found as a companion animal. The histological studies revealed that the plicae circulares were not visible in the tunica mucosa. The maximum height and width of the villi were observed in the duodenum, which then decreased toward the ileum. The muscularis mucosa was scattered, whereas the tunica submucosa was composed of dense connective tissue. The lymphatic nodules were seen in the submucosa of the distal part of the jejunum and ileum, and Brunner's glands were embedded in the initial portion of the duodenum. The tunica muscularis was significantly thicker in the ileum, and the circular muscle layer was thicker than the longitudinal muscle layer throughout the entire length of the small intestine. The mucin histochemistry, which was examined using the periodic acid-Schiff (PAS) and alcian blue (AB) (pH 1.0 and 2.5) and also PAS-AB (pH 2.5) and aldehyde fuchsin-AB (pH 2.5) techniques coupled with methylation and saponification reaction for some sections, showed that the small intestine mucous content included both carboxylated and sulfated acidic mucins with few neutral mucins. The results of this study contribute to the knowledge of the histological and histochemical characteristics of the gastrointestinal tracts of exotic mammals and provide data for comparison with other mammals. PMID- 23096152 TI - Effect of temperature on rotational viscosity in magnetic nano fluids. AB - Flow behavior of magnetic nano fluids with simultaneous effect of magnetic field and temperature is important for its application for cooling devices such as transformer, loud speakers, electronic cooling and for its efficiency in targeted drug delivery and hyperthermia treatment. Using a specially designed horizontal capillary viscometer, temperature-sensitive and non-temperature-sensitive magnetic nano fluids are studied. In both these case the temperature-dependent rotational viscosity decreases, but follows a quite different mechanism. For temperature-sensitive magnetic nano fluids, the reduction in rotational viscosity is due to the temperature dependence of magnetization. Curie temperature ((T)(c)) and pyromagnetic coefficient are extracted from the study. A fluid with low T(c) and high pyromagnetic coefficient is useful for thermo-sensitive cooling devices and magnetic hyperthermia. For non-temperature-sensitive magnetic nano fluids, reduction in rotational viscosity is due to removal of physisorbed secondary surfactant on the particle because of thermal and frictional effects. This can be a good analogy for removal of drug from the magnetic particles in the case of targeted drug delivery. PMID- 23096151 TI - Reverse buoyancy in a vibrated granular bed: Computer simulations. AB - We have performed molecular dynamics simulations of an intruder in a vibrated granular bed including interstitial fluid effects to account for the phenomenon of reverse buoyancy. We show that our model is able to reproduce the overall behaviour observed by previous experimental works and is the first finite elements simulation to show the sinking of intruders lighter than the granular bed. To further advance our comprehension of this phenomenon, we studied the motion of the intruders in a single vibration cycle with respect to the bottom of the granular column, finding a substantial qualitative difference for heavy and light intruders and we compare these results with experiments using fine-sized glass beads. We show that, though heavy intruders seem unaffected by the force due to the fluid, the effect on light intruders is remarkable. PMID- 23096150 TI - Suicide risk and psychopathology in immigrants: a multi-group confirmatory factor analysis. AB - BACKGROUND: Immigrants may experience several negative consequences as a result of their migration including discrimination, unsatisfactory economic conditions, and rejection from the host countries, which may contribute to psychiatric illness and vulnerability to suicidal behaviors. The purpose of the current study was to determine whether or not the theorized components of measured dimensions of suicide risk and psychopathology vary across samples of Italians and immigrants. METHODS: We investigated 237 Italians and 234 immigrants, who were administered self-report questionnaires to assess temperament (TEMPS-A), hopelessness (BHS), personality (EPQ-R), and self-other perception (9AP). RESULTS: Multi-group confirmatory factor analyses were conducted, which yielded a final model with an excellent fit to the data (chi (53) (2) = 57.56; CFI = 0.994; RMSEA = 0.014). This final model fits significantly better than the previously tested models and indicated that the same pattern of relationships was found between suicide risk and psychopathology across both groups. CONCLUSIONS: Although immigrants represent a unique population and may experience specific stressors contributing to psychopathology and suicide risk, our findings suggest that the samples of Italians and immigrants may be more similar on the study variables under investigation than previously thought. Implications are offered for the improved identification and treatment of immigrants and resident citizens in Europe in general and in Italy in particular. PMID- 23096154 TI - Conditional statistics of thermal dissipation rate in turbulent Rayleigh-Benard convection. AB - The statistical properties of the thermal dissipation rate in turbulent Rayleigh Benard convection in a cylindrical cell are studied by means of three-dimensional direct numerical simulations for a fixed Prandtl number Pr = 0.7 and aspect ratio Gamma = 1. The Rayleigh numbers Ra are between 10(7) and 3 * 10(10). We apply a criterion that decomposes the cell volume into two disjoint subsets: the plume dominated part and the turbulent background part. The plume-dominated set extends over the whole cell volume and is not confined to the boundary layers. It forms a complex spatial skeleton on which the heat is transported in the convection cell and its volume fraction decreases with increasing Rayleigh number. The latter finding holds also when the threshold, which separates both subvolumes, is varied. The Rayleigh number dependence of the mean moments and probability density functions of the thermal dissipation are analyzed on the subvolumes and related to other possible divisions of the convection volume, such as into boundary layer and bulk. The largest thermal dissipation events are always found in the plume-dominated subset. PMID- 23096153 TI - Boolean versus continuous dynamics in modules with two feedback loops. AB - We investigate the dynamical behavior of simple networks, namely loops with an additional internal regulating connection. Continuous dynamics for mRNA and protein concentrations is compared to a Boolean model for gene activity. Using a generalized method and within a single framework, we study different continuous models and different types of regulatory functions, and establish conditions under which the system can display stable oscillations or stable fixed points. These conditions depend only on general features such as the degree of cooperativity of the regulating interactions and the logical structure of the interactions. There are no simple rules for deciding when Boolean and continuous dynamics agree with each other, but we identify several relevant criteria. PMID- 23096155 TI - Transcriptome characterization of immune suppression from battlefield-like stress. AB - Transcriptome alterations of leukocytes from soldiers who underwent 8 weeks of Army Ranger training (RASP, Ranger Assessment and Selection Program) were analyzed to evaluate impacts of battlefield-like stress on the immune response. About 1400 transcripts were differentially expressed between pre- and post-RASP leukocytes. Upon functional analysis, immune response was the most enriched biological process, and most of the transcripts associated with the immune response were downregulated. Microbial pattern recognition, chemotaxis, antigen presentation and T-cell activation were among the most downregulated immune processes. Transcription factors predicted to be stress-inhibited (IRF7, RELA, NFkappaB1, CREB1, IRF1 and HMGB) regulated genes involved in inflammation, maturation of dendritic cells and glucocorticoid receptor signaling. Many altered transcripts were predicted to be targets of stress-regulated microRNAs. Post-RASP leukocytes exposed ex vivo to Staphylococcal enterotoxin B showed a markedly impaired immune response to this superantigen compared with pre-RASP leukocytes, consistent with the suppression of the immune response revealed by transcriptome analyses. Our results suggest that suppression of antigen presentation and lymphocyte activation pathways, in the setting of normal blood cell counts, most likely contribute to the poor vaccine response, impaired wound healing and infection susceptibility associated with chronic intense stress. PMID- 23096156 TI - Exploring structurally conservative blocks as universal templates for modeling eukaryotic cytochrome P450s. AB - BACKGROUND: An increasing number of crystal structures for eukaryotic P450s have been published, which provided the chance to explore more structural features and construct some knowledge-based methods to facilitate modeling. METHODS: The crystal structures of 14 cytochrome P450s (CYP450) were selected to extract generic spatial anchors typical for three-dimensional (3D) structures of eukaryotic P450s. Multiple sequence alignment and structural superimposition were applied to recognize evolutionarily conserved regions. RESULTS: Regions containing uninterrupted helical components were identified as structurally conservative blocks (SCBs). The reliability and robustness of the SCBs were further evaluated by sequence entropy and structural deviation. Finally, these SCBs were applied and tested directly in constructing the homology model of the P450 1B1. CONCLUSIONS: SCBs could potentially be applied as universal template to standardize the homology modeling procedure and help predict drug metabolism preferences for eukaryotic P450s. PMID- 23096157 TI - An ancient duplication of apple MYB transcription factors is responsible for novel red fruit-flesh phenotypes. AB - Anthocyanin accumulation is coordinated in plants by a number of conserved transcription factors. In apple (Malus * domestica), an R2R3 MYB transcription factor has been shown to control fruit flesh and foliage anthocyanin pigmentation (MYB10) and fruit skin color (MYB1). However, the pattern of expression and allelic variation at these loci does not explain all anthocyanin-related apple phenotypes. One such example is an open-pollinated seedling of cv Sangrado that has green foliage and develops red flesh in the fruit cortex late in maturity. We used methods that combine plant breeding, molecular biology, and genomics to identify duplicated MYB transcription factors that could control this phenotype. We then demonstrated that the red-flesh cortex phenotype is associated with enhanced expression of MYB110a, a paralog of MYB10. Functional characterization of MYB110a showed that it was able to up-regulate anthocyanin biosynthesis in tobacco (Nicotiana tabacum). The chromosomal location of MYB110a is consistent with a whole-genome duplication event that occurred during the evolution of apple within the Maloideae family. Both MYB10 and MYB110a have conserved function in some cultivars, but they differ in their expression pattern and response to fruit maturity. PMID- 23096162 TI - Analysis of flavonoids by graphene-based surface-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is a simple and fast technique for the analysis of large biomolecules but is not suitable for the detection of low molecular weight molecules and compounds, such as flavonoids and phenylpropanoids, mainly due to the lack of an appropriate matrix. Flavonoids and phenylpropanoids, such as coumarin and its derivatives, have attracted much attention recently because of their pharmacological activities and putative therapeutic benefits. In this study, we developed a quick and simple LDI-TOF MS method for the detection of flavonoids and the derivatives of coumarin. Analytes were spotted onto a matrix of graphene-based nanoparticles and then analyzed by LDI-TOF MS in the negative ion mode. Analysis of the sensitivity and effect of different graphene-based nanoparticles including graphene, graphene oxide, and reduced graphene oxide on desorption/ionization of analytes showed that graphene oxide was the most suitable matrix. Moreover, we found that graphene oxide sheets of larger lateral size resulted in better desorption/ionization efficiency. Overall, we show that graphene oxide is a useful matrix for the analysis of flavonoids and the derivatives of coumarin by LDI-TOF MS in the negative ion mode. PMID- 23096158 TI - Production of diploid male gametes in Arabidopsis by cold-induced destabilization of postmeiotic radial microtubule arrays. AB - Whole-genome duplication through the formation of diploid gametes is a major route for polyploidization, speciation, and diversification in plants. The prevalence of polyploids in adverse climates led us to hypothesize that abiotic stress conditions can induce or stimulate diploid gamete production. In this study, we show that short periods of cold stress induce the production of diploid and polyploid pollen in Arabidopsis (Arabidopsis thaliana). Using a combination of cytological and genetic analyses, we demonstrate that cold stress alters the formation of radial microtubule arrays at telophase II and consequently leads to defects in postmeiotic cytokinesis and cell wall formation. As a result, cold stressed male meiosis generates triads, dyads, and monads that contain binuclear and polynuclear microspores. Fusion of nuclei in binuclear and polynuclear microspores occurs spontaneously before pollen mitosis I and eventually leads to the formation of diploid and polyploid pollen grains. Using segregation analyses, we also found that the majority of cold-induced dyads and triads are genetically equivalent to a second division restitution and produce diploid gametes that are highly homozygous. In a broader perspective, these findings offer insights into the fundamental mechanisms that regulate male gametogenesis in plants and demonstrate that their sensitivity to environmental stress has evolutionary significance and agronomic relevance in terms of polyploidization. PMID- 23096163 TI - Pulmonary artery measurements in pulmonary hypertension: the role of computed tomography. AB - PURPOSE: We studied the relationship between pulmonary artery diameter (PAD) as measured on computed tomography (CT) and pulmonary artery pressure (PAP) with the specific goal of assessing the reliability of various measurements on high resolution chest CT as predictors of pulmonary hypertension (PH). MATERIALS AND METHODS: In a preliminary study we determined the method of measuring the main PAD (mPAD) that best correlated with PAP. Using this approach we measured mPAD on CT and correlated the data with PAP obtained from right heart catheterization in 298 patients with known PH and in 102 controls. Various metrics were analyzed for their specificity and sensitivity as screening measurements for PH. RESULTS: The mean PAD and mPAD/ascending aorta diameter (AAD) ratio were found to have the highest correlation with PAP (r=0.51 and 0.53, respectively; P<0.001). A threshold of mPAD>29.5 mm was found to be 70.8% sensitive and 79.4% specific for PH, and an mPAD threshold >31.5 mm had a sensitivity and specificity of 52.0% and 90.2%, respectively. An mPAD/AAD ratio >1 was found to be 70.8% sensitive and 76.5% specific for PH. There was no significant correlation between mPAD and body surface area or age (r=0.04 and 0.07, respectively). A strong statistically significant difference (P<0.0001) was found between mPAD and mPAD/AAD ratio between controls and the PH group. CONCLUSION: mPAD and mPAD/AAD ratio may be used to detect PH in patients of any age or with any body surface area. PMID- 23096159 TI - Influence of host chloroplast proteins on Tobacco mosaic virus accumulation and intercellular movement. AB - Tobacco mosaic virus (TMV) forms dense cytoplasmic bodies containing replication associated proteins (virus replication complexes [VRCs]) upon infection. To identify host proteins that interact with individual viral components of VRCs or VRCs in toto, we isolated viral replicase- and VRC-enriched fractions from TMV infected Nicotiana tabacum plants. Two host proteins in enriched fractions, ATP synthase gamma-subunit (AtpC) and Rubisco activase (RCA) were identified by matrix-assisted laser-desorption ionization time-of-flight mass spectrometry or liquid chromatography-tandem mass spectrometry. Through pull-down analysis, RCA bound predominantly to the region between the methyltransferase and helicase domains of the TMV replicase. Tobamovirus, but not Cucumber mosaic virus or Potato virus X, infection of N. tabacum plants resulted in 50% reductions in Rca and AtpC messenger RNA levels. To investigate the role of these host proteins in TMV accumulation and plant defense, we used a Tobacco rattle virus vector to silence these genes in Nicotiana benthamiana plants prior to challenge with TMV expressing green fluorescent protein. TMV-induced fluorescent lesions on Rca- or AtpC-silenced leaves were, respectively, similar or twice the size of those on leaves expressing these genes. Silencing Rca and AtpC did not influence the spread of Tomato bushy stunt virus and Potato virus X. In AtpC- and Rca-silenced leaves TMV accumulation and pathogenicity were greatly enhanced, suggesting a role of both host-encoded proteins in a defense response against TMV. In addition, silencing these host genes altered the phenotype of the TMV infection foci and VRCs, yielding foci with concentric fluorescent rings and dramatically more but smaller VRCs. The concentric rings occurred through renewed virus accumulation internal to the infection front. PMID- 23096165 TI - Maintenance of Certification (Part IV): practice quality improvement update. PMID- 23096164 TI - Small-animal SPECT/CT of HER2 and HER3 expression in tumor xenografts in athymic mice using trastuzumab Fab-heregulin bispecific radioimmunoconjugates. AB - Heterodimerization of human epidermal growth factor receptor 2 (HER2) with HER3 initiates aberrant downstream growth-signaling pathways in tumors. Our objective was to construct bispecific radioimmunoconjugates (bsRICs) that recognize HER2 and HER3 and evaluate their ability to image tumors in athymic mice that express one or both receptors using small-animal SPECT/CT. METHODS: bsRICs were constructed by reacting the maleimide-derivatized trastuzumab Fab fragments that bind HER2 with a thiolated form of the HER3-binding peptide of heregulin-beta1 (HRG) with or without a 12- or 24 mer polyethylene glycol (PEG) spacer. bsRICs were derivatized with diethylenetriaminepentaacetic acid for labeling with (111)In. The ability of (111)In-bsRICs to bind HER2 or HER3 was determined in competition assays with unlabeled Fab or HRG on cells expressing one or both receptors. Tumor and normal-tissue uptake were examined in CD1 athymic mice bearing subcutaneous tumor xenografts that expressed HER2, HER3, or both receptors, with or without the preadministration of unlabeled Fab or HRG to determine the specificity of uptake. RESULTS: Conjugation of Fab to HRG was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis-Western blot and size-exclusion high-performance liquid chromatography. Improved HER2 and HER3 binding and greater displacement of binding by competitors was found for (111)In-bsRICs that incorporated a PEG spacer, with the PEG(24) spacer being optimal. The highest uptake of (111)In-bsRICs (7.8% +/- 2.1% injected dose per gram [%ID/g]) in BT-474 human breast cancer xenografts (HER2-positive/HER3 positive) occurred at 48 h after injection. The preadministration of trastuzumab Fab decreased uptake in SK-OV-3 (HER2-positive/HER3-negative) human ovarian cancer xenografts from 7.0 +/- 1.2 to 2.6 +/- 1.5 %ID/g (P < 0.001). The preadministration of an excess of HRG decreased uptake in MDA-MB-468 (HER2 negative/HER3-positive) human breast cancer xenografts from 4.4 +/- 0.9 to 2.6 +/ 0.5 %ID/g (P < 0.05). All tumors were imaged by small-animal SPECT/CT. CONCLUSION: (111)In-bsRICs composed of trastuzumab Fab and HRG exhibited specific binding in vitro to tumor cells displaying HER2 or HER3 and were taken up specifically in vivo in tumors expressing one or both receptors, permitting tumor visualization by small-animal SPECT/CT. These agents could be useful for imaging heterodimerized HER2 and HER3 receptors because their bivalent properties may result in preferential binding to the heterodimerized forms. The approach may also be extended to constructing bsRICs for visualizing other peptide growth factor receptors. PMID- 23096166 TI - PET/CT of cancer patients: part 1, pancreatic neoplasms. AB - OBJECTIVE: Pancreatic cancer continues to have a poor prognosis despite impressive improvements in the outcomes of many other types of cancer, often because most pancreatic neoplasms are found to be unresectable at diagnosis. The purpose of this review is to provide an overview of pancreatic cancer and the role of modern imaging in its diagnosis and management with an emphasis on (18)F FDG PET/CT fusion imaging. CONCLUSION: Multimodality imaging is critical in the diagnosis and management of pancreatic cancer. PET/CT is increasingly viewed as a useful, accurate, and cost-effective modality in diagnosing and managing pancreatic cancer, but further studies are warranted. Early data suggest that contrast-enhanced PET/CT performed with modern PET/CT scanners yields high resolution anatomic information for surgical and radiotherapeutic planning and functional information for whole-body staging in the care of patients with this disease. PMID- 23096167 TI - PET/CT of cancer patients: part 2, deformable registration imaging before and after chemotherapy for radiation treatment planning in head and neck cancer. AB - OBJECTIVE: The purpose of this perspective is to discuss the use of deformable registration as a tool for image fusion to integrate information from PET/CT scans obtained before and after chemotherapy to assist definition of radiation targets in the management of head and neck cancer. CONCLUSION: The consistent method for target delineation described capitalizes on the capability of deformable registration to compensate for changes in position and accurately represent evolving spatial relationships between normal anatomy and areas at risk of disease. PMID- 23096168 TI - Xenon-enhanced dual-energy CT of patients with asthma: dynamic ventilation changes after methacholine and salbutamol inhalation. AB - OBJECTIVE: The purpose of this study was to evaluate the use of xenon-enhanced dual-energy CT of the chest to assess ventilation changes after methacholine and salbutamol inhalation in subjects with asthma and healthy subjects. SUBJECTS AND METHODS: Twenty-five subjects with asthma and 10 healthy subjects underwent three phase (basal, after methacholine inhalation, after salbutamol inhalation) xenon enhanced chest CT. Each phase was composed of wash-in and washout scans. For visual analysis, two radiologists evaluated ventilation defects and gas trapping lobe by lobe on a 10-point scale. Total ventilation defect and gas trapping scores were calculated by adding ventilation defect and gas trapping scores. Xenon and total lung volume were quantified automatically. Total xenon concentration index was calculated as total xenon concentration divided by lung volume. Repeated measures analysis of variance and Student t test were used for comparisons of total ventilation defect score, total gas trapping score, and total xenon concentration index between the two groups. The Friedman test was used for within-group analysis. RESULTS: In the basal state, subjects with asthma had a higher total ventilation defect score (p = 0.004) and higher total gas trapping score (p = 0.05) than did healthy subjects. On washout images, total ventilation defect score, total gas trapping score, and total xenon concentration index after methacholine and salbutamol inhalation were statistically different between the two groups (p < 0.05). However, total xenon concentration index on wash-in images was not significantly different between the two groups. In within group analysis, total ventilation defect score and total gas trapping score in subjects with asthma and total ventilation defect score in healthy subjects increased significantly after methacholine inhalation and decreased significantly after salbutamol inhalation (p < 0.05). CONCLUSION: Xenon-enhanced chest CT may be a useful technique for visualizing dynamic changes in airflow in response to methacholine and salbutamol inhalation in patients with asthma. Optimization of the protocol for radiation exposure is warranted. PMID- 23096170 TI - Image quality and radiation dose of pulmonary CT angiography performed using 100 and 120 kVp. AB - OBJECTIVE: The objective of our study was to compare image quality and radiation dose of pulmonary CT angiography (CTA) performed in the same patient cohort using tube potentials of 100 and 120 kVp. MATERIALS AND METHODS: The study group for this retrospective study was 32 patients (22 women, 10 men) with a mean age of 57 years (age range, 28-83 years; body weight < 100 kg). Patients underwent pulmonary CTA studies performed using 120 and 100 kVp while other scanning parameters were kept constant. Two observers measured image signal and image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), and SNR dose and CNR dose. Two additional observers performed qualitative image quality analysis using a 5-point grading scale (5 = excellent). RESULTS: The reduction in tube potential caused image signal to increase by 29% (p < 0.0001), image noise to increase by 68% (p < 0.0001), CNR dose to decrease by 0.8% (p = 0.91) and SNR to decrease by 24% (p = 0.0002) and CNR by 20% (p = 0.0019). Radiation dose (dose length product) was decreased by 37% to 379.26 mGy * cm at 100 kVp from 604.46 mGy * cm at 120 kVp (p < 0.0001). The median pulmonary arteries image quality scores for observers 1 and 2, respectively, were as follows at 100 kVp: main, 5 and 5; lobar, 5 and 4.5; and segmental, 5 and 4. At 120 kVp, the median image quality scores for observers 1 and 2 were as follows: main, 5 and 5; lobar, 5 and 5; segmental, 4 and 4. A Wilcoxon test analysis indicated no significant difference in image quality between the studies (main, p = 0.59; lobar, p = 0.88; segmental, p = 0.79). CONCLUSION: Pulmonary CTA can be performed using a tube potential of 100 kVp in patients who weigh less than 100 kg (220 lb). Reducing the tube potential from 120 to 100 kVp results in a 37% reduction in radiation dose without a significant impact on diagnostic image quality. PMID- 23096169 TI - High-resolution CT findings in fibrotic idiopathic interstitial pneumonias with little honeycombing: serial changes and prognostic implications. AB - OBJECTIVE: This retrospective study evaluates serial changes of lung abnormalities on high-resolution CT (HRCT) and clarifies prognostic determinants among CT findings in fibrotic idiopathic interstitial pneumonias (IIPs) with little honeycombing. MATERIALS AND METHODS: We enrolled 154 patients with a histologic diagnosis of a fibrotic IIP (< 5% honeycombing on CT) who were followed clinically for at least 2 years. One hundred one patients had usual interstitial pneumonia (UIP) and 53 had fibrotic nonspecific interstitial pneumonia (NSIP). On baseline CT, the extent and distribution of lung abnormalities were visually assessed, and serial CT scans were evaluated with a follow-up period of at least 6 months (n = 132). RESULTS: Significant differences were noted in the extent of reticulation and ground-glass opacification (GGO) between the UIP and fibrotic NSIP groups (p < 0.001). On serial scans, honeycombing (5% in UIP and 3% in fibrotic NSIP; p = 0.08) and reticulation (3% in UIP and 8% in fibrotic NSIP; p = 0.03) progressed in extent and GGO (-2% in UIP and -10% in fibrotic NSIP; p = 0.009) decreased in extent. Overall extent of lesions increased in UIP (6%) and decreased in NSIP (-4%) (p = 0.04). On univariate and multivariate Cox proportional hazards analysis, the overall extent of parenchymal abnormalities was a prognostic factor predictive of poor survival duration. CONCLUSION: Even in cases of fibrotic IIP with little honeycombing, serial CT reveals an increase in the extent of honeycombing and reticulation and a decrease in extent of GGO. Overall extent of lung fibrosis on the baseline CT examination appears predictive of survival in fibrotic IIP with little honeycombing. PMID- 23096171 TI - Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis. AB - OBJECTIVE: The hepatorenal index has been reported to be a sensitive and noninvasive test to quantify steatosis, but it is cumbersome and time-consuming and requires specialized software. The aim of this study was to improve and simplify the hepatorenal index calculation and determine whether it is an effective tool for differentiating patients with steatosis from those without steatosis, thereby eliminating the need for biopsy in a large number of patients. MATERIALS AND METHODS: One hundred one patients who had undergone ultrasound guided percutaneous liver biopsy at our institution were selected from a patient database. Patients with renal disease, patients with liver masses, and patients whose liver and right kidney were not included on the same image were excluded. Images were acquired with high-resolution ultrasound, and the hepatorenal index was calculated using freeware based on comparison of hepatic and renal brightness. RESULTS: Of the 101 patients, 63 had 5% or less steatosis and 38 had more than 5% steatosis. Using freeware available online from the National Institutes of Health, we calculated hepatorenal index values for all patients. Our data showed a strong correlation between the hepatorenal index and percentage of fat (r = 0.71, p < 0.0001). A hepatorenal index of 1.28 or greater had a 100% sensitivity for identifying more than 5% fat, 54% specificity, 0.57 positive predictive value, and 1.0 negative predictive value. If this method had been used prospectively to select patients for biopsy in our sample, 34% of biopsies could have been avoided. CONCLUSION: The hepatorenal index is a simple, reliable, and cost-effective screening tool for identifying patients who should not undergo liver biopsy for evaluation of steatosis. PMID- 23096172 TI - Integrated (18)F-FDG PET/CT and perfusion CT of primary colorectal cancer: effect of inter- and intraobserver agreement on metabolic-vascular parameters. AB - OBJECTIVE: The purpose of this article is to assess the effect of observers on combined metabolic-vascular parameters in colorectal cancer. SUBJECTS AND METHODS: Twenty-five prospective patients (12 men and 13 women; mean age, 66.9 years) with proven primary colorectal adenocarcinoma underwent integrated (18)F FDG PET/perfusion CT to assess tumor metabolism (mean and maximum standardized uptake value [SUV(mean) and SUV(max), respectively]) and vascularization (blood flow [BF], blood volume [BV], permeability surface-area product, and standardized perfusion value). Intra- and interobserver agreement for PET, perfusion CT, and combined metabolic-flow parameters were determined by Bland-Altman statistics and intraclass correlation coefficients (ICCs). RESULTS: The mean tumor size was 3.8 +/- 1.6 cm; there were five stage IA/B, six stage IIA/B, eight stage IIIA/B, and six stage IV tumors. Intra- and interobserver agreement for individual parameters was fair to good, with mean differences between observers of -0.74 for SUV(max), 0.16 for SUV(mean), 9.72 for BF, 0.15 for BV, -0.76 for permeability surface-area product, and 0.09 for standardized perfusion value. ICCs were 0.44-0.99 and 0.38 0.89 for intra- and interobserver agreement, respectively. Interobserver agreement was variable for combined metabolic-flow parameters but better for metabolic-flow difference than for metabolic-flow ratio: ICCs were 0.69-0.88 for the metabolic-flow difference and 0.44-0.94 for the metabolic-flow ratio. CONCLUSION: Combined parameters to assess the metabolic-flow relationship are influenced by observer variation. Intra- and interobserver agreement are better for the metabolic-flow differences than for the ratios, suggesting that metabolic flow differences may be a more robust parameter for clinical practice. PMID- 23096173 TI - Pseudolesion of the liver on gadoxetate disodium-enhanced MR images obtained after transarterial chemoembolization for hepatocellular carcinoma: clinicoradiologic correlation. AB - OBJECTIVE: The purpose of this study was to elucidate the clinicoradiologic characteristics of pseudolesions of the liver in patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE) as observed on gadoxetate disodium-enhanced MR images. A particular interest was correlation between the pseudolesion characteristics and TACE-MRI interval, during which sequential changes in pseudolesions may be revealed after TACE. MATERIALS AND METHODS: Forty-eight patients with HCC who underwent gadoxetate disodium-enhanced MRI after TACE were retrospectively recruited. Pseudolesions were defined as areas of decreased signal intensity in treated areas on hepatocellular phase images that were confirmed to be nontumorous areas at follow-up. The prevalence and MRI features of pseudolesions were correlated with various clinical parameters, including TACE-MRI interval. RESULTS: Pseudolesions were found in 14 patients (29%). Within 1 month of TACE, the prevalence of pseudolesions was 83%. All of the pseudolesions had arterial enhancement, mimicking residual HCC. After 1 month, the prevalence of pseudolesions decreased, and these pseudolesions tended to exhibit no abnormality in any sequence other than the hepatocellular phase. Results of multivariate analysis suggested that size of HCC (p < 0.0001), duration of postembolization syndrome (p = 0.012), and TACE-MRI interval (p = 0.038) are independent indicators of the presence of pseudolesions. CONCLUSION: The prevalence and appearance of pseudolesions differ at different intervals from TACE. Radiologists need to recognize the clinicoradiologic characteristics to differentiate pseudolesions from true residual or recurrent HCC. PMID- 23096174 TI - MRI detection of intratumoral fat in hepatocellular carcinoma: potential biomarker for a more favorable prognosis. AB - OBJECTIVE: The purpose of this study was to determine whether the presence of intratumoral fat in hepatocellular carcinoma (HCC) could serve as an imaging biomarker to predict a favorable prognosis. MATERIALS AND METHODS: After a search of the radiology and pathology databases from January 2002 to December 2010, a cohort of patients with fat-containing HCC imaged by chemical-shift MRI techniques was matched with a cohort of patients with nonfat-containing HCC for TNM stage and type of subsequent treatment. The number and type of tumor progression, time to tumor progression (TTP), and overall survival (OS) were determined for each cohort. RESULTS: There were 46 patients included in each cohort. Tumor progression was more prevalent in the non-fat-containing HCC cohort (30 patients, 65.2%) compared with the fat-containing HCC cohort (16 patients, 34.7%; p = 0.001). Distant metastasis occurred more commonly in the non-fat containing HCC cohort (10 patient, 21.7%) compared with the fat-containing HCC cohort (two patients, 4.3%; p = 0.039). The median TTP was significantly longer in the fat-containing HCC group (52 months) compared with the non-fat-containing HCC group (27 months; p = 0.037). The significantly longer TTP was primarily observed in the locoregional treatment subgroup (p = 0.028). No statistical significance in OS and subanalysis by treatment was observed (p = 0.63-0.81). CONCLUSION: Fat-containing HCC, imaged on an MRI unit, may predict a more favorable prognosis compared with nonfat-containing HCC. PMID- 23096175 TI - Dual-source dual-energy CT evaluation of complex cystic renal masses. AB - OBJECTIVE: The purpose of this study was to assess the value of dual-source dual energy CT in the evaluation of complex cystic renal masses. SUBJECTS AND METHODS: Seventy patients underwent contrast-enhanced dual-energy CT that included true unenhanced images acquired in single-energy mode, corticomedullary phase images acquired in dual-energy mode, and nephrographic phase images acquired in single energy mode. Virtual unenhanced, blended weighted-average, and color-coded iodine overlay images were reconstructed. The acceptance level and image quality of virtual and true unenhanced images were evaluated. Contrast enhancement on both true unenhanced or blended weighted-average images and color-coded iodine overlay images was evaluated with both calculation in regions of interest and use of confidence level scales. Radiation dose parameters were estimated. RESULTS: Virtual unenhanced images of 70 lesions (97.2%) and true unenhanced images of 72 lesions (100%) were judged acceptable (p = 0.5). The mean quality score of virtual unenhanced images was 2.0 +/- 0.7 and of true unenhanced images was 1.5 +/- 0.5 (p < 0.001). Mean contrast enhancement measured on true unenhanced and blended weighted-average images was 45.9 +/- 15.9 HU (range, 21-78 HU) and on color-coded iodine overlay images was 47.3 +/- 16.8 HU (range, 22-75 HU) with no significant differences. Enhancement was excluded on color-coded iodine overlay images with a significantly (p < 0.03) higher level of confidence than it was on true unenhanced and blended weighted-average images. The mean dose reduction with use of a combined dual- and single-energy dual-phase CT protocol was 29.1% +/- 11.9% (p < 0.001). CONCLUSION: Dual-source dual-energy CT is a reliable imaging technique in the evaluation of complex cystic renal masses. True unenhanced images can be replaced by virtual unenhanced images with considerable radiation dose reduction. The color-coded iodine overlay technique is a useful tool for both excluding and identifying endocystic enhancement. PMID- 23096176 TI - Role of MDCT angiography in selection and presurgical planning of potential renal donors. AB - OBJECTIVE: The purpose of this study was to determine the prevalence and types of renal and extrarenal abnormalities that preclude renal donation or lead to alteration of the surgical approach on the basis of abdominal CT angiography (CTA) in a large group of potential renal donors. MATERIALS AND METHODS: In this retrospective study, 654 potential renal donors undergoing dual-phase CTA were identified from January 2005 to January 2009. The CT reports were systemically reviewed by two radiologists to determine the presence of renal and extrarenal abnormalities. The operative notes of the renal donors were reviewed by one radiologist to determine whether the presence of renal pathology had affected the surgical approach. In the candidates who did not proceed to kidney donation, the reasons that precluded kidney donation were abstracted from the transplant database. RESULTS: Four hundred seventeen potential donors (269 men and 385 women; mean age, 44.0 years; age range, 17-79 years) proceeded to renal donation and 237 did not. The most common renal abnormalities were cysts (34%) and renal stones (4.4%). Renal artery disease was identified in 3.4% of potential donors, including renal artery stenosis, possible fibromuscular dysplasia, and renal artery aneurysm. Suspicious renal masses were incidentally found in 0.5% of potential donors. The most common extrarenal pathology was an incidental adrenal nodule (2.6%). Other significant extrarenal pathology identified included gallbladder mass (0.2%), Crohn disease (0.2%), ovarian mass (0.2%), and possible sarcoidosis (0.2%). Although renal and extrarenal abnormalities were present in 41% of potential renal donors, abnormalities seen on CT only contributed to exclusion of 27 potential donors (4.1%). The most common reason for exclusion was the presence of renal stones or scarring (1.8%). Significant CT findings also contributed to the selection of the right kidney in 29 donors, most commonly due to presence of ipsilateral vascular disease or complex left vascular anatomy. CONCLUSION: Renal parenchymal and vascular abnormalities are common in asymptomatic potential kidney donors. Although most of these represent incidental CT findings, abnormalities can exclude potential renal donors and alter the surgical approach in a small minority of cases. PMID- 23096177 TI - Perfusion MDCT of prostate cancer: correlation of perfusion CT parameters and immunohistochemical markers of angiogenesis. AB - OBJECTIVE: The aim of our study was to correlate perfusion MDCT parameters and immunohistochemical markers of angiogenesis in prostate cancer. SUBJECTS AND METHODS: Twenty-two patients scheduled for radical surgical prostatectomy because of biopsy-proven prostate cancer underwent perfusion CT on a 64-MDCT scanner. Eight contiguous 5-mm sections were acquired at 1-second intervals for 45 seconds followed by three additional scans every 10 seconds after the administration of 80 mL of iodinated contrast medium (350 mg I/mL). Blood volume, blood flow, mean transit time, and permeability surface-area product were calculated, dividing each slice into nine square regions. Values obtained were correlated with the mean microvessel density (MVD) and mean vascular area of corresponding areas on histologic macrosections. RESULTS: The mean values of the perfusion parameters detected on all square fields of patients with prostate cancer, benign hyperplasia, chronic prostatitis, and healthy tissue were, respectively, 18.36 +/ 6.30, 19.49 +/- 8.46, 19.67 +/- 11.44, and 20.32 +/- 4.53 mL/min/100 g for blood flow; 8.45 +/- 2.75, 6.21 +/- 4.32, 4.94 +/- 2.31, and 5.44 +/- 2.67 mL/100 mg for blood volume; 19.19 +/- 4.45, 18.74 +/- 4.91, 16.24 +/- 4.12, and 16.37 +/- 4.83 seconds for mean transit time; and 26.34 +/- 11.88, 18.67 +/- 9.15, 18.08 +/ 7.72, and 19.93 +/- 7.22 mL/min/100 g for permeability surface-area product. Both blood volume and the permeability surface-area product of cancerous squares showed the highest correlation with mean MVD and mean vascular area (0.618 [p < 0.01] and 0.614 [p < 0.01], respectively) and the highest area under the curve (0.769 and 0.708). CONCLUSION: Our results show that blood volume and permeability surface-area product measurements obtained with perfusion CT have the highest correlation with immunohistochemical markers of angiogenesis in prostate cancer. PMID- 23096178 TI - The adoption of low-osmolar contrast agents in the United States: historical analysis of health policy and clinical practice. AB - OBJECTIVE: In this historical analysis of low- and high-osmolar contrast agents, we outline the reasons for the price depreciation, speculate on motivation for universal adoption by many radiologists despite suboptimal reimbursement, and cast light on important shortcomings of economic analyses in the realm of health policy. CONCLUSION: Early economic analyses regarding low-osmolar contrast agents concluded that universal adoption was not cost-effective. Over time, the price differential between low- and high-osmolar agents narrowed, yet reimbursement patterns lagged behind the narrowing price differential. PMID- 23096179 TI - Ordering of CT by emergency department provider type: analysis of a nationally representative sample. AB - OBJECTIVE: Given the growing concern about CT overutilization, we provide a descriptive trend analysis of CT studies ordered in U.S. emergency departments by nonphysician health care providers and examine whether there is a significant difference in ordering patterns between nonphysicians and physicians. MATERIALS AND METHODS: We used a nationally representative data sample for 2001-2008 to describe trends in CT studies ordered in U.S. emergency departments by nonphysician health care providers. We performed a multivariate logistic regression with hospital fixed effects on the most recently available data to determine whether there is a difference in ordering patterns between the two provider groups. RESULTS: From 2001 to 2008, the number of emergency department visits associated with CT studies managed solely by nonphysician health care providers increased from 100,626 to 620,296. Over this same period, the proportion of emergency department visits associated with CT managed solely by nonphysician providers grew from 1.5% to 3.6%. Controlling for hospital-level and patient-level variables, patient visits managed solely by nonphysician providers had 0.38 times the odds of CT utilization compared with patient visits managed by physicians. CONCLUSION: Although both the total number and the proportion of emergency department visits managed independently by nonphysician providers and associated with CT have grown rapidly in the past decade, nonphysician health care providers are less likely to order CT compared with physicians. The types of ordering providers and their differing practices should become part of the discourse regarding appropriate CT utilization. PMID- 23096180 TI - Assessment of kidney volumes from MRI: acquisition and segmentation techniques. AB - OBJECTIVE: The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, early detection and adequate treatment of kidney disease are important. CONCLUSION: We review state-of-the-art MRI acquisition techniques for CKD, with a special focus on image segmentation methods used for the estimation of kidney volume. PMID- 23096181 TI - Lowering kilovoltage to reduce radiation dose in contrast-enhanced abdominal CT: initial assessment of a prototype automated kilovoltage selection tool. AB - OBJECTIVE: The purpose of this study was to determine whether the use of an automated CT kilovoltage (kV) selection tool (Auto kV) can result in lower radiation dose without sacrificing image quality in contrast-enhanced abdominopelvic CT. MATERIALS AND METHODS: Tube potential, radiation dose, and iodine contrast-to-noise ratio (CNR) were retrospectively evaluated in 36 patients who underwent abdominopelvic CT with Auto kV, and compared with results from size-matched control patients using identical protocols. Two radiologists evaluated image quality (sharpness, noise, and diagnostic confidence) blinded to kV. Volume CT dose index (CTDI(vol)) was also compared with what each patient would have received from scanning at 120 kV. RESULTS: Mean (SD) CTDI(vol) was 16.0 (4.4) mGy after Auto kV versus 19.5 (4.0) mGy using standard 120-kV prescription and was 19.3 (6.0) mGy in control subjects (yielding dose reductions of 18.0% and 17.2%, respectively; p < 0.001 for both). Thirty of 36 patients were scanned at 100 kV (median dose reduction, 25%). Auto kV images were rated as very sharp in 33 (92%) and 36 (100%) cases versus 36 (100%) and 35 (97%) of the control cases, with all cases scored as having optimal noise. Readers had full diagnostic confidence in 34 (94%) and 36 (100%) of Auto kV cases; one reader scored "probably confident" in two cases (6%). Iodine CNRs for the aorta, liver, and portal vein were similar between Auto kV cases and control cases (p > 0.50, all comparisons). CONCLUSION: The use of an automated kV selection tool results in significant dose savings while maintaining diagnostic image quality and iodine CNR. PMID- 23096182 TI - Radial head arthroplasty: a radiologic outcome study. AB - OBJECTIVE: The purpose of this study is to provide a radiographic outcome assessment of radial head arthroplasty in correlation with clinical outcomes and to determine whether there is an association between certain patient factors and clinical and radiographic outcomes. MATERIALS AND METHODS: A 10-year retrospective review was performed to identify patients with metal radial head arthroplasty. At least two follow-up radiographs were reviewed for each patient and were correlated with clinical information. Statistical analysis included calculation of complication rates, phi coefficient for variable association with complications, and Kaplan-Meier survival. RESULTS: A total of 258 radial head implants in 244 patients were reviewed. The mean patient age was 46 years, with mean follow-up time of 12.8 months. Two hundred nineteen (84.9%) implants were unipolar in design, whereas 39 implants were bipolar. The most common indication for arthroplasty was trauma (94% acute and 2% failed internal fixation). Radiographic abnormalities included nonbridging heterotopic ossification (38.0%), secondary radiocapitellar joint osteoarthritis (27.9%), loosening (19.8%), bridging heterotopic ossification (8.9%), fracture (2.3%), and hardware dislocation (2.7%). Overall, there were 62 second surgeries for either revision or removal. Reasons for second surgery included heterotopic ossification (53.2%), synovectomy or capsulectomy (43.5%), and infection (3.2%). There was a statistically significant association between radiographic complications and the presence of patient symptoms (p < 0.05). There was no association between radiographic or clinical complications with age, sex, side, or type of arthroplasty (R < 0.001). CONCLUSION: There is a positive association between radiographic findings and patient symptoms for postoperative complications after radial head arthroplasty. By 9 months, 50% of implants showed radiographic complications. PMID- 23096183 TI - Comparison of qualitative and quantitative evaluation of diffusion-weighted MRI and chemical-shift imaging in the differentiation of benign and malignant vertebral body fractures. AB - OBJECTIVE: The objective of our study was to compare the diagnostic value of qualitative diffusion-weighted imaging (DWI), quantitative DWI, and chemical shift imaging in a single prospective cohort of patients with acute osteoporotic and malignant vertebral fractures. SUBJECTS AND METHODS: The study group was composed of patients with 26 osteoporotic vertebral fractures (18 women, eight men; mean age, 69 years; age range, 31 years 6 months to 86 years 2 months) and 20 malignant vertebral fractures (nine women, 11 men; mean age, 63.4 years; age range, 24 years 8 months to 86 years 4 months). T1-weighted, STIR, and T2 weighted sequences were acquired at 1.5 T. A DW reverse fast imaging with steady state free precession (PSIF) sequence at different delta values was evaluated qualitatively. A DW echo-planar imaging (EPI) sequence and a DW single-shot turbo spin-echo (TSE) sequence at different b values were evaluated qualitatively and quantitatively using the apparent diffusion coefficient. Opposed-phase sequences were used to assess signal intensity qualitatively. The signal loss between in- and opposed-phase images was determined quantitatively. Two-tailed Fisher exact test, Mann-Whitney test, and receiver operating characteristic analysis were performed. Sensitivities, specificities, and accuracies were determined. RESULTS: Qualitative DW-PSIF imaging (delta = 3 ms) showed the best performance for distinguishing between benign and malignant fractures (sensitivity, 100%; specificity, 88.5%; accuracy, 93.5%). Qualitative DW-EPI (b = 50 s/mm(2) [p = 1.00]; b = 250 s/mm(2) [p = 0.50]) and DW single-shot TSE imaging (b = 100 s/mm(2) [p = 1.00]; b = 250 s/mm(2) [p = 0.18]; b = 400 s/mm(2) [p = 0.18]; b = 600 s/mm(2) [p = 0.39]) did not indicate significant differences between benign and malignant fractures. DW-EPI using a b value of 500 s/mm(2) (p = 0.01) indicated significant differences between benign and malignant vertebral fractures. Quantitative DW-EPI (p = 0.09) and qualitative opposed-phase imaging (p = 0.06) did not exhibit significant differences, quantitative DW single-shot TSE imaging (p = 0.002) and quantitative chemical-shift imaging (p = 0.01) showed significant differences between benign and malignant fractures. CONCLUSION: The DW-PSIF sequence (delta = 3 ms) had the highest accuracy in differentiating benign from malignant vertebral fractures. Quantitative chemical-shift imaging and quantitative DW single-shot TSE imaging had a lower accuracy than DW-PSIF imaging because of a large overlap. Qualitative assessment of opposed-phase, DW EPI, and DW single-shot TSE sequences and quantitative assessment of the DW-EPI sequence were not suitable for distinguishing between benign and malignant vertebral fractures. PMID- 23096184 TI - Imaging appearance of the normal and partially torn ligamentum teres on hip MR arthrography. AB - OBJECTIVE: The purpose of this study was to evaluate the MR arthrographic appearance of the normal and partially torn ligament teres and to determine if there are imaging criteria for diagnosing partial tears of the ligamentum teres. MATERIALS AND METHODS: One hundred sixteen patients underwent preoperative MR arthrography and hip arthroscopy. Each MR examination was evaluated independently by two musculoskeletal radiologists for the following: size and width of the ligamentum teres in the proximal, mid, and distal thirds of the ligamentum teres; overall length of the ligamentum; number of bundles (1-3); signal intensity (SI) within the ligamentum teres (low, intermediate, high); ligamentum teres fibers (normal, attenuated, thickened, wavy); ligamentum teres integrity (not torn, degenerated, frayed, partial tear); and femoral head edema at the ligamentum teres origin. Statistical analysis was performed using the Kruskal-Wallis rank sum test and Fisher exact test. RESULTS: Twelve of 116 (10%) subjects had partial ligamentum teres tears. One hundred four subjects had an intact ligamentum teres. The average size and width of the intact ligamentum teres was 12.6 * 4.38, 14.9 * 3.5, and 14.3 * 2.7 mm for proximal, mid, and distal, respectively, with an overall length 27.7 mm. It was most common to visualize two bundles in the proximal portion of the normal ligamentum teres (61 and 64/116). Low, intermediate, and high SI was common on all pulse sequences in normal and partially torn ligamentum teres for both readers (p = 0.33-0.84). For reader 1, there was no statistical difference between ligamentum teres fiber appearance in partial tears (p = 0.20). In contrast, reader 2 found partial tears associated with attenuated and wavy appearance (p = 0.003). Reader 1 diagnosed five of 12 (42%), and reader 2 diagnosed eight of 12 (67%) of the partial ligamentum teres tears (p = 0.47 and p = 0.0004). Edema of the femoral ligamentum teres origin was not associated with partial tears (p = 0.33-0.86). Retrospective review revealed that six partial tears had intra substance linear high SI on T2 images and peripheral irregularity, whereas four other tears had high SI within the ligamentum teres fibers without peripheral irregularity. CONCLUSION: The intact and partially torn ligamentum teres can have similar imaging findings on MR arthrography, making the diagnosis of partial ligamentum teres tears difficult. High SI within the substance of the fibers and irregularity suggest partial tearing; however, further research is warranted. PMID- 23096185 TI - Is there an association between superolateral Hoffa fat pad edema on MRI and clinical evidence of fat pad impingement? AB - OBJECTIVE: Patients with symptomatic Hoffa fat pad impingement often exhibit fat pad edema on MRI. We studied two patient groups to determine the association between MRI fat pad edema and clinical symptoms of Hoffa fat pad impingement. MATERIALS AND METHODS: We studied 34 consecutive patients with an MRI diagnosis of fat pad edema and no injury in the prior year (group 1) and 47 consecutive patients with a knee MRI examination and no injury in the prior year (group 2). Two sports medicine physicians reviewed the clinical records to confirm or exclude symptomatic fat pad impingement. Two musculoskeletal radiologists independently scored 12 Hoffa fat pad locations for the presence of edema, noting the epicenter. RESULTS: Seventeen of the 34 patients in group 1 had clinical symptoms of fat pad impingement, with all 34 having fat pad edema. There was no association between clinical fat pad impingement and fat pad edema in any specific location (p > 0.183), but patients with fat pad impingement had a greater number of regions of edema (p = 0.005, 0.026 for two observers). In group 2, all four patients with clinical fat pad impingement had MRI fat pad edema, but 38 of the 43 patients without clinical impingement had MRI fat edema; 11 of the 38 had edema centered in the superolateral fat pad. CONCLUSION: Edema is present on MRI in the superolateral region of Hoffa fat pad in patients with clinical fat pad impingement. However, such edema can also be present in patients without symptoms of fat pad impingement. PMID- 23096186 TI - Imaging of cervical lymphadenopathy in children and young adults. AB - OBJECTIVE: This article describes the role of imaging in evaluating cervical lymphadenopathy in patients from birth to their mid-20s, illustrates imaging features of normal and abnormal lymph nodes, and highlights nodal imaging features and head and neck findings that assist in diagnosis. CONCLUSION: Cervical lymph node abnormalities are commonly encountered clinically and on imaging in children and young adults. Although imaging findings can lack specificity, nodal characteristics and associated head and neck imaging findings can assist in determining the underlying cause. PMID- 23096187 TI - Whole-body diffusion-weighted MRI compared with (18)F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate carcinoma. AB - OBJECTIVE: The purpose of this study was to evaluate the accuracy of whole-body diffusion-weighted MRI (DWI) and (18)F-NaF PET/CT for detection of bone metastases in patients with high-risk prostate cancer. SUBJECTS AND METHODS: Both patient- and lesion-based analyses were performed on 49 consecutive patients (median age, 67 years; age range, 57-80 years) with recently diagnosed high-risk prostate cancer. All patients underwent bone scintigraphy, whole-body MRI including DWI and (18)F-NaF PET/CT before treatment. Bone scintigraphy, conventional MR images, and follow-up images were used as the standard of reference to evaluate (18)F-NaF PET/CT and DWI. RESULTS: On patient-based analysis, five patients had skeletal metastases on reference imaging that both DWI and (18)F-NaF PET/CT could verify, and (18)F-NaF PET/CT and DWI showed false positive findings in four and one patient, respectively. With lesion-based analysis, (18)F-NaF PET/CT and DWI showed nine and five true-positive lesions, zero and four false-negative lesions, and seven and two false-positive lesions, respectively. Two patients with uncountable bone metastases were analyzed separately. In these patients, (18)F-NaF PET/CT showed more bone metastases than did DWI. CONCLUSION: We believe (18)F-NaF PET/CT is a sensitive modality for detection of bone metastases caused by prostate cancer. Whole-body DWI shows a higher specificity but lower sensitivity than (18)F-NaF PET/CT. Future studies with a larger patient cohort along with analyses of costs and clinical availability are needed before implementation of these methods can be considered. PMID- 23096188 TI - Juvenile osteochondritis dissecans: is it a growth disturbance of the secondary physis of the epiphysis? AB - OBJECTIVE: The primary physis is responsible for longitudinal bone growth. Similarly, epiphysial growth relies on endochondral ossification from the circumferential secondary physeal [corrected]. injury can result in disruption of normal ossification. The cause of juvenile osteochondritis dissecans (OCD) remains elusive. We hypothesized that juvenile OCD results from an insult affecting endochondral ossification from the secondary physis. The purpose of our study was to evaluate the MRI appearance of the distal femoral epiphysis particularly the secondary physis-of children with juvenile OCD and to compare these findings with the MRI findings of unaffected children. MATERIALS AND METHODS: Knee MRI examinations of 30 children (age range, 8 years 8 months to 13 years 4 months) with OCD and 30 matched control patients were evaluated for skeletal maturity; location of the OCD lesion, if present; secondary physeal [corrected] continuity; overlying chondroepiphysial integrity, contour, and width; signal intensity of subchondral bone; and secondary physeal [corrected] conspicuity. Variables were compared using chi-square tests. RESULTS: All children were skeletally immature. Condylar lesions were medial in 24 knees and lateral in six knees. All were in the middle one third, posterior one third, or middle and posterior thirds in the sagittal plane. The majority of lesions spanned the intercondylar and middle one third of the femoral condyle in the coronal plane (73%). There was a significant difference between secondary physeal [corrected] disruption in juvenile OCD condyles compared with unaffected condyles (p < 0.001) and control condyles (p < 0.001). Compared with unaffected and control condyles, the OCD group showed chondroepiphysial widening (p < 0.001) and subchondral bone edema (p < 0.001) on MRI. Neither chondroepiphysial integrity nor chondroepiphysial contour was significantly different between groups (p = 0.21, p = 0.31, respectively). CONCLUSION: MRI of children with OCD consistently showed secondary physis disruption, overlying chondroepiphysial widening, and subchondral bone edema. We suggest that disruption of normal endochondral ossification may be associated with juvenile OCD. PMID- 23096189 TI - Radiation dose estimation for prospective and retrospective ECG-gated cardiac CT angiography in infants and small children using a 320-MDCT volume scanner. AB - OBJECTIVE: The purpose of this study is to determine patient dose estimates for clinical pediatric cardiac-gated CT angiography (CTA) protocols on a 320-MDCT volume scanner. MATERIALS AND METHODS: Organ doses were measured using 20 metal oxide semiconductor field effect transistor (MOSFET) dosimeters. Radiation dose was estimated for volumetrically acquired clinical pediatric prospectively and retrospectively ECG-gated cardiac CTA protocols in 5-year-old and 1-year-old anthropomorphic phantoms on a 320-MDCT scanner. Simulated heart rates of 60 beats/min (5-year-old phantom) and 120 beats/min (1- and 5-year-old phantoms) were used. Effective doses (EDs) were calculated using average measured organ doses and International Commission on Radiological Protection 103 tissue weighting factors. Dose-length product (DLP) was recorded for each examination and was used to develop dose conversion factors for pediatric cardiac examinations acquired with volume scan mode. DLP was also used to estimate ED according to recently published dose conversion factors for pediatric helical chest examinations. Repeated measures and paired Student t test analyses were performed. RESULTS: For the 5-year-old phantom, at 60 beats/min, EDs ranged from 1.2 mSv for a prospectively gated examination to 4.5 mSv for a retrospectively gated examination. For the 5-year-old phantom, at 120 beats/min, EDs ranged from 3.0 mSv for a prospectively gated examination to 4.9 mSv for a retrospectively gated examination. For the 1-year-old phantom, at 120 beats/min, EDs ranged from 2.7 mSv for a prospectively gated examination to 4.5 mSv for a retrospectively gated examination. CONCLUSION: EDs for 320-MDCT volumetrically acquired ECG-gated pediatric cardiac CTA are lower than those published for conventional 16- and 64 MDCT scanners. PMID- 23096190 TI - Long-term follow-up of large atrial septal occluder (Amplatzer device) with cardiac MRI in a pediatric population. AB - OBJECTIVE: The purpose of this study is to evaluate the position and the progress of large Amplatzer septal occluder (ASO) devices relevant to adjacent cardiac structures in growing children using MRI. MATERIALS AND METHODS: Institutional review board approval for this study was obtained. Twenty-five children who underwent large ASO implantation were evaluated using MRI. All subjects were initially imaged 7 years earlier using the same protocol. Spatial and dynamic relationships between the ASO and the adjacent cardiac structures were compared to assess the progress over the 7-year growth span with respect to protrusion, contact, and extrinsic deformity of the mitral valve, the left atrial roof, the aortic annulus and root, and the ostia of adjacent veins. RESULTS: No long-term device-related complications were documented during follow-up. Impingement of the ASO into the opening of the right superior and inferior pulmonary veins and the superior and inferior vena cava resolved completely, compared with initial observations, in five of 16, three of three, five of 10, and three of nine patients, respectively, and significantly regressed in the remaining patients. The device's contact with the mitral valve and the left atrial roof and the aortic root deformity resolved in seven of 10, 11 of 20, and 10 of 18 cases, respectively. CONCLUSION: The distance between the ASO and the surrounding structures increases with time in growing children who require large ASO devices, likely decreasing the risk of long-term complications. PMID- 23096191 TI - Evaluation of renal artery in hypertensive patients by unenhanced MR angiography using spatial labeling with multiple inversion pulses sequence and by CT angiography. AB - OBJECTIVE: The purposes of this study were to determine the performance of a new unenhanced MR angiography (MRA) sequence, spatial labeling with multiple inversion pulses (SLEEK), with regard to its ability to present the renal arteries and to reveal renal artery disease in patients with secondary hypertension. SUBJECTS AND METHODS: Unenhanced MRA using SLEEK was performed on a 1.5-T MRI system for assessing renal arteries in 50 patients with hypertension. Then all patients underwent CT angiography (CTA) within 1-7 days. The ability to present the renal arteries and to reveal renal artery disease with SLEEK was evaluated by two experienced radiologists and was compared with CTA results using a joint reading performed in consensus. RESULTS: Forty-six patients with hypertension successfully underwent SLEEK MRA. A total of 119 renal arteries were assessed, including 86 normal arteries, 26 with stenoses, and seven with fibromuscular dysplasia on CTA. There was excellent correlation between SLEEK and CTA in presenting the degree of renal artery stenosis (r(s) = 0.851; p < 0.05). SLEEK was superior to CTA in revealing the third- and fourth-order segmental branches in the renal parenchyma (p < 0.05). SLEEK has the advantage of avoiding interference from vertebra, atherosclerotic plaques, and early venous system enhancement. CONCLUSION: Unenhanced MRA using SLEEK is a reliable diagnostic method for evaluating renal artery disease and revealing segmental branches in the renal parenchyma. It is relatively inexpensive and is not associated with renal complications. It can be used as an alternative to CTA for screening for renal artery disease, especially in patients with hypertension and renal insufficiency. PMID- 23096192 TI - Comparison of technical success and complications of percutaneous transhepatic cholangiography and biliary drainage between patients with and without transplanted liver. AB - OBJECTIVE: The purpose of this study is to compare technical success and complications of percutaneous transhepatic cholangiography (PTC) and percutaneous transhepatic biliary drainage (PTBD) between patients with and without transplanted liver. MATERIALS AND METHODS: Between 2007 and 2011, 89 PTCs, including 34 PTBDs, in 87 patients with transplanted liver were attempted, and 131 PTCs, including 118 PTBDs, in 126 patients without transplanted liver were attempted. Technical success, diameters of the bile ducts, fluoroscopy time, and complications were statistically compared between the two groups. RESULTS: The technical success rate of PTC for transplanted liver was significantly lower than that for nontransplanted liver (88.8% vs 98.5%; p = 0.004). Consequently, the technical success rate of PTBD for transplanted liver was also significantly lower than that for nontransplanted liver (75.0% vs 95.8%; p < 0.001). The average diameters of the first branches and second branches of the bile ducts of transplanted liver were significantly smaller than those of nontransplanted liver (5.8 +/- 3.4 mm vs 8.7 +/- 3.9 mm for the first branches [p < 0.001]; and 3.7 +/- 1.7 mm vs 5.8 +/- 2.4 mm for the second branches [p < 0.001]). No significant difference of fluoroscopy time of unilateral successful PTBD was observed (21.8 +/- 11.7 vs 19.3 +/- 12.9 min; p = 0.372), and no significant difference of overall complication rates was observed (8.0% vs 8.7%; p = 1.000) between transplanted and nontransplanted liver. CONCLUSION: The technical success rates of PTC and PTBD for transplanted liver are slightly lower than those for nontransplanted liver because the bile ducts are smaller. There is no significant difference in complication rate. PMID- 23096193 TI - Complication rates and effectiveness of uterine artery embolization in the treatment of symptomatic leiomyomas: a systematic review and meta-analysis. AB - OBJECTIVE: The purpose of this meta-analysis was to determine the rates of major complications, other associated adverse events, reintervention, and clinical improvement from studies reporting complications of uterine artery embolization (UAE) for the treatment of symptomatic leiomyomas. MATERIALS AND METHODS: PubMed, Medline, Embase, and Cochrane databases were searched for publications on the treatment of leiomyomas by UAE. Data pertaining to study characteristics, numbers of complications, symptomatic improvement, and reinterventions were collected by two readers. Pooled event rates were calculated using a random effects method. RESULTS: Fifty-four study populations met the inclusion criteria, yielding a total of 8159 patients. There were no reported deaths. Major complications occurred at a rate of 2.9% (95% CI, 2.2-3.8%). The rate of hysterectomy for resolution of a complication from UAE was 0.7% (0.5-0.9%), and the rate of readmission was 2.7% (1.9-3.7%). Multiple other specific complications were recorded including leiomyoma tissue passage (4.7% [3.9-5.7%]), deep venous thrombosis or pulmonary embolism (0.2% [0.2-0.4%]), and permanent amenorrhea (3.9% [2.7-5.3%]). Reintervention rates including repeat UAE, myomectomy, or hysterectomy calculated per patient-year occurred at 5.3% (4.2-6.4%) with follow up ranging from 0.25 to 5 years. Clinical symptomatic improvement ranged from 78% to 90%, with follow-up ranging from 0.25 to 2 years. CONCLUSION: Symptomatic uterine leiomyoma treatment by UAE is an effective procedure with a low rate of major complications supporting its use as an alternative to hysterectomy. PMID- 23096194 TI - Long-term effectiveness of ultrasound-guided laser ablation of hyperfunctioning parathyroid adenomas: present and future perspectives. AB - OBJECTIVE: Although surgery is the first-choice treatment of primary hyperparathyroidism (pHPT), some patients present with contraindications or refuse surgery. Data from alternative nonsurgical therapies are inconclusive. To study the long-term efficacy of laser ablation in the treatment of pHPT, we retrospectively reviewed six cases of laser-treated patients. MATERIALS AND METHODS: Six patients with pHPT were treated with laser ablation using a flat-tip technique. Energy was administered by means of one optic fiber placed into the parathyroid adenoma through a 21-gauge Chiba needle connected to a neodymium:yttrium-aluminum-garnet laser. The mean (+/- SD) delivered energy for all patients was 2.067 +/- 1440 J (range, 1000-4200 J). Treatment was fractionated in two (n = 2 patients) or in three (n = 1 patient) ultrasound guided sessions. Patients' serum parathyroid hormone (PTH) and calcium levels were checked periodically, with neck ultrasound performed. The mean duration of follow-up was 54 +/- 34 months (range, 12-84 months). RESULTS: Two months after laser ablation, serum PTH and calcium levels decreased in six and five patients, respectively. At the last follow-up examination, serum PTH and calcium levels were above the normal range in six and three patients, respectively. Three patients underwent surgery for persistent pHPT. Laser ablation therapy was safe and without permanent side effects. One patient reported transient dysphonia. CONCLUSION: Laser ablation produces a transient reduction of serum PTH and calcium levels but not a lasting resolution of hyperparathyroidism. Laser cannot be proposed as the definitive therapy of pHPT. Thus, studies aiming to identify therapeutic algorithms specific for parathyroid glands are needed to verify the utility of laser ablation in pHPT. PMID- 23096195 TI - Accuracy and value of breast ultrasound for primary imaging evaluation of symptomatic women 30-39 years of age. AB - OBJECTIVE: The purpose of this study was to determine the accuracy and value of breast ultrasound for primary imaging evaluation of women 30-39 years of age who present with focal breast signs or symptoms. METHODS: We identified all women 30 39 years of age who underwent imaging evaluation (ultrasound and mammography) at our institution between January 1, 2002, and August 31, 2006, for focal breast signs or symptoms. Each area of concern was designated a study case. Benign versus malignant outcomes were determined by biopsy or imaging surveillance and through linkage with a tumor registry with a minimum 24-month follow-up. Overall cancer yield, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of ultrasound and mammography were calculated. RESULTS: We identified 1208 cases in 954 patients. Outcomes were benign in 1185 of 1208 (98.1%) and malignant in 23 of 1208 (1.9%) cases. Sensitivities for ultrasound and mammography were 95.7% and 60.9%, respectively. Specificities for ultrasound and mammography were 89.2% and 94.4%, respectively. NPV was 99.9% for ultrasound and 99.2% for mammography. PPV was 13.2% for ultrasound and 18.4% for mammography. Mammography detected one additional malignancy in an asymptomatic area in a 32-year-old woman who was subsequently found to have a BRCA2 gene mutation. CONCLUSION: Breast imaging is warranted in women 30-39 years of age with focal signs or symptoms because of the small (1.9%) but real risk of malignancy. Ultrasound has high sensitivity (95.7%) and high NPV (99.9%) in this setting and should be the primary imaging modality of choice. The added value of adjunct mammography is low. PMID- 23096196 TI - Segmental breast calcifications. PMID- 23096197 TI - Physician impairment and professionalism. PMID- 23096199 TI - Genitourinary imaging: part 2, role of imaging in medical management of advanced renal cell carcinoma. AB - OBJECTIVE: Renal cell carcinoma (RCC) comprises 80-85% of all primary renal neoplasms. Knowledge of the genetic and molecular features of RCC and the advent of molecular targeted therapy have revolutionized the treatment of RCC in the past decade. This article will review the changing role of the radiologist in the management of advanced RCC, especially in terms of the new relevance of RCC subtypes, treatment-related changes on imaging, new tumor response criteria, and commonly encountered molecular targeted therapy-related toxicities. CONCLUSION: In this era of personalized cancer treatment, imaging has assumed a central role in treatment selection and follow-up of advanced RCC. PMID- 23096198 TI - Genitourinary imaging: part 1, congenital urinary anomalies and their management. AB - OBJECTIVE: Congenital urinary anomalies may be symptomatic or encountered during imaging for other clinical indications. The array of abnormalities is related to the embryologic stage at the time of the developmental insult, and these abnormalities result in a spectrum of conditions ranging from insignificant to incompatible with life. CONCLUSION: Understanding the implications of common congenital urinary anomalies is the key to detecting associated anomalies, initiating therapy, and avoiding both complications and unnecessary intervention. PMID- 23096200 TI - Contrast-enhanced MR angiography of cavopulmonary connections in adult patients with congenital heart disease. AB - OBJECTIVE: The purpose of this study is to evaluate combined time-resolved and high-spatial resolution contrast-enhanced MR angiography (MRA) for assessment of cavopulmonary connections in adult patients with congenital heart disease. MATERIALS AND METHODS: Twenty-eight adults with various surgical cavopulmonary connections (Glenn shunt and Fontan connection) underwent high-spatial-resolution contrast-enhanced MRA (voxel size, 1.95 mm(3); temporal resolution, 22 seconds) and time-resolved contrast-enhanced MRA (voxel size, 6.5-9.3 mm(3); temporal resolution, < 1.2 seconds). Ten patients had 2D phase contrast flow quantification measurements performed at the same setting. Two readers independently assessed anatomic dimensions of cavopulmonary connections (using high-spatial-resolution contrast-enhanced MRA) and pulmonary artery (PA) perfusion patterns (using time-resolved contrast-enhanced MRA). RESULTS: High spatial-resolution contrast-enhanced MRA yielded diagnostic-quality images for morphologic assessment of cavopulmonary connections in 27 of 28 (96%) patients. The anatomic dimensions (cross-sectional area) of the PA and cavopulmonary connections showed a wide variation (right PA, 0.99-5.67 cm(2); left PA, 0.80 5.69 cm(2); Glenn shunt, 0.93-6.94 cm(2); and Fontan connection, 1.25-6.67 cm(2)). The anatomic dimensions could be assessed with excellent interobserver agreement on high-spatial-resolution contrast-enhanced MRA (r = 0.895). Time resolved contrast-enhanced MRA yielded diagnostic-quality images in all patients and enabled characterization of PA perfusion via the superior vena cava as follows: preferential inflow to the right PA (n = 12), preferential inflow to the left PA (n = 5), and balanced inflow to the right and left PA (n = 11). In those patients who had technically successful flow quantification measurements, phase contrast data confirmed patency of the cavopulmonary connections. CONCLUSION: Combined time-resolved contrast-enhanced MRA and high-spatial-resolution contrast enhanced MRA allowed detailed morphologic and dynamic evaluation of cavopulmonary connections in adult patients with congenital heart disease. A wide variation in anatomic dimensions and perfusion patterns was confidently identified in this patient population. PMID- 23096201 TI - Hyperintense lesions on gadoxetate disodium-enhanced hepatobiliary phase imaging. AB - OBJECTIVE: The purpose of this article is to illustrate various focal hepatic lesions that may show hyperintensity on hepatobiliary phase images on gadoxetate disodium-enhanced MRI. CONCLUSION: Hyperintense lesions on gadoxetate disodium enhanced MRI include focal nodular hyperplasia (FNH) or FNH-like nodules, hepatocellular adenoma, dysplastic nodules, and hepatocellular carcinoma. Understanding the contrast enhancement patterns on hepatobiliary phase images and other imaging findings is important to ensure correct diagnosis. PMID- 23096202 TI - Perforated pyloroduodenal peptic ulcer and sonography. AB - OBJECTIVE: The purpose of this article is to illustrate the spectrum of sonographic findings in perforated pyloroduodenal peptic ulcer and discuss the potential role of sonography in the diagnosis. CONCLUSION: Although sonography is not the first-line investigation of choice in suspected perforated peptic ulcer, understanding of the characteristic appearances seen during general abdominal sonography may aid the reader in the diagnosis of this important and sometimes overlooked cause of nonspecific abdominal pain. This may shorten time to the diagnosis and ultimate surgical management. PMID- 23096203 TI - Anastomotic leak after robot-assisted laparoscopic radical prostatectomy: evaluation with MDCT cystography with multiplanar reformatting and 3D display. AB - OBJECTIVE: This article reviews the pattern of anastomotic leak after robot assisted laparoscopic radical prostatectomy (RALRP) on MDCT cystography with multiplanar reformatting and 3D display and discusses key surgical procedures to explain intraperitoneal leak and the incidence and clinical significance of anastomotic leak. CONCLUSION: RALRP is a minimally invasive surgery for localized prostate cancer, and its use has increased recently. Intraperitoneal extension of vesicourethral anastomotic leak after RALRP can occur, which is not associated with radical retropubic prostatectomy. MDCT cystography is a fast and accurate method for detection and evaluation of the extent of anastomotic leak after RALRP. PMID- 23096204 TI - Quantitative whole-body MRI in familial partial lipodystrophy type 2: changes in adipose tissue distribution coincide with biochemical improvement. AB - OBJECTIVE: Familial partial lipodystrophy type 2 (Online Mendelian Inheritance in Man no. 151660) is a systemic disorder characterized by regional lipoatrophy and lipohypertrophy, severe insulin resistance, and early cardiovascular death. At initial presentation, whole-body MRI allows the radiologist to accurately characterize patients with familial partial lipodystrophy and helps differentiate familial partial lipodystrophy from many other subtypes of lipodystophy. We present the findings of serial quantitative MRI analysis in two patients with familial partial lipodystrophy type 2 and outline the objective imaging changes that occur during medical therapy with oral rosiglitazone. CONCLUSION: Cervical adipose volume and visceral adipose area increased by 105% and 60% in the two patients and hepatic fat fraction decreased by 55% during a 21-month period of medical therapy. These changes coincided with a decrease in biochemical indexes of insulin resistance. Whole body quantitative MRI may therefore help to demonstrate the subclinical changes in fat deposition that occur as a result of novel treatment of familial partial lipodystrophy and with continued research may play a role in guiding the choice, duration, and intensity of novel medical therapy. PMID- 23096205 TI - Femoral and tibial torsion measurements with 3D models based on low-dose biplanar radiographs in comparison with standard CT measurements. AB - OBJECTIVE: The purpose of this study was to evaluate the interchangeability of femoral and tibial torsion measurements obtained with 3D models based on low-dose biplanar radiographs and standard CT measurements by testing the following two hypotheses: that there is excellent agreement between the two methods and that there is excellent interreader agreement. MATERIALS AND METHODS: Two independent readers used 3D models based on low-dose simultaneous biplanar radiographs and axial CT images to measure femoral and tibial torsion in 35 patients (mean age, 65 years; range, 46-89 years) with osteoarthritis of the knee who were to undergo prosthesis insertion. The two measurements were compared by means of Bland-Altman plots and descriptive statistics. Interreader agreement was quantified with intraclass correlation coefficients. RESULTS: The average differences between readers on the CT measurements were 1.3 degrees (range, 0 degrees -11 degrees ) for the femur and 1.5 degrees (range, 0 degrees -12 degrees ) for the tibia. The average differences for the measurements obtained with the 3D model were 0.1 degrees (range, 0 degrees -9 degrees ) for the femur and 0.8 degrees (range, 0 degrees -10 degrees ) for the tibia. The average differences between the two methods were 0 degrees (range, -5 degrees to 7 degrees ) for the femoral measurements and 3 degrees (range, -12 degrees to 5 degrees ) for the tibial measurements. Bland-Altman plots showed no relevant differences between the results of the two measurement modalities. Except for one measurement of femoral torsion and one measurement of tibial torsion, all results based on the 3D models were within the 95% limit of agreement (mean +/- 1.96 SD). Interreader agreement was statistically significant (p < 0.001) for all measurements with high intraclass correlation coefficients (> 0.9). CONCLUSION: Femoral and tibial torsion measurements obtained with 3D models based on biplanar radiographs are interchangeable with standard CT measurements in patients with osteoarthritis of the knee. PMID- 23096206 TI - Insufficiency and nondisplaced fractures of the talar head: MRI appearances. AB - OBJECTIVE: We present nondisplaced talar head fractures in two patient groups. CONCLUSION: Talar head insufficiency fractures should be considered in older patients, particularly perimenopausal women. Nondisplaced talar head fractures may occur in younger patients after trauma. PMID- 23096207 TI - Imaging of hand and wrist cysts: a clinical approach. AB - OBJECTIVE: Ganglion cysts are common hand masses. This article will answer three questions that the radiologist is often asked: A mass is palpable; is it a cyst? Pain or neurologic symptoms are present; are they related to a cyst? Surgery is being considered; where precisely are the cyst and its origin located? CONCLUSION: Ultrasound is often sufficient for assessing typical cysts. MRI is performed when atypical features or neurologic symptoms are present and in specific preoperative settings. PMID- 23096208 TI - Unenhanced MR angiography of renal arteries: 51 patients. AB - OBJECTIVE: The purpose of this research was to assess the feasibility and performance of an unenhanced 3D balanced steady-state free precession (SSFP) sequence, compared with contrast-enhanced MR angiography (CEMRA), which is the reference standard to detect and quantify renal artery stenoses (RAS). SUBJECTS AND METHODS: Fifty-one patients were included in this prospective study. Balanced SSFP sequence (Native) and CEMRA were performed using a 1.5-T magnet. Signal quality and stenosis grade were assessed per segment for renal arteries and for ostia of celiac trunk and superior mesenteric artery (SMA). We compared signal quality of Native and CEMRA. Sensitivity, specificity, negative predictive value (NPV), and accuracy were also calculated. RESULTS: Evaluation involved 114 renal arteries, 51 celiac trunks, and 51 SMAs. By use of CEMRA, 20 significant stenoses were found for renal arteries, 10 stenoses and three occlusions for celiac trunk, and three stenoses for SMA. At artery-by-artery analysis, sensitivity, specificity, accuracy, and NPV of the balanced SSFP sequence in detecting stenosis were respectively 85%, 96%, 94%, and 96% for renal arteries; 100%, 97%, 98%, and 100% for celiac trunk; and 100%, 100%, 100%, and 100% for SMA. No significant difference of signal quality was found for the entire examination and for the different segments evaluated except for hilar and intrarenal branches, which showed better signal quality on balanced SSFP sequence. CONCLUSION: The NPV results in our study suggest that unenhanced balanced SSFP MR angiography can be the first-choice imaging method to exclude RAS in patients at high risk of nephrogenic systemic fibrosis. However, when stenosis is found, other imaging modalities are necessary for better estimation. PMID- 23096209 TI - Comprehensive MDCT evaluation of patients with suspected May-Thurner syndrome. AB - OBJECTIVE: The purpose of this essay is to introduce the MDCT protocol and interpretation techniques for optimal evaluation of patients with suspected May Thurner syndrome. CONCLUSION: May-Thurner syndrome is always the working diagnosis when a patient presents with unilateral left lower limb swelling without signs of infection. MDCT is useful for fast, comprehensive evaluation of the vascular system to determine whether May-Thurner syndrome or an alternative condition is present. PMID- 23096210 TI - Automatic bone removal technique in whole-body dual-energy CT angiography: performance and image quality. AB - OBJECTIVE: The purpose of this study was to evaluate the efficiency of automatic bone removal in dual-energy CT angiography (CTA) of the trunk. SUBJECTS AND METHODS: Nineteen patients underwent dual-energy CTA of the trunk (tube A, 140 kV; tube B, 100 kV). In addition to the dual-energy dataset, an image equivalent to that of a standard 120-kV single-energy examination was generated with both tubes. Automated bone segmentation was performed on both datasets, and the results were analyzed. The time required for and subjective image quality of the maximum intensity projections (MIPs) generated were evaluated. RESULTS: Errors in bone segmentation were found for 1.5% of bones on dual-energy images and 12.4% of bones on single-energy images (p < 0.01). The most important differences were found in the rib cage, sternum, and pelvis. The times required for postprocessing of MIPs were similar for the dual-energy (113.5 seconds) and single-energy (106.8 seconds) techniques. The subjective image quality of the arteries was considered better for dual-energy CTA (4.5 points) than for single-energy CTA (4.1 points) owing to false cutoff of vessels during the bone removal process on the single energy images (p = 0.026). CONCLUSION: For CTA of the trunk, the dual-energy postprocessing capabilities for 3D visualization are superior to the threshold based bone removal of single-energy CT. Dual-energy CTA can generate boneless MIP images of substantial quality. PMID- 23096211 TI - MRI-guided vacuum-assisted breast biopsy performed at 3 T with a 9-gauge needle: preliminary experience. AB - OBJECTIVE: The purpose of this study was to test the feasibility of 3-T vacuum assisted large-bore core biopsy of lesions detected with MRI of the breast. CONCLUSION: Our preliminary experience revealed that 3-T MRI-guided vacuum assisted biopsy is a safe and effective interventional method that enables accurate biopsy of lesions identified with a 3-T MRI system. Artifacts on 3-T images did not result in failed biopsy; therefore, 3-T MRI systems can be used reliably for both diagnostic and interventional breast studies. PMID- 23096212 TI - Who should notify an emergency department patient when a preliminary radiologic reading is found to be incorrect? PMID- 23096213 TI - Is there a difference between "standard of care" and "standard of practice"? PMID- 23096214 TI - Liver lesion characterization: the wrong choice of contrast agent can mislead the diagnosis of hemangioma. PMID- 23096215 TI - Vacuum phenomenon on CT and fluid on MRI in degenerative disks. PMID- 23096216 TI - Haller index in patients with pectus excavatum. PMID- 23096217 TI - Breast lesion excision system biopsy: the learning curve. PMID- 23096218 TI - Prognostic significance of RACGAP1 mRNA expression in high-risk early breast cancer: a study in primary tumors of breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial. AB - PURPOSE: RACGAP1 is a Rac GTPase-activating protein involved in cell growth regulation, cell transformation and metastasis. The aim of the present study was to explore the prognostic and/or predictive significance of RACGAP1 mRNA expression on disease-free survival (DFS) and overall survival (OS) in high-risk early breast cancer patients and compare it to that of Ki67 protein expression and to the Nottingham prognostic index (NPI). METHODS: A total of 595 high-risk breast cancer patients were treated in a two-arm trial evaluating postoperative dose-dense sequential chemotherapy with epirubicin followed by CMF with or without paclitaxel. RNA was extracted from 314 formalin-fixed paraffin-embedded primary tumor tissue samples followed by one-step quantitative RT-PCR for assessing RACGAP1 mRNA expression. RESULTS: High RACGAP1 mRNA expression (above the median) was associated with poor DFS (log-rank, p = 0.002) and OS (p < 0.001). High histological grade, as well as high Ki67 protein expression, was more frequent in the high-expression group of RACGAP1. Results of the Cox multivariate regression analysis revealed that high RACGAP1 mRNA expression independently predicted poor overall survival (Wald's p = 0.008). High Ki67 protein expression was also an adverse prognostic factor for death (p = 0.016), while high NPI score values were not. CONCLUSIONS: High RACGAP1 mRNA expression, as assessed by qRT-PCR, was found to be of adverse prognostic significance in high-risk early breast cancer patients treated with dose-dense sequential chemotherapy. The utility of RACGAP1 mRNA expression in patient selection for treatment with aggressive chemotherapy regimens should be further explored and validated in larger cohorts. PMID- 23096219 TI - Effect of topical chamomile on immunohistochemical levels of IL-1beta and TNF alpha in 5-fluorouracil-induced oral mucositis in hamsters. AB - PURPOSE: The aim of the present study was to evaluate the effect of topical chamomile and corticosteroid treatment on the profile of tissue cytokines (IL 1beta and TNF-alpha) in 5-fluorouracil-induced oral mucositis in hamsters. METHODS: Thirty-six hamsters were randomly separated into three groups (12 animals each): Group I--without treatment (control); Group II-treatment with chamomile (Ad-Muc((r))); and Group III--treatment with corticosteroid (betamethasone elixir- Celestone((r))). The animals received an intraperitoneal injection of 5--fluorouracil on Days 0 and 2. On Days 3 and 4, the buccal mucosa was scratched and therapy was initiated on Day 5. Three animals from each group were killed on Days 0, 5, 10, and 14 and the buccal mucosa was removed. The streptavidin-biotin complex method was used to delineate the in situ distribution, localization, and semiquantitative analysis of IL-1beta and TNF alpha. Data from the semiquantitative analysis of immunohistochemical staining were comparatively analyzed using the Kruskal-Wallis test, followed by Dunn's multiple comparisons test. RESULTS: The distribution and localization of IL-1beta and TNF-alpha immunolabeling were similar. These proteins exhibited a diffuse pattern distributed throughout the connective tissue. The epithelium and adipose tissue were negative for both proteins. The semiquantitative analysis revealed that immunolabeling of IL-1beta and TNF-alpha increased in all groups with the development of mucositis. On Day 10 (period of peak mucositis), the group treated with chamomile had lower scores for both pro-inflammatory cytokines. CONCLUSIONS: Treatment with topical chamomile reduced the tissue levels of IL-1beta and TNF alpha, thereby demonstrating anti-inflammatory action in oral mucositis in hamsters. PMID- 23096220 TI - The importance of stochastic transitions for the origin of life. AB - We discuss the origin of life in terms of an RNA World scenario in which the creation of autocatalytic sequences is the key step. Our computational models illustrate that life arises by a rare stochastic event that occurs due to spatially localized concentration fluctuations. This allows the chemical system to jump from a non-living state with very low ribozyme concentration to a living state that is controlled by ribozymes. Once the living state is established locally, it can spread deterministically through the rest of the system. These are generic features also possessed by more complex models with a greater degree of chemical realism. PMID- 23096222 TI - Does clinical rehabilitation impose sufficient cardiorespiratory strain to improve aerobic fitness? AB - OBJECTIVE: To investigate the cardiorespiratory strain experienced by patients over a day and during different types of rehabilitation therapies during a clinical rehabilitation programme. In addition, to investigate the use of the Borg scale as an instrument to monitor exercise intensity. DESIGN: An observational, cross-sectional study. SETTING: Rehabilitation centre in the Netherlands. PARTICIPANTS: Eleven people after stroke (age range 20-71 years), 9 people with a lower limb amputation (age range 21-66 years) and 11 people with a spinal cord injury (age range 28-65 years). All participants were inpatients undergoing clinical rehabilitation. MAIN OUTCOME MEASURES: Frequency distribution of percentage heart rate reserve (%HRR) and length of time heart rate (HR) > 40%HRR over one day, and mean %HRR, length of time HR > 40%HRR and HR > 70%HRR during different types of rehabilitation therapies were compared with the American College of Sports Medicine guidelines for achieving an aerobic training effect. The correlation coefficient between the Borg scale score and %HRR was assessed. RESULTS: Patients' mean HR was 114 min/day (standard deviation 92) > 40%HRR, of which 1 h was spent in therapy. In 5 out of 10 rehabilitation therapies (fitness, hydrotherapy, walking group, wheelchair group and cycling/handbike group) a mean HR > 40%HRR was reached and more than half of the time was spent > 40%HRR. A moderate correlation (R = 0.56) was found between Borg scale score and %HRR. All outcome measures showed large variation between and within patients. CONCLUSION: In general, patients in a clinical rehabilitation programme experience adequate cardiorespiratory strain to potentially induce an aerobic training effect. The large variation in cardiorespiratory strain, however, necessitates individual monitoring to ensure proper exercise intensity. The Borg scale was shown to be of limited value for this monitoring, and therefore the use of HR monitors during rehabilitation should be considered. PMID- 23096221 TI - Birt-Hogg-Dube: tumour suppressor function and signalling dynamics central to folliculin. AB - The cellular function of folliculin (FLCN) is a mystery that still needs to be solved. It is known that mutation of FLCN can predispose Birt-Hogg-Dube (BHD) patient's to renal cell carcinoma , renal and lung cysts, as well as skin fibrofolliculomas. FLCN has been classed as a tumour suppressor, but it is probable that cystic and the skin manifestations do not occur as a consequence of FLCN loss of heterozygosity. Discovery that FLCN is a direct substrate of AMP dependent protein kinase (AMPK) placed FLCN on the cell signalling map, downstream of AMPK. This breakthrough suggested that FLCN might be involved in cell energy homeostasis. Over these more recent years, BHD research has become much more complicated and interesting from a cell signalling perspective. Folliculin has been linked to numerous cell pathways that are known to cause cancer, involving cell growth, metabolism, cell adhesion, cell motility, cytokinesis, and cell survival. The collective evidence implies that FLCN may have a broader housekeeping role in the cell. Of particular importance, FLCN was recently been reported to have guanine exchange factor activity towards the small G protein Rab35 and implicates FLCN in vesicular trafficking and/or membrane sorting. This newer discovery will undoubtedly help in the continued challenge of solving the signalling puzzle that shrouds FLCN function. PMID- 23096224 TI - Key lipid oxidation products can be used to predict sensory quality of fish oils with different levels of EPA and DHA. AB - Despite its many health benefits, many consumers avoid fish oil supplements due to fishy tastes and odors. Common chemical measures of oxidation have little correlation with sensory properties, making it difficult to determine the sensory quality of fish oil without the use of an expensive sensory panel. Here we investigate an alternative method to assess oxidation using solid phase microextraction and gas chromatography-mass spectrometry. Fish oils containing different amounts of eicosapentaenoic acid and docosahexaenoic acid were oxidized, and headspace volatiles were monitored over time and compared to sensory evaluations by a taste panel. Peroxide value and anisidine value were also measured. Sensory panel scores and headspace volatile data were analyzed using principal component analysis and linear regression to identify key volatiles responsible for changes in sensory degradation of oils over time. A total of eight compounds were identified, primarily aldehydes and ketones. By monitoring these volatiles, it may be possible to create a simple method to assess oxidation in fish oils that correlates well with sensory properties of the oil without the use of a sensory panel. PMID- 23096226 TI - [From the expert's office: acute acoustic trauma induced by burst of a food carton package?]. PMID- 23096223 TI - High serum apolipoprotein E determines hypertriglyceridemic dyslipidemias, coronary disease and apoA-I dysfunctionality. AB - The relevance of serum apolipoprotein E (apoE) levels to two hypertriglyceridemic dyslipidemias has not been clarified. We explored, in a cross-sectional (and short-term prospective) evaluation, the independent relationship of serum apoE to the atherogenic dyslipidemia, hypertriglyceridemia with elevated apoB (HtgB) and to apoA-I dysfunctionality, previously shown in Turkish adults to be independent of apoE genotype. Serum apoE concentrations were measured by immunonephelometry in 1,127 middle-aged adults. In multivariable regression analysis, apoE concentrations showed log-linear associations with apoB and apoA-I levels, waist circumference, independent of C-reactive protein (CRP), homeostatic model assessment (HOMA) index and other confounders. The likelihood of atherogenic dyslipidemia and of HtgB roughly tripled per 1-SD increment in apoE concentrations, additively to apoE genotype, HOMA, apoA-I, CRP concentrations and waist circumference; yet apoA-I, protective against atherogenic dyslipidemia, appeared to promote HtgB, a finding consistent with apoA-I dysfunctionality in this setting. Each 1-SD increment in the apoE level was moreover, associated in both genders with MetS (at OR 1.5), after adjustment for sex, age, apoB, apoA-I and CRP, or for apoE genotypes. Circulating apoE predicted in both genders age adjusted prevalent and incident coronary heart disease (CHD), independent of apoE genotype and CRP (OR 1.32 [95 % CI 1.11; 1.58]). To conclude, in a general population prone to MetS, elevated apoE concentrations are strongly linked to HtgB and atherogenic dyslipidemia, irrespective of apoE genotype, are associated with MetS and CHD. Excess apoE reflects pro-inflammatory state and likely autoimmune activation. PMID- 23096227 TI - [Food hypersensitivity]. PMID- 23096228 TI - Adverse effects of 2,2',4,4'-tetrabromodiphenyl ether on semen quality and spermatogenesis in male mice. AB - 2,2',4,4'-Tetrabromodiphenyl ether (BDE47) is an environmental contaminant. To determine the reproductive toxicity, we studied groups of adult male mice and found that the rate of sperm capacitation was decreased significantly in three BDE47-exposed groups (0.0015, 0.045 and 30 mg kg(-1) day(-1)). Sperm motility parameters (MOT, PRO, VCL and BCF) after capacitation were also declined in treated groups. Moreover, exposure to BDE47 at concentrations of >=0.045 mg kg( 1) day(-1) caused increased germ cell loss and apoptosis in some seminiferous tubules. Our results suggest that short-term exposure to low-dose BDE47 may have adverse effects on semen quality and spermatogenesis in adult male mice. PMID- 23096229 TI - Dysfunction of large-conductance Ca2+-activated K+ channels in vascular: risks developed in fetal origins. PMID- 23096230 TI - Home blood pressure variability on one occasion is a novel factor associated with arterial stiffness in patients with type 2 diabetes. AB - Recent studies have suggested that not only mean blood pressure but also variability in blood pressure might be related to cardiovascular disease. The aim of this study was to investigate the association between home blood pressure variability on one occasion and markers of arterial stiffness in patients with type 2 diabetes. We investigated the relationship between the s.d. of clinic- or home-measured systolic blood pressure on one occasion and pulse wave velocity (PWV) in 332 patients with type 2 diabetes, and we evaluated whether the SD of clinic- or home-measured systolic blood pressure on one occasion was an independent determinant of PWV by multivariate linear regression analysis, after adjustment for known risk factors for arterial stiffness, including sex, age, duration of diabetes, body mass index, hemoglobin A1c, serum total cholesterol, triglycerides, smoking status, drinking alcohol, presence of antihypertensive medication, average systolic blood pressure and heart rate. Age, average morning home-measured systolic blood pressure, heart rate and PWV (r=0.259, P<0.0001) were positively correlated with the s.d. of morning home blood pressure on one occasion. Multiple regression analysis demonstrated that age, average morning home-measured systolic blood pressure (P=0.0019), heart rate and the s.d. of morning home-measured systolic blood pressure on one occasion (P=0.0159) were independently associated with PWV. In conclusion, home blood pressure variability on one occasion was correlated with PWV, independent of other known risk factors, in Japanese patients with type 2 diabetes. PMID- 23096231 TI - The occurrence rate of cerebrovascular and cardiac events in patients receiving antihypertensive therapy from the post-marketing surveillance data for valsartan in Japan (J-VALID). AB - It is well known that blood pressure (BP) management reduces the incidence of cerebrovascular and cardiovascular events. However, it is unclear how many of these events occur in hypertensive patients who receive pharmacological treatment. The aim of this survey was to evaluate the occurrence rate of both types of events in patients receiving valsartan-based treatment. Of 30 366 patients treated with valsartan, 28 356 patients were observed for 2.93 years. Antihypertensive drugs other than valsartan were used in 56.8% of patients. After the administration of valsartan, the systolic and diastolic BP significantly decreased from 161.1+/-19.1/90.4+/-13.1 to 139.9+/-18.1/79.6+/-11.9 mm Hg. Cerebrovascular events were observed in 550 patients (1.94%, 9.29/1000 patient years), and cardiac events were observed in 576 patients (2.03%, 9.73/1000 patient-years). A comparative analysis of the hazard ratios for cerebrovascular and cardiac events according to the BP level at the endpoint showed a BP dependent reduction of risk for cerebrovascular events, and the change in risk exhibited a J-curve phenomenon in the relationship between cardiac events and systolic BP. The J-curve phenomenon was not observed in patients aged <75 years, but it was observed for the systolic BP in patients aged ?75 years. Adverse drug reactions were observed in 1925 of 28 420 patients (6.77%). This post-marketing surveillance data for valsartan showed the outcomes for treated hypertensive patients in a large population in Japan who were followed for up to 3 years. These data will add important knowledge regarding the treatment of hypertension in Japan. PMID- 23096232 TI - DNA damage and oxidative status in newly diagnosed, untreated, dipper and non dipper hypertensive patients. AB - DNA damage occurs more often in hypertensive patients than in non-hypertensive individuals. We sought to investigate lymphocyte DNA damage and total antioxidant status (TAS) levels in patients with dipper hypertension (DH) and non-dipper hypertension (NDH). Thirty-three patients with NDH (NDH group), 31 patients with DH (DH group) and 20 healthy volunteers (control group) were included in the study. Measurements from ambulatory blood pressure monitoring were obtained for all subjects. DNA damage was assessed in peripheral lymphocytes by comet assay, and plasma TAS levels were determined using an automated measurement method. The mean DNA damage value of the NDH group was higher than that of both the DH and control groups (P=0.002 and P<0.001, respectively). The mean DNA damage value of the DH group was higher than that of the control group (P<0.001). The mean TAS level of the NDH group was lower than that of both the DH and control groups (P=0.001 and P<0.001, respectively), and the mean TAS level of the DH group was lower than that of the control group (P<0.001). DNA damage was negatively associated with TAS level (r=-0.692, P<0.001) and positively associated with high sensitive c-reactive protein level (r=0.315, P=0.012). DNA damage increased in the NDH group compared with both the DH group and control group. This condition may be related to increased oxidative stress in the NDH group compared with the DH and control groups. PMID- 23096233 TI - Upregulation of catalase and downregulation of glutathione peroxidase activity in the kidney precede the development of hypertension in pre-hypertensive SHR. AB - Although oxidative stress has been implicated in the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs), there is little information on the levels of primary antioxidant enzymes status (AOEs) in pre-hypertensive SHR. This study therefore determined the activities of primary AOEs and their mRNA levels, levels of hydrogen peroxide (H2O2), malondialdehyde (MDA) and total antioxidant status (TAS) in whole kidneys of SHR and age-matched Wistar-Kyoto (WKY) rats aged between 2 and 16 weeks. Compared with age-matched WKY rats, catalase (CAT) activity was significantly higher from the age of 2 weeks (P<0.001) and glutathione peroxide (GPx) activity was lower from the age of 3 weeks (P<0.001) in SHR. CAT mRNA levels were significantly higher in SHR aged 2, 4, 6 and 12 weeks. GPx mRNA levels were significantly lower in SHR at 8 and 12 weeks. Superoxide dismutase activity or its mRNA levels were not different between the two strains. H2O2 levels were significantly lower in SHR from the age of 8 weeks (P<0.01). TAS was significantly higher in SHR from the age of 3 weeks (P<0.05). MDA levels were only significantly higher at 16 weeks of age in the SHR (P<0.05). The data suggest that altered renal CAT and GPx mRNA expression and activity precede the development of hypertension in SHR. The raised CAT activity perhaps contributes to the higher TAS and lower H2O2 levels in SHR. In view of these findings, the precise role of oxidative stress in the pathogenesis of hypertension in SHR needs to be investigated further. PMID- 23096234 TI - Rationale, study design, baseline characteristics and blood pressure at 16 weeks in the HONEST Study. AB - On the basis of the studies that investigated the relationship between baseline clinic blood pressure (CBP) or home blood pressure (HBP) values and cardiovascular (CV) events, HBP has been reported to have a stronger prognostic ability. However, few studies have compared the prognostic ability of on treatment CBP and HBP. The relationship between on-treatment HBP, measured twice in the morning and twice at bedtime, and CV events was investigated in over 20 000 patients in the HONEST (Home blood pressure measurement with Olmesartan Naive patients to Establish Standard Target blood pressure) Study, a prospective, 2 year observational study of treatment with an angiotensin receptor blocker, olmesartan (OLM), in OLM-naive hypertensive patients. This report summarizes the study protocol, the baseline characteristics of the patients and CBP and HBP at 16 weeks. A total of 22 373 patients were registered across Japan; baseline data from 22 162 patients were collected. Baseline HBP (mean+/-s.d.) in the morning (the first measurement) was 151.6+/-16.4/87.1+/-11.8 mm Hg and at bedtime was 144.3+/-16.8/82.8+/-11.9 mm Hg, whereas CBP was 153.6+/-19.0/87.1+/-13.4 mm Hg. At 16 weeks, morning HBP was 135.0+/-13.7/78.8+/-9.9 mm Hg and bedtime HBP was 129.7+/-13.8/74.7+/-10.1 mm Hg, whereas CBP was 135.6+/-15.4/77.6+/-10.9 mm Hg. The follow-up period for each patient ends on 30 September 2012. The HONEST Study is expected to provide evidence showing the relationship between baseline and on treatment CBP and HBP levels (both first and second measurements) and CV events. PMID- 23096235 TI - Mineralocorticoid receptors/epithelial Na(+) channels in the choroid plexus are involved in hypertensive mechanisms in stroke-prone spontaneously hypertensive rats. AB - Increase in cerebrospinal fluid (CSF) Na(+) concentration ([Na(+)]) precedes hypertension and is a key step in the development of salt-induced hypertension. In the choroid plexus (CP), epithelial Na(+) channels (ENaCs) have an important role in Na(+) transport from the blood into the CSF. However, it remains unknown whether the mineralocorticoid receptors (MR)/ENaCs pathway in the CP of stroke prone spontaneously hypertensive rats (SHRSP) is involved in neural mechanisms of hypertension. Therefore, we examined the role of the MR/ENaCs pathway in the CP in the development of hypertension in SHRSP associated with an increase in CSF [Na(+)]. As a marker of MR activation, serum/glucocorticoid-inducible kinase 1 (Sgk1) expression levels in the CP were measured and found to be greater in SHRSP than in Wistar-Kyoto (WKY) rats. CSF [Na(+)] levels were also higher in SHRSP than in WKY rats. In SHRSP, high-salt intake (8%) increased blood pressure and urinary norepinephrine excretion compared with those in animals fed a regular salt diet (0.5%) for 2 weeks. Furthermore, the expression levels of MR, Sgk1 and ENaCs in the CP and the increase in CSF [Na(+)] were greater in SHRSP fed a high salt diet than in those fed a regular salt diet. These alterations were attenuated by intracerebroventricular infusion of eplerenone (10 MUg kg(-1) per day), except for alpha-ENaC and beta-ENaC. We conclude that activation of the MR/ENaCs pathway in the CP contributes to hypertension via an increase in CSF [Na(+)], thereby exaggerating salt-induced hypertension with sympathetic hyperactivation in SHRSP. PMID- 23096236 TI - Brief report: Focused transthoracic echocardiography training in a cohort of Canadian anesthesiology residents: a pilot study. AB - PURPOSE: Bedside transthoracic echocardiography (TTE) is useful for rapid assessment and treatment of hemodynamic disturbances. Transthoracic echocardiography is not standard in Canadian anesthesia training even though undifferentiated hemodynamic disturbances are common in the perioperative setting. The objectives of this pilot study were to determine 1) whether it is feasible to implement a focused bedside TTE curriculum within core anesthesiology training, 2) whether changes could be detected and quantified following the program of study, and 3) whether curriculum implementation might lead to a significant increase in anesthesiology residents' TTE knowledge-base. METHODS: In this single-centre cohort pilot investigation, anesthesiology residents at Queen's University received focused bedside TTE training during the winter of 2011. The curriculum consisted of four three-hour sessions with both didactic and practical components. Pre- and post-curriculum examinations were administered, and examination results were compared using non-parametric tests. The primary outcome was the difference in mean pre- and post-curriculum examination scores. RESULTS: Ten participants completed pre- and post-curriculum examinations. Four residents were unable to participate in the curriculum but served as controls. Mean pretest scores (out of 50) were similar between the two groups (participants 23.9 vs controls 23.5; P = 0.83, Mann-Whitney U). Mean scores improved by 13.0 points following intervention but improved by only 1.3 points for controls, (P = 0.009, Mann-Whitney U). CONCLUSION: This pilot investigation suggests that implementation of a focused bedside TTE curriculum within anesthesia training is feasible, quantifiable, and effective for increasing anesthesia residents' TTE knowledge-base. This pilot study suggests that further investigation is warranted to determine the impact of this perioperative TTE curriculum. PMID- 23096237 TI - Protective effects of a novel sea buckthorn wine on oxidative stress and hypercholesterolemia. AB - We developed a novel sea buckthorn wine containing significant in vitro free radical-scavenging activity. High-performance liquid chromatographic analysis of the sea buckthorn wine revealed that it contains high rutin, myricetin and quercetin levels compared to Cabernet Shiraz wine. In this study, we evaluated the protective effects of sea buckthorn wine against phorone-induced oxidative stress and high-cholesterol diet induced hypercholesterolemia in male LACA mice. Oral administration of sea buckthorn wine increased the redox ratio accompanied by reduction of oxidized glutathione levels leading to attenuation of phorone induced oxidative stress. Furthermore, the sea buckthorn wine supplementation reduced hepatic lipid peroxidation and increased the superoxide dismutase activity indicating improved resistance to oxidative stress. In addition, high cholesterol-fed mice administered with sea buckthorn wine exhibited a 197% increase in the HDL-C/LDL-C ratio compared to high-cholesterol diet treated mice. These studies provide important evidence that sea buckthorn wine exerts protective effects against oxidative stress and hypercholesterolemia. PMID- 23096238 TI - Bombesin receptor regulation of emotional memory. AB - Mammalian bombesin-like peptides neuromedin B (NMB) and gastrin-releasing peptide (GRP) act by activating NMB receptors (NMBR, BBl) and GRP receptors (GRPR,BB2), respectively. These two bombesin receptors are members of the G-protein-coupled receptor (GPCR) superfamily.In the brain, NMBR and GRPR are highly expressed in the brain areas involved in memory processing and emotional responses, such as the hippocampus and the amygdaloid nuclei. An increasing number of pharmacological and genetic studies in rodents indicate that NMBRs and GRPRs in brain regions including the dorsal hippocampus,the nucleus tractus solitarius, the basolateral amygdala,and cortical areas, regulate memory formation and expression, particularly for memories related to emotionally arousing tasks. GRPR signaling interacts with multiple protein kinase pathways as well as with other neurotransmitter,hormone, and growth factor systems in influencing memory formation. Together with evidence from human studies, the findings from rodent experiments suggest that bombesin receptors may be therapeutic targets in brain disorders involving memory dysfunction and anxiety. PMID- 23096239 TI - Preponderance of evidence proves "big" weights optimize hypertrophic and strength adaptations. PMID- 23096242 TI - [Globalization of health policies; JCR SCI-E 2011 report is a source of happiness]. PMID- 23096240 TI - Development of fibroblast-seeded collagen gels under planar biaxial mechanical constraints: a biomechanical study. AB - Prior studies indicated that mechanical loading influences cell turnover and matrix remodeling in tissues, suggesting that mechanical stimuli can play an active role in engineering artificial tissues. While most tissue culture studies focus on influence of uniaxial loading or constraints, effects of multi-axial loading or constraints on tissue development are far from clear. In this study, we examined the biaxial mechanical properties of fibroblast-seeded collagen gels cultured under four different mechanical constraints for 6 days: free-floating, equibiaxial stretching (with three different stretch ratios), strip-biaxial stretching, and uniaxial stretching. Passive mechanical behavior of the cell seeded gels was also examined after decellularization. A continuum-based two dimensional Fung model was used to quantify the mechanical behavior of the gel. Based on the model, the value of stored strain energy and the ratio of stiffness in the stretching directions were calculated at prescribed strains for each gel, and statistical comparisons were made among the gels cultured under the various mechanical constraints. Results showed that gels cultured under the free-floating and equibiaxial stretching conditions exhibited a nearly isotropic mechanical behavior, while gels cultured under the strip-biaxial and uniaxial stretching conditions developed a significant degree of mechanical anisotropy. In particular, gels cultured under the equibiaxial stretching condition with a greater stretch ratio appeared to be stiffer than those with a smaller stretch ratio. Also, a decellularized gel was stiffer than its non-decellularized counterpart. Finally, the retained mechanical anisotropy in gels cultured under the strip-biaxial stretching and uniaxial stretching conditions after cell removal reflected an irreversible matrix remodeling. PMID- 23096243 TI - Therapeutic effect of aqueous extract from Ecliptae herba on bone metabolism of ovariectomized rats. AB - OBJECTIVE: Ecliptae herba (EH) has long been used in China to strengthen bones. Accumulating evidence indicates that EH may have antiosteoporotic effects. The aim of this study was to evaluate the effects of aqueous EH extract (EHE) on rats that had osteoporosis-like features induced by ovariectomy, using aqueous Fructus Ligustri Lucidi extract as positive control agent. METHODS: Three-month-old female rats that underwent ovariectomy were treated with EHE (1.4 g/kg per day). After 12 weeks, bone mineral density and bone histomorphometric indices of tibiae were measured. Protein and messenger RNA expressions of osteoprotegerin and receptor activator of nuclear factor kappa-B ligand (RANKL) in tibiae were evaluated by immunohistochemistry and in situ hybridization. In addition, serum concentrations of osteocalcin, interleukin-1beta, interleukin-6 (IL-6), calcitonin (CT), and parathyroid hormone were determined by enzyme-linked immunosorbent assay. RESULTS: EHE treatment prevented body weight gain and loss of uterine wet weight in ovariectomized rats. It remarkably increased bone mass in ovariectomized rats compared with ovariectomized controls. EHE treatment significantly down-regulated RANKL expression in tibiae from ovariectomized rats compared with controls; however, it had no significant effect on osteoprotegerin expression. In addition, EHE treatment significantly reduced serum IL-6 levels and remarkably increased CT levels but had no effect on parathyroid hormone. CONCLUSIONS: EHE increases bone mass in ovariectomized rats by inhibiting bone loss: down-regulated RANKL expression in tibiae and IL-6 level in serum, and up regulated CT level in serum. This suggests that EHE may be developed as an alternative therapeutic agent for osteoporosis induced by postmenopause. PMID- 23096244 TI - Prevalence, risk factors, and predictors of pelvic organ prolapse: a community based study. AB - OBJECTIVE: This study aimed to determine the prevalence of pelvic organ prolapse (POP) in a village in East Lebanon and to evaluate related risk factors and clinical predictors. METHODS: Five hundred four ever-married women, aged 15 to 60 years, were interviewed and underwent physical and pelvic examinations and laboratory testing. Prolapse was determined according to a simplified version of the POP quantification system. RESULTS: Two hundred fifty-one (49.8%) women had clinically significant POP. When stratified by life decade, POP prevalence was 20.4% for women aged 20 to 29 years, 50.3% for women aged 30 to 39 years, 77.2% for women aged 40 to 49 years, and 74.6% for women aged 50 to 59 years, suggesting a plateau in prevalence in the decade after menopause. Clinically significant POP was found in 3.6% of nulliparous, 6.5% of primiparous, 22.7% of secondiparous, 32.9% of triparous, and 46.8% of tetraparous women. Increasing age, increasing vaginal parity, and a body mass index higher than 24 kg/m were found to be significant risk factors for POP, with relative risks of 1.09 (P < 0.001), 2.31 (P < 0.0001), and 1.62 (P = 0.048) respectively. Combined clinical symptoms of pelvic heaviness, urinary disturbances, and a feeling of bulge in the vagina were predictive of POP. CONCLUSIONS: Our findings suggest that cost efficient interventions to reduce the burden of POP in this and similar remote communities include the following: family planning awareness campaigns focusing on the risks of grand multiparity; nutritional education and weight management programs to help reduce the progression of POP before the age of menopause; and consideration of symptom-based screening to identify affected women who might benefit from a referral to specialty care at a tertiary care center. PMID- 23096246 TI - Assessment of sleep quality and correlates in a large cohort of Colombian women around menopause. AB - OBJECTIVE: The aim of this study was to determine the relationship between self reported sleep quality, menopausal symptom intensity, and correlates (including ethnicity) among middle-aged women. METHODS: The present cross-sectional study involved 1,078 Colombian women aged 40 to 59 years who completed the Pittsburgh Sleep Quality Index (PSQI), the Menopause Rating Scale (MRS), and a general questionnaire exploring sociodemographic data. RESULTS: The median [interquartile range] age of the whole sample was 49.0 [9.0] years. Among the participants, 45.4% were postmenopausal, 57.2% had increased body mass index values, 13.9% were black, 20.7% had hypertension, 74.1% had a stable partner, and 3.8% used hormone therapy. The prevalence of poor sleep quality was 57.1% (PSQI global score >=5). Significant correlations between PSQI global scores and MRS total and subscale scores were found. Multiple linear regression analysis found that higher PSQI scores (poorer quality of sleep) correlated with higher MRS psychological and somatic subscale scores (more severe symptoms), smoking habit, and hypertension. Menopause status and black ethnicity were excluded from the final regression model. CONCLUSIONS: Despite study limitations, poor sleep quality is highly prevalent in this large middle-aged Colombian female sample and is related to menopausal symptom severity, tobacco use, and presence of hypertension. PMID- 23096247 TI - Impact of a moderate-intensity walking program on cardiometabolic risk markers in overweight to obese women: is there any influence of menopause? AB - OBJECTIVE: The aim of this study was to examine the effect of brisk walking on cardiometabolic risk profile and on the gene expression (ie, messenger RNA [mRNA] levels) of inflammatory and thrombotic markers in abdominal and femoral subcutaneous adipose tissues (SATs) among sedentary overweight to obese women with different menopause statuses. METHODS: Sixteen late premenopausal (mean [SD] age, 49 [3] y; mean [SD] body mass index, 31.9 [3.0] kg/m) and 14 early postmenopausal (53 [2] y; 30.8 [1.9] kg/m) women were involved in a 16-week walking program (three sessions of 45 min/wk at 60% of heart rate reserve). Glucose-insulin homeostasis, lipid-lipoprotein profile, and inflammatory (tumor necrosis factor-alpha, interleukin-6 [IL-6], and adiponectin) and thrombotic (plasminogen activator inhibitor-1) SAT mRNA and plasma levels were measured before and after the intervention. RESULTS: Glucose area under the curve was reduced in all participants (P = 0.03) after the walking program. Increases in plasma tumor necrosis factor-alpha were observed in both groups (P = 0.001), whereas increases in plasminogen activator inhibitor-1 levels were found in postmenopausal women only (P = 0.014). However, plasma IL-6 and adiponectin levels remained unchanged after the intervention (0.07 < P < 0.98). Although femoral SAT adiponectin mRNA levels decreased in postmenopausal women only (P = 0.008), abdominal SAT IL-6 mRNA levels were reduced in both groups (P = 0.01). CONCLUSIONS: Taken together, our results show that, despite a reduced abdominal SAT IL-6 expression, brisk walking does not seem to exert a favorable impact on the cardiometabolic risk profile of overweight to obese women, irrespective of their menopause status. PMID- 23096251 TI - One-year long-term safety extension study of ospemifene for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. AB - OBJECTIVE: The aim of this study was to assess the safety of ospemifene, a novel selective estrogen receptor modulator, for the treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, long-term safety extension study, nonhysterectomized women aged 40 to 80 years (n = 180) received daily oral doses of placebo, ospemifene 30 mg/day, or ospemifene 60 mg/day for 40 weeks (continued as blinded treatments from the initial 12-week pivotal efficacy study of ospemifene). The total treatment period was 52 weeks. Safety assessments included adverse events, cervical Papanicolaou tests, endometrial histology, endometrial thickness, gynecological examination, breast palpation, mammography, physical examination, and clinical safety laboratory assessments. RESULTS: No clinically significant adverse changes in safety assessments were observed in any treatment group. Most treatment-emergent adverse events were mild or moderate in severity. Hot flushes, the most frequently occurring treatment-emergent adverse event related to the study drug, had a low discontinuation rate (1.6%). No study participants discontinued because of endometrial or cervical pathology; no endometrial findings were clinically meaningful. On week 52, more than 95% of endometrial biopsy samples either were classified as atrophic or inactive or had insufficient tissue for diagnosis. There were no treatment-emergent adverse events of pelvic organ prolapse or venous thromboembolism. No cases of endometrial hyperplasia or carcinoma were observed. Only three participants (1.7%) taking ospemifene experienced vaginal bleeding or spotting, which was self limiting. CONCLUSIONS: Daily doses of ospemifene 30 mg and ospemifene 60 mg yielded few treatment-emergent adverse events and demonstrated no significant endometrial changes during the 1-year treatment of vulvar and vaginal atrophy in postmenopausal women with a uterus. PMID- 23096248 TI - Relationship between dietary phytoestrogens and development of urinary incontinence in midlife women. AB - OBJECTIVE: Because exogenous estrogen treatment has been associated with a higher risk of urinary incontinence, our objective was to evaluate the longitudinal relationships of dietary phytoestrogen intakes (isoflavones, coumestans, and lignans) and the development of incontinence in midlife women transitioning through menopause. METHODS: The Study of Women's Health Across the Nation (SWAN) Phytoestrogen Study was developed within SWAN, a community-based, multisite, multiracial/ethnic, prospective cohort study. SWAN interviewers administered a food consumption assessment at baseline and on follow-up visits 5 and 9. The SWAN Phytoestrogen Study created a phytonutrient database that allowed estimation of the usual daily intakes of four isoflavones, four lignans, and coumestrol. On an annual self-administered questionnaire, participants reported on the frequency and type of incontinence. We used discrete proportional hazards models to evaluate whether the estimated daily intake of each phytoestrogen class on the visit previous to the first report of incontinence was associated with the development of monthly or more incontinence versus remaining continent. RESULTS: We found no association or patterns of association between developing any, stress, or urge incontinence and the reported daily dietary intake of isoflavones, coumestrol, and lignans on the visit previous to the onset of incontinence. CONCLUSIONS: The results of this longitudinal study provide important information to better understand estrogenlike substances in the continence mechanism of midlife women. Our study shows that neither high nor low dietary intakes of isoflavones, coumestrol, and lignans prevent stress or urge incontinence. Future studies should evaluate whether serum levels of phytoestrogens or their metabolites impact incontinence symptoms. PMID- 23096252 TI - Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis susceptibility in a Han Chinese population. AB - PURPOSE: To investigate whether rs11190870 near LBX1 correlates with the susceptibility or curve progression of adolescent idiopathic scoliosis (AIS) in a Han Chinese population. METHODS: A total of 949 AIS patients and 976 age-matched healthy controls were recruited. All the subjects were genotyped using the PCR based invader assay. Case-control study and case-only study were performed to define the contribution of rs11190870 to predisposition and curve severity of AIS. Additionally, we further conducted a meta-analysis of the study findings together with those of previously reported studies. RESULTS: A significant association of rs11190870 with AIS was observed in the Han Chinese population (P = 1.8 * 10(-9); odd ratio = 1.51; 95 % confidence interval = 1.33-1.71), and AIS patients with TT genotype had a larger Cobb angle than those with TC or CC genotype (P = 0.005). The meta-analysis confirmed that the positive association of this SNP with AIS in the East Asian population. CONCLUSIONS: The SNP rs11190870 near LBX1 is associated with both susceptibility and curve progression of AIS. PMID- 23096254 TI - Catalytic activity and stability of glucose oxidase/horseradish peroxidase co confined in macroporous silica foam. AB - Investigation of the catalytic activity and stability of enzymes in confined nano/microspace provides valuable contributions to the fundamental understanding of biological reactions taking place on a mesoscopic scale within confined spaces. In this paper, macroporous silica foam (MSF) is used as a nanoreactor to co-confine glucose oxidase (GOD) and horseradish peroxidase (HRP). Then, the enzymatic cascade reactions, which act in tandem inside nanoreactors, for oxidation of glucose and 3,3',5,5'-tetramethylbenzidine (TMB) were studied. The catalytic kinetic parameters of apparent Michaelis constant (K(m)(app)) and maximum rate (V(max)) were obtained from Lineweaver-Burk plot by UV-vis spectrometry. Results showed that the catalytic activity of the co-confined enzymes is reduced compared to that of free enzymes in solution at room temperature. The stabilities of co-confined enzymes in denaturing agents, such as guanidinium chloride (GdmCl) and urea, were higher than those of free enzymes in solution. When employing a co-confined bienzyme system as a biosensor for the detection of glucose, a wider linear range of glucose was obtained for the co confined bienzyme system than for free enzymes in solution. PMID- 23096256 TI - Pharmacokinetic evaluation of visnagin and Ammi visnaga aqueous extract after oral administration in rats. AB - The furanochromone visnagin is one of the main compounds of Ammi visnaga L. (syn. Khella) with potential effects on kidney stone prevention. After determination of the pharmacokinetic properties of visnagin after intravenous bolus administration in rats, the aim of the present study was to evaluate the pharmacokinetic properties of visnagin and an aqueous Ammi visnaga extract after oral administration in rats. In two separate experiments, three doses of visnagin (2.5, 5, and 10 mg/kg) solubilized in 25 % Captisol(r) and three doses of Ammi visnaga extract (standardized on visnagin and containing equivalent amounts of visnagin) were administered by oral gavage to male Sprague-Dawley rats, respectively. Plasma samples were extracted and subsequently analyzed using a validated LC-MS/MS method. Plasma concentration-time profiles were explored by non-compartmental analysis. Visnagin plasma exposure (median AUClast and AUCinf) was significantly increased for all three doses (more than 10-fold for the low dose) when administered as an extract compared to the pure agent. For both the Ammi visnaga extract and the pure compound, AUClast and AUCinf increased disproportionately with an increase in dose. Visnagin resided significantly longer in the body when given in the form of AVE with up to a three times longer median MRTlast and MRTinf for the low dose. Cmax values after AVE administration were elevated and occurred at later time points in comparison to equivalent doses of pure visnagin. The terminal half-life increased with the dose for both AVE and pure visnagin, reaching a maximum value of 1.94 h for the 10 mg/kg pure compound group.In conclusion, the exposure of visnagin is enhanced after extract administration and could result in a superior efficacy of AVE compared to an equivalent dose of visnagin. PMID- 23096253 TI - Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. AB - Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to IL-17-producing CD4 T helper (Th17) cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a solely Th2-polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6. The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the production of IL 23 and IL-1beta by antigen presenting cells following recognition of egg antigens; analyses of several F2 progenies of (high * low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with intestinal nematodes can also dampen pathogenic Th17 cell responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases. PMID- 23096257 TI - In vitro schistosomicidal activity of balsaminol F and karavilagenin C. AB - Five cucurbitane-type triterpenes (1-5), previously isolated from the African medicinal plant Momordica balsamina, along with five ester derivatives (6-10) of karavilagenin C (2), were evaluated for their potential schistosomicidal activity against Schistosoma mansoni adult worms. The natural compounds were isolated from the ethyl acetate-soluble fraction of the methanol extract of the aerial parts of M. balsamina. In a preliminary study, a significant schistosomicidal activity was observed for both the crude methanol extract and the ethyl acetate fraction. The compounds responsible for the activity were found to be balsaminol F (1) and karavilagenin C (2) with LC50 values of 14.7 +/- 1.5 and 28.9 +/- 1.8 uM, respectively, after 24 h of incubation (positive control praziquantel, LC50 = 1.2 +/- 0.1 uM). Both compounds (1, 2), at 10-50 uM, induced significant reductions in the motor activity of the worms and significantly decreased the egg production. Furthermore, they were able (at 10-100 uM) to separate the adult worm pairs into male and female after 24 h. Compounds 3-5, bearing a sugar moiety as a substituent, and the acylated derivatives of karavilagenin C (6-10) were inactive, suggesting that the presence of free hydroxyl groups in the tetracyclic skeleton might be important for the activity. A correlation between activity and the molecular volume/weight of compounds was also found. PMID- 23096258 TI - Novel dibenzo[b,e]oxepinones from the freshwater-derived fungus Chaetomium sp. YMF 1.02105. AB - Six new dibenzo[b,e]oxepinone metabolites, chaetones A-F (1-6), as well as three known compounds, 1-hydroxy-6-methyl-8-hydroxymethylxanthone (7), citreorosein (8), and emodin (9), were obtained from a freshwater-derived fungal strain Chaetomium sp. YMF 1.02105. Their structures were established on the basis of extensive spectroscopic data analysis and comparison with spectroscopic data reported. Compounds 1-6 are further additions to the small group of dibenzo[b,e]oxepinones represented by arugosins A-H. Compounds 1-7 were tested for their cytotoxic activities against A549, Raji, HepG2, MCF-7, and HL-60 cell lines. The results showed that compound 3 had significant cytotoxicity with IC50 values of 1.2, 1.8, 1.9, 2.3, and 1.6 ug/mL, respectively, against the five cancer cell lines. All compounds showed modest antimicrobial activity against Staphylococcus aureus (ATCC 6538) in standard disk assays. PMID- 23096259 TI - Flexible stabilization of the distal tibiofibular syndesmosis: clinical and biomechanical considerations: a review of the literature. AB - Syndesmotic rupture is present in 10 % of ankle fractures and must be recognized and treated to prevent late complications. The method of fixation is classically rigid fixation with one or two screws. Knowledge of the biomechanics of the syndesmosis has led to the development of new dynamic implants to restore physiologic motion during walking. One of these implants is the suture-button system. The purpose of this paper is to review the orthopaedic trauma literature, both biomechanical and clinical, to present the current state of knowledge on the suture-button fixation and to put emphasis on the advantages and disadvantages of this technique. Two investigators searched the databases of Pubmed/Medline, Cochrane Clinical Trial Register and Embase independently. The search interval was from January 1980 to March 2011. The search keys comprised terms to identify articles on biomechanical and clinical issues of flexible fixation of syndesmotic ruptures. Ninety-nine publications met the search criteria. After filtering using the exclusion criteria, 11 articles (five biomechanical and six clinical) were available for review. The biomechanical studies involved 90 cadaveric ankles. The suture-button demonstrated good resistance to axial and rotational loads (equivalent to screws) and resistance to failure. Physiologic motion of the syndesmosis was restored in all directions. The clinical studies (149 ankles) demonstrated good functional results using the AOFAS score, indicating faster rehabilitation with flexible fixation than with screws. There were few complications. Preliminary results from the current literature support the use of suture-button fixation for syndesmotic ruptures. This method seems secure and safe. As there is no strong evidence for its use, prospective randomized controlled trials to compare the suture-button to the screw fixation for ankle syndesmotic ruptures are required. PMID- 23096260 TI - The Essex-Lopresti lesion. AB - The Essex-Lopresti lesion represents a severe injury of the forearm unit. In the 1940s, it's pathology and consequences have already been mentioned by several authors. Over the course of time, the pathophysiology of the lesion was displayed in more detail. Therefore, an intensive analysis of the involved anatomic structures was done. The interosseous membrane was shown to play a major role in stabilising the forearm unit, in the situation of a fractured radial head, which is the primary stabiliser of the longitudinal forearm stability. Moreover, biomechanical analyses showed a relevant attribution of the distal radio-ulnar joint to the forearm stability. If, in the case of a full-blown Essex-Lopresti lesion, the radial head, the interosseous membrane and the distal radio-ulnar joint are injured, proximalisation of the radius will take place and will come along with secondary symptoms at the elbow joint and the wrist. According to actual studies, the lesion seems to occur more often than realised up to now. Thus, to avoid missing the complex injury, subtle clinical diagnosis combined with adequate imaging has to be undertaken. If the lesion is confirmed, several operative treatment options are available, yet not proofed to be sufficient. PMID- 23096261 TI - [Experiences with cement leakage after balloon kyphoplasty]. AB - BACKGROUND: Kyphoplasty is associated with a low incidence of cement leakage and this usually tends to be clinically asymptomatic. However, there is a potential for life-threatening complications from extraspinal leakage resulting in vascular, cardiac and pulmonary embolisms. A total of eight cases of open surgical thrombectomy for cardiopulmonary cement leakage have been published in the current literature to date. Besides the description of a consecutive series with special reference to extraspinal cement leakage this article presents the results after successful endovascular removal of intravenous cement fragments following kyphoplasty in two patients. MATERIALS AND METHODS: In 46 cases following balloon kyphoplasty the number and amount of extraspinal venous cement leakage was retrospectively determined using computed tomography (CT). The number of cement embolisms into the pulmonary venous system was differently revealed for patients showing no extravertebral leakage or leakage only into the external vertebral venous plexus compared to leakage into the major venous vessels, azygos and hemiazygos vein or inferior vena cava. RESULTS: In 8 out of 046 cases (17.4 %) leakage into the external vertebral venous plexus was detected. In 5 out of 8 cases without involvement of the azygos/hemiazygos vein or inferior vena cava no pulmonary cement embolism was detected. In 3 out of 8 cases the inferior vena cava or azygos/hemiazygos vein was reached and additionally asymptomatic peripheral pulmonary cement embolism was induced in these cases. In two cases harboring residual intravasal cement fragments treatment was successful using endovascular extraction techniques. CONCLUSIONS: A computed tomography scan after kyphoplasty is recommended for all cases. If there is involvement of the inferior vena cava or the azygos/hemiazygos vein an additional CT scan of the chest should follow, even in asymptomatic cases. Residual intravasal cement fragments are safely extractable using endovascular techniques. PMID- 23096262 TI - [Joint preserving surgery of the adult hip: pelvic osteotomies]. AB - Deformity and malposition of the acetabulum can occur during the development of the hip. Developmental hip dysplasia and acetabular retroversion are possible causes of osteoarthritis in the young adult. Surgical management with reorientation of the acetabulum allows causal therapy of the deformity and preservation of the native hip joint. Established techniques are the Bernese periacetabular osteotomy (PAO) and the Tonnis and Kalchschmidt triple osteotomy of the pelvis. Both techniques permit three-dimensional correction of the position of the acetabulum. Advantages and disadvantages of each technique must be considered and are summarized in the present paper. If performed early (osteoarthritis grade Tonnis 0 and 1) with correct indication and proper technique, good results can be expected. PMID- 23096263 TI - Rural-urban disparities in health status among US cancer survivors. AB - BACKGROUND: Although rural residents are more likely to be diagnosed with more advanced cancers and to die of cancer, little is known about rural-urban disparities in self-reported health among survivors. METHODS: The authors identified adults who had a self-reported history of cancer from the National Health Interview Survey (2006-2010). Rural-urban residence was defined using US Census definitions. Logistic regression with weighting to account for complex sampling was used to assess rural-urban differences in health status after accounting for differences in demographic characteristics. RESULTS: Of the 7804 identified cancer survivors, 20.8% were rural residents. This translated to a population of 2.8 million rural cancer survivors in the United States. Rural survivors were more likely than urban survivors to be non-Hispanic white (P < .001), to have less education (P < .001), and to lack health insurance (P < .001). Rural survivors reported worse health in all domains. After adjustment for sex, race/ethnicity, age, marital status, education, insurance, time since diagnosis, and number of cancers, rural survivors were more likely to report fair/poor health (odds ratio, 1.39; 95% confidence interval, 1.20-1.62), psychological distress (odds ratio, 1.23; 95% confidence interval, 1.00-1.50), >=2 noncancer comorbidities (odds ratio, 1.15; 95% confidence interval, 1.01 1.32), and health-related unemployment (odds ratio, 1.66; 95% confidence interval, 1.35-2.03). CONCLUSIONS: The current results provide the first estimates of the proportion and number of US adult cancer survivors who reside in rural areas. Rural cancer survivors are at greater risk for a variety of poor health outcomes, even many years after their cancer diagnosis, and should be a target for interventions to improve their health and well being. PMID- 23096264 TI - Classification and histological, immunohistochemical, and molecular diagnosis of inflammatory myocardial disease. AB - In the WHO 1996 classification of cardiomyopathies, myocarditis is defined as an "inflammatory disease of the myocardium associated with cardiac dysfunction" and is listed among "specific cardiomyopathies". Myocarditis is diagnosed on endomyocardial biopsy (EMB) by established histological, immunological, and immunohistochemical criteria, and molecular techniques are recommended to identify viral etiology. Infectious, autoimmune, and idiopathic forms of inflammatory cardiomyopathy are recognized that may lead to dilated cardiomyopathy. According to Dallas criteria, myocarditis is diagnosed in the setting of an "inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes, not typical of ischemic damage associated with coronary artery disease". The majority of experts in the field agree that an actual increase in sensitivity of EMB has now been reached by using immunohistochemistry together with histology. A value of >14 leukocytes/mm(2) with the presence of T lymphocytes >7 cells/mm(2) has been considered a realistic cut off to reach a diagnosis of myocarditis. The development of molecular biological techniques, particularly amplification methods like polymerase chain reaction (PCR) or nested-PCR, allows the detection of low copy viral genomes even from an extremely small amount of tissue such as in EMB specimens. Positive PCR results obtained on EMB should always be accompanied by a parallel investigation on blood samples collected at the time of the EMB. According to the recent Association for European Cardiovascular Pathology guidelines, optimal specimen procurement and triage indicates at least three, preferably four, EMB fragments, each 1-2 mm in size, that should immediately be fixed in 10 % buffered formalin at room temperature for light microscopic examination. In expected focal myocardial lesions, additional sampling is recommended. Moreover, one or two specimens should be snap-frozen in liquid nitrogen and stored at -80 degrees C or alternatively stored in RNA-later for possible molecular tests or specific stains. A sample of peripheral blood (5-10 ml) in EDTA or citrate from patients with suspected myocarditis allows molecular testing for the same viral genomes sought in the myocardial tissue. PMID- 23096265 TI - Macrophage plasticity and polarization in tissue repair and remodelling. AB - Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation. PMID- 23096267 TI - Misdiagnosis of gossypiboma as Meigs' syndrome. PMID- 23096268 TI - Technically assisted analysis of large quantities of numerical data in preclinical tumor research. PMID- 23096269 TI - Technical assistance systems influence the work organisation to challenge the demographical change. PMID- 23096270 TI - Requirement engineering in health care and telemedicine. PMID- 23096272 TI - A low-power embedded communication platform for medical applications. PMID- 23096271 TI - Results from long-term In-vivo Tests of a Wireless, Intravascular Blood-Pressure Monitoring System for Hypertension Patients. PMID- 23096273 TI - Energy budget in mobile health assistance systems. PMID- 23096274 TI - Telemedical monitored training for patients with chronic pulmonary disease. PMID- 23096266 TI - Indian Society of Gastroenterology consensus on ulcerative colitis. AB - In 2010, the Indian Society of Gastroenterology's Task Force on Inflammatory Bowel Diseases undertook an exercise to produce consensus statements on ulcerative colitis. This consensus, produced through a modified Delphi process, reflects our current understanding of the definition, diagnostic work up, treatment and complications of ulcerative colitis. The consensus statements are intended to serve as a reference point for teaching, clinical practice, and research in India. PMID- 23096275 TI - Prediction of surgical work steps in neurosurgery. PMID- 23096276 TI - Home telecare and rehabilitation system with aspect oriented functional integration. PMID- 23096277 TI - Heart failure monitoring with implantable defibrillators. PMID- 23096278 TI - Service oriented architecture based web application model for collaborative biomedical signal analysis. PMID- 23096279 TI - Method for daily-life movement classification of elderly people. PMID- 23096280 TI - Effectiveness and efficiency for ambulatory care assisted by mobile technological devices. PMID- 23096281 TI - Telemonitoring system and central real-time data processing for preventive medicine research. PMID- 23096282 TI - Measuring affect using a standard mouse device. PMID- 23096283 TI - The ELN-Survey: On the potential of laboratory IT systems to support the biomedical research process. PMID- 23096284 TI - Routine mobile applications for emergency medical services in mass casualty incidents. PMID- 23096285 TI - Connecting workflow management to the OR network: Design and evaluation of a bridge to enable dynamic systems behaviour. PMID- 23096286 TI - Development of an Android App in Compliance with the Continua Health Alliance Design Guidelines for Medical Device Connectivity in mHealth. PMID- 23096287 TI - Service based adhoc networking for patient's pain diary on mobile devices. PMID- 23096288 TI - Intelligent capacitive sensor array for removement detection from various surfaces of tagged equipment in hospitals. PMID- 23096289 TI - Modelling the progression of brain metastases. PMID- 23096290 TI - Impact of antiarrhythmic drugs on a virtual model of atrial fibrillation. PMID- 23096291 TI - Adaptive control system for volume-controlled ventilation in small animals. PMID- 23096292 TI - Simulation of fluoroscopic localization for surgical training. PMID- 23096293 TI - Nonlinear femur-hip prosthesis network model. PMID- 23096294 TI - Simulation system for puncture of the Vena jugularis sinistra in horses. PMID- 23096295 TI - Evaluation of an etCO2 predicting model. PMID- 23096296 TI - Simulation of adaptive structures made of textile and shape memory alloy. PMID- 23096297 TI - A GPU-accelerated Performance Optimized RAP-MUSIC Algorithm for Real-Time Source Localization. PMID- 23096298 TI - A hybrid combination of interacting physiological models. PMID- 23096299 TI - Temperature elevation during medical diathermy. PMID- 23096300 TI - Validation and Application of Realistic Head Modelling to MEG. PMID- 23096301 TI - Patient safety and human factors research for surgical automation. PMID- 23096302 TI - Simulating extracellular microelectrode recordings on cardiac tissue preparations in a bidomain model. PMID- 23096303 TI - Simulating the Beating Heart within the Pericardium using Finite Element Analysis. PMID- 23096304 TI - Multivariate biosignal acquisition to assess the potential of remote photoplethysmography. PMID- 23096305 TI - Software Assistance for HIFU Therapy Planning. PMID- 23096306 TI - Development of a test-bench for bio-inspired actuator systems in rehabilitation robotics. PMID- 23096307 TI - Covariance analysis for practical identifiability of an alveolar recruitment model. PMID- 23096308 TI - Sensitivity analysis of the field distribution in Deep Brain Stimulation with respect to the anisotropic conductivity of brain tissue. PMID- 23096309 TI - Mechanical properties of the patient circuit and its analogous model. PMID- 23096310 TI - Brain Atlas based Region of Interest Selection for Real-Time Source Localization using K-Means Lead Field Clustering and RAP-MUSIC. PMID- 23096311 TI - Transmission line model for pulse wave analysis accompanied on experimental measurements at a human model. PMID- 23096312 TI - Iteratively Learning Electromyography (EMG)-based Functional Electrical Stimulation (FES) for Stroke Rehabilitation. PMID- 23096313 TI - Particle release from drug eluting balloons and stents - simulated use testing. PMID- 23096314 TI - Soundcard based Multichannel Live-ECG Simulator for Research, Development and Education. PMID- 23096315 TI - A curve-shaped flexible mesh cage for treatment of large segmental bone defects - a finite element analysis. PMID- 23096316 TI - Comparison of boundary element and finite element approaches to the EEG forward problem. PMID- 23096317 TI - Continuous blood pressure measurement with ultrasound. PMID- 23096318 TI - Sensitivity of EEG leads to volume conductor properties. PMID- 23096319 TI - Development of a phantom to modulate the maternal and fetal pulse curve for pulse oximetry measurements. PMID- 23096320 TI - Neuromuscular Junction Transmission is Effected by Quantum Entanglement of Ion Transition States. PMID- 23096321 TI - Volume conduction effects in tDCS using a 1mm geometry-adapted hexahedral finite element head model. PMID- 23096322 TI - Comparison of six models of the respiratory system based on parametric estimates from three identification models. PMID- 23096323 TI - Flow regulation in multi branched models of blood vessels. PMID- 23096324 TI - Enhancements of a mechanical lung simulator for ex vivo measuring of aerosol deposition in lungs. PMID- 23096325 TI - Biomechanical Modelling of Three-Dimensional Scaffold-Free Cartilage Constructs - A Comparison between Experiment and Simulation. PMID- 23096326 TI - Implementation of dynamic plotting for a ventilation simulator on android mobile devices. PMID- 23096327 TI - Effects of individual spine curvatures - a comparative study with the help of computer modelling. PMID- 23096328 TI - Flow simulation through porous ceramics used as a throttle in an implantable infusion pump. PMID- 23096329 TI - A mathematical model to simulate glioma growth and radiotherapy at the microscopic level. PMID- 23096330 TI - Damping of the dynamic pressure amplitude in the ventilatory circuit during high frequency oscillatory ventilation. PMID- 23096331 TI - Modelling of heterogeneous human atrial electrophysiology. PMID- 23096332 TI - Examination of steroid release from screw-in pacing leads. PMID- 23096333 TI - Electrosurgery: CQM-Simulation without Volunteers. PMID- 23096334 TI - Pressure Pulse Fields: Comparison of optical hydrophone measurements with FEM Simulations. PMID- 23096335 TI - Biological effectiveness in hypofractionation: Modeling tumor survival probability for large doses with a stochastic cell-cycle model. PMID- 23096336 TI - Development of a testing method for the determination of interfacial micromotions of short-stemmed hip endoprosthesis. PMID- 23096337 TI - The Vitreous Model - a new in vitro test method simulating the vitreous body. PMID- 23096338 TI - Examining basilar membrane motion of an auditory model by using tone-burst otoacoustic emissions. PMID- 23096339 TI - Biomechanical Effects of a Spinal Implant - Investigation through MBS Computer Modelling. PMID- 23096340 TI - Intraoperative Applications of OCT in Ophthalmic Surgery. PMID- 23096341 TI - Crystalline lens stretching device for simulation of accommodation. PMID- 23096342 TI - Pulsed wavelength-dependent laser stimulation of the inner ear. PMID- 23096343 TI - Comparative investigation in stray light measurement in the human eye. PMID- 23096344 TI - Evaluation of a novel method to measure the intraocular pressure based on a mechanical eye model. PMID- 23096345 TI - The influence of a spatial and temporal pulse-overlap on the laser-tissue interaction of modern ophthalmic laser systems. PMID- 23096346 TI - Oligomerization of polytopic alpha-helical membrane proteins: causes and consequences. AB - Several polytopic alpha-helical membrane-integrated proteins appear to be organized in higher-ordered oligomeric complexes. While many aspects are still enigmatic, in recent years, the physiological impact of membrane protein oligomerization has been analyzed to some extent. In the present article, oligomerization of structurally well-defined membrane proteins is discussed. The available experimental information indicates the causes and physiological consequences of membrane protein oligomerization, including stabilization, cooperative functions, and control of specific activities. Based on the currently available observations, we aim to derive some general principles and discuss open questions. PMID- 23096347 TI - Highlight: membrane transport and beyond. PMID- 23096348 TI - An acetylation site in lectin domain modulates the biological activity of polypeptide GalNAc-transferase-2. AB - Polypeptide GalNAc-transferases (ppGalNAc-Ts) are a family of enzymes that catalyze the initiation of mucin-type O-glycosylation. All ppGalNAc-T family members contain a common (QXW)3 motif, which is present in the R-type lectin group. The acetylation site K521 is part of the QKW motif of beta-trefoil in the lectin domain of ppGalNAc-T2. We used a combination of acetylation and site directed mutagenesis approaches to examine the functional role of K521 in ppGalNAc-T2. Binding assays of non-acetylated and acetylated forms of the mutant ppGalNAc-T2K521Q to various naked and alphaGalNAc-glycosylated mucin peptides indicated that the degree of interaction of lectin domain with alphaGalNAc depends on the peptide sequence of mucin. Studies of the inhibitory effect of various carbohydrates on the interactions of ppGalNAc-T2 with MUC1alphaGalNAc indicate that point K521Q mutation enhance the carbohydrate specificity of lectin domain for alphaGalNAc. K521Q mutation resulted in an enzyme activity lower than that of the wild-type ppGalNAc-T2, similar to the acetylation of ppGalNAc-T2. We conclude that an acetylation site in the QKW motif of the lectin domain modulates carbohydrate recognition specificity and catalytic activity of ppGalNAc-T2 for partially preglycosylated acceptors and a certain naked peptide. Posttranslational modifications of ppGalNAc-Ts, such as acetylation, may play key roles in modulating the functions of the R-type lectin domains in cellular homeostasis. PMID- 23096349 TI - Nature's way of handling a greenhouse gas: the copper-sulfur cluster of purple nitrous oxide reductase. AB - The tetranuclear Cu(Z) cluster is the unique active site of nitrous oxide reductase, the enzyme that catalyzes the reduction of nitrous oxide to dinitrogen as the final reaction in bacterial denitrification. Three-dimensional structures of orthologs of the enzyme from a variety of different bacterial species were essential steps in the elucidation of the properties of this center. However, while structural data first revealed and later confirmed the presence of four copper ions in spectroscopically distinct forms of Cu(Z), the exact structure and stoichiometry of the cluster showed significant variations. A ligand bridging ions Cu(Z1) and Cu(Z2) was initially assigned as a water or hydroxo species in the structures from Pseudomonas nautica (now Marinobacter hydrocarbonoclasticus) and Paracoccus denitrificans. This ligand was absent in a structure from 'Achromobacter cycloclastes', and could be reconstituted by iodide that acted as an inhibitor of catalysis. A recent structure of anoxically isolated nitrous oxide reductase from Pseudomonas stutzeri revealed the bridging ligand to be sulfide, S2-, and showed an unprecedented side-on mode of nitrous oxide binding to this form of Cu(Z). PMID- 23096350 TI - Structural basis of [NiFe] hydrogenase maturation by Hyp proteins. AB - [NiFe] hydrogenases catalyze reversible hydrogen production/consumption. The active site of [NiFe] hydrogenases contains a complex NiFe(CN)2CO center, and the biosynthesis/maturation of these enzymes is a complex and dynamic process, primarily involving six Hyp proteins (HypABCDEF). HypA and HypB are involved in the Ni insertion, whereas the other four Hyp proteins (HypCDEF) are required for the biosynthesis, assembly and insertion of the Fe(CN)2CO group. Over the last decades, a large number of functional and structural studies on maturation proteins have been performed, revealing detailed functions of each Hyp protein and the framework of the maturation pathway. This article will focus on recent advances in structural studies of the Hyp proteins and on mechanistic insights into the [NiFe] hydrogenase maturation. PMID- 23096351 TI - Structural analysis of the C-terminal domain of the spliceosomal helicase Prp22. AB - Splicing of pre-mRNA requires the activity of at least eight different DEAD/H-box proteins that are involved in distinct steps of the splicing process. These proteins are driving the spliceosomal machinery by ATP-dependent unwinding of dsRNA and/or disrupting protein-RNA complexes. The spliceosomal DEAH-box proteins Prp2, Prp16, Prp22 and Prp43 share homologous C-terminal domains (CTD). We have determined the crystal structure of the CTD of human Prp22 by means of MAD. The fold of the human Prp22-CTD closely resembles that of the yeast Prp43-CTD. The similarity of these helicase-associated CTDs to the winged-helix and ratchet domains of the DNA helicase Hel308 suggests an analogous function in dsRNA binding and unwinding. Here, we also demonstrate that the CTD has a significant impact on the ATPase activity of yPrp22 in vitro. Homology modeling of the CTDs of hPrp2, hPrp16 and hPrp43 suggests that the CTDs of spliceosomal helicases contain conserved positively charged patches on their surfaces representing a common RNA-binding surface as well as divergent regions most likely mediating specific interactions with different proteins of the spliceosome. PMID- 23096352 TI - PhoB transcriptional activator binds hierarchically to pho box promoters. AB - The PhoR-PhoB phosphorelay is a bacterial two-component system that activates the transcription of several genes involved in phosphate uptake and assimilation. The response begins with the autophosphorylation of the sensor kinase PhoR, which activates the response regulator PhoB. Upon binding to the pho box DNA sequence, PhoB recruits the RNA polymerase and thereby activates the transcription of specific genes. To unveil hitherto unknown molecular mechanisms along the activation pathway, we report biochemical data characterizing the PhoB binding to promoters containing multiple pho boxes and describe the crystal structure of two PhoB DNA-binding domains bound in tandem to a 26-mer DNA. PMID- 23096353 TI - In vitro assessment of reproductive toxicity of cigarette smoke and deleterious consequences of maternal exposure to its constituents. AB - Cigarette smoke is known to be a serious health risk factor and considered reproductively toxic. In the current study, we investigated whether constituents of cigarette smoke, pyrazine, 2-ethylpyridine, and 3-ethylpyridine, adversely affect reproductive functioning such as oocyte maturation and sperm capacitation. Our findings indicated that three smoke components were involved in retardation of oocyte maturation in a dose-dependent manner and the lowest-observed-adverse effect level (LOAEL) was determined to be 10(-10)M. However, individual smoke components administrated at the LOAEL did not attenuate oocyte maturation, demonstrating that all three toxicants were equally required for the observed growth impairment. When exposed to all three components at 10(-10)M during in vitro capacitation, murine sperm lost forward progression and were unable to show adequate hyperactivation, which is indicative of the incompletion of the capacitation process. Only sperm administrated with 3-ethylpyridine alone showed significant reduction in capacitation status, suggesting the chemical is the one responsible for disrupting sperm capacitation. Taken together, this is the first report that documents the effect of cigarette smoke components on oocyte maturation and sperm capacitation. The present findings demonstrate the adverse effects of smoke constituents of mammalian reproduction and the differences in sensitivity to smoke components between male and female gametes. Since both processes take place in the female reproductive system, our data provide new insights into deleterious consequences of maternal exposure to cigarette smoke. PMID- 23096354 TI - The cytotoxic and antileishmanial activity of extracts and fractions of leaves and fruits of Azadirachta indica (A Juss.). AB - The leishmaniases are severe parasitic diseases that occur worldwide, caused by protozoa of the genus Leishmania. Studies with medicinal plants can lead to a range of possibilities for treating and improving the patients' quality of life. Research on Azadirachta indica fractions and extracts has shown that they have excellent anti-leishmanial activity based on bioactivity-guided fractionation of ethanolic extracts of leaves and seeds and in vitro activity against promastigotes. In this research the most efficient extracts and fractions were selected for tests on intracellular amastigotes of Leishmania amazonensis. The ethanolic extract of the leaves and dichloromethane and chloroform fractions had IC(50) values of 38, 3.9 and 1.2 MUg/mL for promastigotes and 9.8, 1.1 and 0.6 MUg/mL for amastigotes, respectively, at 72 hours. For the ethanolic extract and dichloromethane fraction from nut tegument, the IC(50) was 2.7 and 2.1 MUg/mL for promastigotes and 0.4 and 0.6 MUg/mL for amastigotes. The cytotoxicity of the fractions presented selectivity that was between 8 to 32 times more toxic to promastigotes and 15 to 72 times to amastigotes than to macrophages. The extracts and fractions from leaves and fruits were more effective against amastigotes, and the fractionation increased activity against both promastigotes and amastigotes, enabling us to obtain potentially active fractions with low toxicity. PMID- 23096355 TI - BRCA1 and BRCA2 mutations in breast cancer patients from Venezuela. AB - A sample of 58 familial breast cancer patients from Venezuela were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIM no. 113705) and BRCA2 (MIM no. 600185) genes by using conformation-sensitive gel electrophoresis. Ashkenazi Jewish founder mutations were not found in any of the samples. We identified 6 (10.3%) and 4 (6.9%) patients carrying germline mutations in BRCA1 and BRCA2, respectively. Four pathogenic mutations were found in BRCA1, one is a novel mutation (c.951_952insA), while the other three had been previously reported (c.1129_1135insA, c.4603G>T and IVS20+1G>A). We also found 4 pathogenic mutations in BRCA2, two novel mutations (c.2732_2733insA and c.3870_3873delG) and two that have been already reported (c.3036_3039delACAA and c.6024_6025_delTA). In addition, 17 variants of unknown significance (6 BRCA1 variants and 11 BRCA2 variants), 5 BRCA2 variants with no clinical importance and 22 polymorphisms (12 in BRCA1 and 10 in BRCA2) were also identified. This is the first genetic study on BRCA gene mutations conducted in breast cancer patients from Venezuela. The ethnicity of our population, as well as the heterogeneous and broad spectrum of BRCA genes mutations, must be considered to optimize genetic counseling and disease prevention in affected families. PMID- 23096356 TI - Rapid in vitro plant regeneration from leaf explants of Launaea sarmentosa (Willd.) Sch. Bip. ex Kuntze. AB - An efficient protocol for organogenesis through leaves has been established for Launaea sarmentosa (Willd.) Sch. Bip. ex Kuntze, a highly valuable medicinal plant. The leaf explants produced microshoots on MS basal medium when fortified with cytokinins and auxins. A combination of 6-benzylaminopurine (BAP) at 0.5mg/l and naphthaleneacetic acid (NAA) at 0.2mg/l resulted in the induction of high frequency microshoots in 30 days. The microshoots were successfully subcultured for shoot elongation and eventually for rooting on MS medium supplemented with indole-3-butyric acid (IBA) at 0.5mg/l. The regenerated plantlets were hardened under greenhouse conditions and transferred to garden, resulting in a 90% survival rate. PMID- 23096357 TI - Angiogenic potential of the cerebrospinal fluid (CSF) of patients with high-grade gliomas measured with the chick embryo chorioallantoic membrane assay (CAM). AB - High-grade gliomas are highly vascularized tumors. Neo-angiogenesis plays a key role in tumor growth and resistance to therapy. A cerebrospinal fluid (CSF) sample could be a useful way to obtain pro-angiogenic predictive or prognostic markers at different stages of the disease. As a first step we looked for pro angiogenic activity in the CSF of patients with high-grade gliomas. We performed the chicken embryo chorio-allantoic membrane (CAM) assay to study the angiogenic potential of the cerebrospinal fluid (CSF), obtained either by lumbar puncture (LP) or craniotomy from six patients with high-grade brain tumors (three glioblastoma (WHO grade IV), one anaplastic oligodendroglioma (WHO grade III), two anaplastic ganglioglioma (WHO grade III)), and four healthy controls. Significantly increased neo-angiogenesis was observed on the surface of the growing CAM in the 6 patients with high-grade gliomas compared to controls (3.69 +/- 1.23 versus 2.16 +/- 0.97 capillaries per area (mean +/- SD), p<0.005). There was no statistical difference related to the hystological grade of the tumor (WHO grade III or IV), previous treatment (radio-chemotherapy plus temozolomide, temozolomide alone or no treatment), or the site of CSF sample (surgery or lumbar puncture). Our results suggest a pro-angiogenic potential in the CSF of patients with high-grade gliomas. PMID- 23096358 TI - Diversity of foliar endophytic fungi from the medicinal plant Sapindus saponaria L. and their localization by scanning electron microscopy. AB - Endophytic fungi inhabit vegetable tissues or organs, without causing them any harm. Endophytes can co-evolve with plant hosts and possess species-specific interactions. They can protect the plant from insect attacks and diseases, and are also able to produce substances of biotechnological interest. In folk medicine, the bark, roots and fruits of Sapindus saponaria is used to produce substances with anxiolytic, astringent, diuretic and expectorant properties, as well as tonics, blood depuratives and cough medicine. This study evaluated the diversity of endophytic fungi present in the leaves of S. saponaria L. and observed the colonization of host plants by endophytes, using light and scanning electron microscopy. We verified that these fungi are found in intercellular and intracellular spaces. The genera of some isolates of S. saponaria were identified mainly by sequencing of ITS region of rDNA and, when possible, also by their microscopic features, as follows: Cochliobolus, Alternaria, Curvularia, Phomopsis, Diaporthe and Phoma. Phylogenetic analysis showed the existence of genetic variability of the genera Phomopsis and Diaporthe and interspecific variation among the Curvularia, Alternaria and Phoma, belonging to family Pleosporaceae. PMID- 23096359 TI - Modification of fatty acid composition in broiler chickens fed canola oil. AB - This article describes the possibility of modifying the composition of fat tissue in broiler chickens fed canola oil, which is high in monounsaturated fatty acids. 128 one-day old broiler chickens, randomly assigned into 4 groups of 32 chicks each, received one of four diets containing 15% oil with different percentages of canola oil (diet 1: 0% canola oil, diet 2: 5% canola oil, diet 3: 10% canola oil and diet 4: 15% canola oil), for 31 days. Each group was divided into 4 subgroups of 8 chicks. The birds were sacrificed at day 45 to obtain tissue samples. The fatty acid composition was measured in meat (legs and breasts), fat (abdominal and subcutaneous) and plasma. An increase in oleic acid (p<0.01) was detected, as well as a decrease in linoleic acid (p<0.01), together with a slight increase in alpha-linolenic acid (p<0.05) with a higher percentage of canola oil. The composition of fat tissue was more representative of the dietary fatty acids than muscle tissue. In conclusion, canola oil increased the content of omega 9 and omega 3 fatty acids and decreased the content of omega 6 fatty acids in meat, fat and plasma in broiler chickens. PMID- 23096360 TI - Oscillatory fluid flow elicits changes in morphology, cytoskeleton and integrin associated molecules in MLO-Y4 cells, but not in MC3T3-E1 cells. AB - Interstitial fluid flow stress is one of the most important mechanical stimulations of bone cells under physiological conditions. Osteocytes and osteoblasts act as primary mechanosensors within bones, and in vitro are able to respond to fluid shear stress, both morphologically and functionally. However, there is little information about the response of integrin-associated molecules using both osteoblasts and osteocytes. In this study, we investigated the changes in response to 2 hours of oscillatory fluid flow stress in the MLO-Y4 osteocyte like cell line and the MC3T3-E1 osteoblast-like cell line. MLO-Y4 cells exhibited a significant increase in the expression of integrin-associated molecules, including OPN, CD44, vinculin and integrin alphavbeta3. However, there was no or limited increase observed in MC3T3-E1 osteoblast-like cells. Cell area and fiber stress formation were also markedly promoted by fluid flow only in MLO-Y4 cells. But the numbers of processes per cell remain unaffected in both cell lines. PMID- 23096361 TI - Variation in concentrations of major bioactive compounds in Prunella vulgaris L. related to plant parts and phenological stages. AB - Prunella vulgaris L. (Labiatae) contains a variety of structurally diverse natural products, primarily rosmarinic acid (RA), ursolic acid (UA) and oleanolic acid (OA), which possess a wide array of biological properties. In the present study, P. vulgaris was harvested at three developmental stages (vegetative, full flowering and mature-fruiting stages), dissected into stem and leaf tissues and assayed for chemical contents using high performance liquid chromatography. Significant changes in the concentrations of the major secondary metabolites (RA, UA and OA) were observed at the different development stages. The highest concentrations of RA, UA and OA were found at the full-flowering stage (15.83 mg/g dry weight (DW) RA, 1.77 mg/g DW UA and 0.65 mg/g DW OA). Among the different aerial parts of the plant, the concentrations of RA, UA and OA were higher in the leaves than in the stems at the different developmental stages. These results suggest that the full-flowering stage is characterized by the highest concentrations of bioactive compounds. Therefore, this stage may be the optimum point for harvesting P. vulgaris plants. In additional, the leaves of P. vulgaris demonstrated higher RA, UA and OA concentrations than the stems, suggesting higher utilization potential. PMID- 23096362 TI - Response of the G2-prophase checkpoint to genotoxic drugs in lymphocytes from healthy individuals. AB - We analyzed the in vitro effects of the anti-tumoral drugs doxorubicin, cytosine arabinoside and hydroxyurea on the G2-prophase checkpoint in lymphocytes from healthy individuals. At biologically equivalent concentrations, the induced DNA damage activated the corresponding checkpoint. Thus: i) there was a concentration dependent delay of G2 time and an increase of both the total DNA lesions produced and repaired before metaphase and; ii) G2-checkpoint adaptation took place as chromosome aberrations (CAs) started to appear in the metaphase, indicating the presence of unrepaired double-strand breaks (DSBs) in the previous G2. The checkpoint ATM/ATR kinases are involved in DSB repair, since the recorded frequency of CAs increased when both kinases were caffeine-abrogated. In genotoxic-treated cells about three-fold higher repair activity was observed in relation to the endogenous background level of DNA lesions. The maximum rate of DNA repaired was 3.4 CAs/100 metaphases/hour, this rise being accompanied by a modest 1.3 fold lengthening of late G2 prophase timing. Because of mitotic chromosome condensation, no DSBs repair can take place until the G1 phase of the next cell cycle, when it occurs by DNA non-homologous end joining (NHEJ). Chromosomal rearrangements formed as a consequence of these error-prone DSB repairs ensure the development of genome instability through the DNA-fusion bridge cycle. Hence, adaptation of the G2 checkpoint supports the appearance of secondary neoplasia in patients pretreated with genotoxic drugs. PMID- 23096363 TI - Structurally conserved C-RFa revealed prolactin releasing activity in vitro and gene expression changes in pituitary of seasonally acclimatized carp. AB - Here we show the cloning and characterization of a novel homolog of prepro C-RFa cDNA from Cyprinus carpio. The deduced preprohormone precursor of 115 amino acids leads to a mature bioactive peptide of 20 amino acids with identical sequence to other teleost C-RFa. Modeling of the mature C-RFa peptide highlighted significant similarity to homologous human PrRP20, specifically the conserved amphipathic system defined by the C-terminal alpha-helix. Clearly, the synthetic C-RFa peptide stimulated prolactin release from primary cultured fish pituitary cells. For the first time, significant variation was shown in C-RFa mRNA and protein levels in the hypothalamus and pituitary between summer- and winter-acclimatized carp. Furthermore, C-RFa protein distribution in carp central nervous tissue was visualized by immunodetection in fibers and cells in hypothalamus, olfactory tract, cerebellum and pituitary stalk. In conclusion, we demonstrated the structure conservation of C-RFa in teleosts and mammals and immunopositive cells and fibers for C-RFa in brain areas. Finally, the increase of C-RFa expression suggests the participation of this hypothalamic factor in the mechanism of modulation in PRL expression in carp. PMID- 23096364 TI - IL-17A levels increase in the infarcted region of the left ventricle in a rat model of myocardial infarction. AB - Th17 cells, a recently described subtype of CD4+ effector lymphocytes, have been linked to cell-mediated autoimmune and inflammatory diseases as well as to cardiovascular diseases. However, the participation of IL-17A in myocardial ischemic injury has not been clearly defined. We therefore conducted the present study to evaluate IL-17A and Th17-related cytokine levels in a rat model of myocardial infarction (MI). MI was induced in male Sprague Dawley rats by coronary artery ligation. Controls were sham-operated (Sh) or non-operated (C). Blood and samples from the left ventricle (LV) were collected at weeks 1 and 4 post-MI. At week 1, MI animals exhibited increased IL-6, IL-23 and TGF-beta mRNA levels with no apparent change in IL-17 mRNA or protein levels in whole LV. Only TGF-beta mRNA remained elevated at week 4 post-MI. However, further analysis revealed that IL-17A mRNA and protein levels as well as IL-6 and IL-23 mRNA were indeed increased in the infarcted region, though not in the remote non infarcted region of the LV, except for IL-23 mRNA. The increased expression of IL-17A and Th17-related cytokines in the infarcted region of LV, suggests that this proinflammatory pathway might play a role in early stages of post MI cardiac remodelling. PMID- 23096365 TI - Microbial evolution in vivo and in silico: methods and applications. AB - Microbial evolution has been extensively studied in the past fifty years, which has lead to seminal discoveries that have shaped our understanding of evolutionary forces and dynamics. It is only recently however, that transformative technologies and computational advances have enabled a larger in scale and in-depth investigation of the genetic basis and mechanistic underpinnings of evolutionary adaptation. In this review we focus on the strengths and limitations of in vivo and in silico techniques for studying microbial evolution in the laboratory, and we discuss how these complementary approaches can be integrated in a unifying framework for elucidating microbial evolution. PMID- 23096367 TI - [Atrial fibrillation in the real world]. AB - In the last two decades atrial fibrillation (AF) has become one of the most important public health problems and a significant cause of increasing healthcare costs in developed countries. The prevalence of AF is ever increasing, and at present, in Italy, it is twice higher (1.85%) than that reported in the past decade. In addition, the ratio of AF frequency among males and females in each age subgroup is always >1.2. In the real world, the commonest AF treatment strategy is "rate control" accounting for 51-56% of all AF patients. Anticoagulant therapy is still underused, in particular among several selected AF patient subgroups. The present findings suggest the need for improving AF patient management through ad hoc educational programs. PMID- 23096368 TI - [New antiarrhythmic drugs for the treatment of atrial fibrillation]. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and a difficult-to-treat arrhythmia. Conventional antiarrhythmic drugs, including flecainide, propafenone, sotalol and amiodarone, have several limitations in terms of efficacy and tolerability, and have made new drug development crucial. In the last decade, intensive research was undertaken to find new pharmacological options for the treatment of AF, and two new drugs are now available. Vernakalant is an atrial-selective drug specifically designed to block sodium channels at the atrial level, and its intravenous formulation has recently been recommended for approval by the Food and Drug Administration for pharmacological conversion of AF. Dronedarone is a chemical derivative of amiodarone (though having a significantly different clinical profile) with effects on multiple ion channels that proved effective in reducing the rate of the combined endpoint of death from any cause and cardiovascular hospitalization in patients with non-permanent AF enrolled in the ATHENA study. The available evidence on the efficacy of dronedarone has led to approval for recommendation in many clinical situations in which rhythm control is desirable. The complexity of the mechanisms underlying AF and the large variability of associated comorbidities render the AF patient a unique entity, making the identification of patients who may benefit from these novel approaches challenging. PMID- 23096366 TI - Renal renin secretion as regulator of body fluid homeostasis. AB - The renin-angiotensin system is essential for body fluid homeostasis and blood pressure regulation. This review focuses on the homeostatic regulation of the secretion of active renin in the kidney, primarily in humans. Under physiological conditions, renin secretion is determined mainly by sodium intake, but the specific pathways involved and the relations between them are not well defined. In animals, renin secretion is a log-linear function of sodium intake. Close associations exist between sodium intake, total body sodium, extracellular fluid volume, and blood volume. Plasma volume increases by about 1.5 mL/mmol increase in daily sodium intake. Several lines of evidence indicate that central blood volume may vary substantially without measurable changes in arterial blood pressure. At least five intertwining feedback loops of renin regulation are identifiable based on controlled variables (blood volume, arterial blood pressure), efferent pathways to the kidney (nervous, humoral), and pathways operating via the macula densa. Taken together, the available evidence favors the notion that under physiological conditions (1) volume-mediated regulation of renin secretion is the primary regulator, (2) macula densa mediated mechanisms play a substantial role as co-mediator although the controlled variables are not well defined so far, and (3) regulation via arterial blood pressure is the exception rather than the rule. Improved quantitative analyses based on in vivo and in silico models are warranted. PMID- 23096369 TI - [Antithrombotic prevention in atrial fibrillation: the new anticoagulant drugs]. AB - Thromboembolic events are the most dangerous complications in patients with atrial fibrillation, affecting the central nervous system in 93% of cases. Vitamin K antagonists have been in clinical use since the '50s for the prevention of thromboembolism. Although effective, vitamin K antagonists have several limitations that render them difficult to administer, which have prompted the need for new antithrombotic strategies. The new class of oral anti-IIa and anti Xa agents appears to be a promising alternative to overcome these limitations. PMID- 23096370 TI - [Radiofrequency catheter ablation of atrial fibrillation: how it has changed since 1996]. AB - By the mid '90s, transcatheter ablation of atrial fibrillation (AF) has undergone a strong and impetuous advance, becoming a well known and worldwide accepted therapeutic procedure offered to patients with different types of AF and clinical features. The present paper aims to describe the main concepts behind the evolution of transcatheter ablation of AF, to review clinical indications, and to analyze current outcomes in terms of efficacy and safety. PMID- 23096371 TI - [Cryoablation: patient selection and current results]. AB - During the last years, cyoablation of atrial fibrillation has become a widely used method for pulmonary vein isolation. This evolution in the use of cryoenergy has been largely justified by the reduction in complications that occurs with radiofrequency energy (pulmonary vein stenosis and atrial-esophageal fistula), in the use of three-dimensional navigation technology, and hence procedural costs. The purpose of this paper is to evaluate the results of this new technology and its safety in terms of its risk-to-benefit profile. PMID- 23096372 TI - [Resuscitated victims of out-of-hospital cardiac arrest: is it always indicated emergent coronary angiography and revascularization?]. AB - Out-of-hospital cardiac arrest with return of spontaneous circulation represents a great challenge even for advanced healthcare systems because of the high risk and frequency of this event. The most common cause of out-of-hospital cardiac arrest is an acute coronary syndrome, and noninvasive diagnostic tools are quite inadequate. The poor outcome observed so far seems to improve significantly when early treatment with hypothermia and myocardial revascularization is performed. Emergent coronary angiography and myocardial revascularization seem to be reasonable and appropriate therapeutic option not only for patients with ST elevation myocardial infarction but also for other patient subsets. PMID- 23096373 TI - [New implantable devices for patient management: role and perspectives of remote monitoring of implantable cardioverter-defibrillators]. AB - A large number of studies have demonstrated that remote control of implantable devices (home monitoring, HM) is beneficial for patients, as it allows strict and tailored controls with earlier identification of potential problems, by avoiding unnecessary visits. HM is also beneficial for hospitals, as it progressively reduces the resources necessary for routine controls and contributes to a better management of critical patients. According to current European and Italian guidelines, HM can replace standard ambulatory monitoring, thereby decreasing the number of outpatient visits for each individual patient (it is possible to schedule a comprehensive clinical evaluation at 1 year rather than every 6-8 months, while performing controls at 1 and 3 months by remote transmission). At present, however, reimbursement of HM services is not covered by the National Health System and, as a consequence, cannot be performed as an institutional activity within the hospital. In addition, many critical issues remain to be resolved before the HM system can be fully implemented into daily clinical management, particularly in patients with heart failure at higher risk for sudden cardiac death. PMID- 23096374 TI - [Subcutaneous implantable cardioverter-defibrillators]. AB - Transvenous implantable cardioverter-defibrillators (ICD) for the primary and secondary prevention of sudden cardiac death due to ventricular tachycardia/fibrillation have led to a significant improvement in survival in high-risk populations. Although conventional transvenous ICD therapy is currently widely used, it is associated with severe intra- and perioperative complications related to the use of transvenous leads, mostly occurring late after implantation. The recent introduction of a new ICD system with fully subcutaneous sensing and shocking capabilities has provided a valuable therapeutic option for special patient groups, allowing to identify and stop malignant ventricular arrhythmias while discriminating them from high-rate supraventricular tachyarrhythmias. This has also given us the opportunity to analyze the advantages and limitations of both implantable lifesaving electrical therapies. In the present paper, the technical characteristics of subcutaneous ICDs are described along with the recent advances in clinical and experimental research that have led to the introduction of these devices into clinical practice (over 1000 patients have been treated worldwide since 2009). Subcutaneous ICDs are indicated for both primary and secondary prevention of cardiac arrest in patients at risk for acquired or congenital arrhythmogenic diseases, including those with an underlying genetic molecular mechanism, provided that they do not require antibradycardia or antitachycardia pacing or cardiac resynchronization therapy, which represent the main limitations of these new devices. A subcutaneous ICD system has the advantage of avoiding the need for transvenous leads, making its implantation or removal much simpler without requiring fluoroscopic guidance. In addition, subcutaneous ICDs can be used in children, young subjects and athletes, and in all patients for whom venous access may be difficult to achieve. PMID- 23096375 TI - [Public access defibrillation in the Sorrento Peninsula]. AB - Early cardiac defibrillation is the only effective therapy to stop ventricular fibrillation or pulseless ventricular tachycardia. It is still considered the gold standard for the treatment of ventricular tachycardia/fibrillation, and is the only intervention capable of improving survival in cardiac arrest survivors. Timing of intervention, however, is crucial because after only 10 min success rates are very low (0-2%). Unfortunately, adequate relief cannot always be provided within the necessary time. The purpose of the public access defibrillation project in Sorrento was to create fixed and mobile first aid with automated external defibrillators in combination with the local 118 emergency system. With the involvement of pharmacies, bathing establishments and schools, 31 equally distant sites for public access defibrillation were made available. This organization was supplemented by mobile units on the cars of the Municipal Police and Civil Protection, and on patrol boats in the harbor. PMID- 23096376 TI - [New pharmacological approaches to ischemic heart disease]. AB - Major steps have been made in the treatment of ischemic heart disease from the discovery of nitrates as antianginal medication to the techniques of percutaneous angioplasty. This incredible therapeutic progress has resulted in a reduced incidence of ischemic heart disease and related mortality and morbidity. However, statistical and epidemiological data indicate that in ischemic heart disease, despite the achievement of great success, there is a necessity for a further step toward treatment, considering the fact that the characteristics of this population are changing (increased prevalence of subendocardial infarction compared with classic transmural infarction, especially in the elderly population). Furthermore, the need for alternative therapeutic approaches to traditional ones is recognized. Ranolazine is a selective inhibitor of Na channels that prevents pathological extension of late Na current developing in the ischemic myocardial cell. This current is responsible for calcium overload, with consequent impairment of diastolic relaxation. Ranolazine reduces Na overload induced by calcium and improves diastolic relaxation and coronary subendocardial flow, without affecting hemodynamic parameters such as blood pressure, heart rate, or inotropic state of the heart, avoiding undesirable side effects. Efficacy of ranolazine has been evaluated in several trials, using clinical and instrumental endpoints (MARISA and CARISA) or, more recently, using endpoints such as mortality and reinfarction (ERICA and MERLIN-TIMI 36). Ivabradine acts through the inhibition of late Na current (also known as If), which controls the spontaneous diastolic depolarization of sinus node cells. The partial inhibition of these channels reduces the frequency of sinus node action potential initiation, resulting in decreased heart rate without effects on contractility, atrio-ventricular conduction, or repolarization. The BEAUTIFUL trial has tested whether the effect of ivabradine in lowering heart rate is able to reduce mortality and cardiovascular morbidity in patients with coronary artery disease and left ventricular systolic dysfunction. The most significant results were obtained in the subgroup of patients with life-limiting exertional angina. In this group, ivabradine significantly reduced the primary endpoint, a composite of cardiovascular death, hospitalization for fatal and nonfatal acute myocardial infarction (AMI) or heart failure, by 24%, and hospitalizations for AMI by 42%. In the subgroup of patients with baseline heart rate >70 bpm, hospitalizations for AMI and revascularization were reduced by 73% and 59%, respectively. PMID- 23096377 TI - [Efficacy of ACE-inhibitors in patients with recent myocardial infarction. Studies with zofenopril]. AB - Several large-scale trials have demonstrated improved survival with the administration of ACE-inhibitors to patients with a recent myocardial infarction. Many ACE-inhibitors with different pharmacological properties have been shown to be safe and effective. More recently the data provided by the Survival of Myocardial Infarction Long-term Evaluation (SMILE) program indicate that zofenopril may favorably affect the prognosis of patients with a recent myocardial infarction and, according to the results of the SMILE-4 study, it may be superior to ramipril with respect to some variables (cardiovascular hospitalizations) when both these ACE-inhibitors are administered combined with acetylsalicylic acid. PMID- 23096378 TI - [Treatment of acute coronary syndromes in the elderly: key messages from the Italian Elderly ACS Study]. AB - Elderly patients account for one third of those admitted to cardiac care units with non-ST-elevation acute coronary syndromes, but are largely underrepresented in randomized clinical trials which form the basis of practice guidelines. Conducting trials in this patient population is especially difficult due to coexisting pathologies, informed consent issues, a perceived higher risk of interventional procedures, and complexity of follow-up. The Italian Elderly ACS Study has been a positive experience in terms of accepting this challenge, carrying it on with limited resources and delineating convincing results, although not statistically conclusive due to its final limited sample size. The indications from the study are straightforward in patients with elevated troponin levels on admission and other high-risk characteristics: in these patients, an early invasive approach has reduced by 40% to 60% the risk of fatal and nonfatal ischemic complications at 1-year follow-up. This result has been achieved with an incidence of bleeding complications which was by far lower than previously reported in the literature, probably due to a systematic radial approach to vascular interventions and a cautious use of antithrombotic treatments in the acute phase. PMID- 23096379 TI - [Management of acute coronary syndromes in elderly patients: a single-center experience]. AB - Demographic studies show an ever increasing number of subjects >65 years among the Italian population. In particular, subjects aged >75 years represent nowadays 9% of the Italian population and are expected to exceed 14% by 2030. In the district of Crema (Italy), subjects aged >75 years are 16 000, and are expected to reach 25 000 by 2030. This phenomenon will result in an increasing number of elderly patients with acute coronary syndromes (ACS) admitted to our hospital. It is therefore necessary to define appropriate guidelines for clinical management of this subset of patients, in order to pursue a reduction in mortality rates and rehospitalizations, while maintaining an acceptable quality of life. These strategies are not adequately supported by international guidelines or randomized studies, where advanced age often represents an exclusion criterion. In our Cardiology Unit, hemodynamic evaluation is performed in all patients >75 years presenting with ST-elevation myocardial infarction (STEMI), ACS, positive troponin I, recurrent episodes of heart failure associated with clinical and instrumental suspicion of ischemia, or in survivors of cardiac arrest without neurological deficit. In all patients, presence of comorbidities is also evaluated, in particular renal insufficiency, disabling cerebrovascular disease, and residual quality of life. From February 2011 to February 2012, 974 coronary angiographies and 692 coronary angioplasties (PTCA) were performed. Of these, 194 procedures were performed in patients >=75 years, the remaining in younger patients. The reason for hospitalization was ACS in 71% of elderly patients versus 53% in younger patients. In elderly patients, drug-eluting stents were used in 30% of the procedures. PTCA was successful in 98% of cases. Main complications included major bleeding (0.8%), access site-related bleeding (all femoral) (2%), and arterial rupture (n = 1). From a technical viewpoint, the radial access was predominantly used (78%), single plain old balloon angioplasty was performed in 12% of the procedures, with tirofiban administration in 42% of cases. Periprocedural and in-hospital mortality was 5%, mainly occurring in patients with STEMI and/or diffuse coronary artery disease. During follow-up, 80% of patients achieved a fairly good quality of life; 15% of patients required rehospitalization for cardiovascular reasons. In conclusion, patient's age should not be regarded as the main key factor for decision-making when evaluating different clinical approaches to patients with ACS. PMID- 23096381 TI - [Indications for percutaneous myocardial revascularization]. AB - Indications and timing of myocardial revascularization procedures are discussed based on the case of a 78-year-old woman suffering from effort angina due to three-vessel coronary artery disease with normal left ventricular function. At present, atherosclerotic patients have a relatively long history of their disease, so that physicians should organize therapeutic strategies resulting from a right trade-off between guidelines of international scientific societies and the peculiar clinical requirements of the individual patient in the particular stage of his/her disease. This kind of tailored therapy may result from a multidisciplinary approach (heart team), which should involve many specialists as comorbidities and frailty of the patients are numerous and significant. PMID- 23096380 TI - [Role of nutrition in heart failure patients]. AB - Heart failure is the leading cause of death and hospitalization in industrialized countries and a major cause of healthcare costs. It is associated with severe symptoms and its prognosis remains poor. Further improvement is needed beyond the results of pharmacological treatment and devices. The role of nutrition has therefore been studied both in the early stages of heart failure, as a tool for the reduction of cardiovascular risk factors and in symptomatic heart failure, for the prevention and treatment of congestion and fluid overload. In addition, dietary supplements, such as n-3 polyunsaturated fatty acids and amino acids, may contribute to the improvement of prognosis and cardiac function, respectively. Finally, in advanced heart failure, nutrition may counteract the effects of muscle wasting and cardiac cachexia through an increase in caloric and protein intake and amino acid supplementation. PMID- 23096382 TI - [Invasive intracoronary imaging in ischemic heart disease]. AB - In the last years, both the increase in percutaneous coronary revascularization and the instance of more reliable and individualized treatments have led interventional cardiologists to seek for a valuable adjunct to angiography in order to improve assessment and treatment of atherosclerotic coronary disease. Intravascular ultrasound (IVUS) allows precise tomographic measurement of lumen area, plaque size, and, to some extent, composition, with low risks and affordable costs. It is not yet clear whether routine use of IVUS provides a middle-to-long-term benefit in prevention of recurrent cardiovascular events. This review reports the main studies on IVUS imaging, underlining impact of ultrasound in the development of contemporary percutaneous revascularization techniques. PMID- 23096383 TI - [Percutaneous treatment of valvular heart diseases]. AB - Surgical valve replacement represents the treatment of choice for symptomatic and severe valvular heart disease. However, the operative risk is increased in presence of advanced age and comorbidities, therefore such patients are often not deemed suitable for surgical treatment. Recently, percutaneous valve replacement has emerged as an optional treatment for such patients, particularly for treating severe aortic stenosis and severe mitral regurgitation. PMID- 23096384 TI - [New frontiers in aortic surgery]. AB - In cardiac surgery, aortic diseases represent an important chapter, and include treatments from the aortic valve to the descending aorta. The infra-diaphragmatic abdominal aorta, generally and historically, is the domain of vascular surgery. Despite the excellent and consolidated results obtained in the treatment of thoracic aortic disease, surgical mortality and morbidity are still relevant, also due to the presence of older patients with more extensive and complex aortic disease. In the last decades, the better knowledge of the aortic issues and the availability of new grafts have resulted in an important evolution of the management, both at the aortic valve and vessel level, with use of transcatheter grafts (transcatheter aortic valve implantation and thoracic endovascular aortic repair). The evidence of the right indications and the long-term results will determine the real usefulness and effectiveness of these "new" procedures and their role as safe and definitive aortic therapies. PMID- 23096385 TI - [Transseptal catheterization: technique and complications]. AB - Transseptal puncture was first described by Ross and Cope, independently, in 1959. This technique was developed predominantly for the diagnostic evaluation of valvular heart disease. After a few years, transseptal catheterization has been replaced by indirect measurements of left atrial pressure using the Swan-Ganz catheter. Recently, there has been a renewed interest in transseptal puncture because of emerging therapeutic procedures for structural heart disease and atrial fibrillation ablation. Current transseptal technique has changed very little since the initial reports, but new tools are now available to facilitate transseptal puncture including echocardiographic imaging (three-dimensional, transesophageal, or intracardiac), radiofrequency powered wires and needle-tipped guidewires. Transseptal catheterization can be performed with high success rates and low complication rates. An Italian survey reported a success rate of 99% with a complication rate of 0.76%. Complications included aortic perforation, pericardial tamponade, ST-segment elevation, cerebral air embolization, systemic embolization, and thrombus formation on the transseptal sheath. PMID- 23096386 TI - [Lights and shadows of guidelines on peripheral arterial disease]. AB - Guidelines have become increasingly important in the choice of the best treatment for each disease. At present, they should be regarded as recommendations drawn from a multidisciplinary and shared interpretation of available scientific information to assist physicians and patients in deciding the most appropriate program of care for a specific clinical condition. Since many years, the TransAtlantic Inter-Society Consensus (TASC) guidelines have represented the reference guidelines for peripheral arterial disease, widely accepted by the scientific community. A continuous update of guidelines should be advisable, at least on a 2-year basis, in order to include new evidence derived from clinical research and practice. In particular, endovascular treatment should be considered the first-line therapeutic option for all patients with peripheral arterial disease, different from what suggested by current guidelines. The results obtained at our Division of Vascular Surgery support this indication, showing a low complication rate and reserving surgery only to selected cases or hybrid procedures. PMID- 23096387 TI - [Early defibrillation with automated external defibrillators during sports events]. AB - Sports-related cardiovascular events may occur in both young athletes and the general population, the latter having a higher absolute risk. In mass gathering sports events, the availability of an onsite emergency response plan including early access to automated external defibrillators by trained lay rescuers has been shown to improve survival among spectators and staff with out-of-hospital cardiac arrest and to reduce subsequent neurological deficit. In addition, in athletes experiencing cardiac arrest, the implementation of public access defibrillation programs demonstrated a favorable mortality trend, with survival rates comparable to those observed in adult sedentary subjects. In Italy and much of Europe, current emergency action plans at sporting events still need full implementation. In particular, in Italy no scientific statements on this topic have been developed. In order to compensate this lack of information, an ad hoc task force has been established with representatives of the major scientific societies involved in sports-based health and disease prevention, with the aim to address public access defibrillation programs for sporting events, and to promote awareness of appropriate cardiovascular emergency care at sports arenas. PMID- 23096388 TI - [Provocative tests and electrophysiological study in athletes]. AB - Provocative tests can be divided into three main categories: first-level or screening tests, consisting basically of step test, which all athletes undergo during pre-participation screening; second-level tests, which include exercise test (simple or cardiopulmonary), performed on the basis of specific clinical indications or for the assessment of functional capacity; and third-level tests, consisting of complex methods such as myocardial scintigraphy and stress echo (or exercise echo), which are performed in subjects adequately selected according to clinical characteristics or to the results of first- and second-level tests. The electrophysiological endocavitary study has specific indications in sustained or frequent ventricular arrhythmias, while it is not useful in diagnostic evaluation of athletes with supraventricular arrhythmias, where it has been replaced in most cases by transesophageal electrophysiological study. PMID- 23096389 TI - [Pathophysiology of atrioventricular conduction disturbances in sports practitioners]. AB - In athletes practicing endurance sports, atrioventricular conduction disturbances may be physiological. This holds true for first-degree atrioventricular blocks, type 1 second-degree atrioventricular blocks, and slight ventricular activation delays (slurred S wave in V1). On the contrary, right (RBBB) and left bundle branch blocks (LBBB) and fascicular blocks (left anterior [LAH] and left posterior hemiblocks [LPH]), either isolated or associated with RBBB, are rare in asymptomatic athletes. The latter can be the consequence of structural heart disease or primary degeneration of the intraventricular conduction system (Lev Lenegre disease). In our experience, LPH and LPH+RBBB have always a pattern of familial recurrence. LAH+RBBB may be familial (40-60%). Isolated RBBB is rarely familial. LBBB is never familial. Families with hereditary conduction disorders may also have a history of juvenile sudden death. Patients with LBBB may show coronary artery anomalies. The long-term prognosis of intraventricular conduction disorders in asymptomatic subjects, without apparent heart disease, is unknown. PMID- 23096390 TI - [Competitive sports and leisure-time physical activity in patients with coronary heart disease]. AB - During recent years, the central role of exercise in the prevention of cardiovascular disease has gradually been demonstrated, and in 2003 the consensus document of the Council on Clinical Cardiology and Council on Nutrition, Physical Activity and Metabolism on the role of physical exercise in the prevention and treatment of coronary artery disease defined sedentary lifestyle as a modifiable independent cardiovascular risk factor, responsible for 12% of total mortality in the United States and for a 1.9-fold increase in the risk of ischemic heart disease. The reduction in cardiovascular mortality and cardiac ischemic events in subjects who perform regular physical activity is mainly due to the action that exercise plays on the control of cardiovascular risk factors. In particular, physical training has proved capable of improving lipid profile, reducing blood pressure and body weight, and improving glycemic control in diabetic subjects. In patients with coronary artery disease, combined exercise training, including both aerobic activities and strength training, is currently recommended. However, physical training in patients suffering from ischemic heart disease should be carefully prescribed, in order to maximize the positive effects and minimize the risks. It is also important that physical training programs are conducted in suitable facilities, with appropriately trained staff and with technical equipment suitable to deal with any emergency situations. PMID- 23096392 TI - [Novel fitness techniques: patient selection and cardiovascular impact]. AB - The main objective of this study was to evaluate a number of metabolic and cardiovascular variables during a standard 50 min class performed by spinning bike instructors of both sexes: 6 males and 6 females. Mean power output, heart rate, and oxygen uptake during the performance were 120 +/- 4 W, 136 +/- 13 bpm, and 32.8 +/- 5.4 ml/kg/min respectively for males, and 73 +/- 43 W, 143 +/- 25 bpm, and 30 +/- 9.9 ml/kg/min respectively for females. The analysis of individual performances showed that these were compatible with a physical exercise that ranged from moderate to heavy, to very heavy, the latter condition definitely prevailing. Results show that this type of fitness activity has a high impact on cardiovascular function, and suggest that it is unsuitable for unfit or sedentary individuals, especially if middle aged or elderly, who are willing to begin a recreational physical activity program. PMID- 23096391 TI - [Italian cold cuts evolution. New opportunities for diet in athletes]. AB - Italian cold cuts were not recommended for cardiac patients, healthy people, and athletes because of their high content in salt, fat, calories, and cholesterol. Recent studies from INRAN (National Institute of Research for Food and Nutrition) have provided new insights into Italian cold cuts, showing that they are more digestible, with less sodium, fat, cholesterol and calories, than previous products. Thanks to these new chemical-physical characteristics, Italian cold cuts can now be indicated for nutrition in the general population and athletes. PMID- 23096393 TI - [Heart failure: epidemiology, costs and healthcare programs in Italy]. AB - Epidemiological data show an even greater prevalence of heart failure in the general population, in particular in elderly people, both in Italy and the other European countries. Patients admitted to hospital because of heart failure are commonly complex patients with relevant comorbidities and frequent readmissions. Hospital care accounts largely for the costs due to heart failure, whereas expenditure for therapies (drugs, devices and surgery) is less significant; non medical and social costs represent also a relevant part of total costs. By far, the real challenge in the care of heart failure patients consists in the efforts to reduce hospital readmissions. A broad spectrum of interventions has been proposed for improving care of heart failure patients: multidisciplinary interventions involving physicians and nurses consisting of different modalities of transtelephonic monitoring have been demonstrated to be effective in reducing readmission rates and improving patient outcome. New technologies for remote monitoring with implantable devices (defibrillators and pacemakers) are becoming the standard of clinical practice in a great number of cardiology departments in our country. In addition, implantable devices for automatic and continuous hemodynamic monitoring are in an advanced phase of clinical evaluation. In conclusion, new modalities of care, centered on out-of-hospital assistance by means of interactive as well as automatic remote monitoring, are now available and seem to impact positively on the growing need for resources to be allocated to the care of heart failure patients. PMID- 23096394 TI - [Chronic heart failure therapy: where we are and where we are going to]. AB - Despite significant advances in pharmacological and non-pharmacological therapy, epidemiological data from European and US hospitals show that the prevalence of heart failure (HF) hospitalization, especially for patients >65 years, continues to rise. Hospitalization for worsening HF is one of the most important predictors of short- and long-term outcomes in patients with chronic HF. There is therefore a clear need for new therapies that can work synergistically with standard medications to reverse the progression of the disease and improve myocardial efficiency. In the last years, researches in chronic HF focused on drugs that can exert a greater attenuation of neurohormonal activation and that can improve cardiac energy and substrate utilization. PMID- 23096395 TI - [How to identify non-responders to cardiac resynchronization therapy]. AB - Cardiac resynchronization therapy (CRT) has been shown to improve survival, morbidity, symptoms, quality of life and exercise capacity, and to promote a beneficial reverse remodeling of the left ventricle in patients with heart failure, dilated hypokinetic left ventricle and wide QRS. The totality of evidence supports the use of CRT also in patients with mild symptoms (NYHA class II). However, the wider diffusion of CRT is determining a growing clinical and economic impact on national health systems. In clinical practice, in spite of "all-or-none" response, variable degrees of therapy response are commonly observed, but several evidence gaps remain to be addressed. According to recent guidelines for CRT implantation, a multiparametric combination of predictive factors emerging from the analysis of clinical trials, observational studies and registries, represents a useful tool for patient selection. PMID- 23096396 TI - [What benefits of cardiac resynchronization therapy in patients with narrow QRS?]. AB - Cardiac resynchronization therapy (CRT) is indicated for patients with electrical dyssynchrony (QRS >=120 ms). However, mechanical dyssynchrony may also occur in patients with narrow QRS. Echocardiographic criteria of intraventricular dyssynchrony are not univocal; moreover, responsiveness to CRT depends on the criteria utilized for judgment. A unique randomized trial compared CRT with no therapy in patients with heart failure and narrow QRS, but it failed to demonstrate increased peak oxygen consumption with CRT. The results of this study probably depend on the lack of correspondence between activation and contraction delays, at least in ischemic cardiomyopathy. PMID- 23096397 TI - [Medical-legal issues in remote monitoring of implantable cardioverter defibrillators]. AB - Patients with implanted automatic defibrillators should undergo careful monitoring during follow-up and may require access to the emergency department or hospitalization for device-related problems. Nowadays, the progressive development of information technology allows remote monitoring of patients with cardiac defibrillators using dedicated systems which make it possible to transfer clinical and technical data derived from device interrogation to the Cardiology Center through telephonic line. In patients with an implantable defibrillator, remote monitoring is effective in identifying device malfunctioning and clinical problems, such as heart failure, to an extent similar to traditional ambulatory monitoring, while allowing significant advantages for the patient quality of life and savings in resource management. This different way of organizing care has created new problems in terms of responsibility for manufacturers, responsible for the technical aspect, for the healthcare system, responsible for service supply and management, and for the physician, who should supervise the whole process and ensure the safety of the information provided. Telemedicine is configured as a highly complex activity and therefore any treatment provided through it will, in terms of responsibility, be assessed bearing in mind that "if performance involves the solution of technical problems of special difficulty, lenders are not liable for damages, except in cases of intent or gross negligence". Also important are minor legal issues, such as permissions, problems of inaccessibility to the service, the assessment of medical liability compared to the activity of the team, and all issues related to informed consent and privacy protection. PMID- 23096399 TI - [Presentation]. PMID- 23096398 TI - [Cardiovascular complications of chemotherapy]. AB - In the last decades, oncological therapy has changed the natural history of many types of cancer, which can now be considered curable or as chronic or slowly progressive diseases. It is well known that chemotherapy and radiotherapy may induce cardiotoxicity. Anthracyclines are among the most active antineoplastic agents, and their cardiac effects have been known for a long time. In addition, there is an emerging role for potential cardiovascular effects of other chemotherapy drugs such as taxanes, antimetabolites (capecitabine) as well as targeted agents (monoclonal antibody trastuzumab and bevacizumab and the tyrosin kinase inhibitor sunitinib). Patient treated with chemotherapy are at higher risk of cardiovascular events than the general population, so that having undergone chemotherapy may be considered as a novel cardiovascular risk factor. This review briefly summarizes the most important cardiovascular toxicities caused by antineoplastic pharmacological treatment and how cardiologists, oncologists and general practitioners should approach cancer patients while on treatment or during follow-up to prevent or manage cardiovascular events. PMID- 23096400 TI - Metabolically active microbial communities in marine sediment under high-CO(2) and low-pH extremes. AB - Sediment-hosting hydrothermal systems in the Okinawa Trough maintain a large amount of liquid, supercritical and hydrate phases of CO(2) in the seabed. The emission of CO(2) may critically impact the geochemical, geophysical and ecological characteristics of the deep-sea sedimentary environment. So far it remains unclear whether microbial communities that have been detected in such high-CO(2) and low-pH habitats are metabolically active, and if so, what the biogeochemical and ecological consequences for the environment are. In this study, RNA-based molecular approaches and radioactive tracer-based respiration rate assays were combined to study the density, diversity and metabolic activity of microbial communities in CO(2)-seep sediment at the Yonaguni Knoll IV hydrothermal field of the southern Okinawa Trough. In general, the number of microbes decreased sharply with increasing sediment depth and CO(2) concentration. Phylogenetic analyses of community structure using reverse transcribed 16S ribosomal RNA showed that the active microbial community became less diverse with increasing sediment depth and CO(2) concentration, indicating that microbial activity and community structure are sensitive to CO(2) venting. Analyses of RNA-based pyrosequences and catalyzed reporter deposition fluorescence in situ hybridization data revealed that members of the SEEP-SRB2 group within the Deltaproteobacteria and anaerobic methanotrophic archaea (ANME 2a and -2c) were confined to the top seafloor, and active archaea were not detected in deeper sediments (13-30 cm in depth) characterized by high CO(2). Measurement of the potential sulfate reduction rate at pH conditions of 3-9 with and without methane in the headspace indicated that acidophilic sulfate reduction possibly occurs in the presence of methane, even at very low pH of 3. These results suggest that some members of the anaerobic methanotrophs and sulfate reducers can adapt to the CO(2)-seep sedimentary environment; however, CO(2) and pH in the deep-sea sediment were found to severely impact the activity and structure of the microbial community. PMID- 23096401 TI - The role of local environment and geographical distance in determining community composition of arbuscular mycorrhizal fungi at the landscape scale. AB - Arbuscular fungi have a major role in directing the functioning of terrestrial ecosystems yet little is known about their biogeographical distribution. The Baas Becking hypothesis ('everything is everywhere, but, the environment selects') was tested by investigating the distribution of arbuscular mycorrhizal fungi (AMF) at the landscape scale and the influence of environmental factors and geographical distance in determining community composition. AMF communities in Trifolium repens and Lolium perenne roots were assessed in 40 geographically dispersed sites in Ireland representing different land uses and soil types. Field sampling and laboratory bioassays were used, with AMF communities characterised using 18S rRNA terminal-restriction fragment length polymorphism. Landscape-scale distribution of AMF was driven by the local environment. AMF community composition was influenced by abiotic variables (pH, rainfall and soil type), but not land use or geographical distance. Trifolium repens and L. perenne supported contrasting communities of AMF, and the communities colonising each plant species were consistent across pasture habitats and over distance. Furthermore, L. perenne AMF communities grouped by soil type within pasture habitats. This is the largest and most comprehensive study that has investigated the landscape-scale distribution of AMF. Our findings support the Baas-Becking hypothesis at the landscape scale and demonstrate the strong influence the local environment has on determining AMF community composition. PMID- 23096402 TI - Nutrient requirements for growth of the extreme oligotroph 'Candidatus Pelagibacter ubique' HTCC1062 on a defined medium. AB - Chemoheterotrophic marine bacteria of the SAR11 clade are Earth's most abundant organisms. Following the first cultivation of a SAR11 bacterium, 'Candidatus Pelagibacter ubique' strain HTCC1062 (Ca. P. ubique) in 2002, unusual nutritional requirements were identified for reduced sulfur compounds and glycine or serine. These requirements were linked to genome streamlining resulting from selection for efficient resource utilization in nutrient-limited ocean habitats. Here we report the first successful cultivation of Ca. P. ubique on a defined artificial seawater medium (AMS1), and an additional requirement for pyruvate or pyruvate precursors. Optimal growth was observed with the collective addition of inorganic macro- and micronutrients, vitamins, methionine, glycine and pyruvate. Methionine served as the sole sulfur source but methionine and glycine were not sufficient to support growth. Optimal cell yields were obtained when the stoichiometry between glycine and pyruvate was 1:4, and incomplete cell division was observed in cultures starved for pyruvate. Glucose and oxaloacetate could fully replace pyruvate, but not acetate, taurine or a variety of tricarboxylic acid cycle intermediates. Moreover, both glycine betaine and serine could substitute for glycine. Interestingly, glycolate partially restored growth in the absence of glycine. We propose that this is the result of the use of glycolate, a product of phytoplankton metabolism, as both a carbon source for respiration and as a precursor to glycine. These findings are important because they provide support for the hypothesis that some micro-organisms are challenging to cultivate because of unusual nutrient requirements caused by streamlining selection and gene loss. Our findings also illustrate unusual metabolic rearrangements that adapt these cells to extreme oligotrophy, and underscore the challenge of reconstructing metabolism from genome sequences in organisms that have non-canonical metabolic pathways. PMID- 23096403 TI - Comparable light stimulation of organic nutrient uptake by SAR11 and Prochlorococcus in the North Atlantic subtropical gyre. AB - Subtropical oceanic gyres are the most extensive biomes on Earth where SAR11 and Prochlorococcus bacterioplankton numerically dominate the surface waters depleted in inorganic macronutrients as well as in dissolved organic matter. In such nutrient poor conditions bacterioplankton could become photoheterotrophic, that is, potentially enhance uptake of scarce organic molecules using the available solar radiation to energise appropriate transport systems. Here, we assessed the photoheterotrophy of the key microbial taxa in the North Atlantic oligotrophic gyre and adjacent regions using (33)P-ATP, (3)H-ATP and (35)S-methionine tracers. Light-stimulated uptake of these substrates was assessed in two dominant bacterioplankton groups discriminated by flow cytometric sorting of tracer labelled cells and identified using catalysed reporter deposition fluorescence in situ hybridisation. One group of cells, encompassing 48% of all bacterioplankton, were identified as members of the SAR11 clade, whereas the other group (24% of all bacterioplankton) was Prochlorococcus. When exposed to light, SAR11 cells took 31% more ATP and 32% more methionine, whereas the Prochlorococcus cells took 33% more ATP and 34% more methionine. Other bacterioplankton did not demonstrate light stimulation. Thus, the SAR11 and Prochlorococcus groups, with distinctly different light-harvesting mechanisms, used light equally to enhance, by approximately one-third, the uptake of different types of organic molecules. Our findings indicate the significance of light-driven uptake of essential organic nutrients by the dominant bacterioplankton groups in the surface waters of one of the less productive, vast regions of the world's oceans-the oligotrophic North Atlantic subtropical gyre. PMID- 23096404 TI - Collaborative cloud-enabled tools allow rapid, reproducible biological insights. PMID- 23096405 TI - Antagonism influences assembly of a Bacillus guild in a local community and is depicted as a food-chain network. AB - Understanding the principles that govern community assemblages is a central goal of ecology. There is limited experimental evidence in natural settings showing that microbial assembly in communities are influenced by antagonistic interactions. We, therefore, analyzed antagonism among bacterial isolates from a taxonomically related bacterial guild obtained from five sites in sediments from a fresh water system. We hypothesized that if antagonistic interactions acted as a shaping force of the community assembly, then the frequency of resistance to antagonism among bacterial isolates originating from a given site would be higher than the resistance to conspecifics originating from a different assemblage. Antagonism assays were conducted between 78 thermoresistant isolates, of which 72 were Bacillus spp. Sensitive, resistant and antagonistic isolates co-occurred at each site, but the within-site frequency of resistance observed was higher than that observed when assessed across-sites. We found that antagonism results from bacteriocin-like substances aimed at the exclusion of conspecifics. More than 6000 interactions were scored and described by a directed network with hierarchical structure that exhibited properties that resembled a food chain, where the different Bacillus taxonomic groups occupied specific positions. For some tested interacting pairs, the unidirectional interaction could be explained by competition that inhibited growth or completely excluded one of the pair members. This is the first report on the prevalence and specificity of Bacillus interactions in a natural setting and provides evidence for the influence of bacterial antagonist interactions in the assemblage of a taxonomically related guild in local communities. PMID- 23096406 TI - Pitfalls in screening streptococci for retrieving superior streptokinase (SK) genes: no activity correlation for streptococcal culture supernatant and recombinant SK. AB - Streptokinase (SK), the heterogeneous protein family secreted by some groups of beta-hemolytic streptococci (betaHS), is a plasminogen activator and well-known drug for thrombolytic therapy. Differences in plasminogen activation property of streptococcal culture supernatants (SCS) have been traditionally used to identify superior producer strains and SK genes (skc) for recombinant SK (rSK) production. However, the role of SK heterogeneity and whether SK activities in SCS correlate with that of their corresponding rSK is a matter of debate. To address these concerns, SCS of nine group C streptococci (GCS) screened among 252 betaHS clinical isolates were compared for plasminogen activation using S-2251 chromogenic assay. The GCS (Streptococcus equisimilis) showing the highest (GCS S87) and lowest (GCS-S131) activities were selected for PCR-based isolation of skc, cloning and rSK production in Escherichia coli. The 6*His-tagged rSK proteins were purified by NI-NTA chromatography, analyzed by SDS-PAGE and Western blotting and their activities were determined. While SCS of GCS-S87 and GCS-S131 showed different plasminogen activations (95 and 35 %, respectively) compared to that of the reference strain (GCS-9542), but interestingly rSK of all three strains showed close specific activities (1.33, 1.70, and 1.55 * 10(4) IU mg( 1)). Accordingly, SKS87 and SKS131 had more than 90 % sequence identity at the amino acids level compared to SK9542. Therefore, SK heterogeneity by itself may not contribute to the differences in plasminogen activation properties of SCS and evaluation of this activity in SCS might not be a proper assay for screening superior skc. PMID- 23096407 TI - Low aerobic capacity and physical activity not associated with fatigue in patients with rheumatoid arthritis: a cross-sectional study. AB - OBJECTIVE: To explore whether low aerobic capacity and physical activity are associated with fatigue, when controlling for age, gender, pain and depressive symptoms in persons with rheumatoid arthritis. METHODS: In 60 individuals fatigue (Multidimensional Assessment of Fatigue scale; MAF), disease activity (Disease Activity Score-28; DAS 28), pain, physical and psychological status (Arthritis Impact Measurement Scales 2; AIMS 2), depression (Hospital Anxiety and Depression Scale; HADS), aerobic capacity and physical activity (Short Questionnaire to Assess Health-enhancing physical activity; SQUASH) were measured. Regression was performed to study the variance of fatigue explained by aerobic capacity and physical activity. RESULTS: Mean (standard deviation (SD)) age of participants was 51.8 (SD 10.4) years and 73.3% were women. Duration of disease was 10.2 (SD 0 41) years and mean disease activity score was 3.4 (SD 1.4). Mean Global Fatigue Index was 20.3 (SD 10.5). Physical function was 1.6 (SD 1.1) and psychological status 3.1 (SD 0-8) on the AIMS2. Pain score was 4.1 (SD 2.0) and median depression score was 3.2 (range 0-15). Total amount of physical activity was 176.9 (10.6-1,492.3) METhours/week and VO2max was 27.8 (SD 3.8) ml/kg/min. Backward multiple regression showed a statistically significant relationship with depressive symptoms only (t = 5.4, p < 0.001), which explained 33% of variance of fatigue in patients with RA. CONCLUSION: Depression, but not aerobic capacity or physical activity, contributed to fatigue. However, no relationship was found between aerobic capacity and fatigue. PMID- 23096408 TI - Low density lipoprotein receptor-related protein 1 is upregulated in epicardial fat from type 2 diabetes mellitus patients and correlates with glucose and triglyceride plasma levels. AB - Lipoprotein receptor expression plays a crucial role in the pathophysiology of adipose tissue in in vivo models of diabetes. However, there are no studies in diabetic patients. The aims of this study were to analyze (a) low-density lipoprotein receptor-related protein 1 (LRP1) and very low-density lipoprotein receptor (VLDLR) expression in epicardial and subcutaneous fat from type 2 diabetes mellitus compared with nondiabetic patients and (b) the possible correlation between the expression of these receptors and plasmatic parameters. Adipose tissue biopsy samples were obtained from diabetic (n = 54) and nondiabetic patients (n = 22) undergoing cardiac surgery before the initiation of cardiopulmonary bypass. Adipose LRP1 and VLDLR expression was analyzed at mRNA level by real-time PCR and at protein level by Western blot analysis. Adipose samples were also subjected to lipid extraction, and fat cholesterol ester, triglyceride, and free cholesterol contents were analyzed by thin-layer chromatography. LRP1 expression was higher in epicardial fat from diabetic compared with nondiabetic patients (mRNA 17.63 +/- 11.37 versus 7.01 +/- 4.86; P = 0.02; protein 11.23 +/- 7.23 versus 6.75 +/- 5.02, P = 0.04). VLDLR expression was also higher in epicardial fat from diabetic patients but only at mRNA level (231.25 +/- 207.57 versus 56.64 +/- 45.64, P = 0.02). No differences were found in the expression of LRP1 or VLDLR in the subcutaneous fat from diabetic compared with nondiabetic patients. Epicardial LRP1 and VLDLR mRNA overexpression positively correlated with plasma triglyceride levels (R(2) = 0.50, P = 0.01 and R(2) = 0.44, P = 0.03, respectively) and epicardial LRP1 also correlated with plasma glucose levels (R(2) = 0.33, P = 0.03). These results suggest that epicardial overexpression of certain lipoprotein receptors such as LRP1 and VLDLR expression may play a key role in the alterations of lipid metabolism associated with type 2 diabetes mellitus. PMID- 23096409 TI - Inhibitory potential of a novel imidazole derivative as evaluated by time-kill and dehydrogenase activity. AB - Antibacterial activity of 1,1'-methandiylbis(2-methyl-1H-imidazole) (AIM) has been estimated both qualitatively and quantitatively against reference and clinical strains of Gram-positive and Gram-negative bacteria. MICs showed little variability among strains tested, ranging from 360 to 450 MUg/ml and indicating rather a moderate antibacterial activity. Inhibition of dehydrogenase activity was significant in Escherichia coli ATCC 25922 and followed closely time-kill dynamics. Although moderate, AIM proved also to be useful on the ability to successfully inhibit the growth of antibiotic resistant clinical strains. PMID- 23096410 TI - Attempting homicide by inserting sewing needles into the brain. PMID- 23096412 TI - Double arterial catheterization technique for embolization of brain arteriovenous malformations with onyx. AB - BACKGROUND: Arteriovenous malformation (AVM) treatment is multidisciplinary, and the patient may undergo embolization, neurosurgery, or radiosurgery combined. Great improvement in endovascular techniques was provided by the introduction of Onyx with different kinds of approach. OBJECTIVE: To evaluate the efficacy and the safety of Onyx embolization of brain AVMs with the double arterial catheterization technique (DACT). METHODS: This was a retrospective study. From January 2006 until June 2011, 61 AVMs eligible for the DACT were treated. Forty one of the 61 AVMs were treated with single arterial catheterization technique and 20 of 61 with DACT; patient age and Spetzler-Martin AVM grade were similar in the 2 groups. RESULTS: In the DACT group, we obtained complete occlusion of the nidus in all small AVMs, whereas in the single arterial catheterization technique group, we obtained complete occlusion in only 1 of the 36% of the cases. Among the medium-size AVMs, there were no significant differences in the 2 groups, but we performed fewer procedures per patient when we used the DACT (1.4 vs 2.2). In the DACT group, we observed fewer hemorrhagic complications (3.4% vs 12.5% per procedure) and lower morbidity (5% vs 7% per patient) and mortality (0% vs 2.4%) rates. CONCLUSION: The DACT in multifeeder AVMs may lead to a higher occlusion rate of the nidus for small AVMs and reduce the number of procedures, ensuring a higher standard of safety because of the possibility of managing the progression of Onyx into venous drainage. PMID- 23096411 TI - ELTD1, a potential new biomarker for gliomas. AB - BACKGROUND: Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. OBJECTIVE: To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma associated marker via a bioinformatic method. METHODS: We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry, which was used to detect levels of ELTD1 in human high grade gliomas and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular magnetic resonance imaging. RESULTS: ELTD1 was found to be significantly higher (P = .03) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients) and compared well with traditional immunohistochemistry markers including vascular endothelial growth factor, glucose transporter 1, carbonic anhydrase IX, and hypoxia-inducible factor 1alpha. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P < .001) in vivo levels of ELTD1 were additionally found in F98 tumors compared with normal brain tissue. CONCLUSION: Results of this study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas and may serve as an additional biomarker for gliomas in preclinical and clinical diagnosis of gliomas. PMID- 23096414 TI - Aneurysm formation in proinflammatory, transgenic haptoglobin 2-2 mice. AB - BACKGROUND: Inflammation and macrophages in particular are believed to play a role in aneurysm formation. The haptoglobin (Hp) 2-2 genotype is associated with a proinflammatory state. OBJECTIVE: To investigate the role of inflammation in the formation of aneurysms using a murine model of aneurysm formation in transgenic, proinflammatory Hp2-2 mice and wild-type Hp1-1 mice. METHODS: Carotid artery aneurysms were induced in the left common carotid artery of wild-type Hp1 1 mice and transgenic Hp2-2 mice using elastase to degrade the arterial wall of the common carotid artery and angiotensin II to induce hypertension. There were 4 experimental groups: (1) sham surgery (n = 11); (2) angiotensin II only (n = 10); (3) elastase only (n = 20); and (4) elastase + angiotensin II (n = 20). Aneurysm size was determined by measuring the outer circumference and luminal circumference of the blood vessel. Macrophages that infiltrated the aneurysm wall were quantified by immunohistochemistry. Results were analyzed using 2-way analysis of variance with a Bonferroni post-test. RESULTS: Aneurysms in Hp2-2 mice were significantly larger than aneurysms in Hp1-1 mice in the setting of vessel wall degradation and hypertension (P = .02 for outer circumference, P = .01 for luminal circumference). Furthermore, the number of macrophages infiltrating the aneurysm wall was significantly increased in Hp2-2 mice (P < .001). CONCLUSION: Hp2-2 mice formed aneurysms that were significantly larger and had a significantly greater number of macrophages in the aneurysm wall compared with Hp1-1 mice. This suggests that the proinflammatory state associated with the Hp2-2 protein is involved in aneurysm formation and that the Hp genotype may be a useful biomarker in predicting aneurysm progression. PMID- 23096413 TI - Increased xCT expression correlates with tumor invasion and outcome in patients with glioblastomas. AB - BACKGROUND: xCT is a light chain of the cystine/glutamate antiporter system xc. Glutamate that is released by system xc plays an important role in the infiltration of glioblastoma (GBM) cells. Furthermore, increased glutathione synthesis by system xc may protect tumor cells against oxidative stress induced by radiotherapy and chemotherapy. OBJECTIVE: To investigate whether the levels of xCT expression correlated with infiltrative imaging phenotypes on magnetic resonance imaging and outcomes in patients with GBMs. METHODS: Forty patients with histologically confirmed primary GBMs were included in the study. Patient charts were retrospectively reviewed for age, sex, Karnofsky Performance Status Scale score, Mini-Mental State Examination score, magnetic resonance imaging features, xCT expression, isocitrate dehydrogenase 1 R132H expression, O methylguanine-DNA methyltransferase promoter methylation status, type of surgery, progression-free survival, and overall survival. RESULTS: In invasive margins, xCT expression was weak in 20 patients and strong in 20 patients. A Cox regression model revealed that a Karnofsky Performance Status Scale score less than 60 (hazard ratio [HR]: 4.525; P = .01), partial removal (HR: 2.839; P = .03), and strong xCT expression (HR: 4.134; P < .001) were significantly associated with shorter progression-free survival and that partial removal (HR: 2.865; P = .03), weak isocitrate dehydrogenase 1 R132H expression (HR: 15.729; P = .01), and strong xCT expression (HR: 2.863; P = .04) were significantly associated with shorter overall survival. CONCLUSION: These findings suggest that xCT is an independent predictive factor in GBMs. PMID- 23096415 TI - The postnatal human filum terminale is a source of autologous multipotent neurospheres capable of generating motor neurons. AB - BACKGROUND: Neural progenitor cells (NPCs) are undifferentiated and mitotic and can be induced to differentiate into neurons and glia, the building blocks of the nervous system. NPCs have great therapeutic potential for nervous system trauma and degenerative disorders. They have been identified in the mammalian central nervous system, but current sources are difficult to access surgically and come from regions that are critical for normal brain function. OBJECTIVE: To identify and characterize in detail a novel source of human NPCs in the filum terminale (FT), a vestigial structure at the caudal end of the spinal cord, which is easily accessed and plays no functional role in the postnatal nervous system. METHODS: Cells were isolated and cultured in vitro from the FT of terminated fetuses and from children and adolescents who had undergone surgical resections for tethered spinal cords. Cell culture techniques, immunohistochemistry, and immunocytochemistry were applied to examine FT cells. RESULTS: : FT cells gave rise to neurospheres that proliferated over extended periods of time in culture. These neurospheres were positive for neural stem/progenitor cell markers by immunocytochemical staining. The neurospheres were able to be induced to differentiate in vitro into neurons and glial cells, which were confirmed by the use of antibodies against the cell type-specific markers. Moreover, they have been induced to form motor neurons capable of innervating striated muscle in vitro. CONCLUSION: Multipotent NPC cells from the FT are both accessible and expendable. They may allow autologous cell-based transplantation therapy that circumvents immunological rejection. PMID- 23096416 TI - Patterns of aneurysm recurrence after microsurgical clip obliteration. AB - BACKGROUND: Microsurgical clip obliteration remains a time-honored and viable option for the treatment of select aneurysms with very low rates of recurrence. OBJECTIVE: We studied previously clipped aneurysms that were found to have recurrences to better understand the patterns and configurations of these rare entities. METHODS: A retrospective review was performed of 2 prospectively maintained databases of aneurysm treatments from 2 institutions spanning 14 years to identify patients with recurrence of previously clipped intracranial aneurysms. RESULTS: Twenty-six aneurysm recurrences were identified. Three types of recurrence were identified: type I, proximal to the clip tines; type II, distal; and type III, lateral. The most common type of recurrence was that arising distal to the clip tines (46.1%), and the least frequently encountered recurrence was that arising proximal to the tines (19.2%). Laterally located recurrences were found in 34.6% of cases. CONCLUSION: We describe 3 different patterns of aneurysm recurrence with respect to clip application: those occurring proximal, distal, or lateral to the clip tines. PMID- 23096417 TI - Point-of-Care Programming for Neuromodulation: A Feasibility Study Using Remote Presence. AB - BACKGROUND: The expansion of neuromodulation and its indications has resulted in hundreds of thousands of patients with implanted devices worldwide. Because all patients require programming, this growth has created a heavy burden on neuromodulation centers and patients. Remote point-of-care programming may provide patients with real-time access to neuromodulation expertise in their communities. OBJECTIVE: To test the feasibility of remotely programming a neuromodulation device using a remote-presence robot and to determine the ability of an expert programmer to telementor a nonexpert in programming the device. METHODS: A remote-presence robot (RP-7) was used for remote programming. Twenty patients were randomly assigned to either conventional programming or a robotic session. The expert remotely mentored 10 nurses with no previous experience to program the devices of patients assigned to the remote-presence sessions. Accuracy of programming, adverse events, and satisfaction scores for all participants were assessed. RESULTS: There was no difference in the accuracy or clinical outcomes of programming between the standard and remote-presence sessions. No adverse events occurred in any session. The patients, nurses, and the expert programmer expressed high satisfaction scores with the remote-presence sessions. CONCLUSION: This study establishes the proof-of-principle that remote programming of neuromodulation devices using telepresence and expert telementoring of an individual with no previous experience to accurately program a device is feasible. We envision a time in the future when patients with implanted devices will have real-time access to neuromodulation expertise from the comfort of their own home. PMID- 23096418 TI - Spinal glomus (type II) arteriovenous malformations: a pooled analysis of hemorrhage risk and results of intervention. AB - BACKGROUND: The natural history and treatment results for spinal glomus (type II) arteriovenous malformations (AVMs) remain relatively obscure. OBJECTIVE: To calculate spinal glomus (type II) AVM hemorrhages rates and amalgamate results of intervention. METHODS: We performed a pooled analysis via the PubMed database through May 2012, including studies with at least 3 cases. Data on individual patients were extracted and analyzed using a Cox proportional hazards regression model to obtain hazard ratios for hemorrhage risk factors. RESULTS: The annual hemorrhage rate before treatment was 4% (95% confidence interval [confidence interval]: 3%-6%), increasing to 10% (95% CI: 7%-16%) for AVMs with previous hemorrhage. The hazard ratio for hemorrhage after hemorrhagic presentation was 2.25 (95% CI: 0.71-7.07), increasing to 13.0 within the first 10 years (95% CI: 1.44-118). The overall rates of complete obliteration were 78% (95% CI: 72%-83%) for surgery and 33% (95% CI: 24%-43%) for endovascular treatment. Long-term clinical worsening occurred in 12% of patients after surgical treatment (95% CI: 8%-16%) and in 13% after endovascular treatment (95% CI: 7%-21%). No hemorrhages occurred after complete obliteration. After partial surgical treatment, the annual hemorrhage rate was 3% (95% CI: 1%-6%); no hemorrhages were reported over 196 patient-years after partial endovascular treatment. CONCLUSION: Spinal glomus (type II) AVMs with previous hemorrhage, particularly within 10 years, demonstrated a greater risk of hemorrhage. Complete obliteration and even partial endovascular treatment significantly decreased their hemorrhage rate. PMID- 23096419 TI - Microsurgical treatment of a premotor arteriovenous malformation: 3-dimensional illustration. PMID- 23096420 TI - The use of susceptibility-weighted imaging as an indicator of retrograde leptomeningeal venous drainage and venous congestion with dural arteriovenous fistula: diagnosis and follow-up after treatment. AB - BACKGROUND: Retrograde leptomeningeal venous drainage (RLVD) in dural arteriovenous fistulas (DAVFs) is associated with intracerebral hemorrhage and nonhemorrhagic neurological deficits or death. Angiographic evidence of RLVD is a definite indication for treatment, but less invasive methods of identifying RLVD are required. OBJECTIVE: To evaluate the efficacy of susceptibility-weighted magnetic resonance imaging (SWI) in detecting RLVD in DAVFs. METHODS: We retrospectively identified 17 DAVF patients who had angiographic evidence of RLVD and received treatment. Conventional angiography and SWI were assessed at pretreatment and posttreatment time points. The presence of RLVD on SWI was defined as cortical venous hyperintensity, and the presence of venous congestion on SWI venograms was defined as increased caliber of cortical or medullary veins. RESULTS: Cortical venous hyperintensity was identified in pretreatment SWI of 15 patients. Cortical venous hyperintensity was absent in early posttreatment SWI, consistent with the absence of RLVD in posttreatment angiography, in all but one of these patients. In 2 patients, cortical venous hyperintensity was identified during follow-up, indicating the recurrence of RLVD. Cortical venous hyperintensity was not identified in the pretreatment SWI of 2 patients despite angiographic evidence of RLVD. Venous congestion was identified in pretreatment SWI venograms of 11 patients and had an appearance similar to that identified from angiography. Venous congestive signs improved over the follow-up period. CONCLUSION: The presence of SWI hyperintensity within the venous structure could be a useful indicator of RLVD in DAVF patients. Thus, SWI offers a noninvasive alternative to angiography for the identification of RLVD in pretreated and posttreated DAVF patients. PMID- 23096422 TI - Microsurgical management of jugular foramen schwannomas. AB - BACKGROUND: Jugular foramen schwannomas are uncommon and surgically challenging lesions. OBJECTIVE: To determine the importance of surgical technique on morbidity and recurrence of jugular foramen schwannomas. METHODS: A retrospective review and case-control analysis of a single-senior-surgeon series of 81 patients with surgically treated jugular foramen schwannomas was performed, focusing on operative technique. Patients undergoing an aggressive, total tumor resection (series 1) were compared with those undergoing more conservative resection focusing on preserving the pars nervosa (series 2). RESULTS: There was a statistically significant (P = .04) decrease in permanent deficits of the cranial nerve 9/10 complex with a conservative technique. Recurrence was seen in 3 patients (5.7%) in series 1 and in 3 patients (10.7%) in series 2 (P = .36). Recurrence was treated with reoperation in 1 patient, radiation in 1 patient, and observation in the others. CONCLUSION: Although radical gross total resection is desirable, it is not optimal for cranial nerve preservation in patients with jugular foramen schwannomas. A more conservative approach resulted in a statistically significant decrease in lower cranial nerve deficits. There was a nonstatistically significant trend toward increasing recurrence, which may be treated with multiple modality therapy in the modern era. PMID- 23096423 TI - Oxidative stress is associated with cell death, wall degradation, and increased risk of rupture of the intracranial aneurysm wall. AB - BACKGROUND: The cause of rupture of intracranial aneurysms (IA) is not well understood. We previously demonstrated that loss of cells from the IA wall is associated with wall degeneration and rupture. OBJECTIVE: To investigate the mechanisms mediating cell death in the IA wall. METHODS: Snap-frozen tissue samples from aneurysm fundi were studied with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunostaining (14 unruptured and 20 ruptured), as well as with Western blot (12 unruptured and 12 ruptured). RESULTS: : Ruptured IA walls had more TUNEL-positive cells than unruptured walls (P < .001). Few cells positive for cleaved caspase-3 were detected. Cleaved caspase-9 (intrinsic activation of apoptosis) was significantly increased in ruptured IA walls, whereas cleaved caspase-8 (extrinsic activation of apoptosis) was not detected. Increased expression of hemeoxygenase-1, a marker for oxidative stress, was associated with IA wall degeneration and rupture. CONCLUSION: Our results show that programmed cell death is activated in the IA wall via the intrinsic pathway. High oxidative stress in the IA wall is probably a significant cause of the intrinsic activation of cell death. PMID- 23096424 TI - Emergency management of acute urinary retention: results from an all-Ireland urologist practice survey. AB - INTRODUCTION: Anecdotal evidence suggests that current service restrictions and operative cancellations are resulting in increased numbers of catheterized men in the community awaiting definitive management of their bladder outlet obstruction. We wished to analyse current admission policies and management strategies of acute urinary retention (AUR) secondary to benign prostatic enlargement (BPE) in Ireland. METHODS: A total of 58 consultant urologists practicing in Ireland were sent a questionnaire about their management of AUR secondary to BPE. Data was collected relating to initial emergency management, timing of trial without catheter (TWOC), their use of alpha-blockers and follow-up policy. RESULTS: Urethral catheterization is the initial management of choice by all 42 respondents. The patient is routinely admitted after catheterization by 20/42 consultants (48 %) and 22/42 (52 %) discharge the patient home with a urinary catheter (UC). TWOC is performed on day 2 in 11/20 (55 %) and on day 3 in 9/20 (45 %). In terms of individuals who admit patients presenting with AUR one failed TWOC is an indication for transurethral resection of the prostate in 10/20 (50 %), with 6/20 (30 %) performing a second TWOC on the same admission and 4/20 (20 %) discharging the patient for interval TURP. A total of 83 % of respondents, all of whom work in public institutions, expressed concerns relating to elective admission difficulties for definitive management of catheterized patients following AUR. CONCLUSION: There is variation in the admission policy for AUR in Ireland. Elective admission and operative restrictions for catheterized patients following episodes of AUR are causing concern to the urologists in Ireland. PMID- 23096425 TI - Signal transduction in leaf senescence. AB - Leaf senescence is a complex developmental phase that involves both degenerative and nutrient recycling processes. It is characterized by loss of chlorophyll and the degradation of proteins, nucleic acids, lipids, and nutrient remobilization. The onset and progression of leaf senescence are controlled by an array of environmental cues (such as drought, darkness, extreme temperatures, and pathogen attack) and endogenous factors (including age, ethylene, jasmonic acid, salicylic acid, abscisic acid, and cytokinin). This review discusses the major breakthroughs in signal transduction during the onset of leaf senescence, in dark and drought-mediated leaf senescence, and in various hormones regulating leaf senescence achieved in the past several years. Various signals show different mechanisms of controlling leaf senescence, and cross-talks between different signaling pathways make it more complex. Key senescence regulatory networks still need to be elucidated, including cross-talks and the interaction mechanisms of various environmental signals and internal factors. PMID- 23096427 TI - Enhanced clearance of carbamazepine using albumin-containing dialysate during CVVHDF. PMID- 23096426 TI - Volatile isoflurane sedation in cerebrovascular intensive care patients using AnaConDa((r)): effects on cerebral oxygenation, circulation, and pressure. AB - PURPOSE: The anesthetic-conserving device AnaConDa((r)), a miniature vaporizer, allows volatile sedation in the intensive care unit (ICU). We investigated the effects of isoflurane sedation on cerebral and systemic physiology parameters in neuromonitored ICU stroke patients. METHODS: Included in the study were 19 consecutive ventilated patients with intracerebral hemorrhage (12), subarachnoid hemorrhage (4), and ischemic stroke (3) who were switched from intravenous propofol or midazolam to inhalative isoflurane sedation for an average of 3.5 days. During the sedation transition, the following parameters were assessed: mean arterial pressure (MAP), intracranial pressure (ICP), cerebral perfusion pressure (CPP), middle cerebral artery mean flow velocity (MFV) and cerebral fractional tissue oxygen extraction (FTOE), as well as systemic cardiopulmonary parameters and administered drugs. RESULTS: After the first hour, mean ICP showed an increase of 2.1 mmHg that was not clinically relevant. Likewise, MFV did not change. MAP and CPP, however, decreased by 6.5 and 6.3 mmHg, respectively. FTOE was reduced slightly from 0.24 to 0.21 (p = 0.03). Over an observation period of 12 h, ICP remained stable, while MAP and thus CPP showed distinct decreases (CPP: -10 mmHg at 6 h, p < 0.001; -7.5 mmHg at 12 h, p = 0.005, when compared to preswitch levels) despite a 1.5-fold increase in vasopressor administration. CONCLUSIONS: We suggest that that it is possible to reach sufficient sedation levels in cerebrovascular ICU patients by applying volatile isoflurane long-term without a relevant increase in ICP, if baseline ICP values are low or only moderately elevated. However, caution should be exercised in view of isoflurane's decreasing effect on MAP and CPP. Multimodal neuromonitoring is strongly recommended when applying this off-label sedation method. PMID- 23096428 TI - Mesenteric blood flow, glucose absorption and blood pressure responses to small intestinal glucose in critically ill patients older than 65 years. AB - PURPOSE: To compare nutrient-stimulated changes in superior mesenteric artery (SMA) blood flow, glucose absorption and glycaemia in individuals older than 65 years with, and without, critical illness. METHODS: Following a 1-h 'observation' period (t (0)-t (60)), 0.9 % saline and glucose (1 kcal/ml) were infused directly into the small intestine at 2 ml/min between t (60)-t (120), and t (120)-t (180), respectively. SMA blood flow was measured using Doppler ultrasonography at t (60) (fasting), t (90) and t (150) and is presented as raw values and nutrient stimulated increment from baseline (Delta). Glucose absorption was evaluated using serum 3-O-methylglucose (3-OMG) concentrations during, and for 1 h after, the glucose infusion (i.e. t (120)-t (180) and t (120)-t (240)). Mean arterial pressure was recorded between t (60)-t (240). Data are presented as median (25th, 75th percentile). RESULTS: Eleven mechanically ventilated critically ill patients [age 75 (69, 79) years] and nine healthy volunteers [70 (68, 77) years] were studied. The magnitude of the nutrient-stimulated increase in SMA flow was markedly less in the critically ill when compared with healthy subjects [Deltat (150): patients 115 (-138, 367) versus health 836 (618, 1,054) ml/min; P = 0.001]. In patients, glucose absorption was reduced during, and for 1 h after, the glucose infusion when compared with health [AUC(120-180): 4.571 (2.591, 6.551) versus 11.307 (8.447, 14.167) mmol/l min; P < 0.001 and AUC(120-240): 26.5 (17.7, 35.3) versus 40.6 (31.7, 49.4) mmol/l min; P = 0.031]. A close relationship between the nutrient-stimulated increment in SMA flow and glucose absorption was evident (3-OMG AUC(120-180) and ?SMA flow at t (150): r (2) = 0.29; P < 0.05). CONCLUSIONS: In critically ill patients aged >65 years, stimulation of SMA flow by small intestinal glucose infusion may be attenuated, which could account for the reduction in glucose absorption. PMID- 23096429 TI - Research participants' opinions of delayed consent for a randomised controlled trial of glucose control in intensive care. AB - PURPOSE: Critically ill patients are often unable to give informed consent to participate in clinical research. A process of delayed consent, enrolling patients into clinical trials and obtaining consent as soon as practical from either the participant or their substitute decision maker, has sometimes been used. The objective of this study was to determine the opinion of participants, previously enrolled in the NICE-SUGAR study, of the delayed consent process. METHODS: This observational study was conducted from 2009 to 2010 in the ICU of a tertiary referral hospital in Australia. Participants who were enrolled in the NICE-SUGAR study with delayed consent who survived, were cognitively intact, and proficient in English were posted a questionnaire regarding their opinion of the delayed consent process. The questionnaire was returned by post, fax, email, or completed during a telephone interview. RESULTS: Of 298 eligible participants, 210 responded, with an overall response rate of 79 %. Delayed consent to participate in the NICE-SUGAR study was obtained from participants (57/210; 27.1 %) or the substitute decision maker (152/210; 72.4 %). Most respondents (195/204; 95.6 %) would have consented to participate in the NICE-SUGAR study if asked before enrolment; most (163/198; 82.3 %) ranked first "the person who consented on their behalf for the NICE Study" as most preferred to make decisions, should they be unable; and most (177/202; 87.6 %) agreed with the decision made by their relative. CONCLUSION: Delayed consent to participate in a clinical trial that includes critically ill patients is acceptable from research participant's perspectives. PMID- 23096430 TI - An unusual cause of hyperammonemia in a critically ill patient. PMID- 23096431 TI - A stable sulfone based electrolyte for high performance rechargeable Li-O2 batteries. AB - A tetramethylene sulfone based electrolyte was used in rechargeable Li-O(2) batteries for the first time. Without a catalyst, superior battery performances were successfully obtained, and desired lithium peroxide (Li(2)O(2)) dominates the discharge product. PMID- 23096433 TI - [Imaging findings in H3N2-related pulmonary infection]. PMID- 23096443 TI - [20% of MTRA full time positions are vacant]. PMID- 23096432 TI - Intratumoral estrogen concentration and expression of estrogen-induced genes in male breast carcinoma: comparison with female breast carcinoma. AB - It is speculated that estrogens play important roles in the male breast carcinoma (MBC) as well as the female breast carcinoma (FBC). However, estrogen concentrations or molecular features of estrogen actions have not been reported in MBC, and biological significance of estrogens remains largely unclear in MBC. Therefore, we examined intratumoral estrogen concentrations, estrogen receptor (ER) alpha/ERbeta status, and expression profiles of estrogen-induced genes in MBC tissues, and compared these with FBC. 17beta-Estradiol concentration in MBC (n = 4) was significantly (14-fold) higher than that in non-neoplastic male breast (n = 3) and tended to be higher than that in FBC (n = 7). Results of microarray analysis clearly demonstrated that expression profiles of the two gene lists, which were previously reported as estrogen-induced genes in MCF-7 breast carcinoma cell line, were markedly different between MBC and FBC. In the immunohistochemistry, MBC tissues were frequently positive for aromatase (63 %) and 17beta-hydroxysteroid dehydrogenase type 1 (67 %), but not for steroid sulfatase (6.7 %). A great majority (77 %) of MBC showed positive for both ERalpha and ERbeta, and its frequency was significantly higher than FBC cases. These results suggest that estradiol is locally produced in MBC tissue by aromatase. Different expression profiles of the estrogen-induced genes may associate with different estrogen functions in MBC from FBC, which may be partly due to their ERalpha/ERbeta status. PMID- 23096449 TI - Value of Doppler sonography near term: can umbilical and uterine artery indices in low-risk pregnancies predict perinatal outcome? AB - AIM: The goal of this study was to evaluate the umbilical and uterine Doppler velocimetry waveforms for predicting the perinatal outcome of low-risk pregnancies at term. METHODS: We prospectively recruited 514 women with low risk pregnancies and performed umbilical and uterine artery Doppler assessments between 37 and 41 weeks of gestation. Ultrasound measurements (completed in 365 patients) were correlated with the perinatal outcome. RESULTS: The velocimetry waveforms of the umbilical artery were significantly associated with birthweight, placental weight, and postpartal umbilical artery pH. Low pH, placental weight, and birthweight were correlated with increasing pulsatility index (PI) and resistance index (RI). An umbilical artery PI > 1.2 and a uterine artery RI > 0.5 were associated with statistically higher rates of infants that were small for gestational age (SGA). Also, high cesarean delivery rates were correlated with an umbilical artery PI > 1.2. CONCLUSIONS: In our low-risk pregnancies population, the elevated umbilical artery indices at term appeared to be associated with the higher rates of infants that were SGA and cesarean deliveries. The Doppler waveforms at term had low prognostic value for predicting neonatal acidosis or decreased Apgar scores. PMID- 23096450 TI - Methylation status of TUSC3 is a prognostic factor in ovarian cancer. AB - BACKGROUND: Current prognostic information in ovarian cancer is based on tumor stage, tumor grade, and postoperative tumor size. Reliable molecular prognostic markers are scarce. In this article, the authors describe epigenetic events in a frequently deleted region on chromosome 8p22 that influence the expression of tumor suppressor candidate 3 (TUSC3), a putative tumor suppressor gene in ovarian cancer. METHODS: Messenger RNA expression and promoter hypermethylation of TUSC3 were studied in ovarian cancer cell lines and in tumor samples from 2 large, independent ovarian cancer cohorts using polymerase chain reaction-based methods. RESULTS: The results indicated that TUSC3 expression is decreased significantly because of promoter methylation in malignant ovarian tumors compared with benign controls. Almost 33% of ovarian cancer samples had detectable TUSC3 promoter methylation. Furthermore, methylation status of the TUSC3 promoter had a significant and independent influence on progression-free and overall survival. CONCLUSIONS: TUSC3 hypermethylation predicted progression-free and overall survival in ovarian cancer. The current observations suggested a role for N glycosylating events in ovarian cancer pathogenesis in general and identified the epigenetic silencing of TUSC3 as a prognostic factor in this disease. PMID- 23096451 TI - Coroneo extra-aortic annuloplasty ring could stabilize even the pulmonary autograft annulus in a Ross operation. AB - The Ross procedure is an alternative technique to mechanical prosthesis and recent evidence suggests that it is associated with improved long-term survival and quality of life. However, late pulmonary autograft failure can occur more frequently in patients with significant dilation of the aortic annulus. Here, we present a technical modification of the Ross procedure--a case report of a patient who underwent a Ross procedure in which the gross dilation of the aortic annulus was reduced by implantation of an extra-aortic Coroneo annuloplasty ring. Before discharge, we performed a multidetector computed tomography (MDCT) to verify the effect of extra-aortic annuloplasty on the geometry of the neoaortic root and particularly on the dimension of the aortic annulus. The result of the MDCT demonstrated that the ring sits in the optimal position at the level of aortoventricular base and that aortic annulus is significantly reduced. PMID- 23096452 TI - Near-infrared spectroscopy for neuromonitoring of unilateral cerebral perfusion. AB - OBJECTIVES: There is neither consensus regarding which methods of neuromonitoring are adequate and reliable for assessing cerebral cross-perfusion during unilateral cerebral perfusion (UCP) nor are any threshold values defined. The aim of the study was to evaluate the usefulness of near-infrared spectroscopy (NIRS) for the neuromonitoring of right-sided UCP, which is increasingly used for cerebral protection as a consequence of the recent rise in supra-aortic cannulation methods. METHODS: For the purpose of the study, 122 patients (mean age 67 +/- 12 years) who underwent open aortic arch surgery between August 2007 and July 2011 using right-sided UCP with a duration time exceeding 20 min were evaluated. The neuromonitoring consisted of NIRS and pressure measurement in both radial arteries in all patients. Forty-four (36%) patients suffered acute aortic dissection (3 having cerebral malperfusion), and 89 (73%) underwent total or subtotal arch replacement. Logistic regression analysis was used to model neurological adverse outcome (permanent and temporary neurological dysfunctions) as a function of cerebral oxygen saturation and other covariates. RESULTS: During UCP (mean duration 38 +/- 18 min) performed at a constant blood temperature of 28 degrees C, the mean brain oxygen saturation dropped on the non-direct perfused side from 66 to 61% on average, corresponding to 92% of the baseline. In only 1 patient, an insufficient cross-over perfusion was presumed due to an intense drop of the saturation to 15% and was treated by employment of bilateral perfusion. In all remaining patients, the drop was not below 40% and/or 70% of the baseline. In the adjusted analysis, acute aortic dissection could be found as an independent predictor of an adverse neurological outcome (5 permanent, all in acute dissections, and 9 temporary dysfunctions), while there was no association between the occurrence of adverse neurological outcome and the values of regional cerebral oxygen saturation during UCP. CONCLUSIONS: NIRS seems to be a reliable instrument to recognize a relevant disruption of cerebral cross-perfusion during UCP. A drop of brain oxygen saturation to 40% and/or 70% of the baseline can be considered a threshold value for sufficient cerebral cross-perfusion, at least under the flow and temperature management presented. PMID- 23096453 TI - Aortic dissection as a first sign of polycystic kidney disease in a 26-year old young adult. PMID- 23096454 TI - Long-term survival of patients with pulmonary disease undergoing coronary artery bypass surgery. AB - OBJECTIVES: We sought to investigate the long-term survival of patients with obstructive, restrictive and chronic obstructive pulmonary disease (COPD) as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD). METHODS: A prospective database was retrospectively analysed and cross-correlated with the UK strategic tracking service to evaluate survival after primary coronary artery bypass grafts (CABG). Univariate and multivariate Cox regression analyses were performed. Three separate multivariate analyses were performed: COPD GOLD criteria for obstructive and/or restrictive lung disease, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and the FEV1/FVC ratio to investigate the effect of FEV1 and FVC individually. RESULTS: We analysed 13 337 primary CABG procedures. The median follow-up was 7 years. Univariate analysis demonstrated that obstructive (P < 0.0001), restrictive (P < 0.0001) and mixed obstructive and restrictive pulmonary disease (P < 0.0001), and COPD as defined by the GOLD criteria (P < 0.0001), are all significant factors determining long-term survival. Cox regression analysis identified age, diabetes, moderate LV, poor LV, peripheral vascular disease, dialysis, left internal mammary artery (LIMA) usage, EuroSCORE, cardiopulmonary bypass and creatinine kinase muscle-brain isoenzyme as significant factors in addition to pulmonary disease that determine long-term survival. Moderate and severe COPD defined by GOLD criteria were significant factors determining long-term survival, but mild COPD had no significant effect. Obstructive and restrictive lung disease were both significant factors determining long-term survival. Restrictive lung disease, however, carried a greater prognostic significance (higher hazard ratio 2.2 vs 1.6) than obstructive. LIMA utilization in patients with COPD was not associated with an increased intensive care unit stay, re-intubation rate or in hospital mortality rate. CONCLUSIONS: Pulmonary disease is a significant factor determining long-term survival. Patients with severe COPD still have a relatively good long-term survival and should not be denied surgery. LIMA utilization in patients with COPD results in a significantly increased long-term survival, without an increased intensive care unit stay, re-intubation rate or in-hospital mortality rate. PMID- 23096455 TI - Treatment of catamenial pneumothorax with absorbable mesh, pleurectomy and pleural abrasion. PMID- 23096456 TI - When coronary arteries need systolic pressure: surgical considerations. AB - OBJECTIVES: Patients with pulmonary atresia and intact ventricular septum (PA IVS) may have coronary sinusoids connected to a hypertensive right ventricle. Coronary perfusion may then completely depend on the right ventricular systolic pressure wave; decompression of the right ventricle can be deleterious in these patients. This study was set to investigate the treatment strategies and outcomes of patients with coronary sinusoids. METHODS: National multicentre retrospective analysis over 15 years (1985-2010) in a population of ~10.2 million people. All patients with PA-IVS and coronary sinusoids were identified from local databases. All angiograms, echocardiograms, surgical reports and outcome data were reviewed. RESULTS: Thirty patients were identified. Right ventricular-dependent coronary circulation was present in nine patients (30%). A systemic-to-pulmonary artery shunt was created in 23 patients (77%) at a median age of 13.0 days (range: 1 479). A bidirectional Glenn was performed in 20 children at a median age of 7.8 months (range: 2.1-112.9) and 11 children proceeded to a Fontan repair at a median age of 3.6 years (range: 2.1-19.6). Pulmonary valve perforation and angioplasty were performed in six children and in three a simultaneous decompression procedure was also done. Ten patients died (33%). Four died at the time of systemic-to-pulmonary artery shunt and three during the bidirectional Glenn shunt. In all these patients myocardial ischaemia was reported. CONCLUSIONS: Mortality in PA-IVS with sinusoids is high. Right ventricular coronary dependence may lead to early death if the right ventricular systolic pressure wave is interrupted. Adequate understanding of the underlying pathology and pathophysiology is essential before attempting any procedure in this subgroup of children. PMID- 23096457 TI - A wire in the heart. PMID- 23096458 TI - Should the mind be a matter? The impact of depression and anxiety on cardiac surgery outcomes. PMID- 23096459 TI - A ductal aneurysm rapidly developing into coarctation of the aorta. PMID- 23096460 TI - Thermal ablation in the treatment of lung cancer: present and future. AB - Surgery is considered the best choice for stage I non-small cell lung cancer and also in treatment of selected patients with lung metastasis. However, surgery is often a high-risk procedure because of severe medical comorbidities affecting this cohort of patients. Thermal ablation (TA) has recently been proposed to achieve destruction of lung tumours whilst avoiding the use of general anaesthesia, thereby limiting the invasiveness of the procedure. For pulmonary malignancies, there are two methods of TA based on tissue heating: radio frequency ablation (RFA) and microwave ablation (MWA). Both are mini-invasive procedures, delivering energy to the tumour through single or multiple percutaneous needles introduced under guidance of computed tomography. The procedure may be performed under conscious sedation or general anaesthesia to avoid pain caused by needle insertion and tissue heating. Local efficacy is directly correlated to tumour target size: for RFA, tumours smaller than 2 cm can be completed ablated in 78-96% of cases; for MWA-according to the largest available study-95% of initial ablations are reported to be successful for tumours smaller than 5 cm. Very few series provide survival data beyond 3 years. For nodules smaller than 3 cm, the registered survival rate is higher: 50% at five years. The data collected in the last 10 years allow us to conclude that TA is an established alternative treatment for patients who cannot undergo surgery because of their compromised general condition. In the case of pulmonary metastasis, most authors agree to offer TA only if lesions are smaller than 5 cm. PMID- 23096461 TI - RNF43 is a tumour suppressor gene mutated in mucinous tumours of the ovary. AB - Mucinous carcinomas represent a distinct morphological subtype which can arise from several organ sites, including the ovary, and their genetic characteristics are largely under-described. Exome sequencing of 12 primary mucinous ovarian tumours identified RNF43 as the most frequently somatically mutated novel gene, secondary to KRAS and mutated at a frequency equal to that of TP53 and BRAF. Further screening of RNF43 in a larger cohort of ovarian tumours identified additional mutations, with a total frequency of 2/22 (9%) in mucinous ovarian borderline tumours and 6/29 (21%) in mucinous ovarian carcinomas. Seven mutations were predicted to truncate the protein and one missense mutation was predicted to be deleterious by in silico analysis. Six tumours had allelic imbalance at the RNF43 locus, with loss of the wild-type allele. The mutation spectrum strongly suggests that RNF43 is an important tumour suppressor gene in mucinous ovarian tumours, similar to its reported role in mucinous pancreatic precancerous cysts. PMID- 23096462 TI - [Morphological and molecular identification of canine filariae in a semi-rural district of the Metropolitan Region in Chile]. AB - INTRODUCTION: To date, there has been no definitive confirmation of the presence of zoonotic dirofilariasis in dogs in Chile. OBJECTIVES: To study the presence of dirofilarias in blood samples from dogs collected in a semi-rural district near Santiago and to compare their frequency in dogs with and without dermatological manifestations. METHODS: We examined 100 blood samples for dog filariae infections using microscopic methods (modified Knott technique). 50 dogs presented dermatological symptoms or signs compatible with filarial infections and 50 were asymptomatic. ITS-2 and 12s rDNA gene amplification by PCR and sequencing were performed in samples microscopically positive for microfilariae. Results. We observed microfilariae in 22 dogs (22%). Of these, 16/50 (32%) were symptomatic and 6/50 (12%) were asymptomatic (p = 0.02). Morphologically, the majority of micro-filariae were similar to Dirofilaria repens, although many had a bigger size than previously described. Nucleotide sequencing of the amplified genes showed no more than 95% homology with the D. repens sequences available for comparison. D. reconditum and D. dracunculoides infections were also identified. CONCLUSIONS: These features might indicate the presence of new species of Dirofilaria or a D. repens close related variant in Chile. PMID- 23096463 TI - [Infection by Bordetella pertussis: towards its erradication?]. PMID- 23096464 TI - [Occupational exposure risk to body fluids in the Felix Bulnes Hospital during eleven years]. AB - Accidents with risk of occupational exposure to body fluids constitute more of a third of labor accidents. OBJECTIVE: To describe the annual incidence of accidents with exposure to body fluids in the Felix Bulnes Hospital from 1998 to 2008. MATERIAL AND METHODS: A retrospective analysis of reports from the Infection Control Committee. RESULTS: During 11 years, there were 415 accidents with exposure to body fluids, with the cumulative incidence of 3,4% (range 1.3% to 6%). Sharp instrument accidents accounted for 92,5% of cases. The main health care providers affected were the paramedical technicians and the students. The highest frequency of accidents occurred in the obstetrical operating rooms (20%) and in the central operating rooms (17%). There were no cases of seroconversion and no exposure to HCV or HBV. The estimated costs were USD $35638,6 or USD $271 per 1000 staff per year. CONCLUSIONS: The incidence increased during the first years of the study and then remained stable since 2001, despite efforts in training personnel. Many factors contribute to the development of these accidents, such as lack of experience, type of clinical benefit and even daytime working hours. PMID- 23096465 TI - [Bacterial identification based on protein mass spectrometry: A new insight at the microbiology of the 21st century]. AB - Bacterial identification is important for the proper treatment of infected patients hospitalized with serious infections especially in critical care units. Identification by conventional methods used in microbiology laboratories takes at least 16 hours since a culture is positive. The introduction of mass spectrometry, specifically MALDI-TOF MS (matrix-assisted laser desorption/ ionization time-of-flight mass spectrometer) in the microbiology laboratory could mean a radical change in the identification accuracy, turn around time (6 minutes per bacteria) and cost (about 5 times cheaper than conventional identification). Since its introduction in clinical microbiology laboratories in 2008, many reports about its usefulness in identifying microorganisms from colonies, as well as directly from positive blood cultures and urine samples have been published. This review describes MALDI-TOF MS methodology, its identification performance for bacteria (aerobic and anaerobic), mycobacterium and yeasts, its future applications in microbiology and its main disadvantages. PMID- 23096466 TI - [First Travel Medicine Center in a public hospital from Buenos Aires Province, Argentina Republic: The first 2 years of experience]. AB - INTRODUCTION: Although Buenos Aires is the biggest province in Argentina, there was no program for Travel Medicine in any public hospital until 2008, when the Travel Medicine Center (CEMEVI) was established in our hospital. OBJECTIVE: To analyze the first 24 months of experience in the CEMEVI. RESULTS: A total of 278 travelers were assisted. Most of them consulted before traveling (pre-travel visits). The most common destinations were countries in South America and urban as well as rural areas. Travelling to malaria and yellow fever endemic countries represented 35% and 16% of the total of destinations, respectively. Only 4% were post-travel interviews. CONCLUSION: It is feasible and fruitful to implement a Travel Medicine Center in the public health system. PMID- 23096467 TI - [Comparison of Helicobacter pylori in oral cavity and gastric mucosa according to virulence genotype (cagA and vacA m 1)]. AB - OBJECTIVE: To compare the virulence genotype (cagA and vacA ml genes) of Helicobacter pylori obtained simultaneously from gastric mucosa and oral cavity. MATERIAL AND METHODS: Gastric samples of 18 patients were obtained by endoscopic biopsies. Oral samples of these patients were obtained from dental plaque and saliva swabs from the floor of the mouth and the base of the tongue. All samples were studied by conventional PCR and real-time PCR (RT-PCR). Virulence genes cagA and vacA ml were studied by RT- PCR. RESULTS: According to presence and/or absence of cagA and vacAm1 genes, seven different combinations were observed. CONCLUSION: These results suggest that there is a variety of genetic profiles of Helicobacter pylori in the stomach and oral cavity, with a predominance of less virulent genotypes in the patients included in this study (cagA-, vacA m1-). PMID- 23096468 TI - [Severe pertussis: State of the art]. AB - Pertussis is a contagious disease that has reappeared in the recent years as a public health problem in our country. The clinical presentation has changed especially in the main risk group, children under one year old, evolving in occasions to a highly lethal course called malignant or severe Pertussis. The present review discusses the epidemiology and the mechanisms of pathogenicity, and also describes the risk factors, clinical features and pathophysiology of this particular form. The current evidence and effectiveness of new treatments are described, and a treatment algorithm is proposed. PMID- 23096469 TI - [Modification of pertussis vaccination schedule in Chile, immunization of special groups and control strategies: Commentary from the Consultive Committee of Immunizations of The Chilean Society of Infectious Diseases]. AB - In Chile, an increased number of notifications of cases of whooping cough was detected at the beginning of October 2010, and maintained through 2012. Accumulated cases during 2011 were 2,581 (15.0 per 100,000), which is greater than the number of cases registered during the period 2008-2010 (2,460 cases). On the other hand, the local sanitary authority introduced a modification of pertussis vaccination schedule (starting 2012), which consists in the replacement of the second booster of pertussis vaccine (DTwP, administered to 4-year-old children) as well as diphtheria-tetanus toxoid (dT, administered to second grade scholars) for an acellular pertussis vaccine with reduced antigenic content (dTpa), which will be administrated to first grade scholars. The Consultive Committee of Immunizations considers that the modification is adequate, since it extends the age of protection, reducing at least in theory the infection in older scholars and adolescents -who are significant sources of transmission of Bordetella pertussis to infants- using an adequate vaccine formulation (acellular pertussis vaccine). The available evidence regarding vaccination in special groups (adolescents and adults, health-care workers and pregnant women) and cocooning strategy are commented. PMID- 23096470 TI - [Resilient people in a resilient planet]. PMID- 23096472 TI - [Experience with tigecycline compassionate use in pediatric patients infected with carbapenem resistant Klebsiella pneumoniae]. AB - INTRODUCTION: Infections produced by multidrug-resistant pathogens represent a therapeutic challenge because of the few therapeutic options available. Tigecycline is a relatively new antibiotic, with a wide spectrum of activity including some of these resistant bacteria. In adults is prescribed for the treatment of some infections caused by carbapenem resistant K. pneumoniae, however it has not been approved in children because of potential adverse effects in the dental enamel. MATERIALS AND METHODS: Case series study. Medical records were reviewed in all children from 0 to 14 years of age that received tigecycline between January of 2008 and March of 2010. RESULTS: 9 patients received Tigecycline mainly for treatment of peritonitis, bacteremia, pneumonia and sepsis caused by carbapenem resistant K. pneumoniae. A dose of 1 mg/kg q 12 hours was administered to all patients. No adverse events were reported and a total of 6 patients had complete resolution of the infection. CONCLUSIONS: Tigecycline could be considered a therapeutic option for treating infections produced by multidrug resistant pathogens in children. The use in children is still compassionate and in this series of cases Tigecycline was well tolerated and safe. PMID- 23096471 TI - [Enterocolitis, antimicrobials and hemolytic-uremic syndrome in children: Review of a concept]. AB - BACKGROUND: Treatment of children with Escherichia coli O157:H7 enterocolitis could be related with risk of Hemolytic-Uremic Syndrome (HUS). The proscription of antibiotics use until cultures ruled out this infection has been proposed (Wong et al.). This concept became generalized causing dilemma in clinical decisions and research. The objective of this study was to review the evidence related with this topic. METHODS: A 1999-2011 literature review of studies related with E.coli O157:H7, antibiotics and HUS in children. RESULTS: We found one randomized controlled trial, three cohort studies, one case-control and one meta-analysis with pediatric data on the topic. After methodological and metrical analysis, five studies showed opposite results as compared to Wong et al. All had statistical power enough to detect Wong's association but did not happen. Wong's study had no statistical power to detect risk ratios <= 11. CONCLUSION: These results are neither reproducible nor generalizable, consequently clinical decisions should be solved following local epidemiology. PMID- 23096473 TI - [Demographics, morbidity, and mortality febrile neutropenic adult patients treated with cefepime]. AB - INTRODUCTION: Cefepime efficacy for treatment of febrile neutropenia (FN) in cancer adult patients is a controversial issue. OBJECTIVE: To describe the demographic characteristics and general mortality of patients suffering from febrile neutropenia treated with cefepime in a fourth-level Latin American hospital. PATIENTS AND METHODS: A cross-sectional observational study was performed. Study settled at San Ignacio of Bogota, Colombia. University Hospital from January 2004 to December 2008. RESULTS: A total of 333 patients were treated with cefepime, of whom 125 had suffered FN and met pre established inclusion and exclusion criteria. The general mortality was 14.4%, which was similar to the overall mortality in FN in other reports. CONCLUSIONS: Although there is still no clarity regarding the efficacy of cefepime in FN, its use has not been restricted. This study did not identify an excess risk of mortality in patients treated with cefepime. PMID- 23096474 TI - [Cancer, febrile neutropenia and pulmonary images: Findings in bronchoalveolar lavage in children]. AB - INTRODUCTION: Lung infections are a serious complication in children with cancer. Bronchoalveolar lavage (BAL) has been demonstrated to be an effective procedure for achieving etiologic diagnosis. METHOD: We did a retrospective analysis of BAL data performed between November 2005 and October 2008 in children with cancer, severe neutropenia and lung infiltrates for assessing its performance, clinical utility and safety. Thirty-seven BAL were evaluated in 35 patients. RESULTS: Focal infiltrates were demonstrated in imaging studies associated with 19/37 BAL; in 8 an infectious agent was found. Interstitial pattern was observed in 15/37, in which there were 4 positive studies, proving a higher microbiological performance in BAL associated with focal lesions. BAL yielded significant microbiological findings in 32.4% (12/37). Sixteen microorganisms were identified in the study: bacteria in 8 cases, Mycobacterium tuberculosis (n: 2), Pseudomonas aeruginosa (n: 2), Acinetobacter baumannii (n: 1), A. Iwoffii (n: 1), group viridans Streptococcus (n: 1), Mycoplasma pneumoniae (n: 1); viruses in 3 cases, metapneumovirus (n: 2) cytomegalovirus (n: 1) and fungal infection in 5 cases, Pneumocystis jiroveci (n: 2) Aspergillus fumigatus (n: 1), Aspergillus niger (n: 1), Candida albicans (n: 1). Therapeutic adjustments were done in 6/37 episodes (16.2%). CONCLUSION: BAL has a significant role in the evaluation of pulmonary infiltrates in pediatric oncological patients, requiring a prompt and safe diagnosis, which is crucial for the survival with minimal morbidity. Our results suggest that BAL by fiberbronchoscopy should be considered as an initial diagnostic tool in these patients. PMID- 23096475 TI - [Scedosporium/Pseudallescheria]. PMID- 23096476 TI - [A decade of antiretroviral therapy: a profile of patients with 10 years of highly effective triple therapy]. AB - INTRODUCTION: Highly effective antiretroviral triple therapy (TAR3) has led to a significant increase in survival of patients (pts) infected with human immunodeficiency virus. In 1999 it was started in the Chilean public health system, including Arriaran Foundation (FA) access to TAR, reaching full coverage since 2003. By October 31, 2009 124 pts had reached 10 years of uninterrupted TAR3 in FA. OBJECTIVE: To describe and analyze the profile of pts, their therapeutic regimen (s) and clinical outcomes during 10 years of TAR3. METHODS: Retrospective descriptive study. We reviewed the records of pts who had reached 10 years of uninterrupted TAR3 in FA. Demographic data, baseline and virological staging at start of TAR3, comorbidities and complications were recorded. Drug regimens used were analyzed, as well as toxicity, virological and immunological outcomes, frequency and reasons for change in therapy. Complications were classified as opportunistic and not opportunistic during this evolution and the latest known clinical and laboratory data were registered. A database program based on Excel was used. RESULTS: 121/124 pts were available for analysis, 76.8% male, male-female ratio was 3.3:1. Baseline median age: 36 years (20-69); CD4 cells 176/ mm3 (8-1,224) with 65.3% < 200; median viral load (STL): 60,078 copies/ml (1,100- 7,900,000); 36.3% were in clinical AIDS stage. Patients received an average of 3.5 therapies regimens during the decade (range, 1 [14 pts, 11.5%] to 7 [3 pts, 2.4%]), with average duration of 42 months each and a median of 36 months. As initial TAR3 regimen 2 backbone nucleoside analogues (ITRN) was the most frequent, with a protease inhibitor (PI) in 51.2% and non nucleoside RTIs (NNRTIs) in 38.8%. Adverse reactions were the main reason for change of therapy (24.7%), followed by virological failure (24.2%) and treatment simplification (16.6%). At the latest assessment, all with > 10 years of TAR3 median CD4 was 602 cells/mm3, 11 pts (9%) had CD4 < 200/mm3; 85.2% had undetectable VL (< 80 copies/mL); the remaining 14.8% had a median of 1,800 copies/mL. Only 2 pts (1.7%) were in AIDS clinical stage. Current regimens were 2 NRTI plus 1 NNRTI in 61 pts (50.4%), 2 or more NRTI plus 1 PI in 46 (38%). Seventy two pts (60.3%) had chronic comorbidities at latest follow up. Dyslipidemia, hypertension, diabetes mellitus and renal failure were the most frequent conditions; 17 pts (14%) had clinical lipodystrophy secondary to TAR. CONCLUSION: Achieving a decade of TAR is already a reality and in the short term will be routine. This is rarely achieved with the initial therapeutic regimen. The major obstacles to prolonged maintenance of a single therapeutic regimen have been adverse effects and virological failure, although current drugs with better efficacy and safety profile may allow longer use for each regimen. Despite the difficulty of treating these pts, they can achieve long-term survival with good virologic control, immune recovery and absence of opportunistic complications associated with HIV infection. Nonetheless, the high frequency of non opportunistic chronic comorbidities and antiretroviral therapy side effects after prolonged or life-long use is becoming a major issue. PMID- 23096477 TI - [Multiple-organ dysfunction caused by dissemination of Strongyloides stercoralis infection: A case report]. AB - We report here the case of a 50-year-old male patient, from a rural setting, with past history of alcoholism. He was admitted in the Intensive Care Unit due to a worsening health status after a febrile syndrome of 25 days. In addition, he had diarrhea, intense muscle ache predominantly on upper extremities and abdomen, weight loss, confusion, seizures, psychomotor agitation, tachycardia, tachipnea, anuria, septic shock, coma, and multiple-organ dysfunction syndrome. The hyperinfection syndrome caused by Strongyloides stercoralis was suspected because of severe eosinophilia (52 percent of peripheral blood leukocytes). This diagnosis was verified by the parasitological examination of stool samples by direct wet mount and Baermann techniques. Treatment with thiabendazole at 25 mg/kg per day was started, as well as cefepime, vasoactive drugs, artificial mechanic ventilation, and hemodialysis. The patient died 12 hours after admission, probably due to secondary infection with Escherichia coli. PMID- 23096478 TI - [Who saw them the first?]. AB - From the theory of Girolamo Fracastoro in 1530, suggesting the participation of invisible seeds in the contagion of some diseases, to the universal genius Athanasius Kircher, who saw little worms in the blood of patients suffering from plague in 1659 and the final discovery of Anthony Van Leeuwenhoek in 1674, the existence of bacteria was surely in the mind of a few investigators. Kirchner, who seems to be the winner of this race, did not give any special meaning to his observations. Leeuwenhoek, instead, was deeply concerned about the importance of his discovery in the field of biology, but was unable to establish a link between these animalcula and human epidemic diseases. PMID- 23096479 TI - [Pharmacological interaction between meropenem and valproic acid: a report of two cases]. AB - The pharmacological interaction between meropenem and valproic acid is potentially serious, especially in critically ill patients, resulting in low plasmatic levels of the anticonvulsant. However, to our knowledge, this interaction between meropenem and reduced valproic acid plasma levels has not been reported in the pediatric chilean population. We present two clinical cases of chilean children, thus reporting that this interaction is present in our population, with an aim at educating physicians about the possibility of such interaction. PMID- 23096480 TI - [Bacteremia by Kocuria rosea in an AIDS patient]. AB - Kocuria rosea is an uncommon pathogen may cause opportunistic infections in immunocompromised patient. We report a HIV patient, who presented bacteremia caused by Kocuria rosea. He was successfully treated with vancomycin and by catheter removal. PMID- 23096481 TI - [In Process Citation]. PMID- 23096482 TI - [In Process Citation]. PMID- 23096483 TI - The musculoskeletal abnormalities of the Similaun Iceman ("OTZI"): clues to chronic pain and possible treatments. AB - BACKGROUND AND INTRODUCTION: In 1991, a deceased human male was found frozen in a glacier pool in the Italian Alps in north west Italy, and is now carefully preserved in the South Tyrol Museum of Archaeology, in Bolzano, Italy. The bodily tissues of the 5,300 year old male (colloquially referred to as the Iceman or Otzi) were well preserved despite damage related to freezing, and glacial movement. Associated articles of well-preserved clothing, tools, weapons and other devices were also present and have been studied in detail. Clinical examination and imaging investigations have also shown that the Icemen had experienced possible illnesses in his lifetime and had identifiable areas of arthritis and musculoskeletal injury. This report includes some key observations on the musculoskeletal state of Otzi and reference to the involvement of tattoo markings. Some aspects about the aetiology of his abnormalities and inflammatory arthritis are considered along with possible treatments that he might have employed. METHODS AND RESULTS: We (WFK and MK) undertook a clinical musculoskeletal examination of the Iceman, details of which with available photographs and radiographic imaging pertaining to the musculoskeletal findings of the Iceman are reported here. The skin of the Iceman has numerous linear carbon tattoos, which are not of a decorative type. These have been presumed to possibly be "medicinal" tattoos administered for therapeutic reasons and may have been used in acupuncture-like treatment of pain. Spinal imaging identified areas of spinal damage and our observations have provided clues as to possible sites of spinal initiated pain and hence sites for administration of the "medicinal" tattoos. We observed body areas of the Iceman, in which imaging demonstrated arthritis and other forms of long-term musculoskeletal damage, but which do not have adjacent or corresponding "medicinal" tattoos. We contend that the back and leg "medicinal" tattoos correspond directly to sites of chronic right knee and right ankle pain, and left thoracolumbar pain. They also correspond to lower lumbar and sciatic referred radicular pain which may have a contributory cause related to the presence of a transitional lumbar 5 vertebra. Using recent published data (Keller et al. in Nature Commun 3:698, 2012. doi: 10.1038/ncomms1701 ) of the genome structure of the Iceman, we suggest some potential causes of the osteoarthritis or inflammatory joint injury may relate to presence of coronary heart disease (CHD) and Lyme disease (Borrelia burgdorferi) infection. We speculate on possible medical applications of natural products for self-medication. CONCLUSIONS: These observations highlight several diagnostic features of musculoskeletal conditions in the Iceman with the possibility that tattoos may have been used for diagnosis or location of his painful states. The origins of his musculoskeletal conditions are unclear but there are indications that Lyme disease and CHD may have been factors. The associations or use of natural products may give insights into their applications at the time of the life of the Iceman. PMID- 23096484 TI - The pharmacological modulation of allergen-induced asthma. AB - Aeroallergens are the most common triggers for the development of asthma. Recent birth cohort studies have identified viral infections occurring against a background of aeroallergen sensitization as a potent risk factor for initiation of asthma. Viral infection enhances immunopathogenic potential of pre-existing inhalant allergy via modulating airway mucosal dendritic cells. By using an allergen inhalation challenge clinical model, studies have shown that the late asthma response (LAR) is associated with more pronounced allergen-induced airway inflammation and airway hyperresponsiveness. The degree of airway eosinophilia, regulated by bone marrow progenitor cells and interleukin-5 level, correlates with the magnitude of the LAR and the increase in hyperresponsiveness. Both myeloid and plasmacytoid dendritic cell subsets have been involved in the pathogenesis of allergen-induced LAR. Myeloid dendritic cells are responsible for the allergen presentation and induction of inflammation and plasmacytoid dendritic cells play a role in the resolution of allergen-induced inflammation. A variety of potential new classes of asthma medication has also been evaluated with the allergen inhalation challenge in mild asthmatic subjects. Examples are TPI ASM8, an inhaled anti-sense oligonucleotide drug product, which attenuated both early and LARs via inhibition of the target gene mRNA of chemokine receptor 3, and the common beta chain of interleukin-3, interleukin-5 and granulocyte macrophage colony-stimulating factor receptor. Anti-human antibody interleukin-13 (IM-638) significantly attenuated both early and late allergen-induced asthma response. Pitrakinra, which targets both interleukin-4 and interleukin-13, substantially diminishes allergen-induced airway responses. Allergen-induced airway responses are a valuable way to evaluate the activity of possible new therapies in asthmatic airways. PMID- 23096486 TI - Female parity, male aggression, and the Challenge Hypothesis in wild chimpanzees. AB - The Challenge Hypothesis proposes that testosterone mediates aggression during periods of heightened conflict between males, especially episodes that have important fitness consequences. Considerable evidence from seasonally breeding species provides support for this hypothesis, but few data exist in animals that mate year-round. We tested predictions generated by the Challenge Hypothesis in chimpanzees, a non-seasonally breeding primate, through a study of individuals living in an exceptionally large community at Ngogo, Kibale National Park, Uganda. Results indicated that dominance rank had no influence on testosterone levels. Instead of rank influencing testosterone production, additional analyses revealed an important role for reproductive competition. Male chimpanzees displayed more aggression when they were in the same party as parous estrous females than when reproductively active females were unavailable. Male chimpanzees competed more intensely for mating opportunities with parous females than with nulliparas, and as a consequence, males displayed more aggression around the former than the latter. When males accompanied parous estrous females, their urinary testosterone concentrations were significantly higher than baseline concentrations. In contrast, urinary testosterone concentrations did not exceed baseline when males associated with nulliparous estrous females. These differences in testosterone levels could not be attributed to mating per se because males copulated equally often with parous and nulliparous females. Furthermore, variation in testosterone concentrations were not due to males gathering together in large parties, as their levels in these situations did not exceed baseline. Taken together, these findings, derived from a relatively large sample of males and estrous females, replicate those from a prior study and furnish additional support for the Challenge Hypothesis. Our results suggest that the Challenge Hypothesis is likely to be broadly applicable to chimpanzees and increase our understanding of the physiological costs to males who compete for estrous females. PMID- 23096485 TI - How to manage hyperglycemia in an acute coronary syndrome patient. AB - OPINION STATEMENT: Evidences on hyperglycemia management in patients with acute coronary syndrome (ACS) are scarce and controversial. While approaches such as infusion of glucose, insulin, and potassium (GIK therapy) have not demonstrated any improvement in outcome, glycemic control by means of either continuous insulin infusion or subcutaneous on-demand boluses may be useful only when glycaemia is successfully controlled. Nevertheless, results from several studies are controversial and there is no consensus on glycaemia target values. Concerning oral antidiabetic treatment, previous reports stated an increase in heart attacks throughout their chronic use, however no studies have addressed the effects of either starting or continuing oral antidiabetics during ACS setting. Therefore, there is not enough evidence to strongly recommend any specific therapy to manage hyperglycemia in an ACS patient other than trying to keep glycaemia within reasonable levels (usually defined by consensus), and there is evidence discouraging the use of GIK therapy since no beneficial effect has been observed. PMID- 23096487 TI - Characterization of mitochondrial dicarboxylate/tricarboxylate transporters from grape berries. AB - Grape berries (Vitis vinifera L fruit) exhibit a double-sigmoid pattern of development that results from two successive periods of vacuolar swelling during which the nature of accumulated solutes changes significantly. Throughout the first period, called green or herbaceous stage, berries accumulate high levels of organic acids, mainly malate and tartrate. At the cellular level fruit acidity comprises both metabolism and vacuolar storage. Malic acid compartmentation is critical for optimal functioning of cytosolic enzymes. Therefore, the identification and characterization of the carriers involved in malate transport across sub-cellular compartments is of great importance. The decrease in acid content during grape berry ripening has been mainly associated to mitochondrial malate oxidation. However, no Vitis vinifera mitochondrial carrier involved in malate transport has been reported to date. Here we describe the identification of three V. vinifera mitochondrial dicarboxylate/tricarboxylate carriers (VvDTC1 3) putatively involved in mitochondrial malate, citrate and other di/tricarboxylates transport. The three VvDTCs are very similar, sharing a percentage of identical residues of at least 83 %. Expression analysis of the encoding VvDTC genes in grape berries shows that they are differentially regulated exhibiting a developmental pattern of expression. The simultaneous high expression of both VvDTC2 and VvDTC3 in grape berry mesocarp close to the onset of ripening suggests that these carriers might be involved in the transport of malate into mitochondria. PMID- 23096489 TI - The first 10 years with multiple sclerosis: the longitudinal course of daily functioning. AB - OBJECTIVE: To determine the course of daily functioning in patients with multiple sclerosis in the 10 years after their definite diagnosis. METHODS: A long-term prospective follow-up study including an incidence cohort of 156 patients with multiple sclerosis. Participants were examined systematically, beginning immediately after definite diagnosis, then at the following time-points: 6 months, 1, 2, 3, 6 and 10 years. The various domains of daily functioning were assessed with the Expanded Disability Status Scale, the Functional Independence Measure, and the Medical Outcome Study Short Form-36 (SF-36). RESULTS: Neurological disability and physical functioning worsened significantly, with a time course dependent on whether a patient had multiple sclerosis of the relapse onset type or non-relapse onset type. Cognitive and social functioning worsened significantly over time, but with the same (accelerated) rate of change in both the RO and NRO groups. Scores on SF-36 mental health, SF-36 role physical, and SF 36 general health changed only slightly. CONCLUSION: In the first 10 years after definite diagnosis, patients with multiple sclerosis showed a more pronounced decline in physical functioning than in cognitive and social functioning. There was no time-related decline in mental health, social role due to physical limitations, or general health. PMID- 23096488 TI - Expression of CsSEF1 gene encoding putative CCCH zinc finger protein is induced by defoliation and prolonged darkness in cucumber fruit. AB - To find a marker gene for photoassimilate limitation in cucumber fruit, genes induced in young fruit by total defoliation were cloned using the subtraction method. Almost every clone matched perfectly to a member of cucumber unigene ver. 3 of the Cucurbit Genomics Database. From the clones obtained, six genes were selected and the effect of defoliation on their expression was analyzed. In particular, expression of a gene that is highly homologous to the cucumber gene CsSEF1 (CAI30889) encoding putative CCCH zinc finger protein, which is reported to be induced at somatic embryogenesis in suspension culture, was enhanced by the treatment by about 50 times. The sequencing of the full-length cDNA and BLAST search in the Cucurbit Genomics Database indicated that our cloned gene is identical to CsSEF1. In control fruit, the expression of CsSEF1 did not change markedly in terms of development. By contrast, the expression of CsSEF1 was enhanced by prolonged darkness at the transcript level. This increase in the expression of CsSEF1 was temporally correlated with the decline in the fruit respiration rate. In mature leaves under prolonged darkness, enhanced expression was observed in the asparagine synthetase gene, but not in CsSEF1. These results suggest that the asparagine synthetase gene can be a good marker for sugar starvation and that CsSEF1 might be involved in the signal transduction pathway from photoassimilate limitation to growth cessation in cucumber fruit. PMID- 23096490 TI - Influence of tibial slope asymmetry on femoral rotation in patients with lateral patellar instability. AB - PURPOSE: The geometry of the tibial plateau and its influence on the biomechanics of the tibiofemoral joint has gained increased significance. However, no quantitative data are available regarding the inclination of the medial and lateral tibial slope in patients with patellar instability. It was therefore the purpose of this study to evaluate tibial slope characteristics in patients with patellar dislocations and to assess the biomechanical effect of medial-to-lateral tibial slope asymmetry on lateral patellar instability. METHODS: Medial and lateral tibial slope was measured on knee magnetic resonance images in 107 patients and in 83 controls. The medial-to-lateral tibial slope asymmetry was assessed as the intra-individual difference between the medial and lateral tibial plateau inclination considering severity of trochlear dysplasia. The effect of tibial slope asymmetry on femoral rotation was calculated by means of radian measure. RESULTS: Severity of trochlear dysplasia was significantly associated with an asymmetric inclination of the tibial plateau. Whereas the medial tibial slope showed identical values between controls and study patients (n.s.), lateral tibial plateau inclination becomes flatter with increasing severity of trochlear dysplasia (p < 0.01). Consequently, the intra-individual tibial slope asymmetry increased steadily (p < 0.01) and increased internal femoral rotation in 20 degrees and 90 degrees of knee flexion angles in patients with severe trochlear dysplasia (p < 0.01). In addition, the extreme values of internal femoral rotation were more pronounced in patients with patellar instability, whereas the extreme values of external femoral rotation were more pronounced in control subjects (p = 0.024). CONCLUSION: Data of this study indicate an association between tibial plateau configuration and internal femoral rotation in patients with lateral patellar instability and underlying trochlear dysplasia. Thereby, medial-to-lateral tibial slope asymmetry increased internal femoral rotation during knee flexion and therefore might aggravate the effect of femoral antetorsion in patients with patellar instability. LEVEL OF EVIDENCE: III. PMID- 23096491 TI - Structural properties of the MAPK pathway topologies in PC12 cells. AB - In this paper we propose and analyze parameter-free models for the mitogen activated protein kinase (MAPK) pathway in PC12 rat neural cells. Experiments show that the dynamic behavior of this pathway depends on the input growth factor. The response to epidermal growth factor (EGF) is a short peak followed by a relaxation, while the response to nerve growth factor (NGF) is sustained. In the latter case, the system can be driven to a new state, which persists after the stimulus has vanished. Ultimately, these dynamic behaviors correspond to different cell fates: EFG stimulation induces proliferation, while NGF stimulation induces differentiation. The biochemical mechanisms responsible for the different input-dependent dynamic response are still unclear. One hypothesis is that each input generates a specific interaction topology among the kinases. Starting from experimental results that support this hypothesis, we derive and analyze qualitative models for the two network topologies. Our approach is based on invariant set theory and non-smooth Lyapunov functions. We demonstrate analytically that the network behaviors and stability properties are structurally dependent on the topology, and do not depend on specific parameter values of the underlying biochemical interactions. PMID- 23096492 TI - Chromatic aberration in heterocentric astigmatic systems including the eye. AB - PURPOSE: There is inconsistency in the literature in the definitions of longitudinal and transverse chromatic aberration, and there appear to be no definitions that make allowance for astigmatism and heterocentricity. The purpose is to propose definitions of longitudinal and transverse chromatic aberration that hold for systems which, like the typical eye, may be heterocentric and astigmatic and to develop the associated optics. METHODS: Common definitions of longitudinal and transverse chromatic aberration based on Gaussian optics are generalized naturally in terms of linear optics to accommodate heterocentricity and astigmatism. CONCLUSIONS: The definitions offered here apply to systems in general, including the visual optical system of the eye, and hold for homocentric stigmatic systems in particular. Care is advocated in the use of the terms longitudinal and transverse chromatic aberration. PMID- 23096493 TI - Radiologic presentation of pituitary adenoma. AB - PURPOSE: This case report aims to educate the importance of ordering radiographic studies when suspicion arises: visual field defects and optic nerve appearance may lead to the discovery of otherwise asymptomatic central nervous system disease. CASE REPORT: We describe a patient who was previously diagnosed and successfully treated for a pituitary adenoma but who presents with worsening visual acuity and visual field defects. CONCLUSIONS: Pituitary tumors are the most common of all tumors arising from the sellar and parasellar region. Owing to the high prevalence and proximity of these tumors to the optic nerve, chiasm, and tract, it is especially important to incorporate an appropriate history, examination, and radiographic workup in patients with suspicious visual field or optic nerve appearances. It is also critical to have anatomic and physiologic familiarity with the sellar and parasellar region. This case report explores the clinical presentation, test results, anatomy and physiology, interdisciplinary co management, and current and future treatments of pituitary adenomas. PMID- 23096494 TI - Lipid-containing lubricants for dry eye: a systematic review. AB - PURPOSE: Dry eye is a common eye condition with significant impact on its sufferers' quality of life. We conducted a systematic review of randomized controlled treatment trials to assess the effectiveness of lipid-containing lubricants (LCLs) on dry eye treatment. METHODS: An online database was searched without any language or date restrictions. Clinical trials on LCL with non-lipid containing control eyedrops were included. The outcome measures of each study (including symptoms and clinical signs), their risk of bias (assessed using the Cochrane tool), and strength of evidence were discussed. RESULTS: Three studies on liposomal lid sprays and four on lipid-containing eyedrops were included. All studies found significant improvements in most of the symptoms/signs of dry eye in patients who used LCL during the study period. Subjects in all trials reported greater symptom relief with LCLs, although this was shown to be short lived in two studies. Lipid layer structure improvement after LCLs application was demonstrated in two studies, although only up to 90 min in one study. Improvement in Schirmer test results was shown in two out of four studies, tear breakup time in four out of five studies, meibomian gland status in three out of three studies, conjunctival folds and tear evaporation rates in two out of two studies each. None of the studies were completely free of risks of bias; only three studies were double masked. Three of the studies were assigned high level of evidence, three were assigned as moderate evidence, and the final one low level of evidence. CONCLUSIONS: Most studies have demonstrated the effectiveness of LCLs on improving select signs of dry eye. Based on the overall substantial level of evidence, this type of eyedrop can be recommended for use in clinical practice where the aim is to reduce the signs and symptoms of dry eye. PMID- 23096495 TI - Protein tyrosine phosphatase receptor-like genes are frequently hypermethylated in sporadic colorectal cancer. AB - The activity of phosphatases could be influenced by genetic, as well as epigenetic alterations. In our study, we have investigated the methylation status of four PTPRs: PTPRM, PTPRT, PTPRR and PTPRZ1, which were pre-selected using microarray techniques as being alternatively methylated in sporadic colorectal cancer (CRC). The analyses were carried out on 131 surgical specimens obtained from sporadic CRC patients. The methylation status of the four genes was examined using methyl specific PCR (MSP). The analysis of promoter methylation using an Illumina 27K microarray revealed four protein tyrosine phosphatases PTPRM, PTPRT, PTPRR and PTPRZ1 as being hypermethylated with beta-value >=0.2 and P<=0.05. Subsequent analysis using MSP confirmed these observations-the frequency of promoter methylation was significantly higher in tumor cells compared with matched normal tissue for each of the analyzed genes. There was no association observed between the methylation status of PTPRs and either CIMP, K-ras (codon 12) and BRAF (exon 15, V600E) mutations or tumor localization (proximal/distal). The results of our study show a statistically significant difference between promoter methylation in cancerous and healthy tissue. This result supports the hypothesis that the PTPR family has an important role in the etiology of CRC. PMID- 23096496 TI - Measuring acceptance in irritable bowel syndrome: preliminary validation of an adapted scale and construct utility. AB - PURPOSE: It has been well established that how irritable bowel syndrome (IBS) patients respond to their illness experiences (physical, psychological) has a great impact on their symptoms, psychosocial functioning and quality of life. Recently it has been shown that using acceptance coping strategies (rather than control coping strategies) is linked to positive outcomes in several chronic illness contexts (e.g. chronic pain, diabetes, epilepsy).This study is intended to evaluate the factor structure and other psychometric properties of an acceptance measure adapted for the IBS population (IBSAAQ) and to investigate its possible utility in the prediction of key IBS outcomes. METHODS: A sample of 121 IBS patients attending a specialized gastroenterology clinic completed a series of self-report measures assessing acceptance of IBS, general acceptance, symptom severity, IBS impact on quality of life, general quality of life, gastrointestinal-specific anxiety, avoidant coping behaviours, depression, anxiety and stress. RESULTS: Factor analysis supported a 2-factor structure explaining 48.5% of variance. The total scale and its subscales (activity engagement/IBS willingness) were found to have adequate internal consistency (all alpha's > 0.80) and test-retest stability. Correlation analyses showed good convergent and concurrent validity. Regression analyses showed that the IBSAAQ and its subscales significantly contributed to the prediction of IBS outcomes. CONCLUSION: The IBSAAQ is a valid and reliable measure of acceptance in IBS. This measure might be of use for the study of the impact of coping strategies on outcomes in IBS and of the effectiveness of acceptance-based approaches (e.g. acceptance and commitment therapy). PMID- 23096497 TI - Prenatal diagnosis and termination of pregnancy: perspectives of South African parents of children with Down syndrome. AB - This study aims to evaluate the attitudes of a group of South African parents with a preschool child with Down syndrome (DS) towards prenatal diagnosis (PND) and termination of a Down syndrome-affected pregnancy (TAP). This study employs a qualitative phenomenological approach with the use of semi-structured interviews. Twelve participants were recruited from two state sector hospitals in Cape Town, South Africa. Thematic analysis was used to interpret the data. The participants had a positive attitude towards PND and felt that it was every parent's right to have the option. They considered a benefit of PND the fact that it allowed parents time to prepare for the arrival of a baby with DS. The induced miscarriage risk associated with invasive prenatal testing procedures caused major negative feelings. They were totally opposed to the termination of a Down syndrome-affected pregnancy due to their personal experience, moral, ethical or religious convictions. South African parents of preschool children with Down syndrome are comfortable with PND for Down syndrome; however, they do not support TAP. These findings will provide health care providers with further insight into the motivations behind the decisions their patients make. PMID- 23096499 TI - [Health physicists in the German Radiological Society]. PMID- 23096498 TI - Atrial fibrillation occurring early after cardiovascular surgery: impact of the surgical procedure. AB - PURPOSE: Postoperative atrial fibrillation/flutter (AF) is still the most common complication after cardiovascular surgery, and it is important to determine the risk factors in order to establish effective management for recent postoperative AF. This study investigated the clinical predictors of postoperative AF using a prospectively collected database. METHODS: A total of 418 patients underwent cardiovascular surgery and were enrolled in this study. The relationship between postoperative AF and perioperative factors was examined. RESULTS: Postoperative AF occurred in 134 patients (32.1%). A univariate analysis showed that an older age, hypertension, perioperative transfusion, use of cardiopulmonary bypass and thoracic aortic surgery were significantly associated with postoperative AF. The incidence of fibrillation was 49.4% (39/79) in patients having aortic surgery. A multivariate analysis revealed that an older age, transfusion, and aortic surgery were all independent predictors of postoperative AF. CONCLUSIONS: An older age, transfusion, and aortic surgery are strong independent predictors of postoperative AF. These findings help to identify high-risk patients for AF after cardiovascular surgery. Careful perioperative management is required for older patients undergoing aortic surgery with cardiopulmonary bypass. PMID- 23096501 TI - Rhodium and copper-catalyzed asymmetric conjugate addition of alkenyl nucleophiles. AB - Since the initial reports in the mid-90s, metal catalyzed asymmetric conjugate addition (ACA) reactions evolved as an important tool for the synthetic chemist. Most of the research efforts have been done in the field of rhodium and copper catalyzed ACA reactions employing aryl and alkyl nucleophiles. Despite the great synthetic value of the double bond, the addition of alkenyl nucleophiles remains insufficiently explored. In this account, an overview of the developments in the field of rhodium and copper catalyzed ACA reactions with organometallic alkenyl reagents (B, Mg, Al, Si, Zr, Sn) will be provided. The account is intended to give a comprehensive overview of all the existing methods. However, in many cases only selected examples are displayed in order to facilitate comparison of different ligands and methodologies. PMID- 23096502 TI - [Propensity score is a useful tool for non randomized studies]. PMID- 23096503 TI - Re-coarctation of aorta in an 80 year old patient. PMID- 23096504 TI - [Uterine rupture by placenta accreta at 13 weeks gestation]. PMID- 23096505 TI - [Bowel preparation : what's new ?]. AB - BACKGROUND: The efficiency of bowel preparation directly affects the quality and the reliability of total colonoscopy. Inadequate bowel cleansing is a common cause of incomplete colonoscopy with a risk of ignoring pre-neoplastic lesions represented primarily as adenomas with a size below centimetre. Due to the numerous factors interfering with preparation, an adapted choice of the type of preparation and the follow-up of diverse methods to optimize bowel preparation allows to improve diagnostic accuracy and to reduce costs while guaranteeing to the patient good tolerabilty and safety. AIM: To report the news about the terms of the bowel preparation for colonoscopy quality and to propose practical ways to optimize it. METHODS: Review of literature and lecture of recommendations. RESULTS: The pre-colonoscopy consultation, prescription of a split dose bowel preparation and a brief time between the last dose of preparation and colonoscopy are the means currently available to optimize bowel preparation. CONCLUSION: A better understanding of terms of bowel preparation and the factors influencing the degree of preparation improve the diagnostic efficacy of colonoscopy especially in the detection and treatment of colorectal cancer. PMID- 23096506 TI - [Resistance in Gram negative bacteria: what is the current situation?]. AB - Emergence of antibiotic resistance put an end to the antibiotic miracle. According to recent review data, the number of cases of multiresistant bacteria, which are resistant to all antibiotics available, is increasing as well in the developed countries as in the developing countries. To face the emergence of these bacteria, it is necessary to evaluate the situation in Tunisian hospitals and act consequently. This review provide recent data on antibiotic resistance in Gram negative bacilli in Tunisian hospitals by focusing on some emergent resistances, which represent a daily challenge for the medical profession, such as extended spectrum beta-lactamases, carbapenem resistance, and fluoroquinolone resistance. PMID- 23096507 TI - [Spinal anesthesia versus general anesthesia for inguinal hernia repair: propensity score analysis]. AB - BACKGROUND: Administrative database, used previously for control of cost, patient flow and invoicing, offer to researchers a large sample of patients representative of population providing interesting information's in the field of descriptive and analytic epidemiology with less cost. AIM: To compare spinal to general anesthesia for inguinal hernia repair concerning a population extracted from administrative database after propensity matched analysis. METHODS: Prospective study concerning 4690 hospitalizations in Department B of General Surgery of Charles Nicolle hospital during a period of 18 months, between June 1st, 2008 and December 31st, 2009. A descriptive analysis followed by a comparison between spinal and general anesthesia according propensity matched analysis were performed. Resultats: 595 inguinal hernias were operated on. Mean age was 55+/-15.We mentioned a male predominance: 326 men (84.2%) and 61 women (15.8%). 137 patients had previous medical diseases(35.4%). 47(12.1%) patients were operated on in emergent situation on the other hand 340(87.9%) had elective surgery.264(68.2%) were ASA I, 110(28.4%) ASA II, 13(3.4%) ASA III. Post operative course were uneventful in 96.1% (372) and complicated in 11 patients (2.9%).Four deaths were observed (1%). Comparison before and after propensity matched analysis showed a statistical difference regarding postoperative stay and all hospital stay in favor of spinal anesthesia (p=0.007). CONCLUSION: Postoperative stay is significantly shorter in the group of spinal anesthesia (p=0.007). A randomized clinical trial comparing spinal anesthesia to general anesthesia is needed. PMID- 23096508 TI - [Prospective study of 45 cases of disseminated intravascular coagulation]. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) in obstetric disorders is a severe complication. AIM: To study the frequency and means of diagnosis of DIC and the therapeutic care and maternal morbidity induced. METHODS: Monocentric, prospective and descriptive study about 45 cases of intravascular coagulation in an obstetrical service collected at the University Hospital of Obstetrics and Gynecology Hedi Chaker of Sfax over a period ranging from June 2007 to June 2010. All the pregnant patients who have given birth beyond 28 weeks and have presented a DIC were selected for this study. RESULTS: The mean age of patients was 31.4 years. The mean parity was 2.6. The main diseases during pregnancy were: severe preeclampsia (22.2%), diabetes (28.8%), intrauterine fetal death (17.7%), previa placenta (8.8%). The main causes of DIC were: uterine atony (44.4%), abruptio placenta (22.2%), Hellp syndrome (11.1%) and uterine rupture (6, 6%). The lowest rate of platelets was 21000/mm3. The fibrinogen level was <0.5 g in 40% of cases. Despite reanimation and transfusion with blood products, surgical treatment was necessary in 77.7% of cases. All the patients were transferred in intensive care unit with an average stay of about three days. No maternal death was reported. CONCLUSION: DIC is a frequent complication of many obstetrical diseases. The treatment is urgent. It requires first to the cause and the shock by massive transfusions of packed red blood cells, fresh frozen plasma, and platelets, associated with antifibrinolytic drugs, if necessary. PMID- 23096509 TI - [Evaluation of a protocol of spinal anesthesia for cesarean section in a Tunisian maternity unit: hemodynamic repercussions and risk factors for hypotension]. AB - AIM: To evaluate hemodynamic repercussion of a protocol of spinal anesthesia (SA) for cesarean and release the predictive factors of maternal arterial hypotension post spinal anesthesia. METHODS: We included parturients proposed for Cesarean under SA. They were not included the women of statute ASA > II, preeclamptics, eclamptics and/or having counter-indications of SA. We excluded the cases where there were technical difficulties at the time of the realization of SA, a failure or a complication of this SA. We injected 10 Mg of bupivacaine 0.5% isobar, 10 MUg of fentanyl and 100 MUg of morphine. The data were collected before the realization of SA (anthropometric parameters; antecedents; basic systolic and diastolic blood pressures (BSBP and DSBP) and basic heart rate (BHR)) and after SA (systolic and diastolic blood pressure (SBP and DBP), heart rate (HR); occurred or not of a sympathetic block (falls of the SBP of more than 20% of its basic value or a SBP<90 mm Hg); the time of installation of the sympathetic block and the duration of hypotension. RESULTS: The full number of parturients included was 1016 among whom 16 were excluded. Only 1000 parturients finished the study and were divided into 2 groups (group 1: 500 emergency cesarean and group 2: 500 elective cesarean). The incidence of the sympathetic block was of 44.2% as a whole and this block was significantly more frequent in group 2 (p=0.0001). There was a significant relation between the incidence of a sympathetic block and the advanced age of the parturient (p=0.0001), the important weight (p=0.047), high ASA statute (p=0.0001), the presence of hypertension (p=0.0001), diabetes (p=0.001) or cesarean (p=0.00015) in the antecedents and the low BSBP (p=0.015). CONCLUSION: In spite of the beneficial effect of the reduction in the amounts of local anesthetic in the SA, the sympathetic block remains frequent after SA for Cesarean. Thus, it is essential to detect the high risk women of occurred of sympathetic block after SA, and to propose strategies of prevention, monitoring and management for this population. PMID- 23096510 TI - [Prospective study of the contribution of hydrosonography in the exploration of the uterine cavity]. AB - BACKGROUND: Recent developments in ultrasound have led to a new exploration technique: hydrosonography. AIM: To evaluate diagnostic performance of hysterosonography in the assessment of the uterine cavity, by comparing it with standard transvaginal ultrasound and particularly with diagnostic hysteroscopy. METHODS: This is a prospective study over a period of nine months from 1st January to 30 September 2009. Transvaginal ultrasound was performed for all patients followed by hydrosonography then by diagnostic hysteroscopy. RESULTS: Sixty-two patients underwent three examinations. The mean age of our patients was 42.2 years. Bleeding disorders of the menstrual cycle were the most common reasons for seeking. Referring to the pathological examination, hysteroscopy is the most accurate technique in the diagnosis of endometrial hyperplasia and intracavitary masses, followed by hydrosonography then by transvaginal ultrasound. The concordance between hydrosonography and hysteroscopy in the diagnosis of submucosal fibroids and hyperplasia of the endometrium is very good (K> 0.8). CONCLUSION: The hysterosonography seems a relevant exam, allowing a complete assessment of the uterine cavity. PMID- 23096511 TI - [Fournier's gangrene : what are the prognostic factors? Our experience with 40 patients]. AB - BACKGROUND: Fournier's gangrene (FG) is a serious, extensive fulminant infection of the genitals and perineum. Indeed, despite antibiotics and aggressive debridement, the mortality rate of FG remains high. AIM: Through our experience, we intent to identify effective factors in the survival of patients with FG and we try to determine how the Fournier's gangrene severity index score (FGSIS) is accurate. METHODS: Between 1995 and 2010, 40 patients with Fournier's gangrene were treated in our institution. All of them were treated with broad spectrum triple antimicrobial therapy, broad debridement and exhaustive cleaning. Then they underwent skin grafts or delayed closure as needed. Data were collected on demographics, medical history, predisposing factors of FG, etiological infection agents, admission signs and symptoms, physical examination, admission laboratory studies and bacteriology. Timing and degree of surgical debridement as well as outcomes were also reviewed. The extent of disease was calculated from body surface area nomograms. RESULTS: All the 40 patients included in this study were males; their mean age was 52,75 years (21-75 years). Twelve patients (30%) had FG secondary to anorectal pathological conditions. No etiologic factors of FG were found in 6 patients (15%). Diabetes mellitus as predisposing factor was found in 13 patients (32.5%). The mean hospital stay was 8.72 days (range, 3 to 30). All the patients underwent surgical debridement. Orchidectomy was done in 7 cases (17.5%). Skin grafts were applied to 6 patients (15%) and the remaining wounds, once cleaned, were approximated. The overall mortality rate was 17.5% (7 patients) due to severe metabolic acidosis in relation to diabetic decompensation and sepsis. We individualized two groups: those who died (n = 7) and those who survived (n = 33). We evaluated the admission laboratory parameters that are significantly correlated with outcome included hematocrit (p=0.003) and serum sodium (p=0.05). The extent of body surface area involved among patients who died was not found significantly different statistically between the two groups (4.07% and 3,14%, p=0,4). The mean FGSIS (without counting bicarbonate serum level) for survivors was 9.1 compared with 6,8 for nonsurvivors (p=0.16). CONCLUSION: FG is a rapidly progressive, fulminant infection's condition. Hematocrit and serum sodium levels were found to be the only prognostic factors. It doesn't seem that the FGSIS has a prognostic value. PMID- 23096512 TI - [Clinical characteristics, management and prognostic evolution of patients admitted within six hours of symptom onset with st-segment elevation acute myocardial infarction complicated by cardiogenic shock : twenty year monocentric study]. AB - BACKGROUND: Cardiogenic shock is one of the most serious complications of the acute myocardial infarction. Advances in interventional cardiology and early reperfusion strategy improved its management. AIM: Analysis of the clinical characteristics, management and prognostic evolution of patients admitted within 6 hours onset with ST-segment elevation acute myocardial infarction complicated by cardiogenic shock. METHODS: Follow-up study based on 2200 consecutive patients admitted with STEMI within 6 hours of symptom onset from 1988 to 2008. Among them 114 matched the criteria of cardiogenic shock. These were divided in two groups, according to the period: group 1 (N=57, among the first 1100 STEMI from 1988 to 1998) and group 2 (N=57, among the following 1100 STEMI from 1999 to 2008). RESULTS: This trial shows a similar rate of cardiogenic shock in STEMI (5%) in both 1100 patients groups. There is no overall change in patient's clinical characteristics, but improvements in earlier management, prehospital fibrinolysis and ventricular fibrillation treatment have been detected. Primary percutaneous coronary intervention was the most common revascularisation strategy. The proportion of patients achieving acute TIMI-3 flow in the infarct related artery increased (61% vs 80%, p= 0.11) but the mortality was still high (74% vs 63%, p= 0.22). CONCLUSION: The clinical characteristics of cardiogenic shock remain unchanged; its management is more successful with more often early reperfusion. The decline of mortality is unfortunately not significant. More aggressive treatment should probably be considered to improve outcomes. PMID- 23096513 TI - [Single versus bilateral internal thoracic artery grafts for multi vessel coronary artery bypass grafting: mid-term results]. AB - BACKGROUND: The issue of superiority of single internal thoracic artery grafting versus bilateral internal thoracic artery grafting remains unresolved. AIM: The aim of this study was to compare the early results and midterm outcome of single and bilateral internal thoracic artery grafting for multivessel coronary artery bypass grafting. METHODS: Between January 2005 and March 2010, 196 patients underwent primary coronary artery bypass grafting with at least one internal thoracic artery grafts. Early results and Outcomes of patients undergoing single internal thoracic artery (SIMA) plus saphenous vein grafting (n=145) and bilateral internal thoracic artery (BIMA) plus saphenous vein grafting (n=51) were obtained at a mean followup of 29 months. RESULTS: Patients with bilateral internal thoracic artery grafting were younger, had less hypertension, higher left main disease and better Euroscore than patients undergoing single internal thoracic artery grafting. In-hospital mortality was similar for the two groups: 6.9 % for patients undergoing SIMA versus 5.9 % for those undergoing BIMA (p=0.8). Sternal wound infection was also similar (2.8% versus 3.9% p=0.68). Mid term mortality was (4% VS 4.8% p=0.71) and event free survival probability at 28 months was 75% for the single-graft group compared with 85.7% for the bilateral graft group (P =0.46). CONCLUSION: Our study found similar early and mid-term clinical outcomes for patients undergoing SIMA plus saphenous vein grafting and those undergoing BIMA plus saphenous vein grafting for multivessel coronary artery bypass grafting. PMID- 23096514 TI - [Emphysematous pyelonephritis. Epidemiological, clinical, biological, bacteriological, radiological, therapeutic and prognostic features. Retrospective study of 30 cases]. AB - BACKGROUND: Emphysematous pyelonephritis is an uncommon, necrotizing bacterial infection of the kidney. It is a severe, life threatening affection. AIMS: To study the epidemiological, clinical, biological, bacteriological and radiological features of this affection, and to describe its therapeutic management and prognostic characteristics. METHODS: We conducted a retrospective study including 30 patients who were treated for an emphysematous pyelonephritis, in Charles Nicolle hospital department of urology, from 1987 to 2009. RESULTS: Emphysematous pyelonephritis generally affects adults. It is especially favored by diabetes and urinary tract obstruction. Escherichia coli is the main causative agent. Uroscan is the key of diagnosis. It is both medical and surgical emergency; the treatment combines intensive care with appropriate antibiotics and often drainage. Nephrectomy may be necessary from the outset, or after drainage failure. Prognosis is poor, with a high mortality rate (23 %), in our series. CONCLUSION: Management of emphysematous pyelonephritis poses real problems. This affection is still threatening, despite of advances in intensive care. PMID- 23096515 TI - [The role of neutrophils in the formation of peritoneal adhesions]. AB - BACKGROUND: The use of antibiotics during peritonitis appears to decrease the formation of postoperative intra peritoneal adhesions and reduce their severity. The effect of this antibiotic is still controversial. AIM: To study the relationship between the decrease postoperative adhesions induced by rifamycin, and the number of neutrophils and the number of intraperitoneal bacteria. METHODS: This is an experimental prospective, randomized singleblind study performed on adult male rats. The product used for the peritoneal lavage was rifamycin s. The animals were randomized into three groups: Group S: intra peritoneal lavage with saline to 9%, R25 Group: intra peritoneal lavage with rifamycin at a dose of 25 mg / kg group and 12.5 R: intra peritoneal lavage with rifamycin at a dose of 12.5 mg / kg. Adhesions score was evaluated according to Zulkhe by the same operator. RESULTS: The adhesion score was significantly lower between groups S and R12.5 (p = 0.000) and group S and group R25 (P = 0.01). However, the difference was not significant between the two groups R 25 and R12.5 compared to S group (p = 0.655). The number of bacteria between the time of caecal resection (before peritoneal lavage) and the time of death or sacrifice was significantly decreased significantly in the groups R25, comparing the group S (p = 0.003). However, there is no significant difference between groups S and R12, 5 (p = 0.106). The number of neutrophils between the time of cecal resection (before peritoneal lavage) and the time of death or sacrifice decreased significantly in the groups R25 and R12, 5 in comparison to the group S. Between the group R25 and the S group, the difference is significant (p = 0.037) as well between the group R12, 5 and S (p = 0.026). However, there is no significant difference between the two groups R 25 and R12, 5 (p = 0.712). CONCLUSION: The action of rifamycin sodium on neutrophils seems to be independent of its antibacterial action. These findings deserve to be explored at the end to clarify the mechanism of neutropenia by intra peritoneal washing with rifamycin and the relationship between neutropenia and post-operative adhesions. PMID- 23096516 TI - [Continuous glucose monitoring in glimipiride plus metformin treated type 2 diabetic patients during the month of Ramadan]. AB - BACKGROUND: Fasting during Ramadan may be a cause of poor glycaemic control in diabetic patients. AIM: To assess glucose excursions during Ramadan by using a continuous glucose monitoring system (CGMS). METHODS: The interstitial glucose level was recorded over 72 hours during Ramadan and three months later, in five type 2 diabetic patients, aged 56 +/- 5, treated with glimepiride and metformin. RESULTS: During Ramadan, four patients experienced at least one episode of low glucose level (<0.7 g/l) during the monitoring. The frequency of these episodes was 0.6 episode/d with an average duration of 36 mn / d. These episodes occurred in the morning in half of the cases and in the hour before breaking the fast in 37.5 % of the cases. Four patients experienced at least one episode of high glucose level (>1.8 g/l), with an average duration of 403 mn /d and with a frequency of two episodes /d. More than half episodes (53) occurred after the breaking of the fast. After Ramadan, CGM records showed at least one episode of low glucose in two patients with an average duration of 58 mn /d and a frequency of 1.3 episodes/d. Three patients experienced at least one episode of high glucose level with an average duration of 525 mn /d and a frequency of 1.46 episodes/day. CONCLUSION: The blood glucose profile of our patients during Ramadan is characterized by important glycaemic excursions. PMID- 23096517 TI - [Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis]. PMID- 23096518 TI - [Primary cerebral lymphoma]. PMID- 23096519 TI - Hypertrichosis, gingival hypertrophia, epilepsy and mental retardation: a separate entity? PMID- 23096520 TI - [Gastric adenocarcinoma developed after lymphoma]. PMID- 23096521 TI - [DRESS syndrome]. PMID- 23096522 TI - [Digestive cancer in pregnancy]. PMID- 23096523 TI - [Eosinophilic nodule of the breast: a rare manifestation in the Churg-Strauss syndrome]. PMID- 23096524 TI - [Esophagectomy and gastric tube for isolated esophageal involvement of Crohn's disease]. PMID- 23096525 TI - [Cystic mediastinal hemolymphangioma]. PMID- 23096526 TI - [Gaucher disease type 1 in late onset]. PMID- 23096527 TI - Adult separation anxiety during pregnancy and its relationship to depression and anxiety. AB - AIMS: The current study, the first of its kind, investigated the overlap between adult separation anxiety (ASA) and the symptoms of depression and anxiety in the context of pregnancy. METHODS: Women attending an antenatal clinic were screened using the Adult Separation Anxiety Scale (ASA-27). As most perinatal clinics use the Edinburgh Depression Scale (EDS), this study explored the relationship between ASA and the anxiety and depression symptoms by comparing the ASA-27 scores with the scores on the EDS. A subsample including both screen positives and screen negatives on ASA-27 was clinically interviewed using the Mini International Neuropsychiatric Interview (MINI). RESULTS: Women with ASA were significantly more likely to be screened positive for depression (EDS total score) and anxiety (EDS-3A anxiety subscale) than those without ASA. The diagnosis of ASA disorder in this population had only a moderate but significant association with the diagnoses of generalized anxiety disorder [chi2 (1) = 25.9, P = 0.000, Phi = 0.443] and major depression [chi2 (1) = 16, P = 0.000, Phi = 0.348] made using the MINI. CONCLUSION: Adult separation anxiety warrants independent assessment in order to tailor appropriate interventions for the individual subtypes of anxiety in the perinatal period. PMID- 23096528 TI - Evaluation of the effect of statin use on the acenocoumarol and phenprocoumon maintenance dose. AB - BACKGROUND: Statins and coumarins are prescribed in combination on a regular basis. Some case reports suggested that statins might affect the dose requirements of coumarins. The aim of the study was to investigate whether acenocoumarol and phenprocoumon maintenance doses are influenced by statin use. METHODS: The Pre-EU-PACT database was used, which contains information on 471 acenocoumarol and 624 phenprocoumon users. The influence of individual statins on the acenocoumarol and phenprocoumon maintenance dose was investigated by comparing unadjusted and adjusted mean differences of the maintenance dose between statin and non-statin users. RESULTS: Lower adjusted acenocoumarol dose requirements were observed for patients using atorvastatin, simvastatin, pravastatin, and rosuvastatin. These patients had a reduction in adjusted mean acenocoumarol maintenance dose of 0.11, 0.29, 0.38, and 0.69 mg/day, respectively, compared with a mean adjusted dose of 2.60 mg/day for the patients not using a statin. There was no significant effect of statin use on unadjusted and adjusted phenprocoumon maintenance dose (p=0.23 and p=0.35, respectively). CONCLUSIONS: Mean acenocoumarol maintenance dosages were decreased when acenocoumarol is co-administered with the different statins. Statin use does not affect phenprocoumon maintenance doses significantly. PMID- 23096529 TI - First human isolate of Mycobacterium madagascariense in the sputum of a patient with tracheobronchitis. PMID- 23096530 TI - Urinary symptoms and urodynamics following obstetric genitourinary fistula repair. AB - INTRODUCTION AND HYPOTHESIS: The aim of this study was to evaluate urinary symptoms and urodynamic diagnoses in women following repair of obstetric fistula of the lower urinary tract. METHODS: Women with previous genital tract fistula and ongoing urinary symptoms were evaluated at the Addis Ababa Fistula Hospital. The women were referred to the Urodynamic Unit by doctors reviewing women at the hospital. Consecutive women between December 2008 and September 2009 were assessed (including urodynamic studies) and data collected RESULTS: One hundred and fifty-four women were referred for urodynamic assessment. Only women with previous obstetric fistula were included in the study. Of the 154 women, 5 were excluded from the study-1 declined the assessment, 1 had a non-obstetric fistula and 3 were found to have recurrence of the fistula. Forty-nine percent had urodynamic stress incontinence only, 3 % had detrusor overactivity only and 43 % had both urodynamic stress incontinence and detrusor overactivity. Five percent of women had neither detrusor overactivity nor urodynamic stress incontinence. Seven percent had post-void residual volume of 150 ml or more. CONCLUSIONS: Non surgical management of post-obstetric fistula urinary symptoms may be neglected. The reduced success rates in surgery for post-obstetric fistula urinary incontinence may be due to the lack of attention to the other reasons for urinary symptoms and markedly impaired urethral function. Urethral closure pressures in this group of women often did not reflect the severity of urinary incontinence. PMID- 23096531 TI - Measuring urinary incontinence in a population of women in northern Mexico: prevalence and severity. AB - INTRODUCTION AND HYPOTHESIS: This study was designed to estimate the prevalence of urinary incontinence and its associated risk factors among women in northern Mexico. The type and severity of incontinence were also assessed. METHODS: This cross-sectional population-based study assessed self-reported urinary incontinence in a random sample of 1,307 women aged 25-54 years. Logistic regression was used to estimate the association of urinary incontinence with sociodemographic and reproductive characteristics and other medical conditions. RESULTS: Overall, 18.4% of participants reported having involuntary loss of urine at some time within the last 12 months (95% CI, 16.4-20.7%). Among women reporting urinary incontinence, stress incontinence was the most common form (56.8%), followed by mixed (31.1%) and urge incontinence (10.0%). Approximately half of the women with urinary incontinence symptoms reported a severity index of moderate (25.8%) to severe (26.2%), with 30% stating that their leakage was extremely bothersome. Forty percent of incontinent women reported use of some sort of protection, although only 28% had ever talked to a physician about their symptoms. In adjusted analyses, high body mass index (BMI) >= 25 kg/m(2), chronic urinary tract infections, and a history of a hysterectomy or uterine leiomyomata were associated with increased odds of reporting incontinence symptoms. Increased odds of reporting severe urinary incontinence was associated with chronic urinary tract infections, current smoking and high BMI. CONCLUSION: Our results suggest that there might be a need to develop a culturally sensitive screening questionnaire in order to identify and counsel women with mild incontinence symptoms in the primary care setting. PMID- 23096532 TI - Repeat versus primary slings in patients with intrinsic sphincter deficiency. AB - INTRODUCTION AND HYPOTHESIS: Our goal was to compare outcomes of repeat vs. primary synthetic slings in patients with stress urinary incontinence (SUI) with intrinsic sphincter deficiency (ISD). MATERIALS AND METHODS: We reviewed patients who underwent a sling for SUI with ISD from 2003 to 2010. The patients were divided into two groups according to whether they underwent primary or repeat sling. Surgical success was defined as no incontinence and no reintervention (i.e., urethral bulking) during follow-up. Statistical analysis included the unpaired t test, Wilcoxon rank sums test, chi-squared/Fisher's exact tests, and logistic regression to identify risk factors associated with failure. RESULTS: Six hundred and thirty-seven patients with ISD underwent a sling procedure at our institution; 557 (87 %) a primary sling and 80 (13 %) a repeat sling. Patient demographics were similar. Preoperatively, patients with recurrent SUI reported more subjective bother. Mean follow-up was 66.5 weeks (24-374). Success was achieved in 81 % of primary compared with 55 % of repeat slings (p<0.0001). Repeat patients were 3.4 times more likely to fail surgery [odds ratio (OR) =3.43, 95 % confidence interval (CI) 2.1-5.6]. Additionally 30 % of the repeat group underwent urethral bulking postoperatively compared with 8.6 % in the primary group (OR=4.4, 95 % CI 2.5-7.7). Prior incontinence procedures, a positive supine stress test, and transobturator sling were independent risk factors for failure. Among the types of slings placed (transobturator, retropubic, tensioned pubovaginal), pubovaginal slings were most successful (OR=2.7, 95 % CI 1.4-5.2). CONCLUSION: In women with ISD, repeat slings are associated with lower success rates compared with primary slings. Pubovaginal slings resulted in the highest success rate compared with both transobturator and retropubic slings. PMID- 23096535 TI - [Medical students at risk: prevalence and incidence of tuberculin skin test conversion]. AB - INTRODUCTION: One third of the world population is affected by latent tuberculosis, with 9.4 million new cases; medical students have 2 to 50 times the probability of acquiring the infection. OBJECTIVES: Establish the baseline prevalence of positive tuberculin skin test (TST) at the beginning of medical studies and determine the incidence and variables associated with TST conversion in medical students. MATERIALS AND METHODS: Secondary analysis of a historical cohort (2007-2010) of medical students in a private Peruvian university. The TST conversion was evaluated. A binomial regression analysis was applied for each associated variable. RESULTS: 707 medical students were included, of whom 219 (31%) were male. The basal prevalence of reactive TST was 14.4%. Significant associations were found with the year of university entry of 2007-08 (p = 0.007) and a history of tuberculosis (p = 0.02). With a total of 822 person-years, the incidence of conversion was 2.92 cases per 100 person-years (CI95%: 1.96-4.36). The TST conversion was associated with the year of university entry (RR = 2,55; IC95%: 1,06-6,30) and a body mass index > 25 kg/m2 (RR = 0,16; IC95%: 0,01-0,97). No association was detected with gender, tobacco or alcohol use. CONCLUSIONS: There is evidence of a high basal prevalence of latent tuberculosis infection in medical students. The incidence rate is within expected values and high in comparison with the general population. People with BMI > 25 kg/m2 have protection against a latent infection. In medical students, more attention should be paid to biosecurity. PMID- 23096533 TI - The impact of dose-escalated radiotherapy plus androgen deprivation for prostate cancer using 2 linked nomograms. AB - BACKGROUND: Randomized trials have demonstrated that escalated-dose external-beam radiotherapy (EDRT) is better than standard-dose radiotherapy (SDRT) for patients with prostate cancer and that adding androgen-deprivation therapy (ADT) to SDRT is better than SDRT alone; however, no trials have compared EDRT versus SDRT plus ADT or EDRT versus EDRT plus ADT. The authors designed a model to estimate the results of various doses of radiotherapy (RT) combined with various durations of ADT. METHODS: From 1989 to 2007, 3215 men consecutively received definitive EDRT with or without ADT. In total, 2012 patients had complete records available for creating the nomogram. The duration of ADT varied for patients who received no RT (n = 1562), <=6 months of RT (n = 145), from >6 months to <24 months of RT (n = 140), and >=24 months of RT (n = 165) with a median follow-up of 65.7 months, 66.2 months, 60.1 months, and 63 months, respectively. The model included the following covariates: palpation T-category, biopsy Gleason score, the percentage of tumor cells with a Gleason pattern of 4 or 5, the percentage of tumor tissue, initial pretreatment prostate-specific antigen (PSA) level, ADT duration, and RT dose. Two nomograms, for outcomes with and without ADT, were created from a single competing-risks model. Biochemical failure was defined as a rise in serum PSA of 2 ng/mL over the post-treatment PSA nadir. RESULTS: According to the results from analyzing representative intermediate-risk to high-risk patient parameters, the gains from increasing the RT dose from 70 Gray (Gy) to 80 Gy were far less than the gains from adding >=3 months of ADT. CONCLUSIONS: The nomograms provided unique patient-specific estimates of the effects of various doses and durations of RT and ADT. The results indicated that adding ADT to treatment for intermediate-risk and high-risk prostate cancer is far more beneficial than a modest RT dose escalation. PMID- 23096536 TI - [Epidemiological and clinical characteristics of influenza A (H1N1) 2009 at San Felipe, Valparaiso Region, Chile: June-August 2009]. AB - In order to understand the clinical and epidemiological aspects of infection with the AH1N1 influenza virus in Chile, a prospective study in the city of San Felipe was undertaken. It analyses the trends in consultations for respiratory causes in three primary care centers and hospital discharges by comparing data from years 2008 and 2009 until epidemiological week 37.It also includes a study of cases of ILI / SARI (influenza like disease/severe acute respiratory disease) in which viruses were detected by direct immunofluorescence (DIF) of nasopharyngeal aspirates and by real-time polymerase chain reaction in the case of influenza A (H1N1) 2009. A household survey was conducted in those cases with confirmed A (H1N1) infection, to identify contacts and history related to influenza virus transmission. The results indicate that the behavior of the pandemic was similar to that observed in the rest of the country, with an increase in emergency room visits for ILI. The most affected age group was from 5 to 14 years (26.5 per thousand inhabitants) and the least affected 60 years or older (1.2 per thousand). A 2.78% of the cases corresponded to SARI and the fatality rate was 0.11%. PMID- 23096537 TI - [Epidemiological dynamics of Dengue on Easter Island]. AB - Dengue is considered an emerging disease with an increasing prevalence especially in South America. In 2002, an epidemic of classic Dengue (DENV-1) occurred unexpectedly on Easter Island, where it had never been detected before. It reappeared in 2006-2007 and 2008, 2009 and 2011. The aim of this study was to estimate the most relevant parameters of the epidemiological dynamics of transmission of Dengue on Easter Island and to model the dynamics since 2002, comparing the predictions with the actual situation observed. Of the total cases, 52.27% were females and 47.73% men. The average age of infection was 31.38 +/- 18.37 years, similar in men and women. We estimated the reproductive number R0 = 3.005 with an IC0,95 = [1.92, 4.61]. The inter-epidemic period reached an estimated T = 5.20 to 6.8 years. The case simulation showed recurrent epidemics with decreasing magnitude (damped oscillations), which is a known phenomenon in models of dengue and malaria. There was good qualitative fit to the epidemiological dynamics from 2002 onwards. It accurately predicted the rise in cases between 2006 and 2011. The predicted number of cases during the 2002 epidemic is greater than the confirmed cases and the predicted epidemic was faster than notified cases. Interepidemic period in the simulation was 6.72 years between 2002 and 2008 and 4.68 years between 2008 and 2013. From the theoretical perspective, the first epidemic had affected 94% of the population (approximately 3500 cases), but 639 were reported suggesting underreporting and a lot of sub clinical cases occurred. Future epidemic of decreasing size are expected, although the main danger are epidemics of hemorrhagic dengue fever resulting from the introduction of different dengue virus serotypes. PMID- 23096538 TI - [Risk factors related to surgical site infection in orthopedic prosthesis surgery]. AB - OBJECTIVE: to identify the risk factors for surgical site infections (SSI) in patients with surgical management fractures with internal fixation or prosthetic material. MATERIALS AND METHODS: a cross-sectional study was conducted in a tertiary institution in Armenia-Colombia in 2008 and 2009 in 223 patients. RESULTS: The superficial incisional infection frequency was 9,4% (n: 21), and deep incisional infection was 7,6% (n: 17); there were no organ/space SSI.; the highest rates of infection were observed in patella fractures (50%), acromio clavicular joint (25%), and femur (23,7%). The infections were caused by: S. aureus, Enterobactergergoviae y Enterobacteraerogenes. There was an association with clean-contaminated wounds compared to clean wounds (OR 2,2), comminuted fractures (OR 2,1) multiple fractures (OR 2,9) and patella surgery (OR 3,1). CONCLUSIONS: the severity of the fracture and the degree of contamination were predisposing factors to infection. PMID- 23096539 TI - [Sporothrix globosa isolation related to a case of lymphocutaneous sporotrichosis]. AB - INTRODUCTION: Sporothrix schenckii complex comprises a group of environmental dimorphic fungi that cause sporotrichosis. In Chile, isolated cases have been reported in humans, though no environmental isolates have been described. OBJECTIVE: To achieve isolation of Sporothrix complex from the soil where a 75 year old patient with lymphocutaneous sporotrichosis performs horticulture work. MATERIALS AND METHODS: In March and July 2011 soil and plant debris from five sectors where the patient does his work in horticulture was extracted. The soil samples were diluted and inoculated in Sabouraud agar with cycloheximide and chloramphenicol at 26 degrees C. The plant debris was directly inoculated in the same medium. Colonies suggestive of Sporothrix complex were reseeded in PDA agar at 26 degrees C and identified as recommended by Marimon et al. RESULTS: Of the 10 plates from the first sampling, one colony was identified as Sporothrix globosa. In the second sampling, Sporothrix globosa grew in two plates seeded with soil, with a total of 6 colonies. There was no growth of Sporothrix complex in plant debris. The isolate from the patient was also identified as Sporothrix globosa. CONCLUSION: For the first time in Chile a species of Sporothrix complex was isolated from the environment. Sporothrix globosa was the species identified both in the ground and from the patient with sporotrichosis. PMID- 23096540 TI - [Quality indicators for blood culture: three years of monitoring at a university hospital in Chile]. AB - Blood culture is considered the "gold standard" for the diagnosis of bacteremia, critical condition with high morbidity and mortality. Because of its importance, it is estimated that the blood culture is a critical test that requires close monitoring on the quality with which the process is performed. The objective of this work is to show the results of the monitoring carried out during the past three years, of 5 quality indicators of blood cultures in the laboratory of the Hospital Clinico de la Pontificia Universidad Catolica de Chile, considering pre analytical, analytical and post-analytical aspects. In the 3 years monitored the mean contamination was 0,7%, 46% of adult bottles had adequate volume, match between Gram stain with final identification was 99.4%, 100% of correct participations were achieved in surveys of external quality control and Gram staining notification before 1 hour was 88.7%. With regard to proposed aims, in 2011 the laboratory complies with all, except the percentage of bottles with appropriate volume of blood inoculated. This indicator is very low and should be corrected as soon as possible since it is known that it is an important condition for optimum performance of blood cultures. PMID- 23096541 TI - [Pharmaceutical follow up of antirretroviral treatment in outpatients]. AB - Adherence to antiretroviral therapy is key contributor to decreasing morbidity and mortality from HIV/ AIDS infection. However, it is affected by treatment related factors including the multiple adverse reactions and interactions arising from chronic polypharmacy. In order to determine drug-related problems, 66 outpatients from Hospital Carlos Van Buren on antiretroviral therapy were monitored. 100 % had medication-related problems and 46.1% of those problems were related to the safety of the therapy. Hypertriglyceridemia associated to the combined use of both nucleoside reverse transcriptase inhibitor and a non nucleoside reverse transcriptase inhibitor was the most frequent adverse reaction. Results show that pharmacological monitoring of patients on antiretroviral treatment is necessary for the early identification of drug related problems and for the proposal of alternatives that promote therapeutic safety and efficacy. PMID- 23096542 TI - [Outbreak of human A (H1N1) influenza in turkeys of a commercial poultry farm, Valparaiso, Chile: August 2009]. AB - The Chilean Ministry of Health (MINSAL) led an investigation to identify associated factors to human influenza A (H1N1) infection in turkeys from poultry farms, Valparaiso. The Agriculture and Livestock Farming Service (SAG) informed the detection of influenza A (low pathogenicity) in turkeys and the Public Health Institute (ISP) confirmed influenza A (H1N1).The study included 100% of operative wards: 31% presented positive event (influenza A (H1N1)); 60% if considered only reproductive wards. Dissemination and dispersion velocity of 13 wards in 18 days evidenced a continuous common source. Interviews were performed to 89% of workers of whom 20% presented influenza-like disease: 26% from reproductive wards and 4% from raising and rearing farms. Of15 risk factors studied insemination and age in females showed statistically significant RR in low oviposition index wards. A man bird transmission is proposed, through direct transmission of saliva during manual insemination or indirect transmission through contaminated semen. To the authors, this is the first turkey 2009 influenza H1N1 outbreak detected worldwide,in this case with a documented cloacal transmission path. PMID- 23096543 TI - [Urinary tract infection in pediatrics: controversies]. AB - Urinary tract infection is a frequent event in children. The correct diagnosis, management and study has been involved in major controversies in the last decade as a result of better design of scientific studies and evidence-based medicine in this area. A significant amount of our knowledge must be subjected to critical analysis because of new information available. This article describe some of the controversies in pediatric urinary tract infection that should be considered by the health team, highlighting the relevance of sample collection and the significant number of bacterial colonies, the type and duration of antibiotic treatment, the prescription of antibiotic prophylaxis and the required imaging study. PMID- 23096544 TI - [Clostridium difficile associated infections: an updated view]. AB - Clostridium difficile is an emerging anaerobic, spore forming pathogen, recognized as the etiological agent of ~ 30% of antibiotic associated diarrheas. Clinical symptoms can fluctuate from mild to moderate diarrhea, pseudomembranous colitis and toxic megacolon. The incidence of C. difficile associated infections (CDAI) is ~ 1% of total hospitalized patients. CDAI has a mortality rate of ~1 to 5%, and a relapse rate of ~ 20%. The appearance of severe outbreaks of CDAI could be attributed to changes in the production of the two major virulence factors, the enterotoxins TcdA and TcdB, which produce massive epithelial damage. C. difficile spores play an essential role in transmission, initiation and persistence of CDAI. Recent advances in detection methods, development of novel therapies and prevention methods could allow a reduction on the frequency of CDAI. The objective of this review is to provide an updated view on the mechanisms of pathogenesis, epidemiology, risk factors, detection methods, treatment and prevention of CDAI. PMID- 23096547 TI - [What represented Blood Hospitals?]. PMID- 23096548 TI - [Human intestinal spirochetosis: clinical series and literature review]. AB - INTRODUCTION: Human intestinal spirochetosis (HIE) is defined as colonization by spirochetes of the large intestine. Is associated with chronic diarrhea. The incidence and prevalence ranges from 0.4% to 12%. OBJECTIVE: To determine the prevalence of HIE in the Salvador's Hospital, between 2003 and 2008 in patients with a history of chronic diarrhea and without abnormalities in colonoscopy, in 2 separate groups: patients with and without a history of HIV infection. MATERIAL AND METHODS: Retrospective morphology evaluation of the large bowel endoscopic biopsies to the selected groups. RESULTS: We reviewed 115 biopsies, 98 were from HIV-negative and 17 HIV from positive patients. Two cases of intestinal spirochetosis were detected, both HIV negative, with a prevalence of 1.7%. COMMENT: The prevalence of HIE is similar to that reported in Western countries. Population studies are needed to determine the real epidemiological impact in our environment. PMID- 23096549 TI - [Achromobacter xylosoxidans]. PMID- 23096550 TI - [Thoracic actinomycosis in the differential diagnosis of neoplasm: a propos of a case]. AB - Actinomycosis is an infrequent infection caused by bacteria from Actinomyces genus that manifests as a chronic, suppurative and progressive disease. It's more common in men. Thoracic actinomycosis occurs in 15% of the cases, and infection of the chest wall is less frequent. The clinical presentation mimics tuberculosis or neoplastic processes. In this article we present the case of a 63 year-old man with no comorbidity, with pulmonary actinomycosis involving the chest wall mimicking a neoplastic process, basing the diagnosis on histopathologic findings. PMID- 23096551 TI - [Actinomycotic mycetoma due to Actinomadura madurae]. AB - Mycetoma is a chronic, granulomatous, subcutaneous, inflammatory lesion caused by true fungi (eumycetoma) or filamentous bacteria (actinomycetoma). Mycetoma commonly affects young people between 20 and 40 years old. The most common affected site is the foot. The characteristic clinical triad is tumefaction, draining sinuses and discharging grains. We report a healthy 31-year-old male, with a 6-year history of a progressive inflammatory tumor associated with sinus tracts and granules on his left sole. Actinomycetoma was suspected. The clinical diagnosis was confirmed by microbiological and histopathological study. Polymerase chain reaction and DNA sequencing identified Actinomadura madurae. To our knowledge, this is the second case of mycetoma reported in Chile. Our report emphasizes the need to consider this diagnosis in patients with chronic granulomatous disease associated with sinus tracts, fistulas and grains. PMID- 23096552 TI - [Neonatal herpes simplex encephalitis: clinical profile versus molecular biology]. AB - Herpes simplex encephalitis is a diagnostic challenge and causes high morbidity and mortality in children. Early suspicion of the disease and a rapid, safe and useful diagnostic test are relevant because up to 70% of the cases may die. We report the case of a newborn girl aged 25 days, who presented with a clinical picture that was compatible with herpes simplex encephalitis where the confirmation of the etiological diagnosis was delayed. Only by repeated real-time polymerase chain reaction it was possible to confirm the presence of herpes simplex virus type 1 in the cerebrospinal fluid. PMID- 23096553 TI - [Historical notes on Infectious Diseases Hospital Francisco Javier Muniz in Buenos Aires, Argentina]. AB - The Infectious Diseases Hospital Francisco Javier Muniz, Buenos Aires, Argentina, is the oldest in Latin America. It is over 100 years old and has a history worthy of pride. It became known as "Hospital of the pests" and was preceded by the old House of Insulation, which served as a quarantine station during epidemics of cholera, yellow fever and smallpox. The new House of Insulation, built in the neighborhood of Parque Patricios ("Barracks Hospital"), was renamed in 1904 in memory of Francisco Javier Muniz, a former military doctor, naturalist and paleontologist. Its technical name is "Porteno Care Centre and National Reference Regional Infectious-Contagious Disease". It receives numerous national and foreign undergraduate and postgraduate students in its Departments of Infectious Diseases and Respiratory Diseases. PMID- 23096554 TI - [Clostridium difficile epidemic, Chile 2012: report of the Chilean Society for Infectious Diseases. A scientific historical analysis]. AB - A Summary Report from the Chilean Society for Infectious Diseases regarding the presence of a Clostridium difficile epidemic with several fatalities in Chile's premier emergency public hospital in Santiago is used to make a scientific historical analysis of the situation. This Summary Report identifies several hygienic and sanitary shortcomings that may have played a role in triggering this major epidemic. These include deficiencies in hand washing policies, overcrowding of beds in wards, relaxation of infection control policies, antimicrobial therapy mismanagement and lack of laboratory support. The relevance of these shortcomings to the epidemic is further supported by the lack of any laboratory evidence for the presence of hypertoxigenic strains of C. difficile. In an era of whole genome sequencing of pathogens to guide therapy, prevention, and epidemiological studies of infectious diseases, it is illuminating and sobering, as this report so clearly demonstrates, to realize that many epidemics of hospital infections still result from breakdowns in classical and ancillary asepsis and infection control measures developed in the nineteenth century by Semmelweis, Nightingale and Lister. As the Summary Report suggests, such hygienic breakdowns in countries like Chile are usually brought about by lack of implementation and regulation of national hospital infection control policies resulting from the shift of economic resources from the public to the private sector, despite the former being responsible for health care of 80% of the population. PMID- 23096555 TI - [Case Report: first case of hantavirus cardiopulmonary syndrome diagnosed in the Second Region of Antofagasta]. AB - Cases of Hantavirus cardiopulmonary syndrome (HCPS) have been reported in Chile between Region V and XI. In our country HCPS is caused by Andes virus. Hantavirus infection is acquired mainly through inhalation of aerosolized rodent fluids. Person to person transmission is considered exceptional. The identified rodent reservoir of the virus extends throughout Region III to XII, and no cases have been reported in the north of Chile. The incubation period is prolonged. We report the first diagnosed patient with HCPS in the north of Chile. In this case we suggest the possibility of person to person transmission. PMID- 23096556 TI - [Bad sleeping quality in patients receiving HAART]. PMID- 23096557 TI - [Catheter-related fungemia cause by Candida sp. in neonatology]. PMID- 23096558 TI - Potential role of adenosine deaminase in the diagnosis of adult-onset Still's disease. AB - Adult-onset Still's disease (AOSD) is a systemic inflammatory autoimmune disorder of unknown etiology and pathogenesis. There are no specific laboratory tests for AOSD. To investigate the potential role of adenosine deaminase (ADA) in the diagnosis of AOSD and analyze the correlation among ADA, LDH and WBC (white blood cell count), the serum levels of ADA and LDH in 26 patients with active untreated AOSD, 40 patients with active systemic lupus erythematosus (SLE) as disease control and 48 healthy volunteers as healthy control were determined using automatic biochemical analyzer (Olympus AU2700, Japan). WBC was examined by automatic blood cell analyzer (Beckman Coulter Hmx, America). Significantly higher levels of serum ADA, LDH and WBC were found in active untreated AOSD patients than in active SLE patients and healthy volunteers (F = 27.823; P = 0.000; F = 28.458, P = 0.000; F = 51.929, P = 0.000). Serum ADA were related to LDH level in patients with AOSD patients (r = 0.786, P = 0.000 < 0.01). Both ADA and LDH were not related to WBC (r = 0.244, P = 0.229 > 0.01; r = 0.054, P = 0.794 > 0.01). This is the first study to show that serum ADA could play an important role in AOSD and may be an important biomarker for the diagnosis of AOSD. Serum ADA could be another diagnostic marker independent from whole blood WBC. PMID- 23096565 TI - Structure of the Ca(2+)-saturated C-terminal domain of scallop troponin C in complex with a troponin I fragment. AB - Troponin C (TnC) is the Ca(2+)-sensing subunit of troponin that triggers the contraction of striated muscles. In scallops, the striated muscles consume little ATP energy in sustaining strong contractile forces. The N-terminal domain of TnC works as the Ca(2+) sensor in vertebrates, whereas scallop TnC uses the C terminal domain as the Ca(2+) sensor, suggesting that there are differences in the mechanism of the Ca(2+)-dependent regulation of muscles between invertebrates and vertebrates. Here, we report the crystal structure of Akazara scallop (Chlamys nipponensis akazara) adductor muscle TnC C-terminal domain (asTnCC) complexed with a short troponin I fragment (asTnIS) and Ca(2+). The electron density of a Ca(2+) ion is observed in only one of the two EF-hands. The EF-hands of asTnCC can only be in the fully open conformation with the assistance of asTnIS. The number of hydrogen bonds between asTnCC and asTnIS is markedly lower than the number in the vertebrate counterparts. The Ca(2+) modulation on the binding between asTnCC and asTnIS is weaker, but structural change of the complex depending on Ca(2+) concentration was observed. Together, these findings provide a detailed description of the distinct molecular mechanism of contractile regulation in the scallop adductor muscle from that of vertebrates. PMID- 23096566 TI - HbG200-mediated preinduction of heme oxygenase-1 improves bile flow and ameliorates pericentral downregulation of Bsep and Mrp2 following experimental liver ischemia and reperfusion. AB - We studied the downregulation of hepatobiliary transport systems and the effect of pharmacological heme oxygenase-1 (HO-1) preinduction by Hemoglobin-Glutamer 200 (HbG200) in cold ischemia-reperfused rat liver (I/R). Cold I/R reduced bile flow in the reperfusion period from 3.10+/-0.10 ml/3 h to 0.54+/-0.20 ml/3 h (p<0.05) and biliary taurocholate excretion from 45.9+/-13.81 MUmol/3 h to 1.87+/ 0.46 MUmol/3 h (p<0.05). Mrp2, Bsep and Ntcp peak immunofluorescence in pericentral hepatocytes decreased to 79.0+/-2.6% (p<0.001), 80.6+/-8.4% (p<0.05) and 65.8+/-5.0% (p<0.01), respectively. Pre-induction of HO-1 by HbG200 was largely confined to pericentral hepatocytes. HO-1 induction attenuated the decreased bile flow (0.91+/-0.16 ml/3 h, p<0.05) and canalicular taurocholate secretion (4.33+/-1.71 MUmol/3 h, p<0.05). Bsep and Mrp2 peak immunofluorescence in pericentral hepatocytes was largely restored. Activation of JNK and Fyn by cold I/R was significantly attenuated by HO-1. Inhibiting HO activity by tin protoporphyrin IX after HbG200 administration reversed the effect on bile flow and canalicular transporter expression. In conclusion, pericentral downregulation of Bsep and Mrp2 following cold I/R is ameliorated by inducing HO-1 and was associated with diminished hepatocellular JNK and Fyn signaling. HO-1 may serve as a therapeutic target to attenuate hepatocellular cholestasis following I/R injury. PMID- 23096567 TI - New insight into the molecular switch mechanism of human Rho family proteins: shifting a paradigm. AB - Major advances have been made in understanding the structure, function and regulation of the small GTP-binding proteins of the Rho family and their involvement in multiple cellular process and disorders. However, intrinsic nucleotide exchange and hydrolysis reactions, which are known to be fundamental to Rho family proteins, have been partially investigated in the case of RhoA, Rac1 and Cdc42, but for others not at all. Here we present a comprehensive and quantitative analysis of the molecular switch functions of 15 members of the Rho family that enabled us to propose an active GTP-bound state for the rather uncharacterized isoforms RhoD and Rif under equilibrium and quiescent conditions. PMID- 23096568 TI - Microcompartments within the yeast plasma membrane. AB - Recent research in cell biology makes it increasingly clear that the classical concept of compartmentation of eukaryotic cells into different organelles performing distinct functions has to be extended by microcompartmentation, i.e., the dynamic interaction of proteins, sugars, and lipids at a suborganellar level, which contributes significantly to a proper physiology. As different membrane compartments (MCs) have been described in the yeast plasma membrane, such as those defined by Can1 and Pma1 (MCCs and MCPs), Saccharomyces cerevisiae can serve as a model organism, which is amenable to genetic, biochemical, and microscopic studies. In this review, we compare the specialized microcompartment of the yeast bud neck with other plasma membrane substructures, focusing on eisosomes, cell wall integrity-sensing units, and chitin-synthesizing complexes. Together, they ensure a proper cell division at the end of mitosis, an intricately regulated process, which is essential for the survival and proliferation not only of fungal, but of all eukaryotic cells. PMID- 23096570 TI - Multifunctional silica nanoparticles for optical and magnetic resonance imaging. AB - The surface of spherical, nonporous silica nanoparticles (SiO2-NPs) was modified with gadolinium (Gd) complexes, fluorophores, and cell-penetrating peptides to achieve multifunctionality on a single particle. The Gd surface concentrations were 9-16 MUmol/g resulting in nanomaterials with high local longitudinal and transversal relaxivities (~1*10(5) and ~5*10(5) /mm/s/NP, respectively). Rapid cellular uptake was observed in vitro; however, larger extracellular agglomerates were also formed. In vivo administration revealed a fast distribution throughout the body followed by a nearly complete disappearance of fluorescence in all organs except the lungs, liver, and spleen after 24 h. Such NPs have the potential to serve as efficient multimodal probes in molecular imaging. PMID- 23096572 TI - Reengineering of subtilisin Carlsberg for oxidative resistance. AB - Mild bleaching conditions by in situ production of hydrogen peroxide or peroxycarboxylic acid is attractive for pulp, textile, and cosmetics industries. The enzymatic generation of chemical oxidants is often limited by enzyme stability. The subtilisin Carlsberg variant T58A/L216W/M221 is a promiscuous protease that was improved in producing peroxycarboxylic acids. In the current article, we identified two amino acid positions (Trp216 and Met221) that are important for the oxidative resistance of subtilisin Carlsberg T58A/L216W/M221. Site-saturation mutagenesis at positions Trp216 and Met221, which are located close to the active site, resulted in variants M4 (T58/W216M/M221) and M6 (T58A/W216L/M221C). Variants M4 (T58/W216M/M221) and M6 (T58A/W216L/M221C) have a 2.6-fold (M4) and 1.5-fold (M6) increased oxidative resistance and 1.4-fold increased kcat values for peroxycarboxylic acid formation, compared with wild type subtilisin Carlsberg. PMID- 23096575 TI - Diversity, abundance, and sex-specific expression of chemosensory proteins in the reproductive organs of the locust Locusta migratoria manilensis. AB - Chemosensory proteins (CSPs) are small soluble proteins often associated with chemosensory organs in insects but include members involved in other functions, such as pheromone delivery and development. Although the CSPs of the sensory organs have been extensively studied, little is known on their functions in other parts of the body. A first screening of the available databases has identified 70 sequences encoding CSPs in the oriental locust Locusta migratoria manilensis. Applying proteomic analysis, we have identified 17 of them abundantly expressed in the female reproductive organs, but only one (CSP91) in male organs. Bacterially expressed CSP91 binds fatty acids with a specificity for oleic and linoleic acid, as well as medium-length alcohols and esters. The same acids have been detected as the main gas chromatographic peaks in the dichloromethane extracts of reproductive organs of both sexes. The abundance and the number of CSPs in female reproductive organs indicates important roles for these proteins. We cannot exclude that different functions can be associated with each of the 17 CSPs, including delivery of semiochemicals, solubilization of hormones, direct control of development, or other unknown tasks. PMID- 23096573 TI - Cerebral cavernous malformation is a vascular disease associated with activated RhoA signaling. AB - Cerebral cavernous malformation (CCM) involves the homozygous inactivating mutations of one of three genes, ccm1, -2, or -3 resulting in hyperpermeable blood vessels in the brain. The CCM1, -2, and -3 proteins form a complex to organize the signaling networks controlling endothelial cell physiology including actin dynamics, tube formation, and adherens junctions. The common biochemical defect with the loss of CCM1, -2, or -3 is increased RhoA activity leading to the activation of Rho-associated coiled coil-forming kinase (ROCK). Inhibition of the ROCK rescues CCM endothelial cell dysfunction, suggesting that the inhibition of RhoA-ROCK signaling may be a therapeutic strategy to prevent or arrest the progression of the CCM lesions. PMID- 23096577 TI - Thiolase engineering for enhanced butanol production in Clostridium acetobutylicum. AB - Biosynthetic thiolases catalyze the condensation of two molecules acetyl-CoA to acetoacetyl-CoA and represent key enzymes for carbon-carbon bond forming metabolic pathways. An important biotechnological example of such a pathway is the clostridial n-butanol production, comprising various natural constraints that limit titer, yield, and productivity. In this study, the thiolase of Clostridium acetobutylicum, the model organism for solventogenic clostridia, was specifically engineered for reduced sensitivity towards its physiological inhibitor coenzyme A (CoA-SH). A high-throughput screening assay in 96-well microtiter plates was developed employing Escherichia coli as host cells for expression of a mutant thiolase gene library. Screening of this library resulted in the identification of a thiolase derivative with significantly increased activity in the presence of free CoA-SH. This optimized thiolase comprised three amino acid substitutions (R133G, H156N, G222V) and its gene was expressed in C. acetobutylicum ATCC 824 to assess the effect of reduced CoA-SH sensitivity on solvent production. In addition to a clearly delayed ethanol and acetone formation, the ethanol and butanol titers were increased by 46% and 18%, respectively, while the final acetone concentrations were similar to the vector control strain. These results demonstrate that thiolase engineering constitutes a suitable methodology applicable to improve clostridial butanol production, but other biosynthetic pathways involving thiolase-mediated carbon flux limitations might also be subjected to this new metabolic engineering approach. PMID- 23096578 TI - [The STICH Viability substudy]. PMID- 23096579 TI - [The CORONARY study]. PMID- 23096580 TI - [Evolution in surgical repair of heart valves: implications for follow-up]. AB - The number of patients undergoing surgical heart valve repair has been increasing during the last years, particularly in high-volume centers. Several factors related to poor outcomes after surgical repair have been identified in different observational studies, leading to a better preoperative patient selection and improved long-term clinical and echocardiographic follow-up. PMID- 23096581 TI - [Evolution of coronary artery bypass graft techniques]. AB - The results of coronary surgical revascularization are constantly improving despite the worsening of patient's risk profiles. Nowadays this procedure represents the gold standard for patients with multivessel disease or critical left main stenosis, according to European and American guidelines. Recent data show that these guidelines are poorly implemented in the "real world". Different reasons can explain this phenomenon, among these, the invasiveness and morbidity of surgical procedures, which determine low acceptance rates by the patients. In recent years, several procedures have been developed in order to improve surgical therapy; the most promising include complete arterial revascularization, the "no touch aorta technique", mini-invasive techniques, improvement of biocompatibility of extracorporeal circulation, and hybrid revascularization. Although these procedures still need statistical evidence, some data support their use in specific patient subsets. If these trends will be confirmed, it will be possible to choose the best surgical strategy for each individual patient. At present, there are no data suggesting the best choice between on-pump and off-pump techniques; there are indications to use arterial conduits in young patients, whereas the no-touch aorta technique, which seems to reduce cerebrovascular complications, requires further statistical confirmation; the mini-invasive and hybrid approaches need additional data to confirm their effectiveness. This accounts for the great variability among centers regarding the strategies of myocardial revascularization, often restricted to few techniques. In our opinion, nowadays, every heart surgery unit should offer all of these modern techniques. In order to decide for the best treatment between medical, surgical and percutaneous therapies, the creation of a Heart Team has been demonstrated to be effective. All components of the Heart Team should be familiar not only with the use of anatomical and clinical risk scores, but they should also know the main aspects of each therapeutic option along with their availability. This condition is fundamental in order to discuss and set up the best surgical option for each patient, and consequently improve quality of treatment and clinical outcome. In order to suggest the best therapy to the patient, the Heart Team should take into consideration the guideline recommendations and available operative setting within the cardiac unit. PMID- 23096582 TI - [Pharmacological prevention of coronary relapses in Italian clinical practice: a literature review]. AB - Scientific advances in cardiovascular research during the last decades have afforded effective pharmacological treatment to those surviving their first acute myocardial infarction. This secondary prevention treatment, based upon the combined administration of statins, aspirin, beta-blockers and renin-angiotensin blockers, might avert great part of the relapses contributing substantially to the overall incidence of acute coronary syndromes in the general population. However, a treatment gap separates evidence-based recommendations from their daily clinical application, a condition frequently explored even in the Italian medical setting. However, a general overview of the problem is missing insofar, a contribution that might eventually help to improve the status of secondary coronary prevention in our national environment. PMID- 23096583 TI - [Psychological well-being, cardiovascular prevention and stress resistance. A dynamic harmony between Apollonian and Dionysian impulses]. PMID- 23096584 TI - [Reoperative aortic root replacement: short- and long-term outcomes in 111 patients]. AB - BACKGROUND: The aim of this study was to report results of aortic root reoperations and to identify predictors of in-hospital and long-term mortality. METHODS: Between 1986 and 2011, 111 consecutive patients (mean age 55.4 years, 85 male [76.6%]) were reoperated on the aortic root after previous aortic surgery at our institution. An urgent/emergent operation was performed in 24 patients (21.6%). Indications for reoperation were degenerative aneurysm (n = 56), chronic post-dissection aneurysm (n = 27), active prosthetic infection (n = 14), false aneurysm (n = 10) and acute dissection (n = 4). Surgical procedures were limited to the aortic root in 68 patients (61.3%), and involved the entire proximal thoracic aorta in 43 patients (38.7%). RESULTS: In-hospital mortality was 12.6%, being 6.9% and 33.3% in elective and urgent cases, respectively (p=0.002). On multivariate analysis, cardiopulmonary bypass time (odds ratio 1.029/min; p=0.011) and urgent/emergent status (odds ratio 8.486; p=0.044) were independent predictors of in-hospital mortality. Follow-up was 99.1% complete. Estimated 1-, 5-, and 10-year survival rates were 82.5%, 71.9% and 50.6%, respectively. Six redo procedures were performed during follow-up. Freedom from reoperation at 1, 5, and 10 years was 100%, 91.7% and 86.1%, respectively. On Cox regression analysis, chronic aortic dissection (hazard ratio 21.2; p=0.009) was an independent predictor of reintervention at follow-up. CONCLUSIONS: Reoperation on the aortic root can be performed with acceptable mortality and good mid- and long term outcomes, in particular when carried out on an elective basis. Cardiopulmonary bypass time and urgent/emergent status remain the most important risk factors for reduced survival in aortic surgery. PMID- 23096585 TI - [The new guidelines on cardiopulmonary resuscitation. The clinical cardiologist's point of view]. PMID- 23096586 TI - [The new guidelines on cardiopulmonary resuscitation. The anesthesiologist's point of view]. PMID- 23096587 TI - [Incidental myocardial mass: differential diagnosis, clinical approach and literature review]. AB - A 30-year-old male was evaluated in our hospital for the presence of transient palpitations. The ECG showed sporadic ventricular extrasystolic beats with normal ventricular depolarization and repolarization phases. Two-dimensional transthoracic echocardiography demonstrated a localized intraventricular myocardial mass (measuring 3 x 2 mm) in the basal lateral wall. To further characterize the mass, the patient was addressed to cardiac magnetic resonance imaging (MRI). Noninvasive myocardial tissue characterization with T2-weighted sequences (with and without fat suppression), and T1-weighted after contrast suggested the presence of fat tissue associated with undiversified muscle tissue. The intramyocardial mass was not capsulated and partially infiltrated the surrounding myocardium. The imaging features suggested the diagnosis of a benign myocardial mass with mixed aspects between cardiac hamartoma and lipoma. To monitor mass growth and in the absence of new symptoms, the patient is followed up yearly with transthoracic echocardiography, and with cardiac MRI exams every 3 years. This case highlights the utility of cardiac MRI to assess a myocardial mass noninvasively and delineate its anatomy and tissue characterization, which potentially avoids myocardial biopsy. PMID- 23096588 TI - [Degenerated mitral bioprosthesis and severe aortic valve stenosis in a high-risk patient: a two-step transcatheter valve implantation]. AB - Recently, small case series have described successful off-label use of transcatheter aortic valve implantation (TAVI) in patients with degenerated bioprosthetic valves in mitral position. We here report the case of a 78-year-old female patient who underwent TAVI for severe aortic stenosis and transapical valve-in-valve implantation for degenerated mitral bioprosthesis. There was no evidence of intraprosthetic regurgitation and/or paraprosthetic leaks on control angiography and transesophageal echocardiography. The postoperative course was uneventful. Following accurate patient selection and evaluation by an experienced multidisciplinary team, the transcatheter approach for double valve implantation in aortic and mitral position may represent a viable treatment option for those high-risk patients who otherwise would be inoperable. PMID- 23096589 TI - [Transcatheter aortic valve implantation in patients with severe symptomatic aortic stenosis: position statement of the Italian Society of Interventional Cardiology (SICI-GISE) on minimum standards for hospitals and operators]. AB - At present, transcatheter aortic valve implantation (TAVI) is a proven treatment option for patients with symptomatic degenerative aortic stenosis at high risk for conventional surgery. In countries where TAVI is currently performed, the number of procedures and centers involved has been continuously increasing. The present document from the Italian Society of Interventional Cardiology (SICI GISE) aims to improve the available evidence and current consensus on this topic through the definition of training needs and knowledge base for both operators and centers. PMID- 23096590 TI - Amine-functionalized zirconium metal-organic framework as efficient visible-light photocatalyst for aerobic organic transformations. AB - An amine-functionalized zirconium metal-organic framework (MOF) was used as a visible-light photocatalyst for selective aerobic oxygenation of various organic compounds including alcohols, olefins and cyclic alkanes, at high efficiency and high selectivity. This study shows the great potential for design and application of MOF-based photocatalysts. PMID- 23096591 TI - Two days of antithymocyte globulin are associated with a reduced incidence of acute and chronic graft-versus-host disease in reduced-intensity conditioning transplantation for hematologic diseases. AB - BACKGROUND: The optimal combination of fludarabine, busulfan, and antithymocyte globulin (ATG) for reduced-intensity conditioning (RIC) transplantation has not been established. ATG plays a pivotal role in the prevention of graft-versus-host disease (GvHD), but it is associated with a higher relapse rate and an elevated incidence of infections when high doses are used. METHODS: The authors retrospectively compared 2 different doses of ATG combined with fludarabine and busulfan in 229 adult patients who underwent transplantation at their institution. ATG was administered over 1 day (FBA1) or over 2 days (FBA2) at a daily dose of 2.5 mg/kg. RESULTS: There were 124 patients in the FBA2 cohort and 105 patients in the FBA2 cohorts. Patients in the FBA2 cohort were older and more frequently underwent transplantation from an unrelated donor; 93% of patients in the FBA2 cohort received intravenous busulfan versus only 5% in the FBA1 cohort. The incidence of grade 2 through 4 acute GvHD was 23% in the FBA2 cohort versus 42% in the FBA1 cohort (P = .002); the incidence of grade 3 through 4 acute GvHD was 10% versus 23%, respectively (P = .006); and the incidence of chronic GvHD was 35% versus 69%, respectively (P < .0001). The 2-year rates of overall survival, nonrelapse mortality, and relapse/progression for the FBA1 and FBA2 cohorts were 65% versus 67%, respectively (P = .99), 20% versus 19%, respectively (P = .61), and 30% versus 19%, respectively (P = .09). The results were confirmed in multivariate analysis. CONCLUSIONS: The use of ATG at a dose of 5 mg/kg was correlated significantly with reduced incidence and severity of GvHD without impairing disease control. Taken together, the current results suggest that this conditioning represents a step forward in the optimization of RIC. PMID- 23096592 TI - An effective system for detecting protein-protein interaction based on in vivo cleavage by PPV NIa protease. AB - Detection of protein-protein interaction can provide valuable information for investigating the biological function of proteins. The current methods that applied in protein-protein interaction, such as co-immunoprecipitation and pull down etc., often cause plenty of working time due to the burdensome cloning and purification procedures. Here we established a system that characterization of protein-protein interaction was accomplished by co-expression and simply purification of target proteins from one expression cassette within E. coli system. We modified pET vector into co-expression vector pInvivo which encoded PPV NIa protease, two cleavage site F and two multiple cloning sites that flanking cleavage sites. The target proteins (for example: protein A and protein B) were inserted at multiple cloning sites and translated into polyprotein in the order of MBP tag-protein A-site F-PPV NIa protease-site F-protein B-His(6) tag. PPV NIa protease carried out intracellular cleavage along expression, then led to the separation of polyprotein components, therefore, the interaction between protein A-protein B can be detected through one-step purification and analysis. Negative control for protein B was brought into this system for monitoring interaction specificity. We successfully employed this system to prove two cases of reported protien-protein interaction: RHA2a/ANAC and FTA/FTB. In conclusion, a convenient and efficient system has been successfully developed for detecting protein-protein interaction. PMID- 23096593 TI - Voltage-dependent open-channel block of G protein-gated inward-rectifying K(+) (GIRK) current in rat atrial myocytes by tamoxifen. AB - Tamoxifen (Tmx) is a nonsteroidal selective estrogen receptor antagonist and is frequently used in the treatment and prevention of breast cancer. The compound and its metabolites have been reported to inhibit functions of different classes of membrane proteins, including various ion channels. For members of the inward rectifying K(+) (Kir) channel family, interference of Tmx with binding of phosphatidylinositol 4,5-bisphosphate (PIP(2)) has been suggested as the mechanism underlying such inhibition. We have studied the inhibition of G protein activated K(+) (GIRK) current by Tmx in isolated myocytes from hearts of adult rats using whole-cell voltage clamp and experimental conditions for measuring K(+) currents as inward currents (E (K) -50 mV; holding potential -90 mV). Extracellular Tmx reversibly inhibited GIRK current activated by acetylcholine (I (K(ACh))) with an EC(50) of 7.4 * 10(-7) M. This inhibition was composed of two components, a basal reduction in peak current and a block that required opening of channels by ACh. The open-channel block was partially relieved by depolarizing voltage steps in a voltage- and time-dependent fashion. A voltage-dependent open channel block was not observed when I (K(ACh)) was measured as outward current (E (K) -90 mV; holding potential -40 mV). Intracellular application of Tmx via the patch clamp pipette at a concentration (7 * 10(-6) M) that caused a rapid inhibition of I (K(ACh)) upon extracellular application did not affect the current. Intracellular application of the H(2)O-soluble PIP(2) analog diC(8) PIP(2) reduced the voltage-independent component of inhibition but had no effect on voltage-dependent open-channel block. The effects of 4-hydroxy-Tmx, a major active metabolite, tested at 2 * 10(-6) M, had effects on I (K(ACh)) analogous to those of Tmx. Inhibition of constitutive inward-rectifying K(+) current (I (K1)) in ventricular myocytes, carried by Kir2 complexes, by Tmx was devoid of a voltage-dependent component. This study suggests the voltage-dependent open channel block of GIRK inward current as a novel mechanism of Tmx action. PMID- 23096594 TI - Analysis of zearalenone and alpha-zearalenol in 100 foods and medicinal plants determined by HPLC-FLD and positive confirmation by LC-MS-MS. AB - BACKGROUND: Mycotoxins, which may contaminate many foods and medicinal plants, are poisonous to humans. A high-performance liquid chromatography with fluorescence detection (HPLC-FLD) method was successfully developed for analysing the contamination levels of zearalenone (ZON) and its metabolite alpha-zearalenol (alpha-ZOL) in 100 widely consumed foods and medicinal plants in China. Samples were extracted with methanol-water (80:20, v/v), and cleaned up by using an immunoaffinity column. RESULTS: The limits of detection of this developed method for ZON and alpha-ZOL were 4 ug kg(-1) and 2.5 ug kg(-1) , respectively. Recoveries for the samples spiked with three levels (30, 60 and 300 ug kg(-1) for ZON and alpha-ZOL) ranged from 85.8% to 96.1% with relative standard deviation (RSD) of 2.6-7.1% for ZON, and from 89.9% to 98.7% with RSD of 1.9-9.2% for alpha ZOL. Twelve (12%) of these tested samples were contaminated with ZON at levels ranging from 5.3 to 295.8 ug kg(-1). The most contaminated samples were Semen coicis, four of them in a concentration level exceeding 60 ug kg(-1) 'maximum level' (range 68.9-119.6 ug kg(-1)). Positive samples were further confirmed by liquid chromatography-tandem mass spectrometry. CONCLUSION: The results suggest that it is necessary to control ZON contamination in medicinal plants, especially Semen coicis. This is a successful study on the analysis of ZON and alpha-ZOL in medicinal plants in China by HPLC-FLD. Immunoaffinity clean-up and HPLC-FLD proved to have broad applicability in the field of simultaneously detecting ZON and alpha-ZOL in foods and medicinal plants and other complicated matrices. PMID- 23096596 TI - Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa. AB - Hidradenitis suppurativa is a chronic skin condition, characterized clinically by painful, recurrent, deep- seated nodules and suppuration, and histologically by hyper-trophic scarring of apocrine gland bearing skin and sinus tracts. The overall consequence of the disease is considerable tissue remodelling and the underlying alterations in innate immunity are poorly understood. The aim of this study was to evaluate the expression of human beta-defensin 2, tumour necrosis factor (TNF)-alpha and matrix metalloproteinase-2 in skin lesions of patients with hidradenitis suppurativa. A total of 14 skin samples from patients and 2 skin samples from healthy volunteers were evaluated by immunohistochemistry. Human beta-defensin 2 was negative in 12/14 specimens. Elevated expression of metalloproteinase-2 was observed in keratinocytes, fibroblasts and inflammatory cells in dermis, sweat glands, hair follicles and sinus tracts, suggesting a key role for hidradenitis suppurativa pathogenesis. Decreased human beta-defensin 2 in the presence of inflammatory (TNF-alpha-containing) cells suggests a decreased innate immunity in hidradenitis suppurativa-affected skin. PMID- 23096597 TI - ABO blood group and risk of coronary artery disease. PMID- 23096595 TI - Interactions between cardiovascular and cerebrovascular disease. AB - OPININION STATEMENT: All patients with ischemic stroke should undergo a comprehensive assessment of cardiovascular risk. Patients with carotid artery disease, symptoms of cerebral ischemia and high cardiovascular risk profiles should be considered for noninvasive testing for coronary artery disease (CAD). Routine testing for CAD before carotid endarterctomy is not recommended. Patients with coexisting coronary and carotid artery disease should be more aggressively treated for reducing their "very high" risk of cardiovascular events. In patients candidates to carotid revascularization, a preoperative coronary angiography and coronary revascularization are not recommended. Warfarin is recommended in all patients with moderate to high risk of stroke. Novel oral anticoagulants represent an attractive alternative to warfarin. However, their place in therapy in clinical practice is not yet established. Percutaneous closure of the left atrial appendage for stroke prophylaxis may be considered in selected patients with atrial fibrillation and contraindications for oral anticoagulant therapy. Warfarin is not indicated in patients with heart failure who are in sinus rhythm. Percutaneous closure of patent foramen does not seem to be superior to medical therapy for the prevention of recurrences in patients with cryptogenic stroke. PMID- 23096598 TI - Five-year follow-up data from the U.S. clinical trial for Sientra's U.S. Food and Drug Administration-approved Silimed(r) brand round and shaped implants with high strength silicone gel. AB - BACKGROUND: In March of 2012, the U.S. Food and Drug Administration approved Sientra's application for premarket approval for its Silimed brand silicone gel implants, based on data from the largest silicone gel breast implant study to date. This was the first approval for shaped silicone gel breast implants. This article presents the results of Sientra's study through 5 years. METHODS: Sientra's study is an ongoing, 10-year, open-label, prospective, multicenter clinical study designed to assess the safety and effectiveness of Sientra's implants in patients undergoing augmentation and reconstruction. A total of 1788 subjects were implanted with 3506 implants, including 1116 primary augmentation, 363 revision-augmentation, 225 primary reconstruction, and 84 revision reconstruction subjects. Physical evaluations and complications were recorded at each visit. Effectiveness was measured by postimplantation bra cup size and assessment of subject satisfaction and quality of life. Of the 1788 subjects, 571 underwent magnetic resonance imaging to assess silent rupture. Safety endpoints were analyzed using the Kaplan-Meier method. RESULTS: Across all cohorts, the risk of rupture was 1.8 percent (95 percent CI, 1.2 to 2.6 percent), the risk of capsular contracture (Baker grade III/IV) was 9.0 percent (95 percent CI, 7.6 to 10.6 percent), and the risk of reoperation was 23.8 percent (95 percent CI, 21.8 to 26.0 percent). Over 99 percent of surgeons reported satisfaction with the postoperative results, and subject satisfaction remained high 5 years after implantation. CONCLUSION: The 5-year results of Sientra's study continue to provide a comprehensive safety and effectiveness profile of Sientra's portfolio of Silimed brand shaped and round implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096599 TI - Discussion: Five-year follow-up data from the U.S. clinical trial for Sientra's U.S. Food and Drug Administration-approved Silimed(r) brand round and shaped implants with high-strength silicone gel. PMID- 23096600 TI - The advantages of free abdominal-based flaps over implants for breast reconstruction in obese patients. AB - BACKGROUND: The authors hypothesized that, for obese patients, delayed abdominal based free flap (rather than implant-based and immediate) breast reconstruction would result in fewer overall complications and reconstruction losses. METHODS: The authors retrospectively analyzed consecutive implant- and abdominal-based free flap breast reconstructions performed in obese patients between 2005 and 2010 by utilizing the World Health Organization obesity classifications: class I, 30.0 to 34.9 kg/m2; class II, 35.0 to 39.9 kg/m2; and class III, >=40 kg/m2. Primary outcome measures included flap failures and overall complications. Logistic regression analysis identified associations among patient, defect, and reconstructive characteristics and surgical outcomes. RESULTS: The analysis included 990 breast reconstructions (548 flaps versus 442 implants) in 700 patients. Mean follow-up was 17 months. Age, smoking, medical illness, and body mass index greater than 37 predicted overall complications on regression analysis. Implants demonstrated a higher failure rate (15.8 percent) than flaps (1.5 percent). Although failure rates were similar for immediate and delayed flap reconstructions overall (1.3 versus 1.9 percent) and among obesity classifications, there was a trend toward more implant failures in immediate rather than delayed reconstructions (16.8 versus 5.3 percent). Differences between immediate implant versus flap reconstruction failure rates were highest among more obese patients [class II (24.7 versus 1.3 percent) and class III (25.4 versus 0 percent) compared with class I (11.7 versus 1.4 percent)]. CONCLUSIONS: Obese patients (particularly class II and III) experience higher failure rates with implant-based breast reconstruction, particularly immediate reconstruction. Free flap techniques or delayed implant reconstruction may be warranted in this population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 23096601 TI - Propranolol accelerates adipogenesis in hemangioma stem cells and causes apoptosis of hemangioma endothelial cells. AB - BACKGROUND: Infantile hemangiomas can cause significant morbidity during proliferation, yet there is no U.S. Food and Drug Administration-approved treatment. They are believed to form from hemangioma stem cells, which differentiate toward a hemangioma endothelial cell phenotype. Recently, propranolol has demonstrated effectiveness in treating complicated infantile hemangiomas. The authors hypothesize that propranolol facilitates their involution by altering cellular behavior in both hemangioma endothelial and stem cells. METHODS: Hemangioma endothelial and stem cells were isolated from resected infantile hemangioma specimens. Cells were treated with 100 MUM propranolol for 48 hours, and apoptosis was determined by the presence of annexin V antibody. Proliferation of stem and endothelial cells was assessed after treatment with 50 or 100 MUM propranolol or vehicle, for 72 and 96 hours, respectively. Adipogenesis was induced in stem cells with and without propranolol. Pro adipogenic genes PPARdelta, PPARgamma, C/EBPalpha, C/EBPbeta, C/EBPdelta, RXRalpha, and RXRgamma were analyzed by quantitative polymerase chain reaction. RESULTS: Annexin V levels were increased in propranolol-treated endothelial cells but not in stem cells. Proliferation of stem and endothelial cells was inhibited by propranolol in a dose-dependent manner. Propranolol-treated stem cells demonstrated accelerated adipogenesis when compared with untreated controls. Transcript levels of C/EBPbeta (p < 0.05), RXRgamma (p < 0.05), and PPARgamma (p < 0.02) were significantly increased when treated with 50 or 100 MUM propranolol; and C/EBPdelta (p < 0.05), RXRalpha (p < 0.05), and PPARdelta (p < 0.01) transcripts were increased when treated with 100 MUM propranolol. C/EBPalpha transcript levels remained unchanged at either dose. CONCLUSIONS: Propranolol increased apoptosis of hemangioma endothelial cells, but not stem cells, and accelerated adipogenesis of hemangioma stem cells. Thus, propranolol likely accelerates involution to fibrofatty residuum. PMID- 23096602 TI - A shift from the osteocutaneous fibula flap to the prelaminated osteomucosal fibula flap for maxillary reconstruction. AB - BACKGROUND: Reconstruction of the maxilla with the fibula free flap is a popular and well-described technique. The ideal intraoral lining would be mucosa, which is moist, thin, and non-hair-bearing. Prelamination of the fibula with buccal mucosa replaces like tissue with like tissue, obviates the need for a skin paddle, and facilitates placement of osseointegrated implants in a single stage. For central maxillary defects, the authors have shifted from using an osteocutaneous to a prelaminated free fibula flap. In this article, the authors report their experience using the prelaminated osteomucosal fibula for maxillary reconstruction. METHODS: From 2003 to 2011, 24 patients underwent reconstruction of a central maxillary defect using a free fibula flap. The first 10 patients had osteoseptocutaneous flaps, and the other 14 patients had prelaminated flaps. Data collected included patient age, cause of defect, type and number of operations, complications at both the donor and recipient sites, and placement of osseointegrated implants. RESULTS: The majority of patients in the series (n = 21) had central maxillary defects caused by loss of the premaxilla during early repair of bilateral cleft lip-cleft palate. There was one flap failure in the nonprelaminated flap group and one in the prelaminated group. Repeated debulking to thin the skin paddle was required in all of the patients with osteocutaneous flaps. CONCLUSIONS: Prelamination delivers like tissue to the recipient site, obviates the need for debulking, and may reduce donor-site wound problems. To the authors' knowledge, this is the largest series of prelaminated fibulas for maxillary reconstruction in the literature. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096603 TI - Redefining the surface anatomy of the parotid duct: an in vivo ultrasound study. AB - BACKGROUND: The surface anatomy of the parotid duct is important when assessing facial lacerations and in facial rejuvenation surgery but is inconsistently described in reference texts. The aim of this study was to map the surface anatomy of the adult parotid duct using ultrasound. METHODS: Fifty healthy adults (31 women; mean age, 33 years) were scanned by an experienced sonographer using a 13-5 MHz linear probe and a Siemens Sonoline Antares ultrasound machine. The caliber, length, and course of the parotid duct were recorded bilaterally. RESULTS: The parotid duct was identified bilaterally in all participants. One subject had a double duct bilaterally. In the remaining 49 individuals (98 ducts), the duct had a mean maximum internal caliber of 0.6 +/- 0.2 mm and length 42 +/- 7.5 mm. Ninety-two (94 percent) ducts were below the most popular surface marking, which is reported as a line between the lower border of the tragus and mid philtrum. In 93 percent of individuals, the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and cheilion. CONCLUSION: A more accurate description of the surface anatomy of the parotid duct should assist with early diagnosis of parotid duct injuries and avoidance of iatrogenic injury. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 23096604 TI - Patient safety in the operating room: I. Preoperative. AB - BACKGROUND: Beyond the controlled trauma of surgery, the operating room can be a hazardous place for patients and health care workers alike. Modern plastic surgery requires a thorough knowledge of various perioperative risks and methods to minimize these risks. As the importance of teamwork becomes more evident, clear communication skills preoperatively, intraoperatively, and postoperatively become equally critical. To facilitate an improvement in perioperative patient safety, this article will review aspects of communication, including crew resource management, root cause analysis, and surgical-site verification. In addition, the authors will discuss patient positioning, antiseptic hand and patient preparations, and barriers, such as surgical scrubs, gowns, gloves, and drapes. METHODS: The authors reviewed the literature regarding operating room safety, both primary research and secondary reviews, via multiple PubMed queries and literature searches. Topics most relevant to inpatient plastic surgery were included in the final analysis and summarized, as a full review of each topic is beyond the scope of this article. RESULTS: Many possible interventions were identified, with the goal of reducing perioperative complications, such as wrong site surgery, neuropathies, myopathies, compartment syndromes, pressure ulcers, surgical-site infections, and blood-borne disease transmissions among plastic surgeons and their patients. CONCLUSIONS: There are ample opportunities for the reduction of preventable adverse events in plastic surgery. This article aims to provide its reader with the tools to research adverse events and a basic education in avoiding specific preoperative events. A second article addressing intraoperative and postoperative patient safety follows. PMID- 23096605 TI - Patient safety in the operating room: II. Intraoperative and postoperative. AB - BACKGROUND: The perioperative environment can be hazardous to patients and providers alike. Although many risks are best addressed preoperatively, some hazards require constant attention by the surgeon, anesthesiologist, and staff in the operating room. In a previous article, the authors discussed preoperative aspects of patient safety. In this article, the authors review intraoperative and postoperative risks and techniques to decrease these risks. METHODS: The authors reviewed the literature regarding operating room safety, both primary research and secondary reviews, via multiple PubMed queries and literature searches. Topics most relevant to inpatient plastic surgery were included in the final analysis and summarized, as a full review of each topic is beyond the scope of this article. RESULTS: Several intraoperative and postoperative risks were identified, in addition to methods designed to decrease the incidence of those risks, complications, and other adverse events among plastic surgeons and their patients. CONCLUSIONS: In this article covering intraoperative and postoperative hazards, the authors build upon a previous article addressing preoperative risks to patients during inpatient plastic surgery. Although neither article covers an exhaustive list of potential risks, the goal is to provide the modern plastic surgeon with the means to prevent common adverse events, as well as the tools to research new hazards. PMID- 23096606 TI - A new recipient artery for reconstruction of soft-tissue defects in the lower limb with a free anterolateral thigh flap: the reversed descending branch of the lateral femoral circumflex artery. AB - BACKGROUND: Complex and severe leg defects remain a persistent challenge in reconstructive surgery, especially when no feasible local or regional flaps are available. An operative solution is yet to be found. The descending branch of the lateral circumflex femoral artery of the injured leg was used as the recipient artery in a reverse-flow fashion in these difficult wounds. METHODS: From March of 2005 to May of 2010, 11 male and four female patients with soft-tissue defects in the lower leg were treated. Causes of injury were industrial machinery injuries in six patients and traffic accidents in nine patients. Mean patient age at surgery was 36.6 years. The mean soft-tissue defect size was 17.6 * 7.4 cm, and the mean anterolateral thigh flap was 19.3 * 8.7 cm. The mean length of flap pedicles was 11.8 cm, and the mean length of recipient pedicles was 15.7 cm. RESULTS: Fourteen flaps survived completely. Partial necrosis at the distal edge of the flap occurred in one case. No patient needed operative revision due to postoperative thrombosis of the vessels. At the mean follow-up period of 10.5 months, wound coverage was achieved in all patients. CONCLUSIONS: The reverse descending branch of the lateral circumflex femoral artery is a reliable recipient artery for the free anterolateral thigh flap taken from the opposite thigh. The technique can be used to reconstruct defects in the lower leg when use of local or regional flaps is not feasible and commonly used recipient arteries are not available. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096607 TI - Obturator nerve transfer for femoral nerve reconstruction: anatomic study and clinical application. AB - BACKGROUND: Femoral nerve lesion causes significant disability. In many cases, the availability of the proximal stump is in question and further complicates surgical management by severely limiting reconstructive options and precluding nerve graft reconstruction. The purpose of this report is to describe the successful restoration of quadriceps function by distal nerve transfer at the level of the thigh without functional donor morbidity and the findings of cadaveric dissections of the obturator and femoral nerve branches. METHODS: Eight fresh frozen cadaveric lower limbs were dissected at the region of the groin and thigh. Two patients were referred to us with complete femoral nerve palsy and unavailability of the proximal femoral nerve for reconstruction by conventional methods. Distal nerve transfers were performed using the anterior branch of the obturator nerve and in one case, the motor branch to the tensor fasciae latae to reinnervate the rectus femoris and vastus medialis muscles. RESULTS: As measured in cadaveric specimens, the transferable lengths of each donor nerve branch when used to innervate any combination of quadriceps muscles provide plenty of length for tension-free end-to-end coaptations. One patient recovered 3 to 4/5 Medical Research Council grade knee extension and the other 4+/5 knee extension. The latter patient is able to walk, run, and use stairs normally, whereas the former still has difficulty with fast ambulation, running, and stairs. CONCLUSION: The authors present a novel reconstructive approach that yields good clinical outcomes, as well as an anatomic study that demonstrates the feasibility of this technique. PMID- 23096608 TI - Discussion: Sensory reconstruction of a finger pulp defect using a dorsal homodigital island flap. PMID- 23096609 TI - Reconstruction of proper digital nerve defects in the thumb using a pedicle nerve graft. AB - BACKGROUND: Traumatic defects of the proper digital nerve in the thumb affect tactile perception of the thumb pulp. This article reports on the treatment of the defect using a pedicle nerve graft taken from the dorsal branch of the proper digital nerve of the index or long finger, or both. METHODS: From May of 2006 to March of 2010, the pedicle nerve graft was used in 16 thumbs in 16 patients. There were 13 male and three female patients, with an average age of 33 years. Nerve repair was performed on one side in six thumbs and on both sides in 10 thumbs. The average length of the defects was 2.5 cm, between the middle of the distal phalanx and metacarpophalangeal joint. The average length of the nerve grafts was 2.7 cm. For comparison, we also collected a consecutive series of 27 patients with thumb proper digital nerve defects treated using a nonvascularized graft taken from the sural nerve (n = 15) or the medial antebrachial cutaneous nerve (n = 12). RESULTS: At a mean follow-up of 22 months, the mean static two point discrimination and Semmes-Weinstein monofilament scores on the thumb pulps were 6.7 mm and 3.62, respectively. The measurements of patients treated using nonvascularized nerve grafts were 9.4 mm and 3.90, respectively. The outcomes of the two groups were significantly different. CONCLUSIONS: The pedicle nerve graft is useful and reliable for reconstructing proper digital nerve defects in the thumb. Superior sensory recovery was achieved using vascularized instead of unvascularized nerve grafts. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23096610 TI - Advanced cranial reconstruction using intracranial free flaps and cranial bone grafts: an algorithmic approach developed from the modern battlefield. AB - BACKGROUND: The objective of this study was to report outcomes after initiation of an algorithmic approach (Bethesda protocol) using intracranial free flaps, cranial bone autografts, and dermal/fat grafts to treat warfare-related cranial frontofacial defects after war-related decompressive craniectomy. METHODS: A retrospective review of personnel undergoing complex cranial defect reconstruction that required free flap interpositions for dead space obliteration, cranial bone grafting, or dermal/fat grafting for orbital defects was performed over a 52-month period. RESULTS: From March of 2003 to July of 2011, 13 patients were identified who underwent complex craniofacial defect reconstruction. All patients were male (average age, 25 years). Average follow-up was 3.6 years. Glasgow Coma Scale score was 7 initially and 9 on arrival to the continental United States. Average evacuation time was 4.2 days. Forty-six percent of injuries were blast injuries. Nine patients (69 percent) underwent hemicraniectomies and four (31 percent) underwent bifrontal craniectomies. Two patients required free flaps and four required free flaps and cranial bone grafts for skull base reconstruction. Five patients required cranial bone grafts and two required cranial bone grafts with dermal fat grafts for reconstruction. All patients were complication free at conclusion of the study. The initial free flap success rate was 86 percent (six of seven flaps). Successful frontal bar/free flap reconstruction was present in 100 percent and the secondary cranioplasty rate was 77 percent. CONCLUSION: Decompressive craniectomy defects associated with orbital, sinus, and skull base defects can be successfully reconstructed using an algorithmic approach with low morbidity and high secondary cranioplasty retention rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096611 TI - How "successful" is calvarial reconstruction using frozen autologous bone? AB - BACKGROUND: The authors investigated the long-term outcome of frozen autologous bone cranioplasty in patients who had undergone decompressive craniectomy for severe traumatic brain injury. METHODS: A retrospective analysis was undertaken of all patients who had undergone decompressive craniectomy at the two major trauma hospitals in Western Australia between 2004 and 2010. A specific note was made regarding "failure" of frozen autologous bone because of either infection or bone flap resorption. RESULTS: A total of 194 patients required either unilateral or bilateral decompressive craniectomy for severe traumatic brain injury during the study period. Of these patients, 156 had had an autologous cranioplasty. Among these patients, the cranioplasty was judged a failure in 45 (29 percent). Thirteen (8.5 percent; 95 percent confidence interval, 5.0 to 14.0 percent) developed an infection requiring removal of the cranioplasty. Thirty-two (21 percent; 95 percent confidence interval, 15 to 28 percent) developed clinical symptoms or signs relating to resorption of the cranioplasty. Fourteen (9 percent) required secondary titanium cranioplasty, two were offered surgical augmentation but declined, and 16 (10 percent) developed significant bone resorption through both the inner and outer tables of the skull. CONCLUSIONS: This study has demonstrated that the use of frozen autologous bone is associated with a high long-term failure rate; however, this does not necessarily imply that alternative materials should be routinely used. Although a number are available, their efficacy over and above frozen autologous bone remains to be established and perhaps this will only be demonstrated in the setting of a formal clinical trial. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096612 TI - Discussion: How "successful" is calvarial reconstruction using frozen autologous bone? PMID- 23096613 TI - Intraoperative vascular anatomy, arterial blood flow velocity, and microcirculation in unilateral and bilateral cleft lip repair. AB - BACKGROUND: Cleft lip repair aims to normalize the disturbed anatomy and function. The authors determined whether normalization of blood circulation is achieved. METHODS: The authors measured the microcirculatory flow, oxygen saturation, and hemoglobin level in the lip and nose of controls (n = 22) and in patients with unilateral and bilateral cleft lip-cleft palate. The authors measured these parameters before lip repair (n = 29 and n = 11, respectively), at the end of lip repair (n = 27 and 10, respectively), and in the late postoperative period (n = 33 and n = 20, respectively). The arterial flow velocity was measured in unilateral groups at the same time points (n = 13, n = 11, and n = 12, respectively). Statistical differences were determined using analysis of variance. RESULTS: Before surgery, the arterial flow velocities and microcirculation values were similar on each side of the face and between groups. The microcirculatory flow was significantly higher in the prolabium of bilateral patients than in the philtrum of controls. All circulation values in unilateral and bilateral patients in the late postoperative period were within the range of controls and of those before surgery. Intraoperatively, the authors consistently found a perforating artery on the superficial side of the transverse nasalis muscle. CONCLUSIONS: There appears to be no intrinsic circulatory deficit in unilateral and bilateral cleft lip-cleft palate patients. The increased flow in the prolabium indicates a strong hemodynamic need in this territory, compelling its vascular preservation. Whether surgical preservation of the nasalis perforator artery is of long-term benefit should be addressed in future studies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23096614 TI - Pilot study of timing of biofilm formation on closed suction wound drains. AB - BACKGROUND: Closed suction drains are used in a variety of surgical procedures as a means of preventing hematoma formation or other fluid accumulation. The literature shows that they may be linked to postoperative infection. The aim of this study was to determine the timing of biofilm formation on drains, the route of colonization, and whether simple measures to increase sterility made any difference in biofilm formation. METHODS: A group of 12 patients, undergoing a variety of procedures, had drains removed at intervals between 2 and 42 hours. Cross-sections of these drains were sampled at three different sites: where the drain entered the skin, the middle of the drain, and the tip of the drain. The samples were sectioned longitudinally to view the lumen and outer wall. Specimens were viewed under scanning electron microscopy to compare the extent of biofilm formation in the drains on the left side with those on the right side. The drains on the left side were placed with increased attention to sterility. RESULTS: Biofilm formation was evident on drains removed from as early as 2 hours after insertion. Statistical conclusions could not be drawn about route of colonization or enhanced sterility measures taken. From subjective analysis alone, route of colonization seemed to be a combination of on-table contamination and contamination from breast tissue. No difference in the amount of biofilm formation was found between normally inserted drains and those inserted with increased attention to sterility. CONCLUSION: Biofilm formation occurs within 2 hours on closed-suction wound drains. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 23096615 TI - To scip ... or not to scip ... the Surgical Care Improvement Project protocol. PMID- 23096618 TI - Novel animal model of calvarial defect: part III. Reconstruction of an irradiated wound with rhBMP-2. AB - BACKGROUND: Recombinant human bone morphogenetic protein-2 (rhBMP-2) has been shown to be an effective therapy in the acute calvarial defect wound and in calvarial defects complicated by chronic scar. The authors compared the effectiveness of rhBMP-2 with the accepted standard of autologous graft for repair of irradiated calvarial defects. METHODS: Nineteen adult New Zealand White rabbits underwent subtotal calvariectomy. Four days postoperatively, animals received 15 Gy to their wound. Six weeks postoperatively, scars were debrided and defects reconstructed in one of four groups: empty (n = 3), vehicle (buffer solution/absorbable collagen sponge; n = 3), cryopreserved autograft, (n = 3), or rhBMP-2 repair (rhBMP-2/absorbable collagen sponge, n = 10). Animals underwent computed tomography imaging at 0, 2, 4, and 6 weeks, followed by euthanization and histological analysis. Percent healing was determined and a 4 * 3 mixed model analysis of variance was performed on healing versus treatment group/postoperative time. RESULTS: According to radiopacity, rhBMP-2/sponge and autografts were statistically equivalent, with 99 and 89 percent healing at 6 weeks. Empty and vehicle treatment groups, with 35 and 34 percent healing, were inferior to the rhBMP-2/sponge and autograft groups (p < 0.05). Histologically, bone in the surgical control (autograft) group was less cellular and trabecular than bone formed after rhBMP-2/sponge treatment. CONCLUSIONS: rhBMP-2 therapy was as effective in reconstructing calvarial defects in the unfavorable irradiated wound as in the acute, favorable calvarial wound. Compared with cryopreserved autologous graft, rhBMP-2-regenerated bone resulted in equal defect coverage, similar thickness, and greater cellularity. Further studies are necessary to demonstrate the long-term viability and remodeling rhBMP-2/sponge-generated bone. PMID- 23096619 TI - The effect of perineurotomy on nerve regeneration in diabetic rats. AB - BACKGROUND: One of the main causes of diabetic neuropathy is endoneurial edema, which increases the internal pressure of the perineurium, which has a tight structure. The treatment used to reduce internal pressure is perineurotomy, in which a surgical incision is made into the perineurium. METHODS: Forty male Sprague-Dawley rats were used in the study. They were classified into four groups. Streptozotocin-induced diabetes was created in groups III and IV. The sciatic nerve was transected and repaired epineurally in all groups. Perineurotomy was performed additionally in group II and IV to the sciatic, peroneal, tibial, and sural nerves from the most proximal side to their most distal ends. The sciatic function indices were calculated for functional assessment. Light and electron microscopic evaluations were performed for morphometric assessment. In addition, the myelinated and degenerated fibers were counted in all groups. RESULTS: The sciatic function indices of the diabetic perineurotomy group were found to be significantly higher than those of the other groups (p < 0.05). Based on the myelinated fiber counts, there was insignificant difference between group I and group II, whereas the difference was significant (p < 0.05) between group III and group IV. Presence of peripheric nerves in light microscopic evaluation revealed normal characteristics of myelinated fibers in group I and group II. The myelinated axon profile in group IV was similar to that of groups I and II in electron microscopic evaluation. CONCLUSION: It is concluded that perineurotomy may be established as a useful adjunctive procedure for nerve repair in diabetic patients. PMID- 23096620 TI - Comparison of hemihypoglossal nerve versus masseteric nerve transpositions in the rehabilitation of short-term facial paralysis using the Facial Clima evaluating system. AB - BACKGROUND: Masseteric and hypoglossal nerve transfers are reliable alternatives for reanimating short-term facial paralysis. To date, few studies exist in the literature comparing these techniques. This work presents a quantitative comparison of masseter-facial transposition versus hemihypoglossal facial transposition with a nerve graft using the Facial Clima system. METHODS: Forty six patients with complete unilateral facial paralysis underwent reanimation with either hemihypoglossal transposition with a nerve graft (group I, n = 25) or direct masseteric-facial coaptation (group II, n = 21). Commissural displacement and commissural contraction velocity were measured using the Facial Clima system. Postoperative intragroup commissural displacement and commissural contraction velocity means of the reanimated versus the normal side were first compared using a paired sample t test. Then, mean percentages of recovery of both parameters were compared between the groups using an independent sample t test. Onset of movement was also compared between the groups. RESULTS: Significant differences of mean commissural displacement and commissural contraction velocity between the reanimated side and the normal side were observed in group I but not in group II. Mean percentage of recovery of both parameters did not differ between the groups. Patients in group II showed a significantly faster onset of movement compared with those in group I (62 +/- 4.6 days versus 136 +/- 7.4 days, p = 0.013). CONCLUSIONS: Reanimation of short-term facial paralysis can be satisfactorily addressed by means of either hemihypoglossal transposition with a nerve graft or direct masseteric-facial coaptation. However, with the latter, better symmetry and a faster onset of movement are observed. In addition, masseteric nerve transfer avoids morbidity from nerve graft harvesting. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 23096621 TI - An individualized approach to surgical reconstruction for lateral polydactyly of the foot with an emphasis on collateral ligament reconstruction. AB - BACKGROUND: Most previous studies concerning the treatment of polydactyly of the foot have focused on surgical techniques for aesthetic improvement rather than functional alignment of the reconstructed toe. The purpose of this study was to present the authors' surgical procedures for preventing postoperative malalignment of the reconstructed toe and evaluate whether those procedures were useful for the treatment of polydactyly of the foot. METHODS: The study included 30 feet from 26 patients, four male and 22 female, with four bilateral cases. The average age of the patients at surgery was 20 months, and average duration of the postoperative follow-up was 32 months. The ligamentous stability of the toe joint was reconstructed using the collateral ligament/periosteal sleeve from the excised toe. The authors evaluated postoperative complications of the toe involving varus or valgus deformities, thickening of the reconstructed toe, pigmentation of the grafted skin, and scar formation. RESULTS: No cases revealed any varus or valgus deformities, pigmentation of the grafted skin, functional disturbance, or pain in the reconstructed toe after surgery. Regarding postoperative complications, the authors observed visible thickening in eight toes and scar formation in three toes, although the parents' evaluation in each case was "very satisfied" or "satisfied." CONCLUSION: The authors recommend reconstruction of the ligamentous stability of the toe joint using the collateral ligament/periosteal sleeve from the excised toe to prevent postoperative malalignment. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096622 TI - Raised intracranial pressure is frequent in untreated nonsyndromic unicoronal synostosis and does not correlate with severity of phenotypic features. AB - BACKGROUND: In a small number of children with unicoronal synostosis, the phenotype is mild and the aesthetic benefit of surgical correction is potentially outweighed by surgical risk. Raised intracranial pressure, however, would necessitate intervention. The authors documented the incidence of raised intracranial pressure in children with mild features and/or parental reluctance to proceed directly to surgery. METHODS: A retrospective review of all children with (1) a clinical diagnosis of nonsyndromic unicoronal synostosis; (2) unicoronal synostosis confirmed on computed tomographic scanning; (3) negative family history for unicoronal synostosis; and (4) negative genetic screening (including P250R encoded by FGFR3, exons IIIa and IIIc in FGFR2 and TWIST1) was completed. RESULTS: Of the 80 children studied, seven (9 percent) underwent formal intracranial pressure monitoring because of a combination of mild clinical features (n = 4) and/or parental reluctance to proceed with surgery (n = 3). Intracranial pressure monitoring was reported as high in three (42 percent), borderline in two (29 percent), and normal in two patients (29 percent). The findings did not correlate with the degree of clinical deformation or age at presentation. There was little correlation with clinical and radiographic features of raised intracranial pressure in this genetically screened nonsyndromic group. CONCLUSIONS: High or borderline raised intracranial pressure was present in five of seven cases. The risk did not correlate with degree of deformity or age at presentation. Formal intracranial pressure monitoring should be considered in all children with unicoronal synostosis not proceeding directly to surgical intervention, in combination with routine long-term follow-up and repeated intracranial pressure monitoring where indicated. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, V. PMID- 23096623 TI - Quantitative assessment of medial orbit fracture repair using computer-designed anatomical plates. AB - BACKGROUND: The purpose of this study was to objectively assess the accuracy of orbital reconstruction in patients with medial wall fractures following placement of computer-designed, prebent anatomical mesh plates by means of a transconjunctival-retrocaruncular approach. METHODS: This was a retrospective, cohort study of consecutive subjects with facial trauma who underwent reconstruction of medial wall/orbital floor defects over a 12-month period at a level I trauma center. All subjects had preoperative and postoperative computed tomographic scans with 1.25-mm slices formatted in the axial, coronal, and sagittal planes with a minimum of 3 months' follow-up. Preoperative and postoperative orbital volumes were computed using integrated analysis over the orbital slices. The volumes were compared using nonparametric paired samples comparisons (Wilcoxon signed ranks test). For all analyses, p <= 0.05 was considered significant. RESULTS: Fifteen subjects underwent repair of 17 medial wall fractures. The mean patient age was 37 +/- 16 years (range, 18 to 59 years); one subject was female. Motor vehicle-related incidents and assaults were the most common mechanisms of injury. The average postoperative volume for the fractured sides was 22. 2 +/- 2.1 cm3 (range, 19.9 to 26.9 cm3) and was statistically significantly lower than the preoperative volume on the fractured side (24.18 +/- 2.57 cm3; p < 0.001). One patient (6.7 percent) experienced a postoperative complication requiring reoperation. CONCLUSION: Computer-designed, prebent anatomical mesh plates placed using a transconjunctival-retrocaruncular approach for reconstruction of medial wall fractures with orbital floor components reliably results in restoration of contour and volume, with a low complication rate. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 23096624 TI - Reducing wound complications in gluteal augmentation surgery. AB - BACKGROUND: Over the past 30 years, many techniques have been proposed for gluteal augmentation with implants. The intramuscular technique provided greatly improved results and a consequent increase in the number of such procedures performed in Brazil. However, the data available in the medical literature reveal high rates of wound complications, mostly seroma and dehiscence. The aim of this study was to present changes in the management of the wound of augmentation gluteoplasty with silicone implants in an attempt to reduce the rates of postoperative complications. METHODS: Twenty female candidates for augmentation gluteoplasty were selected prospectively and submitted to the procedure with a modified technique. The incidence of wound complications was compared with the data of the authors and of the literature. RESULTS: In the comparison between homogeneous groups of patients, the modified technique reduced the rate of wound complications from 35 percent to 5 percent. The most frequent complications were seroma and dehiscence. The combination of liposuction of the flanks was not a risk factor for the occurrence of these complications. CONCLUSIONS: Reduction of the undermined subcutaneous area, application of adhesion stitches, and maintenance of good vascularization in the sacral region are the keystones of the authors' proposal. The modifications of the technique presented here are simple and easy to perform, and have proved effective in reducing complications during augmentation gluteoplasty with silicone implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23096625 TI - Evaluation of the long-term stability of sheath plication using absorbable sutures in 51 patients with diastasis of the recti muscles: an ultrasonographic study. AB - BACKGROUND: Rectus sheath plication within abdominoplasty is a standard treatment for diastasis of the recti muscles. There are questions regarding the efficacy and long-term stability of the correction of rectus diastasis and whether absorbable sutures work as well as nonabsorbable sutures. METHODS: The authors conducted a case-control study to assess the outcomes of recti muscle diastasis correction with absorbable suture. The authors assessed the outcomes by physical and ultrasonographic examinations and a patient questionnaire, which asked about the number of pregnancies and the types of deliveries, other abdominal operations before or after the abdominoplasty, and the interval of time required to return to full activity. During the examination, the interrecti distances were measured at three levels: halfway between the xiphoid and umbilicus, just above the umbilicus, and halfway between the umbilicus and the pubis. The same examination was performed on a control group of nulliparous women. RESULTS: The authors examined a group of 51 patients aged 25 to 64 years (mean, 41 years). The time interval between the operation and the ultrasonographic examination was 12 to 41 months (mean, 20.8 months). There was no statistically significant difference between the studied group and the control group with respect to their interrecti distances. CONCLUSION: Rectus sheath plication using absorbable sutures in patients with diastasis of the recti muscles is a reliable method that maintains the long-term stability of the abdominal wall. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 23096626 TI - Discussion: Evaluation of the long-term stability of sheath plication using absorbable sutures in 51 patients with diastasis of the recti muscles: an ultrasonographic study. PMID- 23096627 TI - Common fractures and dislocations of the hand. AB - LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Describe the concept of early protected movement with Kirschner-wired finger fractures to the hand therapist. 2. Choose the most appropriate method of fracture fixation to achieve the goal of a full range of motion. 3. Describe the methods of treatment available for the most common fractures and dislocations of the hand. BACKGROUND: The main goal of treatment of hand and finger fractures and dislocations is to attain a full range of wrist and nonscissoring finger motion after the treatment is accomplished. This CME article consists of literature review, illustrations, movies, and an online CME examination to bring the participant recent available information on the topic. METHODS: The authors reviewed literature regarding the most current treatment strategies for common hand and finger fractures and dislocations. Films were created to illustrate operative and rehabilitation methods used to treat these problems. A series of multiple-choice questions, answers, discussions, and references were written and are provided online so that the participant can receive the full benefit of this review. RESULTS: Many treatment options are available, from buddy and Coban taping to closed reduction with immobilization; percutaneous pins or screws; and open reduction with pins, screws, or plates. Knowledge of all available options is important because all can be used to achieve the goal of treatment in the shortest time possible. The commonly used methods of treatment are reviewed and illustrated. CONCLUSIONS: Management of common hand and finger fractures and dislocations includes the need to focus on achieving a full range of motion after treatment. A balance of fracture reduction with minimal dissection and early protected movement will achieve the goal. PMID- 23096628 TI - Lysis of the orbicularis retaining ligament and orbicularis oculi insertion. PMID- 23096630 TI - Blindness following cosmetic injections of the face. PMID- 23096632 TI - Correction of severe ptosis with a silicone implant suspensor. PMID- 23096634 TI - "Nougat graft": diced cartilage graft plus human fibrin glue for contouring and shaping of the nasal dorsum. PMID- 23096635 TI - Vascular basis of the facial artery perforator flap: analysis of 101 perforator territories. PMID- 23096636 TI - Strategies for recognizing and managing intraoperative vascular insufficiency in abdominally based autologous breast reconstruction. PMID- 23096638 TI - Radiotherapy and implant-based, two-stage breast reconstruction: how to minimize complications and maximize aesthetic outcomes. PMID- 23096640 TI - Microsurgical primary prevention of lymphatic injuries following breast cancer treatment. PMID- 23096642 TI - Successful DIEP flap for breast reconstruction in a patient with prior abdominoplasty. PMID- 23096643 TI - Are Pfannenstiel scars a boon or a curse for DIEP flap breast reconstructions? PMID- 23096644 TI - Correction of severe ptosis with a silicone implant suspensor: 22 years of experience. PMID- 23096645 TI - Impact of obesity on breast surgery complications. PMID- 23096646 TI - Brava and autologous fat transfer as a safe and effective breast augmentation alternative. PMID- 23096647 TI - Improved skin contraction after VASER-assisted lipoplasty: is it a change we can believe in? PMID- 23096648 TI - A review of 32 free flaps in patients with collagen vascular disorders. PMID- 23096649 TI - The importance of a skin bridge in peripheral tissue perfusion in perforator flaps. PMID- 23096651 TI - Intraoperative use of the lacrimal endoscope for accurate reduction of bony nasolacrimal duct fracture. PMID- 23096652 TI - Radiometric infrared temperature detection in skin expansion. PMID- 23096653 TI - Modified Millard repair of the incomplete unilateral cleft lip. PMID- 23096654 TI - Mandibular distraction instead of tracheostomy in Pierre Robin sequence patients: is it worth it? PMID- 23096655 TI - Double-pedicled abdominal free flap using an entirely new microvascular combination of DIEP and SIEA vascular pedicles for unilateral breast reconstruction: a novel addition to the Hamdi classification. PMID- 23096656 TI - If based on citation volume, perforator flaps have landed mainstream. PMID- 23096657 TI - Diagnostic efficacy of preoperative 64-section multidetector computed tomographic angiography in identifying the cutaneous perforators in the anterolateral thigh flap: an evidence-based review. PMID- 23096658 TI - Does the left hand know what the right hand is doing? What plastic surgeons need to know about radiation therapy techniques. PMID- 23096659 TI - [Frequency of minor histocompatibility antigens among Chilean blood donors]. AB - BACKGROUND: Minor histocompatibility antigens (mHAgs) play a critical role in the immune responses associated with allogeneic stem cell transplantation, such as graft versus host disease (GVHD) and graft-versus-tumor (GVT). AIM: To determine the gene frequencies of the mHAgs HA-1, HA-2 and HA-8 in Chilean Blood Bank donors. MATERIAL AND METHODS: Blood from 192 blood donors was analyzed. The presence of haplotype HLA-A*02 was determined by flow cytometry. The frequency of mHAgs was determined by allele specific polymerase chain reaction in genomic DNA. RESULTS: Sixty one participants were carriers of the haplotype HLA-A*02. The relative allele frequency HA-1H was 45%, HA-Ir 55%, HA-2V 80.6%, HA-2M 19.4%, HA 8R 49.8% and HA-8P was 50.2%. Based on mHAgs disparity between HA-1, HA-2 or HA 8, the probability to generate a GVT response in HLA-A*02 individuals was 40%. CONCLUSIONS: The mHAgs frequency in Chilean population is under Hardy-Weinberg equilibrium and they are similar to those of other ethnic populations in the world. PMID- 23096660 TI - [Current status of cardiac rehabilitation in Chile]. AB - BACKGROUND: Cardiac rehabilitation (CR) programs play an important role in the control and prevention of new cardiac events. AIM: A survey was performed to evaluate the current situation of CR programs in Chile. MATERIAL AND METHODS: A questionnaire evaluating the structure of rehabilitation centers, characteristics of the rehabilitation programs and patients, management of risk factors, reimbursement methods, human resources and potential barriers for an efficient rehabilitation, was mailed to centers dedicated to CR in Chile. RESULTS: Eight centers were contacted and seven responded. Coronary heart disease is the most common underlying disease of attended patients and CR is carried out mainly during phases II and III. All CR centers perform an initial assessment, stratify patients, plan and provide tips on physical activity and nutrition. Only three centers provide help to quit smoking. Lipid profile and blood sugar are assessed in 62% of centers. Most practitioners involved are cardiologists, nurses, physiotherapists and nutritionists, all trained in cardiopulmonary resuscitation. The main barrier for their development is the lack of patient referral from practitioners. CONCLUSIONS: Despite the recognized value of CR in the care of patients after a cardiac event, this study reveals the need for further development of such programs and improvement of patient referrals. PMID- 23096661 TI - [C-Reactive protein levels in patients with chronic obstructive pulmonary disease]. AB - BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have elevated serum levels of ultrasensitive C reactive protein (CRPus). This raise may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as smoking status, disease severity, acute exacerbations, or associated complications. AIM: To evaluate the potential causes of raised levels of CRPus in stable COPD patients. PATIENTS AND METHODS: Cohorts of 133 mild-to-very severe COPD patients (41 current smokers), 31 never-smokers, and 33 current smoker controls were compared. Clinical assessments included body mass index (BMI), fat (FM) and fat-free mass (FFM) measurement by DEXA, forced expiratory volume in one second (FEV1), arterial oxygen tension (PaO2), six minute walking test (SMWT), emphysema (EMPH) and right thigh muscle cross sectional area (TMCSA), both quantified by high resolution computed tomography. RESULTS: Serum CRPus levels were significantly higher in COPD patients than in controls (7 +/- 4.2 and 3.7 +/- 2.7 mg/L respectively; p < 0.0001). Being smoker did not influence CRPus levels. These levels were significantly correlated with FM (r = 0.30), BMI (r = 0.21), FEV1 (r = -0.21), number of acute exacerbations of the disease in the last year (r = 0.28), and PaO2 (r = -0.27). Using multivariate analysis FM, PaO2, and number of acute exacerbations of the disease in the last year had the strongest association with CRPus levels. CONCLUSIONS: CRPus is elevated in COPD patients, independent of smoking status. It is weakly associated with fat mass, arterial oxygen tension and frequency of exacerbations. PMID- 23096662 TI - [A structural model to measure effectiveness of hospital services]. AB - BACKGROUND: One of the main determinants of quality in the public health care services is the perceived user satisfaction. AIM: To analyze the relationship between supply (User Orientation of Management) (UO), demand (User Satisfaction with service components) (US) and subjective indicators of effectiveness, such as Perceived Global Quality (PGQ) and Global Satisfaction (GS) among hospital service users. MATERIAL AND METHODS: A survey was applied to users of hospital services, asking about management and quality of hospital services and satisfaction with the service provided. Data was analyzed with exploratory and confirmatory factorial analyses. Structural Equation Models were used to test the hypotheses implied in the theoretical model of effectiveness. RESULTS: The cause effect relationship between UO and US was confirmed. There was also a direct relationship between PGQ and GS. CONCLUSIONS: Efficient nursing and administrative personnel are of highest importance to improve user satisfaction. The hospital management must pay extreme attention to this kind of staff in order to be effective from the point of view of their patients. PMID- 23096663 TI - [Sex-hormone binding globulin (SHBG) levels during pregnancy as predictors for pre-eclampsia and fetal growth restriction]. AB - BACKGROUND: Sex-Hormone Binding Globulin (SHBG) may be associated to Pre eclampsia (PE) and Fetal Growth Restriction (RCIU). AIM: To determine if maternal serum SHBG concentrations during the first and second trimesters are predictive biomarkers of Pre-eclampsia and RCIU. PATIENTS AND METHODS: Prospective cohort study carried out in the Fetal Medicine Unit, Universidad de Chile Clinical Hospital between January, 2005 and December, 2006. Blood samples were obtained from unselected pregnant women during routine 11-14 week and 22-25 week ultrasound examinations, conforming two different study groups. Posteriorly, serum SHBG concentrations were determined in women who developed Pre-eclampsia, RCIU and their respective controls. RESULTS: Fifty five patients were included in the 11-14 weeks group. Nine women that developed PE, 10 that developed RCIU and 36 controls were selected from this group. There were no significant differences in SHBG levels between patients with PE, RCIU or controls (324.7 (26.6), 336.8 (33.9) and 377.5 (24.3) nmol/L, respectively). Fifty four women were included in the 22-25 weeks group. Eight women who developed Pre-eclampsia, 15 who developed RCIU and 31 controls were selected. Again, there were no significant differences in SHBG levels between patients with PE, RCIU or controls (345.5 (151.1), 383.8 (143.4) and 345.5 nmol/l (151.1), respectively). CONCLUSIONS: Maternal SHBG serum levels did not predict subsequent development of Pre-eclampsia and RCIU. PMID- 23096664 TI - [Frequency of pulmonary mycoses determined by analyzing lung secretion samples]. AB - BACKGROUND: The frequency of pulmonary mycoses has increased in the past few years specially in immunocompromised patients. AIM: To determine the frequency of invasive fungal diseases by analyzing lung secretion samples. MATERIAL AND METHODS: Samples of bronchoalveolar lavage (BAL) tracheal aspiration (TA) and induced sputum (IS) were obtained from patients of five hospitals in the Valparaiso Region for the diagnosis of invasive or non-invasive fungal disease, and pneumocystis (PCP), in the period 2007-2010. Clinical data of patients was obtained reviewing medical records or interviewing attending physicians. The diagnosis considered the clinical condition of the patient (immunocompromised or prior lung damage), computed tomography imaging, direct microscopy and cultures. European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria was used for the diagnosis of invasive fungal diseases. RESULTS: Ninety respiratory samples were received and 39 fungal infections were diagnosed. Eleven were probably invasive, seven were non-invasive and 21 were PCP. All patients with probable invasive disease had neutropenia. Most patients with non-invasive infections had bronchiectasis. Aspergillus fumigatus was the main causing agent in both invasive and non-invasive fungal diseases. Patients with PCP were mostly adults with AIDS and children with leukemia. The total mortality rate of patients with invasive fungal disease was of 73%. No deaths were recorded among patients with non-invasive disease. Among patients with PCP, three of 11 HIV and six of 10 non HIV subjects died. CONCLUSIONS: Aspergillus fumigatus predominates both in invasive and non-invasive pulmonary mycoses. The former has a high mortality. PCP occurred mainly in adult patients with HIV-AIDS. PMID- 23096665 TI - [Cardiovascular risk factors in a group of health care workers]. AB - BACKGROUND: Health promotion can be carried out at work places. AIM: To assess cardiovascular risk factors among workers of a University hospital. MATERIAL AND METHODS: Cross sectional study of 888 participants (aged 41 +/- 11 years, 76% women), who answered a survey about cardiovascular risk factors. Body mass index, waist, blood pressure and total cholesterol (TC) by capillary method were determined. RESULTS: Self reported prevalence of risk factors were as follows: 19% of participants had high blood pressure, 30% hypercholesterolemia, 6% diabetes, 41% smoked, 88% were sedentary and 26% had a family history of cardiovascular diseases. Five percent of participants did not have any risk factor, 20% had one risk factor, 32% had two and 43% had three or more. The highest frequency of lack of awareness was about blood glucose values. A high blood cholesterol level was found in 27% of those reporting normal cholesterol levels. Likewise, a high body mass index was found in 18% of those reporting a normal weight. CONCLUSIONS: The prevalence of cardiovascular risk factors in this group of participants is similar to that found in the last national health survey in Chile. Noteworthy is the lack of awareness about these risk factors. PMID- 23096666 TI - [Interests and perspectives of first and last year medical students]. AB - BACKGROUND: The interests that motivate medical students to study this career are diverse and they may change during the seven years of study. In Chile, 22 universities offer medicine and the number of graduated students has increased by more than 50% over the last 10 years. AIM: To determine the motivational profile of medical students at admission, and at the end of their career. SUBJECTS AND METHODS: A voluntary anonymous survey was applied to 275 first and 140 seventh year medical students from one traditional public and two private schools. RESULTS: The main reason for applying to medical school was social interest (68.7%), followed by interest in science and academia. Thirty six percent of students from seventh year would not study medicine again. In the seventh year, the interest in medical care persists in 88% of students, followed by academic interests in 64%. Only 24% had research interests. Fifty nine and 57% of students projected their medical work in private and public hospital settings, respectively. Only 11% projected themselves as doing research. Sixty nine percent of students would like to receive more information about post graduate education. CONCLUSIONS: There is a low interest in research and a high percentage of seventh year students that would not apply to medicine again. Medical schools should perform a systematic analysis of students' interests to improve faulty areas. PMID- 23096667 TI - [Evaluation of a teaching ambulatory module of respiratory diseases in the undergraduate medical curriculum]. AB - BACKGROUND: As the focus of healthcare provision shifts towards ambulatory care, increasing attention must now be given to develop opportunities for clinical teaching in this setting. AIM: To assess teacher and students' views about the strengths and weaknesses of real and simulated patient interactions for teaching undergraduate students clinical skills in the ambulatory setting. MATERIAL AND METHODS: Fourth-year medical students were exposed in a systematic way, during two weeks, to real and simulated patients in an outpatient clinic, who presented common respiratory problems, such as asthma, chronic obstructive pulmonary disease, smoking and sleep apnea syndrome. After the clinical interview, students received feedback from the tutor and their peers. The module was assessed interviewing the teachers and evaluating the results qualitatively. Students evaluated the contents and quality of teaching at the end of the rotation. RESULTS: Tutors identified the factors that facilitate ambulatory teaching. These depended on the module design, resources and patient care, of characteristics of students and their participation, leadership and interaction with professors. They also identified factors that hamper teaching activities such as availability of resources, student motivation and academic recognition. Most students evaluated favorably the interaction with real and simulated patients in the ambulatory setting. CONCLUSIONS: Teaching in the ambulatory setting was well evaluated by students and teachers. The use of qualitative methodology allowed contrasting the opinions of teachers and students. PMID- 23096668 TI - [Paretic neurosyphilis: report of five patients]. AB - We report five male patients, aged 35 to 63 years who suffered from paretic neurosyphilis. The clinical course was that of a subacute dementia with a frontal syndrome, with more apathy than euphoria. All were HIV negative and four were heterosexual. In all, the cerebrospinal fluid had a mononuclear pleocytosis and a positive VDRL. EEG was abnormal in the 3 cases in whom it was performed. One patient in whom a brain angiography was performed, had images of vasculitis. Treatment with 18-24 million units of penicillin per day during two weeks or more, was partially effective. PMID- 23096669 TI - [Metanephric adenoma of the kidney associated with polycythemia and erythromelalgia: report of one case]. AB - BACKGROUND: We report a 21-year-old male, presenting with erythromelalgia and polycythemia. A solid renal mass of the lower pole of the right kidney was discovered. The patient was subjected to a right open partial nephrectomy. The pathological study of the surgical specimen showed a metanephric adenoma of the kidney. The patient had an uneventful postoperative evolution. Currently the patient is in good health without evidence of recurrence of the tumor and normal hematological parameters. PMID- 23096670 TI - [Subcorneal pustular dermatosis: report of one case]. AB - BACKGROUND: We report a 35-year-old female patient with a one year history of a pustular and painful erythematous dermatitis, located in great folds, pubis and abdomen. She was evaluated in primary health care, receiving antifungal treatment, antimicrobials, topical and systemic non-steroidal anti-inflammatory drugs, with no response. A skin biopsy was compatible with subcorneal pustular dermatosis. She was initially treated with prednisone (0.8 mg/kg), observing a partial response. Therefore clotrimoxazole was initiated, obtaining an excellent response after 30 days of treatment. PMID- 23096671 TI - [Rosacea fulminans: report of two cases]. AB - BACKGROUND: Rosacea fulminans is a rare condition, characterized by a sudden onset of papulopustules, cysts, edema, and draining sinuses usually confined to the facial area. It is often accompanied by low-grade fever, myalgias and leukocytosis. Patients usually have a background of mild rosacea. We report two male patients aged 29 and 54 years, presenting with rosacea fulminans and ocular involvement, triggered by the use of topical steroids. Both responded to systemic treatment with corticosteroids, isotretinoin and metronidazole. Rosacea fulminans should be considered as a variant of rosacea that includes papulopustular, ocular, phymatous and erythematotelangiectatic types. PMID- 23096672 TI - [Meta-analysis of coronary artery bypass surgery compared to percutaneous transluminal angioplasty with stent in diabetic patients]. AB - BACKGROUND: Diabetic patients are a group of primary interest in the study of myocardial revascularization. AIM: To compare coronary artery bypass grafting surgery (CABG) and percutaneous angioplasty with stents (PCI-S) in diabetic patients with coronary three-vessel or left main coronary artery disease. MATERIAL AND METHODS: Meta-analysis of MEDLINE randomized controlled studies comparing CABG and PCI-S in diabetic patients. The primary outcome measure was major adverse cardiovascular events (MACCE), death, myocardial infarction, cerebrovascular accident (CVA) and coronary re-intervention. Secondary outcomes were the individual components of MACCE. RESULTS: Three studies comparing CABG and PCI-S met the inclusion criteria. One thousand sixty two patients were studied: 565 in the CABG group and 597 in the PCI-S group. At one year follow up MACCE occurred in 24.9 and 12.7% of patients in PCI-S and CABG groups, respectively (Odds ratio (OR) 2.27; 95% confidence intervals (CI) 1.66-3.09). There were no differences in death or myocardial infarction. Strokes were less common in the PCI-S group (OR 0.25, 95% CI0.09-0.68) and coronary re-intervention was required with higher frequency in the PCI-S group (OR 5.32, 95% CI 3.27 8.67). CONCLUSIONS: In diabetic patients with three-vessel coronary disease or left main coronary artery, revascularization with CABG had significantly less MACCE at one year than those treated with PCI-S. Stroke frequency was higher in CABG, coronary re-intervention was higher in PCI-S. These results must be interpreted cautiously. PMID- 23096673 TI - [Breast cancer in older women]. AB - BACKGROUND: Due to the increase in life expectancy in Chile, more than 10% of the population is 60 years or older. Since the incidence of most cancers increases with age, one of every two men and one in three women will develop a malignancy during their lifetime. In Chile breast cancer is the first leading cause of death from cancer among women. Its detection in postmenopausal women has steadily increased since the eighties, due to the expanded use of mammography. Less than 10% of patients participating in randomized controlled trials for the treatment of breast cancer, are older than 60 years, despite the fact that biological characteristics of breast cancer in older women are different and that most patients with breast cancer are of that age. Due to the high incidence of estrogen receptor positive tumors in this age group, most patients are candidates for hormone therapy. However, in those who need chemotherapy, therapeutic decisions are based on the existence of concomitant diseases and the tolerance to cytotoxic therapy. We review the relationship between age and cancer, the particular characteristics of breast cancer in older women and the alternatives of treatment with chemotherapy in advanced disease. PMID- 23096674 TI - [Narrative and faculty development: results of a five years experience with a creative writing workshop]. AB - BACKGROUND: Narrative medicine has showed to be a powerful instrument to reinforce relationships, identity, and self-knowledge among health professionals. Subjective issues have been recently recognized as relevant for faculty development in addition to the technical aspects. Since 2006 a creative writing workshop has been included as part of the Diploma in Medical Education at the medical school of the Pontificia Universidad Catolica de Chile. AIM: To describe the experience and results of the creative writing workshop (2006-2010). MATERIAL AND METHODS: Descriptive and retrospective study with a qualitative and quantitative design. Thirty-six teachers of the School of Medicine attended a 12 hour workshop. The Kirkpatrick model for evaluation of educational outcomes was used to report the data obtained in the course evaluation survey and in the stories produced. RESULTS: There were positive results at the four levels of Kirkpatrick evaluation model. The learning objectives of the workshop were achieved and 83 stories were created, compiled and published. CONCLUSIONS: The creative writing workshop can provide faculty with protected time for reflective practice about academic experiences and produce educational outcomes at different levels of the Kirkpatrick model. PMID- 23096676 TI - [Subgroup analyses: do they help or mislead when interpreting study results?]. PMID- 23096678 TI - [Positive psychology in medical education]. PMID- 23096679 TI - [It seems dermatological..., but it's neurological]. PMID- 23096680 TI - [New urinary markers in patients with prostatic cancer: analysis of the screening problem]. PMID- 23096681 TI - Isolation and in silico functional analysis of MtATP6, a 6-kDa subunit of mitochondrial F1F0-ATP synthase, in response to abiotic stress. AB - Mitochondrial F(1)F(0)-ATP synthase is a key enzymatic complex of energy metabolism that provides ATP for the cell. Subunits of this enzyme over-express under stress conditions. Little is known about the structure and regulatory mechanism of the F(0) portion of this enzyme. We isolated the full-length coding sequence of the RMtATP6 gene from rice and wheat, and partial sequences from Aegilops crassa and Triticum monococcum (Poaceae). We found that the sequence of rice RMtATP6 is 1965 bp long and contains two exons and one intron in 3'-UTR. Then, we analyzed the 2000-bp upstream region of the initiation codon ATG of the RMtATP6 and AtMtATP6, as promoter. The RMtATP6 coding sequence was found to be much conserved in the different plant species, possibly because of its key role under stress conditions. Promoter analysis demonstrated that RMtATP6 and AtMtATP6 include cis-acting elements such as ABRE, MYC/MYB, GT element in the upstream region, which respond to abscisic acid stress hormone and might show vital its roles in biotic and abiotic tolerance as an early-stress responsive gene. A mitochondrial signal peptide of 30 amino acids in length and an N terminal cleavage site between amino acids 20 and 21 were discovered in RMtATP6. In addition, we found a transmembrane domain with an alpha helix structure that possibly passed through the mitochondrial inner membrane and established the 6 kDa subunit in the F(0) portion of the enzyme complex. Apparently, under stress conditions, with increasing ATP consumption by the cell, the 6-kDa subunit accumulates; by switching on F(1)F(0)-ATP synthase it provides additional energy needed for cell homeostasis. PMID- 23096682 TI - Polymorphisms in the ovine myostatin gene are associated with birth weight but not with weight gain in Iranian Makoei sheep. AB - Myostatin, a transforming growth factor-beta superfamily member, has been well documented as a negative regulator of muscle growth and development. Myostatin, which has 376 amino acids, is synthesized as a precursor protein. Polymorphism of the myostatin gene in Makoei sheep was investigated by PCR and single-strand conformation polymorphism technique (SSCP). Genomic DNA of 92 sheep was isolated from whole blood. A 417-bp myostatin intron I segment was amplified by standard PCR, using locus-specific primers. Four SSCP patterns, representing four different genotypes, were identified. The frequencies of the genotypes were 0.413, 0.293, 0.130, and 0.163 for AD, AC, AE, and BC, respectively. Allele frequencies were 0.4185, 0.0815, 0.2283, 0.2065, and 0.0652 for A, B, C, D, and E, respectively. Observed heterozygosity was 0.7192. There was significant deviation from Hardy-Weinberg equilibrium for this locus. Analysis of myostatin gene sequences revealed heterozygous SNPs, which were in agreement with results obtained in the SSCP analysis. We concluded that SSCP analysis is a quick, sensitive and reliable technique for determination of DNA polymorphisms. The effect of these genotypes on some traits was investigated, and the AD genotype was found to be associated with birth weight. No phenotypic associations were detected with the other genotypes. No associations of myostatin variants with weight gain were detected. We conclude that polymorphism in the ovine myostatin gene is associated with birth weight, but not with weight gain in Iranian Makoei sheep. PMID- 23096683 TI - In silico characterization of three two-component systems of Ehrlichia canis and evaluation of a natural plant-derived inhibitor. AB - Two-component signal transduction systems (TCS) are important elements in the interaction of endobacteria with host cells. They are basically composed of two proteins, an environmental signal sensor and a response regulator, which activate genes involved in a wide range of bacterial responses to their environment. We analyzed three sets of genes corresponding to TCS of Ehrlichia canis, a common tick-borne canine pathogen and the etiologic agent of canine monocytic ehrlichiosis, in order to identify the characteristic domains of the sensor and response regulator components. Analysis of sequence alignments of the corresponding proteins indicated a high degree of similarity to other members of the Anaplasmataceae TCS proteins, demonstrating that they could be useful as universal targets for development of new drugs against these bacteria. We also evaluated by quantitative PCR inhibition of E. canis by (2H)-1,4-benzoxazin-3(4H) one (BOA), the core compound of the plant phenolic compound DIMBOA, which shows inhibitory action against TCS of the phytopathogen Agrobacterium tumefasciens. This bacterium exerts its pathogenicity by transferring oncogenic DNA (T-DNA) into plant cells; this transfer is mediated through a type-IV secretion system, which is regulated by the VirA/VirG TCS. The process of infection and pathogenesis of E. canis is associated with the secretion of effector proteins into the host cell cytoplasm through a T4SS system, which blocks the cell defense response. We suggest that BOA, and possibly other plant phenolic compounds that are TCS inhibitors, can be exploited in the search for new antiehrlichial drugs to be used alone or as complements in the treatment of canine monocytic ehrlichiosis. PMID- 23096684 TI - Molecular characterization of the pathogenic plant fungus Rhizoctonia solani (Ceratobasidiaceae) isolated from Egypt based on protein and PCR-RAPD profiles. AB - Twenty-one isolates of Rhizoctonia solani were categorized into three anastomosis groups consisting of AG-4-HG-I (eight isolates), AG-2-2 (nine isolates) and AG-5 (four isolates). Their pathogenic capacities were tested on cotton cultivar Giza 86. Pre-emergence damping-off varied in response to the different isolates; however, the differences were not significant. Soluble proteins of the fungal isolates were electrophoresed using SDS-PAGE and gel electrophoreses. A dendrogram of the protein banding patterns by the UPGMA of arithmetic means placed the fungal isolates into distinct groups. There was no evidence of a relationship between protein dendrogram, anastomosis grouping or level of virulence or geographic origin. The dendrogram generated from these isolates based on PCR analysis with five RAPD-PCR primers showed high levels of genetic similarity among the isolates from the same geographical locations. There was partially relationship between the genetic similarity and AGs or level of virulence or geographic origin based on RAPD dendrogram. These results demonstrate that RAPD technique is a useful tool in determining the genetic characterization among isolates of R. solani. PMID- 23096685 TI - Spittle protein profile of Mahanarva spectabilis (Hemiptera: Cercopidae) fed various elephant grass genotypes. AB - An understanding of the interaction between spittlebugs and forage grasses is essential for establishing factors that favor productive pastures. In the present study, we evaluated the protein profiles of the spittle of Mahanarva spectabilis (Distant, 1909) (Hemiptera: Cercopidae) fed various elephant grass genotypes. Each plant was infested with a single fifth-instar M. spectabilis. After 24 h, samples of the spittle produced by each nymph were collected and stored at -20 degrees C, after which their protein profiles were analyzed. The exclusivity or interactions of the proteins present in the spittle produced by the insects revealed the susceptibility of the tested genotypes. The results indicate that groups of genotypes show identical spittle protein profiles when subjected to attack by spittlebugs. Resistant and susceptible elephant grass genotypes exhibited high similarity indices within each group. The similarity index was low for the resistance control species (Brachiaria brizantha) compared with that of the tested elephant grass genotypes. Qualitative and quantitative studies of the proteins expressed in the most promising materials will be performed in an ongoing genetic improvement program seeking to develop genotypes resistant to spittlebugs, which are the main biotic pests of elephant grasses. PMID- 23096686 TI - Evolutive and structural characterization of Nostoc commune iron-superoxide dismutase that is fit for modification. AB - Superoxide dismutase (SOD) has extensive clinical applications for protecting organisms from toxic oxidation. In this study, the integrated iron-superoxide dismutase gene (fe-sod) coding sequence of Nostoc commune stain CHEN was cloned from genomic DNA and compared to sods from other reported algae. These analyses of immunology and phylogenetics indicated that this Fe-SOD is considerably homologous with SODs from lower prokaryotes (Fe-SOD or Mn-SOD) but not those from higher animals (Cu/Zn-SOD). In addition, the N. commune Fe-SOD shows 67 to 93% protein sequence identity to 10 other algal Fe-SODs (or Mn-SODs) and 69 to 93% gene sequence identity. Rare nonsynonymous substitutions imply that algal SODs are being subjected to strong natural selection. Interestingly, the N. commune Fe-SOD enzyme molecule has a compact active center that is highly conserved (38.1% of residues are absolutely conserved), and 2 loose ends localized outside the molecule and inclined to mutate (only 11.5% of residues are absolutely conserved). Based on associative analyses of evolution, structure, and function, this special phenomenon is attributed to function dependent evolution through negative natural selection. Under strong natural selection, although the mutation is random on the gene level, the exterior region is inclined to mutate on the protein level owing to more nonsynonymous substitutions in the exterior region, which demonstrates the theoretical feasibility of modifying Fe-SOD on its ends to overcome its disadvantages in clinical applications. PMID- 23096687 TI - Association of p53 Arg72Pro and MDM2 SNP309 polymorphisms with glioma. AB - Epidemiological studies of the association of variants p53 Arg72Pro and MDM2 single-nucleotide polymorphism 309 (SNP309) with glioma risk have produced inconsistent results. The aim of the current study was to evaluate the association of these 2 variants with glioma susceptibility using a meta-analysis approach. For p53 Arg72Pro, 10 case-control studies including 2587 glioma patients and 4061 unrelated controls were identified. The pooled odds ratios (ORs) for Arg/Pro heterozygotes and Pro/Pro homozygotes were 1.08 [95% confidence interval (95%CI) = 0.85-1.37] and 1.08 (95%CI = 0.85-1.36), respectively, when compared to Arg/Arg carriers. Under the dominant effect model, Pro allele carriers also showed no significantly elevated glioma risk (pooled OR = 1.11, 95%CI = 0.90-1.38), and similar results were found under the recessive-effect model (pooled OR = 1.17, 95%CI = 0.85-1.61). For variant MDM2 SNP309, 3 case-control studies including 606 cases and 309 controls were identified. A marginal association with glioma risk was found for heterozygous G/T carriers (pooled OR = 1.95, 95%CI = 1.00- 3.81), whereas homozygous G/G carriers showed an increased but not significantly elevated risk of glioma (pooled OR = 2.14, 95%CI = 0.71-6.45) compared with that of T/T homozygotes. We also found no significant association between the MDM2 SNP309 polymorphism and glioma risk (pooled OR = 1.86, 95%CI = 0.94-3.67 and pooled OR = 1.25, 95%CI = 0.62-2.56, respectively) under the dominant and recessive models. Taken together, the current data suggested that the 2 polymorphisms may not contribute to glioma susceptibility. PMID- 23096688 TI - Stability analysis of oil yield in oil palm (Elaeis guineensis) progenies in different environments. AB - We evaluated 38 dura x pisifera (DP) oil palm progenies in four locations in Malaysia for genotype by environment interaction and genotypic stability studies. The DP progenies derived from crosses between pisifera palms of AVROS, Serdang S27B, Serdang 29/36, and Lever Cameroon were chosen to be the males' parent and Deli dura palms designated as females' parent. All the locations differed in terms of soil physical and chemical properties, and the soil types ranged from coastal clay to inland soils. The genotype by environment interaction and stability of the individual genotypes were analyzed for oil yield trait using several stability techniques. A genotype by environment interaction was detected for oil yield and it had a larger variance component than genotypic variance (sigma(2)(gl)/sigma(2)(g) = 139.7%). Genotype by environment interaction of oil yield was largely explained by a non-linear relationship between genotypic and environmental values. Overall assessment of individual genotypic stability showed that seven genotypes were highly stable and had consistent performance over the environments for the oil yield trait [total individual genotype stability scored more than 10 and mean oil yielded above the average of the environment (genotype means are more than 34.37 kg.palm(-1).year(-1))]. These genotypes will be useful for oil palm breeding and tissue culture programs for developing high oil yielding planting materials with stable performance. PMID- 23096689 TI - Expression of splice variants of cancer-testis genes ODF3 and ODF4 in the testis of a prostate cancer patient. AB - The outer dense fiber (ODF) genes encode proteins that co-assemble along the axoneme of the sperm tail. Recently, it was demonstrated that some ODF genes are aberrantly expressed in tumors, including prostate adenocarcinoma, basal cell carcinoma, and chronic myeloid lymphoma. We cloned ODF3 and ODF4 cDNA from the testis of a patient suffering from prostate adenocarcinoma and found two alternative splice variants of these genes. PMID- 23096690 TI - RAPD fingerprint construction and genetic similarity of Mesona chinensis (Lamiaceae) in China. AB - Mesona chinensis is an economically important agricultural crop, primarily cultivated for making grass jelly. It was originally discovered in South China. We examined 18 cultivars, including cultivars from Guangdong, Fujian, and Guangxi, China, Taiwan, and Indonesia, and a hybrid (a cross between cultivars from Indonesia and Guangdong), based on RAPD markers. The genetic similarity coefficient was calculated by NTSYS 2.10 and the clustering analysis was made by UPGMA. PCR amplification with 10 primers produced 163 bands; 94% of the amplified loci were polymorphic. The primers S208, S206, and S253 could completely distinguish all 19 samples by constructing a DNA fingerprint. Cluster analysis divided the 19 cultivars into five groups, with an overall genetic similarity coefficient of 0.68. Correlations were found among regional distributions, parental sources, and RAPD markers, demonstrating the rich genetic diversity of these 19 cultivars of M. chinensis. This study provides useful information for the classification, identification, and breeding of M. chinensis. PMID- 23096691 TI - Mitochondrial haplogroup D4 confers resistance and haplogroup B is a genetic risk factor for high-altitude pulmonary edema among Han Chinese. AB - High-altitude pulmonary edema (HAPE) is a life-threatening condition caused by acute exposure to high altitude. Accumulating evidence suggests that genetic factors play an important role in the etiology of HAPE. However, conclusions from association studies have been hindered by limited sample size due to the rareness of this disease. It is known that mitochondria are critical for hypoxic adaptation, and mitochondrial malfunction can be an important factor in HAPE development. Therefore, we tested the hypothesis that mitochondrial DNA haplotypes and polymorphisms affect HAPE susceptibility. We recruited 204 HAPE patients and 174 healthy controls in Tibet (3658 m above sea level), all Han Chinese, constituting the largest sample size of all HAPE vulnerability studies. Among mtDNA haplogroups, we found that haplogroup D4 is associated with resistance to HAPE, while haplogroup B is a genetic risk factor for this condition. Haplogroup D4 (tagged by 3010A) may enhance the stability of 16S rRNA, resulting in reduced oxidative stress and protection against HAPE. Within haplogroup B, subhaplogroup B4c (tagged by 15436A and 1119C) was associated with increased risk for HAPE, while subhaplogroup B4b may protect against HAPE. We indicate that there are differences in HAPE susceptibility among mtDNA haplogroups. We conclude that mitochondria are involved in adverse reactions to acute hypoxic exposure; our finding of differences in susceptibility as a function of mitochondrial DNA haplotype may shed light on the pathogenesis of other disorders associated with hypoxia, such as chronic obstructive pulmonary disease. PMID- 23096692 TI - Small molecule-enrichment analysis in response to osmotic stimuli in the intervertebral disc. AB - The intervertebral disc (IVD) is a heterogeneous structure that contributes to load support and flexibility in the spine. IVD cells experience a broad range of physical stimuli under physiological conditions, including alterations in their osmotic environment. To date, the molecular mechanisms regulating the response of IVD to osmotic pressure are still not well understood. We obtained the gene expression profile of human IVD cells from NCBI and looked for potential therapeutic drug candidates. Based on microarray data, we concluded that RAP2A and GNA13 appear to have a role in response to osmotic stimuli in intervertebral discs. Using a computational bioinformatics method, we determined that thioridazine has potential as a therapeutic drug candidate for regulating osmotic pressure changes in IVD cells. We anticipate that our results will be used to generate hypotheses for laboratory, patient, and population-based studies. PMID- 23096693 TI - Co-evolution of genomic islands and their bacterial hosts revealed through phylogenetic analyses of 17 groups of homologous genomic islands. AB - Horizontal gene transfer is an important mechanism for the evolution of microbial genomes, and many horizontal gene transfer events are facilitated by genomic islands (GIs). Until now, few reports have provided evidence for the co evolution of horizontally transferred genes and their hosts. We obtained 17 groups of homologous GIs, all of which appear in 8 or more bacterial strains of the same species or genus. Using phylogenetic analyses, we found that the topological structure of a distance tree based on the proteins of each group of homologous GIs was consistent with that based on the complete proteomes of the hosts. This result clearly indicates that GIs and their bacterial hosts have co evolved. In addition to presenting and providing evidence for a novel concept, i.e., the co-evolution of GIs and their bacterial hosts, we also describe a new and interesting detail for the phylogenetic analysis of horizontally transferred genes: consistent phylogenetic trees can be obtained by focusing on homologous GIs despite the commonly accepted theory that the phylogenies of horizontally transferred sequences and host organisms should be inconsistent. PMID- 23096694 TI - Novel SNPs of the mannan-binding lectin 2 gene and their association with production traits in Chinese Holsteins. AB - The mannan-binding lectin gene (MBL) participates as an opsonin in the innate immune system of mammals, and single nucleotide polymorphisms (SNPs) in MBL cause various immune dysfunctions. In this study, we detected SNPs in MBL2 at exon 1 using polymerase chain reaction single-strand conformation polymorphism analysis and DNA sequencing techniques in 825 Chinese Holstein cows. Four new SNPs with various allele frequencies were also found. The g.1164 G>A SNP was predicted to substitute arginine with glutamine at the N-terminus of the cysteine-rich domain. In the collagen-like domain, SNPs g.1197 C>A and g.1198 G>A changed proline to glutamine, whereas SNP g.1207 T>C was identified as a synonymous mutation. Correlation analysis showed that the g.1197 C>A marker was significantly correlated to somatic cell score (SCS), and the g.1164 G>A locus had significant effects on SCS, fat content, and protein content (P < 0.05), suggesting possible roles of these SNPs in the host response against mastitis. Nine haplotypes and nine haplotype pairs corresponding to the loci of the 4 novel SNPs were found in Chinese Holsteins. Haplotype pairs MM, MN, and BQ were correlated with the lowest SCS; MN with the highest protein yield; MM with the highest protein rate, and MN with the highest 305- day milk yield. Thus, MM, MN, and BQ are possible candidates for marker-assisted selection in dairy cattle breeding programs. PMID- 23096695 TI - Isolation and identification of the immune-relevant ribosomal protein L10 (RPL10/QM-like gene) from the large yellow croaker Pseudosciaena crocea (Pisces: Sciaenidae). AB - In order to investigate the immune role of ribosomal protein L10 (RPL10/QM-like gene) in marine fish, we challenged the large yellow croaker Pseudosciaena (= Larimichthys) crocea, the most important marine fish culture species in China, by injection with a mixture of the bacteria Vibrio harveyi and V. parahaemolyticus (3:1 in volume). Microarray analysis and real-time PCR were performed 24 and 48 h post-challenge to isolate and identify the QM-like gene from the gill P. crocea (designated PcQM). The expression level of the PcQM gene did not changed significantly at 24 h post-challenge, but was significantly downregulated at 48 h post-challenge, suggesting that the gene had an immune-modulatory effect in P. crocea. Full-length PcQM cDNA and genomic sequences were obtained by rapid amplification of cDNA ends (RACE)-PCR. The sequence of the PcQM gene clustered together with those of other QM-like genes from other aquatic organisms, indicating that the QM-like gene is highly conserved in teleosts. PMID- 23096697 TI - Host range and genetic diversity of croton yellow vein mosaic virus, a weed infecting monopartite begomovirus causing leaf curl disease in tomato. AB - Croton yellow vein mosaic virus (CYVMV) is a widely occurring begomovirus in Croton bonplandianum, a common weed in the Indian subcontinent. In this study, CYVMV (genus Begomovirus, family Geminiviridae) was transmitted by whiteflies (Bemisia tabaci) to as many as 35 plant species belonging to 11 families, including many vegetables, tobacco varieties, ornamentals and weeds. CYVMV produced bright yellow vein symptoms in croton, whereas in all the other host species, the virus produced leaf curl symptoms. CYVMV produced leaf curl in 13 tobacco species and 22 cultivars of Nicotiana tabacum and resembled tobacco leaf curl virus (TobLCV) in host reactions. However, CYVMV was distinguished from TobLCV in four differential hosts, Ageratum conyzoides, C. bonplandianum, Euphorbia geniculata and Sonchus bracyotis. The complete genome sequences of four isolates originating from northern, eastern and southern India revealed that a single species of DNA-A and a betasatellite, croton yellow vein mosaic betasatellite (CroYVMB) were associated with the yellow vein mosaic disease of croton. The sequence identity among the isolates of CYVMV DNA-A and CroYVMB occurring in diverse plant species was 91.8-97.9 % and 83.3-100 %, respectively. The CYVMV DNA-A and CroYVMB generated through rolling-circle amplification of the cloned DNAs produced typical symptoms of yellow vein mosaic and leaf curling in croton and tomato, respectively. The progeny virus from both the croton and tomato plants was transmitted successfully by B. tabaci. The present study establishes the etiology of yellow vein mosaic disease of C. bonplandianum and provides molecular evidence that a weed-infecting monopartite begomovirus causes leaf curl in tomato. PMID- 23096696 TI - Expression of the luteinizing hormone receptor (LHR) gene in ovine non-gonadal tissues during estrous cycle. AB - Luteinizing hormone (LH) is an important glycoprotein hormone that regulates gonadal function in mammals and in turn regulates physiological status changes during the estrous cycle. The function of LH is mediated by luteinizing hormone receptor (LHR). In order to examine the expression patterns of the LHR gene in non-gonadal tissues during the 4 phases of the ovine estrous cycle, tissues from healthy non-pregnant adult Hu sheep were examined according to the estrous cycle for normal ovaries using real-time fluorescence quantitative PCR and ELISA methods with GAPDH as the reference gene. LHR mRNA expression levels were significantly correlated with protein concentrations and the LHR gene was abundantly expressed in olfactory bulb, hypothalamus, rumen, small intestine, kidney, and uterine tissues. When comparing the expression levels of LHR during the 4 estrous phases in particular tissues, the results showed that LHR expression levels were significantly different and relatively lower at the estrous stage in a number of non-gonadal tissues. The trends of change in LHR expression levels were highly significantly correlated between hypothalamus and rectum, hypophysis and oviduct, ileum and uterus, and among jejunum, olfactory bulb, and kidney (P < 0.01), and there was also significant correlation between duodenum and oviduct, hypothalamus and medulla oblongata, jejunum and uterus, omasum and abomasum, and reticulum and colon (P < 0.05). These results indicate that the ovine LHR gene (or LH) might control important mechanisms in non gonadal tissues and that the level of LH activity in some tissues may be influenced by hormonal status during the estrous cycle. PMID- 23096698 TI - Pancreatic ductal adenocarcinoma is associated with a distinct urinary metabolomic signature. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor prognosis in part due to the lack of early detection and screening methods. Metabolomics provides a means for noninvasive screening of tumor associated perturbations in cellular metabolism. METHODS: Urine samples of PDAC patients (n = 32), healthy age and gender-matched controls (n = 32), and patients with benign pancreatic conditions (n = 25) were examined using (1)H-NMR spectroscopy. Targeted profiling of spectra permitted quantification of 66 metabolites. Unsupervised (principal component analysis, PCA) and supervised (orthogonal partial-least squares discriminant analysis, OPLS-DA) multivariate pattern recognition techniques were applied to discriminate between sample spectra using SIMCA-P(+) (version 12, Umetrics, Sweden). RESULTS: Clear distinction between PDAC and controls was noted when using OPLS-DA. Significant differences in metabolite concentrations between cancers and controls (p < 0.001) were noted. Model parameters for both goodness of fit, and predictive capability were high (R (2) = 0.85; Q (2) = 0.59, respectively). Internal validation methods were used to confirm model validity. Sensitivity and specificity of the multivariate OPLS-DA model were summarized using a receiver operating characteristics (ROC) curve, with an area under the curve (AUROC) = 0.988, indicating strong predictive power. Preliminary analysis revealed an AUROC = 0.958 for the model of benign pancreatic disease compared with PDAC, and suggest that the cancer-associated metabolomic signature dissipates following RO resection. CONCLUSIONS: Urinary metabolomics detected distinct differences in the metabolic profiles of pancreatic cancer compared with healthy controls and benign pancreatic disease. These preliminary results suggest that metabolomic approaches may facilitate discovery of novel pancreatic cancer biomarkers. PMID- 23096699 TI - Factors affecting prognosis of patients with giant cell tumors of the mobile spine: retrospective analysis of 102 patients in a single center. AB - BACKGROUND: Giant cell tumor (GCT) of the mobile spine is a benign tumor, but it can be potentially aggressive. There is not much published information on GCT of the mobile spine as a result of rarity of the disease, and there are controversies over prognostic factors of the condition. METHODS: A retrospective analysis of GCT of the mobile spine was performed by survival analysis. Recurrence-free survival (RFS) was defined as the interval between the date of surgery and the date of recurrence. The postoperative RFS rate was estimated by the Kaplan-Meier method. Factors with P values of <=0.1 were subjected to multivariate analysis for RFS by proportional hazard analysis. P values of <=0.5 were considered statistically significant. RESULTS: A total of 102 patients with GCT of the mobile spine were included in the study. The mean follow-up period was 39.9 (median 26.0, range 2-153) months. Thirty-eight patients developed recurrence. The univariate and multivariate analysis suggested that age less than 40 years, total spondylectomy either by en bloc or piecemeal method, and administration of bisphosphonate were independent favorable prognostic factors. Subgroup analysis by excluding patients before the year 2000 further confirmed our findings. CONCLUSIONS: The removal of the entire osseous compartment either by en bloc or piecemeal method in combination with the long-term use of bisphosphonate could significantly reduce the recurrence rate of GCT of the mobile spine. Age less than 40 years is a favorable prognostic factor for GCT in the mobile spine. PMID- 23096700 TI - Copy number variation analysis in 98 individuals with PHACE syndrome. AB - PHACE syndrome is the association of large segmental facial hemangiomas and congenital anomalies, such as posterior fossa malformations, cerebral arterial anomalies, coarctation of the aorta, eye anomalies, and sternal defects. To date, the reported cases of PHACE syndrome have been sporadic, suggesting that PHACE may have a complex pathogenesis. We report here genomic copy number variation (CNV) analysis of 98 individuals with PHACE syndrome as a first step in deciphering a potential genetic basis of PHACE syndrome. A total of 3,772 CNVs (2,507 duplications and 1,265 deletions) were detected in 98 individuals with PHACE syndrome. CNVs were then eliminated if they failed to meet established criteria for quality, spanned centromeres, or did not contain genes. CNVs were defined as "rare" if not documented in the database of genomic variants. Ten rare CNVs were discovered (size range: 134-406 kb), located at 1q32.1, 1q43, 3q26.32 3q26.33, 3p11.1, 7q33, 10q24.32, 12q24.13, 17q11.2, 18p11.31, and Xq28. There were no rare CNV events that occurred in more than one subject. Therefore, further study is needed to determine the significance of these CNVs in the pathogenesis of PHACE syndrome. PMID- 23096701 TI - Transcription factor Ctip2 controls epidermal lipid metabolism and regulates expression of genes involved in sphingolipid biosynthesis during skin development. AB - The stratum corneum is composed of protein-enriched corneocytes embedded in an intercellular matrix of nonpolar lipids organized as lamellar layers and giving rise to epidermal permeability barrier (EPB). EPB defects have an important role in the pathophysiology of skin diseases such as eczema. The transcriptional control of skin lipid metabolism is poorly understood. We have discovered that mice lacking transcription factor COUP-TF-interacting protein 2 (Ctip2) exhibit EPB defects including altered keratinocyte terminal differentiation, delayed skin barrier development, and interrupted neutral lipid distribution in the epidermis. Here we adapted a targeted lipidomic approach using mass spectrometry and have determined that Ctip2(-/-) mice (germline deletion of the Ctip2 gene) display altered composition of major epidermal lipids, such as ceramides and sphingomyelins, compared with wild-type mice at different stages of skin development. Interestingly, expressions of several genes involved in skin sphingolipid biosynthesis and metabolism were altered in mutant skin. Ctip2 was found to be recruited to the promoter region of a subset of those genes, suggesting their possible direct regulation by Ctip2. Our results confirm an important role of Ctip2 in regulating skin lipid metabolism and indicate that profiling of epidermal sphingolipid could be useful for designing effective strategies to improve barrier dysfunctions. PMID- 23096702 TI - NRAS and BRAF mutations in cutaneous melanoma and the association with MC1R genotype: findings from Spanish and Austrian populations. AB - There is increasing epidemiologic and molecular evidence that cutaneous melanomas arise through multiple causal pathways. To further define the pathways to melanoma, we explored the relationship between germline and somatic mutations in a series of melanomas collected from 134 Spanish and 241 Austrian patients. Tumor samples were analyzed for melanocortin-1 receptor (MC1R) variants and mutations in the BRAF and NRAS genes. Detailed clinical data were systematically collected from patients. We found that NRAS-mutant melanomas were significantly more likely from older patients and BRAF-mutant melanomas were more frequent in melanomas from the trunk. We observed a nonsignificant association between germline MC1R status and somatic BRAF mutations in melanomas from trunk sites (odds ratio (OR) 1.8 (0.8-4.1), P=0.1), whereas we observed a significant inverse association between MC1R and BRAF for melanomas of the head and neck (OR 0.3 (0.1-0.8), P=0.02). This trend was observed in both the Spanish and Austrian populations. PMID- 23096703 TI - Suppression of UV-induced wrinkle formation by induction of HSP70 expression in mice. AB - UV-induced wrinkle formation owing to the degeneration of the extracellular matrix (ECM) is a major dermatological problem in which abnormal activation of matrix metalloproteinases (MMPs) and elastases have important roles. Heat shock protein 70 (HSP70) has cytoprotective and anti-inflammatory activities. In this study, we examined the effect of HSP70 expression on UV-induced wrinkle formation. Mild heat treatment (exposure to heated water at 42 degrees C) of the dorsal skin of hairless mice induced the expression of HSP70. The long-term repeated exposure to UV induced epidermal hyperplasia, decreased skin elasticity, degeneration of ECM, and wrinkle formation, which could be suppressed in mice concomitantly subjected to this heat treatment. The UV-induced epidermal hyperplasia, decreased skin elasticity, and degeneration of ECM were less apparent in transgenic mice expressing HSP70 than in wild-type mice. UV-induced fibroblast cell death, infiltration of inflammatory cells, and activation of MMPs and elastase in the skin were also suppressed in the transgenic mice. This study provides evidence for an inhibitory effect of HSP70 on UV-induced wrinkle formation. The results suggest that this effect is mediated by various properties of HSP70, including its cytoprotective and anti-inflammatory activities. We propose that HSP70 inducers used in a clinical context could prove beneficial for the prevention of UV-induced wrinkle formation. PMID- 23096705 TI - Retinoid metabolism is altered in human and mouse cicatricial alopecia. AB - C57BL/6 mice develop dermatitis and scarring alopecia resembling human cicatricial alopecias (CAs), particularly the central centrifugal CA (CCCA) type. To evaluate the role of retinoids in CA, the expression of retinoid metabolism components were examined in these mice with mild, moderate, or severe CA compared with hair cycle-matched mice with no disease. Two feeding studies were conducted with dams fed either NIH 31 diet (study 1) or AIN93G diet (study 2). Adult mice were fed AIN93M diet with 4 (recommended), 28, or 56 IU vitamin A g(-1) diet. Feeding the AIN93M diet to adults increased CA frequency over NIH 31 fed mice. Increased follicular dystrophy was seen in study 1 and increased dermal scars in study 2 in mice fed the 28 IU diet. These results indicate that retinoid metabolism is altered in CA in C57BL/6J mice that require precise levels of dietary vitamin A. Human patients with CCCA, pseudopelade (end-stage scarring), and controls with no alopecia were also studied. Many retinoid metabolism proteins were increased in mild CCCA, but were undetectable in pseudopelade. Studies to determine whether these dietary alterations in retinoid metabolism seen in C57BL/6J mice are also involved in different types of human CA are needed. PMID- 23096707 TI - gamma-Secretase mutations in hidradenitis suppurativa: new insights into disease pathogenesis. AB - Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin condition of unclear etiology. It may segregate as an autosomal dominant trait, and heterozygous mutations in the gamma-secretase genes NCSTN, PSENEN, and PSEN1 have recently been reported in a small number of multiplex kindreds and sporadic cases. These mutations highlight gamma-secretase (an enzyme that has been extensively investigated in familial Alzheimer's disease) to have an integral role in cutaneous biology and, more specifically, in HS. In this article, we review the recent genetic data, how they inform disease pathogenesis, and the long-term implications in HS and related diseases. PMID- 23096706 TI - MAGE-C2 promotes growth and tumorigenicity of melanoma cells, phosphorylation of KAP1, and DNA damage repair. AB - Melanoma-associated antigen-encoding (MAGE) genes are expressed in melanoma and other cancers but not in normal somatic cells. MAGE expression is associated with aggressive tumor growth, poor clinical outcome, and resistance to chemotherapy, but the mechanisms have not been completely elucidated. In this study, we show that downregulation of MAGE-C2 in A375 melanoma cells and low-passage cultures from human metastatic melanomas (MRA cells) results in increased apoptosis and decreased growth of tumor xenografts in athymic nude mice. Previously, we showed that MAGE-C2 binds KAP1, a scaffolding protein that regulates DNA repair. Phosphorylation of KAP1-Serine 824 (Ser824) by ataxia-telangiectasia-mutated (ATM) kinase is necessary for repair of DNA double-strand breaks (DSBs); now we show that MAGE-C2 knockdown reduces, whereas MAGE-C2 overexpression increases, ATM kinase-dependent phosphorylation of KAP1-Ser824. We demonstrate that MAGE-C2 increases co-precipitation of KAP1 with ATM and that binding of MAGE-C2 to KAP1 is necessary for increased KAP1-Ser824 phosphorylation. Furthermore, ectopic expression of MAGE-C2 enhances repair of I-SceI endonuclease-induced DSBs in U 2OS cells. As phosphorylation of KAP1-Ser824 facilitates relaxation of heterochromatin, which is necessary for DNA repair and cellular proliferation, our results suggest that MAGE-C2 can promote tumor growth by phosphorylation of KAP1-Ser824 and by enhancement of DNA damage repair. PMID- 23096708 TI - Epigallocatechin-3-gallate improves acne in humans by modulating intracellular molecular targets and inhibiting P. acnes. AB - Acne vulgaris is a highly prevalent skin disorder characterized by hyperseborrhea, inflammation, and Propionibacterium acnes overgrowth. Only isotretinoin and hormonal therapy reduce sebum production. To identify a new drug candidate that modulates sebum, we examined the effects of EGCG, the major polyphenol in green tea, on human SEB-1 sebocytes and in patients with acne. In SEB-1 sebocytes, we found that EGCG reduced sebum by modulating the AMPK-SREBP-1 signaling pathway. EGCG also reduces inflammation by suppressing the NF-kappaB and AP-1 pathways. EGCG also induces cytotoxicity of SEB-1 sebocytes via apoptosis and decreases the viability of P. acnes, thus targeting almost all the pathogenic features of acne. Finally, and most importantly, EGCG significantly improved acne in an 8-week randomized, split-face, clinical trial, and was well tolerated. Our data provide a therapeutic rationale for the use of EGCG in acne. PMID- 23096709 TI - Mosaic activating RAS mutations in nevus sebaceus and nevus sebaceus syndrome. PMID- 23096710 TI - Treatment of dermal fibroblasts with GPI-anchored human TIMP-1 protein moderates processes linked to scar formation. AB - Tissue inhibitors of metalloproteinases exhibit diverse physiological/biological functions including moderation of the proteolytic processing of growth factors and turnover of extracellular matrix. These various biological activities are linked in part to the stoichiometry of tissue inhibitor of metalloprotein/matrix metalloprotein (TIMP/MMP)/surface protein interactions. TIMP-1, a secreted protein, can be detected on the cell surface only through its interaction with surface-bound proteins. Proteins anchored by glycosylphosphatidylinositol (GPI), when purified and added to cells or tissues, are efficiently incorporated into their surface membranes. A GPI anchor was fused to TIMP-1 to focus defined concentrations of the inhibitory protein independently on the surface of primary dermal fibroblast cells. Exogenously added recombinant TIMP-1-GPI effectively inserted into the cell membrane of fibroblasts blocked the secretion of MMPs and markedly altered the stoichiometry of MMP association with the cell surface. TIMP 1-GPI treatment resulted in inhibition of fibroblast-reduced proliferation, and transiently reduced expression of fibrosis-associated genes. These effects were dose dependent. Treated cells also showed a more proapoptotic phenotype based on apoptotic assays and western blot analysis for apoptosis-associated protein expression. GPI-anchored TIMP-1 may represent a more effective version of the protein for use in therapeutic approaches to help control fibrosis and scar formation. PMID- 23096711 TI - Lysophosphatidic acid promotes cell migration through STIM1- and Orai1-mediated Ca2+(i) mobilization and NFAT2 activation. AB - Lysophosphatidic acid (LPA) enhances cell migration and promotes wound healing in vivo, but the intracellular signaling pathways regulating these processes remain incompletely understood. Here we investigated the involvement of agonist-induced Ca(2+) entry and STIM1 and Orai1 proteins in regulating nuclear factor of activated T cell (NFAT) signaling and LPA-induced keratinocyte cell motility. As monitored by Fluo-4 imaging, stimulation with 10 MUM LPA in 60 MUM Ca(2+)(o) evoked Ca(2+)(i) transients owing to store release, whereas addition of LPA in physiological 1.2 mM Ca(2+)(o) triggered store release coupled to extracellular Ca(2+) entry. Store-operated Ca(2+) entry (SOCE) was blocked by the SOCE inhibitor diethylstilbestrol (DES), STIM1 silencing using RNA interference (RNAi), and expression of dominant/negative Orai1(R91W). LPA induced significant NFAT activation as monitored by nuclear translocation of green fluorescent protein-tagged NFAT2 and a luciferase reporter assay, which was impaired by DES, expression of Orai1(R91W), and inhibition of calcineurin using cyclosporin A (CsA). By using chemotactic migration assays, LPA-induced cell motility was significantly impaired by STIM1, CsA, and NFAT2 knockdown using RNAi. These data indicate that in conditions relevant to epidermal wound healing, LPA induces SOCE and NFAT activation through Orai1 channels and promotes cell migration through a calcineurin/NFAT2-dependent pathway. PMID- 23096712 TI - Whole-exome sequencing reveals somatic mutations in HRAS and KRAS, which cause nevus sebaceus. PMID- 23096713 TI - Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. AB - The dermal extracellular matrix (ECM) provides strength and resiliency to skin. The ECM consists mostly of type I collagen fibrils, which are produced by fibroblasts. Binding of fibroblasts to collagen fibrils generates mechanical forces, which regulate cellular morphology and function. With aging, collagen fragmentation reduces fibroblast-ECM binding and mechanical forces, resulting in fibroblast shrinkage and reduced function, including collagen production. Here, we report that these age-related alterations are largely reversed by enhancing the structural support of the ECM. Injection of dermal filler, cross-linked hyaluronic acid, into the skin of individuals over 70 years of age stimulates fibroblasts to produce type I collagen. This stimulation is associated with localized increase in mechanical forces, indicated by fibroblast elongation/spreading, and mediated by upregulation of type II TGF-beta receptor and connective tissue growth factor. Interestingly, enhanced mechanical support of the ECM also stimulates fibroblast proliferation, expands vasculature, and increases epidermal thickness. Consistent with our observations in human skin, injection of filler into dermal equivalent cultures causes elongation of fibroblasts, coupled with type I collagen synthesis, which is dependent on the TGF-beta signaling pathway. Thus, fibroblasts in aged human skin retain their capacity for functional activation, which is restored by enhancing structural support of the ECM. PMID- 23096714 TI - Isotretinoin use and the risk of inflammatory bowel disease: a population-based cohort study. AB - Limited evidence suggests that isotretinoin may be associated with inflammatory bowel disease (IBD). To explore this association, we conducted a retrospective population-based cohort study in British Columbia, Canada, among participants who were newly treated with isotretinoin or topical acne medications. The entire population of untreated provincial residents aged 12-29 years served as the reference group. During the 12-year study period, we identified 46,922 participants treated with isotretinoin, 184,824 treated with a topical acne medication, and 1,526,946 untreated individuals. Compared with untreated individuals, we observed no significant association between isotretinoin use and IBD (rate ratio (RR) 1.14; 95% confidence interval (CI) 0.92-1.41). As expected, we found no association with topical acne medications (RR 1.11; 95% CI 0.99 1.24). In prespecified secondary analyses, isotretinoin was associated with IBD among individuals aged 12-19 years (RR 1.39; 95% CI 1.03-1.87) and topical acne medications were associated with ulcerative colitis (RR 1.19; 95% CI 1.00-1.42). Our primary analyses found no association between isotretinoin and IBD. In prespecified secondary analyses, some evidence was found of associations with isotretinoin as well as topical acne medications, suggesting a possible association between IBD and acne itself. Additional research is needed to explore this possibility. PMID- 23096715 TI - Autoimmune disease induction in a healthy human organ: a humanized mouse model of alopecia areata. PMID- 23096716 TI - The immunocytokine L19-IL2 eradicates cancer when used in combination with CTLA-4 blockade or with L19-TNF. AB - Systemic high-dose IL2 promotes long-term survival in a subset of metastatic melanoma patients, but this treatment is accompanied by severe toxicities. The immunocytokine L19-IL2, in which IL2 is fused to the human L19 antibody capable of selective accumulation on tumor neovasculature, has recently shown encouraging clinical activity in patients with metastatic melanoma. In this study, we have investigated the therapeutic performance of L19-IL2, administered systemically in combination with a murine anti-CTLA-4 antibody or with a second clinical-stage immunocytokine (L19-TNF) in two syngeneic immunocompetent mouse models of cancer. We observed complete tumor eradications when L19-IL2 was used in combination with CTLA-4 blockade. Interestingly, mice cured from F9 tumors developed new lesions when rechallenged with tumor cells after therapy, whereas mice cured from CT26 tumors were resistant to tumor rechallenge. Similarly, L19-IL2 induced complete remissions when administered in a single intratumoral injection in combination with L19-TNF, whereas the two components did not lead to cures when administered as single agents. These findings provide a rationale for combination trials in melanoma, as the individual therapeutic agents have been extensively studied in clinical trials, and the antigen recognized by the L19 antibody has an identical sequence in mouse and man. PMID- 23096717 TI - An in vivo screen of secreted proteins identifies adiponectin as a regulator of murine cutaneous wound healing. AB - Skin wounds comprise a serious medical issue for which few pharmacological interventions are available. Moreover, the inflammatory, angiogenic, and proliferative facets of a typical response to a wound each have broader relevance in other pathological conditions. Here we describe a genomics-driven approach to identify secreted proteins that modulate wound healing in a mouse ear punch model. We show that adiponectin, when injected into the wound edge, accelerates wound healing. Notably, adiponectin injection causes upregulation of keratin gene transcripts within hours of treatment, and subsequently promotes collagen organization, formation of pilosebaceous units, and proliferation of cells in the basal epithelial cell layer and pilosebaceous units of healing tissue. The globular domain of adiponectin is sufficient to mediate accelerated dorsal skin wound closure, and the effects are lost in mice that are homozygous null for the adiponectin receptor 1 gene. These findings extend recent observations of a protective role of adiponectin in other tissue injury settings, suggest modulation of AdipoR1 for the clinical management of wounds, and demonstrate a new approach to the identification of regulators of a wound healing response. PMID- 23096718 TI - Increased KGF expression promotes fibroblast activation in a double paracrine manner resulting in cutaneous fibrosis. AB - Fibrotic disorders of the skin share the characteristic features of increased production and deposition of extracellular matrix components by activated fibroblasts. Their clinical course ranges from benign with localized cutaneous involvement to a systemic, life-threatening disease. The molecular cause for fibroblast activation remains unknown, yet epithelial-mesenchymal interactions draw mounting attention in the research field of fibrogenesis. We examined keratinocyte growth factor (KGF), a crucial molecule in fibroblast-keratinocyte cross talk, exemplarily in keloid and scleroderma, and found its expression to be increased in disease-derived fibroblasts and tissues compared with healthy controls. This overexpression induces fibroblast activation through a double paracrine mode of action. Upon KGF stimulation, the keratinocytes produced and secreted OSM (oncostatin M). Fibroblasts were in turn activated by OSM reacting with the increased expression of collagen type I-alpha1, fibroblast activation protein, and enhanced migration. The observed increase in collagen expression and fibroblast migration can be traced back to OSM-regulated STAT3 phosphorylation, leading to enhanced urokinase plasminogen activator expression. Hence, we propose a causative loop in the pathogenesis of fibrosing disorders of the skin mediated by the overexpression of KGF in mesenchymal cells. PMID- 23096719 TI - No evidence for viral sequences in mycosis fungoides and Sezary syndrome skin lesions: a high-throughput sequencing approach. PMID- 23096720 TI - [Multimodal imaging in bone metastases]. AB - The skeleton is one main sites of metastasis of solid tumors, and metastatic bone disease are most common malignant disease of the bone. The diagnosis and assessment of bone metastases require integrated multimodality combined approach of different diagnostic methods, including both different radionuclides that radiological techniques such as X-rays, CT and MRI. In this scenario the nuclear medicine gives a significant contribution to the evaluation of skeletal metastases. In this article we will analyze the main approaches. PMID- 23096721 TI - [Peptide imaging: the somatostatine model]. AB - Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Main approach has been the use of 111In Octreotide as functional imaging to find NETs. In some tumor types, it is considered the diagnostic gold standard. This article focuses on the current status of peptide-receptor scintigraphy in different tumors, in other oncologic and non oncologic applications and on future developments in these fields. PMID- 23096722 TI - [New diagnostic imaging approaches in multiple myeloma]. AB - Multiple myeloma (MM) is a neoplastic monoclonal proliferation of plasma cells, mainly involving bone marrow. To properly stage and manage patients with MM the clinician needs at first a complete skeletal survey. Today none of diagnostic imaging methods is able to answer alone to all questions in staging, treatment and follow up. Bone scintigraphy is affected by a low sensitivity. Tc-99m MIBI has been proposed in staging and in follow-up , with most relevant clinical information deriving from the correlation of its whole body uptake's distribution with extent and activity of the disease. PET - FDG has been proposed in MM for its skill to detect whole-body metabolic active disease, producing relevant information in staging and prognosis. First studies demonstrated that PET-FDG is more sensitive than other imaging modalities for localizing extra medullary sites of disease. PMID- 23096723 TI - [Inflammatory bowel disease: possibilities and limits in multidetector computed tomography]. AB - Technical advances in computed tomography (CT), including helical CT and multidetector CT, have resulted in an improved ability to evaluate the small intestine. CT examination of the small bowel requires the use of dedicated techniques for optimal evaluation of inflammatory bowel disease in order to select the most appropriate therapeutic strategy for the individual patient and to monitor disease progression over time.Although intraluminal contrast media combined with intravenous iodinated contrast agents with a biphasic injection protocol provide good visualization of the typical lesions of the disease, accurate estimation of the degree of disease activity can only be achieved with nuclear imaging. Owing to continuous technical improvements, magnetic resonance imaging is expected to play an increasing role in the near future. However, in selected patients, three-dimensional endoanal ultrasonography remains the gold standard technique for assessing the anal sphincter and the recto-anal junction. PMID- 23096724 TI - [Actual role of MR in the small bowel studies: dynamic sequences and bowel distension]. AB - Magnetic resonance (MR) is even more becoming important in the evaluation of the small bowel, thanks to the technologic advances of the machines and thanks to the improvement of specific diagnostic protocols of study. MR is a pivotal in identifying acute stenosis and alterations of the bowel wall and in differentiating between inflammatory and fibrotic alterations. Diffusion techniques and dynamic MRI allows the assessment of the degree of disease activity of IBD, although nuclear medicine represents the gold standard. PMID- 23096725 TI - [Gastroenteric diseases in the third millennium: a rational approach to optimal imaging technique and patient selection]. AB - In the last twenty years, the study of gastroenteric disorders underwent a radical change as a result of rapid advances in diagnostic imaging, with the introduction of more sophisticated and better performing techniques. Although this evolution has significantly contributed to improve diagnostic accuracy, also allowing assessment of different areas of the gastroenteric tract that could not be well evaluated in the past, clinicians may feel confused about deciding the most appropriate diagnostic approach according to lesion type and site. The aim of this paper is to provide an overview of available imaging techniques to guide the diagnostic approach to gastroenteric diseases. PMID- 23096726 TI - [Role of nuclear imaging in the management and follow-up of patients with inflammatory bowel disease]. AB - The modern approach to diagnostic imaging includes multimodal evaluation of patients. Physician knowledge of the clinical potential of each available imaging technique combined with efficient integration of functional and morphological data is mandatory in order to achieve a timely diagnosis and treatment, and to avoid unnecessary invasive examinations. Recent years have witnessed important advances in nuclear medicine techniques, including the development of a great variety of metabolic tracers that allow accurate detection, characterization and staging of diverse disease states other than neoplastic conditions. Nuclear medicine techniques play an important role in the diagnostic evaluation of different forms of inflammatory bowel disease (Crohn's disease, ulcerative rettocolitis, indeterminate colitis), and can provide optimal anatomo-functional information when used in association with multidetector CT and MRI, enabling tailored therapeutic interventions. PMID- 23096727 TI - [Diagnosis of acute mesenteric ischemia/infarction in the era of multislice CT]. AB - Acute mesenteric ischemia/infarction is a complex and often misdiagnosed syndrome. The availability of new imaging methods, namely multislice computed tomography, has enabled early recognition of signs and symptoms of acute mesenteric ischemia, resulting in timely therapeutic intervention. PMID- 23096728 TI - [Dw-MRI and bone scintigraphy in monitoring radio-therapy response in bone metastases]. AB - Bone is one of the most common sites of metastatic spread of malignancy, with possible deleterious effects including pain, hypercalcemia, and pathologic fracture. External beam radiotherapy (EBRT) remains the mainstay for treatment of painful bone metastases. Diffusion-weighted MRI (DW-MRI) has been described as an efficient method to differentiate good and poor responders to radiotherapy in bone metastases patients. The addition of DWI to conventional whole-body MRI sequences enhanced lesion conspicuity and improved diagnostic accuracy. We evaluate bone metastases patients with bone scintigraphy and DW-MRI. With technical optimization, whole-body MRI with DWI, as a nonionizing imaging modality, may potentially be useful as an alternative method to bone scintigraphy in the management of bone metastases. PMID- 23096729 TI - [Whole Body Magnetic Resonance and CT/PET in patients affected by multiple myeloma during staging before treatment]. AB - The diagnostic imaging plays a pivotal role in the staging of multiple myeloma (MM). Traditional imaging techniques allow a precise disease extension before treatment, but some drawbacks have been demonstrated after treatment. WBMRI and CT/PET represent alterative procedures during staging, but few comparative data are available to date. Aim of our study was to estimate the diagnostic accuracy of WB-MRI and CT/PET in 28 consecutive patients affected by MM before therapy. CT/PET was positive in 22/28 patients, whereas WB-MRI correctly identified 100% of patients. In this setting of patients WB MRI have demonstrated to be superior respect to CT/PET in term of diagnostic accuracy, especially when a diffuse disease is detected with a bone marrow aspiration with more than 40% of plasma cells. WBMRI shows a diagnostic accuracy higher than FDG-CT/PET in staging especially when diffuse. However a whole body coverage is crucial to properly manage MM patients irrespective of which technique is used. PMID- 23096730 TI - [Quantitative analysis of myocardial glucose metabolism by using dynamic FDG-PET acquisition]. AB - In today's diagnostic imaging the heart with Pet 18F - FDG finds its highest expression in' identify the extent, severity, and the possibility of recovery of dysfunctional myocardium. Aim of this study was to extract some parameters "unique" as the regional metabolic rate, the speed of fractional irreversible binding of the tracer to the receptor sites in order to obtain a quantization of a possible damage of the tissue under examination. We used a dedicated software, the PMOD, implemented with compartmental models and graphical analysis methods in order to obtain absolute and repeatable results. In our results these parameters can give a qualitative data integration and definition to which, as is known, do not allow the identification of objective criteria to identify a possible ischemic damage and, most important, a possible recovery of dysfunctional myocardium. PMID- 23096731 TI - [Evaluation of the small bowel with computed tomography enteroclysis: technical applications and clinical indications]. AB - CT enteroclysis is an imaging technique that allows better visualization of the small bowel than standard abdomino-pelvic CT. It is more accurate than CT enterography and provides complementary diagnostic information to digestive endoscopy. Multiplanar reconstruction allows better evaluation of the diseases arising from the small bowel wall, or from surrounding organs, resulting in increased accuracy and effectiveness of this imaging technique. CT enteroclysis often enables a comprehensive assessment of small bowel disease, allowing a definite diagnosis and characterization of intestinal bowel disease, or of other related pathological conditions. PMID- 23096732 TI - [Role of computed tomography in the diagnosis of acute lung injury/acute respiratory distress syndrome]. AB - Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a complex pulmonary pathology with high mortality rates, manifesting over a wide range of severity. Clinical diagnosis relies on the following 4 criteria stated by the American-European Consensus Conference: acute onset of impaired gas exchange, severe hypoxemia defined as a PaO2 to FiO2 ratio <300 (PaO2 in mmHg), bilateral diffuse infiltration on chest X-ray; pulmonary artery wedge pressure of <=18 mmHg to rule out cardiogenic causes of pulmonary edema. The aim of this study was to determine the usefulness of CT in the diagnosis and management of this condition. PMID- 23096733 TI - [Accuracy of multislice CT in restaging patients with non-small cell lung carcinoma after neoadjuvant chemotherapy using a multiparametric approach]. AB - The aim of this study was to assess diagnostic accuracy of multislice CT in restaging patients with N2 non-small cell lung carcinoma after neoadjuvant chemotherapy, using a multiparametric approach as compared with traditional size based radiological criteria. All patients staged as N2 at histologic examination after neoadjuvant chemotherapy were correctly staged with multislice CT (sensitivity, specificity, positive and negative predictive value, and accuracy were 100%, 80%, 85%, 100% and 93,7% respectively, vs 34%, 60%, 34%, 60% and 50% using size-based criteria), suggesting that a multiparametric approach results in improved diagnostic accuracy. PMID- 23096734 TI - [Small renal cell carcinoma (<= 4 cm): enhancement patterns on triphasic spiral CT]. AB - The aim of this study was to define enhancement patterns of small renal cell carcinoma (RCC) (<=4 cm) by triphasic spiral CT. In 24 patients with RCC, hypervascularity and hypovascularity were identified in 12 and 12 RO, respectively, in the cortico-medullary phase (CMP). Hypervascular RCC showed increased density in the CMP (170,7+/-46,3 UH) and a gradual wash-out in the nephrographic phase (NP) (152,5+/-41 UH) and pielographic phase (PF) (99,2+/-38 UH). Hypovascular RCC showed increased density in the CMP (52,9+/-24,7 UH) and a gradual wash-out in NP (64,5+/-16,9 UH) and PP phases (55,0+/-17,3 UH). PMID- 23096735 TI - [Small renal oncocytoma (<= 4 cm): enhancement patterns on triphasic spiral computed tomography]. AB - In 18 patients with 19 RO, 9 hypervascularity and hypovascularity was identified in 9 and 10 RO, respectively, in the cortico-medullary phase (CMP). Hypervascular RO showed increased density in the CMP (151.4+/-38.5 HU) and a gradual wash-out in the nephrographic phase (133.8+/-34.6 HU) and excretory phase (79+/-23 HU). Hypovascular RO showed increased density in the CMP (87.8+/-20.1 UH) and a gradual wash-out in the nephrographic phase (100.3+/-33 UH) and excretory phase (20.9+/-86.9 UH). PMID- 23096736 TI - [Multidetector CT for the assessment of the groin region]. AB - Assessment of the complex anatomy of the groin region using different imaging modalities is important to identify those pathological conditions that may present with atypical symptoms. In obese patients or in the presence of complications, physical examination may be unremarkable and instrumental studies based on non-invasive techniques (e.g., ultrasounds) do not allow accurate assessment of this region. Multidetector CT scanning and reconstruction can provide useful information on inguinal canal anatomy and its related diseases, contributing to timely therapeutic interventions. PMID- 23096737 TI - [Role of multidetector CT in the evaluation of large bowel obstruction]. AB - The aim of the study was to assess the accuracy of multidetector CT (MDCT) with MPR reformation in the evaluation of large bowel obstruction. Thirty-one patients were evaluated retrospectively in a blinded fashion by two radiologists. All patients underwent MDCT with multiplanar reformation (MPR). The two radiologists interpreted independently the axial images and then the reconstructions. Each patient received a score from 1 (absent occlusion) to 5 (confirmed occlusion). The results were compared with surgical findings. Both axial and MPR images showed a very high accuracy in the diagnosis of bowel obstruction with a significant advantage of MPRs over native images and without any difference between the two radiologists. MDCT is an accurate technique in the evaluation of large bowel obstruction and use of MPRs facilitates the interpretation of imaging findings. PMID- 23096738 TI - [Gatrointestinal imaging with multidetector CT and MRI]. AB - Computed tomography (CT) and magnetic resonance imaging (MRI) are important diagnostic tools for evaluating gastrointestinal disorders. A rigorous examination protocol is needed to achieve the best results. This paper describes the technical issues of CT and MRI for the study of gastrointestinal tracts (esophagus, stomach, small and large bowel). PMID- 23096739 TI - [Striatal dopamine transporter levels in patients with REM sleep behavior disorder: assessment with 123I-FP-CIT SPECT]. AB - REM sleep Behaviour Disorder (RBD) is a sleep disorder that can precedes the development of motor signs of Parkinson's disease by years. The aim of this study was to assess the functional integrity of nigrostriatal dopaminergic system in RBD patients using 123I-2b-carbomethoxy-3b-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) Single-Photon Emission Computed Tomography (SPECT). 5 patients with RBD and 5 normal healthy controls were included in the study and underwent SPECT imaging 3 hours after injection of 111-185 MBq of 123I-FP-CIT. All RBD patients showed reduced 123I-FP-CIT striatal binding. 123I-FP-CIT SPECT is a useful diagnostic tool in RBD patients. PMID- 23096740 TI - [Lymphoscintigrams with anatomical landmarks obtained with vector graphics]. AB - Nuclear medicine images are difficult to interpret because they do not include anatomical details. The aim of this study was to obtain lymphoscintigrams with anatomical landmarks that could be easily interpreted by General Physicians. Traditional lymphoscintigrams were processed with Adobe(c) Photoshop(r) CS6 and converted into vector images created by Illustrator(r). The combination with a silhouette vector improved image interpretation, without resulting in longer radiation exposure or acquisition times. PMID- 23096741 TI - [Peritoneal carcinomatosis from ovarian cancer: role of 18F-FDG-PET/CT and CA125]. AB - The purpose of this study was to evaluate the contribution of 18F-FDG-PET/CT in highlighting the peritoneal involvement in patients with ovarian cancer, also in relation to the biomarker CA125. We retrospectively analyzed 64 female patients with histological diagnosis of ovarian cancer who underwent 18F-FDG-PET/CT and CA125 measurement. Sensitivity and specificity of 18F-FDG-PET/CT were both 90.63% (95% CI: 80-100%). Sensitivity and specificity of CA125 were 93.33% (95% CI: 80 100%) and 33.33% (95% CI: 25-64%), respectively. In patients with peritoneal carcinomatosis from ovarian cancer, it is recommended to perform 18F-FDG-PET/CT, in particular when elevated CA125 levels are detected. PMID- 23096742 TI - [Role of 18F-FDG-PET/CT in the assessment of carotid atherosclerosis]. AB - The aim of this study was to determine the role of 18F-FDG-PET/CT in the evaluation of carotid plaques and its relationship with cardiovascular risk factors. 18F-FDG-PET/CT scan was performed in 25 patients with ultrasound diagnosis of carotid atherosclerosis and >=70% stenosis, who were scheduled for carotid endoarterectomy. 18F-FDG uptake was measured by ROIs drawn on PET/CT carotid artery slices. A statistically significant difference in 18F-FDG uptake was observed in relation to body mass index values between 25 and 29 kg/m2. Our results suggest that PET/CT imaging has utility in risk stratification of atherosclerotic patients. PMID- 23096743 TI - [Role of CT in the preoperative diagnosis of a giant benign solitary fibrous tumor of the pleura]. AB - The authors emphasize the role of CT in the preoperative diagnosis of a giant benign solitary fibrous tumor of the pleura. CT can provide evidence of complete resection of the lesion, showing a pedunculated stalk. Aspiration cytology is not a reliable diagnostic approach. PMID- 23096744 TI - [Cough-induced intercostal lung herniation successfully diagnosed with imaging techniques]. AB - We report the case of a 78-year-old man presenting with pain in right hemithorax that occurred suddenly after coughing. A palpable chest wall mass, soft in consistency, was noted on physical examination, and chest X-ray and CT allowed to make diagnosis of spontaneous lung hernia. PMID- 23096745 TI - [Posterior reversible encephalopathy syndrome: description of a case in the setting of severe infection]. AB - Posterior reversible encephalopathy syndrome (PRES) is a well recognized neurotoxic state coupled with a unique neuroradiological appearance. This syndrome is associated with a broad spectrum of complex conditions (preeclampsia/eclampsia, bone marrow/organ transplantation, chemotherapy, autoimmune disease). We report the case of a female patient who developed PRES in the setting of severe infection, and we discuss the possible mechanisms underlying the development of cerebral edema by describing the inherent neuroradiological features. PMID- 23096746 TI - [Orbital non-Hodgkin's lymphoma: description of a case diagnosed with magnetic resonance imaging]. AB - Orbital non-Hodgkin's lymphoma is a rare tumor. Correct diagnosis and accurate staging are of paramount importance for timely treatment and better outcome. We report the case of a female patient with bilateral orbital lymphoma, and describe the clinical-pathological aspects of the disease and its neuroradiological features. PMID- 23096747 TI - [Spontaneous dissection of the internal carotid artery: description of a case with lower cranial nerve palsy]. AB - Spontaneous dissection of the extracranial internal carotid artery is a well recognized cause of headache and juvenile stroke; lower cranial nerve palsy as a complication of dissection is rare. We report the case of a female patient with bilateral dissecting aneurysm of the internal carotid artery, associated with unilateral cranial nerve XII palsy and oculosympathetic palsy. Neuroradiological findings, in particular those obtained by Magnetic Resonance imaging, allow the identification of the dissecting pathology and the correlation of the aneurysmal formation with nerve palsy. PMID- 23096748 TI - [Perineural tumor spread from the ophthalmic branch of the trigeminal nerve: a case report]. AB - Perineural tumor spread of head and neck malignancies is a well known form of metastatic disease in which a lesion can migrate away from the primary site along the cranial nerves. Nerve function can be preserved even in advanced stages of the disease, making neuroradiological assessment of perineural tumor location and extension of utmost importance, as radiological or pathological examination may reveal normal or nonspecific nerve function. Computed Tomography is useful in detecting foraminal enlargement or more destructive bone patterns. Magnetic Resonance imaging is the modality of choice because it can provide direct (nerve enlargement and enhancement) and indirect evidence of the disease (neuropathic muscular atrophy, obliteration of fat planes) owing to its superior soft-tissue contrast resolution, its multiplanar imaging and the decreased amount artifacts from dental hardware. Fat suppression images after contrast injection are mandatory to better detect nerve enhancement. We report the case of a female patient with perineural diffusion along the ophthalmic branch. This clinical picture is very rare, compared to those involving the mandibular and maxillary branches of the fifth cranial nerve. PMID- 23096749 TI - [Atypical appearance of pneumatosis intestinalis at multidetector CT]. AB - Pneumatosis intestinalis may be caused by bowel ischemia and may display different patterns of appearance. We report a case of pneumatosis intestinalis with an atypical target pattern, detected by multidetector computed tomography (CT) in a 66-year-old male presenting with acute abdominal syndrome. Abdominal CT scan showed a double gas collection within the wall of a jejunal segment, with a characteristic target air distribution. The patient was surgically treated and successfully discharged from our hospital with the diagnosis of acute bowel ischemia. The target air sign can be an initial CT finding of the typical pneumatosis intestinalis and it can be useful in the early diagnosis of bowel ischemia. PMID- 23096750 TI - [Relapse of primary testicular non-Hodgkin's lymphoma detected by 18F-FDG PET/CT]. AB - We report the case of a 62-year-old male with a history of primary testicular non Hodgkin's lymphoma, treated with orchidectomy. After 14 months, the patient developed left leg swelling and pain, and was diagnosed and treated as having leg vein thrombosis. 18F-FDG-PET/CT showed a relapse of testicular lymphoma in the cutaneous muscle tissue of the left leg. PMID- 23096751 TI - [Morpho-functional imaging of a rare case of tako-tsubo syndrome in a young pregnant woman]. AB - We report the case of a pregnant patient who developed the typical pattern of tako-tsubo syndrome after delivery (i.e., electrocardiographic changes, elevated cardiac enzymes, and no evidence of coronary stenosis). SPECT imaging showed myocardial perfusion defects and altered motility, which reversed 6 months later. PMID- 23096752 TI - [Distribution of 18F-FDG in a patient with evolving abdominal aortic aneurysm]. AB - We report the case of a patient with abdominal aortic aneurysm who underwent serial 18F-FDG PET/CT examinations to evaluate the risk of rupture and to guide appropriate surgical or medical management. PMID- 23096753 TI - [Role of imaging techniques in the evaluation of chyluria]. AB - Lymphoscintigraphy is a first-line imaging technique for the assessment of abnormal lymphatic drainage in chyluria. It can provide information about the site of origin of chyluria, and may be helpful in selecting patients for surgery and assessing treatment efficacy. We report the case of a 59-year-old male with chyluria correctly diagnosed with lymphoscintigraphy. PMID- 23096755 TI - Biological applications of the electrochemical sensing of nitric oxide: fundamentals and recent developments. AB - Nitric oxide (NO) is a unique cellular messenger linked to a number of important biological processes. Its free radical nature, small size and fast diffusivity make it highly reactive and membrane permeable. Unfortunately, its reactivity, coupled with the inherent complexity of in situ biological measurements, makes it a challenge to detect. For the past 20 years, electrochemical methods have been used to investigate the role of NO in a number of biological processes, including vascular physiology, immune response, neuronal mediation, tissue growth and oxidative stress. This review examines the biological applications of electrochemical NO sensors and the technologies used to elucidate different physiological phenomena associated with this unique biomolecule with a specific focus on the developments and innovations reported in the last 3 years. PMID- 23096756 TI - Measurement of nitrite in plasma and serum: still a challenging analytical task. PMID- 23096757 TI - Human epididymis protein 4 as a serum marker for diagnosis of endometrial carcinoma and prediction of clinical outcome. AB - BACKGROUND: The purpose of this study was to assess the diagnostic and prognostic impact of preoperative serum determination of human epididymis protein 4 (sHE4), and to investigate its potential correlation with clinicopathological features and survival endpoints in endometrial cancer patients. METHODS: Preoperative serum samples from 193 endometrial cancer patients and 125 women with normal endometrium were measured for sHE4 and serum CA125 (sCA125) concentrations by quantitative chemiluminescent microparticle immunoassays on the automated Architect instrument. RESULTS: sHE4 concentrations were significantly higher in endometrial cancer patients regardless of tumour stage and grade compared with normal controls. Setting the specificity at 95 % , the sensitivities in detecting endometrial cancer patients were 66 % for HE4, 33 % for CA125 and 64 % for the combination of the two markers. High concentrations of both HE4 and CA125 significantly correlated with all clinicopathological features characterising a more aggressive tumour phenotype.In multivariate analysis, only high preoperative sHE4 concentrations, but not sCA125, were independent prognostic factors for shorter Overall Survival, Disease-Free Survival and Progression-Free Survival. CONCLUSIONS: HE4 is more sensitive and specifi c than CA125in distinguishing endometrial cancer patients from women with normal endometrium, regardless of tumour stage and grade. sHE4 appears to be associated with a more aggressive tumour variant and it could be clinically useful, in identifying high-risk endometrial cancer patients, for a tailored surgical and postoperative therapy. HE4 significant correlation with decreased Overall Survival, Disease Free Survival and Progression Free Survival suggests its potential role as a novel prognostic marker for endometrial cancer. PMID- 23096754 TI - Exon skipping of AGAMOUS homolog PrseAG in developing double flowers of Prunus lannesiana (Rosaceae). AB - KEY MESSAGE : Two transcript isoforms of AGAMOUS homologs, from single and double flower Prunus lannesiana, respectively, showed different functions. The Arabidopsis floral homeotic C function gene AGAMOUS (AG) confers stamen and carpel identity. Loss of AG function results in homeotic conversions of stamens into petals and formation of double flowers. In order to present a molecular dissection of a double-flower cultivar in Prunus lannesiana (Rosaceae), we isolated and identified a single-copy gene, AG homolog from two genetically cognate P. lannesiana bearing single and double flowers, respectively. Sequence analysis revealed that the AG homolog, prseag-1, from double flowers showed a 170 bp exon skipping as compared to PrseAG (Prunus serrulata AGAMOUS) from the single flowers. Genomic DNA sequence revealed that abnormal splicing resulted in mutant prseag-1 protein with the C-terminal AG motifs I and II deletions. In addition, protein sequence alignment and phylogenetic analyses revealed that the PrseAG was grouped into the euAG lineage. A semi-quantitative PCR analysis showed that the expression of PrseAG was restricted to reproductive organs of stamens and carpels in single flowers of P. lannesiana 'speciosa', while the prseag-1 mRNA was highly transcribed throughout the petals, stamens, and carpels in double flowers from 'Albo-rosea'. The transgenic Arabidopsis containing 35S::PrseAG displayed extremely early flowering, bigger stamens and carpels and homeotic conversion of petals into staminoid organs, but ectopic expression of prseag-1 could not mimic the phenotypic ectopic expression of PrseAG in Arabidopsis. In general, this study provides evidences to show that double flower 'Albo-rosea' is a putative C functional ag mutant in P. lannesiana. PMID- 23096758 TI - Serum ferritin concentrations predict incidence of metabolic syndrome in rural Korean adults. PMID- 23096759 TI - Evaluation of the cross-reactivity of 25-hydroxyvitamin D2 on seven commercial immunoassays on native samples. PMID- 23096760 TI - Urinary iodine concentrations of pregnant women in Ukraine. AB - BACKGROUND: Iodine requirements increase during pregnancy and previous studies have reported the inadequate iodine status of pregnant women in areas that have achieved iodine sufficiency in the general population. We examined the urinary iodine (UI) concentrations of pregnant women in Ukraine, where the iodine status is showing improvement among the general population. METHODS: We enrolled 148 pregnant women<16 weeks pregnant and 80 healthy women as a control group living in Zhitomir, Ukraine. UI concentration, thyroid-stimulating hormone (TSH), antithyroglobulin antibodies (TGAb), and antithyroid peroxidase antibodies (TPOAb) were measured. RESULTS: The median UI concentrations were significantly lower in pregnant women than in control women [13.0 (ND-51.0) MUg/L vs. 62.0 (35.3-108.5) MUg/L, p<0.001]. TSH concentrations were significantly lower in pregnant women than in control women [1.7 (1.2-2.7) IU/L vs. 2.2 (1.4-3.1) IU/L, p=0.011], but this difference disappeared when adjusted for age (2.1+/-0.1 IU/L vs. 2.4+/-0.2 IU/L, p=0.097). The frequency of TSH over 6.2 IU/L and the frequency of positive TGAb and/or TPOAb were not statistically different between groups (p=0.70 and p=0.48, respectively). The UI concentrations of 142 pregnant women (95.9%) were <150 MUg/L indicating insufficient iodine intake. CONCLUSIONS: The UI concentration of pregnant women in Ukraine revealed severe iodine deficiency. Regular monitoring and appropriate nutrition education are essential because iodine deficiency can be easily prevented by adequate iodine intake. The risk of iodine deprivation during pregnancy needs to be assessed locally over time because it may occur in areas that are not globally recognized as being iodine-deficient. PMID- 23096761 TI - Association between serum gamma-glutamyltransferase and pulmonary dysfunction. PMID- 23096762 TI - Association of urinary albumin and serum high molecular weight-adiponectin with metabolic syndrome in patients with essential hypertension. PMID- 23096763 TI - Synthesis of prebiotic carbohydrates derived from cheese whey permeate by a combined process of isomerisation and transgalactosylation. AB - BACKGROUND: Lactose from cheese whey permeate (WP) was efficiently isomerised to lactulose using egg shell, a food-grade catalyst, and the subsequent transgalactosylation reaction of this mixture with beta-galactosidase from Bacillus circulans gave rise to a wide array of prebiotic carbohydrates derived from lactose and lactulose. RESULTS: Lactulose obtained by efficient isomerisation of WP (16.1% by weight with respect to the initial amount of lactose) showed great resistance to the hydrolytic action of beta-galactosidase from B. circulans, which preferentially hydrolysed lactose, acting as a galactosyl donor and acceptor. Lactulose had capacity as an acceptor, leading to the formation of lactulose-derived oligosaccharides. The enzymatic synthesis was optimised by studying reaction conditions such as pH, temperature, time, enzyme concentration and carbohydrate concentration. The maximum formation of galactooligosaccharides with degrees of polymerisation from 2 to 4 was achieved after 5 h of reaction at pH 6.5 and 50 degrees C with 300 g kg(-1) carbohydrates and 3 U mL(-1) beta-galactosidase. CONCLUSION: These findings indicate that the transgalactosylation of isomerised WP with beta-galactosidase from B. circulans could be a new and efficient method to obtain a mixture with 50% of potentially prebiotic carbohydrates composed of lactulose, and galactooligosaccharides derived from lactose and lactulose. PMID- 23096765 TI - Tunable nano-oleosomes derived from engineered Yarrowia lipolytica. AB - Oleosomes are discrete organelles filled with neutral lipids surrounded by a protein-embedded phospholipid monolayer. Their simple yet robust structure, as well as their amenability to biological, chemical, and physical processing, can be exploited for various biotechnology applications. In this study, we report facile biosynthesis of functionalized oleosomes within oleaginous yeast Yarrowia lipolytica, through expression of oleosin fusion proteins. By fusing a cDNA clone of a sesame oleosin with either the coding sequence of a red fluorescent protein mCherry or a cellulosomal scaffolding protein cohesin from Clostridium cellulolyticum, these oleosin-fusion proteins were efficiently expressed and specifically targeted to and anchored on the surface of the oleosomes within the Y. lipolytica cells. The engineered oleosomes can be easily separated from the Y. lipolytica cell extract via floating centrifugation and both mCherry and cohesin domains are shown to be functional. Upon sonication, the engineered Yarrowia oleosomes exhibit a mean diameter of 200-300 nm and are found to be highly stable. The feasibility of co-displaying multiple proteins on the Yarrowia oleosomes was demonstrated by incubating cohesin-displaying oleosomes with different dockerin-fusion proteins. Based on this strategy, engineered oleosomes with both cell-targeting and reporting activities were created and shown to be functional. Taken together, the Yarrowia oleosome surface display system in which oleosin serves as an efficient membrane anchor motif shows great promise as a simple platform for creating tunable nanoparticles. PMID- 23096764 TI - Motor, emotional, and cognitive empathy in children and adolescents with autism spectrum disorder and conduct disorder. AB - It is unclear which aspects of empathy are shared and which are uniquely affected in autism spectrum disorder (ASD) and conduct disorder (CD) as are the neurobiological correlates of these empathy impairments. The aim of this systematic review is to describe the overlap and specificity of motor, emotional, and cognitive aspects of empathy in children and adolescents with ASD or CD. Motor and cognitive empathy impairments are found in both ASD and CD, yet the specificity seems to differ. In ASD facial mimicry and emotion recognition may be impaired for all basic emotions, whereas in CD this is only the case for negative emotions. Emotional empathy and the role of attention to the eyes therein need further investigation. We hypothesize that impaired motor and cognitive empathy in both disorders are a consequence of lack of attention to the eyes. However, we hypothesize major differences in emotional empathy deficits between ASD and CD, probably due to emotional autonomic and amygdala hyper-responsivity in ASD versus hypo-responsivity in CD, both resulting in lack of attention to the eyes. PMID- 23096766 TI - Effect of palm kernel cake as protein source in a concentrate diet on intake, digestibility and live weight gain of goats fed Napier grass. AB - The effects of palm kernel cake (PKC) as a protein source in a concentrate diet (comprising 35 % crushed maize, 30 % rice bran, 32 % PKC, 2 % vitamin mineral premix and 1 % salt) were examined on intake, live weight (LW) gain and digestibility in female goats (average LW of 12.4 +/- 2.6 kg). Four goats were randomly allocated to each of the four treatment diets: (a) Napier grass (Pennisetum purpureum) offered ad libitum (T1), (b) T1 + concentrate at 0.5 % of LW (T2), (c) T1 + concentrate at 1.0 % of LW (T3) and (d) T1 + concentrate at 2.0 % of LW (T4). A 7-day digestibility trial and an 82-day growth experiment were conducted. No differences were observed among diets for intakes of roughage dry matter (DM), total DM, organic matter (OM) and neutral detergent fibre (NDF). The crude protein (CP) intake increased (P < 0.05) as the level of concentrate in the diets increased. Goats fed the T2, T3 and T4 diets gained 10.2, 34.1 and 52.5 g/head/day, respectively, while the control group (T1) lost weight (-12.7 g/head/day). The apparent digestibilities of DM, OM and CP were similar (P > 0.05) among treatments. The digestibility of dietary NDF decreased (P < 0.05) with increasing levels of concentrate, but there was no significant (P > 0.05) difference between T2 and T3 diets. Supplementing a basal diet of Napier grass with PKC-based concentrate improved CP intake and LW gain. The PKC-based concentrate diet can therefore be exploited for the use of local feed resources for goat production; however, further research is required to achieve the best growth response. PMID- 23096767 TI - The population structure of Salmonella enterica Enteritidis in Iran analyzed by multiple-locus variable-number tandem repeat analysis. AB - Salmonella enterica Enteritidis is the most frequent etiological agent of salmonellosis in humans and poultry. To understand the genetic diversity of S. Enteritidis in Iran, we examined 69 chicken isolates from 18 broiler farms and six non-epidemic human isolates from six geographically distant provinces by multi-locus variable-number tandem repeat analysis (MLVA). Among SE2, SE3, SE5, SE7, SE8, SENTR4, and SENTR7, only SE5 with four and SENTR7 with two alleles, respectively, proved variable giving estimates of locus genetic diversity of 0.58 and 0. In all, six closely related MLVA profiles were identified among which three were commonly represented by human and chicken isolates. This population homogeneity contrasts with the high diversity at these loci reported elsewhere and is likely a consequence of a single clone of S. Enteritidis distributed across Iran. PMID- 23096768 TI - Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer. AB - BACKGROUND: Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT-related toxicity. METHODS: One hundred thirty-two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5-fluorouracil (5 FU) and radiation (RT), and 80 patients also received modified infusional 5-FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX-6). Grade >=3 adverse events (AEs) that occurred during 5-FU/RT and during combined 5-FU/RT + mFOLFOX-6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment-related grade >=3 AEs. RESULTS: Overall, 27 of 132 patients (20%) had grade >=3 AEs; 18 patients had a complication associated only with 5-FU/RT, 3 patients experienced toxicity only during mFOLFOX-6, and 6 patients had grade >=3 AEs associated with both treatments before surgery. Polymorphisms in the genes x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade >=3 AEs during NT (P < .05). Specifically, 2 polymorphisms-an arginine-to-glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine-to-glutamine substitution at codon 751 (K751Q) in XPD-were associated with increased toxicity to 5-FU/RT (P < .05), and an arginine-to proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX-6 (P = .008). CONCLUSIONS: Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance. PMID- 23096769 TI - Cognitive effects of intramuscular ketamine and oral triazolam in healthy volunteers. AB - RATIONALE: Several studies have documented impairments in memory processes as a result of ketamine administration; however, few studies have compared the profile of cognitive effects of ketamine to other drugs. OBJECTIVES: The aim of this study was to compare the cognitive effects of ketamine with those of triazolam in healthy volunteers. METHODS: Doses of ketamine (0.2, 0.4 mg/kg intramuscular (i.m.)), triazolam (0.2, 0.4 mg/70 kg p.o.), and double-dummy placebos were administered to 20 volunteers under repeated measures, counterbalanced, double blind conditions. Peak physiological, psychomotor, subjective, and cognitive effects were examined. RESULTS: Ketamine impaired balance when balance was assessed early in the task order, whereas triazolam impaired psychomotor coordination and divided attention irrespective of task order. Triazolam also tended to produce greater effects on working memory and episodic memory tasks than ketamine at doses that produced lower subjective effects and higher estimates of performance. CONCLUSIONS: Ketamine produces less cognitive impairment than triazolam at doses that produced greater subjective effects. Thus ketamine does not produce the underestimation of cognitive impairment typically seen with triazolam. PMID- 23096771 TI - The relationship between impulsivity and craving in alcohol dependent patients. AB - RATIONALE: Impulsivity and craving are both associated with higher relapse rates and a worse prognosis in patients with a substance use disorder, but the relationship between these two phenomena has been largely ignored in the field of alcohol use disorders. OBJECTIVES: The primary aim of this study was to investigate the relationship between different dimensions of impulsivity and different forms of self-reported craving. Additionally, the influence of the severity of alcohol dependence on impulsivity, craving, and on their relationship was exploed. METHODS: Impulsivity and craving levels were investigated in 87 abstinent alcohol-dependent (AD) patients using a broad range of self-report questionnaires and behavioral impulsivity measures. Alcohol use was measured by means of the timeline followback method. RESULTS: Higher scores of emotional craving (Alcohol Urge Questionnaire-AUQ) were significantly related to higher self-reported impulsivity (Barratt Impulsiveness Scale, version 11) and to higher cognitive impulsivity (information sampling task). Additionally, exploratory analyses suggest that these relationships are more pronounced in severe AD patients compared to less severe AD patients. No significant relationships were found between emotional craving (AUQ) and motor impulsivity (stop signal task) or delay discounting and between obsessive-compulsive craving (Obsessive Compulsive Drinking Scale) and measures of impulsivity. CONCLUSIONS: Emotional craving is related to self-reported impulsivity and to cognitive impulsivity. These relationships seem to be more pronounced in AD patients with severe alcohol dependence. Further research is needed to explore the effect of this relationship on treatment outcome and relapse. PMID- 23096772 TI - Re-skilling the social practices: open source and life-towards a commons-based peer production in agro-biotechnology? AB - Inspired by the thinking of authors such as Andrew Feenberg, Tim Ingold and Richard Sennett, this article sets forth substantial criticism of the 'social uprooting of technology' paradigm, which deterministically considers modern technology an autonomous entity, independent and indifferent to the social world (practices, skills, experiences, cultures, etc.). In particular, the authors' focus on demonstrating that the philosophy,methodology and experience linked to open source technological development represent an emblematic case of re encapsulation of the technical code within social relations (reskilling practices). Open source is discussed as a practice, albeit not unique, of community empowerment aimed at the participated and shared rehabilitation of technological production ex-ante. Furthermore, the article discusses the application of open source processes in the agro-biotechnological field, showing how they may support a more democratic endogenous development, capable of binding technological innovation to the objectives of social (reducing inequalities) and environmental sustainability to a greater degree. PMID- 23096770 TI - Role of orexin/hypocretin in conditioned sucrose-seeking in rats. AB - RATIONALE: The orexin/hypocretin system has recently been implicated in reward seeking, especially for highly salient food and drug rewards. We reasoned that this system may be strongly engaged during periods of reward restriction, including food restriction. OBJECTIVES: This study examined the involvement of the orexin (Orx) system in responding for sucrose, and in cue-induced reinstatement of extinguished sucrose-seeking, in ad libitum fed versus food restricted male subjects. METHODS: Sprague-Dawley rats (n = 108) were trained to self-administer sucrose, and we determined the effects of pretreatment with the OxR1 receptor antagonist SB-334867 (SB; 10-30 mg/kg) on fixed ratio (FR) or progressive ratio (PR) sucrose self-administration, as well as on cue-induced reinstatement of sucrose-seeking. Finally, expression of the immediate early gene c-fos in Orx neurons was examined after self-administration, late extinction or cue-induced reinstatement of sucrose seeking. RESULTS: SB decreased lever responding (by about 1/3) and the number of reinforcers earned during FR, and less so during PR, schedules and decreased cue-induced reinstatement to sucrose seeking to extinction levels, predominately in food-restricted rats. Additionally, Fos expression in Orx neurons in perifornical and dorsomedial hypothalamus was increased during extinction. CONCLUSIONS: These results indicate that signaling at the OxR1 receptor is involved in pronounced sucrose reinforcement, and reinstatement of sucrose-seeking elicited by sucrose-paired cues, in food-restricted subjects. These findings lead us to conclude that conditioned activation of Orx neurons increases motivation for food reward during food restriction. PMID- 23096773 TI - The scientist's education and a civic conscience. AB - A civic science curriculum is advocated. We discuss practical mechanisms for (and highlight the possible benefits of) addressing the relationship between scientific knowledge and civic responsibility coextensively with rigorous scientific content. As a strategy, we suggest an in-course treatment of well known (and relevant) historical and contemporary controversies among scientists over science policy or the use of sciences. The scientific content of the course is used to understand the controversy and to inform the debate while allowing students to see the role of scientists in shaping public perceptions of science and the value of scientific inquiry, discoveries and technology in society. The examples of the activism of Linus Pauling, Alfred Nobel and Joseph Rotblat as scientists and engaged citizens are cited. We discuss the role of science professors in informing the social conscience of students and consider ways in which a treatment of the function of science in society may find, coherently, a meaningful space in a science curriculum at the college level. Strategies for helping students to recognize early the crucial contributions that science can make in informing public policy and global governance are discussed. PMID- 23096774 TI - Relationships between the Survey of Organizational Research Climate (SORC) and self-reported research practices. AB - The Survey of Organizational Research Climate (SORC) is a validated tool to facilitate promotion of research integrity and research best practices. This work uses the SORC to assess shared and individual perceptions of the research climate in universities and academic departments and relate these perceptions to desirable and undesirable research practices. An anonymous web- and mail-based survey was administered to randomly selected biomedical and social science faculty and postdoctoral fellows in the United States. Respondents reported their perceptions of the research climates at their universities and primary departments, and the frequency with which they engaged in desirable and undesirable research practices. More positive individual perceptions of the research climate in one's university or department were associated with higher likelihoods of desirable, and lower likelihoods of undesirable, research practices. Shared perceptions of the research climate tended to be similarly predictive of both desirable and undesirable research practices as individuals' deviations from these shared perceptions. Study results supported the central prediction that more positive SORC-measured perceptions of the research climate were associated with more positive reports of research practices. There were differences with respect to whether shared or individual climate perceptions were related to desirable or undesirable practices but the general pattern of results provide empirical evidence that the SORC is predictive of self-reported research behavior. PMID- 23096776 TI - Midstream modulation in biotechnology industry: redefining what is 'part of the job' of researchers in industry. AB - In response to an increasing amount of policy papers stressing the need for integrating social and ethical aspects in Research and Development (R&D) practices, science studies scholars have conducted integrative research and experiments with science and innovation actors. One widely employed integration method is Midstream Modulation (MM), in which an 'embedded humanist' interacts in regular meetings with researchers to engage them with the social and ethical aspects of their work. While the possibility of using MM to enhance critical reflection has been demonstrated in academic settings, few attempts have been made to examine its appropriateness in industry. This paper describes the outcomes of a case study aiming to find out firstly whether MM can effectively be deployed to encourage and facilitate researchers to actively include social and ethical aspects in their daily R&D practice, and secondly to what extent the integration activities could form an integral part of the engaged industrial researchers' professional activities. Our data show that after MM, researchers display increased reflexive awareness on the social and ethical aspects of their work and acknowledge the relevance and utility of such aspects on their daily practice. Also, all participants considered actively reflecting on social and ethical aspects to be part of their work. Future research on the role of MM in industrial settings could focus on how to embed social and ethical integration as a regular part of innovation practice. We suggest that one possibility would be through aligning social and ethical aspects with innovation Key Performance Indicators. PMID- 23096775 TI - Development and validation of the Survey of Organizational Research Climate (SORC). AB - Development and targeting efforts by academic organizations to effectively promote research integrity can be enhanced if they are able to collect reliable data to benchmark baseline conditions, to assess areas needing improvement, and to subsequently assess the impact of specific initiatives. To date, no standardized and validated tool has existed to serve this need. A web- and mail based survey was administered in the second half of 2009 to 2,837 randomly selected biomedical and social science faculty and postdoctoral fellows at 40 academic health centers in top-tier research universities in the United States. Measures included the Survey of Organizational Research Climate (SORC) as well as measures of perceptions of organizational justice. Exploratory and confirmatory factor analyses yielded seven subscales of organizational research climate, all of which demonstrated acceptable internal consistency (Cronbach's alpha ranging from 0.81 to 0.87) and adequate test-retest reliability (Pearson r ranging from 0.72 to 0.83). A broad range of correlations between the seven subscales and five measures of organizational justice (unadjusted regression coefficients ranging from 0.13 to 0.95) document both construct and discriminant validity of the instrument. The SORC demonstrates good internal (alpha) and external reliability (test-retest) as well as both construct and discriminant validity. PMID- 23096777 TI - Differential reflectometry versus tactile sense detection of subgingival calculus in dentistry. AB - Detecting dental calculus is clinically challenging in dentistry. This study used typodonts with extracted premolar and molar teeth and simulated gingival tissue to compare the performance of differential reflectometry and periodontal probing. A total of 30 extracted teeth were set in an anatomical configuration in stone to create three typodonts. Clear polyvinyl siloxane impression material was placed to replicate the periodontal soft tissues. Pocket depths ranged from 10 to 15 mm. The three models were placed in a phantom head, and an experienced dentist assessed the presence of subgingival calculus first using the DetecTar (differential reflectometry) and then a periodontal probe. Scores from these two different methods were compared to the gold standard (direct examination of the root surface using 20* magnification) to determine the accuracy and reproducibility. Differential reflectometry was more accurate than tactile assessment (79% versus 60%), and its reproducibility was also higher (Cohen kappa 0.54 versus 0.39). Both methods performed better on single rooted premolar teeth than on multirooted teeth. These laboratory results indicate that differential reflectometry allows more accurate and reproducible detection of subgingival calculus than conventional probing, and supports its use for supplementing traditional periodontal examination methods in dental practice. PMID- 23096779 TI - Quantitative proteomic profiling reveals photosynthesis responsible for inoculum size dependent variation in Chlorella sorokiniana. AB - High density cultivation is essential to industrial production of biodiesel from microalgae, which involves in variations of micro-environment around individual cells, including light intensity, nutrition distribution, other abiotic stress and so on. To figure out the main limit factor in high inoculum cultivation, a quantitative proteomic analysis (iTRAQ-on-line 2-D nano-LC/MS) in a non-model green microalga, Chlorella sorokiniana, under different inoculum sizes was conducted. The resulting high-quality proteomic dataset consisted of 695 proteins. Using a cutoff of P < 0.05, 241 unique proteins with differential expression levels were identified between control and different inoculum sizes. Functional analysis showed that proteins participating in photosynthesis (light reaction) and Calvin cycle (carbon reaction pathway) had highest expression levels under inoculum size of 1 * 10(6) cells mL(-1), and lowest levels under 1 * 10(7) cells mL(-1). Canonical correlation analysis of the photosynthesis related proteins and metabolites biomarkers showed that a good correlation existed between them (canonical coefficient was 0.987), suggesting photosynthesis process greatly affected microalgae biodiesel productivity and quality. Proteomic study of C. sorokiniana under different illuminations was also conducted to confirm light intensity as a potential limit factor of high inoculum size. Nearly two thirds of proteins showed up-regulation under the illumination of 70-110 umol m( 2) s(-1), compared to those of 40 umol m(-2) s(-1). This result suggested that by elegantly adjusting light conditions, high cell density cultivation and high biodiesel production might be achieved. PMID- 23096778 TI - Atypical protein kinase C in cell motility. AB - Cell motility is defined as cell movement in the three-dimensional space leading to repositioning of the cell. Atypical protein kinase C (aPKC, including zeta and lambda/iota) are a subfamily of PKC. Different from classic PKC and novel PKC, the activation of atypical PKC is not dependent on diacylglycerol or calcium. PKCzeta can be activated by lipid components, such as phosphatidylinositols, phosphatidic acid, arachidonic acid, and ceramide. Both phosphatidylinositol (3,4,5)-trisphosphate and PDK1 are necessary for the complete and stable activation of PKCzeta. Atypical PKC is involved in the regulation of cell polarization, directional sensing, formation of filopodia, and cell motility. It is essential for migration and invasion of multiple cancer cell types. Particularly, atypical PKC has been found in the regulation of the motility of hematopoietic cells. It also participates in the regulation of proteolytic activity of podosomes and invadopodia. It has been found that atypical PKC can work coordinately with other PKC subfamily members and other signaling pathways. Research on the roles of atypical PKC in cell motility may lead to new therapeutic strategies for cancer and other diseases. PMID- 23096780 TI - Short peptide constructs mimic agonist sites of AT(1)R and BK receptors. AB - Extracellular peptide ligand binding sites, which bind the N-termini of angiotensin II (AngII) and bradykinin (BK) peptides, are located on the N terminal and extracellular loop 3 regions of the AT(1)R and BKRB(1) or BKRB(2) G protein-coupled receptors (GPCRs). Here we synthesized peptides P15 and P13 corresponding to these receptor fragments and showed that only constructs in which these peptides were linked by S-S bond, and cyclized by closing the gap between them, could bind agonists. The formation of construct-agonist complexes was revealed by electron paramagnetic resonance spectra and fluorescence measurements of spin labeled biologically active analogs of AngII and BK (Toac(1) AngII and Toac(0)-BK), where Toac is the amino acid-type paramagnetic and fluorescence quencher 2, 2, 6, 6-tetramethylpiperidine-1-oxyl-4-amino-4 carboxylic acid. The inactive derivatives Toac(3)-AngII and Toac(3)-BK were used as controls. The interactions characterized by a significant immobilization of Toac and quenching of fluorescence in complexes between agonists and cyclic constructs were specific for each system of peptide-receptor construct assayed since no crossed reactions or reaction with inactive peptides could be detected. Similarities among AT, BKR, and chemokine receptors were identified, thus resulting in a configuration for AT(1)R and BKRB cyclic constructs based on the structure of the CXCR(4), an alpha-chemokine GPCR-type receptor. PMID- 23096902 TI - A coumarin-Meldrum's acid conjugate based chemodosimetric probe for cyanide. AB - A highly reactive and selective chemodosimetric probe for cyanide was synthesized based on alkylidene Meldrum's acid as a novel cyanide reaction site. A theoretical study was conducted to rationalize the high reactivity and the photophysical properties of probe 1 and the 1-CN adduct. PMID- 23096903 TI - Phylogeny and systematics of Indian Polygonum sensu lato in the subfamily Polygonoideae based on ITS sequences of nuclear ribosomal DNA. AB - The nuclear ribosomal DNA internal transcribed spacer (ITS) sequences from 44 Indian Polygonum taxa were examined to investigate relationships among various sections proposed by earlier researchers. The maximum parsimony trees obtained from analysis of the ITS sequences suggested eight major groups of the Indian Polygonum spp. The relationships among different sections were largely congruent with those inferred from morphological characters as described by Hooker. Also, the treatment of the Persicaria suggested by Haraldson on the basis of anatomical characters proved to be nearly in line with that based on our molecular data. We provide a high resolution of phylogeny of the Himalayan Polygonum sensu lato and support merger of the section Amblygonon in the section Persicaria. Moreover, we made the first phylogenetic analysis of many of the less known Himalayan Polygonums, including Polygonum microcephalum, P. assamicum, P. recumbens, and P. effusum. Molecular differences were detected among Persicaria barbata collected from different geographical locations of India, although these were not differentiated at the morphological level. PMID- 23096904 TI - Human papillomavirus viral load in cervical intraepithelial neoplasia as a prognostic factor in a Mexican population. AB - Persistent infection with human papillomavirus (HPV) has been recognized as the main etiological factor of morbimortality in cervical cancer. Several factors have been associated with the development of cervical disease, but viral load has recently been proposed as an indicator of cervical neoplasia. Therefore, a single measurement of viral load could be a suitable biomarker. We examined HPV viral load as a prognostic biomarker of cervical neoplasia. We used cervical scrapes to determine the total HPV viral load of 46 Mexican patients with various stages of cervical intraepithelial neoplasia (CIN) using hybrid capture assay coupled with a quantitative polymerase chain reaction method for cellularity estimation. Viral load values of CIN2 and CIN3 samples were compared with samples without cervical pathology (WP); all values of viral load were normalized by number of cells analyzed. The analysis showed significant differences in viral load between CIN2 and WP samples (P = 0.01) and between CIN3 and WP samples (P = 0.02). By contrast, no significant difference was detected between viral loads in CIN2 and CIN3 samples. The results showed significant difference between viral loads in CIN2 and CIN3 samples and that in WP samples. HPV viral load was significantly different between patients with CIN2-CIN3 and those with WP and can be used as a predictor of lesions. PMID- 23096905 TI - Clinical and molecular genetic study of 12 Italian families with autosomal recessive Stargardt disease. AB - Stargardt disease was diagnosed in 12 patients from 12 families using complete ophthalmologic examination, fundus photography, fundus autofluorescence, and spectral-domain optical coherence tomography. DNA was extracted for polymerase chain reaction (PCR) and direct DNA sequencing (ABCA4 gene). Genetic counseling and eye examination were offered to 16 additional family members. Various patterns of presentation were observed in patients with clinical diagnoses of Stargardt disease. The genetic study identified 2 mutations in 75% of families (9/12); a second mutation could not be found in the remaining 25% of families (3/12). The most frequent mutation was G1961E, found in 17% of families (2/12). This finding is similar to that of a previous analysis report of an Italian patient series. Four new mutations were also identified: Tyr1858Asp, Leu1195fsX1196, p.Tyr850Cys, and p.Thr959Ala. Our results suggest that PCR and direct DNA sequencing are the most appropriate techniques for the analysis of the ABCA4 gene. However, this method requires supplementation with specific PCR analysis to diagnose large deletions. The study of the families identified healthy carriers and affected subjects in presymptomatic stages and was also useful for evaluating the risk of transmission to progeny. Combined ophthalmologic and genetic evaluation enabled better clinical management of these families. PMID- 23096906 TI - Allelic database and accession divergence of a Brazilian mango collection based on microsatellite markers. AB - Allelic patterns and genetic distances were examined in a collection of 103 foreign and Brazilian mango (Mangifera indica) accessions in order to develop a reference database to support cultivar protection and breeding programs. An UPGMA dendrogram was generated using Jaccard's coefficients from a distance matrix based on 50 alleles of 12 microsatellite loci. The base pair number was estimated by the method of inverse mobility. The cophenetic correlation was 0.8. The accessions had a coefficient of similarity from 30 to 100%, which reflects high genetic variability. Three groups were observed in the UPGMA dendrogram; the first group was formed predominantly by foreign accessions, the second group was formed by Brazilian accessions, and the Dashehari accession was isolated from the others. The 50 microsatellite alleles did not separate all 103 accessions, indicating that there are duplicates in this mango collection. These 12 microsatellites need to be validated in order to establish a reliable set to identify mango cultivars. PMID- 23096907 TI - Polymorphic microsatellite loci in the rapid racerunner Eremias velox (Squamata: Lacertidae). AB - We isolated and characterizated 12 polymorphic microsatellite loci in the rapid racerunner Eremias velox (Squamata: Lacertidae). The loci were screened in 37 E. velox individuals. The number of alleles ranged from 6 to 16. The observed heterozygosity ranged from 0.432 to 0.919, and the expected heterozygosity ranged from 0.685 to 0.902. These microsatellite markers should prove useful for population genetic studies of E. velox and other Eremias species. PMID- 23096908 TI - Mutations in NR5A1 and PIN1 associated with idiopathic hypogonadotropic hypogonadism. AB - We tested the hypothesis that mutations in NR5A1 and PIN1 cause disorders in gonadotropin-gonadal system development and function, throught direct DNA sequencing of the coding sequence and splice-sites of NR5A1 and PIN1 in 50 subjects with sporadic idiopathic hypogonadotropic hypogonadism. These patients were recruited from the Pediatrics section of Tongji Hospital, Tongji Medical College, in Wuhan, China. None of the affected subjects had clinical signs of adrenal insufficiency. The NR5A1 and PIN1 mutations were found in 7 of the 50 cases. These 7 individuals presented severely low serum concentrations of testosterone or of estradiol and gonadotropin. Adrenal insufficiency was not diagnosed in any of these patients. Consequently, NR5A1 and PIN1 mutations should be considered in idiopathic hypogonadotropic hypogonadism patients with normal karyotypes and without adrenal insufficiency. PMID- 23096909 TI - Identification and expression analysis of multiple FRO gene copies in Medicago truncatula. AB - Iron (Fe) is an essential element for plant growth. Commonly, this element is found in an oxidized form in soil, which is poorly available for plants. Therefore, plants have evolved ferric-chelate reductase enzymes (FRO) to reduce iron into a more soluble ferrous form. Fe scarcity in plants induce the FRO enzyme activity. Although the legume Medicago truncatula has been employed as a model for FRO activity studies, only one copy of the M. truncatula MtFRO1 gene has been characterized so far. In this study, we identified multiple gene copies of the MtFRO gene in the genome of M. truncatula by an in silico search, using BLAST analysis in the database of the M. truncatula Genome Sequencing Project and the National Center for Biotechnology Information, and also determined whether they are functional. We identified five genes apart from MtFRO1, which had been already characterized. All of the MtFRO genes exhibited high identity with homologous FRO genes from Lycopersicon esculentum, Citrus junos and Arabidopsis thaliana. The gene copies also presented characteristic conserved FAD and NADPH motifs, transmembrane regions and oxidoreductase signature motifs. We also detected expression in five of the putative MtFRO sequences by semiquantitative RT-PCR analysis, performed with mRNA from root and shoot tissues. Iron scarcity might be a condition for an elevated expression of the MtFRO genes observed in different M. truncatula tissues. PMID- 23096910 TI - Chloroplast DNA polymorphism and evolutional relationships between Asian cultivated rice (Oryza sativa) and its wild relatives (O. rufipogon). AB - We analyzed chloroplast DNA (cpDNA) polymorphism and phylogenic relationships between 6 typical indica rice, 4 japonica rice, 8 javanica rice, and 12 Asian common wild rice (Oryza rufipogon) strains collected from different latitudes in China by comparing polymorphism at 9 highly variable regions. One hundred and forty-four polymorphic bases were detected. The O. rufipogon samples had 117 polymorphic bases, showing rich genetic diversity. One hundred and thirty-one bases at 13 sites were identified with indica/japonica characteristics; they showed differences between the indica and japonica subspecies at these sites. The javanica strains and japonica shared similar bases at these 131 polymorphic sites, suggesting that javanica is closely related to japonica. On the basis of length analyses of the open reading frame (ORF)100 and (ORF)29-tRNA-Cys(GCA) (TrnC(GCA)) fragments, the O. rufipogon strains were classified into indica/japonica subgroups, which was consistent with the results of the phylogenic tree assay based on concatenated datasets. These results indicated that differences in indica and japonica also exist in the cpDNA genome of the O. rufipogon strains. However, these differences demonstrated a certain degree of primitiveness and incompleteness, as an O. rufipogon line may show different indica/ japonica attributes at different sites. Consequently, O. rufipogon cannot be simply classified into the indica/japonica types as O. sativa. Our data support the hypothesis that Asian cultivated rice, O. indica and O. japonica, separately evolved from Asian common wild rice (O. rufipogon) strains, which have different indica-japonica differentiation trends. PMID- 23096911 TI - Sexual dimorphism of STGC3 tumor suppressor function in nasopharyngeal carcinoma CNE2 cells. AB - STGC3 is a potential tumor suppressor in nasopharyngeal carcinoma. We previously found that CNE2 cells that re-expressed STGC3 formed smaller tumors in female mice than in male mice. Here, we investigated the sexual dimorphism of STGC3 as a tumor-suppressor in female and male nude mice injected subcutaneously with pcDNA3.1(+)-STGC3/CNE2 cells. ER-alpha was positively expressed in vitro in the CNE2 cells. The pcDNA3.1(+)-STGC3/CNE2 cell growth rate decreased after treatment with beta-estradiol in vitro. There were significant differences in tumor size or mass between pcDNA3.1(+)-STGC3/CNE2 and control cases (P < 0.05), but there were significant differences in tumor size between female and male nude mice in the STGC3 transfection groups, and the pcDNA3.1(+)-STGC3/CNE2 tumor growth rate in the female nude mice was the lowest in all cases (P < 0.05). There were no significant differences between female and male nude mice in control groups. Furthermore, a greater number of cells were blocked in the G(0)/G(1) phase in pcDNA3.1(+)-STGC3/ CNE2 tumor xenografts in the female mice. Protemic analysis found 9 differentially expressed proteins in the pcDNA3.1-STGC3/CNE2 xenograft tissues in females and males. A heat shock 70 protein 8 isoform 2 variant was identified as a down-regulated protein associated with cell cycle control and its downstream factor cyclin D1 was also decreased in STGC3-repressed xenografts in female mice. The data above suggest that STGC3 and its associated proteins play an important role in nasopharyngeal carcinoma gender differences. PMID- 23096912 TI - IL-8 mRNA expression in the mouse mammary glands during pregnancy and lactation. AB - Interkeukin-8 (IL-8) is an important inflammatory mediator. It is an angiogenic factor associated with inflammation and carcinogenesis. To date, research on IL-8 has been limited to its role as an indicator of inflammation. There has been no systematic research concerning IL-8 expression levels in the mouse mammary gland during pregnancy and lactation. Mouse mammary gland samples were collected on days 1, 6, 12, 18 of pregnancy and of lactation (6 mice per group). The expression levels of IL-8 mRNA were measured by semi-quantitative RT-PCR, with GAPDH as an internal control. IL-8 mRNA was highly expressed on day 1 of pregnancy in the mouse mammary glands (IL-8(IOD)/GAPDH(IOD) = 1.68), and then suddenly declined; it reached 0.74 and 0.71 on days 6 and 12 of pregnancy. On day 18 of pregnancy, it started to increase (IL-8(IOD)/GAPDH(IOD) = 1.02). However, the expression levels of IL-8 mRNA were not significant during pregnancy. During lactation, IL-8 expression level was lower than during pregnancy, but it stabilized at 0.32-0.41 (IL-8(IOD)/GAPDH(IOD)) from day 1 to day 18 of lactation, although the difference was not significant. We suggest that the changes in IL-8 expression level during development is related to its regulatory role in mouse mammary gland immunity. PMID- 23096913 TI - Structure and polymorphism of 16 novel Y-STRs in Chinese Han population. AB - Y-chromosome short tandem repeats (Y-STRs) are useful tools for identifying paternity origin and male-female mixed samples because of their male-specificity, haploid inheritance and relatively simplicity. We focused on novel Y-STRs deposited in the human Genome database from DYS708 to DYS726. We typed 16 male specific Y-STRs from males of a Chinese Han population residing in Shanxi Province (north China), including DYS708-719, DYS721-723, and DYS726, but failed in typing DYS720, DYS724 and DYS725. The 16 Y-STRs, with mean gene diversity (GD) of 0.79, included three trinucleotide Y-STRs (711, 718, 719), nine tetranucleotide STRs (708, 709, 710, 712, 713, 715, 722, 723, 726) and four pentanucleotide repeat STRs (714, 716, 717, 721). DYS712, consisting of eight alleles, was the most informative STR in our population, with a GD of 0.843. The STRs were classified as simple STRs and complex STRs, according to their structures based on sequencing. Genetic indexes, including allele frequencies, haplotype distribution and male-specificity were determined. The Y-STRs, especially those male-specific, tetra- and penta-nucleotide, with only one copy on Y-chromosome, and relative simple structures, such as DYS709, DYS714, DYS715, DYS716, DYS718, DYS719, and DYS726, were suggested for the future forensic DNA analysis, while DYS724 and DYS725 were not recommended for their multi-copy distribution. The population data provided putative Y-STRs for future genetic and forensic applications. PMID- 23096914 TI - Isolation and characterization of 48 polymorphic microsatellite markers for the blood clam Scapharca broughtonii (Arcidae). AB - Blood clams (Scapharca broughtonii) are widely cultivated and consumed in noutheast Asia. Forty-eight polymorphic microsatellite loci were developed for this clam using magnetic-bead hybridization enrichment. The number of alleles per locus ranged from 2 to 14. Polymorphism of these loci was assessed in 30 individuals from a population collected from coastal areas of Qingdao, China. The values of observed heterozygosity, expected heterozygosity and polymorphism information content per locus ranged from 0.1034 to 0.9655, from 0.1831 to 0.9208, and from 0.1638 to 0.8964, respectively. Forty-three of 48 loci conformed to Hardy-Weinberg equilibrium. These microsatellite loci would be useful for molecular genetic breeding, population genetics, genome mapping, and other relevant research on S. broughtonii. PMID- 23096915 TI - Genetic diversity of ITS sequences of Bursaphelenchus xylophilus. AB - The sequence variation of internal transcribed spacer (ITS) regions of ribosomal DNA has been routinely used for species identification and species-level phylogeny of the pinewood nematode, Bursaphelenchus xylophilus. In this study, the intraspecies ITS genetic diversity of B. xylophilus was evaluated. Three pinewood nematode isolates from the United States, Japan, and Portugal were used for polymerase chain reaction (PCR) ITS region amplification and sequencing. Multiple peaks were observed in sequencing chromatograms from ITS regions of American and Japanese isolates, suggesting the presence of more than one ribosomal sequence for each isolate. PCR products were further cloned and 10 clones of each isolate were subsequently sequenced. Additionally, the ITS regions of individual nematodes from each isolate were amplified, cloned and sequenced. Among the 3 B. xylophilus isolates analyzed, an intraspecific and intra-isolate molecular variability was found. The intra-isolate ITS molecular diversity in the American isolate was higher than that in the Japanese and Portuguese isolates. However, the level of sequence variation observed within isolates was about the same as that described among ITS repeats within individuals. PMID- 23096916 TI - Association of HTTLPR and 5-HT2A T102C polymorphisms with smoking characteristics and anthropometric profiles of Thai males. AB - Nicotine increases serotonin release in the brain. Gene polymorphisms in the serotonergic system have been suggested to be associated with smoking behavior. We investigated a possible association between two polymorphisms in the serotonergic system - HTTLPR of a serotonin transporter gene and 5-HT(2A) at position T102C - with biochemical and anthropometric parameters, and with cigarette smoking in an investigation of 200 smokers and 111 non-smokers. The two polymorphisms, HTTLPR and 5-HT(2A) at position T102C, were genotyped by PCR-RFLP. They were not significantly associated with smoking status in these Thai males. Among the smokers, thiocyanate concentrations and quantity of cigarettes smoked (cigarette pack-years) were significantly higher for individuals with LL/LS genotypes than SS genotypes of 5-HTTLPR (all P < 0.05), whereas "age at starting smoking" and "duration of smoking" were not significantly different between these two genotypes. Moreover, anthropometric variables, comprising triceps skinfold thickness, arm circumference, waist circumference, hip circumference, and waist to-hip ratio, were significantly higher for the CC/TC genotypes of 5-HT(2A) than the TT genotype (all P < 0.05), except for body mass index. HTTLPR and 5-HT(2A) T102C polymorphisms were not significantly associated with smoking status among Thai males; however, the HTTLPR polymorphism among smokers appears to be an indicator of increased smoking intensity consisting of cigarette pack-years and thiocyanate concentrations. The 5-HT(2A) T102C polymorphism plays a role in the anthropometric profiles, triceps skinfold thickness, arm circumference, waist circumference, hip circumference, and waist-to-hip ratio, but not smoking status in Thai subjects. PMID- 23096917 TI - Epstein-Barr virus DNA associated with gastric adenocarcinoma and adjacent non cancerous mucosa in patients from Manaus, Brazil. AB - Gastric cancer is one of most frequent causes of death in Brazil. The city of Manaus has one of the highest incidences of this disease in Brazil. The Epstein Barr virus (EBV) is a ubiquitous herpesvirus that is classified as a group 1 carcinogen by the International Agency for Research on Cancer. We obtained biopsies from 6 control subjects and 10 patients with gastric carcinomas living in Manaus. In the patients, the samples were taken from tumors and from adjacent non-cancerous mucosa. These samples were screened for EBV DNA by PCR to amplify the 288-bp fragments from the Bam M region. The EBV DNA was detected in 8 of the 10 tumor cases and in none of the 6 control subjects. In the positively identified samples, EBV DNA was detected in five corresponding resection margins. Previous research indicated only a weak association between EBV and gastric cancer. We suggest that EBV should be considered as a risk factor for gastric adenocarcinomas in Manaus. PMID- 23096918 TI - Two chitin metabolic enzyme genes from Hyriopsis cumingii: cloning, characterization, and potential functions. AB - Chitin, the second most important natural polymer in the world, and its N deacetylated derivative chitosan are found in a wide variety of organisms. These versatile biopolymers are associated with a broad range of biological functions. This article is the first to report the potential functions of 2 chitin metabolic enzyme genes from Hyriopsis cumingii. A chitinase-3 gene (Chi-3) and a chitin deacetylase gene (Cda) were cloned from H. cumingii and characterized. Semi-quantitative reverse transcription polymerase chain reaction analysis revealed that the Cda gene was expressed in blood, mantle, liver, stomach, kidney, intestine, gill, and foot, whereas Chi-3 was also expressed in those tissues but not in blood. The tissue-specific expression of H. cumingii Chi-3 indicated that other Chi genes may be involved in the H. cumingii immune system. Real-time quantitative polymerase chain reaction analysis showed that the expression of Chi-3 was significantly (P < 0.05) upregulated 12 h after shell damage, suggesting that Chi-3 might hydrolyze superfluous chitin after shell recovery and play a role in shell formation. Conversely, Cda expression did not change significantly (P > 0.05) to maintain a certain degree of acetylation in chitin/chitosan. This study enriches the basic research on chitin metabolic genes and lays foundations for further research of shell regeneration in mussels. PMID- 23096919 TI - Activation of the ERK1/2 pathway by the CaMEK gene via adeno-associated virus serotype 9 in cardiomyocytes. AB - Extracellular signal-regulated kinase (ERK1/2) is one of the mitogen-activated protein kinases, key components of the reperfusion injury salvage kinase pathway, which plays an important role in protecting the myocardium from lethal ischemia reperfusion injury. Constitutive activation of the mitogen-activated protein kinase kinase 1 (CaMEK) can promote ERK1/2 expression, which is thereby expected to exert protective action on the heart against ischemia-reperfusion injury. The adeno-associated virus serotype 9 vector (AVV9) is a novel tool for gene therapies targeting human diseases owing to its nonpathogenic capability for transducing nondividing cells and its long-term transgene expression. We used a recombinant AAV9 vector to deliver the CaMEK gene into cardiomyocytes and assessed whether AAV9 vector-mediated CaMEK gene transfection could enhance the long-term expression and activity of ERK1/2. Our observations suggest that AAV9 mediated gene expression is preferentially restricted to cardiomyocytes and that mediated CaMEK gene transfection enhanced the expression of ERK1/2 phosphorylation and consequently upregulated the expression of downstream components of ERK1/2 and its transcription factors. PMID- 23096920 TI - Genetic correlations between heifer subsequent rebreeding and age at first calving and growth traits in Nellore cattle by Bayesian inference. AB - We estimated heritability for subsequent rebreeding (SR) of heifers and genetic correlations between this trait and weaning weight (WW), weight gain from weaning to yearling (WG), age at first calving (AFC), and mature cow weight (MW), in order to evaluate whether SR could be included as selection criterion in Nellore cattle. The SR of heifers was defined by attributing a value of 1 (success) or 0 (failure) to heifers that calved or not, respectively, given that they had calved once before. Records from 127,430 Nellore animals were analyzed. Genetic parameters were estimated by Bayesian inference using a nonlinear (threshold) animal model for SR and a linear animal model for the other traits in three-trait analyses, including SR and WW in all analyses. The posterior means of heritability for SR, WW, WG, AFC, and MW were 0.18 +/- 0.02, 0.21 +/- 0.01, 0.30 +/- 0.01, 0.21 +/- 0.01, and 0.45 +/- 0.04, respectively. The posterior mean estimates of genetic correlations between SR and WW, WG, AFC, and MW were -0.20 +/- 0.06, 0.31 +/- 0.07, -0.77 +/- 0.05, and -0.15 +/- 0.09, respectively. Based on these genetic correlations, selection for higher gains for WG and younger AFC should result in an increase in heifer SR rates, while long-term selection for increasing WW should promote unfavorable responses in heifer SR. The use of breeding values for heifer SR as a selection criterion of Nellore bulls could increase heifer SR rate without significant changes in MW. PMID- 23096921 TI - Patterns of synonymous codon usage bias in the model grass Brachypodium distachyon. AB - Brachypodium distachyon has been proposed as a new model for the temperate grass because it is related to the major cereal grain species (such as wheat, barley, oat, maize, rice, and sorghum) and many forage and turf species. In this study, a multivariate statistical analysis was performed to investigate the characteristics of codon bias and the main factors affecting synonymous codon usage in Brachypodium. We found that low- and high-GC content genes with different codon usage occur frequently in the genome. The results of neutrality, correspondence, and correlation analyses indicated that mutational pressure and selective constraint were the main factors in shaping codon usage. Coding sequence length and the hydrophobicity of each protein were also identified as influences on codon usage bias, although their effect was minor. In addition, 27 codons, defined as "optimal codons", might provide useful information for gene engineering, gene prediction, and molecular evolution studies. PMID- 23096922 TI - Benchmark comparison of ab initio microRNA identification methods and software. AB - MicroRNAs (miRNAs) are short, non-coding RNA molecules that play an important role in the world of genes, especially in regulating the gene expression of target messenger RNAs through cleavage or translational repression of messenger RNA. Ab initio methods have become popular in computational miRNA detection. Most software tools are designed to distinguish miRNA precursors from pseudo hairpins, but a few can mine miRNA from genome or expressed sequence tag sequences. We prepared novel testing datasets to measure and compare the performance of various software tools. Furthermore, we summarized the miRNA mining methods that study next-generation sequencing data for bioinformatics researchers who are analyzing these data. Because secondary structure is an important feature in the identification of miRNA, we analyzed the influence of various secondary structure prediction software tools on miRNA identification. MiPred was the most effective for classifying real-/pseudo-pre-miRNA sequences, and miRAbela performed relatively better for mining miRNA precursors from genome or expressed sequence tag sequences. RNA-fold performed better than m-fold for extracting secondary structure features of miRNA precursors. PMID- 23096923 TI - Analysis of genetic diversity among wild bermudagrass germplasm from southwest China using SSR markers. AB - Fifty-five wild accessions of bermudagrass (Cynodon dactylon) were collected from southwest China (Sichuan, Chongqing, Yunnan, Guizhou, and Tibet), and their genetic diversity was analyzed using simple sequence repeat markers. A total of 267 polymorphic bands were detected with 18 primer combinations. The genetic similarity among the accessions ranged from 0.688 to 0.894 with an average of 0.797. All 55 wild accessions were clustered into 7 eco-geographic groups. Our data showed that the dendrogram was almost in accordance with geographic distribution, and accessions from the same collection sites tended to be clustered into the same group. A genetic differentiation analysis revealed that the percentage of genetic variance was 70.07 and 29.93% within and among groups, respectively. Finally, we discuss the implications of these results for C. dactylon in southwest China. PMID- 23096924 TI - Genome-wide analysis of the AP2/ERF superfamily in peach (Prunus persica). AB - We identified 131 AP2/ERF (APETALA2/ethylene-responsive factor) genes in material from peach using the gene sequences of AP2/ERF amino acids of Arabidopsis thaliana (Brassicaceae) as probes. Based on the number of AP2/ERF domains and individual gene characteristics, the AP2/ERF superfamily gene in peach can be classified broadly into three families, ERF (ethylene-responsive factor), RAV (related to ABI3/VP1), and AP2 (APETALA2), containing 104, 5, and 21 members, respectively, along with a solo gene (ppa005376m). The 104 genes in the ERF family were further divided into 11 groups based on the group classification made for Arabidopsis. The scaffold localizations of the AP2/ERF genes indicated that 129 AP2/ERF genes were all located on scaffolds 1 to 8, except for two genes, which were on scaffolds 17 and 10. Although the primary structure varied among AP2/ERF superfamily proteins, their tertiary structures were similar. Most ERF family genes have no introns, while members of the AP2 family have more introns than genes in the ERF and RAV families. All sequences of AP2 family genes were disrupted by introns into several segments of varying sizes. The expression of the AP2/ERF superfamily genes was highest in the mesocarp; it was far higher than in the other seven tissues that we examined, implying that AP2/ERF superfamily genes play an important role in fruit growth and development in the peach. These results will be useful for selecting candidate genes from specific subgroups for functional analysis. PMID- 23096925 TI - Transferability and characterization of simple sequence repeat markers from Anacardium occidentale to A. humile (Anacardiaceae). AB - Use of molecular markers can be limited by the high cost and extensive time required for their development. Transfer of simple sequence repeat (SSR) markers reduces the cost and time limitations and has allowed the use of these markers in a larger number of species. We tested 11 SSR markers previously developed for Anacardium occidentale on A. humile. The 11 loci were successfully amplified in A. humile. All loci were polymorphic and generated a mean of 5.4 alleles per locus. The observed heterozygosity was lower than the expected heterozygosity under Hardy-Weinberg equilibrium for most loci, with mean values of 0.463 and 0.696, respectively. The endogamy coefficients were positive and significant for seven loci. However, the combined probability of paternity exclusion was high, and the combined probability of genetic identity was low. None of the pairs of loci were in linkage disequilibrium. The informative power of these loci demonstrates that they are suitable for studies of diversity and genetic structure of natural populations of A. humile. In addition, the loci are suitable for estimating gene flow between populations, assessing species crossing preferences, and performing interspecific comparisons. PMID- 23096926 TI - Isolation and characterization of microsatellite loci for the herbaceous tuber crop, Amorphophallus konjac (Araceae). AB - Amorphophallus konjac is an herbaceous tuber crop with tremendous potential for commercial development. We report the development of microsatellite primers for this important crop species. Thirteen polymorphic microsatellite markers were developed and tested in two populations of A. konjac from the Wuling Mountain Region (WL population) and the Yunnan Province (YN population) in China. The number of alleles per locus ranged from 1 to 7; the observed and expected heterozygosities ranged from 0 to 1 and from 0 to 0.844, respectively, in the two populations. These microsatellite markers will facilitate further studies in population genetics and utilization of A. konjac. PMID- 23096927 TI - Single nucleotide polymorphisms in the ORM1-like 3 gene associated with childhood asthma in a Chinese population. AB - Single nucleotide polymorphism (SNP)-based genome-wide association studies have revealed that polymorphisms of the ORM1-like 3 (ORMDL3) gene are associated with childhood asthma. We investigated genetic associations of SNPs in and around the ORMDL3 gene with childhood asthma in a Chinese population. Genomic DNA was extracted from peripheral venous blood drawn from 152 subjects with childhood asthma and from 190 control subjects. SNP genotyping was performed with the MassARRAY system (Sequenom) by means of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Among the six SNPs, only the genotype frequencies of rs7216389 were significantly different between asthmatic children and controls. Asthmatic children had a significantly higher frequency of T alleles [odds ratio (OR) = 1.653, 95% confidence interval (95%CI) = 1.170-2.333] in rs7216389, than controls. The TT genotype of rs7216389 was found to be a significant risk factor for childhood asthma by logistic regression analysis (OR = 1.704, 95%CI = 1.105-2.628). There was no significant association between the TT genotype of rs7216389 and clinical features of childhood asthma. We conclude that the ORMDL3 gene influences childhood asthma and that the TT genotype of the rs7216389 polymorphism is associated with childhood asthma in the Chinese population. PMID- 23096928 TI - PPARalpha agonist Wy14643 suppresses cathepsin B in human endothelial cells via transcriptional, post-transcriptional and post-translational mechanisms. AB - Cathepsin B has been shown to be important in angiogenesis; therefore, understanding its regulation in endothelial cells should provide fundamental information that will aid in the development of new treatment options. Peroxisome proliferator-activated receptors (PPARs) have been shown to have anti inflammatory, anti-angiogenic and anti-tumorigenic properties. We explored the influence of a PPARalpha agonist on cathepsin B expression in human endothelial cells. The PPARalpha agonist, Wy14643, was found to inhibit cathepsin B protein expression. Further studies demonstrated the Wy14643-dependent but PPARalpha independent suppression of cathepsin B. This has been previously described for other PPAR agonists. Wy14643 suppressed the accumulation of cathepsin B mRNA, which was accompanied by the selective suppression of a 5'-alternative splice variant. Consistent with these results, luciferase promoter assays and electrophoretic mobility shift analysis demonstrated that the suppression was facilitated by reduced binding of the transcription factors USF1/2 to an E-box within the cathepsin B promoter. Additionally, Wy14643 treatment resulted in a reduction in cathepsin B half-life, suggesting a posttranslational regulatory mechanism. Overall, our results suggest that the PPARalpha-dependent anti angiogenic action of Wy14643 seems to be mediated, in part, by Wy14643-dependent but PPARalpha-independent regulation of cathepsin B expression. PMID- 23096933 TI - Synthesis of optically active tertiary silanes via Pd-catalyzed enantioselective arylation of secondary silanes. AB - We herein describe the development of an efficient enantioselective catalytic system that promotes the arylation of secondary silanes. Our method involves treatment of secondary silanes and aryl iodides with a Pd(2)(dba)(3)-asymmetric phosphoramidite ligand system to afford optically active tertiary silanes with good enantioselectivities. PMID- 23096929 TI - Thyroid transcription factor-1 expression is an independent predictor of recurrence and correlates with the IASLC/ATS/ERS histologic classification in patients with stage I lung adenocarcinoma. AB - BACKGROUND: In the current study, the authors investigated whether thyroid transcription factor-1 (TTF-1) expression is correlated with the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and whether it stratifies patients with stage I lung adenocarcinoma with respect to disease recurrence. METHODS: Patients with stage I lung adenocarcinoma were classified according to the IASLC/ATS/ERS classification. Tissue microarrays were constructed and immunostaining for TTF-1 was performed. A total of 452 cases were available for analysis. Tumors were dichotomized based on the intensity of nuclear TTF-1 expression as negative (score of 0) or positive (score of 1-3). The cumulative incidence of recurrence (CIR) was used to estimate disease recurrence probabilities. RESULTS: TTF-1 expression was identified in 92% of patients, including 100% of patients with minimally invasive or lepidic-predominant adenocarcinoma, 94% of patients with acinar-predominant adenocarcinoma, 98% of patients with papillary-predominant adenocarcinoma, 93% of patients with micropapillary-predominant adenocarcinoma, 86% of patients with solid-predominant adenocarcinoma, 67% of patients with colloid-predominant adenocarcinoma, and 47% of patients with invasive mucinous carcinoma. The CIR for patients with negative TTF-1 expression (n = 34 patients; 5-year CIR, 40%) was significantly higher than that for patients with positive TTF-1 expression (n = 418 patients; 5-year CIR, 15%) (P < .001). Among the patients with intermediate-grade tumors, the CIR for patients with negative TTF-1 expression (n = 16 patients; 5-year CIR, 45%) was significantly higher than that for patients with positive TTF-1 expression (n = 313 patients; 5-year CIR, 14%) (P < .001). On multivariate analysis, negative TTF 1 expression was found to be significantly correlated with an increased risk of disease recurrence (hazards ratio, 2.55; P = .009). CONCLUSIONS: TTF-1 expression was found to be an independent predictor of disease recurrence, stratifying intermediate-grade tumors into 2 prognostic subsets, and it correlates with the IASLC/ATS/ERS classification. PMID- 23096934 TI - Dynamics of spiking neurons: between homogeneity and synchrony. AB - Randomly connected networks of neurons driven by Poisson inputs are often assumed to produce "homogeneous" dynamics, characterized by largely independent firing and approximable by diffusion processes. At the same time, it is well known that such networks can fire synchronously. Between these two much studied scenarios lies a vastly complex dynamical landscape that is relatively unexplored. In this paper, we discuss a phenomenon which commonly manifests in these intermediate regimes, namely brief spurts of spiking activity which we call multiple firing events (MFE). These events do not depend on structured network architecture nor on structured input; they are an emergent property of the system. We came upon them in an earlier modeling paper, in which we discovered, through a careful benchmarking process, that MFEs are the single most important dynamical mechanism behind many of the V1 phenomena we were able to replicate. In this paper we explain in a simpler setting how MFEs come about, as well as their potential dynamic consequences. Although the mechanism underlying MFEs cannot easily be captured by current population dynamics models, this phenomena should not be ignored during analysis; there is a growing body of evidence that such collaborative activity may be a key towards unlocking the possible functional properties of many neuronal networks. PMID- 23096935 TI - Does valgus femoral osteotomy improve femoral head roundness in severe Legg-Calve Perthes disease? AB - BACKGROUND: Many surgeons perform a varus femoral or Salter pelvic osteotomy in patients with Legg-Calve-Perthes (LCP) disease. However, more severely deformed femoral heads show greater congruency in adduction rather than in abduction. Therefore, a valgus-(flexion) femoral osteotomy (VFO) seems preferable rather than a varus femoral or Salter pelvic osteotomy. QUESTIONS/PURPOSES: We evaluated whether the VFO improves (1) femoral head roundness, (2) radiographic parameters reflecting hip subluxation, and (3) function. METHODS: We treated 25 patients (25 hips; 18 lateral pillar C and seven B) in the late fragmentation stage by VFO. Seven patients had additional pelvic procedures. VFO was performed at a mean age of 9.8 years. Three hips were Stulberg Class II, 20 were Class III, and two were Class IV. The following components of femoral head roundness were calculated from preoperative MRI and final radiographs: lateral and medial head roundness (LHR and MHR); anterior and posterior head roundness (AHR and PHR); central head height; and the ratios MHR/LHR and PHR/AHR. Continuity of Shenton's line, medial gap ratio were evaluated. Function was determined with the Iowa hip score. Minimum followup was 3.1 years (mean, 6.3 years; range, 3.1-11.2 years). RESULTS: All femoral head roundness measurements improved, with greatest improvement in the lateral and anterior head. Pillar C hips showed greater relative improvement than pillar B hips. The continuity of Shenton's line improved and the mean medial gap ratio decreased. Mean Iowa hip score improved from 71 before surgery to 90 at the last followup. CONCLUSIONS: VFO appears to help the deformed femoral head in the fragmentation stage to remodel to fit the acetabulum. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23096936 TI - Protective effects of resveratrol on salivary gland damage induced by total body irradiation in rats. AB - OBJECTIVES/HYPOTHESIS: One of the most common acute side effects of irradiation is xerostomia, which results from damage to the salivary gland cells by direct ionization. Resveratrol is a natural compound with profound anti-inflammatory and antioxidant properties. The purpose of the present study was to investigate the potential protective effects of resveratrol on injury to the salivary glands of rats that were exposed to total body irradiation. STUDY DESIGN: An experimental study at the Inonu University School of Medicine. METHODS: Twenty-nine female rats were randomized into four groups: group 1, high-dose (100 mg/kg) resveratrol group (n = 7); group 2, low-dose (10 mg/kg) resveratrol group (n = 7); group 3, control (vehicle) rats (n = 7); and group 4, sham-irradiation group (n = 8). The medications were administered as single doses, and the rats were exposed to total body irradiation 24 hours after the treatment. The animals were sacrificed the following day, and the parotid and submandibular glands were excised. Salivary gland histology and the tissue levels of glutathione (GSH), nitric oxide (NO), and malondialdehyde (MDA) were investigated. RESULTS: The rats in group 1 showed significantly decreased acinar loss and less ductal damage and cell necrosis than those of the control group (P < .05). Antioxidant GSH levels were significantly increased by high doses of resveratrol treatment. The tissue activities of MDA in both the parotid and submandibular glands were significantly reduced in group 1. Low-dose resveratrol treatment did not significantly alter the tissue levels of MDA. CONCLUSIONS: Resveratrol at relatively high doses can reduce the irradiation dependent salivary gland damage, suggesting that this natural antioxidant may be effectively used to lessen the side effects related to salivary gland dysfunction that is induced by irradiation. PMID- 23096938 TI - Multidrug-resistant hepatitis B virus resulting from sequential monotherapy with lamivudine, adefovir, and entecavir: clonal evolution during lamivudine plus adefovir therapy. AB - Whether multidrug-resistant (MDR) hepatitis B virus (HBV) harbors mutations co located in the same HBV clones that confer reduced sensitivity to antiviral therapy remains uncertain. This study investigated the evolution of MDR HBV strains developed from sequential monotherapy with lamivudine (LAM), adefovir (ADV), and entecavir (ETV) during LAM plus ADV salvage therapy. Sera were obtained from six patients who had developed sequential resistance to LAM, ADV, and ETV before and during LAM plus ADV therapy. The HBV genomes from each patient were amplified, cloned, and sequenced. Among 6 sets of 20 clones obtained before salvage therapy, all clones harbored the rtM204V mutation, and ETV-resistant mutations were detected with the rtM204V in 108 clones. The rtA181 mutation was not detected at baseline, but emerged in five patients during therapy. Among 9 sets of 20 clones obtained during salvage therapy, 39 clones harbored rtA181T/V +/- rtN236T mutations, which were detected in the absence of rtM204 and ETV resistant mutations in 37 clones (94.9%). Only two clones (5.1%) harbored both rtA181T/V and ETV-resistant mutations. The rtA181T/V mutation emerged after reversion from ETV-resistant mutants to wild-type HBV. Five patients achieved a partial virologic response to LAM plus ADV therapy. In conclusion, the majority of MDR mutations existed in different genomes. Suboptimal response to LAM plus ADV therapy may not result from the co-localization of MDR HBV mutations in the same genome, but instead the low antiviral potency of these drugs. Thus, more potent antiviral drug combinations may be an effective salvage therapy for patients infected with MDR HBV. PMID- 23096937 TI - Radiofrequency ablation of benign non-functioning thyroid nodules: 4-year follow up results for 111 patients. AB - OBJECTIVES: To evaluate the clinical outcomes and safety of radiofrequency (RF) ablation for benign non-functioning thyroid nodules over a 4-year follow-up. METHODS: We evaluated 126 benign non-functioning thyroid nodules of 111 patients treated with RF ablation and followed-up more than 3 years. RF ablation was performed using the Cool-Tip RF system and an internally cooled electrode. Nodule volume and cosmetic and symptom scores were evaluated before treatment and during follow-up. Complications and factors related to efficacy were evaluated. RESULTS: The mean follow-up duration was 49.4 +/- 13.6 months. Thyroid nodule volume decreased significantly, from 9.8 +/- 8.5 ml before ablation to 0.9 +/- 3.3 ml (P < 0.001) at final evaluation: a mean volume reduction of 93.4 +/- 11.7 %. The mean cosmetic (P < 0.001) and symptom scores (P < 0.001) improved significantly. Factors related to efficacy were initial solidity and volume. The overall recurrence rate was 5.6 % (7/126). The overall complication rate was 3.6 % (4/111). CONCLUSIONS: RF ablation was effective in shrinking benign thyroid nodules and in controlling nodule-related problems over a 4-year follow-up. There were no life-threatening complications or sequelae. Therefore, RF ablation can be used as a non-surgical treatment for patients with benign non-functioning thyroid nodules. PMID- 23096939 TI - Population pharmacokinetics of digoxin in elderly patients. AB - This study was aimed at determining the population pharmacokinetics of digoxin and identifying factors that explain pharmacokinetic variability in elderly patients. The data of 142 elderly patients and 448 samples were collected after repetitive oral digoxin. Blood samples were drawn at various times after administration. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling program (NONMEM). A one-compartment model with first order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices as well as other commonly used co-medications were explored. The typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 8.9 L h(-1) (43.2 %) and 420 L (65.8 %), respectively. The residual variability was 31.6 %. CL/F decreased significantly with renal function, total body weight, calcium channel blockers or spironolactone co therapy and symptom with congestive heart failure. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5 % of the estimates from NONMEM. These results provide important information for clinicians to optimize digoxin regimens in elderly patients. PMID- 23096940 TI - Different approaches to the study of chelating agents for iron and aluminium overload pathologies. AB - Our objective is to illustrate the activity of the groups operating in Italy involved in identification and study of new chelating agents, mainly intended for treatment of human pathology correlated with metal overload. The objective of "chelation therapy" is removal of toxic metal ions from the human body or attenuation of their toxicity by transforming them into less toxic compounds or by dislocating them from the site at which they exert a toxic action. Because most of this research activity is related to chelating agents for iron and aluminium, diseases related to these two metal ions are briefly treated. Iron overload is the most common metal toxicity disease worldwide. The toxicity of aluminium in dialysis patients was a serious problem for haemodialysis units in the seventies and eighties of the last century. In particular, this review focuses on research performed by the group at Cagliari and Ferrara, and by that at Padova. The former is studying, above all, bisphosphonate and kojic acid derivatives, and the latter is investigating 3,4-hydroxypyridinecarboxylic acids with differently substituted pyridinic rings. PMID- 23096941 TI - A novel, disposable, screen-printed amperometric biosensor for ketone 3-beta hydroxybutyrate fabricated using a 3-beta-hydroxybutyrate dehydrogenase mesoporous silica conjugate. AB - A disposable amperometric biosensor for ketone 3-beta-hydroxybutyrate (3HB) has been developed successfully. The sensor is based on a screen-printed carbon electrode containing Meldola's Blue (MB) and sensing components containing nicotinamide adenine dinucleotide (NAD(+)) and 3-beta-hydroxybutyrate dehydrogenase (3HBDH) immobilized in mesoporous silica (FSM8.0) using an aqueous photo-cross-linkable polymer matrix of polyvinyl alcohol (O-391), and it requires only a small sample volume of 10 MUL for the measurement. The behavior of a resulting biosensor, i.e., 3HBDH-FSM8.0/NAD(+)/MB-SPCE, was examined in terms of NAD(+) concentration for construction, pH, applied potential, operational range, selectivity, and storage stability. The sensor showed an optimum response at a pH of 7.6 and at an applied potential of -50 mV. The determination range and the response time for 3HB were from 30 MUM to 8 mM and approximately 30 s, respectively. In addition, the sensor was quite stable and maintained >90% of its initial response after being stored for over 6 months. This result implies that our method provides a novel biosensor for ketone 3-beta-hydroxybutyrate which is easy-to-use, cost-effective, and has good reproducibility, which are vital for commercial purposes. PMID- 23096942 TI - Phyllochron dynamics during the course of late shoot development might be affected by reproductive development in rice (Oryza sativa L.). AB - Phyllochron, defined as the interval time between appearances of successive leaves on a shoot, is an important measurement to know the developmental state of a shoot apex in rice. Previous studies revealed that phyllochron dynamics during the course of shoot development of rice was divided into three stages, regardless of environment and genotype: (1) maintenance of short phyllochron in the early developmental stage, (2) drastic increase of phyllochron depending on leaf number from the base in the late stage, and (3) decrease of phyllochron before final leaf stage. Recent studies of shoot development of rice suggested that the first and the second stage might reflect the internal state of juvenile and adult phase, respectively. The remaining question is what internal state is related to the third stage. In the present study, to give a suggestion for the question, we performed the two experiments using near-isogenic lines (NILs) for flowering-time genes. First, using new data from the previous study, we statistically showed that reproductive initiation significantly affected the decreasing point of phyllochron dynamics during the late shoot development. Second, we demonstrated that photoperiod-strongly sensitive NILs tended to maintain increase of phyllochron during the course of late development when reproductive initiation was inhibited by an extremely long day condition. Then, we suggest that reproductive initiation might trigger suppression of internal increase of phyllochron during the late development. Variation of pattern of the phyllochron dynamics between environments and between genotypes, which has been identified by the previous studies, was discussed based on the suggestion. PMID- 23096943 TI - Effects of head positioning on cephalometric measurements. AB - OBJECTIVE: The goal of the present work was to evaluate different head positions for their effects on cephalometric analysis. MATERIALS AND METHODS: Cephalograms were obtained from a skull phantom adjusted to various degrees of inclination (0 degrees , 2 degrees , 4 degrees , 6 degrees , 8 degrees , 10 degrees ), lateral tilting (0 degrees , 2 degrees , 4 degrees , 6 degrees , 8 degrees , 10 degrees ), and rotation (0 degrees , 3 degrees , 6 degrees , 9 degrees , 12 degrees , 15 degrees , and 21 degrees ). All these combinations resulted in a total of 210 digital cephalograms for assessment. On-screen analysis of these images by an orthodontist was completed within a few days. RESULTS: Lateral tilting and rotation revealed considerably stronger effects on the values measured than inclination. Starting at 2 degrees of tilting or 3 degrees of rotation, numerous parameters yielded deviations of >= 2 degrees or 2 mm from the baseline values. Increasing degrees of rotation showed more pronounced value changes than increasing degrees of lateral tilting. Skeletal and dental parameters whose landmarks are mainly located in the median plane were less susceptible than parameters whose reference points had to be averaged. Values of parameters located in the median plane were less affected by rotation when combined with higher degrees of initial lateral tilting (> 6 degrees ) than with lower ones. CONCLUSION: The usefulness of cephalometric data becomes limited once the head is rotated by 3 degrees or laterally tilted by 2 degrees . Values obtained in the median plane are more stable than those obtained in peripheral locations. Various degrees of inclination applied to the skull phantom with its solid structures had no measurable effects. Accurate head positioning is an essential prerequisite for obtaining meaningful results from cephalograms based on reproducibly identifiable landmarks. PMID- 23096944 TI - Gene analysis of signal transduction factors and transcription factors in periodontal ligament cells following application of dynamic strain. AB - OBJECTIVE: Orthodontic treatment is usually associated with the application of forces to teeth and periodontium. Instrumental in transmitting these forces are the cells of the periodontal ligament (PDL). In the present study, we used an established strain model to investigate the potential role of biophysical stimulation in modulating the gene expression pattern of these PDL cells. MATERIALS AND METHODS: PDL cells derived from non-carious and periodontally healthy teeth of six patients were grown on culture plates coated with collagen type I. Upon completion of culture, dynamic strain was applied to the cells for 24 h, using 3% of tensile force and a frequency of 0.05 Hz. This loading protocol for biomechanical stimulation was followed by extracting the RNA from the cells and using a RT(2) PCR array((r)) for analysis. RESULTS: Compared to non stimulated control cells, this analysis revealed the induction of several factors (e.g., RELA, IRF1, MAX, MYC, CDKN1B, BCL2, BCL2A1) known to influence tissue homeostasis by contributing essentially to cell proliferation, cell differentiation, and the inhibition of apoptosis. CONCLUSION: This study demonstrates that the biomechanical stimulation of PDL cells is an important factor in periodontal tissue homeostasis. PMID- 23096945 TI - Material testing of reconditioned orthodontic brackets. AB - OBJECTIVE: While all manufacturers of orthodontic brackets label these products for single use, there are commercial providers offering bracket reconditioning (or "recycling"). We conducted this study to investigate the effects of different recycling techniques on material-related parameters in orthodontic brackets, aiming to derive indications for clinical use and conclusions about the biocompatibility, longevity, and application of recycled brackets. MATERIALS AND METHODS: New metal brackets (equilibrium((r)); Dentaurum, Ispringen, Germany) were compared to brackets recycled by different techniques, including direct flaming with a Bunsen burner, chemical reconditioning in an acid bath, a commercial unit (Big Jane; Esmadent, IL, USA), and outsourcing to a company (Ortho Clean, Dellstedt, Germany). Material-related examinations included the following: (1) corrosion behavior by static immersion testing and use of a mass spectrometer to determine nickel-ion concentrations in the corrosive medium, (2) surface features in scanning electron micrographs before and after corrosion testing, (3) Vickers hardness using a hardness testing machine, (4) shear bond strength as defined in DIN 13990-1, (5) dimensional stability of the bracket slots by light microscopy, and (6) frictional loss as assessed by an orthodontic measurement and simulation system (OMSS). Each examination was performed on ten brackets. Student's t-test was used for statistical analysis. RESULTS: Compared to the new brackets, those recycled in an acid bath or by a commercial provider revealed significant dimensional changes (p<0.05). Corrosion on the recycled brackets varied according to the recycling techniques employed. The group of brackets recycled by one company revealed hardness values that differed from those of all the other groups. No significant differences were observed in nickel ion release, frictional loss, and shear bond strength. CONCLUSION: Recycling was found to significantly reduce the corrosion resistance and dimensional stability of orthodontic brackets. As the savings generated by recycling do not justify the risks involved, the practice of labeling orthodontic brackets for single use remains a responsible precaution that safeguards patients and orthodontists against definite risks. PMID- 23096946 TI - Self-assessment and dialogue: can it improve learning? PMID- 23096947 TI - IL-17F co-expression improves cell growth characteristics and enhances recombinant protein production during CHO cell line engineering. AB - The generation of a high productivity cell line is a critical step in the production of a therapeutic protein. Many innovative engineering strategies have been devised in order to maximize the expression rate of production cells for increased process efficiency. Less effort has focused on improvements to the cell line generation process, which is typically long and laborious when using mammalian cells. Based on unexpected findings when generating stable CHO cell lines expressing human IL-17F, we studied the benefit of expressing this protein during the establishment of production cell lines. We demonstrate that IL-17F expression enhances the rate of selection and overall number of selected cell lines as well as their transgene expression levels. We also show that this benefit is observed with different parental CHO cell lines and selection systems. Furthermore, IL-17F expression improves the efficiency of cell line subcloning processes. IL-17F can therefore be exploited in a standard manufacturing process to obtain higher productivity clones in a reduced time frame. PMID- 23096948 TI - Prospective study of physical activity and quality of life in Japanese women undergoing total hip arthroplasty. AB - BACKGROUND: Improvement in quality of life (QoL) in patients who went through total hip arthroplasty (THA) is well studied, while the number of studies on improvement in actual daily activity in THA patients is limited. The purpose of the study was (1) to describe the pre- to postoperative changes in physical activity (PA) levels, (2) compare PA levels with healthy controls, and (3) examine the association between PA levels and QoL in Japanese women undergoing THA. METHODS: PA was measured by pedometers, and QoL was assessed by the Short Form 8 and the Oxford Hip Scale questionnaires. Consecutive patients undergoing primary THA at Saga University Hospital, Japan, in 2008 were eligible for the study. QoL and pedometers with accelerometers were mailed to THA patients 1 month pre-THA and 6 and 12 months post-THA. The control group completed a single assessment of questionnaires and pedometers. RESULTS: Thirty-eight THA patients completed the study. Preoperatively, the patient group had significantly lower QoL scores than the comparison group. However, these differences disappeared by 12 months post-THA. When improvement of PA function in THA patients was compared with healthy controls, light PA was already 78 % of the healthy controls at the pre-THA period and improved to 90 % at 12 months. In contrast, moderate PA was 27 % of the controls and rose to 77 % by 12 months, and vigorous PA remained low throughout the study period. PA was correlated with QoL scores. CONCLUSION: The study shows the relative recovery process of PA indicators in THA patients and the contribution of PA to the improvement of QoL. PMID- 23096949 TI - Neglected neck femur fractures in adolescents and young adults: factors predicting the surgical outcome. AB - BACKGROUND: Neglected femoral neck fracture in young adults is an intriguing problem. This retrospective study tried to solve that challenge through open reduction, cannulated screw internal fixation, autogenous iliac bone and bone marrow grafting. METHODS: Thirty-six cases were studied; they were classified according to Sandhu et al.'s classification. Twenty cases were type I and 16 cases were type II fractures; the mean age was 26.8 years; fracture neglect averaged 44.6 days. Twenty cases had posterior comminution and 16 cases had anterior comminution. All cases had open reduction, cannulated screw internal fixation, autogenous iliac bone and bone marrow grafting. The Harris hip score and Matta et al. grading system were applied for functional and radiological evaluation, respectively. RESULTS: The average postoperative follow-up was 25.3 months; 94.4 % of the cases had solid union in a mean of 19.6 weeks. Functionally, the Harris hip score averaged 87.8 points. Nonunion, avascular necrosis and coxa vara complicated two, two and four cases, respectively. Fair and poor radiological results were related to coxa vara and avascular necrosis, respectively. Nonunion was significantly related to posterior comminution, type II neglected fracture, and a neglect of more than 45 days. Age groups more than 30 years old and postoperative neck-shaft angles <140 degrees were significantly associated with late-onset radiological healing and nonunion. CONCLUSIONS: Cannulated screw osteosynthesis augmented by autogenous bone and bone marrow grafting is a simple, easy-to-perform surgical procedure with encouraging clinical outcomes for selected patients complaining of that difficult problem. PMID- 23096950 TI - The use of tissue sealants to deliver antibiotics to an orthopaedic surgical site with a titanium implant. AB - BACKGROUND: Orthopaedic surgery is associated with unacceptable infection rates that respond poorly to systemic antibiotics. The objective of this study was to use an animal model for orthopaedic implant infection to examine the ability of a new-generation fibrin tissue sealant to effectively deliver antibiotics to the surgical site. METHODS: The antibiotics cefazolin, fusidic acid or 5-fluorouracil were blended into Vitagel tissue sealant. The release rate of the drugs was measured using HPLC methods and bioactivity was measured by the zone of inhibition method with pathogenic Staphylococcus aureus. The antibiotic activity of the drug-loaded sealant was then tested in rats using infected orthopaedic surgical sites (titanium clip on spine). Efficacy was evaluated by residual bacterial counts on clips, clinical observations of infection, and histological findings. RESULTS: The drugs were released in a controlled manner over 2-4 days. All three antibiotics demonstrated strong antibacterial activity when released from the sealants. None of the treated animals demonstrated systemic illness. Post mortem dissection revealed a well-encapsulated abscess surrounding the titanium clip with erosion of the bony process. Using an inoculum of 1-5 * 10(3) CFU, treatment with antibiotic-loaded fibrin sealant demonstrated reduced infective swelling and reduced bacterial counts on surgical clip swabs compared to control rats or rats treated with antibiotic only. This model allowed for almost 100 % infectivity with a 0 % mortality rate due to infection, mimicking the clinical features of human implant infection. CONCLUSION: The results support the use of antibiotic-loaded commercially available fibrin sealants to prevent infection after implant surgery. PMID- 23096951 TI - The influence of patellar resurfacing on patellar kinetics and retropatellar contact characteristics. AB - BACKGROUND: Femoropatellar complications are one of the most common problems after total knee arthroplasty (TKA). However, the question of whether to resurface the patella remains controversial. Therefore, we evaluated the kinetics and the retropatellar contact characteristics of patella resurfacing with fixed and gliding surfaces. METHODS: Eight Thiel-embalmed cadaver knees were tested- first intact, then after TKA without patellar resurfacing, and finally with additional patellar resurfacing--while flexing the knee from 0 degrees to 100 degrees . We tested a fixed as well as a gliding patella surface. During the examination, quadriceps and hamstring forces were applied. The retropatellar pressure was determined with a special patella sensor, and the patellar kinetics were measured using an optical three-dimensional motion analysis system. RESULTS: Resurfacing the patella caused a significant increase in retropatellar pressure and a significant decrease in retropatellar contact area. Using a fixed patella, the retropatellar pressure nearly quadrupled in higher flexion compared to the native patella. Furthermore, the lateral movement of the patella increased after TKA, especially after additional patellar resurfacing. CONCLUSIONS: Resurfacing the patella routinely is not advised. When osteoarthritis of the patella is found, the gliding patella should be preferred. PMID- 23096952 TI - Over 10-year follow-up of functional outcome in patients with bone tumors reconstructed using distraction osteogenesis. AB - BACKGROUND: The aim of this study was to investigate the long-term functional capabilities of patients who underwent bone distraction for the treatment of bone defects caused by bone tumor excision. METHODS: Bone distraction was indicated for patients with stage IIB malignant bone tumors when chemotherapy was judged to be effective and an epiphysis could be preserved or for patients with low-grade or aggressive benign bone tumors. Twenty-two patients who underwent reconstruction with bone distraction and were followed up for at least 10 years were retrospectively investigated. Patients included 8 males and 14 females, with a mean age of 25.3 years. Tumor types included seven osteosarcomas, two osteofibrous dysplasias, one Ewing's sarcoma, five low-grade osteosarcomas, two adamantinomas, and five giant cell tumors. Chemotherapy was performed during bone distraction in 8 cases. Bone transport was used in 17 cases, while shortening distraction was used in 5 cases. RESULTS: The mean distraction length was 8.1 cm, and the mean external fixation period was 301 days. The average Musculoskeletal Tumor Society score (used to measure functional outcome) was 91.5 % at mean follow-up of 202 months. Fourteen patients were able to play sports without any difficulty. CONCLUSIONS: Epiphyseal preservation and reconstruction by bone distraction require both time and effort, but can provide excellent long-term outcomes, resulting in a stable reconstruction that functionally restores the natural limb. PMID- 23096953 TI - Minimum invasive posterior decompression for cervical spondylotic amyotrophy. AB - BACKGROUND: Cervical spondylotic amyotrophy (CSA), characterized by amyotrophy and muscular weakness of the upper limbs, is caused by damage to anterior spinal root or anterior horn of the spinal cord. Formerly, anterior decompression and fusion were performed for treatment of CSA, but it has recently been reported that posterior decompression is also effective. However, a consensus on the choice of procedure has not yet been reached. Selective laminoplasty as minimally invasive surgery is a posterior decompression procedure that alleviates axial neck pain. Because, for CSA patients, the responsible lesion level is localized, this procedure combined with foraminotomy enables simultaneous spinal cord and root decompression. Therefore, we report the results of this treatment for CSA. METHODS: Subjects were 28 patients (25 males, 3 females), average age 50.6 years and average follow-up 43.5 months. The muscles involved were deltoid for 14 patients, biceps for 11, and extensor digitorum communis and/or intrinsic muscles of the hand for 9. MMT scores were grade 2 for 23 cases and grade 3 for 5 cases. To evaluate the results of minimally invasive surgery, cervical ROM (C2-7) and postoperative neck pain (VAS) on the first postoperative day and 1 week after surgery were evaluated. RESULTS: Muscle strength improvement was rated as "excellent" for 18 patients, "good" for 9, and "fair" for 1, with none rated "poor". Four of 10 patients whose muscle strength did not fully improve had distal type CSA and/or had preoperative MMT scores of 2. Average %ROM was 91.2 % and almost complete cervical ROM was maintained. The average postoperative VAS score was 2.6 on the first postoperative day and 1.2 1 week after surgery. CONCLUSIONS: Selective laminoplasty with segmental decompression is advantageous for minimizing postoperative neck pain and for simultaneous decompression of the affected spinal cord segment and nerve root. PMID- 23096954 TI - Selective genetic deletion of cacna1c in the mouse prefrontal cortex. PMID- 23096955 TI - In memoriam: Wylie Walker Vale, Jr. PMID- 23096956 TI - Artefact reduction in optoacoustic tomographic imaging by estimating the distribution of acoustic scatterers. AB - The quality of optoacoustic tomographic reconstructions can be severely affected by acoustic reflections or scattering arising at interfaces of highly mismatched organs, such as bones, lungs, or other air-containing cavities. We present a procedure to reduce the associated artefacts based on estimation of the acoustic scatterers distribution within the imaged object. Signals generated by a strong optical absorber are processed and used in a weighted back-projection algorithm. Experimental results in a tissue-mimicking phantom clearly demonstrate improved performance as compared to the case in which no information on the distribution of acoustic scatterers is available. PMID- 23096958 TI - Focus on technique: two-stage implant-based breast reconstruction. AB - BACKGROUND: Acellular dermal matrix has become a frequent adjunct to traditional expander-based breast reconstruction. Its putative advantages include improved positioning of the prosthesis, better definition of the inframammary fold, amelioration of potential contracture, and overall enhancement of cosmesis. Concomitantly, there may be an increased risk of seroma, infection, and reconstructive failure. METHODS: A thorough review of the techniques and outcomes of two-stage acellular dermis-assisted breast reconstruction was performed. RESULTS: Key technical aspects of two-stage acellular dermal matrix-based reconstruction are presented. Indications, techniques of handling and inset, and select strategies to avoid and manage common complications are discussed. Evidence-based outcomes are reviewed. CONCLUSIONS: Acellular dermal matrix-based two-stage reconstruction continues to evolve as a viable option in breast reconstruction. Future studies will better delineate the risks and benefits of the technique. PMID- 23096959 TI - Discussion: Focus on technique: two-stage implant-based breast reconstruction. PMID- 23096960 TI - The role of acellular dermal matrices in capsular contracture: a review of the evidence. AB - Despite advances in breast implant surgery, capsular contracture remains a challenging sequela of reconstructive and cosmetic breast implant surgery. Although there are established modalities for treatment, most recently, acellular dermal matrix products have been suggested to have a role in preventing or diminishing the pathologic process of capsular contracture. In this article, the author presents a review of the literature to highlight the level of evidence on the role of acellular dermal matrices in the treatment of capsular contracture. PMID- 23096961 TI - Discussion: The role of acellular dermal matrices in capsular contracture: a review of the evidence. PMID- 23096962 TI - Use of dermal matrix to prevent capsular contracture in aesthetic breast surgery. AB - Capsular contracture remains a challenging complication of implant-based aesthetic breast surgery despite improvements in implant design. The lowering of capsular contracture rates noted with the past use of polyurethane foam-covered implants has increased awareness of the importance of the biologic response at the interface between the implant surface and breast tissue. Emerging evidence indicates that much like the polyurethane foam, acellular dermal matrices alter the biologic response at the surface interface, resulting in a more vascular and less constrictive pattern of collagen deposition. This study reports on the authors' clinical experience using Strattice Reconstructive Tissue Matrix (LifeCell Corporation, Branchburg, N.J.) for the treatment of capsular contracture in patients with established capsules and for prevention in patients undergoing primary augmentation or augmentation/mastopexy. Of 80 patients (154 breasts) in whom Strattice was used, clinically significant contracture (Baker grade III/IV) occurred in three breasts (3.75 percent), all of which were in the treatment of previous contracture group. In addition, the authors noted two seromas requiring implant removal (both patients developed capsules, as mentioned above) and two hematomas requiring revision, for an overall failure rate of 6.25 percent for Strattice-assisted surgery. The data confirm that the use of Strattice significantly lowers the incidence of capsular contracture in the first 3.5 years after implant placement. PMID- 23096963 TI - Discussion: Use of dermal matrix to prevent capsular contracture in aesthetic breast surgery. PMID- 23096964 TI - Acellular dermal matrices in secondary aesthetic breast surgery: indications, techniques, and outcomes. AB - Acellular dermal matrices are integrally involved in the majority of expander implant reconstructions and complex hernia repairs today, and they are now making their way into secondary aesthetic breast surgery. The number of revisional breast surgery cases has continued to increase as the materials and repair techniques have improved. The aesthetic outcome bar is constantly being raised, and the complexity of patient deformities often requires additional tissues to achieve a successful repair. The most common complications in breast augmentation are reviewed, along with indications and some current repair techniques, general principles, and specific caveats to help plastic surgeons deal with these complex and challenging patient problems utilizing acellular dermal matrices. PMID- 23096965 TI - Discussion: Acellular dermal matrices in secondary aesthetic breast surgery: indications, techniques, and outcomes. PMID- 23096966 TI - Complications of acellular dermal matrices in breast surgery. AB - Acellular dermal matrices have been used in breast surgery for a decade. They are widely used in implant-based breast reconstruction to provide coverage of the inferolateral aspects of the prosthesis. Numerous benefits have been reported with this approach including improved fold control, better support and control of the implant pocket with concomitant reduced risk of malposition, and improved lower pole expansion. Seroma, infection, mastectomy skin necrosis, and expander/implant loss are the most commonly reported complications with this approach, and the incidences vary widely among studies. Patient selection and adherence to established intraoperative technique principles related to acellular dermal matrix use are both critical to minimizing the risk of complications. Acellular dermal matrices are also being used in aesthetic breast surgery, revision breast surgery, and nipple reconstruction, but clinical experience is limited. This article reviews the complications associated with the use of matrices in breast surgery from the published literature. PMID- 23096967 TI - Discussion: Complications of acellular dermal matrices in breast surgery. PMID- 23096968 TI - The use of acellular dermal matrices in chest wall reconstruction. AB - Surgeons are faced with increasingly complex and larger chest wall defects as a result of a variety of pathologies, the majority of which are oncologic. Skeletal reconstruction of these resulting defects and subsequent soft-tissue coverage remain a challenge for thoracic and plastic and reconstructive surgeons. A variety of techniques and grafts have been utilized to support the thoracic cage. This review focuses on the use of acellular dermal matrices in thoracic skeletal reconstruction, with a focus on the indications, published data, and surgical techniques for utilizing acellular dermal matrices in chest wall reconstruction. PMID- 23096969 TI - Acellular dermal matrices in abdominal wall reconstruction: a systematic review of the current evidence. AB - BACKGROUND: Reconstruction of the anterior abdominal wall is a complex procedure that can be complicated by contamination, loss of domain, previous scarring or radiotherapy, and reduced availability of local tissues. With the introduction of acellular dermal matrices to clinical use, it was hoped that many of the problems associated with previous synthetic materials could be overcome. With their enhanced biocompatibility, acellular dermal matrices are believed to integrate with surrounding tissues while demonstrating resistance to infection, extrusion, erosion, and adhesion formation. METHODS: The MEDLINE database was reviewed, including all publications as of December 31, 2011, using the search terms "dermal matrix" or "human dermis" or "porcine dermis" or "bovine dermis," applying the limits "human" and "English language." Prospective and retrospective clinical articles were identified. RESULTS: A total of 40 eligible articles were identified and included in this review. Thirty-five of the studies were level IV; the remaining studies were level III. Acellular dermal matrix was used to reconstruct the abdominal wall in a wide range of clinical settings, including trauma, tumor resection, sepsis, and hernia repairs. The operative methods varied widely among clinical studies. While the heterogeneity of the patient populations and techniques limited interpretation of the data, concerns were identified regarding high rates of hernia recurrence with acellular dermal matrix use. CONCLUSION: High-quality data derived from level I, II, and III studies are necessary to determine the indications for acellular dermal matrix use and the optimal surgical techniques to maximize outcomes in abdominal wall reconstruction. PMID- 23096970 TI - Cross-linking in biomaterials: a primer for clinicians. AB - The purpose of this primer is to provide the clinical surgeon with a survey overview of the basic biochemistry of collagen and the methods and rationale of collagen cross-linking in the processing and preparation of bioprosthetics for surgical implantation. The author highlights the critical biologic factors, such as strength over time, integration, and rate, and type of remodeling, that are to an extent controllable by the cross-linking of collagen tissues so that clinicians may be better capable of understanding differences among the devices, which may be more applicable to their clinical indications. PMID- 23096971 TI - A decade of ventral incisional hernia repairs with biologic acellular dermal matrix: what have we learned? AB - BACKGROUND: Innovative types of biologic mesh have provided new alternatives to ventral incisional hernia repair, especially in the face of contamination. The authors studied the experience and outcomes of patients who underwent repair of a ventral incisional hernia with biologic mesh. METHODS: Online database and detailed reference searches were conducted. Studies chosen for review had a sample size of at least 40 patients, level IV evidence at most, and a Methodological Index for Nonrandomized Studies index of at least 10. Indications for use of biologic mesh, type of mesh, patient comorbidities, and surgical techniques were also noted. RESULTS: Eight studies fulfilled the search criteria and included 635 patients using AlloDerm, Surgisis, and Strattice biologic tissue matrices. In one study, indications and surgical techniques were standardized, and follow-up was prospective. In the other seven studies, indications, surgical techniques, and follow-up were assessed retrospectively. The mean patient age, when reported, was 55.7 years. Body mass index ranged from 30 to 35 kg/m2 in 44 percent of the reported patients. In seven of the eight studies [565 patients (89 percent)], the mean follow-up was 25.8 months and the mean hernia recurrence rate was 21 percent. Complication rate exceeded 20 percent in most studies. CONCLUSIONS: Biologic tissue matrices are mostly used in contaminated fields, which has allowed for a one-stage repair with no or little subsequent mesh removal. Ventral incisional hernia repair with these matrices continues to be plagued by a high recurrence rate and complications. Prospective randomized trials are needed to properly direct practice in the use of these meshes and evaluate their ultimate value. PMID- 23096972 TI - Current concepts in the use of acellular dermal matrices in surgery. PMID- 23096973 TI - Discussion: A decade of ventral incisional hernia repairs with biologic acellular dermal matrix: what have we learned? PMID- 23096975 TI - Discussion: Adhesions and meshes: synthetic versus bioprosthetic. PMID- 23096974 TI - Adhesions and meshes: synthetic versus bioprosthetic. AB - Adhesions are common after intra-abdominal surgery and are associated with significant morbidity, including bowel obstruction, pain, and infertility. Abdominal wall reconstruction carries the risk of adhesion formation, notably to synthetic or bioprosthetic mesh. This article reviews the pathophysiology of adhesion formation, adhesion grading, and adhesions to synthetic and biologic mesh in vitro and clinically. Bioprosthetic mesh in vitro appears to elicit fewer lower-grade adhesions than synthetic mesh. However, direct comparisons in humans of adhesions with synthetic versus bioprosthetic mesh are lacking. Future studies are warranted to determine whether there are significant differences in clinical outcomes, especially regarding secondary complications from adhesions. PMID- 23096976 TI - Complications of acellular dermal matrices in abdominal wall reconstruction. AB - BACKGROUND: Acellular dermal matrices have been increasingly used in abdominal wall reconstruction. Unique characteristics of these grafts have allowed surgeons to reconstruct increasingly complex abdominal wall defects. This has resulted in a myriad of complications related to the acellular dermal matrix with unique management strategies as compared with synthetic mesh. METHODS: A review of the literature was performed to identify studies evaluating the use and efficacy of acellular dermal matrices in abdominal wall reconstruction. Complication profiles were identified and are compared. Differences between porcine and human derivatives were identified. RESULTS: Hernia recurrence, infection, skin necrosis, and fluid collections were among the most common complications following abdominal wall reconstruction identified in the literature. Differences among various acellular dermal matrix products make certain types more suitable for abdominal wall reconstruction. CONCLUSIONS: Complications are frequent in abdominal wall reconstruction. Many acellular dermal matrices have properties that allow for conservative management and maintenance of reconstruction when complications occur. With traditional synthetic mesh reconstruction, complications likely result in mesh explantation and prolonged morbidity. With acellular dermal matrix reconstruction, however, more conservative treatment strategies will allow for mesh salvage. PMID- 23096977 TI - Acellular dermal graft reinforcement at the hiatus. AB - The ideal technique to repair large hiatal and diaphragmatic defects remains controversial. Due to high recurrence rates with primary repair alone, attempts at crural reinforcement with various products has been investigated. Initial evaluation of synthetic mesh at the hiatus in retrospective studies led to the conclusion that there were too many serious complications with these products. The next step was to see how biologic grafts fared in this location. Beginning with porcine intestine submucosa in a laminated array and progressing through human and porcine acellular dermal matrices, multiple, retrospective studies looked at the efficacy and safety of these products. Unfortunately, most of these studies evaluated a small sample size with a relatively short follow-up period. The one study followed out to 5 years failed to show any benefit using the biologic (porcine intestinal submucosa) compared with the primary repair alone. Additional, prospective, randomized studies with ample numbers carried out for years will be necessary to see which biologic graft is not only safe but also successful in preventing recurrent herniations. PMID- 23096978 TI - Wound healing in the upper and lower extremities: a systematic review on the use of acellular dermal matrices. AB - BACKGROUND: Use of biologically engineered acellular dermal matrices in the upper and lower extremities is increasingly recognized as a means of achieving definitive healing in the setting of both acute and chronic injuries but data and evidence supporting their use are limited. The authors performed this systematic review to identify all available evidence for the use of matrices in nonburn extremity reconstruction. METHODS: A systematic review of the Cochrane and MEDLINE databases was performed to identify all reports of the application of matrices in wounds of the upper and lower extremities. Reports that included fewer than five patients and that involved cellular seeding, nonhuman studies, and burn injuries were excluded. Studies were evaluated for quality of statistical measures and outcomes, and a level of evidence was assigned in accordance with the American Society of Plastic Surgeons' Rating Levels of Evidence. RESULTS: Of an initial 2422 reports, 13 primary reports were identified (10 case series and three randomized controlled trials) representing a total of 432 patients and 441 discrete wounds. After evidence review, 10 of these studies represented level IV evidence, two studies represented level II evidence, and one study achieved level I evidence. CONCLUSIONS: Extremity wound management continues to rely on adequate vascular supply, debridement with eradication of infection, off-loading, and/or immobilization. Current data, although limited, appear to support the use of acellular dermal matrices in chronic and acute injuries where there is exposed bone, tendon, and/or muscle. They may provide a simple technique to achieve timely and durable tissue coverage in extremity wounds. PMID- 23096979 TI - The use of biological materials in urogynecologic reconstruction: a systematic review. AB - There are numerous randomized controlled trials examining biological materials in urogynecologic surgery. For prolapse surgery, the addition of a biological graft adds no benefit compared with native tissue repairs for rectocele repair. Conflicting data exist regarding cystocele repair. Synthetic mesh repairs provide superior anatomical support for sacral colpopexy and cystocele repair compared with biologic grafts. However, biological and synthetic mesh slings have equivalent success rates for the treatment of stress urinary incontinence. Contrary to prior assumptions that biologic grafts add tissue strength without graft-related complications, there appears to be no benefit to the use of biological materials for prolapse and incontinence surgery. PMID- 23096980 TI - Discussion: The use of biological materials in urogynecologic reconstruction: a systematic review. PMID- 23096981 TI - Acellular dermal matrices in hand reconstruction. AB - BACKGROUND: The goal of this article is to review the current literature on the use of acellular dermal matrix in forearm, wrist, and hand reconstruction. METHODS: A comprehensive literature search was performed using the Cochrane Database of Systematic Reviews, MEDLINE, PubMed, and Web of Knowledge. Articles were categorized as acellular dermal matrix used in soft-tissue repair and in ligament reconstruction. Search terms included "acellular dermal matrix," "biologic dressing," "skin replacement," "dermal allograft," "AlloDerm," "FlexHD," "Permacol," and "Strattice." These were all cross-referenced with "forearm," "wrist," and "hand." Data extraction focused on indications, surgical techniques, clinical outcomes, and complications. Exclusion criteria included regeneration templates, neonatal foreskin, and review articles. RESULTS: More than 100 articles published between 1994 and 2011 were identified. Upon final review, five prospective case-control studies, three retrospective case-control studies, four case reports, one cross-sectional cohort, one prospective consecutive series, and one study type unknown were evaluated. Matrix was most commonly used in burn reconstruction. It has also been used in ligament and joint reconstruction for first carpometacarpal arthritis. One article illustrated the use of porcine matrix in basal joint arthritis, a practice that was abruptly terminated because of a concern over increased infections. CONCLUSIONS: The clinical indications for acellular dermal matrix have increased throughout the last 15 years. Hand surgeons have been cautious but diligent in developing alternative treatment options in hand reconstruction, with a focused effort to reduce donor-site morbidity. Although acellular dermal matrices continue to find innovative uses to solve upper extremity surgical problems, more comparative prospective trials are needed. PMID- 23096982 TI - Acellular dermal matrix in irradiated tissue expander/implant-based breast reconstruction: evidence-based review. AB - BACKGROUND: The benefits of acellular dermal matrix for breast reconstruction have been well described. However, its clinical impact for breast reconstruction in the setting of radiation therapy has not been well reported. METHODS: The MEDLINE and EMBASE databases were reviewed for articles published between January of 2005 and February of 2012 on breast reconstruction using acellular dermal matrix in the setting of radiation therapy. The authors also reviewed their institutional experience of consecutive patients who met these criteria between January of 2008 and October of 2011. RESULTS: Thirteen articles were identified for review: three animal studies on acellular dermal matrix and 10 with level III evidence of its use in humans. The 10 clinical studies included 246 irradiated patients. The M. D. Anderson experience included 30 irradiated acellular dermal matrix patients for a total of 276 irradiated patients evaluated in this review. Use of acellular dermal matrix in implant-based breast reconstruction in the setting of radiation therapy did not predispose to higher infection or overall complication rates or prevent bioprosthetic mesh incorporation. However, the rate of mesh incorporation may be slowed. Its use allowed for increased intraoperative saline fill volumes, which improved aesthetic outcomes and allowed patients to awake from surgery with a formed breast. CONCLUSIONS: Use of acellular dermal matrix for implant-based breast reconstruction does not appear to increase or decrease the risk of complications, but it might provide psychological and aesthetic benefits. Multicenter or single-center randomized controlled trials that provide high-quality, level I evidence are warranted. PMID- 23096983 TI - A systematic review of acelluar dermal matrices in head and neck reconstruction. AB - BACKGROUND: The use of acellular dermal matrices has been well described in the scientific literature since the early 1990 s and has been utilized for multiple applications in the head and neck for both aesthetic and reconstructive efforts. METHODS: After systematically searching the PubMed database and following further refinement (based on the authors' inclusion and exclusion criteria), the authors identified 30 studies that provided information about patients who had undergone head and neck reconstruction with the use of acellular dermal matrix. Studies had to report quantifiable objective results in patients who were older than 1 year and younger than 90 years. The authors excluded single case reports, studies with fewer than 10 patients, and studies not published in English. RESULTS: The optimal material used as an implant for reconstruction possesses the following properties: facilitation of vascular ingrowth, decreased propensity to incite inflammation, biologic inertness, resistance to infection, and ease of handling. Acellular dermal matrix possesses many of these properties and is utilized in reconstructing nasal soft tissue and skeletal support, tympanic membrane, periorbital soft tissue, extraoral and intraoral defects, oropharyngeal defects, dura mater, and soft-tissue deficits from parotidectomy. Furthermore, it is used to assist in preventing Frey syndrome following parotidectomy and surgical treatment of facial paralysis. CONCLUSIONS: Use of acellular dermal matrix for head and neck reconstruction has expanded exponentially and is validated in many studies. Further prospective randomized control trials are warranted to further investigate the efficacy of acellular dermal matrix in head and neck reconstruction. PMID- 23096984 TI - Acellular dermal matrices in primary breast reconstruction: principles, concepts, and indications. AB - Prosthetic breast reconstruction using acellular dermal matrix is currently used by many plastic surgeons. As our understanding of these matrices expands, our results and outcomes are becoming more reproducible and predictable. As with most new technologies, there is a learning curve associated with using acellular dermal matrix. There are principles and concepts that should be heeded when considering their use. The purpose of this article is to review some of the important principles and concepts to improve our understanding of how these matrices perform and what can be expected of them. PMID- 23096986 TI - Discussion: Acellular dermal matrices in primary breast reconstruction: principles, concepts, and indications. PMID- 23096988 TI - Discussion: The use of acellular dermal matrices in two-stage expander/implant reconstruction: a multicenter, blinded, randomized controlled trial. PMID- 23096990 TI - Acellular dermal matrices in surgery. PMID- 23096989 TI - The use of acellular dermal matrices in revisional breast reconstruction. AB - BACKGROUND: The use of acellular dermal matrices in breast surgery has become popular in the last two decades, with a corresponding increase in experience and literature. The authors reviewed the literature and summarize key technical points regarding use of acellular dermal matrices in reconstructive breast surgery. METHODS: Current applications have emphasized both primary and secondary breast reconstruction. Newer approaches focus on breast revisional surgery, especially when matrix material is used to correct deformities commonly arising after breast implant placement. In these situations, matrices have widened the indications and improved results by providing additional support to the lower pole, extending the pectoralis major muscle, and smoothing surface irregularities. Increased use of these products has also spurred our understanding of their biological properties of cell infiltration, tolerance, and inflammation. RESULTS: Acquired deformities, such as symmastia, rippling, malposition, and lower pole bottoming out, that were previously difficult to treat are significantly improved by placement of acellular dermal matrix in the affected area. Although most of the available studies demonstrate short-term results (1 to 2 years of follow-up), our technical ability to treat complications after breast augmentation and mastopexy has expanded. Use of onlay grafts of matrix in areas of capsulectomy and capsulorrhaphy, placement of grafts of varying thickness for thinned tissues, and the wide variety of shapes and sizes of product available are reducing unfavorable aesthetic results. CONCLUSIONS: Increased complications, including seroma formation, infection, wound dehiscence, and implant exposure, remain challenging problems. Long-term studies will be needed to prove the durability of acellular dermal matrices in breast revisional surgery. PMID- 23096987 TI - The use of acellular dermal matrices in two-stage expander/implant reconstruction: a multicenter, blinded, randomized controlled trial. AB - BACKGROUND: Current efficacy data supporting the routine use of acellular dermal matrices in postmastectomy tissue expander/implant reconstruction are limited. A multicenter, blinded, randomized controlled study was designed to evaluate the effectiveness of acellular dermal matrix in the setting of tissue expander/implant reconstruction. The primary objective of the study was to determine whether the use of matrix would decrease patient-reported postoperative pain. The secondary objective was to determine whether its use would accelerate the rate of postoperative expansion. METHODS: The randomized controlled trial was conducted at two U.S. centers from 2008 to 2011. Immediately following mastectomy, all patients were randomized to one of two treatment arms: (1) acellular dermal matrix-assisted, tissue expander/implant reconstruction; and (2) submuscular tissue expander/implant placement. All patients were blinded to their treatment arm. RESULTS: One hundred eight consented to participate; 38 were excluded prior to randomization. In total, 70 patients were randomized. There were no differences seen in immediate postoperative pain (p = 0.19) or pain during the expansion phase (p = 0.65) between treatment arms. There was similarly no difference in postoperative narcotic use (p = 0.38). The rate of postoperative expansion did not differ between groups (p = 0.83). CONCLUSIONS: The results suggest that the use of acellular dermal matrix in the setting of tissue expander/implant reconstruction neither reduces postoperative pain nor accelerates the rate of postoperative expansion. An examination of its efficacy in improving long-term outcomes following tissue expander/implant reconstruction is warranted. PMID- 23096991 TI - Discussion: The use of acellular dermal matrices in revisional breast reconstruction. PMID- 23096992 TI - Focus on technique: supporting the soft-tissue envelope in breast reconstruction. AB - Prosthetic-based breast reconstruction commonly involves device placement in either a total submuscular pocket or a partial subpectoral position for just superior pole coverage, with various possible strategies for inferior pole coverage. Historically, the pectoralis major muscle is managed either by suturing the muscle to the inferior flap or with marionette sutures; alternatively, the device is placed under total muscle/fascia coverage (under the pectoralis major, plus the serratus anterior and rectus abdominis muscles or fascia). For many plastic surgeons, acellular dermal matrix is now used instead to function as a sling or "hammock" supporting the periprosthetic pocket and thus covering the inferior pole of the device, attached to the pectoralis major muscle above and to the inframammary fold below. In addition to its added soft-tissue support in the inferior pole, acellular dermal matrix may help to stabilize the pectoralis major muscle along its inferolateral margin, create a well-defined inframammary fold, provide the opportunity to significantly increase intraoperative fill volume of the tissue expander, and reduce the incidence or severity of significant or symptomatic capsular contracture, particularly in a patient whose breast has been treated with radiation. In addition to its indications in primary breast reconstruction, acellular dermal matrix has been increasingly used in secondary revision reconstruction cases. It can be used to buttress capsulorrhapy and capsulotomy sites and it can be used to replace periprosthetic capsule following capsulectomy. While clinical experience is accruing for these indications, acellular dermal matrix continues to be used in primary and secondary breast reconstruction. PMID- 23096993 TI - Focus on technique: one-stage implant-based breast reconstruction. AB - BACKGROUND: Direct-to-implant reconstruction with acellular dermal matrix has expanded the surgeon's repertoire and given the patient an opportunity to have a one-stage option after skin- or nipple-sparing mastectomy. The technique produces total implant coverage without the need for expansion, repeated operations, and delayed return of normal body image. METHODS: In patients with adequate, good quality mastectomy skin, a subpectoral pocket is created after mastectomy. The inferomedial pectoralis major muscle is elevated for implant placement. The acellular dermal matrix is sutured to the released inferior pole of the pectoralis muscle along its entire lower course and to the lateral mammary fold. The implant is introduced beneath the muscle-matrix layer, and the matrix is sutured to the inframammary fold at its desired position. Two suction drains are placed, one subpectorally and the other subcutaneously, through separate stab incisions, followed by skin closure. RESULTS: Over a 10-year period, the author has performed this technique in 439 patients (790 breasts). Consistently low complication rates and good aesthetic outcomes have been obtained. Major complications, including implant loss (1.6 percent), skin necrosis requiring reoperation (1.3 percent), infection (1.1 percent), hematoma (0.6 percent), seroma (0.5 percent), and capsular contracture (0.5 percent), have remained at an incidence of less than 2 percent. CONCLUSIONS: The author's 10-year results using acellular dermal matrix in direct-to-implant breast reconstructions demonstrate the effectiveness of the procedure, as well as its long-term safety and aesthetic benefits. Its success, however, relies on appropriate patient selection and specific intraoperative technique principles. PMID- 23096995 TI - Peptidic macrocyclization via palladium-catalyzed chemoselective indole C-2 arylation. AB - A highly efficient macrocyclization reaction has been developed via the palladium catalyzed C-H arylation of the side-chains of tryptophan with halophenyl containing amino acids. This method allows for direct access to 15- to 25 membered biaryl macrocycles in 40-75% yield, at moderate concentration, with C-H arylation proceeding exclusively at the C-2 position of the tryptophan indole. PMID- 23096994 TI - The biology of biologics: basic science and clinical concepts. AB - The repair of complex abdominal wall defects remains one of the most challenging procedures facing reconstructive surgeons. Through these collaborative efforts, defects that were once thought to be impossible to reconstruct can now be repaired, and patients who were left to a miserable quality of life are now offered hope. Among the most important advances in this field have been the adoption of component separation and many of its modifications, the development of new lightweight synthetic mesh, and the explosion of biologic mesh into the surgical armamentarium of the reconstructive surgeon. While biologic grafts are gaining in popularity, the molecular processes and host reactions to biologic grafts are not only unclear but often misunderstood and misrepresented. As a result, comprehensive analysis of basic science concepts presented in this review should help a practicing surgeon with understanding what biologics actually do and what we can expect biologic meshes to accomplish. This article focuses on summarizing the current basic science evidence and the clinical outcomes of utilization of these grafts published in the peer-reviewed literature. PMID- 23096996 TI - Hepatitis C virus NS2 protease inhibits host cell antiviral response by inhibiting IKKepsilon and TBK1 functions. AB - Hepatitis C virus (HCV) encodes for several proteins that can interfere with host cell signaling and antiviral response. Previously, serine protease NS3/4A was shown to block host cell interferon (IFN) production by proteolytic cleavage of MAVS and TRIF, the adaptor molecules of the RIG-I and TLR3 signaling pathways, respectively. This study shows that another HCV protease, NS2 can interfere efficiently with cytokine gene expression. NS2 and its proteolytically inactive mutant forms were able to inhibit type I and type III IFN, CCL5 and CXCL10 gene promoters activated by Sendai virus infection. However, the CXCL8 gene promoter was not inhibited by NS2. In addition, constitutively active RIG-I (DeltaRIG-I), MAVS, TRIF, IKKepsilon, and TBK1-induced activation of IFN-beta promoter was inhibited by NS2. Cotransfection experiments with IKKepsilon or TBK1 together with interferon regulatory factor 3 (IRF3) and HCV expression constructs revealed that NS2 in a dose-dependent manner inhibited IKKepsilon and especially TBK1 induced IRF3 phosphorylation. GST pull-down experiments with GST-NS2 and in vitro translated and cell-expressed IKKepsilon and TBK1 demonstrated direct physical interactions of the kinases with NS2. Further evidence that the IKKepsilon/TBK1 kinase complex is the target for NS2 was obtained from the observation that the constitutively active form of IRF3 (IRF3-5D) activated readily IFN-beta promoter in the presence of NS2. The present study identified HCV NS2 as a potent interferon antagonist, and describes an explanation of how NS2 downregulates the major signaling pathways involved in the development of host innate antiviral responses. PMID- 23096998 TI - Purification studies on a thermo-active amidase of Geobacillus pallidus BTP-5x MTCC 9225 isolated from thermal springs of Tatapani (Himachal Pradesh). AB - An intracellular aliphatic amide degrading inducible thermo-active amidase produced by Geobacillus pallidus BTP-5x MTCC 9225 was purified to apparent homogeneity using anion exchange and gel filtration chromatography, giving a yield of 6.7 % and a specific activity of 30.49 units mg(-1). The purified protein migrated as a single band of estimated molecular mass of 158 kDa (homo tetramer) in 8 % polyacrylamide gel electrophoresis and ~38.5 kDa in 12 % sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Optima of pH and temperature varied widely in broad pH range (pH 6-9) and temperature range (45-70 degrees C). The purified amidase was stable up to 6 h at 50 degrees C, with a t (1/2) of 7 h at 55 degrees C. The multimeric nature of the holozyme (tetramer) contributed to protection of the enzyme against thermal denaturation. The enzyme showed resistance to metal chelating agents (EDTA, 8-hydroxyquinoline, and sodium azide), explaining its non-metallic nature, and is strongly inhibited by thiol reagents that means cysteine is involved in catalysis. The amidase of G. pallidus BTP-5x preferentially hydrolyzed only small aliphatic amides and has a narrow substrate spectrum. The K (M) value for acrylamide is 10.54 mM, V (max) 45.19 MUmol(-1) min(-1) mg(-1) protein, and k (cat) 4.29 min(-1). The sequence of amino acids of the purified enzyme MRHGDISSSHDTVGI appears similar to thermophilic amidases. Sequence analysis of the amidase gene showed that the enzyme is 347 amino-acid-long with a molecular weight of 38.4 kDa (as observed in SDS-PAGE), theoretical pI 5.38, and show strong similarity to thermostable amidases, possessing unique restriction sites. PMID- 23096997 TI - Creation and characterization of BAC-transgenic mice with physiological overexpression of epitope-tagged RCAN1 (DSCR1). AB - The chromosome 21 gene RCAN1, encoding a modulator of the calcineurin (CaN) phosphatase, is a candidate gene for contributing to cognitive disability in people with Down syndrome (DS; trisomy 21). To develop a physiologically relevant model for studying the biochemistry of RCAN1 and its contribution to DS, we generated bacterial artificial chromosome-transgenic (BAC-Tg) mouse lines containing the human RCAN1 gene with a C-terminal HA-FLAG epitope tag incorporated by recombineering. The BAC-Tg was expressed at levels only moderately higher than the native Rcan1 gene: approximately 1.5-fold in RCAN1 (BAC-Tg1) and twofold in RCAN1 (BAC-Tg2). Affinity purification of the RCAN1 protein complex from brains of these mice revealed a core complex of RCAN1 with CaN, glycogen synthase kinase 3-beta (Gsk3b), and calmodulin, with substoichiometric components, including LOC73419. The BAC-Tg mice are fully viable, but long-term synaptic potentiation is impaired in proportion to BAC-Tg dosage in hippocampal brain slices from these mice. RCAN1 can act as a tumor suppressor in some systems, but we found that the RCAN1 BAC-Tg did not reduce mammary cancer growth when present at a low copy number in Tp53;WAP-Cre mice. This work establishes a useful mouse model for investigating the biochemistry and dose-dependent functions of the RCAN1 protein in vivo. PMID- 23096999 TI - Effectiveness of sport-based HIV prevention interventions: a systematic review of the evidence. AB - Interest in sport as a tool for behavioral HIV prevention has grown substantially in the past decade. With dozens of organisations now using sport-based HIV prevention (SBHP) approaches and upcoming randomized controlled trials in South Africa and Zimbabwe, there is a pressing need to synthesize previous evaluation findings and identify gaps in existing research. A systematic review on the effectiveness of SBHP interventions was carried out, identifying both published and unpublished studies on SBHP interventions that measured effectiveness quantitatively. Study quality was scored using an adapted Newcastle-Ottawa Scale. Random-effects meta-analyses were carried out across studies for effects on six categories of HIV-related outcomes. The review identified 952 publications, 21 of which met inclusion criteria. No randomised controlled trials on SBHP interventions and no studies assessing biological outcomes were identified. Mean study quality score was 5.1 (SD 3.1) out of 20 points. Overall strong evidence was observed for positive effects on HIV-related knowledge (RR = 1.26, 95 % CI = 1.15-1.37), stigma (RR = 1.13, 95 % CI = 1.02-1.24), self-efficacy (RR = 1.22, 95 % CI = 1.02-1.41), reported communication (RR = 1.24, 95 % CI = 1.06-1.41), and reported recent condom use (RR = 1.29, 95 % CI = 1.00-1.59). Generally, the review found encouraging evidence for some short-term effects but relied predominantly on low-quality studies. More rigorous research on SBHP is needed to objectively assess effectiveness. Randomised controlled trials could play an important role in guiding policies, strategies, and funding related to SBHP. PMID- 23097001 TI - Is it possible for Fe2+ to approach protoporphyrin IX from the side of Tyr-13 in Bacillus subtilis ferrochelatase? An answer from QM/MM study. AB - We previously reported the insertion process of the ferrous ion into the protoporphyrin IX from the side of the residue His-183 (J. Inorg. Biochem. 103 (2009) 1680-1686). Sellers et al. suggested that the ferrous ion probably approaches the protoporphyrin IX via the opposite side in the human enzyme. In this paper, we simulated the insertion process of Fe(2+) into the protoporphyrin IX from the side of the residue Tyr-13 at the opposite site of His-183 by QM/MM method on Bacillus subtilis ferrochelatase. The model was built with Fe(2+) ion coordinated by Tyr-13, His-88 and two water molecules. Geometries were optimized at the BP86/6-31G* level and energies were calculated at the B3LYP/6-311+G(2d,2p) level. The overall process involves the displacement of the residues Tyr-13, His 88 and one water molecule and deprotonation of the porphyrin ring. All the local minimum structures and energy barriers were obtained and an optimal insertion pathway was suggested. The rate-determining step is the removing of the second proton from the porphyrin accompanied by the formation of the fourth Fe-N bond with an energy barrier of 138.00 kJ/mol. PMID- 23097002 TI - Nitrous oxide adsorption on pristine and Si-doped AlN nanotubes. AB - Using density functional theory, we studied the adsorption of an N(2)O molecule onto pristine and Si-doped AlN nanotubes in terms of energetic, geometric, and electronic properties. The N(2)O is weakly adsorbed onto the pristine tube, releasing energies in the range of -1.1 to -5.7 kcal mol(-1). The electronic properties of the pristine tube are not influenced by the adsorption process. The N(2)O molecule is predicted to strongly interact with the Si-doped tube in such a way that its oxygen atom diffuses into the tube wall, releasing an N(2) molecule. The energy of this reaction is calculated to be about -103.6 kcal mol(-1), and the electronic properties of the Si-doped tube are slightly altered. PMID- 23097000 TI - Cancer cachexia: impact, mechanisms and emerging treatments. AB - Many forms of cancer present with a complex metabolic profile characterised by loss of lean body mass known as cancer cachexia. The physical impact of cachexia contributes to decreased patient quality of life, treatment success and survival due to gross alterations in protein metabolism, increased oxidative stress and systemic inflammation. The psychological impact also contributes to decreased quality of life for both patients and their families. Combination therapies that target multiple pathways, such as eicosapentaenoic acid administered in combination with exercise, appetite stimulants, antioxidants or anti inflammatories, have potential in the treatment of this complex syndrome and require further development. PMID- 23097003 TI - Interaction of dihydrofolate reductase and aminoglycoside adenyltransferase enzyme from Klebsiella pneumoniae multidrug resistant strain DF12SA with clindamycin: a molecular modelling and docking study. AB - Klebsiella pneumoniae strain DF12SA (HQ114261) was isolated from diabetic foot wounds. The strain showed resistance against ampicillin, kanamycin, gentamicin, streptomycin, spectinomycin, trimethoprim, tetracycline, meropenem, amikacin, piperacillin/tazobactam, augmentin, co-trimoxazole, carbapenems, penicillins and cefoperazone, and was sensitive to clindamycin. Molecular characterization of the multidrug-resistance phenotype revealed the presence of a class 1 integron containing two genes, a dihydrofolate reductase (DHFR) (PF00186), which confers resistance to trimethoprim; and aminoglycoside adenyltransferase (AadA) (PF01909), which confers resistance to streptomycin and spectinomycin. A class 1 integron in K. pneumoniae containing these two genes was present in eight (18.18%) out of 44 different diabetic foot ulcer (DFU) patients. Hence, there is a need to develop therapeutics that inhibit growth of multidrug resistant K. pneumoniae in DFU patients and still achieve amputation control. Am attempt was made to create a 3D model and find a suitable inhibitor using an in silico study. Rational drug design/testing requires crystal structures for DHFR and AadA. However, the structures of DHFR and AadA from K. pneumoniae are not available. Modelling was performed using Swiss Model Server and Discovery Studio 3.1. The PDBSum server was used to check stereo chemical properties using Ramachandran plot analysis of modeled structures. Clindamycin was found to be suitable inhibitor of DHFR and AadA. A DockingServer based on Autodock & Mopac was used for docking calculations. The amino acid residues Ser(32), Ile(46), Glu(53), Gln(54), Phe(57), Thr(72), Met(76), Val(78), Leu(79), Ser(122), Tyr(128), Ile(151) in case of DHFR and Phe(34), Asp(60), Arg(63), Gln(64), Leu(68), Glu(87), Thr(89), Val(90) for AadA were found to be responsible for positioning clindamycin into the active site. The study identifies amino acid residues crucial to 'DHFR and AadA -drug' and 'DHFR and AadA -inhibitor' interactions that might be useful in the ongoing search for a versatile DHFR and AadA -inhibitor. PMID- 23097004 TI - Regioselectivity in Sonogashira synthesis of 6-(4-nitrobenzyl)-2 phenylthiazolo[3,2-b]1,2,4-triazole: a quantum chemistry study. AB - In the present research, the experimentally observed regioselectivity in Sonogashira synthesis of 6-(4-nitrobenzyl)-2-phenylthiazolo[3,2-b]1,2,4triazole has been modeled by means of density functional theory (DFT) employed to investigate the structural and thermochemical aspects of this synthesis in the gas and solution phases. Comparison of our calculated structural parameters of the title compound with the available X-ray crystallographical data demonstrate a reliable agreement. Then, the effect of two different solvents, DMF and ethanol, are examined via polarized continuum model calculations, showing a significant decrease in the computed values of the reaction enthalpy and free energy changes compared with the gas phase results. We have also considered two tautomeric structures of the intermediate species that it seems the mode of its intermolecular cyclization has an important role in regioselectivity of the final products. Moreover, all obtained results in the gas and solution phases also confirm that the synthesis of the title compound is thermodynamically more favorable than the other regioisomeric product. We also discuss the thermodynamical feasibility of this reaction at higher temperatures. Finally, we concentrate on the survey of substituent effect by choosing electron-withdrawing and electron-donating groups on the aryl iodide. Our calculated thermochemical data in the gas and solution phases indicate that the use of electron-withdrawing moieties is more favorable thermodynamically than electron-donating ones which has been previously concluded via the experimental elucidations. PMID- 23097006 TI - Pulmonary vein re-isolation for atrial fibrillation using duty-cycled phased radiofrequency ablation: safety and efficacy of a primary 2:1 bipolar/unipolar ablation mode. AB - PURPOSE: Pulmonary vein isolation (PVI) using phased radiofrequency (RF) energy has been shown to be effective in the treatment of paroxysmal atrial fibrillation (AF). We characterize pulmonary vein (PV) conduction at repeat ablation in patients with AF after an initial successful PVI using phased RF technology and analyze the effects of a primary 2:1 ablation mode. METHODS AND RESULTS: A primary 4:1 bipolar/unipolar mode in group A patients (n = 22) was compared with a primary 2:1 mode in group B (n = 22) acutely and during follow-up. Of all PVs, 81 % showed reconnection(s); 52 % of them had reconnected in all PVs. PVI was achieved in all patients without complications. Procedure and fluoroscopy times were shorter in group B (108 +/- 15 vs. 126 +/- 24 min and 17 +/- 5 vs. 23 +/- 7 min, respectively). This was attributed to a significant decrease of early PV reconnections within the first 30 min in 17 % of group B patients vs. 45 % of group A patients (p < 0.001). After 9.5 +/- 4 months, recurrence of AF was detected in 5 of 22 patients (22.7 %) in group A vs. 3 of 22 patients (13.6 %) in group B (p = 0.722). CONCLUSIONS: Phased RF energy applied by a 2:1 bipolar/unipolar mode seems safe and effective in redo-PVI procedures, resulting in a mid-term freedom from AF in 86.4%. Significant shorter procedure and fluoroscopy times compared with a primary 4:1 ablation mode during repeat PVI are mainly attributed to a lower incidence of acutely reconnected PVs within the first 30 min. PMID- 23097005 TI - Histopathological, immunohistochemical and molecular spectrum of myoepithelial tumours of soft tissues. AB - Primary soft tissue myoepithelial tumours (METs) are rare. Recent studies have shown EWSR1 rearrangement in certain METs. We present clinicopathological, immunohistochemical and molecular features of 14 primary soft tissue METs. Fourteen tumours, five benign and nine malignant, occurred in 12 men and two women, with an age range of 18-60 years (mean, 39.2); in upper extremities, four (29 %); chest wall, three (21 %); paraspinal region, three (21 %); pelvis, two (14 %) and lower extremities, two (14 %). Tumour size varied from 2 to 21.6 cm (mean, 8.7). Microscopically, most tumours were at least focally circumscribed. Morphological heterogeneity was noted, commonest patterns being cord-like and diffuse arrangement of polygonal cells in a myxoid stroma. By immunohistochemistry, tumours were positive for epithelial membrane antigen (EMA) (10/12, 83 %), cytokeratin (CK)/MNF116 (3/12, 25 %), p63 (7/10, 70 %), CD10 (4/6, 67 %), calponin (6/6, 100 %), S-100P (11/13, 85 %), glial fibrillary acidic protein (GFAP) (6/12, 50 %), smooth muscle actin (SMA) (3/9, 33 %), INI1/SMARCB1 (6/10, 60 %), brachyury (0/11), CD34 (0/5) and vimentin (4/4, 100 %), implying 93 % positivity for at least one epithelial marker. EWSR1 gene rearrangement was detected in 3/6 (50 %) METs (one benign and two malignant) and in an eccrine porocarcinoma which was included for reasons of comparison. Outcome details were available for six patients all surgically treated; three tumours (two malignant and one benign) resected with unknown marginal status recurred; two patients died and a single patient with myoepithelial carcinoma, who underwent a wide excision, is disease-free. This study illustrates the wide morphological spectrum of soft tissue METs, including benign and malignant subtypes. EMA and S-100P are optimal markers that should be supplemented with broad spectrum keratins, such as AE1/AE3, along with p63, GFAP and calponin in case of need but the results must be correlated with morphological features. Brachyury is useful in separating parachordoma/myoepithelioma from chordoma. EWSR1 rearrangement mostly occurs in METs that are deep-seated, irrespective of benign or malignant behaviour. Most malignant METs are INI1 negative. PMID- 23097008 TI - Sealing old plaques, seeding new plaques. PMID- 23097007 TI - Long-term outcomes (>2 years) of atrial fibrillation ablation using a multi electrode ablation catheter in patients with paroxysmal atrial fibrillation. AB - PURPOSE: Catheter ablation for paroxysmal atrial fibrillation (PAF) is an effective treatment. Favourable outcomes at 6-12 months post-ablation have been reported using the multi-electrode catheter 'pulmonary vein ablation catheter (PVAC)' but little is known about longer term outcomes. There are also limited data on quality of life (QoL) post-atrial fibrillation (AF) ablation beyond 2 years of follow-up. METHODS: Two hundred three consecutive patients (77 % male, mean age 57.7 +/- 11 years) who had a PAF ablation were included. Patients underwent conventional pulmonary vein isolation (PVI) (n = 128) or PVAC ablation (n = 75). Patients' symptoms were scored at baseline, at clinic follow-up and on questionnaire follow-up using the validated Canadian Cardiovascular Society Severity of AF (CCS-SAF) scale. The 'AF Effect on QualiTy of life' (AFEQT) questionnaire was used on questionnaire follow-up. RESULTS: Mean questionnaire follow-up was 854 +/- 176 days with 74 % response rate. The majority of patients (91.6 % overall) were highly symptomatic at baseline with CCS-SAF class 3 or 4 symptoms. CCS-SAF class on follow-up questionnaire decreased significantly from baseline for both groups (mean 1.69 +/- 1.7 for PVAC and 1.45 +/- 1.5 for PVI, p = 0.001 and p < 0.001, respectively) with no difference between groups (p = 0.52) and the majority being class 0 or 1 (59.9 % overall). Mean AFEQT questionnaire scores were similar between both groups (78.1 +/- 25 vs. 82 +/- 23, p = 0.35). Total procedure time was significantly shorter in the PVAC group (135 +/- 54 vs. 178 +/- 43 min, p < 0.001). CONCLUSION: There was a comparable and significant improvement in QoL post-ablation in patients who underwent ablation using PVAC catheter and conventional techniques. PMID- 23097009 TI - Multimodality cardiac imaging in Clozapine-induced eosinophilic constrictive perimyocarditis. PMID- 23097010 TI - Effect of the P450 oxidoreductase 28 polymorphism on the pharmacokinetics of tacrolimus in Chinese healthy male volunteers. AB - PURPOSE: To assess the influence of the P450 oxidoreductase 28 SNP (POR 28) on tacrolimus pharmacokinetics in the Chinese population. METHODS: Seventy-one healthy Chinese volunteers enrolled in the study received an oral dose of 2 mg of tacrolimus after providing written informed consent. CYP3A5 3 was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and POR*28 was genotyped by PCR-direct sequencing. Tacrolimus whole blood concentrations were determined by ultra performance liquid chromatography-tandem mass spectrometry and the pharmacokinetics analyses was evaluated by nonparametric methods. RESULTS: The frequencies of CYP3A5 3 and POR 28 allele were 73.3 % and 29.6 %, respectively. No significant differences existed in tacrolimus pharmacokinetics between the POR 28 CC homozygotes (n = 32) and the POR 28 T allele (n = 39) in all subjects. The mean tacrolimus AUC0-24, AUC0 infinity and Cmax for the POR 28 CC (n = 14) homozygotes in CYP3A5 expressers (CYP3A5 1/ 1 or 1/ 3 genotype) were 71.5 +/- 38.9 h ng/mL, 94.3 +/- 58.3 h ng/mL and 17.6 +/- 9.8 ng/mL, which were much higher than the POR 28 CT heterozygotes (n = 17) of 46.7 +/- 24.9 h ng/mL, 57.4 +/- 33.9 h ng/mL and 11.2 +/- 6.4 ng/mL (P < 0.05, respectively). We did not observe any significant differences in tacrolimus pharmacokinetics between the POR 28 CC homozygotes (n = 18) and POR 28 T carriers (n = 22) in CYP3A5 nonexpressers (CYP3A5 3/ 3 carriers). CONCLUSIONS: The POR 28 CT genotype presented a significantly lower level of tacrolimus exposure (AUC, Cmax) compared with the POR 28 CC genotype in CYP3A5-expressing subjects. It suggested that the POR 28 genetic polymorphism might also be responsible for the marked interindividual variability of tacrolimus besides the CYP3A5 3 genetic polymorphism. PMID- 23097011 TI - Exercise-induced paradoxical vocal fold motion disorder: diagnosis and management. AB - OBJECTIVES/HYPOTHESIS: To review our experience with the diagnosis and treatment of exercise-induced paradoxical vocal fold motion disorder (EPVFMD). STUDY DESIGN: Single-institution retrospective review and cohort analysis. METHODS: A single-institution retrospective review was performed identifying patients with paradoxical vocal fold motion disorder (PVFMD). Patients with isolated exercise induced dyspnea were selected for further review. Flexible fiberoptic laryngoscopy (FFL) performed on these patients were reviewed with regard to presence of laryngeal pathology as well as the presence of PVFMD at rest and/or with exertion. The type of therapy was reviewed. Symptom outcomes were graded as complete resolution, improvement, or unchanged following therapy. RESULTS: There were 758 patients who were identified with PVFMD. A total of 104 patients demonstrated symptoms of PVFMD that were only exercise related (EPVFMD). There were 93/104 (89%) patients who underwent a pre- and post-trigger FFL. Of these, 48/93 (52%) patients had no evidence of PVFMD on initial FFL. After subjecting these patients to exertion, 83/93 (89%) had evidence of PVFMD on postexertion FFL, and 39/93 (42%) patients had evidence of PVFMD on both pre-exertion and postexertion FFL. There were 87/104 (84%) patients who had evidence of laryngeal edema, and 23/104 (23%) had one or more laryngeal lesion on examination. A total of 67 patients were enrolled in laryngeal control therapy and attended at least one session, with 48/67 (72%) demonstrating improvement or complete resolution of their symptoms. CONCLUSIONS: The diagnosis of EPVFMD is augmented with the addition of provocation testing. Findings of PVFMD can be identified at rest when asymptomatic. Laryngeal control therapy is an effective treatment for EPVFMD. PMID- 23097012 TI - Helical spring template fabrication of cell-laden microfluidic hydrogels for tissue engineering. AB - Cell-laden microfluidic hydrogels find great potential applications in microfluidics, tissue engineering, and drug delivery, due to their ability to control mass transport and cell microenvironment. A variety of methods have been developed to fabricate hydrogels with microfluidic channels, such as molding, bioprinting, and photopatterning. However, the relatively simple structure available and the specific equipment required limit their broad applications in tissue engineering. Here, we developed a simple method to fabricate microfluidic hydrogels with helical microchannels based on a helical spring template. Results from both experimental investigation and numerical modeling revealed a significant enhancement on the perfusion ability and cell viability of helical microfluidic hydrogels compared to those with straight microchannels. The feasibility of such a helical spring template method was also demonstrated for microfluidic hydrogels with complex three-dimensional channel networks such as branched helical microchannels. The method presented here could potentially facilitate the development of vascular tissue engineering and cell microenvironment engineering. PMID- 23097014 TI - Reply to prostate-specific antigen screening for prostate cancer and the risk of overt metastatic disease at presentation : analysis of trends over time. PMID- 23097015 TI - Recent developments of proton-transfer reaction mass spectrometry (PTR-MS) and its applications in medical research. AB - Proton-transfer reaction mass spectrometry (PTR-MS) allows for real-time, on-line determination of absolute concentrations of volatile organic compounds (VOCs) with a high sensitivity and low detection limits (in the pptv range). The technique utilizes H3O+ ions for proton-transfer reactions with many common VOCs while having little to no reaction with any constituents commonly present in air. Over the past decades, research has greatly improved the applications and instrumental design of PTR-MS. In this article, we give an overview of the development of PTR-MS in recent years and its application in medical research. The theory of PTR-MS and various methods for discriminating isobaric VOCs are also described. We also show several specialized designs of sample inlet system, some of those may make PTR-MS suitable for the detection of aqueous solution and/or non-volatile samples. PMID- 23097016 TI - Sherley v Sebelius and the future of stem cell research. PMID- 23097017 TI - Halomonas cibimaris sp. nov., isolated from jeotgal, a traditional Korean fermented seafood. AB - Two moderately halophilic, facultatively aerobic, motile bacteria with flagella, designated strains 10-C-3(T) and 30-C-3, were isolated from jeotgal, a traditional Korean fermented seafood. Cells of the strains were observed to be ovoid-rods showing catalase- and oxidase-positive reactions and production of creamy-pink pigments. Growth of strain 10-C-3(T) was observed at 15-35 degrees C (optimum, 25-30 degrees C), at pH 5.5-9.0 (optimum, pH 7.0-7.5), and in the presence of 3-15 % (w/v) salts (optimum: 5-10 %). The two strains were found to contain C(18:1) omega7c, C(16:0), summed feature 3 (as defined by the MIDI system, comprising C(16:1) omega7c and/or C(16:1) omega6c), and C(12:0) 3-OH as the major cellular fatty acids. The G+C contents of the genomic DNA of strains 10 C-3(T) and 30-C-3 were determined to be 63.2 and 63.1 mol%, respectively and the respiratory quinone detected was ubiquinone 9 (Q-9) only. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strains 10-C-3(T)and 30-C-3 formed a distinct phyletic lineage within the genus Halomonas and are most closely related to Halomonas fontilapidosi 5CR(T) with 95.2 % of 16S rRNA sequence similarity. Strains 10-C-3(T)and 30-C-3 shared 99.2 % of 16S rRNA gene sequence similarity and their DNA-DNA relatedness value was 96.6 +/- 0.9 %. On the basis of phenotypic, chemotaxonomic and molecular features, strains 10-C 3(T)and 30-C-3 represent a novel species of the genus Halomonas, for which the name Halomonas cibimaris sp. nov. is proposed. The type strain is 10-C-3(T) (= KACC 14932(T) = JCM 16914(T)). PMID- 23097018 TI - Transamidation of primary amides with amines catalyzed by zirconocene dichloride. AB - Zirconocene dichloride (Cp(2)ZrCl(2)) has been shown to be an effective catalyst for the transamidation of primary amides with amines in cyclohexane at 80 degrees C in 5-24 hours. For favourable substrates, the reaction can be performed at temperatures as low as 30 degrees C. PMID- 23097019 TI - Refractive surgery for accommodative esotropia: past, present, and future. AB - INTRODUCTION: Refractive surgery has the potential to be a definitive treatment for accommodative esotropia, yet it has not been widely embraced. This article reviews the current literature on refractive surgery to treat accommodative esotropia. METHODS: A literature search was performed using the following terms: refractive surgery, photorefractive keratectomy, laser-assisted keratomileusis, intraocular lens, hyperopia, accommodative esotropia, children, pediatric. RESULTS: Fifteen series of patients treated with refractive surgery for accommodative esotropia were identified and summarized. CONCLUSIONS: Refractive surgery holds promise for the treatment of accommodative esotropia, although treatment risks are present and additional investigation is needed. PMID- 23097020 TI - Temporary management of diplopia with botulinum toxin in multiple ocular motor cranial neuropathies. AB - PURPOSE: To report management of diplopia with botulinum toxin injection in traumatic multiple ocular motor cranial neuropathies. ? METHODS: Alternate prism and cover measurement of deviation in different positions of gaze, examination of ductions, field of binocular single vision, and complete ocular anterior and posterior segment evaluation were carried out. CT and MRI of the orbit were available. ? RESULTS: We describe a case of traumatic VI, IV, and mainly superior III cranial nerve palsies, with left hypotropia of 35 prism diopters and esotropia of 45 prism diopters and incapacitating diplopia, due to fracture of the roof and lateral wall of the orbit, extending to the superior orbital fissure, as demonstrated by CT and MRI of the orbit. Severe limitation of abduction, elevation, and depression of the left eye was found. A single botulinum toxin injection in the medial rectus with diffusion to the inferior rectus was effective as a temporary measure for the treatment of diplopia and attainment of a small field of binocular single vision. The patient remained symptom-free for 5 months after injection.? CONCLUSIONS: Botulinum toxin injection may be useful for the temporary management of diplopia in multiple ocular motor cranial neuropathies. PMID- 23097021 TI - IEF-based multidimensional applications in proteomics: toward higher resolution. AB - This review focuses on the alternative isoelectrofocusing methods and IEF-related techniques in protein analysis and characterization. The main emphasis is placed on the evaluation of the resolving power of new approaches, as well as potential advantages of IEF-related techniques for multidimensional analysis. In particular, the inverse 2D gel electrophoresis where the Mw separation stage precedes IEF mode is considered. PMID- 23097022 TI - Differential effect of curcumin on the nanomechanics of normal and cancerous Mammalian epithelial cells. AB - Though the pharmacological activity of curcumin inhibiting the proliferation of certain cancer cells in culture was demonstrated, its effect on early-stage modifications induced in cell mechanics influencing hereby cell growth and cell adhesion are still questionable. We investigate the morphology and the elastic properties of live cultured, non-malignant human mammalian epithelial cells (HMEC) and cancerous breast epithelial cells (MCF7) by atomic force microscopy. We describe the different behavior of the two similar cell lines under curcumin treatment and we use fluorescence microscopy to identify the microtubules as the cytoskeleton structures responding to curcumin. The first changes in the HMEC cell morphology are observed after already 2 h incubation with curcumin. A 6-h long treatment leaves the MCF7 cells morphology non-affected, but the microtubules of HMEC cells disassemble and form a ring-like organization circumscribing the nuclear area. The observed morphological changes were correlated to modifications in cell's mechanics via elasticity force mapping measurements. Curcumin treatment modified elasticity of the HMEC cells increasing the cell's average Young's modulus two- to threefold, especially in the cytoplasmic area. Contrariwise, a slight decrease in the Young's modulus was noticed for the MCF7 cells, as they become softer due to the action of curcumin. Chemotherapeutic drugs exert their effect via the perturbation of the dynamic instability of the microtubule, hence the cell-specific perturbation induced by curcumin can help in future understanding of drug induced events on the cell behavior. PMID- 23097023 TI - Upregulation of tissue and urinary nicotinamide N-methyltransferase in bladder cancer: potential for the development of a urine-based diagnostic test. AB - Carcinoma of the bladder is one of the most common urologic malignancies occurring worldwide. Diagnosis and monitoring of bladder urothelial carcinoma (UC) are based on cystoscopy and urinary cytology. However, these diagnostic methods still have some limitations, mainly related to invasive nature and lack of sensitivity. New reliable and non-invasive biomarkers for bladder cancer detection are therefore required. To explore the involvement of enzymes of drug metabolism in bladder cancer, in the present study, we analyzed the gene expression profiles of tumor and normal looking tissues obtained from the same patient by cDNA macroarray. The enzyme nicotinamide N-methyltransferase (NNMT) was identified as a highly expressed gene in bladder cancer. RT-PCR, Real-Time PCR, Western blot analysis, and catalytic activity assay, performed on a large cohort of patients with bladder UC, confirmed NNMT upregulation. NNMT mRNA and protein levels were also determined in urine specimens obtained from patients with bladder UC and healthy subjects. We found that NNMT expression levels were significantly higher in patients with bladder tumor compared to controls that showed very low or undetectable amounts of NNMT transcript and protein. Our results indicate that a marked NNMT increase is a peculiar feature of bladder UC and suggest the potential suitability of urine NNMT expression levels determination for early and non-invasive diagnosis of bladder cancer. PMID- 23097024 TI - Simulated microgravity exposure modulates the phenotype of cultured vascular smooth muscle cells. AB - Evidence from ground-based animal studies using tail-suspended hindlimb unloaded rats model has clearly demonstrated that simulated microgravity-induced smooth muscle cell phenotype conversion, a characteristic vascular structural and functional remodeling, may be one of the key contributors to postspaceflight orthostatic intolerance. However, the rats model involves multiple collective effects of microgravity including cephalic fluid shift and postural muscle unloading on smooth muscle cells (SMCs). It cannot isolate a single factor from the collective ones and therefore is not ideal to study the effects of gravitational vector alteration alone on SMCs. To test the hypothesis that gravitational vector alteration per se might affect smooth muscle cell phenotype, a roller culture apparatus was employed to expose cultured rat aortic smooth muscle cells (RASMCs) to simulated microgravity. Cell proliferation, cell cycle distribution, apoptosis, migration, and nitric oxide production rates were measured and compared between the control and the simulated microgravity groups. Cell cytoskeleton reorganization induced by simulated microgravity was observed by confocal microscopy. Specific contractile and synthetic Gene expression at the mRNA level was quantified by reverse transcriptional polymerase chain reaction. It was observed that simulated microgravity suppressed RASMC proliferation and migration, enhanced cell apoptosis, stimulated NO release, and destroyed the original well-organized cytoskeleton. Moreover, at the mRNA level, long-time exposure (>= 72 h) to simulated microgravity induced a contractile phenotype tendency by up-regulating smMHC expression. All these findings suggest that the phenotype modulation of vascular smooth muscle cells may be gravity dependent. PMID- 23097025 TI - Silencing of FABP3 inhibits proliferation and promotes apoptosis in embryonic carcinoma cells. AB - Fatty acid-binding protein 3 (FABP3) facilitates the movement of fatty acids in cardiac muscle. Previously, we reported that FABP3 is highly upregulated in the myocardium of ventricular septal defect patients and overexpression of FABP3 inhibited proliferation and promoted apoptosis in embryonic carcinoma cells (P19 cells). In this study, we aimed to investigate the effect of FABP3 gene silencing on P19 cell differentiation, proliferation and apoptosis. We used RNA interference and a lentiviral-based vector system to create a stable FABP3 silenced P19 cell line; knockdown of FABP3 was confirmed by quantitative real time PCR. Expression analysis of specific differentiation marker genes using quantitative real-time PCR and observation of morphological changes using an inverted microscope revealed that knockdown of FABP3 did not significantly affect the differentiation of P19 cells into cardiomyocytes. CCK-8 proliferation assays and cell cycle analysis demonstrated that FABP3 gene silencing significantly inhibited P19 cell proliferation. Furthermore, Annexin V-FITC/propidium iodide staining and the caspase-3 activity assay revealed that FABP3 gene silencing significantly promoted serum starvation-induced apoptosis in P19 cells. In agreement with our previous research, these results demonstrate that FABP3 may play an important role during embryonic heart development, and that either overexpression or silencing of FABP3 will lead to an imbalance between proliferation and apoptosis, which may result in embryonic cardiac malformations. PMID- 23097026 TI - Clinical spectrum and outcome of critically ill patients suffering from prosthetic joint infections. AB - PURPOSE: To report the clinical characteristics and prognosis of prosthetic joint infections (PJIs) in Intensive care units (ICUs). METHODS: Forty-one patients consecutively admitted to ICUs for PJIs between January 2004 and June 2011 were included in a retrospective case series. RESULTS: A majority of patients (73 %) had severe underlying disease. Acute infection affected 26 patients (63 %). Blood cultures were positive in 16 patients (39 %). Staphylococcus species were the most commonly implicated causative organisms (n = 36, 88 %). The surgical strategy was two-stage replacement in 25 cases (61 %). The surgical procedure leading to ICU admission was mainly prosthesis removal with spacer implantation (n = 13, 32 %). Initial antibiotherapy was a broad-spectrum beta-lactam antibiotic combined with a glycopeptide, linezolid, or daptomycin in 26 cases (63 %). Mortality in the ICU was 20 %. In nonsurvivors, diabetes, acute infection, and American Society of Anesthesiologists (ASA) score >3 were more frequent. The distribution of surgical strategies and procedures was not statistically different in survivors and nonsurvivors. The proportion of patients treated with antibiotherapy adjusted according to previous microbiological findings was higher in nonsurvivors (50 vs. 12 %, p = 0.02). CONCLUSIONS: In our case series of critically ill patients suffering from PJI, factors associated with a poor outcome were diabetes mellitus, ASA score >3, and acute infection. Surgical strategies and surgical procedures had no significant impact on the ICU mortality. Adjustment of initial antibiotherapy according to previous microbiological findings should be made with caution. PMID- 23097028 TI - Parahydrogen-induced polarization in heterogeneous catalytic processes. AB - Parahydrogen-induced polarization of nuclear spins provides enhancements of NMR signals for various nuclei of up to four to five orders of magnitude in magnetic fields of modern NMR spectrometers and even higher enhancements in low and ultra low magnetic fields. It is based on the use of parahydrogen in catalytic hydrogenation reactions which, upon pairwise addition of the two H atoms of parahydrogen, can strongly enhance the NMR signals of reaction intermediates and products in solution. A recent advance in this field is the demonstration that PHIP can be observed not only in homogeneous hydrogenations but also in heterogeneous catalytic reactions. The use of heterogeneous catalysts for generating PHIP provides a number of significant advantages over the homogeneous processes, including the possibility to produce hyperpolarized gases, better control over the hydrogenation process, and the ease of separation of hyperpolarized fluids from the catalyst. The latter advantage is of paramount importance in light of the recent tendency toward utilization of hyperpolarized substances in in vivo spectroscopic and imaging applications of NMR. In addition, PHIP demonstrates the potential to become a useful tool for studying mechanisms of heterogeneous catalytic processes and for in situ studies of operating catalytic reactors. Here, the known examples of PHIP observations in heterogeneous reactions over immobilized transition metal complexes, supported metals, and some other types of heterogeneous catalysts are discussed and the applications of the technique for hypersensitive NMR imaging studies are presented. PMID- 23097027 TI - Methanogen genotypes involved in methane formation during anaerobic decomposition of Microcystis blooms at different temperatures. AB - The main goal of this work was to determine which methanogens were present during the anaerobic degradation of Microcystis biomass in the water columns of freshwater lakes. Simulation experiments were performed in which 30 ml Microcystis slurries were anaerobically incubated in 60 ml airtight bottles at three temperatures (15, 25, and 35 degrees C) for over 90 days. The production of CH(4) was monitored, and the methanogenic community was analyzed by cloning and sequencing the mcrA genes in samples incubated at the three different temperatures. In total, four clusters were detected at different temperatures by phylogenetic analysis of mcrA genes; these included members of Methanomicrobiales, Methanobacteriaceae, and Methanosarcina. An apparent linkage between temperature and phylogeny of the methanogenic community was observed: Methanomicrobiales and Methanobacteriaceae dominated the incubation system at the lower temperatures of 15 and 25 degrees C, whereas Methanosarcina prevailed at 35 degrees C. The dominance of these hydrogenotrophic methanogens suggested that, at least at lower temperatures, H(2) and CO(2) might be the primary substrates for CH(4) production during Microcystis anaerobic decomposition. PMID- 23097029 TI - Polymerization by classical and frustrated Lewis pairs. AB - Main-group classical and frustrated Lewis pairs (CLPs and FLPs) comprising strong Lewis acids (LAs) and strong Lewis bases (LBs) are highly active for polymerization of conjugated polar alkenes, affording typically high molecular weight polymers with relatively narrow molecular weight distributions. Especially effective systems are the Lewis pairs (LPs) consisting of the strong LA Al(C6F5)3 and strong LBs, such as achiral phosphines and chiral chelating diphosphines, N heterocyclic carbenes, and phosphazene superbases, for polymerization of methacrylates and acrylamides as well as renewable alpha-methylene-gamma butyrolactones. Chain initiation involves cooperative addition of LPs to the monomer to generate zwitterionic active species, and chain propagation proceeds via a bimetallic, activated-monomer addition mechanism. Transition metal nucleophile/electrophile pairs comprising neutral metallocene bis(ester enolate)s and strong LAs E(C6F5)3 (E = Al, B) generate two drastically different polymerization systems, depending on the LA. With E = Al, catalyst activation and chain initiating events lead to dually active ion-pairs, thereby effecting ion pairing polymerization that affords polymers with unique stereo-multiblock microstructures. With E = B, on the other hand, the FLP-induced catalyst activation generates metallacyclic cations paired with the hydridoborate anion [HB(C6F5)3](-); uniquely, such ion-pairs effect catalytic polymerization of conjugated polar alkenes by an H-shuttling mechanism, with the cation catalyzing chain growth and the anion promoting chain transfer by shuttling the hydride between the cation and anion centers through the neutral borane. PMID- 23097030 TI - Indenofluorenes and derivatives: syntheses and emerging materials applications. AB - The growing demand for flexible electronic devices and hydrogen storage materials has spurred a resurgence of interest in polyaryl hydrocarbons including graphene, acenes, fullerenes, polythiophenes, etc. Indenofluorenes are another polyaryl molecular scaffold that has shown utility in the organic and hybrid materials arena, with polymers incorporating the indeno[1,2-b]fluorene moiety being common in organic light emitting diodes. This review examines the syntheses and properties of the five distinct indenofluorene regioisomers, with a focus on small molecule applications in organic electronics of this intriguing and somewhat underexplored family of polyaryl hydrocarbons. PMID- 23097031 TI - Computational studies of lewis acidity and basicity in frustrated lewis pairs. AB - Computational studies that characterize the effects of Lewis acidity/basicity on FLP formation and reactivity are reviewed. Formation of the FLP encounter complex "cage" depends on Lewis acidities and basicities of substituent "external" atoms, and their abilities to interact intramolecularly. Computations indicate that these interactions are worth 9-18 kcal mol-1 for partly fluorinated FLPs such as (F5C6)3B...P(t-Bu)3, and less for less fluorinated species such as (H5C6)3B...P(t Bu)3. Reactivity within the cage depends on the "classical" Lewis acidities/basicities of the internal atoms. Energetics here fall into the range of 5-50 kcal mol-1; the larger the value, the greater the ability of the FLP to capture or split a substrate. In several cases the computationally predicted reaction barriers differ little with internal Lewis acidity/basicity, indicating that the rate-determining step involves the substrate entering the cage rather than attack by the Lewis acid/base atoms. In others, barriers vary sizably with Lewis acidity/basicity, indicating the opposite. In one case it was shown that these effects cancel, such that the three component barriers are identical for a range of substituted Lewis acid FLP components. PMID- 23097032 TI - N-heterocyclic carbenes in FLP chemistry. AB - The use of N-heterocyclic carbenes (NHCs) for the design and construction of frustrated Lewis pairs (FLPs) is outlined in this review. Stable carbene-borane adducts are briefly discussed, followed by a detailed survey of the reactivity of NHCs, in particular Arduengo-type imidazolin-2-ylidenes, towards B(C6F5)3. Structural and electronic NHC modification by variation of substituents and ring size affords either stable normal adducts or FLPs, which undergo manifold deactivation reactions in the absence of substrates, e.g., by abnormal adduct formation, self-dehydrogenation, and other types of C-H and C-F bond activation. The degree of frustration is correlated with the calculated energies for the formation of the normal adducts NHC.B(C6F5)3, allowing one to predict and rationalize their reactivity towards small molecules such as dihydrogen, ethers, alkynes, main group elements, carbon dioxide, and nitrous oxide. Other carbene based FLP systems with a variety of alternative Lewis acids such as boranes, alanes, and carbon-based Lewis acids are also covered, whenever "frustration" is observed. A brief introduction of structurally related bifunctional FLPs based on borylated N-heterocycles is also included. PMID- 23097033 TI - Advances of MALDI-TOF MS in the analysis of traditional Chinese medicines. AB - Traditional Chinese medicines (TCMs) are attracting more and more attention because of their long historical clinical experience and reliable therapeutic efficacy for preventing and/or treating various human diseases. Many techniques and methods were developed for the analysis of TCMs to support new drug discovery and quality control. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), a soft ionization mass spectrometric technique, has been widely used in the analysis of a wide variety of large molecular compounds including proteins, peptides, and polymers since it was introduced in the late 1980s. In the present chapter, advances of MALDI-TOF MS in TCMs analysis have been reviewed. The review covers MALDI-TOF MS applications in the identification of new bioactive ingredients, analysis of alkaloids, determination of small molecular compounds with new matrices, proteomics analysis associated with TCMs, direct analysis of plant tissue, and other applications in TCMs. PMID- 23097035 TI - First analysis of immune cell infiltration in stage pT1 urothelial bladder carcinoma: CD3 positivity as a prognostic marker for cancer-specific survival. PMID- 23097034 TI - Oncologic outcomes obtained after laparoscopic, robotic and/or single port nephroureterectomy for upper urinary tract tumours. AB - INTRODUCTION: Open surgery (ONU) is still considered to be the gold standard approach for nephroureterectomy (NU); however, with the introduction of laparoscopic surgery, minimally invasive techniques have been applied to surgical therapy of upper urinary tract tumours (UUT-UC) and they are gaining adepts. However, several concerns still exist about the safety of laparoscopic nephroureterectomy (LNU) in the treatment of UUT-UC, and different authors suggest that, although it could be equivalent to open surgery, this equivalence is not accomplished in all UUT-UC, suggesting that more advanced disease should undergo open surgery. More controversial still is the application of robotic surgery (RALNU) or really novel minimally invasive techniques, such as laparoendoscopic single-site surgery (LESSNU), for the treatment of UUT-UC. Although all these techniques seem feasible, their influence on oncologic results is still a matter of concern. METHODOLOGY: We present a review on the oncologic outcomes of minimally invasive laparoscopic techniques in the treatment of UUT UC. We focus our analysis on oncologic outcomes and we also analyze the different techniques proposed for the treatment of the distal ureter during minimally invasive surgery for UUT-UC. In the absence of prospective randomized studies with large patient samples, we must base our conclusions on retrospective studies and longer follow-up. CONCLUSION: Given the evidence accumulated so far, LNU has proven to be equivalent or non-inferior, in terms of recurrence-free survival (RFS) and cancer-specific survival (CSS) to ONU. Nevertheless, comparative studies are needed with longer follow-up before determining the equivalence of LNU in advanced tumours. PMID- 23097036 TI - Understanding white matter integrity stability for bilinguals on language status and reading performance. AB - Recent studies using diffusion tensor imaging (DTI) have described overall white matter integrity in bilinguals but have not related structural neural pathways to language functions. The current study examined white matter integrity and its relationship to reading skill in monolingual English and bilingual Chinese English speakers. Eleven monolingual speakers (mean age 28.5 years) and 13 bilingual speakers (mean age 24.2 years; English as a second language was acquired post 5 years of age) participated. Behavioural response times and accuracy rates to name regular and exception words were recorded. Participants were then scanned using a standardized DTI protocol. Fractional anisotropy (FA) and mean diffusivity values were derived from a voxelwise statistical analysis for comparisons between participant groups. Tests for relationships between response time and FA were also conducted. Our results show minimal regions of higher FA for monolinguals when compared to bilinguals and no regions of higher FA for bilinguals when compared to monolinguals, which indicates that white matter integrity may not stabilize in bilinguals until late adulthood. We do show several regions where an increase in FA is associated with faster response times. Interestingly, the FA-response time relationship varies between groups and between word types, which may reflect an increased processing demand for retrieval of difficult words (e.g., exception words). These results provide some support for the interference control and reduced frequency hypotheses outlined by Jones et al. (Cerebr Cortex 22:892-902, 2012). The current findings advance our understanding of the underlying cortical networks associated with language status and reading skill in monolingual and bilingual adults. PMID- 23097038 TI - Expression and function of dectin-1 is defective in monocytes from patients with systemic lupus erythematosus and rheumatoid arthritis. AB - The aim of this work was to study the expression and function of the innate immune receptor dectin-1 in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). We studied twenty-six patients with SLE not receiving immunosuppressive therapy, twenty-six patients with RA, and fifteen controls. We found that monocytes from SLE patients showed a diminished expression of dectin-1 compared to healthy controls, and an inverse correlation between percent of dectin-1(+) cells and the disease activity score was detected. In addition, cells from SLE patients showed an abnormal calcium flux response induced by dectin-1 ligands as well as an enhanced release of IL-1beta, IL-6 and TNF-alpha, but not IL-23, upon dectin-1 engagement. Monocytes from patients with RA also showed a diminished expression, and a defective function of dectin-1. Our data suggest that dectin-1 receptor defects could contribute to the pathogenesis of autoimmune inflammatory conditions. PMID- 23097037 TI - Soluble levels of osteopontin in patients with Behcet's disease: association with disease activity and vascular involvement. AB - AIM: Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases. We aimed to assess the plasma OPN levels in Behcet's disease (BD) patients and identify potential associations between these levels with disease activity, severity and clinical manifestations with special emphasis on vascular affection. METHODS: We studied 55 BD patients and 31 age- and gender-matched healthy controls. Demographic, clinical and serological data were prospectively assessed. Activity and severity of BD were assessed using clinical scores and laboratory parameters. Plasma OPN levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: Plasma OPN levels were significantly higher in patients with BD compared to healthy controls (p < 0.000). The means for plasma OPN levels in active and inactive BD patients were significantly higher than that for the normal controls (with p < 0.000 and p = 0.002 respectively). The mean OPN levels significantly associated with the BD clinical severity score from mild to severe (p = 0.011). BD patients with vascular involvement had significant elevation of plasma OPN levels than those without (P = 0.03). OPN levels positively correlated with severity score, IL6, hsCRP, ESR, leucocytes count and neutrophil count. CONCLUSION: Plasma OPN levels were higher in BD patients than in healthy controls and were found to be associated with disease activity, severity and vascular involvement. To confirm our results we propose that larger scale, multicentre studies with longer evaluation periods are needed. PMID- 23097039 TI - Anti-annexin V antibodies in primary fibromyalgia syndrome: relation to associated Sjogren's syndrome. PMID- 23097040 TI - The functions of anionic phospholipids during clathrin-mediated endocytosis site initiation and vesicle formation. AB - Anionic phospholipids PI(4,5)P2 and phosphatidylserine (PS) are enriched in the cytosolic leaflet of the plasma membrane where endocytic sites form. In this study, we investigated the roles of PI(4,5)P2 and PS in clathrin-mediated endocytosis (CME) site initiation and vesicle formation in Saccharomyces cerevisiae. Live-cell imaging of endocytic protein dynamics in an mss4(ts) mutant, which has severely reduced PI(4,5)P2 levels, revealed that PI(4,5)P2 is required for endocytic membrane invagination but is less important for endocytic site initiation. We also demonstrated that, in various deletion mutants of genes encoding components of the Rcy1-Ypt31/32 GTPase pathway, endocytic proteins dynamically assemble not only on the plasma membrane but also on intracellular membrane compartments, which are likely derived from early endosomes. In rcy1Delta cells, fluorescent biosensors indicated that PI(4,5)P2 only localized to the plasma membrane while PS localized to both the plasma membrane and intracellular membranes. Furthermore, we found that polarized endocytic patch establishment is defective in the PS-deficient cho1Delta mutant. We propose that PS is important for directing endocytic proteins to the plasma membrane and that PI(4,5)P2 is required to facilitate endocytic membrane invagination. PMID- 23097041 TI - The APC activator fizzy-related-1 (FZR1) is needed for preimplantation mouse embryo development. AB - In early embryos of a number of species the anaphase-promoting complex (APC), an important cell cycle regulator, requires only CDC20 for cell division. In contrast, fizzy-related-1 (FZR1), a non-essential protein in many cell types, is thought to play a role in APC activation at later cell cycles, and especially in endoreduplication. In keeping with this, Fzr1 knockout mouse embryos show normal preimplantation development but die due to a lack of endoreduplication needed for placentation. However, interpretation of the role of FZR1 during this period is hindered by the presence of maternal stores. In this study, therefore, we used an oocyte-specific knockout to examine FZR1 function in early mouse embryo development. Maternal FZR1 was not crucial for completion of meiosis, and furthermore viable pups were born to Fzr1 knockout females mated with normal males. However, in early embryos the absence of both maternal and paternal FZR1 led to a dramatic loss in genome integrity, such that the majority of embryos arrested having undergone only a single mitotic division and contained many gamma H2AX foci, consistent with fragmented DNA. A prominent feature of such embryos was the establishment of two independent spindles following pronuclear fusion and thus a failure of the chromosomes to mix (syngamy). These generated binucleate 2 cell embryos. In the 10% of embryos that progressed to the 4-cell stage, division was so slow that compaction occurred prematurely. No embryo development to the blastocyst stage was ever observed. We conclude that Fzr1 is a surprisingly essential gene involved in the establishment of a single spindle from the two pronuclei in 1-cell embryos as well as being involved in the maintenance of genomic integrity during the mitotic divisions of early mammalian embryos. PMID- 23097042 TI - Axonal transport of neural membrane protein 35 mRNA increases axon growth. AB - Many neuronal mRNAs are transported from cell bodies into axons and dendrites. Localized translation of the mRNAs brings autonomy to these processes that can be vast distances from the cell body. For axons, these translational responses have been linked to growth and injury signaling, but there has been little information about local function of individual axonally synthesized proteins. In the present study, we show that axonal injury increases levels of the mRNA encoding neural membrane protein 35 (NMP35) in axons, with a commensurate decrease in the cell body levels of NMP35 mRNA. The 3' untranslated region (3'UTR) of NMP35 is responsible for this localization into axons. Previous studies have shown that NMP35 protein supports cell survival by inhibiting Fas-ligand-mediated apoptosis; however, these investigations did not distinguish functions of the locally generated NMP35 protein. Using axonally targeted versus cell-body-restricted NMP35 constructs, we show that NMP35 supports axonal growth, and overexpression of an axonally targeted NMP35 mRNA is sufficient to increase axonal outgrowth. PMID- 23097043 TI - The alpha2Na+/K+-ATPase is critical for skeletal and heart muscle function in zebrafish. AB - The Na(+)/K(+)-ATPase generates ion gradients across the plasma membrane, essential for multiple cellular functions. In mammals, four different Na(+)/K(+) ATPase alpha-subunit isoforms are associated with characteristic cell-type expression profiles and kinetics. We found the zebrafish alpha2Na(+)/K(+)-ATPase associated with striated muscles and that knockdown causes a significant depolarization of the resting membrane potential in slow-twitch fibers of skeletal muscles. Abrupt mechanosensory responses were observed in alpha2Na(+)/K(+)-ATPase-deficient embryos, possibly linked to a postsynaptic defect. The alpha2Na(+)/K(+)-ATPase deficiency reduced the heart rate and caused a loss of left-right asymmetry in the heart tube. Similar phenotypes from knockdown of the Na(+)/Ca(2+) exchanger indicated a role for the interplay between these two proteins in the observed phenotypes. Furthermore, proteomics identified up- and downregulation of specific phenotype-related proteins, such as parvalbumin, CaM, GFAP and multiple kinases, thus highlighting a potential proteome change associated with the dynamics of alpha2Na(+)/K(+)-ATPase. Taken together, our findings show that zebrafish alpha2Na(+)/K(+)-ATPase is important for skeletal and heart muscle functions. PMID- 23097044 TI - Lysosomes shape Ins(1,4,5)P3-evoked Ca2+ signals by selectively sequestering Ca2+ released from the endoplasmic reticulum. AB - Most intracellular Ca(2+) signals result from opening of Ca(2+) channels in the plasma membrane or endoplasmic reticulum (ER), and they are reversed by active transport across these membranes or by shuttling Ca(2+) into mitochondria. Ca(2+) channels in lysosomes contribute to endo-lysosomal trafficking and Ca(2+) signalling, but the role of lysosomal Ca(2+) uptake in Ca(2+) signalling is unexplored. Inhibition of lysosomal Ca(2+) uptake by dissipating the H(+) gradient (using bafilomycin A1), perforating lysosomal membranes (using glycyl-L phenylalanine 2-naphthylamide) or lysosome fusion (using vacuolin) increased the Ca(2+) signals evoked by receptors that stimulate inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] formation. Bafilomycin A1 amplified the Ca(2+) signals evoked by photolysis of caged Ins(1,4,5)P(3) or by inhibition of ER Ca(2+) pumps, and it slowed recovery from them. Ca(2+) signals evoked by store-operated Ca(2+) entry were unaffected by bafilomycin A1. Video-imaging with total internal reflection fluorescence microscopy revealed that lysosomes were motile and remained intimately associated with the ER. Close association of lysosomes with the ER allows them selectively to accumulate Ca(2+) released by Ins(1,4,5)P(3) receptors. PMID- 23097046 TI - Tubulin detyrosination promotes monolayer formation and apical trafficking in epithelial cells. AB - The role of post-translational tubulin modifications in the development and maintenance of a polarized epithelium is not well understood. We studied the balance between detyrosinated (detyr-) and tyrosinated (tyr-) tubulin in the formation of MDCK cell monolayers. Increased quantities of detyrosinated microtubules were detected during assembly into confluent cell sheets. These tubules were composed of alternating stretches of detyr- and tyr-tubulin. Constant induction of tubulin tyrosination, which decreased the levels of detyr tubulin by overexpression of tubulin tyrosine ligase (TTL), disrupted monolayer establishment. Detyr-tubulin-depleted cells assembled into isolated islands and developed a prematurely polarized architecture. Thus, tubulin detyrosination is required for the morphological differentiation from non-polarized cells into an epithelial monolayer. Moreover, membrane trafficking, in particular to the apical domain, was slowed down in TTL-overexpressing cells. This effect could be reversed by TTL knockdown, which suggests that detyr-tubulin-enriched microtubules serve as cytoskeletal tracks to guide membrane cargo in polarized MDCK cells. PMID- 23097045 TI - Src binds cortactin through an SH2 domain cystine-mediated linkage. AB - Tyrosine-kinase-based signal transduction mediated by modular protein domains is critical for cellular function. The Src homology (SH)2 domain is an important conductor of intracellular signaling that binds to phosphorylated tyrosines on acceptor proteins, producing molecular complexes responsible for signal relay. Cortactin is a cytoskeletal protein and tyrosine kinase substrate that regulates actin-based motility through interactions with SH2-domain-containing proteins. The Src kinase SH2 domain mediates cortactin binding and tyrosine phosphorylation, but how Src interacts with cortactin is unknown. Here we demonstrate that Src binds cortactin through cystine bonding between Src C185 in the SH2 domain within the phosphotyrosine binding pocket and cortactin C112/246 in the cortactin repeats domain, independent of tyrosine phosphorylation. Interaction studies show that the presence of reducing agents ablates Src cortactin binding, eliminates cortactin phosphorylation by Src, and prevents Src SH2 domain binding to cortactin. Tandem MS/MS sequencing demonstrates cystine bond formation between Src C185 and cortactin C112/246. Mutational studies indicate that an intact cystine binding interface is required for Src-mediated cortactin phosphorylation, cell migration, and pre-invadopodia formation. Our results identify a novel phosphotyrosine-independent binding mode between the Src SH2 domain and cortactin. Besides Src, one quarter of all SH2 domains contain cysteines at or near the analogous Src C185 position. This provides a potential alternative mechanism to tyrosine phosphorylation for cysteine-containing SH2 domains to bind cognate ligands that may be widespread in propagating signals regulating diverse cellular functions. PMID- 23097047 TI - The conserved P body component HPat/Pat1 negatively regulates synaptic terminal growth at the larval Drosophila neuromuscular junction. AB - The temporal and spatial regulation of protein synthesis plays an important role in the control of neural physiology. In axons and dendrites, translationally repressed mRNAs are actively transported to their destinations in a variety of ribonucleoprotein particles (RNPs). A subset of these neuronal RNPs has been shown to contain proteins associated with mRNA processing bodies (P bodies). P bodies are a class of highly conserved cytoplasmic granules that have been linked to both mRNA decay and translational repression via general and miRNA-mediated pathways. Here, we characterize functions for HPat/Pat1 (also known as Patr-1), a core component of P bodies, at the glutamatergic larval Drosophila neuromuscular junction (NMJ). We show that hpat mutants exhibit a strong synaptic hyperplasia at the NMJ. The synaptic defects observed in hpat mutants are associated with rearrangement of the axonal microtubule cytoskeleton suggesting that HPat negatively regulates presynaptic microtubule-based growth during NMJ development. Consistent with this, overexpression of HPat also blocks the rapid growth of presynaptic boutons induced by spaced depolarization. Finally, we demonstrate that HPat interacts genetically with the catalytic subunit of the deadenylase complex (twin/CCR4) and the miRNA pathway (Argonaute 1) to control bouton formation. We propose that HPat is required to target mRNAs involved in the control of microtubule architecture and synaptic terminal growth for repression, presumably in P bodies, via both general and miRNA-mediated mechanisms. PMID- 23097049 TI - Fibroblast growth factor homologous factor 1 interacts with NEMO to regulate NF kappaB signaling in neurons. AB - Neuronal survival and plasticity critically depend on constitutive activity of the transcription factor nuclear factor-kappaB (NF-kappaB). We here describe a role for a small intracellular fibroblast growth factor homologue, the fibroblast growth factor homologous factor 1 (FHF1/FGF12), in the regulation of NF-kappaB activity in mature neurons. FHFs have previously been described to control neuronal excitability, and mutations in FHF isoforms give rise to a form of progressive spinocerebellar ataxia. Using a protein-array approach, we identified FHF1b as a novel interactor of the canonical NF-kappaB modulator IKKgamma/NEMO. Co-immunoprecipitation, pull-down and GAL4-reporter experiments, as well as proximity ligation assays, confirmed the interaction of FHF1 and NEMO and demonstrated that a major site of interaction occurred within the axon initial segment. Fhf1 gene silencing strongly activated neuronal NF-kappaB activity and increased neurite lengths, branching patterns and spine counts in mature cortical neurons. The effects of FHF1 on neuronal NF-kappaB activity and morphology required the presence of NEMO. Our results imply that FHF1 negatively regulates the constitutive NF-kappaB activity in neurons. PMID- 23097048 TI - Matrix stiffness reverses the effect of actomyosin tension on cell proliferation. AB - The stiffness of the extracellular matrix exerts powerful effects on cell proliferation and differentiation, but the mechanisms transducing matrix stiffness into cellular fate decisions remain poorly understood. Two widely reported responses to matrix stiffening are increases in actomyosin contractility and cell proliferation. To delineate their relationship, we modulated cytoskeletal tension in cells grown across a physiological range of matrix stiffnesses. On both synthetic and naturally derived soft matrices, and across a panel of cell types, we observed a striking reversal of the effect of inhibiting actomyosin contractility, switching from the attenuation of proliferation on rigid substrates to the robust promotion of proliferation on soft matrices. Inhibiting contractility on soft matrices decoupled proliferation from cytoskeletal tension and focal adhesion organization, but not from cell spread area. Our results demonstrate that matrix stiffness and actomyosin contractility converge on cell spreading in an unexpected fashion to control a key aspect of cell fate. PMID- 23097050 TI - [Intermittent Pringle manoeuvre: no reduction of blood loss according to recent RCT]. PMID- 23097051 TI - [Effect of obesity on the outcome in patients after esophagectomy for cancer]. PMID- 23097053 TI - Violent video games stress people out and make them more aggressive. AB - It is well known that violent video games increase aggression, and that stress increases aggression. Many violent video games can be stressful because enemies are trying to kill players. The present study investigates whether violent games increase aggression by inducing stress in players. Stress was measured using cardiac coherence, defined as the synchronization of the rhythm of breathing to the rhythm of the heart. We predicted that cardiac coherence would mediate the link between exposure to violent video games and subsequent aggression. Specifically, we predicted that playing a violent video game would decrease cardiac coherence, and that cardiac coherence, in turn, would correlate negatively with aggression. Participants (N = 77) played a violent or nonviolent video game for 20 min. Cardiac coherence was measured before and during game play. After game play, participants had the opportunity to blast a confederate with loud noise through headphones during a reaction time task. The intensity and duration of noise blasts given to the confederate was used to measure aggression. As expected, violent video game players had lower cardiac coherence levels and higher aggression levels than did nonviolent game players. Cardiac coherence, in turn, was negatively related to aggression. This research offers another possible reason why violent games can increase aggression-by inducing stress. Cardiac coherence can be a useful tool to measure stress induced by violent video games. Cardiac coherence has several desirable methodological features as well: it is noninvasive, stable against environmental disturbances, relatively inexpensive, not subject to demand characteristics, and easy to use. PMID- 23097054 TI - Nanofiber adsorbents for high productivity downstream processing. AB - Electrospun polymeric nanofiber adsorbents offer an alternative ligand support surface for bioseparations. Their non-woven fiber structure with diameters in the sub-micron range creates a remarkably high surface area. To improve the purification productivity of biological molecules by chromatography, cellulose nanofiber adsorbents were fabricated and assembled into a cartridge and filter holder format with a volume of 0.15 mL, a bed height of 0.3 mm and diameter of 25 mm. The present study investigated the performance of diethylaminoethyl (DEAE) derivatized regenerated cellulose nanofiber adsorbents based on criteria including mass transfer and flow properties, binding capacity, and fouling effects. Our results show that nanofibers offer higher flow and mass transfer properties. The non-optimized DEAE-nanofiber adsorbents indicate a binding capacity of 10% that of packed bed systems with BSA as a single component system. However, they operate reproducibly at flowrates of a hundred times that of packed beds, resulting in a potential productivity increase of 10-fold. Lifetime studies showed that this novel adsorbent material operated reproducibly with complex feed material (centrifuged and 0.45 um filtered yeast homogenate) and harsh cleaning in-place conditions over multiple cycles. DEAE nanofibers showed superior operating performance in permeability and fouling over conventional adsorbents indicating their potential for bioseparation applications. PMID- 23097052 TI - Detection of early neuronal damage in CADASIL patients by q-space MR imaging. AB - INTRODUCTION: q-Space imaging is a novel magnetic resonance (MR) technique that enables the assessment of ultrastructural changes of white matter. We hypothesized that this technique would facilitate the assessment of the progressive nature of neuronal damage seen in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). METHODS: This study was approved by the institutional review board. Seven consecutive adult patients (five men and two women) with the CADASIL gene mutation were studied. Two patients were preclinical cases without overt episodes of stroke. The control group consisted of five normal volunteers. All MR examinations were performed using a 1.5-T whole-body imager. q-Space imaging was performed using a single-shot, echo-planar imaging technique and Delta/delta = 142/17 ms. Gradient magnitudes were increased in nine steps to reach a maximal b value of 10,000 s/mm2. Total acquisition time of q-space imaging was 25 min. The ADC maps calculated from the b = 1,000 images were used for comparisons. RESULTS: Both q-space imaging and ADC maps depicted progressive neuronal damage. Early neuronal damage was especially well depicted using q-space imaging, with preferential involvement of the frontal lobes and central gray matters. Later progression was better depicted by b = 1,000 ADC maps at the temporal lobes. Visual assessment of images revealed a trend for occipital lobe sparing, especially on q-space imaging. CONCLUSION: q-Space imaging demonstrated early neuronal damage in a characteristic distribution. Since this method appears to be sensitive to early neuronal damage, it could conceivably aid in monitoring patients in the preclinical stage and may help in assessing the effects of future medical interventions. PMID- 23097055 TI - Prostate-specific antigen screening for prostate cancer and the risk of overt metastatic disease at presentation : analysis of trends over time. PMID- 23097056 TI - The risks of smoking in patients with spondyloarthritides. PMID- 23097057 TI - The relationship between serum TSH and free T4 in older people. AB - The frequency distribution of serum thyroid stimulating hormone (TSH) shows a skewed pattern that may change with age. The set point of the hypothalamic pituitary-thyroid axis for an individual is thought to be genetically determined and has been described as a log-linear relationship of serum TSH to free thyroxine (T4); however, the validity of this hypothesis has yet to be established in older people. The aim of the study was to describe the relationship between serum TSH and free T4 in older people and define factors influencing this relationship. We conducted a cross-sectional, observational study of thyroid function in a community population of older subjects over 65 years of age. The relationship between serum TSH and free T4 was not linear as previously described, but is best described as a fourth-order polynomial. Both gender and smoking status affected the relationship. This suggests that more complex modelling is required when investigating the hypothalamic-pituitary thyroid axis. PMID- 23097058 TI - Odyssey. PMID- 23097065 TI - Complementary workflow for global phosphoproteome analysis. AB - We described a workflow involving a combination of titanium dioxide (TiO(2)) enrichment, strong anion exchange (SAX), and strong cation exchange (SCX) fractionation for global phosphoproteome analysis. The workflow proposed TiO(2) based high efficient enrichment with optimum peptide-to-beads ratio prior to robust IEC fractionation. With the optimum peptide-to-beads ratio, offline TiO(2) enrichment provides high selectivity and large sample loading capacity compared with online TiO(2) chromatography. The eluate with highly enriched phosphopeptides is then subjected to online SAX and SCX fractionation coupled to RP-LC-MS/MS analysis. The identification of phosphopeptides from SAX, SCX, and flow-through fractions showed high complementary features. Importantly, large amount of multiphosphopeptides could be recovered in SAX fractionations. In total, up to 5063 unique phosphosites were identified from 4557 unique phosphopeptides using 4-mg HeLa cell lysate as the starting material. PMID- 23097066 TI - Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. AB - BACKGROUND: Fracture is the major complication of osteoporosis, and it allows the identification of individuals needing medical intervention for osteoporosis. After nonvertebral fracture, patients often do not receive osteoporosis medical treatment despite evidence that this treatment reduces the risk of subsequent fracture. In this pre planned analysis of the results of the three-year, placebo controlled FREEDOM trial, we evaluated the effect of denosumab administration on fracture-healing to address theoretical concerns related to initiating or continuing denosumab therapy in patients presenting with a nonvertebral fracture. METHODS: Postmenopausal women aged sixty to ninety years with osteoporosis were randomized to receive 60 mg of denosumab (n = 3902) or a placebo (n = 3906) subcutaneously every six months for three years. Investigators reported complications associated with a fracture or its management and with fracture healing for all nonvertebral fractures that occurred during the study. Delayed healing was defined as incomplete fracture-healing six months after the fracture. RESULTS: Six hundred and sixty-seven subjects (303 treated with denosumab and 364 who received a placebo) had a total of 851 nonvertebral fractures (386 in the denosumab group and 465 in the placebo group), including 199 fractures (seventy nine in the denosumab group and 120 in the placebo group) that were treated surgically. Delayed healing was reported in seven subjects (two in the denosumab group and five in the placebo group), including one with subsequent nonunion (in the placebo group). Neither delayed healing nor nonunion was observed in any subject who had received denosumab within six weeks preceding or following the fracture. A complication associated with the fracture or intervention occurred in five subjects (2%) and twenty subjects (5%) in the denosumab and placebo groups,respectively (p = 0.009). CONCLUSIONS: Denosumab in a dose of 60 mg every six months does not seem to delay fracture-healing or contribute to other complications, even when it is administered at or near the time of the fracture. PMID- 23097067 TI - Sildenafil in Heart failure (SilHF). An investigator-initiated multinational randomized controlled clinical trial: rationale and design. AB - AIMS: Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the mortality remains high and quality of life poor. Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status in single-centre trials Methods The Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months. PERSPECTIVE: The authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH. PMID- 23097068 TI - Incidence and trends of heart failure admissions after coronary artery bypass grafting surgery. AB - AIMS: Factors related to hospitalization for heart failure (HF) following coronary artery bypass grafting (CABG) surgery were studied. METHODS AND RESULTS: Patients (n = 65 377) undergoing CABG surgery in New Jersey from 1998 to 2007 were identified from the state cardiac surgery database; subsequent hospitalizations for HF were assessed using the Myocardial Infarction Data Acquisition System database. Patients were classified based on pre-operative ejection fraction (EF). Multivariate models were used to identify factors related to HF admission and mortality. Post-CABG HF admission rates among patients with pre-operative EF <35% increased over the 10-year period (P = 0.02), but no significant trend was seen among patients with EF >=35%. Independent factors associated with post-CABG HF admission within 2 years were: EF, age, female gender, Black race, smoking, diabetes, renal disease, hypertension, and cerebrovascular disease. Pre-operative use of beta-blockers increased over the years (P < 0.0001) and reduced the risk of admission for HF by 13%, with greater benefit in patients with lower EF. Mortality remained unchanged from 1998 to 2007, averaging 1.8% in-hospital and 5.1% and 7.2% at 1-year and 2-year follow up, respectively. CONCLUSIONS: Pre-operative EF is a strong predictor of HF admission within 2 years after CABG surgery. The use of beta-blockers decreased HF admission after CABG, especially in patients with EF <35%. Despite the more pronounced benefit and increasing use of beta-blockers in patients with a low EF, HF admission rates in this group of patients are rising. This suggests that more comprehensive management of factors associated with HF is necessary. PMID- 23097069 TI - Exposure to carbonyl compounds in charcoal production plants in Bahia, Brazil. AB - Studies have investigated the exposure levels of carbonyl compounds (CC) in the indoor and outdoor air of homes, vehicles, workplaces, urban and industrial areas, and rural sites. However, an investigation of these emissions and occupational exposure to CC in charcoal production facilities has not been previously conducted. The objective of this study was to measure the atmospheric concentrations of several CC to assess the exposure of workers of two charcoal plants located north of Salvador, Bahia, Brazil. Stationary and personal samples were collected using Sep-Pak(r) C18 cartridges that were coated with a 0.2 % acidic solution of 2,4-dinitrophenylhydrazine. The quantification of the resulting 2,4-dinitrophenylhydrazone derivatives was conducted using a high performance liquid chromatography system with UV detection. In the personal samples, the concentrations of formaldehyde, acetaldehyde, propanone, furfural, and C4 isomers (n-butanal-isobutanal-butanone) ranged from 12 to 139, 38 to 165, 136 to 483, 39 to 114, and 63 to 132 MUg m(-3), respectively. In the stationary samples, the concentrations of these CC ranged from 20 to 160, 111 to 284, 328 to 644, 70 to 163, and 100 to 176 MUg m(-3), respectively. When compared to the occupational exposure limits for 8 h, the concentrations of formaldehyde were often greater than the levels recommended by the American National Institute for Occupational Safety and Health, which indicates a health risk for charcoal workers. These results are the first reported concerning the occupational exposure to CC in charcoal plants. PMID- 23097070 TI - Leaching potential of phenylurea herbicides in a calcareous soil: comparison of column elution and batch studies. AB - The transfer of eleven phenylurea herbicides through soil columns was investigated in laboratory conditions in order to determine leaching properties in a calcareous soil. Elution curves with distilled water were plotted after herbicide application on the soil column. Phenylurea retention by the soil indicating interactions with soil can be classified as follows: fenuron < fluometron <= isoproturon = monuron < metoxuron < monolinuron < metobromuron < chlorotoluron < linuron = diuron < chlorbromuron. The number and nature of halogen atoms on the phenyl ring had an important influence on leaching. Retention was higher for molecules with higher number of halogen, and it was also higher for bromine than chlorine. Column elution experiments were compared to batch experiments from which the distribution coefficients K d were determined. According to Kendall correlation coefficients, parameter m/m 0 max from column experiments was relatively well linked to K d. In case of phenylurea, a linear relationship between K d and m/m 0 max was established. PMID- 23097071 TI - Application of artificial neural network for prediction of Pb(II) adsorption characteristics. AB - The adsorption of Pb(II) onto the surface of microwave-assisted activated carbon was studied through a two-layer feedforward neural network. The activated carbon was developed by microwave activation of Acacia auriculiformis scrap wood char. The prepared adsorbent was characterized by using Brunauer-Emmett-Teller (BET) surface area analyzer, scanning electron microscope (SEM), and X-ray difractometer. In the present study, the input variables for the proposed network were solution pH, contact time, initial adsorbate concentration, adsorbent dose and temperature, whereas the output variable was the percent Pb(II) removal. The network had been trained by using different algorithms and based on the lowest mean squared error (MSE) value and validation error, resilient backpropagation algorithm with 12 neurons in the hidden layer was selected for the present investigation. The tan sigmoid and purelin transfer function were used in the hidden and the output layers of the proposed network, respectively. The model predicted and experimental values of the percent Pb(II) removal were also compared and both the values were found to be in reasonable agreement with each other. The performance of the developed network was further improved by normalizing the experimental data set and it was found that after normalization, the MSE and validation error were reduced significantly. The sensitivity analysis was also performed to determine the most significant input parameter. PMID- 23097072 TI - Exposure of juvenile Danio rerio to aged TiO2 nanomaterial from sunscreen. AB - The toxicity of dietary exposure to artificially aged TiO2 nanomaterial (T-Lite) used in sunscreen cream was studied on Danio rerio. Embryolarval assays were conducted to assess the effects of TiO2 residues of nanomaterial (RNM) on fish early life stages. Juvenile fishes were exposed by the trophic route in two experiments. During the first experiment, juvenile fishes were exposed to TiO2 RNM for 14 days by adding RNM to commercial fish food. The second one consisted in producing a trophic food chain. Pseudokirchneriella subcapitata algae, previously contaminated with TiO2 RNM in growth medium, was used to feed Daphnia magna neonates over a 48-h period. Daphnia were used next to feed juvenile fishes for 7 days. Accumulation of Ti, life traits (survival and growth) and biochemical parameters such as energy reserves, digestive (trypsin, esterase, cellulose and amylase) and antioxidant (superoxide dismutase and catalase) enzyme activity were measured at the end of exposures. As expected in the receiving aquatic system, TiO2 RNM at low concentrations caused a low impact on juvenile zebrafish. A slight impact on the early life stage of zebrafish with premature hatching was observed, and this effect appeared mainly indirect, due to possible embryo hypoxia. When juvenile fish are exposed to contaminated food, digestive enzyme activity indicated a negative effect of TiO2 RNM. Digestive physiology was altered after 14 days of exposure and seemed to be an indirect target of TiO2 RNM when provided by food. PMID- 23097073 TI - Review: advances in electrochemical genosensors-based methods for monitoring blooms of toxic algae. AB - Harmful algal blooms (HABs), which have expanded worldwide in their occurrence and frequency, are a serious menace to aquatic ecosystems and humans. The development of rapid, accurate and cost-effective detection systems for toxic algal monitoring in aquatic environments is urgently required. Although many efforts have been devoted to develop reliable tools to monitor the entire spectrum of existing toxic algae, a portable semi-automated system that enables HAB monitoring at a low cost is still not available for general purchase. This work reviews the challenges and opportunities in translating the remarkable progress of electrochemical genosensors-based methods towards practical in situ HAB monitoring applications. It is specifically focused on reviewing the optimised methods for a detection system based on a sandwich hybridisation assay (SHA) performed over transducer platforms of different materials, geometries and dimensions and presenting the diverse advantages and disadvantages among them. Probe design and specificity and optimisation of the genosensor in terms of hybridisation conditions and electrochemical signal are discussed as well as their long-term stability and storage and semi-automation attempts. With continuous innovation and attention to key challenges, we expect semi-automatic devices containing DNA-based electrochemical biosensors to have an important impact upon monitoring of serious HAB events. PMID- 23097074 TI - Duo-molecularly imprinted polymer-coated magnetic particles for class-selective removal of endocrine-disrupting compounds from aqueous environment. AB - The removal of steroid and phenolic endocrine-disrupting compounds (EDCs) from an aqueous environment was investigated using magnetic particles encapsulated by a duo-molecularly imprinted polymer (duo-MIP). The effect of environmental variables on the binding efficiency was studied. Experimental results showed that the amount of EDCs adsorbed was neither affected by up to 10.0 mM NaCl nor significantly interfered by up to 10.0 mg/L humic acid. Negligible influence was observed from pH 3.3 to pH 6.8, but a decrease started at pH 9. Freundlich isotherm parameters indicated binding capacities in the order of DES > E2 ~ E1 > BPA. The applicability of class-selective removal was verified using river water samples spiked with these EDCs at 10 MUg/L; the binding efficiencies were 90, 90, 88, and 98 % for estrone (E1), 17beta-estradiol (E2), bisphenol A (BPA), and diethylstilbestrol (DES), respectively. A reuse investigation verified constant binding capacities exhibiting <2 % reduction after seven cycles of regeneration. PMID- 23097075 TI - Multiple-type dynamic culture of highly oriented fiber scaffold for ligament regeneration. AB - The ruptured anterior cruciate ligament does not heal spontaneously as it has a low capacity for healing. Therefore, the development of new healing techniques employing tissue engineering is vital. As a potentially new approach for ligament regeneration, this study used a highly oriented fiber scaffold made of elastin and collagen (the mean diameters were 1.7 +/- 0.4 MUm and 0.5 +/- 1.4 MUm, respectively), which comprise the extracellular matrix of the ligament. In addition, a multiple-type dynamic culture consisting of a combination of pressure and twist stimulation was performed to examine the influence of mechanical force on the functional maintenance of ligament cells and on the differentiation of ligament cells to osteoblast-like cells. Our results show that a pressure stimulation and elastin A upregulated the expression of alkaline phosphatase (ALP) (a marker of osteogenic differentiation) and promoted the osteogenic differentiation of ligament cells. In addition, the twist stimulation upregulated the expression of type III collagen (the main component of ligament tissue). Furthermore, the combination of pressure and twist stimulation promoted the expression of type III collagen and ALP protein depending on the portion of scaffold. PMID- 23097076 TI - High signal intensity on T2-weighted cardiac magnetic resonance imaging correlates with the ventricular tachyarrhythmia in hypertrophic cardiomyopathy. AB - Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) can predict ventricular arrhythmia and poor prognosis in hypertrophic cardiomyopathy (HCM) patients. Although myocardial T2-high signal has been reported to appear within LGE in those patients, its clinical significance remains unclear. We investigated the relationship between the T2-high signal and nonsustained ventricular tachycardia (NSVT) in HCM patients. Eighty-one HCM patients who underwent Holter ECG and CMR including T2-weighted and LGE imaging were retrospectively recruited. They were divided into NSVT-positive and NSVT-negative groups. We compared the clinical and CMR characteristics between both of the groups, and assessed predictors of NSVT with multivariate analysis. Myocardial T2 high signal was observed in 15/81 (18.5 %) patients. Each T2-high signal was localized within LGE. Significantly in the NSVT-positive group, the prevalence of atrial fibrillation [5/17 (29.4 %) vs. 2/64 (3.1 %), p = 0.0006] and T2-high signal [9/17 (52.9 %) vs. 6/64 (9.4 %), p < 0.0001] and the left ventricular (LV) end-systolic volume index (32.2 +/- 15.9 ml/m(2) vs. 23.3 +/- 14.9 ml/m(2), p = 0.034) and the number of segments with LGE (5.8 +/- 3.3 vs. 2.7 +/- 2.7, p < 0.0001) was increased, and the LV ejection fraction (54.8 +/- 10.9 % vs. 65.1 +/- 10.6 %, p = 0.0007) was decreased, compared to the NSVT-negative group. On multivariate analysis, the presence of atrial fibrillation (OR 29.49, p = 0.0025) and DM (OR 7.36, p = 0.0455) and T2-high signal (OR 14.96, p = 0.0014) and reduced LV ejection fraction (OR 0.93, p = 0.0222) were significantly associated with NSVT. The presence of myocardial T2-high signal is a significant independent predictor of NSVT in HCM patients. PMID- 23097077 TI - Implications of global climate change for natural resource damage assessment, restoration, and rehabilitation. AB - Various international and national regulations hold polluters liable for the cleanup of released hazardous substances and the restoration/rehabilitation of natural resources to preincident baseline conditions, a process often referred to as natural resource damage assessment and restoration (NRDAR). Here, we, the authors, describe how global climate change (GCC) will challenge each of the steps of NRDAR processes and offer eight recommendations to improve these processes in light of GCC. First, we call for a better understanding of the net effects of GCC and contaminants on natural resources. Second, we urge facilities and environmental managers to plan for GCC-related factors that are expected to increase the probability of contaminant releases. Third, we suggest re-evaluating definitions of baseline and reference conditions given that GCC will alter both their trajectories and variability. Fourth, we encourage long-term monitoring to improve the quantification of baseline conditions that will change as climate changes. This will enhance the accuracy of injury assessments, the effectiveness of restoration, and the detection of early warning signs that ecosystems are approaching tipping points. Fifth, in response to or anticipation of GCC, restoration projects may need to be conducted in areas distant from the site of injury or focused on functionally equivalent natural resources; thus, community involvement in NRDAR processes will be increasingly important. Sixth, we promote using NRDAR restoration projects as opportunities to mitigate GCC-related impacts. Seventh, we recommend adaptive management approaches to NRDAR processes and communication of successes and failures widely. Finally, we recommend focusing on managing the stressors that might be exacerbated by GCC, such as pollution and habitat loss, because there is a long history of successfully mitigating these stressors, which can be more easily managed on local scales than climate change. We believe that adoption of these recommendations will lead to a more efficacious NRDAR process, despite the challenges posed by climate change. PMID- 23097078 TI - Elucidation of the DNA-interacting properties and anticancer activity of a Ni(II) coordinated mithramycin dimer complex. AB - Mithramycin (Mith) forms a drug-metal complex with a 2:1 stoichiometry by chelation with a Ni(II) ion, which was determined using circular dichroism spectroscopy. Mith exhibits an increased affinity (~55 fold) for Ni(II) in the presence of DNA compared to the absence of DNA, suggesting that DNA acts as an effective template to facilitate chelation. Also, we characterized the DNA-acting properties of a Ni(II) derivative of Mith. Kinetic analysis using surface plasmon resonance and UV melting studies revealed that Ni(II)(Mith)(2) binds to duplex DNA with a higher affinity compared to Mg(II)(Mith)(2). The thermodynamic parameters revealed a higher free energy of formation for duplex DNA in the presence of Ni(II)(Mith)(2) compared to duplex DNA in the presence of Mg(II)(Mith)(2). The results of a DNA-break assay indicated that Ni(II)(Mith)(2) is capable of promoting one-strand cleavage of plasmid DNA in the presence of hydrogen peroxide; the DNA cleavage rate of Ni(II)(Mith)(2) was calculated to be 4.1 * 10(-4) s(-1). In cell-based experiments, Ni(II)(Mith)(2) exhibited a more efficient reduction of c-myc and increased cytotoxicity compared to Mith alone because of its increased DNA-binding and cleavage activity. The evidence obtained in this study suggests that the biological effects of Ni(II)(Mith)(2) require further investigation in the future. PMID- 23097079 TI - Nickel induces apoptosis in human neutrophils. AB - Nickel is an ubiquitous transition metal that is industrially applied in many forms, which inevitably leads to a high degree of occupational and environmental exposure. Over-exposure to nickel can produce a variety of adverse effects on human health, including allergy and lung and nasal cancers. In the present study, it is demonstrated, for the first time, that nickel [(Ni(II)] (as a nickel nitrate salt) at concentrations that may be attained in vivo, induces neutrophils' apoptosis by the intrinsic pathway. The use of diphenyleneiodonium, a NADPH oxidase inhibitor, delayed Ni(II)-induced apoptosis, suggesting that NADPH oxidase-derived reactive oxygen species and subsequent signaling could contribute to this event. This is an important finding since increased apoptosis mediated by nickel may disrupt the physiological activities of neutrophils, with potential impact in its immunological and antimicrobial role. PMID- 23097080 TI - Effects of lanthanum chloride on glutamate level, intracellular calcium concentration and caspases expression in the rat hippocampus. AB - Lanthanum chloride (LaCl(3)) can affect neurobehavioral development and impair cognitive abilities. The mechanism underlying LaCl(3)-induced neurotoxic effects is still unknown. The purpose of this research was to investigate the neuronal impairment induced by LaCl(3) and discuss the possible mechanism from the aspects of the alteration of glutamate level, intracellular calcium concentration ([Ca(2+)](i)), Bax, Bcl-2 and caspases expression in the hippocampus. Lactational rats were exposed to 0, 0.25, 0.50 and 1.0 % LaCl(3) in drinking water, respectively. Their offspring were exposed to LaCl(3) by parental lactation and then administrated with 0, 0.25, 0.50 and 1.0 % LaCl(3) in drinking water for 1 month. The results showed that 0.25, 0.50 and 1.0 % LaCl(3) exposure induced neuronal impairment in the hippocampus of young rat. Hippocampal glutamate level, [Ca(2+)](i) and ratio of Bax and Bcl-2 expression increased significantly after LaCl(3) exposure. Besides, LaCl(3) exposure increased GRP78, GRP94, GADD153 and p JNK expression, promoted the activation of caspase-3, caspase-9 and caspase-12, induced PARP cleavage and caused excessive apoptosis. These results indicate that LaCl(3) increases glutamate level, [Ca(2+)](i) and ratio of Bax and Bcl-2 expression, which cause excessive apoptosis by the mitochondrial and endoplasmic reticulum stress-induced pathway, and thus neuronal damages in the hippocampus. PMID- 23097081 TI - Increasing activity and thermal resistance of Bacillus gibsonii alkaline protease (BgAP) by directed evolution. AB - Bacillus gibsonii Alkaline Protease (BgAP) is a recently reported subtilisin protease exhibiting activity and stability properties suitable for applications in laundry and dish washing detergents. However, BgAP suffers from a significant decrease of activity at low temperatures. In order to increase BgAP activity at 15 degrees C, a directed evolution campaign based on the SeSaM random mutagenesis method was performed. An optimized microtiter plate expression system in B. subtilis was established and classical proteolytic detection methods were adapted for high throughput screening. In parallel, the libraries were screened for increased residual proteolytic activity after incubation at 58 degrees C. Three iterative rounds of directed BgAP evolution yielded a set of BgAP variants with increased specific activity (K(cat)) at 15 degrees C and increased thermal resistance. Recombination of both sets of amino acid substitutions resulted finally in variant MF1 with a 1.5-fold increased specific activity (15 degrees C) and over 100 times prolonged half-life at 60 degrees C (224 min compared to 2 min of the WT BgAP). None of the introduced amino acid substitutions were close to the active site of BgAP. Activity-altering amino acid substitutions were from non charged to non-charged or from sterically demanding to less demanding. Thermal stability improvements were achieved by substitutions to negatively charged amino acids in loop areas of the BgAP surface which probably fostered ionic and hydrogen bonds interactions. PMID- 23097082 TI - [Immunotherapy of melanomas]. AB - Even early clinical studies showed that adjuvant chemotherapy achieved no therapeutic benefit for melanomas so that in the current guidelines its use is only recommended within the framework of clinical studies. For over 30 years interferons have been used in the adjuvant treatment of primary high risk melanomas as well as in the treatment of metastasized melanomas. They function in an antiviral, immune modulating and antitumor fashion. Direct and indirect effects on tumor cells could be demonstrated for interferons. In Europe low dosage interferon therapy is approved and has become widely established for stage II melanomas, whereas in the USA high dosage therapy for stage III and since March 2011 therapy with pegylated interferon in stage III are also approved. In this article the most important study results will be dealt with in detail. In summary, according to the current study situation therapy with interferon should be offered especially to patients with ulcerated primary melanoma and microscopic lymph node infiltration. Many attempts have been made in the last decades to positively influence the survival time of distant metastasized melanoma by systemic therapy. The recent development of the antibody ipilimumab against cytotoxic T-lymphocyte protein 4 (CTLA-4) could show for the first time a survival advantage in the therapy of melanoma patients in advance stage disease. The licensing of ipilimumab has meant that there is now a new standard available for the second line therapy of malignant melanoma which will be included in the guidelines on therapy of malignant melanoma. A further interesting option for adjuvant therapy is currently vaccination with the recombinant melanoma associated protein 3 (MAGE-A3) protein in combination with the adjuvant AS015. PMID- 23097083 TI - Deviancy and normative training processes in experimental groups of delinquent and nondelinquent male adolescents. AB - The goal of this study was to identify the predictors and the moderators of group characteristics that influence deviancy and normative training processes in delinquent male adolescents. The authors experimentally tested the effects of group composition on deviant talk interaction processes among groups in which all members presented delinquent behaviors ("pure" delinquent group condition), those that included adolescents with no delinquent behaviors ("pure" normative group condition), and adolescents with both profiles ("mixed" group condition). Participants were 70 male adolescents aged 15-18 (M = 16.5; 56% Caucasian), with a random assignment to groups. Data were collected among three group sessions (T1, T2, T3), one session a week, using videotape. Two contents of interactions were also measured: antisocial and normative stories, counterbalanced across sessions. Results showed a significant group effect for antisocial talk and its reinforcement, with less antisocial talk within the mixed group condition in comparison to the pure delinquent group condition. The topic of interaction was also observed as a predictor of antisocial talk, with less normative interactions and more antisocial talk associated with antisocial topics. Finally, time moderated some relations between experimental groups and talk. We conclude with a discussion of the implications of this work for future research on deviancy training processes. PMID- 23097084 TI - Multidisciplinary therapy reduces risk factors for metabolic syndrome in obese adolescents. AB - This study aims to assess the effects of a 16-week multidisciplinary program of obesity treatment on the control of metabolic syndrome (MS) and dyslipidemia in obese adolescents. Eighty-six adolescents aged 10-18 years were allocated in either the intervention group (IG; n = 44) or control group (CG; n = 42). IG was submitted to a multidisciplinary intervention based on cognitive behavioral therapy that aimed to modify eating habits and exercise behavior. We analyzed, before and after the intervention period, anthropometric parameters, body composition, bone mineral density, cardiorespiratory fitness, blood pressure, glucose, insulin, and lipid profile of the subjects. MS was classified according to International Diabetes Federation (2007) and the presence of dyslipidemia according to Back et al. (Arq Bras Cardiol 85:4-36, 2005). In the beginning of the intervention, the median number (range) of risk factors for MS present was 2.0 (0.0-5.0) in the IG and 2.0 (0.0-4.0) in the CG. After the intervention, this parameter reduced significantly in the IG (1.0 (0.0-5.0); p = 0.004) while no change was observed in the CG (2.0 (0.0-4.0); p = 0.349). In addition, we observed improvements in body mass index, waist circumference, hip circumference, maximal oxygen uptake, absolute and relative body fat, systolic blood pressure, diastolic blood pressure, and total cholesterol in the IG which was not identified in the CG. Conclusio n: We suggest that a 16-week multidisciplinary intervention based on cognitive behavioral therapy was adequate to reduce risk factors for MS in obese adolescents. PMID- 23097085 TI - Response to article: Langford et al. racial and ethnic differences in direct-to consumer genetic tests awareness in HINTS 2007: sociodemographic and numeracy correlates. J Genet Counsel (2012) 21:440-447. PMID- 23097086 TI - Response to letter written by Shelly Cummings, MS, CGC of Myriad Genetics Laboratories, Inc. regarding the paper, "racial and ethnic differences in direct to-consumer genetic tests awareness in HINTS 2007: sociodemographic and numeracy Correlates." J Genet Counsel (2012) 21:440-447. PMID- 23097090 TI - Stereoselective determination of metoprolol and its metabolite alpha hydroxymetoprolol in plasma by LC-MS/MS: application to pharmacokinetics during pregnancy. AB - Metoprolol is available for clinical use as a racemic mixture. The S-(-) metoprolol enantiomer is the one expressing higher activity in the blockade of the beta(1)-adrenergic receptor. The alpha-hydroxymetoprolol metabolite also has activity in the blockade of the beta(1)-adrenergic receptor. The present study describes the development and validation of a stereoselective method for sequential analysis of metoprolol and of alpha-hydroxymetoprolol in plasma using high-performance liquid chromatography with tandem mass spectrometry (LC-MS/MS). 1-ml aliquots of plasma were extracted with dichloromethane : diisopropyl ether (1:1, v/v). Metoprolol enantiomers and alpha-hydroxymetoprolol isomers were separated on a Chiralpak AD column (Daicel Chemical Industries, New York, NY, USA) and quantitated by LC-MS/MS. The limit of quantitation obtained was 0.2 ng of each metoprolol enantiomer/ml plasma and 0.1 ng/ml of each alpha hydroxymetoprolol isomer/ml plasma. The method was applied to the study of kinetic disposition of metoprolol in plasma samples collected up to 24 h after the administration of a single oral dose of 100-mg metoprolol tartrate to a hypertensive parturient with a gestational age of 42 weeks. The clinical study showed that the metoprolol pharmakokinetics is enantioselective, with the observation of higher area under the curve (AUC)(0-infinity) values for S-(-) metoprolol (AUC(S-(-)) /AUC(R-(+)) = 1.81) and the favoring of the formation of the new chiral center 1'R of alpha-hydroxymetoprolol (AUC(0-infinity) (1'R/1'S) = 2.78). PMID- 23097088 TI - Intercellular adhesion molecule-2 is involved in apical ectoplasmic specialization dynamics during spermatogenesis in the rat. AB - In this study, we investigated the role of intercellular adhesion molecule-2 (ICAM2) in the testis. ICAM2 is a cell adhesion protein having important roles in cell migration, especially during inflammation when leukocytes cross the endothelium. Herein, we showed ICAM2 to be expressed by germ and Sertoli cells in the rat testis. When a monospecific antibody was used for immunolocalization experiments, ICAM2 was found to surround the heads of elongating/elongated spermatids in all stages of the seminiferous epithelial cycle. To determine whether ICAM2 is a constituent of apical ectoplasmic specialization (ES), co immunoprecipitation and dual immunofluorescence staining were performed. Interestingly, ICAM2 was found to associate with beta1-integrin, nectin-3, afadin, Src, proline-rich tyrosine kinase 2, annexin II, and actin. Following CdCl2 treatment, ICAM2 was found to be upregulated during restructuring of the seminiferous epithelium, with round spermatids becoming increasingly immunoreactive for ICAM2 by 6-16 h. Interestingly, there was a loss in the binding of ICAM2 to actin during CdCl2-induced germ cell loss, suggesting that a loss of ICAM2-actin interactions might have facilitated junction restructuring. Taken collectively, these results illustrate that ICAM2 plays an important role in apical ES dynamics during spermatogenesis. PMID- 23097091 TI - The role of promoter hypermethylation in fibroblast activation and fibrogenesis. AB - The aberrant methylation of CpG island promoters of selected genes is the prominent epigenetic mechanism by which gene transcription can be effectively silenced. Aberrant hypermethylation of a few selected genes plays an important role in facilitating fibrotic fibroblast activation and in driving fibrogenesis. Here we review mechanisms of DNA methylation and demethylation and their implications for fibroblast activation and tissue fibrosis. PMID- 23097092 TI - Phosphorylation of NuMA by Aurora-A kinase in PC-3 prostate cancer cells affects proliferation, survival, and interphase NuMA localization. AB - Aurora-A is a serine/threonine kinase that has oncogenic properties in vivo. The expression and kinase activity of Aurora-A are up-regulated in multiple malignancies. Aurora-A is a key regulator of mitosis that localizes to the centrosome from the G2 phase through mitotic exit and regulates mitotic spindle formation as well as centrosome separation. Overexpression of Aurora-A in multiple malignancies has been linked to higher tumor grade and poor prognosis through mechanisms that remain to be defined. Using an unbiased proteomics approach, we identified the protein nuclear mitotic apparatus (NuMA) as a robust substrate of Aurora-A kinase. Using a small molecule Aurora-A inhibitor in conjunction with a reverse in-gel kinase assay (RIKA), we demonstrate that NuMA becomes hypo-phosphorylated in vivo upon Aurora-A inhibition. Using an alanine substitution strategy, we identified multiple Aurora-A phospho-acceptor sites in the C-terminal tail of NuMA. Functional analyses demonstrate that mutation of three of these phospho-acceptor sites significantly diminished cell proliferation. In addition, alanine mutation at these sites significantly increased the rate of apoptosis. Using confocal immunofluorescence microscopy, we show that the NuMA T1804A mutant mis-localizes to the cytoplasm in interphase nuclei in a punctate pattern. The identification of Aurora-A phosphorylation sites in NuMA that are important for cell cycle progression and apoptosis provides new insights into Aurora-A function. PMID- 23097093 TI - Lens particle glaucoma secondary to untreated ?congenital cataract and persistent fetal vasculature. AB - Purpose. To present a case of lens particle glaucoma in a child with an untreated unilateral congenital cataract and persistent fetal vasculature (PFV) and to discuss the implications for the management of unilateral congenital cataract.?Methods. A 4-year-old boy presented with a unilateral congenital cataract affecting the right eye. Examination revealed a cataract and PFV. Intraocular pressure (IOP) measured 18 mmHg right, 14 mmHg left, and he was managed conservatively. Nine months later, he attended clinic with a painful right eye. He had quiet anterior and posterior segments but free lens particles in the anterior vitreous and an IOP of 12 mmHg. Over 4 weeks, the IOP rose to 23 mmHg and the patient underwent vitreolensectomy.?Results. The affected eye has at no point become inflamed but macrophages laden with lens proteins were identified during histopathologic analysis of the vitreous. The proposed mechanism in this case is that the PFV weakened the posterior capsule leading to its rupture. The resultant macrophages then caused mechanical obstruction of aqueous outflow through the trabecular meshwork.?Conclusions. Lens particle glaucoma secondary to posterior capsular rupture is a rare form of lens-induced glaucoma. It is common practice to manage conservatively those patients who present late with unilateral congenital cataract. This case highlights the need for vigilant follow-up of these patients to enable lens-induced glaucoma to be detected at an early stage. PMID- 23097094 TI - Region-specific localization of IMDS-60 protein in mouse epididymis and its relationship with sperm maturation. AB - Spermatozoa acquire forward motility and fertilizing capacity during their transit through the epididymis. This maturation process involves modifications of the sperm surface by different proteins secreted by a series of specialized regions in the epididymal epithelium. Previously, our lab has reported IMDS-60 gene, which is highly expressed in mouse corpus and cauda epididymidis. Here, to perform further characterization of IMDS-60 protein, the specific polyclonal antisera were raised to the C-terminal peptide of the IMDS-60 protein. Western blot and immunohistochemistry assay revealed that IMDS-60 protein was specifically localized in the corpus and cauda regions of epididymidis. IMDS-60 could be transported from epididymal epithelium to the surface of epididymal spermatozoa. Finally, the results of the antibody block experiments suggested that IMDS-60 might play important roles in sperm maturation in the epididymis. PMID- 23097095 TI - Thyroxine treatment: absorption, malabsorption, and novel therapeutic approaches. PMID- 23097096 TI - Steroid modulation of cytokine release and desmosine levels in bilateral total knee replacement: a prospective, double-blind, randomized controlled trial. AB - BACKGROUND: The perioperative inflammatory response as measured by elevated levels of interleukin-6 (IL-6) has been linked to acute respiratory distress syndrome, postoperative confusion, and fever. Because of the extent of surgery,patients undergoing bilateral total knee arthroplasty may be at high risk of complications. We had found a significant decrease in IL-6 in patients having bilateral total knee replacement who received two doses of 100 mg of hydrocortisone eight hours apart; however, by twenty-four hours, IL-6 levels were equal to those in the group that received a placebo. In the present study, we investigated whether the administration of three doses would reduce IL-6 levels at twenty-four hours and affect other outcomes such as desmosine level, a marker of lung injury. METHODS: After institutional review board approval, a total of thirty-four patients (seventeen patients and seventeen control subjects) were enrolled in this double-blind, randomized, placebo-controlled study. Three doses of intravenous hydrocortisone (100 mg) or placebo were given eight hours apart. Urinary desmosine levels were obtained at baseline and at one and three days postoperatively. The level of IL-6 was measured at baseline and at six, ten, twenty-four, and forty-eight hours postoperatively. Pain scores, presence of fever, and functional outcomes were recorded. RESULTS: The level of IL-6 increased in both groups, but was significantly higher in the control group, peaking at twenty-four hours (mean and standard deviation, 623.74 +/- 610.35 pg/mL versus 148.13 +/- 119.35 pg/mL; p = 0.006). Urinary desmosine levels significantly increased by twenty-four hours in the control group, but remained unchanged in the study group (134.75 +/- 67.88 pmol/mg and 79.45 +/- 46.30 pmol/mg, respectively; p = 0.006). Pain scores at twenty-four hours were significantly lower in the study group (1.4 +/- 0.9 versus 2.4 +/- 1.2; p = 0.01) as was the presence of fever (11.8%versus 47.1%; p = 0.03). Range of motion at the knee was significantly greater in the study group (81.6 +/- 11.6 versus 70.6 +/- 14.0 in the right knee [p = 0.02] and 81.4 +/- 11.3 versus 73.4 +/- 9.4 in the left knee [p = 0.03]). CONCLUSIONS: Hydrocortisone (100 mg) given over three doses, each eight hours apart, decreased and maintained a lower degree of inflammation with bilateral total knee replacement as measured by IL-6 level. Corticosteroids decreased the prevalence of fever, lowered visual analog pain scores, and improved knee motion. The significantly lower values of desmosine in the study group suggest that this treatment may be protective against lung injury. PMID- 23097097 TI - Progress towards Drosophila epithelial cell culture. AB - Drosophila epithelial research is at the forefront of the field; however, there are no well-characterized epithelial cell lines that could provide a complementary in vitro model for studies conducted in vivo. Here, a protocol is described that produces epithelial cell lines. The method uses genetic manipulation of oncogenes or tumor suppressors to induce embryonic primary culture cells to rapidly progress to permanent cell lines. It is, however, a general method and the type of cells that comprise a given line is not controlled experimentally. Indeed, only a small fraction of the lines produced are epithelial in character. For this reason, additional work needs to be done to develop a more robust epithelial cell-specific protocol. It is expected that Drosophila epithelial cell lines will have great utility for in vitro analysis of epithelial biology, particularly high-throughput analyses such as RNAi screens. PMID- 23097098 TI - Culture of choroid plexus epithelial cells and in vitro model of blood-CSF barrier. AB - Chemical homeostasis in the extracellular fluid of the central nervous system (CNS) is maintained by two brain barrier systems, i.e., the blood-brain barrier (BBB) that separates the blood circulation from brain interstitial fluid and the blood-cerebrospinal fluid barrier (BCB) that separates the blood from the cerebrospinal fluid (CSF). The choroid plexus, where the BCB is located, is a polarized tissue, with the basolateral side of the choroidal epithelium facing the blood and the apical microvilli in direct contact with the CSF. The tissue plays a wide range of roles in brain development, aging, nutrient transport, endocrine regulation, and pathogenesis of certain neurodegenerative disorders. This chapter describes two in vitro cultures that have been well established to allow for study of the BCB structure and function. The primary choroidal epithelial cell culture can be established from rat choroid plexus tissue, and a similar immortalized murine choroidal epithelial cell culture known as Z310 cells has also been established. Both cultures display a dominant polygonal morphology, and immunochemical studies demonstrate the presence of transthyretin, a thyroxine transport protein known to be exclusively produced by the choroidal epithelia in the CNS. These cultures have been adapted for use on freely permeable Transwell((r)) membranes sandwiched between two culture chambers, facilitating transport studies of various compounds across this barrier in vitro. These choroidal epithelia cultures with the Transwell system will perceivably assist blood-CSF barrier research. PMID- 23097099 TI - Methods for culture of human corneal and conjunctival epithelia. AB - The surface of the eye is exposed to the outside world and is, thus, subject to surface abrasion, infections, and drying, cicatrizing diseases. Availability of in vitro methods for culture of the human corneal and conjunctival epithelia, which cover the ocular surface, is therefore important in understanding the biology of these epithelia and their response to disease/infections, as well as for providing human-relevant models for preclinical testing of potential therapeutic agents. The ensuing chapter describes several methods for primary culture of both corneal and conjunctival epithelia and culture of immortalized cell lines, and methods employed to induce differentiation in the cultured epithelia. PMID- 23097100 TI - The culture and maintenance of functional retinal pigment epithelial monolayers from adult human eye. AB - The retinal pigment epithelium (RPE) is implicated in many eye diseases, including age-related macular degeneration, and therefore isolating and culturing these cells from recently deceased adult human donors is the ideal source for disease studies. Adult RPE could also be used as a cell source for transplantation therapy for RPE degenerative disease, likely requiring first in vitro expansion of the cells obtained from a patient. Previous protocols have successfully extracted RPE from adult donors; however improvements in yield, cell survival, and functionality are needed. We describe here a protocol optimized for adult human tissue that yields expanded cultures of RPE with morphological, phenotypic, and functional characteristics similar to freshly isolated RPE. These cells can be expanded and cultured for several months without senescence, gross cell death, or undergoing morphological changes. The protocol takes around a month to obtain functional RPE monolayers with accurate morphological characteristics and normal protein expression, as shown through immunohistochemistry analysis, RNA expression profiles via quantitative PCR (qPCR), and transepithelial resistance (TER) measurements. Included in this chapter are steps used to extract RPE from human adult globes, cell culture, cell splitting, cell bleaching, immunohistochemistry, and qPCR for RPE markers, and TER measurements as functional test. PMID- 23097101 TI - Oral and pharyngeal epithelial keratinocyte culture. AB - Primary human oral epithelial cells are readily available and have been recently employed for tissue engineering. These cells are currently being widely utilized in multiple research efforts, ranging from the study of oral biology, mucosal immunity, and carcinogenesis to stem cell biology and tissue engineering. This chapter describes step-by-step protocols for the successful isolation and culture of human oral epithelial cells and fibroblasts, and techniques for their use in two-dimensional and three-dimensional culture systems. The described methods will enable to generate reconstituted tissues that resemble epithelial like structures in vitro, which can recapitulate some of the key features of the oral epithelium in vivo. PMID- 23097102 TI - Primary culture of the human olfactory neuroepithelium. AB - The central cell type involved in the initial perception of odors and transduction of the sensory signal are the olfactory receptor neurons (ORNs) located in the olfactory neuroepithelium of the nasal cavities. The olfactory epithelium is a unique system similar to the neuroepithelium of the embryonic neural tube, in which new neurons are continually generated throughout adult life. Olfactory neurons are derived from precursor cells that lie adjacent to the basal lamina of the olfactory epithelium; these precursor cells divide several times and their progeny differentiate into mature sensory neurons throughout life. Thus, the human olfactory epithelium has the potential to be used as a tool to examine certain human disorders resulting from abnormal development of the nervous system. This chapter presents methods for primary culture of human ORNs, which have been used successfully by multiple investigators. The protocol provides a consistent, heterogeneous cell population, which demonstrates functional responses to odorant mixtures and exhibits a complex neuronal phenotype, encompassing receptors and signaling pathways pertinent to both olfaction and other aspects of CNS function. These cultured neural cells exhibit neurotransmitter pathways important in a number of neuropsychiatric disorders, and the ability to culture cells from living human subjects provides a tool for assessing cellular neuropathology at the individual patient level. PMID- 23097103 TI - Primary culture of mammalian taste epithelium. AB - Establishment of primary and immortalized cultures of many cell types has facilitated efforts to understand the signals involved in proliferation and differentiation and yielded tools to rapidly assay new molecules targeting specific receptor pathways. Taste cells are specialized sensory epithelial cells which reside within taste buds on the lingual epithelium. Only recently have successful culturing protocols been developed which maintain essential molecular and functional characteristics. These protocols provide a tractable tool to examine the molecular, regenerative, and functional properties of these unique sensory cells within a controlled environment. The method involves an enzymatic isolation procedure and standardized culture conditions, and may be applied to either dissected rodent tissue or human fungiform papillae obtained by biopsy. Human fungiform cells can be maintained in culture for more than seven passages, without loss of viability and with retention of the molecular and biochemical properties of acutely isolated taste cells. Cultured primary human fungiform papillae cells also exhibit functional responses to taste stimuli indicating the presence of taste receptors and at least some relevant signaling pathways. While the loss of the three-dimensional structure of the intact taste bud must be taken into consideration in interpreting results obtained with these cells, this culture protocol provides a useful model for molecular studies of the proliferation, differentiation, and physiological function of mammalian taste receptor cells. PMID- 23097104 TI - Human nasal and tracheo-bronchial respiratory epithelial cell culture. AB - Human airway epithelial (hAE) cell cultures are instrumental for studying basic and applied aspects of respiratory tract biology, disease, and therapy. When primary epithelial cells from the human nasal passages or tracheo-bronchial airways are grown on porous supports at an air-liquid interface (ALI) they undergo mucociliary differentiation, reproducing both the in vivo morphology and key physiologic processes. These cultures are useful for studying basic biology, disease pathogenesis, gene therapy and aerosol administration of drugs. This chapter gives detailed protocols for tissue procurement, cell isolation, production of complex media, and cell culture initiation and maintenance needed for hAE cell ALI cultures with non-proprietary reagents. PMID- 23097105 TI - Culture and differentiation of mouse tracheal epithelial cells. AB - Airway epithelial cell biology has been greatly advanced by studies of genetically defined and modified mice; however it is often difficult to isolate, manipulate, and assay epithelial cell-specific responses in vivo. In vitro proliferation and differentiation of mouse airway epithelial cells are made possible by a high-fidelity system for primary culture of mouse tracheal epithelial cells described in this chapter. Using this method, epithelial cells purified from mouse tracheas proliferate in growth factor-enriched medium. Subsequent culture in defined medium and the use of the air-liquid interface condition result in the development of well-differentiated epithelia composed of ciliated and non-ciliated cells with characteristics of native airways. Methods are also provided for manipulation of differentiation and analysis of differentiation and gene expression. These approaches allow the assessment of global responses and those of specific cell subpopulations within the airway epithelium. PMID- 23097106 TI - Isolation and culture of alveolar epithelial Type I and Type II cells from rat lungs. AB - The pulmonary alveolar epithelium, comprised of alveolar Type I (TI) and Type II (TII) cells, covers more than 99% of the internal surface area of the lungs. The study of isolated and cultured alveolar epithelial TI and TII cells has provided a large amount of information about the functions of both cell types. This chapter provides information about methods for isolating and culturing both of these cell types from rat lungs. PMID- 23097107 TI - Classical human epidermal keratinocyte cell culture. AB - It has been more than 30 years since the serial cultivation of human keratinocytes in monolayer culture was first described by Rheinwald and Green. Initially, isolation of primary keratinocytes from disaggregated human skin tissue and subsequent propagation was promoted through use of replication inactivated murine fibroblast feeder layers. Since then numerous advances have been made to the cultivation of human keratinocytes in both two-dimensional monolayer and three-dimensional organotypic culture. Monolayer culture facilitates keratinocyte proliferation, whereas organotypic culturing techniques promote keratinocyte differentiation using conditions permissive for stratification. The protocols presented here describe traditional culturing methods, providing guidance for isolation and serial cultivation of primary human keratinocytes and dermal fibroblasts, as well as the use of these cells types for generation of stratified skin tissue. PMID- 23097108 TI - Mouse epidermal keratinocyte culture. AB - Cultured mouse epidermal keratinocytes provide a powerful model for studying epidermal proliferation, differentiation, pathogenesis, and oncogenic transformation. Primary mouse keratinocytes can be isolated from newborn mice, and their growth and differentiation can be manipulated by changing calcium concentrations in culture medium. Primary mouse keratinocytes proliferate in medium containing 0.05 mM calcium but cease to proliferate and start to terminally differentiate, when the calcium concentration in the culture medium is increased to 0.10 mM or greater. PMID- 23097109 TI - Three-dimensional culture of human breast epithelial cells: the how and the why. AB - Organs are made of the organized assembly of different cell types that contribute to the architecture necessary for functional differentiation. In those with exocrine function, such as the breast, cell-cell and cell-extracellular matrix (ECM) interactions establish mechanistic constraints and a complex biochemical signaling network essential for differentiation and homeostasis of the glandular epithelium. Such knowledge has been elegantly acquired for the mammary gland by placing epithelial cells under three-dimensional (3D) culture conditions.Three dimensional cell culture aims at recapitulating normal and pathological tissue architectures, hence providing physiologically relevant models to study normal development and disease. The specific architecture of the breast epithelium consists of glandular structures (acini) connected to a branched ductal system. A single layer of basoapically polarized luminal cells delineates ductal or acinar lumena at the apical pole. Luminal cells make contact with myoepithelial cells and, in certain areas at the basal pole, also with basement membrane (BM) components. In this chapter, we describe how this exquisite organization as well as stages of disorganization pertaining to cancer progression can be reproduced in 3D cultures. Advantages and limitations of different culture settings are discussed. Technical designs for induction of phenotypic modulations, biochemical analyses, and state-of-the-art imaging are presented. We also explain how signaling is regulated differently in 3D cultures compared to traditional two dimensional (2D) cultures. We believe that using 3D cultures is an indispensable method to unravel the intricacies of human mammary functions and would best serve the fight against breast cancer. PMID- 23097111 TI - Isolation, characterization, and reaggregate culture of thymic epithelial cells. AB - The thymus organ is composed of a three-dimensional (3D) network of adjoining epithelium and stromal cells. Bone marrow-derived T cell precursors, upon entering the thymus, interact with and migrate through this cellular network as they differentiate and mature. An essential component of the stroma is the thymic epithelial cells (TEC), which play a vital role in T cell development and induction of self-tolerance for adaptive immunity. TEC can be isolated from the embryonic and adult thymus by a series of gentle enzymatic digestions and characterized into discrete subpopulations based on their expression of surface markers by flow cytometry. Enrichment of adult TEC can be achieved by depletion of hematopoietic cells, allowing sufficient numbers to be purified for subsequent functional and molecular analysis. Although monolayer cultures have been used to study TEC phenotype and T cell interaction, methods that mimic the 3D thymic microenvironment, such as fetal and reaggregate thymic organ cultures, are more accurate for the analysis of TEC function and support more complete T cell development. Herein, we describe methods for the efficient isolation and enrichment of TEC for downstream analyses as well as the reaggregation of embryonic progenitor epithelium to form a functional thymus graft under the kidney capsule. PMID- 23097112 TI - Enrichment and clonal culture of hepatic stem/progenitor cells during mouse liver development. AB - Liver regenerates after hepatectomy or chemical-induced injury. In contrast to cells in other tissues that can regenerate, mature cells (hepatocytes), but not undifferentiated stem cells, are mainly responsible for acute liver regeneration. Liver stem cells take part in liver regeneration in some forms of chronic liver injury, when the proliferative ability of differentiated hepatocytes is impaired. During liver development, both hepatocytes and cholangiocytes are differentiated from common precursor cells, called hepatoblasts. By combining fluorescence activated cell sorting (FACS) and an in vitro clonal culture system for stem/progenitor cells, we established a method to isolate stem/progenitor cells prospectively from mouse fetal and adult livers. FACS clone-sorted single CD45( )Ter119(-)c-kit(-)CD13(+)CD133(+) cells (from fetal mid-gestational livers) or CD45(-)Ter119(-)c-kit(-)Sca1(-)CD13(+)CD49f(+)CD133(+) cells (from adult livers) can form a colony containing both albumin-positive hepatocytes and cytokeratin 19 positive bile ductal cells, indicating that these cells have the characters of liver stem/progenitor cells (proliferative capability and bipotency for hepatic and for biliary epithelial differentiation). These cells can maintain these capabilities for several months in culture. PMID- 23097110 TI - Three-dimensional cultures of mouse mammary epithelial cells. AB - The mammary gland is an ideal "model organism" for studying tissue specificity and gene expression in mammals: it is one of the few organs that develop after birth and it undergoes multiple cycles of growth, differentiation and regression during the animal's lifetime in preparation for the important function of lactation. The basic "functional differentiation" unit in the gland is the mammary acinus made up of a layer of polarized epithelial cells specialized for milk production surrounded by myoepithelial contractile cells, and the two layered structure is surrounded by basement membrane. Much knowledge about the regulation of mammary gland development has been acquired from studying the physiology of the gland and of lactation in rodents. Culture studies, however, were hampered by the inability to maintain functional differentiation on conventional tissue culture plastic. We now know that the microenvironment, including the extracellular matrix and tissue architecture, plays a crucial role in directing functional differentiation of organs. Thus, in order for culture systems to be effective experimental models, they need to recapitulate the basic unit of differentiated function in the tissue or organ and to maintain its three dimensional (3D) structure. Mouse mammary culture models evolved from basic monolayers of cells to an array of complex 3D systems that observe the importance of the microenvironment in dictating proper tissue function and structure. In this chapter, we focus on how 3D mouse mammary epithelial cultures have enabled investigators to gain a better understanding of the organization, development and function of the acinus, and to identify key molecular, structural, and mechanical cues important for maintaining mammary function and architecture. The accompanying chapter of Vidi et al. describes 3D models developed for human cells. Here, we describe how mouse primary epithelial cells and cell lines- essentially those we use in our laboratory--are cultured in relevant 3D microenvironments. We focus on the design of functional assays that enable us to understand the intricate signaling events underlying mammary gland biology, and address the advantages and limitations of the different culture settings. Finally we also discuss how advances in bioengineering tools may help towards the ultimate goal of building tissues and organs in culture for basic research and clinical studies. PMID- 23097114 TI - Tissue culture correlational study of genetic cholangiopathy of autosomal recessive polycystic kidney disease. AB - Cholangiocytes are epithelial cells that line the biliary tract and are also known as biliary epithelial cells (BECs). In vitro culture studies of BECs in correlation with tissue section examination may give us a comprehensive analysis of biliary tract diseases. Herein, we discuss genetic cholangiopathy of autosomal recessive polycystic kidney disease (ARPKD), mainly using a polycystic kidney (PCK) rat, an animal model of ARPKD. The hepatobiliary lesions in ARPKD patients (Caroli's disease and congenital hepatic fibrosis) and in PCK rats are speculated to be related to mutations to polycystic kidney and hepatic disease 1 (PKHD1) which have been recently demonstrated, though the exact causal relation between these mutations and hepatobiliary pathology remain to be clarified. Recently we clarified that BECs of PCK rat showed increased cell proliferation followed by irregular dilatation of intrahepatic bile ducts. We also identified the essential involvement of the MEK5-ERK5 pathway in the abnormal proliferation of BECs in the PCK rat. The degradation of laminin and type IV collagen (basal membrane components of bile ducts) was closely related to the biliary dysgenesis and cystogenesis in the PCK rats. BECs also showed mesenchymal phenotype followed by progressive portal tract fibrosis, indicating TGF-beta1 may be involved in this acquisition of mesenchymal phenotype. Detailed tissue culture correlation studies of ARPKD and PCK rats are mandatory to evaluate the pathogenesis of this genetic cholangiopathy. PMID- 23097113 TI - Long-term culture and coculture of primary rat and human hepatocytes. AB - The liver is the largest internal organ in mammals, serving a wide spectrum of vital functions. Loss of liver function due to drug toxicity or viral infection is a major cause of death in the United States. The development of Bioartificial Liver (BAL) devices and the demand for pharmaceutical and cosmetic toxicity screening require the development of long-term hepatocyte culture techniques. However, primary hepatocytes rapidly lose their cuboidal morphology and liver specific functions over a few days in culture. Accumulation of stress fibers, loss of metabolic function, and cell death are known phenomena. In recent years, several techniques were developed that can support high levels of liver-specific gene expression, metabolic and synthetic function for several weeks in culture. These include the collagen double-gel configuration, hepatocyte spheroids, coculture with endothelial cells, and micropatterned cocultures with 3T3-J2 fibroblasts. This chapter covers the current status of hepatocyte culture techniques, including: hepatocyte isolation, media formulation, oxygen supply, heterotypic cell-cell interactions, and basic functional assays. PMID- 23097115 TI - Primary mouse small intestinal epithelial cell cultures. AB - The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently shown that Lgr5 (Leucine-rich repeat-containing G protein-coupled receptor) is expressed in intestinal stem cells by an in vivo genetic lineage tracing strategy. In the past, extensive efforts have been made to establish primary small intestinal culture systems. However, no defined, reproducible and robust culture system had been developed. To establish such a system, we screened for optimal growth factor combinations based on genetic evidence of self-renewal regulation, differentiation, and carcinogenesis of intestinal stem cells. Here, we describe methods that we have established for the isolation and culture of primary small intestinal epithelial stem cells. In this culture system, isolated crypts form "organoid structures" with a histological hierarchy recapitulating in vivo small intestinal epithelium. Single isolated Lgr5+ intestinal stem cells also form these organoid structures, in which stem cells are maintained by self-renewal and give rise to all lineages of the intestinal epithelium. This culture system is particularly useful for studying the regulation of intestinal stem cell self-renewal and differentiation. PMID- 23097116 TI - Isolation, growth, and characterization of human renal epithelial cells using traditional and 3D methods. AB - The kidney is a highly heterogeneous organ that is responsible for fluid and electrolyte balance. Much interest is focused on determining the function of specific renal epithelial cells in humans, which can only be accomplished through the isolation and growth of nephron segment-specific epithelial cells. However, human renal epithelial cells are notoriously difficult to maintain in culture. This chapter describes the isolation, growth, immortalization, and characterization of the human renal proximal tubule cell. In addition, we describe new paradigms in 3D cell culture which allow the cells to maintain more in vivo-like morphology and function. PMID- 23097117 TI - Human female reproductive tract epithelial cell culture. AB - The female reproductive system is a complex system. Epithelia of the female reproductive system including the ovaries, the oviduct, and the uterus are important sites for follicular development, ovulation, fertilization, implantation, and embryo development. They are also able to synthesize and secrete various hormones, growth factors, and cytokines, which are essential to women's health, sexuality, and reproduction. Conversely, their dysfunction has been implicated in disorders such as infertility, endometriosis, and many other gynecological diseases, as well as cancer. In this chapter, we describe detailed procedures for establishing and maintaining primary cultures of human ovarian surface epithelium, oviductal epithelium, and endometrium. We also provide protocols for cell immortalization, clonal isolation, and in coculture with stromal cells. These cultures can be useful models for investigating the molecular and cellular functions of these epithelia in both normal and pathological states. PMID- 23097118 TI - Primary culture and propagation of human prostate epithelial cells. AB - Basic and translational (or preclinical) prostate cancer research has traditionally been conducted with a limited repertoire of immortalized cell lines, which have homogeneous phenotypes and have adapted to long-term tissue culture. Primary cell culture provides a model system that allows a broader spectrum of cell types from a greater number of patients to be studied, in the absence of artificially induced genetic mutations. Nevertheless, primary prostate epithelial cell culture can be technically challenging, even for laboratories experienced in immortalized cell culture. Therefore, we provide methods to isolate and culture primary epithelial cells directly from human prostate tissue. Initially, we describe the isolation of bulk epithelial cells from benign or tumor tissues. These cells have a predominantly basal/intermediate phenotype and co-express cytokeratin 8/18 and high molecular weight cytokeratins. Since prostatic stem cells play a major role in disease progression and are considered to be a therapeutic target, we also describe a prospective approach to specifically isolate prostatic basal cells that include both stem and transit amplifying basal populations, which can be studied independently or subsequently differentiated to supply luminal cells. This approach allows the study of stem cells for the development of new therapeutics for prostate cancer. PMID- 23097119 TI - Urothelial cell culture: stratified urothelial sheet and three-dimensional growth of urothelial structure. AB - Urothelial cells line the urinary tract, including the renal pelvis, ureters, bladder, superior urethra, and the central ducts of the prostate. They are highly specialized epithelial cell types possessing unique features, imparting important functional roles in the urinary system. They act as a permeability barrier and protect underlying muscle tissues from the caustic effects of urine while also expanding with bladder filling to adjust urine pressures. The multilayered urothelium is typically structured with differentiated, mature surface cells and less mature basal cells. The basal cell layer contains tissue-specific stem cells able to self-renew for the lifetime of the mammal and also produces a pool of maturing cells for tissue homeostasis. Maintaining regenerative basal cells in a culture facilitates urothelial cell growth in vitro. Additionally, epithelial mesenchymal communication, epithelial-matrix interactions, and cytokines/growth factors are required to maintain the normal structure and function of mature urothelial cells in vitro and to induce stem cell differentiation into urothelial cells. These cultures are useful to study the biology and physiology of the urinary tract, particularly for the development of cell-based tissue engineering strategies in urology. This chapter describes methods for the isolation of urothelial cells and their maintenance in monolayer culture, and methods for the production of multilayer urothelial cell sheets and three-dimensional cocultures of urothelial and mesenchymal cells. PMID- 23097120 TI - Analysis of tissue interactions in ectodermal organ culture. AB - The morphogenesis of ectodermal organs is regulated by epithelial mesenchymal interactions mediated by conserved signaling molecules. Analyzing the roles of these molecules will increase our understanding of mechanisms regulating organogenesis, and organ culture methods provide powerful tools in this context. Here we present two organ culture methods for skin and tooth development: the hanging drop method for the short-term culture of small explants and the Trowell type method for the long-term cultures of variable size explants. The latter allows manipulations such as combining separated epithelial and mesenchymal tissues and the use of signal-releasing beads. The effects of signaling molecules on morphogenesis can be observed during culture by using tissues from GFP reporter mice. After culture, the effects of signals on gene expression can be analyzed by in situ hybridization or quantitative RT-PCR. PMID- 23097121 TI - Generation of human cell lines using lentiviral-mediated genetic engineering. AB - Even now, most human cell lines used in research are derived from tumor cells. They are still widely used because they grow well in vitro and so far have helped answering several basic biological questions. However, as modern biology moves into more sophisticated areas, scientists now need human cell lines closer to normal primary cells and further from transformed cancerous cells. The recent identification of cellular genes involved in cell cycling and senescence, together with the development of molecular tools capable of cleanly integrating transgenes into the genome of target cells, have moved the frontier of genetic engineering. In this chapter, we present a detailed hands-on protocol, based on lentivirus-derived vectors and a combination of two native cellular genes that has proven very efficient in generating immortal cell lines from several human primary cells, while preserving most of their original properties. PMID- 23097122 TI - Viral transformation of epithelial cells. AB - Approximately 18% of human cancers have a viral etiology and the majority of these involve transformation of epithelial cells. Viral proteins transform epithelia by inducing alterations in the normal cell growth and differentiation pathways through the targeting of host proteins. Among the DNA viruses responsible for causing carcinomas are the human papillomaviruses as well as several members of the herpes and polyomavirus families. A number of techniques have been developed to study the mechanisms by which viruses immortalize epithelial cells and alter differentiation properties. These methods include the generation of immortalized lines by transfection or infection as well as the use of organotypic raft cultures, suspension in methylcellulose, and treatment with high calcium levels to examine how differentiation is altered. PMID- 23097123 TI - Various types of intracorporeal esophagojejunostomy after laparoscopic total gastrectomy for gastric cancer. AB - BACKGROUND: Even for expert surgeons, esophagojejunostomy after laparoscopic total gastrectomy (LTG) is not always easy to perform. Herein, we compare various types of esophagojejunostomy in terms of the technical aspects and postoperative outcomes. METHODS: A total of 48 patients underwent LTG for gastric cancer by the same surgeon. Four types of intracorporeal esophagojejunostomies have been applied after LTG: type A, a conventional anvil head method; type B, an OrVilTM system method; type C, a hemi-double stapling technique with anvil head; and type D, side-to-side esophagojejunostomy with linear stapler. We describe and review these types of esophagojejunostomy using a step-by-step approach. RESULTS: The mean reconstruction times were longer for types A and B than for types C and D (p < 0.05). In terms of complications, there were five cases (10.4%) of anastomosis leakage, which was more common in types A and B: two cases in each of type A and B and one case in type C. Moreover, anastomosis stricture requiring intervention was more common in types A and B (p < 0.05). CONCLUSIONS: To date, there are no reliable reconstruction methods after LTG. Therefore, special care is needed to prevent postoperative complication regardless of methods; also, technical innovations to support development of the safest methods of esophagojejunostomy are warranted. PMID- 23097124 TI - A time since recovery model with varying rates of loss of immunity. AB - For many infectious diseases, immunity wanes over time. The majority of SIRS models assume that this loss of immunity takes place at a constant rate. We study temporary immunity within a SIRS model structure if the rate of loss of immunity can depend on the time since recovery from disease. We determine the conditions under which the endemic steady state becomes unstable and periodic oscillations set in, showing that a fairly rapid change between slow and rapid immunity loss is necessary to produce oscillations. PMID- 23097125 TI - The influence of hindered transport on the development of platelet thrombi under flow. AB - Vascular injury triggers two intertwined processes, platelet deposition and coagulation, and can lead to the formation of an intravascular clot (thrombus) that may grow to occlude the vessel. Formation of the thrombus involves complex biochemical, biophysical, and biomechanical interactions that are also dynamic and spatially-distributed, and occur on multiple spatial and temporal scales. We previously developed a spatial-temporal mathematical model of these interactions and looked at the interplay between physical factors (flow, transport to the clot, platelet distribution within the blood) and biochemical ones in determining the growth of the clot. Here, we extend this model to include reduction of the advection and diffusion of the coagulation proteins in regions of the clot with high platelet number density. The effect of this reduction, in conjunction with limitations on fluid and platelet transport through dense regions of the clot can be profound. We found that hindered transport leads to the formation of smaller and denser clots compared to the case with no protein hindrance. The limitation on protein transport confines the important activating complexes to small regions in the interior of the thrombus and greatly reduces the supply of substrates to these complexes. Ultimately, this decreases the rate and amount of thrombin production and leads to greatly slowed growth and smaller thrombus size. Our results suggest a possible physical mechanism for limiting thrombus growth. PMID- 23097126 TI - Capillary electrophoresis/frontal analysis versus equilibrium dialysis in dexamethasone sodium phosphate-serum albumin binding studies. AB - Plasma protein binding of drugs may have significant effect on its pharmacodynamic, toxicological and pharmacokinetic properties, since only the free drug can pass across biological membrane and get to its specific site of action. Many drugs show a high affinity to albumin which is the most abundant plasma protein. In the present study capillary electrophoresis in the frontal analysis mode (CE/FA), as promising technique for assessment of drug-protein interaction was used. The free drug concentration was measured from height of the frontal peak and calculated based on the external drug standard in absence of protein. With a known concentration of total drug, the percentage of protein bound drug was determined. The binding parameters were also estimated based on the equilibrium dialysis experiment which is considered to be a reference method. This study was designed to examine the interaction of dexamethasone sodium phosphate (DXM) with BSA and HSA under simulated physiological conditions (pH 7.4, 67 mM phosphate buffer, I = 0.17). Using fixed, at physiological level, HSA and BSA concentrations and increasing DXM concentrations, the number of binding sites (n) and binding constant (K(a) ) was calculated from both nonlinear regression fitting and Scatchard Plot. Despite some differences, it can be concluded that the CE/FA is comparable with equilibrium dialysis, but since the first one offers advantages such as low sample consumption, short analysis time, and high separation efficiency, it can be used in high-throughput screening of drug protein binding at the early stage of drug discovery. Interspecies differences in binding of a drug to albumins have been observed and it should be taken into account in interpretation of the results. PMID- 23097127 TI - Multiple cerebral and coronary aneurysms in a patient with left atrial myxoma. AB - Cardiac myxomas accompanied by multiple embolic complications in cerebral and visceral arteries have been well documented in scientific literature. However, cerebral artery aneurysms have rarely been reported as a possible embolic complication of myxomas. This study describes a patient who had multiple episodes of cerebral infarctions and was found to have left atrial myxoma with old renal infarction as well as cerebral and coronary artery aneurysms. This is the first case report of coronary artery aneurysms associated with cardiac myxoma. PMID- 23097128 TI - Effects of hypertrophy and fibrosis on regional and global functional heterogeneity in hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a disease that typically has heterogeneous hypertrophy and dysfunction of the myocardium. Cardiac magnetic resonance imaging (CMR) can be used to accurately assess ventricular wall thickness and regional fibrosis. We investigated the effects of hypertrophy and fibrosis on the heterogeneity of regional and global myocardial function in HCM. Forty patients who were diagnosed with HCM were consecutively enrolled. Echocardiography and CMR with delayed hyper-enhancement imaging (DHE) was performed for each patient. Left ventricular (LV) regional and global longitudinal strain (SL(R) and SL(G)) were obtained by two-dimensional speckle tracking method on echocardiography. With CMR, regional myocardial wall thickness was measured, and the amount of DHE was calculated semi-quantitatively in each segment. Overall, 720 segments were analyzed. SL(R) was significantly decreased in the hypertrophied segments (thickness > 11 mm) and segments with DHE (P < 0.001). SL(R) was correlated with myocardial wall thickness (r = 0.47, P = 0.001) and amount of regional DHE (r = 0.39, P < 0.001). On multivariate analysis, regional LV wall thickness and amount of DHE were the only independent determinants of SL(R). SL(G) was associated with LV diastolic functional parameters in echocardiography, total DHE volume, and LV mass index. Total DHE volume and LV mass index were independent determinants of SL(G) on multivariate analysis. The extent of regional myocardial fibrosis is associated with regional myocardial function independently of morphological changes of the myocardium, and the correlation extended to global LV function. In this context, DHE may be a useful parameter to discover early myocardial dysfunction independently of LV hypertrophy. PMID- 23097129 TI - Anaerobic ammonia oxidation (ANAMMOX) for side-stream treatment of anaerobic digester filtrate process performance and microbiology. AB - A laboratory scale semi-batch fed anaerobic ammonia oxidation (ANAMMOX) reactor was operated in the lab under two different feeding operations. In the first scenario, termed as phase I, the reactor was seeded and operated with NO(2) -N added externally with the filtrate to the reactor in the ratio needed for the successful ANAMMOX. A second reactor was also initiated shortly after the start up of the ANAMMOX to accomplish partial nitrification (nitritation reactor) to generate NO(2) -N. In phase II, the operation of the ANAMMOX reactor was switched to the mode in which case the partially nitrified effluent from the nitritation reactor was fed to the ANAMMOX reactor. In both phases, real filtrate from a local wastewater treatment plant was used as the feed. The ANAMMOX reactor sustained a loading rate (average 0.33 +/- 0.03 with a max of 0.4 g N (L day)(-1) ) which is comparable with many other fed-batch reactors in the literature. Consistent total N removal (average of 82 +/- 4%) could be sustained in the ANAMMOX reactor during both phases. The nitritation reactor also consistently enabled a NO(2) -N to NH(3) -N ratio of 1.2:1 which was needed for the successful operation of the ANAMMOX reactor in phase II. Sequence analysis and FISH showed that Kuenenia stuttgartiensis dominated the enriched ANAMMOX community along with several unidentified, but seemingly enriched, potential ANAMMOX strains. Microbial ecology analysis for nitritation reactor showed the dominance of Nitrosomonas europaea. In summary, this manuscript provides important information on the start-up and operation of anammox reactor with detailed investigation on microbial ecology in this reactor. PMID- 23097130 TI - The influence of global climate change on the scientific foundations and applications of Environmental Toxicology and Chemistry: introduction to a SETAC international workshop. AB - This is the first of seven papers resulting from a Society of Environmental Toxicology and Chemistry (SETAC) international workshop titled "The Influence of Global Climate Change on the Scientific Foundations and Applications of Environmental Toxicology and Chemistry." The workshop involved 36 scientists from 11 countries and was designed to answer the following question: How will global climate change influence the environmental impacts of chemicals and other stressors and the way we assess and manage them in the environment? While more detail is found in the complete series of articles, some key consensus points are as follows: (1) human actions (including mitigation of and adaptation to impacts of global climate change [GCC]) may have as much influence on the fate and distribution of chemical contaminants as does GCC, and modeled predictions should be interpreted cautiously; (2) climate change can affect the toxicity of chemicals, but chemicals can also affect how organisms acclimate to climate change; (3) effects of GCC may be slow, variable, and difficult to detect, though some populations and communities of high vulnerability may exhibit responses sooner and more dramatically than others; (4) future approaches to human and ecological risk assessments will need to incorporate multiple stressors and cumulative risks considering the wide spectrum of potential impacts stemming from GCC; and (5) baseline/reference conditions for estimating resource injury and restoration/rehabilitation will continually shift due to GCC and represent significant challenges to practitioners. PMID- 23097131 TI - An empirical study of gender differences in online gambling. AB - Gambling has typically been considered a predominately male activity. However, recent prevalence surveys have shown greater numbers of females are now gambling. Much of the gambling literature suggests online gamblers are more likely to be male, and that problem gamblers are more likely to be male. Males and females are also likely to be gambling for different reasons and have a preference for different gambling activities. Little is known about the pattern of play among female online gamblers. The aim of this survey was to develop a better profile of female online gamblers and to examine any gender differences between males and females in terms of how and why they gamble online, their frequency of online gambling, patterns of play, as well as attitudes to online gambling. The survey was posted on 32 international online gambling websites and was completed by 975 online gamblers (including 175 female online gamblers). Chi-square tests of association were conducted to examine the association between gender and a range of variables. The results showed that females had been gambling online for a shorter duration of time than males, had much shorter online gambling sessions, different motivations for gambling online (i.e., to practice for free, to spend less money and out of boredom), and experienced online gambling differently to males, with increased feelings of guilt and shame for gambling online. This suggests there is still a stigma around gambling particularly evident among females in this study. The findings indicate that clinicians and treatment providers need to be aware of these potential gender differences in online gambling to develop appropriately tailored interventions. PMID- 23097132 TI - Wnt signalling in kidney diseases: dual roles in renal injury and repair. AB - Wnt signalling is a complex, highly conserved, cell-to-cell communication pathway in multicellular organisms, regulating cell fate, function and phenotype in development, and diseases, including neoplasia. Although the critical role of the Wnt pathway in nephrogenesis is well established, recent investigations have shown its involvement in many adult kidney diseases, including ischaemic kidney injury, glomerular diseases, diabetic nephropathy, interstitial fibrosis and cystic kidney diseases. Overall, activation of the Wnt pathway is deleterious to many chronic diseases of the kidney, contributing to the maintenance of cells in an activated state. In addition, the Wnt pathway is activated during repair and regeneration in animal models of acute ischaemic injury, a scenario that is frequently encountered in human acute kidney injury. This activation recapitulates features of nephrogenesis and appears to play an indispensable role in repair and regeneration in this acute setting. As tools are being developed to regulate the Wnt pathway intracellularly and at the cell surface, the Wnt pathway has become a potential avenue for urgently required novel therapeutics for treating human kidney diseases. In this review, we describe consensus models for major Wnt signalling cascades and then discuss their roles in kidney diseases. PMID- 23097133 TI - [Etiology and classification of septic coxitis]. AB - Septic coxitis is a rare disesase which can be caused by a variety of pathogens. Primary and secondary coxitis can be differentiated depending on the etiology. In the initial stages the diagnosis is difficult but a delay in making the correct diagnosis or delayed therapy can result in fatal consequences for the patient, therefore, therapy should be started even in cases of suspected septic coxitis. Septic coxitis is classified into four stages depending on the arthroscopic findings. The best results are usually achieved by a combination of arthroscopic lavage and antibiotic therapy. PMID- 23097134 TI - Sodium valproate potentiates staurosporine-induced apoptosis in neuroblastoma cells via Akt/survivin independently of HDAC inhibition. AB - Sodium valproate (VPA) has been recently identified as a selective class I histone deacetylase (HDAC) inhibitor and explored for its potential as an anti cancer agent. The anti-cancer properties of VPA are generally attributed to its HDAC inhibitory activity indicating a clear overlap of these two actions, but the underlying mechanisms of its anti-tumor effects are not clearly elucidated. The present study aimed to delineate the molecular mechanism of VPA in potentiating cytotoxic effects of anti-cancer drugs with focus on inhibition of HDAC activity. Using human neuroblastoma cell lines, SK-N-MC, SH-SY5Y, and SK-N-SH, we show that non-toxic dose (2 mM) of VPA enhanced staurosporine (STS)-induced cell death as assessed by MTT assay, PARP cleavage, hypodiploidy, and caspase 3 activity. Mechanistically, the effect of VPA was mediated by down regulation of survivin, an anti-apoptotic protein crucial in resistance to STS-mediated cytotoxicity, through Akt pathway. Knock down of class I HDAC isoforms remarkably inhibited HDAC activity comparable with that of VPA but had no effect on STS-induced apoptosis. Moreover, MS-275, a structurally distinct class I HDAC inhibitor did not affect STS-mediated apoptosis, nor decrease the levels of survivin and Akt. Valpromide (VPM), an amide analog of VPA that does not inhibit HDAC also potentiated cell death in NB cells associated with decreased survivin and Akt levels suggesting that HDAC inhibition might not be crucial for STS-induced apoptosis. The study provides new information on the possible molecular mechanism of VPA in apoptosis that can be explored in combination therapy in cancer. PMID- 23097135 TI - Early SAPIEN transcatheter heart valve dysfunction due to tissue ingrowth in an octogenarian. PMID- 23097136 TI - Permanent tooth mineralization in bonobos (Pan paniscus) and chimpanzees (P. troglodytes). AB - The timing of tooth mineralization in bonobos (Pan paniscus) is virtually uncharacterized. Analysis of these developmental features in bonobos and the possible differences with its sister species, the chimpanzee (P. troglodytes), is important to properly quantify the normal ranges of dental growth variation in closely related primate species. Understanding this variation among bonobo, chimpanzee and modern human dental development is necessary to better contextualize the life histories of extinct hominins. This study tests whether bonobos and chimpanzees are distinguished from each other by covariance among the relative timing and sequences of tooth crown initiation, mineralization, root extension, and completion. Using multivariate statistical analyses, we compared the relative timing of permanent tooth crypt formation, crown mineralization, and root extension between 34 P. paniscus and 80 P. troglodytes mandibles radiographed in lateral and occlusal views. Covariance among our 12 assigned dental scores failed to statistically distinguish between bonobos and chimpanzees. Rather than clustering by species, individuals clustered by age group (infant, younger or older juvenile, and adult). Dental scores covaried similarly between the incisors, as well as between both premolars. Conversely, covariance among dental scores distinguished the canine and each of the three molars not only from each other, but also from the rest of the anterior teeth. Our study showed no significant differences in the relative timing of permanent tooth crown and root formation between bonobos and chimpanzees. PMID- 23097137 TI - A single-cell NMR membrane transport assay. PMID- 23097138 TI - Treatment of status epilepticus: an international survey of experts. AB - BACKGROUND: As part of the development of the Neurocritical Care Society (NCS) Status Epilepticus (SE) Guidelines, the NCS SE Writing Committee conducted an international survey of SE experts. METHODS: The survey consisted of three patient vignettes (case 1, an adult; case 2, an adolescent; case 3, a child) and questions regarding treatment. The questions for each case focused on initial and sequential therapy as well as when to use continuous intravenous (cIV) therapy and for what duration. Responses were obtained from 60/120 (50%) of those surveyed. RESULTS: This survey reveals that there is expert consensus for using intravenous lorazepam for the emergent (first-line) therapy of SE in children and adults. For urgent (second-line) therapy, the most common agents chosen were phenytoin/fosphenytoin, valproate sodium, and levetiracetam; these choices varied by the patient age in the case scenarios. Physicians who care for adult patients chose cIV therapy for RSE, especially midazolam and propofol, rather than a standard AED sooner than those who care for children; and in children, there is a reluctance to choose propofol. Pentobarbital was chosen later in the therapy for all ages. CONCLUSION: There is close agreement between the recently published NCS guideline for SE and this survey of experts in the treatment of SE. PMID- 23097139 TI - Effect of heparin-derived oligosaccharide on vascular smooth muscle cell proliferation and the signal transduction mechanisms involved. AB - PURPOSE: In this study, the effect of heparin-derived oligosaccharide (HDO) on vascular endothelial growth factor (VEGF) induced vascular smooth muscle cell (VSMC) proliferation and the signal transduction mechanisms involved were investigated. METHODS: MTT assays were used to measure VSMC proliferation, flow cytometry to analyze cell cycle distribution, RT-PCR for detection of gene transcript levels, and cell-based ELISA, Western blotting and immunocytochemical methods to detect the expression of PKC-alpha, ERK 1/2, p-ERK 1/2, Akt, p-Akt, p PDK1 and p-GSK-3beta. RESULTS: HDO at concentrations of 0.01, 0.1 and 1 MUmol.L( 1) dose-dependently inhibited VEGF-induced VSMC proliferation with inhibition indices of 6.8 %, 13.1 % and 28.9 %, respectively. Similar concentrations of HDO dose-dependently decreased the percentage of VEGF-induced cells in S phase to 3.6 %, 3.4 %, and 5.4 %, while increasing that of cells arrested in the G0/G1 phase to 80 %, 82 % and 83.6 %. HDO at 0.01, 0.1 or 1 MUmol.L(-1) inhibited VEGF induced PKC-alpha mRNA expression, with inhibition indices of 9.2 %, 16.1 % and 54.0 %. HDO at 0.1 or 1 MUmol.L(-1) inhibited VEGF-induced proto-oncogene mRNA expression, with inhibition indices of 5.2 % and 6.6 % for c-jun, 8.8 % and 11.6 % for c-myc, and 6.5 % and 11.9 % for c-fos, respectively. Additionally, treatment with 0.01, 0.1 or 1 MUmol.L(-1) HDO, inhibited VEGF-induced expression of some proliferation related proteins with inhibition indices of 33.2 %, 56.3 % and 77.0 % for PKC-alpha, 33.7 %, 38.7 % and 53.2 % for p-Akt, 3.5 %, 24.2 % and 49.3 % for p-ERK 1/2, 39.2 %, 71.8 % and 80.7 % for p-PDK 1 and 41.4 %, 89.4 % and 92.4 % for p-GSK-3beta, respectively. The results showed that HDO inhibited PKC-alpha, c-jun, c-fos and c-myc mRNA transcription, and also down-regulated phosphorylation levels of ERK 1/2 and Akt. CONCLUSION: Our study demonstrates that HDO inhibits transcription of proliferation-related proto-oncogenes and arrests G1/S transition through inhibition of the PKC, MAPK and Akt/PI3K pathways in association with inhibition of VSMC proliferation. This altered molecular signature may explain one mechanism of HDO-mediated inhibition of VSMC proliferation. PMID- 23097140 TI - Resorption pattern and radiographic diagnosis of invasive cervical resorption. A correlative microCT, scanning electron and light microscopic evaluation of a case series. AB - The aim of this study was to evaluate, whether and how the histologic structure of invasive cervical resorption (external granulomas) affect their clinical radiographic diagnosis. For this purpose, nine more or less intact extracted teeth, of which intraoral radiographs were available, were processed for examination in the scanning electron (SEM) and light microscope. From some of the specimens non-decalcified ground sections were prepared and some were decalcified for preparation of histologic sections. Five teeth were scanned in an X-ray microtomography (microCT) device and digitally reconstructed in three dimensions. Three histologic characteristics, namely (1) the location and extension of the resorptive defect, (2) the size of the communication with the periodontium, and (3) the amount of mineralized substitution tissue formed in the lesion affected the radiographic diagnosis. At early and advanced stages, invasive cervical resorption had encircled the pulp cavities, however, without destroying the innermost dentin. Even if the dentinal wall adjacent to the pulp was histologically intact and thick, this important diagnostic feature frequently could not be recognized in conventional radiographs. Also, the communication between the resorptive lesion and the periodontium often was not visible radiographically, although it could always be identified in the microscopic evaluation, particularly at early stages when it proved to be very small. Invasive cervical resorption lesions containing large amounts of mineralized substitution tissue were difficult to recognize and, therefore, could easily be overseen. Thus, three features which are deemed essential for the differential diagnosis of invasive cervical resorption were not readily apparent in conventional radiographs. From these three features, the dentinal wall against the pulp cavity and the communication to the peri-odontium were, however, clearly visible in the microCT reconstructions. PMID- 23097141 TI - Neuron navigator 3 alterations in nervous system tumors associate with tumor malignancy grade and prognosis. AB - Copy number changes or reduced expression of the Neuron navigator 3 (NAV3) gene occurs in neuroblastomas and malignancies of epithelial or lymphoid origin. To elucidate whether NAV3 has a role in the tumorigenesis of nervous system tumors in general, we studied central and peripheral nervous system tumors for NAV3 copy number changes. In search for common tumorigenic denominators, we analyzed 113 central and peripheral nervous system tumors, including glial tumors (grades I-IV gliomas), medulloblastomas, and neuroblastomas. NAV3 copy number changes were studied by fluorescence in situ hybridization and correlated to survival analyses. To identify target genes of NAV3 deletion, NAV3 was silenced by siRNA in glioblastoma cell lines and gene expression profiles were analyzed by Agilent 4*44k dual-color microarrays. Selected upregulations were confirmed by immunohistochemistry and quantitative polymerase chain reaction. We found NAV3 amplifications to dominate in neuronally differentiated tumors, whereas glial tumors showed almost equal proportions of NAV3 deletion and amplification. However, Grade IV gliomas had more frequent NAV3 deletions than grades I-III gliomas. Silencing of NAV3 in glioma cell lines led to the upregulation of receptor genes associated with gonadotropin-releasing hormone and Jak-Stat signaling pathways. Kaplan-Meier analysis of the entire clinical tumor material showed association between NAV3 amplifications and favorable prognosis, as well as NAV3 deletions and unfavorable prognosis. With Cox regression model, a hazard ratio of 0.51 was observed for NAV3 amplifications and 1.36 for NAV3 deletions. We conclude that NAV3 may be a potential new prognostic biomarker and a potential therapeutic target. PMID- 23097142 TI - Heavy metal complexation on hybrid mesoporous silicas: an approach to analytical applications. AB - Recent advances in the development of new materials are having a major impact on Analytical Chemistry. For example, the unique properties of ordered mesoporous silicas have been shown to enhance the analytical performance of many existing techniques or allow new, exciting ones to be developed. Likewise, the introduction of organo-functional groups makes mesoporous silicas highly versatile and enables them to perform specialized tasks, such as the adsorption of toxic heavy metals from aqueous solutions. In this tutorial review, we present readers with a brief introduction to the most relevant achievements in the preparation of hybrid mesoporous silicas functionalized with chelating ligands for the complexation of heavy metals. We also provide some recent examples from the last ten years regarding the analytical applications of such hybrid silicas. Two topics of great current interest in environmental water analysis for heavy metal detection, namely the use of hybrid mesoporous silicas as sorbents for solid-phase extraction and the use of these materials to develop new strategies for electrochemical detection of heavy metals by stripping voltammetry, are addressed. PMID- 23097143 TI - Pasteurian segregation on a surface imaged in situ at the molecular level. PMID- 23097144 TI - Engineering hyperthermostability into a mesophilic family 11 xylanase from Aspergillus oryzae by in silico design of N-terminus substitution. AB - A mesophilic xylanase from Aspergillus oryzae CICC40186 (abbreviated to AoXyn11A) belongs to glycoside hydrolase family 11. The thermostability of AoXyn11A was significantly improved by substituting its N-terminus with the corresponding region of a hyperthermostable family 11 xylanase, EvXyn11(TS) . The suitable N terminus of AoXyn11A to be replaced was selected by the comparison of B-factors between AoXyn11A and EvXyn11(TS) , which were generated and calculated after a 15 ns molecular dynamic (MD) simulation process. Then, the predicted hybrid xylanase (designated AEx11A) was modeled, and subjected to a 2 ns MD simulation process for calculating its total energy value. The N-terminus substitution was confirmed by comparing the total energy value of AEx11A with that of AoXyn11A. Based on the in silico design, the AEx11A was constructed and expressed in Pichia pastoris GS115. After 72 h of methanol induction, the recombinant AEx11A (reAEx11A) activity reached 82.2 U/mL. The apparent temperature optimum of reAEx11A was 80 degrees C, much higher than that of reAoXyn11A. Its half-life was 197-fold longer than that of reAoXyn11A at 70 degrees C. Compared with reAoXyn11A, the reAEx11A displayed a slight alteration in K(m) but a decrease in V(max). PMID- 23097148 TI - Continued statin therapy could improve the outcome after spontaneous intracerebral hemorrhage. AB - Spontaneous intracerebral hemorrhage (ICH) often represents a devastating event despite maximal therapeutic efforts. Statins are drugs primarily used as cholesterol reducers with several pleiotropic effects that may result in neuroprotection. In this study, we assessed the continued use of statins after acute ICH. From January 2008 to October 2010, we analyzed a retrospective cohort of 178 patients with acute ICH. Patients with head injury, cerebral tumors, hemorrhage after ischemic stroke, and having a National Institute Health Stroke Scale (NIHSS) score of greater than 30 points on admission were excluded. In 29 patients, statins were continued within the first 24 h after onset of ICH and, subsequently, given daily until discharge, whereas 149 nonusers were used as controls. Inpatient mortality, NIHSS, and Glasgow Outcome Score (GOS) at discharge as well as mortality after 10 days, 3 months, and 6 months were recorded as outcomes. Additionally, changes of C-reactive protein (CRP) and white blood cell (WBC) counts, as well as aspartate transaminase and alanine transaminase levels were assessed. Except for the number of hypertensive and diabetic patients, characteristics on admission were similar between both groups. No mortality was observed in statin users, whereas 19 controls (12.7 %) died (p = 0.04) until discharge; after 10 days, 3 months, and 6 months, a similar trend was found. After 6 months, statin use was associated to lower mortality in regression models (OR = 0.32, 95 % CI = 0.11-0.95, p = 0.04). In the same way, statin use was related to NIHSS reduction (-3.53, 95 % CI = -7.59 to 0.42, p = 0.07). In mixed models, changes of WBC counts and CRP levels were associated with statin use. The hepatic enzymes were similar between groups. The continued use of statins after ICH could be associated to early neurological improvement and may reduce mortality within 6 months. Immunomodulation as a pleiotropic effect of statins may represent one of the underlying mechanisms. PMID- 23097150 TI - Comment on "Relationship of nonvisualization of the fetal gallbladder and amniotic fluid digestive enzymes analysis to outcome". PMID- 23097149 TI - Intracranial arterial stenoses: current viewpoints, novel approaches, and surgical perspectives. AB - Ten percent of all strokes occurring in the USA are caused by intracranial arterial stenosis (IAS). Symptomatic IAS carries one of the highest rates of recurrent stroke despite intensive medical therapy (25 % in high-risk groups). Clinical results for endovascular angioplasty and stenting have been disappointing. The objectives of this study were to review the contemporary understanding of symptomatic IAS and present potential alternative treatments to resolve factors not addressed by current therapies. We performed a literature review on IAS pathophysiology, natural history, and current treatment. We present an evaluation of the currently deficient aspects in its treatment and explore the role of alternative surgical approaches. There is a well-documented interrelation between hemodynamic and embolic factors in cerebral ischemia caused by IAS. Despite the effectiveness of medical therapy, hemodynamic factors are not addressed satisfactorily by medications alone. Collateral circulation and severity of stenosis are the strongest predictors of risk for stroke and death. Indirect revascularization techniques, such as encephaloduroarteriosynangiosis, offer an alternative treatment to enhance collateral circulation while minimizing risk of hemorrhage associated with hyperemia and endovascular manipulation, with promising results in preliminary studies on chronic cerebrovascular occlusive disease. Despite improvements in medical management for IAS, relevant aspects of its pathophysiology are not resolved by medical treatment alone, such as poor collateral circulation. Surgical indirect revascularization can improve collateral circulation and play a role in the treatment of this condition. Further formal evaluation of indirect revascularization for IAS is a logical and worthy step in the development of intracranial atherosclerosis treatment strategies. PMID- 23097153 TI - Detection and characterization of urinary metabolites of boldione by LC-MS/MS. Part II: Conjugates with cysteine and N-acetylcysteine. AB - The occurrence of boldione metabolites conjugated with cysteine and N acetylcysteine in human urine was evaluated. Methods based on precursor ion scan of the protonated aminoacid (m/z 122 and m/z 164 for cysteine and N acetylcysteine respectively) and neutral losses of the aminoacids (121 Da and 163 Da for cysteine and N-acetylcysteine respectively) were applied for the open detection of conjugates. Results for urine samples collected before and after boldione administration were compared. Using this approach, 24 metabolites (eleven conjugates with cysteine and thirteen conjugated with N-acetylcysteine) were detected. The metabolites were characterized by mass spectrometry and their potential structures were proposed based on this information. The structures of nine of these metabolites were confirmed by the synthesis of the conjugates. According to these results, a metabolic pathway for boldione involving this type of conjugation was presented. Up to our knowledge this is the first time that cysteine conjugates are presented for exogenous anabolic androgenic steroids and the first report of N-acetylcysteine conjugates for steroids. PMID- 23097152 TI - The ant genomes have been invaded by several types of mariner transposable elements. AB - To date, only three types of full-length mariner elements have been described in ants, each one in a different genus of the Myrmicinae subfamily: Sinvmar was isolated from various Solenopsis species, Myrmar from Myrmica ruginodis, and Mboumar from Messor bouvieri. In this study, we report the coexistence of three mariner elements (Tnigmar-Si, Tnigmar-Mr, and Tnigmar-Mb) in the genome of a single species, Tapinoma nigerrimum (subfamily Dolichoderinae). Molecular evolutionary analyses of the nucleotide sequence data revealed a general agreement between the evolutionary history of most the elements and the ant species that harbour them, and suggest that they are at the vertical inactivation stage of the so-called Mariner Life Cycle. In contrast, significantly reduced levels of synonymous divergence between Mboumar and Tnigmar-Mb and between Myrmar and Botmar (a mariner element isolated from Bombus terrestris), relative to those observed between their hosts, suggest that these elements arrived to the species that host them by horizontal transfer, long after the species' split. The horizontal transfer events for the two pairs of elements could be roughly dated within the last 2 million years and about 14 million years, respectively. As would be expected under this scenario, the coding sequences of the youngest elements, Tnigmar-Mb and Mboumar, are intact and, thus, potentially functional. Each mariner element has a different chromosomal distribution pattern according to their stage within the Mariner Life Cycle. Finally, a new defective transposable element (Azteca) has also been found inserted into the Tnigmar-Mr sequences showing that the ant genomes have been invaded by at least four different types of mariner elements. PMID- 23097154 TI - Silver nanoparticles cause oxidative damage and histological changes in medaka (Oryzias latipes) after 14 days of exposure. AB - Silver nanoparticles (AgNPs) can exert negative effects on cell lines and embryos of freshwater fish. However, information on their distribution and long-term toxicity in adult species is limited. In the present study, a subchronic (14-d) toxicity test was designed to evaluate the bioaccumulation of AgNPs and their effects on the antioxidant defense system and histology of adult medaka. Purified AgNPs were well dispersed in water, and stability was maintained during the exposure period. After 14 d of exposure, a significant accumulation of Ag in the AgNP-dosed group was observed in the gill and intestinal tissues, with the highest levels found in the liver. Biochemical analysis indicated a dose-related decrease in the activity of lactate dehydrogenase and antioxidant enzymes in the liver, but not in the gills. However, dose-dependent increases in glutathione depletion and lipid peroxidation in the liver and gills were observed. Exposure to a graded dose of AgNPs also resulted in varying degrees of histological lesions in the tissues. Toxicological endpoints combined with metal distribution analysis suggested that AgNPs induced tissue-specific toxicity and that the liver is the organ most damaged by the Ag that might have been released from NPs. The oxidative damage caused by AgNPs may be associated with a large number of histological changes in the fish. PMID- 23097155 TI - Acculturation and health survey question comprehension among Latino respondents in the US. AB - Although research has documented cultural variability in respondent comprehension and interpretation of survey questions, little information is currently available on the role that acculturation might play in minimizing cross-cultural differences in the comprehension or interpretation of survey questions. To investigate this problem, we examine the potential effects of acculturation to host culture on respondent comprehension of a set of health survey questions among two distinct Latino populations on the US mainland: Mexican-Americans and Puerto Ricans. Specifically, comprehension-related respondent behaviors coded from 345 face-to-face interviews conducted with Mexican-American, Puerto Rican, African American, and non-Latino White adults living in Chicago are examined. Findings indicate that Latino respondents who were born outside of the US and who have a preference for communicating in Spanish, relative to English, were more likely to express comprehension difficulties. These findings suggest that pretest survey instruments with immigrant populations may be a useful strategy for identifying problematic questions. PMID- 23097156 TI - Dying and death in some Roma communities: ethical challenges. AB - The Roma people have specific values, therefore their views and beliefs about illness, dying and death are important to be known for health care providers caring for members of this community. The aim of this qualitative study based on 48 semi-structured interviews with Roma patients and caregivers in communities in two regions of Romania was to examine their selfdescribed behaviors and practices, their experiences and perceptions of illness, dying and death. Five more important themes about the Roma people facing dying and death have been identified: (1) The perception of illness in the community as reason for shame and the isolation that results from this, as well as the tendency for Roma people to take this on in their self image; (2) The importance of the family as the major support for the ill/dying individual, including the social requirement that family gather when someone is ill/dying; (3) The belief that the patient should not be told his/her diagnosis for fear it will harm him/her and that the family should be informed of the diagnosis as the main decision maker regarding medical treatment; (4) The reluctance of the Roma to decide on stopping life prolonging treatment; (5) The view of death as 'impure'. These results can be useful for health care providers working with members of the Roma community. By paying attention to and respecting the Roma patients' values, spirituality, and relationship dynamics, the medical staff can provide the most suitable healthcare by respecting the patients' wishes and expectations. PMID- 23097157 TI - A single-device universal logic gate based on a magnetically enhanced memristor. AB - Memristors are one of the most promising candidates for future information and communications technology (ICT) architectures. Two experimental proofs of concept are presented based on the intermixing of spintronic and memristive effects into a single device, a magnetically enhanced memristor (MEM). By exploiting the interaction between the memristance and the giant magnetoresistance (GMR), a universal implication (IMP) logic gate based on a single MEM device is realized. PMID- 23097159 TI - Vertebral morphology influences the development of Schmorl's nodes in the lower thoracic vertebrae. AB - Schmorl's nodes are the result of herniations of the nucleus pulposus into the adjacent vertebral body and are commonly identified in both clinical and archaeological contexts. The current study aims to identify aspects of vertebral shape that correlate with Schmorl's nodes. Two-dimensional statistical shape analysis was performed on digital images of the lower thoracic spine (T10-T12) of adult skeletons from the late medieval skeletal assemblages from Fishergate House, York, St. Mary Graces and East Smithfield Black Death cemeteries, London, and postmedieval Chelsea Old Church, London. Schmorl's nodes were scored on the basis of their location, depth, and size. Results indicate that there is a correlation between the shape of the posterior margin of the vertebral body and pedicles and the presence of Schmorl's nodes in the lower thoracic spine. The size of the vertebral body in males was also found to correlate with the lesions. Vertebral shape differences associated with the macroscopic characteristics of Schmorl's nodes, indicating severity of the lesion, were also analyzed. The shape of the pedicles and the posterior margin of the vertebral body, along with a larger vertebral body size in males, have a strong association with both the presence and severity of Schmorl's nodes. This suggests that shape and/or size of these vertebral components are predisposing to, or resulting in, vertically directed disc herniation. PMID- 23097158 TI - Danger-associated molecular patterns (DAMPs) in acute lung injury. AB - Danger-associated molecular patterns (DAMPs) are host-derived molecules that can function to regulate the activation of pathogen recognition receptors (PRRs). These molecules play a critical role in modulating the lung injury response. DAMPs originate from multiple sources, including injured and dying cells, the extracellular matrix, or exist as immunomodulatory proteins within the airspace and interstitium. DAMPs can function as either toll-like receptor (TLR) agonists or antagonists, and can modulate both TLR and nod-like receptor (NLR) signalling cascades. Collectively, this diverse group of molecules may represent important therapeutic targets in the prevention and/or treatment of acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). PMID- 23097160 TI - Differential in vitro and cellular effects of iron chelators for hypoxia inducible factor hydroxylases. AB - Hypoxia inducible factor 1alpha (HIF-1alpha), an essential transcriptional factor, is negatively regulated by two different types of oxygen and Fe(2+) dependent HIF hydroxylases, proline hydroxylase (PHD) and factor inhibiting HIF (FIH), under normoxia. Iron chelators have therefore been used for inducing HIF 1alpha expression by inhibiting the hydroxylases. In this study, the iron chelators displayed differential effects for PHD and FIH in cells depending on their iron specificity and membrane permeability rather than their in vitro potencies. The membrane permeability of the strict Fe(2+) -chelator potentially inhibited both hydroxylases, whereas the membrane impermeable one showed no inhibitory effect in cells. In contrast, the depletion of the extracellular Fe(3+) ion was mainly correlated to PHD inhibition, and the membrane permeable one elicited low efficacy for both enzymes in cells. The 3'-hydroxyl group of quercetin, a natural flavonoid, was critical for inhibition of intracellular hydroxylases. Since the 3'-methylation of quercetin is induced by catechol-O methyl transferase, the enzyme may regulate the intracellular activity of quercetin. These data suggest that the multiple factors of iron-chelators may be responsible for regulating the intracellular activity HIF hydroxylases. PMID- 23097161 TI - New dimensions in imaging: the awakening of dual-energy CT. PMID- 23097163 TI - Dual-energy CT: radiation dose aspects. AB - OBJECTIVE: Various applications for dual-energy CT (DECT) have been investigated and have shown substantial clinical benefits. However, only limited data are available regarding the radiation dose associated with DECT imaging. The purpose of this article is to review the available literature regarding the radiation dose associated with DECT imaging applications in comparison with conventional single-energy CT techniques. CONCLUSION: The rediscovery of DECT and the increasing availability of this technique on clinical CT systems have opened new dimensions for CT. The advanced spectral differentiation of materials within the human body as well as the selective visualization or subtraction of iodinated contrast material or xenon provides both advanced visualization of disease specific molecular substrates as well as additional functional information within a single scan. PMID- 23097164 TI - Dual-energy CT of the brain and intracranial vessels. AB - OBJECTIVE: The purpose of this review is to summarize the principles and applications of dual-energy CT in evaluation of the brain and the intracranial blood vessels. CONCLUSION: One major advantage of dual-energy CT is the capability of material differentiation. In general, this property can be applied to bone removal in CT angiography for easier and faster postprocessing. In neuroradiology, material decomposition allows detection of hemorrhage on contrast enhanced CT scans and facilitates the search for the underlying pathologic mechanism of hematomas. The combination of low radiation dose and advantageous spectral information (blood vs contrast) from these datasets justifies broad clinical implementation of dual-energy CT in neuroradiology. PMID- 23097165 TI - Dual-energy CT: general principles. AB - OBJECTIVE: In dual-energy CT (DECT), two CT datasets are acquired with different x-ray spectra. These spectra are generated using different tube potentials, partially also with additional filtration at 140 kVp. Spectral information can also be resolved by layer detectors or quantum-counting detectors. Several technical approaches-that is, sequential acquisition, rapid voltage switching, dual-source CT (DSCT), layer detector, quantum-counting detector-offer different spectral contrast and dose efficiency. Various postprocessing algorithms readily provide clinically relevant spectral information. CONCLUSION: DECT offers the possibility to exploit spectral information for diagnostic purposes. There are different technical approaches, all of which have inherent advantages and disadvantages, especially regarding spectral contrast and dose efficiency. There are numerous clinical applications of DECT that are easily accessible with specific postprocessing algorithms. PMID- 23097166 TI - Dual-energy CT applications in head and neck imaging. AB - OBJECTIVE: Dual-energy scanning is a breakthrough in CT technology that has several applications in chest and abdominal imaging. Dual-energy CT also has potential for head and neck imaging. This review describes the role of dual energy CT in head and neck imaging. CONCLUSION: As with other body regions, both image fusion and material characterization dual-energy applications can be used for head and neck imaging. Early results are promising, and further research is encouraged. PMID- 23097167 TI - Dual-energy CT of the lung. AB - OBJECTIVE: The introduction of dual-energy CT (DECT) has ushered in the ability of material differentiation and tissue characterization beyond the traditional CT attenuation scale. This quality has been exploited for visualizing and quantifying the specific tissue content using radiographic contrast agents, such as iodine-based contrast media or inhaled xenon gas. Applications of this paradigm in the thorax include characterization of the pulmonary blood pool in the setting of acute or chronic pulmonary embolism (PE) and characterization of diseases of the lung parenchyma. Selective xenon detection is being explored for imaging of lung ventilation. In addition, the usefulness of DECT-based selective iodine uptake measurements has been described for the diagnosis and surveillance of thoracic malignancies. This article reviews the current applications of DECT based imaging techniques in the chest with an emphasis on the diagnosis and characterization of pulmonary thromboembolic disorders. CONCLUSION: DECT can provide both anatomic and functional information about the lungs in a variety of pulmonary disease states based on a single contrast-enhanced CT examination. This quality has been shown to improve the diagnosis of acute and chronic PEs, other vascular disorders, lung malignancies, and parenchymal diseases. Further developments in DECT techniques and CT scanner technology will further foster and enhance the utility of this application and open new avenues in lung imaging. PMID- 23097168 TI - Dual-energy CT of the heart. AB - OBJECTIVE: Interest in dual-energy CT (DECT) for evaluating the myocardial blood supply, as an addition to coronary artery assessment, is increasing. Although it is still in the early clinical phase, assessment of myocardial ischemia and infarction by DECT constitutes a promising step toward comprehensive evaluation of coronary artery disease with a single noninvasive modality. CONCLUSION: Compared with dynamic CT approaches, DECT has advantages regarding radiation dose and clinical applicability. In this review, the literature on DECT of the heart is discussed. PMID- 23097169 TI - Dual-energy CT applications in the abdomen. AB - OBJECTIVE: The purpose of this article is to give a brief overview of the technical background of dual-energy CT (DECT) imaging and to review various DECT applications in the abdomen that are currently available for clinical practice. In a review of the recent literature, specific DECT applications available for abdominal organs, liver, pancreas, kidneys including renal stones, and adrenal glands, will be discussed in light of reliability and clinical usefulness in replacing true unenhanced imaging, increased lesion conspicuity, iodine extraction, and improved tissue/material characterization (e.g., renal stone composition). Radiation dose considerations will be addressed in comparison with standard abdominal imaging protocols. CONCLUSION: Modern DECT applications for the abdomen expand the use of CT and enable advanced quantitative methods in the clinical routine on the basis of differences in material attenuation observed by imaging at two different distinct photon energies. PMID- 23097170 TI - Best practice: implementation and use of abdominal dual-energy CT in routine patient care. AB - OBJECTIVE: The purpose of this perspective is to document an experience with the adoption of dual-energy CT (DECT) for routine clinical imaging. CONCLUSION: Successful implementation of DECT requires that technologists understand standards of image quality, be empowered to select appropriate patients, and understand networks for image routing. Radiologists need minimal facility with workstations to access the information embedded in DECT. DECT can be performed at a reduced effective radiation dose compared with single-energy CT and with lower doses of IV contrast material. PMID- 23097171 TI - Dual-energy CT: a promising new technique for assessment of the musculoskeletal system. AB - OBJECTIVE: Dual-energy CT (DECT) characterizes the chemical composition of material according to its differential x-ray attenuation at two different energy levels. Applications of DECT in musculoskeletal imaging include imaging of bone marrow edema, tendons, and ligaments and the use of monoenergetic techniques to minimize metal prosthesis beam-attenuating artifacts. CONCLUSION: The most validated application of DECT is undoubtedly its noninvasive and highly specific ability for confirming the presence of monosodium urate deposits in the assessment of gout. PMID- 23097172 TI - Dual-energy CT: vascular applications. AB - OBJECTIVE: Dual-energy CT permits a variety of image reconstructions for the depiction and characterization of vascular disease. Techniques include visualization of low- and high-peak-kilovoltage spectra image datasets and also material-specific reconstructions combining both low- and high-peak-kilovoltage data. CONCLUSION: This article focuses on four main vascular areas: the aorta, the major visceral, lower limb, and cervical arteries. For each territory, the current status, potential advantages, and limitations of these techniques are described. PMID- 23097173 TI - Dual-energy CT-based monochromatic imaging. AB - OBJECTIVE: We summarize how virtual monochromatic images are synthesized from dual-energy CT using image-domain and projection-domain methods. The quality of virtual monochromatic images is compared with that of polychromatic single-energy images acquired at different tube potentials and the same radiation dose. Clinical applications of dual-energy CT-based virtual monochromatic imaging are reviewed, including beam-hardening correction, contrast and noise optimization, metal artifact reduction, and material differentiation. CONCLUSION: Virtual monochromatic images synthesized from dual-energy CT data have the potential to reduce beam-hardening artifacts and to provide quantitative measurements. If there is no desire to obtain material-specific information or to correct for metal or beam-hardening artifacts from the dual-energy data, however, it is better to perform a conventional single-energy scan at the optimal tube potential. PMID- 23097174 TI - Dual-energy CT: oncologic applications. AB - OBJECTIVE: Dual-energy CT (DECT) is an innovative imaging technique that operates on the basic principle of application of two distinct energy settings that make the transition from CT attenuation-based imaging to material-specific or spectral imaging. The purpose of this review is to describe the use of DECT in oncology. CONCLUSION: Applications of DECT in clinical practice are based on two capabilities: material differentiation and material identification and quantification. The capability of obtaining different material-specific datasets (iodine map, virtual unenhanced, and monochromatic images) in the same acquisition can improve lesion detection and characterization. This approach can also affect evaluation of the response to therapy and detection of oncology related disorders. DECT is an innovative imaging technique that can dramatically affect the care of oncologic patients. PMID- 23097176 TI - Challenges for academic drug discovery. PMID- 23097177 TI - Dietary fat manipulation has a greater impact on postprandial lipid metabolism than the apolipoprotein E (epsilon) genotype-insights from the SATgenepsilon study. AB - SCOPE: Our aim was to determine the effects of chronic dietary fat manipulation on postprandial lipaemia according to apolipoprotein (APO)E genotype. METHODS AND RESULTS: Men (mean age 53 (SD 9) years), prospectively recruited for the APOE genotype (n = 12 E3/E3, n = 11 E3/E4), were assigned to a low fat (LF), high fat, high-saturated fat (HSF), and HSF diet with 3.45 g/day docosahexaenoic acid (HSF DHA), each for an 8-week period in the same order. At the end of each dietary period, a postprandial assessment was performed using a test meal with a macronutrient profile representative of that dietary intervention. A variable postprandial plasma triacylglycerol (TAG) response according to APOE genotype was evident, with a greater sensitivity to the TAG-lowering effects of DHA in APOE4 carriers (p <= 0.005). There was a lack of an independent genotype effect on any of the lipid measures. In the groups combined, dietary fat manipulation had a significant impact on lipids in plasma and Svedberg flotation rate (S(f) ) 60-400 TAG-rich lipoprotein fraction, with lower responses following the HSF-DHA than HSF intervention (p < 0.05). CONCLUSION: Although a modest impact of APOE genotype was observed on the plasma TAG profile, dietary fat manipulation emerged as a greater modulator of the postprandial lipid response in normolipidaemic men. PMID- 23097175 TI - With or without sugar? (A)glycosylation of therapeutic antibodies. AB - Antibodies and antibody-based drugs are currently the fastest-growing class of therapeutics. Over the last three decades, more than 30 therapeutic monoclonal antibodies and derivatives thereof have been approved for and successfully applied in diverse indication areas including cancer, organ transplants, autoimmune/inflammatory disorders, and cardiovascular disease. The isotype of choice for antibody therapeutics is human IgG, whose Fc region contains a ubiquitous asparagine residue (N297) that acts as an acceptor site for N-linked glycans. The nature of these glycans can decisively influence the therapeutic performance of a recombinant antibody, and their absence or modification can lead to the loss of Fc effector functions, greater immunogenicity, and unfavorable pharmacokinetic profiles. However, recent studies have shown that aglycosylated antibodies can be genetically engineered to display novel or enhanced effector functions and that favorable pharmacokinetic properties can be preserved. Furthermore, the ability to produce aglycosylated antibodies in lower eukaryotes and bacteria offers the potential to broaden and simplify the production platforms and avoid the problem of antibody heterogeneity, which occurs when mammalian cells are used for production. In this review, we discuss the importance of Fc glycosylation focusing on the use of aglycosylated and glyco engineered antibodies as therapeutic proteins. PMID- 23097178 TI - Factors associated with serum/plasma concentrations of vitamins A, C, E and carotenoids in older people throughout Europe: the EUREYE study. AB - PURPOSE: To report on plasma/serum levels of antioxidant vitamin and carotenoids in older adults resident in multiple countries in Europe and examine relationships with potential modifiers. METHODS: Population-based cross-sectional European Eye Study in 7 centres from northern to southern Europe. In total, 4,133 participants aged 65 years or over, collected by random sampling, were recruited. Questionnaires relating to diet, lifestyle and medical history were administered. Non-fasting blood samples were analysed in a single laboratory for vitamins A, C and E and a panel of carotenoids. Associations were analysed by bootstrapped multivariable regression analysis. RESULTS: Centre and season influenced the serum and plasma concentrations of all antioxidant vitamins and carotenoids. Gender, BMI, smoking, age, education, alcohol consumption and supplement use were also significantly associated with some, but not all, of the antioxidant vitamins and carotenoids examined. The proportion of variance explained ranged from 4.8 % for retinol to 25.2 % for zeaxanthin. CONCLUSIONS: In older people, antioxidant vitamin and carotenoid status varies by centre and season, but is also associated with other behavioural and lifestyle variables. Studies aiming to demonstrate an association between antioxidant vitamins and carotenoid status and chronic disease risk should consider these potential confounders. PMID- 23097179 TI - Dystrophin and utrophin "double knockout" dystrophic mice exhibit a spectrum of degenerative musculoskeletal abnormalities. AB - Duchenne muscular dystrophy (DMD) is a degenerative muscle disorder characterized by the lack of dystrophin expression at the sarcolemma of muscle fibers. In addition, DMD patients acquire osteopenia, fragility fractures, and scoliosis indicating that a deficiency in skeletal homeostasis coexists but little is known about the effects of DMD on bone and other connective tissues within the musculoskeletal system. Recent evidence has emerged implicating adult stem cell dysfunction in DMD myopathogenesis. Given the common mesenchymal origin of muscle and bone, we sought to investigate bone and other musculoskeletal tissues in a DMD mouse model. Here, we report that dystrophin-utrophin double knockout (dko) mice exhibit a spectrum of degenerative changes, outside skeletal muscle, in bone, articular cartilage, and intervertebral discs, in addition to reduced lifespan, muscle degeneration, spinal deformity, and cardiomyopathy previously reported. We also report these mice to have a reduced capacity for bone healing and exhibit spontaneous heterotopic ossification in the hind limb muscles. Therefore, we propose the dko mouse as a model for premature musculoskeletal aging and posit that a similar phenomenon may occur in patients with DMD. PMID- 23097181 TI - Writing life. PMID- 23097180 TI - Quantitative fluorescence PCR analysis of >40,000 prenatal samples for the rapid diagnosis of trisomies 13, 18 and 21 and monosomy X. AB - OBJECTIVE: To present the results of 10 years of quantitative fluorescence PCR (QF-PCR) analysis of prenatal samples for the rapid diagnosis of the common aneuploidies. This represents the largest QF-PCR data set from a single testing centre. METHODS: QF-PCR analysis using a single assay containing 17 microsatellite markers was applied to all prenatal samples for the identification of trisomies 13, 18 and 21 and triploidy. A separate assay containing 14 sex chromosome markers was targeted to prenatal samples at increased risk of monosomy X. RESULTS: Results from 40,624 prenatal samples comprising 14,144 chorionic villus and 26,480 amniotic fluid samples are summarised. A QF-PCR result was not possible for 2.24% amniotic fluid and 0.25% chorionic villus samples because of the presence of an additional genotype consistent with maternal cell contamination. Just 0.08% samples were uninformative for one or more chromosomes and 0.05% of samples failed to produce a genotype. Ninety-eight percent of samples were reported the following working day from sample receipt. Consumable costs were L 5/sample. CONCLUSION: QF-PCR analysis is proven to be an accurate, robust and efficient method for the rapid diagnosis of common aneuploidies in prenatal samples. It has the advantage of detecting triploidy and mosaicism and benefits from considerable economy of scale. PMID- 23097182 TI - Enhanced nitrogen removal in single-chamber microbial fuel cells with increased gas diffusion areas. AB - Single-chamber microbial fuel cells (MFCs) with nitrifiers pre-enriched at the air cathodes have previously been demonstrated as a passive strategy for integrating nitrogen removal into current-generating bioelectrochemical systems. To further define system design parameters for this strategy, we investigated in this study the effects of oxygen diffusion area and COD/N ratio in continuous flow reactors. Doubling the gas diffusion area by adding an additional air cathode or a diffusion cloth significantly increased the ammonia and COD removal rates (by up to 115% and 39%), ammonia removal efficiency (by up to 134%), the cell voltage and cathode potentials, and the power densities (by a factor of approximately 2). When the COD/N ratio was lowered from 13 to 3, we found up to 244% higher ammonia removal rate but at least 19% lower ammonia removal efficiency. An increase of COD removal rate by up to 27% was also found when the COD/N ratio was lowered from 11 to 3. The Coulombic efficiency was not affected by the additional air cathode, but decreased by an average of 11% with the addition of a diffusion cloth. Ammonia removal by assimilation was also estimated to understand the ammonia removal mechanism in these systems. These results showed that the doubling of gas diffusion area enhanced N and COD removal rates without compromising electrochemical performance. PMID- 23097183 TI - A backup plan for self-protection: S-methylation of holomycin biosynthetic intermediates in Streptomyces clavuligerus. AB - Biosynthesis of the dithiolopyrrolone antibiotic holomycin in Streptomyces clavuligerus involves the closure of a pair of enethiols to a cyclic disulfide. We have shown that the dithiol oxidase HlmI is responsible for the disulfide formation and this enzyme also plays a role in self-protection. In the present study, we examine how S. clavuligerus deals with the proposed toxic dithiol intermediates when hlmI is deleted. We used differential NMR spectroscopy and mass spectrometry to profile the metabolomes of hlmI deletion mutants along with the wild-type strain and a holomycin-overproducing strain. A number of metabolites unique to DeltahlmI strains were identified. In these metabolites the enethiols have been incapacitated by a combination of mono- and di-S-methylation. We also observed an intriguing dimeric thioether adduct in low quantities in the wild-type strain and at much higher levels in the DeltahlmI strains. The structures of these novel metabolites highlight the reactivity of the dihydrodithiolopyrrolone scaffold. Furthermore, bioassays suggest that modification of the enethiol warhead by S-alkylation provides a host strategy for detoxification, one that is shared amongst multiple species producing such bioactive disulfide natural products. PMID- 23097184 TI - Identification and characterization of the Plasmodium falciparum RhopH2 ortholog in Plasmodium vivax. AB - Plasmodium vivax is one of the most important human malaria species that is geographically widely endemic and potentially affects a larger number of people than its more notorious cousin, Plasmodium falciparum. During invasion of red blood cells, the parasite requires the intervention of high molecular weight complex rhoptry proteins (RhopH) that are also essential for cytoadherence. PfRhopH2, a member of the RhopH multigene family, has been characterized as being crucial during P. falciparum infection. This study describes identifying and characterizing the pfrhoph2 orthologous gene in P. vivax (hereinafter named pvrhoph2). The PvRhopH2 is a 1,369-amino acid polypeptide encoded by PVX_099930 gene, for which orthologous genes have been identified in other Plasmodium species by bioinformatic approaches. Both P. falciparum and P. vivax genes contain nine introns, and there is a high degree of similarity between the deduced amino acid sequences of the two proteins. Moreover, PvRhopH2 contains a signal peptide at its N-terminus and 12 cysteines predominantly in its C-terminal half. PvRhopH2 is localized in one of the apical organelles of the merozoite, the rhoptry, and the localization pattern is similar to that of PfRhopH2 in P. falciparum. The recombinant PvRhopH2 protein is recognized by serum antibodies of patients naturally exposed to P. vivax, suggesting that PvRhopH2 is immunogenic in humans. PMID- 23097186 TI - Analysis of level A in vitro-in vivo correlations for an extended-release formulation with limited bioavailability. AB - A two-stage, numerical deconvolution approach was employed to develop level A in vitro-in vivo correlations using data for three formulations of an extended release oral dosage form. The in vitro dissolution data for all formulations exhibited near-complete dissolution within the time frame of the test. The pharmacokinetic concentration-time profiles for 16 subjects in a cross-over study demonstrated notably limited bioavailability for the slowest formulation. These data were used as the basis for the IVIVC model development. Two models were identified that satisfied the nominal requirements for a conclusive internal predictability of the IVIVC, provided that all three formulations were used as internal datasets. These were a simple linear model with absorption cut-off and a piecewise-linear variable absorption scale model. A subsequent cross-validation of the models' robustness indicated that neither model predicted satisfactorily the pharmacokinetic characteristics of all formulations in a conclusive manner. The piecewise-linear variable absorption scale model provided the most accurate results, particularly with respect to the prediction of the slowest formulation's pharmacokinetic metrics. But this latter model also involved additional free parameters compared with the simple linear model with absorption cut-off. It is argued that more complex IVIVC models with extra parameterization require comprehensive validation to ascertain the accuracy and robustness of the model. In order to achieve this, it is necessary to ensure a complete suite of supporting datasets for internal and external validation, irrespective of the mathematical approach used subsequently to develop the IVIVC. PMID- 23097185 TI - Rapid gradient-echo imaging. AB - Gradient-echo sequences are widely used in magnetic resonance imaging (MRI) for numerous applications ranging from angiography to perfusion to functional MRI. Compared with spin-echo techniques, the very short repetition times of gradient echo methods enable very rapid 2D and 3D imaging, but also lead to complicated "steady states." Signal and contrast behavior can be described graphically and mathematically, and depends strongly on the type of spoiling: fully balanced (no spoiling), gradient spoiling, or radiofrequency (RF)-spoiling. These spoiling options trade off between high signal and pure T(1) contrast, while the flip angle also affects image contrast in all cases, both of which can be demonstrated theoretically and in image examples. As with spin-echo sequences, magnetization preparation can be added to gradient-echo sequences to alter image contrast. Gradient-echo sequences are widely used for numerous applications such as 3D perfusion imaging, functional MRI, cardiac imaging, and MR angiography. PMID- 23097188 TI - Use of dental loupes among dental trainers and trainees in the UK. AB - INTRODUCTION: Magnification loupes are used in dentistry where increased visual performance is needed. The interest and use of loupes among dental practitioners and students appears to be growing. Despite this little quantitative data regarding the use of loupes in clinical practice and factors governing their purchase among dental trainers and trainees is available. OBJECTIVE: To determine the extent of use of loupes among dental trainers and trainees in the UK and identify what factors influence their choice of selection. METHOD: A proforma questionnaire was designed to collect the information required and was handed out dental trainers and trainees. RESULTS: Use of loupes is more common among the dental trainers (44%) than trainees (28%). Of the nonusers, increased interest among the trainees (83.6%) and trainers (50%) in purchasing loupes was noted. Price was found to be the most important factor during purchase. The majority of users opted for 2.5*; and a light source was a popular choice. Both users and nonusers in the study group had an affinity towards "through-the-lens" type. No significant variation in back/neck discomfort between the users and nonusers was found. CONCLUSION: Use of loupes among dental trainers and trainees remains low. Reduction in price and provision of information could increase the number of loupe users. PMID- 23097187 TI - Upregulation of CD200R1 in lineage-negative leukemic cells is characteristic of AML1-ETO-positive leukemia in mice. AB - Activating mutations of c-Kit are frequently found in acute myeloid leukemia (AML) patients harboring t(8;21) chromosomal translocation generating a fusion protein AML1-ETO. Here we show that an active mutant of c-Kit cooperates with AML1-ETO to induce AML in mouse bone marrow transplantation models. Leukemic cells expressing AML1-ETO with c-Kit(D814V) were serially transplantable. Transplantation experiments indicated that lineage(-)c-Kit(+)Sca-1(+) (KSL) leukemic cells, but not lineage(+) leukemic cells, were enriched for leukemia stem cells (LSCs). Comparison of gene expression profiles between KSL leukemic and normal cells delineated that CD200R1 was highly expressed in KSL leukemic cells as compared with KSL normal cells. Upregulation of CD200R1 was verified in lineage(-) leukemic cells, but not in lineage(+) leukemic cells. CD200R1 expression in the lineage(-) leukemic cells was not correlated with the frequency of LSCs, indicating that CD200R1 is not a useful marker for LSCs in these models. Interestingly, CD200R1 was upregulated in KSL cells transduced with AML1-ETO, but not with other leukemogenic mutants, including c-Kit(D814V), AML1(D171N), and AML1(S291fsX300). Consistently, upregulation of CD200R1 in lineage(-) leukemic cells was observed only in the BM of mice suffering from AML1-ETO-positive leukemia. In conclusion, AML1-ETO upregulated CD200R1 in lineage(-) cells, which was characteristic of AML1-ETO-positive leukemia in mice. PMID- 23097189 TI - Tumor necrosis factor-alpha promotes bile ductular transdifferentiation of mature rat hepatocytes in vitro. AB - We previously showed that mature hepatocytes could transdifferentiate into bile ductular cells when placed in a collagen-rich microenvironment. To explore the mechanism of transdifferentiation, we examined whether inflammatory cytokines affected the phenotype of hepatocytes in a three-dimensional culture system. Spheroidal aggregates of rat hepatocytes were embedded within a type I collagen gel matrix and cultured in the presence of various cytokines. In the control, hepatocytes gradually lost expression of albumin, tyrosine aminotransferase, and hepatocyte nuclear factor (HNF)-4alpha, while aberrantly expressed bile ductular markers, including cytokeratin 19 (CK 19) and spermatogenic immunoglobulin superfamily (SgIGSF). Among the cytokines examined, tumor necrosis factor (TNF) alpha inhibited expression of albumin and HNF-4alpha, both at mRNA and protein levels. After culturing for 2 weeks with TNF-alpha, hepatocytic spheroids were transformed into extensively branching tubular structures composed of CK 19- and SgIGSF-positive small cuboidal cells. These cells responded to secretin with an increase in secretion and expressed functional bile duct markers. TNF-alpha also induced the phosphorylation of Jun N-terminal kinase (JNK) and c-Jun, and the morphogenesis was inhibited by SP600125, a specific JNK inhibitor. Furthermore, in chronic rat liver injury induced by CCl(4) , ductular reaction in the centrilobular area demonstrated strong nuclear staining of phosphorylated c-Jun. Our results demonstrate that TNF-alpha promotes the ductular transdifferentiation of hepatocytes and suggest a role of TNF-alpha in the pathogenesis of ductular reaction. PMID- 23097190 TI - Investigating the binding mode of an inhibitor of the MBNL1.RNA complex in myotonic dystrophy type 1 (DM1) leads to the unexpected discovery of a DNA selective binder. PMID- 23097191 TI - Placental histopathological correlates of umbilical artery Doppler velocimetry in pregnancies complicated by fetal growth restriction. AB - OBJECTIVE: The objective of the study was to evaluate the association between placental histological patterns and umbilical artery (UA) Doppler velocimetry in pregnancies complicated by fetal growth restriction (FGR). METHODS: A cohort of 126 FGR pregnancies was followed according to a standard protocol. Placental lesions were diagnosed according to consensus nomenclature and standardized criteria. RESULTS: Pulsatility index was normal in 45 (35.7%) and increased in 44 (34.9%) women. End-diastolic UA Doppler flow was absent in 27 (21.4%) and reversed in 10 (7.9%). Fifty-four women (42.9%) had preeclampsia. In preeclampsia, increasing Doppler abnormalities, from normal to reversed UA end diastolic flow, were directly associated only with an increased number of placental syncytial knots. In normotensive pregnancies, Doppler abnormalities were associated with increased intervillous fibrin deposits, villous hypoplasia, syncytial knots, placental site giant cells, immature intermediate trophoblast, and with pattern of lesions indicating superficial implantation and maternal vascular underperfusion. In the whole cohort, increase of syncytial knots [odds ratio (OR) = 28.7; 95% confidence interval (CI) = 2.75-298.5], intervillous fibrin deposits (OR = 2.1; 95% CI = 1.04-4.28), placental site giant cells (OR = 3.0; 95% CI = 1.05-8.84), and patterns suggesting maternal underperfusion (OR = 2.9; 95% CI = 1.0-7.1) were independently associated with increased rates of absent/reversed UA end-diastolic flow. CONCLUSIONS: In pregnancies complicated by FGR, abnormalities of UA Doppler velocimetry were associated with placental lesions indicating superficial implantation and maternal vascular underperfusion. PMID- 23097192 TI - Reciprocal cross talk between fatty acid and antibiotic biosynthesis in a nematode symbiont. PMID- 23097193 TI - Brief communication: could Kadanuumuu (KSD-VP-1/1) and Lucy (AL 288-1) have walked together comfortably? AB - The estimated lower limb length (0.761-0.793 m) of the partial skeleton of Australopithecus afarensis from Woranso-Mille (KSD-VP-1/1) is outside the previously known range for Australopithecus and within the range of modern humans. The lower limb length of KSD-VP-1/1 is particularly intriguing when juxtaposed against the lower limb length estimate of the other partial skeleton of A. afarensis, AL 288-1 (0.525 m). A sample of 36 children (age, >7 years, trochanteric height = 0.56-0.765 m) and 16 adults (trochanteric height = 0.77 1.00 m) walked at their self-selected slow, preferred, and fast walking velocities, while their oxygen consumption was monitored. Lower limb length and velocity were correlated with slow (P < 0.001, r(2) = 0.44), preferred (P < 0.001, r(2) = 0.55), and fast (P < 0.001, r(2) = 0.69) walking velocity. The relationship between optimal velocity and lower limb length was also determined and lower limb length explained 47% of the variability in optimal velocity. The velocity profile for KSD-VP-1/1 (slow = 0.73-0.75 m/s, preferred = 1.08-1.11 m/s, and fast = 1.48-1.54 m/s) is 36-44% higher than that of AL 288-1 (slow = 0.53 m/s, preferred = 0.78 m/s, and fast = 1.07 m/s). The optimal velocity for AL 288 1 is 1.04 m/s, whereas that for KSD-VP-1/1 is 1.29-1.33 m/s. This degree of lower limb length dimorphism suggests that members of a group would have had to compromise their preferences to walk together or to split into subgroups to walk at their optimal velocity. PMID- 23097194 TI - Alternation in colonization behaviors of Escherichia coli cells with rpoS or yggE deficiency on solid surfaces. AB - Colonization on a solid surface is influenced by the cell surface appendages such as flagella and curli, of which expressions are regulated by rpoS gene encoding a sigma factor. In this study, we investigated the effect of rpoS or yggE (a rpoS related and stress-responsive gene) deficiency on the colonization of Escherichia coli BW25113. Under a static condition, the deletion of rpoS or yggE induced 3.9- and 3.7-fold higher colonization as compared to wild-type cells, respectively, on the solid surfaces. However, under a liquid flow condition, only DeltayggE cells maintained the stable colonization on the surface, and the values of cell layer thickness and cell coverage on the surface were 17 and 9.2 times as high as those of wild-type cells, respectively. Gene expression analyses revealed that the deletion of rpoS or yggE positively impacted the expressions of genes involved in flagellum formation. On the other hand, curli assembly was severely prohibited by the rpoS deficiency. Here, we proposed that the plentiful flagella on the DeltarpoS and DeltayggE cell surfaces facilitated mainly the colonization under the static condition. Meanwhile, curli existing on the DeltayggE cell surface played an important role in keeping stable cell attachment and developing attached colonies under the flow stress condition. PMID- 23097196 TI - Inflammation, wound repair, and fibrosis: reassessing the spectrum of tissue injury and resolution. AB - Estimates from various disease-specific registries suggest that chronic inflammatory and fibrotic disorders affect a large proportion of the world's population, yet therapies for these conditions are largely ineffective. Recent advances in our collective understanding of mechanisms underlying both physiological and pathological repair of tissue injury are informing new clinical approaches to deal with various human inflammatory and fibrotic diseases. This 2013 Annual Review Issue of The Journal of Pathology offers an up-to-date glimpse of ongoing research in the fields of inflammation, wound healing, and tissue fibrosis, and highlights novel pathways and mechanisms that may be exploited to provide newer, more effective treatments to patients worldwide suffering from these conditions. PMID- 23097197 TI - Multilayer appearance on contrast-enhanced susceptibility-weighted images on patients with brain abscesses: Possible origins and effects of postprocessing. AB - PURPOSE: To demonstrate the presence of a multilayer appearance of the capsule on contrast-enhanced (CE) susceptibility-weighted imaging (SWI) in patients with pyogenic brain abscesses. Possible origins for the appearance and effects of postprocessing settings are discussed. MATERIALS AND METHODS: Fourteen patients with pyogenic brain abscesses underwent post gadolinium-enhanced SWI at 1.5 T. All SWI images were postprocessed with various filter and mask settings to compare the image appearance. Computer simulations using a paramagnetic spherical shell model were performed to verify the clinical findings. RESULTS: Pyogenic brain abscesses demonstrated a multilayer appearance with a darkened ring within the enhanced capsule on CE-SWI in all patients. The multilayer appearance was slice-orientation-dependent, decreased with larger widths of the high-pass filter, and increased with larger numbers of phase mask multiplication operations, consistently on both simulation results and the clinical images. CONCLUSION: CE-SWI shows the multilayer appearance of the capsule in pyogenic brain abscesses, which may arise from postprocessing procedures originally designed to enhance susceptibility contrast. Although SWI may provide additional information valuable in the diagnosis of pyogenic brain abscesses, image interpretation should be exercised with caution, particularly for CE-SWI. PMID- 23097198 TI - Polymorphisms in genes involved in the metabolism and transport of soy isoflavones affect the urinary metabolite profile in premenopausal women following consumption of a commercial soy supplement as a single bolus dose. AB - SCOPE: Genetic variation in relevant enzymes and transporters may contribute to discordant observations concerning health outcomes of dietary isoflavone consumption, so we examined the association of the UGT1A1*28 promoter polymorphism and of other SNPs with isoflavone metabolites in urine. METHODS AND RESULTS: We genotyped prospectively for polymorphisms in UGT1A1 (UGT1A1*28), LPH (666G>A), CBG (1368T>A), ABCG2 (421C>A), and ABCC2 (1249G>A) to select 100 women (18-50 years) to receive a commercial soy supplement as a single dose and collect all urine over 24 h for analysis by RP-HPLC. We observed large differences in isoflavone recovery (mean 39%, eightfold variation) and metabolites. Glucuronides were the major metabolites (72% of total). UGT1A1*28 was associated only with percentage of glycitein as sulphate (positive; p = 0.046), but excluding five participants with both minor alleles of CBG and ABCG2 uncovered additional associations with percentage of glycitein as glucuronide (negative; p = 0.028), combined isoflavones as sulphate (positive; p = 0.035) and sulphate-to glucuronide ratio for combined isoflavones (positive; p = 0.036). CBG1368T>A, ABCG2 421C>A, and ABCC2 1249G>A were also associated with differences in isoflavone metabolites in urine. CONCLUSION: Genetic variation in UGT1A1, CBG, ABCG2, and ABCC2 influences isoflavone metabolism so may affect benefits of dietary consumption. PMID- 23097199 TI - Nilotinib preclinical pharmacokinetics and practical application toward clinical projections of oral absorption and systemic availability. AB - Nilotinib is a highly potent and selective bcr-abl tyrosine kinase inhibitor used for the treatment of patients who are in the chronic and accelerated phases of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Nilotinib preclinical data and its use for practical predictions of systemic exposure profiles and oral absorption are described. The systemic clearance (CL) of nilotinib was relatively low in rodents with a value of less than 25% of hepatic blood flow (Q(H)), while it was moderate in monkeys and dogs (CL/Q(H) = 32-35%). The steady state volume of distribution (V(ss) ) ranged from 0.55 to 3.9 l/kg across the species tested. The maximum concentration (C(max)) of nilotinib occurred at 0.5-4 h and the bioavailability was moderate (17-44%). The plasma protein binding was high (> 97.5%) in preclinical species and humans. The human CL (~ 0.1 l/h/kg) and V(ss) (~2.0 l/kg) were best predicted by the rat-dog-human proportionality method and allometric scaling method, respectively. The human intravenous pharmacokinetic profile was projected by the Wajima 'C(ss)-MRT' method. The predicted micro-constants from human intravenous profiles were incorporated into the advanced compartmental absorption and transit model within the GastroPlus program to simulate the oral concentration-time curves in humans. Overall, the simulated oral human pharmacokinetic profiles showed good agreement with observed clinical data, and the model predicted that the C(max) , AUC, t(1/2) , V(z) /F and CL/F values were within 1.3-fold of the observed values. The absolute oral bioavailability of nilotinib in healthy humans was predicted to be low (< 25%). PMID- 23097200 TI - BMP-6 and BMPR-1a are up-regulated in the growth plate of the fractured tibia. AB - Bone overgrowth is a known phenomenon occurring after fracture of growing long bones with possible long-term physical consequences for affected children. Here, the physeal expression of bone morphogenetic proteins (BMPs) was investigated in a fracture-animal model to test the hypothesis that a diaphyseal fracture stimulates the physeal expression of these known key regulators of bone formation, thus stimulating bone overgrowth. Sprague-Dawley rats (male, 4 weeks old), were subjected to a unilateral mid-diaphyseal tibial fracture. Kinetic expression of physeal BMP-2, -4, -6, -7, and BMP receptor-1a (BMPR-1a) was analyzed in a monthly period by quantitative real time-polymerase chain reaction and immunohistochemistry. On Days 1, 3, 10, and 14 post-fracture, no changes in physeal BMPs gene-expression were detected. Twenty-nine days post-fracture, when the fracture was consolidated, physeal expression of BMP-6 and BMPR-1a was significantly upregulated in the growth plate of the fractured and contra-lateral intact bone compared to control (p<0.005). This study demonstrates a late role of BMP-6 and BMPR-1a in fracture-induced physeal growth alterations and furthermore, may have discovered the existence of a regulatory "cross-talk" mechanism between the lower limbs whose function could be to limit leg-length-discrepancies following the breakage of growing bones. PMID- 23097202 TI - [Percutaneous tracheostomy in intensive care medicine - Update 2012]. AB - Percutaneous tracheostomy has become an established procedure in airway management of critically ill patients. It offers advantages over prolonged tracheal intubation. To date, there is no evidence of the optimal timing of the procedure. The Ciaglia Blue Rhino technique is the most common technique and, as any other techniques of percutaneous tracheostomy, is performed under general anaesthesia and with continuous bronchoscopic control. The recently introduced Ciaglia Blue Dolphin technique is based on radial dilatation with a fluid-filled high pressure balloon. Provided that specific contraindications are observed (e.g. difficult tracheal intubation, inability to identify anatomic landmarks, severe coagulopathy etc.), all techniques have low complication rates. The use of ultrasound may further enhance perioperative safety. Finally it must be noted that percutaneous tracheostomy is an elective procedure that requires informed consent from the patient or an attorney of law. PMID- 23097203 TI - [Anesthesia for laparoscopic surgery]. AB - Among clinical benefits like reduction in blood loss, faster postoperative recovery of gastrointestinal and lung function, lower rate of perioperative complications and less postoperative pain level, cost reduction by shortening of hospital stay plays a pivotal role for high incidence of laparoscopic surgery.Elevated intraabdominal pressure due to creation of pneumoperitoneum induces various pathophysiologic changes. Most of these changes are clinical inapparent in case of appropriate anesthesiologic management. This paper aims to sensibilize the anaesthesiologist for pathophysiologic changes, particularly with regard to hemodynamic and pulmonary complications, differential diagnosis and therapies. PMID- 23097204 TI - [Anaesthesia in endoscopic and percutaneous procedures in cardio-thoracic and cardiovascular interventions, part 2 - endoscopic thoracic interventions and endovascular percutaneous aortic aneurysm repair (EVAR)]. AB - Despite the ongoing further development of high definition imaging techniques (CT, MRI), mediastinoscopy and thoracoscopy remain essential instruments e.g. for extracting mediastinal lymph nodes allowing further histological diagnostics, or increasingly complex thoracoscopic procedures. Furthermore, in the course of the development of endoscopic thoracic and percutaneous interventions, the therapy of thoracic aortic aneurysms is increasingly the domain of endovascular procedures. In the second part of this review the anaesthesiological procedure and specialties concerning endoscopic thoracic interventions and percutaneous aortic aneurysm repair (EVAR) will be described. PMID- 23097205 TI - [Pssst ... AINS-Secrets! -- today in maxillo-facial surgery]. PMID- 23097206 TI - [Lung replacement procedure -- advanced treatment options for acute lung injury]. PMID- 23097207 TI - [Which kind of therapy for which patient? Choosing the ventilator strategy in ARDS]. AB - Ventilator-induced lung injury (VILI) contributes to the high mortality of ALI/ARDS. Lung protective ventilation with a tidal volume of 6 ml / kgIBW (Ideal Body Weight) and a plateau pressure <30 cm H2O has shown to reduce mortality and was thus selected as one of ten quality indicators for critical care in Germany. The optimal level of PEEP is currently unclear; however, patients with severe disorders of gas exchange seem to benefit from higher PEEP levels.Adjusting the respirator settings to the mechanical properties of the individual patient will change the treatment of ARDS in the next few years. Measurements of transpulmonary pressure by an oesophageal probe or electrical impedance tomography (EIT) are promising approaches, but still need to proof their superiority. Until then, every clinician must aim to translate the recommendations of lung protective ventilation into daily practice. PMID- 23097208 TI - [If mechanical ventilation comes to its limits: extracorporeal lung assist]. AB - Extracorporeal lung assist can be performed pumpless by using the arterio-venous driving pressure or pumpdriven in a veno-venous mode. Oxygenation is maintained via the native lungs and depends mainly on mean airway pressure during mechanical ventilation.Extracorporeal lung assist can be part of a multimodal treatment concept in patients with acute lung injury. It aims at a further reduction of the applied tidal volume and peak pressures in order to reduce the intensity of the pulmonary and systemic inflammatory response which is the main factor for the development of multi-organ failure in this group of patients. Eventually patients with acute exacerbation of a chronic pulmonary disease might also benefit from extracorporeal ventilation. PMID- 23097209 TI - [If the extracorporeal lung assist comes to its limit: use and management of extracorporeal membrane oxygenation in severe acute respiratory distress syndrome]. AB - In patients with the most severe forms of acute respiratory distress syndrome (ARDS) refractory to conventional mechanical ventilation and adjunctive or rescue therapies like kinetic therapy, inhaled vasodilators or extracorporeal CO2 elimination (extracorporeal lung assist), the use of the extracorporeal membrane oxygenation (ECMO) can secure gas exchange. Due to technical improvements and miniaturization, the new ECMO system is safer and simpler. Nowadays the ECMO systems are heparin-coated, so that there is no need of therapeutic systemic anticoagulation, and thus bleeding complications are less frequent. Recent data suggests, that outcome of patients with severe ARDS treated with ECMO may improve. This review describes the function and the management of ECMO-therapy in ARDS-patients. PMID- 23097212 TI - beta2-Adrenergic receptor solutions for structural biology analyzed with microscale NMR diffusion measurements. AB - Microcoil NMR measurements were performed to determine the final composition of solutions of the beta(2)-adrenergic receptor (beta(2)AR) reconstituted with a detergent and to study the hydrodynamic properties of the detergent micelles containing beta(2)AR. Standards are established for the reproducible preparation of G-protein-coupled receptor solutions for crystallization trials and solution NMR studies. PMID- 23097213 TI - Novel screening assay for the selective detection of G-protein-coupled receptor heteromer signaling. AB - Drugs targeting G-protein-coupled receptors (GPCRs) make up more than 25% of all prescribed medicines. The ability of GPCRs to form heteromers with unique signaling properties suggests an entirely new and unexplored pool of drug targets. However, current in vitro assays are ill equipped to detect heteromer selective compounds. We have successfully adapted an approach, using fusion proteins of GPCRs and chimeric G proteins, to create an in vitro screening assay (in human embryonic kidney cells) in which only activated heteromers are detectable. Here we show that this assay can demonstrate heteromer-selective G protein bias as well as measure transinhibition. Using this assay, we reveal that the delta-opioid receptor agonist ADL5859, which is currently in clinical trials, has a 10-fold higher potency against delta-opioid receptor homomers than delta/MU opioid receptor heteromers (pEC(50) = 6.7 +/- 0.1 versus 5.8 +/- 0.2). The assay enables the screening of large compound libraries to identify heteromer-selective compounds that could then be used in vivo to determine the functional role of heteromers and develop potential therapeutic agents. PMID- 23097214 TI - Prasugrel metabolites inhibit neutrophil functions. AB - Clopidogrel and prasugrel belong to a thienopyridine class of oral antiplatelet drugs that, after having been metabolized in the liver, can inhibit platelet function by irreversibly antagonizing the P2Y(12) receptor. Furthermore, thienopyridines influence numerous inflammatory conditions, but their effects on neutrophils have not been evaluated, despite the important role of these cells in inflammation. Therefore, we investigated the effect of prasugrel metabolites on neutrophils to further clarify the role of thienopyridines in inflammation. Interestingly, a prasugrel metabolite mixture, produced in vitro using rat liver microsomes, significantly inhibited N-formyl-methionyl-leucyl-phenylalanine (fMLP)- and platelet-activating factor (PAF)-induced neutrophil activation. More specifically, prasugrel metabolites inhibited neutrophil transmigration, CD16 surface expression, and neutrophil-platelet aggregation. Moreover, prasugrel metabolite pretreatment also significantly decreased fMLP- or PAF-induced extracellular-signal-regulated kinase phosphorylation as well as calcium mobilization. To determine the target of prasugrel in neutrophils, the role of both P2Y(12) and P2Y(13) receptors was studied using specific reversible antagonists, AR-C69931MX and MRS2211, respectively. Neither antagonist had any direct effect on the agonist-induced neutrophil functional responses. Our findings indicate that prasugrel metabolites may directly target neutrophils and inhibit their activation, suggesting a possible explanation for their anti inflammatory effects previously observed. However, these metabolites do not act through either the P2Y(12) or P2Y(13) receptor in neutrophils. PMID- 23097215 TI - Vapor-phase fabrication of beta-iron oxide nanopyramids for lithium-ion battery anodes. AB - The other polymorph: A vapor-phase route for the fabrication of beta-Fe(2)O(3) nanomaterials on Ti substrates at 400-500 degrees C is reported. For the first time, the beta polymorph is tested as anode for lithium batteries, exhibiting promising performances in terms of Li storage and rate capability. PMID- 23097216 TI - Evaluation of subgingivally delivered 0.5% clarithromycin as an adjunct to nonsurgical mechanotherapy in the management of chronic periodontitis: a short term double blinded randomized control trial. AB - OBJECTIVE: As the risk involved with systemic antimicrobials (high doses, microbial resistance, adverse reactions, etc.) restricts their use and local delivery of antimicrobials into periodontal pockets improves periodontal health, this study was designed to investigate the effects of subgingivally delivered clarithromycin (CLM; 0.5%) as an adjunct to nonsurgical mechanotherapy in chronic periodontitis subjects. METHODS: Ninety-eight patients were categorized into two treatment groups: scaling and root planing (SRP) plus 0.5% CLM (test; group 1) and SRP plus placebo (control; group 2). Clinical parameters included gingival index (GI), sulcus bleeding index (SBI), plaque index (PI), probing depth (PD), and periodontal attachment level (PAL), recorded at 4, 8 and 12 weeks. The concentration of 0.5% CLM in gingival fluid was estimated by reverse-phase high pressure liquid chromatography. anova, the chi-square test and the Scatterthwaite test were used for statistical analysis. RESULTS: Patients treated with SRP + CLM showed enhanced reductions in GI, SBI, and PD, and gains in PAL (P < 0.001) over time, as compared with the placebo group. However, no statistically significant differences were noted for PI. The mean concentration of CLM was detected in gingival crevicular fluid for up to 7 weeks, fulfilling the conditions for a controlled-release device. CONCLUSION: Adjunctive use of 0.5% CLM as a controlled drug delivery system enhanced the clinical outcome up to 3 months. PMID- 23097217 TI - Exendin-4 inhibits iNOS expression at the protein level in LPS-stimulated Raw264.7 macrophage by the activation of cAMP/PKA pathway. AB - Glucagon-like peptide-1 (GLP-1) and its potent agonists have been widely studied in pancreatic islet beta-cells. However, GLP-1 receptors are present in many extrapancreatic tissues including macrophages, and thus GLP-1 may have diverse actions in these tissues and cells. Therefore, we examined the mechanism by which exendin-4 (EX-4), a potent GLP-1 receptor agonist, inhibits lipopolysaccharide (LPS)-induced iNOS expression in Raw264.7 macrophage cells. EX-4 significantly inhibited LPS-induced iNOS protein expression and nitrite production. However, Northern blot and promoter analyses demonstrated that EX-4 did not inhibit LPS induced iNOS mRNA expression and iNOS promoter activity. Electrophoretic mobility shift assay (EMSA) showed that EX-4 did not alter the binding activity of NF kappaB to the iNOS promoter. Consistent with the result of EMSA, LPS-induced IkappaBalpha phosphorylation and nuclear translocation of p65 were not inhibited by EX-4. Also, actinomycin D chase study and the promoter assay using the construct containing 3'-untranslated region of iNOS showed that EX-4 did not affect iNOS mRNA stability. Meanwhile, cycloheximide chase study demonstrated that EX-4 significantly accelerated iNOS protein degradation. The EX-4 inhibition of LPS-induced iNOS protein was significantly reversed by adenylate cyclase inhibitors (MDL-12330A and SQ 22536), a PKA inhibitor (H-89) and PKAalpha gene silencing. These findings suggest that EX-4 inhibited LPS-induced iNOS expression at protein level, but not at transcriptional mechanism of iNOS gene and this inhibitory effect of EX-4 was mainly dependent on cAMP/PKA system. PMID- 23097218 TI - Zonal rate model for axial and radial flow membrane chromatography. Part I: knowledge transfer across operating conditions and scales. AB - The zonal rate model (ZRM) has previously been applied for analyzing the performance of axial flow membrane chromatography capsules by independently determining the impacts of flow and binding related non-idealities on measured breakthrough curves. In the present study, the ZRM is extended to radial flow configurations, which are commonly used at larger scales. The axial flow XT5 capsule and the radial flow XT140 capsule from Pall are rigorously analyzed under binding and non-binding conditions with bovine serum albumin (BSA) as test molecule. The binding data of this molecule is much better reproduced by the spreading model, which hypothesizes different binding orientations, than by the well-known Langmuir model. Moreover, a revised cleaning protocol with NaCl instead of NaOH and minimizing the storage time has been identified as most critical for quantitatively reproducing the measured breakthrough curves. The internal geometry of both capsules is visualized by magnetic resonance imaging (MRI). The flow in the external hold-up volumes of the XT140 capsule was found to be more homogeneous as in the previously studied XT5 capsule. An attempt for model-based scale-up was apparently impeded by irregular pleat structures in the used XT140 capsule, which might lead to local variations in the linear velocity through the membrane stack. However, the presented approach is universal and can be applied to different capsules. The ZRM is shown to potentially help save valuable material and time, as the experiments required for model calibration are much cheaper than the predicted large-scale experiment at binding conditions. PMID- 23097219 TI - Efficient DNA condensation induced by ruthenium(II) complexes of a bipyridine functionalized molecular clip ligand. AB - Complexes of the type [Ru(bxbg)(2) (N-N)](2+), where N-N denotes 2,2'-bipyridine (bpy) (1), 1,10-phenanthroline (phen) (2), dipyrido[3,2-d:2',3-f] quinoxaline (dpq) (3), and dipyrido[3,2-a:2',3'-c]phenazine (dppz) (4), incorporating bis(o xylene)bipyridine-glycoluril (bxbg) as an ancillary "molecular clip" ligand, have been synthesized and characterized. These ruthenium(II) complexes of bis(o xylene)bipyridine-glycoluril self-associate in water through specific molecular recognition processes to form polycationic arrays. These arrays containing electrostatic binders as well as intercalator ligands at micromolar doses rapidly condense free DNA into globular nanoparticles of various sizes. The DNA condensation induced by these complexes has been investigated by electrophoretic mobility assay, dynamic light scattering, and transmission electron microscopy. The cellular uptake of complex-DNA condensates and the low cytotoxicity of these complexes satisfy the requirements of a gene vector. PMID- 23097220 TI - The discourse around usefulness, morality, risk and trust: a focus group study on prenatal genetic testing. AB - OBJECTIVE: This study explores the underlying values and beliefs that guide women's reasoning on prenatal genetic test (PGT) uptake, as framed by their own words, during a group discussion, in a Catholic country such as Italy. METHODS: Women's reasoning was explored by means of five focus group consisting of seven pregnant women and 13 new mothers. RESULTS: The focus group material content was analysed using the Nudist software. The discourse around PGT was rooted into four frames of reference: The usefulness dimension was used to express the positions in favour of PGT, whereas morality, risk and trust were used to express negative evaluations on such a technology. Participants advocated for themselves the choice of being tested, besides giving some credit to the partner's opinion. Moreover, participants reported little knowledge on PGT. CONCLUSION: The research shed some light on the frames of reference used by participants to build their positions on PGT uptake, confirming the public's ability to translate scientific accounts into personally meaningful information. A more complete understanding of the reasons for decisions to test would help counsellors to better communicate with women and couples, and to better assist them to make a better informed testing decision. PMID- 23097221 TI - The role of dimethylarginine dimethylaminohydrolase (DDAH) in pulmonary fibrosis. AB - Pulmonary fibrosis is a devastating and progressive parenchymal lung disease with an extremely poor prognosis. Patients suffering from idiopathic pulmonary fibrosis (IPF) display a compromised lung function alongside pathophysiological features such as highly increased production of extracellular matrix, alveolar epithelial cell dysfunction, and disordered fibroproliferation - features that are due to a dysregulated response to alveolar injury. Under pathophysiological conditions of IPF, abnormally high concentrations of nitric oxide (NO) are found, likely a result of increased activity of the inducible nitric oxide synthase (NOS2), giving rise to products that contribute to fibrosis development. It is known that pharmacological inhibition or knockdown of NOS2 reduces pulmonary fibrosis, suggesting a role for NOS inhibitors in the treatment of fibrosis. Recent reports identified a critical enzyme, dimethylarginine dimethylaminohydrolase (DDAH), which is exceedingly active in patients suffering from IPF and in mice treated with bleomycin. An up-regulation of DDAH was observed in primary alveolar epithelial type II (ATII) cells from mice and patients with pulmonary fibrosis, where it co-localizes with NOS2. DDAH is a key enzyme that breaks down an endogenous inhibitor of NOS, asymmetric dimethylarginine (ADMA), by metabolizing it to l-citrulline and dimethylamine. DDAH was shown to modulate key fibrotic signalling cascades, and inhibition of this enzyme attenuated many features of the disease in in vivo experiments, suggesting a possible new therapeutic strategy for the treatment of patients suffering from IPF. PMID- 23097222 TI - Asymptomatic cerebral lesions during pulmonary vein isolation under uninterrupted oral anticoagulation. AB - AIMS: Left atrial radiofrequency ablation has been shown to carry a risk of asymptomatic cerebral lesions. No data exist in patients under continued oral anticoagulation during the ablation procedure. The aim of this study was to quantify the amount of silent cerebral lesions assessed by pre-procedural and post-procedural magnetic resonance imaging (MRI) in patients under therapeutic international normalized ratio (INR) and to identify clinical or procedural parameters that correlate with cerebral embolism. METHODS AND RESULTS: A total of 131 consecutive patients undergoing catheter ablation for paroxysmal (n = 80, 61.1%) or persistent (n = 51, 38.9%) atrial fibrillation were included in the study. Pulmonary vein antrum isolation (PVI), roofline, mitral isthmus line, and complex fractionated atrial electrogram (CFAE) ablation using 3.5 mm open irrigated tip catheters were performed, as needed. All patients underwent pre procedural and post-procedural cerebral MRI. Post-procedural MRI revealed new embolic lesions in 16 patients (12.2%), all of them asymptomatic. Clinical parameters showing a significant correlation with cerebral embolism in univariate analysis were age (P = 0.027), persistent atrial fibrillation (vs. paroxysmal; P = 0.039), and spontaneous echo contrast in transesophageal echocardiography (P = 0.029). Significant procedural parameters were electric cardioversion (P = 0.041), PVI only (P = 0.008), and ablation of complex atrial electrograms (P = 0.005). Independent risk factors in multivariate analysis were age (P = 0.009), spontaneous echo contrast (P = 0.029) and CFAE ablation (P = 0.006). CONCLUSION: Radiofrequency ablation in patients under continued oral therapeutic anticoagulation is associated with a substantial risk of silent embolism detected by cerebral MRI. Therefore, continuation of oral anticoagulation is not able to prevent cerebral embolism. A variety of different clinical and procedural factors seem to contribute to the risk of cerebral lesions. PMID- 23097223 TI - Pacemaker follow-up: are the latest guidelines in line with modern pacemaker practice? AB - AIMS: Guidelines regarding pacemaker (PM) follow-up (FU) are not precisely defined. The study aim is to describe long-term routine in-hospital FU, evaluate compliance to guidelines, and assess the portion of visits-with-an-action (VWA). METHODS AND RESULTS: The multicentre prospective FOLLOWPACE study collected data in the period 2003-2010, regarding FU of 1517 patients with a first PM for bradycardia indications in 23 Dutch hospitals. A total of 15 472 visits were analysed with a median FU of 4.9 years, adding up to 6750 patient years. The median time to the first three visits was 35, 127, and 303 days, respectively. Thereafter the median interval between visits was 180 days. Most patients had 2 FU/year, 22% had 1 FU/year, and 18% had >3 FU/year. Seventy-three percent of patients with single-chamber PMs had at least 1 FU/year, whereas 36% of patients with dual-chamber PMs received at least 2 FU/year. During the first year, 52% of visits were VWA, as opposed to 17% after 6 years. Battery status was assessed in 98%, and stimulation and sensing thresholds in 90% and 77% of visits, respectively. Reprogramming markedly declined from ~ 60% in the first FU visit to 10-20% after the fifth visit. CONCLUSION: Although the measurements during PM FU are according to guidelines, the frequency of FU is not. Moreover, in the vast majority of performed FU, PM programming is left unchanged. This suggests that a large portion of FU visits is redundant, such that their frequency after the first year can be diminished, or replaced by remote FU. PMID- 23097224 TI - Risk factors for infection of implantable cardiac devices: data from a registry of 2496 patients. AB - AIMS: The increased use of implantable cardiac devices has been accompanied by an increase in infection. However, risk factors for infection of implanted devices are poorly documented. We aimed to identify risk factors in patients with long term follow-up after implantation of cardiac devices. METHODS AND RESULTS: Patients with first implantation of a cardiac device in our centre between October 1996 and July 2007 were entered in a registry. Each confirmed infection of the implanted device was matched to two controls for age, sex, and implantation year. We recorded cardiovascular risk factors (hypertension, diabetes), previous history of heart disease, renal failure, antiplatelet or anticoagulant therapy, as well as pre- and post-procedural characteristics (antibiotic prophylaxis, hyperthermia, number of leads, associated interventions, and early complications). During the study period, 2496 patients underwent implantation of a cardiac device; 35 infections were diagnosed (1.2%). Among these, 75% occurred during the first year after implantation. Early non infectious complication requiring surgical intervention was observed only in patients with infection (9 of 35, P < 0.001). Factors independently associated with infection were diabetes [odds ratio (OR) 3.5, 95% confidence interval (CI) [1.03, 12.97]], underlying heart disease (OR 3.12, 95% CI [1.13; 8.69]), and use of >1 lead (OR 4.07, 95% CI [1.23, 13.47]). These latter two risk factors were also independently associated with occurrence of infection within 1 year of implantation. CONCLUSION: Our data show that the presence of diabetes and underlying heart disease are independent risk factors for infection after cardiac device implantation. As regards procedural characteristics, the use of several leads and early re-intervention are associated with a higher infection rate. PMID- 23097225 TI - Anionic complexes of MWCNT with supergiant cyanobacterial polyanions. AB - Multi-walled carbon nanotubes (MWCNTs) were well dispersed in an aqueous solution of the cyanobacterial polysaccharide, sacran, with an ultra-high molecular weight >10 million g/mol. MWCNTs powder was put into aqueous solutions of various polysaccharides including sacran and was dispersed under sonication. As a result of the turbidity measurement of the supernatant, it was found that sacran showed the highest MWCNT-dispersion efficiency of all the polysaccharides used here. Cryogenic transmission electron microscopic (Cryo-TEM) studies directly demonstrated the existence of MWCNTs in the supernatant, and high-resolution TEM observation revealed that MWCNTs covered by sacran chains made their efficient dispersion in water. Raman spectroscopy demonstrated the existence of MWCNT in dried sample from supernatant and the interaction between MWCNT and sacran. The zeta-potential measurement of the dispersion indicated the negative surface charges of the sacran/MWCNT complexes. Then the MWCNT complexes were able to fabricate by ionic interaction; electrophoresis of the anionic complex formed the sacran/MWCNT gels on the anode while the droplet of sacran/MWCNT dispersion formed gel beads in the presence of the lanthanoid cations. PMID- 23097226 TI - Outside-binding site mutations modify the active site's shapes in neuraminidase from influenza A H1N1. AB - The recent occurrence of 2009 influenza A (H1N1) pandemic as well as others has raised concern of a far more dangerous outcome should this virus becomes resistant to current drug therapies. The number of clinical cases that are resistant to oseltamivir (Tamiflu(r)) is larger than the limited number of neuraminidase (NA) mutations (H275Y, N295S, and I223R) that have been identified at the active site and that are associated to oseltamivir resistance. In this study, we have performed a comparative analysis between a set of NAs that have the most representative mutations located outside the active site. The recently crystallized NA-oseltamivir complex (PDB ID: 3NSS) was used as a wild-type structure. After selecting the target NA sequences, their three-dimensional (3D) structure was built using 3NSS as a template by homology modeling. The 3D NA models were refined by molecular dynamics (MD) simulations. The refined models were used to perform a docking study, using oseltamivir as a ligand. Furthermore, the docking results were refined by free-energy analysis using the MM-PBSA method. The analysis of the MD simulation results showed that the NA models reached convergence during the first 10 ns. Visual inspection and structural measures showed that the mutated NA active sites show structural variations. The docking and MM-PBSA results from the complexes showed different binding modes and free energy values. These results suggest that distant mutations located outside the active site of NA affect its structure and could be considered to be a new source of resistance to oseltamivir, which agrees with reports in the clinical literature. PMID- 23097227 TI - Ab initio based conformational study of the crystalline alpha-chitin. AB - The equilibrium structure including the network of hydrogen bonds of an alpha chitin crystal is determined combining density-functional theory (DFT), self consistent DFT-based tight-binding (SCC-DFTB), and empirical forcefield molecular dynamics (MD) simulations. Based on the equilibrium geometry several possible crystal conformations (local energy minima) have been identified and related to hydrogen bond patterns. Our results provide new insight and allow to resolve the contradicting alpha-chitin structural models proposed by various experiments. PMID- 23097228 TI - Strain stiffening in collagen I networks. AB - Biopolymer gels exhibit strain stiffening that is generally not seen in synthetic gels. Here, we investigate the strain-stiffening behavior in collagen I gels that demonstrate elasticity derived from a variety of sources including crosslinking through telopeptides, bundling through low-temperature gelation, and exogenous crosslinking with genipin. In all cases, it is found that these gels exhibit strain stiffening; in general, onset of strain stiffening occurs earlier, yield strain is lower, and degree of strain stiffening is smaller in higher concentration gels and in those displaying thick fibril bundles. Recovery after exposure to high strains is substantial and similar in all gels, suggesting that much of the stiffening comes from reversible network deformations. A key finding of this study is that collagen I gels of identical storage and loss moduli may display different nonlinear responses and different capacities to recover from high strain. PMID- 23097229 TI - Structural and dynamical properties of KTS-disintegrins: A comparison between Obtustatin and Lebestatin. AB - Obtustatin and Lebestatin are lysine-threonine-serine (KTS)-disintegrins, which are a family of low molecular weight polypeptides present in many viperidae venoms and are potent and specific inhibitors of collagen-binding integrins. The integrin binding loop, harboring the (21)KTS(23) motif, and the C-terminal tail are known to be responsible for the selective binding to the alpha1beta1 integrin. Despite a very high sequence homology (only two mutations are present in Lebestatin relative to Obtustatin, namely R24L and S38L), Lebestatin exhibits a higher inhibitory effect than Obtustatin on cell adhesion and cell migration to collagens I and IV. Here we show, by means of molecular dynamics simulations of the two polypeptides in aqueous solution, that Lebestatin possesses a higher flexibility of the C-terminal tail and a greater solvent accessibility of the integrin binding loop than Obtustatin. It may be hypothesized that these properties may contribute to the higher binding-affinity of Lebestatin to its biological partner. PMID- 23097231 TI - Exchangeability of the flagellin (FliC) and the cap protein (FliD) among different species in flagellar assembly. AB - Flagellar filament self-assembles from the component protein, flagellin or FliC, with the aid of the capping protein, HAP2 or FliD. Depending on the helical parameters of filaments, flagella from various species are divided into three groups, family I, II, and III. Each family coincides with the traditional classification of flagella, peritrichous flagella, polar flagella, and lateral flagella, respectively. To elucidate the physico-chemical properties of flagellin to separate families, we chose family I flagella and family II flagella and examined how well the exchangeability of a combination of FliC and/or FliD from different families is kept in filament formation. FliC or FliD of Salmonella enterica serovar Typhimurium (Salty; family I) were exchanged with those of Escherichia coli (Escco; family I) or Pseudomonas aeruginosa (Pseae; family II). In a Salty fliC deletion mutant, Escco FliC formed short filaments, but Pseae FliC did not form filaments. In a Salty fliD deletion mutant, both Escco FliD and Pseae FliD allowed Salty FliC to polymerize into short filaments. In conclusion, FliC can be exchanged among the same family but not between different families, while FliD serves as the cap protein even in different families, confirming that FliC is essential for determining families, but FliD plays a subsidiary role in filament formation. PMID- 23097230 TI - Effect of detergents on the thermal behavior of elastin-like polypeptides. AB - Elastin-like polypeptide (ELP) fusions have been designed to allow large-scale, nonchromatographic purification of many soluble proteins by using the inverse transition cycling (ITC) method; however, the sensitivity of the aqueous lower critical solubility phase transition temperature (T(t)) of ELPs to the addition of cosolutes, including detergents, may be a potential hindrance in purification of proteins with surface hydrophobicity in such a manner. To identify detergents that are known to solubilize such proteins (e.g., membrane proteins) and that have little effect on the T(t) of the ELP, we screened a number of detergents with respect to their effects on the T(t) and secondary structures of a model ELP (denoted here as ELP180). We found that mild detergents (e.g., n-dodecyl-beta-D maltoside, Triton-X100, and 3-[(3-cholamidopropyl) dimethylamino]-1 propanesulfonate) do not alter the phase transition behavior or structure (as probed by circular dichroism) of ELP180. This result is in contrast to previous studies that showed a strong effect of other detergents (e.g., sodium dodecylsulfate) on the T(t) of ELPs. Our results clearly indicate that mild detergents do not preclude ITC-based separation of ELPs, and thus that ELP fusions may prove to be useful in the purification of detergent-solubilized recombinant hydrophobic proteins, including membrane proteins, which are otherwise notoriously difficult to extract and purify by conventional separation methods (e.g., chromatography). PMID- 23097232 TI - Effect of amylose deposition on potato tuber starch granule architecture and dynamics as studied by lintnerization. AB - The effect of amylose deposition on the amylopectin crystalline lamellar organization in potato starch granules was studied by mild acid, so-called lintnerization, of potato tuber starch transgenically engineered to deposit different levels of amylose. The starch granules were subjected to lintnerization at different temperatures (25, 35, and 45 degrees C) and to two levels of solubilization, ~ 45 and 80%. The rate of the lintnerization increased with temperature but was suppressed by amylose. The molecular size of the lintner dextrins increased with temperature, but this effect was suppressed by the presence of amylose. At high temperatures and low-amylose content, the degree of branches was high with the concomitant increase in size in the dextrins. A portion of the branches was resistant to debranching enzymes possibly due to specific structural formations. The effects of temperature suggested a unique granular architecture of potato starch, and a model showing the dependence of temperature on the dynamic arrangement of amylopectin and amylose in the crystalline and amorphous lamellae for the potato starch is suggested. PMID- 23097233 TI - Surface functionalization of carbon nanomaterials by self-assembling hydrophobin proteins. AB - Class I fungal hydrophobins are small surface-active proteins that self-assemble to form amphipathic monolayers composed of amyloid-like rodlets. The monolayers are extremely robust and can adsorb onto both hydrophobic and hydrophilic surfaces to reverse their wettability. This adherence is particularly strong for hydrophobic materials. In this report, we show that the class I hydrophobins EAS and HYD3 can self-assemble to form a single-molecule thick coating on a range of nanomaterials, including single-walled carbon nanotubes (SWCNTs), graphene sheets, highly oriented pyrolytic graphite, and mica. Moreover, coating by class I hydrophobin results in a stable, dispersed preparation of SWCNTs in aqueous solutions. No cytotoxicity is detected when hydrophobin or hydrophobin-coated SWCNTs are incubated with Caco-2 cells in vitro. In addition, we are able to specifically introduce covalently linked chemical moieties to the hydrophilic side of the rodlet monolayer. Hence, class I hydrophobins provide a simple and effective strategy for controlling the surfaces of a range of materials at a molecular level and exhibit strong potential for biomedical applications. PMID- 23097235 TI - Affective scenes influence fear perception of individual body expressions. AB - In natural viewing conditions, different stimulus categories such as people, objects, and natural scenes carry relevant affective information that is usually processed simultaneously. But these different signals may not always have the same affective meaning. Using body-scene compound stimuli, we investigated how the brain processes fearful signals conveyed by either a body in the foreground or scenes in the background and the interaction between foreground body and background scene. The results showed that left and right extrastriate body areas (EBA) responded more to fearful than to neutral bodies. More interestingly, a threatening background scene compared to a neutral one showed increased activity in bilateral EBA and right-posterior parahippocampal place area (PPA) and decreased activity in right retrosplenial cortex (RSC) and left-anterior PPA. The emotional scene effect in EBA was only present when the foreground body was neutral and not when the body posture expressed fear (significant emotion-by category interaction effect), consistent with behavioral ratings. The results provide evidence for emotional influence of the background scene on the processing of body expressions. PMID- 23097237 TI - Optimization of the position of the acetabulum in a ganz periacetabular osteotomy by finite element analysis. AB - Periacetabular osteotomy (PAO) is a surgical procedure to correct acetabular orientation in developmental dysplasia of the hip (DDH). It changes the position of the acetabulum to increase femoral head coverage and distribute the contact pressure over the cartilage surface. The success of PAO depends significantly on the surgeon's experience. Using computed tomography data from patients with DDH, we developed a 3D finite element (FE) model to investigate the optimal position of the acetabulum following PAO. A virtual PAO was performed with the acetabulum rotated in increments from the original center edge (CE) angle. Contact area, contact pressure, and Von Mises stress in the femoral and pelvic cartilage were analyzed. Five dysplastic hips from four patients were modeled. Contact area, contact pressure, and Von Mises stress in the cartilage all varied according to the change of CE angle through virtual PAO. An optimal position could be achieved for the acetabulum that maximizes the contact area while minimizing the contact pressure and von Mises stress in the pelvic and femoral cartilage. The optimal position of the acetabulum was patient dependent and did not always correspond to what would be considered a "normal" CE angle. We demonstrated for the first time the interrelation of correction angle, contact area, and contact pressure between the pelvic and femoral cartilage in PAO surgery. PMID- 23097238 TI - Bistability loss as a key feature in azobenzene (non-)switching on metal surfaces. PMID- 23097236 TI - Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance. AB - SCOPE: Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. METHODS AND RESULTS: We examined the effects of selenium-deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium-supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. CONCLUSION: Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. PMID- 23097239 TI - Differentiation of malignant and benign breast lesions using magnetization transfer imaging and dynamic contrast-enhanced MRI. AB - PURPOSE: To evaluate feasibility of using magnetization transfer ratio (MTR) in conjunction with dynamic contrast-enhanced MRI (DCE-MRI) for differentiation of benign and malignant breast lesions at 3 Tesla. MATERIALS AND METHODS: This prospective study was IRB and HIPAA compliant. DCE-MRI scans followed by MT imaging were performed on 41 patients. Regions of interest (ROIs) were drawn on co-registered MTR and DCE postcontrast images for breast structures, including benign lesions (BL) and malignant lesions (ML). Initial enhancement ratio (IER) and delayed enhancement ratio (DER) were calculated, as were normalized MTR, DER, and IER (NMTR, NDER, NIER) values. Diagnostic accuracy analysis was performed. RESULTS: Mean MTR in ML was lower than in BL (P < 0.05); mean DER and mean IER in ML were significantly higher than in BL (P < 0.01, P < 0.001). NMTR, NDER, and NIER were significantly lower in ML versus BL (P < 0.007, P < 0.001, P < 0.001). IER had highest diagnostic accuracy (77.6%), sensitivity (86.2%), and area under the ROC curve (.879). MTR specificity was 100%. Logistic regression modeling with NMTR and NIER yielded best results for BL versus ML (sensitivity 93.1%, specificity 80%, AUC 0.884, accuracy 83.7%). CONCLUSION: Isolated quantitative DCE analysis may increase specificity of breast MR for differentiating BL and ML. DCE-MRI with NMTR may produce a robust means of evaluating breast lesions. PMID- 23097241 TI - Reversible binding of molecular oxygen to catecholate and amidophenolate complexes of SbV: electronic and steric factors. AB - Edge of reactivity: The reactions of reversible binding of molecular oxygen to catecholate and amidophenolate complexes of Sb(V) are investigated by analyzing the position of electronic (E(HOMO)) and steric (G-parameter) factors. The optimal electronic and steric parameters for such type reactions are found. PMID- 23097240 TI - Effects of ketoconazole treatment on the pharmacokinetics of safinamide and its plasma metabolites in healthy adult subjects. AB - The purpose of this mechanistic drug interaction study was to investigate the effects of ketoconazole on the pharmacokinetics of safinamide. Ketoconazole was applied as a potent prototypic inhibitor of cytochrome CYP3A4, to determine the role of CYP3A4 in the metabolic clearance of safinamide. In an open-label, randomized, two-period, two-sequence cross-over study, 14 healthy adult subjects (7 males/7 females) received two single doses of 100 mg safinamide: alone and on top of multiple doses of ketoconazole (200 mg b.i.d.) given over 6 days. Serial blood samples were collected over 240 h post dose to quantify safinamide parent drug and metabolite concentrations for pharmacokinetic evaluation. Safinamide exposure was essentially unchanged when administered with and without ketoconazole: C(max) and AUC(0-infinity) point estimates (90% CIs) for the treatment comparison were 106.6 (101.0; 112.4) and 112.9 (109.8; 116.03), respectively. Similarly, ketoconazole did not influence the formation and clearance of safinamide metabolites to a clinically relevant extent. Overall, the study shows that CYP3A4 plays a minor role in the metabolism of safinamide in vivo. Therefore, safinamide can be administered together with potent CYP3A4 inhibitors without any requirement for dose adjustment. PMID- 23097242 TI - Reply: To PMID 22473917. PMID- 23097243 TI - Influence of the sequence environment and properties of neighboring amino acids on amino-acetylation: relevance for structure-function analysis. AB - Proteins function is regulated by co-translational modifications and post translational modifications (PTMs) such as phosphorylation, glycosylation, and acetylation, which induce proteins to perform multiple tasks in a specified environment. Acetylation takes place post-translationally on the epsilon-amino group of Lys in histone proteins, allowing regulation of gene expression. Furthermore, amino group acetylation also occurs co-translationally on Ser, Thr, Gly, Met, and Ala, possibly contributing to the stability of proteins. In this work, the influence of amino acids next to acetylated sites has been investigated by using MAPRes (Mining Association Patterns among preferred amino acid residues in the vicinity of amino acids targeted for PTMs). MAPRes was utilized to examine the sequence patterns vicinal to modified and non-modified residues, taking into account their charge and polarity. The PTMs data were further sub-divided according to their sub-cellular location (nuclear, mitochondrial, and cytoplasmic), and their association patterns were mined. The association patterns mined by MAPRes for acetylated and non-acetylated residues are consistent with the existing literature but also revealed novel patterns. These rules have been utilized to describe the acetylation and its effects on the protein structure function relationship. PMID- 23097244 TI - Interaction between anions and molybdenum allyl dicarbonyl complexes of 1,4,7 trithiacyclononane. AB - The labile complex [MoCl(eta(3)-methallyl)(CO)(2)(NCMe)(2)] reacts with the ligand 1,4,7-trithiacyclononane ([9]aneS(3)) and the salt NaBAr'(4) to afford [Mo(eta(3)-methallyl)(CO)(2)([9]aneS(3))][BAr'(4)] (1?BAr'(4)). An analogous reaction of [MoBr(eta(3)-allyl)(CO)(2)(NCMe)(2)] yields [Mo(eta(3) allyl)(CO)(2)([9]aneS(3))][BAr'(4)] (2?BAr'(4)). The new compounds 1?BAr'(4) and 2?BAr'(4) were characterized by IR and NMR spectroscopic analysis and X-ray diffraction studies. Both compounds feature the cyclic thioether [9]aneS(3) coordinated as a tridentate ligand to the molybdenum center. The allyl ligand in 2?BAr'(4) is aligned with the middle of the OC-Mo-CO angle, which is acute. Both of these features are typical of most pseudo-octahedral allyl dicarbonyl molybdenum complexes. In contrast, the allyl group is rotated in 1?BAr'(4), which is attributed to steric hindrance between the methyl substituent and the ligated thioether, and the OC-Mo-CO angle is obtuse. Compound 1?BAr'(4) undergoes rapid substitution of [9]aneS(3) by either chloride and fluoride ions in dichloromethane, and the products include the known species [{Mo(eta(3) methallyl)(CO)(2)}(2)(MU-Cl)(3)](-) and a structurally similar new anionic complex with two fluoro and one hydroxo bridging ligands, respectively. Stable supramolecular adducts were formed in the reactions of 1?BAr'(4) and 2?BAr(4) with bromide, iodide, hydrogensulfate, and methanesulfonate compounds. The binding constants of these adducts in dichloromethane were calculated from (1)H NMR spectroscopic titration data, and the solid-state structures of the 1?Br, 1?HSO(4), 1?I, and 2?I adducts were determined by X-ray diffraction studies. The surprising slightly higher stability of the iodide adduct relative to that of bromide was investigated theoretically, with the results pointing to an effect of the differential solvation of the halide ions. PMID- 23097245 TI - Bioreducible poly(amido amine)s with different branching degrees as gene delivery vectors. AB - Based on the knowledge that cationic polymers with different topographical structures behave differently in gene transfection process, herein, we synthesized three biodegradable poly(amido amine)s (PAAs) with the same repeating units and molecular weights except for degree of branching: linear PAA (LPAA), low-branched PAA (LBPAA), and high-branched PAA (HBPAA). We found that LBPAA could more effectively compact pDNA into positively charged nanoparticles than both HBPAA and LPAA. LBPAA polyplexes had the highest transfection efficiency among the three PAA polyplexes, and the difference in transfection efficiency is mainly attributed to the endocytosis rate. The cytotoxicity of PAAs was negligible at the transfection doses, probably due to the degradable disulfide bonds. Therefore, we could use branching as a parameter to simply tune a polymer's cellular uptake behavior and transfection efficiency. PMID- 23097246 TI - A case of a transient enlargement of the intracranial translucency. PMID- 23097247 TI - Attention modulates the dorsal striatum response to love stimuli. AB - In previous functional magnetic resonance imaging (fMRI) studies concerning romantic love, several brain regions including the caudate and putamen have consistently been found to be more responsive to beloved-related than control stimuli. In those studies, infatuated individuals were typically instructed to passively view the stimuli or to think of the viewed person. In the current study, we examined how the instruction to attend to, or ignore the beloved modulates the response of these brain areas. Infatuated individuals performed an oddball task in which pictures of their beloved and friend served as targets and distractors. The dorsal striatum showed greater activation for the beloved than friend, but only when they were targets. The dorsal striatum actually tended to show less activation for the beloved than the friend when they were distractors. The longer the love and relationship duration, the smaller the response of the dorsal striatum to beloved-distractor stimuli was. We interpret our findings in terms of reinforcement learning. By virtue of using a cognitive task with a full factorial design, we show that the dorsal striatum is not activated by beloved related information per se, but only by beloved-related information that is attended. PMID- 23097249 TI - Interactions of engineered nanoparticles with organs protected by internal biological barriers. AB - Engineered nanomaterials may exert adverse effects on human health which, in turn, may be linked to their propensity to cross biological barriers in the body. Here, available evidence is discussed, based on in vivo studies for interactions of commercially relevant nanoparticles with critical internal barriers. The internal barriers in focus in this review are the blood-brain barrier, protecting the brain, the blood-testis barrier, protecting the male germ line, and the placenta, protecting the developing fetus. The route of exposure (pulmonary, gastro-intestinal, intravenous, intraperitoneal, dermal), and, hence, the portal of entry of nanoparticles into the body, is of critical importance. Different physico-chemical properties, not only size, may determine the ability of nanoparticles to breach biological barriers; the situation is further compounded by the formation of a so-called corona of biomolecules on the surfaces of nanoparticles, the composition of which may vary depending on the route of exposure and the translocation of nanoparticles from one biological compartment to another. The relevance of nanoparticle interactions with internal biological barriers for their impact on the organs protected by these barriers is also discussed. PMID- 23097248 TI - Decreased membrane complement regulators in the retinal pigmented epithelium contributes to age-related macular degeneration. AB - Dysregulated complement is thought to play a central role in age-related macular degeneration (AMD) pathogenesis, but the specific mechanisms have yet to be determined. In maculae of AMD specimens, we found that the complement regulatory protein, CD59, was increased in regions of uninvolved retinal pigmented epithelium (RPE) of early AMD, but decreased in the RPE overlying drusen and in geographic atrophy, an advanced form of AMD. While CD46 immunostaining was basolaterally distributed in the RPE of unaffected controls, it was decreased in diseased areas of early AMD samples. Since oxidized low-density lipoproteins (oxLDL) collect in drusen of AMD and are a known complement trigger, we treated ARPE-19 cells with oxLDL and found that cellular CD46 and CD59 proteins were decreased by 2.9- and nine-fold (p < 0.01), respectively. OxLDLs increased complement factor B mRNA and Bb protein, but not factor D, I or H. OxLDLs increased C3b, but not C3a, C5 or C5b-9. C5b-9 was increased by 27% (p < 0.01) when the medium was supplemented with human serum, which was sufficient to induce poly(ADP-ribose) polymerase cleavage, a marker of apoptosis. The decreased levels of CD46 and CD59 were in part explained by their release in exosomal and apoptotic membranous particles. In addition, CD59 was partially degraded through activation of IRE1alpha. Collectively, these results suggest that a combination of impaired complement regulators results in inadequately controlled complement by the RPE in AMD that induces RPE damage. PMID- 23097250 TI - Frequency of 'warning signs of cancer' in Norwegian general practice, with prospective recording of subsequent cancer. AB - BACKGROUND: Early diagnosis of cancer is an important challenge in general practice. Symptoms are the most common starting points. OBJECTIVE: To assess the association between symptoms presented and subsequent cancer. DESIGN: A cohort study of all patients seen consecutively by GPs. Prospective recording of cancer diagnosis, new cancer or new recurrence. SETTING: Two hundred and eighty-three general practice surgeries and 10 working days. METHOD: During patient consultations, GPs registered seven focal symptoms and three general symptoms, commonly considered as warning signs of cancer (WSC). Follow-up 6-11 months later with registration of any subsequent diagnosis of cancer was done. RESULTS: Of 51 073 patients, 6321 (12.4%) had recordings of 7704 WSC. During a median follow-up period of 8 months, 263 patients were diagnosed with cancer and 59 of them with recurrence of a previously diagnosed cancer. Of the cancer patients, 106 (40%) had presented one or more WSC during a preceding consultation. Examined symptoms had likelihood ratios for cancer from 1.5 to 8.2 and positive predictive values (PPVs) from 0.8% to 3.8%. Limited to older age groups, PPVs were a little higher. General symptoms were rarely associated with cancer unless a focal symptom had been recorded as well. Multiple symptoms increased the probability of cancer. CONCLUSION: 12.4% of GP patients presented with WSC. A general symptom may have cancer diagnostic value, but usually, only when it occurs along with a focal symptom. PPV of any single symptom is low, and decisions about referral require additional information. PMID- 23097252 TI - High performance of a new PCR-based urine assay for HPV-DNA detection and genotyping. AB - Human papillomavirus (HPV) testing has been proposed as a means of replacing or supporting conventional cervical screening (Pap test). However, both methods require the collection of cervical samples. Urine sample is easier and more acceptable to collect and could be helpful in facilitating cervical cancer screening. The aim of this study was to evaluate the sensitivity and specificity of urine testing compared to conventional cervical smear testing using a PCR based method with a new, designed specifically primer set. Paired cervical and first voided urine samples collected from 107 women infected with HIV were subjected to HPV-DNA detection and genotyping using a PCR-based assay and a restriction fragment length polymorphism method. Sensitivity, specificity, Positive Predictive Value (PPV), and Negative Predictive Value (NPV) were calculated using the McNemar's test for differences. Concordance between tests was assessed using the Cohen's unweighted Kappa (k). HPV DNA was detected in 64.5% (95% CI: 55.1-73.1%) of both cytobrush and urine samples. High concordance rates of HPV-DNA detection (k = 0.96; 95% CI: 0.90-1.0) and of high risk-clade and low-risk genotyping in paired samples (k = 0.80; 95% CI: 0.67-0.92 and k = 0.74; 95% CI: 0.60-0.88, respectively) were observed. HPV-DNA detection in urine versus cervix testing revealed a sensitivity of 98.6% (95% CI: 93.1-99.9%) and a specificity of 97.4% (95% CI: 87.7-99.9%), with a very high NPV (97.4%; 95% CI: 87.7-99.9%). The PCR-based assay utilized in this study proved highly sensitive and specific for HPV-DNA detection and genotyping in urine samples. These data suggest that a urine-based assay would be a suitable and effective tool for epidemiological surveillance and, most of all, screening programs. PMID- 23097251 TI - Predicting three-dimensional patellofemoral kinematics from static imaging-based alignment measures. AB - Patellofemoral pain syndrome causes significant discomfort and disability among much of the general population. Despite recent breakthroughs in dynamic three dimensional imaging technologies to assess pathological patellofemoral motion, such tools remain costly for clinical diagnostics applications. Thus, this study investigated whether three-dimensional patellofemoral kinematics could be predicted from routine two-dimensional static measures of patellofemoral joint alignment quantified from magnetic resonance imaging (MRI) data acquired in full knee extension. Twenty-six volunteers clinically diagnosed with patellofemoral pain (19 F/7 M, 25.9 +/- 11.1 years) and 26 control subjects (19 F/7 M, 25.3 +/- 7.7 years) were included in this IRB-approved study. Static three-dimensional sagittal T1-weighted gradient recall echo and dynamic MRI scans were acquired. For the dynamic image acquisition, subjects cyclically flexed and extended their knee (at 30 cycles/min) while a full cine-phase contrast MRI set (24 time frames of anatomic images and x-, y-, and z-velocity images) was acquired. From these data, static measures of patellofemoral alignment and three-dimensional patellofemoral kinematics were derived. Single and multiple regressions between static and kinematic variables were evaluated. Although shown reliable, the static MRI measures could only partially predict patellofemoral kinematics, with r(2) -values ranging from 16% to 77%. This makes it imperitave that the current precise, accurate, 3D, dynamic imaging techniques be translated into clinical tools. PMID- 23097254 TI - Dual-source parallel RF transmission for diffusion-weighted imaging of the abdomen using different b values: image quality and apparent diffusion coefficient comparison with conventional single-source transmission. AB - PURPOSE: To prospectively and intraindividually evaluate what effects dual-source parallel radiofrequency (RF) transmission have on image quality and apparent diffusion coefficient (ADC) of abdomen diffusion-weighted imaging (DWI) using different b values, compared with the single-source RF transmission. MATERIALS AND METHODS: Eighteen healthy male volunteers were enrolled in this Health Insurance Portability and Accountability Act (HIPAA)-compliant Institutional Review Board (IRB)-approved study. Abdominal DWI was performed with dual-source and single-source RF transmission at 3.0 T using a series of b-value combinations: 0/100, 0/500, 0/800, and 0/100/800. RF field homogeneity, subjective image quality, and signal to noise ratio (SNR) of each abdominal organ were evaluated. ADC values were calculated for each abdominal organ. Wilcoxon test and repeated-measures analysis of variance was used to calculate statistical significance. RESULTS: The parallel RF transmission significantly improved homogeneity of the RF field (P = 0.0001-0.008) and subjective image quality (P < 0.0001) at each b value and also increased SNR. At lower and higher b value, the measured ADC of lateral left hepatic lobe and spleen between dual-source and single-source images were significantly different (P = 0.0001-0.047). At b = 0/500, there was no significant difference in ADC measurements between dual source and single-source RF transmission for abdominal organs, except a slight statistically significant difference for spleen (P = 0.047). CONCLUSION: Parallel RF transmission significantly improved the image quality and homogeneity of the RF field. The RF transmission had a significant influence on measured ADC of lateral left hepatic lobe and spleen. At b = 0/500 the influence was minimum for all abdominal organs. PMID- 23097253 TI - Norovirus GII.4 virus-like particles recognize galactosylceramides in domains of planar supported lipid bilayers. PMID- 23097255 TI - Soy food intake and risk of lung cancer: evidence from the Shanghai Women's Health Study and a meta-analysis. AB - The authors prospectively evaluated the association of soy food intake with lung cancer risk, overall and by tumor aggressiveness, and performed a meta-analysis of published data. Included in the analysis were 71,550 women recruited into the Shanghai Women's Health Study (Shanghai, China) in 1997-2000. Usual soy food intake was assessed at baseline and reassessed during follow-up through in-person interviews. During a mean follow-up period of 9.1 years, 370 incident lung cancer cases were identified; 340 patients were lifetime never smokers. After adjustment for potential confounders, soy food intake was inversely associated with subsequent risk of lung cancer (P(trend) = 0.004); the hazard ratio for the highest quintile of intake compared with the lowest was 0.63 (95% confidence interval: 0.44, 0.90). This inverse association appeared predominately among women with later age at menopause (P(interaction) = 0.01) and for aggressive lung cancer as defined by length of survival (<12 months vs. >=12 months; P(heterogeneity) = 0.057). Meta-analysis of 7 studies conducted among nonsmokers found a summary relative risk of 0.59 (95% confidence interval: 0.49, 0.71) for the highest categories of soy or isoflavone intake versus the lowest. This study suggests that soy food consumption may reduce lung cancer risk in nonsmoking women, particularly for aggressive tumors, and its effect may be modified by endogenous estrogens. PMID- 23097256 TI - Arsenic exposure, diabetes prevalence, and diabetes control in the Strong Heart Study. AB - This study evaluated the association of arsenic exposure, as measured in urine, with diabetes prevalence, glycated hemoglobin, and insulin resistance in American Indian adults from Arizona, Oklahoma, and North and South Dakota (1989-1991). We studied 3,925 men and women 45-74 years of age with available urine arsenic measures. Diabetes was defined as a fasting glucose level of 126 mg/dL or higher, a 2-hour glucose level of 200 mg/dL or higher, a hemoglobin A1c (HbA1c) of 6.5% or higher, or diabetes treatment. Median urine arsenic concentration was 14.1 ug/L (interquartile range, 7.9-24.2). Diabetes prevalence was 49.4%. After adjustment for sociodemographic factors, diabetes risk factors, and urine creatinine, the prevalence ratio of diabetes comparing the 75th versus 25th percentiles of total arsenic concentrations was 1.14 (95% confidence interval: 1.08, 1.21). The association between arsenic and diabetes was restricted to participants with poor diabetes control (HbA1c >=8%). Arsenic was positively associated with HbA1c levels in participants with diabetes. Arsenic was not associated with HbA1c or with insulin resistance (assessed by homeostatic model assessment to quantify insulin resistance) in participants without diabetes. Urine arsenic was associated with diabetes control in a population from rural communities in the United States with a high burden of diabetes. Prospective studies that evaluate the direction of the relation between poor diabetes control and arsenic exposure are needed. PMID- 23097258 TI - Obesity, assisted reproductive technology, and early preterm birth--Florida, 2004 2006. AB - Florida resident birth certificates for 2004-2006 were linked to the Centers for Disease Control and Prevention's National ART Surveillance System and were used to investigate 1) whether the association of assisted reproductive technology (ART) with preterm birth varies by prepregnancy body mass index and 2) whether the association varies by plurality. Preterm birth was defined as early preterm birth (gestation <34 weeks) and late preterm birth (gestation 34-36 weeks). Descriptive statistics and multinomial logistic regression were used to explore maternal and infant differences by ART status and plurality. Of 581,403 women included in the study, 24.0% were overweight, 18.6% were obese, 7.3% had late preterm birth, 2.6% had early preterm birth, and 0.67% conceived through ART. Among singleton births, ART was associated with increased early preterm birth risk among underweight (odds ratio (OR) = 2.94, 95% confidence interval (CI): 1.27, 6.81), overweight (OR = 1.75, 95% CI: 1.12, 2.72), and obese (OR = 2.37, 95% CI: 1.51, 3.71) women. Among twins, ART was significantly associated with increased risk among overweight (OR = 1.61, 95% CI: 1.12, 2.32) and obese (OR = 1.85, 95% CI: 1.18, 2.90) women. Differences in the associations between ART and early preterm birth by body mass index and plurality warrant further investigation. PMID- 23097257 TI - Assessment of changes in risk behaviors during 3 years of posttrial follow-up of male circumcision trial participants uncircumcised at trial closure in Rakai, Uganda. AB - Risk compensation associated with male circumcision has been a concern for male circumcision scale-up programs. Using posttrial data collected during 2007-2011 on 2,137 male circumcision trial participants who were uncircumcised at trial closure in Rakai, Uganda, the authors evaluated their sexual behavioral changes during approximately 3 years' follow-up after trial closure. Eighty-one percent of the men self-selected for male circumcision during the period, and their sociodemographic and risk profiles were comparable to those of men remaining uncircumcised. Linear models for marginal probabilities of repeated outcomes estimate that 3.3% (P < 0.0001) of the male circumcision acceptors reduced their engagement in nonmarital relations, whereas there was no significant change among men remaining uncircumcised. Significant decreases in condom use occurred in both male circumcision acceptors (-9.2% with all partners and -7.0% with nonmarital partners) and nonacceptors (-12.4% and -13.5%, respectively), and these were predominantly among younger men. However, the magnitudes of decrease in condom use were not significantly different between the 2 groups. Additionally, significant decreases in sex-related alcohol consumption were observed in both groups (-7.8% in male circumcision acceptors and -6.1% in nonacceptors), mainly among older men. In summary, there was no evidence of risk compensation associated with male circumcision among this cohort of men during 3 years of posttrial follow-up. PMID- 23097259 TI - Population-based prospective study on the incidence of osteoporosis-associated fractures in a German population of 200,413 inhabitants. AB - BACKGROUND: A limited body of data is available with regard to the incidence of osteoporotic fractures in Germany. Most of the data published thus far have been derived from hospital records or health insurance settlements. The aim of the present study was to prospectively register four types of fractures in an urban population. The data we obtained were compared with the results of retrospective analysis procedures in order to determine the differences and underlying errors. METHODS: An urban population of 200 413 residents was investigated prospectively with regard to osteoporosis-associated fractures over a period of 12 months. All fractures were recorded and confirmed on radiographs. The results of this analysis were compared with the data from the Statistical Bureau and the International Classification of Disease (ICD) registers of the hospitals. RESULTS: A total of 979 fractures occurred during the period of investigation. The most common type was the distal radius fracture (395; 197.1 per 100 000). The retrospective detected data of the Statistical Bureau were 31, 56% lower than the actual number of fractures. A retrospective analysis of fractures based on the ICD registers of the hospitals revealed an over-registration rate of 26.67%. CONCLUSIONS: Retrospective methods of fracture registration do not provide sufficiently reliable data. PMID- 23097260 TI - Health professionals' migration in emerging market economies: patterns, causes and possible solutions. AB - BACKGROUND: About a third of the countries affected by shortage of human resources for health are the emerging market economies (EMEs). The greatest shortage in absolute terms was found to be in India and Indonesia leading to health system crisis. This review identifies the patterns of migration of health workers, causes and possible solutions in these EMEs. METHODS: A qualitative synthesis approach based on the 'critical review' and 'realist review' approaches to the literature review was used. RESULTS: The patterns of migration of health professionals' in the EMEs have led to two types of discrepancies between health needs and healthcare workers: (i) within country (rural-urban, public-private or government healthcare sector-private sector) and (ii) across countries (south to north). Factors that influence migration include lack of employment opportunities, appropriate work environment and wages in EMEs, growing demand in high-income countries due to demographic transition, favourable country policies for financial remittances by migrant workers and medical education system of EMEs. A range of successful national and international initiatives to address health workforce migration were identified. CONCLUSIONS: Measures to control migration should be country specific and designed in accordance with the push and pull factors existing in the EMEs. PMID- 23097261 TI - Finding a single lanthanide ion through upconversion. AB - Beyond detection: Detection of a single lanthanide ion can be optically achieved by implementing a two-step upconversion process in YAG:Pr(3+) nanocrystals (see picture). PMID- 23097262 TI - Stem cells as promising therapeutic options for neurological disorders. AB - Due to the limitations of pharmacological and other current therapeutic strategies, stem cell therapies have emerged as promising options for treating many incurable neurologic diseases. A variety of stem cells including pluripotent stem cells (i.e., embryonic stem cells and induced pluripotent stem cells) and multipotent adult stem cells (i.e., fetal brain tissue, neural stem cells, and mesenchymal stem cells from various sources) have been explored as therapeutic options for treating many neurologic diseases, and it is becoming obvious that each type of stem cell has pros and cons as a source for cell therapy. Wise selection of stem cells with regard to the nature and status of neurologic dysfunctions is required to achieve optimal therapeutic efficacy. To this aim, the stem cell-mediated therapeutic efforts on four major neurological diseases, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke, will be introduced, and current problems and future directions will be discussed. PMID- 23097263 TI - Level of the indication of biologic agents in the 2012 American College of Rheumatology recommendations for the treatment of rheumatoid arthritis: comment on the article by Singh et al. PMID- 23097264 TI - Lithium choreography: intramolecular arylations of carbamate-stabilised carbanions and their mechanisms probed by in situ IR spectroscopy and DFT calculations. AB - Deprotonation of O-allyl, O-propargyl or O-benzyl carbamates in the presence of a lithium counterion leads to carbamate-stabilised organolithium compounds that may be quenched with electrophiles. We now report that when the allylic, propargylic or benzylic carbamate bears an N-aryl substituent, an aryl migration takes place, leading to stereochemical inversion and C-arylation of the carbamate alpha to oxygen. The aryl migration is an intramolecular S(N) Ar reaction, despite the lack of anion-stabilising aryl substituents. Our in situ IR studies reveal a number of intermediates along the rearrangement pathway, including a "pre lithiation complex," the deprotonated carbamate, the rearranged anion, and the final arylated carbamate. No evidence was obtained for a dearomatised intermediate during the aryl migration. DFT calculations predict that during the reaction the solvated Li cation moves from the carbanion centre, thus freeing its lone pair for nucleophilic attack on the remote phenyl ring. This charge separation leads to several alternative conformations. The one having Li(+) bound to the carbamate oxygen gives rise to the lowest-energy transition structure, and also leads to inversion of the configuration. In agreement with the IR studies, the DFT calculations fail to locate a dearomatised intermediate. PMID- 23097266 TI - Are fetuses with isolated echogenic bowel at higher risk for an adverse pregnancy outcome? Experiences from a tertiary referral center. AB - OBJECTIVE: The purpose of this study was to determine the risk of poor perinatal outcome in normal karyotype second-trimester fetuses with the sonographic finding of isolated echogenic bowel. METHOD: Medical records, ultrasonographic findings and outcome details were reviewed for 97 cases of isolated fetal echogenic bowel, after excluding cases of aneuploidy and major congenital anomalies, and compared with a cohort of 400 fetuses without pathologic intra-abdominal findings. RESULTS: The incidence of echogenic bowel during the 14-year study period was 0.8%. Eighty (82.5%) pregnancies resulted in healthy, live-born infants. Congenital infection and cystic fibrosis was reported in 6.2% and 4.4%, respectively. The incidence of intrauterine growth restriction and intrauterine fetal demise was significantly higher in the group of isolated echogenic bowels compared with the control group (9.9% versus 1.3%, p <= 0.001; 8.9% versus 0.5% p <= 0.001). CONCLUSION: Echogenic bowel is a risk factor for an adverse pregnancy outcome, even in normal karyotype fetuses without congenital anomalies. This information should be considered when counseling patients after midtrimester echogenic bowel is diagnosed. PMID- 23097265 TI - Long-term follow-up of haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for the treatment of leukemia: nine years of experience at a single center. AB - BACKGROUND: Many patients who require allogeneic hematopoietic stem cell transplantation (allo-HSCT) lack a human leukocyte antigen (HLA)-matched donor. Recently, a new strategy was developed for HLA-mismatched/haploidentical transplantation from family donors without in vitro T cell depletion (TCD). METHODS: Over the past 9 years, 756 patients underwent haploidentical transplantation using a protocol developed by the authors, which combines granulocyte-colony stimulating factor-primed bone marrow (G-BM) and peripheral blood stem cells without in vitro TCD. The long-term outcome with this treatment modality was reported, and a risk-factor analysis was provided. RESULTS: Of these patients, 752 (99%) achieved sustained, full donor chimerism. The incidence of grades 2 through 4 acute graft-versus-host disease (GVHD) was 43%, and the 2-year cumulative incidence of total chronic GVHD was 53%. The 3-year cumulative incidence of nonrelapse mortality was 18%. The 2-year cumulative incidences of relapse were 15% and 26% in the standard-risk and high-risk groups, respectively. Of the 756 patients, 480 survived throughout the follow-up period of 1154 days (range: 335-3511 days) with the 3-year leukemia-free survival rates of 68% and 49% in the standard-risk and high-risk groups, respectively. Lower leukemia-free survival was associated with high-risk disease status (P = .001), chronic myelogenous leukemia disease type (P = .004), neutrophil engraftment beyond 13 days after transplant (P = .012), and the occurrence of grades 2 through 4 acute GVHD (P = .019). CONCLUSIONS: The results from the authors' 9-year experience showed that G-BM combined with peripheral blood stem cells from haploidentical donors, without in vitro TCD, is a reliable source of stem cells for transplantation by using the protocol developed by the authors. PMID- 23097267 TI - Consumption of artificial sweetener- and sugar-containing soda and risk of lymphoma and leukemia in men and women. AB - BACKGROUND: Despite safety reports of the artificial sweetener aspartame, health related concerns remain. OBJECTIVE: We prospectively evaluated whether the consumption of aspartame- and sugar-containing soda is associated with risk of hematopoetic cancers. DESIGN: We repeatedly assessed diet in the Nurses' Health Study (NHS) and Health Professionals Follow-Up Study (HPFS). Over 22 y, we identified 1324 non-Hodgkin lymphomas (NHLs), 285 multiple myelomas, and 339 leukemias. We calculated incidence RRs and 95% CIs by using Cox proportional hazards models. RESULTS: When the 2 cohorts were combined, there was no significant association between soda intake and risks of NHL and multiple myeloma. However, in men, >=1 daily serving of diet soda increased risks of NHL (RR: 1.31; 95% CI: 1.01, 1.72) and multiple myeloma (RR: 2.02; 95% CI: 1.20, 3.40) in comparison with men who did not consume diet soda. We observed no increased risks of NHL and multiple myeloma in women. We also observed an unexpected elevated risk of NHL (RR: 1.66; 95% CI: 1.10, 2.51) with a higher consumption of regular, sugar-sweetened soda in men but not in women. In contrast, when sexes were analyzed separately with limited power, neither regular nor diet soda increased risk of leukemia but were associated with increased leukemia risk when data for men and women were combined (RR for consumption of >=1 serving of diet soda/d when the 2 cohorts were pooled: 1.42; 95% CI: 1.00, 2.02). CONCLUSION: Although our findings preserve the possibility of a detrimental effect of a constituent of diet soda, such as aspartame, on select cancers, the inconsistent sex effects and occurrence of an apparent cancer risk in individuals who consume regular soda do not permit the ruling out of chance as an explanation. PMID- 23097268 TI - Effects of energy-restricted high-protein, low-fat compared with standard protein, low-fat diets: a meta-analysis of randomized controlled trials. AB - BACKGROUND: It is currently unclear whether altering the carbohydrate-to-protein ratio of low-fat, energy-restricted diets augments weight loss and cardiometabolic risk markers. OBJECTIVE: The objective was to conduct a systematic review and meta-analysis of studies that compared energy-restricted, isocaloric, high-protein, low-fat (HP) diets with standard-protein, low-fat (SP) diets on weight loss, body composition, resting energy expenditure (REE), satiety and appetite, and cardiometabolic risk factors. DESIGN: Systematic searches were conducted by using MEDLINE, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials to identify weight-loss trials that compared isocalorically prescribed diets matched for fat intake but that differed in protein and carbohydrate intakes in participants aged >=18 y. Twenty-four trials that included 1063 individuals satisfied the inclusion criteria. RESULTS: Mean (+/-SD) diet duration was 12.1 +/- 9.3 wk. Compared with an SP diet, an HP diet produced more favorable changes in weighted mean differences for reductions in body weight (-0.79 kg; 95% CI: -1.50, -0.08 kg), fat mass (FM; -0.87 kg; 95% CI: -1.26, -0.48 kg), and triglycerides (-0.23 mmol/L; 95% CI: -0.33, -0.12 mmol/L) and mitigation of reductions in fat-free mass (FFM; 0.43 kg; 95% CI: 0.09, 0.78 kg) and REE (595.5 kJ/d; 95% CI: 67.0, 1124.1 kJ/d). Changes in fasting plasma glucose, fasting insulin, blood pressure, and total, LDL, and HDL cholesterol were similar across dietary treatments (P >= 0.20). Greater satiety with HP was reported in 3 of 5 studies. CONCLUSION: Compared with an energy-restricted SP diet, an isocalorically prescribed HP diet provides modest benefits for reductions in body weight, FM, and triglycerides and for mitigating reductions in FFM and REE. PMID- 23097269 TI - Appropriateness of the probability approach with a nutrient status biomarker to assess population inadequacy: a study using vitamin D. AB - BACKGROUND: There are questions about the appropriate method for the accurate estimation of the population prevalence of nutrient inadequacy on the basis of a biomarker of nutrient status (BNS). OBJECTIVE: We determined the applicability of a statistical probability method to a BNS, specifically serum 25-hydroxyvitamin D [25(OH)D]. The ability to meet required statistical assumptions was the central focus. DESIGN: Data on serum 25(OH)D concentrations in adults aged 19-70 y from the 2005-2006 NHANES were used (n = 3871). An Institute of Medicine report provided reference values. We analyzed key assumptions of symmetry, differences in variance, and the independence of distributions. We also corrected observed distributions for within-person variability (WPV). Estimates of vitamin D inadequacy were determined. RESULTS: We showed that the BNS [serum 25(OH)D] met the criteria to use the method for the estimation of the prevalence of inadequacy. The difference between observations corrected compared with uncorrected for WPV was small for serum 25(OH)D but, nonetheless, showed enhanced accuracy because of correction. The method estimated a 19% prevalence of inadequacy in this sample, whereas misclassification inherent in the use of the more traditional 97.5th percentile high-end cutoff inflated the prevalence of inadequacy (36%). CONCLUSIONS: When the prevalence of nutrient inadequacy for a population is estimated by using serum 25(OH)D as an example of a BNS, a statistical probability method is appropriate and more accurate in comparison with a high-end cutoff. Contrary to a common misunderstanding, the method does not overlook segments of the population. The accuracy of population estimates of inadequacy is enhanced by the correction of observed measures for WPV. PMID- 23097271 TI - Association of food form with self-reported 24-h energy intake and meal patterns in US adults: NHANES 2003-2008. AB - BACKGROUND: Laboratory studies suggest that food form (beverages compared with solid foods) evokes behavioral and physiologic responses that modify short-term appetite and food intake. Beverage energy may be less satiating and poorly compensated, which leads to higher energy intake. OBJECTIVE: We examined associations between 24-h energy consumed in beverages and a variety of meal and dietary attributes to quantify the contribution of beverage consumption to the energy content of diets in free-living individuals consuming their self-selected diets. DESIGN: We used dietary recall data for adults (n = 13,704) in NHANES 2003 2008 to examine the multiple covariate-adjusted associations between 24-h energy from beverages and nonbeverages and associations between beverage intake, eating behaviors, and the energy density of beverage and nonbeverage foods. RESULTS: In the highest tertile of 24-h beverage energy intake, beverages provided >30% of energy. Total 24-h energy and nonbeverage energy consumption and energy density (kcal/g) of both beverage and nonbeverage foods increased with increasing energy from beverages (P < 0.0001). With increasing 24-h beverage energy consumption, the reported frequency of all, snack, and beverage-only ingestive episodes and length of the ingestive period increased, whereas the percentage of energy from main meals decreased (P < 0.0001). CONCLUSIONS: Higher 24-h beverage energy intake was related to higher energy intake from nonbeverage foods, quality of food selections, and distribution of 24-h energy into main meal and snack episodes. Moderation of beverage-only ingestive episodes and curtailing the length of the ingestion period may hold potential to lower uncompensated beverage energy consumption in the US population. PMID- 23097270 TI - Novel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study. AB - BACKGROUND: Complex interplays of diet and metabolism influence circulating fatty acids (FAs), possibly constituting FA patterns related to cardiovascular disease (CVD) risk. OBJECTIVES: We aimed to derive FA patterns from circulating FAs, relate the patterns to CVD incidence, and extend the derived patterns to atherosclerosis progression in another independent cohort. DESIGN: We used principal component analysis (PCA) to derive FA patterns from 38 plasma phospholipid FAs in 2972 older adults in the Cardiovascular Health Study (CHS). Identified patterns were evaluated for prospective associations with 14-y incidence of CVD [ischemic heart disease (IHD) or stroke]. In another independent cohort of postmenopausal women with IHD, we evaluated associations of the CHS derived patterns with 3.2-y progression of angiographically defined coronary atherosclerosis. RESULTS: Three distinct patterns were identified, characterized by higher proportions of trans FAs, de novo lipogenesis (DNL) FAs, and long-chain MUFAs (LCMUFAs). During 32,265 person-years, 780 incident CVD events occurred. The trans FA pattern was associated with higher CVD risk (multivariable-adjusted HR for the highest compared with the lowest quintiles = 1.58; 95% CI: 1.17, 2.12; P-trend = 0.006), primarily attributable to higher risk of stroke (HR: 2.46; 95% CI: 1.54, 3.92; P-trend = 0.005). The DNL and LCMUFA patterns were not associated with CVD incidence or with IHD or stroke (P-trend > 0.11 each). In the second cohort, the trans FA pattern, but not the other 2 patterns, was positively associated with progression of coronary atherosclerosis (P-trend < 0.05). CONCLUSIONS: PCA appears to provide informative circulating FA patterns. A pattern driven mainly by trans FA levels related to greater CVD risk in older adults and coronary atherosclerosis progression in women with IHD. PMID- 23097272 TI - Effects of iron and n-3 fatty acid supplementation, alone and in combination, on cognition in school children: a randomized, double-blind, placebo-controlled intervention in South Africa. AB - BACKGROUND: Little is known about the combined effects of iron and n-3 (omega-3) fatty acid (FA) supplementation on cognitive performance. The provision of either DHA/EPA or iron alone in rats with combined iron and n-3 FA deficiency has been reported to exacerbate cognitive deficits associated with deficiency. OBJECTIVE: We investigated the effects of iron and DHA/EPA supplementation, alone and in combination, in children with poor iron and n-3 FA status. DESIGN: In a 2-by-2 factorial trial, children with iron deficiency (ID) (n = 321; aged 6-11 y) were allocated to receive 1) iron (50 mg) plus DHA/EPA (420/80 mg), 2) iron plus placebo, 3) placebo plus a mixture of DHA and EPA (DHA/EPA), or 4) placebo plus placebo as oral supplements (4/wk) for 8.5 mo. Cognition was assessed at baseline and endpoint by using the Hopkins Verbal Learning Test (HVLT) and subscales of the Kaufman Assessment Battery for Children. RESULTS: Both iron and DHA/EPA significantly increased weight-for-age z scores. Iron increased the number of words recalled at HVLT recall 2 (intervention effect: 0.90; 95% CI: 0.18, 1.62), and in anemic children, iron increased scores in the Atlantis Delayed test (1.51; 95% CI: 0.03, 2.99) and HVLT recall 2 (2.02; 95% CI: 0.55, 3.49). DHA/EPA showed no benefit in any of the cognitive tests but decreased Atlantis test scores ( 2.48; 95% CI: -3.99, -0.96) in children who were anemic at baseline and decreased Atlantis delayed scores (-0.9; 95% CI: -1.45, -0.36) in girls with ID, whereas boys tended to perform better. CONCLUSIONS: In children with poor iron and n-3 FA status, iron supplementation improved verbal and nonverbal learning and memory, particularly in children with anemia. In contrast, DHA/EPA supplementation had no benefits on cognition and impaired working memory in anemic children and long term memory and retrieval in girls with ID. PMID- 23097273 TI - Brain connectivity abnormalities extend beyond the sensorimotor network in peripheral neuropathy. AB - OBJECTIVES: To investigate, using resting state (RS) functional connectivity (FC), the selectivity of involvement of the sensorimotor network in patients with acquired (A) and with hereditary (H) peripheral neuropathies (PN) and the correlations of RS FC abnormalities with clinical impairment and structural brain damage. Temporal associations among RS networks were also explored. EXPERIMENTAL DESIGN: RS fMRI scans were acquired from 13 APN, 12 HPN, and 18 age- and sex matched healthy controls. Independent component analysis and functional network connectivity were used to investigate RS FC within and among RS networks with potential functional relevance. PRINCIPAL OBSERVATIONS: Compared to controls, patients had a decreased FC of the right precentral gyrus and an increased RS FC of the precuneus within the sensorimotor network. Both decreased and increased RS FC also involved the visual and auditory networks, which additionally had an increased coherence of function with the sensorimotor network (more pronounced in HPN). RS FC modifications in patients extended to several cognitive networks and were correlated with disease duration. In APN, they were also correlated with the severity of clinical impairment and corpus callosum atrophy. CONCLUSIONS: In PN, RS FC modifications extend beyond the sensorimotor network and involve other sensory and cognitive networks. The correlations between RS FC patterns and disease duration in patients as well as with clinical impairment in patients with APN suggest that modifications of FC might reflect an adaptive mechanism, which takes time to occur and helps to limit the clinical consequences of peripheral damage. PMID- 23097274 TI - The stem cell E3-ligase Lin-41 promotes liver cancer progression through inhibition of microRNA-mediated gene silencing. AB - Lin-41 is a stem cell-specific E3 ligase and a known target of the tumour suppressor microRNA (miRNA) let-7. Lin-41 was recently reported to mediate ubiquitylation and degradation of the miRNA pathway protein Ago2. We demonstrate that Lin-41 is over-expressed in hepatocellular carcinoma (HCC). Lin-41 over expression correlates with high alpha-fetoprotein level, high tumour grade and high tumour stage and predicts early tumour recurrence. Lin-41 is a strong predictor of poor long-term survival for patients with HCC. Lin-41 knock-down by RNA interference in HCC cell lines Huh7 and Hep3B suppressed proliferation in vitro and reduced in vivo tumour growth in NOD/SCID mice. On the other hand, over expression of Lin-41 in the HCC cell line SK-Hep1 enhanced tumourigenicity. Over expression and knock-down of Lin-41 led to inverse changes in the levels of Ago1 and Ago2 proteins. Over-expression of Ago1 and Ago2 reduced in vivo tumour growth. Lin-41 over-expression suppressed let-7 activity in HCC cell lines and expression of Lin-41 enhanced the expression of let-7-regulated oncogenes c-Myc, Lin-28B, HMGA2 and type 1 insulin-like growth factor receptor (IGF1R). Expression of Lin-28B and c-Myc enhanced the expression of Lin-41. Chromatin immunoprecipitation and reporter assays revealed direct association of c-Myc with the Lin-41 promoter, resulting in transcriptional transactivation. Our results indicate that Lin-41 plays an important role in the growth of HCC by regulating RISC complex proteins Ago1 and Ago2 to inhibit miRNA-mediated gene silencing and promote the expression of oncogenic proteins. Lin-41 is also a strong prognostic factor for patients with HCC. PMID- 23097275 TI - Human metapneumovirus associated with community-acquired pneumonia in children in Beijing, China. AB - Community-acquired pneumonia is a major cause of morbidity and mortality in children worldwide. However, few studies have been conducted on the infection of human metapneumovirus (hMPV) associated with pediatric community-acquired pneumonia in China. Nasopharyngeal aspirates were collected between July 2008 and June 2010 from 1,028 children, aged <=16.5 years, who were diagnosed with community-acquired pneumonia in Beijing, China. Reverse-transcriptase polymerase chain reaction was used to screen the samples for hMPV and common respiratory viruses. hMPV was detected in 6.3% of the patients with community-acquired pneumonia. This detection rate is the third highest for a respiratory virus in children with community-acquired pneumonia, after that of rhinovirus (30.9%) and respiratory syncytial virus (30.7%). The detection rate of hMPV in 2008/2009 (42/540, 7.8%) was significantly higher than in 2009/2010 (23/488, 4.7%; chi(2) = 4.065, P = 0.044). The hMPV subtypes A2, B1, and B2 were found to co-circulate, with A2 being most prevalent. These results indicate that hMPV plays a substantial role in pediatric community-acquired pneumonia in China. Overall, these findings provide a better understanding of the epidemiological and clinical features of hMPV infections. PMID- 23097278 TI - Arterial enhancing-only nodules less than 2 cm in diameter in patients with liver cirrhosis: predictors of hepatocellular carcinoma diagnosis on gadobenate dimeglumine-enhanced MR imaging. AB - PURPOSE: To assess whether gadobenate dimeglumine (Gd-BOPTA)-enhanced MR imaging could predict hepatocellular carcinoma (HCC) diagnosis in small arterial enhancing-only nodules detected by contrast-enhanced computed tomography (CT) in patients with liver cirrhosis. MATERIALS AND METHODS: We prospectively recruited 125 cirrhotic patients (67 males, and 58 females; age: 68 +/- 12.36 years) with 151 small (<2 cm in diameter) arterial enhancing-only nodules identified by contrast-enhanced CT. All patients were scanned by MR imaging before and after Gd BOPTA injection during the hepatic arterial phase (HAP), portal venous phase (PVP), equilibrium phase (EP), and hepatobiliary phase (HP). Nodule characterization was based on reference imaging criteria (n = 29 nodules), follow up (n = 105), or histology (n = 17). Two radiologists (5 and 10 years experience) analyzed the MR images, and logistic regression was conducted to assess how well MR imaging findings could predict HCC diagnosis. RESULTS: Final diagnoses included 115 benign nodules and 36 HCCs. Nodule T2 hyperintensity, T1 hypointensity, PVP-EP hypointensity, and HP hypointensity were the best predictors of HCC on univariate analysis. Nodule T2 hyperintensity, T1 hypointensity, and HP hypointensity, were independent predictors of HCC on multivariate analysis. CONCLUSION: Gd-BOPTA-enhanced MR imaging provides imaging findings which may predict a diagnosis of HCC in small arterial enhancing-only nodules in cirrhotic patients. PMID- 23097279 TI - An orthopedic tissue adhesive for targeted delivery of intraoperative biologics. AB - Tissue adhesives can bind together damaged tissues and serve as tools to deliver and localize therapeutics to facilitate regeneration. One emerging therapeutic trend in orthopedics is the use of intraoperative biologics (IOB), such as bone marrow (BM) and platelet-rich plasma (PRP), to stimulate healing. Here, we introduce the application of the biomaterial chondroitin sulfate succinimidyl succinate (CS-NHS) to deliver IOB in a hydrogel adhesive. We demonstrate the biomaterial's ability to bind various tissue types and its cellular biocompatibility with encapsulated human mesenchymal stem cells (hMSCs). Further, we examine in detail the CS-NHS adhesive combined with BM aspirate for use in bone applications. hMSCs were encapsulated in CS-BM and cultured for 5 weeks in osteogenic medium. Quantitative RT-PCR demonstrated osteogenesis via upregulation of the osteogenic transcription factor Runx2 and bone markers alkaline phosphatase and osteocalcin. Significant deposition of calcium and osteocalcin was detected using biochemical, histological, and immunohistochemical techniques. Shear testing demonstrated that the CS-BM adhesive exhibited an adhesive strength approximately an order of magnitude stronger than fibrin glue and approaching that of a cyanoacrylate adhesive. These results indicate that CS-NHS is a promising delivery tool for IOB in orthopedic applications requiring a strong, degradable, and biocompatible adhesive that supports bone growth. PMID- 23097280 TI - Measuring illness behavior in patients with systemic sclerosis. AB - OBJECTIVE: Illness behaviors (cognitive, affective, and behavioral reactions) among individuals with systemic sclerosis (SSc; scleroderma) are of clinical concern due to relationships between these behaviors and physical and mental quality of life, such as pain and symptoms of depression. Self-report measures with good psychometric properties can aid in the accurate assessment of illness behavior. The Illness Behavior Questionnaire (IBQ) was designed to measure abnormal illness behaviors; however, despite its longstanding use, there is disagreement regarding its subscales. The goal of the present study was to evaluate the validity of the IBQ in a cohort of patients with SSc. METHODS: Patients with SSc (n = 278) completed the IBQ at enrollment into the Genetics Versus Environment in Scleroderma Outcome Study. Structural validity of previously derived factor solutions was investigated using confirmatory factor analysis. Exploratory factor analysis was utilized to derive SSc-specific subscales. RESULTS: None of the previously derived structural models were supported for SSc patients. Exploratory factor analysis supported an SSc-specific factor structure with 5 subscales. Validity analyses suggested that the subscales were generally independent of disease severity, but were correlated with other health outcomes (i.e., fatigue, pain, disability, social support, and mental health). CONCLUSION: The proposed subscales are recommended for use in SSc, and can be utilized to capture illness behavior that may be of clinical concern. PMID- 23097282 TI - Ligand- and pH-induced conformational changes of RNA domain helix 69 revealed by 2-aminopurine fluorescence. PMID- 23097281 TI - Development of Zn-ProPhenol-catalyzed asymmetric alkyne addition: synthesis of chiral propargylic alcohols. AB - The development of a general and practical zinc-catalyzed enantioselective alkyne addition methodology is reported. The commercially available ProPhenol ligand (1) has facilitated the addition of a wide range of zinc alkynylides to aryl, aliphatic, and alpha,beta-unsaturated aldehydes in high yield and enantioselectivity. New insights into the mechanism of this reaction have resulted in a significant reduction in reagent stoichiometry, enabling the use of precious alkynes and avoiding the use of excess dimethylzinc. The enantioenriched propargylic alcohols from this reaction serve as versatile synthetic intermediates and have enabled efficient syntheses of several complex natural products. PMID- 23097283 TI - The intravascular stent and the future of device technology. PMID- 23097284 TI - Impending savior: Impella 2.5 circulatory support system in high-risk PCI. PMID- 23097285 TI - The age of generativity, or forever jung. PMID- 23097286 TI - Intracoronary EKG assessment: getting the right data in the nick of time. PMID- 23097287 TI - Statin pleiotropy in acute myocardial infarction--is it about timing? PMID- 23097288 TI - Coronary angiography is not picture perfect for determining perioperative MI pathophysiology. PMID- 23097289 TI - Mitral regurgitation in acute ST segment myocardial infarction: it still matters. PMID- 23097290 TI - Bioresorbable polymers: a temporary solution? PMID- 23097291 TI - Subintimal space: the final frontier? PMID- 23097292 TI - Those who run away...may not need to fight another day. PMID- 23097293 TI - Does the "cold" laser simply need a cover up? PMID- 23097294 TI - Clipping the neck of pseudoaneurysm. PMID- 23097295 TI - Irrelevant vessel or ischemic culprit? Rethinking the importance of the inferior mesenteric artery. PMID- 23097296 TI - Mechanisms underlying the inhibition of murine sperm capacitation by the seminal protein, SPINKL. AB - SPINKL, a serine protease inhibitor kazal-type-like protein initially found in mouse seminal vesicle secretions, possesses structurally conserved six-cysteine residues of the kazal-type serine protease inhibitor family. However, it has no inhibitory activity against serine proteases. Previously, it was found to have the ability to suppress murine sperm capacitation in vitro. Herein, we investigated the mechanisms underlying the suppressive effect of SPINKL on sperm capacitation. Three in vitro capacitation-enhancing agents, including bovine serum albumin (BSA), methyl-beta-cyclodextrin (MBCD), and dibutyryl cyclic AMP (dbcAMP), coupled with 3-isobutyl-1-methylxanthine (IBMX), were used to evaluate the influence of SPINKL on capacitation signaling. Preincubation of sperm with SPINKL suppressed BSA- and MBCD-induced sperm capacitation by blocking three upstream signals of capacitation that is the cholesterol efflux from sperm plasma membranes, extracellular calcium ion influx into sperm, and increases in intracellular cAMP. Moreover, SPINKL also inhibited downstream signal transduction of capacitation since it suppressed dbcAMP/IBMX and N(6) -phenyl cAMP (6-Phe-cAMP)-activated cAMP-dependent protein kinase-associated protein tyrosine phosphorylation. Such inhibition is probably mediated by attenuation of SRC tyrosine kinase activity. Furthermore, SPINKL could not reverse capacitation once sperm had been capacitated by capacitation-enhancing agents or capacitated in vivo in the oviduct. SPINKL bound to sperm existed in the uterus but had disappeared from sperm in the oviduct during the sperm's transit through the female reproductive tract. Therefore, SPINKL may serve as an uncapacitation factor in the uterus to prevent sperm from precocious capacitation and the subsequent acrosome reaction and thus preserve the fertilization ability of sperm. PMID- 23097297 TI - Identification of brain-targeted bioactive dietary quercetin-3-O-glucuronide as a novel intervention for Alzheimer's disease. AB - Epidemiological and preclinical studies indicate that polyphenol intake from moderate consumption of red wines may lower the relative risk for developing Alzheimer's disease (AD) dementia. There is limited information regarding the specific biological activities and cellular and molecular mechanisms by which wine polyphenolic components might modulate AD. We assessed accumulations of polyphenols in the rat brain following oral dosage with a Cabernet Sauvignon red wine and tested brain-targeted polyphenols for potential beneficial AD disease modifying activities. We identified accumulations of select polyphenolic metabolites in the brain. We demonstrated that, in comparison to vehicle-control treatment, one of the brain-targeted polyphenol metabolites, quercetin-3-O glucuronide, significantly reduced the generation of beta-amyloid (Abeta) peptides by primary neuron cultures generated from the Tg2576 AD mouse model. Another brain-targeted metabolite, malvidin-3-O-glucoside, had no detectable effect on Abeta generation. Moreover, in an in vitro analysis using the photo induced cross-linking of unmodified proteins (PICUP) technique, we found that quercetin-3-O-glucuronide is also capable of interfering with the initial protein protein interaction of Abeta(1-40) and Abeta(1-42) that is necessary for the formation of neurotoxic oligomeric Abeta species. Lastly, we found that quercetin 3-O-glucuronide treatment, compared to vehicle-control treatment, significantly improved AD-type deficits in hippocampal formation basal synaptic transmission and long-term potentiation, possibly through mechanisms involving the activation of the c-Jun N-terminal kinases and the mitogen-activated protein kinase signaling pathways. Brain-targeted quercetin-3-O-glucuronide may simultaneously modulate multiple independent AD disease-modifying mechanisms and, as such, may contribute to the benefits of dietary supplementation with red wines as an effective intervention for AD. PMID- 23097298 TI - Factors associated with the clinical outcomes of the osteochondral autograft transfer system in osteochondral lesions of the talus: second-look arthroscopic evaluation. AB - BACKGROUND: Identifying factors associated with the clinical outcomes of the osteochondral autograft transfer system would be helpful for treating patients with an osteochondral lesion of the talus. PURPOSE: To investigate the clinical and second-look arthroscopic results of the osteochondral autograft transfer system and to identify the prognostic factors associated with this procedure. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The authors retrospectively evaluated 52 ankles that underwent osteochondral autograft transfer for a medial osteochondral lesion of the talus. Second-look arthroscopies were performed at a mean of 13.1 months postoperatively. Clinical outcomes were evaluated according to a visual analog scale (VAS) for pain, American Orthopaedic Foot and Ankle Society (AOFAS) score, and the Tegner activity scale. Statistical analyses were performed to identify various prognostic factors associated with the clinical outcomes. RESULTS: The mean VAS, AOFAS, and Tegner activity scale scores were all significantly improved from 6.9 +/- 0.9 to 3.3 +/- 1.4 (VAS), from 67.4 +/- 4.9 to 82.6 +/- 7.8 (AOFAS), and from 3.0 +/- 0.8 to 3.9 +/- 0.9 (Tegner; P < .05). Regarding overall patient satisfaction with the operation, 49 (95%) patients reported good to excellent results. Prognostic factors including the patient's age, sex, body mass index, duration of symptoms, defect size and depth, location of osteochondral lesion of the talus, and the existence of a subchondral cyst did not significantly influence clinical outcomes (P > .05), except for body mass index on the Tegner activity scale score (P = .021). Significant differences were observed among clinical outcomes for second-look arthroscopy according to the presence of soft tissue impingement and uncovered areas around the graft (P < .05). The VAS and AOFAS score at the last follow-up were significantly worse when the articular surface of the tibial plafond at the malleolar osteotomy site was uneven (P = .031 and .012, respectively). CONCLUSION: This study showed that the articular surface of the tibial plafond at the malleolar osteotomy site, soft tissue impingement, and uncovered areas around the graft were important factors affecting the clinical outcomes, as observed through second-look arthroscopy. Therefore, surgeons should restore the articular surface accurately after the osteotomy, and more caution should be taken to avoid soft tissue impingement and uncovered areas around the graft when performing osteochondral autograft transfer. PMID- 23097299 TI - Wortmannin efficiently suppresses the recovery from radiation-induced damage in pimonidazole-unlabeled quiescent tumor cell population. AB - Labeling of proliferating (P) cells in mice bearing EL4 tumors was achieved by continuous administration of 5-bromo-2'-deoxyuridine (BrdU). Tumors were irradiated with gamma-rays at 1 h after pimonidazole administration followed by caffeine or wortmannin treatment. Twenty-four hours later, assessment of the responses of quiescent (Q) and total (= P + Q) cell populations were based on the frequencies of micronucleation and apoptosis using immunofluorescence staining for BrdU. The response of the pimonidazole-unlabeled tumor cell fractions was assessed by means of apoptosis frequency using immunofluorescence staining for pimonidazole. The pimonidazole-unlabeled cell fraction showed significantly enhanced radio-sensitivity compared with the whole cell fraction more remarkably in Q cells than total cells. However, a significantly greater decrease in radio sensitivity in the pimonidazole-unlabeled than the whole cell fraction, evaluated using an assay performed 24 hours after irradiation, was more clearly observed in Q cells than total cells. In both the pimonidazole-unlabeled and the whole cell fractions, wortmannin efficiently suppressed the reduction in sensitivity due to delayed assay. Wortmannin combined with gamma-ray irradiation is useful for suppressing the recovery from radiation-induced damage especially in the pimonidazole-unlabeled cell fraction within the total and Q tumor cell populations. PMID- 23097301 TI - Association between human parainfluenza virus type 1 and smoking history in patients with an abdominal aortic aneurysm. AB - Several studies have suggested that infectious agents may induce the development of abdominal aortic aneurysms and/or accelerate their progression. The aim of this study was to evaluate the presence of the respiratory-transmitted viruses such as influenza A and B and parainfluenza type 1 genomes in bioptic fragments of abdominal aortic aneurysms. Furthermore, the association between viral infection and traditional risk factors for aneurysms was investigated employing multivariate logistic regression models. The genome of parainfluenza 1 was detected in 11 out of 57 patients with abdominal aortic aneurysm, influenza A only in one, whereas none of the specimens analyzed resulted positive for influenza B. After adjustment of age, gender, and clinical diagnosis, being current smokers was associated independently with parainfluenza 1 detection in aneurysms. The identification of parainfluenza 1 in aortic aneurysm biopsies supports previous observations of a possible role of viruses in the lesion development. Smoking, by interfering with the respiratory tract's ability to defend itself and predisposing to upper and lower respiratory tract infections may accelerate the onset and progression of abdominal aortic aneurysms. PMID- 23097300 TI - The human amygdala and pain: evidence from neuroimaging. AB - The amygdala, a small deep brain structure involved in behavioral processing through interactions with other brain regions, has garnered increased attention in recent years in relation to pain processing. As pain is a multidimensional experience that encompasses physical sensation, affect, and cognition, the amygdala is well suited to play a part in this process. Multiple neuroimaging studies of pain in humans have reported activation in the amygdala. Here, we summarize these studies by performing a coordinate-based meta-analysis within experimentally induced and clinical pain studies using an activation likelihood estimate analysis. The results are presented in relation to locations of peak activation within and outside of amygdala subregions. The majority of studies identified coordinates consistent with human amygdala cytoarchitecture indicating reproducibility in neuroanatomical labeling across labs, analysis methods, and imaging modalities. Differences were noted between healthy and clinical pain studies: in clinical pain studies, peak activation was located in the laterobasal region, suggestive of the cognitive-affective overlay present among individuals suffering from chronic pain; while the less understood superficial region of the amygdala was prominent among experimental pain studies. Taken together, these findings suggest several important directions for further research exploring the amygdala's role in pain processing. PMID- 23097302 TI - Ferumoxytol in clinical practice: implications for MRI. AB - Ferumoxytol is an iron-containing parenteral treatment for iron deficiency anemia that was recently approved by the Food and Drug Administration. The iron is in the form of a superparamagnetic iron oxide that causes T1, T2, and T2* shortening on magnetic resonance imaging (MRI). Furthermore, the drug has a long intravascular half-life of 14-15 hours; a standard dose can affect MRI for days to months. We describe a case in which a patient underwent contrast-enhanced MRI of the liver 2 days after receiving a dose of ferumoxytol, which was unknown to the radiology team. The blood pool and soft tissues were hyperintense on T1 weighted images, concealing enhancement from the gadolinium-based contrast agent that was administered during the exam and rendering the exam nondiagnostic. Radiologists must be aware of this potential effect in screening patients for MRI and interpreting exams. PMID- 23097303 TI - Need for online information and support of patients with systemic sclerosis. AB - OBJECTIVE: Interactive health communication applications (IHCAs) offer interesting possibilities to support systemic sclerosis (SSc) patients, since SSc is an uncommon, severe disease that needs a multidisciplinary treatment. This study aimed to investigate patients' needs for a hospital-based IHCA. METHODS: A survey study was conducted among a large sample (n = 429) of SSc patients of the University Medical Centre St. Radboud in Nijmegen, The Netherlands. Patients were asked about their current disease-related internet use, their perceived importance of diverse information topics, and their usefulness of 8 widely used online health services. To examine how disease specific their needs were, the results of SSc patients were compared with the results of a sample of rheumatoid arthritis (RA) patients (n = 1,284). RESULTS: In total, 746 patients (44% of the approached patients) returned a completed questionnaire and fulfilled all of the inclusion criteria. Of them, 569 (76%) had internet access. SSc patients used the internet especially for information (85%), and they expressed a need for information on physical, psychological, and social consequences of the disease. Concerning a hospital-based IHCA, e-consults, information about disease and treatment, and home access to their electronic medical records were perceived as most useful. SSc patients were more positive about the usefulness of the online applications than were RA patients, especially for e-consults and peer support forums. CONCLUSION: It would be valuable to offer SSc patients a hospital-based IHCA, including the online information and support they desire. When taking the needs of patients into account, an IHCA could become a valuable addition to their regular treatment. PMID- 23097304 TI - Assembly of graphene nanosheets and SiO2 nanoparticles towards transparent, antireflective, conductive, and superhydrophilic multifunctional hybrid films. AB - A new approach for the fabrication of transparent, antireflective, conductive and superhydrophilic multifunctional hybrid films through the layer-by-layer (LbL) assembly of reduced graphene oxide (RGO) nanosheets and SiO(2) nanoparticles is reported. The RGO nanosheets, SiO(2) nanoparticles and films were characterized by means of transmission electron microscopy, UV/Vis absorption spectrophotometry, Raman spectroscopy, atomic force microscopy, contact angle/interface system, and a four-point probe. It was found that the graphene/SiO(2) hybrid films exhibited a significant increase in transmittance as compared with RGO films. The optical, electronic and wetting properties of hybrid films could be manipulated by rational design of the film structure and variation of the cycle number of the LbL assembly. The obtained transparent, conductive, and superhydrophilic graphene/SiO(2) hybrid films showed excellent antireflective, antistatic, and antifogging behaviors. The remarkable performance could be attributed to the combination of electrical conductivity of RGO nanosheets and superhydrophilic antireflective surface derived from SiO(2) nanoparticles. PMID- 23097305 TI - Vinyl and alkynyl azides: well-known intermediates in the focus of modern synthetic methods. PMID- 23097306 TI - Spodoptera frugiperda FKBP-46 is a consensus p53 motif binding protein. AB - p53 protein, the central molecule of the apoptosis pathway, is mutated in 50% of the human cancers. Of late, p53 homologues have been identified from different invertebrates including Drosophila melanogaster, Caenorhabditis elegans, Squid, and Clams. We report the identification of a p53-like protein in Spodoptera frugiperda (Sf9) insect cells, which is activated during oxidative stress, caused by exposure to UV-B or H(2) O(2) , and binds to p53 consensus DNA binding motifs as well as other p53 cognate motifs. Sf9 p53 motif-binding protein is similar to murine and Drosophila p53 in terms of molecular size, which is around 50-60 kDa, as evident from UV cross-linking, and displays DNA binding characteristics similar to both insect and vertebrate p53 as seen from electrophoretic mobility shift assays. The N-terminal sequencing of the purified Sf9 p53 motif-binding protein reveals extensive homology to the pro-apoptotic FK-506 binding protein (FKBP-46), earlier identified in Sf9 cells as a factor which interacts with murine casein kinase. FKBP, an evolutionarily conserved protein of mammalian origin functions as a pro-apoptotic factor. Identification of FKBP-46 as a novel p53 motif-binding protein in insect cells adds a new facet to our understanding of the mechanisms of apoptosis under oxidative stress in the absence of a typical p53 homologue. PMID- 23097307 TI - Multimodality image fusion to guide peripheral artery chronic total arterial occlusion recanalization in a swine carotid artery occlusion model: unblinding the interventionalist. AB - OBJECTIVES: To demonstrate the feasibility of magnetic resonance imaging (MRI) to X-ray fluoroscopy (XRF) image fusion to guide peripheral artery chronic total occlusion (CTO) recanalization. BACKGROUND: Endovascular peripheral artery CTO revascularization is minimally invasive, but challenging, because the occlusion is poorly visualized under XRF. Devices may steer out of the artery, which can lead to severe perforation. Merging preacquired MRI of the CTO to the live XRF display may permit upfront use of aggressive devices and improve procedural outcomes. METHODS: Swine carotid artery CTOs were created using a balloon injury model. Up to 8 weeks later, MRI of the carotid arteries was acquired and segmented to create three-dimensional surface models, which were then registered onto live XRF. CTO recanalization was performed using incrementally aggressive CTO devices (group A) or an upfront aggressive directed laser approach (group B). Procedural success was defined as luminal or subintimal device position without severe perforation. RESULTS: In this swine model, MRI to XRF fusion guidance resulted in a procedural success of 57% in group A and 100% in group B, which compared favorably to 33% using XRF alone. Fluoroscopy time was significantly less for group B (8.5 +/- 2.6 min) compared to group A (48.7 +/- 23.9 min), P < 0.01. Contrast dose used was similar between groups A and B. CONCLUSIONS: MRI to XRF fusion-guided peripheral artery CTO recanalization is feasible. Multimodality image fusion may permit upfront use of aggressive CTO devices with improved procedural outcomes compared to XRF-guided procedures. PMID- 23097308 TI - Effect of storage time on haematological parameters in mullet, Mugil cephalus. AB - The aim of the present study was to assess the effect of storage time at +4 degrees C on red blood cell count (RBC), haematocrit (Hct), haemoglobin (Hb), white blood cell count (WBC), thrombocyte count (TC), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) in mullet (Mugil cephalus) using an automatic method. After blood collection (T0 ), all samples were analyzed using both the manual and automatic method. To test the validation of the automatic method, a paired t-test was applied, and no statistical difference was observed. The samples were successively divided into four different aliquots and stored at +4 degrees C to assess the haematological parameters using the automatic method. The first aliquot was refrigerated for 6 h, the second one for 24 h, the third one for 48 h and the last one at for 72 h. One-way repeated-measures ANOVA showed a significant effect of storage time (P < 0.05) on Hb, WBC, TC, MCH and MCHC. These results suggest that haematological parameters can be assessed within 6 h from blood collection when samples are stored at +4 degrees C because long-term storage modifies the results of the analyses. Further studies on these parameters could be still needed in various fish species to validate an appropriate method for haematological analysis useful not only for the evaluation of the health status of animal living in captivity and in aquaculture but also to have reliability environmental haematological biomarkers. PMID- 23097309 TI - Altered loading in the injured knee after ACL rupture. AB - Articular loading is an important factor in the joint degenerative process for individuals with anterior cruciate ligament (ACL) rupture. Evaluation of loading for a population that exhibits neuromuscular compensation for injury requires an approach which can incorporate individual muscle activation strategies in its estimation of muscle forces. The purpose of this study was to evaluate knee joint contact forces for patients with ACL deficiency using an EMG-driven modeling approach to estimate muscle forces. Thirty athletes with acute, unilateral ACL rupture underwent gait analysis after resolving range of motion, effusion, pain, and obvious gait impairments. Electromyography was recorded bilaterally from 14 lower extremity muscles and input to a musculoskeletal model for estimation of muscle forces and joint contact forces. Gait mechanics were consistent with previous reports for individuals with ACL-deficiency. Our major finding was that joint loading was altered in the injured limb after acute ACL injury; patients walked with decreased contact force on their injured knee compared to their uninjured knee. Both medial and lateral compartment forces were reduced without a significant change in the distribution of tibiofemoral load between compartments. This is the first study to estimate medial and lateral compartment contact forces in patients with acute ACL rupture using an approach which is sensitive to individual muscle activation patterns. Further work is needed to determine whether this early decreased loading of the injured limb is involved in the development of osteoarthritis in these patients. PMID- 23097310 TI - Brain systems involved in arithmetic with positive versus negative numbers. AB - Positive number arithmetic is based on combining and separating sets of items, with systematic differences in brain activity in specific regions depending on operation. In contrast, arithmetic with negative numbers involves manipulating abstract values worth less than zero, possibly involving different operation activity relationships in these regions. Use of procedural arithmetic knowledge, including transformative rules like "minus a negative is plus a positive," may also differ by operand sign. Here, we examined whether the activity evoked in negative number arithmetic was similar to that seen in positive problems, using region of interest analyses (ROIs) to examine a specific set of brain regions. Negative-operand problems demonstrated a positive-like effect of operation in the inferior parietal lobule with more activity for subtraction than addition, as well as increased activity across operation. Interestingly, while positive operand problems demonstrated the expected addition > subtraction activity difference in the angular gyrus, negative problems showed a reversed effect, with relatively more activity for subtraction than addition. Negative subtraction problems may be understood after translation to addition via rule, thereby invoking more addition-like activity. Whole-brain analyses showed increased right caudate activity for negative-operand problems across operation, indicating a possible overall increase in usage of procedural rules. Arithmetic with negative numbers may thus shows some operation-activity relationships similar to positive numbers, but may also be affected by strategy. This study examines the flexibility of the mental number system by exploring to what degree the processing of an applied usage of a difficult, abstract mathematical concept is similar to that for positive numbers. PMID- 23097311 TI - Immunogenicity, safety, and efficacy of abatacept administered subcutaneously with or without background methotrexate in patients with rheumatoid arthritis: results from a phase III, international, multicenter, parallel-arm, open-label study. AB - OBJECTIVE: To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy. METHODS: This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. RESULTS: Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] 2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, 2.27; monotherapy) at month 18. CONCLUSION: SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX. PMID- 23097313 TI - DNA-based chemiluminescent nanoprobes for highly sensitive and selective detection of mercury(II) ion. AB - A simple and sensitive DNA-stablized gold nanoparticle (AuNP)-based chemiluminescent (CL) probe for detecting mercury ion (Hg(2+)) in aqueous solution has been developed. The CL strategy relies upon the catalytic activity of unmodified AuNPs on the luminol-H2 O2 CL reaction, and the interaction of unmodified AuNPs with DNA. The unmodified AuNPs can effectively differentiate unstructured and folded DNA. The DNA desorbs from AuNPs in the presence of Hg(2+), leading to the increase in CL signal. By rationally varying the number of thymine in single-strand oligonucleotides, the detection range could be tuned. Employing single-strand oligonucleotides with 14 thymine in the detecting system, a sensitive linear range for Hg(2+) ions from 5.0 * 10(-10) to 1.0 * 10(-7) mol/L and a detection limit of 2.1 * 10(-10) mol/L are obtained. Changing the number of thymine to 10 and 6, it leads to a narrow detection range but a high sensitivity. Besides, DNA-based CL nanoprobes exhibit a remarkable selectivity for Hg(2+) ions over a variety of competing metal ions. PMID- 23097312 TI - Growth factor transgenes interactively regulate articular chondrocytes. AB - Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-beta1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair. PMID- 23097314 TI - Supramolecular polymer hydrogels from bolaamphiphilic L-histidine and benzene dicarboxylic acids: thixotropy and significant enhancement of Eu(III) fluorescence. AB - Supramolecular polymers from the bolaamphiphilic L-histidine (BolaHis) and benzene dicarboxylic acids (o-phthalic acid, OPA; isophthalic acid, IPA and terephthalic acid, TPA) were found to form hydrogels although neither of the single components could gel water. It was suggested that the hydrogen bond and ionic interactions among different imidazole and carboxylic acid groups are responsible for the formation of the supramolecular polymer as well as the hydrogel formation. Depending on the structures of the dicarboxylic acids, different behaviors of the gels were observed. The hydrogels from OPA/BolaHis and IPA/BolaHis showed thixotropic properties, that is, the hydrogel was destroyed by hand shaking and then slowly gelated again at room temperature. However, the hydrogels of TPA/BolaHis could not. Interestingly, when Eu(III) was doped into IPA/BolaHis supramolecular polymers, very strong luminescence enhancement was observed. FT-IR spectroscopies and XRD analysis revealed that the strong luminescence enhancement could be attributed to the matched supramolecular nanostructures, which render the correct binding and a good dispersion of Eu(III) ions. The work offers a new approach for fabricating functional hydrogels through the supramolecular polymers. PMID- 23097315 TI - A matrix-isolation and quantum-chemical investigation of FeF4. PMID- 23097316 TI - MIR-34c regulates mouse embryonic stem cells differentiation into male germ-like cells through RARg. AB - Embryonic stem cells (ESCs) have the capacity to differentiate into nearly all sorts of cell types, including germ cells, which were regarded as one type of highly specialized cells in mammals, taking the responsibility of transferring genetic materials to the next generation. Studies on induction differentiation of murine embryonic stem cells (mESCs) into male germ cells, but with a low efficiency, basic reason is that the regulation mechanism of germ cell development in mammals is still unclear. miRNA might play an important role in spermatogenesis in mammals. In this study, several miRNAs, which might be related to spermatogenesis, were initially selected and detected in the mouse tissues by semi-polymerase chain reaction (PCR) and quantitative real time (qRT)-PCR to find a testis-specific miRNA. To study its effect on mESCs differentiation into male germ cells, miR-34c mimics were synthesized and pri-miR-34c-GFP plasmid was constructed, transfected into mESCs and combined with retinoic acid induction. The effects of miR-34c were analysed by morphology, alkaline phosphatase staining, qRT-PCR_and immunofluorescent staining. The results showed that miR-34c promoted mESCs differentiation into male germ-like cells, to some extent. Then miR-34c targeted genes were predicted by bioinformatics; Retinoic acid receptor gamma (RARg) was selected, and two dual-luciferase reporter vectors contained the normal and mutated 3'untranslated region of RARg were constructed, respectively. By miRNA mimics and vector co-transfection experiment, the predicted target gene RARg was confirmed. In conclusion, we found a mammalian male germ cell specific miRNA--miR-34c, and it might be pivotal in mESCs differentiation into male germ cells through its target--RARg. PMID- 23097317 TI - Dissociable dorsal and ventral frontostriatal working memory circuits: evidence from subthalamic stimulation in Parkinson's disease. AB - In this study, we investigated the neural substrates involved in visual working memory (WM) and the resulting effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD). Cerebral activation revealed by positron emission tomography was compared among Parkinson patients with (PD-ON) or without (PD-OFF) STN stimulation, and a group of control subjects (CT) in two visual WM tasks with spatial (SP) and nonspatial (NSP) components. PD-OFF patients displayed significant reaction time (RT) deficits for both memory tasks. Although there were no significant differences in RT between patients with PD-ON and -OFF stimulation, patients with PD-ON stimulation performed comparably to controls. The memory tasks were executed with normal error rates in PD-ON and -OFF stimulation. In contrast to these behavioral results, whether the corresponding prefrontal activation was differentially affected by deep brain stimulation status in patients depended on whether the WM modality was SP versus NSP. Thus, SP WM was associated with (1) abnormal reduction in dorsolateral prefrontal activity in PD-OFF and -ON stimulation and (2) abnormal overactivation in parieto temporal cortex in PD-OFF and in limbic circuits in PD-ON stimulation. In NSP WM, normal activation of the ventral prefrontal cortex was restored in PD-ON stimulation. In both visual modalities the posterior cerebral regions including fusiform cortex and cerebellum, displayed abnormally reduced activity in PD. These results indicate that PD induces a prefrontal hypoactivation that STN stimulation can partially restore in a modality selective manner by additional recruitment of limbic structures in SP WM or by recovery of the ventral prefrontal activation in NSP WM. PMID- 23097319 TI - In vivo implant fixation of carbon fiber-reinforced PEEK hip prostheses in an ovine model. AB - Carbon fiber-reinforced polyetheretherketone (CFR/PEEK) is theoretically suitable as a material for use in hip prostheses, offering excellent biocompatibility, mechanical properties, and the absence of metal ions. To evaluate in vivo fixation methods of CFR/PEEK hip prostheses in bone, we examined radiographic and histological results for cementless or cemented CFR/PEEK hip prostheses in an ovine model with implantation up to 52 weeks. CFR/PEEK cups and stems with rough textured surfaces plus hydroxyapatite (HA) coatings for cementless fixation and CFR/PEEK cups and stems without HA coating for cement fixation were manufactured based on ovine computed tomography (CT) data. Unilateral total hip arthroplasty was performed using cementless or cemented CFR/PEEK hip prostheses. Five cementless cups and stems and six cemented cups and stems were evaluated. On the femoral side, all cementless stems demonstrated bony ongrowth fixation and all cemented stems demonstrated stable fixation without any gaps at both the bone cement and cement-stem interfaces. All cementless cases and four of the six cemented cases showed minimal stress shielding. On the acetabular side, two of the five cementless cups demonstrated bony ongrowth fixation. Our results suggest that both cementless and cemented CFR/PEEK stems work well for fixation. Cup fixation may be difficult for both cementless and cemented types in this ovine model, but bone ongrowth fixation on the cup was first seen in two cementless cases. Cementless fixation can be achieved using HA-coated CFR/PEEK implants, even under load-bearing conditions. PMID- 23097318 TI - Sex-biased transcriptome evolution in Drosophila. AB - Sex-biased genes are thought to drive phenotypic differences between males and females. The recent availability of high-throughput gene expression data for many related species has led to a burst of investigations into the genomic and evolutionary properties of sex-biased genes. In Drosophila, a number of studies have found that X chromosomes are deficient in male-biased genes (demasculinized) and enriched for female-biased genes (feminized) and that male-biased genes evolve faster than female-biased genes. However, studies have yielded vastly different conclusions regarding the numbers of sex-biased genes and forces shaping their evolution. Here, we use RNA-seq data from multiple tissues of Drosophila melanogaster and D. pseudoobscura, a species with a recently evolved X chromosome, to explore the evolution of sex-biased genes in Drosophila. First, we compare several independent metrics for classifying sex-biased genes and find that the overlap of genes identified by different metrics is small, particularly for female-biased genes. Second, we investigate genome-wide expression patterns and uncover evidence of demasculinization and feminization of both ancestral and new X chromosomes, demonstrating that gene content on sex chromosomes evolves rapidly. Third, we examine the evolutionary rates of sex-biased genes and show that male-biased genes evolve much faster than female-biased genes, which evolve at similar rates to unbiased genes. Analysis of gene expression among tissues reveals that this trend may be partially due to pleiotropic effects of female biased genes, which limits their evolutionary potential. Thus, our findings illustrate the importance of accurately identifying sex-biased genes and provide insight into their evolutionary dynamics in Drosophila. PMID- 23097320 TI - Validation of a screening instrument for nephrogenic systemic fibrosis. AB - OBJECTIVE: To develop and pilot test a screening tool to identify cases of nephrogenic systemic fibrosis (NSF) among patients exposed to gadolinium containing contrast agents. METHODS: Sixty English-speaking subjects were enrolled: 10 subjects diagnosed as having NSF, 10 subjects with other fibrosing skin diseases, 20 subjects with nonfibrosing skin diseases, and 20 subjects without a skin disease. Subjects answered a questionnaire with 8 closed-ended (yes/no) questions focusing on cutaneous and musculoskeletal manifestations of NSF. The subjects were evaluated by a dermatologist for the presence of clinical signs of NSF. We compared the number of affirmative responses in the NSF group to those in the other groups, and the optimal cutoff that would differentiate groups was calculated. Discrimination, positive and negative predictive values, and internal consistency were also assessed. RESULTS: Subjects in the NSF group tended to provide more affirmative answers. Using a cutoff of >=3 affirmative responses yields a sensitivity of 90% and a specificity of 70%, with an area under the curve of 0.85, indicating good discrimination. Sensitivity analysis using modified control group or weighted scores exhibited only slightly better discriminatory power. The positive predictive value of the questionnaire ranged from 0.3% to 39.7%, and its negative predictive values ranged from 97% to >99% with the different proposed prevalence estimates. The instrument had high internal consistency. CONCLUSION: This pilot study demonstrates that this questionnaire has both high internal consistency and good discriminatory ability. Thus, it may be used to screen populations for NSF. PMID- 23097321 TI - Characterization of Oct4-GFP spermatogonial stem cell line and its application in the reprogramming studies. AB - Establishment of mouse spermatogonial stem cell (SSC) culture systems offers a useful stem cell model for studies of proliferation and self-renewal of mammalian germline stem cells. In addition, spontaneous development of pluripotent stem cells from cultured SSCs emphasizes their possible applications in regenerative medicine as a substitute for embryonic stem cells (ESCs). These pluripotent stem cells termed multipotent germline stem cells (mGSCs) or germline-derived pluripotent stem cells (gPSCs) exhibit almost identical properties in terms of morphology and gene expression patterns to mouse ESCs (mESCs). In this study, to help understand mechanisms underlying reprogramming of SSCs into pluripotent stem cells, we established a culture system of SSCs derived from mice harboring green fluorescence protein (GFP) transgene whose expression is modulated by Oct4 regulatory sequences. Our results indicated that GFP intensity faithfully reflected cellular states upon reprogramming of SSCs or treatment with a selective extracellular signal-regulated kinase (ERK) inhibitor PD0325901. Moreover, in contrast to mESCs, regulation of Nanog expression did not appear to couple to the Oct4 level in SSCs. Further analysis of Oct4-GFP SSCs demonstrated that a posttranscriptional control of pluripotency marker genes such as Oct4 and Sox2 might play an important role as an inhibitory mechanism preventing the acquisition of pluripotency. PMID- 23097322 TI - Chiral bases as useful probes of lithium amide reactivity. PMID- 23097323 TI - Alternated stacks of nonpolar oligo(p-phenyleneethynylene)-BODIPY systems. AB - Supramolecular chemistry: The self-assembly of an oligo(p-phenyleneethynylene) 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (OPE-BODIPY) system into alternated 1D pi stacks in solution exhibited liquid-crystalline properties at room temperature. This system represents a new approach towards a controlled dye organization exclusively driven by pi-pi interactions (see figure). PMID- 23097324 TI - Putting the spotlight on internally displaced animals (IDAs): a survey of primate sanctuaries in Africa, Asia, and the Americas. AB - As anthropogenic activity makes deeper incursions into forests, fragmenting habitat, wildlife is forced into closer proximity to humans leading to increased incidences of human-wildlife conflict and wildlife displacement. These same incursions facilitate poaching for the commercial trade in dead and live animals. As a direct result, the number of sanctuaries and internally displaced animals (IDAs) in need of sanctuary placement and rehabilitation are increasing. We focus on internally displaced primates given the prevalence of primate-focused facilities and anthropomorphic considerations surrounding this taxonomic group. Surveys were distributed globally to map the extent and range of native primate sanctuaries and species. Over 70 facilities care for more than 6,000 native primates comprising 64 species, with almost half listed as endangered or critically endangered. As not all sanctuaries were identified at the time of the survey distribution, we estimate that the actual number of facilities is closer to double this number with a captive population in excess of 10,000 individual primates. Native primate sanctuaries hold significant numbers of primates in long term captive care, with less than half (37%) identified as candidates for release. The surveyed sanctuary population accounts for 35% of the world's captive primates, as compared to ISIS-registered (where ISIS is International Species Information System) zoological facilities, although we estimate that the actual population is closer to 58%. For some species, the sanctuary population represents the only population in captivity. We discuss the prevalence of range state sanctuaries and their primate populations, and issues surrounding their future development and management. PMID- 23097325 TI - Managing outbreaks of the citrus long-horned beetle Anoplophora chinensis (Forster) in Europe: molecular diagnosis of plant infestation. AB - BACKGROUND: Anoplophora chinensis (Forster) (Coleoptera Cerambycidae) is a polyphagous long-horned beetle native to Eastern Asia that infests a wide range of broadleaved plants, causing disruption of vascular tissue, structural weakness and tree death. As a result, A. chinensis is a quarantine pest for the European Union. In order to confirm its infestations on plants, it is necessary to obtain adult or larval specimens on which morphological or molecular analysis can be performed. However, obtaining such specimens from infested plants can be a demanding and difficult task. Therefore, a diagnostic tool that is non-invasive for the plant and able to be performed in the absence of any insect stages may be useful to confirm infestations of A. chinensis on plants. RESULTS: A protocol is presented that is based on polymerase chain reaction amplification using DNA extracted from A. chinensis faecal material collected in the field. CONCLUSION: Results obtained in the present work show that the non-invasive approach is a reliable and accurate alternative diagnostic tool in phytosanitary surveys. PMID- 23097326 TI - Mechanical effectiveness of lateral foot wedging in medial knee osteoarthritis after 1 year of wear. AB - The use of lateral foot wedging in the management of medial knee osteoarthritis is under scrutiny. Interestingly, there have been minimal efforts to evaluate biomechanical effectiveness with long-term use. Therefore, we aimed to evaluate dynamic knee loading (assessed using the knee adduction moment) and other secondary gait parameters in patients with medial knee osteoarthritis wearing lateral foot wedging at a baseline visit and after 1 year of wear. Three dimensional gait data were captured in an intervention group of 19 patients with symptomatic medial knee osteoarthritis wearing their prescribed laterally wedged foot orthoses at 0 and 12 months. Wedge amounts were prescribed based on symptom response to a step-down test. A control group of 19 patients wearing prescribed neutral orthoses were also captured at 0 and 12 months. The gait of the intervention group wearing neutral orthoses was additionally captured. Walking speed and shoes were controlled. Analyses of variance were conducted to examine for group-by-time (between the groups in their prescribed orthoses) and condition by-time (within the intervention group) interactions, main effects, and simple effects. We observed increased knee adduction moments and frontal plane motion over time in the control group but not the intervention group. Further, within the intervention group, the mechanical effectiveness of the lateral wedging did not decrease. In patients with medial knee osteoarthritis, the effects of lateral foot wedging on pathomechanics associated with medial knee osteoarthritis were favorable and sustained over time. PMID- 23097327 TI - Functional limitations due to axial and peripheral joint impairments in patients with ankylosing spondylitis: are focused measures more informative? AB - OBJECTIVE: Functional limitations in ankylosing spondylitis (AS) may be due to peripheral joint or axial involvement. To determine if the Bath Ankylosing Spondylitis Functional Index (BASFI), an axial-focused measure, can detect limitations related to peripheral joint involvement equally as well as the Health Assessment Questionnaire modified for the spondyloarthropathies (HAQ-S), a peripheral arthritis-focused measure, and vice versa, we compared associations of each questionnaire with spinal and hip range of motion, peripheral arthritis, and enthesitis in patients with AS. METHODS: We examined patients every 4-6 months in this prospective longitudinal study. We used mixed linear models to analyze the associations between 10 physical examination measures and the BASFI and HAQ-S. RESULTS: We studied 411 patients for a median of 1.5 years (median 3 visits). In multivariate analyses, cervical rotation, chest expansion, lateral thoracolumbar flexion, hip motion, tender joint count, and tender enthesis count were equally strongly associated with the BASFI and HAQ-S. Peripheral joint swelling was more strongly associated with the HAQ-S. Individual items of the BASFI were more likely than items of the HAQ-S to be associated with unrelated physical examination measures (e.g., the association between difficulty rising from a chair and cervical rotation), which may have diminished the axial/peripheral distinction for the BASFI. CONCLUSION: The BASFI and HAQ-S had similar associations with impairments in axial measures, while the HAQ-S had stronger associations with the number of swollen peripheral joints. The HAQ-S should be considered for use in studies focused on spondyloarthritis with peripheral joint involvement. PMID- 23097328 TI - Role of neuregulin-1/ErbB signaling in stem cell therapy for spinal cord injury induced chronic neuropathic pain. AB - Chronic neuropathic pain is a common and debilitating consequence of spinal cord injury (SCI). In a rat contusion injury model, we observed that chronic neuropathic pain is present on day 7 after SCI and persists for the entire 56-day observation period. However, currently available pain therapies are inadequate for SCI-induced neuropathic pain. In this study, we show that spinal transplantation of mouse embryonic stem cell-derived oligodendrocyte progenitor cells (OPCs) enhances remyelination in the injured spinal cord and reduces SCI induced chronic neuropathic pain. Moreover, we found that SCI reduces the protein level of neuregulin-1 and ErbB4 in the injured spinal cord and that OPC transplantation enhances the spinal expression of both proteins after SCI. Finally, intrathecal injection of neuregulin-1 small interfering RNA, but not the control nontarget RNA, diminishes OPC transplantation-produced remyelination and reverses the antinociceptive effect of OPC transplantation. Our findings suggest that the transplantation of embryonic stem cell-derived OPCs is an appropriate therapeutic intervention for treatment of SCI-induced chronic neuropathic pain, and that neuregulin-1/ErbB signaling plays an important role in central remyelination under pathological conditions and contributes to the alleviation of such pain. PMID- 23097329 TI - Stem cell-based therapy for Huntington's disease. AB - Huntington's disease (HD) is a late-onset neurodegenerative disease characterized by a progressive loss of medium spiny neurons in the basal ganglia. The development of stem cell-based therapies for HD aims to replace lost neurons and/or to prevent cell death. This review will discuss pre-clinical studies which have utilized stem or progenitor cells for transplantation therapy using HD animal models. In several studies, neural stem and progenitor cells used as allotransplants and xenografts have been shown to be capable of surviving transplantation and differentiating into mature GABAergic neurons, resulting in behavioral improvements. Beneficial effects have also been reported for transplantation of stem cells derived from non-neural tissue, for example, mesenchymal- and adipose-derived stem cells, which have mainly been attributed to their secretion of growth and neurotrophic factors. Finally, we review studies using stem cells genetically engineered to over-express defined neurotrophic factors. While these studies prove the potential of stem cells for transplantation therapy in HD, it also becomes clear that technical and ethical issues regarding the availability of stem cells must be solved before human trials can be conducted. PMID- 23097330 TI - Nursing home culture change: legal apprehensions and opportunities. AB - There continue to be serious deficiencies in the quality of life available to many nursing home residents in the United States. One significant response to this undesirable situation is the nursing home "Culture Change" movement, which attempts to improve the nursing home environment-and consequently residents' quality of life-by making facilities less institutional and more homelike. One of the impediments often interfering with the adoption and implementation of culture change in specific facilities is apprehension by staff, administrators, and governing boards about potential legal liability and regulatory exposure if residents suffer injuries that might arguably be attributed to facility conditions or policies that were inspired and encouraged by the culture change movement. This article addresses and responds to the provider liability and regulatory apprehensions that impede the progress of culture change in nursing homes, using proposed new dietary services standards as an example. PMID- 23097331 TI - Highly efficient benzannulation of poly(phenylene ethynylene)s. PMID- 23097332 TI - Epigenetic change detection and pattern recognition via Bayesian hierarchical hidden Markov models. AB - Epigenetics is the study of changes to the genome that can switch genes on or off and determine which proteins are transcribed without altering the DNA sequence. Recently, epigenetic changes have been linked to the development and progression of disease such as psychiatric disorders. High-throughput epigenetic experiments have enabled researchers to measure genome-wide epigenetic profiles and yield data consisting of intensity ratios of immunoprecipitation versus reference samples. The intensity ratios can provide a view of genomic regions where protein binding occur under one experimental condition and further allow us to detect epigenetic alterations through comparison between two different conditions. However, such experiments can be expensive, with only a few replicates available. Moreover, epigenetic data are often spatially correlated with high noise levels. In this paper, we develop a Bayesian hierarchical model, combined with hidden Markov processes with four states for modeling spatial dependence, to detect genomic sites with epigenetic changes from two-sample experiments with paired internal control. One attractive feature of the proposed method is that the four states of the hidden Markov process have well-defined biological meanings and allow us to directly call the change patterns based on the corresponding posterior probabilities. In contrast, none of existing methods can offer this advantage. In addition, the proposed method offers great power in statistical inference by spatial smoothing (via hidden Markov modeling) and information pooling (via hierarchical modeling). Both simulation studies and real data analysis in a cocaine addiction study illustrate the reliability and success of this method. PMID- 23097333 TI - ALS herbicide resistance mutations in Raphanus raphanistrum: evaluation of pleiotropic effects on vegetative growth and ALS activity. AB - BACKGROUND: Gene mutations that endow herbicide resistance may cause pleiotropic effects on plant ecology and physiology. This paper reports on the effect of a number of known and novel target-site resistance mutations of the ALS gene (Ala 122-Tyr, Pro-197-Ser, Asp-376-Glu or Trp-574-Leu) on vegetative growth traits of the weed Raphanus raphanistrum. RESULTS: The results from a series of experiments have indicated that none of these ALS resistance mutations imposes negative pleiotropic effects on relative growth rate (RGR), photosynthesis and resource competitive ability in R. raphanistrum plants. The absence of pleiotropic effects on plant growth occurs in spite of increased (Ala-122-Tyr, Pro-197-Ser, Asp-376 Glu) and decreased (Trp-574-Leu) extractable ALS activity. CONCLUSION: The absence of detrimental pleiotropic effects on plant growth associated with the ALS target-site resistance mutations reported here is a contributing factor in resistance alleles being at relatively high frequencies in ALS-herbicide unselected R. raphanistrum populations. PMID- 23097334 TI - Discerning single molecule interactions of DNA and quantum dots. AB - Measurements of interactions between nanoparticles and DNA at the molecular level offer insight to the rationale design of nano-complexes for biomedical imaging and sensing. This commentary describes the work of Kungang Li and colleagues, who report a study of atomic force microscopy-enabled single molecule imaging of quantum dots and DNA. PMID- 23097335 TI - Micro-RNA profiling as biomarkers in flap ischemia-reperfusion injury. AB - BACKGROUND: Ischemia-reperfusion injury (IRI) is usually the key and often plays an irreversible role to induce flap compromise in microvascular tissue transfers. This article aims to profile the expression of micro-RNAs (miRs) in free flap surgeries following IRI. METHODS: The miRs expression profiling was initially surveyed in rat epigastric flap vessels using Agilent 350-Microarrayed miRs after IRI, and then quantified by real-time reverse transcription polymerase chain reaction in flap vessels and tissues (n = 5) at three intervals: before induction of ischemia (normoxia without IRI, sham), 2 and 72 hours after reperfusion following 2 hours of ischemia. Furthermore, for seven patients with free anterolateral thigh flap reconstruction, the miRs expression patterns in these flaps before induction of ischemia (normoxia), at 2 and 72 hours after reperfusion following an ischemic interval were investigated. RESULTS: Four miRs (miR-96, miR-193-3p, miR-210, and miR-21) of 350 tested rat miRs were found to be positively significant. In rat flap vessels, the upregulation of these miRs at 72 hour reperfusion was statistically significant. These patterns were not noted in rat flap tissues, except for miR-96. However, there seemed to be no significant difference in human flap vessels between normoxia and 2-hour reperfusion following ischemia. In human flap tissue, significant upregulation of miR-193-3p, miR-210, and miR-21 was detected at 72-hour perfusion. CONCLUSIONS: Our findings show some changes of four upregulated miRs in our model of IRI. We suggest that further investigation is needed to determine the role of miRs in IRI of microsurgical reconstruction. PMID- 23097337 TI - A two-coordinate palladium complex with two dialkylphosphinyl ligands. PMID- 23097336 TI - Cell autonomous and nonautonomous mechanisms drive hematopoietic stem/progenitor cell loss in the absence of DNA repair. AB - Daily, cells incur tens of thousands of DNA lesions caused by endogenous processes. Due to their long-lived nature, adult stem cells may be particularly susceptible to the negative impact of this constant genotoxic stress. Indeed, in murine models of DNA repair deficiencies, there is accumulation of DNA damage in hematopoietic stem cells and premature loss of function. Herein, we demonstrate that mice expressing reduced levels of ERCC1-XPF DNA repair endonuclease (Ercc1 /Delta mice) spontaneously display a progressive decline in the number and function of hematopoietic stem/progenitor cells (HSPCs). This was accompanied by increased cell death, expression of senescence markers, reactive oxygen species, and DNA damage in HSPC populations, illustrating cell autonomous mechanisms that contribute to loss of function. In addition, the bone marrow microenvironment of Ercc1-/Delta mice was not permissive for the engraftment of transplanted normal stem cells. Bones from Ercc1-/Delta mice displayed excessive osteoclastic activity, which alters the microenvironment in a way that is unfavorable to HSPC maintenance. This was accompanied by increased proinflammatory cytokines in the bone marrow of Ercc1-/Delta mice. These data provide novel evidence that spontaneous, endogenous DNA damage, if not repaired, promotes progressive attrition of adult stem cells via both cell autonomous and nonautonomous mechanisms. PMID- 23097338 TI - Transforming the Model T: random effects meta-analysis with stable weights. AB - Standard meta-analytic theory assumes that study outcomes are normally distributed with known variances. However, methods derived from this theory are often applied to effect sizes having skewed distributions with estimated variances. Both shortcomings can be largely overcome by first applying a variance stabilizing transformation. Here we concentrate on study outcomes with Student t distributions and show that we can better estimate parameters of fixed or random effects models with confidence intervals using stable weights or with profile approximate likelihood intervals following stabilization. We achieve even better coverage with a finite sample bias correction. Further, a simple t-interval provides very good coverage of an overall effect size without estimation of the inter-study variance. We illustrate the methodology on two meta-analytic studies from the medical literature, the effect of salt reduction on systolic blood pressure and the effect of opioids for the relief of breathlessness. Substantial simulation studies compare traditional methods with those newly proposed. We can apply the theoretical results to other study outcomes for which an effective variance stabilizer is available. PMID- 23097339 TI - Dietary phosphilipids and sterols protective against peptic ulceration. AB - The prevalence of duodenal ulceration in regions of developing countries with a stable diet is related to the staple food(s) in that diet. A higher prevalence occurs in areas where the diet is principally milled rice, refined wheat or maize, yams, cassava, sweet potato or green bananas, and a lower prevalence in areas where the staple diet is based on unrefined wheat or maize, soya, certain millets or certain pulses. Experiments using animal peptic ulcer models showed that the lipid fraction in foods from the staple diets of low prevalence areas gave protection against both gastric and duodenal ulceration, including ulceration due to non-steroidal anti-inflammatory drugs (NSAIDs), and also promoted healing of ulceration. The protective activity was found to lie in the phospholipid, sterol and sterol ester fractions of the lipid. Amongst individual phospholipids present in the phospholipid fraction, phosphatidyl ethanolamine (cephalin) and phosphatidyl choline (Lecithin) predominated. The sterol fraction showing activity contained beta-sitosterol, stigmasterol and an unidentified isomer of beta-sitosterol. The evidence shows that dietary phytosterols and phospholipids, both individually and in combination, have a protective effect on gastroduodenal mucosa. These findings may prove to be important in the prevention and management of duodenal and gastric ulceration including ulceration due to NSAIDs. PMID- 23097340 TI - Impacts of Salmonella enteritidis infection on liver transcriptome in broilers. AB - Salmonella enterica serovar enteritidis is an enteric bacterium that can contaminate chicken eggs and meat, resulting in production losses and consumer illness. To provide insight into the systemic metabolic effects of S. enteritidis infection, liver samples were harvested 10-days postinfection from broiler hens. Hepatic global gene expression levels were assessed using a chicken 44K Agilent microarray. Forty-four genes were differentially expressed at a significance level of q value < 0.05. One hundred eighty-three genes were differentially expressed at a suggestive significance level of q value < 0.1. A predominance of downregulation existed among significantly differentially expressed genes. Cell cycle and metabolism networks were created from the differentially expressed genes. Mitochondria-mediated apoptosis, electron transport, peptidase activity, vein constriction, cell differentiation, IL-2 signaling, Jak-Stat signaling, B cell receptor signaling, GDP/GTP exchange, and protein recycling were among the functions of the differentially expressed genes that were down-regulated in response to S. enteritidis. The effects of S. enteritidis infection on the liver transcriptome profiles of broilers reflect a predominance of downregulation of genes with cell cycle and metabolic functions. The most pronounced response was the downregulation of genes that function in metabolic pathways, inflammation, and mitochondria-mediated apoptosis. These results provide insight into important systemic metabolic mechanisms that are active in the chicken liver in response to S. enteritidis infection at 10-days postinfection. PMID- 23097341 TI - Aromatic core extension in the series of N-cyclic bay-substituted perylene G quadruplex ligands: increased telomere damage, antitumor activity, and strong selectivity for neoplastic over healthy cells. AB - Based on previous work on both perylene and coronene derivatives as G-quadruplex binders, a novel chimeric compound was designed: N,N'-bis[2-(1-piperidino)-ethyl] 1-(1-piperidinyl)-6-[2-(1-piperidino)-ethyl]-benzo[ghi]perylene-3,4:9,10 tetracarboxylic diimide (EMICORON), having one piperidinyl group bound to the perylene bay area (positions 1, 12 and 6, 7 of the aromatic core), sufficient to guarantee good selectivity, and an extended aromatic core able to increase the stacking interactions with the terminal tetrad of the G-quadruplex. The obtained "chimera" molecule, EMICORON, rapidly triggers extensive DNA damage of telomeres, associated with the delocalization of telomeric protein protection of telomeres 1 (POT1), and efficiently limits the growth of both telomerase-positive and negative tumor cells. Notably, the biological effects of EMICORON are more potent than those of the previously described perylene derivative (PPL3C), and more interestingly, EMICORON appears to be detrimental to transformed and tumor cells, while normal fibroblasts expressing telomerase remain unaffected. These results identify a new promising G-quadruplex ligand, structurally and biologically similar on one side to coronene and on the other side to a bay-monosubstituted perylene, that warrants further studies. PMID- 23097342 TI - Generalized INverse imaging (GIN): ultrafast fMRI with physiological noise correction. AB - An ultrafast functional magnetic resonance imaging (fMRI) technique, called generalized inverse imaging (GIN), is proposed, which combines inverse imaging with a phase constraint-leading to a less underdetermined reconstruction-and physiological noise correction. A single 3D echo planar imaging (EPI) prescan is sufficient to obtain the necessary coil sensitivity information and reference images that are used to reconstruct standard images, so that standard analysis methods are applicable. A moving dots stimulus paradigm was chosen to assess the performance of GIN. We find that the spatial localization of activation for GIN is comparable to an EPI protocol and that maximum z-scores increase significantly. The high temporal resolution of GIN (50 ms) and the acquisition of the phase information enable unaliased sampling and regression of physiological signals. Using the phase time courses obtained from the 32 channels of the receiver coils as nuisance regressors in a general linear model results in significant improvement of the functional activation, rendering the acquisition of external physiological signals unnecessary. The proposed physiological noise correction can in principle be used for other fMRI protocols, such as simultaneous multislice acquisitions, which acquire the phase information sufficiently fast and sample physiological signals unaliased. PMID- 23097344 TI - Functionalization of Csp3-H and Csp2-H bonds: synthesis of spiroindenes by enolate-directed ruthenium-catalyzed oxidative annulation of alkynes with 2-aryl 1,3-dicarbonyl compounds. PMID- 23097343 TI - Brief report: The potential role of epigenetics on multipotent cell differentiation capacity of mesenchymal stromal cells. AB - Human umbilical cord perivascular cells (HUCPVCs) are a readily available source of mesenchymal stromal cells (MSCs) for cell therapy. We were interested in understanding how differences from human bone marrow (BM)-derived MSCs might yield insights into MSC biology. We found that HUCPVCs exhibited increased telomerase activity and longer telomeres compared with BM-MSCs. We also observed enhanced expression of the pluripotency factors OCT4, SOX2, and NANOG in HUCPVCs. The methylation of OCT4 and NANOG promoters was similar in both cell types, indicating that differences in the expression of pluripotency factors between the MSCs were not associated with epigenetic changes. MSC methylation at these loci is greater than reported for embryonic stem cells but less than in dermal fibroblasts, suggesting that multipotentiality of MSCs is epigenetically restricted. These results are consistent with the notion that the MSC population (whether BM- or HUCPV-derived) exhibits higher proliferative capacity and contains more progenitor cells than do dermal fibroblasts. PMID- 23097345 TI - L-theanine administration results in neuroprotection and prevents glutamate receptor agonist-mediated injury in the rat model of cerebral ischemia reperfusion. AB - While the neuroprotective effect of green tea (Camellia sinensis) might be explained by the presence of amino acid L-theanine in the tea leaves, it is not known whether postischemic administration of L-theanine could also provide neuroprotection. In the present study, we investigated the neuroprotective effect of L-theanine (1 and 4 mg/kg) administered at 3, 12, and 24 h after reperfusion in the rat model of stroke. We also studied the effect of L-theanine on brain injury caused by exogenous administration of N-methyl-D-aspartate and alpha-amino 3-hydroxy-5-methyl-isoxazole-4-propionate/kainate receptor agonists during reperfusion. Rats were subjected to 30-min middle cerebral artery occlusion followed by 48-h reperfusion. Neurological deficit and infarct size were determined at the end of reperfusion. At 3 and 12 h, but not at 24 h of reperfusion, L-theanine substantially reduced the size of brain infarct. Neurological status was improved when L-theanine was administered 3, 12, and 24 h after reperfusion. Repeated intrastriatal injections of L-theanine at a total dose of 800 ug/kg during reperfusion prevented brain injury caused by glutamate receptor agonists. In conclusion, L-theanine at reperfusion exerts neuroprotective effect in the in vivo rat model of stroke. Local treatment with L theanine at reperfusion prevents glutamate receptor agonist-mediated brain injury. PMID- 23097346 TI - Epithelial-to-mesenchymal transition in epicardium is independent of Snail1. AB - The epicardium is the outer epithelial covering the heart. This tissue undergoes an epithelial-to-mesenchymal transition (EMT) to generate mesenchymal epicardial derived cells (EPDCs) that populate the extracellular matrix of the subepicardium and contribute to the development of the coronary vessels and cardiac interstitial cells. Although epicardial EMT plays a crucial role in heart development, the molecular regulation of this process is incompletely understood. Here we examined the possible role of the EMT regulator Snail1 in this process. Snail1 is expressed in the epicardium and EPDCs during mouse cardiac development. To determine the function of Snail1 in epicardial EMT, we deleted Snail1 in the epicardium using Wt1- and Tbx18-Cre drivers. Unexpectedly, epicardial-specific Snail1 mutants are viable and fertile and do not display any obvious morphological or functional cardiac abnormalities. Molecular analysis of these mice reveals that epicardial EMT occurs normally, and epicardial derivatives are established in these mutants. We conclude that Snail1 is not required for the initiation and progression of embryonic epicardial EMT. PMID- 23097347 TI - Development of a metabolically stable neurotensin receptor 2 (NTS2) ligand. AB - Subtype-selective neurotensin receptor 2 (NTS2) ligands can be used as molecular probes to investigate the physiological role of neurotensinergic systems and serve as lead compounds to initiate the development of drugs for the treatment of tonic pain. Starting from our recently described NTS2 ligand 1, structural variants of type 2 were synthesized to further improve binding affinity and selectivity to gain metabolic stability. The peptide-peptoid hybrid 2 b showed excellent NTS2 binding affinity (K(i) =2.8 nM) and 22 000-fold selectivity over NTS1, as well as metabolic stability over 32 h in a serum degradation assay. Employing a MAPK-driven luciferase reporter gene assay and an IP accumulation assay, the neurotensin mimetic 2 b displayed respective inhibitions of constitutive activity exceeding 4.3- and 3.9-fold that of the inverse agonist activity of the endogenous ligand neurotensin. PMID- 23097348 TI - Parkinson's disease: evidence for environmental risk factors. AB - Parkinson's disease (PD) has no known cause. Although recent research has focused particularly on genetic causes of PD, environmental causes also play a role in developing the disease. This article reviews environmental factors that may increase the risk of PD, as well as the evidence behind those factors. Enough evidence exists to suggest that age has a causal relationship to PD. Significant evidence exists that gender, tobacco use, and caffeine consumption are also associated with the development of PD. Other environmental factors (pesticide exposure, occupation, blood urate levels, NSAID use, brain injury, and exercise) have limited or conflicting evidence of a relationship to PD. Future research must not neglect the impact of these environmental factors on the development of PD, especially with respect to potential gene-environment interactions. PMID- 23097350 TI - Organocatalytic synthesis of highly substituted furfuryl alcohols and amines. PMID- 23097349 TI - Mesenchymal stem cells and endothelial progenitor cells decrease renal injury in experimental swine renal artery stenosis through different mechanisms. AB - Endothelial progenitor cells (EPC) and mesenchymal stem cells (MSC) augment tissue repair but possess slightly different properties. How the cellular phenotype affects the efficacy of this approach in renovascular disease is incompletely understood. This study tested the hypothesis that EPC and MSC protect the poststenotic kidney by blunting different disease pathways. Peripheral blood EPC and adipose-derived MSC were expanded and characterized by cell surface markers (e.g., CD34/kinase insert domain receptor, or CD44/CD90). Single-kidney hemodynamics and function were assessed in pigs after 10 weeks of renal artery stenosis (RAS) treated 4 weeks earlier with an intrarenal infusion of vehicle (n = 7), EPC (RAS+EPC) or MSC (RAS+MSC) (both 10 * 10(6), n = 6), and normal controls (n = 7). Kidney disease mechanisms were evaluated ex vivo. The ability of EPC and MSC to attenuate endoplasmic reticulum (ER) stress was also studied in isolated ER and in tubular cells cocultured with EPC and MSC. Glomerular filtration rate in RAS was lower than controls, increased in RAS+EPC, and further improved in RAS+MSC, although both improved renal blood flow similarly. EPC prominently enhanced renal growth factor expression and decreased oxidative stress, while MSC more significantly attenuated renal inflammation, ER stress, and apoptosis. Furthermore, MSC induced a greater decrease in caspase-3 and CHOP expression in cultured tubular cells through mechanisms involving cell contact. EPC and MSC achieve a comparable decrease of kidney injury in RAS by different mechanisms, although MSC elicited slightly superior improvement of renal function. These results support development of cell-based approaches for management of renovascular disease and suggest cell selection based on the underlying pathophysiology of kidney injury. PMID- 23097352 TI - Separation membranes constructed from inorganic nanofibers by filtration technique. AB - Nanofibrous materials have been extensively investigated and used as building blocks for various nanodevices, due to their unique one-dimensional structures. Recently, novel membranes constructed by using nanofibers have been reported by various techniques. Here, we will give a critical review of our recent research on the general solution processed unique sub-3 nm thin metal hydroxide nanofibers and their application for constructing ultrathin separation membranes via filtration technique. The superior separation performances of these membranes hold the promising future for pressure-driven membrane separation processes. PMID- 23097351 TI - Antiulcerogenic activities of the extracts and isolated flavonoids of Euphorbia cuneata Vahl. AB - The total alcohol extracts of Euphorbia cuneata Vahl.(Euphorbiaceae) were screened for antiulcerogenic activity using an ethanol-induced ulcer model at doses of 125, 250 and 500 mg/kg. The extracts possessed antiulcerogenic activity in a dose-dependent manner. Four flavonoidal compounds were isolated and identified as naringenin, aromadendrin, apigenin and 4'-O-methoxy-luteolin-7-O rhamnoglucoside, each demonstrating antiulcerogenic activity with curative ratios ranging from 75.78% to 88.23%. In addition, the alcohol extracts and isolated compounds were shown to scavenge the 1,1-diphenyl,2-picrylhydrazyl radical by different ratio, with the most effective being 4'-O-methoxy-luteolin-7-O rhamnoglucoside (91.14%). The antioxidant activity of the alcohol extracts and the isolated compounds may explain the antiulcerogenic properties. No side effects were observed on either liver or kidney functions. PMID- 23097353 TI - Functionalization of hexa-peri-hexabenzocoronenes: investigation of the substituent effects on a superbenzene. AB - We have demonstrated that the iridium-catalyzed direct borylation of hexa-peri hexabenzocoronene (HBC) enables regioselective introduction of boryl groups to the para-, ortho-, and meta-substituted HBCs in high yields. The boryl groups have been transformed into various functionalities such as hydroxy, cyano, ethynyl, and amino groups. We have elucidated that the substituents significantly influence the photophysical properties of HBCs to enhance fluorescence quantum yields. DFT calculations revealed that the origin of the substituent effect is the lift in degeneracy in the frontier orbitals by an interaction with electron donating and electron-withdrawing substituents at the para- and ortho-positions. The change in molecular orbitals results in an increase of the transition probability from the S(0)->S(1) states. In addition, the two-photon absorption cross-section values of para-substituted HBCs are significantly larger than those of ortho- and meta-substituted HBCs. PMID- 23097354 TI - Best practices of ASRM and ESHRE: a journey through reproductive medicine. AB - BACKGROUND: The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) are the two largest societies in the world whose members comprise the major experts and professionals working in the field of reproductive medicine and embryology. These societies have never before had a joint scientific meeting. METHODS: A 3-day meeting was planned and took place in March of 2012. The goal was to present and debate key topics, as well as modes of practice in reproductive medicine and to discuss recent developments in the field. RESULTS: Presentations by members of ASRM and ESHRE were of three types: 'state of the art' lectures, 'back-to-back' presentations of two points of view and debates. CONCLUSIONS: For the first time, ASRM and ESHRE held a joint meeting where a special emphasis was given to presentations on the hottest topics in the field. Although different opinions and approaches sometimes exist on the two sides of the Atlantic, an appreciation and acceptance of these differences was evident, and there was more commonality than divergence of opinion. PMID- 23097356 TI - Deoxygenation of biomass-derived feedstocks: hurdles and opportunities. PMID- 23097355 TI - Fibroblast growth factor receptor signaling is essential for normal mammary gland development and stem cell function. AB - Fibroblast growth factor (FGF) signaling plays an important role in embryonic stem cells and adult tissue homeostasis, but the function of FGFs in mammary gland stem cells is less well defined. Both FGFR1 and FGFR2 are expressed in basal and luminal mammary epithelial cells (MECs), suggesting that together they might play a role in mammary gland development and stem cell dynamics. Previous studies have demonstrated that the deletion of FGFR2 resulted only in transient developmental defects in branching morphogenesis. Using a conditional deletion strategy, we investigated the consequences of FGFR1 deletion alone and then the simultaneous deletion of both FGFR1 and FGFR2 in the mammary epithelium. FGFR1 deletion using a keratin 14 promoter-driven Cre-recombinase resulted in an early, yet transient delay in development. However, no reduction in functional outgrowth potential was observed following limiting dilution transplantation analysis. In contrast, a significant reduction in outgrowth potential was observed upon the deletion of both FGFR1 and FGFR2 in MECs using adenovirus-Cre. Additionally, using a fluorescent reporter mouse model to monitor Cre-mediated recombination, we observed a competitive disadvantage following transplantation of both FGFR1/R2 null MECs, most prominently in the basal epithelial cells. This correlated with the complete loss of the mammary stem cell repopulating population in the FGFR1/R2-attenuated epithelium. FGFR1/R2-null MECs were partially rescued in chimeric outgrowths containing wild-type MECs, suggesting the potential importance of paracrine mechanisms involved in the maintenance of the basal epithelial stem cells. These studies document the requirement for functional FGFR signaling in mammary stem cells during development. PMID- 23097357 TI - Protein kinase a mediated anti-inflammatory effects exerted by adenosine treatment in mouse chondrocytes stimulated with IL-1beta. AB - Hyaluronan (HA) fragments produced by degradation of native highly polymerized HA during inflammation may exacerbate proinflammatory responses in different pathologies. In contrast, the nucleoside adenosine (ADO) interacting with cell surface adenosine receptors A(2A) R, A(2B) R, A(1,) and A(3) , acts as endogenous modulator of the inflammation. The engagement of high-affinity A(2A) R by ADO activates a pathway leading to increased cAMP production. Elevated levels of cAMP associate with the activation of protein kinase A (PKA) able to inhibit NF-kB, hence exerting anti-inflammatory activity. In this study the effect of ADO treatment in normal murine chondrocytes stimulated with interleukin-1beta (IL 1beta) was investigated. mRNA and related protein levels were measured for enzymes, receptors and pro-inflammatory cytokines TNF-alpha, IL-6 and Il-18. IL 1beta stimulation significantly up-regulated HA levels, its fragmentation, cAMP, PKA, cytokine levels, and activated NF-kB. ADO treatment increased cAMP and PKA levels, while reduced NF-kB activation and cytokine levels. HA inhibition by specific synthetic HA blocking peptide (Pep-1) reduced IL-1beta action but not ADO activity. While A(2A) R inhibition by specific small interference RNA (siRNA) increased inflammation and decreased cAMP and PKA levels. This study suggests that HA is partially responsible for the up-regulation of proinflammatory cytokines in chondrocytes and that endogenous/exogenous ADO may reduce inflammation via PKA. PMID- 23097358 TI - Issue editors' notes: youth success and adaptation in times of globalization and economic change. PMID- 23097359 TI - Executive summary. Changes in the economy, the labor market, and expectations for the future: What might Europe and the United States look like in twenty-five years. PMID- 23097360 TI - Changes in the economy, the labor market, and expectations for the future: what might Europe and the United States look like in twenty-five years? AB - In times of globalization, modern societies' labor markets have been marked by an increasing segmentation and growing social inequality. Youths in particular have experienced a worsening of their employment chances in the past three decades. However, what will the future bring? PMID- 23097361 TI - Changing contexts of youth development: an overview of recent social trends and a psychological model. AB - Globalization and economic change are translated into a variety of changes in the proximal contexts of youth development, which are perceived and tackled differently by different individuals. PMID- 23097362 TI - Large-scale economic change and youth development: the case of urban China. AB - This chapter considers how large-scale economic change in urban China affects youth development and outlines developmental mechanisms and labor-market moderators. PMID- 23097363 TI - Academic expectations and well-being from school to work during the economic downturn. AB - Academic well-being and expectations change in educational transitions during economic downturn. PMID- 23097364 TI - Is uncertainty bad for you? It depends .... AB - Parents and educators should be more concerned about uncertainty in educational aspirations than uncertainty regarding career choice among adolescents. Moreover, the impact of uncertainty on young people's attainment varies by socio-historical context, the timing of uncertainty, the available resources, and individual characteristics of the adolescents themselves. PMID- 23097365 TI - The future of young women's economic role in a globalized economy: new opportunities, persisting constraints. AB - Young women in advanced industrial countries have been outperforming young men in educational attainment at the same time that their labor market outcomes are still lagging. Sex segregation in education and the labor market is identified as an important source of this imbalance. PMID- 23097366 TI - Families, schools, and major demographic trends in the United States. AB - The ability of schools to serve young people may be jeopardized if their approaches to parental involvement do not evolve to reflect the growing diversity of their students brought on by long-term demographic changes. PMID- 23097367 TI - Technology and youth. AB - Long-term studies monitoring the process of young people adopting new media patterns of social interaction and communication with parents and peers are needed to better understand how young people cope with perpetual peer communication, how parents and adolescents deal with intergenerational conflicts, and the outcomes of these practices and conflicts. PMID- 23097368 TI - Competent youth in a "disorderly world": findings from an eighteen-nation study. AB - Future- and school-related stressors are salient for adolescents from different regions of the world, and they cope with these stressors competently. PMID- 23097369 TI - Promoting positive youth development in the face of contextual changes and challenges: the roles of individual strengths and ecological assets. AB - Experiencing positive and healthy youth development may be particularly challenging in the face of abrupt, major, rapid, or nonnormative ecological changes. Aligning individual youth strengths and ecological assets may promote youth thriving in the face of these changes. PMID- 23097370 TI - The facial and subjective emotional reaction in response to a video game designed to train emotional regulation (Playmancer). AB - Several aspects of social and emotional functioning are abnormal in people with eating disorders. The aim of the present study was to measure facial emotional expression in patients with eating disorders and healthy controls whilst playing a therapeutic video game (Playmancer) designed to train individuals in emotional regulation. Participants were 23 ED patients (11 AN, 12 BN) and 11 HCs. ED patients self reported more anger at baseline but expressed less facial expression of anger during the Playmancer game. The discrepancy between self report and non-verbal expression may lead to problems in social communication. PMID- 23097371 TI - Extracorporeal membrane oxygenation with spontaneous breathing as a bridge to lung transplantation. AB - OBJECTIVES: A large number of transplantation centres consider extracorporeal membrane oxygenation as an inappropriate option for bridging critical patients to lung transplantation. Technical improvements such as the introduction of a polymethylpentene membrane, new centrifugal pumps and heparin-coated circuits have led to a safer application of extracorporeal membrane oxygenation, and an increasing number of centres are reporting their positive experiences. The aim of this study was to review our practice in bridging critical candidates to lung transplantation with extracorporeal membrane oxygenation, by comparing patients with invasive mechanical ventilation with patients with spontaneous breathing. METHODS: The records of candidates for lung transplantation treated with extracorporeal membrane oxygenation have been revised. RESULTS: From February 2008 to 2012, 11 patients who experienced an abrupt worsening of their respiratory conditions were treated with extracorporeal membrane oxygenation; mean age: 33.9 +/- 13.2 years, male/female ratio: 5/6, 6 patients were affected by cystic fibrosis, 2 had chronic rejection after transplantation, 2 had pulmonary fibrosis and 1 had systemic sclerosis. Seven patients were awake, while 4 patients received invasive mechanical ventilation. The sequential organ failure assessment score significantly increased during bridging time and this increase was significantly higher in the intubated patients. All the patients had bilateral lung transplantation. Spontaneously breathing patients showed a tendency to require a shorter duration of invasive mechanical ventilation, intensive care unit stay and hospital stay after transplantation. One-year survival rate was 85.7% in patients with spontaneous breathing vs 50% in patients with invasive mechanical ventilation. CONCLUSIONS: Extracorporeal membrane oxygenation in spontaneously breathing patients is a feasible, effective and safe bridge to lung transplantation. PMID- 23097373 TI - Asymmetric (4+3) cycloadditions of enantiomerically enriched epoxy enolsilanes. PMID- 23097376 TI - Delayed reversal learning and association with repetitive behavior in autism spectrum disorders. AB - An important aspect of successful emotion regulation is the ability to adjust emotional responses to changing environmental cues. Difficulties with such adaptation may underlie both marked symptoms of behavioral inflexibility and frequent severe anxiety in the autism spectrum disorders (ASDs). Thirty children and adolescents diagnosed with ASD and 29 age- and intelligence quotient-matched controls completed a reversal learning paradigm following partial reinforcement Pavlovian fear conditioning, using a surprising air puff as the unconditioned stimulus. After initial reversal of cue contingencies, where a previously safe cue now predicted the air puff threat, the control group but not the ASD group responded more strongly to the new threat cue. The ASD group showed evidence for reversal learning only during later trials. Reversal learning in the ASD group was significantly negatively correlated with everyday symptoms of behavioral inflexibility but not with everyday anxiety. Understanding shared associations between inflexibility, anxiety, and autism, with regard both to clinical symptoms and neurobiological mechanisms, can provide important markers for better characterizing the substantial heterogeneity across the autism spectrum. PMID- 23097374 TI - Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature. AB - BACKGROUND: In regions where prenatal screening for anencephaly and spina bifida is widespread, many cases of these defects are diagnosed prenatally. The purpose of this study was to estimate the frequency of termination of pregnancy (TOP) following prenatal diagnosis of anencephaly or spina bifida and to investigate factors associated with TOP that might lead to selection bias in epidemiologic studies. METHODS: We included articles indexed in Medline or Embase between 1990 and May 2012 reporting the frequency of TOP following prenatal diagnosis of anencephaly or spina bifida with English-language abstracts, 20 or more prenatally diagnosed cases, and at least half of the study years in 1990 or later. We summarized the frequency of TOP across studies using random-effects metaanalysis and stratified results by fetal and study characteristics. RESULTS: Among the 17 studies identified, 9 included anencephaly and 15 included spina bifida. Nine were from Europe, six were from North America, and one each was from South America and Asia. The overall frequency of TOP following prenatal diagnosis was 83% for anencephaly (range, 59-100%) and 63% for spina bifida (range, 31 97%). There were insufficient data to stratify the results for anencephaly; TOP for spina bifida was more common when the prenatal diagnosis occurred at less than 24 weeks' gestation, with defects of greater severity, and in Europe versus North America. CONCLUSIONS: Because underascertainment of birth defects might be more likely when the pregnancy ends in TOP and TOP is associated with fetal characteristics, selection bias is possible in epidemiologic studies of anencephaly or spina bifida. PMID- 23097377 TI - In the presence of IL-21 human cord blood T cells differentiate to IL-10 producing Th1 but not Th17 or Th2 cells. AB - IL-21, a member of the IL-2 cytokine family, is mainly produced by activated CD4(+) T cells and controls the activity of immune and also non-immune cells. As a pleiotropic cytokine, IL-21 acts on both innate and adaptive immune responses, suggesting that IL-21 may be a master regulator of the T-cell-dependent adaptive immune response. Although IL-21 is described as mostly promoting inflammation, evidence also suggests inhibitory effects of IL-21. However, its role, particularly in the human neonatal immune system, has not been detailed so far. Here, we assessed the effect of IL-21 in the specific context of the neonatal immune response and delineated differences between the human newborn and adult immune response. In umbilical cord blood, we demonstrated that IL-21 polarized naive CD4(+) T cells into T(h)1 cells, producing IL-10, a key negative regulator during certain infections and autoimmunity. Furthermore, IL-21 stimulation increased IFNgamma secretion and inhibited the development of T(h)2 and T(h)17 cells and molecules associated with their function. Thus, in neonates, known to show limitations in establishing T(h)1 responses, IL-21 played a clear role in supporting T(h)1 responses in vitro, while appearing irrelevant for the adult immune response. Overall, we demonstrated the capability of IL-21 to induce the immunosuppressive cytokine IL-10 and outlined its potential to compensate the restricted T(h)1 response in human newborns and consequently to reduce the susceptibility for infectious diseases in the first period of life. PMID- 23097379 TI - Letter to the editor: neurodevelopmental outcomes following prenatal exposure to serotonin reuptake inhibitor antidepressants: a "social teratogen" or moderator of developmental risk. PMID- 23097381 TI - A self-contained regeneration scheme for spent ammonia borane based on the catalytic hydrodechlorination of BCl3. PMID- 23097380 TI - Autism risk gene MET variation and cortical thickness in typically developing children and adolescents. AB - MET receptor tyrosine kinase (MET) has been proposed as a candidate risk gene for autism spectrum disorder (ASD) based on associations between MET polymorphisms and ASD diagnosis, as well as evidence from animal studies that MET protein may regulate early development of cortical regions implicated in the neurobiology of ASD. The relevance of differences in MET signaling for human cortical development remains unexamined, however. We sought to address this issue by relating genotype at a functional single nucleotide polymorphism within the MET promoter (rs1858830, G->C) to in vivo measures of cortical thickness (CT) development derived from 222 healthy children and adolescents with 514 longitudinally acquired structural magnetic resonance imaging brain scans between ages 9 and 22 years. We identified a statistically significant, developmentally fixed, and stepwise CT reduction with increasing C allele dose in superior and middle temporal gyri, ventral precentral and postcentral gyri, and anterior cingulate bilaterally, and in the right frontopolar cortex. We were also able to demonstrate that mean CT within these cortical regions showed a statistically significant reduction with increasing scores on a continuous measure of autistic traits (the Social Responsiveness Scale). The cortical regions highlighted by our analyses are not only established areas of MET expression during prenatal life but are also key components of the "social brain" that have frequently shown structural and functional abnormalities in autism. Our results suggest that genetic differences in the MET gene may influence the development of cortical systems implicated in the neurobiology of ASD. PMID- 23097382 TI - Inhibition of guanosine monophosphate synthetase by the substrate enantiomer L XMP. PMID- 23097383 TI - Feasibility of arterial spin labeling on a 1T open MRI scanner. AB - PURPOSE: To determine the clinical feasibility of arterial spin labeling (ASL) on a 1T open bore scanner. MATERIALS AND METHODS: First, the optimal postlabeling delay (PLD) at 1T was determined (n = 5), with and without vascular crushing. Second, the effect of different labeling approaches (pseudo-continuous ASL [pCASL] vs. pulsed ASL [PASL]), background suppression (BSup) and readout options (GRASE vs. EPI) was investigated (n = 9). Each effect was quantified by calculating the signal-to-noise ratio (SNR), convergence, and number of significant gray matter (GM) voxels in the ASL images. Finally, an example of an obese volunteer who could not have been scanned in a cylindrical scanner is presented. RESULTS: The optimal PLDs were found to be 1300 msec for pCASL with and without vascular crushing. pCASL labeling outperformed PASL labeling in terms of convergence, anatomical correspondence between GM and perfusion maps, and SNR (P < 0.05). BSup appeared to have no additional value on the convergence, anatomical GM correspondence, and SNR (P > 0.05). EPI readout yielded a slightly better convergence, while the SNR of the GRASE readout was higher (P < 0.05). CONCLUSION: ASL on 1T is clinically feasible using state-of-the-art sequences that were primarily developed for higher field strengths. PMID- 23097384 TI - Evaluation of left atrial contraction contribution to left ventricular filling using cardiovascular magnetic resonance. AB - PURPOSE: To describe a new method to quantify the left atrial contraction contribution (ACC) to left ventricular (LV) filling using cardiovascular magnetic resonance (CMR). MATERIALS AND METHODS: We assessed 120 normal subjects (50% female) using steady-state free precession CMR volumetry. Volumes measurements were performed using short axis and rotational long axis views. The percentage of ACC was calculated by dividing the LV filling volume resulting from left atrial (LA) contraction by the LV stroke volume (LVSV). RESULTS: The described method was well reproducible. The ACC in normal subjects was 15 +/- 5% for ages <40 years, 28 +/- 8% for ages 40 to 55 years, and 38 +/- 5% for ages >55 years. When adjusted for age, ie, dividing the ACC percentage by age, a value between 0.4 and 0.7 was found to represent the normal range of ACC at any age. CONCLUSION: The study presents a new and accurate CMR volumetric method to quantify ACC to LV filling. ACC ranges from 10%-40%, depending on age. PMID- 23097385 TI - An unusual eyelid swelling. PMID- 23097387 TI - Might the beneficial effects of statin drugs be related to their action on iron metabolism? AB - Although the cholesterol-heart hypothesis is often regarded as a dogmatic belief, controversy continues to surround the aetiology and pathogenesis of atherosclerosis. In fact, lowering cholesterol with statin drugs has been shown to reduce cardiovascular risk. However, statins have pleiotropic effects independent of their capacity to lower cholesterol. We highlight that statin drugs exert an important action on iron metabolism, which in turn may prevent progression and destabilization of atherosclerotic plaque. If it is found that the effect of statins on iron metabolism is a mechanism of their beneficial action, this consequence of statin use can be clinically replicated by other methods, such as controlled reduction of body iron stores. This might allow the use of lower doses or even obviate the use of statins in primary cardiovascular prevention, and therefore avoid the side effects and expense of these drugs. PMID- 23097388 TI - Successful living related kidney transplantation for end-stage renal failure caused by orellanine syndrome. PMID- 23097386 TI - Indications, stains and techniques in chromoendoscopy. AB - Early detection of malignancies within the gastrointestinal tract is essential to improve the prognosis and outcome of affected patients. However, conventional white light endoscopy has a miss rate of up to 25% for gastrointestinal pathology, specifically in the context of small and flat lesions within the colon. Chromoendoscopy and other advanced imaging techniques aim at facilitating the visualization and detection of neoplastic lesions and have been applied throughout the gastrointestinal tract. Chromoendoscopy, particularly in combination with magnifying endoscopy has significantly improved means to detect neoplastic lesions in the gastrointestinal mucosa, particularly in ulcerative colitis and Crohn's colitis. In addition, chromoendoscopy is beneficial in the upper gastrointestinal tract, especially when evaluating Barrett's oesophagus (BO) for the presence of dysplasia. Furthermore, it also improves characterization, differentiation and diagnosis of endoscopically detected suspicious lesions, and helps to delineate the extent of neoplastic lesions that may be amenable to endoscopic resection. This review discusses the dyes, indications and advanced endoscopic imaging methods used in various chromoendoscopic techniques, and presents a critical overview of the existing evidence supporting their use in current practice with a particular emphasis on the role in inflammatory bowel disease and BO. PMID- 23097389 TI - Newly diagnosed human immunodeficiency virus infection in an octogenarian with acute respiratory failure. PMID- 23097390 TI - A critical overview on ticagrelor in acute coronary syndromes. AB - Until a few years ago, the mainstay of anti-platelet therapy in patients with acute coronary syndrome (ACS) was the combination of aspirin and clopidogrel, a P2Y12 receptor inhibitor. However, current clinical practice has now changed with the introduction of ticagrelor, a more potent cardiovascular drug than clopidogrel, without the limitations related to clopidogrel therapy. In this review, we provide a critical overview of ticagrelor in ACS, highlight the results with ticagrelor in several subgroups of patients and discuss the future trials. PMID- 23097391 TI - Pseudo-tumoral intestinal amyloidosis. PMID- 23097392 TI - Disseminated cysticercosis. PMID- 23097393 TI - Multiple pulmonary nodules. Wegener's granulomatosis simulating pulmonary metastases. PMID- 23097394 TI - What is causing my arthritis, doctor? A glimpse beyond the usual suspects in the pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a common, but heterogeneous, disease. Usually, when it comes to the pathogenesis of RA the physician faces a complex network of cytokines and cells of the immune system-the so-called effector level. However, is this network 'the cause' of the disease? Or is this rather the level most physicians are somewhat familiar with, as modern anti-rheumatic medications are having their targets there? In this review, we are looking beyond the usual culprits from the physician's perspective and discuss how other factors, such as genes, epigenetics, environmental factors, local joint characteristics or processes of aging might influence the clinical phenomenon RA. PMID- 23097395 TI - Natural induction of spontaneous liver steatosis in Greylag Landaise geese (Anser anser). AB - The present experiment aimed at demonstrating that the Greylag geese (Anser anser), commonly used for the production of foie gras, are able to develop spontaneous hyperphagia and subsequent liver steatosis under specific handling conditions and without overfeeding. One hundred and eighty male geese were used in this experiment. After a period of feed restriction, at the age of 19 wk, corn was provided ad libitum. From wk 21 to 23, the daylight duration was progressively reduced from 10 to 7 h and kept as such until the end of the experiment (wk 31). Thirty birds were slaughtered at wk 19, 23, 25, 27, 29, and 31. During the first 2 wk after corn delivery, the average consumption rose up to 600 g/bird/d and decreased slowly thereafter to reach 270 g at wk 31. The liver weight increased from 95 (wk 19) to 514 g (wk 31), and most of these changes were due to the increase in liver lipid content from 6 to 50% of liver weight. There was no mortality during the experimental period. Histological observations indicate that the accumulation of fat in the livers occurred through a large increase in the size of the hepatocytes without modification of the cell boundaries and without any sign of inflammation or degeneration. Our data clearly show that under specific management conditions of feeding and photoperiod, the geese are able to initiate spontaneous liver steatosis. These results demonstrate their natural ability to store fat in the liver without any visible sign of tissue alteration. However, the variability in the response remains very high (at wk 31, the CV in liver weight was 45%). Further research is needed to better understand the origin of this variability. PMID- 23097397 TI - Transgenerational effects of feeding genetically modified maize to nulliparous sows and offspring on offspring growth and health. AB - This study assessed the effect of feeding genetically modified maize expressing a truncated form of the Cry1Ab protein from Bacillus thuringiensis (Bt MON810 maize) to sows during gestation and lactation and their offspring from weaning to 115 d postweaning on offspring growth and health. After weaning at approximately 28 d of age (d 0), individually penned, mixed sex pigs (approximately 8 kg BW) from sows fed isogenic or Bt maize diets were blocked by sow treatment, sex, and BW and randomly assigned to Bt or isogenic maize diets as follows: i) isogenic maize-fed sow/isogenic maize-fed offspring (iso/iso); ii) isogenic maize-fed sow/Bt maize-fed offspring (iso/Bt); iii) Bt maize-fed sow/isogenic maize-fed offspring (Bt/iso); and iv) Bt maize-fed sow/Bt maize-fed offspring (Bt/Bt). Growth performance was recorded at intervals to harvest at approximately 105 kg BW (n=15/treatment) and blood samples were taken for biochemical analysis on d 0, 30, 70, 100, and 115 postweaning (n=10/treatment). Pigs were harvested on d 115 postweaning (n=10/treatment), and carcass weight, backfat depth, and organ weights (heart, kidney, spleen, and liver) were recorded. Kidney, liver, lymph nodes, and small intestine were collected for histological analysis. Offspring from Bt maize-fed sows were heavier than offspring from isogenic maize-fed sows on d 30 (P<0.05), 100 (P<0.05), and 115 postweaning (P<0.05) and had greater overall ADG (P<0.05). Overall ADFI was greater for offspring from sows fed Bt maize (P<0.05) and for Bt maize-fed pigs (P<0.05). Offspring from Bt maize-fed sows had greater carcass (P<0.05) and lighter spleen (P<0.05) weights. Dressing percentage was greater for Bt maize-fed pigs than isogenic maize-fed pigs (P<0.05), and livers were lighter for pigs in the Bt/Bt group than pigs in the iso/Bt or Bt/iso group (P<0.05). Offspring from Bt maize-fed sows also had greater duodenal crypt depths (P<0.05) and lower villus height/crypt depth ratios (P<0.05). No pathology was observed in the organs, and serum biochemistry values generally remained within normal limits and no overall differences were observed, with the exception of overall gamma glutamyltransferase, which was less for pigs on the Bt/Bt treatment than pigs on the iso/Bt and Bt/iso treatments. These results indicate that transgenerational consumption of Bt maize diets is not detrimental to pig growth and health. PMID- 23097399 TI - Breeding and Genetics Symposium: building single nucleotide polymorphism-derived gene regulatory networks: Towards functional genomewide association studies. AB - The advent of economically viable high-throughput genetic and genomic techniques has equipped animal geneticists with an unprecedented ability to generate massive amounts of molecular data. As a result, large lists of genes differentially expressed in many experimental conditions of interests have been reported and, likewise, the association of an ever growing number of DNA variants with phenotypes of importance is now a routine endeavor. Although these studies have greatly improved our understanding of the genetic basis of complex phenotypes, they have also revealed the difficulty in explaining more than a fraction of the genetic variance. Inspired by this data-rich and knowledge-poor dichotomy, systems biology aims at the formal integration of seemingly disparate datasets allowing for a holistic view where key properties of the systems emerge as an intuitive feature and enable the generation of testable hypotheses. Herein, we present 2 examples of integrating molecular data anchored in the power of gene network inference. The first example is concerned with the onset of puberty in Bos indicus-influenced cows bred in Australia. Using the results from genomewide association studies across a range of phenotypes, we developed what we termed an association weight matrix to generate a gene network underlying phenotypes of puberty in cattle. The network was mined for the minimal set of transcription factor genes whose predicted target spanned the majority of the topology of the entire network. The second example deals with piebald, a pigmentation phenotype in Merino sheep. Two networks were developed: a regulatory network and an epistatic network. The former is inferred based on promoter sequence analysis of differentially expressed genes. The epistatic network is built from 2-locus models among all pairwise associated polymorphisms. At the intersection between these 2 networks, we revealed a set of genes and gene-gene interactions of validated and de novo predicted relevance to the piebald phenotype. We argue that these new approaches are holistic and therefore more appropriate than traditional approaches for investigating genetic mechanisms underlying complex phenotypes of importance in livestock species. PMID- 23097398 TI - Follicular characteristics and luteal development after follicle-stimulating hormone induced multiple ovulations in heifers. AB - A protocol based on small doses of FSH was examined for the induction of double or triple (multiple) ovulations in cattle. Ovulation rate, follicular characteristics, and luteal responses were determined. In Exp. 1, three groups of estrous-synchronized, cyclic Holstein heifers were treated once daily, on d 3 to 6 of the cycle, with a FSH product (Folltropin-V): large FSH dose (total of 150 mg; n=18), medium FSH dose (total of 130 mg, n=12), and small FSH dose (total of 80 mg; n=7). Controls received saline (n=6). Prostaglandin F(2alpha) was injected on d 6, ultrasound-guided aspiration of surplus follicles (if needed) was performed on d 7, and GnRH was injected on d 8 to induce ovulation. The large FSH dose induced growth of more (2.6+/-0.3, P<0.05) large follicles than controls on d 8; medium and small FSH doses insufficiently stimulated growth of <2 large follicles. Ovulation rates were determined in subgroups of heifers (n=10, 13, 4, and 6, respectively). The large FSH dose induced greater rates (P<0.01) of mostly double and triple ovulations (90% multiple ovulations, 70% double ovulations), most of which (89%) were bilateral, with only 2 out of 10 heifers requiring aspiration of surplus follicles. Medium and small FSH doses induced fewer multiple ovulations (38% and 25%, respectively). Estradiol concentrations on d 8 did not differ among treatments, but the concentration per large follicle in controls was greater (P<0.05) than in FSH treatments. Mean corpus luteum (CL) volume in single-ovulation controls was greater (P<0.05) than that of multiple ovulations in the large FSH group and total CL volume and progesterone concentrations were numerically greater in multiple ovulations. In Exp. 2, the characteristics of follicles aspirated on d 7 from large FSH (n=11) and control heifers (n=10) were compared. Based on estradiol-to-progesterone ratio, 57% of the large FSH-treated follicles were classified as codominant/healthy follicles and 43% as subordinate/early atretic. Although concentrations of estradiol and androstenedione in FSH-treated codominant follicles were less (P<0.05) than in controls, estradiol-to-progesterone ratio indicated that those follicles were steroidogenically active. Finely tuned small doses of FSH administered during the first follicular wave can induce a large incidence of double/triple, mainly bilateral, ovulations in cattle, which may serve as a basis for treatment aimed at promoting twinning in beef cattle. PMID- 23097400 TI - Placental nutrient transport is affected by pregnancy rank in sheep. AB - Understanding the link between placental function and fetal growth is critical to comprehend the mechanisms underlying altered fetal growth. This study investigated the relationship between fetal weight and placentome type and size in placentae of singleton and twin fetuses and fetuses within a twin pair from ad libitum-fed ewes at d 140 of pregnancy. In addition, insulin, IGF-I, metabolites, and free AA profiles in fetal, umbilical artery, and vein plasma of singleton and twin fetuses were investigated and used as an indicator of placental nutrient transport. Individual placentae per fetus were dissected, placentomes were classed per type (A to D) and size (light to heavy), and placentome number and individual weight were recorded. Twin fetuses were 16% lighter (P = 0.01) than singletons and had a smaller placenta, with 28% decreased placentome weight (P = 0.03) and 35% fewer placentomes (P = 0.001). Twins also had a different distribution of placentome type and size compared with placentae of singletons, such that twins showed a greater proportion of type B and light placentomes compared with singletons. In twins, umbilical artery plasma had less Glu (P < 0.05) and greater Gln (P < 0.05) concentrations than fetal plasma or umbilical vein plasma, but no differences in AA concentrations were observed between these pools in singletons. Glutamate is a major oxidation energy source for the placenta, and the fetal liver is the net producer of Glu using Gln as its main precursor, indicating that the functionality of the fetoplacental unit may be different between singletons and twins. Twin fetuses had 13% less insulin (P = 0.04) concentrations in umbilical artery plasma than singletons. plasma of twin fetuses had 39% less IGF-I (P = 0.003), 33% less His (P = 0.03), and 22% less Gln (P = 0.02) concentrations and tended to have 44% less Arg (P = 0.07) and 20% less Leu (P = 0.06) concentrations than singletons. Arginine, His, and Leu are examples of AA that can promote insulin secretion, and in turn, insulin can increase fetal IGF-I concentrations. In addition, insulin and IGF-I are important fetal growth factors by stimulating and regulating AA transport across the placenta. Collectively, these results indicate that the functionality of the fetoplacental unit may be different between singletons and twins and that AA transport may be reduced in twin placentae. PMID- 23097401 TI - An analysis of survey data by size of the breeding herd for the reproductive management practices of North American sow farms. AB - A survey was performed to assess whether reproductive management differed among small-sized (Sm, <500 sows), medium-sized (M, 501 to 2,000 sows), and large-sized (Lg, 2,001 to 8,000 sows) farms (n=113). Farms with 501 to 4000 sows/barn were most frequent with sows kept in stalls on 90% of farms. More Lg farms (P<0.05) functioned as breed to wean and more Sm and M as farrow to finish. More Sm and Lg farms weaned at >21 d, whereas M farms were more likely to wean at 18 to 21 d (P<0.05). More Lg farms had farrowing rates above 89% than Sm and M farms (P<0.05), and culling rates above 40% were more frequent on M and Lg farms than on S. On M and Lg farms, sows were bred in larger batches, using lower person to sow ratios, and with more people required than on Sm farms (P<0.05). More (P<0.05) M and Lg farms spent time moving sows and on records, but hours devoted to estrous detection, breeding, and other tasks did not differ among farms (P>0.10). More M and Lg farms used more boars for estrus detection, rotated boars, and controlled boar movement than Sm farms (P<0.05). Farm size also influenced semen sourcing, number of doses received, and frequency of semen delivery (P<0.05). More M and Lg farms performed AI in the presence of a boar, left the AI rod in after AI, checked for returns, and diagnosed pregnancy than Sm farms (P<0.05). Start of boar exposure after weaning began on 69% of farms within 2 d, occurring most often in the AM, but with exposure times varying from 1 to 5 min/sow. Semen was thermally protected for 50% of farms receiving shipments, and semen storage was consistent among farms. For AI, service occurred within minutes to hours after detection of estrus on 61% of farms. During AI, procedures such as back-pressure were required, whereas techniques such as hands-free AI were prohibited on most farms. Sow movement was allowed only once at 4 wk after breeding on 50% of farms, and pregnancy diagnosis occurred at 3 to 5 wk on 78% of farms. Most sows were allowed >=1 chance for breeding after conception failure before culling. Incidence of fail to farrow was <5% and litter size was 10 to 13 pigs on >82% of farms. Summer infertility was observed on 69% of farms with estrus and pregnancy failures the leading causes. Over 70% of farms reported a technician effect on fertility. These results suggest that reproductive management of farms in key areas related to weaning, breeding, gestation, and labor use could be a source of variation in reproductive performance. PMID- 23097402 TI - Physiology and Endocrinology Symposium: biological role of interferon tau in endometrial function and conceptus elongation. AB - This review integrates established and new information on the biological role of ovarian progesterone (P4) and interferon tau as well as conceptus- and endometrial-derived factors, PG and cortisol, in endometrial function and conceptus elongation during the periimplantation period of pregnancy in ruminants. Interferon tau is the maternal recognition of pregnancy signal that inhibits production of luteolytic pulses of PGF2alpha by the endometrium to maintain corpora lutea and their production of P4, the unequivocal hormone of pregnancy. Conceptus-endometrial interactions in ruminants are complex and involve carefully orchestrated temporal and spatial alterations in endometrial gene expression during pregnancy. Available results from studies in sheep support the idea that the individual, interactive, and coordinated actions of P4, interferon tau, PG, and cortisol regulate expression of elongation- and implantation-related genes in the endometrial epithelia and that P4 and PG are essential regulators of conceptus elongation. The outcome of these gene expression changes is alterations in endometrial secretions that govern conceptus elongation via effects on trophectoderm proliferation, migration, attachment, and adhesion. An increased knowledge of conceptus-endometrial interactions during early pregnancy in ruminants is necessary to understand and elucidate the causes of recurrent pregnancy loss and to provide a basis for new strategies to improve pregnancy outcome and reproductive efficiency. PMID- 23097403 TI - Effect of sunflower oil supplementation and milking frequency reduction on sheep milk production and composition. AB - The aim of this study was to investigate the effects of milking frequency reduction and dietary lipid supplementation on intake, BW, and milk yield and composition in high yielding dairy ewes. Ten lactating Assaf ewes were allocated into 2 experimental groups (n=5). Ewes were fed alfalfa hay ad libitum and 34 g.kg(-1) of BW of a concentrate feed with either 0 (Control group) or 43 g of sunflower oil.kg(-1) of DM (SO group). The experiment lasted 63 d and consisted of 3 periods. During Period 1 (from d 1 to 21), ewes were milked twice a day. During Period 2 (from d 22 to 49), ewes were unilaterally milked, so that each gland of each ewe was milked either once or twice daily. During Period 3 (from d 50 to the end of the experiment), both udder halves were again milked twice daily. Intake, BW, and milk composition were controlled weekly and milk production from each half udder was recorded twice a week. Total DM intake, BW, and milk yield in Period 1 were not significantly (P>0.10) affected by dietary treatments. Milk yield tended to be increased in the ewes fed the SO diet in periods 2 (P=0.093) and 3 (P=0.067). Oil supplementation (SO diet) significantly (P<0.05) decreased milk protein and total solids concentrations in the 3 experimental periods and fat content in Period 3, and tended (P=0.077) to decline fat content in Period 2. Lactose content and somatic cell count (SCC) were unaffected (P>0.10) by dietary lipid supplementation in any of the experimental periods. There were no significant (P>0.10) differences between half udders in milk yield and composition in Period 1, and in SCC in any of the experimental periods. Fat and total solids contents were unaffected (P>0.10) by reducing milking frequency. Nevertheless, milk protein content was increased (P<0.001) when glands were milked only once daily whereas milk yield and lactose content were decreased (P=0.001). The interaction between gland and diet was significant for lactose in Period 2, suggesting a greater effect of milking frequency reduction on tight junctions in Control ewes. In fact, the ratio between glands for milk yield was significantly (P<0.05) greater in SO (0.82) than in Control (0.72) ewes. In Period 3, this ratio increased but it was still lower in Control ewes (0.92 vs. 0.78, P<0.05). Thus, milking frequency reduction and SO supplementation seem to have counteracting effects on milk production and composition. Our results suggest that SO-supplemented ewes have a better capacity of adaptation to changes in milking frequency, probably due to processes induced in the mammary gland. PMID- 23097404 TI - Breeding and Genetics Symposium: networks and pathways to guide genomic selection. AB - Many traits affecting profitability and sustainability of meat, milk, and fiber production are polygenic, with no single gene having an overwhelming influence on observed variation. No knowledge of the specific genes controlling these traits has been needed to make substantial improvement through selection. Significant gains have been made through phenotypic selection enhanced by pedigree relationships and continually improving statistical methodology. Genomic selection, recently enabled by assays for dense SNP located throughout the genome, promises to increase selection accuracy and accelerate genetic improvement by emphasizing the SNP most strongly correlated to phenotype although the genes and sequence variants affecting phenotype remain largely unknown. These genomic predictions theoretically rely on linkage disequilibrium (LD) between genotyped SNP and unknown functional variants, but familial linkage may increase effectiveness when predicting individuals related to those in the training data. Genomic selection with functional SNP genotypes should be less reliant on LD patterns shared by training and target populations, possibly allowing robust prediction across unrelated populations. Although the specific variants causing polygenic variation may never be known with certainty, a number of tools and resources can be used to identify those most likely to affect phenotype. Associations of dense SNP genotypes with phenotype provide a 1-dimensional approach for identifying genes affecting specific traits; in contrast, associations with multiple traits allow defining networks of genes interacting to affect correlated traits. Such networks are especially compelling when corroborated by existing functional annotation and established molecular pathways. The SNP occurring within network genes, obtained from public databases or derived from genome and transcriptome sequences, may be classified according to expected effects on gene products. As illustrated by functionally informed genomic predictions being more accurate than naive whole-genome predictions of beef tenderness, coupling evidence from livestock genotypes, phenotypes, gene expression, and genomic variants with existing knowledge of gene functions and interactions may provide greater insight into the genes and genomic mechanisms affecting polygenic traits and facilitate functional genomic selection for economically important traits. PMID- 23097405 TI - Joint Alpharma-Beef Species Symposium: implications of beef heifer development systems and lifetime productivity. AB - Research emphasis has been placed on heifer development strategies in recent years, comparing traditional, more intensive systems to more extensive systems using less feed and relying on compensatory gain to reach a target BW. Recent research has indicated that developing heifers to a lighter target BW at breeding (i.e., 50 to 57% of mature BW compared with 60 to 65% BW) reduced development costs and did not impair reproductive performance. Research published through the late 1980s demonstrated greater negative effects of limited postweaning growth on age at puberty and pregnancy rates whereas more recent studies demonstrate less of a negative impact of delayed puberty on pregnancy rate. A limitation of most research concerning influences of nutrition on heifer development and cow reproductive performance is little or limited consideration of long-term implications. Longevity has relatively low heritability; therefore, heifer development and other management strategies have a greater potential to impact cow retention. Establishing the impact of heifer development protocols on longevity is complex, requiring consideration of nutritional factors after the start of breeding and through subsequent calvings. Lower-input heifer development, where all heifers are managed together after the postweaning period, did not impair rebreeding, but continued subsequent restriction in the form of marginal winter supplementation resulted in decreased retention in the breeding herd. Therefore, the compensatory BW gain period for restricted-growth heifers may be important to longevity and lifetime productivity. Adequate growth and development to ensure minimal calving difficulty can be of critical importance for longevity; however, providing additional supplemental feed during postweaning development to accomplish this may be less efficient than later in development. Restricting gain during postweaning development by limiting DMI or developing heifers on dormant winter forage resulted in increased economic advantages compared with developing heifers at greater rates of ADG to achieve a greater target BW. Implications of heifer development system on cow longevity must be considered when evaluating economics of a heifer enterprise; however, studies evaluating the effects of heifer development systems on cow longevity are extremely limited. PMID- 23097406 TI - Effects of lauric acid on ruminal protozoal numbers and fermentation pattern and milk production in lactating dairy cows. AB - The objectives of this study were to evaluate lauric acid (LA) as a practical ruminal protozoa-suppressing agent and assess effects of protozoal suppression on fermentation patterns and milk production in dairy cows. In a pilot study, 6 lactating Holstein cows fitted with ruminal cannulae were used in a randomized complete-block design trial. Cows were fed a basal total mixed ration (TMR) containing (DM basis) 15% alfalfa silage, 40% corn silage, 30% rolled high moisture shelled corn, and 14% solvent soybean meal, and assigned to 1 of 3 treatments: 1) control, 2) 160 g/d of LA, or 3) 222 g/d of sodium laurate, which is equimolar to 160 g/d of LA, all given as a single dose into the rumen via cannulae before feeding. Both agents showed high antiprotozoal activity when pulse dosed at these amounts via ruminal cannulae, reducing protozoa by 90% (P<0.01) within 2 d of treatment. Lauric acid reduced ruminal ammonia concentration by 60% (P<0.01) without altering DMI. Both agents reduced ruminal total free AA concentration (P<0.01) and LA did not affect ruminal pH or total VFA concentration. In a large follow-up feeding trial, 52 Holstein cows (8 with ruminal cannulae) were used in a randomized complete-block design trial. Cows were assigned to 1 of 4 diets and fed only that diet throughout the study. The TMR contained (DM basis) 29% alfalfa silage, 36% corn silage, 14% rolled high moisture shelled corn, and 8% solvent soybean meal. The 4 experimental diets were similar, except part of the finely ground dry corn was replaced with LA in stepwise increments from 0 to 0.97% of dietary DM, which provided (as consumed) 0, 83, 164, and 243 g/d of LA. Adding these amounts of LA to the TMR did not affect DMI, ruminal pH, or other ruminal traits, and milk production. However, LA consumed at 164 and 243 g/d in the TMR reduced the protozoal population by only 25% and 30% (P=0.05), respectively, showing that these levels, when added to the TMR, were not sufficient to achieve a concentration within the rumen that promoted the antiprotozoal effect of LA. PMID- 23097407 TI - Effect of heat intensity and persistency on prolificacy and preweaning kit growth at different stages of the rabbit production cycle. AB - The aim of this research was to assess the effect of temperature intensity and variation both throughout the day and between days within different periods of the reproductive cycle and the lactation of the rabbit. This information would help in establishing optimal patterns of environmental temperature control in rabbitries. The traits analyzed were total number of kits born (TB), number of kits alive at weaning (NW), and average individual weight at weaning (AvgWW). For each trait, several mixed models were fitted to the data, differing only in the number and type of temperature descriptors included in the vector of fixed effects. Those descriptors were the average daily mean, maximum, and range of temperatures (AvgTmean, AvgTmax, and AvgRg, respectively) and the CV of daily mean temperature (CVTmean). All were calculated for periods in which important physiological processes related to the studied traits occur. High environmental temperature was found to have a detrimental effect on prolificacy and preweaning growth of the kits. When the average daily mean reached 20 degrees C, it produced a linear decay of TB of around 0.1 kit/ degrees C. The most sensitive period for TB could cover from spermatogenesis to embryo implantation. However, the high correlation between descriptors calculated for different periods makes it difficult to assign an effect to each specific period and therefore to the specific physiological process occurring in that period. The effect on NW was smaller and quadratic, with an optimum value between 18 degrees C and 21 degrees C. Weaning weight was the most strongly affected trait similar to NW. It also showed a quadratic response to AvgTmean, with an optimum value in the same temperature interval as NW and a strong decline in weaning weight with temperatures higher than 21 degrees C (-14 g/ degrees C). There were no differences on the effect of heat at different stages of lactation on NW and AvgWW. The impact of high environmental temperatures on prolificacy is alleviated if a drop in temperature is produced during the day. Thus, the effect of AvgRg was relevant and positive for TB and NW. However, it had a quadratic negative effect for AvgWW at late lactation. The temperature variation between days within a period has a positive effect on TB and AvgWW but a negative effect on NW when it is produced at middle lactation, whereas there is no effect at other stages of lactation. PMID- 23097408 TI - Evaluating quantitative approaches to dynamic susceptibility contrast MRI among carotid endarterectomy patients. AB - PURPOSE: To evaluate two dynamic susceptibility contrast (DSC) quantification methods in symptomatic carotid artery disease patients undergoing carotid endarterectomy (CEA) surgery by comparing methods directly and assessing the reliability of each method in the hemisphere contralateral to surgery. MATERIALS AND METHODS: Absolute cerebral blood flow (CBF) and volume (CBV) was calculated in putamen and sensorimotor gray matter of 17 patients using two methods: 1) The Bookend method that scales relative DSC images to CBV values calculated from the ratio of pre- and postcontrast T1-weighted images, and 2) the Tail-scaling method that uses the ratio of area under the tails of the venous and arterial concentration time-courses to scale the DSC images. RESULTS: There was a positive correlation between the methods with significant correlation post-CEA (P < 0.035). Intersession correlation was greater when using the Tail-scaling method contralateral to surgery (P < 0.004). CONCLUSION: We have demonstrated correlation between methods that is significant after surgery and have found that the Tail-scaling method produces better test-retest reliability than our implementation of the Bookend method. Results from this study suggest that DSC has the potential to measure hemodynamic changes after endarterectomy and future work is required to establish clinical value. PMID- 23097410 TI - Industrial production and professional application of manufactured nanomaterials enabled end products in Dutch industries: potential for exposure. AB - BACKGROUND: In order to make full use of the opportunities while responsibly managing the risks of working with manufactured nanomaterials (MNM), we need to gain insight into the potential level of exposure to MNM in the industry. Therefore, the goal of this study was to obtain an overview of the potential MNM exposure scenarios within relevant industrial sectors, applied exposure controls, and number of workers potentially exposed to MNM in Dutch industrial sectors producing and applying MNM-enabled end products in the Netherlands. METHODS: A survey was conducted in three phases: (i) identification of MNM-enabled end products; (ii) identification of relevant industrial sectors; and (iii) a tiered telephone survey to estimate actual use of the products among 40 sector organizations/knowledge centres (Tier 1), 350 randomly selected companies (Tier 2), and 110 actively searched companies (Tier 3). RESULTS: The most dominant industrial sectors producing or applying MNM-enabled end products (market penetration >5%) are shoe repair shops, automotive, construction, paint, metal, and textile cleaning industry. In the majority of the companies (76%), potential risks related to working with MNM are not a specific point of interest. The total number of workers potentially exposed to MNM during the production or application of MNM-enabled end products was estimated at approximately 3000 workers in the Netherlands. The results of this study will serve as a basis for in-depth exposure and health surveys that are currently planned in the Netherlands. In addition, the results can be used to identify the most relevant sectors for policy makers and future studies focussing on evaluating the risks of occupational exposure to MNM. PMID- 23097409 TI - Automated unsupervised multi-parametric classification of adipose tissue depots in skeletal muscle. AB - PURPOSE: To introduce and validate an automated unsupervised multi-parametric method for segmentation of the subcutaneous fat and muscle regions to determine subcutaneous adipose tissue (SAT) and intermuscular adipose tissue (IMAT) areas based on data from a quantitative chemical shift-based water-fat separation approach. MATERIALS AND METHODS: Unsupervised standard k-means clustering was used to define sets of similar features (k = 2) within the whole multi-modal image after the water-fat separation. The automated image processing chain was composed of three primary stages: tissue, muscle, and bone region segmentation. The algorithm was applied on calf and thigh datasets to compute SAT and IMAT areas and was compared with a manual segmentation. RESULTS: The IMAT area using the automatic segmentation had excellent agreement with the IMAT area using the manual segmentation for all the cases in the thigh (R(2): 0.96) and for cases with up to moderate IMAT area in the calf (R(2): 0.92). The group with the highest grade of muscle fat infiltration in the calf had the highest error in the inner SAT contour calculation. CONCLUSION: The proposed multi-parametric segmentation approach combined with quantitative water-fat imaging provides an accurate and reliable method for an automated calculation of the SAT and IMAT areas reducing considerably the total postprocessing time. PMID- 23097411 TI - Changes in apparent diffusion coefficient and T2 relaxation during radiotherapy for prostate cancer. AB - PURPOSE: To evaluate regional and temporal changes in apparent diffusion coefficient (ADC) and T2 relaxation during radiation therapy (RT) in patients with low and intermediate risk localized prostate cancer. MATERIALS AND METHODS: Seventeen patients enrolled on a prospective clinical trial where MRI was acquired every 2 weeks throughout eight weeks of image-guided prostate IMRT (78 Gy/39 fractions). ADC and T2 quantification used entire prostate, central gland, benign peripheral zone, and tumor-dense regions-of-interest, and mean values were evaluated for common response trends. RESULTS: Overall, the RT responses were greater than volunteer measurement repeatability, and week 6 appeared to be an optimum time-point for early detection. RT effects on the entire prostate were best detected using ADC (5-7% by week 2, P < 0.0125), effects on peripheral zone were best detected using T2 (19% reduction at week 6; P = 0.004) and effects on tumors were best detected using ADC (14% elevation at week 6; P = 0.004). CONCLUSION: ADC and T2 may be candidate biomarkers of early response to RT warranting further investigation against clinical outcomes. PMID- 23097412 TI - A guide to in silico vaccine discovery for eukaryotic pathogens. AB - In this article, a framework for an in silico pipeline is presented as a guide to high-throughput vaccine candidate discovery for eukaryotic pathogens, such as helminths and protozoa. Eukaryotic pathogens are mostly parasitic and cause some of the most damaging and difficult to treat diseases in humans and livestock. Consequently, these parasitic pathogens have a significant impact on economy and human health. The pipeline is based on the principle of reverse vaccinology and is constructed from freely available bioinformatics programs. There are several successful applications of reverse vaccinology to the discovery of subunit vaccines against prokaryotic pathogens but not yet against eukaryotic pathogens. The overriding aim of the pipeline, which focuses on eukaryotic pathogens, is to generate through computational processes of elimination and evidence gathering a ranked list of proteins based on a scoring system. These proteins are either surface components of the target pathogen or are secreted by the pathogen and are of a type known to be antigenic. No perfect predictive method is yet available; therefore, the highest-scoring proteins from the list require laboratory validation. PMID- 23097413 TI - Evaluation of the tibial tunnel after intraoperatively administered platelet-rich plasma gel during anterior cruciate ligament reconstruction using diffusion weighted and dynamic contrast-enhanced MRI. AB - PURPOSE: To evaluate effect of platelet-rich plasma gel (PRPG), locally administered during the anterior cruciate ligament (ACL) reconstruction, with two MRI methods. The proximal tibial tunnel was assessed with diffusion weighted imaging (DWI) and with dynamic contrast-enhanced imaging (DCE-MRI). MATERIALS AND METHODS: In 50 patients, standard arthroscopic ACL reconstructions were performed. The patients in the PRPG group (n = 25) received a local application of PRPG. The proximal tibial tunnel was examined by DWI and DCE-MRI, which were used to calculate apparent diffusion coefficient (ADC) values, as well as the contrast enhancement gradient (G(enh)) and enhancement factor (F(enh)) values. RESULTS: At 1 month, the calculated average ADC value in the PRPG group was significantly lower than in the control group. At 2.5 and at 6 months, G(enh) was significantly higher in the PRPG group. There were no significant differences in F(enh) between the groups at any control examination. CONCLUSION: DWI and DCE-MRI measurements indicate a reduced extent of edema during the first postoperative month as well as an increased vascular density and microvessel permeability in the proximal tibial tunnel at 1 and 2.5 postoperative months as the effect of the application of PRPG. PMID- 23097414 TI - Fall risk increasing drugs and injuries of the frail elderly - evidence from administrative data. AB - BACKGROUND: Society benefits on a large scale from improved medical care and pharmaceuticals. The prescription of pharmaceuticals, however, also carries risks such as the possibility of an increased hazard of falls, which may lead to severe injuries and increased health expenditures associated with these injuries. This study investigates the relationship of several fall risk increasing drugs (FRIDs) and injuries of elderly persons using multivariate regression models. METHOD: Routine data from the Techniker Krankenkasse of frail elderly persons aged >= 65 years is analysed for the year 2009 by estimating count data models, in order to take the data generating process of the number of injuries into account. The results of this model are compared to those from logistic regressions, which is the default regression model in this field of research. RESULTS: The empirical results suggest that the incidence of injuries strongly increases with doses of antidepressants, anxiolytics, hypnotics and sedatives, antiarrhythmics and drugs from the Priscus-list. However, antihypertensives and antiparkinsonian agents show no significant association and neuroleptics indicate a significant negative association. CONCLUSION: As recurrent injuries are common, the analysis of the number of injuries rather than just the probability of having an injury provides a more informative analysis of FRIDs. According to the empirical results, antidepressants, anxiolytics, hypnotics and sedatives, antiarrhythmics as well as drugs from the Priscus-list should be prescribed carefully, because these drugs are positively correlated with the incidence of injuries. PMID- 23097415 TI - Absence of 'over-the-counter' medicinal products in on-line prescription records: a risk factor of overlooking interactions in the elderly. AB - PURPOSE: To assess possible origins of harmful interactions in elderly patients arising from the current absence of information on over-the-counter (OTC) medicines in the Danish 'on-line prescription record'. METHODS: Information on current use of prescription drugs and OTC medicinal products (non-prescription drugs, herbal medicine, dietary supplements, and others) was collected by home visit interviews. The latter OTC products were not listed in an on-line prescription record that covered the previous two years. Information on interactions between OTC medicines and between OTC products and prescription drugs was obtained from the Danish National Drug Interaction Database. RESULTS: Of the 309 patients recruited (median age 75 years, interquartile range (IQR) 70 81), 229 (74%) used 568 OTC medicines not listed in the Danish 'on-line prescription record', amongst which we identified 166 potential interactions - between OTC treatments or between OTC and prescription drugs. Fifty percent of patients taking OTC medicines were exposed to potential interactions, i.e. one to three instances per patient. Twenty-five percent of patients exposed to interactions experienced interaction listed as 'Can be used with certain precautions'. CONCLUSION: The absence of information on OTC products in an on line prescription record entails a risk of overlooking interactions in elderly patients. Such products should be included in on-line medication records to prevent adverse effects from interactions. However, online medication records are not available in all countries and as inclusion of data on OTC drugs seem not to be feasible presently. Still, it is highly recommended that the patient's drug list is reviewed on a regular basis. PMID- 23097416 TI - Parenting stress and neurocognitive late effects in childhood cancer survivors. AB - BACKGROUND: Surveillance of neurocognitive late effects has typically focused on the pediatric survivor alone and rarely has focused on the potential family burden. We investigated the impact of child neurocognitive effects on parenting stress and hypothesized that parents of childhood cancer survivors with greater executive difficulties experience higher stress relative to parents of children with less adverse impact. METHODS: Parents of 44 children who survived cancer involving central nervous system-directed treatments and who had documented neurocognitive deficits completed standardized questionnaires assessing their perceived level of stress and perception of their child's executive functioning abilities in daily life. Data from performance-based cognitive tests were obtained on the children. Multiple regression models examined socio-demographic, clinical, and child's executive functioning as predictors of parent stress. Differences in parenting stress based on child's level of executive functioning were evaluated. RESULTS: Parent stress was significantly associated with both performance-based and parent report measures of child executive functioning. Child executive functioning significantly predicted parent stress even after controlling for socio-demographic and clinical factors, and the final model accounted for 42% of the variance in parent stress levels. Significant differences in parent stress were found when comparing higher versus lower levels of child executive functioning. The nature of the executive difficulties, however, appears important, as we found increased parenting stress among children with behavioral regulation problems rather than metacognitive difficulties. CONCLUSIONS: The associations between parenting stress and neurocognitive problems found in this study suggest the need for further research, along with professional monitoring and appropriate intervention. PMID- 23097417 TI - Social support and quality of life among lung cancer patients: a systematic review. AB - OBJECTIVE: This systematic review analyzed the relationships between social support and quality of life (QOL) indicators among lung cancer patients. In particular, the patterns of relationships between different social support facets and sources (received and perceived support from healthcare professionals, family, and friends) and QOL aspects (emotional, physical symptoms, functional, and social) as well as the global QOL index were investigated. METHODS: The review yielded 14 original studies (57% applying cross-sectional designs) analyzing data from a total of 2759 patients. RESULTS: Regarding healthcare professionals as support source, corroborating evidence was found for associations between received support (as well as need for and satisfaction with received support) and all aspects of QOL, except for social ones. Overall, significant relations between support from healthcare personnel and QOL were observed more frequently (67% of analyzed associations), compared with support from families and friends (53% of analyzed associations). Corroborating evidence was found for the associations between perceived and received support from family and friends and emotional aspects of QOL. Research investigating perceived social support from unspecified sources indicated few significant relationships (25% of analyzed associations) and only for the global QOL index. CONCLUSIONS: Quantitative and qualitative differences in the associations between social support and QOL are observed, depending on the source and type of support. Psychosocial interventions may aim at enabling provision of social support from healthcare personnel in order to promote emotional, functional, and physical QOL among lung cancer patients. PMID- 23097418 TI - Two distinct SSB protein families in nucleo-cytoplasmic large DNA viruses. AB - MOTIVATION: Eukaryote-infecting nucleo-cytoplasmic large DNA viruses (NCLDVs) feature some of the largest genomes in the viral world. These viruses typically do not strongly depend on the host DNA replication systems. In line with this observation, a number of essential DNA replication proteins, such as DNA polymerases, primases, helicases and ligases, have been identified in the NCLDVs. One other ubiquitous component of DNA replisomes is the single-stranded DNA binding (SSB) protein. Intriguingly, no NCLDV homologs of canonical OB-fold containing SSB proteins had previously been detected. Only in poxviruses, one of seven NCLDV families, I3 was identified as the SSB protein. However, whether I3 is related to any known protein structure has not yet been established. RESULTS: Here, we addressed the case of 'missing' canonical SSB proteins in the NCLDVs and also probed evolutionary origins of the I3 family. Using advanced computational methods, in four NCLDV families, we detected homologs of the bacteriophage T7 SSB protein (gp2.5). We found the properties of these homologs to be consistent with the SSB function. Moreover, we implicated specific residues in single-stranded DNA binding. At the same time, we found no evolutionary link between the T7 gp2.5 like NCLDV SSB homologs and the poxviral SSB protein (I3). Instead, we identified a distant relationship between I3 and small protein B (SmpB), a bacterial RNA binding protein. Thus, apparently, the NCLDVs have the two major distinct sets of SSB proteins having bacteriophage and bacterial origins, respectively. PMID- 23097420 TI - AffyRNADegradation: control and correction of RNA quality effects in GeneChip expression data. AB - MOTIVATION: Gene expression experiments aim to accurately quantify thousands of transcripts in parallel. Factors posterior to RNA extraction can, however, impair their accurate representation. RNA degradation and differences in the efficiency of amplification affect raw intensity measurements using Affymetrix expression arrays. The positional intensity decay of specifically hybridized probes along the transcript they intend to interrogate is used to estimate the RNA quality in a sample and to correct probe intensities for the degradation bias. This functionality, for which no previous software solution is available, is implemented in the R/Bioconductor package AffyRNADegradation presented here. AVAILABILITY: The package is available via Bioconductor at the URL http://bioconductor.org/packages/release/bioc/html/AffyRNA Degradation.html PMID- 23097419 TI - Simultaneous alignment and clustering of peptide data using a Gibbs sampling approach. AB - MOTIVATION: Proteins recognizing short peptide fragments play a central role in cellular signaling. As a result of high-throughput technologies, peptide-binding protein specificities can be studied using large peptide libraries at dramatically lower cost and time. Interpretation of such large peptide datasets, however, is a complex task, especially when the data contain multiple receptor binding motifs, and/or the motifs are found at different locations within distinct peptides. RESULTS: The algorithm presented in this article, based on Gibbs sampling, identifies multiple specificities in peptide data by performing two essential tasks simultaneously: alignment and clustering of peptide data. We apply the method to de-convolute binding motifs in a panel of peptide datasets with different degrees of complexity spanning from the simplest case of pre aligned fixed-length peptides to cases of unaligned peptide datasets of variable length. Example applications described in this article include mixtures of binders to different MHC class I and class II alleles, distinct classes of ligands for SH3 domains and sub-specificities of the HLA-A*02:01 molecule. AVAILABILITY: The Gibbs clustering method is available online as a web server at http://www.cbs.dtu.dk/services/GibbsCluster. PMID- 23097421 TI - FFPopSim: an efficient forward simulation package for the evolution of large populations. AB - MOTIVATION: The analysis of the evolutionary dynamics of a population with many polymorphic loci is challenging, as a large number of possible genotypes needs to be tracked. In the absence of analytical solutions, forward computer simulations are an important tool in multi-locus population genetics. The run time of standard algorithms to simulate sexual populations increases as 8(L) with the number of loci L, or with the square of the population size N. RESULTS: We have developed algorithms to simulate large populations with arbitrary genetic maps, including multiple crossovers, with a run time that scales as 3(L). If the number of crossovers is restricted to at most one, the run time is reduced to L2(L). The algorithm is based on an analogue of the Fast Fourier Transform (FFT) and allows for arbitrary fitness functions (i.e. any epistasis). In addition, we include a streamlined individual-based framework. The library is implemented as a collection of C++ classes and a Python interface. PMID- 23097422 TI - Human tRNA(Sec) associates with HeLa membranes, cell lipid liposomes, and synthetic lipid bilayers. AB - We have shown previously that simple RNA structures bind pure phospholipid liposomes. However, binding of bona fide cellular RNAs under physiological ionic conditions is shown here for the first time. Human tRNA(Sec) contains a hydrophobic anticodon-loop modification: N6-isopentenyladenosine (i6A) adjacent to its anticodon. Using a highly specific double-probe hybridization assay, we show mature human tRNA(Sec) specifically retained in HeLa intermediate-density membranes. Further, isolated human tRNA(Sec) rebinds to liposomes from isolated HeLa membrane lipids, to a much greater extent than an unmodified tRNA(Sec) transcript. To better define this affinity, experiments with pure lipids show that liposomes forming rafts or including positively charged sphingosine, or particularly both together, exhibit increased tRNA(Sec) binding. Thus tRNA(Sec) residence on membranes is determined by several factors, such as hydrophobic modification (likely isopentenylation of tRNA(Sec)), lipid structure (particularly lipid rafts), or sphingosine at a physiological concentration in rafted membranes. From prior work, RNA structure and ionic conditions also appear important. tRNA(Sec) dissociation from HeLa liposomes implies a mean membrane residence of 7.6 min at 24 degrees C (t(1/2) = 5.3 min). Clearly RNA with a 5 carbon hydrophobic modification binds HeLa membranes, probably favoring raft domains containing specific lipids, for times sufficient to alter biological fates. PMID- 23097423 TI - RNase III-independent microRNA biogenesis in mammalian cells. AB - RNase III enzymes are fundamental to the biogenesis of microRNAs (miRNAs) and small interfering RNAs (siRNAs) in all species studied. Although alternative miRNA pathways independent of Drosha or Dicer exist, each still requires one RNase III-type enzyme. Here, we describe two strategies that marry either RNase Z or the Integrator complex with the slicing activity of Argonaute2 to generate highly functional mature miRNAs. We provide stringent validation of their RNase III independence by demonstrating efficient miRNA biogenesis and activity in Drosha and Dicer knockout cells. These data provide proof-of-principle evidence for additional mechanistic possibilities for efficient generation of small regulatory RNAs, and represent novel silencing triggers that may be exploited for technical purposes. PMID- 23097424 TI - An RNAi screen identifies additional members of the Drosophila Integrator complex and a requirement for cyclin C/Cdk8 in snRNA 3'-end formation. AB - Formation of the 3' end of RNA polymerase II-transcribed snRNAs requires a poorly understood group of proteins called the Integrator complex. Here we used a fluorescence-based read-through reporter that expresses GFP in response to snRNA misprocessing and performed a genome-wide RNAi screen in Drosophila S2 cells to identify novel factors required for snRNA 3'-end formation. In addition to the known Integrator complex members, we identified Asunder and CG4785 as additional Integrator subunits. Functional and biochemical experiments revealed that Asunder and CG4785 are additional core members of the Integrator complex. We also identified a conserved requirement in both fly and human snRNA 3'-end processing for cyclin C and Cdk8 that is distinct from their function in the Mediator Cdk8 module. Moreover, we observed biochemical association between Integrator proteins and cyclin C/Cdk8, and that overexpression of a kinase-dead Cdk8 causes snRNA misprocessing. These data functionally define the Drosophila Integrator complex and demonstrate an additional function for cyclin C/Cdk8 unrelated to its function in Mediator. PMID- 23097425 TI - Cotranscriptional splicing efficiency differs dramatically between Drosophila and mouse. AB - Spliceosome assembly and/or splicing of a nascent transcript may be crucial for proper isoform expression and gene regulation in higher eukaryotes. We recently showed that cotranscriptional splicing occurs efficiently in Drosophila, but there are not comparable genome-wide nascent splicing data from mammals. To provide this comparison, we analyze a recently generated, high-throughput sequencing data set of mouse liver nascent RNA, originally studied for circadian transcriptional regulation. Cotranscriptional splicing is approximately twofold less efficient in mouse liver than in Drosophila, i.e., nascent intron levels relative to exon levels are ~0.55 in mouse versus 0.25 in the fly. An additional difference between species is that only mouse cotranscriptional splicing is optimal when 5'-exon length is between 50 and 500 bp, and intron length does not correlate with splicing efficiency, consistent with exon definition. A similar analysis of intron and exon length dependence in the fly is more consistent with intron definition. Contrasted with these differences are many similarities between the two systems: Alternatively annotated introns are less efficiently spliced cotranscriptionally than constitutive introns, and introns of single intron genes are less efficiently spliced than introns from multi-intron genes. The most striking common feature is intron position: Cotranscriptional splicing is much more efficient when introns are far from the 3' ends of their genes. Additionally, absolute gene length correlates positively with cotranscriptional splicing efficiency independently of intron location and position, in flies as well as in mice. The gene length and distance effects indicate that more "nascent time" gives rise to greater cotranscriptional splicing efficiency in both systems. PMID- 23097427 TI - RNA-ID, a highly sensitive and robust method to identify cis-regulatory sequences using superfolder GFP and a fluorescence-based assay. AB - We have developed a robust and sensitive method, called RNA-ID, to screen for cis regulatory sequences in RNA using fluorescence-activated cell sorting (FACS) of yeast cells bearing a reporter in which expression of both superfolder green fluorescent protein (GFP) and yeast codon-optimized mCherry red fluorescent protein (RFP) is driven by the bidirectional GAL1,10 promoter. This method recapitulates previously reported progressive inhibition of translation mediated by increasing numbers of CGA codon pairs, and restoration of expression by introduction of a tRNA with an anticodon that base pairs exactly with the CGA codon. This method also reproduces effects of paromomycin and context on stop codon read-through. Five key features of this method contribute to its effectiveness as a selection for regulatory sequences: The system exhibits greater than a 250-fold dynamic range, a quantitative and dose-dependent response to known inhibitory sequences, exquisite resolution that allows nearly complete physical separation of distinct populations, and a reproducible signal between different cells transformed with the identical reporter, all of which are coupled with simple methods involving ligation-independent cloning, to create large libraries. Moreover, we provide evidence that there are sequences within a 9-nt library that cause reduced GFP fluorescence, suggesting that there are novel cis regulatory sequences to be found even in this short sequence space. This method is widely applicable to the study of both RNA-mediated and codon-mediated effects on expression. PMID- 23097426 TI - Post-developmental microRNA expression is required for normal physiology, and regulates aging in parallel to insulin/IGF-1 signaling in C. elegans. AB - Regulation of gene expression by microRNAs (miRNAs) is essential for normal development, but the roles of miRNAs in the physiology of adult animals are poorly understood. We have isolated a conditional allele of DGCR8/pash-1, which allows reversible and rapid inactivation of miRNA synthesis in vivo in Caenorhabditis elegans. This is a powerful new tool that allows dissection of post-developmental miRNA functions. We demonstrate that continuous synthesis of miRNAs is dispensable for cellular viability but critical for the physiology of adult animals. Loss of miRNA synthesis in the adult reduces lifespan and results in rapid aging. The insulin/IGF-1 signaling pathway is a critical determinant of lifespan, and is modulated by miRNAs. We find that although miRNA expression is required for some mechanisms of lifespan extension, it is not essential for the longevity of animals lacking insulin/IGF-1 signaling. Further, misregulated insulin/IGF-1 signaling cannot account for the reduced lifespan caused by disruption of miRNA synthesis. We show that miRNAs act in parallel with insulin/IGF-1 signaling to regulate a shared set of downstream genes important for physiological processes that determine lifespan. We conclude that coordinated transcriptional and post-transcriptional regulation of gene expression promotes longevity. PMID- 23097428 TI - Trmt61B is a methyltransferase responsible for 1-methyladenosine at position 58 of human mitochondrial tRNAs. AB - In human mitochondria, 1-methyladenosine (m1A) occurs at position 58 of tRNA(Leu(UUR)). In addition, partial m1A58 modifications have been found in human mitochondrial tRNA(Lys) and tRNA(Ser(UCN)). We identified human Trmt61B, which encodes a mitochondria-specific tRNA methyltransferase responsible for m1A58 in these three tRNAs. Trmt61B is dominantly localized to the mitochondria. m1A58 formation in human mitochondrial tRNA(Leu(UUR)) could be reconstituted in vitro using recombinant Trmt61B in the presence of Ado-Met as a methyl donor. Unlike the cytoplasmic tRNA m1A58 methyltransferase that consists of an alpha2beta2 heterotetramer formed by Trmt61A and Trmt6, Trmt61B formed a homo-oligomer (presumably a homotetramer) that resembled the bacterial homotetrameric m1A58 methyltransferase. The bacterial origin of Trmt61B is supported by the results of the phylogenetic analysis. PMID- 23097429 TI - Alternative polyadenylation: new insights from global analyses. AB - Recent studies have revealed widespread mRNA alternative polyadenylation (APA) in eukaryotes and its dynamic spatial and temporal regulation. APA not only generates proteomic and functional diversity, but also plays important roles in regulating gene expression. Global deregulation of APA has been demonstrated in a variety of human diseases. Recent exciting advances in the field have been made possible in a large part by high throughput analyses using newly developed experimental tools. Here I review the recent progress in global studies of APA and the insights that have emerged from these and other studies that use more conventional methods. PMID- 23097430 TI - Transcriptomic profiling of the oyster pathogen Vibrio splendidus opens a window on the evolutionary dynamics of the small RNA repertoire in the Vibrio genus. AB - Work in recent years has led to the recognition of the importance of small regulatory RNAs (sRNAs) in bacterial regulation networks. New high-throughput sequencing technologies are paving the way to the exploration of an expanding sRNA world in nonmodel bacteria. In the Vibrio genus, compared to the enterobacteriaceae, still a limited number of sRNAs have been characterized, mostly in Vibrio cholerae, where they have been shown to be important for virulence, as well as in Vibrio harveyi. In addition, genome-wide approaches in V. cholerae have led to the discovery of hundreds of potential new sRNAs. Vibrio splendidus is an oyster pathogen that has been recently associated with massive mortality episodes in the French oyster growing industry. Here, we report the first RNA-seq study in a Vibrio outside of the V. cholerae species. We have uncovered hundreds of candidate regulatory RNAs, be it cis-regulatory elements, antisense RNAs, and trans-encoded sRNAs. Conservation studies showed the majority of them to be specific to V. splendidus. However, several novel sRNAs, previously unidentified, are also present in V. cholerae. Finally, we identified 28 trans sRNAs that are conserved in all the Vibrio genus species for which a complete genome sequence is available, possibly forming a Vibrio "sRNA core." PMID- 23097431 TI - A transmembrane domain and GxxxG motifs within L2 are essential for papillomavirus infection. AB - During cellular invasion, human papillomavirus type 16 (HPV16) must transfer its viral genome (vDNA) across the endosomal membrane prior to its accumulation at nuclear PML bodies for the establishment of infection. After cellular uptake, the capsid likely undergoes pH-dependent disassembly within the endo-/lysosomal compartment, thereby exposing hidden domains in L2 that facilitate membrane penetration of L2/vDNA complexes. In an effort to identify regions of L2 that might physically interact with membranes, we have subjected the L2 sequence to multiple transmembrane (TM) domain prediction algorithms. Here, we describe a conserved TM domain within L2 (residues 45 to 67) and investigate its role in HPV16 infection. In vitro, the predicted TM domain adopts an alpha-helical structure in lipid environments and can function as a real TM domain, although not as efficiently as the bona fide TM domain of PDGFR. An L2 double point mutant renders the TM domain nonfunctional and blocks HPV16 infection by preventing endosomal translocation of vDNA. The TM domain contains three highly conserved GxxxG motifs. These motifs can facilitate homotypic and heterotypic interactions between TM helices, activities that may be important for vDNA translocation. Disruption of some of these GxxxG motifs resulted in noninfectious viruses, indicating a critical role in infection. Using a ToxR-based homo-oligomerization assay, we show a propensity for this TM domain to self-associate in a GxxxG dependent manner. These data suggest an important role for the self-associating L2 TM domain and the conserved GxxxG motifs in the transfer of vDNA across the endo-/lysosomal membrane. PMID- 23097433 TI - Genomic characterization of Japanese macaque rhadinovirus, a novel herpesvirus isolated from a nonhuman primate with a spontaneous inflammatory demyelinating disease. AB - Japanese macaque rhadinovirus (JMRV) is a novel gamma-2 herpesvirus that was isolated from a Japanese macaque (JM) with an inflammatory demyelinating encephalomyelitis referred to as Japanese macaque encephalomyelitis, a disease that possesses clinical and histopathological features resembling multiple sclerosis in humans. Genomic DNA sequence analysis reveals that JMRV is a gammaherpesvirus closely related to rhesus macaque rhadinovirus (RRV) and human herpesvirus 8. We describe here the complete nucleotide sequence and structure of the JMRV genome, as well as the sequence of two plaque isolates of this virus. Analysis of the JMRV genome not only demonstrates that this virus shares a number of genes with RRV that may be involved in pathogenesis but also indicates the presence of unique JMRV genes that could potentially contribute to disease development. The knowledge of the genomic sequence of JMRV, and the ability to easily propagate the virus in vitro, make JMRV infection of JM an attractive model for examining the potential role of an infectious viral agent in the development of demyelinating encephalomyelitis disease in vivo. PMID- 23097432 TI - Reassortment between two serologically unrelated bluetongue virus strains is flexible and can involve any genome segment. AB - Coinfection of a cell by two different strains of a segmented virus can give rise to a "reassortant" with phenotypic characteristics that might differ from those of the parental strains. Bluetongue virus (BTV) is a double-stranded RNA (dsRNA) segmented virus and the cause of bluetongue, a major infectious disease of livestock. BTV exists as at least 26 different serotypes (BTV-1 to BTV-26). Prompted by the isolation of a field reassortant between BTV-1 and BTV-8, we systematically characterized the process of BTV reassortment. Using a reverse genetics approach, our study clearly indicates that any BTV-1 or BTV-8 genome segment can be rescued in the heterologous "backbone." To assess phenotypic variation as a result of reassortment, we examined viral growth kinetics and plaque sizes in in vitro experiments and virulence in an experimental mouse model of bluetongue disease. The monoreassortants generated had phenotypes that were very similar to those of the parental wild-type strains both in vitro and in vivo. Using a forward genetics approach in cells coinfected with BTV-1 and BTV-8, we have shown that reassortants between BTV-1 and BTV-8 are generated very readily. After only four passages in cell culture, we could not detect wild-type BTV-1 or BTV-8 in any of 140 isolated viral plaques. In addition, most of the isolated reassortants contained heterologous VP2 and VP5 structural proteins, while only 17% had homologous VP2 and VP5 proteins. Our study has shown that reassortment in BTV is very flexible, and there is no fundamental barrier to the reassortment of any genome segment. Given the propensity of BTV to reassort, it is increasingly important to have an alternative classification system for orbiviruses. PMID- 23097434 TI - Molecular requirements for T cell recognition of N-myristoylated peptides derived from the simian immunodeficiency virus Nef protein. AB - We have recently isolated a rhesus macaque cytotoxic T cell line, 2N5.1, that specifically recognizes an N-myristoylated 5-mer peptide (C(14)-Gly-Gly-Ala-Ile Ser [C14nef5]) derived from the simian immunodeficiency virus (SIV) Nef protein. Such C14nef5-specific T cells expand in the circulation of SIV-infected monkeys, underscoring the capacity of T cells to recognize viral lipopeptides; however, the molecular basis for the lipopeptide antigen presentation remains to be elucidated. Here, functional studies indicated that the putative antigen presenting molecule for 2N5.1 was likely to have two separate antigen-binding sites, one for interaction with a C(14)-saturated acyl chain and the other for anchorage of the C-terminal serine residue. Mutants with alanine substitutions for the second glycine residue and the fourth isoleucine residue were not recognized by 2N5.1 but interfered with the presentation of C14nef5 to 2N5.1, indicating that these structural analogues retained the ability to interact with the antigen-presenting molecules. In contrast to the highly specific recognition of C14nef5 by 2N5.1, an additional cytotoxic T cell line, SN45, established independently from a C14nef5-stimulated T cell culture, showed superb reactivity to both C14nef5 and an N-myristoylated Nef 4-mer peptide, and therefore, the C terminal serine residue was dispensable for the recognition of lipopeptides by the SN45 T cells. Furthermore, the mutants with alanine substitutions were indeed recognized by the SN45 T cells. Given that N-myristoylation of the Nef protein occurs in the conserved motifs and is critical for viral pathogenesis, these observations predict that the lipopeptide-specific T cell response is difficult for viruses to avoid by simply introducing amino acid mutations. PMID- 23097435 TI - The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. AB - Following entry of the HIV-1 core into target cells, productive infection depends on the proper disassembly of the viral capsid (uncoating). Although much is known regarding HIV-1 entry, the actions of host cell proteins that HIV-1 utilizes during early postentry steps are poorly understood. One such factor, transportin SR2 (TRN-SR2)/transportin 3 (TNPO3), promotes infection by HIV-1 and some other lentiviruses, and recent studies have genetically linked TNPO3 dependence of infection to the viral capsid protein (CA). Here we report that purified recombinant TNPO3 stimulates the uncoating of HIV-1 cores in vitro. The stimulatory effect was reduced by RanGTP, a known ligand for transportin family members. Depletion of TNPO3 in target cells rendered HIV-1 less susceptible to inhibition by PF74, a small-molecule HIV-1 inhibitor that induces premature uncoating. In contrast to the case for TNPO3, addition of the CA-binding host protein cyclophilin A (CypA) inhibited HIV-1 uncoating and reduced the stimulatory effect of TNPO3 on uncoating in vitro. In cells in which TNPO3 was depleted, HIV-1 infection was enhanced 4-fold by addition of cyclosporine, indicating that the requirement for TNPO3 in HIV-1 infection is modulated by CypA CA interactions. Although TNPO3 was localized primarily to the cytoplasm, depletion of TNPO3 from target cells inhibited HIV-1 infection without reducing the accumulation of nuclear proviral DNA, suggesting that TNPO3 facilitates a stage of the virus life cycle subsequent to nuclear entry. Our results suggest that TNPO3 and cyclophilin A facilitate HIV-1 infection by coordinating proper uncoating of the core in target cells. PMID- 23097436 TI - Efficient herpes simplex virus 1 replication requires cellular ATR pathway proteins. AB - Herpes simplex virus 1 (HSV-1) is a double-stranded DNA virus that replicates in the nucleus of the host cell and is known to interact with several components of the cellular DNA-damage-signaling machinery. We have previously reported that the DNA damage response kinase, ATR, is specifically inactivated in HSV-1-infected cells. On the other hand, we have also shown that ATR and its scaffolding protein, ATRIP, are recruited to viral replication compartments, where they play beneficial roles during HSV-1 replication. In order to better understand this apparent discrepancy, we tested the hypothesis that some of the components of the ATR pathway may exert an antiviral effect on infection. In fact, we learned that all 10 of the canonical ATR pathway proteins are stable in HSV-infected cells and are recruited to viral replication compartments; furthermore, short hairpin RNA (shRNA) knockdown shows that several, including ATRIP, RPA70, TopBP1, Claspin, and CINP, are required for efficient HSV-1 replication. We also determined that activation of the ATR kinase prior to infection did not affect virus yield but did result in reduced levels of recombination between coinfecting viruses. Together, these data suggest that ATR pathway proteins are not antiviral per se but that activation of ATR signaling may have negative consequences during viral replication, such as inhibiting recombination. PMID- 23097437 TI - Deep RNA sequencing reveals complex transcriptional landscape of a bat adenovirus. AB - Bat adenoviruses are a group of recently identified adenoviruses (AdVs) which are highly prevalent in bats yet share low similarity to known AdVs from other species. In this study, deep RNA sequencing was used to analyze the transcriptome at five time points following the infection of a bat AdV in a kidney cell line derived from a myotis bat species. Evidence of AdV replication was observed with the proportion of viral RNAs ranging from 0.01% at 6 h to 1.3% at 18 h. Further analysis of viral temporal gene expression revealed three replication stages, the early-stage genes encoding mainly host interaction proteins, the intermediate stage genes for the DNA replication and assembly proteins, and the late-stage genes for most structural proteins. Several bat AdV genes were expressed at stages that differed from those of their counterpart genes previously reported for human AdV type 2. In addition, single-base resolution splice sites of several genes and promoter regions of all 30 viral genes were fully determined. Simultaneously, the temporal cellular gene expression profiles were identified. The most overrepresented functional categories of the differentially expressed genes were related to cellular immune response, transcription, translation, and DNA replication and repair. Taken together, the deep RNA sequencing provided a global, transcriptional profile of the novel bat AdV and the virus-host interactions which will be useful for the understanding and investigation of AdV replication, pathogenesis, and specific virus-bat interactions in future research. PMID- 23097438 TI - APOBEC3G restricts HIV-1 to a greater extent than APOBEC3F and APOBEC3DE in human primary CD4+ T cells and macrophages. AB - APOBEC3 proteins inhibit HIV-1 replication in experimental systems and induce hypermutation in infected patients; however, the relative contributions of several APOBEC3 proteins to restriction of HIV-1 replication in the absence of the viral Vif protein in human primary CD4(+) T cells and macrophages are unknown. We observed significant inhibition of HIV-1Deltavif produced in 293T cells in the presence of APOBEC3DE (A3DE), APOBEC3F (A3F), APOBEC3G (A3G), and APOBEC3H haplotype II (A3H HapII) but not APOBEC3B (A3B), APOBEC3C (A3C), or APOBEC3H haplotype I (A3H HapI). Our previous studies showed that Vif amino acids Y(40)RHHY(44) are important for inducing proteasomal degradation of A3G, whereas amino acids (14)DRMR(17) are important for degradation of A3F and A3DE. Here, we introduced substitution mutations of (40)YRHHY(44) and (14)DRMR(17) in replication-competent HIV-1 to generate vif mutants NL4-3 YRHHY>A5 and NL4-3 DRMR>A4 to compare the antiviral activity of A3G to the combined antiviral activity of A3F and A3DE in activated CD4(+) T cells and macrophages. During the first 15 days (round 1), in which multiple cycles of viral replication occurred, both the NL4-3 YRHHY>A5 and NL4-3 DRMR>A4 mutants replicated in activated CD4(+) T cells and macrophages, and only the NL4-3 YRHHY>A5 mutant showed a 2- to 4-day delay in replication compared to the wild type. During the subsequent 27 days (round 2) of cultures initiated with peak virus obtained from round 1, the NL4-3 YRHHY>A5 mutant exhibited a longer, 8- to 10-day delay and the NL4-3 DRMR>A4 mutant exhibited a 2- to 6-day delay in replication compared to the wild type. The NL4-3 YRHHY>A5 and NL4-3 DRMR>A4 mutant proviruses displayed G-to-A hypermutations primarily in GG and GA dinucleotides as expected of A3G- and A3F- or A3DE-mediated deamination, respectively. We conclude that A3G exerts a greater restriction effect on HIV-1 than A3F and A3DE. PMID- 23097440 TI - Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374. AB - GS-8374 is a potent HIV protease inhibitor (PI) with a unique diethyl-phosphonate moiety. Due to a balanced contribution of enthalpic and entropic components to its interaction with the protease (PR) active site, the compound retains activity against HIV mutants with high-level multi-PI resistance. We report here the in vitro selection and characterization of HIV variants resistant to GS-8374. While highly resistant viruses with multiple mutations in PR were isolated in the presence of control PIs, an HIV variant displaying moderate (14-fold) resistance to GS-8374 was generated only after prolonged passaging for >300 days. The isolate showed low-level cross-resistance to darunavir, atazanavir, lopinavir, and saquinavir, but not other PIs, and contained a single R41K mutation in PR combined with multiple genotypic changes in the Gag matrix, capsid, nucleocapsid, and SP2 domains. Mutations also occurred in the transframe peptide and p6* domain of the Gag-Pol polyprotein. Analysis of recombinant HIV variants indicated that mutations in Gag, but not the R41K in PR, conferred reduced susceptibility to GS 8374. The Gag mutations acted in concert, since they did not affect susceptibility when introduced individually. Analysis of viral particles revealed that the mutations rendered Gag more susceptible to PR-mediated cleavage in the presence of GS-8374. In summary, the emergence of resistance to GS-8374 involved a combination of substrate mutations without typical resistance mutations in PR. These substrate changes were distributed throughout Gag and acted in an additive manner. Thus, they are classified as primary resistance mutations indicating a unique mechanism and pathway of resistance development for GS-8374. PMID- 23097439 TI - Transcriptional profiling of experimental CD8(+) lymphocyte depletion in rhesus macaques infected with simian immunodeficiency virus SIVmac239. AB - CD8(+) T cells inhibit virus replication in SIV-infected rhesus macaques. However, it is unclear to what extent the viral suppression mediated by CD8(+) T cells reflects direct killing of infected cells as opposed to indirect, noncytolytic mechanisms. In this study, we used functional genomics to investigate noncytolytic mechanisms of in vivo viral suppression mediated by CD8(+) lymphocytes. Eight chronically SIVmac239-infected rhesus macaques underwent CD8(+) lymphocyte depletion, and RNA from whole blood was obtained prior to depletion, during the nadir of CD8(+) cell depletion, and after CD8(+) lymphocyte numbers had rebounded. We observed significant downregulation of the expression of genes encoding factors that can suppress SIV replication, including the CCR5-binding chemokine CCL5/RANTES and CCL4 and several members of the tripartite motif-containing (TRIM) family. Surprisingly, we also noted a strong, widespread downregulation of alpha- and theta-defensins with anti-HIV activity, which are not expressed by CD8(+) T cells. After cessation of depleting antibody treatment, we observed induction of a transcriptional signature indicative of B lymphocyte activation. Validation experiments demonstrated that animals during this period had elevated levels of B cells coupled with higher expression of the proliferative marker Ki67, indicating that CD8(+) depletion triggered a potent expansion of B cell numbers. Collectively, these data identify antiviral pathways perturbed by in vivo CD8(+) T cell depletion that may contribute to noncytolytic control of SIV replication. PMID- 23097441 TI - A novel function of RNAs arising from the long terminal repeat of human endogenous retrovirus 9 in cell cycle arrest. AB - The human genome contains approximately 50 copies of the replication-defective human endogenous retrovirus 9 (ERV-9) and thousands of copies of its solitary long term repeat (sLTR) element. While some sLTRs are located upstream of critical genes and have enhancer activity, other sLTRs are located within introns and may be transcribed as RNAs. We found that intronic RNAs arising from U3 sLTRs of ERV-9 were expressed as both sense (S) and antisense (AS) transcripts in all human cells tested but that expression levels differed in malignant versus nonmalignant cells. In nonmalignant cells, AS was expressed at higher levels than S and at higher levels than in malignant cells; in malignant cells, AS was expressed at amounts equivalent to those of S RNA. Critically, U3 AS RNA was found to physically bind to key transcription factors for cellular proliferation, including NF-Y, p53, and sp1, indicating that such RNA transcripts may function as decoy targets or traps for NF-Y and thus inhibit the growth of human cancer cells. Indeed, short U3 oligodeoxynucleotides (ODNs) based on these RNA sequences ably inhibited proliferation of cancer cell lines driven by cyclins B1/B2, the gene targets of NF-Y. PMID- 23097442 TI - Japanese encephalitis virus core protein inhibits stress granule formation through an interaction with Caprin-1 and facilitates viral propagation. AB - Stress granules (SGs) are cytoplasmic foci composed of stalled translation preinitiation complexes induced by environmental stress stimuli, including viral infection. Since viral propagation completely depends on the host translational machinery, many viruses have evolved to circumvent the induction of SGs or co-opt SG components. In this study, we found that expression of Japanese encephalitis virus (JEV) core protein inhibits SG formation. Caprin-1 was identified as a binding partner of the core protein by an affinity capture mass spectrometry analysis. Alanine scanning mutagenesis revealed that Lys(97) and Arg(98) in the alpha-helix of the JEV core protein play a crucial role in the interaction with Caprin-1. In cells infected with a mutant JEV in which Lys(97) and Arg(98) were replaced with alanines in the core protein, the inhibition of SG formation was abrogated, and viral propagation was impaired. Furthermore, the mutant JEV exhibited attenuated virulence in mice. These results suggest that the JEV core protein circumvents translational shutoff by inhibiting SG formation through an interaction with Caprin-1 and facilitates viral propagation in vitro and in vivo. PMID- 23097443 TI - Enterovirus 71 uses cell surface heparan sulfate glycosaminoglycan as an attachment receptor. AB - Enterovirus 71 (EV-71) infections are usually associated with mild hand, foot, and mouth disease in young children but have been reported to cause severe neurological complications with high mortality rates. To date, four EV-71 receptors have been identified, but inhibition of these receptors by antagonists did not completely abolish EV-71 infection, implying that there is an as yet undiscovered receptor(s). Since EV-71 has a wide range of tissue tropisms, we hypothesize that EV-71 infections may be facilitated by using receptors that are widely expressed in all cell types, such as heparan sulfate. In this study, heparin, polysulfated dextran sulfate, and suramin were found to significantly prevent EV-71 infection. Heparin inhibited infection by all the EV-71 strains tested, including those with a single-passage history. Neutralization of the cell surface anionic charge by polycationic poly-d-lysine and blockage of heparan sulfate by an anti-heparan sulfate peptide also inhibited EV-71 infection. Interference with heparan sulfate biosynthesis either by sodium chlorate treatment or through transient knockdown of N-deacetylase/N-sulfotransferase-1 and exostosin-1 expression reduced EV-71 infection in RD cells. Enzymatic removal of cell surface heparan sulfate by heparinase I/II/III inhibited EV-71 infection. Furthermore, the level of EV-71 attachment to CHO cell lines that are variably deficient in cell surface glycosaminoglycans was significantly lower than that to wild-type CHO cells. Direct binding of EV-71 particles to heparin-Sepharose columns under physiological salt conditions was demonstrated. We conclude that EV 71 infection requires initial binding to heparan sulfate as an attachment receptor. PMID- 23097444 TI - Quantification of the dynamics of enterovirus 71 infection by experimental mathematical investigation. AB - Enterovirus 71 (EV71) is the causative agent of hand-foot-and-mouth disease and can trigger neurological disorders. EV71 outbreaks are a major public health concern in Asia-Pacific countries. By performing experimental-mathematical investigation, we demonstrate here that viral productivity and transmissibility but not viral cytotoxicity are drastically different among EV71 strains and can be associated with their epidemiological backgrounds. This is the first report demonstrating the dynamics of nonenveloped virus replication in cell culture using mathematical modeling. PMID- 23097445 TI - Cellular LITAF interacts with frog virus 3 75L protein and alters its subcellular localization. AB - Iridoviruses are a family of large double-stranded DNA (dsDNA) viruses that are composed of 5 genera, including the Lymphocystivirus, Ranavirus, Megalocytivirus, Iridovirus, and Chloriridovirus genera. The frog virus 3 (FV3) 75L gene is a nonessential gene that is highly conserved throughout the members of the Ranavirus genus but is not found in other iridoviruses. FV3 75L shows high sequence similarity to a conserved domain found in the C terminus of LITAF, a small cellular protein with unknown function. Here we show that FV3 75L localizes to early endosomes, while LITAF localizes to late endosomes/lysosomes. Interestingly, when FV3 75L and LITAF are cotransfected into cells, LITAF can alter the subcellular localization of FV3 75L to late endosomes/lysosomes, where FV3 75L then colocalizes with LITAF. In addition, we demonstrated that virally produced 75L colocalizes with LITAF. We confirmed a physical interaction between LITAF and FV3 75L but found that this interaction was not mediated by two PPXY motifs in the N terminus of LITAF. Mutation of two PPXY motifs in LITAF did not affect the colocalization of LITAF and FV3 75L but did change the location of the two proteins from late endosomes/lysosomes to early endosomes. PMID- 23097446 TI - SUMO-conjugating enzyme E2 UBC9 mediates viral immediate-early protein SUMOylation in crayfish to facilitate reproduction of white spot syndrome virus. AB - Successful viruses have evolved superior strategies to escape host defenses or exploit host biological pathways. Most of the viral immediate-early (ie) genes are essential for viral infection and depend solely on host proteins; however, the molecular mechanisms are poorly understood. In this study, we focused on the modification of viral IE proteins by the crayfish small ubiquitin-related modifier (SUMO) and investigated the role of SUMOylation during the viral life cycle. SUMO and SUMO ubiquitin-conjugating enzyme 9 (UBC9) involved in SUMOylation were identified in red swamp crayfish (Procambarus clarkii). Both SUMO and UBC9 were upregulated in crayfish challenged with white spot syndrome virus (WSSV). Replication of WSSV genes increased in crayfish injected with recombinant SUMO or UBC9, but injection of mutant SUMO or UBC9 protein had no effect. Subsequently, we analyzed the mechanism by which crayfish SUMOylation facilitates WSSV replication. Crayfish UBC9 bound to all three WSSV IE proteins tested, and one of these IE proteins (WSV051) was covalently modified by SUMO in vitro. The expression of viral ie genes was affected and that of late genes was significantly inhibited in UBC9-silenced or SUMO-silenced crayfish, and the inhibition effect was rescued by injection of recombinant SUMO or UBC9. The results of this study demonstrate that viral IE proteins can be modified by crayfish SUMOylation, prompt the expression of viral genes, and ultimately benefit WSSV replication. Understanding of the mechanisms by which viruses exploit host components will greatly improve our knowledge of the virus-host "arms race" and contribute to the development of novel methods against virulent viruses. PMID- 23097447 TI - Naturally acquired picornavirus infections in primates at the Dhaka zoo. AB - The conditions in densely populated Bangladesh favor picornavirus transmission, resulting in a high rate of infection in the human population. Data suggest that nonhuman primates (NHP) may play a role in the maintenance and transmission of diverse picornaviruses in Bangladesh. At the Dhaka Zoo, multiple NHP species are caged in close proximity. Their proximity to other species and to humans, both zoo workers and visitors, provides the potential for cross-species transmission. To investigate possible interspecies and intraspecies transmission of picornaviruses among NHP, we collected fecal specimens from nine NHP taxa at the Dhaka Zoo at three time points, August 2007, January 2008, and June 2008. Specimens were screened using real-time PCR for the genera Enterovirus, Parechovirus, and Sapelovirus, and positive samples were typed by VP1 sequencing. Fifty-two picornaviruses comprising 10 distinct serotypes were detected in 83 fecal samples. Four of these serotypes, simian virus 19 (SV19), baboon enterovirus (BaEV), enterovirus 112 (EV112), and EV115, have been solely associated with infection in NHP. EV112, EV115, and SV19 accounted for 88% of all picornaviruses detected. Over 80% of samples from cages housing rhesus macaques, olive baboons, or hamadryas baboons were positive for a picornavirus, while no picornaviruses were detected in samples from capped langurs or vervet monkeys. In contrast to our findings among synanthropic NHP in Bangladesh where 100% of the picornaviruses detected were of human serotypes, in the zoo population, only 15% of picornaviruses detected in NHP were of human origin. Specific serotypes tended to persist over time, suggesting either persistent infection of individuals or cycles of reinfection. PMID- 23097448 TI - Characterizing the picornavirus landscape among synanthropic nonhuman primates in Bangladesh, 2007 to 2008. AB - The term synanthropic describes organisms that thrive in human-altered habitats. Where synanthropic nonhuman primates (NHP) share an ecological niche with humans, cross-species transmission of infectious agents can occur. In Bangladesh, synanthropic NHP are found in villages, densely populated cities, religious sites, and protected forest areas. NHP are also kept as performing monkeys and pets. To investigate possible transmission of enteric picornaviruses between humans and NHP, we collected fecal specimens from five NHP taxa at16 locations in Bangladesh during five field sessions, from January 2007 to June 2008. Specimens were screened using real-time PCR assays for the genera Enterovirus, Parechovirus, and Sapelovirus; PCR-positive samples were typed by VP1 sequencing. To compare picornavirus diversity between humans and NHP, the same assays were applied to 211 human stool specimens collected in Bangladesh in 2007 to 2008 for acute flaccid paralysis surveillance. Picornaviruses were detected in 78 of 677 (11.5%) NHP fecal samples. Twenty distinct human enterovirus (EV) serotypes, two bovine EV types, six human parechovirus serotypes, and one virus related to Ljungan virus were identified. Twenty-five additional enteroviruses and eight parechoviruses could not be typed. Comparison of the picornavirus serotypes detected in NHP specimens with those detected in human specimens revealed considerable overlap. Strikingly, no known simian enteroviruses were detected among these NHP populations. In conclusion, enteroviruses and parechoviruses may be transmitted between humans and synanthropic NHP in Bangladesh, but the directionality of transmission is unknown. These findings may have important implications for the health of both human and NHP populations. PMID- 23097449 TI - Rapid intracellular competition between hepatitis C viral genomes as a result of mitosis. AB - Cells infected with hepatitis C virus (HCV) become refractory to further infection by HCV (T. Schaller et al., J. Virol. 81:4591-4603, 2007; D. M. Tscherne et al., J. Virol. 81:3693-3703, 2007). This process, termed superinfection exclusion, does not involve downregulation of surface viral receptors but instead occurs inside the cell at the level of RNA replication. The originally infecting virus may occupy replication niches or sequester host factors necessary for viral growth, preventing effective growth of viruses that enter the cell later. However, there appears to be an additional level of intracellular competition between viral genomes that occurs at or shortly following mitosis. In the setting of cellular division, when two viral replicons of equivalent fitness are present within a cell, each has an equal opportunity to exclude the other. In a population of dividing cells, the competition between viral genomes proceeds apace, randomly clearing one or the other genome from cells in the span of 9 to 12 days. These findings demonstrate a new mechanism of intracellular competition between HCV strains, which may act to further limit HCV's genetic diversity and ability to recombine in vivo. PMID- 23097450 TI - Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. AB - Retroviruses integrate into cellular DNA nonrandomly. Lentiviruses such as human immunodeficiency virus type 1 (HIV-1) favor the bodies of active genes and gene enriched transcriptionally active regions of chromosomes. The interaction between lentiviral integrase and the cellular protein lens epithelium-derived growth factor (LEDGF)/p75 underlies the targeting of gene bodies, whereas recent research has highlighted roles for the HIV-1 capsid (CA) protein and cellular factors implicated in viral nuclear import, including transportin 3 (TNPO3) and nucleoporin 358 (NUP358), in the targeting of gene-dense regions of chromosomes. Here, we show that CA mutations, which include the substitution of Asp for Asn74 (N74D), significantly reduce the dependency of HIV-1 on LEDGF/p75 during infection and that this difference correlates with the efficiency of viral DNA integration. The distribution of integration sites mapped by Illumina sequencing confirms that the N74D mutation reduces integration into gene-rich regions of chromosomes and gene bodies and reveals previously unrecognized roles for NUP153 (another HIV-1 cofactor implicated in viral nuclear import) and LEDGF/p75 in the targeting of the viral preintegration complex to gene-dense regions of chromatin. A role for the CA protein in determining the dependency of HIV-1 on LEDGF/p75 during infection highlights a connection between the viral capsid and chromosomal DNA integration. PMID- 23097451 TI - Influenza A viruses grow in human pancreatic cells and cause pancreatitis and diabetes in an animal model. AB - Influenza A viruses commonly cause pancreatitis in naturally and experimentally infected animals. In this study, we report the results of in vivo investigations carried out to establish whether influenza virus infection could cause metabolic disorders linked to pancreatic infection. In addition, in vitro tests in human pancreatic islets and in human pancreatic cell lines were performed to evaluate viral growth and cell damage. Infection of an avian model with two low pathogenicity avian influenza isolates caused pancreatic damage resulting in hyperlipasemia in over 50% of subjects, which evolved into hyperglycemia and subsequently diabetes. Histopathology of the pancreas showed signs of an acute infection resulting in severe fibrosis and disruption of the structure of the organ. Influenza virus nucleoprotein was detected by immunohistochemistry (IHC) in the acinar tissue. Human seasonal H1N1 and H3N2 viruses and avian H7N1 and H7N3 influenza virus isolates were able to infect a selection of human pancreatic cell lines. Human viruses were also shown to be able to infect human pancreatic islets. In situ hybridization assays indicated that viral nucleoprotein could be detected in beta cells. The cytokine activation profile indicated a significant increase of MIG/CXCL9, IP-10/CXCL10, RANTES/CCL5, MIP1b/CCL4, Groa/CXCL1, interleukin 8 (IL-8)/CXCL8, tumor necrosis factor alpha (TNF-alpha), and IL-6. Our findings indicate that influenza virus infection may play a role as a causative agent of pancreatitis and diabetes in humans and other mammals. PMID- 23097452 TI - ADP ribosylation factor 1 plays an essential role in the replication of a plant RNA virus. AB - Eukaryotic positive-strand RNA viruses replicate using the membrane-bound replicase complexes, which contain multiple viral and host components. Virus infection induces the remodeling of intracellular membranes. Virus-induced membrane structures are thought to increase the local concentration of the components that are required for replication and provide a scaffold for tethering the replicase complexes. However, the mechanisms underlying virus-induced membrane remodeling are poorly understood. RNA replication of red clover necrotic mosaic virus (RCNMV), a positive-strand RNA plant virus, is associated with the endoplasmic reticulum (ER) membranes, and ER morphology is perturbed in RCNMV infected cells. Here, we identified ADP ribosylation factor 1 (Arf1) in the affinity-purified RCNMV RNA-dependent RNA polymerase fraction. Arf1 is a highly conserved, ubiquitous, small GTPase that is implicated in the formation of the coat protein complex I (COPI) vesicles on Golgi membranes. Using in vitro pulldown and bimolecular fluorescence complementation analyses, we showed that Arf1 interacted with the viral p27 replication protein within the virus-induced large punctate structures of the ER membrane. We found that inhibition of the nucleotide exchange activity of Arf1 using the inhibitor brefeldin A (BFA) disrupted the assembly of the viral replicase complex and p27-mediated ER remodeling. We also showed that BFA treatment and the expression of dominant negative Arf1 mutants compromised RCNMV RNA replication in protoplasts. Interestingly, the expression of a dominant negative mutant of Sar1, a key regulator of the biogenesis of COPII vesicles at ER exit sites, also compromised RCNMV RNA replication. These results suggest that the replication of RCNMV depends on the host membrane traffic machinery. PMID- 23097453 TI - Pathogenesis of neonatal herpes simplex 2 disease in a mouse model is dependent on entry receptor expression and route of inoculation. AB - Herpes simplex virus (HSV) pathogenesis in mice differs based on availability of the principal entry receptors herpesvirus entry mediator (HVEM) and nectin-1 in a manner dependent upon route of inoculation. After intravaginal or intracranial inoculation of adult mice, nectin-1 is a major mediator of neurologic disease, while the absence of either receptor attenuates disease after ocular infection. We tested the importance of receptor availability and route of infection on disease in mouse models of neonatal HSV. We infected 7-day-old mice lacking neither or one principal HSV receptor or both principal HSV receptors with HSV-2 via a peripheral route (intranasal), via a systemic route (intraperitoneal), or by inoculation directly into the central nervous system (intracranial). Mortality, neurologic disease, and visceral dissemination of virus were significantly attenuated in nectin-1 knockout mice compared with HVEM knockout or wild-type mice after intranasal inoculation. Mice lacking both entry receptors (double-knockout mice) showed no evidence of disease after inoculation by any route. Nectin-1 knockout mice had delayed mortality after intraperitoneal inoculation relative to wild-type and HVEM knockout mice, but virus was able to spread to the brain and viscera in all genotypes except double-knockout mice. Unlike in adult mice, HVEM was sufficient to mediate disease in neonatal mice after direct intracranial inoculation, and the absence of HVEM delayed time to mortality relative to that of wild-type mice. Additionally, in wild-type neonatal mice inoculated intracranially, HSV antigen did not primarily colocalize with NeuN-positive neurons. Our results suggest that differences in receptor expression between adults and newborns may partially explain differences in susceptibility to HSV-2. PMID- 23097454 TI - The C-terminal region of Rift Valley fever virus NSm protein targets the protein to the mitochondrial outer membrane and exerts antiapoptotic function. AB - The NSm nonstructural protein of Rift Valley fever virus (family Bunyaviridae, genus Phlebovirus) has an antiapoptotic function and affects viral pathogenesis. We found that NSm integrates into the mitochondrial outer membrane and that the protein's N terminus is exposed to the cytoplasm. The C-terminal region of NSm, which contains a basic amino acid cluster and a putative transmembrane domain, targeted the protein to the mitochondrial outer membrane and exerted antiapoptotic function. PMID- 23097455 TI - Cooperativity in virus neutralization by human monoclonal antibodies to two adjacent regions located at the amino terminus of hepatitis C virus E2 glycoprotein. AB - A challenge for hepatitis C virus (HCV) vaccine development is defining conserved epitopes that induce protective antibodies against this highly diverse virus. An envelope glycoprotein (E2) segment located at amino acids (aa) 412 to 423 contains highly conserved neutralizing epitopes. While polyclonal antibodies to aa 412 to 423 from HCV-infected individuals confirmed broad neutralization, conflicting findings have been reported on polyclonal antibodies to an adjacent region, aa 434 to 446, that may or may not interfere with neutralization by antibodies to aa 412 to 423. To define the interplay between these antibodies, we isolated human monoclonal antibodies (HMAbs) to aa 412 to 423, designated HC33 related HMAbs (HC33 HMAbs), and characterized their interactions with other HMAbs to aa 434 to 446. A subset of the HC33 HMAbs neutralized genotype 1 to 6 infectious cell culture-derived HCV virions (HCVcc) with various activities. Although nonneutralizing HC33 HMAbs were isolated, they had lower binding affinities than neutralizing HC33 HMAbs. These antibodies could be converted to neutralizing antibodies by affinity maturation. Unidirectional competition for binding to E2 was observed between HC33 HMAbs and HMAbs to aa 434 to 446. When HMAbs to aa 434 to 446, which mediated neutralization, were combined with neutralizing HC33 HMAbs, biphasic patterns in neutralization were observed. A modest degree of antagonism was observed at lower concentrations, and a modest degree of synergism was observed at higher concentrations. However, the overall effect was additive neutralization. A similar pattern was observed when these antibodies were combined to block E2 binding to the HCV coreceptor, CD81. These findings demonstrate that both of these E2 regions participate in epitopes mediating virus neutralization and that the antibodies to aa 412 to 423 and aa 434 to 446 do not hinder their respective virus-neutralizing activities. PMID- 23097456 TI - Lymphotoxin alpha-deficient mice clear persistent rotavirus infection after local generation of mucosal IgA. AB - Rotavirus is a major cause of pediatric diarrheal illness worldwide. To explore the role of organized intestinal lymphoid tissues in infection by and immunity to rotavirus, lymphotoxin alpha-deficient (LTalpha(-/-)) mice that lack Peyer's patches and mesenteric lymph nodes were orally infected with murine rotavirus. Systemic rotavirus was cleared within 10 days in both LTalpha(-/-) and wild-type mice, and both strains developed early and sustained serum antirotavirus antibody responses. However, unlike wild-type mice, which resolved the intestinal infection within 10 days, LTalpha(-/-) mice shed fecal virus for approximately 50 days after inoculation. The resolution of fecal virus shedding occurred concurrently with induction of intestinal rotavirus-specific IgA in both mouse strains. Induction of intestinal rotavirus-specific IgA in LTalpha(-/-) mice correlated with the (late) appearance of IgA-producing plasma cells in the small intestine. This, together with the absence of rotavirus-specific serum IgA, implies that secretory rotavirus-specific IgA was produced locally. These findings indicate that serum IgG responses are insufficient and imply that local intestinal IgA responses are important for the clearance of rotavirus from intestinal tissues. Furthermore, they show that while LTalpha-dependent lymphoid tissues are important for the generation of IgA-producing B cells in the intestine, they are not absolutely required in the setting of rotavirus infection. Moreover, the induction of local IgA-producing B cell responses can occur late after infection and in an LTalpha-independent manner. PMID- 23097458 TI - SURROGACY: 'A CAUTIONARY TALE': Re T (a child) (surrogacy: residence order) [2011] EWCH 33 (Fam). PMID- 23097457 TI - Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and KSHV activation of mitogen-activated protein kinases (MAPKs) initiates a number of key pathogenic determinants of KS. Direct inhibition of signal transduction as a therapeutic approach presents several challenges, and a better understanding of KSHV-induced mechanisms regulating MAPK activation may facilitate the development of new treatment or prevention strategies for KS. MAPK phosphatases, including dual-specificity phosphatase-1 (DUSP1), negatively regulate signal transduction and cytokine activation through MAPK dephosphorylation or interference with effector molecule binding to MAPKs, including the extracellular signal-regulated kinase (ERK). We found that ERK dependent latent viral gene expression, the induction of promigratory factors, and cell invasiveness following de novo infection of primary human endothelial cells are in part dependent on KSHV suppression of DUSP1 expression during de novo infection. KSHV-encoded miR-K12-11 upregulates the expression of xCT (an amino acid transporter and KSHV fusion/entry receptor), and existing data indicate a role for xCT in the regulation of 14-3-3beta, a transcriptional repressor of DUSP1. We found that miR-K12-11 induces endothelial cell secretion of promigratory factors and cell invasiveness through upregulation of xCT dependent, 14-3-3beta-mediated suppression of DUSP1. Finally, proof-of-principle experiments revealed that pharmacologic upregulation of DUSP1 inhibits the induction of promigratory factors and cell invasiveness during de novo KSHV infection. These data reveal an indirect role for miR-K12-11 in the regulation of DUSP1 and downstream pathogenesis. PMID- 23097459 TI - Sediment suppresses herbivory across a coral reef depth gradient. AB - Sediments are a ubiquitous feature of all coral reefs, yet our understanding of how they affect complex ecological processes on coral reefs is limited. Sediment in algal turfs has been shown to suppress herbivory by coral reef fishes on high sediment, low-herbivory reef flats. Here, we investigate the role of sediment in suppressing herbivory across a depth gradient (reef base, crest and flat) by observing fish feeding following benthic sediment reductions. We found that sediment suppresses herbivory across all reef zones. Even slight reductions on the reef crest, which has 35 times less sediment than the reef flat, resulted in over 1800 more herbivore bites (h(-1) m(-2)). The Acanthuridae (surgeonfishes) were responsible for over 80 per cent of all bites observed, and on the reef crest and flat took over 1500 more bites (h(-1) m(-2)) when sediment load was reduced. These findings highlight the role of natural sediment loads in shaping coral reef herbivory and suggest that changes in benthic sediment loads could directly impair reef resilience. PMID- 23097460 TI - Climate change and elevational diversity capacity: do weedy species take up the slack? AB - Climate change leads to species range shifts and consequently to changes in diversity. For many systems, increases in diversity capacity have been forecast, with spare capacity to be taken up by a pool of weedy species moved around by humans. Few tests of this hypothesis have been undertaken, and in many temperate systems, climate change impacts may be confounded by simultaneous increases in human-related disturbance, which also promote weedy species. Areas to which weedy species are being introduced, but with little human disturbance, are therefore ideal for testing the idea. We make predictions about how such diversity capacity increases play out across elevational gradients in non-water-limited systems. Then, using modern and historical data on the elevational range of indigenous and naturalized alien vascular plant species from the relatively undisturbed sub Antarctic Marion Island, we show that alien species have contributed significantly to filling available diversity capacity and that increases in energy availability rather than disturbance are the probable underlying cause. PMID- 23097461 TI - North American ornithology in transition. PMID- 23097462 TI - Female happy wrens select songs to cooperate with their mates rather than confront intruders. AB - Vocal duetting occurs in many taxa, but its function remains much-debated. Like species in which only one sex sings, duetting birds can use their song repertoires to signal aggression by singing song types that match those of territorial intruders. However, when pairs do not share specific combinations of songs (duet codes), individuals must choose to signal aggression by matching the same-sex rival, or commitment by replying appropriately to their mate. Here, we examined the song types used by female happy wrens (Pheugopedius felix) forced to make this decision in a playback experiment. We temporarily removed the male from the territory and then played songs from two loudspeakers to simulate an intruding female and the removed mate's response, using song types that the pair possessed but did not naturally combine into duets. Females were aggressive towards the female playback speaker, approaching it and overlapping the female playback songs, but nevertheless replied appropriately to their mate's songs instead of type matching the intruding female. This study indicates that females use song overlapping to signal aggression but use their vocal repertoires to create pair-specific duet codes with their mates, suggesting that duetting functions primarily to demonstrate pair commitment. PMID- 23097463 TI - Nestling erythrocyte resistance to oxidative stress predicts fledging success but not local recruitment in a wild bird. AB - Stressful conditions experienced by individuals during their early development have long-term consequences on various life-history traits such as survival until first reproduction. Oxidative stress has been shown to affect various fitness related traits and to influence key evolutionary trade-offs but whether an individual's ability to resist oxidative stress in early life affects its survival has rarely been tested. In the present study, we used four years of data obtained from a free-living great tit population (Parus major; n = 1658 offspring) to test whether pre-fledging resistance to oxidative stress, measured as erythrocyte resistance to oxidative stress and oxidative damage to lipids, predicted fledging success and local recruitment. Fledging success and local recruitment, both major correlates of survival, were primarily influenced by offspring body mass prior to fledging. We found that pre-fledging erythrocyte resistance to oxidative stress predicted fledging success, suggesting that individual resistance to oxidative stress is related to short-term survival. However, local recruitment was not influenced by pre-fledging erythrocyte resistance to oxidative stress or oxidative damage. Our results suggest that an individual ability to resist oxidative stress at the offspring stage predicts short-term survival but does not influence survival later in life. PMID- 23097464 TI - Evolutionary rescue of a green alga kept in the dark. AB - Chlamydomonas (Chlorophyta) can grow as a heterotroph on medium supplemented with acetate in the dark. A long-term experiment to investigate adaptation to dark conditions was set up with hundreds of replicate lines. Growth was initially slow, and most lines became extinct when transferred every few weeks. Some lines survived through the expansion of lineages derived from cells with extreme phenotypes and exhibited a U-shaped curve of collapse and recovery. Two short term experiments were set up to evaluate the effect of sex on the frequency of 'evolutionary rescue' by deriving replicate lines from ancestral populations with contrasting sexual histories that had been cultured in the light for hundreds of generations. When transferred to dark conditions of growth, lines derived from obligately sexual populations survived more often than lines derived from facultatively sexual or asexual populations. This reflected the higher initial frequency of cells able to grow in the dark, due to greater genetic diversity supported by sexual fusion and recombination. The greater probability of evolutionary rescue suggests a general reason for the prevalence of sexual species. PMID- 23097465 TI - Role of protein kinase C-alpha in hypertonicity-stimulated urea permeability in mouse inner medullary collecting ducts. AB - The kidney's ability to concentrate urine is vitally important to our quality of life. In the hypertonic environment of the kidney, urea transporters must be regulated to optimize function. We previously showed that hypertonicity increases urea permeability and that the protein kinase C (PKC) blockers chelerythrine and rottlerin decreased hypertonicity-stimulated urea permeability in rat inner medullary collecting ducts (IMCDs). Because PKCalpha knockout (PKCalpha(-/-)) mice have a urine-concentrating defect, we tested the effect of hypertonicity on urea permeability in isolated perfused mouse IMCDs. Increasing the osmolality of perfusate and bath from 290 to 690 mosmol/kgH(2)O did not change urea permeability in PKCalpha(-/-) mice but significantly increased urea permeability in wild-type mice. To determine whether the response to protein kinase A was also missing in IMCDs of PKCalpha(-/-) mice, tubules were treated with vasopressin and subsequently with the PKC stimulator phorbol dibutyrate (PDBu). Vasopressin stimulated urea permeability in PKCalpha(-/-) mice. Like vasopressin, forskolin stimulated urea permeability in PKCalpha(-/-) mice. We previously showed that, in rats, vasopressin and PDBu have additive stimulatory effects on urea permeability. In contrast, in PKCalpha(-/-) mice, PDBu did not further increase vasopressin-stimulated urea permeability. Western blot analysis showed that expression of the UT-A1 urea transporter in IMCDs was increased in response to vasopressin in wild-type mice as well as PKCalpha(-/-) mice. Hypertonicity increased UT-A1 phosphorylation in wild-type mice but not in PKCalpha(-/-) mice. We conclude that PKCalpha mediates hypertonicity-stimulated urea transport but is not necessary for vasopressin stimulation of urea permeability in mouse IMCDs. PMID- 23097466 TI - Transport efficiency and workload distribution in a mathematical model of the thick ascending limb. AB - The thick ascending limb (TAL) is a major NaCl reabsorbing site in the nephron. Efficient reabsorption along that segment is thought to be a consequence of the establishment of a strong transepithelial potential that drives paracellular Na(+) uptake. We used a multicell mathematical model of the TAL to estimate the efficiency of Na(+) transport along the TAL and to examine factors that determine transport efficiency, given the condition that TAL outflow must be adequately dilute. The TAL model consists of a series of epithelial cell models that represent all major solutes and transport pathways. Model equations describe luminal flows, based on mass conservation and electroneutrality constraints. Empirical descriptions of cell volume regulation (CVR) and pH control were implemented, together with the tubuloglomerular feedback (TGF) system. Transport efficiency was calculated as the ratio of total net Na(+) transport (i.e., paracellular and transcellular transport) to transcellular Na(+) transport. Model predictions suggest that 1) the transepithelial Na(+) concentration gradient is a major determinant of transport efficiency; 2) CVR in individual cells influences the distribution of net Na(+) transport along the TAL; 3) CVR responses in conjunction with TGF maintain luminal Na(+) concentration well above static head levels in the cortical TAL, thereby preventing large decreases in transport efficiency; and 4) under the condition that the distribution of Na(+) transport along the TAL is quasi-uniform, the tubular fluid axial Cl(-) concentration gradient near the macula densa is sufficiently steep to yield a TGF gain consistent with experimental data. PMID- 23097468 TI - Interleukin-18 binding protein therapy is protective in adriamycin nephropathy. AB - Adriamycin nephropathy (AN) is an experimental model of focal segmental glomerulosclerosis (FSGS) in which macrophages are considered to play a pathogenic role. We hypothesize that interleukin-18 (IL-18), largely derived from macrophages, is a key contributor to kidney injury in AN and a potential therapeutic target. In this study, BALB/c mice received adriamycin (9.6 mg/kg) via tail vein injection and subsequently were treated with either neutralizing IL 18 binding protein (IL-18BP; 250 MUg) or normal saline (control). At 5 wk, IL-18 was upregulated in AN, and IL-18BP therapy afforded significant protection against the development of AN, resulting in less proteinuria (P < 0.01), kidney dysfunction (P < 0.01), glomerulosclerosis (P < 0.001), and interstitial accumulation of macrophages and T cells (P < 0.001). Gene expression of IL-18 downstream inflammatory molecules, including inducible nitric oxide synthase (P < 0.001), TNF-alpha (P < 0.001), and IFN-gamma (P < 0.01); IL-17 (P < 0.001) and the chemokines CCL2 (P < 0.01) and CCL5 (P < 0.005), was reduced. We demonstrate that IL-18 plays a significant role in the pathogenesis of AN. The protective effect of IL-18BP therapy illustrates the importance of immune mediators in chronic proteinuric kidney disease and highlights the potential of IL-18BP therapy. PMID- 23097469 TI - Fluid dilution and efficiency of Na(+) transport in a mathematical model of a thick ascending limb cell. AB - Thick ascending limb (TAL) cells are capable of reducing tubular fluid Na(+) concentration to as low as ~25 mM, and yet they are thought to transport Na(+) efficiently owing to passive paracellular Na(+) absorption. Transport efficiency in the TAL is of particular importance in the outer medulla where O(2) availability is limited by low blood flow. We used a mathematical model of a TAL cell to estimate the efficiency of Na(+) transport and to examine how tubular dilution and cell volume regulation influence transport efficiency. The TAL cell model represents 13 major solutes and the associated transporters and channels; model equations are based on mass conservation and electroneutrality constraints. We analyzed TAL transport in cells with conditions relevant to the inner stripe of the outer medulla, the cortico-medullary junction, and the distal cortical TAL. At each location Na(+) transport efficiency was computed as functions of changes in luminal NaCl concentration ([NaCl]), [K(+)], [NH(4)(+)], junctional Na(+) permeability, and apical K(+) permeability. Na(+) transport efficiency was calculated as the ratio of total net Na(+) transport to transcellular Na(+) transport. Transport efficiency is predicted to be highest at the cortico medullary boundary where the transepithelial Na(+) gradient is the smallest. Transport efficiency is lowest in the cortex where luminal [NaCl] approaches static head. PMID- 23097467 TI - Renal dopamine and angiotensin II receptor signaling in age-related hypertension. AB - Kidneys play a vital role in long-term regulation of blood pressure. This is achieved by actions of many renal and nonrenal factors acting on the kidney that help maintain the body's water and electrolyte balance and thus control blood pressure. Several endogenously formed or circulating hormones/peptides, by acting within the kidney, regulate fluid and water homeostasis and blood pressure. Dopamine and angiotensin II are the two key renal factors that, via acting on their receptors and counterregulating each other's function, maintain water and sodium balance. In this review, we provide recent advances in the signaling cascades of these renal receptors, especially at the level of their cross talk, and discuss their roles in blood pressure regulation in the aging process. PMID- 23097470 TI - Role of angiotensin II in arterial pressure and renal hemodynamics in rats with altered renal development: age- and sex-dependent differences. AB - Numerous studies have demonstrated that angiotensin II (ANG II) is involved in hypertension and renal changes occurring as a consequence of an adverse event during renal development. However, it was unknown whether this involvement is sex and age dependent. This study examines whether the increments in arterial pressure (AP) and in the renal sensitivity to ANG II are sex and age dependent in rats with altered renal development. It also evaluates whether the ANG II effects are accompanied by increments in AT(1) receptors and oxidative stress. Experiments were performed in 3- to 4- and 10- to 11-mo-old rats treated with vehicle or an AT(1) receptor antagonist (ARAnp) during the nephrogenic period. ARAnp-treated rats were hypertensive, but an age-dependent rise in AP was only found in males. Three days of treatment with candesartan (7 mg.kg(-1).day(-1)) led to a fall of AP that was greater (P < 0.05) in male than in female 10- to 11 mo-old ARAnp-treated rats. Oxidated proteins were elevated (P < 0.05), and the decrease in AP elicited by candesartan was reduced (P < 0.05) when these rats are also treated with tempol (18 mg.kg(-1).day(-1)). Hypertension was not maintained by an elevation of AT(1) receptors in kidneys and mesenteric arteries. The acute renal hemodynamic response to ANG II (30 ng.kg(-1).min(-1)) was similarly enhanced (P < 0.05) in both sexes of ARAnp-treated rats at 3-4 but not at 10-11 mo of age. Our results suggest that an adverse event during the nephrogenic period induces an ANG II-dependent increment in AP that is aggravated only in males during aging and that oxidative stress but not an increase in AT(1) receptor contributes to the rise in AP. This study also shows that the renal hemodynamic sensitivity to ANG II is transitorily enhanced in both sexes of rats with altered renal development. PMID- 23097473 TI - Advancing sports cardiology: blue sky thinking in Qatar. PMID- 23097471 TI - Immune reactivity to heat shock protein 70 expressed in the kidney is cause of salt-sensitive hypertension. AB - Hypertension affects one-third of the adult population of the world. The causes of hypertension are incompletely understood, but relative impairment of sodium excretion is central to its pathogenesis. Immune cell infiltration in the kidney is a constant finding in hypertension that in association with local angiotensin and oxidants causes a defect in sodium excretion. However, it is unclear if the T cell influx into the kidney responds to nonspecific chemokine cues or is due to antigen-driven immune attraction. We found that T cells in experimentally induced salt-driven hypertension present a CD4 clonal response to heat shock protein 70 (HSP70) that is overexpressed in the kidney. We used a highly preserved amino acid sequence within the HSP molecule to induce immune tolerance associated with the generation of IL-10 producing regulatory T cells. Immune tolerant rats to HSP70 developed minimal renal inflammation and were protected from the development of salt-sensitive hypertension. Adoptive transfer of T lymphocytes isolated from spleen of tolerized rats also reversed hypertension. HSP70 gene delivery to the renal vein of the kidneys of rats sensitized to HSP70 caused an increment in blood pressure in response to a high-salt diet. The HSP70 peptide used in this work induces a strong proliferative response in peripheral blood lymphocytes of patients with essential hypertension. These studies provide evidence that autoimmunity plays a role in salt-sensitive hypertension and identifies HSP70 expressed in the kidney as one key antigen. These findings raise the possibility of novel approaches to the treatment of this condition. PMID- 23097475 TI - Sports cardiology: current updates and new directions. PMID- 23097472 TI - Regulation of human endometrial stromal proliferation and differentiation by C/EBPbeta involves cyclin E-cdk2 and STAT3. AB - During each menstrual cycle, the human uterus undergoes a unique transformation, known as decidualization, which involves endometrial stromal proliferation and differentiation. During this process, the stromal cells are transformed into decidual cells, which produce factors that prepare the uterus for potential embryo implantation. We previously identified the transcription factor CCAAT/enhancer-binding protein (C/EBP)beta as a regulator of endometrial stromal proliferation and differentiation in mice. In this study, we addressed the role of C/EBPbeta in human endometrial decidualization. Using small interfering RNA targeted to C/EBPbeta mRNA, we demonstrated that C/EBPbeta controls the proliferation of primary human endometrial stromal cells (HESCs) by regulating the expression of several key cell cycle-regulatory factors during the G(1)-S phase transition. Additionally, loss of C/EBPbeta expression blocked the differentiation of HESCs in response to estrogen, progesterone, and cyclic AMP. Gene expression profiling of normal and C/EBPbeta-deficient HESCs revealed that the receptor for the cytokine IL-11 and its downstream signal transducer signal transducer and activator of transcription 3 (STAT3) are targets of regulation by C/EBPbeta. Chromatin immunoprecipitation analysis indicated that C/EBPbeta controls the expression of STAT3 gene by directly interacting with a distinct regulatory sequence in its 5'-flanking region. Attenuation of STAT3 mRNA expression in HESCs resulted in markedly reduced differentiation of these cells, indicating an important role for STAT3 in decidualization. Gene expression profiling, using STAT3-deficient HESCs, showed an extensive overlap of pathways downstream of STAT3 and C/EBPbeta during stromal cell differentiation. Collectively, these findings revealed a novel functional link between C/EBPbeta and STAT3 that is a critical regulator of endometrial differentiation in women. PMID- 23097474 TI - Aetiology of sudden cardiac death in sport: a histopathologist's perspective. AB - In the UK, when a young person dies suddenly, the coroner is responsible for establishing the cause of death. They will ask a consultant pathologist to carry out an autopsy in order to ascertain when, where and how that person died. Once the cause of death is established and is due to natural causes, the coroner can issue a death certificate. Importantly, the coroner is not particularly interested in the cause of death as long as it is due to natural causes, which avoids the need for an inquest (a public hearing about the death). However, if no identifiable cause is established at the initial autopsy, the coroner can refer the heart to a cardiac pathologist, since the cause of death is usually due to heart disease in most cases. Consultant histopathologists are responsible for the analysis of human tissue from both living individuals and the dead in order to make a diagnosis of disease. With recent advancements in the management protocols for routine autopsy practice and assessment following the sudden death of a young individual, this review describes the role of the consultant histopathologist in the event of a sudden death of a young athletic individual, together with the older middle-aged 'weekend warrior' athlete. It provides concise mechanisms for the main causes of sudden cardiac death (including coronary artery disease, cardiomyopathies, valve abnormalities, major vessel ruptures and electrical conduction abnormalities) based on detailed autopsy data from our specialised cardiac pathology laboratory. Finally, the review will discuss the role of the histopathologist in the event of a 'negative' autopsy. PMID- 23097476 TI - The endurance athletes heart: acute stress and chronic adaptation. AB - The impact of endurance exercise training on the heart has received significant research and clinical attention for well over a century. Despite this, many issues remain controversial and clinical interpretation can be complex of biomarkers of cardiomyocyte insult. This review assesses the current state of knowledge related to two areas of research where problems with clinical decision making may arise: (1) the impact of chronic endurance exercise training on cardiac structure, function and electrical activity to the point where the athletic heart phenotype may be similar to the expression of some cardiac pathologies (a diagnostic dilemma referred to as the 'grey-zone') and (2) the impact of acute bouts of prolonged exercise on cardiac function and the presentation of biomarkers and cardiomyocyte insult in the circulatory system. The combination of acute endurance exercise stress on the heart and prolonged periods of training are considered together in the final section. PMID- 23097477 TI - Atrial fibrillation and atrial flutter in athletes. AB - Atrial fibrillation (AF) is the most common arrhythmia in clinical practice, with an estimated prevalence of 0.4% to 1% in the general population, increasing with age to 8% in those above 80 years. The recognised risk factors for developing AF include age, structural heart disease, hypertension, diabetes mellitus or hyperthyroidism. However, the mechanisms underlying the initiation of AF in patients below 60 years of age, in whom no cardiovascular disease or any other known causal factor is present, remain to be clarified. This condition, termed as lone AF, may be responsible for as many as 30% of patients with paroxysmal AF seeking medical attention. Recent studies suggest that long-term endurance exercise may increase the incidence of AF and atrial flutter (AFl) in this population. This review article is intended to analyse the prevalence of AF and AFl, the pathophysiological mechanisms responsible for the association between endurance sport practice and AF or AFl and the recommended therapeutic options in endurance athletes. PMID- 23097478 TI - Cardiac screening: time to move forward! PMID- 23097479 TI - Ventricular arrhythmias associated with long-term endurance sports: what is the evidence? AB - Athletic performance tests the limits of the human body and mind. Awe-inspiring achievements is what makes sports so fascinating. It is well appreciated however that top-level sports may sometimes overtax the body, and can lead to injuries, most notably of musculo-skeletal nature. This paper defends the thesis that the heart can also develop sports injuries at the ventricular level. We will elaborate on our hypothesis, originally put forward in 2003, that intense endurance activities put a particularly high strain on the right ventricle (RV), which over time, may lead to a proarrhythmic state resembling right (or less often) left ventricular cardiomyopathy. This can develop even in the absence of underlying demonstrable genetic abnormalities, probably just as a result of excessive RV wall stress during exercise. The syndrome of 'exercise-induced arrhythmogenic RV cardiomyopathy' may easily be overlooked. Sports cardiologists, like orthopaedic specialists, should be prepared to realise that excessive sports activity can lead to cardiac sports injuries in some, which will help to council on safe participation in all. PMID- 23097480 TI - Significance of deep T-wave inversions in asymptomatic athletes with normal cardiovascular examinations: practical solutions for managing the diagnostic conundrum. AB - Preparticipation screening programmes for underlying cardiac pathologies are now commonplace for many international sporting organisations. However, providing medical clearance for an asymptomatic athlete without a family history of sudden cardiac death (SCD) is especially challenging when the athlete demonstrates particularly abnormal repolarisation patterns, highly suggestive of an inherited cardiomyopathy or channelopathy. Deep T-wave inversions of >= 2 contiguous anterior or lateral leads (but not aVR, and III) are of major concern for sports cardiologists who advise referring team physicians, as these ECG alterations are a recognised manifestation of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequently, inverted T waves may represent the first and only sign of an inherited heart muscle disease, in the absence of any other features and before structural changes in the heart can be detected. However, to date, there remains little evidence that deep T-wave inversions are always pathognomonic of either a cardiomyopathy or an ion channel disorder in an asymptomatic athlete following long-term follow-up. This paper aims to provide a systematic review of the prevalence of T-wave inversion in athletes and examine T-wave inversion and its relationship to structural heart disease, notably HCM and ARVC with a view to identify young athletes at risk of SCD during sport. Finally, the review proposes clinical management pathways (including genetic testing) for asymptomatic athletes demonstrating significant T wave inversion with structurally normal hearts. PMID- 23097481 TI - Advising a cardiac disease gene positive yet phenotype negative or borderline abnormal athlete: is sporting disqualification really necessary? AB - The sudden cardiac death (SCD) of an athlete is a rare and tragic event, often caused by a number of inherited heart muscle disorders, namely the cardiomyopathies and primary arrhythmia syndromes (also known as cardiac ion channelopathies). Recent advances in the understanding of the molecular genetics of these heritable cardiovascular diseases present new challenges for clinicians who manage athletes with these types of heart muscle conditions. Unfortunately, the clinical heterogeneity of many of these SCD diseases are also matched by the genotypic heterogeneity associated with the pathogenesis of the disease. A particularly challenging situation arises when the sports physician and attending cardiologist are presented with an athlete who demonstrates a familial context of inherited cardiac disease or presents mild cardiac abnormalities suggestive of inherited cardiac disease. Alongside the complete cardiac evaluation, genetic testing may be proposed as an additional diagnostic tool in this clinical conundrum. However, debate still remains on how extensive the screening should be, in particular the use and interpretation of genetic testing in that setting. The aim of this review is to examine the role of genetic testing within the diagnostic algorithm of preparticipation screening of athletes. This will be achieved by providing the sports medicine physician with simple current cardiac genetic knowledge for the main inherited cardiac conditions known to cause SCD. Furthermore, it will examine current knowledge for the role of genetic testing upon the prediction of SCD, concluding with its impact on the sport eligibility and disqualification conundrum using case examples from our genetic testing laboratory. PMID- 23097482 TI - Standardised criteria for ECG interpretation in athletes: a practical tool. PMID- 23097483 TI - Imaging focal and interstitial fibrosis with cardiovascular magnetic resonance in athletes with left ventricular hypertrophy: implications for sporting participation. AB - Long-term high-intensity physical activity is associated with morphological changes, termed as the 'athlete's heart'. The differentiation of physiological cardiac adaptive changes in response to high-level exercise from pathological changes consistent with an inherited cardiomyopathy is imperative. Cardiovascular magnetic resonance (CMR) imaging allows definition of abnormal processes occurring at the tissue level, including, importantly, myocardial fibrosis. It is therefore vital in accurately making this differentiation. In this review, we will review the role of CMR imaging of fibrosis, and detail CMR characterisation of myocardial fibrosis in various cardiomyopathies, and the implications of fibrosis. Additionally, we will outline advances in imaging fibrosis, in particular T1 mapping. Finally we will address the role of CMR in pre participation screening. PMID- 23097484 TI - Performance enhancing drug abuse and cardiovascular risk in athletes: implications for the clinician. AB - The use of performance-enhancing and social drugs by athletes raises a number of ethical and health concerns. The World Anti-Doping Agency was constituted to address both of these issues as well as publishing a list of, and testing for, banned substances in athletes. Despite continuing methodological developments to detect drug use and associated punishments for positive dope tests, there are still many athletes who choose to use performance and image enhancing drugs. Of primary concern to this review are the health consequences of drug use by athletes. For such a large topic we must put in place delimitations. Specifically, we will address current knowledge, controversies and emerging evidence in relation to cardiovascular (CV) health of athletes taking drugs. Further, we delimit our discussion to the CV consequences of anabolic steroids and stimulant (including amphetamines and cocaine) use. These drugs are reported in the majority of adverse findings in athlete drug screenings and thus are more likely to be relevant to the healthcare professionals responsible for the well being of athletes. In detailing CV health issues related to anabolic steroid and stimulant abuse by athletes we critique current research evidence, present exemplar case studies and suggest important avenues for on-going research. Specifically we prompt the need for awareness of clinical staff when assessing the potential CV consequences of drug use in athletes. PMID- 23097485 TI - Emergency cardiac care in the athletic setting: from schools to the Olympics. AB - Medical providers at sporting events must be well-trained in the care of cardiac emergencies. Optimal outcomes are most likely achieved through comprehensive emergency planning that ensures prompt and appropriate care. The diversity of athletic venues, as well as the age and competition level of different athlete populations, present challenges to the provision of appropriate emergency care in sport. An efficient and coordinated medical response to cardiac emergencies requires an established emergency action plan, training of potential first responders in cardiopulmonary resuscitation and use of an automated external defibrillator, coordinating communication and transportation systems, and ensuring access to appropriate medical equipment and supplies. Prompt recognition and early defibrillation are critical in the management of athletes suffering sudden cardiac arrest. This article reviews emergency planning and cardiac care in athletics, with special considerations presented for the school, large arena, mass event and Olympic settings. PMID- 23097486 TI - Debate: challenges in sports cardiology; US versus European approaches. PMID- 23097487 TI - Do big athletes have big hearts? Impact of extreme anthropometry upon cardiac hypertrophy in professional male athletes. AB - AIM: Differentiating physiological cardiac hypertrophy from pathology is challenging when the athlete presents with extreme anthropometry. While upper normal limits exist for maximal left ventricular (LV) wall thickness (14 mm) and LV internal diameter in diastole (LVIDd, 65 mm), it is unknown if these limits are applicable to athletes with a body surface area (BSA) >2.3 m(2). PURPOSE: To investigate cardiac structure in professional male athletes with a BSA>2.3 m(2), and to assess the validity of established upper normal limits for physiological cardiac hypertrophy. METHODS: 836 asymptomatic athletes without a family history of sudden death underwent ECG and echocardiographic screening. Athletes were grouped according to BSA (Group 1, BSA>2.3 m(2), n=100; Group 2, 2-2.29 m(2), n=244; Group 3, <1.99 m(2), n=492). RESULTS: There was strong linear relationship between BSA and LV dimensions; yet no athlete with a normal ECG presented a maximal wall thickness and LVIDd greater than 13 and 65 mm, respectively. In Group 3 athletes, Black African ethnicity was associated with larger cardiac dimensions than either Caucasian or West Asian ethnicity. Three athletes were diagnosed with a cardiomyopathy (0.4% prevalence); with two athletes presenting a maximal wall thickness >13 mm, but in combination with an abnormal ECG suspicious of an inherited cardiac disease. CONCLUSION: Regardless of extreme anthropometry, established upper limits for physiological cardiac hypertrophy of 14 mm for maximal wall thickness and 65 mm for LVIDd are clinically appropriate for all athletes. However, the abnormal ECG is key to diagnosis and guides follow-up, particularly when cardiac dimensions are within accepted limits. PMID- 23097488 TI - Peripheral vascular structure and function in hypertrophic cardiomyopathy. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterised by idiopathic cardiac enlargement and represents the most frequent cause of sudden cardiac death in athletes under the age of 35 years. Differentiation between physiological (ie, exercise-related) and pathological (ie, HCM-related) cardiac remodelling is challenging. In line with cardiac remodelling, vascular structure and function are altered following training, but little is known about peripheral vascular adaptations in HCM. We hypothesised that, while HCM patients and athletes would exhibit similar cardiac characteristics, differences would be apparent in their brachial and carotid arteries. METHODS: In age-matched groups of HCM patients (n = 18, 39 +/- 15 years), highly competitive athletes (n = 18, 38 +/- 12 years) and recreational controls (n = 10, 37 +/- 14 years), we used high-resolution ultrasound to assess the diameter and wall thickness of the carotid and brachial arteries, with flow-mediated dilator function (FMD) of the brachial arteries also assessed. RESULTS: A significant difference between athletes and HCM was evident in arterial wall thickness (carotid 519 +/- 60 vs 586 +/- 102 um, p<0.05; brachial 345 +/- 80 vs 456 +/- 76 um, p<0.05) and the brachial artery peak blood flow response following forearm ischaemia, an index of resistance artery remodelling (998 +/- 515 vs 725 +/- 248 ml/min, p<0.05). Similar differences were noted between athletes and controls, while controls and HCM did not differ. Brachial FMD% was not different between groups. CONCLUSIONS: Athletes and HCM subjects, who can be difficult to differentiate on the basis of cardiac measures, exhibit differences in indices of arterial structure. While this may be a disease-related effect, we cannot discount a generic impact of physical activity on arterial structure, as the athlete's arteries were also different to untrained control subjects. Future studies should assess artery function and structure in athletic HCM subjects. PMID- 23097489 TI - Radil controls neutrophil adhesion and motility through beta2-integrin activation. AB - Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates beta1- and beta2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP-dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either beta2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, beta2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to beta2-integrin activation. PMID- 23097490 TI - Integrin alpha5/fibronectin1 and focal adhesion kinase are required for lens fiber morphogenesis in zebrafish. AB - Lens fiber formation and morphogenesis requires a precise orchestration of cell- extracellular matrix (ECM) and cell-cell adhesive changes in order for a lens epithelial cell to adopt a lens fiber fate, morphology, and migratory ability. The cell-ECM interactions that mediate these processes are largely unknown, and here we demonstrate that fibronectin1 (Fn1), an ECM component, and integrin alpha5, its cellular binding partner, are required in the zebrafish lens for fiber morphogenesis. Mutations compromising either of these proteins lead to cataracts, characterized by defects in fiber adhesion, elongation, and packing. Loss of integrin alpha5/Fn1 does not affect the fate or viability of lens epithelial cells, nor does it affect the expression of differentiation markers expressed in lens fibers, although nucleus degradation is compromised. Analysis of the intracellular mediators of integrin alpha5/Fn1 activity focal adhesion kinase (FAK) and integrin-linked kinase (ILK) reveals that FAK, but not ILK, is also required for lens fiber morphogenesis. These results support a model in which lens fiber cells use integrin alpha5 to migrate along a Fn-containing substrate on the apical side of the lens epithelium and on the posterior lens capsule, likely activating an intracellular signaling cascade mediated by FAK in order to orchestrate the cytoskeletal changes in lens fibers that facilitate elongation, migration, and compaction. PMID- 23097491 TI - Tor1 regulates protein solubility in Saccharomyces cerevisiae. AB - Accumulation of insoluble protein in cells is associated with aging and aging related diseases; however, the roles of insoluble protein in these processes are uncertain. The nature and impact of changes to protein solubility during normal aging are less well understood. Using quantitative mass spectrometry, we identify 480 proteins that become insoluble during postmitotic aging in Saccharomyces cerevisiae and show that this ensemble of insoluble proteins is similar to those that accumulate in aging nematodes. SDS-insoluble protein is present exclusively in a nonquiescent subpopulation of postmitotic cells, indicating an asymmetrical distribution of this protein. In addition, we show that nitrogen starvation of young cells is sufficient to cause accumulation of a similar group of insoluble proteins. Although many of the insoluble proteins identified are known to be autophagic substrates, induction of macroautophagy is not required for insoluble protein formation. However, genetic or chemical inhibition of the Tor1 kinase is sufficient to promote accumulation of insoluble protein. We conclude that target of rapamycin complex 1 regulates accumulation of insoluble proteins via mechanisms acting upstream of macroautophagy. Our data indicate that the accumulation of proteins in an SDS-insoluble state in postmitotic cells represents a novel autophagic cargo preparation process that is regulated by the Tor1 kinase. PMID- 23097492 TI - Calcineurin-dependent cofilin activation and increased retrograde actin flow drive 5-HT-dependent neurite outgrowth in Aplysia bag cell neurons. AB - Neurite outgrowth in response to soluble growth factors often involves changes in intracellular Ca(2+); however, mechanistic roles for Ca(2+) in controlling the underlying dynamic cytoskeletal processes have remained enigmatic. Bag cell neurons exposed to serotonin (5-hydroxytryptamine [5-HT]) respond with a threefold increase in neurite outgrowth rates. Outgrowth depends on phospholipase C (PLC) -> inositol trisphosphate -> Ca(2+) -> calcineurin signaling and is accompanied by increased rates of retrograde actin network flow in the growth cone P domain. Calcineurin inhibitors had no effect on Ca(2+) release or basal levels of retrograde actin flow; however, they completely suppressed 5-HT dependent outgrowth and F-actin flow acceleration. 5-HT treatments were accompanied by calcineurin-dependent increases in cofilin activity in the growth cone P domain. 5-HT effects were mimicked by direct activation of PLC, suggesting that increased actin network treadmilling may be a widespread mechanism for promoting neurite outgrowth in response to neurotrophic factors. PMID- 23097493 TI - Histone H1 compacts DNA under force and during chromatin assembly. AB - Histone H1 binds to linker DNA between nucleosomes, but the dynamics and biological ramifications of this interaction remain poorly understood. We performed single-molecule experiments using magnetic tweezers to determine the effects of H1 on naked DNA in buffer or during chromatin assembly in Xenopus egg extracts. In buffer, nanomolar concentrations of H1 induce bending and looping of naked DNA at stretching forces below 0.6 pN, effects that can be reversed with 2.7-pN force or in 200 mM monovalent salt concentrations. Consecutive tens-of nanometer bending events suggest that H1 binds to naked DNA in buffer at high stoichiometries. In egg extracts, single DNA molecules assemble into nucleosomes and undergo rapid compaction. Histone H1 at endogenous physiological concentrations increases the DNA compaction rate during chromatin assembly under 2-pN force and decreases it during disassembly under 5-pN force. In egg cytoplasm, histone H1 protects sperm nuclei undergoing genome-wide decondensation and chromatin assembly from becoming abnormally stretched or fragmented due to astral microtubule pulling forces. These results reveal functional ramifications of H1 binding to DNA at the single-molecule level and suggest an important physiological role for H1 in compacting DNA under force and during chromatin assembly. PMID- 23097494 TI - Human Asunder promotes dynein recruitment and centrosomal tethering to the nucleus at mitotic entry. AB - Recruitment of dynein motors to the nuclear surface is an essential step for nucleus-centrosome coupling in prophase. In cultured human cells, this dynein pool is anchored to nuclear pore complexes through RanBP2-Bicaudal D2 (BICD2) and Nup133- centromere protein F (CENP-F) networks. We previously reported that the asunder (asun) gene is required in Drosophila spermatocytes for perinuclear dynein localization and nucleus-centrosome coupling at G2/M of male meiosis. We show here that male germline expression of mammalian Asunder (ASUN) protein rescues asun flies, demonstrating evolutionary conservation of function. In cultured human cells, we find that ASUN down-regulation causes reduction of perinuclear dynein in prophase of mitosis. Additional defects after loss of ASUN include nucleus-centrosome uncoupling, abnormal spindles, and multinucleation. Coimmunoprecipitation and overlapping localization patterns of ASUN and lissencephaly 1 (LIS1), a dynein adaptor, suggest that ASUN interacts with dynein in the cytoplasm via LIS1. Our data indicate that ASUN controls dynein localization via a mechanism distinct from that of either BICD2 or CENP-F. We present a model in which ASUN promotes perinuclear enrichment of dynein at G2/M that facilitates BICD2- and CENP-F-mediated anchoring of dynein to nuclear pore complexes. PMID- 23097495 TI - LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice. AB - Dietary arachidonic acid (AA) has roles in growth, neuronal development, and cognitive function in infants. AA is remarkably enriched in phosphatidylinositol (PI), an important constituent of biological membranes in mammals; however, the physiological significance of AA-containing PI remains unknown. In an RNA interference-based genetic screen using Caenorhabditis elegans, we recently cloned mboa-7 as an acyltransferase that selectively incorporates AA into PI. Here we show that lysophosphatidylinositol acyltransferase 1 (LPIAT1, also known as MBOAT7), the closest mammalian homologue, plays a crucial role in brain development in mice. Lpiat1(-/-) mice show almost no LPIAT activity with arachidonoyl-CoA as an acyl donor and show reduced AA contents in PI and PI phosphates. Lpiat1(-/-) mice die within a month and show atrophy of the cerebral cortex and hippocampus. Immunohistochemical analysis reveals disordered cortical lamination and delayed neuronal migration in the cortex of E18.5 Lpiat1(-/-) mice. LPIAT1 deficiency also causes disordered neuronal processes in the cortex and reduced neurite outgrowth in vitro. Taken together, these results demonstrate that AA-containing PI/PI phosphates play an important role in normal cortical lamination during brain development in mice. PMID- 23097496 TI - Unassembled CD147 is an endogenous endoplasmic reticulum-associated degradation substrate. AB - Degradation of folding- or assembly-defective proteins by the endoplasmic reticulum-associated degradation (ERAD) ubiquitin ligase, Hrd1, is facilitated by a process that involves recognition of demannosylated N-glycans by the lectin OS 9/XTP3-B via the adaptor protein SEL1L. Most of our knowledge of the machinery that commits proteins to this fate in metazoans comes from studies of overexpressed mutant proteins in heterologous cells. In this study, we used mass spectrometry to identify core-glycoslyated CD147 (CD147(CG)) as an endogenous substrate of the ERAD system that accumulates in a complex with OS-9 following SEL1L depletion. CD147 is an obligatory assembly factor for monocarboxylate transporters. The majority of newly synthesized endogenous CD147(CG) was degraded by the proteasome in a Hrd1-dependent manner. CD147(CG) turnover was blocked by kifunensine, and interaction of OS-9 and XTP3-B with CD147(CG) was inhibited by mutations to conserved residues in their lectin domains. These data establish unassembled CD147(CG) as an endogenous, constitutive ERAD substrate of the OS 9/SEL1L/Hrd1 pathway. PMID- 23097497 TI - FilGAP, a Rho/Rho-associated protein kinase-regulated GTPase-activating protein for Rac, controls tumor cell migration. AB - Tumor cells exhibit two interconvertible modes of cell motility referred to as mesenchymal and amoeboid migration. Mesenchymal mode is characterized by elongated morphology that requires high GTPase Rac activation, whereas amoeboid mode is dependent on actomyosin contractility induced by Rho/Rho-associated protein kinase (ROCK) signaling. While elongated morphology is driven by Rac induced protrusion at the leading edge, how Rho/ROCK signaling controls amoeboid movement is not well understood. We identified FilGAP, a Rac GTPase-activating protein (GAP), as a mediator of Rho/ROCK-dependent amoeboid movement of carcinoma cells. We show that depletion of endogenous FilGAP in carcinoma cells induced highly elongated mesenchymal morphology. Conversely, forced expression of FilGAP induced a round/amoeboid morphology that requires Rho/ROCK-dependent phosphorylation of FilGAP. Moreover, depletion of FilGAP impaired breast cancer cell invasion through extracellular matrices and reduced tumor cell extravasation in vivo. Thus phosphorylation of FilGAP by ROCK appears to promote amoeboid morphology of carcinoma cells, and FilGAP contributes to tumor invasion. PMID- 23097499 TI - NOTICE OF RETRACTION: 'MicroRNA 21: response to hormonal therapies and regulatory function in leiomyoma, transformed leiomyoma and leiomyosarcoma cells' by Qun Pan, Xiaoping Luo and Nasser Chegini, Molecular Human Reproduction (MHR) 16: 215 227 (2010). doi:10.1093/molehr/gap093. PMID- 23097498 TI - Positive selection within a diatom species acts on putative protein interactions and transcriptional regulation. AB - Diatoms are the most species-rich group of microalgae, and their contribution to marine primary production is important on a global scale. Diatoms can form dense blooms through rapid asexual reproduction; mutations acquired and propagated during blooms likely provide the genetic, and thus phenotypic, variability upon which natural selection may act. Positive selection was tested using genome and transcriptome-wide pair-wise comparisons of homologs in three genera of diatoms (Pseudo-nitzschia, Ditylum, and Thalassiosira) that represent decreasing phylogenetic distances. The signal of positive selection was greatest between two strains of Thalassiosira pseudonana. Further testing among seven strains of T. pseudonana yielded 809 candidate genes of positive selection, which are 7% of the protein-coding genes. Orphan genes and genes encoding protein-binding domains and transcriptional regulators were enriched within the set of positively selected genes relative to the genome as a whole. Positively selected genes were linked to the potential selective pressures of nutrient limitation and sea surface temperature based on analysis of gene expression profiles and identification of positively selected genes in subsets of strains from locations with similar environmental conditions. The identification of positively selected genes presents an opportunity to test new hypotheses in natural populations and the laboratory that integrate selected genotypes in T. pseudonana with their associated phenotypes and selective forces. PMID- 23097501 TI - Simple robot suggests physical interlimb communication is essential for quadruped walking. AB - Quadrupeds have versatile gait patterns, depending on the locomotion speed, environmental conditions and animal species. These locomotor patterns are generated via the coordination between limbs and are partly controlled by an intraspinal neural network called the central pattern generator (CPG). Although this forms the basis for current control paradigms of interlimb coordination, the mechanism responsible for interlimb coordination remains elusive. By using a minimalistic approach, we have developed a simple-structured quadruped robot, with the help of which we propose an unconventional CPG model that consists of four decoupled oscillators with only local force feedback in each leg. Our robot exhibits good adaptability to changes in weight distribution and walking speed simply by responding to local feedback, and it can mimic the walking patterns of actual quadrupeds. Our proposed CPG-based control method suggests that physical interaction between legs during movements is essential for interlimb coordination in quadruped walking. PMID- 23097500 TI - Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds. AB - The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies. PMID- 23097502 TI - Bactericidal strontium-releasing injectable bone cements based on bioactive glasses. AB - Strontium-releasing injectable bone cements may have the potential to prevent implant-related infections through the bactericidal action of strontium, while enhancing bone formation in patients suffering from osteoporosis. A melt-derived bioactive glass (BG) series (SiO2-CaO-CaF2-MgO) with 0-50% of calcium substituted with strontium on a molar base were produced. By mixing glass powder, poly(acrylic acid) and water, cements were obtained which can be delivered by injection and set in situ, giving compressive strength of up to 35 MPa. Strontium release was dependent on BG composition with increasing strontium substitution resulting in higher concentrations in the medium. Bactericidal effects were tested on Staphylococcus aureus and Streptococcus faecalis; cell counts were reduced by up to three orders of magnitude over 6 days. Results show that bactericidal action can be increased through BG strontium substitution, allowing for the design of novel antimicrobial and bone enhancing cements for use in vertebroplasty or kyphoplasty for treating osteoporosis-related vertebral compression fractures. PMID- 23097503 TI - Swimming like algae: biomimetic soft artificial cilia. AB - Cilia are used effectively in a wide variety of biological systems from fluid transport to thrust generation. Here, we present the design and implementation of artificial cilia, based on a biomimetic planar actuator using soft-smart materials. This actuator is modelled on the cilia movement of the alga Volvox, and represents the cilium as a piecewise constant-curvature robotic actuator that enables the subsequent direct translation of natural articulation into a multi segment ionic polymer metal composite actuator. It is demonstrated how the combination of optimal segmentation pattern and biologically derived per-segment driving signals reproduce natural ciliary motion. The amenability of the artificial cilia to scaling is also demonstrated through the comparison of the Reynolds number achieved with that of natural cilia. PMID- 23097504 TI - The modulatory effect of cell-cell contact on the tumourigenic potential of pre malignant epithelial cells: a computational exploration. AB - Malignant development cannot be attributed alone to genetic changes in a single cell, but occurs as a result of the complex interplay between the failure of cellular regulation mechanisms and the presence of a permissive microenvironment. Although E-cadherin is classified as a 'metastasis suppressor' owing to its role in intercellular adhesion, the observation that it may be downregulated at a premalignant stage is indicative of additional roles in neoplastic development. We have used an agent-based computational model to explore the emergent behaviour resulting from the interaction of single and subpopulations of E-cadherin compromised cells with unaffected normal epithelial cells within a monolayer environment. We have extended this to investigate the importance of local tissue perturbations in the form of scratch-wounding, or ablation of randomly-dispersed normal cells, on the growth of a single cell exhibiting E-cadherin loss. Our results suggest that the microenvironment with respect to localized cell density and normal/E-cadherin-compromised neighbours is crucial in determining whether an abnormal individual cell proliferates or remains dormant within the monolayer. These predictions raise important questions relating to the propensity for individual mutations to give rise to disease, and future experimental exploration of these will enhance our understanding of a complex, multifactorial pathological process. PMID- 23097505 TI - Offspring social network structure predicts fitness in families. AB - Social structures such as families emerge as outcomes of behavioural interactions among individuals, and can evolve over time if families with particular types of social structures tend to leave more individuals in subsequent generations. The social behaviour of interacting individuals is typically analysed as a series of multiple dyadic (pair-wise) interactions, rather than a network of interactions among multiple individuals. However, in species where parents feed dependant young, interactions within families nearly always involve more than two individuals simultaneously. Such social networks of interactions at least partly reflect conflicts of interest over the provision of costly parental investment. Consequently, variation in family network structure reflects variation in how conflicts of interest are resolved among family members. Despite its importance in understanding the evolution of emergent properties of social organization such as family life and cooperation, nothing is currently known about how selection acts on the structure of social networks. Here, we show that the social network structure of broods of begging nestling great tits Parus major predicts fitness in families. Although selection at the level of the individual favours large nestlings, selection at the level of the kin-group primarily favours families that resolve conflicts most effectively. PMID- 23097506 TI - Experimental evidence for adaptive personalities in a wild passerine bird. AB - Individuals of the same species differ consistently in risky actions. Such 'animal personality' variation is intriguing because behavioural flexibility is often assumed to be the norm. Recent theory predicts that between-individual differences in propensity to take risks should evolve if individuals differ in future fitness expectations: individuals with high long-term fitness expectations (i.e. that have much to lose) should behave consistently more cautious than individuals with lower expectations. Consequently, any manipulation of future fitness expectations should result in within-individual changes in risky behaviour in the direction predicted by this adaptive theory. We tested this prediction and confirmed experimentally that individuals indeed adjust their 'exploration behaviour', a proxy for risk-taking behaviour, to their future fitness expectations. We show for wild great tits (Parus major) that individuals with experimentally decreased survival probability become faster explorers (i.e. increase risk-taking behaviour) compared to individuals with increased survival probability. We also show, using quantitative genetics approaches, that non genetic effects (i.e. permanent environment effects) underpin adaptive personality variation in this species. This study thereby confirms a key prediction of adaptive personality theory based on life-history trade-offs, and implies that selection may indeed favour the evolution of personalities in situations where individuals differ in future fitness expectations. PMID- 23097507 TI - Long-term differences in extinction risk among the seven forms of rarity. AB - Rarity is widely used to predict the vulnerability of species to extinction. Species can be rare in markedly different ways, but the relative impacts of these different forms of rarity on extinction risk are poorly known and cannot be determined through observations of species that are not yet extinct. The fossil record provides a valuable archive with which we can directly determine which aspects of rarity lead to the greatest risk. Previous palaeontological analyses confirm that rarity is associated with extinction risk, but the relative contributions of different types of rarity to extinction risk remain unknown because their impacts have never been examined simultaneously. Here, we analyse a global database of fossil marine animals spanning the past 500 million years, examining differential extinction with respect to multiple rarity types within each geological stage. We observe systematic differences in extinction risk over time among marine genera classified according to their rarity. Geographic range played a primary role in determining extinction, and habitat breadth a secondary role, whereas local abundance had little effect. These results suggest that current reductions in geographic range size will lead to pronounced increases in long-term extinction risk even if local populations are relatively large at present. PMID- 23097508 TI - Continent-wide tracking to determine migratory connectivity and tropical habitat associations of a declining aerial insectivore. AB - North American birds that feed on flying insects are experiencing steep population declines, particularly long-distance migratory populations in the northern breeding range. We determine, for the first time, the level of migratory connectivity across the range of a songbird using direct tracking of individuals, and test whether declining northern populations have higher exposure to agricultural landscapes at their non-breeding grounds in South America. We used light-level geolocators to track purple martins, Progne subis, originating from North American breeding populations, coast-to-coast (n = 95 individuals). We show that breeding populations of the eastern subspecies, P. s. subis, that are separated by ca. 2000 km, nevertheless have almost completely overlapping non breeding ranges in Brazil. Most (76%) P. s. subis overwintered in northern Brazil near the Amazon River, not in the agricultural landscape of southern Brazil. Individual non-breeding sites had an average of 91 per cent forest and only 4 per cent agricultural ground cover within a 50 km radius, and birds originating from declining northern breeding populations were not more exposed to agricultural landscapes than stable southern breeding populations. Our results show that differences in wintering location and habitat do not explain recent trends in breeding population declines in this species, and instead northern populations may be constrained in their ability to respond to climate change. PMID- 23097509 TI - Transcriptional regulation of brain gene expression in response to a territorial intrusion. AB - Aggressive behaviour associated with territorial defence is widespread and has fitness consequences. However, excess aggression can interfere with other important biological functions such as immunity and energy homeostasis. How the expression of complex behaviours such as aggression is regulated in the brain has long intrigued ethologists, but has only recently become amenable for molecular dissection in non-model organisms. We investigated the transcriptomic response to territorial intrusion in four brain regions in breeding male threespined sticklebacks using expression microarrays and quantitative polymerase chain reaction (qPCR). Each region of the brain had a distinct genomic response to a territorial challenge. We identified a set of genes that were upregulated in the diencephalon and downregulated in the cerebellum and the brain stem. Cis regulatory network analysis suggested transcription factors that regulated or co regulated genes that were consistently regulated in all brain regions and others that regulated gene expression in opposing directions across brain regions. Our results support the hypothesis that territorial animals respond to social challenges via transcriptional regulation of genes in different brain regions. Finally, we found a remarkably close association between gene expression and aggressive behaviour at the individual level. This study sheds light on the molecular mechanisms in the brain that underlie the response to social challenges. PMID- 23097510 TI - The genomics of adaptation. AB - The amount and nature of genetic variation available to natural selection affect the rate, course and outcome of evolution. Consequently, the study of the genetic basis of adaptive evolutionary change has occupied biologists for decades, but progress has been hampered by the lack of resolution and the absence of a genome level perspective. Technological advances in recent years should now allow us to answer many long-standing questions about the nature of adaptation. The data gathered so far are beginning to challenge some widespread views of the way in which natural selection operates at the genomic level. Papers in this Special Feature of Proceedings of the Royal Society B illustrate various aspects of the broad field of adaptation genomics. This introductory article sets up a context and, on the basis of a few selected examples, discusses how genomic data can advance our understanding of the process of adaptation. PMID- 23097511 TI - An end to insight? New Caledonian crows can spontaneously solve problems without planning their actions. AB - Animals rarely solve problems spontaneously. Some bird species, however, can immediately find a solution to the string-pulling problem. They are able to rapidly gain access to food hung on the end of a long string by repeatedly pulling and then stepping on the string. It is currently unclear whether these spontaneous solutions are produced by insight or by a perceptual-motor feedback loop. Here, we presented New Caledonian crows and humans with a novel horizontal string-pulling task. While the humans succeeded, no individual crow showed a significant preference for the connected string, and all but one failed to gain the food even once. These results clearly show that string pulling in New Caledonian crows is generated not by insight, but by perceptual feedback. Animals can spontaneously solve problems without planning their actions. PMID- 23097512 TI - Traits, trees and taxa: global dimensions of biodiversity in mammals. AB - Measures of biodiversity encompass variation along several dimensions such as species richness (SR), phylogenetic diversity (PD) and functional/trait diversity (TD). At the global scale, it is widely recognized that SR and PD are strongly correlated, but the extent to which either tends to capture variation in TD is unclear. Here, we assess relationships among PD, SR and TD for a number of traits both across clades and regional assemblages of mammals. We also contrast results using two different measures of TD, trait variance and a new measure we refer to as trait bin filling (the number of orders of magnitude of variation that contain at least one species). When TD is defined as trait variance, PD is a much stronger correlate of TD than SR across clades, consistent with hypotheses about the conservation value of PD. However, when TD is defined as bin filling, PD and SR show similar correlations with TD across clades and space. We also investigate potential losses of SR, PD and TD if species that are currently threatened were to go extinct, and find that threatened PD is often a similar predictor of threatened TD as SR. PMID- 23097513 TI - Eye shape and the nocturnal bottleneck of mammals. AB - Most vertebrate groups exhibit eye shapes that vary predictably with activity pattern. Nocturnal vertebrates typically have large corneas relative to eye size as an adaptation for increased visual sensitivity. Conversely, diurnal vertebrates generally demonstrate smaller corneas relative to eye size as an adaptation for increased visual acuity. By contrast, several studies have concluded that many mammals exhibit typical nocturnal eye shapes, regardless of activity pattern. However, a recent study has argued that new statistical methods allow eye shape to accurately predict activity patterns of mammals, including cathemeral species (animals that are equally likely to be awake and active at any time of day or night). Here, we conduct a detailed analysis of eye shape and activity pattern in mammals, using a broad comparative sample of 266 species. We find that the eye shapes of cathemeral mammals completely overlap with nocturnal and diurnal species. Additionally, most diurnal and cathemeral mammals have eye shapes that are most similar to those of nocturnal birds and lizards. The only mammalian clade that diverges from this pattern is anthropoids, which have convergently evolved eye shapes similar to those of diurnal birds and lizards. Our results provide additional evidence for a nocturnal 'bottleneck' in the early evolution of crown mammals. PMID- 23097514 TI - Quantifying temporal change in biodiversity: challenges and opportunities. AB - Growing concern about biodiversity loss underscores the need to quantify and understand temporal change. Here, we review the opportunities presented by biodiversity time series, and address three related issues: (i) recognizing the characteristics of temporal data; (ii) selecting appropriate statistical procedures for analysing temporal data; and (iii) inferring and forecasting biodiversity change. With regard to the first issue, we draw attention to defining characteristics of biodiversity time series--lack of physical boundaries, uni-dimensionality, autocorrelation and directionality--that inform the choice of analytic methods. Second, we explore methods of quantifying change in biodiversity at different timescales, noting that autocorrelation can be viewed as a feature that sheds light on the underlying structure of temporal change. Finally, we address the transition from inferring to forecasting biodiversity change, highlighting potential pitfalls associated with phase-shifts and novel conditions. PMID- 23097515 TI - Understanding specialism when the Jack of all trades can be the master of all. AB - Specialism is widespread in nature, generating and maintaining diversity, but recent work has demonstrated that generalists can be equally fit as specialists in some shared environments. This no-cost generalism challenges the maxim that 'the jack of all trades is the master of none', and requires evolutionary genetic mechanisms explaining the existence of specialism and no-cost generalism, and the persistence of specialism in the face of selection for generalism. Examining three well-described mechanisms with respect to epistasis and pleiotropy indicates that sign (or antagonistic) pleiotropy without epistasis cannot explain no-cost generalism and that magnitude pleiotropy without epistasis (including directional selection and mutation accumulation) cannot explain the persistence of specialism. However, pleiotropy with epistasis can explain all. Furthermore, epistatic pleiotropy may allow past habitat use to influence future use of novel environments, thereby affecting disease emergence and populations' responses to habitat change. PMID- 23097516 TI - Grey matter volume in early human visual cortex predicts proneness to the sound induced flash illusion. AB - Visual perception can be modulated by sounds. A drastic example of this is the sound-induced flash illusion: when a single flash is accompanied by two bleeps, it is sometimes perceived in an illusory fashion as two consecutive flashes. However, there are strong individual differences in proneness to this illusion. Some participants experience the illusion on almost every trial, whereas others almost never do. We investigated whether such individual differences in proneness to the sound-induced flash illusion were reflected in structural differences in brain regions whose activity is modulated by the illusion. We found that individual differences in proneness to the illusion were strongly and significantly correlated with local grey matter volume in early retinotopic visual cortex. Participants with smaller early visual cortices were more prone to the illusion. We propose that strength of auditory influences on visual perception is determined by individual differences in recurrent connections, cross-modal attention and/or optimal weighting of sensory channels. PMID- 23097517 TI - A congruent phylogenomic signal places eukaryotes within the Archaea. AB - Determining the relationships among the major groups of cellular life is important for understanding the evolution of biological diversity, but is difficult given the enormous time spans involved. In the textbook 'three domains' tree based on informational genes, eukaryotes and Archaea share a common ancestor to the exclusion of Bacteria. However, some phylogenetic analyses of the same data have placed eukaryotes within the Archaea, as the nearest relatives of different archaeal lineages. We compared the support for these competing hypotheses using sophisticated phylogenetic methods and an improved sampling of archaeal biodiversity. We also employed both new and existing tests of phylogenetic congruence to explore the level of uncertainty and conflict in the data. Our analyses suggested that much of the observed incongruence is weakly supported or associated with poorly fitting evolutionary models. All of our phylogenetic analyses, whether on small subunit and large subunit ribosomal RNA or concatenated protein-coding genes, recovered a monophyletic group containing eukaryotes and the TACK archaeal superphylum comprising the Thaumarchaeota, Aigarchaeota, Crenarchaeota and Korarchaeota. Hence, while our results provide no support for the iconic three-domain tree of life, they are consistent with an extended eocyte hypothesis whereby vital components of the eukaryotic nuclear lineage originated from within the archaeal radiation. PMID- 23097519 TI - Cost of reproduction in the Queensland fruit fly: Y-model versus lethal protein hypothesis. AB - The trade-off between lifespan and reproduction is commonly explained by differential allocation of limited resources. Recent research has shown that the ratio of protein to carbohydrate (P : C) of a fly's diet mediates the lifespan reproduction trade-off, with higher P : C diets increasing egg production but decreasing lifespan. To test whether this P : C effect is because of changing allocation strategies (Y-model hypothesis) or detrimental effects of protein ingestion on lifespan (lethal protein hypothesis), we measured lifespan and egg production in Queensland fruit flies varying in reproductive status (mated, virgin and sterilized females, virgin males) that were fed one of 18 diets varying in protein and carbohydrate amounts. The Y-model predicts that for sterilized females and for males, which require little protein for reproduction, there will be no effect of P : C ratio on lifespan; the lethal protein hypothesis predicts that the effect of P : C ratio should be similar in all groups. In support of the lethal protein hypothesis, and counter to the Y-model, the P : C ratio of the ingested diets had similar effects for all groups. We conclude that the trade-off between lifespan and reproduction is mediated by the detrimental side-effects of protein ingestion on lifespan. PMID- 23097520 TI - Air kerma to HP(3) conversion coefficients for photons from 10 keV to 10 MeV, calculated in a cylindrical phantom. AB - In the framework of the ORAMED project (Optimization of RAdiation protection for MEDical staff), funded by the European Union Seventh Framework Programme, different studies were aimed at improving the quality of radiation protection in interventional radiology and nuclear medicine. The main results of the project were presented during a final workshop held in Barcelona in January 2011, the proceedings of which are available in the open literature. One of the ORAMED tasks was focused on the problem of eye-lens photon exposure of the medical staff, a topic that gained more importance especially after the ICRP decision to lower the limiting equivalent dose to 20 mSv per year. The present technical note has the scope, besides briefly summarising the physical reasons of the proposal and the practical implications, to provide, in tabular form, a set of air kerma to Hp(3) conversion coefficients based on the adoption of a theoretical cylindrical model that is well suited for reproduction of the mass and the shape of a human head. PMID- 23097518 TI - Increased longevity evolves from grandmothering. AB - Postmenopausal longevity may have evolved in our lineage when ancestral grandmothers subsidized their daughters' fertility by provisioning grandchildren, but the verbal hypothesis has lacked mathematical support until now. Here, we present a formal simulation in which life spans similar to those of modern chimpanzees lengthen into the modern human range as a consequence of grandmother effects. Greater longevity raises the chance of living through the fertile years but is opposed by costs that differ for the sexes. Our grandmother assumptions are restrictive. Only females who are no longer fertile themselves are eligible, and female fertility extends to age 45 years. Initially, there are very few eligible grandmothers and effects are small. Grandmothers can support only one dependent at a time and do not care selectively for their daughters' offspring. They must take the oldest juveniles still relying on mothers; and infants under the age of 2 years are never eligible for subsidy. Our model includes no assumptions about brains, learning or pair bonds. Grandmother effects alone are sufficient to propel the doubling of life spans in less than sixty thousand years. PMID- 23097521 TI - Assessment and management of psoriasis: summary of NICE guidance. PMID- 23097522 TI - Keeping the customer satisfied. PMID- 23097524 TI - Larger scale trials are needed to show what really works. PMID- 23097525 TI - GMC inconsistency. PMID- 23097527 TI - We must join forces with our patients. PMID- 23097526 TI - Golden ages have their dark sides. PMID- 23097528 TI - Asking the right questions is key. PMID- 23097529 TI - Not all "good" doctors do it anyway. PMID- 23097531 TI - Video cameras identify the causes of falls in care homes. PMID- 23097530 TI - Statement on reduced risk is misleading. PMID- 23097532 TI - Cognitive function is unaffected by tight glucose control in paediatric intensive care. PMID- 23097533 TI - Adults in India given second hand cardioverter defibrillators from the US. PMID- 23097534 TI - Mixed results after 10 years for men given postoperative radiotherapy for prostate cancer. PMID- 23097535 TI - Daily interruptions to sedation for critically ill adults? PMID- 23097536 TI - Availability of junk food should be reduced. PMID- 23097537 TI - The "least worst" course of action? PMID- 23097538 TI - We need evidence based tools to identify medically at risk drivers. PMID- 23097540 TI - Fashionable to criticise the drug industry? PMID- 23097541 TI - How a fake hip showed up failings in European device regulation. PMID- 23097542 TI - Dramatic trial results are often too good to be true. PMID- 23097543 TI - Adults with depression report widespread discrimination. PMID- 23097544 TI - Finding the smoking gun: a speech by Richard Peto. PMID- 23097545 TI - The EU's system for regulating medical devices. PMID- 23097546 TI - Concentration of hands. PMID- 23097547 TI - UK drug service is ill equipped to deal with new "legal highs" taken by clubbers, conference is told. PMID- 23097548 TI - Half of latest NHS efficiency savings came from staff pay freeze. PMID- 23097550 TI - Calorie restriction and longevity: fast and loose? PMID- 23097551 TI - A sinister cause of shoulder pain, with numbness and weakness in the ipsilateral hand. PMID- 23097552 TI - Anatomy of the pituitary region. PMID- 23097553 TI - Psychotic depression. PMID- 23097549 TI - Use of 3x2 tables with an intention to diagnose approach to assess clinical performance of diagnostic tests: meta-analytical evaluation of coronary CT angiography studies. AB - OBJECTIVE: To determine whether a 3 * 2 table, using an intention to diagnose approach, is better than the "classic" 2 * 2 table at handling transparent reporting and non-evaluable results, when assessing the accuracy of a diagnostic test. DESIGN: Based on a systematic search for diagnostic accuracy studies of coronary computed tomography (CT) angiography, full texts of relevant studies were evaluated to determine whether they could calculate an alternative 3 * 2 table. To quantify an overall effect, we pooled diagnostic accuracy values according to a meta-analytical approach. DATA SOURCES: Medline (via PubMed), Embase (via Ovid), and ISI Web of Science electronic databases. ELIGIBILITY CRITERIA: Prospective English or German language studies comparing coronary CT with conventional coronary angiography in all patients and providing sufficient data for a patient level analysis. RESULTS: 120 studies (10,287 patients) were eligible. Studies varied greatly in their approaches to handling non-evaluable findings. We found 26 studies (including 2298 patients) that allowed us to calculate both 2 * 2 tables and 3 * 2 tables. Using a bivariate random effects model, we compared the 2 * 2 table with the 3 * 2 table, and found significant differences for pooled sensitivity (98.2 (95% confidence interval 96.7 to 99.1) v 92.7 (88.5 to 95.3)), area under the curve (0.99 (0.98 to 1.00) v 0.93 (0.91 to 0.95)), positive likelihood ratio (9.1 (6.2 to 13.3) v 4.4 (3.3 to 6.0)), and negative likelihood ratio (0.02 (0.01 to 0.04) v 0.09 (0.06 to 0.15); (P<0.05)). CONCLUSION: Parameters for diagnostic performance significantly decrease if non evaluable results are included by a 3 * 2 table for analysis (intention to diagnose approach). This approach provides a more realistic picture of the clinical potential of diagnostic tests. PMID- 23097554 TI - EU approval system leaves door open for dangerous devices. PMID- 23097555 TI - Notified bodies: are they fit for purpose? PMID- 23097556 TI - UK health secretary promises to tighten regulatory procedures for medical devices. PMID- 23097557 TI - The truth behind "made in Europe" labels on medical devices. PMID- 23097558 TI - Romney commits to denationalise Medicaid in third presidential debate. PMID- 23097559 TI - miR-18a promotes malignant progression by impairing microRNA biogenesis in nasopharyngeal carcinoma. AB - Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and cell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3' untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC. PMID- 23097560 TI - Intrablastocyst injection with human CD34+/CD133+ cells increase survival of immunocompetent fumarylacetoacetate hydrolase knockout mice. AB - Mice harbouring a humanized liver represent a powerful tool for translating preclinical studies of drug metabolism and pharmacokinetics into humans, as well as the exploitation of basic studies on liver pathophysiology including hepatitis C virus (HCV) infection. Human adult stem cells injected into immunocompetent mice at preimmune stages of development, generate chimeric animals harbouring a liver with relatively discrete foci of human hepatocyte-like cells. In this study, we have evaluated whether similar protocol of xenotransplantation in the presence of selective pressure might lead to a higher human-into-mouse liver repopulation, leading to a relevant improvement of liver function. Human CD34(+)/CD133(+) cells were microinjected into blastocysts from genetically modified mice committed to develop a lethal hepatopathy, due to the absence of the enzyme fumarylacetoacetate hydrolase (FAH). Following xenotransplantation, mouse survival was followed over time and histochemical evidence of liver chimerism was assessed. The survival expectancy of seven out of 21 intrablastocyst xenotransplanted FAH knockout (Fah-/-) mice was significantly higher as compared with non-xenotransplanted mice. Several nodules of human hepatocyte-like cells were revealed by immunohistochemistry in the liver of rescued mice. Our data positively support the hypothesis that preimmune xenotransplantation of human stem cells into immunocompetent mice harbouring a lethal hepatic disease might lead to a functionally relevant human-mouse liver chimerism and marks a significant advancement towards the establishment of a novel translational preclinical model for liver diseases. PMID- 23097561 TI - Optimizing the dosing interval of buprenorphine in a multimodal postoperative analgesic strategy in the rat: minimizing side-effects without affecting weight gain and food intake. AB - Buprenorphine is commonly used as (part of) postoperative analgesic treatment with dosage dependent side-effects such as pica behaviour. No strict consensus exists about the optimal dosing interval of buprenorphine, as its duration of action has been described as being in the range of 6-12 h. In this study, dosing intervals of 8 h (thrice-a-day) and 12 h (twice-a-day) for buprenorphine in a multimodal analgesic strategy (concurrent administration of a non-steroidal anti inflammatory drug) were compared on food intake, weight and side-effects (gnawing on plastic Petri dishes and growth rate, indicative of pica behaviour) in rats. The food intake and weight of both intervals were comparable, as the animals from the twice-a-day group did not lose more weight or consumed less food during the analgesic period. The rats from the thrice-a-day group suffered from more side effects, as the growth rate was decreased and more plastic was gnawed on. It is recommended to carefully evaluate analgesic and side-effects when using buprenorphine. When side-effects are observed, the possibility of increasing the dosing interval of buprenorphine should be explored. In this study, increasing the dosing interval of buprenorphine in a multimodal analgesic regimen resulted in reduced unwanted side-effects, without increasing weight loss or decreasing food intake. Although this is suggestive of provision of comparable analgesia, future studies including more pain-related readout parameters to assess the effect of the dosing interval on analgesic efficacy are recommended. PMID- 23097562 TI - Development of a rat respiratory mask and its application in experimental chronic myocardial ischaemia. AB - In addressing the challenge of the low survival rates of rats with myocardial ischaemia, we developed a novel respiratory mask. We tested this mask on the rat model. We gave attention to several features of the mask: (1) shape, (2) size, (3) inlet, (4) outlet, (5) compatibility between rat head and the mask, (6) connection between mask and ventilator. We found certain features, especially to influence mask efficacy. These features include: mask shape, mask inlet and outlet, mask connection to the respiratory machine, mask mount on the rat head. We examined the rat mask in a model of chronic myocardial ischaemia; our model was the ligation of the coronary artery. The rats with the masks experienced an increase in survival by a factor of 50-90% compared with rats deprived of the masks. Towards the examination of myocardial ischaemia, our new mask may offer a platform replete with both efficiency and stability. PMID- 23097564 TI - A comparison of abdominal and scrotal approach methods of vasectomy and the influence of analgesic treatment in laboratory mice. AB - Vasectomized mice are needed in the production of genetically-modified animals. The BVAAWF/FRAME/RSPCA/UFAW Joint Working Group on Refinement recommended that vasectomy should be performed via an incision in the scrotal sac, rather than via laparotomy, arguing that the former could be less painful due to minimal tissue trauma. This study was undertaken to assess the validity of this recommendation. Mice underwent vasectomy via either abdominal or scrotal approach surgery. Mice were filmed for 15 min presurgery and at one, 24 and 48 h postsurgery. Data were obtained using automated behaviour recognition software (HomeCageScan). Meloxicam was administered either alone or combined with acetaminophen prior to surgery. A third group received only saline subcutaneously. Postsurgery behaviour changes were compared between groups at each time point. Exploratory behaviours such as rearing, walking and sniffing were most greatly reduced at one hour following surgery whereas the duration of grooming increased. By 48 h these changes had largely subsided. Results indicated mice undergoing scrotal approach surgery fared better at one hour postsurgery, but the magnitude of this was relatively insignificant compared with the overall effects of surgery. If the observed behaviour changes resulted from pain, results suggested there was no significant advantage of scrotal versus abdominal approach vasectomy. These and other recently obtained data on the effects of non-steroidal anti-inflammatory drugs (NSAIDs) in mice suggest considerably larger doses of these or more potent analgesics, more precise monitoring of surgical outcomes, or a combination of these factors are needed to determine the extent of pain experienced by mice undergoing vasectomy. PMID- 23097563 TI - In vitro fertility rate of 129 strain is improved by buserelin (gonadotropin releasing hormone) administration prior to superovulation. AB - The 129 mice are well recognized for their low fertility and it is speculated that this lack of fertility may be due to the oocyte condition. In this study we investigated superovulation regimens for the 129S1/SvImJ mouse strain to improve the oocyte quality and fertility rate of in vitro fertilization (IVF). Female mice were divided into four groups based on hormone and timing of injection. Group 1 received pregnant mare serum gonadotropin (PMSG) and 48 h later human chorionic gonadotropin (hCG); using the same dose, group 2 received hCG 52 h post PMSG and group 3, 55 h post-PMSG. Group 4 received buserelin (gonadotropin releasing hormone agonist [GnRH]) followed 24 h later by PMSG and then hCG 55 h post-PMSG. IVF was performed using 129S1/SvImJ oocytes and sperm; C57BL/6J sperm with 129S1/SvImJ oocytes was used as fertility control. The IVF fertility rate was 1% (Groups 1 and 2), 17% (Group 3) and 55% (Group 4) for 129 oocytes fertilized with 129 sperm. For 129 oocytes fertilized with C57BL/6J sperm, the fertility rate was 5% (Group 1), 10% (Group 2), 40% (Group 3) and 59% (Group 4). These results suggest that extending the interval time between PMSG and hCG and giving GnRH in addition to the standard PMSG and hCG treatments can improve IVF fertility rate of 129S1/SvImJ mouse strains significantly. PMID- 23097565 TI - A novel intubation technique for minimally invasive longitudinal studies of rat lungs using hyperpolarized 3He magnetic resonance imaging. AB - Hyperpolarized noble gas (HNG) magnetic resonance imaging (MRI) has been shown to be useful for studying rodent models of lung disease. Image quality can be substantially degraded by signal loss from molecular oxygen entering the airway, requiring invasive surgery to ensure a good seal between the endotracheal (ET) tube and trachea. A modified Foley catheter having an inflatable cuff near the tip provides a novel approach for ensuring image quality for HNG MRI, thereby enabling longitudinal studies and reducing animal numbers. A Foley catheter was modified for rodent intubation and to minimize dead space. Three pairs of age matched male Sprague Dawley rats 400 (30) g were used. Two pairs were intubated using the Foley and the third with an intravenous catheter. Leak rates were measured from pressure versus time curves within each animal. The pairs were euthanized immediately or six days postrecovery to assess the effects of the procedure on animal health, as reflected by histological examination. The Foley catheter resulted in minimal leak rates (-0.20 (0.03) versus -0.16 (0.05) cmH(2)O/s), and were shown to be well below upper-limit leak rates of -0.5 and 0.7 cmH(2)O/s. Tracheal samples from rats in a separate Foley group (not mechanically ventilated) showed superficial damage six days postextubation (grade = 0). (3)He imaging performed using the Foley showed good image quality. Though some technical issues remain to be solved, a modified Foley catheter used as an ET tube offers the potential to enable longitudinal studies in rodents and reduce animal numbers. PMID- 23097566 TI - Individual housing of female mice: influence on postsurgical behaviour and recovery. AB - Individual housing of laboratory mice may increase vulnerability to surgical stress, and interfere with postsurgical recovery. To analyse the effect of housing conditions on recovery, pair- and single-housed female C57BL/6J mice underwent a minor laparotomy +/- analgesia, anaesthesia only or no treatment. Animals were monitored using non-invasive methods during the immediate postsurgical period to assess pain and general impairment. While no appearance or posture abnormalities were observed postexperiment, home cage behaviours were affected distinctly. Discriminant analysis identified self-grooming, locomotion, climbing and resting as mainly responsible for experimental group separation. Behavioural rhythmicity was disrupted, and behaviours related to wellbeing, such as nest building, climbing and burrowing, decreased. Behavioural pain signs (e.g. press) increased. Most behavioural alterations showed a gradation between treatments, e.g. burrowing latency ranged from an intermediate level following anaesthesia only and surgery with analgesia, to pronounced prolongation after surgery without analgesia. Significantly lower burrowing performance after surgery without analgesia in individually-housed animals indicates better recovery in pairs. Social interaction in pairs--an important component of normal behaviour (64%) and a potential indicator for direct social support--was nearly absent (0.3-0.5%). While anaesthesia and surgery resulted in clear changes in behaviour, differences between housing conditions were minor. Hence, despite a tendency towards better recovery in pairs, we found no distinct negative effect of individual housing. In conclusion, both housing conditions are acceptable during the period immediately following minor surgery, though social housing is always preferable in female mice. PMID- 23097567 TI - Selective inbreeding does not increase gut microbiota similarity in BALB/c mice. AB - Inflammatory diseases in mouse models are under strong impact from the gut microbiota. Therefore increased interindividual gut microbiota similarity may be seen as a way to reduce group sizes in mouse experiments. The composition of the gut microbiota is to a high extent defined by genetics, and it is known that selecting siblings as mothers even in inbred colonies may increase the gut microbiota similarity among the mice with 3-4%. We therefore hypothesized that selective breeding of mice aiming at a high similarity in the gut microbiota would increase the interindividual similarity of the gut microbiota. BALB/cCrl mice were, however, found to have a mean heterozygosity of only 0.8% in their genome, and selection of breeders with a high similarity in the gut microbiota for three generations did not change the overall gut microbiota similarity, which was 66% in the P generation and 66%, 64% and 63% in the F1, F2 and F3 generations, respectively. Increased gut microbiota similarity in closely related mice in inbred mouse colonies is, therefore, more likely to be caused by other factors, such as imprinting or different intrauterine conditions, rather than by residual heterozygosity. PMID- 23097568 TI - Anatomical anomalies of the laryngeal branches of the vagus nerve in pigs (Sus scrofa). AB - To delineate the anomaly and frequency of their occurrence in a pig model, we reported the topography of the vagus laryngeal branches and compared the differences with humans. Thirty sides of cervical vagus nerve in 15 fresh cadavers (Sus scrofa) were microdissected. We measured the branch diameters and lengths of the laryngeal branches using a Vernier caliper with a resolution of 0.01 mm. Two patterns of the vagus laryngeal branches were shown: 56.7% with the cranial laryngeal nerve (CLN) and 43.3% without the CLN. The diameters and the length of the CLN were not affected by the side of the neck (P > 0.05), but the diameters of the recurrent laryngeal nerve (RLN) and the nodose ganglion were significantly different between left and right sides (P < 0.05). The left RLN was thinner than the right side in diameter (P < 0.05). Four of the 30 sides had anastomoses between the vagus and the cervical sympathetic chain. There were some differences between the pig anatomy and human anatomy, but the patterns were largely similar. The similarities support the utility of this model, which is closer in size to humans than the standard rodent models. PMID- 23097569 TI - Estimation of glomerular filtration rate in rabbits by a single-sample method using iodixanol. AB - To estimate the glomerular filtration rate (GFR) in conscious rabbits, a single sample method using the non-ionic contrast medium iodixanol was compared with a three-sample method using the standard agent inulin. Iodixanol and inulin were co administered intravenously to male New Zealand White rabbits at 60 mg I/kg and 40 mg/kg, respectively, and blood was collected 30, 60, 90 and 120 min later. Serum iodixanol and inulin concentrations were separately determined by high performance liquid chromatography and colorimetry, respectively. Serum urea nitrogen (UN) and creatinine concentrations were also determined. Based on the data from healthy and cisplatin-treated rabbits, the GFR estimated by iodixanol was well consistent with that by inulin. Further, when the GFR decreased to more than 60% of the reference value, serum creatinine concentrations became elevated. However, serum UN concentrations exhibited wide fluctuations, presumably due to a difference in renal handlings. The single-sample method using iodixanol was considered to be an expedient tool in both clinical and research settings, because the stress due to a multi-sample method was reduced. PMID- 23097570 TI - Spontaneous fibrosarcoma in an experimental aged Lewis rat. AB - This case report describes the results of the gross pathological, histological and immunohistological examinations of a fibrosarcoma that spontaneously developed in the left neck region of an aged male Lewis rat that participated in a long-term facial nerve regeneration study. A 10 mm long polylactic acid (PLA) tube was implanted into a 7 mm critical defect gap of the buccal branch of the left facial nerve of a male eight-week-old Lewis rat. Forty-two weeks after implantation, an approximately 8 cm * 9 cm * 2.5 cm rapidly growing mass with ulceration of the overlying skin was found in the left neck region. Gross examination of the tumour and the surrounding tissues before tumour excision revealed that the tumour had clear boundaries, and had not invaded any facial tissues, the facial nerve and the PLA nerve guide. Gross examination of the tumour's cut surface revealed that the tumour comprised numerous smooth nodules with a homogeneous white tan colour. Examination of the haematoxylin and eosin stained sections of the tumour revealed that the tumour was predominantly composed of bundles of spindle-shaped atypical proliferating cells that were mixed with bundles of collagen fibres and arranged in a storiform pattern. Tumour emboli and skin invasion were also observed. Immunohistological examination revealed that the tumour cells were weakly positive for vimentin, but negative for keratin, alpha-smooth muscle actin, S-100 protein and CD34. From the results of these analyses, the final pathological diagnosis of this tumour was a fibrosarcoma. PMID- 23097571 TI - Response to Roustan et al. 'Evaluating methods of mouse euthanasia on the oocyte quality: cervical dislocation versus isoflurane inhalation': animal welfare concerns regarding the aversiveness of isoflurane and its inability to cause rapid death. PMID- 23097573 TI - Infarct-remodelled hearts with limited oxidative capacity boost fatty acid oxidation after conditioning against ischaemia/reperfusion injury. AB - AIMS: Infarct-remodelled hearts are less amenable to protection against ischaemia/reperfusion. Understanding preservation of energy metabolism in diseased vs. healthy hearts may help to develop anti-ischaemic strategies effective also in jeopardized myocardium. METHODS AND RESULTS: Isolated infarct remodelled/sham Sprague-Dawley rat hearts were perfused in the working mode and subjected to 15 min of ischaemia and 30 min of reperfusion. Protection of post ischaemic ventricular work was achieved by pharmacological conditioning with sevoflurane. Oxidative metabolism was measured by substrate flux in fatty acid and glucose oxidation using [(3)H]palmitate and [(14)C]glucose. Mitochondrial oxygen consumption was measured in saponin-permeabilized left ventricular muscle fibres. Activity assays of citric acid synthase, hydroxyacyl-CoA dehydrogenase, and pyruvate dehydrogenase and mass spectrometry for acylcarnitine profiling were also performed. Six weeks after coronary artery ligation, the hearts exhibited macroscopic and molecular signs of hypertrophy consistent with remodelling and limited respiratory chain and citric acid cycle capacity. Unprotected remodelled hearts showed a marked decline in palmitate oxidation and acetyl-CoA energy production after ischaemia/reperfusion, which normalized in sevoflurane-protected remodelled hearts. Protected remodelled hearts also showed higher beta-oxidation flux as determined by increased oxygen consumption with palmitoylcarnitine/malate in isolated fibres and a lower ratio of C16:1+C16OH/C14 carnitine species, indicative of a higher long-chain hydroxyacyl-CoA dehydrogenase activity. Remodelled hearts exhibited higher PPARalpha-PGC-1alpha but defective HIF-1alpha signalling, and conditioning enabled them to mobilize fatty acids from endogenous triglyceride stores, which closely correlated with improved recovery. CONCLUSIONS: Protected infarct-remodelled hearts secure post-ischaemic energy production by activation of beta-oxidation and mobilization of fatty acids from endogenous triglyceride stores. PMID- 23097574 TI - Myofibrillar Ca(2+) sensitivity is uncoupled from troponin I phosphorylation in hypertrophic obstructive cardiomyopathy due to abnormal troponin T. AB - AIMS: We studied the relationship between myofilament Ca(2+) sensitivity and troponin I (TnI) phosphorylation by protein kinase A at serines 22/23 in human heart troponin isolated from donor hearts and from myectomy samples from patients with hypertrophic obstructive cardiomyopathy (HOCM). METHODS AND RESULTS: We used a quantitative in vitro motility assay. With donor heart troponin, Ca(2+) sensitivity is two- to three-fold higher when TnI is unphosphorylated. In the myectomy samples from patients with HOCM, the mean level of TnI phosphorylation was low: 0.38 +/- 0.19 mol Pi/mol TnI compared with 1.60 +/- 0.19 mol Pi/mol TnI in donor hearts, but no difference in myofilament Ca(2+) sensitivity was observed. Thus, troponin regulation of thin filament Ca(2+) sensitivity is abnormal in HOCM hearts. HOCM troponin (0.29 mol Pi/mol TnI) was treated with protein kinase A to increase the level of phosphorylation to 1.56 mol Pi/mol TnI. No difference in EC(50) was found in thin filaments containing high and low TnI phosphorylation levels. This indicates that Ca(2+) sensitivity is uncoupled from TnI phosphorylation in HOCM heart troponin. Coupling could be restored by replacing endogenous troponin T (TnT) with the recombinant TnT T3 isoform. No difference in Ca(2+) sensitivity was observed if TnI was exchanged into HOCM heart troponin or if TnT was exchanged into the highly phosphorylated donor heart troponin. Comparison of donor and HOCM heart troponin by mass spectrometry and with adduct-specific antibodies did not show any differences in TnT isoform expression, phosphorylation or any post-translational modifications. CONCLUSION: An abnormality in TnT is responsible for uncoupling myofibrillar Ca(2+) sensitivity from TnI phosphorylation in the septum of HOCM patients. PMID- 23097575 TI - Mullerianosis: a rare cause of acute renal colic. AB - A 50-year-old woman presented to the urology department with an acute history suggestive of left-sided renal colic. There were no other associated symptoms, but urine dipstick revealed non-visible haematuria. CT-KUB revealed a soft tissue mass at the left vesico-ureteric junction. Flexible cystoscopy demonstrated a mass intruding into the posterior bladder. A transurethral resection of the bladder 'tumour' was undertaken, and it was noted that the mass was not macroscopically consistent with transitional cell carcinoma. Histology demonstrated Mullerianosis, a rare lesion characterised by locally invasive growth of tissue originating from the Mullerian (paramesonephric) duct. The patient was seen by gynaecologist who initiated hormone treatment with an lutenising hormone--releasing hormone (LH-RH) analogue. Urological follow-up 3 months later highlighted ongoing pelvic pain but no further colicky loin pain. Repeat cystoscopy showed the mass had become smaller and the left ureter was laterally displaced. Further gynaecological input is planned if symptoms are ongoing. PMID- 23097576 TI - Chiari malformation and central sleep apnoea: successful therapy with adaptive pressure support servo-ventilation following surgical treatment. AB - Sleep apnoea is a common disorder with significant morbidity. It is categorised into obstructive and central sleep apnoea. There are a variety of conditions associated with central sleep apnoea ranging from cardiac failure to structural brain anomalies. We herein report a case of 57-year-old woman with Chiari malformation associated with significant sleep-disordered breathing. There was a family history of Chiari malformation. Although neurosurgical intervention had a significant impact on apnoea hypopnoea index (AHI) with a reduction from 81/h preoperatively to 22.1/h after the surgical treatment, it failed to cure the sleep disorder breathing completely and adaptive non-invasive servo-ventilation had a dramatic effect on symptoms and normalised the AHI. Although, central sleep apnoea is associated with a number of common disorders, this case illustrates that there may be an unusual cause. Moreover, adaptive pressure support servo ventilation may provide a promising treatment option following surgical correction of Chiari malformation. PMID- 23097577 TI - A cough conundrum in a patient with a previous history of BCG immunotherapy for bladder cancer. AB - We describe a non-smoker who presented with a persistent cough, weight loss and general malaise, and had a medical history of bladder carcinoma that had been successfully treated with intravesical BCG immunotherapy. Radiology revealed hilar lymphadenopathy, a predominantly mid-zone and lower-zone lung parenchymal nodular pattern with a perilymphatic distribution, a few thickened interlobular septae, and small pleural effusions bilaterally. The T-SPOT.TB blood test was negative. Video-assisted thoracoscopic surgery showed multiple pleural nodules, the histopathology of which showed multiple well-defined non-caseating granulomata. The patient was started on antituberculosis medication for presumed BCGosis--a systemic complication of previous BCG immunotherapy--and the patient showed an excellent clinical and radiological response. This case further adds to previous reports and reinforces the recommendation that all patients should be made fully aware of the potential systemic and delayed complications of BCG immunotherapy when they are consented for treatment. PMID- 23097578 TI - Central nervous system infection with Acanthamoeba in a malnourished child. AB - A 3-year-old male child presented with moderate-to-high grade fever and non projectile vomiting, generalised seizures and altered sensorium for 1 month. CT scan revealed a communicating hydrocephalus with no basal exudates. The microbiological tests were negative for Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitides, brucellosis, cryptococcosis, HIV and Mycobacterium tuberculosis. Intracranial pressure was relieved by ventriculo peritoneal shunt, and the child was empirically started on ceftriaxone, and antitubercular therapy with isoniazid, rifampicin, ethambutol and streptomycin, along with steroids and supportive treatment for seizures. The symptoms persisted. On further investigation the cerebrospinal fluid showed growth of Acanthamoeba spp., following which the initial treatment was stopped and a combination antiamoebic regimen of cotrimoxazole, rifampicin and ketoconazole was started, after which he showed clinical improvement. The treatment was continued for 6 months and on follow-up at 1, 3 and 6 months, there was a remarkable clinical improvement with no residual symptoms. PMID- 23097579 TI - A candidate molecular biomarker panel for the detection of bladder cancer. AB - BACKGROUND: Bladder cancer is among the five most common malignancies worldwide, and due to high rates of recurrence, one of the most prevalent. Improvements in noninvasive urine-based assays to detect bladder cancer would benefit both patients and health care systems. In this study, the goal was to identify urothelial cell transcriptomic signatures associated with bladder cancer. METHODS: Gene expression profiling (Affymetrix U133 Plus 2.0 arrays) was applied to exfoliated urothelia obtained from a cohort of 92 subjects with known bladder disease status. Computational analyses identified candidate biomarkers of bladder cancer and an optimal predictive model was derived. Selected targets from the profiling analyses were monitored in an independent cohort of 81 subjects using quantitative real-time PCR (RT-PCR). RESULTS: Transcriptome profiling data analysis identified 52 genes associated with bladder cancer (P <= 0.001) and gene models that optimally predicted class label were derived. RT-PCR analysis of 48 selected targets in an independent cohort identified a 14-gene diagnostic signature that predicted the presence of bladder cancer with high accuracy. CONCLUSIONS: Exfoliated urothelia sampling provides a robust analyte for the evaluation of patients with suspected bladder cancer. The refinement and validation of the multigene urothelial cell signatures identified in this preliminary study may lead to accurate, noninvasive assays for the detection of bladder cancer. IMPACT: The development of an accurate, noninvasive bladder cancer detection assay would benefit both the patient and health care systems through better detection, monitoring, and control of disease. PMID- 23097580 TI - Online pre-column derivatization with chromatographic separation to determine folic acid. AB - A simple, sensitive, and selective online pre-column derivatization high performance liquid chromatographic method was developed and validated for the first time to determine trace levels of folic acid (FA). An oxidant cerium (IV) trihydroxyhydroperoxide packed reactor was used for pre-column oxidation and was combined by column switching with a C18 analytical column for sample enrichment and separation. The method was based on oxidative cleavage of FA into highly fluorescence products, 2-amino-4-hydroxypteridine-6-carboxaldehyde and the corresponding 2-amino-4-hydroxypteridine-6-carboxylic acid, during the flow of 0.04 M phosphate buffer (pH 3.5) containing the analyte through packed reactor at a flow rate of 0.2 mL/min and 40 degrees C. The fluorescent products were enriched on the head of the analytical column for the final separation. The separation was performed at room temperature using a mobile phase consisting of phosphate buffer (0.04 M, pH 3.5) and acetonitrile (90:10, v/v). The eluents were monitored at emission and excitation wavelengths of 463 and 367 nm, respectively. The method showed excellent recovery, precision and accuracy with detection limits of 0.067 ng/mL from 500 uL of sample FA. The developed method was successfully applied to the determination of FA in pharmaceutical formulations and showed a recovery of 99.31% and a relative standard deviation of 1.72%. PMID- 23097581 TI - Stability-indicating HPLC method for the determination of darunavir ethanolate. AB - A novel stability-indicating reversed-phase high-performance liquid chromatographic (HPLC) method has been developed for the quantitative determination of darunavir ethanolate, an HIV-1 protease inhibitor. The chromatographic separation was achieved using an X-Bridge C18 (150 * 4.6 mm * 3.5 um) HPLC column in isocratic mode employing 0.01M ammonium formate (pH.3.0) buffer and acetonitrile in the ratio of 55:45 (v/v) with a flow rate of 1.0 mL/min. The detector wavelength was monitored at 265 nm and the column temperature was maintained at 30 degrees C. Darunavir ethanolate was exposed to thermal, photolytic, acid, base and oxidative stress conditions. Considerable degradation of the drug substance was found to occur under acid, base and oxidative stress conditions. The peak homogeneity data of darunavir ethanolate obtained by photodiode array detection demonstrated the specificity of the method in the presence of degradants. The degradation products were well resolved from primary peak of darunavir, indicating that the method is specific and stability indicating. The HPLC method was validated as per International Conference on Harmonization guidelines with respect to specificity, precision, linearity, accuracy and robustness. Regression analysis showed a correlation coefficient value greater than 0.999. The accuracy of the method was established based on the recovery obtained for darunavir ethanolate. PMID- 23097582 TI - Risk factors and primary prevention of congenital Chagas disease in a nonendemic country. AB - BACKGROUND: In this longitudinal cohort study we evaluated the congenital transmission of Chagas disease (CD) in a nonendemic area. The aim of this work was to analyze the predictive value of a Trypanosoma cruzi-positive polymerase chain reaction (PCR) result in pregnant women for the diagnosis of vertical transmission and to evaluate the use of PCR as a tool for early detection of infection. METHODS: The offspring of 59 seropositive pregnant mothers were followed up. The parasitological status of mothers was studied by PCR in a total of 64 pregnancies; 10 of these women had received treatment before pregnancy. Sixty-five infants (including a pair of twins) were monitored at 0, 6, 9, and 12 months of age by PCR and serology. In cases of congenital transmission, hemoculture and parasite lineage typing were performed. RESULTS: Nine infants had acquired CD congenitally. This represents a transmission rate of 13.8% among seropositive mothers (9 infected newborns of 65 total live births). All infants were infected with T. cruzi discrete typing unit V strain. A statistically significant correlation was found between T. cruzi vertical transmission and a positive PCR result during pregnancy (31%; 9 infected newborns in 29 live births). No infected infants were detected among 10 mothers who were treated before they became pregnant, compared with 16.4% (9 of 55 live births) among untreated mothers. CONCLUSIONS: PCR is a useful tool for the detection of congenital CD, and the treatment of infected women of childbearing age seems to be useful for preventing vertical transmission. PMID- 23097583 TI - Bone mineral density increases in HIV-infected children treated with long-term combination antiretroviral therapy. AB - The long-term treatment of human immunodeficiency virus (HIV)-infected children with combination antiretroviral therapy (cART) requires assessment of potential adverse effects, such as osteoporosis. Longitudinal data on bone mineral density (BMD) in HIV-infected children showed that cumulative treatment with cART had a positive impact on BMD over time. PMID- 23097584 TI - Frequency, severity, and prediction of tuberculous meningitis immune reconstitution inflammatory syndrome. AB - BACKGROUND: Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)-infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. METHODS: We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM IRIS. RESULTS: Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non TBM-IRIS patients (median, 50 vs 3 cells *10(6)/L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4-62.2). The combination of high CSF tumor necrosis factor (TNF)-alpha and low interferon (IFN)-gamma at TBM diagnosis predicted TBM IRIS (area under the curve = 0.91 [95% CI, .53-.99]). CONCLUSIONS: TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-gamma and TNF-alpha concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART. PMID- 23097585 TI - Importance of timing of maternal combined tetanus, diphtheria, and acellular pertussis (Tdap) immunization and protection of young infants. AB - BACKGROUND: Pertussis booster vaccine (Tdap) recommendations assume that pertussis-specific antibodies in women immunized preconception, during, or after previous pregnancies persist at sufficient levels to protect newborn infants. METHODS: Pertussis-specific immunoglobulin G (IgG) was measured by IgG-specific enzyme-linked immunosorbent assay (ELISA) in maternal-umbilical cord serum pairs where mothers received Tdap during the prior 2 years. Geometric mean concentrations (GMCs) of pertussis antibodies and cord-maternal GMC ratios were calculated. RESULTS: One hundred five mothers (mean age, 25.3 years [range, 15.3 38.4 years]; mean gestation, 39 weeks [range, 37-43 weeks]) immunized with Tdap vaccine a mean of 13.7 months (range, 2.3-23.9 months) previously were included; 72 (69%) had received Tdap postpartum, 31 at a routine healthcare visit and 2 as contacts of another newborn. There was no difference in GMCs for pertussis specific IgG in maternal delivery or infant cord sera for women immunized before (n = 86) or during (n = 19) early pregnancy. Placental transport of antibodies was 121%-186% from mothers immunized before and during pregnancy, respectively. Estimated GMC of IgG to pertussis toxin was <5 ELISA units (EU)/mL at infant age 2 months (start of infant immunization series). More infants of mothers immunized during pregnancy had pertussis toxin levels estimated to be higher than the lower limit of quantitation of the assay (4 EU/mL) through age 2 months (52% vs 38%; P = .34). CONCLUSIONS: Infants of mothers immunized preconception or in early pregnancy have insufficient pertussis-specific antibodies to protect against infection. Maternal immunization during the third trimester, immunization of other infant contacts, and reimmunization during subsequent pregnancies may be necessary. PMID- 23097586 TI - National outbreak of type a foodborne botulism associated with a widely distributed commercially canned hot dog chili sauce. AB - BACKGROUND: On 7 and 11 July 2007, health officials in Texas and Indiana, respectively, reported 4 possible cases of type A foodborne botulism to the US Centers for Disease Control and Prevention. Foodborne botulism is a rare and sometimes fatal illness caused by consuming foods containing botulinum neurotoxin. METHODS: Investigators reviewed patients' medical charts and food histories. Clinical specimens and food samples were tested for botulinum toxin and neurotoxin-producing Clostridium species. Investigators conducted inspections of the cannery that produced the implicated product. RESULTS: Eight confirmed outbreak associated cases were identified from Indiana (n = 2), Texas (n = 3), and Ohio (n = 3). Botulinum toxin type A was identified in leftover chili sauce consumed by the Indiana patients and 1 of the Ohio patients. Cannery inspectors found violations of federal canned-food regulations that could have led to survival of Clostridium botulinum spores during sterilization. The company recalled 39 million cans of chili. Following the outbreak, the US Food and Drug Administration inspected other canneries with similar canning systems and issued warnings to the industry about the danger of C. botulinum and the importance of compliance with canned food manufacturing regulations. CONCLUSIONS: Commercially produced hot dog chili sauce caused these cases of type A botulism. This is the first US foodborne botulism outbreak involving a commercial cannery in >30 years. Sharing of epidemiologic and laboratory findings allowed for the rapid identification of implicated food items and swift removal of potentially deadly products from the market by US food regulatory authorities. PMID- 23097587 TI - An international multicenter performance analysis of cytomegalovirus load tests. AB - BACKGROUND: Quantification of cytomegalovirus (CMV) load is central to the management of CMV infections in immunocompromised patients, but quantitative results currently differ significantly across methods and laboratories. METHODS: The COBAS AmpliPrep/COBAS TaqMan CMV Test (CAP/CTM CMV test), developed using the first World Health Organization CMV standard in the calibration process, was compared to local assays used by 5 laboratories at transplant centers in the United States and Europe. Blinded plasma panels (n = 90) spiked with 2.18-6.7 log(10) copies/mL and clinical plasma samples from immunocompromised patients (n = 660) were tested. RESULTS: Observed mean panel member concentrations by site and 95% confidence intervals (CIs) of the data combined across sites were narrower for CAP/CTM CMV test compared with local assays. The 95% CI in log(10) copies/mL of the combined data per panel member for CAP/CTM CMV test vs comparator assays was .17 vs 1.5 at 2.18 log(10) copies/mL; .14 vs .52 at 2.74 log(10) copies/mL; .16 vs .6 at 3.3 log(10) copies/mL; .2 vs 1.11 at 4.3 log(10) copies/mL; .21 vs 1.13 at 4.7 log(10) copies/mL; and .18 vs 1.4 at 6.7 log(10) copies/mL. In clinical specimens, constant and variable quantification differences between the CAP/CTM CMV test and comparator assays were observed. CONCLUSIONS: High interlaboratory agreement and precision of CAP/CTM CMV test results across 5 different laboratories over 4 orders of magnitude suggest that this assay could be valuable in prospective studies identifying clinical viral load thresholds for CMV treatment. PMID- 23097588 TI - Cardiac disease in adolescents with delayed diagnosis of vertically acquired HIV infection. AB - BACKGROUND: At least one-third of human immunodeficiency virus (HIV)-infected infants survive to adolescence even without antiretroviral therapy (ART), but are at high risk of complications including cardiac disease. We investigated the characteristics of cardiac disease among adolescents with HIV infection diagnosed in late childhood who were receiving ambulatory HIV care in Harare, Zimbabwe. METHODS: Consecutive adolescents with vertically acquired HIV attending 2 HIV outpatient treatment clinics were studied. Assessment included clinical history and examination, and 2-dimensional, M-mode, pulsed- and continuous-wave Doppler echocardiography. RESULTS: Of 110 participants (47% male; median age, 15 years; interquartile range, 12-17 years), 78 (71%) were taking ART. Exertional dyspnea, chest pain, palpitations, and ankle swelling were reported by 47 (43%), 43 (39%), 10 (9%), and 7 (6%), respectively. The New York Heart Association score was >= 2 in 41 participants (37%). Echocardiography showed that 74 participants (67%) had left ventricular (LV; septal and/or free wall) hypertrophy and 27 (24%) had evidence of impaired LV relaxation or restrictive LV physiology. The estimated pulmonary artery systolic pressure (ePASP) was >30 mm Hg in 4 participants (3.6%); of these 2 also had right ventricular (RV) dilatation. Another 32 participants (29%), without elevated ePASP, had isolated RV dilatation. CONCLUSIONS: A significant burden of cardiac disease was seen among adolescents with vertically acquired HIV infection. More than half were asymptomatic yet had significant echocardiographic abnormalities. These findings highlight the need to screen this population in order to better define the geography, natural history, etiopathogenic mechanisms, and management (including the timing and choice of optimal therapeutic ART and cardiac drug interventions) to prevent development and/or progression of HIV-associated cardiac disease. PMID- 23097589 TI - The long road toward standardization of viral load testing for cytomegalovirus. PMID- 23097590 TI - Editorial commentary: maternal pertussis vaccination: protecting neonates from infection. PMID- 23097591 TI - Fungal outbreak update from IDWeek. PMID- 23097592 TI - Magnetic Cellular Switches. AB - This paper focuses on the development of magnetic cellular switches to enable magnetic control of intracellular functions in living mammalian cells, including receptor signal transduction and gene transcription. Our approach takes advantage of the mechanosensitivity of adenosine 3',5'-monophosphate (cAMP) induction and downstream transcription controlled by the cAMP regulatory element (CRE) to engineer gene constructs that optically report gene expression in living cells. We activate transcription of these gene reporters by applying magnetic (mechanical) stress to magnetic microbeads bound to cell surface integrin receptors. In these gene reporter constructs, CRE motifs drive the expression of fluorescent proteins or enzymes that produce fluorescent products, such as DsRed and beta-lactamase (BLA), respectively. We demonstrate that a chemical inducer of cAMP (forskolin) increases expression of CRE-DsRed in living cells. More importantly, a threefold increase in CRE-BLA expression is induced by application of mechanical stress to magnetic microbeads (4.5 um) bound to cell surface integrin receptors. Induction of cAMP could be detected within 5 min using a protein fragment complementation assay involving interactions between the KID and KIX domains of the CRE binding protein linked to complementary halves of the BLA enzyme. These studies confirm that application of magnetic stress to integrins induces gene transcription by activating the cAMP-dependent transcription factor CREB. Ongoing studies focus on optimizing sensitivity and reducing signal-to noise by establishing stable cell lines that express these gene reporters. These studies collectively demonstrate the feasibility of using magnetic technologies to control function in living mammalian cells and, hence, support the possibility of developing magnetically-actuated cellular components for use in future micro- and nanotechnologies. PMID- 23097593 TI - Relationship between Discordance in Parental Monitoring and Behavioral Problems among Chilean Adolescents. AB - This study investigated the role of discrepancies between parent and youth reports of perceived parental monitoring in adolescent problem behaviors with a Chilean sample (N= 850). Higher levels of discordance concerning parental monitoring predicted greater levels of maladaptive youth behaviors. A positive association between parent-youth discordance and externalizing problems indicated that large adult-youth disagreement in parental monitoring may impose a great risk, despite protective efforts of parental monitoring. Although the direct relationship between parental monitoring and youth internalizing behaviors was not significant, parent-youth incongruence in monitoring was associated with greater levels of internalizing behaviors. Therefore, differing assessments of parental behaviors, as an indicator of less optimal family functioning, may provide important information about youth maladjustment and may potentially provide a beginning point for family-focused intervention. PMID- 23097594 TI - The Validity of a Holistically Scored Retell Protocol for Determining the Reading Comprehension of Middle School Students. AB - In this study, the authors examined the validity of a holistically scored retell within a confirmatory factor analysis framework by comparing the fit of a three factor model of reading with the data from a diverse sample of seventh and eighth graders. The final model demonstrated adequate fit, chi(2)(32) = 97.316; comparative fit index = .96; Tucker-Lewis index = .94; and root mean square error of approximation = .08. Retell's chi-square difference, Deltachi(2)(1) = 16.652, p < .001, and factor loading (.250, p < .001) were higher for the comprehension construct. Similarly, retell's correlation to comprehension measures (r = .155 .257, p < .01) was stronger than its relationship to measures of fluency (r = .158-.183, p < .01) or word identification (r = .132, p < .05). However, retell had a large residual variance (.938) and low interrater reliability (kappa = .37), suggesting that improvements to the instrument are needed. Despite overall latent differences, retell did not demonstrate differential item functioning. PMID- 23097596 TI - The potential of cellulosic ethanol production from grasses in Thailand. AB - The grasses in Thailand were analyzed for the potentiality as the alternative energy crops for cellulosic ethanol production by biological process. The average percentage composition of cellulose, hemicellulose, and lignin in the samples of 18 types of grasses from various provinces was determined as 31.85-38.51, 31.13 42.61, and 3.10-5.64, respectively. The samples were initially pretreated with alkaline peroxide followed by enzymatic hydrolysis to investigate the enzymatic saccharification. The total reducing sugars in most grasses ranging from 500-600 mg/g grasses (70-80% yield) were obtained. Subsequently, 11 types of grasses were selected as feedstocks for the ethanol production by simultaneous saccharification and cofermentation (SSCF). The enzymes, cellulase and xylanase, were utilized for hydrolysis and the yeasts, Saccharomyces cerevisiae and Pichia stipitis, were applied for cofermentation at 35 degrees C for 7 days. From the results, the highest yield of ethanol, 1.14 g/L or 0.14 g/g substrate equivalent to 32.72% of the theoretical values was obtained from Sri Lanka ecotype vetiver grass. When the yields of dry matter were included in the calculations, Sri Lanka ecotype vetiver grass gave the yield of ethanol at 1,091.84 L/ha/year, whereas the leaves of dwarf napier grass showed the maximum yield of 2,720.55 L/ha/year (0.98 g/L or 0.12 g/g substrate equivalent to 30.60% of the theoretical values). PMID- 23097595 TI - Preconception and contraceptive care for women living with HIV. AB - Women living with HIV have fertility desires and intentions that are similar to those of uninfected women, and with advances in treatment most women can realistically plan to have and raise children to adulthood. Although HIV may have adverse effects on fertility, recent studies suggest that antiretroviral therapy may increase or restore fertility. Data indicate the increasing numbers of women living with HIV who are becoming pregnant, and that many pregnancies are unintended and contraception is underutilized, reflecting an unmet need for preconception care (PCC). In addition to the PCC appropriate for all women of reproductive age, women living with HIV require comprehensive, specialized care that addresses their unique needs. The goals of PCC for women living with HIV are to prevent unintended pregnancy, optimize maternal health prior to pregnancy, improve maternal and fetal outcomes in pregnancy, prevent perinatal HIV transmission, and prevent HIV transmission to an HIV-uninfected sexual partner when trying to conceive. This paper discusses the rationale for preconception counseling and care in the setting of HIV and reviews current literature relevant to the content and considerations in providing PCC for women living with HIV, with a primary focus on well-resourced settings. PMID- 23097600 TI - Improving the course of muscular dystrophy? PMID- 23097597 TI - Cell surface remodeling by plasmin: a new function for an old enzyme. AB - Plasmin, one of the most potent and reactive serine proteases, is involved in various physiological processes, including embryo development, thrombolysis, wound healing and cancer progression. The proteolytic activity of plasmin is tightly regulated through activation of its precursor, plasminogen, only at specific times and in defined locales as well as through inhibition of active plasmin by its abundant natural inhibitors. By exploiting the plasminogen activating system and overexpressing distinct components of the plasminogen activation cascade, such as pro-uPA, uPAR and plasminogen receptors, malignant cells can enhance the generation of plasmin which in turn, modifies the tumor microenvironment to sustain cancer progression. While plasmin-mediated degradation and modification of extracellular matrix proteins, release of growth factors and cytokines from the stroma as well as activation of several matrix metalloproteinase zymogens, all have been a focus of cancer research studies for decades, the ability of plasmin to cleave transmembrane molecules and thereby to generate functionally important cleaved products which induce outside-in signal transduction, has just begun to receive sufficient attention. Herein, we highlight this relatively understudied, but important function of the plasmin enzyme as it is generated de novo at the interface between cross-talking cancer and host cells. PMID- 23097599 TI - Lim mineralization protein 3 induces the osteogenic differentiation of human amniotic fluid stromal cells through Kruppel-like factor-4 downregulation and further bone-specific gene expression. AB - Multipotent mesenchymal stem cells with extensive self-renewal properties can be easily isolated and rapidly expanded in culture from small volumes of amniotic fluid. These cells, namely, amniotic fluid-stromal cells (AFSCs), can be regarded as an attractive source for tissue engineering purposes, being phenotypically and genetically stable, plus overcoming all the safety and ethical issues related to the use of embryonic/fetal cells. LMP3 is a novel osteoinductive molecule acting upstream to the main osteogenic pathways. This study is aimed at delineating the basic molecular events underlying LMP3-induced osteogenesis, using AFSCs as a cellular model to focus on the molecular features underlying the multipotency/differentiation switch. For this purpose, AFSCs were isolated and characterized in vitro and transfected with a defective adenoviral vector expressing the human LMP3. LMP3 induced the successful osteogenic differentiation of AFSC by inducing the expression of osteogenic markers and osteospecific transcription factors. Moreover, LMP3 induced an early repression of the Kruppel like factor-4, implicated in MSC stemness maintenance. KLF4 repression was released upon LMP3 silencing, indicating that this event could be reasonably considered among the basic molecular events that govern the proliferation/differentiation switch during LMP3-induced osteogenic differentiation of AFSC. PMID- 23097598 TI - The plasminogen activation system and the regulation of catecholaminergic function. AB - The local environment of neurosecretory cells contains the major components of the plasminogen activation system, including the plasminogen activators, tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), as well as binding sites for t-PA, the receptor for u-PA (uPAR), and also the plasminogen activator inhibitor, PAI-1. Furthermore, these cells express specific binding sites for plasminogen, which is available in the circulation and in interstitial fluid. Colocalization of plasminogen and its activators on cell surfaces provides a mechanism for promoting local plasminogen activation. Plasmin is retained on the cell surface where it is protected from its inhibitor, alpha(2)-antiplasmin. In neurosecretory cells, localized plasmin activity provides a mechanism for extracellular processing of secreted hormones. Neurotransmitter release from catecholaminergic cells is negatively regulated by cleavage products formed by plasmin-mediated proteolysis. Recently, we have identified a major plasminogen receptor, Plg-R(KT). We have found that Plg-R(KT) is highly expressed in chromaffin cells of the adrenal medulla as well as in other catecholaminergic cells and tissues. Plg-R(KT)-dependent plasminogen activation plays a key role in regulating catecholaminergic neurosecretory cell function. PMID- 23097601 TI - The heart and cardiac pacing in Steinert disease. AB - Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment. PMID- 23097602 TI - Survival in Duchenne muscular dystrophy. AB - OBJECTIVE: To determine the survival in a population of German patients with Duchenne muscular dystrophy. PATIENTS AND METHODS: Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected. RESULTS: 67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years. CONCLUSION AND CLINICAL RELEVANCE: our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients. PMID- 23097604 TI - The impact of permanent muscle weakness on quality of life in periodic paralysis: a survey of 66 patients. AB - The periodic paralyses are hereditary muscle diseases which cause both episodic and permanent weakness. Permanent weakness may include both reversible and fixed components, the latter caused by fibrosis and fatty replacement. To determine the degree of handicap and impact of permanent weakness on daily life, we conducted a 68-question online survey of 66 patients over 41 years (mean age, 60 +/- 14 years). Permanent weakness occurred in 68%, muscle pain in 82% and muscle fatigue in 89%. Eighty-three percent of patients reported themselves as moderately to very active between ages 18-35. At the time of the survey only 14% reported themselves as moderately to very active. Contrary to the literature, only 21% of patients reported decreased frequency of episodic weakness with increased age. Sixty-seven percent had incurred injuries due to falls. Mobility aids were required by 49%. Strength increased in 49% of patients receiving professional physiotherapy and in 62% performing self-managed exercise routines. A decline of strength was observed by 40% with professional and by 16% with self-managed exercise routine, suggesting that overworking muscles may not be beneficial. There is an average of 26 years between age at onset and age at diagnosis indicating that diagnostic schemes can be improved. In summary our data suggests that permanent muscle weakness has a greater impact on the quality of life of patients than previously anticipated. PMID- 23097603 TI - Improvement of survival in Duchenne Muscular Dystrophy: retrospective analysis of 835 patients. AB - Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23 38.6) in patients who could benefit of mechanical ventilation.This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age. PMID- 23097605 TI - TARDBP mutations are not a frequent cause of ALS in Finnish patients. AB - In previous studies 1-3 % of ALS patients have TARDBP mutations as the cause of the disease. TARDBP mutations have been reported in ALS patients in different populations but so far there are no studies on the frequency of TARDBP mutations in Finnish ALS patients. A cohort of 50 Finnish patients, 44 SALS and 6 FALS patients, were included in the study. Genomic DNA was extracted from venous blood or muscle tissue and a mutation analysis of TARDBP was performed. No definitely pathogenic mutations could be identified in TARDBP in our patient cohort. However, two previously unknown variations were found: one silent mutation in exon 2 and one relatively deep intronic single nucleotide insertion in intron 5. In addition, two previously known non-pathogenic polymorphisms in intron 5 were detected. The size of our cohort is obviously not large enough to conclusively exclude TARDBP mutations as a very rare cause of ALS in Finland. However, based on our results TARDBP mutations do not appear to be a frequent cause of familial or sporadic ALS in Finland. PMID- 23097606 TI - Right atrial preference pacing algorithm in the prevention of paroxysmal atrial fibrillation in myotonic dystrophy type 1 patients: a long term follow-up study. AB - Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods. PMID- 23097607 TI - ClC1 chloride channel in myotonic dystrophy type 2 and ClC1 splicing in vitro. AB - Myotonic dystrophy type 2 (DM2) is caused by CCTG-repeat expansions. Occurrence of splicing and mutations in the muscle chloride channel gene CLCN1 have been reported to contribute to the phenotype. To examine the effect of CLCN1 in DM2 in Germany, we determined the frequency of a representative ClC1 mutation, R894X, and its effect on DM2 clinical features. Then, we examined CLCN1 mRNA splice variants in patient muscle functionally expressed the most abundant variant, and determined its subcellular localization. Finally, we established a cellular system for studying mouse clcn1 pre-mRNA splicing and tested effects of expression of (CCUG)18, (CUG)24 and (AAG)24 RNAs. The R894X mutation was present in 7.7% of DM2 families. DM2 R894X-carriers had more myotonia and myalgia than non-carriers. The most abundant CLCN1 splice variant in DM2 (80% of all transcripts) excluded exons 6-7 and lead to a truncated ClC1(236X) protein. Heterologous ClC1(236X) expression did not yield functional channels. Co expression with ClC1 did not show a dominant negative effect, but a slightly suppressive effect. In C2C12 cells, the clc1 splice variants generated by (CCUG)18-RNA resembled those in DM2 muscle and differed from those generated by (CUG)24 and (AAG)24. We conclude that ClC1 mutations exert gene dose effects and enhance myotonia and pain in DM2 in Germany. Additionally, the ClC1(236X) splice variant may contribute to myotonia in DM2. Since splice variants depend on the types of repeats expressed in the cellular C2C12 model, similar cell models of other tissues may be useful for studying repeatdependent pathogenetic mechanisms more easily than in transgenic animals. PMID- 23097608 TI - Cardiac resynchronization improves heart failure in one patient with myotonic dystrophy type 1. A case report. AB - We report an improvement in symptoms of heart failure, a reduced left ventricular dysfunction and induced reverse remodelling in one patient with Myotonic Dystrophy type 1, showing an early onset ventricular dysfunction secondary to a complete left bundle branch block (LBBB) who underwent cardioverter defibrillator CRT (ICD- CRT) implantation. PMID- 23097609 TI - Introducing corticosteroids therapy from 1969 to 1990 at the Centre/Institute for Neuromuscular Diseases, KBC Rebro, Zagreb, Croatia. AB - The author presents the chronological development of therapy by corticosteroids in myasthenia gravis (MG), as well as dilemmas connected to this kind of treatment at the Centre/Institute Zagreb, she founded. The improvement of postoperative prognosis of thymectomy with corticosteroids is described and transfer of positive experiences to other neurological diseases. The side effects can be reduced significantly by respecting the basic rules: the choice of corticosteroids (fluocortolone, methyprednisolone, no dexamethasone), single dose administered in the morning, not later than 8 a.m. (respecting the circadian rhythm of concentration of cortisol in blood). Initially, the high dose is administered daily, until the stabilisation of signs and symptoms improvement. Then, in my early modification, the initial dose, administered every other day, becames gradually lowered. The diet is similar to diabetic, with the potassium added. In the period from 1973 to 1990, 212 myasthenia gravis and 37 polymyositis patients were treated that way.We recommend to continue endocrinological research, on which we already reported, now with contemporary methods. The value of the "pulse therapy" should be analysed in more details, with peroral corticosteroids added afterwards. PMID- 23097610 TI - On nosological place of facioscapuloperoneal (or facioscapulolimb, type 2) 4q35 linked muscular dystrophy. PMID- 23097611 TI - Severe ocular hypertension secondary to systemic corticosteroid treatment in a child with nephrotic syndrome. AB - PURPOSE: To report a case of severe, acute ocular hypertension in a 6-year-old child, 7 days after initiating treatment with oral prednisolone, due to nephrotic syndrome. METHODS: A 6-year-old female Caucasian child was diagnosed with nephrotic syndrome and treated with oral prednisolone (60 mg/day). Seven days later the child initiated complaints of headache, vomiting, ocular pain, and photophobia. Ophthalmologic examination revealed a severely increased intraocular pressure (IOP) of 52 mmHg in the right eye and 56 mmHg in the left eye. Anterior segment morphology was evaluated with ultrasound biomicroscopy. Optic disc status was evaluated by disc photography, kinetic perimetry, and optical coherence tomography. RESULTS: Treatment was initiated with latanoprost, brimonidine, and the fixed association of timolol and dorzolamide. At each follow-up examination, progressively better control of IOP was obtained. Simultaneous with corticosteroid dosage decrease we were able to reduce antiglaucomatous medication while maintaining IOP under control. Ultrasound biomicroscopy revealed an open angle with normal anterior segment echographic findings. Perimetric evaluation revealed normal visual fields in both eyes. Four months after presentation, steroid treatment had been completed and IOP was 10 mmHg in both eyes without any antiglaucomatous medication. Optical coherence tomography revealed normal retinal nerve fiber layer thickness in all peripapillary sectors. CONCLUSIONS: Systemic steroid treatment can cause a severe, acute increase in IOP in children. Children undergoing steroid treatment should have routine ophthalmologic examinations during treatment duration. Prompt antiglaucomatous treatment prevents retinal nerve fiber layer damage and visual acuity loss. PMID- 23097612 TI - Microperimetric evaluation of chronic central serous chorioretinopathy after half dose photodynamic therapy. AB - BACKGROUND: The purpose of this study was to determine baseline clinical factors to correlate the outcome of half-dose verteporfin photodynamic therapy (PDT) in eyes with chronic central serous chorioretinopathy (CSC). METHODS: In this prospective, non-comparative, interventional case series, 14 eyes of 14 patients with chronic CSC who received half-dose verteporfin PDT were examined. The best corrected visual acuity (BCVA), macular sensitivity in the central 4, 8, and 12 degrees, and fixation stability were evaluated at baseline and at months 1, 3, 6, and 12 after half-dose verteporfin PDT. Macular sensitivity and fixation stability were determined by MP-1 microperimetry. RESULTS: Mean retinal sensitivity in the central 4 and 8 degrees was significantly better at 1, 3, 6, and 12 months after half-dose verteporfin PDT than at baseline. BCVA was significantly better after half-dose verteporfin PDT but only after 3 months. Fixation was relatively unstable in three eyes at baseline, but became stable at 12 months. BCVA at 12 months was significantly correlated with pre-PDT fixation stability (r = 0.7120, P = 0.0038). CONCLUSION: Half-dose verteporfin PDT results in a significant increase in mean central retinal sensitivity for at least 12 months. Our findings indicate that microperimetry is a useful method for evaluating the functional benefits of half-dose verteporfin PDT in eyes with chronic CSC. PMID- 23097613 TI - Long-term persistence of IgE anti-influenza A HIN1 virus antibodies in serum of children and adults following influenza A vaccination with subsequent H1N1 infection: a case study. AB - BACKGROUND AND METHODS: The role of immunoglobulin (Ig) E in immunity against influenza A H1N1 has not been studied. Total serum IgE and specific IgE and IgG anti-H1N1 virus responses were studied in children and adults (n = 2) who received influenza virus vaccination (Flumist((r)) or Fluzone((r)) ) in autumn 2008 and 2009, and then subsequently became infected with the H1N1 virus in spring 2009. Twelve months after infection, antibodies in their serum were compared with those in the serum of subjects who were either vaccinated but not infected (n = 4) or nonvaccinated and noninfected subjects (n = 2), using UniCAP total IgE fluoroenzyme immunoassay, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and Western blotting. Band sizes for the influenza virus (58, 56, 40, 30, 25, and 17 kDa) and H1N1 viral proteins (58, 56, 25, and 17 kDa) were determined, using sodium dodecyl sulfate polyacrylamide gel electrophoresis and Coomassie brilliant blue. RESULTS: We found that the serum of vaccinated and subsequently infected children and adults contained IgE and IgG antibodies to both H1N1 and influenza virus, with a strong IgE and IgG band intensity at 56 kDa. Interestingly, in subjects who were vaccinated but not infected, band intensity at 56 kDa was lowered by approximately two-fold. Serum of nonvaccinated and noninfected subjects had no detectable IgE or IgG antibodies to influenza virus or H1N1. CONCLUSION: This is the first description of IgE anti-influenza A H1N1 antibodies in human serum and the first demonstration of their long-term persistence. The decreased intensity of the 56 kDa band in vaccinated noninfected subjects compared with vaccinated infected subjects suggests augmented IgE and IgG antibody responses to influenza A H1N1. PMID- 23097614 TI - Phytotherapy of chronic abdominal pain following pancreatic carcinoma surgery: a single case observation. AB - A patient with pancreatic carcinoma diagnosed in 2005 suffered from chronic abdominal pain 6 years later that did not respond to conventional pain treatment according to guidelines. Furthermore, several complementary medical approaches remained ineffective. In the long run, only an Iberis amara drug combination relieved pain sufficiently. The drug is registered in Germany for the indications irritable bowel syndrome and dyspepsia. The multi-target approach of this combination drug may account for the effectiveness under these fundamentally different pathophysiological conditions. No serious undesired effects have been described in the use of this drug for other indications and none were observed in this case. PMID- 23097616 TI - Vitamin D deficiency: A potential risk factor for Clostridium difficile infection. PMID- 23097615 TI - The economic burden of patient safety targets in acute care: a systematic review. AB - BACKGROUND: Our objective was to determine the quality of literature in costing of the economic burden of patient safety. METHODS: We selected 15 types of patient safety targets for our systematic review. We searched the literature published between 2000 and 2010 using the following terms: "costs and cost analysis," "cost-effectiveness," "cost," and "financial management, hospital." We appraised the methodologic quality of potentially relevant studies using standard economic methods. We recorded results in the original currency, adjusted for inflation, and then converted to 2010 US dollars for comparative purposes (2010 US$1.00 = 2010 ?0.76). The quality of each costing study per patient safety target was also evaluated. RESULTS: We screened 1948 abstracts, and identified 158 potentially eligible studies, of which only 61 (39%) reported any costing methodology. In these 61 studies, we found wide estimates of the attributable costs of patient safety events ranging from $2830 to $10,074. In general hospital populations, the cost per case of hospital-acquired infection ranged from $2132 to $15,018. Nosocomial bloodstream infection was associated with costs ranging from $2604 to $22,414. CONCLUSION: There are wide variations in the estimates of economic burden due to differences in study methods and methodologic quality. Greater attention to methodologic standards for economic evaluations in patient safety is needed. PMID- 23097617 TI - Real-time PCR: Benefits for Detection of Mild and Asymptomatic Giardia Infections. AB - The majority of Giardia infections are transmitted by the fecal-oral route and cause giardiasis. Children who live in crowded conditions or low socio-economic areas are the risk group for Giardia infection. Interestingly, most of them are asymptomatic or only mildly infected and can shed the Giardia cysts in the environment. Thus, the diagnosis of Giardia infection in asymptomatic or mild infection plays an important role in achieving control of Giardia duodenalis transmission. The objective of this study was to examine parasitic infections using microscopy and to develop a real-time PCR method for detection of Giardia infection in the stool samples of children living on the Thai-Myanmar border. Both species-specific primers and fluorescent labeled G. duodenalis probe were designed using small-subunit ribosomal RNA (ssrRNA). The results showed that 10 (7.69%) and 40 (30.77%) of 130 stool samples were positive for G. duodenalis by microscopy and real-time PCR respectively. Only 3 out of 9 liquid stools revealed G. duodenalis positive using microscopy, but all of them were G. duodenalis positive using real-time PCR. The detection limit of real-time PCR for G. duodenalis was 0.1 pg/25 ul reaction. It can detect both mild and asymptomatic Giardia infections in children living on the Thai-Myanmar border. PMID- 23097618 TI - Preservation of wild isolates of human malaria parasites in wet ice and adaptation efficacy to in vitro culture. AB - Wild isolates of malaria parasites were preserved in wet ice for 2-12 days and cultivated by a candle jar method. In four isolates of Plasmodium falciparum collected from Myanmar and preserved for 12 days, all failed to grow. In 31 isolates preserved for 5-10 days, nine were transformed to young gametocytes, but 22 isolates grew well. From Ranong, Thailand, nine isolates preserved for 7 days were examined, and six grew well. On the other hand, all of the 59 isolates collected from eastern Indonesian islands failed to establish as culture-adapted isolates, even most of them were preserved only for 2-3 days: 10 isolates stopped to grow, and 49 isolates were transformed to sexual stages by Day 10. These results indicated that a great difference in adaptation to in vitro culture may exist between wild isolates distributed in continental Southeast Asia and in eastern Indonesia and that gametocytogenesis might be easily switched on in Indonesian isolates. In wild isolates of P. vivax, P. malariae and P. ovale preserved for 2-9 days, ring forms or young trophozoites survived, but adaptation to in vitro culture failed. These results indicate that wild isolates can be preserved in wet ice for 9-10 days. PMID- 23097619 TI - One Injection of DsRed Followed by Bites from Transgenic Mosquitoes Producing DsRed in the Saliva Elicits a High Titer of Antibody in Mice. AB - It has been proposed that transgenic mosquitoes can be used as a "flying syringe" for infectious disease control. We succeeded in generating a transgenic (TG) mosquito, Anopheles stephensi, excreting and discharging DsRed in saliva. DsRed was deposited on the membrane where the TG mosquito probed with its proboscis. Repeated feeding by the TG mosquitoes induced anti-DeRed as well as anti-SG antibodies in mice. This indicates that the TG mosquitoes can immunize the animal. Moreover, in this report, we employed a pre-immunization method before exposing mice to the TG mosquitoes. We injected DsRed to mice to prepare memory B cells and exposed the mice to bites by the TG mosquitoes excreting DsRed. The mice produced a higher titer of antibody to DsRed, suggesting that the bites from TG mosquitoes act as a booster and that primary immunization with a vaccine protein and exposure to TG mosquitoes excreting the vaccine protein in the saliva produces a synergistic effect. PMID- 23097620 TI - Distribution of Two Subgroups of Human T-Lymphotropic Virus Type 1 (HTLV-1) in Endemic Japan. AB - Endemic areas of human T-lymphotropic virus type 1 (HTLV-1) have been reported in Japan as well as tropical Africa, Central and South America and Melanesia. The existence of two subgroups, i.e., the transcontinental and Japanese subgroups, was reported in Japan. In the present study, we provide data on the ratio of the two subgroups in each endemic area and infection foci and examine the distribution of HTLV-1 in Japan and neighboring areas. A 657 bp fragment of env region of HTLV-1 proviral genome was successfully amplified for 183 HTLV-1 positive DNA samples. The subgroup determination was done by RFLP reactions using endonucleases HpaI and HinfI. The northern part of mainland Kyushu, represented by Hirado and Kumamoto, was monopolized by the Japanese subgroup, while the transcontinental subgroup ranged from 20 to 35% in the Pacific coast areas of Shikoku (Kochi), the Ryukyu Archipelago (Kakeroma and Okinawa) and Taiwan. An interesting finding in the present study is the presence of the transcontinental subgroup in Kochi, suggesting the endemicity of the transcontinental subgroup along the Kuroshio Current. PMID- 23097622 TI - Erratum. AB - [This corrects the article on p. 15-17 in vol. 40.]. PMID- 23097621 TI - Ethnicity and delay in measles vaccination in a nairobi slum. AB - The influence of ethnicity on vaccination uptake in urban slums in Kenya is largely unknown. We examined the disparities in timeliness and coverage of measles vaccination associated with ethnicity in the Korogocho slum of Nairobi. The study used data from the Maternal and Child Health component of the Urbanization, Poverty and Health Dynamics Research Programme undertaken in the Korogocho and Viwandani slums by the African Population and Health Research Center from 2006 to 2010. Vaccination information was collected from children recruited into the study during the first year after birth, and a sub-sample of 2,317 who had been followed throughout the period and had the required information on measles vaccination was included in the analysis. Cox regression analysis was used to determine the association of ethnicity with delayed measles in the slum. We found significant disparities in the coverage and timeliness of measles vaccination between the ethnic groups in Korogocho. The Luhya and minor ethnic groups in the slum were more likely than the Kikuyu to have delayed measles vaccination. Ethnic groups with a high proportion of children with delayed measles vaccination need to be targeted to address cultural barriers to vaccination as part of efforts to improve coverage in urban slums. PMID- 23097623 TI - Opposite roles of furin and PC5A in N-cadherin processing. AB - We recently demonstrated that lack of Furin-processing of the N-cadherin precursor (proNCAD) in highly invasive melanoma and brain tumor cells results in the cell-surface expression of a nonadhesive protein favoring cell migration and invasion in vitro. Quantitative polymerase chain reaction analysis of malignant human brain tumor cells revealed that of all proprotein convertases (PCs) only the levels of Furin and PC5A are modulated, being inversely (Furin) or directly (PC5A) correlated with brain tumor invasive capacity. Intriguingly, the N terminal sequence following the Furin-activated NCAD site (RQKR?DW(161), mouse nomenclature) reveals a second putative PC-processing site (RIRSDR?DK(189)) located in the first extracellular domain. Cleavage at this site would abolish the adhesive functions of NCAD because of the loss of the critical Trp(161). This was confirmed upon analysis of the fate of the endogenous prosegment of proNCAD in human malignant glioma cells expressing high levels of Furin and low levels of PC5A (U343) or high levels of PC5A and negligible Furin levels (U251). Cellular analyses revealed that Furin is the best activating convertase releasing an ~17 kDa prosegment, whereas PC5A is the major inactivating enzyme resulting in the secretion of an ~20-kDa product. Like expression of proNCAD at the cell surface, cleavage of the NCAD molecule at RIRSDR?DK(189) renders the U251 cancer cells less adhesive to one another and more migratory. Our work modifies the present view on posttranslational processing and surface expression of classic cadherins and clarifies how NCAD possesses a range of adhesive potentials and plays a critical role in tumor progression. PMID- 23097624 TI - Deubiquitinase USP9x confers radioresistance through stabilization of Mcl-1. AB - Myeloid cell leukemia sequence 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family, is often overexpressed in tumor cells limiting the therapeutic success. Mcl-1 differs from other Bcl-2 members by its high turnover rate. Its expression level is tightly regulated by ubiquitylating and deubiquitylating enzymes. Interaction of Mcl-1 with certain Bcl-2 homology domain 3 (BH3)-only members of the Bcl-2 family can limit the access to Mcl-1 ubiquitin ligase E3 and stabilizes the antiapoptotic protein. In addition, the overexpression of the deubiquitinase ubiquitin-specific protease 9x (USP9x) can result in the accumulation of Mcl-1 by removing poly-ubiquitin chains from Mcl-1 preventing its proteasomal degradation. Analyzing radiation-induced apoptosis in Jurkat cells, we found that Mcl-1 was downregulated more efficiently in sensitive parental cells than in a resistant subclone. The decline of Mcl-1 correlated with cell death induction and clonogenic survival. Knockdown of BH3-only proteins Bim, Puma, and Noxa did not affect Mcl-1 level or radiation-induced apoptosis. However, ionizing radiation resulted in activation of USP9x and enhanced deubiquitination of Mcl-1 in the radioresistant cells preventing fast Mcl-1 degradation. USP9x knockdown enhanced radiation-induced decrease of Mcl-1 and sensitized the radioresistant cells to apoptosis induction, whereas USP9x knockdown alone did not change Mcl-1 level in unirradiated cells. Together, our results indicate that radiation-induced activation of USP9x inhibits Mcl-1 degradation and apoptosis resulting in increased radioresistance. PMID- 23097625 TI - Role of transcriptional corepressor CtBP1 in prostate cancer progression. AB - Transcriptional repressors and corepressors play a critical role in cellular homeostasis and are frequently altered in cancer. C-terminal binding protein 1 (CtBP1), a transcriptional corepressor that regulates the expression of tumor suppressors and genes involved in cell death, is known to play a role in multiple cancers. In this study, we observed the overexpression and mislocalization of CtBP1 in metastatic prostate cancer and demonstrated the functional significance of CtBP1 in prostate cancer progression. Transient and stable knockdown of CtBP1 in prostate cancer cells inhibited their proliferation and invasion. Expression profiling studies of prostate cancer cell lines revealed that multiple tumor suppressor genes are repressed by CtBP1. Furthermore, our studies indicate a role for CtBP1 in conferring radiation resistance to prostate cancer cell lines. In vivo studies using chicken chorioallantoic membrane assay, xenograft studies, and murine metastasis models suggested a role for CtBP1 in prostate tumor growth and metastasis. Taken together, our studies demonstrated that dysregulated expression of CtBP1 plays an important role in prostate cancer progression and may serve as a viable therapeutic target. PMID- 23097626 TI - STAT5b as molecular target in pancreatic cancer--inhibition of tumor growth, angiogenesis, and metastases. AB - The prognosis of patients suffering from pancreatic cancer is still poor and novel therapeutic options are urgently needed. Recently, the transcription factor signal transducer and activator of transcription 5b (STAT5b) was associated with tumor progression in human solid cancer. Hence, we assessed whether STAT5b might serve as an anticancer target in ductal pancreatic adenocarcinoma (DPAC). We found that nuclear expression of STAT5b can be detected in approximately 50% of DPAC. Blockade of STAT5b by stable shRNA-mediated knockdown showed no effects on tumor cell growth in vitro. However, inhibition of tumor cell motility was found even in response to stimulation with epidermal growth factor or interleukin-6. These findings were paralleled by a reduction of prometastatic and proangiogenic factors in vitro. Subsequent in vivo experiments revealed a strong growth inhibition on STAT5b blockade in subcutaneous and orthotopic models. These findings were paralleled by impaired tumor angiogenesis in vivo. In contrast to the subcutaneous model, the orthotopic model revealed a strong reduction of tumor cell proliferation that emphasizes the meaning of assessing targets in an appropriate microenvironment. Taken together, our results suggest that STAT5b might be a potential novel target for human DPAC. PMID- 23097627 TI - Novel model for basaloid triple-negative breast cancer: behavior in vivo and response to therapy. AB - INTRODUCTION: The basaloid triple-negative breast cancer (B-TNBC) is one of the most aggressive, therapy-resistant, and metastatic tumors. Current models do not recapitulate the basaloid phenotype of TNBC, thus limiting the understanding of its biology and designing new treatments. We identified HCC1806 as a line expressing typical B-TNBC markers, engineered a subline with traceable reporters, and determined growth, drug sensitivity, recurrence, and vascular and metastatic patterns of orthotopic xenografts in immunodeficient mice. METHODS: mRNA and protein analyses showed that HCC1806 expresses basal but not luminal or mesenchymal markers. HCC1806-RR subline stably expressing red fluorescent protein and Renilla luciferase was generated and characterized for sensitivity to chemodrugs, orthotopic growth, vascular properties, recurrence, metastasis, and responsiveness in vivo. RESULTS: The HCC1806 cells were highly sensitive to paclitaxel, but cytotoxicity was accompanied by pro-survival vascular endothelial growth factor-A loop. In vivo, HCC1806-RR tumors display linear growth, induce peritumoral lymphatics, and spontaneously metastasize to lymph nodes (LNs) and lungs. Similarly to human B-TNBC, HCC1806-RR tumors were initially sensitive to taxane therapy but subsequently recur. Bevacizumab significantly suppressed recurrence by 50% and reduced the incidence of LN and pulmonary metastases by, respectively, 50% and 87%. CONCLUSIONS: The HCC1806-RR is a new model that expresses bona fide markers of B-TNBC and traceable markers for quantifying metastases. Combination of bevacizumab with nab-paclitaxel significantly improved the outcome, suggesting that this approach can apply to human patients with B TNBC. This model can be used for defining the metastatic mechanisms of B-TNBC and testing new therapies. PMID- 23097629 TI - Vitamin D metabolism and effects on pluripotency genes and cell differentiation in testicular germ cell tumors in vitro and in vivo. AB - Testicular germ cell tumors (TGCTs) are classified as either seminomas or nonseminomas. Both tumors originate from carcinoma in situ (CIS) cells, which are derived from transformed fetal gonocytes. CIS, seminoma, and the undifferentiated embryonal carcinoma (EC) retain an embryonic phenotype and express pluripotency factors (NANOG/OCT4). Vitamin D (VD) is metabolized in the testes, and here, we examined VD metabolism in TGCT differentiation and pluripotency regulation. We established that the VD receptor (VDR) and VD-metabolizing enzymes are expressed in human fetal germ cells, CIS, and invasive TGCTs. VD metabolism diminished markedly during the malignant transformation from CIS to EC but was reestablished in differentiated components of nonseminomas, distinguished by coexpression of mesodermal markers and loss of OCT4. Subsequent in vitro studies confirmed that 1,25(OH)(2)D(3) (active VD) downregulated NANOG and OCT4 through genomic VDR activation in EC-derived NTera2 cells and, to a lesser extent, in seminoma derived TCam-2 cells, and up-regulated brachyury, SNAI1, osteocalcin, osteopontin, and fibroblast growth factor 23. To test for a possible therapeutic effect in vivo, NTera2 cells were xenografted into nude mice and treated with 1,25(OH)(2)D(3), which induced down-regulation of pluripotency factors but caused no significant reduction of tumor growth. During NTera2 tumor formation, down regulation of VDR was observed, resulting in limited responsiveness to cholecalciferol and 1,25(OH)(2)D(3) treatment in vivo. These novel findings show that VD metabolism is involved in the mesodermal transition during differentiation of cancer cells with embryonic stem cell characteristics, which points to a function for VD during early embryonic development and possibly in the pathogenesis of TGCTs. PMID- 23097628 TI - Bone marrow-derived myofibroblasts are the providers of pro-invasive matrix metalloproteinase 13 in primary tumor. AB - Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM)-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13) and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or alpha-smooth muscle actin (alpha-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively alpha-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs) from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13 deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived alpha-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion. PMID- 23097630 TI - Tumor angiogenesis phenotyping by nanoparticle-facilitated magnetic resonance and near-infrared fluorescence molecular imaging. AB - One of the challenges of tailored antiangiogenic therapy is the ability to adequately monitor the angiogenic activity of a malignancy in response to treatment. The alpha(v)beta(3) integrin, highly overexpressed on newly formed tumor vessels, has been successfully used as a target for Arg-Gly-Asp (RGD) functionalized nanoparticle contrast agents. In the present study, an RGD functionalized nanocarrier was used to image ongoing angiogenesis in two different xenograft tumor models with varying intensities of angiogenesis (LS174T > EW7). To that end, iron oxide nanocrystals were included in the core of the nanoparticles to provide contrast for T(2)*-weighted magnetic resonance imaging (MRI), whereas the fluorophore Cy7 was attached to the surface to enable near infrared fluorescence (NIRF) imaging. The mouse tumor models were used to test the potential of the nanoparticle probe in combination with dual modality imaging for in vivo detection of tumor angiogenesis. Pre-contrast and post-contrast images (4 hours) were acquired at a 9.4-T MRI system and revealed significant differences in the nanoparticle accumulation patterns between the two tumor models. In the case of the highly vascularized LS174T tumors, the accumulation was more confined to the periphery of the tumors, where angiogenesis is predominantly occurring. NIRF imaging revealed significant differences in accumulation kinetics between the models. In conclusion, this technology can serve as an in vivo biomarker for antiangiogenesis treatment and angiogenesis phenotyping. PMID- 23097631 TI - Tight junction proteins claudin-3 and claudin-4 control tumor growth and metastases. AB - The extent of tight junction (TJ) formation is one of many factors that regulate motility, invasion, and metastasis. Claudins are required for the formation and maintenance of TJs. Claudin-3 (CLDN3) and claudin-4 (CLDN4) are highly expressed in the majority of ovarian cancers. We report here that CLDN3 and CLDN4 each serve to constrain the growth of human 2008 cancer xenografts and limit metastatic potential. Knockdown of CLDN3 increased in vivo growth rate by 2.3 fold and knockdown of CLDN4 by 3.7-fold in the absence of significant change in in vitro growth rate. Both types of tumors exhibited increase in birth rate as measured by Ki67 staining and decrease in death rate as reflected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Knockdown of either claudin did not alter expression of other TJ protein but did reduce TJ formation as measured by transepithelial resistance and paracellular flux of dextran, enhance migration and invasion in in vitro assays, and increase lung colonization following intravenous injection. Knockdown of CLDN3 and CLDN4 increased total lung metastatic burden by 1.7-fold and 2.4-fold, respectively. Loss of either CLDN3 or CLDN4 resulted in down-regulation of E-cadherin mRNA and protein, increased inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), and activation of beta-catenin pathway signaling as evidenced by increases in nuclear beta-catenin, the dephosphorylated form of the protein, and transcriptional activity of beta-catenin/T-cell factor (TCF). We conclude that both CLDN3 and CLDN4 mediate interactions with other cells in vivo that restrain growth and metastatic potential by sustaining expression of E-cadherin and limiting beta-catenin signaling. PMID- 23097632 TI - Functional analysis of in-frame indel ARID1A mutations reveals new regulatory mechanisms of its tumor suppressor functions. AB - AT-rich interactive domain 1A (ARID1A) has emerged as a new tumor suppressor in which frequent somatic mutations have been identified in several types of human cancers. Although most ARID1A somatic mutations are frame-shift or nonsense mutations that contribute to mRNA decay and loss of protein expression, 5% of ARID1A mutations are in-frame insertions or deletions (indels) that involve only a small stretch of peptides. Naturally occurring in-frame indel mutations provide unique and useful models to explore the biology and regulatory role of ARID1A. In this study, we analyzed indel mutations identified in gynecological cancers to determine how these mutations affect the tumor suppressor function of ARID1A. Our results demonstrate that all in-frame mutants analyzed lost their ability to inhibit cellular proliferation or activate transcription of CDKN1A, which encodes p21, a downstream effector of ARID1A. We also showed that ARID1A is a nucleocytoplasmic protein whose stability depends on its subcellular localization. Nuclear ARID1A is less stable than cytoplasmic ARID1A because ARID1A is rapidly degraded by the ubiquitin-proteasome system in the nucleus. In frame deletions affecting the consensus nuclear export signal reduce steady-state protein levels of ARID1A. This defect in nuclear exportation leads to nuclear retention and subsequent degradation. Our findings delineate a mechanism underlying the regulation of ARID1A subcellular distribution and protein stability and suggest that targeting the nuclear ubiquitin-proteasome system can increase the amount of the ARID1A protein in the nucleus and restore its tumor suppressor functions. PMID- 23097633 TI - Thermographic imaging of the superficial temperature in racing greyhounds before and after the race. AB - A total of 47 racing greyhounds were enrolled in this study on two race days (in July and September, resp.) at a racetrack. Twelve of the dogs participated in the study on both days. Thermographic images were taken before and after each race. From the images, superficial temperature points of selected sites (tendo calcaneus, musculus gastrocnemius, musculus gracilis, and musculus biceps femoris portio caudalis) were taken and used to investigate the differences in superficial temperatures before and after the race. The thermographic images were compared between the right and left legs of a dog, between the raced distances, and between the two race days. The theoretical heat capacity of a racing greyhound was calculated. With regard to all distances raced, the superficial temperatures measured from the musculus gastrocnemius were significantly higher after the race than at baseline. No significant differences were found between the left and right legs of a dog after completing any of the distances. Significant difference was found between the two race days. The heat loss mechanisms of racing greyhounds during the race through forced conduction, radiation, evaporation, and panting can be considered adequate when observing the calculated heat capacity of the dogs. PMID- 23097634 TI - Genomic profiling of a human leukemic monocytic cell-line (THP-1) exposed to alpha particle radiation. AB - This study examined alpha (alpha-) particle radiation effects on global changes in gene expression in human leukemic monocytic cells (THP-1) for the purposes of mining for candidate biomarkers that could be used for the development of a biological assessment tool. THP-1 cells were exposed to alpha-particle radiation at a dose range of 0 to 1.5 Gy. Twenty-four hours and three days after exposure gene expression was monitored using microarray technology. A total of 16 genes were dose responsive and classified as early onset due to their expression 24 h after exposure. Forty-eight transcripts were dose responsive and classified as late-onset as they were expressed 72 h after exposure. Among these genes, 6 genes were time and dose responsive and validated further using alternate technology. These transcripts were upregulated and associated with biological processes related to immune function, organelle stability and cell signalling/communication. This panel of genes merits further validation to determine if they are strong candidate biomarkers indicative of alpha-particle exposure. PMID- 23097635 TI - Effects of dual-channel functional electrical stimulation on gait performance in patients with hemiparesis. AB - The study objective was to assess the effect of functional electrical stimulation (FES) applied to the peroneal nerve and thigh muscles on gait performance in subjects with hemiparesis. Participants were 45 subjects (age 57.8 +/- 14.8 years) with hemiparesis (5.37 +/- 5.43 years since diagnosis) demonstrating a foot-drop and impaired knee control. Thigh stimulation was applied either to the quadriceps or hamstrings muscles, depending on the dysfunction most affecting gait. Gait was assessed during a two-minute walk test with/without stimulation and with peroneal stimulation alone. A second assessment was conducted after six weeks of daily use. The addition of thigh muscles stimulation to peroneal stimulation significantly enhanced gait velocity measures at the initial and second evaluation. Gait symmetry was enhanced by the dual-channel stimulation only at the initial evaluation, and single-limb stance percentage only at the second assessment. For example, after six weeks, the two-minute gait speed with peroneal stimulation and with the dual channel was 0.66 +/- 0.30 m/sec and 0.70 +/- 0.31 m/sec, respectively (P < 0.0001). In conclusion, dual-channel FES may enhance gait performance in subjects with hemiparesis more than peroneal FES alone. PMID- 23097638 TI - Pleosporales. AB - One hundred and five generic types of Pleosporales are described and illustrated. A brief introduction and detailed history with short notes on morphology, molecular phylogeny as well as a general conclusion of each genus are provided. For those genera where the type or a representative specimen is unavailable, a brief note is given. Altogether 174 genera of Pleosporales are treated. Phaeotrichaceae as well as Krie-geriella, Zeuctomorpha and Muroia are excluded from Pleosporales. Based on the multigene phylogenetic analysis, the suborder Massarineae is emended to accommodate five families, viz. Lentitheciaceae, Massarinaceae, Montagnulaceae, Morosphaeriaceae and Trematosphaeriaceae. PMID- 23097636 TI - Noni juice improves serum lipid profiles and other risk markers in cigarette smokers. AB - Cigarette smoke-induced oxidative stress leads to dyslipidemia and systemic inflammation. Morinda citrifolia (noni) fruit juice has been found previously to have a significant antioxidant activity. One hundred thirty-two adult heavy smokers completed a randomized, double blind, placebo-controlled clinical trial designed to investigate the effect of noni juice on serum cholesterol, triglyceride, low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), high-sensitivity C-reactive protein (hs-CRP), and homocysteine. Volunteers drank noni juice or a fruit juice placebo daily for one month. Drinking 29.5 mL to 188 mL of noni juice per day significantly reduced cholesterol levels, triglycerides, and hs-CRP. Decreases in LDL and homocysteine, as well increases in HDL, were also observed among noni juice drinkers. The placebo, which was devoid of iridoid glycosides, did not significantly influence blood lipid profiles or hs-CRP. Noni juice was able to mitigate cigarette smoke induced dyslipidemia, an activity associated with the presence of iridoids. PMID- 23097639 TI - Effect of Soil Nutrient on Production and Diversity of Volatile Terpenoids from Plants. AB - Terpenoid production (emission and storage) within foliage plays direct and indirect defensive and protective functions for the plant, mediates complex trophic relationships and controls the oxidation capacity of the atmosphere. Both biotic and abiotic conditions alter terpenoid production, with herbivory, light and temperature effects being reasonably well understood. In this manuscript, the state of the science about nutrient effect on terpenoid production is reviewed. The focus is on isoprene emissions and mono- and sesquiterpenoid emissions and concentrations according to fertilizing treatments and their potential interaction with other environmental factors. Ecological, physiological, biochemical and biophysical hypothesis formulated over research investigations are exposed and several points are highlighted as future research perspectives which could help to elucidate the apparent contrasting results. PMID- 23097637 TI - Antibiotic, pesticide, and microbial contaminants of honey: human health hazards. AB - Agricultural contamination with pesticides and antibiotics is a challenging problem that needs to be fully addressed. Bee products, such as honey, are widely consumed as food and medicine and their contamination may carry serious health hazards. Honey and other bee products are polluted by pesticides, heavy metals, bacteria and radioactive materials. Pesticide residues cause genetic mutations and cellular degradation and presence of antibiotics might increase resistant human or animal's pathogens. Many cases of infant botulisms have been attributed to contaminated honey. Honey may be very toxic when produced from certain plants. Ingestion of honey without knowing its source and safety might be problematic. Honey should be labeled to explore its origin, composition, and clear statement that it is free from contaminants. Honey that is not subjected for analysis and sterilization should not be used in infants, and should not be applied to wounds or used for medicinal purposes. This article reviews the extent and health impact of honey contamination and stresses on the introduction of a strict monitoring system and validation of acceptable minimal concentrations of pollutants or identifying maximum residue limits for bee products, in particular, honey. PMID- 23097640 TI - Neuroimaging in mental health care: voices in translation. AB - Images of brain function, popularly called "neuroimages," have become a mainstay of contemporary communication about neuroscience and mental health. Paralleling media coverage of neuroimaging research and the high visibility of clinics selling scans is pressure from sponsors to move basic research about brain function along the translational pathway. Indeed, neuroimaging may offer benefits to mental health care: early or tailored intervention, opportunities for education and planning, and access to resources afforded by objectification of disorder. However, risks of premature technology transfer, such as misinterpretation, misrepresentation, and increased stigmatization, could compromise patient care. The insights of stakeholder groups about neuroimaging for mental health care are a largely untapped resource of information and guidance for translational efforts. We argue that the insights of key stakeholders-including researchers, healthcare providers, patients, and families have an essential role to play upstream in professional, critical, and ethical discourse surrounding neuroimaging in mental health. Here we integrate previously orthogonal lines of inquiry involving stakeholder research to describe the translational landscape as well as challenges on its horizon. PMID- 23097641 TI - Sensory prediction on a whiskered robot: a tactile analogy to "optical flow". AB - When an animal moves an array of sensors (e.g., the hand, the eye) through the environment, spatial and temporal gradients of sensory data are related by the velocity of the moving sensory array. In vision, the relationship between spatial and temporal brightness gradients is quantified in the "optical flow" equation. In the present work, we suggest an analog to optical flow for the rodent vibrissal (whisker) array, in which the perceptual intensity that "flows" over the array is bending moment. Changes in bending moment are directly related to radial object distance, defined as the distance between the base of a whisker and the point of contact with the object. Using both simulations and a 1*5 array (row) of artificial whiskers, we demonstrate that local object curvature can be estimated based on differences in radial distance across the array. We then develop two algorithms, both based on tactile flow, to predict the future contact points that will be obtained as the whisker array translates along the object. The translation of the robotic whisker array represents the rat's head velocity. The first algorithm uses a calculation of the local object slope, while the second uses a calculation of the local object curvature. Both algorithms successfully predict future contact points for simple surfaces. The algorithm based on curvature was found to more accurately predict future contact points as surfaces became more irregular. We quantify the inter-related effects of whisker spacing and the object's spatial frequencies, and examine the issues that arise in the presence of real-world noise, friction, and slip. PMID- 23097642 TI - Tolerance to high-intensity intermittent running exercise: do oxygen uptake kinetics really matter? AB - We examined the respective associations between aerobic fitness ([Formula: see text]max), metabolic control ([Formula: see text] kinetics) and locomotor function, and various physiological responses to high-intensity intermittent (HIT) running exercise in team sport players. Eleven players (30.5 +/- 3.6 year) performed a series of tests to determine their [Formula: see text]max and the associated velocity (v[Formula: see text]max), maximal sprinting speed (MSS) and [Formula: see text] kinetics at exercise onset in the moderate and severe intensity domains, and during recovery ([Formula: see text] SEV). Cardiorespiratory variables, oxygenation and electromyography of lower limbs muscles and blood lactate ([La]) concentration were collected during a standardized HIT protocol consisting in 8 sets of 10, 4-s runs. During HIT, four players could not complete more than two sets; the others finished at least five sets. Metabolic responses to the two first sets of HIT were negatively correlated with [Formula: see text]max, v[Formula: see text]max, and [Formula: see text] SEV (r = -0.6 to -0.8), while there was no clear relationship with the other variables. [Formula: see text], oxygenation and [La] responses to the first two sets of HIT were the only variables that differed between the players which could complete at least five sets or those who could not complete more than two sets. Players that managed to run at least five sets presented, in comparison with the others, greater v[Formula: see text]max [ES = +1.5(0.4; 2.7), MSS(ES = +1.0(0.1; 1.9)] and training load [ES = +3.8 (2.8; 4.9)]. There was no clear between-group difference in any of the [Formula: see text] kinetics measures [e.g., ES = -0.1( 1.4; 1.2) for [Formula: see text] SEV]. While [Formula: see text]max and v[Formula: see text]max are likely determinant for HIT tolerance, the importance of [Formula: see text] kinetics as assessed in this study appears limited in the present population. Knowing the main factors influencing tolerance to HIT running exercise may assist practitioners in personalizing training interventions. PMID- 23097643 TI - Issues determining direct airways hyperresponsiveness in mice. AB - Airways hyperresponsiveness (AHR) is frequently a primary outcome in mouse models of asthma. There are, however, a number of variables that may affect the outcome of such measurements and the interpretation of the results. This article highlights issues that should be kept in mind when designing experiments using AHR as an outcome by reviewing techniques commonly used to assess AHR (unrestrained plethysmography and respiratory input impedance using forced oscillations), discussing the relationship between structure and function and, then exploring how the localization of AHR evolves over time, how the airway epithelium may affect the kinetics of methacholine induced AHR and finally how lung volume and positive end expiratory pressure (PEEP) can be used as tools assessing respiratory mechanics. PMID- 23097644 TI - Inter-Individual Variation during Transcranial Direct Current Stimulation and Normalization of Dose Using MRI-Derived Computational Models. AB - BACKGROUND: Transcranial Direct Current Stimulation (tDCS) is a non-invasive, versatile, and safe neuromodulation technology under investigation for the treatment of neuropsychiatric disorders, adjunct to rehabilitation, and cognitive enhancement in healthy adults. Despite promising results, there is variability in responsiveness. One potential source of variability is the intensity of current delivered to the brain which is a function of both the operator controlled tDCS dose (electrode montage and total applied current) and subject specific anatomy. We are interested in both the scale of this variability across anatomical typical adults and methods to normalize inter-individual variation by customizing tDCS dose. Computational FEM simulations are a standard technique to predict brain current flow during tDCS and can be based on subject specific anatomical MRI. OBJECTIVE: To investigate this variability, we modeled multiple tDCS montages across three adults (ages 34-41, one female). RESULTS: Conventional pad stimulation led to diffuse modulation with maximum current flow between the pads across all subjects. There was high current flow directly under the pad for one subject while the location of peak induced cortical current flow was variable. The High-Definition tDCS montage led to current flow restricted to within the ring perimeter across all subjects. The current flow profile across all subjects and montages was influenced by details in cortical gyri/sulci. CONCLUSION: This data suggests that subject specific modeling can facilitate consistent and more efficacious tDCS. PMID- 23097646 TI - Antiphospholipid-related chorea. AB - Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is beta2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment. PMID- 23097648 TI - CYP4F2 polymorphism as a genetic risk factor for major hemorrhagic complications in Chinese patients on warfarin therapy. PMID- 23097649 TI - Number of medications is associated with outcomes in the elderly patient with metabolic syndrome. AB - BACKGROUND: The diagnosis of metabolic syndrome indicates a clustering of metabolic imbalances which in sum have been recognized as a major predictor of cardiovascular and all-cause mortality. The aim of this study was to assess the level of under-pharmacy and poly-pharmacy and its prognostic impact in elderly patients with metabolic syndrome. METHODS: Retrospective chart-review at a tertiary medical center, of 324 patients greater than 65 years of age who met the International Diabetes Foundation criteria for metabolic syndrome diagnosis [Body Mass Index (BMI) > 30 kg/m(2), diagnosis of type 2 diabetes, hypertension, and dyslipidemia]. RESULTS: There were 60 (18.5%) patients in the low (<= 5) medication burden group, 159 (49.1%) in the medium (> 5 and <= 10) medication burden group, and 105 (32.4%) in the high (> 10) medication burden group. At baseline, the groups differed only by systolic blood pressure. At two years follow-up, the medium group had significantly better improvement in high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), HbA1c, and systolic blood pressure compared to the low medication burden group and significantly better improvement in triglycerides, Haemoglobin A1c (HbA1c) and systolic blood pressure compared to the high medication group. Decrease in HDL-C was the only variable associated with strokes. High medication burden predicted hospitalization burden. The number of anti-hypertensives, history of tobacco use, low and high medication burdens and decrease in HDL-C were all associated with death. CONCLUSIONS: Both poly-pharmacy and under-pharmacy are associated with a decreased therapeutic benefit among patients with metabolic syndrome in terms of important laboratory measurements as well as clinical outcomes such as myocardial infarctions, hospitalization, and death. PMID- 23097647 TI - Molecules affecting hypothalamic control of core body temperature in response to calorie intake. AB - Core body temperature (CBT) and calorie intake are main components of energy homeostasis and two important regulators of health, longevity, and aging. In homeotherms, CBT can be influenced by calorie intake as food deprivation or calorie restriction (CR) lowers CBT whereas feeding has hyperthermic effects. The finding that in mice CBT prolonged lifespan independently of CR, suggested that the mechanisms modulating CBT may represent important regulators of aging. Here we summarize the current knowledge on the signaling molecules and their receptors that participate in the regulation of CBT responses to calorie intake. These include hypothalamic neuropeptides regulating feeding but also energy expenditure via modulation of thermogenesis. We also report studies indicating that nutrient signals can contribute to regulation of CBT by direct action on hypothalamic preoptic warm-sensitive neurons that in turn regulate adaptive thermogenesis and hence CBT. Finally, we show the role played by two orphans G protein-coupled receptor: GPR50 and GPR83, that were recently demonstrated to regulate temperature-dependent energy expenditure. PMID- 23097645 TI - Putative role of prostaglandin receptor in intracerebral hemorrhage. AB - Each year, approximately 795,000 people experience a new or recurrent stroke. Of all strokes, 84% are ischemic, 13% are intracerebral hemorrhage (ICH) strokes, and 3% are subarachnoid hemorrhage strokes. Despite the decreased incidence of ischemic stroke, there has been no change in the incidence of hemorrhagic stroke in the last decade. ICH is a devastating disease 37-38% of patients between the ages of 45 and 64 die within 30 days. In an effort to prevent ischemic and hemorrhagic strokes we and others have been studying the role of prostaglandins and their receptors. Prostaglandins are bioactive lipids derived from the metabolism of arachidonic acid. They sustain homeostatic functions and mediate pathogenic mechanisms, including the inflammatory response. Most prostaglandins are produced from specific enzymes and act upon cells via distinct G-protein coupled receptors. The presence of multiple prostaglandin receptors cross reactivity and coupling to different signal transduction pathways allow differentiated cells to respond to prostaglandins in a unique manner. Due to the number of prostaglandin receptors, prostaglandin-dependent signaling can function either to promote neuronal survival or injury following acute excitotoxicity, hypoxia, and stress induced by ICH. To better understand the mechanisms of neuronal survival and neurotoxicity mediated by prostaglandin receptors, it is essential to understand downstream signaling. Several groups including ours have discovered unique roles for prostaglandin receptors in rodent models of ischemic stroke, excitotoxicity, and Alzheimer disease, highlighting the emerging role of prostaglandin receptor signaling in hemorrhagic stroke with a focus on cyclic adenosine monophosphate and calcium (Ca(2+)) signaling. We review current ICH data and discuss future directions notably on prostaglandin receptors, which may lead to the development of unique therapeutic targets against hemorrhagic stroke and brain injuries alike. PMID- 23097650 TI - An initial study on left ventricular diastolic function in patients with hypertrophy cardiomyopathy using single-beat, real-time, three-dimensional echocardiography. AB - OBJECTIVES: To assess the regional diastolic function in patients with hypertrophic cardiomyopathy (HCM) by using single-beat, real-time, three dimensional echocardiography (RT-3DE). METHODS: Sixty-five patients with HCM in sinus rhythm together with fifty age- and gender-matched normal controls were studied by two dimensional echocardiography (2DE) and RT-3DE. The parameters analyzed by RT-3DE included: left ventricular (LV) volumes, left ventricular ejection fraction (LVEF), end diastolic sphericity index (EDSI), diastolic dyssynchrony index (DDI), dispersion end diastole (DISPED), and normalized 17 segmental volume-time curves. RESULTS: Evaluated by RT-3DE, LVEF was slightly lower compared with 2DE (63.2 +/- 6.8% vs. 59.1 +/- 6.4%, P < 0.0001). Normal subjects had relatively uniform volumetric curves for all LV segments. In HCM patients, the segmental volumetric curves were dyssynchronous. Increased DDI and DISPED in end diastole were observed in patients with HCM (9.95 +/- 3.75, 41.76 +/- 17.19, P < 0.0001), and not all abnormal volumetric segments occurred in the hypertrophic regions. CONCLUSIONS: Patients with HCM have presented regional diastolic dyssynchrony in the diastole phase, and this preclinical lesion can be recognized by single-beat RT-3DE. PMID- 23097651 TI - A randomized, open-label, multicentre study to evaluate plasma atherosclerotic biomarkers in patients with type 2 diabetes mellitus and arteriosclerosis obliterans when treated with Probucol and Cilostazol. AB - OBJECTIVES: To evaluate the plasma atherosclerotic biomarkers in patients with type 2 diabetes mellitus (T2DM) and arteriosclerosis obliteran (ASO) when treated with Probucol plus Cilostazol in combination and individually. METHODS: In this open-label study, patients aged 40-75 years were randomized to receive conventional therapy alone, or with Cilostazol 100 mg bid, or with Probucol 250 mg bid, or with both in combination. Endpoints included changes in plasma biomarker and safety at 12 weeks. RESULTS: Of the 200 randomized patients, 165 for per-protocol and 160 for the safety (QTc intervals) were set, respectively. Probucol significantly reduced total cholesterol (P < 0.001), low-density lipoprotein cholesterol (LDL-C), (P = 0.01), and high-density lipoprotein cholesterol (HDL-C) (P < 0.001) compared with conventional therapy. Cilostazol was effective in increasing HDL-C (P = 0.002) and reducing triglycerides levels (P < 0.01) compared with conventional therapy. A trend towards significance was observed for the difference between conventional therapy alone and Probucol plus Cilostazol group for the change in oxidized low-density lipoprotein (Ox-LDL, P = 0.065). No significant effects on the majority of the remaining biomarkers were found across the treatment groups. CONCLUSIONS: We have confirmed that Ox-LDL could be a possible plasma atherosclerotic biomarker among the evaluated biomarkers, which reflected the synergetic effect of Cilostazol plus Probucol in patients with T2DM and ASO shown previously in preclinical studies. PMID- 23097652 TI - Digoxin intoxication: An old enemy in modern era. AB - OBJECTIVES: Although development of new treatment modalities limited digoxin usage, digoxin intoxication is still an important issue which could be easily overlooked. In this report, we analyzed a case series definitively diagnosed as digoxin intoxication in the modern era. METHODS: We analyzed 71 patients hospitalized with digoxin intoxication confirmed by history, complaints, clinical and electrocardiograph (ECG) findings, and serum digoxin levels > 2.0 ng/mL, during a five year period. The demographic and clinical data, indications for digoxin use, digoxin dosage, concurrent medications, laboratory data, hospital monitoring, and ECG findings were obtained from all patients. RESULTS: Thirty eight of 71 patients (53.5%) had symptoms of heart failure during admission or later. Sixty-four percent of patients were older than 75 years. The percentage of females was 67%. Atrial fibrillation, hypertension and gastrointestinal complaints were more frequent in the females (64% in females, 30% in males, P = 0.007; 81% in female, 52% in males, P = 0.01; 50% in female, 17.3% in males, P = 0.008, respectively). The mortality rate during the hospital course was 7%. CONCLUSIONS: This report demonstrated the reduced mortality rates in patients with digoxin intoxication over the study period. Gastrointestinal complaints are the most common symptoms in this population. PMID- 23097653 TI - Safety and predictors of adherence of a new rehabilitation program for older women with congestive heart failure. AB - OBJECTIVES: To assess the safety of a cardiac rehabilitation program for older women with Congestive Heart Failure (CHF) and determine if certain factors influence adherence. METHODS: Women over the age of 65 with CHF attended an exercise program supervised by a physiotherapist. Quality of life was measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and severity of disease by the New York Heart Association (NYHA) Class. Subjects were classified into those who attended 90% or more of the sessions and those who attended less than 90% of the sessions. RESULTS: Fifty-one subjects were studied. Eight subjects did not attend any sessions. Of the 43 attendees, the average percentage of sessions attended was 87%. There were no significant differences between the two groups in age, MLHFQ or NYHA Class. There was only one adverse event out of 280 participant attendances. CONCLUSIONS: The program had a high level of adherence in this population. Age, MLHFQ or NYHA Class did not impact on session attendance. Our data suggests this program is safe for this population. Further research is needed to determine other predictors of attendance and the examination of safety issues and long-term adherence to exercise in this population. PMID- 23097654 TI - Off-pump coronary artery bypass grafting using a bilateral internal mammary artery Y graft. AB - OBJECTIVE: To evaluate the outcome of off-pump coronary artery bypass grafting (OPCABG) using a bilateral internal mammary artery (BIMA) Y configuration graft to achieve total arterial myocardial revascularization. METHODS: From October 2002 to December 2008, 208 patients (196 males and 12 females) underwent OPCABG using a BIMA Y configuration graft. The average age of the patients was 56.5 +/- 11.3 years, with an age range of 33-78 years. A total of 167 (80.2%) cases had triple-vessel disease. Left main stem disease was found in 33 (15.9%) cases, and double-vessel disease was found in 8 (3.9%) cases. The semi-skeletonization technique was used to harvest the two internal mammary arteries (IMAs), and then the free right internal mammary artery was connected end-to-side to the left internal mammary artery (LIMA) in situ to complete the Y configuration graft. Off pump and sequential anastomosis methods were used to perform coronary artery bypass surgery in all patients. Graft patency was assessed intra-operatively with the HT311 transit time flowmeter. RESULTS: A total of 728 distal anastomoses were performed in 208 patients, with the average being 3.5 +/- 1.3 per person. No one died or experienced recurrent angina within 30 days after the operation. CONCLUSIONS: OPCABG using the BIMA Y graft was safe and effective to achieve total arterial revascularization. This method avoids surgical operation on the ascending aorta and other incisions. PMID- 23097655 TI - Cardiovascular and cerebrovascular outcomes in elderly hypertensive patients treated with either ARB or ACEI. AB - BACKGROUND: Although angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are equally important in the treatment of hypertension, there is less evidence whether they have equal cardiovascular and cerebrovascular protective effects, especially in elder hypertensive patients. This study aims to clarify this unresolved issue. METHODS: This cross-sectional study included clinical data on 933 aged male patients with hypertension who received either an ARB or ACEI for more than two months between January 2007 and May 2011. The primary outcome was the composite of cardiovascular death, non fatal myocardial infarction, and non-fatal stroke. The secondary endpoints were unstable angina, new atrial fibrillation, and transient ischemic attack. RESULTS: The median follow-up time was 24 months. Age, drug types, cerebral infarction history, renal dysfunction history were the independent predictors of the primary endpoint. The risk of an occurrence of a primary endpoint event was higher in the ARB group than the ACEI group [P = 0.037, hazard ratios (HR): 2.124, 95% confidence interval (95% CI): 1.048-4.306]. The Kaplan-Meier method also suggests that the rate of primary endpoint occurrence was higher in the ARB group than the ACEI group (P = 0.04). In regard to the secondary endpoints, there were no significant differences between the two treatment arms (P = 0.137, HR: 1.454, 95% CI: 0.888-2.380). Patient age and coronary heart disease history were independent predictors of the secondary endpoint. CONCLUSION: ACEI were more effective than ARB in reducing cardiovascular and cerebrovascular morbidity and mortality in aged patients with hypertension. PMID- 23097656 TI - Salubrinal protects against tunicamycin and hypoxia induced cardiomyocyte apoptosis via the PERK-eIF2alpha signaling pathway. AB - OBJECTIVES: This study examined the protective effect of salubrinal and the mechanism underlying this protection against tunicamycin (TM)- and hypoxia induced apoptosis in rat cardiomyocytes. METHODS: Neonatal rat cardiomyocytes were cultured from the ventricles of 1-day-old Wistar rats. Cells were exposed to different concentrations of salubrinal (10, 20, and 40 umol/L) for 30 min followed by TM treatment or hypoxia for 36 h. Apoptosis was measured by a multiparameter HCS (high content screening) apoptosis assay, TUNEL assay and flow cytometry. The phosphorylation of eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha) and the expression of cleaved caspase-12 were determined by Western blotting. C/EBP homologous protein (CHOP) was detected by immunocytochemistry. RESULTS: HCS, TUNEL assays and flow cytometry showed that salubrinal protected cardiomyocytes against apoptosis induced by TM or hypoxia. Western blotting showed that salubrinal protected cardiomyocytes against apoptosis by inducing eIF2alpha phosphorylation and down-regulating the expression of the endoplasmic reticulum stress-mediated apoptotic proteins, CHOP and cleaved caspase-12. CONCLUSIONS: Our study suggests that salubrinal protects rat cardiomyocytes against TM- or hypoxia-associated apoptosis via a mechanism involving the inhibition of ER stress-mediated apoptosis. PMID- 23097657 TI - Ameliorated stress related proteins are associated with improved cardiac function by sarcoplasmic reticulum calcium ATPase gene transfer in heart failure. AB - BACKGROUND: Previous studies showed that overexpression of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) in a variety of heart failure (HF) models was associated with greatly enhanced cardiac performance. However, it still undefined the effect of SERCA2a overexpression on the systemic inflammatory response and neuro-hormonal factors. METHODS: A rapid right ventricular pacing model of experimental HF was used in beagles. Then the animals underwent recombinant adeno associated virus 1 (rAAV1) mediated gene transfection by direct intra-myocardium injection. HF animals were randomized to receive the SERCA2a gene, enhanced green fluorescent protein (control) gene, or equivalent phosphate buffered saline. Thirty days after gene delivery, the cardiac function was evaluated by echocardiographic testing. The protein level of SERCA2a was measured by western blotting. The proteomic analysis of left ventricular (LV) sample was determined using two-dimensional (2-D) gel electrophoresis and MALDI-TOF-MS. The serum levels of the systemic inflammatory and neuro-hormonal factors were assayed using radioimmunoassay kits. RESULTS: The cardiac function improved after SERCA- 2a gene transfer due to the significantly increased SERCA2a protein level. Beagles treated with SERCA2a had significantly decreased serum levels of the inflammatory markers (interleukin-6 and tumor necrosis factor-alpha) and neuro-hormonal factors (brain natriuretic peptide, endothelin-1 and angiotensin II) compared with HF animals. The myocardial proteomic analysis showed that haptoglobin heavy chain, heat shock protein (alpha-crystallin-related, B6) were down-regulated, and galectin-1 was up-regulated in SERCA2a group compared with HF group, companied by up-regulated contractile proteins and NADH dehydrogenase. CONCLUSIONS: These findings demonstrate that regional intramyocardial injections of rAAV1-SERCA2a vectors may improve global LV function, correlating with reverse activation of the systemic inflammatory, excessive neuroendocrine factors and the stress associated myocardial proteins, suggesting that the beneficial effects of SERCA2a gene transfer may involve the attenuation of stress-associated reaction. PMID- 23097658 TI - Clinical applications of fractional flow reserve in bifurcation lesions. AB - Percutaneous coronary intervention (PCI) for coronary bifurcation lesions has been associated with lower procedural success rates and worse clinical outcomes compared with PCI for simple coronary lesions. Angiographic evaluation alone is sometimes inaccurate and does not reflect the functional significance of bifurcation lesions. The fractional flow reserve (FFR) is an easily obtainable, reliable, and reproducible physiologic parameter. This parameter is epicardial lesion specific and reflects both degree of stenosis and the myocardial territory supplied by the specific artery. Recent studies have shown that FFR-guided provisional side branch intervention strategy for bifurcation lesions is feasible and effective and can reduce unnecessary complex interventions and related complications. However, an adequate understanding of coronary physiology and the pitfalls of FFR is essential to properly use FFR for PCI of complex bifurcation lesions. PMID- 23097659 TI - Endovascular abdominal aortic aneurysm repair in the geriatric population. AB - Abdominal aortic aneurysm (AAA) is a relatively common pathology among the elderly. More people above the age of 80 will have to undergo treatment of an AAA in the future. This review aims to summarize the literature focusing on endovascular repair of AAA in the geriatric population. A systematic review of the literature was performed, including results from endovascular abdominal aortic aneurysm repair (EVAR) registries and studies comparing open repair and EVAR in those above the age of 80. A total of 15 studies were identified. EVAR in this population is efficient with a success rate exceeding 90% in all cases, and safe, with early mortality and morbidity being superior among patients undergoing EVAR against open repair. Late survival can be as high as 95% after 5 years. Aneurysm-related death over long-term follow-up was low after EVAR, ranging from 0 to 3.4%. Endovascular repair can be offered safely in the geriatric population and seems to compare favourably with open repair in all studies in the literature to date. PMID- 23097660 TI - Cardiorenal biomarkers in acute heart failure. AB - Managing patients with heart failure (HF) is a challenging task within itself, but the presence of associated worsening renal function can greatly increase mortality and morbidity. Early diagnosis and treatment is the key to prevent re hospitalizations and reduce healthcare costs. Biomarkers have long been established as highly sensitive and specific tools in diagnosing and prognosticating patients with HF. Reflecting distinct pathophysiological events and ongoing cellular insult, biomarkers have been proven superior to conventional laboratory tests. Availability of better assays and rapid analysis has allowed the use of biomarkers as point-of-care tests in the emergency department and at the patient's bed-side. Acute HF patients often go on to develop worsening renal function, termed as acute cardiorenal syndrome. The growing breadth of studies has shown the implications of combining multiple biomarkers to better chart outcomes and produce desirable results in such patients. PMID- 23097662 TI - Reversible cardiogenic shock caused by atrioventricular junctional rhythm after percutaneous coronary intervention. AB - An 82-year-old female patient undergoing cardiogenic shock caused by atrioventricular junctional rhythm immediately after percutaneous coronary intervention (PCI) is described. Pharmacotherapy was invalid, and subsequent application of atrial pacing reversed the cardiogenic shock. PCI-related injury of sinuatrial nodal artery leading to acute atrial contractility loss, accompanied by atrioventricular junctional arrhythmia, was diagnosed. We recommend that preoperative risk evaluation be required for multi-risk patients. Likewise, emergent measures should to be established in advance. This case reminds us that atrial pacing can be an optimal management technique once cardiogenic shock has occurred. PMID- 23097661 TI - Atherosclerosis: from biology to pharmacological treatment. AB - A recent explosion in the amount of cardiovascular risk has swept across the globe. Primary prevention is the preferred method to lower cardiovascular risk. Lowering the prevalence of obesity is the most urgent matter, and is pleiotropic since it affects blood pressure, lipid profiles, glucose metabolism, inflammation, and atherothrombotic disease progression. Given the current obstacles, success of primary prevention remains uncertain. At the same time, the consequences of delay and inaction will inevitably be disastrous, and the sense of urgency mounts. Pathological and epidemiological data confirm that atherosclerosis begins in early childhood, and advances seamlessly and inexorably throughout life. Risk factors in childhood are similar to those in adults, and track between stages of life. When indicated, aggressive treatment should begin at the earliest indication, and be continued for many years. For those patients at intermediate risk according to global risk scores, C-reactive protein, coronary artery calcium, and carotid intima-media thickness are available for further stratification. Using statins for primary prevention is recommended by guidelines, is prevalent, but remains under prescribed. Statin drugs are unrivaled, evidence-based, major weapons to lower cardiovascular risk. Even when low density lipoprotein cholesterol targets are attained, over half of patients continue to have disease progression and clinical events. Though clinical evidence is incomplete, altering or raising the blood high density lipoprotein cholesterol level continues to be pursued. The aim of this review is to point out the attention of key aspects of vulnerable plaques regarding their pathogenesis and treatment. PMID- 23097664 TI - The role of serum cytokines in the pathogenesis of hepatic osteodystrophy in male cirrhotic patients. AB - Objective. In this study, we aimed to investigate the possible role of serum cytokines in the development of hepatic osteodystrophy. Matherial and Methods. 44 consecutive male cirrhotic patients (17 alcoholic, 20 hepatitis B, 7 hepatitis C), 15 age- and sex-matched chronic alcoholics without liver disease, and 17 age- and sex-matched healthy controls were included in the study during one year period. Bone mineral density was measured by dual X-ray absorptiometry in the lumbar vertebrate and femoral neck. Serum interleukin levels were measured by ELISA method. Results. Although osteopenia frequency between our cirrhotic patients was 20%, there was no difference in T-scores among the controls and other groups. Serum interleukin-1, interleukin-8, and tumor necrosis factor-alpha levels were not different between all groups. Serum interleukin-2 and interleukin 6 levels were higher in the cirrhotics than controls (P < 0.001). However, there were no significant difference between osteopenic and nonosteopenic cirrhotics. Conclusion. According to the results of the study in this small population of 44 male cirrhotic patients, frequency of hepatic osteopenia is small and serum interleukins 1, 2, 6, 8, and tumor necrosis factor-alpha may not play a role in the pathogenesis of hepatic osteodystrophy. Further studies in which large number of patients involved are necessary in this field. PMID- 23097663 TI - Brain connectivity analysis: a short survey. AB - This short survey the reviews recent literature on brain connectivity studies. It encompasses all forms of static and dynamic connectivity whether anatomical, functional, or effective. The last decade has seen an ever increasing number of studies devoted to deduce functional or effective connectivity, mostly from functional neuroimaging experiments. Resting state conditions have become a dominant experimental paradigm, and a number of resting state networks, among them the prominent default mode network, have been identified. Graphical models represent a convenient vehicle to formalize experimental findings and to closely and quantitatively characterize the various networks identified. Underlying these abstract concepts are anatomical networks, the so-called connectome, which can be investigated by functional imaging techniques as well. Future studies have to bridge the gap between anatomical neuronal connections and related functional or effective connectivities. PMID- 23097665 TI - Perioperative anesthesiological management of patients with pulmonary hypertension. AB - Pulmonary hypertension is a major reason for elevated perioperative morbidity and mortality, even in noncardiac surgical procedures. Patients should be thoroughly prepared for the intervention and allowed plenty of time for consideration. All specialty units involved in treatment should play a role in these preparations. After selecting each of the suitable individual anesthetic and surgical procedures, intraoperative management should focus on avoiding all circumstances that could contribute to exacerbating pulmonary hypertension (hypoxemia, hypercapnia, acidosis, hypothermia, hypervolemia, and insufficient anesthesia and analgesia). Due to possible induction of hypotonic blood circulation, intravenous vasodilators (milrinone, dobutamine, prostacyclin, Na-nitroprusside, and nitroglycerine) should be administered with the greatest care. A method of treating elevations in pulmonary pressure with selective pulmonary vasodilation by inhalation should be available intraoperatively (iloprost, nitrogen monoxide, prostacyclin, and milrinone) in addition to invasive hemodynamic monitoring. During the postoperative phase, patients must be monitored continuously and receive sufficient analgesic therapy over an adequate period of time. All in all, perioperative management of patients with pulmonary hypertension presents an interdisciplinary challenge that requires the adequate involvement of anesthetists, surgeons, pulmonologists, and cardiologists alike. PMID- 23097667 TI - Flux Analysis of the Trypanosoma brucei Glycolysis Based on a Multiobjective Criteria Bioinformatic Approach. AB - Trypanosoma brucei is a protozoan parasite of major of interest in discovering new genes for drug targets. This parasite alternates its life cycle between the mammal host(s) (bloodstream form) and the insect vector (procyclic form), with two divergent glucose metabolism amenable to in vitro culture. While the metabolic network of the bloodstream forms has been well characterized, the flux distribution between the different branches of the glucose metabolic network in the procyclic form has not been addressed so far. We present a computational analysis (called Metaboflux) that exploits the metabolic topology of the procyclic form, and allows the incorporation of multipurpose experimental data to increase the biological relevance of the model. The alternatives resulting from the structural complexity of networks are formulated as an optimization problem solved by a metaheuristic where experimental data are modeled in a multiobjective function. Our results show that the current metabolic model is in agreement with experimental data and confirms the observed high metabolic flexibility of glucose metabolism. In addition, Metaboflux offers a rational explanation for the high flexibility in the ratio between final products from glucose metabolism, thsat is, flux redistribution through the malic enzyme steps. PMID- 23097668 TI - Suppression of aldosterone synthesis and secretion by ca(2+) channel antagonists. AB - Aldosterone, a specific mineralocorticoid receptor (MR) agonist and a key player in the development of hypertension, is synthesized as a final product of renin angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin II type 1 receptor antagonists (ARBs). However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called "aldosterone breakthrough" effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS) inhibitors) gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca(2+) channel blockers (CCBs) have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients. PMID- 23097670 TI - Staphylococcal sepsis with multiple abscesses, urinary tract infection, and bilateral renal vein thrombosis in a patient with uncontrolled diabetes mellitus. AB - We report a case of staphylococcal sepsis with vascular complications including peripheral emboli and renal vein thrombosis. Bilateral renal vein thrombosis has not been reported as a complication of Staphylococcus aureus (SA) axillary abscess. Uncontrolled diabetes was the only detected predisposing medical condition. The patient was treated successfully with incision and drainage of soft-tissue abscesses and intravenous antibiotic for six weeks and with anticoagulation for renal vein thrombosis. PMID- 23097669 TI - Practical approaches to the use of lenalidomide in multiple myeloma: a canadian consensus. AB - In Canada, lenalidomide combined with dexamethasone (Len/Dex) is approved for use in relapsed or refractory multiple myeloma (RRMM). Our expert panel sought to provide an up-to-date practical guide on the use of lenalidomide in the managing RRMM within the Canadian clinical setting, including management of common adverse events (AEs). The panel concluded that safe, effective administration of Len/Dex treatment involves the following steps: (1) lenalidomide dose adjustment based on creatinine clearance and the extent of neutropenia or thrombocytopenia, (2) dexamethasone administered at 20-40 mg/week, and (3) continuation of treatment until disease progression or until toxicity persists despite dose reduction. Based on available evidence, the following precautions should reduce the risk of common Len/Dex AEs: (1) all patients treated with Len/Dex should receive thromboprophylaxis, (2) erythropoiesis-stimulating agents (ESAs) should be used cautiously, and (3) females of child-bearing potential and males in contact with such females must use multiple contraception methods. Finally, while Len/Dex can be administered irrespective of prior therapy and in all prognostic subsets, patients with chromosomal deletion 17(p13) have less favorable outcomes with all treatments, including Len/Dex. New directions for the use of lenalidomide in RRMM are also considered. PMID- 23097671 TI - Influence of first-time mothers' early employment on severe early childhood caries in their child. AB - Aim. To examine whether mothers' early employment status is related to the development of severe early childhood caries in their child. Methods. Questionnaire survey of 429 first-time mothers in metropolitan Adelaide, South Australia, and dental examinations of their child at 20 months of age. Results. At 20 +/- 2.5 months of age, 5.6% of children exhibited caries defined as one or more demineralized or cavitated lesions on the upper incisors. Of the mothers, 52.2% had no paid employment, 39.6% were part-time and 8.2% full-time employed. Overall, mothers' participation in the workforce had no influence on the frequency of severe early childhood caries in their child, but there was a significant interaction with family structure. For mothers without employment there was no difference between single, and two-parent families, but children with an employed single mother more frequently had caries than those with a working mother in a two-parent family (P < 0.04). However, there were no significant differences in children's reported general health. Conclusions. The data indicate a need to explore strategies that may assist single mothers and especially those in the workforce to prevent severe early childhood caries in their child. PMID- 23097672 TI - Immune-related disorders and extrahepatic diseases in chronic HCV infection. PMID- 23097666 TI - Global fluoroquinolone resistance epidemiology and implictions for clinical use. AB - This paper on the fluoroquinolone resistance epidemiology stratifies the data according to the different prescription patterns by either primary or tertiary caregivers and by indication. Global surveillance studies demonstrate that fluoroquinolone resistance rates increased in the past years in almost all bacterial species except S. pneumoniae and H. influenzae, causing community acquired respiratory tract infections. However, 10 to 30% of these isolates harbored first-step mutations conferring low level fluoroquinolone resistance. Fluoroquinolone resistance increased in Enterobacteriaceae causing community acquired or healthcare associated urinary tract infections and intraabdominal infections, exceeding 50% in some parts of the world, particularly in Asia. One to two-thirds of Enterobacteriaceae producing extended spectrum beta-lactamases were fluoroquinolone resistant too. Furthermore, fluoroquinolones select for methicillin resistance in Staphylococci. Neisseria gonorrhoeae acquired fluoroquinolone resistance rapidly; actual resistance rates are highly variable and can be as high as almost 100%, particularly in Asia, whereas resistance rates in Europe and North America range from <10% in rural areas to >30% in established sexual networks. In general, the continued increase in fluoroquinolone resistance affects patient management and necessitates changes in some guidelines, for example, treatment of urinary tract, intra-abdominal, skin and skin structure infections, and traveller's diarrhea, or even precludes the use in indications like sexually transmitted diseases and enteric fever. PMID- 23097673 TI - Immunotherapy of cancer: reprogramming tumor-immune crosstalk. AB - The advancement of cancer immunotherapy faces barriers which limit its efficacy. These include weak immunogenicity of the tumor, as well as immunosuppressive mechanisms which prevent effective antitumor immune responses. Recent studies suggest that aberrant expression of cancer testis antigens (CTAs) can generate robust antitumor immune responses, which implicates CTAs as potential targets for immunotherapy. However, the heterogeneity of tumor cells in the presence and quantity of CTA expression results in tumor escape from CTA-specific immune responses. Thus, the ability to modulate the tumor cell epigenome to homogenously induce expression of such antigens will likely render the tumor more immunogenic. Additionally, emerging studies suggest that suppression of antitumor immune responses may be overcome by reprogramming innate and adaptive immune cells. Therefore, this paper discusses recent studies which address barriers to successful cancer immunotherapy and proposes a strategy of modulation of tumor immune cell crosstalk to improve responses in carcinoma patients. PMID- 23097675 TI - Acupuncture Alleviates Colorectal Hypersensitivity and Correlates with the Regulatory Mechanism of TrpV1 and p-ERK. AB - Here we used a mouse model of zymosan-induced colorectal hypersensitivity, a similar model of IBS in our previous work, to evaluate the effectiveness of the different number of times of acupuncture and elucidate its potential mechanism of EA treatment. Colorectal distension (CRD) tests show that intracolonic zymosan injection does, while saline injection does not, induce a typical colorectal hypersensitivity. EA treatment at classical acupoints Zusanli (ST36) and Shangjuxu (ST37) in both hind limbs for 15 min slightly attenuated and significantly blunted the hypersensitive responses after first and fifth acupunctures, respectively, to colorectal distention in zymosan treatment mice, but not in saline treatment mice. Western blot results indicated that ion channel and TrpV1 expression in colorectum as well as ERK1/2 MAPK pathway activation in peripheral and central nerve system might be involved in this process. Hence, we conclude that EA is a potential therapeutic tool in the treatment and alleviation of chronic abdominal pain, and the effectiveness of acupuncture analgesia is accumulative with increased number of times of acupuncture when compared to that of a single time of acupuncture. PMID- 23097674 TI - Sustained high level of serum VEGF at convalescent stage contributes to the renal recovery after HTNV infection in patients with hemorrhagic fever with renal syndrome. AB - To investigate the role of vascular endothelial growth factor (VEGF) in the increased permeability of vascular endothelial cells after Hantaan virus (HTNV) infection in humans, the concentration of VEGF in serum from HTNV infected patients was quantified with sandwich ELISA. Generally, the level of serum VEGF in patients was elevated to 607.0 (542.2-671.9) pg/mL, which was dramatically higher compared with healthy controls (P < 0.001). There was a rapid increase of the serum VEGF level in all patients from the fever onset to oliguric stage, at which the serum creatinine reached the peak level of the disease, indicating that VEGF may be involved in the pathogenesis of renal hyper-permeability. Moreover, the serum VEGF level at convalescent stage was positively correlated with the degree of the disease severity. The sustained high level of serum VEGF at convalescence was observed in critical HFRS patients, suggesting that VEGF would probably contribute to the renal recovery after the virus clearance. Taken together, our results suggested that the VEGF would be involved in the pathogenesis of renal dysfunction at the oliguric stage after HTNV infection, but may function as a recovery factor during the convalescence to help the body self repair of the renal injury. PMID- 23097676 TI - Evaluation of topical tocopherol cream on cutaneous wound healing in streptozotocin-induced diabetic rats. AB - Diabetes is a common cause of delayed wound healing. The aim of the study was to determine the effect of topical administration of tocopherol cream on the wound healing process in diabetic rats. The study was conducted using 18 male Sprague Dawley rats which were divided into three groups: (I) diabetic rats receiving control cream (n = 6), (II) diabetic rats receiving 0.06% tocopherol cream (n = 6), and (III) diabetic rats receiving 0.29% tocopherol cream (n = 6). Four cutaneous wounds were created at the dorsal region of the rats. Wound healing was assessed by total protein content, rate of wound closure estimation, and histological studies on the tenth day after wounding. Tocopherol treatment enhanced the wound healing process by increasing rate of wound closure and total protein content significantly (P < 0.05) compared to the control group. Histological observation also showed better organized epithelium and more collagen fibers in the tocopherol treated groups. Application of tocopherol cream enhances wound healing process in diabetic condition which is known to cause delay in wound healing. PMID- 23097677 TI - Elimination of cancer stem-like "side population" cells in hepatoma cell lines by chinese herbal mixture "tien-hsien liquid". AB - There are increasing pieces of evidence suggesting that the recurrence of cancer may result from a small subpopulation of cancer stem cells, which are resistant to the conventional chemotherapy and radiotherapy. We investigated the effects of Chinese herbal mixture Tien-Hsien Liquid (THL) on the cancer stem-like side population (SP) cells isolated from human hepatoma cells. After sorting and subsequent culture, the SP cells from Huh7 hepatoma cells appear to have higher clonogenicity and mRNA expressions of stemness genes such as SMO, ABCG2, CD133, beta-catenin, and Oct-4 than those of non-SP cells. At dose of 2 mg/mL, THL reduced the proportion of SP cells in HepG2, Hep3B, and Huh7 cells from 1.33% to 0.49%, 1.55% to 0.43%, and 1.69% to 0.27%, respectively. The viability and colony formation of Huh7 SP cells were effectively suppressed by THL dose-dependently, accompanied with the inhibition of stemness genes, e.g., ABCG2, CD133, and SMO. The tumorigenicity of THL-treated Huh7 SP cells in NOD/SCID mice was also diminished. Moreover, combination with THL could synergize the effect of doxorubicin against Huh7 SP cells. Our data indicate that THL may act as a cancer stem cell targeting therapeutics and be regarded as complementary and integrative medicine in the treatment of hepatoma. PMID- 23097678 TI - Source space analysis of event-related dynamic reorganization of brain networks. AB - How the brain works is nowadays synonymous with how different parts of the brain work together and the derivation of mathematical descriptions for the functional connectivity patterns that can be objectively derived from data of different neuroimaging techniques. In most cases static networks are studied, often relying on resting state recordings. Here, we present a quantitative study of dynamic reconfiguration of connectivity for event-related experiments. Our motivation is the development of a methodology that can be used for personalized monitoring of brain activity. In line with this motivation, we use data with visual stimuli from a typical subject that participated in different experiments that were previously analyzed with traditional methods. The earlier studies identified well defined changes in specific brain areas at specific latencies related to attention, properties of stimuli, and tasks demands. Using a recently introduced methodology, we track the event-related changes in network organization, at source space level, thus providing a more global and complete view of the stages of processing associated with the regional changes in activity. The results suggest the time evolving modularity as an additional brain code that is accessible with noninvasive means and hence available for personalized monitoring and clinical applications. PMID- 23097679 TI - Reliability of semiautomated computational methods for estimating tibiofemoral contact stress in the Multicenter Osteoarthritis Study. AB - Recent findings suggest that contact stress is a potent predictor of subsequent symptomatic osteoarthritis development in the knee. However, much larger numbers of knees (likely on the order of hundreds, if not thousands) need to be reliably analyzed to achieve the statistical power necessary to clarify this relationship. This study assessed the reliability of new semiautomated computational methods for estimating contact stress in knees from large population-based cohorts. Ten knees of subjects from the Multicenter Osteoarthritis Study were included. Bone surfaces were manually segmented from sequential 1.0 Tesla magnetic resonance imaging slices by three individuals on two nonconsecutive days. Four individuals then registered the resulting bone surfaces to corresponding bone edges on weight bearing radiographs, using a semi-automated algorithm. Discrete element analysis methods were used to estimate contact stress distributions for each knee. Segmentation and registration reliabilities (day-to-day and interrater) for peak and mean medial and lateral tibiofemoral contact stress were assessed with Shrout Fleiss intraclass correlation coefficients (ICCs). The segmentation and registration steps of the modeling approach were found to have excellent day-to day (ICC 0.93-0.99) and good inter-rater reliability (0.84-0.97). This approach for estimating compartment-specific tibiofemoral contact stress appears to be sufficiently reliable for use in large population-based cohorts. PMID- 23097680 TI - Genetic Deficiency of Complement Component 3 Does Not Alter Disease Progression in a Mouse Model of Huntington's Disease. AB - Several genes and proteins of the complement cascade are present at elevated levels in brains of patients with Huntington's disease (HD). The complement cascade is well characterized as an effector arm of the immune system, and in the brain it is important for developmental synapse elimination. We hypothesized that increased levels of complement in HD brains contributes to disease progression, perhaps by contributing to synapse elimination or inflammatory signaling. We tested this hypothesis in the R6/2 mouse model of HD by crossing mice deficient in complement component 3 (C3), a crucial complement protein found at increased levels in HD brains, to R6/2 mice and monitoring behavioral and neuropathological disease progression. We found no alterations in multiple behavioral assays, weight or survival in R6/2 mice lacking C3. We also quantified the expression of several complement cascade genes in R6/2 brains and found that the large scale upregulation of complement genes observed in HD brains is not mirrored in R6/2 brains. These data show that C3 deficiency does not alter disease progression in the R6/2 mouse model of HD. PMID- 23097681 TI - Simvastatin attenuates contrast-induced nephropathy through modulation of oxidative stress, proinflammatory myeloperoxidase, and nitric oxide. AB - Contrast media- (CM-) induced nephropathy is a serious complication of radiodiagnostic procedures. Available data suggests that the development of prophylaxis strategies is limited by poor understanding of pathophysiology of CM induced nephropathy. Present study was designed to determine the role of oxidative stress, myeloperoxidase, and nitric oxide in the pathogenesis of iohexol model of nephropathy and its modification with simvastatin (SSTN). Adult Sprague Dawley rats were divided into seven groups. After 24 h of water deprivation, all the rats except in control and SSTN-only groups were injected (10 ml/kg) with 25% glycerol. After 30 min, SSTN (15, 30, and 60 mg/kg) was administered orally, daily for 4 days. Twenty-four hours after the glycerol injection, iohexol was infused (8 ml/kg) through femoral vein over a period of 2 min. All the animals were sacrificed on day 5 and blood and kidneys were collected for biochemical and histological studies. The results showed that SSTN dose dependently attenuated CM-induced rise of creatinine, urea, and structural abnormalities suggesting its nephroprotective effect. A significant increase in oxidative stress (increased lipid hydroperoxides and reduced glutathione levels) and myeloperoxidase (MPO) and decreased nitric oxide in CM group were reversed by SSTN. These findings support the use of SSTN to combat CM-induced nephrotoxicity. PMID- 23097683 TI - Epigenetic Therapy in Breast Cancer. AB - Breast carcinogenesis is a multistep process involving both genetic and epigenetic changes. Epigenetics is defined as reversible changes in gene expression, not accompanied by alteration in gene sequence. DNA methylation, histone modification, and nucleosome remodeling are the major epigenetic changes that are dysregulated in breast cancer. Several genes involved in proliferation, anti-apoptosis, invasion, and metastasis have been shown to undergo epigenetic changes in breast cancer. Because epigenetic changes are potentially reversible processes, much effort has been directed toward understanding this mechanism with the goal of finding effective therapies that target these changes. Both demethylating agents and the histone deacetylase inhibitors (HDACi) are under investigation as single agents or in combination with other systemic therapies in the treatment of breast cancer. In this review, we discuss the role of epigenetic regulation in breast cancer, in particular focusing on the clinical trials using therapies that modulate epigenetic mechanisms. PMID- 23097682 TI - Study of alphaB-crystallin expression in Gerbil BCAO model of transient global cerebral ischemia. AB - alphaB-crystallin (alpha-BC), the fifth member of mammalian small heat shock protein family (HspB5), is known to be expressed in many tissues and has a distinctive interaction with cytoskeleton components. In this study, we investigated that alpha-BC and microtubule-associated protein-2 (MAP-2), a neuron specific cytoskeleton protein, were coexpressed in neurons of Gerbil cortex, while in subcortex Gerbil brains, we found that several MAP-2-negative glia cells also express alpha-BC. When subjected to 10-minute bilateral carotid artery occlusion (BCAO), an increment was observed in alpha-BC-positive cells after 6 hour reperfusion and peaked at around 7 days after. In the same circumstances, the number and the staining concentration of MAP-2 positive neurons significantly decreased immediately after 6-hour reperfusion, followed by a slow recovery, which is consistent with the increase of alpha-BC. Our results suggested that alpha-BC plays an important role in brain ischemia, providing the early protection of neurons by giving intracellular supports through the maintenance of cytoskeleton and extracellular supports through the protection of glia cells. PMID- 23097684 TI - Regulation of DNA damage following termination of Hedgehog (HH) survival signaling at the level of the GLI genes in human colon cancer. AB - Transcriptional regulation of the Hedgehog (HH) signaling response is mediated by GLI genes (GLI1, GLI2) downstream of SMO, that are also activated by oncogenic signaling pathways. We have demonstrated the importance of targeting GLI downstream of SMO in the induction of cell death in human colon carcinoma cells. In HT29 cells inhibition of GLI1/GLI2 by the small molecule inhibitor GANT61 induced DNA double strand breaks (DSBs) and activation of ATM, MDC1 and NBS1; gammaH2AX and MDC1, NBS1 and MDC1 co-localized in nuclear foci. Early activation of ATM was decreased by 24 hr, when p-NBS1(Ser343), activated by ATM, was significantly reduced in cell extracts. Bound gammaH2AX was detected in isolated chromatin fractions or nuclei during DNA damage but not during DNA repair. MDC1 was tightly bound to chromatin at 32 hr as cells accumulated in early S-phase prior to becoming subG1, and during DNA repair. Limited binding of NBS1 was detected at all times during DNA damage but was strongly bound during DNA repair. Transient overexpression of NBS1 protected HT29 cells from GANT61-induced cell death, while knockdown of H2AX by H2AXshRNA delayed DNA damage signaling. Data demonstrate following GLI1/GLI2 inhibition: 1) induction of DNA damage in cells that are also resistant to SMO inhibitors, 2) dynamic interactions between gammaH2AX, MDC1 and NBS1 in single cell nuclei and in isolated chromatin fractions, 3) expression and chromatin binding properties of key mediator proteins that mark DNA damage or DNA repair, and 4) the importance of NBS1 in the DNA damage response mechanism. PMID- 23097686 TI - Nanoscale interference patterns of gap-mode multipolar plasmonic fields. AB - Arbitrary spatial distributions of the electric field of light are formed through the interference of individual wavenumber mode fields with appropriate amplitudes and phases, while the maximum wavenumber in the far field is limited by the wavelength of light. In contrast, localized surface plasmons (LSPs) possess the ability to confine photons strongly into nanometer-scale areas, exceeding the diffraction limit. In particular, gap-mode LSPs produce single-nanometer-sized, highly intense localized fields, known as hot spots. Here, we show the nanoscale spatial profiles of the LSP fields within hot spots, which exhibit complicated fine structures, rather than single peaks. The nanopatterns are created by constructive and destructive interferences of dipolar, quadrupolar, and higher order multipolar plasmonic modes, which can be drastically altered by controlling parameters of the excitation optical system. The analysis in this study would be useful for proposing new concepts for manipulation and control of light-matter interactions in nanospaces. PMID- 23097685 TI - The connection between lymphangiogenic signalling and prostaglandin biology: a missing link in the metastatic pathway. AB - Substantial evidence supports important independent roles for lymphangiogenic growth factor signaling and prostaglandins in the metastatic spread of cancer. The significance of the lymphangiogenic growth factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, is well established in animal models of metastasis, and a strong correlation exits between an increase in expression of VEGF-C and VEGF-D, and metastatic spread in various solid human cancers. Similarly, key enzymes that control the production of prostaglandins, cyclooxygenases (COX-1 and COX-2, prototypic targets of Non-steroidal anti inflammatory drugs (NSAIDs)), are frequently over-expressed or de-regulated in the progression of cancer. Recent data have suggested an intersection of lymphangiogenic growth factor signaling and the prostaglandin pathways in the control of metastatic spread via the lymphatic vasculature. Furthermore, this correlates with current clinical data showing that some NSAIDs enhance the survival of cancer patients through reducing metastasis. Here, we discuss the potential biochemical and cellular basis for such anti-cancer effects of NSAIDs through the prostaglandin and VEGF signaling pathways. PMID- 23097687 TI - 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? AB - We have interrogated a 12-chemokine gene expression signature (GES) on genomic arrays of 14,492 distinct solid tumors and show broad distribution across different histologies. We hypothesized that this 12-chemokine GES might accurately predict a unique intratumoral immune reaction in stage IV (non locoregional) melanoma metastases. The 12-chemokine GES predicted the presence of unique, lymph node-like structures, containing CD20+ B cell follicles with prominent areas of CD3+ T cells (both CD4+ and CD8+ subsets). CD86+, but not FoxP3+, cells were present within these unique structures as well. The direct correlation between the 12-chemokine GES score and the presence of unique, lymph nodal structures was also associated with better overall survival of the subset of melanoma patients. The use of this novel 12-chemokine GES may reveal basic information on in situ mechanisms of the anti-tumor immune response, potentially leading to improvements in the identification and selection of melanoma patients most suitable for immunotherapy. PMID- 23097688 TI - Polymer-drug conjugates for intracellar molecule-targeted photoinduced inactivation of protein and growth inhibition of cancer cells. AB - For most molecule-targeted anticancer systems, intracellular protein targets are very difficult to be accessed by antibodies, and also most efforts are made to inhibit protein activity temporarily rather than inactivate them permanently. In this work we firstly designed and synthesized multifunctional polymer-drug conjugates (polythiophene-tamoxifen) for intracellular molecule-targeted binding and inactivation of protein (estrogen receptor alpha, ERalpha) for growth inhibition of MCF-7 cancer cells. Small molecule drug was conjugated to polymer side chain for intracellular signal protein targeting, and simultaneously the fluorescent characteristic of polymer for tracing the cellular uptake and localization of polythiophene-drug conjugates by cell imaging. Under light irradiation, the conjugated polymer can sensitize oxygen to produce reactive oxygen species (ROS) that specifically inactivate the targeted protein, and thus inhibit the growth of tumor cells. The conjugates showed selective growth inhibition of ERalpha positive cancer cells, which exhibits low side effect for our intracellular molecule-targeted therapy system. PMID- 23097689 TI - Multifunctional, supramolecular, continuous artificial nacre fibres. AB - Nature has created amazing materials during the process of evolution, inspiring scientists to studiously mimic them. Nacre is of particular interest, and it has been studied for more than half-century for its strong, stiff, and tough attributes resulting from the recognized "brick-and-mortar" (B&M) layered structure comprised of inorganic aragonite platelets and biomacromolecules. The past two decades have witnessed great advances in nacre-mimetic composites, but they are solely limited in films with finite size (centimetre-scale). To realize the adream target of continuous nacre-mimics with perfect structures is still a great challenge unresolved. Here, we present a simple and scalable strategy to produce bio-mimic continuous fibres with B&M structures of alternating graphene sheets and hyperbranched polyglycerol (HPG) binders via wet-spinning assembly technology. The resulting macroscopic supramolecular fibres exhibit excellent mechanical properties comparable or even superior to nacre and bone, and possess fine electrical conductivity and outstanding corrosion-resistance. PMID- 23097690 TI - Tricuspid valve regurgitation after orthotopic heart transplantation: prevalence and etiology. AB - Background. Tricuspid valve regurgitation (TR) after orthotopic heart transplantation (OHT) is common. The aims of this study were to determine the prevalence of TR after OHT, to examine the correlation between its development and various variables, and to determine its outcomes. Methods. All 163 OHT patients who were followed up between 1988 and 2009 for a minimal period of 12 months were divided into those with no TR/mild TR and those with at least mild moderate TR, as assessed by doppler echocardiography. These groups were compared regarding preoperative hemodynamic variables, surgical technique employed, number of endomyocardial biopsies, number of acute cellular rejections, incidence of graft vasculopathy, and clinical outcomes. Results. At the end of the followup (average 8.2 years) significant TR was evident in 14.1% of the patients. The development of late TR was found by univariate, but not multivariate, analysis to be significantly correlated with the biatrial surgical technique (P < 0.01) and the presence of graft vasculopathy (P < 0.001). TR development was found to be correlated with the need for tricuspid valve surgery but not with an increased mortality. Conclusions. The development of TR after OHT may be related to the biatrial anastomosis technique and to graft vasculopathy. PMID- 23097691 TI - Incidence and Characteristics of Patients with Visual Impairment due to Macular Edema Secondary to Retinal Vein Occlusion in a Representative Canadian Cohort. AB - Retinal vein occlusion (RVO) is an obstruction of the retinal venous system, and macular edema (ME) is a complication of RVO that can lead to blindness. The Canadian incidence of visual impairment (VI) due to ME secondary to RVO is unknown. This observational, retrospective study used records from the Southwestern Ontario database to observe the annual incidence, demographics, and comorbidity characteristics of patients with VI due to ME secondary to RVO. From 47,166 patients, 73 with RVO (>40 years old) were identified: 53 with branch retinal vein occlusion (BRVO), 20 with central retinal vein occlusion (CRVO). The annual incidence of VI (visual acuity <20/40 in Snellen equivalent) due to ME secondary to BRVO was (mean (95%CI)) 0.056% (0.011-0.072), and to CRVO was 0.021% (0.008-0.081). Furthermore, a greater proportion of RVO patients had hypertension (68% versus 14%) or dyslipidemia (16% versus 10%), when compared to a healthy control cohort of 76,077 subjects (P < 0.05). This study presents a description of the characteristics of patients with VI due to ME secondary to RVO in a real world Canadian setting. The results demonstrate that BRVO was more frequent than CRVO, and that RVO in this patient population was associated with several vascular comorbidities. PMID- 23097692 TI - Smoking cessation intervention in a cardiovascular hospital based clinical setting. AB - Introduction. Smoking is a leading cause of morbidity and mortality globally and it is a significant modifiable risk factor for cardiovascular disease (CVD) and other chronic diseases. Efforts to encourage and support smokers to quit are critical to prevent premature smoking-associated morbidity and mortality. Hospital settings are seldom equipped to help patients to quit smoking thus missing out a valuable opportunity to support patients at risk of smoking complications. We report the impact of a smoking cessation clinic we have established in a tertiary care hospital setting to serve patients with CVD. Methods. Patients received behavioural and pharmacological treatments and were followed up for a minimum of 6 months (mean 541 days, SD 197 days). The main study outcome is >=50% reduction in number of cigarettes smoked at followup. Results. One hundred and eighty-six patients completed >=6 months followup. More than half of the patients (52.7%) achieved >=50% smoking reduction at follow up. Establishment of a plan to quit smoking and use of nicotine replacement therapy (NRT) were significantly associated with smoking reduction at followup. Conclusions. A hospital-based smoking cessation clinic is a beneficial intervention to bring about smoking reduction in approximately half of the patients. PMID- 23097693 TI - Genetically encoded libraries of nonstandard peptides. AB - The presence of a nonproteinogenic moiety in a nonstandard peptide often improves the biological properties of the peptide. Non-standard peptide libraries are therefore used to obtain valuable molecules for biological, therapeutic, and diagnostic applications. Highly diverse non-standard peptide libraries can be generated by chemically or enzymatically modifying standard peptide libraries synthesized by the ribosomal machinery, using posttranslational modifications. Alternatively, strategies for encoding non-proteinogenic amino acids into the genetic code have been developed for the direct ribosomal synthesis of non standard peptide libraries. In the strategies for genetic code expansion, non proteinogenic amino acids are assigned to the nonsense codons or 4-base codons in order to add these amino acids to the universal genetic code. In contrast, in the strategies for genetic code reprogramming, some proteinogenic amino acids are erased from the genetic code and non-proteinogenic amino acids are reassigned to the blank codons. Here, we discuss the generation of genetically encoded non standard peptide libraries using these strategies and also review recent applications of these libraries to the selection of functional non-standard peptides. PMID- 23097694 TI - Evaluation of ENA-6 Profile by ELISA Immunoassay in Patients with Systemic Lupus Erythematodes. AB - Autoimmune diseases occur in 3-5% of the population. Study included 30 patients with clinically diagnosed SLE and 30 healthy controls (American college of Rheumatology, 1997). SLE was diagnosed according to criteria issued in 1997 by the American College of Rheumatology (ACR). The aim of this study was to evaluate concentration values of each antigen of ENA-6 profile in SLE, to investigate possible correlation between the concentration of Sm antibodies and CIC, and to test their use as possible immunobiological markers in SLE. Furthermore, the aim of our study was to determine whether there is a correlation between Sm antibodies and CIC and SLE activity. The results revealed that all of these ENA-6 and Sm antibodies as biomarkers complement diagnoses of active SLE but their use as solo markers does not allow classifying patients with SLE. Our study has shown that based on calculations from ROC curves, Sm/RNP was clearly a very important marker for diagnosis of SLE (cut off >= 9.56 EU, AUC 0,942). The high incidence of Scl-70 (10%) reactivity suggests that ELISA monitoring of this antibody produces more false positive results than other multiplex assay. An important conclusion that can be drawn from the results of our study is that laboratory tests are no more effective than clinical examination for detecting disease relapse, but are helpful in the confirmation of SLE activity. PMID- 23097695 TI - Medium- and short-term interventions with ma-pi 2 macrobiotic diet in type 2 diabetic adults of bauta, havana. AB - Background. In Cuba, the Ma-Pi 2 macrobiotic diet has shown positive results in 6 month assays with type 2 diabetic patients. The objective of this study was to assess the influence of this diet at short and medium terms. Methods. Sixty-five type 2 diabetic volunteers were included for dietary intervention, institutionally based for 21 days and followed later at home, until completing 3 months. 54 of them stayed until assay end. Before intervention, and after both assay periods, they were submitted to anthropometric records, body composition analyses and measurements of serum biochemical indicators, glycemic profile in capillary blood, blood pressure, and medication consumption; food intake was evaluated by the 3-day dietary recall. Results. During the intervention, the energy intake was 200 kcal higher at instance of more complex carbohydrates and dietary fiber and despite less fat and protein. Blood pressure and serum biochemical indicators decreased significantly in both periods; the safety nutritional indicators (hemoglobin, serum total proteins, and albumin) showed no variations. The global cardiovascular risk decreased and insulin consumption dropped by 46% and 64%, in both periods, respectively. Conclusions. The Ma-Pi 2 macrobiotic diet was a successful therapy at short term and after 3-month home based intervention, for type 2 diabetics. PMID- 23097696 TI - The role of anticoagulation clinics in the era of new oral anticoagulants. AB - Anticoagulation Clinics (ACs) are services specialized in management of patients on anticoagulant treatment. At present, ACs manage patients chiefly on antivitamin K antagonists (AVKs), but patient population has already changed in the last few years, because of an increase of treatments with other anticoagulant drugs, which require different management systems. The strong increase in the number of patients at AC, mainly on long-term treatment, has determined the development of web management, through telemedicine systems, improving the quality of life and maintaining the same clinical quality levels. New oral anticoagulants (NOAs) have shown to be as effective as AVK antagonists in stroke prevention in atrial fibrillation and for treatment of venous thromboembolism in addition to VTE prophylaxis in orthopaedic surgery, when administered at a fixed dose, but patient adherence and compliance are crucial for good quality treatment. At present, lacking data from the real world, an oversimplification of treatment with NOAs could cause unjustified risks for patients and also a possible future underuse of good drugs. For these reasons the vigilance must be high and ACs can have a crucial role in defining which is the best management for NOA patients and how to do it, as it happened for AVKs. PMID- 23097697 TI - Levels of Ca(V)1.2 L-Type Ca(2+) Channels Peak in the First Two Weeks in Rat Hippocampus Whereas Ca(V)1.3 Channels Steadily Increase through Development. AB - Influx of calcium through voltage-dependent channels regulates processes throughout the nervous system. Specifically, influx through L-type channels plays a variety of roles in early neuronal development and is commonly modulated by G protein-coupled receptors such as GABA(B) receptors. Of the four isoforms of L type channels, only Ca(V)1.2 and Ca(V)1.3 are predominately expressed in the nervous system. Both isoforms are inhibited by the same pharmacological agents, so it has been difficult to determine the role of specific isoforms in physiological processes. In the present study, Western blot analysis and confocal microscopy were utilized to study developmental expression levels and patterns of Ca(V)1.2 and Ca(V)1.3 in the CA1 region of rat hippocampus. Steady-state expression of Ca(V)1.2 predominated during the early neonatal period decreasing by day 12. Steady-state expression of Ca(V)1.3 was low at birth and gradually rose to adult levels by postnatal day 15. In immunohistochemical studies, antibodies against Ca(V)1.2 and Ca(V)1.3 demonstrated the highest intensity of labeling in the proximal dendrites at all ages studied (P1-72). Immunohistochemical studies on one-week-old hippocampi demonstrated significantly more colocalization of GABA(B) receptors with Ca(V)1.2 than with Ca(V)1.3, suggesting that modulation of L-type calcium current in early development is mediated through Ca(V)1.2 channels. PMID- 23097699 TI - Microradiography of microcalcifications in breast specimen: a new histological correlation procedure and the effect of improved resolution on diagnostic validity. AB - Introduction. Does high-resolution visualization of microcalcifications improve diagnostic reliability? Method. X-rays were taken of mamma specimens with microcalcifications in 32 patients (10 malignant; 22 benign) using conventional radiography (12 Lp/mm) and high-resolution radiography (2000 Lp/mm). Histological sections were subsequently prepared and correlated to the microradiographic image and every calcification was assigned an exact malignant or benign histological diagnosis. Five radiologists classified single groups of calcifications in both methods according to the BIRADS classification system. Results. Using microradiography microcalcifications can be shown in high resolution at the cell level including histological correlation. In some cases, the diagnostic validity was improved by the high resolution in microradiography. In other cases, the high resolution resulted in more visible calcifications, thus giving benign calcifications a malignant appearance. In the BIRADS 2 and 3 group, the probability of malignancy was 28.6% in the conventional radiography evaluation and 37.8% in the microradiography evaluation. In the BIRADS 4 and 5 group, the probability of malignancy was 34.2% in the conventional radiography evaluation and 24.4% in the microradiography evaluation. The differences were not significant. Summary. Overall, the improved resolution in microradiography did not show an improvement in diagnostic accuracy compared to conventional radiography. PMID- 23097698 TI - Respiratory Consequences of Mild-to-Moderate Obesity: Impact on Exercise Performance in Health and in Chronic Obstructive Pulmonary Disease. AB - In many parts of the world, the prevalence of obesity is increasing at an alarming rate. The association between obesity, multiple comorbidities, and increased mortality is now firmly established in many epidemiological studies. However, the link between obesity and exercise intolerance is less well studied and is the focus of this paper. Although exercise limitation is likely to be multifactorial in obesity, it is widely believed that the respiratory mechanical constraints and the attendant dyspnea are important contributors. In this paper, we examined the evidence that critical ventilatory constraint is a proximate source of exercise limitation in individuals with mild-to-moderate obesity. We first reviewed existing information on exercise performance, including ventilatory and perceptual response patterns, in obese individuals who are otherwise healthy. We then considered the impact of obesity in patients with preexisting respiratory mechanical abnormalities due to chronic obstructive pulmonary disease (COPD), with particular reference to the effect on dyspnea and exercise performance. Our main conclusion, based on the existing and rather sparse literature on the subject, is that abnormalities of dynamic respiratory mechanics are not likely to be the dominant source of dyspnea and exercise intolerance in otherwise healthy individuals or in patients with COPD with mild to-moderate obesity. PMID- 23097700 TI - Invalidity of SUV Measurements of Lesions in Close Proximity to Hot Sources due to "Shine-Through" Effect on FDG PET-CT Interpretation. AB - It is well known that many technical and physiologic factors can affect the reliability of the standardized uptake value (SUV) on FDG PET-CT. Another potential problem of which we may be aware but has not been previously discussed is significant SUV overestimation of lesions in the direct neighborhood of large hot sources, namely, areas with high FDG uptake or activity such as a tumor, myocardium, urinary bladder, kidney, or gastrointestinal tract. The magnitude of SUV overestimation of the lesions directly neighboring the large hot sources is varied among the different cases, and it is possibly secondary to "shine-through" effect of the hot sources, which would warrant further systematic investigation such as phantom simulation experiment. If the lesion is in the close territory of the hot source, measured SUV is often overestimated and invalid. Visual interpretation should be used for evaluation of FDG avidity of the lesion. PMID- 23097701 TI - Usefulness of patients-reported outcomes in rheumatoid arthritis focus group. AB - Objective. Patient-reported outcomes (PROs) have become an essential part of the assessment of patients with rheumatoid arthritis (RA). We aimed to evaluate the agreement and correlation between PROs and the physician's measurements. Methods. This was a cross-sectional analytical study in which 135 patients with RA were clinically evaluated during two different sessions of focus group interviews. Rheumatologist recorded 28 swollen (SJCs) and tender joint counts (TJCs). The patients filled out the PROs instruments (MDHAQ, RADAI, RAPID3, 4, and 5 and self report articular index (SAI) diagram for pain and joint swelling). DAS28 was calculated (C-reactive protein). An adjusted multiple lineal regression model was done (DAS28 as dependent variable). Results. Highly significant agreements were found between SJC and TJC registered by the physician and patient. There was moderate correlation between DAS28 with patient SJC (r = 0.52), patient TJC (r = 0.55), RADAI (r = 0.56), RAPID3 (r = 0.52), RAPID4 (r = 0.56), RAPID5 (r = 0.66), and VAS-Global (r = 0.51). Likewise, we found moderate to high correlations between CDAI and SDAI with all variable measurements done by the patients. The resulting predictive equation was DAS28(CRP) = 2.02 + 0.037 * RAPID4 + 0.042* patient SJC. Conclusion. PROs applied in focus groups interview are a useful tool for managing patients with RA regardless of gender, educational level, and duration of disease. PMID- 23097702 TI - Novel drugs targeting the epidermal growth factor receptor and its downstream pathways in the treatment of colorectal cancer: a systematic review. AB - Colorectal cancer is the second most common malignancy among men and women in the United States, and the 5-year survival rate remains poor despite recent advances in chemotherapy and targeted agents. The mainstay of therapy for advanced disease remains the cytotoxic chemotherapy including 5-FU, irinotecan, and oxaliplatin. The USFDA approval and introduction of targeted therapies, including cetuximab and panitumumab (monoclonal antibodies targeting the epidermal growth factor receptor (EGFR)) and bevacizumab (monoclonal antibody targeting the vascular epithelial growth factor (VEGF)), has improved the median survival of patients with metastatic colorectal cancer to around 24 months. Clearly, better and more efficacious drugs are needed, and target-specific agents remain the future of cancer treatment. On this front, rapid advances are being made, which are likely to change the future of the management of metastatic colorectal cancer. However, absence of specific biomarkers for the use of targeted agents, in the subset of population who will benefit from the treatment, remains a major drawback. In this paper, we review agents that are in phases 1 and 2 clinical development, specifically targeting the EGFR and its subsequent downstream pathways. PMID- 23097704 TI - Neurological emergencies. PMID- 23097703 TI - The influence of endothelial function and myocardial ischemia on peak oxygen consumption in patients with coronary artery disease. AB - Impaired endothelial function has been shown to limit exercise in coronary artery disease (CAD) patients and has been implicated in myocardial ischemia. However, the association of endothelial function and ischemia on peak exercise oxygen consumption (VO(2)) has not been previously reported. A total of 116 CAD patients underwent standard exercise stress testing, during which VO(2) was measured. On a separate day, endothelial-dependent and -independent function were assessed by ultrasound using flow-mediated arterial vasodilation (FMD) and sublingual glyceryl trinitrate administration (GTNMD) of the brachial artery. Patients with exercise-induced myocardial ischemia had lower FMD than nonischemic patients (3.64 +/- 0.57 versus 4.98 +/- 0.36, P = .050), but there was no difference in GTNMD (14.11 +/- 0.99 versus 15.47 +/- 0.63, P = .249). Analyses revealed that both FMD (P = .006) and GTNMD (P = .019) were related to peak VO(2). However, neither the presence of ischemia (P = .860) nor the interaction of ischemia with FMD (P = .382) and GTNMD (P = .151) was related to peak VO(2). These data suggest that poor endothelial function, potentially via impaired NO production and smooth muscle dysfunction, may be an important determinant of exercise capacity in patients with CAD, independent of myocardial ischemia. PMID- 23097705 TI - Mild brain injury. PMID- 23097706 TI - The Role of HLA in Cord Blood Transplantation. AB - In recent years, umbilical cord blood (CB), a rich source of hematopoietic stem cells (HSC), has been used successfully as an alternative HSC source to treat a variety of hematologic, immunologic, genetic, and oncologic disorders. CB has several advantages, including prompt availability of the transplant, decrease of graft versus host disease (GVHD) and better long-term immune recovery, resulting in a similar long-term survival. Studies have shown that some degree of HLA mismatches is acceptable. This review is intended to outline the main aspects of HLA matching in different settings (related, pediatric, adult, or double-unit HSCT), its effect on transplantation outcome and the role of HLA in donor selection. PMID- 23097708 TI - Understanding Viral Transmission Behavior via Protein Intrinsic Disorder Prediction: Coronaviruses. AB - Besides being a common threat to farm animals and poultry, coronavirus (CoV) was responsible for the human severe acute respiratory syndrome (SARS) epidemic in 2002-4. However, many aspects of CoV behavior, including modes of its transmission, are yet to be fully understood. We show that the amount and the peculiarities of distribution of the protein intrinsic disorder in the viral shell can be used for the efficient analysis of the behavior and transmission modes of CoV. The proposed model allows categorization of the various CoVs by the peculiarities of disorder distribution in their membrane (M) and nucleocapsid (N). This categorization enables quick identification of viruses with similar behaviors in transmission, regardless of genetic proximity. Based on this analysis, an empirical model for predicting the viral transmission behavior is developed. This model is able to explain some behavioral aspects of important coronaviruses that previously were not fully understood. The new predictor can be a useful tool for better epidemiological, clinical, and structural understanding of behavior of both newly emerging viruses and viruses that have been known for a long time. A potentially new vaccine strategy could involve searches for viral strains that are characterized by the evolutionary misfit between the peculiarities of the disorder distribution in their shells and their behavior. PMID- 23097707 TI - Controversies and recent advances in hematopoietic cell transplantation for follicular non-hodgkin lymphoma. AB - Commonly designated as an indolent non-Hodgkin lymphoma, follicular lymphoma (FL) presents with striking pathobiological and clinical heterogeneity. Initial management strategies for FL have evolved to involve combination chemoimmunotherapy and/or radio-immunoconjugates. Unfortunately even with the best available nontransplant treatment, which nowadays results in higher frequency of response, FL remains incurable. Although considered a feasible therapeutic option, the use of hematopoietic cell transplantation (HCT) remains controversial. The appropriate timing, graft source, and intensity of HCT conditioning regimens in FL are often matters of debate. Herein we review the available published data pertaining to the use of autologous or allogeneic HCT in patients with FL across different stages of the disease, discuss major recent advances in the field, and highlight avenues for future research. The current literature does not support a role of HCT for FL in first remission, but in the relapsed setting autologous HCT remains appropriate for patients with early chemosensitive relapses, while allogeneic transplantation remains the sole curative modality for this disease, in relatively younger patients without significant comorbidities. PMID- 23097709 TI - Evaluating surveillance breast imaging and biopsy in older breast cancer survivors. AB - Background. Patterns of surveillance among breast cancer survivors are not well characterized and lack evidence-based practice guidelines, particularly for imaging modalities other than mammography. We characterized breast imaging and related biopsy longitudinally among breast cancer survivors in relation to women's characteristics. Methods. Using data from a state-wide (New Hampshire) breast cancer screening registry linked to Medicare claims, we examined use of mammography, ultrasound (US), magnetic resonance imaging (MRI), and biopsy among breast cancer survivors. We used generalized estimating equations (GEE) to model associations of breast surveillance with women's characteristics. Results. The proportion of women with mammography was high over the follow-up period (81.5% at 78 months), but use of US or MRI was much lower (8.0%-first follow-up window, 4.7% by 78 months). Biopsy use was consistent throughout surveillance periods (7.4%-9.4%). Surveillance was lower among older women and for those with a higher stage of diagnosis. Primary therapy was significantly associated with greater likelihood of breast surveillance. Conclusions. Breast cancer surveillance patterns for mammography, US, MRI, and related biopsy seem to be associated with age, stage, and treatment, but need a larger evidence-base for clinical recommendations. PMID- 23097710 TI - Comparison of the subgross distribution of the lesions in invasive ductal and lobular carcinomas of the breast: a large-format histology study. AB - To compare the lesion distribution and the extent of the disease in ductal and lobular carcinomas of the breast, we studied 586 ductal and 133 lobular consecutive cancers. All cases were documented on large-format histology slides. The invasive component of ductal carcinomas was unifocal in 63.3% (371/586), multifocal in 35.5% (208/586), and diffuse in 1.2% (7/586) of the cases. The corresponding figures in the lobular group were 27.8% (37/133), 45.9% (61/586), and 26.3% (35/133), respectively. When the distribution of the in situ and invasive component in the same tumors was combined to give an aggregate pattern, the ductal carcinomas were unifocal in 41.6% (244/586), multifocal in 31.6% (185/586), and diffuse in 26.8% (157/586) of the cases. The corresponding figures in the lobular category were 15.0% (20/133), 54.2% (72/133), and 30.8% (41/133), respectively. Ductal cancers were extensive in 45.7% (268/586), lobular in 65.4% (87/133) of the cases. All these differences were statistically highly significant (P < 0.0001). While the histological tumor type itself (ductal versus lobular) did not influence the lymph node status, multifocal and diffuse distribution of the lesions were associated with significantly increased risk of lymph node metastases in both ductal and lobular cancers. PMID- 23097711 TI - Etiology and management of hemorrhagic complications of portal hypertension in children. AB - PORTAL HYPERTENSION IN CHILDREN REPRESENTS A PARTICULAR DIAGNOSTIC AND MANAGEMENT CHALLENGE FOR SEVERAL REASONS: (1) treatment outcomes should be evaluated in relationship with a long-life expectancy, (2) pediatric patients with portal hypertension constitute an heterogeneous population, both in terms of individual characteristics and diversity of liver diseases; making comparison between treatment outcomes very difficult, (3) application of techniques and procedures developed in adult patients (v.gr. TIPS) face size limitations in small children, and (4) absence of data from well-controlled trials in children forces pediatric specialists to adapt results obtained from adult cohorts suffering from diseases such as HCV and alcoholic cirrhosis. Despite those limitations, substantial progress in the treatment of children with portal hypertension has been achieved in recent years, with better outcomes and survival. Two main factors influence our therapeutic decision: age of the patient and etiology of the liver disease. Therefore, diagnosis and treatment of complications of portal hypertension in children need to be described taking such factors into consideration. This paper summarizes current knowledge and expert opinion. PMID- 23097712 TI - Utility of First Trimester Ultrasonography before 11 Weeks of Gestation: A Retrospective Study. AB - We showed the utility of first trimester ultrasonography before 11 weeks of gestation for antenatal followup. We retrospectively analyzed 1295 records of patients who underwent first trimester ultrasonography (transvaginal/abdominal) in our antenatal clinic in Ankara, Turkey. Maternal age, parity, gestational age, and maternal gestational history were compared with ultrasonographic findings. Patients were divided into 12 groups based on ultrasonographic diagnoses in the first ultrasonographic scan, and called for a control examination within 10 days if the diagnostic findings were abnormal. The data were statistically analyzed using Kruskal-Wallis and chi-square tests. We noted 81.3% patients to have single, viable, intrauterine pregnancies, while 18.7% had abnormal or complicated pregnancies with uterine anomalies, ovarian cysts, fibroids, or subchorionic hematomas. Normal and anembryonic pregnancies had significantly lower median diagnostic period in the control ultrasonography than in the first examination. First trimester ultrasonography before 11 weeks of gestation is valuable in determining pregnancy outcomes. PMID- 23097713 TI - Unveiling New Molecular Factors Useful for Detection of Pelvic Inflammatory Disease due to Chlamydia trachomatis Infection. AB - Background. Untreated Chlamydia trachomatis infections in women can result in disease sequelae such as pelvic inflammatory disease (PID), ultimately culminating in tubal occlusion and infertility. While nucleic acid amplification tests can effectively diagnose uncomplicated lower genital tract infections, they are not suitable for diagnosing upper genital tract pathological sequelae. Objective. The purpose of this paper was to provide a comprehensive review of new molecular factors associated with the diagnosis and prognosis of PID. Material and Methods. The literature was searched using the key words "Chlamydia trachomatis infections," "pelvic inflammatory disease," and "molecular factors" in the PubMed database. Relevant articles published between 1996 and 2012 were evaluated. Conclusions. The use of new molecular factors could potentially facilitate earlier diagnosis and prognosis in women with PID due to C. trachomatis infection. PMID- 23097714 TI - Common Dermatoses in Children Referred to a Specialized Pediatric Dermatology Service in Mexico: A Comparative Study between Two Decades. AB - Background. Skin diseases among pediatric patients differ from those in adults. Epidemiological studies are scarce, and those performed in Mexican population date back thirty years. It is likely that these diseases might have changed their frequency. Material and Methods. Retrospective study in first-time patients referred to a pediatric dermatology service between January 1994 and December 2003. Demographics and diagnosis were recorded and compared with the results of a previous study performed in the same institution. Results. We included 5250 patients (52.55% female, 47.47% male) with 6029 diagnoses. The most frequent dermatoses found were atopic dermatitis (14.59%), viral warts (6.62%), acne (5.53%), pityriasis alba (3.98%), melanocytic nevi (3.85%), xerosis (3.57%), keratosis pilaris (3.19%), seborrheic dermatitis (2.37%), hemangioma (2.26%), and papular urticaria (2.24%). Most dermatoses increased their frequency when compared to the previous study. Conclusion. The frequency of pediatric dermatoses in our institution has changed in the last two decades. Environmental and sociocultural factors and institutional policies might account for these results. PMID- 23097715 TI - Translating community connectedness to practice: a qualitative study of midlevel health workers in rural guatemala. AB - Background. The performance of midlevel health workers is a critical lever for strengthening health systems and redressing inequalities in underserved areas. Auxiliary nurses form the largest cadre of health workers in Guatemala. In rural settings, they provide essential services to vulnerable communities, and thus have great potential to address priority health needs. This paper examines auxiliary nurses' motivation and satisfaction, and the coping strategies they use to respond to challenges they confront in their practice. Methods. Semistructured interviews were conducted with 14 auxiliary nurses delivering health services in Alta Verapaz, Guatemala. Results. Community connectedness was central to motivation in this rural Guatemalan setting. Participants were from rural communities and conveyed a sense of connection to the people they were serving through shared culture and their own experiences of health needs. Satisfaction was derived through recognition from the community and a sense of valuing their work. Auxiliary nurses described challenges commonly faced in low-resource settings. Findings indicated they were actively confronting these challenges through their own initiative. Conclusions. Strategies to support the performance of midlevel health workers should focus on mechanisms to make training accessible to rural residents, support problem-solving in practice, and emphasize building relationships with communities served. PMID- 23097716 TI - Depression in multiple sclerosis: a review of assessment and treatment approaches in adult and pediatric populations. AB - Multiple sclerosis is a chronic demyelinating disease affecting one million people worldwide, with a significant burden of psychiatric comorbidity. Depression is the commonest psychiatric manifestation but still remains largely underdiagnosed and undertreated. The present work reviews current knowledge on diagnosis, assessment, and somatic and psychotherapeutic treatment interventions for depression in adult and pediatric populations of patients with multiple sclerosis. PMID- 23097718 TI - Recent developments in home sleep-monitoring devices. AB - Improving our understanding of sleep physiology and pathophysiology is an important goal for both medical and general wellness reasons. Although the gold standard for assessing sleep remains the laboratory polysomnogram, there is an increasing interest in portable monitoring devices that provide the opportunity for assessing sleep in real-world environments such as the home. Portable devices allow repeated measurements, evaluation of temporal patterns, and self experimentation. We review recent developments in devices designed to monitor sleep-wake activity, as well as monitors designed for other purposes that could in principle be applied in the field of sleep (such as cardiac or respiratory sensing). As the body of supporting validation data grows, these devices hold promise for a variety of health and wellness goals. From a clinical and research standpoint, the capacity to obtain longitudinal sleep-wake data may improve disease phenotyping, individualized treatment decisions, and individualized health optimization. From a wellness standpoint, commercially available devices may allow individuals to track their own sleep with the goal of finding patterns and correlations with modifiable behaviors such as exercise, diet, and sleep aids. PMID- 23097720 TI - Clinical evaluation of a mobile heart rhythm telemonitoring system. AB - Purpose. To evaluate the clinical applicability of a telemonitoring system: telemetric system for collection and distant surveillance of medical information (TEMEO). Methods. We evaluated 60 patients, applying simultaneously standard Holter ECG and telemonitoring. Two different comparisons were performed: (1) TEMEO ECG with standard 12-lead ECG; (2) TEMEO Holter with standard ECG Holter. Results. We found a very high coincidence rate (99.3%) between TEMEO derived ECGs and standard ECGs. Intraclass correlation coefficient analysis revealed high and significant correlation coefficients regarding average, maximal, and minimal heart rate, % of time in tachycardia, single supraventricular ectopic beats (SVEB), and single and couplets of ventricular ectopic beats (VEB) between Holter ECG and TEMEO derived parameters. Couplets of SVEB were recorded as different by the two monitoring systems, however, with a borderline statistical significance. Conclusions. TEMEO derived ECGs have a very high coincidence rate with standard ECGs. TEMEO patient monitoring provides results that are similar to those derived from a standard Holter ECG. PMID- 23097717 TI - Innate immune regulation by toll-like receptors in the brain. AB - The innate immune system plays an important role in cerebral health and disease. In recent years the role of innate immune regulation by toll-like receptors in the brain has been highlighted. In this paper the expression of toll-like receptors and endogenous toll-like receptor ligands in the brain and their role in cerebral ischemia will be discussed. Further, the ability of systemic toll like receptor ligands to induce cerebral inflammation will be reviewed. Finally, the capacity of toll-like receptors to both increase (sensitization) and decrease (preconditioning/tolerance) the vulnerability of the brain to damage will be disclosed. Studies investigating the role of toll-like receptors in the developing brain will be emphasized. PMID- 23097721 TI - The sweet spot: continued search for the glycemic threshold for macrovascular disease-a retrospective single center experience. AB - Background. Atherosclerotic cardiovascular disease (ASCVD) is a common complication of diabetes mellitus and impaired fasting glucose (IFG). We hypothesized that the relation of fasting glucose levels to ASCVD is linear, with the prevalence of clinical ASCVD beginning to increase even among individuals currently categorized as normoglycemic. Methods. Patient charts were retrospectively reviewed from our Dyslipidemic Preventive Cardiology Clinic. We evaluated the prevalence of ASCVD relative to fasting glucose levels in a cross section of patients at high risk for ASCVD. Results. In 558 dyslipidemic patients, ASCVD prevalence increased with increasing fasting glucose levels. A significantly higher prevalence of ASCVD was observed among patients with fasting glucose levels between 90 and 99 mg/dL versus lower levels. As glucose levels increased from 90 to 125 mg/dL, the prevalence of ASCVD continued to rise in parallel. Logistic regression analysis with forward likelihood ratio stepwise selection indicated that individuals with fasting blood glucose of 90-99 mg/dL were 2.6 times more likely to have ASCVD than those with lower levels of fasting blood glucose. Conclusion. Our findings suggest that the current cutoff for impaired fasting glucose of 100 mg/dL may be somewhat conservative and that a level above 90 mg/dL may be more appropriate as an ASCVD risk factor, particularly in patients with a lipid disorder. PMID- 23097723 TI - Degradation Pathway for Eplerenone by Validated Stability Indicating UP-LC Method. AB - Degradation pathway for eplerenone is established as per ICH recommendations by validated and stability-indicating reverse phase liquid chromatographic method. Eplerenone is subjected to stress conditions of acid, base, oxidation, and thermal and photolysis. Significant degradation is observed in acid and base stress conditions. Four impurities are studied and the major degradant (RRT about 0.31) was identified by LC-MS and spectral analysis. The stress samples are assayed against a qualified reference standard and the mass balance is found close to 99.5%. Efficient chromatographic separation is achieved on a Waters symmetry C18 stationary phase with simple mobile phase combination delivered in gradient mode and quantification is carried at 240 nm at a flow rate of 1.0 mL min(-1). In the developed LC method the resolution between eplerenone and four potential impurities (imp-1, imp-2, imp-3, and imp-4) is found to be greater than 4.0. Regression analysis shows an r value (correlation coefficient) of greater than 0.999 for eplerenone and four potential impurities. This method is capable to detect the impurities of eplerenone at a level of 0.020% with respect to test concentration of 1.0 mg mL(-1) for a 20 MUL injection volume. The developed UPLC method is validated with respect to specificity, linearity and range, accuracy, precision, and robustness for impurities and assay determination. PMID- 23097722 TI - Inflammatory malignant fibrous histiocytoma associated with leukemoid reaction or leukocytosis: a comprehensive review. AB - Inflammatory malignant fibrous histiocytoma (IMFH) associated with leukemoid reaction (LR)/leukocytosis is a rare entity. In this paper, we search PubMed for all known cases of IMFH associated with LR/leukocytosis in an attempt to draw conclusions about this variant's response to treatments and its pathophysiology. Medline electronic database was searched using key words such as malignant fibrous histiocytoma, leukemoid reaction, and leukocytosis. A total of 16 patients were found, twelve males (75%) and 4 female (25%), with a mean age of 62.6 years, ranging from 47 to 77. The mean survival was 770 days, ranging from 14 to 6570 days. Four patients were alive at last follow-up: 6570 days, 1095 days, 335 days, and 180 days, respectively. Of the 12 patients that expired, death occurred approximately 92 days after the onset of LR or leukocytosis, ranging from 3 to 334 days. We conclude that IMFH associated with LR/leukocytosis does not completely respond to chemoradiation. Overproduction of growth factors and cytokines by IMFH cells and their interactions with the inflammatory infiltrate seem to promote immunological effector cell's dysfunction and substantiate the development and growth of this neoplasm. A clear understanding of these molecular pathways is crucial in order to identify targets for potential therapy. PMID- 23097724 TI - Regional aggressive root resorption caused by neuronal virus infection. AB - During orthodontic treatment, root resorption can occur unexplainably. No clear distinction has been made between resorption located within specific regions and resorption occurring generally in the dentition. The purpose is to present cases with idiopathic (of unknown origin) root resorption occurring regionally. Two cases of female patients, 26 and 28 years old, referred with aggressive root resorption were investigated clinically and radiographically. Anamnestic information revealed severe virus diseases during childhood, meningitis in one case and whooping cough in the other. One of the patients was treated with dental implants. Virus spreading along nerve paths is a possible explanation for the unexpected resorptions. In both cases, the resorptions began cervically. The extent of the resorption processes in the dentition followed the virus infected nerve paths and the resorption process stopped when reaching regions that were innervated differently and not infected by virus. In one case, histological examination revealed multinuclear dentinoclasts. The pattern of resorption in the two cases indicates that innervation is a factor, which under normal conditions may protect the root surface against resorption. Therefore, the normal nerve pattern is important for diagnostics and for predicting the course of severe unexpected root resorption. PMID- 23097725 TI - Focal bronchiectasis causing abnormal pulmonary radioiodine uptake in a patient with well-differentiated papillary thyroid carcinoma. AB - Background. False-positive pulmonary radioactive iodine uptake in the followup of differentiated thyroid carcinoma has been reported in patients with certain respiratory conditions. Patient Findings. We describe a case of well differentiated papillary thyroid carcinoma treated by total thyroidectomy and radioiodine ablation therapy. Postablation radioiodine whole body scan and subsequent diagnostic radioiodine whole body scans have shown persistent uptake in the left hemithorax despite an undetectable stimulated serum thyroglobulin in the absence of interfering thyroglobulin antibodies. Contrast-enhanced chest computed tomography has confirmed that the abnormal pulmonary radioiodine uptake correlates with focal bronchiectasis. Summary. Bronchiectasis can cause abnormal chest radioactive iodine uptake in the followup of differentiated thyroid carcinoma. Conclusions. Recognition of potential false-positive chest radioactive iodine uptake, simulating pulmonary metastases, is needed to avoid unnecessary exposure to further radiation from repeated therapeutic doses of radioactive iodine. PMID- 23097719 TI - Current perspectives on the neurobiology of drug addiction: a focus on genetics and factors regulating gene expression. AB - Drug addiction is a chronic, relapsing disorder defined by cyclic patterns of compulsive drug seeking and taking interspersed with episodes of abstinence. While genetic variability may increase the risk of addictive behaviours in an individual, exposure to a drug results in neuroadaptations in interconnected brain circuits which, in susceptible individuals, are believed to underlie the transition to, and maintenance of, an addicted state. These adaptations can occur at the cellular, molecular, or (epi)genetic level and are associated with synaptic plasticity and altered gene expression, the latter being mediated via both factors affecting translation (epigenetics) and transcription (non coding microRNAs) of the DNA or RNA itself. New advances using techniques such as optogenetics have the potential to increase our understanding of the microcircuitry mediating addictive behaviours. However, the processes leading to addiction are complex and multifactorial and thus we face a major contemporary challenge to elucidate the factors implicated in the development and maintenance of an addicted state. PMID- 23097726 TI - Adrenal Incidentalomas with Supraphysiologic Response to ACTH Stimulus: A Case Report. AB - We present the diagnostic approach of a patient with adrenal incidentalomas. A 72 year-old African American male had a CT scan of the abdomen showing right and left adrenal masses measuring 5 * 3.5 cm and 3.7 * 2.9 cm, respectively. The patient had negative hormonal workup. The radiologist insisted that the CT findings are consistent with adrenal hyperplasia, and therefore he underwent ACTH stimulation to rule out late-onset congenital adrenal hyperplasia (CAH). The stimulation test revealed that 17-hydroxyprogesterone and 11-deoxycortisol increased to levels high enough to confirm CAH, but cortisol had exaggerated response as well, thus making the diagnosis of CAH unlikely where metabolism is shifted to precursors. Subsequently, the patient underwent screening for Cushing's syndrome (CS) with a dexamethasone suppression test. Patient failed the suppresion test, raising the issue for subclinical CS (SCS), likely due to ACTH independent macronodular adrenal hyperplasia. Our patient had been diagnosed with MGUS and so far there are only 3 case reports of extramedullary plasmacytoma arising from the adrenals. One was bilateral and one had functional abnormalities. Our differential diagnosis includes subclinical CS with aberrant receptors versus a functioning extramedullary plasmacytoma. PMID- 23097727 TI - Placenta percreta invading broad ligament and parametrium in a woman with two previous cesarean sections: a case report. AB - Introduction. The incidence of placenta accreta has dramatically increased due to increasing caesarean section rate all over the world. Placenta percreta is the most severe form of placenta accretes. It frequently results in maternal morbidity and mortality mainly caused by massive obstetric hemorrhage or emergency hysterectomy. Percreta invading into the broad ligament has rarely been previously reported. Case presenting. We presented a case of placenta percreta invading left broad ligament and parametrium in a woman with two previous cesarean sections, which led to massive intraoperative hemorrhage during hysterectomy and transient ischemic encephalopathy. Conclusion. In cases of parametrial involvement, it would be more difficult to decide whether to remove placenta or leave it in site. In surgical removal neither local excision of placental bed and uterine repair nor traditional hysterectomy is adequate if parametrium invaded by placenta. We suggest delayed elective hysterectomy in such cases. So, pregnancy-induced pelvic congestion would be decreased, we can gather an expert team of gynecologists, urologists, and vascular surgeons, we could get plenty of blood products, and we may have the chance to administer methotrexate. PMID- 23097728 TI - Spontaneous Resolution of Mirror Syndrome following Demise of Hydropic Twin. AB - Maternal mirror syndrome is a rare consequence of fetal hydrops. By convention, delivery is recommended in pregnancies complicated by mirror syndrome due to grave fetal prognosis. We describe a case of a dichorionic, diamniotic twin gestation complicated by hydrops fetalis of twin B. The patient declined selective feticide. Two weeks later, intrauterine fetal demise of fetus B was diagnosed and complete resolution of mirror syndrome followed. Unaddressed, mirror syndrome can lead to significant maternal and fetal complications. This case illustrates resolution of mirror syndrome following spontaneous intrauterine demise of the hydropic fetus. PMID- 23097729 TI - Transorbital craniocerebral occult penetrating injury with cerebral abscess complication. AB - Transorbital intracranial penetrating injury is an uncommon mechanism of head injury. These injuries can be occult during the initial clinical presentation. Certain patients develop an intracranial cerebral infection. Herein, we report a 5-year-old child with an occult transorbital intracranial penetrating injury caused by a pen. A retained pen tip was found at the superior orbital roof and was not noticed at initial presentation. This was complicated by a right frontal lobe cerebral abscess. This paper emphasizes the importance of orbitocranial imaging in any penetrating orbital injury. A review of the literature on intracranial infection locations in relation to the route and mechanism of injury is included to complement this report. PMID- 23097731 TI - Ipsilateral rotational autokeratoplasty for the management of traumatic corneal scar. AB - A 40-years-old male patient with a corneal scar secondary to perforating eye injury had undergone ipsilateral rotational autokeratoplasty in our clinics. The corneal scar involved the pupillary area. The patient had a preoperative visual acuity of counting fingers. The patient's cornea was trephined with a 0.5 mm temporal decentration. The 8.0 mm autograft was rotated approximately 180 degrees to relocate the scar to the temporal aspect of the cornea. The final position of the corneal scar was temporal of the visual axis and central area was clear. The visual acuity at 1-, 3-, and 6-months followups was better than the first visual acuity in the patient. Ipsilateral rotational autokeratoplasty has many advantages over conventional keratoplasty. There is no risk of immunological rejection of the graft, postoperative corticosteroids are not needed as frequently, and donor cornea is not required. A rotational autograft can be a powerful alternative to conventional keratoplasty for some patients with traumatic corneal scars. PMID- 23097730 TI - Surgical Management of Pseudophakic Malignant Glaucoma via Anterior Segment Peripheral Iridectomy Capsulo-Hyaloidectomy and Anterior Vitrectomy. AB - Purpose. To describe our surgical technique in the management of pseudophakic malignant glaucoma refractory to conventional treatment. Methods. Two pseudophakic eyes with malignant glaucoma underwent peripheral iridectomy, lens capsulectomy, hyaloidectomy, and anterior vitrectomy through a clear corneal incision by using a vitreous cutter. Results. Prompt resolution of malignant glaucoma was achieved in both cases and no recurrence was observed during postoperative followup of five months. Conclusions. An anterior segment surgeon can treat pseudophakic malignant glaucoma successfully by using a vitreous cutter inserted through a corneal incision and performing peripheral iridectomy, capsulo hyaloidectomy, and anterior vitrectomy. PMID- 23097732 TI - Rhinosporidiosis: intraoperative cytological diagnosis in an unsuspected lesion. AB - Rhinosporidiosis is a disease endemic to South India, Sri Lanka and some areas of the African continent. The nasal lesions can sometimes be confused with nasopharyngeal malignancy. We report here a clinically unsuspected case of rhinosporidiosis, diagnosed correctly by intraoperative FNAC, and later confirmed by histopathological examination. PMID- 23097733 TI - Sclerosing stromal tumor of ovary: a case report. AB - Sclerosing stromal tumor (SST) is an extremely rare and distinctive sex cord stromal tumor which occurs predominantly in the second and third decades of life. We report a case of a 32-year-old woman who developed a sclerosing stromal tumor of ovary and presented with irregular menstruation and pelvic pain. Her hormonal status was normal but CA-125 was raised. She was suspected to have a malignant tumor on computed tomography and underwent bilateral salpingo-oopherectomy. It is therefore necessary to keep in mind the possibility of sclerosing stromal tumor in a young woman. PMID- 23097734 TI - Diagnosis of rosai-dorfman disease in elderly female on fine needle aspiration cytology: a case report. AB - Rosai-Dorfman disease (RDD) is a rare benign disorder of histiocytic proliferation that usually presents with bilateral cervical lymphadenopathy in children. We describe the case of a 50-year-old lady suffering from this disease who presented with generalized lymphadenopathy and a left sided chest wall lump. Fine needle aspiration cytology (FNAC) from all the lesions showed abundant benign histiocytes with lymphophagocytosis which was compatible with the diagnosis of RDD. This case is being reported for its rarity in presentation in an elderly female with both generalized nodal as well as extranodal manifestations. PMID- 23097735 TI - A rare chromosome 3 imbalance and its clinical implications. AB - The duplication of chromosome 3q is a rare disorder with varying chromosomal breakpoints and consequently symptoms. Even rarer is the unbalanced outcome from a parental inv(3) resulting in duplicated 3q and a deletion of 3p. Molecular karyotyping should aid in precisely determining the length and breakpoints of the 3q+/3p- so as to better understand a child's future development and needs. We report a case of an infant male with a 57.5 Mb duplication from 3q23-qter. This patient also has an accompanying 1.7 Mb deletion of 3p26.3. The duplicated segment in this patient encompasses the known critical region of 3q26.3-q27, which is implicated in the previously reported 3q dup syndrome; however, the accompanying 3p26.3 deletion is smaller than the previously reported cases. The clinical phenotype of this patient relates to previously reported cases of 3q+ that may suggest that the accompanying 1.7 Mb heterozygous deletion is not clinically relevant. Taken together, our data has refined the location and extent of the chromosome 3 imbalance, which will aid in better understanding the molecular underpinning of the 3q syndrome. PMID- 23097736 TI - ADHD, ODD, and CD: Do They Belong to a Common Psychopathological Spectrum? A Case Series. AB - Purpose of Research. Numerous studies have reported comorbidities, overlapping symptoms, and shared risk factors among cases of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). We present three adolescent males aged 13-16 years with conduct disorder having past history of ADHD and ODD. Principal Result. The symptom profile especially in domains of aggression, hostility, and emotionality as well as the manner of progression from ADHD to ODD and CD in the above cases shows a similar pattern. Conclusion. These common developmental pathways and overlapping symptoms suggest the possibility of a common psychopathological spectrum encompassing the three externalizing disorders. PMID- 23097737 TI - Intestinal infarction and portal vein thrombosis in a patient with henoch schonlein purpura. AB - Henoch Schonlein purpura is a systemic vasculitis that commonly affects children and teenagers but also affects adults of all ages. In most instances it has a benign course. Organ involvement, particularly in adults, and notably the kidneys and gastrointestinal tract may require therapeutic intervention and may have a less favorable outcome. We report a case of a 58-year-old man who presented with purpura and who rapidly developed catastrophic intestinal vasculitis, leading to his demise. PMID- 23097738 TI - Internal jugular vein entrapment in a multiple sclerosis patient. AB - We describe a multiple sclerosis patient presenting with compression of the internal jugular vein caused by aberrant omohyoid muscle. Previously this patient underwent balloon angioplasty of the same internal jugular vein. Ten months after this endovascular procedure, Doppler sonography revealed totally collapsed middle part of the treated vein with no outflow detected. Still, the vein widened and the flow was restored when the patient's mouth opened. Thus, the abnormality was likely to be caused by muscular compression. Surgical exploration confirmed that an atypical omohyoid muscle was squeezing the vein. Consequently, pathological muscle was transected. Sonographic control three weeks after surgical procedure revealed a decompressed vein with fully restored venous outflow. Although such a muscular compression can be successfully managed surgically, future research has to establish its clinical relevance. PMID- 23097739 TI - Virilisation during Pregnancy in a Patient with Metastatic Colorectal Cancer. AB - This paper describes the case of a 25-year-old woman with virilisation occurring during pregnancy in the presence of metastatic colorectal cancer. Virilisation during pregnancy is rare. The potential causes include adrenal, foetal, or ovarian pathologies. The most common causes during pregnancy are pregnancy luteoma and hyperreactio luteinalis. The incidence of cancer during pregnancy is rare and the incidence of colorectal cancer (CRC) in pregnancy is even rarer. The presenting signs and symptoms of CRC can be confused with symptoms commonly encountered during pregnancy, thereby delaying diagnosis and commencement of treatment. Diagnosis and staging also proves more problematic in the pregnant patient as the usual modalities of colonoscopy with biopsy and imaging with CT are relatively contraindicated. Treatment is dependent on gestational age of the foetus. There is currently no agreed best practice as to the role of prophylactic oophorectomy in the prevention of metachronous ovarian metastases. Surgical and adjuvant treatments have implications for females of child-bearing age. PMID- 23097740 TI - Trends in prevalence and mortality of dementia in elderly Hong Kong population: projections, disease burden, and implications for long-term care. AB - Background. We describe the trends in prevalence and mortality of dementia among older people in Hong Kong over time. Projections of the number of older people with dementia through 2039 and estimation of the disease burden are also included. Methods. Prevalence data were extracted from previous studies in Hong Kong. Mortality data were obtained from the Department of Health of Hong Kong. Projections of the number of people with dementia were calculated by applying the prevalence rates of dementia obtained from previous studies to Hong Kong population projections. The burden of dementia was measured by Disability Adjusted Life Years (DALYs). Results. The number of people aged 60 and above with dementia is projected to increase by 222%, from 103,433 in 2009 to 332,688 in 2039, with a large proportion of those living in institutions. The number of deaths due to dementia among people aged 60 and above has more than doubled between 2001 and 2009. Mortality rates for dementia have also risen. In 2006, about 286,313 DALYS were lost due to dementia. Conclusions. The information presented may be used to formulate a long-term care strategy for dementia of the ageing population in Hong Kong. PMID- 23097741 TI - Artesunate Exerts a Direct Effect on Endothelial Cell Activation and NF-kappaB Translocation in a Mechanism Independent of Plasmodium Killing. AB - Artemisinin and its derivates are an important class of antimalarial drug and are described to possess immunomodulatory activities. Few studies have addressed the effect of artesunate in the murine malaria model or its effect on host immune response during malaria infection. Herein, we study the effect of artesunate treatment and describe an auxiliary mechanism of artesunate in modulating the inflammatory response during experimental malaria infection in mice. Treatment with artesunate did not reduce significantly the parasitemia within 12 h, however, reduced BBB breakdown and TNF-alpha mRNA expression in the brain tissue of artesunate-treated mice. Conversely, mefloquine treatment was not able to alter clinical features. Notably, artesunate pretreatment failed to modulate the expression of LFA-1 in splenocytes stimulated with parasitized red blood cells (pRBCs) in vitro; however, it abrogated the expression of ICAM-1 in pRBC stimulated endothelial cells. Accordingly, a cytoadherence in vitro assay demonstrated that pRBCs did not adhere to artesunate-treated vascular endothelial cells. In addition, NF-kappaB nuclear translocation in endothelial cells stimulated with pRBCs was impaired by artesunate treatment. Our results suggest that artesunate is able to exert a protective effect against the P. berghei induced inflammatory response by inhibiting NF-kappaB nuclear translocation and the subsequent expression of ICAM-1. PMID- 23097742 TI - Insights to the evolution of Nucleobase-Ascorbate Transporters (NAT/NCS2 family) from the Cys-scanning analysis of xanthine permease XanQ. AB - The nucleobase-ascorbate transporter or nucleobase-cation symporter-2 (NAT/NCS2) family is one of the five known families of transporters that use nucleobases as their principal substrates and the only one that is evolutionarily conserved and widespread in all major taxa of organisms. The family is a typical paradigm of a group of related transporters for which conservation in sequence and overall structure correlates with high functional variations between homologs. Strikingly, the human homologs fail to recognize nucleobases or related cytotoxic compounds. This fact allows important biomedical perspectives for translation of structure-function knowledge on this family to the rational design of targeted antimicrobial purine-related drugs. To date, very few homologs have been characterized experimentally in detail and only two, the xanthine permease XanQ and the uric acid/xanthine permease UapA, have been studied extensively with site directed mutagenesis. Recently, the high-resolution structure of a related homolog, the uracil permease UraA, has been solved for the first time with crystallography. In this review, I summarize current knowledge and emphasize how the systematic Cys-scanning mutagenesis of XanQ, in conjunction with existing biochemical and genetic evidence for UapA and the x-ray structure of UraA, allow insight on the structure-function and evolutionary relationships of this important group of transporters. The review is organized in three parts referring to (I) the theory of use of Cys-scanning approaches in the study of membrane transporter families, (II) the state of the art with experimental knowledge and current research on the NAT/NCS2 family, (III) the perspectives derived from the Cys-scanning analysis of XanQ. PMID- 23097744 TI - Hydroxyl radical generation theory: a possible explanation of unexplained actions of mammalian catalase. AB - Catalase is well known antioxidant enzyme which catalyses the dissociation of hydrogen peroxide directly into H(2)O and O(2). Mammalian catalase has been considered as 'a venerable enzyme with new mysteries'. Some aspects of its mechanism of action are mystifying and many of new findings are still unexplained. To fill up the gap we propose the 'Hydroxyl Radical Generation Theory (HRGT)' with possible mechanism. According to HRGT, mammalian catalase apart from its known catalytic reaction generates hydroxyl radicals (HRs). The HR generation mainly depends on concentration of specific substrate, hydrogen peroxide. The present theory is supported by previous experimental findings and has great deal of observational evidences. The proposed mechanism of generation of HRs answer several unexplained features of mammalian catalase, however, should be tested further. PMID- 23097743 TI - Induction of cell senescence by targeting to Cullin-RING Ligases (CRLs) for effective cancer therapy. AB - Cullin-RING ligases (CRLs) are the biggest family of multiunit ubiquitin E3 ligases, controlling many biological processes by promoting the degradation of a broad spectrum of proteins associated with cell cycle, signal transduction and cell growth. The dysfunction of CRLs causes a lot of diseases including cancer, which meanwhile offers us a promising approach to cancer therapy by targeting to CRLs. Recent studies have demonstrated that genetic or pharmaceutical inactivation of CRLs often leads to cancer cell death by activating multiple cell killing pathways including senescence, an emerging anticancer mechanism of therapeutic agents. Here, we summarize the induction of cellular senescence and its mechanism of action, triggered by targeting to specific subunits of CRLs via multiple approaches including siRNA silencing, genetic knockout as well as small molecule inhibitor, exhibiting anticancer effect in vitro and in vivo. PMID- 23097745 TI - Human Organic Solute Transporter (hOST): protein interaction and membrane sorting process. AB - The human organic solute transporter (hOST) is a heterodimer composed of alpha and beta subunits. Physical association of hOSTalpha and beta subunits is essential for their polarized basolateral plasma membrane localization and function in the export of bile acids and steroids. To understand the role of carboxyl- and amino-tails of OSTbeta and mechanisms underlying membrane localization of hOST, the effects of tail deletion of the hOSTbeta subunit and biological reagents on membrane distribution and transport function of hOST were investigated in stably transfected MDCK cells. After deletion of 35 amino acids from the amino-tail of hOSTbeta, the efflux transport activity and polarized membrane distribution of the truncated hOSTbeta was abolished. A co immunoprecipitation study verified that the amino-tail of hOSTbeta is essential for the association with hOSTalpha subunit. Treatments with acytochalasin D (interrupting ctin-filaments), bafilomycin A1 (inhibiting vacuolar H(+)-ATPase), brefeldin A (disrupting the Golgi complex), and calphostin C (inhibiting protein kinase C), significantly disrupted the polarized membrane distribution of hOST and markedly reduced transport activity in stably transfected MDCK cells. In summary, the 35 amino acid amino-terminal fragment of hOSTbeta contains critical information for interaction with the hOSTalpha subunit and subsequent trafficking to the plasma membrane. These studies suggest that the membrane sorting process of hOST is mediated by a bafilomycin A1-sensitive vesicular pathway that is associated with the actin-cytoskeleton network. The membrane localization of hOST is also partially mediated through a brefeldin A sensitive mechanism, which controls its transit from the ER to Golgi and is regulated by PKC. PMID- 23097747 TI - Inhibition of catalytic activities of botulinum neurotoxin light chains of serotypes A, B and E by acetate, sulfate and calcium. AB - The catalytic domain, known as light chain (Lc), of the most poisonous botulinum neurotoxins (BoNTs), possesses endoprotease activity that triggers the ultimate poisonous effect to animals and humans. X-ray crystallographic structure of Lc of several BoNT serotypes has identified at least four small ligands at or near the respective active sites. They are sulfate ions in LcA, LcB, and LcE; an acetate ion in LcA; a calcium ion in LcB; and a potassium ion in LcD. Roles of these ligands on the structure and function of the proteins are not known. We have investigated the roles of sulfate, acetate, and calcium on the catalytic activities of LcA, LcB, and LcE using 17-35-residue synthetic peptide substrates. All three ligands inhibited all Lc activities. For LcA and LcB, the order of inhibition effectiveness was calcium>sulfate>acetate. The inhibition effectiveness expressed as IC(50), did not correlate with the occurrence or proximity of the ions to the active site. Moreover, addition of acetate or sulfate to LcA did not affect the near-UV circular dichroism spectra, tryptophan, and tyrosine fluorescence spectra, and mid points of thermal denaturation of LcA. Our results suggest that acetate, sulfate, and calcium nonspecifically interact with BoNT Lc, and their occurrence in the crystal structures could have been due to opportunistic binding to complementary pockets. PMID- 23097746 TI - Comparison of the functions of glutathionylspermidine synthetase/amidase from E. coli and its predicted homologues YgiC and YjfC. AB - Protein function prediction is very important in establishing the roles of various proteins in bacteria; however, some proteins in the E. coli genome have their function assigned based on low percent sequence homology that does not provide reliable assignments. We have made an attempt to verify the prediction that E. coli genes ygiC and yjfC encode proteins with the same function as glutathionylspermidine synthetase/amidase (GspSA). GspSA is a bifunctional enzyme that catalyzes the ATP-dependent formation and hydrolysis of glutathionylspermidine (G-Sp), a conjugate of glutathione (GSH) and spermidine. YgiC and YjfC proteins show 51% identity between themselves and 28% identity to the synthetase domain of the GspSA enzyme. YgiC and YjfC proteins were expressed and purified, and the properties of GspSA, YgiC, and YjfC were compared. In contrast to GspSA, proteins YgiC and YjfC did not bind to G-Sp immobilized on the affinity matrix. We demonstrated that all three proteins (GspSA, YgiC and YjfC) catalyze the hydrolysis of ATP; however, YgiC and YjfC cannot synthesize G-Sp, GSH, or GSH intermediates. gsp, ygiC, and yjfC genes were eliminated from the E. coli genome to test the ability of mutant strains to synthesize G-Sp conjugate. E. coli cells deficient in GspSA do not produce G-Sp while synthesis of the conjugate is not affected in DeltaygiC and DeltayjfC mutants. All together our results indicate that YgiC and YjfC are not glutathionylspermidine synthetases as predicted from the amino acid sequence analysis. PMID- 23097748 TI - Regulation of human organic anion transporter 4 by parathyroid hormone-related protein and protein kinase A. AB - Human organic anion transporter 4 (hOAT4) belongs to a family of organic anion transporters that play critical roles in the body disposition of clinically important drugs, including anti-human immunodeficiency virus therapeutics, anti tumor drugs, antibiotics, antihypertensives, and anti-inflammatories. hOAT4 is abundantly expressed in the kidney and placenta. In the current study, we examined the regulation of hOAT4 by parathyroid hormone-related protein (PTHrP) and protein kinase A (PKA) in kidney COS-7 cells. PTHrP induced a time- and concentration-dependent stimulation of hOAT4 transport activity. The stimulation of hOAT4 activity by PTHrP mainly resulted from an increased cell surface expression without a change in total cell expression of the transporter. Activation of PKA by Bt2-cAMP also resulted in a stimulation of hOAT4 activity through an increased cell surface expression of the transporter. However, PTHrP induced stimulation of hOAT4 activity could not be prevented by treating hOAT4 expressing cells with the PKA inhibitor H89. We concluded that both PTHrP and activation of PKA stimulate hOAT4 activity through redistribution of the transporter from intracellular compartments to the cell surface. However, PTHrP regulates hOAT4 activity by mechanisms independent of PKA pathway. PMID- 23097749 TI - Genetic Circuits in Salmonella typhimurium. AB - Synthetic biology has rapidly progressed over the past decade and is now positioned to impact important problems in health and energy. In the clinical arena, the field has thus far focused primarily on the use of bacteria and bacteriophages to overexpress therapeutic gene products. The next generation of multigene circuits will control the triggering, amplitude, and duration of therapeutic activity in vivo. This will require a host organism that is easy to genetically modify, leverages existing successful circuit designs, and has the potential for use in humans. Here, we show that gene circuits that were originally constructed and tested in Escherichia coli translate to Salmonella typhimurium, a therapeutically relevant microbe with attenuated strains that have exhibited safety in several human clinical trials. These strains are essentially nonvirulent, easy to genetically program, and specifically grow in tumor environments. Developing gene circuits on this platform could enhance our ability to bring sophisticated genetic programming to cancer therapy, setting the stage for a new generation of synthetic biology in clinically relevant microbes. PMID- 23097750 TI - In Vivo Gene Expression Dynamics of Tumor-Targeted Bacteria. AB - The engineering of bacteria to controllably deliver therapeutics is an attractive application for synthetic biology. While most synthetic gene networks have been explored within microbes, there is a need for further characterization of in vivo circuit behavior in the context of applications where the host microbes are actively being investigated for efficacy and safety, such as tumor drug delivery. One major hurdle is that culture-based selective pressures are absent in vivo, leading to strain-dependent instability of plasmid-based networks over time. Here, we experimentally characterize the dynamics of in vivo plasmid instability using attenuated strains of S. typhimurium and real-time monitoring of luminescent reporters. Computational modeling described the effects of growth rate and dosage on live-imaging signals generated by internal bacterial populations. This understanding will allow us to harness the transient nature of plasmid-based networks to create tunable temporal release profiles that reduce dosage requirements and increase the safety of bacterial therapies. PMID- 23097751 TI - Pregnancy amelioration of arthritis in SKG mice corresponds with alterations in serum amyloid A3 levels. AB - OBJECTIVES: Pregnancy leads to rheumatoid arthritis remission in humans. The objective of this study was to determine if the SKG mouse could serve as a model for pregnancy-associated inflammatory arthritis amelioration. In addition, the maternal peripheral blood mononuclear cell (PBMC) transcriptome was assessed to define a biomarker associated with remission. METHODS: Cohorts of zymosan treated pregnant SKG mice and controls were monitored for arthritis progression. Microarray analysis evaluated alterations in gene expression in maternal PBMCs at embryonic day 14.5 (E14.5) between arthritic and pregnancy-remitted mice. A selected target, serum amyloid A3 (SAA3), was further investigated using quantitative reverse transcriptase PCR (qRT-PCR) and an enzyme-linked immunosorbent assay (ELISA). RESULTS: Pregnancy resulted in complete or partial remission in the majority of the zymosan-treated SKG mice. Twenty-seven transcripts were differentially expressed in the PBMCs between arthritic and pregnancy-remitted mice. Expression and plasma SAA3 levels decreased with pregnancy-induced arthritis amelioration and plasma SAA3 levels correlated with arthritis severity. CONCLUSIONS: These results establish the SKG mouse as a model system to study pregnancy-induced amelioration of arthritis. These studies also establish SAA3 as a biomarker of arthritis amelioration in SKG mice. This model can be used to elucidate the molecular and cellular mechanisms underlying the impact of pregnancy on the maternal immune system that results in arthritis amelioration. PMID- 23097752 TI - Letter from Olle Bjorkman. PMID- 23097753 TI - [New combination therapy against malaria]. PMID- 23097755 TI - Professional misconduct (Med10/161P). PMID- 23097756 TI - Professional misconduct--possession of objectionable matter (Med11/175P). PMID- 23097754 TI - [Fewer dying of measles]. PMID- 23097757 TI - Professional misconduct (Med11/181P). PMID- 23097758 TI - [Root cause analysis in surgery - learning from adverse events - appropriate for routine clinical practice?]. PMID- 23097759 TI - [Decision of the OLG Bamberg of 10.07.2012, Az.: 4 U 250 / 11 - comorbidity hepatitis A and B diagnosis]. PMID- 23097761 TI - The irresistible rise of the Cohort Profile. PMID- 23097760 TI - [Death of the patient - when the end is in sight]. PMID- 23097762 TI - Statistical inquiries into the efficacy of prayer. PMID- 23097763 TI - Abstracts of the 23rd Great Wall International Congress of Cardiology, Asia Pacific Heart Congress 2012. October 11-14, 2012. Beijing, China. PMID- 23097764 TI - Abstracts of the 3rd Congress of Asian Psychiatry (WCAP 2011). Melbourne, Australia. July 31-August 4, 2011. PMID- 23097765 TI - Abstracts of the Annual Congress of the European Association of Nuclear Medicine (EANM). October 27-31, 2012. Milan, Italy. PMID- 23097766 TI - Abstracts of the 19th Annual Conference of the International Society for Quality of Life Research. October 24-27, 2012. Budapest, Hungary. PMID- 23097767 TI - Of pirates and pogos. PMID- 23097768 TI - Patent watch: post-approval testing shielded from patent infringement. PMID- 23097769 TI - Nitrogen use efficiency in plants. PMID- 23097770 TI - Cryoglobulin deposits on a blood smear. PMID- 23097771 TI - Interview with Judy Illes. PMID- 23097772 TI - Understanding by seeing before treating: present and future of medical imaging. AB - In the last three decades, the development of medical imaging gave a burst to modern medicine. A considerable budget has been affected to develop and equip departments of radiology, nuclear medicine, medical imaging, radiotherapy, and emergency services. Several imaging installations have become intensively and exclusively used by the clinic where most of the imaging exams are performed for diagnoses, while for other imaging installations, the time of usage is shared between the clinical and research departments. However, very few centers restrain their installations to the research groups only,as their budgets are not sufficient to maintain the devices. The increase in medical imaging demand is mainly attributed to: (1) the drastic increase in the technology of electronic and computing sciences, which has made the imaging devices efficient and easy to operate, and (2) to the public and private insurers who consent the reimbursement of the imaging fees for some determined medical exams. Because the imaging modalities are based on different physical properties, they can be used individually, complementary but distinctly, or jointly. Despite their beneficial contribution, the imaging devices should be used with care as they can provoke undesirable effects. The future of the imaging technologies is, a priori, to exploit the full potential of the actual instruments, to target experiments at the molecular level, and to be able to monitor a biological phenomenon at its time of occurrence. In this paper,rapid overview and perspectives are proposed as the field of medical imaging is vast and encompasses several domains of knowledge. PMID- 23097775 TI - FDA approves Belviq to treat some overweight or obese adults. PMID- 23097776 TI - Moving bottom-up science closer to the top. PMID- 23097777 TI - The author file: Scott Manalis. PMID- 23097778 TI - Into the third dimension. PMID- 23097779 TI - Abstracts 26th Annual Meeting of the European Association for Cardio-Thoracic Surgery. October 27-31, 2012. Barcelona, Spain. PMID- 23097780 TI - Behavioral neurobiology of alcohol addiction. Preface. PMID- 23097781 TI - Life, simulated. PMID- 23097782 TI - DNA: stretch for the camera. PMID- 23097783 TI - Making PTMs a priority. PMID- 23097784 TI - When pathogens come in handy. PMID- 23097785 TI - Moved by sound. PMID- 23097786 TI - Cancer gene discovery goes viral. PMID- 23097787 TI - A sensor that makes sense. PMID- 23097788 TI - Abstracts of the 20th European Conference on General Thoracic Surgery. June 10 13, 2012. Messen, Essen, Germany. PMID- 23097789 TI - Abstracts of the 59th Annual Scientific Meeting of the Society for Gynecologic Investigation. March 21-24, 2012. San Diego, California, USA. PMID- 23097790 TI - I.T. tries to score. PMID- 23097792 TI - Individuals: each a majority of one. PMID- 23097791 TI - A closer look what's 'meaningful'. PMID- 23097793 TI - Cerebral hemispheric structures. PMID- 23097794 TI - Joint Commission's Wyatt says collaboration is the key. PMID- 23097795 TI - Stroke reduction gets another weapon. PMID- 23097796 TI - Waiting for the waiting to end. PMID- 23097797 TI - Seeing the forest and the trees. PMID- 23097799 TI - Know the benefits and risks of daily aspirin therapy. A small dose can have big benefits for many patients with heart disease. PMID- 23097798 TI - Where health care workers train matters. PMID- 23097800 TI - Take your pulse to save your life. Knowing how and when to check your heart rate can alert you to potential problems before they become too serious. PMID- 23097801 TI - Doubts surround study results touting polypill's benefits. The experimental pill contains four heart medications. PMID- 23097802 TI - Omega-3 fatty acids offer heart protection in multiple ways. These healthy essential fats provide benefits whether consumed as supplements or from dietary sources. PMID- 23097803 TI - Heart attack recovery can be hampered by fear of death. Study shows heightened fears may trigger a harmful inflammatory response during a heart attack. PMID- 23097804 TI - Your temperament may help determine your cardiac future. Research suggests that patients who embrace change and remain optimistic may have a more positive prognosis. PMID- 23097805 TI - I heard for a long time that raising your HDL was crucial to cardiovascular health and would help reduce the risk of heart attacks. But I recently read about research that said raising HDL may not make a difference. What do you think? PMID- 23097806 TI - My cardiologist is retiring soon, and he has recommended that I start seeing a younger doctor in his practice. I don't really care for this other doctor, having had a couple of appointments with him in the past. I may look elsewhere in town. How should I handle all this? PMID- 23097807 TI - High HDL may not protect the heart. Concentrate on lowering LDL for now, experts advise. PMID- 23097808 TI - The promise of a total artificial heart. Advanced device buys time until a transplant can be performed. PMID- 23097809 TI - Blood clot in the lungs. Prompt treatment may be lifesaving. PMID- 23097810 TI - Health tips. Avoiding allergic skin reactions. PMID- 23097811 TI - Active body and mind cut risk of cognitive decline. PMID- 23097812 TI - Fruits, vegetables reduce stroke risk: it's quantity, not type. PMID- 23097813 TI - Devices for pain. When all else fails. PMID- 23097815 TI - Core muscles. Strengthen and maintain for better stability. PMID- 23097814 TI - Basic pain relievers. It's wise to use caution. PMID- 23097816 TI - I'm 76 and an avid walker. Lately, though, I've noticed a burning sensation and pain on the ball of my foot when I walk or stand--it's even worse if I'm barefoot or in socks. It feels like I'm walking on pebbles. The pain goes away when I'm off my feet. What might cause this? PMID- 23097817 TI - I recently had a kidney stone. My doctor said that part of the reason I got it was because I have too much calcium in my urine. So why didn't my doctor tell me to consume less calcium? PMID- 23097819 TI - Abstracts of the Fall Meeting 2011 of the Swiss Chemical Society, September 13, 2012, Honggerberg, Switzerland. PMID- 23097818 TI - NTDB(r) data points: Surf's up. PMID- 23097820 TI - Abstracts of the National Conference of Surgery, May 19-21, 2012, Sibiu, Romania. PMID- 23097821 TI - Apoptosis - is it good or bad. PMID- 23097822 TI - Skin inflammation and cardiovascular health. PMID- 23097823 TI - Passion smassion. PMID- 23097824 TI - Encouraging home care. PMID- 23097825 TI - Rule of double causes. PMID- 23097826 TI - White-spot lesions could create negative perception of treating orthodontist. PMID- 23097827 TI - Pulp hyperthermia during tooth preparation: the effect of rotary--instruments, lasers, ultrasonic devices, and airborne particle abrasion. AB - The rise in pulp temperature during restorative therapy can compromise vitality of the dental pulp. Of the various reasons for the increase in intrapulpal temperature, tooth preparation is considered to be the primary cause. This article describes the reasons for the rise in pulp temperature during various modalities of tooth preparation. The article also comments on the measures that need to be taken to avoid the risk of pulp hyperthermia during tooth preparation. PMID- 23097828 TI - Oral fluid nanosensor test: saliva as a diagnostic tool for oral health. AB - High-impact diseases, especially cancer, are challenging to diagnose without supplementing laboratory testing. Even with laboratory tools, definitive diagnosis often remains elusive. The oral fluid nanosensor test technology platform combines cutting-edge technologies--such as self-assembled monolayers, bionanotechnology, cyclic enzymatic amplification, and microfluidics--with several well-established techniques including microinjection molding, hybridization-based detection, and molecular purification. The intended use of the OFNASET is for the point-of-care multiplex detection of salivary biomarkers for oral cancer. PMID- 23097829 TI - Atypical odontalgia--an update. AB - Atypical odontalgia is a commonly misdiagnosed condition that frequently leads to unnecessary dental treatments such as extraction and endodontic therapy. These treatments often worsen the pain. Despite greater recognition and understanding of this condition, proper diagnosis and treatment remains a challenge. It is believed that atypical odontalgia is a neuropathic condition. This article updates the current understanding of the etiology and pathophysiology of atypical odontalgia, and provides appropriate diagnostic and management approaches for this condition. PMID- 23097830 TI - Peripheral Ossifying fibroma: a clinical report. AB - Most localized growths on the gingiva are considered to be reactive rather than neoplastic in nature. The authors describe a 20-year-old male patient with a peripheral ossifying fibroma in the maxilla exhibiting significant size with the disease duration of one year. The signs of recurrence in spite of thorough excision a debridement exposed the need for further study of the causes of recurrence. Clinical, radiographical, and histological characteristics are discussed. PMID- 23097831 TI - Felonious flosser flees to freedom. PMID- 23097832 TI - Stay hungry! The desire to know more makes a great professional. PMID- 23097833 TI - The edge of our lives. Respecting and preplanning for big risks. PMID- 23097834 TI - Pregnant pause. No prenatal care, and now she's 'bleeding like crazy'. PMID- 23097836 TI - Q&A with Bill Metcalf. Securing the future of EMS. Interview by Jenifer Goodwin. PMID- 23097835 TI - Fatal mistakes in prehospital medicine. The laryngoscope, the syringe and the ink pen can all cause great harm. PMID- 23097837 TI - Strength in numbers. Group purchasing organizations can open the door to big savings. PMID- 23097839 TI - First five minutes program trains police to deliver lifesaving care. PMID- 23097838 TI - Are you under stress in EMS. Understanding the slippery slope of burnout and PTSD. AB - Burnout and PTSD are closely linked and often underreported in EMS. EMS classrooms do little or nothing to prepare providers for the inherent emotional stresses of emergency response and the "thick skin" culture of EMS may make many providers apprehensive about sharing their true feelings. Burnout is triggered by many of the same stresses that lead to the symptoms of PTSD and providers experiencing burnout that doesn't resolve within a few weeks may actually be experiencing PTSD. Be mindful of yourself and your fellow coworkers, particularly after a very traumatic response. And remember traumatic responses don't need to be as dramatic as Sept. 11, New Orleans after Hurricane Katrina or the Aurora, CO shootings to bother an EMS worker. In contrast, these are the calls where providers often receive the most attention. Instead, watch for the new father who just performed CPR on an infant the same age as his own, or the provider who just watched his or her friend die following a motor vehicle collision. Pay attention to yourself and colleagues, and be responsible and honest with yourself and others about when coping strategies are enough, and when they aren't. Finally, don't ever be afraid to seek help. PMID- 23097840 TI - How we built a better ambulance. PMID- 23097841 TI - Plan B. Do you have a career to fall back on? PMID- 23097842 TI - Mary Cesare-Murphy: steps to leadership in consumer-centered care. PMID- 23097843 TI - IT vendor survey 2012. PMID- 23097845 TI - Recovery art often says what words cannot. PMID- 23097846 TI - Habits of a highly effective nurses association. PMID- 23097844 TI - Doubts about Medicaid expansion: practical or political? PMID- 23097847 TI - Clinical excellence: voices of nursing brilliance. PMID- 23097848 TI - Legislative activism: not as difficult as you might think. PMID- 23097849 TI - Making sure our patients are covered. And I'm not just talking about insurance. PMID- 23097850 TI - Repairing dentistry's tattered safety net. PMID- 23097851 TI - 10 trends shifting the foundations of Indiana dentistry. How new federal law affects your patients and practice. Healthcare reform. PMID- 23097852 TI - Changing practice models: the rise of large group practices. PMID- 23097853 TI - A national and Indiana perspective: the rising cost of dental education. AB - Indiana University School of Dentistry remains committed to graduate competent general dentists. In the face of the cost of dental education, we are open to explore alternative educational and clinical models to enhance the educational experience for all students, while reducing the cost to provide that education. As dean, I welcome your thoughts and ideas to further reduce educational costs. PMID- 23097854 TI - Demolition derby: who will win the battle to defeat barriers to care? PMID- 23097855 TI - Dental ethics: an obituary. PMID- 23097856 TI - Insurance continues to impact the doctor-patient relationship. Three's a crowd. PMID- 23097857 TI - Continuing education. PMID- 23097858 TI - Diversity: a new course for IDA leadership. PMID- 23097859 TI - The business side of dentistry. PMID- 23097860 TI - The unretired dentist. PMID- 23097862 TI - [The true job of a general practitioner? The daily management of difficult decisions]. PMID- 23097861 TI - What does it all mean? The race for relevance. PMID- 23097863 TI - [Vitamin B12 deficiency: what's new?]. AB - Vitamin B12 screening is only recommended among symptomatic patients or in those with risk factors. The main cause of vitamin B12 deficiency is the food cobalamin malabsorption syndrom. Holotranscobalamin is a more reliable marker than cyanocobalamin to confirm vitamin B12 deficiency, but it has not been validated yet in complex situations. An autoimmune gastritis must be excluded in the absence of risk factors but in the presence of a probable deficiency. Oral substitution treatment is effective but requires excellent therapeutic compliance and close follow-up to monitor the response to treatment. It has not yet been studied among patients suffering from severe symptoms, inflammatory bowel disease and ileal resection. PMID- 23097864 TI - [What to do with a normal urinary strip in case of lower urinary tract symptoms?]. AB - Patients very often consult for lower urinary tract symptoms, that do not necessarily equate to common cystitis. When urinary leucocytes and nitrites are absent, the urinary strip has a very good negative predictive value and makes the diagnosis of a lower urinary tract infection very unlikely. One then has to search for other diagnoses and to clarify the nature of the symptoms, irritating or obstructive ones, their duration and to correlate them to the patient's age and gender. In sexually active young patients, infectious diseases predominate, such as uretritis or vaginitis, while, with age, the prevalence of dysfunction of vesical emptying, benign prostatic hyperplasia or atrophic vaginitis increase. PMID- 23097865 TI - [Dyspepsia and Helicobacter pylori: should it be treated?]. AB - Epigastric pains are currently one of the most frequent reasons of clinic visits in ambulatory medicine, generating high direct and indirect costs each year. Corresponding to pains in the epigastric area, they result from different underlying diseases such as gastro-esophageal reflux, dyspepsia and peptic ulcers. If the role of Helicobacter pylori is well defined in the pathogenesis of gastro-duodenal ulcers, its implication in dyspepsia is less clear. The Maastricht IV Consensus recommends to test and treat Helicobacter pylori among patients with dyspepsia and no alarm symptoms. PMID- 23097866 TI - [Irritable bowel syndrome: an exclusion diagnosis?]. AB - The irritable bowel syndrome has been considered a diagnosis of exclusion and multiple diagnostic procedures were often performed in order to exclude an organic disorder. Nowadays, studies show that in young patients, who match the clinical criteria of irritable bowel syndrome and show no alarm features, the prevalence of underlying organic disorders is low, or at least not higher than in the general population. Based on these findings, current recommendations suggest that no extra diagnostic tests have to be performed in those patients, apart from the serological tests in search of celiac disease, which are recommended for patients presenting an irritable bowel syndrome with diarrhea or a mixed-type irritable bowel syndrome. PMID- 23097867 TI - [Pleural plaques: when and how to treat?]. AB - Which course of action should be taken during the incidental finding of pleural thickening on chest X-ray? Aftereffect, without consequence, of an injury of the pleura, or potentially serious subclinical pathology? The differential diagnosis is wide, the radiograph nonspecific and the interobserver variability significant. In the absence of epidemiological studies and guidelines, the history and clinical examination remain the main factors in dictating investigations and management. Apical pleural thickening, which is nonspecific in the absence of parenchymal lesions, does not influence treatment recommendations for tuberculosis. Pleural plaques do not appear to increase the risk of cancer associated with asbestos and, thus, do not modify post-exposure follow-up. Incidental finding of pleural thickening remains a gray zone that opens the door to new studies. PMID- 23097868 TI - [How to have a clear vision when considering all the different recommendations of moderate alcohol consumption?]. AB - Although use of important amounts of alcohol has clearly been proven to have a negative health impact, large epidemiological studies show that a moderate quantity of alcohol might be beneficial in terms of total mortality, probably through cardiovascular protection. Many countries propose their own official recommandations with regard to moderate or low risk alcohol consumption. In this review, we compare some of these recommandations. Furthermore, risks and benefits of alcohol for the main groups of disease are analysed according to alcohol quantities and drinking patterns. Our final objective is to evaluate the small margin between potentially beneficial use of alcohol versus low risk use, and provide some practical recommandations for the physician advising an individual patient. PMID- 23097869 TI - [Elite senior athletes. Physiological modifications related to performance decrease in elderly]. AB - Results of masters athletes are more and more impressive. With age, VO2max, strength, speed, coordination, recovery decrease. Regular training with enough intensity is the most appropriate, the less expensive measure to prevent morbidity and dependence. It's efficacy in patients is regularly demonstrated. PMID- 23097870 TI - [Screening for ovarian cancer]. PMID- 23097871 TI - [When one only sees the fingertip...]. PMID- 23097872 TI - [On the subject of euthanasia]. PMID- 23097873 TI - [The real experience of Dr James Lind]. PMID- 23097874 TI - [Science and democracy, a rough union]. PMID- 23097875 TI - [SBU: Help us find examples of health care that is not evidence-based]. PMID- 23097876 TI - [Stapled haemorrhoidopexy - risk of rectum perforation and sepsis]. PMID- 23097877 TI - [Many Swedes want to donate--yet the number of donations are low]. PMID- 23097878 TI - [Blood type incompatible kidneys can be transplanted. ABO incompatibility is no longer a barrier for kidney transplantation]. PMID- 23097879 TI - [Improved immunosuppression leads to better kidney transplantations]. PMID- 23097880 TI - [More heart transplantations than ever]. PMID- 23097881 TI - [Mechanical circulatory support devices save lives of children awaiting heart transplantation]. PMID- 23097882 TI - [Lung transplantation is hampered by the organ shortage]. PMID- 23097883 TI - [Selection criteria decisive in hepatocellular carcinoma]. PMID- 23097884 TI - [Transplantation of pancreas, a curative option for type 1 diabetes]. PMID- 23097885 TI - [Promising results in intestinal transplantation]. PMID- 23097886 TI - [The transplant patient at the community health center and the emergency department]. PMID- 23097887 TI - [Kidney transplanted persons with malignant tumors is a growing patient group]. PMID- 23097888 TI - [Symptoms after withdrawal of quetiapine]. PMID- 23097890 TI - [Equalis/SFKK recommends harmonization of units in hormone determinations for safer care]. PMID- 23097891 TI - [Voluntary sexual intercourse and life-threatening hemorrhage--rare but occurs]. PMID- 23097892 TI - [Routine overdosing of folic acid?]. PMID- 23097893 TI - [Clostridium difficile--unfairly set in the corner?]. PMID- 23097894 TI - [The Mexican dream--and hidden memories]. PMID- 23097895 TI - Nurses failed to respond to patient's known difficulty in standing. Horsley v. Halifax Regional Medical Center, Inc., 725 S.E.2d 420 NC App.2012 (7/19/2011)-NC. PMID- 23097896 TI - RNs named by fictitious numbers sued: complaint amended after IDs known. Case on point: Ex parte Nail, 1110742--So. 3d--(8/16/2012)-AL. PMID- 23097897 TI - NY: AROD anesthesia allegedly caused death: denial of motion for summary judgment affirmed. Dmytryszyn v. Herschman, 2012-06061 NYAPP2 (8/29/2012)-NY. PMID- 23097898 TI - PA: Failure to follow employer's computer policy: court reversed award of unemployment benefits. Palmieri v. Unemployment Compensation Board of Review, 2106 C.D. 2011 PACCA (8 /14/2012)-PA. PMID- 23097899 TI - Sponge left in Pt. who sued 'after limitations' but right after 'discovery'. Case on point: Stone v. Coronado, 03-11-00243-CV TXCA3 (6/6/2012)-TX. PMID- 23097900 TI - Did nurse's delay in ordering blood result in death & multi million $ award? University Med. Ctr. v. Beglin, 2009-SC-000289-DG, 2009-SC-00839-S.W.3d (11/1/2011)-KY. PMID- 23097902 TI - NY: RN told not to give insulin-death results: right to punitive damage claim upheld by court. Marsh v. Arnot Ogden Medical Center, 2012-00153 NYAPP3 (1/12/2012)-NY. PMID- 23097901 TI - Error in mitral valve surgery: court reversed $7 million verdict. Case on point: the Methodist Hospital v. German, 01-09-00925-CV (12/29/2011)-TX. PMID- 23097903 TI - NY: RN told not to treat patient put out of ER: RN alleged retaliatory termination for objecting. Novak v. St. Lukes-Roosevelt Hospital Center, Inc., 2012-30083 NYMISC (1/11/2012)-NY. PMID- 23097904 TI - Overdose in NICU-infant died: mom sued for emotional distress. Canfield v. Health Partners, Inc., 49A02-1104-CT-292-(12/12/2011)-IN. PMID- 23097905 TI - Nurse placed feeding tube in trachea: issues re attorney contact. Phoenix Children's Hospital, Inc. v. Grant, ICA-SA 11-0170 AZAPP1 (11/1/2011) -AZ. PMID- 23097907 TI - NY: failure to timely transport baby to hospital: denial of motion summary judgment affirmed. Applewhite v. Accuhealth, Inc., 2011-09002 NY APP1 12/15/2011) NY. PMID- 23097906 TI - Pt. burned in surgery fire claimed fraudulent concealment. CASE ON POINT: Wargo v. Susan White Anesthesia Inc., 2011-Ohio-61,96410, (12/8/2011)-OH. PMID- 23097908 TI - NC: biopsy specimen switched by mistake: court affirmed award for 'unnecessary surgery'. Harmon v. Eastern Dermatology & Pathology, RA., COA 11-195 NCCA(11/15/2011)-NC. PMID- 23097909 TI - Failure to give notice resulted in dismissal & denial of benefits. CASE ON POINT: Sangston v. Unemployment comp.Bd., 2823D-2010 (7/12/2011)-PA. PMID- 23097910 TI - [Individual vulnerability in psychiatry: a new nosography?]. PMID- 23097911 TI - [Hyperthymic and cyclothymic temperaments: attenuated forms of bipolar disorder?]. AB - A temperament is described as a temporally stable dimension, biologically determined. Several temperaments have been described (hyperthymic, depressive, cyclothymic, irritable and anxious) and could represent premorbid characteristics of an affective disorder. Some temperaments could thus correspond to chronic sub affective states expressed as attenuated forms of mood disorder. Several studies suggest that a large proportion of bipolar patients have a hyperthymic or cyclothymic temperament. Moreover, temperaments seem to influence the clinical caracteristics of bipolar disorders. Future investigations will evaluate whether temperaments represent a predisposing factor, an attenuated form of bipolar disorders or a distinct entity. PMID- 23097912 TI - [Adult Attention Deficit/Hyperactivity Disorder (ADHD): current issues]. AB - Attention Deficit/Hyperactivity Disorder (ADHD) has prevalence between 3 and 7% in childhood and adolescence. As high as 60% of childhood cases continue to have clinically significant symptoms of ADHD as adults. Psychiatric comorbidities are often found in ADHD subjects including, in childhood, emotional, behavior and learning disorders. Psychiatric comorbidities in adolescents and adults suffering from ADHD include mood and substance use disorders. Although may one fear giving psychostimulants to ADHD patients with comorbidities, recent studies have shown the benefits of such treatment not only in the clinical but also in the educational and socioprofessional point of views. Psychotherapeutic approaches should ideally accompany pharmacological treatments. PMID- 23097913 TI - [Early intervention for people with alcohol related disorders or at-risk for alcohol use]. AB - Use of alcohol is a leading cause of morbidity and mortality in adolescents and young adults. Early interventions may reduce the burden associated with alcohol misuse and alcohol related disorders. Screening, Brief Intervention and Referral to Treatment (SBIRT) is a comprehensive and integrated approach to the delivery of early interventions for persons with substance use disorders or at risk for substance use. This paper describes the components, rationale and evidence for the SBIRT approach for people with at risk alcohol use or with alcohol abuse or dependence. PMID- 23097914 TI - [Alzheimer disease: from pathogenetic issues to clinical perspectives]. AB - The aim of this article is a critical review of the main pathogenetic issues debated in Alzheimer disease, with a focus on the clinical perspectives that could derive from. The pertinence of the amyloid cascade hypothesis as a unique and causal explanation of cognitive deterioration is challenged in the light of recent therapeutic failures of clinical trials and increasing role of tau protein in clinical expression. The detection of very early and possibly preclinical stages of the disease emerges as a necessary condition for the efficacy of future amyloid or tau-oriented curative strategies. In this respect, the possibility of finding individual vulnerability markers--in the group of patients with "mild cognitive impairment" or even in cognitively intact subjects--represents a major challenge of the clinical research in this field. PMID- 23097915 TI - [Benefits and limitations of risk assessment for criminal recidivism]. AB - The legislatives evolutions imply an important recourse to the psychiatric expertise in order to evaluate the potential dangerousness of a subject. However, in spite of the development of techniques and tools for this evaluation, the dangerousness assessment of a subject is in practice extremely complex and discussed in the scientific literature. The evolution of the concept of dangerousness to the risk assessment involved a technicisation of this evaluation which should not make forget the limits of these tools and the need for restoring the subject, the meaning and the clinic in this evaluation. PMID- 23097916 TI - [From early treatment of psychosis risk to the risks of early intervention: the dilemma of psychosis prevention]. AB - While the development of early psychosis intervention programs have improved outcome of such disorders, primary prevention strategies are still out of reach. The elaboration, over the last 15 years, of scales and criteria to identify populations at high risk for psychosis is a real progress, but their low specificity is still a major obstacle to their use outside of research projects. For this reason, even if "ultra high risk", subjects present with real psychiatric disorders and sometimes significant decrease in functioning level, the fact that only a small proportion will eventually develop full blown psychosis will probably lead to the rejection of a "psychosis risk syndrom" from the future DSM-V classification. PMID- 23097917 TI - [Social policy changes and the health of asylum seekers: 3 years after the introduction of the Asylum Law]. AB - In the canton de Vaud, General Practioners (GPs) caring for asylum seekers under the "aide d'urgence" regime can ask for an adaptation of their housing conditions, by filling out a specific form and addressing it to the medical commission responsible for advising the EVAM (the housing institution for asylum seekers) on these issues. The forms addressed to the commission are indicative of a worrisome state of health in this population, especially for mental health. More than 70% report at least one psychiatric diagnosis. Most frequent are anxiety and depressive disorders, as well as many posttraumatic stress disorders, associated with traumatic events both in the country of origin and in Switzerland. Adapting the housing conditions, based on vulnerabilities that the GP has specifically documented, may contribute to improve the health of the most vulnerable asylum seekers. PMID- 23097918 TI - [Buruli ulcer and HIV: a complex and minimally studied interaction]. PMID- 23097919 TI - [A question of life and death]. PMID- 23097920 TI - [Autism, stem cells, and magical powder]. PMID- 23097921 TI - [The plague according to Saint Yersin (2)]. PMID- 23097922 TI - [Dengue vaccine and nodding syndrome in question]. PMID- 23097924 TI - Certification denied in pharmaceutical class action. PMID- 23097925 TI - Bill S-11-Safe Food for Canadians Act. PMID- 23097926 TI - Proposed changes to Pharmacy Act will clarify the scope of activities that can be performed by pharmacists. PMID- 23097927 TI - Comment on assisted living ruling. PMID- 23097928 TI - 2012: the most important election of the 21st century. PMID- 23097929 TI - How the Missouri Supreme Court ruling on caps on pain and suffering violates the people's right to self-governance. PMID- 23097930 TI - Missouri compromised? PMID- 23097931 TI - Vote yes on Amendment 3. PMID- 23097932 TI - Vote no on Amendment 3. PMID- 23097933 TI - C'mon people now.... Everybody get together. PMID- 23097934 TI - UMKC School of Medicine 40 years of excellence. PMID- 23097935 TI - Accelerated medical education: past, present and future. PMID- 23097936 TI - Is football too dangerous and violent for universities to sponsor? PMID- 23097937 TI - Trauma care for the best in the worst place in the world. PMID- 23097938 TI - Extraordinary dedication: family, profession, country. PMID- 23097939 TI - Use of ultra sound in cardio surgery. PMID- 23097940 TI - Critical care medicine: one of medicine's greatest advances. PMID- 23097941 TI - Acute respiratory distress syndrome. AB - Acute Respiratory Distress Syndrome (ARDS) is defined by bilateral diffuse infiltrates on chest radiography, a PO2/FiO2 ratio < 200, and noncardiogenic pulmonary edema. Pathophysiologically it is characterized by disruption of the alveolar lining and capillary endothelium, alveolar edema, protein exudation coupled with a marked inflammatory response and subsequent fibrosis and a resultant ventilation-perfusion mismatch. Effective treatment strategies include low tidal volume ventilation with positive end expiratory pressure, careful fluid management and good supportive care. PMID- 23097942 TI - Intra-abdominal hypertension and abdominal compartment syndrome. AB - Abdominal compartment syndrome (ACS) is seen with increasing frequency in the critically-ill. Elevated intraabdominal pressures interfere with vital organ function and contribute to mortality. Prevention, when possible and early recognition of occurrence with timely therapy will improve survival. Measurement of bladder pressures plays a critical role in diagnosis and guiding therapy. Treatment includes non-invasive and invasive methodologies designed to decrease the volume of abdominal contents and invasive methods to increase the compartment dimensions. PMID- 23097943 TI - Evaluation and management of acute kidney injury in the intensive care unit. AB - Acute disorders of the kidney occur in up to two-thirds of patients in the intensive care unit. The diagnosis is associated with increased mortality and increased hospital stay. Often recognized but less frequently defined, it is commonly encountered by physicians caring for critically-ill patients. A standardized definition regarding acute kidney injury was published in 2004. This has led to improvements in measuring mortality and treatment outcomes with a more targeted approach to caring for these difficult to treat patients. PMID- 23097944 TI - Evidence-based guidelines for the management of traumatic brain injury. AB - The management of traumatic brain injury has changed as a result of evidence based treatment guideline first established in 1995. They have promoted standardization of care and as a result improved outcomes. In addition, the guidelines have helped identify gaps in our knowledge-base that can direct future research efforts. PMID- 23097945 TI - Immune-enhancing nutrition in surgical critical care. AB - Immune-enhancing nutrition, or "immunonutrition," refers to the use of specialized nutrients, including glutamine, alanine, omega-3 fatty acids, and others, that help regulate the body's response to illness and injury. Clinical studies have demonstrated some very specific benefits, including fewer infectious complications and shorter length of hospitalization, in certain populations including high-risk surgical patients, trauma victims, and the critically-ill. Nationally recognized guidelines support the use of immune-enhancing nutrition in high-risk patients. PMID- 23097946 TI - Nutrition in the critically-ill obese patient. AB - People are fatter than they used to be. Although the upward trend has slowed in recent years, more than one third of all adults in the US are obese, and one in six children are overweight or obese. Reflecting this reality, there are a large number of obese patients in the intensive care unit. Some 30-35% of adult ICU patients are obese, and 5% or more are morbidly obese. Patients who are both critically-ill and morbidly obese present unique challenges to care. These range from basic care, such as prevention of bedsores and ambulation, to sophisticated issues, such as medication dosing and ventilator management. It takes a team of caregivers, for example, to help a 400-pound patient in and out of bed. One of the most difficult aspects of the care of such patients is nutrition support, which is the subject of the present review. PMID- 23097947 TI - Prevalence of grade II and III obesity among patients hospitalized with cardiovascular diagnoses in 2002 v. 2009. AB - BACKGROUND: The prevalence of obesity has increased markedly over the past four decades; however, some reports suggest a recent plateau. There is little information available regarding recent changes in obesity prevalence among patients hospitalized with cardiovascular disease. OBJECTIVE: To define obesity trends among patients hospitalized with cardiovascular disease between 2002 and 2009 at an academic medical center. METHODS: This is a retrospective database analysis of patients admitted with cardiovascular diagnoses in 2002 versus 2009. Using ICD-9 codes, the study population was generated. Body mass index (BMI) was calculated by dividing weight in kilograms by height in meters squared (Quetelet index). Patients were assigned to 1 of 5 BMI categories: normal weight (BMI < 19 24.99), overweight (BMI 25-29.99), Grades I obesity (BMI 30-34.99), Grade II obesity (BMI 35-39.99), and Grade III obesity (BMI > 40). Patient demographics are compared with Student's T-tests for continuous data and chi2 tests for categorical data. Logistic regression models were developed in the overall cohort to ascertain differences in obesity grades I, II & III between the two time points with age, gender, race and primary ICD-9 code included as covariates. The logistic regression models were then repeated for each primary ICD-9 code. RESULTS: Patients admitted with cardiovascular diagnoses in 2002 (n = 1271) and 2009 (n = 1576) were stratified by BMI categories. Over this period of nine years, obesity prevalence increased significantly from 28.5% to 38.4% of patients. In particular, Grades II and III obesity increased markedly from 2002 to 2009 (7.6% versus 9.9%, and 2.7% versus 7.5%; unadjusted p = 0.04, p < 0.001 and adjusted p = 0.09 and p < 0.0001 respectively). Individuals with Grade III obesity had a higher incidence of arrhythmias, coronary heart disease, and valvular heart disease. CONCLUSIONS: Grade II and III obesity has markedly increased among patients admitted to our hospital with major cardiovascular diagnoses in the period 2002 to 2009. With respect to hospitalized patients, the obesity epidemic is still on a steeply rising trajectory, especially for the extremely obese categories. PMID- 23097948 TI - Adenovirus-36 antibody status & BMI comparison among obese Missouri adolescents. AB - Adenovirus-36 (Adv-36) has been implicated in the etiology of obesity. This study attempts to identify the prevalence of Adv-36 antibodies and compare BMI among obese Missouri adolescents. Thirteen obese Missouri adolescents were tested for Adv-36 antibodies via ELISA assay. Adv-36 antibodies were detected among 6 (46.2%) subjects. Mean BMI of the Adv-36 positive group and negative group was 43.5 kg/m2 and 35.4 kg/m2 (p < 0.05), respectively. This is the first such study of Adv-36 status among Missouri adolescents. PMID- 23097949 TI - Breast cancer presentation in an urban health care Safety Net system. AB - We examined the Safety-Net referral process for breast diseases to identify factors contributing to delays within it. Each record was mapped to a time line beginning with first abnormality and concluding with definitive diagnosis/treatment. The median interval between first sign and definitive diagnosis/treatment was 93 days. Need for repeat imaging and missed visits prolonged the interval. System- and patient-specific factors were associated with delayed diagnosis/ treatment in breast patients referred through the Safety-Net specialty clinic. PMID- 23097950 TI - What was your first job? PMID- 23097951 TI - I need a job! PMID- 23097952 TI - Roscoe Filburn review needs fact-checking. PMID- 23097953 TI - Are HRT clinics required to provide follow-up care? PMID- 23097954 TI - She second time around. Medicine as a second profession. PMID- 23097955 TI - The ripple effect of professional licensing discipline. PMID- 23097956 TI - A case of acute agitation with a negative urine drug screen: a new wave of "legal" drugs of abuse. AB - Substance abuse is reportedly the most common cause of patients presenting with severe agitation in the emergency department. With increased access to information, people are now trying different substances for recreational use. Clinicians dealing with these patients have an increased responsibility to be aware of these new substances being abused and their management. We report a case of a 36-year-old male who was brought to the ED with severe agitation. His laboratory results, including urine drug screen, failed to suggest any substance abuse, infection or encephalopathy. Later he was found to have ingested "bath salts," which are available for purchase in gas stations and convenience stores. The patient was treated and discharged home in stable condition. We aim to raise awareness among public and medical personnel, especially physicians, about this new substance of abuse as it is not illegal yet in many states. PMID- 23097957 TI - Improvement in ocular myasthenia gravis during CPAP therapy for sleep apnea. AB - We describe the case of a 73-year-old male with a history of ocular myasthenia gravis (OMG) who was followed through diagnosis and treatment of sleep-disordered breathing (SDB). Therapeutic use of continuous positive airway pressure (CPAP) led to improvement of not only SDB but also OMG. To our knowledge, this is the first paper describing this treatment benefit. This case report emphasizes the need to obtain a sleep history in patients with ocular myasthenia gravis in order to screen for SDB. PMID- 23097958 TI - A case report of acute interstitial nephritis associated with antibiotic impregnated orthopedic bone-cement spacer. AB - Local antibiotics are effective adjunct therapy for the treatment of orthopedic infections and antibiotic loaded bone cement is successfully used in revision procedures of infected hip and knee arthroplasties. Different antibiotics in isolation or in combination can be added into bone cement. The theory behind the use of antibiotic loaded cement is that anti-infective drug incorporated into the cement diffuses into surrounding tissues over a period of weeks to months, thereby providing prolonged high local concentration of antibiotic while minimizing systemic drug toxicities. Although kidney toxicity due to acute tubular necrosis has been previously described, we report for the first time a case of a 58-year-old male who developed acute kidney injury clinically consistent with acute interstitial nephritis, after undergoing revision treatment for septic knee arthritis with the use of cement spacer impregnated with a combination of vancomycin and tobramycin. PMID- 23097959 TI - The history of neurosurgery in Kingsport, Tennessee. PMID- 23097961 TI - UMHS nurse shines on Labor Day stage. PMID- 23097960 TI - Proposal 2 is our chance to make history. PMID- 23097962 TI - Women's health care rights are at stake. PMID- 23097963 TI - Importance of the adrenergic nerve system in the response of gases in the arterial blood following the provoked bronchospasm. AB - INTRODUCTION: This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the beta2-drenergic stimulator-Hexoprenaline and alpha2-adrenergic blocker Tolazoline in the bronchoconstriction caused by a beta-blocker-Propranolol. MATERIAL AND METHODS: in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin). RESULTS AND DISCUSSION: Following the inhalation of the beta-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2 appeared. This shows that stimulation of beta2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases. PMID- 23097964 TI - Mortality after acute myocardial infarction: significance of cardiovascular diabetic autonomic neuropathy (CDAN). AB - The aim of this study was to compare intrahospital and long-term mortalities after more than 10 years of the follow up after the first acute myocardial infarction (AMI) with patients with and without CDAN and without diabetes mellitus (DM). METHODS: The study was based on 76 (43 men and 33 women) with DM type 2, CDAN was detected in 51 patients, and 374 (295 men and 79 women) without DM consecutively hospitalized with the first-ever AMI from January 1998. to December 2000. in Clinical Center of Montenegro Podgorica. Patients were followed until December 31. 2011. CDAN was searched for by standardized five tests evaluating heart rate and blood pressure variations. RESULTS: Intrahospital mortality was presented in 10.53% diabetic patients and 5.61% nondiabetic patients, this difference is significant (p = 0.048). Long-term mortality was presented at 24 (82.75%) patients with CDAN and 5 (17.25%) patients without CDAN (p = 0.029). Long-term mortality rate was significantly higher in diabetic patients 29 (42.64%) than in nondiabetic patients 102 (30.72%) (p = 0.012). CONCLUSION: Intrahospital mortality was significantly higher in diabetic than in nondiabetic patients. Identically the mortality after more than 10 years of the follow up after the first AMI was significantly higher in diabetic with, than in diabetic patients without CDAN, as in diabetic than in nondiabetic patients. PMID- 23097965 TI - The kinetics of virological and biochemical responses in the treatment of chronic hepatitis C by dual antiviral therapy. AB - INTRODUCTION: Infection with hepatitis C is often manifested by a mild clinical course, and in many patients it is revealed incidentally, during routine laboratory ests. Progression of the disease often takes 10-20 years with specified high risk of fibrosis and hepatocellular carcinoma. MATERIAL AND METHODS: The group of subjects with chronic liver disease of viral C etiology was consisted of 50 patients of both sexes, 38 (75%) were male and 13 (25%) females, aged 20-65 years. Patients were selected according to genotype hepatitis C viral infection and subsequently treated according to two current therapeutic protocols. All patients had prior therapy and after completion of treatment using standard methods of laboratory tests were done the following: functional hepatic tests, serological analysis, nucleic acid detection of hepatitis C virus polymerase chain reaction (PCR), quantitatively and qualitatively with the genotyping of the virus C, which determines the length of therapy. In determining the stage of chronic liver disease, histopathological examination of liver tissue samples obtained by biopsy of the liver was done and we analyzed the fibrosis and architectural changes. RESULTS: By analyzing the HCV RNA PCR values at the beginning and end of treatment we tested the effect of treatment on PCR with paired samples t-test logarithm values of the PCR and came to the conclusion that the values after treatment are significantly lower with threshold of significance of 0.01. The results showed that the value of PCR before and after therapy, or achieved a response at the end of therapy, which achieved 77% of patients. The values of ALT in the group of patients with CHC were significantly higher than the values in the group of patients after the therapy. AST values in the patients with CHC were significantly higher than the values in the group of patients after therapy. There was a moderate correlation between ALT values at baseline and ALT values upon completion of treatment (0.5061). There was no correlation between HCV RNA PCR and ALT and AST. CONCLUSION: Upon completion of antiviral treatment response at the end of treatment achieved 77% of patients, regardless of the genotype of the virus. Also, regardless of the genotype of the virus antiviral therapy led to statistically significant reduction of AST and ALT, indicating a direct effect of combination therapy on virological and biochemical response with no significant link between these two studied parameters. PMID- 23097966 TI - Psychosocial problems among children of parents with posttraumatic stress disorder. AB - BACKGROUND: To assess the expression of psychosocial problems among children of parents with posttraumatic stress disorder (PTSD). MATERIAL AND METHODS: A group of 100 children of school age (from 10 to 5 years old) from two randomly chosen schools has been analyzed. Children from complete families whose parents accepted psychometric measurement related to trauma have been chosen. Subjects were divided into two groups: a group of children whose parents express the symptoms of posttraumatic stress disorder (PTSD)-experimental group (N = 50) and group of children whose parents are not suffering from PTSD-control group (N = 50). The assessment of PTSD symptoms and parental traumatisation is done by Harvard Trauma Questionnaire-version for Bosnia and Herzegovina (B&H) (Allden et al., 1998), behavioral problems were assessed by Child Behavior Checklist--as reported by parents (CBCL, Achenbach, 1991), the level of traumatisation and posttraumatic symptoms in children by the Impact of Event Scale (Horowitz, Wilner, Alvarez, 1979), and neurotism and extraversion is estimated by Neurotism and Extraversion Scale (HANES). With regard to gender and parental participation the sample is homogenous. Data are processed by descriptive statistics method. RESULTS: Children whose parents are suffering from PTSD symptoms show statistically significant increase in behavioral problems such as withdrawal, somatic complaints, thought problems, delinquent and aggressive behavior (p < 0.001), anxiety/depression, attention deficit and problems in social relations (p < 0.005). Male subjects showed more prominent delinquent behavior (p < 0.01). Children whose parents have PTSD symptoms show significantly expressed internalisation (p < 0.001) and higher level of stress (Chi2 = 23.528, p < 0.001), compared to children of parents without PTSD. There is statistically significant difference regarding the mean (M) of symptom groups among the analyzed groups of subjects related to the symptoms of intrusion (p < 0.01) and symptoms of avoidance (p < 0.001). Significantly expressed neurotism is present in children of parents with PTSD (p < 0.001). CONCLUSION: The results show that children of parents with PTSD express a significant behavioral problems, higher level of neurotism, internalisations, posttraumatic stress reactions, symptoms of intrusion and avoidance as well as significantly higher level of stress compared to children of parents without PTSD. PMID- 23097967 TI - Human brucellosis in Tuzla Canton. AB - INTRODUCTION: The prevalence of human brucellosis in Bosnia and Herzegovina and the Tuzla Canton reached its peak in 2008, with a reported total of 994 cases within country, and with 104 cases within the Tuzla Canton. AIM: to analyze the clinical and epidemiological features of human brucellosis in patients hospitalized at the University Clinical Center Tuzla during the period from 01/01/2000 till the 31/12/2010. METHODS: We retrospectively analyzed the clinical symptoms, the laboratory and X-ray findings, the treatments, and the course and outcome of the disease. The diagnosis of brucellosis was based on anamnesis, clinical presentation, in correlation with a positive blood-culture, and/or serological tests. RESULTS: The majority of patients (93.18%) were from rural regions. There were more males (79.54%) than females. Most of the patients were aged between 30 to 39 years (21% cases). Contact with infected animals was registered for 83.40% of the patients. The main symptoms and signs were fever, joint-pains, night sweating, anorexia, headaches, and hepatosplenomegaly. The important laboratory findings were increased erythrocyte sedimentation rates, increased values of C-reactive protein, and anemia. Adult patients were treated with a combination of gentamicin or streptomycin with doxycycline, and the children with a combination of gentamicin, and trimethoprim-sulfametaxasol, over at least 6 weeks. Complications were documented in 20.45% of the patients. Relapses were observed in 14.20%, and a chronic form of brucellosis in 5.11% of patients. There were no cases with lethal outcomes. CONCLUSION: Brucellosis is a growing public health problem, not only within the Tuzla Canton, but throughout Bosnia and Herzegovina. PMID- 23097968 TI - Comparison of the motor and sensory block by ropivacaine and bupivacaine in combination with lidocaine in interscalene block. AB - INTRODUCTION: The effects of ropivacaine and bupivacaine in interscalene block have been studied, but we usually combine lidocaine with ropivacaine or bupivacaine to fasten the onset. However, the effects of these combinations are not studied. PURPOSE: To compare the effects of two different concentrations of the combination of ropivacaine or bupivacaine with lidocaine. MATERIALS AND METHODS: One hundred adult patients scheduled for repair of fracture of the upper extremity under interscalene block were randomly allocated into one of the groups receiving the combination of 15 mL of ropivacaine 0.375% (Ropivacaine 0.375 group), ropivacaine 0.75% (Ropivacaine 0.75 group), bupivacaine 0.25% (Bupivacaine 0.25 group), or bupivacaine 0.5% (Bupivacaine 0.5 group) with lidocaine 1.0% 15 mL. The onset and duration of motor and sensory blocks were compared among the 4 groups by Kruskal Wallis test followed by Mann-Whitney U test. RESULTS: Three patients in the Ropivacaine 0.375 group did not show any motor blocks. Ropivacaine groups had significantly slower onset of motor block and longer duration of motor and sensory blocks than Bupivacaine groups. Bupivacaine 0.5 group had significantly longer duration of both blocks than Bupivacaine 0.25 group, while Ropivacaine 0.375 and 0.75 groups had the similar duration of both blocks. CONCLUSIONS: In interscalene block combined with lidocaine, ropivacaine had slower onset of motor block and longer duration of both blocks than bupivacaine. Only bupivacaine showed the different duration of the blocks between two concentrations. PMID- 23097969 TI - Significance of ultrasonography in evaluation of vitreo-retinal pathologies. AB - PURPOSE: To assess the diagnostic value of ultrasonography in the detection of vitreo-retinal pathologies. MATERIAL AND METHODS: This prospective study included all patients from retina department in Eye Clinic University Clinical Center Tuzla first time referred and examined by a single experienced vitreo-retinal surgeon in period from January 2011 to January 2012. Complete ophthalmic examination and ultrasonography-standardized echography were performed to all patients for detection and confirmation of vitreo-retinal pathology. RESULTS: Study included 146 eyes from 122 patients. 58 (39.7%) eyes had poor posterior segment visualization, 21 (14.4%) eyes due to dense cataracts and 37 (25.3%) eyes due to different vitreous opacities. 88 (60.3%) eyes had good or partial posterior eye segment visualization, where 67 (45.9%) eyes had proliferative vitreo-retinopathy and 55 (37.7%) eyes had tractional retinal detachment. Most common causes for referral to vitreo-retinal surgeon were ocular complications of diabetes mellitus 94 (64.4%), ocular trauma 18 (12.3%), rhegmatogenous retinal detachment 16 (10.9%) and intraocular inflammation 9 (6.2%). Ultrasonography confirmed suspected diagnosis and operative management plan in 120 (82.2%) eyes, sublassified previously established diagnosis in 19 (13%) eyes and helped further operative planning and established completely new diagnosis and changed initial management plan in 7 (4.8%) eyes. The final clinical diagnosis confirmed the ultrasonography findings in 142 from 146 (97.3%) eyes. CONCLUSION: Ultrasonography is useful part of ophthalmic examination for detection, evaluation and follow up of different vitreo-retinal pathologies. PMID- 23097970 TI - Comparing two techniques of panretinal photocoagulation on visual acuity on patients with proliferative diabetic retinopathy. AB - We wanted to examine which of two panretinal photocoagulation (PRP) techniques, classical panretinal photocoagulation (CPRP) and modifield peripheral panretinal photocoagulation PPRP), causes less decline of visual acuity (VA) due to macular edema (ME) in patients with proliferative diabetic retinopathy (PRD). This clinical study includes 180 eyes with PDR with initial papillar neovascularization. The patients were divided into two groups according the RP. PPRP and CPRP showed the decline of VA in all patients, more pronounced in the CPRP group after one week. After three and six months, with CPRP and PPRP the values of VA was stabilized. The result suggests that eyes with PDR and starting epipapillar neovascularisation should be treated with PPRP with priority given to CPRP because it caused better VA. PMID- 23097971 TI - Which is a better indicator of bladder outlet obstruction in patients with benign prostatic enlargement--intravesical protrusion of prostate or bladder wall thickness? AB - OBJECTIVE: To determine the correlation of intravesical prostatic protrusion (IPP) and bladder wall thickness (BWT) with clinical and urodynamic parameters, as well as their sensitivity and specificity with regard to bladder outlet obstruction in patients with a benign prostatic enlargement (BPE). MATERIALS AND METHODS: 111 patients with lower urinary tract symptoms and confirmed BPE completed the International Prostatic Symptom Score (I-PSS), as well as a transabdominal ultrasound to determine their prostate volume, a grade of IPP and BWT. All the patients were then subjected to the complete urodynamic studies (UDS). RESULTS: The IPP showed a good correlation with the prostate volume (r = 0.61) and serum PSA (r = 0.48); p = 0.0000, free uroflowmetry (r = -0.27; p = 0.004), as well as the determinants of urodynamic obstruction: bladder outlet obstruction index-BOOI (r = 0.36; p < 0.0001), and ICS and Schaefer obstruction class nomograms (rho = 0.33 and rho = 0.39, respectively; p < 0.001), while the BWT showed only a statistical correlation with age (r = 0.23; p = 0.02) and serum PSA (r = 0.4; p = 0.0000), regardless of an significant correlation with the IPP (r = 0.45; p = 0.0000). The ANOVA test showed a significant difference between the IPP grades for the observed clinical and urodynamic variables with an increase in significance for IPP>10 mm. The area under the ROC curve in the prediction of obstruction for the IPP is 0.71 (sensitivity 59.6, specificity 81.4), while the AUC for the BWT is 0.61 (sensitivity 64.5, specificity 59.2). The stepwise logistic regression model shows that most significant independent variables for the obstruction are the IPP, Q(max) free and age, with the area under the ROC curve of 0.78 (95% CI 0.695 to 0.856). CONCLUSION: The IPP higher than 10 mm as a non-invasive predictor of infravesical obstruction shows good correlations with clinical and urodynamic parameters, while the specificity and PPV against obstruction are significant. Despite a good correlation with IPP, the BWT is only a modest indicator of obstruction. PMID- 23097972 TI - Results of surgery treatment of Dupuytren's contracture in 115 patients. AB - INTRODUCTION: Dupuytren's disease (DD) is a progressive fibroproliferative disorder of the hand causing digital flexion contracture. Treatment goals include removing or releasing the fibrotic cord to allow extension of the affected finger(s) and restoration of hand function. MATERIAL AND METHODS: In study period from 2001 through 2008, evaluation was performed in 115 patients. Limited or extensive fasciectomy was performed in all patients. Tubiana classification sheme to rate severity of DD was used. RESULTS: There were 106 male patients ( mean age 62.6 years) and 9 female patients (mean age 66.3 years). Before the operation, 38% of all patients were at Tubiana stage I, 32% were at stage II, 22% were at stage III and 8% were at stage IV. Of all patients, 43% were diagnosed with Dupuytren's in only one finger, 39% in two fingers and 18% in three fingers. In 23% of patients DD were diagnosed on both hands. Limited fasciectomy was peformed in 90.4% of patients and extensive fasciectomy in 9.6% of patients. The Tubiana stage achived after surgery was lower in 98% of patients. As a final result after surgery, 66% of patients didn't have contracture, stage I was reported in 28% and stage II in 3% of patients. There were no patients with Tubiana stage III or more after surgery. Postoperative complications were noted in 18% of patients. Wound healing problems were present 12% of patients. Haematoma was reported 5% of patients. Of all patients 22% had diabetes mellitus. CONCLUSION: DD is much more common in male than in female patients. Most of the patients are diagnosed at Tubiana stage I and II. Surgical correction has led to an improvement in most patients. Limited fasciectomy is still the gold-standard in DD treatment. Extensive fasciectomy or dermofasciectomy is preformed only in most severe cases. PMID- 23097973 TI - Parenchyma sparing procedures is possible for most pulmonary hydatid disease without recurrence and low complications. AB - OBJECTIVE: A retrospective review of 223 patients (242 operations) of pulmonary hydatid cysts. We analyze and evaluate our experience in the surgical management of this Moroccan endemic disease and concluded that parenchyma-saving must be always used. MATERIALS AND METHODS: In an 8 year period (2002 -2009), 223 patients (242 interventions, 282 pulmonary hydatid cysts) were operated on in our department. There were 166 males and 57 females with a mean age of 45.7 years. The diagnosis was established on the basis of different clinical signs and imaging studies. Surgical approach consisted of a posterolateral thoracotomy in all cases. Different surgical procedures were performed on the pulmonary lesions according to the localization, the size, the complicated or intact cyst and the importance of lung destruction. RESULTS: Parenchyma-saving were done in 217 patients (238 interventions) cases, including cystectomies (189 cysts), pericystectomies (47cysts) with capitonnage of the cavity in 177 cysts. Radical treatment as lobectomies is used in only 6 cases. Postoperative minors complications occurred in 13 cases (5.4%), including 6 prolonged air leak, 4 pneumonias, one wound infection and two transitory residual cavities. There was no postoperative death. All patients were free of recurrence of thoracic hydatid disease in a follow-up ranging from 3 to 90 months (mean: 49 months). CONCLUSION: Hydatid cysts of the lung should be treated before complications. Parenchyma saving is the best procedures for this benign disease; the radical resection must be reserved only for pulmonary destruction. PMID- 23097974 TI - Monitoring of disease biomarkers activity and immunophenotyping as important factors in SLE clinical management. AB - The highly specific biomarkers for monitoring of SLE disease activity are not yet defined up to date, due to existing of different clinical SLE phenotypes caused by individual genetic variation. Basically, numerous clinical complications follow SLE patients such as nephritis, atherosclerosis and cardial, CNS, gastrointestinal and ophthalmological complications, as well. Their monitoring in clinical SLE management can be evaluated by analysing of specific biochemical parameters and require permanent clinical observation. The presence of ANAs and anti-ds-DNAs are usual diagnostic SLE autoimmunity parameters, while SLE disease activity biomarkers are C3 and C4 level, anticardiolipin antibodies, anti-Sm/RNPs and, recently level of CD4 and CD8 lymphocytes. However, the number of TCR molecules on the T-cells surface at SLE patients is lower then in normal condition, and otherwise for these receptors CD molecules make specific connection. On the other hand, the T lymphocytes can be also, therapeutical targets at SLE patients, because of their clear direct involving in SLE pathogenesis. The SLE phenotypes are characterized by double CD negativity ( CD3 +/-, CD4-) caused by abnormal level of IL-2 and IL-17. T-lymphocytes have usually alpha-beta and gamma-delta TCR receptors, but for SLE patients is characteristic lower number gama-delta TCR molecules, detected in the peripheral blood specimens. Taking into account all of the facts, we investigated the level of specific usual SLE activity biomarkers (anti-ds-DNAs, C3, C4, anticardiolipin antibodies (beta-2-IgG, beta-2-IgM, ACA-G, ACA-M, CD4 and CD8 level) in serum specimens of SLE patients who underwent to the corresponding chemotherapy in combination with other biochemical and clinical parameters. Once again proved to be, that SLE biomarker monitoring, could be useful aproach for SLE activity disease and prediction organ damage, as well. In our investigation we used the following methods: immunofluorescence microscopy (IFA-ANA), and nephelometry, Hycor ELISA system and Flow cytometry, for precisely quantitative measurements. We determined correlation between C3 and C4 complement components level, CD3 (T Ly), CD3+/HLA-DR and total HLA-DR with regard to SLE disease activity. Also, CD4 (Th), CD4:CD8 ratio, beta-2-G, beta-2-M not proved to be useful biomarkers in this sense, despite some results specific for some special SLE phenotypes. Anti Sm/ RNPs proved to be better in SLE diagnostic process. PMID- 23097975 TI - Benefits, risks and complications of perioperative use of epidural anesthesia. AB - Use of thoracic epidurals is widespread for intraoperative and postoperative analgesia. Thoracic epidural anaesthesia (TEA) reduces sympathetic activity and thereby influences perioperative function of vital organ systems. A results of recent studies suggest that TEA decreases postoperative morbidity and mortality. There is better pain control with TEA in a wide range of surgical procedures. Use of TEA is associated with the risk of harm, but also the other methods used to control perioperative pain and stress response carry specific risks. Timely diagnosis and treatment of spinal compression or infection are crucial to ensure patient safety with TEA. The benefits of TEA outweigh the risks with respect to the perioperative outcome and organ protection, if basic guidelines are followed. PMID- 23097976 TI - Simultaneous transradial coronary and renal in stent restenosis treatment in diabetic patient with NSTEMI complicated by hypertensive emergency. AB - The elderly diabetic patients are increasingly referred for percutaneous coronary interventions during acute coronary syndromes. A nonegligible proportion of this population includes the in stent restenosis as a possible cause of ischemic syndrome. This population accounts an higher risk of ischemic, bleeding and vascular complications affecting the periprocedural management, the length of hospital stay and also the prognosis. The improvement of strategies concerning site of access choice, antithrombotic drug and timing of interventional treatment have significantly reduced the incidence of complications. This paper reports the case of a 76 years-old diabetic female with a high bleeding risk, referred to our hospital because of NSTEMI complicated by pulmonary edema during hypertensive emergency. The patient had a simultaneous in stent restenosis both in left descending coronary artery and left renal artery, undergoing percutaneous transradial treatment during bivalirudin infusion. The clinical, technical, pharmacological and prognostic implications are discussed. PMID- 23097977 TI - Supernumerary breast in an adolescent boy. AB - We present an adolescent boy with unilateral supernumerary breast. It was a V type by Leung Clasification. Despite the average occurence between 0.22% and 6% in a normal population we have not had other cases in the last 20 years. The patient was an asthenic boy of sixteen in the IV stage of puberty. Sometimes he felt swelling and tenderness in this breast tissue two years ago. These symptoms became worse two months ago. At the admission he was symptom free. In the right hypochondrium inferomedially he had a nipple and areola with a small part of the glandular tissue. The axilla was empty. After an excision we got a 15 x 10 x 8 mm specimen. Pathohistological report described incompletely formed mammary lobule with smooth muscles and lactiferous ducts of nipple in dermis. This was consistent with the diagnosis of ectopic breast tissue. He wanted it removed for esthetic reasons. His hormonal state was normal. All blood checks were normal. Kidney ultrasound was normal. His grandmother had pyelon duplex and frequent uroinfections. As it is known, there is an association between supernumerary breast tissue and renal malformations. Since he did not have it, we think that a routine screening of the uropoetic system should be performed in any patient with supernumerary breast. PMID- 23097978 TI - Recurrent abortions and down syndrome resulting from Robertsonian translocation 21q; 21q. AB - AIM: The purpose of the present research was a presentation of case report of Robertsonian translocation composed of homologous chromosomes 21q;21q and reproductive risk found in the family affected by this type oftranslocation. METHODS: Cytogenetic diagnosis has been done on chromosome preparations of lymphocytes cultured from peripheral blood by Moorhead method. RESULTS: Analyses of cytogenetic diagnosis was performed on the couple who has been through 10 spontaneous miscarriages and two additional births with Down syndrome. The woman had Robertsonian translocation between homologous chromosomes 21: 45XX,der(21;21)(q10;q10), and there was no change in her phenotype, whereas her husband had a normal phenotype and karyotype: 46, XY. Their first child with Down syndrome symptoms did not undergo the cytogenetic analysis. By cytogenetic analysis it was discovered that their second child has Trisomy 21 with Robertsonian translocations between homologous chromosomes 21: 46,XY,+21,der(21;21) (q10;q10)mat, and that he inherited it from his mother. CONCLUSION: Chromosomal aberration that our patient suffered from and that is presented in this paper has caused spontaneous miscarriages and birth of children with Down syndrome. Based on cytogenetic analysis in prenatal diagnosis and genetic consultation of affected family with Robertsonian translocation 21q;21q, it is unlikely to select healthy offspring by a parent with that aberration. PMID- 23097979 TI - Primary cutaneous umbilical endometriosis. AB - INTRODUCTION: Primary umbilical endometriosis a rare case. It is mostly seen in women in the reproductive age group. CASE REPORT: In this case report, a 38 year old woman is discussed who received antibiotherapy for omphalitis diagnosis established due to many complaints of umbilical secretion but who was diagnosed with primary umbilical endometriosis after histopathological examination. CONCLUSION: Endometriosis must be certainly considered in differential diagnosis in especially inflammatory lesions resistant to noncyclic treatment, determined in umbilical region. PMID- 23097980 TI - Renal artery aneurism. AB - BACKGROUND: Renal artery aneurysm is very rare and most often incidental finding and we will present it in our case report. CASE REPORT: We report a case of 65 years old women who was sent to our hospital Clinic of Radiology. We detected a renal artery aneurysm on the left side on the ultrasound and later we confirmed it on the CTA of the abdominal aorta and its visceral branches. DISCUSSION: Renal artery aneurysms can be classified in true anaurysm and pseudoaneurysm. They are more often find at females. They can be fusiform or saccular in appearance and are extraparenchymal in 90% of cases. Most are saccular and noncalcified. CONCLUSION: In the case of renal artery aneurysm that we founded we recommended regular Color Doppler ultrasound examinations, consultation from the urologist and CTA control if there is a need. PMID- 23097981 TI - Minimally invasive mitral valve surgery through right lateral minithoracotomy- early experience of Clinical Centre of University of Sarajevo. AB - INTRODUCTION: In this article we would like to make an institutional report and our early experience in video-assisted right minithoracotomy approach for mitral valve surgery. CASE REPORT: Surgical technique include mitral valve repair or replacement through right lateral minithoracotomy, percutaneous cannulation for venous drainage and optional femoral or distal ascendant aortic cannulation for vacuum assisted CPB, direct cross clamping of the aorta with anterograde administration of the cardioplegic solution for inducing cardiac arrest. Mean CPB time was 128 min +/- 41 min, mean Cross clamping time was 70 min +/- 14 min. Mean ICU stay was 1.2 days, while mean blood transfusion was 0.8 package/patient, no complications has occurred and the patients were discharged between the 4th and 7th postoperative day. Echocardiographically follow-up (2-6 months) showed absence of mitral valve regurgitation in the mitral repair patients and good functioning of prosthetic valves. CONCLUSION: Minimally invasive mitral valve procedures through right lateral minithoracotomy might be effective alternative to full sternotomy approach in mitral valve surgery. PMID- 23097982 TI - [The biological reaction of inflammation, methylglyoxal of blood plasma, functional and structural alterations in elastic type arteries at the early stage of hypertension disease]. AB - The article deals with studying of the relationship between biologic reaction of inflammation with glycosylation reaction and content of methylglyoxal in blood serum. The positive correlation between pulse wave velocity and content of methylglyoxal, C-reactive protein in intercellular medium and malleolar brachial index value was established. This data matches the experimental results concerning involvement of biological reaction of inflammation into structural changes of elastic type arteries under hypertension disease, formation of arteries' rigidity and increase of pulse wave velocity. The arterial blood pressure is a biological reaction of hydrodynamic pressure which is used in vivo by several biological functions: biological function of homeostasis, function of endoecology, biological function of adaptation and function of locomotion. The biological reaction of hydrodynamic (hydraulic) pressure is a mode of compensation of derangement of several biological functions which results in the very high rate of hypertension disease in population. As a matter of fact, hypertension disease is a syndrome of lingering pathological compensation by higher arterial blood pressure of the biological functions derangements occurring in the distal section at the level of paracrine cenoses of cells. The arterial blood pressure is a kind of in vivo integral indicator of deranged metabolism. The essential hypertension disease pathogenically is a result of the derangement of three biological functions: biological function of homeostasis, biological function of trophology - nutrition (biological reaction of external feeding - exotrophia) and biological function of endoecology. In case of "littering" of intercellular medium in vivo with nonspecific endogenic flogogens a phylogenetically earlier activation of biological reactions of excretion, inflammation and hydrodynamic arterial blood pressure occur. In case of derangement of biological function of homeostasis, decreasing of perfusion even in single paracrine cenoses and derangement of biological function of endoecology ("purity" of intercellular medium) the only response always will be the increase of arterial blood pressure. PMID- 23097983 TI - [The biochemical markers of endothelium dysfunction in patients with diabetic nephropathy]. AB - The article deals with studying the degree of increase of the von Willebrand factor and the concentration of endothelin-1 in blood plasma in the subgroups of patients with diabetes mellitus formed depending on of type of disease and presence of phenotype with affection of kidneys. The sampling of 176 patients with diabetes mellitus (65 patients with diabetes mellitus type 1, 111 patients with diabetes mellitus type II) was examined. The control group consisted of 30 healthy persons. In the capacity of biochemical markers of endothelium dysfunction the activity of the von Willebrand factor and the concentration of endothelin-1 in blood were considered. In all patients with diabetes mellitus the biochemical characteristics of endothelium dysfunction are present manifesting by increase of concentration of endothelin-1 in blood which is especially expressed under disease phenotype with affection of kidneys. Despite of the apparent lesion of endothelium in patients with diabetes mellitus compromised with diabetic nephropathy the thrombocytes aggregation induced by ristomicine does not undergo natural changes. Hence, to consider in these patients the increasing activity of the von Willebrand factor as a reliable marker of endothelium dysfunction is not seemed possible. PMID- 23097984 TI - [The role of imbalance of fatty acids in formation of endothelium dysfunction in women in menopause]. AB - The article deals with the results of examination of 203 women in condition of natural (61 female patients) and surgical (142 female patients) post menopause. The rate of occurrence of impairment of functional state of endothelium made up to 67% (136 of examined female patients). The nitroxide-producing function of endothelium was decreased in all female patients, most of all in women with surgical menopause. The patients with endothelium dysfunction symptoms had a significant decrease of amount of omega-3 polyunsaturated fatty and arachidonic acids in erythrocytes' membranes and an increase of amount of gamma-linolenic and dihomo-gamma-linolenic acids. The multidirectional correlation dependences between indicators of endothelium function and amount of various fatty acids in erythrocytes' membranes was established. PMID- 23097985 TI - [The methods of analysis of DNA methylation]. AB - The article deals with the review of methods of analysis of DNA methylation as one of key mechanisms of regulation of gene expression. The sites of aberrant methylation are potential markers of neoplastic transformation. At the present time, the development of clinical tests is in the process on basis of analysis of methylation to make prognosis and to diagnose oncologic diseases, micro metastases detection and prenatal diagnostics of certain hereditary syndromes. The comparative analysis of methods applied in clinical practice and in carrying out fundamental studies was made. PMID- 23097986 TI - [The analytical setting of rotary speed of centrifuge rotor and centrifugation time in chemical, biochemical and microbiological practice]. AB - The researchers happen to face with suspensions in their chemical, biochemical and microbiological practice. The suspensions are the disperse systems with solid dispersed phase and liquid dispersion medium and with dispersed phase particle size > 100 nm (10-7 m). Quite often the necessity occurs to separate solid particles from liquid. To use for this purpose the precipitation in gravitation field can make the process to progress too long. In this respect an effective mode is the precipitation in the field of centrifugal forces--the centrifugation. The rotary speed of centrifuge rotor and centrifugation time can be set analytically using regularities of general dynamics and hydrodynamics. To this effect, should be written and transformed the equation of First and Second Newton Laws for suspension particle being in the field of centrifugal forces and forces of resistance of liquid and vessel wall. The force of liquid resistance depends on particle motion condition in liquid. To determine the regimen the Archimedes and Reynolds numerical dimensionless criteria are to be applied. The article demonstrates the results of these transformations as analytical inverse ratio dependence of centrifugation time from rotary speed. The calculation of series of "rate-time" data permits to choose the optimal data pair on the assumption of centrifuge capacity and practical reasonability. The results of calculations are validated by actual experimental data hence the physical mathematical apparatus can be considered as effective one. The setting progress depends both from parameter (Reynolds criterion) and data series calculation. So, the most convenient way to apply this operation is the programming approach. The article proposes to use the program Microsoft Excel and VBA programming language for this purpose. The possibility to download the file from Internet to use it for fast solution is proposed. PMID- 23097987 TI - [The multi-central clinical laboratory study of precision of the portative glucometer "Satellite Plus"]. AB - The analysis of 482 blood samples of patients with diabetes mellitus type I and II and healthy persons was made using the portative glucometer "Satellite Plus". The comparison with reference analyzer was made. The results of clinical laboratory tests demonstrated that this glucometer meets the precision requirements of inter-national standard ISO 15197:2003 (97.5% of results are in the limits of standard deviation). The evaluation of results using the technique of analysis of errors array for patients with diabetes mellitus type 1 demonstrated that 99.4% (479 out of 482) were in zone A i.e. are clinically accurate results. The measurement results capable to negatively impact the clinical course of disease, to represent significant medical risk and to result in dangerous outcomes were not registered. So, the portative glucometer "Satellite Plus" can be recommended to detect the concentration of glucose in capillary blood for self-control of the glycaemia level in patients with diabetes mellitus. The device can be applied too for express-diagnostics in conditions of emergency medical care rendering by medical personnel. PMID- 23097988 TI - [The regional indicators of male fertility in the Samara oblast and causative factors of their alterations]. AB - The apparent tendency of decreasing male fertility is observed during last years. Basically, this occurrence is related to deterioration of environment conditions, harmful habits and male's organism state. The WHO standards of indicators of spermogram were formulated by averaging the statistical data collected in various countries. At that, in most cases the data from regional indicators are lacking. The Samara oblast is not exclusion. Hence, the study purpose was to reveal the regional indicators of spermogram among males of the Samara oblast and the comparison of received data with the WHO standards. The study of impact on the fertility indicators of such external factors as age, smoking intensity and alcohol consumption was implemented too. PMID- 23097989 TI - [The condition of endothelium and hemostasis in patients with primary diagnosed acute lymphoblast leucosis]. AB - The evaluation of state of endothelium and plasma hemostasis, thrombocytopenia degree, rate of thrombo-hemorrhagic complications in adult patients with acute lymphoblastic leucosis in the period of disease manifestation was made. The thrombosis developed in 1 out of 24 (4.2%) examined patients, hemorrhagic syndrome in 11 out of 24 (45.8%) examined patients. The last case is closely linked with severity of thrombocytopenia occurred in patients with number of thrombocytes less than 50 x 109/l. At the same time, high correlation between number of leukemic cells and level of B-dimers (rs = 0.703) testifies that the leucosis process activates intravascular thrombus formation. The higher content of B-dimers in 100% of patients validates this assumption. The high levels of soluble thrombo-modulin and von Willebrand factor indicate the loss of thromboresistance by vessel endothelium and the activation of prothrombin mechanisms. The statistically valid coefficients of correlation between concentrations of thrombomodulin and D-dimers (rs = 0.598) and the level of von Willebrand factor and severity of hemorrhagic syndrome prove that disorders of blood coagulation under acute lymphoblast leucosis occur with active involvement of endothelium. PMID- 23097990 TI - [The mutation of genes of hemostasis system in patients with venous cerebral angiodystonia against the background of connective tissue dysplasia]. AB - The examination was applied to sampling of 238 patients of younger age with neurologic symptomatology under connective tissue dysplasia and 46 healthy persons. The venous cerebral angiodystonia was diagnosed in 153 (64.3%) patients with connective tissue dysplasia. The results are confirmed by duplex analysis of cerebral and vertebral vessels. The mutations of genes of blood coagulation system (FV Leiden, FII, MTHFR, FVII and PAI-1) are established. They include combined (61.4%) and independent (23.5%) groups of mutation. Alongside with it, in 23 (19.6%) patients disorders of hemostasis are presented as von Willebrand factor deficiency and in 105 (89.7%) patients as decrease of aggregation function of thrombocytes and disorders of final coagulation stage of blood coagulation. The results of study indicate the equally frequent risk of thrombotic and hemorrhagic complications in patients with connective tissue dysplasia. PMID- 23097991 TI - [The characteristics of hemostasis condition in women with non-carrying of pregnancy]. AB - The typical changes of hemostasis indicators in different periods of gestation are described. The analysis of blood plasma in pregnant women with menace of miscarriage and compromised anamnestic record on spontaneous or attempted abortion was made. The valid hypercoagulation deviations are detected. They are manifested in the decrease of international normalized ratio indicators and index of activated partial thromboplastin time, the increase of level of soluble fibrin monomeric complex against the background of mild hyperfibrinogenemia and decrease of activity of plasminogen, antihtrombin III and protein C. The lupousus anticoagulant and Leiden mutation occurred more often. The evidence of changes differed depending of presence of complications in the anamnesis and current menace of miscarriage. The established thrombofilic shifts can play certain pathogenic role in development of noncarrying of pregnancy. PMID- 23097992 TI - [The role of flow cytofluorometry in cytological diagnostic of non-Hodgkin's lymphomas]. AB - The techniques of flow cytofluorometry and immune cytochemistry combined with routine cytological analysis were applied to 81 patients with non-Hodgkin's lymphomas to diagnose the malignant lymphomas and to determine their immune phenotypes. The accuracy of proposed techniques combination to diagnose the malignant lymphoma consists 98% and to determine the immune phenotype - 90%. The presented combination of routine cytological analysis combined with techniques of flow cytofluorometry and immune cytochemistry is the express-technique to diagnose lymphoma and its immune phenotype the day of patient visit to the doctor. This approach significantly increases the role of cytological method in diagnostics of lymphomas. The technique makes it possible to analyze simultaneously huge quantity number of lymph nodes, including deep-seated and not only the superficial lymph nodes. PMID- 23097993 TI - [The characteristics of evaluation of expression of ZAP-70 in tumor cells under b cell chronic lymphatic leukemia using the flow cytofluorometry technique]. AB - The b-cell chronic lymphatic leukemia is the most common among all lymphatic proliferative diseases and is characterized by significant variability of its clinical course. The mutation status of genes of variable region of heavy chains of immunoglobulins (IgVH) is the most reliable prognostic factor forecasting time until beginning of treatment in case of b-cell chronic lymphatic leukemia. However its detection nowadays is inaccessible for routine diagnostics. Among surrogate markers of mutation status the indicator of expression of ZAP-70 by tumor cells estimated using flow cytofluorometry. However, in publications there are different guidelines concerning the technique of mentioned marker. To establish the optimal approach to evaluation of expression of ZAP-70 the peripheral blood samples of 5I patients with b-cell chronic lymphatic leukemia and 10 healthy persons were analyzed. The comparison with the results of detection of mutation status of IgVH-genes revealed the advantage of applying the technique of calculation of MFI ratio during interpretation of data of expression of ZAP-70 obtained with flow cytofluorometry. In this framework, the indicator of expression of ZAP-70 can be applied in assessing the course of disease and time until the beginning of treatment of b-cell chronic lymphatic leukemia. PMID- 23097994 TI - [The cytomorphologic characteristics of diagnostics of tumors of soft tissues on paracentetic material]. AB - The retrospective analysis of cytological and histological comparison of paracentetic material of tumors of soft tissues revealed matching in character of pathologic process in 78.72% of findings and in genesis of neoplasms in 70.21% of findings. The complexity of cytological diagnostics is determined by variety of histologic alternatives of neoplasms and their cell similarity. The erroneous interpretation, hipodiagnostics of cytograms of tumors of soft tissues more often is related to in-adequate informativity of paracentetic material. In certain cases, this due to under-estimation of distinctive morphofunctional, structural and background indications. PMID- 23097996 TI - [The extract from the federal law of the Russian Federation No 323-FZ 21.11.2011 "On the fundamentals of protection of health of citizen in the Russian Federation"]. PMID- 23097995 TI - [The content of rosette-forming neutrophils and lysozyme in patients with Q fever]. AB - The article deals with the results of study of 35 patients with Q-fever and 30 donors to determine the content of rosette-forming neutrophils, lysozyme activity of blood and saliva. On the second week of disease it was revealed the activation of compensative immune mechanisms and on third and fourth week inhibition of these mechanisms. PMID- 23097997 TI - Awareness campaign combats the growing problem of violence. PMID- 23097998 TI - Dysfunctional uterine bleeding (DUB)--a term beyond its time. PMID- 23097999 TI - Interdisciplinary education in palliative care: impact on attitudes of students in medicine, nursing, pharmacy, social work, and chaplaincy. AB - INTRODUCTION: Interdisciplinary education among health professions has been recommended, and related evaluation can be found in the literature. However questions remain on how effective interdisciplinary education is and what impact it has. The objective of this study was to determine changes in student attitudes and perceptions upon completion of a 5-week interdisciplinary palliative care seminar. METHODS: Pre-test and post-test instruments were administered at three five-week Interdisciplinary Palliative Care Seminars in Sioux Falls, SD during 2009-2010. The central hypotheses were that, at the conclusion of the seminar, students will have greater familiarity with their role in a team and more understanding of the roles of other disciplines in palliative care, and will identify positive contributions to professional practice and patient care using the team approach. Both quantitative and qualitative data were analyzed. RESULTS: Participating students in medicine, nursing, pharmacy, social work, and chaplaincy (N = 88) completed surveys. Quantitative data suggest that interdisciplinary education enhances students' understanding of their discipline and the work of other disciplines. Data show students perceive the team approach as enhancing patient outcomes, goal setting, and communication among colleagues. Qualitative data reinforced the importance of interdisciplinary education while revealing strains among disciplines in hierarchy and valuing. CONCLUSIONS: Playing one's part in the team strengthens students' confidence and comfort in interdisciplinary settings. Yet, the hazard of experiencing the limitations of teamwork in action must be acknowledged for some. PMID- 23098000 TI - Prothrombin complex concentrate (PCC) and its effect on reversing newer oral anticoagulants. PMID- 23098001 TI - Quality focus: care transitions data. PMID- 23098002 TI - The obsolete image of the ideal physician. PMID- 23098003 TI - West Virginia Medical Professionals Health Program update. PMID- 23098004 TI - Intralobar bronchopulmonary sequestra in adults over age 50: case series and review. AB - INTRODUCTION: Bronchopulmonary sequestration (BPS) is a rare congenital lung malformation, comprising only 0.15 to 6.4% of all cases of congenital lung malformation. It is characterized by an abnormal segment of bronchopulmonary tissue supplied by an aberrant systemic artery. Diagnostic delays are common in the adult patients since the symptoms often mimic other common diseases such as pneumonia, emphysema, and lung abscess. In 60% of cases, intralobar pulmonary sequestration (ILS) is typically diagnosed at age 20 or younger and is rarely found in adults older than 40 years. Since a heightened clinical suspicion needs to be maintained to entertain this diagnosis in the adult population, we conducted a retrospective chart review of all adult patients at our institution over age 50. MATERIALS AND METHODS: A retrospective chart review of all adult patients evaluated at our institution with a pathological proven diagnosis of BPS and subsequent surgical correction from January 1993 through December 2008 was conducted. Data obtained included demographics, clinical presentation, diagnostic procedures, location and origin of the lesion, operative therapy, histology of the surgical specimen, and postoperative complications. RESULTS: Three patients had undergone surgical correction for BPS. All three patients at our institution were female. The average age was 59 years with a range from 57 to 62 years. All three patients had symptoms preoperatively including intermittent cough and recurrent pneumonia. Radiologic evaluation revealed an enlarging lung mass in one patient and lesions suggestive of BPS in two of the patients. Two patients had a right lower lobe sequestration and one patient had a left lower lobe sequestration. All three patients underwent lower lobectomies without any significant postoperative complications. CONCLUSION: BPS in patients older than 50 is very rare. Persistent lower lobe consolidation in medial or posterior basal segments accompanied by an aberrant artery in adults should heighten suspicion for it. Recurrent pneumonias, cough, chest pain occur in the majority of patients. Surgical excision after correctly identifying the aberrant vessel is curative and also diagnostic in some cases. PMID- 23098005 TI - Exploring takotsubo cardiomyopathy in an elderly patient with acute anxiety attack. AB - Takotsubo cardiomyopathy ("broken heart") exhibits a highly possible link between acute emotional stress and the onset of left ventricular dysfunction. This article describes a case report of takotsubo cardiomyopathy in an 89-year-old female; the patient is significantly older than the median age for this condition, which ranges from 63 to 76 years of age. The exact mechanism of this condition is unclear and there are several hypotheses under investigation. Several studies have shown a link between takotsubo cardiomyopathy and elevated catecholamines. Similarly, other studies have documented emotional and physical stress to be the underlying pathophysiology of this condition. Another case study has proposed a novel hypothesis of a link between septal thickening in cases of takotsubo cardiomyopathy. This article is an interesting case report of an elderly patient with takotsubo cardiomyopathy. PMID- 23098006 TI - Invasive pneumococcal disease potentially preventable: a case report. PMID- 23098007 TI - Neurosurgical therapy for central area status epilepticus. AB - The authors report a case of status epilepticus localized to sensorimotor cortex that was successfully treated with surgical resection and multiple subpial transections (MST). A 43 year old woman presented in status epilepticus emanating from a right central area focus as verified by subdural grid and strip electrodes. The seizures were medically intractable but were successfully aborted after surgical intervention. The authors describe their case and review the literature on central area status epilepticus. PMID- 23098008 TI - Mildly reduced preoperative ejection fraction increases the risk of stroke in older adults undergoing coronary artery bypass grafting. AB - INTRODUCTION: Current guidelines based on clinical trials may have inadvertently excluded a representative cohort of older adults. As a result, little is known about the predictors of stroke among elderly patients undergoing coronary artery bypass surgery (CABG). The purpose of this study was to determine how a lower than normal ejection fraction (EF) predicted post surgery stroke among elderly patients undergoing CABG when compared with younger populations. METHODS: Retrospective cross-sectional cohort analysis. setting: Charleston Area Medical Center, a tertiary medical center. PARTICIPANTS: 8661 consecutive CABG cases between 2003 and 2009. measurements: PARTICIPANTS were divided into three different age groups: < 65 years old (Group 1), between 65 and 79 years old (Group 2), and > or = 80 years old (Group 3). We calculated the rate of overall neurological complications after CABG for patients with ejection fraction values: < 40%, between 40% and 59%, and > or = 60. RESULT: Group 3 (age > = 80) with EF < = 39 had the highest odds of developing post CABG stroke (Odds Ratio (OR): 5.6) followed by Group 3 (age > = 80) with EF 40-59 (OR: 3.9). In addition, Group 2 (age 65-79) with EF < = 39 had the next highest odds of developing post CABG stroke (OR: 2.3) followed by Group 2 (age 65-79) with EF 40-59 (OR: 1.9). CONCLUSION: Contrary to current guidelines, in our study population, mildly affected EF increased the overall risk of neurological complications among elderly patients undergoing CABG. PMID- 23098010 TI - When the unthinkable threatens. PMID- 23098009 TI - To scan or not to scan. PMID- 23098011 TI - Opioid consumption before and after the establishment of a palliative medicine unit in an Egyptian cancer centre. AB - Opioid consumption before and after the establishment of a palliative medicine unit (PMU) in an Egyptian cancer centre was reviewed. A comparison of consumption during the year before the PMU was established to consumption during the third year after the PMU's establishment revealed that morphine consumption increased by 698 percent, fentanyl by 217 percent, and tramadol by 230 percent. Expressed in defined daily dose (DDD) and adjusted for 1,000 new cancer patients, consumption increased by 460 percent, from 4,678 DDD/1,000 new patients to 26,175 DDD/1,000 new patients. Expressed in grams of oral morphine equivalent (g OME), consumption increased by 644 percent, from 233 g OME/1,000 new patients to 1,731 g OME/1,000 new patients. The establishment of the PMU was associated with an increase in opioid consumption, especially morphine, which is an indicator of improvement in cancer pain control. The expression of opioid consumption in OME in addition to DDD may provide further information, especially when weak opioids are included in the analysis. PMID- 23098012 TI - The evaluation of a triage tool for a community palliative care service provider. AB - INTRODUCTION: Triage, widely used by the military and emergency departments, has not been reported in community palliative care services. Policy designed to improve equitable provision of this care has led to the development of a triage tool. METHODS: Retrospective data were collected (50 percent of referrals, n = 204) and analyzed using the Wilcoxon signed-rank test to determine the accuracy of the tool in predicting patient status at the first visit. Semi-structured interviews (n = 7) with palliative care service staff added qualitative data. RESULTS: Although significant differences between triage scores compared to outcomes at first visit were observed, issues such as upgrading of triage category compared to priority score occurred in more than 30 percent of cases. When correction for this was made, the tool was found to be an accurate guide to patient needs. CONCLUSION: This tool, when used as intended, was effective in assessing the urgency of need, and it is potentially useful on a wider scale, subject to further evaluation. PMID- 23098013 TI - Being a hospice volunteer influenced medical students' comfort with dying and death: a pilot study. AB - Being comfortable with death and communicating with patients near the end of life are important attributes in palliative care. We developed a hospice volunteer program to teach these attitudes and skills to preclinical medical students. Using a mixed-methods approach, validated surveys measured participants' and non participants fear of death and communication apprehension regarding dying. Journals and focus groups examined participants' subjective experiences as their patient relationships evolved. Survey scores were significantly lower for participant hospice volunteers, indicating lower levels of death anxiety and communication apprehension regarding dying. An explanatory framework, using journals and focus groups, captured participants' sense of development over time into three categories: challenges, learning, and growth. This pilot project provides insight into the medical students' experiential learning as they participate in our hospice volunteer program. PMID- 23098014 TI - Improving resident self-efficacy in pediatric palliative care through clinical simulation. AB - CONTEXT: Pediatric residents have limited training and practice experience with palliative care. This study examined whether clinical simulation improved resident self-efficacy in pediatric palliative care. METHODS: Residents were surveyed on their self-efficacy and how they perceived the importance of pediatric palliative care; they were then randomized into either a control group or an intervention group. The intervention group participated in two simulated pediatric palliative care scenarios. The residents' responses before and after the intervention were analyzed to determine whether simulation training had influenced their responses. RESULTS: Although there were no differences in responses on the importance of pediatric palliative care, respondents were more comfortable with suggesting that conferences are needed with families of children who have life-limiting conditions in order to explain do-not-resuscitate orders. CONCLUSION: Simulation improved pediatric residents' self-efficacy with end-of life discussions. PMID- 23098015 TI - Caring for patients dying with dementia: challenges in subacute care in Australia. PMID- 23098017 TI - Harm reduction and palliative care: is there a role for supervised drug consumption services? PMID- 23098016 TI - Spiritual and emotional support of primary informal end-of-life caregivers in Nova Scotia. PMID- 23098018 TI - Opportunities for improving the quality of life of dying persons: use of technology to connect people at the end of life. PMID- 23098019 TI - [Scientists advocate the planned European Union nursing education reform. The admission requirements should be increased throughout Europe to 12 school years]. PMID- 23098020 TI - [Help for depression: the media are haunted by many misconceptions on the topic of depression]. PMID- 23098021 TI - [Study of the salary of nurses: operating room nurses earn an average of 3,066 euro]. PMID- 23098022 TI - [Bp: language requirements for foreign nurses are revised. DPR supports the requirement of the Europarat. A B2 level is required]. PMID- 23098023 TI - [Geriatrician: malnutrition in the elderly is underestimated. 6 simple questions shed light on the nutritional status of patients]. PMID- 23098024 TI - [From evidence to treatment decision]. PMID- 23098025 TI - [Providing a social practice environment]. PMID- 23098026 TI - [Focusing on the positive]. PMID- 23098027 TI - [A bridge between cultures]. PMID- 23098028 TI - [Have a beer!]. PMID- 23098029 TI - [One in the morning, none at noon, one in the evening]. PMID- 23098030 TI - [Forensic psychiatry: nurses can deal well with stresses]. PMID- 23098031 TI - [The life as a caregiver of a person affected by Chorea Huntington: multiple case study]. AB - Chorea Huntington is an autosomal dominantly inherited, neurodegenerative brain disorder that leads to involuntary hyperkinesia, psychotic symptoms and dementia. The illness not only changes the life of the person itself but also the world of the caregivers. The challenges in the care of a person which is affected by Chorea Huntington have an effect on the daily living as an assemblage of natural and social conditions. METHOD: a multiple case study was conducted. It included semi-structured interviews with three caregivers of people with Chorea Huntington in South Tyrol. The qualitative data was analyzed using the qualitative structured analysis of Mayring (2007). OBJECTIVE: The objective of this study was to describe the phenomenon of change of life from family members that care people affected by Chorea Huntington in a specific cultural setting (South Tyrol, Italy). RESULTS: The caregivers reported that the diagnosis of Chorea Huntington leads to negative changes in "relationship and family". Particularly, frustration, aggression, impatience and apathy were perceived as stressful. At the same time they highlight the positive changes through home care. They report that the relationship became more intimate and integral and it was characterized by more cohesion. Family caregivers get valuable support from the home care service, however, they complain that there is no facility in South Tyrol, which is specialized to care people with Chorea Huntington. Therefore, the caregivers have to "give up a lot" and don't have any personal desires, dreams and expectations for the future. CONCLUSIONS: The caregivers have learned independently to deal with their changed life step by step, and to see also the positive effects of the caring role. The life of family caregivers of a person which is affected by Chorea Huntington is characterized by abandonment. A continuous and professional care would be important for the affected and his caregiver. A continuous and professional care is important for both, addressing the care needs of the persons affected by Chorea Huntington and preparing their caregivers for the changing life. PMID- 23098032 TI - [Comprehending the work process]. PMID- 23098033 TI - [Watch and learn]. PMID- 23098034 TI - [Sound professional knowledge and a capacity for empathy]. PMID- 23098035 TI - ["Reality therapy" in the home environment]. PMID- 23098036 TI - [Judges confirm the fundamental right to physical integrity]. PMID- 23098037 TI - [Treating mentally ill patients in ambulatory care]. PMID- 23098038 TI - Identification of small molecule inhibitors of amyloid beta-induced neuronal apoptosis acting through the imidazoline I(2) receptor. AB - Aberrant activation of signaling pathways plays a pivotal role in central nervous system disorders, such as Alzheimer's disease (AD). Using a combination of virtual screening and experimental testing, novel small molecule inhibitors of tPA-mediated extracellular signal-regulated kinase (Erk)1/2 activation were identified that provide higher levels of neuroprotection from Abeta-induced apoptosis than Memantine, the most recently FDA-approved drug for AD treatment. Subsequent target deconvolution efforts revealed that they all share low micromolar affinity for the imidazoline I(2) receptor, while being devoid of any significant affinity to a list of AD-relevant targets, including the N-methyl-d aspartate receptor (NMDAR), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B). Targeting the imidazoline I(2) receptor emerges as a new mechanism of action to inhibit tPA-induced signaling in neurons for the treatment of AD and other neurodegenerative diseases. PMID- 23098039 TI - Hypofractionated stereotactic radiotherapy of limited brain metastases: a single centre individualized treatment approach. AB - BACKGROUND: We retrospectively report treatment results of our single-centre experience with hypofractionated stereotactic radiotherapy (hfSRT) of limited brain metastases in primary and recurrence disease situations. Our aim was to find the most effective and safe dose concept. METHODS: From 04/2006 to 12/2010, 75 patients, with 108 intracranial metastases, were treated with hfSRT. 52 newly diagnosed metastases (48%), without up-front whole brain radiotherapy (WBRT), received hfSRT as a primary treatment. 56 metastases (52%) received a prior WBRT and were treated in this study in a recurrence situation. Main fractionation concepts used for primary hfSRT were 6-7x5 Gy (61.5%) and 5x6 Gy (19.2%), for recurrent hfSRT 7-10x4 Gy (33.9%) and 5-6x5 Gy (33.9%). RESULTS: Median overall survival (OS) of all patients summed up to 9.1 months, actuarial 6-and 12-month OS was 59% and 35%, respectively. Median local brain control (LC) was 11.9 months, median distant brain control (DC) 3.9 months and intracranial control (IC) 3.4 months, respectively. Variables with significant influence on OS were Gross Tumour Volume (GTV) (p = 0.019), the biological eqivalent dose (calculated on a 2 Gy single dose, EQD2, alpha/beta = 10) < and >= median of 39 Gy (p = 0.012), extracerebral activity of the primary tumour (p < 0.001) and the steroid uptake during hfSRT (p = 0.03). LC was significantly influenced by the EQD2, <= and > 35 Gy (p = 0.004) in both uni- and multivariate Cox regression analysis. Median LC was 14.9 months for EQD2 >35 Gy and 3.4 months for doses <=35 Gy, respectively. Early treatment related side effects were usually mild. Nevertheless, patients with a EQD2 >35 Gy had higher rates of toxicity (31%) than <=35 Gy (8.3%, p=0.026). CONCLUSION: Comparing different dose concepts in hfSRT, a cumulative EQD2 of >=35 Gy seems to be the most effective concept in patients with primary or recurrent limited brain metastases. Despite higher rates of only mild toxicity, this concept represents a safe treatment option. PMID- 23098040 TI - Biotransformation of ceria nanoparticles in cucumber plants. AB - Biotransformation is a critical factor that may modify the toxicity, behavior, and fate of engineered nanoparticles in the environment. CeO(2) nanoparticles (NPs) are generally recognized as stable under environmental and biological conditions. The present study aims to investigate the biotransformation of CeO(2) NPs in plant systems. Transmission electron microscopy (TEM) images show needlelike clusters on the epidermis and in the intercellular spaces of cucumber roots after a treatment with 2000 mg/L CeO(2) NPs for 21 days. By using a soft X ray scanning transmission microscopy (STXM) technique, the needlelike clusters were verified to be CePO(4). Near edge X-ray absorption fine structure (XANES) spectra show that Ce presented in the roots as CeO(2) and CePO(4) while in the shoots as CeO(2) and cerium carboxylates. Simulated studies indicate that reducing substances (e.g., ascorbic acids) played a key role in the transformation process and organic acids (e.g., citric acids) can promote particle dissolution. We speculate that CeO(2) NPs were first absorbed on the root surfaces and partially dissolved with the assistance of the organic acids and reducing substances excreted by the roots. The released Ce(III) ions were precipitated on the root surfaces and in intercellular spaces with phosphate, or form complexes with carboxyl compounds during translocation to the shoots. To the best of our knowledge, this is the first report confirming the biotransformation and in-depth exploring the translocation process of CeO(2) NPs in plants. PMID- 23098041 TI - From the editor. PMID- 23098042 TI - Common factors that enhance the quality of life for women living in their own homes or in aged care facilities. AB - A qualitative study of older women living in their own homes and older women living in aged care facilities found that the concerns of the women living in their own homes were the realities of life for the residents in the aged care facilities. Twenty-five female residents across two facilities and 11 older women living in their own homes were interviewed. The positive outcomes of aging at home are relevant and desirable for residents of aged care facilities. A smooth transition from community living to residential aged care involves retaining some of these positive aspects of their lives. PMID- 23098043 TI - Readability of menopause web sites: a cross-sectional study. AB - More women are frequently referring to the Internet for health information, yet the readability of information about menopause on the Internet has not been widely studied. To address this gap, this study examined the readability of information about menopause on 25 Internet Web sites. Findings included that information on the Web sites had a reading level higher than the recommended sixth-grade level, and culturally appropriate health information was lacking. Health educators and practitioners are in a pivotal role to help women understand information useful for healthcare decisions. Several criteria are discussed to help practitioners evaluate Web sites. PMID- 23098044 TI - Grandmothers offering regular auxiliary care for their grandchildren: an expression of generativity in later life? AB - The study explores the meaning that grandmothers who offer regular childcare attach to that experience and the extent to which the notion of generativity might explain the meaning of the experience of caring for a grandchild. Twenty four Spanish grandmothers aged 60 and over who provided at least 12 hours a week of childcare were interviewed. Interviews were transcribed verbatim and qualitatively analyzed. The results suggest that grandmothers regard their childcare input as being part of their parental duty of helping in times of need. A range of consequences of caregiving were mentioned, generally positive and satisfactory. Our participants apparently began their caregiving task as an expression of parental generativity, although rewards associated with childcare are linked to grandparental generativity. PMID- 23098045 TI - The emotional significance of affective inequalities and why they are important to women in old age. AB - Affective inequality is neglected in the study of old age. Using an egalitarian analysis, this article shows how affective inequalities matter to older women. Findings from the first author's PhD study explain the emotional significance of affective inequalities for Irish women. Twenty-one in-depth interviews were conducted to obtain data about experiences and perceptions of inequalities and how they had an impact on older women's well-being. Thematic analysis revealed that women experienced inequalities in old age as devaluation, obligations, exclusion, and misrecognition (DOEM), and they experienced injustices in areas of their lives that were largely outside of their control. Affective inequality implications are discussed. PMID- 23098046 TI - Dealing with complexity in research processes and findings: how do older women negotiate and challenge images of aging? AB - The Representing Self-Representing Ageing initiative has been funded by the ESRC as part of the New Dynamics of Ageing cross-council research program. It has consisted of four projects with older women using visual research methods and participatory approaches to enable women to articulate their experiences of aging and to create alternative images of aging. Complex research processes were utilized. Innovative methods included the use of art elicitation, photo diaries, film booths, and phototherapy. PMID- 23098050 TI - CdS nanoparticles sensitization of Al-doped ZnO nanorod array thin film with hydrogen treatment as an ITO/FTO-free photoanode for solar water splitting. AB - Aluminum-doped zinc oxide (AZO) nanorod array thin film with hydrogen treatment possesses the functions of transparent conducting oxide thin film and 1-D nanostructured semiconductor simultaneously. To enhance the absorption in the visible light region, it is sensitized by cadmium sulfide (CdS) nanoparticles which efficiently increase the absorption around 460 nm. The CdS nanoparticles sensitized AZO nanorod array thin film with hydrogen treatment exhibits significantly improved photoelectrochemical property. After further heat treatment, a maximum short current density of 5.03 mA cm-2 is obtained under illumination. They not only are much higher than those without CdS nanoparticles sensitization and those without Al-doping and/or hydrogen treatment, but also comparable and even slightly superior to some earlier works for the CdS sensitized zinc oxide nanorod array thin films with indium tin oxide (ITO) or fluorine-doped tin oxide (FTO) as substrates. This demonstrated successfully that the AZO nanorod array thin film with hydrogen treatment is quite suitable as an ITO/FTO-free photoanode and has great potentials in solar water splitting after sensitization by quantum dots capable of visible light absorption. PMID- 23098052 TI - A question module for assessing community stigma towards HIV in rural India. AB - This paper describes a simple question module to assess community stigma in rural India. Fear of stigma is known to prevent people from seeking HIV testing and to contribute to further disease transmission, yet relatively little attention has been paid to community stigma and ways of measuring it. The module, based on a vignette of a fictional HIV-positive woman, was administered to 494 married women and 186 unmarried male and female adolescents in a village in rural Maharashtra, India. To consider the usefulness of the question module, a series of hypotheses were developed based on the correlations found in other studies between HIV related stigma and socio-demographic characteristics (age, education, discussion of HIV with others, knowing someone living with HIV, knowledge about its transmission and whether respondents acknowledged stigmatizing attitudes as their own or attributed them to others). Many of the study's hypotheses were confirmed. Among married women, correlates of stigma included older age, lack of discussion of HIV and lack of knowledge about transmission; among adolescents, lower education and lack of discussion of HIV were the most significant correlates. The paper concludes that the question module is a useful tool for investigating the impact of interventions to reduce stigma and augment social support for people living with HIV in rural India. PMID- 23098051 TI - De novo sequencing and analysis of the Ulva linza transcriptome to discover putative mechanisms associated with its successful colonization of coastal ecosystems. AB - BACKGROUND: The green algal genus Ulva Linnaeus (Ulvaceae, Ulvales, Chlorophyta) is well known for its wide distribution in marine, freshwater, and brackish environments throughout the world. The Ulva species are also highly tolerant of variations in salinity, temperature, and irradiance and are the main cause of green tides, which can have deleterious ecological effects. However, limited genomic information is currently available in this non-model and ecologically important species. Ulva linza is a species that inhabits bedrock in the mid to low intertidal zone, and it is a major contributor to biofouling. Here, we presented the global characterization of the U. linza transcriptome using the Roche GS FLX Titanium platform, with the aim of uncovering the genomic mechanisms underlying rapid and successful colonization of the coastal ecosystems. RESULTS: De novo assembly of 382,884 reads generated 13,426 contigs with an average length of 1,000 bases. Contiguous sequences were further assembled into 10,784 isotigs with an average length of 1,515 bases. A total of 304,101 reads were nominally identified by BLAST; 4,368 isotigs were functionally annotated with 13,550 GO terms, and 2,404 isotigs having enzyme commission (EC) numbers were assigned to 262 KEGG pathways. When compared with four other full sequenced green algae, 3,457 unique isotigs were found in U. linza and 18 conserved in land plants. In addition, a specific photoprotective mechanism based on both LhcSR and PsbS proteins and a C4-like carbon-concentrating mechanism were found, which may help U. linza survive stress conditions. At least 19 transporters for essential inorganic nutrients (i.e., nitrogen, phosphorus, and sulphur) were responsible for its ability to take up inorganic nutrients, and at least 25 eukaryotic cytochrome P450s, which is a higher number than that found in other algae, may be related to their strong allelopathy. Multi-origination of the stress related proteins, such as glutamate dehydrogenase, superoxide dismutases, ascorbate peroxidase, catalase and heat-shock proteins, may also contribute to colonization of U. linza under stress conditions. CONCLUSIONS: The transcriptome of U. linza uncovers some potential genomic mechanisms that might explain its ability to rapidly and successfully colonize coastal ecosystems, including the land-specific genes; special photoprotective mechanism based on both LhcSR and PsbS; development of C4-like carbon-concentrating mechanisms; muti-origin transporters for essential inorganic nutrients; multiple and complex P450s; and glutamate dehydrogenase, superoxide dismutases, ascorbate peroxidase, catalase, and heat shock proteins that are related to stress resistance. PMID- 23098053 TI - Colonization by Candida species of the oral and vaginal mucosa in HIV-infected and noninfected women. AB - Candidiasis in HIV/AIDS patients continues to be a public health problem. Effective antifungal therapies are few in number and have inherent problems such as selecting for drug-resistant strains of Candida species. To evaluate the state of Candida colonization of the oral and vaginal mucosa, we recruited 80 women, both HIV-infected and HIV-uninfected, from the Women's Interagency HIV Study (WIHS). Diet diaries were collected by participants to examine the role of diet on fungal growth. Baseline studies were initially done in participants that followed the colonization of both mucosal sites over 0-90 days. The most common Candida species from both groups of patients were C. albicans and C. glabrata. Among the HIV-infected cohort, the percentage of participants who were positive for Candida spp. was higher than in the HIV-uninfected control group. Furthermore, the frequency of colonization (1 episode versus >1 episode) was also increased in the HIV-infected cohort. These data indicate that Candida species remain an important component of the microbial community in both populations. PMID- 23098054 TI - Proton transfer assisted charge transfer phenomena in photochromic Schiff bases and effect of -NEt2 groups to the anil Schiff bases. AB - Photochromic Schiff bases 5-diethylamino-2-[(4-diethylamino-benzylidene) hydrazonomethyl]-phenol (DDBHP) and N,N'-bis(4-N,N-diethylaminosalisalidene) hydrazine (DEASH) with both the proton and charge transfer moieties have been synthesized, and their photophysical properties such as excited state intramolecular charge transfer (ICT) and proton transfer (ESIPT) processes have been reported on the basis of steady-state and time-resolved spectral measurement in various solvents. The ground-state six-membered intramolecular hydrogen bonding network at the proton transfer site accelerates the ESIPT process for these compounds. Both the compounds show large Stokes-shifted emission bands for proton transfer and charge transfer processes. The hydrogen bonding solvents play a crucial role in these photophysical processes. Excited-state dipole moment of DDBHP and DEASH calculated by the solvatochromic method supports the polar character of the charge transfer excited state. Introduction of -NEt(2) groups to the reported salicylaldehyde azine (SAA) Schiff base results an increase in fluorescence lifetime from femtosecond to picosecond time scale for the proton transfer process. PMID- 23098055 TI - A nitrogenase cluster model [Fe8S6O] with an oxygen unsymmetrically bridging two proto-Fe4S3 cubes: relevancy to the substrate binding mode of the FeMo cofactor. AB - An oxygen-encapsulated iron sulfido cluster, [(DmpS)Fe(4)S(3)O][(DmpS)Fe(4)S(3)](MU-SDmp)(2)(MU-OCPh(3)) (2; Dmp = 2,6 (mesityl)(2)C(6)H(3)), has been synthesized by the reaction of the preformed dinuclear iron thiolate/alkoxide [(Ph(3)CO)Fe](2)(MU-SDmp)(2) (1) with (1/8)S(8) and (1/4)H(2)O in toluene. In the [Fe(8)S(6)O] core, the oxygen atom bridges unsymmetrically two incomplete Fe(4)S(3) cubes, and two coordinatively unsaturated iron atoms are weakly bound to mesityl rings. Relevance of the cluster structure of 2 to the nitrogenase FeMo cofactor and its substrate binding mode is discussed. PMID- 23098056 TI - Extracts of Ficus exasperata leaf inhibit topical and systemic inflammation in rodents and suppress LPS-induced expression of mediators of inflammation in macrophages. AB - The leaves of Ficus exasperata are mashed and prepared as poultices that are placed on swellings, wounds, and arthritic joints to relieve swelling and pains by the Igede tribal community of Nigeria. The leaf and stalk are also squeezed and used to mitigate itching or inflammation. These claimed benefits inspired this study in which topical and systemic (acute, chronic) anti-inflammatory activities of a methanol/methylene chloride leaf extract of F. exasperata (MFE) were assessed in rodents. Effects of an aqueous leaf extract (AFE) on lipopolysaccharide-induced expression of interleukin-1beta (IL-1beta), tumor necrosis factor (TNF)-alpha, and inducible nitric oxide (iNO) were also investigated in murine bone marrow-derived macrophage (BMDM) cultures. Treatment of rats with MFE (200 and 400 mg/kg) led to significant inhibition of acute and chronic inflammation induced by, respectively, agar and formaldehyde in the paws. Topically, pre-application of mice with MFE (5 ug/ear) also significantly inhibited (by up to 21%) ear edema induced by xylene. In vitro, pre-treatment of BMDM with 5-100 ug AFE/ml significantly inhibited IL-1beta, TNFalpha, and iNO production in a dose-related manner. BMDM viability was not significantly affected AFE at concentrations up to 200 ug/ml. Initial studies showed that flavonoids, alkaloids, and terpenoids were the predominant phytoconstituents in each extract. In conclusion, the results of the various investigations indicated that F. exasperata leaf extracts possess anti-inflammatory properties that could underlie the benefits associated with the folklore use of the plant. The results also show that the extracts may be acting through a suppression of mediators of inflammation, such as IL-1beta, TNFalpha, and iNO. PMID- 23098057 TI - Nose and lungs: one way, one disease. AB - It's well established that asthma, allergic rhinitis and rhinosinusitis are three closely related disease. In pediatrics, these conditions represent a common issue in daily practice. The scientific community has recently started to simply evaluate them as different manifestations of a common pathogenic phenomenon. This consideration relates to important implications in the clinical management of these diseases, which may affect the daily activity of a pediatrician. The unity of the respiratory tract is confirmed both from a morphological and from a functional point of view. When treating rhinitis, it is often necessary to assess the presence of asthma. Patients with sinusitis should be evaluated for a possible concomitant asthma. Conversely, patients with asthma should always be evaluated for possible nasal disease, especially those suffering from difficult to-treat asthma, in which an occult sinusitis may be detected. The medications that treat nasal diseases appear to be useful in improving asthma control and in reducing bronchial hyperresponsiveness. It seems therefore important to analyze the link between asthma and sinusitis, both in terms of clinical and pathogenic features, as well the therapeutic approach of those patients presenting with these diseases. PMID- 23098058 TI - Survival of patients with non-Hodgkin lymphoma in Germany in the early 21st century. AB - This study provides up-to-date and detailed cancer survival estimates of German patients with non-Hodgkin lymphoma (NHL, International Statistical Classification of Diseases 10th Revision [ICD-10] codes C82-C85) based on data from 11 cancer registries. Period analysis was used to calculate 5-year relative survival in 2002-2006, overall and by gender, age and histology. Comparison was made with patients with NHL in the United States (US) Surveillance, Epidemiology and End Results database in the same time period. Overall 5-year relative survival for patients with NHL in Germany in 2002-2006 was 62.8% and in the US was 65.1%. Survival decreased with age from 81.7% at age 15-49 to 46.5% at age 75+. Survival in the US was 75.3% at age 15-49 and 52% at age 75+. Survival was higher for women than for men, at 65.2% for women and 60.7% for men. Survivals for diffuse B cell lymphoma and follicular lymphoma, the two most common subtypes of NHL, were 57.3% and 77.5%, respectively. Between 2002 and 2006, overall 5-year relative survival increased by 5.3 percentage points. We conclude that survival for NHL is increasing in Germany in recent years. Survival was higher in Germany than in the US for patients aged 15-49 but lower for older patients. PMID- 23098060 TI - Mastoid subperiosteal abscess in children: drainage or mastoidectomy? AB - OBJECTIVE: To evaluate the management of mastoid subperiosteal abscess using two different surgical approaches: simple mastoidectomy and abscess drainage. METHOD: The medical records of 34 children suffering from acute mastoiditis with subperiosteal abscess were retrospectively reviewed. In these cases, the initial surgical approach consisted of either myringotomy plus simple mastoidectomy or myringotomy plus abscess drainage. RESULTS: Thirteen children were managed with simple mastoidectomy and 21 children were initially managed with abscess drainage. Of the second group, 12 children were cured without further treatment while 9 eventually required mastoidectomy. None of the children developed complications during hospitalisation, or long-term sequelae. CONCLUSION: Simple mastoidectomy remains the most effective procedure for the management of mastoid subperiosteal abscess. Drainage of the abscess represents a simple and risk-free, but not always curative, option. It can be safely used as an initial, conservative approach in association with myringotomy and sufficient antibiotic coverage, with simple mastoidectomy reserved for non-responding cases. PMID- 23098059 TI - Scoliosis detection, patient characteristics, referral patterns and treatment in the absence of a screening program in Norway. AB - BACKGROUND: Early diagnosis of idiopathic scoliosis allows for observation and timely initiation of brace treatment in order to halt progression. School scoliosis screening programs were abolished in Norway in 1994 for lack of evidence that the programs improved outcome and for the costs involved. The consequences of this decision are discussed. OBJECTIVES: To describe the detection, patient characteristics, referral patterns and treatment of idiopathic scoliosis at a scoliosis clinic during the period 2003-2011, when there was no screening and to compare treatment modalities to the period 1976-1988 when screening was performed. METHODS: Patient demographics, age at detection, family history, clinical and radiological charts of consecutive patients referred for scoliosis evaluation during the period 2003-2011, were prospectively registered. Patients were recruited from a catchment area of about 500000 teenagers. Maturity was estimated according to Risser sign and menarcheal status. Severity of pain was recorded by a verbal 5-point scale from no pain to pain at all times. Physical and neurological examinations were conducted. The detector and patient characteristics were recorded. Referral patterns of orthopedic surgeons at local hospitals and other health care providers were recorded. Patient data was obtained by spine surgeons. Treatment modalities in the current period were compared to the period 1976-1988. RESULTS: We registered 752 patients with late onset juvenile and adolescent idiopathic scoliosis from 2003-2011. There were 644 (86%) girls and 108 (14%) boys. Mean age at detection was 14.6 (7-19) years. Sixty percent had Risser sign >= 3, whilst 74% were post menarche with a mean age at menarche of 13.2 years. Thirty-one percent had a family history of scoliosis. The mean major curve at first consultation at our clinic was 38 degrees (10 degrees -95 degrees ). About 40% had a major curve >40 degrees . Seventy-one percent were detected by patients, close relatives, and friends. Orthopaedic surgeons referred 61% of the patients. The mean duration from detection to the first consultation was 20(0-27) months. The proportion of the average number of patients braced each year was 68% during the period with screening compared to 38% in the period without screening, while the proportion for those operated was 32% and 62%, respectively ( p=0.002, OR 3.5, (95%CI 1.6 to 7.5). CONCLUSION: In the absence of scoliosis screening, lay persons most often detect scoliosis. Many patients presented with a mean Cobb angle approaching the upper limit for brace treatment indications. The frequency of brace treatment has been reduced and surgery is increased during the recent period without screening compared with the period in the past when screening was still conducted. PMID- 23098061 TI - Kinematic predictors of single-leg squat performance: a comparison of experienced physiotherapists and student physiotherapists. AB - BACKGROUND: The single-leg squat (SLS) is a common test used by clinicians for the musculoskeletal assessment of the lower limb. The aim of the current study was to reveal the kinematic parameters used by experienced and inexperienced clinicians to determine SLS performance and establish reliability of such assessment. METHODS: Twenty-two healthy, young adults (23.8 +/- 3.1 years) performed three SLSs on each leg whilst being videoed. Three-dimensional data for the hip and knee was recorded using a 10-camera optical motion analysis system (Vicon, Oxford, UK). SLS performance was rated from video data using a 10-point ordinal scale by experienced musculoskeletal physiotherapists and student physiotherapists. All ratings were undertaken a second time at least two weeks after the first by the same raters. Stepwise multiple regression analysis was performed to determine kinematic predictors of SLS performance scores and inter- and intra-rater reliability were determined using a two-way mixed model to generate intra-class correlation coefficients (ICC3,1) of consistency. RESULTS: One SLS per leg for each participant was used for analysis, providing 44 SLSs in total. Eight experienced physiotherapists and eight physiotherapy students agreed to rate each SLS. Variance in physiotherapist scores was predicted by peak knee flexion, knee medio-lateral displacement, and peak hip adduction (R2 = 0.64, p = 0.01), while variance in student scores was predicted only by peak knee flexion, and knee medio-lateral displacement (R2 = 0.57, p = 0.01). Inter-rater reliability was good for physiotherapists (ICC3,1 = 0.71) and students (ICC3,1 = 0.60), whilst intra-rater reliability was excellent for physiotherapists (ICC3,1 = 0.81) and good for students (ICC3,1 = 0.71). CONCLUSION: Physiotherapists and students are both capable of reliable assessment of SLS performance. Physiotherapist assessments, however, bear stronger relationships to lower limb kinematics and are more sensitive to hip joint motion than student assessments. PMID- 23098062 TI - FGF23 is correlated with iron status but not with inflammation and decreases after iron supplementation: a supplementation study. AB - BACKGROUND: Recent studies have described relationships between iron status and fibroblast growth factor-23 (FGF23) but the possible confounding effects of inflammation on iron status have not been considered. The aims of this study were a) to consider a relationship between FGF23 and inflammation b) to identify relationships between iron status and FGF23 whilst correcting for inflammation and c) to assess the relationship between changes in FGF23 and iron status after supplementation. STUDY DESIGN AND METHODOLOGY: Blood samples from an iron supplementation study in children (n=79) were collected at baseline and after 3 months supplementation with iron sulphate. The children were from a rural Gambian population where rates of iron deficiency and infection/inflammation are high. This study identified cross-sectional and longitudinal relationships between FGF23, inflammation (C-reactive protein (CRP)) and iron status (ferritin, haemoglobin, and zinc protoporphyrin). CRP >= 5 mg/dL was used to indicate inflammation and FGF23 >= 125 RU/mL was considered elevated. RESULTS: FGF23 was not significantly correlated with CRP. At baseline, all markers of iron status were significantly correlated with FGF23. Ferritin was the strongest independent inverse predictor of FGF23 in subjects with and without elevated CRP (coefficient (SE)): All subjects=-0.57 (0.12), R2=22.3%, P<=0.0001; subjects with CRP < 5 mg/dL=-0.89 (0.14), R2=38.9%, P<=0.0001. FGF23 was elevated in 28% of children at baseline and 16% post supplementation (P=0.1). Improved iron status was associated with a decrease in FGF23 concentration in univariate (ferritin =-0.41 (0.11), R2=14.1%, P=0.0004; haemoglobin=-2.22 (0.64), R2=12.5%, P=0.0008; zinc protoporphyrin=1.12 (0.26), R2=18.6%, P<=0.0001) and multivariate analysis (R2=33.1%; ferritin=-0.36 (0.10), P=0.0007, haemoglobin = -1.83 (0.61), P=0.004, zinc protoporphyrin=0.62 (0.26), P=0.02). CONCLUSIONS: Iron status rather than inflammation is a negative predictor of plasma FGF23 concentration. Improvements in iron status following iron supplementation are associated with a significant decrease in FGF23 concentration. PMID- 23098063 TI - TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells. AB - Even after development of molecular targeting therapies, platinum-based chemotherapy is still a standard care for treatment of locally advanced non-small cell lung cancer (NSCLC). So far, critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined. We here attempted to identify novel biomarker genes for cisplatin (CDDP) for a tailored therapy. Initial screening to explorer association of IC(50) values of CDDP obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real-time RT-PCR provided 6 candidate genes, namely, NUBPL, C9orf30, ZNF12, TMEM158, GSK3B, and FBLP1 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells. These 6 genes together with 5 reported biomarkers, i.e., GSTP1, ERCC1, BRCA1, FRAP1, and RRM1, were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells: only FBLP1 and TMEM158 genes showed positive associations with statistical significances (P = .016 and .026, respectively). The biological significance of these genes was explored by in vitro experiments: Knockdown experiments in PC-9/CDDP cells revealed that the reduced expression of TMEM158 significantly decreased the chemo resistance against CDDP (P <.0001), while 2 transformants of PC-6 cells stably over-expressing FBLP1 resulted in an enhanced resistance to CDDP (P = .004 and P = .001). Furthermore, a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of TMEM158 and FBLP1 (R(2) = 0.755, P = .0018). TMEM158 and FBLP1 may be powerful predictive biomarkers for CDDP therapy in NSCLC. PMID- 23098064 TI - A new species of Caryospora (Apicomplexa: Eimeriidae) from the sharp-shinned hawk, Accipiter striatus (Aves: Accipitriformes). AB - An injured juvenile sharp-shinned hawk, Accipiter striatus Vieillot, 1807 (Aves: Accipitriformes), housed and treated at the College of Veterinary Medicine Teaching Hospital at Kansas State University, Manhattan, Kansas, USA, was found to be passing oocysts of an undescribed species of Caryospora in its feces. Sporulated oocysts of Caryospora petersoni n. sp. were subspherical, with a bilayered wall, and they measured 43.1 * 39.8 MUm; micropyle, oocyst residuum, and polar granule were absent. Sporocysts were subspherical to spherical, 23.4 * 23.3 MUm; Stieda, substieda, and parastieda bodies were absent, but a spherical sporocyst residuum was present as a compact mass, ~15.1 MUm wide, composed of many homogeneous globules. The new species represents the first caryosporan documented from this species of hawk. PMID- 23098065 TI - Evidence-based support for the all-hazards approach to emergency preparedness. AB - BACKGROUND: During the last decade there has been a need to respond and recover from various types of emergencies including mass casualty events (MCEs), mass toxicological/chemical events (MTEs), and biological events (pandemics and bio terror agents). Effective emergency preparedness is more likely to be achieved if an all-hazards response plan is adopted. OBJECTIVES: To investigate if there is a relationship among hospitals' preparedness for various emergency scenarios, and whether components of one emergency scenario correlate with preparedness for other emergency scenarios. METHODS: Emergency preparedness levels of all acute care hospitals for MCEs, MTEs, and biological events were evaluated, utilizing a structured evaluation tool based on measurable parameters. Evaluations were made by professional experts in two phases: evaluation of standard operating procedures (SOPs) followed by a site visit. Relationships among total preparedness and different components' scores for various types of emergencies were analyzed. RESULTS: Significant relationships were found among preparedness for different emergencies. Standard Operating Procedures (SOPs) for biological events correlated with preparedness for all investigated emergency scenarios. Strong correlations were found between training and drills with preparedness for all investigated emergency scenarios. CONCLUSIONS: Fundamental critical building blocks such as SOPs, training, and drill programs improve preparedness for different emergencies including MCEs, MTEs, and biological events, more than other building blocks, such as equipment or knowledge of personnel. SOPs are especially important in unfamiliar emergency scenarios. The findings support the adoption of an all-hazards approach to emergency preparedness. PMID- 23098066 TI - Conservative treatment of breast ductal carcinoma in situ: results of an Italian multi-institutional retrospective study. AB - BACKGROUND: The incidence of ductal carcinoma in situ (DCIS) has increased markedly in recent decades. In the past, mastectomy was the primary treatment for patients with DCIS, but as with invasive cancer, breast-conserving surgery followed by radiation therapy (RT) has become the standard approach. We present the final results of a multi-institutional retrospective study of an Italian Radiation Oncology Group for the study of conservative treatment of DCIS, characterized by a very long period of accrual, from February 1985 to March 2000, and a median follow-up longer than 11 years. METHODS: A collaborative multi institutional study was conducted in Italy in 10 Radiation Oncology Departments. A consecutive series of 586 women with DCIS histologically confirmed, treated between February 1985 and March 2000, was retrospectively evaluated. Median age at diagnosis was 55 years (range: 29-84); 32 patients were 40 years old or younger. All women underwent conservative surgery followed by whole breast RT. Irradiation was delivered to the entire breast, for a median total dose of 50 Gy; the tumour bed was boosted in 295 cases (50%) at a median dose of 10 Gy. RESULTS: After a median follow-up of 136 months (range: 16-292 months), 59/586 patients (10%) experienced a local recurrence: invasive in 37 cases, intraductal in 20 and not specified in two. Salvage mastectomy was the treatment of choice in 46 recurrent patients; conservative surgery in 10 and it was unknown in three patients. The incidence of local recurrence was significantly higher in women younger than 40 years (31.3%) (p= 0.0009). Five patients developed distant metastases. Furthermore 40 patients developed a contralateral breast cancer and 31 a second primary tumour in a different site. The 10-year actuarial overall survival (OS) was 95.5% and the 10-year actuarial disease-specific survival (DSS) was 99%. CONCLUSIONS: Our results are consistent with those reported in the literature. In particular it has been defined the importance of young age (40 years or less) as a relevant risk factor for local recurrence. This retrospective multi-institutional Italian study confirms the long term efficacy of breast conserving surgery with RT in women with DCIS. PMID- 23098067 TI - Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. AB - BACKGROUND: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort. METHODS: Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umea University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT). RESULTS: In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death. CONCLUSION: In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique. PMID- 23098068 TI - Mechanisms responsible for nilotinib resistance in human chronic myeloid leukemia cells and reversal of resistance. AB - Multidrug resistance remains a significant obstacle to successful chemotherapy. The ability to determine the possible resistance mechanisms and surmount the resistance is likely to improve chemotherapy. Nilotinib is a very effective drug in the treatment of imatinib-sensitive or -resistant patients. Although very successful hematologic and cytogenetic responses have been obtained in nilotinib treated patients, in recent years cases showing resistance to nilotinib have been observed. We aimed to examine the mechanisms underlying nilotinib resistance and to provide new targets for the treatment of chronic myeloid leukemia (CML). There was an up-regulation of antiapoptotic BCR/ABL, GCS and SK-1 genes and MRP1 transporter gene and down-regulation of apoptotic Bax and CerS1 genes in nilotinib-resistant cells. There was no mutation in the nilotinib-binding region of BCR/ABL in resistant cells. Inhibiton of GCS and SK-1 restored nilotinib sensitivity. Targeting the proteins that are involved in nilotinib resistance in addition to the inhibition of BCR/ABL could be a better method of treatment in CML. PMID- 23098070 TI - Comparison of techniques for identification of peripheral vestibular nystagmus. AB - OBJECTIVE: To determine the best clinical method for identifying peripheral vestibular nystagmus, by comparing eye movement examination with optic fixation, and with fixation removed using Frenzel's glasses, infra-red video-Frenzel's goggles or an ophthalmoscope, with results of electronystagmography. METHOD: One hundred patients referred for electronystagmography from the audiovestibular medicine clinic at Queen Alexandra Hospital, Portsmouth, were examined immediately before undergoing electronystagmography. RESULTS: Video-Frenzel's goggles were highly effective at detecting peripheral vestibular nystagmus, with a sensitivity of 85 per cent (95 per cent confidence interval, 62.1-96.8 per cent) and a specificity of 65 per cent (53.5-75.3 per cent), compared with electronystagmography. Ophthalmoscopy had comparable sensitivity to Frenzel's glasses (used in the dark), i.e. 26.3 per cent (9.1-51.2 per cent) compared with 31.6 per cent (12.6-56.6 per cent), respectively. Frenzel's glasses as normally used in ENT clinics (i.e. in dim lighting) were ineffective, with a sensitivity of just 10 per cent (1.2-31.7 per cent). CONCLUSION: Video-Frenzel's goggles should be used in all clinics with substantial numbers of balance-impaired patients. Traditional Frenzel's glasses have no place in clinical practice unless formal black-out facilities are available. PMID- 23098069 TI - Biodegradable polydisulfide dendrimer nanoclusters as MRI contrast agents. AB - Gadolinium-conjugated dendrimer nanoclusters (DNCs) are a promising platform for the early detection of disease; however, their clinical utility is potentially limited due to safety concerns related to nephrogenic systemic fibrosis (NSF). In this paper, biodegradable DNCs were prepared with polydisulfide linkages between the individual dendrimers to facilitate excretion. Further, DNCs were labeled with premetalated Gd chelates to eliminate the risk of free Gd becoming entrapped in dendrimer cavities. The biodegradable polydisulfide DNCs possessed a circulation half-life of >1.6 h in mice and produced significant contrast enhancement in the abdominal aorta and kidneys for as long as 4 h. The DNCs were reduced in circulation as a result of thiol-disulfide exchange, and the degradation products were rapidly excreted via renal filtration. These agents demonstrated effective and prolonged in vivo contrast enhancement and yet minimized Gd tissue retention. Biodegradable polydisulfide DNCs represent a promising biodegradable macromolecular MRI contrast agent for magnetic resonance angiography and can potentially be further developed into target-specific MRI contrast agents. PMID- 23098071 TI - Attenuated total reflectance infrared spectroscopy study of hysteresis of water and n-alcohol coadsorption on silicon oxide. AB - The structure and thickness of the binary adsorbate layers formed on silicon oxide exposed in n-propanol/water and n-pentanol/water vapor mixtures under atmospheric pressure and room temperature conditions were investigated using attenuated total reflectance infrared spectroscopy (ATR-IR). The ATR-IR spectra of the adsorbate layers were analyzed while the vapor composition was varied stepwise by changing the mixing ratios of (a) n-propanol vapor stream with a 94% relative partial pressure (P/P(sat)) and 94% P/P(sat) water stream and (b) 83% P/P(sat)n-pentanol and 85% P/P(sat) water streams. The amount of the adsorbed water with solid-like structure in the binary adsorbate layer was larger in successive cycles of the water/alcohol vapor composition change, while n-alcohol showed negligible hysteresis in the amount adsorbed. The hysteresis behavior of the solid-like water structure was amplified in the coadsorption cycles of alcohol and water as compared to the water-only case. The origin of this behavior must be attributed to the structure of the alcohol/water binary adsorbate layer. The n-alcohol molecules present at the adsorbate/vapor interface can lower the surface energy of the system and stabilize the solid-like water structure in the alcohol-water binary adsorbate layer on silicon oxide. PMID- 23098072 TI - Novel toll-like receptor 2 ligands for targeted pancreatic cancer imaging and immunotherapy. AB - Toll-like receptor 2 (TLR2) is a target for immune system stimulation during cancer immunotherapy and a cell-surface marker for pancreatic cancer. To develop targeted agents for cancer imaging and therapy, we designed, synthesized, and characterized 13 novel, fully synthetic high affinity TLR2 agonists. Analogue 10 had the highest agonist activity (NF-kappaB functional assay, EC(50) = 20 nM) and binding affinity (competitive binding assay, K(i) = 25 nM). As an immune adjuvant, compound 10 stimulated the immune system in vivo by generation and persistence of antigen-specific CD8+ T cells indicating its potential use in cancer immunotherapy. After conjugation of near-infrared dye to 10, agonist activity (EC(50) = 34 nM) and binding affinity (K(i) = 11 nM) were retained in 13. Fluorescence signal was present in TLR2 expressing pancreatic tumor xenografts 24 h after injection of 13, while an excess of unlabeled ligand blocked 13 from binding to the tumor, resulting in significantly decreased signal (p < 0.001) demonstrating in vivo selectivity. PMID- 23098073 TI - Core-binding factor beta increases the affinity between human Cullin 5 and HIV-1 Vif within an E3 ligase complex. AB - HIV-1 Vif masquerades as a receptor for a cellular E3 ligase harboring Elongin B, Elongin C, and Cullin 5 (EloB/C/Cul5) proteins that facilitate degradation of the antiretroviral factor APOBEC3G (A3G). This Vif-mediated activity requires human core-binding factor beta (CBFbeta) in contrast to cellular substrate receptors. We observed calorimetrically that Cul5 binds tighter to full-length Vif((1 192))/EloB/C/CBFbeta (K(d) = 5 +/- 2 nM) than to Vif((95-192))/EloB/C (K(d) = 327 +/- 40 nM), which cannot bind CBFbeta. A comparison of heat capacity changes supports a model in which CBFbeta prestabilizes Vif((1-192)) relative to Vif((95 192)), consistent with a stronger interaction of Cul5 with Vif's C-terminal Zn(2+)-binding motif. An additional interface between Cul5 and an N-terminal region of Vif appears to be plausible, which has therapeutic design implications. PMID- 23098074 TI - Preparation of a diphosphine with persistent phosphinyl radical character in solution: characterization, reactivity with O2, S8, Se, Te, and P4, and electronic structure calculations. AB - A new, easily synthesized diphosphine based on a heterocyclic 1,3,2 diazaphospholidine framework has been prepared. Due to the large, sterically encumbering Dipp groups (Dipp = 2,6-diisopropylphenyl) on the heterocyclic ring, the diphosphine undergoes homolytic cleavage of the P-P bond in solution to form two phosphinyl radicals. The diphosphine has been reacted with O(2), S(8), Se, Te, and P(4), giving products that involve insertion of elements between the P-P bond to yield the related phosphinic acid anhydride, sulfide/disulfide, selenide, telluride, and a butterfly-type perphospha-bicyclobutadiene structure with a trans,trans-geometry. All molecules have been characterized by multinuclear NMR spectroscopy, elemental analysis, and single-crystal X-ray crystallography. Variable-temperature EPR spectroscopy was utilized to study the nature of the phosphinyl radical in solution. Electronic structure calculations were performed on a number of systems from the parent diphosphine [H(2)P](2) to amino substituted [(H(2)N)(2)P](2) and cyclic amino-substituted [(H(2)C)(2)(NH)(2)P](2); then, bulky substituents (Ph or Dipp) were attached to the cyclic amino systems. Calculations on the isolated diphosphine at the B3LYP/6 31+G* level show that the homolytic cleavage of the P-P bond to form two phosphinyl radicals is favored over the diphosphine by ~11 kJ/mol. Furthermore, there is a significant amount of relaxation energy stored in the ligands (52.3 kJ/mol), providing a major driving force behind the homolytic cleavage of the central P-P bond. PMID- 23098075 TI - Experimental and theoretical characterization of a lone pair-pi complex: water hexafluorobenzene. AB - The lone pair-pi interaction between H(2)O and C(6)F(6) was studied using matrix isolation infrared spectroscopy and quantum chemical calculations. Co-deposition of H(2)O with C(6)F(6) in a nitrogen matrix at 17 K followed by annealing to 30 K, results in the appearance of multiple new peaks in the infrared spectrum that are shifted from the H(2)O and C(6)F(6) parent absorptions. These peaks only appear when both the H(2)O and C(6)F(6) are present and have been assigned to distinct structures of a 1:1 H(2)O.C(6)F(6) complex. Similar experiments were performed with D(2)O and HDO and the corresponding infrared peaks for the structures of the D(2)O.C(6)F(6) and HDO.C(6)F(6) complexes have also been observed. Theoretical calculations were performed for the H(2)O.C(6)F(6) complex using the B3LYP, MP2, and CCSD(T) methods. Geometry optimizations at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels of theory located three structural minima, all of which involve the lone pair-pi interaction between the H(2)O and the C(6)F(6) ring, but with different relative orientations of the H(2)O and C(6)F(6) subunits. BSSE corrected interaction energies were estimated at the CCSD(T)/aug-cc-pVTZ level and found to be between -11.2 and -12.3 kJ/mol for the three H(2)O.C(6)F(6) structures. Vibrational frequencies for the each of the structures were calculated at the B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVDZ levels. The frequencies calculated with both methods support the assignments of the observed new peaks in the infrared spectra to the structures of the H(2)O.C(6)F(6) complex; however, the B3LYP calculated frequency shifts were found to be in better quantitative agreement with the experimentally observed frequency shifts. PMID- 23098076 TI - New technologies for diabetes: a review of the present and the future. AB - : This review summarizes the technologies in use and in the pipeline for the management of diabetes. The review focuses on glucose meters, continuous glucose monitoring devices, insulin pumps, and getting clinicians connected to technologies. All information presented can be found in the public domain, and was obtained from journal articles, websites, product review tables in patient publications, and professional conferences. The technology concerns, ongoing development and future trends in this area are also discussed. PMID- 23098077 TI - Fluorescent bioassays for toxic metals in milk and yoghurt. AB - BACKGROUND: From a human health viewpoint, contaminated milk and its products could be a source of long-term exposure to toxic metals. Simple, inexpensive, and on-site assays would enable constant monitoring of their contents. Bioassays that can measure toxic metals in milk or yoghurt might reduce the risk. For this purpose, the green fluorescent protein (GFP)-tagged trans factors, ArsR-GFP and CadC-GFP, together with their cis elements were used to develop such bioassays. RESULTS: ArsR-GFP or CadC-GFP, which binds either toxic metal or DNA fragment including cis element, was directly mixed with cow's milk or yoghurt within a neutral pH range. The fluorescence of GFP, which is reflected by the association/dissociation ratio between cis element and trans factor, significantly changed with increasing externally added As (III) or Cd (II) whereas smaller responses to externally added Pb (II) and Zn (II) were found. Preparation and dilution of whey fraction at low pH were essential to intrinsic zinc quantification using CadC-GFP. Using the extraction procedure and bioassay, intrinsic Zn (II) concentrations ranging from 1.4 to 4.8 mg/l for milk brands and from 1.2 to 2.9 mg/kg for yoghurt brands were determined, which correlated to those determined using inductively coupled plasma atomic emission spectroscopy. CONCLUSIONS: GFP-tagged bacterial trans factors and cis elements can work in the neutralized whole composition and diluted whey fraction of milk and yoghurt. The feature of regulatory elements is advantageous for establishment of simple and rapid assays of toxic metals in dairy products. PMID- 23098079 TI - A new species of nematode (Molineidae) from Rhinella marina (Amphibia: Bufonidae) in Guerrero, Mexico. AB - Oswaldocruzia lamotheargumedoi n. sp., inhabiting the intestine of the cane toad, Rhinella marina (L.), in Laguna de Coyuca, Guerrero, Mexico, is described here. The new species differs from 10 congeners infecting bufonid hosts because it has a type I bursa. In contrast, 7 of these species have type II bursa and 3 more a type III bursa. The species most similar to the species described herein is Oswaldocruzia pipiens Walton, 1929 . These 2 species share traits such as body size, bursa type, presence of cervical alae, and dorsal ray morphology. Nevertheless, both species can be distinguished based on the number of synlophe ridges at mid-body (54-56 for O. lamotheargumedoi vs. 45-48 for O. pipiens) and by the presence of a chitinous support in the long, and well developed, cervical alae of O. pipiens. In the new species, these structures are short, poorly developed, and lack chitinous support. Previous records of species of Oswaldocruzia in Mexico include Oswaldocruzia subauricularis (Rudolphi, 1819) Travassos, 1917 in the Neotropical Realm and O. pipiens in the Nearctic. PMID- 23098080 TI - Mortality rates in Israel from causes amenable to health care, regional and international comparison. AB - BACKGROUND: Mortality from causes amenable to health care is a valuable indicator of quality of the health care system, which can be used to assess inter regional differences and trends over time. This study investigates these mortality rates in Israel over time, and compares inter-regional and international rates in recent years. RESULTS: Age-adjusted amenable mortality rates have been decreasing steadily in Israel, by 31% for males and 28% for females between 1998-2000 and 2007-2009. Amenable mortality was lower in the center of the country than in the Northern, Southern, and Haifa districts. The proportion of mortality from circulatory diseases was highest in the North and Haifa districts and from cancer in the Tel-Aviv and Central districts. A higher proportion of infectious diseases was seen in the Southern district.In comparison with amenable mortality rates in 20 European countries, Israel ranked 8th lowest for males and 12th lowest for females, in 2008. The rate was lower than in Britain, Ireland, and Portugal; lower than in Germany, Spain, Austria, and Finland for males; and higher than France, Netherlands, Sweden, Norway, and Italy. But Israel ranked higher in the decrease in amenable mortality rates between 2001 and 2007 for females than males in a 19 country comparison. Genitourinary diseases were a larger component in Israel than other countries and circulatory diseases were smaller. CONCLUSION: The indicator of amenable mortality shows improvement in health outcomes over the years, but continuing improvement is needed in health care and education, in particular in the periphery of Israel and for females. PMID- 23098078 TI - The role of DNA methylation in aging, rejuvenation, and age-related disease. AB - DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation. PMID- 23098081 TI - Inhaled corticosteroids and the risk of pneumonia in Medicare patients with COPD. AB - OBJECTIVE: To determine the association between inhaled corticosteroid (ICS) use and the risk of pneumonia among Medicare patients with chronic obstructive pulmonary disease (COPD). METHODS: A nested case control analysis was performed to study the relationship between ICS use and pneumonia risk in a cohort of Medicare Advantage members with COPD. Patients were identified through a medical and pharmacy claims database. A case was designated as patient's first inpatient or outpatient pneumonia episode. Cases were matched to controls who entered the COPD cohort at the same time, but had not yet developed pneumonia by the case's index date. The association between ICS use and pneumonia was estimated using logistic regression. Adjusted models controlled for age, sex, race, use of other COPD medications, markers of COPD severity, receipt of the pneumococcal vaccine, and comorbidities. Analyses were also stratified by current or past ICS use, as well as dosage (low, medium, or high). RESULTS: Out of a COPD cohort of 83,455 members, 13,778 pneumonia episodes were identified; these cases were matched to 36,767 controls. Adjusting for covariates, having used any ICS during the past year was associated with increased risk of a pneumonia episode (OR 1.11, 95% CI: 1.05-1.18). Pneumonia risk was highest for current ICS users (OR 1.26, 95% CI: 1.16-1.36) and current high-dose users (OR 1.55, 95% CI: 1.25-1.92), compared to non-users. CONCLUSION: As a retrospective claims analysis, this study had inherent limitations. The pneumonia diagnosis could not be confirmed, smoking history and other health confounders were not included. However, given the large study sample size and extensive number of available controls, the results remain persuasive and confirm previous studies' findings that ICS use, particularly current use and high-dose use, is associated with increased pneumonia risk. PMID- 23098082 TI - Proton therapy versus photon radiation therapy for the management of a recurrent desmoid tumor of the right flank: a case report. AB - Desmoid tumors are benign mesenchymal tumors with a strong tendency for local recurrence after surgery. Radiotherapy improves local control following incomplete resection, but nearby organs at risk may limit the dose to the target volume. The patient in this report presented with a recurrent desmoid tumor of the right flank and underwent surgery with microscopically positive margins. Particular problems presented in this case included that the tumor bed was situated in close proximity to the liver and the right kidney and that the right kidney was responsible for 65% of the patient's renal function. Intensity modulated radiation therapy plans delivering 54 Gy necessarily exposed the right kidney to a V18 of 98% and the liver to a V30 of 55%. Proton therapy plans significantly reduced the right kidney V18 to 32% and the liver V30 to 28%. In light of this, the proton plan was utilized for treatment of this patient. Proton therapy was tolerated without gastrointestinal discomfort or other complaints. Twenty-four months after initiation of proton therapy, the patient is without clinical or radiographic evidence of disease recurrence. In this setting, the improved dose distribution associated with proton therapy allowed for curative treatment of a patient who arguably could not have been safely treated with intensity-modulated radiation therapy or other methods of conventional radiotherapy. PMID- 23098083 TI - Combination coating of chitosan and anti-CD34 antibody applied on sirolimus eluting stents can promote endothelialization while reducing neointimal formation. AB - BACKGROUND: Circulating endothelial progenitor cells (EPCs) capture technology improves endothelialization rates of sirolimus-eluting stents (SES), but the problem of delayed re-endothelialization, as well as endothelial dysfunction, has still not been overcome. Therefore, we investigated whether the combination coating of hyaluronan-chitosan (HC) and anti-CD34 antibody applied on an SES (HCASES) can promote endothelialization, while reducing neointimal formation and inflammation. METHODS: Sirolimus-eluting stents(SES), anti-CD34 antibody stents (GS) and HC-anti-CD34 antibody combined with sirolimus-eluting stents (HCASES) were deployed in 54 normal porcine arteries and harvested for scanning electron microscopy (SEM) and histological analysis. The ratio of endothelial coverage above the stents was evaluated by SEM analysis at 7, 14 and 28 days. The percentage of in-stent stenosis was histologically analyzed at 14 and 28 days. RESULTS: SEM analysis at 7 days showed that endothelial strut coverage was increased in the HCASES group (68+/-7%) compared with that in the SES group (31+/ 4%, p=0.02). At 14 days, stent surface endothelialization, evaluated by SEM, showed a significantly higher extent of endothelial coverage above struts in the GS (95 +/- 2%) and the HCASES groups (87+/-4%) compared with that in the SES group (51+/-6%, p=0.02). Histological examination showed that the percentage of stenosis in the HCASES group was not significantly different to that of the SES and GS groups (both p> 0.05). At 28 days, there was no difference in the rates of endothelial coverage between the HCASES and GS groups. The HCASES group showed less stenosis than that in the GS group (P < 0.05), but it was not significantly different from the SES group (P=0.068). CONCLUSIONS: SEM and histology demonstrated that HCASESs can promote re-endothelialization while enhancing antiproliferative effects. PMID- 23098084 TI - High-performance nanopapers based on benzenesulfonic functionalized graphenes. AB - High-performance graphene nanopapers are prepared from an aqueous solution of functional graphenes with benzenesulfonic acid groups via covalent bonds. The formed hydrophobic graphene nanopapers showed the highest tensile strength of 360 MPa and Young's modulus of 102 GPa for samples with 13.7 wt % functional group and annealed at 150 degrees C. These samples showed a high electrical conductivity of 4.45 * 10(4) S/m after being annealed at 250 degrees C. The aforementioned properties of graphene nanopapers are much higher than any previously reported data. The properties of nanopapers depend on the degree of functionality on graphenes and the annealing temperatures, which are further evidenced by X-ray photoelectron spectroscopy, FTIR, and X-ray diffraction patterns. Such unique nanopapers can be easily bounded and sandwiched onto any solid surface to give rise to great potentials in many applications such as gas diffusion barriers, EMI shielding, thermal management, and anticorrosion. PMID- 23098085 TI - Thermally driven crossover from indirect toward direct bandgap in 2D semiconductors: MoSe2 versus MoS2. AB - Layered semiconductors based on transition-metal chalcogenides usually cross from indirect bandgap in the bulk limit over to direct bandgap in the quantum (2D) limit. Such a crossover can be achieved by peeling off a multilayer sample to a single layer. For exploration of physical behavior and device applications, it is much desired to reversibly modulate such crossover in a multilayer sample. Here we demonstrate that, in a few-layer sample where the indirect bandgap and direct bandgap are nearly degenerate, the temperature rise can effectively drive the system toward the 2D limit by thermally decoupling neighboring layers via interlayer thermal expansion. Such a situation is realized in few-layer MoSe(2), which shows stark contrast from the well-explored MoS(2) where the indirect and direct bandgaps are far from degenerate. Photoluminescence of few-layer MoSe(2) is much enhanced with the temperature rise, much like the way that the photoluminescence is enhanced due to the bandgap crossover going from the bulk to the quantum limit, offering potential applications involving external modulation of optical properties in 2D semiconductors. The direct bandgap of MoSe(2), identified at 1.55 eV, may also promise applications in energy conversion involving solar spectrum, as it is close to the optimal bandgap value of single junction solar cells and photoelechemical devices. PMID- 23098086 TI - Tackling Burkitt lymphoma in older patients: novel strategies and the promise of targeted agents. PMID- 23098087 TI - A case of a 'lost' nasogastric tube. AB - OBJECTIVES: To present the case of a 'lost' nasogastric tube and to highlight the importance of imaging and/or chest X-ray after nasogastric tube insertion, especially in unreliable patients. CASE REPORT: A 50-year-old man, undergoing radiotherapy treatment for squamous cell carcinoma of the tongue base, was admitted for pain control and nasogastric tube feeding. This patient required multiple nasogastric tubes over a two-week period. The patient repeatedly denied pulling the nasogastric tube out and we were unable to establish the exact mode of nasogastric tube removal. On one such occasion another tube was inserted and a check X-ray showed two feeding tubes; the latest one was lying in the left main bronchus and the old nasogastric tube was observed in the oesophagus, with its upper end jutting above the hypopharynx. It was apparent that the patient had somehow cut the tube and swallowed it. CONCLUSION: This case not only illustrates the importance of flexible nasendoscopy and/or chest X-ray for checking the position of the nasogastric tube, but also highlights that some patients are not tolerant of nasogastric tubes. The use of nasogastric tubes should be avoided in these patients to prevent any self-inflicted injury. PMID- 23098088 TI - Oncologic outcomes using real-time peripheral thermometry-guided radiofrequency ablation of small renal masses. AB - BACKGROUND AND PURPOSE: With the increased incidence of low-stage renal cancers, thermal ablation technology has emerged as a viable treatment option for extirpation in selected persons and is supported by the current American Urological Association guidelines. We present a 9-year, single institution experience with radiofrequency ablation (RFA) using real-time peripheral temperature monitoring of small renal masses focusing on oncologic outcomes. PATIENTS AND METHODS: We reviewed our prospectively collected database of patients with renal masses who were treated between November 2001 and January 2011 with laparoscopic (LRFA) or CT-guided percutaneous RFA (CTRFA) with simultaneous real-time peripheral fiberoptic thermometry. Patients were followed radiographically at 1 month, 6 months, 1 year, and then annually. Clinicopathologic outcomes were collected and analyzed. RESULTS: A total of 274 patients (211 male) aged 18 to 88 years (mean 67 years) with 292 renal tumors underwent LRFA (112) or CTRFA (180). Mean tumor size was 2.5 cm (0.7-5.3 cm). An intraoperative preablation biopsy showed 197 (67.4%) renal-cell carcinomas (RCC), and 77 (26.4%) benign tumors. Mean follow-up was 26 months (1-98 mos). The single ablation treatment radiographic success rate was 96% for all tumors and 94% for RCC. Metastatic RCC developed in one patient, who died. The Kaplan-Meier (KM) 3 year and 5-year cancer-specific survival was 100% and 98.6%, respectively. The KM 3-year and 5-year overall survival was 90.4% and 74.2%, respectively. CONCLUSION: RFA is a clinically effective and safe nephron-sparing treatment of patients with small renal masses. Our large cohort and intermediate-term experience adds to the building evidence for the efficacy of RFA for small renal cancers. PMID- 23098089 TI - Activation of Wnt signaling using lithium chloride: inquiry-based undergraduate laboratory exercises. AB - Zebrafish provide researchers and students alike with an excellent model of vertebrate nervous system development due to a high degree of conserved developmental mechanisms and transparent embryos that develop in synchrony. In these laboratory exercises, undergraduate students explore cell biological concepts while performing hypothesis-driven novel research utilizing methodologies such as immunofluorescence, confocal microscopy, image analysis, pharmacology, and basic statistics. In the first block of exercises, students perform anti-acetylated tubulin (anti-AT) immunofluorescence, identify spinal tracts and neuronal subtypes, and perform conventional and confocal microscopy. Building on knowledge acquired in the first block of exercises, during the second block, students subsequently perform pharmacological activation of Wnt signaling through lithium chloride treatments, and assess nervous system integrity through anti-AT immunofluorescence. Students perform various quantitative methods and apply statistics to determine outcomes of Wnt activation. In their final laboratory report, students contextualize their results with foundations of molecular mechanisms of nervous system development. In sum, these exercises offer undergraduate students a model of independent research at the graduate level. PMID- 23098090 TI - Clinical aspects of palliative care in advanced Parkinson's disease. AB - Parkinson's disease (PD) is one of the most common neurodegenerative disorders of the elderly population. Few therapeutic options are available for patients with PD requiring palliative care. Treatment of the early stages of PD is entirely different from later stages. During the later stages, the palliative care model is introduced to provide the patient with comfort and support. Early palliative care in PD requires minimization of dyskinesias and decreasing occurrence of motor and non-motor off times in an effort to maximize independent motor function. In the later stages, the focus of treatment shifts to treating the predominant non-motor symptoms and having a more supportive and palliative nature. The purpose of this review is to provide a summary of the palliative care management issues and palliative care management options of end-stage PD patients. PMID- 23098091 TI - Covalent inhibitors of interleukin-2 inducible T cell kinase (itk) with nanomolar potency in a whole-blood assay. AB - We wish to report a strategy that targets interleukin-2 inducible T cell kinase (Itk) with covalent inhibitors. Thus far, covalent inhibition of Itk has not been disclosed in the literature. Structure-based drug design was utilized to achieve low nanomolar potency of the disclosed series even at high ATP concentrations. Kinetic measurements confirmed an irreversible binding mode with off-rate half lives exceeding 24 h and moderate on-rates. The analogues are highly potent in a cellular IP1 assay as well as in a human whole-blood (hWB) assay. Despite a half life of approximately 2 h in resting primary T cells, the covalent inhibition of Itk resulted in functional silencing of the TCR pathway for more than 24 h. This prolonged effect indicates that covalent inhibition is a viable strategy to target the inactivation of Itk. PMID- 23098092 TI - Enzymatic modification of flaxseed fibers. AB - Flaxseed (Linum usitatissimum L.) fibers were modified by oxidoreductive and cellulolytic enzymes. The lignin amount and intrinsic plant peroxidase activity was evaluated by histochemical and spectrophotometric assays. Peroxidase activity was not found from bast fibers. The flaxseed fibers were further separated and treated with laccase to conjugate the model compounds, that is, the hydrophobic gallate molecules on fiber surfaces. Laccase was able to slowly oxidize fiber conjugated phenolics, but no fundamental changes in fiber cell surface structure or notable coupling of the applied hydrophobic gallate molecules onto the fibers occurred, as revealed by Fourier transform infrared spectroscopy. The reactivity of the mature fibers was further investigated using cellulolytic enzymes. Cellobiohydrolase (CBH) and endoglucanase (EG)-rich enzyme preparations were applied to reach a hydrolysis degree of 1-6% (of the fiber dry matter) using a standard enzyme dosage. The CBH mixture altered the fiber surface morphology distinctly, and SEM images illustrated fibers in which the cellulose fibrils seemed to be loosened and partially hydrolyzed. In contrast, the effect of the EG rich preparation without CBH activity was notable on the fiber surface, polishing the surfaces. The cellulolytic treatments were potentially interesting for specific enzymatic modifications of flax fiber surfaces, whereas the approach to use oxidoreductive enzyme treatments on mature linseed fibers offered little potential, obviously due to the low lignin content of the fibers. PMID- 23098094 TI - Nonexponential solid state 1H and 19F spin-lattice relaxation, single-crystal X ray diffraction, and isolated-molecule and cluster electronic structure calculations in an organic solid: coupled methyl group rotation and methoxy group libration in 4,4'-dimethoxyoctafluorobiphenyl. AB - We investigate the relationship between intramolecular rotational dynamics and molecular and crystal structure in 4,4'-dimethoxyoctafluorobiphenyl. The techniques are electronic structure calculations, X-ray diffractometry, and (1)H and (19)F solid state nuclear magnetic resonance relaxation. We compute and measure barriers for coupled methyl group rotation and methoxy group libration. We compare the structure and the structure-motion relationship in 4,4' dimethoxyoctafluorobiphenyl with the structure and the structure-motion relationship in related compounds in order to observe trends concerning the competition between intramolecular and intermolecular interactions. The (1)H spin lattice relaxation is nonexponential in both the high-temperature short correlation time limit and in the low-temperature long-correlation time limit, albeit for different reasons. The (19)F spin-lattice relaxation is nonexponential at low temperatures and it is exponential at high temperatures. PMID- 23098095 TI - Magnetic and structural studies of the multifunctional material SrFe(0.75)Mo(0.25)O(3-delta). AB - SrFe0.75Mo0.25O3-delta has been recently discovered as an extremely efficient electrode for intermediate temperature solid oxide fuel cells (IT-SOFCs). We have performed structural and magnetic studies to fully characterize this multifunctional material. We have observed by powder neutron diffraction (PND) and transmission electron microscopy (TEM) that its crystal symmetry is better explained with a tetragonal symmetry (I4/mcm space group) than with the previously reported orthorhombic symmetry (Pnma space group). The temperature dependent magnetic properties indicate an exceptionally high magnetic ordering temperature (TN ~ 750 K), well above room temperature. The ordered magnetic structure at low temperature was determined by PND to be an antiferromagnetic coupling of the Fe cations. Mossbauer spectroscopy corroborated the PND results. A detailed study, with X-ray absorption spectroscopy (XAS), in agreement with the Mossbauer results, confirmed the formal oxidation states of the cations to be mixed valence Fe(3+/4+) and Mo(6+). PMID- 23098096 TI - Early adolescents show sustained susceptibility to cognitive interference by emotional distractors. AB - A child's ability to continuously pay attention to a cognitive task is often challenged by distracting events. Distraction is especially detrimental in a learning or classroom environment in which attended information is typically associated with establishing skills and knowledge. Here we report a study examining the effect of emotional distractors on performance in a subsequent visual lexical decision task in 11- to 13-year-old students (n=30). Lexical decisions about neutral verbs and verb-like pseudowords (i.e., targets) were analysed as a function of the preceding distractor type (pleasant, neutral, or unpleasant photos) and the picture-target stimulus-onset asynchrony (SOA; 200 or 600 ms). Across distractor categories, emotionally arousing pictures prolonged decisions about word targets when compared to neutral pictures, irrespective of the SOA. The present results demonstrate that similar to adults, early adolescent students exhibit sustained susceptibility to cognitive interference by irrelevant emotional events. PMID- 23098093 TI - Preclinical Alzheimer disease: identification of cases at risk among cognitively intact older individuals. AB - Since the first description of the case of Auguste Deter, presented in Tubingen in 1906 by Alois Alzheimer, there has been an exponential increase in our knowledge of the neuropathological, cellular, and molecular foundation of Alzheimer's disease (AD). The concept of AD pathogenesis has evolved from a static, binary view discriminating cognitive normality from dementia, towards a dynamic view that considers AD pathology as a long-lasting morbid process that takes place progressively over years, or even decades, before the first symptoms become apparent, and thus operating in a continuum between the two aforementioned extreme states. Several biomarkers have been proposed to predict AD-related cognitive decline, initially in cases with mild cognitive impairment, and more recently in cognitively intact individuals. These early markers define at-risk individuals thought to be in the preclinical phase of AD. However, the clinical relevance of this preclinical phase remains controversial. The fate of such individuals, who are cognitively intact, but positive for some early AD biomarkers, is currently uncertain at best. In this report, we advocate the point of view that although most of these preclinical cases will evolve to clinically overt AD, some appear to have efficient compensatory mechanisms and virtually never develop dementia. We critically review the currently available early AD markers, discuss their clinical relevance, and propose a novel classification of preclinical AD, designating these non-progressing cases as 'stable asymptomatic cerebral amyloidosis'. PMID- 23098097 TI - The HubBLe trial: haemorrhoidal artery ligation (HAL) versus rubber band ligation (RBL) for haemorrhoids. AB - BACKGROUND: Haemorrhoids (piles) are a very common condition seen in surgical clinics. After exclusion of more sinister causes of haemorrhoidal symptoms (rectal bleeding, perianal irritation and prolapse), the best option for treatment depends upon persistence and severity of the symptoms. Minor symptoms often respond to conservative treatment such as dietary fibre and reassurance. For more severe symptoms treatment such as rubber band ligation may be therapeutic and is a very commonly performed procedure in the surgical outpatient setting. Surgery is usually reserved for those who have more severe symptoms, as well as those who do not respond to non-operative therapy; surgical techniques include haemorrhoidectomy and haemorrhoidopexy. More recently, haemorrhoidal artery ligation has been introduced as a minimally invasive, non destructive surgical option.There are substantial data in the literature concerning efficacy and safety of 'rubber band ligation including multiple comparisons with other interventions, though there are no studies comparing it to haemorrhoidal artery ligation. A recent overview has been carried out by the National Institute for Health and Clinical Excellence which concludes that current evidence shows haemorrhoidal artery ligation to be a safe alternative to haemorrhoidectomy and haemorrhoidopexy though it also highlights the lack of good quality data as evidence for the advantages of the technique. METHODS/DESIGN: The aim of this study is to establish the clinical effectiveness and cost effectiveness of haemorrhoidal artery ligation compared with conventional rubber band ligation in the treatment of people with symptomatic second or third degree (Grade II or Grade III) haemorrhoids. DESIGN: A multi-centre, parallel group randomised controlled trial. OUTCOMES: The primary outcome is patient-reported symptom recurrence twelve months following the intervention. Secondary outcome measures relate to symptoms, complications, health resource use, health related quality of life and cost effectiveness following the intervention. PARTICIPANTS: 350 patients with grade II or grade III haemorrhoids will be recruited in surgical departments in up to 14 NHS hospitals. RANDOMISATION: A multi-centre, parallel group randomised controlled trial. Block randomisation by centre will be used, with 175 participants randomised to each group. DISCUSSION: The results of the research will help inform future practice for the treatment of grade II and III haemorrhoids. TRIAL REGISTRATION: ISRCTN41394716. PMID- 23098098 TI - A review of intranasal ketorolac tromethamine for the short-term management of moderate to moderately severe pain that requires analgesia at the opioid level. AB - BACKGROUND: An intranasal (IN) formulation of ketorolac was recently FDA approved in adult patients for the short-term management of moderate to moderately severe pain that requires analgesia at the opioid level. SCOPE: The aim of this paper is to provide an overview of the clinical pharmacology, pharmacokinetics, efficacy, and tolerability of IN ketorolac. Databases used for this literature search include PubMed, International Pharmaceutical Abstracts, Cochrane Library and ClinicalTrials.gov from January 1980 to January 2012. All primary papers on IN ketorolac were eligible, including pharmacologic, pharmacokinetic, clinical, outcomes, and meta-analyses. The approved product labeling was a source of information, as well as the bibliographies of published articles which were reviewed for additional pertinent literature. FINDINGS: The search yielded six relevant studies all of which were selected for this review and included efficacy and safety trials, one pharmacokinetics study, and one preclinical study. IN ketorolac is a non-steroidal inflammatory drug that exhibits its effect mainly by inhibiting cyclo-oxygenase (COX) 1 and 2 with high affinity for COX-1. Absorption of IN ketorolac displays a median t(max) of 0.50-0.75 hours and has a t(1/2) of approximately 5-6 hours. Primary analyses included evaluation of morphine use and summed pain intensity difference (SPID) which was assessed using a visual analog scale. In one of the two phase III studies, the mean SPID6 score was 83.3 in the IN ketorolac group versus 37.2 in the placebo group, p = 0.007. In another phase III study, the mean SPID6 score was 117.4 in the IN ketorolac group versus 89.9 in the placebo group, p = 0.032. IN ketorolac was well-tolerated with most adverse events associated with the route of administration. CONCLUSION: Based on the clinical trials reviewed, IN ketorolac was associated with significant pain reduction in patients with various post-operative procedures, with good tolerability. PMID- 23098099 TI - Knowledge, attitudes and practices of AIDS associated malignancies among people living with HIV in Nigeria. AB - INTRODUCTION: The epidemic of HIV in sub-Saharan Africa varies significantly across countries in the region with high prevalence in Southern Africa and Nigeria. Cancer is increasingly identified as a complication of HIV infection with higher incidence and mortality in this group than in the general population. Without cancer prevention strategies, improved cancer treatment alone would be an insufficient response to this increasing burden among people living with HIV (PLHIV). Although previous studies have noted low levels of awareness of cancers in sub-Saharan Africa none has examined the knowledge and perceptions of cancer among people living with HIV/AIDS. METHODS: Focus group discussions (FGD) and Key Informant Interviews (KII) were carried out in 4 high volume tertiary care institutions that offer HIV care and treatment in Nigeria. FGD and KII assessed participants' knowledge of cancer, attitudes towards cancer risk and cancer screening practices. RESULTS: The mean age (SD) of the FGD participants was 38 (2.8) years. Most participants had heard about cancer and considered it a fatal disease but displayed poor knowledge of the causes of cancer in general and of AIDs associated cancers in particular. PLHIV in Nigeria expressed fear, denial and disbelief about their perceived cancer risk. Some of the participants had heard about cancer screening but very few participants had ever been screened. CONCLUSION: Our findings of poor knowledge of cancer among PLHIV in Nigeria indicate the need for health care providers and the government to intervene by developing primary cancer prevention strategies for this population. PMID- 23098100 TI - The influence of cricket fast bowlers' front leg technique on peak ground reaction forces. AB - High ground reaction forces during the front foot contact phase of the bowling action are believed to be a major contributor to the high prevalence of lumbar stress fractures in fast bowlers. This study aimed to investigate the influence of front leg technique on peak ground reaction forces during the delivery stride. Three-dimensional kinematic data and ground reaction forces during the front foot contact phase were captured for 20 elite male fast bowlers. Eight kinematic parameters were determined for each performance, describing run-up speed and front leg technique, in addition to peak force and time to peak force in the vertical and horizontal directions. There were substantial variations between bowlers in both peak forces (vertical 6.7 +/- 1.4 body weights; horizontal (braking) 4.5 +/- 0.8 body weights) and times to peak force (vertical 0.03 +/- 0.01 s; horizontal 0.03 +/- 0.01 s). These differences were found to be linked to the orientation of the front leg at the instant of front foot contact. In particular, a larger plant angle and a heel strike technique were associated with lower peak forces and longer times to peak force during the front foot contact phase, which may help reduce the likelihood of lower back injuries. PMID- 23098101 TI - Measuring healthcare preparedness: an all-hazards approach. AB - In a paper appearing in this issue, Adini, et al. describe a struggle familiar to many emergency planners-the challenge of planning for all scenarios. The authors contend that all-hazards, or capabilities-based planning, in which a set of core capabilities applicable to numerous types of events is developed, is a more efficient way to achieve general health care system emergency preparedness than scenario-based planning. Essentially, the core of what is necessary to plan for and respond to one kind of disaster (e.g. a biologic event) is also necessary for planning and responding to other types of disasters, allowing for improvements in planning and maximizing efficiencies. While Adini, et al. have advanced the science of health care emergency preparedness through their consideration of 490 measures to assess preparedness, a shorter set of validated preparedness measures would support the dual goals of accountability and improved outcomes and could provide the basis for determining which actions in the name of preparedness really matter. PMID- 23098102 TI - Virus inactivation mechanisms: impact of disinfectants on virus function and structural integrity. AB - Oxidative processes are often harnessed as tools for pathogen disinfection. Although the pathways responsible for bacterial inactivation with various biocides are fairly well understood, virus inactivation mechanisms are often contradictory or equivocal. In this study, we provide a quantitative analysis of the total damage incurred by a model virus (bacteriophage MS2) upon inactivation induced by five common virucidal agents (heat, UV, hypochlorous acid, singlet oxygen, and chlorine dioxide). Each treatment targets one or more virus functions to achieve inactivation: UV, singlet oxygen, and hypochlorous acid treatments generally render the genome nonreplicable, whereas chlorine dioxide and heat inhibit host-cell recognition/binding. Using a combination of quantitative analytical tools, we identified unique patterns of molecular level modifications in the virus proteins or genome that lead to the inhibition of these functions and eventually inactivation. UV and chlorine treatments, for example, cause site specific capsid protein backbone cleavage that inhibits viral genome injection into the host cell. Combined, these results will aid in developing better methods for combating waterborne and foodborne viral pathogens and further our understanding of the adaptive changes viruses undergo in response to natural and anthropogenic stressors. PMID- 23098103 TI - The relation between acculturation and alcohol consumption patterns among older Asian and Hispanic immigrants. AB - This study examines the relation between acculturation and alcohol consumption patterns among older Asian and Hispanic immigrants in the state of California. Data were obtained from the 2009 California Health Interview Survey and included Asian (n = 1264) and Hispanic (n = 571) adults aged 60 and older who were born outside of the US. Outcome variables included presence of past year alcohol consumption, past year binge drinking, and number of binge drinking days. Acculturation was measured with items pertaining to English use and proficiency. Hierarchical multiple or logistic regression analyses were conducted separately for each racial/ethnic group and each dependent variable. Alcohol consumption was found in less than half of the sample for both Asians (43.2%) and Hispanics (39.2%). Binge drinking was found in 3.1% of Asians and 8.4% of Hispanics. Acculturation was significantly related to past year alcohol consumption for Hispanics, past year binge drinking for Asians, and binge drinking days for Asians, such that higher level of acculturation predicted a greater likelihood of alcohol consumption but decreased likelihood of binge drinking and fewer binge drinking days. The results indicate that acculturation may be related to alcohol consumption patterns for older immigrants. This suggests future needs to develop an in-depth understanding of the health behaviors of these immigrant elderly groups. PMID- 23098104 TI - Ultrabright bowtie nanoaperture antenna probes studied by single molecule fluorescence. AB - We report on a novel design for the fabrication of ultrabright bowtie nanoaperture antenna (BNA) probes to breach the intrinsic trade-off between power transmission and field confinement of circular nanoapertures as in near-field scanning optical microscopy (NSOM) or planar zero mode waveguides. The approach relies on the nanofabrication of BNAs at the apex of tapered optical fibers tuned to diameters close to their cutoff region, resulting in 10(3)* total improvement in throughput over conventional NSOM probes of similar confinement area. By using individual fluorescence molecules as optical nanosensors, we show for the first time nanoimaging of single molecules using BNA probes with an optical confinement of 80 nm, measured the 3D near-field emanating from these nanostructures and determined a ~6-fold enhancement on the single molecule signal. The broadband field enhancement, nanoscale confinement, and background free illumination provided by these nanostructures offer excellent perspectives as ultrabright optical nanosources for a full range of applications, including cellular nanoimaging, spectroscopy, and biosensing. PMID- 23098105 TI - Immunomorphologic profile and Epstein-Barr virus status of a cohort of 35 cases of extranodal natural killer/T-cell lymphoma, nasal type of upper aerodigestive tract from a tertiary care center in South India. AB - Extranodal natural killer (NK)/T-cell lymphoma, nasal type (EN-NK/T-NT) is a lymphoma of NK-cell or cytotoxic T-cell origin, which occurs most commonly in the upper aerodigestive tract. We have studied the immunomorphologic profile and Epstein-Barr virus (EBV) status of a cohort of 35 cases of EN-NK/T-NT of the upper aerodigestive tract (UADT) diagnosed in our institution during the period May 2002 to April 2012. At our institution these lymphomas constitute 0.7% of total non-Hodgkin lymphomas (NHLs) and 5.1% of total peripheral T-cell lymphomas (PTCLs). The median age at diagnosis was 40 years with a male-to-female ratio of 4:1, and the most common site of involvement was the nasal cavity. Morphologically, the neoplastic cells were predominantly medium sized in most cases. Necrosis and angiocentricity were common histologic features. Thirty cases (85.7%) showed NK-cell immunophenotype, CD3+ (29/30, 96.7%), CD56+ (30/30, 100%) and TIA1/Granzyme B+ (30/30, 100%). Five cases (14.3%) showed cytotoxic T-cell immunophenotype, CD3+ (5/5, 100%), CD56- (5/5, 100%) and TIA1/Granzyme B+ (5/5, 100%). EBV-encoded RNA-in situ hybridization (EBER-ISH) was positive in all 35 cases, whereas EBV latent membrane protein-1 (EBVLMP1) was positive in only 19/35 (54.3%) of cases. In conclusion, this is the first large study from India to report the immunomorphologic profile and EBV association of EN-NK/T-NT, which is known to have geographic variation. The frequency of these lymphomas in our study is comparable to that of Western and European countries and much less than that of Far Eastern countries. PMID- 23098106 TI - GlideScope-assisted nerve integrity monitoring tube placement for intra-operative recurrent laryngeal nerve monitoring. AB - OBJECTIVE: The proper positioning of the Nerve Integrity Monitoring(r) endotracheal tube during recurrent laryngeal nerve monitoring is of paramount importance. This article describes our experience with the GlideScope(r) and explains how it can facilitate the accurate placement of the Nerve Integrity Monitoring endotracheal tube. METHODS: Endotracheal intubation with the Nerve Integrity Monitoring endotracheal tube was performed in 250 patients undergoing thyroidectomies using the GlideScope video laryngoscope. The correct positioning of the tube was determined according to impedance values of less than 5 kohm and an impedance imbalance of less than 1 kohm. RESULTS: Successful intubation was achieved in all cases. The GlideScope aided the correct placement of the Nerve Integrity Monitoring endotracheal tube in the majority of the cases. CONCLUSION: The GlideScope provides an excellent means to ensure the correct positioning of the Nerve Integrity Monitoring tube. It allows both the surgeon and the anaesthesiologist to participate in the intubation process and confirm correct placement of the tube, whilst also allowing gentle intubation with improved visibility. PMID- 23098107 TI - Optical properties of nanohole arrays in metal-dielectric double films prepared by mask-on-metal colloidal lithography. AB - We present the fabrication and optical characterization of plasmonic nanostructures consisting of nanohole arrays in two thin films, a metal and a dielectric. A novel method called mask-on-metal colloidal lithography is used to prepare high aspect ratio holes, providing efficient mass fabrication of stable structures with close to vertical walls and without the need for an adhesion layer under the metal. Our approach for understanding the transmission properties is based on solving the dispersions of the guided modes supported by the two films and calculating the influence from interference. The methodology is generic and can be extended to multilayered films. In particular, the influence from coupling to waveguide modes is discussed. We show that by rational design of structural dimensions it is possible to study only bonding surface plasmons and the associated hole transmission maximum. Further, numerical simulations with the multiple multipole program provide good agreement with experimental data and enable visualization of the asymmetric near-field distribution in the nanohole arrays, which is focused to the interior of the "nanowells". The refractometric sensitivity is evaluated experimentally both by liquid bulk changes and surface adsorption. We demonstrate how the localized mode provides reasonably good sensitivity in terms of resonance shift to molecular binding inside the voids. Importantly, high resolution sensing can be accomplished also for the surface plasmon mode, despite its extremely low figure of merit. This is accomplished by monitoring the coupling efficiency of light to plasmons instead of conventional sensing which is based on changes in plasmon energy. We suggest that these nanohole structures can be used for studying molecular transport through nanopores and the behavior of molecules confined in volumes of approximately one attoliter. PMID- 23098108 TI - Diphenyl purine derivatives as peripherally selective cannabinoid receptor 1 antagonists. AB - Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID- 23098109 TI - A new era for children with diffuse intrinsic pontine glioma: hope for cure? PMID- 23098110 TI - Targeted treatment for melanoma. PMID- 23098112 TI - Novel aspects of therapy with the dual Src and Abl kinase inhibitor bosutinib in chronic myeloid leukemia. AB - The dual Src/Abl kinase inhibitor bosutinib (SKI-606) targets the tyrosine kinase brc-abl, the key enzyme in the development of chronic myeloid leukemia (CML). In clinical trials, bosutinib yielded promising results with regard to efficacy, tolerability and toxicity in first-, second- and third-line therapy of CML patients. Remarkably, bosutinib is able to overcome most imatinib-resistant BCR ABL1-1 mutations except V299L and T315I. Mostly, low-to-moderate grade gastrointestinal toxicitis are the most common treatment-emergent adverse events observed under bosutinib. Unlike other tyrosine kinase inhibitors approved for CML treatment to date, bosutinib shows only minimal inhibitory activity against c KIT and the PDGF receptor. This may be causative for its favorable hematologic toxicity profile. In this review, the authors give an overview on the mechanism of action and currently available preclinical and clinical data for bosutinib in CML. PMID- 23098113 TI - Cabazitaxel in metastatic castration-resistant prostate cancer. AB - Metastatic castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Prior to 2010, docetaxel chemotherapy was the only treatment shown to improve overall survival, symptom control and quality of life in patients with CRPC. Research efforts focused on overcoming chemoresistance to taxanes eventually led to the development of multiple novel anti-tumor agents, including cabazitaxel. Cabazitaxel has recently been shown to significantly improve overall survival compared with mitoxantrone in a large multicenter Phase III study. This article details the preclinical and clinical development of cabazitaxel and discusses the importance of this novel chemotherapy in CRPC. The authors also discuss the challenges now facing the future use of cabazitaxel in CRPC, including the determination of the optimal dose of cabazitaxel in patients with advanced CRPC, the ideal sequencing of cabazitaxel relative to other anti-tumor treatments, appropriate patient selection and novel strategies for the assessment of treatment response. PMID- 23098114 TI - Regional approaches to the management of patients with advanced, radioactive iodine-refractory differentiated thyroid carcinoma. AB - For patients with advanced, radioactive iodine-refractory differentiated thyroid cancer, current treatment guidelines recommend clinical trial enrollment or small molecule kinase inhibitor therapy. However, details of patient management vary between countries depending on trial availability and national regulatory policies. Insufficient clinical trial data and variable disease characteristics challenge the creation of universal guidelines, and treatment plans often reflect regional influences. A multidisciplinary, multiregional panel of experts met to discuss regional approaches to managing patients with advanced, radioactive iodine-refractory differentiated thyroid cancer and the potential impact of emerging therapies on current treatment strategies. Despite process-oriented regional differences, the decision-making strategies were similar. Multidisciplinary teams used to manage high-risk patients varied in composition across regions, particularly regarding the responsible physician's specialty. Cytotoxic chemotherapy was viewed as limited in clinical benefit, and targeted agents as attractive, based on promising data. Panel members support clinical trial enrollment as the preferred treatment strategy for managing these patients. PMID- 23098116 TI - Management of salivary gland tumors. AB - Surgery after proper imaging (MRI or CT scan) is the main stay of treatment for salivary gland tumors. Although excision margins should be >=5 mm for malignant tumors in cases of parotid gland carcinoma, the facial nerve should be preserved whenever it is not infiltrated. Adjuvant external radiation is indicated for malignant tumors with high-risk features such as close (or invaded) margins, perineural speed, lymphatic and/or vascular invasion, lymph-node involvement and high-grade histology. A Phase II trial testing adjuvant concomitant cisplatin plus radiation therapy versus adjuvant radiation therapy alone after surgery is currently under investigation for high-risk salivary gland cancer. For inoperable cancers, photons combined with proton boost seem to be a valuable option. Even if protons or carbon ions are promising, access to the latter is limited for usual treatment. For recurrent and/or metastatic cancer, polychemotherapy (cisplatin based) gives a 25% response rate in adenoid cystic carcinoma and should be used when the disease is overtly in progression. Targeted therapies with anti-EGF receptor molecules, antiangiogenic agents and tyrosine kinase inhibitors are ongoing, but more trials are needed to establish their efficacy, as is the use of bortezomib followed by doxorubicin. The products of fusion oncogenes, which have a pathogenic role in some adenoid cystic carcinoma and mucoepidermoid carcinomas, are of interest as potential therapeutic targets. PMID- 23098117 TI - Craniofacial resection and its role in the management of sinonasal malignancies. AB - Sinonasal malignancy is rare, and its presentation is commonly late. There is a wide variety of pathologies with varying natural histories and survival rates. Anatomy of the skull base is extremely complex and tumors are closely related to orbits, frontal lobes and cavernous sinus. Anatomical detail and the late presentation render surgical management a challenging task. A thorough understanding of anatomy and pathology combined with modern neuroimaging and reliable reconstruction within a multidisciplinary team is imperative to carry out skull base surgery effectively. While endoscopic approaches are gaining credibility, clearly, it will be some time before meaningful comparisons with craniofacial resection can be made. Until then, craniofacial resection will remain the gold standard for managing the sinonasal malignancies of the anterior skull base, as it has proved to be safe and effective. PMID- 23098115 TI - Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma. AB - New agents and treatment strategies that can be safely and effectively integrated into current treatment paradigms for head and neck squamous cell carcinoma (HNSCC) are urgently needed. To date, the anti-EGF receptor (EGFR) monoclonal antibody, cetuximab, is the first and only molecularly targeted therapy to demonstrate a survival benefit for patients with recurrent or metastatic disease. Other anti-EGFR-targeted therapies, including monoclonal antibodies (e.g., panitumumab and zalutumumab) and reversible and irreversible ErbB family tyrosine kinase inhibitors (e.g., lapatinib, afatinib and dacomitinib) are being actively investigated in Phase II and Phase III clinical trials. In addition, validated biomarkers are needed to predict clinical benefit and resistance to anti-EGFR therapy in HNSCC. This review will compare and contrast the mechanisms of action of anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors and also discuss their role in the management of HNSCC and the potential impact of human papillomavirus status in the development of these targeted agents. PMID- 23098118 TI - Reirradiation for recurrent head and neck cancer. AB - Recurrence of head and neck cancer in a previously irradiated volume presents a challenging problem and has poor prognosis. A minority of patients are eligible for the preferred therapy, surgical resection. Systemic therapy is offered to patients with unresectable disease but offers little, if any, chance of cure. Repeat irradiation with systemic therapy is a potentially curative option. One randomized trial and several cooperative group and institutional studies support its use. Long-term disease-free survival has been observed, albeit with the risk of significant, possibly life threatening, late complications. Intensity modulated radiotherapy has been shown to reduce toxicity and improve disease control. Novel systemic therapies and radiotherapy techniques, including stereotactic body radiotherapy, are under active study. PMID- 23098119 TI - All-trans retinoic acid in the treatment of pediatric acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a rare form of acute myeloid leukemia with specific epidemiological, pathogenetic and clinical features. Its frequency varies widely among nations, with a decreased incidence among 'Nordic' origin populations. The molecular hallmark of the disease is the presence of a balanced reciprocal translocation resulting in the PML/RAR-alpha gene fusion, which represents the target of the all-trans retinoic acid (ATRA) therapy. The introduction of ATRA in conjunction with anthracyclines marked a turning point in the treatment of APL, previously associated with a significant morbidity and mortality. Nowadays the standard front-line therapy for pediatric APL includes ATRA in every phase of the treatment, resulting in a complete remission rate of 90-95%. Here we provide an overview of the role of ATRA in the treatment of pediatric APL, summarizing the most relevant clinical results of recent decades and investigating future therapeutic perspectives for children with APL. PMID- 23098120 TI - Emerging agents for the treatment of mantle cell lymphoma. AB - The characterization of the mantle cell lymphoma (MCL) entity had a major impact on patient management and has played a profound role in improving therapy. Although the prognosis is improving in MCL, there is no definitive proof that the therapies currently available will lead to cure. Few randomized studies have been conducted in MCL patients. In young patients, initial intensive therapy with high dose cytarabine followed by high-dose chemotherapy and hematopoietic stem cell reinfusion has resulted in prolonged progression-free survival. In elderly subjects, who always represent a more heterogeneous group of patients, there is no consensus concerning which drugs can be used during induction chemotherapy. New drugs have essentially been evaluated in patients with recurrent disease or refractory to first-line regimens. Recently, two of them (bortezomib and temsirolimus) with different modes of action were registered in MCL. Targeted therapies are also being investigated extensively in MCL and are yielding interesting activities. PMID- 23098121 TI - Clinical trial end points for assessing efficacy of novel therapies for soft tissue sarcomas. AB - Soft-tissue sarcomas (STS) comprise a heterogeneous group of rare malignancies from mesenchymal tissues. Although outcome varies by histology, adults with disseminated metastatic STS have a poor prognosis despite current treatment options. The authors reviewed commonly used clinical end points for STS and discussed which end points may be appropriate for evaluating the clinical benefit of novel targeted therapies. In sarcoma, surrogates for both overall survival, the gold standard end point, and the objective response rate, measured by Response Evaluation Criteria in Solid Tumors, are commonly used. More appropriate end points for evaluating newly targeted agents include progression-free survival and clinical benefit rate. Results from recently completed Phase III trials of two targeted therapies in advanced STS, the mTOR inhibitor ridaforolimus and the multikinase inhibitor pazopanib, should shed light on whether progression-free survival and clinical benefit rate are appropriate end points in advanced STS. PMID- 23098122 TI - Follow-up procedures for non-muscle-invasive bladder cancer: an update. AB - Bladder carcinoma is the most common malignancy of the urinary tract. Approximately 75-85% of patients present with a disease that is confined to the mucosa (stage Ta, carcinoma in situ) or submucosa (stage T1). The stratification of patients to low-, intermediate- and high-risk groups represents the cornerstone for the indication of adjuvant and follow-up treatment. Owing to the high recurrence rate of bladder tumors, a surveillance protocol is recommended to all patients. Currently, the combination of cystoscopy, imaging and urinary cytology represent the follow-up. A systematic review of the recent English literature on follow-up procedures of non-muscle-invasive bladder cancer is performed. The authors review the existing follow-up procedures, with a focus on novel molecular-targeted approaches. At the present time, the additional use and utility of urine-based molecular markers in the follow-up of patients remains unclear and we have to rely on cystoscopic evaluation adapted to risk group classification. PMID- 23098124 TI - Moral emotions and the envisaging of mitigating circumstances for wrongdoing. AB - Anger may be more responsive than disgust to mitigating circumstances in judgements of wrongdoing. We tested this hypothesis in two studies where we had participants envision circumstances that could serve to mitigate an otherwise wrongful act. In Study 1, participants provided moral judgements, and ratings of anger and disgust, to a number of transgressions involving either harm or bodily purity. They were then asked to imagine and report whether there might be any circumstances that would make it all right to perform the act. Across transgression type, and controlling for covariance between anger and disgust, levels of anger were found to negatively predict the envisioning of mitigating circumstances for wrongdoing, while disgust was unrelated. Study 2 replicated and extended these findings to less serious transgressions, using a continuous measure of mitigating circumstances, and demonstrated the impact of anger independent of deontological commitments. These findings highlight the differential relationship that anger and disgust have with the ability to envision mitigating factors. PMID- 23098125 TI - Vitamin D mitigates age-related cognitive decline through the modulation of pro inflammatory state and decrease in amyloid burden. AB - BACKGROUND: Increasing evidence shows an association between the use of vitamin D and improvement in age-related cognitive decline. In this study, we investigated the possible mechanisms involved in the neuroprotective effects of vitamin D on age-related brain changes and cognitive function. METHODS: Male F344 rats aged 20 months (old) and 6 months (young) were used and randomly assigned to either vitamin D supplementation or no supplementation (control). A total of n = 39 rats were used in the study. Rats were individually housed and the supplementation group received a subcutaneous injection of vitamin D (1, alpha25-dihydroxyvitamin D3) 42 I.U./Kg for 21 days. Control animals received equal volume of normal saline. Behavioral testing in water maze and spontaneous object recognition tasks started on day 14. Levels of interleukin (IL)-1beta and IL-10 were quantified to assess inflammatory state. Also, beta amyloid (Abeta) clearance and Abeta load were measured. RESULTS: Our results show that: (1) aged rats demonstrated significant learning and memory impairment overall compared to younger animals. However, the age-related decline in learning and memory was ameliorated by the supplementation of vitamin D. No vitamin D effect on learning and memory was seen in the young animals; 2) the pro-inflammatory cytokine IL-1beta is significantly increased while the anti-inflammatory cytokine IL-10 is significantly decreased in the aged rats compared to the young animals; but this age-related change in inflammatory state was mitigated by vitamin D supplementation. No effects of vitamin D were seen on the IL-1beta and IL-10 expression in the young rats; (3) vitamin D increased Abeta clearance and decreased amyloid burden in the aged rats while no significant difference was seen between the young animal groups. CONCLUSIONS: Our data suggest that vitamin D supplementation modulated age related increase in pro-inflammatory state and amyloid burden. It is possible that these effects of vitamin D mediated the decrease memory impairment seen in the aged rats making it a useful therapeutic option to alleviate the effects of aging on cognitive function. PMID- 23098127 TI - Improving health outcomes: innovation, coverage, quality and adherence. AB - The Israeli health system has made considerable progress in reducing deaths amenable to medical care but has more to do. This commentary describes how progress in this area results from innovation, coverage, quality, and adherence to treatment. It describes what is being done in Israel and beyond to address each of these factors but concentrates on the often poorly recognised problem of adherence to treatment, describing the growing evidence that it is often sub optimal and reviewing evidence on what can be done to improve it. PMID- 23098128 TI - Design of optimal solvent for extraction of bio-active ingredients from six varieties of Medicago sativa. AB - BACKGROUND: Extensive research has been performed worldwide and important evidences were collected to show the immense potential of plants used in various traditional therapeutic systems. The aim of this work is to investigate the different extracting solvents in terms of the influence of their polarity on the extracting ability of bioactive molecules (phenolic compounds) from the M. sativa flowers. RESULTS: The total phenolic content of samples was determined using the Folin Ciocalteu (FC) procedure and their antioxidant activity was assayed through in vitro radical decomposing activity using the radical DPPH degrees assay (IUPAC name for DPPH is (phenyl)-(2,4,6-trinitrophenyl) iminoazanium). The results showed that water was better than methanol and acetic acid for extracting bioactive compounds, in particular for total phenolic compounds from the flowers of alfalfa. The average content of bioactive molecules in methanol extract was 263.5+/-1.02 mg GAE/100g of dry weight lyophilized extract. The total phenolic content of the tested plant extracts was highly correlated with the radical decomposing activity. However, all extracts were free-radical inhibitors, but the water extract was more potent than the acetic and the methanol ones. The order of inhibitor effectiveness (expressed by IC50) proved to be: water extract (0.924mg/mL) > acetic acid extract (0.154mg/mL) > methanol (0.079mg/mL). The profiles of each extract (fingerprint) were characterized by FT-MIR spectroscopy. CONCLUSIONS: The present study compares the fingerprint of different extracts of the M. sativa flowers, collected from the wild flora of Romania. The total phenolic content of the tested plant extracts was highly correlated with the radical decomposing activity. The dependence of the extract composition on the solvent polarity (acetic acid vs. methanol vs. water) was revealed by UV-VIS spectrometry and Infrared fingerprint. PMID- 23098129 TI - An examination of the migratory transition of elite young European soccer players to the English Premier League. AB - The migration of soccer players has increased in recent years. In this study, we examined the experiences of elite young soccer players as they engaged in a migratory transition from their home country to an English Premier League (EPL) club. Five young players, who made the migratory transition between the ages of 16 and 24, were interviewed. Data were analysed using the principles of content analysis. Verbatim text was then aligned to the emergent themes. Results indicate that young migratory players face the initial frenzy that is associated with an approach from an EPL club before going through a "decision" phase, followed by a period of "migration" and "acculturation" before establishing (or not) their "home from home". The challenges of leaving home and family while trying to establish themselves as a professional player in an environment that (still) appears to be beset with (traditional) English soccer culture (i.e. high tempo, ruthless, macho, and aggressive) are recounted. While the player's family was a significant source of social support, there is still a need for qualified personnel (e.g. sports psychologists) and/or appropriately trained international recruitment staff and football agents (i.e. in areas of social, psychological, and/or performance lifestyle) to support young players through their migratory transition. PMID- 23098130 TI - The value of pancreatic stone protein in predicting acute appendicitis in patients presenting at the emergency department with abdominal pain. AB - BACKGROUND: Pancreatic Stone Protein (PSP) is a protein naturally produced mainly in the pancreas and the gut. There is evidence from experimental and clinical trials that blood PSP levels rise in the presence of inflammation or infection. However, it is not known whether PSP is superior to other established blood tests (e.g. White Blood Count, Neutrophils or C - reactive protein) in predicting appendicitis in patients presenting with abdominal pain and a clinical suspicion of appendicitis at the emergency room. METHODS/DESIGN: The PSP Appendix Trial is a prospective, multi-center, cohort study to assess the value of PSP in the diagnostic workup of acute appendicitis. 245 patients will be prospectively recruited. Interim analysis will be performed once 123 patients are recruited. The primary endpoint of the study concerns the diagnostic accuracy of PSP in predicting acute appendicitis and therefore the evidence of appendicitis on the histopathological specimen after appendectomy. DISCUSSION: The PSP Appendix Trial is a prospective, multi-center, cohort study to assess the value of PSP in the diagnostic workup of acute appendicitis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01610193; Institution Ethical Board Approval ID: KEKZH- Nr. 2011-0501. PMID- 23098131 TI - Diastereoselective formation of tetrahydrofurans via Pd-catalyzed asymmetric allylic alkylation: synthesis of the C13-C29 subunit of amphidinolide N. AB - An efficient synthesis of the C13-C29 fragment of amphidinolide N is described. The synthesis relies on a new strategy involving Pd-catalyzed asymmetric allylic alkylation to generate diastereoselectively the cis- or trans-THF unit simply by varying the enantiomer of the ligand. The C19 hydroxyl-bearing stereocenter was introduced using a chelation-controlled allylation which led exclusively to a single diastereoisomer. PMID- 23098132 TI - Synergy between secondary organic aerosols and long-range transport of polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons (PAHs), known for their harmful health effects, undergo long-range transport (LRT) when adsorbed on and/or absorbed in atmospheric particles. The association between atmospheric particles, PAHs, and their LRT has been the subject of many studies yet remains poorly understood. Current models assume PAHs instantaneously attain reversible gas-particle equilibrium. In this paradigm, as gas-phase PAH concentrations are depleted due to oxidation and dilution during LRT, particle-bound PAHs rapidly evaporate to re establish equilibrium leading to severe underpredictions of LRT potential of particle-bound PAHs. Here we present a new, experimentally based picture in which PAHs trapped inside highly viscous semisolid secondary organic aerosol (SOA) particles, during particle formation, are prevented from evaporation and shielded from oxidation. In contrast, surface-adsorbed PAHs rapidly evaporate leaving no trace. We find synergetic effects between hydrophobic organics and SOA - the presence of hydrophobic organics inside SOA particles drastically slows SOA evaporation to the point that it can almost be ignored, and the highly viscous SOA prevents PAH evaporation ensuring efficient LRT. The data show the assumptions of instantaneous reversible gas-particle equilibrium for PAHs and SOA are fundamentally flawed, providing an explanation for the persistent discrepancy between observed and predicted particle-bound PAHs. PMID- 23098133 TI - Use of the internet in the treatment of obesity and prevention of type 2 diabetes in primary care. AB - Cardiovascular prevention, including emphasising healthy diet and physical activity patterns for weight loss and diabetes prevention, is an important focus of primary care medicine, yet provision of intensive lifestyle counselling in the primary care setting remains uncommon. Online approaches for providing lifestyle counselling are emerging as a new avenue for bringing support to outpatient patient populations. Features of successful programmes include the use of a structured behavioural programme, electronic counselling support and feedback, and uncomplicated user interfaces. Online tools may be used independently or to complement in-person approaches. Limited data also suggest that the internet can be used to support the maintenance of weight loss. In addition, the internet may help overcome various clinical barriers to lifestyle support, including significant time limitations, a need to prioritise acute care and maintain clinical workflow, and the high cost of counselling. Furthermore, the continuity of the primary care patient-provider(s) relationship provides an established source of long-term support which has been difficult to create in other community settings. As the field of online lifestyle counselling matures, nutrition and physical activity experts will face new challenges in providing asynchronous counselling without the assistance of traditional non-verbal communication cues. However, the potential for reaching a wider population in a convenient and accessible manner also creates unique opportunities for providing lifestyle support. PMID- 23098134 TI - Administration-time-dependent effects of hypertension treatment on ambulatory blood pressure in patients with chronic kidney disease. AB - Many published prospective trials have reported clinically meaningful morning evening, treatment-time differences in the blood pressure (BP)-lowering efficacy, duration of action, and safety of most classes of hypertension medications. Most important, it was recently documented that routine ingestion of the full daily dose of >=1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Nocturnal hypertension and non-dipping (<10% decline in the asleep relative to the awake BP mean), as determined by ambulatory BP monitoring (ABPM), are frequent in chronic kidney disease (CKD) and both are associated with increased CVD risk. Here, we investigated the influence of hypertension treatment time on the circadian BP pattern and degree of BP control of hypertensive patients with CKD evaluated by 48-h ABPM. This cross-sectional study evaluated 2659 such patients (1585 men/1074 women), 64.9 +/- 13.2 (mean +/- SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM; 1446 were ingesting all BP-lowering medications upon awakening, whereas 1213 patients were ingesting >=1 medications at bedtime. Among the latter, 359 patients were ingesting all medications at bedtime, whereas 854 were ingesting the full daily dose of some medications upon awakening and the others at bedtime. Those ingesting all medications upon awakening had significantly higher total cholesterol and low density lipoprotein (LDL) cholesterol than those ingesting >=1 medications at bedtime. Moreover, patients ingesting all medications at bedtime had the lowest fasting glucose, serum creatinine, and uric acid. Ingestion of >=1 medications at bedtime was significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than treatment with all medications upon awakening. The sleep-time relative SBP decline was significantly attenuated in patients ingesting all medications upon awakening (p < .001). Thus, the prevalence of non dipping was significantly higher when all hypertension medications were ingested upon awakening (68.3%) than when >=1 of them was ingested at bedtime (54.2%; p < .001 between groups), and even further attenuated (47.9%) when all of them were ingested at bedtime (p < .001). Additionally, the prevalence of a riser BP pattern, associated with highest CVD risk, was much greater (21.5%) among patients ingesting all medications upon awakening, compared with those ingesting some (15.7%) or all medications at bedtime (10.6%; p < .001 between groups), independent of CKD severity (disease stage). The latter group also showed a significantly higher prevalence of properly controlled ambulatory BP (p < .001) that was achieved by a significantly lower number of hypertension medications (p < .001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, in patients with CKD ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for CKD. PMID- 23098135 TI - Large electroabsorption susceptibility mediated by internal photoconductive gain in Ge nanowires. AB - Large spectral modulation in the photon-to-electron conversion near the absorption band-edge of a semiconductor by an applied electrical field can be a basis for efficient electro-optical modulators. This electro-absorption effect in Group IV semiconductors is, however, inherently weak, and this poses the technological challenges for their electro-photonic integration. Here we report unprecedentedly large electro-absorption susceptibility at the direct band-edge of intrinsic Ge nanowire (NW) photodetectors, which is strongly diameter dependent. We provide evidence that the large spectral shift at the 1.55 MUm wavelength, enhanced up to 20 times larger than Ge bulk crystals, is attributed to the internal Franz-Keldysh effect across the NW surface field of ~10(5) V/cm, mediated by the strong photoconductive gain. This classical size-effect operating at the nanometer scale is universal, regardless of the choice of materials, and thus suggests general implications for the monolithic integration of Group IV photonic circuits. PMID- 23098136 TI - The prevalence of methicillin-resistant staphylococcus aureus among out-of hospital care providers and emergency medical technician students. AB - OBJECTIVE: We compared the methicillin-resistant Staphylococcus aureus (MRSA) carrier rate among out-of-hospital care providers with greater than six months' experience in emergency medical services (EMS) care with that of emergency medical technician (EMT) students with two months or less of observation time as part of their clinical training. METHODS: We conducted a prospective study utilizing a convenience sample of out-of-hospital care providers and EMT students in an urban EMS system operating in the Midwest during October and November 2006. One hundred thirty-four out-of-hospital care providers and 152 EMT students were tested for MRSA susceptibility using the cefoxitin disk diffusion method. RESULTS: Contrary to our hypothesis, we did not find a statistically significant difference in MRSA nasal colonization between out-of-hospital care providers (4.5%; 95% confidence interval [CI] 1.0, 8.0) and EMT students (5.3%; 95% CI 1.7, 8.8). A subgroup analysis showed that among out-of-hospital care providers, paramedics had a higher rate of nasal colonization than EMTs (5.6% vs. 2.2%). CONCLUSION: We found that out-of-hospital care providers and EMT students had higher nasal colonization rates than the reported rate for the U.S. population (0.084% at the time the study was conducted and 1.5% currently). It is imperative that both groups adhere to infection control practices. PMID- 23098137 TI - Repositioning HIV-1 integrase inhibitors for cancer therapeutics: 1,6 naphthyridine-7-carboxamide as a promising scaffold with drug-like properties. AB - Among a large number of HIV-1 integrase (IN) inhibitors, the 8-hydroxy [1,6]naphthyridines (i.e., L-870,810) were one of the promising class of antiretroviral drugs developed by Merck Laboratories. In spite of its remarkable potency and efficacy, unfortunately upon completion of phase I clinical studies, development of L-870,810 was halted. Because of its desirable pharmacological and pharmaceutical properties we were intrigued to design novel analogues of L 870,810 with goals to (1) improve upon limitations of naphthyridine-7 carboxamides as antiviral agents and (2) to reposition their use as innovative cytotoxic agents for cancer therapeutics. Herein, we report on the design and synthesis of a series of 1,6-naphthyridine-7-carboxamides with various substitutions at the 5- and 8-positions. All the new 5-substituted-8-hydroxy [1,6]naphthyridines were potent IN inhibitors and the 5-substituted-8-amino [1,6]naphthyridines were significantly cytotoxic. Further optimization of the 5,8 disubstituted-[1,6]naphthyridines with structural variation on 7-carboxamide delivered novel compounds with significant cytotoxicity in a panel of cancer cell lines and effective inhibition against select oncogenic kinases. PMID- 23098138 TI - A systematic review of the role of school-based healthcare in adolescent sexual, reproductive, and mental health. AB - BACKGROUND: Accessible sexual, reproductive, and mental healthcare services are crucial for adolescent health and wellbeing. It has been reported that school based healthcare (SBHC) has the potential to improve the availability of services particularly for young people who are normally underserved. Locating health services in schools has the potential to reduce transport costs, increase accessibility and provide links between schools and communities. METHODS: A systematic review of the literature was undertaken. Pubmed, Psychinfo, Psychnet, Cochrane CENTRAL, and Web of Science were searched for English language papers published between January 1990 and March 2012 RESULTS: Twenty-seven studies were found which fitted the criteria, of which, all but one were from North America. Only three measured adolescent sexual, reproductive, or mental health outcomes related to SBHC and none of the studies were randomized controlled trials. The remaining studies explored accessibility of services and clinic utilization or described pertinent contextual factors. CONCLUSIONS: There is a paucity of high quality research which evaluates SBHC and its effects on adolescent sexual, reproductive, and mental health. However, there is evidence that SBHC is popular with young people, and provides important mental and reproductive health services. Services also appear to have cost benefits in terms of adolescent health and society as a whole by reducing health disparities and attendance at secondary care facilities. However, clearer definitions of what constitutes SBHC and more high quality research is urgently needed. PMID- 23098139 TI - The matrix metalloproteinase inhibitor marimastat promotes neural progenitor cell differentiation into neurons by gelatinase-independent TIMP-2-dependent mechanisms. AB - Metalloproteinases (MMPs) and their endogenous inhibitors (TIMPs), produced in the brain by cells of non-neural and neural origin, including neural progenitors (NPs), are emerging as regulators of nervous system development and adult brain functions. In the present study, we explored whether MMP-2, MMP-9, and TIMP-2, abundantly produced in the brain, modulate NP developmental properties. We found that treatment of NPs, isolated from the murine fetal cerebral cortex or adult subventricular zone, with the clinically tested broad-spectrum MMP inhibitor Marimastat profoundly affected the NP differentiation fate. Marimastat treatment allowed for an enrichment of our cultures in neuronal cells, inducing NPs to generate higher percentage of neurons and a lower percentage of astrocytes, possibly affecting NP commitment. Consistently with its proneurogenic effect, Marimastat early downregulated the expression of Notch target genes, such as Hes1 and Hes5. MMP-2 and MMP-9 profiling on proliferating and differentiating NPs revealed that MMP-9 was not expressed under these conditions, whereas MMP-2 increased in the medium as pro-MMP-2 (72 kDa) during differentiation; its active form (62 kDa) was not detectable by gel zymography. MMP-2 silencing or administration of recombinant active MMP-2 demonstrated that MMP-2 does not affect NP neuronal differentiation, nor it is involved in the Marimastat proneurogenic effect. We also found that TIMP-2 is expressed in NPs and increases during late differentiation, mainly as a consequence of astrocyte generation. Endogenous TIMP-2 did not modulate NP neurogenic potential; however, the proneurogenic action of Marimastat was mediated by TIMP-2, as demonstrated by silencing experiments. In conclusion, our data exclude a major involvement of MMP 2 and MMP-9 in the regulation of basal NP differentiation, but highlight the ability of TIMP-2 to act as key effector of the proneurogenic response to an inducing stimulus such as Marimastat. PMID- 23098141 TI - The potential use of the pregnane X receptor in cardiovascular therapy. PMID- 23098140 TI - Noninvasive imaging in cardiovascular therapy: the promise of coronary arterial 18F-sodium fluoride uptake as a marker of plaque biology. PMID- 23098143 TI - Update on the ROADMAP clinical trial report: olmesartan for the prevention or delay of microalbuminuria development in type 2 diabetes. AB - Albuminuria is associated with renal disease progression and cardiovascular disease development or cardiovascular complications in individuals at low, medium and high risk for these outcomes. Furthermore, in patients with vascular disease, changes in albuminuria independently predict mortality and cardiovascular and renal outcomes, and drug-induced lowering of albuminuria with the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers confers long-term cardiovascular and renal protection. However, few studies have directly examined whether these agents might also prevent the development of albuminuria and whether this translates into protection from cardiovascular disease events. The ROADMAP trial was conducted in an attempt to give answers to these questions. The results provide evidence that pharmacological blockade of angiotensin II receptors is effective in reducing the risk of new-onset albuminuria in type 2 diabetic patients. The study was not able to determine if this will also lead to a long-term reduction of cardiovascular morbidity and mortality. PMID- 23098144 TI - Hypertension targets: a focus on the artery, the kidney and the heart. AB - 2012 Annual Scientific Meeting and Exposition of the American Society of Hypertension New York, NY, USA, 19-22 May 2012. For the last several years, the annual American Society of Hypertension meeting has held a segment called 'Hypertension Highlights' featuring state-of-the art talks by leaders in the field who share current research, and clinical management, organized around themes in hypertension. This year there were nine lectures grouped into three domains: the artery, the kidney and the heart. PMID- 23098145 TI - Evidence for a beneficial effect of glucose-insulin-potassium in patients with acute coronary syndromes: Did the IMMEDIATE trial solve an unanswered question? AB - Evaulation of: Selker HP, Beshansky JR, Sheehan PR et al. Out-of-hospital administration of intravenous glucose-insulin-potassium in patients with suspected acute coronary syndromes: the IMMEDIATE randomized controlled trial. JAMA 9(307), 1925-1933 (2012). Catecholamine release in conjunction with an acute coronary syndrome induces metabolic changes that impair the situation for the ischemic myocardium. Attempts have been made to improve the prognosis in patients with acute coronary syndrome by means of infusing glucose-insulin potassium in order to improve glucose metabolism and decrease beta-oxidation of free fatty acids. A trial, IMMEDIATE, tested this concept in a new way by initiating glucose-insulin-potassium during transportation to hospital, is discussed in this article. PMID- 23098146 TI - MRI of acute vascular syndromes: the emerging role of cardiovascular MRI in the diagnosis and treatment of AMI and stroke. AB - MRI is a safe and reproducible noninvasive method of obtaining high-resolution images of the heart and vascular system. As MRI has developed a more widespread clinical application over the last decade, attention has been increasing on how this technique can be used to aid the diagnosis of cardio- and cerebro-vascular diseases in the acute setting. While much of the initial development of cardiac MRI was based around describing the myocardium in the chronic stable state, much recent research has investigated the use of MRI to assess acute coronary syndromes. Similarly, arterial wall imaging using MRI was initially confined to relatively stable research populations; however, more recent work has suggested a possible future clinical role for vascular MRI techniques in acute settings. This study highlights recent advances in MRI of the cardiovascular system, with a particular emphasis on those techniques that can be of use in the setting of acute vascular syndromes, namely acute coronary syndrome, transient ischemic attack and stroke. PMID- 23098147 TI - A review of the current status of pericardial closure following cardiac surgery. AB - Some cardiac surgeons prefer to close the pericardium whenever possible following surgery, others specifically avoid this practice, and still others believe that neither alternative has any meaningful influence on clinical outcomes. Unfortunately, scientific evidence supporting either approach is scarce, making a consensus regarding best practice impossible. In this article, the known functions of the native intact pericardium are summarized, and the arguments for and against pericardial closure after surgery are examined. In addition, the techniques and materials that have been utilized for pericardial closure previously, as well as those that are currently being developed, are assessed. PMID- 23098148 TI - Experimental biomarkers in heart failure: an update. AB - Over the past 5 years, researchers have examined the utility of many experimental heart failure biomarkers that are not yet widely adopted clinically, to complement the role of B-type natriuretic peptide and its precursor. Candidate biomarkers have been identified from several different pathophysiologic categories, including markers of inflammation, myocyte necrosis, renal dysfunction, neurohumoral activation, oxidative stress and raised intracardiac pressure. Indeed, some biomarkers provide prognostic information that is independent of information obtained from conventional clinical and biomarker assessment. Moreover, some biomarkers studied help to identify dominant pathology that may predict responsiveness to specific therapies. Preliminary data also suggest a potential role for the development of comprehensive biomarker profiling models, integrating biomarkers from several categories to refine risk assessment. PMID- 23098149 TI - A review of the epidemiological profile of patients with atrial fibrillation and heart failure. AB - Heart failure (HF) and atrial fibrillation (AF) are cardiovascular diseases that have a continuously increasing prevelance and both often coexist. The presence of AF in HF patients has been reported as being between 10 and 50% depending on the different study settings. AF patients have a different clinical profile: they are older, with more severe HF and comorbidities than those without AF. Despite this poor clinical profile, observational studies report a lower use of the recommended treatments such as angiotensin-converting enzyme inhibitors and beta blockers. Clinical trials using antiarrhythmic drugs for rhythm control have failed to demonstrate the clinical advantage of a rhythm control approach over one for rate control. The prognostic role of AF in HF remains controversial, while the impact of new AF has been shown to be associated with an adverse outcome. PMID- 23098150 TI - Reassessing the use of vasodilators in heart failure. AB - Heart failure is a growing epidemic that currently affects nearly 6 million people in the USA. Despite the well-documented hemodynamic abnormalities associated with the disease (e.g., elevated systemic vascular resistance), therapies that directly target these derangements have consistently failed to improve important clinical outcomes, unless they also act on the underlying pathophysiology of the disease (e.g., angiotensin-converting enzyme inhibitors). Numerous clinical trials of vasodilators in the treatment of heart failure have resulted in either neutral or negative outcomes suggesting that systemic vascular resistance may be an inappropriate target of therapy. The reasons for failure in these studies are manifold, including a poor understanding of vasodilator agents and their secondary effects, poorly designed studies that include a markedly heterogeneous patient population and a paucity of objective end points that may be used as targets of therapy, to name a few. Future studies of vasodilators will need to consider these issues in trial design. PMID- 23098152 TI - Treatment of recurrent pericarditis. AB - Recurrent pericarditis is the most common and troublesome complication of pericarditis affecting around a third of patients. Treatment of this condition is often one of the most challenging task in pericardial diseases management, especially in corticosteroids-dependent cases. The aim of this review is to report current knowledge on the treatment, prevention and prognosis of this disease, with a special focus on more recently published contributions during the last 5 years. PMID- 23098151 TI - Endocarditis and myocarditis: a brief review. AB - Endocarditis and myocarditis are conditions seen worldwide with considerable morbidity and mortality. Despite the improvements in diagnostic technologies, clinical diagnosis remains crucial as only prompt recognition will lead to appropriate investigations and timely intervention, which may be life saving. In this review, the authors provide a concise overview of endocarditis and myocarditis. PMID- 23098153 TI - Mortality prediction in Chagas heart disease. AB - Chagas disease continues to be an important cause of cardiac disease in many countries of Latin America. Dilated cardiomyopathy constitutes the more severe manifestation and main cause of death in the disease. Typical clinical presentations include three basic syndromes: heart failure, cardiac arrhythmia and thromboembolism. The identification of markers related to the progression of Chagas heart disease is relevant for appropriate patient management. The most important predictors of death are New York Heart Association functional class, left ventricular systolic dysfunction and nonsustained ventricular tachycardia, which reflect the severity of myocardial damage. Several other potential prognostic factors have recently been reported. Scores for mortality prediction using a combination of prognostic variables have contributed to overall improvement in risk stratification in the setting of Chagas disease. PMID- 23098154 TI - Cardiospheres and cardiosphere-derived cells as therapeutic agents following myocardial infarction. AB - Heart disease is a major cause of morbidity and mortality. Cellular therapies hold significant promise for patients with heart disease. Heart-derived progenitor cells are capable of repairing a diseased heart through modulation of growth factor milieu and temporary engraftment leading to endogenous repair. The proof-of-concept CADUCEUS clinical trial using cardiosphere-derived cells has shown evidence of therapeutic cardiac tissue regeneration. Future clinical trials are now being planned to generate additional safety and efficacy data in the hopes of building toward an approved cellular therapy for heart disease. PMID- 23098156 TI - Association of lopinavir concentrations with plasma lipid or glucose concentrations in HIV-infected South Africans: a cross sectional study. AB - BACKGROUND: Dyslipidaemia and dysglycaemia have been associated with exposure to ritonavir-boosted protease inhibitors. Lopinavir/ritonavir, the most commonly used protease inhibitor in resource-limited settings, often causes dyslipidaemia. There are contradictory data regarding the association between lopinavir concentrations and changes in lipids. AIM: To investigate associations between plasma lopinavir concentrations and lipid and glucose concentrations in HIV infected South African adults. METHODS: Participants stable on lopinavir-based antiretroviral therapy were enrolled into a cross-sectional study. After an overnight fast, total cholesterol, triglycerides, and lopinavir concentrations were measured and an oral glucose tolerance test was performed. Regression analyses were used to determine associations between plasma lopinavir concentrations and fasting and 2 hour plasma glucose, fasting cholesterol, and triglycerides concentrations. RESULTS: There were 84 participants (72 women) with a median age of 36 years. The median blood pressure, body mass index and waist: hip ratio were 108/72 mmHg, 26 kg/m2 and 0.89 respectively. The median CD4 count was 478 cells/mm3. Median duration on lopinavir was 18.5 months. The median (interquartile range) lopinavir concentration was 8.0 (5.2 to 12.8) MUg/mL. Regression analyses showed no significant association between lopinavir pre-dose concentrations and fasting cholesterol (beta-coefficient -0.04 (95% CI -0.07 to 0.00)), triglycerides (beta-coefficient -0.01 (95% CI -0.04 to 0.02)), fasting glucose (beta-coefficient -0.01 (95% CI -0.04 to 0.02)), or 2-hour glucose concentrations (beta-coefficient -0.02 (95% CI -0.09 to 0.06)). Lopinavir concentrations above the median were not associated with presence of dyslipidaemia or dysglycaemia. CONCLUSIONS: There was no association between lopinavir plasma concentrations and plasma lipid and glucose concentrations. PMID- 23098157 TI - Extension to the charge fluctuation model for the prediction of the conductivity of apolar, reverse micellar systems. AB - This paper presents an extension to current theory regarding charging behavior in apolar, micellar systems. Electrical conductivity in such systems accompanying the formation of neutral reverse micelles is commonly explained by the possibility of intermicellar collisions resulting in a pair of oppositely charged micelles. The sequestration of the resulting charges within the micelles prevents their immediate recombination. The current theory underlying the charging process has thus far been applied in only approximate form, and is only used to validate experimental trends and to abstract values for the fraction of charged micelles. The extended theory proposed here uses knowledge of the solvent and surfactant characteristics, together with water content, to predict solution conductivity in absolute terms. It is verified in experiments with the solvent Isopar-L and surfactants Aerosol OT, OLOA 11000, and Span 80, in which significant differences from the approximate theory are observed. PMID- 23098159 TI - Bias dependence of sub-bandgap light detection for core-shell silicon nanowires. AB - We experimentally demonstrate a vertically arrayed silicon nanowire-based device that exhibits voltage dependence of photoresponse to infrared sub-bandgap optical radiation. The device is fabricated using a proximity solid-state phosphorus diffusion method to convert the surface areas of highly boron-doped silicon nanowires into n-type, thus forming a radial core-shell p-n junction structure. Prominent photoresponse from such core-shell Si nanowires is observed under sub bandgap illumination at 1310 nm. The strong bias dependence of the photoresponse and other device characteristics indicates that the sub-bandgap absorption is attributed to the intrinsic properties of core-shell Si nanowires rather than the surface states. The attractive characteristics are based on three physical mechanisms: the Franz-Keldysh effect, quasi-quantum confinement effect, and the impurity-state assisted photon absorption. The first two effects enhance carrier tunneling probability, rendering a stronger wave function overlap to facilitate sub-bandgap absorption. The last effect relaxes the k-selection rule by involving the localized impurity states, thus removing the limit imposed by the indirect bandgap nature of Si. The presented device uses single-crystal silicon and holds promise of fabricating nanophotonic systems in a fully complementary metal-oxide semiconductor (CMOS) compatible process. The concept and approach can be applied to silicon and other materials to significantly extend the operable wavelength regime beyond the constraint of energy bandgap. PMID- 23098158 TI - High-risk occupations for suicide. AB - BACKGROUND: High occupational suicide rates are often linked to easy occupational access to a method of suicide. This study aimed to compare suicide rates across all occupations in Britain, how they have changed over the past 30 years, and how they may vary by occupational socio-economic group. Method We used national occupational mortality statistics, census-based occupational populations and death inquiry files (for the years 1979-1980, 1982-1983 and 2001-2005). The main outcome measures were suicide rates per 100 000 population, percentage changes over time in suicide rates, standardized mortality ratios (SMRs) and proportional mortality ratios (PMRs). RESULTS: Several occupations with the highest suicide rates (per 100 000 population) during 1979-1980 and 1982-1983, including veterinarians (ranked first), pharmacists (fourth), dentists (sixth), doctors (tenth) and farmers (thirteenth), have easy occupational access to a method of suicide (pharmaceuticals or guns). By 2001-2005, there had been large significant reductions in suicide rates for each of these occupations, so that none ranked in the top 30 occupations. Occupations with significant increases over time in suicide rates were all manual occupations whereas occupations with suicide rates that decreased were mainly professional or non-manual. Variation in suicide rates that was explained by socio-economic group almost doubled over time from 11.4% in 1979-1980 and 1982-1983 to 20.7% in 2001-2005. CONCLUSIONS: Socio-economic forces now seem to be a major determinant of high occupational suicide rates in Britain. As the increases in suicide rates among manual occupations occurred during a period of economic prosperity, carefully targeted suicide prevention initiatives could be beneficial. PMID- 23098160 TI - Treatment-time regimen of hypertension medications significantly affects ambulatory blood pressure and clinical characteristics of patients with resistant hypertension. AB - Patients with resistant hypertension (RH) are at greater risk for stroke, renal insufficiency, and cardiovascular disease (CVD) events than are those for whom blood pressure (BP) is responsive to and well controlled by therapeutic interventions. Although all chronotherapy trials have compared the effects on BP regulation of full daily doses of medications when ingested in the morning versus at bedtime, prescription of the same medications in divided doses twice daily (BID) is frequent. Here, we investigated the influence of hypertension treatment time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and laboratory medicine parameters of RH patients evaluated by 48-h ambulatory BP monitoring (ABPM). This cross-sectional study evaluated 2899 such patients (1701 men/1198 women), 64.2 +/- 11.8 (mean +/- SD) yrs of age, enrolled in the Hygia Project. Among the participants, 1084 were ingesting all hypertension medications upon awakening (upon-awakening regimen), 1436 patients were ingesting the full daily dose of >=1 of them at bedtime (bedtime regimen), and 379 were ingesting split doses of >=1 medications BID upon awakening and at bedtime (BID regimen). Patients of the bedtime regimen compared with the other two treatment-time regimens had lower likelihood of microalbuminuria and chronic kidney disease; significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; plus higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. The bedtime regimen was also significantly associated with lower asleep systolic (SBP) and diastolic (DBP) BP means than the upon-awakening and BID regimens. The sleep-time relative SBP and DBP decline was significantly attenuated by the upon awakening and BID regimens (p < .001), resulting in significantly higher prevalence of non-dipping in these two treatment-time regimen groups (80.5% and 77.3%, respectively) than in the bedtime regimen (54.4%; p < .001 between groups). Additionally, the prevalence of the riser BP pattern, associated with highest CVD risk, was much greater, 31.0% and 29.8%, respectively, among patients of the upon-awakening and BID-treatment regimens, compared with the bedtime regimen (17.6%; p < .001 between groups). Patients of the bedtime regimen also showed significantly higher prevalence of properly controlled ambulatory BP (p < .001) as a result of a greater proportion of them showing complete control of asleep SBP and DBP means. Our findings demonstrate significantly lower asleep SBP and DBP means and attenuated prevalence of blunted nighttime BP decline, i.e., lower prevalence of CVD risk markers, in RH patients ingesting the full daily dose of >=1 hypertension medications at bedtime than in those ingesting all of them upon awakening or >=1 of them as split doses BID. In RH, ingesting the same medications BID neither improves ambulatory BP control nor reduces the prevalence of non-dipping, and cannot be considered chronotherapy. Collectively, findings of this study indicate that a bedtime hypertension medication regimen, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of true RH and avoid treatment-induced nocturnal hypotension, should be the therapeutic scheme of choice for patients who, by conventional cuff methods (and in the absence of ABPM) and the morning-treatment regimen, have been mistakenly judged to be resistant to therapy. PMID- 23098161 TI - Static winging of the scapula caused by osteochondroma in adults: a case series. AB - INTRODUCTION: Although palsy of the long thoracic nerve is the classical pathogenesis of winging scapula, it may also be caused by osteochondroma. This rare etiopathology has previously been described in pediatric patients, but it is seldom observed in adults. CASE PRESENTATION: We describe three cases of static scapular winging with pain on movement.Case 1 is a Caucasian woman aged 35 years with a wing-like prominence of the medial margin of her right scapula due to an osteochondroma originating from the ventral omoplate. Histopathological evaluation after surgical resection confirmed the diagnosis. The postoperative course was unremarkable without signs of recurrence on examination at 2 years.Case 2 is a Caucasian woman aged 39 years with painful scapula alata and neuralgic pain projected along the left ribcage caused by an osteochondroma of the left scapula with contact to the 2nd and 3rd rib. Following surgical resection, the neuropathic pain continued, demanding neurolysis of the 3rd and 4th intercostal nerve after 8 months. The patient was free of symptoms 2 years after neurolysis.Case 3 is a Caucasian woman aged 48 years with scapular winging due to a large exostosis of the left ventral scapular surface with a broad cartilaginous cap and a large pseudobursa. Following exclusion of malignancy by an incisional biopsy, exostosis and pseudobursa were resected. The patient had an unremarkable postoperative course without signs of recurrence 1 year postoperatively.Based on these cases, we developed an algorithm for the diagnostic evaluation and therapeutic management of scapula alata due to osteochondroma. CONCLUSIONS: Orthopedic surgeons should be aware of this uncommon condition in the differential diagnosis of winged scapula not only in children, but also in adult patients. PMID- 23098162 TI - Acute haematogenous community-acquired methicillin-resistant Staphylococcus aureus osteomyelitis in an adult: case report and review of literature. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) has of late emerged as a cause of community-acquired infections among immunocompetent adults without risk factors. Skin and soft tissue infections represent the majority of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clinical presentations, whilst invasive and life-threatening illness like necrotizing pneumonia, necrotizing fasciitis, pyomyositis, osteomyelitis and sepsis syndrome are less common. Although more widely described in the pediatric age group, the occurrence of CA-MRSA osteomyelitis in adults is an uncommonly reported entity. CASE PRESENTATION: We describe an invasive CA-MRSA infection in a 28 year-old previously healthy male, manifesting with bacteraemia, osteomyelitis of femur, pyomyositis and septic arthritis of the knee. Initially a preliminary diagnosis of osteosarcoma was suggested by imaging studies and patient underwent a bone biopsy. MRSA was subsequently isolated from blood cultures taken on day of admission, bone, tissue and pus cultures. Incision and drainage of abscess was performed and patient was treated with vancomycin, with fusidic acid added later. It took 6 months for the inflammatory markers to normalize, warranting 6-months of anti-MRSA therapy. Patient was a fervent deer hunter and we speculate that he acquired this infection from extensive direct contact with deer.Molecular characterization of this isolate showed that it belonged to multilocus sequence type (MLST) ST30 and exhibited the staphylococcal chromosome cassette mec (SCCmec) type IV, staphylococcus protein A (spa) type t019, accessory gene regulator (agr) type III and dru type dt10m. This strain harbored Panton Valentine leukocidin (pvl) genes together with 3 other virulent genes; sei (enterotoxin), hlg (hemolysin) and fnbA (fibronectin binding protein). CONCLUSION: This case study alerts physicians that beyond the most commonly encountered skin and soft tissue infections, pvl positive CA-MRSA can lead to invasive life-threatening disease especially in an immunocompetent adult. Heightened alertness is needed for osteomyelitis of long bones in adults, as it is not uncommon for this disease to mimic primary bone malignancy. Cure is achievable with early appropriate antibiotics guided by inflammatory markers. PMID- 23098164 TI - Synthesis of naphthalenes via platinum-catalyzed hydroarylation of aryl enynes. AB - An efficient synthetic method of functionalized naphthalenes having hydrogen, alkyl, alkenyl, aryl, or heteroaryl groups on the 4-position and ethoxycarbonyl group on the 2-position was developed through selective Pt-catalyzed 6-endo intramolecular hydroarylation of ethyl (E)-2-ethynyl/alkynyl cinnamates. PMID- 23098163 TI - Habitat-based PCB environmental quality criteria for the protection of endangered killer whales (Orcinus orca). AB - The development of an area-based polychlorinated biphenyl (PCB) food-web bioaccumulation model enabled a critical evaluation of the efficacy of sediment quality criteria and prey tissue residue guidelines in protecting fish-eating resident killer whales of British Columbia and adjacent waters. Model-predicted and observed PCB concentrations in resident killer whales and Chinook salmon were in good agreement, supporting the model's application for risk assessment and criteria development. Model application shows that PCB concentrations in the sediments from the resident killer whale's Critical Habitats and entire foraging range leads to PCB concentrations in most killer whales that exceed PCB toxicity threshold concentrations reported for marine mammals. Results further indicate that current PCB sediment quality and prey tissue residue criteria for fish eating wildlife are not protective of killer whales and are not appropriate for assessing risks of PCB-contaminated sediments to high trophic level biota. We present a novel methodology for deriving sediment quality criteria and tissue residue guidelines that protect biota of high trophic levels under various PCB management scenarios. PCB concentrations in sediments and in prey that are deemed protective of resident killer whale health are much lower than current criteria values, underscoring the extreme vulnerability of high trophic level marine mammals to persistent and bioaccumulative contaminants. PMID- 23098165 TI - Correction to temperature invariance of the nitrogenase electron transfer mechanism. PMID- 23098166 TI - The placental analogue and the pattern of sexual reproduction in the cheilostome bryozoan Bicellariella ciliata (Gymnolaemata). AB - BACKGROUND: Matrotrophy or extraembryonic nutrition - transfer of nutrients from mother to embryo during gestation - is well known and thoroughly studied among vertebrates, but still poorly understood in invertebrates. The current paper focuses on the anatomy and ultrastructure of the oogenesis and placentotrophy as well as formation of the brood chamber (ovicell) in the cheilostome bryozoan Bicellariella ciliata (Linnaeus, 1758). Our research aimed to combine these aspects of the sexual reproduction into an integral picture, highlighting the role of the primitive placenta-like system in the evolution of bryozoan reproductive patterns. RESULTS: Follicular and nutrimentary provisioning of the oocyte occur during oogenesis. Small macrolecithal oocytes are produced, and embryos are nourished in the ovicell via a simple placental analogue (embryophore). Every brooding episode is accompanied by the hypertrophy of the embryophore, which collapses after larval release. Nutrients are released and uptaken by exocytosis (embryophore) and endocytosis (embryo). Embryos lack specialized area for nutrient uptake, which occurs through the whole epidermal surface. The volume increase between the ripe oocyte and the larva is ca. 10 fold. CONCLUSIONS: The ovicell is a complex organ (not a special polymorph as often thought) consisting of an ooecium (protective capsule) and an ooecial vesicle (plugging the entrance to the brooding cavity) that develop from the distal and the fertile zooid correspondingly. Combination of macrolecithal oogenesis and extraembryonic nutrition allows attributing B. ciliata to species with reproductive pattern IV. However, since its oocytes are small, this species represents a previously undescribed variant of this pattern, which appears to represent a transitional state from the insipient matrotrophy (with large macrolecithal eggs) to substantial one (with small microlecithal ones). Altogether, our results substantially added and corrected the data obtained by the previous authors, providing a new insight in our understanding of the evolution of matrotrophy in invertebrates. PMID- 23098167 TI - In vitro and in vivo degradation of myo-inositol hexakisphosphate by a phytase from Citrobacter braakii. AB - Phytases (EC 3.1.3) are widely used in animal feed to increase the availability of phosphorus and decrease the anti nutritive effect of myo-inositol hexakisphosphate (InsP6). The aim of this work was to investigate the stereospecific degradation of InsP6 in vitro and in vivo by a phytase from Citrobacter braakii (C. braakii), and to study gastric survival of the phytase as well as the site of action in the gastrointestinal tract. The in vitro results showed that the C. braakii phytase belongs to the group of 6-phytases (EC 3.1.3.26). However, in approximately one out of 10 instances the phytase initiated hydrolysis at the D-3 (L-1) position, demonstrating that phytase specificity is not unambiguous. Following the main degradation pathway, InsP6 was degraded by stepwise removal of the phosphate groups on positions 6/1/5. The stereospecificity was found to be similar under in vitro and in vivo conditions. The phytase was found to be stable in the gastric environment and to be active in the stomach and possibly also in the proximal small intestine. While InsP4 was accumulated under in vitro conditions this was not the case in vivo, where both InsP5 and InsP4 were seen to be hydrolysed in the small intestine, possibly as a combined action of the C. braakii phytase and endogenous phosphatases present in the mucosa. The ability of the C. braakii phytase to focus its activity on degrading InsP6 to InsP4 is believed to be a favourable complement to the endogenous phosphatases. PMID- 23098168 TI - Jatrophane diterpenes from Euphorbia mellifera and their activity as P glycoprotein modulators on multidrug-resistant mouse lymphoma and human colon adenocarcinoma cells. AB - Three new macrocyclic jatrophane diterpenes, named euphomelliferine (1) and euphomelliferenes A (2) and B (3), and one new tetracyclic triterpene, 19(10->9) abeo-8alpha,9beta,10alpha-tirucalla-5,25-diene-3beta,24-diol (6, C-24 epimers), were isolated from the methanolic extract of Euphorbia mellifera. A known ingenane (7) and two jatrophane diterpenes (4 and 5) were also isolated. Their structures were elucidated by extensive spectroscopic methods, including 1D and 2D homo- and heteronuclear NMR experiments. Jatrophane diterpenes 1-3 and 5 were evaluated for their effects on the reversion of multidrug resistance (MDR) mediated by P-glycoprotein, by using the rhodamine-123 exclusion test, on human MDR1 gene-transfected mouse lymphoma cells (L5178Y MDR) and on human colon adenocarcinoma cells (COLO 320). The apoptosis-inducing activity of these compounds was also tested on COLO 320 cells, using the annexin-V/propidium iodide assay. Diterpenes 1 and 2 displayed significant MDR reversing activity, in a dose dependent manner, on both cancer cell models. The tested compounds did not induce apoptosis in the COLO 320 cells. PMID- 23098169 TI - An aza-Prins cyclization approach to functionalized indolizidines from 2 allylpyrrolidines. AB - The stereoselective synthesis of a diverse set of functionalized indolizidine systems has been accomplished through the aza-Prins cyclization of 2 allylpyrrolidines. The condensation of aldehydes onto 2-allylpyrrolidines yields iminium ions that undergo highly diastereoselective aza-Prins cyclization, producing up to two stereogenic centers and two new rings in one step. PMID- 23098170 TI - Differences between men and women in ambulatory blood pressure thresholds for diagnosis of hypertension based on cardiovascular outcomes. AB - Previous studies have reported sex differences in the pathophysiology of hypertension and responses to blood pressure (BP)-lowering medications. Moreover, men exhibit typically higher BP than women, the differences being greater for systolic (SBP) than diastolic (DBP) BP. These differences become apparent during adolescence and remain significant at least until 55-60 yrs of age. Despite such significant sex-related differences in BP regulation, the current recommended ambulatory BP monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate between men and women. We aimed to derive separate male and female diagnostic thresholds for the awake and asleep SBP and DBP means based upon cardiovascular disease (CVD) outcome. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6 +/- 14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of >=1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00 h and at 30-min intervals at night for 48 h, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in men and women. Men exhibited greater event rates than women of CVD death, myocardial infarction, angina pectoris, coronary revascularization, and heart failure; however, event rates of non-CVD death and cerebrovascular events were comparable. The relationship between progressively higher ambulatory BP and CVD risk increased more rapidly in women than men for awake SBP/DBP means >=125/75 mm Hg and asleep means >=110/70 mm Hg. The derived outcome-based reference thresholds for men were 135/85 mm Hg for the awake and 120/70 mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for women were 125/80 mm Hg for the awake and 110/65 mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 10/5 mm Hg lower for ambulatory SBP/DBP in women than men. This marked sex difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between men and women. PMID- 23098171 TI - Test-retest reliability of self-report measures in a dually diagnosed sample. AB - Many individuals diagnosed with a substance use disorder are also diagnosed with another psychiatric disorder. Little is known regarding which treatments are efficacious for these dually diagnosed individuals (DDI). Characterizing the psychometric properties of assessments used with DDI samples is essential to efficacy studies with DDI. This study examined the internal consistency and test retest reliability of self-report instruments among DDI. Most subscales demonstrated high test-retest reliability; one subscale demonstrated poor reliability. Internal consistency was similar to that of non-DDI samples. This exploratory study suggests that, while some instruments should be interpreted cautiously, DDI samples can be accurately assessed with self-report measures. PMID- 23098172 TI - Using animal thyroids as ultra-sensitive biomonitors for environmental radioiodine. AB - In the course of the Fukushima nuclear accident large amounts of radionuclides relevant to the Comprehensive Nuclear-Test-Ban-Treaty (CTBT) were released and detected globally. We could show that the intake of environmental (131)I into the thyroids of animals can be used for verification of the CTBT. Due to continuous accumulation of (131)I, its apparent half-life in the thyroid biomonitor exceeds the physical one, thus making (131)I detectable three weeks longer than using conventional CTBT-grade high volume air samplers. The maximum (131)I activity concentrations (in Bq/kg) found in Austrian animal thyroids after the Fukushima nuclear accident could be correlated with the maximum activity concentrations found in air (Bq/m(3)) in Austria via a factor of 1.1 * 10(6). In fall 2011, a second (much smaller) release of (131)I occurred from a laboratory in Hungary, where this factor was 1.9 * 10(6). Hence thyroid biomonitors offer even some quantitative information, which allows the estimation of the (131)I activity concentrations in air. It could be shown that thyroid biomonitors can work under dry conditions, which potentially makes them the method of choice for CTBTO on site inspections even in arid environments. PMID- 23098173 TI - Changes in pain catastrophizing predict later changes in fibromyalgia clinical and experimental pain report: cross-lagged panel analyses of dispositional and situational catastrophizing. AB - INTRODUCTION: Fibromyalgia (FM), characterized by wide-spread diffuse pain and sensory abnormalities, is associated with elevated indices of distress and pain related catastrophizing compared to both pain-free samples and those with chronic pain conditions. Catastrophizing is a pervasive negative mental set, and is a strong predictor of negative pain-related outcomes such as clinical pain intensity, and physical disability. Situational catastrophizing, measured in the context of experimentally-induced pain, is strongly related to enhanced pain sensitivity, a core aspect of the pathophysiology of fibromyalgia. However, little is known regarding the temporal course of the association between catastrophizing and pain-related "outcomes". Most studies involve only static assessments of pain and catastrophizing at a single time point, which provides little insight into the direction of the observed associations. We sought to investigate the temporal relationships between catastrophizing and indices of both clinical pain (substudy 1) and experimentally-induced pain (substudy 2) in a larger randomized controlled longitudinal trial. METHODS: Fifty-seven patients with FM completed catastrophizing, depression, and pain questionnaires as well as laboratory cold pressor pain testing at baseline, post-intervention and three month follow-up during a lifestyle physical activity study. Cross-lagged panel analyses were used to address these temporal relationships. RESULTS: In substudy 1, analyses revealed that pre-to-post changes in dispositional catastrophizing ratings prospectively accounted for unique variance in subsequent post-to-follow up changes in clinical pain ratings (p = 0.005), while pre-to-post changes in pain ratings did not account for unique variance in post-to-follow-up changes in catastrophizing ratings. An identical pattern was observed experimentally in substudy 2, with pre-to-post changes in situational catastrophizing ratings prospectively accounting for unique variance in subsequent post-to-follow-up changes in experimental pain ratings (p = 0.014), while pre-to-post changes in pain ratings did not account for unique variance in post-to-follow-up changes in catastrophizing ratings. Specifically, initial alterations in catastrophizing were associated with subsequent alterations in clinical and experimentally induced pain. Controlling for levels of depression did not affect the results. CONCLUSIONS: These findings provide empirical evidence that catastrophizing processes might precede and contribute to subsequent alterations in the pain experience for FM patients. TRIAL REGISTRATION: clinicaltrials.gov: NCT00383084. PMID- 23098175 TI - Inactivation mechanism of glycerol dehydration by diol dehydratase from combined quantum mechanical/molecular mechanical calculations. AB - Inactivation of diol dehydratase during the glycerol dehydration reaction is studied on the basis of quantum mechanical/molecular mechanical calculations. Glycerol is not a chiral compound but contains a prochiral carbon atom. Once it is bound to the active site, the enzyme adopts two binding conformations. One is predominantly responsible for the product-forming reaction (G(R) conformation), and the other primarily contributes to inactivation (G(S) conformation). Reactant radical is converted into a product and byproduct in the product-forming reaction and inactivation, respectively. The OH group migrates from C2 to C1 in the product-forming reaction, whereas the transfer of a hydrogen from the 3-OH group of glycerol to C1 takes place during the inactivation. The activation barrier of the hydrogen transfer does not depend on the substrate-binding conformation. On the other hand, the activation barrier of OH group migration is sensitive to conformation and is 4.5 kcal/mol lower in the G(R) conformation than in the G(S) conformation. In the OH group migration, Glu170 plays a critical role in stabilizing the reactant radical in the G(S) conformation. Moreover, the hydrogen bonding interaction between Ser301 and the 3-OH group of glycerol lowers the activation barrier in G(R)-TS2. As a result, the difference in energy between the hydrogen transfer and the OH group migration is reduced in the G(S) conformation, which shows that the inactivation is favored in the G(S) conformation. PMID- 23098174 TI - Whole genome sequencing of phage resistant Bacillus anthracis mutants reveals an essential role for cell surface anchoring protein CsaB in phage AP50c adsorption. AB - BACKGROUND: Spontaneous Bacillus anthracis mutants resistant to infection by phage AP50c (AP50R) exhibit a mucoid colony phenotype and secrete an extracellular matrix. METHODS: Here we utilized a Roche/454-based whole genome sequencing approach to identify mutations that are candidates for conferring AP50c phage resistance, followed by genetic deletion and complementation studies to validate the whole genome sequence data and demonstrate that the implicated gene is necessary for AP50c phage infection. RESULTS: Using whole genome sequence data, we mapped the relevant mutations in six AP50R strains to csaB. Eleven additional spontaneous mutants, isolated in two different genetic backgrounds, were screened by PCR followed by Sanger sequencing of the csaB gene. In each spontaneous mutant, we found either a non-synonymous substitution, a nonsense mutation, or a frame-shift mutation caused by single nucleotide polymorphisms or a 5 base pair insertion in csaB. All together, 5 and 12 of the 17 spontaneous mutations are predicted to yield altered full length and truncated CsaB proteins respectively. As expected from these results, a targeted deletion or frame-shift mutations introduced into csaB in a different genetic background, in a strain not exposed to AP50c, resulted in a phage resistant phenotype. Also, substitution of a highly conserved histidine residue with an alanine residue (H270A) in CsaB resulted in phage resistance, suggesting that a functional CsaB is necessary for phage sensitivity. Conversely, introduction of the wild type allele of csaB in cis into the csaB deletion mutant by homologous recombination or supplying the wild type CsaB protein in trans from a plasmid restored phage sensitivity. The csaB mutants accumulated cell wall material and appeared to have a defective S layer, whereas these phenotypes were reverted in the complemented strains. CONCLUSIONS: Taken together, these data suggest an essential role for csaB in AP50c phage infection, most likely in phage adsorption. (The whole genome sequences generated from this study have been submitted to GenBank under SRA project ID: SRA023659.1 and sample IDs: AP50 R1: SRS113675.1, AP50 R2: SRS113676.1, AP50 R3: SRS113728.1, AP50 R4: SRS113733.1, AP50 R6: SRS113734.1, JB220 Parent: SRS150209.1, JB220 Mutant: SRS150211.1). PMID- 23098176 TI - Triterpene saponins of Maesa lanceolata stem wood. AB - Phytochemical analysis of aqueous MeOH extract of Maesa lanceolata stem wood has led to the isolation of four new triterpene saponins characterized as 16alpha,21beta-diacetoxy-22alpha-angeloyl-28-hydroxyolean-12-ene 3-O-[alpha rhamnopyranosyl-(1"" -> 6''')-beta-glucopyranosyl-(1''' -> 3')][beta glucopyranosyl-(1" -> 2')]-beta-glucuronopyranoside (1), 16alpha-acetoxy-21beta hydroxy-22alpha-angeloyl-13beta,28-oxydoolean-28alpha-ol 3-O-[alpha rhamnopyranosyl-(1"" -> 6''')-beta-glucopyranosyl-(1''' -> 4')][beta glucopyranosyl-(1" -> 2')]-alpha-arabinopyranoside (2), 16alpha-acetoxy 21beta,22alpha-diangeloyl-13beta,28-epoxyoleanane 3-O-[alpha-rhamnopyranosyl-(1"" -> 6''')-beta-glucopyranosyl-(1''' -> 4')][beta-glucopyranosyl-(1" -> 2')]-beta xylopyranoside (3), and 16alpha,22alpha-diacetoxy-13beta,28-oxydoolean-28alpha-ol 3-O-[beta-glucopyranosyl-(1" -> 2')][beta-glucopyranosyl-(1''' -> 3')]-beta glucuronopyranoside (4), together with the known compounds beta-acetylamyrin, physcion, emodin, chrysophanol, ursolic acid, 16alpha-hydroxy-12-oleanene 3-O glucoside, beta-amyrin, sitosterol 3-O-beta-glucoside, stigmasterol, and 3beta,28 dihydroxyolean-12-ene. Their structural elucidation was accomplished by homo- and heteronuclear 2D NMR technique as well as comparison with data from known compounds. The in vitro antibacterial activity of the aqueous MeOH extract was also investigated and zones of inhibition ranging from 32 +/- 1.1 to 14 +/- 0.2 mm were observed. Among the isolates, compound 1 was the most active with an minimum inhibitory concentration value of 25 MUg/ml against Staphylococcus aureus. PMID- 23098177 TI - Two-step synthesis of 2,3-dihydropyrroles via a formal 5-endo cycloisomerization of Ugi 4-CR/propargyl adducts. AB - A practical two-step synthesis of 2,3-dihydropyrroles from Ugi 4-CR/propargyl adducts is presented. The protocol includes a base-mediated formation of an allenamide functional group and an in situ metal-free formal 5-endo cycloisomerization that occurs in a highly regioselective manner at the allenamide C-gamma. PMID- 23098179 TI - Accurate multiplexed proteomics at the MS2 level using the complement reporter ion cluster. AB - Isobaric labeling strategies, such as isobaric tags for relative and absolute quantitation (iTRAQ) or tandem mass tags (TMT), have promised to dramatically increase the power of quantitative proteomics. However, when applied to complex mixtures, both the accuracy and precision are undermined by interfering peptide ions that coisolate and cofragment with the target peptide. Additional gas-phase isolation steps, such as proton-transfer ion-ion reactions (PTR) or higher-order MS3 scans, can almost completely eliminate this problem. Unfortunately, these methods come at the expense of decreased acquisition speed and sensitivity. Here we present a method that allows accurate quantification of TMT-labeled peptides at the MS2 level without additional ion purification. Quantification is based on the fragment ion cluster that carries most of the TMT mass balance. In contrast to the use of low m/z reporter ions, the localization of these complement TMT (TMT(C)) ions in the spectrum is precursor-specific; coeluting peptides do not generally affect the measurement of the TMT(C) ion cluster of interest. Unlike the PTR or MS3 strategies, this method can be implemented on a wide range of high resolution mass spectrometers like the quadrupole Orbitrap instruments (QExactive). A current limitation of the method is that the efficiency of TMT(C) ion formation is affected by both peptide sequence and peptide ion charge state; we discuss potential routes to overcome this problem. Finally, we show that the complement reporter ion approach allows parallelization of multiplexed quantification and therefore holds the potential to multiply the number of distinct peptides that can be quantified in a given time frame. PMID- 23098180 TI - Effects of microarterial anastomosis torsion on survival of oblique groin flap in rats. AB - A microanastomosis might tolerate a torsion up to 360 degrees , but the effects of arterial microanastomosis torsion on the survival of the flap it supplies are unclear. The aim of this study was to investigate the consequences of microarterial anastomosis torsion on the groin flap in rats. Forty Sprague-Dawley rats were divided into five groups. An oblique groin flap was harvested as an island flap and a patch-to-side arterial anastomosis was performed with torsion angles of 0 degrees , 90 degrees , 180 degrees , 270 degrees , and 360 degrees . Six of eight flaps in Group I (0 degrees torsion), six of eight flaps in Group II (90 degrees ), three of eight flaps in Group III (180 degrees ), and none of the flaps in Groups IV and V (270 degrees and 360 degrees ) were found to be viable after 1 week. The patency and flap survival rates observed in Groups II, III, IV, and V were compared with those in Group I using Fisher's exact test. The patency rates and flap survival rates in Groups IV and V were significantly lower compared with those in Group I. Our data show that skin flaps can survive even if their arterial pedicle is anastomosed with a torsion of up to 180 degrees . PMID- 23098181 TI - A new computer tool for systematic evaluation of intracranial volume and its capacity to evaluate the result of the operation for metopic synostosis. AB - The aim of this project was to develop a tool for systematic evaluation of volumetric changes after surgery for craniosynostosis. A computer program using MATLAB was developed to measure total intracranial volume and frontal volume, anterior to the coronary sutures, by multiplying the area with slice thickness of each slice from just above foramen magnum to just beneath the vertex in CT examinations. The ratio between frontal volume and total volume was used for evaluation of the clinical result in 12 patients operated on for metopic synostosis. In 0.625 and 5 millimetre slices the coefficients of variation were 0.00049 and 0.00058, respectively, for measurements of total volume. The highest coefficient of variation was found in postoperative measurements of the frontal volume and was 0.014 in 0.625 millimetre slices. Measurements in 5 millimetre slices resulted in 3.8% +/- 1.5% (mean +/- SD) lower total volumes and 5.8% +/- 5.3% lower frontal volumes than measurements in 0.625 millimetre slices. In patients operated on for metopic synostosis the ratio between frontal volume and total volume increased 25% +/- 16% for patients operated on with cranioplasty in combination with a spring (n = 6) and 20% +/- 13% for patients operated on with cranioplasty in combination with a bone transplant (n = 6). In summary, this study has developed a tool that can determine frontal and total intracranial volume with little variation. This tool can be used for systematic evaluation of the result of the operation for metopic synostosis. PMID- 23098182 TI - Testosterone is associated with age-related changes in bone health status, muscle strength and body composition in men. AB - OBJECTIVE: Variations in testosterone levels are associated with several outcomes of aging. The present study aimed to examine the relationship between age-related decline of testosterone levels and changes in bone health status, handgrip strength, body fat percentage and fat-free mass. MATERIALS AND METHODS: A total of 335 Malaysian Chinese and Malay men aged 40 years and above were recruited for this study. Their body compositions, calcaneal speed of sound and handgrip strength were measured and their blood was collected. Linear regression analysis was done to examine the relationship among age, testosterone levels and outcomes of aging. RESULTS: The results indicated significant changes in all testosterone measurements, sex hormone binding globulin level, calcaneal speed of sound, handgrip strength, body fat percentage and fat-free mass with age (p < 0.05). Age dependent decline in bioavailable and free testosterone levels were significantly associated with reduction in calcaneal speed of sound, fat-free mass and handgrip strength (p < 0.05). Age-dependent decline in the total testosterone level was significantly associated with an increase in body fat percentage among the elderly men (p < 0.05). CONCLUSION: Testosterone levels are associated with changes in outcome of aging such as bone health status, muscle strength and body composition, and the relationships are age-dependent. PMID- 23098183 TI - Dextran-coated magnetic supports modified with a biomimetic ligand for IgG purification. AB - Dextran-coated iron oxide magnetic particles modified with ligand 22/8, a protein A mimetic ligand, were prepared and assessed for IgG purification. Dextran was chosen as the agent to modify the surface of magnetic particles by presenting a negligible level of nonspecific adsorption. For the functionalization of the particles with the affinity ligand toward antibodies, three methods have been explored. The optimum coupling method yielded a theoretical maximum capacity for human IgG calculated as 568 +/- 33 mg/g and a binding affinity constant of 7.7 * 104 M-1. Regeneration, recycle and reuse of particles was also highly successful for five cycles with minor loss of capacity. Moreover, this support presented specificity and effectiveness for IgG adsorption and elution at pH 11 directly from crude extracts with a final purity of 95% in the eluted fraction. PMID- 23098184 TI - Phosphatidic acid production in the processing of cabbage leaves. AB - Lysophosphatidic acid (LPA) is a lipid mediator involved in various physiological responses, including wound healing. Evidence of the antiulcer activity of LPA has been reported, and soybean LPA at a concentration of 10 MUM is effective in reducing stress-induced gastric ulcer. Because LPA can be formed from phosphatidic acid (PA) by digestive phospholipase A2, dietary PA can be considered a potential antiulcer phospholipid. In this study, PA production in cut processing of cabbage leaves was examined. The amounts of PA in sliced, minced, and homogenized cabbage leaves were 107 +/- 5, 134 +/- 19, and 286 +/- 29 nmol PA/g (wet weight), respectively, all being significantly higher than the amount of PA found in intact leaves. Mixing mayonnaise with sliced cabbage dramatically increased the PA content (1586 +/- 393 nmol/3 g), indicating phospholipase D activity leaked raw cabbage produced PA. These results indicate that fine cutting raw cabbage leaves and mixing them with foods rich in phospholipids resulted in an abundant production of PA. PMID- 23098185 TI - DFT study of the stereoselective formation of cis-W(CO)4(eta2-C2H4)2 in the gas phase consecutive coordination of C2H4 onto doubly coordinatively unsaturated W(CO)4. AB - B3LYP-based density functional theory (DFT) calculations are reported that provide insight into the stereoselective formation of cis-W(CO)(4)(eta(2) C(2)H(4))(2) observed in the pulsed 266 nm laser photolysis of tungsten hexacarbonyl (W(CO)(6)) in the presence of C(2)H(4) in the gas phase at room temperature (J. Phys. Chem. 1995, 99, 4558). W(CO)(4)(eta(2)-C(2)H(4)) formed through the coordination of C(2)H(4) onto coordinatively unsaturated W(CO)(4) was found to have a pseudo-C(2v) symmetry (distorted trigonal bipyramid with an angle of ca. 90 degrees between the two equatorial COs) with a bond dissociation enthalpy (BDE) of W-C(2)H(4) of 125 kJ mol(-1). In the subsequent coordination of C(2)H(4) onto the W(CO)(4)(eta(2)-C(2)H(4)), having one vacant coordinatively unsaturated site, no barrier was found in the reaction path to cis-complex formation, while there was a barrier of about 89 kJ mol(-1) to the trans-complex. The calculations show that the stereoselective formation of cis-W(CO)(4)(eta(2) C(2)H(4))(2) is due to kinetic rather than thermodynamic control. The trans W(CO)(4)(eta(2)-C(2)H(4))(2) was calculated to be more stable than cis W(CO)(4)(eta(2)-C(2)H(4))(2) by about 10 kJ mol(-1). The BDE of W-C(2)H(4) in cis W(CO)(4)(eta(2)-C(2)H(4))(2) was estimated to be 61 kJ mol(-1). PMID- 23098178 TI - Circadian pattern of ambulatory blood pressure in hypertensive patients with and without type 2 diabetes. AB - There is strong association between diabetes and increased risk of end-organ damage, stroke, and cardiovascular disease (CVD) morbidity and mortality. Non dipping (<10% decline in the asleep relative to awake blood pressure [BP] mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and consistently associated with increased CVD risk. The reported prevalence of non dipping in diabetes is highly variable, probably due to differences in the study groups (normotensive subjects, untreated hypertensives, treated hypertensives), relatively small sample sizes, reliance only on a single, low-reproducibility, 24 h ABPM evaluation per participant, and definition of daytime and nighttime periods by arbitrary selected fixed clock-hour spans. Accordingly, we evaluated the influence of diabetes on the circadian BP pattern by 48-h ABPM (rather than for 24 h to increase reproducibility of results) during which participants maintained a diary listing times of going to bed at night and awakening in the morning. This cross-sectional study involved 12 765 hypertensive patients (6797 men/5968 women), 58.1 +/- 14.1 (mean +/- SD) yrs of age, enrolled in the Hygia Project, designed to evaluate prospectively CVD risk by ABPM in primary care centers of northwest Spain. Among the participants, 2954 (1799 men/1155 women) had type 2 diabetes. At the time of study, 525/3314 patients with/without diabetes were untreated for hypertension, and the remaining 2429/6497 patients with/without diabetes were treated. Hypertension was defined as awake systolic (SBP)/diastolic (DBP) BP mean >=135/85 mm Hg, or asleep SBP/DBP mean >=120/70 mm Hg, or BP-lowering treatment. Hypertensive patients with than without diabetes were more likely to be men and of older age, have diagnoses of microalbuminuria, proteinuria, chronic kidney disease, obstructive sleep apnea, metabolic syndrome, and/or obesity, plus higher glucose, creatinine, uric acid, and triglycerides, but lower cholesterol and estimated glomerular filtration rate. In patients with diabetes, ambulatory SBP was significantly elevated (p < .001), mainly during the hours of nighttime sleep and initial hours after morning awakening, independent of presence/absence of BP-lowering treatment. Ambulatory DBP, however, was significantly higher (p < .001) in patients without diabetes, mainly during the daytime. Differing trends for SBP and DBP between groups resulted in large differences in ambulatory pulse pressure (PP), it being significantly greater (p < .001) throughout the entire 24 h in patients with diabetes, even after correcting for age. Prevalence of non-dipping was significantly higher in patients with than without diabetes (62.1% vs. 45.9%; p < .001). Largest difference between groups was in the prevalence of the riser BP pattern, i.e., asleep SBP mean greater than awake SBP mean (19.9% vs. 8.1% in patients with and without diabetes, respectively; p < .001). Elevated asleep SBP mean was the major basis for the diagnosis of hypertension and/or inadequate BP control among patients with diabetes; thus, among the uncontrolled hypertensive patients with diabetes, 89.2% had nocturnal hypertension. Our findings document significantly elevated prevalence of a blunted nocturnal BP decline in hypertensive patients with diabetes. Most important, prevalence of the riser BP pattern, associated with highest CVD risk among all possible BP patterns, was more than twice as prevalent in diabetes. Patients with diabetes also presented significantly elevated ambulatory PP, reflecting increased arterial stiffness and enhanced CVD risk. These collective findings indicate that diabetes should be included among the clinical conditions for which ABPM is recommended for proper CVD risk assessment. PMID- 23098187 TI - Dietary resistant starch dose-dependently reduces adiposity in obesity-prone and obesity-resistant male rats. AB - BACKGROUND: Animal studies show that diets containing resistant starch (RS) at levels not achievable in the human diet result in lower body weight and/or adiposity in rodents. We aimed to determine whether RS dose-dependently reduces adiposity in obesity-prone (OP) and obesity-resistant (OR) rats. METHODS: Male Sprague-Dawley rats (n=120) were fed a moderate-fat, high-energy diet for 4 wk. Rats that gained the most weight (40%) were classified as obesity-prone (OP) and obesity-resistant (OR) rats were the 40% that gained the least weight. OP and OR rats were randomly allocated to one of six groups (n=8 for each phenotype). One group was killed for baseline measurements, the other five groups were allocated to AIN-93 based diets that contained 0, 4, 8, 12 and 16% RS (as high amylose maize starch) for 4 wk. These diets were matched for total carbohydrate content. At 0, 4 and 7 wk from the start of the study insulin sensitivity was calculated by homeostasis model assessment of insulin resistance (HOMA-IR) and adiposity was determined by dual-energy X-ray absorptiometry (DXA). At 8 wk, rats were euthanized and fat pad weights, intestinal digesta short chain fatty acid (SCFA) pools and plasma gut hormone levels were determined. RESULTS: Obesity prone rats gained less weight with 4, 12 and 16% RS compared to 0% RS, but the effect in OR animals was significant only at 16% RS. Irrespective of phenotype, diets containing >=8% RS reduced adiposity compared to 0% RS. Energy intake decreased by 9.8 kJ/d for every 4% increase in RS. All diets containing RS increased total SCFA pools in the caecum and lowered plasma GIP concentrations compared to the 0% RS, whereas plasma GLP-1 and PYY were increased when the diet contained at least 8% RS. Insulin sensitivity was not affected by RS. CONCLUSION: RS in amounts that could be potentially consumed by humans were effective in reducing adiposity and weight gain in OP and OR rats, due in part to a reduction in energy intake, and changes in gut hormones and large bowel carbohydrate fermentation. PMID- 23098188 TI - Sensor fusion for laparoscopic surgery skill acquisition. AB - Surgical techniques are becoming more complex and require substantial training to master. The development of automated, objective methods to analyze and evaluate surgical skill is necessary to provide trainees with reliable and accurate feedback during their training programs. We present a system to capture, visualize, and analyze the movements of a laparoscopic surgeon for the purposes of skill evaluation. The system records the upper body movement of the surgeon, the position, and orientation of the instruments, and the force and torque applied to the instruments. An empirical study was conducted using the system to record the performances of a number of surgeons with a wide range of skill. The study validated the usefulness of the system, and demonstrated the accuracy of the measurements. PMID- 23098186 TI - High expression of QSOX1 reduces tumorogenesis, and is associated with a better outcome for breast cancer patients. AB - INTRODUCTION: The gene quiescin/sulfhydryl oxidase 1, QSOX1, encodes an enzyme directed to the secretory pathway and excreted into the extracellular space. QSOX1 participates in the folding and stability of proteins and thus could regulate the biological activity of its substrates in the secretory pathway and/or outside the cell. The involvement of QSOX1 in oncogenesis has been studied primarily in terms of its differential expression in systemic studies. QSOX1 is overexpressed in prostate cancers and in pancreatic adenocarcinoma. In contrast, QSOX1 gene expression is repressed in endothelial tumors. In the present study, we investigated the role of QSOX1 in breast cancer. METHODS: We analyzed QSOX1 mRNA expression in a cohort of 217 invasive ductal carcinomas of the breast. Moreover, we investigated QSOX1's potential role in regulating tumor growth and metastasis using cellular models in which we overexpressed or extinguished QSOX1 and xenograft experiments. RESULTS: We showed that the QSOX1 expression level is inversely correlated to the aggressiveness of breast tumors. Our results show that QSOX1 leads to a decrease in cell proliferation, clonogenic capacities and promotes adhesion to the extracellular matrix. QSOX1 also reduces the invasive potential of cells by reducing cell migration and decreases the activity of the matrix metalloproteinase, MMP-2, involved in these mechanisms. Moreover, in vivo experiments show that QSOX1 drastically reduces the tumor development. CONCLUSIONS: Together, these results suggest that QSOX1 could be posited as a new biomarker of good prognosis in breast cancer and demonstrate that QSOX1 inhibits human breast cancer tumorogenesis. PMID- 23098189 TI - Hinged external fixator placement at the elbow: navigated versus conventional technique. AB - INTRODUCTION: During the application of a hinged external elbow fixator, exact placement of the central pin remains difficult. Proper placement often necessitates multiple drilling attempts and fluoroscopic localization, which can be time consuming. We hypothesized that use of computerized navigation would enable a more precise placement of the central axis pin and would reduce the total number of drilling attempts. MATERIALS AND METHODS: Twelve elbow models incorporating soft tissue coverage were used in this study. First, the optimal placement trajectory (OPJ) of the axis pin was defined in the anterior-posterior (AP) and lateral planes of the elbow. Six elbows were used with the navigation system and the axis pin was inserted in combination with a conventional fluoroscopy system under constant two-dimensional guidance from the virtual images. The pins for the remaining six elbow specimens were implanted conventionally under fluoroscopic guidance. The distances and angular deviations from the OPJ position were measured, and the results for the conventional placement and computer navigation groups were compared. To determine the definitive axis pin placement, a CT scan of each elbow with 1-mm slice thickness was used and the results were measured based on the defined optimal pin placement. AP plane angulations and lateral plane distances were calculated in relation to the optimal insertion trajectory for each specimen. Finally, we counted the overall number of drilling attempts needed to find the optimal position for the axis pin. RESULTS: For the AP angulations, of the six elbows implanted using the conventional technique, half (n=3) had deviations of >=20 degrees from the optimal axis. In contrast, in the navigated group, all cases (n=6) were within 20 degrees of the optimal axis in the AP plane. The mean AP angulation deviation in the conventional group was 20.5 degrees , compared to 15 degrees in the navigation group (p=0.077). For the lateral distances, the mean distance from the drilling point to the point of optimal placement was 3.83 mm in the conventional group, versus 1.83 mm in the navigation group (p=0.042). For all navigated cases, only one drilling attempt was necessary to achieve the desired position of the axial pin. CONCLUSION: Compared with the conventional method of axis pin placement for an elbow fixator, two-dimensional navigation allows a reduction in the number of drilling attempts required. Furthermore, the accuracy in terms of AP angulation and lateral distance from a defined optimal placement is better when compared to that obtained with the conventional technique. PMID- 23098190 TI - The accuracy of 3D image navigation with a cutaneously fixed dynamic reference frame in minimally invasive transforaminal lumbar interbody fusion. AB - OBJECTIVE: In contrast to preoperative image-based 3D navigation systems, which require surgeon-dependent registration, an intraoperative cone-beam computed tomography (cb-CT) image-based 3D navigation system allows automatic registration during the acquisition of 3D images intraoperatively. Thus, the need for spinal exposure for point matching is obviated, making a cb-CT image-based navigation system ideal for use in minimally invasive spinal procedures. Conventionally, the dynamic reference frame (DRF) is mounted to an adjacent spinous process or iliac bone through a separate incision. However, the close proximity of the DRF to the surgical area may result in its interfering with the surgical procedure or causing streak artifacts on the navigation images. Cutaneous placement of the DRF overlying the sacral hiatus is one possible solution to these problems, but such a placement does not provide a solid bony fixation point and is distant from the surgical area, both of which factors may hinder the accuracy of the navigation. The purpose of this study was to evaluate the accuracy of a novel idea for DRF placement in a series of mini-open transforaminal lumbar interbody fusion (TLIF) procedures performed with intraoperative cb-CT image-based 3D navigation. METHODS: From June 2009 to December 2009, 20 patients underwent mini-open TLIF for a total 82 pedicle screws placed in the lumbar spine with cutaneous placement of the DRF overlying the sacral hiatus. The pedicle screws were inserted under navigational guidance using cb-CT data acquired intraoperatively with a Medtronic O-arm. Screw positions were subsequently checked with a final intraoperative cb CT scan. Nineteen patients underwent single-level fusion (8 at L4-5, 6 at L5-S1, 4 at L3-4, and 1 at L2-3) and one patient underwent two-level fusion (from L3-5). RESULTS: There were 4 (4.9%) pedicle perforations greater than 2 mm out of the 82 pedicle screw insertions in the 20 patients. Two of these breached screws were repositioned and confirmed to be in place with a final intraoperative cb-CT. There were no complications of neural injury associated with these perforations. CONCLUSION: A cutaneously mounted DRF overlying the sacral hiatus provides accuracy in intraoperative 3D image guided navigation for mini-open TLIF that is comparable to that obtained in other reported series using a fixed bony attachment point for the DRF. PMID- 23098192 TI - Structural and kinetic effects on changes in the CO(2) binding pocket of human carbonic anhydrase II. AB - This work examines the effect of perturbing the position of bound CO(2) in the active site of human carbonic anhydrase II (HCA II) on catalysis. Variants of HCA II in which Val143 was replaced with hydrophobic residues Ile, Leu, and Ala were examined. The efficiency of catalysis in the hydration of CO(2) for these variants was characterized by (18)O exchange mass spectrometry, and their structures were determined by X-ray crystallography at 1.7-1.5 A resolution. The most hydrophobic substitutions, V143I and V143L, showed decreases in the level of catalysis, as much as 20-fold, while the replacement by the smaller V143A mutation showed an only moderate 2-fold decrease in activity. Structural data for all three variants show no significant change in the overall position of amino acid side chains in the active site compared with the wild type. However, V143A HCA II showed additional ordered water molecules in the active site compared to the number for the wild type. To further investigate the decrease in the catalytic efficiency of V143I HCA II, an X-ray crystallographic CO(2) entrapment experiment was performed to 0.93 A resolution. This structure revealed an unexpected shift in the CO(2) substrate toward the zinc-bound solvent, placing it ~0.3 A closer than previously observed in the wild type in conjunction with the observed dual occupancy of the product bicarbonate, presumably formed during the acquisition of data. These data suggest that the Ile substitution at position 143 reduced the catalytic efficiency, which is likely due to steric crowding resulting in destabilization of the transition state for conversion of CO(2) into bicarbonate and a decreased product dissociation rate. PMID- 23098193 TI - Siderophore-mediated cargo delivery to the cytoplasm of Escherichia coli and Pseudomonas aeruginosa: syntheses of monofunctionalized enterobactin scaffolds and evaluation of enterobactin-cargo conjugate uptake. AB - The design and syntheses of monofunctionalized enterobactin (Ent, L- and D isomers) scaffolds where one catecholate moiety of enterobactin houses an alkene, aldehyde, or carboxylic acid at the C5 position are described. These molecules are key precursors to a family of 10 enterobactin-cargo conjugates presented in this work, which were designed to probe the extent to which the Gram-negative ferric enterobactin uptake and processing machinery recognizes, transports, and utilizes derivatized enterobactin scaffolds. A series of growth recovery assays employing enterobactin-deficient E. coli ATCC 33475 (ent-) revealed that six conjugates based on L-Ent having relatively small cargos promoted E. coli growth under iron-limiting conditions whereas negligible-to-no growth recovery was observed for four conjugates with relatively large cargos. No growth recovery was observed for the enterobactin receptor-deficient strain of E. coli H1187 (fepA-) or the enterobactin esterase-deficient derivative of E. coli K-12 JW0576 (fes-), or when the D-isomer of enterobactin was employed. These results demonstrate that the E. coli ferric enterobactin transport machinery identifies and delivers select cargo-modified scaffolds to the E. coli cytoplasm. Pseudomonas aeruginosa PAO1 K648 (pvd-, pch-) exhibited greater promiscuity than that of E. coli for the uptake and utilization of the enterobactin-cargo conjugates, and growth promotion was observed for eight conjugates under iron-limiting conditions. Enterobactin may be utilized for delivering molecular cargos via its transport machinery to the cytoplasm of E. coli and P. aeruginosa thereby providing a means to overcome the Gram-negative outer membrane permeability barrier. PMID- 23098195 TI - Up-regulation of gene expression by transfection to hepatocyte spheroids. AB - The gene expression is up-regulated by transfection to spheroids rather than monolayered cells. Monolayered hepatocytes form spheroids on rubbed polyimide membrane after 3 day incubation. The transfection of a rhodamine-labeled plasmid DNA or a green fluorescent protein (GFP) reporter gene to monolayered hepatocytes makes the spheroids exhibiting the fluorescence from the rhodamine or GFP inside the resulting spheroids. On the other hand, the transfection to hepatocyte spheroids makes the spheroids exhibit the fluorescence only outside the resulting spheroids. However, the whole gene expression of the luciferase reporter plasmid DNA from the lysate of the transfected spheroids is up-regulated in early incubation time, as compared to that of the transfected monolayered hepatocytes. Furthermore, the secretion of vascular endothelial growth factor (VEGF) from the VEGF-transfected spheroids is higher than that from the transfected monolayered hepatocytes. These results suggest that the up-regulation of exogenous gene expression is achieved by the control of differentiation and proliferation of hepatocytes via spheroid formation. PMID- 23098194 TI - Rh(I)-catalyzed Pauson-Khand-type cycloaddition reaction of ene vinylidenecyclopropanes with carbon monoxide (CO). AB - An intramolecular Pauson-Khand type cycloaddition reaction of ene vinylidenecyclopropanes with carbon monoxide has been established by using [Rh(COD)Cl](2) as the catalyst. The reaction was found to be highly efficient in solvents of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane to give excellent yields of 90-99%. The reaction provides easy access to a series of fused 6,5-ring structures containing spiro-cyclopropane units that are useful for drug design and development. A mechanism of this cycloaddition process has been proposed accounting for structures of resulting products that were unambiguously assigned by X-ray diffractional analysis. PMID- 23098196 TI - Effect of ageing on the efficacy efficiency of TUVRP. AB - INTRODUCTION: To evaluate the effect of ageing on the efficacy of transurethral vaporization resection of the prostate (TUVRP). METHODS: The clinical outcomes of 285 patients treated by TUVRP were retrospectively analyzed. Patients were divided into three groups by age, Group A with 91 patients less than <=70 years of age, Group B with 127 patients from 71 to 79 years of age, and Group C with 67 patients greater than >=80 years of age. RESULTS: Prostate volume was 53.1 +/- 24.1 ml in Group A, 67.8 +/- 39.7 ml in Group B and 60.0 +/- 43.9 ml in Group C (p < 0.001). More co-existent systemic diseases were identified in Group C than in the other two groups (p < 0.001). American Society of Anesthesiologists (ASA) grade increased with age (p < 0.001). Urological comorbidities associated with BPH, operating time, IPSS score, and QOL index were not different among the three groups. A significant difference was observed in before and after surgery IPSS score, QOL index, and maximum urinary flow rate (Qmax), in all three groups (p < 0.05). Post-operative Qmax decreased with age (p < 0.05). CONCLUSION: TUVRP was safe and effective for the patients greater than 80 years of age, similarly to younger patients. Advanced aged was not a contraindication for surgery, and did not increase the difficulty of the procedure. PMID- 23098197 TI - Stress analysis of a centrally fractured rib fixated by an intramedullary screw. AB - The stress on an intramedullary screw rib fixation device holding together a centrally fractured human rib under in vivo force loadings was studied using finite element analysis (FEA). Validation of the FEA modelling using pullout from porcine ribs proved FEA to be suitable for assessing the structural integrity of screw/bone systems such as rib fixated by a screw. In the human rib fixation investigation, it was found that intramedullary bioresorbable Bioretec screws can fixate centrally fractured human ribs under normal breathing conditions. However, under coughing conditions, simulation showed Bioretec fixating screws to bend substantially. High stresses in the screw are mainly the result of flexion induced by the force loading, and are restricted to thin regions on the outside of the screw shaft. Stiffer screws result in less locally intense stress concentrations in bone, indicating that bone failure in the bone/screw contact regions can be averted with improvements in screw stiffness. PMID- 23098198 TI - Using functional transcranial Doppler ultrasonography to assess language lateralisation: Influence of task and difficulty level. AB - Language is lateralised to the left hemisphere in most people, but it is unclear whether the same degree and direction of lateralisation is found for all verbal tasks and whether laterality is affected by task difficulty. We used functional transcranial Doppler ultrasonography (fTCD) to assess the lateralisation of language processing in 27 young adults using three tasks: word generation (WG), auditory naming (AN), and picture story (PS). WG and AN are active tasks requiring behavioural responses whereas PS is a passive task that involves listening to an auditory story accompanied by pictures. We also examined the effect of task difficulty by a post hoc behavioural categorisation of trials in the WG task and a word frequency manipulation in the AN task. fTCD was used to measure task-dependent blood flow velocity changes in the left and right middle cerebral arteries. All of these tasks were significantly left lateralised: WG, 77% of individuals left, 5% right; AN, 72% left: 4% right; PS, 56% left: 0% right. There were significant positive relationships between WG and AN (r=0.56) as well as AN and PS (r=.76) but not WG and PS (r = -0.22). The task difficulty manipulation affected accuracy in both WG and AN tasks, as well as reaction time in the AN task, but did not significantly influence laterality indices in either task. It is concluded that verbal tasks are not interchangeable when assessing cerebral lateralisation, but that differences between tasks are not a consequence of task difficulty. PMID- 23098199 TI - Hemispheric asymmetries in visual search. AB - We conducted two visual search experiments, and found that target-detection accuracy and speed were better when the target was projected to the right hemisphere in the feature search condition and better when the target was projected to the left hemisphere in the feature-conjunction search condition. We propose that the highly efficient, so-called parallel search performance characteristic of feature search is enabled by a broadly distributed, global view of the visual field, and the right hemisphere is more efficient than the left in such global processing. On the other hand, the less-efficient performance characteristic of conjunction search (demonstrated by the set-size effect) involves serial shifts of focused attention, and the left hemisphere is more efficient than the right in such localised attentional processing. We suggest that hemispheric asymmetries observed in visual search are related to the attentional demands of the task, and that we adjust our attentional distribution to fit task difficulty. When the target is very distinct, a global, low resolution attentional distribution is sufficient, and enables parallel search; but a localised, narrow-aperture attentional distribution is sometimes necessary to find targets that either require feature binding, or are very similar to other "distractor" stimuli in terms of compositional attributes. PMID- 23098200 TI - A new method for selectively enhancing hemisphere processing: voice frequency amplification influences the strength of attribute framing. AB - An attribute framing effect occurs when positive or negative associations produced by positive or negative frames are mapped onto evaluations resulting in a more favourable evaluation for the positively framed attribute. We used a new voice frequency manipulation to differentially enhance right versus left hemisphere processing. In doing so we found a strong attribute framing effect when a speaker with a low-frequency voice enhanced the contextual processing style of the right hemisphere. However, a framing effect was not obtained when a speaker with a high-frequency voice enhanced the inferential/analytical processing style of the left hemisphere. At the theoretical level our results provide evidence that the contextual processing style of the right hemisphere is especially susceptible to associative implications, such as those found in attribute framing manipulations. At the applied level we provide a simple method for altering the effectiveness of persuasion messages. PMID- 23098201 TI - An investigation of measurement validity for a hemispheric activation scale. AB - In this paper we report the outcomes of two attempts to correlate the Zenhausern Preference Questionnaire (PT) with the Polarity Questionnaire (PQ). Across two laboratories we consistently found no correlation between these two scales. Our findings are consistent with a previous attempt to validate the PQ (Genovese, 2005). We conclude that researchers attempting to use the PQ should take note of this validity question. PMID- 23098202 TI - Inheritance patterns of morphological laterality in mouth opening of zebrafish, Danio rerio. AB - The inheritance patterns of asymmetry in mouth opening in zebrafish were investigated using crossing experiments. Zebrafish exhibit asymmetric laterality in mouth opening, with each individual having either a leftward (righty) or rightward (lefty) bias. All righty incrosses produced only righty F(1), whereas all lefty incrosses resulted in an F(1) L:R ratio of 2:1. All test crosses between lefty and righty individuals resulted in an F(1) L:R=1:1. These results were consistent with the hereditary pattern for Japanese medaka, three Tanganyikan cichlids, and a Japanese riverine goby. The pattern suggests a one locus two-allele Mendelian model of inheritance, with the lefty allele being dominant over righty and the dominant homozygote being lethal. To determine the reason for the absence of lefty homozygotes, the survival rates of the offspring were examined according to developmental stage. Survival did not differ among combinations of parent laterality. Thus the mechanism underlying the lethality of the dominant homozygote remains unclear. This study showed that the mouth-opening laterality of zebrafish is genetically determined and that the direction follows a Mendelian inheritance pattern that is shared among cypriniform zebrafish, beloniform medaka, perciform cichlids, and a goby, suggesting a common genetic background in mouth-opening laterality among these species. PMID- 23098206 TI - Preparations of metal trichalcogenophosphonates from organophosphonate esters. AB - A new method for the preparation of metal trichalcogenophosphonates is presented wherein organophosphonate esters are first reduced with LiAlH(4) and subsequently treated with an organometallic reagent and elemental sulfur or selenium to give the desired trichalcogenophosphonate complex. Using this synthetic protocol with (n)BuLi as the organometallic reagent, the lithium trithiophosphonate complexes [Li(2)(S(3)PCH(2)Ph)(THF)(TMEDA)](2) (1) and [Li(4)(S(3)P(n)Pr)(2)(TMEDA)(3)](infinity) (3), where THF = tetrahydrofuran and TMEDA = N,N,N',N'-tetramethylethylenediamine, have been prepared. In both cases, the formation of byproducts is also evident, including, for 1, the tetrathiohypodiphosphonate complex [(PhCH(2)P(S(2)))(2)Li(2)(THF)(4)] (2), which has been structurally characterized. Replacement of (n)BuLi with (n)Bu(2)Mg as the metallating agent led to much cleaner products and improved yields, with the new trithio- and triselenoorganophosphonate complexes [Mg(S(3)PCH(2)Ph)(TMEDA)](2) (4) and [Mg(Se(3)P(n)Pr)(TMEDA)](2) (5) reported. All trichalcogenophosphonate complexes have been structurally characterized in the solid state: 1 adopts a dimer structure in which the [PhCH(2)PS(3)](2-) ligand exhibits a unique MU(3)-eta(2),eta(2),eta(2)-coordination mode; 3 is polymeric comprising of [Li(4)(S(3)P(n)Pr)(2)(TMEDA)(2)] dimers linked via additional bridging bis(monodentate) TMEDA molecules; 4 and 5 both adopt dimeric motifs with MU(2)-eta(2),eta(2) coordination of the magnesium centers. PMID- 23098207 TI - Sampling conditions influence multiple electrode platelet aggregometry in cardiac surgery patients. AB - OBJECTIVES: To investigate the importance of blood sampling conditions for multiple electrode platelet aggregometry (MEA) in cardiac surgery patients. DESIGN: Eighty-one patients undergoing first time CABG surgery were included in three prospective, observational studies. MEA was used to analyze platelet aggregability after addition of adenosine-diphosphate (ADP) or thrombin activating peptide 6 (TRAP). In substudy 1, hirudin and citrate tubes were compared. In substudy 2, samples from peripheral vein, central venous catheter, and radial artery were compared and in substudy 3, the effect of surgery was investigated by analyzing pre- and postoperative samples. RESULTS: Platelet aggregability values were 30% higher in hirudin tubes than in citrate tubes. There was a significant correlation between hirudin and citrate tubes in TRAP induced aggregability (r = 0.84, p < 0.001) but not in ADP-induced aggregability (r = 0.25, p = 0.13). The blood sampling site did not influence platelet aggregability. Surgery reduced ADP-induced aggregability by 31% (p < 0.001) and TRAP-induced aggregability by 30% (p < 0.001) with large intraindividual variations. CONCLUSIONS: MEA results in cardiac surgery patients should not be compared between samples collected in test tubes with different anticoagulants. The choice of blood sampling site does not affect the results. The operation in itself reduces markedly mean platelet aggregability. PMID- 23098209 TI - Promising porous carbon derived from celtuce leaves with outstanding supercapacitance and CO2 capture performance. AB - Business costs and energy/environmental concerns have increased interested in biomass materials for production of activated carbons, especially as electrode materials for supercapacitors or as solid-state adsorbents in CO2 adsorption area. In this paper, waste celtuce leaves were used to prepare porous carbon by air-drying, pyrolysis at 600 degrees C in argon, followed by KOH activation. The as-prepared porous carbon have a very high specific surface area of 3404 m2/g and a large pore volume of 1.88 cm3/g. As an electroactive material, the porous carbon exhibits good capacitive performance in KOH aqueous electrolyte, with the specific capacitances of 421 and 273 F/g in three and two-electrode systems, respectively. As a solid-state adsorbent, the porous carbon has an excellent CO2 adsorption capacity at ambient pressures of up to 6.04 and 4.36 mmol/g at 0 and 25 degrees C, respectively. With simple production process, excellent recyclability and regeneration stability, the porous carbon that was derived from celtuce leaves is among the most promising materials for high-performance supercapacitors and CO2 capture. PMID- 23098208 TI - p130Cas/Cyclooxygenase-2 axis in the control of mesenchymal plasticity of breast cancer cells. AB - INTRODUCTION: Intrinsic plasticity of breast carcinoma cells allows them to undergo a transient and reversible conversion into mesenchymal cells to disseminate into distant organs, where they can re-differentiate to an epithelial like status to form a cohesive secondary mass. The p130Cas scaffold protein is overexpressed in human ER+ and HER2+ breast cancer where it contributes to cancer progression, invasion and resistance to therapy. However, its role in regulating mesenchymal aggressive breast cancer cells remains to be determined. The aim of this study was to investigate the molecular and functional involvement of this adaptor protein in breast cancer cell plasticity. METHODS: We used silencing strategies and rescue experiments to evaluate phenotypic and biochemical changes from mesenchymal to epithelial traits in breast tumor cell lines. In the mouse A17 cell model previously related to mesenchymal cancer stem cells and basal-like breast cancer, we biochemically dissected the signaling pathways involved and performed functional in vivo tumor growth ability assays. The significance of the signaling platform was assessed in a human setting through the use of specific inhibitors in aggressive MDA-MB-231 subpopulation LM2-4175 cells. To evaluate the clinical relevance of the results, we analyzed publicly available microarray data from the Netherlands Cancer Institute and from the Koo Foundation Sun Yat-Sen Cancer Center. RESULTS: We show that p130Cas silencing induces loss of mesenchymal features, by downregulating Vimentin, Snail, Slug and Twist transcriptional factors, resulting in the acquirement of epithelial-like traits. Mechanistically, p130Cas controls Cyclooxygenase-2 transcriptional expression, which in turn contributes to p130Cas-dependent maintenance of mesenchymal phenotype. This cascade of events also compromises in vivo tumor growth through inhibition of cell signaling controlling cell cycle progression. c-Src and JNK kinases are sequential players in p130Cas/ Cyclooxygenase-2 axis and their pharmacological inhibition is sufficient to downregulate Cyclooxygenase-2 leading to an epithelial phenotype. Finally, in silico microarray data analysis indicates that p130Cas and Cyclooxygenase-2 concomitant overexpression predicts poor survival and high probability of breast tumor recurrence. CONCLUSIONS: Overall, these data identify a new p130Cas/Cyclooxygenase-2 axis as a crucial element in the control of breast tumor plasticity, opening new therapeutic strategies leading to inhibition of these pathways in aggressive breast carcinoma. PMID- 23098210 TI - Distinct groups of repetitive families preserved in mammals correspond to different periods of regulatory innovations in vertebrates. AB - BACKGROUND: Mammalian genomes are repositories of repetitive DNA sequences derived from transposable elements (TEs). Typically, TEs generate multiple, mostly inactive copies of themselves, commonly known as repetitive families or families of repeats. Recently, we proposed that families of TEs originate in small populations by genetic drift and that the origin of small subpopulations from larger populations can be fueled by biological innovations. RESULTS: We report three distinct groups of repetitive families preserved in the human genome that expanded and declined during the three previously described periods of regulatory innovations in vertebrate genomes. The first group originated prior to the evolutionary separation of the mammalian and bird lineages and the second one during subsequent diversification of the mammalian lineages prior to the origin of eutherian lineages. The third group of families is primate-specific. CONCLUSIONS: The observed correlation implies a relationship between regulatory innovations and the origin of repetitive families. Consistent with our previous hypothesis, it is proposed that regulatory innovations fueled the origin of new subpopulations in which new repetitive families became fixed by genetic drift. PMID- 23098211 TI - Differences and commonalities in difficulties faced by clinical nursing educators and faculty in Japan: a qualitative cross-sectional study. AB - BACKGROUND: To clarify the current state of communication between clinical nursing educators and nursing faculty members and the perceived difficulties encountered while teaching nursing students in clinical training in Japan. METHODS: We collected data via focus group interviews with 14 clinical nursing educators, two nursing technical college teachers, and five university nursing faculty members. Interview transcripts were coded to express interview content as conclusions for each unit of meaning. Similar compiled content was categorized. RESULTS: Difficulties in providing clinical training mentioned by both clinical educators and faculty members were classified into four categories: "difficulties with directly exchanging opinions," "mismatch between school-required teaching content and clinical teaching content," "difficulties with handling students who demonstrate a low level of readiness for training," and "human and time limitations in teaching." In some categories, the opinions of educators matched those of the faculty members, whereas in others, the problems differed according to position. CONCLUSIONS: The Japanese culture and working conditions may affect communication between clinical educators and faculty members; however, a direct "opinion exchange" between them is crucial for improving the clinical teaching environment in Japan. PMID- 23098212 TI - Tetramerization of ZapA is required for FtsZ bundling. AB - Prokaryotic cell division is a highly orchestrated process requiring the formation of a wide range of biomolecular complexes, perhaps the most important of these involving the prokaryotic tubulin homologue FtsZ, a fibre-forming GTPase. FtsZ assembles into a ring (the Z-ring) on the inner surface of the inner membrane at the site of cell division. The Z-ring then acts as a recruitment site for at least ten other proteins which form the division apparatus. One of these proteins, ZapA, acts to enhance lateral associations between FtsZ fibres to form bundles. Previously we have expressed, purified and crystallized ZapA and demonstrated that it exists as a tetramer. We also showed that ZapA binds to FtsZ polymers, strongly promoting their bundling, while inhibiting FtsZ GTPase activity by inducing conformational changes in the bound nucleotide. In the present study we investigate the importance of the tetramerization of ZapA on its function. We generated a number of mutant forms of ZapA with the aim of disrupting the dimer-dimer interface. We show that one of these mutants, I83E, is fully folded and binds to FtsZ, but is a constitutive dimer. Using this mutant we show that tetramerization is a requirement for both FtsZ bundling and GTPase modulation activities. PMID- 23098213 TI - Trajectories of problem video gaming among adult regular gamers: an 18-month longitudinal study. AB - A three-wave, longitudinal study examined the long-term trajectory of problem gaming symptoms among adult regular video gamers. Potential changes in problem gaming status were assessed at two intervals using an online survey over an 18 month period. Participants (N=117) were recruited by an advertisement posted on the public forums of multiple Australian video game-related websites. Inclusion criteria were being of adult age and having a video gaming history of at least 1 hour of gaming every week over the past 3 months. Two groups of adult video gamers were identified: those players who did (N=37) and those who did not (N=80) identify as having a serious gaming problem at the initial survey intake. The results showed that regular gamers who self-identified as having a video gaming problem at baseline reported more severe problem gaming symptoms than normal gamers, at all time points. However, both groups experienced a significant decline in problem gaming symptoms over an 18-month period, controlling for age, video gaming activity, and psychopathological symptoms. PMID- 23098214 TI - In vivo immunoamplifying effects of di-(2-ethylhexyl) phthalate on cytokine response. AB - A recent epidemiological study has revealed the positive association between atopy morbidity in children and phthalate esters, environmental chemicals in house dust. Nonetheless, experimental and molecular evidences regarding the correlation between phthalates and allergic response/pathophysiology are not fully investigated. Among phthalate esters, di-(2-ethylhexyl) phthalate (DEHP) has been widely used for flexible polyvinyl chloride products including vinyl flooring and wall covering. In the present study, we examined the effects of exposure to DEHP on allergen (ovalbumin: OVA) -induced peritonitis in ICR mice. Repeated administration of OVA via intraperitoneal route induced peritoneal inflammation characterized by infiltration of granulocytes (neutrophils and eosinophils) into the cavity. DEHP synergistically exaggerated the OVA-related neutrophilic inflammation. Furthermore, DEHP + OVA profoundly amplified OVA elicited inflammation- and allergy-related molecules such as interleukin-5, eotaxin, and keratinocyte-derived chemoattractant production/release in the peritoneal cavity. Taken together, DEHP aggravated OVA-related peritoneal inflammation, which is concomitant with local enhanced production/release of inflammation- and allergy-related molecules. PMID- 23098215 TI - Rhodium-catalyzed enantioselective vinylogous addition of enol ethers to vinyldiazoacetates. AB - A highly asymmetric vinylogous addition of acyclic silyl enol ethers to siloxyvinyldiazoacetate is described. The reaction features a diastereoselective 1,4-siloxy group migration event. Products are obtained in up to 97% ee. When more sterically crowded silyl enol ethers are employed, an enantioselective formal [3+2] cycloaddition becomes the dominant reaction pathway. Control experiments reveal the (Z)-olefin geometry to be critical for high levels of enantiocontrol. PMID- 23098217 TI - Development of progressive multifocal leukoencephalopathy in a patient with non Hodgkin lymphoma 13 years after treatment with cladribine. PMID- 23098216 TI - Early turn formation and chain collapse drive fast folding of the major cold shock protein CspA of Escherichia coli. AB - The folding mechanism of the beta-sheet protein CspA, the major cold shock protein of Escherichia coli, was previously reported to be a concerted, two-state process. We have reexamined the folding of CspA using multiple spectroscopic probes of the equilibrium transition and laser-induced temperature jump (T-jump) to achieve better time resolution of the kinetics. Equilibrium temperature dependent Fourier transform infrared (1634 cm(-1)) and tryptophan fluorescence measurements reveal probe-dependent thermal transitions with midpoints (T(m)) of 66 +/- 1 and 61 +/- 1 degrees C, respectively. Singular-value decomposition analysis with global fitting of the temperature-dependent infrared (IR) difference spectra reveals two spectral components with distinct melting transitions with different midpoints. T-jump relaxation measurements of CspA probed by IR and fluorescence spectroscopy show probe-dependent multiexponential kinetics characteristic of non-two-state folding. The frequency-dependent IR transients all show biphasic relaxation with average time constants of 50 +/- 7 and 225 +/- 25 MUs at a T(f) of 77 degrees C and almost equal amplitudes. Similar biphasic kinetics are observed using Trp fluorescence of the wild-type protein and the Y42W and T68W mutants, with comparable lifetimes. All of these observations support a model for the folding of CspA through a compact intermediate state. The transient IR and fluorescence spectra are consistent with a diffuse intermediate having beta-turns and substantial beta-sheet structure. The loop beta3-beta4 structure is likely not folded in the intermediate state, allowing substantial solvent penetration into the barrel structure. PMID- 23098218 TI - Evaluation of the near infrared compound indocyanine green as a probe substrate of p-glycoprotein. AB - The efflux transporter P-glycoprotein (P-gp) affects the pharmacokinetics of many drugs. Currently used methods for characterization of P-gp's functional activity in vivo involve the use of radiolabeled substrates, are costly, and are technically demanding. Our objective was to evaluate whether the FDA-approved near-infrared compound indocyanine green (ICG) can be used as a probe substrate of P-gp. We also characterized the interaction of ICG with another efflux transporter, the breast cancer resistance protein (BCRP). We evaluated ICG accumulation and transport in MDCK cells overexpressing P-gp or BCRP (MDCK-MDR1 and MDCK-BCRP, respectively) compared to control MDCK cells, in the presence or the absence of transporter inhibitors. In vivo imaging of ICG biodistribution in mice was conducted over 3.5 h using valspodar as the P-gp inhibitor. The EC50 values for ICG accumulation in control MDCK and MDCK-MDR1 cells were 9.0 * 10(-6) +/- 5.7 * 10(-7) M and 1.5 * 10(-5) +/- 1.1 * 10(-6) M, respectively. The efflux ratio for ICG in MDCK-MDR1 cells was 6.8-fold greater than in control cells. P-gp inhibition attenuated ICG efflux from MDR1-MDCK cells, and their effects in those cells were greater than in control MDCK cells. In contrast, BCRP level of expression or pharmacological inhibition did not significantly affect ICG cellular accumulation. In vivo imaging indicated enhanced cerebral ICG distribution with valspodar (brain - foot area under the concentration-time curves of 3.0 * 10(10), 5.6 * 10(10) and 3.7 * 10(10) h.[p/s/sr]/MUW in valspodar treated mice vs 9.0 * 10(9) and 5.3 * 10(9) h.[p/s/sr]/MUW in controls). The findings from this pilot study suggest that near-infrared imaging using ICG as the probe substrate should be further characterized as a methodology for in vivo evaluation of P-gp activity. PMID- 23098219 TI - Cytotoxic constituents from the stem bark of Diospyros cuneata Standl. AB - A phytochemical investigation of the stem bark of Diospyros cuneata (Ebenaceae) together with in vitro cytotoxic evaluation of the pure compounds in four human cancer cell lines KB, Hep-2, HeLa and SiHa led to the isolation of plumbagin, elliptinone, lupeol, atraric acid methyl ester, maritinone, betulin and betulinaldehyde. The structural determination of the compounds was established by nuclear magnetic resonance, electron ionisation mass spectrometric analysis as well as comparison with data from the literature. Plumbagin exhibited a potent cytotoxic activity (CC50 = 3.56 ug mL(-1)) against KB cell lines whereas maritinone displayed cytotoxic activity against Hep-2 (CC50 = 17.30 ug mL(-1)), cervical cancer (CC50 = 21.10 ug mL(-1)) and the KB cell lines (CC50 = 20.30 ug mL(-1)). This is the first report on a phytochemical and biological evaluation of D. cuneata. PMID- 23098220 TI - Infant feeding practices and breastfeeding duration in Japan: A review. AB - The Japanese health system places great emphasis on healthy development. However, the prevalence of Exclusive Breastfeeding at one month postpartum between 1980 and 2005 has remained unchanged, fluctuating between 42% and 49%. At the same time, the Any Breastfeeding prevalence has gradually increased from about 80% to 95%. In 2010, the latest national breastfeeding report showed that 'exclusive' and 'any' breastfeeding rates have improved. However, as the World Health Organization (WHO) definition of breastfeeding practices was not used in this study or in other national surveys, it is difficult to interpret these latest results. While the Japanese government has launched several promotion projects, there have been few studies and reviews of risk factors that influence breastfeeding duration. The objectives of this review were to summarise the factors that have influenced the duration of breastfeeding in Japan to provide information relevant to breastfeeding promotion programs. A search of electronic databases in Japanese and English was undertaken up to 2011. The inclusion criteria for this review were studies that focused on infant feeding practices and targeted Japanese mothers, fathers, or health professionals, but excluded mothers' friends and peer groups. In total, 12 articles were selected for the final analysis. Smoking status, low birth weight of infants and maternal perceptions of insufficient breast milk supply were negative influences on breastfeeding duration, while support from husbands/partners is associated with continued breastfeeding. Some factors that have been found to be associated with breastfeeding in other countries, including maternal age, family income, maternal educational levels, and living with grandparents of infants have not been confirmed in Japan. While the national breastfeeding rates were higher than other countries of similar health status, inconsistent knowledge of breastfeeding benefits and inappropriate hospital practices remain in Japan may be associated with increased the use of infant formula and reduced breastfeeding duration. Most of the studies reviewed were cross-sectional in design, with only a limited number of cohort studies. Also many published studies used small sample sizes. Cohort studies of infant feeding practices with larger sample sizes are required to monitor trends in rates and risk factors for breastfeeding outcomes. PMID- 23098222 TI - Lung infiltrates in cancer patients: differentiating metastases from bronchiolitis obliterans organizing pneumonia. AB - Bronchiolitis obliterans organizing pneumonia (BOOP) is a rare condition that affects oncological patients, often during or after chemotherapy, and can easily be mistaken for lung metastases. BOOP should be taken into consideration in cases when patchy nodular infiltrates with uncertain behavior appear in the lung; these infiltrates are often unresponsive to treatment with antibiotics. We report a case in which a patient treated for transitional cell bladder carcinoma with surgery and adjuvant chemotherapy developed multiple bilateral pulmonary nodules one month after the end of treatment. PMID- 23098221 TI - Chances and risks of publication of quality data - the perspectives of Swiss physicians and nurses. AB - BACKGROUND: The release of quality data from acute care hospitals to the general public is based on the aim to inform the public, to provide transparency and to foster quality-based competition among providers. Due to the expected mechanisms of action and possibly the adverse consequences of public quality comparison, it is a controversial topic. The perspective of physicians and nurses is of particular importance in this context. They are mainly responsible for the collection of quality-control data, and are directly confronted with the results of public comparison. The research focus of this qualitative study was to discover what the views and opinions of the Swiss physicians and nurses were regarding these issues. It was investigated as to how the two professional groups appraised the opportunities as well as the risks of the release of quality data in Switzerland. METHODS: A qualitative approach was chosen to answer the research question. For data collection, four focus groups were conducted with physicians and nurses who were employed in Swiss acute care hospitals. Qualitative content analysis was applied to the data. RESULTS: The results revealed that both occupational groups had a very critical and negative attitude regarding the recent developments. The perceived risks were dominating their view. In summary, their main concerns were: the reduction of complexity, the one-sided focus on measurable quality variables, risk selection, the threat of data manipulation and the abuse of published information by the media. An additional concern was that the impression is given that the complex construct of quality can be reduced to a few key figures, and it that it is constructed from a false message which then influences society and politics. This critical attitude is associated with the different value system and the professional self-concept that both physicians and nurses have, in comparison to the underlying principles of a market-based economy and the economic orientation of health care business. CONCLUSIONS: The critical and negative attitude of Swiss physicians and nurses must, under all conditions, be heeded to and investigated regarding its impact on work motivation and identification with the profession. At the same time, the two professional groups are obligated to reflect upon their critical attitude and take a proactive role in the development of appropriate quality indicators for the publication of quality data in Switzerland. PMID- 23098223 TI - Colder is better during hypothermic circulatory arrest for acute type A aortic dissection. AB - OBJECTIVES: To evaluate the influence, on early postoperative outcomes, of temperature during hypothermic circulatory arrest in emergent surgery for acute type A aortic dissection. DESIGN: Hypothermic circulatory arrest (HCA) with antegrade cerebral perfusion was performed in 63 patients who underwent emergent surgery for acute type A aortic dissection between 2000 and 2009. Patients were retrospectively separated in two groups: ( 1 ) deep HCA, lowest nasopharyngeal temperature < 17 degrees C (n = 29; 46%) and ( 2 ) moderate HCA, lowest nasopharyngeal temperature >= 17 degrees C (n = 34; 54%). RESULTS: Hospital mortality reached 27%. The nasopharyngeal temperature did not influence postoperative mortality or neurological outcome. Patients with deep HCA had significantly lower rate of infection (33% vs. 69%; p = 0.009) and shorter median intensive care unit length of stay (4 days ( 17 ) vs. 15.5 days ( 26 ) p = 0.017). Multiple regression analysis revealed that the lowest nasopharyngeal temperature was the only significant variable associated with intensive care unit length of stay (p = 0.005). CONCLUSIONS: Patients suffering from acute type A aortic dissection might benefit from colder hypothermia during circulatory arrest. PMID- 23098224 TI - Design of digital response in enzyme-based bioanalytical systems for information processing applications. AB - We investigate performance and optimization of the "digital" bioanalytical response. Specifically, we consider the recently introduced approach of a partial input conversion into inactive compounds, resulting in the "branch point effect" similar to that encountered in biological systems. This corresponds to an "intensity filter," which can yield a binary-type sigmoid-response output signal of interest in information and signal processing and in biosensing applications. We define measures for optimizing the response for information processing applications based on the kinetic modeling of the enzymatic reactions involved, and apply the developed approach to the recently published data for glucose detection. PMID- 23098225 TI - Stereoselective synthesis of oxa- and aza-angular triquinanes using tandem radical cyclization to vinylogous carbonates and carbamates. AB - Tandem radical cyclization to vinylogous carbonates and carbamates is developed for a new, highly stereoselective synthesis of heterocyclic angular triquinanes. The strategy is also useful to gain access to oxa- and azatriquinanes, which incorporate the spiroindoline moiety. The method is further extended to the synthesis of lactone-bearing as well as uracil-fused angular triquinanes. PMID- 23098226 TI - Interconnected but underprotected? Parents' methods and motivations for information seeking on digital safety issues. AB - Parents need information and skills to meet the demands of mediating connected technology in their homes. Parents' methods and motivations for learning to protect children from digital risks were reported through a survey. This study explores relationships between information seeking, parents' concerns, risks children have experienced, and access to connected devices, in addition to the use and satisfaction of various digital safety resources. Three types of information-seeking behavior were identified: (a) protective information seeking, to protect children from being confronted with harmful content; (b) problem solving information seeking, to help children who have been negatively affected by connected technology; and (c) attentive learning, by attending to media resources passively encountered on this topic. Friends and family are the dominant source of digital safety information, followed by presentations and the Internet. Parents' top concerns for their children using connected technology were accidental exposure to pornography, and sexual content in Internet-based entertainment. Higher numbers of risks experienced by children were positively associated with parents' problem-solving information seeking and level of attentive learning. Parents who were more concerned exhibited more problem solving information seeking; but despite the high level of concern for children's safety online, 65 percent of parents seek information on this subject less than twice per year. Children have access to a mean of five connected devices at home; a higher number of devices was correlated with increased risks experienced by children, but was not associated with increased concern or information seeking from parents. PMID- 23098227 TI - Percutaneous tissue-engineered pulmonary valved stent implantation: comparison of bone marrow-derived CD133+-cells and cells obtained from carotid artery. AB - OBJECTIVE: The aim of tissue engineering is, for instance, to create a new valve or organ that is similar to the native one. This new construct may have the capability of growth, repair, and remodeling. One instance where tissue engineering offers an enormous advantage is in the treatment of Tetralogy of Fallot. After repair of this defect, pulmonary valve regurgitation with late ventricular dysfunction is not uncommonly observed. METHODS: In this study, we compared the use of endothelial cells (ECs) and smooth muscle cells (SMCs) derived from the carotid artery (group 1/n=5) with CD133+-cells derived from the bone-marrow (group 2/n=5) of juvenile sheep. Western blot analysis and histology were done before and after percutaneous pulmonary valved stent implantation. After seeding of the pulmonary valved stent with one of the cell groups, the construct was placed in a dynamic bioreactor for 16 days. After incubation, the valved stent was seeded again for 3 days. Finally, the valved stent was implanted percutaneously under angiographic control. RESULTS: In group 1, alpha-actin and calponin were found in the EC and SMC population by using Western blot analysis. In contrast, CD31 was found in EC, but not in the SMC population. Cells from group 2 demonstrated a pure population. CD133+-cells were detected in the CD133+ cell population and no CD133+-cells were found in the negative fraction. Three months after implantation, the transvalvular gradient was significantly higher in group 1 compared to group 2. CD31-staining demonstrated a confluent monolayer in both groups. Immunohistochemistry revealed strong expression of alpha-smooth muscle-actin and an in-growth into the leaflets of both groups (p=ns). CD3-, CD20 , CD45-, and CD68-staining confirmed no signs of inflammation in group 2, whereas in group 1 small amounts of inflammation were detected in all analyzed animals. Von Kossa staining revealed mild to moderate calcifications in the annular region of group 1. In contrast, less calcification was detected in group 2. CONCLUSION: Autologous CD133+-cells derived from bone marrow had a better outcome with regard to calcification, inflammation, and transvalvular gradient compared to autologous cells derived from the carotid artery. Therefore, CD133+-cells are more advantageous for tissue engineering of heart valves. PMID- 23098228 TI - Synthesis, structure, and electrochemistry of the Ni-Au carbonyl cluster [Ni12Au(CO)24]3- and its relation to [Ni32Au6(CO)44]6-. AB - A detailed study of the reaction between [Ni(6)(CO)(12)](2-) and [AuCl(4)](-) afforded the isolation of the new Ni-Au cluster [Ni(12)Au(CO)(24)](3-) as well as identifying an improved synthesis for the previously reported [Ni(32)Au(6)(CO)(44)](6-). The new [Ni(12)Au(CO)(24)](3-) cluster is composed by two [Ni(6)(CO)(12)](2-) moieties coordinated to a central Au(I) ion, as determined by X-ray diffraction. It is noteworthy that the two [Ni(6)(CO)(12)](2 ) fragments display different geometries, i.e., trigonal antiprismatic (distorted octahedral) and distorted trigonal prismatic (monocapped square pyramidal). The chemical reactivity of these clusters and their electrochemical behavior have been studied. [Ni(12)Au(CO)(24)](3-) is irreversibly transformed, upon electrochemical reduction, into Au(0) and [Ni(6)(CO)(12)](2-), followed by the reversible reduction of the latter homometallic cluster. Conversely, [Ni(32)Au(6)(CO)(44)](6-) displays five reductions, with apparent features of reversibility, confirming the ability of larger metal carbonyl clusters to reversibly accept and release electrons. PMID- 23098229 TI - GTPase of the immune-associated nucleotide-binding protein 5 (GIMAP5) regulates calcium influx in T-lymphocytes by promoting mitochondrial calcium accumulation. AB - Mature T-lymphocytes undergo spontaneous apoptosis in the biobreeding diabetes prone strain of rats due to the loss of the functional GIMAP5 (GTPase of the immune-associated nucleotide-binding protein 5) protein. The mechanisms underlying the pro-survival function of GIMAP5 in T-cells have not yet been elucidated. We have previously shown that GIMAP5 deficiency in T-cells impairs Ca2+ entry via plasma membrane channels following exposure to thapsigargin or stimulation of the T-cell antigen receptor. In the present study we report that this reduced Ca2+ influx in GIMAP5-deficient T-cells is associated with the inability of their mitochondria to sequester Ca2+ following capacitative entry, which is required for sustained Ca2+ influx via the plasma membrane channels. Consistent with a role for GIMAP5 in regulating mitochondrial Ca2+, overexpression of GIMAP5 in HEK (human embryonic kidney)-293 cells resulted in increased Ca2+ accumulation within the mitochondria. Disruption of microtubules, but not the actin cytoskeleton, abrogated mitochondrial Ca2+ sequestration in primary rat T-cells, whereas both microtubules and actin cytoskeleton were needed for the GIMAP5-mediated increase in mitochondrial Ca2+ in HEK-293 cells. Moreover, GIMAP5 showed partial colocalization with tubulin in HEK-293 cells. On the basis of these findings, we propose that the pro-survival function of GIMAP5 in T-lymphocytes may be linked to its requirement to facilitate microtubule dependent mitochondrial buffering of Ca2+ following capacitative entry. PMID- 23098230 TI - Abundant expression of interleukin-21 receptor in follicular lymphoma cells is associated with more aggressive disease. AB - Recombinant interleukin-21 (IL-21) has potential utility in cancer therapy. Stimulation with IL-21 can induce apoptosis in follicular lymphoma (FL) cells, and existing studies have suggested that IL-21 signaling may function in tumor suppression. In order to elucidate the relationship between IL-21 receptor (IL 21R) expression and clinical and pathological features in FL, IL-21R was quantified in 114 pretreatment biopsy samples using either conventional immunohistochemistry or immunofluorescence microscopy and automated quantitative analysis (AQUA). Reduced expression of IL-21R was associated with favorable overall survival (p = 0.048). AQUA analysis showed an association with the presence of diffuse large B-cell lymphoma (DLBCL) in the biopsy sample (p = 0.03), and expression of IL-21R was up-regulated upon transformation of FL to DLBCL in two cases. Our results based on the largest survey to date raise the possibility that IL-21 signaling in FL cells, rather than being tumor suppressive, supports tumor progression and that therapeutic benefit could be realized by blocking IL-21R instead of stimulating it. PMID- 23098231 TI - PTPN22 -1123G > C polymorphism is associated with susceptibility to primary immune thrombocytopenia in Chinese population. AB - Primary immune thrombocytopenia (ITP) is an acquired autoimmune disorder characterized by autoantibody-mediated platelet destruction. Multiple factors have been implicated in ITP pathogenesis, including T-lymphocyte dysfunctions. The protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene encodes lymphoid-specific phosphatase (LYP), a critical negative regulator of T cell activation. Single nucleotide polymorphisms (SNPs) of PTPN22 have been broadly associated with susceptibilities to various autoimmune disorders. Here we conducted a case-control study investigating whether the PTPN22 -1123G > C SNP contributes to the risk of ITP in Chinese population. The study included 191 ITP cases and 216 ethnically matched normal controls. Genotyping of -1123G > C SNP was performed using a single-base extension (SBE) and mass spectrometry method. Allelic and genotypic frequencies were compared between the case-control groups by the chi-square test. We observed significant overrepresentation of -1123G allele (p = 0.034, odds ratio (OR) = 1.374, 95% confidence interval (CI) [1.024 1.843]) and GG genotype (P = 0.038, OR = 1.951, 95% CI [1.031-3.694]) in the patients compared with the controls. Stratified analysis by gender and age of disease onset revealed comparable observations in both male and adult ITP cohorts. These data suggest a moderate association of PTPN22 -1123G > C SNP with susceptibility to ITP. Together with previous reports, our finding provides further evidence for PTPN22 being a general autoimmunity gene. PMID- 23098232 TI - Autocatalytic and cooperatively stabilized dissociation of water on a stepped platinum surface. AB - Water-metal interfaces are ubiquitous and play a key role in many chemical processes, from catalysis to corrosion. Whereas water adlayers on atomically flat transition metal surfaces have been investigated in depth, little is known about the chemistry of water on stepped surfaces, commonly occurring in realistic situations. Using first-principles simulations, we study the adsorption of water on a stepped platinum surface. We find that water adsorbs preferentially at the step edge, forming linear clusters or chains, stabilized by the cooperative effect of chemical bonds with the substrate and hydrogen bonds. In contrast with their behavior on flat Pt, at steps water molecules dissociate, forming mixed hydroxyl/water structures, through an autocatalytic mechanism promoted by H bonding. Nuclear quantum effects contribute to stabilize partially dissociated cluster and chains. Together with the recently demonstrated behavior of water chains adsorbed on stepped Pt surfaces to transfer protons via thermally activated hopping, these findings make these systems viable candidates for proton wires. PMID- 23098234 TI - Quantitative analysis of neurochemical panel in rat brain and plasma by liquid chromatography-tandem mass spectrometry. AB - The dopamine, serotonin, and kynurenine metabolic pathways play pivotal roles on brain function, and their disturbances are closely related to various neurological diseases. Comprehensive measurements of these metabolites is thus essential for monitoring the global neurochemical responses to pathological challenges or drug intervention. However, simultaneous measurement of various neurochemcial metabolites represents a great challenge. We developed herein an original and feasible method using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). A chemical derivatization approach using benzoyl chloride (benzoylation) was developed to achieve better chromatographic behavior and mass-detecting sensitivity. The developed method enables a rapid quantification of 11 metabolites spanning dopamine, serotonin, and kynurenine metabolic pathways within 10.5 min. With this method, we were able to simultaneously monitor inflammation induced alternations of all these metabolites in a rat brain and in particular their dynamics in plasma matrix. The balance between the serotonin and kynurenine branches of tryptophan metabolism was disrupted by lipopolysaccharide (LPS)-induced inflammation, characterized with the overproduction of neurotoxic metabolite 3-hydroxykynurenine and decreased levels of serotonin. The measured levels of this panel of neurotransimtters ranged from 4.3 ng to 10.6 MUg per gram of brain tissue. All these results suggest that the presently developed method is sufficiently sensitive and robust to simultaneously monitor a large panel of metabolites with diverse properties and a large range of concentration differences. Therefore, this method will be expected to be highly useful for comprehensive studies of the pathophysiological roles and mechanisms of these critical neurotransmitters. PMID- 23098233 TI - Effect of the poly(ethylene glycol) (PEG) density on the access and uptake of particles by antigen-presenting cells (APCs) after subcutaneous administration. AB - Lymphatic trafficking of particles to the secondary lymphoid organs, such as lymph nodes, and the cell types that particles access are critical factors that control the quality and quantity of immune responses. In this study, we evaluated the effect of PEGylation on the lymphatic trafficking and accumulation of particles in draining lymph nodes (dLNs) as well as the cell types that internalized particles. As a model system, 200 nm polystyrene (PS) particles were modified with different densities of poly(ethylene glycol) (PEG) and administered subcutaneously to mice. PEGylation enhanced the efficiency of particle drainage away from the injection site as well as the access of particles to dendritic cells (DCs). The accumulation of particles in dLNs was dependent on the PEG density. PEGylation also enhanced uptake by DCs while reducing internalization by B cells at the single cell level. Our results indicate that PEGylation facilitated the trafficking of particles to dLNs either through enhanced trafficking in lymphatic vessels or by enhanced internalization by migratory DCs. This study provides insight into utilizing PEGylated particles for the development of synthetic vaccines. PMID- 23098235 TI - Substrate cycles in Penicillium chrysogenum quantified by isotopic non-stationary flux analysis. AB - BACKGROUND: Penicillium chrysogenum, the main production strain for penicillin-G, has a high content of intracellular carbohydrates, especially reduced sugars such as mannitol, arabitol, erythritol, as well as trehalose and glycogen. In previous steady state C wash-in experiments a delay of labeling enrichments in glycolytic intermediates was observed, which suggests turnover of storage carbohydrates. The turnover of storage pools consumes ATP which is expected to reduce the product yield for energy demanding production pathways like penicillin-G. RESULTS: In this study, a 13C labeling wash-in experiment of 1 hour was performed to systematically quantify the intracellular flux distribution including eight substrate cycles. The experiments were performed using a mixed carbon source of 85% CmolGlc/CmolGlc+EtOH labeled glucose (mixture of 90% [1-13C1] and 10% [U 13C6]) and 15% ethanol [U-13C2]. It was found, that (1) also several extracellular pools are enriched with 13C labeling rapidly (trehalose, mannitol, and others), (2) the intra- to extracellular metabolite concentration ratios were comparable for a large set of metabolites while for some carbohydrates (mannitol, trehalose, and glucose) the measured ratios were much higher. CONCLUSIONS: The fast enrichment of several extracellular carbohydrates and a concentration ratio higher than the ratio expected from cell lysis (2%) indicate active (e.g. ATP consuming) transport cycles over the cellular membrane. The flux estimation indicates, that substrate cycles account for about 52% of the gap in the ATP balance based on metabolic flux analysis. PMID- 23098237 TI - Diversity of Salmonella spp. serovars isolated from the intestines of water buffalo calves with gastroenteritis. AB - BACKGROUND: Salmonellosis in water buffalo (Bubalus bubalis) calves is a widespread disease characterized by severe gastrointestinal lesions, profuse diarrhea and severe dehydration, occasionally exhibiting a systemic course. Several Salmonella serovars seem to be able to infect water buffalo, but Salmonella isolates collected from this animal species have been poorly characterized. In the present study, the prevalence of Salmonella spp. in water buffalo calves affected by lethal gastroenteritis was assessed, and a polyphasic characterization of isolated strains of S. Typhimurium was performed. RESULTS: The microbiological analysis of the intestinal contents obtained from 248 water buffalo calves affected by lethal gastroenteritis exhibited a significant prevalence of Salmonella spp. (25%), characterized by different serovars, most frequently Typhimurium (21%), Muenster (11%), and Give (11%). The 13 S. Typhimurium isolates were all associated with enterocolitis characterized by severe damage of the intestine, and only sporadically isolated with another possible causative agent responsible for gastroenteritis, such as Cryptosporidium spp., Rotavirus or Clostridium perfringens. Other Salmonella isolates were mostly isolated from minor intestinal lesions, and often (78% of cases) isolated with other microorganisms, mainly toxinogenic Escherichia coli (35%), Cryptosporidium spp. (20%) and Rotavirus (10%). The S. Typhimurium strains were characterized by phage typing and further genotyped by polymerase chain reaction (PCR) detection of 24 virulence genes. The isolates exhibited nine different phage types and 10 different genetic profiles. Three monophasic S. Typhimurium (B:4,12:i:-) isolates were also found and characterized, displaying three different phage types and three different virulotypes. The molecular characterization was extended to the 7 S. Muenster and 7 S. Give isolates collected, indicating the existence of different virulotypes also within these serovars. Three representative strains of S. Typhimurium were tested in vivo in a mouse model of mixed infection. The most pathogenic strain was characterized by a high number of virulence factors and the presence of the locus agfA, coding for a thin aggregative fimbria. CONCLUSIONS: These results provide evidence that Salmonella is frequently associated with gastroenteritis in water buffalo calves, particularly S. Typhimurium. Moreover, the variety in the number and distribution of different virulence markers among the collected S. Typhimurium strains suggests that within this serovar there are different pathotypes potentially responsible for different clinical syndromes. PMID- 23098238 TI - Experimental and theoretical approach to aggregation behavior of new di-N-oxide surfactants in an aquatic environment. AB - A homologous series of new dicephalic type surfactants (N,N-bis3,3' (dimethylamino)propyl]alkylamide di-N-oxides) were synthesized and their aggregation phenomena were extensively studied. First, the pH-sensitivity of the investigated surfactants was tested in potentiometric titrations. Then, the adsorption isotherms were measured and interpreted using the Gibbs adsorption equation to determine physicochemical properties. The spin probe EPR technique was employed to monitor the micellization behavior of the surfactants, depending on temperature and surfactant concentration. Critical micelle concentrations (CMC) were determined through an analysis of the calculated spin probe rotational correlation times. A greater insight into the local microenvironment of the formed aggregates was gained by analyzing the properties of the immobilized spin probes. In addition, the CMC values were compared with the ones obtained from tensiometry measurements (taking into account the contributions of the various ionic and nonionic surfactant forms). The approximate size of the micellar aggregates was estimated by the dynamic light scattering (DLS) method. Good agreement between the experimental hydrodynamic radii and those predicted using density functional theory (DFT) guaranteed that the subsequently calculated aggregation numbers, representing the number of molecules in a micelle, were close to the real values. Moreover, the theoretical QSAR methods were used to determine the shape of the micelles via the prediction of the critical packing parameter (CPP). PMID- 23098236 TI - Toll-like receptors expression and interferon-gamma production by NK cells in human sepsis. AB - INTRODUCTION: During the course of infection, natural killer (NK) cells contribute to innate immunity by producing cytokines, particularly interferon gamma (IFN-gamma). In addition to their beneficial effects against infection, NK cells may play a detrimental role during systemic inflammation, causing lethality during sepsis. Little is known on the immune status of NK cells in patients with systemic inflammatory response syndrome (SIRS) or sepsis in terms of cell surface markers expression and IFN-gamma production. METHODS: We investigated 27 sepsis patients and 11 patients with non-infectious SIRS. CD56bright and CD56dim NK cell subsets were identified by flow cytometry and Toll-like receptor (TLR)2, TLR4, TLR9, CX3CR1, CD16 and CD69 expression were analyzed, as well as ex vivo IFN gamma production by NK cells in whole blood samples. RESULTS: We first showed that in NK cells from healthy controls, TLR2 and TLR4 expression is mainly intracellular, similarly to TLR9. Intracellular levels of TLR2 and TLR4, in both CD56bright and CD56dim NK cell subsets from sepsis patients, were increased compared to healthy subjects. In addition, the percentage of CD69+ cells was higher among NK cells of sepsis patients. No difference was observed for TLR9, CX3CR1, and CD16 expression. The ex vivo stimulation by TLR4 or TLR9 agonists, or whole bacteria in synergy with accessory cytokines (IL-15+IL-18), resulted in significant production of IFN-gamma by NK cells of healthy controls. In contrast, for SIRS and sepsis patients this response was dramatically reduced. CONCLUSIONS: This study reports for the first time an intracellular expression of TLR2 and TLR4 in human NK cells. Surface TLR4 expression allows discriminating sepsis and SIRS. Furthermore, during these pathologies, NK cells undergo an alteration of their immune status characterized by a profound reduction of their capacity to release IFN-gamma. PMID- 23098239 TI - Intravital fluorescence imaging of small interfering RNA-mediated gene repression in a dual reporter melanoma xenograft model. AB - Development of RNA interference (RNAi)-based therapeutics has been hampered by the lack of effective and efficient means of delivery. Reliable model systems for screening and optimizing delivery of RNAi-based agents in vivo are crucial for preclinical research aimed at advancing nucleic acid-based therapies. We describe here a dual fluorescent reporter xenograft melanoma model prepared by intradermal injection of human A375 melanoma cells expressing tandem tomato fluorescent protein (tdTFP) containing a small interfering RNA (siRNA) target site as well as enhanced green fluorescent protein (EGFP), which is used as a normalization control. Intratumoral injection of a siRNA specific to the incorporated siRNA target site, complexed with a cationic lipid that has been optimized for in vivo delivery, resulted in 65%+/-11% knockdown of tdTFP relative to EGFP quantified by in vivo imaging and 68%+/-10% by reverse transcription-quantitative polymerase chain reaction. No effect was observed with nonspecific control siRNA treatment. This model provides a platform on which siRNA delivery technologies can be screened and optimized in vivo. PMID- 23098240 TI - Improved inhibition of telomerase by short twisted intercalating nucleic acids under molecular crowding conditions. AB - Human telomeric DNA has the ability to fold into a 4-stranded G-quadruplex structure. Several G-quadruplex ligands are known to stabilize the structure and thereby inhibit telomerase activity. Such ligands have demonstrated efficient telomerase inhibition in dilute conditions, but under molecular crowding conditions mimicking physiological milieu, stabilization of the telomeric G quadruplex is often lost. We attempted to demonstrate the enhanced G-quadruplex stabilizing ability under molecular conditions by using twisted intercalating nucleic acids (TINA)-modified oligonucleotides. We have shown using circular dichroism and ultraviolet spectroscopic methods that these TINA-modified short oligonucleotides function as G-quadruplex, inducing agents and participate in the formation of stabilized 3:1 G-quadruplex with the human telomeric oligonucleotide. Using enzyme-linked immunosorbent assay-based telomerase repeat amplification assay (TRAP) assay as well as nondenaturing polyacrylamide gel electrophoresis-based TRAP, we demonstrate remarkable enhancement in their anti telomerase activity even under molecular crowding conditions. This is the first time in which a G-quadruplex stabilizing agent has demonstrated enhanced activity even under molecular crowding conditions. PMID- 23098241 TI - Why do people choose not to have screening for hemochromatosis? AB - AIM: Hemochromatosis is a common disorder of iron overload most commonly due to homozogosity for the HFE C282Y substitution. A workplace-screening program was conducted in which over 11,000 individuals were screened for this mutation. A substudy of this project was to ascertain why people chose not to attend information and screening sessions offered in their workplace. METHOD: Staff were recruited by email, questionnaires in common areas, and direct approach. A purpose-designed questionnaire sought the reasons for not attending information and screening sessions. RESULTS: The nonattender questionnaire was distributed at 24 workplaces and completed by 872 individuals. The most common reason for not attending sessions, accounting for 70.1%, was practical (e.g., unaware of session, too busy, or unavailable). Other relatively common reasons were that the individual had low iron levels or were a blood donor (14.9%), or that hemochromatosis was considered unimportant (12.2%). Insurance concerns were very rarely cited as the reason for nonattendance (1.0%). CONCLUSION: The nonattender data presented here indicate that concerns about insurance, anxiety, and use of genetic information are not major factors for why people did not attend workplace information and screening sessions for hereditary hemochromatosis. Practical barriers were the major reasons identified. This highlights that when implementing screening programs, as many practical barriers as possible need to be overcome, so that a maximum number of people who would like to be informed about screening are given the opportunity to do so. PMID- 23098243 TI - Desynchronization in synchronous multi-coupled chaotic neurons by mix-adaptive feedback control. AB - In this paper, by means of the invariance principle of differential equations, an adaptive feedback scheme is proposed to realize desynchronization in synchronous multi-coupled chaotic neurons by the mix-adaptive feedback effectively. Numerical simulations for the Hindmarsh-Rose neural model with self-coupling are illustrated which agree well with our theoretical analysis. It is observed that the feedback strengths asymptotically converge to a local fixed value in finite time, especially for linear coupling chaotic neurons with self-coupling. Furthermore, robustness of desynchronization in three coupled chaotic neurons on small mismatch of parameters is shown. PMID- 23098242 TI - Association of uridine diphosphate-glucuronosyltransferase 2B gene variants with serum glucuronide levels and prostate cancer risk. AB - AIMS: Uridine diphosphate-glucuronosyltransferase 2B (UGT2B) enzymes conjugate testosterone metabolites to enable their excretion in humans. The functional significance of the UGT2B genetic variants has never been described in humans. We evaluated UGT2B variants in relation to plasma androstane-3alpha,17beta-diol glucuronide (AAG) levels and the prostate cancer risk. RESULTS: AAG levels were measured in sera from 150 controls and compared to the polymorphisms of UGT2B17, UGT2B15, and UGT2B7. Genomic DNA from controls (301) and cases (148) was genotyped for the polymorphisms, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using unconditional logistic regression analyses. Having two copies of UGT2B17 was associated with higher AAG levels in controls among Whites (p=0.02), but not Blacks (p=0.82). Logistic regression models adjusting for age and race revealed that homozygosity for the G allele of the UGT2B15(D85Y) polymorphism was directly associated with the prostate cancer risk (OR=2.70, 95% CI=1.28, 5.55). CONCLUSIONS: While the small sample size limits inference, our findings suggest that an association between the UGT2B17 copy number variant (CNV) and serum AAG levels in Whites, but unexpectedly not in Blacks. This novel observation suggests that genetic determinants of AAG levels in Blacks are unrelated to the UGT2B17 CNV. This study replicates the results that show an association of UGT215(D85Y) with an increased prostate cancer risk. PMID- 23098244 TI - Body mass index, height and risk of lymphoid neoplasms in a large United States cohort. AB - Results from epidemiologic studies examining associations between body size and risk of non-Hodgkin lymphoma (NHL) are inconsistent, and etiology may vary by histologic subtype of disease. Using Cox proportional hazards regression, multivariable relative risks (RRs) and 95% confidence intervals (CIs) were computed for associations of body mass index (BMI) and height with NHL in the prospective American Cancer Society Cancer Prevention Study-II Nutrition Cohort. From 1992 to 2007, 2074 incident cases of NHL were identified among 152 423 men and women. Obese individuals (BMI >= 30 kg/m(2)) had 23% higher incidence of NHL (95% CI 1.08-1.40) compared to those with normal weight (BMI 18.5-< 25 kg/m(2)). Height was positively associated with NHL (RR = 1.25, 95% CI 1.10-1.43, sex specific quintile 5 vs. 1). BMI associations were strongest for diffuse large B cell lymphoma. Height was most strongly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma and to a lesser extent with multiple myeloma. These findings provide further evidence that body size may play a role in the etiology of NHL, which is of public health importance given the rapid rise in obesity worldwide. PMID- 23098245 TI - Structure and spectroscopic properties of gold(I) diselenophosph(in)ate complexes: a joint experimental and theoretical study. AB - The structure and optical properties of several polynuclear gold(I) species, namely, diselenophosphate [Au{MU-Se(2)P(OR)(2)}](2) complexes (R = (i)Pr, Et, (n)Pr) respectively numbered 1, 2, and 3 and number 4 [Au{MU Se(2)P(CH(2))(2)Ph)(2)}](2), exhibiting interesting structural, absorption, and emission properties have been studied. The synthesis, full characterization, and experimental spectroscopic study of 3 and 4 have first been carried out, 1 and 2 being previously studied. In the solid state, 3 gives polymers, like 1 and 2, whereas 4 exists under a dinuclear monomeric form. The absorption and phosphorescence properties of 4 have been rationalized using DFT and TDDFT computations. In particular, Au-Au bonding seems to appear in its first singlet and triplet states, whereas such a bond does not exist in the ground state. Then, the influence of polymerization through aurophilic bonding on the optical properties of 2 is investigated (1 and 3 behave as 2). It is shown using TDDFT computations that its observed UV-visible excitation spectrum in solution is due to high oligomers and not to monomers or low size oligomers. ESI-MS molecular weight measurements confirm the occurrence of such oligomers of 2 in solution. An assignment of the observed bands of 2 is proposed. The transition corresponding to the first excitation band, which is mainly a HOMO to LUMO one, exhibits metal centered character, i.e., a gold 5d to 6p orbital transition, but concomitantly transfers significant electron density from gold to phosphorus atoms so that it is also a MLCT one. PMID- 23098246 TI - A comparison of semantic feature analysis and phonological components analysis for the treatment of naming impairments in aphasia. AB - Therapy for naming impairments post-stroke typically involves semantic and/or phonologically-based tasks. However, the relationship between individuals' locus of breakdown in word retrieval and their response to a particular treatment approach remains unclear, and direct comparisons of treatments with different targets (semantics, phonology) yet similar formats are lacking. This study examined eight people with aphasia who each received 12 treatment sessions; half the sessions involved a semantically-based treatment task, Semantic Feature Analysis (SFA), and the other half involved a phonologically-based treatment task, Phonological Components Analysis (PCA). Pre-therapy baseline accuracy scores were compared to naming accuracy post-treatment and at follow-up assessment. Seven of the eight participants showed significant improvements in naming items treated with PCA, with six of these seven participants maintaining improvements at follow-up. Four of the eight participants showed significant improvements for items treated with SFA, with three of the four maintaining improvements at follow-up. The semantic therapy was not beneficial for participants with semantic deficits. In contrast, the phonological therapy was beneficial for most participants, despite differences in underlying impairments. Understanding the relationship between an individual's locus of breakdown in word retrieval and response to different treatment tasks has the potential to optimise targeted treatment. PMID- 23098247 TI - Continuous warfarin therapy is safe and feasible in catheter ablation of atrial fibrillation. AB - OBJECTIVES: In the context of catheter ablation of atrial fibrillation, oral anticoagulant therapy has been traditionally replaced by bridging with heparin during the periprocedural period. We wanted to study the feasibility and safety of continuous warfarin therapy compared to traditional bridging therapy. DESIGN: The complication rates were compared retrospectively in a consecutive patient series. In the bridging group, warfarin was discontinued three days and low molecular weight heparin started one day prior to the procedure. Warfarin was reinitiated one day after and low molecular weight heparin was continued until the therapeutic INR target was reached. Patients on continuous therapy received warfarin throughout the periprocedural period. All patients received unfractionated heparin during the procedure. RESULTS: Three thromboembolic cerebrovascular events (1.9%) occurred in the bridging group (n = 157) and seven (0.82%) in the warfarin group (n = 850) (p = 0.142). The number of cardiac tamponades was one (0.64%) and four (0.47%), respectively (p = 0.786). Total number of severe bleeding and thromboembolic complications was more common in the bridging group: 9 (5.7%) versus 22 (2.6%); p = 0.036. In multivariate analysis, female gender, advanced age, and bridging therapy predicted complications. CONCLUSIONS: Continuous oral anticoagulant therapy is a safe and feasible alternative for bridging therapy in patients undergoing catheter ablation of atrial fibrillation. PMID- 23098248 TI - Allergic colitis in monozygotic preterm twins. AB - Allergic colitis (AC) typically develops in the first weeks or months of life and is characterized by the presence of red blood in the stools of healthy breastfed or formula fed infants. In this paper, we describe a case of rectal bleeding in monozygotic preterm twins that was resolved with the introduction of a cow's milk protein-free diet (CMPFD). The occurrence of this disorder in monozygotic twins raises the question as to whether the underlying abnormality in the immune regulation, which leads to poor acquisition of tolerance to cow's milk proteins, might be inherited or environmentally acquired. The case also highlights the use of the probiotic Lactobacillus GG (LGG) in the treatment of allergic colitis. PMID- 23098249 TI - Identifying attentional bias and emotional response after appearance-related stimuli exposure. AB - The effect of media images has been regarded as a significant variable in the construction or in the activation of body images. Individuals who have a negative body image use avoidance coping strategies to minimize damage to their body image. We identified attentional biases and negative emotional responses following exposure to body stimuli. Female university students were divided into two groups based on their use of avoidance coping strategies (high-level group: high avoidance [HA]; low-group: low avoidance [LA]), and were assigned to two different conditions (exposure to thin body pictures, ET, and exposure to oversized body pictures, EO). Results showed that the HA group paid more attention to slim bodies and reported more negative emotions than the LA group, and that the EO had more negative effects than the ET. We suggest that HAs may attend more to slim bodies as a way of avoiding overweight bodies, influenced by social pressure, and in the search for a compensation of a positive emotional balance. However, attentional bias toward slim bodies can cause an upward comparison process, leading to increased body dissatisfaction, which is the main factor in the development of eating disorders (EDs). Therefore, altering avoidance coping strategies should be considered for people at risk of EDs. PMID- 23098250 TI - Efficient Pd-catalyzed direct arylations of heterocycles with unreactive and hindered aryl chlorides. AB - A highly electron-rich Pd complex can efficiently catalyze the direct arylation of heteroaromatics with unreactive and sterically congested aryl chlorides. PMID- 23098251 TI - Resolving low-expression cell surface antigens by time-gated orthogonal scanning automated microscopy. AB - We report a highly sensitive method for rapid identification and quantification of rare-event cells carrying low-abundance surface biomarkers. The method applies lanthanide bioprobes and time-gated detection to effectively eliminate both nontarget organisms and background noise and utilizes the europium containing nanoparticles to further amplify the signal strength by a factor of ~20. Of interest is that these nanoparticles did not correspondingly enhance the intensity of nonspecific binding. Thus, the dramatically improved signal-to background ratio enables the low-expression surface antigens on single cells to be quantified. Furthermore, we applied an orthogonal scanning automated microscopy (OSAM) technique to rapidly process a large population of target-only cells on microscopy slides, leading to quantitative statistical data with high certainty. Thus, the techniques together resolved nearly all false-negative events from the interfering crowd including many false-positive events. PMID- 23098252 TI - Formation mechanism of silver nanoparticles stabilized in glassy matrices. AB - In any given matrix control over the final particle size distribution requires a constitutive understanding of the mechanisms and kinetics of the particle evolution. In this contribution we report on the formation mechanism of silver nanoparticles embedded in a soda-lime silicate glass matrix. For the silver ion exchanged glass it is shown that at temperatures below 410 degrees C only molecular clusters (diameter <1 nm) are forming which are most likely silver dimers. These clusters grow to nanoparticles (diameter >1 nm) by annealing above this threshold temperature of 410 degrees C. It is evidenced that the growth and thus the final silver nanoparticle size are determined by matrix-assisted reduction mechanisms. As a consequence, particle growth proceeds after the initial formation of stable clusters by addition of silver monomers which diffuse from the glass matrix. This is in contrast to the widely accepted concept of particle growth in metal-glass systems, in which it is assumed that the nanoparticle formation is predominantly governed by Ostwald ripening processes. PMID- 23098253 TI - Nanoscale phase analysis of molecular cooperativity and thermal transitions in dendritic nonlinear optical glasses. AB - A broad nanoscopic study of a wide-range of dendritic organic nonlinear optical (NLO) self-assembly molecular glasses reveals an intermediate thermal phase regime responsible for both enhanced electric field poling properties and strong phase stabilization after poling. In this paper, the focus is on dendritic NLO molecular glasses involving quadrupolar, liquid crystal, and hydrogen bonding self-assembly mechanisms that, along with chromophore dipole-dipole interactions, dictate phase stability. Specifically, dendritic face-to-face interactions involving arene-perfluoroarene are contrasted to coumarin-containing liquid crystal mesogen and cinnamic ester hydrogen interactions. Both the strength of dendritic interactions and the impact of dipole fields on the relaxation behavior have been analyzed by nanoscale energetic probing and local thermal transition analysis. The presence of dendritic groups was found to fundamentally alter transition temperatures and the molecular relaxation behavior. Thermal transition analysis revealed that molecules with dendritic groups possess an incipient transition (T(1)) preceding the glass transition temperature (T(2)) that provides increased stability and a well-defined electric field poling regime (T(1) < T < T(2)), in contrast to molecular groups lacking dendrons that exhibit only single transitions. On the basis of enthalpic and entropic energetic analyses, thermally active modes below T(1) were found to be intimately connected to the dendron structure. Their corresponding activation energies, which are related to thermal stability, increased moving from cinnamic ester groups to coumarin moieties to arene-perfluoroarene interacting groups. While dendritic NLO materials were found to possess only enthalpic stabilization energies at temperatures relevant for device operation (T < T(1)), the apparent molecular binding energies above T(1) contain a substantial amount (up to ~80%) of cooperative entropic energy. The multiple interactions (from dipole-dipole interactions to local noncovalent dendritic interactions) are discussed and summarized in a model that describes the thermal transitions and phases. PMID- 23098254 TI - Digital and analog chemical evolution. AB - Living matter is the most elaborate, elegant, and complex hierarchical material known and is consequently the natural target for an ever-expanding scientific and technological effort to unlock and deconvolute its marvelous forms and functions. Our current understanding suggests that biological materials are derived from a bottom-up process, a spontaneous emergence of molecular networks in the course of chemical evolution. Polymer cooperation, so beautifully manifested in the ribosome, appeared in these dynamic networks, and the special physicochemical properties of the nucleic and amino acid polymers made possible the critical threshold for the emergence of extant cellular life. These properties include the precise and geometrically discrete hydrogen bonding patterns that dominate the complementary interactions of nucleic acid base-pairing that guide replication and ensure replication fidelity. In contrast, complex and highly context-dependent sets of intra- and intermolecular interactions guide protein folding. These diverse interactions allow the more analog environmental chemical potential fluctuations to dictate conformational template-directed propagation. When these two different strategies converged in the remarkable synergistic ribonucleoprotein that is the ribosome, this resulting molecular digital-to analog converter achieved the capacity for both persistent information storage and adaptive responses to an ever-changing environment. The ancestral chemical networks that preceded the Central Dogma of Earth's biology must reflect the dynamic chemical evolutionary landscapes that allowed for selection, propagation, and diversification and ultimately the demarcation and specialization of function that modern biopolymers manifest. Not only should modern biopolymers contain molecular fossils of this earlier age, but it should be possible to use this information to reinvent these dynamic functional networks. In this Account, we review the first dynamic network created by modification of a nucleic acid backbone and show how it has exploited the digital-like base pairing for reversible polymer construction and information transfer. We further review how these lessons have been extended to the complex folding landscapes of templated peptide assembly. These insights have allowed for the construction of molecular hybrids of each biopolymer class and made possible the reimagining of chemical evolution. Such elaboration of biopolymer chimeras has already led to applications in therapeutics and diagnostics, to the construction of novel nanostructured materials, and toward orthogonal biochemical pathways that expand the evolution of existing biochemical systems. The ability to look beyond the primordial emergence of the ribosome may allow us to better define the origins of chemical evolution, to extend its horizons beyond the biology of today and ask whether evolution is an inherent property of matter unbounded by physical limitations imposed by our planet's diverse environments. PMID- 23098256 TI - "Direct cloning in Lactobacillus plantarum: electroporation with non-methylated plasmid DNA enhances transformation efficiency and makes shuttle vectors obsolete". AB - BACKGROUND: Lactic acid bacteria (LAB) play an important role in agricultural as well as industrial biotechnology. Development of improved LAB strains using e.g. library approaches is often limited by low transformation efficiencies wherefore one reason could be differences in the DNA methylation patterns between the Escherichia coli intermediate host for plasmid amplification and the final LAB host. In the present study, we examined the influence of DNA methylation on transformation efficiency in LAB and developed a direct cloning approach for Lactobacillus plantarum CD033. Therefore, we propagated plasmid pCD256 in E. coli strains with different dam/dcm-methylation properties. The obtained plasmid DNA was purified and transformed into three different L. plantarum strains and a selection of other LAB species. RESULTS: Best transformation efficiencies were obtained using the strain L. plantarum CD033 and non-methylated plasmid DNA. Thereby we achieved transformation efficiencies of ~ 10(9) colony forming units/MUg DNA in L. plantarum CD033 which is in the range of transformation efficiencies reached with E. coli. Based on these results, we directly transformed recombinant expression vectors received from PCR/ligation reactions into L. plantarum CD033, omitting plasmid amplification in E. coli. Also this approach was successful and yielded a sufficient number of recombinant clones. CONCLUSIONS: Transformation efficiency of L. plantarum CD033 was drastically increased when non-methylated plasmid DNA was used, providing the possibility to generate expression libraries in this organism. A direct cloning approach, whereby ligated PCR-products where successfully transformed directly into L. plantarum CD033, obviates the construction of shuttle vectors containing E. coli specific sequences, as e.g. a ColEI origin of replication, and makes amplification of these vectors in E. coli obsolete. Thus, plasmid constructs become much smaller and occasional structural instability or mutagenesis during E. coli propagation is excluded. The results of our study provide new genetic tools for L. plantarum which will allow fast, forward and systems based genetic engineering of this species. PMID- 23098255 TI - Generation and characterization of a lysosomally targeted, genetically encoded Ca(2+)-sensor. AB - Distinct spatiotemporal Ca2+ signalling events regulate fundamental aspects of eukaryotic cell physiology. Complex Ca2+ signals can be driven by release of Ca2+ from intracellular organelles that sequester Ca2+ such as the ER (endoplasmic reticulum) or through the opening of Ca2+-permeable channels in the plasma membrane and influx of extracellular Ca2+. Late endocytic pathway compartments including late-endosomes and lysosomes have recently been observed to sequester Ca2+ to levels comparable with those found within the ER lumen. These organelles harbour ligand-gated Ca2+-release channels and evidence indicates that they can operate as Ca2+-signalling platforms. Lysosomes sequester Ca2+ to a greater extent than any other endocytic compartment, and signalling from this organelle has been postulated to provide 'trigger' release events that can subsequently elicit more extensive Ca2+ signals from stores including the ER. In order to investigate lysosomal-specific Ca2+ signalling a simple method for measuring lysosomal Ca2+ release is essential. In the present study we describe the generation and characterization of a genetically encoded, lysosomally targeted, cameleon sensor which is capable of registering specific Ca2+ release in response to extracellular agonists and intracellular second messengers. This probe represents a novel tool that will permit detailed investigations examining the impact of lysosomal Ca2+ handling on cellular physiology. PMID- 23098257 TI - Modelling vertical transmission in vector-borne diseases with applications to Rift Valley fever. AB - We present two ordinary differential equation models for Rift Valley fever (RVF) transmission in cattle and mosquitoes. We extend existing models for vector-borne diseases to include an asymptomatic host class and vertical transmission in vectors. We define the basic reproductive number, R(0), and analyse the existence and stability of equilibrium points. We compute sensitivity indices of R(0) and a reactivity index (that measures epidemicity) to parameters for baseline wet and dry season values. R(0) is most sensitive to the mosquito biting and death rates. The reactivity index is most sensitive to the mosquito biting rate and the infectivity of hosts to vectors. Numerical simulations show that even with low equilibrium prevalence, increases in mosquito densities through higher rainfall, in the presence of vertical transmission, can result in large epidemics. This suggests that vertical transmission is an important factor in the size and persistence of RVF epidemics. PMID- 23098258 TI - Empirical use of fluoroquinolones improves the survival of critically ill patients with tuberculosis mimicking severe pneumonia. AB - INTRODUCTION: Empirical use of fluoroquinolones may delay the initiation of appropriate therapy for tuberculosis (TB). This study aimed to evaluate the impact of empirical fluoroquinolone use on the survival of patients with pulmonary TB that mimicked severe community-acquired pneumonia (CAP) requiring intensive care. METHODS: Patients aged >18 years with culture-confirmed pulmonary TB who presented as severe CAP and were admitted to the ICU were divided into fluoroquinolone (FQ) and nonfluoroquinolone (non-FQ) groups based on the type of empirical antibiotics used. Those patients with previous anti-TB treatment or those who died within 3 days of hospitalization were excluded. The primary end point was 100-day survival. RESULTS: Of the 77 patients identified, 43 (56%) were in the FQ group and 34 (44%) were in the non-FQ group. The two groups had no statistically significant difference in co-morbidities (95% vs. 97%, P > 0.99) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores (21.2 +/- 7.1 vs. 22.5 +/- 7.5, P = 0.46) on ICU admission. Overall, 91% and 82% of patients in the FQ and non-FQ groups, respectively, had sputum examinations for TB within 1 week of admission (P = 0.46), and results were positive in 7% and 15% (P = 0.47), respectively. For both groups, 29% received appropriate anti-TB therapy within 2 weeks after ICU admission. The 100-day mortality rate was 40% and 68% for the FQ and non-FQ groups, respectively (P = 0.02). By Cox regression analysis, APACHE score <20, no bacteremia during the ICU stay, and empirical fluoroquinolone use were independently associated with survival. CONCLUSION: Empirical use of fluoroquinolones may improve the survival of ICU patients admitted for pulmonary TB mimicking severe CAP. PMID- 23098259 TI - A hexanuclear mixed-valence oxovanadium(IV,V) complex as a highly efficient alkane oxidation catalyst. AB - The new hexanuclear mixed-valence vanadium complex [V(3)O(3)(OEt)(ashz)(2)(MU OEt)](2) (1) with an N,O-donor ligand is reported. It acts as a highly efficient catalyst toward alkane oxidations by aqueous H(2)O(2). Remarkably, high turnover numbers up to 25000 with product yields of up to 27% (based on alkane) stand for one of the most active systems for such reactions. PMID- 23098260 TI - Training working memory in kindergarten children: effects on working memory and early numeracy. AB - This study investigated the relationship between working memory and early numeracy. It aimed to explore the possibility of training young children's working memory and to investigate the effects of such training both on working memory and on the specific domain of early numerical skills. Measures of working memory and numeracy were used with low-performing children in kindergarten. A total of 51 five-year-old children received one of two different versions of working memory training or no training at all. The two versions differed in the type of information the children were given to practice: non-numerical or numerical. After a pretest, 4 weeks of intervention took place, followed by a posttest. Children who participated in one of the working memory interventions significantly improved their working memory skills. Furthermore, their early numeracy skills also improved. Differences between both experimental conditions were small. PMID- 23098261 TI - Facile functionalization of polyesters through thiol-yne chemistry for the design of degradable, cell-penetrating and gene delivery dual-functional agents. AB - Synthesis of polyesters bearing pendant amine groups with controlled molecular weights and narrow molecular weight distributions was achieved through ring opening polymerization of 5-(4-(prop-2-yn-1-yloxy)benzyl)-1,3-dioxolane-2,4 dione, an O-carboxyanhydride derived from tyrosine, followed by thiol-yne "click" photochemistry with 2-aminoethanethiol hydrochloride. This class of biodegradable polymers displayed excellent cell penetration and gene delivery properties with low toxicities. PMID- 23098263 TI - Sustained remission in a patient with myelodysplastic syndrome and a complex karyotype after erythropoiesis-stimulating therapy followed by colonic T-cell lymphoblastic lymphoma. PMID- 23098262 TI - How do surgeons decide to refer patients for adjuvant cancer treatment? Protocol for a qualitative study. AB - BACKGROUND: Non-small cell lung cancer, breast cancer, and colorectal cancer are commonly diagnosed cancers in Canada. Patients diagnosed with early-stage non small cell lung, breast, or colorectal cancer represent potentially curable populations. For these patients, surgery is the primary mode of treatment, with (neo)adjuvant therapies (e.g., chemotherapy, radiotherapy) recommended according to disease stage. Data from our research in Nova Scotia, as well as others', demonstrate that a substantial proportion of non-small cell lung cancer and colorectal cancer patients, for whom practice guidelines recommend (neo)adjuvant therapy, are not referred for an oncologist consultation. Conversely, surveillance data and clinical experience suggest that breast cancer patients have much higher referral rates. Since surgery is the primary treatment, the surgeon plays a major role in referring patients to oncologists. Thus, an improved understanding of how surgeons make decisions related to oncology services is important to developing strategies to optimize referral rates. Few studies have examined decision making for (neo)adjuvant therapy from the perspective of the cancer surgeon. This study will use qualitative methods to examine decision-making processes related to referral to oncology services for individuals diagnosed with potentially curable non-small cell lung, breast, or colorectal cancer. METHODS: A qualitative study will be conducted, guided by the principles of grounded theory. The study design is informed by our ongoing research, as well as a model of access to health services. The method of data collection will be in-depth, semi structured interviews. We will attempt to recruit all lung, breast, and/or colorectal cancer surgeons in Nova Scotia (n ~ 42), with the aim of interviewing a minimum of 34 surgeons. Interviews will be audiotaped and transcribed verbatim. Data will be collected and analyzed concurrently, with two investigators independently coding and analyzing the data. Analysis will involve an inductive, grounded approach using constant comparative analysis. DISCUSSION: The primary outcomes will be (1) identification of the patient, surgeon, institutional, and health-system factors that influence surgeons' decisions to refer non-small cell lung, breast, and colorectal cancer patients to oncology services when consideration for (neo)adjuvant therapy is recommended and (2) identification of potential strategies that could optimize referral to oncology for appropriate individuals. PMID- 23098264 TI - CCVJ is not a simple rotor probe. AB - The photochemistry of the rotor probe 9-(2-carboxy-2-cyanovinyl)julolidine (CCVJ) was studied to elucidate a curious effect of fluid flow previously reported. The apparent sensitivity to fluid motion observed in CCVJ but not in the closely related molecule 9-(dicyanovinyl)julolidine (DCVJ) is found to be an indirect effect of a photoisomerization reaction. The results presented here demonstrate that it is this isomerization, rather than the commonly assumed TICT process, that confers viscosity-sensing ability on these fluorophores. In micromolar solutions in hydroxylic solvents CCVJ exists primarily in the carboxylate form. Only the E isomer of this anion is initially present in solutions prepared from the solid, but in room light such solutions rapidly achieve a photostationary state in which the E isomer and an essentially nonfluorescent Z isomer exist in comparable concentrations. The Z isomer is metastable in S(0) such that in the absence of light the solution reverts slowly to pure E. Unlike DCVJ where only a single isomer is possible, the production of long-lived photoproducts in CCVJ and other asymmetrically substituted styryenyl probes complicates their fluorescence response. Considerable care is needed when such fluorphores are used as steady state sensors of environmental fluidity are used. PMID- 23098265 TI - Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. AB - The recent launch onto the market of five VEGFR inhibitors indicates the therapeutic value of these agents and the importance of the research in the field of angiogenesis inhibitors for future oncologic therapy. In this Perspective we briefly report the inhibitors that are in clinical use, while we dedicate two wider sections to the compounds that are in clinical trials and to the new derivatives appearing in the literature. We especially consider the medicinal chemistry aspect of the topic and report the structure-activity relationship studies and the binding mode of some inhibitors as well as the biological data of the compounds discovered in the past 5 years. PMID- 23098266 TI - Direct beta-acyloxylation of enamines via PhIO-mediated intermolecular oxidative C-O bond formation and its application to the synthesis of oxazoles. AB - A direct beta-acyloxylation of enamine compounds has been achieved by using iodosobenzene (PhIO) as an oxidant to realize the intermolecular oxidative C(sp(2))-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. The transformation tolerates a wide range of functional groups and furnishes a variety of beta-acyloxy enamines that can be conveniently converted to oxazole compounds via cyclodehydration. PMID- 23098267 TI - A new self-expandable transcatheter aortic valve for transapical implantation: feasibility in acute and chronic animal experiments. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) is currently expanding worldwide, however all available prostheses share some fundamental design drawbacks. We investigated the feasibility, safety and hemodynamic performance of the innovative transapical Acurate TATM self-expandable device, which has the unique advantage of offering anatomically correct self-alignment within the aortic root. DESIGN: Transapical TAVI was performed in six acute swine and six chronic sheep procedures, with follow-up of 7, 14, 21, 28, 60 and 90 days. TAVI was performed under TEE and angiographic guidance without rapid pacing. RESULTS: A partial sternotomy approach was used to access the LV-apex. All valve implantations were performed as planned and all animals survived the implantation procedure. After deployment, no migration, embolization or coronary obstruction was observed during the observation period. Intraoperative TEE examination identified no signs of intravalvular leakage or valve dysfunction. Transvalvular mean pressure gradients were 5.4 +/- 2.2 mmHg decreasing during follow-up (1.6 +/ 0.8 mmHg, 1.8 +/- 0.8 mmHg, 1.3 +/- 0.2, 1.8 +/- 0.7 mmHg, 1.6 +/- 0.8 mmHg), with a slight increase atday 90 (4.0 +/- 2.4 mmHg, P < 0.05). Macroscopic examination at necropsy showed correct anatomical positioning of the valve stent without any signs of structural valve deterioration. CONCLUSIONS: These first results of the innovative self-expandable transapical ACURATE TATM device explore the feasibility and safety of anatomically correct off-pump implantation with optimal hemodynamic results. PMID- 23098268 TI - On avoiding framing effects in experienced decision makers. AB - The present study aimed to (a) demonstrate the effect of positive-negative framing on experienced criminal justice decision makers, (b) examine the debiasing effect of visually structured risk messages, and (c) investigate whether risk perceptions mediate the debiasing effect of visual aids on decision making. In two phases, 60 senior police officers estimated the accuracy of a counterterrorism technique in identifying whether a known terror suspect poses an imminent danger and decided whether they would recommend the technique to policy makers. Officers also rated their confidence in this recommendation. When information about the effectiveness of the counterterrorism technique was presented in a numerical format, officers' perceptions of accuracy and recommendation decisions were susceptible to the framing effect: The technique was perceived to be more accurate and was more likely to be recommended when its effectiveness was presented in a positive than in a negative frame. However, when the information was represented visually using icon arrays, there were no such framing effects. Finally, perceptions of accuracy mediated the debiasing effect of visual aids on recommendation decisions. We offer potential explanations for the debiasing effect of visual aids and implications for communicating risk to experienced, professional decision makers. PMID- 23098269 TI - Measuring romantic love: psychometric properties of the infatuation and attachment scales. AB - Romantic love is ubiquitous and has major influences on people's lives. Because romantic love consists of infatuation and attachment, researchers need to be able to differentiate between these constructs when examining the behavioral, affective, cognitive, and physiological correlates of this intriguing phenomenon. Existing love questionnaires appear less suitable for measuring the two dimensional construct of romantic love. We present here the new 20-item Infatuation and Attachment Scales (IAS) questionnaire. In Study 1, exploratory factor analyses in a Dutch-speaking sample (n = 162) revealed a clear-cut two factor structure, with 10 infatuation and 10 attachment items loading on separate components. This two-factor structure was confirmed in a new Dutch-speaking sample (n = 214, Study 2), and in an English-speaking sample (n = 183, Study 3). In all studies, it was additionally shown that both scales possessed good convergent and discriminant validity, as well as excellent internal consistency and test-retest reliability. We argue that the IAS is a widely applicable, psychometrically sound instrument that will be useful in future research exploring the effects of infatuation and attachment on behavior, emotion, cognition, peripheral physiology, and brain functioning. PMID- 23098270 TI - A strategy for the study of the interactions between metal-dyes and proteins with QM/MM approaches: the case of iron-gall dye. AB - Historical textiles dyed with tannins usually show more extended degradation than fabrics dyed with other coloring materials. In order to shed light on this phenomenon we investigated the molecular interactions between tannin dyes and protein-based textiles using quantum-mechanical tools. In particular, we focused on the iron-gall complex with a fragment of alpha-helix wool keratin. We developed a step by step protocol which moves from the simplest ternary complexes with free amino acids (all treated quantum mechanically) to the more realistic system of the polypeptide fragment (treated at QM/MM level), passing through an intermediate model of interacting sites to evaluate the local environmental effects. The analysis of the interactions between the iron-gall complexes and free amino acids allowed us to identify possible coordination modes as well as determining their relative geometries. However, we also showed that only with the addition of the proteic environment a detailed picture of the interaction sites and binding modes can be achieved. An important role is in fact played by the microenvironment which can favor specific coordinations with respect to others due to both structural and electronic changes in the possible interaction sites. PMID- 23098271 TI - Organelle-localizable fluorescent chemosensors for site-specific multicolor imaging of nucleoside polyphosphate dynamics in living cells. AB - ATP and its derivatives (nucleoside polyphosphates (NPPs)) are implicated in many biological events, so their rapid and convenient detection is important. In particular, live cell detection of NPPs at specific local regions of cells could greatly contribute understanding of the complicated roles of NPPs. We report herein the design of two new fluorescent chemosensors that detect the dynamics of NPPs in specific regions of living cells. To achieve imaging of NPPs on plasma membrane surfaces (2-2Zn(II)), a lipid anchor was introduced into xanthene-based Zn(II) complex 1-2Zn(II), which was previously developed as a turn-on type fluorescent chemosensor for NPPs. Meanwhile, for subcellular imaging of ATP in mitochondria, we designed rhodamine-type Zn(II) complex 3-2Zn(II), which possesses a cationic pyronin ring instead of xanthene. Detailed spectroscopic studies revealed that 2-2Zn(II) and 3-2Zn(II) can sense NPPs with a several-fold increase of their fluorescence intensities through a sensing mechanism similar to 1-2Zn(II), involving binding-induced recovery of the conjugated form of the xanthene or pyronin ring. In live cell imaging, 2-2Zn(II) containing a lipid anchor selectively localized on the plasma membrane surface and detected the extracellular release of NPPs during cell necrosis induced by streptolysin O. On the other hand, rhodamine-type complex 3-2Zn(II) spontaneously localized at mitochondria inside cells, and sensed the local increase of ATP concentration during apoptosis. Multicolor images were obtained through simultaneous use of 2 2Zn(II) and 3-2Zn(II), allowing detection of the dynamics of ATP in different cellular compartments at the same time. PMID- 23098273 TI - Romantic relationship development in the age of Facebook: an exploratory study of emerging adults' perceptions, motives, and behaviors. AB - Social networking sites are becoming a prevalent form of communication in the escalation of romantic relationships. An online survey (n=403) addressed emerging adults' experiences with Facebook and romantic relationships, particularly a unique affordance of Facebook: the ability to declare oneself as "In a Relationship" and actively link one's profile to a romantic partner's, commonly known as going Facebook official. Results identified common social perceptions of the meaning of this status (regarding commitment, intensity, and social response) and both interpersonal and social motives for posting it on Facebook. Additionally, sex differences were identified in perceptions of meaning, wherein women felt this status conveyed commitment and intensity moreso than men did. Implications of this discrepancy on heterosexual relationship satisfaction and the prevailing role of technology in romantic relationships are discussed. PMID- 23098272 TI - Bioplasmonic paper as a platform for detection of kidney cancer biomarkers. AB - We demonstrate that a common laboratory filter paper uniformly adsorbed with biofunctionalized plasmonic nanostructures can serve as a highly sensitive transduction platform for rapid detection of trace bioanalytes in physiological fluids. In particular, we demonstrate that bioplasmonic paper enables rapid urinalysis for the detection of kidney cancer biomarkers in artificial urine down to a concentration of 10 ng/mL. Compared to conventional rigid substrates, bioplasmonic paper offers numerous advantages such as high specific surface area (resulting in large dynamic range), excellent wicking properties (naturally microfluidic), mechanical flexibility, compatibility with conventional printing approaches (enabling multiplexed detection and multimarker biochips), and significant cost reduction. PMID- 23098274 TI - Functionalization of the [closo-1-CB9H10]- anion for the construction of new classes of liquid crystals. AB - The [closo-1-CB(9)H(10)](-) anion is a member of an extensive family of sigma aromatic closo-boranes that possess impressive stability and functionalization characteristics. In contrast to its bigger, more extensively studied brother, the [closo-1-CB(11)H(12)](-) anion, convenient access to the [closo-1-CB(9)H(10)](-) anion has only been recently established, and researchers have only begun to develop and understand its fundamental chemistry. The geometrical and electronic properties of the [closo-1-CB(9)H(10)](-) anion make it an attractive structural element of novel classes of either zwitterionic or ionic liquid crystals suitable for electro-optical and ion transport applications, respectively. Such materials require a 1,10-difunctionalized [closo-1-CB(9)H(10)](-) anion that permits for the formation of molecules of elongated shape. The covalent attachment of an onium fragment or the use of a counterion compensates for the negative charge. This Account highlights the progress made in the advancement and understanding of the fundamental chemistry of the [closo-1-CB(9)H(10)](-) anion. We also describe the development of 1,10-difunctionalized derivatives as key intermediates in the preparation of new classes of liquid crystalline materials. We obtained the first isomerically pure 1,10-difunctionalized derivative of the [closo-1 CB(9)H(10)](-) anion, iodo acid [closo-1-CB(9)H(8)-1-COOH-10-I](-), from decaborane through the Brellochs reaction. Functional group transformation of the C(1)-carboxyl group led to a 1-amino derivative and, subsequently, to a synthetically valuable 1-dinitrogen derivative. The latter exhibits reactivity typical for PhN(2)(+) and undergoes diazocoupling and Gomberg-Bachmann arylation reactions. The B(10)-iodine participated in Negishi alkylation and Buchwald Hartwig amination reactions, leading to 10-hexyl and 10-amino carboxylic acids, respectively. We converted the 10-amino carboxylic acid to a 10-dinitrogen acid [closo-1-CB(9)H(8)-1-COOH-10-N(2)], which proved to be synthetically valuable in the preparation of 10-pyridinium and 10-sulfonium zwitterionic acids and their liquid crystalline esters. We investigated several intermediates using structural, spectroscopic, and kinetic methods. PMID- 23098275 TI - Experimental study on anti-tumor and anti-inflammatory effect of Thespesia populnea phytochemical extract in mice models. AB - In the present study, we have conducted a dose- and duration-dependent response of phytochemical extract of Thespesia populnea (Malvaceae) plant native of costal forest of India. Our earlier studies revealed the anti-oxidant and chemoprotective effect of this plant extract. In the present study, we have attempted to study the anti-tumor and anti-inflammatory response of T. populnea using experimental mouse models. Our studies revealed that administration of T. populnea methanol extract was shown to inhibit the solid tumor development in mice. T. populnea treatment significantly reduced tumor cell glutathione (GSH) levels as well as serum gamma-glutamyl transpeptidase (GGT) and nitric oxide (NO) levels in the tumor-bearing animals (p < 0.01). The total white blood cell count and hemoglobin levels were also significantly increased in extract-treated hosts (p < 0.05, p < 0.01). The use of T. populnea substantially reduced the acute inflammation (assessed as paw edema) induced by carrageenan and also reduced inflammation edema induced by formalin. These studies suggest that T. populnea extract could be used as a (natural) anti-inflammatory and anti-tumor agent. PMID- 23098276 TI - Characterization of Staphylococcus aureus EssB, an integral membrane component of the Type VII secretion system: atomic resolution crystal structure of the cytoplasmic segment. AB - The Type VII protein translocation/secretion system, unique to Gram-positive bacteria, is a key virulence determinant in Staphylococcus aureus. We aim to characterize the architecture of this secretion machinery and now describe the present study of S. aureus EssB, a 52 kDa bitopic membrane protein essential for secretion of the ESAT-6 (early secretory antigenic target of 6 kDa) family of proteins, the prototypic substrate of Type VII secretion. Full-length EssB was heterologously expressed in Escherichia coli, solubilized from the bacterial membrane, purified to homogeneity and shown to be dimeric. A C-terminal truncation, EssB?C, and two soluble fragments termed EssB-N and EssB-C, predicted to occur on either side of the cytoplasmic membrane, have been successfully purified in a recombinant form, characterized and, together with the full-length protein, used in crystallization trials. EssB-N, the 25 kDa N-terminal cytoplasmic fragment, gave well-ordered crystals and we report the structure, determined by SAD (single-wavelength anomalous diffraction) targeting an SeMet (selenomethionine) derivative, refined to atomic (1.05 A; 1 A=0.1 nm) resolution. EssB-N is dimeric in solution, but crystallizes as a monomer and displays a fold comprised of two globular domains separated by a cleft. The structure is related to that of serine/threonine protein kinases and the present study identifies that the Type VII secretion system exploits and re-uses a stable modular entity and fold that has evolved to participate in protein-protein interactions in a similar fashion to the catalytically inert pseudokinases. PMID- 23098277 TI - Malaria research challenges in low prevalence settings. AB - The prevalence of malaria has reduced significantly in some areas over the past decade. These reductions have made local elimination possible and the research agenda has shifted to this new priority. However, there are critical issues that arise when studying malaria in low transmission settings, particularly identifying asymptomatic infections, accurate detection of individuals with microparasitaemic infections, and achieving a sufficient sample size to have an adequately powered study. These challenges could adversely impact the study of malaria elimination if they remain unanswered. PMID- 23098279 TI - Infections following the application of leeches: two case reports and review of the literature. AB - INTRODUCTION: Since the 1980s, leeches have been ingeniously used in the management of venous flap congestion. The presence of anticoagulative substances in their saliva improves the blood drainage. Their digestive tract contains several bacterial species, the main ones being Aeromonas hydrophila and Aeromonas veronii biovar sobria, which contribute to the digestion of ingested blood. These bacteria can be the cause of infections. CASE PRESENTATION: We report two cases of septicemia related to Aeromonas veronii biovar sobria that presented after leeches had been applied to congested transverse rectus abdominis myocutaneous flaps for delayed mammary reconstructions.Patient number 1 was a 55-year-old Caucasian woman who underwent a delayed breast reconstruction procedure. On the sixth postoperative day she showed a clinical presentation of septicemia. Aeromonas veronii biovar sobria was identified in the patient's skin and blood bacteriological samples. Her fever ceased after 4 days of antibiotic treatment.Patient number 2 was a 56-year-old Caucasian woman who underwent a delayed breast reconstruction procedure. On the seventh postoperative day we noticed that she showed a clinical presentation of septicemia. Aeromonas veronii biovar sobria was identified in the patient's blood cultures and local bacteriological samples. An antibiogram showed resistance to amoxicillin/clavulanic acid. Her fever ceased on the eleventh postoperative day after 4 days of antibiotic treatment. CONCLUSION: The rate of infection after application of leeches is not negligible. The concentration of Aeromonas inside the digestive tracts of leeches largely decreases when the patient is under antibiotic therapy. These germs are sensitive to third-generation cephalosporins and fluoroquinolones and resistant to amoxicillin/clavulanic acid. We recommend preventive treatment based on classical measures of asepsis and on oral antibioprophylaxy with a fluoroquinolone during the whole period of treatment by leeches. PMID- 23098278 TI - Matching positive end-expiratory pressure to intra-abdominal pressure improves oxygenation in a porcine sick lung model of intra-abdominal hypertension. AB - INTRODUCTION: Intra-abdominal hypertension (IAH) causes atelectasis, reduces lung volumes and increases respiratory system elastance. Positive end-expiratory pressure (PEEP) in the setting of IAH and healthy lungs improves lung volumes but not oxygenation. However, critically ill patients with IAH often suffer from acute lung injury (ALI). This study, therefore, examined the respiratory and cardiac effects of positive end-expiratory pressure in an animal model of IAH, with sick lungs. METHODS: Nine pigs were anesthetized and ventilated (48 +/- 6 kg). Lung injury was induced with oleic acid. Three levels of intra-abdominal pressure (baseline, 18, and 22 mmHg) were randomly generated. At each level of intra-abdominal pressure, three levels of PEEP were randomly applied: baseline (5 cmH2O), moderate (0.5 * intra-abdominal pressure), and high (1.0 * intra abdominal pressure). We measured end-expiratory lung volumes, arterial oxygen levels, respiratory mechanics, and cardiac output 10 minutes after each new IAP and PEEP setting. RESULTS: At baseline PEEP, IAH (22 mmHg) decreased oxygen levels (-55%, P <0.001) and end-expiratory lung volumes (-45%, P = 0.007). At IAP of 22 mmHg, moderate and high PEEP increased oxygen levels (+60%, P = 0.04 and +162%, P <0.001) and end-expiratory lung volume (+44%, P = 0.02 and +279%, P <0.001) and high PEEP reduced cardiac output (-30%, P = 0.04). Shunt and dead space fraction inversely correlated with oxygen levels and end-expiratory lung volumes. In the presence of IAH, lung, chest wall and respiratory system elastance increased. Subsequently, PEEP decreased respiratory system elastance by decreasing chest wall elastance. CONCLUSIONS: In a porcine sick lung model of IAH, PEEP matched to intra-abdominal pressure led to increased lung volumes and oxygenation and decreased chest wall elastance shunt and dead-space fraction. High PEEP decreased cardiac output. The study shows that lung injury influences the effects of IAH and PEEP on oxygenation and respiratory mechanics. Our findings support the application of PEEP in the setting of acute lung injury and IAH. PMID- 23098281 TI - Toxicity and outcome of intensity-modulated radiotherapy versus 3-dimensional conformal radiotherapy for oropharyngeal cancer: a matched-pair analysis. AB - Because of the scarcity of randomized trials comparing toxicity and outcomes of intensity-modulated radiotherapy (IMRT) for oropharyngeal cancer (OPC) with 3D conformal radiotherapy (3DCRT), we performed a matched-pair analysis from prospectively collected data from the Head and Neck Tumor Registry of our institution. In the absence of phase III trials, we believe this approach provides the highest quality data possible. Ninety-two patients treated with 3DCRT were matched (1:1) to 92 patients treated with IMRT for 9 potential predictive factors for toxicity and outcome: gender, age, T-stage, N-stage, tumor subsite, unilateral neck irradiation, chemotherapy, neck dissection and boost technique. Groups were compared for acute and late toxicity, locoregional control (LRC), disease-free survival (DFS), and overall survival (OS). Oncologic outcomes were estimated using Kaplan-Meier analyses and toxicity was analyzed according to Common Terminology Criteria for Adverse Events v3.0. The overall incidence of grade 3 acute toxicity was significantly reduced by IMRT, compared to 3DCRT (45% vs. 70%, p = 0.001). The need for tube feeding was reduced from 50% to 37% (p = 0.04). The 3-year actuarial incidence of grade >=2 late toxicity was also significantly reduced by IMRT, compared to 3DCRT (20% vs. 45%, respectively; p <= 0.0001). The incidence of grade >= 2 late dysphagia and xerostomia for IMRT vs. 3DCRT were 10% vs. 31% for dysphagia, p = 0.004 and 13% vs. 37%, for xerostomia, respectively (p = 0.001). The 3-year Kaplan-Meier estimates of LRC, DFS, and OS for IMRT vs. 3DCRT were 90% vs. 82% (p = 0.1), 82% vs. 76% (p = 0.3), and 72% vs. 64% (p = 0.2), respectively. In conclusion, the presented non-randomized comparative study of well-matched groups demonstrates the superiority of IMRT vs. 3DCRT for OPC by significantly reducing radiation-induced toxicity without jeopardizing outcomes. The improved therapeutic ratio achieved by the use of IMRT would allow dose escalation of radiotherapy to further improve outcomes of patients with OPC. PMID- 23098282 TI - A comparative analysis of radiobiological models for cell surviving fractions at high doses. AB - For many years the linear-quadratic (LQ) model has been widely used to describe the effects of total dose and dose per fraction at low-to-intermediate doses in conventional fractionated radiotherapy. Recent advances in stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) have increased the interest in finding a reliable cell survival model, which will be accurate at high doses, as well. Different models have been proposed for improving descriptions of high dose survival responses, such as the Universal Survival Curve (USC), the Kavanagh-Newman (KN) and several generalizations of the LQ model, e.g. the Linear-Quadratic-Linear (LQL) model and the Pade Linear Quadratic (PLQ) model. The purpose of the present study is to compare a number of models in order to find the best option(s) which could successfully be used as a fractionation correction method in SRT. In this work, six independent experimental data sets were used: CHOAA8 (Chinese hamster fibroblast), H460 (non small cell lung cancer, NSLC), NCI-H841 (small cell lung cancer, SCLC), CP3 and DU145 (human prostate carcinoma cell lines) and U1690 (SCLC). By detailed comparisons with these measurements, the performance of nine different radiobiological models was examined for the entire dose range, including high doses beyond the shoulder of the survival curves. Using the computed and measured cell surviving fractions, comparison of the goodness-of-fit for all the models was performed by means of the reduced chi (2)-test with a 95% confidence interval. The obtained results indicate that models with dose-independent final slopes and extrapolation numbers generally represent better choices for SRT. This is especially important at high doses where the final slope and extrapolation numbers are presently found to play a major role. The PLQ, USC and LQL models have the least number of shortcomings at all doses. The extrapolation numbers and final slopes of these models do not depend on dose. Their asymptotes for the cell surviving fractions are exponentials at low as well as high doses, and this is in agreement with the behaviour of the corresponding experimental data. This is an important improvement over the LQ model which predicts a Gaussian at high doses. Overall and for the highlighted reasons, it was concluded that the PLQ, USC and LQL models are theoretically well-founded. They could prove useful compared to the other proposed radiobiological models in clinical applications for obtaining uniformly accurate cell surviving fractions encountered in stereotactic high-dose radiotherapy as well as at medium and low doses. PMID- 23098284 TI - Effects of alignment of adjustable collimator on dosimetric parameters of a telecobalt machine. AB - The objectives of this study was to investigate the most appropriate hinge point for the alignment of adjustable collimators/trimmer bars in a telecobalt machine for obtaining acceptable dosimetric parameters of a telecobalt machine. Variations of relative output of the telecobalt machine with selection of different hinge points were also investigated. MCNP code was used for the present the study. A water phantom of dimension 50 x 50 x 40 cm(3) having voxels each of volume 0.72 cm(3) was used in our study for generating beam profiles and depth dose curves. When hinge points are selected at the periphery of the source bottom and the source top, flatness, symmetry and penumbra were found to be well within the recommended tolerance limits whereas values are far beyond with the hinge points selected at the centre of source bottom or the source top. Moreover, it was observed that the relative output of a telecobalt machine with hinge points at centre of the source bottom and the source top are appreciably lower than that of at periphery of source bottom particularly for smaller field sizes. This effect is due to the blockage of the part of the source volume in the radiation field. Therefore, hinge point for the alignment of adjustable collimators/trimmer bars should be selected either at periphery of source bottom or the source top for obtaining clinically acceptable flatness, symmetry and penumbra. However, selecting hinge point at the periphery of the source bottom for the alignment of the adjustable collimators/trimmer bars would be more appropriate as height of the source will vary depending on activity of the source used in the source capsule for given specific activity. PMID- 23098283 TI - Time-domain microwave breast cancer detection: extensive system testing with phantoms. AB - Early detection of breast cancer is known to be a key factor in the successful treatment of the disease. Here, we present a detection technique complementary to the currently used modalities (primarily mammography, ultrasound and magnetic resonance imaging). Our time-domain breast cancer detection system transmits microwave-range pulses into the breast and records the scattering off of the breast in order to detect malignancies. This method is made possible by an intrinsic contrast in the dielectric parameters, specifically the relative permittivity and conductivity, of the healthy and malignant breast tissues over the microwave frequency range. The long-term goal of our work is to develop a system that can be used periodically to monitor for unusual changes in breast tissues; for instance, healthy breasts would be scanned, and follow-up scans at regular intervals would detect any small changes in breast tissue composition that could indicate the presence of a malignant growth. At that point, the patient would be referred to see a doctor for further investigation of the abnormal results. Such a system would compare each new scan with previous ones to determine the level of tissue changes, and would be used by patients at home. We report feasibility and performance tests for our initial system, conducted with breast phantoms made up of tissue-mimicking materials (unique skin, fat, gland and tumor mixtures). We initiated the system testing with simple homogeneous phantoms, consisting solely of adipose tissue. Then, we extended our tests to cases of increasing complexity by adding a skin layer and varying percentages of glandular structures and tumor sizes. In order to optimize the experimental system, we performed tests with multiple antenna arrangements, tumor sizes and locations. This work shows that there are specific antenna arrangements that are advantageous for tumor detection and demonstrates the capabilities of our time domain microwave breast tumor detection system. PMID- 23098285 TI - Simultaneous integrated boost in breast conserving radiotherapy: is replanning necessary following tumor bed change? AB - Tumor bed (TB) change is often seen during the whole breast irradiation (WBI) in early breast cancer patients. The aims of this study were to evaluate change in seroma volume on repeat CTs and to explore whether replanning is necessary in breast conserving radiotherapy (RT) using the intensity modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB). Thirty patients underwent WBI with 84 CT scans (24 with 3 CTs (CT1, CT2 and CT3) and 6 without CT3) during the 6 weeks of RT were reviewed. TB and other target volumes on all CTs were delineated and compared. IMRT-SIB treatment plans with 50.68 Gy to the whole breast and 64.4 Gy to the boost in 28 fractions were constructed in the CT1. Replan and hybrid plan (without replanning) in the CT2 were reproduced. Dosimetric differences between the replans and hybrid plans were also compared. The mean TB volumes for CT1, CT2 and CT3 were 42.1 cm(3), 20.1 cm(3), 17.0 cm(3), respectively. The mean TB volume reduction was 40.5% from the CT1 to CT2 and 4.3% from the CT2 to CT3. The difference of TB volumes between the CT1 and CT2 was statistically significance (p < 0.001), but not significant between the CT2 and CT3 (p = 1.000). For all patients, target coverage remained adequate with either hybrid plans or replans. However, replanning can significantly decrease the whole breast mean dose (35.2 vs. 35.6 Gy, p = 0.026) and breast volume outside the boost receiving 95% of the boost prescribed dose (39.5 vs. 68.2 cm(3), p < 0.001). In summary, boost volume could irradiate adequately after the significance shrinkage of tumor bed with the fractionated schedule of IMRT-SIB, but replanning on a second CT could avoid the undesired high dose irradiated breast tissue outside boost. PMID- 23098286 TI - Impact of a disease management-health promotion nurse intervention on personal assistance use and expenditures. AB - The purpose of this study is to evaluate the effect of a primary care affiliated disease management-health promotion nurse intervention on paid personal assistance (PA) use and expenditures among Medicare beneficiaries with disabilities. We analyzed data on 570 community-dwelling Medicare beneficiaries aged 65 years and older who participated in the Medicare Primary and Consumer Directed Care Demonstration, a randomized controlled trial. We estimated a two part model to test the effect of the nurse intervention on PA use and expenditures during the 2 years after study entry. Adjusting for covariates, average annual PA expenditures were $1,464 (29%) lower per person in the intervention group as compared to the control group. The findings of this study will help policy makers and practitioners understand the potential benefit of primary care affiliated nurse home visiting interventions on PA expenditures. PMID- 23098287 TI - Caregiver assessment of support need, reaction to care, and assessment of depression. AB - The aims of this study were to: (a) identify New Zealand informal carers' support needs; (b) assess caregivers' depression; and (c) assess positive and negative aspects of caregiving. A sample of 287 carers from throughout New Zealand was recruited by advertisements in carer support organizations literature, in 2008. Data were collected using Centre for Epidemiologic Short Depression scale (CES D10), Caregivers Reaction Assessment scale (CRA), and open-ended questions. Carer burden was significant (p <= .01) in the 60 to 69 age group. The relationship between CRA and CES-D10 in carers in the 50 to 59, 60 to 69 carer age groups; and 0 to 29, 60 to 69, 70 to 79, and 80 plus care recipient age groups were also significant. Mean burden was highest in the 50 to 59 age group (77/120) with depression mean highest in the 30 to 39 age group (14/30). Carers commonly discussed the adverse effects of caregiving on identity, lifestyle, health, and financial situation. Lack of information, poor respite care, and combining work with care were major frustrations. If the government wishes to successfully pursue initiatives allowing people to remain at home, more resources are needed to adequately support carers. PMID- 23098288 TI - Functional status assessment for community long-term care: preliminary observations. AB - The Community Long-Term Care (CLTC) program in South Carolina offers services to nursing home eligible persons that allow them to remain at home and receive help with activities of daily living. Variation in the ways potential clients are evaluated often produces inconsistent eligibility determinations. We developed a simple, objective assessment tool to complement CLTC evaluations. A conceptual framework, based on Nagi's model of disablement, was tested on community-dwelling healthy older adults and CLTC clients. Three simple physiologic tasks assessing mobility, functional leg strength, and manual dexterity discriminated between community-dwelling older adults and CLTC clients, classifying them with 80% to 90% accuracy. PMID- 23098289 TI - Photoinduced ligand exchange and covalent DNA binding by two new dirhodium bis amidato complexes. AB - Two new dirhodium complexes, the head-to-tail (H,T) and head-to-head (H,H) isomers of cis-[Rh(2)(HNOCCH(3))(2)(CH(3)CN)(6)](2+), were synthesized, separated, and characterized following the reaction of Rh(2)(HNOCCH(3))(4) with trimethyloxonium tetrafluoroborate in CH(3)CN. The products were characterized by (1)H NMR spectroscopy, mass spectrometry, elemental analysis, and single crystal X-ray diffraction. Each bis-amidato isomer has a total of six CH(3)CN ligands, two along the internuclear Rh-Rh axis, CH(3)CN(ax), two in equatorial positions trans to the oxygen atoms of the bridging amidato groups, CH(3)CN(eq)(O), and two in equatorial positions trans to the amidato nitrogen atoms, CH(3)CN(eq)(N). When aqueous solutions of the complexes are irradiated with low energy light (lambda(irr) >= 495 nm, 60 min), both types of CH(3)CN(eq) ligands undergo efficient ligand exchange with solvent H(2)O molecules to form monoaqua, followed by bis-aqua, adducts, releasing two CH(3)CN(eq) ligands in the process. The quantum yields, Phi(400nm), for the H,T and H,H isomers to form monoaqua adducts are 0.43 and 0.38, respectively, which are substantially greater than the 0.13 yield observed for cis-[Rh(2)(O(2)CCH(3))(2)(CH(3)CN)(6)](2+); importantly, no ligand exchange is observed when the complexes are kept in the dark. Finally, low energy excitation (lambda(irr) >= 610 nm, 30 min) of the H,T isomer was shown to generate photoproducts that covalently bind to linearized DNA, making 2 a potential agent for photochemotherapy that does not require the formation of (1)O(2), as is typical of organic photodynamic therapy (PDT) agents. PMID- 23098290 TI - Hepatitis A in Puglia (South Italy) after 10 years of universal vaccination: need for strict monitoring and catch-up vaccination. AB - BACKGROUND: Raw seafood consumption was identified as the major risk factor for hepatitis A during the large epidemic of 1996 and 1997 in Puglia (South Italy). In Puglia, vaccination for toddlers and preadolescents has been recommended since 1998.The aim of the study was to evaluate the incidence, seroprevalence, molecular epidemiology, and environmental circulation of hepatitis A virus (HAV) in Puglia more than ten years after the introduction of anti-HAV vaccination in the regional immunization program. METHODS: Data on the incidence of acute hepatitis A in Puglia were analyzed. Characteristics and risk factors of 97 acute hepatitis A cases occurring in 2008-2009 were analyzed. Serum samples from 868 individuals aged 0 to 40 years were tested for anti-HAV antibodies. Fecal samples from 49 hepatitis A cases were analyzed by sequence analysis in the VP1/P2A region. In 2008, 203 mussel samples and 202 water samples from artesian wells were tested for HAV-RNA. RESULTS: Between 1998 and 2009, the incidence of acute hepatitis A declined from 14.8 to 0.8 per 100,000. The most frequent risk factors reported by cases in 2008-2009 were shellfish consumption (85%) and travel outside of Puglia or Italy (26%). Seroepidemiologic survey revealed high susceptibility to HAV in children and adults up to age 30 (65%-70%). None of the mussel or water samples were HAV-positive. Phylogenetic analysis revealed co circulation of subtypes IA (74%) and IB (26%) and clustering of strains with strains from Germany and France, and those previously circulating in Puglia. CONCLUSION: Vaccination and improved sanitation reduced the incidence of hepatitis A. Strict monitoring and improved vaccination coverage are needed to prevent disease resurgence. PMID- 23098291 TI - Sources of non-compliance with clinical practice guidelines in trauma triage: a decision science study. AB - BACKGROUND: United States trauma system guidelines specify when to triage patients to specialty centers. Nonetheless, many eligible patients are not transferred as per guidelines. One possible reason is emergency physician decision-making. The objective of the study was to characterize sensory and decisional determinants of emergency physician trauma triage decision-making. METHODS: We conducted a decision science study using a signal detection theory informed approach to analyze physician responses to a web-based survey of 30 clinical vignettes of trauma cases. We recruited a national convenience sample of emergency medicine physicians who worked at hospitals without level I/II trauma center certification. Using trauma triage guidelines as our reference standard, we estimated physicians' perceptual sensitivity (ability to discriminate between patients who did and did not meet guidelines for transfer) and decisional threshold (tolerance for false positive or false negative decisions). RESULTS: We recruited 280 physicians: 210 logged in to the website (response rate 74%) and 168 (80%) completed the survey. The regression coefficient on American College of Surgeons--Committee on Trauma (ACS-COT) guidelines for transfer (perceptual sensitivity) was 0.77 (p<0.01, 95% CI 0.68-0.87) indicating that the probability of transfer weakly increased as the ACS-COT guidelines would recommend transfer. The intercept (decision threshold) was 1.45 (p<0.01, 95% CI 1.27-1.63), indicating that participants had a conservative threshold for transfer, erring on the side of not transferring patients. There was significant between-physician variability in perceptual sensitivity and decisional thresholds. No physician demographic characteristics correlated with perceptual sensitivity, but men and physicians working at non-trauma centers without a trauma-center affiliation had higher decisional thresholds. CONCLUSIONS: On a case vignette-based questionnaire, both sensory and decisional elements in emergency physicians' cognitive processes contributed to the under-triage of trauma patients. PMID- 23098292 TI - ZAP-70 expression and proliferative activity in chronic lymphocytic leukemia. AB - The expression of 70 kDa protein zeta-associated protein (ZAP-70) in chronic lymphocytic leukemia (CLL) has been used to detect those patients with more aggressive disease. The aim of this study was to determine the proliferative activity of ZAP-70(+) leukemic cells by immunocytochemical methods. The study was undertaken on native blood marrow (BM) and peripheral blood (PB) smears from 65 patients with CLL. ZAP-70 was expressed in leukemic cells of 35 patients (54%). We demonstrated that ZAP-70 immunoreactivity correlated with Rai 0-IV (p = 0.002) and Binet A-C stages (p < 0.001), total tumor mass (TTM score) (p < 0.001), beta2 microglobulin (p = 0.006), atypical lymphocytes (p < 0.001) and proliferative activity in bone marrow and peripheral blood (p = 0.014, p = 0.002, respectively) using chi(2) test and Mann-Whitney test. ZAP-70 protein expression is in direct correlation with the poorer prognostic parameters, which additionally confirms the successful method of detection of ZAP-70 expression. Higher Ki-67 expression in BM and PB smears of patients with ZAP-70(+) disease indicates higher proliferating compartments, which may contribute to poorer prognosis. PMID- 23098294 TI - Cognitive impairment in euthymic major depressive disorder: a meta-analysis. AB - BACKGROUND: There is evidence to suggest that cognitive deficits might persist beyond the acute stages of illness in major depressive disorder (MDD). However, the findings are somewhat inconsistent across the individual studies conducted to date. Our aim was to conduct a systematic review and meta-analysis of existing studies that have examined cognition in euthymic MDD patients. METHOD: Following a systematic search across several publication databases, meta-analyses were conducted for 27 empirical studies that compared euthymic adult MDD patients (895 participants) and healthy controls (997 participants) across a range of cognitive domains. The influence of demographic variables and confounding factors, including age of onset and recurrent episodes, was examined. RESULTS: Compared with healthy controls, euthymic MDD patients were characterized by significantly poorer cognitive functions. However, the magnitude of observed deficits, with the exception of inhibitory control, were generally modest when late-onset cases were excuded. Late-onset cases demonstrated significantly more pronounced deficits in verbal memory, speed of information processing and some executive functions. CONCLUSIONS: Cognitive deficits, especially poor response inhibition, are likely to be persistent features, at least of some forms, of adult-onset MDD. More studies are necessary to examine cognitive dysfunction in remitted psychotic, melancholic and bipolar spectrum MDD. Cognitive deficits overall appear to be more common among patients with late-onset depression, supporting the theories suggesting that possible vascular and neurodegenerative factors play a role in a substantial number of these patients. PMID- 23098295 TI - Gassman's cationic [2 + 2] cycloadditions using temporary tethers. AB - An intermolecular equivalent of Gassman's cationic [2 + 2] cycloaddition through the use of temporary tethering is described. Notably, hydrazine and hydroxyamide proved to be robust under the acidic conditions required for the cycloaddition, leading to unique cyclobutane manifolds in a highly regio- and stereoselective manner. This development represents a rare usage of hydrazine and hydroxyamide in the capacity as temporary tethers. PMID- 23098296 TI - Localization of inhibitory antibodies to the biotin domain of human pyruvate carboxylase. AB - Pyruvate carboxylase [EC 6.4.1.1] plays an important anaplerotic role in many species by catalyzing the carboxylation of pyruvate to oxaloacetate. To extend our understanding about the structure and function of pyruvate carboxylase (PC), a series of monoclonal antibodies were raised against sheep liver PC and those displaying inhibitory activity were further characterized. The binding epitopes of two monoclonal antibodies that displayed strong inhibitory activity were mapped. Six overlapping fragments of the human enzyme were expressed as thioredoxin fusion proteins in Escherichia coli and subjected to Western blot analysis. Both monoclonal antibodies (MAbs) recognized fragments encompassing the enzyme's C-terminal region, known to contain the structured biotin domain. Through deletion analysis, this domain was determined to be a minimal size of 80 amino acids. Further deletions that disrupted the conformation of the domain abolished antibody binding, indicating these antibodies recognized discontinuous epitopes. To further define the critical residues required for antibody recognition, a model of the domain was produced and an alanine scan performed on selected surface-exposed residues. Our results show that residues encompassing the biotin attachment site, but not biotin itself, are critical for the binding of both antibodies. These data provide a mechanism to explain the inhibitory activity of the antibodies. PMID- 23098293 TI - Combining topographical and genetic cues to promote neuronal fate specification in stem cells. AB - There is little remedy for the devastating effects resulting from neuronal loss caused by neural injury or neurodegenerative disease. Reconstruction of damaged neural circuitry with stem cell-derived neurons is a promising approach to repair these defects, but controlling differentiation and guiding synaptic integration with existing neurons remain significant unmet challenges. Biomaterial surfaces can present nanoscale topographical cues that influence neuronal differentiation and process outgrowth. By combining these scaffolds with additional molecular biology strategies, synergistic control over cell fate can be achieved. Here, we review recent progress in promoting neuronal fate using techniques at the interface of biomaterial science and genetic engineering. New data demonstrates that combining nanofiber topography with an induced genetic program enhances neuritogenesis in a synergistic fashion. We propose combining patterned biomaterial surface cues with prescribed genetic programs to achieve neuronal cell fates with the desired sublineage specification, neurochemical profile, targeted integration, and electrophysiological properties. PMID- 23098298 TI - Evaluation of the asparagine synthetase level in leukemia cells by monoclonal antibodies. AB - L-Asparaginase (ASNase) is important for the treatment of childhood acute lymphoblastic leukemia. ASNase sensitivity has been shown to correlate with the asparagine synthetase (ASNS) protein content in acute lymphoblastic leukemia cell lines. However, there have been few studies to determine ASNS protein levels in human leukemias, since no appropriate monoclonal antibody is available for such quantitative analysis. In this study, we report the generation of anti-ASNS monoclonal antibodies, which are applicable to flow cytometry and enzyme-linked immunosorbent assay. These monoclonal antibodies should provide a valuable tool for the quantification of ASNS protein level and estimation of ASNase-resistance in leukemia cells. PMID- 23098297 TI - Novel epitopes identified by anti-PrP monoclonal antibodies produced following immunization of Prnp0/0 Balb/cJ mice with purified scrapie prions. AB - Prions, or infectious proteins, cause a class of uniformly fatal neurodegenerative diseases. Prions are composed solely of an aberrantly folded isoform (PrP(Sc)) of a normal cellular protein (PrP(C)). Shared sequence identity of PrP(Sc) with PrP(C) has limited the detection sensitivity of immunochemical assays, as antibodies specific for the disease-causing PrP(Sc) isoform have not been developed. Here we report the generation of three new monoclonal antibodies (MAbs) to PrP, which were isolated following immunization of Prnp(0/0) Balb/cJ mice with highly purified PrP(Sc) isolated from brain lipid rafts. Epitope mapping using synthetic PrP peptides revealed that the three MAbs bind different epitopes of PrP. The DRM1-31 MAb has a conformational epitope at the proposed binding site for the putative prion conversion co-factor "protein X." The DRM1-60 MAb binds a single linear epitope localized to the beta2-alpha2 loop region of PrP, whereas DRM2-118 binds an epitope that includes sequences within the octarepeat region and near the site of N-terminal truncation of PrP(Sc) by proteinase K. Our novel anti-PrP MAbs with defined PrP epitopes may be useful in deciphering the conformational conversion of PrP(C) into PrP(Sc). PMID- 23098299 TI - A versatile monoclonal antibody specific to human SERPINB5. AB - Maspin (SERPINB5) is a member of the Clade B subgroup of the large superfamily of serine protease inhibitors. It is proposed that maspin is a tumor suppressor; however, its molecular role remains to be elucidated. Here we report the characterization of a mouse monoclonal antibody directed against human maspin. This antibody, 16F7, recognizes maspin in both its native and denatured form, unlike several other commercial antibodies tested in this study. It will be a useful and versatile tool for future analyses of the biological function of maspin. PMID- 23098300 TI - Strain-specific monoclonal antibodies to the E2 protein of classical swine fever virus, Paderborn strain. AB - Monoclonal antibodies (MAbs) against the E2 protein of classical swine fever virus (CSFV) are useful for diagnosis and strain characterization. A purified, baculovirus-expressed CSFV E2 protein from the Paderborn strain was formulated with a saponin adjuvant and successfully used to induce an antigen-specific immune response in mice. After cell fusion a panel, designated F92G, of 12 mouse hybridomas (5-2, 11-1, 14-1, 25-2, 28-2, 31-1, 34-1, 35-2, 37-3, 38-2, 39-1, 41 1) producing CSFV-E2 specific MAbs were selected based on their Ig subclass and secretion level (MUg IgG/mL). Nine IgG 1/k, two IgG 2b/k, and one IgG 2a/k MAbs were further characterized using immunoperoxidase reactivity, ELISA, and Western blot analysis. Immunoglobulin concentration-dependent immunoperoxidase and ELISA reactivity was observed for some of the MAbs with certain antigens. In general there were several reactivity patterns exhibited by the MAbs, with CSFV strains representing different genetic subgroups (by immunoperoxidase staining) and recombinant antigens (by ELISA). It was interesting to note that in some cases the strain-specific reactivity of a MAb was dependent on the test, thereby providing a clue regarding the nature of the binding site. PMID- 23098301 TI - Monoclonal antibodies against Actinobacillus pleuropneumoniae TonB2 protein expressed in Escherichia coli. AB - TonB is known to be a bacterial periplasmic protein that transduces proton from the inner membrane to the outer membrane receptor in complex with the ExbB and ExbD proteins. Actinobacillus pleuropneumoniae TonB2 protein is the second TonB protein that is important for iron acquisition and virulence. The TonB2 protein was verified to be immunogenic and could afford partial protection for animals from lethal infection. In the present study, the recombinant TonB2 (rTonB2) was overexpressed in Escherichia coli BL21(DE3) and purified. The rTonB2 was then used as antigen to immunize BALB/c mice for the production of monoclonal antibodies (MAb). Four clones of TonB2-specific MAb secretion hybridomas--2F2, 2G8, 3D2, and 6F10--were selected. The MAbs 2F2, 3D2, and 6F10 were classified as IgG1 isotype and 2G8 was of IgG2a isotype. Western blot and ELISA results indicated that MAbs had specific binding activity to rTonB2. The MAbs generated here will be used for further functional analyses of the TonB2 protein. PMID- 23098302 TI - A monoclonal antibody against F1-F0 ATP synthase beta subunit. AB - As a transmembrane enzyme, ATP synthase plays an important role in energy metabolism of organ tissues, as well as in tumors. In this study we generated a monoclonal antibody, 6G11, to the catalytic subunit of F1-F0 ATP synthase (ATP5B). The SDS-PAGE result demonstrated that the hybridoma clone had a molecular weight of 50 and 27 kDa components that could be the heavy and light chains of the monoclonal antibody, respectively. Chromosome analysis of the hybridoma clone proved that they had 98 to 102 chromosomal numbers that were the sum of the SP2/0 and spleen cells. Western blot assay revealed that the hybridoma clone reacted specifically with the ATP synthase beta subunit, but not with other proteins. In addition, the subclass of the hybridoma clone was identified as IgG1 by capture ELISA. Furthermore, it demonstrated that the antibody retained stability after half a year. These results indicated that the hybridoma clone 6G11 was a monoclonal antibody with significant stability and special reactivity to ATP5B antigen. PMID- 23098303 TI - Monoclonal and polyclonal antibodies specific for foot and mouth disease virus type A and type O VP1. AB - The foot and mouth disease virus (FMDV) is an RNA virus composed of single stranded positive sense RNA. FMDV has been known to infect cloven-hoofed animals, including pigs, cattle, and sheep. FMDV is rapidly spreading outward to neighboring regions, often leading to a high mortality rate. Thus, early diagnosis of FMDV is critical to suppress propagation of FMDV and minimize economic losses. In this study, we report the generation and characterization of polyclonal and six monoclonal antibodies against VP1 through immunoblotting and immunofluorescence microscopy analyses. These VP1 antibodies will be useful as tools to detect serotypes A and O of FMDVs for diagnostic usage. PMID- 23098304 TI - A monoclonal antibody specific for Delta12-prostaglandin J2 and its utilization in the immunological assay in cell culture system of adipocytes. AB - Prostaglandin (PG) D(2) can be produced in adipocytes and dehydrated to PGs of J(2) series, including Delta(12)-PGJ(2) and 15-deoxy-Delta(12,14)-PGJ(2) (15d PGJ(2)), which serve as pro-adipogenic prostanoids through the activation of peroxisome proliferator-activated receptor gamma. To accomplish the quantification of Delta(12)-PGJ(2) in the cell culture system of adipocytes, the present study aimed to develop a sensitive and specific immunological assay for Delta(12)-PGJ(2). Here, we established a cloned hybridoma cell line secreting a monoclonal antibody specifically recognizing Delta(12)-PGJ(2) and utilized for the development of its solid-phase enzyme-linked immunosorbent assay (ELISA). The immobilized antigen using a conjugate of Delta(12)-PGJ(2) and gamma-globulin was competitively allowed to react with the monoclonal antibody in the presence of free Delta(12)-PGJ(2). The assay provided a sensitive calibration curve for Delta(12)-PGJ(2), allowing us to determine a range from 0.16 pg to 0.99 ng with a value of 13 pg at 50% displacement in one assay. The monoclonal antibody showed almost no cross-reactivity with other related prostanoids since PGJ(2) and 15d PGJ(2) were only recognized with much lower values of 0.5% and 0.2%, respectively. The accuracy for determining Delta(12)-PGJ(2) in the culture medium of adipocytes was confirmed by measurement after the culture medium was fortified with known amounts of authentic Delta(12)-PGJ(2) in a range from 10 to 200 pg/mL. The application of our ELISA revealed that the formation of Delta(12)-PGJ(2) became more pronounced after several hours of incubation of PGD(2) at 37 degrees C in fresh maturation medium of cultured adipocytes. Furthermore, we provide evidence for the increased ability of cultured adipocytes to synthesize endogenous Delta(12)-PGJ(2) during the progression of adipogenesis. These results indicate the reliability and usefulness of our solid-phase ELISA for stable Delta(12)-PGJ(2), reflecting the biosynthesis of unstable PGD(2) in the culture system of adipocytes. PMID- 23098305 TI - A monoclonal antibody against leptin. AB - Leptin is an important protein that regulates energy storage and homeostasis in humans and animals. Leptin deficiency results in various abnormalities such as diabetes, obesity, and infertility. Producing a high affinity monoclonal antibody against human leptin provides an important tool to monitor and trace leptin function in different biological fluids. In this study, recombinant human leptin was conjugated to KLH and injected into mice. After immunization, mouse myeloma SP2/0 cells were fused with murine splenocytes followed by selection of antibody producing hybridoma cells. After screening of different hybridoma colonies by ELISA, a high affinity antibody was selected and purified by affinity chromatography. The affinity constant of the antibody was measured by ELISA. Western blot, immunocytochemistry, and flow cytometry experiments were used to characterize the antibody. The anti-leptin antibody had a high affinity (around 1.13 * 10(-9) M) for its antigen. The saturation of the antibody with leptin (20 moles leptin per 1 mole antibody) in Western blot analysis proved that the antibody had specific binding to its antigen. Immunocytochemistry and flow cytometry on JEG-3 (human placental choriocarcinoma cell) cells revealed that the anti-leptin antibody recognized intracellular leptin. In conclusion, we report here the production and characterization of a murine anti-leptin antibody with high affinity for human leptin. PMID- 23098306 TI - Renalase-specific polyclonal antibody and its application in the detection of renalase's expression. AB - Renalase is generated mainly by the kidneys, and renalase's expression in chronic kidney disease patients is reduced due to renal dysfunction. In this study, human renalase recombinant protein with prokaryotic expression was used for immunization of male New Zealand rabbits, and polyclonal antibodies against human renalase were obtained. To prepare and verify renalase polyclonal antibody, renalase recombinant protein was used as antigen and male New Zealand rabbits were immunized to obtain anti-serum for identification. On the basis of renalase antibody, the expression of renalase in renal tubular epithelial cells and renal tissue was detected. Two anti-renalase polyclonal antibodies were obtained. Renalase was constitutively expressed in human renal tubular epithelial cells, with the maximum expression in proximal convoluted tubules in renal tissue, and a small amount of expression in the glomeruli. Anti-renalase polyclonal antibodies were successfully prepared, which lays a foundation for further studies. PMID- 23098307 TI - A mouse monoclonal antibody specific for calreticulin. AB - Calreticulin (CRT) has various versatile functions. It is one of the family of heat shock proteins (HSPs), and is mainly located in the lumen of the endoplasmic reticulum (ER). In order to elucidate the functional and structural properties of CRT, we expressed and purified CRT protein; we then developed a monoclonal antibody (MAb) against mouse CRT by immunizing BALB/c mice with a specific region of the N and P domains of CRT (dCRT) as antigen, which was expressed in Escherichia coli. A stable hybridoma cell line was established by enzyme linked immunosorbent assay (ELISA) screening. The MAb was then prepared from mouse ascites after inoculating the hybridoma cells. Different methods were used to analyze the characterization of the MAb: ELISA, Western blot analysis, immunofluorescence, and flow cytometry. The dCRT protein was expressed and purified and a MAb cell line for CRT was established through immunization, fusion, and screening. ELISA and Western blot analysis indicated that the MAb specifically recognized CRT. In addition, immunofluorescence and flow cytometry demonstrated that the MAb exhibits excellent reactivity to the ecto-CRT when the cells were induced to apoptosis. This CRT MAb will be a valuable tool for further investigation of calreticulin functions. PMID- 23098315 TI - Causal essentialism in kinds. AB - The current study examines causal essentialism, derived from psychological essentialism of concepts. We examine whether people believe that members of a category share some underlying essence that is both necessary and sufficient for category membership and that also causes surface features. The main claim is that causal essentialism is restricted to categories that correspond to our intuitive notions of existing kinds and hence is more attenuated for categories that are based on arbitrary criteria. Experiments 1 and 3 found that people overtly endorse causal essences in nonarbitrary kinds but are less likely to do so for arbitrary categories. Experiments 2 and 4 found that people were more willing to generalize a member's known causal relations (or lack thereof) when dealing with a kind than when dealing with an arbitrary category. These differences between kinds and arbitrary categories were found across various domains-not only for categories of living things, but also for artefacts. These findings have certain real-world implications, including how people make sense of mental disorders that are treated as real kinds. PMID- 23098316 TI - The influence of dietary lipid composition on liver mitochondria from mice following 1 month of calorie restriction. AB - To investigate the role mitochondrial membrane lipids play in the actions of CR (calorie restriction), C57BL/6 mice were assigned to four groups (control and three 40% CR groups) and the CR groups were fed diets containing soya bean oil (also in the control diet), fish oil or lard. The fatty acid composition of the major mitochondrial phospholipid classes, proton leak and H(2)O(2) production were measured in liver mitochondria following 1 month of CR. The results indicate that mitochondrial phospholipid fatty acids reflect the PUFA (polyunsaturated fatty acid) profile of the dietary lipid sources. CR significantly decreased the capacity of ROS (reactive oxygen species) production by Complex III but did not markedly alter proton leak and ETC (electron transport chain) enzyme activities. Within the CR regimens, the CR-fish group had decreased ROS production by both Complexes I and III, and increased proton leak when compared with the other CR groups. The CR-lard group showed the lowest proton leak compared with the other CR groups. The ETC enzyme activity measurements in the CR regimens showed that Complex I activity was decreased in both the CR-fish and CR-lard groups. Moreover, the CR-fish group also had lower Complex II activity compared with the other CR groups. These results indicate that dietary lipid composition does influence liver mitochondrial phospholipid composition, ROS production, proton leak and ETC enzyme activities in CR animals. PMID- 23098318 TI - Phenomenon and mechanism of capsule shrinking in alkaline solution containing calcium ions. AB - Shrinking phenomenon of poly(allylamine hydrochloride) (PAH)/poly(styrene sulfonate, sodium salt) (PSS) multilayer microcapsules was observed when they were incubated in alkaline solutions containing Ca(2+). The shrinking was universal to those polyelectrolyte multilayer capsules regardless of the wall thickness and wall compositions suppose the conditions were proper. The shrinking extent increased along with the increase of solution pH and Ca(2+) concentration, and reached to a maximum value of 70% (from 7.4 to 2.3 MUm). The shrunk capsules with a hollow structure and thick wall could well maintain their spherical shape in a dry state. During the capsule shrinking partial loss of the polyelectrolytes especially PSS took place, and the loss amount increased along with the increase of solution pH although the alteration patterns were different at lower Ca(2+) concentration. The complexation of PSS with Ca(2+), which is believed one of the major reasons governing the capsule shrinking, was demonstrated by X-ray photoelectron spectroscopy and turbidity experiment. The mechanism is proposed, which relies on the synergistic effects of deprotonation of PAH and screening of PSS by Ca(2+) leading to the thermodynamically favored-capsule shrinking. PMID- 23098317 TI - Mechanisms underlying ICU muscle wasting and effects of passive mechanical loading. AB - INTRODUCTION: Critically ill ICU patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life for survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model show that the mechanical silencing associated with CIM is the primary triggering factor. This study aims to unravel the mechanisms underlying CIM, and to evaluate the effects of a specific intervention aiming at reducing mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading for 10 hours per day (2.5 hours, four times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM; that is, severe muscle wasting and a preferential myosin loss (P < 0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of neuronal nitric oxide synthase. Passive mechanical loading for 9 +/- 1 days resulted in a 35% higher specific force (P < 0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSION: Mechanical silencing is suggested to be a primary mechanism underlying CIM; that is, triggering the myosin loss, muscle wasting and myosin PTMs. The higher neuronal nitric oxide synthase expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients. PMID- 23098319 TI - Blood donation practices, motivations and beliefs in Montreal's Black communities: the modern gift under a new light. AB - OBJECTIVES: Through the conceptual lens of the archaic and modern gift, this study aims to examine perceived limitations and facilitators to increasing blood donations within Black communities in Montreal, Canada. The overall objective is to support blood agencies, such as Hema-Quebec, in understanding the challenges and opportunities they face in promoting blood donation among Black communities in pluralistic societies. DESIGN: Thirty-three semi-structured qualitative interviews were conducted with donors and leaders of ethnocultural groups in Montreal: of these, 6 were Hema-Quebec employees; 3 were Caribbean blood drive organizers; 14 were leaders of African, Caribbean or Black multiethnic churches and community groups; and finally, 10 were donors, including 2 African, 4 French speaking Haitian and 4 English-speaking Caribbean. RESULTS: The existence of multiple Black communities in Montreal reflects the various facilitators and obstacles facing Hema-Quebec. Caribbean and African communities have their own experiences with regard to blood donation as well as different relationships with the broader Quebec society, both of which have great impact on how they perceive the cause. Questions of trust, of giving to the family and to the community, as well as perceived social exclusion appear to be fundamental issues for our informants. The current participation of groups interested in bettering the lives of those affected by sickle cell anaemia combined with the fact that leaders felt more comfortable donating to someone close to the community suggests that the promotion of blood donation through this angle would be well received. CONCLUSION: Trust issues, perceived discrimination and social exclusion have structural and historical roots that can only be partly overcome with long-term efforts to increase awareness, develop collaborative partnerships and increase institutional efforts to adapt to the challenges of blood donation from Black citizens. PMID- 23098320 TI - The prevalence of depression and associated factors in Ethiopia: findings from the National Health Survey. AB - BACKGROUND: Integrating mental health into primarily health care and studying risk for mental health particularly depression needs assessment of different factors including those that impede diagnosis and treatment of mental disorders. But so far the numbers of literature for local context to analyze risk factors for depression and its treatment are scare. The objective of this study was to assess risk factors and health service attendance for depression among adults, in Ethiopia. METHODS: For this analysis, data from the Ethiopian National health survey was used. The Ethiopian national health survey studied 4,925 adults aged 18 years and older to obtain among other things, data on depression episodes, socio-demographic, chronic diseases, life style factors and treatment receiving for depression episodes in the past twelve months using questionnaire from world health organization (WHO). Prevalence of Depression in respondents based on ICD 10 criteria was estimated and logistic regression analysis was used to identify risk factors for depression and treatment receiving. RESULTS: The prevalence of depressive episode was 9.1% (95% CI: 8.39-9.90). In a Univariate analysis, residence, age, marital status, educational status, number of diagnosed chronic non communicable diseases (heart diseases, diabetic mellitus and arthritis) and alcohol drinking status were associated with depression. After full adjustment for possible confounding, odds ratios for depression were significantly higher only for older age, divorced and widowed, number of diagnosed chronic non communicable diseases and alcohol drinking status. The proportion of attending health service among those with depression episodes was 22.9%. After full control for all socio-demographic variables the only predictor variable was educational status, being in grade 5-8 had a higher odds (OR=2.6, 95% CI: 1.23-5.43) and 9-12 grade (OR=1.8 95% CI: 1.45-6.12) of attending service for depressive episodes. CONCLUSIONS: Age, marital status, number of diagnosed chronic non communicable diseases and alcohol consumption were the most important risk factors for depressive episodes. Generally there was lower use of health service for depressive episodes and low educational status was found to be barriers for service use. There is a need to formulate policy for mental health and training of primary health care workers in mental health to early identify and treat cases with depression episodes, so as to decrease prevalence of depression episodes and to improve accessibility of service use. PMID- 23098321 TI - Polycation induced potential dependent structural transitions of oligonucleotide monolayers on Au(111)-surfaces. AB - We have studied self-assembled molecular monolayers (SAMs) of several 3'-C3-SH conjugated single-strand (ss) and double-strand (ds) 20-base oligonucleotides (ONs) immobilized on single-crystal, atomically planar Au(111)-electrode surfaces in the presence of the triply positively charged base spermidine (Spd). This cation binds strongly to the polyanionic ON backbone and stabilizes the ds-form relative to the ss-form. A combination of chemical ON synthesis, melting temperature measurements, cyclic voltammetry (CV), and in situ scanning tunneling microscopy (STM) in aqueous biological buffer under electrochemical potential control was used. Spd binding was found to increase notably the ds-ON melting temperature. CV displays capacitive features associated with ss- and ds-ON. A robust capacitive peak around -0.35 V versus saturated calomel electrode (SCE), specific to ds-ON and highly sensitive to base pair mismatches, was consistently observed. The peak is likely to be caused by surface structural reorganization around the peak potential and located close to reported peak potentials of several DNA intercalating or covalently tethered redox molecules reported as probes for long-range electron transfer. PMID- 23098322 TI - Identification of Bacillus anthracis via Raman spectroscopy and chemometric approaches. AB - Raman micro-spectroscopy was applied to compile a large-scale database of Raman spectra of single Bacillus endospores and to calculate classification functions, which were trained to discriminate between endospores of 66 strains from 13 Bacillus and Bacillus-related species including B. anthracis. The developed two stage classification system comprising two support vector machines and one linear discriminant analysis classifier was then challenged by a test set of 27 samples to simulate the case of a real-world-scenario, when "unknown samples" are to be identified. In the end, all 27 test set samples including six B. anthracis strains were identified correctly. The samples thereby covered a diverse selection of species within the phylogenetically broad Bacillus genus and also included strains, which were not incorporated in the database before. All of them were correctly identified on the species level with accuracies between 88 and 100%. The sample analysis itself requires no biomass enrichment step prior to the analysis and qualifies the presented Raman spectroscopic approach to be a rapid analysis system in term of Bacillus endospore typing. PMID- 23098323 TI - Storage and persistence of a candidate fungal biopesticide for use against adult malaria vectors. AB - BACKGROUND: New products aimed at augmenting or replacing chemical insecticides must have operational profiles that include both high efficacy in reducing vector numbers and/or blocking parasite transmission and be long lasting following application. Research aimed at developing fungal spores as a biopesticide for vector control have shown considerable potential yet have not been directly assessed for their viability after long-term storage or following application in the field. METHODS: Spores from a single production run of the entomopathogenic fungi Beauveria bassiana were dried and then stored under refrigeration at 7 degrees C. After 585 days these spores were sub-sampled and placed at either 22 degrees C, 26 degrees C or 32 degrees C still sealed in packaging (closed storage) or in open beakers and exposed to the 80% relative humidity of the incubator they were kept in. Samples were subsequently taken from these treatments over a further 165 days to assess viability. Spores from the same production run were also used to test their persistence following application to three different substrates, clay, cement and wood, using a hand held sprayer. The experiments were conducted at two different institutes with one using adult female Anopheles stephensi and the other adult female Anopheles gambiae. Mosquitoes were exposed to the treated substrates for one hour before being removed and their survival monitored for the next 14 days. Assays were performed at monthly intervals over a maximum seven months. RESULTS: Spore storage under refrigeration resulted in no loss of spore viability over more than two years. Spore viability of those samples kept under open and closed storage was highly dependent on the incubation temperature with higher temperatures decreasing viability more rapidly than cooler temperatures. Mosquito survival following exposure was dependent on substrate type. Spore persistence on the clay substrate was greatest achieving 80% population reduction for four months against An. stephensi and for at least five months against Anopheles gambiae. Cement and wood substrates had more variable mortality with the highest spore persistence being two to three months for the two substrates respectively. CONCLUSIONS: Spore shelf life under refrigeration surpassed the standard two year shelf-life expected of a mosquito control product. Removal to a variety of temperatures under either closed or open storage indicated that samples sent out from refrigeration should be deployed rapidly in control operations to avoid loss of viability. Spore persistence following application onto clay surfaces was comparable to a number of chemical insecticides in common use. Persistence on cement and wood was shorter but in one assay still comparable to some organophosphate and pyrethroid insecticides. Optimized formulations could be expected to improve spore persistence still further. PMID- 23098324 TI - Cost effectiveness of therapeutic interventions in ankylosing spondylitis: a critical and systematic review. AB - OBJECTIVES: This report reviews the cost effectiveness of different therapeutic interventions used in the treatment of ankylosing spondylitis (AS). METHODS: We performed a systematic search of the databases MEDLINE via PubMed, EMBASE and the Cochrane Library and used hand-searching to identify articles on cost effectiveness of therapies for adult patients with AS published up to November 2010. RESULTS: Of 135 articles, 13 studies were analysed. Two articles were on physical therapies, one article was on NSAIDs and ten articles were on tumour necrosis factor (TNF) inhibitors (infliximab = 6, etanercept = 2, infliximab and etanercept = 1 and adalimumab = 1). Of the latter, no article directly compared TNF inhibitors. Articles showed substantial heterogeneity in methodological approaches and thus results, which prevented us from any extensive comparison, data pooling or meta-analysis. The incremental cost-effectiveness ratio (ICER) for spa-exercise treatment was &U20AC;7465 (95% CI 3294, 14 686) per QALY. The ICERs for infliximab, etanercept and adalimumab were &U20AC;5307-237 010, &U20AC;29 815-123 761 and &U20AC;7344-33 303 per QALY, respectively. CONCLUSIONS: Modelling treatment strategies in chronic relapsing diseases such as AS presents specific challenges, as reflected in the variation in the cost-effectiveness results reported. Although quite variable, the cost-effectiveness ratios for AS therapies remain within an acceptable range. PMID- 23098326 TI - Quantitative analysis and design of a spray aerosol inhaler. Part 2: improvements in mouthpiece performance. AB - BACKGROUND: The objective of this study was to utilize previously identified critical design attributes for the capillary aerosol generator as a model spray inhaler in order to develop a second-generation device that minimized aerosol drug deposition in the mouthpiece. MATERIALS AND METHODS: Computational fluid dynamics (CFD) predictive analysis of the critical design attributes indicated that turbulence intensity should be reduced and the effective mouthpiece diameter should be increased. Two second-generation inhaler mouthpieces meeting these specifications were manufactured and tested. The first device (Design 1) implemented a larger cross-sectional area in the mouthpiece and streamlined flow, whereas the second device (Design 2) used a perforated mouthpiece wall. An in vitro deposition study was performed to quantify the deposition of drug mass in the mouthpieces and connected induction ports, and the results were compared with the CFD predictions. RESULTS: The two second-generation mouthpieces reduced in vitro aerosol deposition from the original value of 7.8% to values of 2.1% (Device 1) and 4.3% (Device 2), without largely altering the induction port deposition. This was achieved by design alterations aimed at reducing turbulence intensity and increasing the effective mouthpiece diameter. CFD model predictions were in good agreement with the in vitro experimental data. CONCLUSIONS: A second generation spray inhaler mouthpiece with low drug deposition was developed using a predictive CFD model and in vitro experiments. Applying this quantitative analysis and design methodology to medical devices, which is similar to the Quality by Design paradigm, could provide significant advantages compared with traditional approaches. PMID- 23098325 TI - Long-term safety and efficacy of fluticasone/formoterol combination therapy in asthma. AB - BACKGROUND: The long-term safety of a new asthma therapy combining fluticasone propionate and formoterol fumarate (fluticasone/formoterol; flutiform((r))) was assessed. METHOD: In an open-label study, mild to moderate-severe asthmatics (>=12 years; N=472) were treated twice daily with fluticasone/formoterol 100/10 MUg (n=224) or 250/10 MUg (n=248) for 6 months (n=256) or 12 months (n=216). The primary and secondary objectives were the long-term safety and efficacy of fluticasone/formoterol, respectively. RESULTS: In total, 413 (87.5%) patients completed the study (of which 175 participated for 12 months). Adverse events (AEs) were reported by 174 patients (36.9%): 67 (29.9%) in the 100/10 MUg group and 107 (43.1%) in the 250/10 MUg group. The most common AEs (>2%) were nasopharyngitis, dyspnea, pharyngitis, and headache; the majority were mild to moderate. Only 18 (3.8%) patients reported AEs considered study drug-related. Five patients per group experienced 12 serious AEs; none was study medication related. Asthma exacerbations were reported by 53 patients (11.2%): 46 mild to moderate and nine severe. Clinical laboratory tests and vital signs showed no abnormal trends or clinically important or dose-response-related changes. The efficacy analyses showed statistically significant improvements at every time point throughout the study period at both doses. CONCLUSION: Fluticasone/formoterol had a good safety and efficacy profile over the 6- and 12 month study periods. PMID- 23098327 TI - Prevalence of 25-hydroxyvitamin D deficiency in Korean adolescents: association with age, season and parental vitamin D status. AB - OBJECTIVE: We aimed to assess the prevalence and associated factors of vitamin D deficiency in healthy adolescents and to determine parent-adolescent association in vitamin D status. DESIGN: A cross-sectional study. SETTING: Data from the Korean National Health and Nutrition Examination Survey (KNHANES) 2008-2009. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured using 125I-labelled RIA kits. Vitamin D deficiency in adolescents was defined as 25(OH)D level <27.5 nmol/l, and 25(OH)D levels between 27.5 and <50 nmol/l were considered insufficient. For the parents, vitamin D deficiency was defined as 25(OH)D level <50 nmol/l. SUBJECTS: The study population consisted of 2062 adolescents (1095 boys, 967 girls; aged 10-18 years) and their parents (1005 fathers, 1341 mothers). RESULTS: Overall, 13.4% of adolescents (boys 11.7%, girls 15.4%) were 25(OH)D deficient, 54.7% were 25(OH)D insufficient. Prevalence of vitamin D deficiency increased with age (P < 0.0001). Parental vitamin D deficiency was more prevalent in vitamin D-deficient adolescents than in non-deficient adolescents (all P < 0.0001). In multivariate logistic regression analyses, predictors for vitamin D deficiency were senior high school students (OR = 3.45 4.33), winter/spring season (OR = 3.18-5.11/5.35-7.36) and parental vitamin D deficiency (OR = 1.78-4.88; all P < 0.05). CONCLUSIONS: Vitamin D insufficiency is prevalent among healthy Korean adolescents and the parent-offspring association warrants vitamin D screening for family members of deficient individuals. PMID- 23098328 TI - Direct functionalization processes: a journey from palladium to copper to iron to nickel to metal-free coupling reactions. AB - The possibility of finding novel disconnections for the efficient synthesis of organic molecules has driven the interest in developing technologies to directly functionalize C-H bonds. The ubiquity of these bonds makes such transformations attractive, while also posing several challenges. The first, and perhaps most important, is the selective functionalization of one C-H bond over another. Another key problem is inducing reactivity at sites that have been historically unreactive and difficult to access without prior inefficient prefunctionalization. Although remarkable advances have been made over the past decade toward solving these and other problems, several difficult tasks remain as researchers attempt to bring C-H functionalization reactions into common use. The functionalization of sp(3) centers continues to be challenging relative to their sp and sp(2) counterparts. Directing groups are often needed to increase the effective concentration of the catalyst at the targeted reaction site, forming thermodynamically stable coordination complexes. As such, the development of removable or convertible directing groups is desirable. Finally, the replacement of expensive rare earth reagents with less expensive and more sustainable catalysts or abandoning the use of catalysts entirely is essential for future practicality. This Account describes our efforts toward solving some of these quandaries. We began our work in this area with the direct arylation of N iminopyridinium ylides as a universal means to derivatize the germane six membered heterocycle. We found that the Lewis basic benzoyl group of the pyridinium ylide could direct a palladium catalyst toward insertion at the 2 position of the pyridinium ring, forming a thermodynamically stable six-membered metallocycle. Subsequently we discovered the arylation of the benzylic site of 2 picolonium ylides. The same N-benzoyl group could direct a number of inexpensive copper salts to the 2-position of the pyridinium ylide, which led to the first description of a direct copper-catalyzed alkenylation onto an electron-deficient arene. This particular directing group offers two advantages: (1) it can be easily appended and removed to reveal the desired pyridine target, and (2) it can be incorporated in a cascade process in the preparation of pharmacologically relevant 2-pyrazolo[1,5-a]pyridines. This work has solved some of the challenges in the direct arylation of nonheterocyclic arenes, including reversing the reactivity often observed with such transformations. Readily convertible directing groups were applied to facilitate the transformation. We also demonstrated that iron can promote intermolecular arylations effectively and that the omission of any metal still permits intramolecular arylation reactions. Lastly, we recently discovered a nickel-catalyzed intramolecular arylation of sp(3) C-H bonds. Our mechanistic investigations of these processes have elucidated radical pathways, opening new avenues in future direct C-H functionalization reactions. PMID- 23098329 TI - Patients with bipolar disorders share similar but attenuated prospective memory impairments with patients with schizophrenia. AB - BACKGROUND: Prospective memory (PM) refers to the ability to remember to carry out an intended action in the future. PM is consistently found to be impaired in individuals with schizophrenia. Bipolar disorder and schizophrenia may represent conditions along a continuum, and share similar neurocognitive and genetic architecture. This study aimed to compare the nature and extent of PM impairment in individuals with schizophrenia and bipolar disorder. METHOD: Participants were 38 out-patients with schizophrenia and 40 out-patients with bipolar disorder in an early psychosis intervention programme, and 37 healthy controls. Time-, event- and activity-based PMs were assessed using a dual-task laboratory paradigm. Self reported PM performance was gauged using the Prospective and Retrospective Memory Questionnaire. Analysis of covariance (ANCOVA), with intelligence quotient (IQ) and education included as covariates, was used to examine group difference on various types of PM. Repeated measures of ANCOVA were used to examine the group * PM type interaction effect. Correspondence between laboratory and self-reported PM measures was examined using correlational analysis. RESULTS: The group * PM type interaction effect was not significant, but the main effect of group was significant. Patients with schizophrenia and patients with bipolar disorder both performed more poorly than healthy participants in PM. The two clinical groups did not significantly differ in PM. Laboratory and self-reported PM measures did not correlate significantly with each other. CONCLUSIONS: Patients with bipolar disorder shared a similar PM impairment with those with schizophrenia. Findings of this study extended the similarity in neurocognitive impairments between the two psychiatric disorders to PM. PMID- 23098330 TI - Self-assembly of ovalbumin into amyloid and non-amyloid fibrils. AB - We study the fibrillation pathway of ovalbumin protein and report the simultaneous formation of several types of fibrils, with clear structural and physical differences. We compare the fibrillation mechanisms at low pH with and without salt, and follow the kinetics of fibrils growth by atomic force microscopy (AFM), static and dynamic light scattering (SLS, DLS), and small-angle X-ray scattering (SAXS). We show that, among the morphologies identified, long semiflexible amyloid fibrils (type I), with persistence length Lp~3 MUm, Young's modulus E~2.8 GPa, and cross-beta structure are formed. We also observe much more flexible fibrils (type III, Lp~63 nm), that can assemble into multistranded ribbons with time. They show significantly lower intrinsic stiffness (1.1 GPa) and a secondary structure, which is not characteristic of the well-ordered amyloids, as determined by circular dichroism (CD), wide-angle X-ray scattering (WAXS), and attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR). In between these two main classes of fibrils, a third family, with intermediate flexibility (type II, Lp~300 nm), is also resolved. PMID- 23098331 TI - Dengue hemorrhagic fever and severe thrombocytopenia in a patient on mandatory anticoagulation: balancing two life threatening conditions: a case report. AB - BACKGROUND: Managing a severe dengue infection is a challenge specially when complicated by other comorbidities. We report a patient with dengue haemorrhagic fever and spontaneous bleeding who required mandatory anticoagulation for a prosthetic mitral valve replacement. This is the first case report in published literature describing this therapeutic dilemma. CASE PRESENTATION: A fifty one year old Sri Lankan woman was diagnosed with dengue haemorrhagic fever with bleeding manifestations. During the critical phase of her illness, the platelet count dropped to 5,000/hl. She was also on warfarin 7 mg daily following a prosthetic mitral valve insertion. In managing the patient, the risk of bleeding had to be balanced against the risk of valve thrombosis without anticoagulation. Warfarin was withheld when the platelet count dropped to 100,000/hl and restarted when it recovered above 50,000/hl. The patient was off anticoagulation for 10 days. CONCLUSIONS: We managed this patient with close observation and continuous risk benefit assessments of management decisions. However, experience with one patient cannot be generalized to others. Therefore, it is essential that clinicians share their experiences in managing such difficult patients. PMID- 23098332 TI - Accountability. PMID- 23098333 TI - Correlations and differences between uranium(VI) arsonates and phosphonates. AB - Three new uranium arsonate compounds, UO(2)(C(6)H(5))(2)As(2)O(5)(H(2)O) (UPhAs 1), UO(2)(HO(3)AsC(6)H(4)AsO(3)H)(H(2)O).H(2)O (UPhAs-2), and UO(2)(HO(3)AsC(6)H(4)NH(2))(2).H(2)O (UPhAs-3) have been synthesized under mild hydrothermal conditions. UPhAs-1 is constructed from UO(7) pentagonal bipyramids that are chelated by the pyroarsonate moiety, [PhAs(O(2))OAs(O(2))Ph](2-), forming chains of layered uranyl polyhedra. Two of the phenylarsonic acids are condensed in situ to form the fused tetrahedra of the pyroarsonate moiety through a metal-mediated, thermally induced condensation process. The structure of UPhAs 2 consists of UO(7) pentagonal bipyramids that are chelated by phenylenediarsonate ligands, forming one-dimensional chains of uranyl polyhedra. UPhAs-3 consists of a rare UO(6) tetragonally distorted octahedron (D(4h)) that is on a center of symmetry and linked to two pairs of adjacent 4 aminophenylarsonate ligands. This linear chain structure is networked through hydrogen bonds between the lattice water molecules and the -NH(2) moiety. All three of these compounds fluoresce at room temperature, showing characteristic vibronically coupled charge-transfer based emission. PMID- 23098334 TI - Urea, a structure breaker? Answers from THz absorption spectroscopy. AB - There has been a controversial debate of whether urea can be regarded as structure breaker or a structure maker. Here, we present concentration and temperature dependent absorption coefficients of urea-water mixtures in the THz range (1.5-10 THz, 50-350 cm(-1)). Our results are in agreement with the hypothesis that urea adapts ideally into the water network. Using a semi-ideal chemical association model and accompanying MD simulations, the observed spectra could be decomposed in three contributions: one is attributed to bulk water, a second one to rattling modes of weakly solvated urea in the surrounding water cage, and the third part accounts for THz modes describing a doubly hydrogen bonded strong solvent-solute interaction. The bands attributed to the rattling motion of the solute scale linearly with concentration. The intensity of this contribution is temperature independent in contrast to the water and strongly solvated solute absorption. We find that even at high urea concentrations the majority of water retains a bulklike absorption spectrum, whereas only a small number (about 0.5-1.1 per urea on average) are strongly bound in the temperature range between 9 and 36 degrees C. The THz absorption data provide no evidence for urea aggregation in the concentration range investigated (1-10 M). PMID- 23098335 TI - Nickel-catalyzed synthesis of diarylamines via oxidatively induced C-N bond formation at room temperature. AB - A nickel-catalyzed oxidative coupling of zinc amides with organomagnesium compounds selectively produces diarylamines under mild reaction conditions, with tolerance for chloride, bromide, hydroxyl, ester, and ketone groups. A diamine is bis-monoarylated. A bromoaniline undergoes N-arylation followed by Kumada-Tamao Corriu coupling in one pot. The reaction may proceed via oxidatively induced reductive elimination of a nickel species. PMID- 23098336 TI - Solvent-driven reductive activation of carbon dioxide by gold anions. AB - Catalytic activation and electrochemical reduction of CO(2) for the formation of chemically usable feedstock and fuel are central goals for establishing a carbon neutral fuel cycle. The role of solvent molecules in catalytic processes is little understood, although solvent-solute interactions can strongly influence activated intermediate species. We use vibrational spectroscopy of mass-selected Au(CO(2))(n)(-) cluster ions to probe the solvation of AuCO(2)(-) as a model for a reactive intermediate in the reductive activation of a CO(2) ligand by a single atom catalyst. For the first few solvent molecules, solvation of the complex preferentially occurs at the CO(2) moiety, enhancing reductive activation through polarization of the excess charge onto the partially reduced ligand. At higher levels of solvation, direct interaction of additional solvent molecules with the Au atom diminishes reduction. The results show how the solvation environment can enhance or diminish the effects of a catalyst, offering design criteria for single-atom catalyst engineering. PMID- 23098339 TI - Reconstruction of displaced acromio-clavicular joint dislocations using a triple suture-cerclage: description of a safe and efficient surgical technique. AB - PURPOSE: In this retrospective study we investigated the clinical and radiological outcome after operative treatment of acute Rockwood III-V injuries of the AC-joint using two acromioclavicular (AC) cerclages and one coracoclavicular (CC) cerclage with resorbable sutures. METHODS: Between 2007 and 2009 a total of 39 patients fit the inclusion criteria after operative treatment of acute AC joint dislocation. All patients underwent open reduction and anatomic reconstruction of the AC and CC-ligaments using PDS(r) sutures (Polydioxane, Ethicon, Norderstedt, Germany). Thirty-three patients could be investigated at a mean follow up of 32+/-9 months (range 24-56 months). RESULTS: The mean Constant score was 94.3+/-7.1 (range 73-100) with an age and gender correlated score of 104.2%+/-6.9 (88-123%). The DASH score (mean 3.46+/-6.6 points), the ASES score (94.6+/-9.7points) and the Visual Analogue Scale (mean 0.5+/-0,6) revealed a good to excellent clinical outcome. The difference in the coracoclavicular distance compared to the contralateral side was <5 mm for 28 patients, between 5-10 mm for 4 patients, and more than 10 mm for another patient. In the axial view, the anterior border of the clavicle was within 1 cm (ventral-dorsal direction) of the anterior rim of the acromion in 28 patients (85%). Re-dislocations occured in three patients (9%). CONCLUSION: Open AC joint reconstruction using AC and CC PDS cerclages provides good to excellent clinical results in the majority of cases. However, radiographically, the CC distance increased significantly at final follow up, but neither the amount of re-dislocation nor calcifications of the CC ligaments or osteoarthritis of the AC joint had significant influence on the outcome. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 23098341 TI - The association between the IGF-I axis, thyroid hormones and cortical bone in patients with mild primary hyperparathyroidism. AB - OBJECTIVES: Primary hyperparathyroidism (PHPT) is associated with low bone mineral density (BMD) and increased risk of osteoporotic fractures. This study investigated whether the IGF-I axis and thyroid hormones are associated with BMD and osteoporotic fractures before and after parathyroidectomy (PTX). MATERIALS AND METHODS: Forty-five patients with mild PHPT were examined before and 1 year after PTX. Circulating concentrations of IGF-1, IGFBP-3, and thyroid hormones were measured and related to BMD in hip and lumbar (L:2-L:4) spine. RESULTS: Serum IGFBP-3 concentration decreased 1 year after PTX (p < 0.01), whereas serum IGF-1 and thyroid hormone concentrations were unchanged. Serum IGF1 concentration correlated positively with IGFBP-3 concentration (p < 0.0001) and BMD in the femoral neck (p < 0.05), both pre- and postoperatively. Serum IGFBP-3 concentration correlated positively with BMD in the femoral neck postoperatively (p < 0.05). Serum TSH correlated positively, and free thyroxine (T4) negatively, with all measures of hip BMD at baseline. Patients suffering from previous osteoporotic fractures before inclusion had lower serum TSH concentration compared to patients without fractures (p < 0.01). CONCLUSION: Serum IGFBP-3 concentration decreased after successful PTX in patients with mild PHPT, while serum IGF1 and thyroid hormone concentrations were unchanged. Both the IGF-I axis and thyroid hormones associated with cortical bone as serum IGF-1 and IGFBP-3 concentrations correlated positively, and free T4 negatively with hip BMD. Moreover, serum TSH concentration was reduced in patients with previous osteoporotic fractures. PMID- 23098342 TI - Different injection techniques in the assessment of central haemodynamics in patients with cirrhosis. AB - OBJECTIVE: Patients with cirrhosis often present with an abnormal distribution of blood volume with a reduced central blood volume (CBV) and central circulation time (CCT). In this group of patients it is important to determine the central haemodynamics as accurately as possible. The purpose of the present study was to compare an alternative injection technique by injecting technetium-labelled human serum albumin ((99m)Tc-HSA) from a deposit within the catheter lumen with the conventional injection technique by injecting iodine-labelled human serum albumin ((125)I-HSA) directly from a syringe. MATERIALS AND METHODS: In 192 patients with cirrhosis, CCT, CBV, and cardiac output (CO) were determined according to kinetic principles. Injection of the two radiolabelled HSA were performed simultaneously and followed by arterial blood sampling every second for the first minute. RESULTS: CCT was significantly shorter, and CO and CBV were significantly lower when determined by the alternative catheter deposit injection technique compared to determination by the traditional syringe deposit injection technique. The mean difference (bias) between CCT measured with the two methods was 0.38 s with limits of agreement ranging from - 0.83 s to 1.59 s. CONCLUSION: This study demonstrates that different injection techniques result in a minor but significant difference of the measured haemodynamics. When highly accurate measurements of the central haemodynamics are needed, we recommend using the alternative injection technique by injection of the indicator from a deposit within the catheter in order to reduce overestimation of CCT. PMID- 23098343 TI - Transient impairment of reticulocyte hemoglobin content and hepcidin-25 induction in patients with community-acquired pneumonia. AB - INTRODUCTION: Patients with community-acquired pneumonia (CAP) often exhibit a declining hemoglobin (Hb) concentration. During inflammation pro-inflammatory cytokines and cells of the reticuloendothelial system induce disturbances in iron homeostasis. In this study inflammation markers and hepcidin-25 concentrations were monitored together with short-term alterations in reticulocyte hemoglobinization (RET-He). METHODS: A total of 25 patients with CAP participated in the study. The assay for serum hepcidin-25 is based on a combination of weak cation exchange chromatography and time-of-flight mass spectrometry. RESULTS: At hospital admission serum hepcidin-25 concentrations (14.6 +/- 6.9 nMol/L, mean +/ SD) were established in the upper level of the reference range (0.5-13.9 nMol/L). Results for C-reactive protein (CRP) and Interleukin-6 (IL-6) were obviously increased compared to the reference ranges. From admission until day 14 hepcidin-25, CRP and IL-6 steadily decreased towards the reference ranges. Hb concentrations declined from admission until day 4 from 8.1 +/- 1.0 mMol/L to 7.4 +/- 0.9 mMol/L. At admission Ret-He results were within the lower region of the reference range (1900-2300aMol) and results demonstrated a decline during admission from 1931 +/- 241 aMol until 1845 +/- 199 aMol (NS) at day 4. From a minimum Ret-He value at day 4 results increased towards 2129 +/- 136 aMol at day14. CONCLUSION: A transient increase of cytokine-stimulated serum hepcidin-25 in combination with a temporary decrease of Hb and Ret-He is demonstrated in patients with CAP. Our results support the hypothesis that hepcidin-25 induces transient impairment of reticulocyte hemoglobin content (Ret-He). PMID- 23098344 TI - [Efficacy of the use of coenzyme q10 at the background of traditional therapy of chronic ischemic heart disease]. PMID- 23098345 TI - [Acute non ST-elevation coronary syndrome in real practice of hospitals in Russia. Comparative data from RECORD 2 and RECORD registries]. AB - AIM: to compare data on pre- and in hospital treatment of non ST-elevation (NSTE) acute coronary syndromes (ACS) in Russian ACS registers RECORD (recruitment from 11.2007 to 02.2008) and RECORD-2 (from 04/2009 to 04.2011). MATERIAL: Four of 7 hospitals participating in RECORD-2 were invasive (57.1% vs. 55.6% in RECORD). In RECORD-2 10-30 consecutive patients with NSTEACS were included monthly in each center; recruitment in RECORD was described elsewhere. RESULTS: Mean age of patients was similar in two registries. Portion of women was significantly higher in RECORD-2 (42.9% vs. 26.0% in RECORD; <0.0001). Although markers of necrosis were measured in higher proportion of patients in RECORD-2, frequency of troponin determination was not significantly different (47.0 vs. 43.5% in RECORD; =0.64). Patients in RECORD-2 more frequently received prehospital aspirin (51.6 vs 33.5%; <0.0001), aspirin in recommended initial dose 160-325 mg (64.3 vs. 47.1%; =0.03), and clopidogrel during hospitalization (47.0 vs. 27.6%; <0.0001). Rates of in hospital use of parenteral anticoagulants in both registries were similar, but among anticoagulants in RECORD 2 proportion of fondaparinucs became noticeable (9.5%) and that of low molecular weight heparin (LMWH) became significantly higher (21.2 vs. 11.6% in RECORD). Almost one third of patients in RECORD-2 who were treated with unfractionated heparin (UFH) received it subcutaneously. About half of patients treated with intravenous infusion of UFH received it for less than 48 hours. Although higher proportion of patients hospitalized in invasive hospitals were subjected to diagnostic coronary angiography in RECORD-2 (80.8 vs. 54.3% in RECORD; <0.0001) differences between registries in rates of percutaneous coronary interventions (PCI) (all - 37.3 vs. 29.9%; =0.051; first 72 hours - 22.7 vs. 24.8%; =0.55), and coronary artery bypass graftings (5.6 vs. 5.8%; =0.12) were not significant. There were no significant differences in rates of any in hospital unfavorable events. Analysis of treatment and outcomes in groups of high risk patients (GRACE score >140) gave results close to those in all patients except mortality which was statistically similar but numerically higher in RECORD 2 (9.3 vs. 7.9% in RECORD; p=0.68). CONCLUSION: Comparison of data of 2 limited NSTEACS registers conducted with interval of about 2 years showed only modest shift towards fulfillment of contemporary recommendations which was not associated with increase in rates of PCI and improvement of outcomes especially in high risk patients. PMID- 23098346 TI - [Effectiveness and safety of losartan and its combination with hydrochlorothiazide in patients with hypertension: in result study]. AB - There are limited data on the results of Russia's use of losartan in clinical practice for the treatment of patients with arterial hypertension (AH). The purpose of the study was to assess the efficacy and safety of losartan and its fixed combination with hydrochlorothiazide (HCTZ) in patients with hypertension. Primary care physicians (n=644) for 8 weeks evaluated outcomes of treatment of hypertensive patients who were assigned to losartan monotherapy (12.5, 25, 50 or 100 mg) or a fixed combination with hydrochlorothiazide (losartan 50 mg/hydrochlorothiazide 12.5 mg , losartan 100 mg/hydrochlorothiazide 25 mg). The effectiveness of treatment was assessed by size reduction of systolic/diastolic blood pressure (SBP/DBP), and the frequency of achieving target blood pressure (<140/90 or <130/80 mm Hg in patients with diabetes). Losartan at a dose 12.5 mg was assigned to 382 (3.8%), at a dose of 25 mg - to 1061 (10.7%), at a dose of 50 mg - to 3545 (35.6%), at a dose of 100 mg - to 3247 (32.6%), at a dose of 50 mg / hydrochlorothiazide 12.5 mg - to 893 (9.0%), at a dose of 100 mg / hydrochlorothiazide 25 mg - to 820 (8.2%) of 9948 patients included in the study. According to multivariate analysis, dose selection of losartan was determined by an attending physician, mainly (85% according to the estimate of the explained variance), based on the baseline SBP. As a result of treatment (41 to 53% of patients received losartan only or in combination with HCTZ) SBP decrease in the groups ranged from 20 to 38 mm Hg, DBP - from 10 to 17 mm Hg, the target blood pressure is achieved in 29-66% of patients. At least one adverse event occurred in 141 (1.4%) patients, with lower frequency in patients receiving losartan 50 mg (adjusted odds ratio 0.34, 95% confidence interval 0.19 to 0.63; the reference group - patients receiving losartan 100 mg/hydrochlorothiazide 25 mg). Thus losartan as monotherapy or in fixed combination with HCTZ for hypertensive patients is characterized by high antihypertensive efficacy and safety. PMID- 23098347 TI - [Anxiety-depressive States in elderly patients with chronic heart failure]. AB - Aim of the study was determination of factors of social desadaptation, which negatively affect psychoemotional status and quality of life of elderly patients with chronic heart failure (CHF). We included into the study 248 patients aged 60 85 years and 82 patients aged 39-59 years with NYHA class II-IV CHF. General state of patients we assessed with the help of clinical state assessment scale (CSAS), presence and severity of anxiety and depression -with hospital anxiety and depression scale, exercise tolerance - with 6 minute walk test. Patients of both groups were comparable by sex, severity of the CHF course quality of life, concomitant pathology, and treatment. Clinically manifest depression was found in 22.8% of patients aged 60 years and older and in 16% of patients younger than 60 years (p=0.460), clinically manifest anxiety was found in 22.8% and 20%, respectively (p=0.945). Risk factors of anxiety-depressive state in elderly patients were disability (relative risk [RR] 3.05, 95% confidence interval [CI] 1.04-8.97, p =0.042), insufficient education (RR 2.44, 95%CI 1.08-5.34; p=0.0320, and severe CHF according to CSAS (OR 1.22, 95%CI 1.07-1.4; p=0.003). According to data of multifactorial analysis disability (RR 1.78, 95%CI 1.01-3.13; p=0.045) and severe CHF (RR 1.17, 95%CI 1.07-1.27; p=0.001) were independently related to anxiety-depressive state in elderly patients. CONCLUSION: [corrected] Thus social dysadaptation and medical factors turned out to be leading parameters determining worsening of quality of life and development of anxiety-depressive state in elderly patients with CHF. PMID- 23098348 TI - [Awareness of physicians about the causes of heart failure in hypertensive patients]. AB - We studied awareness of physicians of the city health clinics (polyclinics) about the causes of heart failure in hypertensive patients and their attitude to the prevention of complications of hypertension. The study involved 194 general practitioners from five regions of Russia. The questionnaire method in the form of single-blind questionnaire survey was used. It was found that 36.6% (95% confidence interval [DI] from 29.81 to 43.80) of respondents were aware of the cause-effect relation between hypertension and heart failure. Only 31.44% (95% DI from 24.98 to 38.48) medical professionals perceived left ventricular hypertrophy as risk factor for heart failure in people with high blood pressure. The percentage of internists-respondents who were aware of the major mechanisms of heart failure in hypertension was 28.37% (95% DI from 21.18 to 4.16]. Outdated or incorrect professional notions can become a barrier to early diagnosis, treatment and prevention of heart failure in patients with hypertension. PMID- 23098349 TI - [Functional reserves of the heart under conditions of alimentary magnesium deficit]. AB - Aim of the study was to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests. Magnesium deficit was modeled by 10 week long magnesium deficient diet. After 54% lowering of magnesium level in erythrocytes we registered left ventricular pressure, myocardial contraction and relaxation rates, heart rate, systolic and diastolic arterial pressure, intensity of structures functioning. Than we subjected hearts of these animals to volume load, graded stimulation of cardiac adrenoreceptors, maximal isometric load by clamping ascending aorta. In animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit. PMID- 23098350 TI - [The integrated approach to diagnostics of metabolic syndrome in clinical practice]. AB - Basic criteria of diagnostics and definitions of metabolic syndrome recommended by various international associations and expert groups are discussed. Permanent changes of criteria and usage of various approaches to diagnostics influence prevalence of metabolic syndrome among populations and estimation of its association with unfavorable outcomes. Some definitions of metabolic syndrome are more sensitive in detection of risk groups for cardiovascular diseases, and others in - detection of persons with high risk of type 2 diabetes mellitus. New integrated definition of metabolic syndrome which unites pathophysiological and clinical epidemiological approaches for assessment of metabolic disorders and detection of high risk groups of patients applicable for use in everyday clinical practice is presented. PMID- 23098351 TI - [To the centennial of the myocardial infarction. Priorities of domestic researchers in the study of the problem of modern cardiology]. AB - There are domestic priorities in the 100-year history of myocardial infarction research a description of the disease clinical picture by V.P.Obrazcov and N.D.Strazhesko, development of mammary-coronary bypass by V.I.Kolesov, intracoronary thrombolysis by E.I.Chazov et al. PMID- 23098352 TI - [Long-term arterial pressure variability novel target for antihypertensive therapy. Do differences between -adrenoblockers exist]. AB - The paper contains: definition of arterial pressure (AP) variability and enumeration of its types; consideration of value of different types of AP variability as independent risk factor of stroke; literature data on effect of antihypertensive drug therapy on AP variability; detailed analysis of effect of adrenoblockers on AP variability in dependence on their key pharmacokinetic properties. PMID- 23098353 TI - [Individual coronary heart disease risk prediction as part of primary prevention]. AB - Correction of traditional risk factors (RF) at the population level resulted in considerable progress in prevention of coronary heart disease (CHD) in many countries. At the same time existing approaches to individual prediction of cardiovascular diseases based on the analysis of traditional RF and global risk scoring are in some cases ineffective. This problem most notably relates to a large group of persons with low calculated risk (young patients, persons without multiple RF, women) which accounts for the greatest in absolute numbers quantity of primary cardiovascular events. Attempts of improvement of individual CHD prediction deal with 1) discovering of new RF and their introduction in global scoring models, 2) cardiovascular imaging modalities which facilitate diagnosis of subclinical atherosclerosis, first of all an ultrasonic study of carotids and multi-detector computed tomography of coronary arteries. This review considers the prognostic value of most important standard global risk scoring models, the added value of new RF and role of data received from atherosclerosis imaging. PMID- 23098354 TI - [Cardiovascular and metabolic complications of obstructive sleep apnea]. PMID- 23098355 TI - [Fixed dose combinations of antihypertensive drugs and management of risk of development nephropathy in type 2 diabetes mellitus]. PMID- 23098356 TI - [The environment as a risk factor of coronary heart disease in urbanized region with developed chemical industry]. AB - Tendency to growth of prevalence of ischemic heart disease (IHD) occurring in Russian Federation despite application of preventive measures designates necessity of search for novel nontraditional factors of risk. Among other studied factors of genesis of cardiovascular diseases in general and of IHD in particular is the role of xenobiotics - chemical pollutants, substances foreign to the body. In this paper we present results of a number of epidemiological studies on the problem of xenobiotics and IHD. Special attention is given to the difficulty of isolation of the leading chemical pollutant and as a consequence of pathogenetic link what leads to underestimation of pathological states caused by ecological factors especially in such urbanized region with developed chemical industry as Kusbass. PMID- 23098357 TI - [Sudden death of two sisters in a family with combined progressive impairment of cardiac conduction system]. AB - Sudden cardiac death (SCD) of two sisters from a family with combined progressive impairment of cardiac conduction system (CCS) is described. These two sisters (hetero-ovular twins) died suddenly in a kindergarten at the background of physical and emotional effort in the age of 4.8 and 5 years. Resuscitation and electrical defibrillation conducted in one of them after 20 min of heart arrest were not effective. Autopsy gave no clear-cut data relative to pathology of the heart and other organs. Analysis of preserved ECGs showed that in the age of 8 months both sisters had sharp leftward/upward deviation of electric axis of the heart (-41 in one sister and -43 in another). In 2 years these deviations became even more pronounced reaching -63. This was combined with small q-waves and tall R waves in leads I and aVL what corresponded to signs of block of the anterior branch of bundle of His and could be a manifestation of hereditary disease with progressive CCS involvement first of all of the Lev-Lenegre disease. PMID- 23098358 TI - Physiotherapy after stroke: to what extent is task-oriented practice a part of conventional treatment after hospital discharge? AB - Research has shown that motor training after stroke should be task-oriented. It is still unknown whether the task-oriented approach is implemented into clinical practice. The purpose of the present study was to survey to which extent task specific training was a part of conventional physiotherapy practice given to stroke patients after discharge from hospital. This cross-sectional survey was a sub-study of a randomized controlled trial. Physiotherapists treating patients included in the trial were asked to register their choice of treatment according to 11 predefined activity categories during the second week after discharge from hospital. Nineteen physiotherapists treating 46 patients suffering from mild-to moderate stroke were included. The activities chosen in most patients were sit-to stand (60.9%), balance in standing position (65.2%), walking on even ground (78.3%), and stair climbing (56.5%). Only two patients (4.3%) practiced transfers or balance related to activities of daily living (ADL), such as washing, dressing, and toileting. This study shows that conventional physiotherapy practice for a selected group of Norwegian stroke patients was mainly based on a task-oriented approach, although with very little emphasis on training in relation to ADL. Future research is needed to ensure that evidence-based treatment is given to all stroke patients. PMID- 23098359 TI - Effects of low-dose fluticasone propionate/salmeterol combination therapy on exhaled nitric oxide and nitrite/nitrate in breath condensates from patients with mild persistent asthma. AB - OBJECTIVE: The long-acting beta2-agonist salmeterol in combination with the corticosteroid fluticasone propionate is used in clinical practice for the treatment of mild persistent asthma. Although the effect of fluticasone propionate alone in asthmatic patients is well documented, the effect of fluticasone propionate/salmeterol (FSC) combination therapy on airway inflammation and airway hyperresponsiveness (AHR) is not well characterized. Thus, we evaluated AHR, exhaled nitric oxide (FE(NO)), and nitrite and nitrate in exhaled breath condensates (EBCs) from mild persistent asthmatic patients treated with a low-dose FSC (100/50). METHODS: In this open label study, 18 mild persistent, steroid-naive asthmatics (age, 22-62 years, forced expiratory volume in 1 s (FEV(1)) > 70% predicted, provocative dose resulting in 20% reduction (PD(20)) < 10 mg/mL) were treated with FSC 100/50 for 4 weeks. PD(20) to methacholine, FEV(1), FE(NO), and EBC nitrite and nitrate was measured before and after treatment. RESULTS: After 4 weeks of therapy with FSC 100/50, FE(NO) decreased from 74 ppb (SD = 37) to 34 ppb (SD = 15) (p < .001). FEV(1) (% predicted) increased from 89.4 (SD = 10.7) to 93.3 (SD = 9.5) (p < .01). The PD(20) for methacholine increased from 3.0 (+/-3.2) to 10.3 (+/-8.4) mg/mL (p < .01) in 3 of 18 patients reaching the maximum allowable dose (25 mg/mL). FE(NO) correlated with the log of the methacholine dose. There was no statistically significant change in EBC nitrite and nitrate before and after treatment. CONCLUSIONS: Treatment of mild persistent, steroid-naive asthmatics with low-dose combination therapy is effective in rapidly reducing airway inflammation and AHR. Our results suggest different metabolic origins for nitrite, nitrate, and FE(NO) in this group of patients. PMID- 23098361 TI - Vascular endothelial growth factor in tuberculous meningitis. AB - Vascular endothelial growth factor (VEGF) is linked to brain edema and infarction, but there is paucity of studies correlating VEGF level with magnetic resonance imaging (MRI) changes in tuberculous meningitis (TBM). The aim of this study was to measure serum VEGF level in TBM and correlate it with clinical, laboratory, and MRI findings. Forty patients with TBM underwent cranial evaluation, cranial MRI, and MR angiography (MRA). Presence of exudates, hydrocephalous, infarction, tuberculoma, and MRA abnormalities was noted. Serum VEGF level was measured by enzyme-linked immunosorbent assay and compared in patients and controls. The VEGF level was also correlated with clinical, MRI, and MRA findings. The median age of the patients was 26.5 years. There was a trend towards higher serum VEGF level in TBM patients (100.7 +/- 110.6 pg/ml) compared to the controls (60.6 +/- 20.3 pg/ml). There was also a trend towards higher VEGF level in patients with shorter duration of illness (127.5 +/- 152.4 pg/ml vs 76.5 +/- 40.9 pg/ml), MRI evidence of infarction (131.4 +/- 150.7 pg/ml vs. 73.0 +/- 41.4 pg/ml), and paradoxical response (122.3 +/- 157.6 pg/ml vs. 88.8 +/- 50.8 pg/ml). Five patients died, and death was not related to VEGF level. It can be concluded that serum VEGF level in TBM patients is insignificantly higher in those with shorter duration of illness and infarction. PMID- 23098360 TI - Mechanical strain promotes osteoblast ECM formation and improves its osteoinductive potential. AB - BACKGROUND: The extracellular matrix (ECM) provides a supportive microenvironment for cells, which is suitable as a tissue engineering scaffold. Mechanical stimulus plays a significant role in the fate of osteoblast, suggesting that it regulates ECM formation. Therefore, we investigated the influence of mechanical stimulus on ECM formation and bioactivity. METHODS: Mouse osteoblastic MC3T3-E1 cells were cultured in cell culture dishes and stimulated with mechanical tensile strain. After removing the cells, the ECMs coated on dishes were prepared. The ECM protein and calcium were assayed and MC3T3-E1 cells were re-seeded on the ECM coated dishes to assess osteoinductive potential of the ECM. RESULTS: The cyclic tensile strain increased collagen, bone morphogenetic protein 2 (BMP-2), BMP-4, and calcium levels in the ECM. Compared with the ECM produced by unstrained osteoblasts, those of mechanically stimulated osteoblasts promoted alkaline phosphatase activity, elevated BMP-2 and osteopontin levels and mRNA levels of runt-related transcriptional factor 2 (Runx2) and osteocalcin (OCN), and increased secreted calcium of the re-seeded MC3T3-E1 cells. CONCLUSION: Mechanical strain promoted ECM production of osteoblasts in vitro, increased BMP 2/4 levels, and improved osteoinductive potential of the ECM. This study provided a novel method to enhance bioactivity of bone ECM in vitro via mechanical strain to osteoblasts. PMID- 23098362 TI - Fat area and lipid droplet morphology of porcine oocytes during in vitro maturation with trans-10, cis-12 conjugated linoleic acid and forskolin. AB - Lipid droplets (LD) in porcine oocytes form a dark mass reaching almost all cytoplasm. Herein we investigated changes in fat areas, cytoplasmic tone and LD morphology during in vitro maturation (IVM) of porcine oocytes cultured with 100 MUM trans-10, cis-12 conjugated linoleic acid (t10,c12 CLA) or 10 MUM forskolin at different time periods. Four groups were constituted: control, excipient, t10,c12 CLA and forskolin, with drugs being supplemented during 44 to 48 h and the initial 22 to 24 h in Experiments 1 and 2, respectively. In Experiment 3, forskolin was supplemented for the first 2 h. Matured oocytes were inseminated with frozen-thawed boar semen and cleavage rate recorded. Before and during IVM, samples of oocytes were evaluated for LD, total and fat areas and fat gray value or for meiotic progression. Results showed that forskolin supplementation during 44 to 48 h or 22 to 24 h inhibits oocyte maturation (exp. 1: forskolin = 5.1 +/- 8.0%, control = 72.6 +/- 5.0%; exp. 2: forskolin = 24.3 +/- 7.4%, control = 71.6 +/- 5.6%) and cleavage (exp. 1: forskolin = 0.0 +/- 0.0%, control = 55.4 +/- 4.1%; exp. 2: forskolin = 8.3 +/- 3.3%, control = 54.5 +/- 3.0%). Forskolin also reduced oocyte and fat areas. In Experiment 3, forskolin negative effect on oocyte maturation and cleavage disappeared, although minor (P ? 0.03) LD and oocyte fat areas were identified at 22 to 24 h of IVM. Oocytes supplemented with t10,c12 CLA during 44 to 48 h presented a lighter (P ? 0.04) colour tone cytoplasm than those of control and forskolin. In conclusion, t10,c12 CLA and forskolin were capable of modifying the distribution and morphology of cytoplasmic LD during porcine oocyte maturation, thus reducing its lipid content in a time-dependent manner. PMID- 23098363 TI - Using the analytic hierarchy process to elicit patient preferences: prioritizing multiple outcome measures of antidepressant drug treatment. AB - BACKGROUND AND OBJECTIVE: In health technology assessment, the evidence obtained from clinical trials regarding multiple clinical outcomes is used to support reimbursement claims. At present, the relevance of these outcome measures for patients is, however, not systematically assessed, and judgments on their relevance may differ among patients and healthcare professionals. The analytic hierarchy process (AHP) is a technique for multi-criteria decision analysis that can be used for preference elicitation. In the present study, we explored the value of using the AHP to prioritize the relevance of outcome measures for major depression by patients, psychiatrists and psychotherapists, and to elicit preferences for alternative healthcare interventions regarding this weighted set of outcome measures. METHODS: Supported by the pairwise comparison technique of the AHP, a patient group and an expert group of psychiatrists and psychotherapists discussed and estimated the priorities of the clinical outcome measures of antidepressant treatment. These outcome measures included remission of depression, response to drug treatment, no relapse, (serious) adverse events, social function, no anxiety, no pain, and cognitive function. Clinical evidence on the outcomes of three antidepressants regarding these outcome measures was derived from a previous benefit assessment by the Institute for Quality and Efficiency in Health Care (IQWiG; Institut fur Qualitat und Wirtschaftlichkeit im Gesundheitswesen). RESULTS: The most important outcome measures according to the patients were, in order of decreasing importance: response to drug treatment, cognitive function, social function, no anxiety, remission, and no relapse. The patients and the experts showed some remarkable differences regarding the relative importance of response (weight patients = 0.37; weight experts = 0.05) and remission (weight patients = 0.09; weight experts = 0.40); however, both experts and patients agreed upon the list of the six most important measures, with experts only adding one additional outcome measure. CONCLUSIONS: The AHP can easily be used to elicit patient preferences and the study has demonstrated differences between patients and experts. The AHP is useful for policy makers in combining multiple clinical outcomes of healthcare interventions grounded in randomized controlled trials in an overall health economic evaluation. This may be particularly relevant in cases where different outcome measures lead to conflicting results about the best alternative to reimburse. Alternatively, AHP may also support researchers in selecting (primary) outcome measures with the highest relevance. PMID- 23098364 TI - Effectiveness of trivalent and monovalent influenza vaccines against laboratory confirmed influenza infection in persons with medically attended influenza-like illness in Bavaria, Germany, 2010/2011 season. AB - We estimated the vaccine effectiveness (VE) of trivalent and monovalent influenza vaccines,respectively, against laboratory-confirmed influenza infections in patients with influenza-likeillness who visited physicians participating in the Bayern Influenza Sentinel in Bavaria, Germany during 2010/2011. Swab specimens were analysed for influenza A(H1N1)pdm09, A(H3) andB by PCR. VE was estimated using the test-negative case-control study design and logistic regression. In total, 1866 patients (790 cases, 1076 controls) were included. The VE of trivalentvaccines administered in season 2010/2011 against laboratory-confirmed infection with any influenza virus, adjusted for age group, sex, chronic illness and week of arrival of the specimen,was 67.8% [95% confidence interval (CI) 39.2 82.9)]. The adjusted VE of monovalent influenza vaccines administered in season 2009/2010 against laboratory-confirmed influenza A(H1N1)pdm09 infection in 2010/2011 was 38.6% (95% CI x 70.0 to 77 . 8). This is the first VE study conducted in Bavaria. We concluded that the trivalent influenza vaccines were effective in our study population PMID- 23098366 TI - Novel non-invasive methods of insulin delivery. AB - INTRODUCTION: Insulin has usually been administered subcutaneously in the treatment of diabetes mellitus. Alternative delivery routes of insulin are expected to overcome some limitations, mainly concerned with the possibility of hypoglycemia episodes, weight gain and inadequate post-meal glucose control, in order to lead a better patient compliance. AREAS COVERED: This review article covers all the most relevant non-invasive insulin delivery methods under development, respective technology and clinical data available according to their status of development. Special focus is given to the systems with late clinical trial evidences, their achievements and pitfalls. Pulmonary and oral appear to be the most advantageous routes, with regard to the long list of potentially marketed products. EXPERT OPINION: Alternative insulin delivery to the subcutaneous administration is more and more close to the success, being fundamental that any optimized technology could overcome the overall low mucosal bioavailability of insulin, mostly due to its early degradation before absorption, inactivation and digestion by proteolytic enzymes and poor permeability across mucosal epithelium because of its high molecular weight and lack of lipophilicity. PMID- 23098365 TI - Renal arterial resistive index is associated with severe histological changes and poor renal outcome during chronic kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is a growing public health problem and end stage renal disease (ESRD) represents a large human and economic burden. It is important to identify patients at high risk of ESRD. In order to determine whether renal Doppler resistive index (RI) may discriminate those patients, we analyzed whether RI was associated with identified prognosis factors of CKD, in particular histological findings, and with renal outcome. METHODS: RI was measured in the 48 hours before renal biopsy in 58 CKD patients. Clinical and biological data were collected prospectively at inclusion. Arteriosclerosis, interstitial fibrosis and glomerulosclerosis were quantitatively assessed on renal biopsy in a blinded fashion. MDRD eGFR at 18 months was collected for 35 (60%) patients. Renal function decline was defined as a decrease in eGFR from baseline of at least 5 mL/min/ 1.73 m2/year or need for chronic renal replacement therapy. Pearson's correlation, Mann-Whitney and Chi-square tests were used for analysis of quantitative and qualitative variables respectively. Kaplan Meier analysis was realized to determine renal survival according to RI value using the log-rank test. Multiple logistic regression was performed including variables with p < 0.20 in univariate analysis. RESULTS: Most patients had glomerulonephritis (82%). Median age was 46 years [21-87], eGFR 59 mL/min/ 1.73m2 [5-130], percentage of interstitial fibrosis 10% [0-90], glomerulosclerosis 13% [0-96] and RI 0.63 [0.31-1.00]. RI increased with age (r = 0.435, p = 0.0063), pulse pressure (r = 0.303, p = 0.022), renal atrophy (r = -0.275, p = 0.038) and renal dysfunction (r = -0.402, p = 0.0018). Patients with arterial intima/media ratio >= 1 (p = 0.032), interstitial fibrosis > 20% (p = 0.014) and renal function decline (p = 0.0023) had higher RI. Patients with baseline RI >= 0.65 had a poorer renal outcome than those with baseline RI < 0.65 (p = 0.0005). In multiple logistic regression, RI>=0.65 was associated with accelerated renal function decline independently of baseline eGFR and proteinuria/creatininuria ratio (OR=13.04 [1.984-85.727], p = 0.0075). Sensitivity, specificity, predictive positive and predictive negative values of RI >= 0.65 for renal function decline at 18 months were respectively 77%, 86%, 71% and 82%. CONCLUSIONS: Our results suggest that RI >= 0.65 is associated with severe interstitial fibrosis and arteriosclerosis and renal function decline. Thus, RI may contribute to identify patients at high risk of ESRD who may benefit from nephroprotective treatments. PMID- 23098367 TI - Enhanced N-nitrosamine formation in pool water by UV irradiation of chlorinated secondary amines in the presence of monochloramine. AB - N-Nitrosamines, in particular N-nitrosodimethylamine (NDMA), are carcinogens, which occur as chlorine disinfection by-products (DBPs) in swimming pools and hot tubs. UV treatment is a commonly used technique in swimming pools for disinfection and DBP attenuation. UV irradiation is known to efficiently degrade N-nitrosamines. However, UV irradiation (at lambda = 254 nm) of chlorinated dimethylamine (CDMA) and monochloramine, two NDMA precursors present in swimming pool water, resulted in a substantial UV-induced NDMA formation (~1-2% molar yield based on initial CDMA concentration) simultaneously to NDMA photolysis. Maximum NDMA concentrations were found at UV doses in the range used for advanced oxidation (350-850 mJ cm(-2)). Very similar behaviour was found for other chlorinated secondary amines, namely diethylamine and morpholine. Effectiveness of UV irradiation for N-nitrosamine abatement depends on initial N-nitrosamine and precursor concentrations and the applied UV dose. N-Nitrosamine formation is hypothesized to occur via the reaction of nitric oxide or peroxynitrite with the secondary aminyl radical, which are products from the photolysis of monochloramine and chlorinated secondary amines, respectively. Experiments with pool water showed that similar trends were observed under pool water conditions. UV treatment (UV dose: ~360 mJ cm(-2)) slightly increased NDMA concentration in pool water instead of the anticipated 50% abatement in the absence of NDMA precursors. PMID- 23098368 TI - Outdoor activity and myopia among primary students in rural and urban regions of Beijing. AB - OBJECTIVE: To assess associations among outdoor activity, ocular biometric parameters, and myopia among grade 1 and grade 4 primary students in Beijing. DESIGN: School-based, cross-sectional study. PARTICIPANTS: A total of 382 grade 1 and 299 grade 4 children participated in the study. METHODS: The children underwent a comprehensive eye examination, including ocular biometry by optical low-coherence reflectometry and noncycloplegic refractometry. Parents and children participated in a detailed interview, including questions on time spent indoors and outdoors. MAIN OUTCOME MEASURES: Factors associated with myopia. RESULTS: The study included 681 children, with 382 (56.1%) students from grade 1 (mean age, 6.3 +/- 0.5 years; range, 5-8 years) and 299 students from grade 4 (mean age, 9.4 +/- 0.7 years; range, 8-13 years); 370 students (54.3%) lived in the urban region. The mean daily time spent outdoors was 1.6 +/- 0.8 hours (range, 0.5-5.1 hours). In multivariate analysis, axial length was significantly associated with older age (P<0.001; standardized beta coefficient, 0.28), taller body height (P = 0.001; beta, 0.18), maternal myopia (P = 0.03; beta, 0.09), and urban region of habitation (P<0.001; beta, -0.21), or alternatively to the region of habitation, with less time spent outdoors (P = 0.001; beta, -0.16) and more time spent indoors studying (P = 0.02; beta, 0.10). The axial length-to-corneal curvature radius ratio was associated with older age, urban region of habitation, maternal and paternal myopia, and paternal level of education. Presence of myopia (defined as refractive error <=-1 diopters in the right eye) was associated with older age (P<0.001; odds ratio [OR], 1.45; 95% confidence interval [CI], 1.24 1.69), maternal myopia (P<0.001; OR, 2.99; 95% CI, 1.94-5.35), and urban region of habitation (P<0.001; OR, 0.17; 95% CI, 0.11-0.26), or alternatively to the region of habitation, with less time spent outdoors (P<0.001; OR, 0.32; 95% CI, 0.21-0.48) and more time spent indoors studying (P<0.001; OR, 1.38; 95% CI, 1.09 1.75). CONCLUSIONS: Less outdoor activity, more indoor studying, older age, maternal myopia, and urban region of habitation were associated with longer ocular axial length and myopia in grade 1 and grade 4 primary school children in Greater Beijing. Remaining outdoors more (e.g., during school) may reduce the high prevalence of myopia in the young generation in Beijing. PMID- 23098369 TI - ARMS2 increases the risk of early and late age-related macular degeneration in the European Eye Study. AB - OBJECTIVE: To study associations between severity stages of early and late age related macular degeneration (AMD) and genetic variations in age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH) and to investigate potential interactions between smoking and ARMS2. DESIGN: Population based, cross-sectional European Eye Study in 7 countries in Europe. PARTICIPANTS: Four thousand seven hundred fifty participants, 65 years of age and older, recruited through random sampling. METHODS: Participants were classified on the basis of the more severely affected eye into 5 mutually exclusive AMD severity stages ranging from no AMD, 3 categories of early AMD, and late AMD. History of cigarette smoking was available and allowed classification into never, former, and current smokers, with the latter 2 groups combined into a single category of ever smokers for analysis. Genotyping was performed for single nucleotide polymorphisms rs10490924 and rs4146894 in ARMS2 and rs1061170 in CFH. Associations were analyzed by logistic regression. MAIN OUTCOME MEASURES: Odds ratios (ORs) for stage of AMD associated with genetic variations in ARMS2 and CFH and interactions between ARMS2 and smoking status. RESULTS: Early AMD was present in 36.4% and late AMD was present in 3.3% of participants. Data on both genotype and AMD were available for 4276 people. The ORs for associations between AMD stage and ARMS2 increased monotonically with more severe stages of early AMD and were altered little by adjustment for potential confounders. Compared with persons with no AMD, carriers of the TT genotype for rs10490924 in ARMS2 had a 10 fold increase in risk of late AMD (P<3 * 10(-20)). The ORs for associations with CFH were similar for stage 3 early AMD and late AMD. Interactions between rs10490924 in ARMS2 and smoking status were significant in both unadjusted and adjusted models (P = 0.001). The highest risk was observed in those doubly homozygous for rs10490924 and rs1061170 in CFH (OR, 62.3; 95% confidence interval, 16-242), with P values for trend ranging from 0.03 (early AMD, stage 1) to 1 * 10(-26) (late AMD). CONCLUSIONS: A strong association was demonstrated between all stages of AMD and genetic variation in ARMS2, and a significant gene environment interaction with cigarette smoking was confirmed. PMID- 23098371 TI - Astrocyte mega-domain hypothesis of the autistic savantism. AB - Individuals with autism who show high abilities are called savants. Whereas in their brains a disconnection in and between neural networks has been identified, savantism is yet poorly understood. Focusing on astrocyte domain organization, it is hypothesized that local astrocyte mega-organizations may be responsible for exerting high capabilities in brains of autistic savants. Astrocytes, the dominant glial cell type, modulate synaptic information transmission. Each astrocyte is organized in non-overlapping domains. Formally, each astrocyte contacting n-neurons with m-synapses via its processes generates dynamic domains of synaptic interactions based on qualitative computation criteria, and hereby it structures neuronal information processing. If the number of processes is genetically significantly increased, these astrocytes operate in a mega-domain with a higher complexitiy of computation. From this model savant abilities are deduced. PMID- 23098370 TI - Matrix metalloproteinases and educational attainment in refractive error: evidence of gene-environment interactions in the Age-Related Eye Disease Study. AB - PURPOSE: A previous study of Old Order Amish families showed an association of ocular refraction with markers proximal to matrix metalloproteinase (MMP) genes MMP1 and MMP10 and intragenic to MMP2. A candidate gene replication study of association between refraction and single nucleotide polymorphisms (SNPs) within these genomic regions was conducted. DESIGN: Candidate gene genetic association study. PARTICIPANTS: Two thousand participants drawn from the Age-Related Eye Disease Study (AREDS) were chosen for genotyping. After quality-control filtering, 1912 individuals were available for analysis. METHODS: Microarray genotyping was performed using the HumanOmni 2.5 bead array (Illumina, Inc., San Diego, CA). Single nucleotide polymorphisms originally typed in the previous Amish association study were extracted for analysis. In addition, haplotype tagging SNPs were genotyped using TaqMan assays. Quantitative trait association analyses of mean spherical equivalent refraction were performed on 30 markers using linear regression models and an additive genetic risk model while adjusting for age, sex, education, and population substructure. Post hoc analyses were performed after stratifying on a dichotomous education variable. Pointwise (P(emp)) and multiple-test study-wise (P(multi)) significance levels were calculated empirically through permutation. MAIN OUTCOME MEASURES: Mean spherical equivalent refraction was used as a quantitative measure of ocular refraction. RESULTS: The mean age and ocular refraction were 68 years (standard deviation [SD], 4.7 years) and +0.55 diopters (D; SD, 2.14 D), respectively. Pointwise statistical significance was obtained for rs1939008 (P(emp) = 0.0326). No SNP attained statistical significance after correcting for multiple testing. In stratified analyses, multiple SNPs reached pointwise significance in the lower education group: 2 of these were statistically significant after multiple testing correction. The 2 highest-ranking SNPs in Amish families (rs1939008 and rs9928731) showed pointwise P(emp)<0.01 in the lower-education stratum of AREDS participants. CONCLUSIONS: This study showed suggestive evidence of replication of an association signal for ocular refraction to a marker between MMP1 and MMP10. Evidence of a gene-environment interaction between previously reported markers and education on refractive error also was shown. Variants in MMP1 through MMP10 and MMP2 regions seem to affect population variation in ocular refraction in environmental conditions less favorable for myopia development. PMID- 23098372 TI - Possible mechanism for the gastro-intestinal adverse effects upon topical application of Prostaglandin F2alpha analogs. AB - Prostaglandin F(2)alpha analogs (PGAs), including latanoprost, travoprost and bimatoprost, the first choice for the pharmaceutical treatment of glaucoma, are gaining more attention on their systemic side effects in recent years. The gastro intestinal effects are among the most reported adverse effects upon topical application of PGAs. Yet, the underlying mechanism remains to be unknown. In the current study, we performed a molecular genetic analysis on the patient reported by Yu et al. (BMJ Case Rep, 2009), who developed nausea, vomiting and diarrhea after topical application of travoprost and latanoprost, but not bimatoprost, and then speculated that the mechanism underlying the gastro-intestinal distress secondary to PGA topical application should be attributed to their stimulation of smooth muscles of the gastric and intestinal tract via prostanoid receptors. We postulate that the diversified receptor selectivity of various PGAs might mediate their diversified gastro-intestinal effects. To further verificate the speculation, other three glaucoma patients who exhibited different gastro intestinal responses to different PGA medications were enrolled. The results suggested that the relative expression level of FP receptor, versus EP receptors, might be associated with the severity of gastro-intestinal effects incurred by PGAs. Owing to the differed expression levels of FP receptor, the responses of various patients to different PGAs can be variable. PMID- 23098373 TI - The triblock copolymers hydrogel through intracameral injection may be a new potential ophthalmic drug delivery with antiscarring drugs after glaucoma filtration surgery. AB - The hyperplasia of fiber cell at operation area cause scarring lead to the failure after glaucoma filtration surgery. People are looking for more safe and effective way to advance the success rate in operation. There are many researches demonstrated that ophthalmic drug delivery system can be a treatment. Among this, some biodegradable and thermosensitive triblock copolymers hydrogel are novel candidate for ocular drug release system. But whether they can be used to restrain the hyperplasia of fiber cell through intracameral injection after glaucoma filtration surgery, the research have not been reported. So it suggested a new hypothesis for intracameral injection of the triblock copolymers hydrogel as a new potential in situ sustained ophthalmic drug delivery system with antiscaring formation after glaucoma filtration surgery. Indicating that the new nanomaterials through intracameral injection treating complication of glaucoma filtration surgery is hoped to be a creative and promising ophthalmic drug delivery system in the future. PMID- 23098374 TI - Is there a link between the structural impact of thoracic outlet and the development of central venous stenosis? AB - Central venous stenosis (CVS) is a serious complication for chronic hemodialysis (HD) patients. Previous reports of CVS have focused on prior central venous catheterization, because of the higher prevalence and potential for prevention of such an event. However, recent studies have demonstrated that CVS may also develop without a history of central venous catheterization. Although information about the etiological backgrounds regarding the development of CVS without previous central venous catheterization have gradually accumulated, the clinical impact of the chronic compression of the central venous system by the surrounding structures, which may likely determine the central venous susceptibility to CVS, remains poorly understood. This study proposes the hypothesis that the combination of chronic venous compression at the level of thoracic outlet characterized by the natural physique and elevated venous flow induced by the creation of vascular access should be evaluated as a potential factor for the development of CVS, since they may accelerate the development of venous stenosis, presumably through the stimulation of intimal hyperplasia, and thereby the subclavian venous susceptibility to CVS should be determined. PMID- 23098375 TI - The connection between maternal thiamine shortcoming and offspring cognitive damage and poverty perpetuation in underprivileged communities across the world. AB - The acquisition of cognitive, sensory-motor and social emotional functions depend on a proper development of the Central Nervous System (CNS). This set of functions, known as intelligence, allows a better adaptation to the environment. In the last decades, an increase in the average of intelligence has been reported. However, such an increase cannot be observed in an equivalent way in economically and social underprivileged regions. Children from those regions are in great risk of being affected by mental retardation or impaired cognitive development. In later life they will, probably, be unable to transform and improve themselves and their communities, perpetuating the poverty of the region. Therefore, knowledge of factors involved in CNS development is a matter of health closely related to social improvement. Malnutrition throughout pregnancy and breastfeeding is clearly identifiable as a cause of damage in CNS development. Vitamin B1 (Thiamine) is a micronutrient important to the growth and maturity of the CNS. Thiamine shortcoming may affect 50% of pregnant women. Thiamine function in cerebral development is still not well known. There is a gap in the literature regarding systematical research about the blood thiamine concentration throughout the periods of gestation and breastfeeding. These studies are relevant in populations with a high level of nutritional vulnerability, because in a follow up offspring cognitive exam they could reveal if the maternal thiamine deficiency is related to child CNS impairment. This paper introduce the hypothesis that thiamine shortcoming during pregnancy and breastfeeding is directly related to cognitive impairment of child. Data about the neurophysiological role of thiamine, consequences of its shortcoming in experimental models, populations under the risk of thiamine shortcoming are presented. The hypothesis that maternal thiamine shortcoming causes damage related to child cognitive development needs to be considered. Thus, thiamine shortcoming during gestation and breastfeeding and its effects on children must be studied in many populations in order to know the magnitude of the problem and to indicate actions to overcome it. PMID- 23098376 TI - Does infectious fever relieve autistic behavior by releasing glutamine from skeletal muscles as provisional fuel? AB - First reported formally in 1980, the frequent ability of infectious fever to relieve autistic behavior, often dramatically (and rarely aggravate), has long tantalized parents, practitioners, and researchers - yet its physiology and biochemistry have never been investigated, to judge from the literature. Fever is a complex interplay of immune, metabolic, and stress responses, yet its benefit in autistic disorders (ASD) may derive largely from a single response - release of the amino acid glutamine from skeletal muscles as provisional fuel. This proposal is based on evidence of low blood and brain glutamine in ASD children and adults, notable lack of autistic behavior in children with high brain glutamine from urea cycle disorders, and other events that elicit dramatic improvements - fasting, panic, pain, and the corticosteroid prednisone - that release or synthesize glutamine. Glutamine released from muscles is metabolized by the intestines like ingested glutamine. If glutamine released by fever rarely aggravates autistic behavior, why would supplemental glutamine? PMID- 23098377 TI - Predicting carotid restenosis by comparison of plaque MCP-1 mRNA expression and serum levels. AB - As cardiovascular pathology grows in numbers, research into the discovery of new chemokine biomarkers should not be neglected, as they seem to be paramount in atherosclerosis prevention and its early detection. Chemokines attract and activate leukocytes and are well recognized in the environment of inflammatory response. MCP-1 is a valuable chemokine whose potential to become a new crucial atherosclerosis marker is surely worth investigating. Since quantities of MCP-1 found in lesions are as low as immeasurable, we propose the use of an immunohistochemical method for the quantification of MCP-1 levels in atherosclerotic lesions. Additionally, serum levels of MCP-1 can be measured by commercially available immunoassays. Proposed MCP-1 concentration increase may explain the acceleration in lesion's atherosclerosis progression as chemokine activation occurs once they bind to specific ligands. If proven, this hypothesis would indicate the need for further studies in order to objectively link the increased MCP-1 expression with carotid restenosis. PMID- 23098378 TI - Frequency of well-identified oncogenic driver mutations in lung adenocarcinoma of smokers varies with histological subtypes and graduated smoking dose. AB - PURPOSE: We performed this analysis to reveal the association between six well identified oncogenic driver mutations and clinical and pathological features in lung adenocarcinomas from smokers. It may have the potentiality to optimize existing treatment strategies and clinical trial design. METHODS: In this series, 230 resected lung adenocarcinomas from smoker (>100 cigarettes in lifetime) at single center (Shanghai Cancer Center, Shanghai, China) were tested for mutation in EGFR, KRAS, BRAF, HER2, EML4-ALK and PIK3CA. Further we compared the mutation frequency with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype. RESULTS: Among 230 smokers, we detected 100 (43.5%) EGFR mutations, 38 (16.5%) KRAS mutations, 8 (3.5%) PIK3CA mutations, 7 (3.0%) BRAF mutations and 7 (3.0%) EML4-ALK fusions. No HER2 mutation was found. EGFR mutations occurred at a significantly higher frequency in patients with smoking dose <=20 pack-years (p < 0.001) or age >=60 years old at diagnosis (p = 0.018). Smoking dose >20 pack-years and age <60 years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation frequency, EGFR mutation had positive correlation with histological subtype micropapillary (p = 0.003), lepidic (p = 0.011), as well as papillary (p = 0.05) predominant adenocarcinoma. Negative correlation was found between EGFR mutation and solid predominant (p < 0.001), as well as invasive mucinous adenocarcinoma (IMA) (p = 0.006). Besides, KRAS mutation had positive correlation with IMA (p = 0.043). The frequency of EGFR mutation decreased with increasing tobacco dose. In contrast, higher frequency of KRAS mutations was observed with increasing tobacco dose. Generally, the frequency of these driver mutations tested in our study decreased with increasing smoking dose. CONCLUSIONS: This study represents the first comprehensive and concurrent analysis of these six well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases. PMID- 23098379 TI - Experimental quantification of electrostatics in X-H...pi hydrogen bonds. AB - Hydrogen bonds are ubiquitous in chemistry and biology. The physical forces that govern hydrogen-bonding interactions have been heavily debated, with much of the discussion focused on the relative contributions of electrostatic vs quantum mechanical effects. In principle, the vibrational Stark effect, the response of a vibrational mode to electric field, can provide an experimental method for parsing such interactions into their electrostatic and nonelectrostatic components. In a previous study we showed that, in the case of relatively weak O H...pi hydrogen bonds, the O-H bond displays a linear response to an electric field, and we exploited this response to demonstrate that the interactions are dominated by electrostatics (Saggu, M.; Levinson, N. M.; Boxer, S. G. J. Am. Chem. Soc.2011, 133, 17414-17419). Here we extend this work to other X-H...pi interactions. We find that the response of the X-H vibrational probe to electric field appears to become increasingly nonlinear in the order O-H < N-H < S-H. The observed effects are consistent with differences in atomic polarizabilities of the X-H groups. Nonetheless, we find that the X-H stretching vibrations of the model compounds indole and thiophenol report quantitatively on the electric fields they experience when complexed with aromatic hydrogen-bond acceptors. These measurements can be used to estimate the electrostatic binding energies of the interactions, which are found to agree closely with the results of energy calculations. Taken together, these results highlight that with careful calibration vibrational probes can provide direct measurements of the electrostatic components of hydrogen bonds. PMID- 23098380 TI - Poor sleep quality as a risk factor for lapse following a cannabis quit attempt. AB - Treatments for cannabis dependence are associated with high rates of lapse/relapse, underscoring the importance of identifying malleable risk factors that are associated with quit failure. Whereas research has demonstrated that poor sleep quality following cannabis discontinuation is related to subsequent use, there has yet to be an examination of whether poor sleep quality prior to a quit attempt results in a similar pattern of lapse. The present study addressed this gap by examining the role of pre-quit sleep quality on early lapse to cannabis use following a self-guided quit attempt, among 55 cannabis dependent military veterans. Results indicated that participants who experienced poor pre quit sleep quality had greater risk for lapse within the first 2 days (out of 7) following their quit attempt. Findings are discussed in terms of improving treatments for individuals who report poor sleep quality prior to a cannabis quit attempt. PMID- 23098381 TI - Validation and comparison of diagnostic accuracy of four screening tools for mental disorders in people seeking treatment for substance use disorders. AB - This study aimed to validate and compare performance of four screening tools for mental disorders in a heterogeneous population seeking substance use treatment. A total of 544 clients were recruited prospectively from three treatment centres and completed the screening instruments followed by a reference standard psychiatric interview for research diagnosis. Performance relative to the reference standard was compared across instruments using receiver operator characteristic (ROC) analysis. Screening tools included the GAIN-SS-IDScr; the K6, the Psychiatric Sub-scale of the Addiction Severity Index, and the Psychiatric Diagnostic Screening Questionnaire. All the screening tools performed reasonably well detecting broad groupings of disorders-any past-month disorder, any depressive disorder, anxiety disorder or psychotic disorder, with the GAIN-SS IDScr being most efficient due to its shorter length. Results strengthen previous validation data for each of the tools investigated and support their use in detecting mental disorders in the substance use treatment population specifically. PMID- 23098382 TI - Multimodality cardiac imaging of a ventricular septal rupture post myocardial infarction: a case report. AB - BACKGROUND: Ventricular septal rupture (VSR), a mechanical complication following an acute myocardial infarction (MI), is thought to result from coagulation necrosis due to lack of collateral reperfusion. Although the gold standard test to confirm left-to-right shunting between ventricular cavities remains invasive ventriculography, two-dimensional transthoracic echocardiography (TTE) with color flow Doppler and cardiac MRI (CMR) are reliable tests for the non-invasive diagnosis of VSR. CASE PRESENTATION: A 62-year-old Caucasian female presented with a late case of a VSR post inferior MI diagnosed by multimodality cardiac imaging including TTE, CMR and ventriculography. CONCLUSION: We review the presentation, diagnosis and management of VSR post MI. PMID- 23098383 TI - An fMRI study of the activation of the hippocampus by emotional memory. AB - The current study examined the role of the hippocampus in emotional memory encoding using functional magnetic resonance imaging (fMRI). The present study examined the activation patterns of 12 healthy participants who were associated with memory for words and pictures with moderately high emotional tone. Results revealed significant activation in the temporal and frontal lobes for emotional and neutral stimuli. There was greater activation in the left hippocampus for emotional words and the right hippocampus for emotional pictures. However, a separate analysis of gender suggested that the emotional responses of the women accounted for the activation of the hippocampus; men did not have a pattern of hippocampus activation consistent with the type of stimuli. These findings have important implications for the design of a clinical memory assessment using fMRI. PMID- 23098385 TI - Optimal surgical extent of lateral and central neck dissection for papillary thyroid carcinoma located in one lobe with clinical lateral lymph node metastasis. AB - BACKGROUND: The indications and extent of cervical lymph node dissection in papillary thyroid carcinoma (PTC) are still being debated. The aim of this study was to analyze the patterns of cervical lymph node metastasis in the lateral and central compartment and related factors and suggest the optimal extent of lateral and central neck dissection for PTC patients with clinical lateral lymph node metastasis. METHODS: We retrospectively analyzed 72 patients with unilateral PTC who underwent therapeutic lateral neck dissections with concomitant total thyroidectomy and central neck dissection between January 2001 and December 2009. RESULTS: The 72 patients underwent 79 sides of therapeutic lateral neck dissection. The most frequent metastatic level in the ipsilateral lateral compartment was level IV (75.0%), followed by level III (69.4%), level II (56.9%) and level V (20.8%). Multiple level metastases were common (77.8%) and were correlated with tumor size (>= 10 mm). The central compartment lymph node metastasis rate was 87.5%, including 26.4% of contralateral central compartment metastases. CONCLUSION: In PTC patients with clinical lateral lymph node metastasis, the optimal extent of lateral and central neck dissection should include levels II, III, IV and V as well as the bilateral central compartment. PMID- 23098384 TI - Small things make a big difference: particulate matter and exercise. AB - The increased risk of morbidity and mortality among adults and children with pre existing cardiovascular or respiratory illness from emission-derived particulate matter (PM) is well documented. However, the detrimental effects of PM inhalation on the exercising, healthy population is still in question. This review will focus on the acute and chronic responses to PM inhalation during exercise and how PM exposure influences exercise performance. The smaller ultrafine PM (<0.01 MUm aerodynamic diameter) appears to have the most severe health consequences compared with the larger coarse PM (2.5 < PM <10 MUm aerodynamic diameter). While the response to PM inhalation may affect those with a pre-existing condition, the healthy population is not immune to the effects of PM inhalation, especially during exercise. This population, including the competitive athlete, is susceptible to pulmonary inflammation, decreased lung function (both acute and chronic in nature), the increased risk of asthma, vascular endothelial dysfunction, mild elevations in pulmonary artery pressure and diminished exercise performance. PM exposure is usually associated with vehicular traffic, but other sources of PM, including small engines from lawn and garden equipment, cigarette smoke, wood smoke and cooking, may also impair health and performance. The physiological effects of PM are dependent on the source of PM, various environmental factors, physical attributes and nature of exercise. There are a number of measures an athlete can take to reduce exposure to PM, as well as the deleterious effects that result from the inevitable exposure to PM. Considering the acute and chronic physiological responses to PM inhalation, individuals living and exercising in urban areas in close proximity to major roadways should consider ambient air pollution levels (in particular, PM and ozone) prior to engaging in vigorous exercise, and those exposed to PM through other sources may need to make lifestyle alterations to avoid the deleterious effects of PM inhalation. Although it is clear that PM exposure is detrimental to healthy individuals engaging in exercise, further research is necessary to better understand the role of PM on athlete health and performance, as well as measures that can attenuate the harmful effects of PM. PMID- 23098387 TI - An important role for initial observation in the management of paediatric desmoid fibromatosis. PMID- 23098386 TI - Assessment of unconsciousness in pigs during exposure to nitrogen and carbon dioxide mixtures. AB - The aim of this study was to assess unconsciousness in pigs during and after the exposure to gas mixtures of 70% nitrogen (N(2)) and 30% carbon dioxide (CO(2)) (70N30C), 80% N(2) and 20% CO(2) (80N20C) and 85% N(2) and 15% CO(2) (85N15C) compared with 90% CO(2) in air (90C) by means of the Index of Consciousness((r))(IoC), their behaviour and the absence of brain stem reflexes. The experiment included three trials of 24 pigs divided into four groups according to the number of treatments. Half of the group was exposed for a short time and the other half for a long time (3 and 5 min for the N(2)/CO(2) mixtures exposure and 2 and 3 min in 90C exposure, respectively). During exposure, the IoC and the electroencephalography suppression rate (ESR) were assessed, as well as the time to onset and percentage of gasping, loss of balance, vocalizations, muscular excitation and gagging. At the end of the exposure, the corneal reflex, rhythmic breathing and sensitivity to pain were each assessed at 10 s intervals for 5 min. Brain activity decreased significantly (P < 0.05) 37.60 s after the start of the exposure to 90% CO(2), which was significantly earlier than in 70N30C, 80N20C and 85N15C exposure, (45.18 s, 46.92 s and 43.27 s, respectively). Before brain activity decreased, all pigs experienced gasping and loss of balance and a 98% muscular excitation. The duration of the muscular excitation was longer in animals exposed to 70N30C, 80N20C and 85N15C than 90C (P < 0.01). After a long exposure time, all animals exposed to 90C died, whereas the 30.4% of animals exposed to N(2)/CO(2) gas mixtures survived. Pigs exposed to 85N15C recovered corneal reflex and sensitivity to pain significantly earlier than when exposed to 90C. Exposure to 90C causes a higher aversive reaction but a quicker loss of consciousness than N(2)/CO(2) gas mixtures. Exposure to N(2)/CO(2) gas mixtures causes a lower percentage of deaths and an earlier recovery of the brain stem activity than 90C, whereas the time to recover the cortical activity is similar. In conclusion, the inhalation of N(2)/CO(2) gas mixtures reduces the aversion compared with high concentrations of CO(2); however, the period of exposure for inducing unconsciousness may be longer in N(2)/CO(2) gas mixtures, and the signs of recovery appear earlier, compared to CO(2). PMID- 23098388 TI - Preoperative detection of the neurovascular relationship in trigeminal neuralgia using three-dimensional fast imaging employing steady-state acquisition (FIESTA) and magnetic resonance angiography (MRA). AB - Microvascular decompression is an accepted treatment for trigeminal neuralgia (TN). Preoperative identification of neurovascular compression, therefore, could aid determination of the appropriate treatment for TN. To preoperatively visualize the neurovascular relationship, three-dimensional fast imaging employing steady-state acquisition (3D FIESTA) and magnetic resonance angiography (MRA) were performed on 37 patients with TN in our study. 3D FIESTA in combination with MRA identified surgically verified neurovascular contact in 35 of 36 symptomatic nerves. The offending vessel (artery or vein) was correctly identified in 94.4% of patients, and agreement between preoperative MRI visualization and surgical findings was excellent (k=0.92; 95% confidence interval, 0.67-1.00). Thus, 3D FIESTA in combination with MRA is useful in the detection of vascular contact with the trigeminal nerve in patients with TN. PMID- 23098389 TI - A cross-sectional study of clinical management, and provision of health services and their utilisation, by patients with Parkinson's disease in urban and regional Victoria. AB - Our objective was to evaluate and compare clinical management, utilisation of health services and quality of life (QoL) in patients with Parkinson's disease (PD) attending clinics in urban and regional Victoria. A cross-sectional survey was conducted on 210 patients with PD attending specialist neurological clinics in a regional area (Ballarat) (n=97), and an urban area (Melbourne) (n=113), Victoria. Demographic characteristics of patients with PD, QoL, patterns of disease and management and utilisation of medical and allied health services were analysed. Compared to patients with PD from urban clinics, patients in the regional clinic were significantly older and were diagnosed at a later age with a shorter duration of treatment (all p<0.05). Despite no significant difference in disease severity (measured by Unified Parkinson's Disease Rating Scale scores) between the groups, patients in the urban clinic reported a lower QoL (p=0.003). Patients in the regional clinic were more satisfied with their treatment, despite seeing their medical specialist less frequently (p<0.001) and having a higher rate of early misdiagnosis (p=0.015). Patients from regional clinics reported a poorer understanding of their illness than patients in the urban clinic (p=0.049). Half of all respondents were interested in using telemedicine services. Two-thirds (71%) of all patients used allied health services, with patients in the urban clinic utilising more and desiring greater access to these services (p<0.05). In conclusion, we found significant differences in the presentation, management and use of health services between patients accessing regional and urban PD clinics in Victoria. Telemedicine may be an effective, and even desirable, method for facilitating improved diagnosis and referral for appropriate therapies. PMID- 23098390 TI - Prevalence of headache among children and adolescents in Shanghai, China. AB - The aims of this study were to estimate the prevalence of headache subtypes and headache-specific disability among children and adolescents in Shanghai, China, and to assess the validity and reliability of the ID-migraine questionnaire in this population. Of 4812 students who completed the questionnaire, 466 (9.68%) had experienced a headache in the past 3 months. Of the 466 headache sufferers, 44.85% were classified as having migraine. The proportion of migraine varied with age from 23.29% to 43.48%, and high proportions were found at ages 14 years and 15 years. The average proportion of: tension-type headache was 29.18%, and the proportions of cluster and other headache were 6.22% and 19.74%, respectively. According to the Paediatric Migraine Disability Assessment Score classification, the percentage of headache sufferers with grade I disability ranged from 40.54% to 71.43% across age groups and was 61.24% overall. The overall sensitivity of the ID-migraine screening questionnaire was 39.71% and the specificity was 46.63%. PMID- 23098391 TI - Central nervous system lymphoma in immunocompetent patients: the North Shore-Long Island Jewish Health System experience. AB - Of the 74 immunocompetent patients diagnosed between July 2004 and June 2011 at the North Shore University Hospital and Long Island Jewish Medical Center with primary central nervous system lymphoma, 71 (95.9%) had diffuse large B-cell lymphomas (DLBCL). The median patient age was 68 years (range: 19-87 years) with a slight male preponderance (1.1:1). The overall median survival time was 21 months. For patients older than 70 years, the median survival time was 8 months while for those 70 years or younger, the median survival time was 27 months (p<0.01). Female patients had a worse prognosis than male patients (p<0.05, median survival time, 17 months compared to 23 months). We had enough data from 52 of these 71 patients to define the lymphomas as either germinal center B-cell like (GCB) or activated B-cell-like (ABC) DLBCL. Of these 52 patients, 42 (80.8%) had ABC DLBCL while only 10 (19.2%) had GCB DLBCL. The patients in the GCB subgroup seemed to survive longer than the patients in the ABC subgroup, although the difference did not reach statistical significance. No statistically significant difference in overall survival was seen between patients with BCL-6 positive or negative DLBCL; or between patients with BCL-2 positive or negative DLBCL. PMID- 23098392 TI - [Comparative efficacy of conservative and invasive treatment of patients with stable form of ischemic heart disease (according to results of five year prospective study)]. AB - Despite high immediate efficacy of percutaneous coronary interventions (PCI) in relation to symptoms of angina the problem of influence of this method of treatment on duration of life and prognosis in stable ischemic heart disease (IHD) remains unsolved. Aim of our study was to compare efficacy of conservative therapy with drugs of proven effect on prognosis and of percutaneous coronary interventions in combination with optimal drug therapy in patients with stable ischemic heart disease (IHD) during 5 years of follow up. We included into this study 503 patients (387 men and 116 women, mean age 59 years). Groups of conservative and invasive treatments comprised 179 and 302 patients, respectively; mean durations of follow-up were 5.6+/-1.3 and 4.1+/-1.6 years, respectively, p=0.001. Study end points were fatal and nonfatal cardiovascular complications (CVC) (cardiovascular death, acute coronary syndrome, transitory ischemic attack, peripheral arterial thrombosis) and composite endpoint defined as sum of all CVC and cases of revascularization of the involved vascular bed. Cumulative rates of all fatal and nonfatal CVCs was 5.3 and 4.8 per 100 patient/years in groups of conservative and invasive treatment, respectively (relative risk [RR] 0.96, 95% confidence interval [CI] 0.6 to 1.5; p=0.9). Rates of composite end point were 7.1 and 7.3 per 100 years in groups of conservative and invasive treatment, respectively (relative risk [RR] 1.02, 95% confidence interval [CI] 0.7 to 1.3; p=0.8). According to the presence of independent clinical predictors of worst prognosis (class II-III angina, history of myocardial infarction, three vessel or left main stem coronary artery disease, concomitant signs of atherothrombosis in cerebral and peripheral vascular beds, obesity, abnormal renal function, history of erosive gastritis) all patients were divided in groups of low, moderate, and high risk. In low risk IHD patients invasive strategy worsened remote prognosis of myocardial infarction, stroke, and cardiovascular death, as well as of repetitive revascularization. PMID- 23098393 TI - [Control of myocardial ischemia in patients with effort angina and polyvascular atherosclerotic involvement]. AB - In patients with ischemic heart disease with various degree of severity of atherosclerotic involvement of peripheral arteries maintenance of target levels of arterial pressure and heart rate with the help of therapy which includes cardioselective -adrenoblocker as a preparation of choice with addition if necessary of a calcium antagonist and angiotensin converting enzyme inhibitor allows to successfully control myocardial ischemia and heart rate under conditions of everyday life. PMID- 23098394 TI - [The role of markers of inflammation in assessment of prognosis in patients with ST-elevation myocardial infarction combined with disturbances of carbohydrate metabolism]. AB - Diabetes mellitus (DM) is not only an independent risk factor (RF) of development of atherosclerosis, but it substantially worsens prognosis of patients with acute myocardial infarction (MI). Results of this study evidence that presence of disturbances of carbohydrate metabolism (DM or impaired glucose tolerance (IGT) in patients with ST elevation MI manifests with higher activity of the inflammatory process compared with patients with MI without abnormalities of carbohydrate metabolism. Unfavorable 1 year prognosis in patients with ST elevation MI is associated with higher concentrations of inflammation markers assessed on days 10-14 from onset of the disease: in patients with DM and IGT- of sCD40 ligand, in patients without disturbances of carbohydrate metabolism - C reactive protein, in all patients irrespective of presence of carbohydrate metabolism abnormalities - interleukin 12. PMID- 23098395 TI - [Assessment of the prognostic value of the CRUSADE score in patients with acute coronary syndromes hospitalized in a noninvasive hospital]. AB - Background. The CRUSADE score was created for assessment of bleeding risk in patients with acute coronary syndrome (ACS). However its accuracy was not confirmed in populations of patients treated in Russian hospitals, in noninvasively managed patients, in patients without myocardial infarction (MI). Aim. To assess prognostic value of the CRUSADE score in all pts with ACS, hospitalized in a noninvasive hospital in Russia. Material and methods. Study group comprised 602 patients with ACS admitted to a Moscow community noninvasive hospital (mean age 69.6+/-12.4 years, non-ST elevation ACS - 84.2%). The group was formed by inclusion of 25 consecutively hospitalized patients per month. During hospitalization we registered deaths and all bleeding events classified by TIMI and/or GUSTO criteria. The cut-off of high bleeding risk for CRUSADE score was 40. Results. Any bleedings occurred in 91 patients (15.1%), combination of major and moderate bleedings was registered in 36 patients (6.0%). In high bleeding risk group by CRUSADE score in comparison with non-high risk group bleedings were significantly more frequent (total 20.8 vs. 9.9%, respectively, p=0.0002; major 6.9 vs 1.9%, respectively, p=0.0024; moderate 5.2% vs 1.6%, respectively, p=0.013; combination of major and moderate 9.4 vs 2.9%, respectively, p=0.0007). Sensitivity and specificity of the CRUSADE score for sum of major and moderate bleedings during hospitalization were 77% and 52%, respectively, with area under ROC-curve 0.68. We selected 149 patients (24.8%) who had similar characteristic with patients of the CRUSADE derivation cohort (non-ST elevation MI, no use of vitamin K antagonists, survival and no discharge 48 hours after admission). In this CRUSADE-specific group rate of major/moderate bleedings was significantly higher among high risk compared with other patients (15.6% vs 3.5%, respectively, p=0.016), but for all bleedings difference between these groups was not significant (28.1 vs. 17.6%, p=0.16). In the CRUSADE specific group sensitivity and specificity of the CRUSADE score for major/moderate bleedings during hospitalization were 81 and 59%, respectively, with area under ROC-curve 0.76. Conclusions. In noninvasively treated ACS patients high risk of bleeding by CRUSADE score was closely associated with occurrence of total as well as major and moderate bleedings. Prognostic accuracy of the CRUSADE score for prediction of major or moderate bleeding during hospitalization was higher in CRUSADE-specific group (patients satisfying criteria of the CRUSADE derivation cohort). PMID- 23098396 TI - [Effect of various types of antihypertensive therapy on elasticity of arterial wall in elderly patients with hypertensive disease and nonvalvular atrial fibrillation]. AB - Basing on the data of ultrasound study we compared effects of various antihypertensive therapies on elastic properties of common carotid arteries and the thoracic aorta in 133 patients aged 65-80 years with nonvalvular atrial fibrillation (AF). The use of perindopril, lercanidipin, valsartan and its combination with rosuvastatin was associated with elevation of the distensibility index of common carotid artery and lowering of coefficient of stiffness of aortic wall compared with the initial state. Combination of valsartan (80-160 mg/day) with rosuvastatin 10 (mg/day) produced most pronounced effect on compliance of vascular wall compared with other variants of treatment. Combination of valsartan and rosuvastatin can be considered an optimal strategy of antihypertensive therapy allowing to improve elastic properties of arterial wall in elderly patients with nonvalvular AF. PMID- 23098397 TI - [Biomarkers of inflammation in patients with chronic heart failure and implanted devices for cardiac resynchronization therapy]. AB - The aim of the study was to assess the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and inflammatory markers in patients with congestive heart failure (CHF) treated with cardiac resynchronization therapy (CRT). 97 patients (age 54.9+/-9.9 years; 87% men) with implanted CRT devices (median period after implantation 19.9+/-19.3 months) were enrolled. According to NT-proBNP level patients were divided into tertiles: first (n=36) - less than 848 pg/ml, second (n=29) - from 848 to 2936 pg/ml, and third (n=32) - more than 2936 pg/ml. We didnt find a relationship between inflammatory mediators, NT-probNP level and time after implantation. In the total group NT-proBNP significantly correlated with structural and functional parameters of the heart. In the first group in comparison with the third group levels of IL-6 were lower (pI-III=0.019) and levels of IL-l - higher (pI-III=0.006). IL-10, CRP, TNF- did not differ between groups. In the first group IL-l straightly correlated with IL-6, TNF- , IL-10 and left ventricular ejection fraction (LVEF), in the third group IL-6 straightly correlated with CRP, while correlation of IL-l with LVEF became negative. We suppose that in patients with mild HF IL-l can play an adaptive role. High levels of IL-6, CRP probably can be used as markers of CHF progression in patients treated with CRT. PMID- 23098398 TI - [Special features of coronary artery involvement in women with rheumatoid arthritis]. AB - Aim of the study was to assess the state of coronary arteries and to reveal peculiarities of their involvement in women with rheumatoid arthritis (RA). We examined 51 women: 30 patients with RA and 21 women of the control group. Average age of patients with RA was 49+/-7.4, of control subjects - 47+/-9 years. Examination of coronary arteries was performed by a 64-spiral computer tomography (LightSpeed VCT, GE). Coronary calcium was assessed using the SmartScore and calcium score by the Agatston scale. Different changes of coronary arteries were diagnosed in 44% of patients with RA and in 19% of subjects of the control group. Coronary atherosclerosis was detected in 34%, calcification of coronary arteries in 27% of patients with RA. Average degree of coronary artery stenosis in patients with RA was 2.2 times greater than in the control group. In RA prevailed multiple involvement of coronary arteries with large number of atherosclerotic plaques. Hemodynamically significant stenoses were diagnosed only in patients with RA. PMID- 23098399 TI - [Gender peculiarities of development of atherosclerosis and impairment of brain oxygen supply in excessive body weight]. AB - Aim of the given study was to elucidate special characteristics of mechanisms of development of atherosclerosis and supply of oxygen to the brain in overweight men and women. We included into this study 80 patients with multifocal atherosclerosis without history of myocardial infarction. We analyzed parameters of blood lipid composition, data of cerebral oxymetry, echocardiography, and central hemodynamics. We found gender linked differences in structural-functional parameters of myocardium and in mechanisms of progression of atherosclerosis which increased with increase of excess body weight. This was associated with differences in oxygen brain supply between men and women. PMID- 23098400 TI - [Relationship between carotid artery intima media thickness and risk factors of cardiovascular diseases in young men]. AB - Positive correlation between age, leading risk factors of cardiovascular diseases (CVD), and carotid artery intima-media thickness (IMT) has been shown in numerous studies. Contingent of the present work was a part of long term cohort study initiated in 1983. We included in analysis data from 233 men in 120 of whom we measured IMT of right and left common carotid arteries. Other examinations included use of standard questionnaire for detection of CVD risk factors, measurement of blood serum lipid and glucose levels, arterial pressure, pulse, body mass and length, waist and hip circumferences (WC, HC), skin fold thicknesses on triceps, abdomen and forearm. We found that carotid artery IMT was related to hereditary load by CVD along paternal line. Substantial influence on the realization of unfavorable inheritance exerted level of systolic arterial pressure. Difference in magnitude of carotid artery IMT between groups of men with normal body mass and obesity were conditioned by variations in severity of abdominal obesity (WC/HC). IMT of carotid arteries in men directly depended on magnitude of their abdominal obesity and age. PMID- 23098401 TI - [Functional properties of endothelium of peripheral vessels in adolescents]. AB - In a random sample of adolescent schoolchildren (n=204) we assessed functional state of endothelium of brachial artery by test with reactive hyperemia. The data obtained was compared with values of arterial pressure and nutritional status of these adolescents and results of questionnaire survey of their parents concerning heredity and lifestyle. In 12.4% of examined subject values of flow mediated vasodilation were abnormal (less than 10%). We found that these abnormalities were most often observed in adolescents with hereditary predisposition to cardiovascular diseases, elevated arterial pressure, excess of fatty mass, inactive way of life. PMID- 23098402 TI - [Assessment of fractional coronary blood flow reserve]. AB - Coronary angiography despite all its advantages has a number of limitations. In some cases some supplementary means (methods of visualization such as intravascular ultrasound, optical coherent tomography, as well as determination of functional significance of atherosclerotisc lesions by means of measurement of fractional flow reserve) can help contemporary interventional cardiologist in deciding the problem of necessity of revascularization. We present in this review theoretical aspects of estimation of fractional flow reserve, method of its measurement, and drugs used for achievement of maximal hyperemia. PMID- 23098403 TI - [To the memory of the prominent cardiologist (to the 85th birthday of Academician M.M. Mirrakhimov)]. PMID- 23098404 TI - [Features of urapidil in treatment of resistant hypertension]. AB - The review considers the possibility of using capsule form urapidila for combination therapy for treatment-resistant hypertension. The drug has a dual mechanism of action and combining the properties of -blockers and centrally acting drug, has a high efficiency, comparable to that of other groups of drugs, and good tolerability. In a review of the features of the mechanism of action, pharmacokinetics, and pharmacodynamics of the drug. The data of the major studies that demonstrate the effectiveness of antihypertensive urapidila. Additional features - favorable metabolic effects, the ability to improve the patency of the bronchi and lower the pressure in the pulmonary artery and its organoprotective, allow us to recommend this drug for the treatment of patients with concomitant diseases. PMID- 23098405 TI - [Place of magnesium salts in the treatment of cardiovascular disease]. AB - The article examines the role of magnesium in the metabolism and the pathogenesis of common cardiovascular diseases, and provides research data on the use of magnesium salts as adjunctive therapy of these diseases. PMID- 23098406 TI - [How to prolong life of patients at high cardiovascular risk. Features of rosuvastatin]. PMID- 23098407 TI - [Endovascular application of the WATCHMAN device for prevention of thromboembolic complications in a patient with atrial fibrillation]. PMID- 23098408 TI - The impact of training non-physician clinicians in Malawi on maternal and perinatal mortality: a cluster randomised controlled evaluation of the enhancing training and appropriate technologies for mothers and babies in Africa (ETATMBA) project. AB - BACKGROUND: Maternal mortality in much of sub-Saharan Africa is very high whereas there has been a steady decline in over the past 60 years in Europe. Perinatal mortality is 12 times higher than maternal mortality accounting for about 7 million neonatal deaths; many of these in sub-Saharan countries. Many of these deaths are preventable. Countries, like Malawi, do not have the resources nor highly trained medical specialists using complex technologies within their healthcare system. Much of the burden falls on healthcare staff other than doctors including non-physician clinicians (NPCs) such as clinical officers, midwives and community health-workers. The aim of this trial is to evaluate a project which is training NPCs as advanced leaders by providing them with skills and knowledge in advanced neonatal and obstetric care. Training that will hopefully be cascaded to their colleagues (other NPCs, midwives, nurses). METHODS/DESIGN: This is a cluster randomised controlled trial with the unit of randomisation being the 14 districts of central and northern Malawi (one large district was divided into two giving an overall total of 15). Eight districts will be randomly allocated the intervention. Within these eight districts 50 NPCs will be selected and will be enrolled on the training programme (the intervention). Primary outcome will be maternal and perinatal (defined as until discharge from health facility) mortality. Data will be harvested from all facilities in both intervention and control districts for the lifetime of the project (3-4 years) and comparisons made. In addition a process evaluation using both quantitative and qualitative (e.g. interviews) will be undertaken to evaluate the intervention implementation. DISCUSSION: Education and training of NPCs is a key to improving healthcare for mothers and babies in countries like Malawi. Some of the challenges faced are discussed as are the potential limitations. It is hoped that the findings from this trial will lead to a sustainable improvement in healthcare and workforce development and training. TRIAL REGISTRATION: ISRCTN63294155. PMID- 23098409 TI - Complete mitochondrial genome of Leuciscus waleckii (Cypriniformes: Cyprinidae: Leuciscus). AB - The next generation genome sequencing technology and traditional polymerase chain reaction method were employed to obtain the complete mitochondrial genome of Amur ide (Leuciscus waleckii) from Dalinor Lake in Inner Mongolia, China. The mitogenome of Amur ide was determined to be 16,605 bp in length. It contains 13 protein-coding genes, 2 rRNA and 22 tRNA genes. This is the first report on the complete mitogenome sequence of Amur ide (L. waleckii). PMID- 23098410 TI - Atopy is not associated with poor control of asthma. AB - INTRODUCTION: Atopy is part of the immunopathology of allergic diseases; however, the effect of atopy on the prognosis of asthma in adult patients is not established yet. The aim of this study is to investigate whether there is an association between lack of control of asthma and sensitization to aeroallergens. The relation between rhinitis severity and atopy was also investigated. METHODS: Six hundred and thirty-nine patients aged >= 20 years with uncontrolled and untreated asthma were enrolled. They were followed for 1 year, received inhaled corticosteroids combined with long-acting beta-2 agonists, performed spirometry, skin prick test to aeroallergens, and reported emergency room visits due to asthma. Questionnaires (Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ)) were applied to evaluate asthma symptoms and quality of life. Rhinitis diagnosis and severity were evaluated. RESULTS: Baseline data demonstrated that atopic patients were younger and had earlier onset of asthma. Gender, body mass index, and lung function were similar between atopic and nonatopic patients. Low schooling had a borderline association with nonatopic asthma. Follow-up data demonstrated that there was no significant difference between atopic and nonatopic patients in asthma symptoms, quality of life, frequency of patients with uncontrolled asthma, emergency room visit, hospital admission, airway obstruction, nor response to treatment. Rhinitis severity was also similar between atopic and nonatopic individuals. CONCLUSIONS: In conclusion, positive skin prick test to common aeroallergens was not found to be predictor of asthma control among adults. PMID- 23098411 TI - Validation of a modified Medical Resource Model for mass gatherings. AB - INTRODUCTION: A modified Medical Resource Model to predict the medical resources required at mass gatherings based on the risk profile of events has been developed. This study was undertaken to validate this tool using data from events held in both a developed and a developing country. METHODS: A retrospective study was conducted utilizing prospectively gathered data from individual events at Old Trafford Stadium in Manchester, United Kingdom, and Ellis Park Stadium, Johannesburg, South Africa. Both stadia are similar in design and spectator capacity. Data for Professional Football as well as Rugby League and Rugby Union (respectively) matches were used for the study. The medical resources predicted for the events were determined by entering the risk profile of each of the events into the Medical Resource Model. A recently developed South African tool was used to predetermine medical staffing for mass gatherings. For the study, the medical resources actually required to deal with the patient load for events within the control sample from the two stadia were compared with the number of needed resources predicted by the Medical Resource Model when that tool was applied retrospectively to the study events. The comparison was used to determine if the newly developed tool was either over- or under-predicting the resource requirements. RESULTS: In the case of Ellis Park, the model under-predicted the basic life support (BLS) requirement for 1.5% of the events in the data set. Mean over-prediction was 209.1 minutes for BLS availability. Old Trafford displayed no events for which the Medical Resource Model would have under-predicted. The mean over-prediction of BLS availability for Old Trafford was 671.6 minutes. The intermediate life support (ILS) requirement for Ellis Park was under-predicted for seven of the total 66 events (10.6% of the events), all of which had one factor in common, that being relatively low spectator attendance numbers. Modelling for ILS at Old Trafford did not under-predict for any events. The ILS requirements showed a mean over-prediction of 161.4 minutes ILS availability for Ellis Park compared with 425.2 minutes for Old Trafford. Of the events held at Ellis Park, the Medical Resource Model under-predicted the ambulance requirement in 4.5% of the events. For Old Trafford events, the under-prediction was higher: 7.5% of cases. CONCLUSION: The medical resources that are deployed at a mass gathering should best match the requirement for patient care at a particular event. An important consideration for any model is that it does not continually under-predict the resources required in relation to the actual requirement. With the exception of a specific subset of events at Ellis Park, the rate of under prediction for this model was acceptable. PMID- 23098412 TI - Altitude Sickness in Climbers and Efficacy of NSAIDs Trial (ASCENT): randomized, controlled trial of ibuprofen versus placebo for prevention of altitude illness. AB - OBJECTIVE: To study the effectiveness of ibuprofen versus placebo in preventing acute mountain sickness (AMS) and high altitude headache (HAH). METHODS: Double blind, randomized, placebo-controlled trial. RESULTS: Two hundred ninety-four healthy Western trekkers were recruited on the Everest approach at 4280 m or 4358 m and randomly assigned to receive either 600 mg of ibuprofen or placebo 3 times daily before and during ascent to 4928 m. One hundred eighty-three of 294 participants completed the trial. Of the participants who did not complete the trial, 62 were lost to follow-up and another 49 broke trial protocol. In an intent-to-treat analysis (232 participants), ibuprofen was found to be more effective than placebo in reducing the incidence of AMS (24.4% vs 40.4%; P = .01) and the incidence of HAH (42.3% vs 60.5%; P < .01). Ibuprofen was also superior to placebo in reducing the severity of HAH (4.9% vs 14.7%; P = .01). The end point of oxygen saturation was also higher in the ibuprofen group (80.8 % vs 82.4%; P = .035). For the 183 participants who completed the trial and conformed to the protocol, the incidence of AMS between placebo and treatment groups was not significant (32.9% vs 22.7%; P = .129 for AMS incidence, 9.6% vs 8.2%; P = .74 for AMS severity, 54.8% vs 42.7%; P = .11 for HAH incidence, and 8.2% vs 3.6%; P = .18 for HAH severity). CONCLUSIONS: Ibuprofen was found to be effective in preventing AMS in the intent-to-treat analysis group but not in those who completed the trial. This loss of significance in the subjects who completed the trial may be explained by persons in the placebo group having a higher burden of illness and associated decreased compliance with the protocol. An important limitation of this study may be the possibility that ibuprofen can mask headache, which is a compulsory criterion for the diagnosis of AMS. PMID- 23098414 TI - The influence of teams to sustain quality improvement in nursing homes that "need improvement". AB - OBJECTIVES: Qualitatively describe the use of team and group processes in intervention facilities participating in a study targeted to improve quality of care in nursing homes "in need of improvement." DESIGN/SETTING/PARTICIPANTS: A randomized, two-group, repeated-measures design was used to test a 2-year intervention for improving quality of care and resident outcomes. Intervention group (n = 29) received an experimental multilevel intervention designed to help them: (1) use quality improvement methods, (2) use team and group process for direct-care decision-making, (3) focus on accomplishing the basics of care, and (4) maintain more consistent nursing and administrative leadership committed to communication and active participation of staff in decision-making. RESULTS: The qualitative analysis revealed a subgroup of homes ("Full Adopters") likely to continue quality improvement activities that were able to effectively use teams. "Full Adopters" had either the nursing home administrator or director of nursing who supported and were actively involved in the quality improvement work of the team. "Full Adopters" also selected care topics for the focus of their quality improvement team, instead of "communication" topics of the "Partial Adopters" or "Non-Adopters" in the study who were identified as unlikely to continue to continue quality improvement activities after the intervention. "Full Adopters" had evidence of the key elements of complexity science: information flow, cognitive diversity, and positive relationships among staff; this evidence was lacking in other subgroups. All subgroups were able to recruit interdisciplinary teams, but only those that involved leaders were likely to be effective and sustain team efforts at quality improvement of care delivery systems. CONCLUSIONS: Results of this qualitative analysis can help leaders and medical directors use the key elements and promote information flow among staff, residents, and families; be inclusive as discussions about care delivery, making sure diverse points of view are included; and help build positive relationships among all those living and working in the nursing home. Wide-spread adoption of the intervention in the randomized study is feasible and could be enabled by nursing home Medical Directors in collaborative practice with Advanced Practice Nurses. PMID- 23098413 TI - High-throughput isolation and characterization of untagged membrane protein complexes: outer membrane complexes of Desulfovibrio vulgaris. AB - Cell membranes represent the "front line" of cellular defense and the interface between a cell and its environment. To determine the range of proteins and protein complexes that are present in the cell membranes of a target organism, we have utilized a "tagless" process for the system-wide isolation and identification of native membrane protein complexes. As an initial subject for study, we have chosen the Gram-negative sulfate-reducing bacterium Desulfovibrio vulgaris. With this tagless methodology, we have identified about two-thirds of the outer membrane- associated proteins anticipated. Approximately three-fourths of these appear to form homomeric complexes. Statistical and machine-learning methods used to analyze data compiled over multiple experiments revealed networks of additional protein-protein interactions providing insight into heteromeric contacts made between proteins across this region of the cell. Taken together, these results establish a D. vulgaris outer membrane protein data set that will be essential for the detection and characterization of environment-driven changes in the outer membrane proteome and in the modeling of stress response pathways. The workflow utilized here should be effective for the global characterization of membrane protein complexes in a wide range of organisms. PMID- 23098415 TI - Indicators of benzodiazepine use in nursing home residents in France: a cross sectional study. AB - OBJECTIVES: Little information is available about associations between nursing home (NH) structural and organizational aspects and benzodiazepine prescriptions, particularly for long-acting drugs. This study addressed this knowledge gap. DESIGN: Cross-sectional study. SETTING: One hundred seventy-five NHs from France. PARTICIPANTS: A total of 6275 NH residents, aged 86 years (+/- 8.2), and mostly women (73.7%). MEASUREMENTS: Outcome measures were: (1) benzodiazepine and (2) long-acting benzodiazepine use. NH staff sent to research team all drug prescriptions in the week participants were included in the study; staff also recorded information on residents' characteristics, and NHs structure and internal organization. Binary logistic regressions were performed separately on total and long-acting benzodiazepine. RESULTS: A total of 3350 persons took benzodiazepine; 577 took long-acting benzodiazepine. Subject-related characteristics were the main correlates of benzodiazepine use. NH characteristics were also related to this outcome: number of beds >= 91 (Odds Ratio (OR) 0.820, 95% Confidence Interval (CI) 0.682-0.986), special care unit (OR 1.131, 95% CI 1.000-1.279), pharmacy for internal usage (OR 1.341, 95%CI 1.128-1.594), and date records of the first prescription of psychotropics (OR 1.394, 95% CI 1.209-1.607). Pharmacy for internal usage was also associated with long-acting benzodiazepine (OR 1.374, 95% CI 1.076-1.754). CONCLUSIONS: NH structure- and organization-related indicators impact benzodiazepine use among NH residents. This finding is of particular importance because these indicators are more easily modifiable than subject-related characteristics. Therefore, NH directors and medical staff should be aware about this to implement feasible modifications for reducing inappropriate and chronic benzodiazepine use. PMID- 23098416 TI - Perspective: Interventions are relevant in frail older adults. PMID- 23098417 TI - Physical functioning in older persons with somatoform disorders: a pilot study. AB - OBJECTIVES: The primary objective of this study was to systematically examine the physical functioning of older persons with somatoform disorders, as this has never been carried out before. Second, we wanted to test our hypothesis that higher somatic disease burden in patients with somatoform disorders is associated with a higher level of somatisation. DESIGN AND SETTING: Observational study of patients referred for medically unexplained symptoms (MUS) to our outpatient mental health center for older adults. The patients were offered a standardized, multidisciplinary diagnostic procedure, including a comprehensive geriatric assessment. Inter-rater reliability between two geriatricians assessing the contribution of somatic pathology to the main somatic symptom was assessed. PARTICIPANTS: A total of 37 patients referred for MUS (mean age 75 +/- 6 years). MEASUREMENTS: Timed up and go test (TUG) and hand grip strength were used as measures for frailty; the Cumulative Index Rating Scale for Geriatrics (CIRS-G) sum score and severity index measured the burden of cumulative somatic morbidity. The Groningen Activity Rating Scale (GARS) measured functional status. The Whitely Index was used as measure for somatisation. RESULTS: Patients' main symptom could be completely explained by a somatic disease in 3/37 (8%) patients (kappa between geriatricians = 0.72). A total of 32 patients met the criterion for a Somatoform Disorder according to DSM-IV-TR criteria, but somatic comorbidity partially explained the main symptom in 15/32 patients. These patients were older (P = .049), had more somatic comorbidity (P = .049), a slower gait speed (TUG, P = .035), a lower hand grip strength (P = .050), and a lower functional status (P = .30) compared with the 17 patients without any explanation for their main somatic symptom. In contrast to our hypothesis, a higher level of somatisation was associated with less somatic disease burden. CONCLUSION: Geriatric assessment has an important added value in older patients referred with medically unexplained symptoms because in half of these patients, symptoms can be partially or fully explicable following careful assessment of comorbidity and frailty. PMID- 23098418 TI - Suitability of healthcare robots for a dementia unit and suggested improvements. AB - OBJECTIVES: To investigate the suitability of a new eldercare robot (Guide) for people with dementia and their caregivers compared with one that has been successfully used before (Paro), and to generate suggestions for improved robot enhanced dementia care. DESIGN: Cross-sectional study. A researcher demonstrated both robots in a random order to each staff member alone, or to each resident together with his/her relative(s). The researcher encouraged the participants to interact with each robot and asked staff and relatives a series of open ended questions about each robot. SETTING: A secure dementia residential facility in Auckland, New Zealand. PARTICIPANTS: Ten people with dementia and 11 of their relatives, and five staff members. MEASUREMENTS: Each robot interaction was video taped and coded for the number of times the resident looked at, smiled, touched, and talked to and about each robot, as well as relative interactions with the resident. Qualitative analysis was used to code the open ended questions. RESULTS: Residents smiled, touched and talked to Paro significantly more than Guide. Paro was found to be more acceptable to family members, staff, and residents, although many acknowledged that Guide had the potential to be useful if adapted for this population in terms of ergonomics and simplification. CONCLUSION: Healthcare robots in dementia settings have to be simple and easy to use as well as stimulating and entertaining. This research highlights how eldercare robots may be adapted to have the best effects in dementia settings. It is concluded that Paro's sounds could be modified to be more acceptable to this population. The ergonomic design of Guide could be reviewed and the software application could be simplified and targeted to people with dementia. PMID- 23098419 TI - The utility of administrative data for neurotrauma surveillance and prevention in Ontario, Canada. AB - BACKGROUND: Surveillance of neurotrauma events is necessary to guide the development and evaluation of effective injury prevention initiatives. The aim of this paper is to review potential sources of existing population-based data to inform neurotrauma prevention in Canada, using sources available in Ontario as an example. Data sources, including administrative data holdings from Ontario's publicly funded health care system and ongoing national surveys, were reviewed to determine the degree of relevance for neurotrauma surveillance, using standards outlined by the World Health Organization as a framework. RESULTS: Five key data sources were identified for neurotrauma surveillance. Five other sources were considered useful; cause of injury was not identifiable in 5 additional sources; and 4 sources were not relevant for surveillance purposes. CONCLUSIONS: We provide information about which existing data sources are most relevant for neurotrauma surveillance and research, as well as examine the strengths and limitations of these sources. Administrative data can be used to facilitate surveillance of neurotrauma and are considered both useful and cost effective for the development and evaluation of injury prevention programs. PMID- 23098420 TI - Streaming parallel GPU acceleration of large-scale filter-based spiking neural networks. AB - The arrival of graphics processing (GPU) cards suitable for massively parallel computing promises affordable large-scale neural network simulation previously only available at supercomputing facilities. While the raw numbers suggest that GPUs may outperform CPUs by at least an order of magnitude, the challenge is to develop fine-grained parallel algorithms to fully exploit the particulars of GPUs. Computation in a neural network is inherently parallel and thus a natural match for GPU architectures: given inputs, the internal state for each neuron can be updated in parallel. We show that for filter-based spiking neurons, like the Spike Response Model, the additive nature of membrane potential dynamics enables additional update parallelism. This also reduces the accumulation of numerical errors when using single precision computation, the native precision of GPUs. We further show that optimizing simulation algorithms and data structures to the GPU's architecture has a large pay-off: for example, matching iterative neural updating to the memory architecture of the GPU speeds up this simulation step by a factor of three to five. With such optimizations, we can simulate in better than-realtime plausible spiking neural networks of up to 50 000 neurons, processing over 35 million spiking events per second. PMID- 23098421 TI - En bloc resection of extra-peritoneal soft tissue neoplasms incorporating a type III internal hemipelvectomy: a novel approach. AB - BACKGROUND: A type III hemipelvectomy has been utilized for the resection of tumors arising from the superior or inferior pubic rami. METHODS: In eight patients, we incorporated a type III internal hemipelvectomy to achieve an en bloc R0 resection for tumors extending through the obturator foramen or into the ischiorectal fossa. The pelvic ring was reconstructed utilizing marlex mesh. This allowed for pelvic stability and abdominal wall reconstruction with obliteration of the obturator space to prevent herniations. RESULTS: All eight patients had an R0 resection with an overall survival of 88% and with average follow up of 9.5 years. Functional evaluation utilizing the Enneking classification system, which evaluates motion, pain, stability and strength of the affected extremity, revealed a 62% excellent result and a 37% good result. No significant complications were associated with the operative procedure. Marlex mesh reconstruction provided pelvic stability and eliminated all hernial defects. CONCLUSION: The superior and inferior pubic rami provide a barrier to a resection for tumors that arise in the extra-peritoneal pelvis extending through the obturator foramen or ischiorectal fossa. Incorporating a type III internal hemipelvectomy with a simple marlex mesh reconstruction allows for complete tumor resection without functional compromise, acute infectious issues, obturator or abdominal hernia defects. PMID- 23098422 TI - Update of research on drug resistance in small cell lung cancer chemotherapy. AB - Small cell lung cancer (SCLC) is characterized by a short cell doubling time, rapid progression and early occurrence of blood-borne and lymph metastasis. The malignancy is the highest of all lung cancer types. Although SCLC has a relatively good initial response to chemotherapy as well as radiotherapy, relapse or disease progression may occur quickly after the initial treatment. Drug resistance, especially multi-drug resistance, is the most important cause of failure of SCLC chemotherapy. This article provides a brief update of research on mechanisms of drug resistance in SCLC and reversal strategies. PMID- 23098423 TI - Moderately hypofractionated conformal radiation treatment of thoracic esophageal carcinoma. AB - AIMS: To prospectively assess the efficacy and safety of moderately hypofractionated conformal radiotherapy in patients with thoracic esophageal cancer. METHODS AND MATERIALS: From Sept. 2002 to Oct. 2005, 150 eligible patients with T2-4N0-1M0 stage thoracic esophageal squamous cell cancers were enrolled to receive either conventional fractionated radiation (CFR) or moderately hypofractionated radiation (MHR) with a three- dimensional conformal radiation technique. Of the total, 74 received moderately hypofractionated radiation with total dose of 54-60 Gy/18-20 fractions for 3.5-4 weeks in the MHR arm, and 76 received conventional radiation with total dose of 60 Gy/30 fractions for 6 weeks in the CFR arm. Concurrent chemotherapy comprised of paclitaxel and cisplatin. Safety was evaluated, and local control and overall survival rates were calculated. RESULTS: Statistically significant differences between the CFR versus MHR arms were observed in local/regional failure rate (47.3% v 27.0%, P=0.034) and the percentage of patients with persistent local disease (26.3% v 10.8%, P=0.012). But 3 and 5-year overall survival rates (43.2%, 38.8% v 38.2%, 28.0%, respectively) were not different between the two arms (P=0.268). There were no significant differences in the incidences of grade 3 or higher acute toxicities (66.3% v 50.0%) and late complications rates (27.0% v 22.4%) between the MHR and CFR arms. CONCLUSIONS: Moderately hypofractionated, three-dimensional radiation treatment could improve the local control rate of esophageal cancer and potentially increase patient survival. PMID- 23098424 TI - Exon 8-9 mutations of DNA polymerase beta in ovarian carcinoma patients from Haldia, India. AB - BACKGROUND: Ovarian cancer is the number one killer among all the gynecological cancers. We undertook association study to identify potential alterations in the genomic DNA of a DNA repair gene, DNA polymerase beta (polbeta), involved in base excision repair (BER), in ovarian carcinomas of patients from Haldia, India. Mutations, splice variants have been reported earlier in different tumors other than ovarian tumors. AIM: In this study we explored the possibility of association of any mutation of pol beta (Exon 8) with prognosis in 152 ovarian cancer samples. RESULTS: Alteration in the exon 8 region (Exon 8:468, AgC; 15.1%) was noted among fifty seven polymorphism positive samples. Alteration in the intervening sequence 8 (IVS8, -25, AgC; 3.9%) was also noted. All alterations are heterozygous in nature. CONCLUSIONS: We found no significant association among the samples from serous type, stage IV, and the polbeta mutations (P <= 0.01). Only a slight tendency of association was evident between IVS8, -25, A to C; and stage III. Further analysis with a larger number of samples is needed. PMID- 23098425 TI - Efficacy of aprepitant in patients with advanced or recurrent lung cancer receiving moderately emetogenic chemotherapy. AB - AIMS AND BACKGROUND: To evaluate the efficacy of a combination of aprepitant and conventional antiemetic therapy in patients with advanced or recurrent lung cancer receiving moderately emetogenic chemotherapy (MEC). METHODS: Patients with advanced or recurrent lung cancer who were treated with MEC regimens at the Department of Respiratory Medicine, Fukuoka University Hospital, were included and classified into the following groups: control group (treatment: 5-HT3 receptor antagonists + dexamethasone) and aprepitant group (treatment: 5-HT3 receptor antagonists + dexamethasone + aprepitant). The presence or absence of chemotherapy-induced nausea and vomiting (CINV) was evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0; patients with grade 1 or above were considered positive for CINV. Food intake per day, completion of planned chemotherapy, and progression-free survival (PFS) achieved by chemotherapy were investigated. RESULTS: The complete suppression rate of nausea in the aprepitant group was significantly higher than that in the control group (p = 0.0043). Throughout the study, the food intake in the aprepitant group was greater than that in the control group, with the rate being significantly higher, in particular, on day 5 (p = 0.003). The completion rate of planned chemotherapy was also higher in the aprepitant group (p = 0.042). PFS did not differ significantly, but tended to be improved in the aprepitant group. CONCLUSIONS: The aprepitant group showed significantly higher complete suppression of nausea, food intake on day 5, and completion of planned chemotherapy than the control group. PMID- 23098426 TI - Translating evidence into practice in low resource settings: cervical cancer screening tests are only part of the solution in rural India. AB - BACKGROUND: The majority of women in rural India have poor or no access to cervical cancer screening services, although one-quarter of all cervical cancers in the world occur there. Several large trials have proven the efficacy of low tech cervical cancer screening methods in the Indian context but none have documented the necessary components and processes of implementing this evidence in a low-resource setting. METHODS: This paper discusses a feasible model of implementation of cervical cancer screening programme in low-resource settings developed through a pilot research project carried out in rural Tamilnadu, India. The programme used visual inspection of cervix after acetic acid application (VIA) as a screening tool, nurses in the primary care centres as the primary screeners and peer educators within Self-Help Women groups to raise community awareness. RESULTS: The uptake of screening was initially low despite the access to a screening programme. However, the programme witnessed an incremental increase in the number of women accessing screening with increasing community awareness. CONCLUSIONS: The investigators recommend 4 key components to programme implementation in low-resource setting: 1) Evidence-based, cost-effective test and treatment available within the reach of the community; 2) Appropriate referral pathways; 3) Skilled health workers and necessary equipment; and 4) Optimisation of health literacy, beliefs, attitudes of the community. PMID- 23098427 TI - Tobacco promotion and availability in school neighborhoods in India: a cross sectional study of their impact on adolescent tobacco use. AB - BACKGROUND: Adolescent tobacco use is a major public health problem. However, there is little information about the impact of tobacco advertising and availability near schools on adolescent tobacco use in India. METHODS: The various tobacco products and brands available in outlets within 100 meters of two high schools in an Indian town were identified. A stratified random sample of 172 participants from these two schools completed a questionnaire on tobacco use and socioeconomic status. RESULTS: Eighteen outlets selling tobacco products were identified. In the two schools the current use of smoked and smokeless tobacco was 9.1% and 17.4% respectively. School location and low socio-economic status of adolescents were associated with tobacco awareness of advertisements (p=0.001) and the receipt of a free sample (p= 0.032). Advertisements on billboards, posters and the receipt of a free tobacco sample were significant factors (p=0.031, p=0.016, p=0.017 respectively) in current tobacco use. CONCLUSION: In this study a significant proportion of adolescents used tobacco. Tobacco- promotion activities (advertising, the receipt of a free sample), school location and economic status were found to be associated with adolescent tobacco initiation. The local environment should be included in the prevention of adolescent tobacco initiation. PMID- 23098428 TI - Promoter methylation status of DNA repair gene (hMLH1) in gastric carcinoma patients of the Kashmir valley. AB - Cancer is a multi-factorial disease and variation in genetic susceptibility, due to inherited differences in the capacity to repair mismatches in the genome, is an important factor in the development of gastric cancer (GC), for example. Epigenetic changes, including aberrant methylation of 5/CpG islands in the promoter regions of mismatch repair (MMR) genes like hMLH1, have been implicated in the development of various types of GC. In the present study we evaluated the role of hMLH1 promoter hypermethylation in Kashmiri GC patients and controls, and assessed correlations with various dietary and lifestyle factors. The study included 70 GC patients (56 males and 14 females; age (mean +/- S.D) 50 +/- 11.4 years). Distinction between methylated and unmethylated was achieved with MS-PCR and DNA band patterns. The Chi-square test was applied to assess the risk due to promoter hypermethylation. We found a strikingly high frequency of promoter hypermethylation in GC cases than in normal samples (72.9% (51/70) in GC cases vs 20% (14/70) in normal samples (p=0.0001). We also observed a statistically significant association between methylated hMLH1 gene promoter and smoking, consumption of sundried vegetables and hot salted tea with the risk of GC. This study revealed that hMLH1 hypermethylation is strongly associated with GC and suggested roles for epigenetic changes in stomach cancer causation in the Kashmir valley. PMID- 23098429 TI - Identifying women's knowledge about risk factors of breast cancer and reasons for having mammography. AB - The aim of this study was to identify breast cancer risk factors and reasons for having mammography of the women who applied for mammography, as well as to determine their level of knowledge about risk factors and level of risk perception, and anxiety concerning breast cancer. This cross-sectional descriptive study was conducted from June 15, 2010 through September 10, 2010, in a university hospital in Ankara, Turkey. A questionnaire prepared by the researchers was used to collect the data. The mean age of the women was 52.1 +/- 9.98 years. Sixteen percent of the women had a family history of breast cancer. The majority of participants had mammograms (75.8%) before and had gained knowledge about breast cancer and its screening (73.7%). The leading source of information about breast cancer was physicians (46.2%). Physician recommendations, having breast-related complaints, and family history of breast cancer were important reasons to obtain mammography. The mean knowledge score about risk factors of breast cancer was 4.15 +/- 2.73 and the mean anxiety score was 1.65 +/- 1.61. It was found that some socio-demographic and obstetrical characteristics of women, their family history, and risk perceptions about breast cancer affect their knowledge and anxiety scores about breast cancer. In conclusion, the present study identified a number of factors affecting mammography participation for women. The results of this study can be helpful in promoting screening for breast cancer. PMID- 23098430 TI - Comparison of two ovarian malignancy prediction models based on age sonographic findings and serum CA125 measurement. AB - OBJECTIVE: The aim of our study is to compare an ovarian malignancy prediction model based on age and four sonographic findings (OMPS1) with a new model called OMPS2 which differs just by adding serum CA125 measurement to (OMPS1). METHODS: In a cross sectional comparative study OMPS1 was validated in 830 operated ovarian masses within a 3 years period (2006-2009). Logistic regression analysis was used to construct OMPS2 based on OMPS1 adding serum CA125 findings. The area under the curve for two models was compared in 411 patients. RESULTS: OMPS2 was calculated as follows: OMPS1 + 1.444 (if serum CA125= 36-200) or 3.842 (if serum CA125 is more than 200). AUC of OMPS2 was increased to 84.3% (CI 95% 78.1- 89.8) in comparison to OMPS1 with AUC of 78.1% (CI 95% 71.8-84.5). CONCLUSION: Our second model is more accurate in prediction of ovarian malignancy, compared with our first model. PMID- 23098431 TI - Serum oncofetal fibronectin (onfFN) mRNA in differentiated thyroid carcinoma (DTC): large overlap between disease-free and metastatic patients. AB - AIM: This study assessed if onfFN mRNA in the peripheral blood of patients with DTC can identify individuals with metastatic disease. METHODS: Comparison of onfFN mRNA was made among 3 groups: disease-free, lymph node metastasis, and distant metastasis using real-time RT-PCR on 5 ml blood samples from each DTC patient. RESULTS: Fifty-one patients were included: 30 (59%) were disease-free; 7 (13.7%) had lymph node metastasis; and 14 (27.5%) had distant metastasis. OnfFN mRNA levels in the 3 groups were significantly different (P=0.001) but with a large overlap and the expression being highest in the disease-free group. Subgroup analysis of the metastatic groups did not show any effect of age, cell type, and serum TSH, Tg, and antiTg on onfFN mRNA. The within-run and between-run root mean square coefficients of variations were <2%. CONCLUSION: OnfFN mRNA in patients with DTC cannot identify those with metastatic disease. PMID- 23098432 TI - Targeting tumor metastasis by regulating Nm23 gene expression. AB - The Nm23 gene is a metastatic suppressor identified in a melanoma cell line and expressed in different tumors where their levels of expression are associated with reduced or increased metastatic potential. Nm23 is one of the over 20 metastasis suppressor genes (MSGs) confirmed in vivo. It is highly conserved from yeast to human, implying a critical developmental function. Tumors with alteration of the p53 gene and reduced expression of the Nm23 gene are more prone to metastasis. Nm23-H1 has 3'-5' exonuclease activity. This review focuses on the role of Nm23 in cancer progression and also a potential novel target for cancer therapy. PMID- 23098433 TI - Primary small cell carcinoma of the urinary bladder--mini-review of the literature. AB - Primary small cell carcinoma of urinary bladder is a rare but aggressive disease with poor prognosis and a high mortality rate. It accounts for less than 1 % of all the primary cancers seen in the urinary bladder. Diagnosis and management of this entity poses a challenge to the clinician due to the lack of a standardized protocol for its treatment. Herein we discuss primary small cell carcinoma of the urinary bladder in its entirety. PMID- 23098434 TI - Tumour lysis syndrome: implications for cancer therapy. AB - The tumour lysis syndrome (TLS) is a group of metabolic abnormalities caused by rapid and unexpected release of cellular components into the circulation as a result of massive destruction of rapidly proliferating malignant cells. It usually develops in patients with hematologic malignancies like acute lymphoid leukemia, non-Hodgkin and Burkitt's lymphoma after initiation of chemotherapy or may, rarely, occur spontaneously. Though TLS is seldom observed in relation to solid tumours, there have been reports of connections with examples such as lung, liver, breast, gastric carcinomas. The clinical manifestations of TLS include hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. These indications if untreated lead to life-threatening complications such as acute renal failure, cardiac arrhythmias, seizures, and eventually death due to multiorgan failure. Therefore early detection of TLS is of vital importance. This can be accomplished by identification of high risk patients, implementation of suitable prophylactic measures and monitoring of the electrolyte levels in patients undergoing chemotherapy. PMID- 23098435 TI - Calcium sensing receptor modulation for cancer therapy. AB - The calcium sensing receptor (CaSR) is a member of the largest family of cell surface receptors, the G protein-coupled receptors involved in calcium homeostasis. The role of the CaSR in neoplasia appears to be homeostatic; loss of normal CaSR-induced response to extracellular calcium is observed in cancers of the colon and ovary, while increased release of PTHrP is observed in cancers of the breast, prostate and Leydig cells. Currently CaSR can be considered as a molecule that can either promote or prevent tumor growth depending on the type of cancer. Therefore, recognition of the multifaceted role of CaSR in gliomas and other malignant tumors in general is fundamental to elucidating the mechanisms of tumor progression and the development of novel therapeutic agents. Emphasis should be placed on development of drug-targeting methods to modulate CaSR activity in cancer cells. PMID- 23098436 TI - Importance of social support in cancer patients. AB - Social support is regarded as a complex construct which has long been suggested to have direct and buffering effects on patients' wellbeing and emotional adjustment to cancer. Cross-sectional and prospective studies show a positive association between perceived social support and psychological adjustment following cancer treatment. Research findings suggest that the evidence for the relationship between social support and cancer progression is sufficiently strong. This report points out the importance of social support in cancer and provides recommendations for health care professionals. PMID- 23098437 TI - SENP2 regulates hepatocellular carcinoma cell growth by modulating the stability of beta-catenin. AB - SUMOylation has emerged as an important post-translational modification that modulates the localization, stability and activity of a broad spectrum of proteins. A dynamic process, it can be reversed by a family of SUMO- specific proteases (SENPs). However, the biological roles of SENPs in mammalian development and pathogenesis remain largely elusive. Here, we demonstrated that SENP2 plays a critical role in the control of hepatocellular carcinoma cell growth. SENP2 was found to be down-regulated in hepatocellular carcinoma (HCC) tissues and over-expression suppressed the growth and colony formation of HCC cells. In contrast, silencing of SENP2 by siRNAs promoted cancer cell growth. We further found that stability of beta-catenin was markedly decreased when SENP2 was over-expressed. Interestingly, the decrease was dependent on the de SUMOylation activity of SENP2, because over-expression of a SENP2 catalytic mutant form had no obviously effects on beta-catenin. Our results suggest that SENP2 might play a role in hepatocellular carcinoma cell growth control by modulating the stability of beta-catenin. PMID- 23098438 TI - High and low dose folinic acid, 5-fluorouracil bolus and continuous infusion for poor-prognosis patients with advanced colorectal carcinoma. AB - OBJECTIVE: Evaluation and assessment of response rate, duration and toxicity in patients subjected to 5-FU based chemotherapy. BACKGROUND: The therapeutic ratio shifts with different 5FU/LV regimens and none yet serve as the internationally accepted Gold Standard. A bimonthly regimen of high dose leucovorin is reported to be less toxic and more effective than monthly low dose regimens. We here compare therapeutic responses and survival benefit of the two regimens in poor prognosis patients with advanced colorectal carcinoma. PATIENTS AND METHODS: A total of 35 patients with histologically confirmed colorectal carcinoma were subjected to de Gramont and Mayo Clinic regimen. Nineteen patients were treated with high dose folinic acid (200 mg/m2), glucose 5%, 5-FU (400 mg/m2) and 22 hr. CIV (600 mg/m2) for two consecutive days every two weeks. These patients had failed responses to previous chemotherapy and were above sixty years of age with poor general status. Sixteen patients (six below 60 years) with progressive disease were subjected to low dose folinic acid (20 mg/m2)for five days, 5FU(425 mg/m2) injection bolus for 5 days, every five weeks. An initial evaluation was made in sixty days and responders were reevaluated at sixty days interval or earlier in case of clinical impairment. Based on positive prognosis, the therapy was continued. Evaluation of treatment response was made on the basis of WHO criteria. RESULTS: The response rate was 44% in thirty four evaluable patients, with 4 complete responses (11.8%) and 11 (32.4%) partial responses. The two schedules were well tolerated, whereas, mild toxicity without WHO Grade >= 2 events was assessed. The response duration was extended (12 months) in a few patients with age above sixty years treated by high dose bimonthly regimen of 5FU/LV. CONCLUSION: The regimens are safe and effective in advanced colorectal carcinoma patients with poor general status. PMID- 23098439 TI - Practice and barriers of mammography among Malaysian women in the general population. AB - OBJECTIVE: The objective of this study was to determine the practice and barriers of mammography and associated factors among Malaysian women in the general population. METHODOLOGY: A cross-sectional study was conducted among 200 women in Shah Alam, Selangor; Malaysia. The questionnaire contained 27 questions and was comprised of two sections; socio-demographic characteristics and practices, knowledge and barriers of mammography. All the data were analyzed using the Statistical Package for the Social Sciences (SPSS) 13.0. RESULTS: Of the 200 Malaysian women who participated in this study, the majority were under the age of 50 years (65.5%), Malay (86%), and married (94.5%). Regarding any family history of cancer in general, the majority of the participants had none (78%). However, some did report a close relative with breast cancer (16.5%). While the majority of them knew about mammography (68%), 15% had had a mammogram once in their life and only 2% had the procedure every two or three years. Univariate analysis showed that age, family history of cancer, family history of breast cancer, regular supplement intake, regular medical check-up and knowledge about mammogram were significantly associated with mammogram practice among the general population (p=0.007, p=0.043, P=0.015, p=0.01, p=0.001, p<0.001; respectively). Multivariate analysis using multiple linear regression test showed that age, regular medical check-up and knowledge about mammography testing were statistically associated with the practice of mammography among the general population in Malaysia (p=0.035, p=0.015 and p<0.001; respectively). Lack of time, lack of knowledge, not knowing where to go for the test and a fear of the test result were the most important barriers (42.5%, 32%, 21%, 20%; respectively). CONCLUSION: The practice of mammogram screening is low among Malaysian women. PMID- 23098440 TI - XRCC1 Arg399Gln gene polymorphism and hepatocellular carcinoma risk in the Chinese Han population: a meta-analysis. AB - PURPOSE: Numerous studies have evaluated the association between XRCC1 Arg399Gln gene polymorphism and hepatocellular carcinoma risk in the Chinese Han population. However, the results have been inconsistent. We therefore here examined whether the XRCC1 Arg399Gln gene polymorphism confers hepatocellular carcinoma risk by conducting a meta-analysis. METHODS: PubMed, Google scholar and China National Knowledge Infrastructure databases were searched for eligible articles in English and Chinese that were published before April 2012. RESULTS: 6 studies involving 1,246 patients with hepatocellular carcinoma and 1,953 controls were included. The association between XRCC1 Arg399Gln gene polymorphism and hepatocellular carcinoma in the Chinese Han population was significant under GG vs AA (OR = 1.48, 95% CI = 1.13 to 1.94). Limiting the analysis to the studies with controls in the Hardy-Weinberg equilibrium, the results were persistent and robust. CONCLUSIONS: In the Chinese Han population, the XRCC1 Arg399Gln gene polymorphism is associated with an increased hepatocellular carcinoma risk. PMID- 23098441 TI - Comparison of the gene expression profiles between smokers with and without lung cancer using RNA-Seq. AB - Lung cancer seriously threatens human health, so it is important to investigate gene expression changes in affected individuals in comparison with healthy people. Here we compared the gene expression profiles between smokers with and without lung cancer. We found that the majority of the expressed genes (threshold was set as 0.1 RPKM) were the same in the two samples, with a small portion of the remainder being unique to smokers with and without lung cancer. Expression distribution patterns showed that most of the genes in smokers with and without lung cancer are expressed at low or moderate levels. We also found that the expression levels of the genes in smokers with lung cancer were lower than in smokers without lung cancer in general. Then we detected 27 differentially expressed genes in smokers with versus without lung cancer, and these differentially expressed genes were found to be involved in diverse processes. Our study provided detail expression profiles and expression changes between smokers with and without lung cancer. PMID- 23098442 TI - Diagnostic accuracy, sensitivity, specificity and positive predictive value of fine needle aspiration cytology (FNAC) in intra oral tumors. AB - OBJECTIVE: The objective of this study was to establish the diagnostic accuracy, specificity and sensitivity of fine needle aspiration cytology(FNAC) for intra oral tumors, comparing with histopathology as the gold standard. MATERIALS AND METHODS: Forty cases of FNA cytology from intraoral tumors was performed in AFID along with the demographic data and clinical information and then diagnosed at AFIP, Rawalpindi. Then the cytology results obtained per FNAC were compared with the histopathological biopsy results of the same lesions. The following variables were recorded for each patient: Age, gender, site of biopsy, diagnosis. The data were entered and analyzed using Open-epi version 2.0. Diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value were calculated. Cohen Kappa was further applied to compare the agreement between the biopsy and FNAC diagnoses. A p-value of <0.05 was considered as statistically significant. RESULTS: Among the total patients included in the study there were 24 males and 16 females, with a ratio of 1.5:1. Age of the patients ranged from 24 to 80 years with a mean of 52 years. A total of six sites were aspirated from the oral cavity with maximum (11) aspirates taken from alveolar ridge. The results of FNAC revealed that there were 32 malignant and 8 benign aspirates. Confirmation through histopathological analysis came for 31/32 malignant cases while one was falsely given positive for malignancy on FNAC. Among a total of 40 cases, 31(77%) cases diagnosed were found to be malignant and remaining 9(23%) were benign. The FNAC results revealed 32 malignant and 8 benign lesions. Histopathology of the subsequent surgically excised specimen showed malignant lesions in 31(77%) and benign in 9(23%) patients. As a whole, it was found that the absolute sensitivity for intra oral FNAC was 100% and specificity 89% with positive predictive value of 97% and negative predictive value of 100%. CONCLUSION: Cytological diagnosis was almost corroborative with final histopathological diagnosis in all cases, with very few exceptions, exhibiting high diagnostic accuracy. PMID- 23098443 TI - Coverage, density and completeness of sources used in Tehran Metropolitan Area Cancer Registry: according to the data of esophageal cancer, 2003-2007. AB - BACKGROUND: The completeness of cancer registration is a major validity index of any reported cancer incidence. The present study aimed to evaluate the esophageal cancer incidence registered in the Tehran Metropolitan Area Cancer Registry. MATERIALS AND METHODS: The data on esophageal cancer abstracted from three sources of 1) pathology departments, 2) medical records, and 3) death certificates during 2003 till 2007 were utilized. The completeness of the data sources were evaluated using coverage (defined as the proportion of a community population with esophageal cancer identified by the source) and density (defined as the proportion of non-empty fields of the data by source). RESULTS: A total 1,404 cases of esophageal cancer were reported for the duration of the study. Pathology provided 771, medical records 432, and death certificates 609. The coverage was 0.55 for pathology, 0.31 for medical records, and 0.43 for death certificates. The respective density values were 0.82, 0.96 and 0.98, respectively. Pathology (0.45) was the most complete source followed by medical records (0.42), and death certificates (0.29). DISCUSSION: A low degree of completeness dictates putting more effort into case finding plus abstracting data more thoroughly. PMID- 23098444 TI - Profile of lymphadenopathy in Kashmir valley: a cytological study. AB - Lymphadenopathy is one of the commonest and significant manifestations of local as well as systemic ailments, especially malignancies. Fine needle aspiration cytology (FNAC) helps in diagnosing the disease itself, in general, but more importantly ruling out malignancy, in particular. Hence it saves much of the cost and use of resources incurred with excision biopsy of such lymph nodes. This prompted us to study the cytologic patterns of lymphadenopathy in our setting and the diagnostic utility of FNAC in the evaluation of lymphadenopathy. In this retrospective observational study, 1,579 patients (953 males and 626 females) with lymphadenopathy who were subjected to FNAC over a period of three years (January 2009 to December 2011) were studied. The cervical region was involved in most of the cases (76%) followed by the axillary region (17.5%). Metastatic malignancy (38.2%) was the commonest cause of lymphadenopathy followed by reactive lymphoid hyperplasia (36.9%), tuberculosis (9.1%) and lymphomas (8.6%). Squamous cell carcinoma (32.2%) followed by adenocarcinoma (21.9%) were the most frequent metastatic tumors. FNAC is a useful diagnostic tool in the management of patients presenting with lymphadenopathy and should be considered before more invasive and costly procedures are performed, particularly in developing countries. PMID- 23098445 TI - Increased expression of epithelial cell adhesion molecule (EpCAM) in rat hepatic tumors induced by diethylnitrosamine. AB - The epithelial cell adhesion molecule (EpCAM) is a pan-epithelial differentiation antigen that is expressed on almost all carcinomas. However, a role in rat liver carcinogenesis has never been reported previously. Thus, its expression was investigated herein in rat liver tumors induced by diethylnitrosamine (DEN). Twenty male 5-week-old F344 rats were used in this experiment. Mini-osmotic pumps containing doses of 47.5 mg of DEN were inserted into the abdominal cavity of each animal to initiate liver carcinogenesis. All animals were sacrificed at 26 weeks after DEN treatment. At necropsy, hepatic masses were processed for histopathological examination, which revealed forty-four hepatocellular adenomas (HCAs) and twenty hepatocellular carcinomas (HCC). Tumors were immunohistochemically analyzed for EpCAM, proliferating cell nuclear antigen (PCNA) and co-localization of the two. EpCAM expression was mainly detected in hepatic tumor cells, showing a cytoplasmic staining pattern. However, expression was also slightly observed in normally-appearing surrounding hepatic cells. PCNA expression was highly detected in tumor cells, showing nuclear staining. Double staining of EpCAM and PCNA in tumors showed many cells with co- localization. Taken together, EpCAM and PCNA expression were increased in DEN-induced tumors and many tumor cells showed co-expression. It is suggested that EpCAM may increase during DEN-induced tumors, possibly associated with cell proliferation. PMID- 23098446 TI - Modulation of drug resistance in ovarian cancer cells by inhibition of protein kinase C-alpha (PKC-alpha) with small interference RNA (siRNA) agents. AB - OBJECTIVE: To determine whether silence of PKC-alpha expression by small interference RNA (siRNA) might regulate MDR1 expression and reverse chemoresistance of ovarian cancer. METHODS: We measured gene and protein expression of MDR1 and PKC-alpha in ovarian cancer cells and assessed their correlation with cell drug resistance. We also examined whether blocking PKC alpha by RNA interference (RNAi) affected MDR1 expression and reversed drug resistance in drug sensitivity tests. RESULTS: The drug resistance cell lines, OV1228/DDP and OV1228/Taxol, had higher gene and protein expression of MDR1 and PKC-alpha than their counterpart sensitive cell line, OV1228. SiRNA depressed PKC alpha gene protein expression, as well as MDR1 and protein expression and improved the drug sensitivity in OV1228/DDP and OV1228/Taxol cells. CONCLUSION: These results indicated that decreasing PKC-alpha expression with siRNA might be an effective method to improve drug sensitivity in drug resistant cells with elevated levels of PKC-alpha and MDR1. A new siRNA-based therapeutic strategy targeting PKC-alpha gene could be designed to overcome the chemoresistance of ovarian cancer. PMID- 23098447 TI - Association between XRCC5, 6 and 7 gene polymorphisms and the risk of breast cancer: a HuGE review and meta-analysis. AB - OBJECTIVE: Non-homologous end joining (NHEJ) is a pathway for repairing DNA double-strand breaks. Recent publications indicated that XRCC5, XRCC6 and XRCC7 genes may participate in the pathogenesis of breast cancer. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to investigate associations between XRCC5, XRCC6 and XRCC7 genetic polymorphisms in the NHEJ pathway and breast cancer risk. METHODS: Studies focusing on the relationship between genetic polymorphisms in XRCC5, XRCC6 and XRCC7 genes and susceptibility to breast cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers. The meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. The odds ratio (OR) with 95% confidence interval (95%CI) was calculated based on the extracted data. RESULTS: According to the inclusion criteria, we final included seven studies with a total of 2,864 breast cancer cases and 3,060 healthy controls. Meta-analysis results showed that rs3835 (G>A) and rs828907 (G>T) in XRCC5 gene, and rs132793 (G>A) in XRCC6 gene might increase the risk of breast cancer, while rs132788 G>T and rs6002421 (A>G) might be protective factors. However, there was no relationship between XRCC7 genetic polymorphisms and the risk of breast cancer. CONCLUSION: This meta-analysis suggests that the rs3835 G>A and rs828907 G>T in XRCC5 gene, rs6002421 (A>G), rs132788 (G>T) and rs132793 (G>A) in XRCC6 gene might be risk factors for breast cancer, while the rs132788 (G>T) and rs6002421 (A>G) in XRCC6 gene might be protective. PMID- 23098448 TI - Manual liquid based cytology in primary screening for cervical cancer--a cost effective preposition for scarce resource settings. AB - Conventional pap smear (CPS) examination has been the mainstay for early detection of cervical cancer. However, its widespread use has not been possible due to the inherent limitations, like presence of obscuring blood and inflammation, reducing its sensitivity considerably. Automated methods in use in developed countries may not be affordable in the developing countries due to paucity of resources. On the other hand, manual liquid based cytology (MLBC) is a technique that is cost effective and improves detection of precursor lesions and specimen adequacy. Therefore the aim of the study was to compare the utility of MLBC with that of CPS in cervical cancer screening. A prospective study of 100 cases through MLBC and CPS was conducted from October 2009 to July 2010, in a Medical College in India, by two independent pathologists and correlated with histopathology (22 cases). Morphological features as seen through MLBC and CPS were compared. Subsequently, all the cases were grouped based on cytological diagnosis according to two methods into 10 groups and a subjective comparison was made. In order to compare the validity of MLBC with CPS in case of major diagnoses, sensitivity and specificity of the two methods were estimated considering histological examination as the gold standard. Increased detection rate with MLBC was 150%. The concordance rate by LBC/histopathology v/s CPS/histopathology was also improved (86% vs 77%) The percentage agreement by the two methods was 68%. MLBC was more sensitive in diagnosis of LSIL and more specific in the diagnosis of inflammation. Thus, MLBC was found to be better than CPS in diagnosis of precursor lesions. It provided better morphology with increased detection of abnormalities and preservation of specimen for cell block and ancillary studies like immunocytochemistry and HPV detection. Therefore, it can be used as alternative strategy for cervical cancer prevention in limited resource settings. PMID- 23098449 TI - Hyperin extracted from Manchurian rhododendron leaf induces apoptosis in human endometrial cancer cells through a mitochondrial pathway. AB - BACKGROUND: A number of effective prevention measures have been introduced in attempts to substantially reduce both the incidence and mortality due to many kinds of cancer. The search for new anti-cancer compounds in foods or in plant medicines is one realistic and promising approach to prevention. Chinese medicines provide a rich pool of novel and efficacious agents for cancer prevention and treatment. Previously it was demonstrated that hyperin extracted from the Manchurian rhododendron leaf reduces the proliferation of many cancer cells. The present study was carried out to evaluate its effects on human endometrial cancer cell viability and apoptosis and to investigate its mechanisms of action in RL952 cells. METHODS: Cell viability was measured using the MTT assay. Intracellular calcium ions were detected using laser-scanning confocal microscopy. The effects of hyperin on apoptosis related proteins in RL952 cells were examined using Western blot analysis. RESULTS: The growth of RL952 cells was inhibited by treatment with hyperin. OD values of caspase-3 and caspase-9 were increased and expression of bcl-2 was increased and bax was decreased in protein levels in RL952 cells after 24 h of hyperin treatment, Moreover, intracellular calcium accumulation occurred in hyperin-treated cells. CONCLUSIONS: These results suggest that hyperin may play an important role in tumor growth suppression by inducing apoptosis in human endometrial cells via a Ca2+-related mitochondrion apoptotic pathway in RL952 cells. PMID- 23098450 TI - Detection of HBV resistance to lamivudine in patients with chronic hepatitis B using Zip nucleic acid probes in Kerman, southeast of Iran. AB - HBV infection is contagious and may be transmitted vertically or horizontally by blood products and body secretions. Over 50% of Iranian carriers have contracted the infection prenatally, making this the most likely route of transmission of HBV in Iran. This study assesses the resistance to Lamivudine in patients with chronic hepatitis B infection using a new ZNA probe Real Time PCR method. To evaluate the effectiveness of Lamivudine therapy for chronic hepatitis B infection, a study was conducted on 70 patients (63 men and 7 women), who had received the drug first line. All patients were tested for the presence of HBsAg and HBeAg, the serum ALT level and the HBV DNA load before and after treatment. In all samples resistance to Lamivudine was tested with the ZNA Probe. Our results showed that ZNA Probe Real Time PCR method could detect wild type,YMDD, and its mutants, tyrosine-isoleucine-aspartate-aspartate and tyrosine-valine aspartate-Aspartate. Among an estimated seventy patients with chronic hepatitis B infection, 18 (25.7%) were resistant to lamivudine. Only one patient was negative for presence of HBS-Ag (5.6%) and two patients were negative for HBe-Ag (11.1%). Real-time PCR with Zip nucleic acid probes is a sensitive, specific and rapid detection method for mutations in the YMDD motif, which will be essential for monitoring patients undergoing Lamivudine antiviral therapy. PMID- 23098451 TI - Why is hepatocellular carcinoma less attributable to viral hepatitis in Yemen? AB - The hepatitis B virus (HBV) and the hepatitis C virus (HCV) are still public health problems in Yemen, with older individuals having much higher prevalence than younger generations. However, research on the prevalence of viral hepatitis in association with hepatocellular cancer (HCC) has not yet been undertaken in Yemen. The aim of this study was to determine the prevalence of HBV and HCV infection among HCC patients and to estimate the risk of these infections being associated with the development of HCC. A cross-sectional study was conducted on patients attending oncology outpatient in Sana'a, Yemen, through the period 2008 mid 2010 with confirmed diagnosis of HCC. A total of 88 cases were studied thoroughly with different investigations such as CT-scan, ultrasound, tumour marker, alpha-feto-protein and histopathological biopsy. A structured questionnaire was also applied and physical examination done to assess the general condition of the patients. Statistical package (SPSS version 16) was used for analysis of the data. The mean age of the cases was 61.2 years (+/- 12.6) with half over 60 years. There were fewer male patients (36%) compared to females and most (97%) only had basic /no formal education. Seventy nine (89%) were diagnosed as HCC cases with histopathological biopsy while the rest were diagnosed by ultrasound, CT scan, tumour marker, and alpha-feto-protein. Around one-third of the subjects were positive for HBsAg and HCV antibodies. Multivariate analysis showed infection with HCV and use of smoking was associated with HCC diagnosis. Although an association was observed between the occurrence of HCC and viral hepatitis (either HBV or HCV) and cigarette smoking, but the rate of viral infection was lower than what has been reported elsewhere. PMID- 23098452 TI - Evaluation of xenotropic murine leukemia virus and its R426Q polymorphism in patients with prostate cancer in Kerman, southeast of Iran. AB - A role for the xenotropic murine leukemia virus (XMRV) in prostate cancer development has been postulated. To answer questions regarding the prevalence of XMRV in Iranian patients with prostate cancer and its association with the RNASEL R462Q polymorphism, we here investigated a series of cases in Kerman, in the Southeast of Iran, and sought to verify the association with the R462Q using Real Time PCR Method. Prostate tissue specimens of 200 patients with prostate cancer were genotyped for R462Q by real time polymerase chain reaction allelic discrimination and were screened for XMRV proviral DNA by real time polymerase chain reaction specific for the envelope gene. Of 200 patients in this study 8 (4%) cases were positive for XMRV, the QQ allele being the most frequent regarding the R426Q polymorphism while in negative patients it was the RQ allele. There was significant correlation between high pathological scores and XMRV positive samples. No significant relationship was found between age groups and XMRV results. XMRV was only found in patients with QQ and RQ alleles, not RR. XMRV is detectable in tumor prostate tissue from some patients with prostate cancer, independent of R462Q. PMID- 23098453 TI - Expression of endogenous hypoxia markers in vulvar squamous cell carcinoma. AB - OBJECTIVE: To investigate the expression of endogenous hypoxia-related markers identified as being involved in vulvar squamous cell carcinoma (VSCC). METHODS: We performed immunohistochemical staining of hypoxia-inducible factor-1alpha(HIF 1alpha), glucose transporter-1 (GLUT-1), carbonic anhydrase 9 (CA-9) and vascular endothelial growth factor (VEGF), on tissue sections of 25 VSCC patients, 10 vulvar intraepithelial neoplasia (VIN) patients and 12 healthy controls. RESULTS: HIF-1alpha expression was found in all sections, with no significant difference between controls, VIN and VSCC sections (all P<0.05). Glut-1 expression was found in 25% of control, 90% of VIN and 100% of VSCC sections. A significant difference between control and VIN or VSCC was observed (all P<0.05), while no difference was found between VIN and VSCC sections (P>0.05). CA-9 expression was negative in control sections, but it was found in 30% of VIN sections and 52% of VSCC sections with strong staining. Similarly, CA-9 expression also showed obvious differences between controls and VIN or VSCC sections (all P<0.05). However, there was no significant difference between VIN and VSCC (P>0.05). There were only 25% of control sections with weak VEGF expression, while strong staining was found in about 60% of VIN sections and 25% of VSCC sections (all P<0.05). In addition, a difference was also found between VIN and VSCC sections (P<0.05). CONCLUSION: Expression of endogenous hypoxia markers (HIF-1alpha, GLUT-1, CA-9 and VEGF) might be involved in the malignant progression of VSCC. PMID- 23098454 TI - Transcription regulation network analysis of MCF7 breast cancer cells exposed to estradiol. AB - BACKGROUND: In breast cancer, estrogen receptors have been demonstrated to interact with transcription factors to regulate target gene expression. However, high-throughput identification of the transcription regulation relationship between transcription factors and their target genes in response to estradiol is still in its infancy. PURPOSE: Thus, the objective of our study was to interpret the transcription regulation network of MCF7 breast cancer cells exposed to estradiol. METHODS: In this work, GSE11352 microarray data were used to identify differentially expressed genes (DEGs). RESULTS: Our results showed that the MYB (v-myb myeloblastosis viral oncogene homolog [avian]), PGR (progesterone receptor), and MYC (v-myc myelocytomatosis viral oncogene homolog [avian]) were hub nodes in our transcriptome network, which may interact with ER and, in turn, regulate target gene expression. MYB can up-regulate MCM3 (minichromosome maintenance 3) and MCM7 expression; PGR can suppress BCL2 (B-cell lymphoma 2) expression; MYC can inhibit TGFB2 (transforming growth factor, beta 2) expression. These genes are associated with breast cancer progression via cell cycling and the TGFbeta signaling pathway. CONCLUSION: Analysis of transcriptional regulation may provide a better understanding of molecular mechanisms and clues to potential therapeutic targets in the treatment of breast cancer. PMID- 23098455 TI - Association between the GSTP1 codon 105 polymorphism and gastric cancer risk: an updated meta-analysis. AB - OBJECTIVE: The current meta-analysis was performed to address a more accurate estimation of the association between glutathione S-transferase P1 (GSTP1) codon 105 polymorphism and risk of gastric cancer (GC), which has been widely reported with conflicting results. METHODS: A comprehensive literature search was conducted to identify all the relevant studies. Fixed or random effect models were selected based on the heterogeneity test. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 20 studies containing 2,821 GC cases and 6,240 controls were finally included in the analyses. Overall, no significant association between GSTP1 polymorphism and GC risk was observed in worldwide populations. However, subgroup analysis stratified by ethnicity showed that GSTP1 polymorphism was significantly associated with increased risk of GC in Asians (G vs. A, OR = 1.273, 95%CI=1.011-1.605; GG vs. AA, OR=2.103, 95%CI=1.197- 3.387; GG vs. AA+AG, OR =2.103, 95%CI=1.186-3.414). In contrast, no significant association was found in Caucasians in any genetic models, except for with AG vs. AA (OR=0.791, 95%CI=0.669-0.936). Furthermore, the GSTP1 polymorphism was found to be significantly associated with GC in patients with H. pylori infection and in those with a cardiac GC. Subgroup analysis stratified by Lauren's classification and smoking status showed no significant association with any genetic model. No studies were found to significantly influence the pooled effects in each genetic mode, and no potential publication bias was detected. CONCLUSIONS: This meta-analysis suggested that the GSTP1 polymorphism might be associated with increased risk of GC in Asians, while GSTP1 heterozygote genotype seemed to be associated with reduced risk of GC. Since potential confounders could not be ruled out completely, further studies are needed to confirm these results. PMID- 23098456 TI - Mammalian mediator 19 mediates H1299 lung adenocarcinoma cell clone conformation, growth, and metastasis. AB - Mammalian mediator (MED) is a multi-protein coactivator that has been identified by several research groups. The involvement of the MED complex subunit 19 (MED 19) in the metastasis of lung adenocarcinoma cell line (H1299), which expresses the MED 19 subunit, was here investigated. When MED 19 expression was decreased by RNA interference H1299 cells demonstrated reduced clone formation, arrest in the S phase of the cell cycle, and lowered metastatic capacity. Thus, MED 19 appears to play important roles in the biological behavior of non-small cell lung carcinoma cells. These findings may be important for the development of novel lung carcinoma treatments. PMID- 23098457 TI - Lack of association between Chlamydia trachomatis infection and cervical cancer- Taq Man realtime PCR assay findings. AB - BACKGROUND: Cervical cancer is one of the most common cancers in developing countries and the second most common type of cancer in women globally. Several recent studies suggested a co factor role for Chlamydia trachomatis in pathogenesis of cervical cancer. This study aimed to evaluate existence of C. trachomatis DNA in pathologic blocks of patients with cervical cancer. MATERIALS AND METHODS: Seventy-six formaldehyde fixed paraffin embedded tissue specimens from patients with histologically proven history of cervical cancer as well as 150 blocks from healthy peoples were included in the present study. Thin slices were prepared from selected blocks followed by deparaffinization and DNA extraction; the presence of C. trachomatis DNA was examined by Taq Man real-time PCR. RESULTS: Our TaqMan real time PCR assay with cervical specimens of patients with cervical cancer showed that there was no C. trachomatis DNA. Also, we found three positive specimens among our control group. CONCLUSION: It seems that based on results obtained from the specimens examined in the present study, there is no association between the presence of C. trachomatis DNA in cervical specimens and cervical cancer. PMID- 23098458 TI - Apoptosis of colorectal cancer UTC116 cells induced by Cantharidinate. AB - Effects of Cantharidinate on apoptosis of human colorectal cancer UTC-116 cells were investigated by means of 3-(4, 5-dimethylthiazol-2-yl)-2, 5 diphenyltetrazolium bromide (MTT) assay, H and E staining, flow cytometry, and Raman Spectra analysis. The results showed Cantharidinate to exert inhibitory action on proliferation of human colorectal cancer UTC-116 cells, inducing apoptosis, arresting cells in G1 phase, with decline of S and G2 phases. In addition, the results of Raman spectrum showed significant changes in the UTC-116 cells chemical structure with stretching after the application of Cantharidinate. Taken together, these results suggest that the treatment of human colorectal cancer with Cantharidinate may be associated with multiple molecular mechanisms for apoptosis. Furthermore, similar to fluorouracil, Cantharidinate should be considered as novel assistant drug for controlling the growth of human colorectal cancer UTC-116 cells. PMID- 23098459 TI - Percutaneous radiofrequency ablation guided by contrast-enhanced ultrasound in treatment of metastatic hepatocellular carcinoma after liver transplantation. AB - This study evaluated the advantages and applications of contrast-enhanced ultrasound (CEUS)-supported percutaneous radiofrequency ablation (RFA) in the treatment of metastatic hepatocellular carcinoma after liver transplantation, based on clinical details. CEUS-supported percutaneous RFA was adopted to treat 12 patients with hepatic metastatic carcinomas after liver transplantation. The diameters of the metastatic carcinomas varied from 1 cm to 5 cm, and the foci were discovered after 3 months to 12 months. Each focus was diagnosed and localised by CEUS for RFA once or twice. Curative effects were evaluated by CEUS or contrast-enhanced CT after the treatment. The re-examination results at 2 weeks post-treatment showed that the foci of 11 patients were ablated completely, whereas one patient with the largest focus required retreatment by RFA because of a partial residue. No local recurrence was found one month later in the re examination. CEUS-supported percutaneous RFA in the treatment of hepatic metastatic carcinoma after liver transplantation has the advantages of accurate localisation, good efficacy, easy operation, and minimal invasion without any complications. Therefore, it can be recommended as the preferred therapy for hepatic metastatic carcinoma after liver transplantation. PMID- 23098460 TI - Transmembrane protein 166 expression in esophageal squamous cell carcinoma in Xinjiang, China. AB - OBJECTIVE: Transmembrane protein 166 (TMEM166) expression in esophageal squamous cell carcinoma (ESCC) and remote normal esophageal tissues was examined to assess any role in tumour biology. METHODS: TMEM166 mRNA expression in 36 cases with ESCC (36 tumour samples, 36 remote normal esophageal tissue samples) was detected by RT-PCR. TMEM166 protein expression was analysed in paraffin-embedded tissue samples from the same cases by immunohistochemistry. RESULTS: Semi-quantitative analysis showed TMEM166 mRNA expression in ESCCs to be significantly lower than in remote normal esophageal tissues (0.759 +/- 0.713 vs. 2.622 +/- 1.690, P=0.014). TMEM166 protein expression was also significantly reduced (69.4% vs. 94.4%, P<0.01). CONCLUSION: TMEM166 mRNA and protein expression demonstrated significant reduction in ESCCs compared with remote esophageal tissues, albeit with no correlation with tumour size, differentiation, stage, and lymph node metastasis, suggesting a role in regulating autophagic and apoptotic processes in the ESCC. PMID- 23098461 TI - Lack of association between the CYP1A1 Ile462Val polymorphism and endometrial cancer risk: a meta-analysis. AB - PURPOSE: Any association between the CYP1A1 Ile462Val polymorphism and endometrial cancer risk remains inconclusive. For a more precise estimate, we performed the present meta-analysis. METHODS: PUBMED, OVID and EMBASE were searched for the studies which met inclusion criteria. Data in all eligible studies were evaluated and extracted by two authors independently. The meta analysis estimated pooled odds ratio (OR) with 95% confidence interval (CI) for endometrial cancer risk attributable to the CYP1A1 Ile462Val polymorphism. RESULTS: A total of 7 studies were included in this meta-analysis. The results indicated no association between endometrial cancer risk and the CYP1A1 Ile462Val polymorphism (for Val vs Ile allele model [OR 1.09, 95% CI 0.73-1.62]; for Val.Val vs Ile.Ile genotype model [OR 1.54, 95% CI 0.56-4.23]; for (Ile.Val + Val.Val) vs Ile.Ile genotype model [OR 1.08, 95% CI 0.71-1.63]; for Val.Val vs (Ile.Ile + Ile.Val) genotype model [OR 1.46, 95% CI 0.53-4.04]). CONCLUSIONS: This meta-analysis suggests that there is no association between endometrial cancer risk and the CYP1A1 Ile462Val polymorphism. PMID- 23098462 TI - Understanding barriers to Malaysian women with breast cancer seeking help. AB - Delay in help-seeking behaviour which is potentially preventable has a major effect on the prognosis and survival of patients with breast cancer. The objective of this study was to explore reasons for delay in seeking help among patients with breast cancer from the East Coast of peninsular Malaysia. A qualitative study using face- to-face in-depth interview was carried out involving 12 breast cancer patients who had been histo-pathologically confirmed and were symptomatic on presentation. Respondents were selected purposely based on their history of delayed consultation, diagnosis or treatment. All were of Malay ethnicity and the age range was 26-67 years. Three were in stage ll, seven in stage lll and two in stage lV. At the time of interview, all except one respondent had accepted treatment. The range of consultation time was 0.2-72.2 months with a median of 1.7 months, diagnosis time was 1.4-95.8 months( median 5.4 months )and treatment time was 0-33.3 months (median 1.2 months). The themes derived from the study were poor knowledge or awareness of breast cancer, fear of cancer consequences, beliefs in complementary alternative medicine, sanction by others, other priorities, denial of disease, attitude of wait and see and health care system weakness. Help-seeking behaviour was influenced by a complex interaction of cognitive, environmental, beliefs, culture and psycho-social factors. Breast cancer awareness and psychological counselling are recommended for all patients with breast symptoms to prevent delay in seeking clinical help. PMID- 23098463 TI - Korean epithelial ovarian cancer study (Ko-EVE): protocols and interim report. AB - BACKGROUND: There have been few studies of Asian ovarian cancer and benign tumors. The primary aim of this paper was to report the protocol of the Ko-EVE study to examine epidemiological and molecular factors for ovarian cancer and benign neoplasms and to ascertain the major risk factors for ovarian cancer control in Korea. METHODS: This case-control study covers incident epithelial ovarian cancers and benign neoplasms, four major centers participating in enrolling incident cases and 3 hospitals enrolling healthy controls among health examinees. Standardized questionnaires were administered by trained interviewers, including sections on socio-demographics characteristics, past medical history, medication usage, family history, lifetime consumption of alcohol and tobacco, diet, physical activity, and reproductive factors for women. Various biological specimens were collected in the biorepository according to the standardized protocol. Annual follow-up for cancer cases and follow-up at the 1st year for benign tumor cases are performing to evaluate treatment effect and progression. Passive follow to see long-term survival will be conducting using record linkage with national data. RESULTS: The total number recruited in 2010-2011 was 246 epithelial ovarian cancer cases, 362 benign epithelial tumors and 345 controls. We are planning to collect subjects for at least 1,500 sets of ovarian cancer, 2,000 benign tumors and 1,500 controls till 2018. CONCLUSION: The Ko-EVE will provide unique and important data to probe the etiology and natural history of Korean epithelial ovarian cancer. It will be continued by genomic and proteomic epidemiological analyses and future intervention studies for the prevention of ovarian cancer among Koreans. PMID- 23098464 TI - Bicluster and pathway enrichment analysis of HCV-induced cirrhosis and hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the most common form of liver cancer. However, while it is associated frequently with hepatitis C virus (HCV) there is only an elementary understanding of its molecular pathogenesis. METHODS: To gain insight into the molecular mechanisms of HCV-induced hepatocarcinogenesis, we performed microarray analysis on 75 surgical liver samples from 48 HCV-infected patients. RESULTS: There were 395 differentially expressed genes between cirrhotic samples and HCC samples. Of these, 125 genes were up-regulated and 270 genes were down-regulated. We performed pathway enrichment analysis and screened as described previously. CONCLUSIONS: The differentially expressed genes might be involved in hepatocarcinogenesis through upregulating the pathways of ECM-receptor interaction, focal adhesion, cell adhesion molecules and other cancer-related pathways, and downregulating the pathways of "complement and coagulation cascades". We hope our results could aid in seeking of therapeutic targets for HCV-induced hepatocellular carcinoma. PMID- 23098465 TI - Health-related quality of life among breast cancer patients and its influencing factor in a Chinese population. AB - AIM: The aim of this study was to investigate the quality of life (QOL) of breast cancer patients by using the Functional Assessment of Cancer Therapy-Breast (FACT B) questionnaires. METHODS: A total of 522 adult patients who were admitted to our hospital with breast cancer were collected during the period of Jun. 2007 to Dec. 2009. RESULTS: Our FACT-B questionnaire study suggested that women below 50 years old, employed, higher education and annual income, lower TNM stage and receiving modified radical mastectomy manifested significantly better QOL using the assessment tool of the FACT-B subscale. Moreover, regression analysis indicated patients with young age, low stage cancer, high education and income were more likely to have high score of QOL, with ORs (95% CI) of 2.8 (1.52-4.56), 2.1 (1.15-3.95), 3.1 (1.45-5.12) and 3.54 (1.54-5.43), respectively. CONCLUSION: Our study showed younger age, lower stage of cancer, higher education and income could influence the QOL of breast cancer patients in our Chinese population. Further large sample studies are still needed for confirmation. PMID- 23098466 TI - Effect of tea polyphenols on the adhesion of highly metastatic human lung carcinoma cell lines to endothelial cells in vitro. AB - AIM: Tea polyphenols are known to play roles in critical steps of human lung carcinoma cell metastasis. For understanding the mechanisms whereby they inhibit tumor metastasis, the present study was conducted to investigate their effects on the adhesion of highly metastatic lung carcinoma cell lines (PG cells) to endothelial cells (EC cells) and adhesion molecule expression in vitro. METHODS: The expression of CD44 or CD54 in the PG cells was detected by flow cytometry and adhesion of PG cells to EC cells was assessed by confocal microscopy double fluorescence staining. RESULTS: The results showed that tea polyphenols: (1) inhibited the expression of CD44 and CD54, two important adhesion molecules in the PG cells in a dose-dependent manner; (2) significantly blocked the adhesion of PG cells to EC cells not only in a state of rest but also when active; and (3) influenced CD44 and CD54 expression during the adhesion process of PG cells to EC cells. CONCLUSION: The data indicated that the blocking role of tea polyphenols in the adhesion of PG cells to EC cells is related to CD44 and CD54. The mechanism of tea polyphenol prevention of human lung carcinoma metastasis might be through inhibiting adhesion molecule expression to block cancer cell adhesion. PMID- 23098467 TI - Crocetin induces cytotoxicity in colon cancer cells via p53-independent mechanisms. AB - OBJECTIVE: Crocin has been proposed as a promising candidate for cancer chemoprevention. The purpose of this investigation was to investigate the chemopreventive action and the possible mechanisms of crocin against human colon cancer cells in vitro. METHODS: Cell proliferation was examined using MTT assay and the cell cycle distribution fractions were analyzed using flow cytometric analysis after propidium iodide staining. Apoptosis was detected using the TUNEL Apoptosis Detection Kit with laser scanning confocal microscope. DNA damage was assessed using the alkaline single-cell gel electrophoresis assay, while expression levels of p53, cdk2, cyclin A and P21 were examined by Western blot analysis. RESULTS: Treatment of SW480 cells with crocetin (0.2, 0.4, 0.8 mmol/L) for 48 h significantly inhibited their proliferation in a concentration-dependent manner. Crocetin (0.8 mmol/L) significantly induced cell cycle arrest through p53 independent mechanisms accompanied by P21 induction. Crocetin (0.8 mmol/L) caused cytotoxicity in the SW480 cells by enhancing apoptosis and decreasing DNA repair capacity in a time-dependent manner. CONCLUSIONS: This report provides evidence that crocetin is a potential anticancer agent, which may be used as a chemotherapeutic drug. PMID- 23098468 TI - MTHFR C677T polymorphism and pancreatic cancer risk: a meta-analysis. AB - BACKGROUND: Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in the metabolism of folate, and the role of the MTHFR C677T polymorphism in pancreatic carcinogenesis is still controversial. METHOD: A literature search was performed using Pubmed and CNKI databases for published studies through May 2012. We performed a meta-analysis of all relevant case-control studies that examined the association between MTHFR C677T polymorphism and pancreatic cancer risk. RESULTS: Finally, 9 individual case-control studies with a total of 1,299 pancreatic cancer cases and 2,473 controls were included into this meta-analysis. RESULTS: This meta- analysis showed there was an obvious association between MTHFR C677T polymorphism and pancreatic cancer risk in East Asians (for allele model, OR = 1.67, 95%CI 1.11-2.51; For homozygote model, OR = 2.77, 95%CI 1.40-5.48; for recessive model, OR = 1.96, 95%CI 1.54-2.50; for dominant model, OR = 2.11, 95%CI 1.01-4.41). However, no significant association was found in Caucasians. CONCLUSION: The MTHFR C677T polymorphism is associated with pancreatic cancer risk, and a race-specific effect may exist in this association. More studies with a larger sample size are needed to further clarify this association. PMID- 23098469 TI - Costs during the first five years following cancer diagnosis in Korea. AB - OBJECTIVES: We estimated the total medical costs incurred during the 5 years following a cancer diagnosis and annual medical use status for the six most prevalent cancers in Korea. METHODS: From January 1 to December 31, 2006, new patients registered with the six most prevalent cancers (stomach, liver, lung, breast, colon, and thyroid) were randomly selected from the Korea Central Cancer Registry, with 30% of patients being drawn from each cancer group. For the selected patients, cost data were generated using National Health Insurance claims data from the time of cancer diagnosis in 2006 to December 31, 2010. The total number of patients selected was 28,509. Five-year total medical costs by tumor site and Surveillance, Epidemiology, and End Results (SEER) stage at the time of diagnosis, and annual total medical costs from diagnosis, were estimated. All costs were calculated as per-patient net costs. RESULTS: Mean 5-year net costs per patient varied widely, from $5,647 for thyroid cancer to $20,217 for lung cancer. Advanced stage at diagnosis was associated with a 1.8-2.5-fold higher total cost, and the total medical cost was highest during the first year following diagnosis and decreased by the third or fourth year. CONCLUSIONS: The costs of cancer care were substantial and varied by tumor site, annual phase, and stage at diagnosis. This indicates the need for increased prevention, earlier diagnosis, and new therapies that may assist in reducing medical costs. PMID- 23098470 TI - Factors associated with the use of gastric cancer screening services in Korea: the Fourth Korea National Health and Nutrition Examination Survey 2008 (KNHANES IV). AB - OBJECTIVES: Despite government efforts to increase participation in gastric cancer screening, the rate is still suboptimal in Korea. Therefore, we explored barriers to and predictors of gastric cancer screening participation among a nationally representative sample. METHODS: We used the Health Interview Survey sub-dataset derived from the Fourth Korean National Health and Nutrition Examination Survey 2008 (KNHANES IV) to evaluate participation in gastric cancer screening and factors associated with attendance in individuals age >= 40 years. We enrolled 4,464 subjects who completed the questionnaire and were not previously diagnosed with gastric cancer. Four groups of factors were considered potential predictors of gastric cancer screening in a multivariate analysis: sociodemographic, health behavior, psychological and cognitive, and dietary factors. RESULTS: Overall, 41.3% complied with the gastric cancer screening recommendations. Younger age, lower education level, living without a spouse, frequent binge drinker, and current smoker were significantly associated with less participation in gastric cancer screening. CONCLUSIONS: To improve participation in gastric cancer screening, more focused interventions should be directed to vulnerable populations, such as groups with low socioeconomic status or unhealthy behavior. In addition, there should be new promotional campaigns and health education to provide information targeting these vulnerable populations. PMID- 23098471 TI - Knockdown of Ezrin by RNA interference reverses malignant behavior of human pancreatic cancer cells in vitro. AB - BACKGROUND: Pancreatic cancer is one of the most aggressive tumors with a dismal prognosis. The membrane cytoskeletal crosslinker Ezrin participates in several functions including cell proliferation, adhesion, motility and survival. There is increasing evidence that Ezrin is overexpressed in vast majority of malignant tumors and regulates tumor progression. However, its roles in pancreatic cancer remain elusive. METHODS: Three pairs of specific Ezrin siRNAs were designed and synthetized and screened to determine the most efficient one for construction of a hairpin RNA plasmid targeting Ezrin. After transfection into the Panc-1 pancreatic cancer cell line, real-time quantitative PCR and Western blotting were performed to examine the expression of mRNA and protein. The MTT method was applied to examine the proliferation and the drug sensibility to Gemcitabine. Flow cytometry was used to assess the cycle and apoptosis, while capacity for invasion was determined with transwell chambers. Furthermore, we detected phosphorylated-Erk1/2 protein and phosphorylated-Akt protein by Western blotting. RESULTS: Real-time quantitative PCR and Western blotting revealed that Ezrin expression was notably down-regulated at both mRNA and protein levels by RNA interference (P< 0.01). Proliferation was inhibited and drug resistance to gemcitabine was improved (P< 0.05). Flow cytometry showed that the proportion of cells in the G1/G0 phase increased (P< 0.01), and in G2/M and S phases decreased (P< 0.05), with no apparent differences in apoptosis (P> 0.05). The capacity for invasion was markedly reduced (P< 0.01). In addition, down-regulating Ezrin expression had no effect on phosphorylated-Akt protein (P>0.05), but could decrease the level of phosphorylated-Erk1/2 protein (P< 0.05). CONCLUSIONS: RNA interference of Ezrin could inhibit its expression in the pancreatic cancer cells line Panc-1, leading to a potent suppression of malignant behavior in vitro. Assessment of potential as a target for pancreatic cancer treatment is clearly warranted. PMID- 23098472 TI - Prognostic significance of CD44v6/v7 in acute promyelocytic leukemia. AB - CD44v, especially splice variants containing exon v6, has been shown to be related closely to development of different tumors. High levels of CD44v6/v7 have been reported to be associated with invasiveness and metastasis of many malignancies. The objective of this study was to detect expression of CD44v6 containing variants in patients with acute promyelocytic leukemia (APL) and evaluate the potential of CD44v6/v7 for risk stratification. Reverse transcription polymerase chain reaction (RT-PCR) followed by PCR product purification, ligation into T vectors and positive clone sequencing were used to detect CD44 v6-containing variant isoforms in 23 APL patients. Real-time quantitative PCR of the CD44v6/v7 gene was performed in patients with APL and in NB4 cells that were treated with all-trans retinoic acid (ATRA) or arsenic trioxide (As2O3). Sequencing results identified four isoforms (CD44v6/v7, CD44v6/v8/v10, CD44v6/v8/v9/v10, and CD44v6/v7/v8/v9/v10) in bone marrow mononuclear cells of 23 patients with APL. The level of CD44v6/v7 in high-risk cases was significantly higher than those with low-risk. Higher levels of CD44v6/v7 were found in three patients with central nervous system relapse than in other patients inthe same risk group. Furthermore, in contrast to ATRA, only As2O3 could significantly down-regulate CD44v6/v7 expression in NB4 cells. Our data suggest that CD44v6/v7 expression may be a prognostic indicator for APL. PMID- 23098473 TI - An ester extract of Cochinchina momordica seeds induces differentiation of melanoma B16 F1 cells via MAPKs signaling. AB - Cochinchina momordica seeds (CMS) have been widely used due to antitumor activity by Mongolian tribes of China. However, the details of the underlying mechanisms remain unknown. In the present study, we found that an EtOAc (ethyl ester) extract of CMS (CMSEE) induced differentiation and caused growth inhibition of melanoma B16 F1 cells. CMSEE at the concentration of 5-200 MUg/ml exhibited strongest anti-proliferative effects on B16 F1 cells among other CMS fractions (water or petroleum ether). Moreover, CMSEE induced melanoma B16 F1 cell differentiation, characterized by dendrite-like outgrowth, increasing melanogenesis production, as well as enhancing tyrosinase activity. Western blot analysis showed that sustained phosphorylation of p38 MAP accompanied by decrease in ERK1/2 and JNK dephosphorylation were involved in CMSEE-induced B16 F1 cell differentiation. Notably, 6 compounds that were isolated and identified may be responsible for inducing differentiation of CMSEE. These results indicated that CMSEE contributes to the differentiation of B16 F1 cells through modulating MAPKs activity, which may throw some light on the development of potentially therapeutic strategies for melanoma treatment. PMID- 23098474 TI - Prohibitin induces apoptosis in BGC823 gastric cancer cells through the mitochondrial pathway. AB - Prohibitin (PHB), an evolutionarily-conserved protein, has been found to be over expressed in gastric cancer and be closely related with tumor malignancy. In this study, to investigate the relationship between PHB expression and cell apoptosis in the BGC823 gastric cancer cell line, low and high expression PHB in BGC823 cells was accomplished using RNA interference technology and gene transfer techniques. Cell proliferation, cell cycling, apoptosis, Bax, Bcl-2 and Cyt.c protein expression and the activation of Caspase-3,9 were assessed after 48 h. Over-expression of PHB gene in BGC823 cells resulted in slow cell growth, cell arrest in G2 phase, and an increased apoptosis ratio while the opposite was found for PHB under-expressing cells. In PHB over-expressing cells, the expression of Bax gene was increased, the expression of Bcl-2 was decreased, the activation level of Caspase-3, 9 was increased, but the activation level of Caspase-8 demonstrated no change. These results indicate that PHB induced apoptosis through the mitochondrial pathway. PMID- 23098475 TI - Colorectal cancer in the Kingdom of Saudi Arabia: need for screening. AB - BACKGROUND AND OBJECTIVES: Colorectal cancer (CRC) is a major health problem in the Kingdom of Saudi Arabia (KSA). Our aim was to characterize the epidemiology of CRC in the Saudi population. DESIGN AND SETTING: Retrospective analysis of all cases of CRC recorded in the Saudi Cancer Registry (SCR) between January 2001 and December 2006 amongst Saudi citizens in KSA. PATIENTS AND METHODS: Data were retrieved from the database of the SCR. Descriptive statistics was performed using SPSS. RESULTS: A total of 4,201 cases of CRC were registered in the SCR. The incidence of CRC increased between 2001 and 2006. The mean age of patients at the time of diagnosis was 58 years; most patients were above 45 years of age (n=3322; 79.1%). At the time of diagnosis, 977 patients (23.0%) presented with localized disease and 1,018 (24.0%) had distant metastasis. The most frequent pathological variant was adenocarcinoma (73%), with grade 2 (moderately differentiated) being the most common grade among all variants (61%). For all cancer grades, the frequency of CRC was significantly higher among patients >45 years (P=0.004), who presented with more advanced disease (stages III and IV) (P=0.012). Based on logistic regression, age >45 years was associated with advanced regional presentation (P=0.001). Tumor grade was associated with advanced regional presentation and metastasis. CONCLUSION: There was an increase in the incidence of CRC between 2001 and 2006. The age at the time of diagnosis was low when compared with reports from developed countries. A nationwide approach is needed to encourage and illustrate the importance of screening programs. PMID- 23098476 TI - Increased frequency of Foxp3+ regulatory T cells in mice with hepatocellular carcinoma. AB - The CD4+CD25+ regulatory T cell (Treg) is a special kind of T cell subset. Studies have showed that Treg cells are involved in a number of physiological processes and pathologic conditions such as autoimmune diseases, transplantation tolerance and cancer. Tregs with unique capacity for immune inhibition can impair anti-tumour immunity and help tumor cells to escape from immune surveillance. The aim of our study was to investigate whether Tregs are involved in hepatocellular carcinoma (HCC). A BABL/C mouse with HCC in situ model was established to evaluate the Treg existence in carcinoma tissues and the changes of Tregs in spleen using flow cytometry and immunohistochemistry methods. Granzyme B expression in carcinoma tissues was analyzed by immunohistochemistry to investigate the tumor local immune status. The proportion of CD4+CD25+/CD4+ spleen lymphocytes of tumor bearing mice (18.8% +/- 1.26%) was found to be significantly higher than that in normal mice (9.99% +/- 1.90%) (P<0.01 ). Immunohistochemistry of spleen tissue also confirmed that there was an increase in Treg in tumor-bearing mice, while in carcinomas it showed Treg cells to be present in tumor infiltrating lymphocyte areas while Granzyme B was rarely observed. Anti-tumour immunity was suppressed, and this might be associated with the increase of Tregs. Our observations suggest that the CD4+CD25+Treg/ CD4+ proportion in spleen lymphocytes can be a sensitive index to evaluate the change of Tregs in hepatocellular carcinoma mice and the Treg may be a promising therapeutic target for cancer. PMID- 23098477 TI - Association of four ERCC1 and ERCC2 SNPs with survival of bone tumour patients. AB - AIM: SNPs of ERCC1 and ERCC2 genes have been found to be associated with response to platinum therapy in different clinical settings. In the current study, we investigated the relationship of SNPs in ERCC1 and ERCC2 to cisplatin response and survival in osteosarcoma patients. METHODS: 267 consecutive patients diagnosed with osteosarcoma between January 2003 to January 2005 were followed up until the end of January 2010. ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln polymorphisms were detected based upon the Sequenom MassARRAY platform. RESULTS: For ERCC1 Asn118Asn, the variant genotype T/T was strongly significantly associated with a higher event free survival when compared with the wild-type C/C, with an adjusted OR (95% CI) of 0.39 (0.14-0.95). ERCC2 751 A/A genotype showed increased event free survival of osteosarcoma (HR=0.44; 95%CI=0.10-0.87). However, we did not find significant association of ERCC1 Gln504Lys and ERCC2 Asp312Asn polymorphisms with prognosis of osteosarcoma. CONCLUSION: We first report associations of four SNPs, ERCC1 Asn118Asn, ERCC1 Gln504Lys, ERCC2 Asp312Asn and ERCC2 Lys751Gln, with risk of death from osteosarcoma in a Chinese population, indicating ERCC1 118T/T and ERCC2 A/A may be used as surrogate markers for clinical outcome of osteosarcoma treatment with cisplatin. PMID- 23098478 TI - Combined study of cytogenetics and fluorescence in situ hybridization (FISH) analysis in childhood acute lymphoblastic leukemia (ALL) in a tertiary cancer centre in South India. AB - FISH is one of the most sensitive molecular methods to detect genetic abnormalities with DNA probes. When cytogenetic studies are normal or insufficient, FISH may detect cryptic rearrangements, rare or slowly proliferative abnormal populations in non-mitotic cells. We cytogenetically evaluated 70 childhood ALL - 67.1% were found to have an abnormal karyotype. The 23 patients (32.9%) with a normal karyotype were analyzed by FISH applying two probes; TEL/AML1 and MYB which detect cryptic rearrangements of t(12;21)(p13;q22) and deletion of (6q) respectively, associated with a good prognosis. Out of 23 patients, one was positive for t(12;21)(p13;q22) (4.3%). None of our patients were positive for MYB del(6q). Two patients showed an extra signal for MYB on chromosomes other than 6 (8.6 %) indicating amplification or duplication. Findings were compared with the available literature. Our study clearly indicated the integrated FISH screening method to increase the abnormality detection rate in a narrow range. FISH is less useful for diagnostic study of patients with suspected del(6q) but it helps in detecting known cryptic rearrangements as well as identification of new abnormalities(translocation , duplication and amplification) at the gene level. PMID- 23098479 TI - Practice of breast self-examination among women in Malaysia. AB - OBJECTIVES: The objective of this study was to examine the practice and associated factors of breast self- examination (BSE) among Malaysian women. METHODS: For this cross-sectional study 250 women were selected by a simple random sampling technique. The questionnaire was consisted of three parts: socio demographic characteristics, knowledge about BSE, and practice of BSE. Obtained data was analyzed using SPSS version 13. T-test and ANOVA test were used to explore the relation between socio-demographic characteristics and the practice of BSE. RESULTS: About 32% of the participants reported that they have had family history of cancer and about 20% of the participants reported that they have had family history of breast cancer. The majority of the participants (88.8%) have heard about breast cancer and 78.4% of the participants have heard about BSE. Race, marital status, residency, regular exercise, awareness about breast cancer, belief that breast cancer can be detected early, belief that early detection improves the chance of survival, family history of cancer, family history of breast cancer, awareness about BSE, and belief that BSE is necessary, significantly influenced the practice of BSE among women. Practice of BSE on monthly basis was found to be 47.2% among the study participants. CONCLUSION: The socio-demographic characteristics significantly influence the practice of BSA among women in Malaysia. The findings of this study might not only influence the planning of specific screening interventions and strategies in Malaysia but might also be important for the relevant international communities, interested in the peculiarities of BSE incidence in different countries. PMID- 23098480 TI - Practice of HPV vaccine and associated factors among school girls in Melaka, Malaysia. AB - OBJECTIVE: The objective of this study is to determine the practice and associated factors of HPV vaccine among school girls in Melaka, Malaysia. METHODOLOGY: A total number of 612 secondary school girls participated in this study. The questionnaire consists of 38 questions which included 3 sections. The first section is about socio- demography. The Second section is about knowledge and awareness of HPV vaccines. The third section is about practices with associated barriers of HPV vaccination. Verbal consent was obtained from all participants, and data were analyzed using SPSS 13. RESULTS: A total number of 612 secondary school girl students participated in this study. The mean age was 13.93 +/- SD (1.09); minimum age was 13 years old and maximum was 17 years old. The majority of them was Malay, from rural areas and had a family monthly income of RM 3000 or less (91.8%, 53.1%, 69.6%; respectively). The majority of the parents of the school girls were with secondary education level (56.4%). The majority of the participants did not have a family history of cervical cancer (99.0%). The prevalence of HPV vaccination was 77.9% among school girls in Melaka. The majority of the participants were vaccinated in their schools (77.0%). About 69% knew about cervical cancer and 77.6% had ever heard about HPV vaccine. Regarding the factors that influence the practice of uptake HPV vaccine, they were age, race, income, parents' education, knowledge about cervical cancer, heard about HPV vaccine and place of getting the vaccine (p<0.001). CONCLUSION: The prevalence of HPV vaccine among school girls is high. Age, race, income, parents' education, knowledge about cervical cancer, heard about HPV vaccine and place of getting the vaccine were the significant factors that influence the practice of uptake HPV vaccine among school girls. PMID- 23098481 TI - Knowledge and perceptions of cancer and cancer prevention among Malaysian traditional healers: a qualitative study. AB - OBJECTIVE: The objective of this study was to explore the knowledge and perceptions of Malaysian tradition healers towards cancer and cancer prevention. METHODOLOGY: A total of 25 participants agreed to participate in this qualitative study during the period from 20th July 2011 until 24th of September 2011. The proposal of this study was approved by the Ethics Committee of Management and Science University (MSU). Once the participant agreed to be interviewed, date, time and place of the interviews were determined. Consent form was obtained from participants before the interview began. Participants were briefed about the study and its purpose, and after asking their permission, their replies were recorded. The data was organized into themes and analyzed manually. RESULTS: Twenty-five Malaysian traditional healers participated in this qualitative study. The age of participants ranged between 26 to 78 years old. The majority were in the age group of 31-60 years old, male, Chinese, degree holders with a monthly income ranging from 1,000-5,000 Ringgit Malaysia (RM) and were married (56%, 80%, 48%, 52%, 68%, 84% respectively). The majority defined cancer as having high cholesterol or abscess accumulation. A few of them defined cancer as a type of cell growth. The majority mentioned that food and unhealthy lifestyles are the primary causes of cancer. Surprisingly some of them mentioned that cancer is caused by interference by ghosts. Regarding the diagnosis of cancer, the majority mentioned that they refer their patients to modern physicians' medical report when it comes to diagnosing or treating patients with cancer. The most common cancers that many patients came to seek treatment were breast cancers, followed by colon cancers, liver and lung cancers. CONCLUSION: Despite good knowledge about the causes of cancer among traditional healers, misconceptions still exist. Insufficient knowledge about the definition of cancer was noted among the traditional healers. This urges immediate action by the Ministry of Health of Malaysia to set up a strict regulation and regular monitoring of the traditional healers nationally. Traditional and Complementary Medicine may be integrated into the healthcare system and need to have sustained cooperation for the benefit of patients since about 80% of patients use traditional medicines. PMID- 23098482 TI - Prognostic significance of HER-2/neu and survival of breast cancer patients attending a specialized breast clinic in Kolkata, Eastern India. AB - INTRODUCTION: The worldwide incidence of breast cancer has increased rapidly in recent years. The scenario of Eastern India is also showing the same trend. It is necessary to study the utility of HER-2/neu as a prognostic factor in breast cancer survival. However, there have not been detailed studies in this respect with the breast cancer patients of Eastern India. Thus this study was conducted. MATERIALS AND METHODS: In this hospital-based study 86 breast cancer patients attending a breast clinic of a reputed institute of Eastern India and having invasive ductal carcinomas were observed for a period of 5 years after surgery. Associations between 5 years observed survival and status of ER, PR and HER-2/neu of the patients were critically evaluated. RESULTS: There was statistically significant association between survival pattern for 5 years and the HER-2/neu status (p=0.00001). Better survival was observed for the patients with HER-2/neu negative tumors 67(100%) compared to HER-2/neu positive tumors 7(36.8%). CONCLUSION: There is strong interaction between survival and HER-2/neu expression of breast cancer patients. Thus the patients with HER-2/neu positive tumors need to be treated aggressively. PMID- 23098483 TI - Expression of Bax and Bcl-2 in tumour cells and blood vessels of breast cancer and their association with angiogenesis and hormonal receptors. AB - A total of 96 cases of invasive breast ductal carcinoma were examined for immunohistochemical expression of Bax and Bcl-2 in the epithelial tumor cells and endothelial cells of the blood vessels. We also investigated the association between both proteins in the epithelium in relation to tumor characteristics such as tumor size, grade, lymph node involvement, microvessel density (MVD), hormonal receptors expression and c-erbB-2 overexpression. Bax expression showed a significant association between tumor and endothelial cells (p<0.001) while Bcl-2 expression in tumor cells was inversely associated with that in the endothelial cells (p<0.001). Expression of Bcl-2 in tumor cells was strongly associated with expression of estrogen and progesterone receptors (p=0.003 and p=0.004, respectively). In addition, intratumoral MVD was significantly higher than peritumoral MVD (p<0.001) but not associated with Bax or Bcl-2 expression and other tumor characteristics. We concluded that the number of endothelial cells undergoing apoptosis was in direct linkage with the number of apoptotic tumor cells. Anti-apoptotic activity of the surviving tumor cells appears to propagate cancer progression and this was influenced by the hormonal status of the cells. Tumor angiogenesis was especially promoted in the intratumoral region and angiogenesis was independent of anti-apoptotic activity. PMID- 23098484 TI - Mitochondrial D-Loop polymorphism and microsatellite instability in prostate cancer and benign hyperplasia patients. AB - In this study mitochondrial D-Loop variations in Iranian prostate cancer and benign prostatic hyperplasia (BPH) patients were investigated. Tumour samples and corresponding non-cancerous prostate tissue from 40 prostate cancer patients and 40 age-matched BPH patients were collected. The entire mtD-loop region (16024 576) was amplified using the PCR method and products were gel-purified and subjected to direct nucleotide sequencing. A total of 129 variations were found, the most frequent being 263A-G and 310T-C among both BPH and prostate cancer patients. Variation of 309 C-T was significantly more frequent in prostate cancer patients (P value<0.05). Four novel variations were observed on comparison with the MITOMAP database. Novel variations were np16154delT, np366G-A, np389G-A and 56insT. There was no correspondence between the different variations and the age of subjects. Considering that D-loop variations were frequent in both BPH and prostate cancer patients in our study, the fact that both groups had high average age can be a possible contributing factor. D-loop polymorphisms and microsatellite instability can influence cell physiology and result in a benign or malignant phenotype. Significantly higher frequency of 309 C-T variation in cancer patients is a notable finding and must be a focus of attention in future studies. PMID- 23098485 TI - Prognostic factors in first-line chemotherapy treated metastatic gastric cancer patients: a retrospective study. AB - BACKGROUND: The majority of patients with gastric cancer in developing countries present with advanced disease. Systemic chemotherapy therefore has limited impact on overall survival. Patients eligible for chemotherapy should be selected carefully. The aim of this study was to analyze prognostic factors for survival in advanced gastric cancer patients undergoing first-line palliative chemotherapy. METHODS: We retrospectively reviewed 107 locally advanced or metastatic gastric cancer patients who were treated with docetaxel and cisplatin plus fluorouracil (DCF) as first-line treatment between June 2007 and August 2011. Twenty-eight potential prognostic variables were chosen for univariate and multivariate analyses. RESULTS: Among the 28 variables of univariate analysis, nine variables were identified to have prognostic significance: performance status, histology, location of primary tumor, lung metastasis, peritoneum metastasis, ascites, hemoglobin, albumin, weight loss and bone metastasis. Multivariate analysis by Cox proportional hazard model, including nine prognostic significance factors evident in univariate analysis, revealed weight loss, histology, peritoneum metastasis, ascites and serum hemoglobin level to be independent variables. CONCLUSION: Performance status, weight loss, histology, peritoneum metastasis, ascites and serum hemoglobin level were identified as important prognostic factors in advanced gastric cancer patients. These findings may facilitate pretreatment prediction of survival and can be used for selecting patients for treatment. PMID- 23098486 TI - Colorectal cancer and its association with the metabolic syndrome: a Malaysian multi-centric case-control study. AB - OBJECTIVE: Colorectal cancer (CRC) and the metabolic syndrome (MetS) are both on the rise in Malaysia. A multi-centric case-control study was conducted from December 2009 to January 2011 to determine any relationship between the two. METHODS: Patients with confirmed CRC based on colonoscopy findings and cancer free controls from five local hospitals were assessed for MetS according to the International Diabetes Federation (IDF) definition. Each index case was matched for age, gender and ethnicity with two controls (140: 280). RESULTS: MetS among cases was highly prevalent (70.7%), especially among women (68.7%). MetS as an entity increased CRC risk by almost three fold independently (OR=2.61, 95%CI=1.53 4.47). In men MetS increased the risk of CRC by two fold (OR=2.01, 95%CI, 1.43 4.56), demonstrating an increasing trend in risk with the number of Mets components observed. CONCLUSION: This study provides evidence for a positive association between the metabolic syndrome and colorectal cancer. A prospective study on the Malaysian population is a high priority to confirm these findings. PMID- 23098487 TI - Saudi women's interest in breast cancer gene testing: possible influence of awareness, perceived risk and socio-demographic factors. AB - BACKGROUND: Development of effective educational strategies should accompany increases in public awareness and the availability of genetic testing for breast cancer (BC). These educational strategies should be designed to fulfill the knowledge gap while considering factors that influence women's interest in order to facilitate decision making. OBJECTIVE: To determine the possible correlates of Saudi women's interest in BC genes testing including socio-demographics, the level of awareness towards BC genes, the family history of BC and the perceived personal risk among adult Saudi women in Al Hassa, Saudi Arabia. SUBJECTS AND METHODS: This cross-sectional study was carried out during the second BC community-based campaign in Al Hassa, Saudi Arabia. All Saudi women aged >= 18 years (n=781) attending the educational components of the campaign were invited to a personal interview. Data collection included gathering information about socio- demographics, family history of BC, the perceived personal risk for BC, awareness and attitude towards BC genes and the women's interest in BC genes testing. RESULTS: Of the included women (n=599), 19.5% perceived higher risk for BC development, significantly more among < 40 years of age, and with positive family history of BC before 50 years of age. The participants demonstrated a poor level of awareness regarding the inheritance, risk, and availability of BC genetic testing. The median summated knowledge score was 1.0 (out of 7 points) with a knowledge deficit of 87.8%. The level of knowledge showed significant decline with age (> 40 years). Of the included women 54.7% expressed an interest in BC genetic testing for assessing their BC risk. Multivariate regression model showed that being middle aged (Odds Ratio 'OR'=1.88, confidence intervals 'C.I'=1.14-3.11), with higher knowledge level (OR=1.67, C.I=1.08-2.57) and perceiving higher risk for BC (OR=2.11, C.I=1.61-2.76) were the significant positive correlates for Saudi women interest in BC genetic testing. CONCLUSION: Saudi women express high interest in genetic testing for BC risk despite their poor awareness. This great interest may reflect the presence of inappropriate information regarding BC genetic testing and its role in risk analysis. PMID- 23098488 TI - Relationships between cause of cancer and breast cancer-related factors in breast cancer survivors. AB - AIMS: The purposes of this study were to (1) to identify the causes of cancer in breast cancer survivors in Taiwan; and (2) to investigate the influence of demographic characteristics and breast cancer-related factors on the cause of cancer. MATERIALS AND METHOD: This study details the related investigative results on survivors with breast cancer using a descriptive and correlational design. A convenience sampling approach was employed. A structured questionnaire was used to assess the participants. RESULTS: A total of 230 breast cancer survivors completed the questionnaire. Low-scoring cause of cancer participants were older adults (OR = 2.49, p<0.05) who were already of menopausal status (OR = 2.28, p < 0.05). Around 72% of participants agreed high responsibility. Our breast cancer survivors felt stress had caused their breast cancer. CONCLUSIONS: These findings are helpful in understanding the relationship between cause of cancer and related factors in breast cancer survivors. PMID- 23098489 TI - Cancer incidence and mortality in Osaka, Japan: future trends estimation with an age-period-cohort model. AB - In previous studies we predicted future trends in cancer incidence for each prefecture in order to plan cancer control. Those predictions, however, did not take into account the characteristics of each prefecture. We therefore used the results of age-period-cohort analysis of incidence and mortality data of Osaka, and estimated the incidence and mortality of cancers at all sites and selected sites. The results reflect the characteristics of Osaka, which has and is expected to have large number of patients with liver cancer. We believe our results to be useful for planning and evaluating cancer control activities in Osaka. It would be worthwhile to base the estimation of cancer incidence and mortality in each prefecture on each population-based cancer registry. PMID- 23098490 TI - Functional analysis of B7-H3 in colonic carcinoma cells. AB - B7-H3 is a newly discovered member of the B7/CD28 superfamily which functions as an important T-cell immune molecule. It has been reported recently that B7-H3 is highly expressed in many cancer cells, the data indicating that it may be a regulation factor contributing to tumor-resistance. In our study, we used bioinformatics to identify differentially expressed genes between colonic cancer cells and normal colonic cells, aiming to analyze mechanisms and identify sub pathways closely related to progression, with the final aim of finding small molecule drugs which might interfere this progression. We found that ajmaline is one related factor which may enhance self-immunity in colon carcinoma therapy and B7-H3 plays important roles with regard to immunoreactions of colonic cancer cells. All the results indicate that H7-B3 is a favorable prognostic biomarker for colon carcinomas, providing novel information regarding likely targets for intervention. PMID- 23098491 TI - Pathway crosstalk analysis based on protein-protein network analysis in ovarian cancer. AB - Ovarian cancer is the fifth leading cause of cancer death in women aged 35 to 74 years. Although there are several popular hypothesis of ovarian cancer pathogenesis, the genetic mechanisms are far from being clear. Recently, systems biology approaches such as network-based methods have been successfully applied to elucidate the mechanisms of diseases. In this study, we constructed a crosstalk network among ovarian cancer related pathways by integrating protein protein interactions and KEGG pathway information. Several significant pathways were identified to crosstalk with each other in ovarian cancer, such as the chemokine, Notch, Wnt and NOD-like receptor signaling pathways. Results from these studies will provide the groundwork for a combination therapy approach targeting multiple pathways which will likely be more effective than targeting one pathway alone. PMID- 23098492 TI - Trends in the incidence of 15 common cancers in Hong Kong, 1983-2008. AB - BACKGROUND: The objective of this study WAS to describe cancer incidence rates and trends among THE Hong Kong population for the period 1983-2008. METHODS: Incident cases and population data from 1983 to 2008 were obtained from the Hong Kong Cancer Registry and the Census and Statistics Department, respectively. Age- standardized incidence rates (ASIR) were estimated and joinpoint regression was applied to detect significant changes in cancer morbidity. RESULTS: For all cancers combined, the ASIR showed declining trends (1.37% in men, 0.94% in women), this also being the case for cancers of lung, liver, nasopharynx, stomach, bladder, oesophagus for both genders and cervix cancer for women. With cancer of thyroid, prostate, male colorectal, corpus uteri, ovary and female breast cancer an increase was evident throughout the period. The incidence for leukemia showed a stable trend since early 1990 s, following an earlier decrease. CONCLUSIONS: Although overall cancer incidence rates and certain cancers showed declining trends, incidence trends for colorectal, thyroid and sex-related cancers continue to rise. These trends in cancer morbidity can be used as an important resource to plan and develop effective programs aimed at the control and prevention of the spread of cancer amongst the Hong Kong population. It is particularly useful in allowing projection of future burdens on the society with the increase in certain cancer incidences. PMID- 23098493 TI - Postmenopausal hormone therapy is associated with in situ breast cancer risk. AB - BACKGROUND: The relationship between postmenopausal hormone therapy (HT) and invasive breast cancer has been extensively investigated, but that with breast carcinoma in situ (BCIS) has received relatively little attention. The aim of our present study was to review and summarize the evidence provided by longitudinal studies on the association between postmenopausal HT use and BCIS risk. METHODS: A comprehensive literature search for articles published up to May 2012 was performed. Prior to performing a meta-analysis, the studies were evaluated for publication bias and heterogeneity. Relative risk (RR) or odds ratio (OR) values were calculated using 14 reports (8 case-control studies and 6 cohort studies), published between 1986 and 2012. RESULTS: There was evidence of an association between ever postmenopausal estrogen use and BCIS based on a random-effects model (RR = 1.25, 95% confidence interval (CI) = 1.01, 1.55). However, we found no strong evidence of an association between ever postmenopausal estrogen combined with progesterone use and BCIS using a random- effects model (RR = 1.55, 95% CI = 0.95, 2.51). Furthermore, our analysis showed a strong association between " > 5 years duration" of estrogen or estrogen combined with progesterone use and BCIS. Furthermore, current use of any HT is associated with increased risk of BCIS in cohort studies. Additional well-designed large studies are now required to validate this association in different populations. PMID- 23098494 TI - Literacy and breast cancer prevention: a population-based study from Iran. AB - Breast cancer is the most common cancer in women worldwide and the leading cause of death from cancer among women. Evidence suggests that early diagnosis and screening interventions might help to improve outcomes. This population-based study was conducted to determine breast cancer awareness and screening behavior among Iranian women and to examine its association with women's literacy. The study was carried out in two provinces, with 1,477,045 population, located in central and eastern part of Iran. Overall, 770 women were studied. Of these, 482 (62.7%) were literate and 287 (37.3%) were not. The results obtained from the data analysis indicated that there was a significant difference between literate and illiterate women. Further analysis of the data using logistic regression showed that literacy was an important contributing factor for breast cancer prevention behavior. The findings suggest that in order to improve women's health and breast cancer outcomes providing equal educational opportunities for women seems necessary. PMID- 23098495 TI - Variants on ESR1 and their association with prostate cancer risk: a meta analysis. AB - BACKGROUND: Epidemiological studies evaluating the association of two variants rs9340799 and rs2234693 on estrogen receptor 1 (ESR1) with prostate risk have generated inconsistent results. METHODS: A meta-analysis was here conducted to systematically evaluate the relationship of these two variants with prostate cancer susceptibility. RESULTS: For rs9340799, heterozygosity of T/C carriers showed a significant increased prostate cancer risk with a pooled odds ratio (OR) of 1.34 (95% CI = 1.06-1.69) while homozygote C/C carriers showed an increased but not statistically significant association with prostate cancer risk (pooled OR = 1.29, 95% CI = 0.94-1.79). Compared to the homozygous TT carriers, the allele C carriers showed a 31% increased risk for prostate cancer (pooled OR = 1.31, 95% CI = 1.06-1.63). No significant association between the rs2234693 and prostate cancer risk was found with the pooled OR of 1.15 (95% CI = 0.97-1.39, T/C and C/C vs. T/T) under the dominant genetic model. Compared to the homozygote T/T carriers, the heterozygous T/C carriers did not show any significantly different risk of prostate cancer (pooled OR = 1.13, 95% CI = 0.94-1.36) and the homozygous C/C carriers also did not show a significant change for prostate cancer risk compared to the wide-type T/T carriers (pooled OR = 1.26, 95% CI = 0.98-1.62). CONCLUSIONS: These data suggested that variant rs9340799, but not rs2234693, on ESR1 confers an elevated risk of prostate cancer. PMID- 23098496 TI - MTHFR C677T polymorphism and ovarian cancer risk: a meta-analysis. AB - BACKGROUND: Many studies have investigated possible association between the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and ovarian cancer risk, but the impact is still unclear owing to the obvious inconsistencies. This study was performed to quantify the strength of the association with a meta- analysis. METHODS: We searched the PubMed, Embase, and CNKI databases for studies relating the association between MTHFR C677T polymorphism and ovarian cancer risk and estimated summary odds ratios (ORs) with confidence intervals (CIs) for assessment. RESULTS: Finally, eight studies with a total of 3,379 ovarian cancer cases and 4,078 controls were included into this meta-analysis. Overall the showed that MTHFR C677T polymorphism was not associated with ovarian cancer risk under all genetic models (ORT versus C = 1.03, 95%CI 0.90-1.18; ORTT versus CC = 1.08, 95%CI 0.79-1.47; ORTT versus TC+CC = 1.05, 95%CI 0.80-1.37; ORTT +TC versus CC = 1.05, 95%CI 0.86-1.21). Meta-analyses of studies with confirmation of HWE also showed no significant association. Subgroup analyses by ethnicity showed there was no significant association in the Caucasians but MTHFR C677T polymorphic variant T contributed to increased risk of ovarian cancer in East Asians. No evidence of publication bias was observed. CONCLUSION: Meta-analyses of available data show that MTHFR C677T polymorphism is not associated with ovarian cancer risk in Caucasians, but the MTHFR polymorphic variant T may contribute to increased risk in East Asians. PMID- 23098497 TI - No association between MTHFR A1298C gene polymorphism and head and neck cancer risk: a meta-analysis based on 9,952 subjects. AB - OBJECTIVE: Findings for associations between the methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and head and neck cancer risk have been conflicting. We therefore performed a meta-analysis to derive a more precise relationship. METHODS: Ten published case-control studies were collected and odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association between MTHFR A1298C polymorphism and head and neck cancer risk. Sensitivity analysis and publication bias assessment also were performed to guarantee the statistical power. RESULTS: Overall, no significant association between MTHFR A1298C polymorphism and head and neck cancer risk was found in this meta-analysis (C vs. A: OR=1.04, 95%CI=0.87- 1.25, P=0.668, P heterogeneity<0.001; CC vs. AA: OR=1.07, 95%CI=0.70-1.65, P=0.748, P heterogeneity<0.001; AC vs. AA: OR=1.06, 95%CI=0.88-1.27, P=0.565, P heterogeneity<0.001; CC+AC vs. AA: OR=1.06, 95%CI=0.86-1.30, P=0.571, P heterogeneity<0.001; CC vs. AA+AC: OR=1.02, 95%CI=0.69-1.52, P=0.910, P heterogeneity<0.001). Similar results were also been found in succeeding analysis of HWE and stratified analysis of ethnicity. CONCLUSIONS: In conclusion, our meta analysis demonstrates that MTHFR A1298C polymorphism may not be a risk factor for developing head and neck cancer. PMID- 23098498 TI - Epidemiology and histopathological spectrum of head and neck cancers in Bihar, a state of Eastern India. AB - Head and neck cancers are amongst the commonest malignancies, accounting for approximately 20% of the cancer burden in India. The major risk factors are tobacco chewing, smoking and alcohol consumption, which are all preventable. This retrospective study presents data from the histopathology register for a five year period from 2002-2006 at Patna Medical College and Hospital, a tertiary care hospital drawing patients from the entire Bihar state, the 3rd most populous state of India with the majority of the population residing in rural areas. Incidence rates based on sex, age, site of lesion, including age standardized incidence rates for males and females, with mean age of presentation, distribution of histological variants and year wise trend were calculated. Out of 455 head and neck neoplasias, 241 were benign while 214 were malignant. The most common age group for all malignant biopsies was 7th decade for males and the 5th decade for females. Malignant cases were commoner in males than females with the male:female ratio of 3.1:1, which was found to be statistically significant by the chi-square (chi2) test. The crude rate and age standardized incidence rate was 0.05 and 0.06 per 100,000 population respectively. Squamous cell carcinoma (SCC) contributed about 96% of all cases, with grade I being the most common. Larynx was the most common site for malignancy, the supraglottic region being its most commonly affected sub-site. This observed incidence patterns in the region are a reminder of widespread unawareness, low healthcare utilization with virtually non-existent cancer programs. It also underlines the need to advocate for reliable cost-effective programs to create awareness, for early detection and plan appropriate management strategies. There is a compelling demand for a cancer registry in this region as well as proper implementation of preventive measures to combat this growing threat of cancer, many of whose risk factors are preventable. PMID- 23098499 TI - CD4+, IL17 and Foxp3 expression in different pTNM stages of operable non-small cell lung cancer and effects on disease prognosis. AB - OBJECTIVE: To investigate the effects of CD4+ , IL17 and Foxp3 expression on prognosis of operable non-small cell lung cancer (NSCLC) with different pTNM stages. METHODS: Expression of CD4+ , IL17 and Foxp3 in 102 cases of NSCLC tissues and adjacent cancer tissues was detected by immunohistochemistry and associations with prognosis with different pTNM stages were analyzed. The Chi square test was used to compare count data. Survival differences were evaluated by Kaplan-Meier single factor analysis and the COX regression model was used to analyze the relationship between influential factors and the disease prognosis. The significance level was alpha= 0.05. RESULTS: Expression of CD4, IL-17 and Foxp3 significantly varied in different pTNM stages of NSCLC tissues (P < 0.05). The same was true for CD4 expression (P < 0.05). The median survival time (MST) in the positive CD4 expression group was evidently higher than that in the negative group (25.8/23.9 months). Compared with stage III, the MST difference of stages I and II in the positive CD4 expression group were statistically significant (P < 0.05). The MST in positive IL-17 and Foxp3 expression groups was obviously lower than that in the corresponding negative group (P < 0.05) (25.6/35.1 months and 24/35.3 months, respectively). There was a significant difference of MST between any two of three stages of positive IL-17 expression group (P < 0.05), and it was the same with positive Foxp3 expression group. TNM stage, negative CD4 expression, and positive IL-17 and Foxp3 expression were the main risk factors for the prognosis of NSCLC. CONCLUSIONS: Surgical prognosis of NSCLC can be better assessed by the combination of clinical staging and expression of IL17 and Foxp3. PMID- 23098500 TI - Concurrent chemoradiotherapy versus radiotherapy alone for locoregionally advanced nasopharyngeal carcinoma. AB - OBJECTIVE: To compare the clinical effects of concurrent radiochemotherapy with those of radiotherapy in treating locally advanced nasopharyngeal carcinoma (Stage III~IVa). METHODS: A total of 95 patients suffering from nasopharyngeal carcinoma (Stage III~IVa) were divided into two groups: concurrent radiochemotherapy (Group CCRT, n=49) and radiotherapy (Group RT, n=46). The two groups were both delivered conventional fractionated radiotherapy, while Group CCRT also received three cycles of PF (DDP+5-Fu) or PLF (DDP+5- Fu+CF) chemotherapy. RESULTS: The complete remission rate and total remission rate of Group CCRT were higher than those of Group RT (X2=4.72~7.19, P<0.05). The one year overall survival (OS) rate calculated by the life table method, was also higher than that of Group RT (X2=4.24, P<0.05) as well as the 3-year OS rate, nasopharyngeal control rate and cervical lymph nodes' control rate (X2=4.28~4.40, P<0.05). In addition, the 5-year OS and metastasis-free rates of Group CCRT were higher than those of Group RT and the differences were of statistical importance (X2=3.96~8.26, P<0.05). However, acute toxicity was also obviously higher, the difference in gastrointestinal reactions being statistically significant (X2=11.70, P<0.05). CONCLUSION: This study demonstrated that concurrent radiochemotherapy could improve the remission rate, overall survival rate and locally control rate. The toxicity of concurrent radiochemotherapy could be tolerated by the patients. PMID- 23098501 TI - Multivariate analysis of molecular indicators for postoperative liver metastasis in colorectal cancer cases. AB - AIMS: To explore the relationship between various molecular makers and liver metastasis of colorectal cancer (CRC). METHOD: Using immunohistochemistry, protein expression of CEA, nm23, c-met, MMP2, COX- 2, VEGF, EGFR, and CD44 was assessed in 80 CRC cases. The Chi-square test and logistic regression were performed to analyze the relationship between these indicators and CRC liver metastasis. RESULTS: There were significant differences in expression of CEA, MMP2, CD44, VEGF and EGFR between the liver metastasis and non metastasis groups (P < 0.05); no significant differences were noted for nm23, c-met, and COX-2 expression. Logistic regression analysis showed that only CEA, VEGF, and EGFR entered into the regression equation, and had significant correlations with CRC liver metastasis (alpha inclusion= 0.10, alpha elimination = 0.15, R2 = 0.718). CONCLUSIONS: Combination detection of CEA, VEGF, and EGFR may be an effective means to predict CRC liver metastasis. Nm23, c-met, MMP2, COX-2, and CD44, in contrast, are not suitable as prognostic markers. PMID- 23098502 TI - Oral etoposide for platinum-resistant and recurrent epithelial ovarian cancer: a study by the Anatolian Society of Medical Oncology. AB - BACKGROUND: The aim of this study was to evaluate the efficacy and toxicity of long-term, low-dose oral etoposide as an advanced treatment option in patients with platinum resistant epithelial ovarian cancer. MATERIALS AND METHODS: For the purposes of this study, 51 patients with histologically-confirmed, recurrent or metastatic platinum-resistant epithelial ovarian cancer (EOC) treated at six different centers between January 2006 and January 2011 were retrospectively evaluated. Patients were treated with oral etoposide (50 mg/day for a cycle of 14 days, repeated every 21 days). RESULTS: Among the 51 platinum-resistant patients, 17.6% demonstrated a partial response and 25.5% a stable response. The median progression-free survival (PFS) was 3.9 months (95% CI, 2.1-5.7), while the median overall survival was 16.4 months (11.8-20.9). No significant relationship was observed between the pre-treatment CA 125 levels, post-treatment CA-125 levels and the treatment response rates (p=0.21). Among the 51 patients who were evaluated in terms of toxicity, grade 1 or 4 hematologic toxicity was observed in 19 (37.3%); and grade 1-4 gastrointestinal toxicity occurred in 15 patients (29.4%). CONCLUSIONS: Chronic low-dose oral etoposide treatment is generally effective and well-tolerated in platinum-resistant ovarian cancer patients. PMID- 23098503 TI - Effects of valproic acid on proliferation, apoptosis, angiogenesis and metastasis of ovarian cancer in vitro and in vivo. AB - Inhibitors of histone deacetylase activity are emerging as a potentially important new class of anticancer agents. In this study, we assessed the anticancer effects of valproic acid (VPA) on ovarian cancer in vitro and in vivo. Cultured SKOV3 cells were treated by VPA with different concentrations and time, then the effects on cell growth, cell cycle, apoptosis, and related events were investigated. A human ovarian cancer model transplanted subcutaneously in nude mice was established, and the efficacy of VPA used alone and in combination with diammine dichloroplatinum (DDP) to inhibit the growth of tumors was also assessed. Proliferation of SKOV3 cells was inhibited by VPA in a dose and time dependent fashion. The cell cycle distribution changed one treatment with VPA, with decrease in the number of S-phase cells and increase in G1-phase. VPA could significantly inhibit the growth of the epithelial ovarian cancer SKOV3 cells in vivo without toxic side effects. Treatment with VPA combined with DDP demonstrated enhanced anticancer effects. The result of flow cytometry (FCM) indicated that after VPA in vitro and in vivo, the expression of E-cadherin was increased whereas vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were decreased. This study suggests that VPA could be a novel attractive agent for treatment of ovarian cancer. PMID- 23098504 TI - Participation and barriers to colorectal cancer screening in Malaysia. AB - In Malaysia, colorectal cancer is the most common cancer in males and the third most common in females. Mortality due to colorectal cancer can be effectively reduced with early diagnosis. This study was designed to look into colorectal cancer screening participation and its barriers among average risk individuals in Malaysia. A cross sectional study was conducted from August 2009 till April 2010 involving average risk individuals from 44 primary care clinics in West Malaysia. Each individual was asked whether they have performed any of the colorectal cancer screening methods in the past five years. The barrier questions had three domains: patient factors, test factors and health care provider factors. Descriptive analysis was achieved using Statistical Program for Social Sciences (SPSS) version 12.0. A total of 1,905 average risk individuals responded making a response rate of 93.8%. Only 13 (0.7%) respondents had undergone any of the colorectal cancer screening methods in the past five years. The main patient and test factors for not participating were embarrassment (35.2%) and feeling uncomfortable (30.0%), respectively. There were 11.2% of respondents who never received any advice to do screening. The main reason for them to undergo screening was being advised by health care providers (84.6%). The study showed that participation in colorectal cancer screening in Malaysia is extremely low and multiple factors contribute to this situation. Given the importance of the disease, efforts should be made to increase colorectal cancer screening activities in Malaysia. PMID- 23098505 TI - Anticancer activity of Acacia nilotica (L.) Wild. Ex. Delile subsp. indica against Dalton's ascitic lymphoma induced solid and ascitic tumor model. AB - The aim of the present investigation was to evaluate the effect of A. nilotica extract against Dalton's ascitic lymphoma (DAL) induced solid and ascitic tumors in BALB/c mice. Experimental animals received A. nilotica extract (10 mg/kg.bw) intraperitoneally for 10 and 14 consecutive days before induction of solid and ascitic tumors, respectively. Treatment with A. nilotica extract significantly decreased the development of tumor and percentage increase in body weight when compared to DAL induced solid tumor control group, also increasing the life span, restoring the total white blood cell count and hemoglobin content and significantly decreasing the levels of serum aspartate transaminase (SGPT), alanine transaminase (SGOT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and nitric oxide (NO) when compared to DAL induced ascitic tumor controls. The treatment also reduced significantly the cellular glutathione (GSH) and nitric oxide levels in treated animals. Histopathological studies also confirmed protective influence. The outcome of the present work indicates that A. nilotica extract could be used as natural anticancer agent for human health. PMID- 23098506 TI - Identification of genes and microRNAs involved in ovarian carcinogenesis. AB - MicroRNAs (miRNAs) play roles in the clinic, both as diagnostic and therapeutic tools. The identification of relevant microRNAs is critically required for ovarian cancer because of the prevalence of late diagnosis and poor treatment options currently. To identify miRNAs involved in the development or progression of ovarian cancer, we analyzed gene expression profiles downloaded from Gene Expression Omnibus. Comparison of expression patterns between carcinomas and the corresponding normal ovarian tissues enabled us to identify 508 genes that were commonly up-regulated and 1331 genes that were down-regulated in the cancer specimens. Function annotation of these genes showed that most of the up regulated genes were related to cell cycling, and most of the down-regulated genes were associated with the immune response. When these differentially expressed genes were mapped to MiRTarBase, we obtained a total of 18 key miRNAs which may play important regulatory roles in ovarian cancer. Investigation of these genes and microRNAs should help to disclose the molecular mechanisms of ovarian carcinogenesis and facilitate development of new approaches to therapeutic intervention. PMID- 23098507 TI - Expression of smoothened protein in colon cancer and its prognostic value for postoperative liver metastasis. AB - BACKGROUDS: The hedgehog (Hh) signaling pathway is composed of patched (PTCH) and smoothened (SMO), two transmembrane proteins, and downstream glioma-associated oncogene homolog (Gli) transcription factors. Hh signaling plays a pathological role in the occurrence and development of various cancers. METHODS: To investigate the expression of SMO protein in colon cancer and its association with clinicopathological parameters and postoperative liver metastasis, immunohistochemistry was performed with paraffin-embedded specimens of 96 cases. Relationships between SMO protein expression and clinicopathological parameters, postoperative liver metastasis were analyzed. RESULTS: IHC examination showed that SMO protein expression was significantly increased in colon cancer tissues compared to normal colon tissues (P = 0.042), positively related to lymph node metastases (P = 0.018) and higher T stages (P = 0.026). Postoperative live metastasis-free survival was significantly longer in the low SMO expression group than in those with high SMO expression (48.7 +/- 8.02 months vs 28.0 +/- 6.86 months, P=0.036). Multivariate analysis showed SMO expression level to be an independent prognostic factor for postoperative live metastasis-free survival (95% confidence interval [CI] =1.46-2.82, P = 0.008). CONCLUSIONS: Our results suggest that in patients with colon cancer, the SMO expression level is an independent biomarker for postoperative liver metastasis, and SMO might play an important role in colon cancer progression. PMID- 23098508 TI - Contribution of RIZ1 to regulation of proliferation and migration of a liver fluke-related cholangiocarcinoma cell. AB - PURPOSE: Retinoblastoma-interacting zinc finger gene (RIZ1) is a tumor suppressor gene which is highly inactivated by promoter hypermethylation in patients with liver fluke-related cholangiocarcinoma (CCA). Epigenetic aberration of this gene might withdraw the ability to restrain tumor cell proliferation and migration. We aimed to define the role of RIZ1 on cell proliferation and migration in CCA cell line. MATERIALS AND METHODS: Small interference RNA (siRNA) was used to knock down the expression of RIZ1 in a CCA-derived cell line in which cell proliferation and cell migration were performed. RESULTS: A predominant nuclear localization of RIZ1 was observed. Reduction of RIZ1 by siRNA augmented cell proliferation and migration. CONCLUSION: The result suggested that RIZ1 might play a role in regulating cell proliferation and migration in CCA. Reduction of RIZ1 expression may aggravate the progression of CCA. PMID- 23098510 TI - Risk factors for rectal cancer and methylenetetrahydrofolate reductase polymorphisms in a population in Northeast Thailand. AB - BACKGROUND AND AIM: Polymorphisms in methylenetetrahydrofolate reductase (MTHFR) are known to be associated with predisposition for certain cancers. This study aimed to evaluate the effects of lifestyle factors, family history and genetic polymorphisms in MTHFR C677T and A1298C on rectal cancer risk and possible interactions with lifestyle factors in Northeast Thailand. METHODS: A hospital based case-control study was conducted during 2002-2006 with recruitment of 112 rectal cancer cases and 242 non-rectal cancer patient controls. Information was collected using a structured-questionnaire. Blood samples were obtained for assay of MTHFR C677T and A1298C genotypes by polymerase chain reaction with restriction fragment length polymorphism (PCR-RFLP) techniques. Associations between lifestyle factors, family history and genetic polymorphisms v.s. rectal cancer risk were assessed using logistic regression analysis. RESULTS: Subjects with frequent and occasional constipation had a higher risk (OR adj.=14.64; 95%CI=4.28 50.04 and OR adj.=2.15; 95%CI=1.14-4.06), along with those who reported ever having hemorrhoids (OR adj.=2.82; 95%CI=1.36-5.84) or a family history of cancer (OR adj.=1.90; 95%CI=1.06-3.39). Consumption of a high level of pork was also associated with risk (OR adj.=1.82; 95%CI=1.05-3.15). Interactions were not observed between MTHFR and other risk factors. CONCLUSIONS: This study suggested that the risk factors for rectal cancer in the Thai population are bowel habits, having had hemorrhoids, a family history of cancer and pork consumption. PMID- 23098509 TI - Various aspects, patterns and risk factors in breast cancer patients of Balochistan. AB - PURPOSE: Breast cancer is the commonest malignancy of females throughout the world with one million new cases each year. In Pakistan, the burden of breast cancer disease is high with late stage presentation being a common feature, more than half being stage III or stage IV. The objective of this study was to study various aspects, patterns and risk factors in breast cancer patients of Balochistan. METHOD: Present study was performed on 134 patients of breast cancer who were registered in CENAR. The patients were interviewed by providing a questionnaire. Informed consent was taken from all the patients who took part in this study after explanation of the study aims. Body mass index (BMI) was calculated andbiopsy reports were obtained from patients files. All the cases were classified with respect to age, gender, ethnic group (Baloch, Pashtoon, Punjabi, Afghani, Hazara) BMI, cancer type, cancer grade, hormonal status, side of the cancer, fertility and marital status. RESULTS: Out of 134 patients, the most common ethnic group was Pashtoon with a total of 42 and the common age group was 41-50 years with a total of 51. Invasive ductal carcinoma (IDC) was the most common type, accounting for in 128 patients (95.5%) followed by invasive lobular carcinoma (ILC). CONCLUSION: Pashtoon was the most common ethnic group, IDC was common type and most of the patients had an ER/PR positive hormonal status. PMID- 23098511 TI - Is short-term exercise a therapeutic tool for improvement of cardioprotection against DOX-induced cardiotoxicity? An experimental controlled protocol in rats. AB - BACKGROUND AND OBJECTIVE: Cardiotoxicity and oxidative stress is a life threatening side effect of doxorubicin (DOX). We investigate the effects of short term exercise as therapeutic tool for improvement of cardioprotection against DOX induced cardiotoxicity in the rat. METHODS: Wistar males (weighing 257 +/- 28 g) were divided into six groups: (1) control+placebo (2) control+DOX 10 mg.kg(-1) (3) control+DOX 20mg.kg(-1) (4) training+placebo (5) training+ DOX10 mg.kg(-1) (6) training+DOX 20mg.kg(-1). Cardiotoxicity was induced by DOX (10 and 20 mg.kg( 1)). The rats in groups 4, 5 and 6 experienced treadmill running of 25 to 39 min.day(-1) and 15 to 17 m.min(-1), 5 days/ wk for 3 wk. At the end of the endurance training program, rats in the 1 and 4 groups, in the 2 and 5 groups and in the 3 and 6 groups received saline solution, DOX 10 mg.kg(-1) and DOX 20 mg.kg(-1), respectively. RESULT: DOX administration (10 and 20 mg.kg(-1)) caused significant increase in MDA and Apelin, an insignificant increase in NO and a significant decrease in SOD, as compared to the C+P group. Three weeks of the pretreatment endurance exercise resulted in a significant increase of Apelin and SOD, an insignificant increase of NO and an insignificant decrease of MDA, as compared to the C+P group. Furthermore, after three weeks of endurance training and DOX treatment with 10mg.kg(-1) and 20mg.kg(-1), a significant increase in apelin and SOD, and a significant decrease in MDA were detected in comparison to C+DOX10 and/or C+DOX20 groups. There was a significant difference between DOX10 mg.kg(-1) and DOX20 mg.kg(-1) treatments in MDA levels only. CONCLUSION: Pretreatment exercise may improve myocardial tolerance to DOX-induced cardiotoxicity by inhibition of oxidative stress and up- regulation of antioxidants in heart tissue. PMID- 23098512 TI - Reconstructed adeno-associated virus with the extracellular domain of murine PD-1 induces antitumor immunity. AB - BACKGROUND: The negative signaling provided by interactions of the co-inhibitory molecule, programmed death-1 (PD-1), and its ligands, B7-H1 (PD-L1) and B7-DC (PD L2), is a critical mechanism contributing to tumor evasion; blockade of this pathway has been proven to enhance cytotoxic activity and mediate antitumor therapy. Here we evaluated the anti-tumor efficacy of AAV-mediated delivery of the extracellular domain of murine PD-1 (sPD-1) to a tumor site. MATERIAL AND METHODS: An rAAV vector was constructed in which the expression of sPD-1, a known negative regulator of TCR signals, is driven by human cytomegalovirus immediate early promoter (CMV-P), using a triple plasmid transfection system. Tumor-bearing mice were then treated with the AAV/sPD1 construct and expression of sPD-1 in tumor tissues was determined by semi quantitative RT-PCR, and tumor weights and cytotoxic activity of splenocytes were measured. RESULTS: Analysis of tumor homogenates revealed sPD-1 mRNA to be significantly overexpressed in rAAV/sPD-1 treated mice as compared with control levels. Its use for local gene therapy at the inoculation site of H22 hepatoma cells could inhibit tumor growth, also enhancing lysis of tumor cells by lymphocytes stimulated specifically with an antigen. In addition, PD-1 was also found expressed on the surfaces of activated CD8+ T cells. CONCLUSION: This study confirmed that expression of the soluble extracellular domain of PD-1 molecule could reduce tumor microenvironment inhibitory effects on T cells and enhance cytotoxicity. This suggests that it might be a potential target for development of therapies to augment T-cell responses in patients with malignancies. PMID- 23098513 TI - HOCl oxidation-modified CT26 cell vaccine inhibits colon tumor growth in a mouse model. AB - Despite progress in elucidating mechanisms associated with colorectal cancer and improvement of treatment methods, it remains a frequent cause of death worldwide. New and more effective therapies are therefore urgently needed. Recent studies have shown that immunogenicity of whole ovarian tumor cells and subsequent T cell response were potentiated by oxidation modification with hypochlorous acid (HOCl) in vitro and ex vivo. These results prompted us to investigate the protective antitumor response with an HOCl treated CT26 colorectal cancer cell vaccine in an in vivo mouse model. Administration of HOCl modified vaccine triggered robust antitumor immunity to autologous tumor cells in mice and prolonged survival period significantly. In addition, increased necrosis and apoptosis were found in tumor tissue from the oxidation group. Interestingly, ELISPOT assays showed that specific T cell responses were not elicited in response to the immunizing cellular antigen, in contrast to raising sera antibody titer and antibody binding activity shown by ELISA assay and flow cytometry. Further evaluation of the mechanisms underlying HOCl modified vaccine mediated humoral immunity highlighted the role of antibody-dependent cell-mediated cytotoxicity. These results combined with previous studies suggest that HOCl oxidation modified whole cell vaccine has wide applicability as a cancer vaccine because it can target both T cell- and B cell-specific responses. It may thus represent a promising approach for the immunotherapy of colorectal cancer. PMID- 23098514 TI - Conservative neck dissection in oral cancer patients: a 5 year retrospective study in Malaysia. AB - OBJECTIVE: The impact of ablative oral cancer surgery was studied, with particular reference to recurrence and nodal metastasis, to assess survival probability and prognostic indicators and to elucidate if ethnicity influences the survival of patients. METHODS: Patients who underwent major ablative surgery of the head and neck region with neck dissection were identified and clinical records were assessed. Inclusion criteria were stage I-IV oral and oropharyngeal malignancies necessitating resection with or without radiotherapy from 2004 to 2009. All individuals had a pre-operative assessment prior to the surgery. The post operative assessment period ranged from 1 year to 5 years. Survival distributions were analyzed using Kaplan-Meier curves. RESULTS: 87 patients (males:38%; females:62%) were included in this study, with an age range of 21-85 years. Some 78% underwent neck dissections while 63% had surgery and radiotherapy. Nodal recurrence was detected in 5.7% while 20.5% had primary site recurrence within the study period. Kaplan-Meier survival analysis revealed that the median survival time was 57 months. One year overall survival (OS) rate was 72.7% and three year overall survival rate dropped to 61.5%. On OS analysis, the log-rank test showed a significant difference of survival between Malay and Chinese patients (Bonferroni correction p=0.033). Recurrence-free survival (RFS) analysis revealed that 25% of the patients have reached the event of recurrence at 46 months. One year RFS rate was 85.2% and the three year survival rate was 76.1%. In the RFS analysis, the log-rank test showed a significant difference in the event of recurrence and nodal metastasis (p<0.001). CONCLUSION: Conservative neck is effective, in conjunction with postoperative radiotherapy, for control of neck metastases. Ethnicity appears to influence the survival of the patients, but a prospective trial is required to validate this. PMID- 23098515 TI - Pomegranate (Punica granatum) peel extract efficacy as a dietary antioxidant against azoxymethane-induced colon cancer in rat. AB - Functional foods include antioxidant nutrients which may protect against many human chronic diseases by combating reactive oxygen species (ROS) generation. The purpose of the present study was to investigate the protective effect of pomegranate peel extract (PPE) on azoxymethane (AOM)-induced colon tumors in rats as an in vivo experimental model. Forty Sprague-Dawley rats (4 weeks old) were randomly divided into 4 groups containing 10 rats per group, and were treated with either AOM, PPE, or PPE plus AOM or injected with 0.9% physiological saline solution as a control. At 8 weeks of age, the rats in the AOM and PPE plus AOM groups were injected with 15 mg AOM/kg body weight, once a week for two weeks. After the last AOM injection, the rats were continuously fed ad-libitum their specific diets for another 6 weeks. At the end of the experiment (i.e. at the age of 4 months), all rats were killed and the colon tissues were examined microscopically for lesions suspected of being preneoplastic lesions or tumors as well as for biochemical measurement of oxidative stress indices. The results revealed a lower incidence of aberrant crypt foci in the PPE plus AOM administered group as compared to the AOM group. In addition, PPE blocked the AOM induced impairment of biochemical indicators of oxidative stress in the examined colonic tissue homogenates. The results suggest that PPE can partially inhibit the development of colonic premalignant lesions in an AOM-induced colorectal carcinogenesis model, by abrogating oxidative stress and improving the redox status of colonic cells. PMID- 23098516 TI - Awareness regarding risk factors, symptoms and treatment facilities for cancer in selected states of India. AB - OBJECTIVE: To study the level of awareness and knowledge about cancers and associated risk factors among households in selected states of India. METHODS: In the study 3070 households were interviewed from six states viz, West Bengal, Kerala, Madhya Pradesh, Rajasthan and Mizoram. RESULTS: Knowledge of cancers other than those related to tobacco was very low (prostate 8%, colon 11% ) among the communities, with a poor awareness of warning signs and symptoms. The knowledge varied from state to state. It is found that the major source of information related to cancers was television (38%) followed by friends and relatives (36%). Only about 15 % of respondents had knowledge about cancer awareness camps organized in their districts but they did not have knowledge about the organizers of the camp. Findings suggested a strong need for strengthening of DCCP. CONCLUSION: It is important to create awareness among community through educational programs on cancer prevention, preventable cancer risk factors, benefits of early diagnosis, and availability of screening facilities. Integration of District Cancer Control activities with NRHM could be the most cost-effective strategy to prevent cancers and rural population. PMID- 23098517 TI - Clinical outcome of breast cancer BI-RADS 4 lesions during 2003-2008 in the National Cancer Institute Thailand. AB - To determine the clinical outcome of breast cancer BI-RADS 4 lesions and seek a more effective management guideline, we conducted a retrospective study of all BI RADS4 patients diagnosed between 2003-2008 with follow up time not less than 2 years. A total of 392 cases of BI-RADS 4 were identified and 320 could be sub categorised as 4a, 4b and 4c. Overall malignant positive results were 7.65, 38.7 and 58.percent, respectively. In all cases assigned to the close follow up group, no malignancy was detectable (P<0.02). The results of the study suggested that BI RADS sub-categories have benefit for cancer diagnosis and treatment decisions of clinicians and it might be possible to set up a safe follow-up guideline in selected groups of patients to minimize un-necessary tissue biopsy for breast cancer detection. PMID- 23098518 TI - Suppressive effect of pioglitazone, a PPAR gamma ligand, on azoxymethane-induced colon aberrant crypt foci in KK-Ay mice. AB - Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferator- activated receptor gamma(PPARgamma) agonist that induces differentiation in adipocytes and induces growth arrest and/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect of pioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ay obesity and diabetes model mice, and tried to clarify mechanisms by which the PPARgamma ligand inhibits ACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouse to 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice with significant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines, such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceral fat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cell proliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggest that pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulated adipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNA levels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potential chemopreventive agent against obesity-associated colorectal cancer. PMID- 23098519 TI - Anti-proliferation effects of benzimidazole derivatives on HCT-116 colon cancer and MCF-7 breast cancer cell lines. AB - Benzimidazoles 1-4 were obtained using modified synthesis methods and studied for their ability to inhibit cell proliferation of colon cancer cell HCT-116 and breast cancer cell MCF-7 using MTT assays. In the HCT-116 cell line, benzimidazole 2 was found to have an IC50 value of 16.2 +/- 3.85 MUg/mL and benzimidazole 1 a value of 28.5 +/- 2.91 MUg/mL, while that for benzimidazole 4 was 24.08 +/- 0.31 MUg/mL. In the MCF-7 cell line, benzimidazole 4 had an IC50 value of 8.86 +/- 1.10 MUg/mL, benzimidazole 2 a value of 30.29 +/- 6.39 MUg/mL, and benzimidazole 1 a value of 31.2 +/- 4.49 MUg/mL. Benzimidazole 3 exerted no cytotoxicity in either of the cell lines, with IC50 values >50 MUg/mL. The results suggest that benzimidazoles derivatives may have chemotherapeutic potential for treatment of both colon and breast cancers. PMID- 23098520 TI - Use of complementary and alternative medicine among breast cancer survivors. AB - Complementary and alternative medicine (CAM) use is prevalent among individuals with cancer, especially breast cancer survivors. This study was conducted among 394 breast cancer survivors in selected regions of Peninsular Malaysia to identify the pattern and factors associated with CAM use. About 51% of the respondents reported CAM use as complementary treatment. Vitamins (47.2%), spiritual activities (33.2%) and other dietary supplements (30.7%) were the most commonly used CAM therapies. Common reasons for CAM use were to increase the body's ability to perform daily activities (70.9%), enhance immune function (58.3%) and improve emotional well-being (31.7%). Users obtained CAM information mainly from friends and family members (62.5%), physicians (25.0%) and mass media (13.9%). Ethnicity and years of education were significantly associated with CAM use. Although no adverse effects of CAM were reported, breast cancer survivors should discuss their CAM use with health professionals to prevent potential adverse effects of these therapies. PMID- 23098521 TI - Polymorphisms in the thymidylate synthase gene and risk of colorectal cancer. AB - To evaluate the relationship between polymorphisms (28 bp repeated sequences in 5'-UTR and 6-bp ins/ del in 3'-UTR) in then thymidylate synthetase gene (TS) and risk of colorectal, colon and rectal cancers, we conducted a case-control study with 315 cases of colorectal cancer and 439 population-based controls in Jiangsu province, China. TS genotypes were identified using PCR-RFLP (restriction fragment length polymorphism) methods. Odds ratios (ORs) were estimated with an unconditional logistic regression model. We found that the distributions of 5' UTR genotypes in TS were significantly different between controls and male colon cases (chi2 =8.25, P = 0.016). Compared with 3R/3R genotype, individuals with the 2R allele were at an increased risk of colon cancer (age-, BMI-, smoking- and alcohol drinking-adjusted OR=1.98, 95%CI: 1.11-3.53) among men. In contrast, the 6-bp ins/del polymorphism at the TS 3'- UTR did not influence risk of the colorectal, colon and rectal cancers. When combined genotypes for both TS 5'-UTR and 3'-UTR polymorphisms were evaluated, individuals with the 5'-UTR 2R allele had a OR of 3.61 (95%CI: 1.38-9.49) for colon cancer among men with the 3'-UTR 6bp/-6bp genotype. These results show that the polymorphism of the 28 bp repeated sequences in TS 5'-UTR could influence susceptibility to colon cancer and that there was a coordinated effect between TS 3'-UTR and 5'-UTR polymorphisms in increasing risk of colon cancer among Chinese men. PMID- 23098522 TI - Pituitary adenoma biomarkers identified using proteomic fingerprint technology. AB - OBJECTIVE: To determine whether pituitary adenomas can be diagnosed by identifying protein biomarkers in the serum. METHODS: We compared serum proteins from 65 pituitary adenoma patients and 90 healthy donors using proteomic fingerprint technology combining magnetic beads with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). RESULTS: A total of 42 M/Z peaks were identified as related to pituitary adenoma (P<0.01). A diagnostic model established based on three biomarkers (3382.0, 4601.9, 9191.2) showed that the sensitivity of diagnosing pituitary adenoma was 90.0% and the specificity was 88.3%. The model was further tested by blind analysis showing that the sensitivity was 88.0% and the specificity was 83.3%. CONCLUSIONS: These results suggest that proteomic fingerprint technology can be used to identify pituitary adenoma biomarkers and the model based on three biomarkers (3382.0, 4601.9, 9191.2) provides a powerful and reliable method for diagnosing pituitary adenoma. PMID- 23098523 TI - Diabetes mellitus and prostate cancer risk in Asian countries: a meta-analysis. AB - BACKGROUND/AIMS: Diabetes mellitus (DM) is widely considered to be associated with risk of cancer, but studies investigating the association between DM and prostate cancer in Asian countries have reported inconsistent findings. We examined this association by conducting a detailed meta-analysis of studies published on the subject. METHODS: Cohort or case-control studies were identified by searching Pubmed, Embase and Wanfang databases through May 30, 2012. Pooled relative risk (RR) with its corresponding 95% confidence interval (95% CI) were calculated using the random-effects model. Subgroup analyses were performed by the study type. RESULTS: Finally, we identified 7 studies (four cohort studies and three case-control studies) with a total of 1,751,274 subjects from Asians. DM was associated with an increased risk of prostate cancer in Asians (unadjusted RR= 2.82, 95% CI 1.73-4.58, P < 0.001; adjusted RR= 1.31, 95% CI 1.12-1.54, P = 0.001). Subgroup analyses by study design further confirmed an obvious association. CONCLUSION: Findings from this meta-analysis strongly support that diabetes is associated with an increased risk of prostate cancer in Asians. PMID- 23098524 TI - Protective effect of melatonin against radiation induced nephrotoxicity in rats. AB - PURPOSE: The degree of radiation injury to kidneys which are located within the limits of radiotherapy area is determined by the volume and the dose of radiation to which the organ is exposed. When the tolerance dose of the kidney is exceeded after a latent period of 6 months acute nephritis develops and after 18 months chronic nephritis ensues. Melatonin is known to prevent the oxidative injury of toxins and radiotherapy with its free radical scavenging capacity. METHODS AND MATERIALS: In this study 8 weeks old 24 Sprague -Dawley rats were allocated into 4 groups: Control group; Radiotherapy group (20 Gy bilaterally in 5 fractions); Melatonin group (10 mg/kg intraperitoneally), and Melatonin+radiotherapy group (20 Gy Radiotherapy in 5 fractions+ melatonin 10 mg/kg intraperitoneally). After a follow-up period of 6 months BUN was determined in all groups. After rats were euthanized the kidneys were removed for histopathological examination under both light and electron microscopes. RESULTS: After 6 months follow-up, both at light and electron microscopy levels, the rats in radiotherapy+melatonin group were significantly protected against the radiation injury comparing to radiotherapy group (p<0.05). CONCLUSION: It was shown in this experimental model that melatonin has protective effects against radiation injury to kidneys. PMID- 23098525 TI - Green tea polyphenol protection against 4-nitroquinoline 1-oxide-induced bone marrow lipid peroxidation and genotoxicity in Wistar rats. AB - 4-Nitroquinoline 1-oxide (4-NQO) a potent oral carcinogen, widely used for induction of oral carcinogenesis, has been found to induce lipid peroxidation in vivo and in vitro. Green tea contains a high content of polyphenols, which are potent antioxidants. Thus green tea polyphenols (GTP) might be expected play a protective role against 4-NQO induced lipid peroxidation and bone marrow toxicity. In the present study, a dose of 200 mg of GTP/kg b.wt/day was given orally for a week, simultaneously animals received 0.2 ml of 0.5% 4-NQO in propylene glycol (5 mg/ml) injected intramuscularly for three times/week. Oxidants and antioxidants such as malendialdehyde (MDA) and thiols, glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) and catalase (CAT) were significantly decreased in 4-NQO induced animals except MDA, and these parameters were brought back to near normalcy on treatment with GTP. The results suggest that GTP treatment offers significant protection against 4 NQO induced lipid peroxidation and bone marrow toxicity and might be a promising potential candidate for prevention of mutations leading to cancer. PMID- 23098526 TI - Association of poor prognosis subtypes of breast cancer with estrogen receptor alpha methylation in Iranian women. AB - Breast cancer is a prevalent heterogeneous malignant disease. Gene expression profiling by DNA microarray can classify breast tumors into five different molecular subtypes: luminal A, luminal B, HER-2, basal and normal- like which have differing prognosis. Recently it has been shown that immunohistochemistry (IHC) markers including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2), can divide tumors to main subtypes: luminal A (ER+; PR+/-; HER-2-), luminal B (ER+;PR+/-; HER-2+), basal like (ER-;PR-;HER2-) and Her2+ (ER-; PR-; HER-2+). Some subtypes such as basal like subtype have been characterized by poor prognosis and reduced overall survival. Due to the importance of the ER signaling pathway in mammary cell proliferation; it appears that epigenetic changes in the ERalpha gene as a central component of this pathway, may contribute to prognostic prediction. Thus this study aimed to clarify the correlation of different IHC-based subtypes of breast tumors with ERalpha methylation in Iranian breast cancer patients. For this purpose one hundred fresh breast tumors obtained by surgical resection underwent DNA extraction for assessment of their ER methylation status by methylation specific PCR (MSP). These tumors were classified into main subtypes according to IHC markers and data were collected on pathological features of the patients. ERalpha methylation was found in 25 of 28 (89.3%) basal tumors, 21 of 24 (87.5%) Her2+ tumors, 18 of 34 (52.9%) luminal A tumors and 7 of 14 (50%) luminal B tumors. A strong correlation was found between ERalpha methylation and poor prognosis tumor subtypes (basal and Her2+) in patients (P<0.001). Our findings show that ERalpha methylation is correlated with poor prognosis subtypes of breast tumors in Iranian patients and may play an important role in pathogenesis of the more aggressive breast tumors. PMID- 23098527 TI - Retrospective analysis of neoadjuvant chemotherapy for breast cancer in Turkish patients. AB - BACKGROUND: Neoadjuvant systemic chemotherapy is the accepted approach for women with locally advanced breast cancer. Anthracycline- and taxane-based regimens have been extensively studied in clinical trials and consequently are widely used. In this study aimed to research the complete response (pCR) rates in different regimens for neoadjuvant setting and determine associated clinical and biological factors. METHODS: This study included 63 patients diagnosed with breast carcinoma among 95 patients that had been treated with neoadjuvant chemotherapy between 2007 and 2010. TNM staging system was used for staging. The histologic response to neoadjuvant chemotherapy was characterized as a pCR when there was no evidence of residual invasive tumor in the breast or axillary lymph nodes. Biologic subclassification using estrogen receptor (ER), progesterone receptor (PR), HER2 were performed. Luminal A was defined as ER+, PR+, HER2-; Luminal B tumor was defined as ER+, PR-, HER2-; ER+, PR-, HER2+; ER-, PR+, HER2-; ER+, PR+, HER2+, HER2 like tumor ER-, PR+, HER2+; and triple negative tumor ER, PR, HER2 negative. RESULTS: Patients median age was 54.14 (min-max: 30-75). Thirty-two patients (50.8%) were premenopausal and 31 (49.2%) were postmenopausal. Staging was performed postoperatively based on the pathology report and appropriated imaging modalities The TNM (tumor, lymph node, metastasis) system was used for clinical and pathological staging. Fifty-seven (90.5%) were invasive ductal carcinomas, 6 (9.5%) were other subtypes. Thirty nine (61.9%) were grade II and 24 (38.1%) were grade III. Seven (11.1%) patients were stage II and 56 (88.9) patients were stage III. The patients were classified for ER, PR receptor and HER2 positivity. Seventeen patients had complete response to chemotherapy. Forty patients (63.5%) were treated with dose dense regimen (cyclophosphamide 600 mg/m2 and doxorubicine 60 mg/m every two weeks than paclitaxel 175 mg/m2 every two weeks with filgrastim support) 40 patients (48%) were treated anthracycline and taxane containing regimens. Thirteen patients (76%) from 17 patients with pCR were treated with the dose dense regimen but without statistical significance (p=0.06). pCR was higher in HER2(-), ER(-), grade III, premenopausal patients. CONCLUSION: pCR rate was higher in the group that treated with dose dense regimen, which should thus be the selected regimen in neoadjuvant setting. Some other factors can predict pCR in Turkish patients, like grade, menopausal status, triple negativity, percentage of ER positivity, and HER2 expression. PMID- 23098528 TI - Retrospective analysis of 498 primary soft tissue sarcomas in a single Turkish centre. AB - BACKGROUND: Soft tissue sarcomas (STS) must be managed with a team involving pathologists, radiologists, surgeons, radiation therapists and medical oncologists. Treatment modalities and demographic characteristics of Turkish STS were analysed in the current study. MATERIAL-METHODS: Primary adult STS followed between 1999- 2010 in Cukurova University Medical Faculty Department of Medical Oncology were analyzed retrospectively. RESULTS: Of the total of 498 patients, 238 were male and 260 female. The most seen adult sarcomas were leomyosarcoma (23%). Localization of disease was upper extremity (8.8%), lower extremity (24.7%), head-neck 8.2%, thoracic 8%, retroperitoneal 5.6%, uterine 12.4%, abdominal 10%, pelvic region 3.6 and other regions 10%. Some 13.1% were early stage, 10.2% locally advanced, 8.2% metastatic and 12.2% recurrent disease. Patients were treated with neoadjuvant/adjuvant (12%) or palliative chemotherapy (7.2%) and 11.4% patients did not receive chemotherapy. Surgery was performed as radical or conservative. The most preferred regimen was MAID combination chemotherapy in the rate of 17.6%. The most common metastatic site was lung (18.1%). The overall survival was 45 months (95%CI 30-59), 36 months in men and 55 months in women, with no statistically significant difference (p=0.5). The survival rates were not different between the group of adjuvant and palliative chemotherapy (respectively 28 versus 18 months) (p=0.06), but radical surgery at 37 months was better than 22 months for conservative surgery (p=0.0001). No differences were evident for localization (p=0.152). Locally advanced group had higher overall survival rates (72 months) than other stages (p=0.0001). CONCLUSION: STS can be treated successfully with surgery, chemotherapy and radiotherapy. The survival rates of Turkish people were higher in locally advanced group; these results show the importance of multimodality treatment approach and radical surgery. PMID- 23098529 TI - Lack of any relationship between ABO and Rh blood groups and clinicopathological features in patients with gastrointestinal stromal tumors: Turkish Oncology Group. AB - BACKGROUND: An association between the ABO blood group and the risk of certain malignancies, including pancreatic and gastric cancer, has been reported previously. However, it is unclear whether this association is valid for gastrointestinal stromal tumors (GIST). In this study, ABO blood groups and the Rh factor were investigated in a series of GIST cases. MATERIAL AND METHODS: In 162 patients with GIST, blood group and Rh factor were examined and compared with a control group of 3,022,883 healthy volunteer blood donors of the Turkish Red Crescent between 2004 and 2011. The relationship of blood groups with tumor size, mitotic activity, and age were also evaluated. RESULTS: Overall, the ABO blood group and Rh factor distributions of the 162 patients with GIST were similar to those of the general population. There were no significant differences between both ABO blood types and Rh factor in terms of tumor size, mitotic activity, and age. CONCLUSION: This is the first study reported on this issue. In our study, we didn't find any relationship between GIST and ABO blood group and Rh factor. However further studies with larger number of patients are needed to establish the role of blood groups in this population. PMID- 23098530 TI - Survival following non surgical treatments for oral cancer: a single institutional result. AB - AIM: To report the results of radiotherapy with or without chemotherapy in the patients with oral cancer. METHODS: Over the 2003-2009 periods, a total number of 69 patients with squamous cell carcinoma of the oral cavity that refused surgery or had unresectable tumor were enrolled in this study. A total dose of 60 to 70 Gy (2 Gy per day) was given to the primary tumor and clinically positive nodes. In the patients with locoregionally advanced disease (57 patients with T3, T4 lesions and/ or N+) induction chemotherapy following by concomitant chemoradiation was used. Induction chemotherapy consisted of 3 cycles of Cisplatin and 5-Flourouracil with or without Docetaxel. Weekly cisplatin was used in concomitant protocol. Kaplan-Meier method was used to calculate overall survival. Log-rank test and Cox regression model were used for comparison purposes. RESULTS: Median follow-up was 32 months. The mean age of the patients was 59.2 years. The overall response rate after induction chemotherapy was 68.4%. Actuarial overall survival rates after 2 and 3 years were 38% and 26%, respectively. Clinical stage emerged as the only independent predictor of survival. CONCLUSION: Outcome of the patients with oral cancer is poor. Presenting with an advanced stage lesion contributed to this result. The role of chemotherapy in advanced cases remains to be defined. PMID- 23098531 TI - Reconstruction of combined oral mucosa-mandibular defects using the vascularized myoosseous iliac crest free flap. AB - The authors present five cases of combined oral mucosa-mandible defects reconstructed with the vascularized internal oblique-iliac crest myoosseous free flap. This technique has many advantages compared to other conventional methods such as the radial flap, scapula flap, and fibula flap. Vascularized iliac crest flaps provide sufficient high-quality bone suitable for reconstructing segmental mandibular defects. Although fibular flaps allow longer donor bone tissue to be harvested, the iliac crest can provide an esthetic shape for mandibular body reconstruction and also provides sufficient bone height for dental implants. Conventional vascularized iliac crest myoosseous flaps have excessive soft tissue bulk for reconstruction of intraoral soft tissue defects. The modification discussed in the present article can reduce soft tissue volume, resulting in better functional reconstruction of the oral mucosa. Another advantage is that complete replacement of the oral mucosa is observed in as early as one month post operation. The final mucosal texture is much better than that obtained with other skin paddle flaps, which is especially beneficial for the placement of dental implant prostheses. Donor site morbidity looks to be similar to, if not less than that observed for other modalities in terms of function and esthetics. For combined oral mucosa-mandible defects, the vascularized internal oblique-iliac crest myoosseous free flap shows good results with respect to hard and soft tissue reconstruction. PMID- 23098532 TI - Effects of care burdens of caregivers of cancer patients on their quality of life. AB - In this study, the aim was to examine the effects of caring burdens of family caregivers of cancer patients on their quality of life in the east of Turkey. Data were collected at the Chemotherapy unit of Yakutiye Research Hospital of Ataturk University. Participants were 18 years old and older. The sample included 190 family caregivers who were living in the same flats with the patients during caregiving. Data were collected using a questionnaire that included socio demographic questions for family caregivers and the Burden Interview, and the Caregiver Quality of Life Index-Cancer (CQOLC) Scale. SPSS version 14.0 was used to analyse the data. Descriptive statistics were computed for demographic variables of family caregivers. Pearson correlation analysis was used to analyze the relationship between the care burden and quality of life, linear logistic regression analysis was applied to determine the effect care burdens have on the quality of life, and logistic regression analysis was employed to determine the effect descriptive characteristics and care-related properties have on the quality of life. The score mean of the burden interview of caregivers was 36.6 +/ 11.2; and their score mean of CQOLC was 81.4 +/- 17.3. This study concluded that there was a negative relationship between caring burdens and the quality of life (p<0.001); descriptive characteristics, caring-related properties, and caring burden variables were all significant predictors of the quality of life. It is recommended that caregivers are given support by being offered training about providing care. PMID- 23098533 TI - In vitro biological characterization of DCUN1D5 in DNA damage response. AB - BACKGROUND: Novel prognostic biomarkers or therapeutic molecular targets for laryngeal squamous cell carcinoma (LSCC) are an urgent priority. We here sought to identify multiple novel LSCC-associated genes. METHODS: Using high-density microarray expression profiling, we identified multiple genes that were significantly altered between human LSCCs and paired normal tissues. Potential oncogenic functions of one such gene, DCUN1D5, were further characterized in vitro. RESULTS: Our results demonstrated that DCUN1D5 was highly expressed in LSCCs. Overexpression of DCUN1D5 in vitro resulted in 2.7-fold increased cellular migration, 67.5% increased invasive capacity, and 2.6-fold increased proliferation. Endogenous DCUN1D5 expression was decreased in a time-dependent manner after genotoxic stress, and silencing of DCUN1D5 by siRNA decreased the number of cells in the S phase by 10.2% and increased apoptosis by 11.7%. CONCLUSION: Our data suggest that DCUN1D5 in vitro might have vital roles in DNA damage response, but further studies are warranted to assess its significance in vivo. PMID- 23098534 TI - Cancer registration in the Peoples Republic of China. AB - The current situation of cancer registration in China was systematically reviewed. So far, cancer registration in China has been making a great progress in the following aspects: the number of cancer registries and covered population have increased dramatically; a registration network has been established and completed gradually; regulations and rules improved remarkably; more attention is being paid by every level of government; a lot of registration software has been created and financial support ensured. However, we are still facing some problems and challenges, such as no stable groups of registrars, shortage of training opportunities, poor data quality, insufficient utilization and lack of multidisciplinary mechanisms, so that the cancer registration system still needs to be enhanced and improved. Along with the development of economy, science and information technology, methods and patterns of cancer registration is changing. It is to be expected that cancer registration will be automatic, nationwide and integrated with community healthcare in the near future. PMID- 23098535 TI - Advanced diagnostic aids in oral cancer. AB - Oral cancers are one of the most common cancers worldwide today. They are usually neglected by the common population when compared to systemic cancers such as the lung cancer, colon cancer etc. However, they also may be extremely fatal if left untreated even at a very initial stage of the lesion. Early detection and treatment gives the best chance for its cure. The five-year survival rate of oral cancer still remains low and delayed diagnosis is suggested to be one of the major reasons. The detection and diagnosis are currently based on clinical examination, histopathological evaluation of the biopsy material and molecular methods. Several diagnostic aids have been developed over the years for early detection of oral cancer. The purpose of this article is to review the advanced available diagnostic adjuncts for the detection of oral cancer. PMID- 23098536 TI - Silencing of PDK1 gene expression by RNA interference suppresses growth of esophageal cancer. AB - The current study was conducted to explore the inhibitory effects of a small interfering RNA (siRNA) on 3-phosphoinositide-dependent protein kinase 1 (PDK1) expression in esophageal cancer 9706 (EC9706) cells and the influence on their biological behavior. After transfection of a synthesized PDK1 siRNA, PDK1 mRNA and protein expression and the phosphorylation level of the downstream Akt protein were assessed using RT-PCR and Western blot analysis. Proliferation, apoptosis, cell invasion and in vivo tumor formation capacity were also investigated using MTT, flow cytometry, Transwell invasion trials, and nude mouse tumor transplantation, respectively. PDK1 siRNA effectively suppressed PDK1 mRNA and protein expression, and down-regulated the phosphorylation level of the Akt protein in the EC9706 cells (P<0.05). It also inhibited cell proliferation and invasion, and promoted apoptosis; such effects were particularly obvious at 48 h and 72 h after transfection (P<0.05). Growth of transplanted tumors was inhibited in nude mice, with decreased PDK1 expression in tumor tissues. PDK1 may be closely correlated with proliferation, apoptosis and invasion of esophageal cancer cells and thus may serve as an effective target for gene therapy. PMID- 23098537 TI - Retrospective study of gemcitabine based chemotherapy for unresectable or recurrent esophagus squamous cell carcinoma refractory to first line chemotherapy. AB - PURPOSE: To investigate the efficacy and toxicity of a combination of gemcitabine with nedaplatin (GN) or cisplatin (GC) for patients with unresectable or recurrent esophagus squamous cell carcinoma. METHODS: Gemcitabine was administered at 1 g/m2 intravenously on days 1 and 8; and nedaplatin or cisplatin were administered at 80 mg/m2 intravenously on day 1. We analyzed the response rate, overall survival time, progression-free survival time, and toxicity in 21 patients treated with GN and 27 patients treated with GC. RESULTS: In patients treated with gemcitabine plus nedaplatin, the ORR was 47.6%, the median progression-free survival time was 4.1 months, and the median survival time was 9.3 months. In patients treated with gemcitabine plus cisplatin, the ORR was 48.2%, the median progression-free survival time was 3.9 months, and the median survival time was 9.1 months, respectively. There were no statistically significant differences in ORR, PFS and OS between the two groups. In both, the most commonly observed toxicities were thrombocytopenia and fatigue. Nausea and vomiting was more frequent in the GC group than in the GN group. CONCLUSION: Gemcitabine based chemotherapy was effective and tolerable for patients with unresectable or recurrent esophagus squamous cell carcinoma refractory to first line chemotherapy. PMID- 23098538 TI - External validation of the Bayesian Estimated Tools for Survival (BETS) models in patients with surgically treated skeletal metastases. AB - BACKGROUND: We recently developed two Bayesian networks, referred to as the Bayesian-Estimated Tools for Survival (BETS) models, capable of estimating the likelihood of survival at 3 and 12 months following surgery for patients with operable skeletal metastases (BETS-3 and BETS-12, respectively). In this study, we attempted to externally validate the BETS-3 and BETS-12 models using an independent, international dataset. METHODS: Data were collected from the Scandinavian Skeletal Metastasis Registry for patients with extremity skeletal metastases surgically treated at eight major Scandinavian referral centers between 1999 and 2009. These data were applied to the BETS-3 and BETS-12 models, which generated a probability of survival at 3 and 12 months for each patient. Model robustness was assessed using the area under the receiver-operating characteristic curve (AUC). An analysis of incorrect estimations was also performed. RESULTS: Our dataset contained 815 records with adequate follow-up information to establish survival at 12 months. All records were missing data including the surgeon's estimate of survival, which was previously shown to be a first-degree associate of survival in both models. The AUCs for the BETS-3 and BETS-12 models were 0.79 and 0.76, respectively. Incorrect estimations by both models were more commonly optimistic than pessimistic. CONCLUSIONS: The BETS-3 and BETS-12 models were successfully validated using an independent dataset containing missing data. These models are the first validated tools for accurately estimating postoperative survival in patients with operable skeletal metastases of the extremities and can provide the surgeon with valuable information to support clinical decisions in this patient population. PMID- 23098539 TI - Assessing the role of patient support services on adherence rates in patients using glatiramer acetate for relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To assess predictors of achievement of 80% Medication Possession Ratio (MPR) in patients receiving manufacturer-provided self-management services for relapsing-remitting multiple sclerosis (RRMS) patients taking glatiramer acetate (Copaxone). METHODS: De-identified patient records were selected for study inclusion if patients had been (1) continuously enrolled in one or more aspects of the self-management program for a minimum of 24 months and had adherence measured by MPR between the values of zero and one. Baseline patient univariate measures were assessed using chi-squared statistics for categorical variables and Analysis of Variance (ANOVA) for continuous variables. Bivariate logistic regression models were used to assess predictors of 80% MPR. RESULTS: A total of 5825 patients met the study inclusion criteria. About 70% of patients received manufacturer-provided injection training and 75% were eligible for, and utilized, copayment assistance; 74.3% of patients accessing sponsor provided support achieved a desired MPR of greater than or equal to 80%. Patients were 40% more likely to reach goal if injection training was provided by the manufacturer (OR = 1.435; 95% CI = 1.258-1.636) and were 30.6% more likely to achieve goal when eligible patients utilized copayment assistance programs (OR = 1.306; 95% CI = 1.109-1.570). Patients reinitiating treatment were at risk of lower adherence rates (OR = 0.605; CI = 0.476-0.769) compared to those who were new to therapy. CONCLUSIONS: Manufacturer-provided patient support programs improve adherence to glatiramer acetate therapy. PMID- 23098540 TI - [Postoperative dynamic changes in matrix metalloproteinase levels in patients with coronary artery bypass graft procedure complications]. AB - The purpose of this study was to evaluate diagnostic and prognostic value of matrix metalloproteinases in postoperative complication development after on-pump coronary artery bypass grafting. 29 coronary artery disease patients who had undergone on-pump coronary artery bypass grafting were examined, 4 of those had complicated systemic inflammatory response and 5 of those had isolated renal failure. Serum matrix metalloproteinase/tissue inhibitor of matrix metalloproteinase concentrations were measured before surgery, at day 1 and day 7 after surgery. Postoperative period was found to be characterized by higher levels of serum matrix metalloproteinases (MMP-9, proMMP-1) and lower levels of matrix metalloproteinase 1 tissue inhibitor. Complicated systemic inflammatory response was associated with higher levels of MMP-9, MMP-3 and proMMP-1, on particular, at day 7. PMID- 23098541 TI - [Vascular effects of perindopril arginine and indapamide fixed combination in patients with arterial hypertension]. AB - The aim of the study was to investigate the dynamics of arterial stiffness and endothelial function parameters under the influence of perindopril arginine and indapamide fixed combination in arterial hypertension (AH) patients. 30 persons with 1-3 degree AH were included into the study. The treatment duration was 24 weeks. Central aortic blood pressure (BP), augmentation pressure and index (AIx), carotid-femoral and carotid-radial pulse wave velocity (PWV), brachial artery endothelium-dependent vasodilatation (EDVD), office and ambulatory BP as well as orthostatic BP falls were evaluated under the influence of selected therapy. 27 patients completed the study protocol. Results showed that aortic systolic BP was significantly reduced by 10.7 mmHg, augmentation pressure - by 3.6 mmHg and AIx - by 6.5%. Carotid-radial PWV decreased by 0.8 m/s. Carotid-femoral PWV did not change. We also revealed the EDVD increase by week 12. The EDVD growth was correlated with degree of aortic systolic BP reduction (r=-0.48, p=0.02). Office and ambulatory BP declined by 15.8/10.0 and 10.0/7.5 mmHg respectively. The target BP <140/90 mmHg was achieved in 20 (74.1%) persons. At the same time the orthostatic hypotension did not rise. Conclusion. We concluded that perindopril arginine/indapamide fixed combination improved vascular function in hypertensive patients by wave reflection reduction, peripheral arterial stiffness lowering and endothelial function improvement. PMID- 23098542 TI - [Changes of QT interval during graded exercise test in healthy adolescents aged 11-15 years]. AB - Aim of the study was determination of physiological limits of QT-intervals and its derivative values in healthy children and adolescents during graded exercise tests. We examined 100 healthy boys and girls aged 11-15 years (mean age 13.4+/ 2.1 years) and performed electrocardiography at rest and standard veloergometry (VEM) in all of them. We analyzed corrected intervals according to Bazett (QTc=QT/RR) and Fredericia (FQTc/3RR) formulas. Hysteresis QTc was calculated as difference between QTc durations during recovery and exercise at same heart rate (HR) Baseline HR before VEM exceeded rhythm on resting electrocardiogram by 5-15 bpm (84+/-8 vs 70+/-6, respectively, p<0.05) Increase of HR at exercise (mean 172+/-11 bpm) was similar in both sexes. QT interval decreased by 7-10% (18-31 ms) per each 25 w (p<0.05). Values obtained at determination of FQTc we found values 26-52 ms lower than those calculated by the Bazett formula in the process of whole test. Determination of FQTc compared with calculation by Bazett formula revealed more pronounced (10% from baseline level) shortening of FQT at peak exercise. QT calculated by the Bazett formula at 100 w did not differ from baseline level with tendency to higher level. Corrected QT according to the most often used Bazett formula was maximal at the first stage of exercise (25 w) and did not exceed 450 ms in boys and 460ms in girls. Maximal QTc lengthening in the process of test did not exceed 50 ms in any of the examined persons. Hysteresis of QTc interval was equal to 21+/-6 (15-25) ms. The conclusion was made that algorithm of assessment of QT interval changes during exercise test should include initial values of QTc calculated according to the Bazett formula, maximal QTc value, level of exercise at which it was registered, maximal increase of QTc during exercise, and QTc interval hysteresis. PMID- 23098543 TI - [The value of compliance during chronic administration of acetylsalicylic acid in patients with acute coronary syndrome: results of the study FORPOST]. AB - Found low compliance of admission to long-term acetylsalicylic acid (ASA) in patients with acute coronary syndrome (ACS): 74.9% of patients reported that the suspended or completely stopped taking the drug, and only 16.2% were fully committed to the long-term therapy with ASA. Patients are significantly more likely to discontinue conventional and buffered forms of ASA compared with intestinal-soluble forms of the drug (odds ratio - OR=1.81, 95% confidence interval - CI: 1.20 to 2.72; p=0,0027). The most common causes of low noncompliance were to receive ASA or the development of fear of adverse drug reactions (ADRs) - 47.1%, and the forgetfulness of the patients taking the drug regularly (25.4%). When receiving enteric forms of ASA NLR developed significantly less than in the case of buffered (OR 0.49, 95% CI, 0.35 to 0,69; p=0,00002) and "ordinary" (OR 0.21, 95 % CI 0.13 to 0,33; p=0,00001) forms of ASA. Compliance of the highest among all the drugs ASA, according to estimates by using a 10-point visual analog scale, were observed in enteric-coated forms of ASA (average score of 8.3+/-1.4). Some of the lowest noncompliance were noted to receive the "regular" aspirin tablet (6.9+/-1.4 points). PMID- 23098544 TI - [Contemporary outlook on prevention and correction of early disturbances of carbohydrate metabolism in cardiological practice]. AB - In the search for effective means of prevention and detection of early markers of type 2 diabetes mellitus (DM) the scientists take an interest for early disturbances of carbohydrate metabolism. In this work we present data of international clinical studies confirming that early disturbances of carbohydrate metabolism appear to be an independent risk factor of cardiovascular diseases. In this connection possibilities of prevention and treatment of early disturbances of carbohydrate metabolism are discussed. We also present classification of antihyperglycemic drugs and analysis of their mechanism of action and efficacy from the point of view of evidence based medicine. The data presented evidence that successful primary prevention of type 2 DM at the stage of early disturbances of carbohydrate metabolism can facilitate lowering of cardiovascular complications. PMID- 23098545 TI - [Effectiveness of reveal diagnostics in evaluation of sincope in children]. PMID- 23098546 TI - [Pharmacogenetics of clopidogrel and its clinical significance]. AB - The review is devoted to pharmacogenetics of clopidogrel and its value for the clinic. Mechanism of action of clopidogrel and main trials which has proven its efficacy are presented as well as results of main large studies including authors own results demonstrating dependence of clinical efficacy of clopidogrel on carriage of polymorphisms of gene of CYP2C19 which accomplishes metabolism of the drug in the liver. Problems of interaction of clopidogrel with proton pump inhibitors and other drugs as well as ways of overcoming "resistance" to clopidogrel are considered. Clinical efficacy of other P2Y12 receptors of platelets in patients with IHD is characterized in comparison with clopidogrel. PMID- 23098547 TI - [Modern drug therapy of atrial fibrillation: selection of treatment strategy, antiarrhythmic preparations, and schemes of treatment]. AB - This review presents novel literature data on drug treatment of atrial fibrillation. We discuss here choice of strategy of therapy, antiarrhythmic drugs, and algorithms of preventive measures aimed at prevention of recurrences of this arrhythmia. PMID- 23098548 TI - [Nonpharmacological methods of prevention of thromboembolic complications in patients with atrial fibrillation]. AB - We present in this review modern methods of prevention of thromboembolic complications in patients with atrial fibrillation and give comparative description of evidence base, efficacy and safety of available techniques. PMID- 23098549 TI - [Anticoagulant therapy in connection with cardioversion in patients with atrial fibrillation]. AB - We present data on possibility of anticoagulant therapy in conjunction with electrical cardioversion in patients with atrial fibrillation using novel anticoagulant - dabigatran - and a case of successful lysis of thrombus in the left ventricular cavity at the background of its administration. PMID- 23098550 TI - [The problem of the effectiveness of treatment of arterial hypertension in smokers]. AB - In this review we give short characteristics of investigations devoted to assessment of effectiveness of cardiac drugs in patients who smoke. Basing on results of these investigations point of view is expressed that antihypertensive preparations of various classes differently affect smokers with arterial hypertension (AH). An opinion exists that drugs which improve endothelial function are preferable in smoking patients with AH. However special studies of comparative of efficacy of antihypertensive drugs from different classes in smokers are necessary. PMID- 23098551 TI - [Magnesium in the treatment and prevention of cerebrovascular disease]. AB - To date, the amount of evidences for the role of magnesium in determining the energy potential of the cells increases, which is critical in the pathogenesis of stroke, as well as in the survival and recovery of brain cells. Energy donor in cellular processes is adenosine triphosphate (ATP) as a complex of Mg2+- ATP [1]. In acute and chronic cerebral ischemia deficit Mg2+ is the basis of hypoxia cells, which leads to their subsequent death. [2]. Severe deficiency of selenium, when there is an issue of life and death of the patient, requires a massive correction of magnesium homeostasis. It is an integral component of intensive care in neurology, cardiology, obstetrics. However, in daily practice neurologist frequently has patients with chronic cerebrovascular disease, accompanied by magnesium deficiency. This proves necessitate of the use of magnesium containing drugs with neuroprotective and neurotrophic properties in the treatment and prevention of cerebrovascular disease. PMID- 23098552 TI - [Effect of nicotine and tar present in cigarette smoke on the process of atherogenesis]. AB - Tobacco smoking is a major risk factor of the development of atherosclerosis and thrombosis. Components of tobacco smoke induce changes in the function of thrombocytes, endothelium, macrophages and smooth muscle cells of blood vessels. Smoking causes changes in activity of enzymes of antioxidant system by inducing production of reactive oxygen species. Alterations of cell function and enzyme activity may accelerate formation of atherosclerotic plaques. The compounds of tobacco smoke also promote atherogenesis by affecting gene expression. Aim of the present article is to review published data about molecular mechanisms underlying harmful effects of ingredients of tobacco smoke such as nicotine and tar on the progression of atherosclerosis. PMID- 23098553 TI - [Myocardium non-compaction]. AB - The left ventricular non-compaction (spongy cardiomyopathy) is a rare, poorly known pathology. Disease according to WHO classification applies to unclassified cardiomyopathy. Clinical picture is nonspecific. Diagnosis is established by means of instrumental techniques such as echocardiography and magnetic resonance imaging. Spongy cardiomyopathy usually affects the left ventricle, right ventricular failure occurs much less frequently. We present a description of the disease in 18 years old girl with signs of myocardial infarction and non compaction of both (left and right) ventricles. PMID- 23098554 TI - Social integration and human rights: a view from a low- and middle-income context. PMID- 23098555 TI - Antimicrobial resistance patterns and corresponding multilocus sequence types of the Campylobacter jejuni isolates from human diarrheal samples. AB - A total of 121 Campylobacter isolates from 4,788 humans with gastroenteritis were identified and characterized by biochemical detection methods, polymerase chain reaction, and multilocus sequence typing (MLST). These samples were obtained during a 3-year period, from January 2007 to December 2009, using the National Notifiable Diseases Surveillance System at the Research Institute of Public Health and Environment in Seoul Metropolitan, Korea. Antimicrobial susceptibilities of the bacterium were also determined with the agar dilution method. All 121 isolates were identified as Campylobacter jejuni, with all (100%) of them having two virulence genes (ceuE and cadF) and a toxin gene (cdtB). Twenty-three different sequence types (STs), including 9 new STs, were determined by MLST. The most prevalent ST and clonal complex (CC) observed in this study were ST-45 (28.9%) and ST-45 CC (53.7%), respectively. Percentages of antimicrobial-resistant isolates were 1.9% for ampicillin, 0.8% for chloramphenicol, 24% for ciprofloxacin, 46.3% for enrofloxacin, 0.8% for erythromycin, 6.6% for gentamicin, and 46.3% for tetracycline. This study demonstrated that the majority of the Campylobacter isolates obtained from human samples in Korea were C. jejuni with ST-45 CC, which has been detected mainly in broilers worldwide, and all strains with new STs were uniformly resistant to enrofloxacin and tetracycline. This study indicates that broilers may be a breeding ground for bacteria as well as an important potential source of human campylobacteriosis. PMID- 23098557 TI - Text messaging as a strategy to address the limits of audio-based communication during mass-gathering events with high ambient noise. AB - INTRODUCTION: The provision of medical care in environments with high levels of ambient noise (HLAN), such as concerts or sporting events, presents unique communication challenges. Audio transmissions can be incomprehensible to the receivers. Text-based communications may be a valuable primary and/or secondary means of communication in this type of setting. OBJECTIVES: To evaluate the usability of text-based communications in parallel with standard two-way radio communications during mass-gathering (MG) events in the context of HLAN. METHODS: This Canadian study used outcome survey methods to evaluate the performance of communication devices during MG events. Ten standard commercially available handheld smart phones loaded with basic voice and data plans were assigned to health care providers (HCPs) for use as an adjunct to the medical team's typical radio-based communication. Common text messaging and chat platforms were trialed. Both efficacy and provider satisfaction were evaluated. RESULTS: During a 23 month period, the smart phones were deployed at 17 events with HLAN for a total of 40 event days or approximately 460 hours of active use. Survey responses from health care providers (177) and dispatchers (26) were analyzed. The response rate was unknown due to the method of recruitment. Of the 155 HCP responses to the question measuring difficulty of communication in environments with HLAN, 68.4% agreed that they "occasionally" or "frequently" found it difficult to clearly understand voice communications via two-way radio. Similarly, of the 23 dispatcher responses to the same item, 65.2% of the responses indicated that "occasionally" or "frequently" HLAN negatively affected the ability to communicate clearly with team members. Of the 168 HCP responses to the item assessing whether text-based communication improved the ability to understand and respond to calls when compared to radio alone, 86.3% "agreed" or "strongly agreed" that this was the case. The dispatcher responses (n = 21) to the same item also "agreed" or "strongly agreed" that this was the case 95.5% of the time. CONCLUSION The use of smart phone technology for text-based communications is a practical and feasible tool for MG events and should be explored further. Multiple, reliable, discrete forms of communication technology are pivotal to executing effective on-site medical and disaster responses. PMID- 23098556 TI - Surgical management of inguinal hernias at Bugando Medical Centre in northwestern Tanzania: our experiences in a resource-limited setting. AB - BACKGROUND: Inguinal hernia repair remains the commonest operation performed by general surgeons all over the world. There is paucity of published data on surgical management of inguinal hernias in our environment. This study is intended to describe our own experiences in the surgical management of inguinal hernias and compare our results with that reported in literature. METHODS: A descriptive prospective study was conducted at Bugando Medical Centre in northwestern Tanzania. Ethical approval to conduct the study was obtained from relevant authorities before the commencement of the study. Statistical data analysis was done using SPSS software version 17.0. RESULTS: A total of 452 patients with inguinal hernias were enrolled in the study. The median age of patients was 36 years (range 3 months to 78 years). Males outnumbered females by a ratio of 36.7:1. This gender deference was statistically significant (P=0.003). Most patients (44.7%) presented late (more than five years of onset of hernia). Inguinoscrotal hernia (66.8%) was the commonest presentation. At presentation, 208 (46.0%) patients had reducible hernia, 110 (24.3%) had irreducible hernia, 84 (18.6%) and 50(11.1%) patients had obstructed and strangulated hernias respectively. The majority of patients (53.1%) had right sided inguinal hernia with a right-to-left ratio of 2.1: 1. Ninety-two (20.4%) patients had bilateral inguinal hernias. 296 (65.5%) patients had indirect hernia, 102 (22.6%) had direct hernia and 54 (11.9%) had both indirect and direct types (pantaloon hernia). All patients in this study underwent open herniorrhaphy. The majority of patients (61.5%) underwent elective herniorrhaphy under spinal anaesthesia (69.2%). Local anaesthesia was used in only 1.1% of cases. Bowel resection was required in 15.9% of patients. Modified Bassini's repair (79.9%) was the most common technique of posterior wall repair of the inguinal canal. Lichtenstein mesh repair was used in only one (0.2%) patient. Complication rate was 12.4% and it was significantly higher in emergency herniorrhaphy than in elective herniorrhaphy (P=0.002). The median length of hospital stay was 8 days and it was significantly longer in patients with advanced age, delayed admission, concomitant medical illness, high ASA class, the need for bowel resection and in those with surgical repair performed under general anesthesia (P<0.001). Mortality rate was 9.7%. Longer duration of symptoms, late hospitalization, coexisting disease, high ASA class, delayed operation, the need for bowel resection and presence of complications were found to be predictors of mortality (P<0.001). CONCLUSION: Inguinal hernias continue to be a source of morbidity and mortality in our centre. Early presentation and elective repair of inguinal hernias is pivotal in order to eliminate the morbidity and mortality associated with this very common problem. PMID- 23098559 TI - Spin injection in n-type resonant tunneling diodes. AB - We have studied the polarized resolved photoluminescence of n-type GaAs/AlAs/GaAlAs resonant tunneling diodes under magnetic field parallel to the tunnel current. Under resonant tunneling conditions, we have observed two emission lines attributed to neutral (X) and negatively charged excitons (X-). We have observed a voltage-controlled circular polarization degree from the quantum well emission for both lines, with values up to -88% at 15 T at low voltages which are ascribed to an efficient spin injection from the 2D gases formed at the accumulation layers. PMID- 23098558 TI - EnzymePredictor: a tool for predicting and visualizing enzymatic cleavages of digested proteins. AB - Mass spectrometric analysis of peptides contained in enzymatically digested hydrolysates of proteins is increasingly being used to characterize potentially bioactive or otherwise interesting hydrolysates. However, when preparations containing mixtures of enzymes are used, from either biological or experimental sources, it is unclear which of these enzymes have been most important in hydrolyzing the sample. We have developed a tool to rapidly evaluate the evidence for which enzymes are most likely to have cleaved the sample. EnzymePredictor, a web-based software, has been developed to (i) identify the protein sources of fragments found in the hydrolysates and map them back on it, (ii) identify enzymes that could yield such cleavages, and (iii) generate a colored visualization of the hydrolysate, the source proteins, the fragments, and the predicted enzymes. It tabulates the enzymes ranked according to their cleavage counts. The provision of odds ratio and standard error in the table permits users to evaluate how distinctively particular enzymes may be favored over other enzymes as the most likely cleavers of the samples. Finally, the method displays the cleavage not only according to peptides, but also according to proteins, permitting evaluation of whether the cleavage pattern is general across all proteins, or specific to a subset. We illustrate the application of this method using milk hydrolysates, and show how it can rapidly identify the enzymes or enzyme combinations used in generating the peptides. The approach developed here will accelerate the identification of enzymes most likely to have been used in hydrolyzing a set of mass spectrometrically identified peptides derived from proteins. This has utility not only in understanding the results of mass spectrometry experiments, but also in choosing enzymes likely to yield similar cleavage patterns. EnzymePredictor can be found at http://bioware.ucd.ie/~enzpred/Enzpred.php. PMID- 23098560 TI - A review of dental caries in Australian Aboriginal children: the health inequalities perspective. AB - INTRODUCTION: The purpose of this study was to: (1) describe caries prevalence and experience among Aboriginal children; and (2) investigate the disparity in dental caries between Aboriginal and non-Aboriginal Australian children. As background, dental caries is a widespread disease within Aboriginal communities and it has a particularly severe impact on children. In recognition of the extent and severity of this disease, its impact on childhood nutrition, socialisation and schooling, the control of dental caries has been identified as a key indicator in the reduction of disadvantage among Aboriginal communities. METHODS: Medline was the primary database used in the literature search. Other databases included: PubMed, Web of Science and Google Scholar. Australian National and State departments of health websites were also searched for relevant documents. Articles were included in the review if they reported information on either caries prevalence rates or experience scores or both, for Aboriginal children in Australia. Articles were excluded if the study sample was special needs children, and/or caries statistics were reported only for children over 12 years. RESULTS: Caries prevalence among 6-year-olds in rural non-fluoridated Western Australia in 1963 was 27%, and in 2004 was 85% among 6-year-olds in rural non-fluoridated Queensland. There was a corresponding increase in caries experience scores in this period from 2.07 in 1963 to 6.37 in 2004. National estimates for 2000-2003 reported a caries prevalence of 72% and caries experience (dmft: decayed, missing and filled primary teeth) of 3.68 for 6-year-old Aboriginal Australian children. For 12-year-olds the national estimates were a caries prevalence of 45% and experience (DMFT, Decayed, Missing and Filled Permanent Teeth) of 1.25 (SE=0.07). The magnitude of disparity (relative difference) in 6-year-old caries experience between Aboriginal and non-Aboriginal children was relatively consistent over the period 1983-2007, with Aboriginal children having an approximately two-fold higher caries experience score. The 2000-2003 national estimates for caries experience showed that Aboriginal 6-year-olds had a dmft score that was 2.38 times higher than non-Aboriginal children (3.68 vs 1.54). For the 12-year-olds, the magnitude of disparity was not as marked, though the direction was similar. CONCLUSION: Both caries prevalence and experience are higher in the primary dentition. In rural Queensland and the Northern Territory there are high caries rates for both 6- and 12-year-olds. Rural Aboriginal children are generally at a disadvantage compared with their urban counterparts. The magnitude of disparity in caries rates appears to be relatively unchanged over time but there is indication that it may be increasing. This raises the issue of health inequity and the need to fund practical, culturally appropriate and sustainable preventive programs. It also indicates the urgent need for more research on the determinants of oral health inequalities. PMID- 23098561 TI - A case-control study on the effect of Apolipoprotein E genotypes on gastric cancer risk and progression. AB - BACKGROUND: Apolipoprotein E (ApoE) is a multifunctional protein playing both a key role in the metabolism of cholesterol and triglycerides, and in tissue repair and inflammation. The ApoE gene (19q13.2) has three major isoforms encoded by epsilon2, epsilon3 and epsilon4 alleles with the epsilon4 allele associated with hypercholesterolemia and the epsilon2 allele with the opposite effect. An inverse relationship between cholesterol levels and gastric cancer (GC) has been previously reported, although the relationship between apoE genotypes and GC has not been explored so far. METHODS: One hundred and fifty-six gastric cancer cases and 444 hospital controls were genotyped for apoE polymorphism (epsilon2, epsilon3, epsilon4 alleles). The relationship between GC and putative risk factors was measured using the adjusted odds ratios (ORs) and their 95% confidence intervals (CIs) from logistic regression analysis. A gene-environment interaction analysis was performed. The effect of the apoE genotypes on survival from GC was explored by a Kaplan-Meier analysis and Cox proportional hazard regression model. RESULTS: Subjects carrying at least one apoE epsilon2 allele have a significant 60% decrease of GC risk (OR=0.40, 95% CI: 0.19 - 0.84) compared with epsilon3 homozygotes. No significant interaction emerged between the epsilon4 or epsilon2 allele and environmental exposures, nor epsilon2 or epsilon4 alleles affected the median survival times, even after correcting for age, gender and stadium. CONCLUSIONS: Our study reports for the first time a protective effect of the epsilon2 allele against GC, that might be partly attributed to the higher antioxidant properties of epsilon2 compared with the epsilon3 or epsilon4 alleles. Given the study's sample size, further studies are required to confirm our findings. PMID- 23098562 TI - In pursuit of synthetic modulators for the orphan retina-specific nuclear receptor NR2E3. AB - PURPOSE: NR2E3 is an orphan nuclear receptor expressed exclusively in photoreceptor cells of the retina. NR2E3-specific modulators may prolong photoreceptor survival in patients with dry age-related macular degeneration and other forms of retinal degeneration. To definitively establish NR2E3 as a photoreceptor protection target, identification of small-molecule NR2E3 modulators and their testing in animal models of retinal degeneration are required. Development of the high-throughput screen (HTS)-compatible screen for small-molecule NR2E3 modulators is the first step toward this goal. METHODS: Purification protocol for isolation of the functionally competent soluble NR2E3 protein after its expression in the insect Sf9 cells was developed. The time resolved fluorescence energy-transfer (TR-FRET) assay assessing agonist-sensitive interaction between apo-NR2E3 and transcriptional corepressor RetCOR was used for characterization of the previously reported putative NR2E3 agonist, Compound 11a, and to conduct the HTS for novel small-molecule NR2E3 modulators (direct and inverse agonists). A counterscreen TR-FRET assay that measures the affect of test compounds on PPARgamma interaction with corepressor NCOR was used for assessing the specificity of compounds identified in the HTS. RESULTS: We developed the cell-free TR-FRET assay for small-molecule NR2E3 modulators, which is based on agonist-induced disruption of the interaction between GST-tagged apo-NR2E3 and MBP-tagged fragment of transcriptional corepressor RetCOR. Compound 11a, a putative NR2E3 agonist, did not affect the NR2E3-RetCOR interaction, as was established by its titration in the developed assay. The assay was miniaturized for an ultralow-volume 1,536-well format and automated into 3 simple pipetting steps. Consistent with excellent assay performance, the test runs established a Z'-score within the 0.6-0.8 range. Analysis of the mid-size National Institutes of Health collection of 315,001 structurally diverse drug-like compounds confirmed excellent assay performance, but did not reveal NR2E3-specific agonists or inverse agonists. CONCLUSIONS: A robust and reliable TR-FRET assay for small molecule NR2E3-specific modulators suitable for the analysis of million compound strong HTS libraries was developed. A previously described putative NR2E3 agonist, Compound 11a, is unlikely to represent a direct NR2E3 agonist. Application of the developed assay for screening of a more abundant and diverse compound collection be required for identification of synthetic NR2E3 ligands. PMID- 23098563 TI - Vitreous traction after Ozurdex injection. PMID- 23098565 TI - Social networks and support in early psychosis: potential mechanisms. PMID- 23098564 TI - CXC chemokine ligand 12/stromal cell-derived factor-1 regulates cell adhesion in human colon cancer cells by induction of intercellular adhesion molecule-1. AB - BACKGROUND: The CXC chemokine ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) and CXC receptor 4 (CXCR4) axis is involved in human colorectal cancer (CRC) carcinogenesis and can promote the progression of CRC. Interaction between CRC cells and endothelium is a key event in tumor progression. The aim of this study was to investigate the effect of SDF-1 on the adhesion of CRC cells. METHODS: Human CRC DLD-1 cells were used to study the effect of SDF-1 on intercellular adhesion molecule-1 (ICAM-1) expression and cell adhesion to endothelium. RESULTS: SDF-1 treatment induced adhesion of DLD-1 cells to the endothelium and increased the expression level of the ICAM-1. Inhibition of ICAM 1 by small interfering RNA (siRNA) and neutralizing antibody inhibited SDF-1 induced cell adhesion. By using specific inhibitors and short hairpin RNA (shRNA), we demonstrated that the activation of ERK, JNK and p38 pathways is critical for SDF-1-induced ICAM-1 expression and cell adhesion. Promoter activity and transcription factor ELISA assays showed that SDF-1 increased Sp1-, C/EBP beta- and NF-kappaB-DNA binding activities in DLD-1 cells. Inhibition of Sp1, C/EBP-beta and NF-kappaB activations by specific siRNA blocked the SDF-1-induced ICAM-1 promoter activity and expression. The effect of SDF-1 on cell adhesion was mediated by the CXCR4. CONCLUSION: Our findings support the hypothesis that ICAM 1 up-regulation stimulated by SDF-1 may play an active role in CRC cell adhesion. PMID- 23098566 TI - Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain. AB - The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed. PMID- 23098567 TI - Nutrient intakes of children aged 1-2 years as a function of milk consumption, cows' milk or growing-up milk. AB - OBJECTIVE: To evaluate the nutritional adequacy of diets in early childhood as a function of milk intake, cows' milk (CM) or growing-up milk (GUM). DESIGN: From a cross-sectional food consumption survey, two groups of children aged 1-2 years were defined: group CM fed exclusively on CM >= 250 ml/d and group GUM fed on GUM >= 250 ml/d. Proportions of children at risk of nutrient excess or insufficiency were estimated relative to the French recommended daily allowances, estimated average requirements or adequate intakes. SETTING: Parents participating in the survey were recruited from all regions of France by a polling organization. Distribution was adjusted to that of the French population. SUBJECTS: Sixty-three (group CM) and fifty-five (group GUM) children. RESULTS: Total energy and macronutrient intakes were similar in the two groups except protein intake of group CM, which was much higher than the Recommended Daily Allowance and significantly higher than in group GUM. A high percentage of children of Group CM had intake of linoleic acid (51%) and alpha-linolenic acid (84%) below the lower limit of the adequate intake, and intake of Fe (59%) vitamin C (49%) and alimentary vitamin D (100%) less than the Estimated Average Requirement. Significant differences were observed in the proportions of children with a risk of dietary inadequacy between the two groups for all the mentioned nutrients (P < 0.001). In group GUM, this imbalance was only observed for vitamin D. Intake of foods other than milk and dairy products could not account for these discrepancies. CONCLUSIONS: Consumption of CM (>=250 ml/d) entails the risk of insufficiency in alpha-linolenic acid, Fe, vitamin C and vitamin D. Use of GUM (>=250 ml/d) significantly reduces the risk of insufficiencies in the mentioned nutrients. PMID- 23098568 TI - Chondrodermatitis nodularis helicis: successful treatment with 2% nitroglycerin gel. PMID- 23098569 TI - Transient pigmentary lines of the newborn. PMID- 23098570 TI - Reticulate hyperpigmentation and medullary aplasia. PMID- 23098571 TI - Vogt-Koyanagi-Harada disease: a disorder unfamiliar to dermatologists. PMID- 23098572 TI - Spontaneous regression of primary diffuse large B-cell lymphoma, leg type. AB - Primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL LT) accounts for approximately 20% of all primary cutaneous B-cell lymphomas and tends to present as infiltrated nodules, tumors, and plaques on the legs in the elderly. Unlike other primary cutaneous large B-cell lymphomas, it has a poor prognosis and tends to require treatment with systemic chemotherapy. We present the case of an 82-year-old patient with a 1-year history of nodules and plaques on her right leg. Biopsy led to a diagnosis of PCLBCL LT and the lesions resolved without treatment within 1 month of the first visit. This is an atypical course of PCLBCL LT and we believe that it is the first such case to be reported in the literature. PMID- 23098573 TI - Managing ixabepilone adverse events with dose reduction. AB - Ixabepilone is a synthetic analogue of epothilone B approved for the treatment of patients with metastatic or locally advanced breast cancer in combination with capecitabine for cancer resistant to an anthracycline and a taxane, and as monotherapy for cancer resistant or refractory to anthracyclines, taxanes, and capecitabine. The principal dose-limiting adverse events (AEs) of ixabepilone's standard dose (40 mg/m(2) administered by 3-hour infusion once every 3 weeks) are peripheral neuropathy, neutropenia, and fatigue. An effective strategy to manage ixabepilone-related AEs is dose reduction by 20% (from 40 to 32 to 25 mg/m(2)); this does not appear to affect treatment efficacy and enables continuation of treatment after recovery (grade 1 or resolved). When appropriate, treatment can be restarted with a 20% dose reduction (to 32 mg/m(2)). For heavily pretreated patients, especially those with a low performance status, 32 mg/m(2) is an appropriate initial dose; the dose of capecitabine should also be lowered by 20%. Weekly ixabepilone (15-20 mg/m(2) on days 1, 8, and 15 every 28 days) may have an improved tolerability profile, but prospective studies with a large number of patients are required to determine whether it has therapeutic benefit comparable with the current approved regimen. More information is required on dosage and scheduling of ixabepilone in combination with other agents, including novel targeted therapies. PMID- 23098574 TI - Heterogeneity of triple-negative breast cancer: histologic subtyping to inform the outcome. AB - BACKGROUND: This study assesses outcome in terms of disease-free survival (DFS) and overall survival (OS) of special types of triple-negative breast cancer (TNBC). PATIENTS AND METHODS: We identified 8801 women with first primary nonmetastatic breast cancer operated on at the European Institute of Oncology between 1997 and 2005. Of these patients, 781 consecutive patients with immunohistochemically defined TNBC were selected for the analyses. We explored patterns of recurrence by histologic type. Median follow-up was 5.7 years (range 0-13 years). RESULTS: The 5-year DFS was 77% for TNBC, 68% for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, and 84% and 95% for luminal B and luminal A breast cancer, respectively. From 781 TNBC subtypes, 693 cases (89%) were classified as ductal not otherwise specified (NOS) (invasive ductal carcinoma [IDC]), 29 were classified as apocrine (3.7%), 18 (2.3%) were classified as lobular, 10 (1.2%) were classified as adenoid cystic, and 10 (1.2%) were classified as metaplastic. Five-year DFS and OS were 77% and 84% for patients with ductal carcinoma, 56% and 89% for patients with metaplastic carcinoma, and both 5-year DFS and OS were 100% for patients with adenoid cystic and medullary carcinomas, respectively. CONCLUSION: Distinct prognostic implications may derive from the specific histotype of TNBC. The identification of these special types has a significant clinical utility and should be considered in therapeutic algorithms. PMID- 23098576 TI - Intraoperative embolization with poloxamer 407 during surgical resection of a carotid body tumor. AB - Surgical excision is the preferred definitive treatment for carotid body tumors, although postoperative morbidity rate as quoted in the literature is rather high. Morbidity includes cranial nerve dysfunction, stroke, and the majority severe blood loss. Embolization of the feeding branches of the external carotid artery can be performed a few days prior to surgery with the intention to decrease blood loss during operation, facilitate surgical resection, and reduce operating time and morbidity. The special risk of embolization is migration into the intracranial circulation. Poloxamer 407, a reverse-thermal polymer, is a nontoxic compound that is a viscous liquid at room temperatures but instantly changes to a firm water-soluble gel when warmed to body temperature. It dissolves spontaneously or can be dissolved at will by cooling. We describe an intraoperative technique for complete devascularization of carotid body tumor by using an intraarterial temporary occlusion technique with a poloxamer 407. PMID- 23098575 TI - A prospective study of bone tumor response assessment in metastatic breast cancer. AB - BACKGROUND: In our previous study, new MD Anderson (MDA) bone tumor response criteria (based on computed tomography [CT], plain radiography [XR], and skeletal scintigraphy [SS]) predicted progression-free survival (PFS) better than did World Health Organization (WHO) bone tumor response criteria (plain radiography [XR] and SS) among patients with breast cancer and bone-only metastases. In this pilot study, we tested whether MDA criteria could reveal bone metastasis response earlier than WHO criteria in patients with newly diagnosed breast cancer with osseous and measurable nonosseous metastases. METHODS: We prospectively analyzed bone metastasis response using each imaging modality and set of bone response criteria to distinguish progressive disease (PD) from non-PD and their association with PFS and overall survival (OS). We also compared the response of osseous metastases assessed by both criteria with the response of nonosseous measurable lesions. RESULTS: The median follow-up period was 26.7 months (range, 6.1-53.3 months) in 29 patients. PFS rates differed at 6 months based on the classification of PD or non-PD using either set of criteria (MDA, P = .002; WHO, P = .014), but these rates, as well as OS, did not differ at 3 months. Response in osseous metastases by either set of criteria did not correlate with the response in nonosseous metastases. CONCLUSION: MDA and WHO criteria predicted PFS of patients with osseous metastases at 6 months but not at an earlier time point. We plan a well-powered study to determine the role of MDA criteria in predicting bone tumor response by incorporating 18-fluorodeoxyglucose ((18)F) positron emission tomography (FDG-PET)/CT to see if findings using this modality are earlier than those with WHO criteria. PMID- 23098577 TI - Microencapsulation of protein into biodegradable matrix: a smart solution cross linking technique. AB - Sustained-release albumin microspheres (MSs) can be obtained by chemically cross linking albumin. However, a significant challenge is preventing the cross-linking of the active pharmaceutical (protein or small molecule) ingredient (API) with the MS matrix. To prevent cross-linking of the API with the albumin matrix, a smart "solution cross-linking-microencapsulation" method was developed which involves cross-linking albumin solution with glutaraldehyde first, neutralizing any excess glutaraldehyde with sodium bisulphite, followed by the addition of API and finally spray drying. Using lysozyme as model API, MS formulations FL1 and FL2 were prepared and characterized. Physicochemical characterization using FT-IR and bioactivity evaluation indicate that microencapsulated API did not undergo any significant change in its native structure and the bioactivity was preserved during the formulation processing. Preliminary immunogenicity potential of the cross-linked albumin matrix determined by in vivo studies did not show any significant increase in antigen-specific serum-IgG levels, implying safety and biocompatibility of the cross-linked albumin matrix. PMID- 23098578 TI - Eating lizards: a millenary habit evidenced by Paleoparasitology. AB - BACKGROUND: Analyses of coprolites have contributed to the knowledge of diet as well as infectious diseases in ancient populations. Results of paleoparasitological studies showed that prehistoric groups were exposed to spurious and zoonotic parasites, especially food-related. Here we report the findings of a paleoparasitological study carried out in remote regions of Brazil's Northeast. FINDINGS: Eggs of Pharyngodonidae (Nematoda, Oxyuroidea), a family of parasites of lizards and amphibians, were found in four human coprolites collected from three archaeological sites. In one of these, lizard scales were also found. CONCLUSIONS: Through the finding of eggs of Pharyngodonidae in human coprolites and reptilescales in one of these, we have provided evidence that humans have consumed reptiles at least 10,000 years ago. This food habit persists to modern times in remote regions of Brazil's Northeast. Although Pharyngodonidae species are not known to infect humans, the consumption of raw or undercooked meat from lizards and other reptiles may have led to transmission of a wide range of zoonotic agents to humans in the past. PMID- 23098580 TI - Antithrombotic management and type of stent in atrial fibrillation patients undergoing percutaneous coronary intervention. PMID- 23098579 TI - Health-related quality of life in survivors of stage I-II breast cancer: randomized trial of post-operative conventional radiotherapy and hypofractionated tomotherapy. AB - BACKGROUND: Health-related quality of life (HRQOL) assessment is a key component of clinical oncology trials. However, few breast cancer trials comparing adjuvant conventional radiotherapy (CR) and hypofractionated tomotherapy (TT) have investigated HRQOL. We compared HRQOL in stage I-II breast cancer patients who were randomized to receive either CR or TT. Tomotherapy uses an integrated computed tomography scanner to improve treatment accuracy, aiming to reduce the adverse effects of radiotherapy. METHODS: A total of 121 stage I-II breast cancer patients who had undergone breast conserving surgery (BCS) or mastectomy (MA) were randomly assigned to receive either CR or TT. CR patients received 25 * 2 Gy over 5 weeks, and BCS patients also received a sequential boost of 8 * 2 Gy over 2 weeks. TT patients received 15 * 2.8 Gy over 3 weeks, and BCS patients also received a simultaneous integrated boost of 15 * 0.6 Gy over 3 weeks. Patients completed the EORTC QLQ-C30 and BR23 questionnaires. The mean score (+/- standard error) was calculated at baseline, the end of radiotherapy, and at 3 months and 1, 2, and 3 years post-radiotherapy. Data were analyzed by the 'intention-to treat' principle. RESULTS: On the last day of radiotherapy, patients in both treatment arms had decreased global health status and functioning scores; increased fatigue (clinically meaningful in both treatment arms), nausea and vomiting, and constipation; decreased arm symptoms; clinically meaningful increased breast symptoms in CR patients and systemic side effects in TT patients; and slightly decreased body image and future perspective. At 3 months post-radiotherapy, TT patients had a clinically significant increase in role- and social-functioning scores and a clinically significant decrease in fatigue. The post-radiotherapy physical-, cognitive- and emotional-functioning scores improved faster in TT patients than CR patients. TT patients also had a better long-term recovery from fatigue than CR patients. ANOVA with the Bonferroni correction did not show any significant differences between groups in HRQOL scores. CONCLUSIONS: TT patients had a better improvement in global health status and role- and cognitive-functioning, and a faster recovery from fatigue, than CR patients. These results suggest that a shorter fractionation schedule may reduce the adverse effects of treatment. PMID- 23098581 TI - Assessment of toxic effects of triclosan on the swordtail fish (Xiphophorus helleri) by a multi-biomarker approach. AB - The toxic effects of triclosan (TCS) on the swordtail fish (Xiphophorus helleri) were assessed based on various biomarkers including enzymatic activities of ethoxyresorufin O-deethylase (EROD), erythromycin N-demethylase (ERND) and glutathione-s-transferase (GST) and mRNA expression levels of CYP1A, CYP3A, glutathione S-transferase (GST) and P-glycoprotein (P-gp). The acute toxicity test showed the LC(50) value of 1.47 mg L(-1) for TCS. The mRNA expressions of CYP1A, CYP3A, GST and P-gp showed dose-effect relationships in female swordtail fish when exposed to TCS, These mRNA expression levels were found more sensitive to TCS exposure than the enzymatic activities of EROD, ERND and GST do. In addition, the male fish displayed higher gene expression levels and more dramatic changes in enzyme activities than the females did. Our data further demonstrated that TCS was a typical inducer to Phase I and Phase II metabolism enzymes and genes, suggesting it is a potential ecotoxicological risk to aquatic ecosystems. PMID- 23098582 TI - Phytoremedial assessment of flora tolerant to heavy metals in the contaminated soils of an abandoned Pb mine in Central Portugal. AB - Significant accumulation of heavy metals in soils and flora exists around the abandoned Barbadalhos Pb mine in Central Portugal. Soil and plant samples [49 species] were collected from two line transects, LT 1 and LT 2, in the mineralized and non-mineralized area, respectively to gain a comprehensive picture of heavy metals in soils and flora to assess its potential for phytoremediation. Phytosociological inventories of the vegetation were made using the Braun-Blanquet cover-abundance scale. Metal concentrations in soil ranged from (in mg kg(-1)): 98-9330 [Pb], 110-517 [Zn], 7.1-50 [Co], 69-123 [Cr], 31-193 [Cu], 33400-98500 [Fe], 7.7-51 [Ni], 0.95-13 [Ag], 2.8-208 [As], and 71-2220 [Mn] along LT 1; and 24-93 [Pb], 30-162 [Zn], 3.7-34 [Co], 61-196 [Cr], 21-46 [Cu], 24100-59400 [Fe], 17-87 [Ni], 0.71-1.9 [Ag], 4.3-12 [As], and 44-1800 [Mn] along LT 2. Plant metal content ranged from (in mg kg(-1)): 1.11-548 [Pb], 7.06-1020 [Zn], 0.08-2.09 [Co], 0.09-2.03 [Cr], 2.63-38.5 [Cu], 10.4-4450 [Fe], 0.38-8.9 [Ni], and 0.03-1.9 [Ag] along LT 1; and 0.94-11.58 [Pb], 2.83-96.5 [Zn], 0.12 1.44 [Co], 0.21-1.49 [Cr], 1.61-22.7 [Cu], 4.6-2050 [Fe], 0.51-4.81 [Ni], and 0.02-0.31 [Ag] along LT 2. Plants with highest uptake of metals were: Cistus salvifolius (548 mg Pb kg(-1)), Digitalis purpurea (1017 mg Zn kg(-1) and 4450 mg Fe kg(-1)). Mentha suavolens and Ruscus ulmifolius were seen to hyperaccumulate Ag (1.9 and 1 mg Ag kg(-1), respectively). More metals and higher concentrations were traced in plants from LT 1, especially for Pb and Zn. PMID- 23098583 TI - Laboratory-based experiments to investigate the impact of glyphosate-containing herbicide on pollution attenuation and biodegradation in a model pervious paving system. AB - An experimental investigation was carried out to determine the effect of glyphosate-containing herbicides (GCHs) on the hydrocarbon retention and biodegradation processes known to occur in pervious pavement systems (PPSs). The PPS test rigs were based on the four-layered design detailed in CIRIA C582. This enabled the pollutant retention capacity of the PPS and biodegradation of retained pollutants by microorganisms to be investigated. The use of test rigs also enabled the impact of GCH on PPS eukaryotic organisms to be studied, by the monitoring of protist bioindicators. Results showed that GCH disrupted hydrocarbon retention by the geotextiles relative to rigs with mineral oil only added, as 9.3% and 24.5% of added hydrocarbon were found in herbicide only rigs and herbicide plus oil rigs respectively. In previous studies, PPS contaminated by mineral oil had been shown to retain 98.7% of added oils and over several weeks, biodegrade this oil in situ. Where GCH was added to experimental models, much higher concentrations of heavy metals, including Pb, Cu, and Zn, were released from the PPS in effluent, particularly where GCH and mineral oil were added together. The source of the majority of the metal contamination was thought to be the used engine oil. The herbicide generally increased the total activity of microbial communities in rig systems and had a stimulating effect on bacterial and fungal population numbers. Although the protists, which are part of the microbial community directly or indirectly responsible for biodegradation, were initially strongly affected by the herbicide, they showed resilience by quickly recovering and increasing their population compared with rigs without added herbicide, including the rigs with mineral oil added to them. However, the presence of herbicide was associated with a decrease in the species richness of recorded protist taxa and a predominance of robust, cosmopolitan or ubiquitous protist genera. PMID- 23098584 TI - Diabetic foot reconstruction using free flaps increases 5-year-survival rate. AB - The purpose of this study was to evaluate the outcome of the diabetic foot reconstructed with free flaps and analyse the preoperative risk factors. This study reviews 121 cases of reconstructed diabetic foot in 113 patients over 9 years (average follow-up of 53.2 months). Patients' age ranged from 26 to 78 years (average, 54.6 years). Free flaps used were anterolateral thigh (ALT, 90), superficial circumflex iliac artery perforator (SCIP, 20), anteromedial thigh (AMT, 5), upper medial thigh (UMT, 3), and other perforator free flaps (3). Correlation between the surgical outcome and preoperative risk factors were analysed using logistic regression model. Total loss was seen in 10 cases and 111 free-tissue transfers were successful (flap survival rate of 91.7%). During follow-up, limb was eventually lost in 17 patients and overall limb salvage rate was 84.9% and the 5-year survival was 86.8%. Correlation between flap loss and 14 preoperative risk factors (computed tomography (CT) angiogram showing intact numbers of major vessels, history of previous angioplasty, peripheral arterial disease (PAD), heart problem, chronic renal failure (CRF), American Society of Anaesthesiologists (ASA) physical status classification system, smoking, body mass index (BMI), HBA1c, lymphocyte count, ankle-brachial index (ABI), osteomyelitis, C-reactive protein (CRP) level and whether taking immunosuppressive agents) were analysed. Significant odds ratio were seen in patients who underwent lower extremity angioplasties (odds ratio: 17.590, p<0.001), with PAD (odds ratio: 10.212, p=0.032) and taking immunosuppressive agents after kidney transplantation (odds ratio: 4.857, p<0.041). Diabetic foot reconstruction using free flaps has a high chance for success and significantly increases the 5-year survival rate. Risk factors such as PAD, history of angioplasties in the extremity and using immunosuppressive agents after transplant may increase the chance for flap loss. PMID- 23098585 TI - Gluteal fold flaps for perineal reconstruction. AB - Defects of the perineum are created during ablative procedures for gynaecological, urological and colorectal malignancies. The gluteal fold flap is a reliable means of reconstructing these defects. We retrospectively reviewed case notes of gluteal fold flaps performed for perineal reconstruction over four years (2007-2010) in our institution. 77 perineal defects were reconstructed using unilateral or bilateral gluteal fold flaps (127 flaps in total). 50% of all patients are discharged before 11 days, and 90% were discharged within one month. Mean time to discharge was 13.2 days. 70% of all patients were completely healed at 2 months, and 85% completely healed at three months. Pre-operative radiotherapy was found to have a prolonging effect on the time to discharge (P<0.05) but did not reach statistical significance when considering the eventual time to healing. The number of co-morbidities that each patient had at the time of surgery had a prolonging effect on both time to discharge and time to healing (P<0.03). The type of resected areas that required reconstruction did not have a statistically significant effect on the time to discharge, but defects where the anus had been resected did eventually take longer to heal than those were the anus was not resected (P<0.01). 124 flaps were successful (97.6%) with total or partial flap loss occurring in three. Complications were seen in 34 of the 77 patients (44%), with simple wound breakdown resulting in delayed healing seen most frequently (30%). The gluteal fold fasciocutaneous flap is a versatile option for reconstructing a wide range of pelvic and perineal defects. Patients with multiple co-morbidities, cases with radiotherapy and instances where the anus has been resected are more likely to experience longer healing times. We present our algorithm for management for perineal defects after tumour resection. PMID- 23098586 TI - A new nasal cavity and maxilla reconstruction method using jejunum flap with non vascularised bone. AB - Reconstruction of the midface is still challenging for reconstructive surgeons because of its complex structure and the need for an aesthetic result. We used a free jejunum flap for the nasal cavity and non-vascularised bone covered by the jejunal seromuscular patch for the facial bone structure. One patient who had a midface defect received reconstructive surgery using free jejunum flap with non vascularised bone. The nasal cavity reconstruction using jejunal mucosa was moisturised and had less crust formation. The nasal cavity space was very large and patients could breathe easily via the nose. The non-vascularised bone covered by the jejunal seromuscular patch did not dry out or become less absorbent. The reconstruction of the nasal cavity and maxilla using free jejunum flap with non vascularised bone is novel and useful in some surgical cases. PMID- 23098587 TI - Mus spicilegus. PMID- 23098588 TI - Spontaneous human speech mimicry by a cetacean. AB - Although dolphins (Tursiops truncatus) have been trained to match numbers and durations of human vocal bursts and reported to spontaneously match computer generated whistles, spontaneous human voice mimicry has not previously been demonstrated. The first to study white whale (Delphinapterus leucas) sounds in the wild, Schevill and Lawrence wrote that "occasionally the calls would suggest a crowd of children shouting in the distance". Fish and Mowbary described sound types and reviewed past descriptions of sounds from this vociferous species. At Vancouver Aquarium, Canada, keepers suggested that a white whale about 15 years of age, uttered his name "Lagosi". Other utterances were not perceptible, being described as "garbled human voice, or Russian, or similar to Chinese" by R.L. Eaton in a self-published account in 1979. However, hitherto no acoustic recordings have shown how such sounds emulate speech and deviate from the usual calls of the species. We report here sound recordings and analysis which demonstrate spontaneous mimicry of the human voice, presumably a result of vocal learning, by a white whale. PMID- 23098589 TI - Niche construction drives social dependence in hermit crabs. AB - Organisms can receive not only a genetic inheritance from their ancestors but also an ecological inheritance, involving modifications their ancestors made to the environment through niche construction. Ecological inheritances may persist as a legacy, potentially generating selection pressures that favor sociality. Yet, most proposed cases of sociality being impacted by an ecological inheritance come from organisms that live among close kin and were highly social before their niche construction began. Here, I show that in terrestrial hermit crabs (Coenobita compressus)--organisms that do not live with kin and reside alone, each in its own shell--niche-construction drives social dependence, such that individuals can only survive in remodeled shells handed down from conspecifics. These results suggest that niche construction can be an important initiator of evolutionary pressures to socialize, even among unrelated and otherwise asocial organisms. PMID- 23098590 TI - Dung beetles use their dung ball as a mobile thermal refuge. AB - At midday, surface temperatures in the desert often exceed 60 degrees C. To be active at this time, animals need extraordinary behavioural or physiological adaptations. Desert ants, for instance, spend up to 75% of their foraging time cooling down on elevated thermal refuges such as grass stalks. Ball-rolling dung beetles work under similar thermal conditions in South African savannahs. After landing at a fresh dung pile, a beetle quickly forms a dung ball and rolls it away in a straight line, head down, walking backwards. Earlier studies have shown that some dung beetles maintain an elevated body temperature to gain a competitive advantage, and that heat shunting may prevent overheating during flight. However, we know little about the behavioural strategies beetles might employ to mitigate heat stress while rolling their dung balls. Using infrared thermography and behavioural experiments, we show here that dung beetles use their dung ball as a mobile thermal refuge onto which they climb to cool down while rolling across hot soil. We further demonstrate that the moist ball functions not only as a portable platform, but also as a heat sink, which effectively cools the beetle as it rolls or climbs onto it. PMID- 23098591 TI - Human perception: Visual heuristics in the perception of glossiness. AB - New insights into the perception of surface glossiness embody a conceptual change in perception research. Instead of estimating the physical properties of objects, the brain exploits 'invariants'--even though these sometimes make us get the answer wrong. PMID- 23098592 TI - Behavioral neuroscience: Crawling is a no-brainer for fruit fly larvae. AB - How are stereotyped behaviors organized in a simple nervous system? A new study in the Drosophila larva reports that the foraging routine can be performed in the absence of any input from the brain. PMID- 23098593 TI - Membrane biology: Making light work of lipids. AB - A clever genetic trick allows the lipid composition of the plasma membrane to be manipulated using light, paving the way for new investigations into the many membrane interactions that dictate cell shape, movement and communication. PMID- 23098594 TI - Visual optics: Accommodation in a splash. AB - Gannets are large seabirds that hunt fish from the air, making a plunge dive followed by active swimming pursuit of prey. A recent study shows that they convert from aerial to aquatic vision nearly instantly. PMID- 23098595 TI - RNA interference: Systemic RNAi SIDes with endosomes. AB - Systemic RNAi, the intercellular spreading of RNAi silencing, requires SID-1 and SID-3 to import silencing signals in Caenorhabditis elegans. How are these signals exported? SID-5, an endosome-associated protein, is a candidate for the job. PMID- 23098596 TI - Circadian rhythms: An electric jolt to the clock. AB - The animal circadian pacemaker is composed of two transcriptional feedback loops, which regulate electrical activity in circadian neurons. Surprisingly, a new study reports that electrical activity can reprogram circadian transcription, and identifies CREB proteins as candidates for this reprograming. PMID- 23098597 TI - Affective neuroscience: Food 'wanting' hotspot in dorsal striatum. AB - New research has uncovered a micro-domain within dorsal neostriatum where enkephalin surges are triggered by the opportunity to consume tasty foods and where MU-opioid microinjections generate intense motivational 'wanting' to eat without enhancing food 'liking'. PMID- 23098598 TI - Closed mitosis: A timely move before separation. AB - Faithful chromosome segregation entails long-range chromosome movement into newly dividing cells. A recent study implicates CDK1 function in releasing mitotic telomeres from the nuclear envelope, thereby liberating chromosomes for mitotic segregation. PMID- 23098599 TI - Evolution: Remodelling hermit shellters. AB - Land hermit crabs hollow out the shells in which they live. A new study shows that remodelled shells afford better survival, with important implications for sociality and evolution. PMID- 23098600 TI - Brain plasticity: Paradoxical case of a neurodegenerative disease? AB - A thought-provoking new study has found that symptom-free carriers of the neurodegenerative Huntington's disease present a dramatic two-fold acceleration in perceptual learning. PMID- 23098601 TI - An embodied view of octopus neurobiology. AB - Octopuses have a unique flexible body and unusual morphology, but nevertheless they are undoubtedly a great evolutionary success. They compete successfully with vertebrates in their ecological niche using a rich behavioral repertoire more typical of an intelligent predator which includes extremely effective defensive behavior--fast escape swimming and an astonishing ability to adapt their shape and color to their environment. The most obvious characteristic feature of an octopus is its eight long and flexible arms, but these pose a great challenge for achieving the level of motor and sensory information processing necessary for their behaviors. First, coordinating motion is a formidable task because of the infinite degrees of freedom that have to be controlled; and second, it is hard to use body coordinates in this flexible animal to represent sensory information in a central control system. Here I will review experimental results suggesting that these difficulties, arising from the animal's morphology, have imposed the evolution of unique brain/body/behavior relationships best explained as intelligent behavior which emerges from the octopus's embodied organization. The term 'intelligent embodiment' comes from robotics and refers to an approach to designing autonomous robots in which the behavior emerges from the dynamic physical and sensory interactions of the agent's materials, morphology and environment. Consideration of the unusual neurobiology of the octopus in the light of its unique morphology suggests that similar embodied principles are instrumental for understanding the emergence of intelligent behavior in all biological systems. PMID- 23098602 TI - The relevance of different near infrared technologies and sample treatments for predicting meat quality traits in commercial beef cuts. AB - Visible and near infrared reflectance (Vis-NIR, 350 to 1800 nm), and near infrared transmittance (NIT, 850 to 1050 nm) spectroscopy were used to predict beef quality traits of intact and ground meat samples. Calibration equations were developed from reference data (n = 312) of pH, color traits (L*, a*, and b*), ageing loss (%), cooking loss (%), and Warner-Bratzler shear force (WBSF, N) using partial least squares regressions. Predictive ability of the models was assessed by coefficient of determination of cross-validation (R(2)(CV)) and root mean square error of cross-validation. Quality traits were better predicted on intact than on ground samples, and the best results were obtained using Vis-NIR spectroscopy. Predictions were good (R(2)(CV) = 0.62 to 0.73) for pH, L*, and a*, hardly sufficient (R(2)(CV) = 0.34 to 0.60) for b*, cooking loss, and WBSF, and unsatisfactory for ageing loss (R(2)(CV) = 0.15). Vis-NIR spectroscopy might be used to predict some physical beef quality traits on intact meat samples. PMID- 23098603 TI - [Has application of the decree banning the use of cement with a high chromium VI content led to a reduction in occupational cement dermatitis in salaried workers in the construction industries?]. AB - INTRODUCTION: Active employees in the construction industry are particularly exposed to occupational cement eczema (OCE) which affects the hands in 80 to 90% of cases. The importance of OCE in France and the impact of the application of decree n(o). 2005-577 on 26 May 2005 were estimated from data collected by the Occupational risks division of the French national health insurance fund for salaried workers (CNAMTS). This decree prohibits the placing on the market and use of cement (and preparations containing it) with a chromium VI content above 0.0002% in order to reduce its hazardousness. METHODS: All cases of OCE reported to and recognized by the CNAMTS between 1 January 2004 and 31 December 2008 among construction workers were selected. The following parameters were noted in each case: age, gender, industrial sector concerned, local French National health insurance agency, causal agent and the number of working days lost. The incidence per 100,000 salaried workers could be determined from the total number of salaried workers followed up by occupational medicine as well as those working in the construction industry. RESULTS: For the five years studied, 3698 cases of occupational eczema (OE) were reported in construction workers and this was 17.1% of the total number of cases of OE for all salaried employees (n=12.689). Cement was the causal agent most frequently involved in the construction sector (57.8%, 2139/3698). The annual incidence of OCE decreased from 37.8 to 21.1 new cases per 100,000 employees in the construction industry per year between 2004 and 2008. The total number of days lost from work due to OCE decreased by 39% during the study period. CONCLUSION: This descriptive study highlights the importance and socio-economic impact of OCE in the construction industry. Application of decree n(o). 2005-577 on 26 May 2005 may explain a reduction in OCE. PMID- 23098604 TI - Wisdom of the crowd and natural resource management. AB - The 'wisdom of the crowd' approach suggests that independent estimates of natural resource sizes provided by resource users can be aggregated to approximate true stock sizes. If this hypothesis gains empirical support, an important contributor to sustainable natural resource management in data-poor situations has appeared on the horizon. PMID- 23098605 TI - Exploring the directionality of 5-substitutions in a new series of 5 alkylaminopyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine as a strategy to design novel human a(3) adenosine receptor antagonists. AB - The structure-activity relationship (SAR) of new 5-alkylaminopyrazolo[4,3-e]1,2,4 triazolo[1,5-c]pyrimidines as antagonists of the A(3) adenosine receptor (AR) was explored with the principal aim to establish the directionality of 5 substitutions inside the orthosteric binding site of the A(3) AR. All the synthesized compounds showed affinity for the hA(3) AR from nanomolar to subnanomolar range. In particular, the most potent and selective antagonist presents an (S) alpha-phenylethylamino moiety at the 5 position (26, K(i) hA(3) = 0.3 nM). Using an in silico receptor-driven approach, we have determined the most favorable orientation of the substitutions at the 5 position of the pyrazolo[4,3 e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) scaffold, opening the possibility for further derivatizations aimed at directing the N(5) position toward the extracellular environment. PMID- 23098606 TI - O-Aryl alpha,beta-d-ribofuranosides: synthesis & highly efficient biocatalytic separation of anomers and evaluation of their Src kinase inhibitory activity. AB - A series of peracetylated O-aryl alpha,beta-d-ribofuranosides have been synthesized and an efficient biocatalytic methodology has been developed for the separation of their anomers which was otherwise almost impossible by column chromatographic or other techniques. The incubation of 2,3,5-tri-O-acetyl-1-O aryl-alpha,beta-d-ribofuranoside with Lipozyme(r) TL IM immobilized on silica led to the selective deacetylation of only one acetoxy group, viz the C-5'-O-acetoxy group of the alpha-anomer over the other acetoxy groups derived from the two secondary hydroxyl groups present in the molecule and also over three acetoxy groups (derived from one primary and two secondary hydroxyls of the beta-anomer). This methodology led to the easy synthesis of both, alpha- and beta-anomers of O aryl d-ribofuranosides. All the arylribofuranosides were screened for inhibition of Src kinase. 1-O-(3-Methoxyphenyl)-beta-d-ribofuranoside exhibited the highest activity for inhibition of Src kinase (IC(50)=95.0MUM). PMID- 23098607 TI - Carbonic anhydrase IX as a target for metastatic disease. AB - Metastatic disease is responsible for the majority of cancer related deaths. Tumour-associated carbonic anhydrase IX (CA IX) is a powerful marker to diagnose various types of metastatic cancers including those of cervical, renal, breast and head & neck origin. The precise prognostic role of CA IX in determining local control versus overall survival is complex, although the majority of reports favour CA IX as a marker for poor prognosis in patients with metastatic cancer. Preclinical studies in cell cultures clearly demonstrate that CA IX stimulates features that enhance metastatic properties of cancer cells for example, reducing cell adhesion, increasing motility and migration, inducing vascularisation and activating proteases, in which CA IX-induced acidification of the microenvironment of the tumour is essential. As most findings are consistent with the idea that CA IX is important in metastatic dissemination, small molecular CA IX inhibitors (including fluorescent-tagged or radiolabelled) and monoclonal antibodies targeting the CA IX isoform have been developed. Studies in tumour xenograft models showed that these CA IX-specific inhibitors and antibodies can be very effective in therapy and imaging of a variety of different metastatic cancers. PMID- 23098608 TI - Characterization of chlorophyll pigments in the mutant lacking 8-vinyl reductase of green photosynthetic bacterium Chlorobaculum tepidum. AB - The mutant lacking the enzyme BciA (renamed CT1063), which catalyzed reduction of the 8-vinyl group of a porphyrinoid-type 3,8-divinyl-(proto)chlorophyllide-a [DV (P)Chlide-a] in the green sulfur bacterium Chlorobaculum (Cba.) tepidum, was reconstructed on the basis of the previous study reported by Chew and Bryant [J. Biol. Chem.2007, 282, 2967-2975]. Cba. tepidum biosynthesizes the following three different types of chlorophylls (Chls) through their common precursory DV (P)Chlide-a as its photosynthetically active pigments: bacteriochlorophyll(BChl) c and Chl-a with the partially reduced 17,18-trans-dihydroporphyrin and BChl-a with the further reduced 7,8-trans-17,18-trans-tetrahydroporphyrin. The structures of Chls thus produced were characterized in detail by various spectroscopic techniques. In the mutant, both BChl-c and Chl-a possessing the alkyl group at the 8-position were exclusively replaced by their 8-vinylated derivatives, whereas BChl-a possessed the original 8-ethyl group. The present observations were inconsistent with the previous report. However, it was apparently confirmed that the enzyme BciA was responsible for the reduction of DV (P)Chlide-a to produce BChl-c and Chl-a. Noteworthily, exclusive accumulation of the reduced (8-ethylated) form of BChl-a, not its 8-vinylated derivative, in the mutant indicates the presence of another enzyme catalyzing the 8-vinyl reduction as yet unidentified or any other reduction mechanism using a known enzyme to yield BChl-a. PMID- 23098609 TI - Discovery of novel 2-(3-(2-chlorophenyl)pyrazin-2-ylthio)-N-arylacetamides as potent HIV-1 inhibitors using a structure-based bioisosterism approach. AB - The present work is an extension of our ongoing efforts towards the development and identification of new molecules with anti-HIV activity which have previously led to the discovery of arylazolylthioacetanilides as highly active NNRTIs. In this article, a series of 2-2-(3-(2-chlorophenyl)pyrazin-2-ylthio)-N arylacetamide derivatives were synthesized and evaluated for in vitro anti-HIV activity. Most of the tested compounds exhibited moderate activities against wild type HIV-1. Among them, compound 6k showed significant activity against wild-type HIV-1 with an EC(50) value of 1.7MUM, along with moderate activity against wild type reverse transcriptase (RT). The preliminary structure-activity relationship (SAR) and docking calculations of this new series of compounds were also investigated, which may help designing more potent molecules. PMID- 23098610 TI - [Therapeutic hypothermia and management of sudden death]. AB - Due to its protective effects on the brain and potentially the myocardium, cooling therapy is clearly part of the standard of care of any sudden death especially in the setting of myocardial infarction. Recent guidelines recommend cooling therapy (32 to 34 degrees C) for 12 to 24 hours in unconscious patients with spontaneous circulation after resuscitated sudden death. We provide here a review of clinical evidence, cooling techniques and potential adverse effects of cooling therapy. PMID- 23098611 TI - [Primary coronary angioplasty for myocardial infarction--the view of the cardiologic surgeon]. AB - The aim of this article is not to present a general academic review on primary angioplasty in patients with ST-elevation myocardial infarction, but rather to focus on some practical points that directly concern cardiologists who perform primary percutaneous interventions in these patients. We detail recent data about the use of the radial artery approach, thromboaspiration, new oral inhibitors of P2Y12, selective use of anti-GPIIb/IIIa, high dose of peri-procedural statin therapy, choice of the best stent, and the best approach for treating non-culprit lesions in patients with multivessel coronary artery disease. The changes observed in the overall management of patients undergoing primary PCI for ST elevation myocardial infarction are likely to have participated in the decrease in mortality observed in several registries. New European guidelines on the management of STEMI, taking into account these diverse aspects, have just been published. PMID- 23098612 TI - [The indispensable instrument for rotational atherectomy]. AB - Rotational atherectomy is the treatment of choice for calcified coronary lesions. It should not be used routinely but only in some appropriate cases, especially when the successful deployment of a stent may be uncertain. Complications are rare but serious. Several cases of "off label" use, however, have been reported in the literature without additional complications. PMID- 23098613 TI - Mercury in the Gulf of Mexico: sources to receptors. AB - Gulf of Mexico (Gulf) fisheries account for 41% of the U.S. marine recreational fish catch and 16% of the nation's marine commercial fish landings. Mercury (Hg) concentrations are elevated in some fish species in the Gulf, including king mackerel, sharks, and tilefish. All five Gulf states have fish consumption advisories based on Hg. Per-capita fish consumption in the Gulf region is elevated compared to the U.S. national average, and recreational fishers in the region have a potential for greater MeHg exposure due to higher levels of fish consumption. Atmospheric wet Hg deposition is estimated to be higher in the Gulf region compared to most other areas in the U.S., but the largest source of Hg to the Gulf as a whole is the Atlantic Ocean (>90%) via large flows associated with the Loop Current. Redistribution of atmospheric, Atlantic and terrestrial Hg inputs to the Gulf occurs via large scale water circulation patterns, and further work is needed to refine estimates of the relative importance of these Hg sources in terms of contributing to fish Hg levels in different regions of the Gulf. Measurements are needed to better quantify external loads, in-situ concentrations, and fluxes of total Hg and methylmercury in the water column, sediments, and food web. PMID- 23098614 TI - Metabolomic profiling reveals a role for CPT1c in neuronal oxidative metabolism. AB - BACKGROUND: Carnitine Palmitoyltransferase-1c (CPT1c) is a neuron specific homologue of the carnitine acyltransferase family of enzymes. CPT1 isoenzymes transfer long chain acyl groups to carnitine. This constitutes a rate setting step for mitochondrial fatty acid beta-oxidation by facilitating the initial step in acyl transfer to the mitochondrial matrix. In general, neurons do not heavily utilize fatty acids for bioenergetic needs and definitive enzymatic activity has been unable to be demonstrated for CPT1c. Although there are studies suggesting an enzymatic role of CPT1c, its role in neurochemistry remains elusive. RESULTS: In order to better understand how CPT1c functions in neural metabolism, we performed unbiased metabolomic profiling on wild-type (WT) and CPT1c knockout (KO) mouse brains. Consistent with the notion that CPT1c is not involved in fatty acid beta-oxidation, there were no changes in metabolites associated with fatty acid oxidation. Endocannabinoids were suppressed in the CPT1c KO, which may explain the suppression of food intake seen in CPT1c KO mice. Although products of beta-oxidation were unchanged, small changes in carnitine and carnitine metabolites were observed. Finally, we observed changes in redox homeostasis including a greater than 2-fold increase in oxidized glutathione. This indicates that CPT1c may play a role in neural oxidative metabolism. CONCLUSIONS: Steady state metabolomic analysis of CPT1c WT and KO mouse brains identified a small number of metabolites that differed between CPT1c WT and KO mice. The subtle changes in a broad range of metabolites in vivo indicate that CPT1c does not play a significant or required role in fatty acid oxidation; however, it could play an alternative role in neuronal oxidative metabolism. PMID- 23098615 TI - Thirty-day readmissions after elective spine surgery for degenerative conditions among US Medicare beneficiaries. AB - BACKGROUND CONTEXT: Readmissions within 30 days of hospital discharge are undesirable and costly. Little is known about reasons for and predictors of readmissions after elective spine surgery to help plan preventative strategies. PURPOSE: To examine readmissions within 30 days of hospital discharge, reasons for readmission, and predictors of readmission among patients undergoing elective cervical and lumbar spine surgery for degenerative conditions. STUDY DESIGN: Retrospective cohort study. PATIENT SAMPLE: Patient sample includes 343,068 Medicare beneficiaries who underwent cervical and lumbar spine surgery for degenerative conditions from 2003 to 2007. OUTCOME MEASURES: Readmissions within 30 days of discharge, excluding readmissions for rehabilitation. METHODS: Patients were identified in Medicare claims data using validated algorithms. Reasons for readmission were classified into clinically meaningful categories using a standardized coding system (Clinical Classification Software). RESULTS: Thirty-day readmissions were 7.9% after cervical surgery and 7.3% after lumbar surgery. There was no dominant reason for readmissions. The most common reasons for readmissions were complications of surgery (26%-33%) and musculoskeletal conditions in the same area of the operation (15%). Significant predictors of readmission for both operations included older age, greater comorbidity, dual eligibility for Medicare/Medicaid, and greater number of fused levels. For cervical spine readmissions, additional risk factors were male sex, a diagnosis of myelopathy, and a posterior or combined anterior/posterior surgical approach; for lumbar spine readmissions, additional risk factors were black race, Middle Atlantic geographic region, fusion surgery, and an anterior surgical approach. Our model explained more than 60% of the variability in readmissions. CONCLUSIONS: Among Medicare beneficiaries, 30-day readmissions after elective spine surgery for degenerative conditions represent a target for improvement. Both patient factors and operative techniques are associated with readmissions. Interventions to minimize readmissions should be specific to surgical site and focus on high-risk subgroups where clinical trials of interventions may be of greatest benefit. PMID- 23098616 TI - Recombinant human bone morphogenetic protein-2: adverse events reported to the Manufacturer and User Facility Device Experience database. AB - BACKGROUND CONTEXT: Adverse effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spinal surgery have previously been observed. However, because of its size, scope, and nature, the US Food and Drug Administration's database of postmarketing reports is useful for detecting new and unexpected safety concerns. PURPOSE: To characterize adverse events reported to the FDA; to characterize off-label use of rhBMP-2. STUDY DESIGN: Review of adverse events reported to the FDA after the use of rhBMP-2 (INFUSE Bone Graft) in spinal surgery. METHODS: The Manufacturer and User Facility Device Experience database was searched for the brand name "infuse bone graft," for reports received from July 2, 2002, through August 31, 2011. Adverse events were reviewed, summarized, and classified by an MD. For each report, the most important clinical entity was identified as the principal adverse event. Off-label uses were summarized. RESULTS: Of 834 reports, four (0.5%) described procedures in which rhBMP-2 was used in accordance with the approved indication. Nearly half of all the reports, 370 (44.4%), stated that the patient required revision surgery or other invasive interventions to address the reported adverse event. Swelling, fluid collections, osteolysis, pain/radiculopathy, heterotopic bone, pseudarthrosis, surgical site infections and other wound complications, thromboembolic events, respiratory distress, cancer, and other events were reported. CONCLUSIONS: Because of their duration, scope, and expense, prospective studies designed to estimate the risk of rare adverse events may be impractical. Despite its imperfections, postmarketing surveillance helps to narrow the focus by revealing patterns and prioritizing topics for further research. One should not extrapolate from these results to the rhBMP-2 experience as a whole; the findings reported here might not be representative. This analysis indicates that serious adverse events can occur after the use of rhBMP-2 in spinal surgery and raises many points that surgeons may wish to consider when deciding when and how to use this product in their patients. PMID- 23098617 TI - Retrograde ejaculation after anterior lumbar interbody fusion with and without bone morphogenetic protein-2 augmentation: a 10-year cohort controlled study. AB - BACKGROUND CONTEXT: Retrograde ejaculation (RE) is a complication of anterior lumbar interbody fusion (ALIF) techniques. Most commonly, this results from mechanical or inflammatory injury to the superior hypogastric plexus near the aortic bifurcation. Bone morphogenetic protein-2 (BMP-2) has been used in spinal fusions and has been associated with inflammatory and neuroinflammatory adverse reactions, which may contribute to RE development after anterior lumbar surgery. PURPOSE: While controlling for anterior approach technique, we compared the incidence of RE with and without rhBMP-2 exposure, in large, matched cohorts of patients after ALIF. STUDY DESIGN: Retrospective analysis of 10 years of prospectively gathered outcomes data on consecutive-patient cohorts having the same anterior exposure technique for ALIF with and without rhBMP-2 use. PATIENT SAMPLE: All male patients without baseline sexual incapacity and having ALIF for lumbar spondylosis or spondylolisthesis of the lowest one or two lumbar levels with and without rhBMP-2, from 2002 through 2011. OUTCOME MEASURES: Diagnosis of RE as a new finding after ALIF compared against BMP-2 exposure, comorbid conditions, and other urological complications after ALIF surgery. METHODS: From the comprehensive surgical database at a high volume, university practice, male subjects having ALIF at one (L5/S1) or two levels (L4/5, L5/S1) from 2002 to 2011 were identified. Baseline comorbid factors, postoperative urinary catheter/retention events, and RE events were recorded and comparative incidence compared. RESULTS: There were four consecutive-patient cohorts identified: one before rhBMP-2 use was adopted (n=174), two cohorts in which BMP-2 use was routine (n=88 and n=151), and one final cohort after BMP-2 use was discontinued from routine use (n=59). The cohorts with and without BMP-2 exposure were closely comparable for age, approach, levels of surgery, comorbid factors affecting RE. Of 239 patients with ALIF and exposure to BMP-2, RE was diagnosed in 15 subjects (6.3%), compared with an RE diagnosis rate of two of 233 control patients without BMP-2 exposure (0.9%; p=.0012). Urinary retention after bladder catheter removal was also more frequently observed in patients exposed to BMP-2 (9.7%) compared with control patients (4.6%; p=.043). Of the baseline comorbid factors, medical or surgical treatment for prostatic hypertrophy disease was associated with an increased risk of RE in the BMP-2 patients (p=.034). CONCLUSIONS: This study confirms previous reports of a higher rate of RE in ALIF procedures using rhBMP-2 and an open anterior approach to the spine. This effect may be associated with an increased risk of postoperative urinary retention after BMP-2 exposure. The magnitude of the RE effect may be increased with concomitant prostatic disease treatments. PMID- 23098618 TI - Factors affecting access to healthcare services by intermarried Filipino women in rural Tasmania: a qualitative study. AB - INTRODUCTION: Access to health care services is vital for every migrant's health and wellbeing. However, migrants' cultural health beliefs and views can hinder their ability to access available services. This study examined factors affecting access to healthcare services for intermarried Filipino women in rural Tasmania, Australia. METHODS: A qualitative approach using semi-structured interviews was employed to investigate the factors affecting access to healthcare services for 30 intermarried Filipino women in rural Tasmania. The study used grounded theory and thematic analysis for its data analysis. Nvivo v8 (www.qsrinternational.com) was also used to assist the data coding process and analysis. RESULTS: Five influencing factors were identified: (1) language or communication barriers; (2) area of origin in the Philippines; (3) cultural barriers; (4) length of stay in Tasmania; and (5) expectations of healthcare services before and after migration. CONCLUSION: Factors affecting intermarried Filipino women in accessing healthcare services are shaped by their socio-demographic and cultural background. The insights gained from this study are useful to health policy-makers, healthcare professionals and to intermarried female migrants. The factors identified can serve as a guide to improve healthcare access for Filipino women and other migrants. PMID- 23098619 TI - Erythrocyte stearidonic acid and other n-3 fatty acids and CHD in the Physicians' Health Study. AB - Intake of marine-based n-3 fatty acids (EPA, docosapentaenoic acid and DHA) is recommended to prevent CHD. Stearidonic acid (SDA), a plant-based n-3 fatty acid, is a precursor of EPA and may be more readily converted to EPA than a-linolenic acid (ALA). While transgenic soyabeans might supply SDA at low cost, it is unclear whether SDA is associated with CHD risk. Furthermore, associations of other n-3 fatty acids with CHD risk remain inconsistent. The present ancillary study examined the association of erythrocyte SDA as well as other n-3 fatty acids with the risk of CHD. In a prospective nested case-control study of the Physicians' Health Study, we randomly selected 1000 pairs of incident CHD with matching controls. Erythrocyte fatty acids were measured using GC. We used conditional logistic regression to estimate relative risks. Mean age was 68.7 (SD 8.7) years. In a multivariable model controlling for matching factors and established CHD risk factors, OR for CHD for each standard deviation increase of log-SDA was 1.03 (95% CI 0.90, 1.18). Corresponding values for log-ALA and log marine n-3 fatty acids were 1.04 (95% CI 0.94, 1.16) and 0.97 (95% CI 0.88, 1.07), respectively. In conclusion, the present data did not show an association among erythrocyte SDA, ALA or marine n-3 fatty acids and the risk of CHD in male physicians. PMID- 23098620 TI - The relationship of perceptions of tap water safety with intake of sugar sweetened beverages and plain water among US adults. AB - OBJECTIVE: Research is limited on whether mistrust of tap water discourages plain water intake and leads to a greater intake of sugar-sweetened beverages (SSB). The objective of the present study was to examine demographic differences in perceptions of tap water safety and determine if these perceptions are associated with intake of SSB and plain water. DESIGN: The study examined perceptions of tap water safety and their cross-sectional association with intake of SSB and plain water. Racial/ethnic differences in the associations of tap water perceptions with SSB and plain water intake were also examined. SETTING: Nationally weighted data from the 2010 HealthStyles Survey (n 4184). SUBJECTS: US adults aged >=18 years. RESULTS: Overall, 13.0 % of participants disagreed that their local tap water was safe to drink and 26.4 % of participants agreed that bottled water was safer than tap water. Both mistrust of tap water safety and favouring bottled water differed by region, age, race/ethnicity, income and education. The associations of tap water mistrust with intake of SSB and plain water were modified by race/ethnicity (P < 0.05). Non-white racial/ethnic groups who disagreed that their local tap water was safe to drink were more likely to report low intake of plain water. The odds of consuming >=1 SSB/d among Hispanics who mistrusted their local tap water was twice that of Hispanics who did not (OR = 2.0; 95 % CI 1.2, 3.3). CONCLUSIONS: Public health efforts to promote healthy beverages should recognize the potential impact of tap water perceptions on water and SSB intake among minority populations. PMID- 23098621 TI - Micro-shear bond strength of resin cement to dentin after application of desensitizing toothpastes. AB - OBJECTIVES: The aim of the study was to evaluate the effect of three desensitizing toothpastes on bonding of resin cements to dentin. MATERIALS AND METHODS: The occlusal surfaces of 72 maxillary third molars were ground to obtain flat dentin surfaces and then divided into three groups according to three desensitizing toothpastes used: Sensodyne Rapid Relief (GlaxoSmithKline, SmithKline Beecham Ltd., Slough, UK), Signal Sensitive Expert (Unilever Sanayi ve Ticaret Turk A.S., Umraniye, Istanbul, Turkey) and Colgate Sensitive Pro-Relief (Colgate Palmolive, New York, NY). Following bonding of the resin cement (ClearfilTM SA Cement, Kuraray Co, Osaka, Japan) to dentin, the specimens were light cured for 40 s with a LED (Elipar S10, 3M Espe, St. Paul, MN). The strength measurements were accomplished with a micro-shear testing machine (Bisco, Schaumburg, IL) at a cross-head speed of 0.5 mm/min until the failure occurs. Failure modes were examined using a stereomicroscope and scanning electron microscope. The data were analyzed with one-way analysis of variance (ANOVA) and Tukey HSD test (alpha = 0.05). RESULTS AND CONCLUSION: ANOVA revealed that the application of desensitizing toothpastes had significant effects on bond strength of the resin cement tested to dentin (p < 0.05). Mixed failures were observed in all of the groups. CLINICAL SIGNIFICANCE: The use of a desensitizing toothpaste before cementation might alter the bond strength of adhesively luted restorations. PMID- 23098622 TI - Clinical teachers' views on how teaching teams deliver and manage residency training. AB - BACKGROUND: Residents learn by working in a multidisciplinary context, in different locations, with many clinical teachers. Although clinical teachers are collectively responsible for residency training, little is known about the way teaching teams function. AIM: We conducted a qualitative study to explore clinical teachers' views on how teaching teams deliver residency training. METHOD: Data were collected during six focus group interviews in 2010. RESULTS: The analysis revealed seven teamwork themes: (1) clinical teachers were more passionate about clinical expertise than about knowledge of teaching and teamwork; (2) residents needed to be informed about clinical teachers' shared expectations; (3) the role of the programme director in the teaching team needed further clarification; (4) the main topics of discussion in teaching teams were resident performance and the division of teaching tasks; (5) the structural elements of the organisation of residency training were clear; (6) clinical teachers had difficulty giving and receiving feedback and (7) clinical teachers felt under pressure to be accountable for team performance to external parties. CONCLUSION: The clinical teachers did not consider teamwork to be of any great significance to residency training. Teachers' views of professionalism and their own experiences as residents may explain their non-teamwork directed attitude. Efforts to strengthen teamwork within teaching teams may impact positively on the quality of residency training. PMID- 23098624 TI - Pattern of outsole shoe heel wear in infantry recruits. AB - BACKGROUND: Excessive shoe heel abrasion is of concern to patients, parents and shoe manufacturers, but little scientific information is available. The purpose of this study was to describe the phenomenon in a group of infantry recruits performing similar physical activity, and search for biomechanical factors that might be related. METHODS: Seventy-six subjects (median age 19) enrolled. Pre training parameters measured included height, weight, tibial length, foot arch height and foot progression angle. Digital plantar pressure maps were taken to calculate arch indexes. Shoe heel abrasion was assessed manually after 14 weeks of training with different-sized clock transparencies and a calliper. RESULTS: Outsole abrasion was posterolateral, averaging 12 degrees on each shoe. The average heel volume that was eroded was almost 5 cm3. The angle of maximum wear was related to right foot progression angle (r = 0.27, p = 0.02). Recruits with lateral ankle sprains had higher angles of maximal abrasion (17 degrees versus 10 degrees , p = 0.26) and recruits with lateral heel abrasion had more lateral ankle sprains (14% versus 3%, p = 0.12). CONCLUSION: While shoe heel wear affects many people, very little has been done to measure it. In this study in healthy subjects, we found the main abrasion to be posterolateral. This seems to be related to foot progression angle. It was not related to hindfoot valgus/varus or other factors related to subtalar joint motion. These findings do not warrant modification of subtalar joint motion in order to limit shoe heel abrasion. PMID- 23098626 TI - Age, gender and epicenter proximity effects on post-traumatic stress symptoms in L'Aquila 2009 earthquake survivors. AB - BACKGROUND: Earthquakes are among the most frequently occurring natural disasters affecting the general population and inducing Post-Traumatic Stress Disorder (PTSD). Thus, increasing effort has been devoted to explore risk factors for PTSD onset after exposure. The aim of the present study was to investigate the impact of gender, degree of exposure and age on PTSD and post-traumatic stress symptoms in the general population exposed to the L'Aquila 2009 earthquake (Richter Magnitude 6.3). METHODS: A total sample of 1488 subjects (721 women and 767 men) was assessed by means of the Trauma and Loss Spectrum Self Report (TALS-SR): 939 subjects have been directly and 549 not-directly exposed to the earthquake. We performed a random extraction of units from the population in order to have 8 homogenous comparable subgroups. RESULTS: A main significant effect of exposure (exposed>non exposed subjects) and gender (women>men) emerged on the TALS-SR domain scores. Further significant interaction effects of exposure(*)age and gender(*)age emerged with significantly more TALS-SR symptoms being reported in younger with respect to older non-exposed subjects and in younger with respect to older women. LIMITATIONS: Social support was not examined systematically as well as major depression. Further limitations are the relatively small sample size and the use of lifetime instruments. CONCLUSIONS: Our results corroborate literature on female gender and proximity to the epicenter being correlated to PTSD after earthquake exposure and suggest a possible secondary effect of age. PMID- 23098627 TI - Molar size and diet in the Strepsirrhini: implications for size-adjustment in studies of primate dental adaptation. AB - Among the Strepsirrhini, molar size does not exhibit a consistent dietary signal when body mass is used to size-adjust molar dimensions. This observation is also true for anthropoid primates, but when postcanine size is expressed relative to the size of the facial skeleton in this clade, folivorous anthropoids tend to have relatively larger postcanine teeth than anthropoids in other dietary categories. The contrast in the results generated by these two independent size variables appears to be related to systematic differences in facial size in the Anthropoidea, particularly between short-faced colobines and long-faced cercopithecines. The goal of this study was to determine whether a similar pattern of relationships characterizes strepsirrhines. Data on molar area, facial size, body mass, and diet for forty-three extant strepsirrhines and seven subfossil lemurs were analyzed using phylogenetic generalized least squares. Results indicate that strepsirrhine folivores tend to have larger molars than frugivores relative to the size of the facial skeleton. Insectivorous species exhibit a wide range of variation in relative molar size that appears to be taxonomically patterned: lorisids in this dietary category resemble folivores, whereas galagids resemble frugivores. These results confirm the generality of the anthropoid pattern and support the idea that, in some contexts, it may be useful to consider elements of the masticatory system relative to their functional and developmental environments rather than to overall organismal size. The biological significance of having large postcanine teeth relative to the size of the face, but not body mass, is discussed with reference to a model that identifies the size of the oral cavity as the most functionally relevant standard for assessing the relative size of the postcanine dentition. PMID- 23098625 TI - PR-104 a bioreductive pre-prodrug combined with gemcitabine or docetaxel in a phase Ib study of patients with advanced solid tumours. AB - BACKGROUND: The purpose of this phase Ib clinical trial was to determine the maximum tolerated dose (MTD) of PR-104 a bioreductive pre-prodrug given in combination with gemcitabine or docetaxel in patients with advanced solid tumours. METHODS: PR-104 was administered as a one-hour intravenous infusion combined with docetaxel 60 to 75 mg/m2 on day one given with or without granulocyte colony stimulating factor (G-CSF) on day two or administrated with gemcitabine 800 mg/m2 on days one and eight, of a 21-day treatment cycle. Patients were assigned to one of ten PR-104 dose-levels ranging from 140 to 1100 mg/m2 and to one of four combination groups. Pharmacokinetic studies were scheduled for cycle one day one and 18F fluoromisonidazole (FMISO) positron emission tomography hypoxia imaging at baseline and after two treatment cycles. RESULTS: Forty two patients (23 females and 19 males) were enrolled with ages ranging from 27 to 85 years and a wide range of advanced solid tumours. The MTD of PR-104 was 140 mg/m2 when combined with gemcitabine, 200 mg/m2 when combined with docetaxel 60 mg/m2, 770 mg/m2 when combined with docetaxel 60 mg/m2 plus G CSF and >=770 mg/m2 when combined with docetaxel 75 mg/m2 plus G-CSF. Dose limiting toxicity (DLT) across all four combination settings included thrombocytopenia, neutropenic fever and fatigue. Other common grade three or four toxicities included neutropenia, anaemia and leukopenia. Four patients had partial tumour response. Eleven of 17 patients undergoing FMISO scans showed tumour hypoxia at baseline. Plasma pharmacokinetics of PR-104, its metabolites (alcohol PR-104A, glucuronide PR-104G, hydroxylamine PR-104H, amine PR-104M and semi-mustard PR-104S1), docetaxel and gemcitabine were similar to that of their single agents. CONCLUSIONS: Combination of PR-104 with docetaxel or gemcitabine caused dose-limiting and severe myelotoxicity, but prophylactic G-CSF allowed PR 104 dose escalation with docetaxel. Dose-limiting thrombocytopenia prohibited further evaluation of the PR104-gemcitabine combination. A recommended dose was identified for phase II trials of PR-104 of 770 mg/m2 combined with docetaxel 60 to 75 mg/m2 both given on day one of a 21-day treatment cycle supported by prophylactic G-CSF (NCT00459836). PMID- 23098628 TI - Isolation of methicillin-resistant Staphylococcus lugdunensis in a dog with endocarditis. AB - A 4-year-old male castrated Borzoi dog presented on referral for evaluation of pleural effusion, ventricular arrhythmias, and suspected dilated cardiomyopathy. Echocardiogram identified several masses along the chordae tendineae, as well as a long the annulus of the mitral valve. A blood culture was positive for methicillin resistant Staphylococcus lugdunensis. The dog was also positive for Bartonella DNA on PCR testing. Aggressive antibiotic therapy was instituted. However, the dog continued to have recurrent pleural effusion and progressive azotemia. The dog was euthanized 39 days after diagnosis. Necropsy confirmed the presence of intracardiac abscesses, thrombosis and endocarditis. S. lugdunensis is a recently identified rare cause of endocarditis in humans characterized by intracardiac abscess formation, highly destructive valvular lesions preferentially affecting the mitral valve and a high mortality rate. This is the first reported case of S. lugdunensis isolation in a dog with endocarditis. PMID- 23098629 TI - Evaluation of 4 corneal astigmatic marking methods. AB - PURPOSE: To compare 4 devices used to mark the cornea before astigmatism-reducing surgery. SETTING: Hanusch Krankenhaus, Vienna, Austria. DESIGN: Randomized examiner-masked clinical trial. METHODS: Patients were randomly allocated to 1 of 4 groups for preoperative corneal marking in the sitting position. The 4 methods used were marking at the slitlamp with an insulin needle, a pendular marker, a bubble marker, and a tonometer marker. The marks were then documented with a standardized photographic technique, and the rotational deviation and vertical misalignment were assessed. RESULTS: The study enrolled 60 patients. The pendular marking device showed the least rotational deviation to the reference meridian (mean 1.8 degrees). There was no statistically significant difference between slitlamp marking and pendular marking (P = .05); however, there was a significant difference between the pendular marker and the bubble marker and between the pendular marker and the tonometer marker (P = .01 and P < .01, respectively). The least vertical misalignment was observed with the slitlamp-marking device (mean 0.28 mm). There was no statistically significant difference in vertical misalignment between the 4 groups. CONCLUSIONS: All marking devices showed a slight deviation to the horizontal reference meridian. Because small deviations of the meridian can result in a relevant reduction in the astigmatism-reducing effect with toric intraocular lenses, accurate marking of the cornea before surgery is critical due to the variable cyclotorsion caused by a change from the upright to the supine position. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 23098630 TI - Comparison of visual results with accommodating intraocular lenses versus mini monovision with a monofocal intraocular lens. AB - PURPOSE: To compare near vision and quality of vision after controlling for pseudoaccommodation in patients with single-optic accommodating intraocular lenses (IOLs) or monofocal IOLs targeted for mini-monovision. SETTING: Clinical practice. DESIGN: Prospective randomized controlled clinical trial. METHODS: Patients were randomized to bilateral implantation of the Crystalens HD silicone accommodating IOL, the Tetraflex acrylic accommodating IOL, or the Tecnis 1-piece monofocal (nonaccommodating) control IOL. The target refraction for the control group was mini-monovision (-0.25 diopter [D] and -0.75 D). In the accommodating IOL groups, manufacturer recommendations were followed; that is, a target refraction of mini-monovision (-0.25 D and -0.75 D) in the acrylic accommodating group and +0.25 D in the silicone accommodating group. Pupil size and anterior corneal spherical aberration were measured preoperatively. Main outcome measures were binocular target refraction corrected near vision and contrast sensitivity 3 months postoperatively. RESULTS: There were no statistically significant differences between the 3 groups in age, photopic or mesopic pupil size, anterior corneal spherical aberration, corneal astigmatism, or the power of the IOLs implanted. Binocular distance visual acuity at 4 m was 20/20(-) in all groups, intermediate vision was approximately 20/25, and near vision was 20/40 to 20/50. There were no statistically significant differences between the 3 groups in visual acuity or contrast sensitivity. CONCLUSION: Single-optic accommodating IOLs did not offer a significant advantage in near visual acuity over mini monovision with a monofocal (nonaccommodating) IOL. PMID- 23098631 TI - Parents' views of their child's end-of-life care: subanalysis of primary care involvement. AB - BACKGROUND: The medical literature encourages primary care pediatricians (PCPs) to play a role in the care of patients who are dying. Actual involvement has not been investigated. OBJECTIVE: Our objective was to explore current involvement of PCPs when their patients face the end of life and bereaved parents' attitudes toward it. DESIGN: Individual, in-depth, semi-structured interviews were conducted using a focused ethnographic technique. Qualitative analysis was performed on the interviews. SETTING/SUBJECTS: Most (14/16) interviews were conducted in the family's home, involving parents of Massachusetts children who died aged 1 month to 11 years during 2005. MEASUREMENTS: Themes identified through thematic analysis of interview transcripts were utilized. RESULTS: Interviews were thematically analyzed, revealing four categories of themes: 1) the role of individual PCP in decision making and care at end of life; 2) general attitudes about the care provided by the PCP; 3) the impact of practice infrastructure on the PCP's care; and 4) bereavement involvement. From the interviews we hypothesize that PCPs play a supportive and appreciated role while having limited involvement in decision making and care; an involved PCP acting with knowledge of a family may in some cases provide profound guidance, but that kind of involvement is not typical; and although there is an articulated role for the PCP with the parents' and siblings' bereavement, it is not routinely exercised. CONCLUSIONS: The interviews suggest limited involvement by PCPs in care at the end of life and subsequent bereavement. Parents overall seem to accept this role. Further research is needed to examine these observations from the perspective of PCPs. PMID- 23098632 TI - Augmenting communication and decision making in the intensive care unit with a cardiopulmonary resuscitation video decision support tool: a temporal intervention study. AB - OBJECTIVE: Effective communication between intensive care unit (ICU) providers and families is crucial given the complexity of decisions made regarding goals of therapy. Using video images to supplement medical discussions is an innovative process to standardize and improve communication. In this six-month, quasi experimental, pre-post intervention study we investigated the impact of a cardiopulmonary resuscitation (CPR) video decision support tool upon knowledge about CPR among surrogate decision makers for critically ill adults. METHODS: We interviewed surrogate decision makers for patients aged 50 and over, using a structured questionnaire that included a four-question CPR knowledge assessment similar to those used in previous studies. Surrogates in the post-intervention arm viewed a three-minute video decision support tool about CPR before completing the knowledge assessment and completed questions about perceived value of the video. RESULTS: We recruited 23 surrogates during the first three months (pre intervention arm) and 27 surrogates during the latter three months of the study (post-intervention arm). Surrogates viewing the video had more knowledge about CPR (p=0.008); average scores were 2.0 (SD 1.1) and 2.9 (SD 1.2) (out of a total of 4) in pre-intervention and post-intervention arms. Surrogates who viewed the video were comfortable with its content (81% very) and 81% would recommend the video. CPR preferences for patients at the time of ICU discharge/death were distributed as follows: pre-intervention: full code 78%, DNR 22%; post intervention: full code 59%, DNR 41% (p=0.23). PMID- 23098633 TI - Loss of alignment after closed reduction of distal radius fractures. PMID- 23098634 TI - Mortality in virulent canine babesiosis is associated with a consumptive coagulopathy. AB - The inflammatory response to infection can activate the coagulation system via complex interactions. If uncontrolled, this may lead to a consumptive coagulopathy, a major risk factor for a poor clinical outcome. This prospective observational study was conducted to determine whether consumptive coagulopathy in dogs with Babesia rossi infection is related to mortality. Seventy-two client owned dogs diagnosed with canine babesiosis were included. Diagnosis was confirmed by polymerase chain reaction and reverse line blot and dogs co-infected with Babesia vogeli or Ehrlichia canis were excluded. Blood samples were collected at admission. Coagulation factor-, antithrombin (AT)-, and protein C (PC)-activity, prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and D-dimer concentrations were measured. The mortality rate was 18% (13/72 dogs) and the median activities of all the coagulation factors were significantly lower in the non-survivors compared to the survivors. Median PT and aPTT were significantly longer in the non-survivors compared to the survivors. Median AT activity was not significantly different but median PC activity was significantly decreased in the non-survivors. Median D-dimer concentrations were significantly higher in non-survivors compared to survivors. This study showed that dogs that died from B. rossi infection had a more severe consumptive coagulopathy compared to survivors, characterized by procoagulant activation, inhibitor consumption, and increased fibrinolytic activity. PMID- 23098635 TI - Pharmacokinetics of hydrocodone and hydromorphone after oral hydrocodone in healthy Greyhound dogs. AB - The purpose of this study was to determine the pharmacokinetics of hydrocodone and its active metabolite hydromorphone in six healthy Greyhound dogs. Hydrocodone bitartrate was administered at a targeted dose of 0.5 mg/kg PO. Plasma concentrations of hydrocodone and hydromorphone were determined by liquid chromatography triple quadrupole mass spectrometry. The mean hydrocodone CMAX was 11.73 ng/mL at 0.74 h with a terminal half-life of 1.60 h. The mean hydromorphone CMAX was 5.2 ng/mL at 1.37 h with a terminal half-life of 3.07 h. Mean plasma hydromorphone concentrations exceeded 2 ng/mL from 0.5 to 8 h after hydrocodone administration. Further studies assessing the antinociceptive effects of oral hydrocodone are needed. PMID- 23098636 TI - Evaluation of a novel feather scoring system for monitoring feather damaging behaviour in parrots. AB - Feather damaging behaviour is common in captive psittacine birds and there is a need for reliable methods to evaluate the efficacy of therapeutic and preventive interventions. This study compared the inter- and intra-observer reliabilities of a novel feather scoring system with an existing system to assess the plumage of grey parrots (Psittacus erithacus). Regions of the body were photographed separately at 1 week intervals and shown at random to 35 examiners (avian veterinarians and veterinary students), who used the two scoring systems to assess plumage. Since the quality of the photographs was insufficient to allow accurate assessment of the individual flight and tail feathers, the novel scoring system was only evaluated for its reliability regarding covert and down feathers. Inter- and intra-observer reliabilities were determined using the intra-class correlation coefficient. Bland-Altman analysis was performed to determine absolute reliabilities for both systems. Correlation coefficients were 0.90 and 0.95 for intra-observer reliability and 0.83 and 0.89 for inter-observer reliability for the existing and novel feather scoring systems, respectively. When using the novel system, a change in plumage condition of >=10% was needed to ensure that the change reflected a real difference in 95% of cases, while a change of >=15% was needed for the existing system. Since it may take from 4 weeks (covert or down feathers) to over 1 year (flight or tail feathers) for feathers to regrow, sufficient time should be allowed to elapse between two scoring sessions to reliably evaluate the efficacy of preventive or therapeutic interventions for feather damaging behaviour. PMID- 23098637 TI - Identifying fall-protection training needs for residential roofing subcontractors. AB - Falls remain the leading cause of injuries and fatalities in the small residential roofing industry and analogous investigations are underrepresented in the literature. To address this issue, fall-protection training needs were explored through 29 semi-structured interviews among residential roofing subcontractors with respect to recommendations for the design of fall-protection training. Content analysis using grounded theory was conducted to analyze participants' responses. Results of the analysis revealed six themes related to the design of current fall-protection training: (1) barriers to safety training; (2) problems of formal safety-training programs; (3) recommendations for training implementation; (4) important areas for fall-protection training; (5) training delivery means; and (6) design features of training materials. Results of the study suggest the need for informal jobsite safety training to complement what had been covered in formalized safety training. This work also provides recommendations for the design of a more likely adopted fall-protection training program. PMID- 23098638 TI - A survey of dermatology resident education in cosmetic procedures. AB - BACKGROUND: The demands for cosmetic procedures are increasing. Dermatologists perform many of these procedures, therefore adequate education and training during residency is important. Surveys demonstrate dermatology residents desire more training even while faculty members believe this has already become a more prominent feature of resident education. OBJECTIVE: We sought to assess the time and methods dedicated to education and training of cosmetic procedures in dermatology residency. METHODS: A 26-question survey was developed and electronically distributed in May 2010 to dermatology program directors via the Association of Professors of Dermatology list-serve with their approval. Program directors were asked to forward the e-mail to their instructors of cosmetic/procedural dermatology, and chief residents. Responses were anonymous. RESULTS: A total of 86 responses were collected. In all, 67% (n = 54) of respondents had formal lectures focusing on cosmetic dermatology. Lecture topics reported by more than 50% of respondents included botulinum toxin injection, lasers, soft tissue augmentation, chemical peels, and sclerotherapy. Topics such as dermabrasion, liposuction, and scar revision were less commonly taught. The most commonly encountered and performed procedures were botulinum toxin injection and lasers (100%, n = 86); 98.8% (n = 85) encounter soft tissue augmentation and 95.4% (n = 82) encounter both chemical peels and sclerotherapy. Resident experience performing procedures as the first assistant or as the first surgeon varied widely. LIMITATIONS: The limitations of this study are that the data were subjectively reported so results may differ from the true amount of time spent in any activity. The data may be biased by the population that responded as they may have strong opinions supporting or opposing training in cosmetic procedures. The data also may have been skewed by the small percentage of participants who were instructors of cosmetic dermatology (21%), chief residents (20%), and others respondents (8% total). CONCLUSION: The results demonstrate the variability of training in cosmetic procedures. The challenge for programs is to find the balance between insufficiency and overemphasis. The results of this study will hopefully assist programs in determining the quantity and methods of resident training in cosmetic procedures. PMID- 23098639 TI - Evaluating facial pores and skin texture after low-energy nonablative fractional 1440-nm laser treatments. AB - BACKGROUND: The fractionated nonablative 1440-nm laser creates microscopic thermal wounds within the epidermis and the dermis and is used clinically to improve tone, texture, and color of skin. OBJECTIVE: We sought to investigate the use of this device to treat facial pores and to improve skin texture. METHODS: Twenty patients received 6 treatments at the highest tolerable energy level performed 2 weeks apart. Photographic assessments using the VISIA-CR (Canfield Scientific Inc, Fairfield, NJ) imaging system were performed. The pore score was calculated, which is the percentage of the skin surface that has detected pores. Subjective measurements (0-4 scale) were recorded by both the subject and investigator regarding pore appearance, skin texture, and overall skin appearance. Treatment discomfort was scored by patients (1-10 scale). RESULTS: After 6 treatments there was a significant reduction in pore score (P < .002). Total average pore score at baseline was 2.059 +/- 0.8 and 2 weeks after the final treatment it was 1.700 +/- 0.8, resulting in a 17% average reduction in pore score. Study investigators reported average scores being 1.95 +/- 0.3 for improved pore appearance and 2.75 +/- 0.2 for improved overall appearance (0-4 scale). Subjects noted average scores of 1.9 +/- 0.5 for improvement of the appearance of pores and 2.85 +/- 0.4 for improvement of overall appearance (0-4 scale). The average discomfort score during treatments was reported to be 4.6 +/- 0.1 (1-10 scale). There were no serious adverse effects or long-term side effects. LIMITATIONS: Small sample size and limited follow-up are study limitations. CONCLUSIONS: A series of treatments with the nonablative low-energy fractional 1440-nm laser appears to be safe and effective for reducing detectable pores and improving overall skin appearance. PMID- 23098640 TI - Genotypic diversity and virulent factors of Staphylococcus epidermidis isolated from human breast milk. AB - Staphylococcus epidermidis strains were isolated from the expressed human breast milk (EHM) of 14 healthy donor mothers. Genetic diversity was evaluated using RAPD-PCR REP-PCR and pulse-field gel electrophoresis (PFGE). PFGE allowed the best discrimination of the isolates, since it provided for the greatest diversity of the analyzed genomes. Among the S. epidermidis strains, resistance to gentamicin, tetracycline, erythromycin, clindamycin or vancomycin was detected, whilst four isolates were multiresistant. The results from our study demonstrate that staphylococci from EHM could be reservoirs of resistance genes, since we showed that tetK could be transferred from EHM staphylococci to Gram-negative Escherichia coli. Most of the staphylococcal strains displayed excellent proteolytic and lipolytic activities. Additionally, the presence of ica genes, which was related to their ability to form a biofilm on tissue culture plates, and the presence of virulence factors including autolysin/adhesin AtLE, point to their pathogenic potential. PMID- 23098641 TI - Comparison of deformation texture in FePd alloy via X-ray diffraction and electron backscatter diffraction techniques. AB - In this work, textures measured by electron backscatter diffraction (EBSD) and X ray diffraction in rolled FePd alloys were compared. The effect of scanning size used for EBSD measurements was investigated. The correlation coefficient was first proposed to quantify the similarity of the orientation density profile along the alpha- and beta-fibers after cold rolling. The correlation coefficient is approximately 1 for a scanning step range of 1-20 MUm after 50% and 88% reduction. A large scanning step can capture the main components of the macrotexture in EBSD measurements. Thus, the macrotexture measured by EBSD provides another method for the quality control of texture. PMID- 23098642 TI - A silicon cell cycle in a bacterial model of calcium phosphate mineralogenesis. AB - The prokaryote Corynebacterium matruchotii produces calcium phosphate (bone salt) and may serve as a convenient model for examining individual factors relevant to vertebrate calcification. A factor of current clinical uncertainty is silicon. To investigate its possible role in biomineralisation advanced optical (digital deconvolution and 3D fluorescent image rendering) and electron microscopy (EDX microanalysis and elemental mapping) were applied to calcifying microbial colonies grown in graded Si concentrations (0-60mM). Cell viability was confirmed throughout by TO-PRO-3-iodide and SYTO-9 nucleic acid staining. It was observed that calcium accumulated in dense intracellular microspherical objects (types i iii) as nanoparticles (5 nm, type i), nanospheres (30-50 nm, type ii) and filamentous clusters (0.1-0.5 MUm, type iii), with a regular transitory Si content evident. With bacterial colony development (7-28 days) the P content increased from 5 to 60%, while Si was displaced from 60 to 5%, distinguishing the phenomenon from random contamination, and with a significant relationship (p<0.001) found between calcified object number and Si supplementation (optimum 0.01mM). The Si-containing, intracellular calcified objects (also positive for Mg and negative with Lysensor blue DND-167 for acidocalcisomes) were extruded naturally in bubble-like chains to complete the cycle by coating the cell surface with discrete mineral particles. These could be harvested by lysis, French press and density fractionation when Si was confirmed in a proportion. It was concluded that the unexplained orthopaedic activity of Si may derive from its special property to facilitate calcium phosphorylation in biological systems, thereby recapitulating an ancient and conserved bacterial cycle of calcification via silicification. PMID- 23098643 TI - MUNIX and MUNE in ALS. PMID- 23098644 TI - Effects of acetylcholinesterase inhibitors and memantine on resting-state electroencephalographic rhythms in Alzheimer's disease patients. AB - Acetylcholinesterase inhibitors (AChEIs) are the most widely used symptomatic treatment for mild to severe Alzheimer's disease (AD) patients, while N-methyl-d aspartic acid (NMDA) receptor antagonist memantine is licensed for use in moderate to severe AD patients. In this article, the effect of these compounds on resting state eyes-closed electroencephalographic (EEG) rhythms in AD patients is reviewed to form a knowledge platform for the European Innovative Medicine Initiative project "PharmaCog" (IMI Grant Agreement No. 115009) aimed at developing innovative translational models for drug testing in AD. Indeed, quite similar EEG experiments and the same kind of spectral data analysis can be performed in animal models of AD and in elderly individuals with prodromal or manifest AD. Several studies have shown that AChEIs affect both resting state EEG rhythms and cognitive functions in AD patients. After few weeks of successful treatment, delta (0-3 Hz) or theta (4-7 Hz) rhythms decrease, dominant alpha rhythms (8-10 Hz) increase, and cognitive functions slightly improve. Beneficial effects of these rhythms and cognitive functions were also found in AD responders to the long-term successful treatment (i.e. 6-12 months). In contrast, only one study has explored the long-term effects of memantine on EEG rhythms in AD patients, showing reduced theta rhythms. The present review enlightens the expected effects of AChEIs on resting state EEG rhythms in AD patients as promising EEG markers for the development of translational protocols both within the PharmaCog project and for wider use. PMID- 23098645 TI - A new approach to ensuring oral health care for people living with HIV/AIDS: the dental case manager. AB - INTRODUCTION: The American Dental Association has identified several barriers to adequate dental care for vulnerable populations, including appropriate case management. The objective of this study was to examine the perceptions, attitudes, and beliefs of dental patients living with HIV/AIDS on the role and value of the dental case manager (DCM) and the effect of DCM services on their oral or overall health. METHODS: We used a qualitative descriptive study design and focus groups. Twenty-five people who had received DCM services on Cape Cod, Massachusetts, attended 1 of 5 focus groups in 2009 and 2010. Digital recordings of the groups were transcribed verbatim. Textual data were categorized using directed qualitative content analysis techniques. We identified major themes and representative quotes. RESULTS: The following themes emerged from discussions on the DCM's role: being available, knowledgeable about clients and insurance, and empathetic; increasing access; and providing comfort. Most participants credited their oral and overall health improvements to the DCM. All participants believed that the DCM was a valuable addition to the clinic and noted that other at-risk populations, including the elderly and developmentally disabled, likely would benefit from working with a DCM. CONCLUSION: The addition of a DCM facilitated access to dental care among this sample of people living with HIV/AIDS, providing them with an advocate and resulting in self-reported improvements to oral and overall health. PMID- 23098646 TI - Health care reform and women's insurance coverage for breast and cervical cancer screening. AB - INTRODUCTION: The Patient Protection and Affordable Care Act of 2010 (ACA) will increase insurance coverage for US citizens and for breast and cervical cancer screening through insurance expansions and regulatory changes. The primary objective of this study was to estimate the number of low-income women who would gain health insurance after implementation of the ACA and thus be able to obtain cancer screening. A secondary objective was to estimate the size and characteristics of the uninsured low-income population and the number of women who would still need National Breast and Cervical Cancer Early Detection Program (NBCCEDP) services. METHODS: We used the nationally representative 2009 American Community Survey to estimate the determinants of insurance status for women in Massachusetts, assuming full implementation of the ACA. We extrapolated findings to simulate the effects of the ACA on each state. We used individual-level predicted probabilities of being uninsured to generate estimates of the number of women who would gain health insurance after implementation of the ACA and to predict demand for NBCCEDP services. RESULTS: Approximately 6.8 million low income women would gain health insurance, potentially increasing the annual demand for NBCCEDP cancer screenings initially by about 500,000 mammograms and 1.3 million Papanicolaou tests. Despite a 60% decrease in the number of low income uninsured women, the NBCCEDP would still serve fewer than one-third of the estimated number of women eligible for services. The NBCCEDP-eligible population would comprise a larger number of women with language and literacy-related barriers to care. CONCLUSION: Implementation of the ACA would increase insurance coverage and access to cancer screening for millions of women, but the NBCCEDP will remain essential for the millions who will remain uninsured. PMID- 23098647 TI - [Towards a larger outpatient medicine]. PMID- 23098649 TI - Impact of dietary carotenoid deprivation on macular pigment and serum concentrations of lutein and zeaxanthin. PMID- 23098648 TI - Role of the Skp1 prolyl-hydroxylation/glycosylation pathway in oxygen dependent submerged development of Dictyostelium. AB - BACKGROUND: Oxygen sensing is a near universal signaling modality that, in eukaryotes ranging from protists such as Dictyostelium and Toxoplasma to humans, involves a cytoplasmic prolyl 4-hydroxylase that utilizes oxygen and alpha ketoglutarate as potentially rate-limiting substrates. A divergence between the animal and protist mechanisms is the enzymatic target: the animal transcriptional factor subunit hypoxia inducible factor-alpha whose hydroxylation results in its poly-ubiquitination and proteasomal degradation, and the protist E3SCF ubiquitin ligase subunit Skp1 whose hydroxylation might control the stability of other proteins. In Dictyostelium, genetic studies show that hydroxylation of Skp1 by PhyA, and subsequent glycosylation of the hydroxyproline, is required for normal oxygen sensing during multicellular development at an air/water interface. Because it has been difficult to detect an effect of hypoxia on Skp1 hydroxylation itself, the role of Skp1 modification was investigated in a submerged model of Dictyostelium development dependent on atmospheric hyperoxia. RESULTS: In static isotropic conditions beneath 70-100% atmospheric oxygen, amoebae formed radially symmetrical cyst-like aggregates consisting of a core of spores and undifferentiated cells surrounded by a cortex of stalk cells. Analysis of mutants showed that cyst formation was inhibited by high Skp1 levels via a hydroxylation-dependent mechanism, and spore differentiation required core glycosylation of Skp1 by a mechanism that could be bypassed by excess Skp1. Failure of spores to differentiate at lower oxygen correlated qualitatively with reduced Skp1 hydroxylation. CONCLUSION: We propose that, in the physiological range, oxygen or downstream metabolic effectors control the timing of developmental progression via activation of newly synthesized Skp1. PMID- 23098650 TI - Impact of variants within seven candidate genes on statin treatment efficacy. AB - Statins are the most commonly used drugs in patients with dyslipidemia. Among the patients, a significant inter-individual variability with supposed strong genetic background in statin treatment efficacy has been observed. Genome wide screenings detected variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes that are among the candidates potentially modifying response to statins. Ten variants (SNPs) within these genes (rs599838, rs646776, rs16996148, rs693, rs515135, rs4420638, rs12654264, rs6511720, rs6235, rs11206510) were analyzed in 895 (46 % men, average age 60.3+/ 13.1 years) patients with dyslipidemia treated with equipotent doses of statins (~90 % on simvastatin or atorvastatin, doses 10 or 20 mg) and selected 672 normolipidemic controls (40 % men, average age 46.5 years). Lipid parameters were available prior to the treatment and after 12 weeks of therapy. Statin treatment resulted in a significant decrease of both total cholesterol (7.00+/-1.53- >5.15+/-1.17 mmol/l, P<0.0001) and triglycerides (2.03+/-1.01-->1.65+/-1.23 mmol/l, P<0.0005). Rs599838 variant was not detected in first analyzed 284 patients. After adjustment for multiple testing, there was no significant association between individual SNPs and statin treatment efficacy. Only the rs4420638 (APOE/C1/C4 gene cluster) G allele carriers seem to show more profitable change of HDL cholesterol (P=0.007 without and P=0.06 after adjustment). Results demonstrated that, although associated with plasma TC and LDL cholesterol per se, variants within the CELSR2/PSRC1/SORT1, CILP2/PBX4, APOB, APOE/C1/C4, HMGCoA reductase, LDL receptor and PCSK9 genes do not modify therapeutic response to statins. PMID- 23098651 TI - Positive allosteric modulator of mGluR4 PHCCC exhibits proconvulsant action in three models of epileptic seizures in immature rats. AB - The activation of metabotropic glutamate receptors subtype 4 (mGluR4) potentiates models of absence seizures in adult rats. These seizures are age-dependent, but data concerning the role of mGluR4 in immature brain is insufficient. N-phenyl-7 (hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC), which is a positive allosteric modulator of these receptors, was used in three different models of seizures in immature rats: 1) convulsions induced by high doses of pentetrazol (PTZ; a model of generalised tonic-clonic seizures); 2) rhythmic electro encephalographic (EEG) activity induced by low doses of PTZ (a model of absence seizures); and 3) electrically elicited cortical afterdischarges (ADs, a model of myoclonic seizures). We administered four doses of PHCCC (1, 3, 10 and 20 mg/kg) in PTZ-induced convulsions and two doses (3 and 10 mg/kg) in the two electrophysiological models of freely moving rats with implanted electrodes. Every dose and age group consisted from 8 to 10 rats. PTZ-elicited convulsions were not significantly influenced by PHCCC. In contrast, PHCCC potentiated the effect of a subconvulsant dose (60 mg/kg) of PTZ. The 10-mg/kg dose of PHCCC significantly prolonged the duration of PTZ-induced rhythmic activity episodes and shortened the intervals between individual episodes in 25-day-old rats (P25). In contrast, this potentiation was not seen in P18 rats. Cortical ADs were significantly prolonged with repeated stimulations by both doses of PHCCC in P12 and P18 animals. P25 rats exhibited only slightly longer AD durations. In conclusion, we did not find any anticonvulsant effect of PHCCC. On the contrary, proconvulsant action was demonstrated in all three models in immature rats. PMID- 23098652 TI - Bone response to loading in mice with targeted disruption of the cartilage oligomeric matrix protein gene. AB - Exercise induced bone response although established, little is known about the molecular components that mediate bone response to mechanical loading (ML). In our recent QTL study, we identified one such possible molecular component responding to ML: cartilage oligomeric matrix protein (COMP). To address the COMP role in mediating ML effects on bone formation, COMP expression was evaluated as a function of duration and age in response to ML in female B6 mice. A 9N load was applied using a four-point bending device at 2Hz frequency for 36 cycles, once per day for 2-, 4- and 12-days on the right tibia. The left tibia was used as an internal control. Loading caused an increase in COMP expression by 1.3-, 2- and 4 fold respectively after 2-, 4- and 12-days of loading. This increase was also seen in 16 and 36-week old mice. Based on these findings, we next used COMP knockout (KO) mice to evaluate the cause and effect relationship. Quantitative analysis revealed 2 weeks of ML induced changes in vBMD and bone size in the KO mice (5.9 % and 21 % vs. unloaded bones) was not significantly different from control mice (7 % and 24 % vs. unloaded bones). Our results imply that COMP is not a key upstream mediator of the anabolic effects of ML on the skeleton. PMID- 23098654 TI - Induction of microRNA-24 by HIF-1 protects against ischemic injury in rat cardiomyocytes. AB - MicroRNAs are emerging as important regulators of cardiac function. This study investigated the role of microRNA-24 (miR-24) in ischemic cardiomyocytes, based on the observation that miR-24 expression was significantly enhanced in the ischemic myocardium of rats. Using primary cultured rat cardiomyocytes, cell injury was induced by ischemic conditions, and the cells were evaluated for changes in lactate dehydrogenase (LDH) release, cell viability, apoptosis and necrosis. The results showed that miR-24 was increased in myocytes exposed to ischemia. When miR-24 was further overexpressed in ischemic myocytes using the mimic RNA sequence, LDH release was reduced, cell viability was enhanced, and apoptosis and necrosis rates were both decreased. By contrast, a deficiency in miR-24 resulted in the largest LDH release, lowest cell viability and highest apoptosis and necrosis rates in normal and ischemic myocytes, with significant changes compared to that of non-transfected myocytes. Additionally, the mRNA and protein levels of the pro-apoptotic gene, BCL2L11, were down-regulated by miR-24 overexpression and up-regulated by miR-24 deficiency. The luciferase reporter assay confirmed BCL2L11 to be a target of miR-24. Overall, this study showed a protective role for miR-24 against myocardial ischemia by inhibiting BCL2L11, and may represent a potential novel treatment for ischemic heart disease. PMID- 23098653 TI - Fatty acid composition of adipose tissue triglycerides after weight loss and weight maintenance: the DIOGENES study. AB - Fatty acid composition of adipose tissue changes with weight loss. Palmitoleic acid as a possible marker of endogenous lipogenesis or its functions as a lipokine are under debate. Objective was to assess the predictive role of adipose triglycerides fatty acids in weight maintenance in participants of the DIOGENES dietary intervention study. After an 8-week low calorie diet (LCD) subjects with > 8 % weight loss were randomized to 5 ad libitum weight maintenance diets for 6 months: low protein (P)/low glycemic index (GI) (LP/LGI), low P/high GI (LP/HGI), high P/low GI (HP/LGI), high P/high GI (HP/HGI), and a control diet. Fatty acid composition in adipose tissue triglycerides was determined by gas chromatography in 195 subjects before the LCD (baseline), after LCD and weight maintenance. Weight change after the maintenance phase was positively correlated with baseline adipose palmitoleic (16:1n-7), myristoleic (14:1n-5) and trans-palmitoleic acid (16:1n-7t). Negative correlation was found with baseline oleic acid (18:1n-9). Lower baseline monounsaturated fatty acids (14:1n-5, 16:1n-7 and trans 16:1n-7) in adipose tissue triglycerides predict better weight maintenance. Lower oleic acid predicts lower weight decrease. These findings suggest a specific role of monounsaturated fatty acids in weight management and as weight change predictors. PMID- 23098655 TI - Changes in hind paw epidermal thickness, peripheral nerve distribution and mechanical sensitivity after immobilization in rats. AB - This study was designed to investigate histological changes in skin tissue accompanying immobilization-induced hypersensitivity. Changes in mechanical sensitivity, epidermal thickness, and peripheral nerve profiles in the upper dermis were examined in glabrous skin of rat hind paw after 1, 2, and 4 weeks of ankle joint immobilization by plaster casts. Induction of mechanical hypersensitivity was confirmed after 2 and 4 weeks of joint immobilization. Epidermal thinning and increase in peripheral nerve profiles were observed in skin tissues in immobilized rats. The time course of epidermal thinning and increase in peripheral nerve profiles were similar closely to that of hypersensitivity, with significant differences between the immobilized and control rats after 2 weeks of immobilization, which became even more remarkable at 4 weeks of immobilization. These findings suggest that joint immobilization by cast induces epidermal thinning and increases peripheral nerve profiles in the upper dermis and that these changes might be partly responsible for immobilization-induced hypersensitivity. PMID- 23098656 TI - Ontogenetic development of GABA(B)-receptor signaling cascade in plasma membranes isolated from rat brain cortex; the number of GABA(B)-receptors is high already shortly after the birth. AB - Our data indicate the significant intrinsic efficacy of GABA(B)-receptors in rat brain cortex already at birth (PD1, PD2). Subsequently, baclofen- and SKF97541 stimulated G-protein activity, measured by agonist-stimulated, high-affinity [(35)S]GTPgammaS binding assay, was increased; the highest level of both baclofen and SKF97541-stimulated [(35)S]GTPgammaS binding was detected between PD10 and PD15. In older rats, baclofen- and SKF97541-stimulated [(35)S]GTPgammaS binding was continuously decreased so, that the level in adult, 90-days old animals, was not different from that in newborn animals. The potency of G-protein response to baclofen (characterized by EC(50) values) was also high at birth but unchanged by further postnatal development. An individual variance among different agonists was observed in this respect as the potency of SKF97541 response was decreased between the birth and adulthood. Accordingly, the highest plasma membrane density of GABA(B)-R, determined by saturation binding assay with antagonist [(3)H]CGP54626, was measured in 1-day old animals (2.27+/-0.08 pmol . mg(-1)). The further development was reflected in a decrease of [(3)H]CGP54626 binding as the B(max) values of 1.38+/-0.05 and 0.93+/-0.04 pmol . mg(-1) were determined in PM isolated from 13- and 90-days old rats, respectively. PMID- 23098657 TI - Short-term fasting reduces the extent of myocardial infarction and incidence of reperfusion arrhythmias in rats. AB - The effect of three-day fasting on cardiac ischemic tolerance was investigated in adult male Wistar rats. Anesthetized open-chest animals (pentobarbitone 60 mg/kg, i.p.) were subjected to 20-min left anterior descending coronary artery occlusion and 3-h reperfusion for infarct size determination. Ventricular arrhythmias were monitored during ischemia and at the beginning (3 min) of reperfusion. Myocardial concentrations of beta-hydroxybutyrate and acetoacetate were measured to assess mitochondrial redox state. Short-term fasting limited the infarct size (48.5+/ 3.3 % of the area at risk) compared to controls (74.3+/-2.2 %) and reduced the total number of premature ventricular complexes (12.5+/-5.8) compared to controls (194.9+/-21.9) as well as the duration of ventricular tachycardia (0.6+/-0.4 s vs. 18.8+/-2.5 s) occurring at early reperfusion. Additionally, fasting increased the concentration of beta-hydroxybutyrate and beta-hydroxybutyrate/acetoacetate ratio (87.8+/-27.0) compared to controls (7.9+/-1.7), reflecting altered mitochondrial redox state. It is concluded that three-day fasting effectively protected rat hearts against major endpoints of acute I/R injury. Further studies are needed to find out whether these beneficial effects can be linked to altered mitochondrial redox state resulting from increased ketogenesis. PMID- 23098659 TI - Interaction between single nucleotide polymorphism in catalase gene and catalase activity under the conditions of oxidative stress. AB - Catalase is an antioxidant enzyme the activity of which is crucial for the protection against damage caused by reactive oxygen species. The -262C>T polymorphism in the promoter region of catalase gene was found to be associated with altered catalase levels. In this study, peripheral blood mononuclear cells catalase activity was measured after H(2)O(2)-induced oxidative stress. C/T and T/T genotypes were associated with the decrease of catalase levels in contrast to C/C donors who had elevated catalase activity in the presence of 0.4 and 0.7 mM H(2)O(2). Genotype-dependent response of catalase activity to oxidative stress might be related to the predisposition of catalase mutant allele carriers to disorders mediated by oxidative stress. PMID- 23098658 TI - IB-MECA, an adenosine A(3) receptor agonist, does not influence survival of lethally gamma-irradiated mice. AB - In our previous studies, IB-MECA, an adenosine A(3) receptor agonist, was found to stimulate proliferation of hematopoietic progenitor and precursor cells in mice. This property of IB-MECA was considered to be responsible for its ability to support regeneration of suppressed hematopoiesis after irradiation with sublethal doses of gamma-rays when the drug was given in a post-irradiation treatment regimen. This study was aimed at assessing the ability of IB-MECA to influence a 30-day survival of lethally irradiated mice. In a series of experiments, IB-MECA was administered following various lethal radiation doses in various numbers of drug doses and various administration routes. Though in some of these experiments a moderate increase in 30-day survival was observed in IB MECA-treated mice, the differences in comparison with the controls were not significantly different. It can be inferred from these results and those of previous studies assessing the effects of IB-MECA after sublethal radiation doses that IB-MECA can probably influence only a substantially preserved hematopoiesis like that remaining after sublethal irradiation. Future studies should be aimed at evaluation of the abilities of IB-MECA to influence post-irradiation survival when administered as a part of combined treatment regimens. PMID- 23098660 TI - Natural postmenopause is associated with an increase in combined cardiovascular risk factors. AB - Cardiovascular disease, while rare in women of reproductive age, is the main cause of mortality in menopause. The purpose of our study was to determine the association of natural menopause with cardiovascular risk factors, including their clustering into metabolic syndrome (MS). A random 5 % representative population sample of women aged 45-54 years was examined. In 575 women, we were able to determine their natural reproductive aging status. Multiple regression analysis was used to calculate the association between age, menopausal status, and risk factors under study. After adjustment for age, there was an increase in the odds ratio of developing MS, as defined by NCEP (OR=2.0; 95 % CI [1.1; 3.7]), and an increase in plasma lipid ratios (total cholesterol/HDL-C, LDL-C/HDL-C, apolipoprotein-B/apolipoprotein-A1; p<0.05 for all) in postmenopausal women. Age, but not menopausal status, was associated with some single components of MS; only waist circumference significantly increased after menopause, independently of age. Clustering of risk factors in MS and lipid ratios (combined factors) was strongly associated with menopause whereas worsening of single components of MS was strongly associated with age. In conclusion, based on our results, the menopause may pose a risk to women through clustering of cardiovascular risk factors beyond simple aging. PMID- 23098661 TI - Comparison of male and female rats in avoidance of a moving object: more thigmotaxis, hypolocomotion and fear-like reactions in females. AB - Although male rats generally outperform females in many spatial tasks, sometimes gender differences are not present. This preliminary study examined gender effects in the Enemy avoidance task, in which a rat on a stable circular arena avoids approaching a small mobile robot while collecting randomly dispersed small pellets. Whenever distance between robot and the rat dropped below 25 cm, animal was punished by a mild footshock. Female rats showed thigmotaxis, hypolocomotion and avoidance of robot in the habituation phase, when approaches were not punished. No statistically significant differences in avoidance learning under reinforcement training sessions were observed; but females still spent significantly more time at periphery of the arena and foraged less than males. We conclude that females were able to perform at the same level as males under reinforcement despite different behavioral strategy. The thigmotaxic behavior appears to function as innate escape strategy in female rats triggered by the stressing effect of the moving robot rather then the presence of shocks. PMID- 23098662 TI - Expression of the skeletal calsequestrin isoform in normal and regenerated skeletal muscles and in the hearts of rats with altered thyroid status. AB - We have investigated expression of skeletal calsequestrin (CSQ1) and fiber type composition in normal and regenerated fast and slow skeletal muscles and in the left heart ventricles of euthyroid (EU), hypothyroid (HY) and hyperthyroid (TH) adult inbred Lewis strain rats. The CSQ1 level was determined by SDS-PAGE followed by Western blot analysis. CSQ1 gene expression was assessed using reverse transcription and subsequent real time polymerase chain reaction. Muscle regeneration was achieved by intramuscular grafting of either soleus or extensor digitorum longus (EDL) from 3- to 4-week-old rats to either EDL or soleus muscle of 2-month-old rats. The fiber type composition was assessed by a stereological method applied to stained muscle cross sections. We found that the protein and mRNA levels for CSQ1 were highest in the EDL muscle, the relative CSQ1 protein levels in the soleus muscle were two times lower and the transcript levels more than 5 times lower compared to the EDL. In the left heart ventricle, protein isoform and CSQ1 transcript were also present, although at protein level, CSQ1 was hardly detectable. TH status increased and HY status decreased the expression of CSQ1 in the EDL, but its relative levels in the soleus and in the heart did not change. The regenerated soleus transplanted into EDL, as well as EDL transplanted into soleus exhibited protein and mRNA levels of CSQ1 corresponding to the host muscle and not to the graft source. TH status increased the percentages of the fastest 2X/D and 2B fibers at the expense of slow type 1 and fast 2A fibers in the EDL and that of fast 2A fibers in the soleus at the expense of slow type 1 fibers. HY status led to converse fiber type changes. We suggest that the observed changes in CSQ1 levels in TH and HY compared to EU rats can be related to fiber type changes caused by alteration of the thyroid status rather than to the direct effect of thyroid hormones on CSQ1 gene expression. PMID- 23098663 TI - Effect of resin-modified glass ionomer containing bioactive glass on the flexural strength and morphology of demineralized dentin. AB - INTRODUCTION: Recently, bioactive materials have been incorporated into glass ionomer cements to promote the precipitation of calcium phosphates in surrounding tooth structures. This in vitro study was undertaken to evaluate the effect of resin-modified glass ionomer (RMGI) containing bioactive glass (RMGI-BAG) on the flexural strength (FS) of demineralized dentin. MATERIALS AND METHODS: A total of 120 dentin bars (2*2*6 mm) were prepared from sound human third molars. Of these, 60 bars were immersed in a demineralizing solution for 96 hours. This produced dentin in two demineralization conditions (DC): untreated and demineralized. Each dentin bar was immersed for 14 days in simulated body fluid (SBF) at 37 degrees C. Three immersion conditions (IC) were investigated: IC1-SBF only; IC2-SBF + an RMGI bar; IC3-SBF + an RMGI-BAG bar. The combination of the DCs and ICs produced six groups (n=20). FS values of the specimens were measured using a three-point bending test. The microstructural changes and the elemental contents of dentin surfaces were evaluated by scanning electron microscopy. Data were analyzed using a two-way analysis of variance (ANOVA) for the effects of the two independent variables, ie, DC and IC, on mean flexural strength. Tukey multiple comparison tests and simple main effects models were used as needed. The significance level of all tests was set at alpha=0.05. RESULTS: Both DC (p=0.001) and IC (p=0.049) significantly influenced FS (two-way ANOVA). The interaction between DC and IC did not significantly affect FS (p=0.36). For undemineralized dentin, IC did not affect the mean FS (simple main effects model; p=0.4). However, for demineralized dentin, IC significantly affected FS (small main effects model; p=0.008). The Tukey test showed that for demineralized dentin, the mean FS produced by immersion in SBF + RMGI-BAG was significantly stronger than that produced by either immersion in SBF only (p=0.011) or in SBF + RMGI (p=0.034). Scanning electron microscope/energy-dispersive x-ray spectroscopy analyses revealed more calcium and phosphate ions on the surface of dentin immersed in SBF + RMGI-BAG than on dentin immersed in SBF + RMGI. CONCLUSION: Immersion in SBF + RMGI-BAG increased the FS of demineralized dentin more than immersion in SBF + RMGI. PMID- 23098664 TI - Multiorgan failure in a patient treated with the 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan regimen. PMID- 23098665 TI - Temporal changes in serum IgG4 levels after coronary artery bypass graft surgery. PMID- 23098666 TI - Adverse outcomes in twin pregnancies complicated by early vaginal bleeding. AB - OBJECTIVE: We sought to estimate the risks of adverse pregnancy outcomes associated with early vaginal bleeding in twin pregnancies. STUDY DESIGN: In a retrospective cohort study of consecutive twin pregnancies undergoing anatomic survey, we compared women who reported vaginal bleeding at <22 weeks to those who did not. Exclusion criteria included monoamniotic pregnancies, twin-to-twin transfusion syndrome, and placenta previa. Primary outcomes included preeclampsia, abruption, preterm premature rupture of membranes (PPROM), preterm birth <34 weeks, and intrauterine growth restriction. RESULTS: Of 2106 pregnancies meeting inclusion criteria, 175 reported vaginal bleeding. Twin pregnancies with early vaginal bleeding had significantly higher risks of abruption, PPROM, and preterm birth compared to twin pregnancies without bleeding. The findings were similar when twin pairs were stratified by parity or maternal comorbidities. CONCLUSION: Twin pregnancies complicated by vaginal bleeding in early pregnancy have an increased risk of abruption, PPROM, and preterm birth <34 weeks. PMID- 23098667 TI - Comparison of Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 2.0 (CAP/CTM v2.0) with other real-time PCR assays in HIV-1 monitoring and follow-up of low level viral loads. AB - Viral load monitoring of HIV-1 has become standard of care in HIV-1 positive patients. In this study, we evaluated the performance characteristics of the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 2.0 (CAP/CTM v2.0) in comparison with Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 test version 1.0 (CAP/CTM v1.0) and Abbott RealTime HIV-1 assay (m2000), with special emphasis on the quantitation of clinically controversial low-level viral loads. The performance characteristics of CAP/CTM v2.0 were confirmed by the validation study. All three assays performed comparably, with Abbott m2000 showing slightly decreased sensitivity for detection of viral loads close to the lower limit of quantitation. Follow-up of patients with low-level viral loads revealed that some of those represent single viral blips; however, a significant portion of these patients have intermittent or persistent low-positive viremia. We conclude that CAP/CTM v2.0 is an accurate and reliable assay for HIV-1 viral load monitoring. PMID- 23098668 TI - Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice. AB - The protozoan parasite Toxoplasma gondii has the ability to alter intermediate host behavior, most impressively the natural aversion to cat scent, to favor the predation by the definitive host. However, the underlying mechanism of the observed phenomenon still remains unknown. Since changes in the neurotransmitter level are postulated as a possible contributing factor, the aim of this work was to assess the monoamine systems activity in specified brain regions involved in the natural defense behaviors, emotion evaluation, and motor and sensory stimuli integration in experimentally T. gondii infected mice compared to uninfected controls. Taking into account the natural differences between genders, the experiments were carried out on both male and female mice. Our results revealed statistically significant changes in all tested monoamine systems with regard to both gender and time after T. gondii invasion. Acute toxoplasmosis was accompanied by a decrease in noradrenergic system activity in females and its slight increase in some brain areas of males. Acute invasion also induced a rise in serotonin system activity, mostly in males. The most striking observation was an increase in the dopamine release noted in acutely infected males. We discuss our results in terms of their possible contribution to T. gondii-induced intermediate host behavior alterations and parasite transmission and with regard to postulated relationship between T. gondii seroprevalence and occurrence of certain disorders such as schizophrenia in humans. PMID- 23098669 TI - Functional consequences of work-related spinal musculoskeletal symptoms in a cohort of Australian midwives. AB - BACKGROUND: Early evidence suggests spinal musculoskeletal symptoms are as prevalent in Australian midwives as in samples of nurses. Functional consequences of these symptoms include sick leave and functional incapacity, which are costly at both individual and workplace levels. To date there have been no studies of these consequences in midwives. QUESTION: What risk factors are associated with sick leave and functional incapacity among midwives with spinal musculoskeletal symptoms? METHODS: We undertook a cross-sectional study of qualified Australian midwives who completed the baseline survey of the Nurses and Midwives e-Cohort Study. A comprehensive set of independent variables were examined for bivariate associations with the main outcomes of sick leave and functional incapacity due to work-related musculoskeletal symptoms in the neck, upper or lower back. Associations that achieved a p value<.1 were entered into multiple logistic regression models. FINDINGS: 729 midwives with a mean age of 46 years were eligible for inclusion. Functional incapacity was more than twice as common as sick leave. Severity of worst pain was the explanatory variable most strongly associated with each main outcome and the only one significant for both. Psychological job demands showed a significant association with sick leave, while several individual factors were associated with both outcomes. Only the association of poorer general health with functional incapacity remained significant in all three spinal regions. CONCLUSION: Our sample reported considerable work-related musculoskeletal pain and functional incapacity. Factors associated with sick leave and functional incapacity in midwives should be confirmed by longitudinal studies with the aim of developing tertiary prevention strategies. PMID- 23098670 TI - Functional expression of the damage-associated molecular pattern receptor P2X7 on canine kidney epithelial cells. AB - Epithelial cells are important in inflammation and immunity. In this study, we examined if Madin-Darby canine kidney (MDCK) epithelial cells express functional P2X7 receptors, which bind the damage-associated molecular pattern extracellular adenosine 5'-triphosphate (ATP). Reverse transcription (RT)-PCR and immunoblotting revealed the expression of P2X7 in MDCK cells. A flow cytometric assay demonstrated that ATP or 2'(3')-O-(4-benzoylbenzoyl)ATP induced ethidium(+) uptake into MDCK cells, and that this process was impaired by the P2X7 antagonists KN-62 and A438079. RT-PCR also demonstrated the presence of Toll-like receptor 4, NALP3, caspase-1, interleukin-1beta and interleukin-18 in MDCK cells, as well as in positive control LPS-primed canine monocytes. In conclusion, the MDCK epithelial cell line expresses functional P2X7, as well as Toll-like receptor 4 and molecules associated with the NALP3 inflammasome. This cell line may help elucidate the role of these molecules in kidney epithelial cells and renal disorders in dogs and humans. PMID- 23098671 TI - C57-CD40 ligand deficient mice: a potential model for enterotoxigenic Escherichia coli (H10407) colonization. AB - Enterotoxigenic Escherichia coli (ETEC) are a major cause of diarrheal disease in humans, calves and pigs. In humans, these infections mainly occur in developing countries leading to a high diarrheal morbidity and infant mortality and to travellers' diarrhea. ETEC strains constitute a phenotypically and genetically diverse pathotype with as common characteristics the production of heat-labile (LT) and/or heat-stable enterotoxins (ST) as well as of one or more fimbrial colonization factors. Despite the global importance of these pathogens, a broadly ETEC protective vaccine is not yet available, partially due to the lack of a suitable animal model for human ETEC. Such model would allow to test more ETEC molecules as potential vaccine candidates. The C57-CD40 ligand deficient (C57 cd40l(-/-)) mouse has been successfully used to develop infection models of intestinal pathogens, but little is known about its humoral immune response. Therefore, the aims of this study were to characterize the humoral immune response of C57 and C57-cd40l(-/-) mice and to determine the persistence of ETEC H10407 and two of its variants after oral inoculation. The serum IgM, IgG and IgA and faecal IgG and IgA concentrations, of twelve mice per mouse strain (C57 and C57-cd40l(-/-)), were determined by ELISA. All serum immunoglobulins and the faecal IgG concentration were significantly lower in C57-cd40l(-/-) than in C57 mice. In contrast the faecal IgA concentration was significantly higher in the C57-cd40l(-/-) mice. This high intestinal IgA concentration might be a compensatory T cell-independent production of IgA production. Both mouse strains were orally inoculated with 5*10(8) ETEC H10407 (LT(+), ST-colonization factor antigen I (CFA/I)(+)) and ETEC in animal faeces was established by culture followed by st and lt loci identification by PCR until day 14 post infection. Most C57 mice eliminated the strain within 3 days whereas infection remained in C57-cd40l(-/-) mice until day 14. Subsequently both mouse strains were inoculated with ETEC H10407 variants and followed up until day 113. Likewise C57 mice eliminated both ETEC variants within 4 days. All C57-cd40l(-/-) mice had eliminated the LT(-) variant at day 31, whereas the ST-CFA/I(-) variant remained in mice stools until day 113. These observations suggest that C57-cd40l(-/-) mice are permissive for ETEC H10407 colonization. PMID- 23098673 TI - Taking care of the caregiver. PMID- 23098672 TI - Augmentation of exposure therapy with post-session administration of D cycloserine. AB - BACKGROUND: Pre-session administration of d-cycloserine (DCS) has been found to augment exposure therapy outcomes in a variety of anxiety disorders. To be able to enhance learning only for successful exposure sessions, it would be beneficial to have the option of administering DCS after rather than before the session, a strategy encouraged by pre-clinical work. We believe the present study is the first published report on the efficacy of post-session administration of DCS in humans. METHOD: Adults (N = 29) with a DSM-IV diagnosis of acrophobia were randomized to receive two sessions of virtual reality exposure therapy (VRE) in combination with placebo or 50 mg of DCS. Instead of administering the pill prior to each of the sessions, as has been done in extant work, we administered the pill immediately following each session. Measures of acrophobia severity were collected at baseline, at each treatment session, 1-week post-treatment, and at 1 month follow-up. RESULTS: Mixed-effects repeated-measures ANOVAs and GLMMs revealed significant improvement in all outcome measures over time, but no between-group differences were observed. At post-treatment, 63.5% of patients in the placebo condition vs. 60.0% of those in the DCS condition were in remission. At 1-month follow up, 63.4% of those in the placebo condition vs. 66.6% of those in the DCS condition were in remission. CONCLUSIONS: These findings do not support the application of post-session DCS administration for augmenting the efficacy of exposure-based treatments. Possible reasons for these findings are discussed. TRIAL REGISTRY: The Trial is registered at ClinicalTrials.gov (NCT01102803). PMID- 23098674 TI - Self-management education approach: engaging patients in creating a personal and relevant action plan (part 1) I keep telling patients what to do, so why don't they make progress? PMID- 23098675 TI - The cycling and sea-air exchange of mercury in the waters of the Eastern Mediterranean during the 2010 MED-OCEANOR cruise campaign. AB - An oceanographic cruise campaign on-board the Italian research vessel Urania was carried out from the 26th of August to the 13th of September 2010 in the Eastern Mediterranean. The campaign sought to investigate the mercury cycle at coastal and offshore locations in different weather conditions. The experimental activity focused on measuring mercury speciation in both seawater and in air, and using meteorological parameters to estimate elemental mercury exchange at the sea atmosphere interface. Dissolved gaseous mercury (DGM), unfiltered total mercury (UTHg) and filtered total mercury (FTHg) surface concentrations ranged from 16 to 114, 300 to 18,760, and 230 to 10,990pgL(-1), respectively. The highest DGM, UTHg and FTHg values were observed close to Augusta (Sicily), a highly industrialized area of the Mediterranean region, while the lowest values were recorded at offshore stations. DGM vertical profiles partially followed the distribution of sunlight, as a result of the photoinduced transformations of elemental mercury in the surface layers of the water column. However, at some stations, we observed higher DGM concentrations in samples taken from the bottom of the water column, suggesting biological mercury production processes or the presence of tectonic activity. Moreover, two days of continuous measurement at one location demonstrated that surface DGM concentration is affected by solar radiation and atmospheric turbulence intensity. Atmospheric measurements of gaseous elemental mercury (GEM) showed an average concentration (1.6ngm(-3)) close to the background level for the northern hemisphere. For the first time this study used a numerical scheme based on a two-thin film model with a specific parameterization for mercury to estimate elemental mercury flux. The calculated average mercury flux during the entire cruise was 2.2+/-1.5ngm(-2)h(-1). The analysis of flux data highlights the importance of the wind speed on the mercury evasion from sea surfaces. PMID- 23098676 TI - Rodent models of polycystic ovary syndrome. AB - Rodents are clearly valuable models for assessing disruption of fertility. The effects of different steroid treatments at different stages of reproductive life through from fetal to adult have been assessed for effects on fertility, ovarian morphology, hypothalamic-pituitary function or metabolic consequences. The results show that steroid treatments do disrupt fertility in many cases, but the underlying mechanisms are complicated by the effects of the different treatments at multiple sites. As models for PCOS at the ovarian level however, there are a number of problems particularly related to the fact that rodents are multi-ovular species. Apart from an absence of ovulation and corpora lutea, many of the different steroid regimes result in an increase in large atretic, or cystic follicles that do not parallel PCOS in women. Indeed a number of treatments are given at times when they will cause disruption of the positive feedback effects of estradiol, thus blocking ovulation in adult life. The resulting ovarian morphology thus appears to be like that of PCOS but is in fact not a clear mimic. This review of the various studies highlights parallels and problems with the use of rodents to study the mechanisms underlying the development of PCOS in women. PMID- 23098677 TI - The role of the insulin-like growth factor-I receptor in malignancy: an update. AB - In the past three decades, evidence has been accumulating that the IGF-I receptor/ligand system plays an important role in malignant disease. This has led to a search for specific inhibitors of the IGF receptor for cancer therapy, revealing some predictable, but also unexpected challenges. Here we review recent data that highlight the essential role of the IGF axis in several important steps in cancer cell progression and metastasis and highlight cellular processes that have been the focus of much interest and new insight in recent years. Strategies used to target the IGF axis clinically are summarized and the obstacles encountered are discussed. PMID- 23098678 TI - Abuse liability and reinforcing efficacy of oral tramadol in humans. AB - BACKGROUND: Tramadol, a monoaminergic reuptake inhibitor, is hepatically metabolized to an opioid agonist (M1). This atypical analgesic is generally considered to have limited abuse liability. Recent reports of its abuse have increased in the U.S., leading to more stringent regulation in some states, but not nationally. The purpose of this study was to examine the relative abuse liability and reinforcing efficacy of tramadol in comparison to a high (oxycodone) and low efficacy (codeine) opioid agonist. METHODS: Nine healthy, non dependent prescription opioid abusers (6 male and 3 female) participated in this within-subject, randomized, double blind, placebo-controlled study. Participants completed 14 paired sessions (7 sample and 7 self-administration). During each sample session, an oral dose of tramadol (200 and 400 mg), oxycodone (20 and 40 mg), codeine (100 and 200 mg) or placebo was administered, and a full array of abuse liability measures was collected. During self-administration sessions, volunteers were given the opportunity to work (via progressive ratio) for the sample dose or money. RESULTS: All active doses were self-administered; placebo engendered no responding. The high doses of tramadol and oxycodone were readily self-administered (70%, 59% of available drug, respectively); lower doses and both codeine doses maintained intermediate levels of drug taking. All three drugs dose-dependently increased measures indicative of abuse liability, relative to placebo; however, the magnitude and time course of these and other pharmacodynamic effects varied qualitatively across drugs. CONCLUSIONS: This study demonstrates that, like other mu opioids, higher doses of tramadol function as reinforcers in opioid abusers, providing new empirical data for regulatory evaluation. PMID- 23098679 TI - Implicit and explicit reward learning in chronic nicotine use. AB - BACKGROUND: Chronic tobacco use is related to specific neurobiological alterations in the dopaminergic brain reward system that can be termed "reward deficiency syndrome" in dependent nicotine consumers. The close linkage of dopaminergic activity and reward learning led us to expect implicit and explicit reward learning deficits in dependent compared to non-smokers. Smokers who maintain a less regular, occasional use may also, to a lesser extent, show implicit reward learning deficits. The purpose of our study was to examine the behavioral effects of the neurobiological alterations on reward related learning. We also tested whether any deficits observed in an abstinent state are also present in a satiated state. METHODS: In two studies, we examined implicit and explicit reward learning in smokers. Participants were administered a probabilistic implicit reward learning task, and an explicit reward- and punishment-based trial-and-error learning task. In Study 1, we compared dependent, occasional, and non-smokers, and in Study 2 satiated and abstinent smokers. RESULTS: In Study 1, chronic and occasional smokers showed impairments in both, implicit and explicit reward learning tasks. In Study 2, satiated smokers did not perform better than abstinent smokers. CONCLUSIONS: The results support the hypothesis of reward learning deficits. These deficits are not limited to explicit but extend to implicit reward learning and cannot be explained by tobacco withdrawal. PMID- 23098680 TI - The use of MElatonin in children with neurodevelopmental disorders and impaired sleep: a randomised, double-blind, placebo-controlled, parallel study (MENDS). AB - BACKGROUND: Difficulties in initiating and maintaining sleep are common in children with neurodevelopmental disorders. Melatonin is unlicensed in children yet widely prescribed for sleep problems. OBJECTIVE: To determine whether or not immediate-release melatonin is beneficial compared with placebo in improving total duration of night-time sleep in children with neurodevelopmental problems. DESIGN: Randomised, double-blind, placebo-controlled, parallel study. SETTING: Hospitals throughout England and Wales recruited patients referred by community paediatricians and other clinical colleagues. PARTICIPANTS: Children with neurodevelopmental problems aged from 3 years to 15 years 8 months who did not fall asleep within 1 hour of lights out or who had < 6 hours of continuous sleep. Before randomisation, patients meeting eligibility criteria entered a 4- to 6 week behaviour therapy period in which a behaviour therapy advice booklet was provided. Sleep was measured using sleep diaries and actigraphy. After this period the sleep diaries were reviewed to determine if the sleep problem fulfilled the eligibility criteria. Eligible participants were randomised and followed for 12 weeks. INTERVENTIONS: Melatonin or placebo capsules in doses of 0.5 mg, 2 mg, 6 mg and 12 mg for a period of 12 weeks. The starting dose was 0.5 mg and the dose could be escalated through 2 mg and 6 mg to 12 mg during the first 4 weeks, at the end of which the child was maintained on that dose. MAIN OUTCOME MEASURES: The primary outcome was total night-time sleep time (TST) calculated using sleep diaries at 12 weeks compared with baseline. Secondary outcome measures included TST calculated using actigraphy data, sleep-onset latency (SOL) (time taken to fall asleep), sleep efficiency, Composite Sleep Disturbance Index score, global measure of child's sleep quality, Aberrant Behaviour Checklist, Family Impact Module of the Pediatric Quality of Life Inventory (PedsQLTM), the Epworth Sleepiness Scale, number and severity of seizures and adverse events. Salivary melatonin concentrations and association of genetic variants with abnormal melatonin production were also investigated. RESULTS: A total of 275 children were screened to enter the trial; 263 (96%) children were registered and completed the 4- to 6-week behaviour therapy period and 146 (56%) children were randomised, of whom 110 (75%) contributed data for the primary outcome. The difference in TST time between the melatonin and placebo groups adjusted for baseline was 22.43 minutes [95% confidence interval (CI) 0.52 to 44.34 minutes; p = 0.04] measured using sleep diaries. A reduction in SOL, adjusted for baseline, was seen for melatonin compared with placebo when measured by sleep diaries (-37.49 minutes, 95% CI -55.27 to -19.71 minutes; p < 0.0001) and actigraphy (-45.34 minutes, 95% CI -68.75 to -21.93 minutes; p = 0.0003). There were no significant differences between the two groups in terms of the reporting of adverse events. The results of other secondary outcomes favoured melatonin but were not statistically significant. CONCLUSIONS: On average, the children treated with melatonin slept 23 minutes longer than those in the placebo group; however, the upper limit of the confidence interval was less than 1 hour, the minimum clinically worthwhile difference specified at the outset of the trial. Melatonin is effective in reducing SOL in children with neurodevelopmental delay by a mean of 45 minutes; a value of 30 minutes was specified a priori to be clinically important. Future studies should be conducted over longer periods and directly compare different formulations of melatonin with conventional hypnotic and sedative medications. It would also be important to study groups of children with specific neurological disorders. TRIAL REGISTRATION: Current Controlled Trials ISRCTN05534585. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 16, No. 40. See the HTA programme website for further project information. PMID- 23098681 TI - Enhancing toxic protein expression in Escherichia coli fed-batch culture using kinetic parameters: Human granulocyte-macrophage colony-stimulating factor as a model system. AB - The kinetics of recombinant human granulocyte-macrophage colony-stimulating factor (hGM-CSF) expression was studied under the strong T7 promoter in continuous culture of Escherichia coli using complex medium to design an optimum feeding strategy for high cell density cultivation. Continuous culture studies were done at different dilution rates and the growth and product formation profiles were monitored post-induction. Recombinant protein expression was in the form of inclusion bodies with a maximum specific product formation rate (q(p)) of 63.5 mg g(-1) DCW h(-1) at a dilution rate (D) of 0.3 h(-1). The maximum volumetric product concentration achieved at this dilution rate was 474 mg l(-1), which translated a ~1.4 and ~1.75 folds increase than the values obtained at dilution rates of 0.2 h(-1) and 0.4 h(-1) respectively. The specific product yield (Y(P/x)) peaked at 138 mg g(-1) DCW, demonstrating a ~1.6 folds increase in the values obtained at other dilution rates. A drop in q(p) was observed within 5 6 h of induction at all the dilution rates, possibly due to protein toxicity and metabolic stress associated with protein expression. The data from the continuous culture studies allowed us to design an optimal feeding strategy and induction time in fed-batch cultures which resulted in a maximum product concentration of 3.95 g l(-1) with a specific hGM-CSF yield (Y(P/x)) of 107 mg g(-1) DCW. PMID- 23098682 TI - Current limitations about the cleaning of luminal endoscopes. AB - BACKGROUND: The presence and potential build-up of patient material such as proteins in endoscope lumens can have significant implications, including toxic reactions, device damage, inadequate disinfection/sterilization, increased risk of biofilm development and potential transmission of pathogens. AIM: To evaluate potential protein deposition and removal in the channels of flexible luminal endoscopes during a simple contamination/cleaning cycle. METHODS: The level of contamination present on disposable endoscopy forceps which come into contact with the lumen of biopsy channels was evaluated. Following observations in endoscopy units, factors influencing protein adsorption inside luminal endoscope channels and the action of current initial cleaning techniques were evaluated using a proteinaceous test soil and very sensitive fluorescence epimicroscopy. FINDINGS: Disposable endoscope accessories appear to be likely to contribute to the contamination of lumens, and were useful indicators of the amount of proteinaceous soil transiting through the channels of luminal endoscopes. Enzymatic cleaning according to the manufacturer's recommendations and brushing of the channels were ineffective at removing all proteinaceous residues from new endoscope channels after a single contamination. Rinsing immediately after contamination only led to a slight improvement in decontamination outcome. CONCLUSION: Limited action of current decontamination procedures and the lack of applicable quality control methods to assess the cleanliness of channels between patients contribute to increasing the risk of cross-infection of potentially harmful micro-organisms and molecules during endoscopy procedures. PMID- 23098683 TI - Cost-effectiveness of supplementing a broth-enriched culture test with the Xpert meticillin-resistant Staphylococcus aureus (MRSA) assay for screening inpatients at high risk of MRSA. AB - BACKGROUND: Meticillin-resistant Staphylococcus aureus (MRSA) represents a considerable challenge for health care in terms of complications and costs. Whilst bacteriological culture remains the most common method for detecting MRSA, the polymerase-chain-reaction-based Xpert MRSA assay was introduced to Ulleval Oslo University Hospital, Norway in 2009. AIM: To estimate the cost-effectiveness of supplementing a broth-enriched culture test with the Xpert MRSA assay in comparison with using the culture test alone as part of an active surveillance strategy. METHODS: A decision-tree model was developed to compare the current strategy (broth-enriched culture test) with two new strategies using the Xpert MRSA assay (daytime and 24 h). Costs and outcomes (length of pre-emptive isolation, number of unavailable room-hours, quality of life) were measured. FINDINGS: The current strategy was more expensive (NOK16,984 per patient) than the daytime Xpert strategy and 24 h Xpert strategy (NOK7360 and NOK3690 per patient, respectively). The new strategies reduced the length of pre-emptive isolation per patient (by 43.9 h and 57.5 h for the daytime Xpert strategy and 24 h Xpert strategy, respectively), and also the number of unavailable room-hours per case (by 57.1 h and 77.7 h, respectively). The improvement in patients' quality-adjusted life years (QALYs) was nominal (2.4*10(-4) and 3.0*10(-4) QALYs per patient for the daytime Xpert strategy and 24 h Xpert strategy, respectively). The sensitivity analyses indicated that these results were robust to reasonable changes in the model parameters. CONCLUSIONS: The 24 h Xpert strategy appears to be the best strategy for active surveillance as it reduces costs and unfavourable outcomes compared with the other strategies, while improving favourable outcomes under reasonable assumptions. PMID- 23098685 TI - Inhaler competence in asthma: common errors, barriers to use and recommended solutions. AB - Whilst the inhaled route is the first line administration method in the management of asthma, it is well documented that patients can have problems adopting the correct inhaler technique and thus receiving adequate medication. This applies equally to metered dose inhalers and dry powder inhalers and leads to poor disease control and increased healthcare costs. Reviews have highlighted these problems and the recent European Consensus Statement developed a call to action to seek solutions. This review takes forward the challenge of inhaler competence by highlighting the issues and suggesting potential solutions to these problems. The opportunity for technological innovation and educational interventions to reduce errors is highlighted, as well as the specific challenges faced by children. This review is intended as a policy document, as most issues faced by patients have not changed for half a century, and this situation should not be allowed to continue any longer. Future direction with respect to research, policy needs and practice, together with education requirements in inhaler technique are described. PMID- 23098684 TI - Prospective of colon cancer treatments and scope for combinatorial approach to enhanced cancer cell apoptosis. AB - Colorectal cancer is the leading cause of cancer-related mortality in the western world. It is also the third most common cancer diagnosed in both men and women in the United States with a recent estimate for new cases of colorectal cancer in the year 2012 being around 103,170. Various risk factors for colorectal cancer include life-style, diet, age, personal and family history, and racial and ethnic background. While a few cancers are certainly preventable but this does not hold true for colon cancer as it is often detected in its advanced stage and generally not diagnosed until symptoms become apparent. Despite the fact that several options are available for treating this cancer through surgery, chemotherapy, radiation therapy, immunotherapy, and nutritional-supplement therapy, but the success rates are not very encouraging when used alone where secondary complications appear in almost all these therapies. To maximize the therapeutic effects in patients, combinatorial approaches are essential. In this review we have discussed the therapies previously and currently available to patients diagnosed with colorectal-cancer, focus on some recent developments in basic research that has shaded lights on new therapeutic-concepts utilizing macrophages/dendritic cells, natural killer cells, gene delivery, siRNA-, and microRNA-technology, and specific-targeting of tyrosine kinases that are either mutated or over-expressed in the cancerous cell to treat these cancer. Potential strategies are discussed where these concepts could be applied to the existing therapies under a comprehensive approach to enhance the therapeutic effects. PMID- 23098686 TI - Local and systemic effects of inhaled AZD9164 compared with tiotropium in patients with COPD. AB - There is still a need for new agents which improve upon the therapeutic index of tiotropium, the current standard of care for many patients with chronic obstructive pulmonary disease (COPD). We examined in patients with COPD the efficacy of single doses of AZD9164, an M(3)-selective muscarinic antagonist, to identify an appropriate dose-range for future studies. COPD patients (n = 28) inhaled AZD9164 (100, 400 and 1200 MUg), tiotropium (18 MUg) and placebo at 5 study centre visits (Clinicaltrials.gov identifier NCT00939211). The effects of these test drugs on average (E(av)), peak (E(max)) and trough (E(22-26)) forced expiratory volume in one second (FEV(1)) were assessed, as were systemically mediated effects and the safety and exposure of single doses of AZD9164. AZD9164 100, 400 and 1200 MUg caused increases in FEV(1) to peak effects of 12, 17 and 12% above baseline respectively, following an initial transient and dose-related fall in FEV(1) and associated increase in mild respiratory symptoms such as cough. Bronchodilation was maintained overnight, with minimal FEV(1) decline. AZD9164 400 and 1200 MUg produced larger effects than tiotropium on E(22-26) (p < 0.05; both doses) while AZD9164 400 MUg also had larger effects on E(max) (p = 0.001) and E(av) (p < 0.05). There were no serious adverse events and statistically significant systemic effects were observed only with AZD9164 1200 MUg. AZD9164 may improve upon the therapeutic index of tiotropium, increasing the magnitude and duration of lung function improvements without increasing systemically-mediated adverse events. The initial bronchoconstrictor effect of AZD9164 requires further investigation. PMID- 23098687 TI - Impact of comorbidities on COPD-specific health-related quality of life. AB - BACKGROUND: Comorbidities are frequent in subjects with COPD, but their contribution to health-related quality of life (HRQoL) impairment is not clearly established. METHODS: Cross-sectional analysis of data from the French COPD cohort Initiatives BPCO. Data were recorded in stable state and included spirometry, dyspnea (modified Medical Research Council - mMRC-scale), mood disorders (hospital anxiety-depression scale) and physician-diagnosed comorbidities including diabetes, hypertension, coronary artery disease, chronic heart failure, venous thromboembolism. HRQoL was assessed using the disease specific St. George's Respiratory Questionnaire (SGRQ). Stepwise forward and backward multiple regression analyses were performed to examine the contribution of comorbidities to SGRQ scores. RESULTS: Data are median [IQR]. 326 COPD subjects were analyzed: male 77%, age 65.0 [57.0; 72.0] years, FEV(1) 48.9 [34.7; 65.9]% predicted. SGRQ total score was 44.2 [30.0; 61.2]. In univariate analysis, positive correlations were found between SGRQ total scores and dyspnea and exacerbations/patient/year, whereas negative correlations were found with FEV(1). SGRQ total scores were increased in women (P = 0.06), and in subjects with low BMI, anxiety or depression (each analysis, P < 0.001), but not in subjects with cardiovascular comorbidities or diabetes. In multivariate analyses, major independent determinants of SGRQ total score included dyspnea, exacerbations/patient/year and depression. Low BMI, coronary artery disease and FEV(1) were also independently associated with SGRQ total score, but their contribution was only modest. CONCLUSIONS: These data suggest that in the presence of dyspnea and exacerbation, depression is the most important contributor to HRQoL impairment measured by SGRQ in COPD subjects, whereas other comorbidities and FEV(1) have only limited impact. PMID- 23098690 TI - 1alpha,25-Dihydroxyvitamin D3 and its analogs as modulators of human dendritic cells: a comparison dose-titration study. AB - The biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), presents pronounced immunomodulatory effects, mainly mediated through its actions on different immune cells such as dendritic cells (DC) and T lymphocytes. Because of the high concentrations needed to obtain immune effects, a major limitation in using 1alpha,25(OH)2D3 in clinical immune therapy is its calcemic side effects. TX527 (19-nor-14,20-bis-epi-23-yne-1alpha,25(OH)2D3) is a structural 1alpha,25(OH)2D3 analog showing reduced calcemic activity with maintained immunomodulatory effects in vitro and in vivo. The aim of the present study was to establish the relative potency of TX527 versus the parent molecule as an immunomodulator in vitro. In this regard, we evaluated the morphology, surface marker expression and reactive oxygen species (ROS) production in in vitro-generated human DCs treated with TX527 or 1alpha,25(OH)2D3 at different concentrations. Human CD14(+) monocytes were differentiated toward immature DCs, in the presence or absence of 1alpha,25(OH)2D3 or TX527 in a dose range from 10( 7)M to 10(-10)M. Mature DCs (mDC) were obtained after exposure of cells to LPS/interferon (IFN) gamma or cluster of differentiation (CD) 40 ligand (L). Both compounds potently inhibited down-regulation of the monocytic marker CD14 in mDCs. Interestingly, CD80 and HLA-DR were down-regulated after TX527 treatment, whereas this effect was lost when using 1alpha,25(OH)2D3 at the lowest concentration (10(-10)M). ROS production was especially induced in TX527-treated DCs, without any adverse effects on cell survival. Finally, this altered DC surface phenotype was accompanied by typical morphological features, with control cells forming large clusters of non-adherent cells, whereas TX527 and, to a lesser extent, 1alpha,25(OH)2D3-modulated cells yielding small clusters of mostly adherent spindle-shaped cells. This more pronounced immune potential in vitro combined with the previously shown decreased side effects on calcium and bone metabolism, makes TX527 a promising 1alpha,25(OH)2D3 analog for in vivo applications in autoimmune diseases and transplantation. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23098688 TI - Ocular aldehyde dehydrogenases: protection against ultraviolet damage and maintenance of transparency for vision. AB - Aldehyde dehydrogenase (ALDH) enzymes catalyze the NAD(P)(+)-dependent oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding acids. Some members of the ALDH superfamily of enzymes are abundantly expressed in the mammalian cornea and lens in a taxon-specific manner. Considered to be corneal and lens crystallins, they confer protective and transparent properties upon these ocular tissues. ALDH3A1 is highly expressed in the cornea of most mammals, with the exception of rabbit that expresses exclusively ALDH1A1 in the cornea. ALDH1A1 is present in both the cornea and lens of several animal species. As a result of their catalytic and non-catalytic functions, ALDH3A1 and ALDH1A1 proteins protect inner ocular tissues from ultraviolet radiation and reactive oxygen-induced damage. In addition, these corneal crystallins contribute to cellular transparency in corneal stromal keratocytes, supporting a structural role of these ALDH proteins. A putative regulatory function of ALDH3A1 on corneal cell proliferation has also been proposed. Finally, the three retinaldehyde dehydrogenases cooperatively mediate retinoic acid signaling during the eye development. PMID- 23098689 TI - Epigenetic distortion to VDR transcriptional regulation in prostate cancer cells. AB - The current study aimed to examine the gene specific mechanisms by which the actions of the vitamin D receptor (VDR) are distorted in prostate cancer. Transcriptional responses toward the VDR ligand, 1alpha,25(OH)2D3, were examined in non-malignant prostate epithelial cells (RWPE-1) and compared to the 1alpha,25(OH)2D3-recalcitrant prostate cancer cells (PC-3). Time resolved transcriptional studies for two VDR target genes revealed selective attenuation and repression of VDR transcriptional responses in PC-3 cells. For example, responses in PC-3 cells revealed suppressed responsiveness of IGFBP3 and G0S2. Furthermore, Chromatin Immunoprecipitation (ChIP) assays revealed that suppressed transcriptional responses in PC-3 cells of IGFBP3 and G0S2 were associated with selective VDR-induced NCOR1 enrichment at VDR-binding regions on target-gene promoter regions. We propose that VDR inappropriately recruits co-repressors in prostate cancer cells. Subsequent direct and indirect mechanisms may induce local DNA methylation and stable transcriptional silencing. Thus a transient epigenetic process mediated by co-repressor binding, namely, the control of H3K9 acetylation, is distorted to favor a more stable epigenetic event, namely DNA methylation. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23098691 TI - Synthesis of 1alpha,25-dihydroxyvitamin D3 analogues with alpha-hydroxyalkyl substituents at C12. AB - Convergent syntheses of three new analogues of 1alpha,25-dihydroxyvitamin D3 with alpha-hydroxyalkyl substituents at C12 (4a-c) are described. The A-ring and triene system of each analogue were assembled by a tandem Pd-catalysed intramolecular cyclization and Suzuki-Miyaura coupling process. The stereoselective introduction of substituents at C12 was achieved by Johnson Claisen rearrangement on allylic alcohol 15 as the key step. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23098692 TI - Influence of vitamin D on cisplatin sensitivity in testicular germ cell cancer derived cell lines and in a NTera2 xenograft model. AB - The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) has anti proliferative, pro-apoptotic, and pro-differentiating effects in somatic cancer cells in vitro and in vivo. 1,25(OH)2D3 also augments the anti-tumor effects of several chemotherapeutic agents, including cisplatin, which may have clinical relevance. Given the pro-differentiation effect of vitamin D recently demonstrated in testicular germ cell tumors (TGCTs), we hypothesized that 1,25(OH)2D3 could be a beneficial adjunctive to existing chemotherapy regime used to treat these tumors. In this study, cell survival effects of 1,25(OH)2D3, another pro-differentiation compound, retinoic acid and cisplatin were investigated in TGCT-derived cell lines in vitro. 1,25(OH)2D3 augmented the effect of cisplatin in an embryonal carcinoma-derived cell line (NTera2), possibly through downregulation of pluripotency genes and simultaneous upregulation of the cell cycle regulators p21, p27, p53, p73 and FOXO1, while no significant effects were found in TCam-2 and 2102Ep cell lines (derived from seminoma and embryonal carcinoma, respectively). Anti-tumor effects of cholecalciferol, 1,25(OH)2D3, and cisplatin were subsequently tested in vivo, in a NTera2 xenograft tumor model in nude mice. In xenograft tumors, co-treatment with 1,25(OH)2D3 and cisplatin resulted in downregulation of OCT4 and simultaneous upregulation of p21 and p73, but did not reduce tumor growth significantly more than cisplatin alone. Also, cholecalciferol supplemented diet (1100IU daily) after tumor formation did not increase cisplatin sensitivity in vivo. In conclusion, addition of 1,25(OH)2D3 augmented the antitumor effect of cisplatin monotherapy in vitro, but not in this in vivo testicular germ cell cancer model. Future studies are needed to investigate potential beneficial effects of vitamin D with lower cisplatin doses, and to determine whether 1,25(OH)2D3 may increase cisplatin sensitivity in chemotherapy-resistant TGCTs. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23098693 TI - Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator. AB - Selective androgen receptor modulators (SARMs) are androgens with tissue selective activity. SARMs that have anabolic activity on muscle while having minimal stimulatory activity on prostate are classified as SARM agonists. They can be used to prevent the loss of lean body mass that is associated with cancer, immunodeficiency, renal disease and aging. They may also have anabolic activity on bone; thus, unlike estrogens, they may reverse the loss of bone strength associated with aging or hypogonadism. Our in-house effort on SARM program discovers a nonsteroidal androgen receptor ligand with a unique imidazolopyrazole moiety in its structure. In vitro, this compound is a weak androgen receptor binder and a weak androgen agonist. Despite this, in orchidectomized mature rats it is an effective SARM agonist, with an ED(50) on levator ani muscle of 3.3mg/kg and an ED(50) on ventral prostate of >30mg/kg. It has its maximal effect on muscle at the dose of 10mg/kg. In addition, this compound has mixed agonistic and antagonistic activities on prostate, reducing the weight of that tissue in intact rats by 22% at 10mg/kg. The compound does not have significant effect on gonadotropin levels or testosterone levels in both orchidectomized and intact male rats. It does not have notable progestin, estrogen or glucocorticoid agonistic or antagonistic activity in rats. In a female sexual behavior model, it improves the sexual desire of ovariectomized female rats for sexually mature intact males over nonsexually ovariectomized females. Overall, the imidazolopyrazole is a potent prostate-sparing candidate for development as a SARM agonist with an appropriate pharmacological profile for clinical benefit in muscle-wasting conditions and female sexual function disorders. PMID- 23098694 TI - Tumor size does not predict pathological complete response rates after pre operative chemoradiotherapy for non-small cell lung cancer. PMID- 23098695 TI - Tapping-in method (skin penetration technique) with a placebo needle for double blind acupuncture trials. AB - OBJECTIVES: This study investigated the effect of acupuncture needles developed for double-blind (practitioner-patient blinding) trials employing a tapping-in method that is commonly used to penetrate the skin in Japanese-style acupuncture. DESIGN, SUBJECTS, AND INTERVENTIONS: An acupuncturist applied a penetrating, a skin-touch placebo, and a no-touch control needle designed to blind both practitioners and patients in the forearm in 80 healthy subjects (patients) by tapping-in method. SETTING: The setting was a practice room of the Japan School of Acupuncture, Moxibustion and Physiotherapy, Tokyo, Japan. OUTCOME MEASURES: The outcome measures were the acupuncturist's and subjects' guesses at the type of needles and confidence of their guesses on a 100-mm visual analogue scale (VAS). The subjects were asked about pain with needle application. RESULTS: The number of correct/incorrect guesses (the latter including unidentified) of the acupuncturist were 73/167 with a confidence of 55.2 +/- 16.9 (mean +/- standard deviation) on the VAS. The subjects identified 148 needles correctly and 92 needles incorrectly, the mean confidence being 71.0 +/- 28.4. There were a few penetrating and skin-touch placebo needles that the subjects guessed as "no touch." Whereas few of the 80 no-touch control needles were guessed as "penetrating," 16% of them were guessed as "skin-touch" and 11% were reported as "unidentifiable" by the subjects. Forty percent (40%) of the penetrating needles and 50% of the skin-touch placebo needles did not elicit skin penetration pain. CONCLUSIONS: The effect of practitioner blinding employing the needles for double blinding with the tapping-in method was satisfactory. It was difficult to blind the subjects when no-touch control needles together with penetrating and skin touch placebo needles were used. PMID- 23098697 TI - Insights on personalized medicine from Ayurveda. AB - The "omics" era of research has provided vital information on the genetic and biochemical diversity of individuals. This has lead to the emergence of "personalized medicine," wherein one aims to design specific drugs for individual patients or subtypes of patients. Indeed, the ongoing patent wars on this matter, suggest that personalized medicine represents a major goal for today's pharmaceutical industries. Although the concept of personalized medicine is new to modern medicine, it is a well-established concept in Ayurveda, the traditional system of Indian medicine that is still being practiced. Therefore, this article discusses topics that are crucial for the advancement of modern personalized medicine. These topics include disease susceptibility, disease subtypes, and Ayurvedic therapeutics. First, we explain how Ayurveda, Traditional Chinese Medicine, and Traditional Korean medicine or Sasang Constitutional medicine; conceptualize disease susceptibility and disease subtypes. Next, we focus on conceptual similarities between molecular medicine and Ayurvedic concepts of disease susceptibility and disease subtypes. For each topic, we explain the relevant experimental evidence reported in the literature. We also propose new hypotheses and suggest experimental approaches for their testing and validation. PMID- 23098696 TI - Open-label, randomized, parallel-group controlled clinical trial of massage for treatment of depression in HIV-infected subjects. AB - OBJECTIVES: The study objectives were to determine whether massage therapy reduces symptoms of depression in subjects with human immunodeficiency virus (HIV) disease. DESIGN: Subjects were randomized non-blinded into one of three parallel groups to receive Swedish massage or to one of two control groups, touch or no intervention for eight weeks. SETTINGS/LOCATION: The study was conducted at the Department of Psychiatry and Behavioral Neurosciences at Cedars-Sinai Medical Center in Los Angeles, California, which provided primary clinical care in an institutional setting. SUBJECTS: Study inclusion required being at least 16 years of age, HIV-seropositive, with a diagnosis of major depressive disorder. Subjects had to be on a stable neuropsychiatric, analgesic, and antiretroviral regimen for >30 days with no plans to modify therapy for the duration of the study. Approximately 40% of the subjects were currently taking antidepressants. All subjects were medically stable. Fifty-four (54) subjects were randomized, 50 completed at least 1 week (intent-to-treat; ITT), and 37 completed the study (completers). INTERVENTIONS: Swedish massage and touch subjects visited the massage therapist for 1 hour twice per week. The touch group had a massage therapist place both hands on the subject with slight pressure, but no massage, in a uniform distribution in the same pattern used for the massage subjects. OUTCOME MEASURES: The primary outcome measure was the Hamilton Rating Scale for Depression score, with the secondary outcome measure being the Beck Depression Inventory. RESULTS: For both the ITT and completers analyses, massage significantly reduced the severity of depression beginning at week 4 (p <= 0.04) and continuing at weeks 6 (p <= 0.03) and 8 (p <= 0.005) compared to no intervention and/or touch. CONCLUSIONS: The results indicate that massage therapy can reduce symptoms of depression in subjects with HIV disease. The durability of the response, optimal "dose" of massage, and mechanisms by which massage exerts its antidepressant effects remain to be determined. PMID- 23098698 TI - Nutmeg extracts for painful diabetic neuropathy: a randomized, double-blind, controlled study. AB - OBJECTIVES: Current treatment strategies for painful diabetic neuropathy (PDN) include oral medications, which are costly and may have adverse effects. Topical therapies have been used for PDN with some benefit. Nutmeg has certain properties that may be effective in ameliorating neuropathic pain. The purpose of this study was to determine whether topical nutmeg extracts can reduce pain or improve the quality of life in PDN sufferers. DESIGN: This study was a randomized, double blind, placebo-controlled trial. SETTINGS/LOCATION: It was conducted at a primary care center in Trinidad, Caribbean. SUBJECTS: Seventy-four (74) diabetic subjects who met criteria for painful neuropathy were recruited. INTERVENTIONS: Participants were randomized to receive either topical nutmeg extracts (NEMM; mace oil [2%], nutmeg oil [14%], methyl salicylate [6%], menthol [6%], and coconut oil) or placebo (MM; methyl salicylate [6%], menthol [6%], coconut oil, and alcohol). OUTCOME MEASURES: Outcome measures of pain and quality of life were assessed using the Brief Pain Inventory for Diabetic Painful Neuropathy and Neuropathic Pain Symptom Inventory. RESULTS: An intention-to-treat analysis was done for 24 male and 50 female subjects (30-85 years) with an average duration of diabetes of 11 years. Significant reductions in worst and average pain scores were seen within each group (p <= 0.001). Similarly significant reductions were also noted for interference with walking, sleep, and mood scores as well as burning, pins and needles, and tingling scores within each group (p<0.05). There were no statistically significant differences between both groups after 4 weeks for any outcome measure. CONCLUSIONS: In this trial topical, nutmeg extracts did not add to the improvements observed in PDN symptoms during 4 weeks treatment with preparations containing menthol and methyl salicylate. Further research designed to test the individual components of the topical therapies used in this study may clarify their benefit. PMID- 23098699 TI - Study sequence rules of estrogen receptor alpha-DNA interactions using dual polarization interferometry and computational modeling. AB - Estrogen receptor alpha (ERalpha) is a ligand-activated transcription factor. In a classical model, ERalpha regulates gene expression by binding to DNA sequences called estrogen response elements (EREs). A perfect ERE contains a palindromic consensus sequence of 5'-GGTCAnnnTGACC-3'. A slight variation in ERE sequence alters ERalpha binding affinity and, thus, the gene transcription activity. In this study, all possible singly mutated EREs of 15 sequences (three possible base substitutions at each of one to five positions of one half-site) were created. Dual polarization interferometry (DPI) was used to measure the receptor binding to generate an in vitro binding energy model. A motif discovery algorithm, Thermodynamic Modeling of ChIP-seq (TherMos), was used to compute the binding energy model from in vivo genome-wide ERalpha binding data. The in vitro affinity model measured by DPI correlates very well with the TherMos prediction (in vivo model), with a rank correlation coefficient of 0.91, which indicates that the DPI determined model is reliable and powerful in understanding of ERalpha binding in vivo in the whole genome. This is the first report of DPI study of protein-double stranded DNA (dsDNA) interactions. The assay protocols developed are efficient for screening a large quantity of DNA sequences with single base variation sensitivity. PMID- 23098700 TI - A plasmid-based lacZalpha gene assay for DNA polymerase fidelity measurement. AB - A significantly improved DNA polymerase fidelity assay, based on a gapped plasmid containing the lacZalpha reporter gene in a single-stranded region, is described. Nicking at two sites flanking lacZalpha, and removing the excised strand by thermocycling in the presence of complementary competitor DNA, is used to generate the gap. Simple methods are presented for preparing the single-stranded competitor. The gapped plasmid can be purified, in high amounts and in a very pure state, using benzoylated-naphthoylated DEAE-cellulose, resulting in a low background mutation frequency (~1 * 10(-4)). Two key parameters, the number of detectable sites and the expression frequency, necessary for measuring polymerase error rates have been determined. DNA polymerase fidelity is measured by gap filling in vitro, followed by transformation into Escherichia coli and scoring of blue/white colonies and converting the ratio to error rate. Several DNA polymerases have been used to fully validate this straightforward and highly sensitive system. PMID- 23098701 TI - MTSA--a Matlab program to fit thermal shift data. AB - Thermal shift analysis is becoming widely used as a method to identify initial hit ligands for inhibitor discovery or to identify ligands that may aid crystallization. The data analysis software provided by the equipment manufacturers or in the public domain is cumbersome to use. We have assessed a number of different approaches to generate a value for the melting temperature (T(m)) and implemented these methods in the program MTSA within the commercial software Matlab to provide an easy-to-use and rapid way to process experimental thermal shift data. The program outputs the T(m), the quality of the fit, and the deviation from a standard value, the thermal shift DeltaT(m). Our analysis of these results includes a discussion of some issues with previous publications in this area. We conclude that the most suitable value for T(m) should be taken from the midpoint determined for a curve fitted to the experimental data with a five parameter equation. In addition, we found that different ranking of ligand binding can be obtained using the different techniques when screening for binding of weak ligands such as fragments. Therefore, the technique should be used with caution for such screening. PMID- 23098702 TI - A novel fluorescence reaction for N-terminal Ser-containing peptides and its application to assay caspase activity. AB - Caspases are the key regulatory factors of apoptosis and are also found to be involved in inflammatory cytokinesis. Sensitive and selective determination of caspases has significant importance in evaluation of apoptosis, disease diagnosis, and drug development. Here, we developed an assay method for the determination of caspase activity. This method is based on a novel fluorescence (FL) reaction selective for N-terminal Ser-containing peptides. FL derivatization of peptides requires heating in the presence of catechol, HEPES buffer (pH 7.5), and sodium periodate. Under optimized conditions, the reaction showed a unique sequence preference for N-terminal Ser-containing peptides, and a lower detection limit (signal/noise [S/N] = 3) of approximately 0.1 MUM was obtained for SKTS and SSNSF. Acetylated substrates were enzymatically cleaved to produce N-terminal Ser containing peptides, which were selectively converted to FL compounds. The enzyme activities were simultaneously determined as low as 2 U (4.3 nM) caspase-3 and 2.5 U (3.3 nM) caspase-8 by high-performance liquid chromatography (HPLC) with FL detection. The proposed assay method does not require any labeled substrates and can be applied to evaluate cell-based apoptosis and also to study apoptosis inhibitors or inducers. PMID- 23098703 TI - Development and maturation of the spinal cord: implications of molecular and genetic defects. AB - The human central nervous system (CNS) may be the most complex structure in the universe. Its development and appropriate specification into phenotypically and spatially distinct neural subpopulations involves a precisely orchestrated response, with thousands of transcriptional regulators combining with epigenetic controls and specific temporal cues in perfect synchrony. Understandably, our insight into the sophisticated molecular mechanisms which underlie spinal cord development are as yet limited. Even less is known about abnormalities of this process - putative genetic and molecular causes of well-described defects have only begun to emerge in recent years. Nonetheless, modern scientific techniques are beginning to demonstrate common patterns and principles amid the tremendous complexity of spinal cord development and maldevelopment. These advances are important, given that developmental anomalies of the spinal cord are an important cause of mortality and morbidity (Sadler, 2000); it is hoped that research advances will lead to better methods to detect, treat, and prevent these lesions. PMID- 23098704 TI - Anatomy and biomechanics of the spinal column and cord. AB - The field of biomechanics combines the disciplines of biology and engineering, attempting to quantitatively describe the complicated properties of biological materials. These properties depend not only upon the inherent attributes of its constituents but also upon how the constituents are arranged relative to each other. Its importance in understanding spinal column and spinal cord pathology cannot be overemphasized. This chapter is a primer on the application of biomechanical principles to the normal and pathological spine. The basic concepts of biomechanics will first be reviewed followed by a review of the structural anatomy of the osteoligamentous spinal column and the biomechanics of injury. Relevant spinal cord anatomy will then be addressed as well as current biomechanical theories of spinal cord injury. PMID- 23098705 TI - Clinical diagnosis and prognosis following spinal cord injury. AB - Spinal cord injury (SCI) is a sudden, life-altering event. Injury severity and accompanying recovery vary considerably from individual to individual. The most important determinant of prognosis is whether an injury is clinically complete or incomplete. While approximately 10-20% of complete injuries convert to incomplete during the first year post-injury, the magnitude of motor recovery following complete SCI is limited or absent. Robust functional motor recovery (e.g., weight bearing, ambulation) distal to the zone of injury is rare. Recovery following incomplete SCI is particularly variable, and anywhere from 20% to 75% of individuals will recover some degree of walking capacity by 1 year post-injury. This is related to presenting injury severity (American Spinal Injury Association Impairment Scale grade); however, even 20-50% of individuals who present as motor complete, sensory incomplete will walk in some capacity by 1 year post-injury. Regardless, for both complete and incomplete injuries, the majority of recovery is observed during the initial 9-12 months, with a relative plateau reached by 12 18 months post-injury. Magnetic resonance imaging (MRI) provides valuable adjunct information when a bedside clinical assessment cannot be completed. The presence of intramedullary hemorrhage and extended segments of edema have been associated with clinically complete SCI. PMID- 23098706 TI - Clinical neurophysiology in the prognosis and monitoring of traumatic spinal cord injury. AB - Preclinical studies for the repair of spinal cord injury (SCI) and potential therapies for accessing the inherent plasticity of the central nervous system (CNS) to promote recovery of function are currently moving into the translational stage. These emerging clinical trials of therapeutic interventions for the repair of SCI require improved assessment techniques and quantitative outcome measures to supplement the American Spinal Injuries Association (ASIA) Impairment Scales. This chapter attempts to identify those electrophysiological techniques that show the most promise for provision of objective and quantitative measures of sensory, motor, and autonomic function in SCI. Reviewed are: (1) somatosensory evoked potentials, including dermatomal somatosensory evoked potentials, and the electrical perceptual threshold as tests of the dorsal (posterior) column pathway; (2) laser evoked potentials and contact heat evoked potentials as tests of the anterior spinothalamic tract; (3) motor evoked potentials in limb muscles, in response to transcranial magnetic stimulation of the motor cortex as tests of the corticospinal tract, and the application of the technique to assessment of trunk and sphincter muscles; and (4) the sympathetic skin response as a test of spinal cord access to the sympathetic chain. PMID- 23098707 TI - Concepts of aging with paralysis: implications for recovery and treatment. AB - This chapter deals with the impact of age on the occurrence, clinical presentation, outcome, and course of a spinal cord injury (SCI). This is of importance in a society where the population of elderly people continuously increases. The chapter is focused first, on the actual problems of a SCI in elderly subjects and second, on age-specific sequelae after a SCI. The etiology and clinical presentation of a SCI differs in elderly subjects compared to young subjects. With advanced age, incomplete cervical lesions following falls or due to spondylotic degeneration of the cervical spine and non-traumatic SCI occur more frequently. Research pertaining to the comparison of different age groups is prone to bias due to survival and treatment cohort effects. There is an increased risk of complications and mortality after a complete SCI in elderly people. Surprisingly, the recovery of the neurological deficit does not depend on age. However, elderly subjects with SCI have more problems in transferring an improvement in motor score into a functional improvement in their ability to carry out the activities of daily living. With increasing age after a SCI the completeness and level of injury determine the occurrence of complications and outcome restrictions. In addition, problems in general health (e.g., in circulation, kidney function, diabetes mellitus) may affect the functional independence of elderly subjects with SCI. PMID- 23098709 TI - Advances in the management of spinal cord and spinal column injuries. AB - Spinal cord injury (SCI) is a significant public problem, with recent data suggesting that over 1 million people in the U.S.A. alone are affected by paralysis resulting from SCI. Recent advances in prehospital care have improved survival as well as reduced incidence and severity of SCI following spine trauma. Furthermore, increased understanding of the secondary mechanisms of injury following SCI has provided improvements in critical care and acute management in patients suffering from SCI, thus limiting morbidity following injury. In addition, improved technology and biomechanical understanding of the mechanisms of spine trauma have allowed further advances in available techniques for spinal decompression and stabilization. In this chapter we review the most recent data and salient literature regarding SCI and address current controversies, including the use of pharmacological adjuncts in the setting of acute SCI. We will also attempt to provide a reader with basic understanding of the classifications of SCI and spinal column injury. Finally, we review advances in spinal column stabilization including improvements in instrumented fusion and minimally invasive surgery. PMID- 23098710 TI - Spinal cord injuries in children and adolescents. AB - This chapter provides an overview of spinal cord injuries (SCI) in children and adolescents, including epidemiology, medical and musculoskeletal complications, rehabilitation and psychosocial aspects. Males are more commonly affected than females during adolescence; however, as the age at injury decreases, the preponderance of males becomes less marked, and by 3 years of age the number of females with SCIs equals that of males. The neurologic level and degree of completeness varies with age; among children injured prior to 12 years of age approximately two-thirds are paraplegic and approximately two-thirds have complete lesions. Among adolescents, approximately 50% have paraplegia and 55% have complete lesions. Management of pediatric-onset SCI should be family centered and developmentally based, responsive to the dynamic changes that occur during growth and development. Distinctive anatomical and physiological features of children and adolescents, along with growth and development, are responsible for unique manifestations and complications of pediatric SCI. SCI without radiological abnormalities (SCIWORA), birth injuries, lap-belt injuries, upper cervical injuries, and the delayed onset of neurological deficits are relatively unique to pediatric SCI. Children who sustain their SCI before puberty experience a higher incidence of musculoskeletal complications, such as scoliosis and hip dislocation. PMID- 23098711 TI - The changing landscape of spinal cord injury. AB - In the past quarter century, spinal cord injury medicine has welcomed the proliferation of new medications and technologies that improve the survival and quality of life for people with spinal cord injury, but also endured the failure of strategies we hoped would salvage the cord in the acute phase. Surgical decompression and spinal stabilization should be pursued whenever indicated and feasible; however, there is no compelling evidence that early decompression facilitates neurological improvement. Methylprednisolone, the subject of over two decades of trials, has proven to be of marginal benefit in improving functional outcome. Recent advances in the management of the respiratory, cardiovascular, autonomic, endocrine, skeletal and integumentary systems have not only changed morbidity and survival of spinal cord injury patients but also improved quality of life. Progress has been made in the early diagnosis and effective treatment of cardiac arrhythmias, neurogenic shock, autonomic dysreflexia and orthostatic hypotension. Aggressive respiratory care for high cervical level of injury patients should include an option for phrenic nerve pacing as it is a viable rehabilitative strategy for appropriately selected patients. Pressure ulcers remain a significant psychological, financial, and functional burden for many people with SCI and for healthcare providers. This area will continue to require further work on early prevention and education. Despite extensive scientific and clinical data on neurogenic osteoporosis, there is no consensus regarding the best pharmacotherapeutic agents, dosing regimens, or rehabilitative strategies for prevention and treatment of bone loss. This chapter will focus on the advances. PMID- 23098712 TI - Surgical treatments to restore function control in spinal cord injury. AB - People with spinal cord injury (SCI) have a profound loss of control of their lives and abilities. Surgical procedures are of significant benefit in improving autonomy, self-care, and body function. Functional electrical stimulation (FES) is useful at higher levels of paralysis such as ASIA C5 or C6 where there are no remaining voluntary muscles for tendon transfer and can partially replace respiration, balance, and ambulation. Outcomes studies show that surgical care improves independence, strength of grasp, and measured quality of life. Those with tetraplegia should be referred for consultation for surgical reconstruction, release of contractures, consideration for neuroprostheses, and reconstruction. PMID- 23098708 TI - Advanced MRI strategies for assessing spinal cord injury. AB - Advanced magnetic resonance (MR) approaches permit the noninvasive quantification of macromolecular, functional, and physiological properties of biological tissues. In this chapter, we review the application of advanced MR techniques to the spinal cord. Macromolecular properties of the spinal cord can be studied using magnetization transfer (MT) MR, diffusion tensor imaging (DTI), Q-space diffusion spectroscopy, and selective detection of myelin water. The functional and metabolic status of the spinal cord can be studied using functional MRI (fMRI), perfusion imaging, and magnetic resonance spectroscopy (MRS). Finally, we consider the outlook for advanced MR studies in persons in whom metal hardware has been implanted to stabilize the cord. In spite of the spinal cord's diminutive size, its location deep within the body, and constant motion, recent work shows that the spinal cord can be studied using these advanced MR approaches. PMID- 23098713 TI - Advances in the rehabilitation management of acute spinal cord injury. AB - Aggressive assessment and management of the secondary complications in the hours and days following spinal cord injury (SCI) leads to restoration of function in patients through intervention by a team of rehabilitation professionals. The recent certification of SCI physicians, newly validated assessments of impairment and function measures, and international databases agreed upon by SCI experts should lead to documentation of improved rehabilitation care. This chapter highlights recent advances in assessment and treatment based on evidence-based classification of literature reviews and expert opinion in the acute phase of SCI. A number of these reviews are the product of the Consortium for Spinal Cord Medicine, which offers clinical practice guidelines for healthcare professionals. Recognition of and early intervention for problems such as bradycardia, orthostatic hypotension, deep vein thrombosis/pulmonary embolism, and early ventilatory failure will be addressed although other chapters may discuss some issues in greater detail. Early assessment and intervention for neurogenic bladder and bowel function has proven effective in the prevention of renal failure and uncontrolled incontinence. Attention to overuse and disuse with training and advanced technology such as functional electrical stimulation have reduced pain and disability associated with upper extremity deterioration and improved physical fitness. Topics such as chronic pain, spasticity, sexual dysfunction, and pressure sores will be covered in more detail in additional chapters. However, the comprehensive and integrated rehabilitation by specialized SCI teams of physicians, nurses, therapists, social workers, and psychologists immediately following SCI has become the standard of care throughout the world. PMID- 23098714 TI - Spasticity. AB - Antispastic medications that are directed to reduce clinical signs of spasticity, such as exaggerated reflexes and muscle tone, do not improve the movement disorder. Medication can even increase weakness which might interfere with functional movements, such as walking. In this chapter we address how spasticity affects mobility and how this should be taken into account in the treatment of spasticity. In clinical practice, signs of exaggerated tendon tap reflexes associated with muscle hypertonia are the consequence of spinal cord injury (SCI). They are generally thought to be responsible for spastic movement disorders. Most antispastic treatments are, therefore, directed at the reduction of reflex activity. In recent years, a discrepancy between spasticity as measured in the clinic and functional spastic movement disorder was noticed, which is primarily due to the different roles of reflexes in passive and active states, respectively. We now know that central motor lesions are associated with loss of supraspinal drive and defective use of afferent input with impaired behavior of short-latency and long-latency reflexes. These changes lead to paresis and maladaptation of the movement pattern. Secondary changes in mechanical muscle fiber, collagen tissue, and tendon properties (e.g., loss of sarcomeres, subclinical contractures) result in spastic muscle tone, which in part compensates for paresis and allows functional movements on a simpler level of organization. Antispastic drugs should primarily be applied in complete SCI. In mobile patients they can accentuate paresis and therefore should be applied with caution. PMID- 23098715 TI - Disordered cardiovascular control after spinal cord injury. AB - Damage to the spinal cord disrupts autonomic pathways, perturbing cardiovascular homeostasis. Cardiovascular dysfunction increases with higher levels of injury and greater severity. Disordered blood pressure control after spinal cord injury (SCI) has significant ramifications as cord-injured people have an increased risk of developing heart disease and stroke; cardiovascular dysfunction is currently a leading cause of death among those with SCI. Despite the clinical significance of abnormal cardiovascular control following SCI, this problem has been generally neglected by both the clinical and research community. Both autonomic dysreflexia and orthostatic hypotension are known to prevent and delay rehabilitation, and significantly impair the overall quality of life after SCI. Starting with neurogenic shock immediately after a higher SCI, ensuing cardiovascular dysfunctions include orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. Disordered temperature regulation accompanies these autonomic dysfunctions. This chapter reviews the human and animal studies that have furthered our understanding of the pathophysiology and mechanisms of orthostatic hypotension, autonomic dysreflexia and cardiac arrhythmias. The cardiovascular dysfunction that occurs during sexual function and exercise is elaborated. New awareness of cardiovascular dysfunction after SCI has led to progress toward inclusion of this important autonomic problem in the overall assessment of the neurological condition of cord-injured people. PMID- 23098716 TI - New concepts in the prevention of pressure sores. AB - Pressure sores are a serious, and costly, complication for many patients with reduced mobility and sensation. Some populations, such as those with spinal cord injury (SCI), remain at high risk throughout their lifetime. Prevention is highly preferable and while the concept is readily definable, it is much more challenging to develop valid preventative measures. Subjective and objective approaches to risk factor assessment before pressure sores develop are reviewed, including risk status scales and emerging techniques to assess deep tissue injury. Devices to prevent pressure sores have traditionally focused on pressure relieving cushions and mattresses. Technological advances being applied in the development of new pressure sore prevention devices are presented. Clinical evidence-based practice is integral to pressure sore prevention. Comprehensive assessment must include evaluation of systemic diseases, anatomical and physiological factors, together with environmental and psychosocial factors, which can all contribute to pressure sore development. Extrinsic factors need to be considered in conjunction with intrinsic tissue health factors and are reviewed together with an evaluation of currently available clinical practice guidelines. This chapter presents the broad diversity of factors associated with pressure sore development and highlights the need for an interdisciplinary team approach in order to maximize successful prevention of pressure sores. PMID- 23098717 TI - Functional electrical stimulation for bladder, bowel, and sexual function. AB - The principles of using electrical stimulation of peripheral nerves or nerve roots for restoring useful bladder, bowel, and sexual function after damage or disease of the central nervous system are described. Activation of somatic or parasympathetic efferent nerves can produce contraction of striated or smooth muscle in the bladder, rectum, and sphincters. Activation of afferent nerves can produce reflex activation of somatic muscle and reflex inhibition or activation of smooth muscle in these organs. In clinical practice these techniques have been used to produce effective emptying of the bladder and bowel in patients with spinal cord injury and to improve continence of urine and feces. Stimulation of parasympathetic efferents can produce sustained erection of the penis, and stimulation of the nerves to the seminal vesicles can produce seminal emission. Reflex erection and ejaculation can also be produced by stimulation of afferent nerves. Experimental techniques for controlling emptying and continence by a single device, and prospects for comprehensive control of bladder, bowel, and sexual function by electrical techniques are described. These may include more selective electrodes, inactivation of nerves by specific stimulus parameters, greater use of sensors, and networking of implanted components connected to the central and peripheral nervous system. PMID- 23098719 TI - Functional electrical stimulation: restoration of respiratory function. AB - Tetraplegia can lead to chronic respiratory failure. The need for tracheostomy mechanical ventilation significantly increases the cost of care, decreases the quality of life of the patient, and decreases life expectancy in spinal cord injury (SCI) because of pneumonias. Phrenic nerve stimulation was initially developed in the 1960s and diaphragm pacing was developed in the 1990s; both have the ability to remove a patient from positive pressure ventilation and allow them to breathe with their own diaphragm, decreasing posterior lung lobe atelectasis and pneumonia risk. This chapter summarizes the current surgical techniques, ventilator weaning options, and long-term results of functional electrical stimulation in restoring respiratory function. PMID- 23098718 TI - Evidence-based therapy for recovery of function after spinal cord injury. AB - Physical rehabilitation for individuals coping with neurological deficits is evolving in response to a paradigm shift in thinking about the injured nervous system and using evidence as a basis for clinical decisions. Functional recovery from paralysis was generally believed to be nearly impossible, based on traditional expert opinion, and the priority was to develop compensation strategies to achieve functional goals in the home and community. Research, which began in animal models of neurological insult and is currently being translated to the clinic, has challenged these assumptions. The nervous system, whether intact or injured, has enormous potential for adaptation and modification, which can be harnessed to facilitate recovery. In this chapter we will briefly outline the history of physical rehabilitation as it concerns the development of strategies aimed at compensation, rather than functional recovery. Then we will discuss how new activity-based therapies are being developed, based on evidence from basic science and clinical evidence. One of these activity-based therapies is locomotor training, a program which relies on the intrinsic, automatic, control of locomotion by "lower" neural centers. A brief description of the program, including the four foundational principles, will be followed by an introduction to the use of robotics in these programs. Finally, we will discuss a second activity-based therapy, functional electrical stimulation (FES), and the future of physical rehabilitation for spinal cord injury and other neurological disorders. PMID- 23098720 TI - Spinal cord stimulation: therapeutic benefits and movement generation after spinal cord injury. AB - Spinal cord injury (SCI) is a devastating neurological condition that leads to loss of motor and sensory function. It commonly causes impairments in limb movements, respiration, bowel and bladder function, as well as secondary complications including pain, spasticity, and pressure ulcers. Numerous interventions such as neuroprotection, regeneration, pharmacology, rehabilitation training, and functional electrical stimulation are under investigation for improving function after SCI. This chapter discusses the use of spinal cord stimulation (epidural and intraspinal electrical stimulation) for alleviating pain and spasticity, and restoring standing and walking. Epidural stimulation is effective in reducing the intensity of intractable pain, but its effectiveness in the treatment of spasticity remains unclear. It can induce rhythmic, locomotor like movements in the legs, presumably due to the activation of afferent pathways. Intraspinal microstimulation is a new electrical stimulation approach that activates locomotor-related networks within the ventral regions of the lumbosacral spinal cord. In animals, this approach is capable of producing prolonged, fatigue-resistant standing and stepping of the hindlegs. While the results in animals have been very encouraging, technical advancements are necessary prior to its implementation in humans with SCI. Taken collectively, spinal cord stimulation holds substantial promise in restoring function after neural injury or disease. PMID- 23098721 TI - Promoting optimal functioning in spinal cord injury: the role of rehabilitation psychology. AB - Comprehensive treatment and rehabilitation includes attention to the psychological needs of individuals with SCI and their families. This chapter is designed to familiarize neurologists and other practitioners with psychological issues and care in SCI. While psychologists play a key role, attention to psychosocial health is a responsibility shared by all members of the rehabilitation team, beginning with the patient and family, and including clinicians who are not formally identified as mental health providers. Treatment planning for a person with SCI begins with a thorough assessment of the cognitive, emotional, personality, and social factors that influence functioning and rehabilitation. Rehabilitation psychologists use a mixture of assessment tools, including clinical interviews, behavioral observations, and a wide range of standardized test instruments. Psychological interventions can involve direct intervention with the patient, in individual, family or group-based therapies. Other psychological strategies involve assistance through less direct methods - consultation and training to other rehabilitation team members or facilitating peer role-modeling and support groups. The chapter provides an overview of core clinical issues (emotional responses, substance use, pain, cognitive deficits, sexuality and vocational rehabilitation), delineates the process of psychological assessment and intervention, and provides guidance on incorporation of rehabilitation psychology into SCI rehabilitation. PMID- 23098723 TI - The longitudinal spinal cord injury: lessons from intraspinal plexus, cauda equina and medullary conus lesions. AB - Spinal nerve root avulsion injury interrupts the transverse segmental spinal cord nerve fibers. There is degeneration of sensory, motor, and autonomic axons, loss of synapses, deterioration of local segmental connections, nerve cell death, and reactions among non neuronal cells with central nerve system (CNS) scar formation, i.e., a cascade of events similar to those known to occur in any injury to the spinal cord. This is the longitudinal spinal cord injury (SCI). For function to be restored, nerve cells must survive and there must be regrowth of new nerve fibers along a trajectory consisting of CNS growth-inhibitory tissue in the spinal cord as well as peripheral nervous system (PNS) growth-promoting tissue in nerves. Basic science results have been translated into a successful surgical strategy to treat root avulsion injuries in man. In humans, this technique is currently the most promising treatment of any spinal cord injury, with return of useful muscle function together with pain alleviation. Experimental studies have also identified potential candidates for adjunctive therapies that, together with surgical replantation of avulsed roots after brachial plexus and cauda equina injuries, can restore not only motor but also autonomic and sensory trajectories to augment the recovery of neurological function. This is the first example of a spinal cord lesion that can be treated surgically, leading to restoration of somatic and autonomic activity and alleviation of pain. PMID- 23098722 TI - The changing field of rehabilitation: optimizing spontaneous regeneration and functional recovery. AB - For neurorehabilitation of patients with spinal cord injury (SCI), the traditional emphasis on social adaptation is being expanded to include strategies that promote plasticity and regeneration in the central nervous system. Such strategies are needed to optimize recovery of neurological function. For example, the known dependence of most cellular processes on physical activity has led to the novel concept that activity is important in neural repair. This hypothesis has given rise to activity-based restoration therapies (ABRT), which aim to optimize neural activity in the damaged spinal cord, particularly below the injury level. Here, we review the basic science and clinical evidence supporting the lifelong use of ABRT for recovery from spinal cord injury. We define and describe ABRT, and discuss its components, its clinical applications, its relationship to medical management of spinal cord injury, and the potential influences of medications on recovery. We also discuss the health benefits of ABRT under physiological and pathological conditions. We stress that lifelong ABRT is required to optimize return of function and to allow patients to benefit from any "cures" that will be discovered. PMID- 23098724 TI - Post-traumatic syringomyelia: CSF hydrodynamic changes following spinal cord injury are the driving force in the development of PTSM. AB - Post-traumatic syringomyelia (PTSM) is a disorder that occurs infrequently following spinal cord injury (SCI), characterized by progressive neurological deterioration resulting from syrinx expansion originating in proximity to the traumatic epicenter. Several pathogenetic factors are associated with this disorder, however, the precise mechanism of the development of PTSM is controversial. Combined anatomical alterations and molecular changes following trauma to the spinal cord and arachnoid participate in the development of this condition. These factors include narrowing or obstruction of the subarachnoid space (SAS), central canal occlusion, myelomalacia, and alterations in intramedullary water permeability. If a patient sustains a SCI with delayed progressive deterioration in neurological function, in association with the MRI appearance of syringomyelia (SM), the diagnosis of PTSM is straightforward. The treatment of PTSM has not undergone any significant changes recently. The surgical treatment of PTSM consists of reconstructing the SAS or shunting fluid away from the syrinx to other locations. The advantages and disadvantages of each procedure will be discussed. With greater understanding of the mechanisms contributing to the development of SM, including advanced diagnostic methods and further advances in the development of artificial dural and shunting tubing, future therapies of PTSM will be more effective and long-lasting. Incorporation of alterations of AQP4 expression provides an intriguing possibility for future treatment of PTSM. PMID- 23098725 TI - Post-traumatic deformity: prevention and management. AB - Traumatic spinal column injuries (SCI) can result in devastating deformities that often have long-term impact on the patient's quality of life. These deformities result in pain and occasionally neurological deficits. The deformities affecting adults often differ slightly from those in the pediatric population. In adults, injuries to the spinal column frequently result in a sagittal plane deformity, such as kyphosis or lordosis. However, in children, spinal cord injuries often cause coronal deformities, such as scoliosis. Patients with post-traumatic spinal column deformities may present acutely immediately after the injury, many years after the inciting event, or at any time in-between. Patients with post-traumatic spinal deformity initially complain of pain at the site of the deformity, but with time may complain of pain above or below the deformity as a result of degenerative changes. Any change or worsening of neurological status is a worrisome complaint, and often these patients require surgical intervention. Procedures such as fusions and spinal column osteotomies have shown promising results in treating patients with post-traumatic spinal deformities and have been shown to improve their quality of life. PMID- 23098726 TI - Spinal cord injury clinical trials translational process, review of past and proposed acute trials with reference to recommended trial guidelines. AB - Within the past few years there has been increasing interest in the translation of experimental therapeutic interventions to improve functional outcomes after spinal cord injury (SCI). The number of reported successes using preclinical animal models has been substantial and this has encouraged the development of several clinical trial programs. We will briefly discuss a desired process for the translation of preclinical therapeutic discoveries, as well as the design and conduct of valid human SCI studies. Past SCI trials are examined and current ongoing human studies are outlined. We identify some of the confounding factors that can influence the accurate interpretation of study outcomes. The discussion here will be restricted to treatment strategies that involve drug administration and cell transplants, not that these are currently the most beneficial treatments, but cell transplants are already being offered to patients without completing a valid clinical trial program. PMID- 23098727 TI - Translating preclinical approaches into human application. AB - In recent decades, several novel approaches of spinal cord repair have revealed promising findings in animal models. However, for a successful translation of these into a clinical trial in humans the specific conditions pertaining to human spinal cord injuries (SCI) have to be appreciated. Firstly, transection of the spinal cord is commonly applied in animal models, whereas spinal cord contusion is the predominant type of injury in humans, and generally leads to more extensive injury in two to three spinal cord segments. Secondly, the quadrupedal organization of locomotion in animals and the more complex autonomic functions in humans challenge the translation of animal behavior into recovery from human SCI. Thirdly, so far, no adequate animal model has been developed to resemble spastic movement disorder in human SCI. Fourthly, the extensive damage to spinal motor neurons and nerve roots in human cervical and thoracolumbar in spine trauma is but little addressed in current translational studies. This damage has direct implications for rehabilitation and repair strategies. Fifthly, there is increasing evidence for a neuronal dysfunction below the level of the lesion in chronic complete SCI. The relevance of this dysfunction for a regeneration inducing treatment needs to be investigated. Lastly, an approach to facilitate an appropriate reconnection of regenerating tract fibers by functional training in the postacute stage has yet to be confirmed. PMID- 23098730 TI - Approaches to repairing the damaged spinal cord: overview. AB - Affecting young people during the most productive period of their lives, spinal cord injury (SCI) is a devastating problem for modern society. In the past, treating SCI seemed frustrating and hopeless because of the tremendous morbidity and mortality, life-shattering impact, and limited therapeutic options associated with the condition. Today, however, an understanding of the underlying pathophysiological mechanisms, the development of neuroprotective interventions, and progress toward regenerative interventions are increasing hope for functional restoration. In this chapter, we provide an overview of various repair strategies for the injured spinal cord. Special attention will be paid to strategies that promote spontaneous regeneration, including functional electrical stimulation, cell replacement, neuroprotection, and remyelination. The concept that limited rebuilding can provide a disproportionate improvement in quality of life is emphasized throughout. New surgical procedures, pharmacological treatments, and functional neuromuscular stimulation methods have evolved over the last decades and can improve functional outcomes after spinal cord injury; however, limiting secondary injury remains the primary goal. Tissue replacement strategies, including the use of embryonic stem cells, become an important tool and can restore function in animal models. Controlled clinical trials are now required to confirm these observations. The ultimate goal is to harness the body's own potential to replace lost central nervous system cells by activation of endogenous progenitor cell repair mechanisms. PMID- 23098729 TI - Brain-machine interfaces and transcranial stimulation: future implications for directing functional movement and improving function after spinal injury in humans. AB - Since its origins, the primary goal of transforming thought into action and sensation into perception has been to improve the quality of life for the physically impaired. Brain-machine interfaces (BMI) aim to improve the quality of life for large numbers of neurological patients. In particular, this novel technology is meant to play a major role in the near future as a serious contribution to spinal cord rehabilitation. During the last decade we have witnessed a dramatic increase in BMI research with impressive demonstrations of rodents, nonhuman primates, and humans controlling robots, wheelchairs, and graphical cursors in real time through signals collected from the brain. In this chapter we first review the different techniques used in the field of BMI, including electroencephalography (EEG), electrocorticography (ECoG), magnetoencephalography (MEG), and chronic multielectrode recordings. In addition we review the use of transcranial magnetic stimulation (TMS) for noninvasive modulation of excitability in relatively focal cortical areas. The chapter concludes with a discussion on the future implications of BMIs for directing functional movement and improving function after spinal injury in humans. PMID- 23098731 TI - Limiting spinal cord injury by pharmacological intervention. AB - The direct primary mechanical trauma to neurons, glia and blood vessels that occurs with spinal cord injury (SCI) is followed by a complex cascade of biochemical and cellular changes which serve to increase the size of the injury site and the extent of cellular and axonal loss. The aim of neuroprotective strategies in SCI is to limit the extent of this secondary cell loss by inhibiting key components of the evolving injury cascade. In this review we will briefly outline the pathophysiological events that occur in SCI, and then review the wide range of neuroprotective agents that have been evaluated in preclinical SCI models. Agents will be considered under the following categories: antioxidants, erythropoietin and derivatives, lipids, riluzole, opioid antagonists, hormones, anti-inflammatory agents, statins, calpain inhibitors, hypothermia, and emerging strategies. Several clinical trials of neuroprotective agents have already taken place and have generally had disappointing results. In attempting to identify promising new treatments, we will therefore highlight agents with (1) low known risks or established clinical use, (2) behavioral data gained in clinically relevant animal models, (3) efficacy when administered after the injury, and (4) robust effects seen in more than one laboratory and/or more than one model of SCI. PMID- 23098732 TI - Harmful and beneficial effects of inflammation after spinal cord injury: potential therapeutic implications. AB - Spinal cord injury (SCI) results in immediate damage followed by a secondary phase of tissue damage that occurs over a period of several weeks. The mechanisms underlying this secondary damage are multiple and not fully understood. A number of studies suggest that the local inflammatory response in the spinal cord that occurs after SCI contributes importantly to secondary damage. This response is mediated by cells normally found in the central nervous system (CNS) as well as infiltrating leukocytes. While the inflammatory response mediated by these cells is required for efficient clearance of tissue debris, and promotes wound healing and tissue repair, they also release various factors that can be detrimental to neurons, glia, axons, and myelin. In this chapter we provide an overview of the inflammatory response at the cell and molecular level after SCI, and review the current state of knowledge about its contribution to tissue damage and repair. Additionally, we discuss how some of this work is leading to the development and testing of drugs that modulate inflammation to treat acute SCI in humans. PMID- 23098728 TI - Translational spinal cord injury research: preclinical guidelines and challenges. AB - Advances in the neurobiology of spinal cord injury (SCI) have prompted increasing attention to opportunities for moving experimental strategies towards clinical applications. Preclinical studies are the centerpiece of the translational process. A major challenge is to establish strategies for achieving optimal translational progression while minimizing potential repetition of previous disappointments associated with clinical trials. This chapter reviews and expands upon views pertaining to preclinical design reported in recently published opinion surveys. Subsequent discussion addresses other preclinical considerations more specifically related to current and potentially imminent cellular and pharmacological approaches to acute/subacute and chronic SCI. Lastly, a retrospective and prospective analysis examines how guidelines currently under discussion relate to select examples of past, current, and future clinical translations. Although achieving definition of the "perfect" preclinical scenario is difficult to envision, this review identifies therapeutic robustness and independent replication of promising experimental findings as absolutely critical prerequisites for clinical translation. Unfortunately, neither has been fully embraced thus far. Accordingly, this review challenges the notion "everything works in animals and nothing in humans", since more rigor must first be incorporated into the bench-to-bedside translational process by all concerned, whether in academia, clinical medicine, or corporate circles. PMID- 23098733 TI - Defeating inhibition of regeneration by scar and myelin components. AB - Axon regeneration and the sprouting processes that underlie plasticity are blocked by inhibitory factors in the central nervous system (CNS) environment, several of which are upregulated after injury. The major inhibitory molecules are those associated with myelin and those associated with the glial scar. In myelin, NogoA, MAG, and OMgp are present on normal oligodendrocytes and on myelin debris. They act partly via the Nogo receptor, partly via an unidentified amino-Nogo receptor. In the glial scar, chondroitin sulphate proteoglycans, semaphorins, and the formation of a collagen-based membrane are all inhibitory. Methods to counteract these forms of inhibition have been identified, and these treatments promote axon regeneration in the damaged spinal cord, and in some cases recovery of function through enhanced plasticity. PMID- 23098734 TI - Realizing the maximum potential of Schwann cells to promote recovery from spinal cord injury. AB - Transplantation of Schwann cells (SCs) has been extensively investigated as a therapeutic intervention in rodent models of spinal cord injury (SCI). Here we review both strengths and weaknesses of this approach and discuss additional strategies for maximizing the potential of SCs to repair the injured spinal cord. With no additional treatments, SCs were consistently shown to provide a bridge across the lesion site, supporting the ingrowth of sensory and propriospinal axons, to myelinate axons and to decrease the size of cavities formed after injury. Supraspinal axons did not, however, grow onto the bridge, axons failed to traverse the caudal SC-host cord interface and transplanted SC survival was poor. More recent studies have shown that the potential of SC transplantation as a therapeutic approach can be strongly enhanced by combining additional strategies . For example, combining SC transplantation with elevation of cAMP levels resulted in growth of brainstem axons into the SC graft and caudal to the lesion and in significant improvements in locomotion. Axon growth (and functional improvement) have been increased by strategies to raise neurotrophin levels, either by injection or by genetic modification of the SCs before transplantation. A major problem in maximizing SC potential in injured cord has been in achieving good integration of the transplanted cells with the adjacent cord parenchyma. Several previous studies suggested an ability of SCs to migrate extensively in CNS tissue when astroctyes were absent and to myelinate CNS axons. Furthermore, in some cases involving very limited injury, SCs migrated and integrated well even in the presence of host astrocytes. Consistent with these observations, treatments with an enzyme, chondroitinase, to modify the SC-astrocyte interface surrounding the graft, have shown much promise. Very new studies have shown that SCs derived from SC precursors show a higher ability to survive, integrate well with host tissue and support brainstem axon growth into and beyond the graft, confirming the innate promise of SCs in spinal cord repair. We review one clinical trial already underway in Iran testing SC transplantation in patients with SCI. Finally, we briefly describe a protocol, adaptable to the principles of good manufacturing practice, for generating large numbers of human SCs. Overall, the available evidence suggests that SCs, especially when used in combination with other treatments, offer one of the best hopes we have today of devising an effective treatment for spinal cord repair. PMID- 23098735 TI - Repair of central nervous system lesions by transplantation of olfactory ensheathing cells. AB - Clinical conditions affecting the central nervous system (CNS) fall into two main categories - degenerative conditions in which nerve cells are lost (Alzheimer's, Parkinson's, Huntington's disease, etc.), and traumatic insults which sever nerve fibers but leave their cell bodies and initial parts of the severed axons intact (spinal cord injury, cerebrovascular accidents, or tumors affecting fiber tracts). After injuries of this second type, the survival of the nerve cell bodies and the local sprouting at the severed ends of the proximal stumps of the axons raise the tantalizing possibility of one day learning how to induce these severed fibers to regenerate to their original targets and restore lost functions. This chapter gives an overview of current research into the strategy of transplantation of olfactory ensheathing cells into axotomizing injuries. PMID- 23098736 TI - Cell transplantation: stem cells and precursor cells. AB - Stem cells have been used to approach four different therapeutic repair strategies in spinal cord injury (SCI): (1) replacement of lost neurons, (2) replacement of oligodendrocytes to promote remyelination of demyelinated and/or regenerated axons, (3) providing a permissive substrate for axonal regeneration to overcome the intrinsic inhibition of surface molecules, and (4) engendering host repair. The first two strategies involve cell-specific differentiation of engrafted neural cells and the latter two may involve grafted neural or non neural cells. The preclinical data for all of these approaches is at times contradictory and there is no consensus as to what type of stem cell is optimal to facilitate repair in specific injuries. Remyelination has been the most successful stem cell replacement strategy. Partial lineage restriction and pharmacological and/or genetic manipulation to express additional trophic support or restrict responses to host signals appears necessary for optimal neuronal and oligodendrocytic differentiation. However, these modifications will make their clinical application exceedingly difficult. Effects of grafted stem cells on abrogating host immune responses and engendering intrinsic repair is also a mechanism through which stem cells are likely therapeutically beneficial. While clinical trials with stem cell grafting into the injured spinal cord are ongoing, preclinical studies have yet to define mechanisms of action that can be definitively translated to those clinical approaches. PMID- 23098737 TI - Gene therapy, neurotrophic factors and spinal cord regeneration. AB - Significant advances have been made in understanding the mechanisms that limit axon regeneration in the adult mammalian central nervous system and in addressing some of the obstacles for axon growth. Despite this progress numerous challenges remain to achieve regeneration of a large number of axons sufficient to mediate functional improvement. Given the complexity of injury-induced changes in axon, cell body, and parenchyma surrounding a spinal cord lesion, it seems likely that multiple factors both intrinsic and extrinsic to injured neurons have to be addressed to augment axon regeneration and useful reorganization of spared circuitry. Neurotrophic factors have been shown to be one potent means to increase the number and range of regenerating axons, to guide regenerating axons across a lesion site, and to augment regenerative cell body responses to injury. In this chapter we will review the potential and current limitations of neurotrophic factors and gene therapy, in combination with cellular transplants, for axon regeneration and sprouting in the injured spinal cord. PMID- 23098738 TI - Scaffolds to promote spinal cord regeneration. AB - Substantial research effort in the spinal cord injury (SCI) field is directed towards reduction of secondary injury changes and enhancement of tissue sparing. However, pathway repair after complete transections, large lesions, or after chronic injury may require the implantation of some form of oriented bridging structure to restore tissue continuity across a trauma zone. These matrices or scaffolds should be biocompatible and create an environment that facilitates tissue growth and vascularization, and allow axons to regenerate through and beyond the implant in order to reconnect with "normal" tissue distal to the injury. The myelination of regrown axons is another important requirement. In this chapter, we describe recent advances in biomaterial technology designed to provide a terrain for regenerating axons to grow across the site of injury and/or create an environment for endogenous repair. Many different types of scaffold are under investigation; they can be biodegradable or nondegradable, natural or synthetic. Scaffolds can be designed to incorporate immobilized signaling molecules and/or used as devices for controlled release of therapeutic agents, including growth factors. These bridging structures can also be infiltrated with specific cell types deemed suitable for spinal cord repair. PMID- 23098740 TI - Combination therapies. AB - Spinal cord injury (SCI) has multiple consequences, ranging from molecular imbalances to glial scar formation to functional impairments. It is logical to think that a combination of single treatments implemented in the right order and at the right time will be required to repair the spinal cord. However, the single treatments that compose the combination therapy will need to be chosen with caution as many have multiple outcomes that may or may not be synergistic. Single treatments may also elicit unwanted side-effects and/or effects that would decrease the repair potential of other components and/or the entire combination therapy. In this chapter a number of single treatments are discussed with respect to their multiplicity of action. These include strategies to boost growth and survival (such as neurotrophins and cyclic AMP) and strategies to reduce inhibitory factors (such as antimyelin-associated growth inhibitors and digestion of glial scar-associated inhibitors). We also present an overview of combination therapies that have successfully or unsuccessfully been tested in the laboratory using animal models. To effectively design a combination therapy a number of considerations need to be made such as the nature and timing of the treatments and the method for delivery. This chapter discusses these issues as well as considerations related to chronic SCI and the logistics of bringing combination therapies to the clinic. PMID- 23098739 TI - Molecular target discovery for neural repair in the functional genomics era. AB - A comprehensive understanding of the molecular pathways activated by traumatic neural injury is of major importance for the development of treatments for spinal cord injury (SCI). High-throughput gene expression profiling is a powerful approach to reveal genome-wide changes in gene expression during a specific biological process. Microarray analysis of injured nerves or neurons would ideally generate new hypotheses concerning the progression or deregulation of injury- and repair-related biological processes, such as neural scar formation and axon regeneration. These hypotheses should subsequently be tested experimentally and would eventually provide the molecular substrates for the development of novel therapeutics. Over the last decade, this approach has elucidated numerous extrinsic (mostly neural scar-associated) as well as neuron intrinsic genes that are regulated following an injury. To date, the main challenge is to translate the observed injury-induced gene expression changes into a mechanistic framework to understand their functional implications. To achieve this, research on neural repair will have to adopt the conceptual advances and analytical tools provided by the functional genomics and systems biology revolution. Based on progress made in bioinformatics, high-throughput and high-content functional cellular screening, and in vivo gene transfer technology, we propose a multistep "roadmap" that provides an integrated strategy for molecular target discovery for repair of the injured spinal cord. PMID- 23098743 TI - Unreadiness for postpartum discharge following healthy term pregnancy: impact on health care use and outcomes. AB - OBJECTIVE: To document the association between a lack of readiness, termed "unreadiness," for postpartum discharge and the health of mothers and their term newborns. METHODS: Prospective observational cohort study of 4300 mother-infant dyads in a national, pediatric, practice-based research network. The association between unreadiness for discharge and health care use, health-related behaviors, and health outcomes was analyzed by the use of bivariate, multivariate linear, and logistic models. RESULTS: Sixteen percent of mother-infant dyads were unready for discharge. Unreadiness was significantly associated with maternal and infant health care use and health outcomes but not independently associated with health related behaviors. In multivariable analyses, after we controlled for important covariates and confounders, unready dyads had more calls to health care providers than ready dyads (13.3% increase for mothers, P = .01; 18.7% increase for infants, P < .01) during the first 2 weeks after discharge. In this same time frame, unready dyads also had more symptom days (8.5% increase for mothers, P < .01; 8.7% increase for infants, P < .01). Unready mothers had lower mean physical (5.0% decrease, P < .01) and mental (4.4% decrease, P < .01) health status scores at 4 weeks after discharge. CONCLUSIONS: Unreadiness at postpartum discharge was associated with increased health care use and poorer health outcomes in the first 2 to 4 weeks after discharge. Discharge plans should be individualized and jointly tailored to a family's needs rather than to a set timescale. PMID- 23098744 TI - Anti-hepatitis B virus activities of alpha-DDB-FNC, a novel nucleoside biphenyldicarboxylate compound in cells and ducks, and its anti-immunological liver injury effect in mice. AB - Infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease with high mortality. Herein, we examined both the anti-HBV and hepatoprotective activity of alpha-DDB-FNC. In human HBV-transfected liver cell line HepG2.2.15, alpha-DDB-FNC effectively suppressed the secretion of HBV antigens in a time and dose-dependent manner with 25.11% inhibition on HBeAg and 43.68% on HBsAg at 2.5 MUM on day 9. Consistent with the HBV antigen reduction, alpha-DDB-FNC (2.5 MUM) also reduced HBV DNA level by 77.74% extracellularly and 78.94% intracellularly on day 9. In the duck hepatitis B virus (DHBV) infected ducks, after alpha-DDB-FNC was given once daily for 10 days, the serum and liver DHBV DNA levels were reduced markedly with 96.81% and 97.21% at 10 mgkg(-1) on day 10, respectively. In Con A-induced immunological liver-injury mice, alpha-DDB-FNC significantly inhibited the elevation of serum ALT, AST, TBiL and liver MDA, NO levels. Furthermore, significant improvement of the liver was observed after alpha-DDB-FNC treatment both in ducks and mice, as evaluated by the histopathological analysis. In conclusion, our results demonstrated that alpha-DDB-FNC possesses both antiviral activity against HBV and hepatoprotective effect to Con A-induced liver-injury mice. PMID- 23098745 TI - Differential antiviral and anti-inflammatory mechanisms of the flavonoids biochanin A and baicalein in H5N1 influenza A virus-infected cells. AB - From a panel of 22 flavonoids, we identified six compounds (apigenin, baicalein, biochanin A, kaempferol, luteolin, naringenin) that inhibited influenza A nucleoprotein production in human lung epithelial (A549) cells infected with the highly pathogenic avian influenza H5N1 virus strain A/Thailand/Kan-1/04 in non toxic concentrations. Baicalein (IC(50): 18.79+/-1.17MUM, selectivity index 5.82) and biochanin A (IC(50) 8.92+/-1.87MUM, selectivity index 5.60) were selected for further experiments. Both compounds reduced H5N1 infectious titres (baicalein 40MUM: 29-fold reduction, biochanin A 40MUM: 55-fold reduction after infection at MOI 0.01), virus-induced caspase 3 cleavage, nuclear export of viral RNP complexes, and enhanced the effects of the neuraminidase inhibitor zanamivir. Biochanin A and baicalein also inhibited the replication of the H5N1 strain A/Vietnam/1203/04. Time of addition experiments indicated that both compounds interfere with H5N1 replication after the adsorption period. Further mechanistic investigations revealed clear differences between these two flavonoids. Only baicalein interfered with the viral neuraminidase activity (39+/-7% inhibition at 100MUM, the maximum concentration tested). In contrast to baicalein, biochanin A affected cellular signalling pathways resulting in reduced virus-induced activation of AKT, ERK 1/2, and NF-kB. Moreover, biochanin A inhibited the virus induced production of IL-6, IL-8, and IP-10 while baicalein inhibited IL-6 and IL 8 production without affecting IP-10 levels. In primary human monocyte-derived macrophages, only baicalein but not biochanin A impaired H5N1 virus replication. Both flavonoids interfered with the H5N1-induced production of IL-6, IP-10, and TNF-alpha but not of IL-8 in macrophages. These findings indicate that closely related flavonoids can exert anti-H5N1 effects by different molecular mechanisms. PMID- 23098746 TI - Clinical evaluation of a novel LMA with a color-coded pressure gauge. AB - BACKGROUND: Unintended hyperinflation of the cuff of a laryngeal mask airway (LMA) may be associated with increased airway morbidity and postoperative pain. While the manufacturers recommend a cuff pressure of <= 60 cmH(2)O, in usual clinical practice, there is no method used to determine the intracuff pressure. The purpose of this prospective study was to evaluate the accuracy of a newly designed LMA with a built in pressure gauge intended to alert the clinician to elevated intracuff pressures. The pressure gauge has a color code system intended to reflect the intracuff pressure with green being 40-60 cmH(2)O. METHODS: There was no change dictated in clinical practice for these patients. Per our usual practice, the LMA was removed from the package and inserted with the cuff partially inflated. Additional air was added to the cuff using a syringe as needed to ensure a seal during positive pressure ventilation to a peak inflating pressure (peak ventilating pressure) of 20-25 cmH(2)O. The clinicians placing the LMA did not use the pressure gauge for clinical feedback during cuff inflation. Immediately after LMA placement, the pressure in the cuff of the LMA was measured using a hand held manometer by an independent reviewer not part of the patient's anesthetic management. The color indicated on the pressure gauge (yellow, green or red) was recorded prior to pressure sampling. Additional data collected included the patient's demographic data (age, weight, and gender), the size of the LMA, and whether air was added to the cuff. RESULTS: The study cohort included 100 children, ranging in age from 3 months to 19 years and in weight from 5.4 to 80.1 kg. One patient was excluded due to malfunction of the pressure gauge and pilot balloon of the LMA. The intracuff pressure as measured by manometer correlated appropriately with the color coding of the pressure gauge in 94 of the 99 (95%) of the LMA's tested. CONCLUSIONS: Given the potential association of excessive intracuff pressures with postoperative sore throat and the inability to ensure acceptable intracuff pressures using clinical judgment, this new LMA may allow a simple means of achieving this goal without the use of costly devices (manometers) in every operating room. In 95% of the LMA's tested, the color reading correlated appropriately with the intracuff pressure. PMID- 23098747 TI - Teaching behaviors in the cardiac surgery simulation environment. AB - OBJECTIVE: To understand how teaching behaviors contribute to simulation-based learning, we used a 7-category educational framework to assess the teaching behaviors used in basic skills training. METHODS: Twenty-four first-year cardiothoracic surgery residents and 20 faculty participated in the Boot Camp vessel anastomosis sessions. A portable chest model with synthetic graft and target vessels and a tissue-based porcine model simulated coronary artery anastomosis. After each 2-hour session on days 1 and 2, residents assessed teaching behaviors of faculty using a 20-item questionnaire based on the 5-point Likert scale. After session on day 1, faculty completed a self-assessment questionnaire. At 3 months, faculty completed self-assessment questionnaires regarding teaching behaviors in simulation and clinical settings. Each questionnaire item represents 1 or more teaching categories: "learning climate," "control of session," "communication of goals," "promoting understanding and retention," "evaluation," "feedback," and "self-directed learning." RESULTS: Generally, resident ratings indicated that faculty showed positive teaching behaviors. Faculty self-assessment ratings were all lower (P < .025) than those assigned to them by the residents except for 1 component representative of "feedback," which approached significance (P = .04); 2 items, representative of "promoting understanding and retention" and "evaluation", had mean scores of less than 3. At 3 months, compared with self-assessment at Boot Camp, faculty ratings suggested improved teaching behaviors in their simulation settings in the following: "learning climate," "control of session," "communication of goals," "promoting understanding and retention," and "evaluation." The simulation environment was perceived as more positive for technical skills training in certain aspects compared with clinical setting: instructor reviewed function and operation of equipment with learner before session (representative of "promoting understanding and retention") and instructor allowed the learner ample time to practice (representative of "control of session" and "promoting understanding and retention") (P < .025). CONCLUSIONS: Simulation-based skills training is perceived by residents to be associated with positive teaching behaviors. Faculty self-ratings indicate that they do not always use many of these teaching behaviors and that their performance can be improved. The simulation setting may provide greater opportunity for positive teaching behaviors compared with the clinical environment. PMID- 23098749 TI - Experimental noninferiority trial of synthetic small-caliber biodegradable versus stable vascular grafts. AB - OBJECTIVE: Long-term evolution of polycaprolactone vascular prostheses has been investigated recently. The goal of this study was to evidence a noninferiority of such grafts compared with expanded polytetrafluoroethylene (ePTFE) implants in an aortic replacement model in the rat. METHODS: Fourteen anesthetized Sprague Dawley rats received an infrarenal aortic graft (biodegradable, n = 8; expanded polytetrafluoroethylene, n = 6) replacement (end to end; inner diameter, 2 mm). Biodegradable grafts (polycaprolactone) were produced by random micro-/nanofiber electrospinning. After a median survival of 16.5 months, in vivo ultrasonography and angiography as well as postexplantation microcomputed tomography, histomorphometry, immunohistochemistry, and scanning electron microscopy were performed. RESULTS: Patency was 100% for polycaprolactone and 67% for ePTFE. No aneurysmal dilatation or stenoses were found in either group. Compliance was significantly higher for polycaprolactone compared with ePTFE (8.2 +/- 1.0%/100 mm Hg vs 5.7 +/- 0.7%/100 mm Hg; P < .01), but markedly reduced compared with adjacent native aortas and the control group. Histologically, low cellular in growth was found in ePTFE whereas polycaprolactone showed significantly greater homogenous cellularity, producing an autologous extracellular matrix (10.8% +/- 4.0% vs 32.1% +/- 9.2%, P < .0001). Morphometry showed 100% neo endothelialization for both grafts with a totally confluent endothelial coverage for polycaprolactone grafts by scanning electron microscope. More intimal hyperplasia was found in ePTFE compared with polycaprolactone grafts. Calcification was higher in ePTFE than in polycaprolactone grafts (15.8% vs 7.0%, P = .04) and was absent in controls. CONCLUSIONS: Outcomes of synthetic biodegradable nanofiber polycaprolactone grafts are not inferior compared with the clinically used expanded polytetrafluoroethylene grafts after long-term implantation in the rat aorta. Moreover, these implants show better patency, compliance, endothelialization, and cell in-growth, and less intimal hyperplasia and calcification than their counterparts. PMID- 23098751 TI - A neural model of visual figure-ground segregation from kinetic occlusion. AB - Freezing is an effective defense strategy for some prey, because their predators rely on visual motion to distinguish objects from their surroundings. An object moving over a background progressively covers (deletes) and uncovers (accretes) background texture while simultaneously producing discontinuities in the optic flow field. These events unambiguously specify kinetic occlusion and can produce a crisp edge, depth perception, and figure-ground segmentation between identically textured surfaces--percepts which all disappear without motion. Given two abutting regions of uniform random texture with different motion velocities, one region appears to be situated farther away and behind the other (i.e., the ground) if its texture is accreted or deleted at the boundary between the regions, irrespective of region and boundary velocities. Consequently, a region with moving texture appears farther away than a stationary region if the boundary is stationary, but it appears closer (i.e., the figure) if the boundary is moving coherently with the moving texture. A computational model of visual areas V1 and V2 shows how interactions between orientation- and direction-selective cells first create a motion-defined boundary and then signal kinetic occlusion at that boundary. Activation of model occlusion detectors tuned to a particular velocity results in the model assigning the adjacent surface with a matching velocity to the far depth. A weak speed-depth bias brings faster-moving texture regions forward in depth in the absence of occlusion (shearing motion). These processes together reproduce human psychophysical reports of depth ordering for key cases of kinetic occlusion displays. PMID- 23098752 TI - Artificial vision by multi-layered neural networks: neocognitron and its advances. AB - The neocognitron is a neural network model proposed by Fukushima (1980). Its architecture was suggested by neurophysiological findings on the visual systems of mammals. It is a hierarchical multi-layered network. It acquires the ability to robustly recognize visual patterns through learning. Although the neocognitron has a long history, modifications of the network to improve its performance are still going on. For example, a recent neocognitron uses a new learning rule, named add-if-silent, which makes the learning process much simpler and more stable. Nevertheless, a high recognition rate can be kept with a smaller scale of the network. Referring to the history of the neocognitron, this paper discusses recent advances in the neocognitron. We also show that various new functions can be realized by, for example, introducing top-down connections to the neocognitron: mechanism of selective attention, recognition and completion of partly occluded patterns, restoring occluded contours, and so on. PMID- 23098753 TI - Intrinsically motivated action-outcome learning and goal-based action recall: a system-level bio-constrained computational model. AB - Reinforcement (trial-and-error) learning in animals is driven by a multitude of processes. Most animals have evolved several sophisticated systems of 'extrinsic motivations' (EMs) that guide them to acquire behaviours allowing them to maintain their bodies, defend against threat, and reproduce. Animals have also evolved various systems of 'intrinsic motivations' (IMs) that allow them to acquire actions in the absence of extrinsic rewards. These actions are used later to pursue such rewards when they become available. Intrinsic motivations have been studied in Psychology for many decades and their biological substrates are now being elucidated by neuroscientists. In the last two decades, investigators in computational modelling, robotics and machine learning have proposed various mechanisms that capture certain aspects of IMs. However, we still lack models of IMs that attempt to integrate all key aspects of intrinsically motivated learning and behaviour while taking into account the relevant neurobiological constraints. This paper proposes a bio-constrained system-level model that contributes a major step towards this integration. The model focusses on three processes related to IMs and on the neural mechanisms underlying them: (a) the acquisition of action outcome associations (internal models of the agent-environment interaction) driven by phasic dopamine signals caused by sudden, unexpected changes in the environment; (b) the transient focussing of visual gaze and actions on salient portions of the environment; (c) the subsequent recall of actions to pursue extrinsic rewards based on goal-directed reactivation of the representations of their outcomes. The tests of the model, including a series of selective lesions, show how the focussing processes lead to a faster learning of action-outcome associations, and how these associations can be recruited for accomplishing goal directed behaviours. The model, together with the background knowledge reviewed in the paper, represents a framework that can be used to guide the design and interpretation of empirical experiments on IMs, and to computationally validate and further develop theories on them. PMID- 23098750 TI - Contemporary patterns of surgery and outcomes for aortic coarctation: an analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database. AB - OBJECTIVE: The objective of this study was to describe characteristics and early outcomes across a large multicenter cohort undergoing coarctation or hypoplastic aortic arch repair. METHODS: Patients undergoing coarctation or hypoplastic aortic arch repair (2006-2010) as their first cardiovascular operation in the Society of Thoracic Surgeons Congenital Heart Surgery Database were included. Group 1 patients consisted of those with coarctation or hypoplastic aortic arch without ventricular septal defect (coarctation or hypoplastic aortic arch, isolated); group 2, coarctation or hypoplastic aortic arch with ventricular septal defect (coarctation or hypoplastic aortic arch, ventricular septal defect); and group 3, coarctation or hypoplastic aortic arch with other major cardiac diagnoses (coarctation or hypoplastic aortic arch, other). RESULTS: The cohort included 5025 patients (95 centers): group 1, 2705 (54%); group 2, 840 (17%); and group 3, 1480 (29%). Group 1 underwent coarctation or hypoplastic aortic arch repair at an older age than groups 2 and 3 (groups 1, 2, and 3, 75%, 99%, and 88% <1 year old, respectively; P < .0001). The most common operative techniques for coarctation or hypoplastic aortic arch repair (group 1) were end to-end (33%) or extended end-to-end (56%) anastomosis. Overall mortality was 2.4%, and was 1%, 2.5%, and 4.8% for groups 1, 2, and 3 respectively (P < .0001). Ventricular septal defect management strategies for group 2 patients included ventricular septal defect closure (n = 211, 25%), pulmonary artery band (n = 89, 11%), or no intervention (n = 540, 64%) without significant difference in mortality (4%, 1%, 2%; P = .15). Postoperative complications occurred in 36% of patients overall and were more common in groups 2 and 3. There were no occurrences of spinal cord injury (0/973). CONCLUSIONS: In the current era, primary coarctation or hypoplastic aortic arch repair is performed predominantly in neonates and infants. Overall mortality is low, although those with concomitant defects are at risk for higher morbidity and mortality. The risk of spinal cord injury is lower than previously reported. PMID- 23098754 TI - An in vitro study of the role of beta-boswellic acid in the microtubule assembly dynamics. AB - Structural integrity of microtubule protein (MTP) is pivotal for its physiological roles. Disruption of the MTP network is known to be involved in neurodegenerative disorders. The gum resin of plants of the boswellia species, with beta-boswellic acid (BBA) as the major component, has long been used in Ayurveda and Oriental Medicine to prevent amnesia. In the current study, we addressed the question whether BBA affects assembly dynamics behavior of tubulin. Our in vitro results revealed that BBA increases MTP length distribution and the polymerization rate of tubulin, moderately stabilizing it and diminishing both the critical concentration (C(c)) and the fraction of inactive tubulin (F(i)). PMID- 23098755 TI - A malfunction in triglyceride transfer from the intracellular lipid pool to apoB in enterocytes of SOD1-deficient mice. AB - We compared lipid metabolism in the intestines of Sod1-knockout mice with that found in wild-type mice to elucidate the impact of oxidative stress in vivo. A high-fat diet in wild-type mice induced postprandial hypertriglyceridemia, but this adaptive response was impaired in Sod1-knockout mice. While fewer triglycerides were secreted to the blood in the form of triglyceride-rich lipoprotein, more lipid droplets accumulated in the enterocytes of Sod1-knockout mice fed a high-fat diet. These data collectively suggest that high-fat diet induces oxidative stress, inhibits lipid secretion to the blood, and ultimately leads to dysfunctional lipid metabolism in enterocytes. PMID- 23098756 TI - Crossover inhibition as an indicator of convergent evolution of enzyme mechanisms: a beta-lactamase and a N-terminal nucleophile hydrolase. AB - O-Aryloxycarbonyl hydroxamates and 1,3,4-oxathiazol-2-ones have been identified as covalent inhibitors of beta-lactamases and proteasomes, respectively. The products of these inhibition reactions are remarkably similar, involving carbonyl cross-linking of the active sites. We have cross-checked these inhibitors, showing that the former inhibit proteasomes and the latter beta-lactamases, to form the same inactive carbonyl adducts. These results are discussed in terms of similarities of the active site structures and catalytic mechanisms. It is likely that a mechanistic imperative has led to convergent evolution of these enzyme active sites, of a beta-lactam-recognizing enzyme and a N-terminal protease belonging to different amidohydrolase superfamilies. PMID- 23098757 TI - Functional analysis of MITF gene mutations associated with Waardenburg syndrome type 2. AB - MITF mutations results in an abnormal melanocyte development and lead to Waardenburg syndrome type 2 (WS2). Here, we analyzed the in vitro activities of two recently identified WS2-associated MITF mutations (p.R217I and p.T192fsX18). The R217I MITF retained partial activity, normal DNA-binding ability and nuclear distribution, whereas the T192fsX18 MITF failed to activate TYR promoter and showed aberrant subcellular localization which may be caused by deletion of nuclear localization signal (NLS) at aa 213-218 (ERRRRF). These results suggest that haploinsufficiency may be the underlying mechanism for the mild phenotypes of WS2 caused by these two mutations. PMID- 23098758 TI - ncRNAs and thermoregulation: a view in prokaryotes and eukaryotes. AB - During cellular stress response, a widespread inhibition of transcription and blockade of splicing and other post-transcriptional processing is detected, while certain specific genes are induced. In particular, free-living cells constantly monitor temperature. When the thermal condition changes, they activate a set of genes coding for proteins that participate in the response. Non-coding RNAs, ncRNAs, and conformational changes in specific regions of mRNAs seem also to be crucial regulators that enable the cell to adjust its physiology to environmental changes. They exert their effects following the same principles in all organisms and may affect all steps of gene expression. These ncRNAs and structural elements as related to thermal stress response in bacteria are reviewed. The resemblances to eukaryotic ncRNAs are highlighted. PMID- 23098759 TI - Mitotic centromere-associated kinase (MCAK/Kif2C) regulates cellular senescence in human primary cells through a p53-dependent pathway. AB - Mitotic centromere-associated kinase (MCAK/Kif2C) plays a critical role in chromosome movement and segregation with ATP-dependent microtubule depolymerase activity. However, its role in cellular senescence remains unclear. MCAK/Kif2C expression decreased in human primary cells under replicative and premature senescence. MCAK/Kif2C down-regulation in young cells induced premature senescence. MCAK/Kif2C overexpression in old cells partially reversed cell senescence. Senescence phenotypes by MCAK/Kif2C knockdown were observed in p16 knockdown cells, but not in p53-knockdown cells. These results suggest that MCAK/Kif2C plays an important role in the regulation of cellular senescence through a p53-dependent pathway and might contribute to tissue/organism aging and protection of cellular transformation. PMID- 23098761 TI - Differential localization of LGR5 and Nanog in clusters of colon cancer stem cells. AB - One paradigm of cancer development claims that cancer emerges at the niche of tissue stem cells and these cells continue to proliferate in the tumor as cancer stem cells. LGR5, a membrane receptor, was recently found to be a marker of normal colon stem cells in colon polyps and is also expressed in colon cancer stem cells. Nanog, an embryonic stem cell nuclear factor, is expressed in several embryonic tissues, but Nanog expression is not well documented in cancerous stem cells. Our aim was to examine whether both LGR5 and Nanog are expressed in the same clusters of colon stem cells or cancer stem cells, using immunocytochemistry with specific antibodies to each antigen. We analyzed this aspect using paraffin embedded tumor tissue sections obtained from 18 polyps and 36 colon cancer specimens at stages I-IV. Antibodies to LGR5 revealed membrane and cytoplasm immunostaining of scattered labeled cells in normal crypts, with no labeling of Nanog. However, in close proximity to the tumors, staining to LGR5 was much more intensive in the crypts, including that of the epithelial cells. In cancer tissue, positive LGR5 clusters of stem cells were observed mainly in poorly differentiated tumors and in only a few scattered cells in the highly differentiated tumors. In contrast, antibodies to Nanog mainly stained the growing edges of carcinoma cells, leaving the poorly differentiated tumor cells unlabeled, including the clustered stem cells that could be detected even by direct morphological examination. In polyp tissues, scattered labeled cells were immunostained with antibodies to Nanog and to a much lesser extent with antibodies to LGR5. We conclude that expression of LGR5 is probably specific to stem cells of poorly differentiated tumors, whereas Nanog is mainly expressed at the edges of highly differentiated tumors. However, some of the cell layers adjacent to the carcinoma cell layers that still remained undifferentiated, expressed mainly Nanog with only a few cells labeled with antibodies to LGR5. Considering the different sites and pattern of expression in the tumor, our data imply that targeting the clustered stem cells expressing LGR5 in poorly differentiated colon cancer may require different strategies than targeting the stem cells expressing Nanog in the highly differentiated tumors. Alternatively, combined application of specific inhibitory miRNAs to Nanog and to LGR5 expression may assist therapeutically. PMID- 23098760 TI - The involvement of Type II Neuregulin-1 in rat visuospatial learning and memory. AB - The cognitive deficits observed in schizophrenia are considered a core feature of the disease. Neuregulin-1 is a risk gene for schizophrenia that is involved in many neurodevelopmental and synaptic plasticity-related processes relevant to schizophrenia. Here, we have utilized a rat model (Nrg1(Tn)), which is hypomorphic for the neuregulin-1 (Nrg1) gene, to test whether reduced Type II NRG1 in the rat brain leads to cognitive deficits relevant to schizophrenia. Wild type and homozygous Nrg1(Tn) male rats were tested in memory tasks that evaluated spatial memory (Morris water maze) and visuospatial working and reference memory (Can Test). Nrg1(Tn) rats were not impaired on the Morris water maze, but did show a deficit in the appetitive visuospatial discrimination test. Nrg1(Tn) rats committed more reference and working memory errors in this test. These results indicate that decreased Type II NRG1 in the brain may lead to deficits in visuospatial learning and memory. PMID- 23098762 TI - A randomized double-blind placebo-controlled phase 2 dose-ranging study of onabotulinumtoxinA in men with benign prostatic hyperplasia. AB - BACKGROUND: Botulinum toxin treatment has been investigated as a minimally invasive alternative to oral medications in men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic hyperplasia (LUTS/BPH). OBJECTIVE: To explore the efficacy of onabotulinumtoxinA 100 U, 200 U, and 300 U versus placebo in men with LUTS/BPH in a phase 2 dose-ranging study. DESIGN, SETTING, AND PARTICIPANTS: A multicenter double-blind randomized, placebo-controlled 72-wk study enrolled men >= 50 yr of age with LUTS/BPH, International Prostate Symptom Score (IPSS) >= 12, total prostate volume (TPV) 30-100ml, and maximum flow rate (Q(max)) 5-15 ml/s. INTERVENTION: Single transperineal (n=63) or transrectal (n=311) administration of placebo (n=94) or onabotulinumtoxinA 100 U (n=95), 200 U (n=94), or 300 U (n=97) into the prostate transition zone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy end point was a change from baseline in IPSS at week 12. Secondary end points were Q(max), TPV, and transition zone volume (TZV). Analysis of covariance and the Cochran-Mantel Haenszel method assessed the efficacy and proportion of IPSS responders. Adverse events (AEs) were assessed. RESULTS AND LIMITATIONS: Significant improvements from baseline in IPSS, Q(max), TPV, and TZV were observed for all groups, including placebo, at week 12 (p<0.001), with no significant differences between onabotulinumtoxinA and placebo. However, in an exploratory post hoc analysis, a significant reduction in IPSS versus placebo was observed with onabotulinumtoxinA 200 U in prior alpha-blocker users (n=180) at week 12. AEs were comparable across all groups. CONCLUSIONS: Reductions in LUTS/BPH symptoms were seen in all groups, including placebo, with no significant between-group differences owing to a large placebo effect from the injectable therapy. The findings from the post hoc analysis in men previously treated with alpha-blockers will be further explored in an appropriately designed study. TRIAL REGISTRATION: http://www.Clinical Trials.gov; NCT00284518. PMID- 23098764 TI - From diagnostic tool to disease monitoring: the growing role of prostate biopsies. PMID- 23098765 TI - Intracerebral abscess: a rare complication of Deep Brain Stimulation. AB - INTRODUCTION: Deep Brain Stimulation (DBS) is a therapeutic option for some forms of Parkinson's disease (PD). The main adverse effects of this surgery are: infection (2-9%), haemorrhage (1-4%) and seizures (1-3%). We report a rare complication of DBS: an intracranial abscess. CASE REPORT: A 59-year-old male who had suffered PD for 19 years was submitted to bilateral subthalamic nucleus DBS in September 2003, when he was 52. One month later, he developed an inflammatory reaction of the skin and subcutaneous tissue surrounding the area of the subcutaneous DBS system. No infectious agent was isolated. In the following 12 months he required 5 major surgeries due to a process of systematic inflammation/infection throughout different locations of the DBS system. A few days after removal of the DBS device, he developed a right oculomotor nerve paresis and mild left hemiparesis. A CT scan revealed an abscess in the right thalamo-mesencephalic area. Both the new neurological deficits and the previous tremor and rigidity improved after surgical drainage and medical treatment. CONCLUSION: This case report illustrates a rare complication of DBS surgery. Nevertheless, Parkinsonism improved, probably because the abscess acted like a subthalomotomy. PMID- 23098767 TI - Increased levels of osteopontin in sputum supernatant of smoking asthmatics. AB - Smoking may modify the inflammatory pattern of the asthmatic airways. Osteopontin (OPN) has been associated with inflammation and fibrosis. In asthma, sputum levels of OPN are elevated and have been related to the underlying severity and to mediators expressing remodeling and inflammation. To evaluate the levels of OPN in sputum supernatants of asthmatic patients and to investigate the possible role of smoking as well as associations with mediators and cells involved in the inflammatory and remodeling process. We studied 103 asthma patients (49 smokers) and 40 healthy subjects (20 smokers) who underwent lung function tests, bronchial hyperresponsiveness to methacholine, and sputum induction for cell count identification and measurement of OPN, TGF-beta1, IL-8, IL-13 and ECP in sputum supernatants. The concentrations of all mediators were measured using enzyme immunoassays. OPN levels (pg/ml) were significantly higher in smoking asthmatics compared to non-smoking asthmatics, and both non-smoking and smoking controls [median (interquartile ranges) 1120 (651,1817) vs. 197 (118,341) vs. 50 (42,70) vs. 102 (77,110) pg/ml, respectively; p<0.001]. Regression analysis provided significant associations between OPN and sputum neutrophils, IL-8 and TGF-beta1, the most significant being the one with TGF-beta1. These associations were present only in smoking asthmatics. Smoking habit significantly affects sputum OPN levels in asthma. The associations of OPN with sputum neutrophils, TGF-beta1 and IL-8 in smoking asthmatics suggest a possible role for OPN in the neutrophilic inflammation and remodeling process in this phenotype of asthma. PMID- 23098766 TI - [Anterior cerebral artery aneurism presenting as a third ventricular mass and hydrocephalus. Case report]. AB - Aneurysms which appear as third ventricular masses are uncommon; most are giant aneurysms arising from the basilar apex. We present the case of a 67-year-old male who was admitted to hospital with a 4-week history of gait instability, urinary incontinence and progressive visual loss. A cranial computed tomography scan revealed a hyperdense mass in the third ventricle with triventricular dilatation. Cerebral magnetic resonance imaging, magnetic resonance-angiography and conventional angiography identified this lesion as a partially thrombosed aneurysm of the anterior cerebral artery. To our knowledge, this is the first report of an anterior cerebral artery aneurysm with these clinical and radiological features. PMID- 23098768 TI - Interleukin-21 expanded NKDC in vitro reduces the B16F10 tumor growth in vivo. AB - Innate immunity to tumors is mediated mainly by natural killer cells (NKs) and dendritic cells (DCs). The function of these cells is coordinated by cytokines produced during the inflammatory process. NK cells are highly active against tumors, being an important source of IFN-gamma. Natural killer dendritic cells (NKDCs) were recently identified as a group of hybrid cells; some studies claim that they have lytic activity, produce IFN-gamma and can also stimulate antigen specific T cells. Interleukin 21 (IL-21) regulates the proliferation capacity and cytotoxicity of NK and T cells. The main objective of this study was to investigate if IL-21 influences the frequency of NKDCs in vitro as well as IFN gamma production and also to verify if these cells could enhance the antitumor activity against B16F10 tumor model in vivo. Splenocytes from C57BL/6 mice were isolated and the DC were enriched by immunomagnetic beads and cultured for four days with recombinant IL-21 (10, 20, 40 or 100 ng/ml). NKDC population was characterized as CD11clow/medB220+NK1.1+. Expanded cells were used to treat B16F10 tumor bearing mice and tumor growth was compared between the doses of IL 21 10 ng/ml and 20 ng/ml. The results indicate that IL-21 increases the expansion of splenic NKDCs in vitro in doses of 10 ng/ml and 20 ng/ml and these cells produce IFN-gamma. In vivo, cells expanded with IL-21 and injected directly into the growing tumor efficiently reduced the tumor size. Together, these results showed for the first time that IL-21 influences the biology and the effector activity of NKDCs. PMID- 23098769 TI - Bioenergetic dysfunction in disease. PMID- 23098770 TI - Gene transfer of human CD40Ig does not prevent rejection in a non-human primate kidney allotransplantation model. AB - BACKGROUND: Blockade of costimulation signaling required for immune response, such as CD40/CD40L and CD28/B7, is a reasonable strategy to prevent rejection and in defined combinations may allow donor specific tolerance. Indeed, in rodents, costimulation blockade with CD28/B7 antagonists or with CD40Ig was able to induce regulatory T cells and transplant tolerance whereas in primates, anti-CD40 antibodies, anti-CD40L antibodies or CTLA4Ig, used as monotherapy, significantly delayed graft rejection. METHODS: Using an adeno-associated virus (AAV) vector mediated gene transfer of a human CD40Ig fusion protein (hCD40Ig) in primates, we evaluated the capacity of this costimulation blockade molecule interfering with CD40/CD40L signaling in prolonging kidney transplants in cynomolgus monkeys. RESULTS: This gene transfer strategy allowed for maintaining a plateau of hCD40Ig production within two months and avoided a high-scale production phase of this molecule. Although the hCD40Ig was able to bind efficiently to human and macaque CD40L and high (>200 MUg/ml) transgene expression was obtained, no effect on graft survival was observed. In addition, there was no inhibition of humoral response to vaccination. In vitro, hCD40Ig strongly increased mixed lymphocyte reaction, and when compared to the anti-CD40L antibody h5C8, was not as potent to induce complement-dependent cytotoxicity. CONCLUSION: These data suggest that CD40/CD40L blockade using a non-depleting CD40Ig fusion protein, a therapeutic strategy that showed efficacy in rodents, is not able to modulate the immune response in primates. These data highlight important biological differences between rodent and primate models to evaluate therapeutic strategies at the preclinical level. PMID- 23098771 TI - Aspects of cell growth control illustrated by the Schwann cell. AB - The control of cell biogenesis remains poorly understood, despite being critical for the development and maintenance of all organisms. Studies in vitro and in vivo using the Schwann cell, the glial cell of the peripheral nervous system, have provided important insights into cell growth control. These studies have demonstrated how instructive growth factor signals can control cell growth rates, cell size and organelle biogenesis and how deregulated cell growth can contribute to diseases, such as cancer. Additional studies on Schwann cells highlight the importance of cell size control within a tissue--the size of myelinating Schwann cells is coupled to the size of the axon they ensheath, which is necessary for efficient nerve conduction. PMID- 23098772 TI - Cavus foot, from neonates to adolescents. AB - Pes cavus, defined as a high arch in the sagittal plane, occurs in various clinical situations. A cavus foot may be a variant of normal, a simple morphological characteristic, seen in healthy individuals. Alternatively, cavus may occur as a component of a foot deformity. When it is the main abnormality, direct pes cavus should be distinguished from pes cavovarus. In direct pes cavus, the deformity occurs only in the sagittal plane (in the forefoot, hindfoot, or both). Direct pes cavus may be related to a variety of causes, although neurological diseases predominate in posterior pes cavus. Pes cavovarus is a three-dimensional deformity characterized by rotation of the calcaneopedal unit (the foot minus the talus). This deformity is caused by palsy of the intrinsic foot muscles, usually related to Charcot-Marie-Tooth disease. The risk of progression during childhood can be eliminated by appropriate conservative treatment (orthosis to realign the foot). Extra-articular surgery is indicated when the response to orthotic treatment is inadequate. Muscle transfers have not been proven effective. Triple arthrodesis (talocalcanear, talonavicular, and calcaneocuboid) accelerates the mid-term development of osteoarthritis in the adjacent joints and should be avoided. PMID- 23098773 TI - NCB-plating in the treatment of geriatric and periprosthetic femoral fractures. AB - BACKGROUND: The aim of this study is the presentation of the polyaxial locking NCB-plate in the treatment of femoral fractures, especially in elderly patients and in proximity of a prosthetic implant. The reduction and fixation of these fractures is a challenging surgical procedure with high complication rates reported up to 40%. PATIENTS AND METHODS: A total of 72 patients with femoral fractures had polyaxial locking plate osteosynthesis. Indications included fractures of the shaft and around an implant. Concerning surgical procedures, three different standardized techniques were performed: (1) minimally invasive with percutaneous distal insertion using a targeting device; (2) mini-open with additional cerclage wire via the same approach and (3) a conventional open reduction and internal fixation. Data collection included intraoperative data and early complications at 6, 24 and 52 weeks. Fifty-two patients had an implant or prosthesis in situ. Thirty-three patients were treated by technique (1), 32 patients had mini-open surgery and seven patients conventional open surgery. RESULTS: Thirty-nine patients attended clinical follow-up after 52 weeks. Twenty two patients were interviewed by telephone, two were untraceable and nine patients had died. Bony consolidation without secondary loss of reduction was confirmed after 52 weeks in all patients but two. Plate breakage occurred in these two at 25 and 31 weeks after surgery due to non-union. Implant related complications (17% in total) lead to surgical revision in five other cases: two deep wound infections as well as three minor revisions. When itemizing complications according to surgical technique used, most major complications occurred following open surgery. CONCLUSION: The availability of polyaxial locking implants widened the range of indications for plate fixation in femoral fractures. The advantages of the polyaxial locking implant combined with minimally invasive surgical technique contribute to successful management of this population category. Early revision rate is noticeably lower compared to similar procedures. LEVEL OF EVIDENCE: IV retrospective series. PMID- 23098774 TI - Partial arthroscopic trapeziectomy with ligament reconstruction to treat primary thumb basal joint osteoarthritis. AB - Since the outcome of partial trapeziectomy is not always satisfactory, we proposed using arthroscopy to perform partial trapeziectomy and to perform ligament reconstruction with the abductor pollicis longus tendon. A tendon strip was left intact at its insertion at the base of the first metacarpal and then slipped into the trapeziectomy space. It was fixed into a blind tunnel at the base of the second metacarpal with a bioabsorbable interference screw. Forty-nine patients were surgically treated between 2006 and 2009. With an average follow-up of 3.6 years, 83.5% of patients were satisfied with the procedure; 96% of thumbs were stable and 74% were pain free. The average recovery time was 4.5 months. There were four cases of radial nerve branch irritation and one case of flexor carpi radialis tendinitis; there were no cases of complex regional pain syndrome. This minimally-invasive technique is a less-aggressive treatment approach for thumb carpometacarpal joint arthritis, which simplify postoperative recovery. PMID- 23098775 TI - Practices to prevent multidrug-resistant Acinetobacter baumannii and methicillin resistant Staphylococcus aureus in Thailand: a national survey. AB - BACKGROUND: Multidrug-resistant organisms (MDRO) are increasing challenges for health care institutions worldwide, and there are many factors associated with their distribution. OBJECTIVES: We conducted a national survey of Thai hospitals with 1 or more intensive care units and >=250 hospital beds to evaluate hospital characteristics and current practices to minimize the endemic burden of multidrug resistant (MDR) Acinetobacter baumannii (AB) and methicillin-resistant Staphylococcus aureus (MRSA). METHODS: Research nurses collected survey data from participating hospitals between January 1 and April 30, 2011. Data collection focused on hospital characteristics and practices to prevent endemic MDR-AB and MRSA; logistic regression analyses were used to assess associations between hospital characteristics and infection prevention control (IPC) interventions. RESULTS: There was an 80% survey response (N = 204) from 256 eligible hospitals. Endemic MDR-AB and MRSA were reported in 184 (90%) and 100 (40%) hospitals, respectively. The most frequently reported IPC interventions were contact isolation, hand hygiene campaigns, and antimicrobial stewardship; active surveillance, chlorhexidine gluconate bathing, and multifaceted interventions were uncommon. By multivariate analysis, having a physician as the lead infection control professional and participation in a collaborative effort to prevent MDR organisms were associated with multifaceted interventions to reduce MDR-AB, and medical school affiliation and participating in a collaborative effort to prevent MDR organisms were associated with multifaceted interventions to reduce MRSA. CONCLUSION: Multifaceted interventions to reduce, if not prevent, MDR-AB and MRSA were infrequently reported from Thai hospitals. Our survey findings provide baseline data for IPC interventions for MDR-AB and MRSA. Future efforts that correlate IPC interventions and MDRO trends will help develop evidence-based practices in these resource-limited settings. PMID- 23098776 TI - Glycolytic pathway activity: effect on IVM and oxidative metabolism of bovine oocytes. AB - The aim of the present study was to determine the effect of altering glycolytic pathway activity during bovine IVM on the meiotic maturation rate, oxidative activity, mitochondrial activity and the mitochondrial distribution within oocytes. Glycolytic activity was manipulated using two inhibitors (ATP, NaF) and a stimulator (AMP) of key enzymes of the pathway. Inhibition of glucose uptake, lactate production and meiotic maturation rates was observed when media were supplemented with ATP or NaF. The addition of AMP to the maturation medium had no effect on glucose uptake, lactate production or meiotic maturation. In the absence of gonadotrophin supplementation, AMP stimulated both glucose uptake and lactate production. However, AMP also decreased cytoplasmic maturation, as determined by early cleavage. During IVM, oocyte oxidative and mitochondrial activity was observed to increase at 15 and 22h maturation. Inhibiting glycolysis with ATP or NaF led to a reduced oxidative and mitochondrial pattern compared with the respective control groups. Stimulation of the pathway with AMP increased oxidative and mitochondrial activity. A progressive mitochondrial migration to the central area was observed during maturation; oocytes treated with ATP, NaF or AMP showed limited migration. The present study reveals the effects of altering glycolytic pathway activity in cumulus-oocyte complexes, revealing the link between glycolysis of the cumulus-oocyte complex and the oxidative and mitochondrial activity of the oocyte. PMID- 23098777 TI - The patient's priorities. PMID- 23098778 TI - An observational clinical and video-polysomnographic study of the effects of clonazepam in REM sleep behavior disorder. AB - OBJECTIVE: To analyze the differences in sleep structure and nocturnal motor activity between drug-free REM sleep behavior disorder (RBD) patients and those under therapy with clonazepam, and to evaluate the long-term longitudinal changes under continued therapy with clonazepam. METHODS: Fifty-seven consecutive iRBD patients were recruited (52 men and 5 women, mean age 68.8+/-6.03years). Forty two patients were not taking any medication at the time of the evaluation (iRBD Clo) while 15 were taking clonazepam (0.5-1mg) at bedtime (iRBD+Clo). The Clinical Global Impression-Severity (CGI-S) scale was obtained. Sleep was video polysomnographically recorded and the RBD severity scale (RBDSS) obtained. The chin EMG amplitude was quantitatively assessed and the Atonia Index computed. RESULTS: Disease duration was significantly longer in iRBD+Clo patients who also showed a lower rate of stage shifts, higher sleep efficiency and lower percentage of wakefulness after sleep onset and of sleep stage 1, and an increased percentage of sleep stage 2. The longitudinal long-term follow up study in a subgroup of 13 patients showed moderately increased total sleep time, sleep efficiency, sleep stage 2, slow-wave sleep and decreased wakefulness after sleep onset and sleep stage 1, under clonazepam treatment. The CGI scale clearly tended to improve after treatment, but no common trend was evident for RBDSS or Atonia Index. CONCLUSIONS: This study provides evidence of important objective effects of clonazepam on NREM sleep in RBD; this data might be very important for the development of new and effective treatments for this condition. PMID- 23098779 TI - Complex sleep behavior in a patient with obstructive sleep apnea and nocturnal hypoglycemia: a diagnostic dilemma. PMID- 23098780 TI - The how's and why's of protein folding intermediates. AB - The nature and role of intermediates have been the subject of much heated debate in the field of protein folding. Historically, intermediates were viewed as essential stepping-stones that guide a protein through the folding process to the native state. However, with the experimental identification of numerous small proteins that fold rapidly without intermediates, and the emergence from computational studies of new conceptual frameworks, came the thinking that intermediates can act as energy sinks, kinetic traps that result in less efficient folding. Whether 'good' or 'bad', it is without doubt that folding intermediates provide valuable information to protein chemists: at equilibrium they help to delineate the subdomain architecture of a protein and the hierarchy of subdomain stabilities; under kinetic conditions they provide experimentalists with additional snapshots of the folding reaction and, thereby, fundamental mechanistic details that are often lacking in the case of two-state folders. Intermediates give us valuable insights into the fluctuations from the native structure that may be important in regulating biological function. Lastly, intermediates are often the critical species in misfolding processes that lead to aggregation and disease. Here we review what we have learnt after almost half a century of protein-folding research, and we question two fundamental tests of our understanding: do we know enough about how proteins fold to design folding mechanisms de novo and can we exploit our knowledge to modulate protein-folding mechanisms in the cell for therapeutic benefit? PMID- 23098781 TI - Predictors of ischemia in patients referred for evaluation of exertional dyspnea: a stress echocardiography study. AB - BACKGROUND: There are conflicting data on the incidence of ischemia by stress echocardiography in patients referred for dyspnea without accompanying chest pain. METHODS: A total of 311 consecutive patients with exertional dyspnea (without chest pain) referred to the echocardiography lab for ischemia evaluation from August 2008 to March 2012 were evaluated. Exercise by Bruce protocol or dobutamine stress echocardiography was performed. Resting left ventricular ejection fraction and segmental wall motion abnormalities were assessed. Multivariate logistic regression analysis was used to identify independent predictors of ischemia on stress echocardiography. RESULTS: The mean age was 61 years (range, 20-96 years), with 196 women (63%). Exercise stress was performed in 114 patients (37%); the rest of the patients underwent dobutamine stress. The patient population had a high burden of obesity, diastolic dysfunction, and pulmonary hypertension. Thirty patients (10%) had evidence of stress-induced ischemia (nine [8%] with exercise and 21 [11%] with dobutamine). In multivariate analysis, male gender (odds ratio, 2.8; P = .03), history of coronary artery disease (odds ratio, 3.5; P = .02), and resting wall motion abnormalities (odds ratio, 16.6; P < .01) were independent predictors of inducible ischemia. CONCLUSIONS: The incidence of stress-induced ischemia is low in patients referred for stress echocardiography with exertional dyspnea (without chest pain). Ischemia is more likely to be present in men with histories of coronary artery disease and resting wall motion abnormalities. PMID- 23098782 TI - Subjective evaluation of right ventricular systolic function in hypoplastic left heart syndrome: how accurate is it? AB - BACKGROUND: The geometry and heterogeneity of the right ventricle in hypoplastic left heart syndrome makes objective echocardiographic assessment of systolic function challenging. Consequently, subjective echocardiographic assessment of right ventricular (RV) function is still routinely undertaken. The aims of this study were to compare this with magnetic resonance imaging (MRI), investigate the impact of experience and training on the accuracy of subjective assessment, and critically analyze the role of echocardiography to detect impaired systolic function. METHODS: A retrospective analysis of prospectively acquired data was performed. Children with hypoplastic left heart syndrome underwent routine preoperative cardiac MRI and echocardiography under the same general anesthetic. Echocardiograms were reviewed, and members of the congenital heart disease team with differing echocardiography experience subjectively graded RV systolic function (good, moderate, or poor). This was compared with MRI-derived ejection fraction. RESULTS: Twenty-eight patients at different palliative stages were included. Twenty-eight observers were divided into five experience categories (congenital heart disease junior trainees to attending cardiologists). Median agreement was 47.6% (range, 31.4%-58.2%), with the lowest agreement among junior trainees and the highest among attending cardiologists. When used as a screening test for poor RV systolic function, the median sensitivity of echocardiography was 0.89 (range, 0.86-0.96), and median specificity was 0.45 (range, 0.26-0.55). The highest sensitivity was observed among junior trainees but with the lowest specificity. The highest specificity was observed among attending cardiologists (0.55). CONCLUSIONS: Agreement between echocardiographic and MRI RV ejection fraction improves with experience but remains suboptimal. When used as a screening test for poor RV function, echocardiography is sensitive, but specificity is heavily influenced by operator experience. PMID- 23098783 TI - Urodynamic studies in adults: AUA/SUFU guideline. AB - PURPOSE: The authors of this guideline reviewed the literature regarding use of urodynamic testing in common lower urinary tract symptoms. The findings are intended to assist clinicians in the appropriate selection of urodynamic tests, following an evaluation and symptom characterization. MATERIALS AND METHODS: A systematic review of the literature using the MEDLINE(r) and EMBASE databases (searched from 1/1/90 to 3/10/11) was conducted to identify peer-reviewed publications relevant to using urodynamic tests for diagnosis, determining prognosis, guiding clinical management decisions and improving patient outcomes in patients with various urologic conditions. The review yielded an evidence base of 393 studies after application of inclusion/exclusion criteria. These publications were used to create the evidence basis for characterizing the statements presented in the guideline as Standards, Recommendations or Options. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinion. RESULTS: The evidence-based guideline statements are provided for diagnosis and overall management of common LUTS conditions. CONCLUSIONS: The Panel recognizes that each patient presenting with LUTS is unique. This Guideline is intended to serve as a tool facilitating the most effective utilization of urodynamic testing as part of a comprehensive evaluation of patients presenting with LUTS. PMID- 23098784 TI - Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. AB - PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis, evaluation and follow-up of asymptomatic microhematuria. MATERIALS AND METHODS: A systematic literature review using the MEDLINE(r) database was conducted to identify peer reviewed publications relevant to the definition, diagnosis, evaluation and follow-up for AMH. The review yielded 191 evidence based articles, and these publications were used to create the majority of the guideline statements. There was insufficient evidence-based data for certain concepts; therefore, clinical principles and consensus expert opinions were used for portions of the guideline statements. RESULTS: Guideline statements are provided for diagnosis, evaluation and follow-up. The panel identified multiphasic computed tomography as the preferred imaging technique and developed guideline statements for persistent or recurrent AMH as well as follow-up. CONCLUSIONS: AMH is only diagnosed by microscopy; a dipstick reading suggestive of hematuria should not lead to imaging or further investigation without confirmation of three or greater red blood cells per high power field. The evaluation and follow-up algorithm and guidelines provide a systematic approach to the patient with AMH. All patients 35 years or older should undergo cystoscopy, and upper urinary tract imaging is indicated in all adults with AMH in the absence of known benign causation. The imaging modalities and physical evaluation techniques are evolving, and these guidelines will need to be updated as the effectiveness of these become available. Please visit the AUA website at http://www.auanet.org/content/media/asymptomatic_microhematuria_guideline.pdf to view this guideline in its entirety. PMID- 23098785 TI - Diagnosis and treatment of overactive bladder (non-neurogenic) in adults: AUA/SUFU guideline. AB - PURPOSE: The purpose of this guideline is to provide a clinical framework for the diagnosis and treatment of non-neurogenic overactive bladder (OAB). MATERIALS AND METHODS: The primary source of evidence for this guideline is the systematic review and data extraction conducted as part of the Agency for Healthcare Research and Quality (AHRQ) Evidence Report/Technology Assessment Number 187 titled Treatment of Overactive Bladder in Women (2009). That report searched PubMed, MEDLINE(r), EMBASE and CINAHL for English-language studies published from January 1966 to October 2008. The AUA conducted additional literature searches to capture treatments not covered in detail by the AHRQ report and relevant articles published between October 2008 and December 2011. The review yielded an evidence base of 151 treatment articles after application of inclusion/exclusion criteria. When sufficient evidence existed, the body of evidence for a particular treatment was assigned a strength rating of A (high), B (moderate) or C (low). Additional treatment information is provided as Clinical Principles and Expert Opinions when insufficient evidence existed. RESULTS: The evidence-based guideline statements are provided for diagnosis and overall management of the adult with OAB symptoms as well as for various treatments. The panel identified first through third line treatments as well as non-FDA approved, rarely applicable and treatments that should not be offered. CONCLUSIONS: The evidence-based statements are provided for diagnosis and overall management of OAB, as well as for the various treatments. Diagnosis and treatment methodologies can be expected to change as the evidence base grows and as new treatment strategies become obtainable. PMID- 23098787 TI - [Prostate cancer, androgenic suppression and associated conditions. Practical refinement by a panel of multidisciplinary experts for patient integral management]. PMID- 23098786 TI - Vasectomy: AUA guideline. AB - PURPOSE: The purpose of this guideline is to provide guidance to clinicians who offer vasectomy services. MATERIALS AND METHODS: A systematic review of the literature using the search dates January 1949-August 2011 was conducted to identify peer-reviewed publications relevant to vasectomy. The search identified almost 2,000 titles and abstracts. Application of inclusion/exclusion criteria yielded an evidence base of 275 articles. Evidence-based practices for vasectomy were defined when evidence was available. When evidence was insufficient or absent, expert opinion-based practices were defined by Panel consensus. The Panel sought to define the minimum and necessary concepts for pre-vasectomy counseling; optimum methods for anesthesia, vas isolation, vas occlusion and post-vasectomy follow up; and rates of complications of vasectomy. This guideline was peer reviewed by 55 independent experts during the guideline development process. RESULTS: Vas isolation should be performed using a minimally-invasive vasectomy technique such as the no-scalpel vasectomy technique. Vas occlusion should be performed by any one of four techniques that are associated with occlusive failure rates consistently below 1%. These are mucosal cautery of both ends of the divided vas without ligation or clips (1) with or (2) without fascial interposition; (3) open testicular end of the divided vas with MC of abdominal end with FI and without ligation or clips; and (4) non-divisional extended electrocautery. Patients may stop using other methods of contraception when one uncentrifuged fresh semen specimen shows azoospermia or <= 100,000 non-motile sperm/mL. CONCLUSIONS: Vasectomy should be considered for permanent contraception much more frequently than is the current practice in the U.S. and many other nations. The full text of this guideline is available to the public at http://www.auanet.org/content/media/vasectomy.pdf. PMID- 23098788 TI - [Androgen deprivation therapy for prostate cancer and osteoporotic risk]. AB - Androgen deprivation therapy represents an important part of the management of prostate cancer. However, epidemiological data have shown that it is a well established cause of osteoporosis and increased risk of fracture. So far no consensus guidelines have been published regarding the screening and treatment of osteoporosis in men with prostate cancer. Here we report the design of a new questionnaire, derived from the FRAX((r)) ("Fracture Risk Assessment Tool") algorithm, to evaluate the risk of fracture in those patients. In accordance with recent reviews and on the basis of their experience, our French board of experts recommends systematic screening for osteoporosis with dual energy x- ray absorptiometry scans, practice of exercise and calcium and vitamin D supplementation, and selective treatment with bisphosphonates in men at greatest osteoporotic risk. PMID- 23098789 TI - [Metabolic impact of androgen deprivation therapy for prostate cancer]. AB - Because of the low mortality rates associated with prostate cancer, treatments long-term adverse effects constitute an important parameter in the management of patients. In particular, androgen deprivation has been shown to be linked to several metabolic disorders which are already frequent in men after age 60, such as weight and fat gain, insulin resistance likely to evolve into diabetes, and dyslipidemia. So far no consensus guidelines have been published regarding the screening and treatment of metabolic disorders in men with prostate cancer. It is essential to detect and manage these metabolic disorders, all the more so as they seem to be associated with an increased aggressiveness of prostate cancer. Here we report the development of a new questionnaire, which might contribute to the systematic management, and potentially the screening and treatment or the prevention of these metabolic disorders in patients with prostate cancer. In accordance with recent reviews and on the basis of experience, our French board of experts also recommends systematic screening and selective treatment for diabetes, regular follow-up of fasting glucose rates, lipid profile and blood pressure in all patients under long-term androgen deprivation treatment, as well as lifestyle changes (practice of exercise, nutritional habits). PMID- 23098790 TI - [Androgen deprivation and cardiovascular risk in prostate cancer treatment]. AB - Androgen suppression clearly increases the occurrence of cardiovascular risk factors : increased body fat, dyslipidemia and type II diabetes. Thus, several studies (but not all), showed an increase in coronary artery disease but also of sudden death and ventricular arrhythmias in relation to androgen deprivation, even for a short duration. This risk is particularly important in patients with existing cardiovascular risk factors or a history of heart disease. Cardiovascular risk should be balanced with the benefit of androgen deprivation on overall survival, especially when it is proposed in adjuvant setting, combined with radiotherapy in locally advanced prostate tumors. In practice, it is recommended that patients be referred to their physician for an evaluation before starting treatment, then 3 to 6 months after starting treatment, then once a year. The initial assessment should include: a clinical examination (with measurement of blood pressure and body index) and laboratory test with full lipid profile (total cholesterol, HDL and LDL cholesterol, triglycerides) and glucose. It is also important that patients with heart disease, receive lifestyle advice and low- dose aspirin (80 mg/day). PMID- 23098791 TI - [Prostate cancer in elderly subjects: how diagnosis should be made, why and how geriatric assessment should be implemented]. AB - Managing an elderly subject with prostate cancer brings into play the notion of likelihood of survival before any diagnostic or therapeutic decision can be made. The diagnostic strategy must be specified for each patient in accordance with the clinical presentation so as to determine whether prostate biopsies are indicated in this elderly population. To estimate the likelihood of survival, one must make use of geriatric assessment techniques comprising medical strategies ranging from screening for frailty to detailed geriatric evaluation for the most complex patients. The many tools available for estimating the likelihood of survival requires a critical review of their advantages and disadvantages in daily clinical practice. PMID- 23098792 TI - [Mood and cognitive disorders, and androgen deprivation]. AB - Prostate cancer has become a chronic disease. In this context, it is important to take into account the quality of life of patients and their family in the therapeutic approach. Recent studies have demonstrated the importance of depression and the risk of suicide in patients with prostate cancer as well as the repercussions of the disease on the spouse and their relationship. The implication of hormonal treatment in the increase in risk of depression is difficult to affirm. Few studies have investigated this subject and they present methodological biases. Some authors report an increased risk of cognitive decline in patients on androgen deprivation. However, even if certain physiopathological hypotheses have been put forward, the imputability of the treatment on the alteration of cognitive functions has not been clearly established. Urologists are at the forefront of diagnosis and treatment of prostate cancer occurring most often in elderly subjects. Therefore, given the prevalence of depression syndromes and/or the alteration of cognitive functions in this population, the urologist must be aware of these different factors, which are potentially aggravated by the introduction of androgen deprivation. Based on a review of the recent literature, the authors suggest using a simple depression screening tool: confirmation of the diagnosis and management is within the competence of the general practitioner. As for the risk of cognitive decline, it seems difficult to imagine, and not necessarily relevant, to systematically propose a battery of neuropsychometric screening tests. On the other hand, giving the patient the G8 screening test can allow the urologist to assess whether the patient needs a geriatric consultation or not. PMID- 23098793 TI - [Sexuality and prostate cancer]. AB - All treatments of prostate cancer have a negative effect on both sexuality and male fertility. There is a specific profile of changes in the fields of quality of life, sexual, urinary, bowel and vitality according to the treatment modalities chosen. Maintain a satisfying sex is the main concern of a majority of men facing prostate cancer and its treatment. It is essential to assess the couple's sexuality before diagnosis of prostate cancer in order to deliver complete information and to consider early and appropriate treatment options at the request of the couple. Forms of sexuality sexual preference settings stored (orgasm) may, when the erection is not yet recovered, be an alternative to the couple to maintain intimacy and complicity. In all cases, a specific management and networking will in many cases to find a satisfactory sexuality. Consequences of the treatment on male fertility should be part of the information of patients with prostate cancer and their partners. The choice of treatment must take into account the desire of paternity of the couple. A semen analysis with sperm cryopreservation before any therapy should be routinely offered in men with prostate cancer, particularly among men under 55, with a partner under 43 years old or without children. If the desire for parenthood among couples, sperm cryopreservation before treatment and medical assisted reproduction are recommended. PMID- 23098794 TI - Maternal diet rich in omega-6 polyunsaturated fatty acids during gestation and lactation produces autistic-like sociability deficits in adult offspring. AB - Multiple studies have reported prenatal stress as a potential risk factor for the development of autism spectrum disorder (ASD). In rodents, a significant reduction in sociability is seen in prenatally stressed offspring of genetically stress-susceptible dams. Certain dietary factors that contribute to stress reactivity may, therefore, exacerbate prenatal stress-mediated behavioral changes in adult offspring. Adults with a diet rich in omega-6 polyunsaturated fatty acids (PUFAs) display increased stress reactivity. In the current study, the effects of prenatal diet and prenatal stress on social behavior in adult offspring mice were examined. Pregnant C57BL/6J dams received either chronic variable stress or no stress, and were also placed on a control diet or a diet rich in omega-6 PUFAs, in a 2*2 design. We subsequently tested the adult offspring for sociability, anxiety, and locomotor behaviors using a 3-chambered social approach task, an elevated-plus maze, an open field task and a rotarod task. Results indicated that a maternal diet rich in omega-6 PUFAs during gestation and lactation produce changes in sociability consistent with those observed in ASD. Additionally, offspring exposed to a diet rich in omega-6 PUFAs during gestation and lactation had increased levels of anxiety in the elevated plus maze. Prenatal stress had no effect on offspring behavior. These findings provide evidence for a possible environmental risk factor that contributes to the production of autistic-like behavior in mice. PMID- 23098795 TI - Neonatal whisker clipping alters behavior, neuronal structure and neural activity in adult rats. AB - Early experience plays critical roles during the development of sensory systems. For example, neonatal surgical manipulations of the whiskers in rodents lead to altered neural activity and behaviors later in life. However, while surgical procedures damage the sensory pathway; it is hard to examine the impact of whisker deprivation on adult animals. To address this issue, we performed a neonatal whisker clipping (WC0-3) paradigm, a non-invasive procedure, from the day of birth (P0) to postnatal day (P) 3, and examined behavioral performances in their adult age. With fully regrown whiskers, the WC0-3 rats exhibited shorter crossable distance than controls in a gap-crossing task, suggesting a defect in their whisker-specific tactile function. In their somatosensory cortex, the layer IV spiny stellate neurons had reduced dendritic complexity and spine density. After exploration in a novel environment, the expression of an activity-dependent immediate early gene, c-fos, increased dramatically in the somatosensory cortex. However, in WC0-3 rats, the number of c-Fos positive cells was less than those in control rats, indicating a fault in transducing sensory-related neural activity between cortical layers in WC0-3 rats. Together, our results demonstrate the roles of early tactile experience on the establishment of layer-specific excitatory connection in the barrel cortex. Early sensory insufficiency would leave long-lasting functional deficits in the sensory system. PMID- 23098796 TI - GABA(A) receptor activation in the CA1 area of the dorsal hippocampus impairs consolidation of conditioned contextual fear in C57BL/6J mice. AB - Local infusion of the GABA(A) receptor agonist muscimol is used for reversible inactivation of septohippocampal brain structures associated with cognitive functions. However, information on the effective duration, affected processes and site(s) of action of muscimol in the hippocampus is lacking. Therefore, the dose- and time-dependent effects of bilateral dorsohippocampal infusion of muscimol (0.01-2.0 MUg/mouse) below the CA1 area were examined on processing of fear memory in male C57BL/6J mice. Infusion of muscimol 15 min-6 h but not 9 h or 24 h before training impaired conditioned context-dependent fear tested 24 h or 48 h after training. Post-training infusion of muscimol also impaired context dependent fear when applied either 4 h or 6 h after training, although with lower efficacy. Muscimol was ineffective when administered immediately, 1 h or 24 h after training. Infusion of muscimol 15 min before training impaired context dependent fear 4-6 h after training indicating preserved short-term but impaired long-term memory. Regardless of infusion time and dose, muscimol had no effect on tone-dependent (cued) fear memory. The impairment by the fluorescently-labeled muscimol-bodipy (5.3 MUg/mouse) were similar to those of an equimolar dose of muscimol (1 MUg/mouse). The distribution profile after local infusion indicated that muscimol-bodipy (5.3 MUg/mouse) was confined to the CA1 area of the dorsal hippocampus. These results demonstrated that GABA(A) receptor activation in the CA1 area of the dorsal hippocampus causes a long-term memory impairment of conditioned context-dependent fear mediated by a long-lasting (>=6 h) muscimol action most likely affecting consolidation processes. PMID- 23098797 TI - Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression. AB - We previously revealed that the activation of alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid receptor and mammalian target of rapamycin signaling contributed to the antidepressant-like effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists, suggesting that the signaling pathway may be similar to the molecular mechanisms underlying the antidepressant-like action of ketamine, a noncompetitive N-methyl-D-aspartate receptor antagonist that exertes rapid and sustained antidepressant effects in patients with depressive disorder. Although brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling reportedly participates in the antidepressant-like effects of ketamine, the involvement of BDNF/TrkB signaling in the action of mGlu2/3 receptor antagonists has not been investigated. We therefore examined whether the activation of BDNF/TrkB signaling is required for the antidepressant-like effects of LY341495, an mGlu2/3 receptor antagonist, in animal models of depression such as the tail suspension test (TST) and the novelty-suppressed feeding test (NSFT). The administration of LY341495 at 30 min prior to the test exerted antidepressant like effects (acute effects) lasting for at least 24 h (sustained effects) when evaluated using the TST and NSFT. Pretreatment with K252a, a TrkB tyrosine kinase inhibitor, blocked the sustained, but not the acute, effects of LY341495. These results suggest that BDNF/TrkB signaling may be involved in the sustained antidepressant-like effects of LY341495, as observed for ketamine treatment. PMID- 23098798 TI - Impact of medial orbital cortex and medial subthalamic nucleus inactivation, individually and together, on the maintenance of cocaine self-administration behavior in rats. AB - A reversible neuronal inactivation procedure was used to study the role of the medial orbital cortex (MO) and medial tip of the subthalamic nucleus (mSTN) in maintenance of cocaine self-administration studied under a second-order schedule of drug and cue presentation. Lidocaine or vehicle was infused 5-min before 1-h self-administration test sessions, using bilateral, asymmetric or unilateral manipulations. The results demonstrated that whether the MO was inactivated bilaterally, unilaterally or asymmetrically (with contralateral mSTN inactivation), cocaine seeking and cocaine intake were reduced. In contrast, bilateral mSTN inactivation did not impact cocaine seeking or cocaine intake, suggesting that the reductions in these measures following asymmetric inactivation may have been due to a unilateral influence of lidocaine in MO. Expression of c-Fos protein was measured in sites downstream of the STN to ensure that the lidocaine inactivation procedure was effective in selectively altering activity of neurons in mSTN. Cocaine-induced c-Fos protein expression was augmented only in the ipsilateral nucleus accumbens core after mSTN lidocaine pretreatment, consistent with the expectation that inactivation of mSTN would disinhibit nucleus accumbens core, but not shell, activity. The present investigation shows the critical importance of the MO for maintaining cocaine seeking and cocaine intake in rats, though its projections to mSTN appear to be unimportant for this purpose. Because cocaine seeking was impacted to such a great extent (45% of baseline, on average), it is likely that MO inactivation exerts its influence on maintenance of cocaine self-administration by interfering primarily with cue-controlled behavior rather than by modifying the reinforcing effects of cocaine. PMID- 23098800 TI - The low-frequency blood oxygenation level-dependent functional connectivity signature of the hippocampal-prefrontal network in the rat brain. AB - Interactions between the hippocampus and the prefrontal cortex (PFC) are of major interest in the neurobiology of psychiatric and neurodegenerative disorders and are central to many experimental rodent models. Non-invasive imaging techniques offer a translatable approach to probing this system if homologous features can be identified across species. The objective of the present study was to systematically characterize the rat brain connectivity signature derived from low frequency resting blood oxygenation level-dependent (BOLD) oscillations associated with and within the hippocampal-prefrontal network, using an array of small seed locations within the relatively large anatomical structures comprising this system. A heterogeneous structure of functional connectivity, both between and within the hippocampal-prefrontal brain structures, was observed. In the hippocampal formation, the posterior (subiculum) region correlated more strongly than the anterior dorsal hippocampus with the PFC. A homologous relationship was found in the human hippocampus, with differential functional connectivity between hippocampal locations proximal to the fornix body relative to locations more distal being localized to the medial prefrontal regions in both species. The orbitofrontal cortex correlated more strongly with sensory cortices and a heterogeneous dependence of functional coupling on seed location was observed along the midline cingulate and retrosplenial cortices. These findings are all convergent with known anatomical connectivity, with stronger BOLD correlations corresponding to known monosynaptic connections. These functional connectivity relationships may provide a useful translatable probe of the hippocampal prefrontal system for the further study of rodent models of disease and potential treatments, and inform electrode placement in electrophysiology to yield more precise descriptors of the circuits at risk in psychiatric disease. PMID- 23098799 TI - Effects of chronic treatment with corticosterone and imipramine on fos immunoreactivity and adult hippocampal neurogenesis. AB - In a previous study we showed that rats chronically treated with corticosterone (CORT) display anxiogenic behavior, evidenced by facilitation of avoidance responses in the elevated T-maze (ETM) model of anxiety. Treatment with the tricyclic antidepressant imipramine significantly reversed the anxiogenic effects of CORT, while inhibiting ETM escape, a response related to panic disorder. To better understand the neurobiological mechanisms underlying these behavioral effects, analysis of c-fos protein immunoreactivity (fos-ir) was used here to map areas activated by chronic CORT (200 mg pellets, 21-day release) and imipramine (15 mg/kg, IP) administration. We also evaluated the number of cells expressing the neurogenesis marker doublecortin (DCX) in the hippocampus and measured plasma CORT levels on the 21st day of treatment. Results showed that CORT increased fos ir in the ventrolateral septum, medial amygdala and paraventricular hypothalamic nucleus and decreased fos-ir in the lateral periaqueductal gray. Imipramine, on the other hand, increased fos-ir in the medial amygdala and decreased fos-ir in the anterior hypothalamus. CORT also decreased the number of DCX-positive cells in the ventral and dorsal hippocampus, an effect antagonized by imipramine. CORT levels were significantly higher after treatment. These data suggest that the behavioral effects of CORT and imipramine are mediated through specific, at times overlapping, neuronal circuits, which might be of relevance to a better understanding of the physiopathology of generalized anxiety and panic disorder. PMID- 23098801 TI - Neurotoxins released from interferon-gamma-stimulated human astrocytes. AB - Astrocytes become activated in degenerative neurological diseases. In order to gain a greater understanding of the inflammatory factors released upon activation, we stimulated adult human astrocytes with interferon-gamma and examined the resultant conditioned medium (CM) for toxicity against differentiated human neuroblastoma SH-SY5Y cells. Cell death was measured by lactate dehydrogenase release assay. We then used various treatments of the media to determine the distribution and nature of the toxic components. Removal of interleukin-6 by a specific antibody reduced the toxicity by 22%. Blockade of proteases with an inhibitor cocktail reduced it by a further 22%. When oxygen free radical production was blocked with NADPH oxidase inhibitors, the toxicity was reduced by 15.4%. When prostaglandin production was blocked by cyclooxygenase inhibitors, the toxicity of the CM was reduced by 14.5%. When glutamate was removed by treatment with glutamate decarboxylase, the toxicity was reduced by 10.3%. When the inhibitors were added together to the astrocyte culture, the total toxicity of the CM was reduced by 91%. This was in reasonable agreement with the 85.37% total obtained by adding the individual components. The data show that activated astrocytes release a specific combination of neurotoxic compounds. They suggest that effective anti-inflammatory treatment of such neurodegenerative diseases as Alzheimer's disease, Parkinson's disease and Amyotrophic lateral sclerosis could be improved by using an appropriate combination of anti inflammatory agents instead of relying on any single agent. PMID- 23098802 TI - Opiate-induced changes in brain adenosine levels and narcotic drug responses. AB - We have very little information about the metabolomic changes that mediate neurobehavioral responses, including addiction. It was possible that opioid induced metabolomic changes in brain could mediate some of the pharmacodynamic effects of opioids. To investigate this, opiate-induced brain metabolomic responses were profiled using a semi-targeted method in C57BL/6 and 129Sv1 mice, which exhibit extreme differences in their tendency to become opiate dependent. Escalating morphine doses (10-40 mg/kg) administered over a 4-day period selectively induced a twofold decrease (p<0.00005) in adenosine abundance in the brainstem of C57BL/6 mice, which exhibited symptoms of narcotic drug dependence; but did not decrease adenosine abundance in 129Sv1 mice, which do not exhibit symptoms of dependence. Based on this finding, the effect of adenosine on dependence was investigated in genetically engineered mice with alterations in adenosine tone in the brain and in pharmacologic experiments. Morphine withdrawal behaviors were significantly diminished (p<0.0004) in genetically engineered mice with reduced adenosine tone in the brainstem, and by treatment with an adenosine receptor(1) (A(1)) agonist (2-chloro-N6-cyclopentyladenosine, 0.5mg/kg) or an A(2a) receptor (A(2a)) antagonist (SCH 58261, 1mg/kg). These results indicate that adenosine homeostasis plays a crucial role in narcotic drug responses. Opiate-induced changes in brain adenosine levels may explain many important neurobehavioral features associated with opiate addiction and withdrawal. PMID- 23098803 TI - Evidence for anti-inflammatory and putative analgesic effects of a monoclonal antibody to calcitonin gene-related peptide. AB - BACKGROUND: Calcitonin gene-related peptide (CGRP) is a powerful pro-inflammatory mediator thought to play a significant role in the development of inflammation and pain. We investigated the role of CGRP in trigeminal inflammatory pain by determining the ability of a monoclonal antibody to CGRP to modify central Fos expression in response to stimulation of the inflamed ferret tooth pulp. We also assessed the effect of the antibody on pulpal inflammation. METHODS: Ten adult ferrets were prepared under anaesthesia to allow stimulation of the upper and lower left canine pulps, recording from the digastric muscle and intravenous injections at subsequent experiments. In all animals, pulpal inflammation was induced by introducing human caries into a deep buccal cavity. Four days later animals were treated intravenously with either CGRP antibody (n=5) or vehicle (n=5). After a further 2 days animals were re-anaesthetised and the tooth pulps stimulated at 10 times jaw-opening reflex threshold. Brainstems and tooth pulps were processed immunohistochemically for Fos and the common leucocyte marker CD45, respectively. RESULTS: Fos was expressed in ipsilateral trigeminal subnuclei caudalis (Vc) and oralis (Vo). Significantly fewer Fos-positive nuclei were present within Vc of CGRP antibody-treated animals (p=0.003 vs vehicle treated). Mean percentage area of staining for CD45 was significantly less in antibody-treated animals (p=0.04 vs vehicle-treated). CONCLUSIONS: This is the first direct evidence that sequestration of CGRP has anti-inflammatory and putative analgesic effects. Previous studies using this Fos model have demonstrated that it is able to predict clinical analgesic efficacy. Thus these data indicate that this antibody may have analgesic effects in dental pain and other types of inflammatory-mediated transmission, and suggest that this is in part due to peripheral anti-inflammatory effects. PMID- 23098804 TI - Rotenone-induced neurotoxicity in rat brain areas: a study on neuronal and neuronal supportive cells. AB - The present study was conducted to correlate rotenone-induced neurotoxicity with cellular and molecular modifications in neuronal and neuronal supportive cells in rat brain regions. Rotenone was administered (3, 6 and 12 MUg/MUl) intranigrally in adult male Sprague-Dawley rats. After the 7th day of rotenone treatment, specific protein markers for neuronal cells - tyrosine hydroxylase (TH), astroglial cells - glial fibrillary acidic protein (GFAP), microglial cells - CD11b/c, and Iba-1 were evaluated by immunoblotting and immunofluorescence in the striatum (STR) and mid brain (MB). Apoptotic cell death was assessed by caspase-3 gene expression. Higher doses of rotenone significantly lowered TH protein levels and elevated Iba-1 levels in MB. All the doses of rotenone significantly increased GFAP and CD11b/c protein in the MB. In STR, rotenone elevated GFAP levels but did not affect TH, CD11b/c and Iba-1 protein levels. Caspase-3 expression was increased significantly by all the doses of rotenone in MB but in STR only by higher doses (6 and 12 MUg). It may be suggested that astroglial activation and apoptosis play an important role in rotenone-induced neurotoxicity. MB appeared as more sensitive than STR toward rotenone-induced cell toxicity. The astroglial cells emerged as more susceptible than neuronal and microglial cells to rotenone in STR. PMID- 23098806 TI - Association of menstrual cycle phase with the core components of empathy. AB - Evidence has accumulated that emotion recognition performance varies with menstrual cycle phase. However, according to some empathy models, facial affect recognition constitutes only one component of empathic behavior, besides emotional perspective taking and affective responsiveness. It remains unclear whether menstrual cycle phase and thus estradiol and progesterone levels are also associated with the two other empathy constructs. Therefore, we investigated 40 healthy right-handed females, 20 during their follicular phase and 20 during their midluteal phase and compared their performance in three tasks tapping the empathic components as well as self-report data. Salivary hormone levels were obtained and correlated with performance parameters. Subjects were matched for age and education and did not differ in neuropsychological function. Analysis of empathy performance revealed a significant effect of phase in emotion recognition, showing higher accuracy in the follicular group. Regarding affective responsiveness, we observed a significant difference in reaction times, with faster responses for sad and angry stimuli in the midluteal group. No significant group difference emerged for emotional perspective taking. Furthermore, significant correlations between progesterone levels and emotion recognition accuracy and affective responsiveness emerged only in the luteal group. However, groups did not differ in self-reported empathy. Our results indicate that menstrual cycle phase and thus ovarian hormone concentration are differentially related to empathic behavior, particularly emotion recognition and responsiveness to negative situations, with progesterone covarying with both in the luteal phase. PMID- 23098805 TI - Effects of menstrual cycle phase on cocaine self-administration in rhesus macaques. AB - Epidemiological findings suggest that men and women vary in their pattern of cocaine use resulting in differences in cocaine dependence and relapse rates. Preclinical laboratory studies have demonstrated that female rodents are indeed more sensitive to cocaine's reinforcing effects than males, with estrous cycle stage as a key determinant of this effect. The current study sought to extend these findings to normally cycling female rhesus macaques, a species that shares a nearly identical menstrual cycle to humans. Dose-dependent intravenous cocaine self-administration (0.0125, 0.0250, and 0.0500 mg/kg/infusion) using a progressive-ratio schedule of reinforcement was determined across the menstrual cycle. The menstrual cycle was divided into 5 discrete phases - menses, follicular, periovulatory, luteal, and late luteal phases - verified by the onset of menses and plasma levels of estradiol and progesterone. Dependent variables including number of infusions self-administered per session, progressive ratio breakpoint, and cocaine intake were analyzed according to cocaine dose and menstrual cycle phase. Analysis of plasma hormone levels verified phase-dependent fluctuations of estradiol and progesterone, with estrogen levels peaking during the periovulatory phase, and progesterone peaking during the luteal phase. Progressive ratio breakpoint, infusions self-administered, and cocaine intake did not consistently vary based on menstrual cycle phase. These findings demonstrate that under the current experimental parameters, the reinforcing effects of cocaine did not vary across the menstrual cycle in a systematic fashion in normally cycling rhesus macaques. PMID- 23098807 TI - Impaired intestinal tolerance in the absence of a functional complement system. AB - BACKGROUND: Cells of the innate immune system regulate both adaptive immune responses and the maintenance of tolerance, especially in the gut. However, relatively little is known about the effects of complement on lymphocyte homeostasis. OBJECTIVE: This study explored complement C3 deficiency in mice and human subjects for its effect on intestinal tolerance. METHODS: C3-deficient mice and control C57BL/6 mice were fed ovalbumin (OVA) by means of gavage, and subsequent response to immunization with OVA in Freund's adjuvant was monitored. Serum antibodies against commensal microbes were measured, and the activation status of peripheral blood lymphocytes bearing mucosal homing markers was determined from 2 rare cases of C3-deficient patients. RESULTS: We show in C3 deficient mice and human patients that intestinal tolerance fails in the absence of functional complement. In contrast to wild-type control animals, in which oral tolerance was induced, intragastric administration of OVA did not result in a significantly decreased response to subsequent subcutaneous OVA challenge in C3 deficient mice. In the jejunum of C3-deficient mice the cytokine ratio between IL 10 and IFN-gamma or IL-17 levels was decreased, indicating a shift in favor of proinflammatory cytokines. In 2 C3-deficient children the frequency of gut-homing T cells expressing activation markers was increased, and the patients had increased serum IgG levels against gut commensal microbes. The data also suggest that the impaired oral tolerance was at least partly caused by the absence of signaling through C3-binding complement regulators in T cells. CONCLUSIONS: Taken together, our results identify complement as an important and nonredundant regulator of intestinal tolerance. PMID- 23098809 TI - Antineutrophil cytoplasmic autoantibodies and clinical phenotype in patients with Churg-Strauss syndrome. PMID- 23098811 TI - Manifestation of rheumatoid arthritis during subcutaneous allergen-specific immunotherapy with bee venom. PMID- 23098812 TI - Clinical outcome of extended-spectrum beta-lactamase-producing Escherichia coli bacteremia in an area with high endemicity. AB - OBJECTIVES: This study assessed the impact of discordant empirical antibiotic therapy on the outcome of bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli. METHODS: The clinical features and outcomes of a cohort of patients hospitalized with ESBL E. coli bacteremia between 2007 and 2008 were retrospectively reviewed. The effect of different antimicrobial regimens on patient outcomes was analyzed. RESULTS: ESBL E. coli accounted for 24.2% (207/857) of E. coli bacteremia cases. The urinary tract (43.6%) was the most common source of infection, followed by the hepatobiliary tract (23.0%). Discordant empirical antibiotic therapy was given to 52.0% patients. Admission to the intensive care unit was associated with the use of a carbapenem as empirical antibiotic therapy (p<0.001). Univariate analysis revealed no significant differences in 30-day mortality rates between patients receiving concordant and discordant empirical antibiotic therapy (23.5% vs. 19.8%, p=0.526), carbapenem and non-carbapenem empirical antibiotic therapy (29.8% vs. 19.1%, p=0.118), beta lactam/beta-lactam inhibitor combinations (BLBLIs) and non-BLBLIs empirical antibiotic therapy (20.3% vs. 22.3%, p=0.734), cephalosporin and non cephalosporin empirical antibiotic therapy (19.7% vs. 22.6%, p=0.639), and fluoroquinolone and non-fluoroquinolone empirical antibiotic therapy (8.3% vs. 22.4%, p=0.251). The findings were confirmed by multivariate analysis. CONCLUSIONS: Despite a high proportion of discordant empirical antibiotic therapy, ESBL production had little effect on 30-day mortality. Whether the observation can be applied to different ESBL types is unknown and warrants further study. PMID- 23098814 TI - Pyrolysis behavior of different type of materials contained in the rejects of packaging waste sorting plants. AB - In this paper rejected streams coming from a waste packaging material recovery facility have been characterized and separated into families of products of similar nature in order to determine the influence of different types of ingredients in the products obtained in the pyrolysis process. The pyrolysis experiments have been carried out in a non-stirred batch 3.5 dm(3) reactor, swept with 1 L min(-1) N(2), at 500 degrees C for 30 min. Pyrolysis liquids are composed of an organic phase and an aqueous phase. The aqueous phase is greater as higher is the cellulosic material content in the sample. The organic phase contains valuable chemicals as styrene, ethylbenzene and toluene, and has high heating value (HHV) (33-40 MJ kg(-1)). Therefore they could be used as alternative fuels for heat and power generation and as a source of valuable chemicals. Pyrolysis gases are mainly composed of hydrocarbons but contain high amounts of CO and CO(2); their HHV is in the range of 18-46 MJ kg(-1). The amount of COCO(2) increases, and consequently HHV decreases as higher is the cellulosic content of the waste. Pyrolysis solids are mainly composed of inorganics and char formed in the process. The cellulosic materials lower the quality of the pyrolysis liquids and gases, and increase the production of char. PMID- 23098813 TI - A local outbreak of autochthonous Plasmodium vivax malaria in Laconia, Greece--a re-emerging infection in the southern borders of Europe? AB - OBJECTIVES: Malaria is considered to have been eradicated in Greece and only sporadic cases in travelers are reported. However the migration of populations from endemic countries of Asia to Greece may have caused a re-emergence of the disease. METHODS: A cluster of nine human malaria cases due to Plasmodium vivax infection in the area of Laconia (southern Peloponnesus) from 2009 to 2010 is presented. Patients were hospitalized in Sparta General Hospital. RESULTS: Eight patients were diagnosed in 2009 and one in 2010. Two were refugees from Pakistan and Afghanistan and five were Romas living in a local camp. Apart from the two immigrants, no other patient had any history of travel, blood transfusion, or organ transplantation. All patients had a febrile illness, hematological abnormalities, and irregular liver function tests. Parasites were identified in peripheral blood smears, and PCR confirmed the presence of P. vivax. Sensitivity testing showed chloroquine susceptibility. Combined treatment with chloroquine followed by primaquine was completed uneventfully. Entomological surveillance disclosed the presence of Anopheles saccharovi as the predominant mosquito species, however PCR testing failed to identify P. vivax in the mosquito population. CONCLUSIONS: We have presented the first large outbreak of the local transmission of autochthonous malaria cases in Greece since the 1950s. Enhanced entomological surveillance and early detection of malaria cases are crucial in order to prevent the re-emergence of malaria, not only in Greece, but in Europe as well. PMID- 23098815 TI - Solid waste management challenges for cities in developing countries. AB - Solid waste management is a challenge for the cities' authorities in developing countries mainly due to the increasing generation of waste, the burden posed on the municipal budget as a result of the high costs associated to its management, the lack of understanding over a diversity of factors that affect the different stages of waste management and linkages necessary to enable the entire handling system functioning. An analysis of literature on the work done and reported mainly in publications from 2005 to 2011, related to waste management in developing countries, showed that few articles give quantitative information. The analysis was conducted in two of the major scientific journals, Waste Management Journal and Waste Management and Research. The objective of this research was to determine the stakeholders' action/behavior that have a role in the waste management process and to analyze influential factors on the system, in more than thirty urban areas in 22 developing countries in 4 continents. A combination of methods was used in this study in order to assess the stakeholders and the factors influencing the performance of waste management in the cities. Data was collected from scientific literature, existing data bases, observations made during visits to urban areas, structured interviews with relevant professionals, exercises provided to participants in workshops and a questionnaire applied to stakeholders. Descriptive and inferential statistic methods were used to draw conclusions. The outcomes of the research are a comprehensive list of stakeholders that are relevant in the waste management systems and a set of factors that reveal the most important causes for the systems' failure. The information provided is very useful when planning, changing or implementing waste management systems in cities. PMID- 23098816 TI - Emerging Chlamydia psittaci infections in the chicken industry and pathology of Chlamydia psittaci genotype B and D strains in specific pathogen free chickens. AB - Sera of 30 Belgian and 10 Northern French chicken farms were tested by a Chlamydia (C.) psittaci major outer membrane protein (MOMP) based ELISA. Ninety six percent, 93% and 90% of the Belgian broilers, broiler breeders and layers were seropositive. Ninety-one percent of the French broilers were seropositive. In addition, tissues of 5 Belgian and 5 French broiler farms were examined at slaughter. All French farms were culture positive while C. psittaci was cultured from the lungs of 80% of examined Belgian farms. C. psittaci infections are apparently emerging in chickens raised in Belgium and Northern France. We could proof Hill-Evans postulates for chicken-derived C. psittaci genotype B and D strains. Chicken-processing plant employees should be considered a risk group for human psittacosis. There is a need for higher awareness and for efficient risk assessment and management of C. psittaci infections in chickens as chlamydiosis in broilers seems to be underdiagnosed and infections with highly virulent strains do occur. PMID- 23098817 TI - Ephs and ephrins resurface in inflammation, immunity, and atherosclerosis. AB - Despite significant advancements in treatment regimens, cardiovascular disease remains a worldwide leader of morbidity, mortality, and healthcare cost. A large percentage of cardiovascular disease is directly attributable to the process of atherosclerosis, a chronic inflammatory disease of the vessel wall. In the hunt for novel therapeutic targets in cardiovascular disease, neuronal guidance molecules are emerging as significant regulators of cardiovascular remodeling and inflammation. The Eph family of neuronal guidance molecules comprises the largest family of receptor tyrosine kinases in the mammalian genome. While best characterized in embryogenesis and carcinogenesis, Eph receptors and their ephrin ligands are becoming increasingly recognized as important players in chronic inflammatory diseases and immune function. Herein we discuss the current evidence for how Eph/ephrin interactions, particularly EphA2/ephrinA1 and EphB/ephrinB2, affect inflammation and cardiovascular disease. PMID- 23098818 TI - The catalytic competence of cytochrome P450 in the synthesis of serotonin from 5 methoxytryptamine in the brain: an in vitro study. AB - Brain serotonin has been implicated in the pathophysiology of a wide spectrum of psychiatric disorders, as well as in the mechanism of action of psychotropic drugs. The aim of present study was to identify rat cytochrome P450 (CYP) isoforms which can catalyze the O-demethylation of 5-methoxytryptamine to serotonin, and to find out whether that alternative pathway of serotonin synthesis may take place in the brain. The study was conducted on cDNA-expressed CYPs (rat CYP1A1/2, 2A1/2, 2B1, 2C6/11/13, 2D1/2/4/18, 2E1, 3A2 and human CYP2D6), on rat brain and liver microsomes and on human liver microsomes (the wild-type CYP2D6 or the allelic variant 2D6*4*4). Of the rat CYP isoforms studied, CYP2D isoforms were the most efficient in catalyzing the O-demethylation of 5-methoxytryptamine to serotonin, but they were less effective than the human isoform CYP2D6. Microsomes from different brain regions were capable of metabolizing 5-methoxytryptamine to serotonin. The reaction was inhibited by the specific CYP2D inhibitors quinine and fluoxetine. Human liver microsomes of the wild-type CYP2D6 metabolized 5-methoxytryptamine to serotonin more effectively than did the defective CYP2D6*4*4 ones. The obtained results indicate that rat brain CYP2D isoforms catalyze the formation of serotonin from 5 methoxytryptamine, and that the deficit or genetic defect of CYP2D may affect serotonin metabolism in the brain. The results are discussed in the context of their possible physiological and pharmacological significance in vivo. PMID- 23098819 TI - Negative regulation of inflammation by SIRT1. AB - Sirtuin 1 (SIRT1), the mammalian Sir2 homologue, is a class III histone deacetylase shown to act on a wide range of histones and non-histone substrates. Numerous studies have demonstrated that SIRT1 regulates critical metabolic and physiological processes including senescence, stress resistance, metabolism and apoptosis. Recently, SIRT1 was also found to play an important role in modulating the development and progression of inflammation through deacetylating histones and critical transcription factor such as nuclear factor kappa B (NF-kappaB) and activator protein 1 (AP-1), thus leading to transcriptional repression of various inflammation-related genes. There is increasing evidence that reduction of SIRT1 levels is closely correlated with many inflammatory diseases while pharmacologic activation of SIRT1 would be a promising therapeutic strategy for inflammation related diseases. PMID- 23098820 TI - Four disruptive strategies for removing drug discovery bottlenecks. AB - Drug discovery is shifting focus from industry to outside partners and, in the process, creating new bottlenecks. Technologies like high throughput screening (HTS) have moved to a larger number of academic and institutional laboratories in the USA, with little coordination or consideration of the outputs and creating a translational gap. Although there have been collaborative public-private partnerships in Europe to share pharmaceutical data, the USA has seemingly lagged behind and this may hold it back. Sharing precompetitive data and models may accelerate discovery across the board, while finding the best collaborators, mining social media and mobile approaches to open drug discovery should be evaluated in our efforts to remove drug discovery bottlenecks. We describe four strategies to rectify the current unsustainable situation. PMID- 23098821 TI - Tick-borne encephalitis joins the diseases under surveillance in the European Union. PMID- 23098822 TI - Incubation period as part of the case definition of severe respiratory illness caused by a novel coronavirus. AB - Non-specific symptoms of acute respiratory viral infections make it difficult for many countries without ongoing transmission of a novel coronavirus to rule out other possibilities including influenza before isolating imported febrile individuals with a possible exposure history. The incubation period helps differential diagnosis, and up to two days is suggestive of influenza. It is worth including the incubation period in the case definition of novel coronavirus infection. PMID- 23098823 TI - Listeriosis outbreak caused by Latin-style fresh cheese, Bizkaia, Spain, August 2012. AB - Two cases of laboratory-confirmed listeriosis were detected in Bizkaia, Spain, at the end of August. The epidemiological investigation indicated that these two cases were associated with the consumption of Latin-style fresh cheese made from pasteurised milk in Portugal. Different batches of the same cheese were analysed and confirmed as contaminated with Listeria monocytogenes. The product was withdrawn from the market and the population was advised not to consume this kind of cheese. PMID- 23098824 TI - Measles outbreak in Andalusia, Spain, January to August 2011. AB - On 7 January 2011, a six year-old child living in a Roma community near Seville, southern Spain, was hospitalised with measles. Contact tracing identified a probable index case with onset of symptoms on 20 December 2011 and several unreported cases among children under the age of 15 years in the same town. The outbreak initially spread in districts in the city of Seville with a high proportion of Roma residents, and later to other cities and towns in Andalusia. While some towns experienced wide spread of the disease with significant clusters of cases, most of the affected locations saw non-clustered cases or very few secondary cases. The outbreak resulted in 1,759 confirmed or probable cases of which 393 (19%) required hospitalisation. Measles virus of genotype D4 was diagnosed in more than half of the cases. Significant differences (p<0.0001) by age group were found between clustered and non-clustered cases. The highest proportion of clustered cases occurred in the age group of 5-14 yearolds, while the highest proportion of non-clustered cases was seen in those older than 29 years. The last confirmed case related to this outbreak was reported on 20 August 2011. PMID- 23098826 TI - QnrVC, a new transferable Qnr-like family. PMID- 23098827 TI - Assessment of persistent organic pollutants levels in blood samples from Quintana Roo, Mexico. AB - The Stockholm Convention on persistent organic pollutants (POPs) sought to determine baseline exposures to POPs in the general population; however, in developing countries, exposure to these chemicals in hot spots may be an issue of public health considering its magnitude. Therefore, the aim of this study was to assess the levels of POPs in the blood of children living in three communities in the Southeastern Region of Mexico. During 2007, we studied a total of 96 healthy children (aged 6-12 years). Quantitative analyses were performed using gas chromatography coupled with mass spectrometry. High levels of p,p'-DDT and its principal metabolite, p,p'-DDE, were found in the blood of children living in the three communities studied, the levels ranged from 463.5 to 9046.3 ng/g lipid and from 490.8 to 57,712.4 ng/g lipid for DDT and DDE, respectively. In addition, high levels of lindane (gamma-HCH) were found, with mean levels ranging between 575.4 and 6580.6 ng/g lipid. Moreover, children living in the study region were also exposed to polychlorinated biphenyls (PCBs), and the levels of these compounds in the blood of children were very similar between the communities with mean levels of around 3000 ng/g lipid (total PCBs). In conclusion, we demonstrated that children living in the studied communities were exposed to complex chemical mixtures (DDT, DDE, lindane and PCBs) rather than to individual compounds. Therefore, in future studies it is important to understand the potential interactions between the components of these mixtures. PMID- 23098828 TI - Serum phosphate and hip bone mineral density as additional factors for high vascular calcification scores in a community-dwelling: the Sao Paulo Ageing & Health Study (SPAH). AB - OBJECTIVE: To analyze the association between abdominal aortic calcification scores (AACS) and bone metabolism parameters in a well-characterized general population of older adults. BACKGROUND: Several studies suggest a link between bone mineral metabolism disorders and vascular calcification; although only few of them analyze bone mineral density(BMD), laboratory bone markers and cardiovascular parameters at the same time and none were done in a miscegenated population. METHODS: This cross-sectional study included 815 subjects >= 65 years old. The risk factors for osteoporosis and cardiovascular disease as well as a wide array of demographic and lifestyle characteristics were collected using a standardized questionnaire. BMD was measured by DXA. Kauppila's method was used to quantify the AAC score (AACS) by spine X-rays. Laboratory analyses were also performed. RESULTS: AAC was observed in 63.2% of subjects with a median AACS of 2 (IQR: 0-7). AACS were categorized in quartiles and the highest quartile of AACS (>7) were compared with the three lower quartiles of AACS (<= 7). Logistic regression analysis was performed using parameters with statistical significance in the univariate analysis. The best logistic regression model revealed that AACS>7 was negatively associated with femoral neck BMD and positively associated with phosphorus, adjusted by age, current smoking, LDL, and arterial hypertension in the elderly community-dwelling population. CONCLUSIONS: We identified that higher serum phosphate levels and lower hip BMD are independent bone variables that are associated with elevated vascular calcification scores, supporting the search for effective prevention and treatment strategies that may simultaneously reduce these modifiable risk factors in older subjects. PMID- 23098829 TI - Atypical femoral fractures are a separate entity, characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls. AB - BACKGROUND: Estimations of the risk of bisphosphonate associated atypical femoral fractures vary between different population-based studies, from considerable to neglectable. A possible explanation for these discrepancies could be different definitions of atypical fractures. We aimed to identify specific radiographic fracture characteristics associated with bisphosphonate use. METHODS: In a previous nationwide study, 59 atypical and 218 ordinary fractures were diagnosed. The atypical fractures were defined by their stress-type fracture pattern. All fractures were now re-assessed by a physician in training, without information about bisphosphonate use. The fracture angle (0-180 degrees ) was measured. Presence of local lateral cortical thickening (a callus reaction), more than 2 fragments, or a medial spike was noted. The reader then made a judgment whether the fracture appeared as an atypical fracture based on the ASBMR criteria. RESULTS: Frequency distribution analysis of the fracture angle showed a distinct subgroup, comprising 25% of all 277 fractures, with a mean of 89 and SD of 10 degrees . Forty-two of 57 patients in this subgroup used bisphosphonates, whereas only 27 of 213 others did (specificity 0.93; 95% CI 0.88-0.96). Presence of a callus reaction had also a high specificity for bisphosphonate use (0.96; 95% CI 0.92-0.98). The ASBMR criteria had a lower specificity, increasing the number of atypical fractures without bisphosphonate use from 13 to 31. This led to a decrease in age-adjusted relative risk associated with bisphosphonate use from 47 (95% CI 26-87) to 19 (95% CI 12-29). INTERPRETATION: Stress fractures of the femoral shaft are a specific entity, which is easily diagnosed on radiographs and strongly related to bisphosphonate use. Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies. PMID- 23098830 TI - Callosal dysarthria. PMID- 23098831 TI - A case of 'cryptogenic' type D carotid cavernous fistula presenting initially with cluster-like headache. PMID- 23098832 TI - Neuropsychiatric symptoms and the use of complementary and alternative medicine. AB - OBJECTIVES: To assess the prevalence of complementary and alternative medicine (CAM) use by U.S. adults reporting neuropsychiatric symptoms and whether this prevalence changes based on the number of symptoms reported. Additional objectives include identifying patterns of CAM use, reasons for use, and disclosure of use with conventional providers in U.S. adults with neuropsychiatric symptoms. DESIGN: Secondary database analysis of a prospective survey. PARTICIPANTS: A total of 23,393 U.S. adults from the 2007 National Health Interview Survey. METHODS: We compared CAM use between adults with and without neuropsychiatric symptoms. Symptoms included self-reported anxiety, depression, insomnia, headaches, memory deficits, attention deficits, and excessive sleepiness. CAM use was defined as use of mind-body therapies (eg, meditation), biological therapies (eg, herbs), or manipulation therapies (eg, massage) or alternative medical systems (eg, Ayurveda). Statistical analysis included bivariable comparisons and multivariable logistical regression analyses. MAIN OUTCOME MEASURES: The prevalence of CAM use among adults with neuropsychiatric symptoms within the previous 12 months and the comparison of CAM use between those with and without neuropsychiatric symptoms. RESULTS: Adults with neuropsychiatric symptoms had a greater prevalence of CAM use compared with adults who did not have neuropsychiatric symptoms (43.8% versus 29.7%, P < .001); this prevalence increased with an increasing number of symptoms (trend, P < .001). Differences in the likelihood of CAM use as determined by the number of symptoms persisted after we adjusted for covariates. Twenty percent of patients used CAM because standard treatments were either too expensive or ineffective, and 25% used CAM because it was recommended by a conventional provider. Adults with at least one neuropsychiatric symptom were more likely to disclose the use of CAM to a conventional provider (47.9% versus 39.0%, P < .001). CONCLUSION: More than 40% of adults with neuropsychiatric symptoms commonly observed in many diagnoses use CAM; an increasing number of symptoms was associated with an increased likelihood of CAM use. PMID- 23098833 TI - Infrared spectroscopy of proteins in reverse micelles. AB - Reverse micelles are a versatile model system for the study of crowded microenvironments containing limited water, such as those found in various tissue spaces or endosomes. They also preclude protein aggregation. Reverse micelles are amenable to study by linear and nonlinear infrared spectroscopies, which have demonstrated that the encapsulation of polypeptides and enzymatically active proteins into reverse micelles leads to conformational changes not seen in bulk solution. The potential value of this model system for understanding the folding and kinetic behavior of polypeptides and proteins in biologically important circumstances warrants increased study of reverse micelle systems by infrared spectroscopy. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23098834 TI - Membrane lipid phase transitions and phase organization studied by Fourier transform infrared spectroscopy. AB - Fourier transform infrared (FTIR) spectroscopy is a powerful yet relatively inexpensive and convenient technique for studying the structure and organization of membrane lipids in their various polymorphic phases. This spectroscopic technique yields information about the conformation and dynamics of all regions of the lipid molecule simultaneously without the necessity of introducing extrinsic probes. In this review, we summarize some relatively recent FTIR spectroscopic studies of the structure and organization primarily of fully hydrated phospholipids in their biologically relevant lamellar crystalline, gel and liquid-crystalline phases, and show that interconversions between these bilayer phases can be accurately monitored by this technique. We also briefly discuss how the structure and organization of potentially biologically relevant nonlamellar micellar or reversed hexagonal lipid phases can be studied and how phase transitions between lamellar and nonlamellar phases, or between various nonlamellar phases, can be followed as well. In addition, we discuss the potential for FTIR spectroscopy to yield fairly high resolution structural information about phospholipid packing in lamellar crystalline or gel phases. Finally, we show that many, but not all of these FTIR approaches can also yield valuable information about lipid-protein interactions in membrane protein- or peptide-containing lipid membrane bilayer model or even in biological membranes. This article is part of a Special Issue entitled: FTIR in membrane proteins and peptide studies. PMID- 23098835 TI - Adaptable image cuts for motility inspection using WCE. AB - The Wireless Capsule Endoscopy (WCE) technology allows the visualization of the whole small intestine tract. Since the capsule is freely moving, mainly by the means of peristalsis, the data acquired during the study gives a lot of information about the intestinal motility. However, due to: (1) huge amount of frames, (2) complex intestinal scene appearance and (3) intestinal dynamics that make difficult the visualization of the small intestine physiological phenomena, the analysis of the WCE data requires computer-aided systems to speed up the analysis. In this paper, we propose an efficient algorithm for building a novel representation of the WCE video data, optimal for motility analysis and inspection. The algorithm transforms the 3D video data into 2D longitudinal view by choosing the most informative, from the intestinal motility point of view, part of each frame. This step maximizes the lumen visibility in its longitudinal extension. The task of finding "the best longitudinal view" has been defined as a cost function optimization problem which global minimum is obtained by using Dynamic Programming. Validation on both synthetic data and WCE data shows that the adaptive longitudinal view is a good alternative to the traditional motility analysis done by video analysis. The proposed novel data representation a new, holistic insight into the small intestine motility, allowing to easily define and analyze motility events that are difficult to spot by analyzing WCE video. Moreover, the visual inspection of small intestine motility is 4 times faster then by means of video skimming of the WCE. PMID- 23098836 TI - Temporal and spatial distributions of nutrients under the influence of human activities in Sishili Bay, northern Yellow Sea of China. AB - The temporal and spatial distributions of dissolved inorganic nitrogen (DIN), dissolved organic nitrogen (DON), soluble reactive phosphorus (SRP) and dissolved reactive silica (DRSi) together with chlorophyll-a, temperature and salinity were analyzed monthly from December 2008 to March 2010 at four zones in Sishili Bay located in the northern Yellow Sea. The nutrient distribution was impacted by seasonal factors (biotic factors, temperature and wet deposition), physical factors (water exchange) and anthropogenic loadings. The seasonal variations of nutrients were mainly determined by the seasonal factors and the spatial distribution of nutrients was mainly related to water exchange. Anthropogenic loadings for DIN, SRP and DRSi were mainly from point sources, but for DON, non point sources were also important. Nutrient limitation has changed from DIN in 1997 to SRP and DRSi in 2010, and this has resulted in changes in the dominant red tide species from diatom to dinoflagellates. PMID- 23098837 TI - An optimized method for establishing high purity murine CD8+ T cell cultures. AB - Establishing CD8(+) T cell cultures has been empirical and the published methods have been largely individual laboratory based. In this study, we optimized culturing conditions and show that IL-2 concentration is the most critical factor for the success of establishing CD8(+) T cell cultures. High IL-2 concentration encouraged T cells to non-specifically proliferate, express a B cell marker, B220, and undergo apoptosis. These cells also lose typical irregular T cell morphology and are incapable of sustaining long-term cultures. Using tetramer and intracellular cytokine assessments, we further demonstrated that many antigen specific T cells have been rendered nonfunctional when expanded under high IL-2 concentration. When IL-2 is used in the correct range, B220-mediated cell depletion greatly enhanced the success rate of such T cell cultures. PMID- 23098838 TI - Determination of protein concentration for protein-protein conjugates using ultraviolet absorption. AB - The present study reports a method to determine the total protein concentration or concentration of a protein of interest in a protein-protein conjugate using ultraviolet absorption, after determining the molar ratio of proteins in the conjugates, from which an extinction coefficient can be calculated. A Microsoft Excel solver-based template using amino acid analysis data was developed for determining the molar ratio. The percent mass of each protein in the conjugate is calculated from the amino acid composition data using the least squares method in the Microsoft Excel solver function, and the percent mass is converted to molar portion of each protein using corresponding molecular weight. A molar ratio is obtained by dividing the molar portion of protein 1 by the molar portion of protein 2. A weighted extinction coefficient is calculated using the molar ratio, and the total protein concentration is determined using ultraviolet absorption at 280 nm. The accuracy of the method was verified using mixtures of known proteins. The present study provides a rapid, simple and accurate method for determining protein concentration in protein-protein conjugates. PMID- 23098840 TI - Decoding dendritic cell function through module and network analysis. AB - Systems biology approaches that utilize large genomic data sets hold great potential for deciphering complex immunological process. In this paper, we propose such an approach to derive informative modules and networks from large gene expression data sets. Our approach starts with the clustering of such data sets to derive groups of tightly co-expressed genes, also known as co-expression modules. These modules are then converted into co-expression networks, and combined with transcriptional regulatory and protein interaction data to generate integrated networks that can help decipher the regulatory structure of these modules. We use this approach to derive the first set of modules and networks focused on dendritic cells (DCs). These cells are responsible for sampling the local environment to inform the adaptive immune system about peripheral stimuli, thus leading to the induction of an immune response. Using the ImmGen gene expression data set, we derive co-expression modules and integrated networks for the pDC, cDC and CD8+ DC subsets. In addition to recapitulating genes known to regulate the functions of these subsets, these networks reveal several novel genes and interactions that might have important roles in DC biology. PMID- 23098839 TI - Toxin-antigen conjugates as selection tools for antibody producing cells. AB - The generation of antibodies with designated specificity requires cost-intensive and time-consuming screening procedures. Here we present a new method by which hybridoma cells can be selected based on the specificity of the produced antibody by the use of antigen-toxin-conjugates thus eliminating the need of a screening procedure. Initial experiments were done with methotrexate as low molecular weight toxin and fluorescein as model antigen. Methotrexate and a methotrexate fluorescein conjugate were characterized regarding their toxicity. Afterwards the effect of the fluorescein-specific antibody B13-DE1 on the toxicity of the methotrexate-fluorescein conjugate was determined. Finally, first results showed that hybridoma cells that produce fluorescein specific antibodies are able to grow in the presence of fluorescein-toxin-conjugates. PMID- 23098842 TI - Osteoporosis: chronic kidney disease in rheumatology practice. PMID- 23098843 TI - Vitamin D supplementation in patients with chronic kidney disease. PMID- 23098844 TI - All the articles derived from the panel discussions incorporate the most recent data in the field, in particular those documenting the importance of the vitamin D storage form. PMID- 23098841 TI - Designing of novel antigenic peptide cocktail for the detection of antibodies to HIV-1/2 by ELISA. AB - HIV (human immunodeficiency virus) infection has now become endemic worldwide and AIDS ranks fourth among the world's top killers of mankind. A rapid and accurate HIV testing assay is a pre-requisite for practical applicability of diagnostic tests. The aim of this present study was to design peptide cocktail as an antigen and to develop ELISA test for HIV-1/2 antibody detection, with enhanced sensitivity and specificity. A novel peptide stretch V3-I, covering immunodominant epitope corresponding to V3 hypervariable loop of gp120 antigens of selected Indian isolates, has been studied and incorporated in an antigenic cocktail of gp36, gp41, and rp24 of HIV-1/2. Peptides from these antigens were chemically synthesized and an additional cysteine residue was added at both amino and carboxyl-terminal sequences of each peptide in order to form inter and intramolecular disulfide bond for the folding of peptides. This generated conformational epitopes with increased oligomericity and stability of peptide sequences; and attachment of antigen to the solid support of ELISA plates. The use of antigenic cocktail of folded peptides and recombinant p24 enhanced sensitivity and specificity of the ELISA test. Evaluation of the test using 1123 serum samples in comparison with Boston Biomedical Incorporation (BBI) panels showed 100% sensitivity and 99.3% specificity with no cross reactivity tribulation. In conclusion, "HIV screen test" detects HIV 1/2 antibodies with a high degree of sensitivity and specificity and could be a promising tool for seroscreening of blood during transfusion, counseling and diagnosis of HIV-1/2. PMID- 23098845 TI - Stress fractures in 2011: practical approach. PMID- 23098846 TI - Osteoporotic fractures: challenging cases and diagnostic pitfalls. PMID- 23098847 TI - Osteoporosis and renal tubular dysfunction. PMID- 23098848 TI - Distinctive aspects of laboratory testing to evaluate mineral and bone metabolism in patients with chronic kidney disease. PMID- 23098849 TI - Coronary CT angiography with single-source and dual-source CT: comparison of image quality and radiation dose between prospective ECG-triggered and retrospective ECG-gated protocols. AB - BACKGROUND: This study is conducted to investigate and compare image quality and radiation dose between prospective ECG-triggered and retrospective ECG-gated coronary CT angiography (CCTA) with the use of single-source CT (SSCT) and dual source CT (DSCT). METHODS: A total of 209 patients who underwent CCTA with suspected coronary artery disease scanned with SSCT (n=95) and DSCT (n=114) scanners using prospective ECG-triggered and retrospective ECG-gated protocols were recruited from two institutions. The image was assessed by two experienced observers, while quantitative assessment was performed by measuring the image noise, the signal-to-noise ratio (SNR) and the contrast-to-noise ratio (CNR). Effective dose was calculated using the latest published conversion coefficient factor. RESULTS: A total of 2087 out of 2880 coronary artery segments were assessable, with 98.0% classified as of sufficient and 2.0% as of insufficient image quality for clinical diagnosis. There was no significant difference in overall image quality between prospective ECG-triggered and retrospective gated protocols, whether it was performed with DSCT or SSCT scanners. Prospective ECG triggered protocol was compared in terms of radiation dose calculation between DSCT (6.5 +/- 2.9 mSv) and SSCT (6.2 +/- 1.0 mSv) scanners and no significant difference was noted (p=0.99). However, the effective dose was significantly lower with DSCT (18.2 +/- 8.3 mSv) than with SSCT (28.3 +/- 7.0 mSv) in the retrospective gated protocol. CONCLUSIONS: Prospective ECG-triggered CCTA reduces radiation dose significantly compared to retrospective ECG-gated CCTA, while maintaining good image quality. PMID- 23098850 TI - Incidence and management of life-threatening arrhythmias in Takotsubo syndrome. PMID- 23098851 TI - Cryoenergy is effective in the treatment of resistant hypertension in non responders to radiofrequency renal denervation. PMID- 23098852 TI - Resveratrol for primary prevention of atherosclerosis: clinical trial evidence for improved gene expression in vascular endothelium. PMID- 23098853 TI - Role of somatomedin-B-like domains on ENPP1 inhibition of insulin signaling. AB - The exact mechanism by which ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling is not known. ENPP1 contains two somatomedin-B like domains (i.e. SMB 1 and 2) involved in ENPP1 dimerization in animal cells. The aim of the present study was to investigate if these domains modulate ENPP1 inhibitory activity on insulin signaling in human insulin target cells (HepG2). ENPP1 (ENPP1-3'myc), ENPP1 deleted of SMB 1 (ENPP1-DeltaI-3'myc) or of SMB 2 (ENPP1-DeltaII-3'myc) domain were cloned in frame with myc tag in mammalian expression vector pRK5. Plasmids were transiently transfected in human liver HepG2 cells. ENPP1 inhibitory activity on insulin signaling, dimerization and protein-protein interaction with insulin receptor (IR), reported to mediate the modulation of ENPP1 inhibitory activity, were studied. As compared to untransfected cells, a progressive increase of ENPP1 inhibitory activity on insulin-induced IR beta-subunit autophosphorylation and on Akt-S(473) phosphorylation was observed in ENPP1-3'myc, ENPP1-DeltaI-3'myc and ENPP1-DeltaII 3'myc cells. Under non reducing conditions a 260 kDa homodimer, indicating ENPP1 dimerization, was observed. The ratio of non reduced (260 kDa) to reduced (130 kDa) ENPP1 was significantly decreased by two thirds in ENPP1-DeltaII-3'myc vs. ENPP1-3'myc but not in ENPP1-DeltaI-3'myc. A similar ENPP1/IR interaction was detectable by co-immunoprecipitation in ENPP1-3'myc, ENPP1-DeltaI-3'myc and ENPP1 DeltaII-3'myc cells. In conclusion, SMB 1 and SMB 2 are negative modulators of ENPP1 inhibitory activity on insulin signaling. For SMB 2 such effect might be mediated by a positive role on protein dimerization. PMID- 23098854 TI - Inhibition of ERK activation enhances the repair of double-stranded breaks via non-homologous end joining by increasing DNA-PKcs activation. AB - Non-homologous end joining (NHEJ) is one of the major pathways that repairs double-stranded DNA breaks (DSBs). Activation of DNA-PK is required for NHEJ. However, the mechanism leading to DNA-PKcs activation remains incompletely understood. We provide evidence here that the MEK-ERK pathway plays a role in DNA PKcs-mediated NHEJ. In comparison to the vehicle control (DMSO), etoposide (ETOP) induced DSBs in MCF7 cells were more rapidly repaired in the presence of U0126, a specific MEK inhibitor, based on the reduction of gammaH2AX and tail moments. Additionally, U0126 increased reactivation of luciferase activity, which resulted from the repair of restriction enzyme-cleaved DSBs. Furthermore, while inhibition of ERK activation using the dominant-negative MEK1K97M accelerated the repair of DSBs, enforcing ERK activation with the constitutively active MEK1Q56P reduced DSB repair. In line with MEK activating ERK1 and ERK2 kinases, knockdown of either ERK1 or ERK2 increased DSB repair. Consistent with the activation of DNA PKcs being required for NHEJ, we demonstrated that inhibition of ERK activation using U0126, MEK1K97M, and knockdown of ERK1 or ERK2 enhanced ETOP-induced activation of DNA-PKcs. Conversely, enforcing ERK activation by MEK1Q56P reduced ETOP-initiated DNA-PKcs activation. Taken together, we demonstrate that ERK reduces NHEJ-mediated repair of DSBs via attenuation of DNA-PKcs activation. PMID- 23098855 TI - Graphene quantum dots as a new substrate for immobilization and direct electrochemistry of glucose oxidase: application to sensitive glucose determination. AB - Graphene quantum dots (GQD) were introduced as a novel and suitable substrate for enzyme immobilization. Glucose oxidase (GOx) was immobilized on GQD modified carbon ceramic electrode (CCE) and well-defined quasi-reversible redox peaks were observed. The UV-vis photoluminescence spectroscopy, transition electron microscopy, field emission scanning electron microscopy, electrochemical impedance spectroscopy, and cyclic voltammetry techniques were used for characterizing the electrochemical biosensor. The electron transfer coefficient (alpha) and the heterogeneous electron transfer rate constant (k(s)) for redox reaction of GOx were found to be 0.48 and 1.12 s(-1), respectively. The developed biosensor responds efficiently to glucose presence over the concentration range 5 1270 MUM with the detection limit 1.73 MUM (S/N=3) and sensitivity 0.085 MUA MUM( 1) cm(-2). The high value of surface coverage GOx-GQD|CCE (1.8*10(-9) mol/cm(2)) and the small value of Michaelis-Menten constant (0.76 mM) confirmed an excellent loading of the enzyme and a high affinity of biosensor to glucose. High performance of the biosensor is attributed to the large surface-to-volume ratio, excellent biocompatibility of GQD, porosity of GQD|CCE, and the abundance of hydrophilic edges as well as hydrophobic plane in GQD which enhances the enzyme absorption on the electrode surface. PMID- 23098856 TI - Fluorescent aptamer-functionalized graphene oxide biosensor for label-free detection of mercury(II). AB - Label-free fluorescent detection of Hg(2+) has been realized via quenching of fluorescence of graphene oxide (GO). The water-soluble GO sheets, which are functionalized with single-stranded DNA aptamer, exhibit strong fluorescence emission at 600 nm under the excitation of 488 nm in the absence of Hg(2+) ions. When Hg(2+) ions appear in the aqueous solution, Hg(2+) ions are sandwiched between the hairpin-shaped double-stranded DNA due to the formation of the thymine-Hg(2+)-thymine complex, which holds the Hg(2+) ions in proximity to the surface of GO sheets. As a result, the fluorescence emission of GO is quenched. The present GO-based sensor shows a limit of detection as low as 0.92 nM and excellent selectivity toward Hg(2+) over a wide range of metal ions. The present work indicates that GO is a promising fluorescent probe for detection of metal ions and biomolecules. PMID- 23098857 TI - An organic substrate based magnetoresistive sensor for rapid bacteria detection. AB - A point-of-care diagnostic system has been developed to detect pathogenic bacteria rapidly, of which system contains a magnetoresistive (MR) sensor in cooperation with a magnetic bead coated by specific antibody against bacteria. MR sensor with Teflon passivation layer has been fabricated on organic substrate, being flexible and low cost material, and passivated by Teflon layer for maintaining flexibility. The performance of the MR sensor is demonstrated using Magnetospirillum magneticum AMB-1 and its detection limit was found to be 1.3*10(8) cells/ml. Further, Escherichia coli is captured by immobilised anti-E. coli antibodies on the surface of the sensor and detected using magnetic bead labelled with anti-E. coli antibody. The detection limit of E. coli was found to be 1.2*10(3) cells/ml. The technique is simple, rapid, sensitive and does not require pre-treatment of the sample and can detect a variety of microorganisms. The high performance of sensor fabricated on flexible organic substrate may allow its future use for bio-applications in implantable types of devices. PMID- 23098858 TI - Hormonal contraception and venous thromboembolic risk in midlife women. PMID- 23098859 TI - Studies on the genotoxic effect of chromium oxide (Cr VI): interaction with deoxyribonucleic acid in solution. AB - Chromium is a toxic and carcinogenic compound widely distributed in environment. In the present study we have investigated the interaction of chromium oxide with DNA employing UV/vis and fluorescence spectroscopy as well as Circular dichroism, thermal denaturation, retardation polyacrylamide gel electrophoresis and DNA cellulose affinity techniques. The results showed that the binding of chromium oxide to DNA is concentration dependent; at low concentration shows a little effect but ant higher concentrations (>100MUg/ml) reduced the absorbance at 260 and 210nm producing hypochromicity. Also lambda(max) of the metal at 210, 260 and 350nm was reduced. DNA chromophores quenched with the chromium oxide and decreased fluorescence emission intensity. Upon binding of the metal to DNA the elliplicity at positive extreme was decreased (275nm) and increased the ellipticity of the DNA at negative extreme 245nm. Thermal denaturation profile of DNA shifted to higher degrees upon chromium oxide binding which accompanied by hypochromicity. Also, affinity of chromium oxide to double stranded DNA was higher than single stranded DNA. From the result it is concluded that chromium oxide interacts with DNA via two modes of interaction inducing structural changes and DNA compaction evidence providing chromium oxide genotoxicity. PMID- 23098860 TI - Cryopreservation and storage of mussel (Mytilus spp.) haemocytes for latent analysis by the Comet assay. AB - Estuarine and coastal habitats are known to be polluted by a range of chemical contaminants from both industrial and domestic sources. Blue mussels (Mytilus spp.), which inhabit these areas, are widely used as bio-indicators in eco toxicological studies, because of their sedentary nature and their ability to bio accumulate contaminants. The analysis of DNA damage in mussel haemocytes is a valuable tool for biomonitoring but sampling issues related to storage, handling and transportation have often limited its application in large-scale monitoring programmes. This study uses a trial and error method to evaluate and validate a suitable protocol for cryopreservation of mussel haemocytes, thereby allowing material collected in the field to be analysed later under controlled laboratory conditions. Three different cell-culture media, i.e. Leibovitz-15, Hank's balanced salt solution and mussel physiological saline, along with four different cryoprotectants, i.e. dimethyl sulphoxide (10% and 20%), 1,2-propanediol (10%), ethylene glycol (10%) and glycerol (10%) were tested to assess their suitability for cryopreservation of mussel haemocytes for analysis in the comet assay. Experimental studies where mussel haemocytes were also exposed to UV radiation or benzo(a)pyrene were conducted in order to mimic environmental stresses and to verify the effectiveness of newly defined cryopreservation protocols. The comet assay was used to demonstrate that mussel haemocytes could be preserved at cryogenic temperatures for a month without altering levels of DNA damage, which could possibly be used for lab or field studies where time constraints or facilities do not allow instant analysis. PMID- 23098861 TI - Are we ignoring dysnatremia? PMID- 23098862 TI - Internist diagnosis and management of chronic hepatitis B virus infection. AB - Chronic infection with the hepatitis B virus can lead to hepatocellular carcinoma and cirrhosis in up to 25% of infected individuals. As many as 2 million individuals in the US may have chronic hepatitis B infection, most of whom immigrated to the US from hepatitis B-endemic regions of the world. A 2010 report from the Institute of Medicine noted that two thirds of patients with hepatitis B are unaware of their infection, and most health care providers do not screen for hepatitis B or know how to manage hepatitis B-positive patients. In 2010, the Hepatitis B Foundation convened a group of primary care providers to consider the existing evidenced-based recommendations and strategies for implementation of hepatitis B screening into routine practice. The group designed an easy-to-use algorithm for screening, initial evaluation, ongoing management, and referral to a subspecialist when appropriate. Internal medicine specialists, including primary care providers and subspecialists, need to understand the steps they can take to address this often under-recognized disorder. PMID- 23098863 TI - What started this? Debilitating longitudinally-extensive myelitis. PMID- 23098864 TI - Trends in atrial fibrillation in patients hospitalized with an acute coronary syndrome. AB - BACKGROUND: Atrial fibrillation is common among patients with cardiovascular disease and is a frequent complication of the acute coronary syndrome. Data are needed on recent trends in the magnitude, clinical features, treatment, and prognostic impact of preexisting and new-onset atrial fibrillation in patients hospitalized with an acute coronary syndrome. METHODS: The study population consisted of 59,032 patients hospitalized with an acute coronary syndrome at 113 sites in the Global Registry of Acute Coronary Events Study between 2000 and 2007. RESULTS: A total of 4494 participants (7.6%) with acute coronary syndrome reported a history of atrial fibrillation and 3112 participants (5.3%) developed new-onset atrial fibrillation during their hospitalization. Rates of new-onset atrial fibrillation (5.5%-4.5%) and preexisting atrial fibrillation (7.4%-6.7%) declined during the study. Preexisting atrial fibrillation was associated with older age and greater cardiovascular disease burden, whereas new-onset atrial fibrillation was closely related to the severity of the index acute coronary syndrome. Patients with atrial fibrillation were less likely than patients without atrial fibrillation to receive evidence-based therapies and more likely to develop in-hospital complications, including heart failure. Overall hospital death rates in patients with new-onset and preexisting atrial fibrillation were 14.5% and 8.9%, respectively, compared with 1.2% in those without atrial fibrillation. Short-term death rates in patients with atrial fibrillation declined over the study period. CONCLUSIONS: Despite a reduction in the rates of, and mortality from, atrial fibrillation, this arrhythmia exerts a significant adverse effect on survival among patients hospitalized with an acute coronary syndrome. Opportunities exist to improve the identification and treatment of patients with acute coronary syndrome with, or at risk for, atrial fibrillation to reduce the incidence and resultant complications of this dysrhythmia. PMID- 23098866 TI - An updated focus on internal medicine resident education. PMID- 23098865 TI - Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. AB - OBJECTIVE: Streamlining the initiation of allopurinol could result in a cost benefit for a common medical problem and obviate the perception that no treatment is required once acute attacks have resolved. Our objective was to test the hypothesis that there is no difference in patient daily pain or subsequent attacks with early versus delayed initiation of allopurinol for an acute gout attack. METHODS: A total of 57 men with crystal-proven gout were randomized to allopurinol 300 mg daily or matching placebo for 10 days. All subjects received indomethacin 50 mg 3 times per day for 10 days, a prophylactic dose of colchicine 0.6 mg 2 times per day for 90 days, and open-label allopurinol starting at day 11. Primary outcome measures were pain on visual analogue scale (VAS) for the primary joint on days 1 to 10 and self-reported flares in any joint through day 30. RESULTS: On the basis of 51 evaluable subjects (allopurinol in 26, placebo in 25), mean daily VAS pain scores did not differ significantly between study groups at any point between days 1 and 10. Initial VAS pain scores for allopurinol and placebo arms were 6.72 versus 6.28 (P=.37), declining to 0.18 versus 0.27 (P=.54) at day 10, with neither group consistently having more daily pain. Subsequent flares occurred in 2 subjects taking allopurinol and 3 subjects taking placebo (P=.60). Although urate levels decreased rapidly in the allopurinol group (from 7.8 mg/dL at baseline to 5.9 mg/dL at day 3), sedimentation rates and C-reactive protein levels did not differ between groups at any point. CONCLUSIONS: Allopurinol initiation during an acute gout attack caused no significant difference in daily pain, recurrent flares, or inflammatory markers. PMID- 23098867 TI - Physicians' prescribing patterns for patients with diabetes are changing for the better. PMID- 23098868 TI - When is better care not patient centered? PMID- 23098869 TI - Sleep apnea and risk of deep venous thrombosis: looking for potential confounders. PMID- 23098871 TI - Distance runners lack defined atrial fibrillation therapy. PMID- 23098873 TI - The "risk" of risk assessment models for venous thromboembolism in medical patients. PMID- 23098875 TI - Building a solid foundation in diabetes: the nuts and bolts of insulin therapy. AB - Insulin therapy is required for survival by all individuals with type 1 diabetes mellitus. It is also used to improve glycemic control in some individuals with longstanding type 2 diabetes mellitus who are not profoundly insulin deficient, and may be preferred over other antidiabetic medications for this purpose. As the number of patients with diabetes continues to grow, family physicians will correspondingly care for an increasing number of patients who use insulin therapy. Family physicians need to acquire the essential skills to safely and effectively initiate and titrate common insulin regimens. Several methods to initiate and titrate basal, basal-bolus, and premixed/biphasic insulin therapy, especially in individuals with type 2 diabetes mellitus, are described in this activity. Furthermore, insulin analogues permit more physiologic insulin delivery than recombinant human insulins, but new insulin formulations are currently being developed that have the potential to further reduce glycemic variability and the risk of hypoglycemia. Emerging data on investigational insulins will be reviewed. This webcast is available through the website of The American Journal of Medicine (www.amjmed.com). Click on the "Building a Solid Foundation in Diabetes: The Nuts and Bolts of Insulin Therapy" link in the "CME Multimedia Activities" section, found on the right side of the Journal homepage. PMID- 23098876 TI - Triterpenes and steroids from the leaves of Aglaia exima (Meliaceae). AB - A study on the leaves of Aglaia exima led to the isolation of one new and seven known compounds: six triterpenoids and two steroids. Their structures were elucidated and analyzed mainly by using spectroscopic methods; 1D and 2D NMR, mass spectrometry, UV spectrometry and X-ray. All the triterpenoids and steroids were measured in vitro for their cytotoxic activities against eight cancer cell lines; lung (A549), prostate (DU-145), skin (SK-MEL-5), pancreatic (BxPC-3), liver (Hep G2), colon (HT-29), breast (MCF-7) and (MDA-MB-231). The new cycloartane triterpenoid, 24(E)-cycloart-24-ene-26-ol-3-one 1, showed potent cytotoxic activity against colon (HT-29) cancer cell line (IC(50) 11.5MUM). PMID- 23098877 TI - Phytochemical and therapeutic potential of cucumber. AB - Cucumber (Cucumis sativus L.) is a member of the Cucurbitaceae family like melon, squash and pumpkins. It is a popular vegetable crop used in Indian traditional medicine since ancient times. This vegetable is very high in water content and very low in calories. It has potential antidiabetic, lipid lowering and antioxidant activity. Cucumber has a cleansing action within the body by removing accumulated pockets of old waste materials and chemical toxins. Fresh fruit juice is used for nourishing the skin. It gives a soothing effect against skin irritations and reduces swelling. Cucumber also has the power to relax and alleviate the sunburn's pain. The fruit is refrigerant, haemostatic, tonic and useful in hyperdipsia, thermoplegia etc. The seeds also have a cooling effect on the body and they are used to prevent constipation. Several bioactive compounds have been isolated from cucumber including cucurbitacins, cucumegastigmanes I and II, cucumerin A and B, vitexin, orientin, isoscoparin 2"-O-(6'''-(E)-p-coumaroyl) glucoside, apigenin 7-O-(6"-O-p-coumaroylglucoside) etc. Despite huge exploration of cucumber in agricultural field, comparatively very few studies have been published about its chemical profile and its therapeutic potential. This article reviews the therapeutic application, pharmacological and phytochemical profile of different parts of C. sativus. In this review we have explored the current phytochemical and pharmacological knowledge available with this well known plant and several promising aspects for research on cucumber. PMID- 23098878 TI - Two new anthraquinone dimers from the fruit bodies of Bulgaria inquinans. AB - Two new dimeric anthraquinone derivatives, bulgareone A(1) and bulgareone B(2), were isolated from the fruit bodies of Bulgaria inquinans. Their structures were elucidated on the basis of extensive spectroscopic analysis. The in vitro cytotoxic activity of compounds 1 and 2 was assayed. They displayed inhibitive activities against human cancer cell lines HL60 and K562. PMID- 23098879 TI - A novel furanoeremophilane with an unusual oxygen bridge from Senecio nemorensis. AB - Two new furanoeremophilanes, 1alpha, 6alpha-epoxy-9-oxo-10beta-hydroxyl furanoeremophilane (1), and 9-oxo-1alpha, 6beta, 10beta-trihydroxy furanoeremophilane (2) were isolated from Senecio nemorensis. Their structures were elucidated by spectroscopic methods and X-ray crystallography. This is the first report of the isolation of the C1-C6 oxygen bridge of furanoeremophilane. Their cytotoxic effects on BEL7402 and NF-KB cell lines were tested. PMID- 23098880 TI - Identifying transcriptional miRNA biomarkers by integrating high-throughput sequencing and real-time PCR data. AB - Using both high-throughput sequencing and real-time PCR, the miRNA transcriptome can be analyzed in complementary ways. We describe the necessary bioinformatics pipeline, including software tools, and key methodological steps in the process, such as adapter removal, read mapping, normalization, and multiple testing issues for biomarker identification. The methods are exemplified by the analysis of five favorable (event-free survival) vs. five unfavorable (died of disease) neuroblastoma tumor samples with a total of over 188 million reads. PMID- 23098881 TI - Construction of short tandem target mimic (STTM) to block the functions of plant and animal microRNAs. AB - Small RNAs are widespread in plants and animals. They largely include microRNAs (miRNAs) and short interfering RNAs (siRNAs), and they play key roles in gene and chromatin regulations. Here we describe in detail the method for an effective construction of the recently developed short tandem target mimic (STTM) technology to block small RNA functions in plants and animals. STTM is a powerful technology complementing the previous target mimic (TM) in plants and the miRNA sponge, as well as the recently defined endogenous competing RNA (CeRNA) in animals. We expect STTM will not only be effective in blocking small RNA functions in plants but will also become a popular approach in animals. PMID- 23098882 TI - [Non-Hodgkin's lymphomas in elderly patients]. PMID- 23098883 TI - [Welcome in Nice]. PMID- 23098884 TI - [Geriatric assessment for elderly patients with haematological malignancies]. PMID- 23098885 TI - [Antiphospholipid syndrome in obstetrics]. PMID- 23098886 TI - Pathophysiology of the antiphospholipid syndrome (APS). PMID- 23098887 TI - Impact of lifestyle intervention on body weight and the metabolic syndrome in home-care providers. AB - AIM: The study evaluated the impact of lifestyle intervention on body weight, metabolic syndrome parameters, nutrition and physical activity in home-care providers (HCPs). METHODS: Of 551 screened employees of a nursing agency, 173 were eligible to participate and were assigned to either the intervention (n=129) or the control (n=44) group. Participants in the intervention group followed an educational programme that encouraged physical activity and healthy nutrition, and were equipped with bicycles free of charge. Anthropometric, biological and lifestyle parameters were assessed at baseline, and after 6 and 12 months. RESULTS: Body weight, waist circumference and systolic blood pressure significantly decreased at 12 months in both study groups. Incidence of the metabolic syndrome in the intervention group at 12 months was reduced by 50% (from 17 to 9.2%; P=0.04). There were also decreases in LDL cholesterol (-0.36 mmol/L; P<0.01), total cholesterol/HDL cholesterol ratio (-0.57; P<0.01) and fasting glucose (-0.4 mmol/L; P<0.05), and an increase in HDL cholesterol (+0.22 mmol/L; P<0.01) in the intervention group. At 12 months, a decrease in daily caloric intake (-391 kcal/day; P<0.001) and an increase in the percentage of participants engaging in physical activity (+3.4%; P<0.05) were also observed in the intervention group. CONCLUSION: Lifestyle changes among HCPs are possible with relatively modest behavioural education and within a short period of time. Educational strategies and workshops are effective, efficient and easy to perform, and should be encouraged in HCPs to promote the implementation of lifestyle modifications in their patients. PMID- 23098888 TI - Safety and efficacy of triplet regimens in newly diagnosed light chain amyloidosis. AB - BACKGROUND: The prognosis of patients with systemic light chain (AL) amyloidosis, particularly cardiac, is poor. Treatments have been derived from multiple myeloma, but there are few studies that use triplet regimens in AL amyloidosis because of concern of greater toxicity than seen in myeloma. PATIENTS AND METHODS: We conducted a retrospective review of patients with newly diagnosed AL amyloidosis who were initially treated with a triplet regimen. RESULTS: For the 9 patients included, the median age was 64 years, and 8 were ineligible for stem cell transplantation. At least 2 organs were involved in 4 patients, including 7 with kidney and 4 with heart involvement, 2 of whom had New York Heart Association class 3 heart failure. All the patients received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. With a median follow-up of 13 months, 8 of 9 patients had a hematologic response, including 2 who achieved complete response, with a median time to response of 2.7 months. An organ response was seen in 7 of 9 patients, including all 4 patients with cardiac involvement. There were no deaths, and only 1 patient had progressive disease. The major toxicity observed was fluid overload and syncope, seen only in patients with heart failure, who eventually achieved a partial or complete response. CONCLUSIONS: Dose-attenuated triplet regimens achieved rapid hematologic responses with manageable and reversible toxicity in patients with newly diagnosed AL amyloidosis. PMID- 23098889 TI - Normal karyotype CALLA-positive adult pre-B ALL: dismal outcome with chemotherapy for patients with loss/gain of ABL1 and/or BCR FISH signals. AB - BACKGROUND: Diagnostic karyotype and molecular studies represent the most powerful prognostic indicators in acute myeloid leukemia and provide the framework for risk stratification. Risk stratification in ALL has also a vital role in predicting outcome and identifying patients at higher risk of relapse with multiagent chemotherapy, but the role of diagnostic karyotype and molecular markers in adult ALL is limited to few well recognized cytogenetic abnormalities. PATIENTS AND METHODS: We report a case series of 6 adult ALL patients with a characteristic molecular abnormality that have done poorly with chemotherapy. Between April 2004 and November 2009, 72 adult ALL patients (Pre-B-cell 61; T cell 11) were referred to and treated at the Leukemia/BMT Program of BC in Vancouver, Canada. FISH for BCR-ABL fusion was positive in 12 of 61 Pre-B cell ALL patients. An additional 6 patients were negative for this typical fusion but had FISH abnormalities related to BCR and/or ABL1. RESULTS: In this report, we describe the clinical and hematopathologic characteristics of these 6 patients and their poor outcome. We review the literature where only 2 similar cases with normal karyotype Pre-B ALL and associated FISH BCR/ABL1 numerical abnormalities were found. CONCLUSION: We recommend screening all adult pre-B ALL patients with normal karyotype for this clonal abnormality and suggest classifying these ALL patients into the high-risk category. PMID- 23098891 TI - Two-year treatment with rosuvastatin reduces carotid intima-media thickness in HIV type 1-infected patients receiving highly active antiretroviral therapy with asymptomatic atherosclerosis and moderate cardiovascular risk. AB - Recent studies have shown that rosuvastatin significantly decreases serum levels of inflammatory biomarkers and slows progression of carotid atherosclerosis in the general population. However, there are no data about its effect on progression of atherosclerosis in HIV-infected patients. Adult patients with HIV infection, on stable antiretroviral therapy, with asymptomatic carotid atherosclerosis and hypercholesterolemia, who started a rosuvastatin treatment at 10 mg daily during the period 2007-2009 were enrolled and followed-up for 24 months. Thirty-six patients (30 males) were enrolled, with a mean age of 49 years, a mean duration of current antiretroviral therapy of 38 months, and a mean 10-year risk of myocardial infarction of 18.5%. Rosuvastatin led to a significant decrease in mean values of intima-media thickness in all extracranial carotid arteries, with the greatest magnitude observed in carotid bifurcations (a mean decrease of 18.7% in the right artery and of 21.4% in the left artery) and in internal carotid arteries (a mean decrease of 23.7% in the right artery and of 25.6% in the left artery). Moreover, there was a significant reduction in mean levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides versus respective baseline values associated with a significantly decreased mean cardiovascular risk. The treatment with rosuvastatin was well tolerated, and serious adverse events were not reported. A 24-month treatment with rosuvastatin in HIV-infected patients on highly active antiretroviral therapy (HAART) with subclinical atherosclerosis and a moderate cardiovascular risk seems to promote significantly favorable changes in carotid atherosclerosis, associated with a favorable effect on serum lipid levels and a good tolerability profile. PMID- 23098892 TI - Right atrial myxoma and severe left ventricular dysfunction: which explanations? Which management? AB - A 57 year-old woman with a large right atrial myxoma underwent emergency surgical resection in our institute. It is known that surgical management of such tumours is difficult regarding venous cannulation and embolic risk, but in our patient, the surgery was more challenging because of the severe left ventricular dysfunction. Thus, we aim on the one hand, to discuss the association between the left ventricular dysfunction and the right atrial myxoma, and, on the other hand, to describe the on-pump beating heart technique we used to remove this mass. PMID- 23098890 TI - HIV non-B subtype distribution: emerging trends and risk factors for imported and local infections newly diagnosed in South Australia. AB - Monitoring HIV subtype distribution is important for understanding transmission dynamics. Subtype B has historically been dominant in Australia, but in recent years new clades have appeared. Since 2000, clade data have been collected as part of HIV surveillance in South Australia. The aim of this study was to evaluate the prevalence of and risk factors for HIV-1 non-B subtypes. The study population was composed of newly diagnosed, genotyped HIV subjects in South Australia between 2000 and 2010. We analyzed time trends and subtype patterns in this cohort; notification data were aggregated into three time periods (2000 2003, 2004-2006, and 2007-2010). Main outcome measures were number of new non-B infections by year, exposure route, and other demographic characteristics. There were 513 new HIV diagnoses; 425 had information on subtype. The majority (262/425) were in men who have sex with men (MSM), predominantly subtype B and acquired in Australia. Infections acquired in Australia decreased from 77% (2000 2003) to 64% (2007-2010) (p=0.007) and correspondingly the proportion of subtype B declined from 85% to 68% (p=0.002). Non-B infections were predominantly (83%) heterosexual contacts, mostly acquired overseas (74%). The majority (68%) of non B patients were born outside of Australia. There was a nonsignificant increase from 1.6% to 4.2% in the proportion of locally transmitted non-B cases (p=0.3). Three non-B subtypes and two circulating recombinant forms (CRFs) were identified: CRF_AE (n=41), C (n=36), CRF_AG (n=13), A (n=9), and D (n=2). There has been a substantial increase over the past decade in diagnosed non-B infections, primarily through cases acquired overseas. PMID- 23098893 TI - 5'UTR repeat polymorphisms of the BMPR2 gene in children with pulmonary hypertension associated with congenital heart disease. AB - The mutations of bone morphogenetic protein receptor type 2 (BMPR2) in patients with idiopathic pulmonary hypertension has been well defined. We investigated the occurrence of BMPR2 mutation and genetic polymorphisms in children with pulmonary hypertension associated with congenital heart disease (aPH/CHD) and correlated with the pulmonary haemodynamic and vasoreactivity. METHODS: BMPR2 mutation/polymorphisms were determined in 30 aPH/CHD children. All children underwent cardiac catheterisation to obtain baseline haemodynamic data. The 5'UTR containing promoter region and all the exons [1-13] of BMPR2 gene were genotyped for possible genetic variants that may be related to the aPH/CHD. RESULTS: None of our 30 patients (median-age 90 months) with aPH/CHD (mean PAP 48+/-17mmHg, PVR 6.7+/-4.2WUm(2)) has had any BMPR2 mutation. Fifteen of them had single nucleotide polymorphism, rs1061157 and/or 5'UTR-polymorphism, specifically GGC repeat variant in seven patients; AGC repeat variant in one patient; and nine base pairs duplication (CTTCTTCGG) in one patient. The GGC repeat >=13 was found in three out of six of children with aPH/CHD with normal PVR vs. two out of 24 children with aPH/CHD with high PVR. The odd ratio between these two subgroups of aPH/CHD is 0.09 (95% CI 0.02-0.34). CONCLUSIONS: In our cohort, there was no BMPR2 mutation in children with aPH/CHD while nine out of 30 of them have 5'UTR repeat polymorphisms. Our data suggests the occurrence of GGC repeat >=13 at the 5'UTR region may have some protective effect towards pulmonary vasculopathy in children who have been exposed to high pulmonary blood flow due to CHD. PMID- 23098895 TI - The neurobiological underpinnings of obesity and binge eating: a rationale for adopting the food addiction model. AB - The food addiction model of overeating has been proposed to help explain the widespread advancement of obesity over the last 30 years. Parallels in neural substrates and neurochemistry, as well as corresponding motivational and behavioral traits, are increasingly coming to light; however, there are still key differences between the two disorders that must be acknowledged. We critically examine these common and divergent characteristics using the theoretical framework of prominent drug addiction models, investigating the neurobiological underpinnings of both behaviors in an attempt to justify whether classification of obesity and binge eating as an addictive disorder is merited. PMID- 23098894 TI - A methamphetamine vaccine attenuates methamphetamine-induced disruptions in thermoregulation and activity in rats. AB - BACKGROUND: There are no approved pharmacotherapies for d-methamphetamine (METH) addiction and existing therapies have limited efficacy. Advances in using immunotherapeutic approaches for cocaine and nicotine addiction have stimulated interest in creating a similar approach for METH addiction. This study investigated whether active vaccination against METH could potentially attenuate responses to METH in vivo. METHODS: Male Sprague Dawley rats (n = 32) received a four-boost series with one of three candidate anti-METH vaccines (MH2[R], MH6, and MH7) or a control keyhole limpet hemocyanin conjugate vaccine. Effects of METH on rectal temperature and wheel activity at 27 degrees C ambient temperature were determined. The most efficacious vaccine, MH6, was then contrasted with keyhole limpet hemocyanin conjugate vaccine in a subsequent experiment (n = 16), wherein radiotelemetry determined home cage locomotor activity and body temperature at 23 degrees C ambient temperature. RESULTS: The MH6 vaccine produced high antibody titers with nanomolar affinity for METH and sequestered METH in the periphery of rats. In experiment 1, the thermoregulatory and psychomotor responses produced by METH at 27 degrees C were blocked in the MH6 group. In experiment 2, METH-induced decreases in body temperature and locomotor activity at 23 degrees C were also attenuated in the MH6 group. A pharmacokinetic study in experiment 2 showed that MH6-vaccinated rats had higher METH serum concentrations, yet lower brain METH concentrations, than control rats, and METH concentrations correlated with individual antibody titer. CONCLUSIONS: These data demonstrate that active immunopharmacotherapy provides functional protection against physiological and behavioral disruptions induced by METH. PMID- 23098896 TI - Use of fast conformational sampling to improve the characterization of VEGF A peptide interactions. AB - Protein-peptide interaction is fundamentally important for signal transduction, transcription regulation, protein degradation, cell regeneration, and immune response. Here, we report the use of a fast conformational sampling strategy to improve the prediction of protein-peptide binding affinity. This method generates hundreds of alternative conformers for a protein-peptide complex and then performs classical MM-PB/SA analysis over these conformers to derive a consistent binding energy expression for the complex. We show a proof-of-concept study on vascular endothelial growth factor A (VEGF A) interaction with its peptide ligands. The structures of VEGF A complexed with 13 peptides are modeled with a virtual mutagenesis protocol and their binding energies are subsequently calculated by using the conformational sampling-based method. A good linear correlation between the calculated and experimental values is observed, and we demonstrate that the correlation could be further improved by fitting the decomposed energy terms to experimentally measured affinity. Furthermore, the obtained results are discussed in detail in order to elucidate the structural basis and energetic implication underlying VEGF A-peptide recognition and association. We also give a detailed comparison between the proposed method and other widely used approaches, from which it is suggested that our method exhibits a good compromise between the effectiveness and efficiency in evaluating protein peptide affinity. PMID- 23098897 TI - Small and poor females change sex: a theoretical and empirical study on protogynous sex change in a triggerfish under varying resource abundance. AB - Sex change is known from various fish species. In many polygynous species, the largest female usually changes sex to male when the dominant male disappeared, as predicted by the classical size-advantage model. However, in some fishes, the disappearance of male often induces sex change by a smaller female, instead of the largest one. The halfmoon triggerfish Sufflamen chrysopterum is one of such species. We conducted both field investigation and theoretical analysis to test the hypothesis that variation in female fecundity causes the sex change by less fertile females, even if they are not the largest. We estimated the effect of body length and residual body width (an indicator of nutrition status) on clutch size based on field data. Sex-specific growth rates were also estimated from our investigation and a previous study. We incorporated these estimated value into an evolutionarily stable strategy model for status-dependent size at sex change. As a result, we predict that rich females change sex at a larger size than poor ones, since a rich fish can achieve high reproductive success as a female. In some situations, richer females no longer change sex (i.e. lifelong females), and poorer fish changes sex just after maturation (i.e. primary males). We also analyzed the effect of size-specific growth and mortality. PMID- 23098898 TI - Does planned intravenous sedation affect preoperative anxiety in patients? AB - Dental surgery generally causes stress and fear, which may affect patient physiology and increase perioperative anxiety. Dental anxiety is considered to be an important factor in determining the need for intravenous sedation. One of the gold standards for measuring preoperative anxiety is Spielberger's State-Trait Anxiety Inventory (STAI). The authors have previously assessed preoperative anxiety using STAI and recommended that intravenous sedation be performed for patients whose anxiety level is high. The intravenous cannulation necessary for sedation and sedation itself may increase anxiety. The authors carried out this study to examine whether planning intravenous sedation before surgery increases preoperative anxiety. The subjects were patients who planned to undergo wisdom teeth extraction under local anaesthesia in the authors' hospital. They were divided into two groups on the basis of the planned intravenous sedation. STAI scores were compared between the initial visit and just before surgery. There were no significant differences in the state and trait anxiety scores between the initial visit and the day of the surgery in the two groups. Planned intravenous sedation based on the evaluation of anxiety levels using STAI is effective for promoting a safe operation without aggravating preoperative anxiety. PMID- 23098899 TI - Sesquiterpenoids from Curcuma wenyujin with anti-influenza viral activities. AB - Five sesquiterpenoids, 1alpha,8alpha-epidioxy-4alpha-hydroxy- 5alphaH-guai 7(11),9-dien- 12,8-olide. (1), 8,9-seco-4beta-hydroxy-1alpha,5betaH-7(11)-guaen 8,10-olide (2), 8alpha-hydroxy-1alpha, 4beta,7betaH-guai-10(15)-en- 5beta,8beta endoxide(3), 7beta,8alpha-dihydroxy-1alpha,4alphaH-guai-10(15)-en-5beta,8beta endoxide(4) and 7-hydroxy-5(10),6,8-cadinatriene-4-one(5), together with seven known analogs were isolated from the rhizomes of Curcuma wenyujin. Their structures and relative configurations were determined on the basis of spectroscopic methods including 2D NMR techniques, and the structures of 1 and 2 were confirmed by single-crystal X-ray diffraction experiment. Compounds 1-10 and 12 showed significant in vitro antiviral activity against the influenza virus A with IC50 values ranged from 6.80 to 39.97 MUM, and SI values ranged from 6.35 to 37.25. PMID- 23098900 TI - Aristololactams and aporphines from the stems of Fissistigma oldhamii (Annonaceae). AB - Two aristololactams, aristololactam GI (1) and aristololactam GII (2), and three aporphines, fissistigamide A (3), fissistigamide B (4) and fissistigmine (5), together with nineteen known alkaloids, one flavone and one anthraquinone were isolated from the ethanol extracts of the stems of Fissistigma oldhamii (Annonaceae). Their structures were elucidated primarily by analysis of NMR, IR, UV, MS and CD data. Alkaloid 1 is a chiral aristololactam formed from a phenylpropanoid derivative attached to a 3,4-dihydroxy aristololactam scaffold. The absolute configuration of 1 was determined by comparing experimental and calculated ECD spectra. The anti-inflammatory activity of the crude extracts and the five alkaloids were tested by measuring the amount of TNF-alpha and IL-6 released from LPS stimulated RAW264 cell via ELISA. The results demonstrated that the CHCl(3)-soluble part and alkaloid 2 exhibited significant anti-inflammatory activity in vitro in both assays. PMID- 23098901 TI - Variation in the chemical composition of cone volatiles within the African cycad genus Encephalartos. AB - Volatiles play a key role in attraction of pollinators to cycad cones, but the extent to which volatile chemistry varies among cycad species is still poorly documented. Volatile composition of male and female cones of nineteen African cycad species (Encephalartos; Zamiaceae) was analysed using headspace technique and gas chromatography-mass spectrometry (GC-MS). A total of 152 compounds were identified among the species included in this study, the most common of which were monoterpenes, nitrogen-containing compounds and unsaturated hydrocarbons. Male and female cones emitted similar volatile compounds which varied in relative amounts with two unsaturated hydrocarbons (3E)-1,3-octadiene and (3E,5Z)-1,3,5 octatriene present in the volatile profile of most species. In a multivariate analysis of volatile profiles using non-metric multidimensional scaling (NMDS), a number of species clusters were identified according to shared emission of unsaturated hydrocarbons, pyrazines, benzenoids, aldehydes, alkanes and terpenoids. In comparison, terpenoids are common in Zamia and dominant in Macrozamia species (both in the family Zamiaceae) while benzenoids, esters, and alcohols are dominant in Cycas (Cycadaceae) and in Stangeria (Stangeriaceae). It is likely that volatile variation among Encephalartos species reflects both phylogeny and adaptations to specific beetle pollinators. PMID- 23098902 TI - Characterization of Arabidopsis serine:glyoxylate aminotransferase, AGT1, as an asparagine aminotransferase. AB - Asparagine (Asn) is a major form of nitrogen transported to sink tissues. Results from a previous study have shown that an Arabidopsis mutant lacking asparaginase activity develops relatively normally, highlighting a possible compensation by other types of asparagine metabolic enzymes. Prior studies with barley and tobacco mutants have associated Asn aminotransferase activity with the photorespiratory enzyme, serine (Ser):glyoxylate aminotransferase. This enzyme is encoded by AGT1 in Arabidopsis thaliana. Recombinant N-terminal His-tagged AGT1 purified from Escherichia coli was characterized with Ser, alanine (Ala) and Asn as amino acid donors and glyoxylate, pyruvate and hydroxypyruvate as organic acid acceptors. The V(max) of AGT1 with Asn was higher than with Ser or Ala by ca. 5- to 20-fold. As a result, the catalytic efficiency (V(max)/K(m)) was slightly higher with Asn than with the two other amino acids. In the roots of 10-day-old seedlings treated for 2h with 20mM Asn, the AGT1 transcript levels were raised by 2-fold. During this treatment, the concentration of Asn in root was raised by ca. 5-fold. These results suggest that AGT1 is involved in Asn metabolism in Arabidopsis. PMID- 23098903 TI - Viridin-like steroids from Hymenoscyphus pseudoalbidus. AB - Three furanosteroids were isolated from the ash dieback causing fungus Hymenoscyphus pseudoalbidus along with the known compounds viridiol and demethoxyviridiol. The compounds were characterized by 1D and 2D NMR spectroscopy, LC-HRMS and polarimetry. PMID- 23098904 TI - Intuitive sense of number correlates with math scores on college-entrance examination. AB - Many educated adults possess exact mathematical abilities in addition to an approximate, intuitive sense of number, often referred to as the Approximate Number System (ANS). Here we investigate the link between ANS precision and mathematics performance in adults by testing participants on an ANS-precision test and collecting their scores on the Scholastic Aptitude Test (SAT), a standardized college-entrance exam in the USA. In two correlational studies, we found that ANS precision correlated with SAT-Quantitative (i.e., mathematics) scores. This relationship remained robust even when controlling for SAT-Verbal scores, suggesting a small but specific relationship between our primitive sense for number and formal mathematical abilities. PMID- 23098905 TI - Building a memory palace in minutes: equivalent memory performance using virtual versus conventional environments with the Method of Loci. AB - The Method of Loci (MOL) is an ancient mnemonic strategy used to enhance serial recall. Traditionally, the MOL is carried out by imagining navigating a familiar environment and "placing" the to-be-remembered items in specific locations. For retrieval, the mnemonist re-imagines walking through the environment, "looking" for those items in order. Here we test a novel MOL method, where participants use a briefly studied virtual environment as the basis for the MOL and applied the strategy to 10 lists of 11 unrelated words. When our virtual environments were used, the MOL was as effective, compared to an uninstructed control group, as the traditional MOL where highly familiar environments were used. Thus, at least for naive participants, a highly detailed environment does not support substantially better memory for verbal serial lists. PMID- 23098906 TI - To what extent do politeness expectations shape risk perception? Even numerical probabilities are under their spell! AB - Politeness theory posits that uncertainty quantifiers can be interpreted as hedging strategies and thus be perceived as communicating greater certainty than when they are interpreted as likelihood-communication devices. This has only been tested with verbal probabilities (e.g., it is possible). The present paper aims to test whether numerical probabilities can also be interpreted as face management devices and to investigate the effect of such an interpretation on risk perception. Four experiments focused on the effect of interpretations of numerical probabilities in negative outcome predictions on risk perception (e.g., there is a 50% probability that your stocks will lose their value). Politeness expectation was manipulated by the personality of the speaker (i.e., blunt vs. tactful, Experiments 1 and 2) and according to the conversational partners' need for politeness (Experiments 3 and 4). Results show that numerical probabilities, like verbal ones, were interpreted as likelihood-communication or face-management devices and that the two interpretations led to different risk perceptions. Findings were replicated with different formats, such as percentage (e.g., 50%) and chance ratio (e.g., 1 chance in 3) and with different degrees of certainty (e.g., .30, .50 and .70). Theoretical and practical implications relevant to risk communication are presented and discussed. PMID- 23098907 TI - Testing promotes effector transfer. AB - The retrieval of information from memory during testing has recently been shown to promote transfer in the verbal domain. Motor-related research, however, has ignored testing as a relevant method to enhance motor transfer. We thus investigated whether testing has the potential to induce generalised motor memories by favouring effector transfer. Participants were required to reproduce a spatial-temporal pattern of elbow extensions and flexions with their dominant right arm. We tested the ability of participants to transfer the original pattern (extrinsic transformation; i.e., goal-based configuration) or the mirrored pattern (intrinsic transformation; i.e., movement-based configuration) to the unpractised non-dominant left arm. To evaluate how testing affects motor transfer at 24-h testing, participants were either administered an initial testing session during early practice (early testing group) or shortly after the end of practice (late testing group; i.e., no alternation between practice and testing sessions). No initial testing session was completed for the control group. We found better effector transfer at 24-h testing for the early testing group for both extrinsic and intrinsic transformations of the movement pattern when compared with the control group, while no testing benefit was observed for the late testing group. This indicates that testing positively affects motor learning, yielding enhanced long-term transfer capabilities. We thus demonstrate the critical role of retrieval practice via testing during the process of motor memory encoding, and provide the conditions under which testing effectively contributes to the generalisation of motor memories. PMID- 23098908 TI - Quantitative change of IgA hinge O-glycan composition is a novel marker of therapeutic responses of IgA nephropathy. AB - Aberrant O-glycosylation in the hinge region of serum IgA is suggested to be involved in the pathogenesis of IgA nephropathy (IgAN), because the hypoglycosylation including N-acetylneuraminic acid or galactose has been reported in the mucin-type O-glycan of the hinge portion (HP) of IgA deposited in the IgAN patients' kidney. These aberrant glycosylation has been assessed in most of the previous reports by qualitative but not quantitative methods. In the present study, the molar ratios of GalNAc or Gal to HP were analyzed for serum IgA from IgAN patients. The GalNAc/HP ratio was increased in the patients who achieved remission after a combination therapy of tonsillectomy and intravenous corticosteroid, suggesting any non-innate factors to affect the IgA O glycosylation in IgAN that is thought to be inherently determined. Furthermore, the O-glycosylation status was different among three groups: IgAN patients in the pretreatment stage, IgAN patients in the remission stage after treatment and healthy controls. These results indicated that aberrant O-glycosylation of serum IgA in the IgAN patients would be inherently present and, to some extent, affected by therapeutic intervention. Finally, the quantitative change of O glycan composition is a novel marker of therapeutic response of IgAN. PMID- 23098909 TI - Carbachol ameliorates lipopolysaccharide-induced intestinal epithelial tight junction damage by down-regulating NF-kappabeta and myosin light-chain kinase pathways. AB - Carbachol is a cholinergic agonist that protects the intestines after trauma or burn injury. The present study determines the beneficial effects of carbachol and the mechanisms by which it ameliorates the lipopolysaccharide (LPS)-induced intestinal barrier breakdown. Rats were injected intraperitoneally with 10 mg/kg LPS. Results showed that the gut barrier permeability was reduced, the ultrastructural disruption of tight junctions (TJs) was prevented, the redistribution of zonula occludens-1 and claudin-2 proteins was partially reversed, and the nuclear factor-kappa beta (NF-kappabeta) and myosin light-chain kinase (MLCK) activation in the intestinal epithelium were suppressed after carbachol administration in LPS-exposed rats. Pretreatment with the alpha7 nicotinic acetylcholine receptor (alpha7nAchR) antagonist alpha-bungarotoxin blocked the protective action of carbachol. These results suggested that carbachol treatment can protect LPS-induced intestinal barrier dysfunction. Carbachol exerts its beneficial effect on the amelioration of the TJ damage by inhibiting the NF-kappabeta and MLCK pathways in an alpha7nAchR-dependent manner. PMID- 23098910 TI - alpha-Synuclein accumulation reduces GABAergic inhibitory transmission in a model of multiple system atrophy. AB - Multiple system atrophy is a neurodegenerative disease caused by abnormal alpha synuclein (alpha-syn) accumulation in oligodendrocytes and neurons. We previously demonstrated that transgenic (Tg) mice that selectively overexpressed human alpha syn in oligodendrocytes exhibited neuronal alpha-syn accumulation. Microtubule beta-III tubulin binds to endogenous neuronal alpha-syn to form an insoluble complex, leading to progressive neuronal degeneration. alpha-Syn accumulation is increased in the presynaptic terminals of Tg mice neurons and may reduce neurotransmitter release. To clarify the mechanisms underlying its involvement in neuronal dysfunction, in the present study, we investigated the effects of neuronal alpha-syn accumulation on synaptic function in Tg mice. Using whole-cell patch-clamp recording, we found that the frequency of miniature inhibitory postsynaptic currents was reduced in Tg mice. Furthermore, a microtubule depolymerizing agent restored normal frequencies of miniature inhibitory postsynaptic currents in Tg mice. These findings suggest that alpha-syn and beta III tubulin protein complex plays roles for regulation of synaptic vesicle release in GABAergic interneurons, and it causes to reduce GABAergic inhibitory transmission. PMID- 23098911 TI - Interaction of divalent metal ions with human translocase of inner membrane of mitochondria Tim50. AB - The preprotein translocase of the inner membrane of mitochondria (TIM23 complex) is the main entry gate for proteins of the matrix and the inner membrane. Tim50 is a major receptor for transporting the precursor protein across the mitochondrial inner membrane in TIM23 complex. However, the interaction of divalent metal ions with Tim50 and the contribution in the interaction of presequence peptide with Tim50 are still unknown. Herein, we investigated the interaction of divalent metal ions with the intermembrane space domain of Tim50 (Tim50(IMS)) and the interaction of presequence peptides with Tim50(IMS) in presence of Ca(2+) ion by fluorescence spectroscopy in vitro. The static fluorescence quenching indicates the existence of strong binding between divalent metal ions and Tim50(IMS). The order of the binding strength is Ca(2+), Mg(2+), Cu(2+), Mn(2+), and Co(2+) (from strong to weak). Moreover, the interaction of presequence peptides with Tim50(IMS) is weakened in presence of Ca(2+) ion, which implicates that Ca(2+) ion may play an important role in the protein import by TIM23 complex. PMID- 23098912 TI - Current knowledge and future directions about the disclosure of dementia: a systematic review of the first decade of the 21st century. AB - BACKGROUND: The disclosure of Alzheimer's disease presents a great challenge because it entails emotionally charged communication about a life-threatening, incurable, and stigmatized disease. Although a broad consensus has evolved regarding the potential benefits of early disclosure of the diagnosis, little is known about how these recommendations are actually implemented, and there is limited published research about the process issues of the disclosure. PURPOSE: (1) To systematically obtain and evaluate the relevant literature on disclosing a diagnosis of dementia, with special attention to process issues, and (2) to summarize current research findings and draw conclusions for future research and clinical care in this area. METHODS: A systematic review of the literature on disclosure of dementia during the first decade of the 21st century was conducted. RESULTS: From 265 articles retrieved, 47 were included in the review. Although the studies published in the first years of the decade were concerned with assessing attitudes and preferences of those involved in the process of disclosing the diagnosis, those of the last years have focused more on communication and other process issues. CONCLUSIONS: A conceptual development over time in the area is observed in which in the first years, thought processes begin as an ethical debate among clinicians and researchers about the topic of "truth telling" and dementia, continue as a search of the opinions of those involved in the process of disclosure about truth telling, and evolve (observed more recently) into an examination of how this truth telling is delivered. PMID- 23098913 TI - Rectification of SEMG as a tool to demonstrate synchronous motor unit activity during vibration. AB - The use of surface electromyography (SEMG) in vibration studies is problematic since motion artifacts occupy the same frequency band with the SEMG signal containing information on synchronous motor unit activity. We hypothesize that using a harsher, 80-500 Hz band-pass filter and using rectification can help eliminate motion artifacts and provide a way to observe synchronous motor unit activity that is phase locked to vibration using SEMG recordings only. Multi Motor Unit (MMU) action potentials using intramuscular electrodes along with SEMG were recorded from the gastrocnemius medialis (GM) of six healthy male volunteers. Data were collected during whole body vibration, using vibration frequencies of 30 Hz, 35 Hz, 40 Hz or 50 Hz. A computer simulation was used to investigate the efficacy of filtering under different scenarios: with or without artifacts and/or motor unit synchronization. Our findings indicate that motor unit synchronization took place during WBV as verified by MMU recordings. A harsh filtering regimen along with rectification proved successful in demonstrating motor unit synchronization in SEMG recordings. Our findings were further supported by the results from the computer simulation, which indicated that filtering and rectification was efficient in discriminating motion artifacts from motor unit synchronization. We suggest that the proposed signal processing technique may provide a new methodology to evaluate the effects of vibration treatments using only SEMG. This is a major advantage, as this non-intrusive method is able to overcome movement artifacts and also indicate the synchronization of underlying motor units. PMID- 23098914 TI - The human and animal health impacts of introduction and spread of an exotic strain of West Nile virus in Australia. AB - Vector-borne diseases can have substantial impacts on human and animal health, including major epidemics. West Nile virus (WNV) is of particular international importance due to its recent emergence and impact in the Western Hemisphere. Despite the presence of a sub-type of WNV (Kunjin virus, KUN) in Australia, a potential ecological niche could be occupied by an exotic strain of WNV of the North American type. This study assesses the probability an exotic strain of WNV enters Australia via an infected mosquito in an aircraft from the United States (U.S.) landing at Sydney airport, the probability it spreads to susceptible species and the impact of the resulting outbreak on human and animal health. A release, exposure and consequence assessment were conducted using expert opinion and scientific literature to parameterise the inputs for the models (OIE, 2009). Following establishment of WNV in Australia, the spatio-temporal spread of WNV was predicted over a six year period based on the Australian human and equine populations at-risk, the known distribution of other mosquito-borne flaviviruses in Australia, climatic factors, and the spread of WNV in the U.S. following it's incursion in New York City in 1999. The impact of this spread was measured as a multiplier of human and equine demographics using the U.S. incidence and case fatality rates as a reference. For an 8 month period from September to April (considering seasonal impact on mosquito activity during the coldest months in Australia and the U.S.), and assuming WNV is endemic in the U.S., the median probability an infected mosquito is introduced is 0.17, and the median number of infected mosquitoes introduced is predicted to be zero, with a 95th percentile range of one. The overall probability of a WNV outbreak (WNV released into Australia, susceptible hosts exposed and the virus spread) occurring in the human and the horse population during this time period is estimated to be 7.0*10(-6) and 3.9*10(-6), respectively. These values are largely influenced by the presence of mosquitoes in aircrafts and whether the introduced infected mosquito contacts wild birds. Results of this study suggest there is a low risk of introduction and spread of an exotic strain of WNV from the U.S via aircraft, and provides an insight into the magnitude and impact of the spread among human and horse populations. The generic framework presented could be applied to assess the potential introduction of other mosquito-borne diseases (which involve a wild bird transmission cycle) via international aircraft movements. PMID- 23098915 TI - Plant-bacteria interactions in the removal of pollutants. AB - Rhizoremediation surged in popularity among scientist as an attractive strategy because plant roots provide a rich niche for bacteria to grow at the expense of root exudates; in turn bacteria act as biocatalysts that remove pollutants. The complexity of the beneficial relationships between plants and bacteria is an exciting area of research which has shown steady progress in the last decade. Despite the advances in the field, specific aspects of the interactions between contaminant-degrading rhizobacteria and plants are still unknown; including the expression of degradation genes in the rhizosphere, the influence of horizontal gene transfer in rhizoremediation, and the possibilities of the selection of specific bacteria by plant rhizosphere. We discuss the recent advances in our understanding of the plant-bacteria interactions during rhizoremediation of organic compounds. PMID- 23098916 TI - Orthographic facilitation in Chinese spoken word recognition: an ERP study. AB - Orthographic influences in spoken word recognition have been previously examined in alphabetic languages. However, it is unknown whether orthographic information affects spoken word recognition in Chinese, which has a clean dissociation between orthography (O) and phonology (P). The present study investigated orthographic effects using event related potentials (ERPs) and an auditory lexical decision task. We manipulated the relationship between the phonology and orthography of the first syllable in each prime-target pair using the following four conditions: P+O+, P+O-, P-O+, P-O-. Importantly, we found significantly reduced N400 amplitudes when an item was preceded by an orthographically similar prime. In addition, these reduced N400 amplitudes were positively correlated with participants' reading skill. The findings indicate that orthographic information is activated automatically during Chinese spoken word recognition, supporting the theory that there is a reciprocal connection between speech and print. PMID- 23098917 TI - Semantic processing in native and second language: evidence from hemispheric differences in fine and coarse semantic coding. AB - Previous studies suggest that whereas the left hemisphere (LH) is involved in fine semantic processing, the right hemisphere (RH) is uniquely engaged in coarse semantic coding including the comprehension of distinct types of language such as figurative language, lexical ambiguity and verbal humor (e.g., Chiarello, 2003; Faust, 2012). The present study examined the patterns of hemispheric involvement in fine/coarse semantic processing in native and non-native languages using a split visual field priming paradigm. Thirty native Hebrew speaking students made lexical decision judgments of Hebrew and English target words preceded by strongly, weakly, or unrelated primes. Results indicated that whereas for Hebrew pairs, priming effect for the weakly-related word pairs was obtained only for RH presented target words, for English pairs, no priming effect for the weakly related pairs emerged for either LH or RH presented targets, suggesting that coarse semantic coding is much weaker for a non-native than native language. PMID- 23098918 TI - A biologically active vMIP-II-IgG3-TfN fusion protein, secreted from methylotrophic yeast Pichia pastoris. AB - The viral macrophage inflammatory protein II (vMIP-II) which showed a broad spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cell entry of human immunodeficiency virus. To explore the feasibility of using TfN as a carrier moiety for delivery of therapeutic proteins, a genetically engineered vMIP-II-IgG3-TfN fusion gene was loaded into the yeast expression vector pPICZalpha. The linearized recombinant plasmid pPICZalpha-vMIP-II-IgG3-TfN was transformed into X33 competent cells. The recombinant protein was expressed in methylotrophic yeast Pichia pastoris and was confirmed to have expected molecular mass of 48 kDa by SDS-PAGE. Using methods combining ammonium sulfate precipitation, dialysis, ultrafiltration and affinity chromatography, the vMIP-II-IgG3-TfN fusion protein was successfully purified from the supernatant of the broth. Western-blotting analysis showed that 6* His antibody recognized the purified vMIP-II-IgG3-TfN. CD spectrum revealed a positive peak at 196.5 nm and a negative peak at 209 nm. MALDI-TOF MS analysis showed that the purified vMIP-II-IgG3-TfN was an intact and homogeneous protein. The pepsin digestibility assay showed that the vMIP-II-IgG3 TfN fusion protein could be digested into small fragments by pepsin after 2 min treatment. The vMIP-II-IgG3-TfN fusion protein was found to be stable in human plasma for up to 48 h. Furthermore, in vitro bioactivity assay indicated that the vMIP-II-IgG3-TfN fusion protein can block the chemotaxis of U937 cells induced by SDF1alpha. In total, this study illustrates the development of an active vMIP-II IgG3-TfN fusion protein expressed in P. pastoris. PMID- 23098919 TI - Optimisation of a direct plating method for the detection and enumeration of Alicyclobacillus acidoterrestris spores. AB - A direct plating method for the detection and enumeration of Alicyclobacillus acidoterrestris spores has been optimised. The results of the application of four types of growth media (BAT agar, YSG agar, K agar and SK agar) regarding the recovery and enumeration of A. acidoterrestris spores were compared. The influence of the type of applied growth medium, heat shock conditions, incubation temperature, incubation time, plating technique and the presence of apple juice in the sample on the accuracy of the detection and enumeration of A. acidoterrestris spores was investigated. Among the investigated media, YSG agar was the most sensitive medium, and its application resulted in the highest recovery of A. acidoterrestris spores, while K agar and BAT agar were the least suitable media. The effect of the heat shock time on the recovery of spores was negligible. When there was a low concentration of spores in a sample, the membrane filtration method was superior to the spread plating method. The obtained results show that heat shock carried out at 80 degrees C for 10 min and plating samples in combination with membrane filtration on YSG agar, followed by incubation at 46 degrees C for 3 days provided the optimal conditions for the detection and enumeration of A. acidoterrestris spores. Application of the presented method allows highly efficient, fast and sensitive identification and enumeration of A. acidoterrestris spores in food products. This methodology will be useful for the fruit juice industry for identifying products contaminated with A. acidoterrestris spores, and its practical application may prevent economic losses for manufacturers. PMID- 23098920 TI - Hydrophysical correlation and water mass indication of optical physiological parameters of picophytoplankton in Prydz Bay during autumn 2008. AB - Flow cytometry (FCM) is efficient in detecting both abundance and optical physiological parameters including cell size and cellular carbon content-side scatter (SSC), carotenoids-green and orange fluorescence (FL1 and FL2), and red fluorescence-chlorophylls (FL3) can be obtained by FCM. The utilization of these physiological parameters in indicating water masses in Prydz Bay was investigated for the first time. Picophytoplankton were very sensitive to hydrophysical changes and present distinct characteristics of water masses: Picophytoplankton in water closer to the Amery Ice Shelf were more affected by salinity than by temperature, while temperature became more important than salinity the nearer the picophytoplankton were to the deep sea. The picophytoplankton dealt with declines in light by increasing the size of cells, which increase the fixation of carbon. This can also be increased by high temperature and salinity. Pure water masses can increase the content of chlorophylls and cellular carbon. Generally, the distributions of all the five parameters at upper water depths were less affected by temperature and salinity than by water masses; and these parameters can be as indicators to Summer Surface Water (SSW), Winter Water (WW) and Continental Shelf Water (CSW). PMID- 23098921 TI - Three dimensional quantification of biological samples using micro-computer aided tomography (microCT). AB - MicroCT is increasingly being used to observe soft animal and plant tissues. Conventional electron and light microscope staining protocols used to enhance the contrast of soft tissues have the potential to be adapted for use in microCT. This would increase the versatility of the microCT beyond improving qualitative observations to facilitating quantitative analysis of soft tissues. This paper describes the development of a culture system and staining protocol which has successfully been used to obtain three dimensional (3-D) quantitative data of filamentous and zoosporic soil fungi. The fungi were grown in an artificial matrix that was developed to simulate the particulate nature of soil. The combination of high contrast staining protocol and use of an X-ray translucent matrix allowed for 3-D qualitative and quantitative analysis of fungal growth. A salient point raised by this study is that the effectiveness of a protocol is reliant on the tissue or cell culture system which includes the composition of the sample, the sampling vessel, the depth of a sample and the combination of stains used. The potential use of this method extends to other fields where distribution and growth patterns in 3-D need to be quantified. PMID- 23098922 TI - Performance analysis of complex repairable industrial systems using PSO and fuzzy confidence interval based methodology. AB - The main objective of the present paper is to propose a methodology for analyzing the behavior of the complex repairable industrial systems. In real-life situations, it is difficult to find the most optimal design policies for MTBF (mean time between failures), MTTR (mean time to repair) and related costs by utilizing available resources and uncertain data. For this, the availability-cost optimization model has been constructed for determining the optimal design parameters for improving the system design efficiency. The uncertainties in the data related to each component of the system are estimated with the help of fuzzy and statistical methodology in the form of the triangular fuzzy numbers. Using these data, the various reliability parameters, which affects the system performance, are obtained in the form of the fuzzy membership function by the proposed confidence interval based fuzzy Lambda-Tau (CIBFLT) methodology. The computed results by CIBFLT are compared with the existing fuzzy Lambda-Tau methodology. Sensitivity analysis on the system MTBF has also been addressed. The methodology has been illustrated through a case study of washing unit, the main part of the paper industry. PMID- 23098923 TI - Nuclear lipid droplets: a novel nuclear domain. AB - We investigated nuclear neutral-lipid (NL) composition and organization, as NL may represent an alternative source for providing fatty acids and cholesterol (C) to membranes, signaling paths, and transcription factors in the nucleus. We show here that nuclear NL were organized into nonpolar domains in the form of nuclear lipid droplets (nLD). By fluorescent confocal microscopy, representative nLD were observed in situ within the nuclei of rat hepatocytes in vivo and HepG2 cells, maintained under standard conditions in culture, and within nuclei isolated from rat liver. nLD were resistant to Triton X-100 and became stained with Sudan Red, OsO4, and BODIPY493/503. nLD and control cytosolic-lipid droplets (cLD) were isolated from rat-liver nuclei and from homogenates, respectively, by sucrose gradient sedimentation. Lipids were extracted, separated by thin-layer chromatography, and quantified. nLD were composed of 37% lipids and 63% proteins. The nLD lipid composition was as follows: 19% triacylglycerols (TAG), 39% cholesteryl esters, 27% C, and 15% polar lipids; whereas the cLD composition contained different proportions of these same lipid classes, in particular 91% TAG. The TAG fatty acids from both lipid droplets were enriched in oleic, linoleic, and palmitic acids. The TAG from the nLD corresponded to a small pool, whereas the TAG from the cLD constituted the main cellular pool (at about 100% yield from the total homogenate). In conclusion, nLD are a domain within the nucleus where NL are stored and organized and may be involved in nuclear lipid homeostasis. PMID- 23098924 TI - Role for magnetic resonance imaging in coccydynia with sacrococcygeal dislocation. AB - Sacrococcygeal dislocation is among the many causes of coccydynia. The etiological diagnosis of this fairly rare condition is difficult. Dynamic imaging is the only means of documenting the dislocation. We describe two cases of sacrococcygeal dislocation in patients presenting with coccydynia. Both patients reported a history of trauma in the more or less remote past, with no clear correlation with pain onset. Magnetic resonance imaging (MRI) of the sacrococcygeal junction showed local inflammatory lesions (bursitis, sacrococcygeal arthritis), providing a rationale for a local procedure. Analgesic therapy was inadequately effective and a local glucocorticoid injection into the sacrococcygeal junction was therefore recommended. One of the patients accepted this procedure and subsequently reported complete resolution of the symptoms. PMID- 23098925 TI - Linking systemic angiogenic factors (VEGF, angiogenin, TIMP-2) and Doppler ultrasound to anti-inflammatory treatment in rheumatoid arthritis. AB - OBJECTIVE: To evaluate an association between synovial Doppler flow and serum levels of vascular endothelial growth factor (VEGF), angiogenin and TIMP-2 in patients with rheumatoid arthritis during anti-inflammatory treatment with glucocorticoids and TNF-alpha inhibitors. METHODS: Inflamed wrists of 15 patients with rheumatoid arthritis (RA) were examined by two independent ultrasound investigators prior to and at days 3, 7, 14 and 42 after the initiation of treatment with glucocorticoids in therapy-naive patients or after the beginning of a therapy with a TNF-alpha inhibitor in patients with DMARD failure. Quantitative three-dimensional power Doppler ultrasonographic assessment of synovial vascularization was compared at each visit with serum levels of VEGF, angiogenin and TIMP-2. RESULTS: In the glucocorticoid group, synovial Doppler signals decreased significantly at day 3 (-44%; P=0.003) in comparison to a delayed decrease in the TNF-alpha inhibitor group after 6 weeks (-46%; P=0.001). A significant reduction of serum VEGF levels could be determined with a delay of 1 week after the decrease of Doppler activity but no correlation was found between both parameters (rho: P=0.7; r=-0.03). Angiogenin concentrations decreased in the TNF group and increased in the GC group. Levels of TIMP-2 did not change significantly in both groups. CONCLUSION: The decrease of serum VEGF levels under treatment with glucocorticoids or TNF-alpha inhibitors followed the reduction of the intra-articular synovial Doppler flow. This result supports the idea that the reduction of synovial perfusion due to anti-inflammatory treatment is not regulated by systemic VEGF, but that the inflamed joints are the source for circulating VEGF. PMID- 23098926 TI - Do all lupus patients need statins? AB - Statin therapy decreases cardiovascular morbidity and mortality rates when used as either primary or secondary prevention. An immunomodulating effect of statins has been suggested. Incontrovertible evidence of accelerated atheroma has been obtained in patients with systemic lupus erythematosus (SLE). Routine statin therapy in SLE patients might therefore produce both cardiovascular and immunological benefits. However, routine statin therapy is inappropriate in SLE patients, the main reason being the absence of a vast interventional study done specifically in this population. An immunomodulating role for statins in SLE has not been convincingly established. The effect of statin therapy on markers for subclinical atheroma (intima-media thickness changes over time) is unclear, and there are no studies proving that statins are effective when used for primary or secondary cardiovascular prevention. Nevertheless, we believe that a serum lipid profile should be obtained once a year in all SLE patients. There is a sound rationale for classifying all SLE patients as being at high cardiovascular risk and those receiving secondary prevention as at very high risk. Consequently, the serum LDL-cholesterol level must be kept below 100 mg/dL and 70 mg/dL in these two populations, respectively. Statins are the only widely recommended drugs for achieving these treatment targets. Statin therapy requires specific monitoring precautions (transaminase levels) given the high prevalence of comorbidities and use of concomitant medications in SLE patients. PMID- 23098927 TI - Benner, reflection and expertise: some further thoughts. PMID- 23098928 TI - Invited commentary. PMID- 23098929 TI - Invited commentary. PMID- 23098930 TI - Invited commentary. PMID- 23098931 TI - Invited commentary. PMID- 23098932 TI - Invited commentary. PMID- 23098933 TI - Invited commentary. PMID- 23098934 TI - Invited commentary. PMID- 23098935 TI - Invited commentary. PMID- 23098936 TI - Invited commentary. PMID- 23098937 TI - Invited commentary. PMID- 23098938 TI - Invited commentary. PMID- 23098939 TI - Invited commentary. PMID- 23098940 TI - Invited commentary. PMID- 23098941 TI - Outcomes assessment of the surgical management of esophageal cancer in younger and older patients. AB - BACKGROUND: The aim of this study was to assess the influence of age on disease presentation, clinical and pathologic staging, postoperative outcomes, costs, and long-term survival after esophagectomy for esophageal malignancy. METHODS: All patients undergoing esophagectomy for cancer between 1991 and 2011 were prospectively enrolled in an Institutional Review Board approved database. RESULTS: A total of 493 patients underwent surgical resection during the study period; 58 (11.76%) of these patients were 50 years or less (44 +/- 4.7) and 435 patients were greater than 50 years (67 +/- 8.44). There was no difference in clinical stage; however, patients 50 years or less were more likely to have adenocarcinoma and reduced Charlson comorbidity index and younger patients tended to have a more delayed presentation as manifested by an increased period of dysphagia and a greater degree of weight loss. In the 50 or less age group there was a significantly greater use of neoadjuvant therapy in stage II patients and the use of neoadjuvant chemotherapy significantly decreased with increasing age. Surgery in the 50 or less age group was associated with significantly reduced intensive care unit stay, incidence of postoperative complications, and overall costs. Multivariate analysis also confirmed associations between increasing age and increased incidence of postoperative complications and cost. There were no significant differences in pathologic stage, positive resection margins, incidence of complete response to neoadjuvant therapy, or in overall survival. CONCLUSIONS: This study demonstrates younger patients have fewer complications and lower overall treatment costs after esophagectomy. In spite of having a more delayed presentation, younger patients presented with a similar stage and demonstrated similar overall survival. PMID- 23098942 TI - Invited commentary. PMID- 23098943 TI - Invited commentary. PMID- 23098944 TI - Invited commentary. PMID- 23098945 TI - Invited commentary. PMID- 23098946 TI - Invited commentary. PMID- 23098947 TI - Experimental evaluation of a new apical access and closure device. AB - PURPOSE: Transapical aortic valve implantation (TA-AVI) has evolved as a treatment option for high-risk patients who have severe aortic stenosis. The aim of this study was to evaluate the feasibility of a novel apical closure device to allow for standardized apical access and closure. DESCRIPTION: The Apica ASC system consists of three components: an introducer system, a left ventricular low profile titanium coil, and a closure cap. The ASC introducer system is fixed to the myocardium by anchoring the titanium coil into the epicardium. After the TA AVI procedure, the closure cap is introduced through the system and delivered onto the titanium coil for final sealing. EVALUATION: After sternotomy, fixation of the introducer system was successfully performed in an acute pig model. The apex was safely secured in all attempts, and the titanium coil created an effective seal around the Ascendra sheath. Finally, the closure cap was shown to be secure even when the hearts were pressurized to 200 mm Hg. Postmortem examination showed a uniform depth of the titanium coil through the endocardium into the myocardial wall without penetration into the left ventricular cavity. CONCLUSIONS: Apical access and closure is feasible using the sutureless Apica ASC device. The system seems to have the potential to further standardize the TA-AVI procedure, allowing wider applicability and more generalizability. PMID- 23098948 TI - Management of aortic valve insufficiency in patients supported by long-term continuous flow left ventricular assist devices. AB - Continuous flow (CF) left ventricular assist devices (LVADs) have yielded improved outcomes in patient survival and quality of life compared with first generation pulsatile pumps; however, they have been associated with an increased incidence of postimplant aortic valve insufficiency (AI), which can have can have serious clinical consequences if not diagnosed and treated expeditiously. We reviewed our experience with AI after LVAD since the start of our CF LVAD program. From March 2006 through July 2011, 94 patients with chronic heart failure underwent implantation of a HeartMate II (HM II) LVAD. Severe AI developed in three patients after CF LVAD implantation. The clinical records of these patients were reviewed to analyze the presenting signs and symptoms of AI, identify the duration of LVAD support when the AI occurred, how the AI was treated, and the outcomes. PMID- 23098949 TI - Implantation of a HeartMate II left ventricular assist device via left thoracotomy. AB - Left thoracotomy was used as an approach for the implantation of pulsatile ventricular assist devices. Avoiding the standard approach of median sternotomy is attractive in patients undergoing complicated redo cardiac surgery, especially with prior mediastinal radiation. We report a case of the use of left thoracotomy for the implantation of the HeartMate II axial-flow pump. PMID- 23098950 TI - Ventricular septal avulsion and ventricular septal defect after blunt trauma. AB - Traumatic ventricular septal defect is an uncommon complication of blunt chest trauma. We report a case of ventricular septal avulsion, associated with traumatic ventricular septal defect and the associated management concerns. PMID- 23098951 TI - Stab to the chest causing severe great vessel injury. AB - Penetrating trauma has increased in developed and urban environments. Pulmonary artery injury is rare, but can be associated with significant morbidity. We report a case of delayed cardiac arrest following a stab injury to the chest. The patient had active great vessel bleeding and required extensive surgical intervention. Clinicians should have a high index of suspicion for life threatening thoracic injuries following a stab injury to the chest, despite initial clinical stability or negative baseline radiological findings. PMID- 23098952 TI - Transaortic valve-in-valve implantation after previous aortic root homograft. AB - Catheter-based valve implantation techniques are becoming a viable option in various clinical situations to replace difficult redo open heart surgical procedures. This is a report of a first, to our knowledge, successful valve-in valve (VinV) transcatheter aortic valve implantation (TAVI) into a homograft through the transaortic (TAo) access route using an Edwards SAPIEN valve prosthesis (Edwards Lifesciences, LLC, Irvine, CA) in a patient with poor left ventricular function and generalized severe atherosclerosis. PMID- 23098953 TI - Repair of acute aortic dissection in an octogenarian with prior thoracoplasty. AB - Cardiovascular surgery is challenging in patients who have previously undergone thoracoplasty because of severe chest deformity and impaired pulmonary function. We report a case of an octogenarian with prior left thoracoplasty, who successfully underwent surgical repair of an acute aortic dissection through a standard median sternotomy. We suggest that prior thoracoplasty might not necessarily be an exclusion criterion for aortic surgery in cases with adequate pulmonary function. PMID- 23098954 TI - Combined repair of upper sternal cleft and transposition of the great arteries in a newborn. AB - We report the case of a newborn with the unusual association of an upper sternal defect and transposition of the great arteries. Surgical correction of the cardiac disease consisted of the arterial switch procedure. The already less compliant bony thorax of the infant made direct approximation of the upper sternal defect only possible with adjuvant bilateral chondrotomy. Sternal cleft repair is advised during the very first weeks of life. PMID- 23098955 TI - Myocardial infarction due to a retained epicardial pacing wire. AB - A 20-year-old man with a temporary epicardial pacing wire retained after infant repair of an atrioventricular septal defect presented with cardiopulmonary arrest. After resuscitation with extracorporeal membranous oxygenation, a coronary angiogram demonstrated a retained epicardial pacing wire compressing the left anterior descending artery and obtuse marginals. Owing to poor prognostic findings on a computed tomography scan of his head, he was terminally withdrawn from mechanical support. This case demonstrates a potential devastating complication of a retained temporary epicardial pacing wire. PMID- 23098956 TI - Successful application of subcutaneous adipose tissue with fibrin glue in conservative treatment of tracheobronchial rupture. AB - An 84-year-old woman underwent aortic and mitral valve replacement. After weaning from cardiopulmonary bypass, hemorrhage was observed in the endobronchial tube. The bleeding bronchus was isolated to protect the airway using the blocker cuff of a Univent tube (Fuji Systems Corp, Tokyo, Japan). Computed tomography showed a pulmonary pseudoaneurysm in the left upper lobe. She underwent selective pulmonary angiography and embolization of the pseudoaneurysm. Bronchoscopy revealed a 5-mm bronchial rupture at the left upper lobe bronchus. The laceration was filled with adipose tissue and fibrin glue. Bronchoscopy showed a completely reepithelialized membrane, and she was discharged 38 days postoperatively. PMID- 23098957 TI - Long-survival case of thymic carcinoma with superior vena cava tumor thrombus. AB - Sarcomatoid carcinoma of the thymus is rare and responds poorly to treatment. Invasion of great vessels and metastasis are significant predictors for poor prognosis. Thymic tumors commonly cause superior vena cava (SVC) obstruction by extrinsic compression or invasion, but intraluminal permeation is the most uncommon cause. We report a rare, long-surviving case of sarcomatoid carcinoma with SVC syndrome developed by tumor thrombus. She underwent SVC replacement and extended thymectomy. The resection indicated intracaval extension without direct invasion of thymic tumor, histologically diagnosed as sarcomatoid carcinoma. After adjuvant chemotherapy, she continues to show no apparent recurrence for five years. PMID- 23098958 TI - A primary pulmonary artery chondrosarcoma manifesting as acute pulmonary embolism. AB - Primary cardiac malignancies are rare, and the majority are benign. Malignant tumors are often found to be sarcomas arising from structural cells such as muscle, connective tissue, and blood vessels. We report a case of a 62-year-old woman who presented with pulmonary embolism secondary to a primary pulmonary artery chondrosarcoma. Radical resection with curative intent was impossible, but partial resection and reconstruction of the pulmonary main stem was performed. The remaining tumor was treated with adjuvant chemotherapy. A positron emission tomography-computed tomography scan 6 months postoperatively showed a nearly complete remission. PMID- 23098959 TI - Isolated complete cleft. AB - Cleft sternum is a rare congenital anomaly due to failure of fusion of the sternal bone. The etiology of this defect is not well understood. The anomaly is more common in females and may be associated with Cantrell's pentalogy. It can be partial or complete. An 8-year-old female child presented with complete defect in the sternum which was confirmed with a chest radiograph and computed tomography. Only 24 cases of isolated complete cleft sternum have been reported so far. The treatment ranges from primary closure of the defect to the use of various autologous and prosthetic grafts. Our patient was treated with primary closure of the defect. PMID- 23098960 TI - Respiratory support with venovenous extracorporeal membrane oxygenation during stenting of tracheobronchomalacia. AB - A subset of patients with severe airway disease cannot be adequately supported with conventional mechanical ventilation during complex airway procedures. We report the successful respiratory support of a patient with severe tracheobronchomalacia with venovenous extracorporeal membrane oxygenation during rigid bronchoscopy with stent removal and stent placement. PMID- 23098961 TI - Massive and severe calcific constrictive pericarditis. PMID- 23098962 TI - Bronchial cast expectoration in diffuse chylous disease. PMID- 23098963 TI - Transcervical resection of an ectopic mediastinal parathyroid adenoma. PMID- 23098964 TI - Novel valved graft modification of Cabrol fistula for bleeding after aortic root surgery. AB - The Cabrol fistula, which shunts blood from the perigraft space to the right atrium in cases of refractory bleeding after ascending aortic replacement, is a useful technique. A drawback is the potential for troublesome venous back bleeding into the perigraft space. We describe a modification using a valved Contegra graft, which obligates unidirectional flow and eliminates venous back bleeding. This renders the Cabrol fistula an even more useful technique. PMID- 23098965 TI - Minimally invasive chest wall resection: sparing the overlying, uninvolved extrathoracic musculature of the chest. AB - Patients with non-small cell lung cancer (NSCLC) that invades the chest wall are often thought not to benefit from minimally invasive surgery. Frequently, open techniques involve cutting noninvolved extrathoracic muscles that lie over the cancer to gain access to resect the ribs that contain malignancy. We reviewed a new technique involving 21 patients that eliminates cutting of the extrathoracic (trapezius, rhomboids, serratus anterior) muscles. Ribs with invading cancer are resected from inside of the chest instead of cutting the uninvolved muscles over them. The approach used can be a thoracotomy, robotic, or video-assisted technique. PMID- 23098966 TI - A novel fixation procedure to eliminate covered self-expanding metal stent migration. AB - Leakage from esophageal and gastric perforation carries a high morbidity rate and requires surgical or endoscopic intervention. When stenting is utilized, migration of the stent is a common complication. A novel technique to prevent migration of the stent is described. Fourteen patients presenting with leakage from the foregut underwent stent fixation with this technique. A bridle is created by delivering umbilical tape through each nostril securing the stent for 4 days. None of the 14 patients' X-rays showed migration of the stent. This new technique is both safe and effective when treating leaks and perforations from the foregut. Until nonmigrating stents can be developed, such techniques will be an important resource for treatment. PMID- 23098967 TI - 2012 update to the Society of Thoracic Surgeons guideline on use of antiplatelet drugs in patients having cardiac and noncardiac operations. PMID- 23098968 TI - The elephant trunk procedure for chronic aortic dissection. PMID- 23098970 TI - Thrombosis and recombinant factor VIIa: letter 1. PMID- 23098971 TI - Aortic valve thrombosis after treatment with recombinant factor VIIa: letter 2. PMID- 23098972 TI - A pulmonary artery "chimney" relieves right ventricular assist device anxiety. PMID- 23098974 TI - Perioperative acute kidney injury after cardiac surgery. PMID- 23098976 TI - Dexamethasone and myocardial protection in neonatal arterial switch operation. PMID- 23098978 TI - The safety of selective cerebral perfusion with normothermia in pediatric patients. PMID- 23098979 TI - Recurrence after radiofrequency ablation for stage I non-small cell lung cancer. PMID- 23098981 TI - Side-arm grafts for femoral extracorporeal membrane oxygenation cannulation. AB - Lower extremity ischemia is an important source of morbidity with femoral venoarterial extracorporeal membrane oxygenation support. We describe our experience with the use of a side-arm graft sewn to the femoral artery that facilitates adequate extracorporeal membrane oxygenation flow while preventing lower extremity ischemia. PMID- 23098982 TI - Echocardiography in imaging an extremely rare cause of extrinsic pulmonary stenosis: rapidly progressive primary mediastinal embryonal carcinoma. AB - We report a case of a young man with a very rare cause of atypical chest pain in whom primary mediastinal embryonal carcinoma causing extrinsic pulmonary stenosis was diagnosed with echocardiography and computed tomography. This patient illustrates an unusual presentation of the very rapid progression of the tumor in as little as 6 months. The patient underwent surgical resection and was successfully treated with adjuvant chemotherapy. PMID- 23098983 TI - Three-dimensional computed tomography for a mediastinal basal pulmonary artery. AB - Anatomic variations of the pulmonary artery increase the risks for vessel injury and critical mistakes during pulmonary artery resection. A patient who underwent left lower lobectomy for lung cancer with a mediastinal lingular and basal pulmonary artery that had been detected preoperatively by three-dimensional computed tomography is presented. During thoracoscopic surgery, the mediastinal basal pulmonary arteries were found with careful dissection. The pulmonary arteries were divided, and left lower lobectomy was performed safely. This rare variation of the left pulmonary artery is important to detect before lobectomy to ensure safe surgery. In such cases, three-dimensional computed tomography is necessary. PMID- 23098984 TI - Surgical resection for isolated myeloid sarcoma arising from a rib. AB - We report on a rare manifestation of myeloid sarcoma with chronic myelogenous leukemia. The neoplasm arising from a rib showed osteolytic changes and infiltrated the surrounding muscles. We resected the lesion to relieve chest pain caused by pathologic rib fractures. The patient has continued receiving systemic therapy and is doing well as of 1 year postoperatively. Experience with a surgical approach for myeloid sarcoma is limited in thoracic surgery. The clinical course in our case suggests that surgical resection can be a valid choice of treatment. PMID- 23098985 TI - Spontaneous regression of metastatic pulmonary leiomyoma after resection of contralateral metastatic mass. AB - Pulmonary benign metastatic leiomyoma is a rare entity with a debated pathogenesis. We report a case in which benign metastatic leiomyoma involving the lung had spontaneously regressed after debulking surgery. Although no adjuvant treatment was done, the remaining masses regressed significantly in the 1-year follow-up image. PMID- 23098986 TI - Transoral endoscopic resection of esophageal liposarcoma. AB - A 63-year-old man presented with a 1-month history of dysphagia. Endoscopy showed the patient had a mass in the cervical esophagus. Multiple biopsy specimens were taken, which were inconclusive for a diagnosis. A positron-emission tomography scan showed a hypermetabolic lesion. A transoral endoscopic approach was used to resect the tumor. Final histologic examination revealed a completely resected low grade liposarcoma. PMID- 23098987 TI - Percutaneous closure of left ventricular pseudoaneurysm. AB - The risk of rupture of a left ventricular (LV) pseudoaneurysm ranges from 30% to 45% in the first year. Open surgical repair carries high mortality related to anatomic complexity and patient comorbidities. Percutaneous closure may offer a viable alternative to surgical intervention in this cohort. Herein, we describe 3 unique cases of transcatheter LV pseudoaneurysm closure. PMID- 23098988 TI - Preoperative identification of anomalous drainage vein for posterior segment of right upper lobe. PMID- 23098989 TI - Radio antenna aspiration. PMID- 23098990 TI - Pectoral muscle flap with V-Y skin paddle for covering sternal defects. AB - Deep sternal wound infection (DSWI) after a cardiac operation is a rare but serious complication associated with significant morbidity and mortality. It can lead to wound dehiscence with sternal osteomyelitis and both bony and soft tissue residual defects. When the infection is eradicated, reconstruction of the thoracic wall remains the main challenge. Tissue used for covering the defect must be well nourished and sutures must be tension free. We present our unique modification of the method using the pectoral muscle axial flap with a V-Y skin paddle. PMID- 23098991 TI - MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF. AB - Anti-EGFR monoclonal antibodies (anti-EGFRmAb) serve in the treatment of metastatic colorectal cancer (mCRC), but patients with a mutation in KRAS/BRAF and nearly one-half of those without the mutation fail to respond. We performed microRNA (miRNA) analysis to find miRNAs predicting anti-EGFRmAb efficacy. Of the 99 mCRC patients, we studied differential miRNA expression by microarrays from primary tumors of 33 patients who had wild-type KRAS/BRAF and third- to sixth line anti-EGFRmAb treatment, with/without irinotecan. We tested the association of each miRNA with overall survival (OS) by the Cox proportional hazards regression model. Significant miR-31* up-regulation and miR-592 down-regulation appeared in progressive disease versus disease control. miR-31* expression and down-regulation of its target genes SLC26A3 and ATN1 were verified by quantitative reverse transcriptase polymerase chain reaction. Clustering of patients based on miRNA expression revealed a significant difference in OS between patient clusters. Members of the let-7 family showed significant up regulation in the patient cluster with poor OS. Additionally, miR-140-5p up regulation and miR-1224-5p down-regulation were significantly associated with poor OS in both cluster analysis and the Cox proportional hazards regression model. In mCRC patients with wild-type KRAS/BRAF, miRNA profiling can efficiently predict the benefits of anti-EGFRmAb treatment. Larger series of patients are necessary for application of these miRNAs as predictive/prognostic markers. PMID- 23098992 TI - Visual object complexity limits pigeon short-term memory. AB - The study of visual memory has repeatedly shown qualitatively similar visual short-term memory (VSTM) systems between human and many nonhuman species. In studies of human VSTM using change detection, increasing visual object complexity has an inverse effect on accuracy. In the current study, we assessed the functional relationship between visual object complexity and memory performance in visual change detection in pigeons and humans. Visual object complexity was quantified for each object type within each species using visual target search. Change detection performance was inversely related to object complexity in both species, suggesting that pigeon VSTM, like human VSTM, is limited by visual object complexity. Human participants were able to use a verbal-labeling strategy to mitigate some of the effect of visual object complexity, suggesting a qualitative difference in how the two species may solve certain visual discriminations. Considering the visual complexity of novel objects may also help explain previous failures to transfer relational rules to novel visual objects. PMID- 23098993 TI - The role of transient receptor potential A 1 (TRPA1) in the development and maintenance of carrageenan-induced hyperalgesia. AB - Transient receptor potential ankyrin 1 (TRPA1) is a nonselective cation channel important in setting nociceptive threshold. It is expressed in nociceptive C fibers and in non-neuronal cells involved in pro-inflammatory mediators' release. We asked whether TRPA1 contributes to carrageenan-induced hyperalgesia in rats, and if so, whether this contribution is mediated by mechanisms involved in inflammation such as cytokine release and neutrophil migration and/or by a direct sensitization of the primary afferent nociceptors. Pharmacological blockade of local TRPA1 by its selective antagonist HC 030031 prevented and reversed carrageenan-induced hyperalgesia, which was detected either by a mechanical or chemical (low dose of capsaicin) stimulus. However, it did not affect either carrageenan-induced cytokines expression or neutrophil migration. The neuronal TRPA1 gene silencing induced by intrathecal pre-treatment with antisense oligodoexynucleotide completely prevented carrageenan-induced hyperalgesia over 24 h and significantly reduced TRPA1 expression in the dorsal root ganglia cells (L5-6), which was not affected by carrageenan treatment. We conclude that TRPA1 plays an important role in the development and maintenance of carrageenan-induced inflammatory hyperalgesia by directly contributing to nociceptor excitability. PMID- 23098995 TI - Nano-sized magnetic iron oxides as catalysts for heterogeneous Fenton-like reactions-Influence of Fe(II)/Fe(III) ratio on catalytic performance. AB - Nano-sized Fe(II, III) oxides with various Fe(II)/Fe(III) ratios were characterized and tested as catalysts for the oxidative degradation of phenol via Fenton-like reactions at neutral pH. Under conditions typically applied for wet peroxide oxidation, Fe(II) in magnetite is oxidized to Fe(III), successively converting the mineral into maghemite. The residual Fe(II) content in the catalyst core is of only minor benefit for the catalytic activity in phenol oxidation, i.e. magnetite is not superior to maghemite. Achievable reaction rates for phenol degradation appeared to be rather low, e.g. phenol half-life of about 12 h when 3 g L(-1) magnetite and 5 g L(-1) H(2)O(2) were applied. Preceding surface-reduction of maghemite by NaBH(4), leading to an over-stoichiometric Fe(II) content compared to magnetite, only enhanced the non-productive decomposition of H(2)O(2) rather than the rate of phenol degradation. Reaction rates were shown to be relatively insensitive to catalyst concentration in the range of 1-10 g L(-1), probably resulting from a scavenging of reactive species by the catalyst surface, whereby particle agglomeration seems to play a key role. Degradation experiments with various structurally distinct compounds were carried out, indicating a similar selectivity of the heterogeneous Fenton-like system to that known for oxidation with .OH. PMID- 23098996 TI - Enhanced resistance to nanoparticle toxicity is conferred by overproduction of extracellular polymeric substances. AB - The increasing production and use of engineered nanoparticles, coupled with their demonstrated toxicity to different organisms, demands the development of a systematic understanding of how nanoparticle toxicity depends on important environmental parameters as well as surface properties of both cells and nanomaterials. We demonstrate that production of the extracellular polymeric substance (EPS), colanic acid by engineered Escherichia coli protects the bacteria against silver nanoparticle toxicity. Moreover, exogenous addition of EPS to a control strain results in an increase in cell viability, as does the addition of commercial EPS polymer analogue xanthan. Furthermore, we have found that an EPS producing strain of Sinorhizobium meliloti shows higher survival upon exposure to silver nanoparticles than the parent strain. Transmission electron microscopy (TEM) observations showed that EPS traps the nanoparticles outside the cells and reduces the exposed surface area of cells to incoming nanoparticles by inducing cell aggregation. Nanoparticle size characterization in the presence of EPS and xanthan indicated a marked tendency towards aggregation. Both are likely effective mechanisms for reducing nanoparticle toxicity in the natural environment. PMID- 23098997 TI - [Myocarditis: magnetic resonance imaging diagnosis and follow-up]. AB - Myocarditis, inflammation of the myocardium, is usually due to viral infection. Diagnostic confirmation in ordinary clinical practice is difficult because the findings on the clinical history, physical examination, electrocardiogram, and laboratory tests offer scant diagnostic accuracy, and the differential diagnosis is often done with acute myocardial infarction. Cardiac magnetic resonance imaging (CMR) has become the method of choice for the diagnosis of myocarditis. In this article, we describe the CMR findings at diagnosis and during the follow up of patients with myocarditis, the differential diagnosis with other acute processes like myocardial infarction, and the prognostic factors studied with CMR. PMID- 23098994 TI - Converging levels of analysis on a genomic hotspot for psychosis: insights from 22q11.2 deletion syndrome. AB - Schizophrenia is a devastating neurodevelopmental disorder that, despite extensive research, still poses a considerable challenge to attempts to unravel its heterogeneity, and the complex biochemical mechanisms by which it arises. While the majority of cases are of unknown etiology, accumulating evidence suggests that rare genetic mutations, such as 22q11.2 Deletion Syndrome (22qDS), can play a significant role in predisposition to the illness. Up to 25% of individuals with 22qDS eventually develop schizophrenia; conversely, this deletion is estimated to account for 1-2% of schizophrenia cases overall. This locus of Chromosome 22q11.2 contains genes that encode for proteins and enzymes involved in regulating neurotransmission, neuronal development, myelination, microRNA processing, and post-translational protein modifications. As a consequence of the deletion, affected individuals exhibit cognitive dysfunction, structural and functional brain abnormalities, and neurodevelopmental anomalies that parallel many of the phenotypic characteristics of schizophrenia. As an illustration of the value of rare, highly penetrant genetic subtypes for elucidating pathological mechanisms of complex neuropsychiatric disorders, we provide here an overview of the cellular, network, and systems-level anomalies found in 22qDS, and review the intriguing evidence for this disorder's association with schizophrenia. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'. PMID- 23098998 TI - Clot penetration and retention by plasminogen activators promote fibrinolysis. AB - Tissue-type plasminogen activator (tPA) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism (PE). tPA has not been replaced by third generation plasminogen activators, e.g. Reteplase (Ret) and Tenecteplase (TNK) that circulate with longer life-spans and in theory should have more extended potency in vivo. One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards, which impairs objective comparison. Here, we compare clot permeation, retention and fibrinolytic activities of tPA, TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism (ME). When clots were incubated in the continuous presence of drug, tPA, TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor-1 (e.g. PAI-1). Ret, which has lower fibrin affinity and greater susceptibility to inhibition by PAI-1 than tPA, was less effective in lysing plasma clots, while TNK was less effective when the fibrin content of the clots was enhanced. However, when clots were afforded only brief exposure to drug, as occurs in vivo, Ret showed more extensive clot permeation, greater retention and lysis than tPA or TNK. These results were reproduced in vivo in a mouse model of ME. These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility. PMID- 23098999 TI - F420-dependent enzymes - potential for applications in biotechnology. PMID- 23099001 TI - Transjugular intrahepatic portosystemic shunt creation using intravascular ultrasound guidance. AB - PURPOSE: To describe the use of intravascular ultrasound (US) guidance for creation of transjugular intrahepatic portosystemic shunts (TIPSs) in humans. MATERIALS AND METHODS: The initial 25 cases of intravascular US-guided TIPS were retrospectively compared versus the last 75 conventional TIPS cases during the same time period at the same institution in terms of the number of needle passes required to establish portal vein (PV) access, fluoroscopy time, and needle pass related complications. RESULTS: Intravascular US-guided TIPS creation was successful in all cases, and there was no statistically significant difference in number of needle passes, fluoroscopy time, or needle pass-related complications between TIPS techniques. Intravascular US-guided TIPS creation was successful in cases in which conventional TIPS creation had failed as a result of PV thrombosis or distorted anatomy. Intravascular US guidance for TIPS creation was additionally useful in a patient with Budd-Chiari syndrome and in a patient with intrahepatic tumors. CONCLUSIONS: Intravascular US is a safe and reproducible means of real-time image guidance for TIPS creation, equivalent in efficacy to conventional fluoroscopic guidance. Real-time sonographic guidance with intravascular US may prove advantageous for cases in which there is PV thrombus, distorted anatomy, Budd-Chiari syndrome, or hepatic tumors. PMID- 23099002 TI - Magnetic resonance imaging-guided focused ultrasound treatment of pedunculated subserosal uterine fibroids: a preliminary report. AB - PURPOSE: To evaluate magnetic resonance (MR) imaging-guided focused ultrasound (US) as a treatment for pedunculated subserosal fibroids. MATERIALS AND METHODS: Over a 2-year period (March 2007 to March 2009), 135 women with symptomatic uterine fibroids were treated in the authors' institution using MR imaging-guided focused US. Of these women, nine (mean age, 39 years; range, 25-47 y) had a single pedunculated subserosal fibroid. During treatment, these pedunculated fibroids were targeted, while sparing the stalk connection between the fibroid and the uterus. Contrast-enhanced T1-weighted MR images were obtained immediately after the treatment to measure the nonperfused volume (NPV) ratio and to check stalk viability. Changes in tumor volume, diameter of the stalk, patient symptoms and adverse events were evaluated 6 months after treatment. RESULTS: The volume of the treated fibroids (n=9) ranged from 79-380cm(3) (mean, 198cm(3)), and NPV ratio ranged from 45%-80% (mean, 67%). MR imaging follow-up at 6 months showed a 14%-48% (mean, 30%) reduction in the volume of the treated fibroids (P =.008). In all cases, the pedunculated subserosal fibroids remained connected to the uterus with a 13% average decrease in the mean diameter of the stalks (from 3.5 to 3.0cm; P=.008). Eight of nine patients (89%) reported improvement in bulk-related fibroid symptoms after treatment. CONCLUSIONS: The results of this preliminary study suggest that MR imaging-guided focused US may be a safe and effective treatment for pedunculated subserosal fibroids. Larger prospective studies with longer follow-up are needed to confirm the suitability of MR imaging-guided focused US to treat this type of fibroid. PMID- 23099003 TI - Fibromuscular dysplasia-related carotid pseudoaneurysm and pulsatile tinnitus. PMID- 23099004 TI - Comparing cisplatin-based combination chemotherapy with EMA/CO chemotherapy for the treatment of high risk gestational trophoblastic neoplasia. AB - BACKGROUND: Cisplatin-based chemotherapy (etoposide 100 mg/m(2) days 1-5, methotrexate 300 mg/m(2) day 1, cyclophosphamide 600 mg/m(2) day 1, actinomycin D 0.6 mg/m(2) day 2 and cisplatin 60 mg/m(2) day 4, EMACP) was compared to EMA/CO (etoposide 100 mg/m(2) days 1-2, methotrexate 300 mg/m(2) day 1 and actinomycin D 0.5 mg i.v. bolus day 1 and 0.5 mg/m(2) day 2, alternating with cyclophosphamide 600 mg/m(2) day 8 and vincristine 1 mg/m(2) day 8) for the treatment of high-risk gestational trophoblastic neoplasia (GTN). PATIENTS AND METHODS: In the Netherlands, 83 patients were treated with EMACP and 103 patients with EMA/CO. Outcome measures were remission rate, median number of courses to achieve normal human chorionic gonadotrophin (hCG) concentrations, toxicity, recurrent disease rate and disease specific survival. RESULTS: Remission rates were similar (EMACP 91.6%, EMA/CO 85.4%). The median number of courses of EMA/CO to reach hCG normalisation for single-agent resistant disease and primary high-risk disease was three and five courses, respectively, compared to 1.5 (p=0.001) and three (p<0.001) courses of EMACP. Patients treated with EMACP more often developed fever, renal toxicity, nausea and diarrhoea compared to patients treated with EMA/CO. Patients treated with EMA/CO more often had anaemia, neuropathy and hepatotoxicity. CONCLUSION: EMACP combination chemotherapy is an effective treatment for high-risk GTN, with a remission rate comparable to EMA/CO. However, the difference in duration of treatment is only slightly shorter with EMACP. Cisplatin-based chemotherapy in the form of EMACP in this study was not proven more effective than EMA/CO. PMID- 23099005 TI - Excellent performance of Hemoccult Sensa in organised colorectal cancer screening. AB - BACKGROUND: Faecal occult blood (FOB) testing is the most commonly chosen approach in organised population-based colorectal cancer screening programmes throughout the world. Several FOB tests are available which differ in their test qualities. While immunological tests are gaining popularity due to their lower labour intensive analysis and higher standardisation, they are heat labile and more expensive. We studied the real-life experience of a large population-based, organised, screening programme in Israel which employs FOB testing with Hemoccult Sensa, a guaiac test with increased sensitivity that is similar to that of the immunological tests for cancer. METHODS: Clalit Health Services is the largest health care provider in Israel. All eligible insurees are actively invited to perform a free-of-charge, home-based, faecal occult blood test, using Hemoccult Sensa. All tests with positive results are followed up and information on colonoscopy, surgical procedures and pathology findings is collected. RESULTS: During an 18 month period (July 2007-December 2008) 382,792 FOBT tests (in 325,851 people) were performed by the target population, of them 85% Jews and 15% Arabs. Seven hundred and eighteen colorectal cancers and 2652 adenomas were detected. The overall test positivity rate in repeatedly-tested people was 4.2%. The overall detection rate of colorectal cancer in the subsequent tests was 1.7/1000 reflecting 91% of the expected period-incidence of CRC. 70% of the cancers were detected at stages Duke's B2 and lower. Left-sided cancers were detected at a significantly better stage than right-sided cancers (P<0.001). Detection rates among Arabs were somewhat lower than among Jews but the screening programme led to a meaningful increase in national incidence rate in this subgroup by detecting tumours that were otherwise asymptomatic. CONCLUSION: The Clalit organised colorectal cancer screening programme, using low cost Hemoccult Sensa, has reached the targets of very high detection rate of cancers, most of them at low stage while keeping a low positivity rate. This approach demonstrates an efficient field-tested alternative to other, more costly, screening options. PMID- 23099006 TI - A phase 1 study of OSI-930 in combination with erlotinib in patients with advanced solid tumours. AB - AIM: To determine the maximum tolerated dose (MTD) of OSI-930 that can be combined with erlotinib, and establish recommended phase 2 doses when both agents are administered daily in patients with advanced solid tumours. PATIENTS AND METHODS: Eligible patients with advanced solid tumours were enrolled into this standard "three+three" dose escalation study. Study treatment commenced on day 1 with OSI-930, and erlotinib was introduced on day 8. PK profiles of OSI-930, erlotinib and its active metabolite, OSI-420, were determined. Changes in sVEGFR2 as a pharmacodynamic biomarker of OSI-930 activity were assessed. RESULTS: Twenty one patients were enrolled to 1 of 3 cohorts: 200 mg OSI-930 BID+100 mg erlotinib QD; 200 mg OSI-930 BID+150 mg erlotinib QD; 300 mg OSI-930 BID+150 mg erlotinib QD. The most common adverse events were anorexia (85%), diarrhoea (75%), rash (70%) and lethargy (65%). The MTD was not reached but the onset of cumulative toxicity necessitating dose modification after the 28-d DLT assessment period was common at the highest dose level. A PK interaction was identified with co administration of both agents resulting in a two-fold increase in OSI-930 exposure. Pharmacodynamic activity was observed with a decline in sVEGFR levels detected in all patients. Ten patients had disease stabilization (median duration 119 d). CONCLUSIONS: 200 mg OSI-930 BID+150 mg erlotinib QD were the recommended doses for further evaluation of this combination. PMID- 23099007 TI - High expression of miR-21 and miR-155 predicts recurrence and unfavourable survival in non-small cell lung cancer. AB - We synthesised the evidence of microRNAs as prognostic biomarkers in lung cancer. Studies were identified by searching PubMed, Embase and Web of Science until March 2012. Descriptive characteristics for studies were described and an additional meta-analysis for two specific microRNAs (miR-21 and miR-155) which were studied extensively was performed. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The median study size was 88 patients (interquartile range [IQR]=53-193) and the median HR in the studies that reported statistically significant results was 2.855 (IQR=2.01 5.035). For the studies evaluating miR-21's association with clinical outcomes, the pooled HR suggested that high expression of miR-21 has a negative impact on overall survival (OS) in non-small cell lung cancer (NSCLC) (HR=2.32[1.17-4.62], P<0.05) and recurrence-free survival (RFS)/cancer-specific survival (CSS) in lung adenocarcinoma (HR=2.43[1.67-3.54], P<0.001). As for miR-155, the pooled HR for OS was 2.09 (95%CI: 0.68-6.41, P>0.05) which was not statistically significant, but for RFS/CSS was 1.42 (95% CI: 1.10-1.83, P=0.007). These results indicate that microRNAs show promising associations with prognosis in lung cancer; moreover, specific microRNAs such as miR-21 and miR-155 can predict recurrence and poor survival in NSCLC. PMID- 23099008 TI - Treatment for plexiform neurofibromas in patients with NF1. PMID- 23099011 TI - Intraosseous access EZ-IO in a prehospital emergency service. AB - BACKGROUND: Several scientific and professional associations have made reports and recommendations to regulate the use of intraosseous (IO) access as an alternative to conventional intravenous access (IA) in emergency situations when IA cannot be obtained. It has been well documented that IO access is safe and effective for fluid resuscitation, drug delivery, and blood collection. IO access is attainable in all age groups. OBJECTIVE: The objective of this prospective study was to test the use of a semi-automatic IO infusion system (EZ-IO) as an alternative to vascular access in critical patients treated in a prehospital emergency setting. METHOD: This prospective, cross-sectional study included patients who required immediate peripheral vascular access. This study was performed by reviewing clinical records and through a questionnaire (created by and for nurses who perform the insertion with the EZ-IO). RESULTS: During the study period we identified 107 patients who underwent EZ-IO insertion (114 insertions were performed). Patients were predominantly male (66%) and middle aged (mean age 56 years; range 3-94). Overall, insertion was performed via the proximal tibia (49.4%) distal tibia (25.2%), radius (14.9%), and humerus (10.5%). During the study period, 14 insertions were performed in 2007, 44 in 2008, and 56 in 2009. A majority of patients (50.9%) had medical cardiac arrest, (25.4%) were injured trauma patients, and 12.3% had traumatic cardiac arrest. All patients were transported to a hospital with 2 sites of peripheral vascular access. The first site of access in these patients was IO (100% of cases) and the second site (in 79% of cases) was peripheral intravenous access. All EZ-IO insertions were achieved within 30 seconds and were successful upon the first attempt. CONCLUSION: The use of the EZ-IO provides a quick (100% performed within 30 seconds), easy, and reliable alternative to conventional venous access in critically ill patients. Traditional peripheral venous access requires a minimal preparation that can delay initial treatment in critically ill patients and cause possible interference with resuscitation. The main advantage of using EZ-IO is to obtain secure, immediate, noncollapsible peripheral venous access in critically ill patients. It is possible to obtain a second site of access such as peripheral venous access to administer fluids and drugs, which can improve survival rates. PMID- 23099009 TI - Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. AB - BACKGROUND: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS: Eligible patients had to be aged 3 65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results. FUNDING: Novartis Pharmaceuticals, the Indiana University Simon Cancer Centre, and the Indiana University Herman B Wells Center for Pediatric Research. PMID- 23099010 TI - DNA interstrand crosslinks induce a potent replication block followed by formation and repair of double strand breaks in intact mammalian cells. AB - DNA interstrand crosslinks (ICLs) are highly toxic lesions that covalently link both strands of DNA and distort the DNA helix. Crosslinking agents have been shown to stall DNA replication and failure to repair ICL lesions before encountered by replication forks may induce severe DNA damage. Most knowledge of the ICL repair process has been revealed from studies in bacteria and cell extracts. However, for mammalian cells the process of ICL repair is still unclear and conflicting data exist. In this study we have explored the fate of psoralen induced ICLs during replication, by employing intact mammalian cells and novel techniques. By comparative studies distinguishing between effects by monoadducts versus ICLs, we have been able to link the block of replication to the ICLs induction. We found that the replication fork was equally blocked by ICLs in wild type cells as in cells deficient in ERCC1/XPF and XRCC3. The formation of ICL induced double strand breaks (DSBs), detected by formation of 53PB1 foci, was equally induced in the three cell lines suggesting that these proteins are involved at a later step of the repair process. Furthermore, we found that forks blocked by ICLs were neither bypassed, restarted nor restored for several hours. We propose that this process is different from that taking place following monoadduct induction by UV-light treatment where replication bypass is taking place as an early step. Altogether our findings suggest that restoration of an ICL blocked replication fork, likely initiated by a DSB occurs relatively rapidly at a stalled fork, is followed by restoration, which seems to be a rather slow process in intact mammalian cells. PMID- 23099012 TI - Development of a screening and brief intervention and referral for treatment for ED patients at risk for undiagnosed hypertension: a qualitative study. AB - INTRODUCTION: Providing a screening, brief intervention, and referral for treatment (SBIRT) may encourage patients to obtain provider follow-up for definitive evaluation and treatment of undiagnosed hypertension (HTN). The aims of this study were to determine characteristics of an intervention that would persuade patients to follow-up with a primary care physician for further blood pressure (BP) evaluation, and encourage ED clinicians to provide an SBIRT for patients with elevated BP with no known history of HTN. METHODS: Qualitative methods were used to analyze individual interviews with ED clinicians and patients. Questions focused on participants' opinions of the meaning of elevated BP, and facilitators and barriers to recommending referral for follow-up (clinicians) or facilitators and barriers to making and keeping a follow-up appointment (patients). Three reviewers coded the interviews using grounded theory. RESULTS: Clinicians identified time constraints and patient-specific factors such as difficulty securing follow-up as major barriers. Some clinicians considered an electronic reminder as a potential facilitator to providing counseling. Patients reported family support and information about complications of uncontrolled HTN such as stroke would increase the likelihood of follow-up. Patient-specific barriers to follow-up included inability to obtain time off from work, forgetfulness, and wait time for an appointment. CONCLUSIONS: An SBIRT-HTN could be developed to target patients with elevated BP during an ED visit. The intervention must be simple, easy to implement, and include automated processes to remind clinicians to deliver the intervention. The intervention should include a description of the complications of untreated HTN and an outpatient physician referral. PMID- 23099013 TI - A national survey of emergency nurses and avian influenza threat. AB - INTRODUCTION: The purpose of this study was to determine the perceived likelihood of emergency nurses reporting to work during an avian influenza outbreak, to consider options if nurses decided not to report work, and to explore Protection Motivation Theory constructs as predictors of reporting to work. METHODS: A descriptive, nonexperimental, cross-sectional survey of emergency nurses within the United States. RESULTS: A total of 332 nurses (46%) responded. Most emergency nurses (84%) reported they would report to work (1 in 6 would not). The likelihood of reporting to work differed by education level, nurses' avian influenza information sources, and nurses who had family living with them. Of the nurses who decided not to report to work, the majority were willing to provide health information (90%), administer vaccinations (82%), and triage (74%) neighbors/friends from home. One third of nurses had not attended a disaster preparedness drill within the past year. Only 20% identified formal training while on the job as a source of avian influenza information. A third of emergency nurses would be worried about getting an avian influenza vaccination because of potential adverse effects. Protection Motivation Theory accounted for almost 40% of the variance of likelihood to report to work, with response costs being the largest predictor. DISCUSSION: Disaster drills, avian influenza job training, and vaccination education are necessary to prepare emergency nurses for an outbreak. The findings support emergency nurses' willingness to work from home if they are unable to report to work. This finding is new and may have implications for disaster planning, staffing, and ED operations. PMID- 23099014 TI - One emergency department's management experiment: leadership by team. PMID- 23099015 TI - Early pregnancy loss and bereavement in the emergency department: staff and patient satisfaction with an early fetal bereavement program. PMID- 23099016 TI - The factors that affect the frequency of vital sign monitoring in the emergency department. AB - INTRODUCTION: Vital signs are an important component of the nursing assessment and are used as early warning signs of changes in a patient's condition; however, little research has been conducted to determine how often vital signs are monitored in the emergency department. Additionally, it has not been determined what personal, social, and environmental factors affect the frequency of vital sign monitoring. The purpose of this study was to examine what factors may influence the time between recording vital signs in the emergency department. METHODS: We performed a descriptive, retrospective chart review of 202 randomly selected adult ED patients' charts from representative times to capture a variety of ED levels of occupancy in an urban, Midwestern, teaching hospital. Descriptive and hierarchical regression analyses were used. RESULTS: The strongest predictor of the increased time between vital signs from the personal health factors was lower patient acuity (Emergency Severity Index). This relationship remained strong even when social factors and environmental factors were included. Increased length of stay and fewer routes of medications also had significant relationships to the increased time between vital sign monitoring. DISCUSSION: These findings are clinically important because greater time between vital sign recordings can lead to errors of omission by not detecting changes in vital signs that could reveal changes in the patient's condition. The findings of this study provide direction for future research focusing on determining whether higher frequency of vital signs surveillance contributes to higher quality care and linking quality of care to missing vital signs/inadequate monitoring. PMID- 23099017 TI - Preceptor: blueprint for successful orientation outcomes. PMID- 23099018 TI - Implementing clinical research in the high acuity setting of the emergency department. AB - INTRODUCTION: Clinical research in the emergency department provides supporting evidence needed for the development of practice guidelines, such as door-to needle and door-to-balloon times for treatment of acute coronary syndromes, and is vital to improvements in patient outcomes. The purpose of this article is to describe barriers and lessons learned in launching a multisite clinical research study of symptoms of acute coronary syndromes in the emergency department. METHODS: Participants included ED and research staff in 4 busy emergency departments in 3 states. At each step of the study launch, the principal investigator at the clinical site identified barriers that either were anticipated or experienced and discussed them with the site staff and study principal investigator to validate the issue as a barrier. Orientation sessions and ongoing communication between clinicians, research staff, and the research study team provided opportunity for adjustment of study protocols. RESULTS: Barriers were lack of staff engagement in research, difficulty identifying eligible patients, perception of interference in clinical care, variability in research staff education and training, patient refusals, nurses' perceptions of lack of time, undifferentiated patients, and time-sensitive quality improvement indicators necessitating acceleration in care. DISCUSSION: Important strategies to overcome barriers were developed, including identification and support of unit champions in emergency nursing and medicine; minor protocol modifications to improve enrollment goals; development of specific written expectations, roles, research protocols, and algorithms; and sharing successes among sites. PMID- 23099019 TI - Evaluating left without being seen and against medical advice departures in a rural emergency department. PMID- 23099020 TI - Design optimisation and experimental evaluation of dorsal double plating fixation for distal radius fracture. AB - This study determines the relative effects of changes in osteoporosis condition, plate/screw design factors (plate angle/length/width/thickness and screw diameter) and fixation methods (screw number and screw length) on the biomechanical response of dorsal double plating (DDP) fixation at a distal radius fracture to determine the optimal design and evaluate its biomechanical strength using the dynamic fatigue test. Eighteen CAD and finite element (FE) models corresponding to a Taguchi L18 array were constructed to perform numerical simulations to simulate the mechanical responses of a DDP fixed in a simply distal radius fracture bone. The Taguchi method was employed to determine the significance of each design factor in controlling bone/plate/screw stress and distal fragment displacement under axial (100 N), bending (1 N m) and torsion (1 N m) loads. Simulation results indicated that the order rank to determine the mechanical response was the plate thickness, plate width, screw diameter, and number of screws. Dorsal intermediate (L) plate with 60 mm length, 1.8 mm thickness, 6.0 mm width and 2.8 mm diameter, 20 mm length dual-thread locking screw can be found for optimisation. The DDP, including an L plate with 0 degrees , 30 degrees and 60 degrees angles and a straight I plate, were made with Ti6Al4V to fix onto the sawbones with three corresponding radius fractures to perform the dynamic testing. The specimens were oscillated with loads between 10 N and 150 N at 5 Hz for 20,000 cycles. The average stiffness in 20,000 test cycles was 425.7 N/mm, 461.1 N/mm and 532.1N/mm for the 0 degrees , 30 degrees and 60 degrees constructs, respectively. No difference in stiffness was found in the same angled constructs throughout the 20,000 cycles of testing (p > 0.05). Lack of gross construct failures during cyclic testing and reasonable stiffness corroborated that our new constructs tested to date seem stable enough to support restricted post-operative loads. PMID- 23099022 TI - [Why patient consent is not to be neglected?]. AB - Observation of medical practices still show that, in some institutions, obtaining consent could be in the mode of a trivialization, or even some administrative automaticity. To ensure a truly informed choice, this article explains why the information in the sensitive field of reproductive medicine and perinatology should remain an act of care and relationship. It outlines why medical information issued to couples must take into account not only validated data, but also the doubts and uncertainties. This is especially true when risk management because the meaning we give to the acceptance of risk is not simply the result of a calcul of probability but also the result of a social construction. All signed consent and collected outside of such an approach to quality and completeness of the information would be considered questionable. PMID- 23099021 TI - Crystal structure of the dimeric coiled-coil domain of the cytosolic nucleic acid sensor LRRFIP1. AB - LRRFIP1 binds cytoplasmic double-stranded DNA and RNA and interacts with FLI, the mammalian homolog of Drosophila flightless I, through a highly conserved 87-amino acid domain. Upon binding nucleic acid ligands, LRRFIP1 recruits and activates beta-catenin, leading to the IRF3-dependent production of type I interferon. However, the molecular mechanism of LRRFIP1 signaling is not well understood. Here we show that the FLI-interacting domain of LRRFIP1 forms a classic parallel, homodimeric coiled coil with 10 heptad repeats and 22 helical turns. The coiled coil domain is also a dimer in solution. However, a longer LRRFIP1 construct spanning the coiled coil and DNA binding domains assembles into higher order oligomers in solution. The structure of LRRFIP1-CC constitutes a valuable tool for probing the mechanism of LRRFIP1 signaling and for structural studies of larger LRRFIP1 constructs. PMID- 23099023 TI - [Spontaneous hemoperitoneum during pregnancy and uterine artery aneurysm]. AB - Spontaneous hemoperitoneum is not frequent. We report here a rare cause of spontaneous hemoperitoneum during the second trimester of pregnancy. A ruptured uterine artery aneurysm was revealed in a patient who came for important abdominal pain. A CT scan showed a large hemoperitoneum and an additional arterial image. The patient underwent rapidly an embolization, which allowed a complete closure of the aneurysm. The patient gave birth to a healthy child. The diagnosis of hemoperitoneum must be discussed without delay. Once imagery realised, a good management of the patient must be done depending on the origin of the hemoperitoneum. PMID- 23099024 TI - [Impact of bariatric surgery on obstetric prognosis]. AB - OBJECTIVES: Assessment of pregnancy outcomes after bariatric surgery and analysis of follow-up particularities of such pregnancies. PATIENTS AND METHODS: A retrospective study of 63 post-bariatric surgery pregnancies compared to 259 pregnancies of obese un-operated patients. Pregnancy outcomes, neonatal datas, delay influence between surgery and pregnancy beginning, bariatric surgery type and gastric banding (GB) loosening consequences were analysed. RESULTS: In the surgical brand were developed less gestational diabetes (DG) (P=0,05), deliveries were more often normal (P=0,004) and births shown less macrosomias and small for gestational age newborns (P=0,04). Neonatal state was improved among operated patients: less Apgar scores less than 7 at 1 minute (P=0,05) and less cord blood pH less than 7,2 (P=0,03). They gained more weight during the pregnancy (P=0,0003) and only 53% had a nutritional management and assessment. Patients with GB loosening gained more weight (P=0,0003). Lastly, there were no difference due to the different bariatric surgery techniques or nutritional follow-up in the pregnancy course and neonatal state. DISCUSSION AND CONCLUSION: Bariatric surgery improves obstetric and neonatal prognosis. Improvements have to be developed in the multidisciplinary follow-up in order to avoid nutritional deficiencies or important weight gain pregnancy in case of GB. PMID- 23099025 TI - [Oocyte vitrification and its impact on the clinical practice of assisted reproduction]. AB - Oocyte vitrification is a new technique in cryobiology that will lead to a number of improvements in assisted reproduction practices, oocyte donation and the preservation of female fertility. Professionals already versed in the techniques of micromanipulation will be able to master the new procedures, which should not be delegated to unqualified staff. When adopted by clinical units, oocyte vitrification will require changes in laboratory and administrative organization. The technique will also modify the ethical outlines of reproductive biology. France today is running behind in the application of this major development in cryobiology. The reasons are many and have to do with a long waiting period for authorization from national health authorities, a lack of material and human resources and a foreseeable shake-up in the nationally established egg donation program. However, recently a new law of bioethics has recognized the breakthrough that this new technique represents by allowing couples covered by the French national health care program for Assisted Reproductive Technologies (ART) to choose oocyte vitrification as an option. PMID- 23099026 TI - [Post-partum haemorrhage associated with genital tract lacerations: series of 44 cases]. AB - OBJECTIVES: Genital tract lacerations are responsible for potentially serious postpartum hemorrhage (PPH), and are often underestimated. The objective of this study was to analyze the characteristics of genital tract lacerations associated with severe PPH in a reference center. PATIENTS AND METHODS: All women transferred for treatment of PPH due to genital tract lacerations between January 2008 and April 2011 were included in this observational study. Two populations of patients with genital tract lacerations were defined : patients with "complex" lesions and patients with "simple" genital tract laceration. RESULTS: Forty-four patients were treated for PPH associated with genital tract lacerations. The average age of patients was 30.6 years (17-41 years). All the patients had a vaginal delivery, combined with an instrumental in 70.5% of cases. With the exception of one patient, all patients had a revision of the cervix and vagina before the transport in our Institution. Twenty nine patients (70.7%) had received a suture of genital tract in their maternity. In our Hospital, the patient having a "simple" genital tract lesion received in 54.5% of cases medical drugs alone against 33.3% for patients with complex genital tract lacerations. In 39.4% of cases an embolization was necessary for the group of patients with complex genital tract lacerations against 9.1% in the simple genital tract lesion group. DISCUSSION AND CONCLUSION: Genital tract lacerations are a serious cause of HDD. Their management should be multidisciplinary combining appropriate and timely decisions (resuscitation, embolization and/or surgery). The sequence of these treatments depends on the clinical condition of the patient and justifies a transfer to a referral center. PMID- 23099027 TI - [Ovarian cryopreservation: what future?]. AB - Ovarian cortex cryobanking is a technique of fertility preservation that led to the birth of about 20 children in the world since 2004. Its main limitations are low follicular survival rate after thawing and transplantation and the risk of disease reintroduction. A lot of research is currently conducted in order to optimize both efficacy and safety of the graft and to develop alternative techniques to restore fertility. These advances will allow oncologists to offer this technique to a growing number of patients in the context of fertility preservation (for medical or social indications), but also in other indications such as puberty induction or menopause treatment. PMID- 23099028 TI - [2002-2012: A cursed decade for estrogens]. PMID- 23099029 TI - [Evaluation of D-dimer as a marker for severity in pregnancies with preeclampsia]. AB - OBJECTIVES: Alterations in blood coagulation and fibrinolysis play a major role in the pathogenesis of preeclampsia. HELLP syndrome is associated with hypercoagulability and leads to maternal and perinatal complications. Our purpose was to evaluate D-dimer as a marker for severity in pregnancies with preeclampsia. PATIENTS AND METHODS: Plasma D-dimer levels were measured using an enzyme-linked immunosorbent assay (ELISA) technique. We studied the association between D-dimer levels and clinical and biological characteristics of pregnancies complicated by preeclampsia. RESULTS: D-dimer values increased with increasing gestational age. Patients with HELLP syndrome had mean D-dimer values significantly greater than patients with preeclampsia alone (3848+/-2551 versus 1578+/-1077, P<0.001). However, the level of D-dimer at the time of admission was poorly predictive of occurrence of HELLP syndrome. Area under of the ROC curve was 0.69 (CI 95%: 0,59-0,79). The best threshold was 2170 ng/mL with a sensitivity of 0.91 and a specificity of 0.40. Other severity criteria of preeclampsia were not associated with higher levels of D-dimer. DISCUSSION AND CONCLUSION: In preeclamptic patients, D-dimer levels were related with gestational age and HELLP syndrome. However, accuracy of this test to predict occurrence of HELLP syndrome or severe preeclampsia was too low to recommend its use routinely. PMID- 23099030 TI - [Evaluation of the respect of the clinical practice guidelines in maternal transfer for postpartum haemorrhage in 2011: about 84 cases]. AB - OBJECTIVES: Guidelines for the management of post-partum haemorrhage (PPH) were defined by the "College National des Gynecologues Obstetriciens Francais (CNGOF)" since 2004. The aim of this work was to assess whether the management of PPH before and during the transfer was in accordance with national recommendations. PATIENTS AND METHODS: This is an observational monocentric prospective study concerning 84 patients transferred for PPH in a referent centre in 2011. RESULTS: In 62 cases (73.8%), transfusionnal files were found. Time noted PPH for 60 (71.4%) and amount of blood loss in 55 cases (65.5%) were notified. Evacuation of retained placenta was always performed; the broad-spectrum antibiotic prophylaxis covered only 21 cases of intra uterine procedures. Less than 5% of the patients received intravenous sulprostone before the transfer; 72.6% (n=61) of the patients were transfused before transfer 25% of the patients (n=21) had a very high risk of PPH in ante partum and were not addressed to a centre with appropriate medical and technical facilities. DISCUSSION AND CONCLUSION: Thus improvement can be made in the communication between the health care centre during transfer for PPH and the ante partum transfer of patients with high risk of PPH. PMID- 23099031 TI - [Ultrasound in monitoring of the second stage of labour]. AB - In the second stage of labor, fetal head rotation and fetal head position are determinant for the management of labor to attempt a vaginal delivery or a cesarean section. However, digital examination is highly subjective. Nowadays, delivery rooms are often equipped with compact and high performance ultrasound systems. The clinical examination can be easily completed by quantified and reproducible methods. Transabdominal ultrasonography is a well-known and efficient way to determine the fetal head position. Nevertheless, ultrasound approach to assess fetal head descent is less widespread. We can use translabial or transperineal way to evaluate fetal head position. We describe precisely two different types of methods: the linear methods (3 different types) and the angles of progression (4 different types of measurement). Among all those methods, the main pelvic landmarks are the symphysis pubis and the fetal skull. The angle of progression appears promising but the assessment was restricted to occipitoanterior fetal position cases. In the coming years, ultrasound will likely play a greater role in the management of labor. PMID- 23099032 TI - Antioxidative responses in females and males of the spider Xerolycosa nemoralis (Lycosidae) exposed to natural and anthropogenic stressors. AB - The aim of this study was to assess the intensity of enzymatic antioxidative parameters [i.e., superoxide dismutase (SOD), catalase (CAT), and the glutathione peroxidases each selene dependent, GPOX or selene independent, including GSTPx, glutathione S-transferase, and GST] and non-enzymatic antioxidative parameters [i.e., glutathione total (GSH-t), the heat shock proteins of Hsp70, and metallothioneins (Mt)] in the midgut glands of female and male wolf spiders Xerolycosa nemoralis (Lycosidae) exposed to natural stressors (i.e., heat shock and starvation) and anthropogenic stressors (i.e., the organophosphorous pesticide dimethoate) under laboratory conditions. The spiders were collected from two differentially polluted sites both localized in southern Poland: Olkusz, which is heavily polluted with metals, and Pilica, the reference site. In response to the stressing factors, increases in Hsp70 levels, in the concentrations of total glutathione and in the activity levels of glutathione dependent enzymes (GPOX, GSTPx, and GST) were found in the midgut glands of males. In the females, high levels of activity of CAT and SOD were revealed, as well as an increased percentage of Mt-positive cells. Preexposed females, in comparison to the individuals from the reference site, responded with increased SOD activity, irrespective of the stressing factor. In contrast, the changes in the antioxidative parameters in the midgut glands of male X. nemoralis seem to reflect a short-term reaction to the applied stressors and do not confirm the effects of long-term selection in a polluted environment. PMID- 23099033 TI - Bilateral inferior frontal language-related activation correlates with verbal recall in patients with left temporal lobe epilepsy and typical language distribution. AB - Language fMRI has been used in the presurgical evaluation of drug-resistant temporal lobe epilepsy patients. Previous studies have demonstrated that left temporal lobe epilepsy (LTLE) patients with atypical language lateralization are at lower risk of postsurgical verbal memory decline, hypothesizing co-occurrence of verbal memory and language reorganization presurgically. Furthermore, it has been proposed that the recruitment of right frontal language-related areas is associated with the preservation of verbal memory performance in these patients. However, less is known about the correlation between these functions specifically in LTLE patients with left language dominance, although they are more prone to postsurgical verbal memory decline. The aim of the present study was to investigate whether the relationship between verbal memory scores and frontal language activation is also observed in LTLE patients with typical language dominance. Eighteen healthy controls, 12 right temporal lobe epilepsy patients and 12 LTLE patients with typical language distribution as assessed by an fMRI verbal fluency task were selected. Verbal memory scores were obtained from the patients' neuropsychological presurgical evaluation. Our results showed a positive correlation between verbal recall and activation of bilateral inferior frontal areas in LTLE patients. These results support the hypothesis of a link between language representation in inferior frontal areas and hippocampal functioning, and indicate that both hemispheres are related to the preservation of verbal memory in patients with hippocampal damage and typical language dominance. PMID- 23099034 TI - Hygiene recommendations for interventional radiology. PMID- 23099035 TI - [Do anesthetic techniques influence postoperative outcomes? Part II]. AB - The knowledge of the influence of anesthetic techniques in postoperative outcomes has opened a large field of research in recent years. In this second part, we review some of the major controversies arising from the literature on the impact of anesthetic techniques on postoperative outcomes in 6 areas: postoperative cognitive dysfunction, chronic postoperative pain, cancer recurrence, postoperative nausea/vomiting, surgical outcomes, and resources utilization. The development of protective and preventive anesthetic strategies against short and long-term postoperative complications will probably occupy an important role in our daily anesthetic practice. Dynamic postoperative pain control has been confirmed as one of the basic requirements of accelerated postoperative recovery programs ("fast-track surgery"), and it is also a preventive factor for development of chronic postoperative pain. The weight of anesthetic technique on postoperative immunosuppression is to be defined. The potential influence of anesthesia on cancer recurrence, is a highly controversial area of research. The classic pattern of perioperative fluid therapy may increase postoperative complications. On the other hand, the maintenance of normoglycemia and normothermia was associated with a decreased postoperative morbidity. The high volume of surgical procedures means that the adequacy of human, organizational and technological resources have a major impact on overall costs. PMID- 23099036 TI - [Winged scapula, a condition for the surgical area?]. AB - The winged scapula secondary to long thoracic nerve injury is an uncommon condition. It is most frequently reported in the literature associated with surgical activities, either due to poor positioning during anesthesia or by an iatrogenic traumatic event during surgical procedures. We expose 3 cases and a brief etiological and literature review, to present the multiple origins of this injury, which are not always related to this area of activity, as these are not the only causes of this injury. PMID- 23099038 TI - Features of unilateral hearing loss detected by newborn hearing screening programme in different regions of Turkey. AB - OBJECTIVE: Newborn hearing screening (NHS) works well for babies with bilateral hearing loss. However, for those with unilateral loss, it has yet to be established some standard rules like age of diagnose, risk factors, hearing loss degree. The aim of this study is to identify the demographic characteristics of newborns with unilateral hearing loss to obtain evidence based data in order to see what to be done for children with unilateral hearing loss (UHL). METHOD: Newborn hearing screening data of 123 babies with unilateral hearing loss, 71 (57.7%) male and 52 (42.3%) female, were investigated retrospectively. Data provided from the archives of six referral tertiary audiology centers from four regions in Turkey. Data, including type of hearing loss; age of diagnosis; prenatal, natal and postnatal risk factors; familial HL and parental consanguinity was analyzed in all regions and each of the Regions 1-4 separately. RESULT: The difference between data obtained in terms of gender and type of hearing loss was detected as statistically significant (p<0.05). While UHL was significantly higher in females at Region 1, and in males at other Regions of 2 4; SNHL was the most detected type of UHL in all regions with the rate of 82.9 100.0%. There were not significant differences between regions in terms of the degree of hearing loss, presence of risk factors, family history of hearing loss, age at diagnosis and parental consanguinity (p>0.05). Diagnosis procedure was completed mostly at 3-6 months in Region 4; whereas, in other regions (Regions 1 3), completion of procedure was delayed until 6 months-1 year. CONCLUSION: This study indicates that the effect of postnatal risk factors, i.e. curable hyperbilirubinemia, congenital infection and intensive care is relatively high on unilateral hearing loss, precautions should be taken regarding their prevention, as well as physicians and other health personnel should be trained in terms of these risks. For early and timely diagnosis, families will be informed about hearing loss and NHS programme; will be supported, including financial support of diagnosis process. By dissemination of the NHS programme to the total of country by high participation rate, risk factors can be determined better and measures can be increased. Additionally, further studies are needed with more comprehensive standard broad data for more evidence based consensus. PMID- 23099039 TI - Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS(r)) Society recommendations. AB - BACKGROUND: This review aims to present a consensus for optimal perioperative care in colonic surgery and to provide graded recommendations for items for an evidenced-based enhanced perioperative protocol. METHODS: Studies were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts. For each item of the perioperative treatment pathway, available English-language literature was examined, reviewed and graded. A consensus recommendation was reached after critical appraisal of the literature by the group. RESULTS: For most of the protocol items, recommendations are based on good-quality trials or meta-analyses of good-quality trials (quality of evidence and recommendations according to the GRADE system). CONCLUSIONS: Based on the evidence available for each item of the multimodal perioperative-care pathway, the Enhanced Recovery After Surgery (ERAS) Society, International Association for Surgical Metabolism and Nutrition (IASMEN) and European Society for Clinical Nutrition and Metabolism (ESPEN) present a comprehensive evidence based consensus review of perioperative care for colonic surgery. PMID- 23099040 TI - The neuroprotective effect of acute moderate alcohol consumption on caspase-3 mediated neuroapoptosis in traumatic brain injury: the role of lysosomal cathepsin L and nitric oxide. AB - Our aim in this study was to investigate the effect of moderate acute alcohol administration on cysteine protease mediated neuronal apoptosis and nitric oxide production in the traumatic brain injury. A total of 29 adult Sprague-Dawley male rats weighing 250-300 g were used. The rats were allocated into four groups. The first group was the control (sham-operated) group in which only a craniotomy was performed, the others were alcohol, trauma and trauma+alcohol groups. Caspase-3 enzyme activity in the trauma group increased significantly in comparison with the control group. The alcohol given group showed a decreased caspase-3 enzyme activity compared to the trauma group. The level of caspase-3 enzyme activity in the alcohol+trauma group decreased in comparison to the trauma group. SF/FEL ratio of cathepsin-L enzyme activity in the trauma group was significantly higher than in the control group. Our results indicate that moderate alcohol consumption may have protective effects on apoptotic cell death after traumatic brain injury. Protective effects of moderate ethanol consumption might be related to inhibition of lysosomal protease release and nitric oxide production. PMID- 23099041 TI - Safety and effectiveness of endovascular treatment after 6 hours of symptom onset in patients with anterior circulation ischemic stroke: a matched case control study. AB - BACKGROUND: Endovascular treatment within 6 hours of symptom onset appears to be beneficial in carefully selected patients with ischemic stroke. It is unclear whether endovascular treatment beyond 6 hours of symptom onset is safe and efficacious. METHODS: Over a 6-year period, 52 patients with acute ischemic stroke in the anterior circulation underwent emergent endovascular thrombolytic infusion and mechanical thrombectomy after 6 hours of symptom onset at 3 institutions. Their outcomes were compared to 52 placebo-treated patients matched by baseline National Institutes of Health Stroke Scale (NIHSS) score and nonlacunar anterior circulation location from the Trial of Org 10172 in Acute Stroke Treatment trial using a 1:1 ratio. Univariate and multivariate analyses were performed comparing the rates of symptomatic intracerebral hemorrhage, early neurologic improvement, favorable outcome at 7 days or discharge, and in-hospital mortality between the 2 groups. RESULTS: After adjustment for gender, time interval between symptom onset to treatment, hypertension, hyperlipidemia, and history of cigarette smoking, rates of neurologic improvement at 24 hours (odds ratio [OR] 1.15; 95% confidence interval [CI] 0.43-3.1) and favorable outcome at 7 days or discharge (OR 1.39; 95% CI 0.47-4.05) were similar in the 2 groups. No differences in the rates of symptomatic intracerebral hemorrhage or death were found after adjusting for potential confounders. In an analysis limited to only those patients who underwent computed tomographic perfusion or magnetic resonance imaging before receiving endovascular treatment, the rate of favorable outcome at 7 days or discharge was similar between patients who underwent endovascular treatment and control patients (35.7% v 32.1%; P = .77). CONCLUSIONS: We did not observe any evidence of benefit in halting neurologic worsening or improving outcomes among patients undergoing endovascular treatment for treatment of an anterior circulation ischemic stroke after 6 hours of symptom onset. Strong evidence of both the safety and efficacy of emergent endovascular treatment when administered to patients with stroke in the anterior circulation is needed. PMID- 23099042 TI - Retinal vascular fractal dimension is associated with cognitive dysfunction. AB - Fractal analysis is a method used to quantify the geometric branching complexity and density of retinal vessels. This study examined the relationship of retinal vascular fractal dimension and other retinal vascular parameters with cognitive dysfunction in an older Asian population. Subjects aged 60 years and older from the Singapore Malay Eye Study were selected for analysis. Retinal vascular fractal dimension (Df) and other quantitative retinal vascular parameters (branching angle, tortuosity, and caliber) were measured based on a standardized grading protocol from photographs of the retinal fundus using a computer-assisted program. Qualitative retinal signs were also assessed from photographs. Cognitive dysfunction was defined as a locally validated Abbreviated Mental Test (AMT) score <=6/10 in participants with 0-6 years of formal education and an AMT score <=8/10 in those with more than 6 years of formal education. Cognitive dysfunction was identified in 262 of the 1202 participants (21.8%). Decreased retinal vascular Df was significantly associated with lower AMT score (P = .019). In multivariate logistic regression analysis, participants with lower retinal vascular Df values were more likely to have cognitive dysfunction (odds ratio, 1.71; 95% confidence interval, 1.03-2.82, comparing the lowest and highest Df quintiles). In subgroup analysis stratified for cardiovascular risk factors, this association was present in participants with hypertension and current smokers. Other retinal vascular signs were not associated with cognitive dysfunction. Decreased retinal vascular Df is associated with cognitive dysfunction in older persons. Rarefaction of the retinal vasculature may reflect similar changes in the cerebral microvasculature that may contribute to cognitive deterioration. PMID- 23099043 TI - Reply: To PMID 22516428. PMID- 23099044 TI - Dermatomal sensory manifestations in lateral medullary infarction. AB - A 61-year-old man who experienced a sudden onset of unstable gait followed by nuchal pain was admitted to our department. The neurologic examination revealed right-sided limb ataxia, right partial ptosis, and decreased sensation to 50% of the normal side to pinprick and temperature stimuli on the left side below the level of the T-6 dermatome. A lateral medullary infarction caused by spontaneous vertebral artery dissection was diagnosed by magnetic resonance imaging and computed tomography angiography. In conclusion, lateral medullary infarction is an important entity to consider in the differential diagnosis of dermatomal sensory manifestations. PMID- 23099045 TI - Efficient recombinant protein production and secretion from nuclear transgenes in Chlamydomonas reinhardtii. AB - Microalgae are diverse photosynthetic microbes which offer the potential for production of a number of high value products (HVP) such as pigments, oils, and bio-active compounds. Fast growth rates, ease of photo-autotrophic cultivation, unique metabolic properties and continuing progress in algal transgenics have raised interest in the use of microalgae systems for recombinant protein (RP) production. This work demonstrates the development of an advanced RP production and secretion system for the green unicellular model alga Chlamydomonas reinhardtii. We generated a versatile expression vector that employs the secretion signal of the native extracellular C. reinhardtii carbonic anhydrase for efficient RP secretion into the culture medium. Unique restriction sites were placed between the regulatory elements to allow fast and easy sub-cloning of sequences of interest. Positive transformants can rapidly be identified by high throughput plate-level screens via a coupled Gaussia luciferase marker. The vector was tested in Chlamydomonas wild type CC-1883 (WT) and in the transgene expression transformant UVM4. Compared to the native secretion signal of the Gaussia luciferase, up to 84% higher RP production could be achieved. With this new expression system we could generate transformants that express up to 10 mg RP per liter culture without further optimization. The target RP is found exclusively in culture medium and can therefore easily be isolated and purified. We conclude that this new expression system will be a valuable tool for many heterologous protein expression applications from C. reinhardtii in the future. PMID- 23099046 TI - What is the best fixation target? The effect of target shape on stability of fixational eye movements. AB - People can direct their gaze at a visual target for extended periods of time. Yet, even during fixation the eyes make small, involuntary movements (e.g. tremor, drift, and microsaccades). This can be a problem during experiments that require stable fixation. The shape of a fixation target can be easily manipulated in the context of many experimental paradigms. Thus, from a purely methodological point of view, it would be good to know if there was a particular shape of a fixation target that minimizes involuntary eye movements during fixation, because this shape could then be used in experiments that require stable fixation. Based on this methodological motivation, the current experiments tested if the shape of a fixation target can be used to reduce eye movements during fixation. In two separate experiments subjects directed their gaze at a fixation target for 17s on each trial. The shape of the fixation target varied from trial to trial and was drawn from a set of seven shapes, the use of which has been frequently reported in the literature. To determine stability of fixation we computed spatial dispersion and microsaccade rate. We found that only a target shape which looks like a combination of bulls eye and cross hair resulted in combined low dispersion and microsaccade rate. We recommend the combination of bulls eye and cross hair as fixation target shape for experiments that require stable fixation. PMID- 23099047 TI - Both memory and attention systems contribute to visual search for targets cued by implicitly learned context. AB - Environmental context learned without awareness can facilitate visual processing of goal-relevant information. According to one view, the benefit of implicitly learned context relies on the neural systems involved in spatial attention and hippocampus-mediated memory. While this view has received empirical support, it contradicts traditional models of hippocampal function. The purpose of the present work was to clarify the influence of spatial context on visual search performance and on brain structures involved memory and attention. Event-related functional magnetic resonance imaging revealed that activity in the hippocampus as well as in visual and parietal cortex was modulated by learned visual context even though participants' subjective reports and performance on a post-experiment recognition task indicated no explicit knowledge of the learned context. Moreover, the magnitude of the initial selective hippocampus response predicted the magnitude of the behavioral benefit due to context observed at the end of the experiment. The results suggest that implicit contextual learning is mediated by attention and memory and that these systems interact to support search of our environment. PMID- 23099048 TI - The effects of distractors and spatial precues on covert visual search in macaque. AB - Covert visual search has been studied extensively in humans, and has been used as a tool for understanding visual attention and cueing effects. In contrast, much less is known about covert search performance in monkeys, despite the fact that much of our understanding of the neural mechanisms of attention is based on these animals. In this study, we characterize the covert visual search performance of monkeys by training them to discriminate the orientation of a briefly-presented, peripheral Landolt-C target embedded within an array of distractor stimuli while maintaining fixation. We found that target discrimination performance declined steeply as the number of distractors increased when the target and distractors were of the same color, but not when the target was an odd color (color pop-out). Performance was also strongly affected by peripheral spatial precues presented before target onset, with better performance seen when the precue coincided with the target location (valid precue) than when it did not (invalid precue). Moreover, the effectiveness of valid precues was greatest when the delay between precue and target was short (~80-100 ms), and gradually declined with longer delays, consistent with a transient component to the cueing effect. Discrimination performance was also significantly affected by prior knowledge of the target location in the absence of explicit visual precues. These results demonstrate that covert visual search performance in macaques is very similar to that of humans, indicating that the macaque provides an appropriate model for understanding the neural mechanisms of covert search. PMID- 23099049 TI - Analysis of KIF17 distal tip trafficking in zebrafish cone photoreceptors. AB - Multiple proteins are targeted to photoreceptor outer segments (OSs) where they function in phototransduction. Intraflagellar transport (IFT), a highly conserved bidirectional transport pathway occurring along the microtubules of the ciliary axoneme has been implicated in OS trafficking. The canonical anterograde motor for IFT is the heterotrimeric kinesin II or KIF3 complex. Previous work from our laboratory has demonstrated a role for an additional kinesin 2 family motor, the homodimeric KIF17. To gain a better understanding of KIF17 function in photoreceptor OS we utilized transgenic zebrafish expressing zfKIF17-GFP to assess the localization and dynamics of zfKIF17. Our data indicate that both endogenous KIF17 and KIF17-GFP are associated with the axoneme of zebrafish cones at both early (5dpf) and late (21 dfp) stages of development. Strikingly, KIF17 GFP accumulates at the OS distal tip in a phenomenon referred to as "tipping". Tipping occurs in the large majority of photoreceptors and also occurs when mammalian KIF17-mCherry is expressed in ciliated epithelial cells in culture. In some cases KIF17-GFP is shed with the OS tip as part of the disc shedding process. We have also found that KIF17-GFP moves within the OS at rates consistent with those observed for IFT and other kinesins. PMID- 23099050 TI - Reproductive health awareness among educated young women in Egypt. AB - OBJECTIVE: To assess the awareness of female Egyptian university students regarding reproductive health (RH) issues, and determine the factors contributing to the students' awareness. METHODS: A cross-sectional survey was conducted, in which 220 female Egyptian university students selected by purposive random sampling were interviewed by means of an in-depth questionnaire. The interviews were private and confidential, and the questions concerned female reproductive anatomy and physiology; sexually transmitted diseases and HIV/AIDS; personal preferences, such as age of marriage and spacing between pregnancies; and where young women can access RH care. RESULTS: A large proportion of the participants exhibited misunderstanding or a complete lack of knowledge about important RH issues. This overall result, which was determined to be attributable to age and sociocultural factors such as education level, comes as a source of concern for both health service providers and policy makers. CONCLUSION: Awareness of RH is poor in Egypt, even among young women attending institutions of higher education. The present study not only highlights the persistent need for the ongoing RH information programs, but may also provide policy makers with data that will inform new strategies. PMID- 23099051 TI - Recovery from left ventricular dysfunction after ablation of frequent premature ventricular complexes. AB - BACKGROUND: Patients with frequent premature ventricular complexes (PVCs) and PVC induced cardiomyopathy usually have recovery of left ventricular (LV) dysfunction postablation. The time course of recovery of LV function has not been described. OBJECTIVE: To describe the time course and predictors of recovery from LV dysfunction after effective ablation of PVCs in patients with PVC-induced cardiomyopathy. METHODS: In a consecutive series of 264 patients with frequent idiopathic PVCs referred for PVC ablation, LV dysfunction was present in 87 patients (mean ejection fraction 40%+/-10%). The PVC burden was reduced to<20% of the initial PVC burden in 75 patients. In these patients, echocardiography was repeated 3-4 months postablation. If LV function did not normalize after 3-4 months, a repeat echocardiogram was performed every 3 months until there was normalization or stabilization of LV function. RESULTS: The ejection fraction normalized at a mean of 5+/-6 months postablation. The majority of patients (51 of 75, 68%) with PVC-induced LV dysfunction had a recovery of LV function within 4 months. In 24 (32%) patients, recovery of LV function took more than 4 months (mean 12+/-9 months; range 5-45 months). An epicardial origin of PVCs was more often present (13 of 24, 54%) in patients with delayed recovery of LV function than in patients with early recovery of LV function (2 of 51, 4%; P<.0001). The PVC-QRS width was significantly longer in patients with delayed recovery than in patients with recovery within 4 months (170+/-21 ms vs 159+/-16 ms; P = .02). In multivariate analysis, only an epicardial PVC origin was predictive of delayed recovery of LV function in patients with PVC-induced cardiomyopathy. CONCLUSIONS: PVC-induced cardiomyopathy resolves within 4 months of successful ablation in most patients. In about one-third of the patients, recovery is delayed and can take up to 45 months. An epicardial origin predicts delayed recovery of LV function. PMID- 23099052 TI - Heterogeneous interactome between Litopenaeus vannamei plasma proteins and Vibrio parahaemolyticus outer membrane proteins. AB - A great loss has been suffered by microbial infectious diseases under intensive shrimp farming in recent years. In this background, the understanding of shrimp innate immunity becomes an importantly scientific issue, but little is known about the heterogeneous protein-protein interaction between pathogenic cells and hosts, which is a key step for the invading microbes to infect internet organs through bloodstream. In the present study, bacterial outer membrane (OM) protein array and pull-down approaches are used to isolate both Vibrio parahaemolyticus OM proteins that bind to shrimp serum proteins and the shrimp serum proteins that interact with bacterial cells, respectively. Three interacting shrimp serum proteins, hemocyanin, beta-1,3-glucan binding protein and LV_HP_RA36F08r and thirty interacting OM proteins were determined. They form 63 heterogeneous protein-protein interactions. Nine out of the 30 OM proteins were randomly demonstrated to be up-regulated or down-regulated when bacterial cells were cultured with shrimp sera, indicating the biological significance of the network. The interesting findings uncover the complexity of struggle between host immunity and bacterial infection. Compared with our previous report on heterogeneous interactome between fish grill and bacterial OM proteins, the present study further extends the investigation from lower vertebrates to invertebrates and develops a bacterial OM protein array to identify the OM proteins bound with shrimp serum proteins, which elevates the frequencies of the bound OM proteins. Our results highlight the way to determine and understand the heterogeneous interaction between hosts and microbes. PMID- 23099053 TI - Early ghrelin treatment attenuates disruption of the blood brain barrier and apoptosis after traumatic brain injury through a UCP-2 mechanism. AB - Ghrelin has been shown to be anti-inflammatory and neuroprotective in models of neurologic injury. We hypothesize that treatment with ghrelin will attenuate breakdown of the blood brain barrier (BBB) and apoptosis 24h following traumatic brain injury (TBI). We believe this protection is at least in part mediated by up regulation of UCP-2, thereby stabilizing mitochondria and preventing up regulation of caspase-3. A weight drop model was used to create severe TBI. Balb/c mice were divided into 3 groups. Sham: no TBI or ghrelin treatment; TBI: TBI only; TBI/ghrelin: 20MUg (IP) ghrelin at the time of TBI. BBB permeability to 70kDa FITC-Dextran was measured 24h following injury and quantified in arbitrary integrated fluorescence (afu). Brain tissue was subjected to TUNEL staining and TUNEL positive cells were quantified. Immunohistochemistry was performed on injured tissue to reveal patterns of caspase-3 and UCP-2 expression. TBI increased cerebral vascular permeability by three-fold compared to sham. Ghrelin treatment restored vascular permeability to the level of shams. TUNEL staining showed that ghrelin mitigated the significant increase in apoptosis that follows TBI. TBI increased both caspase-3 compared to sham. Treatment with ghrelin significantly increased UCP-2 compared to TBI alone and this increase in UCP-2 expression was associated with a decrease in expression of caspase-3. Early ghrelin treatment prevents TBI induced BBB disruption and TBI mediated apoptosis 24h following injury. These results demonstrate the neuroprotective potential of ghrelin as a therapy in TBI. PMID- 23099054 TI - Piperine potentiates the protective effects of curcumin against chronic unpredictable stress-induced cognitive impairment and oxidative damage in mice. AB - Life event stressors are the major vulnerability factors for the development of cognitive disorders. A vital therapeutic for stress related disorders is curcumin, derived from curry spice turmeric. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co administration with piperine against chronic unpredictable stress (CUS)-induced cognitive impairment and oxidative stress in mice. Male Laca mice were subjected to undergo a battery of stressors for a period of 28 days. Vehicle/drugs were administered daily 30mins before CUS procedure. Chronic stress significantly impaired memory performance (delayed latency time to reach platform in Morris water maze as well as to reach closed arm in elevated plus maze test) and decreased locomotor activity along with sucrose consumption. Further, there was a significant impairment in oxidative parameters (elevated malondialdehyde, nitrite concentration and decreased reduced glutathione, catalase levels) and mitochondrial enzyme complex activities, along with raised acetylcholinesterase and serum corticosterone levels. Chronic treatment with curcumin (200 and 400mg/kg, p.o.) significantly improved these behavioral and biochemical alterations, restored mitochondrial enzyme complex activities and attenuated increased acetylcholinesterase and serum corticosterone levels. In addition, co administration of piperine (20mg/kg; p.o.) with curcumin (100 and 200mg/kg, p.o.) significantly elevated the protective effect as compared to their effects alone. The results clearly suggest that piperine enhanced the bioavailability of curcumin and potentiated its protective effects against CUS induced cognitive impairment and associated oxidative damage in mice. PMID- 23099055 TI - NGP1-01, a multi-targeted polycyclic cage amine, attenuates brain endothelial cell death in iron overload conditions. AB - Development and progression of neurodegenerative disorders have, amongst other potential causes, been attributed to a disruption of iron regulatory mechanisms and iron accumulation. Excess extracellular iron may enter cells via nontraditional routes such as voltage-gated calcium channels and N-methyl-d aspartate (NMDA) receptors leading to intracellular oxidative damage and ultimately mitochondrial failure. Nimodipine, an L-type calcium channel blocker has been shown to reduce iron-induced toxicity in neuronal and brain endothelial cells. Our current study investigates NGP1-01, a multimodal drug acting as an antagonist at both the NMDA receptor and the L-type calcium channel. Our previous studies support NGP1-01 as a promising neuroprotective agent in diseases involving calcium-related excitotoxicity. We demonstrate here that NGP1-01 (1 and 10MUM) pretreatment abrogates the effects of iron overload in brain endothelial cells protecting cellular viability. Both concentrations of NGP1-01 were found to attenuate iron-induced reduction in cellular viability to a similar extent, and were statistically significant. To further verify the mechanism, the L-type calcium channel agonist FPL 64176 was administered to promote iron uptake. Addition of NGP1-01 dose-dependently reduced FPL 64176 stimulated uptake of iron. These data support further evaluation of NGP1-01 as a neuroprotective agent, not only in diseases associated with excitotoxicity, but also in those of iron overload. PMID- 23099056 TI - Simple one-step ultrasonic synthesis of anatase titania/polypyrrole nanocomposites. AB - In this work, hybrid nanocomposites based on anatase titania:polypyrrole (TiO(2):PPy) were directly obtained from a simple, one-step, ultrasonic (UT) assisted synthesis. The properties of these crystalline nanocomposites were compared with those of others fabricated using cold (Cold)-assisted synthesis without any UT assistance, which required a hydrothermal treatment (HT) to yield crystalline anatase titania in the nanocomposite (TiO(2):PPy) at low temperature (130 degrees C) and in a short time (3h). The SEM results demonstrated that the UT-assisted synthesis is a feasible method to obtain anatase TiO(2):PPy nanocomposites with controlled morphology using low energy. The Fourier transform infrared (FT-IR) bands of the crystalline nanocomposites exhibited a shift with respect to neat components, which was attributed to the strong interaction between the secondary amine groups (N-H) of PPy and the oxygen from TiO(2). The acceptable absorption in the visible region (lambda(max)=670nm) indicates that these nanocomposites are good candidates for harvesting energy in solar cells. Devices based on these nanocomposites were built to evaluate their electrical properties. An increase in the photocurrent was observed for the devices prepared with the nanocomposites from the UT-assisted synthesis. PMID- 23099058 TI - Granzyme B in injury, inflammation, and repair. AB - Fragile skin and susceptibility to skin tearing are major problems among the elderly and can be complicated further by impaired wound healing. Non-healing wounds fail to progress through the normal stages of healing and enter a state of chronic inflammation featuring increased proteolytic activity. Increased expression of the serine protease granzyme B is observed during prolonged inflammation and is implicated in the pathogenesis of several chronic inflammatory diseases. Although its role in cytotoxic lymphocyte-mediated apoptosis is well established, granzyme B can also degrade extracellular matrix proteins and alter inflammation if present in the extracellular milieu. The present review focuses on the emerging evidence for the involvement of granzyme B in chronic inflammation, impaired wound healing, and age-related skin fragility. PMID- 23099059 TI - Default-mode network dysfunction and self-referential processing in healthy siblings of schizophrenia patients. AB - The default-mode network (DMN) of the brain shows highly coherent intrinsic activity in healthy subjects and is implicated in self-referential processing important for social cognitive functioning. Schizophrenia patients show abnormal resting-state connectivity within the DMN and this aberrant connectivity is thought to contribute to difficulties in self-referential and introspective processing. Subjects at increased genetic risk of developing schizophrenia, including unaffected siblings of patients, also exhibit brain abnormalities and impaired social cognitive processing. However, it is unclear whether resting state connectivity within the DMN is abnormal in these subjects. Here, we investigate resting-state DMN connectivity in siblings and whether this is related to the functioning of the network during self-referential processing. Brain activity was measured using functional MRI in 25 unaffected siblings of patients with schizophrenia and 25 healthy controls during an 8-minute resting state period and during a self-referential processing task in which the subjects had to indicate whether a trait adjective (e.g. "lazy") described their personality (self-referential condition) or whether the trait was socially desirable (non-referential condition). Compared with controls, siblings showed exaggerated connectivity during resting-state between the midline areas of the DMN. Moreover, they failed to adequately modulate connectivity between these areas during self-referential processing. No abnormalities in activation during self-referential processing were observed. These findings suggest that subjects at increased genetic risk of developing schizophrenia exhibit abnormal intrinsic connectivity within the midline DMN and that this is associated with aberrant interactions between these regions during self-referential processing. PMID- 23099060 TI - A preliminary, randomized, double-blind, placebo-controlled trial of L-carnosine to improve cognition in schizophrenia. AB - BACKGROUND: Targeting glutamatergic dysfunction provides an exciting opportunity to improve cognitive impairment in schizophrenia. One treatment approach has targeted inadequate antioxidant defenses at glutamatergic synapses. Animal and human data suggest NMDA antagonists worsen executive cognitive controls--e.g. increase perseverative responses and impair set-shifting. We conducted a preliminary study to test the hypothesis that L-carnosine, an antioxidant and anti-glycation agent which is co-localized and released with glutamate would improve executive dysfunction, a cognitive domain associated with glutamate. METHODS: Seventy-five symptomatically stable adults with chronic schizophrenia were randomly assigned to L-carnosine as adjunctive treatment (2 g/day) or a matched placebo in a double-blind manner for 3 months. Cognitive domains (executive dysfunction, memory, attention and motor speed) were assessed using a computerized battery at baseline, 4 and 12 weeks, along with psychopathology ratings and safety parameters. RESULTS: The L-carnosine group performed significantly faster on non-reversal condition trials of the set-shifting test compared with placebo but reversal reaction times and errors were not significantly different between treatments. On the strategic target detection test, the L-carnosine group displayed significantly improved strategic efficiency and made fewer perseverative errors compared with placebo. Other cognitive tests showed no significant differences between treatments. Psychopathology scores remained stable. The carnosine group reported more adverse events (30%) compared with the placebo group (14%). Laboratory indices remained within acceptable ranges. CONCLUSIONS: These preliminary findings suggest that L-carnosine merits further consideration as adjunctive treatment to improve executive dysfunction in persons with schizophrenia. PMID- 23099061 TI - Long-term in vivo biodistribution and toxicity of Gd(OH)3 nanorods. AB - The long-term retention of nanomaterials in the body is one of the biggest concerns about the safety of these materials for in vivo application. So, it is important to develop some nanomaterials which can be relatively more easily excreted. Rare earth hydroxide, that can be degraded under acidic condition in vivo, is one of the suitable candidates. Herein, Gd(OH)(3) nanorods, which are considered as magnetic resonance imaging (MRI) contrast agents, have been synthesized to evaluate their excretion process and potential toxicity. The long term in vivo biodistribution of the materials was investigated using single photon emission computed tomography (SPECT) imaging with (153)Sm-doped Gd(OH)(3) nanorods as probes. Biodistribution results showed that the uptake and retention of the Gd(OH)(3) nanorods took place primarily in the liver, spleen and lung. Then, most of the nanorods were excreted from the bodies of mice very rapidly. Body weight data for the mice indicated that, when intravenously injected with 100 mg/kg of the nanorods, the mice survived for 150 days without any apparent adverse effects to their health. In addition, histological, hematological and biochemical analysis indicated that these nanorods have no overt toxicity. PMID- 23099063 TI - Tumor suppression via paclitaxel-loaded drug carriers that target inflammation marker upregulated in tumor vasculature and macrophages. AB - Clinically approved chemotherapeutic nanoparticles may provide advantages over free drugs by achieving slower clearance and preferential accumulation in tumors. However, the lack of leaky vasculatures can create barriers to the permeation of ~100 nm-sized nanoparticles in solid tumors. We hypothesized that nanoparticles designed to target both tumor and tumor stroma would penetrate deeper into the tumors. To construct such comprehensive drug carriers, we utilized cross-linked amphiphilic polymer nanoparticles and functionalized them to target ICAM-1, a biomarker prevalent in various tumors and inflamed tumor stroma. The targeting moiety was derived from the modular domain present in alpha(L) integrin, which was engineered for high affinity and cross-reactivity with human and murine ICAM 1. ICAM-1-selective delivery of paclitaxel produced potent tumor suppression of not only ICAM-1-positive cervical cancer cells but also ICAM-1-negative tumors, presumably by causing cytotoxicity in tumor-associated endothelium (CD31(+)) and macrophages (CD68(+)) over-expressing ICAM-1. Contrary to the strategies of targeting only the tumor or specific tumor stromal constituents, we present a strategy in delivering therapeutics to the major cellular components of solid tumors. Drug carriers against inflammation-biomarkers may be effective against many different types of tumors, while being less susceptible to the highly mutable nature of tumor markers. PMID- 23099062 TI - Bone regeneration with low dose BMP-2 amplified by biomimetic supramolecular nanofibers within collagen scaffolds. AB - Bone morphogenetic protein-2 (BMP-2) is a potent osteoinductive cytokine that plays a critical role during bone regeneration and repair. In the extracellular environment, sulfated polysaccharides anchored covalently to glycoproteins such as syndecan and also non-covalently to fibronectin fibers have been shown to bind BMP-2 through a heparin-binding domain and regulate its bioactivity. We report here on a synthetic biomimetic strategy that emulates biological BMP-2 signaling through the use of peptide amphiphile nanofibers designed to bind heparin. The supramolecular nanofibers, which integrate the biological role of syndecan and fibronectin, were allowed to form gel networks within the pores of an absorbable collagen scaffold by simply infiltrating dilute solutions of the peptide amphiphile, heparan sulfate, and BMP-2. The hybrid biomaterial enhanced significantly bone regeneration in a rat critical-size femoral defect model using BMP-2 amounts that are one order of magnitude lower than required for healing in this animal model. Using micro-computed tomography, we also showed that the hybrid scaffold was more effective at bridging within the gap relative to a conventional scaffold of the type used clinically based on collagen and BMP-2. Histological evaluation also revealed the presence of more mature bone in the new ossified tissue when the low dose of BMP-2 was delivered using the biomimetic supramolecular system. These results demonstrate how molecularly designed materials that mimic features of the extracellular environment can amplify the regenerative capacity of growth factors. PMID- 23099064 TI - Directing cell migration in continuous microchannels by topographical amplification of natural directional persistence. AB - Discrete micropatterns on biomaterial surfaces can be used to guide the direction of mammalian cell movement by orienting cell morphology. However, guiding cell assembly in three-dimensional scaffolds remains a challenge. Here we demonstrate that the random motions of motile cells can be rectified within continuous microchannels without chemotactic gradients or fluid flow. Our results show that uniform width microchannels with an overhanging zigzag design can induce polarization of NIH3T3 fibroblasts and human umbilical vein endothelial cells by expanding the cell front at each turn. These continuous zigzag microchannels can guide the direction of cell movement even for cells with altered intracellular signals that promote random movement. This approach for directing cell migration within microchannels has important potential implications in the design of scaffolds for tissue engineering. PMID- 23099065 TI - Mammalian cell-adhesion kinetics measured by suspension depletion. AB - Mammalian cell-adhesion kinetics is measured by counting the number of cells lost from suspension due to adhesion to planar or particulate substrata as a function of time rather than by the counting of adherent cells that is widely applied in the literature. A simple statistical model shows that this "suspension-depletion" method is most accurate at low cell counts in the critical early stage of cell adhesion that is diagnostic of forces in close proximity between cell and substratum responsible for cell adhesion. Furthermore, suspension depletion avoids experimental artifacts associated with substratum rinsing and the removal of cells from the substratum using enzymatic and/or mechanical methods. Experimental method is demonstrated for three different cell types (MDCK, epithelioid; MC3T3-E1, pre-osteoblast; MDA-MB-231, human breast tumor) adhering to seven different substrata incrementally sampling the observable water wettability range in Petri-dish format, as well as MDCK adhesion to particulate carriers in stirred suspension. Suspension depletion is ideal for biocompatibility and fouling studies where quantification of "low-and-slow" cell adhesion is important. In particular, it is shown that a typical method of counting adherent cells does not correctly measure adhesion kinetics to hydrophobic surfaces that are generally resistant to mammalian cell adhesion. PMID- 23099066 TI - Thermostats: modeling non-equilibrium dynamics: comment on "Thermostatted kinetic equations as models for complex systems in physics and life sciences" by Carlo Bianca. PMID- 23099067 TI - [Unsuspected bronchial carcinoid tumor detected in a somatostatin receptor scintigraphy in a patient with multiple endocrine neoplasia syndrome type 1 and hypergastrinemia]. AB - Multiple Endocrine Neoplasia type 1 syndrome (MEN1) is characterized by the presence of tumors in parathyroid glands, anterior pituitary gland, endocrine pancreas and duodenum. However, other tumors may also occur. One of them is the carcinoid tumor, which in this context, is more common in the gastrointestinal tract. Less common is the presence of carcinoid tumors of bronchial origin, which with histologic confirmation, may occur in 5-8% of cases and that appears more frequently in patients with hypergastrinemia. We report a patient with MEN1 syndrome, hypergastrinemia and an incidental finding in a somatostatin receptor scintigraphy of an unsuspected bronchial carcinoid tumor that was confirmed histologically. PMID- 23099068 TI - [Atypical localization of urinoma detected by renogram in a kidney transplanted patient with scrotal edema]. PMID- 23099069 TI - Pneumococcal infections and adult with risk factors. AB - Streptococcus pneumoniae is an important bacterium in humans, and is a cause of upper and lower respiratory tract infections, meningitis, bacteremia, and/or invasive infections. An analysis of literature allows identifying the main risk factors; spleen dysfunctions, sickle cell anemia, alcohol abuse, chronic liver disease, cirrhosis, ischemic cardiac diseases, congestive cardiac failure, diabetes mellitus, obesity, chronic lung disease, immunodeficient patients including HIV infection, and old age. S. pneumoniae infections are more frequent and more severe in these patients. The pathophysiological mechanisms involved may be associated. These populations at risk should receive anti-pneumococcal vaccination. The availability of a 13 valent conjugate vaccine for adult opens new perspectives, but its clinical effectiveness needs to be proved for these patients at risk. PMID- 23099070 TI - Retraction and the "de-discovery" of XMRV. PMID- 23099071 TI - GAIN Act legislation: is it enough? PMID- 23099073 TI - Urine antigen test for diagnosis of HIV-associated tuberculosis. PMID- 23099074 TI - Urine antigen test for diagnosis of HIV-associated tuberculosis. PMID- 23099076 TI - Tests for latent tuberculosis infection and isoniazid preventive therapy. PMID- 23099077 TI - US visa law: a clarification. PMID- 23099078 TI - Hand hygiene does work. PMID- 23099079 TI - Counterfeit antimalarial drugs. PMID- 23099080 TI - Universal access to quality medicines: prioritisation of a-priori solutions. PMID- 23099081 TI - Cystic echinococcosis in sub-Saharan Africa. AB - Cystic echinococcosis is regarded as endemic in sub-Saharan Africa; however, for most countries only scarce data, if any, exist. For most of the continent, information about burden of disease is not available; neither are data for the animal hosts involved in the lifecycle of the parasite, thus making introduction of preventive measures difficult. Available evidence suggests that several species or strains within the Echinococcus granulosus complex are prevalent in sub-Saharan Africa and that these strains might be associated with varying virulence and host preference. Treatment strategies (chemotherapy, percutaneous radiological techniques, but mainly surgery) predominantly target active disease. Prevention strategies encompass anthelmintic treatment of dogs, slaughter hygiene, surveillance, and health-educational measures. Existing data are suggestive of unusual clinical presentations of cystic echinococcosis in some parts of the continent, for which the causes are speculative. PMID- 23099082 TI - Klebsiella pneumoniae liver abscess: a new invasive syndrome. AB - Klebsiella pneumoniae is a well known human nosocomial pathogen. Most community acquired K pneumoniae infections cause pneumonia or urinary tract infections. During the past two decades, however, a distinct invasive syndrome that causes liver abscesses has been increasingly reported in Asia, and this syndrome is emerging as a global disease. In this Review, we summarise the clinical presentation and management as well the microbiological aspects of this invasive disease. Diabetes mellitus and two specific capsular types in the bacterium predispose a patient to the development of liver abscesses and the following metastatic complications: bacteraemia, meningitis, endophthalmitis, and necrotising fasciitis. For patients with this invasive syndrome, appropriate antimicrobial treatment combined with percutaneous drainage of liver abscesses increases their chances of survival. Rapid detection of the hypervirulent strain that causes this syndrome allows earlier diagnosis and treatment, thus minimising the occurrence of sequelae and improving clinical outcomes. PMID- 23099084 TI - Elevation of intracellular Zn2+ level by nanomolar concentrations of triclocarban in rat thymocytes. AB - It was recently reported that nanomolar concentrations of triclocarban, an antimicrobial agent, were detected in human blood after the use of soap containing triclocarban. Due to the widespread use of triclocarban in adult and infant personal care products, the report prompted us to study its cytotoxicity. The cytotoxicity of triclocarban was examined in rat thymocytes by using a cytometric technique with propidium iodide for examining cell lethality, FluoZin 3-AM for monitoring the intracellular Zn(2+) level, and 5 chloromethylfluorescencein diacetate for estimating the cellular content of non protein thiol. The incubation with triclocarban at nanomolar concentrations (50 500nM) for 1h did not affect cell lethality but significantly elevated the intracellular Zn(2+) level. The elevation of the intracellular Zn(2+) level by triclocarban was not significantly dependent on external Zn(2+) level. There was a negative correlation (r=-0.9225) between the effect on the intracellular Zn(2+) level and that on the cellular content of non-protein thiol. These results suggest that nanomolar concentrations of triclocarban decrease the cellular content of non-protein thiol, leading to intracellular Zn(2+) release. Since zinc plays physiological roles in mammalian cells, the percutaneous absorption of triclocarban from soap may, therefore, affect some cellular functions. PMID- 23099083 TI - Mitigating the threat of artemisinin resistance in Africa: improvement of drug resistance surveillance and response systems. AB - Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia and has been detected in western Thailand. The situation is ominously reminiscent of the emergence of resistance to chloroquine and to sulfadoxine pyrimethamine several decades ago. Artemisinin resistance is a major threat to global public health, with the most severe potential effects in sub-Saharan Africa, where the disease burden is highest and systems for monitoring and containment of resistance are inadequate. The mechanisms that underlie artemisinin resistance are not fully understood. The main phenotypic trait associated with resistance is a substantial delay in parasite clearance, so far reported in southeast Asia but not in Africa. One of the pillars of the WHO global plan for artemisinin resistance containment is to increase monitoring and surveillance. In this Personal View, we propose strategies that should be adopted by malaria-endemic countries in Africa: resource mobilisation to reactivate regional surveillance networks, establishment of baseline parasite clearance profiles to serve as benchmarks to track emerging artemisinin resistance, improved data sharing to allow pooled analyses to identify rare events, modelling of risk factors for drug resistance, and development and validation of new approaches to monitor resistance. PMID- 23099085 TI - Monoclonal antibodies to mouse butyrylcholinesterase. AB - Our immunization strategy introduced recombinant mouse butyrylcholinesterase (BChE) to naive BChE knockout mice. An extraordinarily strong immune reaction gave rise to a whole spectrum of antibodies with different properties. Two selective and highly efficient monoclonal anti-mouse BChE antibodies 4H1 (IgG1) and 4 C9 (IgG2a), with Kd values in the nanomolar range were generated. ELISA detected BChE in as little as 20-50 nl of mouse plasma using 2 MUg (4H1) or 4 MUg (4C9). Both antibodies cross-reacted with BChE in dog plasma but only 4 H1 reacted with rat BChE, suggesting that the antibodies are targeted towards different epitopes. Surprisingly, neither recognized human BChE. The anti-mouse BChE antibodies were used in immunohistochemistry analysis of mouse muscle where they specifically stained the neuromuscular junction. The antibodies enable visualization of the BChE protein in the mouse tissue, thus complementing activity assays. They can be used to study a long-lasting question about the existence of mixed acetylcholinesterase/BChE oligomers in mouse tissues. Moreover, monoclonal anti-mouse BChE antibodies can provide a simple, fast and efficient way to purify mouse BChE from small amounts of starting material by using a single-step immunomagnetic bead-based protocol. PMID- 23099086 TI - Progressive aggregation of Tomato yellow leaf curl virus coat protein in systemically infected tomato plants, susceptible and resistant to the virus. AB - Tomato yellow leaf curl virus (TYLCV) coat protein (CP) accumulated in tomato leaves during infection. The CP was immuno-detected in the phloem associated cells. At the early stages of infection, punctate signals were detected in the cytoplasm, while in the later stages aggregates of increasing size were localized in cytoplasm and nuclei. Sedimentation of protein extracts through sucrose gradients confirmed that progress of infection was accompanied by the formation of CP aggregates of increasing size. Genomic ssDNA was found in the cytoplasm and in the nucleus, while the dsDNA replicative form was exclusively associated with the nucleus. CP-DNA complexes were detected by immuno-capture PCR in nuclear and cytoplasmic large aggregates. Nuclear aggregates contained infectious particles transmissible to test plants by whiteflies. In contrast to susceptible tomatoes, the formation of large CP aggregates in resistant plants was delayed. By experimentally changing the level of resistance/susceptibility of plants, we showed that maintenance of midsized CP aggregates was associated with resistance, while large aggregates where characteristic of susceptibility. We propose that sequestering of virus CP into midsized aggregates and retarding the formation of large insoluble aggregates containing infectious particles is part of the response of resistant plants to TYLCV. PMID- 23099087 TI - Elements in HIV-1 Gag contributing to virus particle assembly. AB - The Gag polyprotein is the building block of retroviral particles and its expression is sufficient for assembly in cells. In HIV-1, nucleic acid (NA) is required for recombinant Gag molecules to assemble in a defined system in vitro. Experiments performed by Barklis and co-workers suggested that NA contributes to assembly by promoting Gag oligomerization. Gag is composed of four main domains: the matrix (MA), capsid (CA), nucleocapsid (NC), and p6 domains. We have recently shown that the SP1 linker, which lies between the CA and NC domains, assumes a helical structure at high, but not low, concentrations. We suggested that Gag oligomerization mediates assembly via an SP1-dependent conformational switch that exposes new interfaces for assembly. Although NA is required for assembly in vitro, deletion of NC, the main RNA-binding domain, does not eliminate particle formation in vivo; these particles lack NA. We hypothesized that alternative pathways that lead to Gag oligomerization or an increase in local Gag concentration, namely Gag-membrane or inter-protein interactions, rescue assembly in the absence of NC-RNA binding. We constructed mutants in which either Gag membrane binding, the Gag dimer interface, or NC-RNA binding are disrupted. None of these mutants disables assembly. However, combined mutations in any two of these three classes render Gag completely unable to form virus-like particles. Thus, it seems, Gag utilizes at least three types of interactions to form oligomers and any two out of the three are sufficient for assembly. PMID- 23099088 TI - Toxoplasma gondii abortion storm in sheep on a Texas farm and isolation of mouse virulent atypical genotype T. gondii from an aborted lamb from a chronically infected ewe. AB - Sheep are commonly infected with the protozoan parasite, Toxoplasma gondii. Infection may cause early embryonic death and resorption, fetal death and mummification, abortion, stillbirth, and neonatal death. Most sheep acquire T. gondii infection after birth. Recent studies reported that congenital ovine transmission of T. gondii may be more common than previously believed, but these findings are solely based on PCR data and require confirmation using other techniques to verify the findings. In the present study, during the lambing season of 2005 a toxoplasmosis abortion storm occurred in a flock of purebred Suffolk ewes on a farm in Texas. Only 14 healthy lambs were born, and 38 abortuses, mummies and weak or stillborn lambs were delivered. Another 15 fetuses identified by ultrasound were presumably resorbed or were aborted undetected. Antibodies to T. gondii were found in 37 (94.8%) of the 39 ewes and 30 of them had high titers (1:3200 or higher) when tested in the modified agglutination test (MAT). In the 2006 lambing season, two (both with MAT titers of >= 3200 in 2005) of 26 ewes delivered T. gondii infected lambs. T. gondii tissue cysts were found histologically in lesions of encephalitis in a lamb from one ewe and viable T. gondii (designated TgShUs55) was isolated from the brain and heart of a lamb from the second ewe. TheTgShUs55 had an atypical genotype using 10 PCR-RFLP markers, and was 100% lethal for Swiss Webster mice, irrespective of the dose or the stage of the parasite inoculated. In subsequent seasons, the ewes lambed normally. The results of the present study support the hypothesis that most sheep that have aborted due to T. gondii develop protection against future toxoplasmosis induced abortion, but the protection is not absolute. PMID- 23099089 TI - Serological and molecular detection of Theileria equi infection in horses in Hungary. AB - The prevalence of Theileria equi infection was studied in 324 healthy horses from 27 farms in Hungary with cELISA and IFAT and the blood samples of 101 horses selected randomly were also examined by PCR. The results indicate that there are many stud farms where one or more horses are infected with T. equi. Among 27 farms 17 (67.9%) were found to have seropositive horses. The seroprevalence of theileriosis among the tested stud farms ranged between 0 and 100%. No marked differences were found in seropositivity between geographical areas. The overall prevalence of positive samples was 32.0% with cELISA as well as with IFAT. The results obtained with cELISA and IFAT in this study had the strongest agreement, except for 9 samples in which the two serological tests gave different results. The prevalence of infection among 101 horses was 49% with PCR. All 14 sequenced samples were found by BLAST analysis to be closest to the T. equi 18S rRNA gene sequences in GenBank with a similarity of >= 99%. No significant association was found between the seropositivity and the age of horses. Horses below 5 years of age had three times higher chance to be PCR-positive, than older ones. There was no significant association between the gender and the results of diagnostic tests (cELISA: p=0.40; IFAT: p=0.25; PCR: p=0.41). Based on the findings, the prevalence of equine theileriosis is much higher than expected and it occurs in many regions of the country unlike equine babesiosis. To the authors' knowledge, this is the first report of the serological and molecular survey of T. equi infection in horses in Hungary. PMID- 23099090 TI - POMA analyses as new efficient bioinformatics' platform to predict and optimise bioactivity of synthesized 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2 carboxamide/carbothioamide analogues. AB - A series of 43, 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2 carboxamide/carbothioamide analogues (D01-D43) were analysed using Petra, Osiris, Molinspiration and ALOGPS (POMA) to identify pharmacophore, toxicity prediction, lipophilicity and bioactivity. All the compounds were evaluated for anti-HIV activity. 3-(4-Chlorophenyl)-N-(4-fluorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H indeno[1,2-c]pyrazole-2-carboxamide (D07) was found to be the most active with IC(50)>4.83 MUM and CC(50) 4.83 MUM. 3-(4-Fluorophenyl)-6,7-dimethoxy-3a,4 dihydro-3H-indeno[1,2-c]pyrazole-2-carbothioamide (D41) was found to be the most active compound against bacterial strains with MIC of 4 MUg/ml, comparable to the standard drug ciprofloxacin while 3-(4-methoxyphenyl)-6,7-dimethoxy-3a,4-dihydro 3H-indeno[1,2-c]pyrazole-2-carboxamide (D38) was found to be the most active compound against fungal strains with MIC 2-4 MUg/ml, however less active than standard fluconazole. Toxicities prediction by Osiris were well supported and experimentally verified with exception of some compounds. In anticonvulsant screening, 3-(4-fluorophenyl)-N-(4-chlorophenyl)-6,7-dimethoxy-3a,4-dihydro-3H indeno[1,2-c]pyrazole-2-carboxamide (D09) showed maximum activity showing 100% (4/4, 0.25-0.5h) and 75% (3/4, 1.0 h) protection against minimal clonic seizure test without any toxicity. PMID- 23099091 TI - Synthesis and biological evaluation of 5-aryloxypyrazole derivatives bearing a rhodanine-3-aromatic acid as potential antimicrobial agents. AB - Three novel series of 5-aryloxypyrazole derivatives have been synthesized and tested for their antibacterial activity. The majority of the synthesized compounds showed potent inhibitory activity against Gram-positive bacteria Staphylococcus aureus 4220, especially against the strains of multidrug-resistant clinical isolates (MRSA3167/3506 and QRSA3505/3519). Among which compounds IIIb, IIIg and IIIm showed the most potent levels of activity (MIC=1 MUg/mL) against the multidrug-resistant strains. And cytotoxic activity assay showed that the compounds tested did not affect cell viability on the Human cervical (HeLa) cells at their MICs. The current study therefore suggests that 5-aryloxypyrazoles bearing a rhodanine-3-aromatic acid moiety are promising scaffolds for the development of novel Gram-positive antibacterial agents. PMID- 23099092 TI - Tyrosine urea muscarinic acetylcholine receptor antagonists: achiral quaternary ammonium groups. AB - Tyrosine ureas had been identified as potent muscarinic receptor antagonists with promising in vivo activity. Controlling the stereochemistry of the chiral quaternary ammonium center had proved to be a serious issue for this series, however. Herein we describe the preparation and SAR of tyrosine urea antagonists containing achiral quaternary ammonium centers. The most successful such moiety was the 2-methylimidazo[2,1-b][1,3]thiazol-7-ium group which yielded highly potent antagonists with long duration of action in an inhaled animal model of bronchoconstriction. PMID- 23099093 TI - Synthesis and structure-activity relationships of a novel series of pyrimidines as potent inhibitors of TBK1/IKKepsilon kinases. AB - The design, synthesis and structure-activity relationships of a novel series of 2,4-diamino-5-cyclopropyl pyrimidines is described. Starting from BX795, originally reported to be a potent inhibitor of PDK1, we have developed compounds with improved selectivity and drug-like properties. These compounds have been evaluated in a range of cellular and in vivo assays, enabling us to probe the putative role of the TBK1/IKKepsilon pathway in inflammatory diseases. PMID- 23099094 TI - Inhibitors of the acetyltransferase domain of N-acetylglucosamine-1-phosphate uridylyltransferase/glucosamine-1-phosphate-acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides. AB - A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low LogD and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC(50) <0.1 MUM against GlmU isozymes from Gram-negative organisms), and the lipophilicity was increased giving compounds with LogD -1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13. PMID- 23099095 TI - Anti-viral activity of (-)- and (+)-usnic acids and their derivatives against influenza virus A(H1N1)2009. AB - Influenza is a widespread respiratory infection. Every year it causes epidemics, quickly spreading from country to country, or even pandemics, involving a significant part of the human population of the earth. Being a highly variable infection, influenza easy accumulates the resistance mutations to many antivirals. Usnic acid, a dibenzofuran originally isolated from lichens belongs to the secondary metabolites and has a broad spectrum of biological activity. In humans, it can act as an anti-inflammatory, antimitotic, antineoplasic, antibacterial, and antimycotic agent. In this work we studied for the first time the antiviral activity of usnic acid and its derivatives against the pandemic influenza virus A(H1N1)pdm09. A total of 26 compounds representing (+) and (-) isomers of usnic acid and their derivates were tested for cytotoxicity and anti viral activity in MDCK cells by microtetrazolium test and virus yield assay, respectively. Based on the results obtained, 50% cytotoxic dose (CTD(50)) and 50% effective dose (ED(50)) and selectivity index (SI) were calculated for each compound. Eleven of them were found to have SI higher than 10 (highest value 37.3). Absolute configuration was shown to have critical significance for the anti-viral activity. With minor exceptions, in the pair of enantiomers, (-)-usnic acid was more active comparing to (+)-isomer, but its biological activity was reversed after the usnic acid was chemically modified. Based on the obtained results, derivatives of usnic acid should be considered as prospective compounds for further optimization as anti-influenza substances. PMID- 23099096 TI - Novel azulene derivatives for the treatment of erectile dysfunction. AB - Based on the dopamine D(4) receptor partial agonist FAUC 3019, a series of azulenylmethylpiperazines was synthesized and affinities for the monoaminergic GPCRs including dopamine, serotonin, histamine and alpha-adrenergic receptor subtypes were determined. Ligand efficacies of the most promising test compounds revealed the N,N-dimethylaminomethyl substituted azulene 11 to be the most potent D(4) partial agonist (EC(50)=0.41 nM). This candidate was investigated for its ability to promote penile erection. Applying an in vivo animal model, test compound 11 turned out to stimulate penile erection in male rats with superior potency in low concentrations when compared to apomorphine. PMID- 23099097 TI - Synthesis of isoindole and benzoisoindole derivatives of teicoplanin pseudoaglycon with remarkable antibacterial and antiviral activities. AB - The primary amino function of teicoplanin pseudoaglycon has been transformed into arylthioisoindole or benzoisoindole and glycosylthioisoindole derivatives, in a reaction with o-phthalaldehyde or naphtalene-2,3-dicarbaldehyde and various thiols. All of the obtained semisynthetic antibiotics exhibited potent antibacterial activities against Gram-positive bacteria in the ng per ml concentration range. A few of them showed antiviral activity, in particular against influenza virus. PMID- 23099098 TI - Structural modifications of 5,6-dihydroxypyrimidines with anti-HIV activity. AB - A series of 5,6-dihydroxypyrimidine analogs were synthesized and evaluated for their anti-HIV activity in vitro. Among all of the analogs, several compounds exhibited significant anti-HIV activity, especially 1b and 1e, which showed the most potent anti-HIV activity with EC(50) values of 0.14 and 0.15 MUM, and TI (therapeutic index) values of >300 and >900, respectively. Further docking studies revealed that the representative compounds 1e and 3a could meet the HIV-1 integrase inhibition minimal requirements of a chelating domain (two metal ions) and an aromatic domain (pi-pi stacking interactions). PMID- 23099099 TI - Identification of novel scaffold of benzothiazepinones as non-ATP competitive glycogen synthase kinase-3beta inhibitors through virtual screening. AB - Glycogen synthase kinase-3beta (GSK-3beta) is an important serine/threonine kinase that has been proved as a key target for neurodegenerative diseases and diabetes. Up to date, most of known inhibitors are bound to the ATP-binding pocket of GSK-3beta, which might lead widespread effects due to the high homology between kinases. Recently, some of its non-ATP competitive inhibitors had been confirmed having therapeutical effects owing to their high selectivity. This finding opens a new pathway to study hopeful drugs for treatment of these diseases. However, it is still a challenge nowadays on how to efficiently find non-ATP competitors. Here, we successfully discovered a novel scaffold of benzothiazepinones (BTZs) as selective non-ATP competitive GSK-3beta inhibitors through virtual screening approach. A 3D receptor model of substrate binding site of GSK-3beta was constructed and applied to screen against drug-like Maybridge database through Autodock program. BTZ compounds were top ranked as efficient hits and were then synthesized for further screening. Among them, the representative compound 4j showed activity to GSK-3beta (IC(50): 25 MUM) in non ATP competitive mechanism, and nearly no inhibitory effect on other 10 related protein kinases. Overall, the results point out that BTZ compounds might be useful in treatment of Alzheimer's disease and diabetes mellitus as novel GSK 3beta inhibitors. It also suggests, on the other hand, that virtual screening would provide a valuable tool in combination with in vitro assays for the identification of novel selective and potent inhibitors. PMID- 23099100 TI - Rationale and design of the STAR randomized controlled trial to accelerate adoption of childhood obesity comparative effectiveness research. AB - BACKGROUND: Comparative effectiveness research (CER) evidence on childhood obesity provides the basis for effective screening and management strategies in pediatric primary care. The uses of health information technology including decision support tools in the electronic health records (EHRs), as well as remote and mobile support to families, offer the potential to accelerate the adoption of childhood obesity CER evidence. METHODS/DESIGN: The Study of Technology to Accelerate Research (STAR) is a three-arm, cluster-randomized controlled trial being conducted in 14 pediatric offices in Massachusetts designed to enroll 800, 6 to 12 year old children with a body mass index (BMI)>= 95th percentile seen in primary care at those practices. We will examine the extent to which computerized decision support tools in the EHR delivered to primary care providers at the point of care, with or without direct-to-parent support and coaching, will increase adoption of CER evidence for management of obese children. Direct-to parent intervention components include telephone coaching and twice-weekly text messages. Point-of-care outcomes include obesity diagnosis, nutrition and physical activity counseling, and referral to weight management. One-year child level outcomes include changes in BMI and improvements in diet, physical activity, screen time, and sleep behaviors, as well as cost and cost effectiveness. CONCLUSIONS: STAR will determine the extent to which decision support tools in EHRs with or without direct-to-parent support will increase adoption of evidence-based obesity management strategies in pediatric practice and improve childhood obesity-related outcomes. PMID- 23099101 TI - End-tidal CO2: an important parameter for a correct interpretation in functional brain studies using speech tasks. AB - The aim was to investigate the effect of different speech tasks, i.e. recitation of prose (PR), alliteration (AR) and hexameter (HR) verses and a control task (mental arithmetic (MA) with voicing of the result on end-tidal CO2 (PETCO2), cerebral hemodynamics and oxygenation. CO2 levels in the blood are known to strongly affect cerebral blood flow. Speech changes breathing pattern and may affect CO2 levels. Measurements were performed on 24 healthy adult volunteers during the performance of the 4 tasks. Tissue oxygen saturation (StO2) and absolute concentrations of oxyhemoglobin ([O2Hb]), deoxyhemoglobin ([HHb]) and total hemoglobin ([tHb]) were measured by functional near-infrared spectroscopy (fNIRS) and PETCO2 by a gas analyzer. Statistical analysis was applied to the difference between baseline before the task, 2 recitation and 5 baseline periods after the task. The 2 brain hemispheres and 4 tasks were tested separately. A significant decrease in PETCO2 was found during all 4 tasks with the smallest decrease during the MA task. During the recitation tasks (PR, AR and HR) a statistically significant (p<0.05) decrease occurred for StO2 during PR and AR in the right prefrontal cortex (PFC) and during AR and HR in the left PFC. [O2Hb] decreased significantly during PR, AR and HR in both hemispheres. [HHb] increased significantly during the AR task in the right PFC. [tHb] decreased significantly during HR in the right PFC and during PR, AR and HR in the left PFC. During the MA task, StO2 increased and [HHb] decreased significantly during the MA task. We conclude that changes in breathing (hyperventilation) during the tasks led to lower CO2 pressure in the blood (hypocapnia), predominantly responsible for the measured changes in cerebral hemodynamics and oxygenation. In conclusion, our findings demonstrate that PETCO2 should be monitored during functional brain studies investigating speech using neuroimaging modalities, such as fNIRS, fMRI to ensure a correct interpretation of changes in hemodynamics and oxygenation. PMID- 23099103 TI - From kingdom to kingdom, but hopefully not again. PMID- 23099102 TI - Imaging artifacts induced by electrical stimulation during conventional fMRI of the brain. AB - Functional magnetic resonance imaging (fMRI) of brain activation during transcranial electrical stimulation is used to provide insight into the mechanisms of neuromodulation and targeting of particular brain structures. However, the passage of current through the body may interfere with the concurrent detection of blood oxygen level-dependent (BOLD) signal, which is sensitive to local magnetic fields. To test whether these currents can affect concurrent fMRI recordings we performed conventional gradient echo-planar imaging (EPI) during transcranial direct current (tDCS) and alternating current stimulation (tACS) on two post-mortem subjects. tDCS induced signals in both superficial and deep structures. The signal was specific to the electrode montage, with the strongest signal near cerebrospinal fluid (CSF) and scalp. The direction of change relative to non-stimulation reversed with tDCS stimulation polarity. For tACS there was no net effect of the MRI signal. High-resolution individualized modeling of current flow and induced static magnetic fields suggested a strong coincidence of the change EPI signal with regions of large current density and magnetic fields. These initial results indicate that (1) fMRI studies of tDCS must consider this potentially confounding interference from current flow and (2) conventional MRI imaging protocols can be potentially used to measure current flow during transcranial electrical stimulation. The optimization of current measurement and artifact correction techniques, including consideration of the underlying physics, remains to be addressed. PMID- 23099104 TI - Migfilin, alpha-parvin and beta-parvin are differentially expressed in ovarian serous carcinoma effusions, primary tumors and solid metastases. AB - OBJECTIVE: The objective of this study is to analyze the expression and clinical role of integrin-linked kinase (ILK), alpha-parvin, beta-parvin and migfilin in advanced-stage serous ovarian carcinoma. METHODS: Expression of these 4 proteins was investigated in 205 effusions and in 94 patient-matched solid lesions (33 primary tumors and 61 solid metastases) using immunohistochemistry. Protein expression was analyzed for association with clinicopathologic parameters and survival. RESULTS: ILK, alpha-parvin, beta-parvin and migfilin were expressed in tumor cells in 53%, 2%, 28% and 53% of effusions and 57%, 20%, 83% and 25% of solid lesions, respectively. Statistical analysis showed significantly higher alpha-parvin and beta-parvin expression in primary carcinomas (p=0.02 and p=0.001, respectively) and solid metastases (p=0.001 and p<0.001, respectively), compared to effusions, with opposite findings for migfilin (p=0.006 and p=0.008 for primary carcinomas and solid metastases, respectively). ILK expression was comparable at all anatomic sites. beta-Parvin expression in effusions was associated with better response to chemotherapy at diagnosis (p=0.014), with no other significant association with clinicopathologic parameters or survival. Expression in primary tumors and solid metastases was similarly unrelated to clinicopathologic parameters or survival. CONCLUSIONS: This study provides further evidence to our previous observations that the adhesion profile of ovarian serous carcinoma cells in effusions differs from their counterparts in primary carcinomas and solid metastases. beta-Parvin may be a novel marker of chemoresponse in metastatic ovarian carcinoma. PMID- 23099105 TI - [Autoimmune encephalitis, clinical, radiological and immunological data]. AB - INTRODUCTION: Encephalitis is an inflammatory or infectious disease with an acute or subacute presentation. Immunological abnormalities in serum can be found but may be underdiagnosed. In several cases, a paraneoplastic origin with anti-neuron antibodies is noted. In all cases, other auto-antibodies can be found with or without any neoplastic mechanism. OBJECTIVES: The aim of our study was to describe a clinical, radiological and immunological cohort of patients with autoimmune encephalitis and suggest a diagnostic and therapeutic algorithm. PATIENTS AND METHOD: We performed a retrospective study in an immunological unit of neurology. All patients with autoimmune encephalitis between March 2000 and October 2009 were included. The clinical, imaging and immunological evaluations were recorded for each patient. RESULTS: Our cohort included 16 patients (eight men and eight women), mean age 45.3+/-10years. All patients had acute or subacute neuropsychological or neuropsychiatric impairment and all patients but one had temporal lobe dysfunction confirmed by cerebral MRI, PET or SPECT. Epilepsy was observed in 56% of cases, extra-temporal lobe impairment in 50%, including sleep disturbances. A cancer was found in only 25% (two small-cell lung cancers, one testis seminoma, one non-small-cell lung cancer with Merckel cells cancer). Anti neuron antibodies were noted in 56% of cases (two with anti-voltage gate potassium channel complex antibodies (ab), two with anti-NMDA-R ab, two with anti glutamate acid decarboxylase ab, one with anti-Ma2, two with anti-Hu ab and two remained uncharacterized). Systemic antibodies were found in 50% (one anti gangliosides, one anti-SSA and one anti-DNA and four antinuclear ab uncharacterized, two anti-TPO and two anti-phospholipids). All patients received immunomodulatory treatments, including intravenous immunoglobulins (IgIV) and cancer was treated. Five patients achieved complete recovery, partial improvement was observed in 10 patients and two patients died. DISCUSSION: Despite clinical homogeneity at presentation, clinical outcome seems to be different between patients with antibodies against neuronal surface antigens and those with antibodies against intracellular antigens, which are more likely refractory to immunotherapy and paraneoplastic. The frequency of extra-temporal lobe impairment suggests that the term of limbic encephalitis should be changed to autoimmune encephalitis. PMID- 23099106 TI - Globus pallidus interna deep brain stimulation for tardive dyskinesia: case report and review of the literature. AB - Tardive dyskinesia (TD) can be a disabling condition and is frequently refractory to medical therapy. Over the past decade there have been many reports of TD patients experiencing significant benefit with deep brain stimulation (DBS) of the globus pallidus interna (GPi). The growing literature on this treatment option for TD consists predominantly of case reports and series. The reported benefit ranges widely, but the majority of cases experienced at least a 50% improvement in symptoms. The anatomical distribution of dyskinesias has not clearly influenced outcome, though fixed postures appear less likely to improve than phasic movements. Onset of benefit can be immediate or take months, and benefit is sustained in most cases, for at least 6 months and up to several years. A wide variety of voltages, frequencies, and pulse widths have demonstrated efficacy. A small number of reports which examined psychiatric symptoms before and after surgery did not find any decline, and in some cases revealed improvement in mood. However, these overall positive results should be interpreted with caution, as the majority of reports lacked blinded assessments, control groups, or standardized therapy parameters. Finally, we present an illustrative case of refractory tardive dyskinesia treated with GPi-DBS with 5 years of follow-up and 4 accompanying video segments. PMID- 23099107 TI - Versican gene: regulation by the beta-catenin signaling pathway plays a significant role in dermal papilla cell aggregative growth. AB - BACKGROUND: Dermal papilla cells (DPCs), which exhibit a multilayer aggregative growth character in in vitro culture, are closely related to induction of hair follicles (HFs) formation, and are associated with the development and cycle regulation of HFs. Versican, a large chondroitin sulfate proteoglycan and one of the major components of the extracellular matrix, plays an essential role in hair follicle formation. And also the Wnt/beta-catenin signaling pathway performs a crutial function in induction during hair follicle growth and embryogenesis. OBJECTIVE: To characterize the role of versican and beta-catenin in regulating DPCs aggregative growth, and to explore the versican gene expression regulation mechanism by TCF-4/beta-catenin signaling pathway. METHODS: We first cultured DPCs at different passages, and detected the change in beta-catenin and versican expression in DPCs of various passages by RT-PCR and Western blot. Then we knockdowned the versican and beta-catenin gene, evaluated and verificated the binding capability of TCF-4/beta-catenin to TOP elements in versican gene promoter region at varied passage DPCs by EMSA and ChIP Assay, finally observed the effect of Wnt/beta-catenin pathway inhibition on DPC aggregative growth. RESULTS: With the increase of passage, DPCs lost the aggregative property, the versican mRNA and protein level in DPCs was on a gradual decline, while not significant declining tendency of beta-catenin. The mRNA of both beta-catenin and versican reduced simultaneously after beta-catenin siRNA transfection. The binding ability of TCF-4/beta-catenin of varied-passage DPCs to cultured versican promoters diminished with the increase of DPC passages. And versican inhibition or Wnt/beta-catenin pathway blocking could both produce considerable effect on the aggregative growth of low-passage DPCs. CONCLUSION: Wnt/beta-catenin signal transducting system regulates DPC aggregative growth through modifying versican expression by means of acting on the versican gene upstream promoter. PMID- 23099108 TI - Postnatal treatment factors affecting craniofacial morphology of unilateral cleft lip and palate (UCLP) patients in a Japanese population. AB - We have evaluated the craniofacial morphology of Japanese patients with unilateral cleft lip and palate (UCLP) and assessed the various postnatal factors that affect it. Lateral cephalograms of 140 subjects (mean (SD) aged 7 (2) years) with UCLP were taken before orthodontic treatment. Surgeons from Hokkaido University Hospital had done the primary operations. The craniofacial morphology was assessed by angular and linear cephalometric measurements. Cheiloplasty, palatoplasty, and preoperative orthopaedic treatment were chosen as postnatal factors. To compare the assessments of the postnatal factors, we made angular and linear cephalometric measurements for each subject and converted them into Z scores in relation to the mean (SD) of the two variables. Subjects treated by the modified Millard cheiloplasty had larger sella-nasion-point A (SNA) and nasion point A-pogonion (NA-POG) measurements than subjects treated by the modified Millard with a vomer flap cheiloplasty. Two-stage palatoplasty showed consistently better craniofacial morphology than the other palatoplasty. Subjects who had preoperative orthopaedic treatment with a Hotz plate had significantly larger upper incisor/sella-nasion (U1-SN) measurements than who had no preoperative orthopaedic treatment or an active plate. We conclude that in subjects treated by a modified Millard type of cheiloplasty, a two-stage palatoplasty, and a Hotz plate there were fewer adverse effects on craniofacial morphology. PMID- 23099109 TI - Demodicidosis: an uncommon erythema after cranio-maxillofacial surgery. AB - Demodex mites are commonly found in the healthy population, but the pathogenesis of demodicidosis has still not been clarified, though it is usually found in cases of immune deficiency. A 45-year-old man presented with an unusual outbreak of erythema and swelling 6 months after resection and chemoradiotherapy for a squamous cell carcinoma of the anterior floor of the mouth. The cheek was biopsied and histological examination showed demodicidosis. In cases of erythema with a normal blood cell count and no history of allergy, particularly in patients with reduced immunity, demodicidosis should be considered as a diagnosis and should be confirmed by examination of a biopsy specimen. PMID- 23099110 TI - Crossing mice deficient in eNOS with placental-specific Igf2 knockout mice: a new model of fetal growth restriction. AB - We tested the hypothesis that crossing two mouse models of fetal growth restriction (FGR) of differing phenotype would induce more severe FGR than either model alone. Female endothelial nitric oxide synthase knockout mice (eNOS(-/-)) were mated with placental-specific Igf2 knockout males (P0). Resultant fetuses were no more growth restricted than those with P0 deletion alone. However, P0 deletion attenuated the reduced placental system A amino acid transporter activity previously observed in eNOS(-/-) mice. Manipulating maternal and fetal genotypes provides a means to compare maternal and fetal regulation of fetal growth. PMID- 23099111 TI - Efficacy and predictors of long-term treatment success for Cognitive-Behavioral Treatment and Behavioral Weight-Loss-Treatment in overweight individuals with binge eating disorder. AB - OBJECTIVE: The aim of the study was to assess the long-term efficacy of Cognitive Behavioral Treatment (CBT) and Behavioral Weight-Loss-Treatment (BWLT) in patients with binge eating disorder (BED) and to identify potential predictors of long-term treatment success. METHOD: In a sample of overweight to obese BED patients from a randomized comparative trial we evaluated the efficacy of four months of CBT or BWLT, followed by 12 months extended care, and a final follow-up assessment 6 years after the end of active treatment. Outcomes included binge eating, eating disorder pathology, depressive feelings, and body mass index. RESULTS: After a strong improvement during active treatment, outcomes worsened during follow-up, yet remained improved at 6-year follow-up relative to pretreatment values. Long-term effects between CBT and BWLT were comparable. Rapid response during the early treatment phase was the only characteristic that was predictive of favorable treatment outcome in the long term. CONCLUSIONS: Both CBT and BWLT can be considered to be comparably efficacious in the long-term. Patients not responding strongly enough during the first four therapy sessions might be in need of tailored interventions early during the treatment phase. PMID- 23099112 TI - Role of resident liver cells in the pathogenesis of schistosomiasis. AB - Pathology in schistosomiasis occurs as a result of eggs deposited in the liver by the schistosome parasite. A granulomatous reaction occurs, resulting in portal hypertension and hepatic fibrosis. Resident non-parenchymal cells within the liver take part in this process, including hepatic stellate cells, which are responsible for collagen production, and Kupffer cells, the liver macrophages involved in both host protection and in pathology. Other cells such as liver sinusoidal endothelial cells or portal fibroblasts may also be involved in this process. This review discusses the possible role of these resident liver cells in the pathology associated with schistosomiasis and provides information which may assist our understanding of the mechanisms associated with chronic liver disease in general. PMID- 23099113 TI - The built environment and risk of obesity in the United States: racial-ethnic disparities. AB - Using data from the 2003-2008 waves of the continuous National Health Nutrition Examination Survey merged with the 2000 census and GIS-based data, this study conducted genderspecific analyses to explore whether neighborhood built environment attributes are significant correlates of obesity risk and mediators of obesity disparities by race-ethnicity. Results indicate that the built environment is a significant correlate of obesity risk but is not much of a mediator of obesity disparities by race-ethnicity. Neighborhood walkability, density, and distance to parks are significant covariates of obesity risks net of individual and neighborhood controls. Gender differences are found for some of these associations. PMID- 23099115 TI - Are we discussing SUDEP?--A retrospective case note analysis. AB - PURPOSE: Sudden unexplained death in epilepsy (SUDEP) is uncommon. Discussing the risk of SUDEP can be difficult, particularly in those where the risk is considered low, and previous studies have suggested that clinical practice varies widely. The Scottish Intercollegiate Guidelines Network (SIGN) suggest information on SUDEP is "essential" and National Institute of Clinical Excellence (NICE) recommend that "tailored information on the person's relative risk of SUDEP should be part of the counselling process...". The study aimed to evaluate if discussion of SUDEP risk is being documented in clinical records and to determine if there is an association between documented discussion and risk factors for SUDEP. METHODS: A retrospective case note review was undertaken in those with an established diagnosis of epilepsy attending clinic between 1st January 2009 and 30th June 2009. RESULTS: Overall, a documented SUDEP discussion was noted in 14/345 (4%) cases. Patients were statistically more likely to have a documented SUDEP discussion if they had ongoing generalised tonic-clonic seizures, with a trend also towards informing those non-compliant with medication. CONCLUSION: Patients were more likely to be informed of SUDEP if they had potentially modifiable risk factors identified. There was, however, no documented evidence to suggest that SUDEP is being discussed in the majority of cases. PMID- 23099114 TI - Detection of thyroid dysfunction in pregnant women: universal screening is justified. AB - There is a controversy among different scientific societies in relation to the recommendations on whether universal screening for the detection of thyroid dysfunction during gestation should be performed or not. Although various studies have shown an association between subclinical hypothyroidism or hypothyroxinemia with obstetric problems and/or neurocognitive impairment in the offspring, no evidence on the possible positive effects of treatment of such conditions with thyroxin has been demonstrated so far. However, there is a general agreement about the need for treatment of clinical hypothyroidism during pregnancy and the risks of not doing so. Because it is a common, easily diagnosed and effectively treated disorder without special risk, the working Group of Iodine Deficiency Disorders and Thyroid Dysfunction of the Spanish Society of Endocrinology and Nutrition and Spanish Society of Gynaecology and Obstetrics recommends an early evaluation (before week 10) of thyroid function in all pregnant women. Given the complex physiology of thyroid function during pregnancy, hormone assessment should be performed according to reference values for each gestational trimester and generated locally in each reference laboratory. Thyrotropin determination would be sufficient for screening purposes and only if it is altered, free thyroxin or total thyroxin would be required. Adequate iodine nutrition is also highly recommended before and during pregnancy to contribute to a normal thyroid function in the pregnant women and fetus. PMID- 23099116 TI - Finite dose skin mass balance including the lateral part: comparison between experiment, pharmacokinetic modeling and diffusion models. AB - This work investigates in vitro finite dose skin absorption of the model compounds flufenamic acid and caffeine experimentally and mathematically. The mass balance in different skin compartments (donor, stratum corneum (SC), deeper skin layers (DSL), lateral skin parts and acceptor) is analyzed as a function of time. For both substances high amounts were found in the lateral skin compartment after 6h of incubation, which emphasizes not to elide these parts in the modeling. Here, three different mathematical models were investigated and tested with the experimental data: a pharmacokinetic model (PK), a detailed microscopic two-dimensional diffusion model (MICRO) and a macroscopic homogenized diffusion model (MACRO). While the PK model was fitted to the experimental data, the MICRO and the MACRO models employed input parameters derived from infinite dose studies to predict the underlying diffusion process. All models could satisfyingly predict or describe the experimental data. The PK model and MACRO model also feature the lateral parts. PMID- 23099117 TI - Angiopoietin-1 and angiopoietin-2 as serum biomarkers for ectopic pregnancy and missed abortion: a case-control study. AB - BACKGROUND: A case-control study to evaluate whether a single serum measurement of angiopoietin-1 (ANG-1) and angiopoietin-2 (ANG-2) at 6-8 weeks gestation can differentiate failed pregnancies, whether ectopic pregnancies (EP) or missed abortions (MA), from healthy intrauterine pregnancies (IUP). INTERVENTION(S): Serum and tissue mRNA determination of ANG-1 and ANG-2 levels by ELISA and RTPCR, from 60 (30 EP and 30 MA) patients with failed early pregnancy and 33 IUPs. RESULTS: ANG-1 and ANG-2 concentrations and their ratio are lower in EP (median, 689 and 302 pg/ml, respectively) and MA cases (median, 810 and 402 pg/ml, respectively) compared to IUP (median, 963 and 1477 pg/ml, respectively) (p<0.05, for all). Unlike ANG-2, serum ANG-1 discriminates an EP from a MA (p=0.011). Trophoblastic ANG-1 mRNA expression levels are lower in EP compared to MA and IUP (p<0.05), while ANG-2 mRNA is higher in EP and MA than in IUP (p<0.05). CONCLUSIONS: A single measurement of serum ANG-1 and ANG-2 at 6-8 weeks of gestation designate the outcome of a pregnancy, as their levels are significantly decreased in failed than normal pregnancies. Serum ANG-1 showed potential to discriminate MA from EP. PMID- 23099118 TI - Relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver enzymes in Brazilian individuals under anti-tuberculosis drug therapy. AB - The relationship of NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms with mild elevation of liver biomarkers was investigated in individuals under anti tuberculosis drug therapy. Tuberculosis outpatients (18-70 y) with (n=59) and without (n=40) mild increase of liver enzymes (MILE) at two-month treatment were selected. Blood samples were obtained for DNA extraction and evaluation of serum markers of liver function. NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms were detected by DNA sequencing, PCR-RFLP, and PCR multiplex. Frequency of NAT2*5/*5 genotype was higher in MILE than in non-MILE group (p=0.04). Patients carrying NAT2*5/*5 genotype had increased susceptibility to MILE (OR: 9.00, 95CI: 1.46 55.48, p=0.018). CYP2E1*5B allele (*1A/*5B plus *5B/*5B genotypes) carriers had a trend for reduced risk for MILE (OR: 0.34, 95CI: 0.11-1.03, p=0.056) that was confirmed by lower levels of liver markers than CYP2E1*1A/*1A carriers after treatment (p<0.05). Moreover, increased post-treatment ALT, AST and total bilirubin were associated with GSTM1*1/GSTT1*1 genotypes (p<0.05). Patients taking CYP2E1 inhibitors had increased susceptibility to MILE (OR: 7.39, 95CI: 1.93-28.29, p=0.003), which was independent of the studied polymorphisms. These results are suggestive that NAT2, CYP2E1 and GSTM1/GSTT1 polymorphisms and concomitant use of CYP2E1 inhibitors contribute to the susceptibility to mild alterations in liver enzymes in patients under anti-tuberculosis drug therapy. PMID- 23099120 TI - In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a). AB - OBJECTIVE: Lipoprotein(a) [Lp(a)] consists of apolipoprotein B-100 (apoB-100) as part of an LDL-like particle and the covalently linked glycoprotein apolipoprotein(a) [apo(a)]. Detailed mechanisms of its biosynthesis, assembly, secretion and catabolism are still poorly understood. To address the Lp(a) assembly mechanism, we studied the in vivo kinetics of apo(a) and apoB-100 from Lp(a) and LDL apoB-100 in nine healthy probands using stable-isotope methodology. METHODS: The level of isotope enrichment was used to calculate the fractional synthesis rate (FSR), production rate (PR) and retention time (RT) using SAAMII software and multicompartmental modeling. RESULTS: We observed a similar mean PR for apo(a) (1.15 nmol/kg/d) and apoB-100 (1.31 nmol/kg/d) from Lp(a), which differed significantly from the PR for apoB-100 from LDL (32.6 nmol/kg/d). Accordingly, mean FSR and RT values for Lp(a)-apo(a) were similar to those of Lp(a)-apoB and different from those for LDL-apoB. CONCLUSION: Two different kinetic apoB pools within Lp(a) and LDL suggest intracellular Lp(a) assembly from apo(a) and newly synthesized LDL. PMID- 23099119 TI - Leptin treatment inhibits the progression of atherosclerosis by attenuating hypercholesterolemia in type 1 diabetic Ins2(+/Akita):apoE(-/-) mice. AB - AIMS: The impact of leptin deficiency and its replacement in T1D remain unclear in the context of dyslipidemia and atherosclerosis. The current study has investigated the physiologic role of leptin in lipid metabolism and atherosclerosis in T1D. METHODS AND RESULTS: The present study has employed Ins2(+/Akita):apoE(-/-) mouse model that spontaneously develops T1D, hypercholesterolemia, and atherosclerosis. At age 13 weeks, diabetic Ins2(+/Akita):apoE(-/-) mice showed leptin deficiency by ~92% compared with nondiabetic Ins2(+/+):apoE(-/-) mice. From 13 weeks to 25 weeks of age, diabetic Ins2(+/Akita):apoE(-/-) mice were treated with low-dose leptin (at 0.4 MUg/g body weight daily). Leptin treatment diminished food intake by 22-27% in diabetic mice without affecting body weight and lean mass throughout the experiment. Importantly, leptin therapy substantially reduced plasma cholesterol concentrations by ~41%, especially in LDL fractions, in diabetic Ins2(+/Akita):apoE(-/-) mice. Moreover, leptin therapy decreased atherosclerotic lesion in diabetic mice by ~62% comparable to that seen in nondiabetic mice. In addition, leptin restored repressed expression of hepatic sortilin-1, a receptor for LDL clearance, and reversed altered expression of several hepatic genes involved in lipogenesis and cholesterol synthesis characteristic of diabetic mice. These findings were accompanied by normalization of reduced hepatic expression of Irs1 and Irs2 mRNA as well as their protein levels, and improved hepatic insulin-receptor signaling. CONCLUSIONS: The present findings suggest that leptin administration may be useful to improve dyslipidemia and reduce atherosclerosis-related cardiovascular disease in human subjects with T1D. PMID- 23099121 TI - Application of the split-step Pade approach to nonlinear field predictions. AB - We herein propose a new theoretical approach for analyzing the nonlinear propagation of directive sound beams emitted from a planar piston source with a circular aperture. The proposed approach relies on the split-step Pade approximation, which is an efficient method for obtaining wide-angle one-way wave equations, especially in underwater acoustics. Despite including only two Pade terms in the expansion, the theory was applicable to a beam angle of up to +/-40 degrees relative to the main propagation direction, the angle of which is approximately twice that of the Khokhlov-Zabolotskaya-Kuznetsov equation, which is based on parabolic approximation. In order to demonstrate the effectiveness of the newly proposed theoretical approach, we performed an experiment using an airborne ultrasonic emitter with a circular aperture of 7.5cm in radius. We drove the emitter powerfully at a 36-kHz and 40-kHz bi-frequency signal and measured the beam patterns of the primary and secondary waves, such as parametric sounds within wide propagation angles. Excellent agreement between measured data and the corresponding numerical simulations supports the validity of the proposed model equations and the computational methods for their numerical solutions. PMID- 23099122 TI - Synergistic effect of chemical penetration enhancer and iontophoresis on transappendageal transport of oligodeoxynucleotides. AB - Gap junction protein connexin43 (Cx43) specific antisense oligodeoxynucleotides (AsODN) have been shown to improve a number of inflammatory conditions and may therefore offer a novel strategy for persistent pain management. However, for such molecules to be clinically effective, delivery challenges owing to the molecules' high molecular weight, negative charge and hydrophilicity have to be overcome. In this study, the effect of various chemical penetration enhancers and cathodal iontophoresis on transdermal delivery was evaluated. Initial skin permeation studies revealed only a slight increase in the passive flux of the model anionic drug sodium fluorescein using limonene/ethanol. Applying cathodal iontophoresis, the amount of the model drug permeated through untreated skin was tripled, while a combination of chemical and physical penetration enhancement resulted in a fourfold increase in the fluorescein amount permeated. However, even the synergistic effect of limonene/ethanol and iontophoresis was insufficient to achieve complete permeation of Cy3-labeled Cx43 AsODN across the entire skin thickness. Instead, molecules were trapped in the epidermis or permeated deeply into the hair follicles. These results suggest that the synergistic effect of chemical and physical penetration enhancement increases intradermal delivery of oligonucleotides but is insufficient to deliver such large molecules across intact skin. PMID- 23099123 TI - The implicit use of spatial information develops later for crossmodal than for intramodal temporal processing. AB - The integrated use of spatial and temporal information seems to support the separation of two sensory streams. The present study tested whether this facilitation depends on the encoding of sensory stimuli in externally anchored spatial coordinate systems. Fifty-nine children between 5 and 12 years as well as 12 young adults performed a crossmodal temporal order judgment (TOJ) task for simple visual and tactile stimuli. Stimuli were presented either within the same or in different hemifields. Presentation of the two modality inputs in different hemifields improved TOJ only in children aged 10 years and older. In contrast, intramodal TOJ performance (data from Pagel, Heed, & Roder, 2009) was better than crossmodal TOJ performance starting at the age of 6 years. An adult-like level of performance in the crossmodal TOJ task was evident only at the age of 12 years. We speculate that the ability to redundantly code sensory input in modality specific and modality-independent spatial coordinates facilitates intramodal temporal processing. Further refinement of the processes providing external spatial coordinates then results in the integrated use of space and time to decide whether sensory inputs belong to a common object or to separate events. PMID- 23099124 TI - Waiting and weighting: Information sampling is a balance between efficiency and error-reduction. AB - The current study investigates the relative extent to which information utility and planning efficiency guide information-sampling strategies in a classification task. Prior research has pointed to the importance of probability gain, the degree to which sampling a feature reduces the chance of error, in contexts where participants are restricted to one sample. We monitored participants as they sampled information in an unrestricted context and recorded whether they began their search with a high gain feature or an efficient feature that ultimately allowed for fewer samples per trial. Participants preferred to sample the more efficient feature first, especially when feature information had a higher access cost (Experiment 1). When access costs were all but eliminated using eye-tracking (Experiment 2), participants' fixations still emphasized efficiency over high probability gain, though probability gain was shown to influence access patterns. PMID- 23099125 TI - Neurobiological aspects of sleep physiology. AB - Sleep is characterized by changes in neural firing and chemistry compared with wakefulness. Many neurologic diseases affect pathways that regulate control of sleep state and some primary sleep disorders have abnormalities of this circuitry. Nonrapid eye movement (NREM) and rapid eye movement (REM) sleep alternate in an approximately 90-minute cycle. Recent findings have expanded understanding of the control of sleep state, and will facilitate development of novel therapeutics to assist patients with a variety of disorders of sleep and wakefulness. Treatment of sleep and wake disorders can assist patients with a variety of neurologic problems. PMID- 23099126 TI - A neurologist's guide to common subjective and objective sleep assessments. AB - Sleep medicine has been evolving over the past few decades and methods of patient evaluation have changed. Given the strong overlap between neurologic disorders and sleep disorders, neurologists should be familiar with currently available tools in sleep medicine to best care for their patients. This article lists some of the most common assessments that a neurologist might use in clinical practice to evaluate patients with sleep complaints. Both subjective and objective tools have important roles in a complete sleep evaluation; however, knowing when and how to use these assessments is also essential. PMID- 23099127 TI - Treating sleep disorders in neurology practice. AB - Neurologists treat many people with unrecognized sleep disorders. This review recommends that new and established patients routinely complete standard sleep questionnaires as an aid to clinical history. Because there is high prevalence of treatable primary sleep disorders among neurologic patients, routine diagnostic sleep testing is indicated for patients with stroke, neuromuscular disease, dementia, REM behavioral disorder, atypical or treatment-refractory insomnia, and chronic and unexplained fatigue or sleepiness. As local and national regulatory momentum favors increasing care coordination and integration, neurologists should develop a clinical pathway to diagnose and treat sleep disorders within the practice or through a collegial expert network. PMID- 23099128 TI - Hypersomnias of central origin. AB - This article presents a succinct understanding of how to diagnose and manage hypersomnias of central origin, including narcolepsy, idiopathic hypersomnia, and recurrent hypersomnias. PMID- 23099129 TI - Insomnia. AB - Insomnia is a common disorder, with individual and societal consequences. Advances have been made in the understanding of insomnia and its treatment options. However, cognitive behavioral therapy and Food and Drug Administration approved pharmacologic therapies have limitations, the former primarily involving access and the latter involving potential side effects. Further research is needed to optimize management strategies. PMID- 23099130 TI - Parasomnias and their mimics. AB - Parasomnias are classified into nonrapid eye movement and rapid eye movement sleep parasomnias. It is important for the clinician to consider other parasomnia mimics that present to the sleep disorders clinic. These conditions can be differentiated by taking a detailed sleep history and conducting nocturnal polysomnograms to evaluate for potential comorbidities and better characterize the disorder. Mainstays of treatment include treating any underlying primary sleep disorders that induce sleep fragmentation and could trigger the parasomnia, as well as implementing safety precautions to protect patients and their household. Pharmacologic treatment of many parasomnias is also available if needed and clinically indicated. PMID- 23099131 TI - Sleep-disordered breathing. AB - Obesity is a critical factor in the development of sleep-disordered breathing (SDB). Snoring is the most frequent nocturnal symptom suggesting a diagnosis of SDB. Other common nighttime symptoms include snorting, gasping, choking, coughing, and witnessed apneas. The most frequent diurnal symptom in SDB is excessive daytime sleepiness. Patients suspected of having SDB should undergo a full night of in-laboratory polysomnography or in-home oligosomnography. SDB includes a spectrum of disorders; the most common are obstructive sleep apnea and central sleep apnea. PMID- 23099132 TI - Restless legs syndrome and periodic leg movements of sleep. AB - Women are more commonly affected than men by restless legs syndrome, and prevalence is highest amongst those of northern European heritage. The motor manifestations include nonvolitional myoclonus (periodic leg movements). Disinhibition of spinal sensorimotor circuits may underlie these primary features and can be affected by peripheral as well as supraspinal networks. Insufficient mobilizable iron stores increase expressivity in some individuals. The sensorimotor features are relieved by dopamine, especially dopamine agonists, gabapentin and its derivatives, and opioids. A diagnosis relies on recognition of key primary and supportive features, and treatments are generally well tolerated, efficacious, and life-changing. PMID- 23099134 TI - Pediatric sleep-wake disorders. AB - Sleep-wake problems are common during childhood and adolescence. They are of diverse cause, and can contribute significantly to alterations in behavior, cognition, and learning. Obstructive sleep apnea, central hypoventilation syndrome, narcolepsy, periodic hypersomnia, delayed sleep phase syndrome, restless legs syndrome, parasomnias, and sleep disruption consequent to psychiatric disorders are some of the commonly encountered conditions. Some aspects of sleep architecture and its organization change with age and maturation. Diagnostic criteria and sleep laboratory techniques and findings for some childhood sleep disorders differ from those of adults. Most pharmacologic agents used to treat pediatric sleep disorders are off-label. PMID- 23099135 TI - Dementia and sleep. AB - Sleep evaluation can be essential in the treatment of dementia because sleep related issues are common in dementia, often treatable, affect patient function, and are a major cause of caregiver distress. This article provides a practical approach to treatment of sleep in patients with dementia. Certain specific sleep disorders can be associated with certain underlying disorders and greater knowledge of these relationships is leading to more refined treatment approaches. Whether a sleep-related disorder such as obstructive sleep apnea, or limited sleep time, predisposes to the development of dementia is an active area of research. PMID- 23099133 TI - Circadian rhythm sleep disorders. AB - There have been remarkable advances in our understanding of the molecular, cellular, and physiologic mechanisms underlying the regulation of circadian rhythms, and of the impact of circadian dysfunction on health and disease. This information has transformed our understanding of the effect of circadian rhythm sleep disorders (CRSD) on health, performance, and safety. CRSDs are caused by alterations of the central circadian timekeeping system, or a misalignment of the endogenous circadian rhythm and the external environment. This article reviews circadian biology and discusses the pathophysiology, clinical features, diagnosis, and treatment of the most commonly encountered CRSDs in clinical practice. PMID- 23099136 TI - Sleep and epilepsy: opportunities for diagnosis and treatment. AB - Sleep and epilepsy have a dynamic interaction that presents the clinician opportunities for diagnosis and treatment. Sleep complaints are very common in patients with epilepsy and these complaints may be related to the underlying epilepsy, the treatment of epilepsy or other sleep related issues. Appropriate treatment of epilepsy may improve sleep, and treatment of sleep disorders may reduce the frequency of recurrent seizures. Sleep and sleep deprivation may provoke seizures and can provide further diagnostic information about the seizure type and location. For the clinician, understanding the relationship of sleep and epilepsy expands the diagnostic and therapeutic armamentarium. PMID- 23099137 TI - Sleep, stroke and poststroke. AB - There is abundant and still evolving scientific clinical evidence linking sleep apnea with stroke risk factors, cardiovascular disease, and stroke. Sleep apnea is a modifiable risk factor and efforts to control this condition should be pursued vigorously, particularly in patients at risk of vascular disease. Emerging evidence has also linked other sleep disorders, such as periodic limb movements of sleep and restless legs syndrome, with vascular risk. PMID- 23099138 TI - Sleep-related headaches. AB - Irrespective of diagnosis, chronic daily, morning, or "awakening" headache patterns are soft signs of a sleep disorder. Sleep apnea headache may emerge de novo or may present as an exacerbation of cluster, migraine, tension-type, or other headache. Insomnia is the most prevalent sleep disorder in chronic migraine and tension-type headache, and increases risk for depression and anxiety. Sleep disturbance (e.g., sleep loss, oversleeping, schedule shift) is an acute headache trigger for migraine and tension-type headache. Snoring and sleep disturbance are independent risk factors for progression from episodic to chronic headache. PMID- 23099140 TI - The sleep-immunity relationship. AB - Research models show a strong interrelationship between sleep quality and immune function. The proinflammatory cytokines, interleukin-1, interleukin-6, and tumor necrosis factor alpha are classified as official sleep-regulatory substances. However, sleep-promoting properties are also possessed by several other immune and proinflammatory cellular classes. This article reviews the current physiologic evidence for the prominent somnogenic and sleep-regulatory properties inherent to these immune substances. Clinical examples of this relationship are discussed from the perspective of infectious and primarily immune-related conditions associated with significant sleep disruption and from the perspective of immune dysregulation associated with several primary sleep disorders. PMID- 23099139 TI - Traumatic brain injury and sleep disorders. AB - Sleep disturbance is common after traumatic brain injury (TBI). Insomnia, fatigue, and sleepiness are the most frequent post-TBI sleep complaints with narcolepsy (with or without cataplexy), sleep apnea (obstructive or central), periodic limb movement disorder, and parasomnias occurring less commonly. In addition, depression, anxiety, and pain are common TBI comorbidities with substantial influence on sleep quality. Diagnosis of sleep disorders after TBI may involve polysomnography, multiple sleep latency testing, or actigraphy. Treatment is disorder-specific and includes the use of medications, continuous positive airway pressure, or behavioral modifications. Unfortunately, treatment of sleep disorders associated with TBI often does not improve sleepiness or neuropsychologic function. PMID- 23099141 TI - Movement disorders and sleep. AB - This article summarizes what is currently known about sleep disturbances in several movement disorders including Parkinson disease, essential tremor, parkinsonism, dystonia, Huntington disease, myoclonus, and ataxias. There is an association between movement disorders and sleep. In some cases the prevalence of sleep disorders is much higher in patients with movement disorder, such as rapid eye movement sleep behavior disorder in Parkinson disease. In other cases, sleep difficulties worsen the involuntary movements. In many cases the medications used to treat patients with movement disorder disturb sleep or cause daytime sleepiness. The importance of discussing sleep issues in patients with movement disorders cannot be underestimated. PMID- 23099142 TI - Sleep disorders in neuromuscular diseases. AB - Sleep disorders are common in patients with neuromuscular diseases, but are often overlooked. Recognizing and treating issues relating to sleep disturbances improves the quality of life for these patients. This article provides an overview of the sleep dysfunction that occurs in neuromuscular diseases, of which the most common is sleep-disordered breathing. In addition, the current literature is reviewed to provide primary care physicians, sleep specialists, neurologists, and neuromuscular specialists with information on available diagnostic and treatment modalities. PMID- 23099144 TI - Sleep disorders. Preface. PMID- 23099145 TI - In vitro immunomodulatory effects of an oleanolic acid-enriched extract of Ligustrum lucidum fruit (Ligustrum lucidum supercritical CO2 extract) on piglet immunocytes. AB - This study was conducted to evaluate the in vitro immunomodulatory effects of supercritical CO(2)Ligustrum lucidum extract (LLE) on the immune cells of piglets. The results showed that the LLE enhanced the proliferative activity of piglet blood lymphocytes and up-regulated the CD4(+) CD8(+) and CD4(+) CD8(-) cell populations. The LLE also regulated the expression of Th1- and Th2-related cytokines; elevated the levels of IL-2, IFN-gamma and TNF-alpha, which were produced by Th1 lymphocytes; and decreased the levels of IL-4 and IL-10, which were produced by Th2 lymphocytes. Furthermore, the LLE stimulated the NO secretion of lymphocytes. These results indicated that LLE might have potential immunomodulatory effects on the immune system of piglets and provided scientific and experimental foundations for the development of a new kind of LLE immune adjuvant in the pig production. PMID- 23099146 TI - Biogeography and systematics of Aricia butterflies (Lepidoptera, Lycaenidae). AB - Butterflies of the Aricia species group represent a paradigm of unresolved taxonomy, both at the genus and species levels. We studied phylogenetic relationships, biogeography, and systematics based on genetic--nuclear and mitochondrial--and morphometric--external (wings) and internal (genitalia) - data. We show that Aricia is a monophyletic genus comprising the taxa Pseudoaricia, Ultraaricia and Umpria, which are here considered junior synonyms of Aricia. The taxa allous, inhonora, issekutzi, mandzhuriana, myrmecias and transalaica, which have often been raised to species rank, are shown to probably represent subspecies or synonyms. We show that montensis is likely a good species that is sister to all A. artaxerxes populations across the Palearctic region. The species A. anteros and A. morronensis are shown to display deep intraspecific divergences and they may harbor cryptic species. We also discovered that A. cramera and A. agestis exhibit a pattern of mutual exclusion on islands, and a parapatric distribution in mainland with a narrow contact zone where potential hybrids were detected. The lack of a prezygotic barrier that prevents their coexistence could explain this phenomenon. This study will hopefully contribute to the stability of the systematics of Aricia, a group with potential for the study of the link between speciation and biogeography. PMID- 23099147 TI - The relative utility of sequence divergence and phylogenetic informativeness profiling in phylogenetic study design. PMID- 23099148 TI - Phylogenetics of the marine sculpins (Teleostei: Cottidae) of the North American Pacific Coast. AB - With 92 species along the North American Pacific Coast, marine sculpins represent the most species-rich radiation of fishes in this region. I used the mitochondrial cytochrome b gene and the nuclear ribosomal S7 intron for 99 species (76 North American, 19 Asian, and four North Atlantic) to produce the most complete phylogenetic hypothesis yet generated for this assemblage. Maximum likelihood and Bayesian analyses produced highly similar tree topologies. While many previously proposed groupings based on morphology are recovered, the molecular data suggest that a number of genera are para- or polyphyletic. However, this analysis supports the monophyly of one large clade that is found exclusively along the North American Pacific Coast (Chitonotous-Ruscarius Artedius-Orthonopius-Clinocottus-Leiocottus-Oligocottus). Some sibling species have disjunct ranges, suggesting allopatric speciation. However, many other sibling species have largely overlapping ranges, and repeated habitat shifts appear to have facilitated diversification. PMID- 23099143 TI - Psychiatric disorders and sleep. AB - There is growing experimental evidence that the relationship between psychiatric disorders and sleep is complex and includes bidirectional causation. This article provides the evidence that supports this point of view, reviewing data on sleep disturbances seen in patients with psychiatric disorders as well as data on the impact of sleep disturbances on psychiatric conditions. Although much has been learned about the psychiatric disorders-sleep relationship, additional research is needed to better understand the relationship. Such work promises to improve comprehension of these phenomena and lead to better treatment for the many patients with sleep disorders and psychiatric disorders. PMID- 23099149 TI - Evolution of microhabitat association and morphology in a diverse group of cryptobenthic coral reef fishes (Teleostei: Gobiidae: Eviota). AB - Gobies (Teleostei: Gobiidae) are an extremely diverse and widely distributed group and are the second most species rich family of vertebrates. Ecological drivers are key to the evolutionary success of the Gobiidae. However, ecological and phylogenetic data are lacking for many diverse genera of gobies. Our study investigated the evolution of microhabitat association across the phylogeny of 18 species of dwarfgobies (genus Eviota), an abundant and diverse group of coral reef fishes. In addition, we also explore the evolution of pectoral fin-ray branching and sensory head pores to determine the relationship between morphological evolution and microhabitat shifts. Our results demonstrate that Eviota species switched multiple times from a facultative hard-coral association to inhabiting rubble or mixed sand/rubble habitat. We found no obvious relationship between microhabitat shifts and changes in pectoral fin-ray branching or reduction in sensory pores, with the latter character being highly homoplasious throughout the genus. The relative flexibility in coral-association in Eviota combined with the ability to move into non-coral habitats suggests a genetic capacity for ecological release in contrast to the strict obligate coral dwelling relationship commonly observed in closely related coral gobies, thus promoting co-existence through fine scale niche partitioning. The variation in microhabitat association may facilitate opportunistic ecological speciation, and species persistence in the face of environmental change. This increased speciation opportunity, in concert with a high resilience to extinction, may explain the exceptionally high diversity seen in Eviota compared to related genera in the family. PMID- 23099150 TI - High male incidence and evolutionary implications of triploid form in northeast Asia Carassius auratus complex. AB - Carassius auratus complex is believed to originate from East Eurasia and consist of diploid and triploid forms. Diploid form reproduces sexually, whereas triploid form possesses mixture modes of unisexual gynogenesis and sexual reproduction, which makes it a unique case to study evolutionary issues among vertebrates. In this study, we identified 337 triploid individuals from 386 specimens of Carassius auratus complex sampled from 4 different sites of Xingkai Lake and Suifen River on the northeast Asia transboundary areas of Russia and China, and found that triploids were ubiquitous, whereas diploids existed only in SII site of Suifen River. Triploid males were detected in all surveyed sites, and an unusually high triploid male incidence (23%) was found in the Chinese reach of Suifen River. Then, nuclear and cytoplasmic markers were used to analyze their genetic diversity and phylogenetic relationship. A total of 61 distinct tf alleles and 35 mtDNA CR haplotypes were revealed. Higher genetic diversity and divergence were confirmed in triploids than in diploids, and identical genetic background between triploid males and females was demonstrated. Moreover, evolutionary implications and roles of triploid males were suggested in population proliferation and diversity creation of the triploid form. PMID- 23099151 TI - Vitamin E supplementation and lifespan in model organisms. AB - We have conducted a comprehensive literature review regarding the effect of vitamin E on lifespan in model organisms including single-cell organisms, rotifers, Caenorhabditis elegans, Drosophila melanogaster and laboratory rodents. We searched Pubmed and ISI Web of knowledge for studies up to 2011 using the terms "tocopherols", "tocotrienols", "lifespan" and "longevity" in the above mentioned model organisms. Twenty-four studies were included in the final analysis. While some studies suggest an increase in lifespan due to vitamin E, other studies did not observe any vitamin E-mediated changes in lifespan in model organisms. Furthermore there are several studies reporting a decrease in lifespan in response to vitamin E supplementation. Different outcomes between studies may be partly related to species-specific differences, differences in vitamin E concentrations and the vitamin E congeners administered. The findings of our literature review suggest that there is no consistent beneficial effect of vitamin E on lifespan in model organisms which is consistent with reports in human intervention studies. PMID- 23099152 TI - Psychosocial correlates of exclusive breastfeeding: a systematic review. AB - BACKGROUND: the World Health Organization recommends that all infants worldwide are exclusively breastfed for the first 6 months of life for optimal health and development. However, very few women worldwide are meeting this recommendation. Psychosocial factors have been identified as potentially modifiable factors implicated in a woman's ability to successfully exclusively breastfeed, however there is very limited research examining these factors specifically for exclusive breastfeeding to 6 months duration. METHODS: a search of psychological, nursing and medical databases was conducted in June 2011 for studies published from 2000 to 2011 examining psychological correlates of exclusive breastfeeding to four to 6 months duration. RESULTS: nine papers from eight studies were found to be eligible for the review. Psychological factors have been reported to be highly predictive of exclusive breastfeeding outcomes. Research to date shows that psychosocial factors are not only importantly implicated in exclusive breastfeeding duration but they can also be changed through intervention and experiences. CONCLUSIONS: while there is a wealth of literature on the role of psychosocial factors in breastfeeding, there is very limited research specifically examining the role of psychosocial factors of exclusive breastfeeding to 6 months duration. Interpreting the results of the available literature is difficult due to the various methodologies and definitions of exclusive breastfeeding and small sample sizes. Further research, specifically, longitudinal cohort studies are needed which examine psychological determinants of exclusive breastfeeding and infant feeding methods from pregnancy through to 6 months postpartum. PMID- 23099153 TI - Characterization of fibrosis-promoting factors and siRNA-mediated therapies in C protein-induced experimental autoimmune myocarditis. AB - Due to poor proliferation abilities of cardiomyocytes, the repair process in the heart after insults is often associated with fibrosis formation. In this study, we characterized inflammation and/or fibrosis-related molecules in the heart with experimental autoimmune carditis. Immunohistochemical examinations reveled that expression of tenascin-C (TNC), matrix metalloproteinase-9 (MMP-9), transforming growth factorbeta1 (TGF-beta1), connective tissue growth factor (CTGF) and alpha smooth muscle cell actin (alphaSMA) peaked at 2 weeks post-immunization but only TGF-beta1 expression was sustained at 8 weeks. Administration of siRNAs for MMP-2 (siMMP-2) and for MMP-9 (siMMP-9) alone did not modulate inflammation and fibrosis. In contrast, simultaneous administration of siMMP-2 and siMMP-9 significantly reduced inflammation and fibrosis. Of note, siRNA treatment for TGF beta1, which is an anti-inflammatory cytokine, increased inflammation and decreased fibrosis. These findings suggest that in case of diseases characterized by initial inflammation and subsequent fibrosis, immunotherapies should target inflammation, not fibrosis, because the latter therapies exacerbate inflammation. PMID- 23099154 TI - Impairment of lysosomal functions by azithromycin and chloroquine contributes to anti-inflammatory phenotype. AB - Azithromycin and chloroquine have been shown to exhibit anti-inflammatory activities in a number of cellular systems, but the mechanisms of these activities have still not been clarified unequivocally. Since both drugs are cationic, accumulate in acidic cellular compartments and bind to phospholipids with a consequent increase in lysosomal pH and induce phospholipidosis, we examined the relevance of these common properties to their anti-inflammatory activities. We compared also these effects with effects of concanamycin A, compound which inhibits acidification of lysosomes. All three compounds increased lysosomal pH, accumulation of autophagic vacuoles and ubiquitinated proteins and impaired recycling of TLR4 receptor with consequences in downstream signaling in LPS-stimulated J774A.1 cells. Azithromycin and chloroquine additionally inhibited arachidonic acid release and prostaglandin E2 synthesis. Therefore, impairment of lysosomal functions by azithromycin and chloroquine deregulate TLR4 recycling and signaling and phospholipases activation and lead to anti-inflammatory phenotype in LPS-stimulated J774A.1 cells. PMID- 23099155 TI - A study of the molecular structure and spectroscopic properties of 3-hydroxy-2 quinoxalinecarboxylic acid by experimental methods and quantum chemical calculations. AB - The mid-IR and Raman spectra of 3-hydroxy-2-quinoxalinecarboxylic acid (3HQC) were recorded. These spectra were interpreted with the help of B3LYP/6 311++G(d,p) calculations and potential energy distribution (PED) analysis. As a result of the calculations, seven tautomers were determined among many stable conformations. The experimental spectra were concordant with the theoretical data of two tautomers. In the functional group region overtone and combination bands were detected and assigned. In addition, because of several peaks in the IR spectrum, it was proposed that the 3HQC exhibits dimerization in condensed phase. Possible dimeric forms of 3HQC were evaluated at the same level of theory, and it has been seen that the calculation results confirm the above proposal. 1H and 13C NMR chemical shifts of 3HQC have been calculated, and compared with the experimental data. The frontier molecular orbital properties and the atomic charges were also theoretically obtained and presented. PMID- 23099156 TI - DFT, FT-IR and Raman investigations of 1-pyrrolidino-1-cyclopentene. AB - FT-IR and Raman spectra of 1-pyrrolidino-1-cyclopentene (1py1cp) were experimentally reported in the region of 4000-10 cm(-1) and 4000-100 cm(-1), respectively. The optimized geometric parameters, normal mode frequencies and corresponding vibrational assignments of 1py1cp (C9H15N) were theoretically examined by means of the B3LYP hybrid density functional theory (DFT) method together with the 6-31++G(d,p) basis set. Furthermore, reliable vibrational assignments were made on the basis of the potential energy distribution (PED) and the thermodynamics functions, the highest occupied and the lowest unoccupied molecular orbitals (HOMO and LUMO) of 1py1cp were predicted. Calculations were carried out employed for three different conformations of 1py1cp in gas phase. Comparison between the experimental and theoretical results indicates that density functional B3LYP method is able to provide satisfactory results for predicting vibrational wavenumbers and envelope conformer is predicted to be the most stable conformer of 1py1cp. PMID- 23099157 TI - Spectroscopic studies on the interaction of fluorescein and safranine T in PC liposomes. AB - In this study, the fluorescence quenching of fluorescein by safranine T in liposome media had been investigated systematically by fluorescence spectroscopy, UV-vis absorption spectroscopy and fluorescence decay lifetime measurements. The spectroscopic data were analyzed using a Stern-Volmer equation to determine the quenching process. The experimental results showed that the intrinsic fluorescence of fluorescein was strongly quenched by safranine T, and that the quenching mechanism was considered as static quenching by forming a ground complex. The Stern-Volmer quenching constant Ksv, and the bimolecular quenching constant Kq were estimated. The distances between the donor (fluorescein) and the acceptor (safranine T) were calculated according to the Forster non-radiation energy transfer theory. In addition, the partition coefficient of the safranine T (Kp) in the L-egg lecithin phosphatidylcholine liposomes was also calculated by utilizing the fluorescence quenching. PMID- 23099158 TI - Raman spectroscopy of glyoxal oligomers in aqueous solutions. AB - Raman microscopy and Attenuated Total Reflection infrared spectroscopy were utilized to facilitate investigations of equilibria between various hydrated and oligomeric forms of glyoxal in aqueous glyoxal solution droplets. The assignment of spectra is obtained with the assistance of B3LYP density functional quantum chemical calculations of vibrational wavenumbers, Raman activities, and infrared intensities. Several forms of glyoxal derivatives with similar functional groups, e.g., hydroxyl and dioxolane rings, are found to be present. The absence of a Raman spectral peak corresponding to the vibrational carbonyl stretch provides evidence that both carbonyl groups of a glyoxal molecule become hydrated in solutions of a broad concentration range. The presence of bands corresponding to deformation vibrations of the dioxolane ring indicates that dihydrated glyoxal oligomers are formed in glyoxal solutions with concentrations of 1 M and higher. Under typical ambient temperature and humidity conditions, concentrated glyoxal solution droplets undergo evaporation with incomplete water loss. Our results suggest that formation of crystalline glyoxal trimer dihydrate from concentrated solutions droplets is hindered by the high viscosity of the amorphous trimer and requires dry conditions that could rarely be achieved in the atmosphere. However, crystallization may be possible for droplets of low initial glyoxal concentrations, such as those produced by evaporating cloud droplets. PMID- 23099159 TI - Mid-infrared spectroscopic properties and energy transfer of Er3+/Yb3+ co-doped bismuth germanate glass. AB - An Er3+/Yb3+ co-doped bismuth germanate glass is synthesized and analyzed. The radiative characteristics and mid-infrared spectroscopic properties are investigated under excitation of a conventional 980 nm laser diode. The prepared glass possesses higher spontaneous transition probability (68.82 s(-1)) and larger calculated emission cross-section (7.73*10(-21) cm2) corresponding to the 4I11/2->4I13/2 transition. The calculated energy migration coefficient (CDD) among Yb3+ ions is larger than the energy transfer coefficient (CDA) from Yb3+ to Er3+, indicating the energy transfer process assisted with energy migration. The excellent spectroscopic properties along with the outstanding thermal stability suggest that this glass may become an attractive host for developing solid state lasers operating in the mid-infrared range. PMID- 23099160 TI - Kinetic-spectrophotometric determination of methyl parathion in water and vegetable samples. AB - A new selective and sensitive kinetic method has been developed for spectrophotometric determination of methyl parathion based on its inhibitory effect on the redox reaction between bromate and hydrochloric acid. The decolorization of neutral red by the reaction product was used to monitor the reaction spectrophotometrically at 530 nm by measuring the change in absorbance at the fixed time of 5 min after the initiation of the reaction. The variables affecting the rate of the reaction were investigated. Under the selected experimental conditions methyl parathion was determined in the range of 0.025-0.3 MUg mL(-1). Sandell's sensitivity and molar absorptivity for the system were found to be 0.0004 MUg cm(-2) and 6.5*10(5) L mol(-1) cm(-1) respectively. The proposed method was applied for the determination of methyl parathion in different vegetable and water samples with satisfactory results. The results were compared with those obtained by GC-MS, very similar values were found by the two methods. PMID- 23099161 TI - Synthesis and characterization of a series of transition metal complexes with a new symmetrical polyoxaaza macroacyclic Schiff base ligand: X-ray crystal structure of cobalt(II) and nickel(II) complexes and their antibacterial properties. AB - A new symmetrical [N4O2] hexadentate Schiff base ligand, (E)-N-(pyridin-2 ylmethylene)-2-(3-(2-((E)-pyridin-2-lmethyleneamino)phenoxy)naphthalen-2 yloxy)benzenamine, abbreviated to L, and its complexes of Ni(II), Cu(II), Zn(II), Co(II), Cd(II) and Mn(II) have been synthesized in the presence of metal ions. The complexes were structurally characterized by elemental analyses, IR, UV-Vis, NMR and molar conductivity. The crystal structures of two complexes, [NiL(ONO2)2].2H2O and [CoLCl2]CH3OH.0.5H2O, have been determined by a single crystal X-ray diffraction study. In these complexes, the ligand is coordinated in a neutral form via pyridine and azomethine nitrogen atoms. The metal ions complete their six coordination with two coordinated nitrate or chloride ions, forming a distorted octahedral geometry. The synthesized compounds have antibacterial activity against the three Gram-positive bacteria: Enterococcus faecalis, Bacillus cereus and Staphylococcus epid and also against the three Gram negative bacteria: Citrobacter freundii, Enterobacter aerogenes and Salmonella typhi. The activity data show that the complexes are more potent antibacterials than the parent Schiff base. PMID- 23099162 TI - Spectrophotometric determination of the formation constant of triiodide ions in aqueous-organic solvent or polymer mixed media both in absence and presence of a surfactant. AB - The formation constant of triiodide ions from iodine-iodide equilibrium in aqueous-organic solvent or polymer mixed media have been determined spectrophotometrically at three different temperatures 20, 30 and 40 degrees C. The organic solvents chosen for the study are ethylene glycol, 2-methoxy ethanol, and 2-ethoxy ethanol while the polymers include polyethylene glycol (PEG), hydroxypropyl cellulose (HPC) or polyethylene oxide (PEO). Effect of a surfactant on the formation of triiodide ions in the mixed media has also been investigated. Though presence of the organic solvents led to an increase in the triiodide formation except for 2-ethoxy ethanol mixed media at low percentage, the increase in presence of PEG or the other polymer mixed media even at very low percentage was much higher as compared to those in ethylene glycol or its homologues. The increase in the formation constant has been discussed in terms of changes in its solvation properties and the hydrophobic character of the mixed media besides the solvent dielectric effects. The sharp increase in triiodide formation in presence of the polymer under study suggests the possibility of iodine being present as triiodide or other higher polyiodides in the inclusion complexes of iodine with other polymers like starch or PVA. The decrease in the triiodide formation in presence of surfactant micelles may, however, be attributed to solubilization of iodine by the micelles. Iodine was found to be better solubilized in TX-100 micelles as compared to SDS micelles. PMID- 23099163 TI - Investigation of spectroscopic properties, structure and luminescence spectra of Sm3+ doped zinc bismuth silicate glasses. AB - The glasses with compositions 20ZnO.(79.5-x)Bi2O3.xSiO2.0.5Sm2O3 (10<=x<=50, mol%) have been synthesized using normal melt-quench technique. Optical absorption and fluorescence spectra of the glasses were recorded at ambient temperature. Judd-Ofelt (J-O) theory has been successfully applied to characterize the absorption and luminescence spectra of these glasses. From the measured intensities of absorption bands of these glasses, the Judd-Ofelt parameters, Omegalambda (lambda=2, 4, 6) have been evaluated. The variation of Omega2 with Bi2O3 content has been attributed to changes in the asymmetry of the ligand field at the rare earth (RE) ion site (due to structural change) and to changes in RE-O covalency, whereas the variation of Omega6 is found to be strongly dependent on nephlauxetic effect. The shift of the hypersensitive band shows that the covalency of the RE-O decreases with decrease in Bi2O3 content in the host glass. Also, using J-O theory various radiative properties like spontaneous emission probability (Arad), radiative life time (taur), fluorescence branching ratio (betar) and stimulated emission cross-section (sigma) for various emission bands of these glasses in the visible spectral region have been determined. A close correlation is observed between the Bi2O3 content and the spectroscopic, radiative and structural properties of the prepared glasses. The values of radiative properties indicated that 4G5/2->6H7/2 and 4G5/2->6H9/2 transitions responsible for orange luminescence might be used in the development of materials for LED's and other optical devices in the visible region. PMID- 23099164 TI - Spectroscopic analyses on ROS generation catalyzed by TiO2, CeO2/TiO2 and Fe2O3/TiO2 under ultrasonic and visible-light irradiation. AB - In this work, the TiO2, CeO2/TiO2 and Fe2O3/TiO2 powders were irradiated, respectively, by ultrasound and visible-light, and the generation of reactive oxygen species (ROS) were estimated by the method of Oxidation-Extraction Photometry (OEP). That is, the 1,5-diphenyl carbazide (DPCI) can be oxidized by generated ROS into 1,5-diphenyl carbazone (DPCO), which can be extracted by mixed solvent of benzene and carbon tetrachloride. The DPCO extract liquor displays an obvious absorbance at 563 nm wavelength. In addition, some influencing factors, such as (ultrasonic or visible-light) irradiation time, catalyst addition amount and DPCI concentration, on the generation of ROS were also reviewed. The results indicated that the quantities of generated ROS increase with the increase of (ultrasonic or visible-light) irradiation time and catalyst addition amount. Moreover, the displayed quantities of ROS are also related with DPCI concentration. And then, several radical scavengers were used to determine the kinds of the generated ROS. At last, the researches on the sonocatalytic and photocatalytic degradation of several organic dyes have also been performed. It is wished that this paper might offer some important subjects for broadening the applications of sonocatalytic and photocatalytic technologies in future environment treatment. PMID- 23099165 TI - FT-IR, FT-Raman spectral and conformational studies on (E)-2-(2 hydroxybenzylidenamino)-3-(1H-indol-3yl) propionic acid. AB - The (E)-2-(2-hydroxybenzylidenamino)-3-(1H-indol-3yl) propionic acid ((E) 2HBA3IPA) was synthesized. The theoretical conformational analysis was performed to identify the stable structure. Optimized molecular bond parameters were calculated by using B3LYP/6-31G(d,p) basis set. The hyperconjugative interaction energy (E(2)) and electron densities of donor (i) and acceptor (j) bonds were calculated using NBO analysis. First order hyperpolarizability (beta0) was calculated. The band gap energy was analyzed by UV-Visible recorded spectra and compared with theoretical band gap TD-DFT/B3LYP/6-31G(d,p) values. The intra molecular hydrogen bonding interaction was identified between nitrogen and hydroxyl hydrogen (N?H-O). PMID- 23099166 TI - Template synthesis and spectral studies on mononuclear complexes of chromium(III) and manganese(II) with tetradentate N4 donor macrocycles. AB - The present article deals with the synthesis, spectral characterization and antimicrobial activity of a series of new complexes of chromium(III) and manganese(II)of general formula [Cr(Macn)Cl2].Cl and [Mn(Macn)Cl2] respectively. These complexes were prepared via template reaction by mixing methanolic solution of diacetyldihydrazone, diacids (oxalic acid, succinic acid, glutaric acid and adipic acid) with CrCl3.6H2O and MnCl2.4H2O in 2:2:1 M ratios respectively. The newly synthesized complexes were characterized on the basis of chemical analysis and spectral studies like IR, UV, ESR and X-ray diffraction. An octahedral structure has been proposed for the chromium(III) and manganese(II)macrocyclic complexes. The synthesized complexes were further tested in vitro against fungi and bacteria in order to assess their antibacterial and antifungal activities. The studies demonstrate that the complexes possess antimicrobial properties. PMID- 23099167 TI - Spectrofluorimetric determination of trace nitrite with o-phenylenediamine enhanced by hydroxypropyl-beta-cyclodextrin. AB - A simple and sensitive spectrofluorimetric method was developed for the determination of nitrite in environmental and food samples. The method was based on the selective reaction of o-phenylenediamine with nitrite in acidic medium to form benzotriazole, which exhibited strong fluorescence at 568 nm with excitation at 420 nm in alkaline medium. The detection limit and sensitivity of the proposed method were improved by hydroxypropyl-beta-cyclodextrin through complexation. The linear calibration range for nitrite was 0.04-0.8 MUg mL(-1) with a detection limit of 13.6 ng mL(-1) (S/N=3.29). The relative standard deviation for ten determinations of 0.1 and 0.4 MUg mL(-1) nitrite were 1.38% and 2.01%, respectively. Twenty-eight coexistent ions were examined, and no serious interference for most of ions was observed. The proposed method was successfully applied for the determination of nitrite in the water, sausage and soil samples with recoveries of 95.5-108.5%. The results were in good agreement with the recommended AOAC method. PMID- 23099168 TI - Growth and characterization of Melaminium bis (trichloroacetate) dihydrate. AB - Single crystals of melaminium bis (trichloroacetate) dihydrate have been grown successfully by slow evaporation solution growth technique at room temperature. Single crystal X-ray diffraction analysis reveals that the compound crystallizes in monoclinic system with non -centrosymmetric space group C2 with lattice parameters a=17.70 A, b=8.44 A, c=6.09 A, alpha=90 degrees , beta=100.24 degrees , gamma=90 degrees and V=900 (A)3. The UV-Vis transmittance spectrum shows that the crystal has a good optical transmittance in the entire visible region with lower cutoff wavelength of 351 nm. The vibrational frequencies of various functional groups present in the crystal have been derived from FI-IR, FT-Raman and Confocal Raman analyses. The chemical structure of the compound was established by 1H and 13C NMR spectrum. TGA-DTA analysis reveals that the materials have good thermal stability and the melting point of the crystal is found to be 195 degrees C. The dielectric response of the crystals was studied in the frequency range 50 Hz to 5 MHz at different temperatures and the results are discussed. Etching studies show the growth pattern of the crystals. The second harmonic generation efficiency was measured in comparison with KDP by employing powder Kurtz method. PMID- 23099169 TI - Density functional theory study on the molecular structure and vibration spectra of fenbufen. AB - This paper examines the comparative performance of different density functional theory (DFT) methods at various basis sets in predicting molecular and vibration spectra of gamma-oxo-[1,1'-biphenyl]-4-butanoic acid (fenbufen). DFT methods including mPW1PW91, HCTH, SVWN, PBEPBE, B3PW91 and B3LYP were investigated. Different basis sets including LANL2DZ, SDD, LANL2MB, CEP-4G, CEP-31G, and CEP 121G were also considered. It is remarkable that the mPW1PW91/LANL2DZ and mPW1PW91/SDD levels are clearly superior to all of the remaining DFT levels in predicting the structure of fenbufen. The calculated results also indicate that SVWN/LANL2DZ level show better performance in the vibration spectra prediction of fenbufen comparing other DFT methods. PMID- 23099170 TI - Gastric cancer differentiation using Fourier transform near-infrared spectroscopy with unsupervised pattern recognition. AB - The manuscript has investigated the application of near-infrared (NIR) spectroscopy for differentiation gastric cancer. The 90 spectra from cancerous and normal tissues were collected from a total of 30 surgical specimens using Fourier transform near-infrared spectroscopy (FT-NIR) equipped with a fiber-optic probe. Major spectral differences were observed in the CH-stretching second overtone (9000-7000 cm(-1)), CH-stretching first overtone (6000-5200 cm(-1)), and CH-stretching combination (4500-4000 cm(-1)) regions. By use of unsupervised pattern recognition, such as principal component analysis (PCA) and cluster analysis (CA), all spectra were classified into cancerous and normal tissue groups with accuracy up to 81.1%. The sensitivity and specificity was 100% and 68.2%, respectively. These present results indicate that CH-stretching first, combination band and second overtone regions can serve as diagnostic markers for gastric cancer. PMID- 23099171 TI - Cobalt(II), Nickel(II) and Copper(II) complexes of a tetradentate Schiff base as photosensitizers: Quantum yield of 1O2 generation and its promising role in anti tumor activity. AB - In the present investigation, a Schiff base N'1,N'3-bis[(E)-(5-bromo-2 hydroxyphenyl)methylidene]benzene-1,3-dicarbohydrazide and its metal complexes have been synthesized and characterized. The DNA-binding studies were performed using absorption spectroscopy, emission spectra, viscosity measurements and thermal denatuaration studies. The experimental evidence indicated that, the Co(II), Ni(II) and Cu(II) complexes interact with calf thymus DNA through intercalation with an intrinsic binding constant Kb of 2.6*10(4) M(-1), 5.7*10(4) M(-1) and 4.5*10(4) M(-1), respectively and they exhibited potent photodamage abilities on pUC19 DNA, through singlet oxygen generation with quantum yields of 0.32, 0.27 and 0.30 respectively. The cytotoxic activity of the complexes resulted that they act as a potent photosensitizers for photochemical reactions. PMID- 23099172 TI - Mixed alkali effect in Mn2+ doped 20ZnO+xLi2O+(30-x)K2O+50B2O3(5<=x<=25) glasses. AB - Divalent Mn2+ ions containing 20ZnO+xLi2O+(30-x)K2O+50B2O3(5<=x<=25) mol% glasses are prepared by using melt quench technique and are characterized by several spectroscopic techniques. Various physical parameters are evaluated from the measured values of density and refractive index for the observation of mixed alkali effect. Structural changes of Mn2+ doped ZLKB glasses are investigated by Powder XRD, UV-VIS absorption, Electron Paramagnetic Resonance and FT-IR spectroscopic studies. The XRD pattern indicates the amorphous nature of prepared glasses. FT-IR measurements of all glasses revealed that the network structure of glass system are mainly based on BO3 and BO4 units placed in different structural groups in which the BO3 units being dominant. The EPR spectra of Mn2+ ions doped glasses exhibited a characteristic hyperfine sextet around g=2.0. The spectroscopic analyses of the obtained results confirmed near octahedral site symmetry for the Mn2+ impurity ions. Crystal field and Racah parameters are evaluated from optical absorption spectra. The optical band gap and Urbach energies are determined which exhibited the mixed alkali effect. PMID- 23099173 TI - Ab initio, density functional computations, FT-IR, FT-Raman and molecular geometry of 4-morpholine carbonitrile. AB - The 4-morpholine carbonitrile (4MC) was investigated by vibrational spectroscopy and quantum chemical methods. The solid phase FT-IR and FT-Raman spectra were recorded in the region 4000-400 cm(-1) and 3500-50 cm(-1), respectively. The molecular geometry and vibrational frequencies of 4MC have been calculated in the ground state by using the ab initio Hartree-Fock and density functional method (B3LYP) with 6-311++G(d, p) basis set. The observed and calculated frequencies are found to be in good agreement. The calculated HOMO and LUMO energies show the charge transfer occurs within the molecule. Stability of the molecule arising from hyper conjugative interactions and charge delocalization has been analyzed using natural bond orbital (NBO) analysis. The theoretical FT-IR and FT-Raman spectra for the title compound have also been constructed. PMID- 23099174 TI - Lifetime time measurements, Kamlet-Taft and Catalan solvatochromism of some 2 aryl benzimidazole derivatives. AB - Some 2-aryl benzimidazole derivatives (1-6) have been prepared and characterized by different spectral techniques. Fluorescence lifetime of synthesized 2-aryl benzimidazole derivatives was calculated. Kamlet-Taft and Catalan solvatochromism of synthesized 2-aryl benzimidazole derivatives have been discussed. Crystal structure of 1-(4-methylbenzyl)-2-p-tolyl-1H-benzo[d]imidazole has been studied. PMID- 23099175 TI - Structural, spectroscopic characterization and EPR spectra of nitrato-MU-[N,N' ethylenebis(3-methoxysalicylideneimine) Cu(II)Ag(I)] complex. AB - A novel heterodinuclear complex formed by the reaction of silver nitrate with Schiff base complex of copper(II) has been synthesized and characterized by Infrared (IR), ultraviolet-visible (UV-VIS), electron paramagnetic resonance (EPR) and X-ray diffraction methods. Preparation and crystal structure of the heterodinuclear complex, LCuAgNO3, (L=N,N'-ethylenebis(3 methoxysalicylideneimine) are reported. The crystal structure consists of ordered dinuclear units with CuII and AgI ions are bridged by two oxygen atoms of Schiff base ligand. The copper(II) ion has a distorted square-planar geometry involving the N2O2 donor set of Schiff base ligand. The g-values were calculated for title complex both in polycrystalline state at 298 K and in frozen DMF (113 K). The evaluated metal-ligand bonding parameters showed strong in-plane sigma bonding. PMID- 23099176 TI - Distinction of leukemia patients' and healthy persons' serum using FTIR spectroscopy. AB - In this paper, FTIR spectroscopy was applied to compare the serum from leukemia patients with the serum from healthy persons. IR spectra of leukemia patients' serum were similar with IR spectra of healthy persons' serum, and they were all made up of proteins, lipids and nucleic acids, etc. In order to identify leukemia patients' serum and healthy persons' serum, the H1075/H1542, H1045/H1467, H2959/H2931 ratios were measured. The H2959/H2931 ratio had the highest significant difference among these ratios and might be a useful factor for identifying leukemia patients' serum and healthy persons' serum. Furthermore, from curve fitting, the RNA/DNA (A1115/A1028) ratios were observed to be lower in leukemia patients' serum than those in healthy persons' serum. The results indicated FTIR spectroscopic study of serum might be a useful tool in the field of leukemia research and diagnosis. PMID- 23099177 TI - Long-term cognitive and neurochemical effects of "bath salt" designer drugs methylone and mephedrone. AB - INTRODUCTION/AIMS: The use of cathinone-derivative designer drugs methylone and mephedrone has increased rapidly in recent years. Our aim was to investigate the possible long-term effects of these drugs on a range of behavioral tests in mice. Further, we investigated the long-term effects of these drugs on brain neurochemistry in both rats and mice. METHODS: We treated animals with a binge like regimen of methylone or mephedrone (30 mg/kg, twice daily for 4 days) and, starting 2 weeks later, we performed behavioral tests of memory, anxiety and depression and measured brain levels of dopamine (DA), serotonin (5-HT), their metabolites and norepinephrine (NE). 5-HT and DA transporter (5-HTT and DAT) levels were also measured in rats by [(3)H]paroxetine and [(3)H]mazindol binding. RESULTS: Mephedrone reduced working memory performance in the T-maze spontaneous alternation task but did not affect neurotransmitter levels aside from a 22% decrease in striatal homovanillic acid (HVA) levels in mice. Methylone had little effect on behavior or neurotransmitter levels in mice but produced a widespread depletion of 5-HT and 5-HTT levels in rats. CONCLUSIONS: Both methylone and mephedrone appeared to have a long-term effect on either behavioral or biochemical gauges of neurotoxicity in rodents. PMID- 23099182 TI - Same-day diagnosis and treatment of tuberculosis. PMID- 23099183 TI - Diagnostic accuracy of same-day microscopy versus standard microscopy for pulmonary tuberculosis: a systematic review and meta-analysis. AB - BACKGROUND: Sputum smear microscopy is the most widely available diagnostic test for pulmonary tuberculosis in countries with a high burden of the disease. Improving its accuracy is crucial to achievement of case-detection targets established by the Millennium Development Goals. Unfortunately, many patients are unable to submit all of the specimens needed for examination or to return for treatment because standard sputum collection and reporting requires several clinic visits. To inform policy recommendations by a WHO-convened Expert Group, we aimed to assess the accuracy of sputum smear examination with strategies for obtaining sputum on 1 day compared with strategies for obtaining sputum over 2 days. METHODS: We did a systematic review and meta-analysis of research articles comparing the accuracy of front-loaded or same-day microscopy and standard sputum smear microscopy for diagnosis of culture-confirmed pulmonary tuberculosis. We searched Medline, Embase, Biosis, and Web of Science for articles published between Jan 1, 2005, and Feb 14, 2012. Two investigators identified eligible articles and extracted data for individual study sites. We generated pooled summary estimates (95% CIs) for sensitivity and specificity by use of random effects meta-analysis when four or more studies were available. FINDINGS: We identified eight relevant studies from five articles enrolling 7771 patients with suspected tuberculosis in low-income countries. Compared with the standard approach of examination of two smears with Ziehl-Neelsen light microscopy over 2 days, examination of two smears taken on the same day had much the same sensitivity (64% [95% CI 60 to 69] for standard microscopy vs 63% [58 to 68] for same-day microscopy) and specificity (98% [97 to 99] vs 98% [97 to 99]). We noted similar results for studies employing light-emitting diode fluorescence microscopy and for studies examining three smears, whether they were compared with two-smear strategies or with one another. INTERPRETATION: Same-day sputum smear microscopy is as accurate as standard smear microscopy. Data from tuberculosis programmes are needed to document the changes required in the health system to successfully implement the strategy and understand its effects. FUNDING: WHO and US National Institutes of Health. PMID- 23099184 TI - Locating the sural nerve during calcaneal (Achilles) tendon repair with confidence: a cadaveric study with clinical applications. AB - The sural nerve is at risk of iatrogenic injury even during minimally invasive operative procedures to repair the calcaneal (Achilles) tendon. Through 107 cadaveric leg dissections, the data derived from the present study was used to develop a regression equation that will enable surgeons to estimate the intersection point at which the sural nerve crosses the lateral border of the Achilles tendon, an important surgical landmark. In most cases, the sural nerve crossed the lateral border of the Achilles tendon 8 to 10 cm proximal to the superior border of the calcaneal tuberosity. By simply measuring the leg length of the patient (from the base of the heel to the flexor crease of the popliteal fossa), surgeons can approximate the location of this intersection point with an interval length of 0.68 to 1.80 cm, with 90% confidence, or 0.82 to 2.15 cm, with 95% confidence. For example, for a patient with a lower leg length of 47.0 cm, the mean measurement in the present study, a surgeon can be 90% confident that the sural nerve will cross the lateral border of the Achilles tendon 8.28 to 8.96 cm (interval width of 0.68 cm) proximal to the calcaneal tuberosity. Currently, ultrasound and clinical techniques have been implemented to approximate the location of the sural nerve. The results of the present study offer surgeons another method, that is less intensive, to locate reliably and subsequently avoid damage to the sural nerve during calcaneal (Achilles) tendon repair and other procedures of the posterolateral leg and ankle. PMID- 23099185 TI - Arthroscopic management of the septic ankle joint: case report of a stage-guided treatment. AB - Ankle joint sepsis is a serious pathologic entity that, if not effectively treated, can lead to significant dysfunction and morbidity. Minimal published data are available to guide the frequency and extent of surgical irrigation and debridement in patients with ankle joint sepsis. We report on a surgical treatment protocol used at our institution based on intraoperative joint staging. We present the case of a 68-year-old female with well-controlled diabetes who presents with ankle joint sepsis. She represents a typical patient treated by our standard approach. At approximately 1 year postoperatively, the patient reported minimal residual pain and had returned to near previous activity levels, despite an advanced stage of joint sepsis at the initial presentation. The treatment protocol provides supplemental guidance to assist regular clinical judgment in managing the septic ankle joint. PMID- 23099186 TI - The luminal Ca(2+) chelator, TPEN, inhibits NAADP-induced Ca(2+) release. AB - The regulation of Ca(2+) release by luminal Ca(2+) has been well studied for the ryanodine and IP(3) receptors but has been less clear for the NAADP-regulated channel. In view of conflicting reports, we have re-examined the issue by manipulating luminal Ca(2+) with the membrane-permeant, low affinity Ca(2+) buffer, TPEN, and monitoring NAADP-induced Ca(2+) release in sea urchin egg homogenate. NAADP-induced Ca(2+) release was almost entirely blocked by TPEN (IC(50) 17-25MUM) which suppressed the maximal extent of Ca(2+) release without altering NAADP sensitivity. In contrast, Ca(2+) release via IP(3) receptors was 3 to 30-fold less sensitive to TPEN whereas that evoked by ionomycin was essentially unaffected. The effect of TPEN on NAADP-induced Ca(2+) release was not due to an increase in the luminal pH or chelation of trace metals since it could not be mimicked by NH(4)Cl or phenanthroline. The fact that TPEN had no effect upon ionophore-induced Ca(2+) release also argued against a substantial reduction in the driving force for Ca(2+) efflux. We propose that, in the sea urchin egg, luminal Ca(2+) is important for gating native NAADP-regulated two pore channels. PMID- 23099187 TI - Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: a prospective, multicenter study. AB - BACKGROUND & AIMS: The effects of pegylated interferon (PegIFN) alpha and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNalpha2b and RBV. METHODS: This large scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n=863 and cirrhosis, n=150). All patients were treated with PegIFNalpha2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome. RESULTS: Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non virological response (NVR) group (7.6%) (p=0.003 and p=0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p=0.03 and p=0.04, respectively). CONCLUSIONS: SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR. PMID- 23099188 TI - Liver transplantation for HBV-related cirrhosis in Europe: an ELTR study on evolution and outcomes. AB - BACKGROUND & AIMS: HBV-related chronic liver disease is one of the most common indications for liver transplantation (LT) in Europe. The ELTR database was used to evaluate outcomes and evolution over 20 years (01/1988 and 12/2010). METHODS: HBV transplanted patients were analysed according to indication for LT: decompensated cirrhosis (HBVdec) or hepatocellular carcinoma (HBV/HCC). These groups were compared with co-infected patients HBV/HDV (HBDV), HBV/HCV (HBCV), HBV/HDV/HCV (HBDCV); n = 16,664 and with HCV patients (n = 2452) according to LT indication. RESULTS: 5912 patients were transplanted for HBV (78% HBVdec, 22% HBV/HCC), with HBV/HCC patients who increased from 15.8% in 1988-1995 to 29.6% in 2006-2010 (p < 0.001). In HBVdec patients, 1, 3, 5, and 10 year patient and graft survival was 83%, 78%, 75%, 68%, and 80%, 74%, 71%, 64%, respectively, significantly better than HBV/HCC (84%, 73%, 68%, 61%, and 81%, 70%, 65%, 58% respectively; p = 0.001 and p = 0.026). In 2006-2010 patient and graft survival significantly improved compared to 1988-1995, both for HBVdec and HBV/HCC (each p < 0.001). A better patient and graft survival was seen in HBV/HCC patients with HBV-DNA(-) compared to HBV-DNA(+) at the time of LT (p < 0.001). Disease recurrence, as cause of death/graft loss, was significantly reduced in recent years compared to the past: currently <1% for HBVdec and 3% for HBV/HCC. CONCLUSIONS: Outcomes of LT for HBV have improved in recent years, with disease recurrence being no longer a significant cause of death/graft loss. HBV-DNA at the time of LT seems to influence survival only in HBV/HCC patients. PMID- 23099189 TI - Sling revision/removal for mesh erosion and urinary retention: long-term risk and predictors. AB - OBJECTIVE: The objective of the study was to estimate the long-term risk of sling revision/removal after an initial sling and to assess indications (mesh erosion and urinary retention) and predictors of sling revision/removal. STUDY DESIGN: Using a population-based cohort of commercially insured individuals, we identified women 18 years old or older who underwent a sling (Current Procedural Terminology code 57288) between 2001 and 2010 and any subsequent sling revision/removal (Current Procedural Terminology code 57287). We estimated the cumulative risk of revision/removal annually and evaluated predictors of sling revision/removal using Kaplan-Meier survival curves and Cox proportional hazards models, respectively. RESULTS: We identified 188,454 eligible women who underwent an index sling. The 9 year cumulative risk of sling revision/removal was 3.7% (95% confidence interval [CI], 3.5-3.9). At 1 year, this risk was already 2.2% and then increased to 3.2% at 4 years before plateauing. With regard to the indication for the sling revision/removal, a greater proportion was due to mesh erosion compared with urinary retention, with a 9 year risk of 2.5% (95% CI, 2.3 2.6) for mesh erosion vs 1.3% (95% CI, 1.2-1.4) for urinary retention. Age had an effect on the revision/removal rates for both mesh erosion and urinary retention, with the higher risks among those aged 18-29 years. The risk of revision/removal for mesh erosion and urinary retention was also elevated among women who had a concomitant anterior or apical prolapse procedure. CONCLUSION: In this population based analysis, the 9 year risk of sling revision/removal was relatively low at 3.7%, with 60% of revisions/removals caused by mesh erosion. PMID- 23099190 TI - Does the type of surgery for early-stage endometrial cancer affect the rate of reported lymphovascular space invasion in final pathology specimens? AB - OBJECTIVE: Laparoscopically assisted vaginal hysterectomy (LAVH), which usually involves the use of an intrauterine manipulator for optimal surgical control, has been shown to be as effective and safe as conventional total abdominal hysterectomy (TAH) for the staging of endometrial carcinoma. The purpose of this study was to determine whether the use of an intrauterine manipulator was associated with an increase in the pathologic reporting of lymphovascular space invasion (LVSI), which is an important determinant in choosing adjuvant therapy. We hypothesized that intracavitary manipulation and an increase of the intrauterine pressure could cause pseudolymphovascular invasion. STUDY DESIGN: We performed a retrospective chart review of endometrial cancer patients treated at our institution from January 1996 through January 2006. Records were reviewed for patient's age, preoperative diagnosis, procedure type, final surgical staging, and final pathology report. Using the 2009 International Federation of Gynecology and Obstetrics staging, we included all patients having stage IA or IB endometrioid-type endometrial cancer who had undergone either a TAH or LAVH with or without pelvic and paraaortic lymph node dissection. The chi2 and Fisher exact tests were used to measure the association between risk of positive lymphovascular invasion and surgical groups. RESULTS: Of 568 women identified as having endometrioid-type endometrial cancer, 486 (85.6%) met criteria for stage IA-IB endometrioid histology, grade 1, 2, or 3. LVSI was reported in 553/568 cases, with LVSI positivity in 16.9% (n = 96/568). The mean ages of the LAVH and TAH groups were significantly different (59.4 vs 62.4 years, respectively, P = .0050). Also, mean estimated blood loss and uterine weight significantly varied between TAH and LAVH groups (P = .0001 and .008, respectively). For stage IA, 17/220 (7.7%) who had been treated with LAVH had positive LVSI compared with 20/199 (10.1%) of patients receiving TAH (P = .73). For stage IB, 11/25 (44.0%) of patients treated with LAVH had positive LVSI compared with 10/31 (32.3%) of patients receiving TAH (P = .53). The stage I cancer patients were further subdivided into histological grades 1, 2, and 3, and LVSI was not significantly different between TAH and LAVH groups per grade of cancer. We found no differences between TAH and LAVH in early-stage endometrial cancer (stage IA and IB), with respect to the presence of positive peritoneal washings. CONCLUSION: In early-stage endometrial cancer (stage IA and IB), there were no differences between TAH and LAVH in the final pathologic report of LVSI. The use of an intrauterine manipulator for LAVH was not associated with an increased detection of LVSI. PMID- 23099191 TI - Anatomic relationships of single-incision midurethral slings. AB - OBJECTIVE: The objective of the study was to evaluate the anatomic relationships of anchor points of single-incision midurethral slings with 2 common placement trajectories. STUDY DESIGN: In 30 female pelvic halves, a probe was introduced through a suburethral tunnel following 45 degrees and 90 degrees angle trajectories. The corresponding anchor points were tagged. Distances to the obturator canal, accessory obturator vessels, dorsal vein of clitoris, and external iliac vein were recorded. RESULTS: Both suburethral tunnel trajectories and their respective anchor points remained caudad to the obturator internus muscle in 100% of dissections. The closest distance between either anchor point to the obturator canal was 1.6 cm. The closest distance from the 45 degrees and 90 degrees anchor points to the accessory obturator vessels was 1.6 and 1.5 cm, respectively. CONCLUSION: The anchor points of single-incision midurethral slings are in close proximity to vascular structures that could be injured with inadvertent entry into the retropubic space. PMID- 23099192 TI - Antenatal identification of major depressive disorder: a cohort study. AB - OBJECTIVE: The purpose of this study was to estimate the frequency of identification of major depressive disorder by providers during prenatal care. STUDY DESIGN: A cohort of pregnant women who were participating in a randomized controlled trial and who had received a diagnosis of major depressive disorder was examined. Women were included in the current study if prenatal clinic records were available and legible. RESULTS: Clinical depression was noted in 56% of prenatal charts and on 24% of problem lists. Physicians and certified nurse midwives noted depression equally (P = .935); physicians more frequently noted mental health referral (23% vs 0%; P = .01), and midwives more frequently included depression on the problem list (P = .01). Recent medication use, which was stopped before conception or study participation, predicted notation of depression in the chart (P = .001). CONCLUSION: Depression frequently is missed during pregnancy and, when identified, is underacknowledged as a problem. Women who have not recently used antidepressant medication are more likely to be missed. Better screening and acknowledgment are needed. PMID- 23099193 TI - Receptivity assessment of an ultrasonographic homogeneous endometrium in the late follicular phase of infertile women with natural cycles. AB - OBJECTIVE: The purpose of this study was to assess the receptivity of the homogeneous endometrium in the late follicular phase in infertile women with natural cycles. STUDY DESIGN: Twenty-eight infertile women with ultrasonographically homogeneous (group 1) or trilaminar (group 2) endometria in the late follicular phase underwent endometrial biopsies. Some molecular markers and development of pinopodes were evaluated. RESULTS: In the late follicular phase, the mean level of vascular endothelial growth factor was significantly lower in group 1 than in group 2 (0.96 +/- 0.37 marks vs 1.39 +/- 0.46 marks; P = .010). In the mid luteal phase, a decreased leukemia inhibitory factor and integrin alpha v beta 3 levels were found in group 1 (1.58 +/- 0.99 marks vs 2.59 +/- 0.61 marks; 1.85 +/- 0.72 marks vs 2.60 +/- 0.73 marks; 1.92 +/- 0.91 marks vs 2.83 +/- 0.57 marks; P = .003; P = .011; P = .004). The rate of fully developed pinopodes in the mid luteal phase was significantly decreased in group 1 (P = .018). CONCLUSION: An ultrasonographically homogeneous endometrium in the late follicular phase was associated with poor receptivity in infertile women with natural cycles. PMID- 23099194 TI - Measuring the glomerular filtration rate in different age groups using iohexol, the protocol from the Belgian iohexol study. AB - OBJECTIVES: Measuring the exact glomerular filtration rate (GFR) is difficult. Iohexol can be used instead of inulin or labeled EDTA or DTPA. In recent years, different studies have validated GFR-estimating equations in adults. Validation of these estimations in adolescents and elderly is lacking. With this study, we aim to develop a simplified (only 1-3 blood collections) iohexol protocol to measure the true GFR for patients of all ages and try to develop GFR-estimating equations for adolescents and the elderly. DESIGN AND SETTING: Participants of different ages will be recruited: 50 adolescent (14-18 years) and 30 adults (20 65 years), 60 elderly (65-80 years) and 60 very elderly (80+ years old) stratified based on their GFR. Biometric data, serum creatinine and cystatin C will be measured. After injecting 5 mL iohexol, 9 blood samples will be taken between 20 and 360 min. First, the GFR will be calculated by using the double exponential decay method and different GFRs based on 1-3 blood samples, which will be compared with the GFR of the abovementioned 9 samples. Second, the GFR will be calculated by using new and existing equations and compared to the true GFR. DISCUSSION: The availability of a reliable GFR measurement is important in situations such as screening patients for kidney donation or when taking potentially nephrotoxic treatments. This study will allow us to develop a simplified protocol for measuring the true GFR in all ages and will allow us to validate existing equations and develop new eGFR equations for adolescents and the elderly. PMID- 23099195 TI - Mutation spectrum of the ASS1 gene in Korean patients with citrullinemia type I. AB - OBJECTIVES: Citrullinemia type I is a rare metabolic disorder and the distribution of mutations in the ASS1 gene varies among ethnic groups. We aimed to determine the molecular characteristics of citrullinemia type I in Korean patients. DESIGN AND METHODS: Biochemical and clinical findings were investigated and mutations in the ASS1 gene were identified using direct sequencing method in five patients with high citrulline levels. We also reviewed previous genotypes reported for Korean patients with citrullinemia type I. RESULTS: We identified five mutations in 10 mutant alleles from the five patients. The most common mutation was the Gly324Ser mutation, which was present in 40% of the mutant alleles, followed by the c.421-2A>G mutation (30% of the mutant alleles). The other mutations (c.1128-6_1188dup67, Arg127Gln, and Arg279Gln) were identified in one mutant allele each. A comprehensive review of previous Korean reports revealed that Gly324Ser, c.421-2A>G, and c.1128-6_1188dup67 mutations accounted for 80.8% of the total mutations reported to date. In terms of genotype-phenotype correlations, a patient homozygous for the c.421-2A>G mutation had fatal clinical manifestations and two patients who were compound heterozygous for the Gly324Ser and c.1128-6_1188dup67 mutations presented with a mild clinical course. CONCLUSION: We provided important information about the mutational spectrum of ASS1 gene in Korean patients with citrullinemia type I and demonstrated a difference in common mutations in the ASS1 gene according to ethnic and geographic backgrounds. PMID- 23099196 TI - Acute kidney injury: effect of hemodialysis membrane on Hgf and recovery of renal function. AB - OBJECTIVES: Acute kidney injury (AKI) is associated with a high mortality and morbidity rate. In this study we investigated whether dialysis membranes influence the recovery of renal function, through the regulation of hepatocyte growth factor (HGF). DESIGN AND METHODS: 21 patients were enrolled and assigned to hemodialysis (HD) with cellulose (CE, N=11) versus polymethylacrylate (PMMA, N=10) membranes in alternating order. HGF and IL-1 were measured in serum and in peripheral blood mononuclear cells (PBMC) supernatants collected immediately before the first HD session (T0), at 15 minutes (T15), at 240 minutes (T240) and after the last HD, when renal recovery occurred. Eight healthy volunteers were the controls (CON). RESULTS: Time to renal function recovery was lower in CE than in PMMA patients. Serum HGF in HD patients was significantly higher than in CON. HGF levels were higher in CE than in PMMA patients at T15 (13.4+/-2.7 vs 8.9+/ 3.0 ng/mL, P=0.004) and T240. At recovery, HGF levels decreased. IL-1 serum levels showed a similar trend (at T15 CE: 20.5+/-2.9 vs PMMA: 16.9+/-3.2 pg/mL, P=0.005). HGF release significantly increased in the course of HD, resulting in higher levels in CE than that in PMMA patients. Considering all the patients, basal HGF release negatively correlated with time to renal recovery (r2=0.42, P<0.01). CONCLUSIONS: Here we demonstrated that dialysis membranes influence the cytokine profile in AKI patients, HGF release being higher in patients treated with the CE membrane, in comparison to PMMA. Our results suggest that treatment with CE might improve clinical outcomes, possibly through increased release of HGF. PMID- 23099197 TI - Identification of a novel mutation in UDP-glucuronosyltransferase (UGT1A1) gene in a child with neonatal unconjugated hyperbilirubinemia. AB - Genetic alterations of the UGT1A1 gene result in Crigler-Najjar (CNS) and Gilbert's (GS)-Syndromes, two autosomal recessive conditions characterized by non hemolytic unconjugated hyperbilirubinemia. While GS is characterized by mild hyperbilirubinemia, CNS is classified as follows: type I (CNS-I), often associated with irreversible neurological damage due to total deficiency of the UGT1A1 enzyme activity, and type II (CNS-II) where a minimal level of UGT1A1 enzyme activity is maintained. In this context, differential diagnosis of CNS forms needs to be supported by clinical molecular laboratory, in order to correlate biochemical findings to specific genetic mutations. Our paper describes in detail the peculiar clinical feature found in a child with severe neonatal unconjugated hyperbilirubinemia, where DNA analysis showed a new compound heterozygosis determined by two mutations, a known (c.508_510delTTC) and a novel mutation (c.1099C>T) giving a genotype compatible with clinical picture of CNS II. This novel genotype extends the spectrum of known UGT1A1 mutations, which, in our opinion, could be higher than that currently reported in the literature. Finally, genetic analysis may also be helpful for patients' management. PMID- 23099198 TI - Effect of the menstrual cycle on serum diamine oxidase levels in healthy women. AB - OBJECTIVES: Serum diamine oxidase (DAO) level is employed as a useful marker of intestinal mucosal integrity. As reported previously, the range of serum DAO levels in women is wider than that in men. We hypothesized that the menstrual cycle may affect DAO levels. DESIGN AND METHODS: Thirty-six women of Japanese descent were recruited. All participants, aged 20-29 years, were healthy. Food surveys utilized in this study were based on questionnaires validated by dietitians. Complete blood counts, biochemical parameters, female hormones, and serum DAO levels during the follicular and luteal phases were measured in each subject. RESULTS: Biochemical parameters, except for DAO levels, were comparable between the two phases. However, serum DAO levels during the luteal phase were significantly higher than those during the follicular phase. CONCLUSIONS: Serum DAO levels were influenced by the menstrual cycle. Furthermore, our findings suggest that serum DAO levels should be interpreted cautiously in premenopausal women. PMID- 23099199 TI - Analytical performance evaluation of the scanning capillary tube viscometer for measurement of whole blood viscosity. AB - BACKGROUND: Whole blood viscosity (WBV) is the resistance of blood flow in blood vessels. Increased WBV may be a cardiovascular risk factor. The proper screening of WBV can help the early detection of cardiovascular disease. We investigated the performance of a new scanning capillary tube viscometer (SCTV) for the measurement of WBV. METHODS: We evaluated the total precision of the SCTV for 20 days using three control viscosity materials, and the within-day precision with the whole blood samples of three different individuals. For the linearity evaluation, serial dilutions of a high concentration standard material were used. For the method comparison, the results of the SCTV method were compared to those of Brookfield rotating viscometer on 227 subjects. RESULTS: The SCTV had good within-run and total-run coefficient of variant (CV)s at low-, medium-, and high concentration samples, at shear rates of 1 and 300 s(-1). The within-day CVs with the three human blood samples were 6.3%, 3.7% and 3.8% at a shear rate of 1s(-1), and 3.2%, 3.0% and 4.1% at a shear rate of 300 s(-1). The SCTV method showed an excellent linearity in the range of 84.9 to 558.2 milliPoise (mP) and 28.8 to 71.0 mP at shear rates of 1 and 300 s(-1), respectively. For the comparison study, the SCTV and the rotating viscometer showed comparable results. CONCLUSIONS: The SCTV showed a stable analytical performance, and was comparable with the rotational viscometer. This new SCTV method can be used in the clinical laboratory for various needs. PMID- 23099200 TI - Critical review and meta-analysis on the combination of heart-type fatty acid binding protein (H-FABP) and troponin for early diagnosis of acute myocardial infarction. AB - An early diagnosis is crucial for effective triage and management of patients with suspected acute myocardial infarction (AMI). Although troponin testing is the cornerstone of diagnosis, the sensitivity of this biomarker is still suboptimal at patient admission. The heart-type fatty acid binding protein (H FABP) is an early and sensitive biomarker of myocardial ischemia, whose appropriate setting is in combination with troponin testing. We performed a systematic review and meta-analysis of articles that have assessed the combination of troponin and H-FABP in the early diagnosis of AMI. Eight studies, totaling 2735 patients, met the inclusion criteria but none of them used a high sensitivity troponin immunoassay. The between-study variation was high (98.5%), and attributable to heterogeneity. When considered alone, troponin exhibited a significantly greater pooled area under the curve (AUC) than H-FABP alone (0.820 versus 0.784; p<0.001). The pooled specificity was also higher for troponin alone than for H-FABP alone (0.94 versus 0.83; p<0.001), whereas the cumulative sensitivity was lower for troponin than for H-FABP (0.73 versus 0.80; p=0.02). The combination of both biomarkers exhibited a greater AUC than troponin alone (0.881; p<0.001), as well as a higher pooled sensitivity (0.91; p<0.001), which was however counterbalanced by a lower specificity (0.82; p<0.001). These results attest that the combination of H-FABP with a conventional troponin immunoassay seems advantageous for increasing the sensitivity of the former biomarker, at the expense of a lower specificity. The introduction of H-FABP testing would hence require careful assessment of laboratory data or clinical signs and symptoms for excluding sources of elevation different from AMI. Further studies are needed to assess the diagnostic effectiveness of combining H-FABP with a high-sensitivity troponin immunoassay. PMID- 23099201 TI - Patients' survival in lung malignancies treated by microwave ablation: our experience on 56 patients. AB - OBJECTIVES: We retrospectively evaluated percutaneous CT-guided microwave (MW) ablation safety and efficacy in unresectable lung malignancies focusing on patients' survival. MATERIALS AND METHODS: All procedures were approved by the hospital ethical committee. From 2008 to 2012 we treated 69 unresectable lesions (44 lung cancer, 25 lung metastases) in 56 patients (35 men/21 women; mean age: 61.5 years). Treatment was performed under CT guidance using 14 G needles with a 3 cm active tip and a 55 W MW generator (Vivawave Microwave Coagulation System; Valley Lab). Treatment was performed at 45 W for 6-10 min. Patients were scheduled for a 3 and 6 month CT follow-up to evaluate lesion diameter and enhancement. Survival rate was evaluated by Kaplan-Meier analysis. RESULTS: Ablation procedures were completed according to protocol in all patients. Pneumothorax occurred in 18 patients and 8 required chest tube. Four lesions (all >4.3 cm) were retreated 20 days after the ablation because of peripheral focal areas of residual tumor. Follow-up CT evaluation showed a decrease in maximum diameter in 44/69 lesions (64%) and in 42/59 lesions (71%) at 3 and 6 months, respectively. In all cases no pathologic enhancement was observed. Cancer specific mortality yielded a survival rate of 69% at 12 months, 54% at 24 months and 49% at 36 months, respectively. An estimate mean for survival time was 27.8 months with a standard error of 2.8 months (95% confidence interval: 22.4-33.2 months). CONCLUSION: Based on our experience, MW ablation seems to represent a potential safe and effective percutaneous technique in the treatment of lung malignancies. MW ablation may improve survival in patients not suitable to surgery. PMID- 23099202 TI - Mechanical response of animal abdominal walls in vitro: evaluation of the influence of a hernia defect and a repair with a mesh implanted intraperitoneally. AB - Better mechanical knowledge of the abdominal wall is requested to further develop and validate numerical models. The aim of this study was to characterize the passive behaviour of the abdominal wall under three configurations: intact, after creating a defect simulating an incisional hernia, and after a repair with a mesh implanted intraperitonally. For each configuration, controlled boundary conditions were applied (air pressure and then contact loading) to the abdominal wall. 3D local strain fields were determined by digital image correlation. Local strains measured on the internal and external surfaces of the intact abdominal wall showed different patterns. The air pressure and the force applied to the abdominal wall during contact loading were measured and used to determine stiffness. The presence of a defect resulted in a significant decrease of the global stiffness compared to the intact abdominal wall (about 25%). In addition, the presence of the mesh enabled to restore the stiffness to values that were not significantly different from those of the intact wall. These results suggest that intraperitoneal mesh seems to restore the global biomechanics of the abdomen. PMID- 23099203 TI - Murine hepatitis virus nsp4 N258T mutants are not temperature-sensitive. AB - Coronavirus replicase nsp4 is critical for virus-induced membrane modifications. An nsp4 mutant (N258T) of murine hepatitis virus (MHV) has been reported to be temperature-sensitive (ts) and to alter membrane targeting. We engineered and recovered all four possible codon variants of N258T in the cloned MHV-A59 background. All mutant viruses demonstrated impaired replication compared to wildtype MHV, but no nsp4 N258T mutant virus was ts, and all variants colocalized with viral protein markers for replication complexes, but not with markers for mitochondria. This study emphasizes that complete genome sequencing may be necessary, even with directed and confirmed reverse genetic mutants. PMID- 23099204 TI - Evidence for negative-strand RNA virus infection in fungi. AB - Fungal viruses comprise two groups: a major group of five families with double stranded RNA genomes and a minor group with positive-sense single-stranded (ss)RNA genomes. Although many fungal viruses have been identified, no negative stranded (-)ssRNA mycoviruses have been reported. Here we present two lines of evidence suggesting the presence of (-)ssRNA viruses in filamentous fungi based on an exhaustive search using extant (-)ssRNA viruses as queries. This revealed ( )ssRNA virus L protein-like sequences in the genome of a phytopathogenic obligate ascomycete, Erysiphe pisi. A similar search for (-)ssRNA viruses in fungal transcriptome shotgun assembly libraries demonstrated that two independent libraries from Sclerotinia homoeocarpa, another phytopathogenic ascomycete, contained several sequences considered to correspond to the entire mononegavirus L gene and likely originating from an infecting (-)ssRNA virus. These results provide strong evidence for both ancient and extant (-)ssRNA virus infections in fungi. PMID- 23099205 TI - Flavivirus infection from mosquitoes in vitro reveals cell entry at the plasma membrane. AB - Dengue and West Nile viruses are enveloped RNA viruses that belong to genus Flavivirus (family Flaviviridae) and are considered important mosquito-borne viral pathogenic agents worldwide. A potential target for intervention strategies is the virus cell entry mechanism. Previous studies of flavivirus entry have focused on the effects of biochemical and molecular inhibitors on viral entry leading to controversial conclusions suggesting that the process is dependent upon endocytosis and low pH mediated membrane fusion. In this study we analyzed the early events in the infection process by means of electron microscopy and immuno-gold labeling of viral particles during cell entry, and used as a new approach for infecting cells with viruses obtained directly from mosquitoes. The results show that Dengue and West Nile viruses may infect cells by a mechanism that involves direct penetration of the host cell plasma membrane as proposed for alphaviruses. PMID- 23099206 TI - Construction and biological activities of the first infectious cDNA clones of the genus Foveavirus. AB - Grapevine rupestris stem pitting-associated virus (GRSPaV, genus Foveavirus, family Betaflexiviridae) is one of the most prevalent viruses in grapevines and is associated with three distinct diseases: rupestris stem pitting, vein necrosis and Syrah decline. Little is known about the biology and pathological properties of GRSPaV. In this work, we engineered a full-length infectious cDNA clone for GRSPaV and a GFP-tagged variant, both under the transcriptional control of Cauliflower mosaic virus 35S promoter. We demonstrated that these cDNA clones were infectious in grapevines and Nicotiana benthamiana through fluorescence microscopy, RT-PCR, Western blotting and immuno electron microscopy. Interestingly, GRSPaV does not cause systemic infection in four of the most commonly used herbaceous plants, even in the presence of the movement proteins of two other viruses which are known to complement numerous movement-defective viruses. These infectious clones are the first of members of Foveavirus which would allow further investigations into mechanisms governing different aspects of replication for GRSPaV and perhaps related viruses. PMID- 23099207 TI - Characteristics of HER2-positive breast cancer diagnosed following the introduction of universal HER2 testing. AB - The aim of this study was to determine the impact of universal HER2 testing on the clinico-pathologic profile of HER2+ breast cancer. Data were extracted from breast cancer pathology reports spanning two periods: before (2003/4, n = 379), and after (2008/9, n = 560) the introduction of universal testing. In 2003/4, 43.3% of breast cancers were tested for HER2 with 16% of tested cases HER2+. In 2008/9, 98.4% of cases were tested with 14.7% HER2+. In 2008/9, HER2+ status was associated with younger age, higher grade, increased tumour size, lymph node involvement, negative oestrogen and/or progesterone receptor status. HER2+ cases diagnosed in 2003/4 were not significantly different in respect of these features. The rate of HER2+ breast cancer amongst screen detected cases in 2008/9 was 8.3%. The phenotype of HER2+ breast cancer was stable following the introduction of universal testing. The overall rate of HER2+ breast cancer was influenced by screen detection. PMID- 23099208 TI - Of mice, moles and guinea pigs: functional morphology of the middle ear in living mammals. AB - The middle ear apparatus varies considerably among living mammals. Body size, phylogeny and acoustic environment all play roles in shaping ear structure and function, but experimental studies aimed ultimately at improving our understanding of human hearing can sometimes overlook these important species differences. This review focuses on three groups of mammals, bringing together anatomical, zoological and physiological information in order to highlight unusual features of their middle ears and attempt to interpret their function. "Microtype" ears, found in species such as mice and bats, are associated with high-frequency hearing. The orbicular apophysis, the focus of some recent developmental studies on mouse ears, is characteristic of microtype mallei but is not found in humans or other "freely mobile" species. The apophysis increases ossicular inertia about the anatomical axis of rotation: its adaptive purpose in a high-frequency ear is still not clear. Subterranean mammals have convergently evolved a "freely mobile" ossicular morphology which appears to favour lower frequency sound transmission. More unusual features found in some of these animals include acoustically coupled middle ear cavities, the loss of middle ear muscles and hypertrophied ossicles which are believed to subserve a form of inertial bone conduction. Middle ears of the rodent group Ctenohystrica (which includes guinea pigs and chinchillas, important models in hearing research) show some striking characteristics which together comprise a unique type of auditory apparatus requiring a classification of its own, referred to here as the "Ctenohystrica type". These characteristics include a distinctive malleus morphology, fusion of the malleus and incus, reduction or loss of the stapedius muscle, a synovial stapedio-vestibular articulation and, in chinchillas, enormously expanded middle ear cavities. These characteristics may be functionally linked and associated with the excellent low-frequency hearing found in these animals. The application of new experimental and imaging data into increasingly sophisticated models continues to improve our understanding of middle ear function. However, a more rigorous comparative approach and a better appreciation of the complex patterns of convergent and divergent evolution reflected in the middle ear structures of living mammals are also needed, in order to put findings from different species into the appropriate context. This article is part of a special issue entitled "MEMRO 2012". PMID- 23099209 TI - Directing neural plasticity to understand and treat tinnitus. AB - The functional organization of cortical and subcortical networks can be altered by sensory experience. Sensory deprivation destabilizes neural networks resulting in increased excitability, greater neural synchronization and increased spontaneous firing in cortical and subcortical neurons. This pathological activity is thought to generate the phantom percept of chronic tinnitus. While sound masking, pharmacotherapy and cortical stimulation can temporarily suppress tinnitus for some patients, these interventions do not eliminate the pathological activity that is responsible for tinnitus. A treatment that could reverse the underlying pathology would be expected to be effective in alleviating the symptoms, if not curative. Targeted neural plasticity can provide the specificity required to restore normal neural activity in dysfunctional neural circuits that are assumed to underlie many forms of tinnitus. The forebrain cholinergic system and the noradrenergic system play a significant role in modulating cortical plasticity. Stimulation of the vagus nerve is known to activate these neuromodulatory pathways. Our earlier studies have demonstrated that pairing sounds with either nucleus basalis of Meynert (NB) stimulation or vagus nerve stimulation (VNS) generates highly specific and long-lasting plasticity in auditory cortex neurons. Repeatedly pairing tones with brief pulses of VNS reversed the physiological and behavioral correlates of tinnitus in noise exposed rats. We also recently demonstrated that VNS modulates synchrony and excitability in the auditory cortex at least in part by activation of muscarinic acetylcholine receptors, suggesting that acetylcholine is involved in the mechanism of action of VNS. These results suggest that pairing sounds with VNS provides a new avenue of treatment for some forms of tinnitus. This paper discusses neuromodulation as treatment for tinnitus with a focus on the potential value of pairing VNS with sound stimulation as a treatment of chronic tinnitus. PMID- 23099210 TI - Error correction in intracellular transport: numerical investigation of rerouting of a pulse of misdirected axonal cargos in a dendrite. AB - This paper develops a transient three-kinetic state model that simulates rerouting of a pulse of axonal cargos that were initially misdirected to a dendrite. The following three cargo populations are included in the model: (i) anterogradely running cargos, (ii) retrogradely running cargos, and (iii) free (diffusion-driven) cargos that are detached from microtubules. The dynamics of cargo concentrations in various kinetic states are studied. It is demonstrated that the profile of the total cargo concentration is comprised of two major components. The first component is a pulse composed of anterogradely running cargos and the second component is a tail behind this pulse that is composed of free (diffusion-driven) and retrogradely running cargos. The total number of misdirected axonal cargos in the dendrite is also computed. The dependence of this quantity on the amount of time that passed from the moment when the pulse entered the dendrite and on kinetic constants describing transition rates between various kinetic states of misdirected cargos is investigated. PMID- 23099211 TI - Colorization of CT images to improve tissue contrast for tumor segmentation. AB - Segmenting tumors from grayscale medical image data can be difficult due to the close intensity values between tumor and healthy tissue. This paper presents a study that demonstrates how colorizing CT images prior to segmentation can address this problem. Colorizing the data a priori accentuates the tissue density differences between tumor and healthy tissue, thereby allowing for easier identification of the tumor tissue(s). The method presented allows pixels representing tumor and healthy tissues to be colorized distinctly in an accurate and efficient manner. The associated segmentation process is then tailored to utilize this color data. It is shown that colorization significantly decreases segmentation time and allows the method to be performed on commodity hardware. To show the effectiveness of the method, a basic segmentation method, thresholding, was implemented with and without colorization. To evaluate the method, False Positives (FP) and False Negatives (FN) were calculated from 10 datasets (476 slices) with tumors of varying size and tissue composition. The colorization method demonstrated statistically significant differences for lower FP in nine out of 10 cases and lower FN in five out of 10 datasets. PMID- 23099212 TI - Frequency and spatial distribution of cartilage thickness change in knee osteoarthritis and its relation to clinical and radiographic covariates - data from the osteoarthritis initiative. AB - OBJECTIVE: Estimate the frequency and spatial location of rapid femorotibial cartilage thinning or thickening in knees with, or at risk of, osteoarthritis (OA) and examine their association with clinical and radiographic covariates. DESIGN: Knee cartilage thickness change over 12 months was measured using magnetic resonance imaging in the right knee of 757 Osteoarthritis Initiative (OAI) participants that had radiographic findings of osteophytes or joint space narrowing (JSN). Thickness changes in individual knees were classified as having rapid thinning or thickening or no detectable OA-related change when compared to asymptomatic OAI Control cohort knees. RESULTS: Cartilage thinning, found in 18.5% of subjects, was more frequent in knees with OAI calculated Kellgren Lawrence grade (cKLG) > 2 (P < 0.001) and with frequent pain (P = 0.047). No link was found between body mass index, sex, and age and cartilage thinning (P > 0.15). The percent of knees with thickening was small (4.4%), but greater in knees with frequent pain (P = 0.02). Rapid thinning was most common in the central (36.4%) and external (32.1%) subregions of the medial weight-bearing femur. Mean cartilage loss in rapidly thinning subregions ranged from 11.2%/y to 24.6%/y. Knees with cKLG > 2, but classified as having no detectable OA-related change had mean cartilage loss rates significantly >0 (0.4%/y-1.3%/y) in 10 subregions. CONCLUSION: Most observed subregional changes in OA knees were indistinguishable from changes found in an asymptomatic cohort, but a fraction of subregions showed rapid progression. The relative frequency of rapid thinning increases when cKLG > 2, a classification closely associated with JSN and/or frequent knee pain are present. PMID- 23099213 TI - A longitudinal study of the quantitative evaluation of patella cartilage after total knee replacement by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping at 3.0 T: preliminary results. AB - OBJECTIVE: To characterize the quantitative changes of patella cartilage over time after total knee arthroplasty (TKA) by delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) and T2 mapping at 3.0 T. METHOD: Twenty six knees of 26 patients (23 women and three men, mean age, 75 years) with primary osteoarthritis and osteonecrosis of the knee underwent TKA with a zirconia ceramic implant in this prospective study. Twelve patients without patella resurfacing (NR group) and 14 patients with patella resurfacing (R group) had TKA with cemented fixation. The implant position was examined by radiograph, computed tomography (CT) and magnetic resonance imaging (MRI). The clinical scores were checked pre-operatively, 1 year post-operatively and at the final follow-up. Patella cartilage and its thickness were evaluated pre-operatively and 1 year after TKA by dGEMRIC and T2 mapping in the NR group only. Patella cartilage was divided into eight regions of interest: the deep and superficial layers of the outer lateral and medial half, and the inner lateral and medial half from the central ridge. RESULTS: The implant position was appropriate in all cases and clinical scores were not significantly different between the two groups. The post-operative dGEMRIC value of the outer medial half superficial zone in the NR group was significantly decreased compared with the pre-operation value (P<0.05), whereas T2 mapping was not significantly changed in all zones. The cartilage thickness of the outer zone was significantly thinner post operatively (P<0.05). CONCLUSIONS: These findings indicate that osteoarthritic changes in the outer zone of patella cartilage occurred 1 year after TKA. PMID- 23099214 TI - Management of a patient with extensive burns and Sheehan's syndrome. PMID- 23099215 TI - Deformation of a transapical aortic valve after cardiopulmonary resuscitation: a potential risk of stainless steel stents. PMID- 23099216 TI - Transcatheter aortic valve implantation in patients with mitral prosthesis. PMID- 23099217 TI - Blood oxygen level-dependent magnetic resonance imaging in patients with coronary artery disease. PMID- 23099219 TI - Asymptomatic left ventricular mass: prepare for the worst, hope for the best. PMID- 23099220 TI - Effects of dietary inorganic nitrate on static and dynamic breath-holding in humans. AB - Inorganic nitrate has been shown to reduce oxygen cost during exercise. Since the nitrate-nitrite-NO pathway is facilitated during hypoxia, we investigated the effects of dietary nitrate on oxygen consumption and cardiovascular responses during apnea. These variables were measured in two randomized, double-blind, placebo-controlled, crossover protocols at rest and ergometer exercise in competitive breath-hold divers. Subjects held their breath for predetermined times along with maximum effort apneas after two separate 3-day periods with supplementation of potassium nitrate/placebo. In contrast to our hypothesis, nitrate supplementation led to lower arterial oxygen saturation (SaO(2), 77 +/- 3%) compared to placebo (80 +/- 2%) during static apnea, along with lower end tidal fraction of oxygen (FETO(2)) after 4 min of apnea (nitrate 6.9 +/- 0.4% vs. placebo 7.6 +/- 0.4%). Maximum apnea duration was shorter after nitrate (329 +/- 13 s) compared to placebo (344 +/- 13 s). During cycle ergometry nitrate had no effect on SaO(2), FETO(2) or maximum apnea duration. The negative effects of inorganic nitrate during static apnea may be explained by an attenuated diving response. PMID- 23099221 TI - Peripheral chemoreceptors in congenital central hypoventilation syndrome. AB - Congenital central hypoventilation syndrome is a rare disorder caused by a mutation in the PHOX2B gene resulting in hypoventilation that is worse during sleep. Human physiologic studies show that patients with CCHS have absent or decreased rebreathing ventilatory responses to hypercapnia and hypoxemia during sleep as well as during wakefulness. Some ventilatory responses to hypoxia and hyperoxia can be demonstrated using a step change in inspired oxygen. However, these suggest that both central and peripheral chemoreceptor functions are generally defective in all states in children with CCHS. The defect in CCHS may lie in central nervous system pathways regulating ventilation, whose development and function are controlled by PHOX2B. Moreover, the retrotrapezoid nucleus (RTN) may be the major defect in CCHS, where central and peripheral inputs converge. Human physiological studies predicted that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals. New evidence suggests the RTN may be the respiratory controller where chemoreceptor inputs are integrated. In this review we present the clinical presentation of CCHS, revisit results of human physiologic studies, and discuss the findings in light of new knowledge about the role of PHOX2B and RTN in CCHS. PMID- 23099222 TI - Linking definitions, mechanisms, and modeling of drought-induced tree death. AB - Tree death from drought and heat stress is a critical and uncertain component in forest ecosystem responses to a changing climate. Recent research has illuminated how tree mortality is a complex cascade of changes involving interconnected plant systems over multiple timescales. Explicit consideration of the definitions, dynamics, and temporal and biological scales of tree mortality research can guide experimental and modeling approaches. In this review, we draw on the medical literature concerning human death to propose a water resource-based approach to tree mortality that considers the tree as a complex organism with a distinct growth strategy. This approach provides insight into mortality mechanisms at the tree and landscape scales and presents promising avenues into modeling tree death from drought and temperature stress. PMID- 23099223 TI - Soft tissue cephalometric norms for orthognathic and cosmetic surgery. AB - PURPOSE: Proportionality of the lower and middle thirds of the face is a key determinant of successful orthognathic treatment. A flatter profile and marked variance of the soft tissue envelope in the Japanese population complicates the accurate assessment of these proportions. This study aimed to identify gender differences and establish norms for Japanese young adults using the method of soft tissue cephalometric analysis (STCA) by Arnett et al (Am J Orthod Dentofacial Orthop 116:239, 1999). MATERIALS AND METHODS: Lateral cephalograms of 49 young normal Japanese subjects (19 men, 30 women) were selected from the archival records and analyzed with STCA. The Student t test was used to compare mean values of the male and female groups. RESULTS: Significant differences were found between women and men. Men had a flatter occlusal plane and a more acute nasolabial angle than women. Men showed larger values for upper and lower lip thickness, menton soft tissue thickness, and vertical face length, especially in the lower third of the face. Women had a more projected midface than men. Compared with established STCA norms, the Japanese have more midfacial projection. CONCLUSIONS: Significant gender differences were found in the thickness, lower third length, and midface projection in Japanese young adults, which should be taken into account when interpreting measurements for orthognathic surgical planning. These differences can serve as norms for STCA in young Japanese adults. Differences were noted between the reference values of Arnett et al and Japanese subjects. PMID- 23099224 TI - CAD-CAM-assisted esthetic facial surgery. AB - PURPOSE: This report describes a fully digital workflow for computer-assisted esthetic facial surgery planning and guidance. MATERIAL AND METHODS: Using optical scans, virtual surgery is performed according to the 3-dimensional cephalometric results. Next, surgical templates are generated using rapid prototyping. These templates act as a guide during surgery. RESULTS: The workflow has been tested successfully in 4 esthetic facial surgical procedures (rhinoplasty and genioplasty). In addition to surgical assistance, the advantages of the workflow include the possibility of discussing the treatment plan interactively with the patient and comparing and measuring simulation surgery with the actual outcome. As an additional benefit, the appropriate size of the alloplastic implants can be determined preoperatively. CONCLUSIONS: Templates could improve special procedures in esthetic facial surgery. PMID- 23099225 TI - Tent-pole approach to treat severely atrophic fractured mandibles using immediate or delayed protocols: preliminary case series. AB - PURPOSE: To investigate the outcomes of patients with severely resorbed fractured mandibles who were managed with a modified tent-pole procedure. PATIENTS AND METHODS: Four edentulous patients (2 male and 2 female; mean age, 59.5 years; range, 52 to 64 years) with a severely atrophic fractured mandible and less than 10 mm of vertical height of the body of the mandible were treated with an immediate or a delayed protocol (n=2 in each group). In the immediate group, a transcutaneous submental approach was used to provide open reduction with rigid fixation, immediate dental implant placement in the anterior mandible, and an autogenous particulate iliac bone grafting harvested from the posterior iliac crest. In the delayed protocol group, the fractures were treated with an open reduction and rigid fixation. Six months after fracture treatment, the fixation hardware was removed and a tent-pole approach was used to place the dental implants to the anterior mandible with an autogenous bone graft harvested from the posterior iliac crest. Implant fixtures were loaded at 3 months as the patients were fitted with healing caps, and the dental implants were loaded using provisional screw-retained acrylic resin prostheses and bar-retained overdentures afterward. The mean follow-up was 19.8 months (range, 13 to 28 months). RESULTS: The postoperative course and healing of the 4 patients was uneventful, without any fracture nonunion. The average alveolar augmentation+/-standard deviation was 7.5+/-1.17 mm (range, 6.6 to 9.0 mm). There was no bone resorption around any of the endosseous implants on follow-up. All 4 patients wore their dental implant supported prosthesis comfortably. CONCLUSIONS: This preliminary evidence indicates that the modified tent-pole technique may be a safe and effective method to manage the fractured severely resorbed mandible using an immediate or a delayed protocol. Much larger-scale prospective evidence is required to further validate this observation. PMID- 23099226 TI - Gossypiboma in the nasal septum after septorhinoplasty: a case study. AB - This report describes a case of gossypiboma in the septum. A 31-year-old woman presented with nasal obstruction and crusting that started 2 years previously after she underwent rhinoseptoplasty in another private clinic. Physical examination disclosed remaining posterior septal deviation to the left side with septal mucosal erosion on the left side. Under general anesthesia, the septal flap was elevated on the left side of the nasal cavity. A gossypiboma was found around the perpendicular ethmoid plate and between the septal flaps. The perpendicular ethmoid plate was resected and the gossypiboma was removed under endoscopy. Because of severe adhesion between the gossypiboma and the septal mucosa, removal of the gossypiboma resulted in a defect on the left mucoperichondrial flap. Right inferior turbinate mucosa was harvested and grafted on the mucosal defect of the left side. Five months after the operation, the nasal cavity showed a straight septum with a well-healed mucosa without any nasal symptoms. This case is a reminder of the fundamental importance of absolute care at every step of rhinologic surgery. PMID- 23099227 TI - Ameloblastic carcinoma, secondary type, of the mandible: a case report. AB - Ameloblastic carcinoma is a rare, odontogenic, malignant tumor that has features of ameloblastoma in addition to cytologic atypia with or without metastasis. It is classified as primary type; secondary type, intraosseous; and secondary type, peripheral according to the World Health Organization classification of 2005. Ameloblastic carcinoma, secondary type, is extremely rare, and few cases have been reported in the English-language literature. The authors report a case of ameloblastic carcinoma, secondary type, arising at the mandible in a 17-year-old Japanese boy. PMID- 23099228 TI - Author reply: comment to "atorvastatin improves disease activity of nonalcoholic steatohepatitis partly through its tumour necrosis factor-alpha-lowering property". PMID- 23099229 TI - Construction of a doxycycline inducible adipogenic lentiviral expression system. AB - To provide a tool for research on regulating adipocyte differentiation, tetracycline inducible (Tet on) lentiviral expression vectors under the control of an adipose-specific promoter were constructed. The lowest basal expression in the absence of doxycycline and most efficient dose-dependent, doxycycline-induced transient overexpression was observed using vectors constructed with a combination of Tetracycline Responsive Element (TRE) and reverse tetracycline controlled TransActivator advanced (rtTAadv), transfected in white (3T3-L1) and brown (HIB-1B) preadipocytes cell lines. The results demonstrate that doxycycline adipogenic inducible expression can be achieved using a pLenti TRE / rtTA adv under the control of the truncated aP2 promoter in HIB-1B preadipocytes. PMID- 23099230 TI - Adherence to antiepilepsy drug therapy. AB - Adherence to antiepilepsy drug (AED) therapy is critical for effective disease management, yet adherence and persistence rates are low due to several barriers. The definitions of adherence (80% rate of total pills taken, medication possession ratio, and days covered by prescriptions filled) and methods of measurement (patient self-reports, serum drug levels, pill counts, electronic bottle tops, and reviews of pharmacy records) are not without limitations, and their applicability to epilepsy is not clear. The use of simple adherence scales during office visits can provide an overall impression of a patient's adherence and can serve as a basis for practitioner-patient dialog. Efforts to improve adherence should focus on provider and healthcare system determinants versus those focused only on the patient. These interventions include non-judgmental communication, patient education, simplification of the dosage regimen with once daily therapies, and the use of patient reminders. PMID- 23099231 TI - The yield and clinical utility of outpatient short-term video electroencephalographic monitoring: a five-year retrospective study. AB - Outpatient short-term video-electroencephalographic monitoring (OVEM) is recognized as a useful tool in the diagnosis of epilepsy and other paroxysmal disorders. The aim of this retrospective study was to determine the diagnostic yield of OVEM. We analyzed 175 OVEM records of adults (111 females and 64 males) referred over a period of 5 years. The mean length of recording was 3.8 h. The highest yield was found in psychogenic nonepileptic seizures (PNES) (37.1%), followed by interictal epileptiform discharges (17.2%), and epileptic seizures (6.9%). The provisional diagnosis was epilepsy in 77.7% and PNES in 22.3% before the test. Outpatient short-term video-electroencephalographic monitoring changed the pre-test diagnosis in 30.9% of patients. Outpatient short-term video electroencephalographic monitoring is a useful diagnostic test for PNES. It has a higher yield for PNES than epilepsy. PMID- 23099232 TI - Dissociative experiences and quality of life in patients with non-epileptic attack disorder. AB - Dissociative experiences are commonly reported by patients with non-epileptic attack disorder (NEAD). This cross-sectional study examined the prevalence and characteristics of dissociative experiences in patients with NEAD and assessed their association with health-related quality of life (HRQoL). Fifty-three patients diagnosed with NEAD were consecutively recruited (70.0% female, mean age=42 years, 22.0% with comorbid epilepsy) from a specialist neuropsychiatric clinic. Our sample reported high levels of dissociative experiences, with 36.7% of patients scoring >=30 on the Dissociative Experiences Scale (DES). Significant negative correlations were found between total DES scores and HRQoL, as measured by the QOLIE-31 questionnaire (r=-0.64, p<0.001). This association remained significant when accounting for symptoms of depression and anxiety, other psychiatric comorbidities, and attack frequency and severity. These findings suggest a high prevalence of dissociative experiences in this patient population, highlighting the importance of routinely screening patients for dissociative symptoms and their impact on patients' lives. PMID- 23099233 TI - An uncommon cause of acute kidney injury in young children: cystinuria. AB - Bilateral obstructive nephrolithiasis is a rare cause of acute kidney injury (AKI) in early childhood. As soon as the identification of AKI secondary to ureteral stone is made, it will necessitate an emergency treatment. PATIENTS: We report three infants with AKI caused by bilateral obstructive ureteral cystine stones. They were diagnosed with acute post-renal injury due to obstructive bilateral ureteral stones based on ultrasound scan findings. Immediately, bilateral ureteral stents were inserted for urinary drainage. Once renal function recovered to normal, each patient underwent ureteroscopy and percutaneous nephrolithotomy at the same session. Cystinuria was diagnosed by stone analysis and increased urinary excretion of cystine. Patients were advised to maintain a high fluid intake and were treated with potassium citrate in addition to tiopronin. CONCLUSIONS: With these three cases we would like to emphasize the importance of urolithiasis in the differential diagnosis of acute renal failure in young children, since urolithiasis may only cause nonspecific symptoms in this population. An early diagnosis with prompt treatment and a close follow-up are the key for achieving the best long-term outcome in cystinuria. PMID- 23099234 TI - The resurgence and genetic implications of New World primates in biomedical research. AB - There has been a recent resurgence of interest in New World monkeys within the biomedical research community, driven by both the sequencing of the common marmoset (Callithrix jacchus) genome and a growing demand for alternatives to Old World primates. New World monkeys offer attractive advantages over Old World species, including cheaper and simpler husbandry, while still maintaining a greater evolutionary proximity to humans compared with other animal models. Although numerous commonalities across primate species exist, there are also important genetic and reproductive differences that can and should play a critical role in selecting appropriate animal models. Common marmosets in particular have significantly reduced diversity at the major histocompatibility complex (MHC) loci and are born as hematopoietic chimeras. New World primates can make ideal translational models for research, but scientists must necessarily incorporate complete understandings of their genetic and phenotypic differences from humans and other model organisms. PMID- 23099235 TI - Diverse underlying proliferation response to growth factors in imatinib-treated Philadelphia chromosome-positive leukemias. AB - Since BCR-ABL plays an essential role in the growth factor-independent proliferation of Philadelphia chromosome (Ph)+ leukemia cells, imatinib treatment of Ph+ leukemia cells inactivates signaling pathways of BCR-ABL, and subsequent addition of growth factors (GFs) could restore the signaling pathways without reactivating BCR-ABL. Here we demonstrated that non-lymphoid Ph+ leukemia cell lines responded to diverse GFs depending on their immunophenotype and gene expression of transcription factors and GF receptors, while lymphoid Ph+ leukemia cell lines restrictively responded to flit3 ligand and interleukin-7, suggesting that GF sensitivity of imatinib-treated Ph+ leukemia cells could be powerful for specifying their distinctive lineage. PMID- 23099236 TI - Physical activity of pediatric patients with acute leukemia undergoing induction or consolidation chemotherapy. AB - This study aimed to assess the physical activity levels of pediatric patients with acute leukemia undergoing chemotherapy. Thirty-eight pediatric patients and matched controls, aged 3-12 years old, were measured for weight, height, and other anthropometric parameters. Physical activity was assessed using actical accelerometer and activity log book. Patients recorded significantly lower mean total activity counts (26.2+/-30.2 cpm vs. 192.2+/-68.8 cpm; p<0.01) and spent more time in sedentary activities (1301+/-121 min vs. 1020+/-101 min; p<0.001) compared to controls. They also achieved fewer 1-5-min bouts of moderate-vigorous physical activity (MVPA) compared to controls (1.50+/-5.95 vs. 37.38+/-40.36; p<0.001). In conclusion, patients had lower physical activity level and intensity; and simple exercise intervention programs may be needed to minimize the detrimental effects of prolonged sedentary behaviors. PMID- 23099237 TI - TET2, ASXL1 and EZH2 mutations in Chinese with myelodysplastic syndromes. AB - Somatic mutations of epigenetic gene regulators are common in patients with myelodysplastic syndromes (MDS) and correlate with some clinical and laboratory features. We studied mutations in TET2, ASXL1 and EZH2 in 153 Chinese patients with MDS. TET2 mutations were detected in 35 patients (23%), ASXL1 in 33 patients (22%) and EZH2 in 8 (5%). ASXL1 mutations were associated with increased colony formation of BFU-E, CFU-E and CFU-GM (P-values, 0.049, 0.011 and 0.006). EZH2 mutations were common in patients with poor IPSS cytogenetics (P=0.001) and in patients in the IPSS intermediate-2/high-risk cohorts (P=0.06). In uni- but not multi-variate analyses, mutated TET2 was associated with longer survival (P=0.044) whereas EZH2 mutations were associated with an increased risk of transformation to acute myeloid leukemia (AML; P=0.039). These data suggest ASXL1 mutations might results in dominance of the mutant clone in Chinese with MDS whereas EZH2 mutations might predict an increased risk of transformation to AML. PMID- 23099239 TI - Differences in coronary atherosclerotic plaque burden and composition according to increasing age on computed tomography angiography. AB - RATIONALE AND OBJECTIVES: Few data were available regarding the underlying burden of specific plaque types with increasing ages. The aim of this study was to assess the relationship of coronary artery calcium (CAC) score with total coronary plaque burden and the difference of underlying coronary plaque composition across differing aging groups using 64-slice multidetector computed tomography. MATERIALS AND METHODS: Multidetector computed tomographic images of 781 consecutive patients were evaluated using a 15-coronary segment model. Segment involvement score (the total number of segments with any plaque), segment stenosis score (the sum of maximal stenosis score per segment), total plaque score (the sum of the plaque amount per segment), and plaque composition were measured to compare with total CAC scores stratified by age tertile (lowest [n = 274], <55 years; middle [n = 242], 55-65 years; highest [n = 265], >65 years). RESULTS: The mean age of the study population was 59 +/- 13 years (481 men [62%]). With increasing age, higher segment involvement scores, segment stenosis scores, and total plaque scores were noted. Plaque burden was correlated significantly with total CAC scores in all tertiles. The percentage of partially calcified (P < .001) and calcified (P < .001) plaque increased with age, and in the highest age tertile, 87% of plaque contained calcium (calcified or mixed), compared to only 63% in the younger patients (P < .001). Those aged >65 years were highly unlikely to have isolated noncalcified plaque (in the setting of a calcium score of 0). Younger patients were 10 times more likely to have isolated noncalcified plaque (P < .001). CONCLUSIONS: The absence of CAC strongly excludes obstructive disease, and CAC predicts the presence of coronary atherosclerotic plaque. However, the absence of any CAC does not exclude the presence of coronary atherosclerotic plaque, especially in patients aged <55 years. Plaque composition shifted from noncalcified to calcified plaque with increasing age, which may affect the vulnerability of these lesions over time. PMID- 23099240 TI - Diagnosis of inguinal lymph node metastases using contrast enhanced high resolution MR lymphangiography. AB - RATIONALE AND OBJECTIVES: Inguinal lymph nodes can be the first or the only clinical signs of tumor metastases. The aim of the study was to evaluate the role of contrast-enhanced high-resolution magnetic resonance (MR) lymphangiography in diagnosis of inguinal lymph node metastases. MATERIALS AND METHODS: The study enrolled 26 patients with inguinal lymph node metastases. Contrast-enhanced lymphangiography was performed using a 3.0T MR unit after intracutaneous injection of gadobenate dimeglumine into the interdigital webs of the dorsal foot. Images of inguinal lymph nodes were acquired before and after contrast injection. RESULTS: All patients exhibited edema in the subcutaneous layer with significant dilatation of lymphatic collectors in the affected lower limbs on MR images. Before contrast injection, the outline and structure of the affected nodes were unclear on T2 weighted images. Structural changes became evident on postinjection T1-weighted images. Nodal involvement on contrast enhanced MR lymphangiograms was characterized as: 1) heterogeneous structure with partial or marginal enhancement of the node indicating partial occupation by tumor; 2) homogeneous structure of the node without contrast enhancement, indicating total occupation with metastasis, with increase or no change in size; and 3) heterogeneous structure with punctiform nodal enhancement indicating diffuse growth of tumor within the node. Further examinations confirmed the diagnoses of inguinal lymph node metastases of either regional or distal tumors. CONCLUSIONS: Contrast-enhanced high-resolution MR lymphangiography was a sensitive modality in the diagnosis of malignant peripheral lymphedema and the identification of inguinal lymph node metastasis in patients with various tumor origins. PMID- 23099241 TI - 3D multi-parametric breast MRI segmentation using hierarchical support vector machine with coil sensitivity correction. AB - RATIONALE AND OBJECTIVES: The goal of the study is to develop a technique to achieve accurate volumetric breast tissue segmentation using magnetic resonance imaging (MRI) data. This segmentation can be useful to aid in the diagnosis of breast cancers and to assess breast cancer risk based on breast density. Tissue segmentation is also essential for development of acoustic and thermal models used in magnetic resonance guided high-intensity focused ultrasound treatment of breast lesions. MATERIALS AND METHODS: In addition to commonly used T1-, T2-, and proton density-weighted images, three-point Dixon water- and fat-only images were also included as part of the multiparametric inputs to a tissue segmentation algorithm using a hierarchical support vector machine (SVM). The effectiveness of a variety of preprocessing schemes was evaluated through two in vivo datasets. The performance of the hierarchical SVM was investigated and compared to the conventional classification algorithms-conventional SVM and fuzzy C-mean (FCM). RESULTS: The need for co-registration, zero-filled interpolation, coil sensitivity correction, and optimal SNR reconstruction before the final stage classification was demonstrated. The overlap ratios of the hierarchical SVM, conventional SVM and FCM were 93.25%-94.08%, 81.68-92.28%, and 75.96%-91.02%, respectively. Classification outputs from in vivo experiments showed that the presented methodology is consistent and outperforms other algorithms. CONCLUSION: The presented hierarchical SVM-based technique showed promising results in automatically segmenting breast tissues into fat, fibroglandular tissue, skin, and lesions. The results provide evidence that both the multiparametric breast MRI inputs and the preprocessing procedures contribute to the high accuracy of tissue classification. PMID- 23099242 TI - Clinical evaluation and potential radiation dose reduction of the novel sinogram affirmed iterative reconstruction technique (SAFIRE) in abdominal computed tomography angiography. AB - RATIONALE AND OBJECTIVES: Computed tomographic angiography is the standard in routine follow-up after endovascular aneurysm repair, causing radiation exposure; thus, dose-saving strategies should be applied. The aim of this study was to evaluate the novel sinogram-affirmed iterative reconstruction (SAFIRE) algorithm in terms of clinical usability and potential reduction of radiation exposure. MATERIALS AND METHODS: Forty-six patients underwent computed tomographic angiographic follow-up after endovascular aneurysm repair. Data were acquired using a dual-source computed tomographic scanner running both x-ray tubes at the same voltage (120 kV). Raw data were reconstructed using projections of both tubes with filtered back projection (FBP) and of only one tube with FBP and SAFIRE, corresponding to synthetic acquisition with half the radiation dose of the clinical routine radiation dose. Image sets were objectively compared regarding signal-to-noise ratio and edge sharpness. Two radiologists independently assessed a set of subjective criteria, including diagnostic usability, depiction of contrasted vessels, and image noise. RESULTS: Half-dose (HD) SAFIRE images showed significantly higher signal-to-noise ratios compared to full-dose FBP images (P < .001), while having equal edge sharpness (P = .56). Most of the subjectively assessed parameters, such as diagnostic usability and depiction of contrasted vessels, were rated similar for HD SAFIRE and full-dose FBP images. Full-dose FBP images depicted fine anatomic structures more clearly (P < .05), while HD SAFIRE data sets showed less noise (P < .01). HD FBP images performed worse on all criteria (P < .001). Interrater agreement was good (kappa = 0.74-0.80). CONCLUSIONS: Using the SAFIRE algorithm, the radiation dose of high contrast abdominal computed tomographic angiography is reducible from routine clinical levels by up to 50% while maintaining good image quality and diagnostic accuracy. PMID- 23099244 TI - Notch signaling in hepatocellular carcinoma: guilty in association! PMID- 23099245 TI - The great mimicker. PMID- 23099246 TI - Self-association of zwitterionic polymer-lipid conjugates in water as examined by scattering measurements. AB - As a model of lipopeptide, a zwitterionic polymer-lipid conjugate was prepared from carboxymethylbetaine monomer (CMB) using a lipophilic initiator having a cholesteryl or dihexadecylglyceryl end group for atom transfer radical polymerization (ATRP). The polymer-lipid conjugates (Lipid-PCMB) obtained could be dispersed in water, and self-association of the compounds could be characterized by both light scattering (dynamic light scattering, DLS; electrophoretic light scattering, ELS) and small-angle X-ray scattering (SAXS). DLS and ELS measurements showed no secondary aggregation of the self-associated Lipid-PCMB molecules in salt solutions, though their surfaces were almost charge balanced. The hydrophilic PCMB layer of Lipid-PCMB aggregates gave rise to dispersions under ionic conditions. Furthermore, structural analyses by DLS, ELS and SAXS measurements suggested that Lipid-PCMB aggregates consisted of a hydrophobic lipid core and a hydrophilic PCMB layer, that is, a core-shell structure. To the best our knowledge, this is the first study in which SAXS analyses were performed for zwitterionic polymer-lipid conjugates. PMID- 23099247 TI - Near infrared induced optical heating in laser ablated Bi quantum dots. AB - Chemically pure mono-dispersed spherical bismuth (Bi) nanoparticles (NPs) having diameter in the range of 5-20 nm are prepared by liquid pulsed laser ablation technique. The effect of ablation time and the surfactant (C(12)H(25)NaO(4)S) on the size of nanoparticles are studied and both were found to play crucial role in controlling the size of the NPs and consequently, the optical properties. An absorption band observed around 980 nm is attributed to semimetal to semiconductor transition. Interestingly, prepared semiconductor Bi NPs are found to generate intense heat when 976 nm laser wavelength falls on them and thus generates a hope for potential biomedical applications viz. hypothermia treatment. PMID- 23099248 TI - Micellization of amphiphilic block copolymers in binary and ternary solvent mixtures. AB - Amphiphilic block copolymers of the poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) family (commercially available as Pluronics or Poloxamers) are well known for self-assembling in water (selective solvent for PEO) into micelles with a PPO-rich core and a hydrated PEO corona. The micellization of two PEO-PPO-PEO block copolymers (Pluronic P105: EO(37)PO(56)EO(37) and Pluronic F127: EO(100)PO(65)EO(100)) has been studied in binary mixed solvents consisting of water and one of the following organic solvents: ethanol, glycerol, D(+)-glucose monohydrate, propylene carbonate, or triacetin, and also in ternary mixtures of water with 50/50 wt% ethanol+glycerol or 50/50 wt% ethanol+propylene carbonate. Glycerol, glucose, propylene carbonate and triacetin were found to promote micellization when added to water. Glycerol and glucose interact favorably with water, and reduce the block copolymer critical micelle concentration (cmc) by dehydrating the PEO-PPO interface as well as changing the bulk solvent properties. Propylene carbonate and triacetin act by locating at the PEO-PPO interface and increasing its hydrophobicity. The addition of ethanol to water provides better solvent conditions for the block copolymers compared to plain water, and disfavors the formation of micelles. In the case of ternary solvents consisting of water, ethanol (that prevents micelle formation), and glycerol or propylene carbonate (that favor micelle formation), the observed changes in the cmc are subtle. For Pluronic P105, the cmc increase is greater for ethanol+propylene carbonate (50/50 wt%) than for ethanol+glycerol (50/50 wt%). For Pluronic F127, the cmcs remain the same as in plain water, i.e., the effects of the two organic solvents compensate each other. The difference between the free energy of micellization in plain water and that in solvent mixtures varies linearly with the cosolvent concentration, and collapses into a single line for each solvent mixture type when normalized with the number of the block copolymer PO units (N(PO)), indicating that the micelle core is mainly affected by varying solvent condition for different PEO/PPO ratios. PMID- 23099249 TI - Characterization of the Solutol(r) HS15/water phase diagram and the impact of the Delta9-tetrahydrocannabinol solubilization. AB - Here, the phase behavior of the commercial non-ionic surfactant Solutol(r) HS15 in water was investigated. The focus was on the evolution of the system nanostructure at low water content. Particularly, it was demonstrated that spherical micelles found in dilute surfactant solutions coalesce at a surfactant volume fraction close to 0.5. As consequence, a heterogeneous pseudo-binary mixture occurs. No liquid crystalline phases were detected even at the highest HS15 concentrations in water. Alteration of the micellar morphology induced by the addition of Delta(9)-tetrahydrocannabinol to the surfactant/water binary system was also investigated. It was found that the cannabinoid molecules become entrapped within the surfactant hydrophobic tails, thus increasing the surfactant effective packing parameter and inducing a radical change of the micelle shape. At sufficiently low water content (18-35 wt.%), such alteration of the interfacial packing results in a lamellar organization of the surfactant molecules. PMID- 23099250 TI - Semaphorins in cancer: biological mechanisms and therapeutic approaches. AB - The hallmarks of cancer include multiple alterations in the physiological processes occurring in normal tissues, such as cell proliferation, apoptosis, and restricted cell migration. These aberrant behaviors are due to genetic and epigenetic changes that affect signaling pathways controlling cancer cells, as well as the surrounding "normal" cells in the tumor microenvironment. Semaphorins and their receptors (mainly plexins and neuropilins) are aberrantly expressed in human tumors, and multiple family members are emerging as pivotal signals deregulated in cancer. Notably, different semaphorins can promote or inhibit tumor progression, depending on the implicated receptor complexes and responsive cell type. The important role of semaphorin signals in the regulation of tumor angiogenesis, invasion and metastasis has initiated multiple experimental approaches aimed at targeting these pathways to inhibit cancer. PMID- 23099251 TI - Anti-nociceptive activity of Pereskia bleo Kunth. (Cactaceae) leaves extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Local communities in Malaysia consume Pereskia bleo Kunth. (Cactaceae) leaves as raw vegetables or as a concoction and drink as a tea to treat diabetes, hypertension, rheumatism, cancer-related diseases, inflammation, gastric pain, ulcers, and for revitalizing the body. AIM OF THE STUDY: To evaluate anti-nociceptive activity of the extracts and vitexin, isolated for the first time in this species, in two analgesic models; formalin induced licking and acetic acid-induced abdominal writhing. MATERIALS AND METHODS: Three and a half kilos of P. bleo leaves were extracted using Soxhlet apparatus with ethanol for 72 h. The crude ethanol extract was treated with activated charcoal overnight and subjected to a liquid-liquid partition yielding hexane, dichloromethane, ethyl acetate and butanol extracts. All extracts, including the crude ethanol and vitexin isolated from the ethyl acetate partition were tested for peripheral anti-nociceptive activity using formalin test and acetic acid-induced abdominal writhing, besides having their acute toxicity assays performed. RESULTS: The phytochemical analyses resulted in the isolation of vitexin (1), beta-sitosterol glucoside (2) and beta-sitosterol (3) isolated from the ethyl acetate, dichloromethane and hexane extracts, respectively. This is the first time vitexin and beta-sitosterol glucoside are isolated from this species. The anti-nociceptive activities for all extracts were only moderate. Vitexin, which was isolated from the ethyl acetate extract did not show any activity in all models tested when used alone at the same concentration as it appears in the extract. CONCLUSION: This study showed that all the extracts possess moderate anti-nociceptive activity. Vitexin is not the compound responsible for the anti-nociceptive effect in the ethyl acetate extract. Further investigations are needed to identify the compound(s) that might be responsible for the anti-nociceptive activity in this plant. PMID- 23099252 TI - Antifungal study of the resinous exudate and of meroterpenoids isolated from Psoralea glandulosa (Fabaceae). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea glandulosa L. (Fabaceae) is a medicinal resinous shrub used in Chilean folk medicine as antiseptic in treatment of infections and skin diseases caused by bacteria and fungus. AIM OF THE STUDY: To evaluate the in vitro antifungal activity of the resin and the active components from P. glandulosa against clinical yeast isolates. MATERIALS AND METHODS: Active compounds were obtained of the resinous exudate from aerial parts of P. glandulosa. Eight species of yeast were exposed to the resin and two major compounds. Minimum inhibitory concentration (MIC(80)) was determined according to the standard broth microdilution method. RESULTS: Bakuchiol and 3-hydroxy bakuchiol demonstrated potent activity with the MIC(80) ranging from 4 to >16 and 0.125 to 16 MUg/mL, respectively. The resin had some degree of antifungal activity. CONCLUSIONS: The overall results provided important information for the potential application of the 3-hydroxy-bakuchiol from P. glandulosa in the therapy of serious infection and skin diseases caused by clinical yeast. PMID- 23099253 TI - The mystery of the 'resin-of-canuaru': a medicine used by caboclos river-dwellers of the Amazon, Amazonas, Brazil. AB - ETHNOPHARMACOLOGICAL RELEVANCE: 'Resin-of-canuaru' is a medicine utilized by caboclos living in the Amazon Region, Brazil. There is a mystery regarding its origin because the caboclos maintain that this substance is derived only from animal secretions (from a frog called canuaru), whereas the historic literature claims that 'resin-of-canuaru' is derived solely from a plant exudate (resin). Based on our ethnographic studies, we hypothesized that this substance is a combination of both. Because the past reports on this resiniferous material in the literature are based solely on observations, we aimed to present ethnographic, zoological and chemical data to try to elucidate the origin of the 'resin-of-canuaru'. MATERIALS AND METHODS: Ethnographic techniques and methods were applied, including participant observation, the use of field diaries and informal and unstructured interviews. The canuaru frog (Trachycephalus resinifictrix Goeldi, 1907) and 'resin-of-canuaru' were collected for taxonomic identification and chemical analysis, respectively. The resiniferous 'resin-of canuaru' was extracted using MeOH and then analyzed by silica gel TLC and NMR. RESULTS: Canuaru frogs live in tree cavities and secrete a large amount of substances during spawning, resulting in a resiniferous material. NMR analysis of the MeOH extract of this crude material showed peaks assigned to 3,4-secofriedel 4(23)-en-3-oic acid (putranjuvic acid) and its methyl ester derivative (methyl putranjivate) and to biogenetic precursor of these two compounds (a lactone derivative), which is formed by the oxidation of friedelin. Based on evidence that Protium species accumulate primarily tetracyclic/pentacyclic triterpenoids and that the co-occurrence of the compounds listed above is rarely described in plant species, we suggest that these compounds could be products of the biotransformation of friedelin by the frog. CONCLUSIONS: According to our data, the 'resin-of-canuaru' seems to have both animal and vegetal origins. PMID- 23099254 TI - Inhibition of pre-ischeamic conditioning in the mouse caudate brain slice by NMDA or adenosine A1 receptor antagonists. AB - Evidence suggests that pre-ischeamic conditioning (PIC) offers protection against a subsequent ischeamic event. Although some brain areas such as the hippocampus have received much attention, the receptor mechanisms of PIC in other brain regions are unknown. We have previously shown that 10 min oxygen and glucose deprivation (OGD) evokes tolerance to a second OGD event in the caudate. Here we further examine the effect of length of conditioning event on the second OGD event. Caudate mouse brain slices were superfused with artificial cerebro-spinal fluid (aCSF) bubbled with 95%O(2)/5%CO(2). OGD was achieved by reducing the aCSF glucose concentration and by bubbling with 95%N(2)/5%CO(2). After approximately 5 min OGD a large dopamine efflux was observed, presumably caused by anoxic depolarisation. On applying a second OGD event, 60 min later, dopamine efflux was delayed and reduced. We first examined the effect of varying the length of the conditioning event from 5 to 40 min and found tolerance to PIC increased with increasing duration of conditioning. We then examined the receptor mechanism(s) underlying PIC. We found that pre-incubation with either MK-801 or 8-cyclopentyl 1,3-dipropylxanthine (DPCPX) reduced tolerance to the second OGD event. These data suggest that either N-methyl-D-aspartate (NMDA) or adenosine A(1) receptor activation evokes PIC in the mouse caudate. PMID- 23099255 TI - The role of PKC/ERK1/2 signaling in the anti-inflammatory effect of tetracyclic triterpene euphol on TPA-induced skin inflammation in mice. AB - Inflammation underlies the development and progression of a number of skin disorders including psoriasis, atopic dermatitis and cancer. Therefore, novel antiinflammatory agents are of great clinical interest for prevention and treatment of these conditions. Herein, we demonstrated the underlying molecular mechanisms of the antiinflammatory activity of euphol, a tetracyclic triterpene isolated from the sap of Euphorbia tirucalli, in skin inflammation induced by 12 O-tetradecanoylphorbol-13-acetate (TPA) in mice. Topical application of euphol (100 MUg/ear) significantly inhibited TPA-induced ear edema and leukocyte influx through the reduction of keratinocyte-derived chemokine (CXCL1/KC) and macrophage inflammatory protein (MIP)-2 levels. At the intracellular level, euphol reduced TPA-induced extracellular signal-regulated protein kinase (ERK) activation and cyclooxygenase-2 (COX-2) upregulation. These effects were associated with euphol's ability to prevent TPA-induced protein kinase C (PKC) activation, namely PKCalpha and PKCdelta isozymes. Our data indicate that topical application of euphol markedly inhibits the inflammatory response induced by TPA. Thus, euphol represents a promising agent for the management of skin diseases with an inflammatory component. PMID- 23099256 TI - Hippocampal synaptic plasticity restoration and anti-apoptotic effect underlie berberine improvement of learning and memory in streptozotocin-diabetic rats. AB - Chronic diabetes mellitus initiates apoptosis and negatively affects synaptic plasticity in the hippocampus with ensuing impairments of learning and memory. Berberine, an isoquinoline alkaloid, exhibits anti-diabetic, antioxidant and nootropic effects. This study was conducted to evaluate the effect of berberine on hippocampal CA1 neuronal apoptosis, synaptic plasticity and learning and memory of streptozotocin (STZ)-diabetic rats. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was recorded for assessment of synaptic plasticity and field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. PS amplitude and fEPSP significantly decreased in diabetic group versus control, and chronic berberine treatment (100mg/kg/day, p.o.) restored PS amplitude and fEPSP and ameliorated learning and memory impairment and attenuated apoptosis of pyramidal neurons in the CA1 area, as determined by the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling method. In summary, chronic berberine treatment of STZ-diabetic rats significantly ameliorates learning and memory impairment and part of its beneficial effect could be attributed to improvement of synaptic dysfunction and anti-apoptotic property. PMID- 23099257 TI - Role of TRPV1 and TRPA1 in visceral hypersensitivity to colorectal distension during experimental colitis in rats. AB - The aim of the present study is to investigate the effects of TRPV1 and TRPA1 receptor antagonists and their synergism on the visceromotor responses during experimental colitis in rats. Colitis was induced in rats by a TNBS/ethanol enema at day 0 and was assessed at day 3 using endoscopy, histology and a myeloperoxidase assay. The visceromotor response to colorectal distension (10-80 mmHg) was evaluated in conscious rats before (control condition) and 3 days after 2,4,6-trinitrobenzene sulfonic acid (TNBS) administration (colitis condition). At day 3, visceromotor responses were assessed before and after treatment with a TRPV1 (BCTC) or TRPA1 (TCS-5861528) receptor antagonist either alone or in combination and either after intraperitoneal or intrathecal administration. Endoscopy, microscopy and myeloperoxidase activity indicated severe colonic tissue damage 3 days after TNBS administration. Colorectal distension-evoked visceromotor responses demonstrated a 2.9-fold increase during acute colitis (day 3) compared to control conditions. Intraperitoneal and intrathecal administration of BCTC or TCS-5861528 partially reversed the colitis-induced increase in visceromotor responses compared to control conditions (P<0.05). Intraperitoneal blockade of TRPA1 plus TRPV1 further decreased the enhanced visceromotor responses at high distension pressures (40-80 mmHg) compared to blockade of either TRPV1 or TRPA1 alone. This synergistic effect was not seen after combined intrathecal blockade of TRPA1 plus TRPV1. The present study demonstrates that in the rat, TRPV1 and TRPA1 play a pivotal role in visceral hypersensitivity at the peripheral and spinal cord level during acute TNBS colitis. Target interaction, however, is presumably mediated via a peripheral site of action. PMID- 23099258 TI - Anti-depressant-like effect of vitexin in BALB/c mice and evidence for the involvement of monoaminergic mechanisms. AB - The present study was designed to investigate the putative effect of vitexin, a flavone C-glucoside present in some drugs, medicinal plants and nutraceuticals, on the central nervous system. Vitexin (10-30 mg/kg) did not show significant alterations in the behaviour of mice tested in hole-board, plus-maze or activity cage tests. However, immobility time of the mice significantly reduced by vitexin administrations in both the tail-suspension and modified forced swimming tests. The anti-immobility effect of vitexin in the tail-suspension test was reversed with alpha-methyl-para-tyrosine methyl ester (AMPT, an inhibitor of catecholamine synthesis, 100mg/kg, i.p.), yohimbine (an alpha(2)-adrenoceptor antagonist, 1mg/kg, i.p.), NAN 190 (a 5-HT(1A) antagonist, 0.5mg/kg, i.p.), SCH 23390 (a dopamine D(1) antagonist, 0.05 mg/kg, s.c.) and sulpiride (a dopamine D(2)/D(3) antagonist, 50mg/kg, i.p.). The same effect was not reversed, however, by p chlorophenylalanine methyl ester (PCPA; an inhibitor of serotonin synthesis 100mg/kg, i.p., administered for 4 consecutive days), ketanserin (a 5-HT(2A/2C) antagonist, 1-4 mg/kg, i.p.), ondansetron (a 5-HT(3) antagonist, 0.1-0.4 mg/kg, i.p.), prazosin (an alpha(1)-adrenoceptor antagonist, 1-4 mg/kg, i.p.), or propranolol (a non-selective beta-adrenoceptor antagonist, 5-20mg/kg, i.p.). These results suggest that the anti-depressant-like effect of vitexin is mediated through an increase in catecholamine levels in the synaptic cleft as well as through interactions with the serotonergic 5-HT(1A), noradrenergic alpha(2), and dopaminergic D(1), D(2), and D(3) receptors. To our knowledge, this is the first study to show findings that indicate an anti-depressant-like effect of vitexin and its underlying mechanisms. PMID- 23099259 TI - Examination of methylphenidate-mediated behavior regulation by glycogen synthase kinase-3 in mice. AB - Abnormalities in dopaminergic activity have been implicated in psychiatric diseases, such as attention deficit hyperactivity disorder (ADHD), and are treated with therapeutic stimulants, commonly methylphenidate or amphetamine. Amphetamine administration increases glycogen synthase kinase-3 (GSK3) activation, which is necessary for certain acute behavioral responses to amphetamine, including increased locomotor activity and impaired sensorimotor gating. Here, we tested if modulating GSK3 by administration of the GSK3 inhibitor lithium or expression of constitutively active GSK3 altered behavioral responses to methylphenidate administered to mice acutely or daily for 8 days. Methylphenidate or amphetamine was administered to mice intraperitoneally for 1 or 8 days. Open-field activity and pre-pulse inhibition (PPI) were measured. In contrast to lithium's blockade of acute amphetamine-induced locomotor hyperactivity, lithium treatment did not significantly reduce methylphenidate induced locomotor hyperactivity in wild-type mice after acute or 8 days of repeated methylphenidate administration. Lithium treatment significantly increased the impairment in PPI caused by methylphenidate, but significantly reduced the amphetamine-induced PPI deficit. In GSK3 knockin mice, expression of constitutively active GSK3beta, but not GSK3alpha, significantly increased locomotor hyperactivity after acute methylphenidate treatment, and significantly impaired PPI, preventing further methylphenidate-induced impairment of PPI that was evident in wild-type mice and GSK3alpha knockin mice. Lithium does not counteract locomotor activity and PPI responses to methylphenidate as it does these responses to amphetamine, indicating that different mechanisms mediate these behavioral responses to methylphenidate and amphetamine. Only active GSK3beta, not GSK3alpha, modulates behavioral responses to MPH, indicating selectivity in the actions of GSK3 isoforms. PMID- 23099260 TI - Characterization of the Lactobacillus casei group based on the profiling of ribosomal proteins coded in S10-spc-alpha operons as observed by MALDI-TOF MS. AB - The taxonomy of the members of the Lactobacillus casei group is complicated because of their phylogenetic similarity and controversial nomenclatural status. In this study, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) of ribosomal proteins coded in the S10-spc-alpha operon, termed S10-GERMS, was applied in order to classify 33 sample strains belonging to the L. casei group. A total of 14 types of ribosomal protein genes coded in the operon were first sequenced from four type strains of the L. casei group (L. casei JCM 1134(T), L. paracasei subsp. paracasei JCM 8130(T), L. paracasei subsp. tolerans JCM 1171(T), and L. rhamnosus JCM 1136(T)) together with L. casei JCM 11302, which is the former type strain of 'L. zeae'. The theoretical masses of the 14 types of ribosomal proteins used as biomarkers were classified into five types and compiled into a ribosomal protein database. The observed ribosomal proteins of each strain, identified by MALDI-TOF MS, were categorized into types based on their masses, summarized as ribosomal protein profiles, and they were used to construct a phylogenetic tree. The 33 sample strains, together with seven genome-sequenced strains, could be classified into four major clusters, which coincided precisely with the taxa of the (sub)species within the L. casei group. Three "ancient" strains, identified as L. acidophilus and L. casei, were correctly re-identified as L. paracasei subsp. paracasei by S10-GERMS. S10-GERMS would thus appear to be a powerful tool for phylogenetic characterization, with considerable potential for management of culture collections. PMID- 23099261 TI - Expression and characterization of PhzE from P. aeruginosa PAO1: aminodeoxyisochorismate synthase involved in pyocyanin and phenazine-1 carboxylate production. AB - PhzE from Pseudomonas aeruginosa catalyzes the first step in the biosynthesis of phenazine-1-carboxylic acid, pyocyanin, and other phenazines, which are virulence factors for Pseudomonas species. The reaction catalyzed converts chorismate into aminodeoxyisochorismate using ammonia supplied by a glutamine amidotransferase domain. It has structural and sequence homology to other chorismate-utilizing enzymes such as anthranilate synthase, isochorismate synthase, aminodeoxychorismate synthase, and salicylate synthase. Like these enzymes, it is Mg(2+) dependent and catalyzes a similar S(N)2" nucleophilic substitution reaction. PhzE catalyzes the addition of ammonia to C2 of chorismate, as does anthranilate synthase, yet unlike anthranilate synthase it does not catalyze elimination of pyruvate from enzyme-bound aminodeoxyisochorismate. Herein, the cloning of the phzE gene, high level expression of active enzyme in E. coli, purification, and kinetic characterization of the enzyme is presented, including temperature and pH dependence. Steady-state kinetics give K(chorismate)=20+/ 4MUM, K(Mg)(2+)=294+/-22MUM, K(L-gln)=11+/-1mM, and k(cat)=2.2+/-0.2s(-1) for a random kinetic mechanism. PhzE can use NH(4)(+) as an alternative nucleophile, while Co(2+) and Mn(2+) are alternative divalent metals. PMID- 23099263 TI - Structural connectivity in a single case of progressive prosopagnosia: the role of the right inferior longitudinal fasciculus. AB - Progressive prosopagnosia (PP) is a clinical syndrome characterized by a progressive and selective inability to recognize and identify faces of familiar people. Here we report a patient (G.S.) with PP, mainly related to a prominent deficit in recognition of familiar faces, without a semantic (cross-modal) impairment. An in-depth evaluation showed that his deficit extended to other classes of objects, both living and non-living. A follow-up neuropsychological assessment did not reveal substantial changes after about 1 year. Structural MRI showed predominant right temporal lobe atrophy. Diffusion tensor imaging was performed to elucidate structural connectivity of the inferior longitudinal fasciculus (ILF) and the inferior fronto-occipital fasciculus (IFOF), the two major tracts that project through the core fusiform region to the anterior temporal and frontal cortices, respectively. Right ILF was markedly reduced in G.S., while left ILF and IFOFs were apparently preserved. These data are in favour of a crucial role of the neural circuit subserved by right ILF in the pathogenesis of PP. PMID- 23099264 TI - The epidemiology of type 1 diabetes in children. AB - Type 1 diabetes is one of the most common chronic diseases of childhood and adolescence. Multiple registries have assessed its epidemiology and have noted a steady increase in incidence of the disease. This article addresses the epidemiology of type 1 diabetes in children aged 0 to 19 years, by reviewing the available, current data from both US and international registries. The prevalence and incidence data by race, ethnicity, age of onset, sex, season of onset, and temporal trends of the disease are presented. Multiple risk factors have been implicated for the increasing incidence in type 1 diabetes, and these genetic and environmental risk factors are discussed. PMID- 23099262 TI - Hydrogen-exchange mass spectrometry for the study of intrinsic disorder in proteins. AB - Amide hydrogen/deuterium exchange detected by mass spectrometry (HXMS) is seeing wider use for the identification of intrinsically disordered parts of proteins. In this review, we discuss examples of how discovery of intrinsically disordered regions and their removal can aid in structure determination, biopharmaceutical quality control, the characterization of how post-translational modifications affect weak structuring of disordered regions, the study of coupled folding and binding, and the characterization of amyloid formation. This article is part of a Special Issue entitled: Mass spectrometry in structural biology. PMID- 23099265 TI - Update on global intervention studies in type 1 diabetes. AB - Remarkable progress has been made in strategies to arrest pancreatic beta-cell destruction in type 1 diabetes. Although knowledge of the disease has increased, a safe therapeutic intervention to reverse or prevent it remains elusive. The interaction of genes, immune system, and environment result in a complex disease process that has delayed hopes for a cure. Several well-designed prevention and intervention studies have aspired to test potentially efficacious and safe therapies. This article updates the principles used to design prevention and intervention trials, reviews clinical trials, addresses controversial issues, and provides a framework for future efforts to interdict this condition. PMID- 23099266 TI - Update on Turner and Noonan syndromes. AB - Turner syndrome (TS) and Noonan syndrome (NS) have short stature as a constant feature; however, both conditions can present clinicians with a challenging array of genetic, cardiovascular, developmental, and psychosocial issues. In recent years, important advances have been achieved in each of these areas. This article reviews these two syndromes and provides updates on recent developments in diagnostic evaluation, growth and development, psychological issues, and treatment options for patients with TS and NS. PMID- 23099267 TI - Down syndrome and thyroid function. AB - Thyroid dysfunction in children with Down syndrome (DS) can occur as early as birth. As children with DS age, their risk for thyroid autoimmunity manifested as autoimmune hypothyroidism or Graves disease increases. The optimal timing and method for thyroid screening in children with DS remains controversial. The American Academy of Pediatrics recommends annual screening in this population. Consensus is needed to establish working definitions of euthyroidism and mild hypothyroidism in all infants, but especially in those with DS. PMID- 23099268 TI - Growth and growth hormone treatment in children with chronic diseases. AB - Growth hormone has been available for treatment of various conditions for over 50 years. There have been a number of chronic disease states in which it has been used, such as chronic kidney disease, which became a US Food and Drug Administration (FDA)-approved indication in 1993. For other chronic disease states there have been clinical studies supporting its use, but they have not yet been approved as a indications by the FDA. Examples of such diseases are cystic fibrosis, chronic arthritis, short bowel syndrome, burn trauma, and hypophosphatemic rickets. PMID- 23099269 TI - A pathophysiologic approach to growth problems in children with attention deficit/hyperactivity disorder. AB - In recent years there has been an increasing trend in the diagnosis and treatment of children with attention-deficit/hyperactivity disorder (ADHD) worldwide. One of the most frequently discussed side effects of these treatments is related to problems of growth. In order to better understand what ADHD is and the mechanisms by which it could affect growth, this article reviews relevant data from a clinical and neurophysiologic perspective to improve understanding of this controversial issue. PMID- 23099270 TI - Safety of growth hormone treatment in patients previously treated for cancer. AB - This review provides an overview of the safety of growth hormone replacement therapy in individuals previously treated for cancer. The review focuses on the risk of disease recurrence and second neoplasm occurrence with special attention to data on childhood cancer survivors. PMID- 23099271 TI - Cushing syndrome in pediatrics. AB - Cushing syndrome is characterized by truncal obesity, growth deceleration, skin changes, muscle weakness, and hypertension. Cushing syndrome in childhood usually results from the exogenous administration of glucocorticoids. This article presents the causes and discusses the treatment of endogenous Cushing syndrome. It also discusses the clinical and molecular genetics of inherited forms of this syndrome. Cushing syndrome needs to be diagnosed and treated properly when first recognized; improper treatment can turn this otherwise completely curable disorder into a chronic ailment. Barriers to optimal care of a pediatric patient with Cushing syndrome are discussed. PMID- 23099272 TI - Pubertal disorders and bone maturation. AB - Bone age (BA) indicates more clearly than chronologic age how far an individual has progressed toward full maturity, and predicts the potential for further growth. Single or serial skeletal age estimations help to confirm the diagnosis of normal puberty and normal pubertal variants such as constitutional delay of growth and puberty, premature therlache, and precocious adrenarche. BA can aid in the clinical workup of children whose sexual maturation is early or delayed. Although BA is considered a qualitative rather than quantitative measure, it serves to round out the clinical picture, providing information without which diagnosis could not be achieved. PMID- 23099274 TI - Endocrinology and Metabolism Clinics of North America. Pediatric endocrinology. Preface. PMID- 23099273 TI - Endocrinology and Metabolism Clinics of North America. Pediatric endocrinology. Foreword. PMID- 23099276 TI - Oral immunotherapy for food allergy: clinical and preclinical studies. AB - Food allergies affect approximately 5% of the U.S. population and have increased in the last decade. In recent years, oral immunotherapy (OIT) has been tested in clinical trials for peanut, milk, and egg allergies in young children. OIT appears to be fairly well tolerated by most subjects and leads to desensitization with a greatly increased threshold of allergen required to induce reactions. Further approaches being investigated in preclinical studies in mouse models indicate the potential for using adjuvants, such as TLR9 agonists in combination with OIT; peptide OIT; and non-allergen specific applications such as herbal formulations. Further questions about OIT remain, including the optimal dosing and length of treatment; whether tolerance can be developed; and the exact cellular mechanisms resulting in protection following OIT. With many clinical trials underway across the United States and other countries, and a growing pipeline of preclinical research with translational potential, there is great hope for a widely applicable food allergy treatment. PMID- 23099277 TI - Amino acids as promoieties in prodrug design and development. AB - Prodrugs are biologically inactive agents that upon biotransformation in vivo result in active drug molecules. Since prodrugs might alter the tissue distribution, efficacy and the toxicity of the parent drug, prodrug design should be considered at the early stages of preclinical development. In this regard, natural and synthetic amino acids offer wide structural diversity and physicochemical properties. This review covers the use of amino acid prodrugs to improve poor solubility, poor permeability, sustained release, intravenous delivery, drug targeting, and metabolic stability of the parent drug. In addition, practical considerations and challenges associated with the development of amino acid prodrugs are also covered. PMID- 23099278 TI - Risk of tyrosine kinase inhibitors-induced hepatotoxicity in cancer patients: a meta-analysis. AB - INTRODUCTION: Although existing evidence from clinical trials has demonstrated manifestation of hepatic adverse events (AEs) with the use of tyrosine kinase inhibitors (TKIs), overall risks have yet to be reported. Thus we conducted a meta-analysis to determine the risk of hepatotoxicity associated with the use of TKIs, by comparing the occurrence of hepatotoxicity of the TKI arms against that of comparison arms. METHODS: A comprehensive literature search of randomized control trials involving TKIs was performed. Only randomized, double-blind and placebo-controlled phase 2 or phase 3 human trials were included. The included studies must involve the comparison of a TKI against placebo, or the comparison of TKI with chemotherapy agent against placebo with the same chemotherapy agent. RESULTS: Twelve articles were included in the analysis. There was a significant overall increase in the odds of developing high-grade (grade 3 or above) hepatotoxicity with the use of TKIs compared to the control arms (Pooled OR 4.35, 95% CI 2.96-6.39). The odds of developing all-types all-grades (Pooled OR 2.42, 95% CI 1.52-3.85) and high-grade hepatotoxicity due to elevation in alanine transaminase (Pooled OR 5.22, 95% CI 2.88-9.46), aspartate transaminase (Pooled OR 6.15, 95% CI 3.09-12.25) and total bilirubin (Pooled OR 1.76, 95% CI 0.59 5.24) was higher with the use of TKI than compared to the controls. DISCUSSION: This is the first meta-analysis to demonstrate a significantly increased risk of hepatic AEs associated with TKIs use. Clinicians should be aware of this risk and provide close monitoring in patients receiving these therapies. PMID- 23099279 TI - Zygomycosis in children: disseminated infection caused by Cunninghamella bertholletiae. PMID- 23099275 TI - Oral delivery of human biopharmaceuticals, autoantigens and vaccine antigens bioencapsulated in plant cells. AB - Among 12billion injections administered annually, unsafe delivery leads to >20million infections and >100million reactions. In an emerging new concept, freeze-dried plant cells (lettuce) expressing vaccine antigens/biopharmaceuticals are protected in the stomach from acids/enzymes but are released to the immune or blood circulatory system when plant cell walls are digested by microbes that colonize the gut. Vaccine antigens bioencapsulated in plant cells upon oral delivery after priming, conferred both mucosal and systemic immunity and protection against bacterial, viral or protozoan pathogens or toxin challenge. Oral delivery of autoantigens was effective against complications of type 1 diabetes and hemophilia, by developing tolerance. Oral delivery of proinsulin or exendin-4 expressed in plant cells regulated blood glucose levels similar to injections. Therefore, this new platform offers a low cost alternative to deliver different therapeutic proteins to combat infectious or inherited diseases by eliminating inactivated pathogens, expensive purification, cold storage/transportation and sterile injections. PMID- 23099280 TI - Determination of antibodies directed at EBV proteins expressed in both latent and lytic cycles in nasopharyngeal carcinoma. AB - OBJECTIVES: Serologic analyses for anti-EBV antibodies used alone usually have low sensitivity for the diagnosis of nasopharyngeal carcinoma (NPC). We assumed that a combined determination of antibodies directed at EBV proteins expressed in both lytic and latent cycles could increase the sensitivity. MATERIALS AND METHODS: Sixty healthy controls and 100 NPC patients treated with intensity modulated radiation therapy were recruited for the study. Serial blood samples of NPC patients were collected before, during and after the treatment. The titers of antibodies directed at Rta (IgG), EA (IgG), VCA (IgA), and NA1 (IgA) were determined in duplicate by ELISA. RESULTS: Results showed that the combined tests of EA and Rta antibodies significantly improved the sensitivity from 89.0% for EA alone to 95%. For VCA or NA1 in combination with the EA test, it was revealed that either the increase of the specificity was minimal, or the decrease of the specificity was unacceptable. Rta, EA, VCA, and NA1 antibody titers in serial samples were followed from 53 patients of complete remission and 9 patients with recurrence or distal metastasis post the treatment for 2 years. However, the trend of antibody titers of Rta, VCA or NA1 in combination with EA failed to indicate a difference between patients with good and poor prognosis. CONCLUSION: Combined measurements of anti-Rta and anti-EA antibodies could significantly increase the sensitivity for the diagnosis of NPC while maintain a high specificity. PMID- 23099281 TI - Loss of CD151/Tspan24 from the complex with integrin alpha3beta1 in invasive front of the tumour is a negative predictor of disease-free survival in oral squamous cell carcinoma. AB - OBJECTIVES: The study aimed to assess the role of CD151-integrin alpha3beta1 (INGA3) complex as a potential prognostic indicator in OSCC and to examine whether mapping of its expression in the invasive front separately from that in the rest of the tumour would have an impact on the predictive value of the results. CD151/INGA3 profiles were compared with that of EGFR. MATERIALS AND METHODS: Protein distributions were analysed either in the whole tumour (W) or separately, (i) the main tumour mass (TU) and (ii) the invasive front (IF) in 83 OSCC samples using immunohistochemistry. RESULTS AND CONCLUSION: There was no statistical association between any of the proteins scored in W and clinicopathologic features or patient survival. When examined separately, significant associations were shown for (i) CD151 and EGFR in TU (p=0.036) and (ii) tumour grade and EGFR in both TU (p=0.045) and IF (p=0.030). INGA3 was present predominantly in the tumour-host interface, significantly stronger in IF than TU (p=0.021). An association with 5-year disease-free survival was close to significant for INGA3 (TU and IF) (p=0.050) but not the CD151/INGA3 complex. Expression of CD151/INGA3 at the IF might reflect tumour behaviour pertinent to patient outcome. PMID- 23099283 TI - Neurofeedback in ADHD and insomnia: vigilance stabilization through sleep spindles and circadian networks. AB - In this review article an overview of the history and current status of neurofeedback for the treatment of ADHD and insomnia is provided. Recent insights suggest a central role of circadian phase delay, resulting in sleep onset insomnia (SOI) in a sub-group of ADHD patients. Chronobiological treatments, such as melatonin and early morning bright light, affect the suprachiasmatic nucleus. This nucleus has been shown to project to the noradrenergic locus coeruleus (LC) thereby explaining the vigilance stabilizing effects of such treatments in ADHD. It is hypothesized that both Sensori-Motor Rhythm (SMR) and Slow-Cortical Potential (SCP) neurofeedback impact on the sleep spindle circuitry resulting in increased sleep spindle density, normalization of SOI and thereby affect the noradrenergic LC, resulting in vigilance stabilization. After SOI is normalized, improvements on ADHD symptoms will occur with a delayed onset of effect. Therefore, clinical trials investigating new treatments in ADHD should include assessments at follow-up as their primary endpoint rather than assessments at outtake. Furthermore, an implication requiring further study is that neurofeedback could be stopped when SOI is normalized, which might result in fewer sessions. PMID- 23099282 TI - Systematic review: pharmacological treatment of tic disorders--efficacy of antipsychotic and alpha-2 adrenergic agonist agents. AB - We conducted a meta-analysis of randomized, placebo-controlled trials to determine the efficacy of antipsychotic and alpha-2 agonists in the treatment of chronic tic disorders and examine moderators of treatment effect. Meta-analysis demonstrated a significant benefit of antipsychotics compared to placebo (standardized mean difference (SMD)=0.58 (95% confidence interval (CI): 0.36 0.80). Stratified subgroup analysis found no significant difference in the efficacy of the 4 antipsychotic agents tested (risperidone, pimozide, haloperidol and ziprasidone). Meta-analysis also demonstrated a benefit of alpha-2 agonists compared to placebo (SMD=0.31 (95% confidence interval CI: 0.15-0.48). Stratified subgroup analysis and meta-regression demonstrated a significant moderating effect of co-occurring ADHD. Trials which enrolled subjects with tics and ADHD demonstrated a medium-to-large effect (SMD=0.68 (95%CI: 0.36-1.01) whereas trials that excluded subjects with ADHD demonstrated a small, non-significant benefit (SMD=0.15 (95%CI: -0.06 to 0.36). Our findings demonstrated significant benefit of both antipsychotics and alpha-2 agonists in treating tics but suggest alpha-2 agonists may have minimal benefit in tic patients without ADHD. PMID- 23099284 TI - Hypertrophic osteoarthropathy associated to liver cirrhosis. PMID- 23099286 TI - Autonomic epileptic seizures, autonomic effects of seizures, and SUDEP. AB - Many generalized tonic-clonic seizures are accompanied by profound autonomic changes. However, autonomic seizures and autonomic status epilepticus can also be seen with specific electroclinical syndromes (Panayiotopoulos syndrome), etiologies, and localizations. Such autonomic symptoms may impact cardiorespiratory function. While it is likely that several factors contribute to SUDEP, further study of both ictal respiratory and cardiac changes and underlying neuroanatomical mechanisms involved in autonomic seizure semiology are likely to provide important data to improve our understanding of the pathophysiology of this devastating condition. This paper will review the association between autonomic symptoms and epileptic seizures and will highlight the work of three young investigators. Drs. Lisa Bateman and Brian Moseley will review their work on cardiorespiratory effects of recorded seizures and how this assists in our understanding of SUDEP. Dr. John Millichap will review autonomic seizures and autonomic dysfunctions related to childhood epilepsy and will discuss the importance of expanded research efforts in this field. PMID- 23099285 TI - Safety profile of biological intravenous therapy in a rheumatoid arthritis patients cohort. Clinical nursing monitoring (Sebiol study). AB - INTRODUCTION: The Biologics used in the management of rheumatoid arthritis (RA) in recent years, have comprehensively permitted to understand its security, as shown in registries such as BIOBADASER. The present manuscript represents an observational cohort study to describe the safety perinfusional profile of those intravenous treatments. OBJECTIVES: To confirm the safety profile of biological therapies in routine clinical practice, after the administration of intravenous drugs and 24 hours post-administration. MATERIAL AND METHODS: We evaluated a cross-sectional cohort of 114 patients with RA (according to the American College of Rheumatology ACR criteria), attending within one month in 2009 the nursing clinics of day care hospital of 12 Catalonian hospitals. All patients were treated with intravenous biological agents. We recorded the age, sex, current and previous drug treatments, we also collected data about previous vaccination and premedication received and any adverse event occurring at the time of drug administration or within 24 hours. If an adverse event occurred, was categorized by MedDRAv11.0 International Dictionary, and categorized in terms of intensity (mild, moderate, severe), relationship to drug administration according to Karch and Lasagna algorithm (unrelated, unlikely, possible, probable, definite) and the further measures taken. RESULTS: 111 patients met the inclusion criteria, with a mean age of 56.06 years (SD: 12.12), 90 of them women (81.1%) and mean time since diagnosis of the disease of 11.97 years (SD: 7.95). 24 patients (21.6%) had a history of allergy. 12 adverse events were observed in 7 patients, 9 of which at the time of administration and 3 in 24 hours after. There were no serious adverse events and only one of the adverse events (AEs) was rated as moderate (urticaria). The remaining AA were mild. PMID- 23099287 TI - Stress, epilepsy, and psychiatric comorbidity: how can animal models inform the clinic? AB - Psychiatric complaints afflict many patients with epilepsy, and these contribute significantly to the impaired quality of life experienced by sufferers of this common group of neurological conditions. Psychiatric disorders in epilepsy patients are under-diagnosed and under-treated. Moreover, evidence suggests that the psychiatric disorders may act as risk factors for some types of epilepsy and exacerbate disease progression in established cases, promoting the case for a bidirectional relationship between epilepsy and psychopathology. While cause and effect relationships can be difficult to establish in human studies, appropriate animal models provide valuable tools with which to study the interactions between epilepsy and stress-related disorders. Indeed, many epilepsy models exhibit behavioral phenotypes which are reflective of psychiatric disorders, and, conversely, stressful environments appear to promote a vulnerability to developing epilepsy. This review summarizes this research area, exploring the behavioral phenotypes in animal models of epilepsy and then examining the influence of stressful environments on susceptibility to seizures and epilepsy. The ultimate goal of this line of research is to be able to translate these findings to humans. Understanding the relationships between epilepsy and associated psychiatric disorders will facilitate effective treatment of mood disorders in epilepsy, inform about the pathophysiology of each individually, and potentially open up novel therapeutic disease-modifying strategies for patients with epilepsy. PMID- 23099288 TI - Experimental and clinical findings from physical exercise as complementary therapy for epilepsy. AB - Complementary therapies for preventing or treating epilepsy have been extensively used. This review focuses on the positive effects of physical exercise programs observed in clinical studies and experimental models of epilepsy and their significance as a complementary therapy for epilepsy. Information about the antiepileptogenic and neuroprotective effects of exercise is highlighted. Considering that exercise can exert beneficial actions such as reduction of seizure susceptibility, reduction of anxiety and depression, and consequently, improvement of quality of life of individuals with epilepsy, exercise can be a potential candidate as non-pharmacological treatment of epilepsy. PMID- 23099289 TI - A systematic review of cost-effectiveness analyses alongside randomised controlled trials of acupuncture. AB - OBJECTIVE: To summarise the evidence on the cost-effectiveness of acupuncture. METHODS: We identified full economic evaluations such as cost-effectiveness analysis (CEA), cost-utility analysis (CUA) and cost-benefit analysis (CBA) alongside randomised controlled trials (RCTs) that assessed the consequences and costs of acupuncture for any medical condition. Eleven electronic databases were searched up to March 2011 without language restrictions. Eligible RCTs were assessed using the Cochrane criteria for risk of bias and a modified version of the checklist for economic evaluation. The general characteristics and the results of each economic analysis such as incremental cost-effectiveness ratios (ICERs) were extracted. RESULTS: Of 17 included studies, nine were CUAs that measured quality-adjusted life years (QALYs) and eight were CEAs that assessed effectiveness of acupuncture based on improvements in clinical symptoms. All CUAs showed that acupuncture with or without usual care was cost-effective compared with waiting list control or usual care alone, with ICERs ranging from ?3011/QALY (dysmenorrhoea) to ?22 298/QALY (allergic rhinitis) in German studies, and from L3855/QALY (osteoarthritis) to L9951/QALY (headache) in UK studies. In the CEAs, acupuncture was beneficial at a relatively low cost in six European and Asian studies. All CUAs were well-designed with a low risk of bias, but this was not the case for CEAs. CONCLUSIONS: Overall, this review demonstrates the cost effectiveness of acupuncture. Despite such promising results, any generalisation of these results needs to be made with caution given the diversity of diseases and the different status of acupuncture in the various countries. PMID- 23099290 TI - The effectiveness of acupuncture for plantar heel pain: a systematic review. AB - INTRODUCTION: Plantar heel pain (PHP) is a common complaint, yet there are no definitive guidelines for its treatment. Acupuncture is increasingly used by podiatrists, and there is a need for evidence to validate this practice. It is acknowledged that PHP and acupuncture are both complex phenomena. METHOD: A systematic review (PROSPERO no. CRD42012001881) of the effectiveness of acupuncture for PHP is presented. Quality of the studies was assessed by independent assessors with reference to Quality Index (QI), 'STandards for Reporting Interventions in Controlled Trials of Acupuncture' (STRICTA) and 'CONsolidated Standards Of Reporting Trials' (CONSORT) criteria. Pooling of data, or even close comparison of studies, was not performed. RESULTS: Five randomised controlled trials and three non-randomised comparative studies were included. High quality studies report significant benefits. In one, acupuncture was associated with significant improvement in pain and function when combined with standard treatment (including non-steroidal anti-inflammatory drugs). In another, acupuncture point PC7 improved pain and pressure pain threshold significantly more than LI4. Other papers were of lower quality but suggest benefits from other acupuncture approaches. CONCLUSIONS: There is evidence supporting the effectiveness of acupuncture for PHP. This is comparable to the evidence available for conventionally used interventions, such as stretching, night splints or dexamethasone. Therefore acupuncture should be considered in recommendations for the management of patients with PHP. Future research should recognise the complexity of PHP, of acupuncture and of the relationship between them, to explore the optimum use and integration of this approach. There is a need for more uniformity in carrying out and reporting such work and the use of STRICTA is recommended. PMID- 23099291 TI - Explanation and prior knowledge interact to guide learning. AB - How do explaining and prior knowledge contribute to learning? Four experiments explored the relationship between explanation and prior knowledge in category learning. The experiments independently manipulated whether participants were prompted to explain the category membership of study observations and whether category labels were informative in allowing participants to relate prior knowledge to patterns underlying category membership. The experiments revealed a superadditive interaction between explanation and informative labels, with explainers who received informative labels most likely to discover (Experiments 1 and 2) and generalize (Experiments 3 and 4) a pattern consistent with prior knowledge. However, explainers were no more likely than controls to discover multiple patterns (Experiments 1 and 2), indicating that effects of explanation are relatively targeted. We suggest that explanation recruits prior knowledge to assess whether candidate patterns are likely to have broad scope (i.e., to generalize within and beyond study observations). This interpretation is supported by the finding that effects of explanation on prior knowledge were attenuated when learners believed prior knowledge was irrelevant to generalizing category membership (Experiment 4). This research provides evidence that explanation can serve as a mechanism for deploying prior knowledge to assess the scope of observed patterns. PMID- 23099292 TI - Enhanced depth imaging optical coherence tomography in long-standing Vogt Koyanagi-Harada disease. AB - AIM: To evaluate the choroidal thickness (CT) in patients with long-standing Vogt Koyanagi-Harada (VKH) disease using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: A prospective case-control study developed at a tertiary centre at Sao Paulo, Brazil. EDI-OCT images were obtained in 16 patients (30 eyes) with VKH disease who had had the disease for more than 6 months since disease onset, and in 17 normal individuals controlled by age (32 eyes). Comprehensive ophthalmic examination and EDI-OCT evaluation were performed. CT was measured at the fovea and at 1000 um intervals from the foveal centre in both temporal and nasal directions. CT was correlated with disease duration, clinical disease activity and fundus-based disease severity. RESULTS: Mean subfoveal CT was 333 um (+/-85.8) in controls and 250.7 um (+/-93.3) in VKH patients (p=0.002). The choroid was significantly thinner in patients when compared to controls in all but one nasal point. In patients, the CT measurements at the foveal centre presented a negative correlation with disease duration (p<0.001). No significant difference in CT measurements was observed between eyes with and without clinical inflammation (p=0.42). There was a trend towards more severe fundus changes being associated with a thinner choroid (p=0.28). CONCLUSIONS: Patients with VKH and long-standing disease had thinner choroids when compared to controls. Progressive choroidal thinning related to disease duration was observed at the macula of these patients. Whether this finding is part of the natural history of the disease or the result of a clinically undetected choroidal inflammation remains to be determined. PMID- 23099293 TI - Clinical characterisation of the CABP4-related retinal phenotype. AB - BACKGROUND: Calcium binding protein 4 (CABP4), specifically located in photoreceptor synaptic terminals, has been associated with congenital stationary night blindness based on this clinical diagnosis being made for three individuals from two Swiss families with CABP4 mutations; however, the few reported cases limit phenotype-genotype correlation. We expand the number of reported patients with CABP4 mutations and clinically characterise the CABP4-related phenotype. METHODS: A retrospective case series of 11 individuals (age 2a 26 years; four consanguineous families) with early-onset retinal dysfunction found to harbour CABP4 mutations after a strategy of homozygosity analysis and/or candidate gene testing. RESULTS: The 11 patients from four families harboured the same homozygous CABP4 mutation (c.81_82insA; p.Pro28Thrfs*4) and shared a common haplotype. All patients had congenital nystagmus, stable low vision, photophobia and a normal or near-normal fundus appearance. None complained of night blindness when specifically questioned. Eight had hyperopic cycloplegic refractions (>=+ 1.00 dioptre). Electroretinography showed an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased cone responses or was non-recordable. Although these and previously reported families with homozygous mutations were labelled with different clinical diagnoses, all had similar clinical features. CONCLUSION: These typical clinical features, which do not include a symptom of night blindness, suggest CABP4 mutations. The phenotype is best uniformly termed congenital cone-rod synaptic disorder. In Saudi Arabia a founder homozygous c.81_82insA CABP4 mutation is a recurrent cause. PMID- 23099294 TI - Soil mesofauna as bioindicators to assess environmental disturbance at a platinum mine in South Africa. AB - South Africa is rich in mineral resources and is one of the leading raw material exporters in the world. Mining is essential for economic development, but also has detrimental environmental consequences in the form of chemical waste products which are being dumped as tailings material. The aim of this study was to establish whether mesofauna could be utilized to assess the influence of the tailings disposal facility on the surrounding soil environment. The sampled soil was chemically analyzed and the extracted mesofauna identified. High metal concentrations on the tailings dam (Cu, Cr and Ni), apparently had the greatest influence on the soil mesofauna. Only a few mite species were abundant at the two sites on the tailings dam, representing the prostigmatic-, cryptostigmatic- and the mesostigmatic-taxa. Metal pollution is evident in the sites on the tailings dam facility and the number of species generally increased towards the more natural environment. PMID- 23099295 TI - A simulation procedure based on copulas to generate clustered multi-state survival data. AB - Generating survival data with a clustered and multi-state structure is useful to study finite sample properties of multi-state models, competing risks models and frailty models. We propose a simulation procedure based on a copula model for each competing events block, allowing to introduce dependence between times of different transitions and between those of grouped subjects. The effect of simulated frailties and covariates can be added in a proportional hazards way. In order to mimic information from real data, we also propose a method for the tuning of parameters via numerical minimization of a criterion function based on the ratios of target and observed values of median times and of probabilities of competing events. An example is provided on simulation of data mimicking those from a multicenter study on head and neck cancer, where the interest is in studying both time to local relapses and to distant metastases before death. The results demonstrated that data simulated according to our proposed method have characteristics very close to the target values. PMID- 23099296 TI - Xanthine oxidase-mediated denitrosation of N-nitroso-tryptophan by superoxide and uric acid. AB - Recent studies indicate the formation of protein nitrosamines in vivo and tryptophan residues in proteins might represent important targets of nitrosative and oxidative stress. In the present work, we examined the mechanism by which xanthine oxidase (XO) denitrosates N-nitroso Trp residues and determined the applicability of the reactions involved to the detection of nitrosated Trp residues by tri-iodide-based chemiluminescence. We found that - in addition to superoxide - denitrosation of N-acetyl-nitroso Trp (NANT) by hypoxanthine and XO occurred via the intermediacy of uric acid. Zero-order dependence of NANT decay rate with uric acid was achieved with increasing concentrations of uric acid (k(0)~6.0*10(-4)s(-1)) and generated nitric oxide. In contrast, S nitrosoglutathione and nitrosyl-myoglobin were stable in the presence of uric acid. NANT decomposition by uric acid could be reproducibly measured using the tri-iodide-based chemiluminescence assay in the presence of excess nitrite upon pre-treatment with acidified sulfanilamide. N-nitrosated albumin was sensitive to uric acid-induced decomposition only after proteolytic degradation. In conclusion, XO decomposes nitrosated Trp through superoxide and uric acid pathways and in the case of uric acid generates free nitric oxide. Site specificity of this reaction may possibly be used in combination with the tri iodide-based chemiluminescence assay to discern between nitrosated Trp, S nitrosothiols, and nitrosylated heme proteins. PMID- 23099297 TI - High alveolar concentration of nitric oxide is associated with alveolitis in scleroderma. AB - Alveolar concentration of nitric oxide (C(A)NO) is a non invasive prognostic marker of systemic sclerosis (SSc) lung disease. There is, however, as yet no direct evidence showing concomitant increase of C(A)NO and the presence of inflammatory cells in alveoli. We have therefore measured C(A)NO and performed broncho-alveolar lavage (BAL) in SSc patients. Exhaled NO was measured, by the means of two different models, the two-compartment model (2CM) and the trumpet model with axial diffusion (TMAD), in 22 SSc patients and compared with 15 healthy controls. BAL was performed in all SSc patients. Alveolitis was defined as lymphocytes >14%, polymorphonuclears >4%, or eosinophils >3% on cell count in BAL fluid. Comparisons of C(A)NO levels were made between SSc patients with, and without, alveolitis. Levels of C(A)NO were significantly higher in SSc patients as compared with controls (p<0.001). Median C(A)NO was significantly higher in SSc patients with alveolitis as compared with SSc patients without alveolitis (8.4ppb; 1st and 3rd interquartile range: 6.0-10.5 vs 3.3ppb; 2.2-3.5; p=0.004 for 2CM and 5.4ppb; 3.2-9.2 vs 3.2ppb; 1.4-3.3, p=0.02 for TMAD), while bronchial airway output of NO (J'awNO, p=0.19), and fractional exhaled NO (F(E)NO, p=0.12) were comparable. C(A)NO was consistently high in SSc patients with alveolitis irrespective of the methods chosen (TMAD or 2CM). Our findings showed that increased C(A)NO was associated with alveolitis in patients with SSc. We submit that C(A)NO could be used as a reliable non-invasive surrogate biomarker of alveolitis in scleroderma lung disease. PMID- 23099298 TI - Layer-specific intracortical connectivity revealed with diffusion MRI. AB - In this work, we show for the first time that the tangential diffusion component is orientationally coherent at the human cortical surface. Using diffusion magnetic resonance imaging (dMRI), we have succeeded in tracking intracortical fiber pathways running tangentially within the cortex. In contrast with histological methods, which reveal little regarding 3-dimensional organization in the human brain, dMRI delivers additional understanding of the layer dependence of the fiber orientation. A postmortem brain block was measured at very high angular and spatial resolution. The dMRI data had adequate resolution to allow analysis of the fiber orientation within 4 notional cortical laminae. We distinguished a lamina at the cortical surface where diffusion was tangential along the surface, a lamina below the surface where diffusion was mainly radial, an internal lamina covering the Stria of Gennari, where both strong radial and tangential diffusion could be observed, and a deep lamina near the white matter, which also showed mainly radial diffusion with a few tangential compartments. The measurement of the organization of the tangential diffusion component revealed a strong orientational coherence at the cortical surface. PMID- 23099299 TI - Human corneal endothelial cell sheets for transplantation: thermo-responsive cell culture carriers to meet cell-specific requirements. AB - Corneal endothelial diseases lead to severe vision impairment, motivating the transplantation of donor corneae or corneal endothelial lamellae, which is, however, impeded by endothelial cell loss during processing. Therefore, one prioritized aim in corneal tissue engineering is the generation of transplantable human corneal endothelial cell (HCEC) layers. Thermo-responsive cell culture carriers are widely used for non-enzymatic harvest of cell sheets. The current study presents a novel thermo-responsive carrier based on simultaneous electron beam immobilization and cross-linking of poly(vinyl methyl ether) (PVME) on polymeric surfaces, which allows one to adjust layer thickness, stiffness, switching amplitude and functionalization with bioactive molecules to meet cell type specific requirements. The efficacy of this approach for HCEC, which require elaborate cell culture conditions and are strongly adherent to the substratum, is demonstrated. The developed method may pave the way to tissue engineering of corneal endothelium and significantly improve therapeutic options. PMID- 23099300 TI - Modelling the role of surface stress on the kinetics of tissue growth in confined geometries. AB - In a previous paper we presented a theoretical framework to describe tissue growth in confined geometries based on the work of Ambrosi and Guillou [Ambrosi D, Guillou A. Growth and dissipation in biological tissues. Cont Mech Thermodyn 2007;19:245-51]. A thermodynamically consistent eigenstrain rate for growth was derived using the concept of configurational forces and used to investigate growth in holes of cylindrical geometries. Tissue growing from concave surfaces can be described by a model based on this theory. However, an apparently asymmetric behaviour between growth from convex and concave surfaces has been observed experimentally, but is not predicted by this model. This contradiction is likely to be due to the presence of contractile tensile stresses produced by cells near the tissue surface. In this contribution we extend the model in order to couple tissue growth to the presence of a surface stress. This refined growth model is solved for two geometries, within a cylindrical hole and on the outer surface of a cylinder, thus demonstrating how surface stress may indeed inhibit growth on convex substrates. PMID- 23099301 TI - Electrically conductive nanofibers with highly oriented structures and their potential application in skeletal muscle tissue engineering. AB - Recent trends in scaffold design have focused on materials that can provide appropriate guidance cues for particular cell types to modulate cell behavior. In this study highly aligned and electrically conductive nanofibers that can simultaneously provide topographical and electrical cues for cells were developed. Thereafter their potential to serve as functional scaffolds for skeletal muscle tissue engineering was investigated. Well-ordered nanofibers, composed of polyaniline (PANi) and poly(epsilon-caprolactone) (PCL), were electrospun by introducing an external magnetic field in the collector region. Incorporation of PANi into PCL fibers significantly increased the electrical conductivity from a non-detectable level for the pure PCL fibers to 63.6+/-6.6mS cm(-1) for the fibers containing 3wt.% PANi (PCL/PANi-3). To investigate the synergistic effects of topographical and electrical cues using the electrospun scaffolds on skeletal myoblast differentiation, mouse C2C12 myoblasts were cultured on random PCL (R-PCL), aligned PCL (A-PCL), random PCL/PANi-3 (R PCL/PANi) and aligned PCL/PANi-3 (A-PCL/PANi) nanofibers. Our results showed that the aligned nanofibers (A-PCL and A-PCL/PANi) could guide myoblast orientation and promote myotube formation (i.e. approximately 40% and 80% increases in myotube numbers) compared with R-PCL scaffolds. In addition, electrically conductive A-PCL/PANi nanofibers further enhanced myotube maturation (i.e. approximately 30% and 23% or 15% and 18% increases in the fusion and maturation indices) compared with non-conductive A-PCL scaffolds or R-PCL/PANi. These results demonstrated that a combined effect of both guidance cues was more effective than an individual cue, suggesting a potential use of A-PCL/PANi nanofibers for skeletal muscle regeneration. PMID- 23099302 TI - Electrospun biphasic drug release polyvinylpyrrolidone/ethyl cellulose core/sheath nanofibers. AB - The capability of core/sheath nanofibers prepared using coaxial electrospinning to provide adjustable biphasic drug release was investigated. Using ketoprofen (KET) as the model drug, polyvinylpyrrolidone as the sheath polymer, and ethyl cellulose as the core matrix, the coaxial process could be conducted smoothly and continuously without spinneret clogging. Scanning electron microscopy and transmission electron microscopy revealed linear nanofibers with homogeneous and clear core/sheath structures. Differential scanning calorimetry and X-ray diffraction verified that the core/sheath nanofibers were nanocomposites, with the drug present in the polymer matrix in an amorphous state. Attenuated total reflectance-Fourier transform infrared spectra demonstrated that the sheath polymer and core matrix were compatible with KET owing to hydrogen bonding. In vitro dissolution tests showed that the core/sheath nanofibers could provide typical biphasic drug release profiles consisting of an immediate and sustained release. The amount of drug released in the first phase was tailored by adjusting the sheath flow rate, and the remaining drug released in the second phase was controlled by a typical diffusion mechanism. The present study shows a simple and useful approach for the systematic design and fabrication of novel biomaterials with structural characteristics for providing complicated and programmed drug release profiles using coaxial electrospinning. PMID- 23099303 TI - Expanded applications, shifting paradigms and an improved understanding of host biomaterial interactions. AB - The conventional approach to biomaterial design and development typically focuses upon the mechanical and material properties with long-term objectives that include an inert host immune response and long-lasting mechanical and structural support. The emergence of and interest in tissue engineering and regenerative medicine have driven the development of novel cell-friendly biomaterials, materials with tailored degradation rates, materials with highly specific architectures and surfaces, and vehicles for delivery of bioactive molecules, among numerous other advancements. Each of these biomaterial developments supports specific strategies for tissue repair and reconstruction. These advancements in biomaterial form and function, combined with new knowledge of innate and acquired immune system biology, provide an impetus for re-examination of host-biomaterial interactions, including host-biomaterial interface events, spatial and temporal patterns of in vivo biomaterial remodeling, and related downstream functional outcomes. An examination of such issues is provided herein with a particular focus on macrophage polarization and its implications in tissue engineering and regenerative medicine. PMID- 23099304 TI - Molecular characterization of vancomycin-resistant Enterococcus spp. clinical isolates recovered from hospitalized patients among several medical institutions in China. AB - The epidemiology and molecular characteristics of vancomycin-resistant enterococci (VRE) from China deserve further investigation. This study reports on the molecular characterization of 101 unique VRE (96 E. faecium and 5 E. faecalis strains) recovered from diverse samples of 12 hospitals in China. MIC results were obtained by reference broth microdilution methods, and vancomycin resistance and virulence genes were screened by polymerase chain reaction. All strains were subjected to pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing. E. faecalis exhibited vancomycin and teicoplanin MIC results at >=256 MUg/mL and harbored vanA, except for 1 vanB-carrying strain (MIC, 32 and 1 MUg/mL, respectively). This strain had a unique PFGE pattern and was associated with ST410 (clonal complex [CC]4). E. faecium displayed vancomycin MIC values of >=256 MUg/mL with variable results for teicoplanin (1-256 MUg/mL). One E. faecium had a teicoplanin MIC value of 1 MUg/mL and carried a vanB, while the other 2 strains had teicoplanin MIC values of 4 and 8 MUg/mL and harbored vanA. E. faecalis strains were susceptible to ampicillin, and all VRE displayed a susceptible phenotype to daptomycin, linezolid, and tigecycline. Four E. faecalis from a particular hospital were grouped within a single PFGE type and were associated with ST470 and ST471 (CC4), which are double- and triple-locus variants of ST410 and ST4, respectively. Overall, E. faecium displayed genetic variability, but clonal dissemination was noted within and among hospitals. All E. faecium belonged to STs associated with CC17, except for 1 strain (ST362; CC362). A total of 77.2% and 29.7% of all strains carried esp and hyl, respectively. In conclusion, these results show that vanA-carrying isolates predominated in strains from China, and E. faecium strains are usually associated with a common and human-adapted lineage (CC17). Unlike the majority of clinical E. faecalis (CC2 and CC9), strains included in this study showed ST profiles similar to ST4 (CC4), which has been associated with human infections in other Asia-Pacific countries. PMID- 23099305 TI - The contributions of student-run free clinics. PMID- 23099306 TI - Early onset multiple sclerosis: a review for nurse practitioners. AB - Research demonstrates that 3.5% to 5% of persons with multiple sclerosis (MS) present before the age of 18 years. MS can present in early childhood through adolescence and must be considered as a differential diagnosis in patients with motor impairment, sensory changes, and cognitive disability. The diagnosis of early-onset MS is based on findings from a complete history and physical examination along with brain and spine imaging. The purpose of this article is to review recent literature on early-onset MS and offer suggestions or clinical practice in the identification and management of patients with this debilitating disease. PMID- 23099307 TI - Perspectives of nurse practitioners on health care needs among Latino children and families in the rural Southeastern United States: a pilot study. AB - INTRODUCTION: The purpose of this study was to explore perspectives of nurse practitioners on health care needs among Latino children and families in the rural Southeastern United States. METHOD: This qualitative research used semi structured interviews with seven nurse practitioners (NPs) practicing in the rural southeastern part of North Carolina. Flanagan's critical incident technique was used to describe the experiences of NPs providing health care for Latino children and parents. RESULTS: Data analysis indicates that the most commonly reported illnesses by Latino children are upper respiratory infections and asthma, followed by otitis media, obesity, anemia, pneumonia, leukemia, and tumors. Barriers to health care for children included language and cultural differences, lack of access to care (e.g., lack of insurance, cost, and transportation), and health illiteracy/low education level of parents. The findings also suggest that Latinos are preserving their traditional health practices when treating their children's illnesses, such as through use of foods, hot/cold items, herbs, coin on "belly button," traditional juices, healing bracelets, and evil eye. DISCUSSION: The findings of the study imply the need to incorporate culturally sensitive care when providing care for Latino children and parents. PMID- 23099308 TI - Adolescent asthma education programs for teens: review and summary. AB - The purpose of this review is to describe and evaluate education programs for teens with asthma. Although asthma educational programs for children are plentiful, this is not the case for adolescents. The developmental tasks of adolescence require asthma education programs that are uniquely tailored to this age group. Although several well-designed studies appear in the literature, further research is needed to evaluate the efficacy of asthma education programs among teens. Although the quality of research varies, demonstrated program benefits include improved asthma self-management, self-efficacy, family support mechanisms, and quality of life. Practice implications point to the need for education programs in schools and camp settings that are consistent with national asthma guidelines. PMID- 23099309 TI - Use of paid child care health care consultants in early care and education settings: results of a national study comparing provision of health screening services among Head Start and non-Head Start centers. AB - INTRODUCTION: Child care health consultants (CCHCs) are health professionals who provide consultation and referral services to child care programs. The use of CCHCs has been recommended as an important component of high-quality child care. The purpose of this study was to examine the potential association between the use of paid CCHCs and child care center director reports of (a) center maintenance of health records and emergency procedures and (b) center facilitation of health screenings and assessments. METHOD: A national, randomized telephone survey of directors of 1822 licensed child care center directors was conducted. RESULTS: With a response rate of 93%, most directors (72.7%) reported that they did not employ a CCHC. However, directors employing CCHCs were more likely to report provision of health-promoting screenings and assessments for children in their center. This pattern held true for both Head Start and non-Head Start centers. DISCUSSION: This study suggests that CCHCs can serve as health promotion advocates in early care and education settings, helping centers establish appropriate policies and arranging for health assessments and screenings for children. PMID- 23099310 TI - Emotional maltreatment. AB - Child abuse is a problem that affects the lives of many American children. The public is often bombarded with information regarding horrific cases of physical and sexual abuse. Emotional maltreatment, however, has been slow to achieve recognition as a serious social problem for a variety of reasons. Compared with physical or sexual abuse, emotional maltreatment is more difficult to identify and define, and good epidemiological data are not available. An erroneous perception also exists that the sequelae of emotional maltreatment are less severe than that of physical and/or sexual abuse. Prompt identification of emotional maltreatment, appropriate intervention and referral, and reporting of concerns to child protective services are essential to the health and well-being of the child. This article will define emotional maltreatment, discuss consequences of emotional maltreatment, and provide implications for pediatric nurse practitioner practice. PMID- 23099311 TI - Women's understanding of different dosing instructions for a liquid pediatric medication. AB - INTRODUCTION: Dosing errors by caregivers are common and often are directly attributed to poorly designed instructions. The purpose of this study was to assess whether instruction wording--that is, implicit versus explicit dosage intervals--was associated with participants' ability to describe and correctly measure a dose of a commonly prescribed liquid pediatric prescription medication. METHODS: English-speaking women (N = 193) of child-bearing age were recruited to participate in this study from an outpatient residency clinic in the southeastern United States. Based on a priori randomization, each participant was presented with one of two medication bottles that were identical except for the instructions: (1) "shake liquid well and give (child's name) 6 ML by mouth every 12 hours" ("implicit" dosage interval)," or (2) "shake liquid well and give (child's name) 6 ML by mouth at 7 AM and 7 PM" ("explicit" dosage interval). Participants completed a structured interview to assess sociodemographic characteristics, health literacy skills, ability to describe and demonstrate the dosage of the liquid medication, and preferences for label format. RESULTS: Seventy-two participants (37.3%) were able to correctly describe how they would give the medicine to a child during a 24-hour period, while 145 women (75.1%) were able to correctly demonstrate how they would give one dose of the medication. Approximately one third of participants (32.1%) were able to correctly describe and measure a dose of the medication. Slightly more than half of participants (n = 103, 53.4%) indicated that they would prefer instructions with "explicit" dosage intervals. DISCUSSION: This study suggests that few people can accurately describe how liquid medications are to be administered, while more people can demonstrate the correct dose to be administered. PMID- 23099312 TI - Advancements in the treatment of head lice in pediatrics. AB - Head lice infestations occur commonly each year in children of all socioeconomic statuses. However, head lice have become more of a nuisance as resistance to first-line agents, such as permethrin 1% and pyrethrins, has increased. Newer topical products provide unique mechanisms of action without current signs of resistance. As with older agents, proper application of products must be emphasized to ensure that treatment is effective. In addition, nonpharmacologic measures should be taken to avoid reinfestation in the patient and to prevent the spread of lice to close personal contacts. PMID- 23099313 TI - Neurotransmitter noradrenaline downregulate cytoskeletal protein expression of VSMCs. AB - OBJECTIVE: This study investigates the effects of noradrenaline (NA) on cytoskeletal protein expression of vascular smooth muscle cells (VSMCs). METHODS: VSMCs were isolated from rat aortic tissue and cultured. The cultured VSMCs were divided into 4 experimental groups: (1) control group, (2) NA treatment group, (3) starvation group, and (4) NA treatment+starvation group. The expression of cytoskeletal protein (smooth muscle alpha-actin, beta-tubulin and desmin) was evaluated by (i) Coomassie blue staining, (ii) immunofluorescent staining, and (iii) RT-PCR and Western Blot. RESULTS: NA treatment significantly downregulated the expression of SM alpha-actin, beta-tubulin and desmin (P<0.05). The serum starvation did not affect the expression of cytoskeletal protein (SM alpha-actin, beta-tubulin and desmin), but when the cells were treated with the combination of NA and serum starvation, the expression of SM alpha-actin, beta-tubulin and desmin were down-regulated than those of the serum starvation group (P<0.05). CONCLUSION: These results suggested that NA might play a key role in regulating the cytoskeletal protein expression of VSMCs. PMID- 23099314 TI - Host response in tumor diagnosis and prognosis: importance of immunologists and pathologists alliance. AB - Pathologists and immunologists have collaborated over many years in their efforts to understand and properly diagnose cancer. The ability of pathologists to correctly diagnose this disease was facilitated by the development of immunohistology that utilized specificity of antibodies to distinguish between normal cells and cancer cells. Further boost was provided through the advent of monoclonal antibodies. The two disciplines are now together on the brink of a paradigm shift resulting from a better understanding of the importance for cancer diagnosis and prognosis to consider not only the characteristics of the cancer cells, but also the cancer microenvironment reflecting the host response to the disease. This new immunology and pathology alliance named "Immunoscore" will advance research in both disciplines as well as benefit patients. PMID- 23099315 TI - Mixtures of glyphosate and surfactant TN20 accelerate cell death via mitochondrial damage-induced apoptosis and necrosis. AB - Glyphosate, a common herbicide, is not toxic under normal exposure circumstances. However, this chemical, when combined with a surfactant, is cytotoxic. In this study, the mechanism of the additive effect of glyphosate and TN-20, a common surfactant in glyphosate herbicides, was investigated. After exposure of rat H9c2 cells to glyphosate and TN-20 mixtures, following assays were performed: flow cytometry to determine the proportion of cells that underwent apoptosis and necrosis; western blotting to determine expression of mitochondrial proteins (Bcl 2 and Bax); immunological methods to evaluate translocation of cytochrome C; luminometric measurements to determine activity of caspases 3/7 and 9; and tetramethyl rhodamine methyl ester assay to measure mitochondrial membrane potentials. Bcl-1 intensity decreased while Bax intensity increased with exposure to increasing TN-20 and/or glyphosate concentrations. Caspase activity increased and mitochondrial membrane potential decreased only when the cells were exposed to a mixture of both TN-20 and glyphosate, but not after exposure to either one of these compounds. The results support the possibility that mixtures of glyphosate and TN-20 aggravate mitochondrial damage and induce apoptosis and necrosis. Throughout this process, TN-20 seems to disrupt the integrity of the cellular barrier to glyphosate uptake, promoting glyphosate-mediated toxicity. PMID- 23099316 TI - Molecular and bioinformatical characterization of a novel superfamily of cysteine rich peptides from arthropods. AB - The full-length cDNA sequences of two novel cysteine-rich peptides (referred to as HsVx1 and MmKTx1) were obtained from scorpions. The two peptides represent a novel class of cysteine-rich peptides with a unique cysteine pattern. The genomic sequence of HsVx1 is composed of three exons interrupted by two introns that are localized in the mature peptide encoding region and inserted in phase 1 and phase 2, respectively. Such a genomic organization markedly differs from those of other peptides from scorpions described previously. Genome-wide search for the orthologs of HsVx1 identified 59 novel cysteine-rich peptides from arthropods. These peptides share a consistent cysteine pattern with HsVx1. Genomic comparison revealed extensive intron length differences and intronic number and position polymorphisms among the genes of these peptides. Further analysis identified 30 cases of intron sliding, 1 case of intron gain and 22 cases of intron loss occurred with the genes of the HsVx1 and HsVx1-like peptides. It is interesting to see that three HsVx1-like peptides XP_001658928, XP_001658929 and XP_001658930 were derived from a single gene (XP gene): the former two were generated from alternative splicing; the third one was encoded by a DNA region in the reverse complementary strand of the third intron of the XP gene. These findings strongly suggest that the genes of these cysteine-rich peptides were evolved by intron sliding, intron gain/loss, gene recombination and alternative splicing events in response to selective forces without changing their cysteine pattern. The evolution of these genes is dominated by intron sliding and intron loss. PMID- 23099317 TI - A three-dimensional self-learning kinetic Monte Carlo model: application to Ag(111). AB - The reliability of kinetic Monte Carlo (KMC) simulations depends on accurate transition rates. The self-learning KMC method (Trushin et al 2005 Phys. Rev. B 72 115401) combines the accuracy of rates calculated from a realistic potential with the efficiency of a rate catalog, using a pattern recognition scheme. This work expands the original two-dimensional method to three dimensions. The concomitant huge increase in the number of rate calculations on the fly needed can be avoided by setting up an initial database, containing exact activation energies calculated for processes gathered from a simpler KMC model. To provide two representative examples, the model is applied to the diffusion of Ag monolayer islands on Ag(111), and the homoepitaxial growth of Ag on Ag(111) at low temperatures. PMID- 23099319 TI - Sex differences in effects of low level domoic acid exposure. AB - Consumption of seafood containing the phytoplankton-derived toxin domoic acid (DOM) causes neurotoxicity in humans and in animals. It has been reported that DOM-induced symptoms may be more severe in men than women, but to date the effect of sex on DOM-induced effects in adults is not known. We investigated sex differences in DOM-induced effects in adult rats. Since low level exposure is of greatest relevance to human health (due to DOM regulatory limit), we examined the effects of low level exposure. Adult male and female Sprague Dawley rats were administered a single intraperitoneal injection of DOM (0, 1.0, 1.8 mg/kg). Behaviour was monitored for 3h and immunohistochemistry in the dorsal hippocampus and olfactory bulb was also examined. DOM increased locomotor and grooming activity, compared to vehicle group. DOM exposure also significantly increased stereotypic behaviours and decreased phosphorylated cAMP response element-binding protein immunoreactivity (pCREB-IR). There was no effect of sex on the magnitude of the behavioural responses, but the onset of DOM-induced locomotor activity and ear scratches was quicker in females than in males. Mixed effect modelling revealed the predicted peak in locomotor activity in response to DOM was also quicker in females than in males. Severe toxicity was evident in 2/7 male rats and 0/8 female rats dosed with 1.8 mg/kg DOM. These data suggest that males exposed to low level DOM may be more susceptible to severe neurotoxicity, whereas females are affected more quickly. Understanding sex differences in DOM-induced neurotoxicity may contribute to future protective strategies and treatments. PMID- 23099318 TI - Genetic risk for Parkinson's disease correlates with alterations in neuronal manganese sensitivity between two human subjects. AB - Manganese (Mn) is an environmental risk factor for Parkinson's disease (PD). Recessive inheritance of PARK2 mutations is strongly associated with early onset PD (EOPD). It is widely assumed that the influence of PD environmental risk factors may be enhanced by the presence of PD genetic risk factors in the genetic background of individuals. However, such interactions may be difficult to predict owing to the complexities of genetic and environmental interactions. Here we examine the potential of human induced pluripotent stem (iPS) cell-derived early neural progenitor cells (NPCs) to model differences in Mn neurotoxicity between a control subject (CA) with no known PD genetic risk factors and a subject (SM) with biallelic loss-of-function mutations in PARK2 and family history of PD but no evidence of PD by neurological exam. Human iPS cells were generated from primary dermal fibroblasts of both subjects. We assessed several outcome measures associated with Mn toxicity and PD. No difference in sensitivity to Mn cytotoxicity or mitochondrial fragmentation was observed between SM and CA NPCs. However, we found that Mn exposure was associated with significantly higher reactive oxygen species (ROS) generation in SM compared to CA NPCs despite significantly less intracellular Mn accumulation. Thus, this report offers the first example of human subject-specific differences in PD-relevant environmental health related phenotypes that are consistent with pathogenic interactions between known genetic and environmental risk factors for PD. PMID- 23099320 TI - D-Serine ameliorates neonatal PolyI:C treatment-induced emotional and cognitive impairments in adult mice. AB - Polyriboinosinic-polyribocytidilic acid (polyI:C) is a synthetic analog that elicits viral-like immune responses in mammals. We have recently found that polyI:C treatment in neonatal mice induced abnormalities of emotional, cognitive, and sensorimotor gating and dysfunction of glutamatergic neurotransmission in adulthood. In this study, we investigated the effect of the NMDA-receptor co agonist D-serine on polyI:C-induced behavioral abnormalities in mice. Neonatal ICR mice were repeatedly injected with polyI:C for 5 days from postnatal day 2 to 6. At 10 weeks, sensorimotor gating function was analyzed in the prepulse inhibition (PPI) test. Emotional function was analyzed in open field and social interaction tests. Cognitive function was analyzed by novel object recognition tests. D-Serine dose-dependently improved polyI:C-induced impairment of emotional and cognitive behaviors whereas it had no effect on PPI deficit in adults. The ameliorating effects of D-serine were antagonized by pretreatment with an NMDA receptor antagonist, MK-801. Although the mRNA level of D-amino acid oxidase (DAAO) was increased in the prefrontal cortex and hippocampus of neonatal polyI:C treated mice in adulthood, no changes were observed in D-serine content and DAAO enzymatic activity. These results suggest that D-serine ameliorates emotional and cognitive impairments of the polyI:C-treated mice through potentiating NMDA receptor activity. PMID- 23099321 TI - Evaluation of the protective effects of cyclosporin a and FK506 on abnormal cytosolic and mitochondrial Ca2+ dynamics during ischemia and exposure to high glutamate concentration in mouse brain slice preparations. AB - We examined the protective effects of the immunosuppressants cyclosporin A (CsA) and FK506 on abnormal cytosolic Ca2+ ([Ca2+]c) and mitochondrial Ca2+ concentration ([Ca2+]m) dynamics induced by ischemia or high L-glutamate concentration in mouse brain slice preparations. We used fura-4F and rhod-2 as indicators for [Ca2+]c and [Ca2+]m, respectively, in their acetoxymethylester form. Slice preparations loaded with either of these two indicators were exposed to ischemic artificial cerebrospinal fluid (oxygen- and glucose-deprived medium) for 12 min or to aerobic medium with high L-glutamate concentration (isotonic 20 mM L-glutamate) for 5 min. CsA (1 - 10 MUM) showed significant protective effects on the maximum increase in ischemia-induced [Ca2+]c and [Ca2+]m. FK506 (10 MUM) showed significant protective effects on the [Ca2+]m increase, but not on the ischemia-induced [Ca2+]c increase. Both immunosuppressants showed almost equal protective effects on the [Ca2+]c and [Ca2+]m increases induced by high L glutamate concentration. These results suggest that the protective effects of CsA and FK506 on Ca2+ overloading may be dependent upon the common pharmacological sites of actions relating to their effects as immunosuppressants. The small, but significant depressant effects of these drugs could give us important clues for rescuing critical brain damage induced by Ca2+ overloading. PMID- 23099322 TI - Fasudil suppresses fibrosarcoma growth by stimulating secretion of the chemokine CXCL14/BRAK. AB - We previously reported that chemokine CXCL14/BRAK (BRAK) has antitumor activity in several carcinoma cells indicating that BRAK secretion suppresses carcinoma cells. Ras-homologous small GTPase (RhoA) and Rho-associated coiled-coil containing protein kinase (ROCK) are important regulators of secretory processes, and activation of the RhoA/ROCK signaling pathway stimulates tumor invasion and metastasis. We investigated the effects of fasudil, a specific ROCK inhibitor, on BRAK secretion and tumor progression in mesenchymal fibrosarcoma cells (MC57). We demonstrated the antitumor activity of secreted BRAK using MC57 transplantation of BRAK in overexpressed transgenic mice. Further, to eliminate the influence of change in the mRNA expression of endogenous BRAK, we produced stable MC57 cell lines expressing BRAK (MC57-BRAK) or mock vector (MC57-MOCK). Fasudil significantly increased BRAK secretion by MC57-BRAK cells in a dose-dependent manner. To determine the effect of fasudil on tumor growth, MC57-BRAK and MC57 MOCK cells were transplanted into wild-type mice. Fasudil treatment suppressed tumor growth only in mice that had received MC57-BRAK cell transplants. These results indicate that fasudil inhibits fibrosarcoma growth by stimulating BRAK secretion and suggests that fasudil therapy might have clinical efficacy. PMID- 23099323 TI - Neural regeneration: role of traditional Chinese medicine in neurological diseases treatment. AB - The effects of a single compound and a mixture of traditional Chinese medicine (TCM) on promoting proliferation, differentiation, and migration of neural stem cells and regulating their microenvironment have been observed by Chinese scholars in recent years. These results showed good prospects in improving neural regeneration and repair of neurological disorders such as ischemic brain injury, Alzheimer's disease, Parkinson's disease, and depression. According to the TCM theory, the relationship between life of an individual and the disease was regarded as an entirety, and the theory emphasized the treatment based on syndrome differentiation since ancient times. In this paper, we attempted to introduce these medicines, which belong to natural products and have already been proved to possess clear therapeutic action on human bodies in the clinical setting. We summarized their effects promoting brain neurogenesis and repairing brain injuries in animal models and some mechanisms at the cellular and molecular levels. PMID- 23099324 TI - Activation of the liver X receptor-beta potently inhibits osteoclastogenesis from lipopolysaccharide-exposed bone marrow-derived macrophages. AB - Bacterial-induced bone diseases, such as periodontitis and osteomyelitis, are chronic inflammatory diseases characterized by increased bone destruction as a result of enhanced osteoclastogenesis. The LXRalpha and -beta are important modulators of inflammatory signaling and can potently inhibit RANKL-induced osteoclast differentiation. Here, we investigated the effects of the LXR agonist GW3965 on LPS-induced osteoclast differentiation. Mouse BMMs primed with RANKL for 24 h, then exposed to LPS in the presence of GW3965 for 4 days, formed significantly fewer and smaller TRAP(+)-multinucleated osteoclasts with reduced expression of osteoclast markers (Acp5, Ctsk, Mmp-9, Dc-stamp, and Itgbeta3), along with inhibition of actin ring development. GW3965 was able to repress proinflammatory cytokine (TNF-alpha, IL-1beta, IL-6, and IL-12p40) expression in BMMs exposed to LPS alone; however, once BMMs entered the osteoclast lineage following RANKL priming, GW3965 no longer inhibited cytokine expression. The inhibitory action of GW3965 involved the Akt pathway but seemed to be independent of MAPKs (p38, ERK, JNK) and NF-kappaB signaling. GW3965 acted in a LXRbeta dependent mechanism, as osteoclast differentiation was not inhibited in BMMs derived from LXRbeta-/- mice. Finally, activation of LXR also inhibited differentiation in LPS-exposed mouse RAW264.7 cells. In conclusion, GW3965 acts through LXRbeta to potently inhibit osteoclast differentiation from RANKL-primed BMMs in a LPS environment. In this respect, activation of the LXR could have a beneficial, therapeutic effect in the prevention of bacterial-induced bone erosion. PMID- 23099325 TI - Novel splenic antigen-presenting cells derive from a Lin(-) c-kit(lo) progenitor. AB - The main DC subsets in murine spleen arise from BM-derived precursors. Recently, a novel APC type was described in spleen. To determine if spleen contains the progenitors of this subset, a stromal coculture system was used to assess candidate progenitors for their hematopoietic potential. Here, the progenitor of that subset is identified as a spleen endogenous Lin(-)c-kit(lo) hematopoietic progenitor and is most highly enriched among the Lin(-)c-kit(lo)CD34(+) subset. Dendritic-like cells produced in vitro functionally resemble the previously described in vivo equivalent subset with high endocytic capacity and capability for antigen-specific activation of CD8(+) T cells but not CD4(+) T cells. PMID- 23099326 TI - A retrospective study on the use of heparin for peripheral vascular intervention. AB - PURPOSE: To compare immediate outcomes for patients who receive and those who do not receive heparin during lower limb endovascular intervention. METHODS: A retrospective case series of 330 procedures for lower limb peripheral arterial occlusive disease. Patient records were interrogated for bleeding or thrombotic/embolic complications during or immediately after endovascular intervention for peripheral arterial occlusive disease. RESULTS: Of the 220 patients who received heparin, 21 (9.6%) suffered an access site bleed compared with 2 of the 110 patients (2%) who did not receive heparin (odds ratio [OR] = 5.7; 95% confidence interval [CI] = 1.3-25; P = .01). There were 6 embolic/thrombotic complications in the patients who received heparin (2.7%) compared with 4 in those that did not receive heparin (3.6%; P = .74). In 187 cases, a closure or compression device was used (StarClose, n = 109; Angio-Seal, n = 42; FemoStop, n = 35; ProGlide, n = 1), of which there were 3 access bleeding complications (2%). One hundred and forty-three cases did not have a closure or compression device associated with 17 (12%) access bleeding complications (OR = 0.25; 95% CI = 0.09-0.64; P = .004). CONCLUSIONS: In this study, heparin use and nonuse of a closure or compression device was associated with an increased risk of access site bleeding. Embolic/thrombotic complications were uncommon. PMID- 23099327 TI - The impact of new vaccine introduction on the coverage of existing vaccines: a cross-national, multivariable analysis. AB - BACKGROUND: A surge of new and underutilized vaccine introductions into national immunization programmes has called into question the effect of new vaccine introduction on immunization and health systems. In particular, countries deciding whether to introduce a new or underutilized vaccine into their routine immunization programme may query possible effects on the delivery and coverage of existing vaccines. Using coverage of diphtheria-tetanus-pertussis (DTP) vaccine as a proxy for immunization system performance, this study aims to test whether new vaccine introduction into national immunization programs was associated with changes in coverage of three doses of DTP vaccine among infants. METHODS AND FINDINGS: DTP3 vaccine coverage was analyzed in 187 countries during 1999-2009 using multivariable cross-national mixed-effect longitudinal models. Controlling for other possible determinants of DTP3 coverage at the national level these models found minimal association between the introduction of Hepatitis-, Haemophilus influenzae type b-, and rotavirus-containing vaccines and DTP3 coverage. Instead, frequent and sometimes large fluctuations in coverage are associated with other development and health systems variables, including the presence of armed conflict, coverage of antenatal care services, infant mortality, the percent of health expenditures that are private and total health expenditures per capita. CONCLUSIONS: Introductions of new vaccines did not affect national coverage of DTP3 vaccine in the countries studied. Introductions of other new vaccines and multiple vaccine introductions should be monitored for immunization and health systems impacts. PMID- 23099328 TI - Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. AB - There are a number of related goals of influenza vaccination, including elicitation of protective antibodies and induction of cellular CD4 and CD8+ T cell responses. Because CD4+ T cell expansion and functionality are influenced by peptide specificity and T cell gene expression can be modified by repeated re stimulations, it is important to evaluate how frequent influenza vaccinations affect CD4+ T cell dependent functions in protective immunity to influenza. Trivalent influenza vaccines (TIV) have production of neutralizing antibodies to HA as their primary goal and main criteria for efficacy. Accordingly, they are not characterized for any other viral components. In the current study, we evaluated whether other influenza virus proteins were present in commercial TIV at levels sufficient for immunogenicity in vivo. Mice that differed with regard to their expressed class II molecules were used in concert with peptide stimulated cytokine ELISPOT assays to comprehensively evaluate the CD4+ T cell antigen specificity induced by the TIV. Our studies revealed that NA, NP, M1 and NS1 were present in sufficient quantities in the TIV to prime and boost CD4+ T cells. These results suggest that in humans, the broad CD4+ T cell repertoire induced by live infection is continually boosted and maintained throughout life by regular vaccination with licensed intramuscular split vaccines. The implications raised by our findings on CD4+ T cell functionality in influenza are discussed. PMID- 23099330 TI - A strategy of antigen incorporation into exosomes: comparing cross-presentation levels of antigens delivered by engineered exosomes and by lentiviral virus-like particles. AB - Among strategies aimed at developing new nanoparticle-based vaccines, exosomes hold much promise. They are nanovesicles released by basically all eukaryotic cell types originating from intraluminal vesicles which accumulate in multivesicular bodies. Exosomes have immunogenic properties whose strength correlates with the amounts of associated antigens. Engineering antigens to target them in exosomes represents the last frontier in terms of nanoparticle based vaccines. Here we report a new method to incorporate protein antigens in exosomes relying on the unique properties of a mutant of the HIV-1 Nef protein, Nef(mut). This is a biologically inactive mutant we found incorporating into exosomes at high levels also when fused at its C-terminus with foreign proteins. We compared both biochemical and antigenic properties of Nef(mut) exosomes with those of previously characterized Nef(mut) -based lentiviral virus-like particles (VLPs). We found that exosomes incorporate Nef(mut) and fusion protein derivatives with similar efficiency of VLPs. When an envelope fusion protein was associated with both exosomes and VLPs to favor cross-presentation of associated antigens, Nef(mut) and its derivatives incorporated in exosomes were cross presented at levels at least similar to what observed when the antigens were delivered by engineered VLPs. This occurred despite exosomes entered target cells with an apparent lower efficiency than VLPs. The unique properties of HIV-1 Nef(mut) in terms of exosome incorporation efficiency, carrier of foreign antigens, and lack of anti-cellular effects open the way toward the development of a flexible, safe, cost-effective exosome-based CD8(+) T cell vaccine platform. PMID- 23099331 TI - A phase 3, randomized, double-blind trial comparing the safety and immunogenicity of the 7-valent and 13-valent pneumococcal conjugate vaccines, given with routine pediatric vaccinations, in healthy infants in Brazil. AB - BACKGROUND: The inclusion of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs in many countries has significantly decreased the incidence of disease caused by Streptococcus pneumoniae. However, a substantial portion of disease remained and, in some areas, there has been an increase in disease produced by serotypes not included in PCV7. A 13-valent pneumococcal conjugate vaccine (PCV13) was studied in healthy Brazilian infants in a phase 3, double-blind, randomized study. METHODS: Infants were randomized to receive either PCV7 or PCV13 at 2, 4, 6, (doses 1-3), and 12 (toddler dose) months of age, along with routine pediatric vaccinations (diphtheria, tetanus, whole-cell pertussis, and Haemophilus influenzae type b vaccine). Pneumococcal anticapsular polysaccharide-binding immunoglobulin G (IgG) responses and antibody responses to pertussis antigens were measured 1 month after both dose 3 of the infant series and the toddler dose. Safety and tolerability were also assessed. RESULTS: The proportion of subjects achieving a serotype-specific IgG concentration >=0.35MUg/mL measured 1 month after the infant series was comparable in the PCV13 (>=94.2%) and PCV7 (>=93.0%) groups for the 7 serotypes common to both vaccines. The percentage of responders for the 6 additional serotypes ranged from 87.1 to 100% for PCV13. The percentage of responders varied across the pertussis antigens studied, but was not different in PCV13 and PCV7 recipients. Overall, the safety profile of PCV13 was comparable with that of PCV7. CONCLUSIONS: PCV13 was comparable to PCV7 in safety and tolerability, elicited comparable immune responses to the common serotypes, and did not interfere with immune responses to concomitantly administered whole-cell pertussis vaccine. The robust immunogenicity exhibited by PCV13 for the additional serotypes suggests that it could provide significant protection against these serotypes. PMID- 23099329 TI - NDV-3, a recombinant alum-adjuvanted vaccine for Candida and Staphylococcus aureus, is safe and immunogenic in healthy adults. AB - The investigational vaccine, NDV-3, contains the N-terminal portion of the Candida albicans agglutinin-like sequence 3 protein (Als3p) formulated with an aluminum hydroxide adjuvant in phosphate-buffered saline. Preclinical studies demonstrated that the Als3p vaccine antigen protects mice from oropharyngeal, vaginal and intravenous challenge with C. albicans and other selected species of Candida as well as both intravenous challenge and skin and soft tissue infection with Staphylococcus aureus. The objectives of this first-in-human Phase I clinical trial were to evaluate the safety, tolerability and immunogenicity of NDV-3 at two different antigen levels compared to a saline placebo. Forty healthy, adult subjects were randomized to receive one dose of NDV-3 containing either 30 or 300 MUg of Als3p, or placebo. NDV-3 at both dose levels was safe and generally well-tolerated. Anti-Als3p total IgG and IgA1 levels for both doses reached peak levels by day 14 post vaccination, with 100% seroconversion of all vaccinated subjects. On average, NDV-3 stimulated peripheral blood mononuclear cell (PBMC) production of both IFN-gamma and IL-17A, which peaked at day 7 for subjects receiving the 300 MUg dose and at day 28 for those receiving the 30 MUg dose. Six months after receiving the first dose of NDV-3, nineteen subjects received a second dose of NDV-3 identical to their first dose to evaluate memory B- and T-cell immune responses. The second dose resulted in a significant boost of IgG and IgA1 titers in >70% of subjects, with the biggest impact in those receiving the 30 MUg dose. A memory T-cell response was also noted for IFN-gamma in almost all subjects and for IL-17A in the majority of subjects. These data support the continued investigation of NDV-3 as a vaccine candidate against Candida and S. aureus infections. PMID- 23099332 TI - A novel synthetic bipartite carrier protein for developing glycotope-based vaccines. AB - Development of successful vaccines against glycotopes remains a major challenge. In the current studies, we have successfully developed a novel carrier protein for glycotopes based on the concept of antigen clustering and specific stimulation of T helper cells to mount strong antibody response to glycotopes. The bipartite carrier protein consists of a tandem repeat of a cysteine-rich peptide for docking of clustered glycotopes to effectively activate B cells and an Fc domain for antigen delivery to antigen presenting cells (APCs). To demonstrate its utility, we conjugated the tumor-specific monosaccharide antigen Tn to this novel carrier protein and successfully developed a Tn vaccine against cancer in animal models. The Tn vaccine effectively elicited high-titer IgG1 antibodies against Tn in immunized mice, and effectively suppressed the development of prostate cancer in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) mice. Our results suggest that this novel bipartite carrier protein could be effectively used for developing anti-glycotope vaccines such as the anticancer Tn vaccine. PMID- 23099333 TI - Prevalence of prolonged and chronic poliovirus excretion among persons with primary immune deficiency disorders in Sri Lanka. AB - BACKGROUND: The Global Polio Eradication Initiative, established in 1988, has made substantial progress toward achieving this target, with only 3 countries never having eliminated wild poliovirus. Persons with primary immune deficiency disorders (PIDD) exposed to OPV are at increased risk of vaccine-associated paralytic poliomyelitis (VAPP) and of prolonged excretion of Sabin polioviruses. However, the risk for prolonged excretion is not known. Therefore, we studied the prevalence of PIDD with long-term poliovirus excretion in Sri Lanka, a middle income country currently using OPV. METHODS: We stimulated the referral of patients under the age of 35 years, with clinical features suggestive of immune deficiency to the single immunology clinic in the country, where these patients were investigated for the presence of PIDD. Stool samples from patients with PIDD were cultured for the presence of poliovirus (PV). Poliovirus isolates were tested for intratypic differentiation (ITD). The VP1 region of all poliovirus isolates was sequenced. RESULTS: Of 942 patients investigated, 51 (5.4%) were diagnosed with PIDD. Five (10.2%) patients excreted poliovirus. A patient with X linked agammaglobulinemia (XLA) excreted a mixture of all three Sabin like (SL) poliovirus serotypes. One patient with severe combined immune deficiency (SCID) excreted SL type 2, and another with SCID excreted SL type 3. One patient with SCID excreted a P2 vaccine-derived poliovirus (VDPV 2), and another with common variable immune deficiency (CVID) excreted a VDPV 3. The 3 patients with SCID died before scheduled collection of subsequent samples one month later, while the patient with XLA had cleared the virus in stool sample collected after 3 and 11 months. The CVID patient with VDPV 3 excreted for 7 months, and has developed a 23 nucleotide divergence in VP1 (~900 nucleotides) from the parental Sabin virus. CONCLUSIONS: In our study, several patients with SCID, XLA and CVID excreted poliovirus. With improving health care quality patients with CVID and XLA may survive longer especially with provision of intravenous immune globulin. Regular screening of patients with PIDD for excretion of poliovirus is necessary to identify chronic excretors and make available specific therapies. PMID- 23099334 TI - A mathematical model for describing the retinal nerve fiber bundle trajectories in the human eye: average course, variability, and influence of refraction, optic disc size and optic disc position. AB - Previously we developed a mathematical model for describing the retinal nerve fiber bundle trajectories in the superior-temporal and inferior-temporal regions of the human retina, based on traced trajectories extracted from fundus photographs. Aims of the current study were to (i) validate the existing model, (ii) expand the model to the entire retina and (iii) determine the influence of refraction, optic disc size and optic disc position on the trajectories. A new set of fundus photographs was collected comprising 28 eyes of 28 subjects. From these 28 photographs, 625 trajectories were extracted. Trajectories in the temporal region of the retina were compared to the existing model. In this region, 347 of 399 trajectories (87%) were within the 95% central range of the existing model. The model was extended to the nasal region. With this extension, the model can now be applied to the entire retina that corresponds to the visual field as tested with standard automated perimetry (up to approximately 30 degrees eccentricity). There was an asymmetry between the superior and inferior hemifields and a considerable location-specific inter-subject variability. In the nasal region, we found two "singularities", located roughly at the one and five o'clock positions for the right optic disc. Here, trajectories from relatively widespread areas of the retina converge. Associations between individual deviations from the model and refraction, optic disc size and optic disc position were studied with multiple linear regression. Refraction (P = 0.021) and possibly optic disc inclination (P = 0.09) influenced the trajectories in the superior temporal region. PMID- 23099335 TI - The coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia. AB - The dramatic improvements seen in the outcome of paediatric patients with acute lymphoblastic leukaemia (ALL) have led to increasing incorporation of L asparaginase (L-Asp) in adult treatment protocols. However, its use is associated with a disruption in the physiological balance between haemostatic and anticoagulant pathways, with the predominant clinical manifestation being thrombosis. Although L-Asp therapy is known to be associated with an acquired deficiency of antithrombin (AT), the concurrent depletion of fibrinogen and other haemostatic proteins means that the precise mechanism of thrombosis remains to be defined. In vitro coagulation assays are often prolonged but thrombosis rather than haemorrhage is the primary concern. Management of thrombotic events in these patients is based around agents that rely on AT for their anticoagulant effect, even though it is usually depleted. There is currently only limited evidence supporting the use of AT concentrates in either primary prevention or management following an established event. Evidence-based guidelines for prevention and management strategies are lacking. PMID- 23099336 TI - Spatial overlap of combined electroacoustic stimulation determines the electrically evoked response in the guinea pig cochlea. AB - HYPOTHESIS: Limiting spatial overlap between electrical stimulation (ES) and acoustical stimulation (AS) in the cochlea reduces the effects of AS on electrically evoked auditory nerve activity. BACKGROUND: Some hybrid cochlear implant systems have a regular array, whereas others have short arrays that spatially segregate ES from AS. AS settings in hybrid implants may also affect electroacoustic interaction. METHODS: ES (900 MUA) was delivered in the high frequency part of the cochlea, and the electrically evoked compound action potential (eCAP) was recorded to assess auditory nerve activity. Maximal spatial overlap of ES and AS was tested by using normal-hearing animals (NH, n = 6), whereas minimal overlap was modeled by using animals with high-frequency hearing loss (HFHL, n = 6). AS consisted of broadband (BB) or low-frequency (LF) noise (0 100 dB SPL). Effects of AS on eCAP amplitude were statistically tested using 1 sample t tests (alpha = 0.05). RESULTS: BB noise at 60 dB SPL significantly suppressed eCAP amplitude in NH animals but not in HFHL animals up to a 30 dB higher level. Suppression with LF noise at 60 dB SPL was not significant in either the NH or the HFHL group, but at 90 dB SPL, suppression was significant in both groups. CONCLUSION: Minimizing spatial overlap between ES and AS reduces eCAP suppression when moderate sound levels are applied. Overlap can be reduced by applying ES in an acoustically insensitive part of the cochlea or by limiting the acoustic spectrum to low frequencies when ES is applied in acoustically sensitive areas. PMID- 23099337 TI - Caffeine reduces cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis. AB - The aim of this study was to investigate the effects of caffeine (20 mg/L) intake on cadmium (15 mg/L) accumulation in the rat blood, testes, epididymis and prostate as well as cadmium-induced changes to the antioxidant defense system of the epididymis. Caffeine reduced the cadmium concentration in all tissues analyzed. Meanwhile, cadmium reduced catalase activity and increased superoxide dismutase (SOD) activity in the epididymis. Caffeine increased SOD activity, catalase and glutathione tissue expression and sustains the cadmium's effect on catalase and GSP-Px activity. No differences in the expression of metallothionein and lipid peroxidation were observed among the different treatments in the epididymis. In conclusion, low doses of cadmium alter the antioxidant enzymatic profile of the epididymis, but not induced oxidative lipid damage. Caffeine intake reduces overall cadmium accumulation in the organism and enhances the levels of antioxidant protein expression in the epididymis, thus exerting a protective effect against this metal. PMID- 23099338 TI - Reversible effect of maternal exposure to chlorpyrifos on the intermediate granule cell progenitors in the hippocampal dentate gyrus of rat offspring. AB - To examine the effects of developmental exposure to chlorpyrifos (CPF) on neurogenesis in the hippocampal dentate gyrus, pregnant rats were treated with 2.8, 14 or 70 ppm CPF in the diet from gestational day 10 to day 21 after delivery. Dams had decreased cholinesterase (ChE) activities in red blood cells (RBC) at intakes of >=2.8 ppm and in brain at 70 ppm. Offspring on postnatal day (PND) 21 had decreased ChE activities in the RBC and brain at 70 ppm. There were no behavioral abnormalities in the offspring. Immunohistochemical analysis showed decreases in the numbers of cells positive for proliferating cell nuclear antigen and T box brain 2 in the subgranular zone (SGZ) of the dentate gyrus on PND 21 at 70 ppm, while other progenitor cell populations and the apoptotic cell number were unaffected in this zone. However, on PND 77 all changes had disappeared. The distribution of the progenitor cell population expressing nicotinic acetylcholine receptor alpha7 and lacking expression of postmitotic neuron-specific nuclear protein was unchanged by CPF-exposure, suggesting no effect of cholinergic stimulation on neurogenesis. These results suggest that developmental exposure to CPF directly but transiently affect the proliferation of type-2 progenitor cell populations in the hippocampal neurogenesis. The lowest-observed-adverse-effect level (LOAEL) of CPF was determined to be 2.8 ppm (0.36 mg/kg body weight/day) for dams by the inhibition of ChE activity in the RBC at this dose. As for offspring, no-observed-adverse-effect level (NOAEL) was determined to be 14 ppm (1.86 mg/kg body weight/day) by the decrease of type-2 progenitor cell proliferation in the SGZ and the inhibition of ChE activity in the RBC and brain at 70 ppm. The NOAEL of dams based on the offspring's effects was approximately 2800 times higher than the estimated consumption of CPF through food in the general population and in pregnant women as examined in Japan. PMID- 23099339 TI - Teratogenic effects of diabetic conditions in chick heart in ovo and in micromass culture may be prevented by addition of vitamin C and folic acid. AB - Maternal diseases like diabetes mellitus may cause developmental defects. Supplementation with folic acid and vitamin C during the periconceptional period has been shown to prevent some neural tube and congenital heart defects. Hearts were dissected from 5 days-old White Leghorn chick embryos, the cells isolated and cultured in micromass under diabetic conditions, with and without folic acid and vitamin C. Contractile activity, cell viability (resazurin reduction) and protein assays were performed. Results indicated diabetic conditions reduced contractile activity and cell viability, whilst vitamin C (100 MUM) and folic acid (1 mM) administered concurrently significantly improved them to values comparable with the control. Day 3 chick embryos in ovo were injected with glucose+hydroxybutyrate or a combination of these and vitamins. Diabetic conditions caused gross and histological malformations, but these effects were abrogated by vitamin supplement. Teratogenic effects on heart development could possibly be prevented by vitamin supplementation during pregnancy. PMID- 23099344 TI - Slice XVIvoTM: a novel electrophysiology system with the capability for 16 independent brain slice recordings. AB - Here we validate the design and use of a novel, customized electrophysiology system (Slice XVIvoTM) that is capable of recording from 16 independent brain slices. The system consists of 16 independent recording chambers in which individual electrodes can be manually manipulated and fixed in order to stimulate and record extracellular responses from 16 brain slices simultaneously. Responses from each brain slice are elicited with individual stimulus isolator units and recorded through separate channels, thus allowing for independent control and analysis of the evoked extracellular activity from each slice. The system was designed to fit on a standard anti-vibration table, thus the Slice XVIvoTM system occupies considerably less space than other currently available multi-slice recording systems. We have demonstrated the utility of the system to obtain stable, extracellular responses from the CA1 region of the hippocampus, as well as induce long-term potentiation. Additionally, we show the utility of the Slice XVIvoTM system to significantly improved throughput for testing compounds in an oxygen and glucose deprivation assay. Overall, we have designed, created and validated a considerably cost- and space-efficient electrophysiology system that greatly improves throughput while minimizing the number of animals used in experiments. PMID- 23099345 TI - Long-term synchronized electrophysiological and behavioral wireless monitoring of freely moving animals. AB - Parallel electrophysiological recording and behavioral monitoring of freely moving animals is essential for a better understanding of the neural mechanisms underlying behavior. In this paper we describe a novel wireless recording technique, which is capable of synchronously recording in vivo multichannel electrophysiological (LFP, MUA, EOG, EMG) and activity data (accelerometer, video) from freely moving cats. The method is based on the integration of commercially available components into a simple monitoring system and is complete with accelerometers and the needed signal processing tools. LFP activities of freely moving group-housed cats were recorded from multiple intracortical areas and from the hippocampus. EMG, EOG, accelerometer and video were simultaneously acquired with LFP activities 24-h a day for 3 months. These recordings confirm the possibility of using our wireless method for 24-h long-term monitoring of neurophysiological and behavioral data of freely moving experimental animals such as cats, ferrets, rabbits and other large animals. PMID- 23099346 TI - Carbon-modified BiVO4 microtubes embedded with Ag nanoparticles have high photocatalytic activity under visible light. AB - Carbon-modified BiVO(4) microtubes embedded with Ag nanoparticles (BVO@C/Ag MTs) were obtained by a two-step fabrication route. First, the BiVO(4)@carbon core shell microtubes (BVO@C MTs) were fabricated by using BiVO(4) microtubes (BiVO(4) MTs) as a hard-template through a hydrothermal approach. Next, small Ag nanoparticles (Ag NPs) with well-dispersed distribution were assembled inside the carbon layer of the BVO@C MTs via an in situ reduction method. The results showed that small Ag NPs were well dispersed inside the carbon layer of approximately 8 nm in thickness around the BiVO(4) microtubes. The photocatalytic studies revealed that the BVO@C/Ag MTs exhibited the highest photocatalytic activity for photodegradation of rhodamine B (RB) compared to the pure BVO-MTs, BVO@C MTs under visible light irradiation. The high separation efficiency of photogenerated electron-hole pairs based on the photosynergistic effect among the three components of BiVO(4), carbon, and Ag and the improved visible light utilization from the sensitizing effects of carbon layers both contribute to the enhanced photocatalytic activity. The BVO@C/Ag MTs did not exhibit any significant loss of activity after three cycles of RB photodegradation, which results from the fact that the presence of the carbon layer could inhibit loss and oxidation of Ag NPs during repeated applications. The BVO@C/Ag MTs could be easily recovered by sedimentation due to their one-dimensional nanostructural property. PMID- 23099347 TI - Contribution of cells undergoing epithelial-mesenchymal transition to the tumour microenvironment. AB - Human cancer mortality is predominantly determined by the spread of tumour cells from a primary to secondary anatomical location. The metastatic cascade follows tumour cell dissemination, passage through the blood and/or lymphatic system, and colonisation at a distant site. Increased cell motility of cancer cells at the leading tumour edge has been attributed to the epithelial-mesenchymal transition (EMT) which facilitates their release and invasiveness. Mechanisms behind cancer cell dissemination and homing of metastatic cells to a secondary site remain largely unknown. However, certain cancers have a propensity to metastasise to particular organs, and one possible explanation is the seed and soil hypothesis, which is predicated on circulating tumour cells settling in favourable conditions. Extracellular vesicles mediate communication in the tumour microenvironment, stimulate cell migration and invasion, and prepare the pre metastatic niche. In addition, the tumour stroma can initiate EMT in cancer cells at the invasive front which, in turn, secrete a distinct suite of molecules into the tumour microenvironment. As a first step towards understanding precise regulatory mechanisms, it is important to identify secreted modulators residing within the metastatic niche. Determining the signals and stimuli required to initiate and propagate cancer cell spreading will potentially unearth candidates to limit metastasis. PMID- 23099348 TI - Proteomic changes in Actinidia chinensis shoot during systemic infection with a pandemic Pseudomonas syringae pv. actinidiae strain. AB - A pandemic, very aggressive population of Pseudomonas syringae pv. actinidiae is currently causing severe economic losses to kiwifruit crops worldwide. Upon leaf attack, this Gram-negative bacterium systemically reaches the plant shoot in a week period. In this study, combined 2-DE and nanoLC-ESI-LIT-MS/MS procedures were used to describe major proteomic changes in Actinidia chinensis shoot following bacterial inoculation in host leaf. A total of 117 differentially represented protein spots were identified in infected and control shoots. Protein species associated with plant defence, including type-members of the plant basal defence, pathogenesis, oxidative stress and heat shock, or with transport and signalling events, were the most represented category of induced components. Proteins involved in carbohydrate metabolism and photosynthesis were also augmented upon infection. In parallel, a bacterial outer membrane polypeptide component was identified in shoot tissues, whose homologues were already linked to bacterial virulence in other eukaryotes. Semiquantitative RT-PCR analysis confirmed expression data for all selected plant gene products. All these data suggest a general reprogramming of shoot metabolism following pathogen systemic infection, highlighting organ-specific differences within the context of a general similarity with respect to other pathosystems. In addition to present preliminary information on the molecular mechanisms regulating this specific plant-microbe interaction, our results will foster future proteomic studies aimed at characterizing the very early events of host colonization, thus promoting the development of novel bioassays for pathogen detection in kiwifruit material. PMID- 23099349 TI - Profiling the kinome: current capabilities and future challenges. AB - Protein kinases are the second largest human protein family, but in terms of research interest, both basic and applied, they are surely the most popular. Over the past decade, many techniques and approaches for studying the kinome have been described and the pace of development is ever increasing. Presently, a molecular biologist can approach the kinome from many different angles: what kinases are active during a specific cell state of interest or become activated in response to a specific stimulus? What are the effects of controlling the activation status of an individual kinase? What substrates are targeted by a particular kinase, either in general or under particular conditions? And what kinase is responsible for targeting a specific phosphorylation site of interest? These are some of the more commonly asked questions during any kinase-centric research project and different strategies have been devised for answering such queries. In this review, we outline the most promising of these approaches, particularly those with a capacity for high-throughput studies. This article is part of a Special Issue entitled: From protein structures to clinical applications. PMID- 23099350 TI - [Mycoses in Venezuela: Working Groups in Mycology reported cases (1984-2010)]. AB - BACKGROUND: In 1984 the Venezuelan Work Groups in Mycology (VWGM) were created introducing an innovative approach to the study of the mycoses in Venezuela. AIM: To study the occurrence of the mycoses in Venezuela. METHODS: Review the reported cases of mycoses by the newsletter Boletin Informativo Las Micosis en Venezuela (VWGM) from 1984 to 2010. RESULTS: The data collected showed 36,968 reported cases of superficial mycoses, 1,989 of deep systemic cases, and 822 of localized mycoses. Pityriasis dermatophytosis was the most common superficial infection, and paracoccidioidomycosis and histoplasmosis the most frequent deep systemic infection. Chromoblastomycosis was the most frequently diagnosed subcutaneous infection. The data provided showed the distribution by geographical area for each of the fungal infections studied, which may help to establish the endemic areas. DISCUSSION: Superficial mycosis is a public health problem due to its high morbidity and is probably responsible for some of the outbreaks in high-risk groups. Paracoccidioidomycosis and histoplasmosis were reported more often, which agrees with earlier reports prior to the formation of the VWGM. Cases of sporotrichosis and chromoblastomycosis in Venezuela can be considered unique due to the high number of cases. This study highlights the contribution of the VWGM to the behavior of the mycoses in Venezuela, its incidence, prevalence, and the recognition of these infections as a problem of public health importance. The VWGM should keep working in this endeavor, not only reporting new cases, but also unifying the clinical and epidemiological criteria, in order to properly monitor the evolving epidemiological changes reported in these types of infections. PMID- 23099351 TI - Sensitivity enhancement and low-field spin relaxation in singlet NMR. AB - The singlet states of nuclear spin-1/2 pairs often display extended lifetimes that can be an order of magnitude longer than conventional relaxation times. We show that, in favourable circumstances, acquisition of the NMR signal during an extended multiple spin-echo train, followed by suitable data processing, enhances the signal-to-noise ratio of singlet NMR by up to an order of magnitude. The achievable enhancement depends on the transverse relaxation time constant, the magnetic field inhomogeneity, and the acceptable degradation in digital spectral resolution. We use the combination of singlet NMR and multiple spin-echo data acquisition to study the low-field nuclear relaxation processes of (15)N-labelled nitrous oxide ((15)N(2)O) in solution. A general relaxation theory for coupled 2 spin-1/2 systems in low magnetic field is developed. Experimental trajectories of the nuclear spin observables are compared with theoretical expressions, including dipole-dipole and spin-rotation relaxation mechanisms. The estimated values of the spin-rotation tensors are compared with previous estimations from NMR and molecular beam electric resonance. PMID- 23099352 TI - Close relationship between clinicians and DMPK researchers to bridge the non clinical and pharmacotherapy. PMID- 23099353 TI - Effects of UGT1A6, UGT2B7, and CYP2C9 genotypes on plasma concentrations of valproic acid in Chinese children with epilepsy. AB - Valproic acid (VPA) is one of the most commonly prescribed drugs for the treatment of epilepsy. Interindividual variability in VPA dose and plasma concentration may reflect functional consequences of genetic polymorphisms in genes encoding drug-metabolizing enzymes. The aim of this study was to determine the relationship between plasma concentrations of VPA and single nucleotide polymorphisms (SNPs) involving uridine diphosphate glucuronosyltransferase (UGT) 1A6 (UGT1A6), UGT2B7, and cytochrome P450 2C9 (CYP2C9) genes in Chinese children with epilepsy. UGT1A6, UGT2B7, and CYP2C9 polymorphisms were identified by the polymerase chain reaction-restriction fragment length polymorphism approach or direct automated DNA sequencing in 98 epileptic patients treated with VPA monotherapy. Patients with double heterozygosities at nucleotide positions T19G, A541G and A552C in the UGT1A6 gene, were associated with higher VPA doses compared to those with wild type or single heterozygosity (p = 0.010). Lower adjusted plasma VPA concentrations were also observed in patients with UGT1A6 double heterozygosities than those with single heterozygosity (p = 0.027). There were no differences in VPA dose or adjusted plasma VPA concentrations among the UGT2B7*2 or CYP2C9*3 genotypic groups. These results suggest that UGT1A6 mutations affect VPA metabolism in epileptic children. It needs to be further investigated in a larger cohort of patients. PMID- 23099354 TI - A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stress-induced cardiomyopathy. AB - AIM: Stress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. METHODS AND RESULTS: A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes. CONCLUSIONS: The present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines. PMID- 23099355 TI - Effects of Tai Chi training on exercise capacity and quality of life in patients with chronic heart failure: a meta-analysis. AB - AIM: Whether Tai Chi (TC) is effective in the cardiac rehabilitation of patients with chronic heart failure (CHF) remains controversial. We performed a meta analysis to examine the effects of TC on exercise capacity and quality of life (QoL) in CHF patients. METHODS AND RESULTS: PubMed and EMBASE databases were searched (up to May 2012) for relevant studies. Studies including participants with reduced left ventricular systolic function (ejection fraction <= 45%) were selected. Interventions considered were TC with or without comparisons (education or usual care). Weighted mean differences (WMDs) and 95% confidence intervals (CIs) were calculated, and heterogeneity was assessed using the I(2) test. Four randomized controlled trials (RCTs) (n = 242) met the inclusion criteria. TC significantly improved QoL (WMD -14.54 points; 95% CI -23.45 to -5.63). TC was not associated with a significant reduction in N-terminal pro brain natriuretic peptide (WMD -61.16 pg/mL; 95% CI -179.27 to 56.95), systolic blood pressure (WMD -1.06 mmHg; 95% CI -13.76 to 11.63), diastolic blood pressure (WMD -0.08 mmHg; 95% CI -3.88 to 3.73), improved 6 min walking distance (WMD 46.73 m; 95% CI -1.62 to 95.09), or peak oxygen uptake (WMD 0.19 mL/kg/min; 95% CI -0.74 to 1.13). CONCLUSIONS: TC may improve QoL in patients with CHF and could be considered for inclusion in cardiac rehabilitation programmes. However, there is currently a lack of evidence to support TC altering other important clinical outcomes. Further larger RCTs are urgently needed to investigate the effects of TC. PMID- 23099356 TI - Association between glycated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta-analysis. AB - BACKGROUND: Clinical trials to date have not provided definitive evidence regarding the effects of glucose lowering on the incidence of congestive heart failure (CHF). We synthesized available prospective epidemiological data on the association between glycaemia measured by haemoglobin A(1c) (HbA(1c)) and incident CHF in individuals with diabetes. METHODS AND RESULTS: We searched electronic databases and reference lists of selected articles for relevant prospective epidemiological studies. We abstracted data from relevant studies using standardized forms and obtained additional data from investigators when required. We pooled study-specific relative risk estimates using random-effects model meta-analysis. Of the 1044 citations identified, we included 10 studies comprising 178 929 participants with diabetes and 14 176 incident CHF cases. Five studies included only patients with type 2 diabetes, four studies had predominantly patients with type 2 diabetes, and one study included only patients with type 1 diabetes. All studies except one showed an increased risk of CHF with higher HbA(1c). The overall adjusted risk ratio (RR) for CHF was 1.15 [95% confidence interval (CI) 1.10-1.21] for each percentage point higher HbA(1c). There was substantial heterogeneity across the 10 studies (I(2): 83%; 95% CI 69 91%; P < 0.001) not explained by available study-level characteristics such as study design or average HbA(1c) level. In seven studies reporting RRs with more than one degree of adjustment, the association was minimally altered after adjustment for several cardiovascular risk factors. CONCLUSIONS: In observational studies of individuals with diabetes, a higher HbA(1c) level was associated with a significantly increased incidence of CHF. PMID- 23099357 TI - Left cardiac sympathetic denervation for treatment of symptomatic systolic heart failure patients: a pilot study. AB - AIMS: To evaluate the feasibility, safety, and potential beneficial effects of left cardiac sympathetic denervation (LCSD) in systolic heart failure (HF) patients. METHODS AND RESULTS: In this prospective, randomized pilot study, inclusion criteria were New York Heart Association (NYHA) functional class II or III, left ventricular ejection fraction (LVEF) <=40%, sinus rhythm, and resting heart rate >65 b.p.m., despite optimal medical therapy (MT). Fifteen patients were randomly assigned either to MT alone or MT plus LCSD. The primary endpoint was safety, measured by mortality in the first month of follow-up and morbidity according to pre-specified criteria. Secondary endpoints were exercise capacity, quality of life, LVEF, muscle sympathetic nerve activity (MSNA), brain natriuretic peptide (BNP) levels and 24 h Holter mean heart rate before and after 6 months. We studied clinical effects in long-term follow-up. Ten patients underwent LCSD. There were no adverse events attributable to surgery. In the LCSD group, LVEF improved from 25 +/- 6.6 to 33 +/- 5.2 (P = 0.03); 6 min walking distance improved from 167 +/- 35 to 198 +/- 47 m (P = 0.02). Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score physical dimension changed from 21 +/- 5 to 15 +/- 7 (P = 0.06). The remaining analysed variables were unchanged. During 848 +/- 549 days of follow-up, in the MT group, three patients either died or underwent cardiac transplantation (CT), while in the LCSD group six were alive without CT. CONCLUSIONS: LCSD was feasible and seemed to be safe in systolic HF patients. Its beneficial effects warrant the development of a larger randomized trial. Trail registration: NCT01224899. PMID- 23099358 TI - Further insights into the underlying electrophysiological mechanisms for reduction of atrial fibrillation by ranolazine in an experimental model of chronic heart failure. AB - AIMS: Ranolazine (RAN) was reported to be effective and safe in converting atrial fibrillation (AF) to sinus rhythm by administration of a single dose ('pill in the pocket') to patients with structural heart disease. This study examines the underlying mechanisms for the antiarrhythmic benefit of RAN application in chronic heart failure (CHF). METHODS AND RESULTS: In 10 female rabbits, CHF was induced by rapid ventricular pacing, leading to a significant decrease in ejection fraction in the presence of a dilated left ventricle and atrial enlargement. Twelve rabbits were sham-operated and served as controls. Isolated hearts were perfused using the Langendorff method. Burst pacing was used to induce AF. Monophasic action potential recordings showed an increase of atrial action potential duration (aAPD) and effective refractory period (aERP) in CHF hearts compared with sham hearts. Infusion of acetylcholine (1 uM) and isoproterenol (1 uM) led to AF in all failing hearts and in 11 sham hearts. Simultaneous infusion of RAN (10 uM) remarkably reduced inducibility of AF in 50% of sham and 50% of failing hearts. RAN had no effect on aAPD but significantly increased aERP, leading to a marked increase in atrial post-repolarization refractoriness. Moreover, RAN application moderately increased interatrial conduction time. CONCLUSION: RAN has been shown to be effective in reducing the inducibility of AF in an experimental model of AF. The antiarrhythmic effect is mainly due to development of atrial post-repolarization refractoriness and a moderate increase in conduction time. The described electrophysiological mechanisms remain preserved in the setting of CHF. PMID- 23099360 TI - Effect of CDP-choline on age-dependent modifications of energy- and glutamate linked enzyme activities in synaptic and non-synaptic mitochondria from rat cerebral cortex. AB - The effect of aging and CDP-choline treatment (20 mg kg-1 body weight i.p. for 28 days) on the maximal rates (V(max)) of representative mitochondrial enzyme activities related to Krebs' cycle (citrate synthase, alpha-ketoglutarate dehydrogenase, malate dehydrogenase), glutamate and related amino acid metabolism (glutamate dehydrogenase, glutamate-oxaloacetate- and glutamate-pyruvate transaminases) were evaluated in non-synaptic and intra-synaptic "light" and "heavy" mitochondria from frontal cerebral cortex of male Wistar rats aged 4, 12, 18 and 24 months. During aging, enzyme activities vary in a complex way respect to the type of mitochondria, i.e. non-synaptic and intra-synaptic. This micro heterogeneity is an important factor, because energy-related mitochondrial enzyme catalytic properties cause metabolic modifications of physiopathological significance in cerebral tissue in vivo, also discriminating pre- and post synaptic sites of action for drugs and affecting tissue responsiveness to noxious stimuli. Results show that CDP-choline in vivo treatment enhances cerebral energy metabolism selectively at 18 months, specifically modifying enzyme catalytic activities in non-synaptic and intra-synaptic "light" mitochondrial sub populations. This confirms that the observed changes in enzyme catalytic activities during aging reflect the bioenergetic state at each single age and the corresponding energy requirements, further proving that in vivo drug treatment is able to interfere with the neuronal energy metabolism. PMID- 23099359 TI - Glucocerebrosidase inhibition causes mitochondrial dysfunction and free radical damage. AB - Mutations of the gene for glucocerebrosidase 1 (GBA) cause Gaucher disease (GD), an autosomal recessive lysosomal storage disorder. Individuals with homozygous or heterozygous (carrier) mutations of GBA have a significantly increased risk for the development of Parkinson's disease (PD), with clinical and pathological features that mirror the sporadic disease. The mechanisms whereby GBA mutations induce dopaminergic cell death and Lewy body formation are unknown. There is evidence of mitochondrial dysfunction and oxidative stress in PD and so we have investigated the impact of glucocerebrosidase (GCase) inhibition on these parameters to determine if there may be a relationship of GBA loss-of-function mutations to the known pathogenetic pathways in PD. We have used exposure to a specific inhibitor (conduritol-beta-epoxide, CbetaE) of GCase activity in a human dopaminergic cell line to identify the biochemical abnormalities that follow GCase inhibition. We show that GCase inhibition leads to decreased ADP phosphorylation, reduced mitochondrial membrane potential and increased free radical formation and damage, together with accumulation of alpha-synuclein. Taken together, inhibition of GCase by CbetaE induces abnormalities in mitochondrial function and oxidative stress in our cell culture model. We suggest that GBA mutations and reduced GCase activity may increase the risk for PD by inducing these same abnormalities in PD brain. PMID- 23099362 TI - A vote for science. PMID- 23099361 TI - Aberrantly activated EGFR contributes to enhanced IL-8 expression in COPD airways epithelial cells via regulation of nuclear FoxO3A. AB - BACKGROUND: Decreased activity of forkhead transcription factor class O (FoxO)3A, a negative regulator of NF-kappaB-mediated chemokine expression, is implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Previously, we showed that quercetin reduces lung inflammation in a murine model of COPD. Here, we examined the mechanisms underlying decreased FoxO3A activation and its modulation by quercetin in COPD human airway epithelial cells and in a COPD mouse model. METHODS: Primary COPD and normal human airway epithelial cells were treated with quercetin, LY294002 or erlotinib for 2 weeks. IL-8 was measured by ELISA. FoxO3A, Akt, and epidermal growth factor (EGF) receptor (EGFR) phosphorylation and nuclear FoxO3A levels were determined by Western blot analysis. Effects of quercetin on lung chemokine expression, nuclear FoxO3A levels and phosphorylation of EGFR and Akt were determined in COPD mouse model. RESULTS: Compared with normal, COPD cells showed significantly increased IL-8, which negatively correlated with nuclear FoxO3A levels. COPD bronchial biopsies also showed reduced nuclear FoxO3A. Decreased FoxO3A in COPD cells was associated with increased phosphorylation of EGFR, Akt and FoxO3A and treatment with quercetin, LY294002 or erlotinib increased nuclear FoxO3A and decreased IL-8 and phosphorylation of Akt, EGFR and FoxO3A, Compared with control, elastase/LPS exposed mice showed decreased nuclear FoxO3A, increased chemokines and phosphorylation of EGFR and Akt. Treatment with quercetin partially reversed these changes. CONCLUSIONS: In COPD airways, aberrant EGFR activity increases PI 3-kinase/Akt-mediated phosphorylation of FoxO3A, thereby decreasing nuclear FoxO3A and increasing chemokine expression. Quercetin restores nuclear FoxO3A and reduces chemokine expression partly by modulating EGFR/PI 3-kinase/Akt activity. PMID- 23099363 TI - Banish cronyism. PMID- 23099364 TI - Shock and law. PMID- 23099365 TI - Throw off the cloak of invisibility. PMID- 23099376 TI - High stakes for US science. PMID- 23099377 TI - Viral research faces clampdown. PMID- 23099378 TI - Website pitches solutions in search of problems. PMID- 23099379 TI - Ocean-fertilization project off Canada sparks furore. PMID- 23099380 TI - Texas cancer fund seeks fresh start. PMID- 23099381 TI - Toxicology: The learning curve. PMID- 23099382 TI - Biology and ideology: The anatomy of politics. PMID- 23099383 TI - Futures market: Wall Street's thirst for water. PMID- 23099384 TI - Physics: Why symmetry matters. PMID- 23099394 TI - LMB Cambridge: Bureaucracy bypass let research flourish. PMID- 23099395 TI - Awards: Beit fellowships forge a Nobel link. PMID- 23099396 TI - Lunar science: Timely reminder to return to the Moon. PMID- 23099397 TI - Canadian science: Reallocate funds to boost performance. PMID- 23099398 TI - Psychology: Social insight rings true 125 years on. PMID- 23099399 TI - Louise Johnson (1940-2012). PMID- 23099400 TI - Cancer: Destiny from density. PMID- 23099401 TI - Earth science: Signs of instability. PMID- 23099402 TI - Genetics: The inner life of proteins. PMID- 23099403 TI - Cosmology: Infrared light from wandering stars. PMID- 23099405 TI - Near-infrared background anisotropies from diffuse intrahalo light of galaxies. AB - Unresolved anisotropies of the cosmic near-infrared background radiation are expected to have contributions from the earliest galaxies during the epoch of reionization and from faint, dwarf galaxies at intermediate redshifts. Previous measurements were unable to pinpoint conclusively the dominant origin because they did not sample spatial scales that were sufficiently large to distinguish between these two possibilities. Here we report a measurement of the anisotropy power spectrum from subarcminute to one-degree angular scales, and find the clustering amplitude to be larger than predicted by the models based on the two existing explanations. As the shot-noise level of the power spectrum is consistent with that expected from faint galaxies, a new source population on the sky is not necessary to explain the observations. However, a physical mechanism that increases the clustering amplitude is needed. Motivated by recent results related to the extended stellar light profile in dark-matter haloes, we consider the possibility that the fluctuations originate from intrahalo stars of all galaxies. We find that the measured power spectrum can be explained by an intrahalo light fraction of 0.07 to 0.2 per cent relative to the total luminosity in dark-matter haloes of 10(9) to 10(12) solar masses at redshifts of about 1 to 4. PMID- 23099406 TI - Quasi-periodic events in crystal plasticity and the self-organized avalanche oscillator. AB - When external stresses in a system--physical, social or virtual--are relieved through impulsive events, it is natural to focus on the attributes of these avalanches. However, during the quiescent periods between them, stresses may be relieved through competing processes, such as slowly flowing water between earthquakes or thermally activated dislocation flow between plastic bursts in crystals. Such smooth responses can in turn have marked effects on the avalanche properties. Here we report an experimental investigation of slowly compressed nickel microcrystals, covering three orders of magnitude in nominal strain rate, in which we observe unconventional quasi-periodic avalanche bursts and higher critical exponents as the strain rate is decreased. Our experiments are faithfully reproduced by analytic and computational dislocation avalanche modelling that we have extended to incorporate dislocation relaxation, revealing the emergence of the self-organized avalanche oscillator: a novel critical state exhibiting oscillatory approaches towards a depinning critical point. This theory suggests that whenever avalanches compete with slow relaxation--in settings ranging from crystal microplasticity to earthquakes--dynamical quasi-periodic scale invariance ought to emerge. PMID- 23099407 TI - Forming all-carbon quaternary stereogenic centres in acyclic systems from alkynes. AB - The formation of all-carbon quaternary stereocentres in acyclic systems is one of the most difficult contemporary challenges in modern synthetic organic chemistry. Particularly challenging is the preparation of all-carbon quaternary stereocentres in aldol adducts; this difficulty is problematic because the aldol reaction represents one of the most valuable chemical transformations in organic synthesis. The main problem that limits the formation of these stereocentres is the absence of an efficient method of preparing stereodefined trisubstituted enolates in acyclic systems. Here we describe a different approach that involves the formation of two new stereogenic centres--including the all-carbon quaternary one--via a combined carbometalation-oxidation reaction of an organocuprate to give a stereodefined trisubstituted enolate. We use this method to generate a series of aldol and Mannich products from ynamides with excellent diastereomeric and enantiomeric ratios and moderate yields. PMID- 23099408 TI - Recent changes to the Gulf Stream causing widespread gas hydrate destabilization. AB - The Gulf Stream is an ocean current that modulates climate in the Northern Hemisphere by transporting warm waters from the Gulf of Mexico into the North Atlantic and Arctic oceans. A changing Gulf Stream has the potential to thaw and convert hundreds of gigatonnes of frozen methane hydrate trapped below the sea floor into methane gas, increasing the risk of slope failure and methane release. How the Gulf Stream changes with time and what effect these changes have on methane hydrate stability is unclear. Here, using seismic data combined with thermal models, we show that recent changes in intermediate-depth ocean temperature associated with the Gulf Stream are rapidly destabilizing methane hydrate along a broad swathe of the North American margin. The area of active hydrate destabilization covers at least 10,000 square kilometres of the United States eastern margin, and occurs in a region prone to kilometre-scale slope failures. Previous hypothetical studies postulated that an increase of five degrees Celsius in intermediate-depth ocean temperatures could release enough methane to explain extreme global warming events like the Palaeocene-Eocene thermal maximum (PETM) and trigger widespread ocean acidification. Our analysis suggests that changes in Gulf Stream flow or temperature within the past 5,000 years or so are warming the western North Atlantic margin by up to eight degrees Celsius and are now triggering the destabilization of 2.5 gigatonnes of methane hydrate (about 0.2 per cent of that required to cause the PETM). This destabilization extends along hundreds of kilometres of the margin and may continue for centuries. It is unlikely that the western North Atlantic margin is the only area experiencing changing ocean currents; our estimate of 2.5 gigatonnes of destabilizing methane hydrate may therefore represent only a fraction of the methane hydrate currently destabilizing globally. The transport from ocean to atmosphere of any methane released--and thus its impact on climate- remains uncertain. PMID- 23099413 TI - Serotonergic 5-HT(1A) receptor agonist (8-OH-DPAT) ameliorates impaired micturition reflexes in a chronic ventral root avulsion model of incomplete cauda equina/conus medullaris injury. AB - Trauma to the thoracolumbar spine commonly results in injuries to the cauda equina and the lumbosacral portion of the spinal cord. Both complete and partial injury syndromes may follow. Here, we tested the hypothesis that serotonergic modulation may improve voiding function after an incomplete cauda equina/conus medullaris injury. For this purpose, we used a unilateral L5-S2 ventral root avulsion (VRA) injury model in the rat to mimic a partial lesion to the cauda equina and conus medullaris. Compared to a sham-operated series, comprehensive urodynamic studies demonstrated a markedly reduced voiding efficiency at 12 weeks after the VRA injury. Detailed cystometrogram studies showed injury-induced decreased peak bladder pressures indicative of reduced contractile properties. Concurrent external urethral sphincter (EUS) electromyography demonstrated shortened burst and prolonged silent periods associated with the elimination phase. Next, a 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), was administered intravenously at 12 weeks after the unilateral L5 S2 VRA injury. Both voiding efficiency and maximum intravesical pressure were significantly improved by 8-OH-DPAT (0.3-1.0 mg/kg). 8-OH-DPAT also enhanced the amplitude of EUS tonic and bursting activity as well as duration of EUS bursting and silent period during EUS bursting. The results indicate that 8-OH-DPAT improves voiding efficiency and enhances EUS bursting in rats with unilateral VRA injury. We conclude that serotonergic modulation of the 5-HT(1A) receptor may represent a new strategy to improve lower urinary tract function after incomplete cauda equina/conus medullaris injuries in experimental studies. PMID- 23099412 TI - The clock shop: coupled circadian oscillators. AB - Daily rhythms in neural activity underlie circadian rhythms in sleep-wake and other daily behaviors. The cells within the mammalian suprachiasmatic nucleus (SCN) are intrinsically capable of 24-h timekeeping. These cells synchronize with each other and with local environmental cycles to drive coherent rhythms in daily behaviors. Recent studies have identified a small number of neuropeptides critical for this ability to synchronize and sustain coordinated daily rhythms. This review highlights the roles of specific intracellular and intercellular signals within the SCN that underlie circadian synchrony. PMID- 23099414 TI - Lack of the transcription factor C/EBPdelta impairs the intrinsic capacity of peripheral neurons for regeneration. AB - Adult neurons of the peripheral nervous system (PNS), in contrast to those of the central nervous system, have a remarkable capacity to repair themselves after injury, yet the mechanisms underlying this regenerative propensity of peripheral neurons are far from completely understood. Here we show that the transcription factor CCAAT enhancer binding protein delta (C/EBPdelta) is necessary for the efficient axonal regeneration of dorsal root ganglia (DRG) neurons after sciatic nerve crush injury. Loss of C/EBPdelta substantially impairs axonal growth in dissociated cultured DRG neurons. In addition, lack of C/EPBdelta causes a major reduction in the regenerative response of DRG neurons to a conditioning lesion, which is a well known paradigm of injury that enhances axonal growth due to a transcription-dependent cell body response. C/EBPdelta is required for the induction of selected regeneration-associated genes. For example, the expression of SPRR1A (small proline-rich repeat protein 1A) is greatly reduced in DRG neurons of C/EBPdelta knockout mice during axonal regeneration compared to those in wild-type mice, while the expression of GAP-43 (growth associated protein-43) and galanin is not affected. Nevertheless, the expected prompt recovery of sciatic nerve function after injury is severely impaired in C/EBPdelta knockout mice, having a delay time of approximately 1 month for reaching the full function of recovering wild-type mice, suggesting that a transcription mechanism mediated by C/EBPdelta is required for efficient axonal regeneration. Taken together, our results identify C/EBPdelta as a crucial component of the transcriptional regulatory machinery which underlies the intrinsic capacity of peripheral neurons for axonal regeneration. PMID- 23099415 TI - Circadian and sleep disorder in Huntington's disease. AB - Huntington's disease is a progressive neurological disorder that starts insidiously with motor, cognitive or psychiatric disturbance, and progresses through a distressing range of symptoms to end with a devastating loss of function, both motor and executive. There is a growing awareness that, in addition to cognitive and psychiatric symptoms, there are other important non motor symptoms in HD, including sleep and circadian abnormalities. It is not clear if sleep-wake changes are caused directly by HD gene-related pathology, or if they are simply a consequence of having a neurodegenerative disease. From a patient point of view, the answer is irrelevant, since sleep and circadian disturbances are deleterious to good daily living, even in neurologically normal people. The assumption should be that, at the very least, sleep and/or circadian disturbance in HD patients will contribute to their symptoms. At worst, they may contribute to the progressive decline in HD. Here I review the state of our understanding of sleep and circadian abnormalities in HD. I also outline a set of simple rules that can be followed to improve the chances of a good night's sleep, since preventing any 'preventable' symptoms is the a logical first step in treating disease. The long-term impact of sleep disruption in HD is unknown. There have been no large-scale systematic studies of in sleep in HD. Furthermore, there has never been a study of the efficacy of pharmaceuticals that are typically used to treat sleep deficits in HD patients. Thus treatment of sleep disturbance in HD is necessarily empirical. A better understanding of the relationship between sleep/circadian abnormalities and HD pathology is needed, if treatment of this aspect of HD is to be optimized. PMID- 23099416 TI - Human Stiff person syndrome IgG-containing high-titer anti-GAD65 autoantibodies induce motor dysfunction in rats. AB - Stiff person syndrome (SPS) is an autoimmune CNS disorder characterized by muscle rigidity, spasms and anxiety. The majority of patients have high-titer autoantibodies (ab) against glutamate decarboxylase (GAD65). A pathogenic role of SPS-associated IgG with ab against GAD65 has been shown for anxiety-like behavior but not for the core motor signs. We repetitively injected the purified IgG fraction of an SPS patient with severe motor impairment but without anxious comorbidity containing high titers of anti-GAD65 ab (SPS-IgG) into the lateral ventricle (i.c.v.) or intrathecally (i.th.) at the spinal level in experimental rats. We analyzed the effects on motor and anxiety-like behavior. Non-SPS human IgG fractions served as controls. Animals injected i.c.v. with SPS-IgG showed stiffness-like behavior with impaired walking ability and reduced grip strength of the upper limbs as well as postural and sensorimotor dysfunction. Testing for anxiety-like behavior revealed no significant differences between SPS and control IgG-treated rats. IgG deposits were found only in rats treated with SPS-IgG and were localized predominantly in CNS structures involved in motor control including globus pallidus, internal capsule, striatum and anterior thalamus. Double immunofluorescence staining revealed that predominantly GABAergic interneurons were positive for i.c.v. injected SPS-IgG. Rats injected i.th. with SPS-IgG did not present obvious motor symptoms and had a normal synaptic transmission at the spinal level. We conclude that SPS-like motor dysfunction can be induced in rats by passive transfer of IgG from an SPS-patient with high titer of anti-GAD65 ab. GABAergic dysfunction in supraspinal motor pathways rather than in the spinal cord may lead to motor deficits observed in the rats contrasting observations made in SPS with amphiphysin antibodies. PMID- 23099418 TI - Natural history of primary snoring in school-aged children: a 4-year follow-up study. AB - BACKGROUND: The objective of this study was to examine the natural history of childhood primary snoring (PS) and to identify predictive clinical symptoms and risk factors associated with PS progression to obstructive sleep apnea (OSA). METHODS: Children aged 6 to 13 years old who received a diagnosis of PS in our previous community-based OSA prevalence study were invited to undergo repeat polysomnography (PSG) at 4-year follow-up. Subjects with an obstructive apnea hypopnea index (OAHI) >= 1 were classified as having OSA at follow-up. RESULTS: Seventy children (60% boys) with a mean age of 14.7 +/- 1.8 years were analyzed in this follow-up study. The mean duration of follow-up was 4.6 +/- 0.6 years. At follow-up, 26 subjects (37.1%) progressed to OSA, of whom five (7.1%) had moderate to severe disease (OAHI >= 5). Twenty-two (31.4%) remained at PS, and 18 (25.7%) had complete resolution of their snoring with normal PSG. Persistent snoring had a positive predictive value of 47.7% and a negative predictive value of 86.4% for progression from PS to OSA. Multivariate logistic regression analysis showed that persistent overweight/obesity was a significant risk factor for the development of OSA at follow-up, with an OR of 7.95 (95% CI, 1.43-44.09). CONCLUSIONS: More than one-third of school-aged children with PS progressed to OSA over a 4-year period, although only 7.1% developed moderate to severe disease. Weight control may be an important component in the management of PS because obesity was found to be a significant risk factor for PS progression. PMID- 23099417 TI - Angeli's salt counteracts the vasoactive effects of elevated plasma hemoglobin. AB - Plasma hemoglobin (Hb) released during intravascular hemolysis has been associated with numerous deleterious effects that may stem from increased nitric oxide (NO) scavenging, but has also been associated with reactive oxygen species generation and platelet activation. Therapies that convert plasma oxyHb to metHb, or metHb to iron-nitrosyl Hb, could be beneficial because these species do not scavenge NO. In this study, we investigated the effects of Angeli's salt (AS; sodium alpha-oxyhyponitrite, Na2N2O3), a nitroxyl (HNO) and nitrite (NO2(-)) donor, on plasma Hb oxidation and formation of iron-nitrosyl Hb from metHb and on the vasoactivity of plasma Hb. We hypothesized that AS could ameliorate hemolysis associated pathology via its preferential reactivity with plasma Hb, as opposed to red-cell-encapsulated Hb, and through its intrinsic vasodilatory activity. To test this hypothesis, we infused (n=3 per group) (1) cell-free Hb and AS, (2) cell-free Hb+0.9% NaCl, (3) AS+3% albumin, and (4) 3% albumin+0.9% NaCl (colloid controls for Hb and AS, respectively) in a canine model. Co-infusion of AS and cell-free Hb led to preferential conversion of plasma Hb to metHb, but the extent of conversion was lower than anticipated based on the in vivo concentration of AS relative to plasma Hb. This lower metHb yield was probably due to reactions of nitroxyl-derived AS with plasma components such as thiol-containing compounds. From a physiological and therapeutic standpoint, the infusion of Hb alone led to significant increases in mean arterial pressure (p=0.03) and systemic vascular resistance index (p=0.01) compared to controls. Infusion of AS alone led to significant decreases in these parameters and co-infusion of AS along with Hb had an additive effect in reversing the effects of Hb alone on the systemic circulation. Interestingly, in the pulmonary system, the decrease in pressure when AS was added to Hb was significantly less than would have been expected compared to the effects of Hb and AS alone, suggesting that inactivation of scavenging with AS reduced the direct vasodilatory effects of AS on the vasculature. We also found that AS reduced platelet activation when administered to whole blood in vitro. These data suggest that AS-like compounds could serve as therapeutic agents to counteract the negative vasoconstrictive consequences of hemolysis that occur in hemolytic anemias, transfusion of stored blood, and other diseases. Increases in metHb in the red blood cell, the potential of AS for neurotoxicity, and hypotension would need to be carefully monitored in a clinical trial. PMID- 23099419 TI - The recently identified hexosaminidase D enzyme substantially contributes to the elevated hexosaminidase activity in rheumatoid arthritis. AB - Since the 1970s, numerous reports have described elevated hexosaminidase activities in rheumatoid arthritis. However, due to the overlapping substrate specificities of different hexosaminidases, identification of the exact enzyme(s) responsible for the elevated activity remains incomplete. In this work we tested if the recently described enzyme, hexosaminidase D was expressed in human arthritic joints, and could contribute to the elevated hexosaminidase activity in rheumatoid arthritis. Thermostable beta-d-N-acetyl-galactosaminidase (hexosaminidase D) activities were determined in synovial fluid samples, synovial membranes, synovial fibroblast cell strains and synovial fibroblast-derived extracellular vesicles of patients with rheumatoid arthritis and osteoarthritis using chromogenic substrates. Expression of the HEXDC gene was detected both in steady state and in TGF-beta treated synovial fibroblasts by real time PCR. Strikingly, hexosaminidase D accounted for approximately 50% of the total beta-N acetyl-galactosaminidase activity in synovial membranes and synovial fibroblasts, and it was responsible for the vast majority of the beta-d-N-acetyl galactosaminidase activity in synovial fluid samples. TGF-beta downregulated the expression of hexosaminidase D in synovial fibroblasts dose-dependently. Of note, significant activity of hexosaminidase D was also found in association with extracellular vesicles released by synovial fibroblasts. This first study that describes the expression and disease relevance of the HEXDC gene in humans demonstrates the expression of this novel enzyme within the joints, and suggests that its activity may significantly contribute to the overall local exoglycosidase activity. PMID- 23099420 TI - Evaluation of the protective immune response induced in mice by immunization with Schistosoma mansoni schistosomula tegument (Smteg) in association with CpG-ODN. AB - In schistosomiasis, the current control strategy does not prevent reinfection, therefore, vaccine strategies are essential to combat the Schistosoma mansoni. The efficacy vaccine depends on parasite stage and effective adjuvant. We have recently demonstrated that S. mansoni schistosomula tegument (Smteg) is able to activate dendritic cells up regulate CD40 and CD86 molecules and induce a partial protection in mice (43-48%) when formulated with Freund's adjuvant. In this study we evaluated the ability of Smteg + alum or Smteg + alum + CpG-ODN to induce protection in mice. Our results demonstrate that Smteg + alum + CpG-ODN induced a partial reduction in worm burden (43.1%), reduction in the number of eggs eliminated in the feces. The protective response was associated with a predominant Th1 type of immune response, with increased production of specific IgG2c, IFN-gamma and TNF-alpha, B cells proliferation and CD4 cells and macrophages activation. PMID- 23099422 TI - Recent trends in the management of achalasia. AB - Radical treatment for achalasia is currently unavailable. At present, most palliative procedures are designed improve the passage of food through the gastroesophageal junction and thereby alleviate symptoms. Drug therapy is of limited, transient effectiveness. Pneumatic dilation (PD) is considered superior to endoscopic botulinum toxin injection (EBTI). The mainstay of surgical treatment for achalasia is laparoscopic Heller myotomy (LHM) with fundoplication, currently considered superior to PD. Per oral endoscopic myotomy (POEM), a "state of-the-art" procedure for minimally invasive surgery, holds great promise for the future management of achalasia. Definitive conclusions regarding the benefits and risks of currently available treatments for achalasia must await the accumulation of evidence from well-designed clinical trials. PMID- 23099423 TI - The burden of childhood pneumonia in the developed world: a review of the literature. AB - BACKGROUND: Estimates of the disease burden from childhood pneumonia are available for most developed countries, but they are based mainly on models. Measured country-specific pneumonia burden data are limited to a few nations and differ in case definitions and case ascertainment methods. This review describes pneumonia disease burden in developed countries. METHODS: We reviewed studies describing childhood pneumonia incidence in North America, Europe, Australia, New Zealand and Japan. Available estimates suggest that each year in developed countries there are up to 2.6 million cases of pneumonia, including 1.5 million hospitalized cases and around 3000 pneumonia deaths (compared with approximately 640 annual deaths from meningitis) in children <5 years of age. RESULTS: Data to inform policy decisions would be improved by information on burden and etiology of severe pneumonia, population-based incidence of ambulatory visits and hospitalizations and prevalence of complications and sequelae. PMID- 23099421 TI - Transcription termination by the eukaryotic RNA polymerase III. AB - RNA polymerase (pol) III transcribes a multitude of tRNA and 5S rRNA genes as well as other small RNA genes distributed through the genome. By being sequence specific, precise and efficient, transcription termination by pol III not only defines the 3' end of the nascent RNA which directs subsequent association with the stabilizing La protein, it also prevents transcription into downstream DNA and promotes efficient recycling. Each of the RNA polymerases appears to have evolved unique mechanisms to initiate the process of termination in response to different types of termination signals. However, in eukaryotes much less is known about the final stage of termination, destabilization of the elongation complex with release of the RNA and DNA from the polymerase active center. By comparison to pols I and II, pol III exhibits the most direct coupling of the initial and final stages of termination, both of which occur at a short oligo(dT) tract on the non-template strand (dA on the template) of the DNA. While pol III termination is autonomous involving the core subunits C2 and probably C1, it also involves subunits C11, C37 and C53, which act on the pol III catalytic center and exhibit homology to the pol II elongation factor TFIIS and TFIIFalpha/beta respectively. Here we compile knowledge of pol III termination and associate mutations that affect this process with structural elements of the polymerase that illustrate the importance of C53/37 both at its docking site on the pol III lobe and in the active center. The models suggest that some of these features may apply to the other eukaryotic pols. This article is part of a Special Issue entitled: Transcription by Odd Pols. PMID- 23099424 TI - Morbidity after antiretroviral therapy initiation in HIV-1-infected children in West Africa: temporal trends and relation to CD4 count. AB - BACKGROUND: Although 90% of HIV-1-infected children live in sub-Saharan Africa, morbidity data after highly active antiretroviral therapy (HAART) initiation in these settings are limited. The objective of this study was to document the incidence of AIDS-defining events and non-AIDS-defining diseases in African children receiving HAART. METHODS: Incidences rates (IRs) of AIDS-defining events and 10 other common diseases were estimated overall and by current CD4-strata (<15%, 15 - <25% and >=25%) from 2 prospective cohorts of African children. RESULTS: One hundred eighty-eight children contributing to 355 children-years were included. The documented morbidity IRs per 100 children-years were upper respiratory infections, 100 (87-114); infectious diarrhea, 37 (31-44); World Health Organization (WHO) stage 2 events, 22.9 (18.2-28.1); and WHO stage 3/4 events, 12.3 (9.1-16.7). IRs of WHO stage 2 events, severe bacterial infections, infectious diarrhea and pneumonia decreased linearly across all CD4%-strata, whereas WHO stage 3/4 events and viral infections occurred mostly when CD4% <15%. Overall, IRs decreased during the first 2 years on HAART except for upper respiratory infection, mycosis and oral candidiasis. CONCLUSION: This incidence of AIDS- and non-AIDS-defining diseases declined substantially after HAART in 2 African cohorts, although estimates remained high compared with high-resource settings. Without renewed efforts to increase antiretroviral scale-up, children in developing countries will continue to have a high burden of infections. PMID- 23099426 TI - Effect of cardiac resynchronization therapy on quality of life: the best gets the least. PMID- 23099425 TI - Epidemiology of a mumps outbreak in a highly vaccinated island population and use of a third dose of measles-mumps-rubella vaccine for outbreak control--Guam 2009 to 2010. AB - BACKGROUND: Despite high 2-dose measles-mumps-rubella (MMR) vaccine coverage, a large mumps outbreak occurred on the US Territory of Guam during 2009 to 2010, primarily in school-aged children. METHODS: We implemented active surveillance in April 2010 during the outbreak peak and characterized the outbreak epidemiology. We administered third doses of MMR vaccine to eligible students aged 9-14 years in 7 schools with the highest attack rates (ARs) between May 18, 2010, and May 21, 2010. Baseline surveys, follow-up surveys and case-reports were used to determine mumps ARs. Adverse events postvaccination were monitored. RESULTS: Between December 1, 2009, and December 31, 2010, 505 mumps cases were reported. Self-reported Pohnpeians and Chuukese had the highest relative risks (54.7 and 19.7, respectively) and highest crowding indices (mean: 3.1 and 3.0 persons/bedroom, respectively). Among 287 (57%) school-aged case-patients, 270 (93%) had >=2 MMR doses. A third MMR dose was administered to 1068 (33%) eligible students. Three-dose vaccinated students had an AR of 0.9/1000 compared with 2.4/1000 among students vaccinated with <=2 doses >1 incubation period postintervention, but the difference was not significant (P = 0.67). No serious adverse events were reported. CONCLUSIONS: This mumps outbreak occurred in a highly vaccinated population. The highest ARs occurred in ethnic minority populations with the highest household crowding indices. After the third dose MMR intervention in highly affected schools, 3-dose recipients had an AR 60% lower than students with <=2 doses, but the difference was not statistically significant and the intervention occurred after the outbreak peaked. This outbreak may have persisted due to crowding at home and high student contact rates. PMID- 23099427 TI - Electrochemical immunosensor modified with self-assembled monolayer of 11 mercaptoundecanoic acid on gold electrodes for detection of benzo[a]pyrene in water. AB - Well-oriented bio-conjugates on gold electrode surfaces will indirectly influence the molecular recognition of antigens to surface bound antibodies thus improving the detection performance of electrochemical immunosensors. This paper describes the modification of self-assembled monolayers (SAMs) on gold electrode surface with 11-mercaptoundecanoic acid (11-MUA). Activation of carboxylic acid terminal was performed by reaction of a mixture of water soluble carbodiimide and N hydrosuccinimide (NHS) on the electrode surfaces. Characterisation of the SAM formation on the gold electrode was performed using cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and contact angle measurements. An amperometric immunosensor was developed for the screening of polycyclic aromatic hydrocarbons (PAHs) in water. The system consists of gold as the working electrode, platinum as the counter electrode and a Ag/AgCl reference electrode. This three electrode system is integrated on a single chip. The measurement employs the enzyme-linked immunosorbent assay (ELISA) principle. Benzo[a]pyrene (BaP) was detected using an immunological reaction by measuring the alkaline phosphatase (AP) enzymatic reaction towards the substrate para-amino phenyl phosphate (pAPP). A competitive assay was performed within the electrode using AP as the labelled-enzyme. A lower limit of detection (5.6 ng ml(-1)) of BaP was achieved after the activation of the mixture of carbodiimide and succinimide with the alkanethiol SAM on the gold electrode in comparison to that obtained for the unmodified electrode (14.2 ng ml(-1)). The developed surface functionalised sensor demonstrated acceptable reproducibility and good stability, with a wide linear response to BaP (4-140 ng ml(-1)). PMID- 23099428 TI - Intermolecular distances of carboxylated TEMPO derivatives on TiO2 evaluated by spin-probe ESR. AB - Nearest-neighbor intermolecular distances of molecules adsorbed on the surface of nanocrystalline TiO(2) particles were evaluated by the electron spin resonance (ESR) technique with molecules having a nitroxide radical and a carboxyl group as a spin probe to clarify their aggregation behaviors on TiO(2) and the influence of coadsorbates. PMID- 23099429 TI - Staphylococci isolated from carriage sites and infected sites of dogs as a reservoir of multidrug resistance and methicillin resistance. AB - The aim of this study was to compare the spread of multidrug-resistant (MDR) and methicillin-resistant (MR) staphylococci in healthy dogs and in dogs with evident symptoms of infection. The samples from 172 healthy and 197 infected dogs were examined. The staphylococci were identified with conventional methods and by means of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method (MboI). Susceptibility to 15 antibiotics from 10 different antimicrobial classes was tested. Resistance to methicillin was confirmed by the presence of Staphylococcus aureus mecA and S. sciuri mecA genes. Multidrug resistance was defined as resistance to three or more antimicrobial classes. The oral mucosa to be the most frequent site of staphylococcal colonization (55.8 %), followed by nasal cavity (44.2 %), and anus (32.6 %). The prevalence of MDR staphylococci in infected dogs was significantly higher than in the healthy animals (74/137 vs. 34/95, P = 0.006). The MR strains of S. pseudintermedius (2.9 %) originated solely from infected dogs. In contrast, the MR coagulase-negative strains (7.4 %) were isolated solely from healthy dogs. S. aureus strains originated from nasal swabs, MRSA strains were not isolated. MDR staphylococci and MR S. pseudintermedius are more common among infected dogs, but coagulase negative staphylococci (mostly S. sciuri) seem to be a reservoir of methicillin resistance in healthy dogs. PMID- 23099430 TI - Diversity and symbiotic effectiveness of indigenous rhizobia-nodulating Adesmia bicolor in soils of Central Argentina. AB - Native perennial legume Adesmia bicolor reveals characteristics that are key to securing persistence under grazing. Literature on the diversity and symbiotic effectiveness of indigenous rhizobia-nodulating A. bicolor in central Argentina is limited. The purpose of this study was therefore to determine phenotypic and genotypic variability as well as biological N-fixation effectiveness in rhizobia isolated from A. bicolor nodules. To this end, repetitive genomic regions were analyzed using ERIC primers. In the greenhouse, plants were grown under a (i) N fertilized treatment, (ii) N-free control treatment, and (iii) rhizobia inoculation treatment. Dry weight and N-content were analyzed. All isolates belonged to Rhizobium genus and showed high symbiotic effectiveness. The N content/subterranean N-content ratio in aerial and subterranean parts of inoculated plants was higher than that observed in N-fertilized plants during the vegetative stage. Results from this study demonstrate that symbiosis between native rhizobial strains and A. bicolor is very effective. PMID- 23099431 TI - Pharmacokinetic study of Growth Hormone-Releasing Peptide 6 (GHRP-6) in nine male healthy volunteers. AB - GHRP-6 is a growth hormone secretagogue that also enhances tissue viability in different organs. In the present work, we studied the pharmacokinetics of this short therapeutic hexapeptide (His-(D-Trp)-Ala-Trp-(D-Phe)-Lys-NH(2,) MW=872.44 Da) in nine male healthy volunteers after a single intravenous bolus administration of 100, 200 and 400 MUg/kg of body weight. GHRP-6 was quantified in human plasma by a specific LC-MS method, previously developed and validated following FDA guidelines, using (13)C(3)Ala-GHRP-6 as internal standard (Gil et al., 2012, J. Pharm. Biomed. Anal. 60, 19-25). The Lower Limit of Quantification (5 ng/mL) was reached in all subjects at 12h post-administration, which was sufficient for modeling a pharmacokinetic profile including over 85% of the Area under the Curve (AUC). Disposition of GHRP-6 best fitted a bi-exponential function with R(2) higher than 0.99, according to a mathematic modeling and confirmed by an Akaike index (AIC) lower than that of the corresponding one compartment model for all subjects. Averaging all three dose levels, the distribution and elimination half-life of GHRP-6 were 7.6 +/- 1.9 min and 2.5 +/- 1.1h, respectively. These values are coherent with existing data for other drugs whose disposition also fits this model. Dose dependence analysis revealed a noticeable trend for AUC to increase proportionally with administered dose. Atypical GHRP-6 concentration spikes were observed during the elimination phase in four out of the nine subjects studied. PMID- 23099432 TI - TGFbetaRIIb mutations trigger aortic aneurysm pathogenesis by altering transforming growth factor beta2 signal transduction. AB - BACKGROUND: Thoracic aortic aneurysm (TAA) is a common progressive disorder involving gradual dilation of the ascending and/or descending thoracic aorta that eventually leads to dissection or rupture. Nonsydromic TAA can occur as a genetically triggered, familial disorder that is usually transmitted in a monogenic autosomal dominant fashion and is known as familial TAA. Genetic analyses of families affected with TAA have identified several chromosomal loci, and further mapping of familial TAA genes has highlighted disease-causing mutations in at least 4 genes: myosin heavy chain 11 (MYH11), alpha-smooth muscle actin (ACTA2), and transforming growth factor beta receptors I and II (TGFbetaRI and TGFbetaRII). METHODS AND RESULTS: We evaluated 100 probands to determine the mutation frequency in MYH11, ACTA2, TGFbetaRI, and TGFbetaRII in an unbiased population of individuals with genetically mediated TAA. In this study, 9% of patients had a mutation in one of the genes analyzed, 3% of patients had mutations in ACTA2, 3% in MYH11, 1% in TGFbetaRII, and no mutations were found in TGFbetaRI. Additionally, we identified mutations in a 75 base pair alternatively spliced TGFbetaRII exon, exon 1a that produces the TGFbetaRIIb isoform and accounted for 2% of patients with mutations. Our in vitro analyses indicate that the TGFbetaRIIb activating mutations alter receptor function on TGFbeta2 signaling. CONCLUSIONS: We propose that TGFbetaRIIb expression is a regulatory mechanism for TGFbeta2 signal transduction. Dysregulation of the TGFbeta2 signaling pathway, as a consequence of TGFbetaRIIb mutations, results in aortic aneurysm pathogenesis. PMID- 23099433 TI - Childhood thyroid radioiodine exposure and subsequent infertility in the intermountain fallout cohort. AB - BACKGROUND: Above-ground and underground nuclear weapon detonation at the Nevada Test Site (1951-1992) has resulted in radioiodine exposure for nearby populations. Although the long-term effect of environmental radioiodine exposure on thyroid disease has been well studied, little is known regarding the effect of childhood radioiodine exposure on subsequent fertility. OBJECTIVES: We investigated early childhood thyroid radiation exposure from nuclear testing fallout (supplied predominantly by radioactive isotopes of iodine) and self reported lifetime incidence of male or female infertility or sterility. METHODS: Participants were members of the 1965 Intermountain Fallout Cohort, schoolchildren at the time of exposure who were reexamined during two subsequent study phases to collect dietary and reproductive histories. Thyroid radiation exposure was calculated via an updated dosimetry model. We used multivariable logistic regression with robust sandwich estimators to estimate odds ratios for infertility, adjusted for potential confounders and (in separate models) for a medically confirmed history of thyroid disease. RESULTS: Of 1,389 participants with dosimetry and known fertility history, 274 were classified as infertile, including 30 classified as sterile. Childhood thyroid radiation dose was possibly associated with infertility [adjusted odds ratio (AOR) = 1.17; 95% CI: 0.82, 1.67 and AOR = 1.35; 95% CI: 0.96, 1.90 for the middle and upper tertiles vs. the first tertile of exposure, respectively]. The odds ratios were attenuated (AOR = 1.08; 95% CI: 0.75, 1.55 and AOR = 1.29; 95% CI: 0.91, 1.83 for the middle and upper tertiles, respectively) after adjusting for thyroid disease. There was no association of childhood radiation dose and sterility. CONCLUSION: Our findings suggest that childhood radioiodine exposure from nuclear testing may be related to subsequent adult infertility. Further research is required to confirm this. PMID- 23099435 TI - A structural stability diagram of multiple vacancies and defect self-healing in graphene. AB - Various types of multiple vacancies (MVs) in graphene nanoribbons (GNRs) and graphene are explored by quantum calculations. It is surprising that their relative stabilities highly depend on the width of the GNRs and thus is significantly different from those in graphene. A diagram of various MVs in GNRs is drawn and it is predicated that the hole in both GNRs and graphene can be annihilated. A new type of the MVs, which contains pentagon pairs and octagons (5/5|8), shows exceptional stability in GNRs. This study reveals the uniqueness of GNRs and a mechanism of defect self-healing in GNRs and graphene. PMID- 23099434 TI - The recent progress in research on effects of anesthetics and analgesics on G protein-coupled receptors. AB - The exact mechanisms of action behind anesthetics and analgesics are still unclear. Much attention was focused on ion channels in the central nervous system as targets for anesthetics and analgesics in the 1980s. During the 1990s, major advances were made in our understanding of the physiology and pharmacology of G protein coupled receptor (GPCR) signaling. Thus, several lines of studies have shown that G protein coupled receptors (GPCRs) are one of the targets for anesthetics and analgesics and especially, that some of them inhibit the functions of GPCRs, i.e,, muscarinic receptors and substance P receptors. However, these studies had been focused on only G(q) coupled receptors. There has been little work on G(s)- and G(i)-coupled receptors. In the last decade, a new assay system, using chimera G(i/o)-coupled receptor fused to Gq(i5), has been established and the effects of anesthetics and analgesics on the function of G(i) coupled receptors is now more easily studied. This review highlights the recent progress of the studies regarding the effects of anesthetics and analgesics on GPCRs. PMID- 23099436 TI - Novel BRCA1 and BRCA2 genomic rearrangements in Southern Chinese breast/ovarian cancer patients. PMID- 23099437 TI - The HOXB13 p.Gly84Glu mutation is not associated with the risk of breast cancer. AB - Recently, the HOXB13 gene has been shown to be a susceptibility gene for prostate cancer. HOXB13 is overexpressed in breast cancer tissues and HOXB13 expression in combination with low expression of IL17BR is predictive for a tamoxifen response in ER-positive breast cancers. Based on observations, we hypothesized that the HOXB13 p.Gly84Glu mutation might be associated with breast cancer risk. We genotyped this mutation in the germline DNA of 4,037 women with breast cancer (including 1,082 familial cases) and in 2,762 controls from Canada and Poland. Seven heterozygous carriers of the HOXB13 p.Gly84Glu mutation were found in the cases (0.17 %) compared to four carriers among the controls (0.14 %; OR = 1.2, 95 % CI = 0.34-4.1, p = 1.0). Only one of the seven carriers had a family history of breast cancer. This study does not support the hypothesis that women who carry the HOXB13 Gly84Glu mutation are at increased risk of breast cancer. PMID- 23099439 TI - A multi-route model of nicotine-cotinine pharmacokinetics, pharmacodynamics and brain nicotinic acetylcholine receptor binding in humans. AB - The pharmacokinetics of nicotine, the pharmacologically active alkaloid in tobacco responsible for addiction, are well characterized in humans. We developed a physiologically based pharmacokinetic/pharmacodynamic model of nicotine pharmacokinetics, brain dosimetry and brain nicotinic acetylcholine receptor (nAChRs) occupancy. A Bayesian framework was applied to optimize model parameters against multiple human data sets. The resulting model was consistent with both calibration and test data sets, but in general underestimated variability. A pharmacodynamic model relating nicotine levels to increases in heart rate as a proxy for the pharmacological effects of nicotine accurately described the nicotine related changes in heart rate and the development and decay of tolerance to nicotine. The PBPK model was utilized to quantitatively capture the combined impact of variation in physiological and metabolic parameters, nicotine availability and smoking compensation on the change in number of cigarettes smoked and toxicant exposure in a population of 10,000 people presented with a reduced toxicant (50%), reduced nicotine (50%) cigarette Across the population, toxicant exposure is reduced in some but not all smokers. Reductions are not in proportion to reductions in toxicant yields, largely due to partial compensation in response to reduced nicotine yields. This framework can be used as a key element of a dosimetry-driven risk assessment strategy for cigarette smoke constituents. PMID- 23099438 TI - Time to diagnosis and breast cancer stage by race/ethnicity. AB - We examined differences in time to diagnosis by race/ethnicity, the relationship between time to diagnosis and stage, and the extent to which it explains differences in stage at diagnosis across racial/ethnic groups. Our analytic sample includes 21,427 non-Hispanic White (White), Hispanic, non-Hispanic Black (Black) and non-Hispanic Asian/Pacific Islander (Asian) women diagnosed with stage I to IV breast cancer between January 1, 2000 and December 31, 2007 at one of eight National Comprehensive Cancer Network centers. We measured time from initial abnormal mammogram or symptom to breast cancer diagnosis. Stage was classified using AJCC criteria. Initial sign of breast cancer modified the association between race/ethnicity and time to diagnosis. Among symptomatic women, median time to diagnosis ranged from 36 days among Whites to 53.6 for Blacks. Among women with abnormal mammograms, median time to diagnosis ranged from 21 days among Whites to 29 for Blacks. Blacks had the highest proportion (26 %) of Stage III or IV tumors. After accounting for time to diagnosis, the observed increased risk of stage III/IV breast cancer was reduced from 40 to 28 % among Hispanics and from 113 to 100 % among Blacks, but estimates remained statistically significant. We were unable to fully account for the higher proportion of late-stage tumors among Blacks. Blacks and Hispanics experienced longer time to diagnosis than Whites, and Blacks were more likely to be diagnosed with late-stage tumors. Longer time to diagnosis did not fully explain differences in stage between racial/ethnicity groups. PMID- 23099440 TI - Investigation of lead contents in lipsticks by solid sampling high resolution continuum source electrothermal atomic absorption spectrometry. AB - In this study, the lead contents of different kinds of lipsticks were determined by solid sampling high resolution continuum source electrothermal atomic absorption spectrometry (SS-HR-CS ET AAS) and the results were compared with those obtained after microwave-assisted acid digestion of the samples. The experimental parameters for solid sampling such as the maximum amount of sample on the platforms of solid autosampler, graphite furnace program were optimized. Samples were directly loaded on the platforms of solid autosampler between 0.25 and 2.0mg and lead was determined applying 800 degrees C for pyrolysis and 2100 degrees C for atomization. Under optimized conditions, interference-free determination could be performed using aqueous standards. The LOD and the characteristic mass were 21.3 and 12.6 pg, respectively. The lead in the same lipstick samples was determined after microwave-assisted acid digestion and compared with those found by solid sampling. Mostly, there was no significant difference between the lead concentrations found by the two techniques. The lead in 25 lipstick samples with different properties were 0.11-4.48 ng mg(-1) which were not significantly different from those (<0.026-7.19 ng mg(-1)) reported by FDA for around 400 samples. PMID- 23099441 TI - Prevalence and occupational predictors of psychological distress in the offshore petroleum industry: a prospective study. AB - OBJECTIVES: This study investigates the prevalence of psychological distress and stressors in the work environment as prospective predictors of distress, among employees in the offshore petroleum industry. METHODS: Correlation and logistic regression analyses were employed to examine longitudinal relationships between stressors and distress in a randomly drawn sample of 741 employees from the Norwegian petroleum offshore industry. Time lag between baseline and follow-up was 6 months. Work environment stressors included safety factors, leadership, and job characteristics. RESULTS: The prevalence of psychological distress was 9 % at baseline and 8 % at follow-up. All investigated work environment factors correlated with subsequent distress. In bivariate logistic regression analyses, caseness of distress was predicted by baseline distress, near miss accidents, risk perception, poor safety climate, tyrannical leadership, laissez-faire leadership, job demands, and workplace bullying. After adjustment for baseline distress, control variables, and other predictors, laissez-faire leadership (OR = 1.69; 95 % CI: 1.12-2.54) and exposure to bullying (OR = 1.49; 95 % CI: 1.07 2.10) emerged as the most robust predictors of subsequent distress. CONCLUSIONS: The findings show that the prevalence of psychological distress is lower among offshore employees than in the general population. Although offshore workers operate in a physically challenging context, their mental health is mainly influenced by stressors in the psychosocial work environment. This highlights the importance of developing and implementing psychosocial safety interventions within the offshore industry. PMID- 23099442 TI - Multiphasic triacylglycerol dynamics in the intact heart during acute in vivo overexpression of CD36. AB - Cardiac triacylglycerol (TAG) stores buffer the intracellular availability of long chain fatty acid (LCFA) that act as nuclear receptor ligands, substrate for lipotoxic derivatives, and high energy-yield fuel. The kinetic characteristics of TAG turnover and homeostatic mechanisms linking uptake and storage dynamics in hearts have until now remained elusive. This work examines TAG pool dynamics in the intact beating heart, under normal conditions and in response to acute gene expression-induced changes in CD36. Dynamic mode (13)C NMR elucidated multiple kinetic processes in (13)C-palmitate incorporation into TAG: an initial, saturable exponential component and a slower linear rate. Although previous work indicates the linear component to reflect TAG turnover, we hypothesized the saturable exponential to reflect transport of LCFA across the sarcolemma. Thus, we overexpressed the LCFA transporter CD36 through cardiac-specific adenoviral infection in vivo. Within 72 h, CD36 expression was increased 40% in intact hearts, accelerating the exponential phase relative to PBS-infused hearts. TAG turnover also increased with elevations in adipose triglyceride lipase (ATGL) and a modest increase in diacylglycerol acyltransferase 1 (DGAT1), without a significant expansion of the intracellular lipid pools. The results demonstrate a dynamic system of reciprocal gene regulation that couples saturable LCFA uptake across the sarcolemma to TAG synthesis/lipolysis rates. PMID- 23099443 TI - Specific Kv1.3 blockade modulates key cholesterol-metabolism-associated molecules in human macrophages exposed to ox-LDL. AB - Cholesterol-metabolism-associated molecules, including scavenger receptor class A (SR-A), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD36, ACAT1, ABCA1, ABCG1, and scavenger receptor class B type I, can modulate cholesterol metabolism in the transformation from macrophages to foam cells. Voltage-gated potassium channel Kv1.3 has increasingly been demonstrated to play an important role in the modulation of macrophage function. Here, we investigate the role of Kv1.3 in modulating cholesterol-metabolism-associated molecules in human acute monocytic leukemia cell-derived macrophages (THP-1 macrophages) and human monocyte-derived macrophages exposed to oxidized LDL (ox-LDL). Human Kv1.3 and Kv1.5 channels (hKv1.3 and hKv1.5) are expressed in macrophages and form a heteromultimeric channel. The hKv1.3-E314 antibody that we had generated as a specific hKv1.3 blocker inhibited outward delayed rectifier potassium currents, whereas the hKv1.5-E313 antibody that we had generated as a specific hKv1.5 blocker failed. Accordingly, the hKv1.3-E314 antibody reduced percentage of cholesterol ester and enhanced apoA-I-mediated cholesterol efflux in THP-1 macrophages and human monocyte-derived macrophages exposed to ox-LDL. The hKv1.3 E314 antibody downregulated SR-A, LOX-1, and ACAT1 expression and upregulated ABCA1 expression in THP-1 macrophages and human monocyte-derived macrophages. Our results reveal that specific Kv1.3 blockade represents a novel strategy modulating cholesterol metabolism in macrophages, which benefits the treatment of atherosclerotic lesions. PMID- 23099445 TI - Caregivers' appraisals of patients' involuntary hospital treatment: European multicentre study. AB - BACKGROUND: Mental health policies emphasise that caregivers' views of involuntary psychiatric treatment should be taken into account. However, there is little evidence on how caregivers view such treatment. AIMS: To explore caregivers' satisfaction with the involuntary hospital treatment of patients and what factors are associated with caregivers' appraisals of treatment. METHOD: A multicentre prospective study was carried out in eight European countries. Involuntarily admitted patients and their caregivers rated their appraisal of treatment using the Client Assessment of Treatment Scale 1 month after admission. RESULTS: A total of 336 patients and their caregivers participated. Caregivers' appraisals of treatment were positive (mean of 8.5 on a scale from 0 to 10) and moderately correlated with patients' views. More positive caregivers' views were associated with greater patients' symptom improvement. CONCLUSIONS: Caregivers' appraisals of involuntary in-patient treatment are rather favourable. Their correlation with patients' symptom improvement may underline their relevance in clinical practice. PMID- 23099444 TI - Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice. AB - Elevated hepatic expression of fatty acid elongase-5 (Elovl5) induces FoxO1 phosphorylation, lowers FoxO1 nuclear content, and suppresses expression of genes involved in gluconeogenesis (GNG). In this report, we define the molecular and metabolic basis of Elovl5 control of FoxO1 phosphorylation. Adenoviral-mediated (Ad-Elovl5) induction of hepatic Elovl5 in diet-induced obese, glucose-intolerant mice and HepG2 cells increased the phosphorylation of Akt2-S(473) [mammalian target of rapamycin complex-2 (mTORC2) site], but not Akt2-T(308) (PDK1 site). The Akt2 inhibitor Akti1/2 blocked Elovl5 induction of FoxO1-S(256) phosphorylation in HepG2 cells. Elevated Elovl5 activity in liver and HepG2 cells induced rictor mRNA, rictor protein, and rictor-mTOR interaction, whereas rictor knockdown (siRNA) attenuated Elovl5 induction of Akt2-S(473) and FoxO1-S(256) phosphorylation in HepG2 cells. FA analysis revealed that the abundance of cis vaccenic acid (18:1,n-7) was increased in livers of obese mice and HepG2 cells following Ad-Elovl5 infection. Treating HepG2 cells with Elovl5 substrates established that palmitoleic acid (16:1,n-7), but not gamma-linolenic acid (18:3,n-6), induced rictor protein, Akt-S(473), and FoxO1-S(256) phosphorylation. Inhibition of FA elongation blocked 16:1,n-7 but not 18:1,n-7 induction of rictor protein and Akt-S(473) and FoxO1-S(256) phosphorylation. These results establish a novel link between Elovl5-mediated synthesis of 18:1,n-7 and GNG through the control of the mTORC2-Akt-FoxO1 pathway. PMID- 23099446 TI - Choice and rejection of psychiatry as a career: surveys of UK medical graduates from 1974 to 2009. AB - BACKGROUND: Recruitment of adequate numbers of doctors to psychiatry is difficult. AIMS: To report on career choice for psychiatry, comparing intending psychiatrists with doctors who chose other clinical careers. METHOD: Questionnaire studies of all newly qualified doctors from all UK medical schools in 12 qualification years between 1974 and 2009 (33 974 respondent doctors). RESULTS: One, three and five years after graduation, 4-5% of doctors specified psychiatry as their first choice of future career. This was largely unchanged across the 35 years. Comparing intending psychiatrists with doctors who chose other careers, factors with a greater influence on psychiatrists' choice included their experience of the subject at medical school, self-appraisal of their own skills, and inclinations before medical school. In a substudy of doctors who initially considered but then did not pursue specialty choices, 72% of those who did not pursue psychiatry gave 'job content' as their reason compared with 33% of doctors who considered but did not pursue other specialties. Historically, more women than men have chosen psychiatry, but the gap has closed over the past decade. CONCLUSIONS: Junior doctors' views about psychiatry as a possible career range from high levels of enthusiasm to antipathy, and are more polarised than views about other specialties. Shortening of working hours and improvements to working practices in other hospital-based specialties in the UK may have reduced the relative attractiveness of psychiatry to women doctors. The extent to which views of newly qualified doctors about psychiatry can be modified by medical school education, and by greater exposure to psychiatry during student and early postgraduate years, needs investigation. PMID- 23099448 TI - Evidence of vascular endothelial dysfunction in young patients with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis (CF) is a genetic disorder that affects not only pulmonary function but also multiple organ systems. The fl ow-mediated dilation (FMD) test is a noninvasive assessment of endothelial function and nitric oxide bioavailability. Thus, the purpose of this study was to determine (1) whether endothelial dysfunction is present in young patients with CF and (2) whether endothelial function is associated with pulmonary function and exercise capacity. METHODS: Fifteen patients with CF and 15 demographically matched control subjects participated in this study. Spirometry, brachial-artery FMD, and a maximal exercise capacity test on a cycle ergometer were performed on all subjects to determine pulmonary function, endothelial function, and exercise capacity, respectively. RESULTS: No differences ( P . .05) in age, height, or BMI were observed between patients with CF and control subjects. FEV 1 (% predicted), FEV 1 /FVC, and forced expiratory fl ow between 25% and 75% of vital capacity were lower in patients with CF. Volume of oxygen consumption peak (absolute and relative) was similar between groups; however, volume of oxygen consumption (% predicted and mL/kg fat-free mass/min) and peak workload were significantly ( P , .05) lower in patients with CF. FMD (4.9% 2.6% vs 7.5% 3.1%; P 5 .018) was lower in patients compared with control subjects, respectively. Relationships between FMD and both pulmonary function and exercise capacity were identified. CONCLUSIONS: For the fi rst time to our knowledge, these data provide evidence of vascular endothelial dysfunction in a fairly healthy cohort of young patients with CF. In addition, our data demonstrate the complex relationships between endothelial function and both pulmonary function and exercise capacity in young patients with CF. PMID- 23099449 TI - Enhancement of root growth and nitrogen fixation in Trigonella by UV-exclusion from solar radiation. AB - A field experiment was conducted to study the impact of solar UV on root growth and nitrogen fixation in Trigonella foenum-graecum. Plants were grown in iron mesh cages covered with polyester filters that could specifically cut off UV-B (280-315 nm) or UV-A + B (280-400 nm) part of the solar spectrum. The control plants were grown under a polythene filter transmissible to UV. Root biomass, number of nodules and nodule fresh weight were enhanced after exclusion of solar UV. Nitrogenase activity was significantly enhanced by 120% and 80% in the UV-B and UV-A + B excluded plants respectively. Along with nitrogenase there was concomitant increase in leghemoglobin and hemechrome content in the nodules after exclusion of solar UV. These components of sunlight limits nitrogen fixation and their elimination can enhance nitrogen fixation with agricultural advantages like reduction in the use of fertilizers. PMID- 23099447 TI - Efficacy and mood conversion rate during long-term fluoxetine v. lithium monotherapy in rapid- and non-rapid-cycling bipolar II disorder. AB - BACKGROUND: Controversy exists over antidepressant use in rapid-cycling bipolar disorder. AIMS: Exploratory analysis of safety and efficacy of fluoxetine v. lithium monotherapy in individuals with rapid- v. non-rapid-cycling bipolar II disorder. METHOD: Randomised, double-blind, placebo-controlled comparison of fluoxetine v. lithium monotherapy in patients initially stabilised on fluoxetine monotherapy (trial registration NCT00044616). RESULTS: The proportion of participants with depressive relapse was similar between the rapid- and non-rapid cycling groups (P = 0.20). The odds of relapse were similar between groups (P = 0.36). The hazard of relapse was similar between groups (hazard ratio 0.87, 95% CI 0.40-1.91). Change in mania rating scores was similar between groups (P = 0.86). There was no difference between groups in the rate of syndromal (P = 0.27) or subsyndromal (P = 0.82) hypomania. CONCLUSIONS: Depressive relapse and treatment-emergent mood conversion episode rates were similar for lithium and fluoxetine monotherapy and placebo during long-term, relapse-prevention therapy of rapid- and non-rapid-cycling bipolar II disorder. PMID- 23099450 TI - Long-term temporal changes of peripapillary retinal nerve fiber layer thickness before and after panretinal photocoagulation in severe diabetic retinopathy. AB - PURPOSE: To analyze the long-term changes of peripapillary retinal nerve fiber layer (RNFL) thickness before and after panretinal photocoagulation (PRP) in patients with severe diabetic retinopathy. METHODS: In this retrospective observational case series, we reviewed the records of 46 patients (68 eyes) with severe diabetic retinopathy, who were treated with PRP and could be followed for more than 6 months. Peripapillary RNFL thickness and foveal thickness were measured at baseline, 3-month intervals until 1 year post-PRP, and 6- to 12-month intervals after 1 year post-PRP using optical coherence tomography. Long-term changes of peripapillary RNFL thickness and foveal thickness as well as the correlation between the two parameters were analyzed. RESULTS: The average RNFL thickness (360 degrees measurement) decreased significantly from 108.4 MUm to 103.5 MUm at 2 years post-PRP. The average RNFL thickness increased slightly during the initial 3 months post-PRP and thereafter gradually decreased, showing statistically significant reductions at 2 years post-PRP (false discovery rate adjusted P = 0.0051). The superior and inferior quadrant RNFL thicknesses were significantly decreased at 2 years post-PRP (false discovery rate adjusted P = 0.0119 and 0.0051, respectively). The decrease in the nasal quadrant RNFL thickness showed borderline significance at 2 years post-PRP (false discovery rate adjusted P = 0.0854). However, there was no significant decrease in RNFL thickness for the temporal quadrant at any follow-up time. In addition, there was no significant difference in the foveal thickness. But, the pattern of temporal changes in foveal thickness showed a similar pattern with that of temporal RNFL thickness. CONCLUSION: This study shows that average RNFL thickness after PRP undergoes early thickening and subsequent progressive thinning throughout the 2 years post-PRP. This temporal change varies according to the peripapillary RNFL quadrant. Our results also indicate that temporal RNFL and foveal thickness have a similar pattern of long-term change after PRP. PMID- 23099451 TI - Pharmacokinetic comparison of ketorolac after intracameral, intravitreal, and suprachoroidal administration in rabbits. AB - PURPOSE: To investigate the concentrations and pharmacokinetics of ketorolac in the rabbits by three different routes of administrations: a single intracameral, intravitreal, and suprachoroidal injection. METHODS: Fifty-four New Zealand white rabbits received ketorolac (250 MUg/0.05 mL) in one eye by a single intracameral injection (group A, n = 18), single intravitreal injection (group B, n = 18), and single suprachoroidal injection (group C, n = 18). Drug concentrations in the vitreous, retina-choroid (RC), and plasma were determined by the methods of high performance liquid chromatography at 0.5, 1, 2, 4, 8, and 24 hours after injection. The concentrations in the opposite eyes were also investigated. RESULTS: The mean maximum concentrations (Cmax) of ketorolac in the vitreous and RC were 0.378 +/- 0.19 MUg/mL and 3.15 +/- 0.49 MUg/g (at 0.5 hours), respectively, in group A; 156.2 +/- 20.74 MUg/mL (at 0.5 hours) and 208.0 +/- 21.67 MUg/g (at 1 hours), respectively, in group B; and 0.873 +/- 0.34 MUg/mL and 56.71 +/- 22.64 MUg/g (at 0.5 hours), respectively, in group C. In the RC, the area under the curve (AUC0-t) in group B (866.1 +/- 52.67 MUg/g.h) was higher (P < 0.01) than that in group C (77.10 +/- 25.90 MUg/g.h). The elimination half-life (t1/2) in group B (3.09 hours) was longer (P < 0.01) than that in group C (1.19 hours). In the control eyes, a drug level below 2 MUg/g was detected in the RC in group C. Plasma concentrations were below 0.4 MUg/mL in all 3 groups. Ketorolac was detectable in the RC till 24 hours after the intravitreal injection and 8 hours after the suprachoroidal injection. CONCLUSION: Intravitreal injection of ketorolac produced higher intraocular drug concentrations for a longer period compared with the other two routes. Suprachoroidal injection of ketorolac could reach an effective drug level in the RC with short half-lives and low drug levels in the vitreous. The plasma drug concentrations were low by all three routes. PMID- 23099452 TI - New synthesis: plant volatiles as functional cues in intercropping systems. PMID- 23099453 TI - Digital biology: a new era has begun. PMID- 23099454 TI - Performance, personality, and energetics: correlation, causation, and mechanism. AB - The study of phenotypic evolution should be an integrative endeavor that combines different approaches and crosses disciplinary and phylogenetic boundaries to consider complex traits and organisms that historically have been studied in isolation from each other. Analyses of individual variation within populations can act to bridge studies focused at the levels of morphology, physiology, biochemistry, organismal performance, behavior, and life history. For example, the study of individual variation recently facilitated the integration of behavior into the concept of a pace-of-life syndrome and effectively linked the field of energetics with research on animal personality. Here, we illustrate how studies on the pace-of-life syndrome and the energetics of personality can be integrated within a physiology-performance-behavior-fitness paradigm that includes consideration of ecological context. We first introduce key concepts and definitions and then review the rapidly expanding literature on the links between energy metabolism and personality traits commonly studied in nonhuman animals (activity, exploration, boldness, aggressiveness, sociability). We highlight some empirical literature involving mammals and squamates that demonstrates how emerging fields can develop in rather disparate ways because of historical accidents and/or particularities of different kinds of organisms. We then briefly discuss potentially interesting avenues for future conceptual and empirical research in relation to motivation, intraindividual variation, and mechanisms underlying trait correlations. The integration of performance traits within the pace-of-life-syndrome concept has the potential to fill a logical gap between the context dependency of selection and how energetics and personality are expected to interrelate. Studies of how performance abilities and/or aspects of Darwinian fitness relate to both metabolic rate and personality traits are particularly lacking. PMID- 23099455 TI - The relationship between phenotypic and environmental variation: do physiological responses reduce interindividual differences? AB - What is the effect of a variable environment on phenotypic variation? Does the physiological response to a new environment increase or decrease the differences among individuals? We provide a speculative hypothesis suggesting that the induction of a physiological response to environmental change minimizes phenotypic differences among individuals in outbred genetically variable populations. Although this suggestion runs counter to the general idea that environmental variation induces phenotypic variation, we provide evidence that this is not always the case. One explanation for this counterintuitive hypothesis is that in a variable environment, the physiological mechanism that maintains homeostasis changes the concentrations of active transcription factors (TFs). This change in TFs reduces the effectiveness of nucleotide polymorphisms in TF binding sites and thus reduces the variation among individuals in mRNA expression and in the phenotypes affected by these mRNA transcripts. Thus, there are fewer differences among individuals in a variable environment compared with the variation observed in a constant environment. Our conjecture is that the physiological mechanisms that maintain homeostasis in response to environmental variation canalize phenotypic variation. If our hypothesis is correct, then the physiological canalization of gene expression in a variable environment hides genetic variation and thereby reduces the evolutionary costs of polymorphism. This hypothesis provides a new perspective on the mechanisms by which high levels of genetic variation can persist in real-world populations. PMID- 23099456 TI - Why do some fish fight more than others? AB - Reversible changes in how readily animals fight can be explained in terms of adaptive responses to differences in the costs and benefits of fighting. In contrast, long-term differences in aggressiveness raise a number of questions, including why animals are consistent with respect to this trait, why aggressiveness is often linked to general risk taking, and why aggressive and nonaggressive animals often coexist within a population. In fish, different levels of aggressiveness bring several direct fitness-related consequences, such as when aggressive individuals monopolize a limited food supply and grow fast. They also bring indirect consequences, such as when aggressive fish are more susceptible to predation and when they require a larger respiratory surface to service a higher metabolic rate. Fitness consequences of aggressiveness are often context dependent, with aggressive fish tending to do well in simple, predictable conditions but not in complex, less predictable conditions. The diverse, context dependent consequences of aggression mean that aggressive and nonaggressive fish flourish in different conditions and explain in general terms why these behavioral phenotypes often coexist. There are a number of candidate evolutionary frameworks for explaining why individual differences in aggressiveness are often, but not always, consistent over time and often, but not always, linked to differences in general risk taking. PMID- 23099457 TI - Variation in thermal performance among insect populations. AB - Among-population variation in insect thermal performance is important for understanding patterns and mechanisms of evolution and predicting insect responses to altered climate regimes in future or novel environments. Here we review and discuss several key examples of among-population variation in insect thermal performance, including latitudinal gradients in chill coma recovery time, variation in energy consumption and metabolic biochemistry, rapid changes in thermal biology with range expansion in invasive and introduced species, and potential constraints on variation in thermal performance traits. This review highlights that while there is substantial evidence for among-population variation that is generally correlated with local climate regimes, neither the underlying mechanisms nor the implications for whole-animal fitness in the field are well understood. We also discuss the potential limitations of interpreting evolved variation among populations and argue for a genes-to-environment approach to population-level variation in thermal biology of insects. PMID- 23099458 TI - Thermal physiology of warm-spring colonists: variation among lake chub (Cyprinidae: Couesius plumbeus) populations. AB - In northern Canada, lake chub (Cyprinidae: Couesius plumbeus) have colonized a variety of thermal springs that differ substantially from the ancestral environment in both mean temperature and thermal variation. To examine whether this environmental change is associated with differences in physiological traits, we compared the thermal breadth, capacity for acclimation of thermal tolerance, and metabolic enzymes in populations of lake chub from three habitats: a warm but variable hot spring, a thermally constant warm spring, and a seasonally variable temperate lake. Thermal breadth was generally lowest in fish from the constant environment, and this difference was statistically significant in fish acclimated at 10 degrees and 25 degrees C. Critical thermal maximum (CT(max)) increased with increasing acclimation temperature in all populations. CT(max) was similar among populations when acclimated at high temperatures but greater in the variable-spring population acclimated to low temperature (10 degrees C). Critical thermal minimum was also dependent on acclimation temperature in all populations but differed among populations such that fish from the stable-spring habitat were not as tolerant to cold temperature when acclimated to 25 degrees C. Temperate- and variable-spring populations showed an increase in mitochondrial enzyme activities (citrate synthase and cytochrome c oxidase) with decreasing acclimation temperature, but this response was absent in the stable-temperature population. Protein content did not change with acclimation temperature in the stable-temperature population, while it increased with decreasing acclimation temperature in both variable thermal habitat populations. Our study suggests that interpopulation variation in thermal physiology is associated with habitat thermal variability. PMID- 23099459 TI - Geographic variation in the association between exploratory behavior and physiology in rufous-collared sparrows. AB - Increasing research has attempted to clarify the links between animal personality and physiology. However, the mechanisms driving this association remain largely unknown, and knowledge of how ecological factors may affect its direction and strength is scant. In this study, we quantified variation in the association between exploratory behavior, basal metabolic rate (BMR), and total evaporative water loss (TEWL) in rufous-collared sparrows (Zonotrichia capensis) inhabiting desert, Mediterranean, and cold-temperate climates. We found that the exploratory behavior score was highest in birds from the cold-temperate site, which was characterized by a moderate level of ecological variability (seasonality). Moreover, the association between exploratory behavior and physiological variables differed among localities. Only birds from the Mediterranean site showed a positive correlation between exploratory behavior and BMR. We found no association between exploration and TEWL at any study site. Our findings suggest that differences in the ecological conditions experienced by each sparrow population result in a particular combination of behavioral and physiological traits. An understanding of this intraspecific variation along ecological gradients provides unique insights into how specific ecological conditions affect the coupling of behavioral and physiological traits and the mechanisms underlying that relationship. PMID- 23099460 TI - Transgenerational variation in metabolism and life-history traits induced by maternal hypoxia in Daphnia magna. AB - Hypoxic stress can alter conspecific phenotype and additionally alter phenotypes of the filial generation, for example, via maternal or epigenetic processes. Lasting effects can also be seen across development and generations even after stressors have been removed. This study utilized the model of rapidly developing, parthenogenetic Daphnia to examine the intraspecific variability of response of exposure of a parental generation to hypoxia (4 kPa) within a single clone line across development, across broods, and across generations. Body mass across development and reproductive output were monitored in the parental generation and the first three broods of the first filial generation (which were not directly exposed to hypoxia). O(2) consumption across a wide Po(2) range (normoxia to anoxia) was assessed to determine whether exposure of the parental generation to hypoxia conferred hypoxia tolerance on the offspring and whether this transgenerational, epigenetic phenomenon varied intraspecifically. Differences in mass occurred in both the parental generation (hypoxia-exposed smaller during brood 1 and brood 2 neonate production) and the filial generation (e.g., brood 1 and 2 neonates from hypoxic mothers were initially smaller than control neonates). However, differences in mass were not accompanied by changes in reproductive output (assessed by brood number and neonate size). At day 0, first filial generation brood 1 neonates from hypoxia-exposed mothers had a higher metabolic rate than control neonates. However, this effect, like that of body mass, dissipated with development within a brood but also with subsequent broods. An isometric scaling exponent for [Formula: see text] was repeatedly observed across a wide Po(2) range (21-2 kPa) throughout neonatal development. PMID- 23099461 TI - Ontogenetic oxygen changes alter zebra fish size, behavior, and blood glucose. AB - Four male and four female zebra fish were crossed in all possible combinations, resulting in 389 offspring. These offspring were divided among four treatments: normoxia for 90 d, hypoxia for 90 d, normoxia for 30 d followed by hypoxia for 60 d, and hypoxia for 30 d followed by normoxia for 60 d. The effects of early oxygen environment, later oxygen environment, and genotype were then assessed with respect to zebra fish behavior, size, and blood glucose. Fish were tested in an arena where they could shoal with conspecifics before, during, and after the introduction of a novel stimulus. Blood glucose and size were also measured. Early oxygen environment influenced fish size, time spent swimming, and reactivity to a novel stimulus. Environmentally induced plasticity was predominate, with little evidence of among-sire variation for any of the measured parameters. PMID- 23099462 TI - Intraspecific variation in aerobic metabolic rate of fish: relations with organ size and enzyme activity in brown trout. AB - Highly active animals require a high aerobic capacity (i.e., a high maximum metabolic rate [MMR]) to sustain such activity, and it has been speculated that a greater capacity for aerobic performance is reflected in larger organs, which serve as energy processors but are also expensive to maintain and which increase the minimal cost of living (i.e., the basal or standard metabolic rate [SMR]). In this study, we assessed the extent of intraspecific variation in metabolic rate within a group of brown trout (Salmo trutta L.) and tested whether the observed variation in residual (body-mass-corrected) SMR, MMR, and absolute aerobic scope could be explained by variations in the residual size (mass) of metabolically active internal organs. Residual SMR was found to correlate positively with residual MMR, indicating a link between these two metabolic parameters, but no relationship between organ mass and metabolic rate was found for liver, heart, spleen, intestine, or stomach. Instead, activity in the liver of two aerobic mitochondrial enzymes, cytochrome c oxidase and, to a lesser extent, citrate synthase, was found to correlate with whole-animal metabolic rate, indicating that causes for intraspecific variation in the metabolic rate of fish can be found at a lower organizational level than organ size. PMID- 23099463 TI - Morphological and physiological idiosyncrasies lead to interindividual variation in flight metabolic rate in worker bumblebees (Bombus impatiens). AB - Although intraspecific variation in metabolic rate is associated with variation in body size, similarly sized individuals nonetheless vary greatly. At similar masses, hovering bumblebee workers (Bombus impatiens) can differ in metabolic rate up to twofold. We examined how such interindividual variation arises by studying covariation of flight metabolic rate with morphological and other physiological parameters. Body size alone explained roughly half the variation in flight metabolic rate. The remaining variation could be explained as the outcome of variation in wing morphology and possibly an association with variation in flight muscle metabolic enzyme activities. As shown using statistical models, for a given mass, higher metabolic rate was correlated with both higher thoracic temperature and higher wing stroke frequency, in turn resulting from smaller wing surface area. When organismal and cellular metabolism for a given mass were linked, variation in metabolic rate was positively correlated with the activities of trehalase and hexokinase. Altogether, covariation with morphology and other physiological parameters explains up to 75% of the variation in metabolic rate. We also investigated the role of flight experience and show that neither flight restriction nor the number of lifetime flights affected flight energetics or flight muscle phenotype. Additionally, manipulating the level of wing asymmetry increased flight wing stroke frequency, metabolic rate, and thoracic temperature, but it did not alter enzyme activity. We conclude that idiosyncrasies in body morphology largely explained interindividual variation in flight metabolic rate but flight muscle metabolic phenotype shows little variation associated with differences in flight experience. PMID- 23099464 TI - Glucocorticoids, aerobic physiology, and locomotor behavior in California mice. AB - The glucocorticoid hormones corticosterone (CORT) and cortisol influence numerous physiological, morphological, and behavioral functions. However, few studies have addressed possible relationships between individual differences in glucocorticoid concentrations and whole-animal performance or metabolism. Because CORT is important in glucose regulation and energy metabolism and can influence activity levels, we hypothesized that individual variation in baseline circulating CORT levels would correlate with individual differences in energy expenditure (routine and maximal), aerobic physiology, voluntary exercise on wheels, and organ masses. We tested this hypothesis in the California mouse (Peromyscus californicus). We collected data from 54 adult, colony-bred mice on baseline CORT levels (measured near both the circadian peak and the circadian trough), voluntary wheel running and its energetic costs, maximal oxygen consumption during forced treadmill exercise ([Formula: see text]), basal metabolic rate, and relative organ masses. We found surprisingly few statistically significant relationships among CORT, energy metabolism, behavior, and organ masses, and these relationships appeared to differ between males and females. These findings suggest that individual differences in baseline CORT levels are not an important determinant of voluntary activity levels or aerobic performance in California mice. PMID- 23099465 TI - As the sword grows: individual variation and ontogenetic effects of a sexually selected trait on locomotor performance in Xiphophorus hellerii. AB - Previous studies aimed at detecting costs of sexually selected traits have yielded mixed results partly because of variable methods. We present a novel approach: a repeated-measures design to examine individual variation in locomotor performance of male Xiphophorus hellerii as the sexually selected sword develops ontogenetically and to determine whether the growth of a sexually selected trait alters consistency of performance. Individual differences in sprint speed, critical swimming speed (stamina), and relative sword length were statistically repeatable over 9 wk. However, using the Akaike Information Criterion corrected for small sample sizes, the best-fit predictive models for swimming performance did not include sword length or relative sword length. Furthermore, in less supported models and within-week comparisons, there was no statistically significant effect of sword length on performance. These results suggest little effect of the sword on locomotor abilities, which is inconsistent with results from some previous experimental manipulations, possibly because compensatory traits develop ontogenetically in parallel with the sword. However, our results are consistent with correlational studies of natural variation that suggest no locomotor cost of the sword. These results do not necessarily imply a complete lack of a cost to the sword but rather lack of a functional cost for swimming performance. PMID- 23099466 TI - Variation in fast-start performance within a population of polyphenic bluegill (Lepomis macrochirus). AB - Bluegill sunfish Lepomis macrochirus exhibit intraspecific variation in their morphology and swimming performance based on habitat. The pelagic form has a relatively streamlined, fusiform body shape associated with greater steady-state swimming speed and energy economy. In contrast, littoral bluegill have deeper bodies with fins located farther from their center of mass to enhance maneuverability among littoral vegetation. Deeper body shapes have been associated with increased fast-start performance to escape predators or capture prey. We hypothesized that littoral bluegill, which have a deeper body shape, would exhibit greater fast-start performance than pelagic bluegill. A total of 29 bluegill (16 littoral, 13 pelagic) were caught by hook and line, and their fast start performance was analyzed from high-speed video recordings. Body shape appears to be a poor predictor of fast-start performance. Contrary to our expectations, pelagic bluegill had a significantly higher peak velocity, peak acceleration, and angular velocity compared to littoral bluegill. Pelagic bluegill living among larger predators and foraging on mobile prey may be exposed to selection pressures that favor increased fast-start performance. Integrated studies of internal morphology and physiology are needed to fully understand the relationship between morphology and performance in this population. PMID- 23099467 TI - Acceleration performance of individual European sea bass Dicentrarchus labrax measured with a sprint performance chamber: comparison with high-speed cinematography and correlates with ecological performance. AB - Locomotor performance can influence the ecological and evolutionary success of a species. For fish, favorable outcomes of predator-prey encounters are often presumably due to robust acceleration ability. Although escape-response or "fast start" studies utilizing high-speed cinematography are prevalent, little is known about the contribution of relative acceleration performance to ecological or evolutionary success in a species. This dearth of knowledge may be due to the time-consuming nature of analyzing film, which imposes a practical limit on sample sizes. Herein, we present a high-throughput potential alternative for measuring fish acceleration performance using a sprint performance chamber (SPC). The acceleration performance of a large number of juvenile European sea bass (Dicentrarchus labrax) from two populations was analyzed. Animals from both hatchery and natural ontogenies were assessed, and animals of known acceleration ability had their ecological performance measured in a mesocosm environment. Individuals from one population also had their acceleration performance assessed by both high-speed cinematography and an SPC. Acceleration performance measured in an SPC was lower than that measured by classical high-speed video techniques. However, short-term repeatability and interindividual variation of acceleration performance were similar between the two techniques, and the SPC recorded higher sprint swimming velocities. Wild fish were quicker to accelerate in an SPC and had significantly greater accelerations than all groups of hatchery-raised fish. Acceleration performance had no significant effect on ecological performance (as assessed through animal growth and survival in the mesocosms). However, it is worth noting that wild animals did survive predation in the mesocosm better than farmed ones. Moreover, the hatchery-originated fish that survived the mesocosm experiment, when no predators were present, displayed significantly increased acceleration performance during their 6 mo in the mesocosm; this performance was found to be inversely proportional to growth rate. PMID- 23099468 TI - Is behavioral variation along the bold-shy continuum associated with variation in the stress axis in zebrafish? AB - We tested whether boldness is associated with attenuation of the physiological stress response in behaviorally selected lines of zebrafish Danio rerio. We measured three component behaviors of boldness: cortisol levels under control and stressed conditions, growth rate, and expression of key genes linked to the hypothalamic-pituitary-interrenal axis in the brain. Surprisingly, bold animals did not differ from shy animals with respect to cortisol levels. However, significant differences between these animals in the expression of glucocorticoid receptors and genes that regulate production of stress hormones indicate that there may still be a relationship between bold behavior and the stress axis. Perhaps the most surprising result of this study was the degree of sexual dimorphism: female zebrafish were bolder than male zebrafish, had significantly lower levels of cortisol, and differed significantly in the expression of several genes in the brain. Our data indicate that a bold behavioral type is associated with transcriptional attenuation of stress axis genes, but we do not yet know whether evolution along the bold-shy continuum is attributable to genetic changes in the stress axis. The bold and shy zebrafish lines will be valuable tools for additional research into the relationship between stress and behavior and the mechanisms regulating sexual dimorphism in these traits. PMID- 23099469 TI - Population-specific consequences of fisheries-related stressors on adult sockeye salmon. AB - The objective of this study was to determine whether fisheries-related stressors differently influence two populations of adult sockeye salmon (Oncorhynchus nerka) with shared migration timing and location but where one population (i.e., Harrison) spawns 1 mo after the other (i.e., Weaver). Four stressor treatments were used following beach seine capture: (1) immediate release, (2) release after 10-15 min in the beach seine, (3) an additional 3-min gill net entanglement and 1 min air exposure, and (4) an additional 3-min tangle net simulation and 1-min air exposure. A comprehensive acoustic telemetry array and manual tracking revealed that survival was low overall, with more Weaver fish (34.2% of 38 tagged) reaching spawning areas compared to Harrison fish (17.8% of 78 tagged). For the Harrison population but not the Weaver, the gill net treatment influenced immediate (i.e., survived treatment) and short-term (i.e., 5-d postrelease) survival as well as survival to reach spawning areas. Harrison fish were more likely to be injured by the treatment, and reflex impairment predicted their short-term and long-term survival. Physiological condition did not differ between populations at the time of release, although both populations showed signs of severe physiological disturbances from the gill and tangle net simulations. These results suggest that even short durations of gill or tangle net entanglement can result in profound population-specific physiological disturbances and mortality. The notion that there can be population-specific variation in response to fisheries encounters adds complexity to management and provides further evidence for intraspecific differences in migration success. PMID- 23099470 TI - Individual variation in paternal responses of virgin male California mice (Peromyscus californicus): behavioral and physiological correlates. AB - California mice Peromyscus californicus are a rodent species in which fathers provide extensive paternal care; however, behavioral responses of virgin males toward conspecific neonates vary from paternal behavior to tolerance to infanticide. Indirect evidence suggests that paternal responses might be influenced by social status potentially through increased stress and anxiety in subordinate males. To test this hypothesis, we housed 12 virgin male California mice in same-sex dyads on weaning and assessed their within-dyad subordinate or dominant status using food-competition and urine-marking tests. In addition, behavioral responses to an unrelated pup, expression of vasopressin (AVP) and corticotropin-releasing hormone (CRH) mRNA in the paraventricular hypothalamic nucleus (PVN), basal plasma levels of testosterone and corticosterone, and body mass were measured. Food-competition and urine-marking tests did not reveal strong or stable dominance-subordination relationships in male-male dyads. Latency to sniff a newborn pup was correlated negatively with urine marking in the center of a novel environment and positively with expression of AVP mRNA in the PVN. Because these three parameters are all associated with state anxiety in other rodent species, these results suggest that individual differences in paternal responsiveness may be influenced by individual differences in anxiety but not necessarily by social status in virgin male California mice. PMID- 23099472 TI - The crucial roles of IFN-gamma in the development of M3 muscarinic acetylcholine receptor induced Sjogren's syndrome-like sialadenitis. PMID- 23099471 TI - Monitoring C-reactive protein levels to predict favourable clinical outcomes from tocilizumab treatment in patients with rheumatoid arthritis. AB - OBJECTIVES: The inflammatory cytokine interleukin-6 (IL-6) directly stimulates C reactive protein (CRP) expression. The present study aimed to examine how clinical treatment outcomes of rheumatoid arthritis (RA) with tocilizumab (TCZ), a humanised monoclonal anti-IL-6 receptor antibody, are related to CRP levels monitored for 52 weeks. METHODS: One hundred and twenty-two RA patients who underwent TCZ treatment between May 2008 and September 2009 were registered in the Tsurumai Biologics Communication Registry. Data were collected at initiation of treatment (baseline) and over 52 weeks for Disease Activity Score 28-ESR (DAS28-ESR), Boolean core measurements, serum CRP levels and matrix metalloproteinase-3 levels. To compare clinical results, patients were divided into three groups based on treatment time required to achieve normal CRP levels. RESULTS: Multivariate analysis using the Cox proportional-hazards regression model found that higher CRP levels at baseline was a significant and independent factor in predicting normal CRP levels over 52 weeks (hazard ratio 0.86 per 1 mg/dL). In contrast, disease duration, concomitant methotrexate use and previous tumour necrosis factor inhibitor failure were not significant factors. Patients with normal CRP levels at 12 weeks of TCZ treatment achieved better clinical outcomes, including remission based on DAS28-ESR criteria, compared to patients with elevated CRP levels at 12 weeks. CONCLUSIONS: Adequate suppression of pathological IL-6 signalling during TCZ treatment improves clinical outcomes and can be monitored with serum CRP levels, a readily available biomarker in clinical practice. PMID- 23099473 TI - Crystal structure of the ionic liquid EtNH3NO3-insights into the thermal phase behavior of protic ionic liquids. AB - The crystal structure of the salt ethylammonium nitrate (EtNH(3)NO(3)) has been determined. EtNH(3)NO(3) is one of the most widely studied protic ionic liquids (PILs)-ILs formed by proton transfer from a Bronsted acid to a Bronsted base. The structural features from the crystal structure, in concert with a Raman spectroscopic analysis of the ions, provide direct insight as to why EtNH(3)NO(3) melts below ambient temperature, while other related salts (such as EtNH(3)Cl) do not. PMID- 23099475 TI - Vertical etching with isolated catalysts in metal-assisted chemical etching of silicon. AB - Metal assisted chemical etching with interconnected catalyst structures has been used to create a wide array of organized nanostructures. However, when patterned catalysts are not interconnected, but are isolated instead, vertical etching to form controlled features is difficult. A systematic study of the mechanism and catalyst stability of metal assisted chemical etching (MACE) of Si in HF and H(2)O(2) using Au catalysts has been carried out. The effects of the etchants on the stability of Au catalysts were examined in detail. The role of excess electronic holes as a result of MACE was investigated via pit formation as a function of catalyst proximity and H(2)O(2) concentration. We show that a suppression of excess holes can be achieved by either adding NaCl to or increasing the HF concentration of the etching solution. We demonstrate that an electric field can direct most of the excess holes to the back of the Si wafer and thus reduce pit formation at the surface of Si between the Au catalysts. The effect of hydrogen bubbles, generated as a consequence of MACE, on the stability of Au catalysts has also been investigated. We define a regime of etch chemistry and catalyst spacing for which catalyst stability and vertical etching can be achieved. PMID- 23099474 TI - The impact of sleep duration in obstructive sleep apnea patients. AB - PURPOSE: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease. Strong associations have been reported among sleep duration, hypertension, obesity, and cardiovascular mortality. The authors hypothesize that sleep duration may play a role in OSA severity. The aim of this study is to analyze sleep duration in OSA patients. METHODS: Patients who underwent overnight polysomnography were consecutively selected from the Sleep Clinic of Universidade Federal de Sao Paulo database between March 2009 and December 2010. All subjects were asked to come to the Sleep Clinic at 8:00 a.m. for a clinical evaluation and actigraphy. Anthropometric parameters such as weight, height, hip circumference, abdominal circumference, and neck circumference were also measured. RESULTS: One hundred thirty-three patients were divided into four groups based on total sleep time, sleep efficiency, sleep latency, and wake after sleep onset: very short sleepers (n = 11), short sleepers (n = 21), intermediate sleepers (n = 56), and sufficient sleepers (n = 45). Apnea-hypopnea index (AHI) was higher in very short sleepers (50.18 +/- 30.86 events/h) compared with intermediate sleepers (20.36 +/ 14.68 events/h; p = 0.007) and sufficient sleepers (23.21 +/- 20.45 events/h; p = 0.02). Minimal and mean arterial oxygen saturation and time spent below 90 % oxygen saturation exhibited worse values in very short sleepers. After adjustment for gender, age, AHI, and body mass index, mean oxygen saturation was significantly associated to total sleep time (p = 0.01). CONCLUSIONS: In conclusion, the present study suggests that sleep duration may be associated to low mean oxygen saturation in OSA patients. PMID- 23099476 TI - Antigen processing and presentation by dendritic cells is independent of coronin 1. AB - Coronin 1, which is a member of the evolutionary conserved coronin protein family that is highly expressed in all leukocytes is involved in the activation of the Ca(2+)/calcineurin signaling pathway following cell surface stimulation in T cells, B cells as well as macrophages. Mice deficient for coronin 1 have strongly reduced peripheral T cell numbers as a result of a lack of pro-survival signals for naive T cells. Whether or not impaired antigen processing and presentation in the absence of coronin 1 expression contributes to this reduction of T cell numbers is unknown. We here show that coronin 1-deficient bone marrow-derived dendritic cells develop normally, and that wild type and coronin 1-deficient dendritic cells were equally able to induce antigen-specific proliferation of T cells. Furthermore, upon immunization, in vivo proliferation of adoptively transferred antigen-specific T cells was comparable in wild type and coronin 1 deficient mice. Finally, infection of wild type and coronin 1-deficient dendritic cells with an ovalbumin-expressing Listeria monocytogenes strain induced comparable levels of ovalbumin-specific T cells responses. Together these results suggest that coronin 1 is dispensable for antigen processing and presentation by dendritic cells. PMID- 23099477 TI - Identification of IL-34 in teleost fish: differential expression of rainbow trout IL-34, MCSF1 and MCSF2, ligands of the MCSF receptor. AB - The mononuclear phagocyte system is composed of monocytes, macrophages and dendritic cells and has crucial roles in inflammation, autoimmunity, infection, cancer, organ transplantation and in maintaining organismal homeostasis. Interleukin-34 (IL-34) and macrophage colony stimulating factor (MCSF), both signalling through the MCSF receptor, regulate the mononuclear phagocyte system. A single IL-34 and MCSF gene are present in tetrapods. Two types of MCSF exist in teleost fish which is resulted from teleost-wide whole genome duplication. In this report, we first identified and sequence analysed six IL-34 genes in five teleost fish, rainbow trout, fugu, Atlantic salmon, catfish and zebrafish. The fish IL-34 molecules had a higher identity within fish group but low identities to IL-34s from birds (27.2-33.8%) and mammals (22.2-31.4%). However, they grouped with tetrapod IL-34 molecules in phylogenetic tree analysis, had a similar 7 exon/6 intron gene organisation, and genes in the IL-34 loci were syntenically conserved. In addition, the regions of the four main helices, along with a critical N-glycosylation site were well conserved. Taken together these data suggest that the teleost IL-34 genes described in this report are orthologues of tetrapod IL-34. Comparative expression study of the three trout MCSFR ligands revealed that IL-34, MCSF1 and MCSF2 are differentially expressed in tissues and cell lines. The expression of MCSF1 and MCSF2 showed great variance in different tissues and cell lines, suggesting a role in the differentiation and maintenance of specific macrophage lineages in specific locations. The relatively high levels of IL-34 expression across different tissues suggests a homeostatic role of IL-34 for the macrophage lineage in fish. One striking observation in the present study was the lack of induction of MCSF1 and MCSF2 expression but the quick induction of IL-34 expression by PAMPs and inflammatory cytokines in cell lines and primary head kidney macrophages in rainbow trout. In a parasitic proliferative kidney disease (PKD) model, the expression of IL-34 but not the dominant MCSF2 was affected by PKD, suggesting an involvement of macrophage function in this disease model. Thus IL-34 expression is sensitive to inflammatory stimuli and may regulate macrophage biology once up-regulated. PMID- 23099478 TI - Quantitative evaluation of proteins with bicinchoninic acid (BCA): resonance Raman and surface-enhanced resonance Raman scattering-based methods. AB - A rapid and highly sensitive bicinchoninic acid (BCA) reagent-based protein quantitation tool was developed using competitive resonance Raman (RR) and surface-enhanced resonance Raman scattering (SERRS) methods. A chelation reaction between BCA and Cu(+), which is reduced by protein in an alkaline environment, is exploited to create a BCA-Cu(+) complex that has strong RR and SERRS activities. Using these methods, protein concentrations in solutions can be quantitatively measured at concentrations as low as 50 MUg mL(-1) and 10 pg mL(-1). There are many advantages of using RR and SERRS-based assays. These assays exhibit a much wider linear concentration range and provide an additional one (RR method) to four (SERRS method) orders of magnitude increase in detection limits relative to UV-based methods. Protein-to-protein variation is determined using a reference to a standard curve at concentrations of BSA that exhibits excellent recoveries. These novel methods are extremely accurate in detecting total protein concentrations in solution. This improvement in protein detection sensitivity could yield advances in the biological sciences and medical diagnostic field and extend the applications of reagent-based protein assay techniques. PMID- 23099479 TI - Effective treatment of edema and endothelial barrier dysfunction with imatinib. AB - BACKGROUND: Tissue edema and endothelial barrier dysfunction as observed in sepsis and acute lung injury carry high morbidity and mortality, but currently lack specific therapy. In a recent case report, we described fast resolution of pulmonary edema on treatment with the tyrosine kinase inhibitor imatinib through an unknown mechanism. Here, we explored the effect of imatinib on endothelial barrier dysfunction and edema formation. METHODS AND RESULTS: We evaluated the effect of imatinib on endothelial barrier function in vitro and in vivo. In human macro- and microvascular endothelial monolayers, imatinib attenuated endothelial barrier dysfunction induced by thrombin and histamine. Small interfering RNA knock-downs of the imatinib-sensitive kinases revealed that imatinib attenuates endothelial barrier dysfunction via inhibition of Abl-related gene kinase (Arg/Abl2), a previously unknown mediator of endothelial barrier dysfunction. Indeed, Arg was activated by endothelial stimulation with thrombin, histamine, and vascular endothelial growth factor. Imatinib limited Arg-mediated endothelial barrier dysfunction by enhancing Rac1 activity and enforcing adhesion of endothelial cells to the extracellular matrix. Using mouse models of vascular leakage as proof-of-concept, we found that pretreatment with imatinib protected against vascular endothelial growth factor-induced vascular leakage in the skin, and effectively prevented edema formation in the lungs. In a murine model of sepsis, imatinib treatment (6 hours and 18 hours after induction of sepsis) attenuated vascular leakage in the kidneys and the lungs (24 hours after induction of sepsis). CONCLUSIONS: Thus, imatinib prevents endothelial barrier dysfunction and edema formation via inhibition of Arg. These findings identify imatinib as a promising approach to permeability edema and indicate Arg as novel target for edema treatment. PMID- 23099480 TI - Physical stability, antioxidative properties, and photoprotective effects of a functionalized formulation containing black garlic extract. AB - When garlic is fermented, certain aspects of its bioactivity are changed. Black garlic is a type of fermented garlic used as a food ingredient in Asian cuisine. Black garlic's popularity has spread around the world as it has become a sought after ingredient used in high-end cuisine. The formulations containing 10% black garlic extract or 10% normal garlic extract showed stable pH, color, precipitation, and organoleptic features, although these characteristics changed slightly. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2-azino-bis-(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activities of the black garlic formulation were significantly (p<0.05) higher compared to those of the base formulation and normal garlic formulation. Mice treated with the black garlic formulation (119.63 MUM/g) had significant (p<0.05) decreases in thiobarbituric acid reactive substance (TBARS) levels by lipid peroxidation compared to ultraviolet B (UVB)-control mice (142.37 MUM/g). Moreover, significant (p<0.05) prevention of glutathione reduced form (GSH) depletion was observed in the black garlic formulation treated mice (vehicle: 3.46 mM/g vs. black garlic: 5.60mM/g). The formulation containing 10% black garlic extract retained physical stability and had high anti-radical efficiencies. Furthermore, it is possible to suggest that this formulation may be effective in protecting skin from UVB photodamage. PMID- 23099481 TI - Indicators of oxidative stress after ionizing and/or non-ionizing radiation: superoxid dismutase and malondialdehyde. AB - Several authors have suggested that low level laser light may have a positive influence on side effects caused by ionizing radiation therapy. We therefore studied indicators of oxidative stress after exposure to gamma radiation with or without pre-exposure to low level laser light. Groups of mice were exposed to light from a laser diode at a wavelength of 830 nm, delivering an energy of 20 or 100 J to 1cm(2) in the abdominal part of the animal with a power density of 300 mW/cm(2) in continuous regime. Following this treatment (or sham irradiation), mice were irradiated with graded doses of (60)Co gamma rays. Levels of superoxide dismutase and malondialdehyde were measured in murine blood cells 30 min or 3 days after exposure. For both time points, there was a clear increase of superoxide dismutase and malondialdehyde with gamma dose, but laser light (alone or in combination with gamma irradiation) did not seem to have any influence on either parameter. Because the physical parameters in our experiments were similar to those of studies showing a positive effect of laser pre-exposure, we conclude that the lack of an observed effect in our case was due to differences in biological parameters, i.e. to differences between the tissues or cell types studied. It is also possible, of course, that laser effects would be seen mainly in the skin immediately exposed, and not to the same degree in blood cells circulating through that area, which were exposed to considerably smaller laser energies. PMID- 23099482 TI - The pro-apoptotic and anti-invasive effects of hypericin-mediated photodynamic therapy are enhanced by hyperforin or aristoforin in HT-29 colon adenocarcinoma cells. AB - Photodynamic therapy is a rapidly-developing anti-cancer approach for the treatment of various types of malignant as well as non-malignant diseases. In this study, hypericin-mediated photodynamic therapy (HY-PDT) in sub-optimal dose was combined with hyperforin (HP) or its stable derivative aristoforin (AR) in an effort to improve efficacy on the cellular level. The logic of this combination is based on the fact that both bioactive compounds naturally occur in plants of Hypericum sp. At relatively low concentrations up to 5 MUM, hyperforin and aristoforin were able to stimulate onset of apoptosis in HT-29 colon adenocarcinoma cells exposed to HY-PDT, inhibit cell cycle progression, suppress expression of matrixmetalloproteinases-2/-9 together with cell adhesivity, thereby affecting the clonogenic potential of the cells. As the action of aristoforin was more pronounced, in line with our assumption, these changes were also linked in this case with hypericin accumulation and increased ROS generation leading to dissipation of mitochondrial membrane potential in a significant portion of the cells, as well as activation of caspase-3. Comparison of HT-29 cells to another colon adenocarcinoma-derived cell line HCT-116 demonstrated significant differences in sensitivity of different cell lines to PDT, however, accumulated effect of HY-PDT with HP/AR proved similar in both tested cell lines. The presented data may help to elucidate the mechanisms of action for different bioactive constituents of St. John's wort, which are increasingly recognized as being able to regulate a variety of pathobiological processes, thus possessing potential therapeutic properties. PMID- 23099483 TI - Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. AB - CONTEXT: There are no controlled studies on surgical treatment of diffuse low grade gliomas (LGGs), and management is controversial. OBJECTIVE: To examine survival in population-based parallel cohorts of LGGs from 2 Norwegian university hospitals with different surgical treatment strategies. DESIGN, SETTING, AND PATIENTS: Both neurosurgical departments are exclusive providers in adjacent geographical regions with regional referral practices. In hospital A diagnostic biopsies followed by a "wait and scan" approach has been favored (biopsy and watchful waiting), while early resections have been advocated in hospital B (early resection). Thus, the treatment strategy in individual patients has been highly dependent on the patient's residential address. Histopathology specimens from all adult patients diagnosed with LGG from 1998 through 2009 underwent a blinded histopathological review to ensure uniform classification and inclusion. Follow-up ended April 11, 2011. There were 153 patients (66 from the center favoring biopsy and watchful waiting and 87 from the center favoring early resection) with diffuse LGGs included. MAIN OUTCOME MEASURE: The prespecified primary end point was overall survival based on regional comparisons without adjusting for administered treatment. Results Initial biopsy alone was carried out in 47 (71%) patients served by the center favoring biopsy and watchful waiting and in 12 (14%) patients served by the center favoring early resection (P < .001). Median follow-up was 7.0 years (interquartile range, 4.5-10.9) at the center favoring biopsy and watchful waiting and 7.1 years (interquartile range, 4.2-9.9) at the center favoring early resection (P=.95). The 2 groups were comparable with respect to baseline parameters. Overall survival was significantly better with early surgical resection (P=.01). Median survival was 5.9 years (95% CI, 4.5-7.3) with the approach favoring biopsy only while median survival was not reached with the approach favoring early resection. Estimated 5 year survival was 60% (95% CI, 48%-72%) and 74% (95% CI, 64%-84%) for biopsy and watchful waiting and early resection, respectively. In an adjusted multivariable analysis the relative hazard ratio was 1.8 (95% CI, 1.1-2.9, P=.03) when treated at the center favoring biopsy and watchful waiting. CONCLUSIONS: For patients in Norway with LGG, treatment at a center that favored early surgical resection was associated with better overall survival than treatment at a center that favored biopsy and watchful waiting. This survival benefit remained after adjusting for validated prognostic factors. PMID- 23099484 TI - Coplanar polychlorinated biphenyls impair glucose homeostasis in lean C57BL/6 mice and mitigate beneficial effects of weight loss on glucose homeostasis in obese mice. AB - BACKGROUND: Previous studies demonstrated that coplanar polychlorinated biphenyls (PCBs) promote proinflammatory gene expression in adipocytes. PCBs are highly lipophilic and accumulate in adipose tissue, a site of insulin resistance in persons with type 2 diabetes. OBJECTIVES: We investigated the in vitro and in vivo effects of coplanar PCBs on adipose expression of tumor necrosis factor alpha (TNF-alpha) and on glucose and insulin homeostasis in lean and obese mice. METHODS: We quantified glucose and insulin tolerance, as well as TNF-alpha levels, in liver, muscle, and adipose tissue of male C57BL/6 mice administered vehicle, PCB-77, or PCB-126 and fed a low fat (LF) diet. Another group of mice administered vehicle or PCB-77 were fed a high fat (HF) diet for 12 weeks; the diet was then switched from HF to LF for 4 weeks to induce weight loss. We quantified glucose and insulin tolerance and adipose TNF-alpha expression in these mice. In addition, we used in vitro and in vivo studies to quantify aryl hydrocarbon receptor (AhR)-dependent effects of PCB-77 on parameters of glucose homeostasis. RESULTS: Treatment with coplanar PCBs resulted in sustained impairment of glucose and insulin tolerance in mice fed the LF diet. In PCB-77 treated mice, TNF-alpha expression was increased in adipose tissue but not in liver or muscle. PCB-77 levels were strikingly higher in adipose tissue than in liver or serum. Antagonism of AhR abolished both in vitro and in vivo effects of PCB-77. In obese mice, PCB-77 had no effect on glucose homeostasis, but glucose homeostasis was impaired after weight loss. CONCLUSIONS: Coplanar PCBs impaired glucose homeostasis in lean mice and in obese mice following weight loss. Adipose specific elevations in TNF-alpha expression by PCBs may contribute to impaired glucose homeostasis. PMID- 23099485 TI - Passaging and colony expansion of human pluripotent stem cells by enzyme-free dissociation in chemically defined culture conditions. AB - This protocol describes an EDTA-based passaging procedure to be used with chemically defined E8 medium that serves as a tool for basic and translational research into human pluripotent stem cells (PSCs). In this protocol, passaging one six-well or 10-cm plate of cells takes about 6-7 min. This enzyme-free protocol achieves maximum cell survival without enzyme neutralization, centrifugation or drug treatment. It also allows for higher throughput, requires minimal material and limits contamination. Here we describe how to produce a consistent E8 medium for routine maintenance and reprogramming and how to incorporate the EDTA-based passaging procedure into human induced PSC (iPSC) derivation, colony expansion, cryopreservation and teratoma formation. This protocol has been successful in routine cell expansion, and efficient for expanding large-volume cultures or a large number of cells with preferential dissociation of PSCs. Effective for all culture stages, this procedure provides a consistent and universal approach to passaging human PSCs in E8 medium. PMID- 23099486 TI - ZIC-cHILIC as a fractionation method for sensitive and powerful shotgun proteomics. AB - Multidimensional liquid chromatography (LC) combined with mass spectrometry (MS) has become a standard technique in proteomics to reduce sample complexity and to tackle the dynamic range in protein abundance. Fractionation is necessary to obtain a comprehensive analysis of complex biological samples such as tissue and mammalian cell lines. However, extensive fractionation comes at the expense of sample loss, presenting a bottleneck in the analysis of limited amounts of material. In this protocol, we describe a two-dimensional chromatographic strategy based on a combination of hydrophilic interaction liquid chromatography (HILIC; with a zwitterionic packing material, ZIC-cHILIC) and reversed-phase chromatography, which allows proteomic analyses with minimal sample loss. Experimental aspects related to obtaining maximum recovery are discussed, including how to optimally prepare samples for this system. Examples involving protein lysates originating from cultured cell lines and cells sorted by flow cytometry are used to show the power, sensitivity and versatility of the technique. Once the ZIC-cHILIC fractionation system has been optimized and standardized, this protocol requires ~5-6 d, including sample preparation and fraction analysis. PMID- 23099488 TI - Macular choroidal thickness measured by swept source optical coherence tomography in eyes with inferior posterior staphyloma. AB - PURPOSE: To study the choroidal thickness in eyes with inferior posterior staphyloma (IPS) and to elucidate its role in the development of macular complications. METHODS: The macular area of 42 eyes of 32 patients with IPS was studied prospectively with swept source optical coherence tomography at 1050 nm. Using a raster scan protocol with 512 * 128 A-scans, we produced a macular choroidal thickness map (6 * 6-mm(2)). RESULTS: Eyes with IPS showed relatively well-preserved choroid outside of the staphyloma but the inferior-nasal choroid within the staphyloma was thinned substantially. In addition, eyes with IPS often had a belt-shaped area with the thinnest choroid along the superior border of the staphyloma. As patient age increased, choroidal thinning progressed in the entire macular area. The macular choroidal thickness showed a close correlation with age (R(2) = 0.506, P < 0.001). On the superior border of the staphyloma, 13 eyes (30.9%) showed serous retinal detachment and/or pigment epithelial detachment without neovascularization, and eight (19.0%) showed neovascularization. Patients with neovascularization were older and had worse visual acuity (P < 0.001). Macular choroidal thickness in eyes with neovascular complications (76.5 +/- 19.9 MUm) was significantly reduced compared with that of eyes with no complication (133.0 +/- 61.9 MUm, P = 0.035). CONCLUSIONS: Eyes with IPS showed marked choroidal thinning along the superior border of the staphyloma. Reduction of the choroidal thickness progressed with age and seemed to be involved in the development of neovascularization associated with the IPS. PMID- 23099487 TI - Stiffness-controlled three-dimensional extracellular matrices for high-resolution imaging of cell behavior. AB - Regulation of cell functions by the physical properties of the extracellular matrix (ECM) has emerged as a crucial contributor to development and disease. Two specific physical properties of the ECM, stiffness and dimensionality, each influence cell signaling and function. As these ECM physical properties are linked to other properties that also regulate cell behavior, e.g., integrin ligand density, parsing the specific contributions of ECM stiffness and dimensionality has proven difficult. Here we detail a simple protocol, which can be completed in 1-2 d, for combining three-dimensional (3D) ECM engagement with controlled underlying ECM stiffness. In these 'sandwich gels', cells are sandwiched between a 3D fibrillar ECM and an ECM-coupled polyacrylamide gel of defined compliance, allowing the study of the specific effects of ECM compliance on cell function in physiologically relevant 3D ECMs. This type of system enables high-resolution time-lapse imaging and is suitable for a wide range of cell types and molecular perturbations. PMID- 23099489 TI - Posture-induced intraocular pressure changes in eyes with open-angle glaucoma, primary angle closure with or without glaucoma medications, and control eyes. AB - PURPOSE: To compare the posture-induced intraocular pressure (IOP) changes in eyes with open-angle glaucoma (OAG), primary angle closure (PAC) with or without glaucoma medications, and healthy control eyes with normal IOPs. METHODS: The IOP was measured in the sitting position (SP) and the lateral decubitus position (LDP) with a rebound tonometer. The IOP in the LDP was measured in the upper eyes 5 minutes after assuming this posture. RESULTS: Fifty-two patients with OAG, 52 with PAC, and 52 controls with normal IOPs were studied. The IOP in the SP measured with the rebound tonometer was 14.3 +/- 4.0 mm Hg in eyes with OAG, 15.8 +/- 4.5 mm Hg in eyes with PAC, and 13.9 +/- 3.7 mm Hg in eyes with normal IOPs. None of these differences was significant (P = 0.060; ANOVA). The IOP in the LDP was significantly increased to 18.3 +/- 4.6 mm Hg in eyes with OAG, 19.3 +/- 4.4 mm Hg in eyes with PAC, and 17.3 +/- 3.5 mm Hg in eyes with normal IOPs (P = 0.000 for all; paired t-tests). The postural IOP difference was +4.0 +/- 2.2 mm Hg in OAG eyes, +3.5 +/- 2.2 mm Hg in PAC eyes, and +3.4 +/- 1.8 mm Hg in normal eyes, and these increases were not significantly different among the three groups (P = 0.309; ANOVA). The correlation between the posture-induced IOP changes and the axial length was not significant in each group. CONCLUSIONS: Postural IOP changes are comparable among eyes with OAG, PAC with and without glaucoma medications, and control eyes. PMID- 23099490 TI - Development-related splicing regulates pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the retina. AB - PURPOSE: The ubiquitous pituitary adenylate cyclase-activating peptide (PACAP) has a disparate array of functions in development (e.g., proliferation and apoptosis). Among three types of PACAP receptor (VPAC1, VPAC2, and PAC1), PAC1 is subject to alternative splicing that generates isoforms. Although the literature documenting the presence of PACAP receptors in the central nervous system is vast, their expression during development has not been established yet. Here, we performed quantitative analyses on the expression of PACAP receptors during the postnatal development of the rat retina. METHODS: Retinas were harvested from postnatal days 0 to 20 (P0-P20). Using a comprehensive primer system, expression changes were followed employing quantitative real-time PCR. Changes at the protein level were detected by immunoblotting using anti-VPAC1, -VPAC2, and -PAC1 receptor antibodies. RESULTS: The expression of VPAC1 showed increases at P10 and P15. Peaks in VPAC2 expression were observed at P5 and P15. Using splicing variant-specific primers for PAC1 receptor, splicing regulation of Null, Hip, Hop1, and Hiphop1 variants was revealed in correlation with postnatal development. Transcript levels of the Null and Hip variants showed a decline, while Hop1 became the major PACAP receptor by P20. Hiphop1 transcript levels did not display remarkable changes except for a transient increase at P10. Immunoblotting confirmed the presence and expression level changes of the receptors. CONCLUSIONS: We conclude that both VPAC1 and VPAC2 could have roles at all stages of retinal development, that PACAP acts through a specific set of PAC1 isoforms, and that Hip and Hop1 are predominantly involved in the postnatal development of rat retina. PMID- 23099491 TI - Keratitis-associated fungi form biofilms with reduced antifungal drug susceptibility. AB - PURPOSE: To investigate the biofilm-forming capacity of Fusarium solani, Cladosporium sphaerospermum, and Acremonium implicatum, and the activities of antifungal agents against the three keratitis-associated fungi. METHODS: The architecture of biofilms was analyzed using scanning electron microscopy and confocal scanning laser microscopy (CSLM). Susceptibility against six antifungal drugs was measured using the CLSI M38-A method and XTT reduction assay. RESULTS: Time course analyses of CSLM revealed that biofilm formation occurred in an organized fashion through four distinct developmental phases: adhesion, germling formation, microcolony formation, and biofilm maturation. Scanning electron microscopy revealed that mature biofilms displayed a complex three-dimensional structure, consisting of coordinated network of hyphal structures glued by the extracellular matrix (ECM). The antifungal susceptibility testing demonstrated a time-dependent decrease in efficacy for all six antifungal agents as the complexity of fungal hyphal structures developed. Natamycin (NAT), amphotericin B (AMB), and NAT were the most effective against F. solani, C. sphaerospermum, and A. implicatum biofilm, respectively. CONCLUSIONS: Corneal isolates of F. solani, C. sphaerospermum, and A. implicatum could produce biofilms that were resistant to antifungal agents in vitro. PMID- 23099492 TI - Evolution of outer retinal folds occurring after vitrectomy for retinal detachment repair. AB - PURPOSE: To assess the evolution of outer retinal folds (ORFs) occurring after repair of rhegmatogenous retinal detachment (RRD) using spectral domain-optical coherence tomography (sd-OCT) and fundus autofluorescence (FAF), and to discuss their pathogenesis. METHODS: Twenty patients were operated on with 25-gauge pars plana vitrectomy and 20% sulfur hexafluoride gas injection for primary macula-off RRD repair and were followed prospectively. Sd-OCT and FAF images were recorded at 1, 3 and 6 months postoperatively. RESULTS: ORFs appeared on sd-OCT as hyperreflective lesions consisting of folded inner segment/outer segment of photoreceptors band and external limiting membrane band. Corresponding lines of increased or decreased autofluorescence were observed on FAF. Over the follow-up, the thick hypoautofluorescent lines progressively evolved to thick hyperautofluorescent lines and to thin hyperautofluorescent lines and eventually disappeared. Concomitantly, OCT scans revealed that the corresponding hyperreflective lesions decreased in number, height, and size. In six cases FAF assessment at month 6 was precluded by cataract development. CONCLUSIONS: ORFS tend to resolve spontaneously within a few months from operation leaving no or subtle abnormalities at the level of the outer retinal layers. OCT is superior to FAF to follow the evolution of orfs in phakic eyes. The following factors might be involved in ORFS pathogenesis: structural changes occurring in the detached retina, residual pockets of subretinal fluid after retinal reattachment, intravitreal gas, unintentional retinal translocation, and intraoperative or perioperative hypotony. PMID- 23099493 TI - Anti-angiogenic effect of luteolin on retinal neovascularization via blockade of reactive oxygen species production. AB - PURPOSE: Oxidative stress-induced vascular endothelial growth factor (VEGF) is thought to play a critical role in the pathogenesis of retinopathy of prematurity (ROP). This study was performed to investigate the anti-angiogenic effect of luteolin against reactive oxygen species (ROS)-induced retinal neovascularization. METHODS: The toxicity of luteolin was evaluated through modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay in human retinal microvascular endothelial cells (HRMECs) as well as TUNEL staining in the retina of C57BL/6J mice. After intravitreal injection of luteolin in the mouse model of ROP, retinal neovascularization was examined by fluorescence angiography and vessel counting. Anti-angiogenic activity of luteolin was evaluated by VEGF-induced migration and tube formation assay. The effect of luteolin on tertiary-butylhydroperoxide (t-BH)-induced ROS production was measured with 2'7'-dichlorofluorescein diacetate. The effect of luteolin on t-BH induced and hypoxia-induced VEGF transcription and expression were evaluated by RT-PCR and Western blot, respectively. RESULTS: Luteolin never affected the viability of HRMECs up to 10 MUM, where luteolin never induced any structural change in all retinal layers. Luteolin inhibited retinal neovascularization in the mouse model of ROP. Moreover, VEGF-induced migration and tube formation were significantly decreased by cotreatment of luteolin. Luteolin attenuated VEGF transcription via blockade of t-BH-induced ROS production. Luteolin suppressed hypoxia-induced VEGF expression via attenuating hypoxia inducible factor 1 alpha expression. CONCLUSIONS: Our results suggest that luteolin could be a potent anti angiogenic agent for retinal neovascularization, which is related to anti oxidative activity to block ROS production and to subsequently suppress VEGF expression and the pro-angiogenic effect of VEGF. PMID- 23099494 TI - Aligning scan locations from consecutive spectral-domain optical coherence tomography examinations: a comparison among different strategies. AB - PURPOSE: We compared intrasession repeatability values produced by different spectral-domain optical coherence tomography (SD-OCT) instruments when measuring macular retinal thickness from consecutive examinations. METHODS: A total of 40 eyes from 23 healthy subjects and 47 eyes from 42 patients with macular edema were enrolled in the study. Subjects underwent two consecutive SD-OCT examinations using three instruments: spectralis HRA+OCT, Cirrus, and RS 3000. For the second SD-OCT examination, the scan location was aligned to the baseline exam using different strategies: RS 3000 eye-tracking (pre-acquisition), Spectralis follow-up (during acquisition), Cirrus fovea finding (postacquisition), and Cirrus macular change analysis (postacquisition). Macular retinal thickness values from the consecutive examinations were evaluated to assess repeatability of the measurements. RESULTS: In healthy subjects all of the strategies used for scan location alignment for the second examination provided good repeatability. For instance, intraclass correlation coefficients (ICC) from the central subfield were between 0.88 (RS 3000 eye-tracking) and 0.99 (Spectralis follow-up). In subjects affected by macular edema, the results were excellent. Cirrus macular change analysis and Spectralis follow-up produced ICC values equaled 1.00 in the central subfield. Cirrus fovea finding and RS 3000 eye tracking produced slightly lower ICC values (0.98 and 0.99, respectively) in the central subfield. CONCLUSIONS: All of the strategies for aligning consecutive SD OCT scan locations produced repeatable retinal thickness values. The best results were obtained using the Spectralis with follow-up and Cirrus with macular change analysis. PMID- 23099495 TI - Pulsatile movement of the optic nerve head and the peripapillary retina in normal subjects and in glaucoma. AB - PURPOSE: To measure the pulsatile movement of neuroretinal tissue at the optic nerve head synchronous with the cardiac cycle. METHODS: We used a noninvasive imaging device based on Fourier domain low-coherence interferometry to measure the pulsatile movements of the optic nerve head, peripapillary retina, and cornea with submicron accuracy along a line across the fundus. We also measured the change in the Axial Distance between the peripapillary Retina and the base of the optic disc Cup (ADRC) during the cardiac cycle. Twelve normal subjects and 20 subjects with open-angle glaucoma were tested. RESULTS: In normal subjects, the mean fundus pulsation amplitude (defined as the fundus movement minus the simultaneous corneal movement) were 13.0 +/- 2.5 MUm, 9.0 +/- 2.1 MUm, and 8.7 +/ 2.9 MUm at the base of the optic nerve head cup, the nasal peripapillary retina, and the temporal peripapillary retina, respectively, compared with 16.7 +/- 6.8 MUm, 17.3 +/- 10.9 MUm, and 12.7 +/- 6.2 MUm for the corresponding values in the glaucoma group (P = 0.26, P = 0.008, and P = 0.12, respectively). The mean changes in ADRC during the cardiac cycle in normal subjects were 10.7 +/- 2.1 MUm and 11.6 +/- 1.8 MUm for the nasal and temporal side of the optic disc, respectively, compared to 14.9 +/- 5.6 MUm and 14.0 +/- 4.9 MUm in glaucoma subjects (P = 0.03 and P = 0.10, respectively). CONCLUSIONS: There was an approximately 11-MUm pulsatile change in the ADRC in normal subjects, and on the nasal side of the disc, this amount was significantly greater in glaucoma patients. PMID- 23099496 TI - Foveal involvement by acquired retinoschisis: long-term visual outcomes. AB - PURPOSE: To report the long-term findings of acquired retinoschisis whose posterior border was <10 degrees from the fovea. METHODS: Retrospective case series. RESULTS: Over a 43-year period, 2 patients retained central vision when the foveola was involved by retinoschisis alone. In these two and in another four patients, the development of outer layer holes eventually was followed by either outer layer or full thickness retinal detachment into the foveola with loss of central vision. Laser treatment or vitrectomy prevented this in three patients. A seventh patient is being monitored by periodic spectral domain optical computerized tomography. CONCLUSION: Acquired retinoschisis that progress into the foveola without an outer layer detachment is compatible with preservation of some degree of central vision. If an outer layer detachment develops under the foveola, such patients lose central vision. Periodic monitoring by spectral domain optical computerized tomography should help to avoid or detect this complication. PMID- 23099498 TI - Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up. AB - PURPOSE: To evaluate ocular function and systemic development in premature infants treated with intravitreal bevacizumab injections for retinopathy of prematurity over a period of 5 years. METHODS: A prospective, interventional, noncomparative case study. The primary outcome measure was visual acuity. The secondary outcomes were structural assessment, other ocular functional measurements, and developmental state. RESULTS: Eighteen eyes of 13 consecutive patients were divided into 3 groups: Group 1, Stage 4 unresponsive to previous conventional treatment (n = 4); Group 2, in which conventional treatment was difficult or impossible because of inadequate visualization of the retina (n = 5); and Group 3, newly diagnosed high-risk prethreshold or threshold retinopathy of prematurity (n = 9). All patients showed initial regression of neovascularization. One patient was diagnosed with recurrence of neovascularization and was treated with intravitreal bevacizumab. Visual acuity was preserved, and median vision was 20/25 (excluding 2 operated eyes). Twelve eyes developed mainly low myopia over the years, with an overall mean value of 3.2 diopters. Electroretinograph was normal in 4 eyes that had no previous detachment. One patient showed delay in growth and neurodevelopment, whereas all the others were within the normal range. CONCLUSION: Five years of follow-up in a small series suggest that intravitreal bevacizumab for retinopathy of prematurity results in apparently preserved ocular function and systemic development. PMID- 23099497 TI - Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab. AB - PURPOSE: To evaluate the effect of concomitant systemic therapy in patients with choroidal neovascularization secondary to age-related macular degeneration (AMD) treated by intravitreal bevacizumab and to propose a mechanism for different interindividual response. METHODS: Retrospective, nonrandomized, single-center, consecutive interventional case series study. Forty-six eyes from 46 patients with choroidal neovascularization secondary to age-related macular degeneration were treated by monthly intravitreal 1.25 mg bevacizumab injections on a pro re nata regime. Patients' files were revised and changes in Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, central foveal thickness as determined by spectral domain optical coherence tomography, number of injections performed, occurrence of severe adverse effects, and systemic concomitant medication were recorded. The effect of systemic medication on final best corrected visual acuity, central foveal thickness, and number of injections performed was evaluated. RESULTS: The most frequent systemic medications recorded were angiotensin-converting-enzyme inhibitors in 19 patients, beta-adrenergic blocking agents (n = 18), nonsteroidal antiinflammatory drugs (n = 17), diuretics (n = 16), calcium channel blockers (n = 14), benzodiazepines (n = 11), proton pump inhibitors (n = 9), and statins (n = 8). Thirty-two patients had arterial hypertension. Average follow-up was 25.1 months (standard deviation [SD] = 8.9). Average gain in best-corrected visual acuity was 0.9 (SD = 13.6) and -2.1 letters (SD = 15.9) at 12 months and 24 months, respectively. The average reduction in central foveal thickness was 111 MUm (SD = 54) and 105 MUm (SD = 71) at 12 months and 24 months, respectively. The average number of intravitreal injections required was 6.7 (SD = 3.2). Patients on treatment with systemic beta-adrenergic blocking agents required less intravitreal injections (5.2, SD = 2.4 vs. 7.9, SD = 3.4) and this difference was statistically significant (P = 0.0068, multiple linear regression). CONCLUSION: Concomitant systemic beta-adrenergic blocking agents treatment may reduce the need for repeated intravitreal injections of bevacizumab in patients with choroidal neovascularization associated with age related macular degeneration. PMID- 23099499 TI - Yield of CT angiography and contrast-enhanced MR imaging in patients with dizziness. AB - BACKGROUND AND PURPOSE: Dizziness is a common symptom in emergency and outpatient settings. The purpose of our study was to compare the diagnostic and therapeutic efficacy of CTA of the head and neck, contrast-enhanced MR imaging of the brain (CE-MR), and contrast-enhanced MR imaging of the internal auditory canals and temporal bones in patients with isolated dizziness, to determine which of these modalities should be preferred in the evaluation of dizziness. MATERIALS AND METHODS: We retrospectively identified patients presenting with dizziness from January 2011 to June 2012 who underwent a CTA, CE-MR, or MRIAC. We excluded patients with signs or symptoms suggestive of other neurologic pathology or a history of an abnormality known to cause dizziness. We calculated the proportion of patients with abnormal findings on a study, tabulated the nature of the abnormality, and reviewed the medical records to determine whether imaging changed management. RESULTS: Two hundred twenty-eight CTAs, 304 CE-MRs, and 266 MRIACs were included. Five patients (2.2%) with CTAs, 4 (1.3%) with CE-MRs, and 4 (1.5%) with MRIACs demonstrated significant findings that related to the history of dizziness or were incidental but judged to be clinically significant. Of these, 3 CTA (1.3%), 2 CE-MR (0.7%), and 3 MRIAC (1.1%) examinations resulted in a change in clinical management. CONCLUSIONS: Imaging evaluation of the patient with uncomplicated dizziness is unlikely to identify clinically significant imaging findings and is very unlikely to result in a change in clinical management, with an overall TE of 1.0%. Thus, the routine use of imaging in the evaluation of the patient with dizziness cannot be recommended. PMID- 23099500 TI - Interobserver variability in retreatment decisions of recurrent and residual aneurysms. AB - BACKGROUND AND PURPOSE: The degree of variation in retreatment decisions for residual or recurrent aneurysms among endovascular therapists remains poorly defined. We performed a multireader study to determine what reader and patient variables contribute to this variation. MATERIALS AND METHODS: Seven endovascular therapists (4 neuroradiologists, 3 neurosurgeons) independently reviewed 66 cases of patients treated with endovascular coil embolization for ruptured or unruptured aneurysm. Cases were rated on a 5-point scale recommending for whether to retreat and a recommended retreatment type. Reader agreement was assessed by intraclass correlation coefficient and by identifying cases with a "clinically meaningful difference" (a difference in score that would result in a difference in treatment). Variables that affect reader agreement and retreatment decisions were examined by using the Wilcoxon signed-rank test, Pearson chi(2) test, and linear regression. RESULTS: Overall interobserver variability for decision to retreat was moderate (ICC = 0.50; 95% CI, 0.40-0.61). Clinically meaningful differences between at least 2 readers were present in 61% of cases and were significantly more common among neuroradiologists than neurosurgeons (P = .0007). Neurosurgeons were more likely to recommend "definitely retreat" than neuroradiologists (P < .0001). Previously ruptured aneurysms, larger remnant size, and younger patients were associated with more retreat recommendations. Interobserver variability regarding retreatment type was fair overall 0.25 (95% CI, 0.14-0.41) but poor for experienced readers 0.14 (95% CI, 0-0.34). CONCLUSIONS: There is a large amount of interobserver variability regarding the decision to retreat an aneurysm and the type of retreatment. This variability must be reduced to increase consistency in these subjective outcome measurements. PMID- 23099501 TI - Follow-Up MR Imaging for Cerebral Sparganosis. PMID- 23099502 TI - Toxicokinetic study and absolute oral bioavailability of deoxynivalenol, T-2 toxin and zearalenone in broiler chickens. AB - Mycotoxins lead to economic losses in animal production. A way to counteract mycotoxicosis is the use of detoxifiers. The European Food Safety Authority stated that the efficacy of detoxifiers should be investigated based on toxicokinetic studies. Little information is available on the absolute oral bioavailability and the toxicokinetic parameters of deoxynivalenol, T-2 and zearalenone in broilers. Toxins were administered intravenously and orally in a two-way cross-over design. For deoxynivalenol a bolus of 0.75mg/kg BW was administered, for T-2 toxin 0.02mg/kg BW and for zearalenone 0.3mg/kg BW. Blood was collected at several time points. Plasma levels of the mycotoxins and their metabolite(s) were quantified using LC-MS/MS methods and toxicokinetic parameters were analyzed. Deoxynivalenol has a low absolute oral bioavailability (19.3%). For zearalenone and T-2 no plasma levels above the limit of quantification were observed after an oral bolus. Volumes of distribution were recorded, i.e. 4.99, 0.14 and 22.26L/kg for deoxynivalenol, T-2 toxin and zearalenone, respectively. Total body clearance was 0.12, 0.03 and 0.48L/minkg for deoxynivalenol, T-2 toxin and zearalenone, respectively. After IV administration, T-2 toxin had the shortest elimination half-life (3.9min), followed by deoxynivalenol (27.9min) and zearalenone (31.8min). PMID- 23099503 TI - Citrus peel polymethoxylated flavones extract modulates liver and heart function parameters in diet induced hypercholesterolemic rats. AB - The primary aim of this study was to investigate the effects of Ortanique peel polymethoxylated flavones extract (PMF(ort)) on organ function parameters in the serum of hypercholesterolemic and normal rats. Thirty Sprague-Dawley rats were fed high cholesterol diets supplemented with 1.5% PMF(ort) and niacin respectively for 49days. Hypercholesterolemic rats fed PMF(ort) had significant reductions in the activities of aspartate aminotransferase and alkaline phosphatase (69.12+/-3.34 and 87.22+/-8.42U/L respectively) compared to the untreated hypercholesterolemic group (118.61+/-4.85 and 132.62+/-10.62U/L respectively, p<0.05). Supplementation of the diet with niacin or PMF(ort) resulted in no significant differences in the serum levels of creatinine or urea in any of the groups. Total bilirubin was highest in the untreated hypercholesterolemic group. Supplementation of the diets of hypercholesterolemic rats with PMF(ort) resulted in significant reductions in the activities of serum creatine kinase and lactate dehydrogenase (119.3+/-25.3; 222.5+/-50.3U/L, p<0.05) respectively relative to the untreated hypercholesterolemic group (257.2+/-48.3; 648.8+/-103U/L, p<0.05). The results would suggest that PMF(ort) modulates hypercholesterolemia-associated organ injury in rats. PMF(ort) could therefore be a suitable candidate for prophylactic and therapeutic treatment of hypercholesterolemia-associated organ injury. PMID- 23099504 TI - Radioprotective activity and cytogenetic effect of resveratrol in human lymphocytes: an in vitro evaluation. AB - Trans-resveratrol is a natural occurring polyphenol, obtained from grapes and other berries. This compound has shown antioxidant, anti-inflammatory, immunostimulant or anti-carcinogenic properties. Our aim was to evaluate the radioprotective efficacy, in vitro, of trans-resveratrol against radiation induced chromosomal damage and to study the genotoxicity and cytotoxicity of this polyphenol in cell cultures without irradiation. The study was carried out by the pre-treatment of human lymphocytes at concentrations from 0 to 219MUM of trans resveratrol. The results showed that all concentrations tested reduced radiation induced chromosomal damage compared with cells with any treatment. Maximum damage protection was observed at the concentration of 2.19MUM. Concerning genotoxic results, all tested trans-resveratrol concentrations increased the sister chromatid exchange (SCE) index compared with no trans-resveratrol treatment. Cytotoxic indexes (Mitotic and Proliferation Index) showed that the lowest concentrations could enhance the cell proliferation rates and the highest ones could negatively affect to human peripheral lymphocytes growth. PMID- 23099505 TI - In vitro and in vivo antioxidant activity of ethanolic extract of white button mushroom (Agaricus bisporus). AB - The antioxidant activities of ethanolic extract from edible mushroom Agaricus bisporus (A. bisporus) were evaluated by various methods in vitro and in vivo. In antioxidant assays in vitro, ethanolic extract of A. bisporus was found to have strong reducing power, superoxide radical, hydroxyl radical and 2,2-diphenyl-1 picrylhydrazyl radical scavenging activity, and moderate hydrogen peroxide scavenging activity. In antioxidant assays in vivo, mice were administered with ethanolic extract of A. bisporus via gavage for 30 consecutive days. As a result, administration of ethanolic extract significantly enhanced the activities of antioxidant enzymes in serums, livers and hearts of mice. In addition, the total phenolic content in the extract determined by Folin-Ciocalteu method was 6.18mg of gallic acid equivalents per gram of dry weight. The main phenolic compounds in ethanolic extract analyzed by ultra-high performance liquid chromatography tandem mass spectrometry were determined as gallic acid, protocatechuic acid, catechin, caffeic acid, ferulic acid and myricetin. These results suggested that ethanolic extract of A. bisporus had potent antioxidant activity and could be explored as a novel natural antioxidant. PMID- 23099506 TI - Compulsory treatment and patient responsibility. AB - OBJECTIVE: Current legislative provisions for compulsory treatment of people with mental illness allow decisions to treat people under compulsion to be made on the basis of presence of a mental illness or mental disorder without consideration of whether the patient has the capacity to make decisions that are in his/her best interest. Issues of autonomy, equity, justice and beneficence in relation to treatment of people with mental illness are explored to determine decision-making rules that should be applied for compulsory mental health treatment. CONCLUSIONS: It is proposed that assessment of the capacity of the individual to make decisions in his/her best interest, rather than presence of diagnosable mental illness, should be the key consideration for compulsory mental health treatment. PMID- 23099507 TI - The future of psychiatry. AB - OBJECTIVE: The objective of this paper is to forecast the future of psychiatry in the first world in the next 20 years. CONCLUSIONS: There are no indications that psychiatry might significantly change in the near future. Yet two factors affecting today's psychiatry will most likely become more pronounced in years to come, first, the shrinking of psychiatrists' domain, and second, the declining interest in psychiatry among medical graduates. PMID- 23099508 TI - Reclaiming the best of the biopsychosocial model of mental health care and 'recovery' for older people through a 'person-centred' approach. AB - AIM: The 'biopsychosocial', 'person-centred care' (PCC) and 'recovery' models of care can be seen as distinct and competing paradigms. This paper proposes an integration of these valuable perspectives and suggestions for effective implementation in health services for the elderly. METHOD: An overview of PCC and recovery models, and their application for older people with mental health problems, is provided. Their overlap and contrast with the familiar 'biopsychosocial' model of mental health care is considered, together with obstacles to implementation. RESULTS: Utilisation of PCC and recovery concepts allow clinicians to avoid narrow application of the biopsychosocial approach and encourages clinicians to focus on the person's right to autonomy, their values and life goals. CONCLUSIONS: Service reform and development is required to embed these concepts into core clinical processes so as to improve outcomes and the quality of life for older people with mental health problems. PMID- 23099509 TI - Anxiety and depression in Australian chronic hepatitis C outpatients: prevalence and predictors. AB - OBJECTIVE: The present study aimed to assess the prevalence and predictors of anxiety and depression in Australian chronic hepatitis C (CHC) outpatients. METHOD: Hospital Anxiety and Depression Scale scores at referral and other patient data was analysed for 395 CHC outpatients attending the Royal Adelaide Hospital liver clinic from 2006 to 2010. RESULTS: Results revealed probable prevalence rates of 41% for anxiety and 27% for depression. CHC patients had rates of anxiety and depression 1.2 and 2.4 times higher than community norms, respectively. Younger patients were found to experience increased anxiety, while married patients or those in a de facto relationship experienced decreased anxiety and depression. CONCLUSION: Regular psychiatric screening, and subsequent referral for mental health treatment, where necessary, is recommended for Australian CHC patients. Younger patients or those lacking social supports may be at increased risk. Research is needed to develop and evaluate psychological interventions. PMID- 23099510 TI - A nosological review of depressive disorders based on observations in clinical practice, part 1: Terminology and phenomenology. AB - OBJECTIVE: The purpose of this paper is to describe the problems with the contemporary nosology of 'depression' and to discuss the key linguistic and phenomenological aspects that are essential prerequisites for a clinically meaningful typology of depressive disorders. The paper comprises observations and reflections drawn from clinical work. CONCLUSIONS: First, the use of the unqualified, stock term 'depression' is counterproductive, as are the diagnostic non-entities of 'major depression' and 'dysthymia'. Second, the core psychopathology in melancholic depression is a loss of self-confidence, which helps explain the frequent co-occurrence of 'anxiety' with 'depression'. Third, descriptive, non-technical terms such as 'demoralisation' and 'grief' are most helpful in formulating non-melancholic forms of depression and thus useful in differential diagnosis. PMID- 23099511 TI - Integrating recovery-oriented practice into psychiatric registrar training. AB - OBJECTIVE: This paper describes a new initiative in training for psychiatry trainees in the 'recovery' paradigm. CONCLUSIONS: Supporting patients in their personal recovery and promoting wellbeing has become a key principle in the delivery of specialist mental health services. This requires psychiatrists to develop (or perhaps return to) a worldview that promotes a hopeful stance and acknowledges the importance of relationships when working with people experiencing mental ill health. In 2011, the authors developed and trialed training about personal recovery and wellbeing within psychiatry. A crucial factor was that the training was delivered by a person who has expertise both as a result of their own recovery journey and their experience in peer support work. The feedback from participants has supported further national and international developments and there are plans to extend this component of the program. PMID- 23099512 TI - Dual-source coronary CT angiography in patients with high heart rates using a prospectively ECG-triggered axial mode at end-systole. AB - To determine the feasibility of dual-source coronary CT angiography (CTA) using a prospectively electrocardiogram (ECG)-triggered axial mode to target end-systole in patients with high heart rates (HR) as compared with the retrospective mode. One hundred fifty consecutive patients with regular HR > 75 bpm who underwent coronary CTA were enrolled; 75 patients underwent prospectively ECG-triggered coronary CTA targeting only end-systole (Prospective Axial Group) and 75 patients underwent retrospectively ECG-gated coronary CTA (Retrospective Helical Group). The image quality of multiple coronary artery segments was evaluated and radiation doses were recorded. The diagnostic performance of coronary CTA was compared to the reference standard of invasive coronary angiography in 52 patients (35 %) (28 patients in Prospective Axial Group and 24 patients in Retrospective Helical Group). Image quality was not significantly different between the 2 groups (P = 0.784). In subgroup analysis, segment-based sensitivity, specificity, and positive and negative predictive values of coronary CTA were 98, 96, 88 and 99 %, respectively, in the Prospective Axial Group and were 97, 95, 82, and 99 %, respectively, in the Retrospective Helical Group. Mean radiation dose was significantly lower for the Prospective Axial Group than for the Retrospective Helical Group (2.9 +/- 1.4 vs. 7.4 +/- 3.3 mSv; P < 0.0001). Dual source coronary CTA with a prospective ECG-triggered axial mode targeting end-systole is feasible in patients with regular high HRs for evaluation of coronary artery disease. It provides comparable image quality and diagnostic value with substantially lower radiation exposure as compared to the retrospective ECG-gated helical technique. PMID- 23099513 TI - Taxonomy and phylogeny of the genus Megasporoporia and its related genera. AB - Taxonomic and phylogenetic studies on Megasporoporia s.l. were carried out. Phylogenetic analysis based on ITS and nLSU sequences showed that Megasporoporia s.l. belonging to the core polyporoid clade, however, it is not monophyletic, and four clades were recognized. The Megasporoporia s.s. clade includes M. setulosa and two new species, M. bannaensis and M. minor spp. nov. Two monophyletic clades were segregated from Megasporoporia s.l., and two new genera were established. Megasporia gen. nov. is composed of M. cystidiolophora, M. ellipsoidea, M. hexagonoides, M. major, M. violacea, and two new species, M. guangdongensis and M. hengduanensis spp. nov. Megasporoporiella gen. nov. including M. cavernulosa, M. rhododendri, M. subcavernulosa, and two new species, M. lacerata and M. pseudocavernulosa spp. nov. Megasporoporia quercina grouped with Grammothele fuligo in the Grammothele clade, so it is transferred to Grammothele and a new combination, G. quercina, is proposed. The main morphological characters of Megasporoporia and the two new genera are discussed, and identification keys to the three genera are provided. PMID- 23099514 TI - Pseudorhizidium is a new genus with distinct zoospore ultrastructure in the order Chytridiales. AB - A chytrid isolate (JEL 221) we identified as the rarely reported species, Rhizidium endosporangiatum Karling, was cultured axenically for the first time. The purposes of this study are to characterize the developmental morphology of isolate JEL 221 and to elucidate its zoospore ultrastructural features. Thallus development and morphology of isolate JEL 221 are characteristic of R. endosporangiatum as it was originally described. However, thallus morphology of R. endosporangiatum is not entirely typical of the genus Rhizidium, especially that of the type R. mycophilum. The presence of an endosporangium, a layer of material encapsulating the edges of the protoplast protruding through multiple discharge pores, makes this a distinctive species. Consistent with its published molecular-based phylogenetic placement, we found that isolate JEL 221 shared ultrastructural features with the two major zoospore types described for the Chytridiales but had distinct zoospore architecture. A new genus, Pseudorhizidium, is erected for this chytrid based on its thallus morphology, molecular phylogenetic placement and unique zoospore ultrastructure. This new genus does not fit into either of the described families (Chytridiaceae or Chytriomycetaceae) in the Chytridiales because of its unique zoospore ultrastructure, especially the two-layered nature of the electron-opaque plug in the base of the flagellum. PMID- 23099515 TI - Phialemoniopsis, a new genus of Sordariomycetes, and new species of Phialemonium and Lecythophora. AB - In molecular studies involving numerous clinical isolates of the genera Acremonium, Phialemonium and Lecytophora some of them could not be identified. To clarify the phylogenetic relationships among these fungi and other related taxa, we performed a polyphasic study based on a detailed morphological study and on the analysis of sequences of four loci: the internal transcribed spacer regions, the D1/D2 domains of the 28S rRNA, actin and beta-tubulin genes. The combination of the resulting data let us propose the new genus Phialemoniopsis to accommodate the opportunistic fungi Phialemonium curvatum and Sarcopodium oculorum and two new species, Phialemoniopsis cornearis and Phialemoniopsis pluriloculosa. The taxonomy of Phialemoniopsis has not been completely resolved, however, remaining incertae sedis within the Sordariomycetes. In addition, the new species Lecythophora luteorubra, Lecythophora cateniformis and Phialemonium globosum are described and the species Acremonium atrogriseum and Taifanglania inflata are transferred to the genus Phialemonium. Lecythophora and Phialemonium are currently monophyletic genera of the families Coniochaetaceae (Coniochaetales) and Cephalothecaceae (Sordariales) respectively, according to our results. Tables summarizing key morphological features to distinguish the current species of Lecythophora, Phialemonium and Phialemoniopsis are provided. PMID- 23099517 TI - Fusarium torreyae sp. nov., a pathogen causing canker disease of Florida torreya (Torreya taxifolia), a critically endangered conifer restricted to northern Florida and southwestern Georgia. AB - During a survey for pathogens of Florida torreya (Torreya taxifolia) in 2009, a novel Fusarium species was isolated from cankers affecting this critically endangered conifer whose current range is restricted to northern Florida and southwestern Georgia. Published multilocus molecular phylogenetic analyses indicated that this pathogen represented a genealogically exclusive, phylogenetically distinct species representing one of the earliest divergences within the Gibberella clade of Fusarium. Furthermore, completion of Koch's postulates established that this novel species was the causal agent of Florida torreya canker disease. Here we formally describe this pathogen as a new species, Fusarium torreyae. Pure cultures of this species produced long and slender multiseptate sporodochial conidia that showed morphological convergence with two distantly related fusaria, reflecting the homoplasious nature of Fusarium conidial morphology. PMID- 23099516 TI - Meredithblackwellia eburnea gen. et sp. nov., Kriegeriaceae fam. nov. and Kriegeriales ord. nov.--toward resolving higher-level classification in Microbotryomycetes. AB - A field survey of ballistosporic yeasts in a Neotropical forest yielded a new species isolated from a fern leaf. The isolate is a cream-colored butyrous yeast that reproduces by budding. Budding occurs at both the apical and basal cell poles; occasionally multiple budding events co-occur, giving rise to rosette-like clusters of cells at both poles of the yeast mother cell. DNA sequences of large and small subunit and the internal transcribed spacer regions of the nuclear ribosomal DNA cistron indicated an affinity to Microbotryomycetes, Pucciniomycotina. A new genus, Meredithblackwellia, is proposed to accommodate the new species, M. eburnea (type strain MCA4105). Based on phylogenetic analyses, Meredithblackwellia is related to Kriegeria eriophori, a sedge parasite, to an aquatic fungus Camptobasidium hydrophilum and to several recently described anamorphic yeasts that have been isolated from plant material or psychrophilic environments. Morphological and ultrastructural studies confirm the relatedness of M. eburnea to these taxa and prompted the re-evaluation of higher level classification within Microbotryomycetes. We propose here a new order, Kriegeriales, and place two families, Kriegeriaceae fam. nov. and Camptobasidiaceae R.T. Moore, within it. Our study re-emphasizes the need for systematic revision of species described in Rhodotorula. PMID- 23099518 TI - Evolution of fungal sexual reproduction. AB - We review here recent advances in our understanding of the genetic, molecular and genomic basis of sex determination and sexual reproduction in the fungal kingdom as a window on the evolution of sex in eukaryotes more generally. In particular, we focus on the evolution of the mating-type locus and transitions in modes of sexual reproduction using examples from throughout the kingdom. These examples illustrate general principles of the origins of mating-type loci/sex chromosomes and the balance between inbreeding and outcrossing afforded by different modes of sexual reproduction involving tetrapolar, bipolar and unipolar sexual cycles. PMID- 23099519 TI - Two new Ramicandelaber species from Taiwan. AB - Two new species of Ramicandelaber isolated from soil in Taiwan are described. Ramicandelaber fabisporus sp. nov. is characterized by having bean-shaped spores that are the smallest in the genus and also by the absence of lateral branches on the sporangiophores. Ramicandelaber taiwanensis sp. nov. is characterized by small, fusiform spores and it produces lateral branches that arise from the sporangiophores. Morphological characters and molecular phylogenetic analysis (D1/D2 domains of the LSU rRNA genes and ITS region) justify these new species of Ramicandelaber. A key is provided to the recognized species of Ramicandelaber. PMID- 23099520 TI - Molecular systematics of Woswasia atropurpurea gen. et sp. nov. (Sordariomycetidae), a fungicolous ascomycete with globose ascospores and holoblastic conidiogenesis. AB - The monotypic genus Woswasia is described for wood-inhabiting and mycotrophic fungi classified in the Sordariomycetidae. It is characterized by unicellular, hyaline, globose to ellipsoid, verruculose ascospores; unitunicate long-stipitate asci with an apical annulus staining blue in aqueous cotton blue and perithecia with a long neck immersed in a stroma exhibiting a conspicuous pH-dependent color reaction. In vitro, it produces branched subhyaline to hyaline conidiophores with terminally arranged sympodial conidiogenous cells and holoblastic hyaline conidia. The remarkable morphological similarity of Woswasia to Amplistroma of the Amplistromataceae, although suggestive of a close relationship, was not confirmed by molecular data. Phylogenetic analysis based on two functional ribosomal genes (large and small subunits of the nuclear rDNA) and one protein coding gene (second largest subunit of RNA polymerase II) supports the placement of Woswasia in the Sordariomycetidae incertae sedis. Woswasia atropurpurea, the type and only species of the genus, groups within a large heterogeneous clade containing other small or monotypic genera of wood-inhabiting saprobic fungi, which are distantly related and of which the majority lacks an ordinal or familial affiliation. Within the clade a relationship of Woswasia to the freshwater genus Cyanoannulus is suggested. PMID- 23099521 TI - Genome-wide alternative polyadenylation in animals: insights from high-throughput technologies. AB - Alternative polyadenylation (APA) plays an important role in gene expression by affecting mRNA stability, translation, and translocation in cells. However, genome-wide APA events have only recently been subjected to more systematic analysis with newly developed high-throughput methods. In this review, we focus on the recent technological development of APA analyses on a genome-wide scale, as well as the impact of APA switches on a number of critical biological processes in animals, including cell proliferation, differentiation, and oncogenic transformation. With the highly enlarged scope of genome-wide APA analyses, the APA regulations of various biological processes have increasingly become a new paradigm for the regulation of gene transcription and translation. PMID- 23099522 TI - Coping with flow: behavior, neurophysiology and modeling of the fish lateral line system. AB - With the mechanosensory lateral line fish perceive water motions relative to their body surface and local pressure gradients. The lateral line plays an important role in many fish behaviors including the detection and localization of dipole sources and the tracking of prey fish. The sensory units of the lateral line are the neuromasts which are distributed across the surface of the animal. Water motions are received and transduced into neuronal signals by the neuromasts. These signals are conveyed by afferent nerve fibers to the fish brain and processed by lateral line neurons in parts of the brainstem, cerebellum, midbrain, and forebrain. In the cerebellum, midbrain, and forebrain, lateral line information is integrated with sensory information from other modalities. The present review introduces the peripheral morphology of the lateral line, and describes our understanding of lateral line physiology and behavior. It focuses on recent studies that have investigated: how fish behave in unsteady flow; what kind of sensory information is provided by flow; and how fish use and process this information. Finally, it reports new theoretical and biomimetic approaches to understand lateral line function. PMID- 23099523 TI - Dynamics and stability of a three-dimensional model of cell signal transduction. AB - In this paper, we consider a three-dimensional model of cell signal transduction. In this model, the deactivation of signalling proteins occur throughout the cytosol and activation is localized to specific sites in the cell. We use matched asymptotic expansions to construct the dynamic solutions of signalling protein concentrations. The result of the asymptotic analysis is a system of ordinary differential equations. This reduced system is compared to numerical simulations of the full three-dimensional system. As well, we consider the stability of equilibrium solutions. We find that the systems under consideration may undergo sustained oscillations, hysteresis and other complex behaviors. The simulations of the full three-dimensional system agree with simulations of the reduced ordinary differential equations. PMID- 23099525 TI - Differences in recourse to HIV testing according to migration origin in the Paris metropolitan area in 2010. AB - In France, HIV prevention within Maghrebi or French of Maghrebi origin has been seldom studied. The purpose of this study is to compare the recourse to HIV test according to nationality and origin. Data were from the 2010 SIRS cohort, which included 3,006 households representative of the Paris metropolitan area. Results of the study show comparatively low HIV testing rate among Maghrebi and French of Maghrebi origin compared to French with French parents. PMID- 23099524 TI - Animal models for scoliosis research: state of the art, current concepts and future perspective applications. AB - PURPOSE: The purpose of this study was to provide the readers with a reliable source of animal models currently being utilized to perform state-of-the-art scoliotic research. MATERIALS AND METHODS: A comprehensive search was undertaken to review all publications on animal models for the study of scoliosis within the database from 1946 to January 2011. RESULTS: The animal models have been grouped under specific headings reflecting the underlying pathophysiology behind the development of the spinal deformities produced in the animals: genetics, neuroendocrine, neuromuscular, external constraints, internal constraints with or without tissue injury, vertebral growth modulation and iatrogenic congenital malformations, in an attempt to organize and classify these multiple scoliotic animal models. As it stands, there are no animal models that mimic the human spinal anatomy with all its constraints and weaknesses, which puts it at risk of developing scoliosis. What we do have are a multitude of models, which produce spinal deformities that come close to the idiopathic scoliosis deformity. CONCLUSION: All these different animal models compel us to believe that the clinical phenotype of what we call idiopathic scoliosis may well be caused by a variety of different underlying pathologies. PMID- 23099526 TI - Evaluation of dried blood spot (DBS) technology versus plasma analysis for the determination of MK-1775 by HILIC-MS/MS in support of clinical studies. AB - The collection of human blood samples as dried blood spots (DBS) for the pharmacokinetic assessment of investigational drugs in clinical trials offers a number of advantages over conventional plasma sampling, namely, small sample volume, simplified sample handling, and cost-effective shipping and storage. The use of DBS coupled with liquid chromatography-tandem mass spectrometry analysis was evaluated for the quantification of MK-1775, a Wee-1 inhibitor under development as a chemo/radio-sensitizer for the treatment of cancer. The DBS method exhibited an assay performance comparable to that of the existing plasma assay, which is currently used in support of clinical studies. Both assays used the same linear dynamic range of 2-1,000 ng/mL, with a lower limit of quantification of 2 ng/mL. Based on the intra-day assay validation results, the accuracy of the DBS method ranged from 94.0 to 105.0%, with a coefficient of variation of <4.8%. The blood-to-plasma ratio calculated from the DBS data (blood concentrations) and the plasma data (plasma concentrations) was in good agreement with the one obtained from the in vitro assessment using conventional methodology. No significant hematocrit impact on the assay was observed as hematocrit ranged from 16 to 85%. The correlation between the measured MK-1775 concentrations in plasma and that determined in dried blood spots from oncology patients during the ongoing clinical study was discussed. PMID- 23099528 TI - delta15N measurement of organic and inorganic substances by EA-IRMS: a speciation dependent procedure. AB - Little attention has been paid so far to the influence of the chemical nature of the substance when measuring delta(15)N by elemental analysis (EA)-isotope ratio mass spectrometry (IRMS). Although the bulk nitrogen isotope analysis of organic material is not to be questioned, literature from different disciplines using IRMS provides hints that the quantitative conversion of nitrate into nitrogen presents difficulties. We observed abnormal series of delta(15)N values of laboratory standards and nitrates. These unexpected results were shown to be related to the tailing of the nitrogen peak of nitrate-containing compounds. A series of experiments were set up to investigate the cause of this phenomenon, using ammonium nitrate (NH(4)NO(3)) and potassium nitrate (KNO(3)) samples, two organic laboratory standards as well as the international secondary reference materials IAEA-N1, IAEA-N2-two ammonium sulphates [(NH(4))(2)SO(4)]-and IAEA-NO 3, a potassium nitrate. In experiment 1, we used graphite and vanadium pentoxide (V(2)O(5)) as additives to observe if they could enhance the decomposition (combustion) of nitrates. In experiment 2, we tested another elemental analyser configuration including an additional section of reduced copper in order to see whether or not the tailing could originate from an incomplete reduction process. Finally, we modified several parameters of the method and observed their influence on the peak shape, delta(15)N value and nitrogen content in weight percent of nitrogen of the target substances. We found the best results using mere thermal decomposition in helium, under exclusion of any oxygen. We show that the analytical procedure used for organic samples should not be used for nitrates because of their different chemical nature. We present the best performance given one set of sample introduction parameters for the analysis of nitrates, as well as for the ammonium sulphate IAEA-N1 and IAEA-N2 reference materials. We discuss these results considering the thermochemistry of the substances and the analytical technique itself. The results emphasise the difference in chemical nature of inorganic and organic samples, which necessarily involves distinct thermochemistry when analysed by EA-IRMS. Therefore, they should not be processed using the same analytical procedure. This clearly impacts on the way international secondary reference materials should be used for the calibration of organic laboratory standards. PMID- 23099527 TI - Comparison of the performance of Chromolith Performance RP-18e, 1.8-MUm Zorbax Eclipse XDB-C18 and XTerra MS C18, based on modelling approaches. AB - Achievement of the highest separation efficiency and quick delivery of results are key requirements in liquid chromatography for enhancing productivity and reducing analysis cost, especially in the pharmaceutical industry. This work concerns two of the most popular current solutions to get fast separations: the use of a silica-based monolithic column (Chromolith Performance RP-18e) and a small-particle packed column (1.8-MUm Zorbax Eclipse XDB-C18, which needs dedicated instruments allowing higher backpressures). Both columns succeeded in the full separation of phenols and beta-adrenolytic drugs, which are compounds that interact with residual silanols, giving rise to wider peaks. The results were compared with those obtained with a special column designed to avoid silanol interaction, containing 5 MUm particles (XTerra MS C18). Chromolith gave the shortest times at the expense of higher solvent consumption at the high flow rates needed. In contrast to other studies, comprehensive conclusions on the chromatographic performance, in terms of selectivity, peak shape, resolution, and analysis time, are derived from the inspection of the whole experimental domain using retention and peak shape modelling. In the literature, column comparison is usually carried out based on the performance for selected mobile phases (very often a single one), which offers deceiving results. PMID- 23099529 TI - Electrochemical detection of miRNA-222 by use of a magnetic bead-based bioassay. AB - MicroRNAs (miRNAs, miRs) are naturally occurring small RNAs (approximately 22 nucleotides in length) that have critical functions in a variety of biological processes, including tumorigenesis. They are an important target for detection technology for future medical diagnostics. In this paper we report an electrochemical method for miRNA detection based on paramagnetic beads and enzyme amplification. In particular, miR 222 was chosen as model sequence, because of its involvement in brain, lung, and liver cancers. The proposed bioassay is based on biotinylated DNA capture probes immobilized on streptavidin-coated paramagnetic beads. Total RNA was extracted from the cell sample, enriched for small RNA, biotinylated, and then hybridized with the capture probe on the beads. The beads were then incubated with streptavidin-alkaline phosphatase and exposed to the appropriate enzymatic substrate. The product of the enzymatic reaction was electrochemically monitored. The assay was finally tested with a compact microfluidic device which enables multiplexed analysis of eight different samples with a detection limit of 7 pmol L(-1) and RSD = 15 %. RNA samples from non-small cell lung cancer and glioblastoma cell lines were also analyzed. PMID- 23099531 TI - Cage the firefly luciferin! - a strategy for developing bioluminescent probes. AB - Bioluminescent imaging (BLI) has been widely applicable in the imaging of process envisioned in life sciences. As the most conventional technique for BLI, the firefly luciferin-luciferase system is exceptionally functional in vitro and in vivo. The state-of-the-art strategy in such a system is to cage the luciferin, in which free luciferin is conjugated with distinctive functional groups, thus accommodating an impressive toolkit for exploring various biological processes, such as monitoring enzymes activity, detecting bioactive small molecules, evaluating the properties of molecular transporters, etc. This review article summarizes the rational design of caged luciferins towards diverse biotargets, as well as their applications in bioluminescent imaging. It should be emphasized that these caged luciferins can stretch out the applications of bioluminescence imaging and shed light upon understanding the pathogenesis of various diseases. PMID- 23099532 TI - Smectic order parameters via liquid crystal NMR spectroscopy: Application to a partial bilayer smectic A phase. AB - Solute molecules were dissolved in the liquid crystal 4-cyano-4'-n octyloxybiphenyl (8OCB), known to form a partial bilayer smectic-A phase. Through measurement of solutes' and solvent's orientational order parameters via nuclear magnetic resonance spectroscopy, and their analysis via a statistical thermodynamic density functional theory, values of the solvent's positional order parameters and solutes' positional-orientational distribution functions were obtained. Near to the transition to the nematic phase, the main positional order parameter of the smectic liquid crystal turned out to be comprised in the interval 0.4-0.6, though the quality of the fittings assuming the phase as nematic all across the temperature range investigated was only slightly worse. This may be ascribed to the looseness of the partial bilayer smectic structure. Solutes were found to preferentially lie in those regions where liquid crystal molecule terminal chains are located. PMID- 23099533 TI - Modelling the fluid mechanics of cilia and flagella in reproduction and development. AB - Cilia and flagella are actively bending slender organelles, performing functions such as motility, feeding and embryonic symmetry breaking. We review the mechanics of viscous-dominated microscale flow, including time-reversal symmetry, drag anisotropy of slender bodies, and wall effects. We focus on the fundamental force singularity, higher-order multipoles, and the method of images, providing physical insight and forming a basis for computational approaches. Two biological problems are then considered in more detail: 1) left-right symmetry breaking flow in the node, a microscopic structure in developing vertebrate embryos, and 2) motility of microswimmers through non-Newtonian fluids. Our model of the embryonic node reveals how particle transport associated with morphogenesis is modulated by the gradual emergence of cilium posterior tilt. Our model of swimming makes use of force distributions within a body-conforming finite-element framework, allowing the solution of nonlinear inertialess Carreau flow. We find that a three-sphere model swimmer and a model sperm are similarly affected by shear-thinning; in both cases swimming due to a prescribed beat is enhanced by shear-thinning, with optimal Deborah number around 0.8. The sperm exhibits an almost perfect linear relationship between velocity and the logarithm of the ratio of zero to infinite shear viscosity, with shear-thickening hindering cell progress. PMID- 23099534 TI - Mesoscopic models for DNA stretching under force: New results and comparison with experiments. AB - Single-molecule experiments on double-stranded B-DNA stretching have revealed one or two structural transitions, when increasing the external force. They are characterized by a sudden increase of DNA contour length and a decrease of the bending rigidity. The nature and the critical forces of these transitions depend on DNA base sequence, loading rate, salt conditions and temperature. It has been proposed that the first transition, at forces of 60-80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA, while the second one, at stronger forces, is a strand peeling resulting in single-stranded DNAs (ssDNA), similar to thermal denaturation. But due to experimental conditions these two transitions can overlap, for instance for poly(dA-dT). In an attempt to propose a coherent picture compatible with this variety of experimental observations, we derive an analytical formula using a coupled discrete worm-like chain-Ising model. Our model takes into account bending rigidity, discreteness of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit of zero force, this model simplifies into a coupled model already developed by us for studying thermal DNA melting, establishing a connection with previous fitting parameter values for denaturation profiles. Our results are summarized as follows: i) ssDNA is fitted, using an analytical formula, over a nano-Newton range with only three free parameters, the contour length, the bending modulus and the monomer size; ii) a surprisingly good fit on this force range is possible only by choosing a monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase length; iii) mesoscopic models are not able to fit B to ssDNA (or S to ss) transitions; iv) an analytical formula for fitting B to S transitions is derived in the strong force approximation and for long DNAs, which is in excellent agreement with exact transfer matrix calculations; v) this formula fits perfectly well poly(dG-dC) and lambda-DNA force-extension curves with consistent parameter values; vi) a coherent picture, where S to ssDNA transitions are much more sensitive to base pair sequence than the B to S one, emerges. This relatively simple model might allow one to further study quantitatively the influence of salt concentration and base-pairing interactions on DNA force-induced transitions. PMID- 23099536 TI - Water soluble carbon nano-onions from wood wool as growth promoters for gram plants. AB - Water-soluble carbon nano-onions (wsCNOs) isolated from wood wool-a wood-based pyrolysis waste product of wood, can enhance the overall growth rate of gram (Cicer arietinum) plants. Treatment of plants with upto 30 MUg mL(-1) of wsCNOs for an initial 10 day period in laboratory conditions led to an increase in the overall growth of the plant biomass. In order to examine the growth stimulating effects of wsCNOs under natural conditions, 10 day-old plants treated with and without wsCNOs were transplanted into soil of standard carbon and nitrogen composition. We observed an enhanced growth rate of the wsCNOs pre-treated plants in soil, which finally led to an increased productivity of plants in terms of a larger number of grams. On analyzing the carbon, hydrogen, and nitrogen (CHN) content for the shoot and fruit sections of the plants treated with and without wsCNOs, only a minor difference in the composition was noticed. However, a slight increase in the percentage of carbon and hydrogen in shoots reflects the synthesis of more organic biomass in the case of treated plants. This work shows that wsCNOs are non-toxic to plant cells and can act as efficient growth stimulants which can be used as benign growth promoters. PMID- 23099535 TI - Efficient division and sampling of cell colonies using microcup arrays. AB - A microengineered array to sample clonal colonies is described. The cells were cultured on an array of individually releasable elements until the colonies expanded to cover multiple elements. Single elements were released using a laser based system and collected to sample cells from individual colonies. A greater than an 85% rate in splitting and collecting colonies was achieved using a 3 dimensional cup-like design or "microcup". Surface modification using patterned titanium deposition of the glass substrate improved the stability of microcup adhesion to the glass while enabling minimization of the laser energy for splitting the colonies. Smaller microcup dimensions and slotting the microcup walls reduced the time needed for colonies to expand into multiple microcups. The stem cell colony retained on the array and the collected fraction within released microcups remained undifferentiated and viable. The colony samples were characterized by both reporter gene expression and a destructive assay (PCR) to identify target colonies. The platform is envisioned as a means to rapidly establish cell lines using a destructive assay to identify desired clones. PMID- 23099537 TI - Black holes in the early Universe. AB - The existence of massive black holes (MBHs) was postulated in the 1960s, when the first quasars were discovered. In the late 1990s their reality was proven beyond doubt in the Milky way and a handful nearby galaxies. Since then, enormous theoretical and observational efforts have been made to understand the astrophysics of MBHs. We have discovered that some of the most massive black holes known, weighing billions of solar masses, powered luminous quasars within the first billion years of the Universe. The first MBHs must therefore have formed around the time the first stars and galaxies formed. Dynamical evidence also indicates that black holes with masses of millions to billions of solar masses ordinarily dwell in the centers of today's galaxies. MBHs populate galaxy centers today, and shone as quasars in the past; the quiescent black holes that we detect now in nearby bulges are the dormant remnants of this fiery past. In this review we report on basic, but critical, questions regarding the cosmological significance of MBHs. What physical mechanisms led to the formation of the first MBHs? How massive were the initial MBH seeds? When and where did they form? How is the growth of black holes linked to that of their host galaxy? The answers to most of these questions are works in progress, in the spirit of these reports on progress in physics. PMID- 23099538 TI - Mn(II) binding to human serum albumin: a 1H-NMR relaxometric study. AB - Human serum albumin (HSA) displays several metal binding sites, participating to essential and toxic metal ions disposal and transport. The major Zn(II) binding site, called Site A, is located at the I/II domain interface, with residues His67, Asn99, His247, and Asp249 contributing with five donor atoms to the metal ion coordination. Additionally, one water molecule takes part of the octahedral coordination geometry. The occurrence of the metal-coordinated water molecule allows the investigation of the metal complex geometry by water (1)H-NMR relaxation, provided that the diamagnetic Zn(II) is replaced by the paramagnetic Mn(II). Here, the (1)H-NMR relaxometric study of Mn(II) binding to HSA is reported. Mn(II) binding to HSA is modulated by Zn(II), pH, and myristate through competitive inhibition and allosteric mechanisms. The body of results indicates that the primary binding site of Zn(II) corresponds to the secondary binding site of Mn(II), i.e. the multimetal binding site A. Excess Zn(II) completely displaces Mn(II) from its primary site suggesting that the primary Mn(II) site corresponds to the secondary Zn(II) site. This uncharacterized site is functionally-linked to FA1; moreover, metal ion binding is modulated by myristate and pH. Noteworthy, water (1)H-NMR relaxometry allowed a detailed analysis of thermodynamic properties of HSA-metal ion complexes. PMID- 23099540 TI - The role of early resection vs biopsy in the management of low-grade gliomas. PMID- 23099542 TI - Coexistence of papillary thyroid cancer with Hashimoto thyroiditis. AB - AIMS: Conflicting data have been reported with regard to Hashimoto thyroiditis (HT) and risk of malignancy. The aim of this study was to evaluate coexistence of papillary thyroid cancer (PTC) with HT. PATIENTS AND METHODS: This is a retrospective cohort study in which HT was diagnosed in 452 (F/M ratio = 405:47, median age 53.5 +/- 12.1 years) of 7,545 patients qualified for thyroidectomy throughout the years 2002 to 2010. Pathological reports were reviewed to identify prevalence of PTC in HT vs. non-HT patients. RESULTS: PTC was diagnosed in 106 of 452 (23.5 %) HT patients vs. 530 of 7,093 (7.5 %) non-HT patients (p < 0.001). Metastases to level VI lymph nodes were observed in 81 of 106 (76.4 %) patients with PTC in HT vs. 121 of 530 (22.8 %) patients with PTC in non-HT disease (p < 0.001). CONCLUSIONS: HT was associated with a threefold increase of PTC prevalence as compared to other non-HT thyroid diseases, and the spread of PTC to level VI lymph nodes was four times more frequent in HT than in non-HT patients. PMID- 23099543 TI - Evaluation of four Agrobacterium tumefaciens strains for the genetic transformation of tomato (Solanum lycopersicum L.) cultivar Micro-Tom. AB - KEY MESSAGE : Agrobacterium tumefaciens strains differ not only in their ability to transform tomato Micro-Tom, but also in the number of transgene copies that the strains integrate in the genome. The transformation efficiency of tomato (Solanum lycopersicum L.) cv. Micro-Tom with Agrobacterium tumefaciens strains AGL1, EHA105, GV3101, and MP90, harboring the plasmid pBI121 was compared. The presence of the nptII and/or uidA transgenes in regenerated T(0) plants was determined by PCR, Southern blotting, and/or GUS histochemical analyses. In addition, a rapid and reliable duplex, qPCR TaqMan assay was standardized to estimate transgene copy number. The highest transformation rate (65 %) was obtained with the Agrobacterium strain GV3101, followed by EHA105 (40 %), AGL1 (35 %), and MP90 (15 %). The mortality rate of cotyledons due to Agrobacterium overgrowth was the lowest with the strain GV3101. The Agrobacterium strain EHA105 was more efficient than GV3101 in the transfer of single T-DNA insertions of nptII and uidA transgenes into the tomato genome. Even though Agrobacterium strain MP90 had the lowest transformation rate of 15 %, the qPCR analysis showed that the strain MP90 was the most efficient in the transfer of single transgene insertions, and none of the transgenic plants produced with this strain had more than two insertion events in their genome. The combination of higher transformation efficiency and fewer transgene insertions in plants transformed using EHA105 makes this Agrobacterium strain optimal for functional genomics and biotechnological applications in tomato. PMID- 23099544 TI - Sudden death due to black esophagus: a case report. AB - Black esophagus, also known as acute esophageal necrosis syndrome, is a rare but often fatal pathology. It can be identified during autopsy examination and should be diagnosed by the forensic examiner via simple macroscopic examination. We report the case of an elderly man who was found dead, presenting with this pathology. A microscopic examination was carried out that confirmed the diagnosis. We consider that all forensic examiners should be made aware of this pathology to make the diagnosis quickly, in turn allowing the deceased to be returned promptly to their loved ones. PMID- 23099545 TI - An autopsy case of acute carbon monoxide poisoning after a long-term vegetative state. AB - A 23-year-old woman was rescued from an accidental fire in a state of cardiopulmonary arrest. Based on the diagnosis of carbon monoxide (CO) poisoning, she received hyperbaric oxygen therapy and survived in a vegetative state. After 1 and a half years, she died without recovering from the vegetative state. At autopsy, the brain was observed to be moderately softened with a severely atrophied appearance and ventricular enlargement. In addition, a characteristic damage of hypoxic-ischemic leukoencephalopathy was also observed clearly in both the bilateral globus pallidus and cerebral white matter, which are typical findings of past acute CO poisoning. A long-term vegetative state causes the brain to soften and liquefy because of reactive gliosis and autolytic change. The cause of death becomes difficult to diagnose only from the autopsy findings in general. This case is rare in that the past acute CO poisoning could be diagnosed from the remaining typical cerebral findings even after a long-term vegetative state. PMID- 23099546 TI - Debates about assisted suicide in Switzerland. AB - Assisted suicide is allowed in 3 states of the United States (Oregon, Washington, Montana) but only if performed by a physician.On the opposite, in Switzerland, at the beginning of the 20th century, the Swiss Penal Code referred to assisted suicide in the context of honor or an unhappy love affair. It was only in 1985 that Exit Deutsche Schweiz (Exit for German-speaking Switzerland) "medically" assisted the first patient to end his life.Even if authorized by the Swiss law upon certain conditions, assisted suicide is subject to debates for ethical reasons. The Swiss Academy of Medical Sciences described directives to guide physicians on this difficult subject.Different studies showed an increase in the number of medical-assisted suicide in Switzerland since the 1990s. Now, this number seems to be quite stable. Assisted suicide is authorized in a few hospitals under strict conditions (especially when returning home is impossible).Thus, according to the Swiss law, any person could perform assisted suicide; this is essentially performed by 3 main associations, using pentobarbital on medical prescription as lethal substance.Generally speaking, the Swiss population is rather in favor of assisted suicide. Among politics, the debate has been tough until 2010, when the Federal Council decided not to modify the Swiss Penal Code concerning assisted suicide. PMID- 23099548 TI - The distribution of quick phase interval durations in human optokinetic nystagmus. AB - There is an interesting dichotomy between models that predict the quick phase interval durations (QPIDs) of human optokinetic nystagmus (OKN). Accumulator models describe a stochastic signal in a neural network that triggers a response once the signal reaches a fixed threshold value. However, it is also possible that quick phases are triggered after eye position reaches a variable amplitude threshold. In this study, we fitted a range of probability density functions previously predicted by stochastic models of OKN (including those of the reciprocal truncated Normal, inverse Gaussian, gamma, lognormal and the mixture of two reciprocal truncated Normal distributions) to individual QPID histograms. We compared the goodness of fit between these models, and a model where the distribution of QPIDs is determined by the ratio of two correlated and truncated Normal random variables. The ratio distribution gave the best fit to the data, and we propose this is due to the approximately linear trajectory of slow phases (SPs) and that QPIDs are given by the ratio of a variable SP amplitude threshold and variable SP velocity. PMID- 23099547 TI - Persistent impairments in hippocampal, dorsal striatal, and prefrontal cortical function following repeated photoperiod shifts in rats. AB - Cognitive impairments are observed when learned associations are being acquired or retrieved during a period of circadian disruption. However, the extent of the functional impacts on previously acquired associations following circadian rhythm re-entrainment is unknown. The impacts of repeated photoperiod shifts on learning and memory in male and female rats were examined. For these experiments, rats were trained on a spatial version of the Morris water task (MWT) and a visual discrimination task designed for the 8-arm radial maze. Following asymptotic performance on these tasks, rats experienced a repeating photoperiod shift procedure and were then re-entrained. Following circadian re-entrainment, retention of pre-photoperiod-shift-acquired associations was tested. In addition, an extra-dimensional set shift was performed using the 8-arm radial maze. Impaired retention of the MWT platform location was observed in photoperiod shifted subjects relative to subjects with stable, unmanipulated photoperiods. Repeated photoperiod shifts negatively impacted retention in males and females compared with subjects with stable photoperiods. Retention and the ability to detect extra-dimensional shifts on the visual discrimination task were also impaired, though not consistently by sex or photoperiod condition. Running wheel availability was also included in the analyses to determine whether exercise influenced the effects of photoperiod shifting. The absence of a running wheel produced significant declines in memory retention on both MWT and the visual discrimination task, but only for male rats. The observed impairments indicate that multiple neural systems supporting different learning and memory functions are susceptible to circadian disruption, even if the association is acquired prior to rhythm fragmentation and tested following rhythm re-entrainment. PMID- 23099549 TI - Felt heaviness is used to perceive the affordance for throwing but rotational inertia does not affect either. AB - Bingham et al. discovered a perceptible affordance property, composed of a relation between object weight and size, used to select optimal objects for long distance throwing. Subsequent research confirmed this finding, but disconfirmed a hypothesis formulated by Bingham et al. about the information used to perceive the affordance. Following this, Zhu and Bingham investigated the possibility that optimal objects for throwing are selected as having a particular felt heaviness. The results supported this hypothesis. Perceived heaviness exhibits the size weight illusion: to be perceived as equally heavy, larger objects must weigh more than smaller ones. Amazeen and Turvey showed that heaviness perception is determined by rotational inertia. We investigated whether rotational inertia would determine both perceived heaviness and throw-ability when spherical objects were held in the hand and wielded about the wrist. We found again that a particular judged heaviness corresponded to judged throw-ability. However, rotational inertia was found to have no effect on either judgment, suggesting that rotational inertia does not determine perceived heaviness of spherical objects held in the hand, as it did for the weighted-rod-type objects used by Amazeen and Turvey. PMID- 23099550 TI - Additional load decreases movement time in the wrist but not in arm movements at ID 6. AB - An experiment using reciprocal arm and wrist aiming movements with an amplitude of 16(o) and target width of .5 degrees (ID = 6) was conducted to determine the impact of adding external loads. We predicted that wrist and arm performance may be differentially impacted by the added mass. Participants were asked to flex/extend their limb/lever in a horizontal plane at the wrist (arm stabilized) or elbow joint (wrist stabilized) in an attempt to move back and forth between the two targets as quickly and accurately as possible. External loads of 0, .568, or 1.136 kg were fixed at the distal end of the limb/lever. The targets and the current position of the limb were projected on the screen in front of the participant. The results indicated significant Group * Load interactions for movement time and percent time to peak velocity. Movement time decreased as load increased for the wrist but remained stable across loads for arm movements. Percent movement time utilized to accelerate the limb increased as load increased for wrist movements but only increased from 0 to .568 kg load for the arm movements. For both groups increased load had no significant effect on endpoint variability. The present findings suggest that the additional load allowed the control advantages of the wrist muscles to be exploited. PMID- 23099551 TI - Novel odour recognition memory is independent of the hippocampus in rats. AB - We examined the effects of hippocampal (HPC) damage on odour recognition memory, using a novel odour recognition task that was adapted from the more common novel object recognition task. Three separate experiments were conducted. In Experiment 1, we tested rats in novel odour recognition across different retention intervals (i.e. 15 min, 24 h, 1 week, 5 weeks). Given a single acquisition session, rats' performance deteriorated after 24 h, but given multiple acquisition sessions (i.e. four sessions over 2 days), rats were able to perform well after retention intervals up to 5 weeks. In Experiment 2, we examined the possible anterograde amnesic effects of HPC damage on novel odour recognition, finding that pre training damage to the entire HPC failed to cause amnesia for retention delays extending up to 5 weeks. In Experiment 3, we examined whether post-training HPC damage would cause retrograde amnesia, but failed to find any evidence of an impairment. The combined results suggest that the neural network supporting odour recognition is independent of the HPC. PMID- 23099552 TI - Word production and the picture-word interference paradigm: the role of learning. AB - Psycholinguistic experiments conducted with the picture-word interference paradigm are typically preceded by a phase during which participants learn the words they will have to produce in the experiment. In Experiment 1, the pictures (e.g., a frog) were to be named and were presented with a categorically related (e.g., cat) or unrelated distracter (e.g., pen). In the related condition responses were slower relative to the unrelated condition for the participants who had gone through the learning phase. In contrast, participants who had not been previously familiarized with the materials showed facilitation. In Experiment 2 one group of participants, as usual, learned to produce the targets upon presentation of the corresponding pictures (e.g., a frog). The other group learned to produce the same targets upon presentation of unrelated pictures (e.g., a clock). They showed very similar semantic effects. The implications of the findings in the study of word production are discussed. PMID- 23099553 TI - Special issue: wearable computing and communication for e-Health. PMID- 23099554 TI - Remote sensing of patterns of cardiac activity on an ambulatory subject using millimeter-wave interferometry and statistical methods. AB - Using a 94-GHz millimeter-wave interferometer, we are able to calculate the relative displacement of an object. When aimed at the chest of a human subject, we measure the minute motions of the chest due to cardiac activity. After processing the data using a wavelet multiresolution decomposition, we are able to obtain a signal with peaks at heartbeat temporal locations. In order for these heartbeat temporal locations to be accurate, the reflected signal must not be very noisy. Since there is noise in all but the most ideal conditions, we created a statistical algorithm in order to compensate for unconfident temporal locations as computed by the wavelet transform. By analyzing the statistics of the peak locations, we fill in missing heartbeat temporal locations and eliminate superfluous ones. Along with this, we adapt the processing procedure to the current signal, as opposed to using the same method for all signals. With this method, we are able to find the heart rate of ambulatory subjects without any physical contact. PMID- 23099555 TI - Kinematic description of soft tissue artifacts: quantifying rigid versus deformation components and their relation with bone motion. AB - This paper proposes a kinematic approach for describing soft tissue artifacts (STA) in human movement analysis. Artifacts are represented as the field of relative displacements of markers with respect to the bone. This field has two components: deformation component (symmetric field) and rigid motion (skew symmetric field). Only the skew-symmetric component propagates as an error to the joint variables, whereas the deformation component is filtered in the kinematic analysis process. Finally, a simple technique is proposed for analyzing the sources of variability to determine which part of the artifact may be modeled as an effect of the motion, and which part is due to other sources. This method has been applied to the analysis of the shank movement induced by vertical vibration in 10 subjects. The results show that the cluster deformation is very small with respect to the rigid component. Moreover, both components show a strong relationship with the movement of the tibia. These results suggest that artifacts can be modeled effectively as a systematic relative rigid movement of the marker cluster with respect to the underlying bone. This may be useful for assessing the potential effectiveness of the usual strategies for compensating for STA. PMID- 23099556 TI - Integrated analyses of proteins and their glycans in a magnetic bead-based multiplex assay format. AB - BACKGROUND: Well-annotated clinical samples are valuable resources for biomarker discovery and validation. Multiplex and integrated methods that simultaneously measure multiple analytes and generate integrated information about these analytes from a single measurement are desirable because these methods help conserve precious samples. We developed a magnetic bead-based system for multiplex and integrated glycoprotein quantification by immunoassays and glycan detection by lectin immunosorbent assays (LISAs). METHODS: Magnetic beads coupled with antibodies were used for capturing proteins of interest. Biotinylated antibodies in combination with streptavidin-labeled phycoerythrin were used for protein quantification. In the LISAs, biotinylated detection antibodies were replaced by biotinylated lectins for glycan detection. RESULTS: Using tissue inhibitor of metallopeptidase 1 (TIMP-1), tissue plasminogen activator, membrane metallo-endopeptidase, and dipeptidyl peptidase-IV (DPP-4) as models, we found that the multiplex integrated system was comparable to single immunoassays in protein quantification and LISAs in glycan detection. The merits of this system were demonstrated when applied to well-annotated prostate cancer tissues for validation of biomarkers in aggressive prostate cancer. Because of the system's multiplex ability, we used only 300 ng of tissue protein for the integrated detection of glycans in these proteins. Fucosylated TIMP-1 and DPP-4 offered improved performance over the proteins in distinguishing aggressive and nonaggressive prostate cancer. CONCLUSIONS: The multiplex and integrated system conserves samples and is a useful tool for validation of glycoproteins and their glycoforms as biomarkers. PMID- 23099558 TI - Lower urinary tract symptoms of neurological origin in urological practice. AB - PURPOSE: The present study aimed to reveal the neurological origin of lower urinary tract symptoms (LUTS) in routine urological examination. METHODS: We retrospectively analyzed 70 cases to identify cases in which the neurologist and/or urologist suspected the relation between neurological diseases and LUTS. The compromised neurological areas were categorized into brain and spinal cord based on the appearance time of LUTS and presence/absence of disease specificity. We classified the lesion site based on the imaging result and the neurologic finding. We compared LUTS appearance time: from LUTS appearance till the first visit to urologist (first visit urologist) and from the aforementioned visit till the neurological diagnosis confirmation (neurological diagnosis). Finally, we conducted a detailed investigation of the surgical cases, as well as those with urodynamic studies (UDS) performed prior to the neurological examination. RESULTS: The neurological diseases involved 31 cases (44 %) of multiple system atrophy, 11 (16 %) of multiple sclerosis, and 4 (6 %) of Parkinson's disease. Associated symptoms comprised gait disturbance (38) and lower limb dysesthesia (20), while no associated symptoms were observed in 13 (19 %). Both the periods proved significantly shorter for spinal cord disease. Urological surgeries were performed in 10 cases (14 %). UDS findings revealed 10 cases of decrease in bladder compliance, and 15 of detrusor underactivity; no normal cases were observed. CONCLUSIONS: Consideration of detailed medical history, enforcement of UDS, and closer cooperation between urologists and neurologists are required to ascertain early and correct diagnosis, and to avoid unnecessary surgery. PMID- 23099557 TI - Unleashing the power of proteomics to develop blood-based cancer markers. AB - BACKGROUND: There is an urgent need for blood-based molecular tests to assist in the detection and diagnosis of cancers at an early stage, when curative interventions are still possible, and to predict and monitor response to treatment and disease recurrence. The rich content of proteins in blood that are impacted by tumor development and host factors provides an ideal opportunity to develop noninvasive diagnostics for cancer. CONTENT: Mass spectrometry instrumentation has advanced sufficiently to allow the discovery of protein alterations directly in plasma across no less than 7 orders of magnitude of protein abundance. Moreover, the use of proteomics to harness the immune response in the form of seropositivity to tumor antigens has the potential to complement circulating protein biomarker panels for cancer detection. The depth of analysis currently possible in a discovery setting allows the detection of potential markers at concentrations of less than 1 MUg/L. Such low concentrations may exceed the limits of detection of ELISAs and thus require the development of clinical assays with exquisite analytical sensitivity. Clearly the availability for discovery and validation of biospecimens that are highly relevant to the intended clinical application and have been collected, processed, and stored with the use of standard operating procedures is of crucial importance to the successful application of proteomics to the development of blood-based tests for cancer. SUMMARY: The realization of the potential of proteomics to yield blood biomarkers will benefit from a collaborative approach and a substantial investment in resources. PMID- 23099559 TI - How do interactions between early caregiving environment and genes influence health and behavior? AB - To promote optimal health and behavioral outcomes in children, nurses have long supported parents in providing the best possible care and nurturance to their offspring. A growing body of neuroscience research argues convincingly for the combined influences of genes and early caregiving on producing an individual's unique health and behavioral phenotype. In this article, we systematically review studies that demonstrate the relationship between qualities of early caregiving and genetic propensity to health and behavioral outcomes. From an initial set of 255 articles, 24 articles met our inclusion criteria. The outcomes fall into four distinct groups: hypothalamic-pituitary-adrenal (HPA) response to stress, externalizing behavior, internalizing behavior, and disorganized attachment. In the articles, authors examined genes that code for the 5-hydroxy tryptamine (serotonin) transporter genes linked polymorphic region [5-HTTLPR] serotonin transporter promoter, D4 dopamine receptor, brain-derived neurotrophic factor, and monoamine oxidase A promoter. The reviewed studies suggest that the effect of the early rearing environment on gene expression relates mainly to HPA response to stress, whereas interactions between genes and caregiving mainly relate to behavior and attachment. Findings have implications for nurses focused on advocacy, prevention, and intervention to support the healthy development of children in families faced with adversity. PMID- 23099560 TI - State filling dependent luminescence in hybrid tunnel coupled dot-well structures. AB - A strong dependence of quantum dot (QD)-quantum well (QW) tunnel coupling on the energy band alignment is established in hybrid InAs/GaAs-In(x)Ga(1-x)As/GaAs dot well structures by changing the QW composition to shift the QW energy through the QD wetting layer (WL) energy. Due to this coupling a rapid carrier transfer from the QW to the QD excited states takes place. As a result, the QW photoluminescence (PL) completely quenches at low excitation intensities. The threshold intensities for the appearance of the QW PL strongly depend on the relative position of the QW excitonic energy with respect to the WL ground state and the QD ground state energies. These intensities decrease by orders of magnitude as the energy of the QW increases to approach that of the WL due to the increased efficiency for carrier tunneling into the WL states as compared to the less dense QD states below the QW energy. PMID- 23099562 TI - Photonic crystal light-emitting sources. AB - Photonic crystals (PhCs) are periodically structured optical media offering the opportunity for spontaneous emission (SpE) to be strongly controlled in spatial terms (directions) or in absolute terms (rates). We discuss the application of this concept for practical light-emitting sources, summarizing the principles and actual merits of various approaches based on two- and three-dimensional PhCs. We take into consideration the numerous constraints on real-world light-emitting structures and materials. The various mechanisms through which modified photonic bands and band gaps can be used are first revisited in view of their use in light sources. We then present an in-depth discussion of planar emitters and enhanced extraction of light thanks to grating diffraction. Applications to conventional III-V semiconductors and to III-nitrides are reviewed. Comparison with random surface roughening reveals some common physical limitations. Some advanced approaches with complex structures or etched active structures are also discussed. Finally, the most promising mechanism to enhance the SpE rate, the Purcell effect, is considered. Its implementation, including through plasmonic effects, is shown to be effective only for very specific sources. We conclude by outlining the mix of physics and material parameters needed to grasp the relevant issues. PMID- 23099561 TI - The significance of acid/base properties in drug discovery. AB - While drug discovery scientists take heed of various guidelines concerning drug like character, the influence of acid/base properties often remains under scrutinised. Ionisation constants (pK(a) values) are fundamental to the variability of the biopharmaceutical characteristics of drugs and to underlying parameters such as logD and solubility. pK(a) values affect physicochemical properties such as aqueous solubility, which in turn influences drug formulation approaches. More importantly, absorption, distribution, metabolism, excretion and toxicity (ADMET) are profoundly affected by the charge state of compounds under varying pH conditions. Consideration of pK(a) values in conjunction with other molecular properties is of great significance and has the potential to be used to further improve the efficiency of drug discovery. Given the recent low annual output of new drugs from pharmaceutical companies, this review will provide a timely reminder of an important molecular property that influences clinical success. PMID- 23099564 TI - Selenoprotein P and Yunnan endemic sudden cardiac death--an ecological study. AB - The aim of the present study was to explore the role of selenoprotein P (SePP) in the etiology of the endemic sudden cardiac death in Yunnan, China. The levels of SePP of 124 subjects and glutathione peroxidase (GPx) of 119 subjects were measured. The subjects were from the old and new endemic areas and non-endemic areas. The levels of SePP and GPx of the subjects of the old endemic area were significantly higher than those of the subjects of the new endemic area and the non-endemic areas, respectively. The Pearson's correlation among SePP, GPx, and the number of the incident cases of the disease were statistically significant. These correlations show that there is an inverse relationship among the number of patients and the levels of SePP (r = - 0.9800, P = 0.0200) and GPx (r = - 0.961, P = 0.009). The results show that selenium deficiency might play an important role in the incidence of the disease. PMID- 23099563 TI - Influence of trace elements on stabilization of aqueous solutions of ascorbic acid. AB - Together with vitamin C, zinc, selenium, manganese, and magnesium play a vital role in the preservation of organs scheduled for transplantation. In the present study, it is shown that addition of 1 mg/l of these elements influences the stability of 0.3 mM ascorbic acid solutions. The solution's stability was estimated using an accelerated stability test. The concentration of vitamin C was measured using a validated spectrophotometric method, which uses the reduction of 2,6-dichlorophenoloindophenol by ascorbic acid. Elevated temperatures, the factor accelerating substances' decomposition reaction rate, were used in the tests. The research was conducted at two temperatures at intervals of 10 degrees C: 80 +/- 0.1 and 90 +/- 0.1 degrees C. It was stated that the studied substances' decomposition occurred in accordance with the equation for first-order reactions. The function of the logarithmic concentration (log%C) over time was revealed to be rectilinear. This dependence was used to determine the kinetics of decomposition reaction rate parameters. The stabilization of vitamin C solutions was measured as the time in which 10 % of the substance decomposed at 20 and 0 degrees C. Addition of Se(IV) or Mg(II) ions significantly increase the stability of ascorbic acid solution (~34 and ~16 %, respectively), but Zn(II) causes a significant decrease in stability by ~23 %. Addition of Mn(II) has no significant influence on vitamin C stability. PMID- 23099566 TI - The hidden wounds of war. PMID- 23099565 TI - Multi-component analysis of bile acids in natural Calculus bovis and its substitutes by ultrasound-assisted solid-liquid extraction and UPLC-ELSD. AB - An ultrasound-assisted solid-liquid extraction (USLE) coupled to ultra performance liquid chromatography-evaporative light scattering detection (UPLC ELSD) method has been developed for the simultaneous extraction and determination of six bile acids (BAs) in natural Calculus bovis and its substitutes, collected from different origins. The USLE conditions, UPLC chromatographic and ELSD conditions for BAs were optimized. Under optimum conditions, the six target analytes were efficiently extracted and baseline separated within 10 min. The limits of detection (LODs) and quantification (LOQs) for six BAs were less than 7 ng and 22 ng, respectively. Average recoveries were within the range of 98.8 100.7% with relative standard deviations (RSDs) <2% for the six analytes. This method, due to its convenience, high selectivity, fast analysis efficiency and good reproducibility can be employed for analyzing the content differences of six BAs in 40 batches of natural C. bovis and its existing substitutes. The differences of the content of each BA in natural C. bovis and its substitutes were significant, and the total contents of six BAs in 13 batches of natural C. bovis were in the range of 7.96-160.17 mg g(-1), in 20 natural C. bovis of 0 245.89 mg g(-1), in 2 artificial cultivated C. bovis of 178.48-194.22 mg g(-1), in 3 cultured C. bovis of 41.01-107.3 mg g(-1), and in 2 counterfeit C. bovis of 144.9-340.25 mg g(-1). The significant differences of multi-component contents reflected the various inherent qualities of these samples, so, the use of these substitutes as the replacers of natural source in clinic should be paid more attention. Some substitutes could not be used as the replacers. PMID- 23099567 TI - We can improve the safety of PICC lines. PMID- 23099568 TI - Living with von Willebrand disease. PMID- 23099569 TI - Ethical writing. PMID- 23099570 TI - Nurses at the WHO. PMID- 23099571 TI - Balloon pump support for cardiogenic shock after AMI. PMID- 23099574 TI - Reducing nurse burnout might reduce hospital-acquired infections. PMID- 23099572 TI - Preprocedure antibiotics reduce infection after cesarean delivery. PMID- 23099577 TI - Adults born between 1945 and 1965 need one-time hepatitis C testing. PMID- 23099579 TI - Improving access to specialty care for veterans. PMID- 23099587 TI - PTSD among our returning veterans. PMID- 23099588 TI - Professional licensure: investigation and disciplinary action. AB - This is the second article in a three-part series on nursing boards' disciplinary actions and what nurses need to know to maintain their license in good standing. This article discusses common reasons boards of nursing conduct investigations and take disciplinary action. The third and final article will discuss strategies for protecting your license. PMID- 23099590 TI - A nurse? What was I thinking? PMID- 23099589 TI - Protecting refrigerated vaccines with water bottles: an evidence-based strategy. PMID- 23099591 TI - Revising the Declaration of Helsinki: a work in progress. PMID- 23099593 TI - Compensation for trial-related injury: does simplicity compromise fairness? PMID- 23099592 TI - IMA strike: need for public debate. PMID- 23099594 TI - Good epidemiology, good ethics: empirical and ethical dimensions of global public health. AB - This paper examines the following ethically and epidemiologically relevant challenges, as yet neglected in public health ethics: how to distribute resources and health risks and benefits, how to define evidentiary criteria that justify public health interventions, and how to define terms in which programme goals, successes, and failures will be assessed and monitored. We illuminate critical intersections of empirical and ethical dimensions of public health work, drawing upon three global public health interventions-inclusion of the Hepatitis B vaccine in the Universal Immunisation Programme, Universal Salt Iodisation, and the Global Polio Eradication Initiative-and suggest strategies for addressing and responding to them. PMID- 23099595 TI - Perceptions about training and knowledge of HIV/AIDS ethics among health care providers at teaching hospitals of a medical college in Karnataka, India. AB - A cross sectional study was conducted to evaluate perceptions of HIV/AIDS ethics among health care professionals at three associate hospitals of Kasturba Medical College Mangalore. A total of 144 health care professionals were included, of which 106 (73.6%) were doctors and 38 (26.4%) were nurses.Only 52.8% of doctors and 56.6% of nurses agreed that they had received adequate training related to HIV data confidentiality. 85.8% of doctors and 76.3% of nurses perceived that they need additional training in HIV policies & procedures. With respect to rights of HIV-positive clients 92.5% of doctors and 84.2% of nurses felt the need for further training. 69% of doctors and 52.6% of nurses agreed that confidentiality could be breached in case of subpoena or other judicial processes. Only 68.4% nurses agreed that it is an offence to intentionally disclose HIV/AIDS confidential information to anyone who is not legally authorised. PMID- 23099596 TI - A social media self-evaluation checklist for medical practitioners. AB - Increasing numbers of medical practitioners and medical students are using online social and business-related networking websites such as Facebook, Doc2doc and LinkedIn. These rapidly evolving and growing social media have potential to promote public health by providing powerful instruments for communication and education. However, evidence is emerging from studies, legal cases, and media reports that the use of these new technologies is creating several ethical problems for medical practitioners as well as medical students. Improper online activities may harm not only individual reputations and careers, but also the medical profession as a whole, for example by breach of patient confidentiality, defamation of colleagues and employers, undisclosed conflict of interests that bias the medical practitioner's medical advice, posting of advice/information without an evidence base, and infringement of copyright. We developed a self evaluation checklist for medical practitioners using social media. The checklist addresses three key elements in the use of social media: personal information and accessibility, connections, and postings. It contains questions specifically formulated to evaluate a medical practitioner's social media profile, to prevent unintended, improper online activities and to promote professional online behaviour. PMID- 23099597 TI - Medical students' views on the migration of doctors: self-interest vs altruism. AB - The migration of doctors from developing to developed countries is an ongoing phenomenon. There is scant information on the attitudes of medical students to the ethical aspects of this trend. This paper reports on a study of 50 first-year medical students and 52 interns in a college in Vellore city, Tamil Nadu. Only 13 of 102 respondents thought that migrant doctors contributed significantly to the health system in India. 17% thought that doctor migration was not an ethical issue, and 40% thought that individual altruism had no role in solving public problems. The responses to case scenarios suggest that first-year medical students are more likely to have an altruistic and communitarian attitude whereas interns tended to emphasise individual liberty and autonomy. PMID- 23099598 TI - Sensitising doctors: a pedagogical approach to medical humanities. AB - The first part of this paper explores what we mean by the word 'sensitising' and presents an argument for conceiving of 'sensitising' in a way that respects the intellectual as well as the healing roles of medical practitioners, while taking the concept further as 'informed reflection'. It also makes a case for the importance of sensitising in medical 'praxis'. The second part of the paper describes an approach which is based partly on a module that has been taught in a medical programme. PMID- 23099599 TI - Review of multinational human subjects research: experience from the PHFI-Emory Center of Excellence partnership. AB - Public Health Foundation of India (PHFI), New Delhi, India and Emory University, Atlanta, USA, are lead partners in the National Heart, Lung and Blood Institute/UnitedHealth funded Center of Excellence (COE) in Cardio-metabolic Risk Reduction in South Asia which provides a vehicle for the development of collaborative research projects. With funding from the National Institutes of Health/ Fogarty International Center, a project was commenced to ensure seamless, thorough and efficient review of this collaborative research. The primary activities of the project are: 1) fact-finding activities which included conduct of a case study and review of policies and procedures of the involved ethics review committees (ERCs); 2) training workshops for COE ERC members and staff and 3) piloting of parallel review of continuing reviews and amendments. A process of parallel review of collaborative research has now been initiated and projects are now submitted simultaneously to the Emory institutional review board (IRB) and PHFI institutional ethics committee (IEC). PMID- 23099600 TI - Doctors and health in India: an outsider's perspective. PMID- 23099601 TI - Medical humanities in the undergraduate medical curriculum. AB - The medical humanities have been introduced in medical curricula over the past 30 years in the western world. Having medical humanities in a medical school curriculum can nurture positive attitudes in the regular work of a clinician and contribute equally to personality development. Though substantial evidence in favour of a medical humanities curriculum may be lacking, the feedback is positive. It is recommended that medical humanities be introduced into the curriculum of every medical school with the purpose of improving the quality of healthcare, and the attitudes of medical graduates. PMID- 23099602 TI - Pre-employment medical testing in Brazil: ethical challenges. AB - Pre-employment medical tests, considered to be a practice within the subspecialty of occupational medicine, are ordered by physicians on behalf of employers. Candidates for a job may be rejected if they are found to suffer from a condition that can be worsened by the job, or one that may put other workers at risk. As the physician who orders pre-employment tests is chosen by the employer, pre employment tests can violate both the autonomy and the privacy of the individual. This paper discusses ethical conflicts inherent in pre-employment medical testing. PMID- 23099603 TI - Private medical education in Sri Lanka. AB - Medicine is one of the most sought after professions in the world. However, opportunities for students to realise this dream are few, particularly due to the competitive nature of university entrance examinations. This essay discusses the establishment of private medical schools in Sri Lanka and the expanded opportunities now available for medical students. There are differing perspectives on these developments, among medical professionals as well as the public. We give a background to the controversy followed by opposing views from the first and second author on the regulatory framework in Sri Lanka and providers' commercial agenda. PMID- 23099604 TI - Mainstreaming AYUSH: an ethical analysis. AB - The National Rural Health Mission has stated as one of its key mandates the mainstreaming of the Ayurveda, Yoga, Naturopathy, Unani, Siddha and Homeopathy (AYUSH) systems in order to help solve the human resource shortage in Indian healthcare. This has been planned at the primary level by providing training to AYUSH practitioners on primary care and national health programmes; at the secondary level by establishing departments of AYUSH in the district and taluka level hospitals; and at the tertiary level by establishing AYUSH centres of excellence as referral centres, and research, development and supervision points. The practical challenges to be considered include a gross divergence in the basic philosophy of practice; disparities in approach to specific clinical conditions; differences in their normative approach in decision making; an unclear policy for cross referral and problems of cross practice that could potentially rise in this condition. Mainstreaming of AYUSH into the existing public health system can have certain ethical implications: not doing good by failing to concentrate on the community value judgments about AYUSH; doing harm by a confusing plurality in approach and unhealthy segregation of practices without healthy dialogue between practitioners of either system; not disclosing which type of practitioners (AYUSH or allopathy) the patient is seeing; lack of proper public accountability mechanisms at the primary care and grassroots levels; and, finally, lack of social justice. These ethical issues have to be considered while mainstreaming AYUSH. PMID- 23099605 TI - Patients rights in India: an ethical perspective. AB - Patient autonomy is affected by a number of factors, including severity of illness, socio-economic status and dependence. Many patients find that they are not treated with due consideration and compassion, and also have no control over their own care. PMID- 23099606 TI - Ethics of pandemic planning in India. PMID- 23099607 TI - Problems of isolated private hospitals in a rural setting. PMID- 23099608 TI - Ethical aspects of operating on seropositive patients. PMID- 23099609 TI - Pathologising alternate sexuality: shifting psychiatric practices and a need for ethical norms and reforms. PMID- 23099610 TI - Critical perspectives on the NIMH initiative "Grand Challenges to Global Mental Health". PMID- 23099611 TI - Psychiatric advance directives: cultural reflections. PMID- 23099612 TI - Medical humanities: addition to academic burden. PMID- 23099613 TI - Using bioabsorbable fixation systems in the treatment of pediatric skull deformities leads to good outcomes and low morbidity. AB - BACKGROUND: Bioabsorbable fixation systems have been widely employed in pediatric patients for cranial reconstruction, obviating the complications of hardware migration and imaging artifact occurring with metallic implants. Recent concern over complications unique to bioabsorbable materials, such as inflammatory reaction and incomplete resorption, necessitates additional conclusive studies to further validate their use in pediatric neurosurgery and craniofacial surgery. Likewise, long-term follow-up in this clinical cohort has not previously been described. METHODS: We included consecutive pediatric patients under the age of 2, from Lucile Packard Children's Hospital, who underwent cranial vault reconstruction with the use of a bioabsorbable fixation system between 2003 and 2010. Hospital records were queried for patient characteristics, intraoperative data, and postoperative complications. RESULTS: Ninety-five patients with the following preoperative pathologies were analyzed: craniosynostosis (87), cloverleaf skull (5), frontonasal dysplasia (1), and frontonasal encephalocele (2). Median age was 6 months (range 1-24 months). Average case duration was 204 minutes (range 40-392 min), with median of 154 mL blood loss (range 30-500 mL). Ninety-three percent of patients had 1-4 plates implanted with 48% receiving three plates. The median number of screws used was 59 (range 0-130). The median length of hospital stay was 4 days (range 2-127 days) with an average follow-up of 22 months (five postoperative visits). The complications related to hardware implantation included swelling (1%) and broken hardware (1%), the latter of which required reoperation. DISCUSSION: The bioabsorbable fixation systems for cranial vault reconstruction in children less than 2 years of age is safe with tolerable morbidity rates. PMID- 23099614 TI - A model for the role of defined spirituality in South African specialist psychiatric practice and training. AB - The current bio-psycho-social approach in South African psychiatry refers to Engel's extended model of health care. It forms the basis of the existing collaboration between medicine, nursing, psychology, occupational therapy and social work. Psychiatry also has to bridge the multi-cultural, multi-religious and spiritual diverse reality of everyday practice. It has become important to establish how, within accepted boundaries, spirituality should be incorporated into the model for practice. Referring to methods described for nursing theory development, a defined core concept was used to construct a model. It may contribute to the discourse on spirituality in local psychiatry, health and mental health. PMID- 23099615 TI - Effects of a novel poly (AA-co-AAm)/AlZnFe2O4/potassium humate superabsorbent hydrogel nanocomposite on water retention of sandy loam soil and wheat seedling growth. AB - A novel poly(acrylic acid-co-acrylamide)AlZnFe2O4/potassium humate( )superabsorbent hydrogel nanocomposite (PHNC) was synthesized and its physical properties characterized using SEM, Energy Dispersive X-ray (EDX) and FTIR spectroscopic techniques. Air dried sandy loam soil was amended with 0.1 to 0.4 w/w% of PHNC to evaluate its soil moisture retention attributes. Effect of PHNC amendment on pH, electrical conductivity (EC), porosity, bulk density and hydraulic conductivity of sandy loam soil was also studied. The soil amendment with 0.1 to 0.4 w/w% of PHNC remarkably enhanced the moisture retention at field capacity as compared to the un-amended soils. Seed germination and seedling growth of wheat (Triticum aestivum L.) was considerably increased and a delay by 6-9 days in wilting of seedlings was observed in the soil amended with PHNC, resulting in improved wheat plant establishment and growth. PMID- 23099616 TI - Growth inhibition of Streptococcus from the oral cavity by alpha-amyrin esters. AB - Five terpenoids were tested by the macrodilution broth method to determine their inhibition activity on cariogenic bacterial growth. In general, α-, β amyrin and α-amyrin phenylacetate proved to be active, reducing the bacterial viability to less than 20%. PMID- 23099617 TI - Phenolic content and antioxidant activity of Hibiscus cannabinus L. seed extracts after sequential solvent extraction. AB - A sequential solvent extraction scheme was employed for the extraction of antioxidant compounds from kenaf (Hibiscus cannabinus L.) seeds. Yield of extracts varied widely among the solvents and was the highest for hexane extract (16.6% based on dry weight basis), while water extract exhibited the highest total phenolic content (18.78 mg GAE/g extract), total flavonoid content (2.49 mg RE/g extract), and antioxidant activities (p < 0.05). DPPH and hydroxyl radical scavenging, β-carotene bleaching, metal chelating activity, ferric thiocyanate and thiobarbituric acid reactive substances assays were employed to comprehensively assess the antioxidant potential of different solvent extracts prepared sequentially. Besides water, methanolic extract also exhibited high retardation towards the formation of hydroperoxides and thiobarbituric acid reactive substances in the total antioxidant activity tests (p < 0.05). As conclusion, water and methanol extracts of kenaf seed may potentially serve as new sources of antioxidants for food and nutraceutical applications. PMID- 23099618 TI - Improved antileishmanial activity of Dppz through complexation with antimony(III) and bismuth(III): investigation of the role of the metal. AB - Two novel trivalent antimony(III) and bismuth(III) complexes with the nitrogen donor heterocyclic ligand dipyrido[3,2-a:2',3'-c]phenazine (dppz) were synthesized and characterized as [Sb(dppz)Cl3]?H2O?CH3OH and [Bi(dppz)Cl3]. The crystal structure of Sb(III) complex was determined by X-ray crystallography. These complexes were evaluated for their activity against the promastigote form of Sb(III)-sensitive and -resistant Leishmania infantum chagasi and Leishmania amazonensis strains. Both complexes were more effective than dppz alone in inhibiting the growth of Leishmania promastigotes and were at least 77 and 2,400 times more active than potassium antimonyl tartrate in Sb(III)-sensitive and resistant Leishmania, respectively. The cytotoxicity of dppz and its complexes against mouse peritoneal macrophages occurred at dppz concentrations at least 6 fold greater than those found to be active against Leishmania promastigotes.To investigate the role of the metal in the improved antileishmanial activity of dppz, the activity of the Sb(III) complex was compared between the Sb-resistant mutants and their respective parental sensitive strains. The lack of cross resistance to the Sb(III)-dppz complex together with the much lower activity of antimonyl tartrate, SbCl3 and BiCl3 strongly support the model that the metal is not active by itself but improves the activity of dppz through complexation. PMID- 23099619 TI - Two novel phenolic compounds from the rhizomes of Cyperus rotundus L. AB - Two novel compounds, 1alpha-methoxy-3beta-hydroxy-4alpha-(3',4'-dihydroxyphenyl) 1, 2,3,4-tetrahydronaphthalin (1) and 1alpha,3beta-dihydroxy-4alpha-(3',4' dihydroxyphenyl)-1,2,3,4-tetrahydronaphthalin (2), were isolated along with six known compounds 3-8 from the rhizomes of Cyperus rotundus. This paper reports the isolation and full spectroscopic characterization of these new compounds by NMR, UV, IR and MS data. PMID- 23099621 TI - Sclerosing encapsulating peritonitis after living donor liver transplantation: a case successfully treated with tamoxifen: report of a case. AB - Sclerosing encapsulating peritonitis (SEP) is a rare cause of bowel obstruction. It is difficult to diagnose and the prognosis is poor. This report describes a case of SEP after living donor liver transplantation that was successfully treated with tamoxifen. A 56-year-old male, that had received a liver transplant for hepatitis C virus-related hepatocellular carcinoma 5 years earlier, was admitted with continuous abdominal pain and nausea. He had increased C-reactive protein levels and white blood cell count, and underwent laparotomy 5 days after hospitalization. The surgical findings showed ascites and SEP of the small bowel. An attempt to peel off the adhesions was stopped because there was a strong risk of intestinal tract damage. Tamoxifen treatment was initiated for SEP after surgery. The patient's symptoms gradually improved and he was able to resume feeding. He had been symptom-free for over 3 years at the last follow-up. PMID- 23099620 TI - Ticlopidine inhibits both O-demethylation and renal clearance of tramadol, increasing the exposure to it, but itraconazole has no marked effect on the ticlopidine-tramadol interaction. AB - PURPOSE: We assessed possible drug interactions of tramadol given concomitantly with the potent CYP2B6 inhibitor ticlopidine, alone or together with the potent CYP3A4 and P-glycoprotein inhibitor itraconazole. METHODS: In a randomized, placebo-controlled cross-over study, 12 healthy subjects ingested 50 mg of tramadol after 4 days of pretreatment with either placebo, ticlopidine (250 mg twice daily) or ticlopidine plus itraconazole (200 mg once daily). Plasma and urine concentrations of tramadol and its active metabolite O-desmethyltramadol (M1) were monitored over 48 h and 24 h, respectively. RESULTS: Ticlopidine increased the mean area under the plasma concentration-time curve (AUC0-infinity) of tramadol by 2.0-fold (90 % confidence interval (CI) 1.6-2.4; p < 0.001) and Cmax by 1.4-fold (p < 0.001), and reduced its oral and renal clearance (p < 0.01). Ticlopidine reduced the AUC0-3 of M1 (p < 0.001) and the ratio of the AUC0 infinity of M1 to that of tramadol, but did not influence the AUC0-infinity of M1. Tramadol or M1 pharmacokinetics did not differ between the ticlopidine alone and ticlopidine plus itraconazole phases. CONCLUSIONS: Ticlopidine increased exposure to tramadol, reduced its renal clearance and inhibited the formation of M1, most likely via inhibition of CYP2B6 and/or CYP2D6. The addition of itraconazole to ticlopidine did not modify the outcome of the drug interaction. Concomitant clinical use of ticlopidine and tramadol may enhance the risk of serotonergic effects, especially when higher doses of tramadol are used. PMID- 23099623 TI - [Food hypersensitivities]. PMID- 23099622 TI - Randomized prospective trial comparing clinical outcomes 3 years after surgery by Marcy repair and Prolene Hernia System repair for adult indirect inguinal hernia. AB - PURPOSE: The use of mesh in the surgical repair of adult indirect inguinal hernias is widely recommended in Western countries, but no randomized controlled trials have so far been reported in Japan. The purpose of the present randomized prospective trial was to compare a mesh method with non-mesh method for surgical repair of primary adult indirect inguinal hernias in which the diameter of the internal inguinal ring was up to 3.0 cm (I-1 or I-2 of Japanese Hernia Society Classification). METHODS: Patients with a primary unilateral inguinal hernia and I-1 or I-2 surgical findings were randomized to undergo either Marcy repair or Prolene Hernia System repair. Primary endpoints were recurrence, infection, and pain, with follow-up continued for 3 years postoperatively. RESULTS: Ninety-one of 479 patients with an inguinal hernia during the study period did not meet the exclusion criteria, and 46 were allocated to Marcy repair and 45 were allocated to Prolene Hernia System repair. No recurrence was observed in either group, and no significant differences were identified between the groups in any of the primary endpoints. CONCLUSION: This randomized prospective trial of I-1 and I-2 inguinal hernias suggests that Marcy repair is not inferior to PHS repair. A large-scale randomized controlled trial appears warranted to confirm whether to use mesh for Japanese adult I-1 and I-2 hernias. PMID- 23099624 TI - Nuclear medicine and oncology. PMID- 23099626 TI - Daily substance use and mental health symptoms among a cohort of homeless adults in Vancouver, British Columbia. AB - Substance use can be a barrier to stable housing for homeless persons with mental disorders. We examined DSM-IV symptoms among homeless adults (N = 497), comparing those who reported daily substance use (DSU) with non-daily substance users. Multivariable linear regression modeling was used to test the independent association between DSU and symptoms using the Colorado Symptom Index total score. DSU was independently associated with higher symptoms (beta = 3.67, 95 % CI 1.55-5.77) adjusting for homelessness history, age, gender, ethnicity, education, marital status, and mental disorder sub-type (adjusted R (2) = 0.24). We observed a higher prevalence of DSU in our sample than has been previously reported in a Housing First intervention. DSU was also independently associated with more DSM-IV symptomatology. We have an opportunity to observe this cohort longitudinally and examine if there are changes in substance use based on treatment assignment and commensurate changes in housing stability, community integration, health status, and quality of life. PMID- 23099625 TI - The geography of recreational open space: influence of neighborhood racial composition and neighborhood poverty. AB - The geography of recreational open space might be inequitable in terms of minority neighborhood racial/ethnic composition and neighborhood poverty, perhaps due in part to residential segregation. This study evaluated the association between minority neighborhood racial/ethnic composition, neighborhood poverty, and recreational open space in Boston, Massachusetts (US). Across Boston census tracts, we computed percent non-Hispanic Black, percent Hispanic, and percent families in poverty as well as recreational open space density. We evaluated spatial autocorrelation in study variables and in the ordinary least squares (OLS) regression residuals via the Global Moran's I. We then computed Spearman correlations between the census tract socio-demographic characteristics and recreational open space density, including correlations adjusted for spatial autocorrelation. After this, we computed OLS regressions or spatial regressions as appropriate. Significant positive spatial autocorrelation was found for neighborhood socio-demographic characteristics (all p value = 0.001). We found marginally significant positive spatial autocorrelation in recreational open space (Global Moran's I = 0.082; p value = 0.053). However, we found no spatial autocorrelation in the OLS regression residuals, which indicated that spatial models were not appropriate. There was a negative correlation between census tract percent non-Hispanic Black and recreational open space density (r S = 0.22; conventional p value = 0.005; spatially adjusted p value = 0.019) as well as a negative correlation between predominantly non-Hispanic Black census tracts (>60 % non-Hispanic Black in a census tract) and recreational open space density (r S = -0.23; conventional p value = 0.003; spatially adjusted p value = 0.007). In bivariate and multivariate OLS models, percent non-Hispanic Black in a census tract and predominantly Black census tracts were associated with decreased density of recreational open space (p value < 0.001). Consistent with several previous studies in other geographic locales, we found that Black neighborhoods in Boston were less likely to have recreational open spaces, indicating the need for policy interventions promoting equitable access. Such interventions may contribute to reductions and disparities in obesity. PMID- 23099627 TI - A catalytically driven organometallic molecular motor. AB - We have observed by NMR spectroscopy that the diffusive movement of a ruthenium based Grubbs' catalyst increases during ring-closing metathesis as a function of the substrate concentration. This is one of the smallest single molecule motors to exhibit catalytically driven motion. PMID- 23099628 TI - Disordered eating in a digital age: eating behaviors, health, and quality of life in users of websites with pro-eating disorder content. AB - BACKGROUND: Much concern has been raised over pro-eating disorder (pro-ED) website communities, but little quantitative research has been conducted on these websites and their users. OBJECTIVE: To examine associations between levels of pro-ED website usage, disordered eating behaviors, and quality of life. METHODS: We conducted a cross-sectional, Internet-based survey of adult pro-ED website users. Main outcomes were Eating Disorder Examination Questionnaire (EDE-Q) and Eating Disorder Quality of Life (EDQOL) scores. RESULTS: We included responses from 1291 participants; 1254 (97.13%) participants were female. Participants had an average age of 22.0 years and a mean body mass index of 22.1 kg/m(2); 24.83% (296/1192) were underweight; 20.89% (249/1192) were overweight or obese. Over 70% of participants had purged, binged, or used laxatives to control their weight; only 12.91% (163/1263) were in treatment. Mean EDE-Q scores were above the 90th percentile and mean EDQOL scores were in the severely impaired range. When compared with moderate and light usage, heavy pro-ED website usage was associated with higher EDE-Q global (4.89 vs 4.56 for medium and 4.0 for light usage, P < .001) and EDQOL total scores (1.64 vs 1.45 for medium and 1.25 for light usage, P < .001), and more extreme weight loss behaviors and harmful post-website usage activities. In a multivariate model, the level of pro-ED website usage remained a significant predictor of EDE-Q scores. CONCLUSIONS: Pro-ED website visitors reported many disordered eating behaviors, although few had been treated. Heavy users reported poorer quality of life and more disordered eating behaviors. PMID- 23099629 TI - Magnetic resonance diffusion and relaxation characterization of water in the unfrozen vein network in polycrystalline ice and its response to microbial metabolic products. AB - Polycrystalline ice, as found in glaciers and the ice sheets of Antarctica, is a low porosity porous media consisting of a complicated and dynamic pore structure of liquid-filled intercrystalline veins within a solid ice matrix. In this work, Nuclear Magnetic Resonance measurements of relaxation rates and molecular diffusion, useful for probing pore structure and transport dynamics in porous systems, were used to physically characterize the unfrozen vein network structure in ice and its response to the presence of metabolic products produced by V3519 10, a cold tolerant microorganism isolated from the Vostok ice core. Recent research has found microorganisms that can remain viable and even metabolically active within icy environments at sub-zero temperatures. One potential mechanism of survival for V3519-10 is secretion of an extracellular ice binding protein that binds to the prism face of ice crystals and inhibits ice recrystallization, a coarsening process resulting in crystal growth with ice aging. Understanding the impact of ice binding activity on the bulk vein network structure in ice is important to modeling of frozen geophysical systems and in development of ice interacting proteins for biotechnology applications, such as cryopreservation of cell lines, and manufacturing processes in food sciences. Here, we present the first observations of recrystallization inhibition in low porosity ice containing V3519-10 extracellular protein extract as measured with Nuclear Magnetic Resonance and Magnetic Resonance Imaging. PMID- 23099630 TI - A - postgraduate educational programme. PMID- 23099631 TI - B - scientific sessions. PMID- 23099632 TI - C - scientific and educational exhibits. PMID- 23099633 TI - D - satellite symposia. PMID- 23099635 TI - F - list of authors and co-authors. PMID- 23099636 TI - G - list of moderators. PMID- 23099637 TI - Colon carcinoma in childhood: review of the literature with four case reports. AB - PURPOSE: Colorectal cancer (CRC) in childhood is extremely rare, and only a few case reports exist. We hereby present four cases of childhood CRC along with a literature review. METHODS: A retrospective review of four cases from our institute was conducted, and 15 articles from PubMed describing childhood CRC were reviewed. RESULTS: CASE REPORTS: Four patients ranging in age from 11 to 14 years were treated for colon cancer between the years 2000 and 2011. The presenting symptoms varied and included abdominal pain, nausea, vomiting, diarrhea, constipation, and hematochezia, with symptom duration ranging from a few days to 4 months. No patient had a predisposing disease or syndrome. All patients underwent surgical resections, with the most prevalent histology being mucinous adenocarcinoma. Despite radical surgery followed by systemic chemotherapy, the disease progressed in all patients. LITERATURE REVIEW: A total of 239 cases were reviewed. The youngest patient was 6 years old. The most frequent predisposing conditions were hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis. Most of the patients presented advanced stage, with the most common histopathologic diagnosis being mucinous adenocarcinoma, followed by poorly differentiated adenocarcinoma and signet ring cell carcinoma. Even though most of the patients underwent aggressive treatment, the overall prognosis was poor. CONCLUSIONS: Childhood CRC has an aggressive pathology and distinct genetic features, which result in an advanced stage at diagnosis and consequently a poor prognosis. Although the incidence is very low, every physician should be aware of CRC as a possible childhood diagnosis. PMID- 23099638 TI - The inherent problem of transflection-mode infrared spectroscopic microscopy and the ramifications for biomedical single point and imaging applications. AB - Transflection-mode FTIR spectroscopy has become a popular method of measuring spectra from biomedical and other samples due to the relative low cost of substrates compared to transmission windows, and a higher absorbance due to a double pass through the same sample approximately doubling the effective path length. In this publication we state an optical description of samples on multilayer low-e reflective substrates. Using this model we are able to explain in detail the so-called electric-field standing wave effect and rationalise the non-linear change in absorbance with sample thickness. The ramifications of this non-linear change, for imaging and classification systems, where a model is built from tissue sectioned at a particular thickness and compared with tissue of a different thickness are discussed. We show that spectra can be distorted such that classification fails leading to inaccurate tissue segmentation which may have subsequent implications for disease diagnostics applications. PMID- 23099639 TI - Object-based correspondence effects for action-relevant and surface-property judgments with keypress responses: evidence for a basis in spatial coding. AB - It has been proposed that grasping affordances produce a Simon-type correspondence effect for left-right keypress responses and the location of the graspable part of an object for judgments based on action-relevant properties such as shape, but not on surface properties. We tested the implications of this grasping affordance account and contrasted them with the ones derived from a spatial coding account that distinguishes holistic processing of integral dimensions and analytic processing of separable dimensions. In Experiments 1-3, judgments about the color of a door handle showed a Simon effect relative to the handle's base, whereas judgments about the handle's shape showed no Simon effect. In Experiment 4, when the middle of the handle was colored, the Simon effect was obtained relative to the base, but when the color was at the tip of the handle or near the base, Simon effects were obtained relative to the color location. For Experiment 5, only the base was colored, and the Simon effect was larger for a passive rather than active handle state, as in the color-judgment conditions of Experiments 2-4 in which the colored region overlapped with the base. In Experiment 6, orientation judgments showed no Simon effect, as the shape judgments did in Experiments 1 and 2. The findings of (a) an absence of Simon effects for shape and orientation judgments, (b) no larger Simon effects for active than passive handle states, and (c) isolation of the changing component for color judgments are consistent with the spatial coding account, according to which the distinction between object shape/orientation and color is one of integral versus separable dimensions. PMID- 23099640 TI - Mapped! A machinery of degranulation in mast cells. Focus on "Serum- and glucocorticoid-inducible kinase SGK1 regulates reorganization of actin cytoskeleton in mast cells upon degranulation". PMID- 23099642 TI - Salt, skeletons, and suicide. Focus on "Hyperosmotic stress regulates the distribution and stability of myocardin-related transcription factor, a key modulator of the cytoskeleton". PMID- 23099641 TI - Apical vacuole formation by gastric parietal cells in primary culture: effect of low extracellular Ca2+. AB - In primary culture, the gastric parietal cell's deeply invaginated apical membrane, seen in microscopy by phalloidin binding to F-actin (concentrated in microvilli and a subapical web), is engulfed into the cell, separated from the basolateral membrane (which then becomes the complete plasma membrane), and converted, from a lacy interconnected system of canaliculi, into several separate vacuoles. In this study, vacuolar morphology was achieved by 71% of parietal cells 8 h after typical collagenase digestion of rabbit gastric mucosa, but the tight-junctional protein zonula occludens-1 (ZO-1) was completely delocalized after ~2 h, when cells were ready for culturing. Use of low-Ca(2+) medium (4 mM EGTA) to release cells quickly from gastric glands yielded parietal cells in which ZO-1 was seen in a small spot or ring, a localization quickly lost if these cells were then cultured in normal Ca(2+) but remaining up to 20 h if they were cultured in low Ca(2+). The cells in low Ca(2+) mostly retained, at 20 h, an intermediate morphology of many bulbous canalicular expansions ("prevacuoles"), seemingly with narrow interconnections. Histamine stimulation of 20-h cells with intermediate morphology caused colocalization of proton-pumping H-K-ATPase with canaliculi and prevacuoles but little swelling of those structures, consistent with a remaining apical pore through which secreted acid could escape. Apparent canalicular interconnections, lack of stimulated swelling, and lingering ZO-1 staining indicate inhibition of membrane fission processes that separate apical from basolateral membrane and vacuoles from each other, suggesting an important role for extracellular Ca(2+) in these, and possibly other, endocytotic processes. PMID- 23099643 TI - Hypoxia-augmented constriction of deep femoral artery mediated by inhibition of eNOS in smooth muscle. AB - In contrast to the conventional belief that systemic arteries dilate under hypoxia, we found that alpha-adrenergic contraction of rat deep femoral artery (DFA) is largely augmented by hypoxia (HVC(DFA)) while hypoxia (3% Po(2)) alone had no effect. HVC(DFA) was consistently observed in both endothelium-intact and denuded vessels with partial pretone by phenylephrine (PhE) or by other conditions (e.g., K(+) channel blocker). Patch-clamp study showed no change in the membrane conductance of DFA myocytes by hypoxia. The RhoA-kinase inhibitor Y27632 attenuated HVC(DFA). The nitric oxide synthase inhibitor [nitro-L-arginine methyl ester (L-NAME)] and soluble guanylate cyclase inhibitor [oxadiazole quinoxalin (ODQ)] strongly augmented the PhE-pretone, while neither of the agents had effect without pretone. NADPH oxidase type 4 (NOX4) inhibitors (diphenylene iodonium and plumbagin) also potentiated PhE-pretone, which was reversed by NO donor. No additive HVC(DFA) was observed under the pretreatment with L-NAME, ODQ, or plumbagin. Western blot and immunohistochemistry analysis showed that both NOX4 and endothelial nitric oxide synthase (eNOS) are expressed in smooth muscle layer of DFA. Various mitochondria inhibitors (rotenone, myxothiazol, and cyanide) prevented HVC(DFA). From the pharmacological data, as a mechanism for HVC(DFA), we suggest hypoxic inhibition of eNOS in myocytes. The putative role of NOX4 and mitochondria requires further investigation. The HVC(DFA) may prevent imbalance between cardiac output and skeletal blood flow under emergent hypoxia combined with increased sympathetic tone. PMID- 23099644 TI - Relationship between wettability and lubrication characteristics of the surfaces of contacting phospholipid-based membranes. AB - The wettability of the articular surface of cartilage depends on the condition of its surface active phospholipid overlay, which is structured as multi-bilayer. Based on a hypothesis that the surface of cartilage facilitates the almost frictionless lubrication of the joint, we examined the characteristics of this membrane surface entity in both its normal and degenerated conditions using a combination of atomic force microscopy, contact angle measurement, and friction test methods. The observations have led to the conclusions that (1) the acid-base equilibrium condition influences the lubrication effectiveness of the surface of cartilage and (2) the friction coefficient is significantly dependent on the hydrophobicity of the surface of the tissue, thereby confirming the hypothesis tested in this paper. Both wettability angle and interfacial energy were obtained for varying conditions of the cartilage surface both in its wet, dry and lipid depleted conditions. The interfacial energy also increased with mole fraction of the lipid species reaching an asymptotic value after 0.6. Also, the friction coefficient was found to decrease to an asymptotic level as the wettability angle increased. The result reveal that the interfacial energy increased with pH till pH = 4.0, and then decreased from pH = 4.0 to reach equilibrium at pH = 7.0. PMID- 23099645 TI - Association of NDRG1 gene promoter methylation with reduced NDRG1 expression in gastric cancer cells and tissue specimens. AB - NDRG1 (N-myc downstream-regulated gene 1) plays a role in cell differentiation and suppression of tumor metastasis. This study aims to determine the expression of NDRG1 mRNA and protein in gastric cancer cell lines and tissue specimens and then assess the possible cause of its aberrant expression. Six gastric cancer cell lines and 20 pairs of normal and gastric cancer tissue samples were used to assess NDRG1 expression using Real-time PCR and Western blot. High-resolution melting analysis (HRM) and methylation-specific PCR (MSP) were performed to detect gene mutation and methylation, respectively, in cell lines and tissues samples. Expression of NDRG1 mRNA and protein was downregulated in gastric cancer cell lines and tissues. Specifically, expression of NDRG1 mRNA and protein was lower in all six gastric cancer cell lines than that of normal gastric cells, while 15 out of 20 cases of gastric cancer tissues had the reduced levels of NDRG1 mRNA and protein. HRM data showed that there was no mutation in NDRG1 gene, but MSP data showed high levels of NDRG1 gene promoter methylation in the CpG islands in both cell lines and tissue samples. Moreover, treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine upregulated NDRG1 expression in gastric cancer HGC27 cells, but not in the histone deacetylase inhibitor trichostatin A-treated HGC27 cells. In conclusion, this study has shown that expression of NDRG1 mRNA and protein was reduced in gastric cancer cell lines and tissues, which is due to methylation of NDRG1 gene promoter. Further study will unearth the clinical significance of the reduced NDRG1 protein in gastric cancer. PMID- 23099646 TI - The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. AB - BACKGROUND: DYRK1A plays different functions during development, with an important role in controlling brain growth through neuronal proliferation and neurogenesis. It is expressed in a gene dosage dependent manner since dyrk1a haploinsufficiency induces a reduced brain size in mice, and DYRK1A overexpression is the candidate gene for intellectual disability (ID) and microcephaly in Down syndrome. We have identified a 69 kb deletion including the 5' region of the DYRK1A gene in a patient with growth retardation, primary microcephaly, facial dysmorphism, seizures, ataxic gait, absent speech and ID. Because four patients previously reported with intragenic DYRK1A rearrangements or 21q22 microdeletions including only DYRK1A presented with overlapping phenotypes, we hypothesised that DYRK1A mutations could be responsible for syndromic ID with severe microcephaly and epilepsy. METHODS: The DYRK1A gene was studied by direct sequencing and quantitative PCR in a cohort of 105 patients with ID and at least two symptoms from the Angelman syndrome spectrum (microcephaly < -2.5 SD, ataxic gait, seizures and speech delay). RESULTS: We identified a de novo frameshift mutation (c.290_291delCT; p.Ser97Cysfs*98) in a patient with growth retardation, primary severe microcephaly, delayed language, ID, and seizures. CONCLUSION: The identification of a truncating mutation in a patient with ID, severe microcephaly, epilepsy, and growth retardation, combined with its dual function in regulating the neural proliferation/neuronal differentiation, adds DYRK1A to the list of genes responsible for such a phenotype. ID, microcephaly, epilepsy, and language delay are the more specific features associated with DYRK1A abnormalities. DYRK1A studies should be discussed in patients presenting such a phenotype. PMID- 23099648 TI - Risk of malignant paraganglioma in SDHB-mutation and SDHD-mutation carriers: a systematic review and meta-analysis. AB - The main objective of this study was to perform a systematic review and meta analysis on the risk of developing malignant paraganglioma (PGL) in SDHB-mutation and SDHD-mutation carriers. PubMed, EMBASE, Web of Science, COCHRANE and Academic Search Premier (2000-August 2011) and references of key articles were searched to identify potentially relevant studies. The main outcomes were the pooled incidence and prevalence of malignant PGL in SDHB-mutation and SDHD-mutation carriers. A meta-analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Twelve studies were included. The pooled incidence of malignant PGL in populations comprising both asymptomatic mutation carriers and mutation carriers with manifest non-malignant PGL was 17% (95% CI 10 to 28) for SDHB-mutation carriers and 8% (95% CI 2 to 26) for SDHD-mutation carriers. The pooled risk in prevalence studies was 13% (95% CI 4 to 34) and 4% (95% CI 2 to 7), respectively. In studies comprising only mutation carriers with manifest disease, the pooled prevalence was 23% (95% CI 16 to 33) for SDHB-mutation and 3% (95% CI 1 to 10) for SDHD-mutation carriers. Incidence and prevalence of malignant PGL are higher in SDHB-mutation than in SDHD-mutation carriers, but lower in SDHB-mutation carriers than hitherto appreciated. PMID- 23099647 TI - Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis. AB - BACKGROUND: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant disorder characterised by coarse, wiry, twisted hair developed in early childhood and subsequent progressive hair loss. MUHH is a genetically heterogeneous disorder. No gene in 1p21.1-1q21.3 region responsible for MUHH has been identified. METHODS: Exome sequencing was performed on two affected subjects, who had normal vertex hair and modest alopecia, and one unaffected individual from a four-generation MUHH family of which our previous linkage study mapped the MUHH locus on chromosome 1p21.1-1q21.3. RESULTS: We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3. Sanger sequencing confirmed the cosegregation of this mutation with the disease phenotype in the family by demonstrating the presence of the heterozygous mutation in all the eight affected and absence in all the seven unaffected individuals. This mutation was found to be absent in 676 unrelated healthy controls and 781 patients of other disease from another unpublished project of our group. CONCLUSIONS: Taken together, our results suggest that EPS8L3 is a causative gene for MUHH, which was helpful for advancing us on understanding of the pathogenesis of MUHH. Our study also has further demonstrated the effectiveness of combining exome sequencing with linkage information for identifying Mendelian disease genes. PMID- 23099649 TI - Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. AB - Adrenomedullin (AM) is a potent lymphangiogenic factor that promotes lymphatic endothelial cell (LEC) proliferation through a pharmacologically tractable G protein-coupled receptor. Numerous types of human cancers have increased levels of AM; however, the functional consequences of this fact have not been characterized. Therefore, we evaluated whether modulating adrenomedullin (Adm) gene dosage within tumor cells affects lymphangiogenesis. Murine Lewis lung carcinoma (LLC) cells that overexpress or underexpress Adm were injected subcutaneously into C57BL/6 mice, and tumors were evaluated for growth and vascularization. A dosage range from ~10 to 200% of wild-type Adm expression did not affect LLC proliferation in vitro or in vivo, nor did it affect angiogenesis. Notably, the dosage of Adm markedly and significantly influenced tumor lymphangiogenesis. Reduced Adm expression in tumors decreased the proliferation of LECs and the number of lymphatic vessels, while elevated tumor Adm expression led to enlarged lymphatic vessels. Moreover, overexpression of Adm in tumors induced sentinel lymph node lymphangiogenesis and led to an increased incidence of Ki67-positive foci within the lung. These data show that tumor-secreted AM is a critical factor for driving both tumor and lymph node lymphangiogenesis. Thus, pharmacological targeting of AM signaling may provide a new avenue for inhibition of tumor lymphangiogenesis. PMID- 23099650 TI - Effects of spaceflight and ground recovery on mesenteric artery and vein constrictor properties in mice. AB - Following exposure to microgravity, there is a reduced ability of astronauts to augment peripheral vascular resistance, often resulting in orthostatic hypotension. The purpose of this study was to test the hypothesis that mesenteric arteries and veins will exhibit diminished vasoconstrictor responses after spaceflight. Mesenteric arteries and veins from female mice flown on the Space Transportation System (STS)-131 (n=11), STS-133 (n=6), and STS-135 (n=3) shuttle missions and respective ground-based control mice (n=30) were isolated for in vitro experimentation. Vasoconstrictor responses were evoked in arteries via norepinephrine (NE), potassium chloride (KCl), and caffeine, and in veins through NE across a range of intraluminal pressures (2-12 cmH(2)O). Vasoconstriction to NE was also determined in mesenteric arteries at 1, 5, and 7 d postlanding. In arteries, maximal constriction to NE, KCl, and caffeine were reduced immediately following spaceflight and 1 d postflight. Spaceflight also reduced arterial ryanodine receptor-3 mRNA levels. In mesenteric veins, there was diminished constriction to NE after flight. The results indicate that the impaired vasoconstriction following spaceflight occurs through the ryanodine receptor mediated intracellular Ca(2+) release mechanism. Such vascular changes in astronauts could compromise the maintenance of arterial pressure during orthostatic stress. PMID- 23099651 TI - Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. AB - The activity of single-agent targeted molecular therapies in glioblastoma has been limited to date. The North American Brain Tumor Consortium examined the safety, pharmacokinetics, and efficacy of combination therapy with sorafenib, a small molecule inhibitor of Raf, vascular endothelial growth factor receptor 2, and platelet-derived growth factor receptor-beta, and temsirolimus (CCI-779), an inhibitor of mammalian target of rapamycin. This was a phase I/II study. The phase I component used a standard 3 * 3 dose escalation scheme to determine the safety and tolerability of this combination therapy. The phase II component used a 2-stage design; the primary endpoint was 6-month progression-free survival (PFS6) rate. Thirteen patients enrolled in the phase I component. The maximum tolerated dosage (MTD) for combination therapy was sorafenib 800 mg daily and temsirolimus 25 mg once weekly. At the MTD, grade 3 thrombocytopenia was the dose limiting toxicity. Eighteen patients were treated in the phase II component. At interim analysis, the study was terminated and did not proceed to the second stage. No patients remained progression free at 6 months. Median PFS was 8 weeks. The toxicity of this combination therapy resulted in a maximum tolerated dose of temsirolimus that was only one-tenth of the single-agent dose. Minimal activity in recurrent glioblastoma multiforme was seen at the MTD of the 2 combined agents. PMID- 23099652 TI - A phase I/II trial of vandetanib for patients with recurrent malignant glioma. AB - Vandetanib is a once-daily multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and the rearranged-during-transfection oncogene. A phase I trial was conducted to describe the pharmacokinetics of vandetanib in patients with recurrent glioma on enzyme-inducing anti-epileptic drugs (EIAEDs) and to identify the maximum tolerated dose (MTD) in this population. A phase II trial evaluated the efficacy of vandetanib in patients with recurrent malignant glioma not on EIAEDs as measured by 6-month progression-free survival (PFS6). In the phase I trial, 15 patients were treated with vandetanib at doses of 300, 400, and 500 mg/day, in a standard dose-escalation design. The MTD in patients on EIAEDs was 400 mg/day, and steady-state levels were similar to those measured in patients not on EIAEDs. Dose-limiting toxicities were prolonged QTc and thromboembolism. Thirty-two patients with recurrent glioblastoma multiforme (GBM) and 32 patients with recurrent anaplastic gliomas (AGs) were treated in the phase II trial, at a dosage of 300 mg/day on 28-day cycles. Six patients (4 GBM, 2 AG) had radiographic response. PFS6 was 6.5% in the GBM arm and 7.0% in the AG arm. Median overall survival was 6.3 months in the GBM arm and 7.6 months in the AG arm. Seizures were an unexpected toxicity of therapy. Vandetanib did not have significant activity in unselected patients with recurrent malignant glioma. PMID- 23099653 TI - Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children's Oncology Group trial A9961. AB - The purpose of the trial was to determine the survival and incidence of secondary tumors in children with medulloblastoma receiving radiotherapy plus chemotherapy. Three hundred seventy-nine eligible patients with nondisseminated medulloblastoma between the ages of 3 and 21 years were treated with 2340 cGy of craniospinal and 5580 cGy of posterior fossa irradiation. Patients were randomized between postradiation cisplatin and vincristine plus either CCNU or cyclophosphamide. Survival, pattern of relapse, and occurrence of secondary tumors were assessed. Five- and 10-year event-free survivals were 81 +/- 2% and 75.8 +/- 2.3%; overall survivals were 87 +/- 1.8% and 81.3 +/- 2.1%. Event-free survival was not impacted by chemotherapeutic regimen, sex, race, age at diagnosis, or gender. Seven patients had disease relapse beyond 5 years after diagnosis; relapse was local in 4 patients, local plus supratentorial in 2, and supratentorial alone in 1. Fifteen patients experienced secondary tumors as a first event at a median time of 5.8 years after diagnosis (11 >5 y postdiagnosis). All non-CNS solid secondary tumors (4) occurred in regions that had received radiation. Of the 6 high-grade gliomas, 5 occurred >5 years postdiagnosis. The estimated cumulative 10-year incidence rate of secondary malignancies was 4.2% (1.9%-6.5%). Few patients with medulloblastoma will relapse >= 5 years postdiagnosis; relapse will occur predominantly at the primary tumor site. Patients are at risk for development of secondary tumors, many of which are malignant gliomas. This may become an increasing issue as more children survive. PMID- 23099654 TI - Dialysis Outcomes and Practice Patterns Study (DOPPS): its strengths, limitations, and role in informing practices and policies. PMID- 23099655 TI - AKI in a hospitalized patient with cellulitis. AB - AKI occurs commonly in hospitalized patients with multiple comorbidities. In this Attending Rounds, a woman with AKI in the setting of an infection, use of antibiotics and other medications, bacteremia, and hypotension is considered. Such patients lead to a broad differential diagnosis for AKI including prerenal AKI, acute tubular injury/acute tubular necrosis, infection-related GN, and drug induced acute interstitial nephritis. The roles of an accurate history, physical examination, laboratory data, and kidney biopsy are highlighted in establishing the correct diagnosis in such patients. PMID- 23099656 TI - The Central American epidemic of CKD. AB - Recent reports have described an apparent epidemic of CKD along the Pacific coast of Central America, such that CKD is a leading cause of death among working-age men in lower-altitude agricultural communities in this region. Given the limited availability of kidney replacement therapies in this region, CKD often is a terminal diagnosis, lending greater urgency to the identification of a modifiable cause. This article discusses the epidemiology of CKD in this region, reviews the clinical features of this CKD outbreak, discusses potential causes and the evidence supporting these hypotheses, and highlights the wider implications of this epidemic of CKD. PMID- 23099657 TI - Conducting shorter VEP tests to estimate visual acuity via assessment of SNR. AB - INTRODUCTION: The estimation of visual acuity (VA) via visual evoked potentials (VEP) is a valuable measure for all preverbal and non-verbal subjects whether adults or children. The aim of this study is to introduce a novel technique of VEP acquisition based on estimates of signal-to-noise ratio (SNR) and comparison to a predefined detection threshold. We aim to demonstrate the reduction in total study time without compromising the accuracy of the VEP-determined acuity estimate. METHODS: The VEP-determined acuity of twelve normal subjects was assessed via a spatial frequency (SF) sweep. A pattern reversal checkerboard stimulus utilised SFs ranging from 0.1 to 28 cycles per degree (cpd). Using linear extrapolation and Bland-Altman analysis, VEP-acquired acuity was compared to a conventional Snellen Acuity measurement. An SNR test, Fsp, assessed signal quality to determine the minimum amount of sweep data required for VEP-based VA estimation. RESULTS: VEP acuity estimates correlated strongly (r2=0.91, SD=0.06), leading to a VA limit via extrapolation. Bland-Altman analysis revealed agreement between tests is statistically valid (95% CI -0.11 to 0.42 logMAR). The Fsp statistic indicated SFs 1.3-3.6 cpd yielded Fsp>3.1 within 15 s of acquisition with frequencies>3.6 cpd being sub-threshold. The Kruskal-Wallis statistic compared final Fsp values for SFs as groups, where F=208.82 ranking each frequency, with frequencies>7.2 cpd ranking lowest. DISCUSSION: The Fsp as an SNR measurement shows that rapid, quality-driven clinical tests for VEP-based acuity estimates can be conducted without compromising accuracy. PMID- 23099658 TI - Making health promotion evidenced-informed: an organizational priority. AB - This large urban health unit identified a need for explicit, strategic, long-term organizational priority toward practical application of evidence in health promotion practice. Becoming a Best Practice Spotlight Organization (BPSO(r)) candidate provided an opportunity to systematically implement this commitment. The primary goals were to support incorporation of evidence-informed practice throughout the organization, increase interprofessional collaboration, and provide opportunities for knowledge exchange for staff. A mixed-methods evaluation consisting of three phases, including an analysis of previous evaluations, a survey of Champions, and an online focus group with the Steering Committee, demonstrated very positive outcomes. Staff reported increased incorporation of evidence in practice and program delivery. Collaboration and consultation amongst interdisciplinary staff across program areas also increased and staff responded very positively to increased opportunities for knowledge exchange. BPSO(r) candidacy opportunities should be used by health organizations to increase evidence-informed practice and inspire excellence in health promotion practice. PMID- 23099659 TI - The development of a culturally relevant, theoretically driven HPV prevention intervention for urban adolescent females and their parents/guardians. AB - Human papillomavirus (HPV) is the most common sexually transmitted infection in the United States, accounting for the large majority of cervical cancer and anogenital warts cases. Two HPV vaccines are currently licensed and recommended for women and girls. However, vaccination rates have been suboptimal, with evidence of disparities influencing both uptake and series completion among African American and Hispanic adolescents. There has been a dearth of theory based, behavioral interventions targeted to prevent HPV infection and increase HPV vaccine uptake among urban adolescents. This article describes the development of two skills-based intervention curricula aimed to increase HPV prevention and vaccination among low-income urban adolescent females 9 to 18 years old. Guided by the theory of planned behavior, elicitation research was conducted to elucidate the social psychological factors that underlie HPV vaccination intentions (N = 141). The findings were subsequently used to identify theoretical mediators of behavioral change to drive the intervention. Culturally relevant strategies to promote HPV vaccination were translated into the curricula content. Both curricula were designed to motivate and empower participants to reduce risk of being infected with HPV. Targeting theoretical mediators of behavioral change, derived from the voices of the community, may prove to be successful in increasing HPV vaccination and preventing HPV. PMID- 23099660 TI - Promoting positive youth development and highlighting reasons for living in Northwest Alaska through digital storytelling. AB - Using a positive youth development framework, this article describes how a 3-year digital storytelling project and the 566 digital stories produced from it in Northwest Alaska promote protective factors in the lives of Alaska Native youth and serve as digital "hope kits," a suicide prevention approach that emphasizes young people's reasons for living. Digital stories are short, participant produced videos that combine photos, music, and voice. We present process data that indicate the ways that digital stories serve as a platform for youth to reflect on and represent their lives, important relationships and achievements. In so doing, youth use the digital storytelling process to identify and highlight encouraging aspects of their lives, and develop more certain and positive identity formations. These processes are correlated with positive youth health outcomes. In addition, the digital stories themselves serve as reminders of the young people's personal assets--their reasons for living--after the workshop ends. Young people in this project often showed their digital stories to those who were featured positively within as a way to strengthen these interpersonal relationships. Evaluation data from the project show that digital storytelling workshops and outputs are a promising positive youth development approach. The project and the qualitative data demonstrate the need for further studies focusing on outcomes related to suicide prevention. PMID- 23099661 TI - The use of concept mapping to identify community-driven intervention strategies for physical and mental health. AB - Research that partners with youth and community stakeholders increases contextual relevance and community buy-in and therefore maximizes the chance for intervention success. Concept mapping is a mixed-method participatory research process that accesses the input of the community in a collaborative manner. After a school-wide health needs assessment at a low-income, minority/immigrant K-8 school identified bullying and obesity as the most important health issues, concept mapping was used to identify and prioritize specific strategies to address these two areas. Stakeholders including 160 K-8 students, 33 college students working in the school, 35 parents, 20 academic partners, and 22 teachers/staff brainstormed strategies to reduce and prevent obesity and bullying. A smaller group of stakeholders worked individually to complete an unstructured sorting of these strategies into groups of similar ideas, once for obesity and again for bullying. Multidimensional scaling and cluster analysis was applied to the sorting data to produce a series of maps that illustrated the stakeholders' conceptual thinking about obesity and bullying prevention strategies. The maps for both obesity and bullying organized specific strategies into themes that included education, parental role, teacher/school supervision, youth role, expert/professional role, and school structure/support. PMID- 23099662 TI - Trek across Maine 25th anniversary: a public health strategy to increase physical activity. AB - Could an annual event be an effective strategy to improve physical activity? Based on 25 years of data, we argue that it could be. Although there are eight recommended strategies to promote physical activity in the Community Guide, there is insufficient evidence for six others. Qualitative data collected from Trek Across Maine participants and other cause-specific events suggests that goal setting (i.e., individually adapted health behavior change) and family-based social support may be key factors in helping individuals become more physically active. PMID- 23099663 TI - Toward the optimum measurement of visual acuity. PMID- 23099664 TI - Total anomalous pulmonary venous connection to the unroofed coronary sinus in a neonate. AB - This report describes the unique case of a newborn with total anomalous pulmonary venous connection to an unroofed coronary sinus associated with Ullrich-Turner syndrome and aortic coarctation. Total anomalous pulmonary venous connection to the unroofed coronary sinus is an extremely uncommon cardiac abnormality. This congenital heart disease is difficult to diagnose and rarely ever reported. Few symptoms are to be expected when it is not associated with other congenital heart defects. This lesion results in a "naturally" corrected total anomalous pulmonary venous return and a coronary sinus atrial septal defect presenting as a left-to right shunting lesion. Making the diagnosis of this cardiac defect, and if possible, surgical repair is of importance because cardiac dysfunction due to significant atrial left-to-right shunting is a known long-term complication in the older adult patient. PMID- 23099665 TI - Stenting a pulmonary artery stenosis through the pulmonary native outflow tract in a congenitally corrected transposition of the great arteries. PMID- 23099666 TI - Pitfalls in the interpretation of structural changes in mutant proteins from crystal structures. AB - PpcA is a small protein with 71 residues that contains three covalently bound hemes. The structures of single mutants at residue 58 have shown larger deviations in another part of the protein molecule than at the site of the mutation. Closer examination of the crystal packing has revealed the origin of this unexpected structural change. The site of mutation is within Van der Waals distance from another protein molecule related by a crystallographic twofold axis within the crystal. The structural changes occurred at or near the mutation site have led to a slight adjustment of the surface residues in contact. The observed deviations between the native and the mutant molecular structures are derived from the new crystal packing even though the two crystals are essentially isomorphous. Without careful consideration of the crystal lattice a non-expert looking at only the coordinates deposited in the Protein Data Bank could draw erroneous conclusion that mutation in one part of the molecule affected the structure of the protein in a distant part of the molecule. PMID- 23099668 TI - My own bitter experience. PMID- 23099667 TI - How gullible are we? PMID- 23099669 TI - Banana root fracture. PMID- 23099670 TI - Alf's results. PMID- 23099671 TI - Increase in referrals. PMID- 23099672 TI - A lighter preference. PMID- 23099673 TI - Taking prevention to the child. PMID- 23099674 TI - Completely without foundation. PMID- 23099675 TI - Useless mountain of paperwork. PMID- 23099676 TI - Narrower skulls. PMID- 23099677 TI - Dislocated jaw. PMID- 23099689 TI - The difficulties of making 'CPD verifiability' a legitimate measure of learning outcomes. AB - This article offers further thoughts and raises wider issues in the continuing debate over the value of current CPD programmes and the way in which they are measured in terms of input rather than learning outcomes benefiting patients. PMID- 23099691 TI - Oral diagnosis and treatment planning: part 8. Reviews and maintenance of restorations. AB - The oral environment is hostile to dental materials and to dental treatments. Microorganisms, warmth, moisture and high stresses impose severe limitations on the ability to maintain the initial results of dental treatment. Therefore, continuous periodic reviews and maintenance of oral health are required to retain the restored dentition. PMID- 23099697 TI - Summary of: the impact of General Dental Council registration and continuing professional development on UK dental care professionals: (2) dental technicians. PMID- 23099698 TI - Summary of: an investigation of antibiotic prophylaxis in implant practice in the UK. PMID- 23099699 TI - A profile of Frank Harrison: a pioneering Sheffield dentist from 100 years ago. AB - A review of the personal papers relating to Frank Harrison and held by the School of Clinical Dentistry in Sheffield reveal what a dedicated clinician he was and the significance of his achievements from over 100 years ago, both locally and nationally for his chosen profession and also for the people of Sheffield. In addition to being one of the first dentists in the world to experiment with X rays in dentistry, and the first to write up his findings in a dental journal, he designed and patented dental instruments, wrote books, lectured on fine art (particularly Venetian and Florentine art), and gave lectures to the public in the hope that they would heed his message on the importance of maintaining good oral health. A search of national archives and library resources has added further information about his family and professional accomplishments. PMID- 23099700 TI - Improving the quality of oral surgery referrals. AB - INTRODUCTION: General referral letters to any hospital specialty are universally poor. These letters are the main source of information regarding the clinical problem and shortfalls can compromise the management of the patient. METHOD: One hundred retrospective randomly selected oral surgery referral letters in the form of proformae, made to oral and maxillofacial departments were examined against a set standard. Following the audit, a redesigned proforma, guidance and feedback questionnaires were distributed, followed by re-audit of 100 redesigned referral proformae. RESULTS: The main improvements seen were increases of: 52% in stating type of anaesthesia, 48% medical history, 38% referral date, 35% duration of symptoms, 32% use of the 'clinical details section', 31% stating treatment provided, 23% symptoms, 21% in clarity, 18% general medical practioner's (GMP's) address, 18% reason for referral, 15% social history, 14% diagnosis, 13% in using diagrams to aid explanation and 10% inclusion of a radiograph. DISCUSSION: Improvements in the quality of referral communications from local dentists were successfully made. CONCLUSION: Designing a pro-forma in close accordance with gold standards can achieve notable improvements to allow us to provide the best possible service and management for all our patients. PMID- 23099716 TI - Tim Newton: 'The government must get back to the idea of working with the professions'. Interview by Ruth Doherty. AB - Tim Newton, leader of King's Health Psychology Service, talks to the BDJ about his views on UK health policy and tells us why a dentist's visit can still cause a lot of anxiety for patients. PMID- 23099723 TI - The impact of General Dental Council registration and continuing professional development on UK dental care professionals: (2) dental technicians. AB - OBJECTIVE: To investigate the impact of General Dental Council (GDC) registration and mandatory CPD on dental technicians' views, job satisfaction and intention to leave the profession. DESIGN: Postal/online survey, conducted in parallel with a survey of dental nurses. SETTING: UK private and NHS practices, community services, dental hospitals. SUBJECTS AND METHODS: Representative sample of GDC registrants. MAIN OUTCOME MEASURES: job satisfaction; intention to leave profession (dependent variable in regression analysis). RESULTS: 605 were sampled: 40 were ineligible (left the register in July 2011, re-qualified in another dental care profession, shared a practice address with another selected DT); 193 responded (response rate 34%). 22% were female (mean age 38.2 years) and 78% male (mean age 49.4 years). The general principle of registration was endorsed by 52%, and compulsory registration by 54%, but the fee level by only 13%. Most technicians felt that registration had had either no effect or a negative effect on their view of their career (80%), role (78%) or status within the dental team (85%), and 66% did not agree that training helped them to do their job better. Fifty-one percent were not satisfied with their job and 20% intended to leave the profession. Intention to leave was predicted by greater dissatisfaction with remuneration. CONCLUSIONS: Criticisms regarding the cost and relevance of registration and the cost, relevance and accessibility of CPD, coupled with potentially high level of attrition from the profession, suggest a review of the fee and salary structure and greater support for CPD is warranted. PMID- 23099724 TI - An investigation of antibiotic prophylaxis in implant practice in the UK. AB - BACKGROUND: There is increasing evidence of the inappropriate use of antimicrobials in dentistry and this may contribute to the problem of antimicrobial resistance. The research to date with regard to efficacy of antimicrobial prophylaxis in reducing failure of integration and postoperative complications when placing dental implants remains equivocal. The aim of this study was to investigate how dentists in the UK use antimicrobials prophylactically in implant practice. METHOD: An e-mail link was provided in 2011 to an anonymous online (Smart-Survey) questionnaire using three databases of dentists who, by being on them, had registered an interest in placing dental implants. Absolute frequencies were used to describe the study sample demographics and examine the distribution of responses for all the variables investigated. RESULTS: One hundred and nine completed questionnaires were received. Seventy-two percent (n = 76) routinely prescribed prophylactic antibiotics for all procedures. There was a wide variation in the pre-operative and postoperative prescription regimens with the majority (84%) stating that it was to prevent infection at the site of surgery or to reduce a bacteraemia. CONCLUSIONS: Although this was a small study with a low response rate, wide variations in antibiotic prescribing regimens with respect to drug, dose and duration were found. Further research is needed and guidelines developed to prevent antibiotic overprescribing and misuse. PMID- 23099725 TI - Trends in World Dental Research: an overview of the last three decades using the Web of Science. AB - OBJECTIVE: The objective of this paper is to analyse the scientific activity of dental sciences over the last 30 years. MATERIALS AND METHODS: Dental-research output was identified by retrieving all citable dental documents in the Web of Science (WoS) database in the periods 1986-1988, 1996-1998, and 2006-2008. For this, a two-phase search strategy was designed: firstly, output in Dentistry, Oral Surgery, and Medicine (DOSM) Journal Citation Reports (JCR) category journals were compiled; secondly, for journal documents of other JCR categories but related to Dentistry (Non-DOSM), an innovative search strategy was designed based on a double criterion, thematic and institutional. RESULTS: The results showed that DOSM production increased in absolute but decreased in relative terms over the last 30 years. The JCR categories where dental researchers publish also varied. Surprisingly, the geographic distribution of the production shows a growing concentration of the steadily fewer countries, a previously undescribed phenomenon, while the thematic analysis reveals that this production continued to form four broad thematic areas encompassing the remaining specialties: Dental Materials Prosthodontics, Orthodontics, and General Dentistry. CONCLUSIONS: Scientific production in dentistry has changed in the past three decades both quantitatively and qualitatively, as well as their geographical distribution despite being structured around the same specialties. CLINICAL RELEVANCE: In this study, along with some key messages about the key shifts in publication trends, in terms of subject, where published and by whom, we propose a new methodology which could be useful to professionals as well as researchers, in which the exhaustivity and precision rates for scientific information retrieval improve. PMID- 23099727 TI - Volume reduction of cystic lesions after surgical decompression: a computerised three-dimensional computed tomographic evaluation. AB - OBJECTIVES: This study was performed to evaluate the three-dimensional radiographic variation in mandibular odontogenic cystic lesions after decompression. MATERIALS AND METHODS: Pre- and post-decompression computed tomography (CT) evaluations in 20 patients affected by keratocysts (n = 10), dentigerous cysts (n = 9) and ameloblastoma (n = 1) were analysed using software designed for three-dimensional measurement of volumes; the results were correlated with treatment duration, age, sex and histological type. RESULTS: The mean (range) decompression time was 5.70 (3-12) months. The mean (SD) pre- and post-decompression volumes were 9.50 (7.74) and 4.65 (4.34) cm(3), respectively (P < 0.001), with a mean (SD) reduction of 49.86 % (19.34 %). The volume reduction was positively correlated with the duration of decompression (P < 0.001), whereas no correlations with other variables were found (P = 0.2357). The median monthly reduction in cyst volume was 11.34 % (mean, 13.52 %; range, 4.45 30.43 %) (P < 0.001). CONCLUSIONS: This three-dimensional CT investigation demonstrated the effectiveness of decompression in the treatment of mandibular odontogenic cystic lesions and showed a positive correlation between the duration of treatment and volume reduction. CLINICAL RELEVANCE: Decompression treatment, which is simple to perform and generally well-accepted by patients, is a reliable method to considerably reduce the volume of mandibular odontogenic cystic lesions before surgical removal. Extended decompression time seems to improve results of the reduction process. PMID- 23099728 TI - Short- and long-term outcomes after laparoscopic and open hepatectomy for hepatocellular carcinoma: a global systematic review and meta-analysis. AB - BACKGROUND: Laparoscopic hepatectomy (LH) has been proposed as a safe and feasible treatment option for liver diseases. However, the short- and long-term outcomes of LH versus open hepatectomy (OH) for hepatocellular carcinoma (HCC) have not been adequately assessed. Thus, as another means of surgical therapy for hepatocellular carcinoma (HCC), we assessed the feasibility of performing LH as the standard procedure for disease in the left lateral lobe and peripheral right segments for HCC in selected patients. METHODS: Literature search included PubMed, Embase, Science Citation Index, SpringerLink, and secondary sources, from inception to March 2012, with no restrictions on languages or regions. The fixed effects and random-effects models were used to measure the pooled estimates. The test of heterogeneity was performed by the Q statistic. Subgroup and sensitivity analyses were performed to explore heterogeneity between studies and to assess the effects of study quality. RESULTS: A total of 1238 patients (LH 485, OH 753) from 15 studies were included. The pooled odds ratios for postoperative morbidity and incidence of negative surgical margin in LH were found to be 0.37 (95 % confidence interval [CI] 0.27-0.52; P < 0.01) and 1.63 (95 % CI 0.82-3.22; P = 0.16), respectively, compared with OH. Blood loss was significantly decreased in the LH (weighted mean difference -224.63; 95 % CI -384.87 to -64.39; P = 0.006). No significant difference was observed between the both groups for long-term outcomes of overall survival and recurrence-free survival. CONCLUSIONS: In patients with solitary left lateral lobe/right peripheral subcapsular tumors treated with minor resection, this meta-analysis demonstrated that compared to OH, LH may have short-term advantages in terms of blood loss and postoperative morbidity for HCC. Both procedures have similar long-term outcomes. It may be time to consider changing the standard procedures for treatment of HCC in the left lateral lobe and peripheral subcapsular right segments in selected patients. PMID- 23099729 TI - Predictors of survival in patients with soft tissue surgical margin involvement at radical cystectomy. AB - BACKGROUND: The presence of positive soft tissue surgical margins (STSM) at radical cystectomy (RC) is rare. Although some patients with STSM experience disease recurrence rapidly, some have long-term local disease control. We sought to describe the oncologic outcomes, identify predictors, and assess the impact of location and multifocality in patients with positive STSMs at RC. METHODS: We retrospectively collected the data of 4,335 patients treated with RC and pelvic lymphadenectomy at 11 academic centers from 1981 to 2008. STSM was defined as the presence of tumor at inked areas of soft tissue on the RC specimen. Univariate and multivariate Cox regression models addressed recurrence-free survival and cancer-specific survival after surgery. RESULTS: STSM were identified in 231 patients (5%). Actuarial recurrence-free survival estimates at 2 and 5 years after RC were 26 +/- 3 and 21 +/- 3%, respectively. Actuarial cancer-specific survival estimates at 2 and 5 years after RC were 33 +/- 3 and 25 +/- 4%, respectively. Higher body mass index (p = 0.050), higher tumor stage (p = 0.017), presence of grade 3 disease (p = 0.046), lymphovascular invasion (p = 0.003), and lymph node involvement (p = 0.003) were all independently associated with disease recurrence. Furthermore, higher tumor stage (p = 0.015), lymphovascular invasion (p = 0.006), and lymph node involvement (p = 0.006) were independently associated with cancer specific mortality. Location and multifocality of STSM were not associated with outcomes. CONCLUSIONS: Although most patients with STSM at RC had poor outcomes, more than one-fifth had durable cancer control. Pathologic features associated with disease recurrence in the general RC population also stratify patients with STSM into differential risk groups. PMID- 23099730 TI - Prevention of anastomotic leakage after total gastrectomy with perioperative supplemental oxygen administration: a prospective randomized, double-blind, controlled, single-center trial. AB - BACKGROUND: The role of supplemental oxygen therapy in the healing of esophagojejunal anastomosis is still very much in an experimental stage. The aim of the present prospective, randomized study was to assess the effect of administration of perioperative supplemental oxygen therapy on esophagojejunal anastomosis, where the risk of leakage is high. METHODS: We enrolled 171 patients between January 2009 and April 2012 who underwent elective open esophagojejunal anastomosis for gastric cancer. Patients were assigned randomly to an oxygen/air mixture with a fraction of inspired oxygen (FiO2) of 30 % (n = 85) or 80 % (n = 86). Administration commenced after induction of anesthesia and was maintained for 6 h after surgery. RESULTS: The overall anastomotic leak rate was 14.6 % (25 of 171): 17 patients (20 %) had an anastomotic dehiscence in the 30 % FiO2 group and 8 (9.3 %) in the 80 % FiO2 group (P < 0.05). The risk of anastomotic leak was 49 % lower in the 80 % FiO2 group (relative risk 0.61; 95 % confidence interval 0.40-0.95) versus 30 % FiO2. CONCLUSIONS: Supplemental 80 % FiO2 provided during and for 6 h after major gastric cancer surgery to reduce postoperative anastomotic dehiscence should be considered part of ongoing quality improvement activities related to surgical care, with few risks to the patient and little associated cost. PMID- 23099731 TI - Coronally advanced flap for root coverage: long-term outcomes. PMID- 23099733 TI - Biomechanical implant treatment complications: a systematic review. PMID- 23099734 TI - Appendicitis and benign appendiceal mucocele presenting as large bowel obstruction. AB - INTRODUCTION: Appendiceal mucocele is most commonly encountered incidentally during appendectomy. METHODS: We report a case of large bowel obstruction presenting as a closed loop with an appendiceal mucocele as the lead point, superimposed on a chronic ileal stricture that had been misdiagnosed as irritable bowel syndrome. RESULTS: The patient underwent ileocecal resection and primary anastomosis. She did well postoperatively, and her irritable bowel syndrome disappeared. CONCLUSIONS: Appendiceal mucocele can present in a variety of ways, and surgeons should be alert for atypical presentations. Moreover, some patients with intermittent abdominal pain deserve anatomic investigation before being dismissed as having irritable bowel. PMID- 23099735 TI - Post Roux-en-Y gastric bypass biliary dilation: natural process or significant entity? AB - BACKGROUND: Changes in the biliary system after gastric bypass are not well defined. Dilation may be normal or due to biliary tract pathology. The purpose of this study is to review patients who underwent imaging of their biliary system both before and after Roux-en-Y gastric bypass in an effort to elucidate the effect this operation has on hepatic duct diameter. METHODS: Patients with imaging both before and at least 3 months after gastric bypass were analyzed. Hepatic duct was measured at the level of the porta hepatis to determine interval changes. RESULTS: Thirty-three patients had postoperative imaging at least 3 months following gastric bypass. Mean hepatic duct diameter was 5.2 +/- 2 and 7.1 +/- 2.6 mm preoperatively and postoperatively, respectively (p < 0.01). Patients with prior cholecystectomy had hepatic duct diameters of 7.9 +/- 1.3 and 9.5 +/- 3.5 mm preoperatively and postoperatively, respectively (p = 0.3). Patients who had not previously undergone cholecystectomy had hepatic duct diameters of 4.3 +/ 1.1 and 6.4 +/- 1.8 mm preoperatively and postoperatively, respectively (p < 0.01). CONCLUSIONS: Hepatic duct diameter increases after Roux-en-Y gastric bypass. A better understanding of this phenomenon may limit the need for further work-up in patients with incidentally detected biliary dilation. PMID- 23099737 TI - Hollow CuO nanospheres uniformly anchored on porous Si nanowires: preparation and their potential use as electrochemical sensors. AB - Hollow CuO nanospheres have been prepared via a reduction reaction of copper ions on porous Si nanowires combined with calcination in air and uniformly anchored on their surfaces. Scanning electron microscopy (SEM), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) were employed to characterize and analyze as-synthesized samples. The results reveal that Si nanowires fabricated from heavily doped Si wafer are formed with a meso-porous structure by an Ag-assisted etching approach, and Cu nanoparticles are formed and uniformly decorated on the Si nanowires through a reaction of copper ions reduced by silicon. After annealing in air, Cu nanoparticles are in situ oxidized and transformed into CuO, leading to the formation of hollow nanospheres because of the Kirkendall effect. The diameter size of as-prepared CuO hollow spheres anchored on porous Si nanowires is mainly around 30 nm. Finally, in order to illuminate the advantages of this novel hybrid nanostructure of nanosized hollow spheres supported on porous nanowires, its electrochemical sensing performance to hydrazine as an example has been further investigated. The results confirm that it is a good potential application to detect hydrazine. PMID- 23099736 TI - Phase II study of single intraperitoneal chemotherapy followed by systemic chemotherapy for gastric cancer with peritoneal metastasis. AB - BACKGROUND: We conducted a phase II study involving a single administration of intraperitoneal chemotherapy with paclitaxel followed by sequential systemic chemotherapy with S-1+ paclitaxel for advanced gastric cancer patients with peritoneal metastasis. METHODS: Gastric cancer patients with peritoneal metastasis were enrolled. Paclitaxel (80 mg/m(2)) was administered intraperitoneally at staging laparoscopy. Within 7 days, patients received systemic chemotherapy with S-1 (80 mg/m(2)/day on days 1-14) plus paclitaxel (50 mg/m(2) on days 1 and 8), followed by 7-days rest. The responders to this chemotherapy underwent second-look laparoscopy, and gastrectomy with D2 lymph node dissection was performed in patients when the disappearance of peritoneal metastasis had been confirmed. The primary endpoint of the study was overall survival rate. RESULTS: Thirty-five patients were enrolled. All patients were confirmed as having localized peritoneal metastasis by staging laparoscopy. Eventually, gastrectomy was performed in 22 patients. The median survival time of the total patient population and those patients in which gastrectomy was performed was 21.3 and 29.8 months, respectively. The overall response rate was 65.7 % for all patients. The frequent grade 3/4 toxic effects included neutropenia and leukopenia. CONCLUSIONS: Sequential intraperitoneal and intravenous paclitaxel plus S-1 was well tolerated in gastric cancer patients with peritoneal metastasis. PMID- 23099738 TI - Opto-electrokinetic manipulation for high-performance on-chip bioassays. AB - This communication first demonstrates bio-compatibility of a recently developed opto-electrokinetic manipulation technique, using microorganisms. Aggregation, patterning, translation, trapping and size-based separation of microorganisms performed with the technique firmly establishes its usefulness for development of a high-performance on-chip bioassay system. PMID- 23099739 TI - Internet use during anesthesia care: does it matter? PMID- 23099740 TI - [Men, health and public policies: gender equality in question]. AB - The scope of this article is to pose questions on the theme of Men, Health and Public Policies to render debate on the subject viable, based on theoretical and empirical references related to these issues. Initially, some historical landmarks on the theme are presented to provide guidelines for debate. An overview of the gender agenda in public policies is then presented to introduce the discussion about the inclusion of a gender perspective in healthcare policies. After this discussion, queries are raised about whether or not policies geared to men's health promote gender equality. In the closing remarks, the complexity involved in the development, implementation and evaluation of health policies aimed at gender equality is highlighted. The need for the Brazilian policy geared towards men's health to be implemented with other policies such that the gender matrix is transversal in the healthcare field is also stressed. PMID- 23099741 TI - [Gender of/in men: strands of a proto-genealogy]. PMID- 23099742 TI - [Reflections on gender and the Brazilian Comprehensive Healthcare Policy for Men]. PMID- 23099743 TI - [On "Men, health and public policies: gender equality in question"]. PMID- 23099744 TI - [Gender, a useful category (to guide policies)?]. PMID- 23099746 TI - [Meanings attributed to policy directed to Men's Health]. AB - This study analyzed the meanings given to the Brazilian National Men's Health Policy (PNAISH) by those involved in its implementation to find out how a policy formulated at national level is reflected in local contexts. In five cities, from each macro region of the country, a set of 6 narratives and 21 semi-structured interviews were held with health managers and professionals; the information on the Policy was developed according to the Meaning Interpretation Method. The Policy is generally perceived as positive. Among the meanings given, it is emphasized that the policy is seen, by some, as a comprehensive care that guides actions to address men as a whole in Primary Care; then again, others perceived it as a reduction to urological problems. The policy was also perceived as something vague, which does not detail how to proceed to take men to the services and to better assist them, or something episodic, being the policy reduced to the accomplishment of specific events rather than ongoing actions in everyday services. The different meanings guide practices and actions, which may signal the effective and continued engagement of the professional with the policy, being a key element for its monitoring and evaluation. PMID- 23099747 TI - [Brazilian men's integral health attention: using indicators for monitoring health's promotion and attention]. AB - This article presents and discusses the initial actions of Brazilian National Men's Health Policy (PNAISH) concerning indicators used for monitoring promotion and assistance actions of men's health. This multiple case study was developed among five Brazilian cities which had implanted the PNAISH: (Goiania (GO), Joinville (SC), Petrolina (PE), Rio Branco (AC) and Rio de Janeiro (RJ). A questionnaire was applied to verify the use of data and information required to calculate the indicators recommended by the PNAISH, concerning health's promotion, implementation and expansion of the men's health assistance system, according to the planned goals contained in the cities' local action plans. The results revealed a critical situation concerning monitoring of the activities through the proposed indicators taking into account the lack of standardized procedures to calculate them. Another specific limitation encountered was the limited access to or availability of data by age and sex in the health information systems. These results point out a lack of necessary indicators to define a base line situation, which weakens the systematic monitoring and future evaluation of the actions. PMID- 23099748 TI - [Charting the Brazilian Comprehensive Healthcare Policy for Men (PNAISH), from its formulation through to its implementation in local public health services]. AB - The scope of this article is to see how the Brazilian Comprehensive Healthcare Policy for Men (PNAISH) has been implemented in the Unified Health System, from the standpoint of health professionals. A case study, involving five cases (each from a different macro region of Brazil) conducted using ethnographic techniques of data collection charted the progress of PNAISH implementation based on an anthropological approach using Lipsky's idea of street-level bureaucracy. PNAISH is contextualized in historical terms with national and international documents. Acknowledging the inevitable gap between the formulation and the implementation of any policy, an attempt is made to see how this gap has evolved by analyzing the transition of PNAISH into city Action Plans (PAs). It was revealed that the implementing agents had little knowledge of PNAISH, of the local health care network for men, of the techniques required to meet men's specific needs and of the concept of gender. It faced institutional obstacles, such as lack of an organizational structure, of a consolidated healthcare network - where the user receives services with different degrees of complexity within the system - and resources in general, especially human resources. PMID- 23099749 TI - [The standpoint of professionals on the presence and demands of men on the healthcare services: perspectives for the analysis of the implementation of the Comprehensive Healthcare Policy for Men]. AB - In 2009, the Brazilian Comprehensive Healthcare Policy for Men (PNAISH) was launched in Brazil, seeking to reduce morbidity and mortality in this population group. This article strives to analyze the conceptions that health professionals have about the specific demands and behaviors of the male population served by the healthcare services. The data analyzed are part of a larger research project, the objective of which was to evaluate the initial actions of the implementation of PNAISH. Ethnographic observations in 11 health services and semi-structured interviews were conducted with 21 health professionals. From the perspective of health professionals, the presence of men in the healthcare services is still limited. According to them, it is comprised of two types of clients: workers and the elderly. The male behavior characteristics - haste, objectivity, fear and resistance - and the difficulty faced by health services in receiving this population are the main factors that drive men away from health services. Although the concept of gender is central to PNAISH, it is only triggered by healthcare professionals in order to justify the social standards expected in terms of men's behavior. The attribution of men's behavior to cultural factors ultimately obscures the relations of power that underlie gender relations. PMID- 23099750 TI - Gender inequalities in non communicable disease mortality in Brazil. AB - The relative burden due to non communicable diseases (NCD) is increasing worldwide and has been shown to be generally greater for men than women. The objective of this paper is to describe gender differences in NCD mortality rates and trends in Brazil. Standardized mortality rates for the years 1991-2010 were corrected for sub notification and ill defined causes of death and calculated using sex specific five year age grades. Trends in standardized mortality were studied using joinpoint regression models. In 2010, rates for NCDs (men: 479/100000; women: 333/100000) and for most major NCD categories (cardiovascular diseases, cancer, chronic respiratory diseases and other chronic diseases) were higher for men than women. Age standardized mortality rates declined for both sexes over the period, beginning in 1993 and attenuating in more recent years. From its peak in 1993 to 2010, the unconditional probability of dying between the ages of 30 and 70 due to one of the four principal NCD groupings decreased for men from 32.3% to 22.8%; for women, from 23.5% to 15.4%. In conclusion, age standardized NCD mortality, though decreasing dramatically over the past two decades in Brazil, remains notably greater in men than in women and, this difference, in relative terms, will increase if these trends continue. PMID- 23099751 TI - [Healthcare needs, public policies and gender: the perspective of professional practices]. AB - This paper examines the relationship between public policies and professional practices with respect to healthcare needs. Taking a theoretical-conceptual approach, practices are defined as acts that are permeated by technical scientific and socio-historical determinants for the social production of work, and the possibilities for cultural, ethical and political changes were analyzed in order to take critical action regarding gender inequalities. With comprehensive healthcare for men as the reference point, the relevance of a distinction between male and female needs, as partial and not necessarily convergent realities in (re)producing these inequalities, is examined. Likewise, professional practices are examined as partial and distinct realities of policies that establish non-immediate relationships. It is considered that the following are symbolic and practical obstacles to change: the reduction of needs through biomedical normalization; the culture of self-employment and approaches that individualize needs; the traditional gender-based culture that conserves unequal practices for men and women; and the lack of registration of rights as part of professional action. This requires proposals specifically geared to healthcare practices and male needs, in order to achieve greater convergence with policy reforms. PMID- 23099752 TI - [Accessed through sex: the medicalization of male sexuality at two different moments]. AB - The scope of this article is to reflect upon the medicalization of male sexuality based on the counterpoint between two distinct historical processes. The first of these is the major trend towards intervention in male sexuality which occurred in the early twentieth century in Brazil as a result of syphilis and the broader campaign against venereal disease. The second concerns the medicalization of sexuality through the focus on erectile dysfunction and the creation of a new pharmacology of sex which has become inevitable with the transition to the twenty first century. This contrast enables us to see some important differences. The study highlights the new emphasis on the notion of sexual health based on individual improvement and use of medications. It also demonstrates that the promotion of male interest in sexual performance serves as a gateway to approach the treatment of male health. PMID- 23099753 TI - [Sexuality and trans experiences: from the hospital to the bedroom]. AB - In the aftermath of studies on masculinity, it is impossible to consider the production of gender identities without linking them to the relationship aspect. This change was due to the incorporation of the relationship perspective in this field of study and criticism of the concept of gender founded upon an alleged concept of femininity and masculinity to create interpretations of the place of bodies in the gender order. The objectives of this paper are: 1) to show how a given concept of gender can render multiple expressions of gender visible, like the trans identities (transsexuals, transvestites, cross dressers, drag queens, drag kings, transgenders) or sublimate them and contribute to their pathologization. The second objective will be to present narratives of trans men and trans women, who will tell us about their sexual experiences. Psycho physicians contend the non-existence of sexuality in their bodies as being one of the indicators to lead to a diagnosis of transsexualism. I will attempt to argue that the theoretical basis that supports the pathologization of trans identities and the assertion that trans people are asexual is based on a conception that links and renders gender identities conditional upon biological structures. PMID- 23099754 TI - [Suicide of elderly men in Brazil]. AB - This paper assesses the suicide of elderly men in Brazil. The text is based on studies of gender and masculinity and emphasizes the sense of "hegemonic masculinity" within the logic of patriarchalism that, in the case of suicide, is expressed in the loss of employment as an existential reference and as a loss of honor. The study includes 40 cases of men over 60 who committed suicide between 2007 and 2010 in ten districts of the country. Using the psychosocial autopsy technique, data were collected and analyzed from their history and lifestyle; evaluation of the background to the act; the impact on their families; lethality of the method; proximity to sources of support; previous attempts; mental status which preceded the act; reaction of families and communities. Although many factors are associated with self-inflicted death in this social group, the influence of a hegemonic masculinity culture in the predominance of suicides among elderly men compared with elderly women is undeniable. It is essential to give special attention to men at the moment of transition from working life to retirement, loss or important family members, and when they are diagnosed with chronic and degenerative diseases that cause disabilities, loss of autonomy or sexual impotence. PMID- 23099755 TI - [The use of phytotherapy and medicinal plants in primary healthcare units in the cities of Cascavel and Foz do Iguacu - Parana: the viewpoint of health professionals]. AB - Phytotherapy and the use of medicinal plants are part of the practice of folk medicine, which complements treatment traditionally employed for the lower income population. This work analyzed the knowledge of health managers and professionals who work in primary health care (PHC) about phytotherapy in the cities of Cascavel and Foz do Iguacu in the State of Parana. An exploratory, descriptive, and qualitative study using a structured questionnaire was conducted between February and July 2009. A health manager manifested interest in introducing the program. The other professionals interviewed did not receive training during undergraduate studies or within the Basic Health Units (BHU) where they work. Six professionals (60%) reported having access to information on phytoterapy through folk wisdom, one (10%) via training in a BHU, two (20%) from journals, four (40%) from the media and four mentioned more than one source. In Foz do Iguacu, in the BHU where the therapy is deployed, the professionals were not consulted before its implementation. To include phytotherapy in the BHUs of these two cities, it is necessary to train the professionals on the topic, including cultivation and prescription, thereby enhancing the rational use of these medicines. PMID- 23099756 TI - [Healthcare practices of Family Health Teams in four major cities]. AB - This paper examines reports on how care is administered by Family Health Teams (FHT) doctors and nurses in four state capitals. It identifies issues relating to priority actions, routine activities and the association between the professional profile and how selected activities are performed, in an attempt to ascertain how far these approximate to the comprehensive approach to primary health care. The cross-section reflects results from data collected via self-applied questionnaires. Cross-analyses were made using the Pearson chi-square (/(2)) test for categorical variables. A and B variables are, or are not, associated, at a 5% level of significance. The analyses point to a tendency to strike a balance in meeting programmed and spontaneous demand, corroborating the person-centered approach. Action to address chronic infectious disorders is not a priority for all FHTs, which impairs health surveillance actions and comprehensive care. Home visits are not yet a weekly activity for all personnel. Lack of involvement in community activities restricts care to conventional practices and undermines the logic of change of model. Contradictions identified between training and practice indicate a need to review policies for ongoing professional development. PMID- 23099757 TI - [Female urinary incontinence: a systematic review of qualitative studies]. AB - Urinary incontinence has broad repercussions on female daily life. The objective of this study was to conduct a systematic review seeking to analyze results of qualitative research concerning female urinary incontinence published prior to 2009. After an electronic search, 53 research reports were identified with 30 fulfilling the exclusion and inclusion criteria. After classification according to the Critical Appraisal Skills Program, 13 constituted the analytical body for review. The data were synthesized according to the meta-ethnographical approach through reciprocal translation. Two categories emerged: life experiences among incontinent women; and proposals for care models for incontinent women. The restructuring of one's personal life metacategory points to individual adjustments necessary for dealing with the problem. In essence, the results reveal the option of the majority of women facing the loss of urine "silently" and point to the need for professionals to understand family perceptions in order to better comprehend the personal, family, and social implications involved in female urinary incontinence. PMID- 23099758 TI - [Court-ordered access to treatment of rare genetic diseases: Fabry Disease in the state of Rio Grande do Sul, Brazil]. AB - Court-ordered access to high-cost drugs for rare genetic diseases, such as Fabry Disease (alpha-galactosidase-A deficiency), is a growing phenomenon as yet lacking systematic study. An observational, cross-sectional and retrospective study was conducted to characterize the lawsuits related to access to treatment for Fabry Disease by Enzyme Replacement Therapy in the State of Rio Grande do Sul prior to 2007. The study identified 13 lawsuits and 17 plaintiffs, 11 requesting alfa and 6 betagalsidase. The State of RS, the Federal Government, and 5 municipalities figured as defendants, in the form of joinder of parties or otherwise. There were 13 requests for interlocutory relief of which 12 were granted, and 2 sentences were handed down, both favorable. "Risk of death" was alleged by doctors in 4 prescriptions and by lawyers in the 13 lawsuits. The data suggest the lack of discussions combining aspects of medical efficacy and safety, cost-effectiveness, economic impact, and legal and constitutional arguments, which requires a specific policy for rare genetic diseases to standardize access to treatment. PMID- 23099759 TI - [Quality of the Information System on Live Births /SINASC: a critical analysis of published studies]. AB - The scope of this study was to carry out a review of scientific literature about the quality of data from the Information System on Live Births (SINASC). Studies in the Medline, Lilacs and SciELO databases were then reviewed. The articles were characterized according to journal of publication, location and period of the study, evaluation parameters, methodology and main results. A total of thirteen articles were reviewed. Eight studies analyzed coverage, four assessed completeness and seven evaluated reliability. Coverage higher than 90% was presented in the majority of the studies, indicating its viability for the calculation of indicators. However, the under-reporting of births in SINASC prevailed with variation between 75.8% and 99.5%. The mother's educational level, number of prior childbirths and frequency of prenatal visits were the variables that led to greater inconsistency. For its part, the parity variable was the one that led to greater incompleteness. In conclusion, the development of studies to find new ways of assessing SINASC is highlighted as a privileged strategy for the enhancement of the quality of the system. PMID- 23099760 TI - [Interviews with family members: a fundamental tool for planning the disclosure of a diagnosis of HIV/aids for children and adolescents]. AB - The scope of this study was to present the participation of caregivers in creating strategies for disclosure of their condition to HIV-positive children, as well as discussing the interventions that might contribute to overcoming the difficulties that commonly prevent family members from accepting this process. The participants included 23 caregivers of 18 patients referred for diagnosis disclosure, monitored at two pediatric AIDS units in the municipality of Sao Paulo, Brazil. This is a qualitative study and data were collected through semi structured interviews. The results showed that legitimating reasons why caregivers are reluctant to disclose the diagnosis to the children, as well as their motivations, are interventions that contribute to reduce resistance, facilitating the acceptance of disclosure. The collaboration of caregivers has provided valuable insights for conducting the work, and has enabled the establishment of a receptive and supportive relationship minimizing inhibitions that could be harmful to the continuity of the process. PMID- 23099761 TI - [The evolution of maternal and child healthcare and birth weight in the State of Pernambuco in 1997 and 2006]. AB - The scope of this paper was to assess the evolution and influence of maternal and child care on birth weight variation in the state of Pernambuco. The study used data from two cross-sectional population-based household surveys conducted with under-five children in the state of Pernambuco in 1997 (n = 1906) and 2006 (n = 1555). The sample was calculated to ensure the representativeness of two geo economic strata: urban and rural areas. The variables studied were prenatal, delivery care and birth weight. The x(2) test was used to compare the categorical variables and mean difference in birth weight was calculated between the years studied with the respective 95% confidence interval. A marked improvement was seen in prenatal care and an increase in the frequency of caesarean section. In the rural area there was a significant 112 g decrease in mean birth weight. In 2006, access to at least one prenatal care appointment occurred irrespective of maternal schooling, however, in 1997 and 2006 access to adequate prenatal care was higher among mothers with better schooling. In spite of the improvement in prenatal and delivery care, poor access, excess of medical interventions and the increase in newborn survival may be influencing the variations in mean birth weight in the State of Pernambuco. PMID- 23099762 TI - [Healthcare value chain: a model for the Brazilian healthcare system]. AB - This article presents a model of the healthcare value chain which consists of a schematic representation of the Brazilian healthcare system. The proposed model is adapted for the Brazilian reality and has the scope and flexibility for use in academic activities and analysis of the healthcare sector in Brazil. It places emphasis on three components: the main activities of the value chain, grouped in vertical and horizontal links; the mission of each link and the main value chain flows. The proposed model consists of six vertical and three horizontal links, amounting to nine. These are: knowledge development; supply of products and technologies; healthcare services; financial intermediation; healthcare financing; healthcare consumption; regulation; distribution of healthcare products; and complementary and support services. Four flows can be used to analyze the value chain: knowledge and innovation; products and services; financial; and information. PMID- 23099763 TI - [Psychogical autopsies into suicide among the elderly in Rio de Janeiro]. AB - This study analyses psychological autopsies and contextualizes problems and issues that led to elderly people taking their own lives in the city of Rio de Janeiro between 2004 and 2007. The study began with an analysis of 26 expert findings of elderly men and women who committed suicide in the central, northern and southern areas of Rio de Janeiro. The sample was contacted by letter and telephone and after that, by a one-on-one conversation. Eight psychological autopsies were conducted, in which identification data and family genograms were collected followed by an interview to profile the life style and the reasons for the self-inflicted violence. The interviewees were family members, friends and acquaintances of the victims. The suicides are associated with depression, serious physical and mental illness, as well as socio-cultural factors related to professional and socio-economic decline. The suicides occurred with and without family support, with and without medical care. The cumulative fragility of personal and social resources within the life cycle reveals that the risk of suicide among the elderly demands permanent care from the public health authorities. PMID- 23099764 TI - [Qualitative evidence of monitoring by doulas during labor and childbirth]. AB - The objective of this study was to conduct a metasynthesis of evidence of the work of doulas assisting women in labor and during childbirth. Articles between 2000 and 2009 were located in the Medline, PubMed, SciELO, and Lilacs databases using the key search words: doulas, gestation, labor, and alternative therapy. Seven articles were selected for the study and four categories were created: the support provided by doulas; the birth mother's experiences; professional relationship: and opinions and experiences of professionals. The doulas offered physical, emotional, spiritual and social support. Experiments showed that the professionals stimulated the mother/child relationship, oriented towards successful breastfeeding, and contributed to the prevention of post-partum depression. Controversy was observed among professionals regarding acceptance of the role of the doula as a member of the obstetrics team. The doula's care was considered innovative, calming, encouraging, and attended all the needs of the pregnant woman. The conclusion is that qualitative studies on the work of doulas are recent, incipient, but revealing as to the important possibility of humanizing labor and childbirth. PMID- 23099765 TI - [Knowledge of physicians and obstetric nurses about the prevention of neural tube defects]. AB - The scope of this study was to evaluate the knowledge of obstetricians and obstetric nurses about folic acid in the prevention of neural tube defects (NTD). A cross-sectional study was conducted in which 118 volunteers (95 physicians and 23 nurses) answered a questionnaire with 21 questions about prevention of NTD. The data were analyzed according to the reported knowledge, the recommendations made by the Brazilian Ministry of Health (MOH) and the scientific evidence (SE) available in the literature on the topic. The knowledge based on the SE and recommendations of MOH was different (4.64 +/- 0.20 vs. 5.55 +/- 0.15, p <0.001, Mean +/- SEM). There was no difference between the knowledge of respondents compared to their training, the time spent in prenatal care and between the two classes of professionals evaluated. There were differences between the reported knowledge and that based on SE (6.76 +/- 0.18 vs. 4.64 +/- 0.15, p <0.001) and based on the MOH recommendations (6.76 +/- 0.18 vs. 5.55 +/- 0.20, p <0.001). Thus, the conclusion reached was that 94.1% of those evaluated reported knowing the importance of folic acid in preventing NTD, though 64.2% reported that they did not know when to begin administration of the supplement. PMID- 23099766 TI - [Evaluation of the prenatal nutritional care process in seven family health units in the city of Rio de Janeiro]. AB - Nutritional care is of great importance in the prenatal period and the family health teams play a significant role in expanding the coverage of prenatal care. In this manner, the scope of this study was to evaluate the prenatal nutritional care process in seven family health units in the city of Rio de Janeiro. In 2008, a cross-sectional study was conducted and 230 pregnant women were interviewed and copies of their prenatal cards were obtained. The compliance of the process with the pre-established norms and criteria of the Ministry of Health was evaluated. Measurement and recording of blood pressure and weight and prescription of supplements and blood tests on the prenatal card are established steps in routine prenatal care. However, the results indicated that there was under-recording of stature, initial weight, edema, BMI by gestational age and laboratory tests results on the prenatal card. A lack of specific instruction on adequate use of the iron supplement, food consumption and weight gain was observed. The results indicated a pressing need for prenatal nutritional care and revealed deficiencies in this process, stressing the importance of minimum training for the health teams and the implementation of Family Health Support Centers. PMID- 23099767 TI - [From surveillance to work-related accident prevention: the contribution of the ergonomics of the activity]. AB - Work-related accidents are complex phenomena determined by the work organization process, the dimensions of which are usually invisible to surveillance agents. The scope of this paper was a case study based on documentary evidence to analyze and compare the success of an intervention conducted at a meat processing and packaging factory, by focusing on checking health and safety norms in 1997, and incorporating ergonomic concepts in 2008. In 1997, surveillance actions focused primarily on visible risk factors. Despite fulfilling sanitation requirements, the company still had an annual accident rate of 26% in 2008, which motivated the search for a new approach. In 2008, it was seen that accidents were caused by a vicious cycle involving intense work, technical inadequacy, absenteeism and high turnover (84%) that led the company to recruit inexperienced workers. This scenario was aggravated by authoritarian management practices. The ergonomics of the activity contributed to the understanding of organizational causes -thus superseding the normative aspects of traditional surveillance - which revealed the importance of ensuring that surveillance actions for prevention are more effective. PMID- 23099768 TI - Migrant labor and wear-out in manual sugarcane harvesting in Sao Paulo, Brazil. AB - The scope of this paper is to describe the work of manual sugarcane harvesters, assessing the nutritional behavior and body composition between the beginning and the end of the harvest. A descriptive longitudinal study was made of harvesters in Piracicaba, Sao Paulo, Brazil, who answered a socio-demographic questionnaire and authorized measurement of Body Mass Index, Body Fat Percentage and Arm Muscle Circumference at three stages. Creatine kinase on the skeletal isoform, C reactive protein and plasma urea were measured at the end of the harvest. Thirty male migrant harvesters with ages ranging from 18 to 44 from the Northeast (Ceara) were assessed over a nine-month period. The workers suffered significant body fat and weight loss in the first half of the harvest. Eighteen workers had abnormal levels of creatine kinase and four - out of 24 who had donated blood - had altered urea levels. Sugarcane harvesting work causes weight and body fat loss and gains in the lean body mass index, which suffers wear-out when working on consecutive harvests. It can also cause changes in biochemical markers of chronic systemic inflammation. Further studies will make it possible to comprehend the relationships between stress, wear-out, labor longevity and health in sugarcane harvesting. PMID- 23099769 TI - [Evolution of worker's health in the social security medical examination in Brazil]. AB - In order to analyze the practice of the social security medical examination starting from the introduction of the worker's health paradigms, data was gathered on the granting of social security disability benefits to assess worker illness based on notification of work-related accidents in the cement industries of Rio de Janeiro. From 2007 to 2009 there was only one notification, which involved a worker handling toxic waste instead of the energy matrix. However, the analysis revealed sources and mechanisms of illness overlooked in the social security medical examination, which is still focused on the one-cause-only logic of occupational medicine. To achieve the worker's health paradigms, changes are required to alter the way of conducting the social security medical examination, by re-establishing partnerships, training human resources, adopting epidemiological indicators, as well as setting and assessing social security goals that transcend the mere granting of disability benefits. PMID- 23099771 TI - Students knowledge as a contribution to dengue control programs with a great interest. PMID- 23099772 TI - [Brazilian scientific production indexed on MEDLINE]. PMID- 23099774 TI - Histological evidence: housekeeping genes beta-actin and GAPDH are of limited value for normalization of gene expression. AB - Housekeeping genes are widely used as internal controls for gene expression normalization for western blotting, northern blotting, RT-PCR, etc. They are generally thought to be expressed in all cells of the organism at similar levels because it is assumed that these genes are required for the maintenance of basic cellular function as constitutive genes. However, real-time RT-PCR experiments revealed that their expression may vary depending on the developmental stage, type of tissue examined, experimental condition, and so on. To date, no histological data on their expression are available for embryonic development. In the present study, we compared the histological expression profile of two commonly used housekeeping genes, GAPDH and beta-actin, in the developing chicken embryo by using section and whole mount in situ hybridization supplemented by RT PCR. Our results show that neither GAPDH mRNA nor beta-actin mRNA is expressed in all cell types or tissues at high levels. Strikingly, expression levels are very low in some organs. Moreover, the two genes show partially complementary expression patterns in the liver, the vascular system and the digestive tract. For example, GAPDH is more strongly expressed in the liver than beta-actin, but at lower levels in the arteries. Vice versa, beta-actin is more strongly expressed in the gizzard than GAPDH, but it is almost absent from cardiac muscle cells. Researchers should consider these histological results when using GAPGD and beta-actin for gene expression normalization in their experiments. PMID- 23099775 TI - Aptasensor based on triplex switch for SERS detection of cytochrome c. AB - We report a sensitive approach for SERS detection of cytochrome c using target binding-induced conformational changes of signal transduction probe (STP). STP labeled with a SERS-active molecule, carboxy-X-rhodamine (ROX), is immobilized on the substrate where the formation of a rigid triplex switching structure with aptamers does not allow SERS amplification to take place. The target binding event leads to an enhancement in SERS intensity of ROX adsorbed on the gold surface. Meanwhile, we found that an appropriate STP surface density could shield the SERS signal produced by protein adsorption which would foul the sensing surface. In addition, cytochrome c aptamers used were not the original sequence but reorganized in the nonspecific binding site to adapt to our design. This method provides a low detection limit of 2 nM (10 fmol within 5 MUL sample solution), and shows good selectivity toward cytochrome c compared to interfering proteins such as hemoglobin and immunoglobulin G. The general strategy of the method can also be extended to aptamer or DNA based sensors. PMID- 23099776 TI - Prediction of ligand binding site by insilico approach in cold resistant protein isolated from cold resistant mutant of Pseudomonas fluorescens. AB - Cold shock proteins perform vital functions, such as mRNA masking, coupling of transcription to translation and developmental timing and regulation, which aids in survival of microbes in cold stress. Pseudomonas fluorescens is an ecologically important bacterium which helps in plant growth promotion. Since the cold tolerant mutant of the bacterium is able to grow at the temperature ranges from 30 to 4 degrees C, it is of interest to study the process of its survival in the extreme temperatures. Therefore, this study is focused on the three dimensional structure and molecular modeling of cold resistant protein (CRP) from P. fluorescens to predict its molecular mechanism. Investigating the structure of CRP confirmed the presence of a conserved domain characteristic of the cold shock domain (CSD) family and a single nucleotide binding domain. When 3D structure of CRP was compared with the existing cold shock proteins, major deviations were found in the loop regions connecting the beta2-beta3, beta3-beta4 and beta4-beta5 sheets. Docking studies showed that CRP forms a significant clamp like structure at the substrate binding cleft which stabilizes the ligand. Therefore, it can be concluded that CRP has a strong affinity for the poly thymidine (poly T) stretch and can be considered a candidate for transcription regulation. PMID- 23099777 TI - Quaternion maps of global protein structure. AB - The geometric structures of proteins are vital to the understanding of biochemical interactions. However, there is much yet to be understood about the spatial arrangements of the chains of amino acids making up any given protein. In particular, while conventional analysis tools like the Ramachandran plot supply some insight into the local relative orientation of pairs of amino acid residues, they provide little information about the global relative orientations of large groups of residues. We apply quaternion maps to families of coordinate frames defined naturally by amino acid residue structures as a way to expose global spatial relationships among residues within proteins. The resulting visualizations enable comparisons of absolute orientations as well as relative orientations, and thus generalize the framework of the Ramachandran plot. There are a variety of possible quaternion frames and visual representation strategies that can be chosen, and very complex quaternion maps can result. Just as Ramachandran plots are useful for addressing particular questions and not others, quaternion tools have characteristic domains of relevance. In particular, quaternion maps show great potential for answering specific questions about global residue alignment in crystallographic data and statistical orientation properties in Nuclear Magnetic Resonance (NMR) data that are very difficult to treat by other methods. PMID- 23099778 TI - [Progesterone receptor-mediated molecular mechanisms on mammalian female reproduction]. AB - The steroid hormone, progesterone, plays a critical role in regulation of mammalian female reproductive activities. Besides the non-genomic activity of progesterone on target cells, its main physiological effect is caused through genomic action by the ligand-dependent nuclear progesterone receptor. The genomic and non-genomic effects of progesterone collectively mediate various female reproductive functions, including ovulation, embryo implantation, maintenance of pregnancy, initiation of parturition, and development of mammary gland. Although a large number of candidate genes regulated by progesterone have been identified by gene chip technology, the traditional progesterone response elements located in the promoter region of downstream target genes havenot been detected. Accordingly, it was suggested thatthe mechanism of nuclear progesterone receptors regulating transcription may be different from other nuclear steroid receptors. In this review, we summarized the mechanisms of progesterone receptors mediating the physiological effects in various female re-productive activities. PMID- 23099779 TI - [Progress on miRNA in mammal breast milk]. AB - As an important regulator in eukaryote, miRNAs could be in the animal body fluids, including serum, blood plasma, saliva, urine and so on. More recently, it was reported that miRNAs were also in the breast milk of human or cow, which indicates that miRNAs could probably be transferred into the body of the next generation by lactation and play their key roles. This might be the prelude of studies on the regulation function of miRNAs in generations. Here, we introduced the process of finding miRNAs in mammal milk, the format of miRNAs in milk and the method for isolating miRNAs, and reviewed the main functions of several miRNAs in milk. We also discussed the research task and challenge associated with miRNAs in milk at the next. PMID- 23099780 TI - [Bovine disease-related DNA mutations and their genetic control strategies in breeding for disease resistance]. AB - Bovine genomic DNA mutations and their genetic effects on gene expression and protein function influence disease susceptibility and resistance of cattle. The genetic loci related to cattle diseases are mainly divided into two types: single locus-disease genes and multigenic-disease loci. The single-locus-disease genes are called causal mutations; their genetic basis is simply and normally detected in the coding and non-coding regions inducing substitution of amino acid, premature termination of translation, and complete deletion of entire exon(s). In contrast, the genetic basis of disease related to multiple genes is more complex since susceptibility or resistance of these diseases is affected by the interactions among host, pathogen, and environment. This article reviewed current research and application of the major diseases of cattle con-trolled by single gene or polygenic genes. The genetic control strategies of effective identification and control of these dis-eases in bovine breeding and production were also analyzed. PMID- 23099781 TI - [Detecting selection signatures on X chromosome in pig through high density SNPs]. AB - In the process of domestic pig breeding, many important economic traits were subject to strong artificial se-lection pressure. With the availability of high density single nucleotide polymorphism (SNP) markers in farm animals, selection occurring in those traits could be traced by detecting selection signatures on genome, and the genes experiencing selection can also be further mined based on selection signatures. Due to the special characteristic of X chromosome, many approaches of genetic analysis fitted for autosome are not plausible for X chromosome. Fortunately, detecting selection signature provides an effective tool to settle such situation. In this study, the Cross Population Extend Haplotype Homozygosity Test (XP-EHH) was implemented to identify selection signatures on chromosome X in three pig breeds (Landrace, Songliao, and Yorkshire) using high density SNPs, and the genes located within selection signature regions were revealed through bioinformatic analysis. In total, 29, 13, and 15 selection signature regions, with 3.59, 4.92, and 4.07 SNPs on average in each region, were identified in Landrace, Songliao, and Yorkshire, respectively. Some overlaps of selection signature regions were observed between Songliao and Landrace, and between Landrace and Yorkshire, while no overlaps between Yorkshire and Songliao were found. Bioinformatic analysis revealed that many genes in the selection signature regions were related to reproduction and immune traits, and some of them have not been reported in pigs, which might serve as important candidate genes in future study. PMID- 23099782 TI - [Genome-wide association study of total number born and number born alive in pigs using both compressed mixed linear model and Bayes model]. AB - GWAS (Genome-wide association study) strategy has been extensively used for identification of economical trait loci in livestock animals. Using Illumina's PorcineSNP60 BeadChip, a GWA study of 820 commercial pigs with reproductive traits recorded was performed. The PCA analysis showed that there was no significant population stratification. Two different statistical models Compressed Mixed Linear Model(GAPIT program package)and Bayes CPi (GenSel software) were used to implement GWAS on total number born and number born alive of the first and second parity. To compare the most significant 50 SNPs from each method, a total of 31 and 20 coincided SNPs for total number born in the first parity were identified, and there were 20 coincided SNPs for number born alive in the first parityinthe results of bothmethods. The most significant SNPs were also significant in the results of the other method. The most significantly associated regions for total number born in the first parity were located on SSC1, 2, 3, 7, 13, 16, and 18. The most significantly associated regions for number born alive in the first parity were locatedon SSC1, 3, 4, 13, and 16. There were 5 common regions significantly associated with bothtraits on SSC1, 3, 13, and 16. The most significantly associated regions forbothtotal number born and number born alive for the second parity were mainly located on six common regions on SSC7, 10, 12, 13, 14, and 16. PMID- 23099783 TI - [Genome-wide selective sweep analysis on Large White and Tongcheng pigs]. AB - The production performance of pigs has been significantly improved due to long term artificial selection, and the specific variation characterizations (selection signatures) emerged from the selected genome regions. Different types of breeds are subjected to different selection intensities and had different selection signatures. Selective sweep analysis is one of major methods to detect the selection signatures. In this study, based on the 60K BeadChip genotyping data of both commercial Large White (n=45) and local Tongcheng pigs (n=45), genetic differentiation coefficient Fst was applied to detect the selection signatures. Using gPLINK software to set quality control standards, a total of 34 304 SNPs were selected for statistical analysis. Fst values between two breeds were estimated with Genepop package and the average Fst value was 0.3209. Setting Fst>0.7036 (1% of total number of Fst values) as selection threshold, 344 SNPs were obtained and SNP location annotation indicated that there were 79 candidate genes (Sus scrofa Build 9). Furthermore, network analysis was performed using Ingenuity Pathway Analysis and the preliminary results suggested that most genes were involved in growth, reproduction, and immune response, such as NCOA6, ERBB4, RUNX2, and APOB genes. The findings from this study will contribute to further identification of candidate genes and causal mutations implying for meat production and disease resistance in pig. PMID- 23099784 TI - [Effects of PI3K/AKT inhibitor wortmannin on proliferation and apoptosis of primary porcine preadipocytes]. AB - The purpose of this study was to determine the proper concentration of wortmannin that effectively inhibits PI3K/AKT but does not affect the proliferation and apoptosis of primary porcine preadipocytes. Firstly, primary porcine preadipocytes were isolated and their abilities to be induced to differentiation into mature adipocytes were evaluated. The preadipocytes were then treated with different concentrations of wortmannin, and the proliferation of the cells was detected with methanethiosulfonate (MTS). Annexin V- FITC/PI double-staining was used to detect the level of cell apoptosis. The apoptosis-related gene expressions were also quantified by qRT-PCR. At the same time, single cell electrophoresis was used to examine the extent of cellular DNA damage. Our data demonstrated that the primary porcine preadipocytes could differ-entiate into mature adipocytes. Up to 200 nmol/L of wortmannin had no effect on the proliferation ability of primary porcine preadipocytes (P>0.05). Results from the flow cytometry Annexin V- FITC/PI double-staining showed that 200 nmol/L wortmannin significantly induced apoptosis of the primary porcine preadipocytes (P<0.05). QRT-PCR results also showed that the expressions of caspase8, TNFR1, GZMB, and Bcl-x1 were significantly upregulated, while the expression of GZMA and cFLIP were not significantly affected when treated with 200 nmol/L wortmannin. In addition, results from the single cell gel electrophoresis indicated that 100 nmol/L wortmannin did not induce DNA damage. In conclusion, our results col lectively showed that 100 nmol/L wortmanin can be used to study the role of PI3k pathway on the preadipocytes differen-tion without affecting the cell proliferation and apoptosis. PMID- 23099785 TI - [Molecular cloning, expression profile analysis and construction of adipose tissue specific expression vector of pig Gli1 gene]. AB - The Hedgehog (Hh) signaling pathway inhibits fat accumulation, which is conserved in a wide variety of organisms from Drosophila to vertebrates, but few reports about its effect on pigs are available. In this study, pig Gli1 gene was cloned for the first time by rapid amplification of cDNA ends (RACE) and RT-PCR. Pig Gli1 expression profiles were then studied in different tissues and in different developmental stages of the adipose tissue of pigs using real-time PCR. Finally, the eukaryotic expression vector and the adipose tissue specific expression vector were constructed. The results showed that the full pig Gli1 cDNA length was 3 576 bp, the genomic sequence contained 10 715 bp with 12 exons, and 1 106 amino acids were encoded. Pig Gli1 was predicted as an unstable hydrophilic protein without a tans-membrane structure or a signal peptide. The C2H2 zinc finger domain and a nuclear localization sequence were found in pig Gli1. A homology analysis of the Gli1 amino acids and the genomic sequences among seven species showed that the identities were all greater than 80%, which indicates that Gli1 is highly conserved among different species. Tissue expression profile analysis showed that pig Gli1 was only expressed in the tone tissue of adult pigs. Analysis of the pig adipose tissue developmental process showed that Gli1 was detected in the adipose tissue of one-week-old pigs, but not in one-month-old and three-month-old pigs. Finally, a pig Gli1 eukaryotic expression vector was constructed and properly expressed with cell transfection. An adipose tissue specific expression vector was constructed for transgenic animal studies. PMID- 23099786 TI - [Differential expression analysis of proteins in neutrophils between clinical mastitis and healthy dairy cows]. AB - Neutrophils provide the first line of defense against invading pathogens and have been reported to play a key role in bovine mammary immune. To examine the differential expression of proteins in neutrophils between clinical mastitis and healthy dairy cows, a 2-dimensional electrophoresis gel map with high repeatability was constructed for bovine neutrophils. From this map, seven differentially expressed proteins were identified by MALDI-TOF MS which are believed to be involved in pathways such as cell metabolism, oxidative stress, and inflammatory reaction. The differentially expressed proteins identified in this study may provide the basis for bovine mastitis resistance breeding research. PMID- 23099787 TI - [Artificial selection for cattle based on high-density SNP markers]. AB - With the implementation of genetic improvement in recent years, artificial selection has greatly improved beef cattle production performance and its genetic basis has been dramatically changed. In this study, based on the Illumina BovineSNP50 (54K) and BovineHD (770K) BeadChip and the FST value, we analyzed the genetic differentiation of cattle and screened the imprints of selection in bovine genome. Finally, we found 47104 OUTLIER SNP loci and 3064 candidate genes, for example, CLIC5, TG, CACNA2D1, and FSHR etc. The biological processes and molecular functions of genes were analyzed through gene annotation.The results of this study established a genome-wide map of selection footprints in beef cattle genome and a clue for in-depth study of artificial selection and understanding of biological evolution.Our results indicate that artificial selection has played an important role in cattle breed genetic improvement. PMID- 23099788 TI - [Expression levels of Slc7a11 in the skin of Kazakh sheep with different coat colors]. AB - Slc7a11 belongs to solute transporter gene family, encoding cystine/glutamate transporter xCT. It regulates switching between eumelanin and pheomelanin synthesis. In the present study, Real-time PCR was used to detect the mRNA expression levels of Slc7a11 in the skin of Kazakh lambs with different coat colors (black, brown and white), and then the prokaryotic expression plasmid PET 32a-sxCT was constructed to induce the expression of fusion protein. The target pro-tein was purified by Ni-NTA affinity chromatographic separation, and then was used to immunize rabbit in order to produce rabbit anti-sxCT polyclonal antibody. Finally, the expression levels of sxCT were detected in the skin of Kazakh lambs with different hair colors by Western blotting analysis. Results showed that the mRNA expression levels of Slc7a11 differed significantly in the skin of Kazakh lambs with different coat colors, with the highest level in brown coat color, followed by the black, and then the white. The sxCT protein was also detected in the skin of different coat colors by polyclonal antibody, with the highest level in brown coat color, followed by the black, and then the white. It is, therefore, concluded that slc7a11 gene might be associated with the phenotype of coat color in Kazakh sheep. PMID- 23099789 TI - [Association of single nucleotide polymorphism of RB1 gene with body weight traits in chicken]. AB - The Northeast Agricultural University broiler lines divergently selected for abdominal fat content (NEAUHLF) were used in the current study to investigate the effects of Retinoblastoma1 (RB1) gene on chicken body weight (BW). The single nucleotide polymorphisms (SNPs) of the individuals were detected by MALDI-TOF-MS and PCR-RFLP methods and the genotypes of 27 SNPs were obtained. Haplotypes were constructed by liding window approach. Association analysis between single SNPs and haplotypes and body weight were conducted, respectively. Based on the results of single SNPs and haplotype association analyses. Four SNPs with significant effects on body weight at 1 week of age (BW1) and 2 SNPs with significant effects on BW1 and BW3 were determined. These results suggested that RB1 is an important candidate gene that affects chicken early growth and development. PMID- 23099790 TI - [Animal gene pyramiding in cross populations]. AB - Gene pyramiding aims at producing individuals with one superior economic trait according to the optimal breeding scheme involving selection of favorable target alleles or linked markers after crossing basal populations and pyramiding them into a single individual. In consideration of animal traditional cross program along with the features of animal segregating population, four types of cross programs and two types of selection strategies for gene pyramiding are performed from practice perspective of view, two population cross for pyramiding two genes (denoted II), three populations cascading cross for pyramiding three genes (denoted III), four population symmetrical (denoted IV-S) and cascading cross for pyramiding four genes (denoted IV-C), and various schemes (denoted cross program A-E) were designed for each cross program with different levels of initial favorable allele frequencies, basal population sizes, and trait heritabilities. The process of gene pyramiding for various schemes were simulated and compared based on the population hamming distance, average superior genotype frequencies, and average phenotypic values. By simulation, the results showed that larger base population size and higher initial favorite allele frequency resulted in higher efficiency of gene pyramiding. The order of parent crossing was shown to be the most important factor in cascading cross, but had no significant influence on the symmetric cross. The results also showed that genotypic selection strategy was superior to phenotypic selection in accelerating gene pyramiding. The method and corresponding software would be used to compare different cross schemes and selection strategies. Moreover, our study would help to build the optimal gene pyramiding simulation platform. PMID- 23099791 TI - [Manual annotation of the pig whole genomic sequence using Otterlace software]. AB - In November 2009, scientists from the US, UK, and other countries announced the complete genome sequence draft of the domestic pig. With the release of improved versions of the pig genome assembly and the increase of correctly assembled sequenced fragments over the past two years, it is particularly urgent to have the pig genes annotated at whole-genome level. This article is aimed at introducing an excellent manual annotation tool, Otterlace software, developed by Sanger institute. We used CFL1 (Cofilin 1) gene as an example to expound the usage of the three main components of Otterlace, Zmap, Blixem, and Dotter tools, and developed a practical procedure for manual annotations. We have analyzed 243 immune-related genes, among which 180 genes have been completely or partially annotated, offering novel information to the porcine functional genomics. PMID- 23099793 TI - Informational and neuromuscular contributions to anchoring in rhythmic wrist cycling. AB - Continuous rhythmic movements are often geared toward particular points in the movement cycle, as evidenced by a local reduction in trajectory variability. These so-called anchor points provide a window into motor control, since changes in the degree of anchoring may reveal how informational and/or neuromuscular properties are exploited in the organization of rhythmic movements. The present experiment examined the relative contributions of informational timing (metronome beeps) and neuromuscular (wrist postures) constraints on anchoring by systematically varying both factors at movement reversal points. To this end, participants cycled their right wrist in a flexed, neutral, or extended posture, either self-paced or synchronized to a metronome pacing peak flexion, peak extension, or both peak flexion and extension. The effects of these manipulations were assessed in terms of kinematics, auditory-motor coordination, and muscle activity. The degree of anchoring seen at the reversal points depended on the degree of compatibility of the prevailing configuration of neuromuscular and informational timing constraints, which had largely independent effects. We further observed systematic changes in muscular activity, which revealed distinct contributions of posture- and muscle-dependent neuromuscular properties to motor control. These findings indicate that the anchor-based discretization of the control of continuous rhythmic wrist movements is determined by both informational timing and neuromuscular constraints in a task-specific manner with subtle interactions between the two, and exemplify how movement variability may be exploited to gain such insights. PMID- 23099795 TI - How to avoid plagiarism. PMID- 23099792 TI - Physical non-viral gene delivery methods for tissue engineering. AB - The integration of gene therapy into tissue engineering to control differentiation and direct tissue formation is not a new concept; however, successful delivery of nucleic acids into primary cells, progenitor cells, and stem cells has proven exceptionally challenging. Viral vectors are generally highly effective at delivering nucleic acids to a variety of cell populations, both dividing and non-dividing, yet these viral vectors are marred by significant safety concerns. Non-viral vectors are preferred for gene therapy, despite lower transfection efficiencies, and possess many customizable attributes that are desirable for tissue engineering applications. However, there is no single non viral gene delivery strategy that "fits-all" cell types and tissues. Thus, there is a compelling opportunity to examine different non-viral vectors, especially physical vectors, and compare their relative degrees of success. This review examines the advantages and disadvantages of physical non-viral methods (i.e., microinjection, ballistic gene delivery, electroporation, sonoporation, laser irradiation, magnetofection, and electric field-induced molecular vibration), with particular attention given to electroporation because of its versatility, with further special emphasis on NucleofectionTM. In addition, attributes of cellular character that can be used to improve differentiation strategies are examined for tissue engineering applications. Ultimately, electroporation exhibits a high transfection efficiency in many cell types, which is highly desirable for tissue engineering applications, but electroporation and other physical non-viral gene delivery methods are still limited by poor cell viability. Overcoming the challenge of poor cell viability in highly efficient physical non-viral techniques is the key to using gene delivery to enhance tissue engineering applications. PMID- 23099796 TI - Combination therapy with risedronate and teriparatide in male osteoporosis. AB - Most studies of combination therapy with teriparatide and a bisphosphonate have not shown greater efficacy over monotherapy. The bisphosphonate risedronate, has not been studied in this context. The purpose of this proof-of-concept study was to assess whether combination risedronate and teriparatide increases bone mineral density (BMD) more than monotherapy with either drug alone. This was a randomized, double-blinded study of risedronate (35 mg weekly plus placebo injection), teriparatide (20 MUg subcutaneously daily plus placebo tablet), or both risedronate plus teriparatide (combination) for 18 months in 29 men with low BMD. The primary endpoint was percentage change in lumbar spine (LS) BMD at 18 months. Secondary outcomes included changes in bone markers and BMD at other sites and interim time-points. All therapies increased LS BMD as compared with baseline (p < 0.05), but there were no between-group differences at 18 months. Total hip (TH) BMD increased to a greater extent in the combination group (mean +/- SEM, 3.86 +/- 1.1 %) versus teriparatide (0.29 +/- 0.95 %) or risedronate (0.82 +/- 0.95 %; p < 0.05 for both). Femoral neck (FN) BMD also increased more in the combination group (8.45 +/- 1.8 %) versus risedronate (0.50 +/- 1.7 %; p = 0.002), but was not different from teriparatide alone. In the combination group, P1NP and CTX increased rapidly, mirroring the teriparatide-alone arm. There were no between-group differences in adverse events. Combination teriparatide and risedronate increased BMD at the LS, TH as well as the FN and provided greater BMD increases at the TH than monotherapy. The results suggest combination risedronate and teriparatide therapy holds promise as a treatment for osteoporosis. PMID- 23099797 TI - Looking at graduates of Title V MCHB-funded training programs through the lens of the MCH pyramid. AB - OBJECTIVES: To examine the distribution of professional responsibilities as reflected in each level of the MCH Pyramid for 208 graduates of five Maternal and Child Health Bureau (MCHB)-funded training programs-Leadership Education in Neurodevelopmental and Related Disabilities, nutrition, pediatric dentistry, public health, and social work-at the University of North Carolina at Chapel Hill. METHODS: Graduates completed a web-based survey, 1-8 years after graduation. For each program, we constructed means of the reported percentages of total work time spent in infrastructure-building, population-based, enabling, and direct health care services. RESULTS: Although generally consistent with the goals of the training programs, the percentages of time spent in each level of the Pyramid varied substantially among the five programs. For example, for a clinically focused program like pediatric dentistry, 80.2 % of time is spent in direct care services in contrast to 14.8 % for public health graduates. For each program, however, graduates report responsibilities among the different levels of the Pyramid. CONCLUSIONS: Reporting job responsibilities within the MCH Pyramid provides a more informative picture of the contributions of training program graduates than do conventional metrics such as institutional or agency appointments. The fact that graduates from all five programs engage multiple roles is consistent with the MCHB workforce training goal to develop leaders in the field of MCH. Given the central role of the MCH Pyramid in planning and reporting for the MCH Services Block Grant, MCH training programs should include metrics such as graduates' roles according to the MCH Pyramid to assure that training goals are more closely aligned with workforce needs. PMID- 23099798 TI - Preconception health of reproductive aged women of the Mississippi River delta. AB - Optimal preconception health (PCH) may improve maternal and infant outcomes, priority issues in Mississippi (MS). Our study objective was to compare the PCH of women in the MS Delta to other regions. We analyzed Behavioral Risk Factor Surveillance System data from 2005, 2007, and 2009, and limited analyses to 171,612 non-pregnant black and white women 18-44 years of age. Region was defined as 14 MS Delta counties (MS Delta), remainder of MS (MS non-Delta), Delta states (LA, AR, TN), and non-Delta US states. We calculated adjusted prevalence ratios (aPR) to assess associations between region and 16 indicators of optimal PCH, controlling for demographic characteristics. Healthy PCH factors such as consuming >=5 fruits and vegetables daily and normal body mass index (18.5 kg/m(2) to <25 kg/m(2)), respectively, were more prevalent in the MS non-Delta (aPR = 1.3; 95 % CI: 1.0,1.7 and aPR = 1.2; 95 % CI: 1.0,1.4), non-MS Delta (aPR = 1.5; 95 % CI: 1.2,2.0 and aPR = 1.3; 95 % CI: 1.1,1.5) and non-Delta states (aPR = 1.7; 95 % CI: 1.3,2.2 and aPR = 1.4; 95 % CI: 1.2,1.6) compared to the MS Delta. Physical activity levels were higher among non-Delta US states compared to the MS Delta (aPR = 1.3; 95 % CI: 1.1,1.4). Household income and race confounded the associations between region and PCH. Reproductive aged women in the MS Delta had poorer PCH, particularly for physical activity and nutrition, than women in other regions. MS Delta service providers and public health practitioners should consider implementing or enhancing lifestyle, nutrition, and physical activity interventions, with a special focus on reducing income-based and racial disparities. PMID- 23099800 TI - State of the art in diffusion tensor imaging. PMID- 23099799 TI - A systematic review of communication quality improvement interventions for patients with advanced and serious illness. AB - BACKGROUND: Effective communication is an interaction between two or more people that produces a desired effect and is a key element of quality of care for patients with advanced and serious illness and their family members. Suboptimal provider-patient/family communication is common, with negative effects on patient/family-centered outcomes. OBJECTIVES: To systematically review the evidence for effectiveness of communication-related quality improvement interventions for patients with advanced and serious illness and to explore the effectiveness of consultative and integrative interventions. DATA SOURCES: MEDLINE, CINAHL, PsycINFO, Cochrane, and DARE from 2000 through December 2011 and reference list of eligible articles and reviews. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS AND INTERVENTIONS: Prospective, controlled quality improvement studies in populations with life-limiting or severe life-threatening illness with a primary intervention focus of improving communication with patients and/or families. STUDY APPRAISAL AND SYNTHESIS METHODS: Two investigators independently screened and abstracted data on patient/family-centered outcomes. RESULTS: We included 20 studies; 13 (65 %) were in intensive care. We found four intervention types: (1) family meetings with the usual team (11 studies, 77 % found improvement in healthcare utilization), (2) palliative care teams (5 studies, 50 % found improvement in healthcare utilization), (3) ethics consultation (2 studies, 100 % found improvement in healthcare utilization), and (4) physician patient communication (2 studies, no significant improvement in healthcare utilization). Among studies addressing the outcomes of patient/family satisfaction, 22 % found improvement; among studies addressing healthcare utilization (e.g., length of stay), 73 % found improvement. Results suggest that consultative interventions, as opposed to integrative ones, may be more effective, but more research is needed. LIMITATIONS: Study heterogeneity did not allow quantitative synthesis. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Communication in the care of patients with advanced and serious illness can be improved using quality improvement interventions, particularly for healthcare utilization as an outcome. Interventions may be more effective using a consultative approach. PMID- 23099802 TI - Association of creatine kinase and skin toxicity in phase I trials of anticancer agents. AB - BACKGROUND: We investigated the association between skin rash and plasma creatine kinase (CK) levels in oncology phase I trials. METHODS: We analysed data from 295 patients treated at our institution within 25 phase I trials which included CK measurements in the protocol. Trials involved drugs targeting EGFR/HER2, m-TOR, VEGFR, SRC/ABL, aurora kinase, BRAF/MEK, PARP, CDK, A5B1 integrin, as well as oncolytic viruses and vascular disrupting agents. RESULTS: Creatine kinase measurements were available for 278 patients. The highest levels of plasma CK during the trial were seen among patients with Grade (G) 2/3 rash (median 249 U l(-1)) compared with G1 (median 81 U l(-1)) and no rash (median 55 U l(-1)) (P<0.001). There was a significant reduction in CK after the rash resolved (mean 264.2 vs 100.1; P=0.012) in 25 patients, where serial CK values were available. In vitro exposure of human keratinocytes to EGFR, MEK and a PI3Kinase/m-TOR inhibitor led to the increased expression of CK-brain and not CK-muscle or mitochondrial-CK. CONCLUSION: Plasma CK elevation is associated with development of skin rash caused by novel anticancer agents. This should be studied further to characterise different isoforms as this will change the way we report adverse events in oncology phase I clinical trials. PMID- 23099803 TI - KRAS gene amplification and overexpression but not mutation associates with aggressive and metastatic endometrial cancer. AB - BACKGROUND: Three quarter of endometrial carcinomas are treated at early stage. Still, 15 to 20% of these patients experience recurrence, with little effect from systemic therapies. Homo sapiens v-Ki-ras2 Kirsten rat sarcoma viral oncogenes homologue (KRAS) mutations have been reported to have an important role in tumorigenesis for human cancers, but there is limited knowledge regarding clinical relevance of KRAS status in endometrial carcinomas. METHODS: We have performed a comprehensive and integrated characterisation of genome-wide expression related to KRAS mutations and copy-number alterations in primary- and metastatic endometrial carcinoma lesions in relation to clinical and histopathological data. A primary investigation set and clinical validation set was applied, consisting of 414 primary tumours and 61 metastatic lesions totally. RESULTS: Amplification and gain of KRAS present in 3% of the primary lesions and 18% of metastatic lesions correlated significantly with poor outcome, high International Federation of Gynaecology and Obstetrics stage, non-endometrioid subtype, high grade, aneuploidy, receptor loss and high KRAS mRNA levels, also found to be associated with aggressive phenotype. In contrast, KRAS mutations were present in 14.7% of primary lesions with no increase in metastatic lesions, and did not influence outcome, but was significantly associated with endometrioid subtype, low grade and obesity. CONCLUSION: These results support that KRAS amplification and KRAS mRNA expression, both increasing from primary to metastatic lesions, are relevant for endometrial carcinoma disease progression. PMID- 23099804 TI - Efficacy of adjuvant aromatase inhibitor in hormone receptor-positive postmenopausal breast cancer patients according to the body mass index. AB - BACKGROUND: Increased adiposity may trigger signalling pathways that induce aromatase expression. As aromatase inhibitors exert their effects by blocking the aromatase enzyme, higher body mass index (BMI) can reduce the effect of aromatase inhibitors. Thus, we aimed to investigate retrospectively the effect of BMI on the efficacy of aromatase inhibitors in hormone receptor-positive postmenopausal patients with breast cancer. METHODS: Newly diagnosed hormone receptor-positive breast cancer patients who were postmenopausal and non-metastatic were enrolled to the study. Patients with BMI ranging between 18.5 and 24.9 kgm(-2) were considered as normal weight patients (Arm A, n=102), and patients with a BMI ranging >= 25 kgm(-2) were grouped as overweight and obese patients (Arm B, n=399). RESULTS: In both normal weight and overweight patients, the baseline clinico-pathologic properties and the treatment history with radiotherapy and chemotherapy were similar, and with no statistically significant difference. In normal weight patients disease-free survival (DFS) rate was 93.7% and 77.6%, whereas in overweight and obese patients DFS rate was 96.8% and 85.5% in the first and third years, respectively, (P=0.08). Three year survival rate in Arm A patients was 98.3%, whereas in Arm B was 98.0% (P=0.57). When anastrozole was compared with letrozole in the subgroup analysis no difference with regard to DFS and overall survival was detected. CONCLUSION: These results, contradictory to the prior results, show that BMI has no worse effect on outcomes of aromatase inhibitors in postmenopausal hormone receptor-positive breast cancer patients. In the subgroup analysis, letrozole and anastrozole had similar survival outcomes. PMID- 23099805 TI - Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma. AB - BACKGROUND: Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients. METHODS: We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol). RESULTS: Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis. CONCLUSION: This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol. PMID- 23099806 TI - The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. AB - BACKGROUND: Germline mutations in BRCA1 and BRCA2 predispose to pancreatic cancer. We estimated the incidence of pancreatic cancer in a cohort of female carriers of BRCA1 and BRCA2 mutation. We also estimated survival rates in pancreatic cancer cases from families with a BRCA mutation. METHODS: We followed 5149 women with a mutation for new cases of pancreatic cancer. The standardised incidence ratios (SIR) for pancreatic cancer were calculated based on age group and country of residence. We also reviewed the pedigrees of 8140 pedigrees with a BRCA1 or a BRCA2 mutation for those with a case of pancreatic cancer. We recorded the year of diagnosis and the year of death for 351 identified cases. RESULTS: Eight incident pancreatic cancer cases were identified among all mutation carriers. The SIR for BRCA1 carriers was 2.55 (95% CI=1.03-5.31, P=0.04) and for BRCA2 carriers was 2.13 (95% CI=0.36-7.03, P=0.3). The 5-year survival rate was 5% for cases from a BRCA1 family and 4% for cases from a BRCA2 family. CONCLUSION: The risk of pancreatic cancer is approximately doubled in female BRCA carriers. The poor survival in familial pancreatic cancer underscores the need for novel anti-tumoural strategies. PMID- 23099807 TI - Role of IL-12p40 in cervical carcinoma. AB - BACKGROUND: Previously, we have shown that low IL-12p40 mRNA expression by cervical cancer cells is associated with a poor survival of cervical cancer patients. As IL-12p40 is both a subcomponent of interleukin (IL)-12 and IL-23, the aim of this study was to elucidate the role of IL-12p40 in cervical cancer. METHODS: We have measured the expression of IL-23p19 mRNA, IL-12p35 mRNA and IL 12p40 mRNA using mRNA in situ hybridisation. The IL-1 and IL-6 were measured by immunohistochemistry. RESULTS: As IL-23 is a component of the IL-17/IL-23 pathway, a pathway induced by IL-1 and IL-6 in humans, we have studied IL-1 and IL-6 expression. Only a high number of stromal IL-6-positive cells was shown to associate with poor disease-specific survival. The worst disease-specific survival was associated with a subgroup of patients that displayed a high number of IL-6-positive cells and low IL-12p40 expression (P<0.001). Both a high number of IL-6-positive cells and a high number of IL-6-positive cells, plus low IL 12p40 expression were shown to be clinicopathological parameters independent of lymph node metastasis, parametrial involvement and Sedlis score (P=0.009 and P=0.007, respectively). CONCLUSION: Our results with IL-6 and IL-12p40 are in accordance with the hypothesis that the IL-17/IL-23 pathway has a suppressive role in cervical cancer. PMID- 23099808 TI - Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma. AB - BACKGROUND: Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity. METHODS: We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases. RESULTS: In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3). CONCLUSION: CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome. PMID- 23099810 TI - Prediction of spontaneous preterm birth: no good test for predicting a spontaneous preterm birth. AB - PURPOSE OF REVIEW: Spontaneous preterm birth complicates 3-11% of pregnancies and is a major cause of neonatal mortality and morbidity worldwide. If accurate tests can be identified, a potentially effective screening strategy with an adjunct preventive therapy may be trialled to reduce the rate of spontaneous preterm birth or effective measures be deployed at an early stage of a suspected spontaneous preterm labour before the onset of cervical changes to ameliorate prematurity complications. RECENT FINDINGS: There are many tests predicting spontaneous preterm births, published in the literature individually or in a systematic review. The information has not been collated about all candidate tests simultaneously in a systematic review incorporating a framework on how these tests may be evaluated, modelled with an intervention to provide a number needed to treat and test to inform decision-making. SUMMARY: There were 319 studies evaluating 22 tests. There are many promising tests, for example, history of previous spontaneous preterm birth, cervicovaginal swabs for markers such as fibronectin or HCG, cervical ultrasound, serum CRP and amniotic fluid interleukins for predicting spontaneous preterm birth, but none have exceptional accuracy and the quality of studies was generally poor. Some tests were able to achieve high LR+, but at the expense of LR-, that is, tests good for ruling in disease were poor for ruling out disease and vice versa. PMID- 23099809 TI - Expression of cyclin D1a and D1b as predictive factors for treatment response in colorectal cancer. AB - BACKGROUND: The aim of this study was to investigate the value of the cyclin D1 isoforms D1a and D1b as prognostic factors and their relevance as predictors of response to adjuvant chemotherapy with 5-fluorouracil and levamisole (5-FU/LEV) in colorectal cancer (CRC). METHODS: Protein expression of nuclear cyclin D1a and D1b was assessed by immunohistochemistry in 335 CRC patients treated with surgery alone or with adjuvant therapy using 5-FU/LEV. The prognostic and predictive value of these two molecular markers and clinicopathological factors were evaluated statistically in univariate and multivariate survival analyses. RESULTS: Neither cyclin D1a nor D1b showed any prognostic value in CRC or colon cancer patients. However, high cyclin D1a predicted benefit from adjuvant therapy measured in 5-year relapse-free survival (RFS) and CRC-specific survival (CSS) compared to surgery alone in colon cancer (P=0.012 and P=0.038, respectively) and especially in colon cancer stage III patients (P=0.005 and P=0.019, respectively) in univariate analyses. An interaction between treatment group and cyclin D1a could be shown for RFS (P=0.004) and CSS (P=0.025) in multivariate analysis. CONCLUSION: Our study identifies high cyclin D1a protein expression as a positive predictive factor for the benefit of adjuvant 5-FU/LEV treatment in colon cancer, particularly in stage III colon cancer. PMID- 23099811 TI - Influence of dietary carbon on mercury bioaccumulation in streams of the Adirondack Mountains of New York and the Coastal Plain of South Carolina, USA. AB - We studied lower food webs in streams of two mercury-sensitive regions to determine whether variations in consumer foraging strategy and resultant dietary carbon signatures accounted for observed within-site and among-site variations in consumer mercury concentration. We collected macroinvertebrates (primary consumers and predators) and selected forage fishes from three sites in the Adirondack Mountains of New York, and three sites in the Coastal Plain of South Carolina, for analysis of mercury (Hg) and stable isotopes of carbon (delta(13)C) and nitrogen (delta(15)N). Among primary consumers, scrapers and filterers had higher MeHg and more depleted delta(13)C than shredders from the same site. Variation in delta(13)C accounted for up to 34 % of within-site variation in MeHg among primary consumers, beyond that explained by delta(15)N, an indicator of trophic position. Consumer delta(13)C accounted for 10 % of the variation in Hg among predatory macroinvertebrates and forage fishes across these six sites, after accounting for environmental aqueous methylmercury (MeHg, 5 % of variation) and base-N adjusted consumer trophic position (Deltadelta(15)N, 22 % of variation). The delta(13)C spatial pattern within consumer taxa groups corresponded to differences in benthic habitat shading among sites. Consumers from relatively more-shaded sites had more enriched delta(13)C that was more similar to typical detrital delta(13)C, while those from the relatively more-open sites had more depleted delta(13)C. Although we could not clearly attribute these differences strictly to differences in assimilation of carbon from terrestrial or in-channel sources, greater potential for benthic primary production at more open sites might play a role. We found significant variation among consumers within and among sites in carbon source; this may be related to within-site differences in diet and foraging habitat, and to among-site differences in environmental conditions that influence primary production. These observations suggest that different foraging strategies and habitats influence MeHg bioaccumulation in streams, even at relatively small spatial scales. Such influence must be considered when selecting lower trophic level consumers as sentinels of MeHg bioaccumulation for comparison within and among sites. PMID- 23099812 TI - Hyperhomocysteinemia in Alzheimer's disease: the hen and the egg? AB - Hyperhomocysteinemia is associated with Alzheimer's disease (AD). The causality of this association is controversial. In this study we tested the effect of a hyperhomocysteinemia-inducing diet in the ArcAbeta transgenic AD mouse model. At 14 months of age, the hyperhomocysteinemia-inducing diet yielded higher plasma homocysteine levels in ArcAbeta mice compared with wild-type mice. Levels of plasma 5-methyltetrahydrofolate (5-MTHF) in 14-month-old mice on hyperhomocysteinemia-inducing diet were lower in the transgenic than in the wild type mice. The folate derivate 5-MTHF serves as cofactor in homocysteine metabolism. Oxidative stress, which occurs in the course of disease in the ArcAbeta mice, consumes 5-MTHF. Thus, the transgenic mice may plausibly be more vulnerable to 5-MTHF-depleting effects of hyperhomocysteinemia and more vulnerable to hyperhomocysteinemia-inducing diet. This argues that AD pathology predisposes to hyperhomocysteinemia, i.e., as a facultative consequence of AD. However, we also observed that dietary-induced folate reduction and homocysteine increase was associated with an increase of plasma (young animals) and brain (older animals) amyloid-beta concentrations. This suggests that the hyperhomocysteinemia-inducing diet worsened pathology in the transgenic mice. In conclusion, this data may argue that folate reduction and hyperhomocysteinemia may contribute to neurodegeneration and may also be triggered by neurodegenerative processes, i.e., represent both a cause and a consequence of neurodegeneration. Such a vicious cycle may be breakable by dietary or supplementation strategies increasing the availability of 5-MTHF. PMID- 23099813 TI - Chronic administration of dimebon ameliorates pathology in TauP301S transgenic mice. AB - Dimebon belongs to a fast-growing group of "old" drugs that were suggested to be effective for therapy of pathological conditions different from their original targets. Following initial reports of successful Phase II clinical trials for mild-to-moderate Alzheimer's and Huntington's diseases, effects of Dimebon on various neurodegenerative conditions were investigated both in follow-up clinical trials and in various model systems. Although results of Phase III clinical trials carried out so far were disappointing, there is growing body of evidence that this drug can affect neuronal physiology in a way that would be beneficial at particular stages of development of certain types of neurodegeneration. To reveal what molecular and cellular pathological processes might be affected by Dimebon, we tested the ability of this drug to ameliorate pathology in model systems recapitulating particular pathogenic mechanisms involved in the development and progression of neurodegenerative diseases. Here we assessed the ability of Dimebon to modify several prominent features of tauopathies using transgenic tauP301S mice as a model. Chronic treatment with Dimebon was found to partially protect against the progressive decline in motor function and accumulation of tau-positive dystrophic neurons characteristic of tauP301S mice. Similar results were obtained with two further gamma-carbolines structurally similar to Dimebon. Our data suggest that Dimebon and Dimebon-like compounds might be considered as drugs possessing disease-modifying activity for diseases with prominent tau pathology. PMID- 23099814 TI - Light therapy and Alzheimer's disease and related dementia: past, present, and future. AB - Sleep disturbances are common in persons with Alzheimer's disease or related dementia (ADRD), resulting in a negative impact on the daytime function of the affected person and on the wellbeing of caregivers. The sleep/wake pattern is directly driven by the timing signals generated by a circadian pacemaker, which may or may not be perfectly functioning in those with ADRD. A 24-hour light/dark pattern incident on the retina is the most efficacious stimulus for entraining the circadian system to the solar day. In fact, a carefully orchestrated light/dark pattern has been shown in several controlled studies of older populations, with and without ADRD, to be a powerful non-pharmacological tool to improve sleep efficiency and consolidation. Discussed here are research results from studies looking at the effectiveness of light therapy in improving sleep, depression, and agitation in older adults with ADRD. A 24-hour lighting scheme to increase circadian entrainment, improve visibility, and reduce the risk of falls in those with ADRD is proposed, and future research needs are discussed. PMID- 23099816 TI - beta-alanyl-L-histidine rescues cognitive deficits caused by feeding a high fat diet in a transgenic mouse model of Alzheimer's disease. AB - Our goal in this study was to determine whether or not feeding young (4 months old) Alzheimer's disease model transgenic mice with a high fat diet (HFD), consisting of 32% fat, is capable of causing cognitive decline and whether treatment with beta-alanyl-L-histidine (carnosine) is capable of reducing these effects. Carnosine is an endogenous antioxidant and antiglycating agent that is abundantly present in the brain and muscle tissues of vertebrates. After 8 weeks of feeding with HFD, we observed a significant decline in the contextual memory in transgenic mice fed with HFD as compared to transgenic mice fed with a normal diet as well as to normal diet-wild type mice. Treatment with carnosine at a dose of 5 mg/day for 6 weeks was effective in preventing cognitive decline, as the transgenic group fed with HFD and treated with carnosine displayed a level of cognition comparable to controls. No differences in senile plaque load were observed between all groups. However, we observed an increase in the expression of RAGE in blood vessels as well as increased microglial activation in the hippocampus of animals fed with HFD, effects that were reversed when treated with carnosine. Given these results, there is a possibility that inflammation and cerebrovascular abnormalities might be the cause of cognitive decline in this model. PMID- 23099815 TI - Effect of cholinergic signaling on neuronal cell bioenergetics. AB - Alzheimer's disease (AD) patients have reduced brain acetylcholine and reversing this deficit yields clinical benefits. In this study we explored how increased cholinergic tone impacts cell bioenergetics, which are also perturbed in AD. We treated SH-SY5Y neuroblastoma cells with carbachol, a cholinergic agonist, and tested for bioenergetic flux and bioenergetic infrastructure changes. Carbachol rapidly increased both oxidative phosphorylation and glycolysis fluxes. ATP levels rose slightly, as did cell energy demand, and AMPK phosphorylation occurred. At least some of these effects depended on muscarinic receptor activation, ER calcium release, and ER calcium re-uptake. Our data show that increasing cholinergic signaling enhances cell bioenergetics, and reveal mechanisms that mediate this effect. Phenomena we observed could potentially explain why cholinesterase inhibitor therapy increases AD brain glucose utilization and N-acetyl aspartate levels. The question of whether cholinesterase inhibitors have a disease modifying effect in AD has long been debated; our data suggest a theoretical mechanism through which such an effect could potentially arise. PMID- 23099817 TI - Posttraumatic stress symptoms and mental health services utilization in adolescents with social anxiety disorder and experiences of victimization. AB - Recent findings from studies on adults show similarities between social anxiety disorder (SAD) and posttraumatic stress in the form of recurrent memories and intrusive and distressing images of earlier aversive events. Further, treatment models for SAD in adults have been successfully developed by using transdiagnostic knowledge on posttraumatic stress symptoms (PTSS). Studies on adolescents are though missing. The present study aimed at exploring the association between PTSS and SAD in Swedish adolescents. A second aim was to study mental health services utilization in relation to these conditions. A total of 5,960 high-school students participated and reported on SAD, life time victimization, PTSS and mental health service utilization. Socially anxious adolescents reported significantly higher levels of PTSS than adolescents not reporting SAD and this difference was seen in victimized as well as non victimized subjects. Contact with a school counselor was the most common mental health service utilization in subjects with SAD and those with elevated PTSS. In the prediction of contact with a CAP-clinic, significant odds ratios were found for a condition of SAD and elevated PTSS (OR = 4.88, 95% CI = 3.53-6.73) but not for SAD only. Screening of PTSS in adolescents with SAD is recommended. The service of school counselors is important in detecting and helping young people with SAD and elevated PTSS. Clinical studies on SAD and PTSS in adolescents could aid in modifying treatment models for SAD. PMID- 23099818 TI - QTL detection for forage quality and stem histology in four connected mapping populations of the model legume Medicago truncatula. AB - Forage quality combines traits related to protein content and energy value. High quality forages contribute to increase farm autonomy by reducing the use of energy or protein-rich supplements. Genetic analyses in forage legume species are complex because of their tetraploidy and allogamy. Indeed, no genetic studies of quality have been published at the molecular level on these species. Nonetheless, mapping populations of the model species M. truncatula can be used to detect QTL for forage quality. Here, we studied a crossing design involving four connected populations of M. truncatula. Each population was composed of ca. 200 recombinant inbred lines (RIL). We sought population-specific QTL and QTL explaining the whole design variation. We grew parents and RIL in a greenhouse for 2 or 3 seasons and analysed plants for chemical composition of vegetative organs (protein content, digestibility, leaf-to-stem ratio) and stem histology (stem cross-section area, tissue proportions). Over the four populations and all the traits, QTL were found on all chromosomes. Among these QTL, only four genomic regions, on chromosomes 1, 3, 7 and 8, contributed to explaining the variations in the whole crossing design. Surprisingly, we found that quality QTL were located in the same genomic regions as morphological QTL. We thus confirmed the quantitative inheritance of quality traits and tight relationships between quality and morphology. Our findings could be explained by a co-location of genes involved in quality and morphology. This study will help to detect candidate genes involved in quantitative variation for quality in forage legume species. PMID- 23099819 TI - Cardiomyocyte-restricted overexpression of extracellular superoxide dismutase increases nitric oxide bioavailability and reduces infarct size after ischemia/reperfusion. AB - Increased levels of extracellular superoxide dismutase (ecSOD) induced by preconditioning or gene therapy protect the heart from ischemia/reperfusion injury. To elucidate the mechanism responsible for this action, we studied the effects of increased superoxide scavenging on nitric oxide (NO) bioavailability in a cardiac myocyte-specific ecSOD transgenic (Tg) mouse. Results indicated that ecSOD overexpression increased cardiac myocyte-specific ecSOD activity 27.5-fold. Transgenic ecSOD was localized to the sarcolemma and, notably, the cytoplasm of cardiac myocytes. Ischemia/reperfusion injury was attenuated in ecSOD Tg hearts, in which infarct size was decreased and LV functional recovery was improved. Using the ROS spin trap, DMPO, electron paramagnetic resonance (EPR) spectroscopy demonstrated a significant decrease in ROS in Tg hearts during the first 20 min of reperfusion. This decrease in ROS was accompanied by an increase in NO production determined by EPR using the NO spin trap, Fe-MGD. Attenuated ROS in ecSOD Tg myocytes was also supported by decreased production of peroxynitrite (ONOO(-)). Increased NO bioavailability was confirmed by attenuated guanylate cyclase-dependent (p-VASP) signaling. In conclusion, attenuation of ROS levels by cardiac-specific ecSOD overexpression increases NO bioavailability in response to ischemia/reperfusion and protects against reperfusion injury. These findings are the first to demonstrate increased NO bioavailability with attenuation of ROS by direct measurement of these reactive species (EPR, reactive fluorescent dyes) with cardiac-specific ecSOD expression. This is also the first indication that the predominantly extracellular SOD isoform is capable of cytosolic localization that affects myocardial intracellular signal transduction and function. PMID- 23099820 TI - Increased afterload induces pathological cardiac hypertrophy: a new in vitro model. AB - Increased afterload results in 'pathological' cardiac hypertrophy, the most important risk factor for the development of heart failure. Current in vitro models fall short in deciphering the mechanisms of hypertrophy induced by afterload enhancement. The aim of this study was to develop an experimental model that allows investigating the impact of afterload enhancement (AE) on work performing heart muscles in vitro. Fibrin-based engineered heart tissue (EHT) was cast between two hollow elastic silicone posts in a 24-well cell culture format. After 2 weeks, the posts were reinforced with metal braces, which markedly increased afterload of the spontaneously beating EHTs. Serum-free, triiodothyronine-, and hydrocortisone-supplemented medium conditions were established to prevent undefined serum effects. Control EHTs were handled identically without reinforcement. Endothelin-1 (ET-1)- or phenylephrine (PE) stimulated EHTs served as positive control for hypertrophy. Cardiomyocytes in EHTs enlarged by 28.4 % under AE and to a similar extent by ET-1- or PE stimulation (40.6 or 23.6 %), as determined by dystrophin staining. Cardiomyocyte hypertrophy was accompanied by activation of the fetal gene program, increased glucose consumption, and increased mRNA levels and extracellular deposition of collagen-1. Importantly, afterload-enhanced EHTs exhibited reduced contractile force and impaired diastolic relaxation directly after release of the metal braces. These deleterious effects of afterload enhancement were preventable by endothelin-A, but not endothelin-B receptor blockade. Sustained afterload enhancement of EHTs alone is sufficient to induce pathological cardiac remodeling with reduced contractile function and increased glucose consumption. The model will be useful to investigate novel therapeutic approaches in a simple and fast manner. PMID- 23099821 TI - Endovascular treatment of ruptured dissecting aneurysms of the posterior inferior cerebellar artery. AB - BACKGROUND: Dissecting aneurysms of the posterior inferior cerebellar artery (PICA) are rare, with optimal treatment strategies not well established according to the location of the aneurysm on the PICA. We present our single-center experience of endovascular treatment of ruptured dissecting aneurysms of the PICA. METHODS: Nine patients with ruptured dissecting aneurysms of the PICA were treated with endovascular embolization at our facility from August 1997 to December 2011. A retrospective chart review study was conducted to examine the efficacy of endovascular treatment and clinical outcome. RESULTS: The shape of the aneurysms was saccular in five cases, fusiform in three cases and an abrupt cut-off of the PICA in one case. Aneurysmal sac embolization was feasible in five cases and parent artery (PICA) occlusion was performed in four cases. Eight cases (89%) achieved good recovery (modified Rankin Score <= 2). There were no clinical/technical complications in this small series. CONCLUSIONS: Endovascular treatment of ruptured dissecting aneurysms of the PICA is safe and efficient. PMID- 23099823 TI - Congenital malformations: from superstition to understanding. PMID- 23099824 TI - Colorimetric and "turn-on" fluorescent determination of Cu2+ ions based on rhodamine-quinoline derivative. AB - A novel rhodamine-quinoline derivative-based indicator for Cu(2+) ion determination was designed and synthesized. It exhibited highly selective and sensitive colorimetric and "turn-on" fluorescent responses toward Cu(2+) ions based on the ring-opening mechanism of the rhodamine spirolactam in aqueous solution. The colorimetric and fluorescent responses were recorded using a domestic scanner and camera-based home-made fluorescent imaging unit, separately. The images were digitized, and the red (R), green (G), and blue (B) values were investigated. Both colorimetric and fluorescent methods showed good selectivity, and the color/fluorescence changes were remarkable for the Cu(2+) ion detection even in the presence of other metal ions. The good linear relationship was easily obtained between the color/fluorescence changes and the concentrations in the range of 20-120 MUM. PMID- 23099825 TI - Nutritional and epidemiological aspects of patients with chronic renal failure undergoing hemodialysis from Brazil, 2010. AB - INTRODUCTION: The Nutrition Committee of the Brazilian Society of Nephrology (SBN) held in 2010 the first Brazilian Nutrition Census in hemodialysis patients. Multicenter data contribute to clinical development and nutritional intervention. OBJECTIVE: To describe epidemiological and nutritional aspects of hemodialysis patients. METHOD: Cross-sectional study in 36 dialysis clinics and 2,622 randomly selected participants. Socio-demographical, clinical, biochemical and anthropometric records were collected. RESULTS: 60.45% of the patients lived in the Brazilian Southeast. 13.53% came from Northeast region, while 12.81% from South, 10.33% from Midwest and 2.86% from North regions. Approximately 58% were male and 63.1% were below 60 years old. 58.5% of patients were married or in cohabitation. Around 80% of them depended on the government Unified Health System. Smoking showed a difference between gender and age. Presumptive etiologies were Hypertensive Nephrosclerosis (26.4%), Diabetic Nephropathy (24.6%), unknown/undiagnosed causes (19.9%), Glomerulopathies (13.6%) and others (11.2%). Both Hypertension and Diabetes Mellitus affect approximately 30% of patients, especially over 60 years. Body Mass Index did not differ between genders, although it differed between age groups and when used different evaluation criteria. Men and women average waist circumference were respectively 90.5 and 88.0 cm. Lipid profile did not differ between age groups, but it did between genders. Albumin values were lower in women and in patients older than 60 years. CONCLUSION: This study characterized Brazilian hemodialysis patients in 2010, and may support further studies to monitor nutrition and epidemiological transitions of the population. PMID- 23099826 TI - Survival analysis and associated factors to mortality of renal transplant recipients in a University Hospital in Maranhao. AB - INTRODUCTION: Renal transplantation is regarded as the best treatment for patients with Chronic Kidney Disease. Factors associated to survival of renal transplant recipients must be evaluated in order to implement appropriate conducts in these patients. AIMS: To analyze the renal transplant patients survival and associated factors to their mortality. METHODS: Observational, retrospective cohort study, including all the 215 patients who underwent kidney transplantation in the Renal Transplant Service of the Hospital Universitario da Universidade Federal do Maranhao (HUUFMA), from March 18, 2000 to September 18, 2008, with a follow-up ranging from 12 to 101 months. Demographic and clinical characteristics were observed. The Kaplan-Meier method was used for construction of survival curves, and they were compared by log-rank test. The Cox proportional hazards model was used for identification of factors associated to mortality. RESULTS: The prevalence of deaths was 10,6%. The survival rates at 1, 3 and 5 years for living donors recipients were 97,8%, 94,1% and 92,9%, respectively and for deceased donors recipients, 95,6% and 95,6%, at 1 and 3 years, respectively. Factors statistically associated to a lower survival were: recipient age above 40 years (RR = 6.19; p = 0.001; 95% CI = 2.01-18.99) and surgery complications (RR = 4.98; p = 0.041; 95% CI = 1.07-23.27). CONCLUSIONS: Kidney recipients survival rates at HUUFMA were similar to the rates related in other, Brazilian and international studies. Recipient age above 40 years and surgery complications were significantly associated to mortality in this study. PMID- 23099827 TI - Prospective study of 2151 patients with chronic kidney disease under conservative treatment with multidisciplinary care in the Vale do Paraiba, SP. AB - INTRODUCTION: Chronic Kidney Disease (CKD) is common, severe and treatable. Its detection involves low cost tests. AIM: To evaluate the effect of a multidisciplinary (nephrologist, social worker, nurse, nutritionist, and psychologist) intervention comparing clinical and laboratory parameters in patients with CKD. METHODS: A prospective study with 2,151 patients attended at the State Center for Kidney Diseases of the Vale do Paraiba, Sao Paulo, from February 2008 to March 2011. The kidney function was measured using albuminuria and estimated glomerular filtration rate (eGRF) using the MDRD formula The clinical outcomes were the occurrence of cardiovascular disease (CAD), hospitalization episodes, need of renal replacement therapy (RRT) and death. RESULTS: Participants had a mean (range) age of 62 years (14-101), a mean follow up of 546 days (90-1540) and the majority was in the stage 3 of CKD (59%). The most common primary diagnoses were hypertension (41.2%) and diabetes (32.4%). Mean blood pressure values at the beginning and at the end of treatment were 143 +/- 26 mmHg x 87 +/- 14 mmHg and 123 +/- 16 mmHg x 79 +/- 9 mmHg, respectively (p < 0.001); the eGRF decreased from 58.5 +/- 31 ml/min. to 56.3 +/- 23 ml/min (p < 0.01). Mean value of proteinuria decreased from 1.04 +/- 1.44 g/day to 0.61 +/- 1.12 g/day, p < 0.001, and the fasting glicemia decreased from 137 +/- 73 mg/dl to 116 +/- 42 mg/dl. One hundred and twenty-two patients (5.7%) had a CAD episode, the hospitalization rate was 6.6% (n = 143 patients), 7.3% patients died (n = 156), and 1.1% (n = 23) patients needed to start RRT. The risk of cardiovascular events, hospitalization, or death was inversely related to eGRF, and the rates of these events were low compared with the international literature. CONCLUSION: The multidisciplinary care with well defined targets is effective for the preservation of renal function and reduction in morbidity and mortality of CKD patients. PMID- 23099828 TI - Electrocardiographic findings in chronic hemodialysis patients. AB - INTRODUCTION: Cardiovascular disease is the leading cause of mortality among patients on dialysis. When considering all causes of death, about 30% are classified as cardiac arrest, death of unknown cause or cardiac arrhythmia. The increasing time of ventricular depolarization and repolarization, measured non invasively by measuring the QT interval on the electrocardiogram at rest, has emerged as a predictor of complex ventricular arrhythmias, a major cause of sudden cardiac death. AIMS: To determine the electrocardiographic alterations present in hemodialysis (HD) patients, measuring the QT interval and its relationship with clinical and laboratory variables. METHODS: Patients above 18 years on dialysis were approached to participate in the study and, after consent, were submitted to the examination of 12-lead electrocardiogram. Clinical data were reviewed to assess the presence of comorbidities, as well as anthropometric and blood pressure measures. Blood samples were collected to determinate hemoglobin and serum levels of calcium, phosphorus and potassium. RESULTS: One hundred and seventy nine patients were included in the study. The majority of the patients were male (64.8%) and white (54.7%); the average age was 58.5 +/- 14.7 years old. About 50% of all patients had, at least, one electrical conduction disturb. About 50% of all patients had QTc prolongation and experienced a significant increase in the frequency of Left Ventricular Hypertrophy (LVH), changes of the cardiac rhythm and bundle branch blocks, and a lower body mass index (BMI), when compared with normal QTc interval patients. CONCLUSIONS: Patients with chronic kidney disease (CKD) on hemodialysis had high frequency of abnormal electrocardiographic findings, including a high prevalence of patients with prolonged QTc interval. This study also found a significant association between prolonged QTc interval and the presence of Diabetes and lower values of BMI. PMID- 23099829 TI - Research of multiarterial atherosclerotic disease in hypertensive patients with renal artery stenosis. AB - INTRODUCTION: The detection of the renal artery stenosis in hypertensive patients can be a signal of systemic arterial atherosclerosis. AIMS: To identify and characterize clinical-epidemiologically the hypertensive patients with renal artery stenosis, evaluating factors of cardiovascular risk and presence of symptomatic multiarterial atherosclerotic. METHOD: Were selected the hypertensive patients who were assisted at the Nephrological Clinic of Universidade Federal do Triangulo Mineiro (UFTM) between 2000-2010, with diagnosis of renal artery stenosis of atherosclerotic etiology. Epidemiological data were evaluated (gender, age, ethnicity), factors of cardiovascular risk (diabetes, hypercholesterolemia, hypertriglyceridemia, tabagism, metabolic syndrome), information on hypertension (time of diagnosis, family report, number of used medicines), previous cardiovascular events (acute myocardial infarctation, ischemic stroke, peripheral arterial disease). Blood pressure levels, global cardiovascular risk and Score Framingham were stratified. RESULTS: Casuistry of 30 patients, feminine majority (73.3%), average of 66 year-old age, 86.67% white, medium time of hypertension of 19.94 years, 89.92 without family report, 13.8 with diabetes, 65.51% smoking, 17.25% hypertriglyredemia, 62.06% with hypercholesterolemia and 66.7% with metabolic syndrome. Average number of medicines in use: 3.26. Dominant right-sided renal artery stenosis separately (46.7%) and in proximal third (56.7%). High creatinine levels in 40% of the patients. As for the hypertension phase, majority phase 2 (47%) and 73.3% with high global cardiovascular risk. Average Framingham Score of 13%. 66.7% presented atherosclerotic disease in another place, being infarctation the main one (53.3%). CONCLUSION: The most common correlation was with acute myocardial infarctation, what implicates in the search of the coronary compromising to the diagnosis of renal artery stenosis in hypertensive patients to try avoid future damages to the patient. PMID- 23099830 TI - Translation, cultural adaptation, and validation of the screening for occult renal disease (SCORED) questionnaire to Brazilian Portuguese. AB - Screening Chronic Kidney Disease (CKD) allows early interventions, which may alter the natural course of the disease, including cardiovascular morbidity and mortality. Screening for Occult Renal Disease (SCORED) is questionnaire with nine questions with different weights, and predicts a 20% chance for CKD if a individual score > 4 points. AIM: Translate to Portuguese, perform the adaptation to the Brazilian culture and validate the original version of SCORED questionnaire. METHODS: Steps of the process: Translation from English into Brazilian Portuguese; back-translation into English; application to a population sample; and Proof-reading and completion. The translations and reviews were made by professionals experts in Portuguese and English. The questionnaire was applied to 306 participants and CKD was diagnosed as suggested by the NKF KDOQI?. RESULTS: The participants mean age was 49 +/- 13 years, 61% were women, 69% were white, and 68% had education below high school, 38.5% had hypertension, and 12.3% diabetics. The final Brazilian Portuguese version of the SCORED questionnaire was well understood. CKD was diagnosed in 20 (6.5%) of the participants. The Brazilian version of the SCORED questionnaire showed sensitivity of 80%, specificity of 65%, positive predictive value of 14%, negative predictive value of 97%, and accuracy of 66%. CONCLUSION: The steps used for the translation, transcultural adaptation, and validation allowed a Brazilian Portuguese version of the SCORED questionnaire which was well understood, acceptable and costless, characteristics that make it a useful tool in the identification of people that chance of having CKD. PMID- 23099831 TI - Variations in adiponectin levels in patients with chronic kidney disease: a prospective study of 12 months. AB - BACKGROUND: Cardiovascular complications remain the main cause of mortality in patients with chronic kidney disease (CKD). Adiponectin is an adipose tissue derived protein that carries important cardioprotective properties. We aimed at investigating the determinants of adiponectin levels in CKD patients. METHODS: This prospective observational study included 98 CKD patients [glomerular filtration rate (GFR) 36.1+-14.4 ml/min, 56.5+-10.4 y, 63% male, 31% diabetics, and body mass index (BMI) 27.1+-5.2 kg/m2]. Evaluation of adiponectin (imunoenzimatic assay), laboratory parameters, nutritional status (subjective global assessment), total body fat (dual x-ray energy absorptiometry), and visceral and subcutaneous abdominal fat (computed tomography) was performed at baseline and after 12 months. RESULTS: Adiponectin correlated with GFR (r = 0.45; p < 0.001), proteinuria (r = 0.21; p = 0.04), BMI (r = -0.33; p < 0.01), and visceral fat (r = -0.49; p < 0.001). In the linear regression analysis, the determinants of adiponectin levels were sex (female beta = 3.8; p < 0.01), age (beta = 0.14; p = 0.03), GFR (beta = -0.15; p < 0.01) and visceral fat (beta = 0.04; p < 0.001) (R2 = 0.41). After 12 months, a progression of the disease was evidenced by the reduction of GFR (-1.6+-6.3 ml/min; p = 0.01) and increase of proteinuria (0.3+-0.8 g/d; p < 0.01). An accumulation of visceral fat was observed, from 97+-73 cm2 to 111+-82 cm2 (p < 0.001), with a concomitant reduction of adiponectin concentration, from 27.6+-7.5 mg/l to 22.2+-11.6 mg/l (p < 0.001). Body weight, BMI, total body fat, and subcutaneous abdominal fat remained unchanged. After adjustments for the baseline determinants of adiponectin, the increase in visceral fat was independently associated with overtime decrease in adiponectin levels (beta = -0.04; p = 0.025; R2 = 0.21). CONCLUSION: Age, sex, renal function and visceral fat were independently associated with adiponectin levels in nondialyzed CKD patients. However, variation in visceral fat was the only predictor of variation in adiponectin levels over 12 months. PMID- 23099832 TI - [Comparison between the central and brachial blood pressure values in patients with hypertension undergoing cineangiocoronarography]. AB - INTRODUCTION: Systolic blood pressure (SP) and pulse pressure (PP) rise gradually during the aging process as a consequence of a reduction in arterial elasticity. The measure of systemic arterial pressure (SAP) taken at the root of the aorta has been considered an independent determinant of cardiovascular mortality superior to the values of brachial SAP. AIM: To compare the values of SAP central to those of braquial SAP in patients of different age brackets who have systemic hypertension. METHOD: We evaluated the central SAP at the root of the aorta and the brachial SAP in the left arm using the ocillometric method 244 hypertensive patients who had been submitted to cineangiocoronarography. Five groups of patients were constituted: Group I, 39-49 years-old (y.o.), n = 36; Group II, 50 59 y.o., n = 67; Group III, 60-69 y.o., n = 69; Group IV, 70-79 y.o., n = 46; Group V, > 80 y.o., n = 26. RESULTS: When central SP was compared to brachial SP, it was possible to find significance in patients who were 50 y.o and upwards. It was not possible to find a statistical difference between central diastolic pressure and brachial except in patients between the ages of 60-69 y.o. When comparing central to brachial PP, we observed that central PP was significantly greater (between 11 and 15 mmHg) in all patient above the age of 50 y.o. CONCLUSION: In older people, the values of SP and PP, taken directly at the root of the aorta, are superior to those obtained by indirect means from the brachial artery. These differences are significant from the age of 50 y.o. onwards. PMID- 23099833 TI - [Chronic dialysis in Brazil: report of the Brazilian dialysis census, 2011]. AB - INTRODUCTION: National data on maintenance dialysis are important for treatment planning. AIM: To describe the results of the dialysis census of the Brazilian Society of Nephrology for 2011 and observed trends from 2000 to 2011. METHODS: A survey was conducted using questionnaire filled online by the dialysis units, with July as reference month for estimates. From a total of 645 units, 353 (54.9%) responded to the survey. RESULTS: The estimated number of patients on dialysis in Brazil was 91,314 in 2011 (42,629 in 2010; 92,091 in 2011). For approximately 85% of the patients the treatment was provided by the Brazilian Unified Health Care System. The estimated prevalence and incidence rates in 2011 were 475 and 149 maintenance dialysis patients per million population, respectively. For prevalent patients, 90.6% were on hemodialysis, 31.5% 65 years of age or older, 28% diabetic and 35.5% (n=32,454) on waiting list for transplantation in 2011. The estimated number of patients starting dialysis in 2011 was 28,680 (18,972 in 2010) and annual mortality rate 19.9% (17.9% in 2010). CONCLUSIONS: The data indicate pronounced increase in the dialysis population across the years in Brazil with a trend for stabilization in the last two years. The reason for the increase in incidence and mortality in 2011 deserves investigation. A large number of patients were on waiting list for renal transplantation. By providing a picture of the situation and trends on maintenance dialysis treatment in Brazil the census is useful to guide resources allocation and interventions to improve treatment quality. PMID- 23099834 TI - [Identification of risk factors for chronic kidney disease among schoolchildren]. AB - Aiming at identifying risk factors for chronic kidney disease (CKD) among schoolchildren, a cross-sectional population study was carried out in six municipal schools in Goiania, Brazil. We investigated: history of birthweight, enuresis, urinary incontinence, mictional urgency, family history of kidney disease, diabetes, arterial hypertension, percentiles of arterial blood pressure, waist circumference and body mass index (BMI). We evaluated 274 children, mean age of 8.06 +/- 1.33 years, among which 139 (50.7%) were female. We detected: enuresis in 50 (18.2%); urinary incontinence in 34 (12.4%); mictional urgency in 49 (17.9%); BMI above P85 in 18.8% (45); waist circumference above P90 in 17 (6.9%); arterial blood pressure above P95 in 17 (7.1%). Also, we observed correlation between arterial blood pressure, obesity, and increased waist circumference, (p < 0.05). The study showed high frequency of abnormal voiding habits and increased BMI in this population. PMID- 23099835 TI - [Crossed renal ectopia with fusion: report of two cases and review of the literature]. AB - Renal ectopia is one of the most common renal abnormalities of kidney development. However, only a few cases of crossed fused renal ectopia have been reported in the literature. Although crossed renal ectopia is usually clinically silent, they is sometime responsible for infection and urinary stones and may be associated with a high incidence of ureteropelvic junction obstruction, vesicoureteral reflux and renal multicystic dysplasia. We report two new cases of crossed renal ectopia with fusion diagnosed in a context of kidney stones and urinary tract infection and review the mechanism and clinical features of this abnormality. We believe that Nephrologist must be familiar with this abnormality of kidney development, as a number of complications may appear during follow-up. PMID- 23099836 TI - [Unknown significance monoclonal gammopathy (USMG) and primary hyperparathyroidism (PH) on diferential diagnosis of hypercalcemia: case report]. AB - The monoclonal gammopathy of undetermined significance (USMG) is a pre-malignant rare asymptomatic disease, defined by a concentration of immunoglobulin in serum monoclonal more than 3 g/dL and a proportion of plasma cells in bone marrow more than 10% in the absence of lytic bone lesions, anemia, hypercalcemia and renal failure related to monoclonal cell proliferation. Primary hyperparathyroidism (PH) is a relatively frequent disease, affecting approximately one in 1,000 individuals. Some studies suggest that the frequency of PH is increased in cancer, broadening the spectrum of etiology of hypercalcemia in these patients. We report here a case of a 63 years-old patient admitted for investigation of anemia, paresthesias, pain in the lower limbs and kidney failure. During investigation, there was hypercalcemia, serum monoclonal peak of IgA/lambda without criteria for multiple myeloma and with parathyroid adenoma. Patient was submitted to parathyroidectomy, which anatomicopathological revealed parathyroid adenoma. After surgery, levels of calcium and kidney function returned to normal. PMID- 23099837 TI - [Renal glycosuria: report of two cases]. AB - Glycosuria as an accidental finding implies a diagnostic workout. We present the cases of two asymptomatic female teenagers referred to a hospital outpatient clinic due to isolated glycosuria detected in a routine analysis. The diagnostic workout revealed isolated glycosuria in the absence of other abnormalities. The genetic study confirmed the diagnosis of renal glycosuria, by revealing SCL5A2 gene mutations. Renal glycosuria is characterized by persistent glycosuria in the absence of hyperglycaemia or generalized renal tubular dysfunction. It's usually asymptomatic and has good prognosis. The authors call the attention to this rare entity, since it can be the reason for reference to a hospital outpatient clinic, underlining the importance of a differential diagnosis with more serious diseases that require proper treatment. PMID- 23099838 TI - [Health literacy: importance of assessment in nephrology]. AB - Health literacy (HL) or basic reading and numeracy that allow an individual to function in the health care environment, is a relatively new topic, yet has increasingly been gaining interest over the past few years both in the research and policy agendas, particularly in the develop countries. Where studied, inadequate HL has been associated with poor health care quality and more cost. Yet many physicians do not recognize the problem or is not skilled enough to approach the subject with their patients. In this review, important aspects of HL, such as its epidemiology, associations with poor outcomes, assessment, determinants and interventions, particularly in nephrology, are discussed. Because it is common and associated to adverse clinical outcomes, inadequate HL should be incorporated into the list of assessments of patients with renal disease. PMID- 23099839 TI - [Posttransplant chronic anemia: parvovirus B19]. AB - Anemia is frequent in kidney transplant patients, and its prevalence varies according to posttransplant time and the adopted diagnostic criteria. Parvovirus B19 (PV B19) infection is an underdiagnosed cause of anemia in this particular population. To illustrate epidemiologic and clinical data regarding it, we present a case of PV B19 infection complicated by pure red cell aplasia (PRCA), pointing out the pitfalls we encountered in diagnosis and treatment. The use of viral DNA detection by polymerase chain reaction (PCR), and correct interpretation of morphological features of bone marrow histology are particularly important for the diagnosis of this condition in kidney transplant patients, who fail to develop a proper humoral response against PV B19, thus importantly decreasing the sensitivity of serological methods in this setting. PMID- 23099840 TI - [Practical markers of renal function in cystinosis patients]. AB - BACKGROUND: Cystinosis is an autossomic recessive systemic disease that leads to renal insufficiency early in life unless cysteamine be started early. Unfortunately, even in this situation the patients will develop chronic renal disease with need of renal replacement therapy about second decade of life. Therefore, the renal function evaluation is essential to these patients. The aim of this study was to evaluate cystatin C, serum creatinine and creatinine clearance estimated by stature (Schwartz Formula) in cystinosis patients, with different degrees of renal function, and to correlate these parameters. METHODS: We studied cystinosis patients, aged lower than 18 years, with different degrees of renal function, classified according to KDOQI in Chronic Kidney Disease stage 1 to 4. No patient was under renal replacement therapy. In these patients we evaluate the serum creatinine, cystatin C and creatinine clearance according to Schwartz Formula. RESULTS: We analyzed 103 blood samples of 26 patients. We detected a significant statistical correlation between serum creatinine and cystatin C (r = 0.81, p < 0.0001), cystatin C and creatinine clearance estimated by stature (r = -0.84, p < 0.0001) and between serum creatinine and creatinine clearance estimated by stature (r = -0.97, p < 0.0001). CONCLUSIONS: The expensive measurement of cystatin C showed no advantage in relation to serum creatinine and creatinine clearance according to Schwartz Formula in cystinosis patients to estimate the glomerular filtration rate. This is the first report checking the value of serum creatinine, creatinine clearance estimated by stature and cystatin C in cystinosis patients. PMID- 23099841 TI - [Nomogram for estimation of glomerular filtration rate based on the CKD-EPI formula]. PMID- 23099842 TI - The future of hybrid imaging-part 1: hybrid imaging technologies and SPECT/CT. AB - Since the 1990s, hybrid imaging by means of software and hardware image fusion alike allows the intrinsic combination of functional and anatomical image information. This review summarises in three parts the state-of-the-art of dual technique imaging, with a focus on clinical applications. We will attempt to highlight selected areas of potential improvement of combined imaging technologies and new applications. In this first part, we briefly review the origins of hybrid imaging and comment on the status and future development of single photon emission tomography (SPECT)/computed tomography (CT). In short, we could predict that, within 10 years, we may see all existing dual-technique imaging systems, including SPECT/CT, in clinical routine use worldwide. SPECT/CT, in particular, may evolve into a whole-body imaging technique with supplementary use in dosimetry applications. PMID- 23099843 TI - Skeletal muscle mitochondrial dysfunction precedes right ventricular impairment in experimental pulmonary hypertension. AB - We assessed the time courses of mitochondrial biogenesis factors and respiration in the right ventricle (RV), gastrocnemius (GAS), and left ventricle (LV) in a model of pulmonary-hypertensive rats. Monocrotaline (MT) rats and controls were studied 2 and 4 weeks after injection. Compensated and decompensated heart failure stages were defined according to obvious congestion signs. mRNA expression and protein level of peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha), citrate synthase (CS) mRNA and activity, and mitochondrial respiration were investigated. In addition, mRNA expression of sirtuin1, nuclear respiratory factor 1, and mitochondrial transcription factor A were studied. As early as 2 weeks, the expression of the studied genes was decreased in the MT GAS. At 4 weeks, the MT GAS and MT RV showed decreased mRNA levels whatever the stage of disease, but PGC-1alpha protein and CS activity were significantly reduced only at the decompensated stage. The functional result was a significant fall in mitochondrial respiration at the decompensated stage in the RV and GAS. The mRNA expression and mitochondrial respiration were not significantly modified in the MT LV. MT rats demonstrated an early decrease in expression of genes involved in mitochondrial biogenesis in a skeletal muscle, whereas reduced protein expression, and the resulting mitochondrial respiratory dysfunction appeared only in rats with overt heart failure, in the GAS and RV. Dissociations between mRNA and protein levels at the compensated stage deserve to be further studied. PMID- 23099844 TI - Lyoniresinol inhibits melanogenic activity through the induction of microphthalmia-associated transcription factor and extracellular receptor kinase activation. AB - Lyoniresinol was one of the eight lignans purified from methanol extract of Vitex negundo and was shown to have robust tyrosinase inhibitory capacity. However, the mechanism of its action is not known. Hence, the goal of the current study was to study the effects of Lyoniresinol on cytotoxicity and melanin content in murine B16F10 melanoma cells and to delineate the underlying mechanism of tyrosinase inhibition. Lyoniresinol was purified from methanol extract of Vitex negundo root and when tested in B16F10, cells showed robust anti-melanogenic activity. It caused the downregulation of microphthalmia-associated transcription factor (MITF) and tyrosinase steady state protein expression levels. Flow cytometry analysis of Lyoniresinol-treated cells showed that the latter activates extracellular receptor kinase (ERK) phosphorylation, which causes MITF protein degradation and suppression of tyrosinase activity. Lyoniresinol decreased tyrosinase activity and melanin biosynthesis in B16F10 cells by activating ERK signaling, which downregulated MITF, tyrosinase, but not TRP-1 and TRP-2 protein expression. Contingent to more vigorous in vitro and in vivo experiments, Lyoniresinol can perhaps be incorporated into clinical dermatologic use as a skin lightening agent. PMID- 23099845 TI - Safety of a DVT chemoprophylaxis protocol following traumatic brain injury: a single center quality improvement initiative. AB - BACKGROUND: Venous thromboembolism (VTE) is a complication that affects approximately 30 % of moderate and severe traumatic brain injury (TBI) patients when pharmacologic prophylaxis is not used. Following TBI, specifically in the case of contusions, the safety and efficacy of pharmacologic thromboembolism prophylaxis (PTP) has been studied only in small sample sizes. In this study, we attempt to assess the safety and efficacy of a PTP protocol for TBI patients, as a quality improvement (QI) initiative, in the neuroscience intensive care unit (NSICU). METHODS: Between January 1st and December 31st, 2009, consecutive patients discharged from the University of Wisconsin NSICU after >a 48 h minimum stay were evaluated as part of a QI project. A protocol for the initiation of PTP was designed and implemented for NSICU patients. The protocol did not vary based on type of intracranial injury. The rate of VTE was reported as was heparin induced thrombocytopenia and PTP-related expansion of intracranial hemorrhage (IH) requiring reoperation. The number of patients receiving PTP and the timing of therapy were tracked. Patients were excluded for persistent coagulopathy, other organ system bleeding (such as the gastrointestinal tract), or pregnancy. Faculty could opt out of the protocol without reason. Using the same criteria, patients discharged during the preceding 6 months, from July 1st to December 31st, 2008, were evaluated as controls as the PTP protocol was not in effect during this time. RESULTS: During the control period, there were 48 head trauma admissions who met the inclusion criteria. In 22 patients (45.8 %), PTP was initiated at an average of 4.9 +/- 5.4 days after admission. During the protocol period, there were 87 head trauma admissions taken from 1,143 total NSICU stays who met criteria. In 63 patients (72.4 %), the care team in the NSICU successfully initiated PTP, at an average of 3.4 +/- 2.8 days after admission. All 87 trauma patients were analyzed, and the rate of clinically significant deep venous thrombosis (DVT) was 6.9 % (6 of 87). Three protocol patients (3.45 %) went to the operating room for surgery after the initiation of PTP; none of these patients had a measurable change in hemorrhage size on head CT. The change in percentage of patients receiving PTP was significantly increased by the protocol (p < 0.0001); while the average days to first PTP dose trended down with institution of the protocol, this change was not statistically significant. CONCLUSION: A PTP protocol in the NSICU is useful in controlling the number of complications from DVT and pulmonary embolism while avoiding additional IH. This protocol, based on a published body of literature, allowed for VTE rates similar to published rates, while having no PTP-related hemorrhage expansion. The protocol significantly changed physician behavior, increasing the percentage of patients receiving PTP during their hospitalization; whether long-term patient outcomes are affected is a potential goal for future study. PMID- 23099846 TI - Factors associated with the withdrawal of life-sustaining therapies in patients with severe traumatic brain injury: a multicenter cohort study. AB - PURPOSE: To identify factors associated with decisions to withdraw life sustaining therapies in patients with severe traumatic brain injury (TBI). MATERIALS AND METHODS: We conducted a 2-year multicenter retrospective cohort study (2005-2006) in mechanically ventilated patients aged 16 years and older admitted to the intensive care units (ICUs) of six Canadian level I trauma centers following severe TBI. One hundred and twenty charts were randomly selected at each center (n = 720). Data on ICU management strategies, patients' clinical condition, surgical procedures, diagnostic imaging, and decision to withdraw life-sustaining therapies were collected. The association of factors pertaining to the injury, interventions, and management strategies with decisions to withdraw life-sustaining therapies was evaluated among non-survivors. RESULTS: Among the 228 non-survivors, 160 died following withdrawal of life-sustaining therapies. Patients were predominantly male (69.7 %) with a mean age of 50.7 (+/ 21.7) years old. Brain herniation was more often reported in patients who died following decisions to withdraw life-sustaining therapies (odds ratio [OR] 2.91, 95 % confidence interval [CI] 1.16-7.30, p = 0.02) compared to those who died due to other causes (e.g., cardiac arrest, shock, etc.). Epidural hematomas (OR 0.18, 95 % CI 0.06-0.56, p < 0.01), craniotomies (OR 0.12, 95 % CI 0.02-0.68, p = 0.02), and other non-neurosurgical procedures (OR 0.08, 95 % CI 0.02-0.43, p < 0.01) were less often associated with death following withdrawal of life sustaining therapies than death from other causes. CONCLUSIONS: Death following decisions to withdraw life-sustaining therapies is associated with specific patient and clinical factors, and the intensity of care. PMID- 23099847 TI - Causes and outcomes of persistent vegetative state in a Chinese versus American referral hospital. AB - OBJECTIVE: To compare the etiologies and clinical outcomes of patients in a persistent vegetative state (PVS) between a Chinese and US referral hospital. METHODS: A retrospective, observational study at the Peking Union Medical College Hospital, Beijing, China and Johns Hopkins Hospital, Baltimore, USA (2001-2010) was performed. RESULTS: There were 36 cases of PVS diagnosed. In Beijing, there were 19 cases: mean age 57 years, range 3-86, (42 %) female, with 37 % of patients observed to survive more than 1 year (range >1 month to >28 years, median >6 months). Causes of PVS in Beijing were hemorrhagic stroke (n = 4, 21 %), ischemic stroke (n = 2, 11 %), cardiac arrest (n = 5, 26 %, including 4 with attempted cardiopulmonary resuscitation (CPR)), traumatic brain injury (n = 3, 16 %), and one each of mitochondrial encephalomyopathy, acute disseminated encephalomyelitis, Lennox Gastaut Syndrome, and epilepsy with craniopharyngioma (n = 4, 21 %). In Baltimore, there were 17 cases of PVS: mean age 43 years, range 15-83, 59 % female, with 41 % observed to survive more than 1 year (range >1 month to >10 years, median >3 years). Causes of PVS in Baltimore were ischemic stroke (n = 3, 18 %), cardiac arrest (n = 3, 18 %, including one with attempted CPR), traumatic brain injury (n = 3, 18 %), neurodegenerative conditions (n = 2, 12 %), and hypoxic ischemic encephalopathy due to respiratory arrest (n = 3, 18 %), metabolic derangements (n = 2, 12 %), and meningitis (n = 1, 6 %). CONCLUSIONS: There may be a long survival period for patients with PVS, including in China where resource constraints exist for acute neurologic care. Stroke appears to be the most common underlying cause of PVS in Chinese patients, followed closely by cardiac arrest with attempted CPR. There appear to be more varied causes of PVS in the US referral hospital with a predominance of stroke, cardiac arrest, and traumatic brain injury. PMID- 23099848 TI - The epidemiology of intracerebral hemorrhage in the United States from 1979 to 2008. AB - BACKGROUND: Intracerebral hemorrhage (ICH) causes 15 % of strokes annually in the United States. METHODS: Using the National Hospital Discharge Survey, we studied the disposition and mortality trends of ICH admissions from 1979 to 2008. Cases were identified using the International Classification of Disease, 9th Revision, Clinical-Modification code 431. RESULTS: There was an annualized increase in the admission rate of ICH from about an average of 24,000 cases (12.9 per 100,000 persons per year) during the first epoch to 40,600 cases (17.0 per 100,000 persons per year) during the second epoch. Thereafter, the annual admission rate after ICH remained stable with about 63,000 cases (21 per 100,000 persons per year) during the last epoch. Nonwhites experienced higher growth rates than whites, and the risk of ICH was higher across all age subgroups, in men than women, and nonwhites compared with whites. In-hospital mortality after ICH fell significantly from 45 % (95 % CI, 31-59 %) during the first epoch (1979-1983) to 34 % (95 % CI, 20-38 %) during the second epoch (1984-1988) (p = 0.03) but did not change significantly after that. Groups with higher in-hospital mortality were whites, women, and persons older than 65 years, black women younger than 45 years, and middle-aged black men. Average days of care for ICH hospitalizations decreased significantly. CONCLUSION: Though the ICH admission rate increased and the in-hospital mortality decreased during the first epochs of the study, these have not significantly changed over the last two decades. ICH remains the most severe form of stroke with limited options to improve survival. More research targeting novel therapies to improve outcomes after ICH is desperately needed. PMID- 23099849 TI - Efficacy of genotypic resistance-guided sequential therapy in the third-line treatment of refractory Helicobacter pylori infection: a multicentre clinical trial. AB - OBJECTIVES: The efficacy of sequential therapy and the applicability of genotypic resistance to guide the selection of antibiotics in the third-line treatment of Helicobacter pylori have not been reported. We aimed to assess the efficacy of genotypic resistance-guided sequential therapy in third-line treatment. METHODS: Genotypic and phenotypic resistances were determined in patients who failed at least two eradication therapies by PCR with direct sequencing and agar dilution test, respectively. The patients were retreated with sequential therapy containing esomeprazole and amoxicillin for the first 7 days, followed by esomeprazole and metronidazole plus clarithromycin, levofloxacin or tetracycline for another 7 days (all twice daily), according to genotypic resistance determined using gastric biopsy specimens. Eradication status was determined by the (13)C-urea breath test. Trial registered at clinicaltrials.gov (identifier: NCT01032655). RESULTS: The overall eradication rate was 80.7% (109/135, 95% CI 73.3%-86.5%) in the intention-to-treat analysis. The presence of amoxicillin resistance (OR 6.83, 95% CI 1.62-28.86, P = 0.009) and prior sequential therapy (OR 4.77, 95% CI 1.315-17.3, P = 0.017), but not tetracycline resistance (tetracycline group), were associated with treatment failure. The eradication rates in patients who received clarithromycin-, levofloxacin- and tetracycline based sequential therapies were 78.9% (15/19), 92.2% (47/51) and 71.4% (25/35) in strains susceptible to clarithromycin, levofloxacin and tetracycline, respectively. CONCLUSIONS: A simple molecular method guiding sequential therapy can achieve a high eradication rate in the third-line treatment of refractory H. pylori infection. PMID- 23099850 TI - Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor. AB - Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class. PMID- 23099852 TI - p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation. PMID- 23099851 TI - miR-125b promotes cell death by targeting spindle assembly checkpoint gene MAD1 and modulating mitotic progression. AB - The spindle assembly checkpoint (SAC) is a 'wait-anaphase' mechanism that has evolved in eukaryotic cells in response to the stochastic nature of chromosome spindle attachments. In the recent past, different aspects of the SAC regulation have been described. However, the role of microRNAs in the SAC is vaguely understood. We report here that Mad1, a core SAC protein, is repressed by human miR-125b. Mad1 serves as an adaptor protein for Mad2 - which functions to inhibit anaphase entry till the chromosomal defects in metaphase are corrected. We show that exogenous expression of miR-125b, through downregulation of Mad1, delays cells at metaphase. As a result of this delay, cells proceed towards apoptotic death, which follows from elevated chromosomal abnormalities upon ectopic expression of miR-125b. Moreover, expressions of Mad1 and miR-125b are inversely correlated in a variety of cancer cell lines, as well as in primary head and neck tumour tissues. We conclude that increased expression of miR-125b inhibits cell proliferation by suppressing Mad1 and activating the SAC transiently. We hypothesize an optimum Mad1 level and thus, a properly scheduled SAC is maintained partly by miR-125b. PMID- 23099853 TI - Granzyme M targets host cell hnRNP K that is essential for human cytomegalovirus replication. AB - Human cytomegalovirus (HCMV) is the most frequent viral cause of congenital defects and HCMV infection in immunocompromised patients may trigger devastating disease. Cytotoxic lymphocytes control HCMV by releasing granzymes towards virus infected cells. In mice, granzyme M (GrM) has a physiological role in controlling murine CMV infection. However, the underlying mechanism remains poorly understood. In this study, we showed that human GrM was expressed by HCMV specific CD8(+) T cells both in latently infected healthy individuals and in transplant patients during primary HCMV infection. We identified host cell heterogeneous nuclear ribonucleoprotein K (hnRNP K) as a physiological GrM substrate. GrM most efficiently cleaved hnRNP K in the presence of RNA at multiple sites, thereby likely destroying hnRNP K function. Host cell hnRNP K was essential for HCMV replication not only by promoting viability of HCMV-infected cells but predominantly by regulating viral immediate-early 2 (IE2) protein levels. Furthermore, hnRNP K interacted with IE2 mRNA. Finally, GrM decreased IE2 protein expression in HCMV-infected cells. Our data suggest that targeting of hnRNP K by GrM contributes to the mechanism by which cytotoxic lymphocytes inhibit HCMV replication. This is the first evidence that cytotoxic lymphocytes target host cell proteins to control HCMV infections. PMID- 23099854 TI - Initial experience with laparoscopic sleeve gastrectomy by a novice bariatric team in an established bariatric center--a review of literature and initial results. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a highly successful approach to morbid obesity with low incidence of complications. The literature suggests a learning curve of 50-100 cases for attaining proficiency and reducing the complication rates for laparoscopic bariatric surgery. The aims of this paper were to review the literature of initial cases by bariatric surgeons worldwide and to report the experience of initial 50 cases of LSG by a novice bariatric team in a single center. The objective was to evaluate the outcomes for laparoscopic bariatric surgery in the first 50 patients by a novice team of bariatric surgeons in an already established bariatric surgery program with short term follow-up. METHODS: All surgeries were done by a new bariatric team who underwent laparoscopic fellowship training under a bariatric team with an experience of over 600 bariatric procedures. Fifty consecutive patients from March 2010 to January 2012 were offered LSG and followed up for a minimum of 6 months. Weight loss and comorbidity resolution were tabulated and assessed. RESULTS: Mean preoperative and postoperative BMIs were 46.6 and 35.7 kg/m2, respectively. There were no life threatening postoperative complications or mortality. The median percent excess weight loss was 50.3% at the end of 6 months. Comorbidity resolution values were 96% for obstructive sleep apnea, 89% for diabetes mellitus, and 87% for joint pains, among the most common comorbidities. CONCLUSION: LSG is effective in achieving weight loss and in improving comorbidities with minimal complications even at the hands of novice bariatric surgeons with good laparoscopic skills and adequate bariatric training. PMID- 23099859 TI - Application of wind-profiling radar data to the analysis of dust weather in the Taklimakan Desert. AB - The Urumqi Institute of Desert Meteorology of the China Meteorological Administration carried out an atmospheric scientific experiment to detect dust weather using a wind-profiling radar in the hinterland of the Taklimakan Desert in April 2010. Based on the wind-profiling data obtained from this experiment, this paper seeks to (a) analyze the characteristics of the horizontal wind field and vertical velocity of a breaking dust weather in a desert hinterland; (b) calculate and give the radar echo intensity and vertical distribution of a dust storm, blowing sand, and floating dust weather; and (c) discuss the atmosphere dust counts/concentration derived from the wind-profiling radar data. Studies show that: (a) A wind-profiling radar is an upper-air atmospheric remote sensing system that effectively detects and monitors dust. It captures the beginning and ending of a dust weather process as well as monitors the sand and dust being transported in the air in terms of height, thickness, and vertical intensity. (b) The echo intensity of a blowing sand and dust storm weather episode in Taklimakan is about -1~10 dBZ while that of floating dust -1~-15 dBZ, indicating that the dust echo intensity is significantly weaker than that of precipitation but stronger than that of clear air. (c) The vertical shear of horizontal wind and the maintenance of low-level east wind are usually dynamic factors causing a dust weather process in Taklimakan. The moment that the low-level horizontal wind field finds a shear over time, it often coincides with the onset of a sand blowing and dust storm weather process. (d) When a blowing sand or dust storm weather event occurs, the atmospheric vertical velocity tends to be of upward motion. This vertical upward movement of the atmosphere supported with a fast horizontal wind and a dry underlying surface carries dust particles from the ground up to the air to form blown sand or a dust storm. PMID- 23099860 TI - Organic matter determination for street dust in Delhi. AB - The organic matter of street dust is considered as one of the causes for high human mortality rate. To understand the association, the street dust samples were collected from four different localities (industrial, residential, residential commercial, and commercial) situated in the greater Delhi area of India. The loss on-ignition method was used to determine the organic matter (OM) content in street dust. The OM content, potassium, calcium, sulfate, and nitrate concentrations of street dust in Delhi, India is measured to understand the spatial variation. Correlation analysis, analysis of variance, and factor analysis were performed to define the sources. The dust OM level ranges from 2.63 to 10.22 %. It is found through correlation and factor analysis that OM is primarily contributed from secondary aerosol and vehicular exhaust. The OM levels suggest that the use of a residential-commercial site for commercial purposes is polluting the street dust and creating the environmental and human health problems. PMID- 23099861 TI - Influence of epidermal growth factor receptor inhibitor AG1478 on epithelial mesenchymal transition in endometrial carcinoma cells. AB - OBJECTIVE: To analyze the influence of epidermal growth factor receptor inhibitor AG1478 on the proliferation and epithelial-mesenchymal transition in endometrial carcinoma cells. MATERIALS AND METHODS: The inhibitory effect of different concentrations of AG1478 on the proliferation of endometrial carcinoma cells was detected by tetrazolium-based assay. Western blot was applied to investigate the influence of AG1478 on expressions of epithelium-cadherin, alpha-catenin, neural cadherin, vimentin, matrix metalloproteinase 9 (MMP9), and MMP2 protein in endometrial carcinoma cells. The influence of AG1478 on migration and invasion of endometrial carcinoma cells was examined by Transwell migration and invasion assay, respectively. RESULTS: AG1478 could suppress the proliferation of different endometrial carcinoma cells, and cells transfected with epidermal growth factor receptor were more sensitive (P < 0.05). The expression of an increase in epithelial marker proteins and a decrease in mesenchymal marker proteins, MMP9, MMP2 were observed in endometrial carcinoma cells after AG1478 treated. This effect was more obvious in cells transfected with epidermal growth factor receptor (P < 0.05). The migration and invasion ability of endometrial carcinoma cells were suppressed by AG1478, and Ishikawa cells transfected with epidermal growth factor receptor were demonstrated to be more sensitive to AG1478 (P < 0.05). CONCLUSIONS: Epidermal growth factor receptor inhibitor AG1478 could effectively inhibit the proliferation and epithelial-mesenchymal transition of endometrial carcinoma cells. PMID- 23099855 TI - Randomized controlled trials in bariatric surgery. AB - To fill a void in the literature, we performed a literature search and subsequently reviewed randomized controlled trials (RCTs) in the field of obesity surgery that were published over the past 40 years. All RCTs published in the English between January 1972 and December 2011 were identified through a literature search using the PubMed database. The following search terms were used: "bariatric surgery", "obesity surgery", and "weight reducing surgery". Studies of basic science and anesthesia-related pain management were excluded. The extracted trials were divided into four groups: comparisons of different interventions, intraoperative surgical techniques, preoperative evaluation, and postoperative care. The literature search produced 753 manuscripts, of which 168 met the eligibility criteria. Among 168 papers, 32 % compared different interventions, 48 % assessed intraoperative surgical techniques, 18 % assessed postoperative care, and the remaining 2 % assessed preoperative evaluation. The RCTs were published in 47 different journals, most commonly in Obesity Surgery (28.6 %) and the Annals of Surgery (11.9 %). Trials were conducted in 25 different countries, with the greatest contribution from the USA (35.1 %). There was a progressive increase in published trials from 1972 to 2011, with 119 RCTs (70.8 %) being published over the last decade. A trend for an increasing number of published RCTs in the field of bariatric surgery was observed over the recent years. Although data from large, adequately powered, long-term RCTs are still lacking, any surgical intervention appears to be more effective than medical care for the treatment of morbid obesity. PMID- 23099862 TI - Ectopic expression of GIP in pancreatic beta-cells maintains enhanced insulin secretion in mice with complete absence of proglucagon-derived peptides. AB - Glucagon and glucagon-like peptide-1 (GLP-1) are produced in pancreatic alpha cells and enteroendocrine L-cells, respectively, in a tissue-specific manner from the same precursor, proglucagon, that is encoded by glucagon gene (Gcg), and play critical roles in glucose homeostasis. Here, we studied glucose homeostasis and beta-cell function of Gcg-deficient mice that are homozygous for a Gcg-GFP knock in allele (Gcg(gfp/gfp)). The Gcg(gfp/gfp) mice displayed improved glucose tolerance and enhanced insulin secretion, as assessed by both oral glucose tolerance test (OGTT) and intraperitoneal glucose tolerance test (IPGTT). Responses of glucose-dependent insulinotropic polypeptide (GIP) to both oral and intraperitoneal glucose loads were unexpectedly enhanced in Gcg(gfp/gfp) mice, and immunohistochemistry localized GIP to pancreatic beta-cells of Gcg(gfp/gfp) mice. Furthermore, secretion of GIP in response to glucose was detected in isolated islets of Gcg(gfp/gfp) mice. Blockade of GIP action in vitro and in vivo by cAMP antagonism and genetic deletion of the GIP receptor, respectively, almost completely abrogated enhanced insulin secretion in Gcg(gfp/gfp) mice. These results indicate that ectopic GIP expression in beta-cells maintains insulin secretion in the absence of proglucagon-derived peptides (PGDPs), revealing a novel compensatory mechanism for sustaining incretin hormone action in islets. PMID- 23099866 TI - Is Lean Management implementable in a department of radiology? AB - OBJECTIVES: Due to an increasing demand for more examinations in a non profitmaking hospital with a fixed budget, Lean Management was introduced in the Department of Radiology in 2006. The process, experience and results are discussed from a management view. METHODS: Lean principles were introduced in the department and ways of working were adjusted accordingly. RESULTS: Higher productivity and shorter waiting lists were achieved, along with extra time for education of the staff. CONCLUSIONS: Lean Management can successfully be used in a hospital radiology department. However, introducing Lean Management caused resistance from especially the mid-level managers. PMID- 23099863 TI - Nonviral-mediated hepatic expression of IGF-I increases Treg levels and suppresses autoimmune diabetes in mice. AB - In type 1 diabetes, loss of tolerance to beta-cell antigens results in T-cell dependent autoimmune destruction of beta cells. The abrogation of autoreactive T cell responses is a prerequisite to achieve long-lasting correction of the disease. The liver has unique immunomodulatory properties and hepatic gene transfer results in tolerance induction and suppression of autoimmune diseases, in part by regulatory T-cell (Treg) activation. Hence, the liver could be manipulated to treat or prevent diabetes onset through expression of key genes. IGF-I may be an immunomodulatory candidate because it prevents autoimmune diabetes when expressed in beta cells or subcutaneously injected. Here, we demonstrate that transient, plasmid-derived IGF-I expression in mouse liver suppressed autoimmune diabetes progression. Suppression was associated with decreased islet inflammation and beta-cell apoptosis, increased beta-cell replication, and normalized beta-cell mass. Permanent protection depended on exogenous IGF-I expression in liver nonparenchymal cells and was associated with increased percentage of intrapancreatic Tregs. Importantly, Treg depletion completely abolished IGF-I-mediated protection confirming the therapeutic potential of these cells in autoimmune diabetes. This study demonstrates that a nonviral gene therapy combining the immunological properties of the liver and IGF I could be beneficial in the treatment of the disease. PMID- 23099865 TI - The future of hybrid imaging-part 2: PET/CT. AB - Since the 1990s, hybrid imaging by means of software and hardware image fusion alike allows the intrinsic combination of functional and anatomical image information. This review summarises the state-of-the-art of dual-modality imaging with a focus on clinical applications. We highlight selected areas for potential improvement of combined imaging technologies and new applications. In the second part, we briefly review the background of dual-modality PET/CT imaging, discuss its main applications and attempt to predict technological and methodological improvements of combined PET/CT imaging. After a decade of clinical evaluation, PET/CT will continue to have a significant impact on patient management, mainly in the area of oncological diseases. By adopting more innovative acquisition schemes and data processing PET/CT will become a fast and dose-efficient imaging method and an integral part of state-of-the-art clinical patient management. PMID- 23099867 TI - Less radiation in a radiology department than at home. AB - OBJECTIVE: To compare the total work-related radiation dose in our department of radiology with the dose in Dutch residences, taking x-ray radiation, external natural radiation and radon into account. METHODS: Annual doses due to exposure to x-rays and external natural radiation were derived from the measured personal dose equivalent [H(p)(10)] of 144 workers. Additionally, departmental (222)Rn concentrations were assessed over 1 year. RESULTS: The departmental radon concentration was 5 +/- 1 Bq/m(3), the personal dose equivalent due to external natural radiation 0.32 +/- 0.10 mSv/year, considerably lower than the average Dutch residential values of 13.5 Bq/m(3) and 0.88 mSv/year. As a consequence, working results in a lower dose than being at home as long as the x-ray-induced personal dose equivalent is lower than 1.25 mSv/year, which was the case for 131 of the 144 radiological workers, as well as for the whole group on average. CONCLUSIONS: Working in our x-ray department results in a reduction in the collective effective dose, not an increase. The worldwide average radon concentration of 40 Bq/m(3), much higher than in the Netherlands, and the large decrease potentially achieved by the high ventilation rates common in hospitals, suggest that even considerably higher reductions are possible in other countries. PMID- 23099868 TI - Timely detection of bronchiolitis epidemics in Guadeloupe. AB - OBJECTIVE: To develop a criterion for early detection of bronchiolitis epidemics in Guadeloupe so that prevention and control strategies can be implemented in a more timely manner. METHODS: Weekly figures of bronchiolitis cases reported from July 2005-July 2010 by Guadeloupe's sentinel network were used. The criterion for detecting epidemics was created with data from the 2005-2009 bronchiolitis seasons. First, the baseline level for bronchiolitis (BL) was predicted by fitting a periodic regression on the non-epidemic observations; then a test was conducted of nine possible criteria to define epidemics by combining a statistical threshold set at different levels and a number of consecutive weeks with observations above and below them; lastly, the optimal criterion was selected considering its performances using expert advice as the gold standard. The selected criterion was validated with data from 2009-2010 season. RESULTS: The BL accounted for a linear trend and two sinusoidal functions of 52 and 26 weeks (R2 = 45%). According to the epidemic criterion selected, the statistical threshold was set at the upper limit of the one-sided 95% Confidence Interval of the predicted BL; 2 consecutive weeks with cases above it were necessary to set the start of an epidemic, and three again below to set the end. The median delay in launching the alerts was 2 weeks; there was one false alert; and the sensitivity, specificity, and positive predictive value for detecting epidemic weeks were 98%, 96%, 95%, respectively. During the validation period, the criterion launched one false alert and detected the epidemic with 4 weeks of delay. CONCLUSIONS: This criterion supports epidemiologists in timely interpretation of bronchiolitis epidemiological data for decision makers in Guadeloupe. In the future, it should be updated in accordance with trends in bronchiolitis epidemiology, and improved by integrating virological indicators. Its inclusion in an integrated management strategy for bronchiolitis prevention and control, supported by a bronchiolitis public health network, should also be encouraged. PMID- 23099869 TI - Developing a research agenda for promoting physical activity in Brazil through environmental and policy change. AB - OBJECTIVE: To identify the highest priorities for research on environmental and policy changes for promoting physical activity (PA) in Brazil; to uncover any gaps between researchers' and practitioners' priorities; and to consider which tools, methods, collaborative strategies, and actions could be useful to moving a research agenda forward. METHODS: This was a mixed-methods study (qualitative and quantitative) conducted by Project GUIA (Guide for Useful Interventions for Activity in Brazil and Latin America) in February 2010-January 2011. A total of 240 individuals in the PA field (186 practitioners and 54 researchers) were asked to generate research ideas; 82 participants provided 266 original statements from which 52 topics emerged. Participants rated topics by "importance" and "feasibility;" a separate convenience sample of 21 individuals categorized them. Cluster analysis and multidimensional scaling were used to create concept maps and pattern matches. RESULTS: Five distinct clusters emerged from the concept mapping, of which "effectiveness and innovation in PA interventions" was rated most important by both practitioners and researchers. Pattern matching showed a divergence between the groups, especially regarding feasibility, where there was no consensus. CONCLUSIONS: The study results provided the basis for a research agenda to advance the understanding of environmental and policy influences on PA promotion in Brazil and Latin America. These results should stimulate future research and, ultimately, contribute to the evidence-base of successful PA strategies in Latin America. PMID- 23099871 TI - Mortality trends from hypertension in Mexico by socioeconomic region and state, 2000-2008. AB - OBJECTIVE: To determine mortality trends from hypertension in Mexico nationwide, by state, by socioeconomic region, and by sex and to establish an association between education, state of residence, and socioeconomic region with mortality from hypertension in 2000-2008. METHODS: Records of mortality associated with hypertension for 2000-2008 were obtained from the National Information System of the Secretariat of Health. This information is generated by the National Institute of Statistics, Geography and Informatics through death certificates issued throughout the country. International Classification of Diseases, 10th Revision, codes corresponding to the basic cause of death from hypertension were identified. Rates of mortality nationwide, by state, and by socioeconomic region were calculated. The strength of association (obtained by Poisson regression) between states where individuals resided, socioeconomic regions, and education with mortality from hypertension was determined. The seven socioeconomic regions were elaborated by the National Institute of Statistics, Geography and Informatics and include the 31 states and Mexico City according to indicators that are related to well-being such as education, occupation, health, housing, and employment. RESULTS: Individuals who did not complete elementary school had a higher risk of dying from hypertension than people with more or no education [relative risk (RR) 1.462, 95% confidence interval (CI) 1.442-1.482]. Mexico City, Oaxaca, and region 7 had the strongest association with dying from hypertension [Mexico City: RR 2.6, CI 2.1-3.2 (2000) and RR 2.5, CI 2.1-3.1 (2005); Oaxaca: RR 2.4, CI2.0-3.0 (2006) and RR 2.7, CI2.3-3.3 (2008); region 7: RR 1.58, CI 1.45-1.72 (2000) and RR 1.25, CI 1.17-1.34 (2008)]. CONCLUSIONS: Age adjusted mortality rates per 100 000 inhabitants who died from hypertension increased from 15.7 to 18.5 between 2000 and 2008, taking the world population age distribution as standard. Mortality was higher in women than in men and in individuals who did not complete elementary school than in those with more or no education. The strongest associations were in Mexico City, Oaxaca, and region 7. PMID- 23099870 TI - [Herd immunity against rubella according to a survey of the population in Medellin, Colombia]. AB - OBJECTIVE: Calculate the critical proportion (Pc) for achieving herd immunity based on a 2009 population study conducted in Medellin, Colombia, by age, globally and disaggregated by sex, location, and socioeconomic stratum. METHODS: A survey of seroprevalence in the population was conducted by means of a random sample of 2 124 individuals aged 6 to 64 that was representative of age, sex, and location. The basic reproduction number was estimated using a quadratic regression of the average IgG titers for rubella by age in unvaccinated individuals with titers greater than or equal to 15 IU/ml. The effective reproduction number (Re) was calculated with the data on the weighted proportion of protection by age, sex, location, and socioeconomic stratum. RESULTS: Overall, the Pc was 90.0% (95% CI, 88.6-95.2%) and the Re was 0.95 (95% CI, 0.8-1.8), for a weighted proportion of protection of 89.4% (95% CI, 86.8- 91.6%). Protection was lower than the expected Pc in both sexes, in high and low socioeconomic strata, and in the rural area. In the urban area, protection was greater than the Pc (89.4%, with a 95% CI, 86.6-91.7%, compared to 87.4% and a 95% CI, 85.2 87.8%). CONCLUSIONS: The urban area has made progress toward herd immunity, but the overall proportion of protection in women, the rural area, and the high socioeconomic strata must be increased. The effective number may be greater than one, indicating the potential for the spread of the disease. PMID- 23099872 TI - [Impact of antiretroviral therapy under different treatment regimens]. AB - OBJECTIVE: Compare the characteristics of AIDS patients and treatment outcomes under three different antiretroviral treatment regimens advocated by the Ministry of Health of Brazil. METHODS: Retrospective cohorts of patients who had survived up to five years after diagnosis were constructed. The data were obtained from medical records, medication dispensing forms, and death certificates of patients in Curitiba, in the Brazilian state of Parana. Six hundred patients were selected from the first six months following the adoption of each of the treatment regimens (1992, 1997, and 2002). RESULTS: The ratio of men to women fell from 6.5:1 in 1992 to 1.4:1 in 2002. There was a proportionate rise in the number of people over 50, which increased from 1.4% in 1992 to 9.9% in 2002. The case fatality rate dropped from 81.9% to 33.9% in the period in question. An analysis of those who survived at least five years from the date of diagnosis showed that the percentage of patients treated increased from 46.2% in 1992 to 94.0% in 1997, finishing at 91.7% in 2002. Multivariate analysis yielded a positive and statistically significant association between survival up to five years after an AIDS diagnosis and years of schooling, age group, year of diagnosis, type of antiretroviral therapy, and treatment adherence (all with P < 0.001). CONCLUSIONS: Continuous improvement of the antiretroviral therapy recommended by the Ministry of Health had a positive impact on survival. There was an association between case fatality and fewer years of schooling, membership in an older age group, a diagnosis obtained in 1992, the type of antiretroviral therapy, and suboptimal adherence to antiretroviral treatment regimens. PMID- 23099873 TI - Hospitalized cases of influenza A(H1N1)pdm09 in the French territories of the Americas, July 2009-March 2010. AB - OBJECTIVE: To describe the methodology used for implementing a surveillance system specifically for influenza A(H1N1)pdm09 in the French West Indies and French Guiana during an outbreak of this new virus in 2009-2010, and to report its main results. METHODS: This was an observational descriptive study of confirmed and probable cases of influenza A(H1N1)pdm09 hospitalized for at least 24 hours in 23 July 2009-3 March 2010. Reverse transcription polymerase chain reaction was performed on nasopharyngeal swab samples according to the Centers for Disease Control and Prevention protocol. A probable case was defined as fever > 38oC or aches or asthenia with respiratory symptoms (cough or dyspnea). All confirmed and probable hospitalized cases were reported, along with patient's age, sex, clinical condition at admission, place and length of hospitalization, antiviral treatment, underlying conditions, complications, and clinical evolution. A case was classified as severe if respiratory assistance or intensive care was required or if death resulted. RESULTS: A total of 331 confirmed and 16 probable cases were hospitalized, with a hospitalization rate ranging from 4.3 per 1 000 clinical cases in Saint Martin to 10.3 in French Guiana. Of these, 36 were severe, and subsequently, 10 were fatal. The median length of stay was 4 days for non-severe cases and 9 days for severe (P < 0.05). The mean patient age was 21 years, and severe cases were significantly older than non-severe (mean: 38 years versus 19 years, P < 0.05). Underlying conditions associated with a higher risk of severity were 65 years of age or more (RR = 7.5, 95%CI = 4.2-13.3), diabetes (RR = 3.7, 95%CI = 1.5-9.4), cardiac insufficiency (RR = 8.4, 95%CI = 5.2-13.6), and morbid obesity (RR = 4.4, 95%CI = 1.8-10.4). Patients who received antiviral treatment within 2 days of symptom onset had shorter hospital stays (mean: 4 days versus 6.5 days, P < 0.05), and the illness tended to become less severe (11.1% versus 19.0%, P = 0.13). CONCLUSIONS: Active research of hospitalized cases enabled almost exhaustive surveillance. The pandemic's hospitalization rates and lethality were more moderate than expected. Some previously known underlying conditions of severity were confirmed during this outbreak. Furthermore, these results show the validity of early antiviral treatment. PMID- 23099874 TI - Validity of cardiovascular risk prediction models in Latin America and among Hispanics in the United States of America: a systematic review. AB - OBJECTIVE: To assess the use and validity of prediction models to estimate the risk of cardiovascular disease (CVD) in Latin America and among Hispanic populations in the United States of America. METHODS: This was a systematic review of three databases: Ovid MEDLINE (1 January 1950-15 April 2010), LILACS (1 January 1988-15 April 2010), and EMBASE (1 January 1988-15 April 2010). MeSH search terms and domains were related to CVD, prediction rules, Latin America (including the Caribbean), and Hispanics in the United States. Database searches were supplemented by correspondence with experts in the field. RESULTS: A total of 1 655 abstracts were identified, of which five cohorts with a total of 13 142 subjects met inclusion criteria. A Mexican cohort showed that the predicted/observed event-rate ratio for coronary heart disease (CHD) according to the Framingham risk score (FRS) was 1.68 (95% CI, 1.26-2.11); incident myocardial infarction, 1.36 (95% CI, 0.90-1.83); and CHD death, 1.21 (95% CI, 0.43-2.00). In Ecuador, a prediction model for CVD and total deaths in hypertensive patients had an area under the curve (AUC) of 0.79 (95% CI, 0.72-0.86), while the World Health Organization method had an AUC of 0.74 (95% CI, 0.67-0.82). A study predicting mortality risk in people with Chagas' disease had an AUC of 0.81 (95% CI, 0.72 0.90). Among a United State s cohort that included Hispanics, FRS overestimated CVD risk for Hispanics with an AUC of 0.69. Another study in the United States that assessed FRS factors predicting CVD death among Mexican-Americans had an AUC of 0.78. CONCLUSIONS: The evidence regarding CVD risk prediction rules in Latin America or among Hispanics in the United States is modest at best. It is likely that the FRS overestimates CVD risk in Hispanics when not properly recalibrated. PMID- 23099875 TI - [Consolidation of international guidelines for the management of canine populations in urban areas and proposal of performance indicators]. AB - The objective of this study is to propose a generic program for the management of urban canine populations with suggestion of performance indicators. The following international guidelines on canine population management were revised and consolidated: World Health Organization, World Organisation for Animal Health, World Society for the Protection of Animals, International Companion Animal Management Coalition, and the Food and Agriculture Organization. Management programs should cover: situation diagnosis, including estimates of population size; social participation with involvement of various sectors in the planning and execution of strategies; educational actions to promote humane values, animal welfare, community health, and responsible ownership (through purchase or adoption); environmental and waste management to eliminate sources of food and shelter; registration and identification of animals; animal health care, reproductive control; prevention and control of zoonoses; control of animal commerce; management of animal behavior and adequate solutions for abandoned animals; and laws regulating responsible ownership, prevention of abandonment and zoonoses. To monitor these actions, four groups of indicators are suggested: animal population indicators, human/animal interaction indicators, public service indicators, and zoonosis indicators. The management of stray canine populations requires political, sanitary, ethologic, ecologic, and humanitarian strategies that are socially acceptable and environmentally sustainable. Such measures must also include the control of zoonoses such as rabies and leishmaniasis, considering the concept of "one health," which benefits both the animals and people in the community. PMID- 23099876 TI - [Reducing chronic malnutrition among the disadvantaged populations to promote health and development]. AB - This article advances theoretical and conceptual arguments to justify efforts to reduce chronic malnutrition as a basic component of any strategy for promoting health and development in countries with a high malnutrition prevalence. The arguments rest on four cardinal principles of contemporary social epidemiology, in whose framework reducing chronic malnutrition would be a key strategic component: the social determinants approach, the life course as the clinical epidemiological paradigm, the concept of heredity and population health, and recognition of the family as a social determinant. Added to these are the close association between nutrition, health, and development, on the one hand, and the political significance of any strategy that makes the fight against chronic malnutrition the most visible focus of programmatic action. PMID- 23099877 TI - Alcohol, diabetes, and public health in the Americas. AB - This article describes epidemiological evidence on the association between alcohol use and diabetes, and the implications for clinical management and public health policies in the Americas. Heavy alcohol use is a risk factor for both diabetes and poor treatment adherence, despite evidence that moderate drinking can protect against type 2 diabetes under some circumstances. The burden of disease from diabetes associated with excessive alcohol consumption warrants both clinical and public health measures. On the clinical level, research on early interventions to prevent hazardous drinking shows that new screening, brief intervention, and referral techniques are effective ways to manage hazardous drinking in primary care settings. On the population level, restrictions on alcohol marketing and other alcohol control policies reduce the frequency and intensity of alcohol consumption in at-risk populations. These policy actions are recommended within the context of the World Health Organization's global strategy to reduce the harmful use of alcohol. PMID- 23099878 TI - [Absence of poliovirus circulation in Colombian departments with vaccination coverage below 80%]. AB - This study aims to explore a possible silent circulation of wild and vaccine derived polioviruses in departments of Colombia with polio vaccination coverage of below 80%. The study collected 52 samples of wastewater concentrated as a result of precipitation with polyethylene glycol and sodium chloride. The viral detection was carried out through isolation and the identification through neutralization of the cytopathic effect, as well as through a conventional polymerase chain reaction following reverse transcription. The isolated polioviruses were characterized by the VP1 gene sequence. In two of the 52 samples, there was a presence of the Sabin type 2 poliovirus with more than 99% sequence similarity with the Sabin type 2 strain polio. Circulation of the nonpolio enterovirus was detected in 17.3% of the samples. The serotypes identified corresponded to coxsackievirus B1, echovirus 30, and echovirus 11. No evidence of the spread of either vaccine-derived poliovirus or wild poliovirus was detected in the departments of Colombia with polio coverage lower than 80%. PMID- 23099879 TI - Immigrant health workers in Chile: is there a Latin American "brain drain"? AB - Most research on the phenomenon of "brain drain" (one-way flow of highly skilled/educated individuals) has focused on movement between the least developed and most highly developed countries. Therefore, the significance of patterns of migration to middle-income countries such as those in Latin America is less clear. The aim of this study was to outline key features of international health worker "brain drain" to Chile to promote discussion and further research on this phenomenon as it pertains to the Latin American region. The study compared immigrant health workers living in Chile to both Chilean-born health workers and other immigrants living in Chile using a qualitative nationwide dataset (the results of Chile's 2009 National Socioeconomic Characterization Survey). Demographic, socioeconomic, and health-related variables were included in the analyses, which were weighted by population to obtain nationally representative estimates. In 2009, immigrant health workers represented 2.2% of all health personnel and 2.6% of all resident immigrants in the country. While most immigrant health workers had a universitylevel education, about 25% had only a high school-level education or less. There was no statistically significant difference between the distribution of immigrant health workers' household income and that of Chilean-born health workers. A significantly higher proportion of the immigrant group reported no entitlement to health care provision. While the results of this study do not indicate a significant international health worker "brain drain" to Chile, they do suggest distinctive patterns of migration within the Latin American region. Future studies in Chile could confirm the validity of these results, using a larger sample of immigrant health workers. PMID- 23099880 TI - [The Lima Como Vamos survey: quality of health care]. PMID- 23099881 TI - Multi-mode waveguides from ultra-long self-assembled hexagonal faceted microtubules of a benzothiadiazole molecule. AB - Length controlled (MUm-mm-cm) self-assembly of hexagonal faceted microtubules has been achieved using a phase-transfer solution processing approach from . The self assembled structures exhibit both polarized light emission and multi-mode waveguide properties over large length scales. The multi-mode waveguide characteristics are analyzed using a combination of experiment and finite difference-time-domain calculations. PMID- 23099882 TI - Alteration of substrate specificities of thermophilic alpha/beta hydrolases through domain swapping and domain interface optimization. AB - Protein domain swapping is an efficient way in protein functional evolution in vivo and also has been proved to be an effective strategy to modify the function of the multi-domain proteins in vitro. To explore the potentials of domain swapping for alteration of the enzyme substrate specificities and the structure function relationship of the homologous proteins, here we constructed two chimeras from a pair of thermophilic members of the alpha/beta hydrolase superfamily by grafting their functional domains to the conserved alpha/beta hydrolase fold domain: a carboxylesterase from Archaeoglobus fulgidus (AFEST) and an acylpeptide hydrolase from Aeropyrum pernix K1 (apAPH) and explored their activities on hydrolyze p-nitrophenyl esters (pNP) with different acyl chain lengths. We took two approaches to reduce the crossover disruptions when creating the chimeras: chose the residue which involved in the least contacts as the splicing site and optimized the newly formed domain interfaces of the chimeras by site-directed mutations. Characterizations of AAM7 and PAR showed that these chimeras inherited the thermophilic property of both parents. In the aspect of substrate specificity, AAM7 and PAR showed highest activity towards short chain length substrate pNPC4 and middle chain length substrate pNPC8, similar to parent AFEST and apAPH, respectively. These results suggested that the substrate-binding domain is the dominant factor on enzyme substrate specificity, and the optimization of the newly formed domain interface is an important guarantee for successful domain swapping of proteins with low-sequence homology. PMID- 23099883 TI - Small interfering RNA targeted to secretory clusterin blocks tumor growth, motility, and invasion in breast cancer. AB - Clusterin/apolipoprotein J (Clu) is a ubiquitously expressed secreted heterodimeric glycoprotein that is implicated in several physiological processes. It has been reported that the elevated level of secreted clusterin (sClu) protein is associated with poor survival in breast cancer patients and can induce metastasis in rodent models. In this study, we investigated the effects of sClu inhibition with small interfering RNAs (siRNAs) on cell motility, invasion, and growth in vitro and in vivo. MDA-MB-231 cells were transfected with pSuper siRNA/sClu. Cell survival and proliferation were examined by 3-(4,5-dimethyl thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium and clonogenic survival assay. The results showed that sClu silencing significantly inhibited the proliferation of MDA-MB-231 cells. The invasion and migration ability were also dramatically decreased, which was detected by matrigel assays. TUNEL staining and caspase-3 activity assay demonstrated that sClu silencing also could increase the apoptosis rate of cells, resulting in the inhibition of cell growth. We also determined the effects of sClu silencing on tumor growth and metastatic progression in an orthotopic breast cancer model. The results showed that orthotopic primary tumors derived from MDA-MB-231/pSuper sClu siRNA cells grew significantly slower than tumors derived from parental MDA-MB-231 or MDA-MB 231/pSuper scramble siRNA cells, and metastasize less to the lungs. These data suggest that secretory clusterin plays a significant role in tumor growth and metastatic progression. Knocking-down sClu gene expression may provide a valuable method for breast cancer therapy. PMID- 23099884 TI - HER3 targeting of adenovirus by fiber modification increases infection of breast cancer cells in vitro, but not following intratumoral injection in mice. AB - Despite the tremendous potential of adenovirus (Ad) as a delivery vector for cancer gene therapy, its use in clinical settings has been limited, mainly as a result of the limited infectivity in many tumors and the wide tissue tropism associated with Ad. To modify the tropism of the virus, we have inserted the epidermal growth factor-like domain of the human heregulin-alpha (HRG) into the HI loop of Ad5 fiber. This insertion had no adverse effect on fiber trimerization nor did it affect incorporation of the modified fiber into infectious viral particles. Virions bearing modified fiber displayed growth characteristics and viral yields indistinguishable from those of wild-type (wt) virus. Most importantly, HRG-tagged virions showed enhanced infection of cells expressing the cognate receptors HER3/ErbB3 and HER4/ErbB4. This was significantly reduced in the presence of soluble HRG. Furthermore, HER3-expressing Chinese hamster ovary (CHO) cells were transduced by the HRG-modified virus, but not by wt virus. In contrast, CHO cells expressing the coxsackie-Ad receptor were transduced with both viruses. However, infection of an in vivo breast cancer xenograft model after intratumoral injection was similar with both viruses, suggesting that the tumor microenvironment and/or the route of delivery have important roles in infection of target cells with fiber-modified Ads. PMID- 23099885 TI - Gene therapy of pancreatic cancer targeting the K-Ras oncogene. AB - Ras mutations are present in ~95% of pancreatic cancer (PC) cases leading to increased proliferation and apoptosis resistance. The aim of this study is to selectively kill Ras-transformed cells by overexpressing the pro-apoptotic protein, p53 upregulated modulator of apoptosis (PUMA) under a Ras-responsive promoter. Colo357, Panc1 and MiaPaca, PC cell lines harboring K-Ras mutations, normal rat IEC18 enterocytes, and their K-Ras transformed R1 counterparts, were tested. We constructed adenoviral vectors containing the PUMA gene downstream to: (1) Four or five repetitive Ras-responsive elements (Ad-PY4/PY5-PUMA) and (2) a negative control (Ad-SV40-PUMA). Cell viability was estimated by 3-(4, 5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and apoptosis was evaluated by FACS. In vivo potency of the adenoviruses was evaluated in athymic nude mice. Infection with Ad-PY4/PY5-PUMA markedly inhibited cell growth (~40 50%), and apoptosis was detected in all cells with high Ras activity, whereas IEC18 cells remained unaffected. The control vector, Ad-SV40-PUMA, did not induce any cell death. Selective and high expression of PUMA was detected in Ad-PY4-PUMA infected cells. In vivo, Ad-PY4-PUMA inhibited by ~35% the growth of established tumors compared with the Ad-SV40-PUMA. Selective overexpression of PUMA efficiently inhibits the growth of Ras-transformed cells while sparing the normal ones. This treatment modality may become a useful, effective and safe approach to selectively target Ras-mutated tumor cells. PMID- 23099886 TI - CCL19 as an adjuvant for intradermal gene gun immunization in a Her2/neu mouse tumor model: improved vaccine efficacy and a role for B cells as APC. AB - The aim of this study was to evaluate the efficacy of the chemokine CCL19 (ELC) as an adjuvant for intradermal gene gun delivery of Her2/neu DNA and to investigate the role of B cells in CCL19-mediated enhancement of immune responses. Balb/c mice were immunized intramuscularly (i.m.) on days 1 and 15 with plasmid DNA (pDNA) (100 MUg DNA) or intradermally (i.d.) by gene gun delivery (1-2 MUg DNA). Administration of pDNA encoding Her2/neu (pDNA(Her2/neu) was compared with pDNA(Her2/neu) plus pDNA(CCL19), pDNA(CCL19), mock vector or uncoated gold particles/phosphate-buffered saline (PBS). Tumor challenge was performed subcutaneously on day 25 with syngeneic Her2/neu(+) tumor cells (D2F2/E2). Intradermal immunization by gene gun led to an enhancement of tumor protection by the DNA vaccine as compared with i.m. immunization. The protective effect of the vaccine was further enhanced by coadministration of pDNA(CCL19) both after i.m. and i.d. immunization. Tumor protection was associated with Her2/neu-specific T cell and humoral immune responses. Experiments in B-cell deficient MUMT mice showed that B cells are crucial for CCL19-mediated enhancement of tumor rejection, most likely as antigen-presenting B cells. DNA vaccines against Her2/neu may play a future role in the treatment of Her2/neu positive breast cancer patients in a clinical situation of minimal residual disease. PMID- 23099888 TI - Microarray analysis of gene expression in mouse (strain 129) embryonic stem cells after typical synthetic musk exposure. AB - Synthetic musks are widely used in personal-care products and can readily accumulate in the adipose tissue, breast milk, and blood of humans. In this study, the Affymetrix Mouse Genome GeneChip was used to identify alterations in gene expression of embryonic stem cells from the 129 strain of the laboratory mouse after treatment with the synthetic musk tonalide (AHTN). Among the 45,037 transcripts in the microarray, 2,879 genes were differentially expressed. According to the microarray analysis, the potential influence of AHTN on the development to embryo should be of concern, and the toxicological effects of it and related musk compounds should be studied further. PMID- 23099887 TI - Interchromosomal clustering of active genes at the nuclear pore complex. AB - Genomes are spatially organized on many levels and the positioning of genes within the nucleus contributes to their proper expression. This positioning can also result in the clustering of genes with similar expression patterns, a phenomenon sometimes called "gene kissing." We have found that yeast genes are targeted to the nuclear periphery through interaction of the nuclear pore complex with small, cis-acting "DNA zip codes" in their promoters. Our recent study demonstrated that genes with the same zip codes cluster together at the nuclear periphery. The zip codes were necessary and sufficient to induce interchromosomal clustering. Finally, we identified a transcription factor (Put3) that binds to the GRS I zip code. Put3 binds to GRS I and is required for both GRS I-dependent positioning at the nuclear periphery and interchromosomal clustering of GRS I targeted genes. We speculate that our findings might provide insight into other types of gene kissing, some of which also require cis-acting DNA sequences and trans-acting proteins. PMID- 23099889 TI - L-carnitine and long-chain acylcarnitines are positively correlated with ambulatory blood pressure in humans: the SABPA study. AB - The prevalence of hypertension in sub-Saharan Africa is increasing rapidly, and treatment remains challenging. Although the use of L-carnitine in treatment has received much attention, studies reporting on physiological L-carnitine levels in hypertensives are limited. Our aim was to determine physiological levels of L carnitine and acylcarnitines in African and Caucasian men, and to investigate associations between ambulatory blood pressure (BP) and carnitine levels. Participants included 101 African and 101 Caucasian teachers. Ambulatory BP measurements were conducted, and L-carnitine and acylcarnitine levels determined. African men showed significantly higher systolic BP (p < 0.001), diastolic BP (p < 0.001) and L-carnitine levels (p = 0.01). In both ethnic groups, partial regression analyses revealed a positive association between BP and L-carnitine, although in Caucasians it was with systolic (r = 0.20, p = 0.045), and in Africans with diastolic BP (r = 0.23, p = 0.023). After adjusting for confounders, an independent positive association between systolic (R(2) = 0.37, beta = 0.12, p = 0.041) and diastolic BP (R(2) = 0.39, beta = 0.14, p = 0.018) and L-carnitine and long-chain acylcarnitines (R(2) = 0.38, beta = 0.17, p = 0.005 and R(2) = 0.39, beta = 0.15, p = 0.011) were found, independent of ethnicity. Physiological L-carnitine levels were not only higher in Africans than in Caucasians but also above the expected reference range. Despite promising results on L-carnitine (and its short-chain derivatives) in hypertension treatment regimens, our findings paradoxically show that elevated BP is significantly associated with higher physiological L-carnitine and long-chain acylcarnitine levels. PMID- 23099892 TI - qPCA: a scalable assay to measure the perturbation of protein-protein interactions in living cells. AB - One of the most important challenges in systems biology is to understand how cells respond to genetic and environmental perturbations. Here we show that the yeast DHFR-PCA, coupled with high-resolution growth profiling (DHFR-qPCA), is a straightforward assay to study the modulation of protein-protein interactions (PPIs) in vivo as a response to genetic, metabolic and drug perturbations. Using the canonical Protein Kinase A (PKA) pathway as a test system, we show that changes in PKA activity can be measured in living cells as a modulation of the interaction between its regulatory (Bcy1) and catalytic (Tpk1 and Tpk2) subunits in response to changes in carbon metabolism, caffeine and methyl methanesulfonate (MMS) treatments and to modifications in the dosage of its enzymatic regulators, the phosphodiesterases. Our results show that the DHFR-qPCA is easily implementable and amenable to high-throughput. The DHFR-qPCA will pave the way to the study of the effects of drug, genetic and environmental perturbations on in vivo PPI networks, thus allowing the exploration of new spaces of the eukaryotic interactome. PMID- 23099891 TI - Neurofibroma-associated macrophages play roles in tumor growth and response to pharmacological inhibition. AB - Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes 30-50 % of affected individuals to develop plexiform neurofibromas. We found that macrophage infiltration of both mouse and human neurofibromas correlates with disease progression. Macrophages accounted for almost half of neurofibroma cells, leading us to hypothesize that nerve macrophages are inflammatory effectors in neurofibroma development and/or growth. We tested the effects of PLX3397, a dual kit/fms kinase inhibitor that blocks macrophage infiltration, in the Dhh-Cre; Nf1(flox/flox) mouse model of GEM grade I neurofibroma. In mice aged 1-4 months, prior to development of nerve pathology and neurofibroma formation, PLX3397 did not impair tumor initiation and increased tumor volume compared to controls. However, in mice aged 7-9 months, after tumor establishment, a subset of mice demonstrating the largest reductions in macrophages after PLX3397 exhibited cell death and tumor volume regression. Macrophages are likely to provide an initial line of defense against developing tumors. Once tumors are established, they become tumor permissive. Macrophage depletion may result in impaired tumor maintenance and represent a therapeutic strategy for neurofibroma therapy. PMID- 23099893 TI - A declaration of healthy dependence: the case of home care. AB - Aging populations have become a major concern in the developed world and are expected to require novel care strategies. Public policies, health-care regimes and technology developers alike stress the need for a more individualized care to meet the increased demand for care services in response to demographic change. Increasingly, care services are offered to individuals with diseases and or disabilities in their homes by means of Personalized Health-Monitoring (PHM) technologies. PHM-based home care is typically portrayed as the key to a cost effective future care that better can accommodate the needs of an aging population and promote care recipients' independence. In light of the emerging technology-based home care, this article sets forth to investigate the significance and implications of a strong emphasis on independence in relation to this novel care form. Notions of independence as used by care planners, care providers and technology developers are examined in relation to ICT-based home care and the reasonableness of independence as an aim for future health-care is critically discussed. In conclusion, the need for a shift from a strong emphasis on independence to a right to healthy dependence is advocated. PMID- 23099894 TI - [Current status of the treatment of colorectal cancer in China--development and limitations]. AB - There is a significant gap between China and the optimal international level in terms of the treatment outcomes of colorectal cancer. In recent years, progresses have been made while limitations still exist in the management of colorectal cancer. Advances are seen including use of multi-disciplinary therapy, neoadjuvant chemoradiation, laparoscopic surgery and management of liver metastasis. Individualized therapy is also applied in colorectal cancer. However, randomized controlled trials based on Chinese population are still lacking. Radiation therapy is inadequate and standardization of surgical technique is to be improved. Although standardization of management of colorectal cancer has gained attention from the government, there is a long way to go. The establishment of subspecialty training and practice has not been satisfactory. National efforts are needed to improve the treatment outcomes of colorectal cancer in China. PMID- 23099895 TI - [Considerations on the therapy of colorectal cancer liver metastasis in China]. AB - The liver is the most common site of colorectal cancer metastasis(CRLM). The importance of how to treat CRLM has attracted attention from doctors world wide and specific academic organization and expect consensus has been established. Relative principals of treatment of CRLM also developed in China, for example, guideline of diagnosis and treatment of colorectal cancer liver metastasis(draft) and standard for diagnosis and treatment of colorectal cancer, which were established in 2008 and 2010, respectively. However, we found that the Chinese doctors still understand these treatment policies inadequately, and easily produce deviation on the treatment progress. Based on the problems of current CRLM treatment, we have some thoughts or suggestions as follows: (1)Promoting the core conception of CRLM treatment actively: surgery is the only method to achieve possible cure of the CRLM. (2) Evaluating the status of new adjuvant chemotherapy for CRLM dialectically. (3)Paying attention to multi-disciplinary team(MDT): MDT is the scientific treatment foundation of CRLM. (4)Changing the treatment conception of primary tumor of CRLM: radical resection of primary tumor is essential for the resectable CRLM.(5)Emphasizing the surgical treatment of CRLM combined with lung metastasis. (6)Do not neglect the safety of patients, when we emphasize the surgery is the optimal treatment of CRLM. These guides of treatment of CRLM will improve the outcomes of CRLM around the world, but we still need pay attention to above mentioned points in order to insure the standardization and scientification of CRLM therapy. PMID- 23099896 TI - [Further understanding of the complete mesocolic excision concept: controversy and consensus]. AB - The precise anatomic surgery is the cornerstone of curative resection and is becoming a trend of modern surgery. Currently, there are still many inadequate resections of colon cancer continue to be performed. Complete mesocolic excision (CME) according to the surgical plane, based on the principles of oncology, is a high-quality radical operation obtaining optimal oncological pathological specimen, with precise surgical concept throughout the entire surgical procedure. CME has been proposed for three years. Although there are still some controversies, CME has set off a worldwide climax of emphasis on quality of colon surgery. It is time to focus on the quality of colon-cancer surgery in order to ensure that all patients with colon cancer receive the highest possible chance for cure. PMID- 23099897 TI - [Transanal endoscopic microsurgery for rectal cancer]. AB - In comparison with the radical resection for rectal cancer, the local excision of rectal cancer is associated with advantages of less trauma, lower risks, anal sphincter preservation, and sexual and urinary function preservation. Being one of the local excision techniques for rectal cancers, transanal endoscopic microsurgery(TEM) becomes increasingly prevailing worldwide in recent years. As compared to traditional local excision procedures, TEM has been proven to improve the operative exposure and provide more adequate operating space. In addition, the TEM is equipped with multiple well-crafted surgical instruments that offer superior performances, which allows delicate surgical dissection and precise tumor excision. TEM provides surgeons with perfect technical support to decrease the chance of or to prevent insufficient removal of the lesion, which leaves an unsafe or positive surgical margin. Good therapeutic results are based on the accurate preoperative evaluation and careful selection of the patient, as well as strict adherence to the indications of this procedure. The best indications for TEM procedure include rectal adenomas with high-grade dysplasia (Tis stage), medium- or low-risk T1 rectal cancers, and cancers that only infiltrate into the Sm1 and Sm2 layers of the submucosa. Patients of T2 and T3 rectal cancers acquiring marked tumor downstaging (or tumor size decreases by more than 50%) after the neoadjuvant therapy may also be candidates for TEM local excision in clinical research studies. TEM technique enables a locally radical excision of the lesion, which is the key to prevent the postoperative recurrence. PMID- 23099898 TI - [Research progress of cylindrical abdominoperineal resection/extralevator abdominoperineal excision for advanced low rectal cancer]. AB - Cylindrical abdominoperineal resection (CAPR), also known as extralevator abdominoperineal excision (ELAPE), has been described as a method for improving the outcome of APR for advanced low rectal cancer, probably because of more pelvic dissection and less positive circumferential resection margin (CRM). Recently, there have been some hot issues associated with CAPR/ELAPE, such as pelvic floor reconstruction methods, prone or lithotomy positioning during pelvic procedure, postoperative chronic perineal pain, postoperative sexual and urinary nerves damage, etc. Individual cylindrical procedure based on clinical and anatomic research may be as effective as CAPR/ELAPE while minimizing the operative trauma and the damage to the nerves of the genital and urinary organs. PMID- 23099899 TI - [Feasibility of complete mesocolic excision in elderly patients with colon cancer]. AB - OBJECTIVE: To explore the short-term outcomes and safety of complete mesocolic excision (CME) in elderly patients with colon cancer. METHODS: The clinical pathological factors of 71 patients with colon cancer undergoing CME procedure by the same group of surgeons were analyzed retrospectively from November 2009 to February 2012. The elderly group(>=70 years) and the non-elderly group(<70 years) were compared regarding short-term outcomes and safety. RESULTS: Similar extent of resection could be achieved in the elderly and non-elderly groups in terms of area of mesentery[(13 049+/-4332) vs. (13 163+/-4725) mm2, P=0.916], distance between the tumor and the high ligation site[(95+/-22) vs. (98+/-20) mm, P=0.516], distance between normal bowel and high ligation site [(130+/-25) vs. (128+/-25) mm, P=0.731], the length of colon [(262+/-60) vs. (245+/-49) mm, P=0.212], and lymph nodes retrieved(22.0+/-6.4 vs. 24.8+/-9.9, P=0.168). The mean operative time, intraoperative blood loss, postoperative complications, time to first flatus, time to first bowel movement, drainage removal time, diet resumption, drainage volume in three days after surgery, and hospital deaths showed no statistical significances(all P>0.05), while hospital stay and expenses of the elderly group were significantly increased(both P<0.01). CONCLUSION: Elderly patients undergoing elective CME operation can achieve similar operative extent and lymph nodes harvest, and the surgical risk is not increased. PMID- 23099900 TI - [Compliance and associated factors of postoperative chemotherapy for elderly patients with colorectal cancer]. AB - OBJECTIVE: To investigate the compliance and associated factors of postoperative chemotherapy for elderly patients with colorectal cancer. METHODS: A total of 386 elderly patients (>70 years old) with stage II(-IIII( colorectal cancer underwent surgery between January 2000 and January 2010. The clinicopathological data were retrospectively reviewed. There were 226 patients received postoperative chemotherapy and 160(41.4%) refused. Logistic regression model was used to analyze factors associated with patients compliance to chemotherapy. Patients were followed up by phone call regarding the reason for refusal. RESULTS: Multivariate analysis showed that gender, body mass index (BMI), body surface area (BSA), age, and complication were independent risk factors associated with chemotherapy compliance(All P<0.05). Follow-up phone questionnaire showed that 63.8%(51/80) of patients with stage II( cancer did not received chemotherapy because of the doctor's uncertainty of chemotherapy benefit. For stage III( patients, fear of chemotherapy (31.2%, 15/48), feeling uncomfortable (18.8%, 9/48), and financial issues(18.8%, 9/48) were the main factors. The desperate feeling was the predominant reason for stage IIII( patients(56.2%, 18/32). CONCLUSIONS: Gender, BSA, age, and postoperative complication are the main factors associated with compliance to postoperative chemotherapy. Doctors' recommendation should be emphasized for stage II( patients. For stage III( patients, treatment recommendation should be enthusiastic. PMID- 23099901 TI - [Medium and long-term outcomes of laparoscopic right hemicolectomy for colon cancer]. AB - OBJECTIVE: To evaluate factors associated with postoperative survival after laparoscopic right hemicolectomy for colon cancer. METHODS: Clinical data of patients undergoing laparoscopic right hemicolectomy in the Department of General Surgery, the Peking University Third Hospital from February 2004 to March 2011 were obtained and analyzed. Kaplan-Meier method was used to calculate survival rate and univariate analysis was performed. Proportional-hazards regression model(Cox model) was used for multivariate analysis. RESULTS: A total of 164 cases were included in this study. The conversion rate was 7.3%(12/164) and the postoperative morbidity was 18.9%(31/164). After a median follow-up period of 27 months(range from 5 to 85 months), the 5-year overall survival rate was 81.5% and the 5-year disease free survival rate was 75.7% and 5-year cancer related survival rate was 78.7%. Both univariate and multivariate analysis showed that the TNM staging and conversion were independent prognostic factors(P<0.05). CONCLUSION: The tumor stage and conversion are independent prognostic factors for patients undergoing the laparoscopic right hemicolectomy. PMID- 23099902 TI - [Safety and efficacy of prophylactic single antibiotics administration in selective open colorectal surgery]. AB - OBJECTIVE: To investigate the safety and efficacy of prophylactic single antibiotic administration in selective open colorectal surgery. METHODS: Two hundred and seventy-five patients undergoing selective open colorectal surgery in the Peking Union Medical College Hospital from October 2009 to October 2011 were retrospectively reviewed. Prophylatic single antibiotic administration was used by intravenous infusion 30-60 min before incision. No antibiotics would be given after operation if there was no surgical site infection(SSI). According to the incidence of postoperative SSI, unexplained use of antibiotics, anastomotic leakage and distant-site infection, the clinical outcome was assessed to be prophylactic success, prophylactic failure or distant-site infection, respectively. RESULTS: There was no intraoperative or postoperative antibiotics related drug anaphylaxis in all the 275 patients. By prophylactic single antibiotic administration, there were prophylactic success in 243 patients(88.4%,243/275), prophylactic failure in 23(8.4%,23/275), distant-site infection in 9(3.3%,9/275). In the 23 patients with failed prophylaxis, there were SSI in 13(4.7%,13/275) patients, postoperative use of broad-spectrum antibiotics for unexplained fever in 2(0.7%,2/275), postoperative anastomotic leakage in 8(3.6%,8/222). CONCLUSION: Prophylactic single antibiotic administration in selective open colorectal surgery is safe and effective. PMID- 23099903 TI - [Comparison of the incidence of postoperative ileus following laparoscopic and open radical resection for colorectal cancer: a meta-analysis]. AB - OBJECTIVE: To compare the incidence of postoperative ileus following laparoscopic and open radical resection for colorectal cancer using meta-analysis. METHODS: The Cochrane library, Pubmed, Ovid databases were searched as of October 2011. Two reviewers extracted the data and assessed the methodological quality independently. The homogeneity of studies was evaluated and the meta-analysis was conducted by the Cochrane Collaboration RevMan 5.0 software. RESULTS: Seven studies including 3630 cases were analyzed. A total of 1814 patients received laparoscopic surgery, of whom 58 developed postoperative ileus. There were 1816 cases undergoing open surgery, of whom 105 developed early postoperative ileus. The pooled relative risk was 0.55 with a 95% confidence interval of 0.41-0.76. The difference was statistically significant(P<0.01). CONCLUSION: Compared with open surgery, laparoscopic colorectal resection can reduce the incidence of postoperative ileus. PMID- 23099904 TI - [Systemic review of fast-track surgery in patients undergoing laparoscopic colorectal resection]. AB - OBJECTIVE: To evaluate the efficacy and safety of fast track surgery(FTS) in patients undergoing laparoscopic colorectal resection. METHOD: Randomized controlled trials(RCT) or clinical controlled trials(CCT) on fast-track surgery in patients undergoing laparoscopic colorectal resection were obtained from databases including CNKI, Wanfang, PubMed, EMBACE, and Cochrane Library between January 2000 and March 2012. Meta-analysis was performed with RevMan 5.1. RESULT: There were 6 RCTs and 7 CCTs including 1795 patients. There were 955 patients in the FTS group and 840 in the control group. The time to passage of flatus was shorter(WMD=-1.37, 95%CI:-1.55~-1.19, P<0.05), time to resumption of diet/drink was shorter(WMD=-2.62, 95%CI:-2.69~-2.55, P<0.05), length of postoperative hospital stay was decreased(WMD=-1.63, 95%CI:-1.92~-1.34, P<0.05) and the incidence of postoperative complications were less(OR=0.52, 95%CI:0.41~0.67, P<0.05) in the FTS group. However, there were no differences in readmission(P>0.05). CONCLUSION: Fast-track surgery in patients undergoing laparoscopic colorectal resection can promote bowel function recovery, decrease the incidence of postoperative complications and length of hospital stay. PMID- 23099905 TI - [Lymph nodes distribution and metastatic pattern of ultra-low rectal cancer after neoadjuvant therapy]. AB - OBJECTIVE: To investigate the lymph nodes distribution and metastatic pattern of the ultra-low rectal cancer after neoadjuvant therapy. METHODS: A total of 21 rectal cancer gross specimen after neoadjuvant therapy and 23 rectal cancer gross specimen without neoadjuvant therapy were investigated by whole mount section and tissue microarray techniques with CK20. All the patients were treated by abdominoperineal resection. RESULTS: There were 138 lymph nodes retrieved from the mesorectum in the neoadjuvant group including 39 metastatic lymph nodes and 12 micro-metastatic lymph nodes. Among these nodes, there were 7 rectal cancer cases with lymph nodes and 2 cases with micro-metastatic lymph nodes, and 6 cases had pathological complete remission. There were 415 lymph nodes retrieved from the mesorectum in the group without neoadjuvant therapy including 169 metastatic lymph nodes and 59 micro-metastatic lymph nodes. Among these nodes, there were 12 rectal cancer cases with lymph nodes and 4 cases with micro-metastatic lymph nodes. The proportions of metastatic lymph nodes in outer zone between the two groups were 21.5% and 29.0%, and those in pre-zone were 17.6% and 17.2% respectively. The ratio of metastatic lymph nodes in ischiorectal fossa between the two groups were 25.0% vs. 22.2% respectively. The rate of metastatic or micro metastatic lymph nodes cases between the two groups were 4.8% vs. 13.0% respectively. CONCLUSIONS: The lymph nodes distribution and metastatic pattern of the ultra-low rectal cancer are affected by neoadjuvant therapy. The proportions of the anal sphincter invasion and metastatic or micro-metastatic lymph nodes in ischiorectal fossa are lower after neoadjuvant therapy. Abdominoperineal resection as the standard treatment of the ultra-low rectal cancer after neoadjuvant therapy should be re-evaluated. PMID- 23099906 TI - [Regional lymph node staging and establishment of prognostic model for stage III( colon cancer]. AB - OBJECTIVE: To evaluate the clinical value of different regional lymph node staging system and to establish a predictive prognostic model for stage III( colon cancer. METHODS: A total of 256 Patients with stage III( colon cancer from January 1999 to December 2008 were identified from the China Medical University Cancer and underwent radical surgery. Based on information on regional lymph nodes, lymph nodes were staged LNR staging using pN stage in the 7th edition of the AJCC, the jN stage of the JGR, and LNR-stage on the basis of Log-rank statistics, respectively. Using the linear trend chi-square test, likelihood ratio Chi-square test, concordant index(c-index) to evaluate the homogeneity, monotonicity, and discrimination power of the staging system. Univariate and multivariate analyses were used to determine the clinical and pathological prognostic impact factors. After relevant diagnostic models were established, the Akaike Information Criterion (AIC) value was calculated to compare and identify the best diagnostic model. RESULTS: Log-rank statistics found that 0.11 and 0.39 were the optimal cut-off point. LNR staging system included LNR1 (LNR<0.11), LNR2 (0.11,0.39), and LNR3(0.39,1). The concordance indices were 0.624 for pN, 0.611 for jN, and 0.700 for LNR. The heterogeneity was the lowest for LNR. Cox regression model was used to establish prognostic models for pN, jN, and LNR, and the AIC was 99.937, 71.631, and 65.548, respectively. The prognostic value was the highest for LNR. CONCLUSION: LNR staging is the ideal staging system for stage III( colon cancer patients, which is better than the latest version of the current AJCC pN stage and JGR jN staging. PMID- 23099907 TI - [Analysis of factors associated with lateral lymph node metastasis in mid and low rectal cancer]. AB - OBJECTIVE: To investigate the factors associated with lateral lymph node metastasis in middle and low rectal cancer. METHODS: Clinical data of 203 patients with middle and low rectal cancer (within 10 cm from anal verge) undergoing lateral lymph node dissection in the Affiliated Cancer Hospital, Xinjiang Medical University between June 2004 to June 2010, were analyzed retrospectively. Logistic regression analysis was used to screen the associated factors. RESULTS: The total number of harvested lateral lymph node was 3349, and average number was 17 per case. The number of positive lateral lymph node was 221, and the lymph node metastasis ratio was 6.6%(221/3349). Univariate analysis showed that age, family history, tumor length, gross type of tumor, histological type, differentiation, depth of invasion, invasion of circumference, serum CEA, tumor thrombus and upper lymph node metastasis were associated with rectal cancer metastasis(P<0.05). Multivariate analysis showed that age, histological type, infiltration depth, gross type, differentiation degree and upper lymph node metastasis were the independent risk factors of the lateral lymph node metastasis in middle and low rectal cancer(P<0.05). CONCLUSION: For patients who is young, or with poorly differentiated cancers, infiltrative type, T4 cancer, or those with upper lymph node metastasis, lateral lymph resection may be indicated because of high risk of lateral node metastasis. PMID- 23099908 TI - [Association of CD133 expression and sensitivity of rectal cancer to preoperative radiotherapy]. AB - OBJECTIVE: To determine the association of CD133 expression with the sensitivity to radiotherapy among rectal cancer patients. METHODS: The clinical data of 32 rectal cancer patients was retrospectively collected for patients who received a short-term preoperative radiotherapy(5 Gy/d,*5 d) from 2008 to 2010. Pretreatment tumor biopsies were immunostained for CD133 expression. Rectal cancer regression grade (RCRG) was used to evaluate the sensitivity of the rectal cancer to preoperative radiotherapy. The correlation of CD133 expression and sensitivity to radiotherapy was analyzed. RESULTS: CD133 differentially expressed in rectal cancer tissue with 17 high expression and 15 low expression. The expression of CD133 was associated with the differentiation of rectal cancer with higher expression of CD133 among poorly differentiated rectal cancers(P<0.05). Among the CD133-high patients, two patients showed 1st RCRG, five patients showed 2nd RCRG and ten patients showed 3rd RCRG. For the CD133-low patients, there were five 1st RCRG, seven 2nd RCRG and three 3rd RCRG. There was a significant association between CD133 expression and sensitivity to radiotherapy (P=0.037). Multivariate logistic regression analysis showed that the expression level of CD133(P=0.027) and the differentiation of rectal cancer(P=0.046) were independent predictive factors for the sensitivity of rectal cancer to radiotherapy. CONCLUSIONS: Correlation between CD133 expression and sensitivity to radiotherapy of rectal cancer may exist, which may be helpful in predicting the sensitivity of rectal cancer to preoperative radiotherapy. PMID- 23099909 TI - [Clinical applications of abdominosacral resection for low rectal cancer]. AB - OBJECTIVE: To explore the feasibility and safety of abdominosacral resection for patients with locally advanced primary low rectal cancer. METHODS: A total of 97 low rectal cancer patients were amenable to surgery but not anal sphincter preservation were included in this study and divided into the abdominoperineal resection group(n=49) and abdominosacral resection group(n=48) according to the order of alternative admission time between June 2010 and January 2012. Intraoperative and postoperative parameters were compared between the two groups. RESULTS: The surgery went well and no perioperative mortality in the two groups. Compared with abdominoperineal resection group, the operative time of abdominosacral resection group(including the 2nd position adjustment time) was longer[(188+/-45) min vs. (143+/-48) min, P=0.000], the unexpected prostate or vagina injury incidence was lower [0 vs. 14.3%(7/49), P=0.032), and the perineal wound infection rate was lower [2.1% (1/48) vs. 18.4% (9/49), P=0.040]. CONCLUSION: Abdominosacral excision is feasible and safe for patients with locally advanced primary low rectal cancer. PMID- 23099910 TI - [Expression and clinical significance of Claudin-1 and Claudin-4 in colorectal cancer tissues]. AB - OBJECTIVE: To investigate the expression of tight junction protein Claudin-1 and Claudin-4 in colorectal cancer tissues and its clinical significance. METHODS: Immunohistochemical staining detected the expression of tight junction protein Claudin-1 and Claudin-4 in 60 cases of colorectal cancer and 20 normal colorectal mucosa tissue. The clinical significance was analyzed. RESULTS: The positive rates of Claudin-1 and Claudin-4 in colorectal cancer tissues were 76.6%(46/60) and 85.0%(51/60), significantly higher than 20.0% (4/20) and 30.0%(6/20) in the normal colorectal mucosa(both P<0.01). The positive rates of Claudin-1 and Claudin-4 were associated with tumor differentiation degree, lymph node metastasis and TNM staging(all P<0.05). CONCLUSIONS: The high expression of the Claudin-1 and Claudin-4 may play a promoting role in colorectal cancer development and progression. Claudin-1 and Claudin-4 may become prognostic markers of colorectal cancer. PMID- 23099911 TI - [Hand-assisted laparoscopic versus laparotomy in total proctocolectomy with ileal pouch-anal anastomosis: a clinical controlled study]. AB - OBJECTIVE: To compare the outcomes of total proctocolectomy with ileal pouch-anal anastomosis performed by hand-assisted laparoscopic(HALS) and laparotomy. METHODS: Clinical data of 78 patients undergoing HALS(n=36) or laparotomy(n=42) from January 2009 to June 2011 were retrospectively studied. All the operations were performed by the same surgical group. Patients safety, postoperative recovery, complications were compared between the two groups. RESULTS: As compared to laparotomy group, HALS group had longer operative time[(300.3+/-56.4) min vs. (227.2+/-34.0) min, P=0.001], less intraoperative bleeding[(150.2+/-42.2) ml vs. (213.5+/-61.0) ml, P=0.043], shorter interval to first flatus[(2.4+/-0.9) d vs. (3.1+/-1.2) d, P=0.026], and shorter hospital stay[(9.3+/-2.6) d vs. (11.6+/-3.4) d, P=0.039]. There were no significant differences in the incidence of complications such as anastomotic separation, hemorrhage, wound infection, pelvic sepsis, and intestinal obstruction between the two groups(P>0.05). CONCLUSIONS: HALS is as safe as open approach for total proctocolectomy with ileal pouch-anal anastomosis, and short-term outcomes are better than laparotomy. PMID- 23099912 TI - Immobilized metal ion affinity chromatography: a review on its applications. AB - After 35 years of development, immobilized metal ion affinity chromatography (IMAC) has evolved into a popular protein purification technique. This review starts with a discussion of its mechanism and advantages. It continues with its applications which include the purification of histidine-tagged proteins, natural metal-binding proteins, and antibodies. IMAC used in conjunction with mass spectroscopy for phosphoprotein fractionation and proteomics is also covered. Finally, this review addresses the developments, limitations, and considerations of IMAC in the biopharmaceutical industry. PMID- 23099913 TI - Fermentation of xylo-oligosaccharides by Bifidobacterium adolescentis DSMZ 18350: kinetics, metabolism, and beta-xylosidase activities. AB - Xylo-oligosaccharides (XOS) are sugar oligomers of beta-1,4-linked xylopyranosyl moieties which exert bifidogenic effect and are increasingly used as prebiotics. The kinetics and the metabolism of Bifidobacterium adolescentis DSMZ 18350 growing on XOS and xylose were investigated. The growth rate was higher on XOS, but greater biomass yield was attained on xylose. Unlike other prebiotics, XOS oligomers were utilized simultaneously, regardless of their chain length. Throughout XOS utilization, xylose concentration slightly increased, being not neatly consumed and remaining unfermented. During growth on XOS, beta-xylosidase activity was present in the cytosol, but it occurred in the supernatant as well. A beta-1,4-xylolytic enzyme was purified from the supernatant of XOS cultures. The enzyme, a homotetramer of a 39-kDa single protein, was capable of complete XOS hydrolysis and exhibited maximum activity at pH 6.0 and 55 degrees C. Based on the molecular weight, the protein can be ascribable to the product of the gene BAD_1527, the activity of which has been inferred as an endo-beta-1,4-xylanase, but has not been characterized so far. This beta-1,4-xylolytic enzyme, found to be active in the cultural supernatant, gives a reason for the never explained accumulation of the monosaccharides in the media of bifidobacterial cultures growing on XOS, without excluding the major role of the intracellular hydrolysis of the imported oligomers. PMID- 23099915 TI - How common is inflammatory marker-negative disease in giant cell arteritis? PMID- 23099914 TI - Seasonal dynamics of ammonia/ammonium-oxidizing prokaryotes in oxic and anoxic wetland sediments of subtropical coastal mangrove. AB - Mangrove wetlands are an important ecosystem in tropical and subtropical regions, and the sediments may contain both oxic and anoxic zones. In this study, ammonia/ammonium-oxidizing prokaryotes (AOPs) in yellow and black sediments with vegetation and non-vegetated sediments in a mangrove wetland of subtropical Hong Kong were investigated in winter and summer. The phylogenetic diversity of anammox bacterial 16S rRNA genes and archaeal and bacterial amoA genes (encoding ammonia monooxygenase alpha-subunit) were analyzed using PCR amplification and denaturing gradient gel electrophoresis to reveal their community structures. Quantitative PCR was also used to detect their gene abundances. The results showed that seasonality had little effect, but sediment type had a noticeable influence on the community structures and abundances of anammox bacteria. For ammonia-oxidizing archaea (AOA), seasonality had a small effect on their community structures, but a significant effect on their abundances: AOA amoA genes were significantly higher in winter than in summer. In winter, the vegetated yellow sediments had lower AOA amoA genes than the other types of sediments, but in summer, the vegetated yellow sediments had higher AOA amoA genes than the other types of sediments. Sediment type had no apparent effect on AOA community structures in winter. In summer, however, the vegetated yellow sediments showed obviously different AOA community structures from the other types of sediments. For ammonia-oxidizing bacteria (AOB), seasonality had a significant effect on their community structures and abundances: AOB amoA genes in winter were apparently higher than in summer, and AOB community structures were different between winter and summer. Sediment type had little effect on AOB community structures, but had a noticeable effect on the abundances: AOB amoA genes of the vegetated yellow sediments were obviously lower than the black ones in both seasons. This study has demonstrated that seasonality and sediment type affected community structures and abundances of AOPs differently in oxic and anoxic sediments of the mangrove wetland. PMID- 23099916 TI - Catatrac: a novel red light-emitting diode device for screening cataracts in the developing world. AB - BACKGROUND/AIMS: The purpose of this study was to critically evaluate the Catatrac device as a potential tool for rapid cataract screening in the developing world. METHODS: Patients attending the day case unit at Gartnavel General Hospital for routine cataract surgery were recruited into the study, and divided into two groups: those with mild cataracts with LogMAR acuities <0.48, and those with advanced cataracts with LogMAR acuities >=0.48. The subjects were examined without pharmacological dilation in a dimly lit room independently by two nurses. Each patient was then examined by an ophthalmologist with a slit lamp, after dilation. If present, cataracts were graded objectively according to the LOCS III classification system. RESULTS: One hundred and twenty-two eyes of 73 patients were screened for the presence or absence of cataract using the Catatrac device. Thirty-nine eyes had mild cataracts, 43 eyes had advanced cataracts, and there were 40 control eyes with no cataracts. For detecting advanced cataracts, the two nurses using the Catatrac device had a specificity of 95.0%, a sensitivity between 86.0 and 93.0%, and kappa values between 0.81 and 0.88 for agreement with slit lamp assessment. For detecting mild cataracts the two nurses using the Catatrac device again had a specificity of 95%, sensitivity of 71-84.6%, and kappa values between 0.67 and 0.80 for agreement with slit lamp assessment. Interobserver agreement between the two nurses had a kappa value of 0.61 for mild cataract and 0.74 for advanced cataract. CONCLUSION: The Catatrac device has a high specificity, sensitivity, and interobserver agreement for advanced cataracts. Although having a slightly lower sensitivity for mild cataracts, the authors believe that this study has demonstrated that it may be a low cost and easy to use device for rapid screening of visually significant cataracts in the developing world. PMID- 23099917 TI - Ranibizumab for the management of Sorsby fundus dystrophy. PMID- 23099918 TI - An unusual case of orbital cellulitis due to Panton Valentine Leucocidine producing Staphylococcus aureus. PMID- 23099919 TI - Live longer, drink (poly)phenols! PMID- 23099920 TI - A novel link between the HER2-Akt and MDM2-p53 pathways via CSN6. PMID- 23099921 TI - Examining the roles of DNA2 during mammalian end resection. PMID- 23099922 TI - Predicting PARP inhibitor sensitivity and resistance. PMID- 23099923 TI - FBW7-Aurora B-p53 feedback loop regulates mitosis and cell growth. PMID- 23099924 TI - Efficacy of rituximab in primary immune thrombocytopenia: an analysis of adult pretreated patients from everyday hematological practice. AB - Although rituximab has seen increasing use in the treatment of immune thrombocytopenia (ITP) for many years, its therapeutic role in this disease remains unclear. We retrospectively analyzed data of all patients with ITP treated with rituximab (375 mg/m(2) once weekly for four consecutive weeks) and consecutively entered the findings into the databases of six large academic centers in the Czech Republic. A total of 114 patients were included in the analysis. All of the patients received rituximab as a second or additional line of therapy. The overall response rate (ORR) after rituximab therapy was 72 % [48 % complete response (CR), 24 % partial response (PR)] at month 6, and 69 % (45 % CR, 24 % PR) at month 12. For the group of patients with newly diagnosed (acute) ITP, the results of treatment were significantly better than for the group of patients with persistent or chronic ITP; nonetheless, this group of patients was far too small (n = 18) for our findings to be generalized. Multivariate analysis revealed that the ORR was significantly influenced primarily by the number of therapies prior to rituximab (the more previous therapies, the worse treatment response). The results of our analysis "from everyday hematological practice" confirm the high efficiency of rituximab treatment in pretreated adult patients with ITP. PMID- 23099925 TI - Huge multinucleated megaloblasts found in a patient with refractory anemia with excess blasts-1. PMID- 23099926 TI - Nitrogen source and placement effects on soil nitrous oxide emissions from no till corn. AB - A nitrogen (N) source comparison study was conducted to further evaluate the effects of inorganic N source and placement on growing-season and non-crop period soil nitrous oxide (NO). Commercially available controlled-release N fertilizers were evaluated for their potential to reduce NO emissions from a clay loam soil compared with conventionally used granular urea and urea-ammonium nitrate (UAN) fertilizers in an irrigated no-till (NT) corn ( L.) production system. Controlled release N fertilizers evaluated were: a polymer-coated urea (ESN), stabilized urea (SuperU), and UAN+AgrotainPlus (SuperU and AgrotainPlus contain nitrification and urease inhibitors). Each N source was surface band applied (202 kg N ha) near the corn row at emergence and watered into the soil the next day. Subsurface banded ESN (ESNssb) and check (no N applied) treatments were included. Nitrous oxide fluxes were measured during two growing seasons and after harvest using static, vented chambers. All N sources had significantly lower growing season NO emissions than granular urea (0.7% of applied N), with UAN+AgrotainPlus (0.2% of applied N) and ESN (0.3% of applied N) having lower emissions than UAN (0.4% of applied N). Similar trends were observed when expressing NO emissions on a grain yield and N uptake basis. Corn grain yields were not different among N sources but were greater than the check. Selection of N fertilizer source can be a mitigation practice for reducing NO emissions in NT, irrigated corn in semiarid areas. In our study, UAN+AgrotainPlus consistently had the lowest level of NO emissions with no yield loss. PMID- 23099927 TI - Biochar and nitrogen fertilizer alters soil nitrogen dynamics and greenhouse gas fluxes from two temperate soils. AB - Biochar (BC) application to agricultural soils could potentially sequester recalcitrant C, increase N retention, increase water holding capacity, and decrease greenhouse gas (GHG) emissions. Biochar addition to soils can alter soil N cycling and in some cases decrease extractable mineral N (NO and NH) and NO emissions. These benefits are not uniformly observed across varying soil types, N fertilization, and BC properties. To determine the effects of BC addition on N retention and GHG flux, we added two sizes (>250 and <250 um) of oak-derived BC (10% w/w) to two soils (aridic Argiustoll and aquic Haplustoll) with and without N fertilizer and measured extractable NO and NH and GHG efflux (NO, CO, and CH) in a 123-d laboratory incubation. Biochar had no effect on NO, NH, or NO in the unfertilized treatments of either soil. Biochar decreased cumulative extractable NO in N fertilized treatments by 8% but had mixed effects on NH. Greenhouse gas efflux differed substantially between the two soils, but generally with N fertilizer BC addition decreased NO 3 to 60%, increased CO 10 to 21%, and increased CH emissions 5 to 72%. Soil pH and total treatment N (soil + fertilizer + BC) predicted soil NO flux well across these two different soils. Expressed as CO equivalents, BC significantly reduced GHG emissions only in the N-fertilized silt loam by decreasing NO flux. In unfertilized soils, CO was the dominant GHG component, and the direction of the flux was mediated by positive or negative BC effects on soil CO flux. On the basis of our data, the use of BC appears to be an effective management strategy to reduce N leaching and GHG emissions, particularly in neutral to acidic soils with high N content. PMID- 23099928 TI - Effects on carbon and nitrogen emissions due to swine manure removal for biofuel production. AB - Methane (CH) and ammonia (NH) are emitted from swine-manure processing lagoons, contributing to global climate change and reducing air quality. Manure diverted to biofuel production is proposed as a means to reduce CH emissions. At a swine confined animal feeding operation in the U.S. Central Great Basin, animal manure was diverted from 12 farms to a biofuel facility and converted to methanol. Ammonia emissions were determined using the De Visscher Model from measured data of dissolved lagoon ammoniacal N concentrations, pH, temperature, and wind speed at the lagoon sites. Other lagoon gas emissions were measured with subsurface gas collection devices and gas chromatography analysis. During 2 yr of study, CO and CH emissions from the primary lagoons decreased 11 and 12%, respectfully, as a result of the biofuel process, compared with concurrently measured control lagoon emissions. Ammonia emissions increased 47% compared with control lagoons. The reduction of CH and increase in NH emissions agrees with a short-term study measured at this location by Lagrangian inverse dispersion analysis. The increase in NH emissions was primarily due to an increase in lagoon solution pH attributable to decreased methanogenesis. Also observed due to biofuel production was a 20% decrease in conversion of total ammoniacal N to N, a secondary process for the removal of N in anaerobic waste lagoons. The increase in NH emissions can be partially attributed to the decrease in N production by a proposed NH conversion to N mechanism. This mechanism predicts that a decrease in NH conversion to N increases ammoniacal N pH. Both effects increase NH emissions. It is unknown whether the decrease in NH conversion to N is a direct or physical result of the decrease in methanogenesis. Procedures and practices intended to reduce emissions of one pollutant can have an unintended consequence on the emissions of another pollutant. PMID- 23099929 TI - Evaluation of a closed tunnel for field-scale measurements of nitrous oxide fluxes from an unfertilized grassland soil. AB - Emissions of the major greenhouse gas NO from soils are characterized by huge spatial variability. An upscaling based on conventional small-scale chamber measurements is thus questionable and may involve a considerable amount of uncertainty. In this feasibility study, we evaluated the applicability of a large, closed tunnel for field-scale measurements of NO fluxes from an unfertilized grassland soil. The tunnel, coupled to an open-path Fourier transform infrared spectrometer, covered 500 m. During a 2-yr campaign, concurrent closed-chamber measurements (area of 0.045 m) were performed at the tunnel plot. The tunnel system enabled high-density and precise NO concentration measurements under dry, stable, nocturnal atmospheric conditions, but higher wind speeds and rain limited its application. To calculate an unbiased, predeployment NO flux from the increase of NO concentrations during tunnel deployment, we propose a novel approach based on inverse modeling (IMQ0). We show that IMQ0 is appropriate for the specific non-steady state tunnel setup. Compared with conventional models, which were developed for gas flux calculation from concentration gradients measured in vented closed chambers, IMQ0 is most accurate. Whereas NO fluxes obtained from the tunnel measurements were generally small and at a typical background level, the chamber measurements revealed high spatial and temporal variability of NO emissions, including slight NO uptake and precipitation-triggered emission peaks. The cumulative NO fluxes of both methods differed by one order of magnitude and were smaller for the tunnel measurements. We argue that the chambers were occasionally susceptible to detection of hotspots and hot moments of NO emission. However, these emissions were evidently not representative for the field scale. Compared with available greenhouse gas measurement techniques, we conclude that the tunnel may serve as a gap-filling method between small-scale chamber and ecosystem-level micrometeorological techniques, particularly during stable nocturnal conditions. PMID- 23099930 TI - A new method of regional eco-environmental quality assessment and its application. AB - Eco-environmental quality assessment (EQA) is an intricate and challenging task that must take into account numerous natural, economic, political, and social factors, which are subject to multiple conflicting criteria. In this paper, a methodological reference framework is developed for EQA that combines the fuzzy Delphi method (FDM) and fuzzy analytical hierarchy process (FAHP) with a geographic information system (GIS). The proposed method significantly improves the accuracy and reliability of evaluation results through the incorporation of fuzzy set theory. A GIS not only has the ability to store and analyze large amounts of spatial data from different sources but also provides a consistent visualization environment for displaying the input data and the results of EQA. Furthermore, unlike prior EQAs, the proposed method can support the dynamic estimation of regional eco-environmental quality by updating historical spatiotemporal data at little additional cost. A case study is presented for the western Tibetan Plateau. The study results show that worse, bad, and moderate eco environmental quality classes comprised 16.58, 20.15, and 24.84% of the total area, respectively. Good and better eco-environmental quality classes accounted for 38.43%. This result indicates that nearly 62% of the total area is eco environmentally vulnerable. The results verified the usefulness and feasibility of the proposed method. The EQA can also help local managers make scientifically based and effective decisions about Tibetan eco-environmental protection and land use. PMID- 23099931 TI - Risk of phosphorus desorption from Canadian agricultural land: 25-year temporal trend. AB - Phosphorus (P) use in excess of crop needs may impact surface water quality and contribute to eutrophication. However, P loss from agricultural land to water has never been estimated at the Canadian national scale. In this paper, the risk of P desorption from Canadian agricultural land is assessed by the source component of the indicator of risk of water contamination by P (IROWC-P). The IROWC-P source component (P_source) characterized the mobilization potential of soluble P and integrated four models of P desorption by water for dominant agricultural soil series of Canada on the soil landscape of Canada polygon scale (1:1,000,000). The objective of our study was to describe and evaluate a standardized method for deriving the P_source component. The P_source was assessed over 5-yr intervals from 1981 to 2006 for scientifically based knowledge by relating annual P balance values, soil test P (STP) analyses, soil P saturation index, and Self-Davis water extractable P extraction values. Results show trends of soil P enrichment for most Canadian provinces over the 25-yr period but also an increased percentage of farmland classified above the water extractable soil P environmental threshold of 4 mg P kg. The Canadian Prairies and Ontario showed small P_source values and almost no farmland above the environmental threshold. Quebec and the Atlantic Provinces had P_source values that exceeded the environmental threshold in 2006; more than 33% of farmland is classified above the environmental threshold value. PMID- 23099932 TI - Assessing the quality of freshwaters in a protected area within the Tagus River basin district (central Portugal). AB - Water-sediment quality was assessed in an agricultural zone of a protected area within the Tagus River basin district (central Portugal) combining chemical analysis to 12 pesticide compounds and whole toxicity testing using the bacterium , the algae , the crustacean , and the midge . The herbicides alachlor, atrazine ethofumesate, metolachlor, terbuthylazine, the insecticides chlorfenvinphos and chlorpyrifos, and the metabolite 3,4-dichloroaniline were detected in surface water samples at four sites and in groundwater samples from six wells, during four sampling occasions. Measured concentrations were compared with parametric values for human consumption, groundwater quality standards, and environmental quality standards applicable to surface water established in European Union legislation. Most severe adverse effects were noted on the growth of and lethality of in nondiluted water samples. Taking into account the values calculated by the method of toxic unit summation for pesticide mixtures, it was not possible to link the pesticides found to the toxicity detected in the water samples. Conducting this study with chemical analyses and biotests provided a more comprehensive quality assessment and realistic picture of the environmental samples analyzed, although additional studies are needed to evaluate the performance of mixture models for predicting mixture toxicity. This study underlines the importance of chemical analysis and whole toxicity testing as tools for assessing the impact of human activity on the status of water, mainly in protected zones. PMID- 23099933 TI - Data related uncertainty in near-surface vulnerability assessments for agrochemicals in the San Joaquin Valley. AB - Precious groundwater resources across the United States have been contaminated due to decades-long nonpoint-source applications of agricultural chemicals. Assessing the impact of past, ongoing, and future chemical applications for large scale agriculture operations is timely for designing best-management practices to prevent subsurface pollution. Presented here are the results from a series of regional-scale vulnerability assessments for the San Joaquin Valley (SJV). Two relatively simple indices, the retardation and attenuation factors, are used to estimate near-surface vulnerabilities based on the chemical properties of 32 pesticides and the variability of both soil characteristics and recharge rates across the SJV. The uncertainties inherit to these assessments, derived from the uncertainties within the chemical and soil data bases, are estimated using first order analyses. The results are used to screen and rank the chemicals based on mobility and leaching potential, without and with consideration of data-related uncertainties. Chemicals of historic high visibility in the SJV (e.g., atrazine, DBCP [dibromochloropropane], ethylene dibromide, and simazine) are ranked in the top half of those considered. Vulnerability maps generated for atrazine and DBCP, featured for their legacy status in the study area, clearly illustrate variations within and across the assessments. For example, the leaching potential is greater for DBCP than for atrazine, the leaching potential for DBCP is greater for the spatially variable recharge values than for the average recharge rate, and the leaching potentials for both DBCP and atrazine are greater for the annual recharge estimates than for the monthly recharge estimates. The data-related uncertainties identified in this study can be significant, targeting opportunities for improving future vulnerability assessments. PMID- 23099934 TI - Phosphorus retention in a 20-year-old septic system filter bed. AB - Septic systems in lakeshore environments often occur where thin soils overlie bedrock and, consequently, filter beds may be constructed of imported filter sand. The objective of this study was to assess the mobility of wastewater phosphorus (P) in such a potentially vulnerable setting by examining a 20-yr-old domestic septic system located near Parry Sound, ON, Canada, where the filter bed is constructed of imported noncalcareous sand. The groundwater plume is acidic (pH 6.0) and has a zone of elevated PO-P (up to 3.1 +/- 1.7 mg L) below the tile lines but no elevated PO-P is present beyond 5 m from the tile lines. Elevated concentrations of desorbable P (up to 137 mg kg) and acid-extractable P (up to 3210 mg kg) occur in the filter sand within 1 m below four of seven tile lines present and the total mass of excess acid-extractable P (39 kg) is similar to the estimated total lifetime P loading to the system (33 kg). Microprobe images reveal abundant Fe and Al-rich authigenic mineral coatings on the sand grains that are increasingly P rich (up to 10% w/w P) near the tile lines. Additionally, 6 yr of monitoring data show that groundwater PO concentrations are not increasing. This indicates that mineral precipitation, not adsorption, dominates P immobilization at this site. This example of robust long-term P retention opens up the possibility of improving P removal in on-site treatment systems by prescribing specific sand types for filter bed construction. PMID- 23099935 TI - Effects of long-term application of biosolids for mine land reclamation on groundwater chemistry: trace metals. AB - Data collected for 35 yr from a 1790-ha strip mine reclamation site in Fulton County, Illinois, where biosolids were applied from 1972 to 2004, were used to evaluate the impacts of long-term biosolids application on metal concentrations in groundwater. Groundwater samples were collected between 1972 and 2006 from wells installed in seven strip-mined fields treated with biosolids at cumulative loading rates of 801 to 1815 dry Mg ha and from another seven fields (also strip mined) treated with mineral fertilizer. Samples were collected monthly between 1972 and 1986 and quarterly between 1987 and 2004 and were analyzed for total metals. The concentrations of metals in groundwater were generally below regulatory limits. Lead, Cd, Cu, Cr, Ni, and Hg concentrations in groundwater were similar for the biosolids-amended and fertilizer-treated sites across all sampling intervals. Zinc concentration was increased by biosolids application only for samples collected before the 1993 promulgation of the USEPA 40 CFR Part 503 rule. Iron and Mn were the only metals that were consistently increased after biosolids application; however, Mn concentrations did not exceed the 10 mg L regulatory limits. Zinc, Cu, Cd, Pb, Fe, Al, and Mn concentrations in groundwater decreased with time, coupled with the change from pre-part 503 to post-Part 503 biosolids. The concentrations of other metals, including Ni, Cr, and Hg, did not increase in groundwater with the prolonged biosolids application. The study suggests that the long-term application of biosolids at high loading rates does not result in trace metal pollution of groundwater. PMID- 23099936 TI - Reduction kinetics of hexavalent chromium in soils and its correlation with soil properties. AB - The toxicity of chromium (Cr) to biota is related to its chemical forms and consequently to the redox conditions of soils. Hexavalent Cr[Cr(VI)] may undergo natural attenuation through reduction processes. In this study, the reduction kinetics of Cr(VI) in seven soils and its relationships with soil properties were investigated with laboratory incubation experiments. The results indicate that the reduction of Cr(VI) can be described by a first-order reaction. The reduction rates of Cr(VI) in the seven soils decreased in the order: Udic Ferrisols > Stagnic Anthrosols > Calcaric Regosols > Mollisol > Typic Haplustalf > Periudic Argosols > Ustic Cambosols. Simple correlation analysis revealed that the reduction of Cr(VI) in soils was positively related to organic matter content, dissolved organic matter content, Fe(II) content, clay fraction, and to the diversity index of the bacterial community but negatively correlated with easily reducible Mn content. Using stepwise regression, the reduction of Cr(VI) in soil could be quantitatively predicted by the measurement of dissolved organic matter content, Fe(II) content, pH, and soil particle size distribution, with a fitting level of 95.5%. The results indicated that the reduction of Cr(VI) in natural soils is not controlled by a single soil property but is the result of the combined effects of dissolved organic matter, Fe(II), pH, and soil particle size distribution. PMID- 23099937 TI - Relations between retired agricultural land, water quality, and aquatic-community health, Minnesota River Basin. AB - The relative importance of agricultural land retirement on water quality and aquatic-community health was investigated in the Minnesota River Basin. Eighty two sites, with drainage areas ranging from 4.3 to 2200 km, were examined for nutrient concentrations, measures of aquatic-community health (e.g., fish index of biotic integrity [IBI] scores), and environmental factors (e.g., drainage area and amount of agricultural land retirement). The relation of proximity of agricultural land retirement to the stream was determined by calculating the land retirement percent in various riparian zones. Spearman's rho results indicated that IBI score was not correlated to the percentage of agricultural land retirement at the basin scale ( = 0.070); however, IBI score was correlated to retired land percentage in the 50- to 400-m riparian zones surrounding the streams ( < 0.05), indicating that riparian agricultural land retirement may have more influence on aquatic-community health than does agricultural land retirement in upland areas. Multivariate analysis of covariance and analysis of covariance models indicated that other environmental factors (such as drainage area and lacustrine and palustrine features) commonly were correlated to aquatic-community health measures, as were in-stream factors (standard deviation of water depth and substrate type). These results indicate that although agricultural land retirement is significantly related to fish communities as measured by the IBI scores, a combination of basin, riparian, and in-stream factors act together to influence IBI scores. PMID- 23099938 TI - Soil persistence and fate of carbamazepine, lincomycin, caffeine, and ibuprofen from wastewater reuse. AB - The reuse of treated wastewater for groundwater recharge is an effective way to provide advanced treatment and water storage. Contaminants such as human drugs have been identified as a potential problem for use of this water. Gilbert, Arizona maintains a 28.3-ha facility designed to recharge 15,150 m d through recharge basins constructed on native soil. The facility averages an infiltration rate of >5 cm d, resulting in the potential of pharmaceutical compounds leaching to groundwater. One 4-ha basin was selected for spatial sampling of four pharmaceutically active compounds (PhACs). The compounds were carbamazepine, lincomycin, ibuprofen, and caffeine. Soils were extracted and analyzed using pressurized liquid extraction and liquid chromatography-mass spectrometry-mass spectrometry. The concentration of ibuprofen was below detection limits in all samples. Lincomycin exhibited no net accumulation from year to year but had significantly higher concentrations from depths of 0 to 5 cm than from depths >10 cm. Carbamazepine had the lowest concentration at 0 to 5 cm (0.18 ng g soil), providing evidence that there is potential degradation of carbamazepine in surface soils. Carbamazepine also exhibited significant accumulation from year to year. Caffeine exhibited net accumulation and had higher concentrations in surface samples. The accumulation of PhACs in the soil beneath recharge basins indicates that PhACs are being removed from the infiltrating water and that, regarding ibuprofen and lincomycin, the treatment is sustainable due to the lack of accumulation. Regarding carbamazepine and caffeine, further investigations are needed to determine possible management and environmental conditions that could prevent accumulation. PMID- 23099939 TI - Occurrence of ciprofloxacin, enrofloxacin, and florfenicol in animal wastewater and water resources. AB - Antimicrobial agent residues are becoming an intractable environmental problem in soil, surface, and underground water. To obtain a broad profile of residues in animal wastewater and surface water, 24 animal wastewater, 8 animal farm effluent, 18 river water, and 8 pond water samples taken in Jiangsu in eastern China were monitored for enrofloxacin, ciprofloxacin, and florfenicol using solid phase extraction and high performance liquid chromatography/electrospray ionization-tandem mass spectrometry (HPLC/ESI-MS/MS) techniques. The results revealed that two antibacterials were detected simultaneously in 49.1% of samples, followed by three antibacterials (22.6%) and one antibacterial (22.6%). Up to 3.35, 5.93, and 2.10 MUg L for ciprofloxacin, 1.09, 4.24, and 0.50 MUg L for enrofloxacin, and 0.95, 2.40, and 2.84 MUg L for florfenicol were detected in animal farm-effluent, river, and pond water, respectively. The maximum concentrations of ciprofloxacin and enrofloxacin in animal wastewaters were 7.49 and 8.77 MUg L, respectively. Furthermore, residue levels of ciprofloxacin and florfenicol showed at least two statistical differences between any two sampling areas or two animal farms. Enrofloxacin showed no statistical difference among the sampling areas and the animal farms. PMID- 23099940 TI - Dissipation of propanil and 3,4 dichloroaniline in three different rice management systems. AB - This study focused on the dissipation of propanil and 3,4 dichloroaniline (3,4 DCA) over time in the soil, field water, inlet water, and outlet water of paddy fields under three management systems: conventional water seeding (CON), conventional water seeding with supplied liquid manure (LMA), and dry seeding (DRY). Propanil dissipation in water was also investigated under laboratory conditions. The field study was conducted from 2004 to 2006 at Vercelli, northern Italy. Propanil and 3,4 DCA showed rapid dissipation in water and soil environments both in the field and in the laboratory. Under controlled conditions, chemical hydrolysis was not detected for either compounds for up to 100 d at pHs of 5, 7, and 9. In the laboratory, the half-life of propanil in irrigation water was 1.1 d; its half-life in soil was routinely measured at <1.0 d (between 0.17 and 1.77 d). 3,4 DCA was found to persist much longer. Measured in all three study years at 50 d after treatment, its concentration ranged between 44 MUg kg (CON) and 140 MUg kg (DRY). Propanil and 3,4 DCA concentrations in paddy water were particularly high in samples collected at 4 d (2004) and 2 d (2005) after treatment. Maximum concentrations were 54.4 MUg L (CON) for propanil (2005) and 113.7 MUg L (LMA) for 3,4 DCA (2004). The concentrations of propanil and 3,4 DCA in inlet water were never above 1.1 and 0.3 MUg L, respectively, whereas the highest concentration of each compound in outlet water was in samples collected first after treatment in 2005 and 2006. Both chemicals dissipated rapidly in all the soil-water environments but displayed no important differences among the three management systems. In conclusion, propanil and 3,4 DCA did not persist longer in paddy fields. A risk of water network contamination by these compounds may occur only early after herbicide spraying. A water-holding period after herbicide spraying may reduce this risk. PMID- 23099941 TI - Long-term sorption and sequestration dynamics of the antibiotic sulfadiazine: a batch study. AB - Understanding the long-term sequestration of veterinary antibiotics into soil fractions with different bioavailability is important in terms of assessing their eco-toxicological impact. We performed 60-d batch sorption experiments with radiolabeled sulfadiazine (SDZ) using samples from two agricultural soils. Sequential extraction with CaCl/MeOH (easily accessible fraction), microwave (residual fraction, RES), and combustion (nonextractable residues, NER) was used to quantify the sequestration dynamics of the C-derived SDZ-equivalent concentration. Multiple harsh extractions allowed us to mathematically extrapolate to the amount of SDZ equivalents that can be potentially extracted, resulting in halving the NER fraction after 60 d. A modified two-stage model with irreversible sorption combined with global parameter optimization was able to display the sequestration dynamics. We demonstrated this with sterilized samples in which no transformation of the parent compound was observed. This also showed that transformation was primarily biologically driven. These modeling results verified the procedure, which was then applied to nontreated samples from both soils to estimate effective parameter values for SDZ-derived equivalents. Observed initial sorption, to which up to 20% of the kinetic sorption sites attributed, was included in the model. Both the RES and NER fractions reached a sorption plateau, with NER occupying about 30% of the kinetic fraction (RES+NER) for all soils. The sorption and sequestration of SDZ were soil-specific and dominated by kinetics. Sequestration in the RES fraction was much slower (characteristic time: 60 d) than the redistribution in the NER fraction (characteristic time: <6 d). The work presented here contributes to the prediction of the dynamics of (bio-)availability. PMID- 23099942 TI - Losses in carbon and nitrogen stocks in soil particle-size fractions along cultivation chronosequences in Inner Mongolian grasslands. AB - Cultivation in semiarid grasslands induces large changes in soil organic matter (SOM) stock. To better predict the effects of cultivation on SOM pools, there is a need to identify the soil fractions that are affected and the extent to which they are affected. Using four cultivation chronosequences in Inner Mongolian grasslands of northern China, we investigated the changes in soil organic carbon (SOC) and total nitrogen (N) stocks in soil particle-size fractions to identify the effect of cultivation on SOM dynamics. The results showed that conversion of native grasslands into croplands significantly decreased the SOC stocks (4.34 31.65 Mg C ha) and N (0.19-2.54 Mg N ha) in the 0- to 100-cm layer after cultivation. Prominent changes were observed in the SOC and N stocks in the 0- to 10-cm layer and were, on average, 6.56 Mg C ha (24.85%) and 0.63 Mg N ha (23.48%), respectively. The effect of cultivation on the SOC and N stocks in soil fractions was in the order sand > silt > clay. The C and N stocks in the 0- to 10 cm soil layer in the sand fraction in croplands decreased, on average, by 4.74 Mg C ha (35.86%) and 0.48 Mg N ha (41.30%), respectively, compared with those in native grasslands. The declines in the silt and clay fractions were small. Thus, sand fraction was a more important contributor to C and N losses in soil after cultivation than silt or clay fraction. Our findings indicate that the preliminary responses of SOC and N to cultivation in a semiarid grassland area and have significant implications for assessing the loss or gain of C and N during grassland conversion. PMID- 23099943 TI - The effects of iron deficiency on lead accumulation in Ailanthus altissima (Mill.) Swingle seedlings. AB - Understanding the effects of root Fe deficiency on the uptake and translocation of toxic metals can be important for improving the phytoremediation strategies of polluted soils. The present study investigated how Fe nutritional status affects the uptake and root-to-shoot-translocation of Pb in hydroponically grown seedlings of (Mill.) Swingle. The interactions of Fe deficiency and Pb were assessed by measuring the root Fe(III) reductase activity, carboxylic acids concentration in root exudates, root and shoot biomass, and accumulation of Pb and other metals (Fe, Zn, Mn, and Cu) in roots and leaves of Fe-sufficient (+Fe) and Fe-deficient (-Fe) plants. The results indicate that Fe deficiency induced 18-fold higher Fe(III) reductase activity in roots compared with +Fe plants, which was followed by increased root exudation of citric acid (28.2 +/- 1.39 in +Fe and 498 +/- 256.4 MUmol g DW 2 h in -Fe plants). Iron deficiency also induces a significant decrease of root and shoot dry weight compared with the control +Fe plants, whereas 2-wk Pb (20 MUM) treatment did not influence root and shoot growth. Iron-sufficient plants accumulated more Pb (56.8 +/- 17.29 MUg g) in leaves than -Fe plants (21.5 +/- 8.10 MUg g). Two weeks of exposure to Pb significantly decreased Fe(III) reductase activity and accumulation of Fe, Zn, and Mn in the roots of -Fe plants. It is hypothesized that 2 wk of root exposure to Pb blocks functioning of a specific Fe transport system activated under Fe deficiency. PMID- 23099944 TI - Evaluation of chloropyromorphite stability in the rhizosphere of and in a sand culture. AB - Chloropyromorphite (Pb(PO)Cl), CP, is the most stable lead (Pb) mineral under normal environmental conditions and precipitates in Pb-contaminated soils by addition of phosphorous (P). A sand culture experiment was conducted to evaluate the efficiency of and roots to dissolve CP in the presence and in the absence of P source. The results showed that the rhizosphere of the plants had lower soluble P and Pb compared with the bulk, which can be attributed to a higher pH in the rhizosphere. Mineralogical transformations of CP in the root surface of the plants including lanarkite (PbSO.PbO) has been confirmed by X-ray diffraction and scanning electron microscopy techniques. Decrease in soluble P in the rhizosphere as a consequence of P uptake by the plant roots may be a reason for CP dissolution. This study indicates that the dissolution of CP can be promoted by rhizosphere processes. PMID- 23099945 TI - Sediment removal by prairie filter strips in row-cropped ephemeral watersheds. AB - Twelve small watersheds in central Iowa were used to evaluate the effectiveness of prairie filter strips (PFS) in trapping sediment from agricultural runoff. Four treatments with PFS of different size and location (100% rowcrop, 10% PFS of total watershed area at footslope, 10% PFS at footslope and in contour strips, 20% PFS at footslope and in contour strips) arranged in a balanced incomplete block design were seeded in July 2007. All watersheds were in bromegrass ( L.) for at least 10 yr before treatment establishment. Cropped areas were managed under a no-till, 2-yr corn ( L.)-soybean [ (L.) Merr.] rotation beginning in 2007. About 38 to 85% of the total sediment export from cropland occurred during the early growth stage of rowcrop due to wet field conditions and poor ground cover. The greatest sediment load was observed in 2008 due to the initial soil disturbance and gradually decreased thereafter. The mean annual sediment yield through 2010 was 0.36 and 8.30 Mg ha for the watersheds with and without PFS, respectively, a 96% sediment trapping efficiency for the 4-yr study period. The amount and distribution of PFS had no significant impact on runoff and sediment yield, probably due to the relatively large width (37-78 m) of footslope PFS. The findings suggest that incorporation of PFS at the footslope position of annual rowcrop systems provides an effective approach to reducing sediment loss in runoff from agricultural watersheds under a no-till system. PMID- 23099946 TI - Macroinvertebrate response and internal phosphorus loading in a Michigan Lake after alum treatment. AB - Alum treatment is a lake restoration technique that is used to address internal phosphorus (P) loading. We evaluated the macroinvertebrate density and P release rates from sediment cores in Spring Lake, Michigan, 5 yr after an alum treatment and compared the findings with conditions before and 1 yr after application. Total macroinvertebrate density recovered to the near pre-alum level after the decline that was measured in 2006. Community structure also shifted, with the dominant group changing from oligochaetes before alum treatment to chaoborids in 2010. Chironomid density in 2010 was similar to pre-alum density, but this represented a decline from an elevated density measured in 2006. Ceratopogonid density increased in 2010 compared with the prior samplings, but absolute densities were very low compared with other macroinvertebrate groups. Maximum P release rates from sediment cores in 2010 averaged from 1.68 to 2.81 mg P m d under anoxic conditions. These rates are an order of magnitude lower than before alum was applied, indicating the alum application was still effectively reducing P release rates from sediments in Spring Lake. However, the release rates have increased since 2006, suggesting that alum efficacy may be declining. The NaOH extractable soluble reactive P fraction has increased since 2006, suggesting that the aluminum hydroxide floc is successfully binding P in the sediments. Despite the low release rates of P from the sediment, water column P and chlorophyll concentrations remain elevated in Spring Lake. This points to the continued need for reductions in external P loads to Spring Lake. PMID- 23099947 TI - Nitrate flux into the sediments of a shallow oligohaline estuary during large flood pulses of Mississippi River water. AB - Lake Pontchartrain is a large, oligohaline estuary located in coastal Louisiana that receives episodic diversions of nitrogen-rich Mississippi River water via the Bonnet Carre Spillway to alleviate flood threats to the city of New Orleans. These events may be linked to expressions of eutrophication, and it is therefore important to investigate pathways of nitrate (NO) loss. Nitrate flux into the sediments of Lake Pontchartrain was investigated using two independent methods: (i) simulating high NO flood events under aerobic and anaerobic incubations in intact sediment cores collected during 2010 and (ii) in situ field measurements of the vertical profiles of dissolved inorganic nitrogen species at the sediment water interface during the 2011 Bonnet Carre Spillway opening. Mean rates of NO flux into sediments based on mass transfer in intact cores collected in 2010 and in situ porewater measurements in 2011 were -17.4 and -1.4 mg NO-N m d, respectively, for water column NO concentrations observed in situ in 2011. During the laboratory incubations, there was no significant difference in NO flux between oxygen treatments. We estimate that NO flux into sediments accounted for up to 3.1% (309 Mg NO-N) of water column NO loss during the 2008 Bonnet Carre Spillway event. Sediment characteristics, field measurements, and results from the laboratory experiment suggest that denitrification is the primary pathway for NO reduction. Even though there is significant NO reduction occurring in Lake Pontchartrain sediments during Mississippi River diversion events, this pathway of NO loss from the water column plays a relatively minor role in the transformation of the very large amount of NO received during these times. PMID- 23099948 TI - Evaluation of variation in nitrate concentration levels in the Raccoon River watershed in Iowa. AB - The Raccoon River Watershed in Iowa has received considerable attention in the recent past due to frequent detections of nitrate concentrations above the federal drinking water standard. This paper econometrically investigates the determinants of variation of nitrate concentrations in the Raccoon River. The analysis relies on a generalized autoregressive conditional heteroscedastic process to model the serial dependence of volatility of the monthly nitrate concentrations in the Raccoon River. Monthly nitrate concentration data from Des Moines Water Works at Van Meter from 1992 to 2008 are used in the study. We found no statistically significant increasing trend in nitrate concentrations over the study period. There are substantial intra-annual variations in nitrate concentrations, and we noted a very strong seasonal pattern. Variations in rainfall and temperature contribute more to the monthly variation in nitrate concentration than do the changes in nitrogen application rates. PMID- 23099949 TI - Eleven-year trend in acetanilide pesticide degradates in the Iowa River, Iowa. AB - Trends in concentration and loads of acetochlor, alachlor, and metolachlor and their ethanasulfonic (ESA) and oxanilic (OXA) acid degradates were studied from 1996 through 2006 in the main stem of the Iowa River, Iowa and in the South Fork Iowa River, a small tributary near the headwaters of the Iowa River. Concentration trends were determined using the parametric regression model SEAWAVE-Q, which accounts for seasonal and flow-related variability. Daily estimated concentrations generated from the model were used with daily streamflow to calculate daily and yearly loads. Acetochlor, alachlor, metolachlor, and their ESA and OXA degradates were generally present in >50% of the samples collected from both sites throughout the study. Their concentrations generally decreased from 1996 through 2006, although the rate of decrease was slower after 2001. Concentrations of the ESA and OXA degradates decreased from 3 to about 23% yr. The concentration trend was related to the decreasing use of these compounds during the study period. Decreasing concentrations and constant runoff resulted in an average reduction of 10 to >3000 kg per year of alachlor and metolachlor ESA and OXA degradates being transported out of the Iowa River watershed. Transport of acetochlor and metolachlor parent compounds and their degradates from the Iowa River watershed ranged from <1% to about 6% of the annual application. These trends were related to the decreasing use of these compounds during the study period, but the year-to-year variability cannot explain changes in loads based on herbicide use alone. The trends were also affected by the timing and amount of precipitation. As expected, increased amounts of water moving through the watershed moved a greater percentage of the applied herbicides, especially the relatively soluble degradates, from the soils into the rivers through surface runoff, shallow groundwater inflow, and subsurface drainage. PMID- 23099950 TI - Water quality effects of herded stream crossings by domestic sheep bands. AB - Livestock impacts on total suspended solids (TSS) and pathogen (e.g., ) levels in rangeland streams are a serious concern worldwide. Herded stream crossings by domestic sheep () are periodic, necessary managerial events on high-elevation rangelands, but their impacts on stream water quality are largely unknown. We evaluated the effects of herded, one-way crossings by sheep bands (about 2000 individuals) on TSS and concentration and load responses in downstream waters. Crossing trials were conducted during the summers of 2005 and 2006 on two reaches within each of three perennial streams in the Centennial Mountains of eastern Idaho and southwestern Montana. Water samples were collected at 2-min intervals at an upstream background station and at stations 25, 100, 500, and 1500 m downstream just before and during each crossing trial. Crossings produced substantial increases in TSS and concentrations and loads downstream, but these concentration increases were localized and short lived. Maximum TSS concentration was highest 25 m downstream, declined as a function of downstream distance, and at 500 m downstream was similar to background. Post-peak TSS concentrations at all downstream stations decreased to <25 mg L within 24 to 48 min after reaching their maxima. Findings for concentration and load responses were similar to that of TSS but less clear cut. Stream-crossing sheep do affect water quality; therefore, producers and resource managers should continue to evaluate the efficacy of herdsmanship techniques for reducing water quality impact. PMID- 23099951 TI - Field-scale evaluation of water fluxes and manure solution leaching in feedlot pen soils. AB - Accumulation of beef cattle manure on feedlot pen surfaces generates large amounts of dissolved solutes that can be mobilized by water fluxes, affecting surface and groundwater quality. Our objective was to examine the long-term impacts of a beef cattle feeding operation on water fluxes and manure leaching in feedlot pens located on sandy loam soils of the subhumid Sandy Pampa region in Argentina. Bulk density, gravimetric moisture content, and chloride concentration were quantified. Rain simulation trials were performed to estimate infiltration and runoff rates. Using chloride ion as a tracer, profile analysis techniques were applied to estimate the soil moisture flux and manure conservative chemical components leaching rates. An organic stratum was found over the surface of the pen soil, separated from the underlying soil by a highly compacted thin layer (the manure-soil interface). The soil beneath the organic layer showed greater bulk density in the A horizon than in the control soil and had greater moisture content. Greater concentrations of chloride were found as a consequence of the partial sealing of the manure-soil interface. Surface runoff was the dominant process in the feedlot pen soil, whereas infiltration was the main process in control soil. Soil moisture flux beneath pens decreased substantially after 15 yr of activity. The estimated minimum leaching rate of chloride was 13 times faster than the estimated soil moisture flux. This difference suggests that chloride ions are not exclusively transported by advective flow under our conditions but also by solute diffusion and preferential flow. PMID- 23099952 TI - Dairy heifer manure management, dietary phosphorus, and soil test P effects on runoff phosphorus. AB - Manure application to cropland can contribute to runoff losses of P and eutrophication of surface waters. We conducted a series of three rainfall simulation experiments to assess the effects of dairy heifer dietary P, manure application method, application rate, and soil test P on runoff P losses from two successive simulated rainfall events. Bedded manure (18-21% solids) from dairy heifers fed diets with or without supplemental P was applied on a silt loam soil packed into 1- by 0.2-m sheet metal pans. Manure was either surface-applied or incorporated (Experiment 1) or surface-applied at two rates (Experiment 2) to supply 26 to 63 kg P ha. Experiment 3 evaluated runoff P from four similar nonmanured soils with average Bray P1-extractable P levels of 11, 29, 51, and 75 mg kg. We measured runoff quantity, total P (TP), dissolved reactive P (DRP), and total and volatile solids in runoff collected for 30 min after runoff initiation from two simulated rain events (70 mm h) 3 or 4 d apart. Manure incorporation reduced TP and DRP concentrations and load by 85 to 90% compared with surface application. Doubling the manure rate increased runoff DRP and TP concentrations an average of 36%. In the same experiment, P diet supplementation increased water extractable P in manure by 100% and increased runoff DRP concentration threefold. Concentrations of solids, TP, and DRP in runoff from Rain 2 were 25 to 75% lower than from Rain 1 in Experiments 1 and 2. Runoff DRP from nonmanured soils increased quadratically with increasing soil test P. These results show that large reductions in P runoff losses can be achieved by incorporation of manure, avoiding unnecessary diet P supplementation, limiting manure application rate, and managing soils to prevent excessive soil test P levels. PMID- 23099953 TI - High-iron biosolids compost-induced changes in lead and arsenic speciation and bioaccessibility in co-contaminated soils. AB - The safety of urban farming has been questioned due to the potential for contamination in urban soils. A laboratory incubation, a field trial, and a second laboratory incubation were conducted to test the ability of high-Fe biosolids-based composts to reduce the bioaccessibility of soil Pb and As in situ. Lead and As bioaccessibility were evaluated using an in vitro assay. Changes in Pb, As, and Fe speciation were determined on select samples after the second laboratory incubation using MU-X-ray fluorescence mapping followed by MU-X ray absorption near-edge structure (XANES). A compost with Fe added to wastewater treatment residuals (Fe WTR compost) added to soils at 100 g kg decreased Pb bioaccessibility in both laboratory incubations. Mixed results were observed for As. Composts tested in the field trial (Fe added as Fe powder or FeCl) did not reduce bioaccessible Pb, and limited reductions were observed in bioaccessible As. These composts had no effect on Pb bioaccessibility during the second laboratory incubation. Bulk XANES showed association of Pb with sulfates and carbonates in the control soil. MU-XANES for three points in the Fe WTR amended soil showed Pb present as Fe-sorbed Pb (88 and 100% of two points) and pyromorphite (12 and 53% of two points). Bulk XANES of the Fe WTR compost showed 97% of total Fe present as Fe. The results of this study indicate that addition of high-Fe biosolids compost is an effective means to reduce Pb accessibility only for certain types of Fe-rich materials. PMID- 23099954 TI - Infiltration mechanism controls nitrification and denitrification processes under dairy waste lagoon. AB - Earthen waste lagoons are commonly used to store liquid wastes from concentrated animal feeding operations. The fate of ammonium (NH) and nitrate (NO) was studied in the vadose zone below earthen-clay dairy farm waste lagoons using three independent vadose zone monitoring systems. The vadose zone was monitored from 0.5 to 30 m below land surface through direct sampling of the sediment porewater and continuous measurement of the sediment profile's water content variations. Four years of monitoring revealed that wastewater infiltration from the lagoon is controlled by two mechanisms: slow (mm d), constant infiltration from the lagoon bed; and rapid (m h) infiltration of wastewater and rainwater via preferential flow in desiccation cracks formed in the unsaturated clay sediment surrounding the lagoon banks. The preferential flow mechanism is active mainly during wastewater-level fluctuations and intensive rain events. The vadose zone below the waste sources remained unsaturated throughout the monitoring period, and all infiltrating NH was oxidized in the upper 0.5 m. The NH oxidation (nitrification) was coupled with NO reduction (denitrification) and depended on the sediment water content, which was controlled by the infiltration mechanism. Coupled nitrification-denitrification (CND) resulted in 90 to 100% reduction in the total nitrogen mass in the vadose zone, with higher removal under high water content (~0.55 m m). Mass balance of nitrogen and isotopic composition of NO indicated that CND, rather than cation exchange capacity, is the key factor regulating nitrogen's fate in the vadose zone underlying earthen waste lagoons. PMID- 23099955 TI - Sulfur turnover and emissions during storage of cattle slurry: effects of acidification and sulfur addition. AB - Slurry acidification using sulfuric acid reduces ammonia emissions but also affects sulfur (S) cycling. Emission of sulfur is a source of malodor and reduces the sulfur fertilizer value of the slurry. We investigated the effect of sulfate and methionine amendments, alone or in combination with acidification, on sulfur transformations in slurry and emissions of volatile sulfur compounds (VSC) during storage of fresh and aged cattle slurry. When pH was lowered to 5.5 it resulted in an almost complete inhibition of sulfate reduction. There was a huge emission of hydrogen sulfide (HS) with addition of sulfate and methionine ( < 0.01). Methanethiol (MT) was emitted in treatments with addition of methionine, especially when simultaneously acidified ( < 0.01). The large HS production in the sulfate-amended slurries resulted in little accumulation of MT and dimethyl sulfide (DMS) under neutral conditions, in contrast to acidic conditions where the degradation was inhibited and both MT and DMS accumulated. Based on odor activity values, untreated slurry had little odor development from S compounds, especially the aged slurry. Acidification did not significantly increase odor contribution from any of the compounds in fresh or aged slurry. Generally, addition of a sulfate increased the contribution from HS dramatically, whereas acidification lowered the HS contribution but increased that of MT. Thus, acidification of slurry with sulfuric acid may potentially produce more odor from S compounds than untreated slurry. PMID- 23099956 TI - Watershed-level comparison of predictability and sensitivity of two phosphorus models. AB - Buildup of phosphorus (P) in agricultural soils and transport of P to nearby surface waters due to excessive, long-term application of poultry litter is an environmental concern in many poultry-producing states. Watershed models are often used to quantify soil and water quality impacts of poultry litter applications. However, depending on how P transport is simulated in watershed models, the anticipated impact could be quite different. The objective of this study was to determine the predictability and sensitivity of the Soil and Water Assessment Tool (SWAT) P model and a newly developed, state-of-the-art manure P model called SurPhos in a poultry litter-applied pasture watershed. A small, predominantly agricultural watershed in Randolph County, Alabama was used for this study. The SWAT model, calibrated for surface runoff and total stream flows (Nash-Sutcliffe coefficient of 0.70 for both), was used to provide runoff inputs to the SurPhos model. Total dissolved P (TDP) exports simulated by the SWAT P and SurPhos models from the hay hydrological response units of the watershed were compared for different poultry litter application rates and different initial soil Solution P levels. Both models showed sensitivity to poultry litter application rates, with SWAT simulating linear and SurPhos simulating nonlinear increases in TDP exports with increase in poultry litter application rates. SWAT showed greater sensitivity to initial soil Solution P levels, which can lead to overestimation of TDP exports, especially at low poultry litter application rates. As opposed to the SurPhos model simulations and contrary to recent studies, SWAT simulated excessive accumulation of Solution P in the top 10 mm of soil. Because SurPhos appears to simulate P transport and build-up processes from manure-applied areas more accurately, this study suggests that SWAT be replaced by SurPhos to more accurately determine watershed-level effectiveness of P management measures. PMID- 23099957 TI - Fate of NO and NH in the treatment of eutrophic water using the floating macrophyte. AB - Use of the floating aquatic macrophyte, , to improve eutrophic water quality is practiced on a large scale in China. Limited information is available on the relative importance of the biological NO or NH removal process during the treatment of eutrophic water using . To investigate the key process responsible for the removal of NO and NH, N-NO (9.98 atom % [at.%] N) or N-NH (10.08 at.% N) was added to obtain eutrophic water with or without the cultivation of . In the unplanted water, considerable proportions of the added N-NO (27.13 +/- 4.87%) or N-NH (42.08 +/- 7.22%) were assimilated by the developed algae. The growth of controlled algae development in the planted water. Furthermore, the cultivation of stimulated gaseous loss of N by microbial denitrification (8.61 +/- 1.70% NO-N loss from N-NO-labeled water). Apart from N loss by denitrification, considerable proportions of the added N-NO (62.01 +/- 6.93%) or N-NH (76.76 +/- 6.21%) were assimilated into the macrophyte N pools. The fine root detritus of contained a proportion of N (4.37 +/- 1.39% in NO-labeled water, 2.03 +/- 0.52% in NH-labeled water) that will be returned to the water after decomposition. In addition to N loss via NO emission, an unaccounted proportion of N could be mainly due to gaseous loss as N by denitrification (25.00% in N-NO-labeled water with Eichhornia crassipes) PMID- 23099958 TI - Temporal and spatial patterns of internal phosphorus recycling in a South Florida (USA) stormwater treatment area. AB - Large constructed wetlands, known as stormwater treatment areas (STAs), have been deployed to remove phosphorus (P) in drainage waters before discharge into the Everglades in South Florida, USA. Their P removal performance depends on internal P cycling under typically hydrated, but with occasionally desiccated, conditions. We examined the spatial and temporal P removal capacity under different hydrologic conditions along a STA flow path. While inflow soils are P enriched, the outflow region of the wetland contained P-unsaturated soils with minimal net recycling of bound soil P to the water column as plant-available P. The outflow region soils were characterized by low porewater soluble reactive P (SRP) (<=40 MUg L) and high total sulfide (TS) (2-9 mg L) concentrations, and total ammoniacal nitrogen (TAN) and SRP flux rates that averaged 1.51 and 0.002 mg m d, respectively. Pronounced increases in porewater and surface-water concentrations of SRP, dissolved organic P (DOP), and TAN were observed immediately after rehydration of the cell after an extended drought. Elevated total P concentrations persisted at the outfall of the cell for several months thereafter, resulting in an annual outflow total P concentration nearly threefold higher than the long-term mean. Relative to processes that can occur during extended periods of inundation, such as sulfate-enhanced P release from organic matter mineralization or iron sulfide formation, aerobic oxidation of organic matter during prolonged dryout periods is a more significant biogeochemical process in compromising soil P retention in STAs. PMID- 23099959 TI - Effect of feeding strategies on pharmaceutical removal by subsurface flow constructed wetlands. AB - This study presents findings on an assessment of the effect of continuous and batch feeding strategies on the removal of selected pharmaceuticals from synthetic wastewater. Six mesocosm-scale constructed wetlands, including three horizontal subsurface flow constructed wetlands and three sand filters, were set up at the campus of Nanyang Technological University, Singapore. The findings showed that ibuprofen and diclofenac removal in the wetlands was significantly ( < 0.05) enhanced in the batch versus continuous mode. In contrast, naproxen and carbamazepine showed no significant differences ( > 0.05) in elimination under either feeding strategy. Our results also clearly showed that the presence of plants exerts a stimulatory effect on pharmaceutical removal for ibuprofen, diclofenac, and naproxen in batch and continuous mode. Estimation of the quantitative role of this stimulatory effect on pharmaceutical elimination of batch operation as compared with the effect of the presence of the higher plant alone showed that batch operation may account for 40 to 87% of the contribution conferred by the aquatic plant. The findings of this study imply that where maximal removal of pharmaceutical compounds is desired, periodic draining and filling might be the preferred operational strategy for full-scale, subsurface flow constructed wetlands. PMID- 23099960 TI - Livestock-generated nitrogen exports from a pastoral wetland. AB - When wetlands are disturbed by cattle, pulses of contaminants may be released. We studied nitrogen exports from a small pastoral wetland (1725 m) in the Lake Taupo Catchment, New Zealand, to which cattle and sheep had periodic access. Flow, turbidity, and water quality samples were collected at the wetland outlet over 2 yr. Turbidity was used to trigger sampling during livestock grazing and as a surrogate for organic N (OrgN) and total N (TN) in flux estimation. The wetland flowed throughout the study (median 0.285 L s) and was baseflow dominated (73%) but responded to rainfall (peak storm flow 166 L s). Organic N was the dominant N form exported (median OrgN:TN ratio 0.86). During cattle grazing periods, concentrations and fluxes of all forms of nitrogen at the outlet were elevated compared with storm and baseflow conditions during nongrazed periods. The TN fluxes were nine times greater when cattle grazed the wetland (306 g d) than under nongrazed baseflow conditions (32 g d). Cattle grazing occurred 9% of the time but accounted for 34% of TN export over 11 mo. Excluding cattle from small wetlands is likely to have immediate water quality benefits. PMID- 23099961 TI - Inherent errors in pollutant build-up estimation in considering urban land use as a lumped parameter. AB - Stormwater quality modeling results are subject to uncertainty. The variability of input parameters is an important source of overall model error. An in-depth understanding of the variability associated with input parameters can provide knowledge on the uncertainty associated with these parameters and can assist in uncertainty analysis of stormwater quality models and decision making based on modeling outcomes. This paper discusses the outcomes of a research study undertaken to analyze the variability related to pollutant build-up parameters in stormwater quality modeling. The study was based on the analysis of pollutant build-up samples collected from 12 road surfaces in residential, commercial, and industrial land uses. It was found that build-up characteristics vary appreciably even within the same land use. Therefore, using land use as a lumped parameter would contribute significant uncertainties in stormwater quality modeling. Additionally, it was found that the variability in pollutant build-up can be significant depending on the pollutant type. This underlines the importance of taking into account specific land use characteristics and targeted pollutant species when undertaking uncertainty analysis of stormwater quality models or in interpreting the modeling outcomes. PMID- 23099962 TI - Phosphorus flow and characterization in dry-grind corn ethanol plants. AB - Both the high phosphorus (P) content and P bioavailability of the animal feed coproducts of the corn-ethanol industry could potentially contribute to increased manure and soil P levels and associated environmental issues (e.g., eutrophication). Therefore, a detailed modeling of total P mass flow to the coproducts (i.e., dry distillers grains with solubles, DDGS) was performed. Distribution of P between inorganic P and phytase-hydrolyzable P forms was quantified for selected coproducts (thin stillage, DDGS, modified DDGS [mDDGS]). The P mass balance indicated that although corn is the major P contributor to the coproducts (80.2%), a substantial portion (19.4%) comes from yeast addition. Of the two components constituting DDGS, wet distillers grains and condensed solubles, the latter contributes to only one-third of the mass but, importantly, yields 70.9% of P. The phytase enzyme used, , was very effective in hydrolyzing the nonorthophosphate P components of thin stillage, DDGS and mDDGS. Our results would help track P movement during various dry-grind processing steps and formulate strategies for phytase enzyme supplementation to various postfermentation coproducts from corn-ethanol plants. PMID- 23099964 TI - Lymph node metastases from differentiated thyroid carcinoma: does radioiodine still play a role? AB - OBJECTIVES: Ultrasonography and surgery have now become the elective diagnostic and therapeutic tools for neck lymph node (LN) metastases from differentiated thyroid carcinoma (DTC), reserving radioiodine therapy (RAI) for surgery failures. Aim of the present retrospective study was to evaluate results of RAI in cases of LN metastases displaying (131)I uptake over a long-term observation period and its possible role today. MATERIALS AND METHODS: From a series of 1276 patients who had undergone surgery for DTC, 130 cases were selected showing (131)I uptaking LN metastases, detected during follow-up scans and who were then submitted to surgery and/or RAI. Patients were divided into groups according both to extent of surgery, with/without lymphectomy, and to following treatment and outcome. RESULTS: The initial surgical approach does not seem to significantly influence the outcome. (131)I therapy alone, sometimes at low doses, can be very effective in the management of LN metastases detected at Whole Body Scan, but multiple doses are often needed. The age at diagnosis is confirmed as a negative prognostic factor. CONCLUSIONS: Considered radioprotection questions, RAI may solve (131)I uptaking LN metastases, above all if < 10 mm. For larger LN metastases and in the case of failure of RAI surgical excision is mandatory, while a subsequent therapeutic dose of (131)I could be useful to reveal incomplete excision. PMID- 23099965 TI - Evaluation of postural control impairment using Balance Error Scoring System among athletes with ankle injury: an effective tool in daily clinical practice. AB - OBJECTIVE: The main objective of the study was to investigate postural control impairment in athletes with history of ankle injury by using Balance Error Scoring System (BESS) and to compare with the controls. PATIENTS AND METHODS: This is a case-control study that compared postural control among subjects with history of ankle injury with the matched controls. A total of sixty subjects (n = 60) were recruited from the department of physical education and sports science from a higher learning institute. Thirty athletes who had history of ankle injury were recruited for case group and the control group had an another thirty participants who were healthy athletes with no history of ankle injury. BESS was used to measure postural control by estimating the errors committed in standing between the two group of athletes. Independent sample t test was used to compare the means between two groups and the level of significance is set at level of 0.05. RESULTS: The athletes with history of ankle injury scored more number of errors in BESS with high mean value of (15.10 +/- 6.52 errors) than the control group (5.63 / 3.81 errors which was significant at p=0.01 level. CONCLUSION: Postural control impairment was identified among athletes with history of ankle injury when compared with control group. PMID- 23099966 TI - Multiparameter immunophenotyping by flow cytometry as a diagnostic tool in multiple myeloma and monoclonal gammopathy of undetermined significance. AB - BACKGROUND: Immunophenotyping by multiparameter flow cytometry (MFC) provides relevant information about prognosis and minimal residual disease detection in multiple myeloma (MM) and might be used to distinguish MM from monoclonal gammopathies of undetermined significance (MGUS). MATERIALS AND METHODS: We evaluated a possible usage of MFC to predict the differential diagnosis between MM and MGUS. One hundred consecutive patients were studied at diagnosis and underwent conventional diagnostic procedures. We carried out a double-blind study. Immunophenotyping was performed on samples from myeloaspirates before establishing diagnosis, while the final clinical diagnosis was established independently from MFC results. A five- or six-color method was carried out by means of monoclonal antibody combinations able to identify abnormal plasma cells (CD19-) and the most relevant immunophenotypic aberrations (loss of CD27; overexpression of CD117, CD56, CD28; asynchronous expression of CD20). MFC was applied following the indications of the European Myeloma Network. When abnormal plasma cells were /= 3.1%, MGUS was predicted. RESULTS: MFC results predicted 63 cases of MM and 37 cases of MGUS. At the end of our study, 61 cases of MM and 39 cases of MGUS were diagnosed. Therefore, 4% of patients were misdiagnosed by MFC parameters alone, with sensitivity and specificity of 0.983 and 0.92, respectively. CONCLUSIONS: Only a small proportion of patients with MM and MGUS were misdiagnosed by MFC alone and a possible systematic application of MFC in all patient with MM and MGUS at diagnosis might be proposed. Novel additional criteria could be necessary to improve the diagnostic impact of MFC in monoclonal gammopathies. PMID- 23099967 TI - Pulmonary embolism following histoacryl glue embolization for a large thigh arteriovenous malformation. AB - Arteriovenous malformation (AVM) are commonly congenital in origin. We hereby describe the case of a 24-year-old male who was diagnosed of left thigh intramuscular AVM at the time of 14 years old. The computerized tomography (CT) scan confirmed a large deep seated intramuscular AVM with the size of 20 x 15 cm, with dilated and distended feeding vessel from profunda femoris artery (PFA) and superficial femoral artery (SFA). He also had another AVM near the left supracondylar region adherent to the sciatic nerve. The main AVM lesion was earlier treated with surgical resection and it remained for asymptomatic for next seven years. Following this, the patient presented again to the clinic with recurring swelling, pain and occasional paraesthesia on the same site. He was then managed with a series of embolization (total of 6 attempts) with histoacryl glue. These attempts of embolization were successful. The interesting case of pulmonary embolism due histoacryl glue following embolization of an AVM is described. PMID- 23099968 TI - Forked rib: an autopsy case report and discussion on its clinical implications. AB - Congenital anomalies of the ribs are relatively uncommon. We report a case of forked rib which was observed during the routine autopsy examination of a male child of aged 7 yrs at our institution. We observed that the right side fourth rib was showing bifurcation at its anterior end. We discuss the clinical implication of this variant along with relevant review of literature. The clinicians, radiologists and surgeons should be familiar with this normal variant to avoid mistaking for an abnormality. PMID- 23099969 TI - Leptospirosis complicating with acute large bowel gangrene: a case report. AB - Leptospirosis is a zoonosis with worldwide distribution. It is often referred to as swineherd's disease, swamp fever or mud fever. In recent years there is increase incidence in leptospirosis in human. The incidence varies from sporadic in temperate zones to endemic in the tropical countries. Leptospirosis generally present with features of bacterial infection in acute phase following with multi organs complications. Acute bowel ischaemia with perforation following leptospirosis is a rare presentation . To the best of our knowledge, this is the first case report of such condition. The surgical management of this rare incidence will be discussed. PMID- 23099970 TI - Hepatic resection for giant haemangioma in a patient with a contemporaneous adult polycystic liver disease. AB - Hepatic resection for giant haemangioma in a patient with a contemporaneous adult polycystic liver disease. According to Gigot classification, and to the characteristics of haemangioma surgery in these patients can be considered safe. We report the case of a 55 year-old man affected by an adult polycystic liver disease (PCLD) and a contemporaneous symptomatic haemangioma of the III segment. At the preoperative imaging scans, APCLD was classified in a type II grading according to Gigot classification. The patient underwent surgery: a wedge resection of the III segment with the exportation of the haemangioma and a fenestration of a large cyst placed in the VIII segment were performed. Post operative course was regular and the patient was discharged uneventfully in post operative 9th day, with a total regress of the initial symptoms. APCLD and haemangioma are two benign conditions that do not require surgery except if they cause important symptoms, such as pain. The good clinical conditions of the patient, the moderate gravity of the APCLD and the particular exofitic localisation of the cavernous haemangioma gave us the possibility to make a safe surgery for the patient. To the best of our knowledge, this is the first case reported in literature in which a liver resection for haemangioma in patient with APCLD was performed. In conclusion, liver resection for haemangioma is not contraindicated, mainly if it is symptomatic, even in the contemporaneous presence of an APCLD. PMID- 23099971 TI - [Hyperglycaemia and Acute Coronary Syndrome]. AB - Hyperglycaemia in patients with Acute Coronary Syndrome (ACS)is common, and is an independent predictor of mortality and morbidity in patients both with and without diabetes mellitus. Hyperglycaemia may be a marker of pre-existing diabetes or glucose intolerance or may also represent a transient stress response mediated through the autonomic nervous system with release of adrenal corticosteroids and catecholamines. Several evidences suggest that an intensive control of hyperglycaemia results in a significant improvement of the adverse outcomes in the short and long term. In fact, an intensive metabolic treatment can counteract the negative effects of hyperglycaemia. However, the main difficulty to intensive glucose control in patients with ACS remains hypoglycaemia that is associated with an increased risk of mortality and myocardial re-infarction. No definitive data are available about the beneficial effects of insulin intensive treatment. Therefore, randomized multicenter clinical trials will be needed to definitively establish whether intensive glucose control will reduce the associated increased mortality rate and higher rates of complications in hospitalized ACS patients with hyperglycaemia. PMID- 23099972 TI - Changes in vital signs during cataract phacoemulsification by using peribulbar or topical anesthesia. AB - AIMS: To compare changes in vital signs and pain level experienced by patients during phacoemulsification and foldable intraocular lens (IOL) implantation using either topical/intracameral or peribulbar anesthesia. MATERIALS AND METHODS: In this prospective, parallel-group clinical study 46 consecutive patients (mean age 72.9 +/- 8.1 years) undergoing cataract surgery were randomized to receive topical/intracameral (group1) or peribulbar (group 2) anesthesia. Systolic, diastolic and mean blood pressures, hearth rate, oxygen saturation and pain level were recorded before and during the anesthesiological procedure and thereafter during each surgical step. RESULTS: Diastolic blood pressure during phacoemulsification and after surgery as well as mean arterial pressure after surgery were significantly higher in group 1 compared to group 2. Variability of systolic and mean arterial pressures across the study phases was significantly higher in group 2 compared to group 1. A significantly higher percentage of patients in group 2 compared to group 1 (35.3% vs 3.4%, p=0.007) showed a heart rate reduction greater than 10% from the anesthesiological to the following surgical phase. Higher incidence of moderate pain in group 2 was reported during the anesthesiological procedure (64.7% vs 3.4%, p<0.00001) while higher incidence of moderate pain was reported in group 1 during phacoemulsification (31% vs 5.9%, p=0.047) and IOL implantation (21.7% vs 2.2%, p=0.02). DISCUSSION: Our short study seems to recommend the use of topical/ intracameral anesthesia for cataract surgery due to more stable heart rate, diastolic and mean blood pressures. However, further studies enrolling a higher amount of patients are necessary to confirm our preliminary data. PMID- 23099973 TI - Pneumotrabeculoplasty as treatment for primary open angle glaucoma: critical review of the literature. AB - PURPOSE: To evaluate with criticism the available evidence shown in the literature about the efficacy of pneumotrabeculoplasty (PNT) as a treatment for primary open angle glaucoma. MATERIALS AND METHODS: PNT is a recent non-surgical and noninvasive technique to safely reduce the intraocular pressure (IOP) in eyes suffering from ocular hypertension or primary open angle glaucoma. The technique consists in the application on the ocular surface of a disposable suction ring that induces a temporary trabecular meshwork stretching, increasing outflow of aqueous humor in the Schlemm's canal. In our study, we compared the results on the efficacy and safety of this treatment published to date in the literature. RESULTS: During follow-up, Authors have observed significant reductions in IOP in about 70% of treated eyes. The first treatment consists in 3 applications at day 0, 7 and 90, repeatable every 90 days. Immediately after suction ring application there is a significant elevation of IOP, however, of short duration and without demonstrable visual field worsening. Side effects observed are of little clinical significance and spontaneously resolving in a short time. CONCLUSIONS: The PNT is a safe and effective technique to reduce IOP in patients with ocular hypertension or open-angle glaucoma. It is repeatable, but can not replace drug treatment in patients already receiving topical therapy for glaucoma; however, it has proven effectiveness in maintaining an IOP target over time if accompanied with only a single topical drug, favoring a reduction of antiglaucoma drugs in polytherapy and increasing the compliance with treatment. PMID- 23099974 TI - Gender-related differences concerning anger expression and interpersonal relationships in a sample of overweight/obese subjects. AB - OBJECTIVES: Obesity and overweight are relevant public health issues. They are frequently associated with increased disability, enhanced morbidity and mortality and are often comorbid with several psychological/psychiatric conditions. The aim of the present study was to explore gender-related differences concerning anger expression and interpersonal relationships in a sample of overweight/obese subjects. MATERIALS AND METHODS: The convenience sample consisted of 40 overweight/obese subjects (18 women, 22 men) who were administered self-report questionnaires to assess eating disorders (EDI-2), anger levels (STAXI) and self/other perception as a measure of interpersonal relationships (9AP). RESULTS: Women had higher scores on the EDI-2 subscales of Bulimia (7.22 vs. 2.20: z=7.61; p<.001), Body Dissatisfaction (15.56 vs. 12.14: z=1.88; p=.03), Interoceptive Awareness (9.89 vs. 5.28: z=4.06; p<.001), Ineffectiveness (11.00 vs 5.22: z=4.91; p <.001) and Perfectionism (6.33 vs. 3.26: z=4.13; p<.001) compared to norms. The overweight/obese men departed from the norms on fewer subscales. Both women and men tended to turn feelings of anger in toward themselves, suppressing their anger. Also, women obtained lower scores for Self Empathy (29.06 vs. 40.15: z = - 2.30; p = .01) and Other Empathy (16.44 vs. 27.10: z =- 2.00; p= .02) whereas overweight/ obese men obtained lower scores for Other Empathy (20.77 vs. 28.47: z=-2.00; p=.02). CONCLUSIONS: Overweight/obese subjects have a tendency to turn feelings of anger inward on to themselves together with impaired interpersonal relationships, especially in women. An adequate clinical assessment in all obese individuals trying to identify the contribution of psychological factors to the perceived distress is critical. PMID- 23099975 TI - Brachial venous pressure measurement for diagnosis of pulmonary embolism. AB - BACKGROUND: Imaging methods for diagnosis of pulmonary embolism (PE) are not available at small medical or rural centres as well as during night time. Herein, we evaluated the diagnostic value of brachial venous pressure measurement in the diagnosis of PE in patients with deep vein thrombosis. MATERIALS AND METHODS: One hundred and fifty consecutive patients with deep vein thrombosis and suspected PE were prospectively evaluated by measuring brachial vein pressure by CW Doppler. Diagnosis of PE was made by computed tomography angiography and pulmonary angiography. RESULTS: Seventy-one patients (47.3%) had PE. A significant correlation was observed between brachial venous pressure and systolic pulmonary artery pressure (sPAP) estimated at echocardiography (rho 0.922, p<0.0001) as well as with invasively measured sPAP (rho 0.965, p<0.0001). Brachial venous pressure was significantly higher in the PE group (38.5 vs. 13.9 mmHg, p<0.0001) and was associated with increased extent of PE (p<0.0001). A cut-off of brachial venous pressure >15 mmHg had a sensitivity of 100%, a specificity of 77% and a negative likelihood ratio of 0.0%. A cut-off of brachial venous pressure > 19 mmHg had a sensitivity of 100% and specificity of 100% as no patient with PE had a brachial venous pressure below 20 mmHg, and no patients without PE had a venous pressure above this value. CONCLUSIONS: Brachial venous pressure may assist in the diagnosis of PE at bed-side in patients with deep vein thrombosis. Further studies are needed to confirm the validity and reliability of this method. PMID- 23099976 TI - Arsenic and peripheral blood count in workers exposed to urban stressors. AB - OBJECTIVES: Previous studies have shown that arsenic at high doses can alter the hematopoietic system. The purpose of the present study is to see whether the same problems may be caused by chronic exposure to low doses. MATERIALS AND METHODS: A sample of 349 policemen of a big urban city was divided into 3 groups according to levels of urinary arsenic. The subjects were further divided according to gender, smoking habits, and work task. We calculated indices of correlation (r) and multiple linear regression (beta), between urinary arsenic, RBC, WBC, HB, HT, MCV, MCH, MCHC, platelets, reticulocytes and leukocyte formula (percentage of lymphocytes, monocytes, neutrophils, eosinophils and basophils). It was also calculated Student's t and chi-square test between the various groups to check for any differences. RESULTS: We found several statistically significant indices of correlation and regression (p(two-tailed) <0.05) between urinary arsenic, red blood cells, white blood cells, hemoglobin, hematocrit, reticulocytes, and all the cell lines of the white series. CONCLUSIONS: Chronic exposure to low doses of arsenic seems to cause decrease in red blood cells, hematocrit and hemoglobin. However, this response is dependent on the amount of absorbed dose, according to an ormetic mechanism. With regard to the white series, arsenic seems to provoke an inflammatory response; the scarcity of literature" available, and the great variety of results, however, not allow us to definitely characterize the damage caused by this metal on white series. PMID- 23099977 TI - Surgical strategies in patients with medullary thyroid carcinoma. AB - OBJECTIVES: Aim of the study was to identify, in 59 operated patients affected by medullary thyroid carcinoma (MTC), the recurrence rate, survival, mortality and incidences of surgically derived hypoparathyroidism and recurrent laryngeal nerve injury (RLNI). MATERIALS AND METHODS: Based on pre-surgical diagnosis of the 59 patients included in the study, 35 underwent total thyroidectomy with central neck dissection (Group A), 14 total thyroidectomy, central neck dissection and monolateral functional neck dissection (Group B) and 10 total thyroidectomy central neck dissection, bilateral functional neck dissection (Group C). Overall survival, recurrences, incidence of hypoparathyroidism and RLNI were evaluated. RESULTS: The survival and recurrences were not statistically different among the three Groups. In Group B there was major probability of re-operation (p=0.042). The mortality rate was clearly major in Group C (p=0.003) due to the stage of pathology. Group C showed a high number of hypoparatiroidism compared to Group B, and B compared to A. In Group A there was only one unexpected RLNI; in 5 cases, 3 in Group B and 2 in Group C, there were a necessity laringeal section due to nerve tumor involvement. CONCLUSIONS: From our data it appears clearly that disease outcome following the different surgical approaches is mainly determinated by the stage of the disease at diagnosis. However, the finding that patients in Group A and B showed a high rate of local-regional recurrences may suggest that homolateral lymphadenectomy in Group A patients and bilateral lymphadenectomy in Group B patients should be always performed. PMID- 23099978 TI - Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines. AB - OBJECTIVES: Anaplastic thyroid carcinomas (ATC) are highly aggressive tumours unresponsive to any available radio- or chemotherapeutic protocol, with a median survival rate of 4-5 months from the time of diagnosis. We previously demonstrated that ATC are characterized by increased expression of the kinases Aurora-A, -B and -C, involved in the regulation of multiple steps of the mitotic phase. In this study, the in vitro effects of SNS-314 mesylate, a pan-inhibitor of the Aurora kinases, on growth and tumorigenicity of ATC cells were evaluated. MATERIALS AND METHODS: The effects of SNS-314 mesylate were assessed on the ATC derived cell lines CAL-62, 8305C, 8505C and BHT-101 by means of cell proliferation assay, immunofluorescence, cytofluorimetry, time lapse microscopy, and colony formation in soft agar. RESULTS: Treatment of the different ATC cells with SNS-314 mesylate inhibited proliferation in a time- and dose-dependent manner, with IC(50) comprised between 2.6 nM and 26.6 nM. CAL-62 cells exposed for 24 h to SNS-314 mesylate 100 nM evidenced a significant augmentation of the apoptotic index. Time-lapse video-microscopy of CAL-62 cells showed that SNS-314 mesylate prevents the completion of mitosis leading to polyploidy. Western blot experiments demonstrated that the auto-phosphorylation of the Aurora kinases as well as histone H3 phosphorylation in CAL-62 treated cells was inhibited. Finally, the drug inhibited colony formation in soft agar of all cell lines. CONCLUSIONS: Our results demonstrated that SNS-314 mesylate is capable to efficiently reduce cell growth and tumorigenicity of different ATC derived cell lines suggesting its potential therapeutic value for ATC treatment. PMID- 23099979 TI - A simple technique to improve residual skin plasticity for scrotal reconstruction in Fournier's Gangrene. AB - A 50 years-old man developed 24 hours after hemorrhoidectomy a severe Fournier's gangrene of the scrotum necessitating surgical exeresis of more than 2/3 of scrotal skin followed by hyperbaric oxygen therapy. After the resolution of the septic phase, scrotum reconstruction was obtained by tissue expansion to avoid more invasive advanced reconstructive techniques. The procedure consisted of an enzymatic and mechanical debridement and progressive skin expansion by package of gauzes of increasing volume covered with a collagenasecloramphenicol ointment (Iruxol(r)- Smith and Nephew, Italy), then closing the wound edges by temporary stitches to put under tension the skin. The reestablishment of the natural elasticity of the scrotal skin was obtained in ten days and at the final closure of the wound edges an acceptable optimal aesthetic result was achieved. PMID- 23099980 TI - [Efficacy of aripiprazole on cognitive and behavioral changes in a young woman with systemic lupus erythematosus]. AB - This paper describes the use of aripiprazole for the management of cognitive deficits and behavioral disorders in a young female patient suffering from systemic lupus erythematosus (SLE). Cognitive impairment, although often transient, is reported up to 75% of patients with SLE. The behavioral changes and, more generally, clear psychotic episodes have an incidence of 5% but they lead to considerable difficulties in clinical and therapeutic management. In cases with psychiatric manifestations of SLE, it is often necessary to introduce psychopharmacological therapy. The choice of aripiprazole has been made especially in light of low liability to cause weight gain and metabolic side effects. In fact aripiprazole is characterized by an original mechanism of action: it combines partial agonist activity on D(2), D(3) and 5-HT(1A) receptor with antagonistic activity on 5-HT(2A) and D(2). Aripiprazole has demonstrated efficacy in the management of behavioral disturbances and has improved some of impaired cognitive functions. Aripiprazole, therefore, could be a great tool in young patients with SLE. PMID- 23099981 TI - Later diagnosed with a neuroendocrine tumor, case report of a 60-year-old. AB - Neuroendocrine tumours of the colon and rectum are infrequent. Clinical manifestations are not different from standard adenocarcinoma. Symptoms are non specific; the most common are abdominal pain, nausea and vomiting, weight loss and gastrointestinal blood loss. We report an advanced case of transverse colon neuroendocrine carcinoma with multiple metastasis. When these tumours are diagnosed, they have distance disease related to a poor prognosis for the patient. Surgery is the treatment that can offer a greater chance of survival to these patients. PMID- 23099982 TI - Isolated pancreatic tuberculosis: a diagnostic challenge. AB - Abdominal tuberculosis is quite commonly found in miliary tuberculosis, especially in countries where TB is endemic, however the abdominal localization of tuberculosis in absence of disseminated disease is a rare condition and the involvement of the pancreas alone is extremely rare. Epidemiology of TB is changing in the latest years, often this illness is found in non-endemic regions and physicians are asked to interpret what happen when an old disease meets new diagnostic technologies. We describe the case of a young male admitted in our hospital for abdominal pain. Echotomography, CT scan and MRI showed a pancreatic mass suspected to be cancer and susceptible to surgical treatment, Endoscopic Ultrasound guided fine needle aspiration (FNA) showed isolated pancreatic tuberculosis. PMID- 23099983 TI - Adrenal pseudocyst as a cause of postpartum abdominal pain. AB - Among adrenal masses only 0.06% to 0.18% are cysts and among them, pseudocysts are the second (39%) most common lesions. Due to the increased use of imaging studies their incidence seems to have increased. Most of these lesions are incidentally found during radiologic investigation or at the time of autopsy, and only rarely they are detected in pregnant women. The latter scenario warrants emergency surgery, due to the risk of rupture. We present a case of a 39-years old woman presenting with unrelenting left flank pain due to a large adrenal pseudocyst soon after her first delivery. Four months after, she presented to our surgical division for persistent pain and anemia so underwent an extensive work up that showed a large pseudocystic mass (8 x 8 cm ) of the left adrenal gland. Once the neoplastic and parasitic etiology of the lesion were excluded, she underwent uneventful laparoscopic adrenalectomy. She was discharged home three days postoperatively. This case is the 13th case in the English literature and at the same time is the first case of adrenal pseudocyst occurred four months after delivery. PMID- 23099984 TI - The heart: a symbol from ancient times to current biomedics. AB - The heart is an essential and central organ in human beings. The heart is a muscular pump which contracts approximately a hundred thousand times a day for a life time, and in the last few decades it has been scientifically documented that it also produces hormones. The symbolic role of the heart has been established from time immemorial; more recently, and intriguingly, modern biomedical evidence has proved that historical knowledge and common language expressions referring to the heart are, in many cases, correct. In this perspective it is interesting to consider that already in the remote past the heart was "at the heart" of the attention of great western and eastern civilizations. From the brief panorama presented in this paper, connections between popular historical knowledge and current biomedical evidence emerge, proving the relevance of the symbolic role of the heart and of its perceived functions from pre-Christian to contemporary times, and documenting how the heart continues to remain strategically central, and epistemologically and linguistically crucial in the physical, psychological and social context of human life. PMID- 23099985 TI - ["New" virus and "old" risks. Reflections on H1N1 pandemic in the newspapers in Italy, France and UK]. AB - AIMS: Social scientist Ulrick Beck links the idea of "risk society" with images of chronic uncertainties. The aim of this paper is to study how health risks are communicated in this social context. MATERIALS AND METHODS: In order to do that we explored a selection of articles published by two of the most popular newspapers in Italy, Corriere della Sera e La Repubblica, the UK, The Times e The Guardian, and France, Le Monde e Le Figaro, during 2009. RESULTS. This study allowed us to identify a transnational interest towards H1N1 pandemic that is characterized by picks of attention followed by periods of general indifference, and an alarmist frame. In alternative to this cross-country representation of H1N1 pandemic, however, we also identified three specific frames, one per each country. According to our analysis these frames can only be understood in close relation to citizens' trust towards the policy of science and the institutions, as well as the local and cultural traditions of science communication. CONCLUSIONS: Having said that, we are convinced that there is no perfect receipt that transcends the local context can be implemented to communicate health risks such as the ones associated H1N1. Nevertheless, our data indicate that there are good examples of health risks communication actually happening in Europe balancing between the risks of generating alarmism and denying the uncertainties of science become that are by now more and more evident. PMID- 23099986 TI - [Hyponatremia and physical exercise]. AB - Exercise Associated Hyponatremia (EAH) is an occurrence of endurance sports that can cause severe clinical manifestations such as cerebral edema or respiratory failure. EAH is a dilutional hyponatremia, variant of SIADH, characterized by a plasma concentration of sodium lower than 135 mEq/l. Female gender and the duration of the competitions are associated with higher risk of hyponatremia. The incidence of hyponatremia, in fact, increases with duration, especially 4-8 hours after the start of the race. Women seem to be at greater risk than men. The pathophysiological mechanisms include increased loss of sodium through sweating and excessive intake of hypotonic fluids during and after the sporting event. In the genesis of EAH seems to have a decisive role the inadequate secretion of AVP by non osmotic stimuli, including IL-6. Indications for the prevention of hyponatremia include education of athletes for adequate consumption of fluids and monitoring of changes in body weight. Following the identification of electrolyte imbalance, the treatment requires a water restriction and infusion of hypertonic solutions 3%, especially in cases of severe hyponatremia. The effectiveness of the V2 receptor antagonists needs further investigation. PMID- 23099987 TI - [Regenerative medicine: orthopaedical applications and medico legal questions]. AB - Over the last decades, the increase in the global population's mean age has implied a corresponding increase in degenerative disease affecting various anatomical areas and tissues, including bones and cartilages, thus provoking a rising number of disabilities and a wider usage of drugs, mostly anti inflammatory and cortisone. New developments in technologic and biomedical fields gave birth to new subjects, such as tissue engineering, cell therapy, gene therapy that, by and large, create a knowledge network falling under the concept of Regenerative Medicine. This science is essentially based on the usage of stem cells that can replicate and renovate themselves originating, if adequately stimulated, a number of cell types. Inter alia, in orthopaedic field a particular type of adult stem cells is used, the mesenchymal stem cells (MSCs). If combined with synthetic material produced in laboratories, the usage of these cells has provided inspiration for new study interests; today, it can be applied in various degenerative and post-traumatic pathologies, with great therapeutic benefits for the patient. Actually, many studies write about an improvement in patients' life quality. In this sense appear significant reflections on legal medicine, both in accidents and insurance, of this innovative therapeutic alternative and is hopefully an equally valid process of improvement of regulatory and case law. PMID- 23099988 TI - [Medical legal issues associated with the evaluation of herniated discs in seafarers to merchant ships]. AB - "Seafarer" means person employed with any job on board a ship offshore, whether publicly or privately, excluding ships of war. Day by day a seafarer is forced to confront a reality in constant motion and live in environments that require awkward movements, and restricting the normal mobility of the person. In order to verify the frequency of herniated discs in this particular category of workers, given the recent introduction of INAIL tabulated diseases, a study was conducted on a sample of seafarers. Data analysis showed that 48.3% of the seafarers of the sample has herniated lumbar disc, and 34.5% of these duties in the deck, and 65.5% of the machine. The study of sample, varied as to age and task being performed, supports the assertion that the individual risk factors, especially age and obesity, are not strongly implicated in the genesis of disk herniation suffered by seafarers while the work factors (vibrations) play a more significant role in the onset of this disease. This consideration is part of a context, that of legal medical evaluation and in particular the causal relationship, which currently seems rather lacking in terms of literature and scientific production. PMID- 23099989 TI - Stabilization and enhanced reactivity of actinorhodin polyketide synthase minimal complex in polymer-nucleotide coacervate droplets. AB - Compartmentalization of the minimal complex of actinorhodin polyketide synthase in coacervate liquid droplets produces enhanced yields of shunt polyketides under conditions of low and high ionic strength. PMID- 23099990 TI - Neck narrowing in resurfacing hip arthroplasty: a vascular insult? AB - INTRODUCTION: Recent reports show increased failure rates in hip resurfacings that display >10 % neck narrowing. The etiology of neck narrowing remains unknown. METHODS: We assessed 80 hip resurfacings at mean 3.5 years follow-up. RESULTS: The overall rate of significant narrowing was 11.25 %. Neck narrowing occurred in 4 % of patients using an anterolateral approach and 23.3 % using a posterior approach (P = 0.019). Logistic regression showed that both surgical approach and cup inclination angle were the most important risk factors for the development of narrowing. The odds of the presence of narrowing increased for every degree increase in cup abduction angle (P = 0.021). There was no significant association with age, sex, pre-operative diagnosis, pre- and post operative SF-36 scores, neck shaft angle, femoral or acetabular component sizes. CONCLUSION: We postulate that neck narrowing is a result of damage to the medial circumflex femoral vessel when resurfacing through a posterior approach. PMID- 23099991 TI - Aggressive giant cell granuloma of the jaws treated with interferon alpha: a report of two cases. AB - BACKGROUND: Giant cell granulomas (GCGs) are benign tumours of the jaws of unknown aetiology. Aggressive lesions are difficult to manage and demonstrate a tendency to recur after surgical curettage. In the early 1980s, interferon alpha 2a was found to inhibit angiogenesis through a series of laboratory experiments and was subsequently used to treat a child with pulmonary haemangiomatosis. It has been hypothesised that GCGs are proliferative vascular lesions and would, therefor, be expected to respond to antiangiogenic therapy. The purpose of this study is to report a treatment protocol consisting of enucleation, followed by subcutaneous interferon alpha. METHODS: Patients with a biopsy-confirmed giant cell lesion satisfying criteria for "aggressive" giant cell tumours were included. All lesions were enucleated, and the patients commenced interferon alpha-2a (3,000,000 units/m(2)) 48-72 h post-operatively. RESULTS: Two patients satisfied the criteria for aggressive giant cell lesions. All tumours were enucleated. There were no post-operative complications, and all patients tolerated the interferon therapy well. To date, there has been no evidence of tumour recurrence. The follow-up periods were 144 and 81 months, respectively. CONCLUSION: Antiangiogenic therapy, in combination with curettage, has proven to be a useful strategy for the management of these tumours. The use of interferon alpha-2a, following enucleation of these lesions, resulted in complete remission of all lesions, and decreased operative morbidity compared with conventional treatment. PMID- 23099993 TI - Potential interactions of complementary and alternative medicine with cancer therapy in outpatients with gynecological cancer in a comprehensive cancer center. AB - PURPOSE: About 40-50 % of cancer patients use complementary and alternative medicine (CAM). Women, and especially those with gynecological cancers, are more active in this field than men. The goal of our study was to estimate the likelihood of CAM use and the likelihood of interactions of CAM with cancer therapy in the setting of a gynecological outpatient clinic at a German Comprehensive Cancer Center (CCC). METHODS: One hundred consecutive gynecological outdoor patients of the CCC in Frankfurt am Main in Germany were interviewed with a standardized questionnaire on CAM use. An investigation on potential interactions was done by matching a scientific database systematically. RESULTS: Sixty-nine of the interviewed 100 women received chemotherapy, 23 endocrine therapy and 41 monoclonal antibodies. In total, 64 % used CAM, 48 % used at least one substance-bound CAM. In 17 out of those 48 cases (35 %), interactions were unlikely, whereas they were probable in 14 patients (29 %). Thus, a third of all patients in this study were in danger of interactions. More than half of all CAM users and three quarters of users of substance-bound CAM are at risk of interactions. This number is independent of whether the patient is taking chemotherapy, endocrine therapy or antibodies. CONCLUSIONS: The frequency of CAM use we found is in line with international data from CCCs in the USA. To our knowledge, this is the first study publishing data on the frequency of potential interactions. Thus, an initiative to protect women from the dangers of uncontrolled CAM use is urgently needed. In the discussion, we propose a concept of how to achieve this aim. PMID- 23099992 TI - Site selection in global clinical trials in patients hospitalized for heart failure: perceived problems and potential solutions. AB - There are over 1 million hospitalizations for heart failure (HF) annually in the United States alone, and a similar number has been reported in Europe. Recent clinical trials investigating novel therapies in patients with hospitalized HF (HHF) have been negative, and the post-discharge event rate remains unacceptably high. The lack of success with HHF trials stem from problems with understanding the study drug, matching the drug to the appropriate HF subgroup, and study execution. Related to the concept of study execution is the importance of including appropriate study sites in HHF trials. Often overlooked issues include consideration of the geographic region and the number of patients enrolled at each study center. Marked differences in baseline patient co-morbidities, serum biomarkers, treatment utilization and outcomes have been demonstrated across geographic regions. Furthermore, patients from sites with low recruitment may have worse outcomes compared to sites with higher enrollment patterns. Consequently, sites with poor trial enrollment may influence key patient end points and likely do not justify the costs of site training and maintenance. Accordingly, there is an unmet need to develop strategies to identify the right study sites that have acceptable patient quantity and quality. Potential approaches include, but are not limited to, establishing a pre-trial registry, developing site performance metrics, identifying a local regionally involved leader and bolstering recruitment incentives. This manuscript summarizes the roundtable discussion hosted by the Food and Drug Administration between members of academia, the National Institutes of Health, industry partners, contract research organizations and academic research organizations on the importance of selecting optimal sites for successful trials in HHF. PMID- 23099995 TI - Endothelial-astrocytic interactions in acute liver failure. AB - Brain edema and the subsequent increase in intracranial pressure are major neurological complications of acute liver failure (ALF), and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in ALF. Recent studies, however, have suggested the co-existence of cytotoxic and vasogenic mechanisms in the brain edema associated with ALF. This review 1) summarizes the nature of the brain edema in humans and experimental animals with ALF; 2) reviews in vitro studies supporting the presence of cytotoxic brain edema (cell swelling in cultured astrocytes); and 3) documents the role of brain endothelial cells in the development of astrocyte swelling/brain edema in ALF. PMID- 23099994 TI - A novel predictive strategy by immunohistochemical analysis of four EGFR ligands in metastatic colorectal cancer treated with anti-EGFR antibodies. AB - PURPOSE: Although KRAS mutation has been identified as a negative predictive biomarker of anti-EGFR antibodies in metastatic colorectal cancer (mCRC), the efficacy in mCRC patients with KRAS wild-type status remains limited. Anti-EGFR antibodies work by blocking ligand binding, but the significance of EGFR ligands in mCRC has not been completely described. This study was conducted to identify the correlation between all seven EGFR ligands and clinical outcomes in mCRC treated with anti-EGFR antibodies. Furthermore, we determined an appropriate predictive strategy for anti-EGFR antibodies using these EGFR ligands. METHODS: Among 36 mCRC patients who had been treated with cetuximab or panitumumab, we identified 26 mCRC patients with wild-type KRAS status treated properly as the second and further lines and analyzed the relationship between immunoreactivity to seven EGFR ligands and clinical outcomes. RESULTS: Good clinical outcomes were associated with immunoreactivity against amphiregulin (AR), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor-alpha (TGF-alpha), and epiregulin (EREG). Further, patients with immunoreactivity to greater than two of these four ligands (AR, HB-EGF, TGF-alpha, and EREG) had significantly higher response rate (53.3 vs. 0.0 %, p = 0.004) and disease control rate (93.3 vs. 9.0 %, p = 0.00002) and longer progression-free survival (median PFS: 231 vs. 79 days, p = 0.000008), when compared with patients with immunoreactivity against zero or one ligand. CONCLUSIONS: Immunohistochemical analysis of four EGFR ligands (AR, HB-EGF, TGF-alpha, and EREG) might be a novel predictive biomarker and may help optimize patient selection for cetuximab and panitumumab therapy in patients with mCRC. PMID- 23099996 TI - Changes in cerebral oxidative metabolism in patients with acute liver failure. AB - Acute liver failure patients with a persistence of hyperammonemia are at an increased risk of intracranial hypertension due to development of brain oedema. In vitro studies of brain tissue and cell cultures that indicates that exposure to ammonium inhibits enzymatic activity in the tricarboxylic acid cycle, induces substrate depletion through marked glutamate utilization for glutamine synthesis and leads to mitochondrial dysfunction. In patients with acute liver failure cerebral microdialysis studies show a linear correlation between the lactate to pyruvate ratio and the glutamine concentration, as well as to some of the adenosine triphosphate degradation products. However, clinical observations of cerebral exchange rates of oxygen, glucose, lactate and amino acids challenge the interpretation of these findings. In this review the conflicting data of cerebral metabolism during acute liver failure is discussed. PMID- 23099997 TI - Patients' access to their health information: a meaningful-use mandate. AB - This department highlights topics in nursing outcomes, research, and evidence based practice relevant to nurse administrators. In this article, the authors describe patient access to personal health information as it relates to the meaningful-use requirement, technologies that have been used to enhance patient engagement, and the nursing leadership implications. PMID- 23099998 TI - Trust: a core value of healthy organizations. AB - In this month's column, the Director of the Magnet Recognition Program provides an overview of the concept of smart trust. After hearing Stephen M. R. Covey speak at the 2012 national Magnet Conference, Mr Luzinski became intrigued by this concept. The 5 smart actions identified as common among highly successful leaders and organizations are reviewed. The application of the smart actions by nurse leaders in Magnet-recognized organizations may lead to creating greater prosperity, energy, and joy in a low-trust world. PMID- 23099999 TI - Leadership imperative: creating and sustaining healthy workplace environments. AB - Healthy workplace practice environments are essential to keeping patients safe. The American Organization of Nurse Executives (AONE) identifies the creation and maintenance of healthful practice environments as an essential role for nurse leaders. In this article, we profile exemplars of nurse leaders who have integrated elements of the AONE Principles and Elements of a Healthful Practice Work Environment in their executive practices. PMID- 23100000 TI - Exploring the charge nurse role: holding the frontline. AB - This study describes the experience of being a charge nurse in acute-care practice. The charge nurse role has become instrumental in achieving safe and effective outcomes. The role remains poorly defined with little focus on charge nurse development. This qualitative study used a descriptive exploratory method. Semistructured interviews were conducted with 20 charge nurses from 4 acute-care facilities. Eight themes emerged to describe the experience of being a charge nurse in acute-care practice. Findings can be used by nursing executives to emphasize the importance of this role to the organization and support leadership development at the charge nurse level. PMID- 23100001 TI - Authentic leadership: becoming and remaining an authentic nurse leader. AB - This article explores how chief nurse executives became and remained authentic leaders. Using narrative inquiry, this qualitative study focused on the life stories of participants. Results demonstrate the importance of reframing, reflection in alignment with values, and the courage needed as nurse leaders progress to authenticity. PMID- 23100002 TI - Estimating design impact on waste reduction: examining decentralized nursing. AB - The objective of this study was to understand the impact that decentralization of nursing support spaces may have on the total distances nurses walk and hence the magnitude of time that can be diverted to productive use. Reducing nurse walking has attracted attention from multiple perspectives-human factor, system performance, lean process, care quality, and safety. A simulation-based experimental study was designed that incorporated task frequency data from a nationwide sample of 700 RNs. The simulation runs were conducted on a 30-bed medical-surgical unit, over 12-hour day shifts, in which physical locations of 8 nursing support spaces were systematically manipulated. Findings suggest that total walking time can be reduced by as much as 67.9%, depending on the level of decentralization. Care quality and efficiency issues can be significantly addressed through appropriate levels of decentralization. PMID- 23100003 TI - The nursing practice environment in rural hospitals: Practice Environment Scale of the Nursing Work Index assessment. AB - Acute-care rural hospitals comprise 41% of US community hospitals, yet little is known about the quality of nursing practice environments (PEs) in these settings. Thus, there is little evidence for rural nurse leaders to access in organizing nursing practice to support quality staff and patient outcomes. The Practice Environment Scale of the Nursing Work Index (PES-NWI) has not been tested with a rural nurse sample and the literature does not provide reference scores for this group. This article presents findings to support the PES-NWI as a measure to describe rural acute-care nurse PEs and provides reference values for nurse leaders to use to implement evidence based nursing practice. PMID- 23100004 TI - Creating an innovative tool to measure Magnet(r) readiness. AB - Magnet designation has become a highly sought-after credential for hospitals across the United States and internationally who want to distinguish themselves for clinical excellence and employee engagement. This article chronicles how Emory Healthcare, the largest, comprehensive academic healthcare system in Georgia, developed the Magnet Readiness IndexTM to assess the status of nursing compared with the standards prior to submission of an application. PMID- 23100005 TI - Increasing nurses' access to evidence through a web-based resource. AB - This article describes an institution's efforts to help nurses integrate evidence into practice through the development of a Web-based resource. After assessing nurses' attitudes and use of evidence resources, a Web site was created to provide a central location for accessing and using evidence. Nurses who utilized the Web site had more favorable attitudes toward evidence-based practice and were more likely to access evidence resources. PMID- 23100006 TI - Mentoring and coaching: a model guiding professional nurses to executive success. AB - Although many nurses aspire to executive positions, they lack the knowledge, support, and guidance to handle the challenges. To succeed at the executive level, ongoing deliberate skill development coupled with support is crucial across a nurse's career trajectory. This article introduces a model emphasizing the importance of mentoring and/or coaching for the aspiring executive nurse leader. PMID- 23100008 TI - The relationship between blood lactate concentration, the Paediatric Index of Mortality 2 (PIM2) and mortality in paediatric intensive care. AB - INTRODUCTION: Blood lactate concentration predicts mortality in neonates, infants, children and adults, with evidence that it has better predictive power than other markers of acid-base status such as absolute base excess or pH. OBJECTIVE: To investigate whether blood lactate concentration on admission predicts mortality in paediatric intensive care and if its addition can improve the performance of the Paediatric Index of Mortality 2 (PIM2) mortality prediction score. DESIGN AND SETTING: Retrospective cohort study in one 20-bed UK paediatric intensive care unit (PICU) using data from the PICU clinical and blood gas analyser databases between 2006 and 2010. Only cases with a blood lactate concentration measured at the same time as the PIM2 variables were included. Logistic regression was used to assess if blood lactate concentration predicted mortality independently of PIM2, adjusting for potential confounders, and if it could replace absolute base excess in the PIM2 model. RESULTS: There were 155 deaths amongst 2,380 admissions (6.5 %). Admission lactate in non-survivors was higher than in survivors (mean [standard deviation, SD]) 6.6 [5.6] versus 3.0 [2.5] mmol/l, had a positive association with mortality [adjusted odds ratio (OR) for death per unit (mmol/l)] increase 1.11 [95 % confidence interval (CI) 1.06 1.16; p < 0.001] and significantly improved the model fit of PIM2 when it replaced absolute base excess (p < 0.001). CONCLUSIONS: PICU admission blood lactate concentration predicts mortality independently of PIM2. Given the limitations of this study, a prospective multi-centre evaluation is required to establish whether it should be added to the PIM2 model with or without replacement of base excess. PMID- 23100009 TI - Not all types of asynchrony are created equal. PMID- 23100007 TI - SuPAR and PAI-1 in critically ill, mechanically ventilated patients. AB - PURPOSE: SuPAR (soluble urokinase plasminogen activator receptor) and PAI-1 (plasminogen activator inhibitor 1) are active in the coagulation-fibrinolysis pathway. Both have been suggested as biomarkers for disease severity. We evaluated them in prediction of mortality, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), sepsis and renal replacement therapy (RRT) in operative and non-operative ventilated patients. METHODS: We conducted a prospective, multicenter, observational study. Blood samples and data of intensive care were collected. Mechanically ventilated patients with baseline suPAR and PAI-1 measurements were included in the analysis, and healthy volunteers were analysed for comparison. Receiver operating characteristics (ROC), logistic regression, likelihood ratios and Kaplan-Meier analysis were performed. RESULTS: Baseline suPAR was 11.6 ng/ml (quartiles Q1-Q3, 9.6-14.0), compared to healthy volunteers with suPAR of 0.6 ng/ml (0.5-11.0). PAI-1 concentrations were 2.67 ng/ml (1.53-4.69) and 0.3 ng/ml (0.3-0.4), respectively. ROC analysis for suPAR 90-day mortality areas under receiver operating characteristic curves (AUC) 0.61 (95 % confidence interval (CI): 0.55-0.67), sepsis 0.68 (0.61-0.76), ALI/ARDS 0.64 (0.56-0.73) and RRT 0.65 (0.56-0.73). Patients with the highest quartile of suPAR concentrations had an odds ratio of 2.52 (1.37-4.64, p = 0.003) for 90-day mortality and 3.16 (1.19-8.41, p = 0.02) for ALI/ARDS. In non-operative patients, the AUC's for suPAR were 90-day mortality 0.61 (0.54-0.68), RRT 0.73 (0.64-0.83), sepsis 0.70 (0.60-0.80), ALI/ARDS 0.61 (0.51-0.71). Predictive value of PAI-1 was negligible. CONCLUSIONS: In non-operative patients, low concentrations of suPAR were predictive for survival and high concentrations for RRT and mortality. SuPAR may be used for screening for patients with potentially good survival. The association with RRT may supply an early warning sign for acute renal failure. PMID- 23100010 TI - [Whether minimally invasive or highly invasive: the patient must always be properly informed]. PMID- 23100011 TI - [Patient's participation during the pre-anesthesia visit --"if you have no more questions ..."]. AB - Preanesthesia visits are highly complex communicative events with legally demanded participation of the patients. The contribution describes the logical communicative course of this communication type as well as the communicative tasks of the participants. It is shown that physicians in fact offer opportunities for patients' questions but combine them with initiatives for the completion of the interaction; formulations of such offerings are also discouraging patients' questions. Initiative questions of patients during the conversation otherwise indicate where patients are in need for questions. PMID- 23100013 TI - Can a decision aid enable informed decisions in neonatal nursery recruitment for a fragile X newborn screening study? AB - PURPOSE: To determine whether a brochure based on principles of informed decision making improved attention to study materials or altered decisions made by parents invited to participate in a fragile X syndrome newborn screening study. METHODS: A total of 1,323 families were invited to participate in a newborn screening study to identify infants with fragile X syndrome as well as premutation carrier infants. Of these families, 716 received the original project brochure and 607 were given a new decision aid brochure. RESULTS: Families were more likely to look at the new decision aid and mothers were more likely to read it completely, but the proportion of mothers who read the entire decision aid was only 14%. Families were more likely to rate the decision aid as very helpful. Consistent with informed decision making theory and research, participants receiving the decision aid brochure were less likely to agree to participate. CONCLUSION: The decision aid increased attention to and perceived helpfulness of educational information about the study, but most families did not read it completely. The study suggests that even well-designed study materials are not fully reviewed in the context of in-hospital postpartum study recruitment and may need to be accompanied by a research recruiter to obtain informed consent. PMID- 23100014 TI - A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents. AB - PURPOSE: This report describes a fast online tool to accelerate and improve clinical interpretation of single nucleotide polymorphism array results for diagnostic purposes, when consanguinity or inbreeding is identified. METHODS: We developed a web-based program that permits entry of regions of homozygosity and, using OMIM, UCSC, and NCBI databases, retrieves genes within these regions as well as their associated autosomal recessive disorders. Relevant OMIM Clinical Synopses can be searched, using key clinical terms permitting further filtering for candidate genes and disorders. RESULTS: The tool aids the clinician by arriving at a short list of relevant candidate disorders, guiding the continued diagnostic work-up. Its efficacy is illustrated by presenting seven patients who were diagnosed using this tool. CONCLUSION: The online single nucleotide polymorphism array evaluation tool rapidly and systematically identifies relevant genes and associated conditions mapping to identified regions of homozygosity. The built-in OMIM clinical feature search allows the user to further filter to reach a short list of candidate conditions relevant for the diagnosis, making it possible to strategize more focused diagnostic testing. The tabulated results can be downloaded and saved to the desktop in an Excel format. Its efficacy is illustrated by providing a few clinical examples.Genet Med 2013:15(5):354-360. PMID- 23100016 TI - Association of ErbB1-4 expression in invasive breast cancer with clinicopathological characteristics and prognosis. AB - BACKGROUND: Human epidermal growth factor receptor type 2 (Her2)/ErbB2 plays a key role in the initiation and progression of invasive breast cancer. However, the prognostic relevance to breast cancer patients of the other ErbB family members has long been a matter of debate. METHODS: In a series of 250 primary invasive breast cancer patients, we performed a comprehensive analysis of ErbB1-4 at the levels of mRNA expression and gene copy number using real-time quantitative PCR. The relationship between the status of ErbB1-4 and the clinicopathological characteristics or prognosis was evaluated. RESULTS: The mRNA expression of ErbB2, but not the other ErbB genes, was significantly correlated to copy number (P = 0.0005). ErbB3 and ErbB4 mRNA expression were positively correlated to each other (P < 0.0001). The mRNA expression of ErbB1/2 was inversely correlated to estrogen receptor (ER) and progesterone receptor (PgR) positivity, although mRNA expression of ErbB3/4 was positively correlated to ER and PgR positivity. Kaplan-Meier survival analysis showed that ErbB1 mRNA expression was associated with reduced survival. Neither ErbB2 nor ErbB3 mRNA expression had any association with survival, because half of the patients with Her2-positive tumors were treated with trastuzumab. High ErbB4 mRNA expression showed good prognosis with respect to breast cancer-specific survival CONCLUSIONS: ErbB3 and ErbB4 mRNA expression, as well as well as that of ErbB1 and ErbB2, could be histopathological factors. ErbB3 mRNA was highly expressed in ER-positive tumors and has controversial prognostic value. ErbB4 mRNA expression was well correlated with ER positivity and good prognosis, indicating that ErbB4 may contribute to ER-dependent growth. PMID- 23100018 TI - Small bowel MRI in adult patients: not just Crohn's disease-a tutorial. AB - OBJECTIVES: To provide an overview of less well-known small bowel and mesenteric diseases found at small bowel magnetic resonance (MR) enterography/enteroclysis and to review the imaging findings. MR enterography and enteroclysis are important techniques for evaluation of small bowel diseases. In most centres these techniques are primarily used in Crohn's disease, and most radiologists are familiar with these MRI findings. However, the knowledge of findings in other diseases is often sparse, including diseases that may cause similar clinical symptoms to those of Crohn's disease. METHODS: We present a spectrum of less common and less well-known bowel and mesenteric diseases (e.g. internal hernia, intussusception, neuroendocrine tumour) from our small bowel MR database of over 2,000 cases. RESULTS: These diseases can be found in patients referred for bowel obstruction, abdominal pain or rectal blood loss. Further, in patients with (or suspected to have) Crohn's disease, some of these diseases (e.g. neuroendocrine tumour, familial Mediterranean fever) may mislead radiologists to erroneously diagnose active Crohn's disease. CONCLUSION: Radiologists should be familiar with diseases affecting the small bowel other than Crohn's disease, including diseases that may mimic Crohn's disease. PMID- 23100019 TI - Two decades of percutaneous transjejunal biliary intervention for benign biliary disease: a review of the intervention nature and complications. AB - OBJECTIVE: To assess outcomes of percutaneous transjejunal biliary intervention (PTJBI) in terms of success and effectiveness in patients with a Roux-en-Y hepaticojejunostomy for benign biliary strictures and stones. METHODS: Clinical and radiographic records of 63 patients with a Roux-en-Y choledochojejunostomy or hepaticojejunostomy for benign disease who underwent at least one PTJBI between 1986 and 2007 were reviewed. Effectiveness was determined by successful access rate, rates of stricture dilatation and/or stone extraction, morbidity, complications and hospitalisation. RESULTS: PTJBI was attempted 494 times. Successful access to the Roux-en-Y was accomplished in 93% of interventions. After access to the Roux-en-Y was granted, all strictures were effectively dilated. Ninety-seven percent of extraction attempts of intrahepatic calculi were successful. The median number of interventions per patient was five. The median interval between interventions was 51.5 weeks (range 2.7-1,279.6 weeks). The early complication rate was 3%. Morbidity, measured in terms of cholangitis episodes was 14%, in 25 out of 63 patients. Mean hospitalisation was 4.1 nights per year. CONCLUSION: PTJBI is safe and effective in treating benign biliary strictures and/or calculi. High success rates and short hospitalisation periods, together with few complications make it a well-accepted and integral part of managing complex biliary problems. PMID- 23100020 TI - Isolation of fucosyltransferase-producing bacteria from marine environments. AB - Fucose-containing oligosaccharides on the cell surface of some pathogenic bacteria are thought to be important for host-microbe interactions and to play a major role in the pathogenicity of bacterial pathogens. Here, we screened marine bacteria for glycosyltransferases using two methods: a one-pot glycosyltransferase assay method and a lectin-staining method. Using this approach, we isolated marine bacteria with fucosyltransferase activity. There have been no previous reports of marine bacteria producing fucosyltransferase. This paper thus represents the first report of fucosyltransferase-producing marine bacteria. PMID- 23100021 TI - Bacterial population dynamics in a laboratory activated sludge reactor monitored by pyrosequencing of 16S rRNA. AB - The microbial population in a laboratory activated sludge reactor was monitored for 245 d at 75 time points by pyrosequencing of 16S rRNA. Synthetic wastewater was used as the influent, and the reactor was operated under the same conditions throughout the experiment. The behaviors of different bacterial operational taxonomic units (OTUs) were observed. Multiple OTUs showed periodic propagation and recession. One of the OTUs showed sharp recession, which suggests that cells in the OTU were selectively killed. The behaviors of different phylogenetic lineages of Candidatus 'Accumulibacter phosphatis' were also visualized. It was clearly demonstrated that pyrosequencing with barcoded primers is a very effective tool to clarify the dynamics of the bacterial population in activated sludge. PMID- 23100022 TI - Resuscitation promoting factor (Rpf) from Tomitella biformata AHU 1821(T) promotes growth and resuscitates non-dividing cells. AB - Functional variation of Rpf, a growth factor found exclusively in Actinobacteria, is differentiated by its source and amino acid sequences. Only purified Rpf proteins from three species have been studied so far. To seek new Rpfs for use in future studies to understand their role in Actinobacteria, the objective of this study was to identify rpf gene homologs in Tomitella biformata AHU 1821(T), a novel Actinobacteria isolated from permafrost ice wedge. Amplification using degenerate primers targeting the essential Rpf domain led to the discovery of a new rpf gene in T. biformata. Gene structure and the deduced Rpf domain amino acid sequence indicated that this rpf gene was not identical to previously studied Rpf. Phylogenetic analysis placed T. biformata Rpf in a monophyletic branch in the RpfB subfamily. The deduced amino acid sequence was 44.9% identical to RpfB in Mycobacterium tuberculosis, the closest functionally tested Rpf. The gene was cloned and expressed in Escherichia coli; the recombinant Rpf protein (rRpf) promoted the growth of dividing cells and resuscitated non-dividing cells of T. biformata. Compared to other studies, this Rpf was required at higher concentrations to promote its growth and to resuscitate itself from a non dividing state. The resuscitation function was likely due to the highly conserved Rpf domain. This study provides evidence that a genetically unique but functional Rpf can be found in novel members of Actinobacteria and can lead to a better understanding of bacterial cytokines in this phylum. PMID- 23100023 TI - Revealing the diversity and quantity of peritrich ciliates in environmental samples using specific primer-based PCR and quantitative PCR. AB - Peritrichs are a diverse, ecologically important ciliate group usually with a complex life cycle. To date, the community of the peritrichs has been investigated by using morphology-based methods such as living observation and silver staining. Here we show a molecular approach for characterizing the diversity and quantity of free-living peritrichs in environmental samples. We newly designed four peritrich-specific primers targeting 18S rRNA genes that allow clone library construction, screening and analysis. A quantitative real time PCR (qPCR) assay was developed to quantify peritrichs in environmental samples by using rDNA copy number as an indicator. DNA extracted from four water samples of contrasting environmental gradients was analysed. The results showed that the peritrich community was differentiated among these samples, and that the diversity decreased with the increase of water salinity. The qPCR results are consistent with the library sequence analysis in terms of quantity variations from sample to sample. The development of peritrich-specific primers, for the first time, for conventional PCR and qPCR assays, provides useful molecular tools for revealing the diversity and quantity of peritrich ciliates in environmental samples. Also, our study illustrates the potential of these molecular tools to ecological studies of other ciliate groups in diverse environments. PMID- 23100024 TI - Phytate degradation by fungi and bacteria that inhabit sawdust and coffee residue composts. AB - Phytate is the primary source of organic phosphorus, but it cannot be directly utilized by plants and is strongly adsorbed by the soil, reducing bioavailability. Composting is a process used to improve the bioavailability of phytate in organic wastes through degradation by microorganisms. In this study, we aimed to investigate the phytate-degrading ability of fungi and bacteria that inhabit sawdust compost and coffee residue compost, and their contribution to the composting process. In the plate assay, the fungi that formed clear zones around their colonies belonged to the genera Mucor, Penicillium, Galactomyces, Coniochaeta, Aspergillus, and Fusarium, while the bacteria belonged to the genera Pseudomonas, Enterobacter, Chitinophaga, and Rahnella. Eight fungal isolates (genera Mucor, Penicillium, Galactomyces, and Coniochaeta) and four bacterial isolates (genera Pseudomonas, Enterobacter, and Rahnella) were selected to evaluate phytase activity in their liquid culture and their ability to degrade phytate in organic materials composed of mushroom media residue and rice bran. The selected fungi degraded phytate in organic materials to varying degrees. Penicillium isolates showed the highest degradation ability and Coniochaeta isolate exhibited relatively high degradation ability. The clear zone diameters of these fungal isolates displayed significantly positive and negative correlations with inorganic and phytate phosphorus contents in the organic materials after incubation, respectively; however, none of the selected bacteria reduced phytate phosphorus in organic materials. It is therefore possible that fungi are major contributors to phytate degradation during composting. PMID- 23100025 TI - Environmental chlamydiae alter the growth speed and motility of host acanthamoebae. AB - Symbiosis between living beings is an important driver of evolutionary novelty and ecological diversity; however, understanding the mechanisms underlying obligate mutualism remains a significant challenge. Regarding this, we have previously isolated two different Acanthamoeba strains harboring endosymbiotic bacteria, Protochlamydia (R18 symbiotic amoebae: R18WT) or Neochlamydia (S13 symbiotic amoebae; S13WT). In this study, we treated the symbiotic amoebae R18WT and S13WT with doxycycline (DOX) and rifampicin (RFP), respectively, to establish the aposymbiotic amoebae R18DOX and S13RFP, respectively. Subsequently, we compared the growth speed, motility, phagocytosis, pinocytosis, and morphology of the symbiotic and aposymbiotic amoebae. The growth speed of R18DOX was decreased, although that of S13RFP was increased. A marked change in motility was observed only for R18DOX amoebae. There was no difference in phagocytic and pinocytic activities between the symbiotic and aposymbiotic amoebae. Meanwhile, we observed a significant change in the phalloidin staining pattern and morphological changes in R18DOX (but not S13RFP) aposymbiotic amoebae, indicating a change in actin accumulation upon removal of the Protochlamydia. Infection of C3 (a reference strain) or S13RFP amoebae with Protochlamydia had a harmful effect on the host amoebae, but R18DOX amoebae re-infected with Protochlamydia showed recovery in both growth speed and motility. Taken together, we conclude that endosymbiont environmental chlamydiae alter the growth speed and/or motility of their host Acanthamoeba, possibly implying an close mutual relationship between amoebae and environmental chlamydiae. PMID- 23100026 TI - Disassociation of insulin action and Akt/FOXO signaling in skeletal muscle of older Akt-deficient mice. AB - The purpose of the present study was to determine the effect of Akt gene ablation on Akt/Forkhead Box O (FOXO) signaling and atrogene expression. This was accomplished by studying wild-type (WT) and isoform-specific Akt knockout (Akt1( /-) and Akt2(-/-)) mice. The ability of insulin to promote Akt phosphorylation on Ser(473) was significantly lower in extensor digitorum longus (EDL) and soleus muscles from Akt1(-/-) and Akt2(-/-) mice compared with WT mice. Total Akt1 protein levels were significantly lower in EDL muscles of Akt2(-/-) mice compared with WT mice, a process that appears to be posttranscriptionally regulated as Akt1 mRNA levels were unchanged. The loss of Akt1 protein in EDL muscles of Akt2( /-) mice does not appear to be due to insulin resistance because 4 mo of a high fat diet failed to reduce Akt1 protein levels in muscles of WT mice. Although FOXO3a phosphorylation and atrogin-1 expression were unaltered in muscles of Akt1(-/-) and Akt2(-/-) mice, the expression of the atrogenes Bnip3 and gabarapl were significantly elevated in muscles of both Akt1 and Akt2 knockout mice. Finally, the expression of striated activator of Rho signaling was significantly increased in muscles of Akt2(-/-) mice compared with Akt1(-/-) and WT mice. Our results demonstrate that the ablation of Akt isoforms disassociates insulin action and Akt/FOXO signaling to atrogenes. PMID- 23100027 TI - Large molecule protein feeding during the suckling period is required for the development of pancreatic digestive functions in rats. AB - We examined if large molecule protein feeding during the suckling period is prerequisite for the proper development of pancreatic digestive functions. Most amino acids in breast milk exist as the constituent of large proteins and not as oligopeptides or free amino acids. Accumulating evidence indicates the nutritional importance of large protein feeding for suckling infants; however, evidence on the physiological significance remains small. We thus artificially reared rat pups on a standard rat formula with milk protein or a formula with milk protein hydrolysate from 7 to 21 days of age, and thereafter, fed a standard solid diet until 42 days of age. Pancreas weight and the stock of pancreatic digestive enzymes in the hydrolysate-fed rats were significantly lower than those in the protein-fed rats during and also after the suckling period. Plasma insulin, a stimulator of amylase synthesis, was also significantly low in the hydrolysate-fed rats compared with the protein-fed rats. At 28 days of age, we evaluated the pancreatic secretory ability in response to dietary protein and cholecystokinin (CCK) by means of pancreatic duct cannulation. Pancreatic secretion stimulated by dietary protein in the hydrolysate-fed rats was significantly weaker than that in the protein-fed rats. No significant difference was observed in the increasing rate of pancreatic enzyme secretion in response to CCK between the two groups. These results suggest that the presence of large proteins in breast milk is significant for the development of pancreatic digestive functions and the outcomes could remain even later on in life. PMID- 23100028 TI - Aryl hydrocarbon receptor agonist, leflunomide, protects the ischemic-reperfused kidney: role of Tregs and stem cells. AB - The aryl hydrocarbon receptor (AHR) has emerged as a major modulator of inflammatory processes. We tested the hypothesis that AHR activation protects the ischemic-reperfused kidney in association with the suppression of the inflammatory response. Accordingly, male mice were treated with the nondioxin AHR agonist, leflunomide (40 mg/kg ip); vehicle-treated animals served as controls. Thereafter, the right kidney was subjected to an ischemia (45 min)-reperfusion (4 h) insult, while the left kidney served as a sham control. Renal cells prepared from ischemic-reperfused kidneys of leflunomide-treated mice displayed preservation of mitochondrial membrane potential (Psi(m)) and decreased apoptosis and necrosis compared with vehicle-treated ischemic-reperfused kidneys. Leflunomide treatment increased regulatory T cells (Tregs; forkhead box P3+) and IL-10-positive cells but reduced IL-17- and IL-23-expressing cells in both the peripheral blood and kidney cells, indicative of down-regulation of inflammatory responses. Leflunomide treatment also increased mobilization of stems cells subsets (i.e., mesenchymal and hematopoietic stem cells and endothelial progenitor cells) in the peripheral blood and promoted their recruitment into the ischemic-reperfused kidney. Collectively, the results indicate that AHR stimulation may represent a novel renoprotective mechanism likely involving mobilization and recruitment of Tregs and stem cells into the damaged kidney. PMID- 23100029 TI - PPARgamma activation attenuates cold-induced upregulation of thyroid status and brown adipose tissue PGC-1alpha and D2. AB - Here, we investigated whether pharmacological PPARgamma activation modulates key early events in brown adipose tissue (BAT) recruitment induced by acute cold exposure with the aim of unraveling the interrelationships between sympathetic and PPARgamma signaling. Sprague-Dawley rats treated or not with the PPARgamma ligand rosiglitazone (15 mg.kg(-1).day(-1), 7 days) were kept at 23 degrees C or exposed to cold (5 degrees C) for 24 h and evaluated for BAT gene expression, sympathetic activity, thyroid status, and adrenergic signaling. Rosiglitazone did not affect the reduction in body weight gain and the increase in feed efficiency, Vo(2), and BAT sympathetic activity induced by 24-h cold exposure. Rosiglitazone strongly attenuated the increase in serum total and free T4 and T3 levels and BAT iodothyronine deiodinase type 2 (D2) and PGC-1alpha mRNA levels and potentiated the reduction in BAT thyroid hormone receptor (THR) beta mRNA levels induced by cold. Administration of T3 to rosiglitazone-treated rats exacerbated the cold induced increase in energy expenditure but did not restore a proper activation of D2 and PGC-1alpha, nor further increased uncoupling protein 1 expression. Regarding adrenergic signaling, rosiglitazone did not affect the changes in BAT cAMP content and PKA activity induced by cold. Rosiglitazone alone or in combination with cold increased CREB binding to DNA, but it markedly reduced the expression of one of its major coactivators, CREB binding protein. In conclusion, pharmacological PPARgamma activation impairs short-term cold elicitation of BAT adrenergic and thyroid signaling, which may result in abnormal tissue recruitment and thermogenic activity. PMID- 23100031 TI - Total synthesis of (+)-bretonin B: access to the (E,Z,E)-triene core by a late stage Peterson elimination of a convergently assembled silyl ether. AB - The title compound was synthesised in a concise route (nine linear steps, 31% overall yield) employing an alpha-silyl epoxide ring opening, a Julia-Kocienski olefination and a late-stage Peterson elimination as key steps. PMID- 23100030 TI - Corpus luteal contribution to maternal pregnancy physiology and outcomes in assisted reproductive technologies. AB - Investigations in the rat model of pregnancy indicate an important role for the corpus luteal (CL) hormone relaxin in the maternal circulatory and osmoregulatory changes in pregnancy, which are epitomized by profound vasodilation and modest hypoosmolality, respectively. In a pilot study of infertile women who became pregnant through donor eggs, in vitro fertilization, and embryo transfer, the gestational rise in glomerular filtration and fall in plasma osmolality were markedly subdued. Because these women were infertile, they lacked a CL and circulating relaxin (and possibly other vasoactive CL hormones). Based on these findings in pregnant rats and women, we hypothesize that infertile women conceiving through donor eggs will have overall subdued circulatory changes (e.g., attenuated reduction in systemic vascular resistance and subdued increase in cardiac output) particularly during early pregnancy when CL hormones predominate before the full development and maturation of the placenta. In contrast, infertile women conceiving by autologous eggs retrieved after ovarian stimulation and fresh embryo transfer may have a relatively hyperdynamic circulation due to the presence of many CL (up to 20 or more) and higher circulating levels of vasodilatory ovarian hormones such as relaxin. Emerging evidence suggests that women undergoing Assisted Reproductive Technologies (ART) have increased risk for adverse pregnancy outcomes such as preeclampsia and small for gestational-age babies. This increased risk may be partly caused by the maternal milieu, which is not physiological in ART pregnancies due to the abnormal status of the CL. PMID- 23100032 TI - The influence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on hematological parameters during experimentally induced pleuritis in rats. AB - Proper functioning of homeostatic mechanisms is characteristic for every healthy organism and enables adapting to environmental changes. These complicated systematic reactions can neutralize the harmful stress factors leading to various inflammatory reactions. The aim of this study was to determine dynamic changes in the inflammatory reaction after single 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) administration of 5 MUg/kg body weight into rats with experimentally induced pleuritis. These changes were observed by monitoring the hematological blood parameters during inflammation. The obtained results proved that dioxins contribute to various changes in the character of the inflammatory response. TCDD administration before pleuritis initiation caused an increase of lymphocytes and significant decrease of the number of neutrophils during inflammation. The current study proved that administration of low TCDD dose (seven times lower than used in other studies) can cause thymus, spleen, or lymphatic gland atrophy. This finding indicates the toxic influence of small TCDD dose especially on the immune system. PMID- 23100034 TI - Three-dimensional distribution of TrkA neurotrophin receptors in neurite varicosities of differentiated PC12 cells treated with NGF determined by immunoelectron tomography. AB - Nerve growth factor (NGF) initiates the activation of TrkA tyrosine kinase receptors and numerous subsequent signaling cascades. However, the dynamics of the process including the translocation of TrkA is still unclear. In this study, the effect of NGF or membrane depolarization on the endocytic process and TrkA localization in the neuronal cell line PC12 was analyzed by live-cell imaging and immunoelectron tomography using an ultra-high voltage electron microscope (UHVEM). Both NGF re-stimulation and high potassium-induced depolarization enhanced the endocytic uptake of the fluorescent indicator into acidic organelles within varicosities as well as cell bodies. However, the transition of uptake differed completely. NGF also significantly increased the number of TrkA containing varicosities. Immunoelectron tomography in whole-mounted cells showed that NGF induced the recruitment of TrkA to the surface membrane of neurite varicosities as well as the multivesicular bodies (MVBs) and lysosomal complexes inside the varicosities. Three-dimensional analysis revealed that invagination pits and intralumenal vesicles of MVBs contained TrkA immunoreactivity. In addition, TrkA immunoreactivity was scattered in the lysosomal matrices after NGF treatment. These results suggest that the neurite varicosities are intensely active in intracellular membrane trafficking, and play an important role in the degradation and accumulation of the NGF receptor, TrkA, after ligand stimulation. PMID- 23100033 TI - Urotensin inhibition with palosuran could be a promising alternative in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive and a life-threatening disease with its high morbidity and mortality ratios. On searching for new shining targets in pathogenesis, we noticed, in our previous studies, urotensin II (UII) in systemic sclerosis with potent angiogenic and pro-fibrotic features. Owing to the mimicking properties of UII with endothelin-1 (ET1), we attempted to investigate the effect of palosuran in a PAH rat model. Thirty rats were randomly divided into three groups, with each group comprising 10 rats: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran group) received subcutaneous MCT and palosuran. Serum UII, ET1, transforming growth factor-beta1 (TGF-beta1) levels, pulmonary arteriolar pathology of different diameter vessels, and cardiac indices were evaluated. The ET1, TGF-beta1, and UII levels were significantly diminished in the treatment group, similar to the controls (p < 0.001). Right ventricular hypertrophy index and mean pulmonary arterial pressure scores were also significantly reduced in the treatment group (p = 0.001). Finally, in the 50-125-MUm diameter arterioles, in contrast to Groups 3 and 1, there was a statistically significant thickness (p < 0.01) in the arteriolar walls of rats in Group 2. The treatment effect on arteries of more than 125-MUm diameters was found to be valuable but not significant. Owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, palosuran as an antagonist of UII might be an optional treatment alternative for PAH. PMID- 23100035 TI - Expression of small leucine-rich proteoglycans in rat anterior pituitary gland. AB - Proteoglycans are components of the extracellular matrix and comprise a specific core protein substituted with covalently linked glycosaminoglycan chains. Small leucine-rich proteoglycans (SLRPs) are a major family of proteoglycans and have key roles as potent effectors in cellular signaling pathways. Research during the last two decades has shown that SLRPs regulate biological functions in many tissues such as skin, tendon, kidney, liver, and heart. However, little is known of the expression of SLRPs, or the characteristics of the cells that produce them, in the anterior pituitary gland. Therefore, we have determined whether SLRPs are present in rat anterior pituitary gland. We have used real-time reverse transcription with the polymerase chain reaction to analyze the expression of SLRP genes and have identified the cells that produce SLRPs by using in situ hybridization with a digoxigenin-labeled cRNA probe. We have clearly detected the mRNA expression of SLRP genes, and cells expressing decorin, biglycan, fibromodulin, lumican, proline/arginine-rich end leucine-rich repeat protein (PRELP), and osteoglycin are located in the anterior pituitary gland. We have also investigated the possible double-staining of SLRP mRNA and pituitary hormones, S100 protein (a marker of folliculostellate cells), desmin (a marker of capillary pericytes), and isolectin B4 (a marker of endothelial cells). Decorin, biglycan, fibromodulin, lumican, PRELP, and osteoglycin mRNA have been identified in S100-protein-positive and desmin-positive cells. Thus, we conclude that folliculostellate cells and pericytes produce SLRPs in rat anterior pituitary gland. PMID- 23100036 TI - The relationship between head injury and facial trauma: a case-control study. AB - INTRODUCTION: In spite of anatomic proximity of the facial skeleton and cranium, there is paucity of information in the literature regarding the relationship between head injuries and facial trauma. The objective of our investigation was to evaluate the pattern of head injuries in patients with maxillofacial trauma, and to study their relationship. MATERIAL AND METHODS: We evaluated 2,692 patients with maxillofacial trauma admitted to the Besat hospital, Hamedan, Iran between 2007 and 2010. Patients with associated head injury (302 cases; study group) were compared with those without head injury (2,390 cases; control group). RESULTS: In our cohort, the rate of head injuries associated with facial bone fractures was 23.3 %. The most common associated head injury was concussion, followed by cerebral contusion and skull fractures. In the unadjusted analysis, motorcycle and car accidents were significantly more frequent in the study group, while stumbling, sports injuries, and work-related injuries were significantly more common in the control group (p < 0.001). Except for Lefort III fractures which was not significantly different between groups, all facial fractures occurred more frequently in the study group (p < 0.001). Logistic regression analysis demonstrated that motorcycle accidents (211-fold), car accidents (139 fold), violence (69-fold), falls (66-fold), frontal sinus fractures (84.5-fold), and Lefort II fractures (27-fold) were the strongest predictors of head injuries. DISCUSSION: Present study revealed that fracture of facial bones, especially bones that are in anatomic proximity to the cranium and need a high magnitude of trauma energy to be fractured, was marker for an increased risk of head injuries. PMID- 23100037 TI - Glycemic management in medical and surgical patients in the non-ICU setting. AB - Hyperglycemia is commonly observed in hospitalized patients with and without previously known diabetes and is associated with adverse outcomes. For this reason, measurement of blood glucose (BG) is recommended for all patients at admission. Measurement of an A1C identifies patients with either newly recognized diabetes or uncontrolled diabetes. Current guidelines advise fasting and premeal BG <140 mg/dl, with maximal random BG <180 mg/dl for the majority of noncritically ill patients. Rational use of basal bolus insulin (BBI) regimens is effective in achieving these glycemic goals, with low risk for hypoglycemia. The safety of BBI relies upon provider knowledge for initiation and adjustment of insulin doses for changes in nutritional status or use of medications affecting glucose metabolism. Smooth transition of care to the outpatient setting is facilitated by providing oral and written instructions regarding timing and dosing of insulin, as well as education in basic skills for home management. PMID- 23100038 TI - Clear cell and papillary serous endometrial carcinomas: survival in a series of 128 cases. AB - PURPOSE: Clear cell (CC) and papillary serous carcinoma (PS) are histotypes at high risk of recurrence. We analyse patients' survival in a retrospective series of 128 CC and PS endometrial cancer cases. METHODS: All women with a histologically confirmed CC and PS endometrial cancer who underwent primary surgery in five institutions in Lombardy, Italy, were eligible for this study. A total of 77 (60.2 %) were PS endometrial cancer cases, 45 (35.2 %) CC cases and 6 (4.6 %) cases had mixed CC and PS histotype. RESULTS: 54 (42 %) cases were diagnosed at stage I, 10 (8 %) at stage II, 47 (37 %) at stage III and 17 (13 %) at stage IV. Recurrence was observed in 49 cases (38.3 %). The median time at recurrence was 12 months (interquartile range 7-18). The rate of recurrence was 20.3 % in cases at stage I-lI and 56.2 % in cases at stage III-IV (p < 0.0001). With regard to the site of recurrence 24 recurrences were in and 52 outside the pelvis. Finally, the rate of recurrence was 32.6 % (14 cases) in CC cases, 43.1 % (31 cases) in PS cases and 66.7 % (4 cases) in cases with mixed histotype. The 5 year progression-free survival was 59.5 % (67.4 % for CC cases, 55.1 % for PS and mixed cases). CONCLUSION: In this study including CC and PS endometrial cancers, the 5-year survival from surgery was 72.7 % and the 5-year progression-free survival was 59.5 %. PMID- 23100039 TI - L'avenir. PMID- 23100041 TI - Retinal nerve fiber layer thickness in Parkinson disease. AB - Dopaminergic neuronal cells have been identified in the inner nuclear and inner plexiform layers of the human retina. The dopaminergic content of the retina is reduced in patients with idiopathic Parkinson disease (PD). These observations led us to study the retinal nerve fiber layer (RNFL) thickness in patients with PD without visual impairment compared to healthy controls using spectral-domain optical coherence tomography (SD-OCT). Eighty-two subjects, including 42 patients with PD, newly diagnosed and untreated (24 men, 18 women, age range: 47-66 years), and 40 healthy controls, were enrolled. Both eyes of patients with PD and controls were imaged with SD-OCT. The mean RNFL thickness was 77 +/- 11.5 MUm in PD patients and 89 +/- 8.7 MUm in healthy controls (P = 0.001). Selective thinning of the RNFL was found in the temporal region with mean temporal RNFL thickness of 66 +/- 6.7 MUm in PD patients and 75 +/- 4.8 MUm in controls (P = 0.001). The thickness of the RNFL is decreased in PD patients. Demonstrating progressive thinning of RNFL over time will be critical for validating optical coherence tomography as a viable biomarker of patients with PD. PMID- 23100042 TI - Prospective crossover comparison between NAVA and pressure control ventilation in premature neonates less than 1500 grams. AB - OBJECTIVE: Neurally adjusted ventilatory assist (NAVA) synchronizes spontaneous respiratory effort with mechanical ventilation. Electrodes detect the electrical activity of the diaphragm (Edi) and transmit this information to the ventilator, allowing the patient to determine their own respiratory rate (RR), peak pressures, and inspiratory and expiratory times in synchrony with the ventilator. The objective of this study was to evaluate if premature neonates ventilate as effectively on NAVA as compared to pressure control ventilation (PCV). STUDY DESIGN: Five ventilated neonates were enrolled (gestational age 25-29 weeks). Each neonate was ventilated on NAVA for 4 h, then switched to PCV for another 4 h. The cycle was repeated three times. Ventilatory parameters were averaged every 30 min to collect eight time points for each ventilatory mode. Data were analyzed using the mixed effects model procedure, utilizing the least-squares means (P<0.05). RESULT: When compared to PCV, neonates ventilated with NAVA had lower peak inspiratory pressures (PIP), fraction of inspired oxygen (FiO2), transcutaneous PCO2 Edi peak and RR. There was an increase in expiratory tidal volume (TV), compliance and Edi minimum. Despite lower PIP and RR, partial pressure of CO2 (PCO2) was lower when ventilated on NAVA. There was no difference in mean airway pressure. CONCLUSION: Premature neonates ventilated with NAVA required less PIP, FiO2 and RR to achieve lower PCO2 and better compliance compared with PCV. PMID- 23100043 TI - Capacity of mesoporous bioactive glass nanoparticles to deliver therapeutic molecules. AB - Inorganic bioactive nanomaterials are attractive for hard tissue regeneration, including nanocomponents for bone replacement composites and nanovehicles for delivering therapeutics. Bioactive glass nanoparticles (BGn) have recently gained potential usefulness as bone and tooth regeneratives. Here we demonstrate the capacity of the BGn with mesopores to load and deliver therapeutic molecules (drugs and particularly genes). Spherical BGn with sizes of 80-90 nm were produced to obtain 3-5 nm sized mesopores through a sono-reacted sol-gel process. A simulated body fluid test of the mesoporous BGn confirmed their excellent apatite forming ability and the cellular toxicity study demonstrated their good cell viability up to 100 MUg ml(-1). Small molecules like chemical drug (Na ampicillin) and gene (small interfering RNA; siRNA) were introduced as model drugs considering the mesopore size of the nanoparticles. Moreover, amine functionalization allowed switchable surface charge property of the BGn (from -20 30 mV to +20-30 mV). Loading of ampicillin or siRNA saturated within a few hours (~2 h) and reflected the mesopore structure. While the ampicillin released relatively rapidly (~12 h), the siRNA continued to release up to 3 days with almost zero-order kinetics. The siRNA-nanoparticles were easily taken up by the cells, with a transfection efficiency as high as ~80%. The silencing effect of siRNA delivered from the BGn, as examined by using bcl-2 model gene, showed dramatic down-regulation (~15% of control), suggesting the potential use of BGn as a new class of nanovehicles for genes. This, in conjunction with other attractive properties, including size- and mesopore-related high surface area and pore volume, tunable surface chemistry, apatite-forming ability, good cell viability and the possible ion-related stimulatory effects, will potentiate the usefulness of the BGn in hard tissue regeneration. PMID- 23100044 TI - Genetic variation in ataxia gene ATXN7 influences cerebellar grey matter volume in healthy adults. AB - An increasing number of candidate genes for common and rare brain disorders are discovered, but the mechanism of action through which these genes cause disease is often still unclear. Some of the genetic factors known to increase the risk for common brain disorders affect brain structure, even in healthy individuals, and therefore possibly have a role in the normal development of specific brain regions. In this study, we explored this principle for a group of rare brain disorders, the spinocerebellar ataxias (SCAs). As a proof of concept, we investigated whether genetic variation in a gene known to cause a polyglutamine expansion SCA is associated with cerebellar volume in healthy adults. The functional single nucleotide polymorphism (SNP) rs3774729 located in ATXN7 was selected as the variant of interest. Cerebellar grey matter volume was determined using volumetry on magnetic resonance imaging data in a discovery sample scanned at 1.5 T (n = 680) and a replication sample scanned at 3 T (n = 683), both consisting of healthy adults aged 18 to 35 years. The volumes were compared as a function of the presence of the minor allele of SNP rs3774729, which was associated with significantly smaller cerebellar grey matter volume in both the discovery and replication sample (p = 0.033 and p = 0.024, respectively). Our results demonstrate that a common genetic variant in the ataxia-causing gene ATXN7 influences cerebellar grey matter volume in healthy young adults. This finding may also imply that genes associated with cerebellar volume in healthy subjects are valid candidates for causing or modifying ataxia. PMID- 23100045 TI - Cardiothoracic CT: one-stop-shop procedure? Impact on the management of acute pulmonary embolism. AB - In the treatment of pulmonary embolism (PE) two groups of patients are traditionally identified, namely the hemodynamically stable and instable groups. However, in the large group of normotensive patients with PE, there seems to be a subgroup of patients with an increased risk of an adverse outcome, which might benefit from more aggressive therapy than the current standard therapy with anticoagulants. Risk stratification is a commonly used method to define subgroups of patients with either a high or low risk of an adverse outcome. In this review the clinical parameters and biomarkers of myocardial injury and right ventricular dysfunction (RVD) that have been suggested to play an important role in the risk stratification of PE are described first. Secondly, the use of more direct imaging techniques like echocardiography and CT in the assessment of RVD are discussed, followed by a brief outline of new imaging techniques. Finally, two risk stratification models are proposed, combining the markers of RVD with cardiac biomarkers of ischemia to define whether patients should be admitted to the intensive care unit (ICU) and/or be given thrombolysis, admitted to the medical ward, or be safely treated at home with anticoagulant therapy. PMID- 23100046 TI - Morphological analysis of the knee joint in patients with hip dysplasia. AB - PURPOSE: The purpose of this study was to investigate the morphological changes of the knee in patients with untreated developmental dysplasia of the hip. METHODS: Morphological analysis of 150 knee joints in 75 patients with developmental dysplasia of the hip was performed by examining computed tomographic (CT) images. Of these patients, 36 had unilateral developmental dysplasia of the hip and 39 had bilateral developmental dysplasia of the hip. Therefore, 36 hips were normal, and 114 hips were dislocated. CT images ranged from the iliac crest to 2 cm inferior to the tibial tuberosity. RESULTS: Compared with the knees in patients with normal hips, the femoral condyles in patients with dislocated hips were smaller and exhibited greater medial and lateral condylar asymmetry. The anterior femoral condylar angle of the femur was increased, as was the groove angle, while the trochlear groove was shallower in patients with dislocated hips. Furthermore, the lateral patella shift was reduced and the patellar tilt angle was increased in patients with dislocated hips compared with patients with normal hips. The extent of changes in these variables differed with the degree of dislocation. However, the posterior condylar angle of the femur was not affected by the degree of dislocation. CONCLUSION: These findings suggest that developmental dysplasia of the hip is associated with morphological changes in the knee joint. These changes should be considered during hip and knee surgery. LEVEL OF EVIDENCE: Prospective study, level II. PMID- 23100047 TI - Is osteoarthritis an inevitable consequence of anterior cruciate ligament reconstruction? A meta-analysis. AB - PURPOSE: Although the occurrence of early osteoarthritis (OA) is commonly associated with a history of anterior cruciate ligament (ACL) reconstruction, its exact prevalence in these patients remains unknown. The goal of this study was to review the current literature on long-term radiographic outcome after autologous ACL reconstruction and subsequently perform a meta-analysis to obtain evidence based prevalences of OA at a mean of 10 years after surgery. In addition, this report aimed at identifying the relationship between meniscal status and the occurrence of radiographic OA in the ACL reconstructed knee. METHODS: A systematic review of the literature was performed in PubMed MEDLINE, EMBASE and Cochrane Library databases to identify all studies concerning radiographic outcome after autologous ACL reconstruction with a follow-up of minimum 10 years. Meta-analyses were performed to obtain the average prevalence of OA and the difference between patients with and without meniscectomy. Considered study estimates were the log-transformed odds and odds ratios, the latter expressing the effect of meniscectomy on OA. RESULTS: A total of 16 studies could be included for meta-analysis, accounting for 1554 ACL reconstructions performed between 1978 and 1997. Of these knees, 453 (28%) showed radiological signs of osteoarthritis (IKDC grade C or D). Furthermore, 50% of the patients with meniscectomy had osteoarthritis, compared with 16% of the patients without meniscectomy. The combined odds ratio for meniscectomy equals 3.54 (95% CI 2.56 4.91). CONCLUSIONS: The main finding of this meta-analysis is that the prevalence of radiographic knee OA after ACL reconstruction is lower than commonly perceived. However, associated meniscal resection dramatically increases the risk for developing OA. LEVEL OF EVIDENCE: Level III. PMID- 23100049 TI - Comparison of the binding characteristics of [18F]THK-523 and other amyloid imaging tracers to Alzheimer's disease pathology. AB - PURPOSE: Extensive deposition of senile plaques and neurofibrillary tangles in the brain is a pathological hallmark of Alzheimer's disease (AD). Although several PET imaging agents have been developed for in vivo detection of senile plaques, no PET probe is currently available for selective detection of neurofibrillary tangles in the living human brain. Recently, [(18)F]THK-523 was developed as a potential in vivo imaging probe for tau pathology. The purpose of this study was to compare the binding properties of [(18)F]THK-523 and other amyloid imaging agents, including PiB, BF-227 and FDDNP, to synthetic protein fibrils and human brain tissue. METHODS: In vitro radioligand binding assays were conducted using synthetic amyloid beta(42) and K18DeltaK280-tau fibrils. Nonspecific binding was determined by the addition of unlabelled compounds at a concentration of 2 MUM. To examine radioligand binding to neuropathological lesions, in vitro autoradiography was conducted using sections of AD brain. RESULTS: [(18)F]THK-523 showed higher affinity for tau fibrils than for Abeta fibrils, whereas the other probes showed a higher affinity for Abeta fibrils. The autoradiographic analysis indicated that [(18)F]THK-523 accumulated in the regions containing a high density of tau protein deposits. Conversely, PiB and BF 227 accumulated in the regions containing a high density of Abeta plaques. CONCLUSION: These findings suggest that the unique binding profile of [(18)F]THK 523 can be used to identify tau deposits in AD brain. PMID- 23100048 TI - Diabetes in older adults. PMID- 23100050 TI - The impact of coaxial core biopsy guided by FDG PET/CT in oncological patients. AB - OBJECTIVE: When deciding on therapy, FDG PET/CT-positive results should be confirmed by histology if possible. We evaluated the impact of percutaneous PET/CT-guided biopsies on histological confirmation of PET/CT-positive lesions. METHODS: We prospectively evaluated 126 patients who had undergone a PET/CT scan with positive results with an indication for histological evaluation of lesions. Imaging was performed in a PET/CT scanner with a fluoroscopic imaging system. A total of 130 lesions were accessed by PET/CT-guided biopsy. The technical feasibility, clinical success and complication rates of PET/CT-guided biopsies were evaluated. RESULTS: Of 130 PET/CT-positive lesions, 128 (98.5 %) were successfully accessed and representative tissue samples obtained. Two lesions were reaccessed due to inconclusive histological results. Histology showed that 99 of the 130 lesions (76.2 %) were malignant, and 31 lesions (23.8 %) were benign (inflammatory cells or necrotic tissue); these patients had no recurrence of disease after a minimum follow-up of 6 months. Also, in 23 of the 130 lesions (17.7 %), the patient was referred for the PET/CT-guided biopsy due to a previous nontumoral biopsy result, and of these 23 lesions, 21 were found to be malignant. The complication rates were: pneumothorax in 15/130 (11.5 %; resolved spontaneously), haemoptysis in 2/130 (1.5 %) and severe haemothorax in 1/130 (0.8 %); there was no procedure-related mortality. CONCLUSION: PET/CT-guided biopsy is feasible and may optimize the diagnostic yield of image-guided interventions. Also, PET/CT-positive lesions with no morphological correlation may now be accessible to percutaneous interventions. PMID- 23100051 TI - Brief report: children with ADHD without co-morbid autism do not have impaired motor proficiency on the movement assessment battery for children. AB - Motor proficiency was investigated in a sample of children with Attention Deficit Hyperactivity Disorder-Combined type (ADHD-CT) without autism. Accounting for the influence of co-morbid autistic symptoms in ADHD motor studies is vital given that motor impairment has been linked to social-communication symptoms in children who have co-morbid ADHD and autistic-like symptoms. Two groups of children aged between 7-14 years were recruited; children with ADHD-CT (n = 16; mean age 10 years, 7 months [SD = 1 year, 10 months]) and a typically developing (n = 16; mean age 10 years, 6 months [SD = 2 years, 6 months]) group. Motor proficiency was measured using the Movement Assessment Battery for Children-2nd Edition, ADHD symptoms were measured using the Conner's Parent Rating Scale. Children with ADHD-CT who had been screened for co-morbid autism did not display motor difficulties on the MABC-2. Higher levels of inattention, but not hyperactivity or impulsivity were associated with poorer motor performance. These findings provide indirect evidence that the motor problems that children with ADHD experience may be related to co-occurring social responsiveness impairments. PMID- 23100054 TI - Jarvik 2000 biventricular assist device conversion from old pin-shaped bearing pumps to new conical bearing pumps. AB - A patient with a Jarvik 2000 (Jarvik Heart, Inc., New York, NY) biventricular assist device had massive hemolysis and device insufficiency of the right ventricular assist device (RVAD) after the anticoagulation was temporarily reversed due to cerebral hemorrhage. After the patient's condition was stabilized by bridge use of CentriMag (Levitronix LLC, Waltham, MA) for right ventricle support, the Jarvik 2000 pumps with pin-shaped bearings were exchanged with new conical bearing pumps. Examination of the removed pumps revealed tight thrombus formation around the pin-shaped bearings. PMID- 23100053 TI - The association between mental health, stress, and coping supports in mothers of children with autism spectrum disorders. AB - Raising a child with an autism spectrum disorder (ASD) can be a stressful experience for parents. When left unmanaged, high stress levels can lead to the development of depressive symptomatology, highlighting the importance of coping supports. The current paper examined the stress level and psychological wellbeing of mothers with a child with ASD in a national survey. After adjusting for child, mother and family level characteristics, it was determined that mothers of children with ASDs were at greater risk for poor mental health and high stress levels compared to mothers of children without ASDs. The presence of maternal coping strategies, in the form of emotional and neighborhood social supports, as well as strong coping skills, reduced these risks between models. PMID- 23100055 TI - Use of an expandable metallic stent with a silicon stent in the treatment of extrinsic tracheal obstruction: a safe method for long-term endotracheal stenting. PMID- 23100056 TI - Enteric nervous system impairment in gastroschisis. AB - INTRODUCTION: After surgical repair of gastroschisis, most neonates exhibit severe intestinal dysmotility. We hypothesized that impaired development of the enteric nervous system or interstitial cells of Cajal (ICC) network contributes to impaired intestinal motility in gastroschisis. We evaluated this hypothesis in a rat model of gastroschisis. MATERIAL AND METHODS: Gastroschisis was created surgically in rat fetuses on gestational day 18, under general anesthesia, and small bowel was harvested on day 22. Intestinal weight-to-length (IW/L) ratio, and small-bowel wall thickness were assessed. Specimens were processed for hematoxylin-eosin staining or immunohistochemistry with specific markers for neuronal cells (Hoxb5), glial cells (GFAP, S100), and ICCs (c-kit). Myenteric plexus maturation was assessed morphologically and compared with sham and control fetuses. Stage of development of the myenteric plexus was graded from 1 (mature) to 3 (very immature) comparatively with specimens from E16 to E22 control fetuses. RESULTS: Compared with sham-operated or control fetuses, gastroschisis was associated with increases in mean intestinal weight/intestinal length (IW/L) ratio, and mean thicknesses of the total, muscular, and submucosal layers of the small-bowel wall. The myenteric plexus were present in the small bowel from fetuses with gastroschisis, however all exhibited abnormal myenteric plexus maturation. Thus, of the gastroschisis fetuses, 55% had an aspect similar to the immature myenteric plexus of E19-E20 fetuses and 45% to the very immature mesenteric plexus observed in E16-E18 fetuses. When compared with sham and control groups, ICCs were less abundant in eviscerated small bowel in the gastroschisis group and often exhibited weak c-kit staining or an abnormally round shape without branches. Hoxb5, a marker for enteric neuroblasts and neuronal precursors, was expressed similarly in myenteric plexuses in all groups. S100 or GFAP staining showed the presence of glial cells within the myenteric plexuses in all groups. The S100 expression level was similar in all groups. In contrast, the GFAP expression level was higher in the gastroschisis group than in the sham and control groups. CONCLUSION: Our results suggest that delayed maturation of the enteric nervous system combined with impaired ICC network development may largely explain the intestinal dysmotility seen in neonates with gastroschisis. PMID- 23100058 TI - Stapled bowel anastomoses in newborn surgery. AB - BACKGROUND: In this work, we have described our experience with repair of bowel discontinuity by applying stapled anastomosis. The aim of this study was to compare two basic intestinal anastomotic techniques and to establish the feasibility of the stapled connection of bowel in neonates and infants. METHODS: Between August 2009 and December 2011, we have performed 23 cases of hand-sewn anastomosis (group I) and 21 cases of mechanical anastomosis (group II) in children during the first 3 months of life. The standard hand technique was typically fashioned by continuous two-layer absorbable suture. A stapled anastomosis was accomplished using the linear endoscopic stapler with 2.5-mm staples (Ethicon Endo-Surgery, Cincinnati, Ohio, United States). The two groups were compared for patients' demographics, operative report, and postoperative outcomes. RESULTS: There were no differences in the preoperative parameters between the two groups regarding age before surgery, and body weight at operation. The "hand" group and "stapler" group had similar mean preoperative age (19.7 vs. 23.2 days; p = 0.096) and average weight (2884.3 vs. 2716.0 g; p = 0.692). The mean operative time for bowel continuity restoration in group I was 77.4 minutes. In contrast, the mean duration of the operation in the group II was 56.4 minutes. The differences between groups were statistically significant (p < 0.0001). The mean time of full enteral feeding for patients with mechanical anastomosis was isochronous for patients with standard hand-sewn technique (6.7 vs. 6.7 days; p = 0.926). The statistically identical postoperative hospital stay was registered in patients of both groups (13.3 vs. 14.1 days; p = 0.852). The postoperative course was uneventful in all the patients. All the anastomoses were fully functional at the end of the study. CONCLUSION: Efficacy of the stapled anastomosis was confirmed by the shorter time of operation with saving of equal time of full enteral feeding and hospitalization. PMID- 23100057 TI - Is mitrofanoff a more socially accepted clean intermittent catheterization (CIC) route for children and their families? AB - AIM: We aimed to examine the social impact of clean intermittent catheterization (CIC) on children with a neurogenic bladder and to compare the impact of urethral CIC with Mitrofanoff catheterization. METHODS: Questionnaires containing 29 questions about the social impact of CIC on the children and their families were administered with their parents or caregivers of 50 children (34 boys and 16 girls) using CIC. The mean (standard deviation [SD]) age of the children was 9.6 (4.32) years and duration on CIC was 6.1 (3.97) years. RESULTS: Seventeen children were using Mitrofanoff catheterization (group I) and 33 children urethral catheterization (group II). Of the respondents, 54% respondents reported that their children accept the use of CIC, 30% respondents reported that they do not like it, and 16% respondents reported that they always refuse and resist it. There was no difference in the level of acceptance between the two groups. Both groups reported that children were social (90%) and had close friends (88%). However, 50% felt that CIC affected mood, with 30% of the children displaying bad temper. Mitrofanoff catheterization was associated with fewer episodes of frequent urinary tract infection (p = 0.004) and greater adherence. All children from group I, who were older than 6 years, were attending school compared with 78% from group II. School performance was significantly better in group I (p = 0.022). CONCLUSION: There was acceptance of CIC by most children but Mitrofanoff catheterization seemed to have a lower social impact in terms of school performance, adherence to therapy, and complications. PMID- 23100059 TI - Long-term catch-up weight gain following fundoplication in children. AB - BACKGROUND: Laparoscopic fundoplication for severe gastroesophageal reflux (GOR) is well established in children. However, there are only a few reports on the long-term nutritional outcome following fundoplication. The aim of this study was to assess weight gain following fundoplication in children. METHODS: In this study, 127 children who underwent laparoscopic fundoplication +/- gastrostomy between July 1998 and April 2007 were followed up for a median of 29.6 months postsurgery. Data (demography, weight) at fundoplication were collected prospectively, with ethical approval. Weights were converted to Z-scores for age (Z-score of 0 is equivalent to 50th percentile, -1 to 16th centile, and -2.0 is equivalent to 2nd centile). Severe failure to thrive (FTT) was defined as a Z score of less than or equal to -2. Data were compared using the two-tailed Student t test, and multilevel regression modeling was applied. RESULTS: At the time of operation, patients had a low weight-for-age Z-score (-1.87 +/- 0.19) and 61 children (48%) had FTT. Children who received a simultaneous gastrostomy had a significantly lower Z-score at operation (-2.80 +/- 0.22) than those who did not (-0.68 +/- 0.25, p < 0.001). Overall, patients exhibited significant catch-up weight gain following surgery (+0.88 +/- 0.14, p < 0.001). The greatest increase in weight was mostly marked in patients who had a gastrostomy inserted (+1.22 +/- 0.20, p < 0.001), but it was also significant in patients who did not receive a gastrostomy (+0.44 +/- 0.17, p = 0.013). Catch-up weight gain occurred in neurologically impaired (NI) patients with (+1.31 +/- 0.22, p < 0.001) or without (+0.81 +/- 0.29, p = 0.012) gastrostomy. Weight of neurologically normal (NN) patients was within normal range but slightly lower than average before surgery ( 0.45 +/- 0.24) and this did not significantly change following surgery. There was no significant catch-up weight gain in patients (n = 9) with "esophageal pathologies" (Z-score of -1.35 +/- 0.61 at operation compared with -0.35 +/- 0.34 at follow-up; p = 0.14). CONCLUSIONS: Laparoscopic fundoplication (with or without gastrostomy placement) resulted in significant weight gain in children with GOR. Insertion of a gastrostomy at the same time resulted in greater weight gain. Pronounced weight gain occurred in NI children, whereas NN children and those with esophageal pathologies did not demonstrate any significant benefit in terms of weight gain following fundoplication. PMID- 23100060 TI - A low-cost improvised nerve stimulator is equivalent to high-cost muscle stimulator for anorectal malformation surgery. AB - AIM: Our hypothesis is that an improvised low-cost peripheral nerve stimulator is equally effective compared with a high-cost muscle stimulator for anorectal malformation surgery. METHODS: A modified Micro Stim (MS) peripheral nerve stimulator was compared with the Pena Muscle Stimulator (PS2) on identification of muscle groups during surgery, tissue energy delivery, and cost. A consecutive series of 6 patients (5 boys) with weight 5.9 to 11 kg underwent posterior sagittal anorectoplasty (PSARP). The types of malformations included four prostatic fistulae, one bulbar fistula, and one vestibular fistula. In the course of each operation, both MS and PS2 devices were used to identify muscle groups in a head-to-head comparison with video documentation. The energy delivery was determined using a digital oscilloscope at settings used during the operations (#9 on the MS and 120 mA on the PS2). Price quotes for each device were obtained from commercial vendors. RESULTS: The subjective assessment of the surgical team was that both devices demonstrated equivalent utility in identifying critical muscle groups, although the MS probe was less convenient to use. There were no intraoperative complications, including tissue burns with either device, and no postoperative complications. The energy delivery of the devices was similar, 23.5 mW and 25.3 mW for the MS and PS2, respectively. The cost of the MS was US$ 162 and the PS2 was US$ 12,371. CONCLUSION: The MS nerve stimulator demonstrated equivalent effectiveness compared with the PS2 muscle stimulator at 75-fold lower cost. The MS device may serve as a low-cost effective tool for PSARP. PMID- 23100061 TI - Role of 320-slice CT imaging in the diagnostic workup of patients with chronic thromboembolic pulmonary hypertension. AB - BACKGROUND: Right-sided heart catheterization (RHC) and pulmonary digital subtraction angiography (PDSA) are the standard methods used in diagnosing suspected or defi nite chronic thromboembolic pulmonary hypertension (CTEPH). We studied the ability of 320-slice CT imaging to detect simultaneously chronic thromboembolic fi ndings in the pulmonary arteries and pulmonary hemodynamics based on the curvature of the interventricular septum (IVS) in CTEPH . METHODS: Forty-four patients with high clinical suspicion of CTEPH underwent RHC, PDSA, and enhanced double-volume retrospective ECG-gated 320-slice CT scan. We measured the sensitivity and specificity of CT imaging to detect thrombi in the pulmonary arteries compared with PDSA. We also compared IVS bowing (expressed as curvature) measured on the short-axis cine heart image with pulmonary arterial pressure (PAP) obtained by RHC. RESULTS: Compared with PDSA, the sensitivity and specificity of CT imaging to detect chronic thromboembolic findings were 97.0% and 97.1% at the main/lobar level and 85.8% and 94.6% at the segmental level, respectively. The correlation coefficients of IVS curvature with systolic PAP and mean PAP were 2 0.79 ( P , .001) and 2 0.86 ( P , .001), respectively. CONCLUSIONS: The use of 320-slice CT imaging allows for less invasive and simultaneous detection of thrombi and evaluation of pulmonary hemodynamics for the diagnostic work-up of CTEPH. PMID- 23100062 TI - Medicinal gold compounds form tight adducts with the copper chaperone Atox-1: biological and pharmacological implications. AB - Based on ESI-MS measurements, we show here that some representative cytotoxic gold(III) compounds produce stable adducts upon reaction with the copper chaperone Atox-1; notably, such adducts contain gold in the oxidation state +1. These findings are of interest to understand the intracellular metabolism of medicinal gold species and to develop new potent inhibitors of the copper trafficking system. PMID- 23100063 TI - Absence of induced resistance in Agaricus bisporus against Lecanicillium fungicola. AB - Lecanicillium fungicola causes dry bubble disease and is an important problem in the cultivation of Agaricus bisporus. Little is known about the defense of mushrooms against pathogens in general and L. fungicola in particular. In plants and animals, a first attack by a pathogen often induces a systemic response that results in an acquired resistance to subsequent attacks by the same pathogen. The development of functionally similar responses in these two eukaryotic kingdoms indicates that they are important to all multi-cellular organisms. We investigated if such responses also occur in the interaction between the white button mushroom and L. fungicola. A first infection of mushrooms of the commercial A. bisporus strain Sylvan A15 by L. fungicola did not induce systemic resistance against a subsequent infection. Similar results were obtained with the A. bisporus strain MES01497, which was demonstrated to be more resistant to dry bubble disease. Apparently, fruiting bodies of A. bisporus do not express induced resistance against L. fungicola. PMID- 23100064 TI - Walleye dermal sarcoma virus: expression of a full-length clone or the rv-cyclin (orf a) gene is cytopathic to the host and human tumor cells. AB - Walleye dermal sarcoma virus (WDSV) is etiologically associated with a skin tumor, walleye dermal sarcoma (WDS), which develops in the fall and regresses in the spring. WDSV genome contains, in addition to gag, pol and env, three open reading frames (orfs) designated orf a (rv-cyclin), orf b and orf c. Unintegrated linear WDSV provirus DNA isolated from infected tumor cells was used to construct a full-length WDSV provirus clone pWDSV, while orf a was cloned into pSVK3 to construct the expression vector porfA. Stable co-transfection of a walleye cell line (W12) with pWDSV and pcDNA3 generated fewer and smaller G418-resistant colonies compared to the control. By Northern blot analysis, several small transcripts (2.8, 1.8, 1.2, and 0.8 kb) were detected using a WDSV LTR-specific probe. By RT-PCR and Southern blot analysis, three cDNAs (2.4, 1.6 and 0.8 kb) were identified, including both orf a and orf b messenger. Furthermore stable co transfection of both a human lung adenocarcinoma cell line (SPC-A-1) and a cervical cancer cell line (HeLa) with pcDNA3 and ether porfA or pWDSV also generated fewer and smaller G418-resistant colonies. We conclude that expression of the full-length WDSV clone or the orf a gene inhibits the host fish and human tumor cell growth, and Orf A protein maybe a potential factor which contributes to the seasonal tumor development and regression. This is the first fish provirus clone that has been expressed in cell culture system, which will provide a new in vitro model for tumor research and oncotherapy study. PMID- 23100065 TI - Relationship between gene polymorphisms of two cytokine genes (TNF-alpha and IL 6) and occurring of lung cancers in the ethnic group Han of China. AB - Tumor necrosis factor (TNF) is a cytokine involved in inflammation and TNF-alpha might be synthesized ectopically in malignant tumors. Interleukin-6 (IL-6) is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. The present study is to investigate the relationship between genetic polymorphisms of the TNF-alpha and IL-6 genes and susceptibility to lung cancers in the ethnic group Han of North China. The genotypes in the -238G locus of TNF alpha gene and the -572C locus of the IL-6 gene were determined by PCR-RFLP method in 138 patients with lung cancers and 138 healthy individuals. Software PHASE 1.0 was used to analyze the experimental data. The non-conditional logistic regression model was used to analyze the statistical association of genotypes and susceptibility in two groups adjusted by multiple factors. We found that the TNF alpha and IL-6 polymorphisms may be a critical risk for the genetic susceptibility to lung cancers in the ethnic group Han of North China. SNP polymorphisms at the -238G locus of TNF-alpha gene and the -572C locus of the IL 6 gene were detected by the RFLP-PCR method. We found that high rates of single base G-to-A alteration at the -238G locus of both alleles and high rates of single-base C-to-G alteration at the -572C locus of both alleles correlated with occurring of lung cancers. It is possible that the SNP markers at the -238G locus of TNF-alpha gene and the -572C locus of the IL-6 gene serve as biological markers of lung cancers upon further study in the future. PMID- 23100067 TI - Variation in the reproductive performance of the Trollius-Chiastocheta mutualism at the edge of its range in north-east Germany. AB - Empirical studies into obligate pollination mutualisms which elucidate the variation in reproductive performance of shrinking populations within human altered environments are rare. This study focuses on the obligate pollination mutualism between Trollius europaeus (Ranunculaceae) and fly species of the genus Chiastocheta which act both as the plant's main pollinators and as predators in that their larvae eat a fraction of the developing seeds. The study area is situated in the lowlands of north-east Germany. Many populations of T. europaeus have become comparatively small and scattered in this region as a consequence of agricultural land use intensification. We studied the plant's reproductive fitness in populations ranging in size from 7 to 12,000 flowers. In a field experiment, we applied four pollination treatments and also recorded fly density in 28 natural T. europaeus populations. The fitness of the offspring from 19 populations was studied in a common garden experiment. In both approaches, a reduction in the fitness of small host plant populations could be demonstrated. Fitness loss can be put down to the quantitative and qualitative limitation of pollen caused by inbreeding and the negative feedback on relative seed set caused by the reduced ability of small plant populations to support a sufficiently large fly population. Although increases in fly density are associated with rising predation costs, the plant species' net benefit is a positive function of its population size. Our study highlights the reproductive variability of the Trollius-Chiastocheta interaction along a population size gradient in a marginal region of its range, thus contributing to the understanding of the overall variability of this mutualism. PMID- 23100068 TI - Surface exciton separation in photoexcited MgO nanocube powders. AB - In MgO nanocube powders surface excitons can separate and the resulting charge carriers provide reactive adsorption sites at well-defined surface elements. We employed photoluminescence (PL) emission bands originating from the photoexcitation of nanocube corners and edges as quantitative probes to explore their chemical reactivity towards molecular hydrogen. Surface excitons which form at corners and edges exhibit similar cross-sections for separation in vacuum. The separation of edge excitons, however, is significantly enhanced in hydrogen atmosphere when hydrogen adsorption occurs as a simultaneous surface process. The electronic structure of MgO nanocube edges which split hydrogen heterolytically upon generation of surface hydroxyls and hydrides is unaffected by the photoexcitation of corners. Respective edges, however, are efficient absorption sites for UV photons. Transfer of exciton energy to oxygen ions in corners is followed by exciton separation which transforms corner ions into surface radicals leading to a well-defined starting point for the site selective functionalization of metal oxide nanostructures. PMID- 23100066 TI - A comparative proteomics analysis of soybean leaves under biotic and abiotic treatments. AB - A comparative proteomic study was made to explore the molecular mechanisms, which underlie soybean root and stem defense response caused by the oomycete Phytophthora sojae strain P6497. Soybean (Glycine max cv. Xinyixiaoheidou) seedling roots were incubated in salicylic acid, methyl jasmonate, 1-amino cyclopropane-1-carboxylic acid, hydrogen peroxide, sodium nitroprusside, vitamin B(1) and P. sojae zoosperm in order to determine whether the corresponding leaves play a role in the defense response at the proteomic level. The results showed that the proteome of leaves had no significant differences. Of the 21 identified proteins identified in the study, 62 % were involved in predominately in energy functions. Those involved in protein synthesis, secondary metabolism and metabolism categories followed in abundance, where proteins involved as transporters and in transcription were the least and represented only 5 %. Those related to energy were shown to be involved in photosynthesis and photorespiration activities. The present study provides important information with regards to proteomic methods aimed to study protein regulations of the soybean-P. sojae pathosystem, especially in terms of host resistance to this pathogen. PMID- 23100070 TI - ECR 2011 Book of Abstracts - A - Postgraduate Educational Programme. PMID- 23100069 TI - AFOMP policy statement no. 4: recommendations for continuing professional development systems for medical physicists in AFOMP countries. AB - This policy statement, which is the fourth of a series of documents being prepared by the Asia-Oceania Federation of Organizations for Medical Physics Committees Professional Development Committee, gives guidance on how member countries could develop a continuing professional development system for ensuring that its clinical medical physicists are up-to-date in their knowledge and practice. It is not intended to be prescriptive as there are already several CPD systems successfully operated by AFOMP member countries and elsewhere that vary considerably in scope and structure according to local culture, practice and legislation but all of which are capable of ensuring that physicists are up-to date. It is intended to be advisory and set out options for member countries to develop their individual CPD systems. PMID- 23100072 TI - ECR 2011 Book of Abstracts - C - Scientific and Educational Exhibits. PMID- 23100071 TI - ECR 2011 Book of Abstracts - B - Scientific Sessions. PMID- 23100073 TI - ECR 2011 Book of Abstracts - D - Satellite Symposia. PMID- 23100075 TI - ECR 2011 Book of Abstracts - F - List of Authors and Co-Authors. PMID- 23100076 TI - ECR 2011 Book of Abstracts - G - List of Moderators. PMID- 23100077 TI - ECR 2011 Book of Abstracts - H - Scientific Sessions for Medical Students. PMID- 23100078 TI - Outcomes after knee joint extensor mechanism disruptions: is it better to fracture the patella or rupture the tendon? AB - OBJECTIVES: The purpose of this study was to compare the outcome after the operative treatment of patella fractures (PFs) as compared with those of quadriceps tendon and patella tendon (PT) ruptures. DESIGN: This pertains to a retrospective case control. SETTING: The setting was in academic teaching hospitals. PATIENTS: Ninety-four patients with 99 extensor mechanism disruptions were treated operatively. Of these, 50 (50%) were PFs; 36 (37%) were quadriceps ruptures; and 13 (13%) were PT ruptures. MAIN OUTCOME MEASURES: The patients were evaluated at 6 and 12 months and were tested for range of motion, quadriceps circumference and strength, SF36, Lysholm, and Tegner outcome scores by independent observers. Radiographs of the knee were obtained to assess bony healing, posttraumatic arthritis, and heterotopic ossification. RESULTS: A minimum of 12-month follow-up (range 12-81 months) was available for 76 patients (77%). PFs were seen more commonly in women (P < 0.001) and PT ruptures tended to occur in younger males (P < 0.001), with no difference in the body mass index. Thigh circumference was significantly smaller than normal in PFs at 1 year as compared with tendon injuries. At latest follow-up, there were no significant differences noted with respect to knee range of motion, radiographic arthritis, Tegner, Lysholm, or SF36 scores. CONCLUSIONS: There were no significant differences with regard to outcome in patients sustaining these injuries. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23100079 TI - Treatment of the stress positive ligamentous SE4 ankle fracture: incidence of syndesmotic injury and clinical decision making. AB - OBJECTIVES: The objective of the study was to review our experience with the treatment of stress positive (+) supination and external pattern injuries using shared decision making with the patients. DESIGN: Retrospective case review. SETTING: Level 1 trauma center. PATIENTS: Over a 9-year period, we treated 114 patients (aged 19-76 years, average 43 years) with stress (+) supination and external rotation type fibula fractures, who were included in the present study. INTERVENTION: X-rays were reviewed, and the medial clear space (MCS) measured on the presentation, stress, and final united radiographs. The decision for surgical or nonsurgical management was made by the patient and surgeon after a discussion of risks/benefits of both. Syndesmotic instability for the operative cases was diagnosed by medial widening and talar subluxation on abduction/external rotation stress after fibular fixation. MAIN OUTCOME MEASURE: MCS measurement at union. RESULTS: Of the 114 cases, 54 were definitively treated in a cast, and 60 were treated operatively. Twenty-seven (45%) of the operative cases demonstrated syndesmotic instability on radiographic examination. The MCS on stress examination was statistically different, with greater widening seen for operatively treated patients (4.8 +/- 0.5 vs. 6.9 +/- 0.86) (P < 0.001). No patient healed with any subluxation on weight bearing x-rays. CONCLUSIONS: Stress (+) SE pattern fibular fractures with minimal MCS widening on stress examination may be treated in a cast to union with predictable healing. In those patients treated operatively, the treating surgeon should be aware of the high rate of syndesmotic injury. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 23100080 TI - Management of pulmonary arterial hypertension during pregnancy: a retrospective, multicenter experience. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with a predilection for young women that is associated with right ventricular failure and premature death. PAH can complicate pregnancy with hemodynamic instability or sudden death during parturition and postpartum. Our aim was to examine the impact of PAH on pregnancy outcomes in the modern era. METHODS: We conducted a retrospective evaluation of pregnant patients with PAH managed between 1999 and 2009 at five US medical centers. Patient demographics, medical therapies, hemodynamic measurements, manner of delivery, anesthetic administration, and outcomes were assessed. RESULTS: Among 18 patients with PAH, 12 continued pregnancy and six underwent pregnancy termination. Right ventricular systolic pressure in patients managed to parturition was 82 +/- 5 mm Hg and in patients with pregnancy termination was 90 +/- 16 mm Hg. Six patients underwent pregnancy termination at mean gestational age of 13 +/- 1.0 weeks with no maternal deaths or complications. Twelve patients elected to continue their pregnancy and were hospitalized at 29 +/- 1.4 weeks. PAH-specific therapy was administered to nine (75%) at time of delivery consisting of sildenafil, IV prostanoids, or combination therapy. All parturients underwent Cesarean section at 34 weeks with one in-hospital death and one additional death 2 months postpartum for maternal mortality of 16.7%. CONCLUSIONS: Compared with earlier reports, maternal morbidity and mortality among pregnant women with PAH was reduced, yet maternal complications remain significant and patients should continue to be counseled to avoid pregnancy. PMID- 23100081 TI - Follow-up strategies in head and neck cancer other than upper aerodigestive tract squamous cell carcinoma. AB - Post-therapy follow-up for patients with head and neck cancer other than upper aerodigestive tract squamous cell carcinoma should meet several objectives: to detect both local, regional or distant recurrences, to evaluate acute and long term treatment-related side effects, to guide the rehabilitation process, and to provide psychosocial support when needed. To our knowledge, there are no published reports in the literature dedicated to the follow-up of patients with these tumours. A comprehensive literature search for post-treatment follow-up strategies spanning from 1980 to 2012 was performed on several databases. This review focuses on malignant salivary gland tumors, soft tissue sarcomas, cutaneous squamous cell carcinomas, and sinonasal adenocarcinomas. Given the varying biological behavior and treatment-related factors and based on the literature, different recommendations are made on the follow-up of patients with the above-mentioned tumors. PMID- 23100082 TI - The evaluation of ozone and betahistine in the treatment of tinnitus. AB - The aim of the study is to evaluate the effectiveness of ozone and betahistine treatments in the treatment of tinnitus. Sixty-eight patients were enrolled in this randomized, prospective controlled study. The ozone group consisted of 27, betahistine group consisted of 26 and control group consisted of 15 patients. The patients in ozone group received 10 sessions of ozone treatment via major autohemotherapy. Betahistine group received 48 mg/day betahistine tablets per oral for 3 months duration. The control group was followed up without any treatment given. The evaluation of tinnitus was made by tinnitus loudness and tinnitus handicap inventory (THI). The changes in findings from baseline to 3rd and 6th months were assessed, and the group results were compared. Comparison of the initial mean tinnitus loudness and 3 and 6 months after treatment in each of the three groups did not reveal a significant difference. The comparison between the groups in terms of the improvement of tinnitus loudness was not significant (p = 0.821). Comparison of the initial mean THI and 3 and 6 months after treatment revealed a significant difference in ozone and betahistine groups but not in the control group. When the delta (Delta) THI (the change of mean THI between the initial and 6th month) was compared between the groups, there was no significant difference. This randomized controlled study investigating the effects of ozone in tinnitus tries to shed light to a new method of treatment in tinnitus. The findings of the study does not provide enough evidence to support ozone and betahistine as a treatment for tinnitus and further research on the subject is necessary. PMID- 23100083 TI - Transnasal endoscopic management of petrous apex and clivus selected lesions. AB - The objective of this study was to report a series of selected primary skull base benign lesions midline located by transnasal endoscopic transsphenoidal approach. A retrospective review of 5 cases is presented: four cholesterol granuloma of the petruos apex and one of the clivus. All patients have been successfully treated via transnasal endoscopic transsphenoidal approach. The mean duration of follow up was 27 months (range 12-50 months). No postoperative complication such as CSF leak, meningitis, or encephalocele and no signs of recurrence have been noticed. The transnasal route is a minimally invasive, safe, and efficient technique to approach the petrous apex and clivus for selected midline skull base lesions removal. PMID- 23100084 TI - Age-related changes in rat intrinsic laryngeal muscles: analysis of muscle fibers, muscle fiber proteins, and subneural apparatuses. AB - We compared age-related changes in the intrinsic laryngeal muscles of aged and young adult rats by determining the number and diameter of muscle fibers, contractile muscle protein (myosin heavy chain isoforms, MHC) composition, and the morphology of the subneural apparatuses. In aged rats, both the numbers and the diameters of muscle fibers decreased in the cricothyroid (CT) muscle. The number of fibers, but not diameter, decreased in the thyroarytenoid (TA) muscle. In the posterior cricoarytenoid (PCA) muscle, neither the number nor the diameter of fibers changed significantly. Aging was associated with a decrease in type IIB and an increase in type IIA MHC isoform levels in CT muscle, but no such changes were observed in the TA or PCA muscles. Morphological examination of primary synaptic clefts of the subneural apparatus revealed that aging resulted in decreased labyrinthine and increased depression types in only the CT muscle. In the aged group, morphologically immature subneural apparatuses were found infrequently in the CT muscle, indicating continued tissue remodeling. We suggest, therefore, that age-related changes in the intrinsic laryngeal muscles primarily involve the CT muscle, whereas the structures of the TA and PCA muscles may better resist aging processes and therefore are less vulnerable to functional impairment. This may reflect differences in their roles; the CT muscle controls the tone of the vocal folds, while the TA and PCA muscles play an essential role in vital activities such as respiration and swallowing. PMID- 23100086 TI - Moist heat postconditioning to increase flap survival. AB - One of the areas of interest within the discipline of reconstructive microsurgery is increasing the amount of tissue harvested along with a given pedicle and sustaining it. The aim of this study is to introduce moist heat postconditioning as a means to increase skin flap survival and evaluate its effectiveness. Eight white New Zealand rabbits weighing 2500 to 3000 g were separated into two groups. In both groups, the truncal flaps spanning four consecutive angiosomes were elevated bilaterally. Flaps were inset back afterwards, and to the flaps in the trial group moist heat was applied for 30 minutes. After 2 weeks, the flaps were photographed and flap survival ratios were calculated via ImageTool(c) software (University of Texas Health Science Center, San Antonio, Texas, USA). With an average necrosis ratio of 4.91% versus 37.31%, the flaps treated with moist heat displayed a significantly better survival rate (p = 0.000). This study presenting our new method demonstrates that application of moderate moist heat right after the flap inset provides a significant increase in flap survival and introduces a noninvasive, cost-effective, and safe method for clinical use. PMID- 23100085 TI - Inner ear decompression sickness in scuba divers: a review of 115 cases. AB - Inner ear decompression sickness (IEDCS) in scuba divers is increasingly observed, but epidemiological data are limited to small case series and the pathogenesis remains elusive. We report our experience over a 13-year period. We also thought to demonstrate that the development of this injury is mainly attributed to a mechanism of vascular origin. Diving information, clinical data, presence of circulatory right-to-left shunt (RLS), and laboratory investigations of 115 recreational divers were retrospectively analyzed. A follow-up study at 3 months was possible with the last 50 consecutive cases. IEDCS (99 males, 44 +/- 11 years) represented 24 % of all the patients treated. The median delay of onset of symptoms after surfacing was 20 min. Violation of decompression procedure was recorded in 3 % while repetitive dives were observed in 33 %. The median time to hyperbaric treatment was 180 min. Pure vestibular disorders were observed in 76.5 %, cochlear deficit in 6 % and combination of symptoms in 17.5 %. Additional skin and neurological disorders were reported in 15 % of cases. In 77 %, a large RLS was detected with a preponderant right-sided lateralization of IEDCS (80 %, P < 0.001). Incomplete recovery was found in 68 % of the followed patients. Time to recompression did not seem to influence the clinical outcome. IEDCS is a common presentation of decompression sickness following an uneventful scuba dive, but the therapeutic response remains poor. The high prevalence of RLS combined with a right-sided predominance of inner ear dysfunction suggests a preferential mechanism of paradoxical arterial gas emboli through a vascular anatomical selectivity. PMID- 23100087 TI - Can cuttlefish learn by observing others? AB - Observational learning is the ability to learn through observing others' behavior. The benefit of observational learning is apparent in that individuals can save time and energy without trial-and-error, thus enhance the chance of survival and reproduction. Cephalopods (octopus, squid, and cuttlefish) have the most sophisticated central nervous system among invertebrates, and it is conceivable that cephalopods can develop some forms of cognition. Although it has been suggested that octopuses have the capacity of observational learning, a previous study indicates that cuttlefish do not improve their predation tactics by observing conspecifics. Given that the danger avoidance is important for animals' survival, we sought to reevaluate whether cuttlefish show some form of observational learning or observational conditioning under threatening conditions. Cuttlefish (Sepia pharaonis) were divided into three groups: the Experiencer group, the Observer group, and the Control group. In the training phase, a toy submarine was remotely controlled to expel the cuttlefish from its initially preferred place to establish the threat-place association in the Experiencer group. In the Observer group, the threat-place association was established by expelling a conspecific demonstrator at the observer's initially preferred place while the observer watched the whole process from behind a transparent divider. In the Control group, the observer watched a conspecific and a static toy submarine without actual threat. In the testing phase, the choice of safe place in the absence of threat was used to probe the learning/conditioning of cuttlefish. In the Experiencer group, we found that animals chose the safe place more often than their initially preferred place after training, an indication of the association learning/conditioning. However, in the Observer group, only a subset of animals showed this threat-place association by observation, while the place preference was unchanged in the Control group. These results indicate that most cuttlefish did not learn by observing others, but individual differences exist, and some cuttlefish may have the potential of observational learning/conditioning within their cognitive capacities. PMID- 23100088 TI - Diagnosis and assessment of Takayasu arteritis by multiple biomarkers. AB - BACKGROUND: Patients with Takayasu arteritis (TA) often show recurrence under steroid treatment without an elevation of C-reactive protein (CRP). There is a report that matrix metalloproteinase (MMP)-2, MMP-3, MMP-9 and pentraxin3 (PTX3) could be sensitive biomarkers, but the characteristics of these biomarkers have not been established. METHODS AND RESULTS: We enrolled 45 consecutive patients; 28 were grouped in an active phase as evidenced by clinical recurrence within 2 years of blood sampling. Circulating levels of high-sensitivity (hs)CRP, MMPs, and PTX3 were determined. Patients in an active phase showed higher levels of hsCRP, MMP-9, and PTX3. Area under the receiving operating characteristics curves of hsCRP and PTX3 were significantly higher than that of MMP-9. Among the 28 patients with active TA, 71% was positive for hsCRP and 82% for PTX3. Patients without recurrence showed significantly higher plasma levels of MMP-9. There was a positive correlation between the plasma MMP-3 level and the prednisolone dose. However, PTX3 and MMP-9 levels did not have such a correlation. CONCLUSIONS: PTX3 and MMP-9, which are not affected by prednisolone, could be sensitive biomarkers for assessing TA activity. Evaluation of MMP-9 may suggest prior existence of TA. PMID- 23100089 TI - Pulmonary artery mapping for differential diagnosis of left-sided atrial tachycardia. AB - BACKGROUND: Distinguishing left-and right-sided atrial tachycardia (AT) is often challenging. The coronary sinus (CS) provides information only concerning the anterior left atrium (LA). Potentials recorded in the pulmonary artery (PA) have been substituted for those of the upper posterior LA because of their anatomical relationship. METHODS AND RESULTS: Three patterns were designed, using potentials in the PA, right atrium (RA) and CS, to predict the side of AT. Two patterns were for left-sided AT and 1 pattern was for right-sided AT. Ten left-sided and 11 right-sided ATs were investigated regardless of mechanism. Electrode catheters were inserted in the RA, His bundle region, and CS, and an ablation catheter was inserted into the left and/or right PA. The sequences from these catheters were analyzed before detailed electroanatomical mapping. Patterns were obtained for 20 of 21 ATs. The mechanism was focal in 16 ATs and macroreentry in 5. The method predicted left-sided AT with a sensitivity of 78%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 84%, and an accuracy of 90%. CONCLUSIONS: The use of potentials in PA combined with conventional RA and CS electrograms is useful for distinguishing left-sided AT from right-sided AT, regardless of mechanism. PMID- 23100090 TI - Association between indoxyl sulfate and cardiac dysfunction and prognosis in patients with dilated cardiomyopathy. AB - BACKGROUND: Serum indoxyl sulfate (IS) is a uremic toxin that accelerates the progression of chronic kidney disease (CKD). The aim of this study was to determine whether serum IS is associated with hemodynamic parameters or cardiac events in patients with nonischemic dilated cardiomyopathy (DCM). METHODS AND RESULTS: The 76 patients with DCM had their serum IS and plasma brain natriuretic peptide (BNP) levels measured, and underwent echocardiographic examination. Mean (+/- standard deviation) left ventricular ejection fraction (LVEF) and BNP levels in the patients were 32.5 +/- 10.7% and 204 +/- 219 pg/ml, respectively. Patients were divided into 2 groups, low IS (<0.9 ug/ml) and high IS (>= 0.9 ug/ml), based on the median value of serum IS. Although there were no significant differences in LVEF and BNP between the groups, E/e' was significantly greater in the high IS group than in the low IS group. Furthermore, E/e' was an independent determinant of serum IS level. The risk of a cardiac event was significantly higher in the high IS group than in the low IS group (P=0.014). Moreover, serum IS was a significant predictor of cardiac events even after adjustment for BNP. CONCLUSIONS: Cardiac dysfunction is associated with the serum IS level, which might serve as a new prognostic marker in DCM patients with normal renal function or mild to moderate CKD. PMID- 23100091 TI - Relaxivity control of magnetic nanoclusters for efficient magnetic relaxation switching assay. AB - 50 nm Magnetic nanocluster (MNC) was deliberately selected as an efficient probe for the magnetic relaxation switching (MRSw) assay. After surface modification of MNCs with poly(acrylic acid) to give PAA-MNCs, and employing streptavidin-biotin interactions for the MRSw assay model, a few tenths pM concentration of strepavidin could be determined. PMID- 23100092 TI - Sinus rhythm with an isolated ST-segment elevation in V2 : Sinus rhythm with an isolated ST-segment elevation in V2. PMID- 23100093 TI - Two cases of aorto-right atrial tunnel: clinical presentation, imaging and percutaneous closure. AB - Communication between the aortic sinus and a cardiac chamber is a rare anomaly that can be diagnosed in children and young adults. We describe two cases with a tunnel between the aortic sinus and right atrium, discuss diagnostic modalities, and review the literature on this anomaly. PMID- 23100094 TI - Ablation time efficiency and lesion volume - in vitro comparison of 4 mm, non irrigated, gold- and platinum-iridium-tip radiofrequency ablation catheters. AB - PURPOSE: We investigated the development of in vitro lesion formation in relation to ablation time and power delivery using 4-mm, non-irrigated, platinum-iridium (Pt/Ir), and gold-tip catheters. METHODS: Radiofrequency catheter ablation was performed on porcine liver preparations in a 5-60-s time range with 5 s increments applied at different lesion sites. Each series was repeated four times for both catheters. The lesion volume, the delivered energy, and the ablation power curves were analyzed in 96 ablations. RESULTS: The delivered energy was higher and the lesion volume was significantly larger when using a gold-tip catheter. The lesion volume that was created with the Pt/Ir-tip electrode within 60 s was created after a shorter 40 s ablation period with the gold-tip electrode (Au, 40 s, 345 +/- 75 mm(3) vs. Pt/Ir, 60 s, 328 +/- 30 mm(3)). CONCLUSION: The gold-tip catheters had a lower tip temperature resulting in higher energy delivery due to the better thermo-conductivity of the gold alloy. A significantly higher lesion volume and a faster lesion creation were found for gold catheters as compared to Pt/Ir catheters. Gold-tip catheters can create the same adequate lesion within 33.3 % less ablation time due to the higher values of delivered energy as compared to those observed with the use of Pt/Ir catheters. PMID- 23100096 TI - Does pre-operative traction on the cervix approximate intra-operative uterine prolapse? Comment. PMID- 23100098 TI - Transvaginal repair of vesicovaginal fistula: surgical techniques to improve access and successful vaginal closure. AB - This video demonstrates surgical techniques to improve closure of high vesicovaginal fistula using the vaginal approach and the Latzko procedure. PMID- 23100099 TI - Extensive expansion of primary human gamma delta T cells generates cytotoxic effector memory cells that can be labeled with Feraheme for cellular MRI. AB - Gamma delta T cells (GDTc) comprise a small subset of cytolytic T cells shown to kill malignant cells in vitro and in vivo. We have developed a novel protocol to expand GDTc from human blood whereby GDTc were initially expanded in the presence of alpha beta T cells (ABTc) that were then depleted prior to use. We achieved clinically relevant expansions of up to 18,485-fold total GDTc, with 18,849-fold expansion of the Vdelta1 GDTc subset over 21 days. ABTc depletion yielded 88.1 +/ 4.2 % GDTc purity, and GDTc continued to expand after separation. Immunophenotyping revealed that expanded GDTc were mostly CD27-CD45RA- and CD27 CD45RA+ effector memory cells. GDTc cytotoxicity against PC-3M prostate cancer, U87 glioblastoma and EM-2 leukemia cells was confirmed. Both expanded Vdelta1 and Vdelta2 GDTc were cytotoxic to PC-3M in a T cell antigen receptor- and CD18 dependent manner. We are the first to label GDTc with ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles for cellular MRI. Using protamine sulfate and magnetofection, we achieved up to 40 % labeling with clinically approved Feraheme (Ferumoxytol), as determined by enumeration of Perls' Prussian blue-stained cytospins. Electron microscopy at 2,800* magnification verified the presence of internalized clusters of iron oxide; however, high iron uptake correlated negatively with cell viability. We found improved USPIO uptake later in culture. MRI of GDTc in agarose phantoms was performed at 3 Tesla. The signal-to-noise ratios for unlabeled and labeled cells were 56 and 21, respectively. Thus, Feraheme-labeled GDTc could be readily detected in vitro via MRI. PMID- 23100100 TI - A general and flexible methodology to define thresholds for heat health watch and warning systems, applied to the province of Quebec (Canada). AB - Several watch and warning systems have been established in the world in recent years to prevent the effects of heat waves. However, many of these approaches can be applied only in regions with perfect conditions (e.g., enough data, stationary series or homogeneous regions). Furthermore, a number of these approaches do not account for possible trend in mortality and/or temperature series, whereas others are generally not adapted to regions with low population densities or low daily mortality levels. In addition, prediction based on multiple days preceding the event can be less accurate if it attributes the same importance to each of these days, since the forecasting accuracy actually decreases with the period. The aim of the present study was to identify appropriate indicators as well as flexible and general thresholds that can be applied to a variety of regions and conditions. From a practical point of view, the province of Quebec constitutes a typical case where a number of the above-mentioned constraints are present. On the other hand, until recently, the province's watch and warning system was based on a study conducted in 2005, covering only the city of Montreal and applied to the whole province. The proposed approach is applied to each one of the other health regions of the province often experiencing low daily counts of mortality and presenting trends. The first constraint led to grouping meteorologically homogeneous regions across the province in which the number of deaths is sufficient to carry out the appropriate data analyses. In each region, mortality trends are taken into account. In addition, the proposed indicators are defined by a 3-day weighted mean of maximal and minimal temperatures. The sensitivity of the results to the inclusion of traumatic deaths is also checked. The application shows that the proposed method improved the results in terms of sensitivity, specificity and number of yearly false alarms, compared to those of the existing and other classical approaches. An additional criterion based on the Humidex is applied in a second step and a local validation is applied to historical observations at reference forecasting stations. An integrated heat health watch and warning system with thresholds that are adapted to the regional climate has thus been established for each sub-region of the province of Quebec and became operational in June 2010. PMID- 23100101 TI - The association between temperature and mortality in tropical middle income Thailand from 1999 to 2008. AB - We have investigated the association between tropical weather condition and age sex adjusted death rates (ADR) in Thailand over a 10-year period from 1999 to 2008. Population, mortality, weather and air pollution data were obtained from four national databases. Alternating multivariable fractional polynomial (MFP) regression and stepwise multivariable linear regression analysis were used to sequentially build models of the associations between temperature variable and deaths, adjusted for the effects and interactions of age, sex, weather (6 variables), and air pollution (10 variables). The associations are explored and compared among three seasons (cold, hot and wet months) and four weather zones of Thailand (the North, Northeast, Central, and South regions). We found statistically significant associations between temperature and mortality in Thailand. The maximum temperature is the most important variable in predicting mortality. Overall, the association is nonlinear U-shape and 31 degrees C is the minimum-mortality temperature in Thailand. The death rates increase when maximum temperature increase with the highest rates in the North and Central during hot months. The final equation used in this study allowed estimation of the impact of a 4 degrees C increase in temperature as projected for Thailand by 2100; this analysis revealed that the heat-related deaths will increase more than the cold related deaths avoided in the hot and wet months, and overall the net increase in expected mortality by region ranges from 5 to 13 % unless preventive measures were adopted. Overall, these results are useful for health impact assessment for the present situation and future public health implication of global climate change for tropical Thailand. PMID- 23100102 TI - Big expectations and little Civil Society Organizations. PMID- 23100104 TI - Global health equity: opportunities and threats. PMID- 23100106 TI - Development and validation of H11B2C2 monoclonal antibody-reactive hyaluronic acid binding protein: overexpression of HABP during human tumor progression. AB - Informative biomarkers of tumor progression have been elusive. The interaction between hyaluronic acid (HA) and its binding proteins (HABP) plays a pivotal role during malignancy. In the present study, we have developed a monoclonal antibody (mAb, termed as H11B2C2 mAb) and showed that this mAb specifically reacts with overexpressed HABP from a wide variety of malignant tumors as compared with benign tumors. In Western blot analysis, H11B2C2 mAb detected a major 80-kDa protein from human cancer cell lines, and the overexpression of 55-57- and 30-kDa proteins in malignant tumors compared with benign tumors. Furthermore, immunohistochemical analysis of different types of benign and malignant tumors with different grades showed higher expression of HABP in all the malignant tumors when compared with the benign tumors. HABP overexpression was specific to tumor cells when compared with the surrounding stroma and localized on the cell surface as well as in the intracellular region. The competitive inhibition experiments using HA polymer and its oligosaccharides in the Western blot and immunohistopathology experiments suggested that the H11B2C2 mAb-reactive protein is HABP. Altogether, the present study showed overexpression of the H11B2C2 mAb reactive HABP in various malignant tumors as compared with benign tumors. Thus, H11B2C2 mAb-reactive HABP can be used as a potential biomarker during tumor progression. PMID- 23100107 TI - Comparison of two populations of the pantropical predator Amblyseius largoensis (Acari: Phytoseiidae) for biological control of Raoiella indica (Acari: Tenuipalpidae). AB - The red palm mite, Raoiella indica Hirst (Acari: Tenuipalpidae), was recently introduced in the Americas. It spread quickly throughout coconut palm growing areas, expanding considerably its host range. The invasion of this species has caused high economic impact in several countries. In Brazil, extensive areas are expected to be affected. For logistical reasons and other concerns, chemical control does not seem desirable for the control of this pest in most Latin American countries. Biological control of R. indica by introducing exotic natural enemies seems to be an important control measure to be considered. Surveys in many countries have shown that Amblyseius largoensis (Muma) (Acari: Phytoseiidae) is a very common predator on coconut palms. This study compared the biology of a population of A. largoensis found for a long time in association with R. indica in La Reunion Island (Indian Ocean) with a population from Roraima State (northern Brazil), where R. indica was first found about two and a half years ago. No significant differences were observed between populations in relation to the duration of different immature stages or total survivorship. However, the oviposition period, prey consumption and net reproductive rate were significantly higher for the La Reunion population, warranting further investigation to determine whether that population should be released in Roraima to control the pest. PMID- 23100108 TI - Life cycle and behavior of Amblyomma rotundatum (Acari: Ixodidae) under laboratory conditions and remarks on parasitism of toads in Brazil. AB - The life cycle and behavior of Amblyomma rotundatum were evaluated under laboratory conditions. The experiment started with four engorged females collected from toads (Rhinella schneideri) naturally infested at the Pirapitinga Ecological Station in the state of Minas Gerais, Brazil. Developmental periods of free-living stages were assessed in an incubator at 27 +/- 1 degrees C, >80 % RH and darkness. The complete life cycle, including pre-attachment periods for each parasitic stage, ranged from 126 to 228 days. The pre-attachment, feeding and molting periods increased as the life cycle progressed from larva to adult female. Oviposition lasted about 20 days, with the peak occurring on days 4 and 5. Longevity of nymphs and adult females was quite similar (approximately 250 and 240 days, respectively) and slightly longer than that of larvae. Lesions caused by tick feeding are discussed and a list of known hosts, including new host records for A. rotundatum, is offered. PMID- 23100109 TI - Distribution of Chaetodactylus krombeini (Acari: Chaetodactylidae) within Osmia cornifrons (Hymenoptera: Megachilidae) nests: implications for population management. AB - Chaetodactylus krombeini (Baker) (Acari: Chaetodactylidae) is a cleptoparasitic mite that negatively affects propagation of Osmia spp. (Hymenoptera: Megachilidae) for orchard pollination in the USA. This study was conducted to determine the effect of C. krombeini on mortality of male and female Osmia cornifrons, the Japanese hornfaced bee. A total of 107 O. cornifrons nests were examined to determine within-nest distribution of C. krombeini with regression analyses. A total of 30 mite-free O. cornifrons nests were observed and within nest distribution of male and female O. cornifrons was determined with non-linear regression analyses. In addition, cocoons from 20 mite-infested O. cornifrons cells were examined to determine whether C. krombeini could be found inside cocoons of O. cornifrons. The results of this study showed that female O. cornifrons and C. krombeini were found more frequently in the inner part of the nest, and male O. cornifrons were found mostly in the center of the nest. No C. krombeini were found inside O. cornifrons cocoons. These results indicate that C. krombeini have a greater negative impact on mortality in the egg and larval stages of female O. cornifrons than in male O. cornifrons. Implications for management of C. krombeini and O. cornifrons populations for orchard pollination are discussed in this article. PMID- 23100110 TI - HIV infection and osteoporosis: pathophysiology, diagnosis, and treatment options. AB - As the population with HIV continues to age, specialists in HIV care are increasingly encountering chronic health conditions, which now include osteoporosis, osteopenia, and fragility fractures. The pathophysiology of the bone effects of HIV infection is complex and includes traditional risk factors for bone loss as well as specific effects due to the virus itself, chronic inflammation, and HAART. Examining risk factors for low bone density and screening of certain patients is suggested, and consideration should be given to treatment for those considered high risk for fracture. PMID- 23100111 TI - Aging, diabetes, and hypertension are associated with decreased nasal mucociliary clearance. AB - BACKGROUND: We showed previously that nasal mucociliary clearance was decreased in critically ill elderly subjects, most of whom had diabetes mellitus (DM) and/or hypertension (HTN). To determine if these changes were due to the effects of aging, disease, or critical illness, we studied nasal mucociliary clearance and mucus properties in an ambulatory population consisting of young, elderly, and healthy subjects and those with DM, HTN, or both. METHODS: Of 440 subjects contacted, 252 entered the study. The subjects were divided into the following groups: (1) healthy (n 5 79, 18-94 years, 50 men) and (2) DM and/or HTN, of which 37 had DM (14-90 years, 12 men), 52 had HTN (23-90 years, 12 men), and 84 had both DM and HTN (25-82 years, 33 men). Subjects were also grouped by age: , 40 years, 40 to 59 years, and 60 years. We assessed demographic and clinical data, quality of life using the 36-Item Short Form Health Survey (SF-36) questionnaire, nasal mucociliary clearance using the saccharine transit test (STT), and in vitro mucus properties by examining the sneeze (high airflow) clearability and contact angle. A logistic regression analysis for prolonged STT . 12 min was used, and we controlled for age, sex, and diseases. RESULTS: Subjects aged . 60 years reported a decreased SF-36 physical component relative to other age groups. Sex, BMI, BP, heart rate, pulse oximetry, blood glucose level, and mucus properties were not associated with prolonged STT. Aging and DM and/or HTN independently increased the risk of prolonged STT. CONCLUSIONS: Aging and DM, HTN, or both diseases are independently associated with decreased nasal mucociliary clearance. This may predispose toward respiratory infections. PMID- 23100113 TI - A silver nanoparticle based surface enhanced resonance Raman scattering (SERRS) probe for the ultrasensitive and selective detection of formaldehyde. AB - Here we report a silver nanoparticle based surface enhanced resonance Raman scattering (SERRS) probe for the ultrasensitive and selective detection of formaldehyde. The detection limit reaches as low as 10(-11) M. PMID- 23100112 TI - Long-term effects of ionising radiation on the brain: cause for concern? AB - There is no clear evidence proving or disproving that ionising radiation is causally linked with neurodegenerative diseases such as Parkinson's and Alzheimer's. However, it is known that high doses of ionising radiation to the head (20-50 Gy) lead to severe learning and memory impairment which is characteristical for Alzheimer's. The cumulative doses of ionising radiation to the Western population are accruing, mostly due to the explosive growth of medical imaging procedures. Children are in particular prone to ionising radiation as the molecular processes within the brain are not completely finished. Furthermore, they have a long lifespan under risk. We wish to open a debate if such low doses of radiation exposure may lead to delayed long-term cognitive and other defects, albeit at a lower frequency than those observed during application of high doses. Further, we want to sensitise the society towards the risks of ionising radiation. To achieve these aims, we will recapitulate the known symptoms of Parkinson's and Alzheimer's on the molecular level and incorporate data of mainly low- and moderate-ionising radiation (<5 Gy). Thus, we want to highlight in general the potential similarities of both the neurodegenerative and radiation-induced pathways. We will propose a mechanistic model for radiation-induced neurodegeneration pointing out mitochondria as a key element. This includes effects of oxidative stress and neuroinflammation-all fundamental players of neurodegenerative diseases. PMID- 23100114 TI - Medial wall of the cavernous sinus: dural or fibrous layer? PMID- 23100115 TI - CpG islands and GC content dictate nucleosome depletion in a transcription independent manner at mammalian promoters. AB - One clear hallmark of mammalian promoters is the presence of CpG islands (CGIs) at more than two-thirds of genes, whereas TATA boxes are only present at a minority of promoters. Using genome-wide approaches, we show that GC content and CGIs are major promoter elements in mammalian cells, able to govern open chromatin conformation and support paused transcription. First, we define three classes of promoters with distinct transcriptional directionality and pausing properties that correlate with their GC content. We further analyze the direct influence of GC content on nucleosome positioning and depletion and show that CpG content and CGI width correlate with nucleosome depletion both in vivo and in vitro. We also show that transcription is not essential for nucleosome exclusion but influences both a weak +1 and a well-positioned nucleosome at CGI borders. Altogether our data support the idea that CGIs have become an essential feature of promoter structure defining novel regulatory properties in mammals. PMID- 23100116 TI - Molecular-based identification of yeasts isolated from bovine clinical mastitis in Japan. AB - This study analyzed molecular-based identification of yeasts that associated with bovine clinical mastitis in Japan. Over 3,200 quarter milk samples from Holstein dairy cows collected in 2011 on Hokkaido and Honshu islands were examined. Yeast isolates were characterized by polymerase chain reaction amplification and sequencing of the D1/D2 region of the 26S rDNA. Molecular characterization confirmed that Candida spp. and Pichia spp. were most frequently isolated species. Our molecular analysis of mastitic milk samples demonstrated the prevalence of Pichia kudriavzevii(22/58) and Candida tropicalis(14/58). In addition, we demonstrated that molecular analysis of the D1/D2 region of the 26S rDNA is a rapid and reliable method for identifying clinically significant yeasts in dairy hygiene, including potentially new or emerging pathogenic species. PMID- 23100117 TI - Effect of different levels of supplemental yeast on body weight, thyroid hormone metabolism and lipid profile of broiler chickens. AB - In poultry, the benefits of probiotic supplementation on broiler performance and health have been reported. The present study examined the effect of supplemental yeast probiotic preparations on body weight, thyroid hormone metabolism and serum lipid profile in broilers. The experiment was carried out on hybrid Marshall broiler chickens (n=200). Two hundred 1-day-old chicks were randomly selected and distributed into 4 groups of 50 1-day-old chicks each (control, C; E10.5%, E21.5% and E32.0%, experimental groups). The birds were housed in an environmentally controlled poultry house with the floor covered with wood shavings. Chicks were fed commercial broiler starter diet for the first 28 days of age, followed by pelleted finisher diet from 29-42 days. Feed and water were provided ad libitum. Chickens fed 2.0% probiotic had a significantly (P<0.05) higher body weight when compared with the control group. The blood glucose concentration was significantly (P<0.05) different in the E31.5% probiotic supplemented group when compared with the control. There was highly significant (P<0.05) difference in T4 level in the E32.0% probiotic group when compared with the control. However, there was a significant difference in cholesterol concentrations observed in the experimental group supplemented with E10.5% probiotic. The concentration of triglycerides was not affected by the probiotic supplementation. Significant differences (P<0.01) were observed in HDL concentrations in all experimental groups supplemented with the probiotic when compared with the control group. In conclusion, supplementing broiler feeds with a yeast probiotic increased body weight, enhanced thyroid hormone metabolism, and decreased cholesterol and lipoproteins in broiler chickens. PMID- 23100118 TI - Alterations of bone microstructure and strength in end-stage renal failure. AB - End-stage renal disease (ESRD) patients have a high risk of fractures. We evaluated bone microstructure and finite-element analysis-estimated strength and stiffness in patients with ESRD by high-resolution peripheral computed tomography. We observed an alteration of cortical and trabecular bone microstructure and of bone strength and stiffness in ESRD patients. INTRODUCTION: Fragility fractures are common in ESRD patients on dialysis. Alterations of bone microstructure contribute to skeletal fragility, independently of areal bone mineral density. METHODS: We compared microstructure and finite-element analysis estimates of strength and stiffness by high-resolution peripheral quantitative computed tomography (HR-pQCT) in 33 ESRD patients on dialysis (17 females and 16 males; mean age, 47.0 +/- 12.6 years) and 33 age-matched healthy controls. RESULTS: Dialyzed women had lower radius and tibia cortical density with higher radius cortical porosity and lower tibia cortical thickness, compared to controls. Radius trabecular number was lower with higher heterogeneity of the trabecular network. Male patients displayed only a lower radius cortical density. Radius and tibia cortical thickness correlated negatively with bone-specific alkaline phosphatase (BALP). Microstructure did not correlate with parathyroid hormone (PTH) levels. Cortical porosity correlated positively with "Kidney Disease: Improving Global Outcomes" working group PTH level categories (r = 0.36, p < 0.04). BMI correlated positively with trabecular number (r = 0.4, p < 0.02) and negatively with trabecular spacing (r = -0.37, p < 0.03) and trabecular network heterogeneity (r = -0.4, p < 0.02). Biomechanics positively correlated with BMI and negatively with BALP. CONCLUSION: Cortical and trabecular bone microstructure and calculated bone strength are altered in ESRD patients, predominantly in women. Bone microstructure and biomechanical assessment by HR pQCT may be of major clinical relevance in the evaluation of bone fragility in ESRD patients. PMID- 23100119 TI - Association between osteoporosis treatment change and adherence, incident fracture, and total healthcare costs in a Medicare Advantage Prescription Drug plan. AB - We examined the association between osteoporosis treatment change and adherence, incident fractures, and healthcare costs among Medicare Advantage Prescription Drug (MAPD) plan members. Treatment change was associated with a small but significant increase in adherence, but was not associated with incident fracture or total healthcare costs. Overall adherence remained low. INTRODUCTION: We examined the association between osteoporosis treatment change and adherence, incident fractures, and healthcare costs among MAPD plan members in a large US health plan. METHODS: We conducted a retrospective cohort study of MAPD plan members aged>=50 years newly initiated on an osteoporosis medication between 1 January 2006 and 31 December 2008. Members were identified as having or not having an osteoporosis treatment change within 12 months after initiating osteoporosis medication. Logistic regression analyses and difference-in difference (DID) generalized linear models were used to investigate the association between osteoporosis treatment change and (1) adherence to treatment, (2) incident fracture, and (3) healthcare costs at 12 and 24 months follow-up. RESULTS: Of the 33,823 members newly initiated on osteoporosis treatment, 3,573 (10.6%) changed osteoporosis treatment within 12 months. After controlling for covariates, osteoporosis treatment change was associated with significantly higher odds of being adherent (medication possession ratio [MPR]>=0.8) at 12 months (odds ratio [OR]=1.18) and 24 months (OR=1.13) follow-up. However, overall adherence remained low (MPR=0.59 and 0.51 for the change cohort and MPR=0.51 and 0.44 for the no-change cohort at 12 and 24 months, respectively). Osteoporosis treatment change was not significantly associated with incident fracture (OR=1.00 at 12 months and OR=0.98 at 24 months) or total direct healthcare costs (p>0.4) in the DID analysis, but was associated with higher pharmacy costs (p<0.004). CONCLUSIONS: Osteoporosis treatment change was associated with a small but significant increase in adherence, but was not associated with incident fracture or total healthcare costs in the MAPD plan population. Overall adherence to therapy remained low. PMID- 23100121 TI - The professional and organizational future of imaging. PMID- 23100120 TI - A meta-analysis characterizing the dose-response relationships for three oral nitrogen-containing bisphosphonates in postmenopausal women. AB - A meta-analysis of spine BMD dose-response relationships for alendronate, risedronate, and ibandronate was performed. Data from all three oral bisphosphonates conform to a log-linear relationship between dose and change in spine BMD relative to placebo at 1 year, with an incremental gain of about 1 % for each doubling of dose. INTRODUCTION: Animal data suggesting differences in potency and differences in approved oral dosage strengths for alendronate, risedronate, and ibandronate in the treatment of osteoporosis raise questions about their dose-response relationships and relative potencies in humans. METHODS: A meta-analysis of dose-response relationships for spine BMD increases for these three bisphosphonates was performed using data from 21 placebo controlled trials that collectively included over 13,000 patients on active treatment and over 8,000 on placebo. RESULTS: For alendronate over the range of 1 to 20 mg/day, there was a strong log-linear relationship between dose and the increase in spine BMD relative to placebo at 1 year (R (2) = 0.994 using sample weighted means). For each doubling in alendronate dose, there was an incremental gain of about 1 % in spine BMD. On the same scale, risedronate and ibandronate are approximately equipotent to alendronate on a weight-for-weight basis. The increases in BMD efficacy with each doubling of dose are parallel for all three nitrogen-containing bisphosphonates (NCBPs). CONCLUSIONS: All three NCBPs are approximately equipotent and exhibit a log-linear relationship between dose and the increase in spine BMD. Differences in efficacy between the available oral bisphosphonate regimens appear to be a function of dose rather than inherent differences in therapeutic potential. PMID- 23100122 TI - ESGAR 2011 Book of Abstracts. PMID- 23100123 TI - Synthetic meniscus replacement: a review. AB - The number of meniscus-related operations continues to rise due to the ageing and more active population. Irreparable meniscal lesions generally require (partial) meniscectomy. Although a majority of the patients benefit from pain relief and functional improvement post-meniscectomy, some remain symptomatic. As an alternative to a meniscal allograft, which is only indicated for the severely damaged meniscus, most patients can nowadays be treated by implantation of a synthetic meniscal substitute. Currently three of these implants, two partial and one total replacement, are clinically available and several others are in the stage of preclinical testing. Grossly, two types of meniscal substitutes can be distinguished: porous, resorbable implants that stimulate tissue regeneration and solid, non-resorbable implants that permanently replace the whole meniscus. Although the implantation of a porous meniscus replacement generally seems promising and improves clinical outcome measures to some degree, their superiority to partial meniscectomy still needs to be proven. The evaluation of new prostheses being developed requires a wider focus than has been adopted so far. Upon selection of the appropriate materials, preclinical evaluation of such implants should comprise a combination of (in vitro) biomechanical and (in vivo) biological tests, while up to now the focus has mainly been on biological aspects. Obviously, well-defined randomised controlled trials are necessary to support clinical performance of new implants. Since the use of a meniscus replacement requires an additional costly implant and surgery compared to meniscectomy only, the clinical outcome of new products should be proven to surpass the results of the conventional therapies available. PMID- 23100125 TI - Is balloon osteoplasty attractive or questionable treatment for Hill-Sachs lesion? PMID- 23100124 TI - Hip resurfacing: a systematic review of literature. AB - PURPOSE: We conducted a systematic review of the literature in order to take stock of hip resurfacing according to the principle of "evidence based medicine". Our main objective was to compare the rate of revision of resurfacing implants with survival limits set by the National Institute of Clinical Excellence (NICE). METHODS: A systematic review was undertaken of all published (Medline, Cochrane, EMBASE) literature research databases up to July 2012 as recommended by the PRISMA statement. Data extraction focused on functional outcomes, complications and survival rates. The survival rates of implants were analysed according to the mean of the series in comparison to the NICE criteria. RESULTS: Fifty-three studies were identified and included 26,456 cases with an average of 499.17 +/- 856.7 (range, 38-5000) cases per study. The median survival was 95.57 % +/- 3.7 % (range, 84-100). The percentage of studies which satisfied the criteria set by NICE was 69.8 %. In terms of cumulative revision rates pondered by the number of implants, BHR(r), Conserve Plus(r) and Cormet(r) showed the best results. The mean postoperative score was 91.2 +/- 7.72 (range, 68.3-98.6). There was no statistically significant difference between implants in terms of functional outcomes. CONCLUSION: On the basis of the current evidence base, this review of the literature emphasises the importance of certain parameters that can improve the results of resurfacing. The type of implant seems to play an important role as does patient selection. PMID- 23100126 TI - Coughing and fever after surfing in Central America. AB - We report the case of a 19-year-old surfer, returning from Central America, who presented with chronic cough. The X-ray and full blood count, which had been performed in Costa Rica, were without pathology; laboratory parameters showed slightly increased C-reactive protein (59 mg/l). Malaria was excluded by thick smear. Immune serological tests for typhus, paratyphus, brucellosis, rickettsioses, leptospirosis and dengue fever were negative. An ambulant antimicrobial treatment was without any clinical effect. A computer tomography of the thorax showed a solid lesion (30 * 20 mm, middle lobe of the right lung). The patient rejected a bronchoscopic examination. He decided to be treated after his return to Austria. Here, we could substantiate a pulmonal histoplasmosis by a positive immune diffusion test. The patient was successfully treated with itraconazole. PMID- 23100127 TI - Medical audible alarms: a review. AB - OBJECTIVES: This paper summarizes much of the research that is applicable to the design of auditory alarms in a medical context. It also summarizes research that demonstrates that false alarm rates are unacceptably high, meaning that the proper application of auditory alarm design principles are compromised. TARGET AUDIENCE: Designers, users, and manufacturers of medical information and monitoring systems that indicate when medical or other parameters are exceeded and that are indicated by an auditory signal or signals. SCOPE: The emergence of alarms as a 'hot topic'; an outline of the issues and design principles, including IEC 60601-1-8; the high incidence of false alarms and its impact on alarm design and alarm fatigue; approaches to reducing alarm fatigue; alarm philosophy explained; urgency in audible alarms; different classes of sound as alarms; heterogeneity in alarm set design; problems with IEC 60601-1-8 and ways of approaching this design problem. PMID- 23100128 TI - Automatically extracting sentences from Medline citations to support clinicians' information needs. AB - OBJECTIVE: Online health knowledge resources contain answers to most of the information needs raised by clinicians in the course of care. However, significant barriers limit the use of these resources for decision-making, especially clinicians' lack of time. In this study we assessed the feasibility of automatically generating knowledge summaries for a particular clinical topic composed of relevant sentences extracted from Medline citations. METHODS: The proposed approach combines information retrieval and semantic information extraction techniques to identify relevant sentences from Medline abstracts. We assessed this approach in two case studies on the treatment alternatives for depression and Alzheimer's disease. RESULTS: A total of 515 of 564 (91.3%) sentences retrieved in the two case studies were relevant to the topic of interest. About one-third of the relevant sentences described factual knowledge or a study conclusion that can be used for supporting information needs at the point of care. CONCLUSIONS: The high rate of relevant sentences is desirable, given that clinicians' lack of time is one of the main barriers to using knowledge resources at the point of care. Sentence rank was not significantly associated with relevancy, possibly due to most sentences being highly relevant. Sentences located closer to the end of the abstract and sentences with treatment and comparative predications were likely to be conclusive sentences. Our proposed technical approach to helping clinicians meet their information needs is promising. The approach can be extended for other knowledge resources and information need types. PMID- 23100129 TI - Changes in end-user satisfaction with Computerized Provider Order Entry over time among nurses and providers in intensive care units. AB - BACKGROUND: Implementation of Computerized Provider Order Entry (CPOE) has many potential advantages. Despite the potential benefits of CPOE, several attempts to implement CPOE systems have failed or met with high levels of user resistance. Implementation of CPOE can fail or meet high levels of user resistance for a variety of reasons, including lack of attention to users' needs and the significant workflow changes required by CPOE. User satisfaction is a critical factor in information technology implementation. Little is known about how end user satisfaction with CPOE changes over time. OBJECTIVE: To examine ordering provider and nurse satisfaction with CPOE implementation over time. METHODS: We conducted a repeated cross-sectional questionnaire survey in four intensive care units of a large hospital. We analyzed the questionnaire data as well as the responses to two open-ended questions about advantages and disadvantages of CPOE. RESULTS: Users were moderately satisfied with CPOE and there were interesting differences between user groups: ordering providers and nurses. User satisfaction with CPOE did not change over time for providers, but it did improve significantly for nurses. Results also show that nurses and providers are satisfied with different aspects of CPOE. PMID- 23100130 TI - The role of energy in the emergence of biology from chemistry. AB - Any scenario of the transition from chemistry to biology should include an "energy module" because life can exist only when supported by energy flow(s). We addressed the problem of primordial energetics by combining physico-chemical considerations with phylogenomic analysis. We propose that the first replicators could use abiotically formed, exceptionally photostable activated cyclic nucleotides both as building blocks and as the main energy source. Nucleoside triphosphates could replace cyclic nucleotides as the principal energy-rich compounds at the stage of the first cells, presumably because the metal chelates of nucleoside triphosphates penetrated membranes much better than the respective metal complexes of nucleoside monophosphates. The ability to exploit natural energy flows for biogenic production of energy-rich molecules could evolve only gradually, after the emergence of sophisticated enzymes and ion-tight membranes. We argue that, in the course of evolution, sodium-dependent membrane energetics preceded the proton-based energetics which evolved independently in bacteria and archaea. PMID- 23100131 TI - Regulation of AMPA and NMDA receptor-mediated EPSPs in dendritic trees of thalamocortical cells. AB - Two main excitatory synapses are formed at the dendritic arbor of first-order nuclei thalamocortical (TC) neurons. Ascending sensory axons primarily establish contacts at large proximal dendrites, whereas descending corticothalamic fibers form synapses on thin distal dendrites. With the use of a multicomparment computational model based on fully reconstructed TC neurons from the ventroposterolateral nucleus of the cat, we compared local responses at the site of stimulation as well as somatic responses induced by both alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated currents. We found that AMPAR-mediated responses, when synapses were located at proximal dendrites, induced a larger depolarization at the level of soma, whereas NMDAR-mediated responses were more efficient for synapses located at distal dendrites. The voltage transfer and transfer impedance were higher for NMDAR than for AMPAR activation at any location. For both types of synaptic current and for both input locations at the dendritic arbor, somatic responses were characterized by a low variability despite the large variability found in local responses in dendrites. The large neurons had overall smaller somatic responses than small neurons, but this relation was not found in local dendritic responses. We conclude that in TC cells, the dendritic location of small synaptic inputs does not play a major role in the amplitude of a somatic response, but the size of the neuron does. The variability of response amplitude between cells was much larger than the variability within cells. This suggests possible functional segregation of TC neurons of different size. PMID- 23100132 TI - ALLN rescues an in vitro excitatory synaptic transmission deficit in Lis1 mutant mice. AB - LIS1 gene mutations lead to a rare neurological disorder, classical lissencephaly, characterized by brain malformations, mental retardation, seizures, and premature death. Mice heterozygous for Lis1 (Lis1(+/-)) exhibit cortical malformations, defects in neuronal migration, increased glutamate mediated synaptic transmission, and spontaneous electrographic seizures. Recent work demonstrated that in utero treatment of Lis1(+/-) mutant dams with ALLN, a calpain inhibitor, partially rescues neuronal migration defects in the offspring. Given the challenges of in utero drug administration, we examined the therapeutic potential of ALLN on postnatal lissencephalic cells. Voltage- and current-clamp studies were performed with acute hippocampal slices obtained from Lis1 mutant mice and age-matched littermate control mice. Specifically, we determined whether postnatal ALLN treatment can reverse excitatory synaptic transmission deficits, namely, an increase in spontaneous and miniature excitatory postsynaptic current (EPSC) frequency, on CA1 pyramidal neurons observed in tissue slices from Lis1(+/ ) mice. We found that acute application of ALLN restored spontaneous and miniature EPSC frequencies to wild-type levels without affecting inhibitory postsynaptic synaptic current. Furthermore, Western blot analysis of protein expression, including proteins involved in excitatory synaptic transmission, demonstrated that ALLN blocks the cleavage of the calpain substrate alphaII spectrin but does not rescue Lis1 protein levels in Lis1(+/-) mutants. PMID- 23100134 TI - Rhythmic activity of feline dorsal and ventral spinocerebellar tract neurons during fictive motor actions. AB - Neurons of the dorsal spinocerebellar tracts (DSCT) have been described to be rhythmically active during walking on a treadmill in decerebrate cats, but this activity ceased following deafferentation of the hindlimb. This observation supported the hypothesis that DSCT neurons primarily relay the activity of hindlimb afferents during locomotion, but lack input from the spinal central pattern generator. The ventral spinocerebellar tract (VSCT) neurons, on the other hand, were found to be active during actual locomotion (on a treadmill) even after deafferentation, as well as during fictive locomotion (without phasic afferent feedback). In this study, we compared the activity of DSCT and VSCT neurons during fictive rhythmic motor behaviors. We used decerebrate cat preparations in which fictive motor tasks can be evoked while the animal is paralyzed and there is no rhythmic sensory input from hindlimb nerves. Spinocerebellar tract cells with cell bodies located in the lumbar segments were identified by electrophysiological techniques and examined by extra- and intracellular microelectrode recordings. During fictive locomotion, 57/81 DSCT and 30/30 VSCT neurons showed phasic, cycle-related activity. During fictive scratch, 19/29 DSCT neurons showed activity related to the scratch cycle. We provide evidence for the first time that locomotor and scratch drive potentials are present not only in VSCT, but also in the majority of DSCT neurons. These results demonstrate that both spinocerebellar tracts receive input from the central pattern generator circuitry, often sufficient to elicit firing in the absence of sensory input. PMID- 23100135 TI - Inhibitory connections in the honeybee antennal lobe are spatially patchy. AB - The olfactory system is a classical model for studying sensory processing. The first olfactory brain center [the olfactory bulb of vertebrates and the antennal lobe (AL) of insects] contains spherical neuropiles called glomeruli. Each glomerulus receives the information from one olfactory receptor type. Interglomerular computation is accomplished by lateral connectivity via interneurons. However, the spatial and functional organization of these lateral connections is not completely understood. Here we studied the spatial logic in the AL of the honeybee. We combined topical application of neurotransmitters, olfactory stimulations, and in vivo calcium imaging to visualize the arrangement of lateral connections. Suppression of activity in a single glomerulus with gamma aminobutyric acid (GABA) while presenting an odor reveals the existence of inhibitory interactions. Stimulating a glomerulus with acetylcholine (ACh) activates inhibitory interglomerular connections that can reduce odor-evoked responses. We show that this lateral network is patchy, in that individual glomeruli inhibit other glomeruli with graded strength, but in a spatially discontinuous manner. These results suggest that processing of olfactory information requires combinatorial activity patterns with complex topologies across the AL. PMID- 23100133 TI - Sensorimotor feedback based on task-relevant error robustly predicts temporal recruitment and multidirectional tuning of muscle synergies. AB - We hypothesized that motor outputs are hierarchically organized such that descending temporal commands based on desired task-level goals flexibly recruit muscle synergies that specify the spatial patterns of muscle coordination that allow the task to be achieved. According to this hypothesis, it should be possible to predict the patterns of muscle synergy recruitment based on task level goals. We demonstrated that the temporal recruitment of muscle synergies during standing balance control was robustly predicted across multiple perturbation directions based on delayed sensorimotor feedback of center of mass (CoM) kinematics (displacement, velocity, and acceleration). The modulation of a muscle synergy's recruitment amplitude across perturbation directions was predicted by the projection of CoM kinematic variables along the preferred tuning direction(s), generating cosine tuning functions. Moreover, these findings were robust in biphasic perturbations that initially imposed a perturbation in the sagittal plane and then, before sagittal balance was recovered, perturbed the body in multiple directions. Therefore, biphasic perturbations caused the initial state of the CoM to differ from the desired state, and muscle synergy recruitment was predicted based on the error between the actual and desired upright state of the CoM. These results demonstrate that that temporal motor commands to muscle synergies reflect task-relevant error as opposed to sensory inflow. The proposed hierarchical framework may represent a common principle of motor control across motor tasks and levels of the nervous system, allowing motor intentions to be transformed into motor actions. PMID- 23100136 TI - Statistically significant contrasts between EMG waveforms revealed using wavelet based functional ANOVA. AB - We developed wavelet-based functional ANOVA (wfANOVA) as a novel approach for comparing neurophysiological signals that are functions of time. Temporal resolution is often sacrificed by analyzing such data in large time bins, increasing statistical power by reducing the number of comparisons. We performed ANOVA in the wavelet domain because differences between curves tend to be represented by a few temporally localized wavelets, which we transformed back to the time domain for visualization. We compared wfANOVA and ANOVA performed in the time domain (tANOVA) on both experimental electromyographic (EMG) signals from responses to perturbation during standing balance across changes in peak perturbation acceleration (3 levels) and velocity (4 levels) and on simulated data with known contrasts. In experimental EMG data, wfANOVA revealed the continuous shape and magnitude of significant differences over time without a priori selection of time bins. However, tANOVA revealed only the largest differences at discontinuous time points, resulting in features with later onsets and shorter durations than those identified using wfANOVA (P < 0.02). Furthermore, wfANOVA required significantly fewer (~1/4;*; P < 0.015) significant F tests than tANOVA, resulting in post hoc tests with increased power. In simulated EMG data, wfANOVA identified known contrast curves with a high level of precision (r(2) = 0.94 +/- 0.08) and performed better than tANOVA across noise levels (P < <0.01). Therefore, wfANOVA may be useful for revealing differences in the shape and magnitude of neurophysiological signals (e.g., EMG, firing rates) across multiple conditions with both high temporal resolution and high statistical power. PMID- 23100137 TI - Ca(2+)-activated ion currents triggered by ryanodine receptor-mediated Ca(2+) release control firing of inhibitory neurons in the prepositus hypoglossi nucleus. AB - Spontaneous miniature outward currents (SMOCs) are known to exist in smooth muscles and peripheral neurons, and evidence for the presence of SMOCs in central neurons has been accumulating. SMOCs in central neurons are induced through Ca(2+)-activated K(+) (K(Ca)) channels, which are activated through Ca(2+) induced Ca(2+) release from the endoplasmic reticulum via ryanodine receptors (RyRs). Previously, we found that some neurons in the prepositus hypoglossi nucleus (PHN) showed spontaneous outward currents (SOCs). In the present study, we used whole cell recordings in slice preparations of the rat brain stem to investigate the following: 1) the ionic mechanisms of SOCs, 2) the types of neurons exhibiting frequent SOCs, and 3) the effect of Ca(2+)-activated conductance on neuronal firing. Pharmacological analyses revealed that SOCs were induced via the activation of small-conductance-type K(Ca) (SK) channels and RyRs, indicating that SOCs correspond to SMOCs. An analysis of the voltage responses to current pulses of the fluorescence-expressing inhibitory neurons of transgenic rats revealed that inhibitory neurons frequently exhibited SOCs. Abolition of SOCs via blockade of SK channels enhanced the frequency of spontaneous firing of inhibitory PHN neurons. However, abolition of SOCs via blockade of RyRs reduced the firing frequency and hyperpolarized the membrane potential. Similar reductions in firing frequency and hyperpolarization were also observed when Ca(2+)-activated nonselective cation (CAN) channels were blocked. These results suggest that, in inhibitory neurons in the PHN, Ca(2+) release via RyRs activates SK and CAN channels, and these channels regulate spontaneous firing in a complementary manner. PMID- 23100139 TI - Mechanisms underlying long-interval cortical inhibition in the human motor cortex: a TMS-EEG study. AB - Long-interval cortical inhibition (LICI) refers to suppression of neuronal activity following paired-pulse transcranial magnetic stimulation (TMS) with interstimulus intervals (ISIs) between 50 and 200 ms. LICI can be measured either from motor-evoked potentials (MEPs) in small hand muscles or directly from the cortex using concurrent electroencephalography (EEG). However, it remains unclear whether EEG inhibition reflects similar mechanisms to MEP inhibition. Eight healthy participants received single- and paired-pulse TMS (ISI = 100 ms) over the motor cortex. MEPs were measured from a small hand muscle (first dorsal interosseus), whereas early (P30, P60) and late (N100) TMS-evoked cortical potentials (TEPs) were measured over the motor cortex using EEG. Conditioning and test TMS intensities were altered, and modulation of LICI strength was measured using both methods. LICI of MEPs and both P30 and P60 TEPs increased in strength with increasing conditioning intensities and decreased with increasing test intensities. LICI of N100 TEPs remained unchanged across all conditions. In addition, MEP and P30 LICI strength correlated with the slope of the N100 evoked by the conditioning pulse. LICI of early and late TEP components was differentially modulated with altered TMS intensities, suggesting independent underlying mechanisms. LICI of P30 is consistent with inhibition of cortical excitation similar to MEPs, whereas LICI of N100 may reflect presynaptic autoinhibition of inhibitory interneurons. The N100 evoked by the conditioning pulse is consistent with the mechanism responsible for LICI, most likely GABA(B) mediated inhibition of cortical activity. PMID- 23100138 TI - Control of position and movement is simplified by combined muscle spindle and Golgi tendon organ feedback. AB - Whereas muscle spindles play a prominent role in current theories of human motor control, Golgi tendon organs (GTO) and their associated tendons are often neglected. This is surprising since there is ample evidence that both tendons and GTOs contribute importantly to neuromusculoskeletal dynamics. Using detailed musculoskeletal models, we provide evidence that simple feedback using muscle spindles alone results in very poor control of joint position and movement since muscle spindles cannot sense changes in tendon length that occur with changes in muscle force. We propose that a combination of spindle and GTO afferents can provide an estimate of muscle-tendon complex length, which can be effectively used for low-level feedback during both postural and movement tasks. The feasibility of the proposed scheme was tested using detailed musculoskeletal models of the human arm. Responses to transient and static perturbations were simulated using a 1-degree-of-freedom (DOF) model of the arm and showed that the combined feedback enabled the system to respond faster, reach steady state faster, and achieve smaller static position errors. Finally, we incorporated the proposed scheme in an optimally controlled 2-DOF model of the arm for fast point to-point shoulder and elbow movements. Simulations showed that the proposed feedback could be easily incorporated in the optimal control framework without complicating the computation of the optimal control solution, yet greatly enhancing the system's response to perturbations. The theoretical analyses in this study might furthermore provide insight about the strong physiological couplings found between muscle spindle and GTO afferents in the human nervous system. PMID- 23100140 TI - On the origin of event-related potentials indexing covert attentional selection during visual search: timing of selection by macaque frontal eye field and event related potentials during pop-out search. AB - Event-related potentials (ERPs) have provided crucial data concerning the time course of psychological processes, but the neural mechanisms producing ERP components remain poorly understood. This study continues a program of research in which we investigated the neural basis of attention-related ERP components by simultaneously recording intracranially and extracranially from macaque monkeys. Here, we compare the timing of attentional selection by the macaque homologue of the human N2pc component (m-N2pc) with the timing of selection in the frontal eye field (FEF), an attentional-control structure believed to influence posterior visual areas thought to generate the N2pc. We recorded FEF single-unit spiking and local field potentials (LFPs) simultaneously with the m-N2pc in monkeys performing an efficient pop-out search task. We assessed how the timing of attentional selection depends on task demands by direct comparison with a previous study of inefficient search in the same monkeys (e.g., finding a T among Ls). Target selection by FEF spikes, LFPs, and the m-N2pc was earlier during efficient pop-out search rather than during inefficient search. The timing and magnitude of selection in all three signals varied with set size during inefficient but not efficient search. During pop-out search, attentional selection was evident in FEF spiking and LFP before the m-N2pc, following the same sequence observed during inefficient search. These observations are consistent with the hypothesis that feedback from FEF modulates neural activity in posterior regions that appear to generate the m-N2pc even when competition for attention among items in a visual scene is minimal. PMID- 23100141 TI - Task contingencies and perceptual strategies shape behavioral effects on neuronal response profiles. AB - We presented optic flow simulating eight directions of self-movement in the ground plane, while monkeys performed delayed match-to-sample tasks, and we recorded dorsal medial superior temporal (MSTd) neuronal activity. Randomly selected sample headings yield smaller test responses to the neuron's preferred heading when it is near the sample's heading direction and larger test responses to the preferred heading when it is far from the sample's heading. Limiting test stimuli to matching or opposite headings suppresses responses to preferred stimuli in both test conditions, whereas focusing on each neuron's preferred vs. antipreferred stimuli enhances responses to the antipreferred stimulus. Match vs. opposite paradigms create bimodal heading profiles shaped by interactions with late delay-period activity. We conclude that task contingencies, determining the prior probabilities of specific stimuli, interact with the monkeys' perceptual strategy for optic flow analysis. These influences shape attentional and working memory effects on the heading direction selectivities and preferences of MSTd neurons. PMID- 23100143 TI - Exonuclease-aided amplification for label-free and fluorescence turn-on DNA detection based on aggregation-induced quenching. AB - A facile, universal and label-free fluorescence turn-on amplification strategy for the detection of DNA has been reported, which can achieve ultralow femtomolar detection of a target gene sequence with high selectivity. PMID- 23100142 TI - Effects of cortical feedback on the spatial properties of relay cells in the lateral geniculate nucleus. AB - Feedback connections to early-level sensory neurons have been shown to affect many characteristics of their neural response. Because selectivity for stimulus size is a fundamental property of visual neurons, we examined the summation tuning and discretely mapped receptive field (RF) properties of cells in the lateral geniculate nucleus (LGN) both with and without feedback from visual cortex. Using extracellular recording in halothane-anesthetized cats, we used small luminance probes displaced in Cartesian coordinates to measure discrete response area, and optimal sinusoidal gratings of varying diameter to estimate preferred optimal summation size and level of center-surround antagonism. In conditions where most cortical feedback was pharmacologically removed, discretely mapped RF response areas showed an overall significant enlargement for the population compared with control conditions. A switch to increased levels of burst firing, spatially displaced from the RF center, suggested this was mediated by changes in excitatory-inhibitory balance across visual space. With the use of coextensive stimulation, there were overall highly significant increases in the optimal summation size and reduction of surround antagonism with removal of cortical feedback in the LGN. When fitted with a difference-of-Gaussian (DOG) model, changes in the center size, center amplitude, and surround amplitude parameters were most significantly related to the removal of cortical feedback. In summary, corticothalamic innervation of the visual thalamus can modify spatial summation properties in LGN relay cells, an effect most parsimoniously explained by changes in the excitatory-inhibitory balance. PMID- 23100144 TI - Immune system dysregulation occurs during short duration spaceflight on board the space shuttle. AB - BACKGROUND: Post-flight data suggests immunity is dysregulated immediately following spaceflight, however this data may be influenced by the stress effects of high-G entry and readaptation to terrestrial gravity. It is unknown if immunity is altered during spaceflight. METHODS: Blood samples were collected from 19 US Astronauts onboard the Space Shuttle ~24 h prior to landing and returned for terrestrial analysis. Assays consisted of leukocyte distribution, T cell blastogenesis and cytokine production profiles. RESULTS: Most bulk leukocyte subsets (WBC, differential, lymphocyte subsets) were unaltered during spaceflight, but were altered following landing. CD8+ T cell subsets, including cytotoxic, central memory and senescent were altered during spaceflight. T cell early blastogenesis varied by culture mitogen. Functional responses to staphylococcal enterotoxin were reduced during and following spaceflight, whereas response to anti-CD3/28 antibodies was elevated post-flight. The level of virus specific T cells were generally unaltered, however virus specific T cell function was depressed both during and following flight. Plasma levels of IFNalpha, IFNgamma, IL-1beta, IL-4, IL-10, IL-12, and TNFalpha were significantly elevated in-flight, while IL-6 was significantly elevated at R + 0. Cytokine production profiles following mitogenic stimulation were significantly altered both during, and following spaceflight. Specifically, production of IFNgamma, IL-17 and IL-10 were reduced, but production of TNFalpha and IL-8 were elevated during spaceflight. CONCLUSIONS: This study indicates that specific parameters among leukocyte distribution, T cell function and cytokine production profiles are altered during flight. These findings distinguish in-flight dysregulation from stress-related alterations observed immediately following landing. PMID- 23100145 TI - Simultaneous positivity for anti-DNA, anti-nucleosome and anti-histone antibodies is a marker for more severe lupus nephritis. AB - OBJECTIVE: The purpose of this study is to examine autoantibody profile of systemic lupus erythematosus (SLE) patients with lupus nephritis (LN) and to establish the correlation between the antibody reactivity and disease activity of LN. METHODS: Autoantibodies and serological parameters were measured and analyzed in 589 SLE patients. The associations of the co-positivity of anti-dsDNA, nucleosome and -histone antibodies (3-pos) with clinical, serological and outcome parameters were analyzed. RESULTS: At the study entry, the prevalence for anti dsDNA (61.52 % vs. 34.11 %, P < 0.0001), anti-nucleosome (56.09 % vs. 37.21 %, P = 0.0002) and anti-histone (49.35 % vs. 33.33 %, P = 0.0013) antibodies in patients with LN were significantly higher than that in patients without LN. Patients with 3-pos had a higher proportion of proliferative renal lesions (class III + IV). The incidence of a poor renal outcome (7.14 % vs. 2.52 %, P = 0.0174) in LN patients with 3-pos was significantly higher than those without 3-pos. Moreover, the rate of remission (73.63 % vs. 82.37 %, P = 0.0245) was significantly reduced and recurrence increased (58.90 % vs. 23.44 %, P < 0.0001) in 3-pos patients as compared to that in non 3-pos within the LN group. CONCLUSION: Our data indicate a strong association between the 3-pos and renal disease activities, especially proliferative glomerulonephritis. The ability of 3 pos to predict renal flares may lead to major additional benefits in the follow up of these patients. PMID- 23100146 TI - Differential reactivity to IMPDH2 by anti-rods/rings autoantibodies and unresponsiveness to pegylated interferon-alpha/ribavirin therapy in US and Italian HCV patients. AB - PURPOSE: Autoantibodies to cytoplasmic structures called rods and rings (RR) are primarily specific to patients with hepatitis C virus (HCV) infection treated with pegylated interferon-alpha/ribavirin (IFN/R). Our aim is to examine anti-RR antibodies specificity and correlation with the response to IFN/R therapy in two independent cohorts (US and Italy) of HCV patients. METHODS: Sera from the US cohort (n = 47) and the Italian cohort (n = 46) pre-selected for anti-RR antibodies were analyzed by immunofluorescence and radioimmunoprecipitation. The prevalence and titers of anti-RR were analyzed for correlation with the response to IFN/R therapy. RESULTS: In the US cohort, anti-RR antibodies were more frequently non-responders to IFN/R (71 % vs 29 % responders). Titers in responder patients (n = 11) were <=1:3200, whereas titers in non-responder patients (n = 27) reached 1:819,200 (p = 0.0016). In the Italian cohort, anti-RR titers ranged from 1:200 to >1:819,200 and only relapsers had the highest anti-RR titers. Radioimmunoprecipitation demonstrated that anti-RR autoantibodies were mainly anti-inosine monophosphate dehydrogenase 2 (IMPDH2) - 96 % in the Italian cohort vs. 53 % in the US cohort. CONCLUSIONS: In the two cohorts analyzed, the anti IMPDH2 response as a component of the anti-RR response is much more prominent in the Italian cohort. The reason for the difference between the US and Italian cohorts is unclear but it possibly illustrates the heterogeneity in response and the overall negative correlation between the production of these autoantibodies and response to IFN/R therapy. Patients with high titer anti-RR antibodies are either relapsers (Italian) or non-responders/relapsers (US). PMID- 23100147 TI - Effects of vertical motion of the centre of mass on walking efficiency in the early stages after total hip arthroplasty. AB - PURPOSE: The purpose of this study was to identify factors related to walking efficiency in the early postoperative period of total hip arthroplasty (THA). METHODS: The subjects of this study were 18 women who had undergone unilateral THA 4 weeks before and 18 healthy women as control. Using a force plate and a 3-D motion analyser, we measured: 1) gait speed, stride length, cadence; 2) centre of mass displacement in the three directions; 3) asymmetry of the centre of mass movement in vertical direction; and 4) the total internal work per unit mass and distance walked (a negative index of walking efficiency). RESULTS: Compared with healthy persons, THA patients showed significantly greater total internal work per unit mass and distance walked. The vertical centre of mass motion of the THA patients demonstrated an asymmetrical pattern. In THA patients, the stepwise multiple regression analysis selected the displacement and the asymmetrical vertical motion of centre of mass as the sole significant variable affecting walking efficiency (R2 = 0.81). CONCLUSIONS: Our findings indicated that rehabilitation programs that control the vertical movement of the centre of mass during gait are important to improve walking ability in the early post-operative phase after THA. PMID- 23100148 TI - The Durom acetabular component. a concise follow-up of early revision rates at a minimum of 2 years. AB - We report our experience with 143 Durom acetabular components. Our data show a survivorship of 99.2% at 5 years, (95% CI 94.8-99.9), which is not consistent with other reports in the literature of high early failure rates. The true natural history of this component is yet to unfold completely. PMID- 23100149 TI - Dislocation of primary total hip arthroplasty and the risk of redislocation. AB - 6554 primary total hip arthroplasties were reviewed. Risk factors for dislocation were analysed to assess which were important in terms of predicting recurrent instability. The patients risk of having a second dislocation was independently associated with the surgical approach adopted (p = 0.03) and the time to first dislocation from the primary hip replacement (p = 0.002). Early dislocators whose surgery was performed through an anterolateral approach had less recurrence than late dislocators through a posterior or transtrochanteric approach. None of the other risk factors including head size (p = 0.59), modularity (p = 0.54), mechanism of dislocation (p = 0.23), leg length discrepancy (p = 0.69) and acetabular inclination (p = 0.31) were influential. The use of an abduction brace was not useful in preventing a further dislocation with 69.2% of those braced re dislocating compared to 68.5% who were not braced (p = 0.96). PMID- 23100150 TI - The medium term outcome of the Omnifit constrained acetabular cup. AB - Recurrent dislocation requiring revision surgery occurs in approximately 4% of primary total hip arthroplasties (THAs). To reduce this risk, or to treat those patients who recurrently dislocate, a constrained acetabular component may be used, however there are concerns over the success of such components due to increased mechanical stresses. The purpose of this study was to analyse the survivorship and radiological results for the Omnifit constrained acetabular component, providing a longer patient reported outcome follow-up than previous studies. 117 patients (median age 82 years) underwent a THA with an Omnifit constrained acetabular component. Of these, 45 were primary replacements and 72 were revisions. Survivorship analysis was performed and patients were assessed both radiologically and functionally. At follow-up, 53 patients (45.3%) had died at a median time of 33 months from operation. The median overall follow-up was 7.0 (5.5-8.2) years. Survivors (median age 83 years) reported a median Oxford Hip Score (OHS) of 16.6 (0-48), 87.8% were satisfied with their surgery. 45 (91.8%) of the acetabular components were stable radiologically, 48 (96%) of the femoral components were stable (5 uncemented, 43 cemented) and two possibly unstable. Four of the 117 patients underwent further surgery. Only one required revision of the prosthesis and this was for a periprosthetic fracture. In the medium term the Omnifit constrained acetabular component prevents dislocation and does not cause excessive loosening of either the acetabular or femoral components in our patient population. Our results support the use of the Omnifit constrained acetabular component in elderly patients at risk of dislocation with low functional demand. PMID- 23100151 TI - Two-year radiologic assessment of the Trident Peripheral Self-Locking cup using EBRA. AB - We performed a radiologic assessment of the Trident Peripheral Self-Locking cup 2 years after implantation to assess early migration behaviour and to establish if incomplete postoperative seating correlated with early instability. A retrospective analysis of 30 cases was performed using EBRA. No cups had acetabular screws. Average total migration was 1.5 mm (range 0.1 to 5.9 mm). Seventeen showed total migration >1 mm and 7 of these showed further migration >2 mm (range 2.3 to 5.9 mm). Twenty cups demonstrated incomplete seating on initial post-operative radiographs (mean 1.4 mm, range 0.3 to 3.0). No relationship between incomplete seating and migration was identified (p = 0.86). The majority of gaps consolidated at differing times within the 2 year period. Oxford Hip scores showed significant improvement after surgery (p = 0.001) and this was independent of migration (p = 0.76). At 5 years there were no revisions for aseptic loosening. CONCLUSION: The majority of the cups demonstrated early radiographic instability, and this was not related to incomplete seating. Five year functional outcome appears good and independent of migration and initial seating. PMID- 23100152 TI - Outcome of an uncemented hydroxyapatite coated hemiarthroplasty for displaced femoral neck fractures: a clinical and radiographic 2-year follow-up study. AB - BACKGROUND AND PURPOSE: Hemiarthroplasty is the preferred treatment for displaced femoral neck fractures (DFNF) in elderly patients. The use of uncemented stems remains controversial and issues regarding inferior fixation in osteoporotic bone, implant-related pain and decreased mobility have discouraged their use. There is limited evidence for the use of modern uncemented femoral stems in the treatment of DFNF, and we wished to investigate the clinical and radiographic performance of an uncemented hydroxyapatite coated hemiarthroplasty at 2-year follow-up. PATIENTS AND METHODS: We included 97 consecutive patients who had an uncemented, hydroxyapatite coated hemiarthroplasty (Corail, Depuy) inserted during a 1-year period. Due to unwillingness or cognitive impairment (n = 6) and death before follow-up (n = 44), a total of 47 patients (39 females) with a mean age of 81 years were available. RESULTS: At two year follow-up 38 of 47 patients lived in their own homes and the median New Mobility Score was 6 (range: 2-9). The median Visual Analogue Scale pain score was 0 (range: 0-5) at rest and 0 (range: 0-8) when walking. Patient satisfaction was a score of 9 (range: 2-10) on the VAS. Anterior or lateral thigh pain or groin pain was reported by 15 patients. The EQ-5D index score at follow-up was 0.72 (range: 0.16-1.00) and the EQ-5D Visual Analogue Score was 70 (range: 15-100). There were no signs of implant loosening in any of the 37 hips undergoing radiographic evaluation at follow-up. CONCLUSION: The results suggest that an uncemented hydroxyapatite coated hemiarthroplasty can be used to treat displaced intracupsular femoral neck fractures with good clinical and radiographic outcomes at short term follow-up. PMID- 23100153 TI - Efficacy of core decompression as treatment for osteonecrosis of the hip: a systematic review. AB - Core decompression (CD) for the treatment of osteonecrosis of the hip has been a surgical option since the 1960s. We performed a systematic review to evaluate CD with regard to pain relief, need for total hip arthroplasty (THA), and lesion size and Ficat stage. Only four articles of level IV evidence (139 total cases) met inclusion criteria. Three reported improvement in outcomes. Overall average outcomes were only "good" in one study and either "fair" or "poor" in the others. One-fourth (25.8%) of patients required THA. Patients with necrotic lesion size <50% had best outcomes with CD. Although CD may become a standard treatment option to prevent THA in early stages of ON, there are not currently rigorous studies that provide long-term outcome measures. PMID- 23100154 TI - Assessing reproducibility for radiographic measurement of leg length inequality after total hip replacement. AB - Leg length inequality (LLI) as a result of total hip replacement can cause considerable morbidity. Although LLI was described when the technique was popularised in the 1960s, it remains a significant challenge to arthroplasty surgeons. This study reviews the established practice for the measurement of LLI on plain antero-posterior radiograph, and compares these techniques to two methods used locally. The radiographs of 35 patients were measured using four techniques. All four methods yielded an interclass correlation co-efficient of >=0.90 for inter reader reliability. This study shows that the four methods are comparable for reliability, while a composite method, measuring from the centre of femoral rotation to the inferior teardrop and then to the lesser trochanter, has the added advantage of providing extra information on component position as well as an overall measure of LLI. PMID- 23100155 TI - A comparison of two resurfacing arthroplasty implants: medium-term clinical and radiographic results. AB - The objective of this study was to perform a medium-term analysis comparing the clinical and radiographic outcomes of the CONSERVE(r) Plus (C+) and Birmingham Hip Resurfacing (BHR) arthroplasty systems. 137 hips were included in each cohort, with a mean follow-up of 60.0 +/- 14.2 months and 63.3 +/- 3.5 months in the C+ and BHR cohorts respectively. Latest review UCLA and HHS scores showed statistically significant improvements when compared with preoperative scores for both cohorts. UCLA and SF-12 physical component outcome scores were significantly different (p<0.01 and p = 0.04, respectively). Median serum chromium and cobalt levels were significantly increased in the BHR cohort (p = 0.001). Both cohorts demonstrated excellent Kaplan-Meier 5-year survival rates (96.9% in the C+ cohort, and 96.4% in the BHR cohort). Overall both implants appear to perform well in the medium term. PMID- 23100157 TI - Assessment of immunotoxicity and genotoxicity in workers exposed to low concentrations of formaldehyde. AB - Formaldehyde (FA), which is an important chemical with a wide commercial use, has been classified as carcinogenic to humans by International Research on Cancer (IARC). The genotoxic and carcinogenic potential of FA has been documented in mammalian cells and in rodents. A recent evaluation by the E.U. Scientific Committee for Occupational Exposure Limits (SCOEL) anticipated that an 8-h time weighted average exposure to 0.2 ppm FA would not be irritating and not genotoxic in humans. In order to verify this prediction, a field study was performed that aimed at evaluating immune alterations and genetic damage in peripheral lymphocytes of workers in medium density fiberboard plants exposed to a level of FA equivalent to the OEL recommended by SCOEL (0.2 ppm). Subsets of peripheral lymphocytes, immunoglobulins (IgG, IgA, IgM), complement proteins, and tumor necrosis factor-alpha (TNF-alpha) levels were evaluated. DNA damage of the workers was assessed by the Comet assay. The absolute numbers and the percentages of T lymphocytes and of natural killer cells, and the levels of TNF-alpha were higher than the controls, whereas IgG and IgM levels were found to be lower in workers. Other examined immunological parameters were not different from those of the controls. There was no increased DNA damage in the workers compared to controls. PMID- 23100156 TI - Influence of surgical approach on postoperative femoral bone remodelling after cementless total hip arthroplasty. AB - We retrospectively evaluated the femoral periprosthetic bone mineral density (BMD) in a consecutive series of patients who had undergone total hip arthroplasty (THA) with a straight, double tapered cementless stem using a muscle sparing anterolateral (group A) and the transgluteal (group B) surgical approach. Dual-energy x-ray absorptiometry (DXA) measurements were performed in the first postoperative week (t1), and after 3 (t2), 6 (t3) and 12 months (t4) using an identical protocol. Patients were clinically and radiographically evaluated at final follow-up (t4). A complete set of four consecutive DXA measurements was obtained for 16 hips in group A and 26 hips in group B. In patients in whom the transgluteal approach was used (Group B), we observed a significantly greater decline in overall periprosthetic BMD (netavg) and in BMD in the periprosthetic regions of interest (ROI) 1, 4, 5 and 6 between t1 and t4. At clinical and radiographic evaluation at t4, no differences between the groups were detected. Femoral periprosthetic BMD is affected by the selected surgical approach in the first postoperative year. This might be attributed to altered femoral loading as a result of differences in intraoperative damage to the abductor muscles. PMID- 23100158 TI - Apoptosis initiation of beta-ionone in SGC-7901 gastric carcinoma cancer cells via a PI3K-AKT pathway. AB - beta-ionone has been shown to hold potent anti-proliferative and apoptosis induction properties in vitro and in vivo. To investigate the effects of beta ionone on apoptosis initiation and its possible mechanisms of action, we qualified cell apoptosis, proteins related to apoptosis and a phosphatidylinositol 3-kinase (PI3K)-AKT pathway in human gastric adenocarcinoma cancer SGC-7901 cells. The results demonstrated that beta-ionone-induced apoptosis in a dose-dependent manner in SGC-7901 cells treated with beta-ionone (25, 50, 100 and 200 MUmol/L) for 24 h. beta-ionone was also shown to induce the expression of cleaved-caspase-3 and inhibit bcl-2 expression in SGC-7901 cells in a dose-dependent manner. The significantly decreased levels of p-PI3K and p-AKT expression were observed in SGC-7901 cells after beta-ionone treatments in a time and dose-dependent manner (P < 0.01). Thus, the apoptosis induction in SGC-7901 cells by beta-ionone may be regulated through a PI3K-AKT pathway. These results demonstrate a potential mechanism by which beta-ionone to induce apoptosis initiation in SGC-7901 cells. PMID- 23100160 TI - Peritoneal dialysis fluid activates calcium signaling and apoptosis in mesothelial cells. AB - A larger diffusion of peritoneal dialysis (PD) is limited by the progressive deterioration of the dialysis membrane structure and function, characterized in vitro and in vivo by mesothelial cell loss and closely related to the use of bioincompatible dialysis solutions. The apoptosis rate of rat and human mesothelial cells incubated in commercial PD fluid (PDF, 4.25 g/dL dextrose) became significant as early as 1 h after PDF addition and reached a plateau at 4 5 h. This pattern was unchanged after exposure to 1.5 g/dL dextrose PDF or freshly prepared PDF, indicating that effects were independent on the dextrose strength and manufacturing procedures but strictly dependent on PDF composition. Molecular studies revealed that PDF exposure inactivated the physiological volume recovery from hypertonic shrinkage, accompanied by an abnormal Ca(2+) signaling: a progressive intracellular Ca(2+) ([Ca(2+)](i)) rise resulting from an increased Ca(2+) entry. PDF also affected cytoskeleton integrity: early dissolution of actin filaments occurred well before the appearance of typical apoptosis features. Lastly, the PDF dependent apoptosis was almost completely prevented by the contemporary Ca(2+) concentration decrease and K(+) addition. This study suggests that the PDF dependent apoptosis arises from the extreme volume perturbations in mesothelial cells, turned out unable to regulate their volume back once exposed to a hyperosmolal medium containing high Ca(2+) levels in the absence of K(+), such PDF. PMID- 23100161 TI - PYRIN domains and their interactions in the apoptosis and inflammation signaling pathway. AB - The PYRIN domain (PYD) is a well known protein interaction module and a prime mediator of the protein interactions necessary for apoptosis, inflammation and innate immune signaling pathway. Because PYD-mediated apoptosis, inflammation and innate immune processes are associated with many human diseases, studies in these areas are of great biological importance. Intensive biochemical and structural studies of PYD have been conducted in the past decade to elucidate PYD-mediated signaling events, and evaluations of the molecular structure of PYDs have shown the underlying molecular basis for the assembly of PYD-mediated complexes and for the regulation of inflammation and innate immunity. This review summarizes the structure and function of various PYDs and proposes a PYD:PYD interaction for assembly of the complexes involved in those signaling pathways. PMID- 23100159 TI - Enhanced carcinogenicity by coexposure to arsenic and iron and a novel remediation system for the elements in well drinking water. AB - Various carcinomas including skin cancer are explosively increasing in arsenicosis patients who drink arsenic-polluted well water, especially in Bangladesh. Although well drinking water in the cancer-prone areas contains various elements, very little is known about the effects of elements except arsenic on carcinogenicity. In order to clarify the carcinogenic effects of coexposure to arsenic and iron, anchorage-independent growth and invasion in human untransformed HaCaT and transformed A431 keratinocytes were examined. Since the mean ratio of arsenic and iron in well water was 1:10 in cancer-prone areas of Bangladesh, effects of 1 MUM arsenic and 10 MUM iron were investigated. Iron synergistically promoted arsenic-mediated anchorage-independent growth in untransformed and transformed keratinocytes. Iron additionally increased invasion in both types of keratinocytes. Activities of c-SRC and ERK that regulate anchorage-independent growth and invasion were synergistically enhanced in both types of keratinocytes. Our results suggest that iron promotes arsenic-mediated transformation of untransformed keratinocytes and progression of transformed keratinocytes. We then developed a low-cost and high-performance adsorbent composed of a hydrotalcite-like compound for arsenic and iron. The adsorbent rapidly reduced concentrations of both elements from well drinking water in cancer-prone areas of Bangladesh to levels less than those in WHO health-based guidelines for drinking water. Thus, we not only demonstrated for the first time increased carcinogenicity by coexposure to arsenic and iron but also proposed a novel remediation system for well drinking water. PMID- 23100163 TI - Immunophenotyping of classical Hodgkin's lymphoma by flow cytometry. PMID- 23100162 TI - Ocular sarcoidosis: when should labial salivary gland biopsy be performed? AB - PURPOSE: To assess the usefulness of a labial salivary gland biopsy (LSGB) in subsets of patients with uveitis. METHODS: A retrospective study of 115 consecutive patients with uveitis for whom a LSGB had been done because of suspected ocular sarcoidosis (n = 86) or unexplained uveitis (n = 29). Eighty-six patients had a suspicion of ocular sarcoidosis because of ocular features (n = 67), an elevated angiotensin converting enzyme (ACE) (n = 29), or because of CT findings (n = 32) suggestive of sarcoidosis. The biopsy results were analyzed together with their ophthalmological features and the results of other relevant examinations, such as the serum levels of ACE and a chest radiography or a CT scan. RESULTS: Six of the 115 patients (5.2 %) with uveitis had sarcoid granulomas on the LSGB. At the end of the study, 32 patients had proven sarcoidois while 22 patients were considered as having either indeterminate or presumed sarcoidosis, according to the criteria of Abad et al. A raised ACE (p = 0.016) and a compatible radiology (p = 0.033) were related to a positive LSGB test, but not to the features of uveitis. Granulomas were only found in the LSGB of the patients with an elevated ACE or compatible CT scans. CONCLUSIONS: In this study, the LSGB sensitivity (18.75 %) in the patients with proven sarcoidosis appears to be lower than in other reports. Our results suggest that this investigation is a possible method of tissue diagnosis in patients with raised ACE and/or CT scan pattern compatible with sarcoidosis, and should not be performed in patients with unexplained uveitis or because of their ophthalmological features. PMID- 23100164 TI - Survival benefit with salvage radiotherapy for patients with locoregionally recurrent extranodal NK/T cell lymphoma, nasal type. AB - The purposes of this study are to evaluate prognosis in patients with locoregionally recurrent extranodal nasal-type NK/T cell lymphoma (NKTCL) and to determine the value of salvage radiotherapy. Forty-two patients with NKTCL who developed first locoregional recurrence with (n = 13) or without (n = 29) systemic failure were reviewed. Retreatment included chemotherapy (n = 20), radiotherapy (n = 13), and radiotherapy plus chemotherapy (n = 9). Fifteen patients were reirradiated for localized recurrent disease. The 5-year overall survival (OS) rate after recurrence was 40 %, with a median survival of 26 months. The 2-year OS rate and median OS were 68 % and 36 months for locoregional recurrence only, compared with 31 % and 14 months for both locoregional and systemic recurrence, respectively (p = 0.034). Subgroup analysis for patients with localized recurrent disease revealed an improved OS with radiotherapy. The 2 year and 5-year OS rates were 77 and 69 % for radiotherapy, respectively, compared with a 2-year OS rate of 50 % and median OS of 16 months for chemotherapy alone (p = 0.006). Patients with localized recurrence had a better prognosis than those with systemic recurrence. Salvage radiotherapy or reirradiation resulted in a favorable prognosis for patients with localized recurrent disease. PMID- 23100166 TI - Implementation of a hospital oral care protocol and recording of oral mucositis in children receiving cancer treatment : a retrospective and a prospective study. AB - PURPOSE: This retrospective/prospective study was carried out to implement a standardized hospital oral care protocol and record the incidence of oral mucositis for inpatients with childhood cancer. METHODS: The implementation process included stages of collaboration, consultation, education, and evaluation. The retrospective part of the study documented the existing hospital oral care protocol and audited medical records of all pediatric patients diagnosed with cancer over a 12-month period. The frequency of recorded oral mucositis and the rate of referral to the pediatric dentistry department were assessed. Following evaluation of the retrospective study, the literature was searched to create a new hospital oral care protocol. Referral to the dental department was standardized and frequent in-service presentations were given to staff. The oral mucositis scale was recorded daily for all inpatients, and compliance rates were assessed. RESULTS: Fifty-nine patients' medical records were audited during the retrospective study. Oral mucositis prevalence was clearly documented at 34%, while an additional 20% lacked a definitive diagnosis. During the prospective study, 38 patients were followed and had a verified incidence of oral mucositis of 33%. The rate of compliance of implementing the oral mucositis scale improved from 41% during the first 4 months to 87% during last 3 months. Referral rates to the dental department increased from 53% during the retrospective study to 100% during the prospective study. CONCLUSIONS: Mutual understanding and collaboration between the oncology and dental departments in hospitals is crucial for standardizing patient care and for improving oral care standards. PMID- 23100167 TI - Pharmacokinetics of a fixed-dose combination of mitiglinide and metformin versus concurrent administration of individual formulations in healthy subjects: a randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover study. AB - BACKGROUND: In the treatment of diabetes mellitus, combined drugs with different mechanisms of action can be effective when adequate glycaemic control is difficult with monotherapy. A fixed-dose combination (FDC) tablet of mitiglinide and metformin has been developed as a second-line treatment for type 2 diabetes. OBJECTIVES: The objective of this study was to compare the pharmacokinetics and safety of a FDC and a free combination of mitiglinide and metformin in healthy male subjects. METHODS: A randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in 24 healthy Korean male subjects. In one period, a FDC tablet of mitiglinide and metformin (10 mg/500 mg) was administered, and in the other period, corresponding doses of individual formulations were administered. RESULTS: Twenty-four subjects were enrolled and 19 subjects completed the study. The geometric mean ratios (90 % confidence interval) of the maximum plasma concentration (C(max)) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) were 0.9694 (0.8120, 1.1573) and 0.8951 (0.8440, 0.9494) for mitiglinide, and 1.0235 (0.9373, 1.1057) and 1.0542 (0.9697, 1.1460) for metformin, which were within the bioequivalence range. Among the 23 subjects who received study drugs, 15 subjects experienced 34 adverse events (AEs). The most frequently reported AEs were feeling hot and compensatory sweating. There were no serious AEs and no significant differences in the incidence of AEs between the two treatments. CONCLUSION: A FDC tablet of mitiglinide and metformin was generally well tolerated in healthy male subjects. Administration of a FDC tablet and concomitant administration of individual formulations did not show significantly different pharmacokinetic profiles. PMID- 23100168 TI - Non-invasive accurate measurement of arterial PCO2 in a pediatric animal model. AB - The PCO2 in arterial blood (PaCO2) is a good parameter for monitoring ventilation and acid-base changes in ventilated patients, but its measurement is invasive and difficult to obtain in small children. Attempts have been made to use the partial pressure of CO2 in end-tidal gas (PETCO2), as a noninvasive surrogate for PaCO2. Studies have revealed that, unfortunately, the differences between PETCO2 and PaCO2 are too variable to be clinically useful. We hypothesized that end inspiratory rebreathing, previously shown to equalize PETCO2 and PaCO2 in spontaneously breathing humans, would also be effective with positive pressure ventilation. Eight newborn Yorkshire pigs were mechanically ventilated via a partial rebreathing circuit to implement end-inspiratory rebreathing. Arterial blood was sampled and tested for PaCO2. A variety of alveolar ventilations resulting in different combinations of end-tidal PCO2 (30-50 mmHg) and PO2 (35 500 mmHg) were tested for differences between PETCO2 and PaCO2 (PET-aCO2). The PET-aCO2 of all samples was (mean +/- 1.96 SD) 0.4 +/- 2.7 mmHg. Our study demonstrates that, in ventilated juvenile animals, end-inspiratory rebreathing maintains PET-aCO2 to what would be a clinically useful range. If verified clinically, this approach could open the way for non-invasive monitoring of arterial PCO2 in critically ill patients. PMID- 23100169 TI - Self-assembled GaN quantum wires on GaN/AlN nanowire templates. AB - We present a novel approach for self-assembled growth of GaN quantum wires (QWRs) exhibiting strong confinement in two spatial dimensions. The GaN QWRs are formed by selective nucleation on {112[combining macron]0} (a-plane) facets formed at the six intersections of {11[combining macron]00} (m-plane) sidewalls of AlN/GaN nanowires used as a template. Based on microscopy observations we have developed a 3D model explaining the growth mechanism of QWRs. We show that the QWR formation is governed by self-limited pseudomorphic growth on the side facets of the nanowires (NWs). Quantum confinement in the QWRs is confirmed by the observation of narrow photoluminescence lines originating from individual QWRs with emission energies up to 4.4 eV. Time-resolved photoluminescence studies reveal a short decay time (~120 ps) of the QWR emission. Capping of the QWRs with AlN allows enhancement of the photoluminescence, which is blue-shifted due to compressive strain. The emission energies from single QWRs are modelled assuming a triangular cross-section resulting from self-limited growth on a-plane facets. Comparison with the experimental results yields an average QWR diameter of about 2.7 nm in agreement with structural characterization. The presented results open a new route towards controlled realization of one-dimensional semiconductor quantum structures with a high potential both for fundamental studies and for applications in electronics and in UV light generation. PMID- 23100170 TI - Effects of chronic sazetidine-A, a selective alpha4beta2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats. AB - RATIONALE: Nicotine and nicotinic agonists have been shown to improve attentional function. Nicotinic receptors are easily desensitized, and all nicotinic agonists are also desensitizing agents. Although both receptor activation and desensitization are components of the mechanism that mediates the overall effects of nicotinic agonists, it is not clear how each of the two opposed actions contributes to attentional improvements. Sazetidine-A has high binding affinity at alpha4beta2 nicotinic receptors and causes a relatively brief activation followed by a long-lasting desensitization of the receptors. Acute administration of sazetidine-A has been shown to significantly improve attention by reversing impairments caused by the muscarinic cholinergic antagonist scopolamine and the NMDA glutamate antagonist dizocilpine. METHODS: In the current study, we tested the effects of chronic subcutaneous infusion of sazetidine-A (0, 2, or 6 mg/kg/day) on attention in Sprague-Dawley rats. Furthermore, we investigated the effects of chronic sazetidine-A treatment on attentional impairment induced by an acute administration of 0.02 mg/kg scopolamine. RESULTS: During the first week period, the 6-mg/kg/day sazetidine-A dose significantly reversed the attentional impairment induced by scopolamine. During weeks 3 and 4, the scopolamine-induced impairment was no longer seen, but sazetidine-A (6 mg/kg/day) significantly improved attentional performance on its own. Chronic sazetidine-A also reduced response latency and response omissions. CONCLUSIONS: This study demonstrated that similar to its acute effects, chronic infusions of sazetidine-A improve attentional performance. The results indicate that the desensitization of alpha4beta2 nicotinic receptors with some activation of these receptors may play an important role in improving effects of sazetidine-A on attention. PMID- 23100171 TI - Surfactant metabolism and anti-oxidative capacity in hyperoxic neonatal rat lungs: effects of keratinocyte growth factor on gene expression in vivo. AB - Development of preterm infant lungs is frequently impaired resulting in bronchopulmoary dysplasia (BPD). BPD results from interruption of physiologic anabolic intrauterine conditions, the inflammatory basis and therapeutic consequences of premature delivery, including increased oxygen supply for air breathing. The latter requires surfactant, produced by alveolar type II (AT II) cells to lower surface tension at the pulmonary air:liquid interface. Its main components are specific phosphatidylcholine (PC) species including dipalmitoyl PC, anionic phospholipids and surfactant proteins. Local antioxidative enzymes are essential to cope with the pro-inflammatory side effects of normal alveolar oxygen pressures. However, respiratory insufficiency frequently requires increased oxygen supply. To cope with the injurious effects of hyperoxia to epithelia, recombinant human keratinocyte growth factor (rhKGF) was proposed as a surfactant stimulating, non-catabolic and epithelial-protective therapeutic. The aim of the present study was to examine the qualification of rhKGF to improve expression parameters of lung maturity in newborn rats under hyperoxic conditions (85% O(2) for 7 days). In response to rhKGF proliferating cell nuclear antigen mRNA, as a feature of stimulated proliferation, was elevated. Similarly, the expressions of ATP-binding cassette protein A3 gene, a differentiation marker of AT II cells and of peroxiredoxin 6, thioredoxin and thioredoxin reductase, three genes involved in oxygen radical protection were increased. Furthermore, mRNA levels of acyl-coA:lysophosphatidylcholine acyltransferase 1, catalyzing dipalmitoyl-PC synthesis by acyl remodeling, and adipose triglyceride lipase, considered as responsible for fatty acid supply for surfactant PC synthesis, were elevated. These results, together with a considerable body of other confirmative evidence, suggest that rhKGF should be developed into a therapeutic option to treat preterm infants at risk for impaired lung development. PMID- 23100172 TI - Serotonin: from top to bottom. AB - Serotonin is a monoamine neurotransmitter, which is phylogenetically conserved in a wide range of species from nematodes to humans. In mammals, age-related changes in serotonin systems are known risk factors of age-related diseases, such as diabetes, faecal incontinence and cardiovascular diseases. A decline in serotonin function with aging would be consistent with observations of age-related changes in behaviours, such as sleep, sexual behaviour and mood all of which are linked to serotonergic function. Despite this little is known about serotonin in relation to aging. This review aims to give a comprehensive analysis of the distribution, function and interactions of serotonin in the brain; gastrointestinal tract; skeletal; vascular and immune systems. It also aims to demonstrate how the function of serotonin is linked to aging and disease pathology in these systems. The regulation of serotonin via microRNAs is also discussed, as are possible applications of serotonergic drugs in aging research and age-related diseases. Furthermore, this review demonstrates that serotonin is potentially involved in whole organism aging through its links with multiple organs, the immune system and microRNA regulation. Methods to investigate these links are discussed. PMID- 23100173 TI - CYP2D6 phenotype indicative for optimized antiestrogen efficacy associates with outcome in early breast cancer patients. AB - BACKGROUND: Endoxifen serum concentrations seem to correlate with outcome in breast cancer (BC) patients. Concurrently, cytochrome P450 2D6 (CYP2D6) enzyme activity and dextromethorphan (DM) metabolism are deemed a surrogate marker for the formation of endoxifen. Here, we conducted a matched cohort study to determine the impact of an extensive CYP2D6 phenotype on relapse in patients with early-stage estrogen receptor (ER)-positive BC and adjuvant tamoxifen intake. METHODS: CYP2D6 extensive metabolism was determined upon appropriate dextromethorphan/dextrorphan (DM/DX) urinary excretion ratios (<=0.30). Fifty nine BC patients were identified as extensive phenotype metabolizers, while for 148 matched controls, CYP2D6 was not determined. Patients and controls did not differ with respect to age, stage, hormone receptor status, HER2, grade, menopausal status, chemotherapy and antihormonal therapy. Survival analysis was performed according to clinical follow-up. RESULTS: Disease-free survival (DFS) of patients identified as extensive CYP2D6 metabolizers did not differ significantly from controls (p = 0.10). However, when patients with ER expression of <= 20 % were excluded from the analysis, DFS was associated with a more favorable outcome (p = 0.06). CONCLUSIONS: This study suggests a positive association between extensive CYP2D6 metabolism and outcome in early-stage ER positive BC patients using tamoxifen and in particular, when a sufficient number ERs are represented on the primary tumor. PMID- 23100175 TI - Management in Radiology: Abstracts from the MIR 2011 Annual Meeting (September 29 30, Nice/FR). PMID- 23100174 TI - XELOX and bevacizumab followed by single-agent bevacizumab as maintenance therapy as first-line treatment in elderly patients with advanced colorectal cancer: the boxe study. AB - PURPOSE: The addition of bevacizumab to oxaliplatin-based chemotherapy significantly improved progression-free survival (PFS) in patients with metastatic colorectal cancer (CRC). An increased risk of arterial thromboembolic events has been observed in some trials in older patients, and the potential benefit of a maintenance therapy with bevacizumab alone has not been clearly demonstrated. This phase II study was designed to evaluate the efficacy and safety of XELOX (capecitabine plus oxaliplatin) plus bevacizumab followed by bevacizumab alone in elderly patients with advanced CRC. METHODS: Treatment consisted of bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m(2) on day 1, plus capecitabine 1,000 mg/m(2) twice daily on days 1-14, every 3 weeks up to a maximum of 8 cycles. Patients then received maintenance therapy consisting of bevacizumab alone (7.5 mg/kg) once every 3 weeks up to disease progression. The primary study end-points were safety and response rate. RESULTS: A total of 44 patients were recruited. In an intention-to-treat analysis, the overall response rate was 52% [95% confidence interval (CI) 37 to 68%], with 86% of patients achieving disease control. Median PFS and overall survival were 11.5 months (95% CI 10.0-12.9 months) and 19.3 months (95% CI 16.5-22.1 months), respectively. In all, 10 patients (23%) had grade 3/4 adverse events (AEs), the most common being diarrhea (9%), neutropenia (7%), peripheral neuropathy (7%), and stomatitis (7%). No patients died because of treatment-related AEs. The rate of bevacizumab related AEs (hypertension, thromboembolic events, and gastrointestinal perforation) was consistent with that reported earlier in the general CRC population. CONCLUSION: The combination of XELOX and bevacizumab is effective and has a manageable tolerability profile when administered to elderly patients with advanced CRC. Maintenance therapy with single-agent bevacizumab may be considered to extend PFS in this setting of patients. PMID- 23100177 TI - Nodular lesions and mesangiolysis in diabetic nephropathy. AB - Diabetic nephropathy is a leading cause of end-stage renal failure all over the world. Advanced human diabetic nephropathy is characterized by the presence of specific lesions including nodular lesions, doughnut lesions, and exudative lesions. Thus far, animal models precisely mimicking advanced human diabetic nephropathy, especially nodular lesions, remain to be fully established. Animal models with spontaneous diabetic kidney diseases or with inducible kidney lesions may be useful for investigating the pathogenesis of diabetic nephropathy. Based on pathological features, we previously reported that diabetic glomerular nodular like lesions were formed during the reconstruction process of mesangiolysis. Recently, we established nodular-like lesions resembling those seen in advanced human diabetic nephropathy through vascular endothelial injury and mesangiolysis by administration of monocrotaline. Here, in this review, we discuss diabetic nodular lesions and its animal models resembling human diabetic kidney lesions, with our hypothesis that endothelial cell injury and mesangiolysis might be required for nodular lesions. PMID- 23100176 TI - Prognostic significance of left ventricular hypertrophy observed at dialysis initiation depends on the pre-dialysis use of erythropoiesis-stimulating agents. AB - BACKGROUND: Recent experimental studies suggest that erythropoietin promotes beneficial myocardial remodeling during left ventricular hypertrophy (LVH); however, such compensatory capacity may be limited due to insufficient erythropoietin production in chronic kidney disease patients. Thus, this study aimed to explore the effect of pre-dialysis erythropoiesis-stimulating agent (ESA) use on the prognostic significance of LVH in dialyzed patients. METHODS: This retrospective study included 404 consecutive patients who started dialysis between 2001 and 2009. The interaction of ESA with the association between left ventricular mass index (LVMI) observed at dialysis initiation and all-cause and cardiovascular mortality was analyzed at the end of 2010 using the Cox model. RESULTS: During a median follow-up of 36.5 months, 164 patients died, 31 of them from heart failure. The frequency of pre-dialysis ESA use was 58.7 % and median LVMI was 160.3 g/m(2). Of interest, patients with the lowest tertile of LVMI had worse survival compared with those with each subsequent tertile. LVMI was inversely associated with all-cause mortality [hazard ratio (HR) 0.991, 95 % confidence interval (CI) 0.988-0.995, P = 0.000] after extensive adjustment including ejection fraction, whereas the prognostic value of LVMI for cardiovascular mortality was dependent on pre-dialysis ESA use [adjusted HR 1.010, 95 % CI 0.999-1.020, P = 0.065 for pre-dialysis ESA(+) and 0.978, 95 % CI 0.967-0.989, P = 0.000 for pre-dialysis ESA(-), respectively]. CONCLUSIONS: Our results suggest that reverse epidemiology may exist between LVH and mortality and that pre-dialysis ESA use may modify the prognostic significance of LVH observed at dialysis initiation for cardiovascular mortality in dialyzed patients. PMID- 23100178 TI - Association between AST-120 and abdominal aortic calcification in predialysis patients with chronic kidney disease. AB - BACKGROUND: Vascular calcification is associated with mortality and cardiovascular events in patients with chronic kidney disease. AST-120, which adsorbs uremic toxins, is reported to reduce the risk of cardiovascular disease and death in chronic kidney disease patients. The aim of the current study was to investigate the association between abdominal aortic calcification and the use of AST-120 in predialysis chronic kidney disease patients. METHODS: A retrospective analysis was conducted including 199 predialysis chronic kidney disease patients (stages 4 and 5) who underwent abdominal plain computed tomography in our institution between 2005 and 2010. Abdominal aortic calcification was assessed by aortic calcification index (ACI). Patients were divided into two groups based on whether or not AST-120 was administered for at least six months, and ACI was compared between the two groups. RESULTS: The aortic calcification index was significantly lower in patients taking AST-120 [12.2 (2.5-30.3) vs. 25.7 (13.4 45.3) %, P < 0.001]. According to multivariate linear regression analysis, the use of AST-120 was independently and significantly correlated with ACI after adjusting for confounding factors. CONCLUSIONS: The use of AST-120 was independently associated with less aortic calcification in predialysis chronic kidney disease patients. PMID- 23100179 TI - Genome-wide analysis of long noncoding RNA expression in peripheral blood mononuclear cells of uremia patients. AB - BACKGROUND: Long noncoding RNAs (lncRNAs) are transcripts longer than ~200 nucleotides with little or no protein-coding capacity. There is evidence that the lncRNAs are involved in a variety of biological functions and are associated with human diseases. The aim of this study was to reveal any potential lncRNA regulatory mechanism in uremia. METHODS: Blood samples were obtained from 20 uremic patients not on dialysis and 20 healthy volunteers. The genome-wide analysis of lncRNA expression in peripheral blood mononuclear cells was completed by microarray assay and validated by quantitative real-time reverse transcriptase polymerase chain reaction (real-time qRT-PCR) analysis. Differentially expressed lncRNAs and mRNAs were identified through fold-change filtering. Gene ontology analysis and pathway analysis were performed with the standard enrichment computation method. The relationship between lncRNAs and adjacent protein-coding genes was determined by complex transcriptional loci analysis. RESULTS: We identified thousands of lncRNAs and mRNA that were differentially expressed in uremic patients. Some lncRNAs are transcribed in complex loci with overlapping and antisense patterns relative to adjacent protein-coding genes. Differential expression of ZAP70 and BC133674 (ZAP70-ncRNA) was confirmed by RT-PCR. CONCLUSIONS: Some lncRNAs and their associated protein-coding genes are closely related and may be part of a potential regulatory mechanism of uremia, and lncRNAs will provide additional opportunities to advance our understanding of the basic biology of uremia. PMID- 23100180 TI - Cross-sectional survey of the prevalence of reduced estimated glomerular filtration rate, albuminuria and cardiovascular risk in a native Spanish population. AB - OBJECTIVES: HERMEX is a population-based study which tries to evaluate the relative weight of cardiovascular risk factors in inhabitants of Extremadura, Spain. This report presents the data about chronic kidney disease (CKD) in a Spanish population sample. METHODS: For an observational cross-sectional population-based study, 3,402 subjects were randomly selected from health care system records. The final sample included 2,813 participants (mean age 51.2 years, 53.5% women). Renal function was estimated from serum creatinine using the 4-variable Modification of Diet in Renal Disease (MDRD-4) Study and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Individual renal risk was calculated using the Kidney Disease Improving Global Outcomes (KDIGO) table. RESULTS: Using the CKD-EPI formula, 3.6% of participants had a glomerular filtration rate (GFR) <60 ml/min. MDRD-4 gave a result of 4.0%. Prevalence of albuminuria was 5.5%. Taken together, in patients with albuminuria and/or reduced GFR, the prevalence of renal disease was 8.1%. The KDIGO renal risk table suggested that 0.05% of patients were at high or very high risk of CKD progression and 1.6% at medium risk. CKD was more common in those who were obese, hypertensive, dyslipidemic or had diabetes. Multivariate analysis showed an independent negative association of CKD as dependent variable with systolic blood pressure and body mass index, but a positive correlation with diastolic blood pressure and male sex. CONCLUSIONS: A low frequency of abnormal GFR was detected in a randomly selected sample of the Spanish general population. This finding agreed with the low rates of cardiovascular mortality and morbidity observed in Spain in spite of a high prevalence of classic cardiovascular risk factors. PMID- 23100181 TI - Home dialysis and the Internet: designing an e-learning platform via brainstorming sessions. AB - BACKGROUND: The resurgence of home hemodialysis (HHD) underlines the importance of educational programs. Brainstorming is a powerful tool for innovation, widely employed in industry but seldom used in medicine. The aim of this study was to define an e-learning Web platform for HHD patients via a brainstorming approach. METHODS: Four brainstorming sessions were held 2-6 weeks apart. Twelve people were involved: 2 dialysis physicians, 2 nurses, 2 HHD patients, 2 caregivers, a filmmaker, 2 computer experts (1 with a psychology degree) and a senior engineer. Each session was summarized as the starting point for the following one. The topics discussed were the platform structure and its logo. RESULTS: For the platform, the following requirements were defined: teaching should be extensive and tailored to different levels of knowledge; all available teaching tools (tutorials, demonstrations, recorded and written materials) should be used; films enhance emotional participation and can be used to reduce fears; the contents should include general information on chronic kidney disease, details of all types of renal replacement therapy (RRT) (how and why), dialysis accidents, blood and imaging tests, laws and reimbursements, direct experiences and history of RRT. Remote monitoring and visual interactions are important for reassurance about HHD and should be provided. The requirements for the logo were that it be innovative, related to daily life, representative of a holistic approach and convey happiness. The logo "Hom-e-hem" was created, playing on the assonance between the religious term Om and the word home, with the e of electronic linking it with hem, short for hemodialysis. CONCLUSION: Brainstorming sessions can be used to design patient-tailored educational interventions. The key message, "self care is a bridge from illness back to life," may apply to a wider context. PMID- 23100182 TI - Anthropometric measures can better predict high blood pressure in adolescents. AB - BACKGROUND: Among children, obesity and overweight may be predictors of cardiovascular (CV) risk. The purpose of this study was to examine whether body mass index (BMI), waist circumference (WC) and waist to height ratio (WHtR) were related to blood pressure (BP) among healthy southern Italian students enrolled in 3 different secondary schools. METHODS: Weight, height, BP and WC were measured; BMI and WHtR were calculated for 872 Italian students. Based on percentiles of BMI, the subjects were classified as underweight, normal weight, overweight or obese. Systolic BP or diastolic BP >95th percentile were considered as high BP values (according to the 2004 guidelines of the US National Heart, Lung, and Blood Institute). Central obesity was defined as WC >75th percentile or WHtR =0.5. RESULTS: Of the students, 8.7% were obese, 29% with WC >75th percentile and 29.5% with WHtR >0.5, while 4.6% showed high BP. Logistic regression showed a strong correlation between BMI and high BP (odds ratio [OR] = 1.030, p<0.0001), between WC and high BP (OR = 1.029, p<0.0001). Also WHtR (OR = 3.403, p<0.0001) was shown to be a predictor of high BP. In the male group, all of the variables considered showed a good capability to predict high BP, while in the females, only BMI (OR = 1.019, p<0.05) and WHtR (OR = 2.685, p<0.05) were associated with high BP. CONCLUSIONS: In this study, we found a different correlation between BMI, WC and BP in the 2 subgroups: males and females. Only WHtR showed a significant ability to predict high BP in both groups. WHtR might represent an easily measurable anthropometric index and a better predictor of CV risk in adolescents. PMID- 23100183 TI - A matched-control evaluation of an antifungal bundle in the intensive care unit at a university teaching hospital. AB - BACKGROUND: Antimicrobial use bundles are becoming a common means of implementing antimicrobial stewardship initiatives in the hospital setting. Although the utility of these bundles has been described for many disease states, their adoption for antifungal therapy management is largely unknown. OBJECTIVE: Our objective was to assess the utility of an antifungal bundle protocol in limiting excessive use of echinocandins in the intensive-care inpatient setting. METHODS: In this matched-control evaluation, pre-protocol control patients were matched with each prospective patient in a 2:1 ratio using five demographic and clinical characteristics. The impact of the antifungal bundle protocol on caspofungin days of therapy, drug costs, and adherence to bundle criteria was assessed. RESULTS: A significant reduction in median days of caspofungin therapy (4.00 vs. 2.00 days, p = 0.001) was found in the bundle group. Most of this reduction in use was realized in the medical ICU (p = 0.002) as opposed to the surgical ICU (p = 0.188). CONCLUSIONS: Use of an antifungal bundle approach appears to facilitate a reduction in caspofungin use in the ICU without adversely affecting patient outcomes. Further trials are needed to assess the utility of such bundles in providing antimicrobial stewardship for antifungal drug use. PMID- 23100184 TI - Association between parental attitudes and self-medication of their children. AB - BACKGROUND: The association between parental attitudes and medication administered to their children has been studied mainly regarding specific diseases and ailments, e.g. asthma, fever and pain. Little is known about how parental attitudes toward medicines in general are associated with how they medicate their children using self-medication. OBJECTIVE: The aim of this study was to identify how parental attitudes toward medicines are associated with how they medicate their children with self-medication including the use of over-the counter (OTC) medicines and complementary and alternative medicines (CAMs). SETTING: A cross-sectional population-based study was conducted in the spring of 2007. The study sample consisted of a random sample of Finnish children under 12 years of age (n = 6,000). METHOD: A questionnaire was sent to parents, and the parent who usually takes responsibility for the child's medication was instructed to answer the questionnaire. MAIN OUTCOME MEASURE: The responding parent was asked to report the child's use of OTC medicines and CAMs during the preceding 2 days. The parent's attitude toward medicines was measured by 18 statements using a 5-item Likert scale. RESULTS: CAM use was least likely among children whose parent had a positive view of prescription medicines. In contrast, a positive attitude toward OTC medicines by a parent was associated with both, OTC medicine and CAM use among children, whereas, parental worry about the risks of medicines predicted the use of CAMs among children. CONCLUSION: This study showed that parental attitudes toward medicines have an impact on how they medicate their children, especially with CAMs. This finding highlights the fact that health care professionals should negotiate a child's treatment, taking into account parental views toward medicines, and previous use of self-medication. PMID- 23100185 TI - Painful patellar clunk or crepitation of contemporary knee prostheses. AB - BACKGROUND: Painful patellar clunk or crepitation (PCC) is a resurgent complication of contemporary posterior-stabilized TKA. The incidence, time to presentation, causes, and treatment of PCC still remain controversial. QUESTIONS/PURPOSES: We therefore (1) compared the incidence of PCC with five contemporary TKA designs, (2) evaluated the time to presentation, (3) identified possible etiologies, and (4) determined recurrence rate and change in knee functional scores after treatment for PCC. METHODS: We reviewed 580 patients who had 826 posterior-stabilized TKAs involving five different designs. The incidences of PCC were compared among the prostheses. The knees were divided into two groups depending on the development of PCC, and possible etiologic factors of PCC, including prosthesis design and surgical or radiographic variables, were compared between groups. We investigated the onset time of PCC and evaluated treatment results by knee outcome scores. Minimum followup was 2.0 years (mean, 3.9 years; range, 2.0-9.8 years). RESULTS: The PCC incidence was higher in the Press-Fit Condylar((r)) Sigma((r)) Rotating Platform/Rotating Platform-Flex Knee System (11 of 113 knees, 9.7%) than in the others (seven of 713 knees, 1.0%). Increased risk of PCC was associated with using a specific prosthesis and patellar retention. PCC occurred in all cases within a year after TKA (mean, 7.4 months). Arthroscopic treatment (16 knees) and patellar replacement (two knees) improved knee scores, with no recurrence observed over an average followup of 29 months. CONCLUSIONS: Prosthesis design and patellar retention were associated with PCC. Surgery resolved the PCC. PMID- 23100187 TI - Letter to editor: operating room traffic is a major concern during total joint arthroplasty. PMID- 23100186 TI - Can radiographic morphometric parameters for the hip be assessed on MRI? AB - BACKGROUND: Although morphometric hip parameters measured on radiographs are valuable tools guiding diagnosis and therapy in patients with hip disorders, some clinicians use MRI for such measurements, although it is unclear whether the parameters assessed on MRI differ from those assessed on radiographs. QUESTIONS/PURPOSES: We asked whether the lateral center-edge angle (LCE), Tonnis angle, extrusion index, and anterior center-edge angle (ACE) are similar on MRI and radiography. METHODS: We retrospectively reviewed the imaging data of 103 hips from 103 patients: 46 with femoroacetabular impingement and 57 with hip dysplasia. We manually measured the LCE, Tonnis angle, extrusion index, and ACE from radiographs and MRI in all 103 hips. Four straight coronal (Ant-10 mm, Ant-5 mm, Center, and Post-5 mm), three straight sagittal (S-Med-5 mm, S-Center, S-Lat 5 mm), and three 25o oblique sagittal (OS-Med-5 mm, OS-Center, OS-Lat-5 mm) reformats were reconstructed from a three-dimensional isotropic morphologic MRI sequence. MRI measurements were compared against the gold standard radiographic measurements. RESULTS: We found good agreement for the LCE angle, Tonnis angle, and extrusion index between radiographic and coronal slice MRI measurements. The mean differences between radiographic and MRI measurements were 5o or less or 5% or less (for the extrusion index) in all coronal MRI slices. However, the differences between ACE angles on sagittal MRI slices and radiographs ranged from 5 degrees to 28o. CONCLUSIONS: LCE, Tonnis angle, and extrusion index can be measured on MRI with comparable results to radiography. The ACE angle on radiographs cannot be estimated reliably from MRI. CLINICAL RELEVANCE: MRI provides similar morphometric measurements as radiography for most hip parameters, except for the ACE angle. PMID- 23100188 TI - Adding triamcinolone improves viscosupplementation: a randomized clinical trial. AB - BACKGROUND: Intraarticular injections, mainly using long-lasting corticosteroid suspensions, have long been used to treat knee osteoarthritis. Viscosupplementation is a relatively new approach with injection of a variety of agents. When comparing viscosupplementation with intraarticular injections of corticosteroids from baseline to the fourth week, steroids have been more effective for pain relief. By the fourth week they provide similar relief, but beyond that viscosupplementation appears to provide greater pain reduction. The delayed onset of symptomatic improvement combined with reports of reactive synovitis may discourage physicians and patients. QUESTIONS/PURPOSES: We therefore addressed three questions: Does the addition of triamcinolone to viscosupplementation (1) improve first-week pain and function compared with viscosupplementation alone, (2) diminish adverse effects of viscosupplementation alone, and (3) alter 6-month pain and function of viscosupplementation alone? METHODS: We prospectively enrolled 104 patients with knee osteoarthritis and randomized them to receive either a single intraarticular injection (6 mL) of hylan GF-20 (Group viscosupplementation [Group VS]), or a single intraarticular injection of hylan GF-20 (6 mL) and 1 mL (20 mg) of triamcinolone hexacetonide (Group VS + T). VAS, WOMACTM, and Lequesne questionnaires were completed at baseline and at Weeks 1, 4, 12, and 24. RESULTS: At Week 1 the WOMAC and VAS scores were lower in Group VS + T, compared with Group VS. There was no difference regarding the adverse effects. At Weeks 4, 12, and 24 there were no differences in the groups. CONCLUSIONS: The addition of triamcinolone hexacetonide improves first-week symptom and functional scores of viscosupplementation, but not beyond. It does not seem to increase the likelihood of adverse effects. LEVEL OF EVIDENCE: Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23100189 TI - Three-dimensional morphologic study of the child's hip: which parameters are reproducible? AB - BACKGROUND: Biplanar x-ray images obtained with patients in a standing weightbearing position allow reconstruction of three-dimensional (3-D) bone geometries, with lower radiation exposure than CT scans and better bone definition than MRI. QUESTIONS/PURPOSES: We determined the reproducibility of 3-D parameter values of the hips and pelves of healthy children, using biplanar x-ray images. METHODS: We built 3-D models of the hips of 33 children without musculoskeletal problems: 10 subjects younger than 9 years and 23 who were 9 years or older. Three anatomic landmarks and nine hip and pelvic parameters were computed for each reconstruction. To determine the reliability of these landmarks and parameters, each bone was reconstructed four times by two independent observers, leading to a total of 264 reconstructions, and parameters were studied for the two age groups and compared between dancers and nondancers. RESULTS: Taking into account all reconstructions, the interobserver reproducibility ranged from 2 to 4 mm for landmark positions or distance parameters, and 2 degrees to 6 degrees for angular parameters. The most reproducible point was the center of the femoral head (range, 0.2-17 mm). The distance between this center and its projection on the plane fitting the edge of the acetabulum, and the pelvic tilt were the most reproducible parameters. CONCLUSIONS: Reproducible 3-D reconstructions of hips and pelves of children were possible using biplanar x-ray images, regardless of the children's ages. Although we report preliminary values for 3-D parameters in healthy children's hips, further work is needed to obtain direct validation of our parameters using CT reconstructions of cadaveric specimens to avoid high doses of radiation. PMID- 23100190 TI - CORR Insights: Ultrasound as a first-line test in the diagnosis of carpal tunnel syndrome: a cost-effectiveness analysis. AB - This CORR Insights is a commentary on the article ''Ultrasound as a first line test in the diagnosis of carpal tunnel syndrome: a cost effectiveness analysis" by John R Fowler and colleagues available at DOI 10.1007/s11999-012-2662-3 . PMID- 23100191 TI - Endoscopic carpal tunnel release is preferred over mini-open despite similar outcome: a randomized trial. AB - BACKGROUND: The decision to perform endoscopic versus the mini-open carpal tunnel release technique is most likely left to surgeons rather than patients with idiopathic carpal tunnel syndrome. QUESTIONS/PURPOSES: We hypothesized that (1) at 3 months after surgery, the subjective outcomes of endoscopic release, performed on one hand, and mini-incision release, performed on the other, would not differ in patients with bilateral carpal tunnel syndrome; however, (2) each patient would likely prefer one technique over the other for specific reasons. METHODS: Fifty-two patients with bilateral carpal tunnel syndrome had one hand randomized to undergo endoscopic release and the other to undergo mini-incision release. Each patient was assessed with the Boston Carpal Tunnel Questionnaire (BCTQ) and DASH preoperatively and at each followup. Three months after surgery, the patients commented on which technique they preferred and completed a questionnaire regarding the reasons for not preferring the other technique. RESULTS: The mean BCTQ symptom/function score and DASH improved similarly in the endoscopic release group and the mini-incision release group. Thirty-four patients preferred endoscopic release and 13 preferred the mini-incision technique. Scar or pillar pain was the most commonly cited factor in not preferring either technique followed by postoperative pain for the open technique and transient worsening of symptoms for the endoscopic technique. CONCLUSIONS: Despite similar improvements in BCTQ and DASH scores after endoscopic and open techniques at 3 months postoperatively, the majority of our patients preferred the endoscopic technique. The most concerning reason for not preferring the other technique was scar or pillar pain. PMID- 23100193 TI - Musculoskeletal ultrasound: technical guidelines. PMID- 23100194 TI - Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma: What is the evidence today? AB - Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10-15% of HCC patients are suitable candidates for hepatic resection and liver transplantation due to the advanced stage of the disease at time of diagnosis and shortage of donors. Therefore, several minimally invasive image-guided therapies for locoregional treatment have been developed. Tumor ablative techniques are either based on thermal tumor destruction, as in radiofrequency ablation, cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound, or chemical tumor destruction, as in percutaneous ethanol injection. Image-guided catheter-based techniques rely on intra-arterial delivery of embolic, chemoembolic or radioembolic agents. These minimally invasive image-guided therapies have revolutionized the management of inoperable HCC. This review provides a description of all minimally invasive image-guided therapies currently available, an up-to-date overview of the scientific evidence for their clinical use, and thoughts for future directions. PMID- 23100195 TI - Pharmacokinetics of non-intravenous formulations of fentanyl. AB - Fentanyl was structurally designed by Paul Janssen in the early 1960s as a potent opioid analgesic (100-fold more potent than morphine). It is a full agonist at MU opioid receptors and possesses physicochemical properties, in particular a high lipophilicity (octanol:water partition coefficient >700), which allow it to cross quickly between plasma and central nervous target sites (transfer half-life of 4.7-6.6 min). It undergoes first-pass metabolism via cytochrome P450 3A (bioavailability ~30 % after rapid swallowing), which can be circumvented by non intravenous formulations (bioavailability 50-90 % for oral transmucosal or intranasal formulations). Non-intravenous preparations deliver fentanyl orally transmucosally, intranasally or transdermally. Passive transdermal patches release fentanyl at a constant zero-order rate for 2-3 days, making them suitable for chronic pain management, as are iontophoretic transdermal systems. Oral transmucosal and intranasal routes provide fast delivery (time to reach maximum fentanyl plasma concentrations 20 min [range 20-180 min] and 12 min [range 12-21 min], respectively) suitable for rapid onset of analgesia in acute pain conditions with time to onset of analgesia of 5 or 2 min, respectively. Intranasal formulations partly bypass the blood-brain barrier and deliver a fraction of the dose directly to relevant brain target sites, providing ultra fast analgesia for breakthrough pain. Thanks to the development of non intravenous pharmaceutical formulations, fentanyl has become one of the most successful opioid analgesics, and can be regarded as an example of a successful reformulation strategy of an existing drug based on pharmacokinetic research and pharmaceutical technology. This development broadened the indications for fentanyl beyond the initial restriction to intra- or perioperative clinical uses. The clinical utility of fentanyl could be expanded further by more comprehensive mathematical characterizations of its parametric pharmacokinetic input functions as a basis for the rational selection of fentanyl formulations for individualized pain therapy. PMID- 23100197 TI - New hope for survivors of stroke and traumatic brain injury. PMID- 23100198 TI - White light augments chemotherapeutic potential of cyclophosphamide: an in vitro study. AB - Cyclophosphamide (CYC) is a known chemotherapeutic drug used widely for the treatment of leukemias, lymphomas and some solid tumors. Copper is an essential constituent of chromatin and its level is usually elevated in various malignancies. Combined modality chemotherapy involves the use of drug with other components for cancer treatment, such as radiation therapy or surgery. Photosensitizer anticancer drugs can be used in combination with light and may have synergistic effect on cancer. The present study is an attempt to show that CYC acts as prooxidant when used in combination with Cu(II) and white light. We hypothesize that CYC when given as a chemotherapeutic agent possibly interact with endogenous copper associated with chromatin of the cancer cells and generate ROS besides acting as DNA alkylating agent. Thus, during chemotherapy the oxidative stress is possibly generated by the drug through mobilizing endogenous Cu(II) which may attribute to the cytotoxic death of cancer cell. PMID- 23100196 TI - Selective TNF inhibition for chronic stroke and traumatic brain injury: an observational study involving 629 consecutive patients treated with perispinal etanercept. AB - BACKGROUND: Brain injury from stroke and traumatic brain injury (TBI) may result in a persistent neuroinflammatory response in the injury penumbra. This response may include microglial activation and excess levels of tumour necrosis factor (TNF). Previous experimental data suggest that etanercept, a selective TNF inhibitor, has the ability to ameliorate microglial activation and modulate the adverse synaptic effects of excess TNF. Perispinal administration may enhance etanercept delivery across the blood-CSF barrier. OBJECTIVE: The objective of this study was to systematically examine the clinical response following perispinal administration of etanercept in a cohort of patients with chronic neurological dysfunction after stroke and TBI. METHODS: After approval by an independent external institutional review board (IRB), a chart review of all patients with chronic neurological dysfunction following stroke or TBI who were treated open-label with perispinal etanercept (PSE) from November 1, 2010 to July 14, 2012 at a group medical practice was performed. RESULTS: The treated cohort included 629 consecutive patients. Charts of 617 patients following stroke and 12 patients following TBI were reviewed. The mean age of the stroke patients was 65.8 years +/- 13.15 (range 13-97). The mean interval between treatment with PSE and stroke was 42.0 +/- 57.84 months (range 0.5-419); for TBI the mean interval was 115.2 +/- 160.22 months (range 4-537). Statistically significant improvements in motor impairment, spasticity, sensory impairment, cognition, psychological/behavioural function, aphasia and pain were noted in the stroke group, with a wide variety of additional clinical improvements noted in individuals, such as reductions in pseudobulbar affect and urinary incontinence. Improvements in multiple domains were typical. Significant improvement was noted irrespective of the length of time before treatment was initiated; there was evidence of a strong treatment effect even in the subgroup of patients treated more than 10 years after stroke and TBI. In the TBI cohort, motor impairment and spasticity were statistically significantly reduced. DISCUSSION: Irrespective of the methodological limitations, the present results provide clinical evidence that stroke and TBI may lead to a persistent and ongoing neuroinflammatory response in the brain that is amenable to therapeutic intervention by selective inhibition of TNF, even years after the acute injury. CONCLUSION: Excess TNF contributes to chronic neurological, neuropsychiatric and clinical impairment after stroke and TBI. Perispinal administration of etanercept produces clinical improvement in patients with chronic neurological dysfunction following stroke and TBI. The therapeutic window extends beyond a decade after stroke and TBI. Randomized clinical trials will be necessary to further quantify and characterize the clinical response. PMID- 23100199 TI - Diagnostic performance of 3D SPACE for comprehensive knee joint assessment at 3 T. AB - OBJECTIVE: To assess the diagnostic performance of 3D sampling perfection with application-optimised contrasts using variable flip-angle evolution (SPACE) turbo spin-echo (TSE) sequences compared to 2D TSE for comprehensive knee assessment at 3 T. METHODS: From January to July 2011, isotropic 3D SPACE was added to a 2D knee protocol at 3 T. Forty patients underwent subsequent arthroscopy. Three readers independently assessed MR images for meniscus, anterior cruciate ligament (ACL) and cartilage lesions. Readers 1 and 2 evaluated 3D and 2D data at separate sittings; reader 3 interpreted the complete exam including 3D and 2D sequences. Accuracies were calculated using arthroscopy as reference standard. McNemar's test (p < 0.05) was used to compare 3D and 2D techniques. RESULTS: The highest diagnostic yield was obtained by reader 3 (accuracies >=88 %). For the medial meniscus, readers performed better with the 2D technique than with 3D SPACE (accuracies 85-88 % vs. 78-80 %, respectively) (p > 0.05). For the lateral meniscus and ACL, 3D and 2D techniques had similar performance (accuracies >=93 %). For cartilage lesions, 3D SPACE had significantly lower specificity (p = 0.0156) than the 2D protocol for one reader. CONCLUSION: The conventional 2D TSE acquisition is more reliable than 3D SPACE for comprehensive assessment of the knee at 3.0 T. MAIN MESSAGES: * 3D SPACE is a valuable component of a knee MR protocol at 3 T. * 3D SPACE cannot be used as a single sequence in the MR evaluation of the knee at 3 T. * Knee MR protocols at 3 T should include both 2D and 3D TSE sequences. PMID- 23100200 TI - Elicitation of health state utilities in soft tissue sarcoma. AB - PURPOSE: Soft tissue sarcomas (STS) are uncommon tumours with varying histological subtypes. There is a paucity of available data concerning the quality-of-life (QoL) impact of STS which could be used to support economic evaluation of future treatments. This study aimed to elicit societal utility values for health states that depict the impact of STS and its treatment. METHODS: Following the development of eight health state vignettes, a sample of 100 members of the UK general public participated in a valuation exercise to elicit utility values using the time trade-off procedure. RESULTS: The treatment response state was valued as the least burdensome by participants followed by the prospect of stable disease (mean utility value: 0.736 SD 0.21). Serious adverse events were associated with a range of disutilities from -0.236 for grade III/IV pain to -0.357 for grade III/IV nausea/vomiting. Progressive disease was deemed the least desirable outcome and was associated with a substantial decline in utility (-0.473). CONCLUSIONS: Findings suggest advanced STS are associated with significant burden for individuals. Treatment-related adverse events were seen as debilitating, however, progression represents an enormous challenge to QoL. This illustrates the significant value to individuals of extending the progression free survival period. PMID- 23100202 TI - Genetic parameters of five new European Standard Set STR loci (D10S1248, D22S1045, D2S441, D1S1656, D12S391) in the population of eastern Croatia. AB - AIM: To establish allele frequencies and genetic parameters in eastern Croatia population and to compare them with those in other populations. The second aim was to compare the genetic profiles obtained with different forensic kits amplifying the same genetic markers. METHODS: Blood samples of 217 unrelated individuals from eastern Croatia were genotyped using AmpFlSTR NGM kit. Allele distribution and other genetic parameters were determined for 15 short tandem repeat (STR) loci, including the 5 loci recently added to the European Standard Set (ESS) of STR loci (D10S1248, D22S1045, D2S441, D1S1656, and D12S391). Ninety six samples underwent duplicate analysis using AmpFlSTR Identifiler kit. RESULTS: Power of discrimination was highest for the two new ESS loci, D1S1656 (0.97254) and D12S391 (0.97339). Comparison of allele frequencies for 5 new ESS loci in our sample with previously published population data showed a significant difference from Maghreb population on D2S441 and from American Caucasian population on D1S1656. Comparison of allele frequencies for standard 10 STR loci with all the neighboring populations' data showed a significant difference only from Albanian population (on D2S1338, D18S51, and TH01). Discordant genotypes were observed in 5 (5.2%) samples at a single locus when amplified with both AmpFlSTR NGM and AmpFlSTR Identifiler kit. CONCLUSION: New ESS STR loci are highly polymorphic and short, and therefore very useful for the analysis of challenging forensic samples. DNA samples purposed for establishing databases should be routinely amplified in duplicate. PMID- 23100201 TI - A single-nucleotide polymorphism (SNP) multiplex system: the association of five SNPs with human eye and hair color in the Slovenian population and comparison using a Bayesian network and logistic regression model. AB - AIM: To analyze two phenotype characteristics--eye and hair color--using single nucleotide polymorphisms (SNPs) and evaluate their prediction accuracy in Slovenian population. METHODS: Twelve SNPs (OCA2 - rs1667394, rs7170989, rs1800407, rs7495174; HERC2 - rs1129038, rs12913832; MC1R - rs1805005, rs1805008; TYR - rs1393350; SLC45A2 - rs16891982, rs26722; SLC24A5 - rs1426654) were used for the development of a single multiplex assay. The single multiplex assay was based on SNaPshot chemistry and capillary electrophoresis. In order to evaluate the accuracy of the prediction of eye and hair color, we used the logistic regression model and the Bayesian network model, and compared the parameters of both. RESULTS: The new single multiplex assay displayed high levels of genotyping sensitivity with complete profiles generated from as little as 62 pg of DNA. Based on a prior evaluation of all SNPs in a single multiplex, we focused on the five most statistically significant in our population in order to investigate the predictive value. The two prediction models performed reliably without prior ancestry information, and revealed very good accuracy for both eye and hair color. Both models determined the highest predictive value for rs12913832 (P<0.0001), while the other four SNPs (rs1393350, rs1800407, rs1805008, and rs7495174) showed additional association for color prediction. CONCLUSION: We developed a sensitive and reliable single multiplex genotyping assay. More samples from different populations should be analyzed before this assay could be used as one of the supplemental tools in tracing unknown individuals in more complicated crime investigations. PMID- 23100203 TI - STR-typing of ancient skeletal remains: which multiplex-PCR kit is the best? AB - AIM: To comparatively test nine co mmercially available short tandem repeat (STR) multiplex kits (PowerPlex 16, 16HS, ES, ESI17, ESX17, S5 [all Promega]; AmpFiSTR Identifiler, NGM and SEfiler [all Applied Biosystems]) for their efficiency and applicability to analyze ancient and thus highly degraded DNA samples. METHODS: Fifteen human skeletal remains from the late medieval age were obtained and analyzed using the nine polymerase chain reaction assays with slightly modified protocols. Data were systematically compared to find the most meaningful and sensitive assay. RESULTS: The ESI, ESX, and NGM kits showed the best overall results regarding amplification success, detection rate, identification of heterozygous alleles, sex determination, and reproducibility of the obtained data. CONCLUSION: Since application of these three kits enables the employment of different primer sequences for all the investigated amplicons, a combined application is recommended for best possible and--most importantly--reliable genetic analysis of ancient skeletal material or otherwise highly degraded samples, e.g., from forensic cases. PMID- 23100204 TI - Evaluation of forensic and anthropological potential of D9S1120 in Mestizos and Amerindian populations from Mexico. AB - AIM: To carry out a deeper forensic and anthropological evaluation of the short tandem repeat (STR) D9S1120 in five Mestizo populations and eight Amerindian groups from Mexico. METHODS: We amplified the STR D9S1120 based on primers and conditions described by Phillips et al, followed by capillary electrophoresis in the genetic analyzer ABI Prism 310. Genotypes were analyzed with the GeneMapper ID software. In each population we estimated statistical parameters of forensic importance and Hardy-Weinberg equilibrium. Heterozygosity and FST-values were compared with those previously obtained with nine STRs of the Combined DNA Index System (CODIS-STRs). RESULTS: Amerindian and Mestizo populations showed high frequencies of the allele 9 and 16, respectively. Population structure analysis (AMOVA) showed a significant differentiation between Amerindian groups (FST=2.81%; P<0.0001), larger than between Mestizos (FST=0.44%; P=0.187). D9S1120 showed less genetic diversity but better population differentiation estimates than CODIS-STRs between Amerindian groups and between Amerindians and Mestizos, but not between Mestizo groups. CONCLUSION: This study evaluated the ability of D9S1120 to be used for human identification purposes and demonstrated its anthropological potential to differentiate Mestizos and Amerindian populations. PMID- 23100205 TI - Does the patient with chest pain have a coronary heart disease? Diagnostic value of single symptoms and signs--a meta-analysis. AB - AIM: To determine the diagnostic value of single symptoms and signs for coronary heart disease (CHD) in patients with chest pain. METHODS: Searches of two electronic databases (EMBASE 1980 to March 2008, PubMed 1966 to May 2009) and hand searching in seven journals were conducted. Eligible studies recruited patients presenting with acute or chronic chest pain. The target disease was CHD, with no restrictions regarding case definitions, eg, stable CHD, acute coronary syndrome (ACS), acute myocardial infarction (MI), or major cardiac event (MCE). Diagnostic tests of interest were items of medical history and physical examination. Bivariate random effects model was used to derive summary estimates of positive (pLR) and negative likelihood ratios (nLR). RESULTS: We included 172 studies providing data on the diagnostic value of 42 symptoms and signs. With respect to case definition of CHD, diagnostically most useful tests were history of CHD (pLR=3.59), known MI (pLR=3.21), typical angina (pLR=2.35), history of diabetes mellitus (pLR=2.16), exertional pain (pLR=2.13), history of angina pectoris (nLR=0.42), and male sex (nLR=0.49) for diagnosing stable CHD; pain radiation to right arm/shoulder (pLR=4.43) and palpitation (pLR=0.47) for diagnosing MI; visceral pain (pLR=2.05) for diagnosing ACS; and typical angina (pLR=2.60) and pain reproducible by palpation (pLR=0.13) for predicting MCE. CONCLUSIONS: We comprehensively reported the accuracy of a broad spectrum of single symptoms and signs for diagnosing myocardial ischemia. Our results suggested that the accuracy of several symptoms and signs varied in the published studies according to the case definition of CHD. PMID- 23100206 TI - Prognostic performance of the Simplified Acute Physiology Score II in major Croatian hospitals: a prospective multicenter study. AB - AIM: To perform an external validation of the original Simplified Acute Physiology Score II (SAPS II) system and to assess its performance in a selected group of patients in major Croatian hospitals. METHODS: A prospective, multicenter study was conducted in five university hospitals and one general hospital during a six-month period between November 1, 2007 and May 1, 2008. Standardized hospital mortality ratio (SMR) was calculated from the mean predicted mortality of all the 2756 patients and the actual mortality for the same group of patients. The validation of SAPS II was made using the area under receiver operating characteristic curve (AUC), 2*2 classification tables, and Hosmer-Lemeshow tests. RESULTS: The predicted mortality was as low as 14.6% due to a small proportion of medical patients and the SMR being 0.89 (95% confidence interval [CI], 0.78-0.98). The SAPS II system demonstrated a good discriminatory power as measured by the AUC (0.85; standard error [SE]=0.012; 95% CI=0.840 0.866; P<0.001). This system significantly overestimated the actual mortality (Hosmer-Lemeshow goodness-of-fit H statistic: chi(2) =584.4; P<0.001 and C statistics: chi(2)(8) =313.0; P<0.001) in the group of patients included in the study. CONCLUSION: The SAPS II had a good discrimination, but it significantly overestimated the observed mortality in comparison with the predicted mortality in this group of patients in Croatia. Therefore, caution is required when an evaluation is performed at the individual level. PMID- 23100207 TI - Relations of the Big-Five personality dimensions to autodestructive behavior in clinical and non-clinical adolescent populations. AB - AIM: To examine the relationship between the Big-Five personality model and autodestructive behavior symptoms, namely Autodestructiveness and Suicidal Depression in two groups of participants: clinical and non-clinical adolescents. METHODS: Two groups of participants, clinical (adolescents with diagnosis of psychiatric disorder based on clinical impression and according to valid diagnostic criteria, N=92) and non-clinical (high-school students, N=87), completed two sets of questionnaires: the Autodestructiveness Scale which provided data on Autodestructiveness and Suicidal Depression, and the International Personality Item Pool (IPIP), which provided data on the Big -Five personality dimensions. RESULTS: Clinical group showed significantly higher values on the Autodestructiveness scale in general, as well as on Suicidal Depression, Aggressiveness, and Borderline subscales than the non-clinical group. Some of the dimensions of the Big-Five personality model, ie, Emotional Stability, Conscientiousness, and Agreeableness showed significant relationship (hierarchical regression analyses, P values for beta coefficients from 0.000 to 0.021) with Autodestructiveness and Suicidal Depression, even after controlling for the sex and group effects or, when analyzing Suicidal Depression, after controlling the effect of other subscales. CONCLUSION: The results indicate that dimensions of the Big-Five model are important when evaluating adolescent psychiatric patients and adolescents from general population at risk of self destructive behavior. PMID- 23100208 TI - Predictive value of dental readiness and psychological dimensions for oral health related quality of life in Croatian soldiers: a cross-sectional study. AB - AIM: To determine the predictive value of dental readiness and psychological dimensions for oral health-related quality of life (OHRQoL) in Croatian soldiers. METHODS: The sample consisted of 402 consecutive soldiers aged 21 to 54 years classified into the following groups according to dental readiness: Class 1 - not requiring dental treatment (N=54), Class 2 - unlikely to need emergency treatment within 12 months (N=205), and Class 3 - very likely to need treatment within 12 months (N=143). OHRQoL was assessed by the Oral Health Impact Profile and psychological dimensions by the Brief Symptom Inventory and Dental Anxiety Scale. RESULTS: Multivariate analysis showed that Class 3 soldiers had higher frequency of psychological discomfort, psychological disability, and physical pain and handicap than Class 1 soldiers (P=0.019). Multiple linear regression showed that longer military experience, higher level of dental anxiety, and dental unreadiness were significant predictors of lower OHRQoL (P<0.050) but accounted for low variability. None of the single psychological symptomatic dimensions was a significant predictor of OHRQoL. CONCLUSION: Although this study found a moderate association between OHRQoL and clinical, military, demographic", and psychological variables, the significant predictors could be used as a basis for further research of clinical and psychosocial factors of OHRQoL. PMID- 23100209 TI - Irrigation of human prepared root canal--ex vivo based computational fluid dynamics analysis. AB - AIM: To analyze the influence of the needle type, insertion depth, and irrigant flow rate on irrigant flow pattern, flow velocity, and apical pressure by ex-vivo based endodontic irrigation computational fluid dynamics (CFD) analysis. METHODS: Human upper canine root canal was prepared using rotary files. Contrast fluid was introduced in the root canal and scanned by computed tomography (CT) providing a three-dimensional object that was exported to the computer-assisted design (CAD) software. Two probe points were established in the apical portion of the root canal model for flow velocity and pressure measurement. Three different CAD models of 27G irrigation needles (closed-end side-vented, notched open-end, and bevel open-end) were created and placed at 25, 50, 75, and 95% of the working length (WL). Flow rates of 0.05, 0.1, 0.2, 0.3, and 0.4 mL/s were simulated. A total of 60 irrigation simulations were performed by CFD fluid flow solver. RESULTS: Closed-end side-vented needle required insertion depth closer to WL, regarding efficient irrigant replacement, compared to open-end irrigation needle types, which besides increased velocity produced increased irrigant apical pressure. For all irrigation needle types and needle insertion depths, the increase of flow rate was followed by an increased irrigant apical pressure. CONCLUSIONS: The human root canal shape obtained by CT is applicable in the CFD analysis of endodontic irrigation. All the analyzed values -irrigant flow pattern, velocity, and pressure - were influenced by irrigation needle type, as well as needle insertion depth and irrigant flow rate. PMID- 23100210 TI - The suitability of using death certificates as a data source for cancer mortality assessment in Turkey. AB - AIM: To compare the quality of the 2008 cancer mortality data of the Istanbul Directorate of Cemeteries (IDC) with the 2008 data of International Agency for Research on Cancer (IARC) and Turkish Statistical Institute (TUIK), and discuss the suitability of using this databank for estimations of cancer mortality in the future. METHODS: We used 2008 and 2010 death records of the IDC and compared it to TUIK and IARC data. RESULTS: According to the WHO statistics, in Turkey in 2008 there were 67255 estimated cancer deaths. As the population of Turkey was 71517100, the cancer mortality rate was 9.4 per 10000. According to the IDC statistics, the cancer mortality rate in Istanbul in 2008 was 5.97 per 10000. CONCLUSION: IDC estimates were higher than WHO probably because WHO bases its estimates on a sample group and because of the restrictions of IDC data collection method. Death certificates could be a reliable and accurate data source for mortality statistics if the problems of data collection are solved. PMID- 23100211 TI - Four-stage teaching technique and chest compression performance of medical students compared to conventional technique. AB - AIM: To compare the 2-stage and 4-stage basic life support teaching technique. The second aim was to test if students' self-evaluated knowledge was in accordance with their actual knowledge. METHODS: A total of 126 first-year students of the Faculty of Medicine in Ljubljana were involved in this parallel study conducted in the academic year 2009/2010. They were divided into ten groups. Five groups were taught the 2-stage model and five the 4-stage model. The students were tested in a scenario immediately after the course. Questionnaires were filled in before and after the course. We assessed the absolute values of the chest compression variables and the proportions of students whose performance was evaluated as correct according to our criteria. The results were analyzed with independent samples t test or Mann-Whitney-U test. Proportions were compared with chi(2) test. The correlation was calculated with the Pearson coefficient. RESULTS: There was no difference between the 2-stage (2S) and the 4-stage approach (4S) in the compression rate (126+/-13 min-1 vs 124+/-16 min -1, P=0.180, independent samples t test), compression depth (43+/-7 mm vs 44+/-8 mm, P=0.368, independent samples t test), and the number of compressions with correct hand placement (79+/-32% vs 78+/-12, P=0.765, Mann-Whitney U-test). However, students from the 4-stage group had a significantly higher average number of compressions per minute (70+/-13 min -1 2S, 78+/-12 min-1 4S, P=0.02, independent samples t test). The percentage of students with all the variables correct was the same (13% 2S, 15% 4S, P=0.741, chi2 test). There was no correlation between the students' actual and self-evaluated knowledge (P=0.158, Pearson coefficient=0.127). CONCLUSIONS: The 4-stage teaching technique does not significantly improve the quality of chest compressions. The students' self evaluation of their performance after the course was too high. PMID- 23100213 TI - From re-pair and re-production to (re)generation: bio-objects as indicators of cultural change. PMID- 23100212 TI - A novel germline MLH1 mutation causing Lynch Syndrome in patients from the Republic of Macedonia. AB - AIM: To implement molecular analysis in the clinical diagnosis and management of Lynch syndrome (LS). METHODS: We analyzed the mutations in MLH1 and MSH2 in the selected LS families from the Republic of Macedonia. RESULTS: We performed the very first genetic identification of LS families and characterized a novel mutation. The novel nonsense germline point mutation c.392C>G in the codon 131 of MLH1(S131X) was identified as the underlying genetic cause of LS in three families. The haplotype analysis suggested a founder effect of this mutation in our population. CONCLUSION: We expect to detect the mutation in other LS patients from the region, and recommend cost-effective screening for this mutation by restriction fragment length polymorphism-polymerase chain reaction or DNA sequencing of MLH1 Exon5 prior to full genetic testing in all LS suspects of Macedonian ancestry. PMID- 23100214 TI - The evaluation of antibiotic prescribing in general practice using a health insurance company database: penicillins use. PMID- 23100215 TI - Walk your way to health: October 15--World Walking Day. PMID- 23100217 TI - beta-blockers for COPD inpatients. PMID- 23100218 TI - Mechanisms and treatment of CKD. AB - As CKD continues to increase worldwide, along with the demand for related life saving therapies, the financial burden of CKD will place an increasing drain on health care systems. Experimental studies showed that glomerular capillary hypertension and impaired sieving function with consequent protein overload play a pathogenic role in the progression of CKD. Consistently, human studies show that proteinuria is an independent predictor of progression and that its reduction is renoprotective. At comparable BP control, inhibitors of the renin angiotensin system (RAS), including angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), more effectively than non RAS inhibitor therapy reduce proteinuria, slow progression to ESRD, and even improve the kidney function achieving disease regression in some cases. In participants with diabetes, RAS inhibitors delay the onset of microalbuminuria and its progression to macroalbuminuria, and ACE inhibitors may reduce the excess cardiovascular mortality associated with diabetic renal disease. In addition to RAS inhibitors, however, multimodal approaches including lifestyle modifications and multidrug therapy will be required in most cases to optimize control of the several risk factors for CKD and related cardiovascular morbidity. Whether novel medications may help further improve the cost-effectiveness of renoprotective interventions is a matter of investigation. PMID- 23100216 TI - Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. AB - BACKGROUND AND OBJECTIVE: The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. METHODS: A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. RESULTS: The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. CONCLUSIONS: This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption. PMID- 23100219 TI - CKD and sudden cardiac death: epidemiology, mechanisms, and therapeutic approaches. AB - Multiple studies demonstrate a strong independent association between CKD and cardiovascular events including death, heart failure, and myocardial infarction. This review focuses on recent clinical studies that expand this spectrum of adverse cardiovascular events to include ventricular arrhythmias and sudden cardiac death. In addition, experimental models suggest structural remodeling of the heart and electrophysiologic changes in this population. These processes may explain the increased arrhythmic risk in kidney disease and aid in identifying patients who are at higher risk for sudden cardiac death. Finally, we review here the data to support the use of pharmacologic and device-based therapies for both the primary and secondary prevention of sudden cardiac death. PMID- 23100221 TI - PPARs: history and advances. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the steroid hormone receptor superfamily, discovered in 1990. To date, three PPAR subtypes have been identified; PPARalpha, PPAR beta/delta, and PPARgamma. These receptors share a high degree of homology but differ in tissue distribution and ligand specificity. PPARs have been implicated in the etiology as well as treatment of several important diseases and pathological conditions such as diabetes, inflammation, senescence-related diseases, regulation of fertility, and various types of cancer. Consequently, significant efforts to discover novel PPAR roles and delineate molecular mechanisms involved in their activation and repression as well as develop safer and more effective PPAR modulators, as therapeutic agents to treat a myriad of diseases and conditions, are underway. This volume of Methods in Molecular Biology contains details of experimental protocols used in researching these receptors. PMID- 23100220 TI - NADPH-oxidase 4 protects against kidney fibrosis during chronic renal injury. AB - NADPH oxidases synthesize reactive oxygen species that may participate in fibrosis progression. NOX4 and NOX2 are NADPH oxidases expressed in the kidneys, with the former being the major renal isoform, but their contribution to renal disease is not well understood. Here, we used the unilateral urinary obstruction model of chronic renal injury to decipher the role of these enzymes using wild type, NOX4-, NOX2-, and NOX4/NOX2-deficient mice. Compared with wild-type mice, NOX4-deficient mice exhibited more interstitial fibrosis and tubular apoptosis after obstruction, with lower interstitial capillary density and reduced expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in obstructed kidneys. Furthermore, NOX4-deficient kidneys exhibited increased oxidative stress. With NOX4 deficiency, renal expression of other NOX isoforms was not altered but NRF2 protein expression was reduced under both basal and obstructed conditions. Concomitant deficiency of NOX2 did not modify the phenotype exhibited by NOX4-deficient mice after obstruction. NOX4 silencing in a mouse collecting duct (mCCD(cl1)) cell line increased TGF-beta1-induced apoptosis and decreased NRF2 protein along with expression of its target genes. In addition, NOX4 silencing decreased hypoxia-inducible factor-1alpha and expression of its target genes in response to hypoxia. In summary, these results demonstrate that the absence of NOX4 promotes kidney fibrosis, independent of NOX2, through enhanced tubular cell apoptosis, decreased microvascularization, and enhanced oxidative stress. Thus, NOX4 is crucial for the survival of kidney tubular cells under injurious conditions. PMID- 23100222 TI - PPAR-alpha cloning, expression, and characterization. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear/steroid receptor gene superfamily that also comprises beta, delta, and gamma isoforms. PPARalpha is a ligand-activated transcription factor that plays an important role in the regulation of many genes involved in key metabolic processes. Today, PPARalpha has been cloned from mammalian, marsupial, and a number of marine species and its expression has been found to be relatively tissue- and species-specific. Here, we describe the methods for cloning of PPARalpha genes by RT-PCR and RACE approaches and related protocols for studying the expression of cloned PPARalpha cDNAs in mammalian cell systems. PMID- 23100223 TI - PPARGC1A and PPARG genotyping: beginner's guide to genotyping with unlabeled probes. AB - Amplicon melting and genotyping with unlabeled probes has become wide spread technique for SNP genotyping. In both methods PCR is performed with new generation of double-strand DNA binding dyes. Nucleic acid melting generates distinct melting curves that can be used to identify the presence of sequence variation within the amplicon. Unlabeled probes are inexpensive and provide the sequence specificity. This chapter provides comprehensive instructions about design of primers and probes and evaluation of their quality. Chapter also contains useful advices on how to perform DNA purification, optimize PCR conditions, how to prepare working solutions, and how to interpret the data of melting analysis. PMID- 23100224 TI - Generation of an inducible, cardiomyocyte-specific transgenic mouse model with PPAR beta/delta overexpression. AB - Peroxisome proliferator-activated receptors (PPARs) consist of three subtypes, each displaying distinctive tissue distribution. In general, the three PPAR subtypes exert overlapping function in transcriptional regulation of lipid metabolism. However, each PPAR subtype possesses distinctive functions in different tissues dependent on their expression abundance, endogenous ligands, and the PPAR coregulators in a specific tissue. Transgenesis is an invaluable technique in defining the in vivo function of a particular gene and its protein. Cre/LoxP-mediated gene targeting has been extensively used to explore the tissue specific function of PPARs. While this tissue-specific loss-of-function approach is extremely useful in determining the essential role of a PPAR, the tissue specific gain-of-function approach is another important technique used to understand the effects of PPAR activation in a particular tissue. Transgenic overexpression of PPAR in a specific tissue has been used. However, this conventional technique requires generating the transgenic models individually for each target tissue. In this chapter, we describe the methodology for a more efficient generation of transgenic mouse models with a constitutively active form of PPARbeta/delta in different tissues. PMID- 23100225 TI - Specific knockdown of PPARdelta gene in colon cancer cells by lentivirus-mediated RNA interfering. AB - Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors. Of this family, PPARdelta has been implicated in the pathogenesis of colorectal cancer, whereas its exact role is highly controversial as available studies yield conflicting results. Therefore, further studies using powerful and duplicable methods are needed to clarify the functions of PPARdelta in colorectal cancer. RNA interference (RNAi) is such a powerful tool for specific suppression of gene expression at the posttranscriptional level. Of available RNAi methods, lentivirus has been shown to mediate RNAi most efficiently and stably based on its remarkable advantages, such as powerful transduction efficiency and a wider range of target cells, integration of expression cassette into host genomics, low immunogenicity and self-inactivated and replication-incompetent after integrating into host genomics. In this chapter, we will introduce the details of using lentivirus-mediated RNAi to specifically knockdown the expression of PPARdelta in colon cancer cell lines. This method includes: designing and cloning short-hairpin RNA cassette into lentivector, constructing and titrating lentiviral particles, infecting target cells with lentivirus and assaying the knockdown efficiency. PMID- 23100226 TI - Dominant-negative and knockdown approaches to studying PPAR activity. AB - Manipulation of PPAR activity is often a valuable approach toward elucidation of the cellular effects of PPARs. The activity of specific PPARs can be decreased using chemical inhibitors, but these approaches can be affected by nonspecific interactions or cell toxicity. Alternative approaches include targeting PPAR gene expression or activity through molecular biology strategies. Here, we describe the targeting of PPARgamma through dominant-negative and siRNA-mediated knockdown constructs. PMID- 23100227 TI - Producing PPARgamma2 knockdown in mouse liver. AB - A high saturated fat diet induces fatty liver in mice. The fatty liver is triggered initially by an increase in PPARgamma2 protein in the liver, which leads to increased expression of lipogenic genes. Inactivation of PPARgamma2 may improve fatty liver induced by a high saturated fat diet. RNA interference of PPARgamma2 should be a powerful tool to elucidate the role of PPARgamma2 in the development of fatty liver. Here, we describe our method for constructing the adenovirus vector containing short hairpin RNA targeted for PPARgamma2. Adenovirus vector-mediated RNA interference for PPARgamma2 should be useful for clarifying the biological role of the PPARgamma2 pathway in various tissues and for therapeutic application in a variety of diseases. PMID- 23100228 TI - Adipose tissue-specific PPARgamma gene targeting. AB - The nuclear receptor peroxisome proliferator activated receptor gamma (PPARgamma) is most abundantly expressed in adipose tissue and has been shown to play imperative roles in controlling adipogenesis and lipogenesis in cultured cell systems in vitro as well as in mice and humans. However, it is unclear how important the role this receptor plays in regulating physiological functions of mature adipocytes in vivo. The Cre-loxP gene targeting strategy is employed to specifically disrupt PPARgamma in mature adipocytes in mice. In this chapter, I will describe generation of "floxed" PPARgamma mice, which bear loxP sequences in the introns of PPARgamma gene locus flanking the coding exons 1 and 2 of PPARgamma and creation of the aP2-Cre transgenic mice, which express Cre recombinase under the control of the promoter of adipocyte fatty acid binding protein (aP2). Crossing of the two mouse lines results in deletion of PPARgamma gene only in differentiated adipocytes in Cre positive mice. PMID- 23100229 TI - Site-directed mutagenesis to study the role of specific amino acids in the ligand binding domain of PPARs. AB - The role of certain amino acids in the interactions of ligands with their cognate nuclear receptors is usually achieved by the resolution of the crystal structure of the receptor complexed with the ligand. As a complementary functional approach, site-directed mutagenesis, a technique broadly used in molecular biology, allows the assessment of the role of a specific amino acid in determining the interaction with a specific ligand. This method makes it possible to evaluate several mutations of a key amino acid for ligand binding and to determine the relationship between protein structure and ligand interaction. Here, we describe an application of this technique to evaluate different point mutations on the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARgamma) in the absence or presence of chemically different ligands. PMID- 23100230 TI - PPAR SUMOylation: some useful experimental tips. AB - Studies on the regulation of nuclear receptors, such as the peroxisome proliferator-activated receptors (PPARs), are important to enhance our understanding of their molecular, cellular, and physiological behavior. A decade ago, it was shown that the SUMOylation pathway plays a very important role in the regulation of transcription factor activity. The SUMOylation process involves the covalent binding of SUMO protein to the target protein. However, experimental procedures to demonstrate that low-expressed proteins, such as PPARs, are SUMOylated, remain tricky, and require specific optimization for each protein.Here, we provide a simple and useful experimental method to investigate the SUMOylation of PPARs in a cellular context. The procedure for studying SUMOylation in living cells is based on the purification under denaturating conditions of total SUMOylated proteins followed by the specific detection of the PPAR proteins. For that purpose, cells are transfected with both 6xHistidine tagged SUMO and PPAR expression vectors. Since the polyHistidine tag binds to nickel cationic ion-linked agarose matrix (Ni-NTA matrix), His-tagged SUMO proteins covalently linked to the protein substrate can be specifically precipitated and separated from the unSUMOylated proteins. The SUMO-modified PPAR proteins can subsequently be visualized by western blotting using anti-PPAR antibodies. Many questions relative to the regulation of PPAR SUMOylation can be appropriately addressed by adapting this protocol. PMID- 23100232 TI - In vivo studies of PPAR-chromatin interactions: chromatin immunoprecipitation for single-locus and genomewide analyses. AB - The immunoprecipitation of protein complexes with associated DNA fragments, termed chromatin immunoprecipitation, allows for the analysis of the binding of endogenous factors. With the advent and widespread use of next generation high throughput sequencing technologies, factor binding can be assessed in an unbiased and genomewide approach. The protocol outlined here yields sufficient material to subsequently carry out such analyses and discusses key steps in detail. PMID- 23100231 TI - Analyzing phosphorylation-dependent regulation of subcellular localization and transcriptional activity of transcriptional coactivator NT-PGC-1alpha. AB - Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that regulates the genes involved in energy metabolism. Recent evidence has been provided that alternative splicing of PPARGC1A gene produces a functional but predominantly cytosolic isoform of PGC 1alpha (NT-PGC-1alpha). We have demonstrated that transcriptional coactivation capacity of NT-PGC-1alpha is directly correlated with its nuclear localization in a PKA phosphorylation-dependent manner. In this chapter, we describe quantitative imaging analysis methods that are developed to measure the relative fluorescence intensity of the protein of interest in the nucleus and cytoplasm in a single cell and the frequency distribution of nuclear/cytoplasmic intensity ratios in the population of cells, respectively. This chapter also describes transient cotransfection and dual-luciferase reporter gene assay that examine the ability of coactivators to activate the transcriptional activity of transcription factors. PMID- 23100233 TI - FISH analysis using PPAR gamma-specific probes for detection of PAX8-PPAR gamma translocation in follicular thyroid neoplasms. AB - Fluorescence in situ hybridization (FISH) is increasingly gaining importance in clinical diagnostics settings. Due to the ability of the technique to detect chromosomal abnormalities in samples with low cellularity or containing a mixed population of cells even at a single-cell level, it has become more popular in cancer research and diagnosis. Here, we describe the FISH technique for detection of PAX8-PPARgamma translocation in follicular thyroid neoplasms, and the optimal protocol for the detection of this fusion gene using in archival formalin-fixed paraffin-embedded (FFPE) thyroid tissue sections. PMID- 23100235 TI - Determination of PPAR expression by western blot. AB - Peroxisome proliferator-activated receptors (PPARs) are key nuclear receptors which mediate the regulation of the transcription of many genes, especially those involved in lipid catabolism and inflammation. In mammals, three types of PPARs named PPARalpha, PPARbeta (also called PPARdelta), and PPARgamma have been identified. Up and down-regulations of one or more of these receptors are encountered during development, physiological adaptations, and in several diseases. Therefore, the ability to accurately measure PPAR expression in cells and tissues is an important aspect of PPAR research. This can be done by Western blot with specific antibodies. In this chapter, we describe the use of our techniques 1,2 to measure PPARs expression, describe the adequate way to extract proteins, the best antibodies currently available and discuss potential misleading results in the absence of appropriate controls. PMID- 23100234 TI - Immunohistochemical techniques to identify and localize proteins of interest in paraffin embedded tissue sections. AB - Proteins carry out cellular functions. Identifying proteins within tissues, which are characteristically comprised of various cell types, is critical to understanding how the tissue functions. Being able to assess protein expression in tissues is also essential to gaining insight into how tissues change under different physiological conditions, in pathological states, in response to treatments, etc. Immunohistochemistry exploits antibody-antigen associations to identify specific proteins within tissues. This is a very powerful technique as it allows for studying tissues intact, preserving cellular relationships, and tissue structure. Here, we discuss the process of using an antibody specific for PPARgamma to identify ovarian cells that express this transcription factor, and how its expression changes during the ovarian cycle. PMID- 23100236 TI - Fluorescence resonance energy transfer techniques to study ligand-mediated interactions of PPARs with coregulators. AB - The capacity to induce the association of peroxisome proliferator-activated receptors (PPARs) with different transcriptional coregulators is determined by the peculiar 3D-structure that the receptors adopt when bound with a specific ligand. The fluorescence resonance energy transfer assay is a technique widely used to evaluate coregulator recruitment to nuclear receptors induced by ligands. With this assay it is possible to quantitatively determine the interaction and the affinity of coregulators with PPARs when these receptors are complexed with ligands. Here, we describe the use of this technique to assess the preferential interaction and the affinity of PPARgamma with coregulators as a function of the chemical structure of the bound ligand. PMID- 23100237 TI - Estimation of the PPARalpha agonism of fibrates by a combined MM-docking approach. AB - Fibrates are peroxisome proliferator-activated alpha receptor (PPARalpha) activators derived from fibric acid and are the most clinically used therapeutics in the treatment of hypertriglyceridemia. Recently, we reported a computational approach for the investigation of the binding properties of fibrates, characterized by similar carboxylic heads but differing in the size and orientation of the hydrophobic portion. This procedure is based on a combination of standard docking and molecular mechanics approaches to better describe the adaptation of the protein target to the bound ligand. The application of our approach to a set of 23 fibrates and the use of an effective regression procedure, allowed the development of predictive models of the PPARalpha agonism. The obtained models are characterized by good performances realizing a fair trade off between accuracy and computational costs. The best model is more specialized in the ranking of fibrate agonists whose binding is mainly controlled by steric rather than by electronic modulation. Here, we describe in details the application of this computational procedure for the prediction of PPARalpha agonism of fibrate ligands. PMID- 23100238 TI - Combined biophysical and cell-based approaches for the assessment of ligand binding to PPARgamma. AB - Transcription factors of the peroxisome proliferator-activated receptor (PPAR) family are ligand-activated receptors that play key roles in lipid metabolism and inflammation. The gamma isoform (PPARgamma) is involved in adipocyte differentiation, insulin sensitization, and vascular pathophysiology, including inflammation and atherosclerosis, for which it is considered an important drug target. PPARgamma ligands display varied structures and include fatty acids, electrophilic lipids, and certain drugs. These agonists promote conformational changes allowing interaction of PPARgamma with coactivators and hence transcriptional regulation. Here we present a panoply of methods to study PPARgamma interactions with ligands and activation in vitro and in cells. The first method is based on the competition of the fluorescent dye 1 anilinonaphthalene-8-sulfonic acid (ANS) with PPARgamma ligands for the ligand binding pocket, allowing detection and quantification of ligand binding to PPARgamma. This method is specific for PPARgamma while ANS displays negligible interaction with other nuclear receptors such as PPARalpha and retinoid X receptor alpha (RXRalpha). The ANS competition assay has been validated through comparison of the affinities determined for well-known PPARgamma ligands by this method with those reported in the literature. We also describe here gel-based competition assays that show limited performance with non-covalently bound ligands. In addition, we present a fluorescence anisotropy assay to analyze PPARgamma activation by ligands in vitro through their capacity of eliciting PPARgamma interaction with a fluorescently labeled peptide derived from one of its coactivators (SRC-1). Finally, we show cell-based assays to investigate PPARgamma activation by interaction with its ligands. We believe that combined approaches using ANS, fluorescent coactivator peptides, and in-cell assays to monitor PPARgamma binding and interactions may provide valuable strategies for the identification and characterization of PPARgamma ligands. PMID- 23100239 TI - Exploring PPAR modulation in experimental mice. AB - The main concern in exploring modulation of PPARs in experimental animals is probably the choice of the model. Although mechanistic studies may be well designed using knockout and transgenic animals, the interpretation of results with respect to inferred results of PPAR activation into humans should be performed cautiously. This is even more important in this field considering that undesired and unexpected effects have been already described in human epidemiologic studies. Taken together, these observations suggest that a global approach using omic technologies, although expensive, is probably the most suitable to obtain useful data. Also, in this approach, we propose all tissues should be explored, not only those obviously relevant to metabolism, or stored in proper conditions if further assessment is required. PMID- 23100240 TI - Induction of adipogenic differentiation in three-dimensional culture model on a novel microfabricated scaffold. AB - The development of a three-dimensional (3D) culture system is very important for regenerative medicine and drug discovery applications of stem cell technology because the 3D culture condition could mimic the stem cell environment in vivo and support accurate differentiation. This chapter describes a novel 3D culture technique for efficient induction of adipogenic differentiation. This 3D culture system provides an easy way to allow cells to form a 3D spheroid structure without any matrix derived from animal and chemical substances. We firstly describe the details of the 3D culture technique using human mesenchymal stem/progenitor cells (MPCs) and its optimization. Then we elaborate on the protocol of efficient induction for adipogenic differentiation and adipocyte specific gene expression, including peroxisome proliferator-activated receptor gamma, with our culture system in human MPCs. PMID- 23100241 TI - Analyzing PPARalpha/ligand interactions by chemical cross-linking and high resolution mass spectrometry. AB - The combination of chemical cross-linking and high-resolution mass spectrometry is an emerging technique for monitoring conformational changes in proteins induced by drug binding. In this chapter, we describe this approach for gaining insights into the conformational changes of the peroxisome proliferator-activated receptor alpha after binding of low-molecular weight ligands. Our strategy provides a basis to efficiently characterize target protein-drug interactions. PMID- 23100242 TI - Synthesis, mass spectrometric characterization, and analysis of the PPARdelta agonist GW1516 and its major human metabolites: targets in sports drug testing. AB - The elucidation of metabolic pathways and the detection of emerging therapeutics potentially enhancing athletic performance are of paramount importance to doping control authorities to protect the integrity of elite sports. A new drug candidate belonging to the family of the peroxisome proliferator-activated receptor-delta agonists termed GW1516 (also referred to as GW501516) has been prohibited by the World Anti-Doping Agency in 2009 due to its potential to artificially increase endurance. Consequently, sports drug testing laboratories need to establish detection methods enabling the identification of the intact substance and/or its metabolite(s) that unambiguously prove the presence or absence of the target substances in doping control specimens. Simulating human metabolic reactions using liver microsomal preparations, minute amounts of possible urinary metabolites were obtained that were characterized by mass spectrometry-based methods. Subsequently, the most abundant metabolic products were chemically synthesized and as well characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Finally, GW1516 and two oxidized metabolites were implemented in a routine doping control analytical assay based on liquid chromatography-(tandem) mass spectrometry (LC-MS/MS), which was tested for its -fitness-for-purpose using spiked urine samples. PMID- 23100243 TI - LC-MS-based method for the qualitative and quantitative analysis of the novel PPARgamma agonist KR-62980. AB - A sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed for a novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, KR-62980, in rat plasma. It involves liquid-liquid extraction (LLE) followed by HPLC separation and electrospray ionization tandem mass spectrometry. The linear ranges of the assay were 0.01-10 MUg/mL with a correlation coefficient (R (2)) greater than 0.99 and the lower limit of quantification was 0.01 MUg/mL. The average recovery was 90.1 and 98.4% from rat plasma for KR-62980 and imipramine, respectively. The coefficients of variation of intra- and inter-assay were 1.2-10.6% and the relative error was 0.8-13.2%. The method was validated and successfully applied to the pharmacokinetic study of KR-62980 in rat. PMID- 23100244 TI - Behavioral paradigms to evaluate PPAR modulation in animal models of brain injury. AB - The use of behavioral testing has become an invaluable tool for assessing the efficacy of therapeutics for a variety of disorders of the central nervous system. This chapter will describe in detail several behavioral paradigms to evaluate the efficacy of PPAR agonists to modulate cognitive impairments in rodent models. When used together as a battery these procedures allow for a global assessment of cognition. These tests are explained in detail below, and include: (1) Novel Object Recognition (NOR), (2) Morris Water Maze (MWM), (3) Delay Match to Place (DMP), and (4) Cue Strategy. PMID- 23100245 TI - Modeling the salivary cortisol profile in population research: the multi-ethnic study of atherosclerosis. AB - In many studies, it has been hypothesized that stress and its biologic consequences may contribute to disparities in rates of cardiovascular disease. However, understanding of the most appropriate statistical methods to analyze biologic markers of stress, such as salivary cortisol, remains limited. The authors explore the utility of various statistical methods in modeling daily cortisol profiles in population-based studies. They demonstrate that the proposed methods allow additional insight into the cortisol profile compared with commonly used summaries of the profiles based on raw data. For instance, one can gain insights regarding the shape of the population average curve, characterize the types of individual-level departures from the average curve, and better understand the relation between covariates and attained cortisol levels or slopes at various points of the day, in addition to drawing inferences regarding common features of the cortisol profile, such as the cortisol awakening response and the area under the curve. The authors compare the inference and interpretations drawn from these methods and use data collected as part of the Multi-Ethnic Study of Atherosclerosis to illustrate them. PMID- 23100246 TI - Characterizing vaccine-associated risks using cubic smoothing splines. AB - Estimating risks associated with the use of childhood vaccines is challenging. The authors propose a new approach for studying short-term vaccine-related risks. The method uses a cubic smoothing spline to flexibly estimate the daily risk of an event after vaccination. The predicted incidence rates from the spline regression are then compared with the expected rates under a log-linear trend that excludes the days surrounding vaccination. The 2 models are then used to estimate the excess cumulative incidence attributable to the vaccination during the 42-day period after vaccination. Confidence intervals are obtained using a model-based bootstrap procedure. The method is applied to a study of known effects (positive controls) and expected noneffects (negative controls) of the measles, mumps, and rubella and measles, mumps, rubella, and varicella vaccines among children who are 1 year of age. The splines revealed well-resolved spikes in fever, rash, and adenopathy diagnoses, with the maximum incidence occurring between 9 and 11 days after vaccination. For the negative control outcomes, the spline model yielded a predicted incidence more consistent with the modeled day specific risks, although there was evidence of increased risk of diagnoses of congenital malformations after vaccination, possibly because of a "provider visit effect." The proposed approach may be useful for vaccine safety surveillance. PMID- 23100247 TI - Implications of M bias in epidemiologic studies: a simulation study. AB - Collider-stratification bias arises from conditioning on a variable (collider) which opens a path from exposure to outcome. M bias occurs when the collider stratification bias is transmitted through ancestors of exposure and outcome. Previous theoretical work, but not empirical data, has demonstrated that M bias is smaller than confounding bias. The authors simulated data for large cohort studies with binary exposure, an outcome, a collider, and 2 predictors of the collider. They created 178 scenarios by changing the frequencies of variables and/or the magnitudes of associations among the variables. They calculated the effect estimate, percentage bias, and mean squared error. M bias in these realistic scenarios ranged from -2% to -5%. When the authors increased one or both relative risks for the relation between the collider and unmeasured factors to >=8, the negative bias was more substantial (>15%). The result was substantially biased (e.g., >20%) if an unmeasured confounder that was also a collider was not adjusted to avoid M bias. In scenarios resembling those the authors examined, M bias had a small impact unless associations between the collider and unmeasured confounders were very large (relative risk > 8). When a collider is itself an important confounder, controlling for confounding would take precedence over avoiding M bias. PMID- 23100248 TI - Is the health burden associated with obesity changing? AB - Prioritization of obesity prevention and management policy is based on one's understanding of the health risks associated with increasing body weight. However, there is evidence that the magnitude of these health risks may be changing over time. Here, the authors analyze the theoretical drivers of these changes and then examine whether there is empirical evidence to support the theory. They conclude that, although the mortality risks associated with increasing body weight may be decreasing over time, the overall health burden appears likely to increase. PMID- 23100249 TI - Association between glucose tolerance level and cancer death in a general Japanese population: the Hisayama Study. AB - The authors examined the associations of glucose tolerance status and fasting and 2-hour postload glucose levels with the risk of cancer death in a 19-year follow up study of 2,438 Japanese subjects aged 40-79 years who underwent a 75-g oral glucose tolerance test (1988-2007). During follow-up, 229 subjects died of cancer. The risk of cancer death was significantly higher in subjects with fasting plasma glucose levels of >=5.6 mmol/L or 2-hour postload glucose levels of >=11.1 mmol/L than in those with the lowest fasting or 2-hour postload glucose levels, after adjustment for potentially confounding factors. According to glucose tolerance status, not only diabetes but also impaired fasting glycemia and impaired glucose tolerance were significant risk factors for cancer death (for impaired fasting glycemia, multivariable-adjusted hazard ratio (HR) = 1.49 (95% confidence interval (CI): 1.05, 2.11); for impaired glucose tolerance, HR = 1.52 (95% CI: 1.05, 2.22); and for diabetes, HR = 2.10 (95% CI: 1.41, 3.12)). With regard to site-specific cancers, elevated fasting or 2-hour postload glucose levels were associated with the risks of death from stomach, liver, and lung cancer. These findings suggest that both prediabetic hyperglycemia and diabetes are significant risk factors for cancer death in the general Japanese population. PMID- 23100250 TI - Constitutive turnover of phosphorylation at Thr-412 of human p57/coronin-1 regulates the interaction with actin. AB - The actin-binding protein p57/coronin-1, a member of the coronin protein family, is selectively expressed in hematopoietic cells and plays crucial roles in the immune response through reorganization of the actin cytoskeleton. We previously reported that p57/coronin-1 is phosphorylated by protein kinase C, and the phosphorylation down-regulates the association of this protein with actin. In this study we analyzed the phosphorylation sites of p57/coronin-1 derived from HL60 human leukemic cells by MALDI-TOF-MS, two-dimensional gel electrophoresis, and Phos-tag(r) acrylamide gel electrophoresis in combination with site-directed mutagenesis and identified Ser-2 and Thr-412 as major phosphorylation sites. A major part of p57/coronin-1 was found as an unphosphorylated form in HL60 cells, but phosphorylation at Thr-412 of p57/coronin-1 was detected after the cells were treated with calyculin A, a Ser/Thr phosphatase inhibitor, suggesting that p57/coronin-1 undergoes constitutive turnover of phosphorylation/dephosphorylation at Thr-412. A diphosphorylated form of p57/coronin-1 was detected after the cells were treated with phorbol 12-myristate 13-acetate plus calyculin A. We then assessed the effects of phosphorylation at Thr-412 on the association of p57/coronin-1 with actin. A co-immunoprecipitation experiment with anti-p57/coronin-1 antibodies and HL60 cell lysates revealed that beta-actin was co-precipitated with the unphosphorylated form but not with the phosphorylated form at Thr-412 of p57/coronin-1. Furthermore, the phosphorylation mimic (T412D) of p57/coronin-1 expressed in HEK293T cells exhibited lower affinity for actin than the wild-type or the unphosphorylation mimic (T412A) did. These results indicate that the constitutive turnover of phosphorylation at Thr 412 of p57/coronin-1 regulates its interaction with actin. PMID- 23100251 TI - Rab13 small G protein and junctional Rab13-binding protein (JRAB) orchestrate actin cytoskeletal organization during epithelial junctional development. AB - During epithelial junctional development, both vesicle transport and reorganization of the actin cytoskeleton must be spatiotemporally regulated. Coordination of these cellular functions is especially important, but the precise mechanism remains elusive. Previously, we identified junctional Rab13-binding protein (JRAB)/molecules interacting with CasL-like 2 (MICAL-L2) as an effector of the Rab13 small G protein, and we found that the Rab13-JRAB system may be involved in the formation of cell-cell adhesions via transport of adhesion molecules. Here, we showed that JRAB interacts with two actin-binding proteins, actinin-1 and -4, and filamentous actin via different domains and regulates actin cross-linking and stabilization through these interactions. During epithelial junctional development, JRAB is prominently enriched in the actin bundle at the free border; subsequently, JRAB undergoes a Rab13-dependent conformational change that is required for maturation of cell-cell adhesion sites. These results suggest that Rab13 and JRAB regulate reorganization of the actin cytoskeleton throughout epithelial junctional development from establishment to maturation of cell-cell adhesion. PMID- 23100252 TI - Site-specific phosphorylation of the p65 protein subunit mediates selective gene expression by differential NF-kappaB and RNA polymerase II promoter recruitment. AB - Phosphorylation of NF-kappaB plays an important role in modulating transcriptional activity of NF-kappaB independently of inhibitor of kappaB (IkappaB) proteins. For the p65 subunit, multiple phosphorylation sites have been mapped in and adjacent to both the N-terminal Rel homology domain and the C terminal transactivation domain. Their impact on NF-kappaB-dependent transcription, however, has never been assessed at a broader level. In this study, we evaluate the importance of differential p65 phosphorylation on four serine acceptor sites in the Rel homology domain for the expression of an array of NF-kappaB-dependent genes in endothelial cells. We find that inhibition of p65 phosphorylation on these serine residues targets NF-kappaB activity to distinctive gene subsets in a kappaB enhancer element-specific context. We show that the phosphorylation-dependent alterations in gene and protein expression are reflective of the amount of p65 and phosphorylated RNA polymerase II (p-RNAP II) bound to respective gene promoter regions. Depending on the gene subset, impaired gene expression was either a result of decreased p65 promoter recruitment or of a failure of bound p65 to recruit p-RNAP II. In conclusion, our findings demonstrate that site-specific p65 phosphorylation targets NF-kappaB activity to particular gene subsets on a global level by influencing p65 and p-RNAP II promoter recruitment. PMID- 23100254 TI - Enantioselective demethylation of nicotine as a mechanism for variable nornicotine composition in tobacco leaf. AB - Nicotine and its N-demethylation product nornicotine are two important alkaloids in Nicotiana tabacum L. (tobacco). Both nicotine and nornicotine have two stereoisomers that differ from each other at 2'-C position on the pyrrolidine ring. (S)-Nicotine is the predominant form in the tobacco leaf, whereas the (R) enantiomer only accounts for ~0.2% of the total nicotine pool. Despite considerable past efforts, a comprehensive understanding of the factors responsible for generating an elevated and variable enantiomer fraction of nornicotine (EF(nnic) of 0.04 to 0.75) from the consistently low EF observed for nicotine has been lacking. The objective of this study was to determine potential roles of enantioselective demethylation in the formation of the nornicotine EF. Recombinant CYP82E4, CYP82E5v2, and CYP82E10, three known tobacco nicotine demethylases, were expressed in yeast and assayed for their enantioselectivities in vitro. Recombinant CYP82E4, CYP82E5v2, and CYP82E10 demethylated (R)-nicotine 3-, 10-, and 10-fold faster than (S)-nicotine, respectively. The combined enantioselective properties of the three nicotine demethylases can reasonably account for the nornicotine composition observed in tobacco leaves, which was confirmed in planta. Collectively, our studies suggest that an enantioselective mechanism facilitates the maintenance of a reduced (R)-nicotine pool and, depending on the relative abundances of the three nicotine demethylase enzymes, can confer a high (R)-enantiomer percentage within the nornicotine fraction of the leaf. PMID- 23100253 TI - Lamin B receptor recognizes specific modifications of histone H4 in heterochromatin formation. AB - Inner nuclear membrane proteins provide a structural framework for chromatin, modulating transcription beneath the nuclear envelope. Lamin B receptor (LBR) is a classical inner nuclear membrane protein that associates with heterochromatin, and its mutations are known to cause Pelger-Huet anomaly in humans. However, the mechanisms by which LBR organizes heterochromatin remain to be elucidated. Here, we show that LBR represses transcription by binding to chromatin regions that are marked by specific histone modifications. The tudor domain (residues 1-62) of LBR primarily recognizes histone H4 lysine 20 dimethylation and is essential for chromatin compaction, whereas the whole nucleoplasmic region (residues 1-211) is required for transcriptional repression. We propose a model in which the nucleoplasmic domain of LBR tethers epigenetically marked chromatin to the nuclear envelope and transcriptional repressors are loaded onto the chromatin through their interaction with LBR. PMID- 23100255 TI - A single residue within the V5 region of HIV-1 envelope facilitates viral escape from the broadly neutralizing monoclonal antibody VRC01. AB - VRC01, a broadly neutralizing monoclonal antibody, is capable of neutralizing a diverse array of HIV-1 isolates by mimicking CD4 binding with the envelope glycoprotein gp120. Nonetheless, resistant strains have been identified. Here, we examined two genetically related and two unrelated envelope clones, derived from CRF08_BC-infected patients, with distinct VRC01 neutralization profiles. A total of 22 chimeric envelope clones was generated by interchanging the loop D and/or V5 regions between the original envelopes or by single alanine substitutions within each region. Analysis of pseudoviruses built from these mutant envelopes showed that interchanging the V5 region between the genetically related or unrelated clones completely swapped their VRC01 sensitivity profiles. Mutagenesis analysis revealed that the asparagine residue at position 460 (Asn-460), a potential N-linked glycosylation site in the V5 region, is a key factor for observed resistance in these strains, which is further supported by our structural modeling. Moreover, changes in resistance were found to positively correlate with deviations in VRC01 binding affinity. Overall, our study indicates that Asn-460 in the V5 region is a critical determinant of sensitivity to VRC01 specifically in these viral strains. The long side chain of Asn-460, and potential glycosylation, may create steric hindrance that lowers binding affinity, thereby increasing resistance to VRC01 neutralization. PMID- 23100256 TI - Physiological and proteomic characterization of salt tolerance in a mangrove plant, Bruguiera gymnorrhiza (L.) Lam. AB - Salinity is a major abiotic stress that is responsible for growth reduction in most higher plants. Bruguiera gymnorrhiza (L.) Lam., a mangrove plant, is a halophyte and is one of the most salt-tolerant plant species. Physiological and proteomic characteristics of B. gymnorrhiza were investigated under three NaCl concentrations (0, 200 and 500 mM) in this study. Maximum seedling growth occurred at 200 mM NaCl. Leaf osmotic potential was more negative as salt levels increased further. Physiological results revealed that inorganic ions (especially Na(+) and Cl(-)) played a key role in osmotic adjustment of B. gymnorrhiza leaves under salinity treatments. Comparative proteomic analysis revealed 23 salt responsive proteins in B. gymnorrhiza leaves, which were differentially expressed under salt treatment compared with control. Ten protein spots were analyzed by liquid chromatography-tandem mass spectrometry, leading to identification of proteins involved in photosynthesis, antioxidation, protein folding, cell organization and metabolism. Salt-responsive mechanism was different between 200 and 500 mM NaCl-treated plants on the basis of the physiological and proteomic analyses. Salt tolerance under 200 mM NaCl treatment was due to effective osmotic adjustment, accumulation of inorganic ions (especially Na(+) and Cl(-)) as well as increased expression of photosynthesis-related proteins and antioxidant enzymes, which improved the salt tolerance of B. gymnorrhiza, and furthermore promoted plant growth. On the other hand, 500 mM NaCl reduced the growth of B. gymnorrhiza, which appears to have been caused by the accumulation of NaCl (ionic effect) and energy consumption by organic solute synthesis. Moreover, the repressed expression of photosynthesis-related proteins and antioxidant enzymes led to the reduction of growth. Protein folding and degradation-related proteins and cell organization-related protein were up-regulated and played important roles in salt tolerance of B. gymnorrhiza under severe salt stress. PMID- 23100257 TI - Revisiting the sequencing of the first tree genome: Populus trichocarpa. AB - Ten years ago, it was announced that the Joint Genome Institute with funds provided by the Department of Energy, Office of Science, Biological and Environmental Research would sequence the black cottonwood (Populus trichocarpa Torr. & Gray) genome. This landmark decision was the culmination of work by the forest science community to develop Populus as a model system. Since its public release in late 2006, the availability of the Populus genome has spawned research in plant biology, morphology, genetics and ecology. Here we address how the tree physiologist has used this resource. More specifically, we revisit our earlier contention that the rewards of sequencing the Populus genome would depend on how quickly scientists working with woody perennials could adopt molecular approaches to investigate the mechanistic underpinnings of basic physiological processes. Several examples illustrate the integration of functional and comparative genomics into the forest sciences, especially in areas that target improved understanding of the developmental differences between woody perennials and herbaceous annuals (e.g., phase transitions). Sequencing the Populus genome and the availability of genetic and genomic resources has also been instrumental in identifying candidate genes that underlie physiological and morphological traits of interest. Genome-enabled research has advanced our understanding of how phenotype and genotype are related and provided insights into the genetic mechanisms whereby woody perennials adapt to environmental stress. In the future, we anticipate that low-cost, high-throughput sequencing will continue to facilitate research in tree physiology and enhance our understanding at scales of individual organisms and populations. A challenge remains, however, as to how genomic resources, including the Populus genome, can be used to understand ecosystem function. Although examples are limited, progress in this area is encouraging and will undoubtedly improve as future research targets the many unique aspects of Populus as a keystone species in terrestrial ecosystems. PMID- 23100258 TI - Three types of cavitation caused by air seeding. AB - There are different opinions of the dynamics of an air bubble entering a xylem conduit. In this paper, we present a thorough mechanical analysis and conclude that there are three types of cavitation caused by air seeding. After an air seed enters a conduit at high xylem pressure P'(1), along with the drop of the water potential, it will expand gradually to a long-shaped bubble and extend continually. This is the first type of air seeding, or the type of expanding gradually. When the xylem pressure is moderate, right after an air seed enters a conduit, it will expand first. Then, as soon as the pressure reaches a threshold the bubble will blow up to form a bubble in long shape, accompanied by acoustic (or ultra-acoustic) emission. It will extend further as xylem pressure decreases continually. This is the second type of air seeding, or the type of expanding exploding, becoming a long-shaped bubble-lengthening by degrees. In the range of P'(1) <= - 3P(o) (P(o) is atmospheric pressure), soon after an air seed is sucked into a conduit it will explode immediately and the conduit will be full of the gas of the bubble instantly. This is the third type of air seeding, or the type of sudden exploding and filling conduit instantly. The third type is the frequent event in daily life of plant. PMID- 23100259 TI - Sleep position does not appear to influence the risk of extreme cardiorespiratory events in vulnerable infants. AB - Implications for practice and research: Extreme cardiorespiratory events can be documented during sleep and are more common in immature preterm infants. The supine sleep position does not appear to decrease the risk of Sudden Infant Death Syndrome (SIDS) by decreasing the risk of extreme cardiorespiratory events in vulnerable infants. Reasons for the physiological advantage of the supine sleep position remain speculative and require ongoing study despite decreases in SIDS death rates in recent years. PMID- 23100260 TI - Greater intake of Western fast food among Singaporean adults is associated with increased risk of diabetes and heart-disease-related death. PMID- 23100261 TI - A three-step critical pathway for community-acquired pneumonia reduces duration of hospital stay and intravenous antibiotic use by 2 days. AB - Implications for practice and research: Although early switch therapy and hospital discharge are well-recognised processes, current practices show that these practices are not well established worldwide. Pathways are useful tools to remind treating physicians about criteria for early switch and discharge. A behavioural change may be necessary in order to decrease the gap between national recommendations and current management of hospitalised patients with community acquired pneumonia. PMID- 23100262 TI - The mental, physical and emotional health of newly qualified nurses may be influenced by their psychological capital and perceived job fit. PMID- 23100263 TI - Intravenous analgesia for out-of-hospital traumatic pain in adults: ketamine gives a greater reduction in pain than morphine but causes more adverse effects. AB - Implications for practice and research: Intravenous ketamine has been shown to be useful for acute pain in a variety of settings. The present study shows that it provides a greater reduction in pain than morphine but causes more adverse effects in out-of-hospital care. PMID- 23100264 TI - In smokers who lapse during nicotine patch treatment, continued patch use increases the likelihood of recovering abstinence. AB - Implications for practice and research: Quitting smokers who use nicotine replacement therapy (NRT) are often advised to stop using this if they restart smoking; quitters often discontinue NRT after brief smoking lapses. Quitters who continue using NRT during brief lapses may be more likely to return to abstinence. Treating lapses with NRT probably encourages shortterm cessation; research should investigate this further and test the impact on smokers' long term abstinence and health gain. PMID- 23100265 TI - Diet and physical activity interventions reduce pregnancy weight gain compared with control, with dietary interventions having the greatest effect. AB - Implications for practice and research: Behavioural interventions can reduce maternal, fetal and neonatal obstetric and weight-related risks. Good-quality research is required to inform the development of behavioural interventions to determine effectiveness and cost-effectiveness for short-term and long-term health outcomes. PMID- 23100266 TI - Excess maternal weight gain during pregnancy is associated with overweight/obesity in offspring at age 16 years, but maternal pre-pregnancy obesity has a greater effect. AB - Implications for practice and research: Children of mothers who are obese prior to pregnancy, and/or gain excessive weight in early pregnancy, carry increased risk for obesity in adolescence. Obese women of childbearing age should be actively supported to achieve lifestyle modification prior to conception or in early pregnancy. Research is needed to identify strategies for optimal gestational weight gain (GWG) and lifestyle modification before and during pregnancy. Studies need to identify women at highest risk of excess GWG plus potential benefits of intense dietary and lifestyle counselling. PMID- 23100267 TI - Swedish nursing students report that campus education supports research utilisation more than clinical education, but support varies between universities. PMID- 23100268 TI - omega-3 Long-Chain Polyunsaturated Fatty Acids and Fatty Acid Desaturase Activity Ratios as Eventual Endophenotypes for ADHD. AB - OBJECTIVE: Epidemiological studies suggest that long-chain polyunsaturated fatty acids (LC-PUFAs) may be suitable as endophenotypes for ADHD. To be appropriated vulnerability traits, endophenotypes should be altered in unaffected relatives of index cases. Serum profiles of LC-PUFAs in unaffected relatives of ADHD patients remain understudied. The main objective of this study was to compare serum LC PUFAs in ADHD patients, unaffected relatives of index cases, and general population unaffected participants. METHOD: LC-PUFA profiles of 72 participants (27 ADHD patients, 27 unaffected relatives, and 18 general-population participants) were obtained by gas chromatography-mass spectrometry (GC-MS). Groups were compared by parametrical statistics. RESULTS: Unaffected females from the general population presented lower Docosapentaenoic acid (DPA; p = .0012) and a-linolenic acid (ALA; p = .0091) levels compared with ADHD females and unaffected relatives. In addition, docosahexaenoic acid (DHA)/ALA and DHA/DPA ratios, addressing desaturase activity, were significantly lower in ADHD patients and unaffected relatives of ADHD patients in the female-subgroup (p = .022 and .04, respectively). CONCLUSION: DHA/ALA, DHA/DPA, serum DPA, and serum ALA may be suitable as endophenotypes for ADHD women. PMID- 23100269 TI - Inhibition of the prothrombinase complex on red blood cells by heparin and covalent antithrombin-heparin complex. AB - The role of red blood cells (RBCs) in coagulation is not well understood. Overt exposure of phosphatidylserine on surfaces of RBCs provide docking sites for formation of the prothrombinase complex, which further aids in amplification of coagulation leading to subsequent thrombosis. No studies to date have evaluated heparin inhibition of the RBC-prothrombinase system. Therefore, this study examines the ability of heparin and a covalent antithrombin-heparin complex (ATH) to inhibit the RBC-prothrombinase system. Discontinuous inhibition assays were performed to obtain k2 values for inhibition of free or prothrombinase-bound Xa by antithrombin and unfractionated heparin (AT + UFH) versus ATH. In addition, components of the complex (prothrombin, RBCs or Va) were excluded prior to reaction with inhibitors to investigate potential mechanisms involved. Inhibition of thrombin generation, fibrinogen conversion and plasma clotting by the RBC prothrombinase system was also examined. Protection of Xa was observed for AT + UFH and not for ATH reactions. Inhibition rates for ATH were significantly faster when compared with AT + UFH results. The greatest impact on Xa inhibition was observed from factor Va omission for both inhibitors. ATH inhibited thrombin generation, fibrinogen conversion and plasma clotting better compared with AT + UFH. This study determined potential control of coagulation contributed by RBCs. Moreover, greater control of coagulation is achieved by covalently linking heparin to AT. PMID- 23100270 TI - The vasohibin family: a novel family for angiogenesis regulation. AB - Angiogenesis, a formation of neovessels, is regulated by the local balance between angiogenesis stimulators and inhibitors. A number of such endogenous regulators of angiogenesis have been found in the body. Recently, vasohibin-1 (VASH1) was isolated as a negative feedback regulator of angiogenesis produced by endothelial cells (ECs) and subsequently vasohibin-2 (VASH2) as a homologue of VASH1. It was then explored that VASH1 is expressed in ECs to terminate angiogenesis, whereas VASH2 is expressed in cells other than ECs to promote angiogenesis in the mouse model of angiogenesis. This review will focus on the vasohibin family members, which are novel regulators of angiogenesis. PMID- 23100271 TI - Small serum protein-1 changes the susceptibility of an apoptosis-inducing metalloproteinase HV1 to a metalloproteinase inhibitor in habu snake (Trimeresurus flavoviridis). AB - Viperidae snakes containing various venomous proteins also have several anti toxic proteins in their sera. However, the physiological function of serum protein has been elucidated incompletely. Small serum protein (SSP)-1 is a major component of the SSPs isolated from the serum of a Japanese viper, the habu snake (Trimeresurus flavoviridis). It exists in the blood as a binary complex with habu serum factor (HSF), a snake venom metalloproteinase inhibitor. Affinity chromatography of the venom on an SSP-1-immobilized column identified HV1, an apoptosis-inducing metalloproteinase, as the target protein of SSP-1. Biacore measurements revealed that SSP-1 was bound to HV1 with a dissociation constant of 8.2 * 10-8 M. However, SSP-1 did not inhibit the peptidase activity of HV1. Although HSF alone showed no inhibitory activity or binding affinity to HV1, the SSP-1-HSF binary complex bound to HV1 formed a ternary complex that non competitively inhibited the peptidase activity of HV1 with a inhibition constant of 5.1 +/- 1.3 * 10-9 M. The SSP-1-HSF complex also effectively suppressed the apoptosis of vascular endothelial cells and caspase 3 activation induced by HV1. Thus, SSP-1 is a unique protein that non-covalently attaches to HV1 and changes its susceptibility to HSF. PMID- 23100272 TI - Modeling susceptibility to periodontitis. AB - Chronic inflammatory diseases like periodontitis have a complex pathogenesis and a multifactorial etiology, involving complex interactions between multiple genetic loci and infectious agents. We aimed to investigate the influence of genetic polymorphisms and bacteria on chronic periodontitis risk. We determined the prevalence of 12 single-nucleotide polymorphisms (SNPs) in immune response candidate genes and 7 bacterial species of potential relevance to periodontitis etiology, in chronic periodontitis patients and non-periodontitis control individuals (N = 385). Using decision tree analysis, we identified the presence of bacterial species Tannerella forsythia, Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and SNPs TNF -857 and IL-1A -889 as discriminators between periodontitis and non-periodontitis. The model reached an accuracy of 80%, sensitivity of 85%, specificity of 73%, and AUC of 73%. This pilot study shows that, on the basis of 3 periodontal pathogens and SNPs, patterns may be recognized to identify patients at risk for periodontitis. Modern bioinformatics tools are valuable in modeling the multifactorial and complex nature of periodontitis. PMID- 23100273 TI - Acoustic emission analysis of tooth-composite interfacial debonding. AB - This study detected tooth-composite interfacial debonding during composite restoration by means of acoustic emission (AE) analysis and investigated the effects of composite properties and adhesives on AE characteristics. The polymerization shrinkage, peak shrinkage rate, flexural modulus, and shrinkage stress of a methacrylate-based universal hybrid, a flowable, and a silorane-based composite were measured. Class I cavities on 49 extracted premolars were restored with 1 of the 3 composites and 1 of the following adhesives: 2 etch-and-rinse adhesives, 2 self-etch adhesives, and an adhesive for the silorane-based composite. AE analysis was done for 2,000 sec during light-curing. The silorane based composite exhibited the lowest shrinkage (rate), the longest time to peak shrinkage rate, the lowest shrinkage stress, and the fewest AE events. AE events were detected immediately after the beginning of light-curing in most composite adhesive combinations, but not until 40 sec after light-curing began for the silorane-based composite. AE events were concentrated at the initial stage of curing in self-etch adhesives compared with etch-and-rinse adhesives. Reducing the shrinkage (rate) of composites resulted in reduced shrinkage stress and less debonding, as evidenced by fewer AE events. AE is an effective technique for monitoring, in real time, the debonding kinetics at the tooth-composite interface. PMID- 23100274 TI - Hydroxyurea responsiveness in beta-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity. AB - beta-thalassemia is caused by mutations in the beta-globin locus resulting in loss of, or reduced, hemoglobin A (adult hemoglobin, HbA, alpha2beta2) production. Hydroxyurea treatment increases fetal gamma-globin (fetal hemoglobin, HbF, alpha2gamma2) expression in postnatal life substituting for the missing adult beta-globin and is, therefore, an attractive therapeutic approach. Patients treated with hydroxyurea fall into three categories: i) 'responders' who increase hemoglobin to therapeutic levels; (ii) 'moderate-responders' who increase hemoglobin levels but still need transfusions at longer intervals; and (iii) 'non responders' who do not reach adequate hemoglobin levels and remain transfusion dependent. The mechanisms underlying these differential responses remain largely unclear. We generated RNA expression profiles from erythroblast progenitors of 8 responder and 8 non-responder beta-thalassemia patients. These profiles revealed that hydroxyurea treatment induced differential expression of many genes in cells from non-responders while it had little impact on cells from responders. Part of the gene program up-regulated by hydroxyurea in non-responders was already highly expressed in responders before hydroxyurea treatment. Baseline HbF expression was low in non-responders, and hydroxyurea treatment induced significant cell death. We conclude that cells from responders have adapted well to constitutive stress conditions and display a propensity to proceed to the erythroid differentiation program. PMID- 23100275 TI - Large inter-individual variation of the pharmacodynamic effect of anticoagulant drugs on thrombin generation. AB - Anticoagulation by a standard dosage of an inhibitor of thrombin generation presupposes predictable pharmacokinetics and pharmacodynamics of the anticoagulant. We determined the inter-individual variation of the effect on thrombin generation of a fixed concentration of direct and antithrombin-mediated inhibitors of thrombin and factor Xa. Thrombin generation was determined by calibrated automated thrombinography in platelet-poor plasma from 44 apparently healthy subjects which was spiked with fixed concentrations of otamixaban, melagatran, unfractionated heparin, dermatan sulfate and pentasaccharide. The variability of the inhibitory effect of the different anticoagulants within the population was determined using the coefficient of variation, i.e. the standard deviation expressed as a percentage of the mean. The inter-individual coefficients of variation of the endogenous thrombin potential and peak height before inhibition were 18% and 16%, respectively and became 20%-24% and 24%-43% after inhibition. The average inhibition of endogenous thrombin potential and peak height (ETP, peak) brought about by the anticoagulants was respectively: otamixaban (27%, 83%), melagatran (56%, 63%), unfractionated heparin (43%, 58%), dermatan sulfate (68%, 57%) and pentasaccharide (25%, 67%). This study demonstrates that the addition of a fixed concentration of any type of anticoagulant tested causes an inhibition that is highly variable from one individual to another. In this respect there is no difference between direct inhibitors of thrombin and factor Xa and heparin(-like) inhibitors acting on the same factors. PMID- 23100277 TI - Correlation between platelet phenotype and NBEAL2 genotype in patients with congenital thrombocytopenia and alpha-granule deficiency. AB - The gray platelet syndrome is a rare inherited bleeding disorder characterized by macrothrombocytopenia and deficiency of alpha (alpha)-granules in platelets. The genetic defect responsible for gray platelet syndrome was recently identified in biallelic mutations in the NBEAL2 gene. We studied 11 consecutive families with inherited macrothrombocytopenia of unknown origin and alpha-granule deficiency. All of them underwent NBEAL2 DNA sequencing and evaluation of the platelet phenotype, including a systematic assessment of the alpha-granule content by immunofluorescence analysis for alpha-granule secretory proteins. We identified 9 novel mutations hitting the two alleles of NBEAL2 in 4 probands. They included missense, nonsense and frameshift mutations, as well as nucleotide substitutions that altered the splicing mechanisms as determined at the RNA level. All the individuals with NBEAL2 biallelic mutations showed almost complete absence of platelet alpha-granules. Interestingly, the 13 individuals assumed to be asymptomatic because carriers of a mutated allele had platelet macrocytosis and significant reduction of the alpha-granule content. However, they were not thrombocytopenic. In the remaining 7 probands, we did not identify any NBEAL2 alterations, suggesting that other genetic defect(s) are responsible for their platelet phenotype. Of note, these patients were characterized by a lower severity of the alpha-granule deficiency than individuals with two NBEAL2 mutated alleles. Our data extend the spectrum of mutations responsible for gray platelet syndrome and demonstrate that macrothrombocytopenia with alpha-granule deficiency is a genetic heterogeneous trait. In terms of practical applications, the screening of NBEAL2 is worthwhile only in patients with macrothrombocytopenia and severe reduction of the alpha-granules. Finally, individuals carrying one NBEAL2 mutated allele have mild laboratory abnormalities, suggesting that even haploinsufficiency has an effect on platelet phenotype. PMID- 23100276 TI - Restoration of microRNA-214 expression reduces growth of myeloma cells through positive regulation of P53 and inhibition of DNA replication. AB - MicroRNA have been demonstrated to be deregulated in multiple myeloma. We have previously reported that miR-214 is down-regulated in multiple myeloma compared to in normal plasma cells. The functional role of miR-214 in myeloma pathogenesis was explored by transfecting myeloma cell lines with synthetic microRNA followed by gene expression profiling. Putative miR-214 targets were validated by luciferase reporter assay. Ectopic expression of miR-214 reduced cell growth and induced apoptosis of myeloma cells. In order to identify the potential direct target genes of miR-214 which could be involved in the biological pathways regulated by this microRNA, gene expression profiling of the H929 myeloma cell line transfected with precursor miR-214 was carried out. Functional analysis revealed significant enrichment for DNA replication, cell cycle phase and DNA binding. miR-214 directly down-regulated the expression of PSMD10, which encodes the oncoprotein gankyrin, and ASF1B, a histone chaperone required for DNA replication, by binding to their 3'-untranslated regions. In addition, gankyrin inhibition induced an increase of P53 mRNA levels and subsequent up-regulation of CDKN1A (p21Waf1/Cip1) and BAX transcripts, which are direct transcriptional targets of p53. In conclusion, MiR-214 functions as a tumor suppressor in myeloma by positive regulation of p53 and inhibition of DNA replication. PMID- 23100278 TI - Genomic breakpoints and clinical features of MLL-TET1 rearrangement in acute leukemias. PMID- 23100279 TI - Development of classical Hodgkin's lymphoma in an adult with biallelic STXBP2 mutations. AB - Experimental model systems have delineated an important role for cytotoxic lymphocytes in the immunosurveillance of cancer. In humans, perforin-deficiency has been associated with occurrence of hematologic malignancies. Here, we describe an Epstein-Barr virus-positive classical Hodgkin's lymphoma in a patient harboring biallelic mutations in STXBP2, a gene required for exocytosis of perforin-containing lytic granules and associated with familial hemophagocytic lymphohistocytosis. Cytotoxic T lymphocytes were found infiltrating the tumor, and a high frequency of Epstein-Barr virus-specific cytotoxic T lymphocytes were detected in peripheral blood. However, lytic granule exocytosis and cytotoxicity by cytotoxic T lymphocytes, as well as natural killer cells, were severely impaired in the patient. Thus, the data suggest a link between defective lymphocyte exocytosis and development of lymphoma in STXBP2-deficient patients. Therefore, with regards to treatment of familial hemophagocytic lymphohistocytosis patients with mutations in genes required for lymphocyte exocytosis, it is important to consider both the risks of hemophagocytic lymphohistocytosis and malignancy. PMID- 23100281 TI - Despite the recession's effects on incomes and jobs, the share of people with high medical costs was mostly unchanged. AB - High medical cost burden is defined as spending more than 10 percent of family income on health care. Despite decreased family income and rising unemployment caused by the recession of 2007-09, the percentage of people under age sixty-five with high medical cost burdens remained largely unchanged between 2006 and 2009, at approximately 19 percent. That unexpected result, based on data from the Medical Expenditure Panel Surveys, contrasts with an increase from 14.4 percent to 19.2 percent in the share of people with high medical cost burdens between 2001 and 2006. The percentage did not change during the recent recession because decreased family income was offset by decreased out-of-pocket health spending. Virtually all of this decreased spending was because of lower spending on prescription drugs as people shifted from brand-name medications to less expensive generics. PMID- 23100280 TI - MicroRNA-34b promoter hypermethylation induces CREB overexpression and contributes to myeloid transformation. AB - MicroRNA-34b down-regulation in acute myeloid leukemia was previously shown to induce CREB overexpression, thereby causing leukemia proliferation in vitro and in vivo. The role of microRNA-34b and CREB in patients with myeloid malignancies has never been evaluated. We examined microRNA-34b expression and the methylation status of its promoter in cells from patients diagnosed with myeloid malignancies. We used gene expression profiling to identify signatures of myeloid transformation. We established that microRNA-34b has suppressor ability and that CREB has oncogenic potential in primary bone marrow cell cultures and in vivo. MicroRNA-34b was found to be up-regulated in pediatric patients with juvenile myelomonocytic leukemia (n=17) and myelodysplastic syndromes (n=28), but was down regulated in acute myeloid leukemia patients at diagnosis (n=112). Our results showed that hypermethylation of the microRNA-34b promoter occurred in 66% of cases of acute myeloid leukemia explaining the low microRNA-34b levels and CREB overexpression, whereas preleukemic myelodysplastic syndromes and juvenile myelomonocytic leukemia were not associated with hypermethylation or CREB overexpression. In paired samples taken from the same patients when they had myelodysplastic syndrome and again during the subsequent acute myeloid leukemia, we confirmed microRNA-34b promoter hypermethylation at leukemia onset, with 103 CREB target genes differentially expressed between the two disease stages. This subset of CREB targets was confirmed to associate with high-risk myelodysplastic syndromes in a separate cohort of patients (n=20). Seventy-eight of these 103 CREB targets were also differentially expressed between healthy samples (n=11) and de novo acute myeloid leukemia (n=72). Further, low microRNA-34b and high CREB expression levels induced aberrant myelopoiesis through CREB-dependent pathways in vitro and in vivo. In conclusion, we suggest that microRNA-34b controls CREB expression and contributes to myeloid transformation from both healthy bone marrow and myelodysplastic syndromes. We identified a subset of CREB target genes that represents a novel transcriptional network that may control myeloid transformation. PMID- 23100282 TI - Impact of common genetic variation on response to simvastatin therapy among 18 705 participants in the Heart Protection Study. AB - AIMS: Statins reduce LDL cholesterol (LDL-C) and the risk of vascular events, but it remains uncertain whether there is clinically relevant genetic variation in their efficacy. This study of 18 705 individuals aims to identify genetic variants related to the lipid response to simvastatin and assess their impact on vascular risk response. METHODS AND RESULTS: A genome-wide study of the LDL-C and apolipoprotein B (ApoB) response to 40 mg simvastatin daily was performed in 3895 participants in the Heart Protection Study, and the nine strongest associations were tested in 14 810 additional participants. Selected candidate genes were also tested in up to 18 705 individuals. There was 90% power to detect differences of 2.5% in LDL-C response (e.g. 42.5 vs. 40% reduction) in the genome-wide study and of 1% in the candidate gene study. None of the associations from the genome-wide study was replicated, and nor were significant associations found for 26 of 36 candidates tested. Novel lipid response associations with variants in LPA, CELSR2/PSRC1/SORT1, and ABCC2 were found, as well as confirmatory evidence for published associations in LPA, APOE, and SLCO1B1. The largest and most significant effects were with LPA and APOE, but were only 2-3% per allele. Reductions in the risk of major vascular events during 5 years of statin therapy among 18 705 high-risk patients did not differ significantly across genotypes associated with the lipid response. CONCLUSIONS: Common genetic variants do not appear to alter the lipid response to statin therapy by more than a few per cent, and there were similar large reductions in vascular risk with simvastatin irrespective of genotypes associated with the lipid response to simvastatin. Consequently, their value for informing clinical decisions related to maximizing statin efficacy appears to be limited. PMID- 23100283 TI - Myocardial gene expression profiles and cardiodepressant autoantibodies predict response of patients with dilated cardiomyopathy to immunoadsorption therapy. AB - AIMS: Immunoadsorption with subsequent immunoglobulin G substitution (IA/IgG) represents a novel therapeutic approach in the treatment of dilated cardiomyopathy (DCM) which leads to the improvement of left ventricular ejection fraction (LVEF). However, response to this therapeutic intervention shows wide inter-individual variability. In this pilot study, we tested the value of clinical, biochemical, and molecular parameters for the prediction of the response of patients with DCM to IA/IgG. METHODS AND RESULTS: Forty DCM patients underwent endomyocardial biopsies (EMBs) before IA/IgG. In eight patients with normal LVEF (controls), EMBs were obtained for clinical reasons. Clinical parameters, negative inotropic activity (NIA) of antibodies on isolated rat cardiomyocytes, and gene expression profiles of EMBs were analysed. Dilated cardiomyopathy patients displaying improvement of LVEF (>=20 relative and >=5% absolute) 6 months after IA/IgG were considered responders. Compared with non responders (n = 16), responders (n = 24) displayed shorter disease duration (P = 0.006), smaller LV internal diameter in diastole (P = 0.019), and stronger NIA of antibodies. Antibodies obtained from controls were devoid of NIA. Myocardial gene expression patterns were different in responders and non-responders for genes of oxidative phosphorylation, mitochondrial dysfunction, hypertrophy, and ubiquitin proteasome pathway. The integration of scores of NIA and expression levels of four genes allowed robust discrimination of responders from non-responders at baseline (BL) [sensitivity of 100% (95% CI 85.8-100%); specificity up to 100% (95% CI 79.4-100%); cut-off value: -0.28] and was superior to scores derived from antibodies, gene expression, or clinical parameters only. CONCLUSION: Combined assessment of NIA of antibodies and gene expression patterns of DCM patients at BL predicts response to IA/IgG therapy and may enable appropriate selection of patients who benefit from this therapeutic intervention. PMID- 23100284 TI - The adult heart responds to increased workload with physiologic hypertrophy, cardiac stem cell activation, and new myocyte formation. AB - AIMS: It is a dogma of cardiovascular pathophysiology that the increased cardiac mass in response to increased workload is produced by the hypertrophy of the pre existing myocytes. The role, if any, of adult-resident endogenous cardiac stem/progenitor cells (eCSCs) and new cardiomyocyte formation in physiological cardiac remodelling remains unexplored. METHODS AND RESULTS: In response to regular, intensity-controlled exercise training, adult rats respond with hypertrophy of the pre-existing myocytes. In addition, a significant number (~7%) of smaller newly formed BrdU-positive cardiomyocytes are produced by the exercised animals. Capillary density significantly increased in exercised animals, balancing cardiomyogenesis with neo-angiogenesis. c-kit(pos) eCSCs increased their number and activated state in exercising vs. sedentary animals. c kit(pos) eCSCs in exercised hearts showed an increased expression of transcription factors, indicative of their commitment to either the cardiomyocyte (Nkx2.5(pos)) or capillary (Ets-1(pos)) lineages. These adaptations were dependent on exercise duration and intensity. Insulin-like growth factor-1, transforming growth factor-beta1, neuregulin-1, bone morphogenetic protein-10, and periostin were significantly up-regulated in cardiomyocytes of exercised vs. sedentary animals. These factors differentially stimulated c-kit(pos) eCSC proliferation and commitment in vitro, pointing to a similar role in vivo. CONCLUSION: Intensity-controlled exercise training initiates myocardial remodelling through increased cardiomyocyte growth factor expression leading to cardiomyocyte hypertrophy and to activation and ensuing differentiation of c kit(pos) eCSCs. This leads to the generation of new myocardial cells. These findings highlight the endogenous regenerative capacity of the adult heart, represented by the eCSCs, and the fact that the physiological cardiac adaptation to exercise stress is a combination of cardiomyocyte hypertrophy and hyperplasia (cardiomyocytes and capillaries). PMID- 23100286 TI - Vasa vasorum and plaque progression, and responses to atorvastatin in a rabbit model of atherosclerosis: contrast-enhanced ultrasound imaging and intravascular ultrasound study. AB - OBJECTIVES: To serially investigate the relationship between vasa vasorum (VV) proliferation and plaque progression in vivo, and the effects of atorvastatin on VV and atherosclerosis as assessed by contrast-enhanced ultrasound (CEUS) and intravascular ultrasound (IVUS) imaging. METHODS: Carotid atherosclerosis was induced in rabbits with a high-cholesterol diet for 20 weeks and balloon injury. At week 16, following the imaging of the right common carotid arteries by CEUS and IVUS, 20 rabbits were randomised into a control or atorvastatin group (2 mg/kg/day). At week 20, CEUS and IVUS were repeated. Normalised maximal video intensity enhancement (MVE) was calculated to quantify the density of VV. Plaque volume was determined by IVUS. RESULTS: When compared with the control group, lipid levels were not significantly lower following 4 weeks of atorvastatin administration. The increases in the normalised MVE over time were greater in the control group than in the atorvastatin group (p=0.001). The increase in plaque volume from 16 to 20 weeks was significantly greater in the control group than in the atorvastatin group (p=0.001). There was a positive relationship between changes in normalised MVE and plaque volume (r=0.72, p=0.002). CONCLUSIONS: There was a positive correlation between VV density and plaque progression. Atorvastatin significantly inhibits the development of adventitial VV and progression of atherosclerosis independent of lowering the cholesterol level. PMID- 23100288 TI - Reply to Demaria et al. PMID- 23100289 TI - Significance of tumour vessel invasion in determining the morphology of isolated tumour cells in the pulmonary vein in non-small-cell lung cancer. AB - OBJECTIVES: The existence of clustered isolated tumour cells (ITCs) in the pulmonary vein (PV) of the lungs of patients with lung cancer has been reported to be a prognostic factor. However, the clinical-pathological characteristics related to their presence in the PV remain unclear. METHODS: We analysed the surgical results and clinical-pathological findings of 130 patients who underwent surgery for non-small-cell lung cancer in regard to blood vessel invasion (BVI), serum carcinoembryonic antigen (CEA) level, maximum standardized uptake value (SUV-max), size of the solid region in computed tomography findings and pathological stage according to an ITC type, i.e. no tumour (N), singular tumour cells (S) and clustered tumour cells (C). RESULTS: ITCs were detected in 96 (74%) of the patients, with C observed in 43, S in 53 and N in 34. Recurrence was seen in 33 (26%) cases, 21 of which were classified as C, 9 as S and 3 as N. The disease-free survival rate was significantly worse in C cases when compared with the others (P < 0.01). The rate of C was high in cases with high serum CEA, advanced p-staging and positive BVI ratio. Furthermore, BVI positive and ITC morphology were strongly related (BVI positive; 79 in C, 40 in S, 9% in N; P < 0.01). CONCLUSIONS: Clustered ITCs were shown to be a prognostic indicator and strongly related to BVI. Our results suggest that determination of BVI has prognostic value, as clustered ITCs with metastatic potential are disseminated from the invaded vein. PMID- 23100290 TI - Risk factors influencing the pleural drainage volume after transthoracic oesophagectomy. AB - OBJECTIVES: The objective of this study was to clarify the factors influencing pleural drainage volume after transthoracic oesophagectomy and to determine criteria for the selection of patients who would benefit from the early removal of chest drains. METHODS: Clinicopathological characteristics of 155 patients who underwent transthoracic oesophagectomy were prospectively collected, and the daily drainage volume of each patient was retrospectively reviewed. Potential risk factors were compared between the high-output group (n = 39) and low-output group (n = 116), which were dichotomized using the 75th percentile of total pleural drainage volume of the total study population. Multivariate logistic regression analyses were used to identify independent risk factors. RESULTS: The median duration of drainage was 10 days, with a median total drainage volume of 2258 ml. Of 27 potential risk factors influencing the drainage volume, creatinine clearance (P = 0.04), operative approach (P = 0.03) and thoracic duct removal (P = 0.01) were significantly associated with the total pleural drainage volume. The removal of the thoracic duct (P = 0.02; odds ratio, 4.02; 95% confidence interval 1.20-13.41) and lower creatinine clearance (P = 0.04; odds ratio, 1.02; 95% confidence interval 1.00-1.04) was independent risk factors for increased pleural drainage volume after transthoracic oesophagectomy. CONCLUSIONS: The early removal of chest drains may be possible in patients without these risk factors. PMID- 23100291 TI - Valve embolization in the left ventricular outflow tract after transcatheter valve implantation. PMID- 23100285 TI - Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. AB - Iron is a micronutrient essential for cellular energy and metabolism, necessary for maintaining body homoeostasis. Iron deficiency is an important co-morbidity in patients with heart failure (HF). A major factor in the pathogenesis of anaemia, it is also a separate condition with serious clinical consequences (e.g. impaired exercise capacity) and poor prognosis in HF patients. Experimental evidence suggests that iron therapy in iron-deficient animals may activate molecular pathways that can be cardio-protective. Clinical studies have demonstrated favourable effects of i.v. iron on the functional status, quality of life, and exercise capacity in HF patients. It is hypothesized that i.v. iron supplementation may become a novel therapy in HF patients with iron deficiency. PMID- 23100292 TI - Hypoxia-preconditioned mesenchymal stromal cells improve cardiac function in a swine model of chronic myocardial ischaemia. AB - OBJECTIVES: Cell loss during cardiac injection and hostility of the host-tissue microenvironment have the potential to diminish the overall effect of stem cell therapy. The purposes of this study were to evaluate the effect of a hypoxic preconditioning of mesenchymal stromal cells (MSC), to determine its safety and effectiveness, and to improve the efficacy of cell therapy using MSC in the setting of chronic myocardial ischaemia in swine. METHODS: Myocardial ischaemia was induced by an ameroid constrictor. Human MSC were cultured under normoxic (20% O2) or hypoxic conditions (1.5% O2) before transplantation. One month after ischaemia, pigs were randomly assigned to saline injection (sham), and 1 * 10(6)/kg normoxic or hypoxic MSC transplantation into the ischaemic inferior lateral zone. RESULTS: Twenty-seven pigs were operated on and the mortality rate was 33.3%. The remaining 18 animals were randomly assigned to sham (n = 4), normoxic (n = 8) or hypoxic MSC (n = 6) treatment. Global systolic (left ventricle ejection fraction, P = 0.04) and diastolic (E/Ea, P = 0.008) functions were increased in the hypoxic group compared with other groups. The peak of 2 dimensional longitudinal strain was less altered in the hypoxic group compared with other groups (P < 0.001). Haemodynamic data showed that dP/dT max was improved in the hypoxic group compared with the other group (P < 0.01). Capillary density was increased in the hypoxic group (P = 0.001). MSC density was significantly higher in the ischaemic zone in the hypoxic group (P < 0.01). CONCLUSION: MSC engraftment with hypoxic preconditioning significantly improves capillary density and cell survival, resulting in improvement in global, regional and diastolic left ventricular functions. This highlights the therapeutic potential of transplanting hypoxic-preconditioned MSC in the setting of chronic ischaemic heart failure. PMID- 23100293 TI - Reply to Hickey et al. PMID- 23100294 TI - Design flaws in EuroSCORE II. PMID- 23100295 TI - Symptomatic pan carpal coalition. PMID- 23100296 TI - Adverse effect of repeated corticosteroid injections for trigger finger on flexor pulley system. PMID- 23100297 TI - An aid to flexor sheath cannulation for closed catheter irrigation of pyogenic flexor tenosynovitis. PMID- 23100298 TI - Ulnar nerve strain at the elbow in patients with cubital tunnel syndrome: effect of simple decompression. AB - Simple decompression of the ulnar nerve at the elbow has not been shown to reduce nerve strain in cadavers. In this study, ulnar nerve strain at the elbow was measured intraoperatively in 11 patients with cubital tunnel syndrome, before and after simple decompression. Statistical analysis was performed using a paired Student's t-test. Mean ulnar nerve strain before and after simple decompression was 30.5% (range 9% to 69%) and 5.5% (range -2% to 11%), respectively; this difference was statistically significant (p < 0.01) with a statistical power of 96%. Simple decompression reduced ulnar nerve strain in all patients by an average of 24.5%. Our results suggest that the pathophysiology of cubital tunnel syndrome may be multifactorial, being neither a simple compression neuropathy nor a simple traction neuropathy, and simple decompression may be a favourable surgical procedure for cubital tunnel syndrome in terms of decompression and reduction of strain in the ulnar nerve. PMID- 23100299 TI - Idiopathic subluxation of extensor pollicis longus and brevis tendon: a cause of congenital clasped thumb. PMID- 23100300 TI - BCR-ABL/p62/SQSTM1: a cannibal embrace. AB - In this issue of Blood, Goussetis et al identify autophagy as a new pathway for the degradation of the oncoprotein BCR-ABL. They show that the therapeutic drug arsenic trioxide (AS(2)O(3)) targets BCR-ABL for autophagic degradation via a p62/SQSTM1-dependent mechanism that is critical for the antileukemic effect of the drug. PMID- 23100301 TI - Blocking VWF platelet binding to treat TTP. AB - Two articles in this issue of Blood from Feys et al and Callewaert et al, respectively, have employed very similar and elegant strategies in attempts to ameliorate the symptoms of thrombotic thrombocytopenic purpura (TTP). PMID- 23100302 TI - HCT survival in ADA-SCID: what's the buzz? AB - In this issue of Blood, Hassan et al have turned the spotlight on hematopoietic stem cell transplantation (HCT) of adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). They opened up the curtain of beliefs on this therapy that enables facts to be separated from fiction. PMID- 23100304 TI - Detection of Clostridium perfringens type C in pig herds following disease outbreak and subsequent vaccination. AB - Immunisation of sows using Clostridium perfringens type C toxoid vaccines is recommended to prevent necrotising enteritis (NE) on pig breeding farms. Absence of disease, however, oftentimes leads to the false assumption of pathogens being eradicated. The prevalence of C perfringens type C was determined by PCR in faecal samples of piglets and sows in three Swiss pig breeding farms two to four years after implementation of a vaccination programme following disease outbreaks. C perfringens type C could still be detected several years after an outbreak despite absence of NE. In-herd prevalence of the pathogens varied significantly between the farms and was also lower compared with a farm which experienced a recent outbreak. In conclusion, C perfringens type C can be detected on once-affected farms, even in the absence of NE for several years. PMID- 23100305 TI - Haemorrhagic disease in cattle with genotype 1 bovine viral diarrhoea virus infection. PMID- 23100306 TI - Possible natural MCF-like disease in a domestic lamb in Scotland. PMID- 23100307 TI - Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia. AB - The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (+/-14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM. PMID- 23100308 TI - Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. AB - Natural killer T (iNKT) cells can help mediate immune surveillance against tumors in mice. Prior studies targeting human iNKT cells were limited to therapy of advanced cancer and led to only modest activation of innate immunity. Clinical myeloma is preceded by an asymptomatic precursor phase. Lenalidomide was shown to mediate antigen-specific costimulation of human iNKT cells. We treated 6 patients with asymptomatic myeloma with 3 cycles of combination of alpha galactosylceramide-loaded monocyte-derived dendritic cells and low-dose lenalidomide. Therapy was well tolerated and led to reduction in tumor-associated monoclonal immunoglobulin in 3 of 4 patients with measurable disease. Combination therapy led to activation-induced decline in measurable iNKT cells and activation of NK cells with an increase in NKG2D and CD56 expression. Treatment also led to activation of monocytes with an increase in CD16 expression. Each cycle of therapy was associated with induction of eosinophilia as well as an increase in serum soluble IL2 receptor. Clinical responses correlated with pre-existing or treatment-induced antitumor T-cell immunity. These data demonstrate synergistic activation of several innate immune cells by this combination and the capacity to mediate tumor regression. Combination therapies targeting iNKT cells may be of benefit toward prevention of cancer in humans. PMID- 23100309 TI - Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience. AB - Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT. PMID- 23100310 TI - A case-control study to assess the risk of immune thrombocytopenia associated with vaccines. AB - The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hematology centers across France recruited 198 incident (ie, newly diagnosed) cases of ITP between April 2008 and June 2011. These cases were compared with 878 age- and sex-matched controls without ITP recruited in general practice. Information on vaccination was obtained from patients' standardized telephone interviews. Sixty-six of 198 cases (33.3%) and 303 of 878 controls (34.5%) received at least 1 vaccine within the 12 months before the index date. We found no evidence of an increase in ITP after vaccination in the previous 6 or 12 months (adjusted odds ratio [OR] for the previous 12 months = 1.0; 95% confidence interval, 0.7-1.4). When the 2-month time window was used, higher ORs were observed for all vaccines (OR = 1.3). This increase was mainly attributable to the vaccination against diphtheria-tetanus-pertussis-poliomyelitis (OR = 1.5) and was not statistically significant. The results of the present study show that in an adult population, the exposure to common vaccines is on average not associated with an observable risk of developing ITP. PMID- 23100312 TI - When you wish upon a star: JNIS is indexed in Medline! PMID- 23100315 TI - 'I'm going to learn how to run quick': exploring violence directed towards staff in the Emergency Department. AB - BACKGROUND: The National Health Service (NHS) depends on a highly skilled workforce. Anything threatening the well-being of that workforce threatens the delivery of healthcare. Violence and aggression directed towards healthcare professionals is a longstanding problem within the NHS, and is particularly acute in the Emergency Department (ED). This study examined ED staff perceptions and experiences of violent behaviour directed towards them within the ED. METHODS: Four EDs were selected to take part in the study. A period of up to 3 days was spent in each ED in order to collect data. Mixed methods were utilised to capture data: incident report forms were examined to establish the reported incidence of violence/aggression, ethnographic observations were noted, and staff interviews were undertaken. RESULTS: Staff defined violence as having both verbal and physical dimensions, and felt that verbal aggression was a regular occurrence. Staff communicated a number of reasons, which went beyond excessive alcohol consumption, as to why EDs are particularly susceptible to aggression/violence. There was variation in reporting behaviour between departments and individuals. This appeared to be linked to the presence of security staff within the hospital, staff disillusionment with the reporting process, and issues with the incident report form itself. CONCLUSIONS: This study adds to current evidence regarding how staff perceive and experience violence in the ED. Given the variation in reporting behaviour, national figures on violence within the NHS are likely to be underestimated. More research is needed to understand the true prevalence of violence occurring in the ED. PMID- 23100316 TI - The provision of diagnosis at emergency department discharge: a pilot study. AB - OBJECTIVES: Understanding the cause of patients' symptoms usually involves identification of a pathological diagnosis. Anecdotal reports suggest that emergency department (ED) providers do not prioritise giving pathological diagnoses, and often reiterate the patient's symptom as the discharge 'diagnosis'. Our pilot study sought to identify the proportion of patients at a large teaching hospital who receive a symptomatic versus pathological diagnosis at ED discharge. METHODS: We performed a chart review of all adult patients who were discharged from an urban ED in the USA, with an 88,000 annual visit volume. All charts of patients presenting with the three most common ED chief complaints (chest pain, abdominal pain and headache) were reviewed by two reviewers. Charts were coded as either symptomatic or pathological diagnosis based on the discharge diagnosis provided by the attending physician. Those with discrepant coding by the two reviewers were subject to review by a third adjudicator. RESULTS: 797 charts met the inclusion criteria. Five charts (0.6%) were coded differently by the two reviewers; a discussion with the third reviewer resulted in consensus in all cases. For patients presenting with chest pain, abdominal pain and headache, the proportion that received a pathological ED discharge diagnosis were 17%, 43% and 41%, respectively. CONCLUSIONS: According to our pilot study, most patients are discharged from the ED without a pathological diagnosis that explains the likely cause of their symptoms. Future studies will investigate whether this finding is consistent across institutions, and whether provision of a pathological diagnosis affects clinical outcomes and patient satisfaction. PMID- 23100311 TI - Lenalidomide-mediated enhanced translation of C/EBPalpha-p30 protein up-regulates expression of the antileukemic microRNA-181a in acute myeloid leukemia. AB - Recently, we showed that increased miR-181a expression was associated with improved outcomes in cytogenetically normal acute myeloid leukemia (CN-AML). Interestingly, miR-181a expression was increased in CN-AML patients harboring CEBPA mutations, which are usually biallelic and associate with better prognosis. CEBPA encodes the C/EBPalpha transcription factor. We demonstrate here that the presence of N-terminal CEBPA mutations and miR-181a expression are linked. Indeed, the truncated C/EBPalpha-p30 isoform, which is produced from the N terminal mutant CEBPA gene or from the differential translation of wild-type CEBPA mRNA and is commonly believed to have no transactivation activity, binds to the miR-181a-1 promoter and up-regulates the microRNA expression. Furthermore, we show that lenalidomide, a drug approved for myelodysplastic syndromes and multiple myeloma, enhances translation of the C/EBPalpha-p30 isoform, resulting in higher miR-181a levels. In xenograft mouse models, ectopic miR-181a expression inhibits tumor growth. Similarly, lenalidomide exhibits antitumorigenic activity paralleled by increased miR-181a expression. This regulatory pathway may explain an increased sensitivity to apoptosis-inducing chemotherapy in subsets of AML patients. Altogether, our data provide a potential explanation for the improved clinical outcomes observed in CEBPA-mutated CN-AML patients, and suggest that lenalidomide treatment enhancing the C/EBPalpha-p30 protein levels and in turn miR-181a may sensitize AML blasts to chemotherapy. PMID- 23100317 TI - An evaluation of a new prehospital pre-alert guidance tool. AB - BACKGROUND: The requirement for guidance regarding ambulance crews pre-alerting patients into hospital emergency departments (ED) has been well established, but a clear guidance tool that supports a decision to pre-alert a receiving hospital is lacking. AIMS: To investigate the impact of a new pre-alert tool on current alerting practice and evaluate its ability to take the place of a prehospital early warning system. METHODS: Data were collected for a sample of patients brought by ambulance to the resuscitation area of Aberdeen Royal Infirmary ED over a 7-week period. Basic demographic information plus alert status and guidance prompt status was collected and compared with a pragmatic alert requirement. Analysis of ambulance crew alert decisions and the pre-alert guidance prompt advice was undertaken and compared. RESULTS: Ambulance crew decisions to alert had a sensitivity of 72% (CI 62% to 80%), specificity of 50% (CI 27% to 73%), positive predictive value (PPV) of 90% and negative predictive value (NPV) of 22%. The pre-alert guidance alert prompt had a sensitivity of 99% (CI 94% to 100%), specificity of 64% (CI 39% to 84%), PPV of 95% and NPV of 90%. 28% of patients were under-alerted by ambulance crews, mostly medical patients presenting with chest pain. CONCLUSIONS: The pre-alert guidance tool shows face validity and superior ability to advise a pre-alert than ambulance crew decisions. It supplements a practitioners' clinical decision-making and has been regarded as having a positive impact on ED triage and utilisation of resources. Further levels of validity are expected to be achieved with continued audit and ongoing use of this tool. PMID- 23100318 TI - The effectiveness of a specially designed shoulder chair for closed reduction of acute shoulder dislocation in the emergency department: a randomised control trial. AB - STUDY OBJECTIVE: The objective of this study was to demonstrate the effectiveness of a specially designed chair for closed reduction of acute shoulder dislocations. METHOD: This was a prospective, non-blinded randomised controlled trial conducted in a university affiliated emergency department (ED). The inclusion criteria were (1) age >=18 years; (2) anterior or posterior shoulder dislocation without fracture of the surgical neck of the humerus; (3) patient who is able to communicate and cooperate. Participants were randomly assigned using a computer generated random number sequence into one of two groups--either the traditional practice group or Oxford chair group. Administration of intravenous sedation was only permitted in the traditional practice group due to the concerns of sedation use in the sitting position while unsupported on the chair. The primary outcome measure was length of ED stay. The secondary outcome measures were length of time for the procedure, successful reduction rate, levels of pain experienced by patients in different time periods before and after the reduction. RESULT: Sixty eligible patients were recruited, 30 in each group. The median lengths of stay in the ED in Oxford chair group (n=30) and traditional method group (n=30) were 152 min and 173 min respectively (p=0.183). The median procedure time was 3 min for the Oxford chair group compared to 5 min in the traditional method group (p=0.179). The success rate for the Oxford chair method was 77% (23/30). There were no statistically or clinically significant differences of pain score at any point. CONCLUSIONS: The chair method had a 77% success rate in reducing acute shoulder dislocations without sedation. There was no difference in pain level experienced by patients between the chair method and the traditional method. Patient factors, including patients who have had previous shoulder surgery and patients who have fracture dislocations, contribute to the reduced efficacy of the chair method. It remains possible that the chair method may reduce patient length of stay in the ED in uncomplicated patients. PMID- 23100319 TI - Prehospital endotracheal intubation; need for routine cuff pressure measurement? AB - In endotracheal intubation, a secured airway includes an insufflated cuff distal to the vocal cords. High cuff pressures may lead to major complications occurring after a short period of time. Cuff pressures are not routinely checked after intubation in the prehospital setting, dealing with a vulnerable group of patients. We reviewed cuff pressures after intubation by Helicopter Emergency Medical Services and paramedics noted in a dispatch database. Initial cuff pressures are almost all too high, needing adjustment to be in the safe zone. Dutch paramedics lack manometers and, therefore, only few paramedic intubations are followed by cuff pressure measurements. We recommend cuff pressure measurements after all (prehospital) intubations and, therefore, all ambulances need to be equipped with cuff manometers. PMID- 23100320 TI - A proposal for field-level medical assistance in an international humanitarian response to chemical, biological, radiological or nuclear events. AB - A capacity for field-level medical assistance for people exposed to chemical, biological, radiological or nuclear (CBRN) agents or medical support for people potentially exposed to these agents is intrinsically linked to the overall risk management approach adopted by the International Committee of the Red Cross (ICRC) for an international humanitarian response to a CBRN event. This medical assistance articulates: ?the characteristics of the agent concerned (if known) ?the need for immediate care particularly for people exposed to agents with high toxicity and short latency ?the imperative for those responding to be protected from exposure to the same agents. This article proposes two distinct capacities for medical assistance--CBRN field medical care and CBRN first aid--that take the above into account and the realities of a CBRN event including the likelihood that qualified medical staff may not be present with the right equipment. These capacities are equally pertinent whether in support of ICRC staff or for assistance of victims of a CBRN event. Training of those who will undertake CBRN field medical care and CBRN first aid must include: ?knowledge of CBRN agents, their impact on health and the corresponding toxidromes ?skills to use appropriate equipment ?use of appropriate means of self-protection ?an understanding of the additional complexities brought by the need for and interaction of triage, transfer and decontamination. The development of CBRN field medical care and CBRN first aid continues within the ICRC while acknowledging that the opportunities for learning in real situations are extremely limited. Comments from others who work in this domain are welcome. PMID- 23100321 TI - Sexual activity-related emergency department admissions: eleven years of experience at a Swiss university hospital. AB - PRINCIPALS: Most people enjoy sexual intercourse without complications, but a significant, if small, number need to seek emergency medical help for related health problems. The true incidence of these problems is not known. We therefore assessed all admissions to our emergency department (ED) in direct relation to sexual intercourse. METHODS: All data were collected prospectively and entered into the ED's centralised electronic patient record database (Qualicare, Switzerland) and retrospectively analysed. The database was scanned for the standardised key words: 'sexual intercourse' (German 'Geschlechtsverkehr') or 'coitus' (German 'Koitus'). RESULTS: A total of 445 patients were available for further evaluation; 308 (69.0%) were male, 137 (31.0%) were female. The median age was 32 years (range 16-71) for male subjects and 30 years (range 16-70) for female subjects. Two men had cardiovascular emergencies. 46 (10.3%) of our patients suffered from trauma. Neurological emergencies occurred in 55 (12.4%) patients: the most frequent were headaches in 27 (49.0%), followed by subarachnoid haemorrhage (12, 22.0%) and transient global amnesia (11, 20.0%). 154 (97.0%) of the patients presenting with presumed infection actually had infections of the urogenital tract. The most common infection was urethritis (64, 41.0%), followed by cystitis (21, 13.0%) and epididymitis (19, 12.0%). A sexually transmitted disease (STD) was diagnosed in 43 (16.0%) of all patients presenting with a presumed infection. 118 (43.0%) of the patients with a possible infection requested testing for an STD because of unsafe sexual activity without underlying symptoms. CONCLUSIONS: Sexual activity is mechanically dangerous, potentially infectious and stressful for the cardiovascular system. Because information on ED presentation related to sexual intercourse is scarce, more efforts should be undertaken to document all such complications to improve treatment and preventative strategies. PMID- 23100322 TI - Antagonism of GxxPG fragments ameliorates manifestations of aortic disease in Marfan syndrome mice. AB - Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-beta) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our findings demonstrate the important role of secondary cellular events caused by GxxPG containing fragments and matrix-induced inflammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS. PMID- 23100323 TI - Seven functional classes of Barth syndrome mutation. AB - Patients with Barth syndrome (BTHS), a rare X-linked disease, suffer from skeletal and cardiomyopathy and bouts of cyclic neutropenia. The causative gene encodes tafazzin, a transacylase, which is the major determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, CL. In addition to numerous frame shift and splice-site mutations, 36 missense mutations have been associated with BTHS. Previously, we established a BTHS-mutant panel in the yeast Saccharomyces cerevisiae that successfully models 18/21 conserved pathogenic missense mutations and defined the loss-of-function mechanism associated with a subset of the mutant tafazzins. Here, we report the biochemical and cell biological characterization of the rest of the yeast BTHS-mutant panel and in so doing identify three additional modes of tafazzin dysfunction. The largest group of mutant tafazzins is catalytically null, two mutants encode hypomorphic alleles, and another two mutants are temperature sensitive. Additionally, we have expanded the defects associated with previously characterized matrix-mislocalized-mutant tafazzins to include the rapid degradation of aggregation-prone polypeptides that correctly localize to the mitochondrial IMS. In sum, our in-depth characterization of the yeast BTHS-mutant panel has identified seven functional classes of BTHS mutation. PMID- 23100324 TI - Calpain-mediated ataxin-3 cleavage in the molecular pathogenesis of spinocerebellar ataxia type 3 (SCA3). AB - Spinocerebellar ataxia type 3 (SCA3) is pathologically characterized by the formation of intranuclear aggregates which contain ataxin-3, the mutated protein in SCA3, in a specific subtype of neurons. It has been proposed that ataxin-3 is cleaved by proteolytic enzymes, in particular by calpains and caspases, eventually leading to the formation of aggregates. In our study, we examined the ability of calpains to cleave ataxin-3 in vitro and in vivo. We demonstrated in cell culture and mouse brain homogenates that cleavage of overexpressed ataxin-3 by calpains and in particular by calpain-2 occur and that polyglutamine expanded ataxin-3 is more sensitive to calpain degradation. Based on these results, we investigated the influence of calpains on the pathogenesis of SCA3 in vivo. For this purpose, we enhanced calpain activity in a SCA3 transgenic mouse model by knocking out the endogenous calpain inhibitor calpastatin. Double-mutant mice demonstrated an aggravated neurological phenotype with an increased number of nuclear aggregates and accelerated neurodegeneration in the cerebellum. This study confirms the critical importance of calcium-dependent calpain-type proteases in the pathogenesis of SCA3 and suggests that the manipulation of the ataxin-3 cleavage pathway and the regulation of intracellular calcium homeostasis may represent novel targets for therapeutic intervention in SCA3. PMID- 23100325 TI - Somatic gain-of-function mutations in PIK3CA in patients with macrodactyly. AB - Macrodactyly is a discrete congenital anomaly consisting of enlargement of all tissues localized to the terminal portions of a limb, typically within a 'nerve territory'. The classic terminology for this condition is 'lipofibromatous hamartoma of nerve' or Type I macrodactyly. The peripheral nerve, itself, is enlarged both in circumference and in length. It is not related to neurofibromatosis (NF1), nor is it associated with vascular malformations, such as in the recently reported CLOVES syndrome. The specific nerve pathophysiology in this form of macrodactyly has not been well described and a genetic etiology for this specific form of enlargement is unknown. To identify the genetic cause of macrodactyly, we used whole-exome sequencing to identify somatic mutations present in the affected nerve of a single patient. We confirmed a novel mutation in PIK3CA (R115P) present in the patient's affected nerve tissue but not in blood DNA. Sequencing PIK3CA exons identified gain-of-function mutations (E542K, H1047L or H1047R) in the affected tissue of five additional unrelated patients; mutations were absent in blood DNA available from three patients. Immunocytochemistry confirmed AKT activation in cultured cells from the nerve of a macrodactyly patient. Additionally, we found that the most abnormal structure within the involved nerve in a macrodactylous digit is the perineurium, with additional secondary effects on the axon number and size. Thus, isolated congenital macrodactyly is caused by somatic activation of the PI3K/AKT cell signaling pathway and is genetically and biochemically related to other overgrowth syndromes. PMID- 23100326 TI - Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells. AB - Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice. PMID- 23100327 TI - A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart. AB - The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function. PMID- 23100328 TI - ORMDL3 modulates store-operated calcium entry and lymphocyte activation. AB - T lymphocytes rely on a Ca(2+) signal known as store-operated calcium entry (SOCE) for their activation. This Ca(2+) signal is generated by activation of a T cell receptor, depletion of endoplasmic reticulum (ER) Ca(2+) stores and activation of Ca(2+) release-activated Ca(2+) currents (I(CRAC)). Here, we report that the ER protein orosomucoid like 3 (ORMDL3), the product of the ORMDL3 gene associated with several autoimmune and/or inflammatory diseases, negatively modulates I(CRAC), SOCE, nuclear factor of activated T cells nuclear translocation and interleukin-2 production. ORMDL3 inhibits the Ca(2+) influx mechanism at the outer mitochondrial membrane, resulting in a Ca(2+)-dependent inhibition of I(CRAC) and reduced SOCE. The effect of ORMDL3 could be mimicked by interventions that decreased mitochondrial Ca(2+) influx and reverted by buffering of cytosolic Ca(2+) or activation of mitochondrial Ca(2+) influx. In conclusion, ORMDL3 modifies key steps in the process of T-lymphocyte activation, providing a functional link between the genetic associations of the ORMDL3 gene with autoimmune and/or inflammatory diseases. PMID- 23100329 TI - Inhaled corticosteroids for chronic obstructive pulmonary disease. PMID- 23100330 TI - Future of WHO hangs in the balance. PMID- 23100331 TI - An abnormality at the hepatic flexure. PMID- 23100332 TI - Device licensing bodies sometimes put business before safety, an investigation finds. PMID- 23100333 TI - Impact of smoking on mortality and life expectancy in Japanese smokers: a prospective cohort study. AB - OBJECTIVE: To investigate the impact of smoking on overall mortality and life expectancy in a large Japanese population, including some who smoked throughout adult life. DESIGN: The Life Span Study, a population-based prospective study, initiated in 1950. SETTING: Hiroshima and Nagasaki, Japan. PARTICIPANTS: Smoking status for 27,311 men and 40,662 women was obtained during 1963-92. Mortality from one year after first ascertainment of smoking status until 1 January 2008 has been analysed. MAIN OUTCOME MEASURES: Mortality from all causes in current, former, and never smokers. RESULTS: Smokers born in later decades tended to smoke more cigarettes per day than those born earlier, and to have started smoking at a younger age. Among those born during 1920-45 (median 1933) and who started smoking before age 20 years, men smoked on average 23 cigarettes/day, while women smoked 17 cigarettes/day, and, for those who continued smoking, overall mortality was more than doubled in both sexes (rate ratios versus never smokers: men 2.21 (95% confidence interval 1.97 to 2.48), women 2.61 (1.98 to 3.44)) and life expectancy was reduced by almost a decade (8 years for men, 10 years for women). Those who stopped smoking before age 35 avoided almost all of the excess risk among continuing smokers, while those who stopped smoking before age 45 avoided most of it. CONCLUSIONS: The lower smoking related hazards reported previously in Japan may have been due to earlier birth cohorts starting to smoke when older and smoking fewer cigarettes per day. In Japan, as elsewhere, those who start smoking in early adult life and continue smoking lose on average about a decade of life. Much of the risk can, however, be avoided by giving up smoking before age 35, and preferably well before age 35. PMID- 23100334 TI - Sensitivity of the ISO 6579:2002/Amd 1:2007 standard method for detection of Salmonella spp. on mesenteric lymph nodes from slaughter pigs. AB - The ISO 6579:2002/Amd 1:2007 (ISO) standard has been the bacteriological standard method used in the European Union for the detection of Salmonella spp. in pig mesenteric lymph nodes (MLN), but there are no published estimates of the diagnostic sensitivity (Se) of the method in this matrix. Here, the Se of the ISO (Se(ISO)) was estimated on 675 samples selected from two populations with different Salmonella prevalences (14 farms with a >= 20% prevalence and 13 farms with a <20% prevalence) and through the use of latent-class models in concert with Bayesian inference, assuming 100% ISO specificity, and an invA-based PCR as the second diagnostic method. The Se(ISO) was estimated to be close to 87%, while the sensitivity of the PCR reached up to 83.6% and its specificity was 97.4%. Interestingly, the bacteriological reanalysis of 33 potential false-negative (PCR positive) samples allowed isolation of 19 (57.5%) new Salmonella strains, improving the overall diagnostic accuracy of the bacteriology. Considering the usual limitations of bacteriology regarding Se, these results support the adequacy of the ISO for the detection of Salmonella spp. from MLN and also that of the PCR-based method as an alternative or complementary (screening) test for the diagnosis of pig salmonellosis, particularly considering the cost and time benefits of the molecular procedure. PMID- 23100335 TI - New proteins for a new perspective on syphilis diagnosis. AB - Syphilis is a sexually transmitted disease caused by Treponema pallidum subsp. pallidum; it can be effectively treated with penicillin yet remains prevalent worldwide, due in part to the shortcomings of current diagnostic tests. Here we report the production of soluble recombinant versions of three novel diagnostic candidate proteins, Tp0326, Tp0453, and a Tp0453-Tp0326 chimera. The sensitivities of these recombinant proteins were assessed by screening characterized serum samples from primary, secondary, and latent stages of infection (n = 169). The specificities were assessed by screening false positives identified with the standard diagnostic testing algorithm (n = 21), samples from patients with potentially cross-reactive infections (Leptospira spp., Borrelia burgdorferi, Helicobacter pylori, Epstein-Barr virus, hepatitis B virus, hepatitis C virus, or cytomegalovirus) (n = 38), and samples from uninfected individuals (n = 11). The sensitivities of Tp0326, Tp0453, and the Tp0453-Tp0326 chimera were found to be 86%, 98%, and 98%, respectively, and the specificities were 99%, 100%, and 99%. In a direct comparison, the Captia syphilis (T. pallidum)-G enzyme immunoassay (Trinity Biotech) was used to screen the same serum samples and was found to have a sensitivity of 98% and a specificity of 90%. In particular, Tp0453 and the chimera exhibited superior accuracy in classifying analytical false-positive samples (100%, compared to 43% for the Captia assay). These findings identify Tp0453 and the Tp0453-Tp0326 chimera as novel syphilis-specific diagnostic candidates that surpass the performance of a currently available diagnostic enzyme immunoassay test for syphilis and that allow accurate detection of all stages of infection. PMID- 23100336 TI - Comparison of the Staphylococcus QuickFISH BC test with the tube coagulase test performed on positive blood cultures for evaluation and application in a clinical routine setting. AB - Many studies demonstrate that delayed proper therapy in bloodstream infections caused by Staphylococcus aureus increases the mortality rate, emphasizing the need to shorten the turnaround time for positive blood cultures. Different techniques are currently available, from phenotypic methods to more complex tests such as matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF), real-time PCR (RT-PCR), and fluorescence in situ hybridization using peptide nucleic acid probes (PNA FISH). This study evaluated the performance of the Staphylococcus QuickFISH BC test (QFT), a novel FISH methodology, compared with the direct tube coagulase test (DTCT) on blood cultures exhibiting Gram-positive cocci in clusters. A total of 173 blood cultures collected from 128 different patients were analyzed using the DTCT, evaluated after both 4 and 24 h, and the QFT. A total of 179 isolates were identified using the Vitek2 system. Thirty-five out of 35 Staphylococcus aureus were correctly identified by the QFT (sensitivity = 100%), with a specificity of 100% (no green fluorescence was detected for strains different from S. aureus). The DTCT was positive after 4 h for 28 out of the 35 samples (sensitivity = 80%) and after 24 h for 31 out of the 35 samples (sensitivity = 88.57%). Among the remaining 144 isolates, one was then identified as Corynebacterium striatum and two as Micrococcus luteus. QFT identified 139 out of the 141 coagulase-negative staphylococci (CoNS) (sensitivity = 98.58%), showing again a specificity of 100% (no fluorescent red signals were detected for strains different from CoNS). We also discuss also the implementation process of this methodology in our setting, with particular emphasis on the workflow and the cost-effectiveness. PMID- 23100337 TI - Detection, identification, and distribution of fungi in bronchoalveolar lavage specimens by use of multilocus PCR coupled with electrospray ionization/mass spectrometry. AB - As pulmonary fungal infections continue to increase due to an increasing number of immunocompromised patients, rapid detection and accurate identification of these fungal pathogens are critical. A broad fungal assay was developed by incorporating broad-range multilocus PCR amplification and electrospray ionization/mass spectrometry (PCR/ESI-MS) to detect and identify fungal organisms directly from clinical specimens. The aims of this study were to evaluate the performance of PCR/ESI-MS for detection, identification, and determination of the distribution of fungal organisms in bronchoalveolar lavage (BAL) fluid specimens. The BAL fluid specimens submitted for fungal culture at Vanderbilt University Medical Center between May 2005 and October 2011 were included. Cultures and identification were done using standard procedures. In addition, DNA was extracted from BAL fluid specimens, and fungal DNA amplification/identification were performed by PCR/ESI-MS. The results were compared with those of the standard cultures. A total of 691 nonduplicated BAL fluid specimens with sufficient leftover volume for molecular testing were evaluated using PCR/ESI-MS. Among them, 134 specimens (19.4%) were positive for fungi by both culture and PCR/ESI-MS testing. Of the dual-positive specimens, 125 (93.3%) were positive for Candida and Aspergillus species, with concordances between culture and PCR/ESI-MS results being 84 (67.2%) at the species level and 109 (87.2%) at the genus level. In addition, 243 (35.2%) and 30 (4.3%) specimens were positive only by PCR/ESI-MS or by culture, respectively (odds ratio [OR] = 11.95, 95% confidence interval [CI] = 7.90 to 18.17, P = 0.0000). Codetection of fungal organisms was noted in 23 (3.3%) specimens by PCR/ESI-MS, which was significantly higher than the 4 (0.6%) in which they were noted by culture (OR = 5.91, 95% CI = 1.93 to 20.27, P = 0.0002). Among 53 specimens in which cultures failed because of bacterial overgrowth, at least one fungus was identified in 26 specimens (47.3%) by PCR/ESI MS. PCR/ESI-MS provides an advanced tool for rapid and sensitive detection, identification, and determination of the distribution of fungal organisms directly from BAL fluid specimens. Moreover, it detected fungal organisms in specimens in which cultures failed because of bacterial overgrowth. The clinical relevance of the significantly higher detection rate of fungal organisms by PCR/ESI-MS merits further investigation. PMID- 23100338 TI - Diagnostic usefulness of ribosomal protein l7/l12 for pneumococcal pneumonia in a mouse model. AB - The capsular antigen detection (CAD) kit is widely used in clinics to detect Streptococcus pneumoniae infection from urine, because it is rapid, convenient, and effective. However, there are several disadvantages, including false-positive results in children colonized with S. pneumoniae and prolonged positive readings even after the bacteria have been cleared. RP-L7/L12 is a component of the 50S ribosome that is abundant in all bacteria and is specific for each bacterial species. We investigated whether RP-L7/L12 could be used to accurately diagnose pneumococcal pneumonia infection in mouse models of pneumonia and colonization generated by infecting CBA/JN or CBA/N mice, respectively, with S. pneumoniae strain 741. RP-L7/L12 detection by enzyme-linked immunosorbent assay accurately assessed active lung infection, as RP-L7/L12 levels decreased simultaneously with the bacterial lung burden after imipenem administration in the pneumonia mouse model. Based on the data, antibodies detecting RP-L7/L12 were applied to rapid immunochromatographic strips (ICS) for urine sample testing. When we compared the ICS test with the CAD kit in the pneumonia model, the results correlated well. Interestingly, however, when the lung bacterial burden became undetectable after antibiotic treatment, the ICS test was correspondingly negative, even though the same samples tested by the CAD kit remained positive. Similarly, while the ICS test exhibited negative results in the nasal colonization model, the CAD kit demonstrated positive results. Bacterial RP-L7/L12 may be a promising target for the development of new methods to diagnose infectious disease. Further studies are warranted to determine whether such a test could be useful in children. PMID- 23100339 TI - Quantitative estimation of the stability of methicillin-resistant Staphylococcus aureus strain-typing systems by use of Kaplan-Meier survival analysis. AB - Knowledge concerning stability is important in the development and assessment of microbial molecular typing systems and is critical for the interpretation of their results. Typing system stability is usually measured as the fraction of isolates that change type after several in vivo passages, but this does not necessarily reflect in vivo stability. The aim of this study was to utilize survival analysis to provide an informative quantitative measure of in vivo stability and to compare the stabilities of various techniques employed in typing methicillin-resistant Staphylococcus aureus (MRSA). We identified 100 MRSA pairs (isolated from the same patient >= 1 month apart) and typed them using multilocus sequence typing (MLST), phage-derived open reading frame (PDORF) typing, toxin gene profiling (TGP), staphylococcal cassette chromosome mec (SCCmec) subtyping, pulsed-field gel electrophoresis (PFGE), and spa sequence typing. Discordant isolate pairs, belonging to different MLST clonal complexes, were excluded, leaving 81 pairs for analysis. The stabilities of these methods were examined using Kaplan-Meier survival analysis, and discriminatory power was measured by Simpson's index of diversity. The probability percentages that the type remained unchanged at 6 months for spa sequence typing, TGP, multilocus variable number of tandem repeats analysis (MLVA), SCCmec subtyping, PDORF typing, and PFGE were 95, 95, 88, 82, 71, and 58, respectively, while the Simpson's indices of diversity were 0.48, 0.47, 0.70, 0.72, 0.89, and 0.88, respectively. Survival analysis using sequential clinical isolates adds an important quantitative dimension to the measurement of stability of a microbial typing system. Of the methods compared here, PDORF typing provides high discriminatory power, comparable with that of PFGE, and a level of stability suitable for MRSA surveillance and outbreak investigations. PMID- 23100340 TI - Development and application of real-time PCR for detection of subgroup J avian leukosis virus. AB - Subgroup J avian leukosis virus (ALV-J) is an avian retrovirus that causes severe economic losses in the poultry industry. The early identification and removal of virus-shedding birds are important to reduce the spread of congenital and contact infections. In this study, a TaqMan-based real-time PCR method for the rapid detection and quantification of ALV-J with proviral DNA was developed. This method exhibited a high specificity for ALV-J. Moreover, the detection limit was as low as 10 viral DNA copies. The coefficients of variation (CVs) of both interassay and intra-assay reproducibility were less than 1%. The growth curves of ALV-J in DF-1 cells were measured by real-time PCR, yielding a trend line similar to those determined by 50% tissue culture infective dose (TCID(50)) and p27 antigen detection. Tissue samples suspected of ALV infection were evaluated using real-time PCR, virus isolation, and routine PCR, and the positivity rates were 60.1%, 41.6% and 44.5%, respectively. Our data indicated that the real-time PCR method provides a sensitive, specific, and reproducible diagnostic tool for the identification and quantification of ALV-J for clinical diagnosis and in laboratory research. PMID- 23100341 TI - Development of a peptide nucleic acid probe to Trichosporon species and identification of trichosporonosis by use of in situ hybridization in formalin fixed and paraffin-embedded (FFPE) sections. AB - In order to identify Trichosporon species in formalin-fixed and paraffin-embedded sections from which visual discrimination of non-glabrata Candida species is mostly ineffective but critical for the choice of antifungals, we tested the usefulness of a newly designed peptide nucleic acid probe (PNA) for in situ hybridization (ISH). Results confirmed the usefulness of ISH with our PNA probe in identifying Trichosporon species from Candida albicans. PMID- 23100342 TI - Human cryptosporidiosis caused by Cryptosporidium tyzzeri and C. parvum isolates presumably transmitted from wild mice. AB - We report a case of severe human cryptosporidiosis caused by Cryptosporidium tyzzeri and C. parvum with an unusually high frequency of liquid stools. Wild mice were the most likely source of infection, demonstrating the potential for wild-mouse-borne Cryptosporidium to infect humans and highlighting the health risks associated with synantropic rodents. PMID- 23100343 TI - Neonatal herpes encephalitis caused by a virologically confirmed acyclovir resistant herpes simplex virus 1 strain. AB - A neonate with herpes simplex virus 1 encephalitis was treated with intravenous acyclovir. During the course of therapy, the infection became intractable to the treatment and a mutation in the viral thymidine kinase gene (nucleotide G375T, amino acid Q125H) developed. This mutation was demonstrated in vitro to confer acyclovir resistance. PMID- 23100344 TI - Detection of SPM-1-producing Pseudomonas aeruginosa and class D beta-lactamase producing Acinetobacter baumannii isolates by use of liquid chromatography-mass spectrometry and matrix-assisted laser desorption ionization-time of flight mass spectrometry. AB - This study evaluates the accuracy of liquid chromatography-mass spectrometry (LC MS) and matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) for detecting carbapenem hydrolytic activity among SPM-1 , GIM-1-, and GES-5-producing Pseudomonas aeruginosa isolates and OXA-143-, IMP 10-, and OXA-58-producing Acinetobacter baumannii isolates. Class A and B carbapenemase activities were rapidly detected by MALDI-TOF in a 2-h assay. However, an extended incubation time was necessary for detection of carbapenem hydrolyzing class D beta-lactamase (CHDL) activity in Acinetobacter spp. PMID- 23100345 TI - Molecular characterization of a respiratory syncytial virus outbreak in a hematology unit in Heidelberg, Germany. AB - In 2011 and 2012, a large outbreak of respiratory syncytial virus (RSV) infections affecting 57 laboratory-confirmed patients occurred in an adult hematology unit in Heidelberg, Germany. During the outbreak investigation, we performed molecular genotyping of RSV strains to differentiate between single versus multiple introductions of the virus into the unit. Furthermore, we assessed the time of viral shedding of consecutive samples from the patients in order to better understand the possible impact of prolonged shedding for outbreak control management. We used subtype-specific reverse transcription-PCR on nasopharyngeal and bronchoalveolar specimens for routine diagnostics and for measuring the viral shedding period. Samples of 47 RSV-infected patients involved in the outbreak were genotyped by sequence analysis and compared to samples from RSV-infected hospitalized children representing the timing of the annual RSV epidemic in the community. Molecular investigation of the virus strains from clinical samples revealed a unique cluster with identical nucleotide sequences of RSV type A (RSV A outbreak strain) for 41 patients, while 3 patients were infected with different RSV A (nonoutbreak) strains and three other patients with RSV type B. Outbreak strains were identified in samples from November 2011 until January 2012, while nonoutbreak strains were from samples coinciding with the community epidemic in February and March 2012. Median duration of viral shedding time was 24.5 days (range, 1 to 168 days) with no difference between outbreak and nonoutbreak strains (P = 0.45). Our investigation suggests a single introduction of the RSV A outbreak strain into the unit that spread among the immunocompromised patients. Prolonged viral shedding may have contributed to nosocomial transmission and should be taken into account in the infection control management of RSV outbreaks in settings with heavily immunosuppressed patients. PMID- 23100346 TI - Evaluation of a simple blood culture amplification and antigen detection method for diagnosis of Salmonella enterica serovar typhi bacteremia. AB - In most areas where typhoid is endemic, laboratory diagnosis is not possible due to the lack of appropriate facilities. We investigated whether the combination of blood culture amplification of Salmonella enterica serovar Typhi with an S. Typhi antigen rapid diagnostic test (RDT) could be an accurate and inexpensive tool for the accelerated diagnosis of patients with acute typhoid in Laos. For a panel of 23 Gram-negative reference pathogens, the Standard Diagnostics (catalog no. 15FK20; Kyonggi-do, South Korea) RDT gave positive results for S. Typhi NCTC 8385, S. Typhi NCTC 786 (Vi negative), Salmonella enterica serovar Enteritidis (ATCC 13076), and Salmonella enterica serovar Ndolo NCTC 8700 (all group D). In a prospective study of 6,456 blood culture bottles from 3,028 patients over 15 months, 392 blood culture bottles (6.1%) from 221 (7.3%) patients had Gram negative rods (GNRs) seen in the blood culture fluid. The sensitivity, negative predictive value, specificity, and positive predictive value were 96.7%, 99.5%, 97.9%, and 87.9%, respectively, for patients with proven S. Typhi bacteremia and 91.2%, 98.4%, 98.9%, and 93.9% for patients with group D Salmonella. The median (range) number of days between diagnosis by RDT and reference assays was 1 (-1 to +2) day for those with confirmed S. Typhi. The use of antigen-based pathogen detection in blood culture fluid may be a useful, relatively rapid, inexpensive, and accurate technique for the identification of important causes of bacteremia in the tropics. PMID- 23100347 TI - A novel, sensitive assay for high-throughput molecular detection of plasmodia for active screening of malaria for elimination. AB - Although malaria remains one of the leading infectious diseases in the world, the decline in malaria transmission in some area makes it possible to consider elimination of the disease. As countries approach elimination, malaria diagnosis needs to change from diagnosing ill patients to actively detecting infections in all carriers, including asymptomatic and low-parasite-load patients. However, few of the current diagnostic methods have both the throughput and the sensitivity required. We adopted a sandwich RNA hybridization assay to detect genus Plasmodium 18S rRNA directly from whole-blood samples from Plasmodium falciparum and Plasmodium vivax patients without RNA isolation. We tested the assay with 202 febrile patients from areas where malaria is endemic, using 20 MUl of each blood sample in a 96-well plate format with a 2-day enzyme-linked immunosorbent assay (ELISA)-like work flow. The results were compared with diagnoses obtained using microscopy, a rapid diagnostic test (RDT), and genus-specific real-time PCR. Our assay identified all 66 positive samples diagnosed by microscopy, including 49 poorly stored samples that underwent multiple freeze-thaw cycles due to resource limitation. The assay uncovered three false-negative samples by microscopy and four false-negative samples by RDT and agreed completely with real-time PCR diagnosis. There was no negative sample by our assay that would show a positive result when tested with other methods. The detection limit of our assay for P. falciparum was 0.04 parasite/MUl. The assay's simple work flow, high throughput, and sensitivity make it suitable for active malaria screening. PMID- 23100348 TI - Screening of male patients for Trichomonas vaginalis with transcription-mediated amplification in a community with a high prevalence of sexually transmitted infection. AB - Trichomonas vaginalis infection in males has been largely uncharacterized. Past reports indicated increased susceptibility to other sexually transmitted infection (STI) agents such as human immunodeficiency virus and Neisseria gonorrhoeae with concurrent T. vaginalis infection. This warrants a more thorough review of male T. vaginalis incidence. A retrospective 3-year investigation of transcription-mediated amplification (TMA)-based urethral swab and first-void urine screening for T. vaginalis within a regional health care system was performed to address T. vaginalis prevalence in males. Of 622 total samples tested, 6.6% were positive for T. vaginalis. Delineation of all specimens by ZIP code of patient residence revealed 11 predominant ZIP codes with respect to testing volume and detection rates. Within these 11 ZIP codes, representing 78.3% of total testing volume, urine was the preferred specimen source compared to urethral swabs. Seven of these 11 ZIP codes contained majority African American populations. The aggregate T. vaginalis detection rate trended higher than that of the remaining four ZIP codes, which were comprised primarily of Caucasian populations (8.9% versus 5.0%, respectively; P = 0.15). The average age of a T. vaginalis-infected male (39.9 years) was significantly greater than those for Chlamydia trachomatis or N. gonorrhoeae (27.6 and 25.9 years, respectively; P < 0.001). Given the significant rate of T. vaginalis detection, with age distribution analogous to that reported in females, TMA-based detection of T. vaginalis can be a routine constituent within a comprehensive STI screening panel for males in high-prevalence STI communities. PMID- 23100349 TI - European surveillance for pantropic canine coronavirus. AB - Highly virulent pantropic canine coronavirus (CCoV) strains belonging to subtype IIa were recently identified in dogs. To assess the distribution of such strains in Europe, tissue samples were collected from 354 dogs that had died after displaying systemic disease in France (n = 92), Hungary (n = 75), Italy (n = 69), Greece (n = 87), The Netherlands (n = 27), Belgium (n = 4), and Bulgaria (n = 1). A total of 124 animals tested positive for CCoV, with 33 of them displaying the virus in extraintestinal tissues. Twenty-four CCoV strains (19.35% of the CCoV positive dogs) detected in internal organs were characterized as subtype IIa and consequently assumed to be pantropic CCoVs. Sequence and phylogenetic analyses of the 5' end of the spike protein gene showed that pantropic CCoV strains are closely related to each other, with the exception of two divergent French viruses that clustered with enteric strains. PMID- 23100350 TI - Candida guilliermondii and other species of candida misidentified as Candida famata: assessment by vitek 2, DNA sequencing analysis, and matrix-assisted laser desorption ionization-time of flight mass spectrometry in two global antifungal surveillance programs. AB - Candida famata (teleomorph Debaryomyces hansenii) has been described as a medically relevant yeast, and this species has been included in many commercial identification systems that are currently used in clinical laboratories. Among 53 strains collected during the SENTRY and ARTEMIS surveillance programs and previously identified as C. famata (includes all submitted strains with this identification) by a variety of commercial methods (Vitek, MicroScan, API, and AuxaColor), DNA sequencing methods demonstrated that 19 strains were C. guilliermondii, 14 were C. parapsilosis, 5 were C. lusitaniae, 4 were C. albicans, and 3 were C. tropicalis, and five isolates belonged to other Candida species (two C. fermentati and one each C. intermedia, C. pelliculosa, and Pichia fabianni). Additionally, three misidentified C. famata strains were correctly identified as Kodomaea ohmeri, Debaryomyces nepalensis, and Debaryomyces fabryi using intergenic transcribed spacer (ITS) and/or intergenic spacer (IGS) sequencing. The Vitek 2 system identified three isolates with high confidence to be C. famata and another 15 with low confidence between C. famata and C. guilliermondii or C. parapsilosis, displaying only 56.6% agreement with DNA sequencing results. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) results displayed 81.1% agreement with DNA sequencing. One strain each of C. metapsilosis, C. fermentati, and C. intermedia demonstrated a low score for identification (<2.0) in the MALDI Biotyper. K. ohmeri, D. nepalensis, and D. fabryi identified by DNA sequencing in this study were not in the current database for the MALDI Biotyper. These results suggest that the occurrence of C. famata in fungal infections is much lower than previously appreciated and that commercial systems do not produce accurate identifications except for the newly introduced MALDI-TOF instruments. PMID- 23100351 TI - Prevention of false resistance results obtained in testing the susceptibility of Mycobacterium tuberculosis to pyrazinamide with the Bactec MGIT 960 system using a reduced inoculum. AB - The susceptibility of 211 clinical isolates of Mycobacterium tuberculosis complex (201 M. tuberculosis and 10 Mycobacterium bovis isolates) to pyrazinamide (PZA) was assessed by the nonradiometric Bactec MGIT 960 system (M960). Detection of PZA resistance was followed by a repeat testing using a reduced inoculum (RI) of 0.25 ml instead of 0.5 ml. According to the first M960 analysis, resistance was observed in 55 samples. In the RI assay, 32 samples turned out to be susceptible and 23 proved to be resistant (58.2% false positivity). The Bactec 460 assay confirmed as resistant those strains detected by the RI assay, while discrepant results were found susceptible. Mutation analysis performed on 13 M. tuberculosis isolates detected pncA mutations in 11 samples. On the basis of our data, we suggest using the RI assay to confirm all PZA resistance results obtained with the standard M960 assay. Further studies are required to confirm our findings. PMID- 23100352 TI - Evaluation of the Abbott HBV RUO sequencing assay combined with laboratory modified interpretive software. AB - The Abbott HBV RUO Sequencing assay (Abbott Molecular Inc., Des Plaines, IL), which combines automated sample processing, real-time PCR, and bidirectional DNA sequencing, was evaluated for detection of nucleos(t)ide analogue (NA) resistance associated mutations located in the hepatitis B virus (HBV) polymerase (Pol) gene. Interpretive software from the assay manufacturer was modified to allow interrogation of the overlapping HBV surface (S) gene sequence for HBV genotype determination and detection of immune escape mutations. Analytical sensitivity (detection and sequencing) of the assay was determined to be 103.9 IU/ml (95% confidence interval [CI], 80.0 to 173.3) for HBV genotype A. Testing of commercially available HBV genotype panels consisting of 23 individual members yielded complete agreement between expected results and results obtained from the laboratory-developed HBV genotype library. Excellent specificity was observed among clinical specimens with serologic or molecular markers for various unrelated blood-borne viruses (n = 6) and sera obtained from healthy, HBV negative blood donors (n = 20). Retrospectively selected clinical specimens tested by a commercial reference laboratory HBV sequencing assay (n = 54) or the Trugene HBV Genotyping kit (n = 7) and the Abbott HBV RUO Sequencing assay showed minor differences in detection and reporting of NA resistance-associated mutations in 7 of 61 (11.5%) specimens but complete agreement of genotype results. The Abbott HBV RUO Sequencing assay provided a convenient and efficient assay workflow suitable for routine clinical laboratory use, with the flexibility to be modified for customized detection of NA resistance-associated mutations, HBV genotype determination, and detection of immune escape mutations from a single contiguous HBV sequence. PMID- 23100353 TI - Carbapenem-resistant Escherichia coli and Klebsiella pneumoniae strains containing New Delhi metallo-beta-lactamase isolated from two patients in Vietnam. PMID- 23100354 TI - Ring infiltrate in staphylococcal keratitis. AB - Smear and culture tests of corneal scrapings from a patient with a ring infiltrate confirmed significant growth of a Staphylococcus species resistant to fluoroquinolones. Because of nonresponse to medical management, the patient underwent therapeutic penetrating keratoplasty. Staphylococcal infection of the cornea may appear as a ring-like infiltrate that is recalcitrant to medical management. PMID- 23100355 TI - Evaluation of the speed-oligo direct Mycobacterium tuberculosis assay for molecular detection of mycobacteria in clinical respiratory specimens. AB - We present the first evaluation of a novel molecular assay, the Speed-oligo Direct Mycobacterium tuberculosis (SO-DMT) assay, which is based on PCR combined with a dipstick for the detection of mycobacteria and the specific identification of M. tuberculosis complex (MTC) in respiratory specimens. A blind evaluation was carried out in two stages: first, under experimental conditions on convenience samples comprising 20 negative specimens, 44 smear- and culture-positive respiratory specimens, and 11 sputa inoculated with various mycobacterium-related organisms; and second, in the routine workflow of 566 fresh respiratory specimens (4.9% acid-fast bacillus [AFB] smear positives, 7.6% MTC positives, and 1.8% nontuberculous mycobacteria [NTM] culture positives) from two Mycobacterium laboratories. SO-DMT assay showed no reactivity in any of the mycobacterium-free specimens or in those with mycobacterium-related organisms. Compared to culture, the sensitivity in the selected smear-positive specimens was 0.91 (0.92 for MTC and 0.90 for NTM), and there was no molecular detection of NTM in a tuberculosis case or vice versa. With respect to culture and clinical data, the sensitivity, specificity, and positive and negative predictive values for the SO-DMT system in routine specimens were 0.76 (0.93 in smear positives [1.0 for MTC and 0.5 for NTM] and 0.56 in smear negatives [0.68 for MTC and 0.16 for NTM]), 0.99, 0.85 (1.00 in smear positives and 0.68 in smear negatives), and 0.97, respectively. Molecular misidentification of NTM cases occurred when testing 2 gastric aspirates from two children with clinically but not microbiologically confirmed lung tuberculosis. The SO-DMT assay appears to be a fast and easy alternative for detecting mycobacteria and differentiating MTC from NTM in smear-positive respiratory specimens. PMID- 23100356 TI - Strategy for overcoming serum interferences in detection of serum (1,3)-beta-D glucans. PMID- 23100357 TI - Clostridium difficile testing: have we got it right? PMID- 23100359 TI - PrP-associated resistance to scrapie in five highly infected goat herds. AB - The PrP gene polymorphisms at codons 142 (I/M), 154 (R/H), 211 (R/Q), 222 (Q/K) and 240 (S/P) and their association with susceptibility to classical scrapie infection were investigated in five French goat herds displaying a high disease prevalence (>10%). On the basis of PrP(Sc) detection in the central nervous system and in various lymphoid tissues, 301 of 1343 goats were found to be scrapie infected. The statistical analyses indicated that while P(240) mutation had no direct impact on scrapie infection risk, the H(154), Q(211) and K(222) mutations were associated with high resistance to scrapie. The M(142) mutated allele was associated with a limited protection level against the disease. These results further reinforce the view that, like in sheep, the control and eradication of classical scrapie through the selection of certain PrP alleles could be envisaged in commercial goat population. PMID- 23100361 TI - Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection. AB - Human cytomegalovirus (HCMV) interferes with MHC class I-restricted antigen presentation and thereby reduces recognition by CD8(+) T-cells. This interference is mediated primarily by endoplasmic reticulum-resident glycoproteins that are encoded in the US2-11 region of the viral genome. Such a suppression of recognition would be of particular importance immediately after infection, because several immunodominant viral antigens are already present in the cell in this phase. However, which of the evasion proteins gpUS2-11 interfere(s) with antigen presentation to CD8(+) T-cells at this time of infection is not known. Here we address this question, using recombinant viruses (RV) that express only one of the immunoevasins gpUS2, gpUS3 or gpUS11. Infection with RV-US3 had only a limited impact on the presentation of peptides from the CD8(+) T-cell antigens IE1 and pp65 under immediate-early (IE) conditions imposed by cycloheximide/actinomycin D blocking. Unexpectedly, both RV-US2 and RV-US11 considerably impaired the recognition of IE1 and pp65 by CD8(+) T-cells, and both US2 and, to a lesser extent, US11 were transcribed under IE conditions. Thus, gpUS2 and gpUS11 are key effectors of MHC class I immunoevasion immediately after HCMV infection. PMID- 23100360 TI - Interspecies protein substitution to investigate the role of the lyssavirus glycoprotein. AB - European bat lyssaviruses type 1 (EBLV-1) and type 2 (EBLV-2) circulate within bat populations throughout Europe and are capable of causing disease indistinguishable from that caused by classical rabies virus (RABV). However, the determinants of viral fitness and pathogenicity are poorly understood. Full length genome clones based on the highly attenuated, non-neuroinvasive, RABV vaccine strain (SAD-B19) were constructed with the glycoprotein (G) of either SAD B19 (SN), of EBLV-1 (SN-1) or EBLV-2 (SN-2). In vitro characterization of SN-1 and SN-2 in comparison to wild-type EBLVs demonstrated that the substitution of G affected the final virus titre and antigenicity. In vivo, following peripheral infection with a high viral dose (10(4) f.f.u.), animals infected with SN-1 had reduced survivorship relative to infection with SN, resulting in survivorship similar to animals infected with EBLV-1. The histopathological changes and antigen distribution observed for SN-1 were more representative of those observed with SN than with EBLV-1. EBLV-2 was unable to achieve a titre equivalent to that of the other viruses. Therefore, a reduced-dose experiment (10(3) f.f.u.) was undertaken in vivo to compare EBLV-2 and SN-2, which resulted in 100 % survivorship for all recombinant viruses (SN, SN-1 and SN-2) while clinical disease developed in mice infected with the EBLVs. These data indicate that interspecies replacement of G has an effect on virus titre in vitro, probably as a result of suboptimal G-matrix protein interactions, and influences the survival outcome following a peripheral challenge with a high virus titre in mice. PMID- 23100362 TI - Evidence of Muller's ratchet in herpes simplex virus type 1. AB - Population bottlenecks can have major effects in the evolution of RNA viruses, but their possible influence in the evolution of DNA viruses is largely unknown. Genetic and biological variation of herpes simplex virus type 1 (HSV-1) has been studied by subjecting 23 biological clones of the virus to 10 plaque-to-plaque transfers. In contrast to large population passages, plaque transfers led to a decrease in replicative capacity of HSV-1. Two out of a total of 23 clones did not survive to the last transfer in 143 TK(-) cells. DNA from three genomic regions (DNA polymerase, glycoprotein gD and thymidine kinase) from the initial and passaged clones was sequenced. Nucleotide substitutions were detected in the TK and gD genes, but not in the DNA polymerase gene. Assuming a uniform distribution of mutations along the genome, the average rate of fixation of mutations was about five mutations per viral genome and plaque transfer. This value is comparable to the range of values calculated for RNA viruses. Four plaque-transferred populations lost neurovirulence for mice, as compared with the corresponding initial clones. LD(50) values obtained with the populations subjected to serial bottlenecks were 4- to 67-fold higher than for their parental clones. These results equate HSV-1 with RNA viruses regarding fitness decrease as a result of plaque-to-plaque transfers, and show that population bottlenecks can modify the pathogenic potential of HSV-1. Implications for the evolution of complex DNA viruses are discussed. PMID- 23100363 TI - Mucosal transmission and pathogenesis of chronic wasting disease in ferrets. AB - Chronic wasting disease (CWD) of cervids is almost certainly transmitted by mucosal contact with the causative prion, whether by direct (animal-to-animal) or indirect (environmental) means. Yet the sites and mechanisms of prion entry remain to be further understood. This study sought to extend this understanding by demonstrating that ferrets exposed to CWD via several mucosal routes developed infection, CWD prion protein (PrP(CWD)) amplification in lymphoid tissues, neural invasion and florid transmissible spongiform encephalopathy lesions resembling those in native cervid hosts. The ferrets developed extensive PrP(CWD) accumulation in the nervous system, retina and olfactory epithelium, with lesser deposition in tongue, muscle, salivary gland and the vomeronasal organ. PrP(CWD) accumulation in mucosal sites, including upper respiratory tract epithelium, olfactory epithelium and intestinal Peyer's patches, make the shedding of prions by infected ferrets plausible. It was also observed that regionally targeted exposure of the nasopharyngeal mucosa resulted in an increased attack rate when compared with oral exposure. The latter finding suggests that nasal exposure enhances permissiveness to CWD infection. The ferret model has further potential for investigation of portals for initiation of CWD infection. PMID- 23100364 TI - Identification of a novel equine infectious anemia virus field strain isolated from feral horses in southern Japan. AB - Although equine infectious anemia (EIA) was described more than 150 years ago, complete genomic sequences have only been obtained from two field strains of EIA virus (EIAV), EIAV(Wyoming) and EIAV(Liaoning). In 2011, EIA was detected within the distinctive feral Misaki horse population that inhabits the Toi-Cape area of southern Japan. Complete proviral sequences comprising a novel field strain were amplified directly from peripheral blood of one of these EIAV-infected horses and characterized by nucleotide sequencing. The complete provirus of Miyazaki2011-A strain is 8208 bp in length with an overall genomic organization typical of EIAV. However, this field isolate possesses just 77.2 and 78.7 % nucleotide sequence identity with the EIAV(Wyoming) and EIAV(Liaoning) strains, respectively, while similarity plot analysis suggested all three strains arose independently. Furthermore, phylogenetic studies using sequences obtained from all EIAV-infected Misaki horses against known viral strains strongly suggests these Japanese isolates comprise a separate monophyletic group. PMID- 23100365 TI - Theiler's murine encephalomyelitis virus contrasts with encephalomyocarditis and foot-and-mouth disease viruses in its functional utilization of the StopGo non standard translation mechanism. AB - The picornaviruses' genome consists of a positive-sense ssRNA. Like many picornaviruses, cardioviruses synthesize two distinct polyprotein precursors from adjacent but non-overlapping genome segments. Both the [L-1ABCD-2A] and the [2BC 3ABCD] polyproteins are proteolytically processed to yield mature capsid and non structural proteins, respectively. An unusual translational event, known as 'StopGo' or 'Stop-Carry on', is responsible for the release of the [L-1ABCD-2A] polyprotein from the ribosome and synthesis of the N-terminal amino acid of the [2BC-3ABCD] polyprotein. A common feature of these viruses is the presence of a highly conserved signature sequence for StopGo: -D(V/I)ExNPG(?)P-, where D(V/I)ExNPG are the last 7 aa of 2A, and the last P- is the first amino acid of 2B. Here, we report that, in contrast to encephalomyocarditis virus and foot-and mouth disease virus, a functional StopGo does not appear to be essential for Theiler's murine encephalomyelitis virus viability when tested in vitro and in vivo. PMID- 23100366 TI - Intratypic changes of the E1 gene and the long control region affect ori function of human papillomavirus type 18 variants. AB - A persistent infection with high-risk human papillomavirus (HPV) constitutes the main aetiological factor for cervical cancer development. HPV16 and 18 are the most prevalent types found in cervical cancer worldwide. It has been proposed that HPV intratype variations may result in differences in biological behaviour. Three different HPV18 variants belonging to the Asian Amerindian (AsAi), European (E) and African (Af) branches have been associated with specific histological types of cervical cancer with different relative prognoses, suggesting that HPV18 genomic variations might participate in disease evolution. The E1 viral protein plays a critical role in controlling viral replication and load, requiring interaction with the E2 protein to bind to the long control region (LCR). In this work, we analysed if intratype variations in the LCR and E1 and E2 genes of HPV18 impact ori replication. While the changes found in E2 genes of the tested variants were irrelevant in replication, we found that variations in E1 and LCR in fact affect ori function. It was demonstrated that nucleotide differences in the LCR variants impact ori function. Nevertheless, HPV18 E1 Af gene was mainly involved in the highest ori replication, compared with the E and AsAi E1 variants. Immunofluorescence analysis showed increased levels of Af E1 in the nucleus, correlating with the enhanced ori function. Site-directed mutagenesis revealed that at least two positions in the N-terminal domain of E1 could impact its nuclear accumulation. PMID- 23100367 TI - Bovine papillomavirus type 2 infects the urinary bladder of water buffalo (Bubalus bubalis) and plays a crucial role in bubaline urothelial carcinogenesis. AB - Bovine papillomavirus type 2 (BPV-2) has been shown to infect and play a role in urinary bladder carcinogenesis of buffaloes grazed on pastures with ferns from the Marmara and Black Sea Regions of Turkey. BPV-2 DNA has been found in both neoplastic and non-neoplastic lesions of the urinary bladder. Furthermore, this virus may be a normal inhabitant of the urinary bladder since BPV-2 DNA has also been detected in clinically normal buffaloes. The viral activation by fern immunosuppressant or carcinogen may trigger the urothelial cell transformation. The E5 oncoprotein was solely detected in urothelial tumours and appeared to be co-localized with the overexpressed and phosphorylated platelet derived growth factor (PDGF) beta receptor in a double-colour immunofluorescence assay. Our results indicate that the E5-PDGF beta receptor interaction also occurs in spontaneous tumours of the bubaline urinary bladder, revealing an additional role of BPV-2 in bladder carcinogenesis of buffaloes. PMID- 23100368 TI - Detection of rhabdovirus viral RNA in oropharyngeal swabs and ectoparasites of Spanish bats. AB - Rhabdoviruses infect a variety of hosts, including mammals, birds, reptiles, fish, insects and plants. As bats are the natural host for most members of the genus Lyssavirus, the specificity of the amplification methods used for active surveillance is usually restricted to lyssaviruses. However, the presence of other rhabdoviruses in bats has also been reported. In order to broaden the scope of such methods, a new RT-PCR, able to detect a diverse range of rhabdoviruses, was designed. The method detected 81 of 86 different rhabdoviruses. In total, 1488 oropharyngeal bat swabs and 38 nycteribiid samples were analysed, and 17 unique rhabdovirus-related sequences were detected. Phylogenetic analysis suggested that those sequences detected in bats did not constitute a monophyletic group, even when originating from the same bat species. However, all of the sequences detected in nycteribiids and one sequence obtained from a bat did constitute a monophyletic group with Drosophila melanogaster sigma rhabdovirus. PMID- 23100371 TI - Food labelling scheme agreed with retailers to remain voluntary. PMID- 23100369 TI - Chimeric elk/mouse prion proteins in transgenic mice. AB - Chronic wasting disease (CWD) of deer and elk is a highly communicable neurodegenerative disorder caused by prions. Investigations of CWD are hampered by slow bioassays in transgenic (Tg) mice. Towards the development of Tg mice that will be more susceptible to CWD prions, we created a series of chimeric elk/mouse transgenes that encode the N terminus of elk PrP (ElkPrP) up to residue Y168 and the C terminus of mouse PrP (MoPrP) beyond residue 169 (mouse numbering), designated Elk3M(SNIVVK). Between codons 169 and 219, six residues distinguish ElkPrP from MoPrP: N169S, T173N, V183I, I202V, I214V and R219K. Using chimeric elk/mouse PrP constructs, we generated 12 Tg mouse lines and determined incubation times after intracerebral inoculation with the mouse-passaged RML scrapie or Elk1P CWD prions. Unexpectedly, one Tg mouse line expressing Elk3M(SNIVVK) exhibited incubation times of <70 days when inoculated with RML prions; a second line had incubation times of <90 days. In contrast, mice expressing full-length ElkPrP had incubation periods of >250 days for RML prions. Tg(Elk3M,SNIVVK) mice were less susceptible to CWD prions than Tg(ElkPrP) mice. Changing three C-terminal mouse residues (202, 214 and 219) to those of elk doubled the incubation time for mouse RML prions and rendered the mice resistant to Elk1P CWD prions. Mutating an additional two residues from mouse to elk at codons 169 and 173 increased the incubation times for mouse prions to >300 days, but made the mice susceptible to CWD prions. Our findings highlight the role of C terminal residues in PrP that control the susceptibility and replication of prions. PMID- 23100370 TI - The X proteins of bornaviruses interfere with type I interferon signalling. AB - Borna disease virus (BDV) is a neurotropic, negative-stranded RNA virus causing persistent infection and progressive neurological disorders in a wide range of warm-blooded animals. The role of the small non-structural X protein in viral pathogenesis is not completely understood. Here we investigated whether the X protein of BDV and avian bornavirus (ABV) interferes with the type I interferon (IFN) system, similar to other non-structural proteins of negative-stranded RNA viruses. In luciferase reporter assays, we found that the X protein of various bornaviruses interfered with the type I IFN system at all checkpoints investigated, in contrast to previously reported findings, resulting in reduced type I IFN secretion. PMID- 23100372 TI - Patients are let down by poor device regulation, warn surgeons. PMID- 23100373 TI - Manufacturers offered helping hand with EU approval. PMID- 23100374 TI - GPs end partnerships with Virgin over conflicts of interest. PMID- 23100377 TI - Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. AB - BACKGROUND: Dabigatran etexilate is a new oral anticoagulant for the therapy and prophylaxis of venous thromboembolism and stroke prevention in patients with atrial fibrillation. To investigate the extent of interactions of this new anticoagulant with frequently used coagulation assays, we completed a multicenter in vitro trial with Conformite Europeenne(CE)-labeled dabigatran-spiked plasma samples. METHODS: Lyophilized plasma samples with dabigatran concentrations ranging from 0.00 to 0.48 MUg/mL were sent to the coagulation laboratories of six major Austrian hospitals for evaluation. Coagulation assays were performed under routine conditions using standard reagents and analyzer. RESULTS: Dabigatran led to a dose-dependent prolongation of the clotting times in coagulometric tests and influenced the majority of the parameters measured. Statistically significant interference could be observed with the prothrombin time (PT), activated partial thromboplastin time (aPTT) and PT/aPTT-based assays (extrinsic/intrinsic factors, APC-resistance test) as well as lupus anticoagulant testing. Even non-clotting tests, such as the colorimetric factor XIII activity assay and to a minor extent the amidolytic antithrombin activity assay (via factor IIa) were affected. CONCLUSIONS: This multicenter trial confirms and also adds to existing data, demonstrating that laboratories should expect to observe strong interferences of coagulation tests with increasing concentrations of dabigatran. This finding might become particularly important in the elderly and in patients with renal impairment as well as patients whose blood is drawn at peak levels of dabigatran. PMID- 23100379 TI - A glossary of theories for understanding policymaking. AB - Public health practitioners and researchers often seek to influence public policies in order to improve population health and/or reduce health inequalities. However, these efforts frequently appear to be uninformed by the many empirically based theories about policymaking that have been developed within political science. This glossary provides a brief overview of some of the most popular of these theories, describing how each: frames the policymaking process; portrays the relationships and influence of specific policy actors; and depicts the potential for policy change (or inertia). Examples of their application to public health are provided to help improve understanding of the material presented. Throughout the article, the implications of the different theories for public health researchers and advocates seeking to inform policy decisions are emphasised. The glossary aims to provide an accessible overview to key theories about policy and decision-making, with a view to supporting public health efforts to achieve healthier public policies. PMID- 23100378 TI - Clinical and pathological features of B-cell non-Hodgkin lymphomas lacking the surface expression of immunoglobulin light chains. AB - BACKGROUND: The flow cytometric analysis of surface immunoglobulin light chains (sIgL) is used as a simple method for evaluating monoclonal B-cell proliferation. However, the sIgL expression, kappa or lambda, is occasionally undetectable in cases with B-cell non-Hodgkin lymphomas (B-NHL). The purpose of this study was to investigate the clinical and pathological characteristics of these B-NHL cases. METHODS: We retrospectively analyzed 50 cases with previously untreated sIgL negative B-NHL. All of these cases had been diagnosed at Tokai University Hospital between January 2001 and February 2011. Their medical charts were reviewed. RESULTS: These cases had several clinical features: diffuse large B cell lymphoma (DLBCL) (72%), a high serum lactate dehydrogenase level (66%), clinical stage III and IV (68%), and complex karyotypes (58%). Seven out of eight evaluated patients (87%) did not express cytoplasmic IgL, and the DNA rearrangement pattern of IgL showed diversity in 10 analyzed patients. The 5-year event-free survival of all the sIgL-negative B-NHL cases was significantly better with rituximab-containing chemotherapies in comparison to the regimens without it (57.9% vs. 17.9%, p=0.0207), although there was no statistical significance when the DLBCL cases were analyzed (56.6% vs. 22.2%, p=0.1530). CONCLUSIONS: These findings suggest that sIgL-negative B-NHL cases predominantly developed DLBCL in advanced disease, but were heterogeneous at the molecular level. PMID- 23100380 TI - Housing and respiratory health at older ages. AB - BACKGROUND: A large proportion of the population of England live in substandard housing. Previous research has suggested that poor-quality housing, particularly in terms of cold temperatures, mould, and damp, poses a health risk, particularly for older people. The present study aimed to examine the association between housing conditions and objectively measured respiratory health in a large general population sample of older people in England. DATA AND METHODS: Data on housing conditions, respiratory health and relevant covariates were obtained from the second wave of the English Longitudinal Study of Ageing. Multivariate regression methods were used to test the association between contemporary housing conditions and respiratory health while accounting for the potential effect of other factors; including social class, previous life-course housing conditions and childhood respiratory health. RESULTS: Older people who were in fuel poverty or who did not live in a home they owned had significantly worse respiratory health as measured by peak expiratory flow rates. After accounting for covariates, these factors had no effect on any other measures of respiratory health. Self-reported housing problems were not consistently associated with respiratory health. CONCLUSIONS: The housing conditions of older people in England, particularly those associated with fuel poverty and living in rented accommodation, may be harmful to some aspects of respiratory health. This has implications for upcoming UK government housing and energy policy decisions. PMID- 23100381 TI - Bed-sharing and risk of hospitalisation due to pneumonia and diarrhoea in infancy: the 2004 Pelotas Birth Cohort. AB - OBJECTIVE: To investigate the association between bed-sharing with the mother at 3 months of age and incidence of hospitalisation due to pneumonia and diarrhoea between 3 and 12 months. METHODS: The 2004 Pelotas Birth Cohort included all live births to mothers living in Pelotas, Brazil, in 2004. Information on bed-sharing was obtained at the 3-month follow-up visit, and on hospitalisations at the 12 month visit, both based on mothers' reports. Only singleton infants with complete information on hospitalisation were analysed. RESULTS: 3906 infants were included. The bed-sharing prevalence at 3 months was 46.4% (95% CI 44.9 to 48.0%). The incidence of pneumonia admissions between 3 and 12 months was 3.6% (95% CI 3.3 to 4.2%) and diarrhoea, 0.9% (95% CI 0.6 to 1.2%). In crude analyses, bed-sharing with the mother was associated with higher incidence of hospitalisation due to both pneumonia and diarrhoea. There was interaction between bed-sharing and duration of breastfeeding regarding the chance of admission due to pneumonia. Among infants breastfed for 3 months or less, the chance of hospitalisation due to pneumonia among bed-sharers was almost twice as high as among non-bed-sharers (adjusted OR 1.96; 95% CI 1.08 to 3.55). There was no association between bed-sharing and hospitalisation due to pneumonia among infants breastfed for longer than 3 months in crude or adjusted analyses. The association between bed-sharing and admissions due to diarrhoea lost statistical significance after allowing for confounders. CONCLUSIONS: The effect of bed sharing in infancy on the risk of hospitalisation due to pneumonia depends on breastfeeding, such that weaned children present higher risk. PMID- 23100382 TI - Fruit and vegetable purchasing and the relative density of healthy and unhealthy food stores: evidence from an Australian multilevel study. AB - BACKGROUND: Evidence of a relationship between residential retail food environments and diet-related outcomes is inconsistent. One reason for this may be that food environments are typically defined in terms of the absolute number of particular store types in an area, whereas a measure of the relative number of healthy and unhealthy stores may be more appropriate. METHODS: Using cross sectional data from the VicLANES study conducted in Melbourne, Australia, multilevel logistic regression analysis was used to estimate the independent associations between absolute measures (numbers of healthy and unhealthy stores) and a relative measure (relative density of healthy stores) of the food environment, and self-reported variety of fruit and vegetable purchasing in local households. Purchasing behaviour was measured as the odds of purchasing above the median level of fruit and vegetables. RESULTS: Compared to households in areas where healthy food stores made up no more than 10% of all healthy and unhealthy stores, households in areas with 10.1-15.0% healthy food stores and >15% healthy stores had increased odds of healthier purchasing (OR=1.48 (95% CI 1.12 to 1.96) and OR=1.45 (95% CI 1.09 to 1.91), respectively). There was less evidence of an association between absolute numbers of healthy or unhealthy stores and fruit and vegetable purchasing. CONCLUSIONS: We found strong evidence of healthier fruit and vegetable purchasing in households located in areas where the proportion of food stores that were healthy was greater. Policies aimed at improving the balance between healthy and unhealthy stores within areas may therefore be effective in promoting greater consumption of fruit and vegetables. PMID- 23100383 TI - [Idiopathic normal pressure hydrocephalus]. PMID- 23100384 TI - [Effect of Gorei-san with tranexamic acid for preventing recurrence of chronic subdural hematoma]. AB - OBJECT: Chronic subdural hematoma is often seen in elderly patients. One burr hole surgery with subdural drainage has been performed and prognosis is good, but the recurrence rate is still about 10%. To prevent the recurrence, we used Kampo medicine Gorei-san with tranexamic acid after surgery. The purpose of this study is to investigate if the recurrence is able to prevent by using these drugs. METHODS: From January 2008 to December 2010, 199 consecutive cases with chronic subdural hematoma were examined at Nagatomi Neurosurgical Hospital. Patients were divided into four groups according to the administered drugs; Gorei-san, tranexamic acid, Gorei-san with tranexamic acid and no drug groups. The recurrence rate was compared between each group. The chi-square test was performed as a statistical analysis. RESULTS: In all patients, the mean age was 77.7+/-10.5 years. There were 140 males and 59 females. Overall recurrence rate was 7.0%. Each recurrence rate was 8.3% in the Gorei-san administration group, and 10.9% in the tranexamic acid group, and 2.9% in Gorei-san with tranexamic acid group, and 5.7% in the no-drug group. There was no significant difference between the four groups in statistical analysis. CONCLUSIONS: Gorei-san with the tranexamic acid administration group had the minimum recurrence. There was no significant difference but these drugs would be preventable recurrence of chronic subdural hematoma. We need to accumulate more cases as a prospective study in the future. PMID- 23100385 TI - [A case of tumor progression after gamma knife radiosurgery for brain metastasis of thyroid papillary carcinoma in deep subcortical white matter]. AB - We report a case of a brain metastasis of thyroid papillary carcinoma. A 67-year old man had undergone a radical operation for thyroid papillary carcinoma 6 years before. He had no neurological deficit, but CT showed an enhanced lesion in the left frontal lobe. He underwent gamma knife radiosurgery. Four months later, the lesion with massive peritumoral edema was identified on magnetic resonance imaging (MRI). The edema was treated medically, however, recovery was seen neither on MRI nor clinically. Then left craniotomy was performed, with total resection of the tumor. During the operation Komai's stereotactic instruments were used for CT guided stereotactic surgery. Histopathological analysis of the surgical specimen confirmed mixed necrosis and papillary carcinoma of the thyroid gland. The patient was discharged without neurological deficit and is now kept under observation as an outpatient. Brain metastases from thyroid cancer are rare and we report a case of resection of brain metastasis of a thyroid papillary carcinoma after gamma knife radiosurgery. PMID- 23100386 TI - [Removal of bamboo fragments transorbitally penetrated into the cerebellum and temporal lobe 30 years after the injury]. AB - A 37-year-old male presented with transorbitally penetrating bamboo fragments, which resulted in multiple brain abscesses during 30 years. Neurological examination revealed left blindness, oculomotor palsy, trigeminal nerve (V1) anesthesia, and cerebellar ataxia. Computed tomography demonstrated foreign bodies and two ring enhanced lesions in the cerebellum. Magnetic resonance imaging demonstrated a hypointense mass penetrating through the cavernous sinus into the posterior fossa, and another mass into the temporal lobe. Cerebral angiography showed that the sylvian vein drained to the pterygoid plexus. Two weeks after the drainage of two cerebellar abscesses using an endoscope, bamboo fragments were removed using a zygomatic anterior petrosal approach. Occlusion of the draining vein to the pterygoid plexus might cause temporal venous infarction. Using indocyanine green intraoperative angiography, we confirmed the collateral venous flow of the sylvian vein after temporary occlusion of the draining vein to the pterygoid plexus. Postoperative course was uneventful. Foreign bodies must be removed even after 30 years to prevent repetitive brain abscesses. PMID- 23100387 TI - [Buccofacial apraxia without limb apraxia or aphasia after right premotor area contusion: a case report]. AB - Facial apraxia, as well as aphasia, has been associated with lesions in the cerebral hemisphere contralateral to the dominant hand. We describe a patient with severe facial apraxia caused by contusion in the right frontal operculum, premotor area and primary motor cortex ipsilateral to the dominant hand. The patient had no aphasia or limb apraxia. Magnetic resonance images of the brain reveal no abnormality of the hemisphere contralateral to the dominant hand. Thus, in some individuals, facial praxis is controlled by the hemisphere non-dominant for both handedness and language. PMID- 23100388 TI - [Retrograde cavernous sinus air embolism after central venous catheter removal]. AB - Air embolism is a rare, but occasionally fatal complication of peripheral and central venous catheterization. We present a case of an 89-year-old female, who had a central venous catheter placed in her right jugular vein during the perioperative period for right femoral subtrochanteric fracture. On the day following her operation, level of consciousness worsened a few minutes after the catheter was removed. CT scan showed air bubbles in bilateral cavernous sinuses and brachiocephalic vein. Administration of 100% oxygen was started, and she regained consciousness a few hours later, finally air bubbles disappeared on a CT scan performed 10 hours after onset. Air embolism should be taken into consideration when treating venous catheters, and appropriate O2 administration and radiological examinations must be performed immediately if level of consciousness or vital signs deteriorate. PMID- 23100389 TI - [Spontaneous occlusion of PICA-involved dissecting aneurysm with development of a collateral channel from the posterior meningeal artery]. AB - A 53-year-old man suffered severe headache, which continued for three days. No abnormality was shown on CT scan, and a dissecting aneurysm of the right vertebral artery was suspected on MRI. Cerebral angiography revealed a dissection aneurysm of the right vertebral artery involved with the posterior inferior cerebellar artery (PICA) as pearl and string sign. The patient was conservatively managed under careful blood pressure control, and was followed by serial MRI. He presented with Wallenberg syndrome three weeks later. Second angiography revealed the occlusion of the PICA-involved dissecting aneurysm and the lateral medullary segment of the PICA supplied by a newly arising vessel from the right posterior meningeal artery (PMA). For the conservative treatment of a vertebral dissection aneurysm involved with PICA presenting with only pain, observation of the course by MRI was effective, and the PMA could develop as the collateral channel to the PICA territory. PMID- 23100390 TI - [Endovascular coiling of thrombosed basilar tip aneurysm using double stents in a y-configuration]. AB - Recent advances in endovascular techniques greatly improved the ability to treat complex cerebral aneurysms. However, patients with wide-necked cerebral aneurysms have posed a special challenge to conventional endovascular therapy. We report a novel method of embolizing wide-necked basilar apex aneurysms by employing a Y configuration, double stent technique. A 40-year-old woman with a partially thrombosed basilar apex aneurysm transferred to our hospital after diagnosis of subarachnoid hemorrhage. Cerebral angiography revealed a wide-necked aneurysm which neck was incorporating the origins of both the posterior cerebral arteries. In treatment procedure, a microcatheter was inserted into the aneurysm followed by coiling of the upper half of the dome. Next, the first stent was deployed in the right P2 segment extending down to the mid basilar artery and the second stent was then deployed with half of the stent in the left P2 and the other half within the lumen of the previously placed stent. Finally, the microcatheter was withdrawn near the neck, and the rest of the aneurysmal dome was packed by additional coils. The result was favorable. Successful coil embolization of a wide-necked bifurcation aneurysm can be achieved by using the double stenting Y configuration in this case. This result continues to provide highly encouraging support of this novel technique to treat a subset of complex, wide-necked aneurysms that until recently were considered poor candidates for endovascular therapies. PMID- 23100391 TI - [Childhood transverse sinus dural arteriovenous fistula treated with endovascular and direct surgery: a case report]. AB - Infantile dural arteriovenous fistula is a rare cerebrovascular malformation carrying a poor prognosis with an anatomic cure of only 9%. Endovascular embolization is mainly selected to treat this entity, aiming to obtain normal development of the patients. We present a case of a 20-month-old girl with epilepsy. Digital subtraction angiography revealed a dural arteriovenous fistula involving the right transverse sinus. The arteriovenous fistula was fed by multiple dural branches from the middle meningeal, occipital, meningohypophyseal, and anteroinferior cerebellar arteries. The right transverse sinus was transvenously embolized with platinum coils. Although the shunt flow remained, the patient was liberated from epilepsy. Nine months later, the patient suffered from a recurrence of epilepsy. Digital subtraction angiography demonstrated some increase in shunt flow. Right middle meningeal, occipital, posterior deep temporal, and tentorial arteries were transarterially embolized using N-butyl cyanoacrylate, followed by complete surgical resection of the right transverse sinus. The shunt flow disappeared after surgery, and her epilepsy improved significantly. Our experience suggests that the combination of endovascular and surgical treatment is effective for recurrent infantile dural arteriovenous fistula. PMID- 23100392 TI - [Perioperative management of endovascular surgery]. PMID- 23100394 TI - "Measure twice, cut once": improving diagnostic accuracy of skin biopsy. PMID- 23100393 TI - DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma. AB - Aberrant DNA methylation plays a relevant role in multiple myeloma (MM) pathogenesis. MicroRNAs (miRNAs) are a class of small non-coding RNAs that recently emerged as master regulator of gene expression by targeting protein coding mRNAs. However, miRNAs involvement in the regulation of the epigenetic machinery and their potential use as therapeutics in MM remain to be investigated. Here, we provide evidence that the expression of de novo DNA methyltransferases (DNMTs) is deregulated in MM cells. Moreover, we show that miR 29b targets DNMT3A and DNMT3B mRNAs and reduces global DNA methylation in MM cells. In vitro transfection of MM cells with synthetic miR-29b mimics significantly impairs cell cycle progression and also potentiates the growth inhibitory effects induced by the demethylating agent 5-azacitidine. Most importantly, in vivo intratumor or systemic delivery of synthetic miR-29b mimics, in two clinically relevant murine models of human MM, including the SCID-synth-hu system, induces significant anti-tumor effects. All together, our findings demonstrate that aberrant DNMTs expression is efficiently modulated by tumor suppressive synthetic miR-29b mimics, indicating that methyloma modulation is a novel matter of investigation in miRNA-based therapy of MM. PMID- 23100395 TI - Default-mode network connectivity in cognitively unimpaired patients with Parkinson disease. AB - OBJECTIVE: Using resting-state (RS) fMRI, we investigated the functional integrity of the default-mode network (DMN) in cognitively unimpaired patients with Parkinson disease (PD). METHODS: RS fMRI at 3 T was collected in 16 cognitively unimpaired patients with PD and 16 age- and gender-matched healthy controls. Single-subject and group-level independent component analysis was used to investigate differences in functional connectivity within the DMN in patients with PD and healthy controls. Statistical analysis was performed using BrainVoyager QX. In addition, we used voxel-based morphometry to test whether between-group differences in RS functional connectivity were related to structural abnormalities. RESULTS: Patients with PD compared with controls showed a decreased functional connectivity of the right medial temporal lobe and bilateral inferior parietal cortex within the DMN. Although patients with PD were cognitively unimpaired, the decreased DMN connectivity significantly correlated with cognitive parameters but not with disease duration, motor impairment, or levodopa therapy. The analysis of regional volume differences did not reveal any differences in local gray matter between patients and controls. CONCLUSIONS: Our findings revealed a functional disruption of the DMN in cognitively unimpaired patients with PD, in the absence of significant structural differences between patients and controls. We hypothesize that a dysfunction of the DMN connectivity may have a role in the development of cognitive decline in PD. PMID- 23100396 TI - Epidermal nerve fibers: confidence intervals and continuous measures with nerve conduction. AB - OBJECTIVES: Our first objective was to explore the value of estimating 95% confidence intervals (CIs) of epidermal nerve fibers (ENFs)/mm for number of sections to be evaluated and for confidently judging normality or abnormality. Our second objective was to introduce a new continuous measure combining nerve conduction and ENFs/mm. METHODS: The 95% CI studies were performed on 1, 1-2, 1-3 - - - 1-10 serial skip sections of 3-mm punch biopsies of leg and thigh of 67 healthy subjects and 23 patients with diabetes mellitus. RESULTS: Variability of differences of ENFs/mm counts (and 95% CIs) from evaluation of 1, 1-2, 1-3 - - - 1-9 compared with 1-10 serial skip sections decreased progressively without a break point with increasing numbers of sections evaluated. Estimating 95% CIs as sections are evaluated can be used to judge how many sections are needed for adequate evaluation, i.e., only a few when counts and 95% CIs are well within the range of normality or abnormality and more when values are borderline. Also provided is a methodology to combine results of nerve conduction and ENFs/mm as continuous measures of normality or abnormality. CONCLUSION: Estimating 95% CIs of ENFs/mm is useful to judge how many sections should be evaluated to confidently declare counts to be normal or abnormal. Also introduced is a continuous measure of both large-fiber (nerve conduction) and small-fiber (ENFs/mm) normal structures/functions spanning the range of normality and abnormality for use in therapeutic trials. PMID- 23100397 TI - Determinants of fitness to drive in Huntington disease. AB - OBJECTIVES: To identify the most accurate clinical predictors of fitness to drive (FTDr) in Huntington disease (HD). METHODS: This cross-sectional study included 60 active drivers: 30 patients with manifest HD (8 women) and 30 age- and gender matched healthy controls. Mean (SD) age of the HD group was 50 (12) years and median (Q1-Q3) disease duration was 24 (12-48) months. A clinical battery consisting of a driving history questionnaire, the cognitive section of the Unified Huntington's Disease Rating Scale (UHDRS), Trail Making Test, and Mini Mental State Examination, as well as a driving simulator evaluation, were administered to all participants. Additionally, the subjects with HD completed the motor, behavioral, and Total Functional Capacity sections of the UHDRS and underwent an official FTDr evaluation comprising visual, neuropsychological, and on-road tests. The blinded neurologist's appraisal of FTDr and the 3 most predictive clinical tests were compared with the official pass/fail FTDr decision. RESULTS: The patients with HD performed worse on all tests of the clinical battery and driving simulator than the healthy controls. Fifteen patients with HD (50) failed the FTDr evaluation. The blinded neurologist correctly classified 21 patients (70%). The Symbol Digit Modalities Test, Stroop word reading, and Trail Making Test B provided the best model (R(2) = 0.49) to predict FTDr, correctly classifying 26 patients (87%). CONCLUSIONS: Half of active drivers with HD fail a driving evaluation and pose a potential hazard on the road. Our results suggest that those at risk can be accurately identified using a clinical screening tool. PMID- 23100398 TI - Extensive genetics of ALS: a population-based study in Italy. AB - OBJECTIVE: To assess the frequency and clinical characteristics of patients with mutations of major amyotrophic lateral sclerosis (ALS) genes in a prospectively ascertained, population-based epidemiologic series of cases. METHODS: The study population includes all ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011. Mutations of SOD1, TARDBP, ANG, FUS, OPTN, and C9ORF72 have been assessed. RESULTS: Out of the 475 patients included in the study, 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Thirty-one (67.4%) of the 46 familial cases and 20 (4.7%) of the 429 sporadic cases had a genetic mutation. According to logistic regression modeling, besides a positive family history for ALS or FTD, the chance to carry a genetic mutation was related to the presence of comorbid FTD (odds ratio 3.5; p = 0.001), and age at onset <=54 years (odds ratio 1.79; p = 0.012). CONCLUSIONS: We have found that ~11% of patients with ALS carry a genetic mutation, with C9ORF72 being the commonest genetic alteration. Comorbid FTD or a young age at onset are strong indicators of a possible genetic origin of the disease. PMID- 23100399 TI - Hormone therapy and Alzheimer disease dementia: new findings from the Cache County Study. AB - OBJECTIVES: Observational studies suggest reduced risk of Alzheimer disease (AD) in users of hormone therapy (HT), but trials show higher risk. We examined whether the association of HT with AD varies with timing or type of HT use. METHODS: Between 1995 and 2006, the population-based Cache County Study followed 1,768 women who had provided a detailed history on age at menopause and use of HT. During this interval, 176 women developed incident AD. Cox proportional hazard models evaluated the association of HT use with AD, overall and in relation to timing, duration of use, and type (opposed vs unopposed) of HT. RESULTS: Women who used any type of HT within 5 years of menopause had 30% less risk of AD (95% confidence interval 0.49-0.99), especially if use was for 10 or more years. By contrast, AD risk was not reduced among those who had initiated HT 5 or more years after menopause. Instead, rates were increased among those who began "opposed" estrogen-progestin compounds within the 3 years preceding the Cache County Study baseline (adjusted hazard ratio 1.93; 95% confidence interval 0.94-3.96). This last hazard ratio was similar to the ratio of 2.05 reported in randomized trial participants assigned to opposed HT. CONCLUSIONS: Association of HT use and risk of AD may depend on timing of use. Although possibly beneficial if taken during a critical window near menopause, HT (especially opposed compounds) initiated in later life may be associated with increased risk. The relation of AD risk to timing and type of HT deserves further study. PMID- 23100400 TI - Estrogens and Alzheimer disease risk: is there a window of opportunity? PMID- 23100401 TI - Do-not-resuscitate orders, quality of care, and outcomes in veterans with acute ischemic stroke. AB - OBJECTIVE: There is concern that do-not-resuscitate (DNR) orders may lead to stroke patients receiving less aggressive treatment and poorer care. Our objectives were to assess the relationship between DNR orders and quality of stroke care among veterans. METHODS: A cohort of 3,965 acute ischemic stroke patients admitted to 131 Veterans Health Administration (VHA) facilities in fiscal year 2007 underwent chart abstraction. DNR codes were identified through electronic orders or by documentation of "no code," "no cardiopulmonary resuscitation," or "no resuscitation." Quality of care was measured using 14 inpatient ischemic stroke quality indicators. The association between DNR orders and quality indicators was examined using multivariable logistic regression. RESULTS: Among 3,965 ischemic stroke patients, 535 (13.5%) had DNR code status, 71% of whom had orders first documented within 1 day of admission. Overall, 4.9% of patients died in-hospital or were discharged to hospice; these outcomes were substantially higher in patients with DNR orders (29.7%), particularly if they were not documented until >=2 days after admission (47.1%). Patients with DNR orders were significantly older, had more comorbidities, and had greater stroke severity. Following adjustment there were few significant associations between DNR status and the 14 quality indicators, with the exception of lower odds of early ambulation (odds ratio = 0.58, 95% confidence interval = 0.41-0.81) in DNR patients. CONCLUSIONS: DNR orders were associated with limited differences in the select quality indicators investigated, which suggests that DNR orders did not impact quality of care. However, whether DNR orders influence treatment decisions that more directly affect survival remains to be determined. PMID- 23100402 TI - Effects of APOE on brain white matter microstructure in healthy adults. AB - OBJECTIVES: APOE is related to cholesterol transport and clearance and brain white matter (WM) properties involving myelin, of which cholesterol is a major component. Diffusion tensor imaging enables in vivo investigations of brain WM, and could increase our understanding of the pathways leading to Alzheimer disease. The main objective was to investigate the association between APOE and diffusion tensor imaging-derived indices of WM microstructure. METHODS: Healthy participants were assessed on a range of neuropsychological measures, genotyped, and underwent MRI. A total of 203 volunteers (aged 21.1-69.9 years, mean = 47.6, SD = 14.9) with APOE genotypes epsilon2/epsilon3 (n = 30), epsilon3/epsilon3 (n = 113), and epsilon3/epsilon4 (n = 60) were included. RESULTS: There were widespread increases in mean and radial diffusion in carriers of the epsilon3/epsilon4 alleles compared with epsilon3/epsilon3 with medium to strong effect sizes (Cohen's d = 0.77-0.79). No interactions between genotype and age were observed, indicating relatively stable differences from early adulthood. The results were independent of presence of dementia in close family. We also observed increased mean and radial diffusion and decreased fractional anisotropy in carriers of the epsilon2/epsilon3 alleles compared with epsilon3/epsilon3 carriers. No significant differences were found between epsilon2/epsilon3 and epsilon3/epsilon4. CONCLUSIONS: APOE affects microstructural properties of the brain WM from early adulthood, but the specific allelic effects do not directly reflect the associated risk of developing Alzheimer disease. The role of APOE in cholesterol transport, the high density of cholesterol in myelin, and the specific effects on radial diffusivity support a putative functional role of APOE in modulating myelin-related processes in the brain. PMID- 23100403 TI - Neurofascin antibodies in inflammatory neuropathy: how many needles make a haystack? PMID- 23100404 TI - Lethal multiple sclerosis relapse after natalizumab withdrawal. PMID- 23100405 TI - Advances with MRI in Parkinson disease: from freezing to festination. PMID- 23100407 TI - Neuronal autophagy, alpha-synuclein clearance, and LRRK2 regulation: a lost equilibrium in parkinsonian brain. PMID- 23100406 TI - Neurofascin as a target for autoantibodies in peripheral neuropathies. AB - OBJECTIVES: We asked whether autoantibodies against neurofascin (NF)186 or NF155, both localized at the nodes of Ranvier, are present in serum of patients with inflammatory neuropathy, and whether NF-specific monoclonal antibodies are pathogenic in vivo. METHODS: We cloned human NF155 and NF186, and developed an ELISA and cell-based assay to screen for antibodies to human NF in a total of 434 donors including 294 patients with Guillain-Barre syndrome variants acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy, and chronic inflammatory demyelinating polyneuropathy (CIDP). We characterized reactive samples by isotyping, tissue section staining, and epitope mapping. We also injected NF-specific monoclonal antibodies IV into rats with experimental autoimmune neuritis. RESULTS: We detected autoantibodies to NF by ELISA in 4% of patients with AIDP and CIDP, but not in controls. Most positive samples contained immunoglobulin G (IgG)1, IgG3, or IgG4 antibodies directed to only one isoform of NF. Two patients with CIDP showed particularly high (1:10,000 dilution) NF155 specific reactivity in both assays and stained paranodes. Two other patients with CIDP who benefited from plasma exchange exhibited antibodies to NF155 by ELISA, and upon affinity purification, antibodies to both isoforms were observed by both assays. Anti-NF monoclonal antibodies enhanced and prolonged induced neuritis in rats. CONCLUSIONS: Autoantibodies to NF are detected in a very small proportion of patients with AIDP and patients with CIDP, but may nevertheless be pathogenic in these cases. PMID- 23100408 TI - A pathway in the brainstem for roll-tilt of the subjective visual vertical: evidence from a lesion-behavior mapping study. AB - The perceived subjective visual vertical (SVV) is an important sign of a vestibular otolith tone imbalance in the roll plane. Previous studies suggested that unilateral pontomedullary brainstem lesions cause ipsiversive roll-tilt of SVV, whereas pontomesencephalic lesions cause contraversive roll-tilts of SVV. However, previous data were of limited quality and lacked a statistical approach. We therefore tested roll-tilt of the SVV in 79 human patients with acute unilateral brainstem lesions due to stroke by applying modern statistical lesion behavior mapping analysis. Roll-tilt of the SVV was verified to be a brainstem sign, and for the first time it was confirmed statistically that lesions of the medial longitudinal fasciculus (MLF) and the medial vestibular nucleus are associated with ipsiversive tilt of the SVV, whereas contraversive tilts are associated with lesions affecting the rostral interstitial nucleus of the MLF, the superior cerebellar peduncle, the oculomotor nucleus, and the interstitial nucleus of Cajal. Thus, these structures constitute the anatomical pathway in the brainstem for verticality perception. Present data indicate that graviceptive otolith signals present a predominant role in the multisensory system of verticality perception. PMID- 23100410 TI - Pain and plasticity: is chronic pain always associated with somatosensory cortex activity and reorganization? AB - The somatosensory cortex remodels in response to sensory deprivation, with regions deprived of input invaded by neighboring representations. The degree of cortical reorganization is correlated with ongoing pain intensity, which has led to the assumption that chronic pain conditions are invariably associated with somatosensory cortex reorganization. Because the presentation and etiology of chronic pain vary, we determined whether cortical changes in human subjects are similar for differing pain types. Using functional and anatomical magnetic resonance imaging, we found that, while human patients with neuropathic pain displayed cortical reorganization and changes in somatosensory cortex activity, patients with non-neuropathic chronic pain did not. Furthermore, cortical reorganization in neuropathic pain patients was associated with changes in regional anatomy. These data, by showing that pain per se is not associated with cortical plasticity, suggest that treatments aimed at reversing cortical reorganization should only be considered for use in patients with certain types of chronic pain. PMID- 23100409 TI - Mapping a complete neural population in the retina. AB - Recording simultaneously from essentially all of the relevant neurons in a local circuit is crucial to understand how they collectively represent information. Here we show that the combination of a large, dense multielectrode array and a novel, mostly automated spike-sorting algorithm allowed us to record simultaneously from a highly overlapping population of >200 ganglion cells in the salamander retina. By combining these methods with labeling and imaging, we showed that up to 95% of the ganglion cells over the area of the array were recorded. By measuring the coverage of visual space by the receptive fields of the recorded cells, we concluded that our technique captured a neural population that forms an essentially complete representation of a region of visual space. This completeness allowed us to determine the spatial layout of different cell types as well as identify a novel group of ganglion cells that responded reliably to a set of naturalistic and artificial stimuli but had no measurable receptive field. Thus, our method allows unprecedented access to the complete neural representation of visual information, a crucial step for the understanding of population coding in sensory systems. PMID- 23100411 TI - Loss of NGF-TrkA signaling from the CNS is not sufficient to induce cognitive impairments in young adult or intermediate-aged mice. AB - Many molecules expressed in the CNS contribute to cognitive functions either by modulating neuronal activity or by mediating neuronal trophic support and/or connectivity. An ongoing discussion is whether signaling of nerve growth factor (NGF) through its high-affinity receptor TrkA contributes to attention behavior and/or learning and memory, based on its expression in relevant regions of the CNS such as the hippocampus, cerebral cortex, amygdala and basal forebrain. Previous animal models carrying either a null allele or transgenic manipulation of Ngf or Trka have proved difficult in addressing this question. To overcome this problem, we conditionally deleted Ngf or Trka from the CNS. Our findings confirm that NGF-TrkA signaling supports survival of only a small proportion of cholinergic neurons during development; however, this signaling is not required for trophic support or connectivity of the remaining basal forebrain cholinergic neurons. Moreover, comprehensive behavioral analysis of young adult and intermediate-aged mice lacking NGF-TrkA signaling demonstrates that this signaling is dispensable for both attention behavior and various aspects of learning and memory. PMID- 23100413 TI - Local category-specific gamma band responses in the visual cortex do not reflect conscious perception. AB - Which neural processes underlie our conscious experience? One theoretical view argues that the neural correlates of consciousness (NCC) reside in local activity in sensory cortices. Accordingly, local category-specific gamma band responses in visual cortex correlate with conscious perception. However, as most studies manipulated conscious perception by altering the amount of sensory evidence, it is possible that they reflect prerequisites or consequences of consciousness rather than the actual NCC. Here we directly address this issue by developing a new experimental paradigm in which conscious perception is modulated either by sensory evidence or by previous exposure of the images while recording intracranial EEG from the higher-order visual cortex of human epilepsy patients. A clear prediction is that neural processes directly reflecting conscious perception should be present regardless of how it comes about. In contrast, we observed that although subjective reports were modulated both by sensory evidence and by previous exposure, gamma band responses solely reflected sensory evidence. This result contradicts the proposal that local gamma band responses in the higher-order visual cortex reflect conscious perception. PMID- 23100412 TI - Endocannabinoids in amygdala and nucleus accumbens mediate social play reward in adolescent rats. AB - The brain endocannabinoid system plays a crucial role in emotional processes. We have previously identified an important role for endocannabinoids in social play behavior, a highly rewarding form of social interaction in adolescent rats. Here, we tested the hypothesis that endocannabinoid modulation of social play behavior occurs in brain regions implicated in emotion and motivation. Social play increased levels of the endocannabinoid anandamide in the amygdala and nucleus accumbens (NAc), but not in prefrontal cortex or hippocampus of 4- to 5-week-old male Wistar rats. Furthermore, social play increased phosphorylation of CB1 cannabinoid receptors in the amygdala. Systemic administration of the anandamide hydrolysis inhibitor URB597 increased social play behavior, and augmented the associated elevation in anandamide levels in the amygdala, but not the NAc. Infusion of URB597 into the basolateral amygdala (BLA) increased social play behavior, and blockade of BLA CB1 cannabinoid receptors with the antagonist/inverse agonist SR141716A prevented the play-enhancing effects of systemic administration of URB597. Infusion of URB597 into the NAc also increased social play, but blockade of NAc CB1 cannabinoid receptors did not antagonize the play-enhancing effects of systemic URB597 treatment. Last, SR141716A did not affect social play after infusion into the core and shell subregions of the NAc, while it reduced social play when infused into the BLA. These data show that increased anandamide signaling in the amygdala and NAc augments social play, and identify the BLA as a prominent site of action for endocannabinoids to modulate the rewarding properties of social interactions in adolescent rats. PMID- 23100414 TI - Electrical stimulation of human fusiform face-selective regions distorts face perception. AB - Face-selective neural responses in the human fusiform gyrus have been widely examined. However, their causal role in human face perception is largely unknown. Here, we used a multimodal approach of electrocorticography (ECoG), high resolution functional magnetic resonance imaging (fMRI), and electrical brain stimulation (EBS) to directly investigate the causal role of face-selective neural responses of the fusiform gyrus (FG) in face perception in a patient implanted with subdural electrodes in the right inferior temporal lobe. High resolution fMRI identified two distinct FG face-selective regions [mFus-faces and pFus-faces (mid and posterior fusiform, respectively)]. ECoG revealed a striking anatomical and functional correspondence with fMRI data where a pair of face selective electrodes, positioned 1 cm apart, overlapped mFus-faces and pFus faces, respectively. Moreover, electrical charge delivered to this pair of electrodes induced a profound face-specific perceptual distortion during viewing of real faces. Specifically, the subject reported a "metamorphosed" appearance of faces of people in the room. Several controls illustrate the specificity of the effect to the perception of faces. EBS of mFus-faces and pFus-faces neither produced a significant deficit in naming pictures of famous faces on the computer, nor did it affect the appearance of nonface objects. Further, the appearance of faces remained unaffected during both sham stimulation and stimulation of a pair of nearby electrodes that were not face-selective. Overall, our findings reveal a striking convergence of fMRI, ECoG, and EBS, which together offer a rare causal link between functional subsets of the human FG network and face perception. PMID- 23100415 TI - A cardinal orientation bias in scene-selective visual cortex. AB - It has long been known that human vision is more sensitive to contours at cardinal (horizontal and vertical) orientations, compared with oblique orientations; this is the "oblique effect." However, the real-world relevance of the oblique effect is not well understood. Experiments here suggest that this effect is linked to scene perception, via a common bias in the image statistics of scenes. This statistical bias for cardinal orientations is found in many "carpentered environments" such as buildings and indoor scenes, and some natural scenes. In Experiment 1, we confirmed the presence of a perceptual oblique effect in a specific set of scene stimuli. Using those scenes, we found that a well known "scene-selective" visual cortical area (the parahippocampal place area; PPA) showed distinctively higher functional magnetic resonance imaging (fMRI) activity to cardinal versus oblique orientations. This fMRI-based oblique effect was not observed in other cortical areas (including scene-selective areas transverse occipital sulcus and retrosplenial cortex), although all three scene selective areas showed the expected inversion effect to scenes. Experiments 2 and 3 tested for an analogous selectivity for cardinal orientations using computer generated arrays of simple squares and line segments, respectively. The results confirmed the preference for cardinal orientations in PPA, thus demonstrating that the oblique effect can also be produced in PPA by simple geometrical images, with statistics similar to those in scenes. Thus, PPA shows distinctive fMRI selectivity for cardinal orientations across a broad range of stimuli, which may reflect a perceptual oblique effect. PMID- 23100417 TI - Changes in neural connectivity underlie decision threshold modulation for reward maximization. AB - Using neuroimaging in combination with computational modeling, this study shows that decision threshold modulation for reward maximization is accompanied by a change in effective connectivity within corticostriatal and cerebellar-striatal brain systems. Research on perceptual decision making suggests that people make decisions by accumulating sensory evidence until a decision threshold is crossed. This threshold can be adjusted to changing circumstances, to maximize rewards. Decision making thus requires effectively managing the amount of accumulated evidence versus the amount of available time. Importantly, the neural substrate of this decision threshold modulation is unknown. Participants performed a perceptual decision-making task in blocks with identical duration but different reward schedules. Behavioral and modeling results indicate that human subjects modulated their decision threshold to maximize net reward. Neuroimaging results indicate that decision threshold modulation was achieved by adjusting effective connectivity within corticostriatal and cerebellar-striatal brain systems, the former being responsible for processing of accumulated sensory evidence and the latter being responsible for automatic, subsecond temporal processing. Participants who adjusted their threshold to a greater extent (and gained more net reward) also showed a greater modulation of effective connectivity. These results reveal a neural mechanism that underlies decision makers' abilities to adjust to changing circumstances to maximize reward. PMID- 23100416 TI - Metalloproteinases and their associated genes contribute to the functional integrity and noise-induced damage in the cochlear sensory epithelium. AB - Matrix metalloproteinases (MMPs) and their related gene products regulate essential cellular functions. An imbalance in MMPs has been implicated in various neurological disorders, including traumatic injuries. Here, we report a role for MMPs and their related gene products in the modulation of cochlear responses to acoustic trauma in rats. The normal cochlea was shown to be enriched in MMP enzymatic activity, and this activity was reduced in a time-dependent manner after traumatic noise injury. The analysis of gene expression by RNA sequencing and qRT-PCR revealed the differential expression of MMPs and their related genes between functionally specialized regions of the sensory epithelium. The expression of these genes was dynamically regulated between the acute and chronic phases of noise-induced hearing loss. Moreover, noise-induced expression changes in two endogenous MMP inhibitors, Timp1 and Timp2, in sensory cells were dependent on the stage of nuclear condensation, suggesting a specific role for MMP activity in sensory cell apoptosis. A short-term application of doxycycline, a broad-spectrum inhibitor of MMPs, before noise exposure reduced noise-induced hearing loss and sensory cell death. In contrast, a 7 d treatment compromised hearing sensitivity and potentiated noise-induced hearing loss. This detrimental effect of the long-term inhibition of MMPs on noise-induced hearing loss was further confirmed using targeted Mmp7 knock-out mice. Together, these observations suggest that MMPs and their related genes participate in the regulation of cochlear responses to acoustic overstimulation and that the modulation of MMP activity can serve as a novel therapeutic target for the reduction of noise-induced cochlear damage. PMID- 23100418 TI - Motor memory is encoded as a gain-field combination of intrinsic and extrinsic action representations. AB - Actions can be planned in either an intrinsic (body-based) reference frame or an extrinsic (world-based) frame, and understanding how the internal representations associated with these frames contribute to the learning of motor actions is a key issue in motor control. We studied the internal representation of this learning in human subjects by analyzing generalization patterns across an array of different movement directions and workspaces after training a visuomotor rotation in a single movement direction in one workspace. This provided a dense sampling of the generalization function across intrinsic and extrinsic reference frames, which allowed us to dissociate intrinsic and extrinsic representations and determine the manner in which they contributed to the motor memory for a trained action. A first experiment showed that the generalization pattern reflected a memory that was intermediate between intrinsic and extrinsic representations. A second experiment showed that this intermediate representation could not arise from separate intrinsic and extrinsic learning. Instead, we find that the representation of learning is based on a gain-field combination of local representations in intrinsic and extrinsic coordinates. This gain-field representation generalizes between actions by effectively computing similarity based on the (Mahalanobis) distance across intrinsic and extrinsic coordinates and is in line with neural recordings showing mixed intrinsic-extrinsic representations in motor and parietal cortices. PMID- 23100420 TI - Ric-8a, a guanine nucleotide exchange factor for heterotrimeric G proteins, regulates bergmann glia-basement membrane adhesion during cerebellar foliation. AB - The cerebellum consists of an intricate array of lobules that arises during the process of foliation. Foliation not only increases surface area, but may also facilitate organization of cerebellar neural circuitry. Defects in cerebellar foliation are associated with a number of diseases. Yet, little is known about how foliation, a process involving large-scale and simultaneous movement of several different cell types, is coordinated by cell-cell signaling at the molecular level. Here we show that Ric-8a, a guanine nucleotide exchange factor in the G-protein-coupled receptor pathway, is specifically required in Bergmann glia during cerebellar foliation. We find that ric-8a mutation in mice results in disorganized Bergmann glial scaffolding, defective granule cell migration, and disrupted Purkinje cell positioning. These abnormalities result from primary defects in Bergmann glia since mutations in granule cells do not show similar effects. They first arise during late embryogenesis, at the onset of foliation, when ric-8a mutant Bergmann glia fail to maintain adhesion to the basement membrane specifically at emerging fissures. This suggests that Ric-8a is essential for the enhanced Bergmann glia-basement membrane adhesion required for fissure formation. Indeed, we find that ric-8a-deficient cerebellar glia show decreased affinity for basement membrane components. We also find that weakening Bergmann glia-basement membrane interaction by beta1 integrin deletion results in a similar phenotype. These results thus reveal a novel role of Ric-8a in modulating Bergmann glia-basement membrane adhesion during foliation, and provide new insights into the signaling pathways that coordinate cellular movement during cerebellar morphogenesis. PMID- 23100419 TI - Autism-associated mutations in ProSAP2/Shank3 impair synaptic transmission and neurexin-neuroligin-mediated transsynaptic signaling. AB - Mutations in several postsynaptic proteins have recently been implicated in the molecular pathogenesis of autism and autism spectrum disorders (ASDs), including Neuroligins, Neurexins, and members of the ProSAP/Shank family, thereby suggesting that these genetic forms of autism may share common synaptic mechanisms. Initial studies of ASD-associated mutations in ProSAP2/Shank3 support a role for this protein in glutamate receptor function and spine morphology, but these synaptic phenotypes are not universally penetrant, indicating that other core facets of ProSAP2/Shank3 function must underlie synaptic deficits in patients with ASDs. In the present study, we have examined whether the ability of ProSAP2/Shank3 to interact with the cytoplasmic tail of Neuroligins functions to coordinate pre/postsynaptic signaling through the Neurexin-Neuroligin signaling complex in hippocampal neurons of Rattus norvegicus. Indeed, we find that synaptic levels of ProSAP2/Shank3 regulate AMPA and NMDA receptor-mediated synaptic transmission and induce widespread changes in the levels of presynaptic and postsynaptic proteins via Neurexin-Neuroligin transsynaptic signaling. ASD associated mutations in ProSAP2/Shank3 disrupt not only postsynaptic AMPA and NMDA receptor signaling but also interfere with the ability of ProSAP2/Shank3 to signal across the synapse to alter presynaptic structure and function. These data indicate that ASD-associated mutations in a subset of synaptic proteins may target core cellular pathways that coordinate the functional matching and maturation of excitatory synapses in the CNS. PMID- 23100421 TI - The role of nitric oxide synthase in cortical plasticity is sex specific. AB - Nitric oxide synthase-1 (NOS1) is involved in several forms of plasticity including hippocampal-dependent learning and memory, experience-dependent plasticity in the barrel cortex, and long-term potentiation (LTP) in the hippocampus and neocortex. NOS1 also contributes to ischemic damage during stroke and has a stronger deleterious effect in males than females. We therefore investigated whether the role of NOS1 in plasticity might also be sex specific. We tested LTP in the layer IV-II/III pathway between barrel columns and experience-dependent plasticity in the barrel cortex of alphaNOS1 knock-out mice and their wild-type littermates. We found that LTP was absent in male alphaNOS1 knock-out mice but not in females and that the residual LTP in females was not NO dependent. We also found that experience-dependent potentiation due to single whisker experience was significantly reduced in male alphaNOS1 knockouts but was unaffected in females. The alphaNOS1 knockout had a small effect on the development of the barrels, which were reduced in size by 20% compared with wild types, but this effect was not sex specific. We therefore conclude that neocortical plasticity mechanisms differ between males and females at the synaptic level, either in their basic plasticity induction pathways or in their ability to compensate for loss of alphaNOS1. PMID- 23100422 TI - Developmental switch in spike timing-dependent plasticity at layers 4-2/3 in the rodent barrel cortex. AB - Sensory deprivation during the critical period induces long-lasting changes in cortical maps. In the rodent somatosensory cortex (S1), its precise initiation mechanism is not known, yet spike timing-dependent plasticity (STDP) at layer 4 (L4)-L2/3 synapses are thought to be crucial. Whisker stimulation causes "L4 followed by L2/3" cell firings, while acute single whisker deprivation suddenly reverses the sequential order in L4 and L2/3 neurons in the deprived column (Celikel et al., 2004). Reversed spike sequence then leads to long-term depression through an STDP mechanism (timing-dependent long-term depression), known as deprivation-induced suppression at L4-L2/3 synapses (Bender et al., 2006a), an important first step in the map reorganization. Here we show that STDP properties change dramatically on postnatal day 13-15 (P13-P15) in mice S1. Before P13, timing-dependent long-term potentiation (t-LTP) was predominantly induced regardless of spiking order. The induction of t-LTP required postsynaptic influx of Ca(2+), an activation of protein kinase A, but not calcium/calmodulin dependent protein kinase II. Consistent with the strong bias toward t-LTP, whisker deprivation (all whiskers in Row "D") from P7-P12 failed to induce synaptic depression at L4-L2/3 synapses in the deprived column, but clear depression was seen if deprivation occurred after P14. Random activation of L4, L2/3 cells, as may occur in response to whisker stimulation before P13 during network formation, led to potentiation under the immature STDP rule, as predicted from the bias toward t-LTP regardless of spiking order. These findings describe a developmental switch in the STDP rule that may underlie the transition from synapse formation to circuit reorganization at L4-L2/3 synapses, both in distinct activity-dependent manners. PMID- 23100423 TI - Mammalian target of rapamycin signaling is a key regulator of the transit amplifying progenitor pool in the adult and aging forebrain. AB - Adult forebrain neurogenesis is dynamically regulated. Multiple families of niche derived cues have been implicated in this regulation, but the precise roles of key intracellular signaling pathways remain vaguely defined. Here, we show that mammalian target of rapamycin (mTOR) signaling is pivotal in determining proliferation versus quiescence in the adult forebrain neural stem cell (NSC) niche. Within this niche, mTOR complex-1 (mTORC1) activation displays stage specificity, occurring in transiently amplifying (TA) progenitor cells but not in GFAP+ stem cells. Inhibiting mTORC1 depletes the TA progenitor pool in vivo and suppresses epidermal growth factor (EGF)-induced proliferation within neurosphere cultures. Interestingly, mTORC1 inhibition induces a quiescence-like phenotype that is reversible. Likewise, mTORC1 activity and progenitor proliferation decline within the quiescent NSC niche of the aging brain, while EGF administration reactivates the quiescent niche in an mTORC1-dependent manner. These findings establish fundamental links between mTOR signaling, proliferation, and aging-associated quiescence in the adult forebrain NSC niche. PMID- 23100424 TI - Dark exposure extends the integration window for spike-timing-dependent plasticity. AB - Metaplasticity, the adaptive changes of long-term potentiation (LTP) and long term depression (LTD) in response to fluctuations in neural activity is well documented in visual cortex, where dark rearing shifts the frequency threshold for the induction of LTP and LTD. Here we studied metaplasticity affecting spike timing-dependent plasticity, in which the polarity of plasticity is determined not by the stimulation frequency, but by the temporal relationship between near coincidental presynaptic and postsynaptic firing. We found that in mouse visual cortex the same regime of deprivation that restricts the frequency range for inducing rate-dependent LTD extends the integration window for inducing timing dependent LTD, enabling LTD induction with random presynaptic and postsynaptic firing. Notably, the underlying mechanism for the changes in both rate-dependent and time-dependent LTD appears to be an increase of NR2b-containing NMDAR at the synapse. Thus, the rules of metaplasticity might manifest in opposite directions, depending on the plasticity-induction paradigms. PMID- 23100426 TI - Hippocampal neural correlates for values of experienced events. AB - Newly experienced events are often remembered together with how rewarding the experiences are personally. Although the hippocampus is a candidate structure where subjective values are integrated with other elements of episodic memory, it is uncertain whether and how the hippocampus processes value-related information. We examined how activity of dorsal CA1 and dorsal subicular neurons in rats performing a dynamic foraging task was related to reward values that were estimated using a reinforcement learning model. CA1 neurons carried significant signals related to action values before the animal revealed its choice behaviorally, indicating that the information on the expected values of potential choice outcomes was available in CA1. Moreover, after the outcome of the animal's goal choice was revealed, CA1 neurons carried robust signals for the value of chosen action and they temporally overlapped with the signals related to the animal's goal choice and its outcome, indicating that all the signals necessary to evaluate the outcome of an experienced event converged in CA1. On the other hand, value-related signals were substantially weaker in the subiculum. These results suggest a major role of CA1 in adding values to experienced events during episodic memory encoding. Given that CA1 neuronal activity is modulated by diverse attributes of an experienced event, CA1 might be a place where all the elements of episodic memory are integrated. PMID- 23100425 TI - AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. AB - AMPA receptors (AMPARs) are tetrameric ion channels assembled from GluA1-GluA4 subunits that mediate the majority of fast excitatory synaptic transmission in the brain. In the hippocampus, most synaptic AMPARs are composed of GluA1/2 or GluA2/3 with the GluA2 subunit preventing Ca(2+) influx. However, a small number of Ca(2+)-permeable GluA1 homomeric receptors reside in extrasynaptic locations where they can be rapidly recruited to synapses during synaptic plasticity. Phosphorylation of GluA1 S845 by the cAMP-dependent protein kinase (PKA) primes extrasynaptic receptors for synaptic insertion in response to NMDA receptor Ca(2+) signaling during long-term potentiation (LTP), while phosphatases dephosphorylate S845 and remove synaptic and extrasynaptic GluA1 during long-term depression (LTD). PKA and the Ca(2+)-activated phosphatase calcineurin (CaN) are targeted to GluA1 through binding to A-kinase anchoring protein 150 (AKAP150) in a complex with PSD-95, but we do not understand how the opposing activities of these enzymes are balanced to control plasticity. Here, we generated AKAP150DeltaPIX knock-in mice to selectively disrupt CaN anchoring in vivo. We found that AKAP150DeltaPIX mice lack LTD but express enhanced LTP at CA1 synapses. Accordingly, basal GluA1 S845 phosphorylation is elevated in AKAP150DeltaPIX hippocampus, and LTD-induced dephosphorylation and removal of GluA1, AKAP150, and PSD-95 from synapses are impaired. In addition, basal synaptic activity of GluA2-lacking AMPARs is increased in AKAP150DeltaPIX mice and pharmacologic antagonism of these receptors restores normal LTD and inhibits the enhanced LTP. Thus, AKAP150-anchored CaN opposes PKA phosphorylation of GluA1 to restrict synaptic incorporation of Ca(2+)-permeable AMPARs both basally and during LTP and LTD. PMID- 23100427 TI - Pleiotrophin suppression of receptor protein tyrosine phosphatase-beta/zeta maintains the self-renewal competence of fetal human oligodendrocyte progenitor cells. AB - Oligodendrocyte progenitor cells (OPCs) persist in human white matter, yet the mechanisms by which they are maintained in an undifferentiated state are unknown. Human OPCs differentially express protein tyrosine phosphatase receptor beta/zeta (PTPRZ1) and its inhibitory ligand, pleiotrophin, suggesting the maintenance of an autocrine loop by which PTPRZ1 activity is tonically suppressed. PTPRZ1 constitutively promotes the tyrosine dephosphorylation of beta-catenin and, thus, beta-catenin participation in T cell factor (TCF)-mediated transcription. Using CD140a/PDGFRalpha-based fluorescence-activated cell sorting to isolate fetal OPCs from the fetal brain at gestational ages 16-22 weeks, we asked whether pleiotrophin modulated the expansion of OPCs and, if so, whether this was effected through the serial engagement of PTPRZ1 and beta-catenin-dependent signals, such as TCF-mediated transcription. Lentiviral shRNAi knockdown of PTPRZ1 induced TCF-mediated transcription and substantially augmented GSK3beta inhibition-induced TCF-reporter luciferase expression, suggesting dual regulation of beta-catenin and the importance of PTPRZ1 as a tonic brake upon TCF-dependent transcription. Pharmacological inhibition of GSK3beta triggered substrate detachment and initiated sphere formation, yet had no effect on either proliferation or net cell number. In contrast, pleiotrophin strongly potentiated the proliferation of CD140a(+)-sorted OPCs, as did PTPRZ1 knockdown, which significantly increased the total number of population doublings exhibited by OPCs before mitotic senescence. These observations suggest that pleiotrophin inhibition of PTPRZ1 contributes to the homeostatic self-renewal of OPCs and that this process is mediated by the tonic activation of beta-catenin/TCF-dependent transcription. PMID- 23100429 TI - Context-dependent learning interferes with visuomotor transformations for manipulation planning. AB - How the CNS transforms visual information of object properties into motor commands for manipulation is not well understood. We designed novel apparatus and protocols in which human subjects had to learn manipulations in two different contexts. The first task involved manipulating a U-shaped object that can afford two actions by grasping different parts of the same object. The second task involved manipulating two L-shaped objects that were posed at different orientations. In both experiments, subjects learned the manipulation over consecutive trials in one context before switching to a different context. For both objects and tasks, the visual geometric cues were effective in eliciting anticipatory control with little error at the beginning of learning of the first context. However, subjects failed to use the visual information to the same extent when switching to the second context as sensorimotor memory built through eight consecutive repetitions in the first context exerted a strong interference on subjects' ability to use visual cues again when the context changed. A follow up experiment where subjects were exposed to a pseudorandom sequence of context switches with the U-shaped object revealed that the interference caused by the preceding context persisted even when subjects switched context after only one trial. Our results suggest that learning generalization of dexterous manipulation is fundamentally limited by context-specific learning of motor actions and competition between vision-based motor planning and sensorimotor memory. PMID- 23100428 TI - Ventral tegmental area glutamate neurons: electrophysiological properties and projections. AB - The ventral tegmental area (VTA) has a central role in the neural processes that underlie motivation and behavioral reinforcement. Although thought to contain only dopamine and GABA neurons, the VTA also includes a recently discovered population of glutamate neurons identified through the expression of the vesicular glutamate transporter VGLUT2. A subset of VGLUT2(+) VTA neurons corelease dopamine with glutamate at terminals in the NAc, but others do not express dopaminergic markers and remain poorly characterized. Using transgenic mice that express fluorescent proteins in distinct cell populations, we now find that both dopamine and glutamate neurons in the medial VTA exhibit a smaller hyperpolarization-activated current (I(h)) than more lateral dopamine neurons and less consistent inhibition by dopamine D(2) receptor agonists. In addition, VGLUT2(+) VTA neurons project to the nucleus accumbens (NAc), lateral habenula, ventral pallidum (VP), and amygdala. Optical stimulation of VGLUT2(+) projections expressing channelrhodopsin-2 further reveals functional excitatory synapses in the VP as well as the NAc. Thus, glutamate neurons form a physiologically and anatomically distinct subpopulation of VTA projection neurons. PMID- 23100431 TI - Deficiency of the microglial receptor CX3CR1 impairs postnatal functional development of thalamocortical synapses in the barrel cortex. AB - Accumulative evidence indicates that microglial cells influence the normal development of brain synapses. Yet, the mechanisms by which these immune cells target maturating synapses and influence their functional development at early postnatal stages remain poorly understood. Here, we analyzed the role of CX3CR1, a microglial receptor activated by the neuronal chemokine CX3CL1 (or fractalkine) which controls key functions of microglial cells. In the whisker-related barrel field of the mouse somatosensory cortex, we show that the recruitment of microglia to the sites where developing thalamocortical synapses are concentrated (i.e., the barrel centers) occurs only after postnatal day 5 and is controlled by the fractalkine/CX3CR1 signaling pathway. Indeed, at this developmental stage fractalkine is overexpressed within the barrels and CX3CR1 deficiency delays microglial cell recruitment into the barrel centers. Functional analysis of thalamocortical synapses shows that CX3CR1 deficiency also delays the functional maturation of postsynaptic glutamate receptors which normally occurs at these synapses between the first and second postnatal week. These results show that reciprocal interactions between neurons and microglial cells control the functional maturation of cortical synapses. PMID- 23100430 TI - Hair cell replacement in adult mouse utricles after targeted ablation of hair cells with diphtheria toxin. AB - We developed a transgenic mouse to permit conditional and selective ablation of hair cells in the adult mouse utricle by inserting the human diphtheria toxin receptor (DTR) gene into the Pou4f3 gene, which encodes a hair cell-specific transcription factor. In adult wild-type mice, administration of diphtheria toxin (DT) caused no significant hair cell loss. In adult Pou4f3(+/DTR) mice, DT treatment reduced hair cell numbers to 6% of normal by 14 days post-DT. Remaining hair cells were located primarily in the lateral extrastriola. Over time, hair cell numbers increased in these regions, reaching 17% of untreated Pou4f3(+/DTR) mice by 60 days post-DT. Replacement hair cells were morphologically distinct, with multiple cytoplasmic processes, and displayed evidence for active mechanotransduction channels and synapses characteristic of type II hair cells. Three lines of evidence suggest replacement hair cells were derived via direct (nonmitotic) transdifferentiation of supporting cells: new hair cells did not incorporate BrdU, supporting cells upregulated the pro-hair cell gene Atoh1, and supporting cell numbers decreased over time. This study introduces a new method for efficient conditional hair cell ablation in adult mouse utricles and demonstrates that hair cells are spontaneously regenerated in vivo in regions where there may be ongoing hair cell turnover. PMID- 23100432 TI - Loss of interleukin receptor-associated kinase 4 signaling suppresses amyloid pathology and alters microglial phenotype in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is typified by the deposition of amyloid in the brain, which elicits a robust microglial-mediated inflammatory response that is associated with disease exacerbation and accelerated progression. Microglia are the principal immune effector cells in the brain and interact with fibrillar forms of Abeta (fAbeta) through a receptor complex that includes Toll-like receptors (TLR) 2/4/6 and their coreceptors. Interleukin receptor-associated kinases (IRAKs) are essential intracellular signaling molecules for transduction of TLR signals. Studies of mouse models of AD in which the individual TLRs are knocked out have produced conflicting results on roles of TLR signaling in amyloid homeostasis. Therefore, we disrupted a common downstream TLR signaling element, IRAK4. We report that microglial IRAK4 is necessary in vitro for fAbeta to activate the canonical pro-inflammatory signaling pathways leading to activation of p38, JNK, and ERK MAP kinases and to generate reactive oxygen species. In vivo the loss of IRAK4 function results in decreased Abeta levels in a murine model of AD. This was associated with diminished microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from the adult mouse brain revealed an altered pattern of gene expression associated with changes in microglial phenotype that were associated with expression of IRF transcription factors that govern microglial phenotype. Further, loss of IRAK4 function also promoted amyloid clearance mechanisms, including elevated expression of insulin degrading enzyme. Finally, blocking IRAK function restored olfactory behavior. These data demonstrate that IRAK4 activation acts normally to regulate microglial activation status and influence amyloid homeostasis in the brain. PMID- 23100433 TI - Ethanol-mediated facilitation of AMPA receptor function in the dorsomedial striatum: implications for alcohol drinking behavior. AB - We found previously that acute ex vivo as well as repeated cycles of in vivo ethanol exposure and withdrawal, including excessive voluntary consumption of ethanol, produces a long-lasting increase in the activity of NR2B-containing NMDA receptors (NR2B-NMDARs) in the dorsomedial striatum (DMS) of rats (Wang et al., 2010a). Activation of NMDARs is required for the induction of long-term potentiation (LTP) of AMPA receptor (AMPAR)-mediated synaptic response. We therefore examined whether the ethanol-mediated upregulation of NMDAR activity alters the induction of LTP in the DMS. We found that ex vivo acute exposure of striatal slices to, and withdrawal from, ethanol facilitates the induction of LTP in DMS neurons, which is abolished by the inhibition of NR2B-NMDARs. We also report that repeated systemic administration of ethanol causes an NR2B-NMDAR dependent facilitation of LTP in the DMS. LTP is mediated by the insertion of AMPAR subunits into the synaptic membrane, and we found that repeated systemic administration of ethanol, as well as cycles of excessive ethanol consumption and withdrawal, produced a long-lasting increase in synaptic localization of the GluR1 and GluR2 subunits of AMPARs in the DMS. Importantly, we report that inhibition of AMPARs in the DMS attenuates operant self-administration of ethanol, but not of sucrose. Together, our data suggest that aberrant synaptic plasticity in the DMS induced by repeated cycles of ethanol exposure and withdrawal contributes to the molecular mechanisms underlying the development and/or maintenance of excessive ethanol consumption. PMID- 23100434 TI - Regulation of zipcode binding protein 1 transport dynamics in axons by myosin Va. AB - Directed transport of the mRNA binding protein, zipcode binding protein1 (ZBP1), into developing axons is believed to play an important role in mRNA localization and local protein synthesis. The role of molecular motors in this process is unclear. We elucidated a role for myosin Va (MyoVa) to modulate the axonal localization and transport of ZBP1 in axons. Using cultured rat hippocampal neurons, ZBP1 colocalized with MyoVa in axons and growth cones. Interaction of MyoVa with ZBP1 was evident by coimmunoprecipitation of endogenous and overexpressed proteins. Inhibition of MyoVa function with the globular tail domain (GTD) of MyoVa protein or short hairpin RNA led to an accumulation of ZBP1 in axons. Live cell imaging of mCherryZBP1 in neurons expressing GTD showed an increase in the number of motile particles, run length, and stimulated anterograde moving ZBP1 particles, suggesting that MyoVa controls availability of ZBP1 for microtubule-dependent transport. These findings suggest a novel regulatory role for MyoVa in the transport of ZBP1 within axons. PMID- 23100435 TI - Differences in sensitivity to neural timing among cortical areas. AB - The basic circuitry of auditory, visual, somatosensory and other cortical areas is highly stereotyped (Douglas and Martin, 2004). However, it remains unclear whether this anatomical stereotypy implies functional homogeneity, or whether instead different cortical areas are specialized to process the diverse sensory inputs they receive. Here we have used a two alternative forced choice task to assess modality-specific differences in the ability of rats to exploit precise neuronal timing. We delivered pairs of electrical pulses directly to different areas of cortex to determine the minimum timing differences subjects could detect. By stimulating the cortex directly, we isolated differences due to cortical circuitry rather than to sensory transduction and subcortical processing. Surprisingly, the minimum detectable timing differences varied over more than an order of magnitude, ranging from 1 ms in barrel cortex to 15 ms in visual cortex. Furthermore, these modality-specific differences depended upon sensory experience: although animals subjected to whisker clipping initially showed an impaired ability to exploit fine timing in barrel cortical stimulation, behavioral training partially rescued this deficit. Our results suggest that different cortical areas are adapted to the specific structure of the input signals they process, and that precise spike timing may play a more important role for some cortical areas than for others. PMID- 23100436 TI - Presynaptic alpha4beta2 nicotinic acetylcholine receptors increase glutamate release and serotonin neuron excitability in the dorsal raphe nucleus. AB - Several behavioral effects of nicotine are mediated by changes in serotonin (5 HT) release in brain areas that receive serotonergic afferents from the dorsal raphe nucleus (DRN). In vitro experiments have demonstrated that nicotine increases the firing activity in the majority of DRN 5-HT neurons and that DRN contains nicotinic acetylcholine receptors (nAChRs) located at both somata and presynaptic elements. One of the most common presynaptic effects of nicotine is to increase glutamate release. Although DRN receives profuse glutamatergic afferents, the effect of nicotine on glutamate release in the DRN has not been studied in detail. Using whole-cell recording techniques, we investigated the effects of nicotine on the glutamatergic input to 5-HT DRN neurons in rat midbrain slices. Low nicotine concentrations, in the presence of bicuculline and tetrodotoxin (TTX), increased the frequency but did not change the amplitude of glutamate-induced EPSCs, recorded from identified 5-HT neurons. Nicotine-induced increase of glutamatergic EPSC frequency persisted 10-20 min after drug withdrawal. This nicotinic effect was mimicked by exogenous administration of acetylcholine (ACh) or inhibition of ACh metabolism. In addition, the nicotine induced increase in EPSC frequency was abolished by blockade of alpha4beta2 nAChRs, voltage-gated calcium channels, or intracellular calcium signaling but not by alpha7 nAChR antagonists. These data suggest that both nicotine and endogenous ACh can increase glutamate release through activation of presynaptic alpha4beta2 but not alpha7 nAChRs in the DRN. The effect involves long-term changes in synaptic function, and it is dependent on voltage-gated calcium channels and presynaptic calcium stores. PMID- 23100437 TI - Emergence of selectivity and tolerance in the avian auditory cortex. AB - The ability to recognize auditory objects like words and bird songs is thought to depend on neural responses that are selective between categories of the objects and tolerant of variation within those categories. To determine whether a hierarchy of increasing selectivity and tolerance exists in the avian auditory system, we trained European starlings (Sturnus vulgaris) to differentially recognize sets of songs, then measured extracellular single unit responses under urethane anesthesia in six areas of the auditory cortex. Responses were analyzed with a novel, generalized linear mixed model that provides robust estimates of the variance in responses to different stimuli. There were significant differences between areas in selectivity, tolerance, and the effects of training. The L2b and L1 subdivisions of field L had the least selectivity and tolerance. The caudal nidopallium (NCM) and subdivision L3 of field L were more selective than other areas, whereas the medial and lateral caudal mesopallium were more tolerant than NCM or L2b. L3 had a multimodal distribution of tolerance. Sensitivity to songs that were familiar and those that were not also distinguished the responses of caudomedial mesopallium and NCM. There were significant differences across areas between neurons with wide and narrow spikes. Collectively these results do not fit the traditional hierarchical view of the avian auditory forebrain, but are consistent with emerging concepts homologizing avian cortical and neocortical circuitry. The results suggest a functional divergence within the cortex into processing streams that respond to complementary aspects of the variability in communicative sounds. PMID- 23100438 TI - Erbin is required for myelination in regenerated axons after injury. AB - Neuregulin 1 (NRG1) is an axon-derived factor that is critical for Schwann cell (SC) development and myelinogenesis in a manner dependent on transmembrane tyrosine kinases ErbB2 and ErbB3. Recent studies suggest that NRG1 signaling plays a role in remyelination of regenerated nerves after injury. In this study, we investigated the role of Erbin, a protein that interacts with ErbB2 in remyelination of injured nerves. We show that Erbin expression increased dramatically in injured nerves. Myelinated axons were fewer, and g-ratios of those that were myelinated were increased in erbin(-/-) mice, which were impaired in functional recovery from nerve injury. These results indicate a necessary role of Erbin in remyelination of regenerating axons. Erbin ablation had little effect on numbers of BrdU-labeled and TUNEL-labeled SCs, suggesting mechanisms independent of altered proliferation or apoptosis. We demonstrated that Erbin mutant mice were impaired in raising or maintaining the levels of ErbB2 and in producing NRG1 in axons. Together, these observations demonstrate that Erbin is required for remyelination of regenerated axons after injury, probably by regulating ErbB2 and NRG1 levels, identifying a novel player in regulating remyelination. PMID- 23100439 TI - Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. AB - Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid beta peptide (Abeta) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Abeta have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE epsilon4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of Abeta oligomerization. Here, we found that the level of Abeta oligomers in APOE epsilon4/epsilon4 AD patient brains is 2.7 times higher than those in APOE epsilon3/epsilon3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Abeta oligomers. To test this hypothesis, we examined the effect of apoE on Abeta oligomer formation. Using both synthetic Abeta and a split-luciferase method for monitoring Abeta oligomers, we observed that apoE increased the level of Abeta oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Abeta oligomers. Together, these data show that lipidated apoE, especially apoE4, increases Abeta oligomers in the brain. Higher levels of Abeta oligomers in the brains of APOE epsilon4/epsilon4 carriers compared with APOE epsilon3/epsilon3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD. PMID- 23100440 TI - Drosophila rugose is a functional homolog of mammalian Neurobeachin and affects synaptic architecture, brain morphology, and associative learning. AB - Neurobeachin (Nbea) is implicated in vesicle trafficking in the regulatory secretory pathway, but details on its molecular function are currently unknown. We have used Drosophila melanogaster mutants for rugose (rg), the Drosophila homolog of Nbea, to further elucidate the function of this multidomain protein. Rg is expressed in a granular pattern reminiscent of the Golgi network in neuronal cell bodies and colocalizes with transgenic Nbea, suggesting a function in secretory regulation. In contrast to Nbea(-/-) mice, rg null mutants are viable and fertile and exhibit aberrant associative odor learning, changes in gross brain morphology, and synaptic architecture as determined at the larval neuromuscular junction. At the same time, basal synaptic transmission is essentially unaffected, suggesting that structural and functional aspects are separable. Rg phenotypes can be rescued by a Drosophila rg+ transgene, whereas a mouse Nbea transgene rescues aversive odor learning and synaptic architecture; it fails to rescue brain morphology and appetitive odor learning. This dissociation between the functional redundancy of either the mouse or the fly transgene suggests that their complex composition of numerous functional and highly conserved domains support independent functions. We propose that the detailed compendium of phenotypes exhibited by the Drosophila rg null mutant provided here will serve as a test bed for dissecting the different functional domains of BEACH (for beige and human Chediak-Higashi syndrome) proteins, such as Rugose, mouse Nbea, or Nbea orthologs in other species, such as human. PMID- 23100442 TI - Psychophysical chromatic mechanisms in macaque monkey. AB - Chromatic mechanisms have been studied extensively with psychophysical techniques in humans, but the number and nature of the mechanisms are still controversial. Appeals to monkey neurophysiology are often used to sort out the competing claims and to test hypotheses arising from the experiments in humans, but psychophysical chromatic mechanisms have never been assessed in monkeys. Here we address this issue by measuring color-detection thresholds in monkeys before and after chromatic adaptation, employing a standard approach used to determine chromatic mechanisms in humans. We conducted separate experiments using adaptation configured as either flickering full-field colors or heterochromatic gratings. Full-field colors would favor activity within the visual system at or before the arrival of retinal signals to V1, before the spatial transformation of color signals by the cortex. Conversely, gratings would favor activity within the cortex where neurons are often sensitive to spatial chromatic structure. Detection thresholds were selectively elevated for the colors of full-field adaptation when it modulated along either of the two cardinal chromatic axes that define cone-opponent color space [L vs M or S vs (L + M)], providing evidence for two privileged cardinal chromatic mechanisms implemented early in the visual processing hierarchy. Adaptation with gratings produced elevated thresholds for colors of the adaptation regardless of its chromatic makeup, suggesting a cortical representation comprised of multiple higher-order mechanisms each selective for a different direction in color space. The results suggest that color is represented by two cardinal channels early in the processing hierarchy and many chromatic channels in brain regions closer to perceptual readout. PMID- 23100441 TI - The dorsal raphe modulates sensory responsiveness during arousal in zebrafish. AB - During waking behavior, animals adapt their state of arousal in response to environmental pressures. Sensory processing is regulated in aroused states, and several lines of evidence imply that this is mediated at least partly by the serotonergic system. However, there is little information directly showing that serotonergic function is required for state-dependent modulation of sensory processing. Here we find that zebrafish larvae can maintain a short-term state of arousal during which neurons in the dorsal raphe modulate sensory responsiveness to behaviorally relevant visual cues. After a brief exposure to water flow, larvae show elevated activity and heightened sensitivity to perceived motion. Calcium imaging of neuronal activity after flow revealed increased activity in serotonergic neurons of the dorsal raphe. Genetic ablation of these neurons abolished the increase in visual sensitivity during arousal without affecting baseline visual function or locomotor activity. We traced projections from the dorsal raphe to a major visual area, the optic tectum. Laser ablation of the tectum demonstrated that this structure, like the dorsal raphe, is required for improved visual sensitivity during arousal. These findings reveal that serotonergic neurons of the dorsal raphe have a state-dependent role in matching sensory responsiveness to behavioral context. PMID- 23100444 TI - Number and burden of cardiovascular diseases in relation to health-related quality of life in a cross-sectional population-based cohort study. AB - OBJECTIVES: To clarify whether a greater number of cardiovascular diseases or a larger burden of disease are associated with poorer health-related quality of life (HRQoL) in an unselected general population. DESIGN: A population-based cross-sectional postal survey. SETTINGS: A random sample of the Swedish general population aged 40-79 years matched for national distributions of age, gender and region. PARTICIPANTS: Out of 6969 eligible individuals, 4910 (70.5%) participated. PRIMARY AND SECONDARY MEASURES: To create a reference database for HRQoL outcomes in the general population. To assess certain diseases and their relation to HRQoL. METHODS: Predefined cardiovascular diseases and HRQoL were assessed from validated questionnaires (EORTC QLQ-C30). Aspects of HRQoL included in the analyses were global quality of life, physical function, role function, emotional function, fatigue and dyspnoea. Individuals were categorised into: 'good function' versus 'poor function' and 'no or minor symptoms' versus 'symptomatic'. Multivariable logistic regression calculated OR with 95% CI for poor HRQoL. The exposures were the number of cardiovascular diseases and the subjective disease burden. RESULTS: Out of the 4910 participants, 1358 (28%) reported having a cardiovascular disease and hypertension was most common. Reporting a greater number of cardiovascular diseases was associated with an increased risk of poor HRQoL, especially regarding dyspnoea. The OR for symptomatic dyspnoea was 1.37 (95% CI 1.08 to 1.74) for participants with one cardiovascular disease, 4.81 (95% CI 3.24 to 7.13) for two diseases and 4.18 (95% CI 2.24 to 7.80) for those with three or more cardiovascular diseases. Among the 271 participants who assessed their cardiovascular disease burden as major, the highest risk for poor HRQoL was found for physical function (OR 6.18, 95% CI 3.72 to 10.30). CONCLUSIONS: Increased number of cardiovascular diseases and a greater burden of disease are generally associated with poorer HRQoL in people with cardiovascular disease from an unselected population. PMID- 23100443 TI - Systematic mutagenesis of alpha-synuclein reveals distinct sequence requirements for physiological and pathological activities. AB - alpha-Synuclein is an abundant presynaptic protein that binds to phospholipids and synaptic vesicles. Physiologically, alpha-synuclein functions as a SNARE protein chaperone that promotes SNARE-complex assembly for neurotransmitter release. Pathologically, alpha-synuclein mutations and alpha-synuclein overexpression cause Parkinson's disease, and aggregates of alpha-synuclein are found as Lewy bodies in multiple neurodegenerative disorders ("synucleinopathies"). The relation of the physiological functions to the pathological effects of alpha-synuclein remains unclear. As an initial avenue of addressing this question, we here systematically examined the effect of alpha synuclein mutations on its physiological and pathological activities. We generated 26 alpha-synuclein mutants spanning the entire molecule, and analyzed them compared with wild-type alpha-synuclein in seven assays that range from biochemical studies with purified alpha-synuclein, to analyses of alpha-synuclein expression in cultured neurons, to examinations of the effects of virally expressed alpha-synuclein introduced into the mouse substantia nigra by stereotactic injections. We found that both the N-terminal and C-terminal sequences of alpha-synuclein were required for its physiological function as SNARE-complex chaperone, but that these sequences were not essential for its neuropathological effects. In contrast, point mutations in the central region of alpha-synuclein, referred to as nonamyloid beta component (residues 61-95), as well as point mutations linked to Parkinson's disease (A30P, E46K, and A53T) increased the neurotoxicity of alpha-synuclein but did not affect its physiological function in SNARE-complex assembly. Thus, our data show that the physiological function of alpha-synuclein, although protective of neurodegeneration in some contexts, is fundamentally distinct from its neuropathological effects, thereby dissociating the two activities of alpha synuclein. PMID- 23100445 TI - Translation and testing of the Risk Assessment Pressure Ulcer Sore scale used among residents in Norwegian nursing homes. AB - OBJECTIVE: The purpose of this study was to translate and test the psychometric properties of the Norwegian-language version of the Risk Assessment Pressure Sore (RAPS) scale. BACKGROUND: Risk assessment scales for pressure ulcer (PU) prevention have become an aspect of quality improvement in healthcare, but their effectiveness depends on the reliability and validity of the scale. METHODS: A convenience sample of 481 residents in 15 nursing homes in rural Norway was included between January and June 2007. The English-language version of the RAPS scale was translated into Norwegian, and this scale was used to collect the data, including a skin examination. The number of PUs and grades were documented. Reliability was assessed in a small group of 26 residents and construct validity in the total study group. RESULTS: Equivalence between two assessments regarding total scores of the RAPS scale was reflected in an intraclass correlation coefficient (ICC) of 0.95. Construct validity was supported, and the RAPS scale could define groups with expected low and high scores. Further evidence of construct validity was shown in a confirmatory factor analysis. CONCLUSION: The Norwegian version of the RAPS scale has shown sufficient psychometric properties to be considered a reliable and valid scale for identifying risk of PUs among nursing home residents. However, further testing is needed. PMID- 23100446 TI - Ankle-Brachial Index determination and peripheral arterial disease diagnosis by an oscillometric blood pressure device in primary care: validation and diagnostic accuracy study. AB - OBJECTIVES: To determine the level of agreement between a 'conventional' Ankle Brachial Index (ABI) measurement (using Doppler and mercury sphygmomanometer taken by a research nurse) and a 'pragmatic' ABI measure (using an oscillometric device taken by a practice nurse) in primary care. To ascertain the utility of a pragmatic ABI measure for the diagnosis of peripheral arterial disease (PAD) in primary care. DESIGN: Cross-sectional validation and diagnostic accuracy study. Descriptive analyses were used to investigate the agreement between the two procedures using the Bland and Altman method to determine whether the correlation between ABI readings varied systematically. Diagnostic accuracy was assessed via sensitivity, specificity, accuracy, likelihood ratios, positive and negative predictive values, with ABI readings dichotomised and Receiver Operating Curve analysis using both univariable and multivariable logistic regression. SETTING: Primary care in metropolitan and rural Victoria, Australia between October 2009 and November 2010. PARTICIPANTS: 250 persons with cardiovascular disease (CVD) or at high risk (three or more risk factors) of CVD. RESULTS: Despite a strong association between the two method's measurements of ABI there was poor agreement with 95% of readings within +/-0.4 of the 0.9 ABI cut point. The multivariable C statistic of diagnosis of PAD was 0.89. Other diagnostic measures were sensitivity 62%, specificity 92%, positive predictive value 67%, negative predictive value 90%, accuracy 85%, positive likelihood ratio 7.3 and the negative likelihood ratio 0.42. CONCLUSIONS: Oscillometric ABI measures by primary care nurses on a population with a 22% prevalence of PAD lacked sufficient agreement with conventional measures to be recommended for routine diagnosis of PAD. This pragmatic method may however be used as a screening tool high-risk and overt CVD patients in primary care as it can reliably exclude the condition. PMID- 23100447 TI - Consensus diagnostic criteria for fetal alcohol spectrum disorders in Australia: a modified Delphi study. AB - OBJECTIVE: To evaluate health professionals' agreement with components of published diagnostic criteria for fetal alcohol spectrum disorders (FASD) in order to guide the development of standard diagnostic guidelines for Australia. DESIGN: A modified Delphi process was used to assess agreement among health professionals with expertise or experience in FASD screening or diagnosis. An online survey, which included 36 Likert statements on diagnostic methods, was administered over two survey rounds. For fetal alcohol syndrome (FAS), health professionals were presented with concepts from the Institute of Medicine (IOM), University of Washington (UW), Centers for Disease Control (CDC), revised IOM and Canadian diagnostic criteria. For partial FAS (PFAS), alcohol-related neurodevelopmental disorder (ARND), and alcohol-related birth defects (ARBD), concepts based on the IOM and the Canadian diagnostic criteria were compared. SETTING/PARTICIPANTS: 130 Australian and 9 international health professionals. RESULTS: Of 139 health professionals invited to complete the survey, 103 (74.1%) responded, and 74 (53.2%) completed one or more questions on diagnostic criteria. We found consensus agreement among participants on the diagnostic criteria for FAS, with the UW criteria most commonly endorsed when compared with all other published criteria for FAS. When health professionals were presented with concepts based on the Canadian and IOM diagnostic criteria, we found consensus agreement but no clear preference for either the Canadian or IOM criteria for the diagnosis of PFAS, and no consensus agreement on diagnostic criteria for ARND. We also found no consensus on the IOM diagnostic criteria for ARBD. CONCLUSIONS: Participants indicated clear support for use of the UW diagnostic criteria for FAS in Australia. These findings should be used to develop guidelines to facilitate improved awareness of, and address identified gaps in the infrastructure for, FASD diagnosis in Australia. PMID- 23100448 TI - Processing of emotional information in the human subthalamic nucleus. AB - BACKGROUND: The subthalamic nucleus (STN) is an efficient target for treating patients with Parkinson's disease as well as patients with obsessive-compulsive disorder (OCD) using high frequency stimulation (HFS). In both Parkinson's disease and OCD patients, STN-HFS can trigger abnormal behaviours, such as hypomania and impulsivity. METHODS: To investigate if this structure processes emotional information, and whether it depends on motor demands, we recorded subthalamic local field potentials in 16 patients with Parkinson's disease using deep brain stimulation electrodes. Recordings were made with and without dopaminergic treatment while patients performed an emotional categorisation paradigm in which the response varied according to stimulus valence (pleasant, unpleasant and neutral) and to the instruction given (motor, non-motor and passive). RESULTS: Pleasant, unpleasant and neutral stimuli evoked an event related potential (ERP). Without dopamine medication, ERP amplitudes were significantly larger for unpleasant compared with neutral pictures, whatever the response triggered by the stimuli; and the magnitude of this effect was maximal in the ventral part of the STN. No significant difference in ERP amplitude was observed for pleasant pictures. With dopamine medication, ERP amplitudes were significantly increased for pleasant compared with neutral pictures whatever the response triggered by the stimuli, while ERP amplitudes to unpleasant pictures were not modified. CONCLUSIONS: These results demonstrate that the ventral part of the STN processes the emotional valence of stimuli independently of the motor context and that dopamine enhances processing of pleasant information. These findings confirm the specific involvement of the STN in emotional processes in human, which may underlie the behavioural changes observed in patients with deep brain stimulation. PMID- 23100449 TI - Effects of ectopic expression of NGAL on doxorubicin sensitivity. AB - Neutrophil gelatinase-associated lipocalin (NGAL, a.k.a Lnc2) is a member of the lipocalin family which has diverse roles including stabilizing matrix metalloproteinase-9 from auto-degradation and as siderocalins which are important in the transport of iron. NGAL also has important biological functions involved in immunity and inflammation as well as responses to kidney damage. NGAL expression has also been associated with certain neoplasia and is important in the metastasis of breast cancer. Many advanced cancer patients have elevated levels of NGAL in their urine and it has been proposed that NGAL may be a prognostic indicator for certain cancers (e.g. breast, brain, and others). NGAL expression is detected in response to various chemotherapeutic drugs including doxorubicin and docetaxel. We were interested in the roles of NGAL expression in cancer and whether it is associated with chemotherapeutic drug resistance. In the present study, we investigated whether increased NGAL expression led to resistance to the chemotherapeutic drug doxorubicin in normal breast epithelial cells (MCF-10A), breast cancer cells (MCF-7), and colorectal cancer cells (HT 29). We infected the various cell lines with a retrovirus encoding NGAL which we constructed. Increased NGAL expression was readily detected in the NGAL-infected cells but not the empty vector-infected cells. However, increased NGAL expression did not alter the sensitivity of the cells to the chemotherapeutic drug doxorubicin. Thus, although NGAL expression is often detected after chemotherapeutic drug treatment, it by itself, does not lead to doxorubicin resistance. PMID- 23100450 TI - Functional neurological recovery after spinal cord injury is impaired in patients with infections. AB - Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham, AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale-classified A and B patients recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials. Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects (non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale conversions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1 year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients with infections [ASIA impairment scale A: 8 (4-12) versus 10 (5-17), P = 0.01; ASIA impairment scale B: 19.5 (8-53.5) versus 42 (20.5-64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients, the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36-2.63, P < 0.0005) or lower gain in ASIA motor score (regression coefficient: -8.21, 95% confidence interval: -12.29 to -4.14, P < 0.0005). Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury. PMID- 23100453 TI - Ab initio investigation of the electronic properties of graphene on InAs(111)A. AB - The equilibrium geometry and electronic structure of graphene on the most stable In-vacancy InAs(111)A surface has been investigated using the density functional and pseudopotential theories. The equilibrium distance between graphene and InAs(111) is found to be 3.05 A with adsorption energy approximately 38 meV/C atom. According to our electronic band calculation, there is a re-distribution of the charge density around the graphene sheet, which leads to the development of a dipole moment along the surface normal. Scanning tunnelling microscopy image simulations suggest that the InAs(111) substrate is visible through the graphene layer. PMID- 23100452 TI - Neutron-activatable holmium-containing mesoporous silica nanoparticles as a potential radionuclide therapeutic agent for ovarian cancer. AB - Mesoporous silica nanoparticles (MSNs) were explored as a carrier material for the stable isotope (165)Ho and, after neutron capture, its subsequent therapeutic radionuclide, (166)Ho (half-life, 26.8 h), for use in radionuclide therapy of ovarian cancer metastasis. METHODS: (165)Ho-MSNs were prepared using (165)Ho acetylacetonate and MCM-41 silica particles, and stability was determined after irradiation in a nuclear reactor (reactor power, 1 MW; thermal neutron flux of approximately 5.5 * 10(12) neutrons/cm(2)s). SPECT/CT and tissue biodistribution studies were performed after intraperitoneal administration of (166)Ho-MSNs to SKOV-3 ovarian tumor-bearing mice. Radiotherapeutic efficacy was studied by using PET/CT with (18)F-FDG to determine tumor volume and by monitoring survival. RESULTS: The holmium-MSNs were able to withstand long irradiation times in a nuclear reactor and did not release (166)Ho after significant dilution. SPECT/CT images and tissue distribution results revealed that (166)Ho-MSNs accumulated predominantly in tumors (32.8% +/- 8.1% injected dose/g after 24 h; 81% +/- 7.5% injected dose/g after 1 wk) after intraperitoneal administration. PET/CT images showed reduced (18)F-FDG uptake in tumors, which correlated with a marked increase in survival after treatment with approximately 4 MBq of (166)Ho-MSNs. CONCLUSION: The retention of holmium in nanoparticles during irradiation and in vivo after intraperitoneal administration as well as their efficacy in extending survival in tumor-bearing mice underscores their potential as a radiotherapeutic agent for ovarian cancer metastasis. PMID- 23100451 TI - The mitochondrial citrate transporter, CIC, is essential for mitochondrial homeostasis. AB - Dysregulation of the pathways that preserve mitochondrial integrity hallmarks many human diseases including diabetes, neurodegeration, aging and cancer. The mitochondrial citrate transporter gene, SLC25A1 or CIC, maps on chromosome 22q11.21, a region amplified in some tumors and deleted in developmental disorders known as velo-cardio-facial- and DiGeorge syndromes. We report here that in tumor cells CIC maintains mitochondrial integrity and bioenergetics, protects from mitochondrial damage and circumvents mitochondrial depletion via autophagy, hence promoting proliferation. CIC levels are increased in human cancers and its inhibition has anti-tumor activity, albeit with no toxicity on adult normal tissues. The knock-down of the CIC gene in zebrafish leads to mitochondria depletion and to proliferation defects that recapitulate features of human velo-cardio-facial syndrome, a phenotype rescued by blocking autophagy. Our findings reveal that CIC maintains mitochondrial homeostasis in metabolically active, high proliferating tissues and imply that this protein is a therapeutic target in cancer and likely, in other human diseases. PMID- 23100454 TI - Hand surgery depends upon the application of scientific knowledge but also technical skill. PMID- 23100456 TI - Smoking-related weight concerns and obesity: differences among normal weight, overweight, and obese smokers using a telephone tobacco quitline. AB - INTRODUCTION: Substantial evidence suggests that concerns about postcessation weight gain interfere with cessation efforts. However, it is unclear to what extent weight pretreatment affects smoking-related weight concerns. Given that the prevalence of overweight and obesity among callers to tobacco quitlines mirrors that of the population at large, and that women and obese smokers may be more concerned about weight gain, we sought to compare weight gain concerns among normal weight, overweight, and obese callers to a quitline. METHODS: A sample of 34.6% (n = 206) normal weight, 30.6% (n = 182) overweight, and 34.8% (n = 207) obese quitline callers completed assessments of tobacco use history and smoking specific weight concerns. Weight categories were compared and gender differences evaluated. RESULTS: Obese smokers endorsed significantly more concerns about postcessation weight gain [F(2, 592) = 20.35, p < .0001], had less confidence in their ability to maintain their weight without smoking [F(2, 592) = 7.67, p = .0005], and were willing to tolerate less weight gain after quitting than normal weight or overweight smokers [F(2,574) = 30.59, p < .0001). There also were gender differences in weight concerns by weight status. Significantly more women callers were obese (38.2% vs. 28.4%, p = .011), and women consistently endorsed more concern about postcessation weight gain than did men [F(1,588) = 24.04, p < .0001). CONCLUSIONS: Overweight and obese smokers, particularly women, express substantial concern about gaining weight after quitting. It is possible that smokers who begin quitline treatment with a BMI in the obese range may benefit from adjunctive interventions designed to address smoking-related weight concerns. PMID- 23100457 TI - Possible reinforcement enhancing effects of bupropion during initial smoking abstinence. AB - INTRODUCTION: Due to a drop in nicotine, smoking cessation may attenuate reinforcement from sensory stimuli unrelated to nicotine intake. Recent rodent research suggests that bupropion may reverse this attenuation, perhaps helping explain its efficacy in aiding cessation. METHODS: In a within-subjects, crossover study, smokers responded on a simple computer task for brief music reward available on a progressive ratio 50% schedule. Testing was done on three separate occasions: after ad lib smoking during prequit baseline and on the first day of two brief quit attempts while taking bupropion or placebo, in counter balanced order. Number of operant responses was the measure of reinforcement. To more clearly assess abstinence and medication effects, those meeting 24-hr abstinence criteria (CO < 5 ppm; n = 5) or clearly failing to abstain (CO > 10 ppm; n = 5) during both medication conditions were compared. RESULTS: Among abstainers, repeated measures ANOVA showed that reinforced responding decreased by nearly 50% from baseline after quitting on placebo (p = .03), while responding after quitting on bupropion was similar to that during baseline (-17%; p = .20). In contrast, those unable to abstain showed virtually identical reinforced responding due to either medication or baseline. CONCLUSIONS: These exploratory findings confirm that responding for a reward unrelated to smoking decreases after abstinence and are consistent with animal research showing bupropion effects on enhancing reinforced responding. PMID- 23100458 TI - Impact of the 2011 Spanish smoking ban in hospitality venues: indoor secondhand smoke exposure and influence of outdoor smoking. AB - INTRODUCTION: The Spanish tobacco control law of 2006 was modified in January 2011, banning smoking in all hospitality venues. The objective of the study was to assess the impact of the 2011 Spanish smoking ban on secondhand smoke (SHS) exposure in hospitality venues, and to analyze the potential impact of outdoor smokers close to entrances on indoor SHS levels after the law came into force. METHODS: Before-and-after evaluation study with repeated measures. The study was carried out in three regions of Spain (Catalonia, Galicia, and Madrid) and included a random sample of 178 hospitality venues. We measured vapor-phase nicotine and particulate matter 2.5 micrometers or less in diameter (PM2.5) as SHS markers at baseline (November-December 2010) and at follow-up (April-June 2011). We also recorded tobacco consumption variables such as the presence of butts, ashtrays, and smokers. In the posttest assessment, we also recorded the number of outdoor smokers close to the entrance. RESULTS: A total of 351 nicotine and 160 PM2.5 measurements were taken. Both nicotine and PM2.5 concentrations decreased by more than 90% (nicotine from 5.73 to 0.57 ug/m(3), PM2.5 from 233.38 to 18.82 ug/m(3)). After the law came into force, both nicotine and PM2.5 concentrations were significantly higher in venues with outdoor smokers close to the entrance than in those without outdoor smokers. All the observational tobacco consumption variables significantly decreased (p < .001). CONCLUSIONS: SHS exposure in hospitality venues dramatically decreased after the 2011 Spanish smoking ban. SHS from outdoor smokers close to entrances seems to drift inside venues. Smoking control legislation should consider outdoor restrictions to ensure complete protection against SHS. PMID- 23100460 TI - Nicotine reduction: strategic research plan. AB - BACKGROUND: Reducing nicotine content in cigarettes and other combustible products to levels that are not reinforcing or addictive has the potential to substantially reduce tobacco-related morbidity and mortality. The authority to reduce nicotine levels as a regulatory measure is provided in the U.S. Family Smoking Prevention and Tobacco Control Act and is consistent with the general regulatory powers envisioned under the relevant articles of the World Health Organization's Framework Convention on Tobacco Control. Many experts have considered reducing nicotine in cigarettes to be a feasible national policy approach, but more research is necessary. PURPOSE: This article describes proceedings from a conference that had the goals of identifying specific research gaps, describing methods and measures to consider for addressing these gaps, and considering ways to foster collaboration. RESULTS AND CONCLUSION: Identified research gaps included determining the dose of nicotine that would be optimal for reducing and extinguishing cigarette use, examining approaches for reducing nicotine levels in the general and special populations of smokers, understanding how constituents other than nicotine may contribute to the reinforcing effects of tobacco, and identifying unintended consequences to determine ways to mitigate them. Methods that can be used ranged from brain imaging to large human clinical trials. The development and availability of valid biomarkers of exposure and effect are important. Infrastructures to facilitate collaboration need to be established. PMID- 23100461 TI - Evidence of spillover of illness among household members: EQ-5D scores from a US sample. AB - BACKGROUND/OBJECTIVES: The effects of illness extend beyond the individual to caregivers and family members. This study identified evidence of spillover of illness onto household members' health-related quality of life. METHODS: Medical Expenditures Panel Survey (MEPS) data from 2000-2003 were analyzed using multivariable regression to identify spillover of household members' chronic conditions onto individuals' health-related quality of life as measured by the EuroQol-5D (EQ-5D) score (N = 24,188). Spillover was assessed by disease category, timing of occurrence (preexisting or new conditions), and age of the household member (adult or child). RESULTS: Controlling for an individual's own health conditions and other known predictors of EQ-5D scores, the authors found that the odds of an individual reporting full health (an EQ-5D score of 1.0, relative to <1.0) were lower with the presence of existing mental (odds ratio 0.71; 95% confidence interval, 0.64-0.79), respiratory (0.85; 0.75-0.97), and musculoskeletal (0.83; 0.75-0.93) conditions among adults and with mental (0.72; 0.62-0.82) and respiratory (0.80; 0.81-0.96) conditions among children in the household. The odds of an individual reporting full health were also lower for newly occurring chronic conditions in the household, including adults' mental (0.79; 0.65-0.97), nervous/sensory system (0.76; 0.61-0.96), and musculoskeletal (0.78; 0.65-0.95) conditions and children's mental conditions (0.64; 0.48-0.86). EQ-5D dimensions may be unsuited to fully capture spillover utility among household members, and MEPS lacks condition severity and caregiver status among household members. CONCLUSIONS: Evidence from a US sample suggests that individuals who live with chronically ill household members have lower EQ-5D scores than those who live either alone or with healthy household members. Averting spillover effects may confer substantial additional benefit at the population level for interventions that prevent or alleviate conditions that incur such effects. PMID- 23100462 TI - Using comparison scenarios to improve prenatal risk communication. AB - The present research provides empirical evidence of whether communicating the prenatal risk of chromosomal anomalies using comparison scenarios influences women's ability to distinguish between different risk levels. In 2 experiments, participants read a description of a hypothetical woman who was learning of the risk of chromosomal anomaly as a result of a prenatal screening test. Both experiments used a 3 (risk level) * 3 (scenario) full between-subjects design. In accordance with the experimental condition, participants were presented with a low (e.g., 1 in 5390), a medium (e.g., 1 in 770), or a high risk value (e.g., 1 in 110). Such risk values were presented either on their own or along with additional information illustrating a comparison scenario that provided 2 numerical comparison points. Participants were asked to evaluate the risk of chromosomal anomaly. In Experiment 2, participants' numeracy skills were also assessed. RESULTS: showed that the use of comparison scenarios results in significant differences in perceived risk across risk levels whereas such differences are not significant without the comparison scenario, but such a technique has differential effects according to participants' capacity to deal with numbers. Although the technique is beneficial for high-numerate participants, it has no effect on low-numerate participants. PMID- 23100463 TI - Can one translocation impact the meiotic segregation of another translocation? A sperm-FISH analysis of a 46,XY,t(1;16)(q21;p11.2),t(8;9) (q24.3;p24) patient and his 46,XY,t(8;9)(q24.3;p24) brother and cousin. AB - Individuals with two independent chromosome rearrangements are rare and meiotic segregation studies are few. Two brothers (P1 and P2) and a cousin (P3) were karyotyped and found to have the same familial reciprocal translocation between the long arm of chromosome 8 and the short arm of chromosome 9: 46,XY,t(8;9)(q24.3;p24). In addition, one brother also had a different de novo reciprocal translocation between the long arm of chromosome 1 and the short arm of chromosome 16: 46,XY,t(1;16)(q21;p11.2)dn,t(8;9)(q24.3;p24)mat. Using locus specific probes for segments involved in the translocations and for other chromosomes, sperm-FISH analysis was used to investigate the products of meiotic segregation of the translocations and the possibility of an interchromosomal effect (ICE). Sperm nucleus fragmentation was also evaluated. For the t(8;9) translocation, the proportion of unbalanced products was higher for P1 (66.3%, P < 0.0001) than P2 (51.9%) and P3 (50.4%), and the proportion consistent with each meiosis I segregation mode was also different for P1. In addition, for P1, 61.6% of the products of the t(1;16) were unbalanced, and 85.6% of spermatozoa overall included both translocations. No evidence of an ICE was found and sperm nucleus fragmentation rates were similar. Our study suggests that co-segregation of the t(8;9) and the t(1;16) resulted in modifying the proportions of t(8;9) meiotic segregation products found in spermatozoa. This could be due to selection associated with meiotic checkpoints and germ cell death. PMID- 23100459 TI - Two decades of smoking cessation treatment research on smokers with depression: 1990-2010. AB - INTRODUCTION: Adults with depression smoke at higher rates than other adults leaving a large segment of this population, who already incur increased health related risks, vulnerable to the enormous harmful consequences of smoking. Yet, the impact that depression has on smoking cessation is not clear due to the mixed results of past research. The primary aims of this review were to synthesize the research examining the relationship of depression to smoking cessation outcomes over a 20-year period, to examine the gender and racial composition of these studies, and to identify directions for future research. METHODS: Potential articles published between January 1, 1990 and December 31, 2010 were identified through a MEDLINE search of the terms "clinical trial," "depression," and "smoking cessation." 68 studies used all three terms and met the inclusion criteria. RESULTS: The majority of studies examined either a past diagnosis of major depression or current depression symptoms. Within the few studies that examined the interaction of gender and depression on smoking cessation, depression had a greater impact on treatment outcomes for women than men. No study reported examining the interactive impact of race and depression on treatment outcomes. CONCLUSIONS: Although attention to the relationship of depression and smoking cessation outcomes has increased over the past 20 years, little information exists to inform a treatment approach for smokers with Current Major Depressive Disorder, Dysthymia, and Minor Depression and few studies report gender and racial differences in the relationship of depression and smoking cessation outcomes, thus suggesting major areas for targeted research. PMID- 23100464 TI - Mutation screening of AURKB and SYCP3 in patients with reproductive problems. AB - Mutations in the spindle checkpoint genes can cause improper chromosome segregations and aneuploidies, which in turn may lead to reproductive problems. Two of the proteins involved in this checkpoint are Aurora kinase B (AURKB), preventing the anaphase whenever microtubule-kinetochore attachments are not the proper ones during metaphase; and synaptonemal complex protein 3 (SYCP3), which is essential for the formation of the complex and for the recombination of the homologous chromosomes. This study has attempted to clarify the possible involvement of both proteins in the reproductive problems of patients with chromosomal instability. In order to do this, we have performed a screening for genetic variants in AURKB and SYCP3 among these patients using Sanger sequencing. Only one apparently non-pathogenic deletion was found in SYCP3. On the other hand, we found six sequence variations in AURKB. The consequences of these changes on the protein were studied in silico using different bioinformatic tools. In addition, the frequency of three of the variations was studied using a high-resolution melting approach. The absence of these three variants in control samples and their position in the AURKB gene suggests their possible involvement in the patients' chromosomal instability. Interestingly, two of the identified changes in AURKB were found in each member of a couple with antecedents of spontaneous pregnancy loss, a fetal anencephaly and a deaf daughter. One of these changes is described here for the first time. Although further studies are necessary, our results are encouraging enough to propose the analysis of AURKB in couples with reproductive problems. PMID- 23100465 TI - eIF4E/4E-BP ratio predicts the efficacy of mTOR targeted therapies. AB - Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs-EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors. PMID- 23100466 TI - Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers. AB - Esophageal cancer incidence is increasing and has few treatment options. In studying receptor tyrosine kinases associated with esophageal cancers, we have identified EPHB4 to be robustly overexpressed in cell lines and primary tumor tissues. In total, 94 squamous cell carcinoma, 82 adenocarcinoma, 25 dysplasia, 13 Barrett esophagus, and 25 adjacent or unrelated normal esophageal tissues were evaluated by immunohistochemistry. EPHB4 expression was significantly higher in all the different histologic categories than in adjacent normal tissues. In 13 esophageal cancer cell lines, 3 of the 9 SCC cell lines and 2 of the 4 adenocarcinomas expressed very high levels of EPHB4. An increased gene copy number ranging from 4 to 20 copies was identified in a subset of the overexpressing patient samples and cell lines. We have developed a novel 4 nitroquinoline 1-oxide (4-NQO)-induced mouse model of esophageal cancer that recapitulates the EPHB4 expression in humans. A specific small-molecule inhibitor of EPHB4 decreased cell viability in a time- and dose-dependent manner in 3 of the 4 cell lines tested. The small-molecule inhibitor and an EPHB4 siRNA also decreased cell migration (12%-40% closure in treated vs. 60%-80% in untreated), with decreased phosphorylation of various tyrosyl-containing proteins, EphB4, and its downstream target p125FAK. Finally, in a xenograft tumor model, an EPHB4 inhibitor abrogated tumor growth by approximately 60% compared with untreated control. EphB4 is robustly expressed and potentially serves as a novel biomarker for targeted therapy in esophageal cancers. PMID- 23100467 TI - Novel DNA damage checkpoints mediating cell death induced by the NEDD8-activating enzyme inhibitor MLN4924. AB - MLN4924 is an investigational small-molecule inhibitor of the NEDD8-activating enzyme (NAE) in phase I clinical trials. NAE inhibition prevents the ubiquitination and proteasomal degradation of substrates for cullin-RING ubiquitin E3 ligases that support cancer pathophysiology, but the genetic determinants conferring sensitivity to NAE inhibition are unknown. To address this gap in knowledge, we conducted a genome-wide siRNA screen to identify genes and pathways that affect the lethality of MLN4924 in melanoma cells. Of the 154 genes identified, approximately one-half interfered with components of the cell cycle, apoptotic machinery, ubiquitin system, and DNA damage response pathways. In particular, genes involved in DNA replication, p53, BRCA1/BRCA2, transcription coupled repair, and base excision repair seemed to be important for MLN4924 lethality. In contrast, genes within the G(2)-M checkpoint affected sensitivity to MLN4924 in colon cancer cells. Cell-cycle analysis in melanoma cells by flow cytometry following RNAi-mediated silencing showed that MLN4924 prevented the transition of cells from S-G(2) phase after induction of rereplication stress. Our analysis suggested an important role for the p21-dependent intra-S-phase checkpoint and extensive rereplication, whereas the ATR-dependent intra-S-phase checkpoint seemed to play a less dominant role. Unexpectedly, induction of the p21-dependent intra-S-phase checkpoint seemed to be independent of both Cdt1 stabilization and ATR signaling. Collectively, these data enhance our understanding of the mechanisms by which inhibition of NEDD8-dependent ubiquitination causes cell death, informing clinical development of MLN4924. PMID- 23100469 TI - The book with a silver lining. PMID- 23100471 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 1: Is exercise-related transient abdominal pain (stitch) while running preventable? AB - A short cut review was carried out to establish whether drinking fluids was better than not drinking fluids at preventing exercise associated abdominal pain (stitch) in runners. 112 papers were found using the reported searches, of which 2 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that drinking fluids before running is associated with stitch. PMID- 23100468 TI - Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. AB - Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53 mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells. PMID- 23100472 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 2: Leg crossing to prevent syncope. AB - A short cut review was carried out to establish whether leg crossing prevents transient loss of consciousness in patients known to have orthostatic hypotension. 9 papers presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. It is concluded that leg crossing can help reduce the incidence of transient loss of consciousness in patients with orthostatic hypotension. PMID- 23100473 TI - Towards evidence based emergency medicine: Best BETs from the Manchester Royal Infirmary. BET 3: Toe fractures in adults. AB - A short cut review was carried out to establish whether intervention and follow up of patients with toe phalanx fractures is better than no treatment at reducing time to return to normal activity and need for surgical intervention. 40 papers were found using the reported searches, of which 1 presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of this best paper is tabulated. It is concluded that there is no evidence to determine whether intervention of any type improves outcome in toe phalanx fractures. PMID- 23100475 TI - Short answer question case series: Abnormal first-trimester pregnancy. PMID- 23100477 TI - Preliminary evaluation of the safety and efficacy of standard intravenous immunoglobulins in pregnant women with primary cytomegalovirus infection. AB - Hyperimmune globulins were reported to prevent and treat fetal cytomegalovirus (CMV) infection during pregnancy. Here, we report that infusions of standard human intravenous immunoglobulin significantly increase CMV IgG titers and avidity indexes in pregnant women, paving the way to their use for passive transfer of maternal CMV humoral immunity to fetuses. Preliminary data on perinatal outcomes of the first 67 newborns are encouraging. PMID- 23100476 TI - Antibody responses to mycobacterial antigens in children with tuberculosis: challenges and potential diagnostic value. AB - The identification of easily detectable biomarkers for active tuberculosis (TB) is a global health priority. Such biomarkers would be of particular value in childhood TB, which poses greater diagnostic challenges than adult TB. Serum antibodies can be detected by simple formats that provide extremely rapid results. However, attempts to develop accurate serodiagnostic tests for TB have been unsuccessful. Whereas antibody responses to mycobacterial antigens in adult TB have been studied extensively and reviewed, the same cannot be said for serologic data in pediatric populations. Here we appraise studies on serological responses in childhood TB and discuss findings and limitations in the context of the developing immune system, the age range, and the spectrum of TB manifestations. We found that the antibody responses to mycobacterial antigens in childhood TB can vary widely, with sensitivities and specificities ranging from 14% to 85% and from 86% to 100%, respectively. We conclude that the limitations in serodiagnostic studies of childhood TB are manifold, thereby restricting the interpretation of currently available data. Concerns about the methodology used in published studies suggest that conclusions about the eventual value of serodiagnosis cannot be made at this time. However, the available data suggest a potential adjunctive value for serology in the diagnosis of childhood TB. Despite the difficulties noted in this field, there is optimism that the application of novel antigens and the integration of those factors which contribute to the serological responses in childhood TB can lead to useful future diagnostics. PMID- 23100478 TI - Low sensitivity of NS1 protein tests evidenced during a dengue type 2 virus outbreak in Santos, Brazil, in 2010. AB - In 2010, a large outbreak of dengue occurred in Santos, Brazil. The detection of the NS1 antigen was used for diagnosis in addition to the detection of IgG, IgM, and RNA. A large number of NS1 false-negative results were obtained. A total of 379 RNA-positive samples were selected for thorough evaluation. NS1 was reactive in 37.7% of cases. Most of the cases were characterized as a secondary infection by dengue 2 virus. Sequencing of NS1 positive and negative isolates did not reveal any mutation that could justify the diagnostic failure. Use of existing NS1 tests in the Brazilian population may present a low negative predictive value, and they should be used with caution, preferentially after performing a validation with samples freshly obtained during the ongoing epidemic. PMID- 23100479 TI - An adenovirus-vectored nasal vaccine confers rapid and sustained protection against anthrax in a single-dose regimen. AB - Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine. PMID- 23100481 TI - Validation of an immunochromatographic assay for the multiple detection of specific antibodies against HIV, HBV, and HCV. PMID- 23100480 TI - Immune complexes isolated from patients with pulmonary tuberculosis modulate the activation and function of normal granulocytes. AB - Circulating immune complexes (ICs) are associated with the pathogenesis of several diseases. Very little is known about the effect of ICs on the host immune response in patients with tuberculosis (TB). The effects of ICs isolated from patients with TB in modulating the release of calcium, cytokines, and granular proteins were studied in normal granulocytes, as were their chemotactic, phagocytic, and oxidative burst processes. ICs from TB patients induced decreased production of cytokines and platelet-activating factor (PAF) from normal granulocytes. ICs from TB patients also induced enhanced chemotaxis and phagocytosis but caused diminished oxidative burst. This was accompanied by an increased release in intracellular calcium. On the other hand, ICs from TB patients induced increased release of the granular proteins human neutrophil peptides 1 to 3 (HNP1-3). Thus, ICs from patients with TB exhibit a profound effect on granulocyte function with activation of certain effector mechanisms and dampening of others. PMID- 23100482 TI - Dual resistance of melon to Fusarium oxysporum races 0 and 2 and to Papaya ring spot virus is controlled by a pair of head-to-head-oriented NB-LRR genes of unusual architecture. PMID- 23100483 TI - DICER-LIKE 4 but not DICER-LIKE 2 may have a positive effect on potato spindle tuber viroid accumulation in Nicotiana benthamiana. PMID- 23100484 TI - How do sugars regulate plant growth and development? New insight into the role of trehalose-6-phosphate. AB - Plant growth and development are tightly controlled in response to environmental conditions that influence the availability of photosynthetic carbon in the form of sucrose. Trehalose-6-phosphate (T6P), the precursor of trehalose in the biosynthetic pathway, is an important signaling metabolite that is involved in the regulation of plant growth and development in response to carbon availability. In addition to the plant's own pathway for trehalose synthesis, formation of T6P or trehalose by pathogens can result in the reprogramming of plant metabolism and development. Developmental processes that are regulated by T6P range from embryo development to leaf senescence. Some of these processes are regulated in interaction with phytohormones, such as auxin. A key interacting factor of T6P signaling in response to the environment is the protein kinase sucrose non-fermenting related kinase-1 (SnRK1), whose catalytic activity is inhibited by T6P. SnRK1 is most likely involved in the adjustment of metabolism and growth in response to starvation. The transcription factor bZIP11 has recently been identified as a new player in the T6P/SnRK1 regulatory pathway. By inhibiting SnRK1, T6P promotes biosynthetic reactions. This regulation has important consequences for crop production, for example, in the developing wheat grain and during the growth of potato tubers. PMID- 23100485 TI - Impact of global warming and rising CO2 levels on coral reef fishes: what hope for the future? AB - Average sea-surface temperature and the amount of CO(2) dissolved in the ocean are rising as a result of increasing concentrations of atmospheric CO(2). Many coral reef fishes appear to be living close to their thermal optimum, and for some of them, even relatively moderate increases in temperature (2-4 degrees C) lead to significant reductions in aerobic scope. Reduced aerobic capacity could affect population sustainability because less energy can be devoted to feeding and reproduction. Coral reef fishes seem to have limited capacity to acclimate to elevated temperature as adults, but recent research shows that developmental and transgenerational plasticity occur, which might enable some species to adjust to rising ocean temperatures. Predicted increases in P(CO(2)), and associated ocean acidification, can also influence the aerobic scope of coral reef fishes, although there is considerable interspecific variation, with some species exhibiting a decline and others an increase in aerobic scope at near-future CO(2) levels. As with thermal effects, there are transgenerational changes in response to elevated CO(2) that could mitigate impacts of high CO(2) on the growth and survival of reef fishes. An unexpected discovery is that elevated CO(2) has a dramatic effect on a wide range of behaviours and sensory responses of reef fishes, with consequences for the timing of settlement, habitat selection, predator avoidance and individual fitness. The underlying physiological mechanism appears to be the interference of acid-base regulatory processes with brain neurotransmitter function. Differences in the sensitivity of species and populations to global warming and rising CO(2) have been identified that will lead to changes in fish community structure as the oceans warm and becomes more acidic; however, the prospect for acclimation and adaptation of populations to these threats also needs to be considered. Ultimately, it will be the capacity for species to adjust to environmental change over coming decades that will determine the impact of climate change on marine ecosystems. PMID- 23100486 TI - Performance and scaling of a novel locomotor structure: adhesive capacity of climbing gobiid fishes. AB - Many species of gobiid fishes adhere to surfaces using a sucker formed from fusion of the pelvic fins. Juveniles of many amphidromous species use this pelvic sucker to scale waterfalls during migrations to upstream habitats after an oceanic larval phase. However, adults may still use suckers to re-scale waterfalls if displaced. If attachment force is proportional to sucker area and if growth of the sucker is isometric, then increases in the forces that climbing fish must resist might outpace adhesive capacity, causing climbing performance to decline through ontogeny. To test for such trends, we measured pressure differentials and adhesive suction forces generated by the pelvic sucker across wide size ranges in six goby species, including climbing and non-climbing taxa. Suction was achieved via two distinct growth strategies: (1) small suckers with isometric (or negatively allometric) scaling among climbing gobies and (2) large suckers with positively allometric growth in non-climbing gobies. Species using the first strategy show a high baseline of adhesive capacity that may aid climbing performance throughout ontogeny, with pressure differentials and suction forces much greater than expected if adhesion were a passive function of sucker area. In contrast, large suckers possessed by non-climbing species may help compensate for reduced pressure differentials, thereby producing suction sufficient to support body weight. Climbing Sicyopterus species also use oral suckers during climbing waterfalls, and these exhibited scaling patterns similar to those for pelvic suckers. However, oral suction force was considerably lower than that for pelvic suckers, reducing the ability for these fish to attach to substrates by the oral sucker alone. PMID- 23100487 TI - Self-cleaning in tree frog toe pads; a mechanism for recovering from contamination without the need for grooming. AB - Tree frogs use adhesive toe pads for climbing on a variety of surfaces. They rely on wet adhesion, which is aided by the secretion of mucus. In nature, the pads will undoubtedly get contaminated regularly through usage, but appear to maintain their stickiness over time. Here, we show in two experiments that the toe pads of White's tree frogs (Litoria caerulea) quickly recover from contamination through a self-cleaning mechanism. We compared adhesive forces prior to and after contamination of (1) the whole animal on a rotatable platform and (2) individual toe pads in restrained frogs mimicking individual steps using a motorised stage. In both cases, the adhesive forces recovered after a few steps but this took significantly longer in single toe pad experiments from restrained frogs, showing that use of the pads increases recovery. We propose that both shear movements and a 'flushing' effect of the secreted mucus play an important role in shedding particles/contaminants. PMID- 23100488 TI - Honeybees consolidate navigation memory during sleep. AB - Sleep is known to support memory consolidation in animals, including humans. Here we ask whether consolidation of novel navigation memory in honeybees depends on sleep. Foragers were exposed to a forced navigation task in which they learned to home more efficiently from an unexpected release site by acquiring navigational memory during the successful homing flight. This task was quantified using harmonic radar tracking and applied to bees that were equipped with a radio frequency identification device (RFID). The RFID was used to record their outbound and inbound flights and continuously monitor their behavior inside the colony, including their rest during the day and sleep at night. Bees marked with the RFID behaved normally inside and outside the hive. Bees slept longer during the night following forced navigation tasks, but foraging flights of different lengths did not lead to different rest times during the day or total sleep time during the night. Sleep deprivation before the forced navigation task did not alter learning and memory acquired during the task. However, sleep deprivation during the night after forced navigation learning reduced the probability of returning successfully to the hive from the same release site. It is concluded that consolidation of novel navigation memory is facilitated by night sleep in bees. PMID- 23100489 TI - Body dynamics and hydrodynamics of swimming fish larvae: a computational study. AB - To understand the mechanics of fish swimming, we need to know the forces exerted by the fluid and how these forces affect the motion of the fish. To this end, we developed a 3-D computational approach that integrates hydrodynamics and body dynamics. This study quantifies the flow around a swimming zebrafish (Danio rerio) larva. We used morphological and kinematics data from actual fish larvae aged 3 and 5 days post fertilization as input for a computational model that predicted free-swimming dynamics from prescribed changes in body shape. We simulated cyclic swimming and a spontaneous C-start. A rigorous comparison with 2 D particle image velocimetry and kinematics data revealed that the computational model accurately predicted the motion of the fish's centre of mass as well as the spatial and temporal characteristics of the flow. The distribution of pressure and shear forces along the body showed that thrust is mainly produced in the posterior half of the body. We also explored the effect of the body wave amplitude on swimming performance by considering wave amplitudes that were up to 40% larger or smaller than the experimentally observed value. Increasing the body wave amplitude increased forward swimming speed from 7 to 21 body lengths per second, which is consistent with experimental observations. The model also predicted a non-linear increase in propulsive efficiency from 0.22 to 0.32 while the required mechanical power quadrupled. The efficiency increase was only minor for wave amplitudes above the experimental reference value, whereas the cost of transport rose significantly. PMID- 23100490 TI - Itpr3 Is responsible for the mouse tufted (tf) locus. AB - The tf (tufted) locus is responsible for a classic phenotype of hair loss and regrowth in mice. It is a characteristic of the BTBR strain. Here, we use a combination of positional cloning methods and complementation mapping to identify Itpr3, the inositol triphosphate receptor type 3, as the gene responsible for the tf locus. PMID- 23100491 TI - Bronchial colonisation in patients with lung cancer: a prospective study. AB - Bronchial colonisation is frequently reported in patients with lung cancer, and has a potential impact on therapeutic management and prognosis. We aimed to prospectively define the prevalence and nature of bronchial colonisation in patients at the time of diagnosing lung cancer. 210 consecutive patients with lung cancer underwent a flexible bronchoscopy for lung cancer. The type and frequency of bacterial, mycobacterial and fungal colonisation were analysed and correlated with the patients' and tumours' characteristics. Potential pathogens were found in 48.1% of samples: mainly the Gram-negative bacilli Escherichia coli (8.1%), Haemophilus influenzae (4.3%) and Enterobacter spp. (2.4%); Gram-positive cocci, Staphylococcus spp. (12.9%) and Streptococcus pneumoniae (3.3%); atypical mycobacteria (2.9%); Candida albicans (42.9%); and Aspergillus fumigatus (6.2%). Aged patients (p=0.02) with chronic obstructive pulmonary disease (p=0.008) were significantly more frequently colonised; however, tumour stage, atelectasis, bronchial stenosis and abnormalities of chest radiography were not associated with a higher rate of colonisation. Squamous cell carcinoma tended to be more frequently colonised than other histological subtypes. Airway colonisation was reported in almost half of patients presenting with lung cancer, mainly in fragile patients, and was significantly associated with worse survival (p=0.005). Analysing colonisation status of patients at the time of diagnosis may help improve the management of lung cancer. PMID- 23100492 TI - Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation. AB - The life span of neutrophilic granulocytes has a determining impact on the intensity and duration of neutrophil driven lung inflammation. Based on the compatible solute ectoine, we aimed to prevent anti-apoptotic reactions in neutrophils triggered by the inflammatory microenvironment in the lung. Neutrophils from chronic obstructive pulmonary disease patients and control individuals were exposed to inflammatory mediators and xenobiotics in the presence or absence of ectoine. The in vivo relevance of this approach was tested in xenobiotic-induced lung inflammation in rats. The reduction of apoptosis rates of ex vivo-exposed neutrophils from all study groups was significantly restored in the presence of ectoine. However, natural apoptosis rates not altered by inflammatory stimuli were not changed by ectoine. Mechanistic analyses demonstrated the preventive effect of ectoine on the induction of anti-apoptotic signalling. Neutrophilic lung inflammation induced by single or multiple expositions of animals to environmental particles was reduced after the therapeutic intervention with ectoine. Analyses of neutrophils from bronchoalveolar lavage indicate that the in vivo effect is due to the restoration of neutrophil apoptosis. Ectoine, a compound of the highly compliant group of compatible solutes, demonstrates a reproducible and robust effect on the resolution of lung inflammation. PMID- 23100493 TI - Outpatient versus inpatient treatment in patients with pulmonary embolism: a meta analysis. AB - Our aim was to study the safety of outpatient treatment in low risk patients with acute pulmonary embolism compared with inpatient treatment, the current clinical standard. We searched Medline, Web of Science, Cochrane and EMBASE databases and included studies on outpatient treatment of pulmonary embolism. The outcomes were 3-month recurrent venous thromboembolism, major bleeding and all-cause mortality. We identified 13 studies (1657 patients) with outpatients (discharge <24 h), three studies (256 patients) with early discharge patients (discharged within 72 h) and five studies (383 patients) with inpatients. The pooled incidence of recurrent venous thromboembolism was 1.7% (95% CI 0.92-3.1%) in outpatients, 1.1% (0.22-5.4%) in patients discharged early and 1.2% (0.16-8.1%) in inpatients. The pooled incidence of major bleeding was 0.97% (0.58-1.6%) in outpatients, 0.78% (0.16-3.7%) in early discharge patients and 1.0% (0.39-2.8%) in inpatients. The pooled incidence of mortality was 1.9% (0.79-4.6%) in outpatients, 2.3% (1.1 5.1%) in early discharge patients and 0.74% (0.04-11%) in inpatients. Incidences of recurrent venous thromboembolism, major bleeding and, after correction for malignancies, mortality were comparable between outpatients, patients discharged early and inpatients. We conclude that home treatment or early discharge of selected low-risk patients with pulmonary embolism is as safe as inpatient treatment. PMID- 23100494 TI - Endotoxin levels in homes and classrooms of Dutch school children and respiratory health. AB - Several studies describe indoor pollutant exposure in homes and to a lesser extent in schools. Population studies that include both environments are sparse. This study aims to assess endotoxin levels in primary schools and homes of children. Endotoxin was also studied in relation to asthma and sensitisation. 10 schools with (index) and without (reference) dampness were selected, based on reports and inspections. Cases and controls were selected from 169 homes based on the presence or absence of asthma-like symptoms of children. Classroom and bedroom airborne settled dust was sampled using electrostatic dust fall collectors. Average endotoxin levels in schools ranged from 2178 to 6914 endotoxin units (EU).m(-2) per week compared with 462-1285 EU.m(-2) per week in homes. After mutual adjustment for home and school endotoxin, school endotoxin was positively associated with nonatopic asthma (OR 1.11, 95% CI 0.97-1.27), while no associations with endotoxin were found at home. The high endotoxin levels in schools compared with homes indicate that exposure at school can contribute considerably to environmental endotoxin exposure of children and teachers. Our results also suggest that endotoxin in schools may be associated with nonatopic asthmatic symptoms in pupils, although the results require reproduction because of the modest sample size. PMID- 23100495 TI - Lung clearance index in adult cystic fibrosis patients: the role of convection dependent lung units. AB - We investigated the extent of convective ventilation heterogeneity contributing to the observed lung clearance index values in adult cystic fibrosis patients, as the result of two simulated scenarios, either 1) a fixed part of the lungs becoming increasingly less compliant, or 2) an increasingly greater part of the lung being less compliant. In 25 cystic fibrosis patients and 25 matched controls, we computed the lung clearance index and also quantified curvilinearity of the washout concentration curve, where curvilinearity is equal to 0 (linear in semilog plot) reflects homogeneous ventilation and curvilinearity equal to 1 corresponds to the presence of an infinitesimally slowly emptying lung unit. In the cystic fibrosis group (forced expiratory volume in 1 s 27-100% predicted), lung clearance index and curvilinearity average+/-sd values were 10.3+/-2.3 and 0.57+/-0.13, respectively, and were significantly different from control values (6.2+/-0.4 and 0.18+/-0.07; both p<0.001); lung clearance index and curvilinearity were also correlated (R = 0.67; p<0.001). The average curvilinearity value in the cystic fibrosis group was found to be compatible with a cumulative volume of underventilated lung of 40-50%, depending on the simulation scenario considered. The degree of washout curvilinearity observed here indicates that a major determinant of the abnormal lung clearance index values observed in adult cystic fibrosis patients is ventilation heterogeneity generated between convection-dependent lung units, while the remainder of lung clearance index abnormality with respect to normal controls potentially represents the small airways within these lung zones. PMID- 23100496 TI - Assessing spatial heterogeneity of multidrug-resistant tuberculosis in a high burden country. AB - Multidrug-resistant tuberculosis (MDR-TB) is a major concern in countries of the former Soviet Union. The reported risk of resistance among tuberculosis (TB) cases in the Republic of Moldova is among the highest in the world. We aimed to produce high-resolution spatial maps of MDR-TB risk and burden in this setting. We analysed national TB surveillance data collected between 2007 and 2010 in Moldova. High drug susceptibility testing coverage and detailed location data permitted identification of subregional areas of higher MDR-TB risk. We investigated whether the distribution of cases with MDR-TB risk factors could explain this observed spatial variation in MDR-TB. 3447 MDR-TB cases were notified during this period; 24% of new and 62% of previously treated patients had MDR-TB. Nationally, the estimated annual MDR-TB incidence was 54 cases per 100 000 persons and >1000 cases per 100 000 persons within penitentiaries. We identified substantial geographical variation in MDR-TB burden and hotspots of MDR-TB. Locations with a higher percentage of previously incarcerated TB cases were at greater risk of being MDR-TB hotspots. Spatial analyses revealed striking geographical heterogeneity of MDR-TB. Methods to identify locations of high MDR TB risk and burden should allow for better resource allocation and more appropriate targeting of studies to understand local mechanisms driving resistance. PMID- 23100497 TI - Sleep disordered breathing in patients receiving therapy with buprenorphine/naloxone. AB - Patients using chronic opioids are at risk for exceptionally complex and potentially lethal disorders of breathing during sleep, including central and obstructive apnoeas, hypopnoeas, ataxic breathing and nonapnoeic hypoxaemia. Buprenorphine, a partial MU-opioid agonist with limited respiratory toxicity, is widely used for the treatment of opioid dependency and chronic nonmalignant pain. However, its potential for causing sleep disordered breathing has not been studied. 70 consecutive patients admitted for therapy with buprenorphine/naloxone were routinely evaluated with sleep medicine consultation and attended polysomnography. The majority of patients were young (mean+/-sd age 31.8+/-12.3 years), nonobese (mean+/-sd body mass index 24.9+/-5.9 kg.m(-2)) and female (60%). Based upon the apnoea/hypopnoea index (AHI), at least mild sleep disordered breathing (AHI >=5 events.h(-1)) was present in 63% of the group. Moderate (AHI >=15- <30 events.h(-1)) and severe (AHI >=30 events.h(-1)) sleep apnoea was present in 16% and 17%, respectively. Hypoxaemia, defined as an arterial oxygen saturation measured by pulse oximetry, of <90% for >=10% of sleep time, was present in 27 (38.6%) patients. Despite the putative protective ceiling effect regarding ventilatory suppression observed during wakefulness, buprenorphine may induce significant alterations of breathing during sleep at routine therapeutic doses. PMID- 23100498 TI - Evaluation of co-trimoxazole in the treatment of multidrug-resistant tuberculosis. AB - Co-trimoxazole (SXT), a combination of sulfamethoxazole and trimethoprim, has shown in vitro activity against Mycobacterium tuberculosis. However, the pharmacokinetic and pharmacodynamic parameters of SXT in multidrug-resistant (MDR) tuberculosis (TB) are, thus far, lacking. Therefore, we evaluated its pharmacokinetics and drug susceptibility, along with its tolerability during treatment. Based on drug susceptibility testing, MDR-TB patients received SXT as a part of their MDR treatment. The pharmacokinetic parameters of sulfamethoxazole, the effective component of SXT against M. tuberculosis, were evaluated. The ratio of the area under the curve from 0 to 24 h (AUC0-24) to minimum inhibitory concentration (MIC) was used as the best pharmacokinetic/pharmacodynamic parameter to predict the efficacy of sulfamethoxazole. Adverse effects of SXT were also evaluated. 10 patients with MDR-TB (one of whom had extensively drug-resistant TB) received 480 mg of SXT with a median dosage of 6.5 mg.kg(-1) of SXT (range 6.1-6.8 mg.kg(-1)) once daily for a median treatment period of 381 days (range 129-465 days). In two patients, the dose was escalated to 960 mg. The free AUC0-24/MIC of sulfamethoxazole exceeded 25 in only one patient. SXT was safe and well-tolerated, except for one patient who had gastrointestinal side-effects after receiving 960 mg of SXT. Additional studies are needed to find the pharmacokinetic and pharmacodynamic targets, and consequently to set the optimal dose, of SXT for MDR-TB treatment. PMID- 23100500 TI - The pathogenesis of pulmonary fibrosis: a moving target. AB - Pulmonary fibrosis is the end stage of many diffuse parenchymal lung diseases. It is characterised by excessive matrix formation leading to destruction of the normal lung architecture and finally death. Despite an exponential increase in our understanding of potentially important mediators and mechanisms, the delineation of primary pathways has proven to be elusive. In this review susceptibility and injurious agents, such as viruses and gastro-oesophageal reflux, and their probable role in initiating disease will be discussed. Further topics that are elaborated are candidate ancillary pathways, including immune mechanisms, oxidative and endoplasmic reticulum stress, activation of the coagulation cascade and the potential role of stem cells. This review will try to provide the reader with an integrated view on the current knowledge and attempts to provide a road map for future research. It is important to explore robust models of overall pathogenesis, reconciling a large number of clinical and scientific observations. We believe that the integration of current data into a "big picture" overview of fibrogenesis is essential for the development of effective antifibrotic strategies. The latter will probably consist of a combination of agents targeting a number of key pathways. PMID- 23100501 TI - Noninvasive cardiac output measurements in patients with pulmonary hypertension. AB - Pulmonary hypertension (PH) is characterised by a progressive decline in cardiac output (CO) and right heart failure. NICOM(r) (noninvasive cardiac output monitor) is a bioreactance-based technology that has been broadly validated, but its specific application in right heart failure and PH is unknown. Cardiac catheterisation was performed in 50 consecutive patients with PH. CO measurements were performed using three different methods (thermodilution, Fick and NICOM) at baseline and after vasodilator challenge. We compared the precision (coefficient of variation) and accuracy of NICOM compared to thermodilution and Fick. The mean CO (L.min(-1)) at baseline as measured by the three methods was 4.73+/-1.15 (NICOM), 5.69+/-1.74 (thermodilution) and 4.84+/-1.39 (Fick). CO measured by NICOM was more precise than by thermodilution (3.5+/-0.3% versus 9.6+/-6.1%, p<0.001). Bland-Altman analyses comparing NICOM to thermodilution and Fick revealed bias and 95% limits of agreement that were comparable to those comparing Fick to thermodilution. All three CO methods detected an increase in CO in response to vasodilator challenge. CO measured via NICOM is precise and reliably measures CO at rest and changes in CO with vasodilator challenge in patients with PH. NICOM may allow for the noninvasive haemodynamic assessment of patients with PH and their response to therapy. PMID- 23100502 TI - Haemodynamics, exercise capacity and clinical events in pulmonary arterial hypertension. AB - The purpose of this study was to clarify whether changes in cardiopulmonary haemodynamics induced by pharmacological therapy correlate with exercise capacity and clinical events in patients with pulmonary arterial hypertension. 16 randomised trials including 2353 patients, followed up for 16.4+/-10.6 weeks, measuring cardiopulmonary haemodynamics by right heart catheterisation and reporting clinical events were included. Meta-analysis and meta-regression analysis were performed to assess the effects of treatments on clinical events and the relationship between haemodynamic changes (pulmonary artery pressure, pulmonary vascular resistance, cardiac index and right atrial pressure) and clinical events. Treatments significantly reduced all-cause death (OR 0.5, 95% CI 0.3-0.7; p<0.01), hospitalisation for pulmonary arterial hypertension (OR 0.4, 95% CI 0.2-0.7; p<0.01), initiation of rescue therapy (OR 0.3, 95% CI 0.2-0.6; p<0.01) and the composite outcome (OR 0.3, 95% CI 0.3-0.5; p<0.01). No relationship was found between changes of haemodynamic parameters and clinical events, whereas changes of cardiac index and pulmonary vascular resistance significantly correlated with changes in the 6-min walking distance (r = 0.64, p = 0.03; r = -0.55, p = 0.04, respectively). In patients with pulmonary arterial hypertension, improvements of cardiopulmonary haemodynamics observed in randomised clinical trials correlate with exercise capacity changes but do not predict clinical events in a short-term follow-up. PMID- 23100499 TI - Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. AB - A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens. PMID- 23100503 TI - Detection of obstructive sleep apnoea by an electronic nose. AB - Diagnosis of obstructive sleep apnoea syndrome (OSAS) is technically demanding, cost-intensive and time-consuming. The measurement of volatile organic compounds by an electronic nose is an innovative method that determines distinct molecular patterns of exhaled breath in different patient groups. We addressed the following questions: What is the diagnostic accuracy of an electronic nose in the detection of OSAS and the ability to detect effects of standard therapy in patients with OSAS? Are these results related to changes in distinct markers of airway inflammation and extracellular remodelling? We included 40 OSAS patients and 20 healthy controls. Exhaled breath of all participants was analysed using the Cyranose 320 electronic nose. Pharyngeal washings were performed to sample the upper airway compartment. For statistical analysis linear discriminant analysis was employed. We identified a linear discriminant function separating OSAS from control (p<0.0001). The corresponding area under the receiver-operating curve was 0.85 (95% CI 0.75-0.96; sensitivity 0.93 and specificity 0.7). In pharyngeal washing fluids of OSAS patients, we observed higher levels of alpha1 antitrypsin and markers of extracellular remodelling compared to controls. The electronic nose can distinguish between OSAS patients and controls with high accuracy. PMID- 23100504 TI - Cell cycle dependence of ACE-2 explains downregulation in idiopathic pulmonary fibrosis. AB - Alveolar epithelial type II cells, a major source of angiotensin-converting enzyme (ACE)-2 in the adult lung, are normally quiescent but actively proliferate in lung fibrosis and downregulate this protective enzyme. It was, therefore, hypothesised that ACE-2 expression might be related to cell cycle progression. To test this hypothesis, ACE-2 mRNA levels, protein levels and enzymatic activity were examined in fibrotic human lungs and in the alveolar epithelial cell lines A549 and MLE-12 studied at postconfluent (quiescent) versus subconfluent (proliferating) densities. ACE-2 mRNA, immunoreactive protein and enzymatic activity were all high in quiescent cells, but were severely downregulated or absent in actively proliferating cells. Upregulation of the enzyme in cells that were progressing to quiescence was completely inhibited by the transcription blocker actinomycin D or by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). In lung biopsy specimens obtained from patients with idiopathic pulmonary fibrosis, immunoreactive enzyme was absent in alveolar epithelia that were positive for proliferation markers, but was robustly expressed in alveolar epithelia devoid of proliferation markers. These data explain the loss of ACE-2 in lung fibrosis and demonstrate cell cycle-dependent regulation of this protective enzyme by a JNK-mediated transcriptional mechanism. PMID- 23100505 TI - Sinonasal inflammation in COPD: a systematic review. AB - In this review, we demonstrate that patients with chronic obstructive pulmonary disease (COPD) frequently report sinonasal symptoms. Furthermore, we present evidence that smoking on its own can cause nasal disease and that, in COPD patients, nasal inflammation mimics that of the bronchi. All this evidence suggests that COPD-related sinonasal disease does exist and that smoking on its own rather than systemic inflammation triggers the condition. However, COPD related sinonasal disease remains to be characterised in terms of symptoms and endoscopic findings. In addition, more studies are needed to quantify the negative impact of sinonasal symptoms on the quality of life in COPD patients. PMID- 23100506 TI - Serodiagnosis of Mycobacterium avium complex pulmonary disease in the USA. AB - Diagnosis of Mycobacterium avium complex pulmonary disease (MAC-PD) can be difficult. A previous study from Japan reported the usefulness of a serodiagnostic test for MAC-PD. The objective of this study was to evaluate the usefulness of the test in similar patients in the USA. 100 patients with known or suspected MAC-PD and 52 healthy volunteers were enrolled into the study at National Jewish Health, Denver, CO, USA. Serum glycopeptidolipid core immunoglobulin A antibody levels were measured with an enzyme immunoassay (EIA) kit and routine clinical evaluations were performed. The patients were divided into two groups based on clinical evaluation: 87 patients with MAC-PD that met American Thoracic Society criteria, and 13 who did not meet the criteria. The sensitivity and specificity (cut-off point 0.3 U.mL(-1)) of the serodiagnostic test for diagnosing MAC-PD were 70.1% and 93.9%, respectively. Among the 44 patients in the MAC-PD group with two or more positive sputum cultures within the previous 6 months, sensitivity was 81.8%. The EIA kit demonstrated good sensitivity and specificity for the identification of MAC-PD, particularly in patients with two or more positive cultures, and may be useful for rapid MAC-PD diagnosis. PMID- 23100507 TI - Effects of inpatient pulmonary rehabilitation in patients with interstitial lung disease. AB - Pulmonary rehabilitation is recommended for patients with chronic lung diseases including idiopathic pulmonary fibrosis according to international guidelines. However, data for patients with interstitial lung disease (ILD) are limited. We examined the effect of an inpatient pulmonary rehabilitation on functional status and quality of life in ILD patients. We evaluated 402 consecutive ILD patients who were admitted to a specialised pulmonary rehabilitation centre (1999-2010). All patients performed a standardised pulmonary rehabilitation programme including pulmonary function tests, blood-gas analysis, 6-min walk test (6MWT), dyspnoea rating and health-related quality of life questionnaire (the 36-item short-form health survey; SF-36) on admission and discharge. Mean duration of pulmonary rehabilitation was 30+/-1 days. 6MWT distance improved by 46+/-3 m (308+/-6 m versus 354+/-6 m; p<0.001). Dyspnoea rating did not change. Lung function testing showed marginal improvement of vital capacity (+1+/-0%; p = 0.002). The SF-36 questionnaire demonstrated an increase in all eight sub-scores as well as in the physical and mental health summary scores (physical 6+/-1 points, p<0.001; mental health 10+/-1 points, p<0.001). Moreover, patients with signs of pulmonary hypertension also benefited from pulmonary rehabilitation. In a large cohort of patients with ILD, pulmonary rehabilitation had a positive impact on functional status and quality of life. Considering the limited treatment options in this patient population pulmonary rehabilitation appears to be a valuable adjunct therapy. PMID- 23100508 TI - Repeatability and responsiveness of exercise tests in pulmonary arterial hypertension. AB - Exercise tolerance in pulmonary arterial hypertension (PAH) is most commonly assessed by the 6-min walk test (6MWT). Whether endurance exercise tests are more responsive than the 6MWT remains unknown. 20 stable PAH patients (mean+/-sd age 53+/-15 years and mean pulmonary arterial pressure 44+/-16 mmHg) already on PAH monotherapy completed the 6MWT, the endurance shuttle walk test (ESWT) and the cycle endurance test (CET) before and after the addition of sildenafil citrate 20 mg three times daily or placebo for 28 days in a randomised double-blind crossover setting. Pre- or post-placebo tests were used to assess repeatability of each exercise test, whereas pre- or post-sildenafil citrate tests were used to assess their responsiveness. Sildenafil citrate led to placebo-corrected changes in exercise capacity of 18+/-25 m (p = 0.02), 58+/-235 s (p = 0.58) and 29+/-77 s (p = 0.09) for the 6MWT, the ESWT and the CET, respectively. The 6MWT was associated with a lower coefficient of variation between repeated measures (3% versus 18% versus 13%), resulting in a higher standardised response mean compared with endurance tests (0.72, 0.25 and 0.38 for the 6MWT, the ESWT and the CET, respectively). The 6MWT had the best ability to capture changes in exercise capacity when sildenafil citrate was combined with patients' baseline monotherapy, supporting its use as an outcome measure in PAH. PMID- 23100509 TI - Bronchiolar epithelial catalase is diminished in smokers with mild COPD. AB - This study aimed to investigate bronchiolar catalase expression and its relationship with smoking and/or chronic obstructive pulmonary disease (COPD) in humans and to determine the dynamic change of bronchiolar catalase expression in response to cigarette smoke in mice. Lung tissue was obtained from 36 subjects undergoing surgery for peripheral tumours, consisting of life-long nonsmokers and smokers with or without COPD. Male C57BL/6 mice were subjected to cigarette smoke exposure for up to 3 months followed by a 28-day cessation period. We quantified bronchiolar catalase mRNA using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction. C22 club cells (Clara cells) in culture were exposed to cigarette smoke extract and monitored for viability when catalase expression was decreased by siRNA. Catalase was decreased at mRNA and protein levels in bronchiolar epithelium in smokers with COPD. In mice, bronchiolar catalase is temporarily upregulated at 1 day after cigarette smoke exposure but is downregulated by repeated cigarette smoke exposure, and is not restored long after withdrawal once emphysema is developed. Decreasing catalase expression in C22 cells resulted in greater cigarette smoke extract-induced cell death. Bronchiolar catalase reduction is associated with COPD. Regulation of catalase depends on the duration of cigarette smoke exposure, and plays a critical role for protection against cigarette smoke-induced cell damage. PMID- 23100510 TI - Influence of perfusate temperature on nasal potential difference. AB - Nasal potential difference (NPD) quantifies abnormal ion transport in cystic fibrosis. It has gained acceptance as an outcome measure for the investigation of new therapies. To quantify the effect of solution temperature on NPD, we first examined the effect of switching from room temperature (20-25 degrees C) to warmed (32-37 degrees C) solutions and vice versa during each perfusion step. Secondly, standard protocols were repeated at both temperatures in the same subjects. Changing solution temperature did not alter NPD during perfusion with Ringer's solution (<1 mV) (p>0.1). During perfusion with zero chloride solution, changing from room temperature to warmed solutions tended to decrease absolute NPD (i.e. it became less negative) by 0.9 mV (p>0.1); changing from warmed to room temperature increased NPD by 2.1 mV (p<0.05). During isoprenaline perfusion, changing from room temperature to warmed solutions increased NPD by 1.5 mV (p<0.01) and from warmed to room temperature decreased NPD by 1.4 mV (p<0.05). For full protocols at room temperature or warmed in the same subjects, mean values were similar (n = 24). During warmed perfusion, group results for total chloride response had a larger standard deviation. As this increased variability will probably decrease the power of trials, this study suggests that solutions at room temperature should be recommended for the measurement of NPD. PMID- 23100511 TI - ATP-binding cassette transporter G1 intrinsically regulates invariant NKT cell development. AB - ATP-binding cassette transporter G1 (ABCG1) plays a role in the intracellular transport of cholesterol. Invariant NKT (iNKT) cells are a subpopulation of T lymphocytes that recognize glycolipid Ags. In this study, we demonstrate that ABCG1 regulates iNKT cell development and functions in a cell-intrinsic manner. Abcg1(-/-) mice displayed reduced frequencies of iNKT cells in thymus and periphery. Thymic iNKT cells deficient in ABCG1 had reduced membrane lipid raft content, and showed impaired proliferation and defective maturation during the early stages of development. Moreover, we found that Abcg1(-/-) mice possess a higher frequency of Vbeta7(+) iNKT cells, suggesting alterations in iNKT cell thymic selection. Furthermore, in response to CD3epsilon/CD28 stimulation, Abcg1( /-) thymic iNKT cells showed reduced production of IL-4 but increased production of IFN-gamma. Our results demonstrate that changes in intracellular cholesterol homeostasis by ABCG1 profoundly impact iNKT cell development and function. PMID- 23100512 TI - Blockade of myeloid-derived suppressor cells after induction of lymphopenia improves adoptive T cell therapy in a murine model of melanoma. AB - Administration of nonmyeloablative chemotherapeutic agents or total body irradiation (TBI) prior to adoptive transfer of tumor-specific T cells may reduce or eliminate immunosuppressive populations such as T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSC). Little is known about these populations during immune reconstitution. This study was designed to understand the reconstitution rate and function of these populations post TBI in melanoma tumor bearing mice. Reconstitution rate and suppressive activity of CD4(+)CD25(+)Foxp3(+) Tregs and CD11b(+)Gr1(+) MDSC following TBI-induced lymphopenia was measured in B16 melanoma tumor-bearing mice. To ablate the rapid reconstitution of suppressive populations, we treated mice with docetaxel, a known chemotherapeutic agent that targets MDSC, in combination with adoptive T cell transfer and dendritic cell immunotherapy. Both Treg and MDSC populations exhibited rapid reconstitution after TBI-induced lymphopenia. Although reconstituted Tregs were just as suppressive as Tregs from untreated mice, MDSC demonstrated enhanced suppressive activity of CD8(+) T cell proliferation compared with endogenous MDSC from tumor-bearing mice. TBI-induced lymphopenia followed by docetaxel treatment improved the efficacy of adoptive T cell transfer and dendritic cell immunotherapy in melanoma-bearing mice, inducing a significant reduction in tumor growth and enhancing survival. Tumor regression correlated with increased CTL activity and persistence of adoptively transferred T cells. Overall, these findings suggest that TBI-induced MDSC are highly immunosuppressive and blocking their rapid reconstitution may improve the efficacy of vaccination strategies and adoptive immunotherapy. PMID- 23100513 TI - Cutting edge: nitric oxide inhibits the NLRP3 inflammasome. AB - Although the NLRP3 inflammasome plays a pivotal role in host defense, its uncontrolled activation is associated with inflammatory disorders, suggesting that regulation of the inflammasome is important to prevent detrimental effects. Type I IFNs and long-term LPS stimulation were shown to negatively regulate NLRP3 activation. In this study, we found that endogenous NO is involved in the regulation of NLRP3 inflammasome activation by either IFN-beta pretreatment or long-term LPS stimulation. Furthermore, S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, markedly inhibited NLRP3 inflammasome activation, whereas the AIM2 and NLRC4 inflammasomes were only partially inhibited by SNAP. An increase in mitochondrial reactive oxygen species induced by ATP was only modestly affected by SNAP treatment. Interestingly, S-nitrosylation of NLRP3 was detected in macrophages treated with SNAP, and this modification may account for the NO mediated mechanism controlling inflammasome activation. Taken together, these results revealed a novel role for NO in regulating the NLRP3 inflammasome. PMID- 23100515 TI - Impact of epidermal growth factor receptor (EGFR) cell surface expression levels on effector mechanisms of EGFR antibodies. AB - The epidermal growth factor receptor (EGFR) is a widely expressed Ag that is successfully targeted in tumor patients by mAbs or tyrosine kinase inhibitors. A clinical study in non-small cell lung cancer patients demonstrated a positive correlation between EGFR expression levels and the therapeutic efficacy of the EGFR mAb cetuximab. However, the impact of EGFR expression on the different mechanisms of action (MoAs) triggered by the EGFR mAb has not been defined. In this study, BHK-21 cells were stably transfected to express different EGFR levels, which were quantified by immunofluorescence and immunohistochemistry and compared with EGFR levels of clinical non-small cell lung cancer samples. These cells were used to systematically investigate the impact of target Ag expression levels on Fab- or Fc-mediated MoAs of EGFR mAb. A negative correlation between EGFR levels and potency of Fab-mediated MoA was observed. Interestingly, Ab dependent cell-mediated cytotoxicity (ADCC) by NK cells, monocytes, or polymorphonuclear cells as well as complement-dependent cytotoxicity positively correlated with the number of EGFR molecules. In comparison with ADCC by mononuclear cells, polymorphonuclear cell-mediated ADCC and complement-dependent cytotoxicity required higher EGFR expression levels and higher mAb concentrations to trigger significant tumor cell killing. This correlation between EGFR expression levels and Fc-mediated MoA was confirmed in an independent panel of human tumor cell lines carrying diverse genetic alterations. Furthermore, RNA interference-induced knockdown experiments reinforced the impact of EGFR expression on tumor cell killing by EGFR mAb. In conclusion, these results suggest that EGFR expression levels may determine distinct patterns of MoAs that contribute to the therapeutic efficacy of EGFR mAb. PMID- 23100514 TI - Abl family kinases regulate FcgammaR-mediated phagocytosis in murine macrophages. AB - Phagocytosis of Ab-coated pathogens is mediated through FcgammaRs, which activate intracellular signaling pathways to drive actin cytoskeletal rearrangements. Abl and Arg define a family of nonreceptor tyrosine kinases that regulate actin dependent processes in a variety of cell types, including those important in the adaptive immune response. Using pharmacological inhibition as well as dominant negative and knockout approaches, we demonstrate a role for the Abl family kinases in phagocytosis by macrophages and define a mechanism whereby Abl kinases regulate this process. Bone marrow-derived macrophages from mice lacking Abl and Arg kinases exhibit inefficient phagocytosis of sheep erythrocytes and zymosan particles. Treatment with the Abl kinase inhibitors imatinib and GNF-2 or overexpression of kinase-inactive forms of the Abl family kinases also impairs particle internalization in murine macrophages, indicating Abl kinase activity is required for efficient phagocytosis. Further, Arg kinase is present at the phagocytic cup, and Abl family kinases are activated by FcgammaR engagement. The regulation of phagocytosis by Abl family kinases is mediated in part by the spleen tyrosine kinase (Syk). Loss of Abl and Arg expression or treatment with Abl inhibitors reduced Syk phosphorylation in response to FcgammaR ligation. The link between Abl family kinases and Syk may be direct, as purified Arg kinase phosphorylates Syk in vitro. Further, overexpression of membrane-targeted Syk in cells treated with Abl kinase inhibitors partially rescues the impairment in phagocytosis. Together, these findings reveal that Abl family kinases control the efficiency of phagocytosis in part through the regulation of Syk function. PMID- 23100516 TI - Dynamics of CD4(+) T cell responses against Listeria monocytogenes. AB - The generation of CD4(+) T cell memory cells is poorly understood. Recently, two different murine CD4(+) TCR transgenic T cell lines, LLO118 and LLO56, both specific for the same epitope but differing in their expression level of the cell surface protein CD5, were generated. Notably, these cell lines showed different behavior upon primary and secondary exposure to Listeria monocytogenes. Whereas LLO118 showed a stronger primary response and generated more robust CD8(+) T cell help upon secondary exposure, LLO56 CD4(+) T cells had a dramatically better recall response. Using different mathematical models, we analyzed the dynamics of the two CD4(+) T cell lines in mice during infection with L. monocytogenes. Our models allowed the quantitative comparison of the two T cell lines and provided predictions for the conversion of naive T cells into memory cells. LLO118 CD4(+) T cells are estimated to have a higher proliferation rate than LLO56 CD4(+) T cells upon primary exposure. This difference can be explained by the lower expression level of CD5 on LLO118 CD4(+) T cells. Furthermore, LLO56 memory cells are predicted to have a 3-fold longer half-life than LLO118 memory cells ($${t}_{1/2}^{?hbox{ LLO }118}$$ ~ 4.3 to 5 d and $${t}_{1/2}^{?hbox{ LLO }56}$$ ~ 11.5 to 13.9 d). Although both cell lines differ in their memory capabilities, our analysis indicates no difference in the rate at which memory cells are generated. Our results show that different CD5 expression levels influence the proliferation dynamics of activated naive CD4(+) T cells while leaving the conversion rate of those cells into memory cells unaffected. PMID- 23100519 TI - Identification of an MHC class I ligand for the single member of a killer cell lectin-like receptor family, KLRH1. AB - Natural killer cells are able to recognize and kill target cells according to differences in MHC class I expression. In rodents, the Ly49 receptors are primarily responsible for this MHC differentiation. We previously described the cloning of a novel C-type lectin-like receptor, KLRH1, encoded in the NK complex adjacent to the Ly49 genes and expressed by subsets of NK and NKT cells. MHC influence on selection of KLRH1(+) NK cells in congenic strains suggested that KLRH1 may have an MHC ligand, although we were unable to identify any such ligand. In this study, we have used a sensitive reporter system and Fc fusion protein to demonstrate that KLRH1 binds specifically to the classical MHC class I molecule RT1-A2 of the RT1(n) haplotype. Cytolytic activity of KLRH1-transfected RNK-16 cells was also inhibited by target cells expressing RT1-A2(n). Thus, KLRH1 represents a novel family of MHC allele-specific inhibitory receptors expressed by NK cells. PMID- 23100517 TI - HIV-1 gp120 impairs the induction of B cell responses by TLR9-activated plasmacytoid dendritic cells. AB - Plasmacytoid dendritic cells (pDCs) play a central role in innate and adaptive immune responses to viral infections, including HIV type 1 (HIV-1). pDCs produce substantial quantities of type I IFN and proinflammatory cytokines upon stimulation via TLRs, specifically TLR7 or TLR9. The HIV-1 envelope glycoproteins, exemplified by the gp120 monomer, are the focus of vaccines aimed at inducing B cell responses. We have studied how the interactions of gp120 with various receptors on human pDCs affect the activation of these cells via TLR9 and their subsequent ability to stimulate B cells. We observed that IFN-alpha production by pDCs in response to TLR9, but not TLR7, stimulation was reduced by exposure to gp120. Specifically, gp120 inhibited the CpG-induced maturation of pDCs and their expression of TNF-alpha, IL-6, TLR9, IFN regulatory factor 7, and BAFF. Receptor-blocking and cross-linking studies showed that these inhibitory effects of gp120 were mediated by interactions with CD4 and mannose-binding C type lectin receptors, but not with the chemokine receptors CCR5 and CXCR4. Of note is that gp120 inhibited the activation of B cells by TLR9-stimulated pDCs. Taken together, our data show that HIV-1 gp120 impairs pDC functions, including activation of B cell responses, and imply that TLR9 ligands may not be good adjuvants to use in combination with envelope glycoprotein vaccines. PMID- 23100520 TI - Time to talk about timing--when to start, stop and change anti-migratory drugs in MS. PMID- 23100518 TI - Prolonged neutrophil dysfunction after Plasmodium falciparum malaria is related to hemolysis and heme oxygenase-1 induction. AB - It is not known why people are more susceptible to bacterial infections such as nontyphoid Salmonella during and after a malaria infection, but in mice, malarial hemolysis impairs resistance to nontyphoid Salmonella by impairing the neutrophil oxidative burst. This acquired neutrophil dysfunction is a consequence of induction of the cytoprotective, heme-degrading enzyme heme oxygenase-1 (HO-1) in neutrophil progenitors in bone marrow. In this study, we assessed whether neutrophil dysfunction occurs in humans with malaria and how this relates to hemolysis. We evaluated neutrophil function in 58 Gambian children with Plasmodium falciparum malaria [55 (95%) with uncomplicated disease] and examined associations with erythrocyte count, haptoglobin, hemopexin, plasma heme, expression of receptors for heme uptake, and HO-1 induction. Malaria caused the appearance of a dominant population of neutrophils with reduced oxidative burst activity, which gradually normalized over 8 wk of follow-up. The degree of neutrophil impairment correlated significantly with markers of hemolysis and HO-1 induction. HO-1 expression was increased in blood during acute malaria, but at a cellular level HO-1 expression was modulated by changes in surface expression of the haptoglobin receptor (CD163). These findings demonstrate that neutrophil dysfunction occurs in P. falciparum malaria and support the relevance of the mechanistic studies in mice. Furthermore, they suggest the presence of a regulatory pathway to limit HO-1 induction by hemolysis in the context of infection and indicate new targets for therapeutic intervention to abrogate the susceptibility to bacterial infection in the context of hemolysis in humans. PMID- 23100521 TI - Assessing spinal cord function in multiple sclerosis with functional neuroimaging: insights and limitations. PMID- 23100522 TI - EDSS improvement: recovery of function or noise? PMID- 23100523 TI - Treat patients with radiologically isolated syndrome when the MRI brain scan shows dissemination in time: no. PMID- 23100524 TI - Treat patients with radiologically isolated syndrome when the MRI brain scan shows dissemination in time: yes. PMID- 23100525 TI - Treat patients with radiologically isolated syndrome when the MRI brain scan shows dissemination in time: commentary. PMID- 23100526 TI - Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. AB - Clinical and/or neuroimaging evidence of disease reactivation has been described in multiple sclerosis (MS) patients after a break from natalizumab. Whether fingolimod might be a therapeutic option following natalizumab needs to be evaluated. Twenty-two relapsing remitting MS patients having JC virus antibodies (JCVAb+) in serum were shifted from natalizumab to fingolimod after a three-month washout period. Neurological evaluation with the Expanded Disability Status Scale (EDSS) was performed monthly for a mean follow-up period of nine months. In 20/22 patients, brain magnetic resonance imaging (MRI) was obtained within one month after therapy initiation. Disease reactivation was observed in 11/22 (50%) patients: clinical relapses in six patients (four patients within the first month of therapy) and MRI activity in a further five patients (three patients within the first month of therapy). Clinical and/or MRI signs suggestive of disease rebound were observed in three patients. Our data indicate that fingolimod does not exert clinical activity quickly enough to stop MS reactivation after a break from natalizumab. PMID- 23100527 TI - Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. AB - In this report we describe a multiple sclerosis patient who developed a relapse with magnetic resonance imaging (MRI) features of tumefactive demyelination after switching therapy from natalizumab to fingolimod. Tumefactive lesions emerged 16 weeks after stopping natalizumab and eight weeks after commencing fingolimod therapy but had been absent at the time of diagnosis and throughout the preceding course of the disease. Thus, the first-time occurrence of atypical lesion features may have been caused by the change in immunotherapy. The possible relevance of natalizumab withdrawal vs fingolimod introduction is discussed against the background of recently published case studies. PMID- 23100528 TI - Response to GS Gronseth and E Ashman. PMID- 23100530 TI - Food safety for the solid organ transplant patient: preventing foodborne illness while on chronic immunosuppressive drugs. AB - Issues regarding food safety are seen increasingly in the news; outbreaks of foodborne illness have been associated with public health concerns ranging from mild illness to death. For the solid organ transplant patient, immunosuppressive and antibacterial drugs, which maintain transplant organ function, can expose the transplant patient to increased risk of foodborne illness from bacteria, viruses, fungi, and parasites. This review article describes the clinical consequences, sources of foodborne illness, and food safety practices needed to minimize risks to the solid organ transplant patient who must take lifelong immunosuppressive drugs. All members of the transplant team share responsibility for education of the solid organ transplant patient in preventing infections. The registered dietitian, as part of the transplant team, is the recognized expert in providing food safety education in the context of medical nutrition therapy to solid organ transplant patients, the patients' caregivers, and other healthcare providers. PMID- 23100532 TI - Kinetics and thermodynamics of binding reactions as exemplified by anthrax toxin channel blockage with a cationic cyclodextrin derivative. AB - The thermodynamics of binding reactions is usually studied in the framework of the linear van't Hoff analysis of the temperature dependence of the equilibrium constant. The logarithm of the equilibrium constant is plotted versus inverse temperature to discriminate between two terms: an enthalpic contribution that is linear in the inverse temperature, and a temperature-independent entropic contribution. When we apply this approach to a particular case-blockage of the anthrax PA(63) channel by a multicharged cyclodextrin derivative-we obtain a nearly linear behavior with a slope that is characterized by enthalpy of about 1 kcal/mol. In contrast, from blocker partitioning between the channel and the bulk, we estimate the depth of the potential well for the blocker in the channel to be at least 8 kcal/mol. To understand this apparent discrepancy, we use a simple model of particle interaction with the channel and show that this significant difference between the two estimates is due to the temperature dependence of the physical forces between the blocker and the channel. In particular, we demonstrate that if the major component of blocker-channel interaction is van der Waals interactions and/or Coulomb forces in water, the van't Hoff enthalpy of the binding reaction may be close to zero or even negative, including cases of relatively strong binding. The results are quite general and, therefore, of importance for studies of enzymatic reactions, rational drug design, small-molecule binding to proteins, protein-protein interactions, and protein folding, among others. PMID- 23100531 TI - Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. AB - Although macrophages are widely recognized to have a profibrotic role in inflammation, we have used a highly tractable CCl(4)-induced model of reversible hepatic fibrosis to identify and characterize the macrophage phenotype responsible for tissue remodeling: the hitherto elusive restorative macrophage. This CD11B(hi) F4/80(int) Ly-6C(lo) macrophage subset was most abundant in livers during maximal fibrosis resolution and represented the principle matrix metalloproteinase (MMP) -expressing subset. Depletion of this population in CD11B promoter-diphtheria toxin receptor (CD11B-DTR) transgenic mice caused a failure of scar remodeling. Adoptive transfer and in situ labeling experiments showed that these restorative macrophages derive from recruited Ly-6C(hi) monocytes, a common origin with profibrotic Ly-6C(hi) macrophages, indicative of a phenotypic switch in vivo conferring proresolution properties. Microarray profiling of the Ly-6C(lo) subset, compared with Ly-6C(hi) macrophages, showed a phenotype outside the M1/M2 classification, with increased expression of MMPs, growth factors, and phagocytosis-related genes, including Mmp9, Mmp12, insulin-like growth factor 1 (Igf1), and Glycoprotein (transmembrane) nmb (Gpnmb). Confocal microscopy confirmed the postphagocytic nature of restorative macrophages. Furthermore, the restorative macrophage phenotype was recapitulated in vitro by the phagocytosis of cellular debris with associated activation of the ERK signaling cascade. Critically, induced phagocytic behavior in vivo, through administration of liposomes, increased restorative macrophage number and accelerated fibrosis resolution, offering a therapeutic strategy to this orphan pathological process. PMID- 23100533 TI - Anthrax toxin protective antigen integrates poly-gamma-D-glutamate and pH signals to sense the optimal environment for channel formation. AB - Many toxins assemble into oligomers on the surface of cells. Local chemical cues signal and trigger critical rearrangements of the oligomer, inducing the formation of a membrane-fused or channel state. Bacillus anthracis secretes two virulence factors: a tripartite toxin and a poly-gamma-d-glutamic acid capsule (gamma-DPGA). The toxin's channel-forming component, protective antigen (PA), oligomerizes to create a prechannel that forms toxic complexes upon binding the two other enzyme components, lethal factor (LF) and edema factor (EF). Following endocytosis into host cells, acidic pH signals the prechannel to form the channel state, which translocates LF and EF into the host cytosol. We report gamma-DPGA binds to PA, LF, and EF, exhibiting nanomolar avidity for the PA prechannel oligomer. We show PA channel formation requires the pH-dependent disruption of the intra-PA domain-2-domain-4 (D2-D4) interface. gamma-DPGA stabilizes the D2-D4 interface, preventing channel formation both in model membranes and cultured mammalian cells. A 1.9-A resolution X-ray crystal structure of a D2-D4-interface mutant and corresponding functional studies reveal how stability at the intra-PA interface governs channel formation. We also pinpoint the kinetic pH trigger for channel formation to a residue within PA's membrane-insertion loop at the inter PA D2-D4 interface. Thus, gamma-DPGA may function as a chemical cue, signaling that the local environment is appropriate for toxin assembly but inappropriate for channel formation. PMID- 23100534 TI - Polygamous particles. AB - DNA is increasingly used as an important tool in programming the self-assembly of micrometer- and nanometer-scale particles. This is largely due to the highly specific thermoreversible interaction of cDNA strands, which, when placed on different particles, have been used to bind precise pairs in aggregates and crystals. However, DNA functionalized particles will only reach their true potential for particle assembly when each particle can address and bind to many different kinds of particles. Indeed, specifying all bonds can force a particular designed structure. In this paper, we present the design rules for multiflavored particles and show that a single particle, DNA functionalized with many different "flavors," can recognize and bind specifically to many different partners. We investigate the cost of increasing the number of flavors in terms of the reduction in binding energy and melting temperature. We find that a single 2-MUm colloidal particle can bind to 40 different types of particles in an easily accessible time and temperature regime. The practical limit of ~100 is set by entropic costs for particles to align complementary pairs and, surprisingly, by the limited number of distinct "useful" DNA sequences that prohibit subunits with nonspecific binding. For our 11 base "sticky ends," the limit is 73 distinct sequences with no unwanted overlaps of 5 bp or more. As an example of phenomena enabled by polygamous particles, we demonstrate a three-particle system that forms a fluid of isolated clusters when cooled slowly and an elastic gel network when quenched. PMID- 23100535 TI - Crystal structure of the Leishmania major peroxidase-cytochrome c complex. AB - The causative agent of leishmaniasis is the protozoan parasite Leishmania major. Part of the host protective mechanism is the production of reactive oxygen species including hydrogen peroxide. In response, L. major produces a peroxidase, L. major peroxidase (LmP), that helps to protect the parasite from oxidative stress. LmP is a heme peroxidase that catalyzes the peroxidation of mitochondrial cytochrome c. We have determined the crystal structure of LmP in a complex with its substrate, L. major cytochrome c (LmCytc) to 1.84 A, and compared the structure to its close homolog, the yeast cytochrome c peroxidase-cytochrome c complex. The binding interface between LmP and LmCytc has one strong and one weak ionic interaction that the yeast system lacks. The differences between the steady state kinetics correlate well with the Lm redox pair being more dependent on ionic interactions, whereas the yeast redox pair depends more on nonpolar interactions. Mutagenesis studies confirm that the ion pairs at the intermolecular interface are important to both k(cat) and K(M). Despite these differences, the electron transfer path, with respect to the distance between hemes, along the polypeptide chain is exactly the same in both redox systems. A potentially important difference, however, is the side chains involved. LmP has more polar groups (Asp and His) along the pathway compared with the nonpolar groups (Leu and Ala) in the yeast system, and as a result, the electrostatic environment along the presumed electron transfer path is substantially different. PMID- 23100536 TI - The neuraminidase of bat influenza viruses is not a neuraminidase. PMID- 23100537 TI - Making connections in insect innate immunity. PMID- 23100538 TI - RAB-5 and RAB-10 cooperate to regulate neuropeptide release in Caenorhabditis elegans. AB - Neurons secrete neuropeptides from dense core vesicles (DCVs) to modulate neuronal activity. Little is known about how neurons manage to differentially regulate the release of synaptic vesicles (SVs) and DCVs. To analyze this, we screened all Caenorhabditis elegans Rab GTPases and Tre2/Bub2/Cdc16 (TBC) domain containing GTPase-activating proteins (GAPs) for defects in DCV release from C. elegans motoneurons. rab-5 and rab-10 mutants show severe defects in DCV secretion, whereas SV exocytosis is unaffected. We identified TBC-2 and TBC-4 as putative GAPs for RAB-5 and RAB-10, respectively. Multiple Rabs and RabGAPs are typically organized in cascades that confer directionality to membrane trafficking processes. We show here that the formation of release-competent DCVs requires a reciprocal exclusion cascade coupling RAB-5 and RAB-10, in which each of the two Rabs recruits the other's GAP molecule. This contributes to a separation of RAB-5 and RAB-10 domains at the Golgi-endosomal interface, which is lost when either of the two GAPs is inactivated. Taken together, our data suggest that RAB-5 and RAB-10 cooperate to locally exclude each other at an essential stage during DCV sorting. PMID- 23100540 TI - Nutrition barriers in abdominal aortic surgery: a multimodal approach for gastrointestinal dysfunction. PMID- 23100539 TI - Highly potent HIV-specific antibody neutralization in vitro translates into effective protection against mucosal SHIV challenge in vivo. AB - Most animal studies using passive administration of HIV broadly neutralizing monoclonal antibodies (bnMAbs) have associated protection against high-dose mucosal viral challenge with relatively high serum concentrations of antibody. We recently identified several bnMAbs remarkable for their in vitro potency against HIV. Of these bnMAbs, PGT121 is one of the most broad and potent antibodies isolated to date and shows 10- to 100-fold higher neutralizing activity than previously characterized bnMAbs. To evaluate the protective potency of PGT121 in vivo, we performed a protection study in rhesus macaques. Animals were i.v. administered 5 mg/kg, 1 mg/kg, or 0.2 mg/kg PGT121 24 h before being vaginally challenged with a single high dose of chimeric simian-human immunodeficiency virus (SHIV)(SF162P3). Sterilizing immunity was achieved in all animals administered 5 mg/kg and 1 mg/kg and three of five animals administered 0.2 mg/kg PGT121, with corresponding average antibody serum concentrations of 95 ug/mL, 15 ug/mL, and 1.8 ug/mL, respectively. The results suggest that a protective serum concentration for PGT121 is in the single-digit ug/mL for SHIV(SF162P3), showing that PGT121 can mediate sterilizing immunity at serum concentrations that are significantly lower than those observed in previous studies and that may be achievable through vaccination with the development of a suitable immunogen. PMID- 23100541 TI - A cohort study of nutrition practices in the intensive care unit following abdominal aortic aneurysm repair. AB - INTRODUCTION: Enteral nutrition within 48 hours of intensive care unit (ICU) admission is recommended for the ICU population. Major vascular surgery patients have a higher incidence of pre- and postoperative malnutrition compared with the general surgical population. Our objectives were to determine if early feeding (within 48 hours of admission) is achievable and well tolerated, identify factors that predict early feeding, and determine if there is an association between early feeding and in-hospital mortality among abdominal aortic aneurysm (AAA) repair patients. METHODS: A retrospective cohort study was conducted among 145 postsurgical AAA repair patients admitted to the ICU within 48 hours of surgery. Kaplan-Meier methods and Cox proportional hazard multiple regression were used to analyze the data. RESULTS: Only 35 (24%) patients received early feeding. Patients were more likely to be fed early if they were male (adjusted hazard ratio [aHR] = 2.3; 95% confidence interval [CI], 0.8-6.7; P = .13), had endovascular AAA repair (aHR = 2.9; 95% CI, 1.4-6.2; P = .006), had less blood loss (<4 L) during surgery (aHR = 2.3; 95% CI, 0.7-7.2; P = .14), and had shorter length of ventilation (<48 hours) (aHR = 2.2; 95% CI, 1.1-4.8; P = .048). Of 44 patients fed via enteral nutrition (EN), 27 (61%) achieved nutrition adequacy (>80% EN goal) during ICU admission. After controlling for other factors, 14-day mortality was not related to feeding time (aHR = 1.1; P = .88). CONCLUSION: Early feeding was achieved in a minority of patients following AAA repair, was related to type of surgery and duration of mechanical ventilation, and was tolerated as well as later introduced feedings. Randomized trials are needed to determine safety and benefits of early feeding in this patient group. PMID- 23100542 TI - Energizing and de-motivating effects of norm-conflict. AB - Norms have a pervasive influence on behavior, yet previous research has not addressed that people often face conflicting norms from multiple ingroups. The current research addresses this gap in the context of proenvironmental behavior and demonstrates two effects predicted by the novel theoretical position we offer: People can be de-motivated by norm-conflict, or conversely, norm-conflict can encourage people to take action. Studies 1 and 2 demonstrated that norm conflict is associated with increased perceived effectiveness for those with positive attitudes to the issue and reduced perceived effectiveness for those with moderate attitudes, and effectiveness perceptions mediated an indirect effect on behavioral intentions. Study 3 found that perceived effectiveness also moderates the effects of norm-conflict such that norm-conflict only influences intentions when perceived effectiveness is high. Norm-conflict is both positively and negatively related to behavioral decision making, suggesting additional considerations in the design of social norms-based interventions. PMID- 23100543 TI - Engineering catalytic properties and thermal stability of plant formate dehydrogenase by single-point mutations. AB - The analysis of the 3D model structure of the ternary complex of recombinant formate dehydrogenase from soya Glycine max (EC 1.2.1.2., SoyFDH) with bound NAD+ and an inhibitor azide ion revealed the presence of hydrophobic Phe290 in the coenzyme-binding domain. This residue should shield the enzyme active site from solvent. On the basis of the alignment of plant FDHs sequences, Asp, Asn and Ser were selected as candidates to substitute Phe290. Computer modeling indicated the formation of two (Ser and Asn) or three (Asp) new hydrogen bonds in such mutants. The mutant SoyFDHs were expressed in Escherichia coli, purified and characterized. All amino acid substitutions increased K(m)(HCOO-) from 1.5 to 4.1 5.0 mM, whereas the K(m)(NAD+) values remained almost unchanged in the range from 9.1 to 14.0 MUM, which is close to wt-SoyFDH (13.3 MUM). The catalytic constants for F290N, F290D and F290S mutants of SoyFDH equaled 2.8, 5.1 and 4.1 s-1, respectively; while that of the wild-type enzyme was 2.9 s-1. The thermal stability of all mutant SoyFDHs was much higher compared with the wild-type enzyme. The differential scanning calorimetry data were in agreement with the results of thermal inactivation kinetics. The mutations F290S, F290N and F290D introduced into SoyFDH increased the T(m) values by 2.9 degrees C, 4.3 degrees C and 7.8 degrees C, respectively. The best mutant F290D exhibited thermal stability similar to that of FDH from the plant Arabidopsis thaliana and exceeded that of the enzymes from the yeast Candida boidinii and the bacterium Moraxella sp. C1. PMID- 23100544 TI - Polysaccharide co-polymerases: the enigmatic conductors of the O-antigen assembly orchestra. AB - The O-antigen lipopolysaccharides on bacterial surface contain variable number of oligosaccharide repeat units with their length having a modal distribution specific to the bacterial strain. The polysaccharide length distribution is controlled by the proteins called polysaccharide co-polymerases (PCPs), which are embedded in the inner membrane in Gram-negative bacteria and form homo oligomers. The 3D structures of periplasmic domains of several PCPs have been determined and provided the first insights into the possible mechanism of polysaccharide length determination mechanism. Here we review the current knowledge of structure and function of these polysaccharide length regulators. PMID- 23100545 TI - Phage selection of cyclic peptide antagonists with increased stability toward intestinal proteases. AB - The oral delivery of protein and peptide drugs is limited by their proteolytic degradation and the poor absorption across the intestinal epithelia. In this work, we exposed a phage library of small bicyclic peptides (<1.5 kDa) to a pancreatic extract of proteases prior to affinity selection to enrich binders with higher stability in the intestinal environment. Panning with the therapeutic target plasma kallikrein yielded potent inhibitors (K(i)s between 5.6 and 336 nM) wherein bicyclic peptides isolated with proteolytic pressure were more stable. A proline residue found in a specific position of several resistant bicyclic peptides proved to be a 'protective mark', rendering the bicyclic peptides resistant to significantly higher concentrations of intestinal proteases while retaining essentially their inhibitory activity. PMID- 23100546 TI - The collaborative communication model for patient handover at the interface between high-acuity and low-acuity care. AB - BACKGROUND: Cross-unit handovers transfer responsibility for the patient among healthcare teams in different clinical units, with missed information, potentially placing patients at risk for adverse events. OBJECTIVES: We analysed the communications between high-acuity and low-acuity units, their content and social context, and we explored whether common conceptual ground reduced potential threats to patient safety posed by current handover practices. METHODS: We monitored the communication of five content items using handover probes for 22 patient transitions of care between high-acuity 'sender units' and low-acuity 'recipient units'. Data were analysed and discussed in focus groups with healthcare professionals to acquire insights into the characteristics of the common conceptual ground. RESULTS: High-acuity and low-acuity units agreed about the presence of alert signs in the discharge form in 40% of the cases. The focus groups identified prehandover practices, particularly for anticipatory guidance that relied extensively on verbal phone interactions that commonly did not involve all members of the healthcare team, particularly nursing. Accessibility of information in the medical records reported by the recipient units was significantly lower than reported by sender units. Common ground to enable interpretation of the complete handover content items existed only among selected members of the healthcare team. CONCLUSIONS: The limited common ground reduced the likelihood of correct interpretation of important handover information, which may contribute to adverse events. Collaborative design and use of a shared set of handover content items may assist in creating common ground to enable clinical teams to communicate effectively to help increase the reliability and safety of cross-unit handovers. PMID- 23100547 TI - Medication discrepancies in integrated electronic health records. AB - INTRODUCTION: Medication discrepancies are associated with adverse drug events. Electronic health records (EHRs) may reduce discrepancies, especially if integrated with pharmacy dispensing. We determined the prevalence of discrepancies within a national healthcare system with EHR-pharmacy linkage to characterise the medications involved and to identify factors associated with discrepancies. METHODS: We conducted a retrospective cohort study of ambulatory care patients at Veterans Affairs Boston Healthcare System, April 2010-July 2011. The primary outcome was the presence of any medication discrepancy or specific types of discrepancies: commission-present in the record but not taken by patient; omission-not present in the record; duplication-present more than once; or alteration in dose or frequency-present but taken differently than documented. RESULTS: Sixty-two patients (60%) had at least one medication discrepancy. Prevalence of commissions, omissions, duplications and alterations were 36%, 27%, 11% and 19%, respectively. The involved medications differed by type of discrepancy, but non-opioid analgesics and herbal therapies were common among commissions and omissions. In adjusted analyses, an increasing number of medications was associated with more commissions (OR 1.2; 95% CI 1.1 to 1.3) and duplications (OR 1.2; 95% CI 1.1 to 1.4) and fewer omissions (OR 0.9; 95% CI 0.8 to 1.0). DISCUSSION: In a system with a well established EHR linked to pharmacy dispensing, medication discrepancies occurred in 60% of ambulatory clinic patients. Patients with a greater number of medications were more likely to have errors of commission and duplication, but less likely to have errors of omission. Our findings highlight that relying on EHRs alone will not ensure an accurate medication list and stress the need to review medication taking thoroughly with patients to capitalise on the full potential of EHRs. PMID- 23100548 TI - Conducting a multicentre and multinational qualitative study on patient transitions. AB - BACKGROUND: A multicentre, multinational research study requires careful planning and coordination to accomplish the aims of the study and to ensure systematic and rigorous examination of all project methods and data collected. OBJECTIVE: The aim of this paper is to describe the approach we used during the HANDOVER Project to develop a multicentre, multinational research project for studying transitions of patient care while creating a community of practice for the researchers. METHOD: We highlight the process used to assure the quality of a multicentre qualitative study and to create a codebook for data analysis as examples of attending to the community of practice while conducting rigorous qualitative research. FINDINGS: Essential elements for the success of this multinational, multilanguage research project included recruiting a strong research team, explicit planning for decision-making processes to be used throughout the project, acknowledging the differences among the study settings and planning the protocols to capitalise upon those differences. CONCLUSIONS: Although not commonly discussed in reports of large research projects, there is an underlying, concurrent stream of activities to develop a cohesive team that trusts and respects one another's skills and that engage independent researchers in a group process that contributes to achieving study goals. We discuss other lessons learned and offer recommendations for other teams planning multicentre research. PMID- 23100549 TI - eComment. The risk of loss of the breast flap after coronary artery bypass grafting. PMID- 23100550 TI - eComment. Local solutions to arrests on the ward. PMID- 23100551 TI - eComment. Organism functionality parameters in predicting the length of intensive care unit stays? PMID- 23100552 TI - eComment. Costs, nursing administrators and predictors of intensive care unit length of stay. PMID- 23100553 TI - eComment. Cardiac computed tomography angiography for evaluation of coronary artery bypass grafts. PMID- 23100554 TI - eComment. Haemodynamic goal-directed therapy in cardiac surgery. PMID- 23100555 TI - eComment. Computed tomography surveillance of lung cancer survivors: the jury is still out. PMID- 23100556 TI - eComment. Immune-mediated neurological disorder after cardiac surgery. PMID- 23100557 TI - eComment. Cardiac resynchronization therapy in cardiac surgery. PMID- 23100560 TI - Interleukin-1 promotes coagulation, which is necessary for protective immunity in the lung against Streptococcus pneumoniae infection. AB - Interleukin (IL)-1 is a well-known cytokine for the initiation of innate immunity in bacterial infection. However, the underlying mechanism of IL-1 on the respiratory infection is not fully elucidated. We studied how IL-1 contributes to the host defense against Streptococcus pneumoniae. IL-1R(-/-) mice showed high mortality, local cytokine storm, and substantial infiltrates in the lower respiratory tract after intratracheal challenge with S. pneumoniae. The IL-1 deficient condition did not suppress the propagation of bacteria in the lung, although the recruitment and the bacteria-killing ability of neutrophils (CD11b(+)Ly6C(+)Ly6G(+)) were not defective compared with wild-type mice. Unexpectedly, we found that the transcription of fibrinogen alpha and gamma genes were highly activated in the lungs of wild-type mice after the infection, whereas no significant changes were found in IL-1R(-/-) mice. Of note, synthesis of fibrinogen was dependent on the IL-1-IL-6-Stat3 cascade. Treatment with recombinant fibrinogen improved survival and bacterial propagation in the IL-1R( /-) mice and blockade of the coagulation increased the susceptibility of wild type mice to pneumococcal pneumonia. Our findings suggest that IL-1 signaling leads to the synthesis of fibrinogen in the lung after pneumococcus infection and is followed by coagulation, which contributes to the control of bacterial infection in the pulmonary tract. PMID- 23100559 TI - Association of a NOD2 gene polymorphism and T-helper 17 cells with presumed ocular toxoplasmosis. AB - Retinochoroiditis manifests in patients infected with Toxoplasma gondii. Here, we assessed 30 sibships and 89 parent/case trios of presumed ocular toxoplasmosis (POT) to evaluate associations with polymorphisms in the NOD2 gene. Three haplotype-tagging single-nucleotide polymorphisms (tag-SNPs) within the NOD2 gene were genotyped. The family-based association test showed that the tag-SNP rs3135499 is associated with retinochoroiditis (P = .039). We then characterized the cellular immune response of 59 cases of POT and 4 cases of active ocular toxoplasmosis (AOT). We found no differences in levels of interferon gamma (IFN gamma) and interleukin 2 produced by T-helper 1 cells when comparing patients with AOT or POT to asymptomatic individuals. Unexpectedly, we found an increased interleukin 17A (IL-17A) production in patients with POT or OAT. In patients with POT or AOT, the main cellular source of IL-17A was CD4(+)CD45RO(+)T-bet(-)IFN gamma(-) T-helper 17 cells. Altogether, our results suggest that NOD2 influences the production of IL-17A by CD4(+) T lymphocytes and might contribute to the development of ocular toxoplasmosis. PMID- 23100561 TI - Early BK polyomavirus (BKV) reactivation in donor kidney is a risk factor for development of BKV-associated nephropathy. AB - The pathogenesis of BK polyomavirus (BKV) infection and associated nephropathy in renal transplant recipients is not clearly understood. To gain insight, urine and plasma samples were collected from 112 renal transplant recipients before and after transplantation and tested for the presence of BKV by polymerase chain reaction. Detection of BKV infection very early (ie, 5 days) after transplantation was identified as a risk factor for subsequent BKV viremia and BKV-associated nephropathy. Phylogenetic analysis of VP1 sequences with corresponding ethnicity data suggests that reactivation was of donor origin. Thus, early testing of urine samples from renal transplant recipients may identify those at risk for BKV-associated nephropathy. PMID- 23100562 TI - Behavioral, virologic, and immunologic factors associated with acquisition and severity of primary Epstein-Barr virus infection in university students. AB - BACKGROUND: University students were studied prospectively to determine the incidence of and risk factors for acquisition of primary Epstein-Barr virus (EBV) infection and the virologic and immune correlates of disease severity. METHODS: EBV antibody-negative freshmen participated in monthly surveillance until graduation. If antibodies developed, proximate samples were assayed for viral load by polymerase chain reaction. Lymphocyte and natural killer (NK) cell numbers and activation were measured by flow cytometry, and plasma cytokine levels were measured by a multiplex assay. RESULTS: Of 546 students screened, 202 (37%) were antibody negative; 143 antibody-negative students were enrolled. During a median of 3 years of observation, 66 subjects experienced primary infection. Of these, 77% had infectious mononucleosis, 12% had atypical symptoms, and 11% were asymptomatic. Subjects reporting deep kissing with or without coitus had the same higher risk of infection than those reporting no kissing (P < .01). Viremia was transient, but median oral shedding was 175 days. Increases were observed in numbers of NK cells and CD8(+) T-cells but not in numbers of CD4(+) T cells during acute infection. Severity of illness correlated positively with both blood EBV load (P = .015) and CD8(+) lymphocytosis (P = .0003). CONCLUSIONS: Kissing was a significant risk for primary EBV infection. A total of 89% of infections were symptomatic, and blood viral load and CD8(+) lymphocytosis correlated with disease severity. PMID- 23100564 TI - Epstein-Barr virus and infectious mononucleosis: what students can teach us. PMID- 23100563 TI - Attenuation of biopterin synthesis prevents Escherichia coli K1 invasion of brain endothelial cells and the development of meningitis in newborn mice. AB - Elevated levels of pterins and nitric oxide (NO) are observed in patients with septic shock and bacterial meningitis. We demonstrate that Escherichia coli K1 infection of human brain microvascular endothelial cells (HBMECs) induces the expression of guanosine triphosphate cyclohydrolase (GCH1), the rate-limiting enzyme in pterin synthesis, thereby elevating levels of biopterin. DAHP (2,4 diamino hydroxyl pyrimidine), a specific inhibitor of GCH1, prevented biopterin and NO production and invasion of E. coli K1 in HBMECs. GCH1 interaction with Ecgp96, the receptor for outer membrane protein A of E. coli K1, also increases on infection, and suppression of Ecgp96 expression prevents GCH1 activation and biopterin synthesis. Pretreatment of newborn mice with DAHP prevented the production of biopterin and the development of meningitis. These results suggest a novel role for biopterin synthesis in the pathogenesis of E. coli K1 meningitis. PMID- 23100565 TI - Estimating the benefits of antiretroviral therapy programs: how certain can we get? PMID- 23100566 TI - Cooling off the host immune response to acute simian immunodeficiency virus infection--is less more? PMID- 23100567 TI - Incorporating loss to follow-up in estimates of survival among HIV-infected individuals in sub-Saharan Africa enrolled in antiretroviral therapy programs. AB - BACKGROUND: Measuring the survival of human immunodeficiency virus-infected adult patients enrolled in antiretroviral therapy (ART) programs is complicated by short observation periods and loss to follow-up. We synthesized data from treatment cohorts in sub-Saharan Africa to estimate survival over 5 years after initiation of ART. METHODS: We used data on retention, mortality, and loss to follow-up from 34 cohorts, including a total of 102,306 adult patients from 18 sub-Saharan African countries. These data were augmented by data from 13 sub Saharan African studies tracking death rates among adult patients who were lost to follow-up (LTFU). We used a Poisson regression model to estimate survival over time, incorporating predicted mortality among LTFU patients. RESULTS: Across studies, the median CD4(+) cell count at ART initiation was 104 cells/mm(3), 65% of patients were female, and the median age was 37 years. Survival at 1 year and 5 years were estimated to be 0.87 (95% confidence interval [CI], 0.72-0.94) and 0.70 (95% CI, 0.36-0.86), respectively, after adjustment for loss to follow-up. The life-years gained by a patient during the 5-year period after starting ART were estimated at 2.1 (95% CI, 1.6-2.3) in the adjusted model, compared with 1.7 (95% CI, 1.1-2.0) if there was 100% mortality among LTFU patients and with 2.4 (1.7-2.7) if there was 0% mortality among LTFU patients. CONCLUSIONS: Accounting for loss to follow-up produces substantial changes in the estimated life-years gained during the first 5 years of ART receipt. PMID- 23100568 TI - Chlamydia public health programs and the epidemiology of pelvic inflammatory disease and ectopic pregnancy. AB - BACKGROUND: Many countries have witnessed a disturbing increase in cases of Chlamydia trachomatis infection despite enhanced control programs. Since the goal of Chlamydia control is to prevent reproductive complications such as pelvic inflammatory disease and ectopic pregnancy, an understanding of recent trends in these conditions is needed to fully evaluate the effect of control efforts. METHODS: We analyzed 2 provincial, comprehensive health services administrative databases (encompassing hospitalizations and all physician-delivered services) for pelvic inflammatory disease and ectopic pregnancy trends from 1992 through 2009 in women of reproductive age in British Columbia, Canada. Trends were compared to provincial Chlamydia surveillance data by time-series analysis, using the cross-correlation function method and Granger causality testing. RESULTS: Chlamydia cases substantially increased from 1992 through 2009. Inpatient, outpatient, and total diagnoses of pelvic inflammatory disease and ectopic pregnancy declined from 1992 through 2003. After 2003, pelvic inflammatory disease rates continued to fall, while ectopic pregnancy rates significantly increased. The male Chlamydia urethritis rate increased from 39.4 to 173.6 cases/100,000 from 1996 to 2009. CONCLUSIONS: In the context of increasing Chlamydia infection rates, the reproductive complications of Chlamydia infection in women are declining overall. A recent increase in rates of ectopic pregnancies is cause for concern. PMID- 23100569 TI - Collaboration between macrophages and vaccine-induced CD4+ T cells confers protection against lethal Pseudomonas aeruginosa pneumonia during neutropenia. AB - The usefulness of vaccine-based strategies to prevent lethal bacterial infection in a host with neutropenia is not well-defined. Here, we show in a neutropenic mouse model that immunity induced by mucosal vaccination with a live-attenuated Pseudomonas aeruginosa vaccine is protective against lethal P. aeruginosa pneumonia caused by both vaccine-homologous and vaccine-heterologous strains, whereas passive immunization confers only vaccine-homologous protection. Cells in the macrophage lineage served as crucial innate cellular effectors in the neutropenic host after active immunization. Vaccine efficacy was CD4(+) T-cell dependent and associated with accumulation of macrophage-lineage cells in the alveolar space after infection, as well as with enhanced P. aeruginosa clearance from the lung. Adaptive CD4(+) T cells produced granulocyte-macrophage colony stimulating factor (GM-CSF) on restimulation in vitro, and local GM-CSF was critical for vaccine efficacy. Thus, collaboration between the innate and adaptive effectors induced by mucosal vaccination can overcome neutropenia and confer protection against lethal bacterial infection in the profoundly neutropenic host. PMID- 23100570 TI - Radiation-induced cellular and molecular alterations in asexual intraerythrocytic Plasmodium falciparum. AB - BACKGROUND: gamma-irradiation is commonly used to create attenuation in Plasmodium parasites. However, there are no systematic studies on the survival, reversion of virulence, and molecular basis for gamma-radiation-induced cell death in malaria parasites. METHODS: The effect of gamma-irradiation on the growth of asexual Plasmodium falciparum was studied in erythrocyte cultures. Cellular and ultrastructural changes within the parasite were studied by fluorescence and electron microscopy, and genome-wide transcriptional profiling was performed to identify parasite biomarkers of attenuation and cell death. RESULTS: gamma-radiation induced the death of P. falciparum in a dose-dependent manner. These parasites had defective mitosis, sparse cytoplasm, fewer ribosomes, disorganized and clumped organelles, and large vacuoles-observations consistent with "distressed" or dying parasites. A total of 185 parasite genes were transcriptionally altered in response to gamma-irradiation (45.9% upregulated, 54.1% downregulated). Loss of parasite survival was correlated with the downregulation of genes encoding translation factors and with upregulation of genes associated with messenger RNA-sequestering stress granules. Genes pertaining to cell-surface interactions, host-cell remodeling, and secreted proteins were also altered. CONCLUSIONS: These studies provide a framework to assess the safety of gamma-irradiation attenuation and promising targets for genetic deletion to produce whole parasite-based attenuated vaccines. PMID- 23100572 TI - Influence of source and micronization of soybean meal on nutrient digestibility and growth performance of weanling pigs. AB - A total of 288 piglets weaned at 28 d and weighing 7.6 +/- 0.2 kg were used in a 35-d experiment to evaluate the effect of CP content (44% vs. 49% CP) of soybean meal (SBM), micronization (fine grinding) of the 49% CP SBM (HP-SBM), and soy protein concentrate (SPC; 65% CP) on total tract apparent digestibility (TTAD) and growth performance. In phase I (d 0 to 21 of experiment), there was a positive control diet that included 6.5% of CP from a SPC with 65% CP and a negative control diet that supplied the same amount of CP as regular SBM (R-SBM) with 44% CP. The other 4 diets included the same amount of dietary CP from 2 different sources of HP-SBM that were either ground (990 MUm) or micronized (60 MUm). All diets were isonutritive, and the main difference was the source of SBM used. Each treatment was replicated 8 times (6 pigs per pen). In phase II (d 21 to 35), all pigs were fed a common commercial starter diet. For the entire phase I, the type of soy product did not affect growth performance of the pigs. However, from 0 to 7 d of experiment, pigs fed the micronized HP-SBM had better G:F (1.11 vs. 0.98; P<0.05) than piglets fed the ground HP-SBM. Also, from 7 to 14 d of experiment, ADFI tended to be greater (P=0.08) for pigs fed the micronized HP-SBM than for piglets fed the ground HP-SBM. During phase II (all the pigs received the same diet), no differences among treatments were observed. In general, TTAD of nutrients at 7 d of experiment was greater for the SPC than the R-SBM diet, with the HP-SBM diets being intermediate. The TTAD of CP was greater (83.8% vs. 81.9%; P<=0.01) for the SPC diet than the average of the SBM diets. Also, the digestibility of OM and DM was greater (P<0.01) for the HP-SBM either ground or micronized than the R-SBM diet. Micronization of the HP-SBM did not affect nutrient digestibility. It is concluded that when the R-SBM is substituted by SPC, CP digestibility is improved, but no effects are observed on growth performance. The use of the HP-SBM in substitution of the R-SBM in the diet improved nutrient digestibility but did not affect piglet performance. The inclusion of micronized HP-SBM in the diet improved G:F during the first week postweaning but did not affect TTAD of nutrients. In general, the inclusion of added-value soy products (SPC or micronized SBM) in the diet presents little advantage in terms of growth performance over the use of HP-SBM in pigs weaned at 28 d of age. PMID- 23100571 TI - Influence of a microbial phytase and zinc oxide on young pig growth performance and serum minerals. AB - Crossbred pigs (n=288; average age=21+/-3 d and BW=7.1+/-0.2 kg) were used in a 42-d trial to determine the influence of a microbial phytase and various doses of ZnO on growth performance and serum minerals. Pigs (6 castrated males or females/pen) were randomly allotted to treatments in a 2*3 factorial arrangement with 2 dietary levels of a microbial phytase (0 or 2,500 phytase units/kg) and 3 dietary levels of supplemental ZnO [0, 1750, or 3,500 mg/kg ZnO (72% Zn)] with 4 pens of castrated males and 4 pens of females per treatment. Diets were formulated to exceed all nutrient requirements, including Ca and P from d 0 to 21 (phase 1) and d 22 to 42 (phase 2). Growth performance, serum Zn, and serum P were not influenced (P>0.05) by a ZnO*phytase interaction during phase 1, phase 2, or overall (d 0 to 42). Phytase increased (P=0.01) ADFI and improved (P=0.02) ADG in phase 1 and improved (P=0.01) overall ADG, regardless of the level of ZnO supplemented. Zinc oxide supplementation linearly reduced (P=0.05) ADG, and ZnO at 3,500 mg/kg reduced (quadratic, P=0.04) G:F in pigs (phase 2). During phase 1, phytase increased serum Ca, but only in the absence of ZnO supplementation, which resulted in a ZnO*phytase interaction (P=0.02). Serum Zn was increased (linear, P<0.001) and serum P was decreased (linear, P=0.05) as ZnO supplementation increased in the diet (phase 1). In phase 2, serum Ca was reduced (linear, P=0.04) and serum Zn was increased (linear, P=0.02) as ZnO supplementation increased in the diet. Phytase supplementation increased (P=0.009) serum Zn and increased (P=0.003) serum P (phase 1). There was no influence of phytase supplementation on serum minerals in phase 2. In summary, supplemental ZnO reduced growth performance in this experiment. Phytase supplementation improved ADG in Ca- and P-adequate diets regardless of the level of ZnO supplemented, which may be attributed to the reduction of phytate as an antinutrient. In addition, through phytate hydrolysis, phytase reduced phytate-Zn interactions and increased serum Zn, Ca, and P. However, supplementing ZnO increased serum Zn, which reduced serum P and Ca, indicating Ca-Zn-P precipitation. In addition, phytase increased serum Ca, but only in the absence of Zn, further indicating a complex interaction between Zn, Ca, and P in the blood. PMID- 23100573 TI - Environmental regulation of pregnancy-specific protein B concentrations during late pregnancy in dairy cattle. AB - Environmental factors, such as photoperiod and heat stress, can be manipulated during the dry period to influence health, productivity, and reproductive performance of dairy cows in their subsequent lactation. The impacts of photoperiod and heat stress on subsequent lactation are related to alterations in prolactin (PRL) signaling and may affect the expression of pregnancy-specific protein B (PSPB). Additionally, exposure of cows to heat stress during the dry period decreases gestation length; however, the mechanism involved in this process is unknown. The objective of these experiments was to evaluate the influence of environmental factors (i.e., heat stress and photoperiod) during late gestation (i.e., dry period) on PSPB concentrations in plasma of dairy cows. In Exp. 1, cows were dried off in the summer months approximately 46 d before expected calving and assigned randomly to heat stress (HT; n=30) or cooling (CL; n=30) treatment. Cooling cows were housed with sprinklers, fans, and shade, whereas HT cows were provided only shade. In Exp. 2, cows were dried off at approximately 60 d before expected calving in summer/fall months and randomly assigned to 3 treatments: long day photoperiod (LDPP: 16L:8D; n=15), short day photoperiod (SDPP: 8L:16D; n=14) and SDPP+PRL implant (12 mg/d of PRL at 28 d or 16 mg/d of PRL at 39 d; n=11). In both experiments, plasma samples were collected at dry off and at -32, -18, -7, -3 and 0 d relative to calving. In Exp. 1, greater concentrations of PSPB were detected in plasma of CL versus HT cows (388.3+/-24.7 vs. 287.4+/-23.8 ng/mL; P<0.01). Concentrations of PSPB did not differ between -46 to -18 d before calving (66.0 ng/mL). However, PSPB concentrations were greater (P<0.01) for CL cows at d -7 (534.7>357.2 ng/mL), -3 (807.2>572.2 ng/mL) and 0 (800.8>563.5 ng/mL) relative to calving. Additionally, HT cows in Exp. 1 had increased PRL plasma concentrations compared with CL cows (21.01+/-1.6 vs. 13.78+/-1.6 ng/mL). In Exp. 2, no differences were detected in plasma concentrations of PSPB (ng/mL) among LDPP, SDPP, or SDPP+PRL groups on d 60 (41.5), -32 (51.7), -18 (58.5), -7 (532.9), -3 (838.2), and 0 (729.4) relative to parturition. Photoperiodic PRL concentrations were 10.81, 7.84, and 4.22 ng/mL for LDPP, SDPP+ PRL, and SDPP, respectively. Results indicate that HT alters PSPB concentrations in late pregnancy, suggesting that placental activity is altered in cows exposed to excessive elevated temperatures around the time of calving. However, the mechanism involved likely is not associated with changes in PRL secretion. PMID- 23100574 TI - Triennial Reproduction Symposium: 2012 Casida Award recipient: philosophy for graduate education in reproductive physiology and endocrinology. AB - The purpose of graduate education in reproductive physiology and endocrinology is to develop scientists and educators who will create new knowledge and impart this knowledge to appropriate end users in animal agriculture. Technology changes over time but the scientific method remains constant. Society needs scientists and educators who are grounded in the fundamentals of biology as well as in animal agriculture. Students in reproductive physiology and endocrinology require a blending of fundamental sciences with application to agricultural species in their training. My philosophy has been to treat each student as a unique individual needing a program designed to eliminate weaknesses and to magnify strengths. Each student must have a background in statistics and biochemistry. These 2 fundamental areas of science are of such importance that they must be included early in the educational process to assure competence in research or teaching. Students must be involved in their own research as early as possible. Collaborative and interdisciplinary research has been a key factor in developing successful scientists and educators in my graduate education program. Success of students after graduation has been a rewarding aspect of training graduate students. PMID- 23100575 TI - Energy, amino acid, and phosphorus digestibility of phytase transgenic corn for growing pigs. AB - Three experiments were conducted to evaluate energy, AA, and P digestibility in a phytase transgenic corn (PTC) containing a phytase gene (phyA2) isolated from Aspergillus niger compared with a nontransgenic near-isoline conventional corn (CC) grown in the same environmental conditions for growing pigs. Experiment 1 was an energy balance experiment conducted to measure DE and ME in PTC and CC. Eighteen growing barrows (initial BW 25.8+/-0.3 kg) from 9 litters were allotted by BW and litter to 1 of 2 dietary treatments with 9 pigs per treatment in a randomized complete block design. Pigs were individually placed in metabolism cages and fed diets based on the 2 corns. The DE and ME in PTC (3,967 and 3,941 kcal/kg of DM, respectively) were greater (P<0.05) than those in CC (3,917 and 3,848 kcal/kg of DM, respectively). Experiment 2 was conducted to measure apparent ileal digestibility (AID) and standardized ileal digestibility (SID) values of CP and AA in the 2 corns. Eighteen growing barrows (initial BW 41.8+/ 0.7 kg) were equipped with a T-cannula in the distal ileum. Pigs were placed in metabolism cages in a completely randomized design with 3 dietary treatments of 6 pigs each. An N-free diet was used to estimate basal endogenous losses of CP and AA. The AID and SID values for CP and all AA did not differ between the 2 corns. Experiment 3 was conducted to measure apparent total tract digestibility (ATTD) and standardized total tract digestibility (STTD) values of P in the 2 corns. Eighteen growing pigs (initial BW 30.5+/-0.5 kg) from 6 litters were placed in metabolism cages in a randomized complete block design with 3 dietary treatments of 6 pigs each based on BW and litter. Two diets were based on the 2 corns, and a P-free diet was used to measure endogenous P losses. The ATTD and STTD values of P were greater (P<0.05) in the PTC diet (71.4% and 76.9%, respectively) than those in the CC diet (27.6% and 33.4%, respectively). Pigs fed the PTC diet had a greater (P<0.05) P retention (70.7%) than those fed the CC diet (27.1%). It was concluded that PTC had a greater digestibility of energy and P than CC for growing pigs. As a consequence, if PTC replaces CC in a pig diet, the DE and ME in the diet will increase, and less inorganic P will need to be supplemented to the diet, and thus P excretion in manure will be decreased. PMID- 23100576 TI - Use of principal component approach to predict direct genomic breeding values for beef traits in Italian Simmental cattle. AB - In the current study, principal component (PC) analysis was used to reduce the number of predictors in the estimation of direct genomic breeding values (DGV) for meat traits in a sample of 479 Italian Simmental bulls. Single nucleotide polymorphism marker genotypes were determined with the 54K Illumina beadchip. After edits, 457 bulls and 40,179 SNP were retained. Principal component extraction was performed separately for each chromosome and 2466 new variables able to explain 70% of total variance were obtained. Bulls were divided into reference and validation population. Three scenarios of the ratio reference:validation were tested: 70:30, 80:20, 90:10. Effect of PC scores on polygenic EBV was estimated in the reference population using different models and methods. Traits analyzed were 7 beef traits: daily BW gain, size score, muscularity score, feet and legs score, beef index (economic index), calving ease direct effect, and cow muscularity. Accuracy was calculated as correlation between DGV and polygenic EBV in the validation bulls. Muscularity, feet and legs, and the beef index showed the greatest accuracies; calving ease, the least. In general, accuracies were slightly greater when reference animals were selected at random and the best scenario was 90:10 and no substantial differences in accuracy were found among different methods. Principal component analysis is entirely based on the factorization of the SNP (co)variance matrix and produced a reduced set of variables (6% of the original variables) which may be used for different phenotypic traits. In spite of this huge reduction in the number of independent variables, DGV accuracies resulted similar to those obtained by using the whole set of SNP markers. Accuracies of direct genomic values found in the present work were always greater than those of traditional parental average (PA). Thus, results of the present study may suggest a possible advantage of use of genomic indexes in the preselection of performance test candidates for beef traits. Moreover, the relevant reduction of variable space might allow genomic selection implementation also in small populations. PMID- 23100577 TI - Meat quality of swine supplemented with ractopamine under commercial conditions in Brazil. AB - Commercial crossbred barrows and gilts (n = 340) were used to study the effects of different dietary inclusions of ractopamine hydrochloride (RAC) on quality of LM and semimembranosus muscle (SM). Pigs were blocked by BW (107.3 +/- 0.76 kg) and allotted to gender-specific pens (10 to 12 pigs/pen), and within blocks, pens of barrows or gilts (10 pens/treatment) were randomly assigned to 1 of 3 dietary RAC inclusions (0, 5, or 10 mg/kg) fed during the last 28 d before slaughter. Initial (45-min) and ultimate (24-h) pH and temperature were measured in LM and SM. Visual and instrumental [lightness (L*), redness (a*), and yellowness (b*) values] color as well as drip loss percentages were measured in both muscles after the 24-h chilling period at 1 to 4 degrees C. The LM was also evaluated for marbling, and samples of the LM were used to measure intramuscular fat (IMF) content, cooking losses, and Warner-Bratzler shear force (WBSF). Pork quality characteristics of the LM (P >= 0.227) and SM (P >= 0.082) did not differ between barrows and gilts. Furthermore, neither pH nor temperature of the LM (P >= 0.164) or SM (P >= 0.284) was affected by feeding pigs RAC. The LM from pigs fed 10 mg/kg of RAC received lesser (P = 0.032) subjective color scores than LM from pigs fed 0 and 5 mg/kg of RAC, and LM from pigs fed 10 mg/kg of RAC was less (P = 0.037) red than LM from pigs fed 0 mg/kg of RAC. In addition, SM from pigs fed 10 mg/kg of RAC had lesser (P <= 0.015) a* and b* values than pork from control-fed pigs; however, L* values for LM and SM were not (P >= 0.081) affected by dietary RAC. Drip loss percentages of the LM were similar (P = 0.815) among RAC treatments, but the SM from RAC-fed pigs had smaller (P = 0.020) drip loss percentages than SM from pigs fed 0 mg/kg of RAC. Marbling scores and IMF content of the LM did not (P >= 0.133) differ among RAC treatments; however, WBSF values were greater (P = 0.005) for LM chops from pigs fed 10 mg/kg than chops from pigs fed 0 and 5 mg/kg of RAC. Even though feeding barrows and gilts 10 mg/kg of dietary RAC reduced (P = 0.050) cooking losses of LM chops compared with feeding 5 mg/kg of RAC, including 10 mg/kg of RAC in the diet of finishing pigs reduced pork tenderness. Therefore, results from this study support the recommendation that including 5 mg/kg of RAC in finishing diets should improve live pig performance without detrimental effects on fresh pork quality and cooked pork palatability. PMID- 23100578 TI - Profiling of differentially expressed microRNA and the bioinformatic target gene analyses in bovine fast- and slow-type muscles by massively parallel sequencing. AB - MicroRNA (miRNA) are highly conserved, noncoding small RNA involved in post transcriptional gene regulation in a variety of biological processes. To elucidate roles of miRNA in bovine muscle type specification and maintenance, we sought to determine differentially expressed miRNA between semitendinosus (STD) and masseter (MS) muscles from 3 Japanese black cattle by massively parallel sequencing. Differential gene expression of myosin heavy chain (MyHC) isoforms confirmed that STD and MS were MyHC-2x- and MyHC-1-abundant muscles, respectively. In total, 192 known miRNA and 20 potential new bovine miRNA were obtained from the sequencing. The differentially expressed miRNA with more than 2 fold difference in each muscle were identified. In particular, miR-196a and miR 885 were exclusively expressed in STD muscle, which was validated by quantitative reverse transcription-PCR (P=0.045 and P<0.001, respectively), whereas a slow type-directing miR-208b was highly expressed in MS compared with STD (false discovery rate<0.05). In addition, 16 potential novel miRNA were mapped and confirmed for their precursor structures by computational analyses. The results of functional annotation combined with in silico target analysis showed that the predicted target genes of miR-196a/b and miR-885 enriched gene ontology (GO) terms related to skeletal system development and regulation of transcription, respectively. Moreover, GO terms enriched from predicted targets miRNA suggested that STD-abundant- and MS-abundant-miRNA were associated with embryonic body planning and organ/tissue pattern formation, respectively. The present results revealed that the differentially expressed miRNA between the STD and MS muscles may play key roles to determine muscle type-specific tissue formation and maintenance in cattle thorough attenuating putative target genes involved in different developmental events. PMID- 23100579 TI - Index selection in terminal sires improves lamb performance at finishing. AB - Lamb meat is often perceived by consumers as fatty, and consumption has decreased in recent decades. A lean growth index was developed in the UK for terminal sire breeds to increase carcass lean content and constrain fat content at a constant age end point. The purposes of this study were 1) to evaluate the effects of index selection of terminal sires on their crossbred offspring at finishing and 2) to evaluate its effectiveness within terminal sire breeds. Approximately 70% of lambs marketed in the UK have been sired by rams of breeds typically thought of as specialized terminal sires. The most widely used are Charollais, Suffolk, and Texel. These breeds participated in sire referencing schemes from the early 1990s by sharing rams among flocks selected on the lean growth index. From 1999 to 2002 approximately 15 "high" and 15 "low" lean growth index score rams were selected from within their sire referencing schemes and mated to Welsh and Scottish Mule ewes. Their crossbred offspring were commercially reared on 3 farms in the UK. Lambs were finished to an estimated 11% subcutaneous fat by visual evaluation. At finishing, lambs were weighed, ultrasonically scanned, and assessed for condition score and conformation. Records were obtained for 6356 lambs on finishing BW (FWT), ultrasonic muscle depth (UMD), ultrasonic fat depth, overall condition score (OCS), and conformation of gigot, loin, and shoulder. Ultrasonic fat depth was log transformed (logUFD) to approach normality. High index-sired lambs were heavier at finishing (1.2+/-0.2 kg) with thicker UMD (0.7+/-0.2 mm) and less logUFD (0.08+/-0.01 mm; P<0.05). There were no differences in OCS or conformation based on the sire index or breed (P>0.08). Suffolk-sired lambs were heavier than Charollais (1.0+/-0.3 kg), which were heavier than Texel (0.9+/-0.3 kg; P<0.001). Texel-sired lambs had thicker UMD than Charollais (0.7+/-0.2 mm; P<0.001) but were not different than Suffolk. Charollais-sired lambs had greater logUFD than both Texel (0.098+/-0.016 mm) and Suffolk (0.061+/-0.017 mm) sired lambs (P<0.001). Within a breed, high- and low index-sired lambs differed in performance with the exceptions of FWT and UMD in Suffolks. Index selection produced heavier and leaner lambs at finishing. Producers have flexibility in choosing the terminal sire that best fits their production system. PMID- 23100580 TI - Postprandial changes of fiber-degrading microbes in the rumen of sheep fed diets varying in type of forage as monitored by real-time PCR and automated ribosomal intergenic spacer analysis. AB - Four ruminally cannulated sheep were used in a crossover design to assess the postprandial changes of fiber-degrading microbes in the solid phase of the rumen of sheep fed 2 high-forage diets. The diets had forage:concentrate ratio of 70:30 (DM basis) and either alfalfa (Medicago sativa) hay (AL) or grass hay (GR) as forage (FOR). Sheep were fed twice daily, and samples from solid rumen digesta were taken at 0, 4, and 8 h after the morning feeding. Postprandial changes of DNA concentrations of all determined microbial populations were similar for the 2 diets. Samples taken at 4 h after feeding had lesser (P < 0.05) concentrations of total bacterial DNA determined with real-time PCR and bacterial diversity and greater (P < 0.05) protozoal DNA concentrations, relative abundance of fungal, Fibrobacter succinogenes, Ruminococcus flavefaciens, and Ruminococcus albus DNA compared with those taken at 0 and 8 h. No effect (P = 0.41 to 0.76) of FOR was detected either on concentrations of bacterial and protozoal DNA or the relative abundance of the 2 Ruminococcus DNA, but GR diet promoted greater (P < 0.001) relative abundance of F. succinogenes and fungal DNA compared with AL diet. Fibrobacter succinogenes was the most abundant (P < 0.05) of the 3 cellulolytic bacteria for both diets, with no differences (P < 0.05) between the 2 Ruminococcus species. Rumen pH and carboxymethylcellulase, Avicelase, and amylase activities were not affected (P = 0.15 to 0.69) by FOR, but xylanase activity was greater (P = 0.01) for GR diet. The influence of FOR on microbial communities in ruminal solid digesta was more evident in the first hours after feeding than at later times after feeding, which highlights the influence of sampling time when investigating dietary effects on rumen function and microbial populations. PMID- 23100581 TI - Effect of dietary acids on growth performance of nursery pigs: a cooperative study. AB - An experiment involving 854 crossbred pigs (20 replicate pens of 4 to 8 pigs per pen) was conducted at 8 experiment stations to determine the effects of acids in nursery pig diets and their inclusion amounts on growth performance using diets and weaning ages typical of those used in the United States commercial pork industry. Diets were formulated to have constant a ME and contain 1.45, 1.45, and 1.30% standardized ileal digestible Lys for phases 1, 2, and 3, respectively. The basal diets were supplemented with various types and concentrations of acid at the expense of corn (Zea mays). Treatment diets included 0% acid (control), 0.1 or 0.2% phosphoric acid, 1 or 2% organic acids, and 0.1% phosphoric acid plus 1% organic acids with or without an antibiotic. The organic acids consisted of 50% citric acid and 50% fumaric acid by weight. All but the final diet contained the antibiotic carbadox. All diets contained 3,000 mg of Zn/kg diet from zinc oxide during phases 1 and 2 and had limited acid buffering capacity, ranging from 142, 127, and 122 mEq/kg of feed for phases 1, 2, and 3, respectively. At each participating station, pigs were randomly allotted to dietary treatments on the basis of their initial BW. Sex and ancestry were equally distributed across the treatments. Results indicated that treatment effects on pig performance were observed in phases 1 and 2 but not in phase 3. In phase 1, ADG of pigs fed 0.2% phosphoric acid was greater than that of pigs fed the combination of acids with no antibiotic (P = 0.041). In phase 2, pigs fed treatments containing an antibiotic had a greater ADG than those fed the combination of acids without antibiotic (P < 0.05). Addition of acids to diets did not affect growth performance during any phase or the overall period. Over the 4-wk study, growth rate was slowest on the treatment without antibiotic, with specific differences that were often statistically significant (P < 0.05). In summary, under the conditions of this experiment, the acid treatments had no effect but the antibiotic improved growth performance. PMID- 23100582 TI - Lactation Biology Symposium: lactocrine signaling and developmental programming. AB - Lactocrine signaling is defined as transmission of bioactive factors from mother to offspring as a consequence of nursing. Lactocrine transmission of signaling molecules may be an evolutionarily conserved process through which bioactive factors necessary for support of neonatal development are delivered postnatally. Dependence on maternal resources for development in eutherian mammals extends into neonatal life for at least that period of time when nutrition is obtained solely from first milk (i.e., colostrum). Data for the pig (Sus scrofa domesticus) provide evidence of lactocrine mediated effects on development of the female reproductive tract and other somatic tissues. Porcine uterine gland development, an estrogen receptor-alpha (ESR1)-dependent process, begins within 2 d of birth [postnatal day (PND) 0]. A lactocrine-driven, ESR1-mediated process was proposed as a regulatory mechanism governing onset of uterine gland development and endometrial maturation in the neonatal pig. Gilts maintained in a lactocrine-null state for 2 d from birth by milk-replacer feeding displayed altered patterns of endometrial gene expression and retarded uterine gland development by PND 14. In lactocrine-null gilts, inhibition of endometrial and cervical ESR1 and vascular endothelial growth factor (VEGFA) expression observed on PND 2 persisted to PND 14, even after gilts were returned to nursing on PND 2. Collectively, data support a role for lactocrine signaling in regulation of critical neonatal developmental events. Maternal lactocrine programming of postnatal development may help to insure healthy developmental outcomes. A systems biology approach will be required to define and understand mechanistic dynamics of lactocrine signaling events that may ultimately connect genotype to phenotype and establish the parameters of reproductive potential. PMID- 23100583 TI - Genotype by diet interactions in European sea bass (Dicentrarchus labrax L.): Nutritional challenge with totally plant-based diets. AB - Aquaculture of carnivorous species has strongly relied on fish meal and fish oil for feed formulation; however, greater replacement by terrestrial plant-based products is occurring now. This rapid change in dietary environment has been a major revolution and has to be taken into consideration in breeding programs. The present study analyzes potential consequences of this nutritional tendency for selective breeding by estimating genetic parameters of BW and growth rates estimated by the thermal growth coefficient (TGC) over different periods with extremely different diets. European sea bass (Dicentrarchus labrax L.) from a factorial cross (1,526 fish) between 25 sires and 9 dams were used to estimate heritabilities and genotype by diet interaction. Starting 87 d after fertilization (2.5 g), one-half of the sea bass were fed a diet containing marine products (M), and the other one-half were fed a totally plant-based (PB) diet (without any fish meal or fish oil). The fish were individually tagged, reared in a recirculated system, and genotyped at 13 microsatellites to rebuild parentage of individuals. Body weight and TGC were measured for 335 d until fish fed the M diet reached 108.3 g of BW. These traits were significantly less in fish fed the PB diet (P<0.05) in the very first stages after the dietary shift, but the difference in TGC between diets rapidly disappeared (P>0.1). Survival was significantly less in fish fed the PB diet (PB=64.7%, M=93.7% after 418 d, P<0.05). This work identified moderate heritabilities (0.18 to 0.46) for BW with both diets and high genetic correlations between diets (0.78 to 0.93), meaning low genotype by diet interactions, although diets were extremely different. Heritabilities of TGC (0.11 to 0.3) were less than for BW as well as genetic correlations between diets (0.43 to 0.64). Using such extremely different diets, predicted BW gains in different scenarios indicated that selecting fish for growth on a marine diet should be the most efficient way to increase growth on plant-based diets, meaning that, in this case, indirect selection should be more efficient than direct selection. PMID- 23100584 TI - Glucocorticoid overexposure in neonatal life alters pancreatic beta-cell function in newborn foals. AB - Studies in humans and animals have linked abnormal programming of adult tissue function to excess glucocorticoids during perinatal development. The current study investigated the hypothesis that physiological variations in glucocorticoid concentrations during early neonatal life of the foal alter the secretory responses of the pancreatic beta cells 2 and 12 wk after treatment. Spontaneously delivered foals received either saline or long-acting ACTH for 5 d from 1 d after birth to maintain an endogenous rise in cortisol concentrations. Starting at d 10, pancreatic beta cell function was studied using an intravenous (i.v.) glucose tolerance test, an i.v. arginine challenge, and an i.v. tolbutamide challenge. The maximum increment in plasma insulin achieved in response to exogenous glucose was less in ACTH-treated foals at both 2 and 12 wk of age (P<0.05). By 12 wk of age, developmental changes also occurred in the magnitude and biphasic pattern of glucose-stimulated insulin release. The area under the insulin curve during the early phase of insulin secretion (0 to 30 min) was not different between the 2- and 12-wk-old animals but was significantly greater during the later phase (30 to 120 min) at 12 wk than at 2 wk (P<0.05). Arginine infusion induced a brief 5 to 15 min increase in plasma concentrations of insulin that was not different in saline- and ACTH-treated foals. The beta-cell response to tolbutamide infusion was rapid and monophasic, and there was no difference (P>0.05) in the area under the insulin curve with treatment at 2 or at 12 wk. However, after tolbutamide, plasma insulin concentrations remained increased for a longer period in the ACTH treated than in the saline-treated foals at 12 wk of age (P<0.05). Hence, this is the first study to show altered pancreatic beta-cell function after ACTH-induced glucocorticoid overexposure during early postnatal life in foals. PMID- 23100585 TI - Use of near-infrared spectroscopy to predict energy content of commercial dog food. AB - Near-infrared spectroscopy (NIRS) is used in the pet food industry for rapid assessment of several macronutrients and GE content, but there is little published data on its usefulness for evaluating GE and GE digestibility (GED) of commercial pet food. Using NIRS spectra of 71 commercial extruded dog foods and reference values determined with calorimetry and in vivo feeding trials, chemometric models were developed for GE, GED, and DE prediction. The SE and R(2) of cross-validation were 0.30 MJ/kg DM and 0.93 for GE, 2.10% and 0.82 for GED, and 0.53 MJ/kg DM and 0.92 for DE. The results indicated that NIRS provides GE, GED, and DE estimation values for dog food with an accuracy similar to that of the 2006 NRC proposed equations for use in pet food. Near-infrared spectroscopy is a fast and accurate method for predicting energy content in commercial extruded dog food, and is a useful and reliable tool to be used by the pet food industry when a wide enough calibration set is available. PMID- 23100586 TI - Phenotypic prediction based on metabolomic data for growing pigs from three main European breeds. AB - Predicting phenotypes is a statistical and biotechnical challenge, both in medicine (predicting an illness) and animal breeding (predicting the carcass economical value on a young living animal). High-throughput fine phenotyping is possible using metabolomics, which describes the global metabolic status of an individual, and is the closest to the terminal phenotype. The purpose of this work was to quantify the prediction power of metabolomic profiles for commonly used production phenotypes from a single blood sample from growing pigs. Several statistical approaches were investigated and compared on the basis of cross validation: raw data vs. signal preprocessing (wavelet transformation), with a single-feature selection method. The best results in terms of prediction accuracy were obtained when data were preprocessed using wavelet transformations on the Daubechies basis. The phenotypes related to meat quality were not well predicted because the blood sample was taken some time before slaughter, and slaughter is known to have a strong influence on these traits. By contrast, phenotypes of potential economic interest (e.g., lean meat percentage and ADFI) were well predicted (R(2) = 0.7; P < 0.0001) using metabolomic data. PMID- 23100587 TI - Effects of increased milking frequency during early lactation on milk yield and udder health of primiparous Holstein heifers. AB - In dairy cows, increased milking frequency (IMF) during early lactation stimulates an increase in milk yield that partially persists through the remainder of lactation. However, the effects of IMF on lactation performance and udder health of primiparous heifers have not been clearly established. The objective of this study was to determine the effects of IMF during early lactation on milk yield and composition, udder edema, and teat-end condition of primiparous Holstein heifers. Thirteen heifers were assigned at parturition to unilateral frequent milking (twice-daily milking of the left udder half (2X), and 4-times-daily milking of the right udder half (4X)) from d 1 to 21 of lactation. Heifers were milked twice daily at 0130 and 1330 h, with additional milking of the right udder half at 0430 and 1630 h. Half-udder milk yield and composition were recorded on d 1 and 4, weekly through 35 d in milk (DIM), monthly through 210 DIM, and on d 270+/-1 of lactation. Udder edema and teat-end scores were evaluated on d 1 and 4, weekly through d 35, and on d 60+/-1 of lactation. A 1 sided paired t test was used to compare milk yield of 4X- to 2X-udder halves. A 2 sided paired t test was used to test for differences in milk composition, udder edema, and teat-end scores. Overall, 4X stimulated an immediate increase in milk yield. Differential milk yield peaked on d 21 of lactation, with 4X udder halves producing 2.8 kg/d more milk than 2X udder halves (P<0.001). After cessation of 4X, the milk yield differential decreased, but 4X udder halves continued to produce 0.8 kg/d more milk than 2X udder halves through d 270 of lactation (P<0.05). Over the entire lactation, milk component yields and 3.5% fat-corrected milk or energy-corrected milk were greater (P<0.05), whereas somatic cell counts in milk were lower, in 4X udder halves (P<0.05). Udder edema and teat-end condition did not differ between 4X and 2X (P>0.19). In conclusion, IMF during early lactation stimulated a persistent increase in milk yield without negatively affecting several indicators of udder health of primiparous dairy heifers. PMID- 23100588 TI - In vitro digestibility of expanded pork skin and rawhide chews, and digestion and metabolic characteristics of expanded pork skin chews in healthy adult dogs. AB - Chews are an important part of the pet product industry, with many having potential to decrease plaque or calculus formation. However, their digestion characteristics and gut transit time are virtually unknown. Two experiments were conducted to determine in vitro DM digestibility of expanded pork skin chews and rawhide chews, and apparent total tract digestibility (ATTD), gastrointestinal transit time, and blood metabolite measurements in healthy adult dogs fed a weight-control commercial diet and expanded pork skin chews. In Exp.1, an in vitro method that simulated gastric and small intestinal digestion was used to determine DM digestibility of expanded pork skin chews and rawhide chews. In Exp. 2, after a 22-d baseline phase, 10 purpose-bred, intact female dogs (5 to 5.5 yr of age; 18.9 to 23.1 kg BW) were fed the diet plus an expanded pork skin chew (~45 g) each day for 22 d. In vitro gastric digestibility of expanded pork skin chews increased with time, with chews being 54.7%, 58.6%, 76.4%, and 86.4% digestible after 6, 12, 18, and 24 h of gastric digestion, respectively. By contrast, gastric digestibility of rawhide chews was 7.6% at 6 h, slowly increased over time, and reached a maximum of 41.6% at 18 h. In vitro gastric plus small intestinal digestibility results indicated near complete digestibility of expanded pork skin chews at all times, whereas rawhide chews were 50 to 85% digestible. In vivo ATTD of DM, OM, and N were greater (P < 0.05) when dogs were fed expanded pork skin chews along with the basal diet, compared with the basal diet alone. However, chew intake did not change transit time measured with a wireless motility device. By contrast, motility index and contraction pattern of the colon were altered (P < 0.05) during chew feeding relative to control. Blood urea N concentrations were greater (P < 0.05) in dogs fed expanded pork skin chews, compared with baseline; this was not surprising, given the increased N intake and absorption from the chews. Intake of expanded pork skin chews resulted in reduced blood cholesterol concentrations (P < 0.05) and tended to decrease blood triglyceride concentrations (P < 0.10). Expanded pork skin had a greater DM digestibility than rawhide chews. In addition, expanded pork skin decreased blood cholesterol and triglyceride concentrations, which may justify further research in this area. PMID- 23100589 TI - Growth and Development Symposium: Stem cell therapy in equine tendon injury. AB - Tendon injuries affect all levels of athletic horses and represent a significant loss to the equine industry. Accumulation of microdamage within the tendon architecture leads to formation of core lesions. Traditional approaches to tendon repair are based on an initial period of rest to limit the inflammatory process followed by a controlled reloading program designed to promote the maturation and linear arrangement of scar tissue within the lesion. However, these treatment protocols are inefficient, resulting in prolonged recovery periods and frequent recurrence. Current alternative therapies include the use of bone marrow-derived mesenchymal stem cells (BMSC) and a population of nucleated cells from adipose containing adipose-derived mesenchymal stem cells (AdMSC). Umbilical cord blood derived stem cells (UCB) have recently received attention for their increased plasticity in vitro and potential as a therapeutic aid. Both BMSC and AdMSC require expansion in culture before implantation to obtain a pure stem cell population, limiting the time frame for implantation. Collected at parturition, UCB can be cryopreserved for future use. Furthermore, the low immunogenicity of the UCB population allows for allogeneic implantation. Current research indicates that BMSC, AdMSC, and UCB can differentiate into tenocyte-like cells in vitro, increasing expression of scleraxis, tenascin c, and extracellular matrix proteins. When implanted, BMSC and AdMSC engraft into the tendon and improve tendon architecture. However, treatment with these stem cells does not decrease recovery period. Furthermore, the resulting regeneration is not optimal, as the resulting tissue is still inferior to native tendon. Umbilical cord blood-derived stem cells may provide an alternate source of stem cells that promote improved regeneration of tendon tissue. A more naive cell population, these cells may have a greater rate of engraftment as well as an increased ability to secrete bioactive factors and recruit additional reparative cells. Further work should clarify the role of distinct stem cell sources in the regenerating tendon and the need for a naive or differentiated cell type for implantation. PMID- 23100590 TI - Expression of kyphosis in young pigs is induced by a reduction of supplemental vitamin D in maternal diets and vitamin D, Ca, and P concentrations in nursery diets. AB - Kyphosis is an idiopathic disease characterized by abnormal, outward spinal curvature. A spontaneous outbreak and subsidence of kyphosis over a 4-mo period in the University of Wisconsin Swine Research and Teaching Center herd coincided with an accidental omission of vitamin D(3) in 1 of 2 premixes used in sow diets. This controlled experiment was conducted to determine whether vitamin D deletion from premixes used in sow diets would induce kyphosis in their offspring. Crossbred (Landrace * Large White), multiparous sows (n = 8) were fed corn soybean meal diets supplemented with either 325 IU vitamin D(3)/kg (+D) or 45 IU vitamin D(3)/kg (-D) diet from breeding through lactation. The vitamin D concentrations duplicated formulations of diets fed during the earlier spontaneous outbreak. At weaning (approximately 4 wk), pigs were fed diets devoid of supplemental vitamin D and formulated to supply either 120% of the Ca and P requirements (HCaP) or 80% of the Ca and P requirements (LCaP) until wk 9. At wk 9, all pigs were fed the HCaP diet until wk 13. No evidence of kyphosis was observed in pigs at weaning. Pigs produced by -D sows and fed LCaP diets exhibited a 17% incidence (4/23 pigs) of kyphosis at wk 9. At wk 13, the incidence of kyphosis had increased to 32% (6/19 pigs). Unexpectedly at wk 13, pigs produced by +D sows and fed LCaP diets exhibited a 26% incidence (5/19 pigs) of kyphosis. None of the pigs fed HCaP diets from wk 4 to 13 displayed kyphosis, regardless of maternal diets. Evidence of kyphosis was detected at a younger age if pigs were produced by sows fed -D diets. Whole body and femur bone mineral content determined with dual energy X-ray absorptiometry were reduced (P < 0.05) in pigs fed LCaP vs. HCaP diets, but pigs produced by -D sows were more severely affected. Femur bending moments were reduced (P < 0.05) at wk 9 and 13 in pigs fed LCaP vs. HCaP diets. At wk 13, pigs produced by -D sows and fed LCaP diets had reduced (P < 0.05) bone mineral density and femur yield bending moment compared with pigs from +D sows fed LCaP diets. In conclusion, the 20 to 30% incidence of kyphosis induced by altering vitamin D, Ca, and P concentrations in maternal and nursery diets mimics the incidence observed in spontaneous outbreaks in afflicted herds. A reproducible vitamin D-induced kyphosis in young pigs offers a suitable model to study skeletal tissue characteristics, fetal skeletal tissue development, and potential treatments for pigs and human patients afflicted by this disease. PMID- 23100591 TI - Avoiding hypothermia in neonatal pigs: effect of duration of floor heating at different room temperatures. AB - The effect of different farrowing room temperatures (15, 20, or 25 degrees C), combined with floor heating (FH) at the birth site, on the postnatal rectal temperature of pigs, use of creep area, and latency to first colostrum uptake was investigated with 61 litters born by loose-housed sows. Pig rectal temperature was measured at birth, as well as at 0.25, 0.5, 1, 1.5, 2, 3, 4, 12, 24, and 48 h after birth. The drop in rectal temperature from birth to 0.5 h postpartum was less (P<0.05) at room temperature of 25 degrees C compared with 20 and 15 degrees C. Minimum rectal temperature was less (P<0.001) at 15 degrees C than either 20 or 25 degrees C, and the time it took for rectal temperature to increase above 37 degrees C was longer (P<0.05) when room temperature was 15 degrees C than 20 and 25 degrees C. Rectal temperatures at 24 (P<0.001) and 48 h (P<0.05) postpartum were also lower at room temperature of 15 degrees C than 20 and 25 degrees C. Duration of FH (12 or 48 h) did not influence (P>0.28) the rectal temperature at 24 or 48 h after birth. More pigs used the creep area 12 to 60 h after birth of the first pig at a room temperature of 15 degrees C with 12 h FH compared with all other treatments. During the latter part of this period, more pigs stayed in the creep area also at 20 degrees C with 12 h FH. After 60 h, more pigs (P<0.01) used the creep area at low compared with high room temperatures (15 degrees C>20 degrees C>25 degrees C). Odds ratio of pigs dying before they had suckled was 6.8 times greater (P=0.03) at 15 than 25 degrees C (95% CI of 1.3 to 35.5), whereas the odds ratio of dying during the first 7 d was 1.6 greater (P=0.05) for 48 vs. 12 h of FH (95% CI of 1.0 to 2.57), mainly due to more pigs being crushed. In conclusion, FH for 48 h was no more favorable than 12 h for pigs because the risk of hypothermia was equal in the 2 treatments, and the risk of dying increased with the longer FH duration. Increasing the room temperature to 25 degrees C reduced hypothermia and the risk of pigs dying before colostrum intake. PMID- 23100592 TI - The effects of freezing and thawing rates on tenderness, sensory quality, and retail display of beef subprimals. AB - The objective of this study was to evaluate processing methods for frozen beef subprimals; the effects of freezing and thawing rates on tenderness, sensory properties, and retail display were evaluated. There were 6 treatments: fresh, never frozen 14 d wet aged (14D); fresh, never frozen 21 d wet aged (21D); blast frozen-fast thawed (BF); blast frozen-slow thawed (BS); conventionally frozen fast thawed (CF); and conventionally frozen-slow thawed (CS). All frozen beef subprimals were aged for 14 d before freezing. Three beef subprimal cuts, rib eye roll (n=90), strip loin (n=90), and top sirloin butt (n=90), were used with 3 replications of 5 samples per treatment per week (total of 9 wk, n=270). Blast freezing occurred by placing spacers between the boxes of meat on pallets at -28 degrees C with high air velocity for 3 to 5 d. Conventional freezing occurred with boxes of meat stacked on pallets and placed in a -28 degrees C freezer with minimal air movement for at least 10 d. Fast thawing of subprimals (to an internal temperature of -1 degrees C to 1 degrees C) occurred by immersion in a circulating water bath (<12 degrees C) for 21 h, and slow thawing of subprimals occurred over a 2-wk period by placing individual subprimals on tables at 0 degrees C. Steaks (2.5 cm thick) were cut from the longissimus thoracis (LT), longissimus lumborum (LL), and gluteus medius (GM) for Warner-Bratzler shear force (WBS), trained sensory evaluation, and retail display. For LL and GM beef steaks, frozen treatments were equal or lower in WBS values to 14D and 21D beef steaks. No differences were detected in WBS among the treatments applied to GM beef steaks (P=0.08). There were no differences in sensory tenderness among the LL, LT, and GM (P>0.05). All LL and LT beef steaks had approximately 4 d to 40% discoloration, and all GM steaks had over 3 d to 40% discoloration. Steaks from the LL and LT began to discolor at about 3 d, and the GM began to discolor after 1 d. For all beef subprimals, purge loss during storage and thawing was significantly greater for the slow-thawed subprimals (P<0.01), and all fast thawed subprimals were equal or superior to 14D and 21D (P<0.01) in storage and thawing purge. During retail display, the greatest purge loss occurred in fast thawed treatments (P<0.01). Overall, freezing rate did not affect purge loss, and neither freezing nor thawing rates had significant meaningful effects on WBS, and sensory properties were comparable with fresh, never-frozen subprimals. PMID- 23100593 TI - Breeding and Genetics Symposium: a systems biology definition for chicken semen quality. AB - Rooster semen is an effluent from paired reproductive tracts. Each tract includes a testis, epididymis, and deferent duct. Upon ejaculation, efficacy of sperm propulsion varies among roosters. This phenotype is sperm mobility, that is, the movement of sperm against resistance at body temperature. The present work 1) compares reproductive tract throughput between lines of chickens selected for low and high sperm mobility, 2) demonstrates how semen quality can be defined in terms of an interaction between reproductive tract throughput and the proportion of mobile sperm ejaculated, 3) confirms that phenotype can be linked to genomewide differences in SNPlotype, and 4) shows how breeding can affect semen quality. Sperm mobility phenotype distributions were based on the average of duplicate observations per male (n = 241 and 262 roosters for low and high lines, respectively). Distributions were skewed and normal for low and high lines, respectively. Subsequent analyses used these base populations as sources for test subjects. In the first analysis, 10 males were selected from the mode of each distribution, and sperm mobility data were evaluated by nested ANOVA. Variation was observed between lines (P < 0.0001) but not among males within lines (P = 0.980). Sperm mobility data along with data from paired reproductive tracts were used to estimate combined reproductive tract throughput. Whereas testicular output was 1.2-fold greater in the low line (P = 0.037), the output of mobile sperm per day was 10.5-fold greater in the high line (P < 0.0001). Deferent duct transit differed between tails of the low line (P < 0.0001) but not between the tails of the high line (P = 0.514). Males from the mode and upper tail of the low line were SNPlotyped using a 60k chip by DNA Landmarks. These test subjects were used to associate phenotype with SNPlotype because founder effects and genetic drift could be discounted. Loci of interest were found on multiple chromosomes. Loci on chromosome Z were of particular interest because roosters are homozygous for this sex chromosome and a pronounced maternal effect was observed in a prior heritability study. Midrange phenotypes were produced by crossing low and high sperm mobility lines. Our experimental outcomes demonstrate that genes affect reproductive tract function as well as sperm cell attributes and thereby make semen quality subject to genetic selection. PMID- 23100594 TI - Lactation Biology Symposium: role of colostrum and colostrum components on glucose metabolism in neonatal calves. AB - In neonatal calves, nutrient intake shifts from continuous glucose supply via the placenta to discontinuous colostrum and milk intake with lactose and fat as main energy sources. Calves are often born hypoglycemic and have to establish endogenous glucose production (eGP) and gluconeogenesis, because lactose intake by colostrum and milk does not meet glucose demands. Besides establishing a passive immunity, colostrum intake stimulates maturation and function of the neonatal gastrointestinal tract (GIT). Nutrients and nonnutritive factors, such as hormones and growth factors, which are present in high amounts in colostrum of first milking after parturition, affect intestinal growth and function and enhance the absorptive capacity of the GIT. Likely as a consequence of that, colostrum feeding improves the glucose status in neonatal calves by increasing glucose absorption, which results in elevated postprandial plasma glucose concentrations. Hepatic glycogen concentrations rise much greater when colostrum instead of a milk-based colostrum replacer (formula with same nutrient composition as colostrum but almost no biologically active substances, such as hormones and growth factors) is fed. In contrast, first-pass glucose uptake in the splanchnic tissue tended to be greater in calves fed formula. The greater plasma glucose rise and improved energy status in neonatal calves after colostrum intake lead to greater insulin secretion and accelerated stimulation of anabolic processes indicated by enhanced maturation of the postnatal somatotropic axis in neonatal calves. Hormones involved in stimulation of eGP, such as glucagon and cortisol, depend on neonatal diet, but their effects on eGP stimulation seem to be impaired. Although colostrum feeding affects systemic insulin, IGF-I, and leptin concentrations, evidence for systemic action of colostral insulin, IGF-I, and leptin in neonatal calves is weak. Studies so far indicate no absorption of insulin, IGF-I, and leptin from colostrum in neonatal calves, unlike in rodents where systemic effects of colostral leptin are demonstrated. Therefore, glucose availability in neonatal calves is promoted by perinatal maturation of eGP and colostrum intake. There may be long-lasting effects of an improved colostrum supply and glucose status on postnatal growth and development, and colostrum supply may contribute to neonatal programming of performance (milk and growth) in later life, but data proving this concept are missing. PMID- 23100595 TI - Meat Science and Muscle Biology Symposium: manipulating mesenchymal progenitor cell differentiation to optimize performance and carcass value of beef cattle. AB - Beef cattle are raised for their lean tissue, and excessive fat accumulation accounts for large amounts of waste. On the other hand, intramuscular fat or marbling is essential for the palatability of beef. In addition, tender beef is demanded by consumers, and connective tissue contributes to the background toughness of beef. Recent studies show that myocytes, adipocytes, and fibroblasts are all derived from a common pool of progenitor cells during embryonic development. It appears that during early embryogenesis, multipotent mesenchymal stem cells first diverge into either myogenic or adipogenic-fibrogenic lineages; myogenic progenitor cells further develop into muscle fibers and satellite cells whereas adipogenic-fibrogenic lineage cells develop into the stromal-vascular fraction of skeletal muscle where reside adipocytes, fibroblasts, and resident fibro-adipogenic progenitor cells (the counterpart of satellite cells). Strengthening myogenesis (i.e., formation of muscle cells) enhances lean growth, promoting intramuscular adipogenesis (i.e., formation of fat cells) increases marbling, and reducing intramuscular fibrogenesis (i.e., formation of fibroblasts and synthesis of connective tissue) improves overall tenderness of beef. Because the abundance of progenitor cells declines as animals age, it is more effective to manipulate progenitor cell differentiation at an early developmental stage. Nutritional, environmental, and genetic factors shape progenitor cell differentiation; however, up to now, our knowledge regarding mechanisms governing progenitor cell differentiation remains rudimentary. In summary, altering mesenchymal progenitor cell differentiation through nutritional management of cows, or fetal programming, is a promising method to improve cattle performance and carcass value. PMID- 23100596 TI - Deoxynivalenol and E.coli lipopolysaccharide alter epithelial proliferation and spatial distribution of apical junction proteins along the small intestinal axis. AB - We investigated a proposed synergistic effect of deoxynivalenol (DON) and lipopolysaccharides (LPS) on small intestinal architecture and epithelial barrier integrity in pigs. Crypt depth and intestinal cell proliferation were analyzed, as well as expression of zonula occludens protein-1 (ZO-1) and beta-catenin of the apical junction complex along the small intestine. Barrows (26.2+/-4.1 kg) were fed restrictedly either a control diet (CON) or a diet naturally contaminated with 3.1 mg DON/kg feed (DON) for 37 d. At d 37, the control group was infused for 1 h either with 100 MUg/kg BW of DON (CON-DON, n=6), 7.5 MUg/kg BW of LPS (CON-LPS, n=6), a combination of both (CON-DON+LPS, n=7), or 0.9% NaCl (CON-CON, n=6) and the DON group with 7.5 MUg/kg BW of LPS (DON-LPS, n=8) or 0.9% NaCl (DON-CON, n=6). Pigs were euthanized 3.25 h after start of infusion. Immunohistochemistry (5'-bromo-2'-deoxyuridine for proliferation) and immunofluorescence (ZO-1 and beta-catenin) from duodenum, proximal jejunum, mid jejunum, proximal ileum, and terminal ileum were analyzed for crypt depth, cell proliferation, and apical junction proteins. Duodenal crypts were deeper compared with the other 4 intestinal regions, and proximal jejunal crypts were deeper than those of mid-jejunum and proximal ileum (P<0.001). Epithelial proliferation showed a bell-shaped distribution along the small intestinal axis. Duodenal proliferating cells had the least number compared with jejunal sections and proximal ileum (P<0.001). Neither DON nor LPS affected these variables. Zonula occludens-1 displayed a distinct spatial distribution in the epithelium with an apical and a cytosolic component. Apical expression of ZO-1 was severely damaged in the mid-jejunum (P<0.001) of CON-DON compared with animals treated with LPS. Also, in all animals receiving LPS systemically, the cytosolic ZO-1 fraction in the 3 upper gut sections disappeared completely. This effect was independent of DON presence. Control pigs had a greater basolateral beta-catenin accumulation (P<0.05) in the cells, whereas the protein distribution did not differ in CON-DON pigs. In conclusion, results of this experiment demonstrated that epithelial proliferation has a distinct pattern along the small intestine and is not necessarily positively linked to crypt depth in pigs. Furthermore, results indicate that LPS changed the spatial distribution of ZO-1. A synergistic effect of DON and LPS on intestinal architecture could not be verified in the present study. PMID- 23100597 TI - Backfat thickness and longissimus dorsi real-time ultrasound measurements in light lambs. AB - The aim of this study was to assess the accuracy of ultrasound measurements for predicting carcass traits in 124 Spanish pascual-type lambs (13 to 16 kg carcass weight). Ultrasound images were taken transversal and longitudinal to the vertebral column and at thoracic (TV; between 12th and 13th ribs) and lumbar (LV; between first and second lumbar vertebrae) locations. Skin thickness, subcutaneous backfat thickness (BFT), and depth (DLD), width (WLD), and area (ALD) of longissimus dorsi were obtained with ImageJ 1.42q software. After slaughter, BFT (TV, 2.30 +/- 0.06 mm; LV, 2.46 +/- 0.06 mm), DLD (TV, 2.47 +/- 0.03 cm; LV, 2.48 +/- 0.03 cm), WLD (TV, 4.50 +/- 0.04 cm; LV, 4.60 +/- 0.04 cm), and ALD (TV, 9.96 +/- 0.12 cm(2); LV, 10.19 +/- 0.13 cm(2)) were directly measured on the lamb carcass. Correlations between ultrasound and direct carcass measurements were greater than 0.61 for DLD, WLD, and ALD (P < 0.05) whereas they fluctuated between 0.32 and 0.60 for BFT (P < 0.05); moreover, correlations were significantly (P < 0.05) greater for transversal than for longitudinal views. In a similar way, linear regression analyses suggested a moderate underestimation for BFT and lumbar DLD when using real-time ultrasound technologies whereas WLD, ALD, and thoracic DLD suffered from under- and overestimation for small and large values of carcass traits, respectively. After decomposing the mean square prediction error (MSPE) for the different ultrasound measurements, we found that the error due to disturbance contributed most to the MSPE followed by the error of central tendency and the error due to regression. The SE of prediction (SEP) was also calculated as an additional precision indicator, obtaining estimates less than that in previous studies with larger lambs. In conclusion, transversal ultrasound measurements at the thoracic and lumbar levels could be a useful tool for predicting DLD, WLD, and ALD in light lambs, perhaps suffering from worse prediction properties when focusing on BFT. This information could be of special relevance for light lamb producers worldwide, with a special emphasis in the Mediterranean basin where this kind of production system accounts for a large percentage of the sheep industry. PMID- 23100598 TI - Comparison of flight speed and exit score as measurements of temperament in beef cattle. AB - Observations were collected for the purpose of comparing exit velocity measurements in the form of exit score (ES; walk, trot, canter, or run) and flight speed (FS) as assessments of cattle temperament. Squeeze chute exit velocity was obtained for 1,181 crossbred yearling steers using ES and FS temperament systems. Flight speed used infrared sensors to determine the time taken for an animal to traverse a fixed distance of 1.83 m after exiting the squeeze chute. Exit score (1=walk, 2=trot, 3=canter, and 4=run) was assigned by 2 different observers when each steer crossed a fixed point between the infrared sensors. All animals were scored with each system (ES and FS) simultaneously on exiting the squeeze chute on d -21 and d -1 of the experiment. Of the 1,181 cattle, 357 were moved to a nearby research feedyard for use in a 140 d feedlot trial. These cattle were scored using both measurement systems and BW was recorded at 35 d intervals throughout the trial. Exit score was assessed for observer reliability, ES and FS were compared for measurement repeatability, and both were assessed on ability to predict ADG. Exit score between observers on a single day showed considerable agreement (weighted Kappa=0.66), indicating the system was reliable between different observers. However, the agreement for a single observer between day was only moderate (weighted Kappa=0.40), indicating a day effect for ES. In addition, although mean velocities for day were not different (P>0.18; FS=2.98+/-.87 and 3.02+/-0.87 m/s for day, respectively), the persistence of FS for each animal was low (Spearman rank correlation coefficient=0.25). The frequency that an animal would be placed into the same third of FS or receive the same ES on consecutive weigh days was 50% and 60.0%, respectively, and both were moderate predictors of ADG (R2=0.14 and R2=0.17). These data indicate that ES and FS are reliable instruments for assessment of temperament on a given day, and show moderate repeatability across days. Exit score and FS show similar ability to predict ADG and can be used interchangeably as measures of temperament. PMID- 23100599 TI - Astaxanthin modulates age-associated mitochondrial dysfunction in healthy dogs. AB - Young (2.97+/-0.01 yr; 8.16+/-0.15 kg BW) and geriatric (10.71+/-0.01 yr; 9.46+/ 0.18 kg BW) healthy female Beagle dogs (n=14/age group) were fed 0 or 20 mg astaxanthin daily for 16 wk to examine modulation of mitochondrial function. Fasted blood was sampled on wk 0, 8, and 16. Mitochondria membrane permeability, ATP production, cytochrome c oxidase/reductase, and number were assessed in leukocytes whereas astaxanthin uptake, glutathione, superoxide dismutase, nitric oxide, 8-hydroxy-2'-deoxyguanosine, 8-isoprostane, and protein carbonyl were measured in plasma. Aging increased (P<0.05) complex III cytochrome c oxidoreductase but decreased (P<0.05) 8-hydroxy-2'-deoxyguanosine and protein carbonyl. Mitochondrial function improved in both young and geriatric dogs by increasing (P<0.05) ATP production, mitochondria mass, and cytochrome c oxidoreductase activity, especially in geriatric dogs compared with young dogs. Astaxanthin feeding also increased (P<0.05) the reduced glutathione to oxidized glutathione ratio in young dogs and decreased (P<0.05) nitric oxide in both young and geriatric dogs. Dietary astaxanthin improved mitochondrial function in blood leukocytes, most likely by alleviating oxidative damage to cellular DNA and protein. PMID- 23100600 TI - Synovex Plus implants coated with a polymeric, porous film improve performance of beef steers and heifers fed in confinement for up to 200 days. AB - Synovex Plus (SP) is a product that delivers 28 mg of estradiol benzoate (EB) and 200 mg of trenbolone acetate (TBA). We studied the impact of a polymeric, porous coating on SP implants (CSP) to prolong release of EB and TBA, and stimulate feedlot performance of feedlot cattle for an extended period. In an explant study, 30 steers were implanted with SP in one ear and CSP in the contralateral ear. Cattle (n = 6/d) were necropsied 40, 81, 120, 160, and 200 d after treatment, and remaining EB and TBA were quantified. Linear regression of EB and TBA remaining as a function of time for each treatment were computed. Rates of EB and TBA depletion from SP were -0.1980 (r(2) = 0.9994) and -1.7073 mg/d (r(2) = 0.9644), respectively, and for CSP rates of EB and TBA depletion were -0.1049 (r(2) = 0.9123) and -0.9466 mg/d (r(2) = 0.9297), respectively. The effect of treatment on depletion rates of each analyte were significant (P < 0.05). Data also showed EB and TBA were delivered from CSP at least 200 d but were delivered from SP about 120 d. Multisite trials with beef-type steers (4 sites) and heifers (4 sites) evaluated feedlot performance and carcass characteristics in response to a CSP implant or when sham implanted (SC). A randomized complete block design with 9 blocks and 2 treatments was used per site within animal gender. Across sites, steers (n = 342, BW = 297 kg) were fed finishing rations for 190 to 202 d (mean 198 d) and heifers (n = 342, BW = 289 kg) were fed finishing rations for 191 to 201 d (mean 198 d). Cattle were harvested and carcasses evaluated. Data were pooled across sites within gender for statistical analysis. Steers and heifers treated with CSP yielded greater (P <= 0.003) ADG, DMI, and G:F than SC steers and heifers. Mean BW differences between CSP and SC continued to increase throughout the study, indicating CSP stimulated growth of steers and heifers for 198 d. Mean carcass weights of CSP steers (P = 0.005) and heifers (P = 0.004) were greater than those of SP steers and heifers by 26.2 and 20.6 kg, respectively. The LM area was larger (P < 0.001) in CSP steers and heifers than SC cattle. Marbling decreased with CSP treatment (P <= 0.031), which caused reductions (P <= 0.006) in proportions of carcasses grading Prime or Choice. Evidence from these studies showed that a single administration of CSP increased feedlot cattle performance for at least 198 d, compared with SC, and may reduce the need to reimplant cattle. PMID- 23100601 TI - Mononuclear leukocyte fatty acid composition and inflammatory phenotype in periparturient and lactating sows. AB - Increased plasma NEFA concentrations and compromised immune responses are associated with increased disease susceptibility during farrowing and lactation. Increased plasma NEFA concentrations cause changes in the fatty acid (FA) content of plasma lipid fractions and peripheral blood mononuclear cells (PBMC) that could modify inflammatory responses. The goals of this study were to describe changes in plasma lipid composition and to characterize the FA content and proinflammatory phenotype of PBMC in periparturient and lactating sows. Blood samples from 10 sows were collected at 2 wk prefarrow, at 2 d after farrowing (hereafter referred to as farrowing), and at 18 d of lactation (hereafter referred to as lactation). Total lipids and lipid fractions were extracted from plasma and PBMC. Isolated PBMC also were assessed for gene expression of proinflammatory cytokines and enzymes involved in lipid mediator biosynthesis using quantitative PCR. The FA profile of plasma NEFA, phospholipids, neutral lipids, and PBMC phospholipids differed from the composition of total lipids in plasma. At farrowing and lactation, the proportion of palmitic and stearic acids increased (P<0.05) in the plasma NEFA and phospholipid fractions in comparison with prefarrowing concentrations. At the same time, the concentration of palmitic and linoleic acids increased (P<0.05) in the PBMC phospholipid fraction. Omega-3 FA, including docosapentaenoic and docosahexaenoic, increased (P<0.05) at farrowing in plasma and PBMC phospholipids compared with prefarrowing and lactation. Gene expression of IL-1beta, IL-6, IL-8, and tumor necrosis factor alpha (TNFalpha) decreased (P<0.05) after farrowing and in lactation. Similarly, cyclooxygenase expression was reduced during lactation when compared with farrowing (P<0.05). This study demonstrated changes in FA composition of serum lipid fractions and PBMC cellular membranes. Furthermore, it provided an initial assessment of inflammatory responses in mononuclear cells as a function of plasma and PBMC content of saturated and omega-3 FA. Future studies need to address the effect of increased NEFA concentrations, the main hallmark of lipid mobilization, and changes in plasma and cellular lipid profiles on immune function. PMID- 23100602 TI - New reports of nuclear DNA content for 407 vascular plant taxa from the United States. AB - BACKGROUND AND AIMS: The amount of DNA in an unreplicated haploid nuclear genome (C-value) ranges over several orders of magnitude among plant species and represents a key metric for comparing plant genomes. To extend previously published datasets on plant nuclear content and to characterize the DNA content of many species present in one region of North America, flow cytometry was used to estimate C-values of woody and herbaceous species collected in Wisconsin and the Upper Peninsula of Michigan, USA. METHODS: A total of 674 samples and vouchers were collected from locations across Wisconsin and Michigan, USA. From these, C-value estimates were obtained for 514 species, subspecies and varieties of vascular plants. Nuclei were extracted from samples of these species in one of two buffers, stained with the fluorochrome propidium iodide, and an Accuri C-6 flow cytometer was used to measure fluorescence peaks relative to those of an internal standard. Replicate extractions, coefficients of variation and comparisons to published C-values in the same and related species were used to confirm the accuracy and reliability of our results. KEY RESULTS AND CONCLUSIONS: Prime C-values for 407 taxa are provided for which no published data exist, including 390 angiosperms, two gymnosperms, ten monilophytes and five lycophytes. Non-prime reports for 107 additional taxa are also provided. The prime values represent new reports for 129 genera and five families (of 303 genera and 97 families sampled). New family C-value maxima or minima are reported for Betulaceae, Ericaceae, Ranunculaceae and Sapindaceae. These data provide the basis for phylogenetic analyses of C-value variation and future analyses of how C values covary with other functional traits. PMID- 23100603 TI - The eighth Asia cancer forum: seeking to advance the outcomes of the UN summit: 'global health as the key to a new paradigm in cancer research'. AB - To date, the Asia Cancer Forum has focused its efforts on creating a common concept for collaborative efforts in international cancer research with a focus on Asia, where cancer incidence is rising dramatically, and also sharing information and knowledge among cancer specialists about the importance of cancer as a global health agenda issue. The Eighth Asia Cancer Forum was held following the historic outcome of the High-level Meeting of the United Nations General Assembly on the Prevention and Control of Non-communicable Diseases held in New York in September 2011, at which cancer was duly recognized as a global health agenda issue. Despite this significant development, however, the issue of cancer, one of the most intractable of all non-communicable diseases, still faces a variety of challenges if it is to be addressed on the global level. The Eighth Asia Cancer Forum sought to address these various issues, seeking ways to capitalize on the outcomes of the UN Meeting and take global collaborative studies and alliances in the field of cancer further. It was recognized that one of the main challenges for the Asia Cancer Forum is to formulate a proposal that demonstrates how middle-income countries can provide a good level of care using only their own limited medical resources. Given that the Asia Cancer Forum is one of the organizations that can provide assistance in working to further boost awareness about cancer research and the situation relating to cancer in Asian countries, discussion also focused on how to concretize activities in the future. PMID- 23100604 TI - The Hepatobiliary and Pancreatic Oncology (HBPO) Group of the Japan Clinical Oncology Group (JCOG): history and future direction. AB - The Hepatobiliary and Pancreatic Oncology Group of the Japan Clinical Oncology Group (JCOG) was constituted in April 2008 to develop new standard treatments for hepatobiliary and pancreatic cancer. In pancreatic cancer, the Hepatobiliary and Pancreatic Oncology Group focuses on establishing standard chemotherapy or chemoradiotherapy for unresectable locally advanced disease. The JCOG 0506 study was a Phase II study of gemcitabine alone to examine its efficacy and safety in patients with locally advanced disease. The results in survival significantly exceeded expectations, and gemcitabine monotherapy has come to be regarded as the provisional standard therapy by our group. Following JCOG 0506, the JCOG 1106 study, which is currently under investigation, is a randomized Phase II study to evaluate the efficacy of induction chemotherapy with gemcitabine in combination with S-1 chemoradiotherapy and select a candidate therapeutic agent in a Phase III study comparing with gemcitabine alone. The JCOG 0805 study was a randomized Phase II study comparing S-1 monotherapy with gemcitabine plus S-1 combination therapy for unresectable biliary tract cancer. As a result, gemcitabine plus S-1 combination therapy was considered the more promising candidate in comparison with the gemcitabine plus cisplatin combination therapy in a subsequent Phase III trial. The Hepatobiliary and Pancreatic Oncology Group is planning a Phase III study to compare gemcitabine plus S-1 combination therapy with gemcitabine plus cisplatin combination therapy (JCOG PC1113 study). No standard postoperative adjuvant treatment has been established. We plan to conduct a Phase III study to compare S-1 as adjuvant therapy after surgery with surgery alone in patients with biliary tract cancer (JCOG PC1202). PMID- 23100605 TI - Occupational exposure assessment in carbon nanotube and nanofiber primary and secondary manufacturers: mobile direct-reading sampling. AB - RESEARCH SIGNIFICANCE: Toxicological evidence suggests the potential for a wide range of health effects from exposure to carbon nanotubes (CNTs) and carbon nanofibers (CNFs). To date, there has been much focus on the use of direct reading instruments (DRIs) to assess multiple airborne exposure metrics for potential exposures to CNTs and CNFs due to their ease of use and ability to provide instantaneous results. Still, uncertainty exists in the usefulness and interpretation of the data. To address this gap, air-monitoring was conducted at six sites identified as CNT and CNF manufacturers or users and results were compared with filter-based metrics. METHODS: Particle number, respirable mass, and active surface area concentrations were monitored with a condensation particle counter, a photometer, and a diffusion charger, respectively. The instruments were placed on a mobile cart and used as area monitors in parallel with filter-based elemental carbon (EC) and electron microscopy samples. Repeat samples were collected on consecutive days, when possible, during the same processes. All instruments in this study are portable and routinely used for industrial hygiene sampling. RESULTS: Differences were not observed among the various sampled processes compared with concurrent indoor or outdoor background samples while examining the different DRI exposure metrics. Such data were also inconsistent with results for filter-based samples collected concurrently at the same sites [Dahm MM, Evans DE, Schubauer-Berigan MK et al. (2012) Occupational exposure assessment in CNT and nanofiber primary and secondary manufacturers. Ann Occup Hyg; 56: 542-56]. Significant variability was seen between these processes as well as the indoor and outdoor backgrounds. However, no clear pattern emerged linking the DRI results to the EC or the microscopy data (CNT and CNF structure counts). CONCLUSIONS: Overall, no consistent trends were seen among similar processes at the various sites. The DRI instruments employed were limited in their usefulness in assessing and quantifying potential exposures at the sampled sites but were helpful for hypothesis generation, control technology evaluations, and other air quality issues. The DRIs employed are nonspecific, aerosol monitors, and, therefore, subject to interferences. As such, it is necessary to collect samples for analysis by more selective, time-integrated, laboratory-based methods to confirm and quantify exposures. PMID- 23100606 TI - Disease activity assessment in childhood vasculitis: development and preliminary validation of the Paediatric Vasculitis Activity Score (PVAS). AB - BACKGROUND: Rare chronic childhood vasculitides lack a reliable disease activity assessment tool. With emerging new treatment modalities such a tool has become increasingly essential for both clinical practice and therapeutic trials to reproducibly quantify change in disease state. OBJECTIVE: To develop and validate a paediatric vasculitis activity assessment tool based on modification of the Birmingham Vasculitis Activity Score (BVASv.3). METHODS: A paediatric vasculitis registry was reviewed to identify clinical features missing in the BVASv.3. A modified nominal group technique was used to develop a working version of the Paediatric Vasculitis Activity Score (PVAS). Prospective validation provided tool reliability, reproducibility and responsiveness to change. Training of assessors was done according to the BVAS principles. RESULTS: BVAS items were redefined (n=22) and eight paediatric items added in Cutaneous (n=4), Cardiovascular (n=3) and Abdominal (n=1) sections. The final PVAS has 64 active items in nine categories. The principles of new/worse and persistently active disease were retained as were the overall score and weighting of categories. The median PVAS in 63 children with systemic vasculitis was 4/63 (0-38/63). There was a high interobserver agreement for the overall as well as for subsystem scores (linear weighted-kappa >=0.87). PVAS correlated with physician's global assessment (p<0.01); treatment decision (p=<0.01) and erythrocyte sedimentation rate (ESR) (p=0.01). In response to treatment, 15/19 patients assessed demonstrated a significant fall in PVAS (p=0.002), with good agreement among assessors for this change. CONCLUSIONS: The PVAS validity in children with systemic vasculitis was demonstrated. Like the BVAS, we anticipate that the PVAS will provide a robust tool to objectively define disease activity for clinical trials and future research. PMID- 23100608 TI - Axial spondyloarthritis: a new disease entity, not necessarily early ankylosing spondylitis. AB - New classification criteria for axial spondyloarthritis have been developed with the goal of increasing sensitivity of criteria for early inflammatory spondyloarthritis. However these criteria substantially increase heterogeneity of the resulting disease group, reducing their value in both research and clinical settings. Further research to establish criteria based on better knowledge of the natural history of non-radiographic axial spondyloarthritis, its aetiopathogenesis and response to treatment is required. In the meantime the modified New York criteria for ankylosing spondylitis remain a very useful classification criteria set, defining a relatively homogenous group of cases for clinical use and research studies. PMID- 23100607 TI - Therapeutic approaches for the treatment of renal disease in juvenile systemic lupus erythematosus: an international multicentre PRINTO study. AB - OBJECTIVES: To evaluate therapeutic approaches and response to therapy in juvenile systemic lupus erythematosus (SLE) with renal involvement in a large prospective international cohort from four geographic areas. METHODS: New onset and flared patients with active renal disease (proteinuria >=0.5 g/24 h) were enrolled in 2001-2004. Therapeutic approaches and disease activity parameters were analysed at baseline, 6, 12 and 24 months. Response was assessed by the PRINTO/ACR criteria. RESULTS: 218/557 (79.8% female subjects, 117 new onset and 101 flared) patients with active renal disease were identified; 66 patients were lost to follow-up and 11 died. Mean age at disease onset for new onset group was higher than for flared group (13.1 vs 10.2 years, p<0.0001). At baseline, both groups had similar renal activity with similar median doses of corticosteroids (1.0-0.76 mg/kg/day). Cyclophosphamide (43.1%) and azathioprine (22%) were the most common immunosuppressive drugs. At baseline, South American patients received higher doses of corticosteroids than in other areas in new onset (median 1.16 vs 0.8-1 mg/kg/day) while cyclophosphamide use was similar in all four regions in the new onset group. There were no differences regarding the use of azathioprine or mycophenolate mofetil worldwide. PRINTO 70 response was reached in a greater percentage of new onset versus flared patients (74.8% vs 53.3%; p=0.005) at 6 months while at 24 months ACR 90 was reached by 69.9% and 56.1%, respectively. CONCLUSIONS: New onset and flared juvenile SLE improved similarly over 24 months with minimal differences in therapeutic approaches worldwide. PMID- 23100609 TI - Usefulness of parental response to questions about adherence to prescribed inhaled corticosteroids in young children. AB - BACKGROUND: Adherence to prescribed inhaled medication is often low in young children. Poor adherence to medication may contribute to lack of symptom control. Doctors are not good at predicting the adherence rates of their patients, and parental report of adherence does not correlate with objective measures of adherence. The objective of this study was to investigate whether parental admission of non-adherence and reasons given for non-adherence correlated with objectively measured adherence. METHODS: Adherence to prescribed inhaled corticosteroid treatment was monitored electronically in 132 children aged 2-6 years who were participating in a randomised controlled trial comparing different inhaler devices. Follow-up was carried out every 3 months for a year. Parental answers to simple questions about adherence were compared to electronically measured adherence. RESULTS: Mean adherence ranged from zero to 100%. Intra participant adherence varied throughout the year-long study period (mean variance for individual children between quarterly periods was 28.5%). Parents who reported missed doses, generally missed at least half of the prescribed doses. Parents who reported that not a single prescribed dose was missed, still missed 20% of doses on average. Adherence was particularly low when parents cited initiating their own trial off medication as a reason for missing doses. CONCLUSIONS: By examining parental response to questions enquiring whether any doses were missed, healthcare providers can gain a modest degree of insight into their patients' true adherence to prescribed medication. Adherence to prescribed asthma medication is extremely variable in young children. TRIAL REGISTRATION NUMBER: Data from this study were derived from a randomised controlled trial (ACTRN12608000294358). PMID- 23100610 TI - Risk factors for sentinel lymph node metastasis and validation study of the MSKCC nomogram in breast cancer patients. AB - OBJECTIVE: To evaluate the risk factors for sentinel lymph node metastasis and validate the value of the Memorial Sloan-Kettering Cancer Center nomogram for the prediction of sentinel lymph node metastasis in breast cancer patients. METHODS: A sentinel lymph node biopsy database containing 1227 consecutive breast cancer patients (416 patients with at least one positive sentinel lymph node) was retrospectively analyzed. The predictive value of the Memorial Sloan-Kettering Cancer Center nomogram was calculated by the trend line and the area under the receiver-operator characteristic curve. Meanwhile, predictors for sentinel lymph node metastasis were also evaluated. RESULTS: Tumor size, histological grade, lymphovascular invasion, mulifocality, estrogen receptor and progesterone receptor status were significant independent predictors for sentinel lymph node metastasis (all P<0.01). The Memorial Sloan-Kettering Cancer Center nomogram presented an area under the receiver-operator characteristic curve value of 0.730. Patients with predictive value<16% had a frequency of sentinel lymph node metastasis of 0.9%. Those with values larger than 70% had a frequency of 96.2%. CONCLUSIONS: The risk factors for sentinel lymph node metastasis in our study were consistent with those in the Memorial Sloan-Kettering Cancer Center nomogram. The Memorial Sloan-Kettering Cancer Center nomogram is a useful tool that could accurately predict the probability of sentinel lymph node metastasis in our breast cancer patients. Axillary surgical staging might be avoided in patients with a predictive value of <16% and axillary lymph node dissection might be done directly in those with a predictive value >70%, while other patients should still accept sentinel lymph node biopsy. PMID- 23100611 TI - A case of hemangiopericytoma of the pelvis. PMID- 23100612 TI - Worldwide burden of cancer incidence in 2002 extrapolated from cancer incidence in five continents Vol. IX. PMID- 23100613 TI - Question 1: Should steroids be used to treat abdominal pain caused by Henoch Schonlein purpura? PMID- 23100615 TI - Question 2: Do steroids prolong ambulation and improve quality of life in children with Duchenne muscular dystrophy? PMID- 23100616 TI - Question 3: Inhaled mannitol improves lung function in patients with cystic fibrosis. PMID- 23100617 TI - Truncation of MIMT1 gene in the PEG3 domain leads to major changes in placental gene expression and stillbirth in cattle. AB - We previously identified a microdeletion (Del) in the maternally imprinted PEG3 domain in cattle that results in loss of paternal MIMT1 expression and causes late-term abortion and stillbirth. The mutation, when inherited from the sire, is semilethal for his progeny, with 85% mortality. Here we precisely delineate the deletion and describe comparative analyses of fetuses carrying the deletion with wild-type (WT) siblings. Global DNA methylation analysis of cotyledon tissue revealed greater global CpG methylation in fetuses with the deletion (P = 0.003). Gene expression microarray analyses identified increased NPSR1A, IL1RN, NOS3, IL4R, ZDHHC22, and SMOC2 expression in fetuses carrying the deletion and decreased GRID1, PLG, and IGF1 expression. Involvement of the NPSR1A, IL1RN, NOS3, and IL4R genes suggests that some form of restriction related to blood supply, perhaps hypoxemia, may play a role in the pathological mechanism. Also, imprinted genes known to play a role in mammalian prenatal development, specifically IGF2, DLK1, MEST, AST1, PEG3, APEG3, and H19, showed differential expression. The most striking difference was abundant abnormal expression of the neuropeptide S receptor 1 (NPSR1) gene in placental cotyledon tissue of 7 of 11 MIMT1(Del/WT) fetuses. The similarity of this proportion to that of the semilethal mortality rate suggests that abnormal NPSR1 expression may be linked to death or survival of MIMT1(Del/WT) fetuses. NPSR1 is expressed as two isoforms (A and B), and isoform A was detected in MIMT1(Del/WT) cotyledons. NPSR1A is normally not expressed in placenta. Its role in the stillbirth phenomenon has yet to be elucidated, but it may provide a useful prognostic indicator. PMID- 23100618 TI - Germline transformation of the silkworm Bombyx mori L. by sperm-mediated gene transfer. AB - The domesticated silkworm Bombyx mori L. has important roles in basic biological research and applied science. To explore the practical use of transgenic technology in agricultural silkworm varieties, we fused the neomycin-resistance gene (Neo(R)) and the green fluorescent protein gene (gfp) into the piggyBac based transposon vector and transduced it into silkworms by sperm-mediated gene transfer (SMGT). Fluorescence observation indicated the positive rate of G0 egg batches is 72.7%. After screening against the antibiotic G418, development of individual larvae in the same brood showed significant size differences. PCR detection indicated the existence of gfp and Neo(R) and confirmed the positive rate of transgenesis as 0.47%. Southern blot analysis confirmed the presence of the exogenous genes in the genome of G7 larvae. These results show that our strategy is practical and markedly improves the efficiency of SMGT. PMID- 23100619 TI - Oral progestin priming increases ovarian sensitivity to gonadotropin stimulation and improves luteal function in the cat. AB - As the only domesticated species known to exhibit both induced and spontaneous ovulation, the cat is a model for understanding the nuances of ovarian control. To explore ovarian sensitivity to exogenous gonadotropins and the influence of progestin priming, we conducted a study of queens that were down-regulated with oral progestin or allowed to cycle normally, followed by low or high doses of equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). Our metrics included 1) fecal steroid metabolite profiles before and after ovulation induction, 2) laparoscopic examination of ovarian follicles and corpora lutea (CL) on Days 2 and 17 (Day 0 = hCG administration), and 3) ovariohysterectomy (Day 17) to assess CL progesterone concentrations, morphometrics, and histology. Reproductive tracts from time-matched, naturally mated queens (n = 6) served as controls. Every progestin-primed cat (n = 12) produced the desired response of morphologically similar, fresh CL (regardless of eCG/hCG dose) by Day 2, whereas 41.7% of unprimed counterparts (n = 12) failed to ovulate or had variable-aged CL suggestive of prior spontaneous ovulation (P < 0.05). The ovarian response to low, but not high, eCG/hCG was improved (P < 0.05) in primed compared to unprimed cats, indicating increased sensitivity to gonadotropin in the progestin-primed ovary. Progestin priming prevented hyperelevated fecal steroid metabolites and normalized CL progesterone capacity, but only when combined with low eCG/hCG. However, priming failed to prevent ancillary CL formation, smaller CL mass, or abnormal luteal cell density, which were common to all eCG/hCG-treated cats. Thus, the domestic cat exposed to eCG/hCG produces CL with structural and functional aberrations. These anomalies can be partially mitigated by progestin priming, possibly due to a protective effect of progestin associated with enhanced ovarian sensitivity to gonadotropins. PMID- 23100620 TI - Insulin-like 3 signaling is important for testicular descent but dispensable for spermatogenesis and germ cell survival in adult mice. AB - Relaxin family peptide receptor 2 (RXFP2) is the cognate receptor of a peptide hormone insulin-like 3 (INSL3). INSL3 is expressed at high levels in both fetal and adult Leydig cells. Deletion of Insl3 or Rxfp2 genes in mice caused cryptorchidism resulting from a failure of gubernaculum development. Using a novel mouse transgenic line with a knock-in LacZ reporter in the Rxfp2 locus, we detected a robust Rxfp2 expression in embryonic and early postnatal gubernaculum in males and in postmeiotic spermatogenic cells in adult testis. To study the role of INSL3/RXFP2 signaling in male reproduction, we produced a floxed Rxfp2 allele and used the Cre/loxP approach to delete Rxfp2 in different tissues. Using Cre transgene driven by retinoic acid receptor beta promoter, conditional gene targeting in gubernacular mesenchymal cells at early embryonic stages caused high intraabdominal cryptorchidism as in males with a global deletion of Rxfp2. However, when the Rxfp2 was deleted in gubernacular smooth or striated muscle cells, no abnormalities of testicular descent or testis development were found. Specific ablation of Rxfp2 in male germ cells using Stra8-icre transgene did not affect testis descent, spermatogenesis, or fertility in adult males. No significant change in germ cell apoptosis was detected in mutant males. In summary, our data indicate that the INSL3/RXFP2 signaling is important for testicular descent but dispensable for spermatogenesis and fertility in adult males. PMID- 23100621 TI - Differential expression of select members of the SLC family of genes and regulation of expression by microRNAs in the chicken oviduct. AB - The yolk and white of eggs from chickens contain proteins and other molecules either secreted or transported by cells of the reproductive tract, or secreted by the liver and transported to the ovarian follicles of laying hens. Nutrients transported by solute carriers (SLCs) include glucose, electrolytes, and amino acids. Although SLC genes have been investigated in mammals, there are few studies of expression of SLC genes in the chicken oviduct. Therefore, we investigated temporal and cell-specific expression of selected SLC genes at 3 h and 20 h postovulation and regulation of their expression by microRNAs (miRs). Expression of SLC1A4 (glutamate and neutral amino acid transporter), SLC13A2 (dicarboxylate transporter), and SLC35B4 (UDP-xylose: UDP-N-acetylglucosamine transporter) mRNAs was limited to glandular epithelium (GE), while SLC4A5 (sodium bicarbonate cotransporter) and SLC7A3 (cationic amino acid transporter) mRNAs were expressed predominantly in the luminal epithelium of the magnum. Interestingly, SLC1A4, SLC4A5, SLC13A2 and SLC35B4 mRNAs were abundant only in GE of the shell gland, whereas SLC7A3 was not detected in the shell gland. In the magnum, SLC7A3 and SLC4A5 were expressed, but SLC1A4, SLC35B4, and SLC13A2 were not expressed at 20 h postovulation. In the shell gland, all SLC mRNAs were expressed at both time points, except for SLC7A3. The miRNA target validation assay revealed that miR-1764 and miR-1700 bind directly to SLC13A2 and SLC35B4 transcripts, respectively, to regulate expression. Results of this study demonstrate cell-specific and temporal changes in expression of selected SLC genes and regulation of SLC13A2 and SLC35B4 expression by miRs in the oviduct of laying hens. PMID- 23100622 TI - Building a life sciences innovation ecosystem. AB - Universities should support research with commercial potential, provide a supportive environment for start-ups, and partner enthusiastically with the private sector. PMID- 23100623 TI - Lupus antibody tops cancer cells. AB - A lupus causing anti-DNA antibody penetrates living cells and targets DNA repair for therapeutic advantage in human cancer cells. PMID- 23100624 TI - Comment on "chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model". AB - In their recent paper, Goldstein et al. show murine brain tau neuropathology after explosive blast with head rotation but do not present additional evidence that would delineate whether this neuropathology was principally caused by blast exposure alone or by blast exposure plus head rotational injury. PMID- 23100625 TI - Comment on "chronic traumatic encephalopathy in blast-exposed military veterans and a blast neurotrauma mouse model". AB - In a case study, the authors report an increase in phosphorylated neurofilament heavy chain, a marker of neuroaxonal damage, in the plasma of a blast-exposed patient immediately after injury. They suggest that this phosphoprotein may be a useful body fluid indicator of acute blast traumatic brain injury. PMID- 23100627 TI - NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by loss of tolerance to self nucleic acids. The source of autoantigen that drives disease onset and progression is unclear. A candidate source of autoantigen is the neutrophil extracellular trap (NET), which releases nucleic acids into the extracellular environment, generating a structure composed of DNA coated with antimicrobial proteins. On the basis of in vitro and patient correlative studies, several groups have suggested that NETs may provide lupus autoantigens. The observation that NET release (NETosis) relies on activity of the phagocyte NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) oxidase (Nox2) in neutrophils of both humans and mice provided a genetic strategy to test this hypothesis in vivo. Therefore, we crossed an X-linked nox2 null allele onto the lupus-prone MRL.Fas(lpr) genetic background and assessed immune activation, autoantibody generation, and SLE pathology. Counter to the prevailing hypothesis, Nox2-deficient lupus-prone mice had markedly exacerbated lupus, including increased spleen weight, increased renal disease, and elevated and altered autoantibody profiles. Moreover, heterozygous female mice, which have Nox2 deficiency in 50% of neutrophils, also had exacerbated lupus and altered autoantibody patterns, suggesting that failure to undergo normal Nox2-dependent cell death may result in release of immunogenic self-constituents that stimulate lupus. Our results indicate that NETosis does not contribute to SLE in vivo; instead, Nox2 acts to inhibit disease pathogenesis, making this enzyme an important target for further study and a candidate for therapeutic intervention. PMID- 23100628 TI - Targeting cancer with a lupus autoantibody. AB - Systemic lupus erythematosus (SLE) is distinct among autoimmune diseases because of its association with circulating autoantibodies reactive against host DNA. The precise role that anti-DNA antibodies play in SLE pathophysiology remains to be elucidated, and potential applications of lupus autoantibodies in cancer therapy have not previously been explored. We report the unexpected finding that a cell penetrating lupus autoantibody, 3E10, has potential as a targeted therapy for DNA repair-deficient malignancies. We find that 3E10 preferentially binds DNA single strand tails, inhibits key steps in DNA single-strand and double-strand break repair, and sensitizes cultured tumor cells and human tumor xenografts to DNA damaging therapy, including doxorubicin and radiation. Moreover, we demonstrate that 3E10 alone is synthetically lethal to BRCA2-deficient human cancer cells and selectively sensitizes such cells to low-dose doxorubicin. Our results establish an approach to cancer therapy that we expect will be particularly applicable to BRCA2-related malignancies such as breast, ovarian, and prostate cancers. In addition, our findings raise the possibility that lupus autoantibodies may be partly responsible for the intrinsic deficiencies in DNA repair and the unexpectedly low rates of breast, ovarian, and prostate cancers observed in SLE patients. In summary, this study provides the basis for the potential use of a lupus anti-DNA antibody in cancer therapy and identifies lupus autoantibodies as a potentially rich source of therapeutic agents. PMID- 23100629 TI - Quantitative image analysis of cellular heterogeneity in breast tumors complements genomic profiling. AB - Solid tumors are heterogeneous tissues composed of a mixture of cancer and normal cells, which complicates the interpretation of their molecular profiles. Furthermore, tissue architecture is generally not reflected in molecular assays, rendering this rich information underused. To address these challenges, we developed a computational approach based on standard hematoxylin and eosin stained tissue sections and demonstrated its power in a discovery and validation cohort of 323 and 241 breast tumors, respectively. To deconvolute cellular heterogeneity and detect subtle genomic aberrations, we introduced an algorithm based on tumor cellularity to increase the comparability of copy number profiles between samples. We next devised a predictor for survival in estrogen receptor negative breast cancer that integrated both image-based and gene expression analyses and significantly outperformed classifiers that use single data types, such as microarray expression signatures. Image processing also allowed us to describe and validate an independent prognostic factor based on quantitative analysis of spatial patterns between stromal cells, which are not detectable by molecular assays. Our quantitative, image-based method could benefit any large scale cancer study by refining and complementing molecular assays of tumor samples. PMID- 23100630 TI - Effects of animal-assisted therapy on behavioral and/or psychological symptoms in dementia: a case report. AB - BACKGROUND: Recently, interest in nonpharmaceutical interventions in dementia care has increased. Animal-assisted therapy has been shown to be one promising intervention but more knowledge is needed. The present article reports on a pilot study involving an 84-year-old woman with vascular dementia who was systematically trained with a therapy dog team for 8 weeks. METHODS: A quasi experimental longitudinal interventional design with pre-post measures was used. Data were collected on 3 occasions. Descriptive statistics were used for data analysis. RESULTS: Some effects on the woman's ability to walk and move were identified. In addition, some effects in the woman's cognitive state were observed. CONCLUSIONS: Physical, psychological, and/or social training with certified therapy dog teams can have effects on behavioral and psychological symptoms in people living with dementia. Further research is needed. PMID- 23100631 TI - REMEDIATING READING DIFFICULTIES IN A RESPONSE TO INTERVENTION MODEL WITH SECONDARY STUDENTS. AB - The research on Response to Intervention (RtI) with secondary students is scant; however, a recently conducted, multiyear, large-scale implementation of RtI with middle-school students provides findings that inform practices and future directions for research. This article provides an overview of the findings from each of the 3 years of an intensive, tiered reading intervention with middle school students. In Year 1, students were provided with a Tier 1 and Tier 2 intervention. In Year 2, minimal responders were provided with another year of intervention (Tier 3), and again in Year 3, minimal responders to the 2-year intervention were provided with a third year of intervention (Tier 4). Using students' responsiveness to intervention as a prerequisite for a subsequent year of intensive instruction, minimal responders received a total of up to 3 years of intervention. The efficacy of an enhanced primary (Tier 1), secondary (Tier 2), and tertiary (Tier 3) intervention, and an individualized, intensive reading intervention (Tier 4) are discussed, as well as the logistics of implementing an RtI model with secondary students. PMID- 23100632 TI - Which is the smallest champion? PMID- 23100633 TI - The genus Amycolatopsis: Indigenous plasmids, cloning vectors and gene transfer systems. AB - The genus Amycolatopsis is a member of the phylogenetic group nocardioform actinomycetes. Most of the members of the genus Amycolatopsis are known to produce antibiotics. Additionally, members of this genus have been reported to metabolize aromatic compounds as the sole sources of carbon and energy. Development of genetic manipulation in Amycolatopsis has progressed slowly due to paucity of genetic tools and methods. The occurrence of indigenous plasmids in different species of Amycolatopsis is not very common. Till date, only three indigenous plasmids viz., pMEA100, pMEA300 and pA387 have been reported in Amycolatopsis species. Various vectors based on the indigenous plasmids, pMEA100, pMEA300 and pA387, have been constructed. These vectors have proved useful for molecular genetics studies of actinomycetes. Molecular genetic work with Amycolatopsis strains is not easy, since transformation methods have to be developed, or at least optimized, for each particular strain. Nonetheless, methods for efficient transformation (polyethyleneglycol (PEG) induced protoplast transformation, transformation by electroporation and direct transformation) have been developed and used successfully for the introduction of DNA into several Amycolatopsis species. The construction of plasmid cloning vectors and the development of gene transfer systems has opened up possibilities for studying the molecular genetics of these bacteria. PMID- 23100634 TI - Relationships among filamentous microorganisms in rotating biological contactors. AB - The existing relationships were studied among the different types of filamentous microorganisms that appear in the biofilm of a biological contactor system. Using the hierarchical cluster analysis it was observed that, in all the stages, Beggiatoa sp. and the Eikelboom's types 0803 and 1863 always appeared associated, while Sphaerotilus natans was always associated with the morphological type 021N. The remaining microorganisms were associated in variable forms in the plants. In addition, different association models were obtained according to the season of the year and the stage-season interaction. It has also been observed that a significant correlation exists among the filamentous microorganisms we have studied and the different physical-chemical parameters. PMID- 23100635 TI - Paddy straw as substrate for ethanol production. AB - Pretreatment of paddy straw with 2% sodium hydroxide at 15 psi for 1 h resulted in 83% delignification. The hydrolysis of alkali treated paddy straw with a commercial preparation of cellulase for 2 h at 50 degrees C resulted in release of 65% total reducing sugars. Maximum sugars were released at enzyme loading of 1.5% (v/v). The fermentation of hydrolysate supplemented with nutrients by S. cerevisiae resulted in the production of 20-30 g L(-1) ethanol after 48 h incubation which was further improved with addition of yeast nitrogen base and inoculated with 1% (w/v) yeast cells. PMID- 23100636 TI - Design and development of a simple laboratory model to detect (15)N enrichment in cyanobacterial biomass and extra cellular ammonia using (15)N gas. AB - A laboratory scale working model that could detect the (15)N enrichment in cyanobacterial biomass and extracellular ammonia, using (15)N gas under in vitro conditions was designed and fabricated. Using the model, (15)N enrichment of 0.48% atom excess was detected in the cyanobacterial biomass on the 30 d after inoculation. The (15)N enrichment increased linearly in the extracellular ammoniacal fraction from the 20 d onward. The model would prove to be a useful tool to quantify the extent of (15)N enrichment under in vitro conditions using (15)N gas. PMID- 23100637 TI - Bench scale conversion of 3-cyanopyidine to nicotinamide using resting cells of Rhodococcus rhodochrous PA-34. AB - The nitrile hydratase (NHase, EC 3.5.5.1) activity of Rhodococcus rhodochrous PA 34 was explored for the conversion of 3-cyanopyridine to nicotinamide. The NHase activity (~18 U/mg dry cell weight, dcw) was observed in 0.1 M phosphate buffer, pH 8.0 containing 1M 3-cyanopyridine as substrate, and 0.75 mg of resting cells (dry cell weight) per ml reaction mixture at 40 degrees C. However, 25 degrees C was more suitable for prolonged batch reaction at high substrate (3 cyanopyridine) concentration. In a batch reaction (1 liter), 7M 3-cyanopyridine (729 g) was completely converted to nicotinamide (855 g) in 12h at 25 degrees C using 9.0 g resting cells (dry cell weight) of R. rhodochrous PA-34. PMID- 23100638 TI - Effect of different additives on the persistence and insecticidal activity of native strains of Bacillus thuringiensis. AB - The persistence and insecticidal activity of native strains of Bacillus thuringiensis was evaluated in formulations containing different additives such as arrow-root powder, carboxy methyl cellulose (CMC), gum acacia, non-food grade (NFG) starch, and soluble starch. Persistence of B. thuringiensis varied with different additives used in the formulations. Among the different additives used, NFG starch provided maximum protection to B. thuringiensis and native strain 42 showed maximum persistence (83%) which was higher than that obtained in commercial formulation. In commercial formulation, the persistence of B. thuringiensis was 47% only after 3 d of spray. The feeding trials conducted on second instar larvae of H. armigera using leaves sprayed with NFG starch formulation revealed 70% larval mortality while commercial formulation showed 50% mortality during the same period. PMID- 23100639 TI - Typing of Aeromonas hydrophila of fish and human diarrhoeal origin by outer membrane proteins and lipopolysaccharides. AB - A study was undertaken to discriminate the strains of Aeromonas hydrophila isolated from fish and diarrhoeal samples by SDS-PAGE analysis of outer membrane proteins (OMPs) and lipopolysaccharides (LPSs). Common bands at 47 kDa positions for OMPs and at 31-38 kDa for LPSs were observed. No strain of A. hydrophila from clinical or fish samples was found identical in either OMPs or LPSs profile. PMID- 23100640 TI - Improvement in symbiotic efficiency of chickpea (Cicer arietinum) by coinoculation of Bacillus strains with Mesorhizobium sp. Cicer. AB - Rhizobacteria belonging to Bacillus sp. were isolated from the rhizosphere of chickpea (Cicer arietinum). Ten Bacillus strains were studied for their antifungal activity, effect on seedling emergence and plant growth promotion. Two Bacillus strains CBS127 and CBS155 inhibited the growth of all the four pathogenic fungi tested on nutrient agar medium plates in vitro. Seed inoculation with different Bacillus strains showed stimulatory effect on root and shoot growth at 10 d of observation in comparison to control whereas four Bacillus strains CBS24, CBS127, CBS129 and CBS155 caused retardation of shoot growth at 10 d. Maximum nodule-promoting effect was observed with Bacillus strains CBS106, CBS127 and CBS155. The symbiotic effectiveness of Mesorhizobium sp. Cicer strain Ca181 was further improved on coinoculation with six Bacillus strains i.e. CBS9, CBS17, CBS20, CBS106, CBS127 and CBS155 at 80 d of plant growth under sterile conditions and shoot dry weight ratios increased 1.62 to 1.74 times those of Mesorhizobium-inoculated treatments, suggesting the usefulness of introduced rhizobacteria in improving crop productivity. PMID- 23100641 TI - Ability of Emericella rugulosa to mobilize unavailable P compounds during Pearl millet [Pennisetum glaucum (L.) R. Br.] crop under arid condition. AB - Phosphate solubilizing microorganisms are ubiquitous in soils and could play an important role in supplying P to plants where plant unavailable P content in soil was more. A phosphatase and phytase producing fungus Emericella rugulosa was isolated and tested under field condition (Pearl millet as a test crop) in a loamy sand soil. In the experimental soil 68% organic phosphorous was present as phytin; less than 1% of phosphorous was present in a plant available form. The maximum effect of inoculation on different enzyme activities (acid phosphatase, alkaline phosphatase, phytase, and dehydrogenase) was observed between 5 and 8 weeks of plant age. The depletion of organic P was much higher than mineral and phytin P. The microbial contribution was significantly higher than the plant contribution to the hydrolysis of the different P fractions. A significant improvement in plant biomass, root length, seed and straw yield and P concentration of root and shoot resulted from inoculation. The results suggest that Emericella rugulosa produces phosphatases and phytase, which mobilize P and enhance the production of pearl millet. PMID- 23100642 TI - Isolation and characterization of mutants of Pseudomonas maltophila PM-4 altered in chitinolytic activity and antagonistic activity against root rot pathogens of clusterbean (Cyamopsis tetragonoloba). AB - Pseudomonas maltophila PM-4, an antagonist of pathogenic fungi including Rhizoctonia bataticola, R. solani, Fusarium oxysporum and Sclerotinia sclerotiorum associated with root rot of clusterbean (Cyamopsis tetragonoloba) was mutagenized with Tn5. Hyperchitinase producing mutants showing large zone of colloidal chitin dissolution were identified on medium containing calcoflor dye as an indicator. A mutant P-48 producing 137% higher chitinase activity than the parent strain PM-4 was identified. Seed bacterization of clusterbean (Cyamopsis tetragonoloba) with P-48 controlled the root rot upto 40.8% in the presence of conglomerate of all the four fungal pathogens Rhizoctonia bataticola, R. solani, F. oxysporum and Sclerotinia sclerotiorum. PMID- 23100643 TI - Using gamma irradiation and low temperature on microbial decontamination of red meat in Iran. AB - Gamma irradiation can be used as one of the most efficient methods to reduce microorganisms in food. The irradiation of food is used for a number of purposes, including microbiological control, insects control and inhibition of sprouting and delay of senescence of living food. The aim of this study was to study effects of gamma irradiation, refrigeration and frozen storage as the combination process for improvement of red meat shelf-life. The bovine meat samples were treated with 0, 0.5, 1, 2 and 3 kGy of gamma irradiation and kept in refrigerator for 3 weeks and in freezer for 8 months. The control and irradiated samples were stored at 4-7 degrees C and at -18 degrees C for refrigeration and frozen storage, respectively; and microbial and chemical analyze was done at 1 week and 2 months intervals. In this study the optimum dose of gamma radiation in order to decrease the total count of Mesophilic bacteria, Coliforms, Staphylococcus aureus and especially for elimination of Salmonella was obtained at 3 kGy. Microbial analysis indicated that irradiation and storage at low temperature had a significant effect on the reduction of microbial loads. There was no significant difference in chemical characteristics during freezing storage in bovine meat. Also, irradiated meat samples (3 kGy) were stored in 4-7 degrees C for 14 days, compared to 3 days for non irradiated samples. PMID- 23100644 TI - Antagonistic and antimicrobial activities of some bacterial isolates collected from soil samples. AB - Thirty seven bacterial cultures isolated from soil samples obtained from different locations were tested for their antagonistic activity against some fungal pathogens, viz., Sclerotium rolfsii, Fusarium oxysporum and Rhizoctonia solani, causal agents of collar rot of sunflower, wilts and root rots, respectively. Among them, 5 bacterial strains, viz., A1 6 (Bacillus sphaericus), K1 24 (Pseudomonas fluorescens), M1 42 (Bacillus circulans), M1 66 (Bacillus brevis) and T1 22 (Bacillus brevis) showed positive antagonistic activity. M1 66 was the most effective in inhibiting mycelial growth of S. rolfsii in vitro followed by M1 42, T1 22, K1 24 and A1 6. Only one bacterial strain i.e. M1 42 exhibited antagonistic activity against F. oxysporum, and none of the bacterial strains gave positive activity against R. solani. Furthermore, antimicrobial activities of all the 5 strains were checked against different test organisms. These strains showed their extensive inhibition effect particularly against gram positive test bacteria (Staphylococcus aureus and Bacillus subtilis) and the test fungal strain (Candida albicans). On the other hand, B. brevis M1 66 and B. brevis T1 22 strains had an inhibitory effect against gram positive and gram negative test bacteria (Escherichia coli and Proteus vulgaris) as well as the test fungal strain. PMID- 23100645 TI - Differential expression of thermophilic phosphatases in the wild type and auxotrophic mutant strains of Thermoactinomyces vulgaris. AB - In the wild type strain (stock no. 1227) of Thermoactinomyces vulgaris, as reported earlier [Sinha and Singh (1980) Biochem. J. 190, 457-460], all phosphatase isoenzymes (three alkaline - AlpI, AlpII and AlpIII, and one acidic - Acp) are present. However, the auxotrophic mutants, the strains 1286 (thi(-)), 1279 (nic(-), ura(-)) and 1278 (thi(-), ura(-)) exhibited two alkaline phosphatase isoenzymes (AlpII and AlpIII), but AlpI was lacking. In the strain 1261 (nic(-), thi(-)), only AlpIII was expressed, and AlpI and AlpII isoenzymes were missing. The results suggest that the strains, which require either thiamine (1286 and 1278) or nicotinamide (1279) for their growth, were AlpI(-) mutants; and the strain (1261), which requires both thiamine and nicotinamide for its growth, was AlpI(-)/AlpII(-) double mutant. There was no direct correlation between uracil auxotrophy and the expression of phosphatases. The uniform expression of AlpIII and Acp in all the strains, irrespective of their nutrient requirements, suggest that these constitutive phosphatases are species-specific. The specific activities of the thermophilic acid and alkaline phosphatases were maximum in the wild type strain (1227) of T. vulgaris. The next in phosphatase activity was the strain 1279 (an AlpI(-) mutant), followed by their decrease, in order, in the strains 1286 and 1278 (which were also AlpI(-) mutants); while least activity of these enzymes was observed in the obligate thermophile strain 1261 (AlpI(-)/AlpII(-) double mutant). PMID- 23100646 TI - Long-term effect of mineral fertilizers and amendments on microbial dynamics in an alfisol of Western Himalayas. AB - The microbial dynamics expressed in terms of culturable microbial populations i.e. bacteria, fungi, actinomycetes and Azotobacter were measured after 33 years of continuous application of mineral fertilizers and amendments to an acid alfisol. The bacterial, fungal and Azotobacter populations were maximum in plots treated with mineral fertilizers and FYM (100%NPK+FYM) while actinomycetes population was maximum in mineral fertilizes and lime treated plots (100%NPK+Lime). The bacterial population decreased and fungal population increased with increasing levels of NPK i.e. from 50% to 150%NPK. Bacillus species of bacteria and Gliocladium, Aspergillus and Rhizopus species of fungi were the main dominating culturable microorganisms in all the treatments. The FYM and lime amended plots sustained crop productivity and microbial populations at higher levels than rest of the mineral fertilizer treatments. The nitrogenous fertilizers alone had the most deleterious effect on crop productivity and the biological soil environment. PMID- 23100647 TI - Terminal restriction fragment length polymorphism (T-RFLP) analysis: Characterizing the unseen. AB - The golden era of microbiology during early 1900s was based on the isolation and characterization of purified single cultures. However, since the understanding of limitations of culturing methods to decipher the majority of the microbial diversity, microbiologists have been keen to assess the abundance and distribution of microbial diversity by alternative methods(1). The quest has been further fueled by the idea of relating such information about the community structure to the ecosystem function. Therefore, the goal of new cohort of modern day microbiologists is to understand microbial community structure and dynamics within their natural habitats. Consequently, a wide variety of culture independent approaches and methods for microbial community structure determination have been developed and applied to varied ecosystems. By far the majority of such methods use direct isolation of genetic content from the environmental samples and PCR amplification of genes of interest for bypassing the culturing biases. Existing methods include Amplified Ribosomal DNA Restriction Analysis (ARDRA), Single Stranded Conformation Polymorphism (SSCP), Thermal and Denaturing Gradient Gel Electrophoresis (TGGE and DGGE), Amplified Length Heterogeneity (ALH) analysis and Terminal Restriction Fragment Length Polymorphism (T-RFLP) analysis(2). PMID- 23100648 TI - Nanobacteria - Not life forms but nano-particulate nidi for calcification. PMID- 23100649 TI - Bacterial batteries. PMID- 23100650 TI - Dr. S. Shivaji - A Zoologist turned microbiologist. PMID- 23100651 TI - Polyphasic approach of bacterial classification - An overview of recent advances. AB - Classification of microorganisms on the basis of traditional microbiological methods (morphological, physiological and biochemical) creates a blurred image about their taxonomic status and thus needs further clarification. It should be based on a more pragmatic approach of deploying a number of methods for the complete characterization of microbes. Hence, the methods now employed for bacterial systematics include, the complete 16S rRNA gene sequencing and its comparative analysis by phylogenetic trees, DNA-DNA hybridization studies with related organisms, analyses of molecular markers and signature pattern(s), biochemical assays, physiological and morphological tests. Collectively these genotypic, chemotaxonomic and phenotypic methods for determining taxonomic position of microbes constitute what is known as the 'polyphasic approach' for bacterial systematics. This approach is currently the most popular choice for classifying bacteria and several microbes, which were previously placed under invalid taxa have now been resolved into new genera and species. This has been possible owing to rapid development in molecular biological techniques, automation of DNA sequencing coupled with advances in bioinformatic tools and access to sequence databases. Several DNA-based typing methods are known; these provide information for delineating bacteria into different genera and species and have the potential to resolve differences among the strains of a species. Therefore, newly isolated strains must be classified on the basis of the polyphasic approach. Also previously classified organisms, as and when required, can be reclassified on this ground in order to obtain information about their accurate position in the microbial world. Thus, current techniques enable microbiologists to decipher the natural phylogenetic relationships between microbes. PMID- 23100652 TI - Functional characterization and mutation analysis of family 11, Carbohydrate Binding Module (CtCBM11) of cellulosomal bifunctional cellulase from Clostridium thermocellum. AB - The non-catalytic, family 11 carbohydrate binding module (CtCBM11) belonging to a bifunctional cellulosomal cellulase from Clostridium thermocellum was hyper expressed in E. coli and functionally characterized. Affinity electrophoresis of CtCBM11 on nondenaturing PAGE containing cellulosic polysaccharides showed binding with beta-glucan, lichenan, hydroxyethyl cellulose and carboxymethyl cellulose. In order to elucidate the involvement of conserved aromatic residues Tyr 22, Trp 65 and Tyr 129 in the polysaccharide binding, site-directed mutagenesis was carried out and the residues were changed to alanine. The results of affinity electrophoresis and binding adsorption isotherms showed that of the three mutants Y22A, W65A and Y129A of CtCBM11, two mutants Y22A and Y129A showed no or reduced binding affinity with polysaccharides. These results showed that tyrosine residue 22 and 129 are involved in the polysaccharide binding. These residues are present in the putative binding cleft and play a critical role in the recognition of all the ligands recognized by the protein. PMID- 23100653 TI - Lactic acid bacteria in Hamei and Marcha of North East India. AB - Hamei and Marcha are mixed dough inocula used as starters for preparation of various indigenous alcoholic beverages in Manipur and Sikkim in India, respectively. These starters are traditionally prepared from rice with wild herbs and spices. Samples of Hamei and Marcha, collected from Manipur and Sikkim, respectively, were analysed for lactic acid bacterial composition. The population of lactic acid bacteria (LAB) was 6.9 and 7.1 Log cfu/g in Hamei and Marcha, respectively. On the basis of phenotypic and genotypic characters, LAB strains isolated from Hamei and Marcha were identified as Pediococcus pentosaceus, Lactobacillus plantarum and Lactobacillus brevis. Technological properties of LAB such as antimicrobial properties, effect on acidification, ability to produce biogenic amines and ethanol, degree of hydrophobicity and enzymatic activities were also performed. Pediococcus pentosaceus HS: B1, isolated from Hamei, was found to produce bacteriocin. None of the strains produced biogenic amines. LAB strains showed a strong acidifying ability and they also produced a wide spectrum of enzymes. PMID- 23100654 TI - Glucose dehydrogenase of a rhizobacterial strain of Enterobacter asburiae involved in mineral phosphate solubilization shares properties and sequence homology with other members of enterobacteriaceae. AB - Glucose dehydrogenase (GDH) of Gram-negative bacteria is a membrane bound enzyme catalyzing the oxidation of glucose to gluconic acid and is involved in the solubilization of insoluble mineral phosphate complexes. A 2.4 kb glucose dehydrogenase gene (gcd) of Enterobacter asburiae sharing extensive homology to the gcd of other enterobacteriaceae members was cloned in a PCR-based directional genome walking approach and the expression confirmed in Escherichia coli YU423 on both MacConkey glucose agar and hydroxyapatite (HAP) containing media. Mineral phosphate solubilization by the cloned E. asburiae gcd was confirmed by the release of significant amount of phosphate in HAP containing liquid medium. gcd was over expressed in E. coli AT15 (gcd::cm) and the purified recombinant protein had a high affinity to glucose, and oxidized galactose and maltose with lower affinities.The enzyme was highly sensitive to heat and EDTA, and belonged to Type I, similar to GDH of E. coli. PMID- 23100655 TI - Statistical optimization for tannase production from Aspergillus niger under submerged fermentation. AB - Statistically based experimental design was employed for the optimization of fermentation conditions for maximum production of enzyme tannase from Aspergillus niger. Central composite rotatable design (CCRD) falling under response surface methodology (RSM) was used. Based on the results of 'one-at-a-time' approach in submerged fermentation, the most influencing factors for tannase production from A. niger were concentrations of tannic acid and sodium nitrate, agitation rate and incubation period. Hence, to achieve the maximum yield of tannase, interaction of these factors was studied at optimum production pH of 5.0 by RSM. The optimum values of parameters obtained through RSM were 5% tannic acid, 0.8% sodium nitrate, 5.0 pH, 5 * 10(7) spores/50mL inoculum density, 150 rpm agitation and incubation period of 48 h which resulted in production of 19.7 UmL(-1) of the enzyme. This activity was almost double as compared to the amount obtained by 'one-at-a-time' approach (9.8 UmL(-1)). PMID- 23100656 TI - Dehalogenation of 4 - Chlorobenzoic Acid by Pseudomonas isolates. AB - Twenty three bacterial isolates either pure or consortium were initially screened on the basis of their ability to degrade as well as dechlorinate 4 - chlorobenzoic acid (4-CBA). Based on comparative growth response, three pure isolates Pseudomonas putida GVS-4, Pseudomonas aeruginosa GVS-18 and Pseudomonas aeruginosa GWS-19 and a consortium SW-2 was finally selected for further studies. The enzyme studies performed with cell free extracts revealed that dehalogenase activity was substrate specific with maximum activity at 300 MUgml(-1) substrate concentration. Catechol 1,2 dioxygenase activity was found to be present in cell free extracts suggesting that 4 - chlorobenzoic acid (4-CBA) is catabolized by ortho-ring cleavage pathway. The dehalogenase enzyme profile showed single enzyme band in case of GVS-4 (Rm 0.76), GVS-18 (Rm 0.84), GWS -19 (Rm 0.85) and two bands in SW-2 (Rm 0.71 & 0.10). PMID- 23100657 TI - Statistical optimization of alkaline xylanase production from Streptomyces violaceoruber under submerged fermentation using response surface methodology. AB - Response surface methodology employing central composite design (CCD) was used to optimize fermentation medium for the production of cellulase-free, alkaline xylanase from Streptomyces violaceoruber under submerged fermentation. The design was employed by selecting wheat bran, peptone, beef extract, incubation time and agitation as model factors. A second-order quadratic model and response surface method showed that the optimum conditions for xylanase production (wheat bran 3.5 % (w/v), peptone 0.8 % (w/v), beef extract 0.8 % (w/v), incubation time 36 h and agitation 250 rpm) results in 3.0-fold improvement in alkaline xylanase production (1500.0 IUml(-1)) as compared to initial level (500.0 IUml(-1)) after 36 h of fermentation, whereas its value predicted by the quadratic model was 1347 IUml(-1). Analysis of variance (ANOVA) showed a high coefficient of determination (R(2)) value of 0.9718, ensuring a satisfactory adjustment of the quadratic model with the experimental data.The economical and cellulase-free nature of xylanase would enhance its applicability in pulp and paper industry. PMID- 23100658 TI - Design and development of batch type acetifier for wine-vinegar production. AB - A batch type acetifier based on the principal of acetic acid fermentation was designed and tested for production of wine-vinegar from the pineapple peel waste. The pineapple peels along with starter solution was fed to the inner SS perforated peel-solid separator tank 130 mm dia having perforations of 50 mm size. The concentric perforated peel-solid separator circular tank was fitted inside the collecting tank having 255 mm dia. The pineapple peels and starter solution in perforated peel-solid separator tank was agitated and atomized by tubing agitator 200 mm long having 1 mm dia. hole to spray fermented solution at 20 rpm. The agitator was connected with stirring pump. Lift pump was fitted at the bottom of the collecting tank to lift and supply fermented solution to agitator. The capacity of the batch type Acetifier based on present working design was 3.5 liters of wine-vinegar per day for 8 hours for a quality end product at 2% acidity. PMID- 23100659 TI - In vitro susceptibility of viridans streptococci to leaf extracts of Mangifera Indica. AB - The susceptibility of Viridans streptococci to leaf extracts of Mangifera indica was studied on 53 clinical isolates from 39 patients. All the isolates were found to be susceptible to both water and methanol extract of M. indica leaves. Minimum inhibitory concentration (MIC) of methanol extract for all isolates were <50 mg/mL and MIC of water extract for all isolates were <200 mg/mL. Methanol extract was found to have better action against Viridans streptococci than water extract. PMID- 23100660 TI - Bio-softening of mature coconut husk for facile coir recovery. AB - Bio-softening of the mature coconut husk using Basidiomyceteous fungi was attempted to recover the soft and whiter fibers. The process was faster and more efficient in degrading lignin and toxic phenolics. Phanerochaete chrysosporium, Pleurotus eryngii and Ceriporiopsis subvermispora were found to degrade lignin efficiently without any appreciable loss of cellulose, yielding good quality fiber ideal for dyeing. PMID- 23100661 TI - A rapid colony screening method for the detection of arsenate-reducing bacteria. AB - A rapid and simple method has been developed for the detection of arsenate reducing bacteria based on the presence of arsenite [As (III)], the end product of anaerobic arsenate [As (V)] respiration. Confirmation of As (III) product is made by the reduction of starch-iodine complex. The method can be used over a large pH range (5.5-9.0) and can easily be determined at arsenite concentration as low as 0.025 mM. Major advantages of this technique are that a large number of samples can be analyzed easily at a time. PMID- 23100662 TI - Optimization of polyhydroxybutyrate production by Bacillus sp. CFR 256 with corn steep liquor as a nitrogen source. AB - Polyhydroxyalkanotes (PHAs), the eco-friendly biopolymers produced by many bacteria, are gaining importance in curtailing the environmental pollution by replacing the non-biodegradable plastics derived from petroleum. The present study was carried out to economize the polyhydroxybutyrate (PHB) production by optimizing the fermentation medium using corn steep liquor (CSL), a by-product of starch processing industry, as a cheap nitrogen source, by Bacillus sp. CFR 256. Response surface methodology (RSM) was used to optimize the fermentation medium using the variables such as corn steep liquor (5-25 g l(-1)), Na(2)HPO(4) 2H(2)O (2.2-6.2 g l(-1)), KH(2)PO(4) (0.5-2.5 g l(-1)), sucrose (5-55 g l(-1)) and inoculum concentration (1-25 ml l(-1)). Central composite rotatable design (CCRD) experiments were carried out to study the complex interactions of the variables.The optimum conditions for maximum PHB production were (g l(-1)): CSL 25, Na(2)HPO(4) 2H(2)O-2.2, KH(2)PO(4) - 0.5, sucrose - 55 and inoculum - 10 (ml l(-1)). After 72 h of fermentation, the amount of PHA produced was 8.20 g l(-1) (51.20% of dry cell biomass). It is the first report on optimization of fermentation medium using CSL as a nitrogen source, for PHB production by Bacillus sp. PMID- 23100663 TI - Lignocellulolytic enzyme production from submerged fermentation of paddy straw. AB - Five strains of cellulolytic bacteria and four strains of Phanerochaete chrysosporium were evaluated for the lignocellulolytic enzyme production during submerged fermentation (SmF) of paddy straw. Extra-cellular enzyme assay for CMCase, FPase, Cellobiase, Xylanase, Lignin peroxidase and Laccase enzymes was performed after 7 and 15 days of submerged fermentation. Cellulomonas cellulans MTCC 23, Cytophaga hutchinsonii NCIM 2338 and Phanerochaete chrysosporium MTCC 787 were found to produce higher lignocellulolytic enzyme activities than rest of the cultures after 15 days of fermentation. PMID- 23100664 TI - Bacterial glycosidases for making universal blood group O - the Holy Grail of blood transfusion. PMID- 23100665 TI - Combating antibiotic resistance in bacteria. AB - Combinations of certain antibiotics select against resistant strains of bacteria. This finding may provide a strategy of combating antibiotic resistant bacteria. PMID- 23100666 TI - Research on marine actinobacteria in India. AB - Marine actinobacteriology is one of the major emerging areas of research in tropics. Marine actinobacteria occur on the sediments and in water and also other biomass (mangrove) and substrates (animal). These organisms are gaining importance not only for their taxonomic and ecological perspectives, but also for their unique metabolites and enzymes. Many earlier studies on these organisms were confined only to the temperate regions. In tropical environment, investigations on them have gained importance only in the last two decades. So far, from the Indian peninsula, 41 species of actinobacteria belonging to 8 genera have been recorded. The genus, Streptomyces of marine origin has been more frequently recorded. Of 9 maritime states of India, only 4 have been extensively covered for the study of marine actinobacteria. Most of the studies conducted pertain to isolation, identification and maintenance of these organisms in different culture media. Further, attention has been focused on studying their antagonistic properties against different pathogens. Their biotechnological potentials are yet to be fully explored. PMID- 23100667 TI - An overview of purification methods of glycoside hydrolase family 70 dextransucrase. AB - The enzyme dextransucrase (sucrose:1, 6-alpha-D-glucan 6-alpha glucosyltransferase, EC 2.4.1.5) catalyses the synthesis of exopolysaccharide, dextran from sucrose. This class of polysaccharide has been extensively exploited in pharmaceutical industry as blood volume expander, as stabiliser in food industry and as a chromatographic medium in fine chemical industry because of their nonionic nature and stability. Majority of the dextrans are synthesized from sucrose by dextransucrase secreted mainly by bacteria belonging to genera Leuconostoc, Streptococcus and Lactobacillus. Bulk of the information on purification of extracellular dextransucrase has been generated from Leuconostoc species. Various methods such as precipitation by ammonium sulphate, ethanol or polyethylene glycol, phase partitioning, ultrafiltration and chromatography have been used to purify the enzyme. Purification of dextransucrase is rendered difficult by the presence of viscous dextran in the medium. However, processes like ultra-filtration, salt and PEG precipitation, chromatography and phase partitioning have been standardized and successfully used for higher scale purification of the enzyme. A recombinant dextransucrase from Leuconostoc mesenteroides B-512F with a histidine tag has been expressed in E. coli cells and purifi ed by immobilized metal ion chromatography. This review reports the available information on purifi cation methods of dextransucrase from Leuconostoc mesenteroides strains. PMID- 23100668 TI - Semi-nested polymerase chain reaction for detection of toxigenic Vibrio cholerae from environmental water samples. AB - A rapid and sensitive direct cell semi-nested PCR assay was developed for the detection of viable toxigenic V. cholerae in environmental water samples. The semi-nested PCR assay amplified cholera toxin (ctxA2B) gene present in the toxigenic V. cholerae. The detection sensitivity of direct cell semi-nested PCR was 2 * 10(3) CFU of V. cholerae whereas direct cell single-step PCR could detect 2 * 10(4) CFU of V. cholerae. The performance of the assay was evaluated using environmental water samples after spiking with known number of Vibrio cholerae O1. The spiked water samples were filtered through a 0.22 micrometer membrane and the bacteria retained on filters were enriched in alkaline peptone water and then used directly in the PCR assay. The semi-nested PCR procedure coupled with enrichment could detect less than 1 CFU/ml in ground water and sea water whereas 2 CFU/ml and 20 CFU/ml could be detected in pond water and tap water, respectively. The proposed method is simple, faster than the conventional detection assays and can be used for screening of drinking water or environmental water samples for the presence of toxigenic V. cholerae. PMID- 23100669 TI - Phylogenetic studies in Ravenelia esculenta and related rust fungi. AB - Ravenelia esculenta Naras. and Thium. is a rust fungus, which infects mostly thorns, inflorescences, flowers and fruits of Acacia eburnea Willd. Aecial stages of the rust produce hypertrophy in infected parts. DNA of the rust fungus was isolated from aeciospores by 'freeze thaw' method. 18S rDNA was amplified and sequenced by automated DNA sequencer. BLAST of the sequence at NCBI retrieved 96 sequences producing significant alignments. Multiple sequence alignment of these sequences was done by ClustalW. Phylogenetic analysis was done by using MEGA 3.1. UPGMA Minimum Evolution tree with bootstrap value of 1000 replicates was constructed using these sequences. From phylogenetic tree it is observed that Ravenelia esculenta and the genus Gymnosporangium share a common ancestry, though Ravenelia esculenta is autoecious on angiosperm and the genus Gymnosporangium is heteroecious with pycnia, aecia on angiosperm and uredia, telia on gymnosperm. Two major clades are recognized which are based on the nature of aecial host (gymnosperm or angiosperm). These clades were also showing shift from pteridophytes to angiosperms as telial hosts. The tree can be interpreted in the other way also where there is separation of 14 families of Uredinales depending upon nature of teliospores, nature of aeciospores and structure of pycnia. These studies determine the phylogenetic position of Ravenelia esculenta among other rust fungi besides broad separation of Uredinales into two clades. These studies also show that there is phylogenetic correlation between molecular and morphological data. This is first report of DNA sequencing and phylogenetic positioning in genus Ravenelia from India. PMID- 23100670 TI - Biodiversity of epilithic cyanobacteria from freshwater streams of Kakoijana reserve forest, Assam, India. AB - The biodiversity of epilithic cyanobacteria from one of the unexplored habitats of freshwater streams of Kakoijana reserve forest of Assam, India was estimated. This paper lists a total of 29 species representing 18 genera of 12 families and 4 orders as per recent system of classification. Morphological descriptions, common habitats and distribution pattern were described for each species identified that were represented systematically. Of these 29 species, 11 were unicellular, 9 non-heterocytous filamentous and 9 heterocytous filamentous forms. All the unicellular (Aphanocapsa crassa, A. muscicola, Aphanothece nidulans, A. saxicola, Chlorogloea purpurea, Chroococcus cohaerens, C. minimus, C. minor, Cyanobacterium cedrorum, Cyanocystis versicolor and Gloeocapsopsis crepidinum) and 13 (Calothrix epiphytica, C. scopulorum, Leptolyngbya boryana, L. calotrichoides, L. fragilis, L. notata, Lyngbya arboricola, Nostoc humifusum, N. oryzae, N. punctiforme, Parthasarathiella prolifica, Porphyrosiphon ceylanicus and Scytonema millei) of the remaining 18 species were recorded for the first time as freshwater epiliths. While, 5 species (Hapalosiphon welwitschii, Leptolyngbya tenuis, Oscillatoria pseudogeminata, Phormidium laetevirens, Tolypothrix fragilis) and 8 species (Aphanothece saxicola, Calothrix scopulorum Chlorogloea purpurea, Chroococcus minor, Gloeocapsopsis crepidinum, Leptolyngbya calotrichoides, L. fragilis and L. tenuis) were reported earlier as freshwater and marine-epilithic forms respectively. All are new records for Assam except 6 species (A. nidulans, H. welwitschii, N. punctiforme, N. oryzae, O. pseudogeminata and P. ceylanicus), while 3 species (C. purpurea, L. boryana and L. calotrichoides) are new records for India. Six nitrogen fixing heterocytous forms such as, C. epiphytica, C. scopulorum, N. humifusum, N. punctiforme, N. oryzae and S. millei, were common to the neighboring paddy fields. PMID- 23100671 TI - Nontubercular Mycobacteria in drinking water of some educational institutes in Jabalpur (M.P.), India. AB - Sixteen isolates of Nontubercular Mycobacteria species were isolated from drinking water supply of some educational institutes in Jabalpur during July 2006 and were identified by biochemical test, thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) analysis and PRA ( PCR restriction enzyme analysis) of rpoB gene. Out of 21 water samples total 16 isolates of nontuberculous mycobacteria were identified, as M. terrae (6), M. szulgai (4), M. gordonae (3), and one each as M. malmoense, M. kansasii, and M. gastri. PMID- 23100672 TI - Development and characterization of nickel accumulating mutants of Aspergillus nidulans. AB - Stable mutants of Aspergillus nidulans, resistant to 1 mM Ni were developed by step-by-step repeated culturing of the fungus on the medium containing increasing concentrations of nickel chloride. Characterization of mutants could differentiate them into two categories Ni(R) I and Ni(R) II. Each category of mutants exhibited alterations in growth, conidial germination and melanin secretion both in Ni-free and Ni-containing media. Ni(R) II mutants were little slow in growth with sparse mycelia and conidiation but showed high melanin secretion and higher Ni-uptake in comparison to Ni(R) I mutant. Studies involving metabolic and translational inhibitors could prove that Ni-accumulation was biphasic. The initial energy independent surface accumulation was found to be followed by energy dependent intarcellular uptake. Increase in the concentration of the metal in the medium or the time of exposure did not proportionately increase the metal uptake by the mutants. Ni-uptake followed Michaelis-Menton saturation kinetics, which was enhanced under optimum pH of 6.5-7.5 and reduced complexity of the medium due to free availability of ions. Resistance to Ni was found to be constitutive in Ni(R)I mutant, and could be induced in Ni(R)II mutant. PMID- 23100673 TI - Evaluation of an indigenous ELISA for diagnosis of Johne's disease and its comparison with commercial kits. AB - Country lacks sensitive and indigenous diagnostic kits for the screening of goats and sheep against Johne's disease. Therefore an indigenous ELISA kit was developed using protoplasmic antigen from native Mycobacterium avium subspecies paratuberculosis 'Bison Type' strain of goat origin (Kit 1). In the present study, kit 1 and two commercial kits (kit 2 and 3) were evaluated with respect to 'Gold Standard' fecal culture in 71 animals (55 goats and 16 sheep). Kit 1 using indigenous antigen (protoplasmic antigen) was sensitive at very low concentration (0.1 MUgm / well) as compared to purified commercial protoplasmic antigen (4 MUgm / well) used in kit 2, in the Type 1 reactors (strong positive as positive). Screening of 71 animals by fecal culture detected 38.0% animals (goats-40.0%, sheep-31.2%) as positive (clinical shedders of bacilli) from these farm animals. Of the farm animals located at Central Institute for Research on Goats, herds of goat were endemic whereas, sheep flocks were comparatively resistant to Johne's disease. The 29.5 and 61.9, 15.4 and 57.7 and 4.2 and 14.0% animals (goats and sheep) were in the category of sero-reactors type 1 and 2 of the ELISA kits 1, 2 and 3, respectively. In the type 1 sero-reactors, sensitivity and specificity of kit 1, 2 and 3 was 53.7 and 86.0, 17.8 and 86.0 and 3.5 and 94.7%, respectively. Indigenous ELISA test (kit 1) was significantly superior for the screening of goatherds and sheep flocks against JD as compared to commercial ELISA kits (Kit 2 and 3). In comparison to kit 2 and 3, kit 1 had highest sensitivity, comparable specificity and substantial to nearly perfect proportional agreement (Kappa Scores) with respect to 'Gold standard' fecal culture in goats and sheep. Disease being endemic in herds and flocks screened using ELISA kits, Type I sero-rectors had better correlation with fecal culture in comparison to Type II sero-reactors therefore, used for estimation of sero-prevalence. Newly developed Indigenous ELISA kit was simple, inexpensive, sensitive and reliable for screening of goats and sheep population against Johne's disease. The study reports high prevalence of Johne's disease in farm goatherds and sheep flocks, using sensitive tests (fecal culture and ELISA kit). Results of Type 1 reaction in kit 1 were optimally correlated with culture and were good for estimating the sero-prevalence. For controlling Johne's disease in endemic herds initial removal of the animals in strong positive category (Tyep 1 reactors), may help to remove heavy shedders. PMID- 23100674 TI - Sporulation and regeneration efficiency of phosphobacteria (Bacillus megaterium var phosphaticum). AB - Sporulation in Bacillus megaterium var phosphaticum (PB - 1) was induced using modified nutrient media. This modified medium induced sporulation within 36 h. After spore induction the spores were kept under refrigerated (5 degrees C) and room temperature (32 degrees C) for five months and survival of spores was studied at 15 days intervals by plating them in nutrient agar medium. It was observed that there was not much variation in the storage temperature (5 degrees C & 32 degrees C). The spore cells of Bacillus megaterium var phosphaticum (PB - 1) were observed up to five months of storage under refrigerated (5 degrees C) and room temperature (32 degrees C). Regeneration of spore cells into vegetative cells was studied in tap water, rice gruel, nutrient broth, sterile lignite and sterile water at different concentrations of spore inoculum. The multiplication of sporulated Bacillus megaterium var phosphaticum culture was fast and reached its maximum (29.5 * 10(8) cfu ml(-1)) in nutrient broth containing 5 per cent inoculum level. PMID- 23100675 TI - Microbiological study of khoa sold in Chambal region (Madhya Pradesh): A case study. AB - Present study was conducted to analyze bacterial contaminants /pathogens in Khoa samples sold in Chambal region of Madhya Pradesh. Total Fifty samples of Khoa were brought from different localities of Chambal region at random and processed. Bacterial colony counts were also performed. Staphylococcus species and Streptococcus species were the predominant isolates. The viable counts obtained ranged from 1.3sX10(4) to 2.1sX10(6) CFU/g. Contamination of Khoa by pathogenic bacteria could be an important factor of gastrointestinal infections including food poisoning and food borne illness. Adequate consumer protection can be achieved by measuring the microbiological data of product. PMID- 23100676 TI - Inhibitory activity of pine needle tannin extracts on some agriculturally resourceful microbes. AB - Crude extracts of water and solvent extractable tannin fractions from pine needles were found to contain tannin concentrations of 10.15% and 13.15% tannic acid equivalents respectively. Thin Layer Chromatography revealed the presence of four distinct phenolic compounds, amongst which two were tannic acid like compounds. Both the extracts were found to be inhibitory to several microbes of agricultural importance. Amongst the bacterial strains studied, Azotobacter sp (VL-A2) was able to tolerate upto 1000 ppm of crude tannin concentration without any growth inhibition. While growth of Rhizobium (VL-R1) and Bacillus halodurans (MTCC 7181) was inhibited by crude tannin concentrations of 50 and 100 ppm respectively of both water and solvent extracted tannins. Among the fungal genera, Pleurotus djamor was found to tolerate up to 10000 ppm of crude tannins, while Trichoderma virescens (MTCC 6321) and T. reesii could tolerate up to 3000 ppm of both water extractable and acetone extractable crude tannins without any growth inhibition. PMID- 23100677 TI - Localization of HCH catabolic genes (lin genes) in Sphingobium indicum B90A. AB - The locations of hexachlorocyclohexane (HCH) catabolic (lin) genes were investigated in HCH degrading sphingomonad, Sphingobium indicum B90A (that was isolated from India). Southern blot analysis revealed the presence of linA1, linC, linDER and linX (linX1 and linX2) on the plasmid DNA in Sphingobium indicum B90A. PMID- 23100678 TI - Indian science: Hesitation or ignorance? PMID- 23100679 TI - Auxotrophy in rhizobia revisited. AB - Among the various types of mutations studied in rhizobia, the auxotrophic mutations (which confer on the mutants the inability to synthesize certain essential substances such as amino acids, vitamins and nucleic acids), are the most favoured ones as these can be used as suitable markers for genetic analysis. An important property of rhizobia is their effectiveness i.e. their ability to fix atmospheric nitrogen into ammonia within the nodule. Special interest in this category of mutations by rhizobial geneticists is due to the fact that there is a strong correlation between the metabolic defects and the ineffectiveness (Nod(-) and/or Fix(-)) of the rhizobial strains. Auxotrophic mutants of various species of rhizobia with defects in the synthesis of nucleic bases, vitamins and amino acids have been obtained by mutagenising with physical, chemical and Tn5 mutagens. These mutants have been used in mapping studies as well as in establishing a correlation between its metabolic requirement and symbiotic relationship with the host plant. The present review deals with the isolation of auxotrophs, and their genetic, biochemical and symbiotic characterization. The review also encompasses the studies on the elucidation of biosynthetic pathways of nutritional substances in rhizobia. PMID- 23100680 TI - Induced systemic resistance (ISR) in plants: mechanism of action. AB - Plants possess a range of active defense apparatuses that can be actively expressed in response to biotic stresses (pathogens and parasites) of various scales (ranging from microscopic viruses to phytophagous insect). The timing of this defense response is critical and reflects on the difference between coping and succumbing to such biotic challenge of necrotizing pathogens/parasites. If defense mechanisms are triggered by a stimulus prior to infection by a plant pathogen, disease can be reduced. Induced resistance is a state of enhanced defensive capacity developed by a plant when appropriately stimulated. Systemic acquired resistance (SAR) and induced systemic resistance (ISR) are two forms of induced resistance wherein plant defenses are preconditioned by prior infection or treatment that results in resistance against subsequent challenge by a pathogen or parasite. Selected strains of plant growth-promoting rhizobacteria (PGPR) suppress diseases by antagonism between the bacteria and soil-borne pathogens as well as by inducing a systemic resistance in plant against both root and foliar pathogens. Rhizobacteria mediated ISR resembles that of pathogen induced SAR in that both types of induced resistance render uninfected plant parts more resistant towards a broad spectrum of plant pathogens. Several rhizobacteria trigger the salicylic acid (SA)-dependent SAR pathway by producing SA at the root surface whereas other rhizobacteria trigger different signaling pathway independent of SA. The existence of SA-independent ISR pathway has been studied in Arabidopsis thaliana, which is dependent on jasmonic acid (JA) and ethylene signaling. Specific Pseudomonas strains induce systemic resistance in viz., carnation, cucumber, radish, tobacco, and Arabidopsis, as evidenced by an enhanced defensive capacity upon challenge inoculation. Combination of ISR and SAR can increase protection against pathogens that are resisted through both pathways besides extended protection to a broader spectrum of pathogens than ISR/SAR alone. Beside Pseudomonas strains, ISR is conducted by Bacillus spp. wherein published results show that several specific strains of species B. amyloliquifaciens, B. subtilis, B. pasteurii, B. cereus, B. pumilus, B. mycoides, and B.sphaericus elicit significant reduction in the incidence or severity of various diseases on a diversity of hosts. PMID- 23100681 TI - An alkaline protease from Bacillus circulans BM15, newly isolated from a mangrove station: characterization and application in laundry detergent formulations. AB - An investigation on the properties of an alkaline protease secreted by Bacillus circulans BM15 strain isolated from a mangrove sediment sample was carried out in order to characterize the enzyme and to test its potency as a detergent additive. The protease was purified to apparent homogeneity by ammonium sulphate precipitation and was a 30-kDa protease as shown by SDS-PAGE and its proteolytic activity was detected by casein zymography. It had optimum activity at pH 7, was stable at alkaline pH range (7 to 11), had optimum temperature of activity 40 degrees C and was stable up to a temperature of 55 degrees C after incubation for one hour. Hg(2+), Zn(2+), Co(2+), and Cu(2+)completely inhibited the enzyme activity, while Ca(2+), Mg(2+), K(+) and Fe(3+) were enhancing the same. The serine protease inhibitor PMSF and metal chelator EDTA inhibited the activity of this protease while the classic metalloprotease inhibitor 1, 10 phenanthroline did not show inhibition. The enzyme was stable in SDS, Triton-X-100 and H(2) O(2) as well as in various commercial detergents after incubation for one hour. The extracellular production of the enzyme, the pH and temperature stability and stability in presence of oxidants, surfactants and commercial detergents suggest its possible use as a detergent additive. PMID- 23100682 TI - Study of mixed function oxidase system in Aspergillus ochraceus (NCIM 1146). AB - Aspergillus ochraceus (NCIM-1146) has shown the ability to degrade cholesterol, camphor and naphthalene, when 96 h grown mycelium incubated in medium containing these organic compounds. Presence of higher level of electron transport components and biotransformation enzyme activity were observed in Aspergillus ochraceus, when grown in potato dextrose medium for 96 h. The enzyme activity preferred NADPH as a cofactor and shows inhibition in the presence of CO, indicating cytochrome P-450 mediated reactions. A significant increase in the levels of electron transport components and biotransformation enzyme activity were observed in presence of different inducers (viz. cholesterol, camphor, naphthalene, veratrole, phenobarbital, n-hexane, kerosene and saffola oil) when compared with mycelium incubated in same way with similar conditions for 2 min incubation. Analyses of the products of cholesterol and camphor using HPLC and GCMS confirm the degradation of these compounds. PMID- 23100683 TI - Optimization of fermentation parameters for production of ethanol from kinnow waste and banana peels by simultaneous saccharification and fermentation. AB - A study was taken up to evaluate the role of some fermentation parameters like inoculum concentration, temperature, incubation period and agitation time on ethanol production from kinnow waste and banana peels by simultaneous saccharification and fermentation using cellulase and co-culture of Saccharomyces cerevisiae G and Pachysolen tannophilus MTCC 1077. Steam pretreated kinnow waste and banana peels were used as substrate for ethanol production in the ratio 4:6 (kinnow waste: banana peels). Temperature of 30 degrees C, inoculum size of S. cerevisiae G 6% and (v/v) Pachysolen tannophilus MTCC 1077 4% (v/v), incubation period of 48 h and agitation for the first 24 h were found to be best for ethanol production using the combination of two wastes. The pretreated steam exploded biomass after enzymatic saccharification containing 63 gL(-1) reducing sugars was fermented with both hexose and pentose fermenting yeast strains under optimized conditions resulting in ethanol production, yield and fermentation efficiency of 26.84 gL(-1), 0.426 gg (-1) and 83.52 % respectively. This study could establish the effective utilization of kinnow waste and banana peels for bioethanol production using optimized fermentation parameters. PMID- 23100684 TI - Isolation and identification of antimicrobial agent-producing bacterium from Taxus baccata rhizosphere antagonistic against clinically significant microbes. AB - A bacterium identified as Pseudomonas fluorescence was isolated from Taxus baccata rhizosphere. Ethyl acetate extract from its culture filtrate yielded an active antimicrobial compound that was purified by TLC. The active metabolites were resolved by column chromatography on silica gel (60-120 mesh). The compound was further characterized on the basis of spectral data (UV, IR and (1)HNMR), which indicated the presence of an aromatic ring and phenolic functionality. The compound showed significant antimicrobial activity against two-gram positive bacteria (B. subtilis and S. aureus), four-gram negative bacteria (E. coli, K. pneumoniae, S. flexneri and P. aeruginosa), and one pathogenic fungus (Candida albicans). The minimum inhibitory concentration (MIC) of the compound ranged between 75MUg to 250 MUg/ml. PMID- 23100685 TI - Cellulolytic enzymes on lignocellulosic substrates in solid state fermentation by Aspergillus niger. AB - The production of cellulolytic enzymes by Aspergillus niger on lignocellulosic substrates groundnut fodder, wheat bran, rice bran and sawdust in solid state fermentation in a laboratory scale was compared. Czapek Dox liquid broth amended with cellulose (0.5%) was used to moisten lignocellulosic solid supports for cultivation of Aspergillus niger. The production of filter paperase, carboxymethyl cellulase and -glucosidase were monitored at daily intervals for 5 days. The peak production of the enzymes occurred within 3 days of incubation. Among solid supports used in the study, wheat bran was the best solid matrix followed by groundnut fodder in production of cellulolytic enzymes in solid state fermentation. Groundnut fodder supported significant production of FPase (2.09 FPU/g), CMCase (1.36 U/g) and -glucosidase activity (0.0117 U/g) in solid state fermentation. Considerable secretion of protein (5.10 mg/g) on groundnut fodder at peak time interval 1st day of incubation was recorded. PMID- 23100686 TI - Characterization of heat resistant mutant strains of Rhizobium sp. [Cajanus] for growth, survival and symbiotic properties. AB - Fourteen heat resistant mutant strains were isolated from a wild-type strain (PP201, Nod(+) Fix(+)) of Rhizobium sp. (Cajanus) by giving it a heat shock of 43 degrees C. These mutant strains showed a greater increase in optical density (O.D.) and a higher viable cell count in both rhizospheric and non-rhizospheric soil at high temperature. Symbiotic studies showed that pigeon pea plants inoculated with a few mutant strains had ineffective nodules (Nod(+) Fix(-)) under controlled temperature (43 degrees C) conditions, but under natural high temperature (40-45 degrees C) conditions, the host plants infected with all the mutant strains showed higher total shoot nitrogen than the plants inoculated with the parent strain. Four mutant strains (HR-3, HR-6, HR-10 and HR-12) were found to be highly efficient for all the symbiotic parameters, and thus have the potential to be used as bioinoculants in the North-Western regions of India during the summer season. PMID- 23100687 TI - Mechanism to combat cobalt toxicity in cobalt resistant mutants of Aspergillus nidulans. AB - Characteristics of fungal species tolerant to high levels of metals in natural environment can be amplified by isolation and selection of resistant mutants. Step-by-step culturing led to identification of highly stable Co-resistant (Co(R)) mutants of A. nidulans. Based on two distinct morphological features, Co resistant mutants were categorized as Co(R)I and Co(R)II. The two mutants varied in their growth behavior and colony morphology that were reflected in supplemented as well as unsupplemented growth media over the generations. As compared to the Co(R)I, Co(R)II mutant exhibited sparse mycelia and conidiation but secreted higher amount of melanin. Co(R) mutants could tolerate up to 2.5mM Co in the medium, however, required a threshold concentration of 0.25mM Co for optimal growth and germination. Absence of Co in the medium caused a stressful situation for the Co(R) mutants and led to the secretion of a white extracellular precipitate found to be a glycoprotein. In response to interactions with Co-ions, Co(R) mutants produced oxalic acid and bioprecipitated Co as Co-oxalate providing scope for metal reclamation as well as oxalic acid extraction. The mutants could help to recover the insoluble Co-oxalate salt from aqueous solutions by entrapping it in their growing mycelial meshwork. PMID- 23100688 TI - Isolation and characterization of a Mastigocladus species capable of growth, N(2) fixation and N-assimilation at elevated temperature. AB - A Mastigocladus species was isolated from the hot spring of Jakrem (Meghalaya) India. Uptake and utilization of nitrate, nitrite, ammonium and amino acids (glutamine, asparagine, arginine, alanine) were studied in this cyanobacterium grown at different temperatures (25 degrees C, 45 degrees C). There was 2-3 fold increase in the heterocyst formation and nitrogenase activity in N-free medium at higher temperature (45 degrees C). Growth and uptake and assimilation of various nitrogen sources were also 2-3 fold higher at 45 degrees C indicating that it is a thermophile. The extent of induction and repression of nitrate uptake by NO(3) (-) and NH(4) (+), respectively, differed from that of nitrite. It appeared that Mastigocladus had two independent nitrate/nitrite transport systems. Nitrate reductase and nitrite reductase activitiy was not NO(3) (-)-inducible and ammonium or amino acids caused only partial repression. Presence of various amino acids in the media partially repressed glutamine synthetase activity. Ammonium (methylammonium) and amino acid uptake showed a biphasic pattern, was energy dependent and the induction of uptake required de novo protein synthesis. Ammonium transport was substrate (NH(4) (+))-repressible, while the amino acid uptake was substrate inducible. When grown at 25 degrees C, the cyanobacterium formed maximum akinetes that remained viable upto 5 years under dry conditions. PMID- 23100689 TI - Cauliflower waste incorporation into cane molasses improves ethanol production using Saccharomyces cerevisiae MTCC 178. AB - Diluted cane molasses having total sugar and reducing sugar content of 9.60 and 3.80% (w/v) respectively was subjected to ethanol production by Saccharomyces cerevisiae MTCC 178. Incorporation of dried Cauliflower Waste (CW) in molasses at the level of 15 % increased ethanol production by nearly 36 % compared to molasses alone. Addition of 0.2 % yeast extract improved ethanol production by nearly 49 % as compared to molasses alone. When the medium containing diluted molasses and 0.2 % yeast extract was supplemented with 15 % CW, 29 % more ethanol was produced compared to molasses with 0.2 % yeast extract. Cell biomass, ethanol production, final ethanol concentration and fermentation efficiency of 2.65 mg mL(-1), 41.2 gL(-1), 0.358 gg(-1) and 70.11 % respectively were found to be best at 15% CW supplementation level besides reduction in fermentation time but further increase in CW level resulted in decline on account of all the above parameters. This is probably the first report to our knowledge, in which CW was used in enhancing ethanol production significantly using a small quantity of yeast extract. PMID- 23100690 TI - Periplasmically located alpha-santonin binding factor in Sphingomonas paucimobilis strain S ATCC 43388. AB - A marked reduction in uptake of alpha-santonin, accompanied by loss of ability of cells to transform the substrate, is observed on shocking Sphingomonas paucimobilis strain S ATCC 43388 cells by freeze - thaw method. The shock fluid shows a 26% quench in fluorescence at 350nm on incubation with the substrate. Addition of shock fluid to the freeze thawed cells restores both uptake as well as transformation of alpha-santonin to near normal. PMID- 23100691 TI - Diversity of Bacillus thuringiensis in the rice field soils of different ecologies in India. AB - Diversity of the Bacillus thuringiensis (Bt) in the rice field soils of different ecologies viz. the island (Port Blair), the Himalayan (Srinagar), brackish water (Mahe) and coastal mesophilic (Mangalore) habitats was analyzed by phenotypic characterization of 5, 66, 14 and 54 Bt isolates, respectively. The Bt isolates produced either monotypic (bipyramidal or spherical) or heterotypic (polymorphic bipyramidal or bipyramidal-rhomboidal) crystals. The organisms were generally resistant to the penicillin group of antibiotics, tolerated 5-12% NaCl and 0.5M Na-acetate. The Bt isolates contained 1-5 plasmids of 0.89-58.61 kbp sizes. The plasmid profiles had no correlation with crystal morphology or salt tolerance of different bacteria. Each soil was inhabited by different types of Bt. Two Bt strains of Mangalore and one strain each of the other places were phenotypically similar. One Bt strain each of Port Blair and Srinagar was different from all other strains. PMID- 23100692 TI - Formation of interspecies fusants of Agaricus bisporus and Agaricus bitorquis mushroom by protoplast fusion. AB - Interspecies fusants are formed between Agaricus bisporus and Agaricus bitorquis by protoplast fusion technique. Protoplasts were isolated and regenerated by using Novozyme 234 lytic enzyme. Twenty slow growing isolates were separated from the protoplast regenerated colonies, which were assumed as homokaryons (putative homokaryons). These twenty isolates were subjected to growth rate, colony morphology and spawn run studies for screening of true homokaryons. Antifungal markers were developed for selection of fusants. PMID- 23100693 TI - Detection of human rotavirus in hospitalized diarrheic children in central India. AB - During the present study, group A human rotaviruses were detected among diarrheic children using polyacrylamide gel electrophoresis (PAGE) technique, with a typical RNA migration pattern of 4:2:3:2, suggestive of group A rotavirus. During the study, a total of 46 fecal samples collected from hospitalized children with acute diarrhea as well as children inhabiting nearby animal farms with history of presence of animal rotaviruses on the farms were processed for detection of human rotavirus. Out of 33 diarrheic children, 12 showed presence of rotavirus infection (36.36%), however, none of the children from animal farm areas showed presence of rotavirus. Female children were more susceptible to rotavirus infection (46.15%) than males (30%). Majority of the cases of rotavirus gastroenteritis belonged up to one year of the age, with an incidence of 40.91%. RNA profile of rotaviruses suggested circulation of 5 different electropherotypes in this geographical locale of the country, indicating existence of genomic diversity among human rotaviruses. Majority of the isolates were of long pattern (66.67%), whereas short pattern was detected only in one third of the viruses. This preliminary study emphasizes for further detailed studies on the molecular characterization of rotaviruses circulating in this part of country and their relationship with other human rotavirus strains and animal strains in the country. PMID- 23100694 TI - Inactivation of Escherichia coli O157:H7 by cinnamon extracts in carrot-kinnow mandarin blends. AB - We investigated the antimicrobial efficacy of cinnamon extracts in laboratory prepared Kinnow-mandarin carrot blends challenged with Escerichia coli O157:H7. Freshly squeezed carrot and kinnow-mandarin juices were mixed to obtain a typical blend, inoculated with E. coli O157:H7 cultures at 10(2) CFU/mL with and without cinnamon extracts (0.3%) and stored at 4, 8 and 28 degrees C for up to 10 hours. Counts on tryptic soy agar (TSA) selective medium (Mac conkey sorbitol agar) and thin agar layer (TAL) were determined at every 2 hour. The TAL method was used for recovery of sublethally injured cells. Inactivation of E. coli O157:H7 in blends containing 0.3% cinnamon extracts were observed, with killing effects being more pronounced at 28 degrees C, similar trends were evident with blends stored under refrigeration conditions (4 and 8 degrees C).The decrease in counts were attributed to several factors namely, pH, storage temperature and addition of cinnamon. The results of our study indicate that cinnamon extracts could be used as an effective, natural antimicrobial for assuring consumer safety at the point of preparation of carrot-kinnow mandarin blends, which is a popular, nutritional beverage consumed in India. PMID- 23100695 TI - Evolution of a microbiologist to an e-Genomicist. PMID- 23100696 TI - Pseudomonas sp. to Sphingobium indicum: a journey of microbial degradation and bioremediation of Hexachlorocyclohexane. AB - The unusual process of production of hexachlorocyclohexane (HCH) and extensive use of technical HCH and lindane has created a very serious problem of HCH contamination. While the use of technical HCH and lindane has been banned all over the world, India still continues producing lindane. Bacteria, especially Sphingomonads have been isolated that can degrade HCH isomers. Among all the bacterial strains isolated so far, Sphingobium indicum B90A that was isolated from HCH treated rhizosphere soil appears to have a better potential for HCH degradation. This conclusion is based on studies on the organization of lin genes and degradation ability of B90A. This strain perhaps can be used for HCH decontamination through bioaugmentation. PMID- 23100697 TI - Bacterial degradation of phthalate isomers and their esters. AB - Phthalate isomers and their esters are used heavily in various industries. Excess use and leaching from the product pose them as major pollutants. These chemicals are toxic, teratogenic, mutagenic and carcinogenic in nature. Various aspects like toxicity, diversity in the aerobic bacterial degradation, enzymes and genetic organization of the metabolic pathways from various bacterial strains are reviewed here. Degradation of these esters proceeds by the action of esterases to form phthalate isomers, which are converted to dihydroxylated intermediates by specific and inducible phthalate isomer dioxygenases. Metabolic pathways of phthalate isomers converge at 3,4-dihydroxybenzoic acid, which undergoes either ortho- or meta- ring cleavage and subsequently metabolized to the central carbon pathway intermediates. The genes involved in the degradation are arranged in operons present either on plasmid or chromosome or both, and induced by specific phthalate isomer. Understanding metabolic pathways, diversity and their genetic regulation may help in constructing bacterial strains through genetic engineering approach for effective bioremediation and environmental clean up. PMID- 23100698 TI - Biodegradation and bioremediation of pesticide in soil: concept, method and recent developments. AB - Biodegradation is a natural process, where the degradation of a xenobiotic chemical or pesticide by an organism is primarily a strategy for their own survival. Most of these microbes work in natural environment but some modifications can be brought about to encourage the organisms to degrade the pesticide at a faster rate in a limited time frame. This capability of microbe is some times utilized as technology for removal of contaminant from actual site. Knowledge of physiology, biochemistry and genetics of the desired microbe may further enhance the microbial process to achieve bioremediation with precision and with limited or no scope for uncertainty and variability in microbe functioning. Gene encoding for enzyme has been identified for several pesticides, which will provide a new inputs in understanding the microbial capability to degrade a pesticide and develop a super strain to achieve the desired result of bioremediation in a short time. PMID- 23100699 TI - Microbial decolorization of spentwash: a review. AB - Spentwash is one of the most complex and cumbersome wastewater with very high BOD, COD and other organic and inorganic toxic constituents. It is dark brown colored and difficult to treat by normal biological process such as activated sludge or anaerobic lagooning. The color is due to the presence of melanoidins, caramels and other polymers. These compounds have anti oxidant properties which render them toxic to microorganisms. Spentwash disposal into the environment is hazardous and has a considerable pollution potential. It affects the aesthetic merit. Its decolorization by physical or chemical methods have been investigated and were found unsuitable. In the recent past, increasing attention has been directed towards utilizing microbial activity for decolorization of spentwash. This review reveals various groups of microorganisms which have potential in spentwash decolorization. The role of enzymes in decolorization and the microbial degradation of individual compounds imparting color to spentwash are also discussed. PMID- 23100700 TI - Microbial extracellular polymeric substances: central elements in heavy metal bioremediation. AB - Extracellular polymeric substances (EPS) of microbial origin are a complex mixture of biopolymers comprising polysaccharides, proteins, nucleic acids, uronic acids, humic substances, lipids, etc. Bacterial secretions, shedding of cell surface materials, cell lysates and adsorption of organic constituents from the environment result in EPS formation in a wide variety of free-living bacteria as well as microbial aggregates like biofilms, bioflocs and biogranules. Irrespective of origin, EPS may be loosely attached to the cell surface or bacteria may be embedded in EPS. Compositional variation exists amongst EPS extracted from pure bacterial cultures and heterogeneous microbial communities which are regulated by the organic and inorganic constituents of the microenvironment. Functionally, EPS aid in cell-to-cell aggregation, adhesion to substratum, formation of flocs, protection from dessication and resistance to harmful exogenous materials. In addition, exopolymers serve as biosorbing agents by accumulating nutrients from the surrounding environment and also play a crucial role in biosorption of heavy metals. Being polyanionic in nature, EPS forms complexes with metal cations resulting in metal immobilization within the exopolymeric matrix. These complexes generally result from electrostatic interactions between the metal ligands and negatively charged components of biopolymers. Moreover, enzymatic activities in EPS also assist detoxification of heavy metals by transformation and subsequent precipitation in the polymeric mass. Although the core mechanism for metal binding and / or transformation using microbial exopolymer remains identical, the existence and complexity of EPS from pure bacterial cultures, biofilms, biogranules and activated sludge systems differ significantly, which in turn affects the EPS-metal interactions. This paper presents the features of EPS from various sources with a view to establish their role as central elements in bioremediation of heavy metals. PMID- 23100702 TI - Rhizoremediation of metals: harnessing microbial communities. AB - With the increasing successful stories of decontamination, different strategies for metal remediation are gaining importance and popularization in developing countries. Rhizoremediation, is one such promising option that harnesses the impressive capabilities of microorganisms associated with roots to degrade organic pollutants and transform toxic metals. Since it is a plant based in-situ phytorestoration technique it is proven to be economical, efficient and easy to implement under field conditions.Plants grown in metal contaminated sites harbor unique metal tolerant and resistant microbial communities in their rhizosphere. These rhizo-microflora secrete plant growth promoting substances, siderophores, phytochelators to alleviate metal toxicity, enhance the bioavailability of metals (phytoremediation) and complexation of metals (phytostabilisation). Selection of right bacteria/consortia and inoculation to seed/ roots of suitable plant species will widen the perspectives of rhizoremediation. PMID- 23100701 TI - The enzymatic basis for pesticide bioremediation. AB - Enzymes are central to the biology of many pesticides, influencing their modes of action, environmental fates and mechanisms of target species resistance. Since the introduction of synthetic xenobiotic pesticides, enzymes responsible for pesticide turnover have evolved rapidly, in both the target organisms and incidentally exposed biota. Such enzymes are a source of significant biotechnological potential and form the basis of several bioremediation strategies intended to reduce the environmental impacts of pesticide residues. This review describes examples of enzymes possessing the major activities employed in the bioremediation of pesticide residues, and some of the strategies by which they are employed. In addition, several examples of specific achievements in enzyme engineering are considered, highlighting the growing trend in tailoring enzymatic activity to a specific biotechnologically relevant function. PMID- 23100703 TI - Cyanobacteria as potential options for environmental sustainability - promises and challenges. AB - Cyanobacteria represent an ancient group of photosynthetic prokaryotes, whose ubiquity, metabolic flexibility and adaptive abilities have made them a subject of research worldwide. These structurally simple organisms combine in themselves interesting facets of plant and bacterial metabolism, which is amenable to genetic exploitation. Despite their globally recognized significance in the sustenance of fertility in rice based cropping systems, they have not been tapped for their extraordinary repertoire of activities, especially their beneficial role as biological agents in remediation and amelioration of soil and water environment and as sinks for greenhouse gases. The information available on these aspects and future lines of research for more efficient utilization of these microorganisms is presented. PMID- 23100705 TI - Impact of pesticides on soil microbiological parameters and possible bioremediation strategies. AB - Intensive agriculture is spectacularly successful since last couple of decades due to the inputs viz; fertilizers and pesticides along with high yielding varieties. The mandate for agriculture development was to feed and adequate nutrition supply to the expanding population by side the agriculture would be entering to into new area of commercial and export orientation. The attention of public health and proper utilization natural resources are also the main issues related with agriculture development. Concern for pesticide contamination in the environment in the current context of pesticide use has assumed great importance [1]. The fate of the pesticides in the soil environment in respect of pest control efficacy, non-target organism exposure and offsite mobility has been given due consideration [2]. Kinetics and pathways of degradation depend on abiotic and biotic factors [6], which are specific to a particular pesticide and therefore find preference. Adverse effect of pesticidal chemicals on soil microorganisms [3], may affect soil fertility [4] becomes a foreign chemicals major issue. Soil microorganisms show an early warning about soil disturbances by foreign chemicals than any other parameters.But the fate and behavior of these chemicals in soil ecosystem is very important since they are degraded by various factors and have the potential to be in the soil, water etc. So it is indispensable to monitor the persistence, degradation of pesticides in soil and is also necessary to study the effect of pesticide on the soil quality or soil health by in depth studies on soil microbial activity.The removal of metabolites or degraded products should be removed from soil and it has now a day's primary concern to the environmentalist. Toxicity or the contamination of pesticides can be reduced by the bioremediation process which involves the uses of microbes or plants. Either they degrade or use the pesticides by various co metabolic processes. PMID- 23100706 TI - Microbial biodiversity and in situ bioremediation of endosulfan contaminated soil. AB - Molecular characterization based on 16s rDNA gene sequence analysis of bacterial colonies isolated from endosulfan contaminated soil showed the presence of Ochrobacterum sp, Burkholderia sp, Pseudomonas alcaligenes, Pseudomonas sp and Arthrobacter sp which degraded 57-90% of alpha-endosulfan and 74-94% of beta endosulfan after 7days. Whole cells of Pseudomonas sp and Pseudomonas alcaligenes showed 94 and 89% uptake of alpha-isomer and 86 and 89% of beta-endosulfan respectively in 120 min. In Pseudomonas sp, endosulfan sulfate was the major metabolite detected during the degradation of alpha-isomer, with minor amount of endosulfan diol while in Pseudomonas alcaligenes endosulfan diol was the only product during alpha-endosulfan degradation. Whole cells of Pseudomonas sp also utilized 83% of endosulfan sulfate in 120 min. In situ applications of the defined consortium consisting of Pseudomonas alcaligenes and Pseudomonas sp (1:1) in plots contaminated with endosulfan showed that 80% of alpha-endosulfan and 65% of beta-endosulfan was degraded after 12 weeks of incubation. Endosulfan sulfate formed during endosulfan degradation was subsequently degraded to unknown metabolites. ERIC-PCR analysis indicated 80% survival of introduced population of Pseudomonas alcaligenes and Pseudomonas sp in treated plots. PMID- 23100704 TI - Bacterial metabolism of polycyclic aromatic hydrocarbons: strategies for bioremediation. AB - Polycyclic aromatic hydrocarbons (PAHs) are compounds of intense public concern due to their persistence in the environment and potentially deleterious effects on human, environmental and ecological health. The clean up of such contaminants using invasive technologies has proven to be expensive and more importantly often damaging to the natural resource properties of the soil, sediment or aquifer. Bioremediation, which exploits the metabolic potential of microbes for the clean up of recalcitrant xenobiotic compounds, has come up as a promising alternative. Several approaches such as improvement in PAH solubilization and entry into the cell, pathway and enzyme engineering and control of enzyme expression etc. are in development but far from complete. Successful application of the microorganisms for the bioremediation of PAH-contaminated sites therefore requires a deeper understanding of the physiology, biochemistry and molecular genetics of potential catabolic pathways. In this review, we briefly summarize important strategies adopted for PAH bioremediation and discuss the potential for their improvement. PMID- 23100707 TI - Biodegradation of gamma-hexachlorocyclohexane (Lindane) by a non-white rot fungus conidiobolus 03-1-56 isolated from litter. AB - Biodegradation of chlorinated pesticide gamma-hexachlorocyclohexane (lindane) by a nonwhite rot fungus Conidiobolus 03-1-56 is reported for the first time. Conidiobolus 03-1-56, a phycomyceteous fungus isolated from litter, completely degraded lindane on the 5th day of incubation in the culture medium, and GC-ECD studies confirmed that lindane removal did not occur via adsorption on the fungal biomass. Degradation studies using different medium compositions showed that nitrogen/carbon limiting conditions (stress conditions) and presence of veratryl alcohol, induced the secretion of extracellular oxidative enzymes, which enhanced the rate of lindance biodegradation. Under optimum nutrient-limiting conditions, GC-ECD and GC-MS analysis showed complete absence of any degradation metabolite, indicating that lindane was completely mineralized. Assays for tannic acid utilization and lignin peroxidase showed similar enzymatic profiles between Conidiobolus 03-1-56 and standard white rot fungi Pleurotus ostreatus 1200 and Trametes versicolor 1086. Although Conidiobolus 03-1-56 showed a reduced enzyme activity compared to white rot fungi, preliminary evidence indicates that enzymes responsible for lignin degradation by white rots play a key role in lindane degradation by Conidiobolus 03-1-56. PMID- 23100708 TI - Bioremediation of multi-metal contaminated soil using biosurfactant - a novel approach. AB - An unconventional nutrient medium, distillery spent wash (1:3) diluted) was used to produce di-rhamnolipid biosurfactant by Pseudomonas aeruginosa strain BS2. This research further assessed the potential of the biosurfactant as a washing agent for metal removal from multimetal contaminated soil (Cr-940 ppm; Pb-900 ppm; Cd-430 ppm; Ni-880 ppm; Cu-480 ppm). Out of the treatments of contaminated soil with tap water and rhamnolipid biosurfactant, the latter was found to be potent in mobilization of metal and decontamination of contaminated soil. Within 36 hours of leaching study, di-rhamnolipid as compared to tap water facilitated 13 folds higher removal of Cr from the heavy metal spiked soil whereas removal of Pb and Cu was 9-10 and 14 folds higher respectively. Leaching of Cd and Ni was 25 folds higher from the spiked soil. This shows that leaching behavior of biosurfactant was different for different metals. The use of wastewater for production of biosurfactant and its efficient use in metal removal make it a strong applicant for bioremediation. PMID- 23100709 TI - Advances in monitoring of catabolic genes during bioremediation. AB - Biodegradation of xenobiotic compounds by microbes is exploited in the clean up of contaminated environments by bioremediation. Catabolic (or functional) genes encode for specific enzymes in catabolic pathways such as key enzymes in xenobiotic degradation pathways. By assessing the abundance or the expression of key genes in environmental samples one can get a potential measure of the degradation activity. One way of assessing the abundance and expression of specific catabolic genes is by analyzing the metagenomic DNA and RNA from environmental samples. Three major challenges in the detection and quantification of catabolic genes in bioremediation studies are 1) the accurate and sensitive quantification from environmental samples 2) the coverage of the enzymatic potential by the targeted genes 3) the validation of the correlation with actual observed degradation activities in field cases. New advances in realtime PCR, functional gene arrays and meta-transcriptomics have improved the applicability of catabolic gene assessment during bioremediation. PMID- 23100710 TI - Microbial genomics: rhetoric or reality? AB - The availability of complete genome sequences of many bacterial species is facilitating numerous computational approaches for understanding bacterial genomes. One of the major incentives behind the genome sequencing of many pathogenic bacteria is the desire to better understand their diversity and to develop new approaches for controlling human diseases caused by these microorganisms. This task has become even more urgent with the rapid evolution of antibiotic resistance among many bacterial pathogens. Novel drug targets are required in order to design new antimicrobials against antibiotic-resistant pathogens. The complete genome sequences of an ever increasing number of pathogenic microbes constitute an invaluable resource and provide lead information on potential drug targets. This review focuses on in silico analyses of microbial genomes, their host-specific adaptations, with specific reference to genome architecture, design, evolution, and trends in computational identification of microbial drug targets. These trends underscore the utility of genomic data for systematic in silico drug target identification in the post genomic era. PMID- 23100711 TI - A biological treasure metagenome: pave a way for big science. AB - The trend of recent researches, in which synthetic biology and white technology through system approaches based on "Omics technology" are recognized as the ground of biotechnology, indicates the coming of the 'metagenome era' that accesses the genomes of all microbes aiming at the understanding and industrial application of the whole microbial resources. The remarkable advance of technologies for digging out and analyzing metagenome is enabling not only practical applications of metagenome but also system approaches on a mixed-genome level based on accumulated information. In this situation, the present review is purposed to introduce the trends and methods of research on metagenome and to examine big science led by related resources in the future. PMID- 23100712 TI - From bacterial genomics to metagenomics: concept, tools and recent advances. AB - In the last 20 years, the applications of genomics tools have completely transformed the field of microbial research. This has primarily happened due to revolution in sequencing technologies that have become available today. This review therefore, first describes the discoveries, upgradation and automation of sequencing techniques in a chronological order, followed by a brief discussion on microbial genomics. Some of the recently sequenced bacterial genomes are described to explain how complete genome data is now being used to derive interesting findings. Apart from the genomics of individual microbes, the study of unculturable microbiota from different environments is increasingly gaining importance. The second section is thus dedicated to the concept of metagenomics describing environmental DNA isolation, metagenomic library construction and screening methods to look for novel and potentially important genes, enzymes and biomolecules. It also deals with the pioneering studies in the area of metagenomics that are offering new insights into the previously unappreciated microbial world. PMID- 23100713 TI - Functional genomics as a tool in virus research. AB - Genomics is the study of an organism's entire genome. It started out as a great scientific endeavor in the 1990s which aimed to sequence the complete genomes of certain biological species. However viruses are not new to this field as complete viral genomes have routinely been sequenced since the past thirty years. The 'genomic era' has been said to have revolutionized biology. This knowledge of full genomes has created the field of functional genomics in today's post-genomic era, which, is in most part concerned with the studies on the expression of the organism's genome under different conditions. This article is an attempt to introduce its readers to the application of functional genomics to address and answer several complex biological issues in virus research. PMID- 23100714 TI - Metagenomics: Future of microbial gene mining. AB - Modern biotechnology has a steadily increasing demand for novel genes for application in various industrial processes and development of genetically modified organisms. Identification, isolation and cloning for novel genes at a reasonable pace is the main driving force behind the development of unprecedented experimental approaches. Metagenomics is one such novel approach for engendering novel genes. Metagenomics of complex microbial communities (both cultivable and uncultivable) is a rich source of novel genes for biotechnological purposes. The contributions made by metagenomics to the already existing repository of prokaryotic genes is quite impressive but nevertheless, this technique is still in its infancy. In the present review we have drawn comparison between routine cloning techniques and metagenomic approach for harvesting novel microbial genes and described various methods to reach down to the specific genes in the metagenome. Accomplishments made thus far, limitations and future prospects of this resourceful technique are discussed. PMID- 23100715 TI - Metagenomics in animal gastrointestinal ecosystem: a microbiological and biotechnological perspective. AB - Metagenomics- the application of the genomics technologies to nonculturable microbial communities, is coming of age. These approaches can be used for the screening and selection of nonculturable rumen microbiota for assessing their role in gastrointestinal (GI) nutrition, plant material fermentation and the health of the host. The technologies designed to access this wealth of genetic information through environmental nucleic acid extraction have provided a means of overcoming the limitations of culture-dependent microbial genetic exploitation. The molecular procedures and techniques will result in reliable insights into the GI microbial structure and activity of the livestock gut microbes in relation to functional interactions, temporal and spatial relationships among different microbial consortia and dietary ingredients. Future developments and applications of these methods promise to provide the first opportunity to link distribution and identity of rumen microbes in their natural habitats with their genetic potential and in situ activities. PMID- 23100717 TI - Identification of a bacterial strain isolated from the liver of a laboratory mouse as Microbacterium paraoxydans and emended description of the species Microbacterium paraoxydans Laffineur et al 2003. AB - A rod-shaped, Gram-positive bacterial strain, designated C57-33, was isolated from the liver of the laboratory mouse strain C57Bl/6J and characterised by a polyphasic approach. 16S rRNA gene sequence similarity placed strain C57-33 in the genus Microbacterium with Microbacterium paraoxydans CF36(T) as the next relative (99.9% sequence similarity). Major fatty acids ai-C(15:0), i-C(16:0) and ai-C(17:0) and peptidoglycan type B2beta with ornithine as the diagnostic cell wall diamino acid and glycolyl residues were in agreement with the description of Microbacterium paraoxydans. The quinone system of C57-33 (major menaquinones MK 12 and MK-11) and polar lipid profile (major polar lipids diphosphatidyl glycerol, phosphatidyl glycerol and two unknown glycolipids) were in accordance with those of Microbacterium paraoxydans strains CF36(T), CF7 and CF40 which were analysed in this study as well. The results of biochemical/physiological characterisation, DNA-DNA hybridization, MALDI-TOF mass spectrometry of cell extracts and comparison of protein patterns after SDS-PAGE demonstrated that our isolate C57-33 (= DSM 15461) is a strain of the species Microbacterium paraoxydans. Based on new characteristics such as quinone system, polar lipid profile and physiological traits analysed for strain C57-33, the type strain of Microbacterium paraoxydans and some additional strains an emended description of the species Microbacterium paraoxydans is provided. PMID- 23100719 TI - Isolation and characterisation of phosphate solubilising microorganisms from the cold desert habitat of Salix alba Linn. in trans Himalayan region of Himachal Pradesh. AB - Phosphate solubilising microorganisms (PSM) (bacteria and fungi) associated with Salix alba Linn. from Lahaul and Spiti valleys of Himachal Pradesh were isolated on Pikovskaya (PVK), modified Pikovskaya (MPVK) and National Botanical Research Institute agar (NBRIP) media by spread plating. The viable colony count of P solubilising bacteria (PSB) and fungi (PSF) was higher in rhizosphere than that of non-rhizosphere. The frequency of PSM was highest on MPVK followed by NBRIP and PVK agar. The maximum proportion of PSM out of total bacterial and fungal count was found in upper Keylong while the least in Rong Tong. The PSB frequently were Gram-positive, endosporeforming, motile rods and belonged to Bacillus sp. The PSF mainly belonged to Penicillium sp., Aspergillus fumigatus, A. niger, A. spp. and non-sporulating sterile. Amongst the isolates with high efficiency for tricalcium phosphate (TCP) solubilisation, seven bacterial and seven fungal isolates dissolved higher amount of P from North Carolina rock phosphate (NCRP) than Mussoorie rock phosphate (MRP) and Udaipur rock phosphate (URP). However, the organisms solubilised higher-P in NBRIP broth than PVK broth. SBC5 (Bacillus sp.) and SBC7 (Bacillus sp.) bacterial isolates exhibited maximun P solubilisation (40 and 33 MUg ml(-1) respectively) whereas FC28 (Penicillium sp.) isolate (52.3 MUg ml(-1)) amongst fungi while solubilising URP. The amount of P solubilised was positively correlated with the decrease in pH of medium. SBC5 (Bacillus sp.), SBC7 (Bacillus sp.) and SBC4 (Micrococcus) decreased the pH of medium from 6.8 to 6.08 while FC28 (Penicillium sp.) and FC39 (Penicillium sp.) isolates of fungi recorded maximum decrease in pH of medium from 6.8 to 5.96 in NBRIP broth. PMID- 23100716 TI - Phylogeny vs genome reshuffling: horizontal gene transfer. AB - The evolutionary events in organisms can be tracked to the transfer of genetic material. The inheritance of genetic material among closely related organisms is a slow evolutionary process. On the other hand, the movement of genes among distantly related species can account for rapid evolution. The later process has been quite evident in the appearance of antibiotic resistance genes among human and animal pathogens. Phylogenetic trees based on such genes and those involved in metabolic activities reflect the incongruencies in comparison to the 16S rDNA gene, generally used for taxonomic relationships. Such discrepancies in gene inheritance have been termed as horizontal gene transfer (HGT) events. In the post-genomic era, the explosion of known sequences through large-scale sequencing projects has unraveled the weakness of traditional 16S rDNA gene tree based evolutionary model. Various methods to scrutinize HGT events include atypical composition, abnormal sequence similarity, anomalous phylogenetic distribution, unusual phyletic patterns, etc. Since HGT generates greater genetic diversity, it is likely to increase resource use and ecosystem resilience. PMID- 23100718 TI - Pyruvate catabolism and hydrogen synthesis pathway genes of Clostridium thermocellum ATCC 27405. AB - Clostridium thermocellum is a gram-positive, acetogenic, thermophilic, anaerobic bacterium that degrades cellulose and carries out mixed product fermentation, catabolising cellulose to acetate, lactate, and ethanol under various growth conditions, with the concomitant release of H(2) and CO(2). Very little is known about the factors that determine metabolic fluxes influencing H(2) synthesis in anaerobic, cellulolytic bacteria like C. thermocellum. We have begun to investigate the relationships between genome content, gene expression, and end product synthesis in C. thermocellum cultured under different conditions. Using bioinformatics tools and the complete C. thermocellum 27405 genome sequence, we identified genes encoding key enzymes in pyruvate catabolism and H(2)-synthesis pathways, and have confirmed transcription of these genes throughout growth on alpha-cellulose by reverse transcriptase polymerase chain reaction. Bioinformatic analyses revealed two putative lactate dehydrogenases, one pyruvate formate lyase, four pyruvate:formate lyase activating enzymes, and at least three putative pyruvate:ferredoxin oxidoreductase (POR) or POR-like enzymes. Our data suggests that hydrogen may be generated through the action of either a Ferredoxin (Fd)-dependent NiFe hydrogenase, often referred to as "Energy-converting Hydrogenases", or via NAD(P)Hdependent Fe-only hydrogenases which would permit H(2) production from NADH generated during the glyceraldehyde-3-phosphate dehydrogenase reaction. Furthermore, our findings show the presence of a gene cluster putatively encoding a membrane integral NADH:Fd oxidoreductase, suggesting a possible mechanism in which electrons could be transferred between NADH and ferredoxin. The elucidation of pyruvate catabolism pathways and mechanisms of H(2) synthesis is the first step in developing strategies to increase hydrogen yields from biomass. Our studies have outlined the likely pathways leading to hydrogen synthesis in C. thermocellum strain 27405, but the actual functional roles of these gene products during pyruvate catabolism and in H 2 synthesis remain to be elucidated, and will need to be confirmed using both expression analysis and protein characterization. PMID- 23100720 TI - Strain improvement of Aspergillus niger for the enhanced production of asperenone. AB - The enhancement of production of asperenone (Fig. 1), an inhibitor of lipoxygenase and human platelet aggregation from Aspergillus niger CFTRI 1105, was achieved by UV and nitrous acid mutagenesis. Nitrous acid mutants exhibited increased inhibitor production when compared with UV irradiated mutants. I N 41 a first-generation nitrous acid mutant produced 5.1 fold increased asperenone over parent strain. Mutant II N 31 obtained by second-generation nitrous acid treatment produced 60.3 mg asperenone/g biomass, which was 131 fold increase when compared to first generated mutant I N 41 and 670 fold increase over the parent strain. This mutant was stable for several generations on production medium. PMID- 23100721 TI - Diversity of 'benzenetriol dioxygenase' involved in p-nitrophenol degradation in soil bacteria. AB - Ring hydroxylating dioxygenases (RHDOs) are one of the most important classes of enzymes featuring in the microbial metabolism of several xenobiotic aromatic compounds. One such RHDO is benzenetriol dioxygenase (BtD) which constitutes the metabolic machinery of microbial degradation of several mono- phenolic and biphenolic compounds including nitrophenols. Assessment of the natural diversity of benzenetriol dioxygenase (btd) gene sequence is of great significance from basic as well as applied study point of view. In the present study we have evaluated the gene sequence variations amongst the partial btd genes that were retrieved from microorganisms enriched for PNP degradation from pesticide contaminated agriculture soils. The gene sequence analysis was also supplemented with an in silico restriction digestion analysis. Furthermore, a phylogenetic analysis based on the deduced amino acid sequence(s) was performed wherein the evolutionary relatedness of BtD enzyme with similar aromatic dioxygenases was determined. The results obtained in this study indicated that this enzyme has probably undergone evolutionary divergence which largely corroborated with the taxonomic ranks of the host microorganisms. PMID- 23100722 TI - Variability in Halothiobacillus neapolitanus type strain cultures. AB - Numerous microbial species are reported to utilize oxidation and/or reduction of sulfur containing compounds in the energy producing portions of their metabolism Halothiobacillus neapolitanus cultures obtained from different commercial sources appear to display considerable variability in terms of growth rate, carbonate consumption and activity of individual enzymes. PMID- 23100723 TI - Molecular typing of colonizing Streptococcus agalactiae strains by enterobacterial repetitive intergenic consensus PCR (ERIC-PCR) in a Chennai based hospital. AB - Streptococcus agalactiae is reported to be an asymptomatic vaginal colonizer in Indian women, although it is considered one of the major causes of neonatal infections in many European countries. DNA based molecular typing methods are more reliable than the conventional serotyping method for identification and typing of this pathogen. In the present study, we have evaluated genetic diversity among colonizing S. agalactiae strains (n=86) by using a PCR-based genotyping method i.e. Enterobacterial Repetitive Intergenic Consensus PCR (ERIC PCR). With ERIC-PCR fingerprinting at 60% similarity level in a dendrogram generated by UPGMA cluster analysis, 10 different ERIC groups were identified, which were subdivided into 62 distinct genotypes at >= 95% similarity level. Based on these findings, we demonstrate that ERIC-PCR is a simple, rapid, and inexpensive tool with sufficient discriminatory power and is applicable for characterization and genotyping of a large number of clinical isolates of S. agalactiae at molecular level. PMID- 23100725 TI - 49th AMI conference: a unique opportunity for microbiologists. PMID- 23100726 TI - Probiotics in aquaculture: importance and future perspectives. AB - Aquaculture is one of the fastest developing growth sectors in the world and Asia presently contributes about 90% to the global production. However, disease outbreaks are constraint to aquaculture production thereby affects both economic development of the country and socio-economic status of the local people in many countries of Asia-Pacifi c region. Disease control in aquaculture industry has been achieved by following different methods using traditional ways, synthetic chemicals and antibiotics. However, the use of such expensive chemotherapeutants for controlling diseases has been widely criticized for their negative impacts like accumulation of residues, development of drug resistance, immunosuppressants and reduced consumer preference for aqua products treated with antibiotics and traditional methods are ineffective against controlling new diseases in large aquaculture systems. Therefore, alternative methods need to be developed to maintain a healthy microbial environment in the aquaculture systems there by to maintain the health of the cultured organisms. Use of probiotics is one of such method that is gaining importance in controlling potential pathogens. This review provides a summary of the criteria for the selection of the potential probiotics, their importance and future perspectives in aquaculture industry. PMID- 23100727 TI - Laccase: enzyme revisited and function redefined. AB - One enzyme, one physiological role, that's how most scientists have traditionally looked at it but there is a growing appreciation that some enzymes "moonlight" i.e. in addition to their "primary" catalytic function, they carry other functions as well. Moonlighting refers to a protein that has multiple functions, which are not because of gene fusion; splice variants or multiple proteolytic fragments. Until recently laccases were reported from eukaryotes, e.g. fungi, plants, insect. However there is some evidence for its existence in prokaryotes, a protein with typical features of multi-copper oxidase enzyme family. The present available knowledge of its structure provides a glimpse of its plasticity, revealing a multitude of binding sites responsible for multifunctional activity. Laccase represents an example of a 'moonlighting' protein that overcomes the one gene-one structure-one function concept to follow the changes of the organism in its physiological and pathological conditions. It is wide spread in plants, where it is involved in biosynthesis of lignin; in fungi it is involved in lignin degradation, development associated pigmentation (melanin synthesis), detoxification and pathogenesis, and in bacteria, laccases are involved in the synthesis of endospore coat protein (cot A). PMID- 23100729 TI - Preparation of FMD type A87/IRN inactivated vaccine by gamma irradiation and the immune response on guinea pig. AB - FMD is one of the most economically damaging diseases that affect livestock animals. In this study FMD Virus type A87/IRN was multiplied on BHK21 cells. The virus was titrated by TCID50 method, it was 10(7.5)/ml. The FMD virus samples were inactivated by gamma ray from 60Co source at -20 degrees C. Safety test was done by IBRS2 monolayer cell culture method, also antigenicity of irradiated and un-irradiated virus samples were studied by Complement Fixation Test. The Dose/Survival curve for irradiated FMD Virus was drawn, the optimum dose range for inactivation of FMDV type A87/IRN and unaltered antigenicity was obtained 40 44 kGy. The inactivated virus samples by irradiation and ethyleneimine (EI) were formulated respectively as vaccine with Al(OH)3 gel and other substances. The vaccines were inoculated to Guinea pigs and the results of Serum Neutralization Test for the normal vaccine and radio-vaccine showed protective titer after 8 months. The potency test of the inactivated vaccines was done, PD50 Value of the vaccines were calculated 7.06 and 5.6 for inactivated vaccine by EI and gamma irradiation respectively. PMID- 23100728 TI - Functional and safety aspects of enterococci in dairy foods. AB - The genus Enterococcus like other LAB has also been featured in dairy industry for decades due to its specific biochemical traits such as lipolysis, proteolysis, and citrate breakdown, hence contributing typical taste and flavor to the dairy foods. Furthermore, the production of bacteriocins by enterococci (enterocins) is well documented. These technological applications have led to propose enterococci as adjunct starters or protective cultures in fermented foods. Moreover, enterococci are nowadays promoted as probiotics, which are claimed for the maintenance of normal intestinal microflora, stimulation of the immune system and improvement of nutritional value of foods. At the same time, enterococci present an emerging pool of opportunistic pathogens for humans as they cause disease, possess agents for antibiotic resistance, and are frequently armed with potential virulence factors. Because of this "dualistic" nature, the use of enterococci remains a debatable issue. However, based on a long history of safe association of particular enterococci with some traditional food fermentations, the use of such strains appears to bear no particular risk for human health. Abundance of knowledge as well as progress in molecular techniques has, however, enabled exact characterization and safety assessment of strains. Therefore, a balanced evaluation of both, beneficial and undesirable nature of enterococci is required. A clear understanding of their status may, therefore, allow their safe use as a starter, or a probiotic strain. The present review describes the broader insight of the benefits and risks of enterococci in dairy foods and their safety assessment. PMID- 23100730 TI - L-asparaginase production by Streptomyces albidoflavus. AB - Attempts were made to optimize the cultural conditions for the production of L asparaginase by Streptomyces albidoflavus under submerged fermentations. Enhanced level of L-asparaginase was found in culture medium supplemented with maltose as carbon source. Yeast extract (2%) was served as good nitrogen source for the production of L-asparaginase. The optimum pH for enzyme production was 7.5 and temperature was 35 degrees C. The release of L-asparaginase from the cells of S. albidoflavus was high when strain was treated with cell disrupting agents like EDTA and lysozyme. The enzyme produced by the strain was purifi ed by ammonium sulfate, Sephadex G-100 and CM-Sephadex C-50 gel fi ltration and the molecular weight was apparently determined as 112 kDa. PMID- 23100731 TI - Production of beta-galactosidase by Kluyveromyces marxianus MTCC 1388 using whey and effect of four different methods of enzyme extraction on beta-galactosidase activity. AB - Whey containing 4.4% (w/v) lactose was inoculated with Kluyveromyces marxianus MTCC 1389 for carrying out studies related to beta-galactosidase production. beta galactosidase activity was found to be maximum after 30 h and further incubation resulted in decline in activity. The maximum cell biomass of 2.54 mg mL(-1) was observed after 36 h of incubation. Lactose concentration dropped drastically to 0.04 % from 4.40% after 36 h of incubation. Out of the four methods tested for extraction of enzyme, SDS - Chlorofom method was found to be best followed by Toluene - Acetone, sonication and homogenization with glass beads in that order. It could be concluded through this study that SDS - Chloroform is cheap and simple method for enzyme extraction from Kluyveromyces cells, which resulted in higher enzyme activity as compared to the activity observed using the remaining extraction methods. The study could also establish that whey could effectively be utilized for beta-galactosidase production thus alleviating water pollution problems caused due to its disposal into the water streams. PMID- 23100732 TI - Plant growth promotion abilities and formulation of Bacillus megaterium strain B 388 (MTCC6521) isolated from a temperate Himalayan location. AB - Bacillus megaterium strain B388, isolated from rhizosphere soil of pine belonging to a temperate Himalayan location has been characterized. The plant growth promotion and biocontrol properties of the bacterium have been evaluated through petridish and broth based assays. The isolate solubilized tricalcium phosphate under in vitro conditions; maximum activity (166 MUg/ml) was recorded at 28 degrees C after 15 days of incubation. Production of indole acetic acid demonstrated in broth assays was another important plant growth promoting character. The bacterium produced diffusible and volatile compounds that inhibited the growth of two phytopathogens viz. Alternaria alternata and Fusarium oxysporum. The carrier based formulations of the bacterium resulted in increased plant growth in bioassays. The rhizosphere colonization and the viability of the cells entrapped in alginate beads were greater in comparison to coal or broth based formulations. The bacterium showed maximum similarity with Bacillus megaterium by 16S rRNA analysis. PMID- 23100733 TI - In vitro antibacterial activity of laboratory grown culture of Spirulina platensis. AB - The hexane, ethyl acetate, dichloromethane, methanol extracts and spent media (extracellular substances) were tested in vitro for their antibacterial activity for which one Gram-positive bacterium (Staphylococcus aureus) and four Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhi, and Klebsiella pneumoniae) were used as test organisms. The methanol extract showed more potent activity than other organic extracts, spent medium of the culture exhibited little activity against E. coli only. No inhibitory effect was found against Klebsiella pneumoniae.The broth microdilution assay gave minimum inhibitory concentrations (MIC) values ranging from 1 to 512 MUg/ml. The MIC of methanol extract against S. aureus and E. coli were 128 MUg/ml and 256 MUg/ml, respectively. PMID- 23100734 TI - In vitro evaluation of Datura innoxia (thorn-apple) for potential antibacterial activity. AB - Various parts of Datura innoxia were examined for potential antibacterial activity by preparing their crude aqueous and organic extracts against Gram negative bacteria (Escherichia coli and Salmonella typhi) and Gram-positive bacteria (Bacillus cereus, Bacillus subtilis and Staphylococcus aureus). The results of agar well diffusion assay indicated that the pattern of inhibition depends largely upon the plant part, solvent used for extraction and the organism tested. Extracts prepared from leaves were shown to have better efficacy than stem and root extracts. Organic extracts provided potent antibacterial activity as compared to aqueous extracts. Among all the extracts, methanolic extract was found most active against almost all the bacterial species tested. Gram-positive bacteria were found most sensitive as compared to Gram-negative bacteria. Staphylococcus aureus was signifi cantly inhibited by almost all the extracts even at very low MIC followed by other Gram-positives. For Escherichia coli (a Gram-negative bacterium), the end point was not reached for ethyl acetate extract while it was very high for other extracts. The study promises an interesting future for designing a potentially active antibacterial agent from Datura innoxia. PMID- 23100735 TI - Cloning, characterization and expression of the chitinase gene of Enterobacter sp. NRG4. AB - A chitinase producing bacterium Enterobacter sp. NRG4, previously isolated in our laboratory, has been reported to have a wide range of applications such as anti fungal activity, generation of fungal protoplasts and production of chitobiose and N-acetyl D-glucosamine from swollen chitin. In this paper, the gene coding for Enterobacter chitinase has been cloned and expressed in Escherichia coli BL21(DE3). The structural portion of the chitinase gene comprised of 1686 bp. The deduced amino acid sequence of chitinase has high degree of homology (99.0%) with chitinase from Serratia marcescens. The recombinant chitinase was purified to near homogeneity using His-Tag affinity chromatography. The purified recombinant chitinase had a specific activity of 2041.6 U mg(-1). It exhibited similar properties pH and temperature optima of 5.5 and 45 degrees C respectively as that of native chitinase. Using swollen chitin as a substrate, the K(m), k(cat) and catalytic efficiency (k(cat)/K(m)) values of recombinant chitinase were found to be 1.27 mg ml(-1), 0.69 s(-1) and 0.54 s(-1)M(-1) respectively. Like native chitinase, the recombinant chitinase produced medicinally important N-acetyl D glucosamine and chitobiose from swollen chitin and also inhibited the growth of many fungi. PMID- 23100736 TI - Characterization of carbonic anhydrase from diversified genus for biomimetic carbon-dioxide sequestration. AB - Diversified group of bacteria were screened for carbonic anhydrase (CA) activity. Significant CA activity was found in crude enzyme extracts of Enterobacter and Aeromonas isolates while minimal or negligible CA activity was observed in case of Shigella and Klebsiella spp. Optimization and characterization study of potent CA producing isolates revealed that the maximum enzyme activity of 3.86 EU/ml was observed in E. taylorae and the optimum pH range for enzyme stability was found to be 7.5-9.0 along with an optimum temperature range of 35-50 degrees C. The molecular mass of CA was 29-kDa indicating alpha-type with periplasmic and cytosolic location. Present investigation for the first time reports CA in diversified genus and optimized parameters for enhanced production of CA in Enterobacter sp. & Aeromonas sp. from fresh water bodies that inturn lay down grounds for exploitation of CA from E. taylorae as an efficient catalyst for CO(2) sequestration within a bioreactor. PMID- 23100737 TI - Species of Gonostomum and Paragonostomum (Ciliophora, Hypotrichida, Oxytrichidae) from the Valley of Flowers, India, with descriptions of Gonostomum singhii sp nov, Paragonostomum ghangriai sp nov and Paragonostomum minuta sp nov. AB - Soil samples taken from the Valley of Flowers, a component of the Nanda Devi Biosphere Reserve in the Himalayan regions of India showed the presence of twenty two free living species of ciliates. There is a preponderance of species which exhibit oral ciliature and ontogenesis in the Gonostomum pattern. Of the four species of the genus Gonostomum, three viz., G affine, G gonostomoida and G kuehnelti are similar to described species; Gonostomum singhii is new. The two species of genus Paragonostomum viz., P minuta and P ghangriai are new. The three new species are described in the present paper. All these species show prominent hypertrophied ciliary structures. Their paroral membranes reveal characteristic differences with respect to their position, number of constituent cilia and the distance between adjacent cilia. It is proposed that such species specific features of the paroral membrane have a bearing in exercising different food organism preferences as they co-exist at many sites. This single factor has possibly played an important role in species diversification of this group of hypotrichs in this isolated habitat. PMID- 23100738 TI - Profile of the extracellular lignocellulolytic enzymes activities as a tool to select the promising strains of Volvariella volvacea (Bull. ex Fr.) sing. AB - Out of 26 strains of Volvariella volvacea used, 18 were of 'typical' type and possessed all the characteristics of a normal V. volvacea mycelium, while the rest 4 'atypical' type strains showed completely distinct mycelial growth characteristics. The remaining 4 strains grew very slowly and exhibited growth characteristics of single spore isolates of V. volvacea. Strains varied in their extracellular lignocellulolytic activities and strains; OE-274, OE-272 and OE-210 with high ligninase enzymes (laccase and polyphenol oxidase) activities, gave highest mushroom yield on pasteurized paddy straw substrate. On the composted paddy straw substrate, additional two strains, OE-213 and OE-215 with lower activities of ligninases also gave higher mushroom yield. Mushrooms were harvested 3 to 4 d early from the composted substrate than on the pasteurized substrate. Activities of endoglucanase, laccase and polyphenol oxidase were found to be more crucial for mushroom yield on pasteurized substrate, while xylanase and beta-glucosidase were more important for composted substrate. Strains also varied in their fruiting bodies quality and the substrate used for mushroom cultivation also affected the fruiting body quality. The superior yielding strains varied in shape, size, weight, colour and contents of sodium and potassium in their fruiting bodies; while contents of carbon, calcium and protein did not vary much with the strains. PMID- 23100739 TI - Metabolism of lysine-chromium complex in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae which cannot utilize lysine as a sole nitrogen source is shown to metabolize a Lysine 3 Cr(3+) (1:1) complex synthesized, as a combined nitrogen and carbon source. It induces rapid uptake of lysine and prevents loss of viability, in contrast with free lysine. That complexation with trivalent chromium has the effect of profoundly influencing intracellular distribution and metabolism of the liganded amino acid is demonstrated. PMID- 23100740 TI - Preparation and evaluation of an experimental iscom-based infectious bursal disease vaccine. AB - The present study was conducted to develop and evaluate an experimental ISCOM based infectious bursal disease (IBD) vaccine. The indigenous very virulent infectious bursal disease virus (vvIBDV) already attenuated and adapted to Vero cell line was used. After denaturation of viral proteins with sodium dodecyl sulphate (SDS), an IBD-ISCOM was constructed. The non-incorporated viral components were separated from ISCOM by centrifugation of dialysate. The pathogenicity and immunogenicity trials were conducted in 3-week-old broiler chicken. A commercial oil-emulsified vaccine (CEVAC IBD K) was used for comparison. There were no clinical signs of disease, gross or microscopic lesions in bursa of Fabricius in group G1 vaccinated with ISCOM-based vaccine and bursa to body weight ratio were comparable to un-vaccinated control group (G3). The virus-neutralizing antibody titers were significantly (P<0.05) higher in group G1 as compared with group G2 which was vaccinated with commercial vaccine. On challenge with vvIBDV, 100%, 75% and 0.00% protection was achieved in G1, G2 and G3, respectively. The results indicated that ISCOM-based IBD vaccine is safe and immunogenic. PMID- 23100741 TI - Isolation of Moraxella bovis from frozen bovine semen and determination of microbial load. AB - In the present study, isolation of Moraxella bovis was done from the microbiological examination of frozen semen straws from clinically healthy twelve Jersey and one Jersey-cross bull supplied by a semen laboratory. The organism was identified on the basis of colonial morphology and biochemical characteristics. Further, viable cell count of the bacterium was studied in detail in the semen sample. PMID- 23100743 TI - Studies on leaf spot disease of Withania somnifera and its impact on secondary metabolites. AB - During an investigation of the disease profile of Withania somnifera, it was observed that leaf spot is the most prevalent disease. Repeated isolations from infected leaf tissues and pathogenicity tests showed the association of fungal pathogen identified as Alternaria alternata (Fr.) Keissler. Scanning electron microscopy showed various histological changes in the leaf tissues of infected plants. A decrease in total content of reducing sugars (20%) and chlorophyll (26.5%) was observed in diseased leaves whereas an increase was noticed in proline (25%), free amino acids (3%) and proteins (74.3%). High performance thin layer chromatography (HPTLC) analysis of secondary metabolites viz. withanolides, withaferin-A and total alkaloids of the diseased leaves vis-a-vis control revealed reduction in withaferin-A and withanolides contents by 15.4% and 76.3% respectively, in contrast to an increase in total alkaloids by 49.3%, information hitherto unreported in W. somnifera. PMID- 23100744 TI - Biofilm formation by Candida albicans isolated from intrauterine devices. AB - Our survey revealed that infected intrauterine devices (IUDs) recovered from patients suffering from reproductive tract infections (RTIs) were tainted with Candida biofilm composed of a single or multiple species. Scanning electron microscopy (SEM) analysis of C. albicans biofilm topography showed that it consists of a dense network of mono- or multilayer of cells embedded within the matrix of extracellular polymeric substances (EPS). Confocal scanning laser microscopy (CSLM) and atomic force microscopy (AFM) images depicted that C. albicans biofilms have a highly heterogeneous architecture composed of cellular and noncellular elements with EPS distributed in the cell-surface periphery or at cell-cell interface. Biochemical analysis showed that EPS produced by C. albicans biofilm contained significantly reduced total carbohydrate (40%), protein (5%) and enhanced amount of hexosamine (4%) in contrast to its planktonic counterparts. The in vitro activity of antifungal agents amphotericin B, nystatin, fluconazole and chlorhexidine against pre-formed C. albicans biofilm, assessed using XTT (2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5 carboxanilide) reduction assay revealed increased resistance of these infectious biofilm (50% reduction in metabolic activity at a concentration of 8, 16, 64, 128 MUg/ml respectively) in comparison to its planktonic form. PMID- 23100745 TI - Molecular diversity, effectiveness and competitiveness of indigenous rhizobial population infecting mungbean Vigna radiata (L. Wilczek) under semi-arid conditions. AB - Nodules from mungbean crop raised for the first time at Ram Dhan Singh (RDS) farm of Chaudhary Charan Singh (CCS) Haryana Agricultural University, Hisar were collected from 17 different locations. Twenty-five mungbean rhizobia were isolated and authenticated by plant infection test. DNA of all these rhizobia was extracted purified and amplified using enterobacterial repetitive intergenic consensus (ERIC) primers. All the mungbean rhizobial isolates were clustered into 4 groups at 65% of similarity and were further divided into 17 subclusters at 80% of similarity. All the 4 types of rhizobia were not present at any of the location and group 2 or 4 rhizobia were invariably present. Efficacy of these rhizobia in terms of nodulation, nitrogen uptake and chlorophyll a fluorescence was determined under pot culture conditions. Strain MB 307 showed maximum nitrogen uptake of 31.9 mg N plant(-1) followed by strain MB 1205, MB 1206(2), MB 308, MB 1524 and strain MB 1521 was found to be the least efficient in terms of N 2 fixation. Nodule occupancy by different rhizobia ranged from 5.5 to 40.3%. Most of the strains belonging to the 2nd group which clustered maximum number of strains were comparatively better competitors and formed 19.5-40.3% of the nodules and were also effective. Isolate MB 307, the most efficient strain, was found to have nodule occupancy of 31.5%. Such type of predominant, efficient and better competitor strains should be selected for enhancing nodule competitiveness. PMID- 23100746 TI - Detection of aerolysin gene in Aeromonas hydrophila isolated from fish and pond water. AB - Aerolysin is a hemolytic toxin encoded by aerolysin gene (1482 bp) that plays a key role in the pathogenesis of Aeromonas hydrophila infection in fish. New speciesspecific primers were designed to amplify 326 bp conserved region of aerolysin gene for A. hydrophila. Twenty-five isolates of A. hydrophila recovered from fish and pond water were studied for detection of aerolysin gene. Aerolysin gene was detected in 85% of the isolates during the study. The designed primers were highly specific and showed no cross reactivity with Escherichia coli, Aeromonas veronii, Vibrio cholerae, Flavobacterium spp., Chyseobacterium spp. and Staphylococcus aureus. The sensitivity limit of primers for detection of aerolysin gene in the genomic DNA of A. hydrophila was 5 pg. PMID- 23100742 TI - Bioactive compounds from marine actinomycetes. AB - Actinomycetes are one of the most efficient groups of secondary metabolite producers and are very important from an industrial point of view. Among its various genera, Streptomyces, Saccharopolyspora, Amycolatopsis, Micromonospora and Actinoplanes are the major producers of commercially important biomolecules. Several species have been isolated and screened from the soil in the past decades. Consequently the chance of isolating a novel actinomycete strain from a terrestrial habitat, which would produce new biologically active metabolites, has reduced. The most relevant reason for discovering novel secondary metabolites is to circumvent the problem of resistant pathogens, which are no longer susceptible to the currently used drugs. Existence of actinomycetes has been reported in the hitherto untapped marine ecosystem. Marine actinomycetes are efficient producers of new secondary metabolites that show a range of biological activities including antibacterial, antifungal, anticancer, insecticidal and enzyme inhibition. Bioactive compounds from marine actinomycetes possess distinct chemical structures that may form the basis for synthesis of new drugs that could be used to combat resistant pathogens. PMID- 23100747 TI - Two years of Springer-IJM association. PMID- 23100748 TI - Ecology and biotechnological potential of Paenibacillus polymyxa: a minireview. AB - Microbial diversity is a major resource for biotechnological products and processes. Bacteria are the most dominant group of this diversity which produce a wide range of products of industrial significance. Paenibacillus polymyxa (formerly Bacillus polymyxa), a non pathogenic and endospore-forming Bacillus, is one of the most industrially significant facultative anaerobic bacterium. It occurs naturally in soil, rhizosphere and roots of crop plants and in marine sediments. During the last two decades, there has been a growing interest for their ecological and biotechnological importance, despite their limited genomic information. P. polymyxa has a wide range of properties, including nitrogen fixation, plant growth promotion, soil phosphorus solubilisation and production of exopolysaccharides, hydrolytic enzymes, antibiotics, cytokinin. It also helps in bioflocculation and in the enhancement of soil porosity. In addition, it is known to produce optically active 2,3-butanediol (BDL), a potentially valuable chemical compound from a variety of carbohydrates. The present review article aims to provide an overview of the various roles that these microorganisms play in the environment and their biotechnological potential. PMID- 23100750 TI - Microbiological and engineering aspects of biohydrogen production. AB - Dramatically rising oil prices and increasing awareness of the dire environmental consequences of fossil fuel use, including startling effects of climate change, are refocusing attention worldwide on the search for alternative fuels. Hydrogen is poised to become an important future energy carrier. Renewable hydrogen production is pivotal in making it a truly sustainable replacement for fossil fuels, and for realizing its full potential in reducing greenhouse gas emissions. One attractive option is to produce hydrogen through microbial fermentation. This process would use readily available wastes as well as presently unutilized bioresources, including enormous supplies of agricultural and forestry wastes. These potential energy sources are currently not well exploited, and in addition, pose environmental problems. However, fuels are relatively low value products, placing severe constraints on any production process. Therefore, means must be sought to maximize yields and rates of hydrogen production while at the same time minimizing energy and capital inputs to the bioprocess. Here we review the various attributes of the characterized hydrogen producing bacteria as well as the preparation and properties of mixed microflora that have been shown to convert various substrates to hydrogen. Factors affecting yields and rates are highlighted and some avenues for increasing these parameters are explored. On the engineering side, we review the potential waste pre-treatment technologies and discuss the relevant bioprocess parameters, possible reactor configurations, including emerging technologies, and how engineering design-directed research might provide insight into the exploitation of the significant energy potential of biomass resources. PMID- 23100751 TI - Relationship of physicochemical properties of rhizosphere soils with native population of mineral phosphate solubilizing fungi. AB - Phosphate solubilizing fungi (PSF) were enumerated in 78 rhizosphere soil samples collected from various sites of Bhavnagar district with agro climatic zone of hot, semi-arid region of Gujarat. 81% of samples were inhabited with indigenous PSF; the count varied ranging from 0.01 to 90 * 10(3) PSF g(-1). PSF population in the rhizosphere soils were maximal at pH 7.4-8.4, electrical conductivity (EC) 1.2 dS m(-1) wherein PSF population decreased with a rise in EC. Optimal moisture content ranged <=10-30% where the abundance of PSF always decreased with increase in moisture levels while suitable organic matter content ranged from <=0.5-4.5%. Available P range 100-300 mg kg(-1) was the most suitable for occurrence of PSF as being noticed from number of soil samples harboring them in rhizosphere soils. Amongst the various rhizosphere soil properties studied, a highly signifi cant positive correlation was established between PSF and soil available P as well as pH. A signifi cant positive association observed between total fungal population and organic matter as well as soil available P. Both abundance and number of PSF were more pronounced in descending order in plant covers: oilseeds, flowers, orchards, vegetables, pulses and cereals. PMID- 23100752 TI - Polymerase chain reaction in detection of porcine endogenous retrovirus (PERV) from porcine tissues. AB - Pigs offer an unlimited source of xenografts for humans. The use of transplants from animal origin offers a potential solution to the limited supply of human organs and tissues. However, like many other mammalian species, pigs harbor porcine endogenous retrovirus (PERV), which are encoded in their genomic DNA and are assumed to have been integrated into the porcine germline. The ability of PERV to infect human cells in vitro has heightened safety concerns regarding the transmission of PERV to pig xenograft recipients. Porcine tissues were analyzed using validated assays specifi c for PERV: polymerase chain reaction (PCR) (for PERV DNA) and reverse transcriptase (RT)-PCR (for PERV RNA). PERV-specifi c gag sequences were found in the porcine heart tissue samples using DNA-PCR and RT PCR. PCR is a rapid and specifi c test for the detection of PERV from xenografts. These fi ndings have demonstrated that the presence of both DNA and RNA forms of PERV in porcine tissues needs to be carefully considered when the infectious disease potential of xenotransplantation is being assessed. PMID- 23100749 TI - Defining mycobacteria: Shared and specific genome features for different lifestyles. AB - During the last decade, the combination of rapid whole genome sequencing capabilities, application of genetic and computational tools, and establishment of model systems for the study of a range of species for a spectrum of biological questions has enhanced our cumulative knowledge of mycobacteria in terms of their growth properties and requirements. The adaption of the corynebacterial surrogate system has simplified the study of cell wall biosynthetic machinery common to actinobacteria. Comparative genomics supported by experimentation reveals that superimposed on a common core of 'mycobacterial' gene set, pathogenic mycobacteria are endowed with multiple copies of several protein families that encode novel secretion and transport systems such as mce and esx; immunomodulators named PE/PPE proteins, and polyketide synthases for synthesis of complex lipids. The precise timing of expression, engagement and interactions involving one or more of these redundant proteins in their host environments likely play a role in the definition and differentiation of species and their disease phenotypes. Besides these, only a few species specific 'virulence' factors i.e., macromolecules have been discovered. Other subtleties may also arise from modifications of shared macromolecules. In contrast, to cope with the broad and changing growth conditions, their saprophytic relatives have larger genomes, in which the excess coding capacity is dedicated to transcriptional regulators, transporters for nutrients and toxic metabolites, biosynthesis of secondary metabolites and catabolic pathways. In this review, we present a sampling of the tools and techniques that are being implemented to tease apart aspects of physiology, phylogeny, ecology and pathology and illustrate the dominant genomic characteristics of representative species. The investigation of clinical isolates, natural disease states and discovery of new diagnostics, vaccines and drugs for existing and emerging mycobacterial diseases, particularly for multidrug resistant strains are the challenges in the coming decades. PMID- 23100753 TI - Structural and biochemical properties of lichenase from Clostridium thermocellum. AB - The recombinant enzyme lichenase of size 30 kDa was over-expressed using E. coli cells and purified by immobilized metal ion affinity chromatography (IMAC) and size exclusion chromatography. The enzyme displayed high activity towards lichenan and beta-glucan. The enzyme showed no activity towards carboxymethyl cellulose, laminarin, galactomannan or glucomannan. Surprisingly, affinity-gel electrophoresis on native-PAGE showed that the enzyme binds only glucomannan and not lichenan or beta-glucan or other manno-configured substrates. The enzyme was thermally stable between the temperatures 60 degrees C and 70 degrees C. Presence of Cu(2+) ions at a concentration of 5 mM enhanced enzyme activity by 10% but higher concentrations of Cu(2+) (>25 mM) showed a sharp fall in the enzyme activity. Heavy metal ions Ni(2+), Co(2+) and Zn(2+) did not affect the activity of the enzyme at low concentrations (0-10 mM) but at higher concentrations (>10 mM), caused a decrease in the enzyme activity. The crystals of lichenase were produced and the 3-dimensional structure of native form of enzyme was previously solved at 1.50 A. Lichenase displayed (beta/alpha)(8)-fold a common fold among many glycoside hydrolase families. A cleft was identified that represented the probable location of active site. PMID- 23100754 TI - Extracellular lipase of Aspergillus niger NRRL3; production, partial purification and properties. AB - Four strains of Aspergillus niger were screened for lipase production. Each was cultivated on four different media differing in their contents of mineral components and sources of carbon and nitrogen. Aspergillus niger NRRL3 produced maximal activity (325U/ml) when grown in 3% peptone, 0.05% MgSO(4).7H(2)O, 0.05% KCl, 0.2% K(2)HPO(4) and 1% olive oil:glucose (0.5:0.5). A. niger NRRL3 lipase was partially purified by ammonium sulphate precipitation. The majority of lipase activity (48%) was located in fraction IV precipitated at 50-60% of saturation with a 18-fold enzyme purification. The optimal pH of the partial purified lipase preparation for the hydrolysis of emulsified olive oil was 7.2 and the optimum temperature was 60 degrees C. At 70 degrees C, the enzyme retained more than 90% of its activity. Enzyme activity was inhibited by Hg(2+) and K(+), whereas Ca(2+) and Mn(2+) greatly stimulated its activity. Additionally, the formed lipase was stored for one month without any loss in the activity. PMID- 23100755 TI - Antimicrobial susceptibility and molecular characterization of Vibrio cholerae from cholera outbreaks in Chennai. AB - The genotype and antibiotic resistance pattern of the toxigenic Vibrio cholerae strains associated with cholera outbreaks vary frequently. Fifty-one V. cholerae strains isolated from cholera outbreaks in Chennai (2002-2005) were screened for the presence of virulence and regulatory genes by multiplex polymerase chain reaction (PCR) assay. Genotyping of the isolates was done by VC1 primers derived from enterobacterial repetitive intergenic consensus (ERIC)-related sequence in V. cholerae. All the isolates possessed toxigenic genes, such as ctxA, ctxB, tcpA, ace, ompU, toxR and zot. Two different El Tor genotypes and one O139 genotype could be delineated by VC1-PCR. One of the El Tor genotypes was similar to the El Tor strains isolated from Bhind district and Delhi during 2004. Antibiotic susceptibility testing revealed greater variability among the isolates tested. All the isolates were found to be susceptible to norfloxacin, ciprofloxacin and tetracycline. Thiry-three per cent of the isolates were found to be resistant to more than 4 antibiotics and could be termed as multiple antibiotic resistant. Coexistence of O139 serogroup along with the El Tor biotype could be identified among the strains recovered during the period 2002-2004. The O139 isolates were found to be more susceptible to the antibiotics tested when compared to the El Tor isolates. PMID- 23100756 TI - Cyanobacterial diversity in the rhizosphere of rice and its ecological significance. AB - This investigation was undertaken to characterize the abundance and genera-wise diversity of cyanobacteria in the rice rhizosphere and nitrogen-fixing ability of the isolated strains. The cyanobacterial strains belonging to the genera Nostoc and Anabaena comprised 80% of the rhizosphere isolates, which were also efficient in enhancing the germination and growth of wheat seeds and exhibited significantly high protein accumulation and IAA production. Distinct profiles for the cyanobacterial strains were obtained on amplification with extended Hip 1 primer - HipTG, indicative of the diversity among these strains. Our investigation helped in identifying promising cyanobacterial isolates from the rhizosphere of rice, which can be utilized in developing efficient plant growth promoting cyanobacterial inoculants. PMID- 23100757 TI - Phosphate solubilization by Rhizobium strains. AB - Forty-six Rhizobium isolates from legume root and stem nodules were examined for their phosphate-solubilizing ability on Pikovskaya's agar medium. Rhizobium isolates from root nodules of Cassia absus, Vigna trilobata and three strains from Sesbania sesban showed zone of tricalcium phosphate (TCP) solubilization. The isolate from C. absus showed maximum solubilization (620 MUg/ml) after 12 d of incubation, while the Rhizobium sp. strain 26 (from S. sesban) showed the least amount (150 MUg/ml) of phosphate solubilization. Among the carbon sources tested for their ability to solubilize TCP, maximum solubilization (620 MUg/ml) was observed in glucose by Rhizobium isolate from C. absus. Phosphate solubilization increased with increase in glucose concentration steeply up to 2% and slowly above this concentration in four isolates. Among the nitrogen sources tested, maximum solubilization (620 MUg/ml) was observed in ammonium sulphate by Rhizobium isolate from C. absus. PMID- 23100758 TI - Genomic tools in bioremediation. AB - Bioremediation is a process that uses microorganisms or their enzymes to remove pollutants from the environment. Generally, bioremediation technologies can be classified as in situ or ex situ. In situ bioremediation involves treating the contaminated material at the site while ex situ involves the removal of the contaminated material to be treated elsewhere. Like so much else in biology, the ease and availability of genomic data has created a new level of understanding this system. Bioremediation capabilities of the microbial population can be analyzed; not only by physiological parameters, but also by the use of genomic tools, and efficient remediation strategies can be planned. PCR and DNA- or oligonucleotide-based microarray technology is a powerful functional genomics tool that allows researchers to view the physiology of a living cell from a comprehensive and dynamic molecular perspective. This paper explores the use of such tools in bioremediation process. PMID- 23100760 TI - Biodiversity of phosphate solubilizing bacteria in rhizosphere of chickpea, mustard and wheat grown in different regions of Haryana. AB - The native population of phosphate solubilizing bacteria (PSB) was studied in the rhizosphere of chickpea, mustard and wheat grown in different regions of Haryana. A total of 193 PSB were isolated from 245 rhizospheric samples collected from south-west and north-east zones. The PSB count showed large variations (3-67 * 10(5)cfu/g) and biodiversity within the crop and place of sampling. Using biochemical analysis, the isolates were tentatively identified as belonging to four genera, Pseudomonas, Aeromonas, Klebsiella and Enterobacter. Phosphate solubilization of these isolates varied from 5.9 to 123.8% and 2.2 to 227.2 MUg/ml in solid and liquid Pikovskaya's medium, respectively. Based on their morphological traits, all the isolates were placed into 20 groups, majority of them falling in the group having white, round and gummy colonies, irrespective of the crop or the region. The intrinsic antibiotic resistance pattern showed large variations among the isolates and most of the isolates were resistant to streptomycin, ampicillin and penicillin. The highest PSB number and greatest variability were found in the rhizosphere of chickpea, followed by wheat and then mustard. PMID- 23100759 TI - Beneficial interactions between insects and gut bacteria. AB - Insects are amongst the most successful of animals, both in terms of diversity and in colonizing all ecological niches. Recent studies have highlighted the benefi ciary roles that bacteria play in the success and establishment of insects. By adopting techniques like 16S rRNA sequencing we are now in a position to understand the diversity of bacteria present in insect guts. It has been shown that some of these bacteria, like Wolbachia and Cardinium are involved in manipulating insect populations and distorting their sex ratio. Attempts have been made to culture these bacteria in insect cell lines, as they are recalcitrant to culture under normal microbiological conditions. The diversity of bacteria associated with insects and the functional role played by them in the insect is discussed below. PMID- 23100761 TI - Plant growth promoting potential of the fungus Discosia sp. FIHB 571 from tea rhizosphere tested on chickpea, maize and pea. AB - The ITS region sequence of a phosphate-solubilizing fungus isolated from the rhizosphere of tea growing in Kangra valley of Himachal Pradesh showed 96% identity with Discosia sp. strain HKUCC 6626 ITS 1, 5.8S rRNA gene and ITS 2 complete sequence, and 28S rRNA gene partial sequence. The fungus exhibited the multiple plant growth promoting attributes of solubilization of inorganic phosphate substrates, production of phytase and siderophores, and biosynthesis of indole acetic acid (IAA)-like auxins. The fungal inoculum significantly increased the root length, shoot length and dry matter in the test plants of maize, pea and chickpea over the uninoculated control under the controlled environment. The plant growth promoting attributes have not been previously studied for the fungus. The fungal strain with its multiple plant growth promoting activities appears attractive towards the development of microbial inoculants. PMID- 23100762 TI - General microflora, arbuscular mycorrhizal colonization and occurrence of endophytes in the rhizosphere of two age groups of Ginkgo biloba L.of Indian Central Himalaya. AB - The populations of the general microflora (bacteria, actinomycetes and fungi) in the rhizosphere and their corresponding non-rhizosphere soil samples of Ginkgo biloba L. of two age groups (Group A, <25 years-young trees; Group B, >60 years old trees) growing under a temperate location of Indian Himalayan Region (IHR) have been determined. Observations were also made for the diversity, distribution and colonization of arbuscular mycorrhizal (AM) fungi and occurrence of endophytes in roots of G. biloba. The population of general microflora was found to be higher in the rhizosphere of Group B trees, more clearly reflected in terms of rhizosphere: soil (R:S) ratios. Contrary to this, per cent colonization and spore densities of AM fungi were higher in the rhizosphere of Group A trees as compared to the rhizosphere of Group B. AM fungal colonization was observed mostly in form of loose coils. All the spores detected, belonged to the genus Glomus with five different types. Presence of endophytes (both bacteria and fungi) was observed in the cortical cells of G. biloba roots, more profound in case of Group B trees. Data suggest that, while the species of Glomus dominated the rhizosphere of G. biloba, an inverse correlation exist between the colonization of general microflora and the colonization of AM fungi including endophytes. PMID- 23100763 TI - An evidence of laccases in archaea. AB - Laccases (benzenediol:oxygen oxidoreductase, EC 1.10.3.2) are a diverse group of multicopper oxidases that catalyze the oxidation of a variety of aromatic compounds. Here we present evidence for distribution of laccases among archaea and their probable functions. Putative laccase genes have been found in different archaeal groups that might have branched off early during evolution, e.g. Haloarcula marismortui ATCC 43049, Natronomonas pharaonis DSM2160, Pyrobaculum aerophilum IM2, Candidatus Nitrosopumilus maritimus SCM1, Halorubrum lacusprofundi ATCC 49239. Most of the archaeal multicopper oxidases reported here are of Type 1 and Type 2 whereas type 3 copper-binding domain could be found in Pyrobaculum aerophilum IM2 and Halorubrum lacusprofundi ATCC49239. An analysis of the genome sequence database revealed the presence of novel types of two-domain laccases in archaea. ed using this method. CyMVin the positive samples of Phalaenopsis sp. and Arachnis sp. was confirmed by DNA sequencing and cp gene homeology blast. The results showed that CyMV extracted from the leaves of orchid in Hangzhou, Zhejiang Province, China, could be derived from Kunming city (KM), Yunnan Province, China. This method characterized by high sensitivity, specificity, and precision is suitable for early diagnosis and quantitative detection of CyMV. PMID- 23100765 TI - A combined vaccine against Brucella abortus and infectious bovine rhinotracheitis. AB - The present study was undertaken to study the immune response in calves vaccinated with Brucella abortus strain 19, infectious bovine rhinotracheitis (IBR) vaccines in monovalent form and combined vaccine containing both antigen. The seroconversion of monovalent and combined vaccines was tested in seronegative cattle calves. IBR vaccine alone and combination with live Brucella abortus S19 vaccine elicited an anamnestic response on day 60 post booster but started declining from day 90 onwards against IBR. B. abortus S19 alone and in combination with IBR vaccine gave more than 2 log protection in mice two weeks post challenge. Fluorescence polarization assay analysis with sera samples of calves vaccinated with B. abortus S19 monovalent vaccine alone and in combination with IBR vaccine revealed the presence of B. abortus antibodies. The components of the combined vaccine did not show any evidence of interference in the development of immunity. This combined vaccine may provide economical and affordable biological for the control of brucellosis and IBR. PMID- 23100764 TI - A 70-kDa molecular chaperone, DnaK, from the industrial bacterium Bacillus licheniformis: gene cloning, purification and molecular characterization of the recombinant protein. AB - The heat shock protein 70 (Hsp70/DnaK) gene of Bacillus licheniformis is 1,839 bp in length encoding a polypeptide of 612 amino acid residues. The deduced amino acid sequence of the gene shares high sequence identity with other Hsp70/DnaK proteins. The characteristic domains typical for Hsps/DnaKs are also well conserved in B. licheniformis DnaK (BlDnaK). BlDnaK was overexpressed in Escherichia coli using pQE expression system and the recombinant protein was purified to homogeneity by nickel-chelate chromatography. The optimal temperature for ATPase activity of the purified BlDnaK was 40 degrees C in the presence of 100 mM KCl. The purified BlDnaK had a V(max) of 32.5 nmol Pi/min and a K(M) of 439 MUM. In vivo, the dnaK gene allowed an E. coli dnaK756-ts mutant to grow at 44 degrees C, suggesting that BlDnaK should be functional for survival of host cells under environmental changes especially higher temperature. We also described the use of circular dichroism to characterize the conformation change induced by ATP binding. Binding of ATP was not accompanied by a net change in secondary structure, but ATP together with Mg(2+) and K(+) ions had a greater enhancement in the stability of BlDnaK at stress temperatures. Simultaneous addition of DnaJ, GrpE, and NR-peptide (NRLLLTG) synergistically stimulates the ATPase activity of BlDnaK by 11.7-fold. PMID- 23100766 TI - Phylogenetic profiling of bacterial community from two intimately located sites in Balramgari, North-East coast of India. AB - Microbial communities in coastal subsurface sediments play an important role in biogeochemical cycles. In this study microbial communities in tidal subsurface sediments of Balramgari in the state of Orissa, India were investigated using a culture independent approach. Two 16S rDNA cloned libraries were prepared from the closely located (100 m along the coast) subsurface sediment samples. Library I sediment samples had higher organic carbon content but lower sand percentage in comparison to Library II. A total of 310 clone sequences were used for DOTUR analysis which revealed 51 unique phylotypes or operational taxonomic units (OTUs) for both libraries. The OTUs were affiliated with 13 major lineages of domain bacteria including Proteobacteria (alpha, beta, delta and lambda), Acidobacteria, Actinobacteria, Cyanobacteria, Chloroflexi, Firmicutes, Verrucomicrobia, Bacteroidetes, Gemmatimonadetes and TM7. We encountered few pathogenic bacteria such as Aeromonas hydrophila and Ochrobactrum intermedium, in sediment from Library I. ?-LIBSHUFF comparison depicts that the two libraries were significantly different communities. Most of the OTUs from both libraries possessed >=85% to <97% similarity to RDP database sequences depicting the putative presence of new species, genera and phylum. This work revealed the complex and unique bacterial diversity from coastal habitat of Balramgari and shows that, in coastal habitat a variability of physical and chemical parameter has a prominent impact on the microbial community structure. PMID- 23100767 TI - Strain improvement of Trichoderma reesei Rut C-30 for increased cellulase production. AB - The strain of Trichoderma reesei Rut C-30 was subjected to mutation after treatment with N-methyl-N'-nitro-N-nitrosoguanidine (NG) for 6 h followed by UV irradiation for 15 min. Successive mutants showed enhanced cellulase production, clear hydrolysis zone and rapid growth on Avicel-containing plate. Particularly, the mutant NU-6 showed approximately two-fold increases in activity of both FPA and CMCase in shake flask culture when grown on basal medium containing peptone (1%) and wheat bran (1%). The enzyme production was further optimized using eight different media. When a mixture of lactose and yeast cream was used as cellulase inducer, the mutant NU-6 yielded the highest enzyme and cell production with a FPase activity of 6.2 U ml(-1), a CMCase activity of 54.2 U ml(-1), a beta glucosidase activity of 0.39 U ml(-1), and a fungal biomass of 12.6 mg ml(-1). It deserved noting that the mutant NU-6 also secreted large amounts of xylanases (291.3 U ml(-1)). These results suggested that NU-6 should be an attractive producer for both cellulose and xylanase production. PMID- 23100768 TI - Molecular diversity of Frankia from root nodules of Hippophae salicifolia D.Don found in Sikkim. AB - Molecular diversity of Frankia was assessed directly from the root nodules of Hippophae salicifolia naturally occurring in North Sikkim. Amplicon restriction patterns (ARPs) were developed by digesting 16S-ITS-23S amplicons with RsaI. Three ARPs were detected, showing diversity among strains of Frankia that nodulate Hippophae. This was confirmed by sequencing one amplicon each for the three ARPs. Therefore, ARP can be used as a tool for screening amplicons for nucleotide sequencing. PMID- 23100769 TI - Swine flu virus H1N1: a threat to human health. PMID- 23100770 TI - Bacteriocin: safest approach to preserve food products. AB - Start of the 21st century with its universal call to feed the hungry is an appropriate time to refocus attention on food security and especially the impact of biopatenting on poor communities who are the primary victims of hunger in our world. Antibacterial metabolites of lactic acid bacteria and Bacillus spp have potential as natural preservatives to control the growth of spoilage and pathogenic bacteria in food. Among them, bacteriocin is used as a preservative in food due to its heat stability, wider pH tolerance and its proteolytic activity. Due to thermo stability and pH tolerance it can withstand heat and acidity/alkanity of food during storage condition. Bacteriocin are ribosomally synthesized peptides originally defined as proteinaceous compound affecting growth or viability of closely related organisms. Research is going on extensively to explore the nascent field of biopreservation. Scientists all over the world are showing their keen interest to isolate different types of bacteriocin producing strains and characterize bacteriocin produced by them for food preservation. PMID- 23100771 TI - Construction and purification of His-tagged staphylococcal ArsB protein, an integral membrane protein that is involved in arsenical salt resistance. AB - Bacterial resistance to arsenical salts encoded on plasmid pI258 occurs by active extrusion of toxic oxyanions from cells of Staphylococcus aureus. The operon encodes for three gene products: ArsR, ArsB and ArsC. The gene product of arsB is an integral membrane protein and it is sufficient to provide resistance to arsenite and antimonite. A poly His-ArsB fusion protein was generated to purify the staphylococcal ArsB protein. Cells containing the His-tagged arsB gene were resistant to arsenite and antimonite. The levels of resistance to these toxic oxyanions by the His-tagged construct were greater than the levels obtained with the wild type gene. These data would indicate that the His-tagged protein is functionally active. A new 36 kDa protein band was visualized on 10% SDS polyacrylamide gel electrophoresis (PAGE), which was confirmed as the His-ArsB protein by immunodetection with polyclonal Hisantibodies. The His-ArsB fusion protein was purified by the use of metal-chelate affinity chromatography with a Ni(+2)-nitrilotriacetic acid column and size-exclusion chromatography suggests that the protein was a homodimer. PMID- 23100772 TI - Optimization of culture conditions and characterization of a new lectin from Aspergillus niger. AB - Lectin activity was determined on solidified medium containing agar and in broth cultures of Aspergillus niger. The fungus was found to express 16 times higher activity in broth cultures, when grown in a medium adjusted to pH 5.5 at 30 degrees C under stationary condition. Lectin activity was found to be expressed by 6-day-old mycelial cultures with maximum activity being expressed on 9th day of incubation. The crude lectin (total titer 1280) was found to be precipitated at 50% saturation of ammonium sulphate with 2.4-fold purifi cation and 83% yield in the precipitate. The partially purifi ed lectin was found to agglutinate all human, rat, mice and pig erythrocytes. It was found to have a strong binding affinity to mucin, asialofetuin and inulin. PMID- 23100773 TI - Impact of commonly used agrochemicals on bacterial diversity in cultivated soils. AB - The effects of three selected agrochemicals on bacterial diversity in cultivated soil have been studied. The selected agrochemicals are Cerox (an insecticide), Ceresate and Paraquat (both herbicides). The effect on bacterial population was studied by looking at the total heterotrophic bacteria presence and the effect of the agrochemicals on some selected soil microbes. The soil type used was loamy with pH of 6.0-7.0. The soil was placed in opaque pots and bambara bean (Vigna subterranean) seeds cultivated in them. The agrochemicals were applied two weeks after germination of seeds at concentrations based on manufacturer's recommendation. Plant growth was assessed by weekly measurement of plant height, foliage appearance and number of nodules formed after one month. The results indicated that the diversity index (Di) among the bacteria populations in untreated soil and that of Cerox-treated soils were high with mean diversity index above 0.95. Mean Di for Ceresate-treated soil was 0.88, and that for Paraquattreated soil was 0.85 indicating low bacterial populations in these treatment-type soils. The study also showed that application of the agrochemicals caused reduction in the number of total heterotrophic bacteria population sizes in the soil. Ceresate caused 82.50% reduction in bacteria number from a mean of 40 * 10(5) cfu g(-1) of soil sample to 70 * 10(4) cfu g(-1). Paraquat-treated soil showed 92.86% reduction, from a mean of 56 * 10(5) cfu g(-1) to 40 * 10(4) cfu g(-1). Application of Cerox to the soil did not have any remarkable reduction in bacterial population number. Total viable cell count studies using Congo red yeast-extract mannitol agar indicated reduction in the number of Rhizobium spp. after application of the agrochemicals. Mean number of Rhizobium population numbers per gram of soil was 180 * 10(4) for the untreated soil. Cerox-treated soil recorded mean number of 138 * 10(4) rhizobial cfu g(-1) of soil, a 23.33% reduction. Ceresate- and Paraquat-treated soils recorded 20 * 10(4) and 12 * 10(4) cfu g(-1) of soil, respectively, representing 88.89% and 93.33% reduction in Rhizobium population numbers. Correspondingly, the mean number of nodules per plant was 44 for the growth in untreated soil, 30 for the plant in the Cerox treated soil, 8 for the plant in Paraquat-treated soil and 3 for the plant in Ceresate-treated soil. The study has confirmed detrimental effect of insecticide on bacterial populations in the soil. Total heterotrophic counts, rhizobial counts as well as the number of nodules of all samples taken from the chemically treated soils were all low as compared to values obtained for the untreated soil. However, the effect of the insecticide was minimal in all cases as compared to the effects of the herbicides on the soil fauna. Indiscriminate use of agrochemicals on farms can therefore affect soil flora and subsequently food production. PMID- 23100774 TI - Hypochlorite digestion method for efficient recovery of PHB from Alcaligenes faecalis. AB - We reported the optimum amount of PHB accumulated by Alcaligenes faecalis during its 24 h growth under nitrogen deficient conditions. After 24 h incubation decrease in the amount of PHB was recorded. Hypochlorite digestion of biomass of organism followed by extraction with a solvent system consisting of 1:1 mixture of ethanol and acetone resulted in efficient recovery of PHB vis-a-vis earlier methods. This solvent system gave a high recovery yield, i.e. 5.6 gL(-1) vis-a vis earlier reported yield, 1.34 gL(-1) (by same method), 0.63 gL(-1) (by chloroform extraction method) and 1.1 gL(-1) (by dispersion method). PMID- 23100775 TI - Prevalence of pulmonary tuberculosis (PTB) among people living with HIV/AIDS (PLWHA) in Keffi and its environs. AB - Coinfection with HIV and Mycobacterium tuberculosis is known to be a lethal combination especially with its attendant mortality and morbidity. The need to have a baseline data in an environment like Keffi with a HIV/AIDS prevalence of 38.6% necessitated this study. Three hundred and ninety people living with HIV/AIDS (PLWHA) were screened for pulmonary tuberculosis. Results of this study showed 16.7% prevalence of coinfection in the population. Gender-related prevalence of coinfection was 19.4% and 14.4% among males and females respectively (P>0.05). Age-related prevalence of coinfection was least among respondents of age below 20 years (13.3%) and highest among those of age above 40 years (20.2%) (P>0.05). Even though statistically insignificant by both parameters, these findings are of public health significance. There is therefore an urgent need for immediate intervention to allow for early TB diagnosis, institution of anti-TB treatment and provision of prophylaxis against TB among TB negative PLWHA. PMID- 23100776 TI - Purification of a hyperactive nitrile hydratase from resting cells of Rhodococcus rhodochrous PA-34. AB - A propionitrile-induced nitrile hydratase (NHase), a promising biocatalyst for synthesis of organic amides has been purified from cell-free extract of Rhodococcus rhodochrous PA-34. About 11-fold purification of NHase was achieved with 52% yield. The SDS-PAGE of the purified enzyme revealed that it consisted of two subunits of 25.04 kD and 30.6 kD. However, the molecular weight of holoenzyme was speculated to be 86 kD by native-PAGE. This NHase exhibited maximum activity at pH 8.0 and temperature 40 degrees C. Half-life was 2 h at 40 degrees C and 0.5 h at 50 degrees C. The Km and Vmax were 167 mM and 250 MUmole/min/mg using 25 mM 3-cyanopyridine as substrate. AgNO(3), Pb(CH(3)COO)(2) and HgCl(2) inhibited the NHase to extent of 89-100%. PMID- 23100777 TI - L-glutaminase production by Trichoderma koningii under solid-state fermentation. AB - Solid state fermentation was conducted for the production of L-glutaminase by Trichoderma koningii Oud.aggr. using different agro-industrial byproducts inlcuding wheat bran, groundnut residues, rice hulls, soya bean meal, corn steep, sesamum oil cake, cotton seed residues and lentil industrial residues as solid substrates. Wheat bran was the best substrate for induction of L-glutaminase (12.1 U/mg protein) by T. koningii. The maximum productivity (23.2 U/mg protein) and yield (45.0 U/gds) of L-glutaminase by T. koningii occurred using wheat bran of 70% initial moisture content, initial pH 7.0, supplemented with D-glucose (1.0%) and L-glutamine (2.0% w/v), inoculated with 3 ml of 6 day old fungal culture and incubated at 30 degrees C for 7 days. After optimization, the productivity of L-glutaminase by the solid cultures of T. koningii was increased by 2.2 fold regarding to the submerged culture. PMID- 23100778 TI - Production and characterization of bacterial polyhydroxyalkanoate copolymers and evaluation of their blends by fourier transform infrared spectroscopy and scanning electron microscopy. AB - Rhizobium meliloti produced a copolymer of short chain length polyhydroxyalkanoate (scl-PHA) on sucrose and rice bran oil as carbon substrates. Recombinant Escherichia coli (JC7623ABC1J4), bearing PHA synthesis genes, was used to synthesize short chain length-co-medium chain length PHA (scl-co-mcl-PHA) on glucose and decanoic acid. Fourier transform infrared spectroscopy (FTIR) spectra of the PHAs indicated strong characteristic bands at 1282, 1723, and 2934 cm(-1) for scl-PHA and at 2933 and 2976 cm(-1) for scl-co-mcl-PHA polymer. Differentiation of polyhydroxybutyrate (PHB) and polyhydroxybutyrate-co hydroxyvalerate-P(HB-co-HV) copolymer was obseverd using FTIR, with absorption bands at 1723 and 1281 for PHB, and at 1738, 1134, 1215 cm(-1) for HV-copolymer. The copolymers were analyzed by GC and (1)H NMR spectroscopy. Films of polymer blends of PHA produced by R. meliloti and recombinant E. coli were prepared using glycerol, polyethylene glycol, polyvinyl acetate, individually (1:1 ratio), to modify the mechanical properties of the films and these films were evaluated by FTIR and scanning electron microscopy. PMID- 23100779 TI - Phenotypic and genotypic characterization of Shigella spp. with reference to its virulence genes and antibiogram analysis from river Narmada. AB - Water samples of the river Narmada from the source to the mouth were analyzed for the presence of shigellae and the Shigella isolates from 180 water samples were characterized by biotyping, serotyping and molecular typing. Out of all the 40 isolates, 23 were identified as S. flexneri, 10 as S. sonnei and 7 as S. dysenteriae. Serotyping was found to be the better identification method than biotyping. In the present investigation, amplified ribosomal DNA restriction analysis (ARDRA) with a probe complementary to 16S rRNA was performed. Repeated ARDRA analysis established the similarities between the isolates and thus suggested ARDRA as authentic and precise detection protocol. The isolates were also analyzed for the presence of virulence genes including ipaBCD, ipaH and stx1. All the 40 isolates of Shigella were found to be positive for the ipaH gene. The plasmid encoded invasion-associated genes ipaBCD were present only in S. flexneri and the stx1 gene was found only in S. dysenteriae. This study demonstrated the existence of Shigella in the river Narmada and the dispersion of different virulence genes among the isolates, which appear to constitute an environmental reservoir of Shigella-specific virulence genes. PMID- 23100780 TI - Cloning, expression and immunogenicity of ferric enterobactin binding protein Fep B from Escherichia coli O157:H7. AB - The gene coding for ferric enterobactin binding protein from E. coli O157:H7 was amplifi ed. This gene was cloned and expressed as C-terminal His (6)-tagged protein. The SDS-PAGE analysis of the total protein revealed only two distinct bands, with molecular masses of 31kDa and 34kDa. The Ni-NTA chromatography purifi ed FepB and the osmotically shocked periplasmic fraction of IPTG induced cells showed only a single band of 31 kDa. Polyclonal mouse antibody was raised against the recombinant protein during 4 weeks after immunization. Western blot analysis of the recombinant FepB with mouse antiserum revealeda single band of 31 kDa. Identification and purification of FepB helped reveal its appropriate molecular mass. Polyclonal antibody raised against the recombinant protein reacted with bacterial FepB. The recombinant protein FepB could have a protective effect against E. coli O157:H7 and might be useful as an effective vaccine. PMID- 23100781 TI - Characterization of Vibrio cholerae from deep ground water in a cholera endemic area in Central India. AB - A total of 8 out of 11 deep ground water samples collected from different villages in Central India were found contaminated with Vibrio cholerae non O1, non O139. In a multiplex PCR, isolates were found positive for ompW gene but negative for ctxAB and rfbO1 genes. However, isolates from two places were positive for tcp and zot genes, indicating their intestinal colonization and toxigenic potential. Antibiotic susceptibility studies revealed that all isolates were multidrug resistant. Although, none of the isolates was found PCR positive for the mobile genetic elements, class 1 integrons and SXT constins. The results of this study corroborated that deep ground water can also be an important reservoir of V. cholerae in plane endemic areas, suggesting a continuous monitoring of water samples for timely prevention of the disease. PMID- 23100782 TI - Effect of morphine on Mycobacterium smegmatis infection in mice and macrophages. AB - The immunomodulatory effects of opioids are known in various infections. However, little is known about the effects of opioids in tuberculosis (TB). In the present study, we report the effects of morphine in Mycobacterium smegmatis infection in mice and macrophages. Morphine exerted a dose-dependent suppression of infection in vivo: 50 and 100 mg/kg morphine exerted significant (P<0.05) suppression whereas 5 mg/kg morphine showed no effect. Analogous to the in vivo effects, incubation of M. smegmatis-infected mouse peritoneal macrophages with morphine (100 MUM) showed significant reduction in intramacrophage CFU counts. However, morphine did not show any direct antimycobacterial activity in broth dilution assay upto 100 MUM concentration. Further, morphine-induced intramacrophage killing of M. smegmatis was abrogated by naloxone and aminoguanidine indicating the involvement of opioid-receptor activation and nitric oxide production in protective effects of morphine. In conclusion, morphine suppressed the progression of experimental TB in both mice and macrophage models. PMID- 23100783 TI - Simultaneous detection of pathogenic B. cereus, S. aureus and L. monocytogenes by multiplex PCR. AB - Three important foodborne pathogens, Bacillus cereus, Listeria monocytogenes and Staphylococcus aureus are of major concern for food safety in terms of frequency and seriousness of the disease. The occurrence these three important pathogens and their coexistence in food matrices are predominant. Moreover, symptoms associated with B. cereus and S. aureus food poisoning not only closely resembles each other but can also be overlapping with other foodborne infections. In this context, detection of these three pathogens simultaneously in food samples by a single multiplex PCR (mPCR) would have advantages in terms of rapidity and cost saving, when compared with single organism specific PCRs. mPCR has been standardized by targeting three major diarrheal enterotoxin genes hbl A, cyt K and nhe A of B. cereus, virulence associated nuc and Ent B genes of S. aureus and virulence associated hly and iap genes of L. monocytogenes along with internal amplification control (IAC). The results showed that mPCR accurately identified all the three organisms individually or in combination without non-specificity. The mPCR was able to detect as low as 10 to 100 organisms per ml of growth following overnight enrichment of spiked food samples (vegetable biriyani and milk) and their presence in naturally contaminated samples also. The high throughput and cost effective multiplex PCR method developed in this study could provide a powerful tool for simultaneous, rapid and reliable detection of B. cereus, S. aureus and L. monocytogenes in food samples. PMID- 23100784 TI - Assessment of mold concentrations in Singapore shopping centers using mold specific quantitative PCR (MSQPCR) analysis. AB - Molds can pose a human health threat and may amplify in buildings in humid climates. The objective of this study was to evaluate the mold growth in Singapore shopping centers based on the collection of 40 dust samples from 15 shopping centers, including one with a history of water damage. The dust was analyzed by a DNA-based technology called mold-specific quantitative PCR (MSQPCR). In a water-damaged shopping center, most of the 26 water-damage indicator species were detected at some concentration and many were much more abundant than the average in the shopping centers. MSQPCR is a useful method for quantifying indoor molds in tropical climates. PMID- 23100785 TI - Cold drink cans contaminated with rat urine can kill. PMID- 23100786 TI - Experimental evidence for cooperation, an important process in evolution of complex systems. PMID- 23100787 TI - Can microbes help crops cope with climate change? PMID- 23100788 TI - A new influenza reassortant - a beast in the making. PMID- 23100789 TI - Diagnosis of influenza viruses with special reference to novel H1N1 2009 influenza virus. AB - On 15 April and 17 April 2009, novel swineorigin influenza A (H1N1) virus was identifi ed in specimens obtained from two epidemiologically unlinked patients in the United States. The ongoing outbreak of novel H1N1 2009 influenza (swine influenza) has caused more than 3,99,232 laboratory confi rmed cases of pandemic influenza H1N1 and over 4735 deaths globally. This novel 2009 influenza virus designated as H1N1 A/swine/California/04/2009 virus is not zoonotic swine flu and is transmitted from person to person and has higher transmissibility then that of seasonal influenza viruses. In India the novel H1N1 virus infection has been reported from all over the country. A total of 68,919 samples from clinically suspected persons have been tested for influenza A H1N1 across the country and 13,330 (18.9%) of them have been found positive with 427 deaths. At the All India Institute of Medical Sciences, New Delhi India, we tested 1096 clinical samples for the presence of novel H1N1 influenza virus and seasonal influenza viruses. Of these 1096 samples, 194 samples (17.7%) were positive for novel H1N1 influenza virus and 197 samples (18%) were positive for seasonal influenza viruses. During outbreaks of emerging infectious diseases accurate and rapid diagnosis is critical for minimizing further spread through timely implementation of appropriate vaccines and antiviral treatment. Since the symptoms of novel H1N1 influenza infection are not specifi c, laboratory confi rmation of suspected cases is of prime importance. PMID- 23100790 TI - Comparative aspects of infectious salmon anemia virus, an orthomyxovirus of fish, to influenza viruses. AB - Infectious salmon anaemia (ISA) is a viral disease that was first recorded in 1984 in farmed Atlantic salmon. The infectious salmon anaemia virus (ISAV) is classified as the type species of the genus Isavirus in the Orthomyxoviridae family and is evolutionary remote to the influenza viruses. The genome consists of eight negative single-stranded RNA segments, and it utilises the same mechanisms as influenza viruses to enter and exit cells. Although a common ancestor of ISAV and other genera of Orthomyxoviruses could be dated back several millions of years, there are still many similarities between ISAV and the influenza viruses regarding morphology, replication cycles and interactions with their respective hosts. PMID- 23100791 TI - Influenza A: From highly pathogenic H5N1 to pandemic 2009 H1N1. Epidemiology and clinical features. AB - The last decade has seen the emergence of two new influenza A subtypes and they have become a cause of concern for the global community. These are the highly pathogenic H5N1 influenza A virus (H5N1) and the Pandemic 2009 influenza H1N1 virus. Since 2003 the H5N1 virus has caused widespread disease and death in poultry, mainly in south East Asia and Africa. In humans the number of cases infected with this virus is few but the mortality has been about 60%. Most patients have presented with severe pneumonia and acute respiratory distress syndrome. The second influenza virus, the pandemic H1N1 2009, emerged in Mexico in March this year. This virus acquired the ability for sustained human to human spread and within a few months spread throughout the world and infected over 4 lakh individuals. The symptoms of infection with this virus are similar to seasonal influenza but it currently affecting younger individuals more often. Fortunately the mortality has been low. Both these new influenza viruses are currently circulating and have different clinical and epidemiological characteristics. PMID- 23100792 TI - Emergence of swine flu in Andhra Pradesh: Facts and future. AB - Swine flu is a common term representing the respiratory viral infections caused by influenza A virus strain H1N1. This disease was noticed for the first time in Mexico during early 2009, spread worldwide very soon and took nearly 4000 lives. It is observed that this infection is due to an evolved virulent version of previously existing H1N1. The first report of this infection was noticed in a traveler from USA to India at the Hyderabad international airport. Later, because of its highly contagious and fast-spreading nature through air, many people reported to have the infection throughout the country. In Andhra Pradesh, there were 735 officially confirmed cases of which 44 died. These cases were not only from Hyderabad which is the state capital having frequent travelers from abroad but are also reported from different parts of the state. The incidence and mortality rate is less in Andhra Pradesh compared to some of the other Indian states. This raises a question whether the type of the strain is different or genetic features of the population is playing the role in reducing the severity of the disease. In this review we have discussed about the occurrence, spread and mortality of the current H1N1 pandemic. We have also discussed about the current status of research on H1N1 and efforts in the state of Andhra Pradesh. PMID- 23100793 TI - Epidemiological update on swine influenza (H1N1) in pigs. AB - The 2009 H1N1 pandemic has slowed down its spread after initial speed of transmission. The conventional swine influenza H1N1 virus (SIV) in pig populations worldwide needs to be differentiated from pandemic H1N1 influenza virus, however it is also essential to know about the exact role of pigs in the spread and mutations taking place in pig-to-pig transmission. The present paper reviews epidemiological features of classical SIV and its differentiation with pandemic influenza. PMID- 23100794 TI - Molecular events leading to the creation of a pandemic influenza virus. AB - Influenza A virus is a potent pathogen of annual respiratory illness with huge potential of causing occasional pandemics of catastrophic consequences. In April 2009, a novel, swine-origin influenza A H1N1/09 virus was identified in Mexico which continued to spread globally. This unique virus emerged from an avian, human, Eurasian swine viral strain and a North American swine strain belonging to the lineage of the 1930 swine virus. Till date H1N1/09 pandemic has been relatively mild and lacks the previously described molecular markers of influenza A pathogenicity and transmissibility. In this review, we will discuss the molecular and antigenic determinants of this virus and its designation as a low pathogenic strain, which carries the potential to develop into a devastating strain with subsequent mutations and reassortments. PMID- 23100795 TI - Molecular character of influenza A/H1N1 2009: Implications for spread and control. AB - The world is experiencing a pandemic of influenza that emerged in March 2009, due to a novel strain designated influenza A/H1N1 2009. This strain is closest in molecular sequence to swine influenza viruses, but differs from all previously known influenza by a minimum of 6.1%, and from prior "seasonal" H1N1 by 27.2%, giving it great potential for widespread human infection. While spread into India was delayed for two months by an aggressive interdiction program, since 1 August 2009 most cases in India have been indigenous. H1N1 2009 has differentially struck younger patients who are naive susceptibles to its antigenic subtype, while sparing those >60 who have crossreactive antibody from prior experience with influenza decades ago and the 1977 "swine flu" vaccine distributed in the United States. It also appears to more severely affect pregnant women. It emanated from a single source in central Mexico, but its precise geographical and circumstantial origins, from either Eurasia or the Americas, remain uncertain. While currently a mild pandemic by the standard of past pandemics, the seriousness of H1N1 2009 especially among children should not be underestimated. There is potential for the virus, which continues to adapt to humans, to change over time into a more severe etiologic agent by any of several foreseeable mutations. Mass acceptance of the novel H1N1 2009 vaccine worldwide will be essential to its control. Having spread globally in a few months, affecting millions of people, it is likely to remain circulating in the human population for a decade or more. PMID- 23100796 TI - Lessons learned from the 1918-1919 influenza pandemic. AB - The 1918 influenza pandemic was one of the most virulent strains of influenza in history. Phylogenic evidence of the novel H1N1 strain of influenza discovered in Mexico last spring (2009) links it to the 1918 influenza strain. With information gained from analyzing viral genetics, public health records and advances in medical science we can confront the 2009 H1N1 influenza on a global scale. The paper analyses the causes and characteristics of a pandemic, and major issues in controlling the spread of the disease. Wide public vaccination and open communication between government and health sciences professionals will be an essential and vital component in managing the 2009 H1N1 pandemic and any future pandemics. PMID- 23100797 TI - On the origin of influenza A hemagglutinin. AB - Recent advances in phylogenetic methods have produced some reassessments of the ages of the most recent common ancestor of hemagglutinin proteins in known strains of influenza A. This paper applies Bayesian phylogenetic analysis implemented in BEAST to date the nodes on the influenza A hemagglutinin tree. The most recent common ancestor (MRCA) of influenza A hemagglutinin proteins is located with 95% confidence between 517 and 1497 of the Common Era (AD), with the center of the probability distribution at 1056 AD. The implications of this revised dating for both historical and current epidemiology are discussed. Influenza A can be seen as an emerging disease of mediaeval and early modern times. PMID- 23100798 TI - In silico genome analysis and drug efficacy test of influenza A virus (H1N1) 2009. AB - The H1N1 2009 virus is pandemic in many countries. The genome of this virus contains eight segments. Among the eight segments maximum numbers of mutation occur at the segment 1 and segment 4 which codes for PB2 subunit and hemagglutinin (HA) and less number of mutations occur in segment 6 which codes for neuraminidase (NA) protein. Neuraminidase (NA) inhibitors (Oseltamivir and Zanamivir) are presently used as an anti-flu drugs. In the present study, the in silico efficacy of different drugs was tested against the swine flu virus. 3D structures of neuraminidase (NA) proteins of H1N1 2009 were generated using Geno3D. The 3D structure of H1N1 1918 was downloaded from PDB. Interaction study was done using Arguslab 4 and PyMol view. Oseltamivir and Zanamivir have good number of interactions with H1N1 2009 virus and the scoring function also support to this result. When compared with the 1918 H1N1 viral protein, 2009 H1N1 NA protein shows more number of interaction and good scoring function. The RMSD value of before and after docking are found to be same at 0.04A degrees for both the drugs. The force field energy of NA protein 2009 was found to be -15603.529 KJ/mol before docking. The force field energy was found to be decreased after docking at -17620.740 KJ/mol with Tamiflu and -17652.242 KJ/mol with Zanamivir. The number of interaction and scoring function shows that Oseltamivir and Zanamivir will be able to effectively control the present pandemic H1N1 virus 2009. PMID- 23100799 TI - Pandemic swine influenza virus (H1N1): A threatening evolution. AB - "Survival of the fittest" is an old axiom laid down by the great evolutionist Charles Darwin and microorganisms seem to have exploited this statement to a great extent. The ability of viruses to adapt themselves to the changing environment has made it possible to inhabit itself in this vast world for the past millions of years. Experts are well versed with the fact that influenza viruses have the capability to trade genetic components from one to the other within animal and human population. In mid April 2009, the Centers for Disease Control and Prevention and the World Health Organization had recognized a dramatic increase in number of influenza cases. These current 2009 infections were found to be caused by a new strain of influenza type A H1N1 virus which is a re-assortment of several strains of influenza viruses commonly infecting human, avian, and swine population. This evolution is quite dependent on swine population which acts as a main reservoir for the reassortment event in virus. With the current rate of progress and the efforts of heath authorities worldwide, we have still not lost the race against fighting this virus. This article gives an insight to the probable source of origin and the evolutionary progress it has gone through that makes it a potential threat in the future, the current scenario and the possible measures that may be explored to further strengthen the war against pandemic. PMID- 23100800 TI - Efficacy of neuraminidase (NA) inhibitors against H1N1 strains of different geographical regions: an in silico approach. AB - This report described the efficacy of NA inhibitors against newly evolved strains of H1N1 viruses. This in silico study was designed to understand the mode of interactions of NA inhibitors with NA. Hence, ligand, oseltamivir, zanamivir and peramivir were docked with modeled NA, ACD65204 (USA/2007), BAA06717 (Japan/1992), ACE77988 (S. Korea/2005) and ACD65204 (USA/2007). This study is based on interaction energies. Ramachandran Z-scores for these modeled structures were found to be -0.998, -1.121, -0.870 and -1.023, respectively, which confirms the accuracy of the modeled structures. These interactions revealed that some of these interacting residues have remained conserved throughout all the pandemics. These amino acid residues were found to be R118, R152, R225, E277, E278, R293 and Y402. Moreover, our study concludes that peramivir is the most efficient inhibitor against NA of H1N1. PMID- 23100801 TI - Microbial production and applications of 1,2-propanediol. AB - 1,2-Propanediol (propylene glycol) is an existing commodity chemical and can be produced from renewable resources using microbes. By virtue of being a natural product, relevant biochemical pathways can be harnessed into fermentation processes to produce 1,2-propanediol. In the present review, the chemical process and different biological strategies for the production of 1,2-propanediol are reviewed and compared with the potentials and limitations of all processes. For the successful commercial production of this diol, it is necessary to establish the metabolic pathways and production hosts (microorganisms), which are capable of delivering final product with high yields and volumetric productivity. Three pathways which have been recognized for 1,2-propanediol production are discussed here. In the first, de-oxy sugars like fucose and rhamnose are used as the carbon sources, while in the other route, the glycolytic intermediate dihydroxyacetonephosphate (DHAP) is used to produce 1,2-propanediol via the formation of methylglyoxal. A new pathway of 1,2-propanediol production by lactic acid degradation under anoxic conditions and the enzymes involved is also discussed. The production of this diol has gained attention because of their newer applications in industries such as polymers, food, pharmaceuticals, textiles, etc. Furthermore, improvement in fermentation technology will permit its uses in other applications. Future prospect in the light of the current research and its potential as a major bulk chemical are discussed. PMID- 23100802 TI - Evaluating the potential of N. calcicola and its bicarbonate resistant mutant as bioameleorating agents for 'usar' soil. AB - The potential of Nostoc calcicola and its bicarbonate resistant mutant as bioameleorating agent was investigated, using laboratory simulation experiments, in terms of their growth potential, glutamine synthetase (GS) activity, heterocyst frequency and effect on pH of soil. Nostoc calcicola, exhibited a tendency to lower the pH of 'usar' soil significantly and showed better growth and pigment content at 20% soil extract as compared to basal medium. The bicarbonate resistant mutant (HCO(3) (-R)) exhibited a better ability to grow at higher percentage of soil extract (60%), besides bringing about a more significant change in soil pH as compared to wild type. The heterocyst frequency was much higher in the mutant strain, which was not significantly affected by growth in various concentrations of soil extract. The mutant strain holds promise as a potential bioameliorant for 'usar' soil after further evaluation of its reclamative properties at field level. PMID- 23100803 TI - Evaluation of in situ functional activity of casing soils during growth cycle of mushroom (Agaricus bisporus (Lange) Imbach) employing community level physiological profiles (CLPPs). AB - Community level physiological profiles (CLPPs) have been rarely applied to mushroom compost ecosystem, probably for the lack of standardized methodology. Recently, however CLPPs have been employed as a tool to investigate the degree of maturity of compost (Mondini and Insam, 2005, Compost Science and Utilization, 13(1): 27-33). The potential of CLPPs to detect compost maturity test is considerably significant in that it provides sensitivity and the simplicity of the assay. The aim of this work was to investigate the maturity of casing that comprised of farm yard manure and spent compost and influence of casing type on the behaviour of bacterial community during the growth cycle of mushroom Agaricus bisporus (Lange) Imbach employing standardized inoculum density and effects of different data interpretation based on the kinetics of colour formation. Casing samples of different age were extracted at a particular dilution and then inoculated in 96 well microtitre plates. Optical density (OD) in well was measured at 590 nm every 24 hours for 5 days. Principal component analysis (PCA) was performed by employing OD values at fixed average well colour development (AWCD). PCA of fresh samples showed that classification and ordination of samples according to their age were significant with fixed AWCD. PMID- 23100804 TI - Characterization of native Bacillus thuringiensis strains by PCR-RAPD based fingerprinting. AB - Seventy isolates of Bacillus thuringiensis were isolated from soil samples collected from cotton fields. These isolates were characterized by randomly amplified poylmorphic DNA (RAPD) markers to determine their genetic diversity pattern based on their source of origin. Different random decamer primers were used for RAPD amplification, which generated a total of 1935 fragments; of these 1865 were polymorphic and 68 monomorphic. The primers OPA03, OPA08, OPD14, OPD19, OPD20, OPE17 and OPD19 produced 100% polymorphic fragments, whereas primers OPC06, OPC20 and OPD17 produced 20, 31 and 17 monomorphic fragments, respectively. When the RAPD banding pattern data was subjected to dendrogram construction, the 70 isolates fell into two separate clusters, cluster I and cluster II, which includes 26 and 44 B. thuringiensis isolates, respectively. These two main clusters were further divided into four subclusters at Eucledian distance of 150 and 80% similarity index. All primers showed amplification and indicated the good diversity of B. thuringiensis isolates. The RAPD pattern showed 4-10 bands per isolate, with MWt in the range of 0.4-3.5 Kb and an average of 193.5 fragments were produced per primer. The primer OPE17 was found to be the most discriminatory as it produced 286 polymorphic bands. PMID- 23100805 TI - Notohymena saprai sp. nov, a new oxytrichid ciliate (Protozoa, Ciliophora) from the Valley of Flowers, a Himalayan bioreserve region; description and morphogenesis of the new species. AB - A new oxytrichid ciliate Notohymena saprai sp. nov was isolated from the Valley of Flowers, an isolated bioreserve in the upper Himalayas. The ciliate was found in the soil samples collected from the peripheral areas of the flowering region of the valley which is covered with permafrost for nearly eight months in a year. Cells were excysted from the soil samples by the non-flooded petridish method. Species identification was performed by observations on live and silver impregnated cells. Notohymena saprai sp. nov is highly flexible, measures 152 * 49 MUm and shows abundant presence of dark green sub-pellicular granules. The species is distinct by virtue of its new combination of morphometric and developmental characters. Prominent distinguishing features of the new species are its relative large size and presence of four macronuclei (other species of this genus have two macronuclei). The study also reports morphogenetic peculiarities which separate it from the other known species of the genus. PMID- 23100806 TI - Microbial diversity in firework chemical exposed soil and water samples collected in Virudhunagar district, Tamil Nadu, India. AB - Microbial diversity of soil and water samples collected from pyrochemicals exposed areas of Virdhunagar district (Tamil Nadu, India) was studied. Soil and water samples from cultivable area, waste land and city area of the same region were also studied for a comparative acount. There is a remarkable reduction in total heterotrophic bacterial population (THB) in pyrochemicals exposed soil and water samples (42 * 10(4) CFU/g and 5.6 * 10(4) CFU/ml respectively), compared to the THB of cultivable area soil and water samples (98 * 10(7) CFU/g and 38.6 * 10(7) CFU/ml). The generic composition the THB of the pyrochemicals exposed samples too exhibited considerable change compared to other samples. Pseudomonas sp. was the predominant one (41.6%) followed by Achromobacter sp. (25%) in pyrochemical exposed soil and Pseudomonas sp. was the predominant one (25%) in pyrochemical exposed water samples followed by Bacillus sp. (25%) and Micrococcus sp. (16.6%). It was observed that Cornybacterium sp. and Micrococcus sp. were absent completely in pyrochemical exposed soil and Achromobacter sp. was missing in the pyrochemical exposed water samples, which were present in the other samples. The outcome of this study clearly demonstrates that pollutants such as chemicals used in pyrotechniques affect the microbial biodiversity and suitable measures have to be taken to control the pollution level and to save biodiversity. PMID- 23100807 TI - Growth promotion of wheat seedlings by Exiguobacterium acetylicum 1P (MTCC 8707) a cold tolerant bacterial strain from the Uttarakhand Himalayas. AB - Exiguobacterium acetylicum strain 1P (MTCC 8707) is a gram-positive, rod-shaped, yellow pigmented bacterium isolated from soil on nutrient agar plates at 4 degrees C. The identity of the bacterium was arrived on the basis of the biochemical characterization, BIOLOG sugar utilization pattern and sequencing of the 16S rRNA gene. It grew at temperatures ranging from 4 to 42 degrees C, with temperature optima at 30 degrees C. It expressed multiple plant growth promotion attributes such as phosphate solubilization, indole acetic acid (IAA), siderophore and hydrogen cyanide (HCN) production, differentially at suboptimal growth temperatures (15 and 4 degrees C). At 15 degrees C it solubilized phosphate (21.1 MUg of P ml(-1) day(-1)), and produced IAA (14.9 MUg ml(-1) day( 1)) in tryptophan amended media. Qualitative detection of siderophore production and HCN were possible at 15 degrees C. At 4 degrees C it retained all the plant growth promotion attributes. Seed bacterization with the isolate, positively influenced the growth and nutrient uptake parameters of wheat seedlings in glass house studies at suboptimal cold growing temperatures. PMID- 23100808 TI - Rock phosphate dissolution by specific yeast. AB - Phosphate solubilizing yeast (PSY) were isolated from rhizosphere, non rhizosphere and fruits from Bhavnagar district. The potential of 25 yeasts were analyzed on the basis of phosphate solubilizing zone to growth on solid medium denoted as solubilization index (SI) which ranged from 1.10 to 1.50. Among 25 yeast isolates, 6 yeast belonging to genus Saccharomyces (2), Hansenula, Klockera, Rhodotorula and Debaryomyces exhibited highest SI (1.33-1.50) were further examined for in vitro tricalcium phosphate (TCP) and low grade rock phosphate (RP) solubilization. TCP proved superior to RP with all the yeasts. Within low grade RPs tested, except isolate Y5, all isolates showed maximum solubilization with Hirapur RP (HRP) ranging from 7.24 to 19.30 mg% P(2)O(5). Among six PSY screened, Debaryomyces hansenii showing maximal HRP solubilization was chosen for further physiological studies. Maximum HRP solubilization was expressed in following condition: pH optima 7.0, temperature optima 28 degrees C and optimal period of incubation were 15 days. Acidic pH of the spent media was a constant feature in all the cases. No correlation could be established between final acidity produced by yeasts and the quantity of phosphate liberated. PMID- 23100809 TI - Extractability of polyhydroxyalkanoate synthesized by Bacillus flexus cultivated in organic and inorganic nutrient media. AB - Bacillus flexus was isolated from local soil sample and identified by molecular methods. In inorganic nutrient medium (IM) containing sucrose as carbon source, yield of biomass and polyhydroxyalkanoate (PHA) were 2 g/l and 1 g/l (50% of biomass), respectively. Substitution of inorganic nitrogen by peptone, yeast extract or beef extract resulted in biomass yields of 4.1, 3.9 and 1.6 g/l, respectively. Corresponding yields of PHA in biomass was 30%, 40% and 44%. Cells subjected to change in nutrient condition from organic to inorganic, lacked diaminopimelic acid in the cell wall and the concentration of amino acids also decreased. Under these conditions the extractability of the polymer from the cells by hot chloroform or mild alkali hydrolysis was 86-100% compared to those grown in yeast extract or peptone (32-56%). The results demonstrated that growth, PHA production and the composition of cell wall of B. flexus are influenced by the organic or inorganic nutrients present in the growth medium. Cells grown in inorganic medium lysed easily and this can be further exploited for easier recovery of the intracellular PHA. PMID- 23100810 TI - Bioleaching of low-grade uranium ore using Acidithiobacillus ferrooxidans. AB - Bioleaching of uranium was carried out with Turamdih ore sample procured from Uranium Corporation of India Limited, Jaduguda. The bacterial strain that was used in the leaching experiments was isolated from the Jaduguda mine water sample. Efficiency of bioleaching was studied by varying parameters like pulp density and initial ferrous concentration as source of energy. It is observed that the efficiency of bioleaching was 49% at 10% pulp density (w/v) and initial pH 2.0. Addition of external has no effect on efficiency of bioleaching showing domination of direct leaching mechanism over indirect. PMID- 23100811 TI - Diversity and exploration of bioactive marine actinomycetes in the Bay of Bengal of the Puducherry coast of India. AB - The present study was designed to investigate the Puducherry coast of the Bay of Bengal, India for the diversity of bioactive actinomycetes. A total of 50 actinomycete strains were isolated from the marine sediments and most of the strains were belongs to Streptomyces. These strains were identified by means of morphological physiological, biochemical and cultural characteristics. The isolates were subjected to shake flask fermentation and the secondary metabolites were extracted with ethyl acetate and screened for cytotoxicity, hemolytic activity and antimicrobial activity against selected bacterial and fungal pathogens. The cytotoxic activity was evaluated using HeLa cell lines by 3-(4,5 Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, a tetrazole (MTT) assay, hemolytic activity on mouse erythrocytes and the antifungal activity was evaluated by MTT cytotoxic assay against Aspergillus niger, Aspergillus fumigatus and Candida albicans. The antibacterial activity was studied against Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella pneumoniae. The cytotoxicity and antimicrobial activity of secondary metabolite was found to be concentration dependent and nearly 24% of isolates showed significant antimicrobial, hemolytic and cytotoxic activity. The results of our study indicate the diversity and bioactive potential of marine actinomycetes isolated in the Puducherry coast. PMID- 23100812 TI - Genomic diversity among group A rotaviruses from diarrheic children, piglets, buffalo and cow calves of Madhya Pradesh. AB - Diarrheal disease continues to be a global health problem, particularly among young ones in developing nations. Amongst several viral and non-viral agents associated with diarrhea, group A rotavirus has been recognized as the major etiological agent of childhood gastroenteritis in human infants as well as several animal species throughout the world. During this study, a total of 181 diarrheic stool samples collected from children, piglets, buffalo and cow calves of Madhya Pradesh, central India were analyzed by electrophoretic mobilities of the 11 segments of dsRNA by polyacrylamide gel electrophoresis (PAGE). This technique revealed prevalence of rotavirus among different species (human-26.09%, pig-25.71%, buffalo-23.61% and cattle-21.43%). Prevalence of existence of circulating 8 different electropherotypes of group A rotaviruses indicated high genomic diversity among rotaviruses in this geographical region. Majority of the electropherotypes from humans and animals were of long pattern (75%) than short electropherotypes (9.09%). Same electropherotype was found to exist either only in a single species or in more than one species implicating the possibility of cross species transmission of the rotavirus strains. As it was found that certain animal rotavirus strains had electropherotypic similarities to some human strains, speculation increased about whether animals play a role as a source of rotavirus infection in humans or vice-versa. There is a need for further detailed study on the molecular characterization of rotaviruses which would have important implication in vaccine evaluation program. PMID- 23100813 TI - Distribution, occurrence and natural invertebrate hosts of indigenous entomopathogenic fungi of Central India. AB - We report here that, during periodical surveys of insects inhabiting diverse habitats for the collection of entomopathogenic fungi; a large number of isolates were recovered belonging to seven species, from various regions of Madhya Pradesh and Chhattisgarh forest areas and agricultural fields. The most common entomopathogenic fungi such as Beauveria bassiana, Nomuraea rileyi, Paecilomyces farinosus and Paecilomyces fumosoroseus were found to infect various insect hosts species naturally viz. Hyblaea puera, Eutectona machaeralis, Diachrysia orichalcea, Spodoptera litura, and few new insect hosts of these fungal pathogens among Indian insect population were collected for the first time from Central India, such as beetles of Agrilus species, hairy caterpillars of Lymantria species. The isolation, identification, maintenance and pathogenicity assay of these isolates was performed prior to deposition in culture collection center. PMID- 23100814 TI - Protoplast formation and regeneration in Lactobacillus delbrueckii. AB - Method for production and regeneration of Lactobacillus delbrueckii protoplasts are described. The protoplasts were obtained by treatment with a mixture of lysozyme and mutanolysin in protoplast buffer at pH 6.5 with different osmotic stabilizers. The protoplasts were regenerated on deMan, Rogosa and Sharpe (MRS) with various osmotic stabilizers. Maximum protoplast formation was obtained in protoplast buffer with sucrose as an osmotic stabilizer using a combination of lysozyme (1 mg/ml) and mutanolysin (10 MUg/ml). Maximum protoplast regeneration was obtained on MRS medium with sucrose (0.5 M) as an osmotic stabilizer. The regeneration medium was also applicable to other species of lactobacilli as well. This is, to our knowledge, the first report on protoplast formation and efficient regeneration in case of L. delbrueckii. PMID- 23100815 TI - Characterization of Vibrio species isolated from freshwater fishes by ribotyping. AB - Three Vibrio species from the resident microflora of gastrointestinal tract of freshwater carps and prawns were isolated and confirmed biochemically as V. fluvialis from Cyprinus carpio/Labeo rohita; V. parahaemolyticus from Macrobrachium rosenbergii and V. harveyi from Macrobrachium malcomsoni. The genetic relationship among these Vibrio species was carried out by polymerase chain reaction (PCR) amplification of 16S rRNA gene followed by restriction digestion with Hae III, Bam HI and Pst I. Dendogram based on ribotyping showed the isolated Vibrios were differentiated into three clusters. V. harveyi was closely related to V. vulnificus (reference Microbial type Culture Collection (MTCC) strain) and distantly related to V. parahaemolyticus as well as V. fluvialis. PMID- 23100816 TI - MeaB-dependent nutrition sensing regulates autolysis in carbon starved Aspergillus nidulans cultures. AB - Carbon starvation induced autolysis is an active process of self-digestion and is under complex regulation in Aspergillus nidulans. In this study we investigated how autolysis depends on the composition of the culture medium, especially on the presence of yeast extract. We demonstrated that the rate of autolytic cell wall degradation as well as the extracellular chitinase and proteinase productions significantly decreased in the presence of this nutrient. The effect of yeast extract on carbon starved cultures was independent of loss-of-function mutations in the carbon and nitrogen regulatory genes creA and areA and in the heterotrimeric G protein signalling genes fadA and ganB. In contrast, the nitrogen regulating transcription factor MeaB was involved in the yeast-extract mediated repression of autolysis. Reverse transcriptase - polymerase chain reaction (RT-PCR) experiments demonstrated that MeaB affects the FluG-BrlA sporulation regulatory pathway by affecting transcription of brlA, a gene also initiating the autolytic cell wall degradation in this fungus. PMID- 23100817 TI - Human microbiomics. AB - The sequencing of the human genome has driven the study of human biology in a significant way and enabled the genome-wide study to elucidate the molecular basis of complex human diseases. Recently, the role of microbiota on human physiology and health has received much attention. The influence of gut microbiome (the collective genomes of the gut microbiota) in obesity has been demonstrated, which may pave the way for new prophylactic and therapeutic strategies such as bacteriotherapy. The significance and recent understandings in the area of "human microbiomics" are discussed here. PMID- 23100818 TI - A new life in a bacterium through synthetic genome: a successful venture by craig venter. PMID- 23100819 TI - Comparative analysis of genetic variation among Xanthomonas axonopodis pv manihotis isolated from the western states of Nigeria using RAPD and AFLP. AB - Xanthomonas axonopodis pv manihotis is the causal agent of cassava bacterial blight (CBB) worldwide. CBB disease is a major constraint to cassava cultivation, and losses can be extremely severe in regions where highly susceptible cultivars are grown. To develop an efficient disease management policy, the genetic diversity of the pathogens population must be known. There is dearth of information on the genetic diversity of X. axonopodis pv manihotis population in Nigeria. We used RAPD (random amplified polymorphic DNA) and AFLP (amplified fragment length polymorphism), a PCR-based technique, to characterize the X. axonopodis pv manihotis isolates from the western States of Nigeria. Thirteen strains Xam and 2 reference strains were tested with eight primers combination of AFLP and 4 RAPD primers. RAPD amplified DNA fragment data showed four major clusters at 80 % similarity coefficient level and two strains were not clustered by this analysis. Strains Kwa76A and Ond48A were also separated in the principal component analysis of the same data. Numerical analysis differentiated the AFLP patterns into four distinct clusters and grouped two strains separately at 66 % similarity. PCA assembly grouped the bacterial strains into 4 and one of the strains was singled out from the others. The two DNA analyses techniques seem to be complimentary to one another and informative on the genomic structure of Xam population in Western Nigeria. The genetic analysis presented here contributes to understanding of the Xam population structure in Western Nigeria. PMID- 23100820 TI - Detection of toxigenic strains of Aeromonas species in foods by a multiplex PCR assay. AB - Aeromonas hydrophila and other aeromonads are ubiquitous organisms found in meat, vegetables, drinking water and various other food items. They cause diarrhea and extra-intestinal infections in normal and immunocompromised patients. The aim of the study was to develop a multiplex PCR assay for the detection of virulence associated genes of Aeromonas including hemolysin (hlyA), aerolysin (aerA), glycerophospholipid-cholesterol acyl transferase (GCAT) alongwith a 16S rRNA gene. Internal amplification control (IAC), which was coamplified with aerA primers, was also included in this study. The results showed that all cultures of Aeromonas were accurately identified by the assay without showing non specificity. A. hydrophila could be detected at a range of 10-50 CFU ml(-1) from experimentally spiked fish, chicken and milk samples following overnight enrichment in alkaline peptone water supplemented with 10 MUg/ml ampicillin (APW A) by this multiplex PCR (mPCR). When evaluated on a total of 74 naturally occurring food samples, four samples were identified to contain Aeromonas by mPCR. All these results were compared to the conventional culture, isolation and biochemical identification procedures. The high throughput and cost-effective mPCR method developed in this study could provide a powerful tool for detection of pathogenic Aeromonas spp. from food and environmental samples and in addition, the method has advantages in terms of specificity, sensitivity and ease of use compared to other reported PCR methods and DNA hybridization assays. PMID- 23100821 TI - Purification and characterization of enterocin FH 99 produced by a faecal isolate Enterococcus faecium FH 99. AB - Enterococcus faecium FH 99 was isolated from human faeces and selected because of its broad spectrum of inhibitory activity against several Gram-positive foodborne spoilage and pathogenic bacteria. Ent. faecium FH 99 accumulates enterocin in large number in early stationary phase of the growth. The enterocin FH 99 was stable over a wide pH range (2-10) and recovered activity even after treatment at high temperatures (10 min at 100 degrees C). The enterocin was subjected to different purification techniques viz., gel filteration, cation exchange chromatography and reverse-phase high-performance liquid chromatography. The activity was eluted as one individual active fraction. SDSPAGE revealed a molecular weight of less than 6.5 kDa. Studies carried out to identify the genetic determinants for bacteriocin production showed that this trait may be plasmid encoded as loss in both of the plasmids (size>chromosomal DNA) led to loss in bacteriocin production by Ent. faecium FH 99. Ent. faecium strain FH 99 is a newly discovered high bacteriocin producer with Activity Units 1.8 * 10(5) AU ml(-1) and its characteristics indicate that it may have strong potential for application as a protective agent against pathogens and spoilage bacteria in foods. PMID- 23100822 TI - Biodegradation of Green HE4B: Co-substrate effect, biotransformation enzymes and metabolite toxicity analysis. AB - A high exhaust reactive dye, Green HE4B (GHE4B) was 98% degraded in nutrient medium by Pseudomonas desmolyticum NCIM 2112 (pd2112) within 72 h at static condition. Decolorization time in synthetic 10 g/l molasses. Addition of 5 g/l peptone to NaCl medium had reduced decolorization time from 108 to 72 h. Beef extract do not contribute more to the inducing effect of peptone, however it is a good co-substrate in sucrose or urea containing NaCl medium. Intracellular lignin peroxidase (Lip), laccase and tyrosinase activities were induced by 150, 355 and 212%, respectively till maximum dye removal took place. Aminopyrine N-demethylase (AND) and dichlorophenol indophenol reductase (DCIP-reductase) activities in pd2112 were induced by 130 and 20%, respectively at 72 h of incubation during GHE4B decolorization. By high performance liquid chromatography (HPLC) analysis, 4-hydroxybenzene sulfonic acid and 4-amino, 6-hydroxynaphthalene 2-sulfonic acids were identified as metabolites formed during 24-72 h incubation. Fourier transform infrared spectroscopy (FTIR) analysis supports the formation of these aromatic amines. pd2112, aerobically degraded GHE4B metabolites (formed at static condition) showing stationary phase of 6 days. There was no germination inhibition of Sorghum bicolor and Triticum aestivum by GHE4B metabolites at 3,000 ppm concentration however untreated dye showed germination inhibition at the same concentration. GHE4B metabolites did not show any microbial toxicity at 10,000 ppm concentration. PMID- 23100823 TI - Multiplex PCR assay for the detection of enterotoxic Bacillus cereus group strains and its application in food matrices. AB - Bacillus cereus, Bacillus thuringiensis and Bacillus anthracis are the major concerns for the food safety in terms of frequency and/or seriousness of the disease. Being members of the same group and sharing DNA homology to a larger extent, they do create problems when their specific detection/identification is attempted from different food and environmental sources. Numerous individual polymerase chain reaction (PCR) and few multiplex PCR (mPCR) methods have been employed to detect these organisms by targeting toxin genes but with lack of internal amplification control (IAC). Therefore, we attempted a mPCR with IAC for the detection of enterotoxic B. cereus group strains by selecting hbl A, nhe A and cyt K genes from B. cereus, indicative of the diarrheal potential and cry I A and pag genes, the plasmid borne phenotypic markers specific to B. thuringiensis and B. anthracis strains, respectively. Multiplex PCR assay validation was performed by simultaneous comparison with the results of single-target PCR assays and correlated to the classical conventional and biochemical identification of the organisms. The mPCR was able to detect as low as 10(1)-10(2) organisms per ml following overnight enrichment of spiked food samples (vegetable biriyani and milk) in buffered peptone water (BPW). The presence of these organisms could also be detected by mPCR in naturally contaminated samples of rice based dishes and milk. The high throughput and cost-effective mPCR method described could provide a powerful tool for simultaneous, rapid and reliable detection of enterotoxic B. cereus group organisms. PMID- 23100824 TI - Evaluation of PCR, DNA hybridization and immunomagnetic separation - PCR for detection of Burkholderia mallei in artificially inoculated environmental samples. AB - Glanders is highly contagious disease of equines, caused by Burkholderia mallei. The disease though rare, can be transmitted to humans. Here, we report a strategy for rapid detection of B. mallei from environmental samples. Different bacteriological media were evaluated and brain heart infusion broth medium with selective supplements (BHIB-SS) of penicillin (200 U/ml) and crystal violet (1:10,00000) was found to support the maximum growth of B. mallei even in the presence of other bacteria like Escherichia coli and Staphylococcus aureus. A polymerase chain reaction (PCR) and a DNA hybridization method was standardized for 823 bp specific dNA sequence of B. mallei. To enable the quicker and direct enrichment of B. mallei bacteria from environmental samples, an immunomagnetic separation (IMS) method was also standardized. Water, husk, grass and gram samples were artificially contaminated by B. mallei bacteria and after enrichment of B. mallei in BHIB-SS, detection was carried out by PCR and DNA hybridization. PCR was found to be a better method of the two with a detection limit of 10(4) 10(6) CFU/ml (6 h enrichment in BHIB-SS) in water and other particulate matrices. Detection by PCR in the above samples without enrichment in BHIBSS was carried out following IMS where the detection limit was about 1-2 log higher than PCR following enrichment in BHIB-SS. We recommend PCR for 823 bp for detection of B. mallei from environmental samples either following enrichment in BHIB-SS or IMS. IMS-PCR method may be preferred in situations where numbers of B. mallei bacteria are expected to be high and results are required in short time. PMID- 23100825 TI - Growth and siderophores production in Alcaligenes faecalis is regulated by metal ions. AB - During stationary phase of growth under low stress of iron in succinic acid medium, Alcaligenes feacalis BCCM ID 2374 produced microbial iron chelators. Increase in iron concentration supported bacterial growth but suppressed siderophores production, 1 MUM and 2 MUM of iron was optimum for maximum siderophore yield, i.e. 354 and 360 MUg/ml in untreated and deferrated medium, respectively. Threshold level of iron, which suppressed siderophores production in A. feacalis BCCM ID 2374, was 20 MUM. Ten micromoles and above concentration of CuCl(2) and CoCl(2), and 20 MUM of MgCl(2), MgSO(4), ZnCl(2) and ZnSO(4) severely affected siderophores production. PMID- 23100826 TI - Analysis of volatile aroma constituents of wine produced from Indian mango (Mangifera indica L.) by GC-MS. AB - Volatile aroma compounds are synthesized by wine yeast during wine fermentation. In this study the volatile aroma composition of two varieties of mango wine were determined to differentiate and characterize the wines. The wine was produced from the fruits of two varieties of mango cultivars namely Banginapalli and Alphonso. The volatile compounds formed in mango wine were analyzed by gas chromatography coupled with mass spectrometry (GC-MS). Thirty-two volatile compounds in wines were determined of which four were new and unidentified present in lower concentration. Apart from the ethanol (8.5 +/- 0.28 and 7.2 +/- 0.28% v/v), 1-propanol (54.11 +/- 0.33 and 42.32 +/- 0.57 mg/l), isobutyl alcohol (102 +/- 1.57 and 115.14 +/- 2.88 mg/l) and isoamyl alcohol (123 +/- 2.88 and 108.40 +/- 0.23 mg/1) were found to be the major flavouring higher alcohols in the mango wines produced from the fruits of Banginapalli and Alphonso respectively. Ethyl acetate (35 +/- 0.57 and 30.42 +/-1.15 mg/l) was the major ester component in both wines produced. Besides, other esters like ethyl octonoate, ethyl hexanoate and ethyl decanoate were also present in the wines. Cyclohexane methanol (1.45 +/- 0.11 mg/l) was present only in wine made from Banginapalli and beta-phenylethyl butanoate (0.62 +/- 0.01 mg/1) was found only in Alphonso wine. The results demonstrate that the wine prepared from Banginapalli variety had better aroma composition and good taste than that from the Alphonso variety. PMID- 23100827 TI - Variability in intra-specific and monosporous isolates of Volvariella volvacea based on enzyme activity, ITS and RAPD. AB - Two parents and 15 monosporous isolates were morphologically characterized and were found to vary in their growth characteristics on malt extract agar medium. The isolates also varied in enzymes activity profile with respect to exoglucanase, endoglucanase, xylanase, laccase and polyphenol oxidase. Further in polymerase chain reaction (PCR) amplification of Internal Transcribed Spacer (ITS) region of 5.8S rDNA, an amplicon of same length (720 bp) was amplified from two parents and all the monosporous isolates, which revealed that all belong to the same species. The combined phylogenetic analysis of random amplified polymorphic DNA (RAPD) profiles obtained with five decamer primers (operon kit B) series primers also revealed intra-specific variation of 60% with in the two parent strains and their single spore isolates (SSIs). However, the variations between the parent strains and their SSIs were lesser and it was 50 and 32% in parent strains, OE-210 and OE-12, respectively. Based upon phylogenetic analysis, the isolates of parent strain, OE-210 formed 7 distinct phylogenetic clades, while of strain OE-12 formed 4 clades. The study elucidates that isolates showing variations in morphological growth characteristics and enzymes activity also showed variations in their RAPD profiles, revealed through phylogenetic analysis of RAPD profiles. It is also evident from the study that morphological characterization along with enzymes activity assay of strains is essential before their use in yield evaluation trials with final authentication from molecular analysis. PMID- 23100828 TI - Genetic diversity of Macrophomina phaseolina isolates from certain agro-climatic regions of India by using RAPD markers. AB - Genetic diversity analysis of Macrophomina phaseolina isolates obtained from different host range and diverse geographical locations in India was carried out using RAPD fingerprinting. Of the thirteen 10-mer random primers used, primer OPB 08 gave the maximum polymorphism and the UPGMA clustering could separate 50 isolates in to ten groups at more than 65% similarity level. The ten clusters correlated well with the geographical locations with exceptions for isolates obtained from Eastern and Western Ghats. There was a segregation of isolates from these two geographical locations in to two clusters thus, distributing 10 genotypes in to eight geographical locations. All the isolates M. phaseolina irrespective of their host and geographical origin, exhibited two representative monomorphic bands at 250 bp and 1 kb, presence of these bands suggests that isolates might have evolved from a common ancestor but due to geographical isolation fallowed by natural selection and genetic drift might have segregated in to subpopulations. Genetic similarity in the pathogenic population reflects the dispersal of single lineage in all locations in India. PMID- 23100829 TI - Diversity of methanotrophs in urea-fertilized tropical rice agroecosystem. AB - Laboratory experiments were conducted to study the population size, diversity and methane oxidation potential of methanotrophs in tropical rice agroecosystem under the influence of N-fertilizer. Results indicate that the diversity of methane oxidizing bacteria (MOB) is altered in fertilizer treated soils compared to untreated control. Nevertheless, Type I MOB still dominated in the fertilized soils whereas the diversity of Type II methanotrophs decreases. Control soils have higher MOB population and CH(4) oxidation capacity than fertilized soils. Rhizospheric soil is more populated than non-rhizospheric soil in both unfertilized and fertilized conditions. Variation in K(m) and V(max) of methane oxidation in soils appears to be due to variation in methanotrophic community. Experimental results indicate that methanotrophic community differs both quantitatively and qualitatively in unfertilized and fertilized soils. PMID- 23100830 TI - Sequence analysis of a salt tolerant metagenomic clone. AB - Metagenome represent an unlimited resource for discovery of novel genes. Here we report, sequence analysis of a salt tolerant metagenomic clone (6B4) from a pond water metagenomic library. Clone 6B4 had an insert of 2254 bp with G+C composition of 64.06%. DNA sequence from 6B4 showed homology to DNA sequences from pro-teobacteria indicating origin of 6B4 metagenomic insert from a yet uncharacterized proteobacteria. Two encoded proteins from clone 6B4 showed match with ATP-depen-dent Clp protease adaptor protein (ClpS) and phasin, while two truncated encoded proteins showed match with poly-3-hydroxybutyrate synthase and permease. Clp complex is known to play a role in stress tolerance. Expression of ClpS from metagenomic clone is proposed to be responsible for salt tolerance of the metagenomic clone 6B4. PMID- 23100831 TI - Multiple antibiotic resistance indexing of coliforms to identify high risk contamination sites in aquatic environment. AB - Bacteriological analysis of the water samples collected from upstream, midstream and downstream points along the bank of the river revealed high populations of Escherichia coli, Citrobacter freundii, Citrobacter diversus, Enterobacter aerogens and Klebsiella species. All these isolates were screened against eight antibiotics to determine the prevalence of multiple antibiotic resistance among isolates at different sites of the river. The study revealed that multiple antibiotic resistance was prominently seen in coliforms at downstream sites (Average multiple antibiotic resistance index, MAR Index = 0.43) while it was low in coliforms at upstream sites (MAR Index = 0.15). These differences in MAR indices provide a method for distinguishing high risk contamination sites in aquatic environment. PMID- 23100832 TI - Association of a potyvirus with mosaic disease of gherkin (Cucumis anguria L.) in India. AB - A virus associated with severe mosaic disease of gherkin (Cucumis anguria L.) in south India was identified. The infected plants showed mosaic, vein banding, blistering on malformed leaves and fruits. Host range, transmission, serological and electron microscopic studies were carried out to identify the virus. The virus was readily transmitted by Sap inoculation and by aphids in a non persistent manner. The host range of the virus was mainly limited to cucurbitaceous and chenopodium species. The virus showed positive serological relationships with members of potyvirus genus but not with cucumo, ilar and taspoviruses. Electron microscopy of leaf dip preparation of infected leaves revealed long flexuous filamentous virus particles measuring 750 * 12 nm. On the basis of symptomotology, host range, transmission, serology and particle morphology the virus associated with mosaic disease of gherkin might be the member of potyvirus genus. PMID- 23100833 TI - Isolation, Characterization and Biological evaluation of secondary metabolite from Aspergillus funiculosus. AB - Screening of Aspergillus funiculosus for bioactive secondary metabolites produced kojic acid, which is know to have wide range of biological properties. It is very active against Gram-negative bacteria, such as Pseudomonas aeruginosa and Escherichia coli, but moderately active against yeasts and Gram-positive bacteria except Staphylococcus epidermidis. Filamentous Fungi are more sensitive to kojic acid. When it exposed to larvicidal activity on Aedes aegypti third instar larvae are more sensitive than early fourth instar larvae. PMID- 23100834 TI - Antimicrobial activities of rhizobacterial strains of Pseudomonas and Bacillus strains isolated from rhizosphere soil of carnation (Dianthus caryophyllus cv. Sunrise). AB - Under the present study, an attempt was made to characterize rhizobacteria i.e. Pseudomonas and Bacillus species isolated from rhizosphere of carnation to evaluate their growth promoting effect on carnation so as to select and develop more efficient indigenous plant growth promoting and disease suppressing bioagents of specific soil type and specific plant type. Maximum strains of Pseudomonas and Bacillus sp. showed significant antimicrobial activities against most of the microorganisms tested. On the basis of in vitro antagonistic activities, the best strains were selected and used in field trial to study the influence of these strains on the growth of carnation. Results have shown marked effect on growth parameters and disease incidence has also been reduced significantly. PMID- 23100835 TI - Screening of marine actinobacteria for amylase enzymes inhibitors. AB - Amylase inhibitor producing actinobacteria were isolated and characterized from terrestrial environment and there is no much report found from marine environment, hence in the present study, 17 strains isolated from the rhizosphere sediments of mangroves were tested for their amylase inhibition ability. Seawater requirement test for the growth of actinobacteria found that the strains SSR-3, SSR-12 and SSR-16 requires at least 50% and SSR-6 requires at least 25% seawater for their growth. The inhibition activity of both prokaryotic and eukaryotic amylase was tested by using Bacillus subtilis and Aspergillus niger. The maximum amylase activity (40mm) produced by the A. niger was taken as positive control, when the test actinobacteria strains grown in the medium they inhibited amylase activity and was evidenced by the reduction in inhibition zone (14-37 mm) similarly the amylase produced by the Bacillus subtilis was also recorded maximum (35 mm) amylase activity and was taken as positive control, and the test atinobacterial strains reduced enzyme action(12-33 mm) it varied levals. This indicates that the actinobacteria strains were controlled amylase enzyme activity in both the cases. The strain SSR-10 was highly effective and SSR-8 was less effective in inhibiting eukaryotic amylase produced by A. niger. The strain SSR-2 was effective and SSR-6 showed very less effect in inhibiting the prokaryotic amylase produced by the B subtilis. PMID- 23100836 TI - Modulation of quorum sensing controlled behaviour of bacteria by growing seedling, seed and seedling extracts of leguminous plants. AB - Effect of growing seedling, seeds and seedlings extracts from seven leguminous plants (Pisum sativum, Vigna radiata, Vigna mungo, Cajanus cajan, Lentil culinaris, Cicer arietinum and Trigonella foenum graecum) were screened for their ability to influence quorum sensing controlled pigment production in Chromobacterium violaceum indicator strains (CV12472 and CVO26). Germinating seedling and seedling extracts of only P. sativum (pea) showed inhibition of violacein production. Interestingly, the T. foenum graecum (fenugreek) seed extracts enhances the pigment production. Quorum sensing regulated swarming motility in Pseudomonas aerugionsa PAO1 was reduced by pea seedling extract while enhanced by the fenugreek seed extracts. These findings suggest that plant metabolites of some legumes interact actively with bacterial quorum sensing and could modulate its associated functions. PMID- 23100837 TI - Characterization of a heat stable anti-listerial bacteriocin produced by vancomycin sensitive Enterococcus faecium isolated from idli batter. AB - Lactic acid bacteria (LAB) are known to produce various types of bacteriocins, ribosomally synthesized polypeptides, which have antibacterial spectrum against many food borne pathogens. Listeria monocytogenes, a pathogenic bacterium, is of particular concern to the food industry because of its ability to grow even at refrigeration temperatures and its tolerance to preservative agents. Some of the bacteriocins of LAB are known to have anti-listerial property. In the present study, the bacteriocin produced by vancomycin sensitive Enterococcus faecium El and J4 isolated from idli batter samples was characterized. The isolates were found to tolerate high temperatures of 60 degrees C for 15 and 30 min and 70 degrees C for 15 min. The bacteriocin was found to be heat stable and had anti listerial activity. The bacteriocin did not lost anti-listerial activity when treated at 100 degrees C for 30 min or at 121 degrees C for 15 min. The bacteriocin lost its antimicrobial activity after treating with trypsin, protinase-K, protease and peptidase. PMID- 23100838 TI - Rumen methanogens: a review. AB - The Methanogens are a diverse group of organisms found in anaerobic environments such as anaerobic sludge digester, wet wood of trees, sewage, rumen, black mud, black sea sediments, etc which utilize carbon dioxide and hydrogen and produce methane. They are nutritionally fastidious anaerobes with the redox potential below -300 mV and usually grow at pH range of 6.0-8.0 [1]. Substrates utilized for growth and methane production include hydrogen, formate, methanol, methylamine, acetate, etc. They metabolize only restricted range of substrates and are poorly characterized with respect to other metabolic, biochemical and molecular properties. PMID- 23100839 TI - Immunological detection of bean common mosaic virus in French bean (Phaseolus vulgaris L.) leaves. AB - Bean common mosaic potyvirus (BCMV) is an important seed borne pathogen of French bean. Differential inoculation with bean common mosaic virus at cotylodonary trifoliate leaf stage and pre-flowering stage of crop growth revealed that cotyledonary leaf infection favored maximum disease expression. Under immunosorbent electron microscopy (ISEM) the virus particles of filamentous structure having a diameter of 750 nm (l) and 15 nm (w) were observed. These particles gave positive precipitin tests with polyclonal antiserum of Potato virus Y. PMID- 23100840 TI - MVA recombinants expressing the fusion and hemagglutinin genes of PPRV protects goats against virulent challenge. AB - Peste des Petits Ruminants (PPR) is a highly contagious animal disease caused by the Peste des Petits Ruminants virus (PPRV) belonging to the genus morbillivirus and family Paramyxoviridae. The disease results in high morbidity and mortality in goats, sheep and in some small wild ruminants. The presence of large number of small ruminants reared in endemic areas makes PPR a notorious disease threatening the livelihood of poor farmers. Conventional vaccination using a live, attenuated vaccine gives adequate protection but cannot be used in case of eradication of the disease due to difficulty in differentiation of infected animals from the vaccinated ones.In the present study, we constructed two recombinant viruses using attenuated Modified Vaccinia virus Ankara virus (MVA) namely MVA-F and MVA H expressing the full length PPRV fusion (F) and hemagglutinin (H) glycoproteins, respectively. Goats were vaccinated intramuscularly with 105 plaque forming units (PFU) each of the recombinant viruses and a live attenuated vaccine (RAKSHA PPR) and challenged 4 months later with PPRV challenge virus (10(3) goat LD(50)). All goats were completely protected from the clinical disease. This study gave an indication that mass vaccination of small ruminants with either of the above or both recombinant inexpensive virus vaccines could help in possible eradication of PPRV from endemic countries like India and subsequent seromonitoring of the disease for differentiation of infected animals from vaccinated ones. PMID- 23100841 TI - Identification of HCV genotypes in HCV infected blood donors. AB - HCV infection is a leading cause of chronic liver disease, including cirrhosis of the liver. There are at least six major genotypes and more than 50 subtypes of HCV. The prevalence and distribution of HCV genotypes depend on geographical location. The aim of this study was to identify and compare the HCV genotypes in HCV infected blood donors and patients. In this cross-sectional study, 167 serum samples from 103 blood donors and 64 patients with hepatitis C were investigated for HCV genotypes. HCV genotyping was carried out using type-specific primers from the core region of the viral genome. The highest frequency was for genotype 1a, with 53 and 34 (51.5% versus 53.1%) of subjects in blood donors and patients respectively. Genotype 3a and 1b were the other frequent genotypes with 4 and 16 (3.9% versus 25%) and 39 and 10 (37.9% versus 15.6%) subjects, respectively. There was not any statistical significant association between the place of infection of the patients and genotype. The results of this study indicate that the distribution of genotypes in the two populations was similar. The dominant HCV genotypes between blood donors and patients were 1a, 3a and 1b respectively. PMID- 23100842 TI - Species confirmation of fungal isolates by molecular analysis. AB - Traditional taxonomy of hyphomycetes has been based on conidial morphology and development. In order to confirm species level for the detection and identification of the entomopathogenic fungus, we analysed the species-specific fingerprints to investigate molecular characteristics within isolates of six species and to resolve morphologically atypical isolates. The extent of fingerprint profile observed by RAPD was sufficient to confirm the species level of all the isolates. The genetic similarity among morphologically identified isolates of each species was considerably higher, allowing us to conclude that all the isolates are of same species. These results establish a molecular framework for further taxonomic, phylogenetic and comparative biological investigations. PMID- 23100843 TI - Molecular characterization of lactic acid bacteria recovered from natural fermentation of beet root and carrot Kanji. AB - The lactic acid bacteria (LAB) play an important role in the fermentation of vegetables to improve nutritive value, palatability, acceptability, microbial quality and shelf life of the fermented produce. The LAB associated with beetroot and carrot fermentation were identified and characterized using different molecular tools. Amplified ribosomal DNA restriction analysis (ARDRA) provided similar DNA profile for the 16 LAB strains isolated from beetroot and carrot fermentation while repetitive extragenic palindromic PCR (rep-PCR) genotyping could differentiate the LAB strains into eight genotypes. Thirteen strains represented by five genotypes could be clustered in five distinct groups while three LAB strains exhibiting distinct genotypes remained ungrouped. These genotypes could be identified to be belonging to L. plantarum group by 16S rDNA sequencing. The recAnested multiplex PCR employing species-specific primers for the L. plantarum group members identified the LAB strains of six genotypes to be L. paraplantarum and the other two genotypes to be L. pentosus. Three genotypes of L. paraplantarum were consistently found on the third and sixth day of beetroot fermentation whereas a distinct genotype of L. paraplantarum and L. pentosus appeared predominant on the tenth day. From carrot Kanji two distinct genotypes of L. paraplantarum and one genotype of L. pentosus were identified. REP-PCR DNA fingerprinting coupled with 16S rDNA sequencing and recA-nested multiplex PCR could clearly identify as well as differentiate the diverse L. plantarum group strains involved in the fermentation. PMID- 23100844 TI - Comparative efficacy and pathogenicity of keratinophilic soil fungi against Culex quinquefasciatus larvae. AB - Out of seven fungal species belonging to four genera isolated from pond and wallow soils using feathers of Pavo cristatus as bait, four species viz., Aspergillus flavus, Aspergillus niger, Chrysosporium pseudomerdarium and Trichophyton ajelloi were most frequent. Chrysosporium and Trichophyton spp. were more pathogenic on Culex quinquefasciatus larvae than Aspergillus and Penicillium. The bioefficacy tests conducted as per the protocol of World Health Organization and the LC(50) values calculated by the Probit analysis showed that 3(rd)-instar C. quinquefasciatus were more susceptible to the conidia of above fungi. Highest mortality was observed in the larvae of C. quinquefasciatus when exposed to T. ajelloi. The density of fungal conidia was greatest on the ventral brush, palmate hair and anal region of the mosquito larvae after exposing for 72 hours. The potentiality of these fungi for use in the control of C. quinquefasciatus is discussed which can be exploited as a suitable biocontrol agent in the tropics. PMID- 23100845 TI - Cyclodextrin glucosyltransferase production by Bacillus megaterium NCR: evaluation and optimization of culture conditions using factorial design. AB - Statistically-based experimental designs were used to optimize the production of cyclodextrin glucosyltransferase (CGTase) from a local isolate of Bacillus megaterium using shack culture fermentation. Seven cultural conditions were examined for enzyme production and specific activity using Plackett-Burman factorial design. Fermentation time and K(2)HPO(4) level were the crucial for factors improving enzyme production process. The steepest ascent design was adopted-based on the results recorded with Plackett-Burman design. Maximal enzyme estimates (activity 56.1 U/ml, and specific activity 62.7 U/mg protein) were achieved. A verification experiment was carried out to examine model validation of this optimization. PMID- 23100846 TI - Partial purification and properties of a laundry detergent compatible alkaline protease from a newly isolated Bacillus species Y. AB - Alkaline protease production by a newly isolated Bacillus species from laundry soil was studied for detergent biocompatibility. From its morphological and nucleotide sequence (about 1.5 kb) of its 16S rDNA it was identified as Bacillus species with similarity to Bacillus species Y (Gen Bank entry: ABO 55095), and close homology with Bacillus cohnii YN-2000 (Gen Bank entry: ABO23412). Partial purification of the enzyme by ammonium sulfate (50-70% saturation) yielded 8-fold purity. Casein zymography and Sodium dodecylsulphate-Polyacrylamide gel electrophoresis (SDS-PAGE) of the partially purified enzyme revealed two isozymes of molecular sizes approximately 66 kDa and 18 kDa, respectively. The enzyme was most active at pH 12 and 50 degrees C. At pH 12 the enzyme was stable for 5 h and retained 60% activity. The enzyme retained 44% activity at 50 degrees C up to 2 h. The protease showed good hydrolysis specificity with different substrates tested. The presence of Mn(2+), Co(2+) and ethylenediaminetetracetic acid (EDTA) showed profound increase in protease activity. The protease of Bacillus species Y showed excellent stability and compatibility with three locally available detergents (Kite, Tide and Aerial) up to 3 h retaining almost 70-80% activity and 10-20% activity at room temperature (30 degrees C) and 50 degrees C, respectively, indicating the potential role of this enzyme for detergent application. PMID- 23100847 TI - Production and partial purification of invertase using Cympopogan caecius leaf powder as substrate. AB - The present study investigates the efficiency of Aspergillus niger to produce invertase, an industrially important enzyme by using powdered stem of Cympopogan caecius (Lemon grass) as sole substrate and sole carbon source for the microorganism. The molecular weight of invertase was estimated to be 66-70 kDa by sodium do decyl sulphate poly acrylamide gel electrophoresis (SDS PAGE). The production of the enzyme was studied at different pH scales ranging from pH 4.0 to 7.0 at a constant temperature of 30 degrees C and 2% substrate concentration. The maximum production of invertase (specific activity -0.0516 MUk/mg protein) was obtained at pH 5.5 at 30 degrees C temperature, and incubation for 48 h. The activity was found to be stable at pH 5.5 for 30 min. The enzyme was found to be stable in the temperature range of 20-55 degrees C. The effect of divalent metal ions Cu(2+), Fe(2+), Co(2+) on the activity of the enzyme invertase showed that these ions affected the activity by a certain factor. The study can be further industrially exploited in a country-like India where lemon grass is found in plenty and can be used as substrate for enzyme production. Moreover, the preparation of the substrate is also a simple process. PMID- 23100848 TI - Influence of micronutrients on yeast growth and beta-d-fructofuranosidase production. AB - beta-d-fructofuranosidase is one of the most important enzymes of the food industry especially due to its application in preparation of soft centered candies, confectioneries and to produce fructose syrups. Although several bacteria and filamentous fungi are reported for its production, yeasts are the most preferred source for this enzyme. In the present study mineral nutrients were screened for their effect on yeast growth and the enzyme production using Plackett-Burman design. Of the 11 nutrients screened, three variables (KH(2)PO(4), FeCl(3) and CoCl(2)) were significantly effecting yeast growth while six variables, i.e. KH(2)PO(4), CaCl(2), MnSO(4), Na(2)MoO(4), ZnSO(4) and CoCl(2) had significant effect on enzyme production. PMID- 23100849 TI - Enzymatic bleaching of kraft pulp by xylanase from Aspergillus sydowii SBS 45. AB - Crude xylanase from Aspergillus sydowii SBS 45 was tested for enzymatic bleaching of kraft (Decker) pulp. After optimization of three parameters, consistency of pulp, retention time and enzyme dose, considerable increase in the release of UV and visible absorbance spectra of materials and reducing sugars was observed, which clearly indicated the action of xylanase on pulp. Final brightness of pulp was increased from 29.42 to 70.42% and kappa number was reduced from 15.93 to 1.61, when 25 U of xylanase was given with a retention time of 5 h and at a consistency of 10%. When 10 U g(-1) xylanase was given, 14.3% elemental chlorine and 14.3% H(2)O(2) could be reduced and when 25 U g(-1) xylanase was given 14.3% elemental chlorine and 28.6% H (2)O(2) could be reduced thereby retaining the brightness at control level. PMID- 23100850 TI - Fungal isolates from natural pectic substrates for polygalacturonase and multienzyme production. AB - Pectin rich wastes and waste dump yard soils were screened and eighty pectinolytic fungal isolates were obtained by enrichment culturing and ruthenium red plate assay. Eight isolates with higher zones of pectin hydrolysis were selected and tested for polygalacturonase production. One isolate identified as Aspergillus awamori MTCC 9166 with highest polygalacturonase activity was tested for utilization of raw pectins for enzyme production. Polygalacturonase production was high in raw pectin sources like Orange peel (16.8 U/ml) Jack fruit rind (38 U/ml) Carrot peel (36U/ml) and Beet root peel (24U/ml). Selected Aspergillus awamori MTCC 9166 was found to be having good polygalacturonase, xylanase, cellulase and weak amylase and protease activities. This isolate with multi-enzyme production could have application for enzymes production and degradation of fruit and vegetable waste in the process of urban waste disposal. PMID- 23100851 TI - Re-emergence of glanders in India - Report of Maharashtra state. AB - Glanders, a notifiable highly contagious disease primarily of equids, is a disease of high zoonotic importance. Caused by gram-negative bacillus, Burkholderia mallei, the disease was restricted to certain pockets of India with sporadic cases. Recently, a major outbreak of glanders occurred in India starting from Maharashtra. Following clinical signs and symptoms and laboratory investigations on serum, nasal swab and pus swab samples, it was confirmed as glanders among equines in Pune and Panchgani areas of Maharashtra. One pus sample and three nasal swabs yielded B. mallei isolates while 23 serum samples were found positive for glanders by complement fixation test (CFT). The disease was successfully controlled in the state by following strategies for prevention of spread of the disease to other areas in accordance with Glanders and Farcy Act, 1899. Follow up of the occurrence in Maharashtra revealed negative status based on testing and physical surveillance on more than 3,500 equines thereafter. Investigations indicated that the nidus of infection may be present elsewhere in North India. PMID- 23100852 TI - Cow dung extract: a medium for the growth of pseudomonads enhancing their efficiency as biofertilizer and biocontrol agent in rice. AB - Some pseudomands are being utilized as biofertilizers and biopesticides because of their role in plant growth promotion and plant protection against root parasites, respectively. Two strains of Pseudomonas, P. jessenii LHRE62 and P. synxantha HHRE81, recovered from wheat rhizosphere, have shown their potential in field bioinoculation tests under rice-wheat and pulse-wheat rotation systems. Normally, pseudomonads are cultivated on synthetic media-like King's B and used for inoculation on seeds/soil drench with talcum or charcoal as carrier material. Cow dung is being used for different purposes from the ancient time and has a significant role in crop growth because of the content in humic compounds and fertilizing bioelements available in it. Here, cow dung extract was tested as a growth medium for strains LHRE62 and HHRE81, in comparison with growth in King's B medium. The log phase was delayed by 2 h as compared to growth in King's B medium. The bacterial growth yield, lower in plain cow dung extract as compared to King's B medium, was improved upon addition of different carbon substrates. Growth of rice var. Pant Dhan 4 in pot cultures was increased using liquid formulation of cow dung extract and bacteria as foliar spray, compared to their respective controls. Biocontrol efficacy of the bioagents was assessed by challenging rice crop with Rhizoctonia solani, a sheath blight pathogen. The growth promotion and biocontrol efficiencies were more pronounced in the case of mixed inocula of strains LHRE62 and HHRE81. PMID- 23100853 TI - Effect of Glomus species on physiology and biochemistry of Catharanthus roseus. AB - The present study on efficacy of different Glomus species, an arbuscular mycorrhizal (AM) fungus (G. aggregatum, G. fasciculatum, G. mosseae, G. intraradices) on various growth parameters such as biomass, macro and micronutrients, chlorophyll, protein, cytokinin and alkaloid content and phosphatase activity of pink flowered Catharanthus roseus plants showed that all Glomus species except G. intraradices enhanced the chlorophyll, protein, crude alkaloid, phosphorus, sulphur, manganese and copper contents of C. roseus plants along with phosphatase activity significantly over uninoculated plants. However only G. mosseae and G. fasciculatum exhibited superior symbiotic relationship with the plant. G. mosseae was found to be the best for increasing the crude alkaloid content (8.19%) in leaf and also in increasing the quantity of important alkaloids vincristine and vinblastine. PMID- 23100855 TI - Visual attention, behavioral inhibition and speech/language outcomes in deaf children with cochlear implants. AB - We investigated relations between sustained visual attention, behavioral inhibition skills, and speech-language outcomes in prelingually deaf children who use cochlear implants (CIs) using two computerized continuous performance tasks (CPTs). One test measured their ability to sustain visual attention to a string of numbers and another test measured their ability to delay a behavioral response. Performance on latter task was related to postimplant scores on tests of vocabulary knowledge, language skills, and speech intelligibility. We conclude that behavioral inhibition skills of prelingually deaf children are related to several audiological outcome measures in deaf children with CIs. Our findings suggest that further investigation is warranted into executive functions and subvocal rehearsal skills of deaf children with CIs. PMID- 23100854 TI - Emotion-Related Self-Regulation in Children. AB - In this article, the authors review basic conceptual issues in research on children's emotion-related self-regulation, including the differentiation between self-regulation that is effortful and voluntary and control-related processes that are less amenable to effortful control. In addition, the authors summarize what researchers know about developmental changes in self-regulatory capacities, give examples of various methods used to assess these abilities, and summarize findings on the relations between self-regulation or effortful control and positive adjustment and maladjustment. Finally, the authors discuss some strategies for effectively teaching students about emotion regulation. PMID- 23100856 TI - Clickable Amphiphilic Triblock Copolymers. AB - Amphiphilic polymers have recently garnered much attention due to their potential use in drug-delivery and other biomedical applications. A modular synthesis of these polymers is extremely desirable since it offers precise individual block characterization and increased yields. We present here for the first time a modular synthesis of poly(oxazoline)-poly(siloxane)-poly(oxazoline) block copolymers that have been clicked together using the copper-catalyzed azide alkyne cycloaddition reaction. Various click methodologies for the synthesis of these polymers have been carefully evaluated and optimized. The approach using copper nanoparticles was found to be the most optimal among the methods evaluated. Furthermore, these results were extended to allow for a reactive Si-H group-based siloxane middle block to be successfully clicked. This enables the design of more complex amphiphilic block copolymers that have additional functionality, such as stimuli responsiveness, to be synthesized via a simple hydrosilylation reaction. PMID- 23100857 TI - Mussel foot protein-1 (mcfp-1) interaction with titania surfaces(). AB - Marine mussels utilize a variety of DOPA-rich proteins for purposes of underwater adhesion, as well as for creating hard and flexible surface coatings for their tough and stretchy byssal fibers. In the present study, moderately strong, yet reversible wet adhesion between the protective mussel coating protein, mcfp-1, and amorphous titania was measured with a surface force apparatus (SFA). In parallel, resonance Raman spectroscopy was employed to identify the presence of bidentate DOPA-Ti coordination bonds at the TiO(2)-protein interface, suggesting that catechol-TiO(2) complexation contributes to the observed reversible wet adhesion. These results have important implications for the design of protective coatings on TiO(2). PMID- 23100858 TI - IFCC methods for the measurement of catalytic concentration of enzymes part 9. IFCC method for alpha-amylase (1-4-alpha-D-Glucan 4-Glucanohydrolase, ec 3.2.1.1). PMID- 23100859 TI - Current concepts of thyroid function and laboratory evaluation. AB - The role of triodothyronine (T(3) in regulating thyroid function is paramount in that at cellular level it interacts with receptors in the nucleus and thereby modulates gene expression. The multiple steps in the processing of lodide by the thyroid gland is under the influence of the thyroid stimulating hormone (TSH). In terms of laboratory evaluation of thyroid function the primary test is TSH. To discriminate between hypothalamic and pitutary dysfunction, the thyroid releasing hormone (TRH) stimulation test is useful. Currently used 2-site Immunometric procedures that employ mouse monoclonal antibodies can be subject to Interference by heterophlle antibodies in patient's serum. Drugs and other extraneous substances can influence the results obtained in some thyroid function tests. Thyroid dysfunction could also be due to autoimmune disease. The limitations of the usefulness of thyroid function tests in non-thyroidal illness should be kept in perspective. In conclusion, the proper interpretation of results of thyroid function tests depends on the sound understanding of concepts of thyroid function and variables affecting laboratory testing. PMID- 23100860 TI - Thyroid autoantibody measurement by enzyme immunoassay. AB - Thyroid antibodies are commonly utilized in the assessment and diagnosis of autoimmune thyroid disorders. We compared the measurements of antithyroglobulin and antithyroidperoxidase antibodies by enzyme immunoassay with that of the conventional agglutination method. This fully automated enzyme immunoassay is more specific and cost effective than the agglutination method. Further this is a very quantitative and rapid method producing results in two hours as compared to at least twenty=four hours required by the conventional method. Antithyroidperoxidase antibodies determined by enzyme immunoassay are more specific and sensitive in the diagnosis of Hashimoto's thyroiditis than the antithyroglobulin antibodies. PMID- 23100861 TI - Interference of anti-T3 autoantibodies in the measurement of total and free T3 in serum. AB - A case of anti-trilodothyronine autoantibodies is presented in this report. The thyroid hormone profile of a hypertensive patient, with multinodular goiter and history of exogenous thyroid hormone therapy, was found to be highly ambiguous. The total as well as free T3 levels were consistently high (out of range) whereas the T4 (total and free) values were always within normal limits. The thyrotropin was found to be partially suppressed. Very low T3-Uptake indicated some kind of interference in the immunoassays. We incubated the sera with the radio-iodine labelled T3 and observed that the patient's serum bound about ten times more radioactivity than a control run in parallel. On further resolving the serum proteins on cellulose acetate electrophoresis, the radioactivity was detected in the gamma-globulin band. Therefore it was established that the patient's serum carried the antibodies reactive with T3 which were interfering in the immunoassays. Elevated anti-thyroid microsomal antibodies were also present in the patient's serum. The anti-T3 antibodies were highly specific for T3 and did not show any cross reactivity with the T4 or its analogues used in the estimation of free T4. PMID- 23100862 TI - A comparative study on the effects of Gemfibrozil, Diltiazem and Isosorbide dinitrate on lipid profile in patients of ischemic heart disease in India. AB - Effects of three drugs, Gemfibrozil, Diltiazem and lsosorbide dinitrate (ISDN) on various lipid parameters were studied in patients with ischemic heart disease (IHD) with positive treadmill stress response. Gemfibrozil and diltiazem significantly lowered the levels of serum total lipids (TL), triglycerides (TG), phospholipids (PL), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C), and incroased the levels of serum high density lipoprotein cholesterol (HDL-C) significantly. However, patients administered with ISDN showed a significant increase in all the lipid parameters except HDL-C, which showed a significant decrease. PMID- 23100863 TI - Characterisation of the canine cardiac sarcolemma in experimental myocardial ischemia. AB - The cardiac sarcolemma was characterized in 13 normal and 11 ischemic dog hearts by enzyme analysis and compositional assays. Significant decreases in the activities of the sodium-potassium and calcium pumps and structural compositional disturbances were observed in ischemia. High concentrations of oleic acid, a fatty acid and palmitoyl carnitine, a fatty acid intermediate caused inhibition of the enzyme pump activities of the normal sarcolemma. Thus, ischemia results in the functional impairment of the sarcolemma. Accumulation of fatty acid and fatty acid intermediates, occurring in myocardial ischemia, could be an underlying mechanism. PMID- 23100864 TI - Hypolipidemic effect ofAlpinia galanga (Rasna) andKaempferia galanga (Kachoori). AB - The rhizome of bothAlpinia galanga andKaempferia galanga are widely used in the Ayurvedic system of medicine in the treatment of various inflammatory diseases, diabetes mellitus and obesity. Present study evaluated the hypolipidemic action of the ethanolic extract of these plantsin vivo. The oral administration of the extracts (20mg/day) of bothA. galanga andK. galanga effectively lowered the serum and tissue levels of total cholesterol, triglycerides, phospholipids and significantly increased the serum levels of high density lipoproteins(HDL) in high cholesterol fed white wistar rats over a period of 4 weeks. The results are indicative of these plants in various lipid disorders especially atherosclerosis. PMID- 23100865 TI - Binding and degradation of native and acetylated low density lipoproteins by monocyte derived macrophages of normal and hypercholesterolemic rabbits. AB - Low density lipoprotein (LDL) was isolated from normal rabbits and was modified with acetic anhydride. Blood monocyte derived macrophages from normal and hypercholesterolemic (HC) rabbits were cultured, and on the 8th day the cells were incubated with native and modified LDL to study their binding and degradation. Macrophages from both normal and hypercholesterolemic rabbits express a limited number of receptors for normal plasma LDL whereas they exhibit a large number of receptors for acetyl LDL. There was no significant difference between binding and degradation of acetyl LDL by normal or hypercholesterolemic cells. However, binding and degradation of native LDL by monocytes of hypercholesterolemic cells were significantly less (p<0.0001) in comparison to binding and degradation of native LDL by normal cells indicating that there is a feedback inhibitory pathway in the cell that inhibits the synthesis of LDL receptors in the presence of excess LDL. PMID- 23100866 TI - Glycoprotein components in the serum of patients with cancer breast. AB - The levels of total sialic acid, lipid bound sialic acid and fucose were estimated in the sera of patients with benign and malignant tumours of breast. An increase was noted in all the three parameters, with a more marked increase in malignancy, when compared with benign and controls. Consequent to surgery, there was an elevation in the serum levels of the above parameters than the values prior to surgery and a decline was noted two months after surgery although none of the values reached the normal range. These results suggest a close association of the glycoproteins with the tumour burden and further signify their role in early detection and staging of cancer breast. PMID- 23100867 TI - Modified method for determination of serum beta-glucuronidase: A comparative study using P-nitrophenyl glucuronide and phenolphthalein glucuronide as substrate in gastrointestinal tract carcinomas. AB - Serum beta-glucuronidase activity was estimated by our modified method using two substrates phenolphthalein glucuronide and p-nitrophenyl glucoronide in 49 healthy subjects and 94 patients with gastrointestinal tract (GIT) carcinoma. The correlation coefficient using the two substrates was found to be r=0.8383. The method of Gabor Szasz was modified wherein the incubation time was decreased from 5 hours to 2 hours and the incubation temperature was increased from 25 degrees C to 37 degrees C. The increase in beta-glucuronidase activity in GIT carcinoma appears to be a good biochemical marker in patients with such type of carcinomas, a finding not reported in literature to-date.The modified quantitative method used for estimation of beta-glucuronidase is reliable, accurate, simple and rapid. PMID- 23100868 TI - Diagnostic potential of fractionatedMycobacterium tuberculosis H(37)R(a) excretory-secretory (EST-DE(1)) antigen in pulmonary tuberculosis. AB - Tuberculosis is emerging as a major public health problem in developing and developed world. Early and precise diagnosis is of prime importance in successful control of infection. Indirect ELISA with penicillinase as marker was developed using purifiedM. tuberculosis excretory-secretory (EST-DE(1)) antigen for detecting IgG antibodies in pulmonary tuberculosis. The assay System gave a overall sensitivity of 82% for both smear positive and smear negative pulmonary tuberculosis cases with a specificity of 84%. The positive and negative predictive values were 75% and 88% respectivaly. Further studies with EST-DE(1) antigen revealed that, it contains two of the active antigen fractions of Mtb EST antigen i.e. Mtb EST-4 (56-68 KDa) and Mtb EST-6 (37-45 KDa), as demonstrated by inhibition ELISA. Reactivity with monoclonal antibodies HGT 3a showed the presence of 38 KDa molecule in EST-DE(1) antigen. PMID- 23100869 TI - A simple method for inhibition free PCR amplification of target DNA directly from clinical specimens. PMID- 23100870 TI - Lipid abnormalities in chronic renal failure. AB - Lipid abnormalities remain to be a major cause of early mortality in patients with chronic renal failure (CRF). In present study, 114 (one hundred fourteen) CRF patients without any additional cause of dyslipidemia were divided into groups on the basis of etiologies of CRF. Blood samples from each group were analyzed for total cholesterol, triglyceride and HDL cholesterol along with blood urea nitrogen and serum creatinine. 25 healthy individuals without any obvious disease were taken as control. Patients from all the groups showed a marked hypertriglyceridemia of 232 (SD+/-77) mg/dl (P<0.001) as compared to control. Levels of HDL cholesterol were found to be significantly low 20 (+/-11) mg/dl (p<0.001) in all the groups. LDL cholesterol showed an increase 104 (+/-30) mg/dl as compared to control group which is not statistically significant. Present study reveals that, CRF patients show an uniform dyslipidemia irrespective of etiologies leading to CRF. This dyslipidemia is also independent of serum creatinine levels. Although, these lipid abnormalities may not solely cause mortality in CRF patients, they may act as modulators in accelerating atherogenesis which in turn cause early mortality in CRF patients. PMID- 23100871 TI - Modulation of convulsive threshold of pentylene tetrazole by zinc. AB - In the present study which was aimed to see the effect of zinc on pentylenetetrazole induced convulsive threshold in rats we found that zinc sulfate 100 MUg intracerebroventricularly) and pentylenetetrazole (50 mg/kg intraperitoneally) produced dose related seizure activity; however, pretreatment with zinc decreased the threshold, increased the severity, incidence of multiple seizures and total duration of pentylenetetrazole induced seizures. Diazepam (5 mg/kg intraperitoneally) pretreatment increased the threshold and lowered the incidence of convulsions in zinc induced seizures which further confirms that the convulsive effect of zinc is through inhibition of gamma aimino butyric acid. PMID- 23100872 TI - Evaluation of the changes in serum iron levels in pre-eclampsia. AB - Serum iron levels were studied in 50 patients with pre-eclampsia and the results were compared with 50 control cases. Their serum iron levels were found to be higher than the controls. Increase in serum iron was directly proportional to the increased levels of uric acid, urea and creatinine. Mean reticulocyte counts, plasma free haemoglobin and unconjugated bilirubin levels were also higher in these patients. It is suggested that haemolysis may be a major contributory factor for the increased levels of serum iron in pre-eclampsia. PMID- 23100873 TI - Standardization of a colorimetric method for the determination of fructose using o-cresol: Sulphuric acid reagent. AB - Fructose developed a pinkish orange chromogen on treatment with o-cresol: 70% sulphuric acid at 32 degrees C for 15 minutes with a lambda max of 500nm. Fructose was 185 times more chromogenic than glucose. Total carbohydrate and fructose values in protein-free filtrate of normal serum samples were in the range, 55.4-86.3 mg/dl and 1.55-3.29 mg/dl, respectively. In diabetes, the observed values were 197-354 mg/dl and 2.91-6.81 mg/dl, respectively. PMID- 23100874 TI - Utility of serum lysosomal enzyme assay in the detection of cerebral sphingolipidoses in patients with progressive neurologic dysfunction. AB - The cerebral sphingolipidoses which form part of a larger group of lysosomal disorders can be detected and conclusively confirmed by the demonstration of the relevent enzyme deficiency in easily available tissue samples like serum. We have assayed acid beta-galactosidase, beta-hexosaminidase and its isozymes hexosaminidase A and B, and arylsulfatase A in the serum of patients with progressive cerebral dysfunction and detected 18 patients with enzyme defects, thereby confirming the diagnosis of a specific type of cerebral lipidosis in these patients. The assay of serum lysosomal enzymes was of immense diagnostic use as it obviated the need for highly invasive techniques like a brain biopsy. PMID- 23100875 TI - Lipid metabolism in tumour bearing mice treated withAeromonas L-asparaginase. AB - The anticancerous drug isolated in our laboratory from estuarineAeromonas was characterised and is found to be an enzyme, L-asparaginase. The antileukaemic effect of this drug was studied in mice by inducing leukaemia with Ehrlich ascites cell lines. It was compared with commercially available drug, Leunase, isolated fromE. coli. The lipid profiles in mice during leukaemia and under treatment was studied. The decreased levels of cholesterol and increased levels of triglycerides and phospholipids in serum, liver and kidney were observed in tumour bearing mice. Significant changes in the above values were observed with enzyme therapy. It could bring some of the values to near normal level. L asparaginase fromAeromonas was found to be more effective. PMID- 23100876 TI - Polymorphonuclear leukocytic sialic acid and sialidase activity in obesity. AB - The level of sialic acid in the obese polymorphonuclear leukocytes (PMNL) was found to be significantly reduced as compared to normal. Activity of sialic acid degrading enzyme, sialidase, was found to be increased in the obese state. Restoration in both sialic acid content and sialidase activity was also evidenced in the PMNL of treated obese patients. PMID- 23100877 TI - Biochemical changes during exchange transfusion in hyperbilirubinemia in term newborn babies. AB - Double volume (170 ml/kg body weight) exchange transfusion was done in 52 term infants in the first week of life for neonatal hyperbilirubinemia. The M:F ratio was 1.08:1 and 37 (71.1%) babies were of low birth weight. Causes of jaundice were hemolytic in 46.2% and non-hemolytic in 41.3% cases; in 13.5% babies no cause of jaundice could be found. After exchange transfusion a fall of 14.6% and 47.4% was observed in the hemoglobin and serum bilirubin levels respectively. There was significant (p=0.0414) rise in the mean mid exchange and post-exchange serum sodium levels as compared to pre-exchange values and it was found to be due to higher donor's serum sodium levels (p=0.007). There was no effect on the serum potassium levels during or after ET.In general serum calcium levels significantly increased at mid-exchange period (p=0.0029) but post-exchange levels were same as pre-exchange. Donor's serum calcium level had no effect on the infant's serum calcium level (p=0.993). There was no change in the serum phosphate and blood urea levels during and after exchange-transfusion. The plasma glucose was significantly raised during and after ET and plasma glucose of the donors had significant effect on the infant's plasma glucose levels (p=0.043). Similarly plasma osmolality also showed significant increase during and after ET which was due to the effect of donor's plasma osmolality (p=0.007). PMID- 23100878 TI - Vitamin E status in protein energy malnutrition. AB - Serum vitamin E and cholesterol concentrations were measured in 50 children with protein energy malnutrition (PEM) and results were compared with a group of 50 normal controls. Mean serum vitamin E concentration as well as vitamin E/cholesterol ratio were found to be reduced in children with PEM while their mean serum cholesterol level was not significantly different from the control group. Data suggest that the reduced levels of serum vitamin E in PEM may be a result of malnutrition per se. PMID- 23100879 TI - Urinary iodine levels in three ecological zones of Bangladesh. AB - Urinary iodine levels in children (5-11 years) and in adult males and females (15 44 years) of three ecological zones (hilly, flood-prone and plains) of Bangladesh were analyzed to determine the status of biochemical iodine deficiency in the country. Data indicated that a large majority of the population all over Bangladesh have biochemical iodine deficiency urinary iodine excretion (UIE) less than the accepted cut-off level of 10 MUg/dl. Adults were deficient to comparable degrees, 31.3% severely iodine deficient. The flood-prone zone was less affected: 71.7% children had iodine deficiency and 25% were severely deficient. Adults of this zone were less affected than the children. Iodine deficiency was least severe in the plain zone: 59.8% children were biochemically iodine deficient and of them 23.4% had UIE less than 2.0 MUg/dl. In the case of the adults of this zone, 60.8% were biochemically iodine deficient and 20.6% had severe iodine deficiency. The results indicate that Bangladesh as a whole is an iodine deficient region, with the hilly zone being the most severely affected. Children were slightly more affected than the adults, and females were more affected than the males. PMID- 23100880 TI - Preparation of lyophilised lipid rich quality control serum by isolating lipids using large scale chromatography technology. AB - The plasma fractionation is a technology to separate therapeutic plasma proteins. The fractionation is carried out either by solvent precipitation (ethanol) or recently by chromatography. During the process of chromatography lipids were found in waste fraction. A new lipid rich lyophilised quality control (Q.C.) sera was prepared inexpensively using this waste plasma fraction. This is probably the first attempt to prepare the Q.C. sera by large scale chromatographic method in India. PMID- 23100881 TI - Method evaluation of an enzymatic method for serum creatinine. AB - Selecting the correct method for routine analysis by 'method evaluation' is an important component of quality assurance. It is a step-wise procedure that evaluates various analytical parameters like accuracy, precision etc of the given method. Finally reference intervals are established for selected population. We evaluated an enzymatic method for serum creatinine. The results show that it is an acceptable method based on the above mentioned criteria. PMID- 23100882 TI - Detection of non-deletional type of hereditary persistence of fetal hemoglobin (HPFH) condition associated with 619 bp beta( degrees )-thalassemia deletion. AB - DNA samples from a family (parents and a son) with hereditary persistence of fetal hemoglobin (HPFH) condition were subjected to amplification of a 1.214 kbp DNA fragment from beta-globin gene using polymerase chain reaction (PCR). The aim of this study was to identify the type of HPFH i.e. deletional or non deletional. Non deletional type of HPFH was identified in two samples and moreover, these samples were found to be associated with 619bp beta( degrees )-thalassemia deletion. This is the first report on the association of non deletional HPFH with 619bp beta( degrees )-thalassemia deletion. PMID- 23100883 TI - Hereditary methaemoglobinaemia due to Cytochrome b-5 reductase deficiency-A case report. PMID- 23100884 TI - From the editor's desk. PMID- 23100885 TI - In vitro released antigens in diagnosis and immunomonitoring of filaria and tuberculosis. AB - In vitro released antigens by living parasites or bacteria underin vitro maintenance or short term culture showing specific humoral immune response have been explored in development of immunodiagnostics for infectious diseases such as filariasis and tuberculosis in our laboratory. ELISA usingB. malayi mf ES antigen has been explored for detecting IgG antibody by Indirect ELISA and antigen by Inhibition ELISA and in immunomonitoring of carriers as well as clinical filarial cases. A ten year follow up of mf carriers with DEC therapy showed disapperance of antigen and antibody followed by reappearance in few cases in an endemic area. None of the cases followed developed clinical symptoms suggesting the need for long term monitoring and treatment of microfilaraemic carriers. Further immunomonitoring was found to be useful in confirming filaria aetiology in the absence of microfilaremia and determining appropriate period of treatment of acute, early clinical and occult filarial infections for clinical relief and cure.Indirect Stick Penicillinase ELISA system using Mtb EST-6 antigen for detecting tuberculous IgG antibody and a Sandwich Penicillinase ELISA system using affinity purified antibody for detecting circulating antigen were explored in tuberculosis. A combination of both the assay systems with a sensitivity of 70% and specificity of 98% was found to be promising in the precise diagnosis of pulmonary tuberculosis. Further antigen detection was found to be useful in bone and joint tuberculosis. PMID- 23100886 TI - Immunodiagnosis of human lymphatic filariasis: A review. AB - A monoclonal antibody-based antigen detection system was used to detect the levels of circulating antigen in filarial patients before and after treatment with DEC and in normal individuals living in an area endemic forW. bancrofti infection in Chennai, India. The present study was to show the use of this assay as a means of efficient screening for filariasis in an endemic area where blood was absorbed onto the filter paper by finger prick during day time. The results of the antigen levels collected onto filter strips correlated with their corresponding plasma antigen levels (r=0.83). In microfilaraemics, DEC treatment did not alter the levels of circulating antigens upto a period of one month. We conclude that this monoclonal antibody based ELISA using filter strips may be used in daytime and can replace the existing routine night blood survey. PMID- 23100887 TI - Detection of filarial antibody using an fiber optics immunosensor (FOI). AB - Optical waveguides based immunoassay has been reported in the literature for the detection of pathogens likeC. botulinum and F1 antigen ofY. pestis (3) and also for the antibodies to pathogens like the Rubella virus (4) in the serum or the whole blood. In this line we have demonstrated the FOI for the detection ofS. digitata antibody. Experiments are in progress in our laboratory to standardise the sensor for detection of Bancroftian filariasis caused byW. bancrofti. Few modifications are also in the process so as to improve the signal amplification at evanescent region as well as to reduce the two step method into single step method. The FOI has an advantage over other conventional methods because no extensive washing steps are required and the whole procedure takes just 15 minutes to get the result. The FOI designed for this experiment can be made portable for use in the field level for epidemiological studies. PMID- 23100888 TI - Surgical management of manifestations in filariasis. PMID- 23100889 TI - Transglutaminase as a target for novel anti-filarial agents. AB - A rational approach for developing effective filaricides awaits greater knowledge on the biochemical pathways operating in filarial parasites. For example, metabolic pathways or key enzymes that are so pivotal to the parasite that their interruption or inhibition causes spontaneous death, could be exploited to develop effective chemotherapeutic agents. Similarly, developing a safe and nontoxic filaricidal will require precise understanding of whether or not the potential molecular target in the parasite is unique or at least different enough from the host system. Recently, we identified a novel transglutaminase enzyme (EC2.3.2.13; TGase) in filarial parasites that plays an important role during their normal growth and development. Based on these principles, TGase may serve as a new target for the development of effective chemotherapeutic agent and vaccine for controlling and preventing the infections caused by these parasites. PMID- 23100890 TI - Cellular responses toBrugia infections inMeriones unguiculatus. PMID- 23100891 TI - Modulation of cellular immune response by cytokines in bancroftian filariasis. AB - Human lymphatic filariasis is a chronic helminth infection caused byWuchereria bancrofti andBrugia malayi. Wide spectrum of clinical manifestations are seen in different clinical groups of filariasis patients which comprises asymptomatic patients with circulating microfilaria (MF), individuals with chronic lymphatic obstruction (CP), Endemic normals (EN) who are asymptomatic and amicrofilaraemic or the relatively rare tropical pulmonary eosinophilia (TPE). The cellular immune response to this infection varies in different clinical groups of filarial patients. ranging from normal lymphocyte proliferative response in EN individuals to lymphocyte hyporesponsiveness in MF to total parasite antigen [Brugia malayi antigen (BMA)]. But in response to recombinant filarial antigen (pRJ51) the lymphocyte proliferation is restored in MF patients. Interestingly the lymphocytes from MFs responded normally to parasite antigen when EN serum was added in the culture whereas sera from MFs failed to revert the lymphocyte hyporesponsiveness. In order to study the molecular mechanisms responsible for parasite antigen specific lymphocyte hyporesponsiveness, we analysed both the Th1 and Th2 type cytokine gene expression profile in different clinical groups of filarasis patients. MF individuals expressed elevated Th2 type cytokines like IL 4, IL-5 and IL-10 and decreased levels of IL-2 and IFN-gamma in response to parasite antigen. Chronic patients have elevated levels of both Th1 and Th2 type cytokines in response to parasite antigen. The EN individuals had a purely Th1 type pattern with absence of IL-4 and IL-5 expression. These studies clearly demonstrate the role of Th2 cytokine like IL-10 in antigen specific hyporesponsiveness seen in MF patients. Any methods to arrest the progression of this disease should concentrate on the means to revert the Th2 type into Th1 type response in the MF patients either by Th1 type cytokine therapy or by using recombinant filarial antigen which stimulates the Th1 response. Further the recombinant filarial antigen which induces Th1 type cytokine response could be used for immunoprophylactic studies. PMID- 23100892 TI - Immunomodulation of excretory secretory materials from the filarial parasiteSetaria digitata. AB - ES materials released along with the release of mf showed immunosuppression as evidenced by a decrease in T lymphocyte levels in the immunised animals. Lipid fractions of the mf associated ES materials and protein fractions of the detergent soluble materials were found to cause suppression of immune response in the host. Further study revealed that the suppression associated with the lipid fractions is actually the end result and that mf associated ES materials is actually a mixture of immunosuppressive and immunopotentiating components and the release of the components is most likely regulated. PMID- 23100893 TI - Our experience with experimentalWuchereria bancrofti infection in Indian langur (Presbytis entellus). PMID- 23100894 TI - Bionomics of Mansonioides mosquitoes in relation to community structure of hydrophytes/breeding habitats in Cherthala, Kerala. AB - Three species of Mansonioides vectors viz.,Ma. annulifera, Ma. uniformis andMa. indiana were found in Cherthala taluk, Kerala which is one of the endemic areas due toB. malayi. The immatures of Mansonioides thrive mainly in association with macrophytic hydrophytes such asP. stratiotes, S. molesta andE. crassipes in perennial habitats (ponds, channels/ canals etc.,) andI. miliaceae in seasonal habitats (fallow lands etc.) Breeding potential was higher (130.19) in clean ponds withP. stratiotes, compared to that of polluted ones (40.69). However, the polluted habitats infested with the same host plants were found to be the most productive forMa. annulifera, with an average daily adult emergence rate of 601/100 sq.m.). The clean habitats played a major role in the contribution ofMa. uniformis, whereS. molesta in the perennial habitats and I. miliaceae in the seasonal fallow lands were the favourable plants contributing a daily output of 12.5/100 sq.m and 221.81/100 sq.m. respectively.E. crassipes infested polluted habitats formed the major source forMa. indiana, the emergence rate being 13.89/100 sq.m. The perennial habitats supported mainly the breeding ofMa. annulifera (70.82%), whereas the seasonal habitats contributed the major chunk ofMa. uniformis (92.54%) andMa. indiana (71.43%). The bionomics of Mansonioides mosquitoes are thus shown to be greatly influenced by the community structure of hydrophytes and also the nature of breeding habitats. PMID- 23100895 TI - Bancroftian filariasis in south east Madhya Pradesh: Pre-control epidemilogical observations. AB - Lymphatic filariasis caused byWuchereria bancrofti is a major health problem next only to malaria. A study had been conducted to estimate the prevalence of microfilaraemia in a rural endemic community near Raipur. The incidence of microfilaramia in the community was found to be about 14% when studied by night finger prick method. The incidence appears to be more in males as compared to females. The infection rate in vector population i.e.,Culex quinquefasciatus was recorded at a rate of 10%. No relationship could be drawn between the rates of vector and human filarial infections or between the density of vector population and the rate of vector/human infection(s). Prior health education is essential before taking up control and preventive measures in given endemic zone. PMID- 23100896 TI - Epidemiological situation of malaria in South East Asia with focus on India. AB - Malaria contributes a most stimulating chapter in the annals of biological parasitism. At present the disease is endemic in 91 countries with about 40% of world population at risk. Among all infections malaria continues to be one of the biggest contributors to disease burden in terms of morbidity, suffering and deaths specially in Africa. By lowering the productivity it is closely linked to poverty and contributes significantly to stunting social and economic development.We, in South East Asia, are living in paradoxical situation, on one side we spent large sums and energy to control/eradicate malaria and on the other hand we simultaneously create malariogenic conditions in the process of development efforts eg. irrigation canals, water supply scheme and urbanisation.The disease is endemic in all the seven countries of South East Asia with P.f.% ranging from 2.47% in Nepaa to 55% in Pakistan. In India although the total number of cases are almost static in last 10 years however the P.f. cases are on increasing trend.The malaria in tribal area is further posing a great threat. Annually 0.2% of the population suffers with malaria. However it is 1.5% in tribal area and 60% of deaths due to malaria are reported from tribal area. In 1984 there were 24% cases ofP. falciparum malaria out of them 57% were in tribal area however in 1995 the total cases increased to 36% and P.f. proportion to 75%. Technical side the chloroquine resistance and insecticidal resistance are also spreading in new area which also complicate the disease epidemiology.The migration of population, deforestation, inadequate resources increase in epidemic potential and neglect of epidemiology are other important factors responsible for changing epidemiological pattern of malaria. PMID- 23100897 TI - Strain variation and gene hunting in malaria. AB - Malaria still remains uncontrolled affecting millions and killing many. We have found the high chloroquine-resistance in Rajasthan epidemic which contains multipleP.falciparum strains. Large number of variantP.falciparum strains exist in India which should be taken into account for future malaria control strategies. We have characterised several parasite molecules which are involved in the hostparasite interaction. They can be used to develop the molecular therapy or antimalarial drugs for malaria. The parasite enzymes described by us will be quite useful in this regard, particularly in drug development. PMID- 23100898 TI - Developing peptide based immunogen against human malaria delivered in liposomes containing non-toxic adjuvants. PMID- 23100900 TI - Surface antigenic profiles of virulent and avirulent Indian strains ofLeishmania donovani. PMID- 23100899 TI - Impairment of cytochrome P(450) during Leishmaniasis: Role of nitric oxide synthase. PMID- 23100901 TI - Medicinal plants in the fight against Leishmaniasis. PMID- 23100902 TI - Serodiagnosis of indian Kala-azar by elisa using purified Leishmania specific antigens. PMID- 23100903 TI - Adenylyl cyclase inMycobacterium tuberculosis H37Rv-A possible virulence factor. AB - Eukaryotic-like adenylyl cyclase has been identified inMycobacterium tuberculosis H37Rv. TheM. tuberculosis adenylyl cyclase gene (cya) was cloned by complementation of a cAMP dependent expression of maltose operon in acya deletionE. coli strain. The nucleotide sequence analysis of thecya gene revealed an open reading frame that coded for 443 amino acids. A comparison ofM. tuberculosis adenylyl cyclase with the protein sequences in the data bank revealed its homology to the eukaryotic Type I and the calmodulin responsive adenylyl cyclases with an average of about 40% identical and 60% similar amino acids in the catalytic domain. The occurrence of eukaryotic-like adenylyl cyclase inM. tuberculosis suggests a role for this important enzyme in cell signaling and perhaps in the pathogenesis ofM. tuberculosis. We suggest that the human pathogenM. tuberculosis might have acquired the eukaryoticcya by a recombination event. PMID- 23100904 TI - Evaluation of routine laboratory methods in the diagnosis of tubercular lymphadenitis. AB - Lymph node biopsies from 64 cases suspected of Tuberculosis were subjected to fluorescent smear microscopy, culture and histopathology. Fluorescent microscopy was found to be the most sensitive technique (32.8%) followed by culture (20.3%) and histopathology (14.06%). Thus, for the diagnosis of tubercular lymphadenitis requisition for bacteriological investigations must be sent along with histopathology, particularly in early cases. PMID- 23100905 TI - Mycobacterium tuberculosis 38kDa antigen and its encoding gene-experience in diagnostic applications. AB - Our experience has revealed that the detection of 38 kDa antigen or antibody to the antigen in various fluids is useful in diagnosis of various mainfestations of tuberculosis. The PCR developed for 340bp sequence of its encoding gene also shows a high degree of sensitivity and specificity. Thus the 38 kDa antigen/antibody combination or the PCR are ideal for development of kits for diagnosis. These immunoassays to be successful, isolation of the 38 kDa antigen in large quantities is essential. Using recombinant DNA technology and expression inE. coli this has been achieved. However, such recombinant antigen does not have the same immunological properties as the native antigen and hence not suitable in immunodiagnosis. To fully realise the potential of the MoAb defined antigens such as the 38 kDa antigen, 19 kDa antigen and others it is essential to devise alternative vector-host systems that help in glycosylation, do not accumulate as inclusion bodies and can be isolated with less damage. PMID- 23100906 TI - Trifluoperazine and CEF-allicin from garlic (Allium sativum) as potential new antitubercular drugs active against drug resistantMycobacterium tuberculosis. AB - Trifluoperazine (TFP) and a compound called CEF-allicin purified from garlic (Allium sativum) possess antitubercular activity against both drug susceptible and resistant clinical isolates ofMycobacterium tuberculosis. They are bactericidal in nature with multiple sites of primary action. This new use for known drug TFP was based on our observation that mycobacteria have calmodulin like protein which regulates their metabolism and a calmodulin antagonist has antitubercular activity. The minimum inhibitory concentration (MIC) of TFP againstM. tuberculosis was 4-5 MUg/ml. It inhibited considerably by 6hrs, the synthesis of total lipids from(14)C-acetate and proteins and DNA as judged by the uptake of(14)C-glycine and(3)H-thymidine respectively by the bacilli. With 50 clinical isolates from our hospital at Delhi, the MIC was 4MUg/ml, for 40% and 8MUg/ml, for 50% of the isolates susceptible as well as resistant to one or more of the five drugs isoniazid, rifampicin, streptomycin, ethambutol and pyrazinamide. The MIC of CEF-allicin was 25MUg/ml, for bothMycobacterium tuberculosis and isoniazid resistant clinical isolate TRC-C 1193. It inhibited in 6hrs or less the synthesis of total lipids completely and proteins and DNA ofM. tuberculosis from its labeled precursors almost completely. PMID- 23100907 TI - Role of immunotherapy in the treatment of tuberculosis. AB - Tuberculosis is caused byMycobacterium tuberculosis, an intracellular pathogen residing in macrophages. Cell mediated immune (CMI) and delayed type of hypersensitive (DTH) responses play a pivotal role in providing protection to the host. The most important cell is the CD4 T lymphocyte, which is divided into TH1 and TH2 subsets depending on the type of cytokines produced. TH1 cells produce the cytokines interferon-gamma and interleukin-2, which are important for activation of antimycobacterial activities and essential for the DTH response. Grange opines that the immune response in an individual with tuberculous infection gets 'locked in' to one or other pattern of response viz. TH1 or TH2 response, the latter response leading to tissue damage and progression of disease.Stanford and co-workers conducted several studies on the effectiveness ofMycobacterium vaccae, as an immunotherapeutic agent for tuberculosis. It is non pathogenic in humans and is thought to be a powerful TH1 adjuvant. A series of small studies pointed thatM. vaccae has a beneficial effect and there is enough evidence now to show that its use as an immunotherapeutic agent, as an adjunct to chemotherapy in the treatment of tuberculosis especially at a time when drug resistance is rampant, appears promising. PMID- 23100908 TI - Protective efficacy of mycobacterial 71 kilodalton cell wall associated protein using poly (DL-lactide-co-glycolide) microparticles as carrier vehicles. AB - A 71 kDa cell wall associated protein ofM.tuberculosis H(37)Ra, on encapsulation in biodegradable microparticles composed of poly-DL-lactide-co-glycolide (DL-PLG) exhibited higher level of T-cell stimulation and cytokine release as compared to 71 kDa-FIA in mice as evaluated till sixteenth week post immunization (p.im.). Further, the protection imparted by immunization with 71 kDa-PLG microparticles (71 kDa-PLG-MPs) was significantly higher (p<0.5) than the 71 kDa-FIA (70%) and BCG (65%) immunized group on the basis of survival rates, when challenged at sixteenth week p.im. The protective effect was consistent with the decreased bacterial load in the infected organs of 71 kDa-PLG primed group as compared to 71 kDa-FIA and BCG immunized groups. PMID- 23100909 TI - Genotypic detection of mutations in rifampicin resistant clinical isolates ofMycobacterium tuberculosis. AB - The resistance of majority ofM. tuberculosis strains to rifampicin a key drug in the tuberculosis therapy, has been cause of major alarm world-wide. Such an association of strain with the drug takes a long time i.e. 2-3 months. We have modified a method for rapid detection of rifampicin resistant strains by screening them through PCR-SSCP.We have identified mutations in rpo, beta region of the gene encoding, beta sub-unit of RNA polymerase in rifampicin resistant 67 clinical isolates ofM. tuberculosis. Mutations were screened in these isolates by single strand confirmation polymorphism (SSCP). When DNA sequencing data was compared with the result of SSCP analysis, direct PCR sequencing results were more easily interpreted and contatined more sequence dependent information. These findings provide the basis for rapid detection of rifampicin esistance, a marker of multidrug resistance. PMID- 23100910 TI - DNA binding protein of mycobacteria and human immune response. AB - A dual step procedure was used to identify a 30 kDa DNA binding protein of mycobacteria (HLPMt) which is a target of human T and B cell response. The immunodominance of HLPMt was estabished by T cell blot assay as well as by subtractive immunoblot assay. This protein is not secreted into the extracellular culture fluid and is different from the 85 ABC complex of proteins as seen by immunoblots and ELISA. The protein is capable of inducingin vitro lymphoproliferation in tuberculin reactors. The protein was purified for the generation of monospecific sera and for amino acid sequencing. The sequence of the 16 amino acid long peptide derived from the 30 kDa protein showed a 100% homology with the translated sequence of a cosmid cY349 (Sanger Centre, Cambridge, UK). The ORF was predicted to code for a protein of 214 amino acids. Oligonucleotide primers were designed against the 5' and 3' end of the gene and the gene was PCR amplified, cloned and expressed inE.coli. The protein has unique dual domains which show homology to both bacterial HU proteins and to eukaryotic histones H1. PMID- 23100911 TI - Effect of adverse environmental conditions onMycobacterium leprae. PMID- 23100912 TI - Serodiagnostic tests for leprosy. AB - All of the specific serodiagnostic tests developed by now only are able to detect advanced stages of the disease. None of these tests can efficiently diagnose leprosy at a ver, early stage of the disease including TT/BT cases. However, 35 kD based SACT and/or PGL-1 (ND-O/NT-P) based ELISA could be applied for confirmation in doubtful situations wherein cardinal signs of leprosy are not fulfilled. In addition, both of these tests can also be applied for efficiently monitoring patients on chemotherapy.The reason for any of the specific tests not becoming useful for detection of early cases of leprosy might be due to the presence of insignificant level of antibody even below the background level of the population. It has been noted by us that majority of tuberculoid leprosy cases have a low level of antibody against the specific and wholeM.leprae antigens (unpublished data). Therefore, attempts have been made to look for the presence of local antibody in the lesions of leprosy patients. It is expected that these studies would lead to the understanding into the mechanism of antibody secretion in early stages of the disease and would help in development of a specific serological test for early leprosy. PMID- 23100913 TI - Cultivation ofMycobacterium leprae in artificial culture medium. AB - The methodology, described here for in-vitro cultivation ofM. leprae may open out a new era in preparation of purified vaccine, production of specific monoclonal antibody and study of in-vitro sensitivity of the organism against the newly discovered drugs, and as such ensures rapid eradication of leprosy. PMID- 23100914 TI - Polymorphic MHC molecules dictate cytokine profile and clinical disease in mycobacterial diseases. PMID- 23100915 TI - Immuno-polymerase chain reaction for detection ofAspergillus fumigatus. AB - A number of Aspergillus infections are caused by the opportunistic fungal pathogenAspergillus fumigatus in humans especially under immunosuppressed conditions. Major forms of the disease include invasive aspergillosis, allergic bronchopulmonary aspergillosis and aspergilloma. A procedure that uses chitinase and microwave treatment is described for the extraction of genomic DNA of Aspergillus species from the sputum and bronchial aspirate of patients with established aspergillosis. Detection ofA.fumigatus was compared by culture, microscopy, serology by ELISA, immunodiffusion, agarose gel electrophoresis of PCR products and colorimetric immuno-PCR. A colorimetric method for the detection of PCR product was developed based on immunoaffinity reactions. Out of the clinical samples tested from nineteen patients, fourteen were positive and five were negative by all the methods tested. It was established that at least 1 pg of DNA was extractable from the clinical samples sufficient to produce enough quantities of PCR product for detection on agarose gel or by immunoaffinity based color reaction. An absorbance value of 0.9 to 1.5 against 0.2 for negative control was obtained at 405 nm for colorimetric immuno-PCR. This method can be exploited for screening large number of clinical samples from immunocompromized as well as from suspected cases of aspergillosis. PMID- 23100916 TI - Elisa based diagnostic test for Aspergillosis. AB - Detection of lgE and lgG antibodies in Aspergillosis is of diagnostic significance. The serological methods, such as agglutination, gel diffusion and counter immuno electrophoresis that are commonly used in the laboratories for diagnosis of Aspergillus induced infections, are less sensitive and high cross reactivity is often encountered. We carried out work on characterization and identification of diagnostically relevant antigens ofA. fumigatus. Well characterized antigens were used to develop an ELISA with 92% sensitivity and 89% specificity for detection of specific lgE and lgG in the sera of patients of allergic bronchopulmonary aspergillosis (ABPA), aspergilloma and invasive aspergillosis. Subsequently, a sample kit having "ready to use type" of dry reagents (powder/tableted buffers and lyophilized antigen, conjugate and reference sera) was formulated. The kit was validated with sera from patients of ABPA, related allergic disorders, tuberculosis, post-Kochs cases and thalassemic children receiving repeated blood transfusions. The performance of the kit was found to be satisfactory with coded sera. PMID- 23100917 TI - Detection of enteropathogens by PCR. AB - The widespread problem of contaminated water by enteric microorganisms necessitates the need to develop a rapid protocol to detect pathogens in water bodies. Usual methods like plating, biochemical tests and use of DNA probes are time consuming which is a limiting factor especially in epidemic situations. Moreover, some cells can exist in a virulent viable but non-culturable state making detection very difficult by plating method. This paper describes a rapid method to detect the enteropathogens,E.coli, Salmonella andVibrio and enteric viruses from water samples by Polymerase Chain Reaction.E.coli was specially chosen as it is an indicator of fecal contamination. The sensitivity ofE.coli detection was improved to 10 cells to keep in tune with the WHO guidelines. The presence ofE.coli would also indicate the probable presence of other pathogens. PMID- 23100918 TI - Sickle cell disease and malaria. AB - Malaria is most common infectious disease spread by female Anopheles mosquitoes especially in tropical and subtropical areas of the world. It is reported by WHO as a 4th leading cause of death in children across the developing countries. Unfortunately no vaccine is currently available. Sickle cell trait (HbAS) patients provide some resistance for malaria over normal persons (HbAA) or their homozygous state (HbSS) due to various reasons. PMID- 23100919 TI - Multidrug resistance 1 gene expression and AgNOR in childhood acute leukemias. AB - The multidrug resistance 1 (MDR1) gene product, P-glycoprotein (Pgp/p170) is a membrane protein, which acts as an ATP dependant efflux pump that expels a wide variety of organic compounds including chemotherapeutic agents from the cell. Pgp over expression has been demonstrated to be linked with poor treatment outcome and poor prognosis in a number of malignant tumors. AgNORs is a simple, reliable and inexpensive method of evaluating the proliferative activity of a tumor. We have studied MDR1 expression and AgNORS in 41 cases of acute leukemia in children. In this study, AgNOR counts in patients with acute lymphoblastic leukemia (ALL) L2 subtype (FAB classification) were significantly higher as compared to the ALL L1 subtype. Similarly, mean AgNOR count in the acute myeloid Leukemia (AML) M2 subtype was significantly higher as compared to the ALL L1 subtype. However, there was no correlation between AgNOR and treatment outcome or between AgNOR counts and MDR1 expression in any of the subtypes of acute leukemia included in this series. In AML, MDR1 gene expression was found to be related to reduced remission induction rates and hence poorer prognosis. In ALL, our study has shown no difference in remission induction between MDR1 positive and MDR1 negative cases. This would suggest that factors other than MDR1 may be of relevance in Pediatric ALL. PMID- 23100920 TI - Prevalence of HBV and HCV in blood donors in Kanpur during the period 1997 through 2005. AB - Viral hepatitis transmitted by parenteral route is emerging as a far more dreaded public health challenge than any other illness. We have collected the data of HBV and HCV seropositivity in replacement and voluntary donors in our Blood Bank during the period January 1997 to December 2005. The results were as follows: Total number of cases studied in 1997 to 2005 - 115073 HbsAg positive cases - 1976 (1.7172%) Anti HCV positive cases - 463 (0.4024%) The overall picture is showing a more or less stable prevalence rate of hepatitis cases among blood donors, who were apparently healthy. PMID- 23100921 TI - Iron status of Hindu brahmin, Jain and Muslim communities in Surat, Gujarat. AB - AIM OF THE STUDY: To determine iron status of healthy, unrelated Brahmin, Jain and Muslim participants having different dietary habits. METHODOLOGY: Control participants other than above three communities, consumed vegetarian or non vegetarian diet. Brahmin and Jain were strictly vegetarian but Jain did not consume roots or tubers. Muslims consumed non-vegetarian food. Standard techniques were used to measure hematological parameters, serum iron, total iron bindings capacity (TIBC), serum ferritin, transferrin and transferrin saturation. For statistical evaluation mean, standard deviation, pair t test, chi2 and ANOVA (F test) were employed. RESULTS: Study includes 565 male and 198 female children and adults. Among them 205 were children and remaining adults. All four categories i.e. control, Brahmin, Jain and Muslims showed higher incidence of anemia and iron deficiency in females compared to males. Mean values of hematological parameters did not vary significantly in four groups. Serum iron, TIBC, transferrin and ferritin levels indicated iron deficiency anemia more frequently in Jains and less frequently in Muslims (p<0.05). Iron status of Brahmin was comparable with controls (p<0.01). Majority of the participants had serum ferritin concentration >15 ng/mL. Except one male Jain child none of the participants had serum ferritin concentration <12 ng/mL. Jain subjects more frequently had serum iron concentration <60 MUg/dL. CONCLUSION: Jain participants had higher incidence of iron deficiency anemia. Vegetarian diet consumed by Gujarati Hindu Brahmin community provided them with a sufficient iron to maintain their iron profile like Muslims consuming non-vegetarian diet. PMID- 23100922 TI - Prevalence of hematinics deficiency amongst female students and its correction. AB - BACKGROUND: Nutritional anemia (NA) is common in India. While iron deficiency (ID) is a well recognized cause of NA, prevalence of deficiencies of other hematinics is not systematically investigated. SETTING: Seventy students of a junior class of a polytechnic and 202 inmates of girl students home were taken up for study. METHODS: Students were given a questionnaire to elicit anemia related symptoms. Blood was collected for complete blood count (CBC), serum ferritin, folic acid and vitamin B12. Students of polytechnic received hematinic at bed time during their menstrual periods whereas inmates of students home received hematinic at bed time, 3 days in a week. After 6 months blood tests were repeated in those who completed the treatment. CBC was done on Coulter counter and ferritin, folic acid and vitamin B12 were assayed by chemiluminescence. Students were divided into three groups-(1) Control group with Hb 12.0 g/dl or more and ferritin 15.0 ng/ml or more; (2) ID Group with Hb 12.0 g/dl or more and ferritin less than 15.0 ng/ml; and (3) Iron Deficiency Anemia (IDA) group with Hb less tha 12.0 g/dl and ferritin less than 15.0 ng/ml. STATISTICS: Basal parameters of three groups were compared using students t test. Change in parameters with treatment was compared using paired students t test. RESULTS: Median age-16 years (range 10-25). Anemia ( Hb < 12.0 g/dl)-94 (34.6%); MCV < 80 fl-153 (56.3%); MCH < 27 pg-167 (61.4%); Ferritin < 15.0 ng/ml-161 (59.2%); Folic acid < 3.5 ng/ml-34 (12.5%); Vitamin B12 < 258 pg/ml-133 (48.9%) Pre-therapy: (1) Hb, MCV, MCH and ferritin significantly lower in ID and IDA Groups compared to control group. (2) Hb, MCV, MCH and Ferritin significantly lower in IDA Group as compared to ID Group. POST-THERAPY: (1) IDA group showed significant increase in Hb, MCV, MCH, ferritin, folic acid and vitamin B12. (2) final Hb (11.26+1.07) and ferritin (7.46+4.81) in IDA Group were subnormal. (3) MCV, MCH, ferritin, folic acid and vitamin B12 increased significantly in ID Group and control group. CONCLUSIONS: (1) Nutritional anemia is common amongst asymptomatic young female students. (2) Deficiencies of iron, folic acid and vitamin B12 are common and coexist. (3) 105 mg elemental iron for 3 days in a week for 6 months is not adequate to correct IDA. (4) 105 mg iron for 3 days in a week is enough to correct ID. (5) Non-anemic individuals with ID have iron deficient erythropoiesis. (6) Non-anemic individuals without ID, in this cohort, also had iron deficient eryhtropoiesis. PMID- 23100923 TI - Hematological profile of sickle cell disease in central India. AB - Hematological profile of homozygous sickle cell disease patients attending RHDMC from Central India is presented. Central India has a huge population of sickle cell disease patients. Though predicted SS in the region is 22-44 %, 81 homozygous of sickle cell patients reported during study period of Jan 2003-Dec 2005. The clinical course of these patients is characterized in most of the cases by relatively long period without any symptoms punctuated by acute clinical events. Hematological profile of these 81 patients with age ranging from 6 month to 64 years is presented. There are 44 males and 37 females with an average age of 14.55yrs in males and 18.13 yrs females. Males out number females in pediatric age group where as females with SCD are attending hospital more in reproductive age group. Very few patients are reported after the age of 30 yrs. Average hemoglobin in males is 7.11 +/- 2.13 gms/dl and in females 6.75 +/- 1.85 gms/dl with parallel low RBC count.Hemoglobin rise is seen after 14 years of age in males and females. Age related rise in MCV is more noted in females after the age of 5 as compared to males. No age or sex related difference was seen in MCHC values. Hb A(2) levels for males is 2.13 +/- 0.95% and for females 2.04 +/- 0.91 %.Hb F in males is 19.58 + 5.86% and in females is 20.99 + 4.9%. There is no age and sex related difference in Hb F levels. Moderate to severe anemia with high Hb F dominate Central Indian sickle cell disease patient's hematological profile. The hematological profile in Central India is similar to the profile in other parts of India and Saudi Arabia but different from Jamaica and Africa. PMID- 23100924 TI - A study-screening of blood donors for blood transmissible diseases. AB - AIMS: Blood donors are of voluntary and replacement type. All donors, especially voluntary, are considered as slow risk for seropositive status for Hepatitis B and C, HIV and syphilis. The present study endeavors to screen blood donors-a slow risk group and evaluate the resultant data. METHODOLOGY: We screened 23,068 donors serologically over 2 years for the above blood transmissible diseases. Serum alanine aminotranferase (ALT) and bilirubin were evaluated as surrogate markers in hepatitis B and C positive donors. RESULTS: Seroprevalence rates were found to be HIV (1.96 %), syphilis (2.15 %), hepatitis B (1.98 %) and hepatitis C (0.9 %). Majority donors were voluntary (70.37 %) and male (96.2 %). However seroprevalence rates showed no significant difference: voluntary (7.02 %), replacement (6.67 %) male (6.85 %) and female (6.95 %). HCV and HIV showed highest (29.6 %) while HBV and HCV (2.5 %) showed lowest concomitance. Serum ALT and bilirubin were not effective surrogate markers. No demographic or behavioral variable was found as a significant risk factor. CONCLUSION: Thus, all donors need adequate privacy, information, counseling and motivation in order to reduce the seropositive rates in donors. Advent of sensitive tests renders surrogate markers redundant. PMID- 23100925 TI - Cefepime versus ceftazidime as empirical therapy for fever in neutropenic patients with haematological malignancies. AB - An open randomized comparative study was conducted to evaluate the efficacy of Cefepime (2 gm iv. 8 hr.) vs. ceftazidime (2 gm iv. every 8 hr.) in empirical therapy of febrile neutropenic patients. A total of 40 eligible febrile episodes were randomized to be treated with study regimen. Twenty febrile episodes were treated with cefepime and 20 were treated with ceftazidime. The two groups were comparable in terms of age, sex, height, underlying neoplasm, number of pretherapy neutrophils, duration of neutropenia. The overall therapeutic success rate of cetepime group (60%) was comparable to that of ceftazidime group (55%). The results of this study suggest that cefepime is an effective and safe agent in empirical therapy of febrile episode in neutropenic patient and its efficacy is comparable with that of ceftazidime. PMID- 23100926 TI - Cyclosporine A responsive pure red cell aplasia in a child with systemic lupus erythematosus. AB - PRCA is a rare complication in SLE. Response to various drugs like steroid, Intravenous Immunoglobin (IVIG), recombinant human erythropoietin and plasmapheresis vary in different cases.Cyclosporin A may be effective in cases even unresponsive to other modalities of therapy. PMID- 23100927 TI - An autopsy case of sudden death in a patient with sickle cell disease. AB - An autopsy finding of sudden death due to disseminated intra-vascular sickling of RBCs in a young adult male from Madhya Pradesh while undergoing army recruitment rally, is reported because of its rarity in this part of the country. PMID- 23100928 TI - Chronic eosinophilic leukemia: a case report and review of literature. AB - Chronic Eosinophilic Leukemia (CEL) is a rare type of chronic myeloproliferative disorder of unknown etiology with no available true incidence. The vaguely overlapping clinico - pathological picture of CEL with idiopathic hypereosinophilic syndrome (IHES) often adds to the diagnostic confusion. An evidence of genetic clonality of eosinophils or an increase in blast cells in the blood or bone marrow is mandatory for diagnosis of CEL while no specific diagnostic tests exist for IHES; making it an entity of exclusion. Till date, CEL is a rarely reported entity in India. We add yet another case of eosinophilic leukemia along with review of available literature. PMID- 23100929 TI - Congenital dyserythropoietic anemia type II - a case report of two siblings in a family. AB - Two children out of three siblings of a family presented with tiredness, fatigue, and breathlessness for more than 6 months. Examination of peripheral blood smear, bone marrow aspirate, and a positive acidified serum test (HEMPAS) revealed these children to be a case of congenital dyserythropoietic anemia type II. This case is reported because of its rarity. PMID- 23100930 TI - Double heterozygous for hemoglobin S and hemoglobin E - a case report from central India. AB - Double heterozygosity for HbS and HbE is rare. HbS and HbE are seen in SC, ST and OBC communities from this part of country. Inter caste marriages amongst these communities have resulted into this compound heterozygous condition. Double heterozygous state for HbS and HbE is clinically silent as compared to HbS-beta Thalassaemia and HbSS cases. At Regional Hemoglobinopathy Detection and Management Center, we report a case of 15-year-old male, Teli (OBC) by caste who came for screening for sickle cell disorder. Sickling, solubility test and Hb electrophoresis on agar gel at alkaline pH was carried out. His sickling and solubility tests were positive and on hemoglobin electrophoresis it showed two bands one at Hb A(2) position and another at HbS position. For further confirmation sample was subjected for quantitation of haemoglobin on high performance liquid chromatography (HPLC), Bio-Rad. On quantitation he was having HbS 59.8%, HbE 33.5% and HbF 3.2% confirming his double heterozygous state for HbS and HbE. On family screening his father turned out to be sickle cell trait and mother as hemoglobin E trait. PMID- 23100931 TI - Disseminated cryptococcosis in an immunocompetent child. AB - Cryptococcosis is caused by cryptococcus neoformans. Immunosuppression is a predisposing factor for the development of cryptococcosis. However, reports exist that cryptococcus neoformans can cause infection in immunocompetent hosts. We report a case of disseminated cryptococcosis in a 7.5-year-old immunocompetent child. PMID- 23100932 TI - Elevated serum endostatin levels is associated with favorable outcome in acute myeloid leukemia. AB - INTRODUCTION: Endostatin is the C-terminal antiangiogenic fragment of the extracellular matrix protein collagen XVIII, and is generated by tumor-derived proteases. The levels and the prognostic relevance of serum endostatin in AML patient is not fully clear. AIM: To evaluate serum levels of endostatin in acute myeloid leukemia patients before chemotherapy and after achieving complete remission and to correlate endostatin levels with patients outcome. MATERIALS AND METHODS: Serum samples from 30 adult patients (22 males and 8 females, median age 37, range 19-66 years) with AML had been taken before chemotherapy was administered. In addition 20 out of 30 patients were reinvestigated again at complete remission (CR). Ten samples from healthy normal persons of matched age and sex were evaluated as a reference control group. Serum endostatin levels were determined using enzyme linked immune sorbent assay (ELISA). RESULTS: Endostatin serum levels were not significantly different in the pretreatment AML patients as compared to that in normal controls (P>0.05). In AML patients the baseline endostatin levels were significantly lower than at CR (P=0.001). No significant correlation were detected between pretreatment serum endostatin levels and age, peripheral blood white cell counts, platelet counts, bone marrow blast cell counts, blast cell distribution ratio. The prognostic value of sE was also evaluated by dividing AML patients into high and low sE groups using the 75 percentile sE levels of the patients group as cutoff. The authors found that patients group in the high sE group survived for significantly longer time than those patients in the low sE group. CONCLUSIONS: Elevated endostatin levels at AML diagnosis is a good prognostic marker for patients' outcome. Wide scale study is recommended in order to establish the clinical value of this study. PMID- 23100933 TI - Hematological malignancies diagnosed by bone marrow examination in a tertiary hospital at Uttarakhand, India. AB - INTRODUCTION: Hematological malignancies are quite common and affect all ages and genders. The diagnosis involves a multiparameter approach. The geographical distribution of various types of hematological malignancies has been provided by various authors but no such data have been published regarding the State of Uttarakhand in India. AIM: To study the hematological malignancies at Uttarakhand in India based on age, sex and the type of malignancy with further sub typing wherever possible. SETTINGS AND DESIGN: A total of 220 cases of hematological malignancies were worked up from the Reference Laboratory of Himalayan Institute of Medical Sciences over an eight year period (1998-2005). MATERIALS AND METHODS: Diagnosis was mainly based on morphological examination of peripheral blood and bone marrow smears stained by Leishman's stain and MPO, Sudan Black and PAS stain as and where required. Distribution of cases was studied based on age, sex and the type of malignancy with further sub typing wherever possible. RESULTS: The most common hematological malignancy was found to be Leukemia 129/220 (58%) followed b Lymphoma 33/220 (14.8%), Multiple Myeloma 55/220 (24.7%) and Metastatic Lesions 3/220 (1.3%). These malignancies were seen to be distributed throughout all ages with a peak at 11-20 years age group 39/220 (17.5%) and another peak at 51-60 years age group 41/220 (18.4%). We found an overall male preponderance with a M:F ratio of 2.3:1. CONCLUSIONS: The commonest haematological malignancy in our series was Leukemia. Other diagnoses were Multiple Myeloma, Lymphoma and Secondaries. Multiple Myeloma which turned out to be the second most common diagnosis was an unusual finding. PMID- 23100934 TI - Prevalence of iron deficiency anemia in chronic diarrhoea and celiac disease - a western UP experience. AB - AIM: To study the prevalence of iron deficiency anaemia in chronic diarrhoea and celiac disease. METHODOLOGY: Cases included 45 children between 1-12 years with chronic diarrhoea, who underwent investigations like haemogram with GBP, RBC indices, serum iron and TIBC. After a course of antibiotic therapy for 6 weeks with iron and folic acid with no improvement noted within 2 weeks, they were subjected to duodenal biopsy. If biopsy showed features of celiac disease, then anti-endomysial antibody test was performed to substantiate the diagnosis. RESULTS: 30 cases (66.7%) were males and 15 (33.3%) females. 8 cases (17.8%) had watery diarrhoea, 20 (44.4%) semiformed and 17 (37.8%) had watery and semiformed diarrhoea. Bloody diarrhoea was present in 5 (11.1%) and abdominal distension in 21 cases (46.7%). Pallor seen in all the cases. The mean age of the cases was 55 +/- 1.5 months and mean duration of diarrhoea was 18 +/- 1.4 months. Mean haemoglobin observed was 8.1 +/- 1.6 gm%. MCV, MCH and MCHC were 79.1 +/- 8.6 fl, 26.9 +/- 3 pg and 29.6 +/- 2.3 g/dl respectively. Mean serum iron was 32.1 +/- 1.2 g/ dl and TIBC was 432 +/- 3.2 g/ dl. On peripheral smear, 28 cases (82.4%) showed microcytic hypochromic anaemia. 26 cases showed evidence of celiac disease on duodenal biopsy. Anti endomysial antibody (AEA) test was positive in 15 of the 19 celiac cases on which performed. Mean duration of diarrhoea (23.5 months) was significantly more in celiacs as compared to non-celiacs (11.6 months). CONCLUSIONS: Better awareness of the clinical profile and early detection of celiac disease would help detection and management of iron deficiency anaemia associated with celiac disease. PMID- 23100935 TI - Therapeutic efficacy of different types of platelet concentrates in thrombocytopenic patients. AB - BACKGROUND: Platelet Rich Plasma-Platelet concentrate (PRP-PC), Buffy Coat poor platelet concentrate (BCPC), and Apheresis - PC were prepared and their therapeutic efficacy were assessed in thrombocytopenic patients. STUDY DESIGN AND METHODS: PRP-PC and BC-PC were prepared from whole blood and Apheresis-PC by automated cell separator. The post transfusion efficacy of transfused platelets was assessed at 1 hour and 20 hours by corrected count increment (CCI) and percentage recovery (PR). RESULTS: A total of 60 patients' (20 each for PRP-PC, BC-PC and Apheresis-PC) were enrolled in this study. Forty one patients received therapeutic and nineteen received prophylactic transfusion support. Patients with aplastic anemia 43% (25/60) and acute leukemia 38% (23/60) formed a majority of study population. Platelet dosage of patients' received PRP-PC, BC-PC and apheresis-PC were 2.4+/-0.82 * 1011 (mean+/-SD), 2.2+/-0.83 * 1011 (mean+/-SD) and 4.14+/-1.82 * 1011 (mean+/-SD) and ranged from 1.16-4.11 * 1011, 1.04-4.20 * 1011 and 1.22-8.90 * 1011 respectively. There was significantly increase in inter transfusion interval with Apheresis-PC than with PRP-PC and BC-PC recipients [(Mean+/-S.D.), 4.7+/-1.33 days Vs 2.7+/-0.82 days Vs 2.5+/-0.7 days respectively] (p < 0.05). CONCLUSIONS: Patients transfused with apheresis-PC had received higher platelet dosage than PRP-PC and BC-PC and this difference was statistically significant (p < 0.001). The post transfusion platelet counts and increments at 1 hour and 20 hours were significantly higher with apheresis-PC than PRP-PC and BC-PC (p < 0.001). However, the corrected count increment (CCI) and percentage recovery (PR) in all three groups were comparable. There was significantly increase in inter-transfusion interval with apheresis-PC than PRPPC and BC-PC (p < 0.05). PMID- 23100936 TI - An analysis of 8 cases of factor X deficiency. AB - BACKGROUND: Factor X deficiency is a rare coagulation defect. There are occasional reports of factor X deficiency from India. Difficulty in accurate diagnosis and non-availability of ideal treatment is discussed. METHODS: Eight cases of factor X deficiency, diagnosed from 1992 to 2007 are reported here RESULTS: Seven were male while one was female. Seven patients were symptomatic from early childhood. One patient became symptomatic from 18 years of age. Factor X assay was done in 4 patients, 3 had severe deficiency and one had mild deficiency. One patient had associated factor IX deficiency. Three patients had repeated bleeding episodes requiring multiple transfusions. Two patients had intracranial bleed and one had umbilical cord bleeding at birth. There was no mortality. No patient received prophylactic transfusion. CONCLUSIONS: Factor X deficiency is a rare coagulation defect. Hereditary deficiency should be distinguished from acquired deficiency. CNS, joints and skin are the common sites of bleeding. PMID- 23100937 TI - PRCA with myelofibrosis: an unusual case report. AB - The association of PRCA and myelofibrosis is very rare with only two such cases reported in the literature. Leukemic transformation in myelofibrosis is known but the progression of PRCA to acute leukemia is very rare. We present an unusual case of PRCA with myelofibrosis which after 14 months of transfusion dependent anemia transformed to acute monocytic leukemia. PMID- 23100938 TI - Superior vena cava syndrome in children. AB - Superior vena cava syndrome (SVCS) is rare in childhood. 18 cases of SVCS were seen in children ranging from 3-14 years with a mean age of 8.8 years. There were 15 males and 3 female children. Diagnosis could be confirmed in 17 cases as one child succumbed to severe respiratory distress without a definitive diagnosis. The commonest cause of SVCS was lymphoma. Non-Hodgkin's lymphoma (NHL) was more common than Hodgkin's disease. In two cases the final diagnosis was tuberculosis of mediastinal lymph nodes. The diagnosis was confirmed by cervical lymph node biopsy in 6 cases, mediastinal biopsy in 6 cases and bone marrow aspiration in the remaining 5 cases. Intravenous Dexamethasone provided relief of symptoms in 13 patients. None of the children received emergency radiotherapy. Anti tubercular treatment produced complete cure in the two patients with tubercular mediastinal lymphadenopathy. PMID- 23100939 TI - Sickle-beta(+) thalassemia with splenic calcification and bone marrow infarction: a case report. AB - We came across an unusual case of a 20 years old male from north India who presented with repeated episodes of pyrexia of unknown origin (PUO) and history of chronic hemolytic anemia. On investigation he was detected to have Sickle beta(+) Thalassemia and subtle features of hyposplenism. Radiological investigations revealed extensive splenic calcification and bone marrow examination to evaluate for PUO showed extensive bone marrow infarction and fibrosis. Molecular diagnosis for beta thalassemia mutation revealed heterozygosity for IVS 1-5 M and alpha globin genes were normal. This case highlights the wide variation of clinical phenotype which is encountered with Sickle-beta(+) Thalassemia where genotyping can predict the clinical phenotype only partially. PMID- 23100940 TI - Crimean congo hemorrhagic fever infection simulating thrombotic thrombocytopenic purpura. AB - Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease that may also be transmitted through person-to-person transmission by exposure to infected body fluids. Despite its wide geographic distribution in animals, CCHF virus is rarely associated with recognized human diseases. We report the first case of CCHF in Kermanshah province, Iran. Clinical presentation was characterized by fever, myalgia, and hemorrhage. The levels of liver enzymes, creatinine phosphokinase, and lactate dehydrogenase were elevated, and bleeding markers were prolonged. PMID- 23100941 TI - Richter syndrome in CLL - an aspiration cytologic diagnosis. PMID- 23100942 TI - Anticoagulant induced artefacts in peripheral blood smears. AB - Microscopic evaluation of a peripheral blood smear is one of the most beneficial test. But anticoagulant induced artefacts could lead to misinterpretation of the smears. The present study was undertaken to identify the anticoagulant induced artefacts and avoid misinterpretation of peripheral blood smears. The blood samples were collected using Ethylene Diaminetetraacetic acid (EDTA) and Sodium citrate, mixed thoroughly and smears were made immediately as well as 1hr apart for 6 hrs, stained and examined under oil immersion microscope. Direct smears were used as controls. Significant morphological artefacts were observed in our study. Artefacts were marked at the end of 2 hrs with EDTA but seen almost immediately with citrate blood. At 6 hrs, artefacts were marked but more severe with citrates than EDTA. Thus the practice of making blood smears before addition of anticoagulant is recommended and a delay up to 1hr is permissible with EDTA blood but not beyond. PMID- 23100943 TI - An experience of single centre at C S M Medical University, Lucknow, for the prevalence of hemophilia in Uttar Pradesh. AB - OBJECTIVE: To evaluate the incidence of hereditary bleeding disorders, registered at our centre from all over Uttar Pradesh over an extended period of 10 years. MATERIAL AND METHODS: A complete coagulation profile of 240 cases conducted, followed by clinical history of the patient. The frequency and type of bleeding, age of onset, treatment taken, consanguinity and the blood transfusion if any, are little information collected from the patient. RESULTS: The complete scenario of bleeders indicated maximum number (92%) of hemophilia 'A' from northern UP as compared from other zones (76.5% +/- 3). Contrarily, hemophilia 'B' registered maximum from eastern zone (26%) and minimum from the northern zone (8%). The age diversity at diagnosis ranged between 1-32 years. The reasons for difference are all speculative. Definite cause needs extensive research. CONCLUSIONS: The study showed that elderly patients with hemophilia had significantly more impairments in physical functioning and depression than younger ones. PMID- 23100944 TI - Rapid purification of high purity thrombin and preparation of a novel hemostat for clinical purposes. AB - Thrombin was prepared from crude prothrombin enriched plasma by activation using Russell's viper venom. Prothrombin was prepared by barium sulphate adsorption and elution of prothrombin enriched fraction using high concentrations of sodium citrate. This fraction was directly activated with venom and thrombin was purified by SP Sepharose ion-exchange chromatography and subsequently over Phenyl sepharose column. This product exhibits a purity of >98% with an activity of at least 6000U/mg or higher. The Thrombin was further used in the preparation of a novel bio-absorbable hemostat using Calcium Alginate fiber sheet which acts as an absorbable hemostat. The present hemostat is highly porous, easy to use and has faster clotting time due to higher solubility of calcium fibers and thereby releasing thrombin. PMID- 23100945 TI - An unusual presentation of pediatric acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) is one of the most common hematological malignancies occurring in children. We report an interesting case of ALL with an unusual presentation. This 3-year-old boy came with a 6 month history of multiple pathological fractures, generalized osteopenia and vertebral compression. All the possible causes responsible for this condition were ruled out. His complete blood count which was normal initially evolved into cytopenias. His physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. The complete blood count showed pancytopenia with blasts in peripheral smear. Bone marrow aspirate was suggestive of B ALL. Pediatric ALL patients usually present with symptoms due to cytopenias, fever and bone pains. Although asymptomatic skeletal involvement may be seen in 40-60% of patients at presentation, pathological fractures and vertebral compressions are very rare. Therefore a high index of suspicion is needed to diagnose such cases. Moreover, these patients are usually associated with good prognostic features. PMID- 23100946 TI - Crystal storing histiocytosis: a rare presentation of plasma cell myeloma. AB - Crystal storing histiocytosis (CSH) is a very rare association with plasma cell dyscrasias. It is presumed to be an intra-lysosomal accumulation of the secreted paraprotein aggregated into crystals and is associated with presence of variable numbers of histiocyte-like cells with phagocytosed crystalline inclusions in the bone marrow and other extramedullary sites Herein we report a case of multiple myeloma associated with CSH with a rapidly downhill clinical course. There was diagnostic confusion at the outset with a histiocytic disorder which was clarified with the use of Immunohistiochemistry along with serum protein electrophoresis and immunofixation. PMID- 23100947 TI - Hypereosinophilia in hodgkin lymphoma. AB - The incidence of eosinophilia in Hodgkin lymphoma is approximately 15%. Both peripheral and tissue eosinophilia have been noted in Hodgkin lymphoma. Eosinophils have important role in pathobiology of Hodgkin lymphoma. The mechanism of eosinophilia remains unknown though various mediators like IL-5 and GM-CSF have been implicated. We present a case who was diagnosed to have Hodgkin lymphoma and hypereosinophilia. PMID- 23100948 TI - Rational use of blood: a study report on single unit transfusion. AB - Rational use of blood and minimise risks of blood transfusion have been repeatedly emphasized by WHO and various other experts. One of the measures is to discourage practice of single unit transfusion as it is avoidable in large majority of cases. The present study explores the data of such transfusions. A pilot study carried out during January 2000-December 2000 and then a follow up study is carried pout during January 2006-June 2007. During the pilot study done during 12 months a total of 10,0100 blood transfusions were given, out of which 55.1% were single unit transfusions. The preliminary results were presented in a regional conference and then a meeting and discussion with various clinical heads were arranged in January 2001. Then a follow up study is carried out from January 2006-June 2007 (18 months). It is found that a total of 12,248 blood transfusions are given during this spell, out of which 52.81% were single unit transfusions. Conclusion and some suggestions are offered to improve blood transfusion services and awareness in our country. PMID- 23100949 TI - Clinico-hematological profile of lysosomal storage disorders - a report of three cases. PMID- 23100950 TI - Interstitial deletion of 9q in a case of acute myeloid leukemia with t(8;21). PMID- 23100951 TI - Multi-organ failure due to Mycobacterium tuberculosis and Aspergillus flavus infection after allogeneic bone marrow transplantation. AB - Mycobacterium tuberculosis (MT) is a serious, but rare infectious complication after allogeneic bone marrow transplantation (BMT). We describe a case of fatal sepsis due to MT and Aspergillus flavus after allogeneic BMT for Aplastic Anemia. The diagnosis was made on bone marrow biopsy and asitic fluid culture. Broadspectrum antituberculous and Amphotericin B therapy was started immediately after diagnosis. The patient developed severe hypoxia and finally died of multi organ failure. Rapid progression of mycobacterial infection as well as fungal infection should be considered in patients post BMT with unexplained fever, particularly in patients from endemic areas. PMID- 23100952 TI - Reporting critical laboratory values in hematology. PMID- 23100953 TI - Flow cytometry in acute leukemia. AB - Immunophenotyping of acute leukemia is one of the most important clinical application of Flow cytometery. The aim of this work is to review recent advances in flow cytometery methods, quality control, troubleshooting and its prevention and data analysis of acute leukemia. Multiparameter flow cytometery is a useful adjunct to morphology and cytochemistry and it is an invaluable tool in the diagnosis of acute leukemia. PMID- 23100954 TI - Management of chronic synovitis in patients with hemophilia: with special reference to developing countries. AB - Chronic synovitis in severe hemophilia is a painful debilitating condition eventually affecting greater than 20% severe hemophilia patients in developing countries. Though this complication is all but eliminated in the countries with advanced hemophilia care and having access to generous factor concentrate replacement, the same can not be said for 80% of the hemophilia patients in the world who live in developing countries. In developing countries chronic synovitis can be treated conservatively with short course of steroid, factor replacement, physiotherapy and splintage. Failing this, chemical or radioactive synoviorthesis give worthwhile remission and relief in 70-80% of the severely affected patients who fail to respond to conservative therapy. We found a short course of Cox-2 (etoricoxib) inhibitor to be an extremely useful adjunct. The role of d Pencillamine, Thalidomide and inhibitors of matrix metalloproteinases needs to be explored. HLA-B27 was found to be strongly associated with chronic synovitis in hemophilia in one of the studies and this marker in a hemophilia patient may suggest need for more intensive replacement and other therapy in these patients to prevent chronic synovitis. PMID- 23100955 TI - Clinico-aetiologic profile of macrocytic anemias with special reference to megaloblastic anemia. AB - PURPOSE OF STUDY: This study was conducted to study the clinical and laboratory parameters in patients with macrocytic anemia and to determine the etiology of macrocytic anemia with special reference to megaloblastic anemia. MATERIALS AND METHODS: This study was a cross-sectional descriptive study carried over a period of 18 months on 60 adult patients (age >=13 years) of macrocytic anemia. Macrocytic anemia was identified when peripheral blood examination showed anemia with a mean red blood corpuscular volume of >95 fl. RESULT: The most common cause of macrocytic anemia was megaloblastic anemia (38.4%). The major causes of nonmegaloblastic macrocytic anemia were primary bone marrow disorders (35%), liver diseases (15%) and hemolytic anemia (8.3%). There was a significant male preponderance in the study (65%). The megaloblastic anemias observed were due to either vitamin B(12) deficiency (78.3%) or combined B(12) and folate deficiency (21.7%). A significant proportion of non-vegetarians (73.9%) had megaloblastic anemia. Patients with an MCV of >110fl were more likely to have megaloblastic anemia (p value 0.0007). Three patients (mean age 55 years) with a megaloblastic marrow did not respond to vitamin replacement and were found to have myelodysplastic syndrome. CONCLUSION: Megaloblastic anemia due to Vitamin B(12) or folate deficiency remains the most important cause of macrocytic anemia. In settings with limited laboratory facilities, a therapeutic trial of vitamins B(12) or folic acid is useful in determining the specific vitamin deficiency. PMID- 23100956 TI - Clinico-pathologic profile of Hodgkin's lymphoma in a rural medical college. AB - PURPOSE OF STUDY: A prospective study was done at North Bengal Medical College and Hospital (NBMCH), Darjeeling, West Bengal, which caters predominantly to the rural and hilly population. All patients diagnosed as Hodgkin's lymphoma (HL) were analyzed for clinical presentation, histological classified and staging. RESULTS: Total of 48 cases reported for HL were studied (n=48). A lower median age of onset (28.1year) and higher male to female ratio (3.8:1) as compared to western countries were observed. We found neck swelling was the commonest presenting symptom (58.28%) and peripheral lymphadenopathy was the commonest sign (83.33%). "B symptoms" was noted in 79.17% cases. Cervical lymph nodes were commonly involved (79.17%), followed by inguinal (45.83%) and axillary (29.17%). Thoracic lymph nodes and abdominal lymph nodes were enlarged in 29.17% of the cases and 25% of the cases respectively. Eosinophilia was noted in 29.17% of cases. Marrow involvement by neoplastic process was observed in 8.33% of cases and reactive changes in the marrow were observed in 12.5% of cases. We found mixed cellularity subtypes was the commonest (45.83%) followed by nodular sclerosis subtypes (33.33%). At presentation 54.17% of cases were of advanced stage of disease (stage III and IV). CONCLUSION: We noticed a distinct geographical pattern of HL in respect of age, sex, presentation, histological typing and staging of the disease, which is comparable to some other Indian studies but is noticeably different from patterns noted in Western countries. PMID- 23100957 TI - HemoCue photometer: a better alternative of hemoglobin estimation in blood donors? AB - PURPOSE OF STUDY: To find out the prevalence of anemia in potential blood donors and to compare the direct cynmethemoglobin and HemoCue methods for assessing hemoglobin concentration. MATERIAL AND METHODS: The study group included 540 potential blood donors; who were tested for their hemoglobin concentration in capillary blood samples by direct cynmethemoglobin and HemoCue methods. RESULTS: Average age of the potential donors was 39.2 year, with 505 males and 35 females. Mean hemoglobin concentration using the HemoCue was 13.2 +/- 2.4 g/dl and 12.8 +/ 2.3 g/dl with the direct cynmethemoglobin method (Table 1). The prevalence of anemia was slightly higher when using the direct cynmethemoglobin method (14.1%) as compared to HemoCue method (13.6%). The sensitivity and specificity for the HemoCue assessment was 94.1% and 95.2% respectively as compared to 90.1% and 94.2% respectively for the direct cynmethemoglobin method. CONCLUSION: Photometric hemoglobin determination (HemoCue) combines the convenience of onsite testing with sufficient accuracy and rapidity. We feel this is a better method for evaluating potential blood donors. PMID- 23100958 TI - Transfusion of neocytes concentrate/pooled neocytes in beta-thalassemic patients. AB - PURPOSE OF STUDY: Study was aimed to observe benefits of transfusion of neocytes/pooled neocytes over packed RBCs by super transfusion regimen in beta thalassemic patients and its comparison with related studies. MATERIALS AND METHODS: Twelve cases were selected and were equally divided into control and study group in which packed RBCs and neocytes were transfused respectively for one year. In study group, average 8 transfusions were required over 14 in control group. RESULTS: A marked extension of transfusion interval was observed in study group patients receiving neocytes transfusion (avg. 45.8 days; range, 32-54) over control group patients i.e. those receiving conventional packed RBCs (avg. 26.1; range 22-30). There is an average 40.8% reduction in the volume of RBCs required in the study group compared to control group and this difference is statistically significant (p = 0.00075). In study group, 20.1% reduction in iron overload and increase of iron by 9.6% in control group was reported. CONCLUSION: We observed that neocytes transfusion is effective in extending the transfusion interval as well as in reducing the blood requirement and iron over load. PMID- 23100959 TI - T-cell prolymphocytic leukemia: a report of two cases with review of literature. AB - T-cell Prolymphocytic Leukemia (T-PLL) is a mature post-thymic T-cell malignancy with aggressive clinical course. The principal disease characteristics are organomegaly, skin lesions and raised lymphocyte counts. We report two cases of T PLL. T-PLL is a rare T-cell malignancy with characteristic clinical and laboratory features and a poor prognosis. It needs to be differentiated from B Cell prolymphocytic leukemia (B-PLL) and other mature T-cell lymphoproliferative disorders with predominant leukemic pattern. Differentiation can be made by a comprehensive approach taking into account the clinical features, the cell morphology and the immunophenotype of leukemic cells. PMID- 23100960 TI - Systemic mastocytosis with acute myelomonocytic leukemia: a case report. AB - Bone marrow mastocytosis may be associated with many clonal non mast cell hematological neoplasms and its association with acute myeloid leukemia especially with t (8; 21) has been described. We describe an interesting case of coexistence of systemic mastocytosis with acute myelomonocytic leukemia in a young child. Diagnosis of acute myelomonocytic leukemia was based on bone marrow aspirate findings coupled with cytochemistry. Systemic mastocytosis was diagnosed on the basis of bone marrow biopsy findings showing blasts as well as multifocal dense mast cell infiltrates with spindling and atypical morphology which was confirmed on toluidine blue staining. PMID- 23100961 TI - Early CNS toxicity after intrathecal methotrexate. PMID- 23100962 TI - Anaplastic myeloma: a morphologic diagnostic dilemma. PMID- 23100963 TI - Recombinant factor VIIa: use in fatal post partum hemorrhage - Indian experience case series and review of literature. AB - Postpartum hemorrhage is leading cause of maternal mortality and still remains a challenging condition to treat and hysterectomy may be required to control the bleeding once medical interventions fail. These strategies are not always successful and a direct approach in activating the coagulation system can be more effective and life saving. We describe here the mechanism of action of rFVIIa, review of literature and its use in 10 cases with different causes for PPH with good response. PMID- 23100964 TI - Can rituximab replace splenectomy in immune thrombocytopenic purpura? AB - AIM: Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by premature platelet destruction. Standard practice is to initiate treatment with corticosteroids, followed by splenectomy. Most published literature for responses from rituximab is in patients with chronic refractory ITP, who have failed multiple prior treatments, including splenectomy. We therefore decided to analyze our patient population with ITP who had been treated with rituximab, mainly as a second line treatment regimen prior to splenectomy. METHODS: We performed a retrospective chart review of patients with a diagnosis of ITP who had been treated with rituximab between January 2001 and December 2006 at our institution. RESULTS: 18/29 patients (62%) had a CR, 2/29 (7%) patients had a PR, representing an overall response rate of 69%. The average time to response was 5 weeks and all patients have maintained their response for more than 12 months after treatment with rituximab. CONCLUSION: Our study shows higher CR, comparable overall response rates, but with a longer duration of response when compared to the published literature. PMID- 23100965 TI - Diagnostic and prognostic values of S-phase fraction and aneuploidy in patients with bone marrow aplasia. AB - AIM: It is often difficult and challenging task to differentiate aplastic anemia (AA) from hypoplastic myelodysplastic syndrome (HMDS) among the patients with bone marrow aplasia. This is possibly because of the considerable clinical, cytological and histological similarities between these two disorders. As prognostic and therapeutic approach to AA and HMDS are different, it is imperative to differentiate them at the time of initial diagnosis. Various attempts have been made in the past to differentiate AA from HMDS. In the present study, we explored the value of certain new parameters i.e. S-phase fraction (SPF) and aneuploidy that could be used for this purpose. MATERIALS AND METHODS: The study included 46 consecutive patients with aplastic anemia, 15 patients with HMDS along with 32 age and sex-matched control subjects. S-phase fraction and aneuploidy analysis was carried out by flow cytometry using Mod Fit-LT V3.0 software. RESULTS: The mean SPF value was significantly lower (p=0.02) in patients with AA and higher (p=0.01) in HMDS as compared to that of the control. Aneuploidy was present in 15.2% patients with AA and in 33.3% HMDS cases. During follow-up, 4 patients with AA developed MDS, out of these, three patients had aneuploidy as well as high SPF value at the time of diagnosis. Two patients with HMDS who had aneuploidy and high SPF, converted into AML. Eleven patients died during the study, in whom 8 had aneuploidy and high SPF value. CONCLUSION: We conclude that high SPF value and presence of aneuploidy favour the diagnosis of HMDS rather than AA. SPF and aneuploidy may be important parameters in patients with AA to predict their propensity to evolve into myelodysplastic syndrome and acute myeloid leukemia. SPF value may also be useful in the early diagnosis of HMDS before morphologically evidence of dysplasia is apparent. PMID- 23100966 TI - Soluble angiopoietin-2/sTie2 receptor ratio is an independent prognostic marker in adult acute myeloid leukemia. AB - AIM: Angiogenesis is the formation of new blood vessels from preexisting one. The angiopoietins act a central role in these process. The aim of the present study is to the assess the impact of the circulating levels of angiopoietin-1 (Angi-1), Angiopoietin-2 (Angi-2), soluble Tie2 receptor (sTie2), and calculated Angi 2/sTie2 ratio on overall survival in 71 acute myeloid leukemia patients and 19 normal controls. MATERIALS AND METHODS: Ang-2, and calculated angi-2/sTie values were significantly higher in AML patients as compared to healthy volunteer (P= 0.002, 0.015 respectively) on the other hand Angi-1 was not significantly different in patients and control. RESULTS: In univariate Cox proportional hazards model Angi-2, sTie2, angi-2/sTie2 ratio were predictive of poor survival. In multivariate analysis the calculated angi-2/sTie2 ratio is independent prognostic factor, with relative risk of 3.939, with 95% confidence interval 0.002-0.001. CONCLUSION: The calculated angiopoietin-2/sTie2 ratio represent an independent prognostic factor in AML and its value should be considered when considering anti angiogenic therapy. PMID- 23100967 TI - Is red cell from an otherwise healthy G6PD-deficient donor efficient for transfusion to fauvism patients? AB - AIM: Glucose-6-Phosphate dehydrogenase (G(6)PD) deficiency is the most common X linked defect of enzyme pathways in human. The aim of this study was to inspect the efficacy of G(6)PD deficient red cell transfusion to G(6)PD patients, who were admitted for hemolysis after Broad bean ingestion, and to find out whether prolong management program and retransfusion are needed as severe hemolysis would take place. METHODS: This was a cross-sectional study, which was performed on patients admitted to hospital due to hemolytic anemia after broad bean ingestion in Jahrom and Shiraz medical school hospitals on February and March 2007. 2(ml) samples of transfusion blood bags, were sent to the laboratory in order to investigate the G(6)PD enzyme sufficiency. Hemoglobin level was checked six hours after blood transfusion. We compared the amount of hemoglobin level elevation after transfusion in patients received G(6)PD sufficient and G(6)PD deficient red cell using independent sample t-test. RESULT: In 114 transfused bags, 14 bags (12.3%) were G(6)PD deficient. We divided patients into two groups. Group A received G(6)PD sufficient red cell and group B were transfused with G(6)PD deficient red cell. Hemoglobin level was significantly raised after transfusion of red cell in each group. The amount of hemoglobin elevation was more in group A in comparison to group B. CONCLUSION: Based on our study results, proper hemoglobin level would be achieved using non G(6)PD deficient red cell for transfusion to G(6)PD deficient patients. PMID- 23100968 TI - Hook's effect - a rare presentation in HBsAg screening. AB - Detection of Hook's effect, the false negative results in HBs Ag immunoassay screening. Two drops of donor's serum was added to the sample well of hepacard device using a dropper and was allowed to react for 20 minutes and results read thereafter. The hepacard device when read after 20 minutes showed only one distinct pink test line and no control line. Serial dilutions (1:10, 1: 20) of the donors sample in normal saline was done and the test was re-run. Sample in 1: 10 dilution showed both control and faint pink test line, which intensified to pink band in 1: 20 diluted sample. The goal in the immunoassay detection of HBsAg should be to minimize erroneous results; so as not to endanger patient health and the blood supply. PMID- 23100969 TI - Ring chromosome 8 and trisomy 8 in a patient with acute myeloid leukemia. AB - We describe a child with Acute Myeloid Leukemia (AML M7) with trisomy 8 and ring chromosome 8. Ring chromosome 8 associated with AML is uncommon and is reported to have a poor outcome. The combination of trisomy 8 and ring chromosome 8 has not been previously reported. This 15-month-old girl had presented with a history of fever, weight loss of 1 kg, gum bleeds and pallor. Clinical examinations revealed no nodes or organomegaly. Investigations revealed pancytopenia and elevated serum LDH. Bone marrow aspirate confirmed the presence of myeloid blasts positive only for CD 41 and CD 61 on flow cytometry. Chromosomal analysis from the bone marrow showed 46, XX [13]/ 47, XX, +8[2]/ 47, XX, +r (8) [5]. The child was treated as per UK MRC AML protocol (ADE 10+3+5). Bone marrow on day 21 post induction was in morphological remission. Repeat karyotyping revealed 46,XX suggesting that the patient was in cytogenetic remission. Cytogenetic sub grouping in AML patients provides guidelines for the choice of optimal treatment strategy. There was no HLA matched family donor and hence an unrelated donor search was commenced as she was in the group with unfavourable cytogenetics. She developed acute myelofibrosis soon after the second cycle of chemotherapy with swinging fever and rapidly enlarging spleen. The marrow showed 11% blasts with intense fibrosis. She went through a stormy period during conditioning for unrelated stem cell transplantation. She passed away on day 11 post transplantation of veno-occlusive disease of liver and multiorgan failure. This case illustrates the poor outcome in paediatric AML with trisomy and ring chromosome 8. PMID- 23100970 TI - Paroxysmal nocturnal hemoglobinuria clone in a case of myelodysplastic syndrome rapidly progressing to acute leukemia. AB - Myelodysplastic syndrome (MDS) comprises a group of stem cell disorders with considerable clinical and morphological heterogeneity. We report a case of MDS in a middle-aged male with clinical features of sepsis, dysplastic neutrophils and 6% blasts on bone marrow aspirate. A clone of neutrophils with deficient expression of CD16, CD55 and CD59 was found. A diagnosis of MDS with excess blasts with co-existent paroxysmal nocturnal hemoglobinuria (PNH) was made. Within a fortnight, the patient progressed to acute myeloid leukemia. We are reporting this unusual case of MDS displaying a sizeable clone of dysplastic neutrophils deficient in glycosyl phosphatidyl inositol anchored proteins, highlighting a common origin of PNH and leukemic clone. PMID- 23100971 TI - Hard palate perforation in acute lymphoblastic leukemia due to mucormycosis - a case report. AB - Palatal perforation can occur due to trauma, infection and malignancy. Mucormycosis is a rare opportunistic fungal infection caused by an organism of class zygomycetes. Rhinocerebral mucormycosis is the most common type of mucormycosis that typically starts in maxillary antrum in immunocompromised patients. Invasion of surrounding structures leads to necrotizing ulcer of the hard palate and ultimately leads to perforation. Here, we report a case of perforation of the hard palate due to mucormycosis in a eight years child having acute lymphoblastic leukemia (ALL), who was on prolonged chemotherapy and corticosteroid therapy. This case is being reported for its rarity. The aim of presenting this case report is to emphasize that the infection due to mucomycosis should be included in the differential diagnosis of hard palate perforation in ALL patients who are immunocompromised. PMID- 23100972 TI - Exploring the (G)old standard treatment in steroid refractory idiopathic thrombocytopenic purpura in resource constraint countries. PMID- 23100973 TI - Microfilariae of Wucheria bancrofti in bone marrow. PMID- 23100974 TI - Pulmonary hypertension in patients with hematological disorders following splenectomy. AB - Prevalence of pulmonary arterial hypertension (PAH) was studied by echocardiography and Doppler in 43 splenectomized patients with various disorders 1-20 years after splenectomy. Pulmonary arterial hypertension was detected only in thalassemia major, intermedia, hereditary sphereocytosis and myelofibrosis groups comprising a total of 21 patients. Six patients out of 21 was found to have PAH with mean pulmonary arterial pressure of 46.28 +/- 28.17 mm of Hg. Twenty-one controls having similar duration and type of disease also were assessed for PAH in this case control study 3/21 had pulmonary arterial hypertension in this control group. The difference in number of patients showing pulmonary hypertension between case and control was not statistically significant (Chi square test P=0.29) though the difference in pulmonary arterial pressure between case and control were significantly different (t test P<0.0029) with control group showing a mean pulmonary arterial pressure of 25 +/- 19 mm Hg.Platelet count in the splenectomized group was significantly higher (P=0.0029) than the controls. Pulmonary thromboembolism was equally high in the PAH patients with and without splenectomy. Patients undergoing splenectomy due to trauma, immune thrombocytopenia, sideroblastic anemia, extrahepatic portal hypertension, autoimmune hemolytic anemia did not show PAH after splenectomy even years after the procedure PAH following splenectomy is common after certain disorders and control patients in these diseases have tendency to develop PAH even without splenectomy. Pulmonary thromboembolism may be an important pathophysiological mechanism leading to this condition. Patients having hemolytic anemia and myelofibrosis should have regular evaluation of pulmonary arterial pressure whether he/she has been splenectomized or not.This is particularly important as availability of phosphodiesterase inhibitors such as sildenafil allows one to manage these cases. PMID- 23100975 TI - Red cell alloimmunization in multitransfused patients and multiparous women. AB - PURPOSE: To determine the incidence of alloimmunization against red cell antigens and the thermal amplitude and specificity of antibodies in multitransfused patients and multiparous women. METHODS: Antibody screening was performed in 30 nontransfused orthopedic surgery cases (control), 504 multitransfused patients and 325 multiparous women. Antibody screening at 4 degrees C, 22 degrees C and 37 degrees C was carried out in a saline phase, by indirect antiglobulin technique (IAT), using papain cystein, low ionic strength solution (LISS) and polyethylene glycol (PEG). RESULTS: In multitransfused patients IgM antibodies were more frequently detected at 4 degrees C and the IgG antibody incidence was 7.1% by enzyme method, 7.7% IAT, 9.4% LISS, 10.2% using PEG & 10.2% multiparous women. Bad obstetric history cases had significantly higher incidence of alloimmunization. The antibody specificity of antibodies was mainly in Lewis, Rh, Kidd and MN systems. CONCLUSION: Antibody screening before transfusion, at set time intervals after transfusion and during antenatal period is recommended. PMID- 23100976 TI - Circadian pattern of acute variceal bleeding among cirrhotic Egyptian patients. AB - BACKGROUND: Liver cirrhosis is the most common cause of portal hypertension which may end in serious bleeding from gastro-esophageal varices. Recent studies have demonstrated a daily pattern of acute upper gastrointestinal bleeding in patients with liver cirrhosis evidenced by one or two peaks throughout the day. AIM: The assessment of the circadian rhythm of acute variceal bleeding with the possible participation of circadian changes of the fibrinolytic parameters. PATIENTS AND METHODS: The study included 264 patients with liver cirrhosis and upper gastrointestinal bleeding in addition to 20 healthy subjects as a control group. A series of hemostatic tests and parameters including prothrombin (PT), activated partial thromboplastin time (APTT), fibrinogen (Fib), Factors II, V, VII, IX, X, XI, platelets counts and fibrinolytic parameters assessement were completed in 60 patients in addition to the control group. The fibrinolytic activity was assessed by estimation of plasminogen, tissue plasminogen activator antigen (tPA: Ag) and plasminogen activator inhibitor antigen (PAI-1: Ag) at hour 09:00 and hour 17:00. The hemostatic tests and liver function tests were assessed once at hour 09.00. RESULTS: We observed statistically significant two time peaks of upper gastrointestinal bleeding at hour 04:00 and hour 17:00 with a peak of the fibrinolytic parameter, tissue plasminogen activator antigen, with the night peak of bleeding. A significant correlation between the levels of fibrinolytic parameters and hemostatic factors as well as liver function tests were detected. CONCLUSION: There are two time peaks of upper gastrointestinal bleeding with a temporal association between the night peak and a relative hyperfibrinolytic state. PMID- 23100977 TI - Anxiety and depression affects life and sleep quality in adults with beta thalassemia. AB - PURPOSE: The aim of this study was to investigate the association of anxiety and depression symptoms with health related quality of life (HRQoL) and sleep quality in patients with beta-thalassemia. METHODS: In a cross-sectional study between 2006 and 2007, 292 thalassemic patients were assessed for symptoms of anxiety and depression (Hospital Anxiety Depression Scale; HADS), HRQoL (Short Form-36, SF 36) and quality of sleep (Pittsburgh Sleep Quality Index; PSQI). Linear regression models were used to determine possible predictive value of high anxiety and depressive symptoms on HRQoL and sleep quality, separately. RESULTS: Mental and physical quality of life scores were predicted by symptoms of depression and somatic comorbidities. Total sleep quality was predicted by anxiety symptoms and somatic comorbidities. CONCLUSIONS: Screening for anxiety and depression in patients with thalassemia is essential. Further studies should test if appropriate treatment of these conditions may improve patients HRQoL and sleep quality or not. PMID- 23100978 TI - Rational use of blood components - an audit. AB - OBJECTIVES: The present study was designed to study appropriateness of use of the blood components in pediatric and neonatal wards. DESIGN: It was an observational study conducted in a tertiary care institute. The patients were selected from various pediatric subsections over a period of six months. MATERIALS AND METHODS: All the patients below 12 years of age, who received blood components in any of the pediatric subsections including general pediatric wards, pediatric intensive care unit, pediatric hematology section, neonatal intensive care unit and pediatric surgery ward were included in the study. Each transfusion episode was assessed to decide whether it satisfied the predetermined criteria. RESULTS: Of the total 184 episodes of blood component transfusions, 153 (83.1%) episodes were appropriate and 31 (16.9%) episodes were inappropriate. Among these, fresh frozen plasma transfusions had highest inappropriate [18/41 (58%)] episodes followed by packed red cell transfusions [11/110 (35.5%)] and platelet transfusions [2/5 (6.45%)]. There was no inappropriate episode of cryoprecipitate transfusion. CONCLUSIONS: The present study reinforces the importance of blood audit in the clinical setting. Judicious implementation of guidelines for use of various blood products may help decrease the inappropriate use of blood components. PMID- 23100979 TI - Effect of iron deficiency anemia and its treatment on cell mediated immunity. AB - Iron deficiency anemia (IDA) is one of the most prevalent micronutrient deficiencies particularly in the developing countries. While there is evidence of an altered immune profile in iron deficiency, the exact immunoregulatory role of iron is not known. Knowledge particularly in children, who are vulnerable to iron deficiency and infection, is lacking. We aimed to study the effects of IDA and its treatment with oral iron supplementation on cell-mediated immunity. The levels of T-lymphocytes, their CD4(+), CD8(+) and CD1a(+) subsets, transferrin receptor (CD71) and serum ferritin were evaluated in 40 iron-deficient and 40 healthy children. The impact of oral iron supplementation for three months on the same parameters was also noted in children with IDA. The level of mature T lymphocytes (CD4(+) and CD8(+)) was significantly lower (P<0.001) while that of the immature T-cells (CD1a(+)) was significantly higher (p<0.001) in IDA children compared to the control. The mature T-cell count was significantly improved after iron therapy. In spite of significant reduction in the immature T-cells (CD1a(+)) level after iron supplementation, it was significantly higher than the control. The present study demonstrated that T-lymphocytes maturation was defective in IDA and improved partially after 3 months of iron supplementation. Therefore, longer time of iron therapy may be required to induce complete maturation of T lymphocytes. PMID- 23100980 TI - Familial hemophagocytic lymphohistiocytosis. AB - A 45-day-old infant presented with hepatosplenomegaly and fever since 15 days. Hemogram revealed bicytopenia and bone marrow aspirate showed hemophagocytosis. With the history of death of two siblings, the baby was diagnosed with hemophagocytic lymphohistiocytosis (HLH), likely to be of familial origin. PMID- 23100981 TI - Primary non-secretory plasma cell leukemia with atypical morphology - a case report. AB - Only one case of primary non-secretory plasma cell leukemia with atypical morphology has been reported thus far. Here we report another such case of plasma cell leukemia diagnosed on fl ow cytometry, as morphological heterogeneity and lack of monoclonal immunoglobulins in both serum and urine, made it difficult to come to a conclusive diagnosis based purely on morphology. PMID- 23100982 TI - Plasma cells in bone marrow - an artifactual change mimicking metastasis. PMID- 23100983 TI - Are medicated adhesive bands at the phlebotomy site useful? PMID- 23100984 TI - Utilization of blood and components in a tertiary care hospital. AB - PURPOSE: Blood transfusion is an important part of patient management. Indications for blood use must be clear in the mind of ordering clinicians, to avoid its misuse and also to avoid unnecessary exposure of the patient to donor blood antigens, adverse reactions and transfusion transmissible diseases. METHODS: In a retrospective pilot study, details of whole blood and components transfused were noted and correlated with the patient's diagnosis and indications for transfusion, during 1 month. RESULTS: The blood units supplied were 720. Whole blood was the most utilized product; followed by packed red blood cells. Supply of blood was maximum to the surgical wards. The patients of trauma followed by malignancy and surgery required whole blood mostly. Anemia was the most common indication for blood products. CONCLUSIONS: Periodic review of blood component usage is very important to assess the blood utilization pattern in any hospital. PMID- 23100985 TI - Flow cytometry detection of platelets autoantibodies in children with idiopathic thrombocytopenic purpura. AB - Immune thrombocytopenic purpura is an acquired disorder, in which accelerated platelet consumption is due to platelet autoantibodies. The aim of this study was to investigate the clinical value of platelet autoantibodies assay in children with ITP and to evaluate flow cytometry in the detection of platelet autoantibodies in comparison with monoclonal antibody specific immobilization of platelet antigen (MAIPA) assay. We measured platelet autoantibodies by flow cytometry and MAIPA in 18 children with ITP (6 acute, 7 chronic and 5 in remission), in addition to 5 healthy children with matched age and sex as a control group. Significant elevation of platelet-associated immunoglobulin G (PAIgG), PAIgM and PAIgA was demonstrated in children with acute ITP compared to controls and children with chronic ITP (P < 0.05). There was significant elevation of PAIgG and PAIgM in children with acute ITP compared to children with ITP in remission (P < 0.05). There was significant negative correlation between platelet count and PAIgG levels in ITP children (r = -0.717; P = 0.001). Flow cytometry found PAIgG in 94.4% of ITP children. MAIPA has detected platelet specific IgG autoantibodies in 83.3% of ITP children. ROC analysis revealed sensitivity of 94%, specificity of 57% with overall accuracy of 83% for detection of PAIgG by flow cytometry compared to MAIPA. CONCLUSIONS: Platelet autoantibodies testing in ITP can discriminate acute from chronic forms of the disease and is helpful in follow up of patients. Determination of PAIgM in combination of PAIgG could be of interest in the investigation of ITP. Flow cytometry is a sensitive method of detection of platelet autoantibodies that could be used in screening of suspected ITP and should be followed by MAIPA assay in positive cases to establish the diagnosis. PMID- 23100986 TI - Potent suppression of agglutinability of human A and B type erythrocytes by KMnO(4)-EDTA concerted action. AB - PURPOSE OF THE STUDY: Study was focused to effectively suppress the agglutinability of human A and B type erythrocyte by concerted chemical oxidation approach. Consequently some major bio-physiological consequences of human erythrocytes were analyzed. MATERIALS AND METHODS: Concerted chemical oxidation of human A and B type erythrocyte were done by potassium permanganate (KMnO(4)) in presence of ethylene diamine tetra-acetic acid (EDTA). All the chemical reactions were carried out at 37 degrees C temperature and pH 7.4 in phosphate buffer. Finally, suppression of agglutinability were determined by using anti-A and anti-B antisera. RESULTS: A marked suppression in agglutinability was observed after chemical treatment on human A and B type erythrocytes in vitro. Effective suppression of agglutinability was observed in 0.57 mM concentration of KMnO(4) in presence of 0.9 mM EDTA at optimum condition. CONCLUSIONS: Results showed that KMnO(4)-EDTA concerted action is feasible. The future work is directed towards the universal human erythrocytes preparation from A and B type human erythrocytes. PMID- 23100987 TI - India's first public cord blood repository - looking back and moving forward. AB - Umbilical cord blood is an established source of stem cells useful for hematopoetic reconstitution. The first clinical transplantation in France by Eliane Gluckman in 1988 using HLA matched umbilical cord blood from a sibling on a 6-year-old boy with Fanconi's anemia is an example of a successful transplantation. So far, more than 8,000 patients worldwide have been treated for malignant and inherent blood disorders [1, 2]. Our cord blood repository (CBR) was established as the part of the Life Sciences initiative, almost 7 years ago. The cord blood program consisted of developing a good network of obstetricians and social workers, develop manpower in various aspects of the banking activity, develop methods of process and analysis and above all, increase the level of awareness among the medical, paramedical fraternity and the general public on the cord blood program. The present paper gives a detailed account of our experience as we set up the repository. PMID- 23100988 TI - CNS relapse in a low risk acute promyelocytic leukemia patient treated with ATRA based regimen: is there a role for prophylactic CNS therapy in acute promyelocytic leukemia? AB - Though the incidence of CNS relapse in acute promyelocytic leukemia (AML-M3 FAB classification) has increased following the advent of all-trans retinoic acid (ATRA), still CNS relapse accounts for only 2-3% of all relapses in AML-M3 trated with standard ATRA plus chemotherapy regimen. We report a case of low risk AML-M3 treated with standard therapy, developing CNS relapse while on maintenance therapy with ATRA + 6-mercaptopurine (6-MP) + methotrexate (MTX). PMID- 23100989 TI - Surgical approach of primary splenic lymphoma: report of a case and review of the literature. AB - A 80-year-old woman was hospitalized due to anemia and fever. Computed tomography depicted a solitary concentric, sharply marginated lesion of the spleen. Laparotomy identified a creamy-white soft tumor. Histopathological examination confirmed the diagnosis of non-Hodgkin B-cells anaplastic lymphoma. Extended range of pathological manifestations explains the variety of radiological appearances and difficulty in accurate diagnostic process of primary splenic lymphoma. PMID- 23100990 TI - Concern on blood safety in case of swine flu. PMID- 23100991 TI - Pulmonary hypertension in patients with hematological disorders following splenectomy. AB - Prevalence of pulmonary arterial hypertension (PAH) was studied by Echocardiography and Doppler in 43 splenectomised patients with various disorders 1-20 years after splenectomy. PAH was detected only in thalassemia major, intermedia, hereditary sphereocytosis and myelofibrosis groups comprising a total of 21 patients. Six patients out of 21 was found to have PAH with mean pulmonary arterial pressure of 46.28 +/- 28.17 mmHg. Twenty one controls having similar duration and type of disease also were assessed for PAH in this case control study 3/21 had PAH in this control group. The difference in number of patients showing pulmonary hypertension between case and control was not statistically significant (chi-square test p = 0.29-though the difference in pulmonary arterial pressure between case and control were significantly different (t-test p<0.0029) with control group showing a mean pulmonary arterial pressure of 25 +/- 19 mmHg.Platelet count in the splenectomised group was significantly higher (p = 0.0029) than the controls. Pulmonary thromboembolism was equally high in the PAH patients with and without splenectomy. Patients undergoing splenectomy due to trauma, immune thrombocytopenia, sideroblastic anemia, extra hepatic portal hypertension, autoimmune hemolytic anemia did not show PAH after splenectomy even years after the procedure PAH following splenectomy is common after certain disorders and control patients with these diseases have tendency to develop PAH even without splenectomy. Pulmonary thromboembolism may be an important pathophysiological mechanism leading to this condition. Patients having hemolytic anemia and myelofibrosis should have regular evaluation of pulmonary arterial pressure whether he/she has been splenectomised or not. This is particularly important as availability of phosphodiesterase inhibitors like sildenafil allows one to manage these cases. PMID- 23100992 TI - Mutation in Rh48: Assessment for possible mutation prone point. AB - Rh antigen is a widely studied but not already known antigen. RH48 (JAL) is a low incidence Rh antigen of unknown molecular background and is proposed for association with weakened expression of RhCE antigens. Here, the author performed a bioinformatics approach to study the probability of JAL mutation. It can be shown that JAL is a highly unstable molecule that is prone for mutation. PMID- 23100993 TI - L-asparaginase induced fatal cortical venous thrombosis in acute lymphoblastic leukemia. AB - L-asparaginase has become an integral part in the treatment of acute lymphoblastic leukemia. The major worry of using L-asparaginase is thromboembolism. The case presented here is a 21-year-old lady who developed fatal cortical venous thrombosis during induction phase of treatment for ALL. Early recognition is very important to treat this potentially catastrophic yet treatable complication. PMID- 23100994 TI - Mycosis fungoides: A case report. AB - Mycosis fungoides is the commonest cutaneous T cell lymphoma. Clinically it is characterized by patch, plaque, tumor nodules; erythrodermic and poikoilodermous stages which may overlap. Extracutaneous spread takes place in late stages where any organ may be involved. The majority of reported cases are in adult males. A rare case of mycosis fungoides in a 38-year-old female is described. She presented in advance stage of disease with nodules all over the body. PMID- 23100995 TI - Ascitic fluid cytology and flow cytometry in the primary diagnosis of lymphoma - a case report. AB - Primary diagnosis of lymphomas from ascitic fluid is rare. We report a case in which a patient being worked up as a case of carcinoma head of pancreas turned out to be a lymphoma on routine ascitic fluid examination and was further sub classified as a CD 10+ B-cell lymphoma on flow cytometric analysis. PMID- 23100996 TI - T lymphoblastic lymphoma relapsing in skin - a rare clinical scenario. PMID- 23100997 TI - Association of polymorphic pattern of the (AT) * (T)y motif of beta-globin gene in North Indian thalassemia patients with variable clinical expression. AB - Among the polymorphic genetic markers of the beta-globin gene cluster, the (AT) * (T)y motif and a common C->T variation at -158 of the Ggamma globin gene were investigate din 20 beta-thalassemia IVSI-5 (G->C) homozygous patients with variable clinical manifestation and 10 normal subjects from north India to deduce any association with the co-inherited genetic polymorphism. We found (AT)(7)(T)(7) repeat motif in all the 20 chromosomes of normal subjects and two different sequence configuration(AT)(8)(T)(5), (AT)(9)(T)(5) in the patient group whereas the presence of -158(C->T) Ggamma was quite polymorphic. We conclude that polymorphism -158(C->T) Ggamma and (AT) * (T)y sequence variation other than (AT)(7)(T)(7) could influence the phenotype by increasing Hb F expression. PMID- 23100998 TI - Comparison of DNA-Reactive Metabolites from Nitrosamine and Styrene Using Voltammetric DNA/Microsomes Sensors. AB - Voltammetric sensors made with films of polyions, double-stranded DNA and liver microsomes adsorbed layer-by-layer onto pyrolytic graphite electrodes were evaluated for reactive metabolite screening. This approach features simple, inexpensive screening without enzyme purification for applications in drug or environmental chemical development. Cytochrome P450 enzymes (CYPs) in the liver microsomes were activated by an NADPH regenerating system or by electrolysis to metabolize model carcinogenic compounds nitrosamine and styrene. Reactive metabolites formed in the films were trapped as adducts with nucleobases on DNA. The DNA damage was detected by square-wave voltammetry (SWV) using [Formula: see text] as a DNA-oxidation catalyst. These sensors showed a larger rate of increase in signal vs. reaction time for a highly toxic nitrosamine than for the moderately toxic styrene due to more rapid reactive metabolite-DNA adduct formation. Results were consistent with reported in vivo TD(50) data for the formation of liver tumors in rats. Analogous polyion/ liver microsome films prepared on 500 nm silica nanoparticles (nanoreactors) and reacted with nitrosamine or styrene, provided LC-MS or GC analyses of metabolite formation rates that correlated well with sensor response. PMID- 23100999 TI - Personality and Parenting Processes Associated with Problem Behaviors: A Study of Adolescents in Santiago, Chile. AB - Considerable research in the U.S. has established that adolescent antisocial, aggressive, and attention problems have a negative influence on adolescents' ability to become productive members of society. However, although these behaviors appear in other cultures, little is known about the development of these problems among adolescents in countries other than the U.S.. This study contributes to our understanding of personality and parenting factors associated with adolescent problem behaviors using an international sample. Data are from a NIDA-funded study of 884 community-dwelling adolescents in Santiago, Chile (Mean age=14, SD=1.4, 48% females) of mid-to-low socioeconomic status. Results revealed that rule-breaking and aggressive behaviors were both associated with greater levels of adolescent drive but lower levels of parental monitoring and positive parenting by both parents. Adolescents who reported more attention problems were more likely to exhibit driven behavior, more behavioral inhibition, to report lower levels of parental monitoring, and positive parenting by mother and father. Results of interactions revealed that the influences of positive parenting and parental monitoring on adolescent aggressive behaviors varied as a function of the gender of the adolescent. Helping parents build on their parenting skills may result in important reductions in adolescent problem behaviors among U.S. and international adolescents. PMID- 23101000 TI - Modeling Of In-Vehicle Human Exposure to Ambient Fine Particulate Matter. AB - A method for estimating in-vehicle PM(2.5) exposure as part of a scenario-based population simulation model is developed and assessed. In existing models, such as the Stochastic Exposure and Dose Simulation model for Particulate Matter (SHEDS-PM), in-vehicle exposure is estimated using linear regression based on area-wide ambient PM(2.5) concentration. An alternative modeling approach is explored based on estimation of near-road PM(2.5) concentration and an in-vehicle mass balance. Near-road PM(2.5) concentration is estimated using a dispersion model and fixed site monitor (FSM) data. In-vehicle concentration is estimated based on air exchange rate and filter efficiency. In-vehicle concentration varies with road type, traffic flow, windspeed, stability class, and ventilation. Average in-vehicle exposure is estimated to contribute 10 to 20 percent of average daily exposure. The contribution of in-vehicle exposure to total daily exposure can be higher for some individuals. Recommendations are made for updating exposure models and implementation of the alternative approach. PMID- 23101001 TI - Multiplying with DNA. AB - A functional machine is not only an assembly of parts, but also an assembly of processes. The processing of each part must obey laws that respect to the property of this part. For example, building any kind of computer entails selecting appropriate components and assembling their properties to function in computation. Here, we describe computation using a DNA strand as the basic unit and we have used this unit to achieve the function of multiplication. We exploit the phenomenon of DNA hybridization, in which each strand can represent two individual units that can pair to form a single unit. We represent the numbers we multiply in binary, with different lengths representing each digit present in the number. In principle, all combinations of the numbers will be present in solution. Following hybridization, there is present a collection of duplex molecules that are tailed by single-stranded ends. These intermediates are converted to fully duplex molecules by filling in the ends with DNA polymerase. The lengths that are present represent the digits that are present, and they may be separated by denaturing PAGE. The results give a series of bands for each power of two. The number of bands in the size domain for a particular power of two is converted to binary and the sum of all present bands is then added together. Experimentally, the result of this process always yields the correct answer. PMID- 23101002 TI - High information throughput analysis of nucleotides and their isotopically enriched isotopologues by direct-infusion FTICR-MS. AB - Fourier transform-ion cyclotron resonance-mass spectrometry (FTICR-MS) is capable of acquiring unmatched quality of isotopologue data for stable isotope resolved metabolomics (SIRM). This capability drives the need for a continuous ion introduction for obtaining optimal isotope ratios. Here we report the simultaneous analysis of mono and dinucleotides from crude polar extracts by FTICR-MS by adapting an ion-pairing sample preparation method for LC-MS analysis. This involves a rapid cleanup of extracted nucleotides on pipet tips containing a C(18) stationary phase, which enabled global analysis of nucleotides and their (13)C isotopologues at nanomolar concentrations by direct infusion nanoelectrospray FTICR-MS with 5 minutes of data acquisition. The resolution and mass accuracy enabled computer-assisted unambiguous assignment of most nucleotide species, including all phosphorylated forms of the adenine, guanine, uracil and cytosine nucleotides, NAD(+), NADH, NADP(+), NADPH, cyclic nucleotides, several UDP-hexoses, and all their (13)C isotopologues. The method was applied to a SIRM study on human lung adenocarcinoma A549 cells grown in [U-(13)C] glucose with or without the anti-cancer agent methylseleninic acid. At m/z resolving power of 400,000, (13)C-isotopologues of nucleotides were fully resolved from all other elemental isotopologues, thus allowing their (13)C fractional enrichment to be accurately determined. The method achieves both high sample and high information throughput analysis of nucleotides for metabolic pathway reconstruction in SIRM investigations. PMID- 23101003 TI - Modulation of Viscoelasticity and HIV Transport as a Function of pH in a Reversibly Crosslinked Hydrogel. PMID- 23101004 TI - Cardiopulmonary resuscitation: new concept. AB - Cardiopulmonary resuscitation (CPR) is a series of life-saving actions that improve the chances of survival, following cardiac arrest. Successful resuscitation, following cardiac arrest, requires an integrated set of coordinated actions represented by the links in the Chain of Survival. The links include the following: immediate recognition of cardiac arrest and activation of the emergency response system, early CPR with an emphasis on chest compressions, rapid defibrillation, effective advanced life support, and integrated post cardiac arrest care. The newest development in the CPR guideline is a change in the basic life support sequence of steps from "A-B-C" (Airway, Breathing, Chest compressions) to "C-A-B" (Chest compressions, Airway, Breathing) for adults. Also, "Hands-Only (compression only) CPR" is emphasized for the untrained lay rescuer. On the basis of the strength of the available evidence, there was unanimous support for continuous emphasis on high-quality CPR with compressions of adequate rate and depth, which allows for complete chest recoil, minimizing interruptions in chest compressions and avoiding excessive ventilation. High quality CPR is the cornerstone of a system of care that can optimize outcomes beyond return of spontaneous circulation (ROSC). There is an increased emphasis on physiologic monitoring to optimize CPR quality, and to detect ROSC. A comprehensive, structured, integrated, multidisciplinary system of care should be implemented in a consistent manner for the treatment of post-cardiac arrest care patients. The return to a prior quality and functional state of health is the ultimate goal of a resuscitation system of care. PMID- 23101005 TI - Increasing trend of isolation of non-tuberculous mycobacteria in a tertiary university hospital in South Korea. AB - BACKGROUND: The isolation of non-tuberculous mycobacteria (NTM) has been increasing in South Korea. To date, however, the cause of this increase has not been determined, and it remains unclear whether the use of liquid media has contributed to this increase. The aim of this study was to evaluate the factors associated with NTM isolation and the impact of liquid media on NTM culture. METHODS: Mycobacterial smear/culture results of respiratory specimens (sputum and bronchial aspirates), obtained during the years 2002, 2005, and 2010, were retrieved and analyzed retrospectively. RESULTS: During the years 2002, 2005, and 2010, 83,096 sputum specimens were collected from 31,104 patients, and were cultured for mycobacteria, using solid media only in the 2002 and 2005 specimens and both solid and liquid media in the 2010. Of these, 3,516 (4.2%) specimens were smear-positive for acid-fast bacilli (AFB). The annual rate of NTM among positive culture specimens increased from 21% in 2002 to 57.8% in 2010 (p<0.001), as did the proportion of NTM, among AFB smear- and culture-positive specimens, from 12.2% in 2002 to 45.2% in 2010 (p<0.001). In 2010, the NTM culture rate was higher in the liquid than in the solid media (13.9% vs. 8.4%, p<0.001). The NTM rate among AFB-positive specimens was higher in patients aged >50 than <=50 years. CONCLUSION: The rate of NTM isolation has steadily been increasing at the hospital in South Korea, likely due in part to the use of liquid media for the culture. PMID- 23101006 TI - Factors Associated with Indeterminate and False Negative Results of QuantiFERON TB Gold In-Tube Test in Active Tuberculosis. AB - BACKGROUND: The sensitivities and specificities of interferon-gamma release assays (IGRAs) vary among different population studies, and the data on the routine use of IGRAs are limited. The aim of this study was to evaluate the role of QuantiFERON-TB Gold In-Tube (QFT-GIT) test in the diagnosis of active tuberculosis. METHODS: We conducted a prospective study, enrolling 77 patients with suspected pulmonary tuberculosis (TB), at a secondary care teaching hospital in Seoul. RESULTS: In total, 12 (15.6%) patients showed indeterminate results due to positive control failure on the QFT-GIT test. Indeterminate results were significantly associated with the elderly, history of the intensive care unit stay, lymphocytopenia, especially low CD4 count, increased C-reactive protein and decreased protein levels. Of the 77 patients, 44 (57.1%) were diagnosed with active pulmonary tuberculosis, and the percentage of false negative results of the QFT-GIT was 36.4% (vs. 31.8% with TST). In the TB group with >65 years old (n=12), the proportions of the indeterminate (33.3% vs. 3.1%) and the false negative results (58.3% vs. 25.0%) of the QFT-GIT were significantly higher than in the younger TB group (n=32). CONCLUSION: Indeterminate and false negative results of QFT-GIT test were not infrequent in tuberculosis, especially in the elderly. Care should be considered for the interpretation with the elderly, immunocompromised, chronic and severely diseased patients. PMID- 23101007 TI - Adherence to varenicline and abstinence rates for quitting smoking in a private health promotion center-based smoking cessation clinic. AB - BACKGROUND: Varenicline is an effective smoking cessation aid. However, smokers prescribed with varenicline do not always receive varenicline for 12 weeks, as recommended. This study analyzed the subjects who received varenicline and investigated the effect of varenicline treatment duration on the success rate of 6-month smoking cessation. METHODS: This study retrospectively analyzed 78 subjects, who received varenicline, out of the 105 smokers that had visited the smoking cessation clinic after medical examination from September 2007 to December 2009. RESULTS: The subjects were all males. Twenty-two subjects (28.2%) had varenicline treatment for 12 weeks or longer; 18 subjects (23.1%) for 8~12 weeks; 22 subjects (28.2%) for 4~8 weeks; and 16 subjects (20.5%) for less than 4 weeks. The total success rate of the 6-month smoking cessation was 47.4%. The success rate of the 6-month smoking cessation was 63.6% in the group that received varenicline for 12 weeks or longer, which was higher than 41.1% of the group that early terminated the varenicline treatment (p=0.074). The period of varenicline treatment was extended for one more week, the odds ratio of the 6 month smoking cessation success increased to 1.172-folds (p=0.004; 95% confidence interval, 1.052~1.305). Adverse events occurred in 30.8% of the subjects who received varenicline, but no serious adverse events were found. CONCLUSION: If varenicline treatment period is extended, the odds ratio of the success rate for the 6-month smoking cessation increases. Therefore, an effort to improve drug compliance for varenicline in clinical practices could be helpful for the long term success of smoking cessation. PMID- 23101008 TI - The effect of body composition on pulmonary function. AB - BACKGROUND: The pulmonary function test is the most basic test method to diagnosis lung disease. The purpose of this study was to research the correlation of the body mass index (BMI), the fat percentage of the body mass (fat%), the muscle mass, the fat-free mass (FFM) and the fat-free mass index (FFMI), waist hip ratio (WHR), on the forced expiratory volume curve. METHODS: Between March and April 2009, a total of 291 subjects were enrolled. There were 152 men and 139 female (mean age, 46.3+/-9.92 years), and they were measured for the following: forced vital capacity (FVC), forced expiratory volume at 1 second (FEV(1)), and forced expiratory flow during the middle half of the FVC (FEF(25-75)) from the forced expiratory volume curve by the spirometry, and the body composition by the bioelectrical impedance method. Correlation and a multiple linear regression, between the body composition and pulmonary function, were used. RESULTS: BMI and fat% had no correlation with FVC, FEV(1) in male, but FFMI showed a positive correlation. In contrast, BMI and fat% had correlation with FVC, FEV(1) in female, but FFMI showed no correlation. Both male and female, FVC and FEV(1) had a negative correlation with WHR (male, FVC r=-0.327, FEV(1) r=-0.36; p<0.05; female, FVC r=-0.175, FEV(1) r=-0.213; p<0.05). In a multiple linear regression of considering the body composition of the total group, FVC explained FFM, BMI, and FFMI in order (r(2)=0.579, 0.657, 0.663). FEV(1) was explained only fat% (r(2)=0.011), and FEF(25-75) was explained muscle mass, FFMI, FFM (r(2)=0.126, 0.138, 0.148). CONCLUSION: The BMI, fat%, muscle mass, FFM, FFMI, WHR have significant association with pulmonary function but r(2) (adjusted coefficient of determination) were not high enough for explaining lung function. PMID- 23101009 TI - Bronchoscopic ethanolamine injection therapy in patients with persistent air leak from chest tube drainage. AB - BACKGROUND: Chest tube drainage (CTD) is an indication for the treatment of pneumothorax, hemothroax and is used after a thoracic surgery. But, in the case of incomplete lung expansion, and/or persistent air leak from CTD, medical or surgical thoracoscopy or, if that is unavailable, limited thoracotomy, should be considered. We evaluate the efficacy of bronchoscopic injection of ethanolamine to control the persistent air leak in patients with CTD. METHODS: Patients who had persistent or prolonged air leak from CTD were included, consecutively. We directly injected 1.0 mL solution of 5% ethanolamine oleate into a subsegmental or its distal bronchus, where it is a probable air leakage site, 1 to 21 times using an injection needle through a fiberoptic bronchoscope. RESULTS: A total of 15 patients were enrolled; 14 cases of spontaneous pneumothorax [idiopathic 9, chronic obstructive pulmonary disease (COPD) 3, post-tuberculosis 2] and one case of empyema associated with broncho-pleural fistula. Of these, five were patients with persistent air leak from CTD, just after a surgical therapy, wedge resection with plication for blebs or bullae. With an ethanolamine injection therapy, 12 were successful but three (idiopathic, COPD and post-tuberculosis) failed, and were followed by a surgery (2 cases) or pleurodesis (1 case). Some adverse reactions, such as fever, chest pain and increased radiographic opacities occurred transiently, but resolved without any further events. With success, the time from the procedure to discharge was about 3 days (median). CONCLUSION: Bronchoscopic ethanolamine injection therapy may be partially useful in controlling air leakage, and reducing the hospital stay in patients with persistent air leak from CTD. PMID- 23101010 TI - Invasive aspergillosis involving the lungs and brain after short period of steroid injection: a case report. AB - Invasive pulmonary aspergillosis (IPA) has emerged as a severe infection in patients with immunocompromised hosts. However, recently, several IPA cases, without an apparent predisposition to immunodeficiency, has been reported. A 72 year-old woman was admitted for evaluation of general weakness and poor oral intake. She reported no medical history, except for intraarticular injection of a corticosteroid for joint pain for the duration of two months. A chest radiography revealed multiple cavitary nodules in both lungs. Examination of specimens, obtained by percutaneous needle biopsy, led to a diagnosis of invasive aspergillosis. Brain magnetic resonance imagining revealed numerous peripheral thin enhancing cystic nodules in both cerebral hemispheres. We initiated intravenous administration of amphotercin B. However, the patient died after nine days. Here, we report an invasive aspergillosis case, which involves the lungs and brain after a short period of steroid injection. PMID- 23101011 TI - Disseminated Mycobacterium intracellulare Infection in an Immunocompetent Host. AB - Disseminated Mycobacterium avium complex (MAC) infection can occur in immunocompromised patients, and rarely in immunocompetent subjects. Due to the extensive distribution of the disease, clinical presentation of disseminated MAC may mimic malignancies, and thorough examinations are required in order to make accurate diagnosis. We report a case of disseminated Mycobacterium intracellulare disease in an immunocompetent patient, which involved the lung, lymph nodes, spleen, and multiple bones. F-18 fluorodeoxyglucose positron-emission tomography imaging showed multiple hypermetabolic lesions, which are suggestive of typical hematogenous metastasis. However, there was no evidence of malignancy in serial biopsies, and M. intracellulare was repeatedly cultured from respiratory specimens and bones. Herein, we should know that disseminated infection can occur in the immunocompetent subjects, and it can mimic malignancies. PMID- 23101012 TI - Validity and Reliability of CAT and Dyspnea-12 in Bronchiectasis and Tuberculous Destroyed Lung. AB - BACKGROUND: The objective of this study was to assess the validity and reliability of the Korean version of chronic obstructive pulmonary disease assessment test (CAT) and Dyspnea-12 Questionnaire for patients with bronchiectasis or tuberculous destroyed lung. METHODS: For 62 bronchiectasis patients and 37 tuberculous destroyed lung patients, 3 questionnaires including St. George's Respiratory Questionnaires (SGRQ), CAT, and Dyspnea-12 were obtained, in addition to spirometric measurements. To assess the validity of CAT and Dyspnea-12, correlation with SGRQ was evaluated. To assess the reliability of CAT and Dyspnea-12, Cronbach's alpha coefficient was calculated. RESULTS: The mean ages of the patients were 60.7+/-8.3 years in bronchiectasis and 64.4+/-9.3 years in tuberculous destroyed lung. 46.8% and 54.1% were male, respectively. The SGRQ score was correlated with the score of the Korean version of CAT (r=0.72, p<0.0001) and Dyspnea-12 (r=0.67, p<0.0001) in bronchiectasis patients. The SGRQ score was correlated with the score of CAT (r=0.86, p<0.0001) and Dyspnea-12 (r=0.80, p<0.0001) in tuberculous destroyed lung patients. The Cronbach's alpha coefficient for the CAT and Dyspnea-12 were 0.84 and 0.90 in bronchiectasis, and 0.88 and 0.94 in tuberculous destroyed lung, respectively. CONCLUSION: We found that Korean version of CAT and Dyspnea-12 are valid and reliable in patients with tuberculous destroyed lung and bronchiectasis. PMID- 23101013 TI - pncA Mutations in the Specimens from Extrapulmonary Tuberculosis. AB - BACKGROUND: Pyrazinamide (PZA) is an effective antitubercular drug that becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by pyrazinamidase (PZase), encoded by mycobacterial pncA. A strong association was noted between the loss of PZase activity and PZA resistance. The causative organisms in extrapulmonary tuberculosis are rarely cultured and isolated. To detect pncA mutations in specimens from extrapulmonary tuberculosis as confirmative diagnosis of mycobacterial infection and alternative susceptibility test to PZA. METHODS: Specimens were collected from clinically proven extrapulmonary tuberculosis. pncA was sequenced and compared with wild-type pncA. RESULTS: pncA from 30 specimens from 23 donors were successfully amplified (56.6% in specimens, 59% in donors). Six mutations in pncA were detected (20.0% in amplified specimens, 26.1% in specimen donors) at nucleotide positions of 169, 248 and 419. The mutation at position 169 results in substitution of aspartic acid for histidine, a possible allelic variation of M. bovis that have intrinsic PZA resistance. The mutation at position 248 changes proline into arginine and that at position 419, arginine into histidine. CONCLUSION: DNA-based diagnosis using pncA may be simultaneously useful for the early diagnosis of mycobacterial infection and the rapid susceptibility to PZA in extrapulmonary tuberculosis. A potential implication of pncA allelic variation at 169 might be suggested as a rapid diagnostic test for M. bovis infection or Bacille Calmette-Guerin (BCG) reactivation. PMID- 23101014 TI - Factors determining the timing of tracheostomy in medical ICU of a tertiary referral hospital. AB - BACKGROUND: Tracheostomy is a common procedure for patients requiring prolonged mechanical ventilation. However, the timing of tracheostomy is quite variable. This study was performed to find out the factors determining the timing of tracheostomy in medical intensive care unit (ICU). METHODS: Patients who were underwent tracheostomy between January 2008 and December 2009 in the medical ICU of Seoul National University Hospital were included in this retrospective study. RESULTS: Among the 59 patients, 36 (61.0%) were male. Median Acute Physiology And Chronic Health Evaluation (APACHE) II scores and Sequential Organ Failure Assessment scores on the admission day were 28 and 7, respectively. The decision of tracheostomy was made on 13 days, and tracheostomy was performed on 15 days after endotracheal intubation. Of the 59 patients, 21 patients received tracheostomy before 2 weeks (group I) and 38 were underwent after 2 weeks (group II). In univariate analysis, days until the decision to perform tracheostomy (8 vs. 14.5, p<0.001), days before tracheostomy (10 vs. 18, p<0.001), time delay for tracheostomy (2.1 vs. 3.0, p<0.001), cardiopulmonary resuscitation (19.0% vs. 2.6%, p=0.049), existence of neurologic problem (38.1% vs. 7.9%, p=0.042), APACHE II scores (24 vs. 30, p=0.002), and PaO(2)/FiO(2)<300 mm Hg (61.9% vs. 91.1%, p=0.011) were different between the two groups. In multivariate analysis, APACHE II scores>=20 (odds ratio [OR], 12.44; 95% confidence interval [CI], 1.14~136.19; p=0.039) and time delay for tracheostomy (OR, 1.97; 95% CI, 1.11~3.55; p=0.020) were significantly associated with tracheostomy after 2 weeks. CONCLUSION: APACHE II scores>=20 and time delay for tracheostomy were associated with tracheostomy after 2 weeks. PMID- 23101015 TI - Clinical experience of rigid bronchoscopy in single center. AB - BACKGROUND: The aim of this study was to analyze clinical situations requiring rigid bronchoscopy and evaluate usefulness of rigid bronchoscopic intervention in benign or malignant airway disorders. METHODS: We retrospectively reviewed 29 patients who underwent rigid bronchoscopy from November 2007 to February 2011 at St. Paul's Hospital, The Catholic University of Korea School of Medicine. RESULTS: Of the 29 patients, the most frequent underlying etiology was benign stenosis of trachea (n=20). Of those 20 patients, 16 had post-intubation tracheal stenosis (PITS), 2 had tracheal stenosis due to inhalation burn (IBTS) and other 2 had obstructive fibrinous tracheal pseudomembrane (OFTP). Other etiologies were airway malignancy (n=6), endobronchial stenosis due to tuberculosis (n=2), and foreign body (n=1). For treatment, silicone stent insertion was done in 16 cases of PITS and IBTS and mechanical removal was performed in 2 cases of OFTP. In 6 cases of malignant airway obstruction mechanical debulking was performed and silicone stents were inserted additionally in 2 cases. Balloon dilatation and electrocautery were used in 2 cases of endobronchial stenosis due to tuberculosis. In all cases of stent, airway obstructive symptom improved immediately. Granulation tissue formation was the most common complication. CONCLUSION: Tracheal stenosis was most common indication and silicone stenting was most common procedure of rigid bronchoscopy in our center. Rigid bronchoscopic procedures, at least tracheal silicone stenting, should be included in pulmonary medicine fellowship programs because it is a very effective and indispensable method to relieve critical airway obstruction which needs training to learn. PMID- 23101016 TI - Clinical Characteristics of Pandemic Influenza A (H1N1) 2009 Pediatric Infection in Busan and Gyeongsangnam-do: One Institution. AB - BACKGROUND: This study investigated the clinical characteristics and risk factors of the severity of pandemic influenza A (H1N1) 2009 infection in pediatric patients in Busan and Gyeongsangnam-do. METHODS: Cases of influenza A (H1N1) 2009 in patients under the age of 18 years, confirmed by reverse transcription polymerase chain reaction, at Pusan National University Hospital and Pusan National University Yangsan Hospital from the last week of August 2009 through the last week of February 2010 were retrospectively analyzed. RESULTS: Of the 3,777 confirmed cases of influenza A (H1N1) 2009, 2,200 (58.2%) were male and 1,577 (41.8%) were female. The average age of the patients was 8.4+/-4.8 years. The total cases peaked during 44th to 46th week. Most of the patients were in the 5- to 9-year-old age group. Oseltamivir was administered to 2,959 (78.3%) of the patients. 221 patients (5.9%) were hospitalized, age an average of 6.7+/-4.5 years. The average duration of hospitalization was 7.4+/-5.6 days. One hundred cases (45.2%) had pneumonia. Risk factors for hospitalization included male gender, <2 years of age, and underlying disease. Children with asthma were at very high risk of hospitalization, over 20 times the non-asthmatic children (odds ratio [OR], 21.684; confidence interval [CI], 13.295~39.791). Likewise the children with neurologic deficits faced a 16 times higher risk (OR, 15.738; CI, 7.961~31.111). Ten of the patients (4.5%) were admitted to the intensive care unit, and eight (3.6%) required mechanical ventilation. CONCLUSION: Of the pediatric patients with pandemic influenza A (H1N1) 2009, most of the patients were in the 5- to 9-year-old age group. Risk factors for hospitalization included male gender, <2 years of age, and underlying disease. The most common complication was pneumonia. The very high risk of severe morbidity in children with asthma or neurologic disease shows the critical importance of targeted vaccine coverage, special awareness and swift care by both guardians and primary care providers. PMID- 23101017 TI - Congenital cystic adenomatoid malformation with bronchial atresia in elderly patients. AB - Congenital cystic adenomatoid malformation (CCAM) is an uncommon, nonhereditary anomaly caused by arrest of lung. Patients with CCAM may present with respiratory distress as newborns, or may remain asymptomatic until later in life. CCAM type I is rarely found in association with bronchial atresia (BA) in adults; we present such a case. CASE: A 54-year-old female presented with chronic cough and blood tinged sputum. Physical examination and laboratory tests were unremarkable. Chest radiographs and a CT scan of the chest showed multiple large air-filled cysts consistent with a CCAM in the right lower lobe, and an oval-shaped opacity in the distal right middle lobal bronchus. Based on the radiologic findings, right middle lobectomy and a medial basal segmentectomy of the right lower lobe were performed via a thoracotomy. These lesions were consistent with Stocker's Type I CCAM and BA in the different lobes. PMID- 23101018 TI - Intralobar Pulmonary Sequestration Showing Increased Serum CA19-9. AB - Carbohydrate antigen 19-9 (CA19-9) is a specific tumor marker of the biliary, pancreatic and gastrointestinal tracts. CA19-9 is occasionally elevated in serum in patiens with benign pulmonary diseases such as bronchiectasis, idiopathic interstitial pneumonia or collagen disease-associated pulmonary fibrosis. Intralobar pulmonary sequestration is an uncommon congenital lung anomaly. It is dissociated from the normal tracheobronchial tree and is supplied by an anomalous systemic artery. There have been some reports of elevation of CA19-9 in this lesion. We report a case of intralobar pulmonary sequestration with elevated serum CA19-9 in a 29-year-old man who was diagnosed with bronchiectasia of left lower lung field on general check up. He had no evidence of any malignant disease in pancreatobiliary or gastrointestinal tracts. Elevated serum CA19-9 level might be encountered with benign pulmonary disease such as pulmonary sequestration. PMID- 23101019 TI - Critical care paper review 2012. AB - Care of patients with sepsis has improved over the last decade. However, in the recent two years, there was no significant progress in the development of a new drug for critically ill patients. In January 2011, it was announced that the worldwide phase 3 randomized trial of a novel anti-Toll-like receptor-4 compound, eritoran tetrasodium, had failed to demonstrate an improvement in the mortality of patients with severe sepsis. In October 2011, Xigris (drotrecogin alfa, a recombinant activated protein C) was withdrawn from the market following the failure of its worldwide trial that had attempted to demonstrate improved outcome. These announcements were disappointing. The recent failure of 2 promising drugs to further reduce mortality suggests that new approaches are needed. A study was published showing that sepsis can be associated to a state of immunosuppression and loss of immune function in human. However, the timing, incidence, and nature of the immunosuppression remain poorly characterized, especially in humans. This emphasizes the need for a better understanding of sepsis as well as new therapeutic strategies. Many clinical experiences of the extracorporeal membrane oxygenator (ECMO) treatment for adult acute respiratory distress syndrome (ARDS) patients, which is caused by the H1N1 influenza A virus, were reported. The use of ECMO in severe respiratory failure, particularly in the treatment of adult ARDS, is occurring more commonly. PMID- 23101020 TI - Promoter Methylation of CDKN2A, RARbeta, and RASSF1A in Non-Small Cell Lung Carcinoma: Quantitative Evaluation Using Pyrosequencing. AB - BACKGROUND: While qualitative analysis of methylation has been reviewed, the quantitative analysis of methylation has rarely been studied. We evaluated the methylation status of CDKN2A, RARbeta, and RASSF1A promoter regions in non-small cell lung carcinomas (NSCLCs) by using pyrosequencing. Then, we evaluated the association between methylation at the promoter regions of these tumor suppressor genes and the clinicopathological parameters of the NSCLCs. METHODS: We collected tumor tissues from a total of 53 patients with NSCLCs and analyzed the methylation level of the CDKN2A, RARbeta, and RASSF1A promoter regions by using pyrosequencing. In addition, we investigated the correlation between the hypermethylation of CDKN2A and the loss of p16(INK4A) immunoexpression. RESULTS: Hypermethylation of CDKN2A, RARbeta, and RASSF1A promoter regions were 16 (30.2%), 22 (41.5%), and 21 tumors (39.6%), respectively. The incidence of hypermethylation at the CDKN2A promoter in the tumors was higher in undifferentiated large cell carcinomas than in other subtypes (p=0.002). Hyperrmethylation of CDKN2A was significantly associated with p16(INK4A) immunoexpression loss (p=0.045). With regard to the clinicopathological characteristics of NSCLC, certain histopathological subtypes were found to be strongly associated with the loss of p16(INK4A) immunoexpression (p=0.016). Squamous cell carcinoma and undifferentiated large cell carcinoma showed p16(INK4A) immunoexpression loss more frequently. The Kaplan-Meier survival curves analysis showed that methylation level and patient survival were barely related to one another. CONCLUSION: We quantitatively analyzed the promoter methylation status by using pyrosequencing. We showed a significant correlation between CDKN2A hypermethylation and p16(INK4A) immunoexpression loss. PMID- 23101021 TI - The effect of post-treatment N-acetylcysteine in LPS-induced acute lung injury of rats. AB - BACKGROUND: Oxidation plays an important role in acute lung injury. This study was conducted in order to elucidate the effect of repetitive post-treatment of N acetylcysteine (NAC) in lipopolysaccaride (LPS)-induced acute lung injury (ALI) of rats. METHODS: Six-week-old male Sprague-Dawley rats were divided into 4 groups. LPS (Escherichia coli 5 mg/kg) was administered intravenously via the tail vein. NAC (20 mg/kg) was injected intraperitoneally 3, 6, and 12 hours after LPS injection. Broncho-alveolar lavage fluid (BALF) and lung tissues were obtained to evaluate the ALI at 24 hours after LPS injection. The concentration of tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) were measured in BALF. Nuclear factor kappaB (NF-kappaB), lipid peroxidation (LPO), and myeloperoxidase (MPO) were measured using lung tissues. Micro-computed tomography (micro-CT) images were examined in each group at 72 hours apart from the main experiments in order to observe the delayed effects of NAC. RESULTS: TNF alpha and IL-1beta concentration in BALF were not different between LPS and NAC treatment groups. The concentration of LPO in NAC treatment group was significantly lower than that of LPS group (5.5+/-2.8 nmol/mL vs. 16.5+/-1.6 nmol/mL) (p=0.001). The activity of MPO in NAC treatment group was significantly lower than that of LPS group (6.4+/-1.8 unit/g vs. 11.2+/-6.3 unit/g, tissue) (p<0.048). The concentration of NF-kappaB in NAC treatment group was significantly lower than that of LPS group (0.3+/-0.1 ng/uL vs. 0.4+/-0.2 ng/uL) (p=0.0001). Micro-CT showed less extent of lung injury in NAC treatment than LPS group. CONCLUSION: After induction of ALI with lipopolysaccharide, the therapeutic administration of NAC partially attenuated the extent of ALI through the inhibition of NF-kappaB activation. PMID- 23101022 TI - Bacterial pathogens of ventilator associated pneumonia in a tertiary referral hospital. AB - BACKGROUND: This study evaluates the bacterial pathogens of Ventilator-associated pneumonia (VAP) in a tertiary referral hospital. METHODS: A total of 109 bacterial pathogens from 91 adult patients with VAP, who were admitted to the medical intensive care unit from January 2008 to December 2009, were examined. Clinical characteristics, bacterial pathogens, and resistance profiles were analyzed. RESULTS: Staphylococcus aureus (44%) was the most frequently isolated. Acinetobacter baumanii (30%), Pseudomonas aeruginosa (12%), Stenotrophomonas maltophilia (7%), Klebsiella pneumoniae (6%), and Serratia marcescens (2%) were isolated from the transtracheal aspirates or bronchoalveolar lavage in patients with VAP. There was no significant difference of bacterial pathogens between early and late onset VAP. All isolated S. aureus were methicillin resistant S. aureus; the imipenem resistance rate of A. baumanii was 69%. CONCLUSION: The two most frequent pathogens of VAP were S. aureus and A. baumanii. There were no pathogenic differences between early and late onset VAP. PMID- 23101023 TI - Risk factors related with mortality in patient with pulmonary tuberculosis. AB - BACKGROUND: The prevalence rate of pulmonary tuberculosis (PTB) is steadily decreasing in South Korea. However, PTB is a disease with relatively high mortality and morbidity rates throughout Korea. Although there are many studies and statistics about the risk factors of PTB mortality in many countries, there are only a limited number of domestic papers on this topic. The aim of this study is to determine predictive factors for mortality among in-hospital patients associated with PTB. METHODS: From December 2006 to January 2011, we reviewed medical records of 2,122 adult patients diagnosed with tuberculosis at a single tertiary hospital in a suburban area. In this study period, 960 patients were diagnosed with PTB by positive Acid fast bacilli smear and/or mycobacterial culture of the respiratory specimen. We compared the groups of patients deceased and patients discharged alive with PTB. The number of dead patients was 82 (47 males, 35 females). RESULTS: Mortality was significantly associated with increased values of white blood cells (WBC), blood urine nitrogen (BUN), creatinine, C-reactive protein (CRP), numbers of involved lung field, and length of hospitalization. Also, it was associated with the decreased values of hemoglobin, lymphocyte, sodium, albumin, and cholesterol. Furthermore, admission through the emergency department, initial intensive care unit admission, and drug resistant PTB affected mortality in PTB patients. Independent predictors associated with PTB mortality are BUN, initial intensive care unit care, and admission during treatment of tuberculosis. CONCLUSION: In our study, mortality of pulmonary tuberculosis was related with parameters associated with nutritional status, disease severity at the time of admission, and drug resistance. PMID- 23101024 TI - The national status of tuberculosis using nationwide medical records survey of patients with tuberculosis in Korea. AB - BACKGROUND: The epidemiology of tuberculosis (TB) has been assessed based on the data of the analysis of TB patients notified to the surveillance system in Korea. However, the national status of TB is not validated through this surveillance system. The objective is to determine the epidemiology of TB and to understand the accurate status of TB patients treated in private institutions. METHODS: Medical records of 53,579 patients who had been diagnosed with TB in 2008 were analyzed. RESULTS: Among 53,579 patients, the number of sputum smear positive cases was 15,639(29.2%) and the number of new cases was 39,191 (73.1%). The drug resistance rate of new cases was 5.3%, while the rate stood at 13.3% for TB patients with treatment history. The number of multi-drug resistant TB (MDR-TB) patients was 2,472 (4.6%), which consists of 2.9% of new cases and 9.3% of TB patients with prior treatment history. The number of extensively drug-resistant TB patients was 749 (1.4%), consisting of 1.1% of new cases and 2.2% of TB patients with prior treatment history. In terms of treatment outcomes, 66.4% of all TB patients, 70.5% of new cases, 64.4% of relapse cases, and 46.8% of MDR-TB cases were cured or completed. It was inferred that in 2008, the total number of TB patients reached 70,767, 145.6 per 100,000 people (95% confidence interval, 145.5~145.7). CONCLUSION: We conclude that the medical records review of the Health Insurance Review and Assessment Service (HIRA) data can be very effective in promoting the understanding of the current status of TB in private institutions. PMID- 23101025 TI - Concurrent diagnosis of pulmonary metastasis of malignant mixed mullerian tumor and small cell lung cancer. AB - A patient who has multiple lung masses with a history of malignancy in organs other than the lung is more likely to be diagnosed with metastatic rather than primary lung cancer. Rarely, metastatic cancer can coexist with primary. We experienced a case of concurrent diagnosis of primary small cell lung cancer and pulmonary metastasis of uterine malignant mixed Mullerian tumor (MMMT). The patient was a 52-year-old female with femur fracture and multiple lung masses with a history of an operation for uterine MMMT. The small cell lung cancer was diagnosed by bronchoscopic biopsy. The central lung mass decreased after chemotherapy for small cell lung cancer but multiple peripheral masses increased. A percutaneous biopsy for one of peripheral masses revealed metastatic uterine MMMT. We suggest that we have to consider the possible presence of concomitant malignancies of different origins in one organ especially with patients who had a history of malignancy in another organ. PMID- 23101026 TI - A Case of Synchronous Lung Adenocarcinoma and Extranodal Marginal Zone B-Cell Lymphoma of Mucosa-Associated Lymphoid Tissue (MALT) Type. AB - Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type (extranodal MZL) is a distinct subgroup of non-Hodgkin's lymphoma. Pulmonary extranodal MZL is a rare entity and accounts for less than 0.5% of primary pulmonary malignancies. Only a few cases of simultaneous occurrence of lung cancer and pulmonary extranodal MZL have been reported. A 60-year-old woman was referred to our hospital with a pulmonary nodule. She was diagnosed with lung adenocarcinoma by percutaneous needle biopsy. The protrusions into the left main bronchus were found by accident while performing bronchoscopy during lung cancer evaluation. The bronchial lesions were diagnosed as extranodal MZL. Although the patient underwent surgical resection for the lung adenocarcinoma, the pulmonary extranodal MZL was left untreated; it was monitored during follow-up visits. To our knowledge, this is the first report of synchronous lung adenocarcinoma and primary extranodal MZL of the main bronchus. PMID- 23101027 TI - Positive and negative selection, self-nonself discrimination and the roles of costimulation and anergy. AB - It is still unclear whether the adaptive immune system can perform accurate self nonself discrimination and what could influence its performance. Starting from simple cellular interaction rules we show that it is possible to achieve perfect self-nonself discrimination in a consistent framework provided positive and negative selection operate during repertoire education, and costimulation and anergy are also considered during T cell activation. In this theory T cell receptors diversity is required for cells to sense differently different peptides; positive selection is needed to guarantee maximal lymphocyte's interactivity and to allow negative selection to reduce conjugation lifetimes maximally; costimulation is necessary to signal that an antigen presenting cell established an uncommon rate of long lived conjugations when presenting foreign peptides; anergy is required to guarantee that these stable contacts involved different T cells and not always the same. These results suggest that accurate self-nonself discrimination can have shaped the adaptive immune system. PMID- 23101028 TI - Asymmetric cryorolling for fabrication of nanostructural aluminum sheets. AB - Nanostructural Al 1050 sheets were produced using a novel method of asymmetric cryorolling under ratios of upper and down rolling velocities (RUDV) of 1.1, 1.2, 1.3, and 1.4. Sheets were rolled to about 0.17 mm from 1.5 mm. Both the strength and ductility of Al 1050 sheets increase with RUDVs. Tensile strength of Al sheets with the RUDV 1.4 is larger 22.3% of that for RUDV 1.1, which is 196 MPa. The TEM observations show the grain size is 360 nm when the RUDV is 1.1, and 211 nm for RUDV 1.4. PMID- 23101029 TI - Nestin overexpression precedes caspase-3 upregulation in rats exposed to controlled cortical impact traumatic brain injury. AB - Our understanding of biological mechanisms and treatment options for traumatic brain injury (TBI) is limited. Here, we employed quantitative real-time PCR (QRT PCR) and immunohistochemical analyses to determine the dynamic expression of cell proliferation and apoptosis in an effort to provide insights into the therapeutic window for developing regenerative strategies for TBI. For this purpose, young adult Sprague-Dawley rats were subjected to experimental TBI using a controlled cortical impactor, then euthanized 1-48 hours after TBI for QRT-PCR and immunohistochemistry. QRT-PCR revealed that brains from TBI exposed rats initially displayed nestin mRNA expression that modestly increased as early as 1 hour post-TBI, then significantly peaked at 8 hours, but thereafter reverted to pre-TBI levels. On the other hand, caspase-3 mRNA expression was slightly elevated at 8 hours post-TBI, which did not become significantly upregulated until 48 hours. Immunofluorescent microscopy revealed a significant surge in nestin immunoreactive cells in the cortex, corpus callosum, and subventricular zone at 24 hours post-TBI, whereas a significant increase in the number of active caspase-3 immunoreactive cells was only found in the cortex and not until 48 hours. These results suggest that the injured brain attempts to repair itself via cell proliferation immediately after TBI, but that this endogenous regenerative mechanism is not sufficient to abrogate the secondary apoptotic cell death. Treatment strategies designed to amplify cell proliferation and to prevent apoptosis are likely to exert maximal benefits when initiated at the acute phase of TBI. PMID- 23101030 TI - Sex-Specific Regulation of Depression, Anxiety-Like Behaviors and Alcohol Drinking in Mice Lacking ENT1. AB - OBJECTIVES: Adenosine signaling has been implicated in the pathophysiology of several psychiatric disorders including alcoholism, depression, and anxiety. Adenosine levels are controlled in part by transport across the cell membrane by equilibrative nucleoside transporters (ENTs). Recent evidence showed that a polymorphism in the gene encoding ENT1 is associated with comorbid depression and alcoholism in women. We have previously shown that deletion of ENT1 reduces ethanol intoxication and elevates alcohol intake in mice. Interestingly, ENT1 null mice display decreased anxiety-like behavior compared to wild-type littermates. However, our behavioral studies were performed only in male mice. Here, we extend our research to include female mice, and test the effect of ENT1 knockout on other behavioral correlates of alcohol drinking, including depressive and compulsive behavior, in mice. METHODS: To assess depression-like behavior, we used a forced swim test modified for mice. We examined anxiety-like behavior and locomotor activity in open field chambers, and perseverant behavior using the marble-burying test. Finally, we investigated alcohol consumption and preference in female mice using a two-bottle choice paradigm. RESULTS: ENT1 null mice of both sexes showed reduced immobility time in the forced swim test and increased time in the center of the open field compared to wild-type littermates. ENT1 null mice of both sexes showed similar locomotor activity levels and habituation to the open field chambers. Female ENT1 null mice displayed increased marble-burying compared to female wild-types, but no genotype difference was evident in males. Female ENT1 null mice showed increased ethanol consumption and preference compared to female wild-types. CONCLUSIONS: Our findings suggest that ENT1 contributes to several important behaviors involved in psychiatric disorders. Inhibition of ENT1 may be beneficial in treating depression and anxiety, while enhancement of ENT1 function may reduce compulsive behavior and drinking, particularly in females. PMID- 23101031 TI - Gender Power Inequality and Continued Sexual Risk Behavior among Racial/Ethnic Minority Adolescent and Young Adult Women Living with HIV. AB - Adolescent and young adult minority women account for approximately 20% of new cases of HIV in this age group each year in the United States. It is vital to understand factors that influence sexual risk behavior in this population in order to prevent secondary transmission of HIV. As part of a larger qualitative study of youths living with HIV, in- depth interviews were conducted with 26 Black and Latina young women aged 16 to 24 years, infected with HIV through heterosexual transmission. The study explored factors related to continued unprotected sex with male partners. Since learning of their HIV infection, 23% reported multiple episodes of unprotected vaginal and/or anal sex, 27% reported condom use for some but not all of the time, 42% reported condom use all of the time and 7% were not sexually active. Among the highest risk participants partner refusal to use a condom, having the same HIV sero-status as partner, negative attitudes toward condoms, beliefs about HIV transmission, and fear of disclosure to new partners were associated with risky sex. The data suggests that more research is needed to develop more intensive interventions that address the role of gender power inequity for this sub-set of young women living with HIV. PMID- 23101032 TI - Continued Sexual Risk Behaviour in African American and Latino Male-to-Female Transgender Adolescents Living with Hiv/Aids: A Case Study. AB - PURPOSE: This study examined the social and contextual factors associated with continued high risk sexual behaviors among male-to-female transgender (MTFTG) adolescents living with HIV/AIDS. The study is part of a larger qualitative study of 59 racial/ethnic minority adolescents living with HIV/AIDS. METHODS: In-depth focused interviews were conducted with five MTFTG adolescents (16-24 years) living with HIV. Content analysis was conducted to identify themes related to continued sexual risk behaviors. RESULTS: Four out of five of MTFTG adolescents reported inconsistent condom use since their HIV diagnosis. Transgender stigma contributed to financial vulnerability leading to the adoption of sex work to support themselves. Sex and drugs were used to manage transgender stigma and sexual risk-taking with sex work partners was influenced by financial vulnerability. CONCLUSIONS: MTFTG adolescents with HIV have unique psychosocial needs related to transgender stigma and structural needs to decrease financial vulnerability that contribute to risky sexual behavior. PMID- 23101033 TI - An Inuksuk award for Gunnar E. Carlsson. PMID- 23101034 TI - Oral rehabilitation of tooth loss: a systematic review of quantitative studies of OHRQoL. AB - PURPOSE: This study aimed to review published quantitative studies for evidence regarding the influence of oral rehabilitation following total or partial tooth loss on self-perceived oral health-related quality of life (OHRQoL). MATERIALS AND METHODS: Three databases were searched using specified indexing terms. The reference lists of relevant publications were also searched manually. Quality of evidence was classified according to GRADE guidelines as high, moderate, low, or very low. RESULTS: The search yielded 2,138 titles and abstracts, 2,102 of which were of a quantitative study design. Based on pre-established criteria, the full text versions of 322 articles were obtained. After data extraction and interpretation, 5 publications of high or moderate study quality remained. The results of these 5 studies showed positive effects of oral rehabilitation on OHRQoL. Two studies showed substantial improvements. CONCLUSIONS: This is a relatively new field of research; there are very few quantitative studies of how patients perceive OHRQoL following tooth loss and subsequent rehabilitation. While this review indicates that treatment has positive effects on quality of life, the scientific basis is insufficient to support general conclusions about the influence of various interventions on the OHRQoL of patients who have experienced total or partial tooth loss. To achieve a more comprehensive analysis, it is recommended that future studies be based on a combination of quantitative and qualitative methods, ie, questionnaires and semi-structured interviews. The follow-up period must also be appropriate for the specific intervention studied. PMID- 23101035 TI - Treatment of adult patients with edentulous arches: a systematic review. AB - PURPOSE: This study aimed to evaluate the outcomes of treatment methods used to rehabilitate adult patients with maxillary and/or mandibular edentulism after at least 5 years of follow-up. The risks, adverse effects, and cost effectiveness of these methods were also evaluated. MATERIALS AND METHODS: Three databases as well as the reference lists of included publications were searched using specified indexing terms. Publications that met the inclusion criteria were read and interpreted using pre-established protocols. Quality of evidence was classified according to the GRADE system (high, moderate, low, or very low). RESULTS: The search yielded 2,130 titles and abstracts. Of these, the full-text versions of 488 publications were obtained. After data extraction and interpretation, 10 studies with moderate study quality of evidence and 1 study with low quality of evidence regarding outcomes, risks, and adverse effects remained. Three studies on the economic aspects of treatment were also included (1 with moderate quality and 2 with low quality). Low-quality evidence showed that the survival rate of implant-supported fixed prostheses is 95% after 5 years in patients with maxillary edentulism and 97% after 10 years in patients with mandibular edentulism. The survival rate of implant-supported overdentures is 93% after 5 years (low-quality evidence). In implant-supported fixed prostheses, 70 of every 1,000 implants are at risk of failing in the maxilla after 5 years and 17 of every 1,000 implants in the mandible are at risk after 10 years. Regarding economic aspects, the evidence was insufficient to provide reliable results. CONCLUSIONS: Due to the low quality of evidence found in the included studies, further research with a higher quality of evidence is recommended to better understand the outcomes of treatment for patients with maxillary and/or mandibular edentulism. PMID- 23101036 TI - Treatment of adult patients with partial edentulism: a systematic review. AB - PURPOSE: The purpose of this systematic review was to identify and critically appraise published studies of treatment methods used in general practice to rehabilitate adult patients with single tooth loss or partial edentulism, with special emphasis on outcomes reported after at least 5 years of follow-up. MATERIALS AND METHODS: Three databases were searched using specified indexing terms. Publications were included if the study design, research questions, and sample size satisfied pre-established criteria. Reference lists of relevant publications and systematic reviews were also searched. The quality of evidence was classified according to the GRADE system as high, moderate, low, or very low. RESULTS: The search yielded 7,675 titles, of which 1,130 were read in full text. A final total of 15 publications were deemed eligible for inclusion: 5 of moderate quality and 10 of low quality. The five studies of moderate quality were all related to implant-based treatment. The 5-year survival rates for implant supported single crowns and prostheses were 91% and 94.7%, respectively (implant survival rates: 98.5% and 94.9%, respectively). The underlying scientific evidence was low in quality. No relevant publications were identified regarding the economic aspects of treatment. CONCLUSION: Due to the low scientific evidence of the included studies, it was not possible to compare various treatment methods used for rehabilitation of single tooth loss or partial edentulism. PMID- 23101037 TI - Effect of preparation taper and height on strength and retention of zirconia crowns. AB - This study aimed to determine the effect of the taper and height of tooth preparations on the fracture strength and retention of zirconia crowns. Sixty four dies were designed to simulate a crown preparation. Dies were machined with a height of either 4 mm (n = 16) or 7 mm (n = 16) and a taper of either 6 degrees (n = 16) or 20 degrees (n = 16). Copings were created from Lava zirconia blanks. Retention tests were performed using a universal testing machine. Copings were recemented on the dies, thermocycled, and tested for fracture strength. Data were analyzed using factorial analysis of variance. Retention was greater in the taller and less-tapered preparation designs. Taller preparations showed superior fracture strength. Preparing posterior teeth with higher axial walls and less taper is recommended to achieve increased retention and strength for zirconia crowns. PMID- 23101038 TI - Zirconia posterior fixed partial dentures: 5-year clinical results of a prospective clinical trial. AB - This study aimed to evaluate three- and four-unit posterior fixed partial dentures (FPDs) with zirconia frameworks after 5 years of function. Of the initial 30 subjects, 25 patients with 25 FPDs were examined after a mean follow up period of 62.1 months. Five patients were not available for recall visits. Two FPDs failed before the 60-month evaluation because of framework fracture or delamination of the veneering ceramic after endodontic treatment. The 5-year survival rate was 92%. Based on these results, it can be suggested that zirconia frameworks have sufficient mechanical requirements for use in the stress-bearing posterior region. Major fracture of the ceramic veneer could be related to inadequate framework design or bruxism. PMID- 23101039 TI - A systematic review and meta-analysis of the survival of feldspathic porcelain veneers over 5 and 10 years. AB - PURPOSE: This systematic review reports on the survival of feldspathic porcelain veneers. MATERIALS AND METHODS: The Cochrane Library, MEDLINE (OVID), Embase, Web of Knowledge, selected journals, clinical trials registers, and conference proceedings were searched independently by two reviewers. Academic colleagues were also contacted to identify relevant research. Inclusion criteria were human cohort studies (prospective and retrospective) and controlled trials assessing outcomes of feldspathic porcelain veneers in more than 15 patients and with at least some of the veneers in situ for 5 years. Of 4,294 articles identified, 116 studies underwent full-text screenings and 69 were further reviewed for eligibility. Of these, 11 were included in the qualitative analysis and 6 (5 cohorts) were included in meta-analyses. Estimated cumulative survival and standard error for each study were assessed and used for meta-, sensitivity, and post hoc analyses. The I2 statistic and the Cochran Q test and its associated P value were used to evaluate statistical heterogeneity, with a random-effects meta analysis used when the P value for heterogeneity was less than .1. Galbraith, forest, and funnel plots explored heterogeneity, publication patterns, and small study biases. RESULTS: The estimated cumulative survival for feldspathic porcelain veneers was 95.7% (95% confidence interval [CI]: 92.9% to 98.4%) at 5 years and ranged from 64% to 95% at 10 years across three studies. A post hoc meta-analysis indicated that the 10-year best estimate may approach 95.6% (95% CI: 93.8% to 97.5%). High levels of statistical heterogeneity were found. CONCLUSIONS: When bonded to enamel substrate, feldspathic porcelain veneers have a very high 10-year survival rate that may approach 95%. Clinical heterogeneity is associated with differences in reported survival rates. Use of clinically relevant survival definitions and careful reporting of tooth characteristics, censorship, clustering, and precise results in future research would improve metaanalytic estimates and aid treatment decisions. PMID- 23101040 TI - The up to 21-year clinical outcome and survival of feldspathic porcelain veneers: accounting for clustering. AB - PURPOSE: This study aimed to investigate the clinical outcome and estimated cumulative survival rate of feldspathic porcelain veneers in situ for up to 21 years while also accounting for clustered outcomes. MATERIALS AND METHODS: Porcelain veneers(n = 499) placed in patients (n = 155) by a single prosthodontist between 1990 and 2010 were sequentially included, with 239 veneers (88 patients) placed before 2001 and 260 veneers (67 patients) placed thereafter. Nonvital teeth, molar teeth, or teeth with an unfavorable periodontal prognosis were excluded. Preparations had chamfer margins, incisal reduction, palatal overlap, and at least 80% enamel. Feldspathic veneers from refractory dies were etched (hydrofluoric acid), silanated, and bonded. Many patients received more than 1 veneer (mean: 5.8 +/- 4.3). Clustered outcomes were accounted for by randomly selecting (random table) 1 veneer per patient for analysis. Clinical outcome (success, survival, unknown, dead, repair, failure) and Kaplan-Meier estimated cumulative survival were reported. Differences in survival were analyzed using the log-rank test. RESULTS: For the random sample of veneers (n = 155), the estimated cumulative survival rates were 96% +/- 2% (10 years) and 96% +/- 2% (20 years). For the entire sample, the survival rates were 96% +/- 1% (10 years) and 91% +/- 2% (20 years). Survival did not statistically differ between these groups (P = .65). Seventeen veneers in 8 patients failed, 75 veneers in 30 patients were classified as unknown, and 407 veneers in 130 patients survived. Multiple veneers in the same mouth experienced the same outcome, clustering the results. CONCLUSIONS: Multiple dental prostheses in the same mouth are exposed to the same local and systemic factors, resulting in clustered outcomes. Clustered outcomes should be accounted for during analysis. When bonded to prepared enamel substrate, feldspathic porcelain veneers have excellent long-term survival with a low failure rate. The 21-year estimated cumulative survival for feldspathic porcelain veneers bonded to prepared enamel was 96% +/- 2%. PMID- 23101041 TI - A preliminary report on the effect of a mandibular advancement device on obstructive sleep apnea using magnetic resonance imaging and polysomnography. AB - This preliminary study investigated the effect of a mandibular advancement device on upper airway collapsibility in seven patients with obstructive sleep apnea. Overnight polysomnography and dynamic magnetic resonance imaging were performed at the retropalatal and retroglossal levels, and the apnea-hypopnea Index(AHI), anteroposterior and lateral distances, and airway volumes were recorded. The tests were repeated following a 3-month period of wearing a customized mandibular advancement device. A significant reduction in AHI (from 31 events per hour to 18.2 events per hour) and improvement in airway dimension at both the retropalatal and retroglossal levels were recorded, suggesting a baseline record for future studies with a larger patient sample. PMID- 23101042 TI - Influence of palatal morphology on strain in maxillary complete dentures: a preliminary report. AB - The purpose of this preliminary investigation was to assess the influence of palatal morphology on deformation of maxillary complete dentures in vivo. The palatal morphology of the maxillae of eight edentulous subjects was measured. Experimental dentures were fabricated, and a strain gauge was attached at the first molar position at the midline of the polished surface of each denture. Subjects were instructed to bite a metal bar placed bilaterally at the denture's first molar region with a force of 49 N. The resultant strains were recorded, and the correlation between strain and palatal morphology was evaluated using the Pearson correlation coefficient. A strong correlation between strain and both palatal depth and radius of curvature was noted, suggesting that edentulous patients with wide, shallow palates have a higher risk of denture deformation, which may lead to material fracture. PMID- 23101043 TI - Five-year clinical evaluation of all-ceramic posterior FDPs made of In-Ceram Zirconia. AB - The aim of this prospective study was to evaluate the clinical outcomes of three and four-unit posterior fixed dental prostheses (FDPs) made of In-Ceram Zirconia. Twenty FDPs were inserted in 15 patients. Over a mean observation period of 74.6 months, the survival rate was 85%. Sixty-five percent of cases did not allow for connector dimensions that met the manufacturer's recommendations without the use of surgical procedures (eg, crown lengthening). Posterior all-ceramic FDPs made of In-Ceram Zirconia appear to be a viable prosthetic treatment option to replace a missing tooth. PMID- 23101044 TI - Evaluation of complete denture quality and masticatory efficiency in denture wearers. AB - PURPOSE: This study aimed to investigate (1) the influence of complete denture quality and years of denture use on masticatory efficiency and (2) the relationship between complete denture quality and years of use. MATERIALS AND METHODS: A cross-sectional study was conducted with 93 edentulous patients (mean age: 65.6 years) wearing both mandibular and maxillary dentures. Patients were classified into two categories according to years of denture use: <= 2 years and >= 5 years. Masticatory efficiency was evaluated via the colorimetric method with beads as the artificial test food. A reproducible method for objective evaluation of the technical quality of complete dentures was employed. The association between denture quality and years of denture use was analyzed using chi-square and Fisher exact tests. The results of masticatory efficiency testing were analyzed using two-way analysis of variance (with the Tukey post hoc test) in terms of years of denture use (<= 2 years, >= 5 years) and denture quality (poor, average, good). RESULTS: A significant relationship was found between denture quality and years of denture use (P < .05). Masticatory efficiency differed significantly (P < .05) between patients with <= 2 years of denture use (0.101 +/ 0.076 absorbance) and >= 5 years of use (0.068 +/- 0.076 absorbance). Masticatory efficiency was not influenced by denture quality. CONCLUSIONS: Complete denture quality and masticatory efficiency significantly decreased over time. However, complete denture quality did not influence masticatory efficiency. PMID- 23101045 TI - Prosthetic eye rehabilitation and management of completely blind patients. AB - Facial prostheses aim to restore the appearance, contours, and esthetics of the face while consequently enhancing patients' self-esteem and reintegration into social life. Restoring unilateral missing ocular and orbital tissues is a challenging task that requires great skill from the clinician (anaplastologist) to accurately mimic the opposing natural tissues. Bilateral defects present additional technical and clinical challenges for clinicians and patients alike. This article presents two cases involving restoration of the ocular and orbital components of bilaterally blind patients. The first case comprised the construction of indwelling scleral eye shells for both eyes, while the second comprised left orbital (implant-retained) and right indwelling eye shell prostheses. Custom-made bilaterally indwelling eyes are more esthetically pleasing than stock options and show better fit and comfort following conventional impression techniques. Clinical challenges include impression taking, prosthesis fabrication, identification of the correct orientation into the socket, communication with the patient, and satisfaction of patient expectations. Since both patients were blind, their families played a vital role in describing their prostheses and thus in improving the patients' self-esteem and satisfaction with treatment. PMID- 23101113 TI - European Commission proposals do not impress researchers. PMID- 23101114 TI - Abstracts of the 17th European Bioenergetics Conference, September 15-20, 2012, Freiburg, Germany. PMID- 23101115 TI - Looking for a good book. Reading and teaching with psychiatric practitioner memoirs. AB - Memoirs can be more interesting to read than textbooks and are frequently just as informative. Many people have written excellent memoirs about their own or family member's psychiatric illness. However, psychiatric practitioner memoirs have the advantage of showing how an enthusiastic but novice clinician develops into a skilled practitioner, something students are usually eager to understand. Twenty nine memoirs by psychiatric practitioners (nurses, advanced practice nurses, psychiatrists, and psychologists) were reviewed and critiqued for clinical accuracy and relevancy, positive role-modeling, advocacy, a promotion of a positive image of nursing, and suitability for use in teaching undergraduate nursing students; of these, 3 are outstanding books written by nurses ( The Comfort Garden: Tales from the Trauma Unit by Barkin and Tales from the page Chronicles and The Pager Chronicles Volume Two by Rancour) and one by psychiatrist(Psychward by Seager). An annotated bibliography of all practitioner memoirs reviewed is provided. PMID- 23101116 TI - Festschrift in honor of Andrew L. Warshaw. PMID- 23101117 TI - Festschrift in honor of Doug Mewhort. PMID- 23101119 TI - Pediatric critical care, glycemic control, and hypoglycemia: what is the real target? PMID- 23101118 TI - Neurocognitive development of children 4 years after critical illness and treatment with tight glucose control: a randomized controlled trial. AB - CONTEXT: A large randomized controlled trial revealed that tight glucose control (TGC) to age-adjusted normoglycemia (50-80 mg/dL at age <1 year and 70-100 mg/dL at age 1-16 years) reduced intensive care morbidity and mortality compared with usual care (UC), but increased hypoglycemia (<=40 mg/dL) (25% vs 1%). OBJECTIVE: As both hyperglycemia and hypoglycemia may adversely affect the developing brain, long-term follow-up was required to exclude harm and validate short-term benefits of TGC. DESIGN, SETTING, AND PATIENTS: A prospective, randomized controlled trial of 700 patients aged 16 years or younger who were admitted to the pediatric intensive care unit (ICU) of the University Hospitals in Leuven, Belgium, between October 2004 and December 2007. Follow-up was scheduled after 3 years with infants assessed at 4 years old between August 2008 and January 2012. Assessment was performed blinded for treatment allocation, in-hospital (83%) or at home/school (17%). For comparison, 216 healthy siblings and unrelated children were tested. MAIN OUTCOME MEASURES: Intelligence (full-scale intelligence quotient [IQ]), as assessed with age-adjusted tests (Wechsler IQ scales). Further neurodevelopmental testing encompassed tests for visual-motor integration (Beery Buktenica Developmental Test of Visual-Motor Integration); attention, motor coordination, and executive functions (Amsterdam Neuropsychological Tasks); memory (Children's Memory Scale); and behavior (Child Behavior Checklist). RESULTS: Sixteen percent of patients declined participation or could not be reached (n = 113), resulting in 569 patients being alive and testable at follow up. At a median (interquartile range [IQR]) of 3.9 (3.8-4.1) years after randomization, TGC in the ICU did not affect full-scale IQ score (median [IQR], 88.0 [74.0-100.0] vs 88.5 [74.3-99.0] for UC; P = .73) and had not increased incidence of poor outcomes (death or severe disability precluding neurocognitive testing: 19% [68/349] vs 18% [63/351] with UC; risk-adjusted odds ratio, 0.93; 95% CI, 0.60-1.46; P = .72). Other scores for intelligence, visual-motor integration, and memory also did not differ between groups. Tight glucose control improved motor coordination (9% [95% CI, 0%-18%] to 20% [95% CI, 5%-35%] better, all P <= .03) and cognitive flexibility (19% [95% CI, 5%-33%] better, P = .02). Brief hypoglycemia evoked by TGC was not associated with worse neurocognitive outcome. CONCLUSION: At follow-up, children who had been treated with TGC during an ICU admission did not have a worse measure of intelligence than those who had received UC. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00214916. PMID- 23101120 TI - How to chart a course for survival. Experts reveal ways EMS can survive the current and coming chaos. PMID- 23101121 TI - Playing the game, fighting the fight. PMID- 23101123 TI - [Nursing care has special significance in psychiatric care]. PMID- 23101122 TI - Third-party drug-test providers continue to grow nationwide. PMID- 23101124 TI - Update on genetic testing for heart disease. It's complicated but promising. Here's what genes can tell us today. PMID- 23101125 TI - Ask the doctors. My potassium level is high, and my physician stopped the medication that has successfully controlled my blood pressure for years, lisinopril. What is the danger from high potassium, and why is lisinopril a problem? PMID- 23101126 TI - Ask the doctors. I have had atrial fibrillation for a year, and I have felt pretty normal on a beta blocker (metoprolol) and digoxin. However, I recently began to feel very fatigued and noticed my heart rate was only 35 beats per minute. We stopped those medications, and my heart rate came up. I feel better. Are these drugs dangerous for me? PMID- 23101127 TI - The dangers of pulmonary hypertension. Treatments can help control symptoms and protect the heart. PMID- 23101128 TI - When a clot interferes with blood flow. It can happen to anyone, but heart disease increases the risk. PMID- 23101129 TI - Viagra and Cialis for heart failure? Erectile dysfunction drugs may do what no others have done. PMID- 23101130 TI - A pacemaker to prevent fainting. If your heart rate slows, a device can stop you from dropping. PMID- 23101132 TI - Notice of retraction. PMID- 23101131 TI - Use food to hold off vascular damage. Color and crunch can lead to better cardiovascular health. PMID- 23101133 TI - Interprofessional education in U.S. and Canadian dental schools: an ADEA Team Study Group report. AB - The state of interprofessional education (IPE) in U.S. and Canadian dental schools was studied by the American Dental Education Association (ADEA) Team Study Group on Interprofessional Education. The study group reviewed the pertinent IPE literature, examined IPE competencies for dental students, surveyed U.S. and Canadian dental schools to determine the current and planned status of IPE activities, and identified best practices. Members of the study group prepared case studies of the exemplary IPE programs of six dental schools, based on information provided by those schools; representatives from each school then reviewed and approved its case study. Six reviewers critiqued a draft of the study group's report, and study group members and reviewers met together to prepare recommendations for schools. This report identifies four domains of competence for student achievement in IPE and summarizes responses to the survey (which had an 86 percent response rate). It also includes the case descriptions of six schools' IPE programs and the study group's recommendations for dental schools. The report concludes that there is general recognition of the goals of IPE across U.S. and Canadian dental schools, but a wide range of progress in IPE on the various campuses. Challenges to the further development of IPE are discussed. PMID- 23101134 TI - [Thoughts on the upcoming specialization of surgery departments in Czech Republic]. PMID- 23101135 TI - Complementary and alternative therapies: can we know what risks they present? PMID- 23101136 TI - The changing face of international medicine. PMID- 23101137 TI - New national guideline for stroke management: where do we go from here? PMID- 23101138 TI - FAST enough? The U.K. general public's understanding of stroke. AB - Good public awareness of stroke symptoms and the need for rapid admission to hospital can improve patient outcomes. However, evidence suggests that this awareness is currently inadequate. Therefore, it is important to identify gaps in public knowledge to target public health campaigns appropriately. This questionnaire study of 356 adults in Birmingham city centre assessed the general public's understanding of stroke, whether demographic factors affect this and the influence of a national campaign (FAST) on knowledge. The mean overall knowledge score was 11.8 out of 15; however, only 54.2% of those questioned knew that diabetes, hypertension and high cholesterol were stroke risk factors. Of those questioned, 60.2% were aware of the FAST campaign. General understanding of stroke was fairly good, although it was found to be worse in the youngest, oldest age and nonwhite groups. Although there was good awareness of the FAST campaign, many people did not know what the individual letters meant. Based on the results of our study, we conclude that it might take considerable time for public awareness campaigns to achieve their full impact. PMID- 23101139 TI - Genomic medicine: challenges and opportunities for physicians. AB - Medicine has always striven to personalise or stratify approaches towards individual patients, but recently these terms have been applied particularly to denote improved disease sub-classification achieved through new genetic and genomic technologies. Techniques to analyse a person's genetic code have improved in sensitivity exponentially over recent years and at the same time the cost of such analyses has become affordable to routine NHS care. This article highlights the significant opportunities that genomics brings to healthcare, as well as some of the practical and ethical challenges. PMID- 23101140 TI - Selecting ambulatory emergency care (AEC) patients from the medical emergency in take: the derivation and validation of the Amb score. AB - Accurate prediction of the likelihood of same-day discharge could make it possible to direct one-third of the medical in-take to an ambulatory care unit, thereby facilitating bed management. In Phase 1 of this study, we identified seven independent factors that contribute to an ambulatory care score (Amb score) that can potentially be used as a tool to select ambulatory emergency care (AEC) patients from the medical emergency in-take. A high score was associated with discharge within 12 hours of assessment and treatment in hospital. In Phase 2, we verified and internally validated the performance of the Amb score in a different cohort of patients, finding that it functioned well in identifying early discharges (ie AEC patients), with an area under the receiver operator curve (AUROC) of 0.91 (95% CI 0.88-0.94). An Amb score of > or = 5 has a sensitivity of 96% (95% CI 90-98) and a specificity of 62% (95% CI 55-68) in identifying potential AEC patients. PMID- 23101141 TI - Alternative therapies for asthma: are patients at risk? AB - Asthma patients often try some form of alternative medicine. This article questions whether this is good or bad. Systematic reviews fail to demonstrate that the treatments in question are demonstrably effective. Other data raise considerable concern over the safety of some forms of alternative medicine. Thus the risk-benefit balance fails to be positive. Patients are often mislead to believe otherwise and physicians should inform their asthma patients responsibly about the value of alternative medicine. PMID- 23101143 TI - Overview of bariatric surgery for the physician. AB - The worldwide pandemic of obesity carries alarming health and socioeconomic implications. Bariatric surgery is currently the only effective treatment for severe obesity. It is safe, with mortality comparable to that of cholecystectomy, and effective in producing substantial and sustainable weight loss, along with high rates of resolution of associated comorbidities, including type 2 diabetes. For this reason, indications for bariatric surgery are being widened. In addition to volume restriction and malabsorption, bariatric surgery brings about neurohormonal changes that affect satiety and glucose homeostasis. Increased understanding of these mechanisms will help realise therapeutic benefits by pharmacological means. Bariatric surgery improves long-term mortality but can cause long-term nutritional deficiencies. The safety of pregnancy after bariatric surgery is still being elucidated. PMID- 23101142 TI - HIV diagnoses and missed opportunities. Results of the British HIV Association (BHIVA) National Audit 2010. AB - The late diagnosis of HIV in patients across the UK is an increasing problem. Here, we report on a retrospective case-notes audit carried out to assess the impact of the 2008 UK HIV testing guidelines on clinical practice and identify missed opportunities for HIV testing. The audit was carried out in 2010 and focussed on patients with newly diagnosed HIV at centres providing adult HIV services across the UK. Data were collected on 1,112 patients, of whom 52.2% were found to have a late HIV diagnosis as defined as a CD4 T lymphocyte count of <350 cells/mm3. Most patients (62.6%) were diagnosed in traditional settings, with a significant increase in those diagnosed with HIV in non-traditional settings (33%) compared with the 2003 audit (18.5%) (p<0.001). The most frequent indicator conditions that patients had experienced were chronic diarrhoea or weight loss, sexually transmitted infection, blood dyscrasia or lymphadenopathy. A quarter of patients were identified as having had a missed opportunity for earlier diagnosis. Based on our results, we suggest that HIV testing needs to continue to expand across clinical settings to reduce the number of patients living with undiagnosed HIV infection. PMID- 23101144 TI - Do NHS services have to be provided by the NHS? PMID- 23101145 TI - A 28-year-old female with persistent back pain and urinary frequency. PMID- 23101146 TI - The Royal College of Physicians Simms Lecture, 6 December 2011: clinical research networks and the benefits of intensive healthcare systems. AB - Clinical research contributes to the evidence base for the planning of improved healthcare services and creates an excellent environment for the delivery of healthcare and the recruitment and retention of excellent and well-motivated staff. In this paper, we consider the evidence that a research-intensive healthcare system might yield improved outcomes as a result of the impact of the process of research on the provision of care. We review progress in establishing clinical research networks for cancer and the evidence of the impact of the conduct of clinical cancer research in the National Health Service. PMID- 23101147 TI - Asthma--it hasn't gone away. AB - Asthma most definitely hasn't gone away. This article provides a review of the Royal College of Physician's conference in March 2012, which progressed attendees' understanding of both the basic science and clinical aspects of asthma care. The article highlights key clinical messages from the programme for general physicians--e.g., how best to approach the assessment of patients with severe asthma. PMID- 23101148 TI - Recent advancements in drug treatment of obesity. AB - The prevalence of obesity is rising worldwide, with the U.K. having the highest prevalence in Europe. Obesity is associated with significant morbidity and has substantial healthcare implications, with current projections estimating that by 2030 obesity will cost the NHS approximately pounds 2 billion each year. Lifestyle modification remains the cornerstone of anti-obesity treatment, but drugs can be introduced as adjuncts to assist and maintain weight loss. Some 1.45 million obesity-related prescriptions were dispensed in 2009, highlighting the high demand for obesity pharmacotherapy. At present, the lipase inhibitor orlistat (Xenical) is the only UK-approved long-term medical therapy for obesity. Double-blind clinical trials have shown that orlistat significantly increases weight loss compared to placebo, but the array of adverse side effects associated with orlistat limits its tolerability. The need for more effective and better tolerated anti-obesity medications is clear and six therapies have reached phase III trials. PMID- 23101149 TI - Membranous nephropathy. PMID- 23101150 TI - Kidney stone disease: pathophysiology, investigation and medical treatment. PMID- 23101151 TI - Approach to the management of endstage renal disease. PMID- 23101152 TI - Renal tubular disorders. PMID- 23101153 TI - Diabetic nephropathy. PMID- 23101154 TI - Young man presenting with recurrent food bolus impaction. PMID- 23101155 TI - Rifaximin may have a dramatic effect on hepatic encephalopathy. PMID- 23101156 TI - Idiopathic aqueductal stenosis. PMID- 23101157 TI - The lesson of Dr. Hasselbacher from Our man in Havana. PMID- 23101158 TI - Star fruit intoxication with acute kidney injury. PMID- 23101159 TI - The case for the physician assistant. PMID- 23101160 TI - Fluid assessment is critical in acute kidney injury (AKI). PMID- 23101161 TI - Impact of the 2011 NICE guidance on dementia drugs in a neurology-led memory clinic. PMID- 23101162 TI - Something. PMID- 23101163 TI - A new term. AB - A new term begins and parents everywhere are breathing a sigh of relief as the reliable routine of school resumes. No more trying to think of interesting things to do with energetic under 10's or tired teenagers. Now the battle of bedtime and the dreaded morning alarm clock begins. PMID- 23101164 TI - Re: The future of surgical assisting and the perloperative practitioner role. PMID- 23101165 TI - Reflections of a newly appointed consultant. AB - I had no idea what kind of medicine I wanted to practise when I left medical school. What I did know was that I didn't want to do psychiatry, and I didn't want to do obstetrics and gynaecology. My father is a GP, and I thought I'd follow in his footsteps, but general practice struck me as a tough specialty. In my opinion the hardest job in the NHS to do well, but one of the easiest to do badly. I was jealous of my peers at medical school who loudly declared their love of a particular specialty, and trauma and orthopaedics was particularly popular. I ended up in Colchester, Essex where I met two people who changed my life forever. PMID- 23101167 TI - Inside clinical what you procurement--didn't know. PMID- 23101166 TI - Preoperative blood tests in elective general surgery: cost and clinical implications. AB - A retrospective observational study was performed in our trust in October 2010 that examined compliance, and the financial and clinical implications of performing inappropriate preoperative blood tests on adult patients prior to elective surgery, against the 2003 NICE guidelines. An unacceptable proportion of inappropriate tests (31.3%) were being performed. None were associated with adverse outcome or changes in management. Based on our results, we estimate that an extrapolated cost of pound 11.2 million is being spent on inappropriate blood tests in NHS England and Wales. PMID- 23101168 TI - Major fund for British medical breakthroughs now open. PMID- 23101170 TI - Using technology to improve product selection. PMID- 23101169 TI - Event gives insight into new NHS procurement strategies. PMID- 23101171 TI - The WHO surgical safety checklist. AB - Surgery plays a prominent role in healthcare worldwide. It has been estimated that the rate of fatal events occurring in surgery is about one in ten thousand exposures and up to one million deaths per year. Most errors are caused by failure of non-technical skills. The WHO surgical safety checklist has shown that patient safety could be improved by using a simple and effective method. However, achieving high compliance requires research, training and local adaptation. PMID- 23101172 TI - Accounting for specialist items in neurosurgery. AB - This short article explores the issues surrounding the use of certain specialist items used during some neurosurgical procedures. It discusses the results of a benchmarking exercise that sought to investigate how these items are accounted for since there appear to be no nationally agreed guidelines for perioperative practice. The returns from the exercise suggest that, while practice for patties seems to be consistent, there is variation between neurosurgical centres in the use of other items. It is hoped that this work may stimulate discourse and that guidance can be produced to assist perioperative practitioners and enhance safe practice for patients. PMID- 23101173 TI - Practitioner led extubation in recovery: a report into viability in the post anaesthetic care unit. AB - Patients entering recovery often have a requirement for their airway to be managed. This can be performed in a variety of ways: either by having an airway adjunct placed in-situ, or by airway manoeuvres performed by recovery practitioners (Scott 2012). One of the adjuncts that patients may have is the endotracheal tube [ETT]. Traditionally patients have been extubated before leaving the operating theatre, with trained anaesthetic assistants helping the anaesthetist to remove the airway in a safe and controlled environment. Alternatively the anaesthetist extubates in recovery with experienced recovery practitioners. PMID- 23101174 TI - Harvey Cushing: Cushing's disease. AB - In 1932 Harvey Cushing published an article entitled 'Basophil adenomas of the pituitary and their clinical manifestations'. These are rare tumours of the anterior pituitary gland, at the base of the brain, with striking manifestations, which include adiposity of the face and trunk, but not the limbs, weakness, fatigue, abdominal striae, facial hair, high blood pressure and raised blood sugar. Although I spent two years in an army neurosurgical unit, I never saw a case. More frequently, the same clinical picture is produced by a benign adenoma of the suprarenal cortex, but today by far the commonest cause of this condition is seen in the patient receiving high dosage of cortisone, when we talk about the person exhibiting 'Cushingoid features'. Most readers of this journal will have seen such cases. PMID- 23101175 TI - Forced eruption without orthodontic brackets using fiber reinforced composite prostheses: a case report. AB - Maintenance of periodontal health is one of the most important factors governing success of the restoration and longevity of teeth. For proper maintenance of periodontal health, the biologic width functions as a protective barrier against the entrance of microorganisms in to the internal medium of the periodontal ligament and osseous connective tissue. This clinical case describes a technique to reestablish the biologic width surrounding a fractured central incisor by forced eruption without orthodontic brackets, using fibre reinforced composite prostheses. Main advantages of using fibre reinforced composite prostheses are aesthetic maintenance during the treatment period, no need for occlusal adjustments, simplicity, low cost, and stability. PMID- 23101176 TI - Comparative evaluation of effect of polymerizable and non-polymerizable desensitizing agents on crown-retentive-strength of zinc-phosphate, glass-ionomer and compomer cements. AB - The Purpose of this study was to evaluate the effect of polymerizable and non polymerizable dentine desensitizers on retention of complete cast crowns cemented with three different types of cements. Freshly extracted human molars (n = 90) were prepared for standardized crown preparation (6-degree taper 4-mm height). The axial surface area of each preparation was determined and specimens were distributed equally among groups (n = 10). Dentine desensitizers, cementing agents, glass ionomer cement and compomer cement. Teeth were prepared and individual castings were made using high noble porcelain-metal alloy. Castings were cemented, thermo-cycled and removed along the path of insertion using a universal testing machine. Tooth surface as well as inner surface of the casting was examined and nature of cement failure was determined. Compomer cement exhibited the highest retentive strength and all dentine treatments resulted in significantly different retentive values. Zinc phosphate was the least retentive. Crown retentive values of Compomer cement were improved with Prime & Bond NT and Gluma Desensitizer Retentive values of zinc phosphate cement with Prime & Bond NT were decreased and not affected with Gluma Desensitizer Retentive values of Glass ionomer cement were not affected by any of the desensitizers used in the study. PMID- 23101177 TI - Prevalence of temporomandibular disorders' signs and symptoms and chewing ability in patients with prosthodontic prostheses. AB - This study aimed to determine the prevalence of temporomandibular disorders among patients wearing dental prostheses including complete and fixed partial dentures and to evaluate the chewing ability of those patients. Questionnaire and clinical examinations were used to assess those objectives. Fifty six percent of all examined subjects exhibited at least one sign or symptom of temporomandibular disorders while 8.0% bad moderate symptoms and 10% had severe symptoms. Patients with fixed partial dentures had a significantly higher prevalence of temporomandibular disorders signs than both complete dentures and dentate. The fixed partial denture group and dentate group exhibited significantly higher chewing ability than did the complete denture group. Therefore, the type of prosthesis correlated significantly with chewing ability. PMID- 23101178 TI - Effect of surface treatments on the bond strengths of facing composite resins to zirconia copings. AB - The present study evaluated and compared the bond strength between zirconia and facing composite resin using different surface conditioning methods before and after thermocycling. Four primers, three opaque resins, and two facing composite resins were used, and 10 surface treatment procedures were conducted. The bond strength was measured before and after 4,000 cycles of thermocycling. The mean values of each group were statistically analyzed using one-way analysis of variance (ANOVA). The bond strengths of facing composite resins to zirconia after various treatments varied depending on the primers, opaque resins, body resins, and thermocycling. The application of primers and opaque resins to the zirconia surface after sandblasting is expected to yield strong bond strength of the facing composite resin (Estenia CG&B) even after thermocycling. PMID- 23101179 TI - The effect of monomer/polymer mixing ratio, time between mixing and packing of heat cured acrylic resin denture base material and bond assisting agents on the bond strength to acrylic resin denture teeth. AB - The aim of the study was to investigate the effect of varying the monomer/polymer mixing ratio, the time from mixing to packing heat cured acrylic resin and the effect of two bond assisting agents on the strength of the bond between denture base acrylic resin and acrylic resin denture teeth. Statistical differences were found in bond strength with monomer/polymer ratio and time between mixing and packing with one of the heat cured resins investigated. The benefit of using the bonding agents was not demonstrated. PMID- 23101180 TI - Influence of Nd:YAG or Er:YAG laser surface treatment on microtensile bond strength of indirect resin composites to resin cement. Lasers surface treatment of indirect resin composites. AB - This study evaluated the influence of the surface pretreatment of indirect resin composite (Signum, Admira Lab and Sinfony) on the microtensile bond strength of a resin cement. Sixty samples made of each brand were divided into 6 groups, according to surface treatment: (1) control; (2) controlled-air abrasion with Al2O3; (3) Er:YAG Laser 200 mJ, 10 Hz, for 10s; (4) Er: YAG Laser 300 mJ, 10 Hz, for 10 s; (5) Nd:YAG 80 mJ, S15Hz for 1 min; (6) Nd:YAG 120mJ, 15 Hz for 1 min. After treatments, all the groups received an application of 37% phosphoric acid and adhesive. The pair of blocks of the same brand were cemented to each other with dual resin cement. The blocks were sectioned to obtain resin-resin sticks (1 x1 mm) and analyzed by microtensile bond testing. The bond strength values were statistically different, irrespective of the surface treatment performed, with highest values for Sinfony (43.81 MPa) and lowest values for Signum (32.33 MPA). The groups treated with the Nd:YAG laser showed the lowest bond strength values and power did not interfere in the results, both for Nd:YAG laser and Er:YAG. Controlled-air abrasion with Al203 is an efficient surface treatment method and the use of the Nd:YAG and Er:YAG lasers reduced bond strength, irrespective of the intensity of energy used. PMID- 23101181 TI - Provision of a swing lock denture for a patient with Gorlin Goltz syndrome. AB - Swinglock dentures are used relatively infrequently but in cases of compromised anatomy or where the pattern of tooth loss is unfavourable, they provide a useful removable partial denture design option. The aim of this article is to provide a clear summary of the clinical and technical considerations necessary when providing a Swinglock denture. PMID- 23101182 TI - The role of inhalant allergens in allergic airways disease. AB - Immunoglobulin (Ig) E-mediated sensitization to domestic inhalant allergens (eg, dust mite, cockroach, cat, and dog) is the most important risk factor for asthma. The severity of asthma increases among atopic patients exposed to high levels of sensitizing allergen. In addition, synergism between high allergen exposure and respiratory virus infection increases the risk of asthma exacerbation. However, opinions on the role of allergen avoidance in the management of asthma are diverse, partly because most currently used allergen avoidance measures are usually tested in highly artificial experimental conditions, often with no assessment of their effect on personal inhaled allergen exposure or their clinical effectiveness. While there is little evidence for the clinical benefits of single avoidance measures (eg, bedding encasings, vacuum cleaners, and air filters), multifaceted intervention in carefully selected patients may be of benefit. Until conclusive evidence is available, a pragmatic approach in clinical practice should involve the following: (a) interventions tailored to the patient's sensitization and allergen exposure (if exposure cannot be estimated, specific IgE antibody level or the results of skin testing can be used as a marker); (b) a multifaceted allergen avoidance regime, based on removal of the accumulating allergen; (c) initiation of the intervention as early as possible. Currently, no evidence-based advice on the use of allergen avoidance for prevention of allergic disease can be given; however, it is increasingly clear that no single strategy will be applicable to all children, only to those with specific genetic susceptibility. PMID- 23101183 TI - Social networks: a new source of psychological stress or a way to enhance self esteem? Negative and positive implications in bronchial asthma. AB - The Internet and, in particular, social networks are an increasingly important part of daily life for both adolescents and adults who maintain a virtual relationship with others sharing interests and goals. Very often, they disclose more about themselves online than they do in person. However, cyberbullying and cyberostracism can be problematic for adolescents and sensitive individuals, who might be negatively affected by social networks. Some studies have shown an increased risk of depression, whereas others suggest beneficial effects through enhanced communication, social connection, and self-esteem. Bronchial asthma is an increasingly frequent disease in the industrialized world, and psychological implications play a role in increasing or in reducing its severity. One year after the case report of an asthma exacerbation that may have been triggered by Facebook, it seems reasonable to analyze the effects of social networks on bronchial asthma. PMID- 23101185 TI - Specific immunoglobulin E antibodies to saprophytic yeasts in sera of atopic patients allergic to house dust mites. AB - BACKGROUND: Atopic dermatitis (AD) is a complex disease caused by genetic and environmental interactions. AD impairs skin barrier function, enabling microorganisms to penetrate and interact with the immune system. OBJECTIVES: This study aimed to investigate the presence of specific immunoglobulin (Ig) E antibodies to the yeast species Candida pelliculosa, Candida guilliermondii, Candida famata, and Rhodotorula rubra in the sera of AD patients and to evaluate possible cross-reactivity between yeasts and allergens of Dermatophagoides pteronyssinus (D1) and Dermatophagoides farinae (D2). METHODS: We analyzed serum samples from 14 healthy individuals and 34 AD patients: 19 were positive to D1 and D2 (Immulite) and 15 were negative. Determinations were made using enzyme linked immunosorbent assay (ELISA), competitive ELISA, and the Immulite inhibition assay. RESULTS: The results of ELISA showed that all house dust mite positive sera had specific IgE antibodies to the yeast species tested: 42% of these sera reacted with all 4 yeast species. The inhibition study demonstrated partial cross-reactivity between IgE class antibodies with the yeast species. This finding indicates that different Candida species and R rubra have species specific and cross-reactive antigens with partially overlapping epitopes, thus suggesting cross-reactivity with mite allergens. C pelliculosa protein extract inhibited IgE binding to D1 (63.4%) and D2 (71%) allergens. The inhibition value for D1 showed a significant correlation with the inhibition value for D2 (r = 0.669, P = .03; Spearman rank correlation). CONCLUSION: The results of the present study suggest that C pelliculosa and house dust mites share common antigens. PMID- 23101184 TI - Association between the functional polymorphism C-159T in the CD14 promoter gene and nasal polyposis: potential role in asthma. AB - BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease that is frequently associated with allergy and asthma. Corticosteroid therapy and surgical removal of polyps are the 2 most common treatment strategies for NP. Various allergic and inflammatory mediators are thought to play a major role in the pathophysiology of this disorder. The CD14 gene is located on chromosome 5q31 32, which is considered a critical region for several allergic and atopic diseases, including asthma. Consequently, variations in CD14 could have functional effects on the etiology and severity of allergy and asthma. The aim of this study was to investigate the association between the polymorphism C-159T in the CD14 gene of patients with NP and controls. METHODS: The study population comprised 106 patients with NP diagnosed based on computed tomography scan of the paranasal sinus, endoscopy, and histological examination. Findings were compared with those from 87 controls. The frequency of C-159T was determined using polymerase chain reaction-restriction fragment length polymorphism analysis. DNA was extracted using the salting out technique. RESULTS: A significant association was observed between C-159T and NP (P = .04). Patients with the CC genotype at position -159 of the CD14 promoter region had an increased risk of asthma (OR, 3.83, 95% CI, 0.99-13.91; P < .02). However, we did not find an association between the distribution of C-159T and serum immunoglobulin E level. CONCLUSIONS: A genetic variation in the CD14 promoter might play a role in the pathogenesis of NP and in the incidence of asthma. PMID- 23101186 TI - Predictive value of lung function trend and FeNO for difficult asthma in children. AB - OBJECTIVE: The aim of this study was to evaluate the predictive value of lung function and fraction of exhaled nitric oxide (FeNO) for difficult asthma in children. PATIENTS AND METHODS: Children with asthma referred to an asthma clinic for uncontrolled persistent asthma on inhaled corticosteroids (ICSs) alone or in combination with a long-acting beta2-agonist and/or a leukotriene receptor antagonist were followed in a prospective 1-year study to identify difficult asthma. At the end of the study period, difficult asthma was considered for children with persistent asthma symptoms and/or frequent moderate/severe asthma exacerbations despite regular intake of ICSs (beclomethasone or equivalent) > 800 microg/d for at least 3 months, after correcting for adherence to treatment, inhalation technique, and comorbidities and after implementing an individualized treatment plan. The difficult asthma phenotype was characterized using a multidimensional approach combining clinical features and pathophysiologic features (lung function and inflammation). Unfavorable lung function trend (persistent airway obstruction and fluctuations in forced expiratory volume in the first second of alpha > 0.5) and persistently high FeNO levels (> 45 ppb despite increasing ICS doses) were analyzed as risk factors for difficult asthma in the logistic regression analysis together with male sex, atopy, concurrent severe rhinitis, obesity, psychopathology, exposure to tobacco smoke, low socioeconomic status, lack of adherence to treatment, and persistent bronchodilator response. RESULTS: Forty-six asthmatic children (34 males, 74%) with a mean (SEM) age of 7.55 (3.04) years were enrolled. After 1 year, 24 children (52%) were labeled as having difficult asthma. Independent risk factors for difficult asthma were persistently high FeNO (P = .04), obesity (P = .04), and severe rhinitis (P = .03). CONCLUSIONS: Persistently high FeNO predicts difficult asthma in children, while unfavorable lung function trend does not. PMID- 23101187 TI - Assessment of nutritional status: vitamin A and zinc in patients with common variable immunodeficiency. AB - BACKGROUND: Patients with common variable immunodeficiency (CVID) present with low antibody levels, impaired lymphocyte function, and chronic inflammation. Vitamin A and zinc are essential components of the immune system and can be redistributed in the body as a result of inflammation. OBJECTIVE: To compare levels of retinol, beta-carotene, and zinc in patients with CVID and healthy controls after evaluating a series of parameters for each participant. PATIENTS AND METHODS: We performed a cross-sectional study of CVID patients and healthy controls matched for age and gender. All participants underwent a nutritional and laboratory evaluation comprising a complete blood count and determination of levels of C-reactive protein (CRP), lipopolysaccharide (LPS), soluble CD14 (sCD14), retinol, beta-carotene, and serum and erythrocyte zinc. RESULTS: We included 17 patients (mean age, 28.54 years) and 17 controls. Mean (SD) retinol levels were lower in patients: 1.99 (0.67) micromol/L vs 2.72 (0.96) micromol/L. Median beta-carotene levels were similar in both groups (0.30 micromol/L). Median serum zinc levels were 50.0 microg/dL (50-100 microg/dL) in the patients and 100.0 microg/dL (50-150 microg/dL) in the controls. Mean levels of erythrocyte zinc were lower among patients: 37.32 (10.51) microgZn/gHb vs 44.91 (7.67) microgZn/gHb in the controls. Median CRP levels were significantly higher among patients: 4.99 (0.15-34.51) mg/L vs 0.55 (0.17-6.06) mg/L. No differences in translocation marker levels were observed between the groups. CONCLUSIONS: CVID patients had lower levels of retinol and zinc than controls. Since micronutrient deficiency could aggravate their disease and contribute to chronic inflammation, micronutrient status should always be assessed in patients with primary immunodeficiency. PMID- 23101188 TI - Lack of association of programmed cell death 1 gene (PDCD1) polymorphisms with susceptibility to chronic urticaria in patients with positive autologous serum skin test. AB - BACKGROUND: Autoimmune mechanisms play an important role in the pathophysiology of chronic urticaria (CU), and the autologous serum skin test (ASST) helps to identify patients with autoreactive CU. One of the factors involved in autoreactive mechanisms is the cell surface receptor programmed death-1 which is encoded by the programmed cell death 1 gene (PDCD1). OBJECTIVE: To investigate whether PDCD1 polymorphisms influence susceptibility to CU. METHODS: We enrolled 93 ASST-positive patients with CU and a control group consisting of 105 healthy volunteers. In all individuals, PD1.3 (7146 A/G; rs 11568821) and PD1.5 (7785 C/T; rs 2227981) polymorphisms were analyzed. RESULTS: No statistically significant differences were found between CU patients and controls for allele or genotype distribution. We also did not observe any association between PDCD1 genotypes and severity of urticaria or age of disease onset. CONCLUSIONS: PD1.3 and PD1.5 polymorphisms were not proven to be implicated in susceptibility to ASST-positive CU in the Polish population. A more comprehensive analysis of the 2q33-2q37 genomic region might reveal whether variants of 1 or more of the genes in this region are involved in susceptibility to CU. PMID- 23101189 TI - Premenstrual asthma and female sex hormones. PMID- 23101190 TI - Anaphylaxis to vapors of roasting chicken controlled by omalizumab. PMID- 23101191 TI - Cutaneous allergy at the supermarket. PMID- 23101192 TI - Peripheral CD8+ T-cell levels are decreased in atopic wheezing children aged less than 4 years. PMID- 23101193 TI - Generalized skin lesions in a patient with common variable immunodeficiency. PMID- 23101194 TI - Delayed anaphylactic reaction to mammalian meat. PMID- 23101195 TI - Rapid desensitization with temozolomide in patients with delayed maculopapular rash. PMID- 23101196 TI - Hev b 5: latex allergen implicated in clinically relevant cross-reactivity with manioc. PMID- 23101197 TI - Neuropsychiatric reactions to montelukast. PMID- 23101198 TI - Hypereosinophilic syndrome associated with regulatory T-cell disruption as a complication of stem cell transplantation. PMID- 23101199 TI - Strongyloides stercoralis infection: a series of cases diagnosed in an allergy department in Spain. PMID- 23101200 TI - Sublingual immunotherapy: factors influencing adherence. PMID- 23101201 TI - [Infectious diseases in Poland in 2010]. AB - The purpose of the study is assessment of the epidemiological condition of infectious diseases in Poland in 2010, especially in comparison with 2009 and the years 2004-2008. MATERIAL AND METHODS: The evaluation of the epidemiological situation of infectious diseases in Poland was based on analysis of data: published in the annual bulletin "Infectious diseases in Poland in 2010" and "Vaccinations in Poland in 2010"/NIPH-NIH, GIS, 2011, the data contained in 27 articles prepared for publication in the Chronicle of epidemiology for 2010; data of Demographic Research Department of the central Statistical Office (GUS) for deaths from infectious and parasitic diseases registered in 2010 and selected earlier years. RESULTS: The most common group of diseases were respiratory diseases--despite a significant relative to 2009, a decrease of 49.1% of cases of influenza and flu-like disease. Still a major epidemiological problem in Poland is food poisoning and foodborne infections--despite the downward trend in the incidence of salmonellosis. In 2010, 9 732 cases were reported, and the incidence of salmonellosis was 25.5 to 100 000. There was an increase of gastro-intestinal infections, caused by viruses, compared to the median of the years 2004-2008 by 58.1%. Particularly important is epidemiological surveillance of the diseases covered by the immunization program. Their situation can be assessed as satisfactory. However, special attention is paid to the spread of viral hepatitis B and C, in which there was an increased incidence, respectively, by 10% and 2%. Decreased by 5.3% the number of newly registered cases of HIV infection. In 2010, total 3 044 people died in Poland due to infectious and parasitic diseases. The share of deaths from these diseases in the total number of deaths in Poland (378 478) was 0.80% - 8 deaths per 100 000. and were comparable to the data for 2009 In the last decade increased mortality due to infectious diseases was observerd, mainly due to the increase in diagnosed cases of sepsis. CONCLUSIONS: Infectious diseases, although a small part in the overall statistics of deaths, have not ceased to be a serious public health problem. As regards epidemiological surveillance is necessary to continue the legislative work on improving its sensitivity and increase microbiologically confirmed diagnoses. PMID- 23101202 TI - [Measles in Poland in 2010]. AB - INTRODUCTION: Since 2001 Poland has endorsed measles elimination programme which is coordinated by the World Health Organization (WHO). To accomplish measles elimination in the country, achievement of vaccination coverage at 95% in the population is needed, as is the monitoring of the epidemiological situation, i.e.: reporting on cases suspected of measles and conducting laboratory diagnostics in WHO Reference Laboratory. Polish Reference Laboratory is located at the Department of Virology (NIPH-NIH). OBJECTIVES: The aim of the article is to analyze the epidemiological situation of measles in Poland in 2010 with presenting the measles vaccination coverage and the progress of the measles elimination programme in Poland. MATERIAL AND METHODS: The epidemiological situation of measles in Poland was analyzed on the basis of the case-based questionnaires of cases suspected of measles sent to NIPH-NIH by the Sanitary and Epidemiological Stations, data from the publications: "Infectious diseases and poisonings in Poland in 2010" and "Vaccinations in Poland in 2010" (MP. Czarkowski et al., Warsaw 2011, NIPH-NIH, Chief Sanitary Inspectorate). RESULTS: In 2010, 13 cases of measles were notified to the surveillance system in Poland (incidence 0.03 per 100 000 population) and only six of them (46.1%) were laboratory confirmed. The highest incidence was observed in the age group 0-4 and was estimated at 0.3 per 100 000 population. Out of all cases, 9 (69.2%) were hospitalized. No fatal cases due to the measles were reported. In 2010 the maintenance of high vaccination coverage among children aged 2 and 11 years old was observed--from 84.9% to 99.7% (primary vaccination, children born in 2009 2004) and from 0.6 % to 96.6% (booster vaccination, children born in 2003-1999). A total of 38 measles cases and cases suspected of measles were reported (10% of the expected notifications). CONCLUSIONS: The epidemiological situation of measles in 2010 in comparison with the situation in 2009, has improved (decline in the incidence amounting to 87%). The low number of measles notifications reflects the low sensitivity of the measles surveillance system. Irrespective of that, the vaccination coverage was sustained at the satisfactory level. In order to achieve the improvement of the measles surveillance system, promoting of the measles elimination programme among the physicians is necessary with focusing on the necessity to report and laboratory confirm all measles cases and the cases suspected of measles. PMID- 23101203 TI - [Mumps in Poland in 2010]. AB - INTRODUCTION: Despite of the decline in the incidence rate of mumps which is the main result of the modifications of the Polish Immunization Programme (the vaccination against mumps has become obligatory since 2003), it is still a disease which occurs frequently in children. OBJECTIVES: The main objective of the present article was to analyze the epidemiological situation of mumps in Poland in 2010 in comparison with the data from previous year. This paper was based on aggregated data published in "Infectious diseases and poisonings in Poland in 2010", "Vaccinations in Poland in 2010", "Case definitions for the infectious diseases used for the surveillance purposes in 2009-2011" and Polish Immunization Programme for 2010. RESULTS: In Poland in 2010, 2 754 cases of mumps were reported. The incidence rate was 7.2 per 100 000 and was lower in comparison with the incidence rate observed in 2009 (7.7) and five times lower than the median incidence reported in 2004-2008. The highest incidence rate was observed in the children aged 5-9 years (53.9). Thirty two out of2 574 notified cases were hospitalized (1.16%). CONCLUSIONS: Realization of the vaccination against mumps using conjugate MMR (measles-mumps-rubella) vaccine contributed to the decrease in the incidence rate of mumps in Polish population. The high vaccination coverage implies that the incidence rate of mumps will be still decreasing. PMID- 23101204 TI - [Rubella in Poland in 2010]. AB - INTRODUCTION: Rubella is the disease subject to the elimination programme coordinated by the World Health Organization (WHO). Generally, rubella is an infection of mild course among children but in the case of pregnant women, who are not immunized, it may contribute to the occurrence of severe congenital abnormalities (congenital rubella syndrome) may amount to 95%. The strategy of the countries belonging to the WHO European Region is directed to the interruption of the rubella virus transmission in the environment in order to prevent the cases of congenital rubella syndrome (CRS). OBJECTIVES: The aims of the present article are to analyze the epidemiological situation of rubella in Poland in 2010 and to discuss the rubella vaccination coverage. MATERIAL AND METHODS: [corrected] The epidemiological situation of rubella in Poland was analyzed on the basis of publications: "Infectious diseases and poisonings in Poland in 2010" (Czarkowski MP et al. Warsaw 2011, NIPH-NIH and "Vaccinations in Poland in 2010". The classification of the rubella cases is based on the definition of the infectious diseases developed by the Department of Epidemiology (NIPH - NIH): "Definitions of the cases of infectious diseases for the purposes of the epidemiological surveillance". RESULTS: Comparing the epidemiological situation in 2009 and 2010, in 2010 a decline in the incidence of rubella was observed--from 19.0 per 100 000 population to 11.0 per 100 000 population. Overall, 4 197 cases of rubella were reported. While analyzing the definition of the rubella case for the purposes of the epidemiological surveillance, none of the cases was reported as the confirmed case, 29 (0.7%) were classified as the probable and the remaining cases were classified only on the basis of clinical criteria. In 2010, one congenital rubella syndrome (CRS) was registered. The rubella incidence among girls and women (9.0) was lower than the incidence observed among boys and men (13.1). The highest incidence--regardless of the gender and surroundings--was reported in children aged 7 years old (96.4 per 100 000) and 8 years old (93.1). The percentage of the 13-year-old girls vaccinated against rubella amounted to 99.2%. CONCLUSIONS: The epidemiological situation of rubella in 2010 in comparison with the situation in 2009, has improved. However, the concern is raised by the low percentage of the laboratory tests aiming at confirmation or exclusion of the rubella. The decline in the number of rubella cases is the consequence of the sustained high vaccination coverage among children. Theoretically, the high rubella vaccination coverage among the girls significantly decreases the probability of congenital rubella syndrome occurrence. On the other hand, the higher incidence of rubella among men who have the contact with the women in the reproductive age poses the risk of infecting the pregnant women who are not immunized. PMID- 23101205 TI - [Chickenpox in Poland in 2010]. AB - INTRODUCTION: Chickenpox is a common childhood disease. It occurs sporadically in persons over the age of 15. Regardless of the fact that chickenpox is considered to be a disease of benign course, it may cause complications of different severity levels and with necessity of hospitalization. Since 2004, a high incidence of chickenpox is observed in Poland. OBJECTIVES: The aim of the present article was to analyze the epidemiological situation of chickenpox in Poland in 2010 with its comparison to the situation observed in the previous years. MATERIAL AND METHODS: The epidemiological situation ofchickenpox in Poland in 2010 was analyzed on the basis of aggregated data on infectious diseases published in the annual bulletins, i.e.: "Infectious diseases and poisonings in Poland in 2010" (Czarkowski MP. et al., Warsaw, NIPH-NIH, Chief Sanitary Inspectorate) and "Vaccinations in Poland in 2010" (Czarkowski MP. et al., Warsaw, NIPH-NIH, Chief Sanitary Inspectorate). In the present article the authors also referred to the Polish Immunization Programme for 2010 (annex to the statement of the Chief Sanitary Inspector of 22 October 2009). The data on the number of hospitalized persons and complications due to the chickenpox was derived from the Department - Centre for Monitoring and Analyses of Population Health Status and Health Care System (NIPH-NIH). RESULTS: In 2010, 183 446 cases of chickenpox were reported. The highest number of chickenpox cases was registered in mazowieckie voivodeship, the lowest--in podlaskie voivodeship. The incidence was estimated at 480.04 per 100 000 population and was significantly higher than the incidence observed in 2009 (367.2). The highest chickenpox incidence, which amounted to 4298.4 per 100 000, was reported in children aged 5 9 years. The highest number ofchickenpox cases (the peak) was reported in the period from January to June. The lowest number of cases was registered in September. The chickenpox incidence was higher in men than women and in the inhabitans of villages (498.6 per 100 000) than in persons residing in towns (468.8). The highest incidence was observed in towns with the number of inhabitants ranging from 55 to 99 thousands (532.2 per 100 000), while the lowest incidence was reported in towns over 100 thousand inhabitants (439.1 per 100 000). Overall, 1007 persons were hospitalized due to the chickenpox. A total of 31 540 persons were vaccinated, of whom 30 513 persons belonged to the age group 0-19 years. CONCLUSIONS: Since 2004, an increase in the number of reported chickenpox cases is observed in Poland. It is a consequence of improvement in chickenpox registration. PMID- 23101206 TI - [Pertussis in Poland in 2010]. AB - INTRODUCTION: Pertussis is an acute infectious disease of the upper respiratory tract. It is the infection of the re-emerging character and affects infants, youth and more frequently adults. The results of the Nationwide Surveillance Study of Pertussis conducted at the Department of Epidemiology (NIPH-NIH) in 2009 2011 confirmed the high incidence of pertussis in adults, among whom the only symptom of Bordetella pertussis infection was prolonged cough. The emphasis should be put on the fact that the infected adults (especially the older adults) are the reservoirs of the pathogen and as consequent there is a risk of transmission of the infection from the adults to the persons who are not immunized, e.g. infants. OBJECTIVES: The aim of the article is to analyze the epidemiological situation of pertussis in Poland in 2010 with presenting the pertussis vaccination coverage. MATERIAL AND METHODS: The epidemiological situation of pertussis in Poland was analyzed on the basis of the case-based questionnaires of cases suspected of pertussis sent to NIPH-NIH by the Sanitary and Epidemiological Stations, data from the publications: "Infectious diseases and poisonings in Poland in 2010" and "Vaccinations in Poland in 2010" (MP. Czarkowski et al., Warsaw 2011, NIPH-NIH, Chief Sanitary Inspectorate). RESULTS: In 2010, 1 266 pertussis cases were reported. The incidence was estimated at 3.3 per 100 000 population and was significantly lower than the incidence observed in the previous year (6.3), i.e. a decrease accounting for 48%. As it was observed in the previous year, the highest incidence of pertussis was reported in children aged 3 years old, 4 years old and in the age group 10-14 and it accounted for 20.5, 20.1 and 13.9, respectively and among the citizens of the towns. Out of 1 266 pertussis cases, 525 (41.5%) were hospitalized. No fatal cases of pertussis were reported in 2010. CONCLUSIONS: The lower incidence ofpertussis observed in 2010 in comparison with the incidence reported in the previous year, indicates the improvement of the pertussis epidemiological situation in the country, but on the other hand it may reflect the low sensitivity of the surveillance system. PMID- 23101207 TI - [Scarlet fever in Poland in 2010]. AB - OBJECTIVE: Assessing the epidemiological situation of scarlet fever in Poland in 2010. MATERIALS AND METHODS: The analysis was based mainly on data published in the bulletin, "Infectious diseases and poisonings in Poland in 2010" (Warsaw 2011, NIPH-NIH , CSI). RESULTS: Since 2004, Poland is observed epidemic growth in the number of scarlet fever cases. However, incidence level is much lower than in previous epidemic periods. There were 13,940 cases registered in 2010 in total and the incidence was 36.5 per 100,000 population ranging from 18.1 in lodzkie voivodeship to 47.5 in mazowieckie voivodeship. Cases among children and adolescents of less than 15 years of age accounted for 97.0% of all cases. The highest incidence was observed among 4 years old children (603.1) and 5 years old children (624.9). Incidence in men (41.8) markedly exceeded the incidence in women (31.6) and incidence in urban areas (41.3) and in rural areas (29.0). Approximately 1.2% of all cases were hospitalized. Due to scarlet fever there were no deaths in Poland in 2010. SUMMARY: Favourable epidemiological situation of scarlet fever in Poland is largely a result of demographic changes--reducing the involvement of children in society. In terms of disease prevention and control is necessary to increase the proportion of cases in which clinical diagnosis is confirmed by the result of bacteriological tests. PMID- 23101208 TI - [Meningitis and encephalitis in Poland in 2010]. AB - INTRODUCTION: Annually 2 000-3 000 cases of meningitis and encephalitis are notified to the Polish surveillance system. The leading etiologic agents of the bacterial infections are: N. meningitidis, S. pneumoniae, H. influenzae type B and L. monocytogenes. The most common causes of bacterial infections in children are: E. coli, S. agalactiae and H. influenzae type B. The viral infections are mainly caused by the following pathogens: Echovirus, Coxsackie virus group A and B. The agents responsible for the viral infections are also: arboviruses, Herpes simplex virus and mumps virus. OBJECTIVES: The objectives of the present article are to analyze the epidemiology of meningitis and encephalitis in Poland in 2010 and to present the information on the vaccines used to prevent the discussed infections. MATERIAL AND METHODS: The analysis was based on the data retrieved from the questionnaires used for the surveillance purposes, aggregated data on meningitis and encephalitis published in "Infectious diseases and poisonings in Poland in 2010", aggregated data on the vaccination coverage published in "Vaccinations in Poland in 2010", "Case definitions for the infectious diseases used for the surveillance purposes in 2009-2011" and Polish Immunization Programme for 2010. RESULTS: In 2010, Poland reported 3 063 neuroinfections- nearly 22% more than in 2009. The incidence rate was 8.03 cases per 100 000 population. From the analysis of data transpired that of the notified cases, 1 619 were of viral etiology, 846--were bacterial and 598 of other or unknown origin. Given the bacterial infections of determined etiology, the leading pathogenic agent was S. pneumoniae (180 cases), following by N. meningitidis (146 cases) and Haemophilus influenzae typu B (11 cases). Among confirmed cases of the viral infections, the predominant were tick-borne encephalitis cases (294). CONCLUSIONS: Compared to the data from 2009, the epidemiologic situation of the meningitis and encephalitis in Poland in 2010 has not changed significantly. PMID- 23101209 TI - [Legionellosis in Poland in 2010]. AB - METHODS: The main objective of this article is to assess the epidemiology of legionellosis in Poland in 2010, using national surveillance data. In Poland, legionellosis is a mandatory notifiable disease based on the European Union (probable or confirmed) case definition, however Legionella pnemophila of unknown serogroup specific antybody response meets also laboratory criteria for case confirmation. RESULTS: The number of legionellosis cases reported has increased over the past years. Between 2004-2008 the median annual number of cases in years 2004-2008 was 21. In 2009, alone, was 10 cases. In 2010 a total 36 legionellosis cases (0.09 per 100,000 inhabitants)--including 9 confirmed cases (6 cases with detected Legionella pneumophila antigen in urine and 3 cases with Legionella spp. specific antybody response) and 27 probable cases--were registered. Among probable cases--21 were reported on the basis of clinical symptoms (e.g. pneumonia) and the presence of an 'epidemiological link' (exposure from the same source), without laboratory confirmation. Sporadic cases (12) represented only one-third of the total number of registered cases. A total of 3 outbreaks were reported, all in the province Slaskie, the largest involved 19 patients. All outbreaks were caused by the presence of Legionella in the public hot water systems. Incidence among men (0.12 per 100 000 population) was slightly higher than the incidence among women (0.07); the highest incidence was observed among people aged 60-69 years. Nearly 78% of cases (28) were people aged over 49 years of age. All patients presented with pneumonia, and all except 1 were hospitalized. No deaths related to the disease were reported. Furthermore, there were no imported cases nor cases associated with travel. CONCLUSIONS: We conclude that there is an urgent need to improve surveillance of Legionellosis in Poland, particularly in terms of laboratory capacity. Introduction of rapid tests for detection of Legionella antigen in urine should increase the number of diagnosed patients who present with symptoms of pneumonia. PMID- 23101210 TI - [Dysentery and amoebiasis in Poland in 2010]. AB - INTRODUCTION: Dysentery as infective and contagious disease is registered by all EU and EFTA countries only as shigellosis according to etiological classification of the infectious diseases. The cases are also registered by ECDC. According to ECDC Report for 2006-2008 the incidence rate in Poland < 0.01/100 000 was the lowest from all EU/EFTA countries that have send the data to ECDC as the cumulative for EU countries was 1.78/100 000. MATERIAL AND METHODS: Epidemiological data were collected by Regional Epidemiological Sanitary Stations, send to the National Register of Infectious Diseases, evaluated, calculated and published by Department of Epidemiology National Institute of Public Health (NIZP-PZH) in Annual Bulletin "Infections and Intoxications in Poland in 2010", Warsaw NIZP-PZH and GIS (Chief Sanitary Inspectorate ) 2010. Laboratory data were collected as reports from all Regional Sanitary Laboratories send to NIZP-PZH Department of Bacteriology, data from epidemiological investigation of outbreaks including data from identification of Shigella strains obtained from the Reference Laboratory for Gram-negative Bacilli of NIZP-PZH Bacteriology Department. RESULTS: In 2010 thirty cases of shigellosis were registered (incidence was 0.08/100 000 inhabitants) the same number of cases and incidence was observed in 2009, nearly the same in 2008 - 33 cases (incidence 0.09). The numbers were lower than the median in 2004-2008 (64 cases, incidence 0.17/100 000). According to laboratory reports in all 16 Regional Sanitary Stations only 14 persons were Shigella positive, in spite that more than 600 000 were examined: 10 persons were infected by S. sonnei, 4 by S. flexneri. Only one strain of S. sonnei was isolated from a patient with diarrhea. It was in the Regional Sanitary Station laboratory of the malopolskie voievodeshaft. No one strain of S. boydii or S. dysenteriae was isolated. DISCUSSION AND CONCLUSION: Most of the dysentery cases were examined by other laboratories than laboratories of sanitary epidemiological service. The obligation of private payment for bacteriological examination of suspected cases is one of reason that patient is treated with antibacterial drugs without determination of etiological agent of the infection. It concern the population of small and medium towns as well as population of farmers living in the country, children and youth. The registration of shigellosis in Poland is not valuable. In 2010 no case of amoebiasis was registered as in 2008 the disease no more should be obligatory registered. PMID- 23101211 TI - [Foodborne infections and intoxications in Poland in 2010]. AB - AIM: The purpose of this paper was to describe the epidemiology of foodborne outbreaks in Poland in 2010. MATERIAL AND METHODS: The evaluation of the epidemiological situation was based on data from outbreak investigation forms, reported by Sanitary and Epidemiological Stations to the Department of Epidemiology, NIPH-NIH. RESULTS: In 2010 a notable increase in the number of cases reported with a bacterial infection was observed. This increase however did not exceeded the median number of cases reported in 2004-2008. In 2010 392 foodborne infections and food poisoning involving 6994 cases (outbreaks involving 4 person or more) and 145 foodborne outbreaks (where 2-3 persons became ill were reported. S. Enteritidis was the most frequently etiological agent in outbreaks associated with bacterial infection (32.9% of outbreaks 22.4% cases). Viruses caused 26% of outbreaks affected 30% of cases. In 38.3% outbreaks the etiological agent could not be established. The main vehicle of foodborne outbreaks were meals prepared from (> 3) raw meats (4.6% of outbreaks, 10.9% cases) and meals prepared using milk and eggs (9.9% of outbreaks 5.7% cases). The most frequent places of contamination included farms who produced goods for human consumption (11.5% of outbreaks, 5.0% of cases). Private residences (113 outbreaks with 745 cases) and hospitals were the most common place where food poisoning outbreaks occurred. In 2010 there were 6 outbreaks where more than 100 people were affected in these settings. CONCLUSIONS: Like in previous years, in 2010 the etiological agents, vehicle and sources of infection were not identified in most foodborne outbreaks. In order to decrease the number of outbreaks with undetermined etiological agent, the spectrum of routine laboratory tests of samples taken in outbreaks should be broaden. PMID- 23101212 TI - [Yersiniosis in Poland in 2010]. AB - MATERIAL AND METHODS: The study was based on data from: the "Infectious diseases and poisonings in Poland" bulletins published annually between 2005-2010 (MP Czarkowski i in., PZH i GIS), individual case interviews conducted by sanitary stations and data from Demographic Surveys Departament based in the Central Statistical Office. Analysis of the incidence of yersiniosis in the country during 2010 was based on data on clinical symptoms associated with the disease, age groups, the number of cases in different provinces and the serotypes of Yersinia which were isolated. RESULTS: A total of 233 yersiniosis cases were reported in 2010 in Poland. The incidence rate was 0.61 per 100 000 inhabitants. In this year 206 cases of intestinal yersiniosis and 27 cases of extraintestinal yersiniosis were notified. No yersiniosis related deaths were reported. Approximately 76% of patients were hospitalized. The most common clinical symptoms of intestinal yersiniosis cases were: diarrhea (82%), high temperature (72%), abdominal pain (39%) and vomiting (34%). The most common symptom of the extraintestinal form of yersiniosis was discomfort to part of the osteoarticular system, which occurred in 59% of patients. The highest incidence rate of intestinal yersiniosis was among children in 0-4 years old. The largest number of yersiniosis cases were reported in Mazowieckie voivodeship, while the least number of cases were reported in Podlaskie and Swietokrzyskie voivodeships. In 2010 only one outbreak of yersiniosis was reported. Three serological types of Yersinia enterocolitica were isolated: 03 (71.2%), 08 (26.3%) and 09 (2.5%). AIM: The aim of this study is to present the epidemiology of intestinal and extraintestinal yersiniosis in Poland in 2010. CONCLUSIONS: A very large percentage (65.6%) of isolated strains of Yersinia were not serotyped. Yersinia serotype 08 remains very common serotype reported, despite a decline in 2010 in the number of cases notified. The high percentage of hospitalization points that patients with gastrointestinal symptoms are relatively rare direct to routine laboratory diagnostic of Yersinia infection. PMID- 23101213 TI - [Campylobacteriosis in Poland in 2010]. AB - AIM: The aim of this work is to evaluate the epidemiological situation of Campylobacter in Poland in 2010. MATERIAL AND METHODS: The evaluation was based on results from analysis of: the yearly bulletin "Infectious Diseases and food poisoning in Poland" between the years 2009-2010 (MP Czarkowski i in., PZH i GIS), reports from individual cases and epidemiological investigations of outbreaks linked to Campylobacter, sent by Epidemiological Departments in Sanitary Stations to the Department of Epidemiology at NIZP-PZH. Data was also collected from the Department of Demographical Research based at the Central Statistics Office. All reported cases were verified in accordance with the case definition required for surveillance. RESULTS: In 2010, 375 cases of Campylobacter were reported in Poland, yielding an incidence of 0.98 per 100,000 inhabitants. Of cases reported 367 were confirmed and 8 probable. No deaths were reported. Over, 46% (171) of all cases reported were from the Slaskie voivodship. The highest incidence of 4.76 per 100,000 was observed in Warminsko-Mazurskie voivodship. Fifty-four per cent of people were hospitalized, the least in Warminsko-Mazurskie voivodship (17.6%) and in 5 voivodships over 90% of their cases were hospitalized. Campylobacter was isolated in 305 people who were ill (approximately 81%). In 2010, 275 (73.3%) people were identified as being infected with C. jejuni and 27 (7.2%) with C. coli. Illness due to infection with C. coli was mainly reported in Malopolskie Voivodship, over 55% of all cases were infected with this species. The highest number of cases (292; 77.6%) was observed among children aged between 0-4 years. In terms of gender, a total of 209 men and 166 women were reported as ill. In 2010 4 family outbreaks caused by Campylobacter were reported. One outbreak was also reported among children attending a summer camp, where 78 people were exposed, 53 children of which were up to 14 years of age. A total of 12 children between 8-14 years became ill. CONCLUSIONS: Despite the increase in cases of Campylobacter reported, the disease remains underdiagnosed and under-reported. The species of Campylobacter responsible for diseases has been identified in a significant number of cases and has steadily increased in recent years. PMID- 23101214 TI - [Salmonellosis in Poland in 2010]. AB - AIM: The aim of this study is to present the epidemiology of salmonellosis in Poland in 2010. MATERIAL AND METHODS: The study was based on data from: "the Infectious diseases and poisonings in Poland 2010", information from laboratories based in sanitary stations, the forms of outbreaks investigations conducted by sanitary stations and data from Demographic Surveys Departament based in the Central Statistical Office. All cases were classified according to the case definition used by surveillance. RESULTS: A total of9 732 salmonellosis cases were reported in Poland. Among them 8 549 cases were intestinal and 183 were extraintestinal. The incidence rate was 25.5 per 100 000 inhabitants. Over 95% of cases met the criteria for a confirmed case. The number of registered cases was higher than in the previous two years, despite this an overall decreasing trend was observed in the number of cases of salmonellosis in Poland. Cases of salmonellosis occurred primarily among children under 5-years old. There were no deaths reported due to salmonellosis. There is still a high percentage, about 70%, hospital admissions of people infected with zoonotic Salmonella. The percentage of hospitalization in outbreaks is almost two and a half times lower 29%. In 2010, 189 outbreaks caused by Salmonella were reported, affecting 1 662 people (almost 18% of all reported cases of intestinal salmonellosis). Most were small family outbreaks. Still the most common etiologic agent in Poland is S. Enteritidis. When compared with previous years, in 2010 there was an increase in the number of cases caused by S. Mbandaka, S. Infantis and S. Virchow. The number of screening tests for carriers among food handlers decreased by over 10% however the percentage diagnosed with positive result increased from 0.3% to 0.5%. CONCLUSIONS: Human salmonellosis is still a significant public health problem in Poland. The very high percentage (70%) of hospitalization, persisting for many years indicates that diagnosis and reporting ofsalmonellosis in Poland is mainly among severe cases. This allows to conclude that the incidence of salmonellosis in Poland is largely under-diagnosis and under-reported. PMID- 23101215 TI - [Botulism in Poland in 2010]. AB - OBJECTIVE: The main objective of this article is to assess the epidemiology of foodborne botulism in Poland in 2010, using national surveillance data. In Poland, botulism is a mandatory notifiable disease based on the European Union case definition (probable or confirmed), however given limited laboratory capacity, in national surveillance we also use "possible" case definition for cases reported by physicians based on clinical symptoms (with no laboratory confirmation). RESULTS: The number of botulism cases reported has decreased over the past years. Between 2004-2008 the median annual number of cases in years 2004 2008 was 49, whereas in 2009 alone, was only 31 cases. In 2010 a total 32 botulism cases (0.08 per 100,000 inhabitants)--including 22 confirmed cases (in 20 cases--toxin type B, and in 2 -toxin type B / E was found) were reported. There was only one--'probable case'--reported on the basis of clinical symptoms and the presence of an 'epidemiological link' (exposure from the same source). Other cases (9 patients) were reported, on the basis of clinical diagnosis without laboratory confirmation and registered as 'possible cases'. Incidence in rural areas (0.18) was 9-fold higher than the incidence in urban areas. Men had higher (0.12) incidence than women (0.05); the highest incidence (0.17) was observed among people aged 50-59 years. All cases were people aged over 25 years of age. In 28% of all cases--homemade canned pork was implicated. Canned fish were also a common vehicle. All patients were hospitalized--for between 5 and 35 days (median 11 days). No deaths related to the disease were reported. CONCLUSIONS: Botulism in Poland is still an important epidemiological problem. A large number of poisonings is primarily due to consumption of homemade canned foods. PMID- 23101216 TI - [Hepatitis A in Poland in 2010]. AB - OBJECTIVES: The purpose of this paper was to describe the epidemiology of hepatitis A in Poland in 2010. MATERIALS AND METHODS: The evaluation of the epidemiological situation was based on data published in the annual bulletins (Czarkowski MP et al. Infectious diseases and poisonings in Poland in 2010 Warsaw, NIPH - NIH and CHI, Vaccinations in Poland in 2010, NIPH - NIH and CHI). RESULTS: In Poland in 2010 were reported 155 cases of hepatitis A. The incidence rate in 2010 were 0.41 per 100 000 population. Most cases were registered in mazowieckie voivodeship (37 cases), slaskie voivodeship and wielkopolskie voivodeship (35 cases). The highest incidence were observed in wielkopolskie voivodeship 1,03 per 100 000 inhabitants. Incidence was higher among men than among women--0.53 and 0.29 per 100 000 population, respectively. In 2010 were notify of 5 foodborne outbreaks involving 10 cases. There were no death cases resulting from the infections hepatitis A. CONCLUSION: In 2010, compared with 2008 - 2009 (0.55 and 1.71 per 100 000 respectively), incidence was lower. However, it is possible to increase the number of cases and a local outbreak of hepatitis A due to a large group susceptible to infection. PMID- 23101217 TI - [Hepatitis B in Poland in 2010]. AB - OBJECTIVES: The objective of this study was to describe the epidemiology of hepatitis B in Poland in 2010 in comparison to previous years. METHODS: The study included cases that were collected and registered by the State Sanitary Inspection in 2010 in Poland. Data reported was verified, processed and published by National Institute of Public Health - National Institute of Hygiene. Analysis of cases was conducted on case-based data for acute hepatitis B and on aggregated data for all stages of hepatitis B. Case classification included confirmed and probable cases of acute hepatitis B. A confirmed case was defined, in accordance with the EU case definition, as any person meeting the clinical criteria (compatible with hepatitis) and having laboratory confirmation through detection of IgM antibodies for hepatitis B core antigen (IgM anti-HBc+). For probable cases both clinical criteria and presence of an epidemiological link to a confirmed case was required. RESULTS: A total of 1,633 hepatitis B cases, including 38 cases of co-infection with hepatitis C (HCV) was reported in 2010. Incidence was 4.28 per 100,000 population, higher than the previous year. Acute cases constituted 7.8% of people reported as hepatitis B positive. Since 2005 a steady downward trend in incidence of acute hepatitis B has been observed, in 2010 the lowest ever rate of 0.34 per 100,000 population was recorded. The number of newly detected chronic infections, however have increased in recent years with a different epidemiological profile. There is a distinct geographical variation in acute and chronic hepatitis B incidences in the country, the acute hepatitis B incidence ranges from 0.04 to 0.64/100,000 and that of chronic from 0.18 to 11.6/100,000. Such diversity may be due to differences in reporting and quality of surveillance between regions. As in 2009, chronic hepatitis B was most frequently diagnosed among people aged 15-19, which is most likely connected to the very high incidence observed among children under 4 years in the early 90s. We observed two peaks of acute hepatitis B--among people aged 25-29 living in urban areas and those over 75 years living in rural areas. Both acute and chronic cases were more often among males than females and those residing in urban areas. In 2010, 99% of acute and 54.6% chronic hepatitis B cases were hospitalized, 5 people died because of acute hepatitis B and 42 due to chronic hepatitis B. CONCLUSIONS: The decreasing trend of acute hepatitis B incidence in Poland is attributed primarily to the universal HBV vaccination among infants and healthcare workers over the past 15 years. Acute hepatitis B infection occurred mainly among unvaccinated young males aged 25-29 years who lived in urban areas, pointing to a change in transmission patterns and increasing sexual transmission, tattooing and injecting drug usage. However the main transmission route in Poland is still attributed to medical procedures in hospital and nonhospital health-care associated settings accounting for 59% of acute infections. PMID- 23101218 TI - [Hepatitis C in Poland in 2010]. AB - BACKGROUND: Hepatitis C is registered as a separate entity in the national infectious diseases system in Poland beginning from 1997. All physicians who diagnose the disease are mandated to report it and, additionally, in the years 2006 - 2008, mandatory reporting of positive results of HCV test by laboratories was also implemented. The initial definition adopted at the European Union level was implemented in Poland in 2005 (2005 definition) and it included cases with symptoms or elevated liver function tests, which coincided with the earlier practice. The amended European definition was implemented in 2009 (2009 definition) to require registration of all laboratory confirmed cases. AIM. To assess epidemiological situation of hepatitis C in Poland in 2010 in comparison to the preceding years. MATERIAL AND METHODS: We performed descriptive analysis of data collected through routine mandatory surveillance system. Case classification according to 2005 definition and 2009 definition was verified based on individual case reports. RESULTS: In 2010 in Poland 2021 hepatitis C cases meeting 2005 definition were registered (incidence 5.29 per 100,000), including 38 with mixed HBV-HCV infection. As compared to 2009 (1939 cases, incidence 5.08) the incidence increased by 4%. In consequence the decreasing trend observed since 2006 slowed down. Overall 2212 reported cases (5.79 per 100,000) met the 2009 definition. This number was higher than in 2009, but still several times lower than the number of newly diagnosed HCV cases registered in 2006 - 2008. In total 167 persons died due to hepatitis C (mortality 0.44 per 100,000), including 8 due to acute hepatitis C. This constitutes the highest hepatitis C mortality observed since 1996. CONCLUSIONS: Low number of registered cases meeting the 2009 definition indicates the necessity to improve the completeness of reporting, in ex. through restoring laboratory reporting. It also justifies maintaining the classification according to 2005 definition in order to monitor trends of the disease, even though the number of cases meeting this definition underestimates the real problem. The increase in mortality suggests that further improvements in diagnosis and access to treatment are necessary. PMID- 23101219 TI - [Tetanus in Poland in 2010]. AB - Epidemiological assessment of the incidence of tetanus in Poland in 2010 was based on the analysis of aggregate data provided by the State Sanitary Inspection and published an annual newsletter: Infectious diseases and intoxications in Poland in 2010, compiled by MP Czarkowski, E Cielebak, B Kondej, E Staszewska, Warsaw in 2011 and based on an annual newsletter: Vaccinations in Poland in 2010, compiled by MP Czarkowski, E Cielebak, B Kondej, E Staszewska, Warsaw 2011. A more accurate characterization of disease was based on the individual reports sent to the Department of Epidemiology, NIPH-NIH. In the last decade the incidence of tetanus has remained below 0.08/100 000 inhabitants. The average annual incidence was lower than in the previous decade, but within the last ten years to the annual variation is difficult to assign a distinct incidence tendency. Rather, they correspond to random fluctuations. In 2010, 16 cases were reported, including which occurred in 2009. All cases was reported as probable- diagnosis based on clinical signs and information about injuries. Overall incidence was 0.042/100 000, which was small and not significanty different from incidence in 2009 (0.05/100 000). All cases in 2010, were over 59 years of age, which is a strong expression of the trend observed for years that the disease is present in older age groups where the level of vaccination against tetanus is particularly low. Among people infected, there were three men and 13 women. Four cases ended with deaths. Three of these were women, among whom mortality was 23.1%, and one death occurred in a man, mortality 33.3%. Three deaths occurred among the 6 cases in people over 79 years of age, mortality 50%. The incubation period of the disease in 3 cases was less than 7 days, in 4 cases 8-14 days, in 4 cases 15-21 days, in 2 cases 22 days and more. Portals of entry of infection in 7 cases accounted for abrasion or laceration, in 6 cases the puncture wound in one it was bitten wound, and in 2 cases, the gates of infection remained unknown. In 3 cases involved people getting vaccinated, and 13 were not given information about the vaccination. No case has not occurred in a person with a documented vaccination. High degree of vaccination of children and adolescents against tetanus makes the tetanus, in these age groups almost completely eliminated, and the few cases occured in people in older age groups. But this is not a disease that can be eliminated from the environment and the risk of non-vaccinated people will always be in the case of injury with rupture of skin and contamination of the wound. Therefore it is important to maintain the current level of children and adolescents vaccinated against tetanus and pay attention to vaccination after injuries and adequate supply of injuries. This is particularly true of the elderly population. PMID- 23101221 TI - [Lyme borreliosis in Poland in 2010]. AB - INTRODUCTION: Lyme borreliosis is an animal, affecting multiple systems infectious disease transmitted to humans by the ticks (vector) belonging to the genus Ixodes. The incidence of Lyme borreliosis is conterminous with the ticks habitat and covers the Northern Hemisphere. The Department of Epidemiology of National Institute of Public Health - National Institute of Hygiene (NIPH-NIH) is liable for the registration of Lyme borreliosis since 1996. The highest incidence of Lyme borreliosis is observed in the north-east region, but it should be noted that the disease is not only restricted to the aforesaid area of Poland. OBJECTIVES: The aim of the present article is to analyze the epidemiological situation of Lyme borreliosis in Poland in 2010 with its comparison to the situation observed in the previous years. MATERIAL AND METHODS: The epidemiological situation of Lyme borreliosis in Poland was analyzed on the basis of case-based questionnaires for Lyme borreliosis sent to Epidemiology Department NIPH-NIH by the Sanitary and Epidemiological Stations and the data from the bulletin--"Infectious diseases and poisonings in Poland in 2010" (MP Czarkowski et al., Warsaw 2011, NIPH-NIH, Chief Sanitary Inspectorate). RESULTS: In 2010, 9005 Lyme borreliosis cases were registered in Poland, which constitutes a 13% decrease in the number of reported cases and incidence (23.6 per 100 000 population) in the comparison with the previous year. The highest incidence, accounting for 76.0 per 100 000 population, was reported in podlaskie voivodeship. 2318 persons were hospitalized due to Lyme borreliosis. CONCLUSIONS: In 2010, for the first time in eight years, an increased tendency of the number of registered Lyme borreliosis cases was not observed. An approximately 13% decline in the number of notified cases was reported in comparison with the previous year. There is still a low number of Western blot tests performed to confirm the disease. PMID- 23101220 TI - [Rabies in Poland in 2010]. AB - AIM: The aim of this work is to evaluate the epidemiological situation of rabies in Poland in 2010. MATERIAL AND METHODS: The evaluation was based on analysis of data submitted by voivodship sanitary stations survey which included information on people who had been vaccinated for rabies following exposure in Poland and other countries. Additional data from the yearly bulletin "Infectious Diseases and food poisoning in Poland" between the years 2009-2010 (MP Czarkowski i in., PZH and GIS) and epizoonotic data provided by the Chief Veterinary Inspectorate was used. RESULTS: In 2010 in Poland, 152 cases of animal rabies were reported. The majority of animals came from Malopolskie voivodship where from June 2010 an increase in the number of cases of animal rabies was observed. Rabies cases reported among terrestrial animals, as in previous years, also occurred in Lublin and Podkarpackie voivodships. One case was also observed in Mazowieckie voivodship. In other regions of the country isolated cases of bat rabies were recorded. In 2010, a total of 7,243 people were vaccinated against rabies of which 261 (3.6%) were due to exposure of an animal that was confirmed to have rabies. Among people who were vaccinated due to contact with animals where rabies infection was confirmed, a total of 92 (more than 35%) were as a result of fox contact. However as reported in previous years the majority of people were vaccinated after exposure to animals, mainly dogs and cats, among whom rabies could not be ruled out- 6326 people (over 87%). In 2010, 106 people were vaccinated as a result of possible exposure to rabies in other countries. CONCLUSIONS: Despite an increase in the number of rabies cases being observed in Poland, the situation remains under control with a steady decreasing trend being observed. This decrease is a direct consequence of the implementation of the oral vaccination of wild animals which was introduced to Poland in 1993. There is a visible, albeit slower, decrease in the number of people being vaccinated against rabies among people who came into contact with animals potentially infected with the virus. PMID- 23101222 TI - [Trichinellosis in Poland in 2010]. AB - INTRODUCTION: Trichinellosis is still an epidemiological problem in Poland as well as in other countries in the European Union (EU). Across the EU, reporting cases oftrichinellosis is mandatory. In Poland, tirchinellosis is an endemic disease, occurring mainly in territories where it is customary to eat raw meat products prepared from pigs and wild boars. AIM: The aim of this work is to evaluate the epidemiological situation of trichinellosis in Poland in the year 2010 in comparison to previous years. MATERIAL AND METHODS: Cases of trichinellosis infections were classified according to criteria contained in the definition approved by the European Committee on 28th April 2008 amending the decision 2002/253/EC, and was introduced in Poland in 2009. Case definitions used in are available at http://www.pzh. gov.pl/oldpage/epimeld/inne/Def_PL2_Rob1 h.pdf. An infection was classified and reported as Trichinella spp. if the genus of Trichinella that caused the infection was not specified using molecular examination. RESULTS: In 2010 the number of registered human trichinellosis cases was similar to the average number of cases from the last several years, and it did not exceed 55 (the exceptions were in 2004 and 2007, when larger outbreaks occurred). In 2010, 51 Trichinella infections were registered, yielding an infection rate of 0.13 per 100 000 inhabitants. The infections occurred in 5 voivodeships (table 1). Using the criteria from the definitions, 41 cases were classified as probable and 10 were confirmed cases. Trichinella infections diagnoses were based on the presence of clinical symptoms and an epidemiological link. Serological diagnostic tests confirming the presence of Trichinella antibodies was performed in approximately 20% of the cases. Four individual cases were reported, along with 4 outbreaks in which a total of 47 people were infected? The infections were generally mild. Twenty-two infected persons were hospitalised (43%). Just like in previous years, no trichinellosis-related deaths were reported. The outbreaks of trichinellosis in 2010 occurred in voivodships where they are reported almost every year. Groups of 10 people and above were affected, consisting of family and friends. The incidence rate in three outbreaks ranged from 24% to 37%. In the Pomorskie voivodship this number was much higher- above 82%. This could mean that the infected products contained a large number of Trichinella larvae or that not all of the infected people were reached by the sanitary services. Small children are very rarely infected. In 2010 in the Wielkopolskie voivodeship, two such cases were reported in children who were 4 and 6 years old. Epidemiological investigation revealed that in the reported outbreaks the infections were most likely caused by the consumption of wild boar meat products, especially raw sausages. This finding was confirmed by analysing meat samples using the artificial digestion method. The particular genus of Trichinella was not specified in any of the cases and therefore they were classified as caused by Trichinella spp. The reason why infected wild boar meat was permitted to be consumed in two of the outbreaks was due to faulty carcass examination results. These examinations were conducted using the trichinoscopy method, which is still allowed in Poland despite being less sensitive than the artificial digestion method. In the Podlaskie voivodship outbreak the carcasses were not examined, and in the Pomorskie voivodship outbreak it could not be determined whether any examinations had been conducted. CONCLUSIONS. The annual occurrence of trichinellosis outbreaks and infections points to insufficient control of consumable meat products and lack of public awareness about the dangers of consuming raw/rare wild boar meat and pork that has not undergone prior veterinary inspection. PMID- 23101223 TI - [Cystic echinococcosis in Poland in 2010]. AB - The study objective was to assess the prevalence of human cystic echinococcosis in Poland in 2010, as compared with the number of registered cases in 2009, and former years. MATERIALS AND METHODS: Evaluation of epidemiological situation was based on the analysis of data published in the annual bulletin Infectious diseases and poisonings in Poland in 2010, M. Czarkowski et al., National Institute of Public Health - National Institute of Hygiene, Chief Sanitary Inspectorate. In addition, the data on taeniases provided to the Department of Medical Parasitology NIPH-NIH by regional sanitary-epidemiological stations were analyzed. RESULTS: 36 cases of echinococcosis (incidence 0.09) were recorded in 2010: 34 cases caused by Echinococcus granulosus (incidence 0.09) and 2 cases triggered by Echinococcus multilocularis (incidence 0.005). There was a slight increase in the incidence of cystic echinococcosis as compared to the preceding year (25 cases in 2009, incidence 0.07). Most cases were reported in the Masovian province (12 cases, 33.3% of all reported cases, incidence 0.23), and the smallest number in the Kuyavian-Pomeranian province (1 case, incidence 0.05). More cases of echinococcosis (25 cases, 69.44%) were recorded in the countryside than in cities (11 cases, 30.56%). Both, in the rural and urban areas, women suffered more frequently (31 cases, 86.11%) than men (5 cases, 13.89%). Multilocular echinococcosis was diagnosed in one woman and one man from the countryside. 26 patients (72.2%) were hospitalized in 2010, which indicates a decline in the percentage of hospital admissions as compared to previous years: 100% of patients were hospitalized in 2008, and 92% in 2009. There were no reported cases of cysticercosis. CONCLUSIONS: It is essential to continually propagate information relative to infection cystic echinococcosis in human in Poland. PMID- 23101224 TI - [HIV and AIDS in Poland in 2010]. AB - INTRODUCTION: Since the implementation of HIV/AIDS surveillance in Poland in 1985 until the end of 2011 15,196 HIV cases among Polish citizens, 2,704 AIDS cases and 1,136 deaths of AIDS patients were registered. OBJECTIVE: To analyze the epidemiological situation of newly diagnosed HIV infections and AIDS cases in Poland in 2010. MATERIALS AND METHODS: The analysis of the epidemiological situation of HIV/AIDS in Poland in 2010 was based on reports of newly detected HIV /AIDS cases provided by physicians and laboratories to the provincial sanitary-epidemiological stations and the testing frequency obtained from annual survey to laboratories offering HIV test RESULTS: In 2010 there were 951 (2.5 per 100,000) HIV cases diagnosed in Poland, including 28 among non-Polish citizens; the total number of AIDS cases was 171 (0.45 per 100,000) and there were 53 (0.14 per 100,000) deaths of AIDS patients. Among the newly diagnosed HIV cases an increase of the share of infections acquired through homosexual contact between men (MSM) (from 34.2% to 51.9% of cases with known transmission route) was observed as compared to 2009. Across the country HIV infection is the most frequently detected among people aged 20 to 39 years (68.8%) and among males (73.0%). Furthermore, the percentage of late diagnosed, as defined by time between HIV and AIDS diagnoses of less than 3 months, remained at the same level (9.1% of newly diagnosed HIV cases), although the number of late presenters increased by 14.5% as compared to 2009. Among non-late presenting AIDS cases 58% never received any antiretroviral treatment before they were diagnosed with AIDS. CONCLUSIONS: The significant increase of HIV infections among MSM calls for intensified prevention measures in this high-risk group. Late HIV diagnosis and failure of referrals for care are two main reasons for AIDS morbidity, which should prompt educational activities and the promotion of testing as well as evaluation of the current testing and referral strategies. Our findings are limited by high rate of missing data on the probable transmission route. PMID- 23101225 TI - [Malaria in Poland in 2010]. AB - OBJECTIVES: The objective of this study was to describe the epidemiology of imported malaria in Poland in 2010 in comparison to previous years. METHODS: The study included malaria cases that were collected and registered by the State Sanitary Inspection in 2010 in Poland. Data reported was verified, processed and published by National Institute of Public Health - National Institute of Hygiene. All cases were laboratory confirmed by blood film, polymerase chain reaction or rapid diagnostic tests outlined by the EU case definition. Differences in the distribution of demographic, parasitological and clinical characteristics, and incidence were analyzed. RESULTS: In 2010, a total of 35 confirmed malaria cases were notified in Poland, 13 more than 2009. All cases were imported, 49% from Africa, including 1 case with relapsing malaria caused by P. vivax and 2 cases of recrudescence falciparum malaria following failure of treatment. The number of cases acquired in Asia (37% of the total), mainly from India and Indonesia, was significantly higher than observed in previous years. Among cases with species specific diagnosis 19 (63%) were caused by P. falciparum, 9 (30%) by P. vivax, one by P. ovale and one by P. malariae. The median age of all cases was 42 years (range 9 months to 71 years), males comprised 69% of patients, females 31%, three patients were Indian citizens temporarily in Poland. Common reasons for travel to endemic countries were tourism (57%), work-related visits (37%), one person visited family and in one case the reason for travel was unknown. Sixteen travelers took chemoprophylaxis, but only three of them appropriately (adherence to the recommended drug regimen, continuation upon return and use of appropriate medicines). In 2010, there were no deaths due to malaria and clinical course of disease was severe in 7 cases. CONCLUSIONS: When compared with 2009, there was a marked increase in the number of imported malaria cases in Poland, however the total number of notified cases remained low. Serious malaria (caused by P. falciparum), most frequently due to delayed diagnosis and treatment, is a continual problem. Such cases underline the need for adequate pre-travel information regarding the risk of malaria and preventive measures available. PMID- 23101226 TI - [Tuberculosis in Poland in 2010]. AB - AIM OF THE STUDY: To evaluate the main features of TB epidemiology in 2010 in Poland and to compare with the corresponding EU data. METHODS: Analysis of case- based clinical and demographic data on TB patients from Central TB Register, of data submitted by laboratories on anti-TB drug susceptibility testing in cases notified in 2010, data from National Institute of Public Health- National Institute of Hygiene on cases of tuberculosis as AIDS-defining disease, from Central Statistical Office on tuberculosis as underlying cause of death based on death certificates, data from ECDC report "Tuberculosis surveillance in Europe 2010". RESULTS: 7509 TB cases were reported in Poland in 2010. The incidence rate was 19.7 cases per 100000, with large variability between voivodeships from 12,8 to 31.9. The mean annual decrease of TB incidence in 2001 - 2010 was 2.9%. 6610 cases had no history of previous treatment i.e. 17.3 per 100000. The number of all notified pulmonary tuberculosis cases was 6992 i.e. 18.3 per 100 000. The proportion ofextrapulmonary tuberculosis was 6.9% (517 cases). TB was diagnosed in 62 children (0.8% of all cases, incidence 1,1). The incidence of tuberculosis increased with age to 34.9 among patients 65 years old and older. The mean age of TB patients was 52.7 years. The incidence among men i.e. 28.0 was more than two times higher than among women i.e. 11.9. The incidence in rural population was slightly lower than in urban, respectively 19.4 and 19.8. Bacteriologically confirmed cases (4585) constituted 65.6% of all pulmonary TB cases. The number of smear positive pulmonary TB cases was 2803 (40.1%). There were 45 cases of tuberculosis registered among foreigners and 215 cases registered among prisoners. There were 30 patients with MDR-TB (0.8% of 3706 cases with DST results). TB was initial AIDS indicative disease in 24 cases. There were 743 deaths due to tuberculosis in 2009 (2.0 TB deaths per 100 000). Mortality among males--3.2--was four times higher than among females--0.8. CONCLUSIONS: In Poland in the last decade the incidence of tuberculosis has decreased by nearly 30% but is higher than the average in EU countries. In 2010 the highest incidence occurred in older age groups and was higher in men. Positive characteristic also when compared with the situation in many EU countries is the low incidence of tuberculosis in children and the low percentage of patients with drug-resistant tuberculosis. PMID- 23101227 TI - [The occurrence of HCV genotypes and single polynucleotide polymorphisms of rs12979860 among HCV infected patients in northeastern Poland]. AB - HCV is responsible for the development of chronic hepatitis C, cirrhosis and hepatocellular carcinoma. The Polish population is mainly dominated by genotype 1 infections, genotypes 3 and 4 are less common. Studies have shown that changes in SNPrs12979860 of human chromosome 19 affect their ability to eliminate infection both spontaneously and during the antiviral therapy. THE AIM OF THIS STUDY was to evaluate the frequency of different HCV genotype infections in the Podlasie region during the period from 2002 to 2011 and to determine the frequency of particular genes associated with rs12979860 polymorphism amongst patients both eligible for treatment and currently undergoing the treatment. METHODS. Research and evaluation of the genotypes was performed in 923 cases of HCV and in 126 cases genes rs 12.97986 were identified (97 patients infected with genotype 1, 17 -genotype 3 and 12--genotype 4). HCV infection was confirmed by the detection of HCV-RNA and it's genotype in serum with RT-nested--PCR (Syngen Biotech, USA). Rs12979860 polymorphism was detected by sequencing, using PCR. The final scores were determined using 3500 Genetic Analyzer (Applied Biosystems, Foster City, USA). RESULTS: HCV infection was more frequent among men (60%). Genotype 1 was found in 66% of patients, genotype 3 in 27% and genotype 4 in 7% of patients. During period of 10 years slow increase of genotype 4 HCV infection prevalence was observed. Among patients infected with genotype 1 HCV waiting for the treatment and those who already completed antiviral therapy the presence of genotype C/C was found in 21%, C/T in 59% and T/T in 20%. CONCLUSIONS: The most common in Northeastern Poland is genotype 1 of HCV. There has been a slow increase of infections with genotype 4. In 79% of patients infected with genotype 1 ofHCV genotypes C/T or T/T have been found which is an adverse prognostic factor of the treatment. PMID- 23101228 TI - [Anti-HCV testing as a basic standard of monitoring HCV mother-to-child infection: advantages and disadvantages of the method]. AB - Vertical transmission is an important route of HCV infection. Infants are considered to be infected if two or more HCV-RNA results are positive and/or anti HCV+ over 18 mo of age. HCV-RNA RT-PCR testing requires high quality certificated centers. Anti-HCV ELISA commercial tests are cheaper and may be performed in all laboratories. AIM: To estimate sufficiency of anti-HCV testing over 18 mo in the diagnostic process of HCV mother-to-child infection. METHODS: 317 children born to HCV infected mothers were observed for 2-4 years. HCV-RNA was determined first at the age of 2-5 mo and subsequent in 6 months intervals, anti-HCV every 3-6 months. RESULTS: HCV infection (HCV-RNA twice presence) was recognized in 26/317 (8.2%). Anti-HCV+ were found in: 288 (91%) children in 3-6 mo of age, 213 (67.2%) in 7-9 mo, 21 (6.6%) above 18 mo. HCV-RNA was negative during all observation in the group with anti-HCV results group in all determinations in the first year of life. Among 21 children anti-HCV+ over 18 mo there were: 18 with chronic infection (HCV-RNA+, anti-HCV+), 3 achieved HCV-RNA clearance (2 became anti-HCV , 1 anti-HCV+ during following observation). Among 296 children anti-HCV over 18 mo there were 5 children HCV-RNA+ twice in the first year of life, but all became HCV-RNA- during follow up. In 4 of them (4/296, 1.3%) in spite of anti-HCV- we transiently found HCV-RNA+ above 18 mo of age. CONCLUSIONS: Anti-HCV presence in children born to HCV infected mothers: a) up to 18 mo of age do not confirm HCV infection. b) over 18 mo of age are indicative of HCV infection, but not always with active HCV replication. Negative results of anti-HCV above 18 mo of age usually allow us to exclude HCV replication, but in 1.3% we found HCV-RNA in anti HCV- children. Anti-HCV testing over 18 mo of age as only diagnostic procedure may be not enough. Missing HCV replication in the first period of life prevents HCV microreplication follow up. PMID- 23101229 TI - Spotted fever rickettsiosis caused by Rickettsia raoultii--case report. AB - We report the case of rickettsial eschar-associated spotted fever, most probable due to Rickettsia raoultii, an emerging pathogen, which was previously described in patients with tick-borne lymphadenopathy (TIBOLA), also called Dermacentor borne necrosis erythema and lymphadenopathy (DEBONEL). The pathogenicity of R. raoultii is not well established. The survey of ticks from Poland (Ixodes ricinus and Dermacentor reticulatus) revealed that R. raoultii occur in all regions of Poland and predominate over other rickettsiae of spotted fever group--R. slovaca and R. helvetica. A 17-year-old otherwise healthy girl was admitted to Department of Zoonotic and Tropical Diseases because of fever, eschar and rash. Multiple disseminated small lesions were present on the skin of her head, trunk and limbs, also palms and soles, and mucosa of her lips. The majority of them had necrotic center slightly elevated with redness around, single ones had vesicular appearance. The lymph nodes on the right side of her neck were enlarged. Laboratory investigations revealed: leukopenia (with 22% of bands in differential), thromocytopenia, slightly elevated C-Reactive Protein, as well as procalcytonin. The quick improvement was observed with a treatment with ceftriaxone and doxycycline. Two weeks after the onset of disease, IgG serum antibodies titer of 128 reacting with R. rickettsii antigen only was detected. IFA tests with six SFG rickettsial species demonstrated the strongest reaction with R. raoultii group antigens in a titer of 64. The case we report, resembling boutonneuse fever, with leukopenia, thrombocytopenia and septic parameters indicates possible higher virulence of R. raoultii than it was previously observed. PMID- 23101230 TI - [Demographic profile of a person with symptomatic hepatitis C in Poland]. AB - In Poland high HCV prevalence was observed among people infected with HIV, injecting drug users, people dialyzed before 1998, people with hemophilia born before 1990. However the majority of cases are diagnosed outside of those groups and the incidence varies by demographic factors. In this study we aimed to distinguish demographic profiles among symptomatic cases diagnosed and reported to the surveillance system and to assess the frequency of exposures previously shown to impact HCV incidence in Poland in relation to the profiles. MATERIAL AND METHODS: We used routine HCV surveillance data collected on all cases registered in 2006: 2935 cases, including 97 (3.3%) classified as acute and 1281 (43.6%) females. The profiles were distinguished by a two stage procedure--firstly constructing 2 most important factors with principal component analysis based on demographic variables. Then cluster analysis by Ward's minimum variance was performed using these 2 factors' scores. RESULTS: 5 profiles were found: (1) young men, inhabiting villages and small towns; (2) older inhabitants of villages and small towns, frequently women; (3) young men, inhabiting large cities; (4) older women inhabiting large cities; (5) inhabitants of Warsaw. The medical exposures were the most common, but the distribution of exposures was significantly different between profiles. For example injecting drug use ever was reported by 3.4% of all cases, but was more common in clusters 3 (6.0%) and 5 (5.5%) and very rare in cluster 4 (0.9%), in which hospitalization in the past was more common (63.1%) then on average (47.2%). CONCLUSION: HCV transmission patterns in Poland vary depending on demographic factors. Our results could help target screening campaigns that ideally should pick up HCV cases before they develop chronic hepatitis symptoms. PMID- 23101231 TI - [New rules of the bathing water quality management]. AB - Directive 2006/7/EC concerning the management of bathing water quality and repealing directive 76/160/ EEC, adopted in 2006, resulted in changes polish laws and regulations of this topic, which were necessary to comply with the new Directive. These included Water Act and three regulations: on bathing water quality surveillance, on bathing waters register and on bathing water profile. The main changes in the sanitary surveillance on bathing waters quality and their consequences for bathers has been discussed in the article. According to new regulations conducting bathing water quality monitoring was handed over to organizers of bathing sites and local government. Bathing water supervision and water quality assessment is in Polish Sanitary Inspection competence. Unique solution of polish law is division of bathing places into two categories: bathing sites and places used for bathing. In a consequence regulations "create" another category of such objects like places used according to custom for bathing by neighbourhood people, which will be left without any supervision. There is significant threat that new formal aspects combined with organisers burdened with supervision and finance responsibilities, will lead to decrease number of bathing sites in favour of growing number of places used for bathing. This can in consequence diminish bathers health safety. PMID- 23101232 TI - [Professor Adam Nowoslawski (1925-2012)--founder of the Polish School of Immunopathology]. AB - Professor dr med. Adam Nowoslawski, has died at age of 87, on February 3, 2012, the founder of the Polish school of immunopathology, member of Polish Academy of Sciences and of Polish Academy of Art and Sciences. Professor was born on April 30, 1925 in Rzeszow (SE Poland). During the Second World War he took part in the anti-nazi resistance movement; he was the soldier of the 'Baszta' regiment of the Home Army. Subsequently, he was imprisoned in the Pawiak and concentration camps: Majdanek and Buchenwald. The medical studies he has completed at Warsaw Medical Academy between 1946-1951. The degree of doctor of medicine Prof. Adam Nowoslawski has obtained in 1963, habilitation degree in the field of immunopathology--in 1966; the title of Professor he has obtained in 1980. His scientific achievements consist of 170 publications, including 101 original papers. His publications were quoted in several American books for students and physicians. Topics of his early papers concerned the immunopatogenesis ofPneumocystis carinii--induced pneumonia in premature babies, immunopatogenesis of rheumatoid arthritis, and the origin of rheumatoid factor. The enormous role in the field of hepatology played research on the virus of hepatitis B. These studies dealt with the discovery of HB core antigen which had the cellular localization different from HB surface antigen and with the parameters of the immune response to infection. Papers published on this topic were the mostly quoted in the literature and earned him national awards. The activity of Prof. Adam Nowoslawski in the field of HIV/AIDS prevention was honored by the special prize of the Minister of Health. Professor was the honorary member of the two Societies: Polish Society of Pathologists and Polish Society of Hepatology. He was also the member of International Association for the Study of the Liver and International Academy of Pathology. Prof. Adam Nowoslawski received the national medals: Polonia Restituta Crosses, Gold Medal for the Merits of the Country Defense, and the 'Auschwitz' Cross. He was also the recipient of the medals: Copernicus (1997) and Gloria Medicinae (2001). PMID- 23101233 TI - [Martin Kacprzak (1888-1968)--non omnis moriar]. AB - AIM: The purpose of this study was to present a scientific profile of Professor Martin Kacprzak with particular emphasis on his relationship with national Institute of Hygiene in Warsaw--where he was working for the longest time. MATERIAL AND METHODS: Information derived from documentation from archives of National Institute of Hygiene (NIH), Medical University of Warsaw, magazine titled "Notatki Plockie", UN and WHO records, including records of the International Health Conference held in New York in 1946, and other sources. RESULTS: Martin Kacprzak was born in peasant family in Mazovia, at that time belonging to Russian Empire (Russian partition). He studied medicine at Sorbonne in Paris. In 1922-1924, as a Rockefeller Foundation Fellow, he studied the hygiene and health care organization at Johns Hopkins University in Baltimore. In 1924-1944 worked in State School of Hygiene in NIH as a head of epidemiology and statistics department. After WWII (1945-1952) he served as its director in 1954 1962 he supervised the school hygiene department in NIH. From 1948 to 1965 he worked at Medical University of Warsaw, also as dean of medical faculty (1948 1954) and president (1955-1962). He participated (1946-1948) in preparatory work to establish World Health Organization. In 1957 he was the sixth recipient of prestigious Leon Bernard Foundation prize, which is presented at World Health Assembly. The first recipient in 1951 was prof. Rene Sand from Belgium, the second in 1952 prof. Charles-Edward Amory Winslow, bacteriologist, not a doctor, author of the first definition of public health. Martin Kacprzak was an honorary member of American Public Health Association. He wrote over 200 articles. PMID- 23101234 TI - [Report of the VIth Tuberculosis Day Conference]. AB - On 23 - 24 Mars in Warsaw a scientific conference was held sixth time organised to celebrate the World TB Day by Warsaw-Otwock Branch of the Polish Respiratory Society in collaboration with WHO, Poland. Welcoming lecture "TB Research in Poland, Past and Present" discussed TB diagnosis scientific research results, achieved during the last two centuries, and which contributed, after practical application, to improvement of TB epidemiological situation in our country. Sessions devoted to, as follows: 1) Discussion of multidrug-resistant TB with special focus on epidemiology, diagnostics and WHU guidelines relative to treatment; 2) Tuberculosis brought into Poland by refugees and methods of diagnosis and treatment; 3) TB among persons detained in penitentiary institutions with an outlook on molecular research (tests?) used in epidemiological investigations. PMID- 23101235 TI - [Development of mechanisms of recognition fragmented images at the preschool and early school ages]. AB - Psychophysical and electrophysiological indices of recognition of incomplete objects with progressive increasing of fragments, were studied in children of three age groups: 5-6, 7-8 and 9-10 years old. It is shown that most pronounced change in the effectiveness of recognition takes place between 5-6 and 7-8 years of age. In the group of children of 5-6, neither significant influence of the recognition process on ERP was found in the prefrontal cortex nor any significant growth of the Nd component was observed over extrastriate cortex. However, in the extrastriate cortex, the amplitude N170-200 component that reflects sensory analysis and encoding extracted features did increase. In the majority of children of this age, the immaturity of the prefrontal cortex manifest itself in the deficit of inhibitory control that results in the tendency to give the impulsive responses and make numerous errors. In children of 7-8, successful recognition is accompanied by the growth of the amplitude of N100 and N250 components over the prefrontal cortex and the growth of NcI component over the extrastriate cortex. In these children, when compared to the children of 5-6, a significant reduction, is observed in the error rate and the recognition threshold. By the age of 9-10 years, the growing role of the prefrontal cortex shows in greater gain in the Nd amplitude and the later ERP component that correspond to cognitive operations related to the recognition process. The results of the study point to the qualitative difference in the mechanisms of recognition between pre-school children and the younger school-children. At the age of 5-6, recognition is carried out on the basis of integration of sensory signs of objects. Since the 7-8 age, in recognition of fragmented images major role belongs to the prefrontal cortex, with its participation search of possible analogs of object in memory and the object identification is carried out. PMID- 23101236 TI - [Brain activity during different stages of the relaxation process]. AB - A group of adults participated in experiment in which they were asked to reach relaxed state by using relaxation techniques (active relaxation) and to maintain this state without any technique (passive relaxation). Some changes of EEG characteristics during relaxation were analyzed. This experiment includes four situations (different functional states): baselinel, active relaxation, passive relaxation, baseline2. EEG was recorded from 10 cortical leads: O1, O2, TPO (left and right), P3, P4, C3, C4, F3 and F4. A comparative EEG analysis was done for 10 frequency bands from 5 to 40 Hz. In each experimental situation we revealed general trends for EEG parameters and also some specific changes in EEG, which characterized brain organization during passive and active relaxed states. PMID- 23101237 TI - [Individual typological features of EEG response in the sportsman to acute hypoxia]. AB - The paper investigated variability of individual EEG parametres: frequency of the maximum peak, width of a range and depth of reaction desynchronization (reduction alpha-rhythm of EEG at opening of eyes) in slowly increasing hypoxia from 20.9% to 10%-s' O2 of the sportsman with various types of physical activity and features of temperament. There were investigated 24 first-class athletes (11 swimmers, 13 skiers) aged 18-26 years. It is shown that dynamics of EEG rhythms during hypoxia, unlike normoxia, characterised by instability of spectral structure and phase during time of hypoxia test. It is established, that individual typological features (typology of nervous system) influence EEG response during hypoxic test. The negative relations between a psychological construct "endurance" for questionnaire (FCB-Ti) and feature alpha-rhythm EEG during hypoxia test are shown. The type of physical training and re-structuring pattern of breath (phenotypic adaptation) modulates sensitivity of brain structures to hypoxia which is reflected in dynamics alpha-rhythm of EEG in hypoxic conditions. PMID- 23101238 TI - [Sex differences in relationship between creativity and hemispheric information processing in global and local levels]. AB - Sex differences in creativity related global-local hemispheric selective processing were examined by hierarchical letter presenting in conditions of their perception and comparison. Fifty-six right-handed males and 68 females (aged 17 22 years) participated in the experiments. Originality-imagery was assessed by a computer-based Torrance 'Incomplete Figures' test software. Verbal creativity was valued by original sentence using of three nouns from remote semantic categories. The results show that irrespectively of the sex factor and the type of creative thinking, its originality is provided by high speed of right-hemispheric processes of information selection on the global level and delay in the interhemispheric communication. Relationships between originality of ideas and hemispheric attentional characteristics are presented mostly in men while verbal creative problem solving, and in women while figurative original thinking. Originality of verbal activity in men is more associated with success of selective processes in the left hemisphere, but in women--with selective functions of both hemispheres. Figurative thinking in men is less related to hemispheric characteristics of attention compared with women. Increase of figurative originality in women is accompanied acceleration of processes of selection of the information in the right hemisphere, and also higher efficiency of local attention as well as speeds ofglobal processing in the left hemisphere. PMID- 23101239 TI - [EEG power spectra in the modeling of disruptiveness]. AB - For analysis of the action of destructive behavior EEG power spectra in groups with different level of disruptiveness in a rest and during the modeling of destructive behavior were researched. The application of functional tests in the group of low-destructive subjects of the experiment goes with a development of activation processes of specific and non-specific character (alpha1-rhythm power loss and beta1-rhythm power growth). It allows us to critique the incoming stimuli and to generate adequate behavioral reactions and to inhibit the aggression. In the group of the subjects of the experiment with a high level of destructiveness activation criteria are defined in a les degree. The criteria of excessive activation from diencephalic structures are observed (delta-rhythm power growth), it can be connected with the development of earlier and less stable mechanisms of behavior regulating and it can help to choose more primitive behavioral models including the aggression. PMID- 23101240 TI - [The microcirculatory blood flow and autonomic regulation's functional state in young people with different levels of subjectively experienced psychological stress]. AB - A comprehensive comparative analysis of hemodynamics, microcirculation (the method of laser Doppler flowmetry with occlusal probe and the optical tissue oxymetry), blood circulation neuro-humoral regulation (analysis of heart rate variability - HRV) between almost healthy young people with different levels of subjectively experienced emotional stress is given. Depending on the degree of everyday stress (acute and/or chronic) the character of neuro-autonomic regulation of blood circulation, as well as the state of the microcirculatory blood flow and its regulation are substantially different. Moderate stress is accompanied sympathetic-parasympathetic regulatory mechanisms co-activation with augmented HRV baroreflex regulation circuits that compensate hemodynamic changes and is not accompanied by hypertensive reactions. An increase in the activity of neurogenic and myogenic tone microhemodynamics in the examinees with moderate stress is discovered, which determines a high probability of blood shunting in tested tissue and decrease of relative oxygen extraction. Moderate levels of stress are also associated with increase in a latency of post-occlusive vasoreactive hyperemia, which is considered to be an initial sign of the endothelium-mediated dysfunction of microcirculation. PMID- 23101241 TI - [Students' knowledge level computer testing results and individual specificity of purposeful activity vegetative support]. AB - The vegetative correlates of individual differences in the effectiveness of the purposeful activity during computer sensory motor test and computer testing of the level of knowledge of students were studied. For the students, who reached the high results of sensory motor and training tests it was characteristic the lability of vegetative indices, which is manifested in a change in the absolute values and relationship of the characteristics of heart rate and hemodynamic in accordance with the stages of activity. These changes were specific for each of the forms of activity and connected with the results of tests. By the physiological prerequisites of the high lability of vegetative characteristics, which ensures the capability of the subject successfully to be adapted for the conditions of activity, appeared high initial values TP, power LF and HF of the ranges of spectrum. PMID- 23101242 TI - [Comparison of aerobic performance of leg and arm muscles in cross country skiers]. AB - Recently there was a tendency to increase usage of double poling during cross country skiing and accordingly to increase loading of the arm muscles. The aim of the study was to compare the aerobic performance of cross country skiers in the incremental double poling and running tests till exhaustion. Eight junior subnational level cross country skiers ( V(O)2max 70 (66-72) ml/min/kg) have participated in the study. The rate of blood lactate increase during double poling test was higher than during running test. Double poling V(O)2peak was 88 (84-93)% from running V(O)2max. Relative anaerobic threshold (% V(O)2max at AT), closely linked to the current aerobic performance, was substantially lower in double poling test compared with running test: 79 (57-83)% and 94 (90-98)% respectively. We suggest that the main reserve for further increase of aerobic performance of cross country skiers lies in an increase of double poling aerobic capacity. PMID- 23101243 TI - [Thermoesthesia-and-algesthesia status in the dermatomes of cauda equina roots in patients with lumbar spine osteochondrosis]. AB - Thermoesthesia-and-algesthesia disorders have been registered in the dermatomes of cauda equina roots of patients with lumbar spine osteochondrosis in all the cases. Negative changes in the sensitivity of this type are manifested themselves as follows: 1) 2-8-degree increases of thresholds; 2) 3-6-degree decreases of thresholds; 3) absence of thermal sense. In the presence of reflex syndromes (lumbalgia and lumbar ischialgia) the disorders in L4, L5, S1 dermatomes have been determined to the greatest degree. Thermoesthesia-and-algesthesia disorders are more pronounced in patients with the radicular syndrome than in those with the reflex syndromes. The most improvement ofthermoesthesia-and-algesthesia values is observed in L5 dermatome of patients with lumbalgia and lumbar ischialgia after complex conservative therapy. The treatment performed does not result in significant thermoesthesia-and-algesthesia improvement for the limb with radiculopathy events and in the dermatome of the root compressed in patients with the radicular syndrome. Positive changes in contralateral limb are more pronounced. PMID- 23101244 TI - [Combination of two signals of danger--a principal cause of activation of chronic inflammatory processes]. AB - Chronic inflammatory processes have long current during which there is a change of remission by an aggravation of disease. Until recently was considered, that occurrence and activation of chronic inflammatory process is caused by one signal of danger. Most often it are served with microorganisms. The sum of our end literary data shows that activation is connected with accumulation in the center of an inflammation of macrophages and their hyperactivation as a result of action of two signals of danger--microorganisms and xenobiotics. PMID- 23101245 TI - [Functional-metabolic estimation of responsiveness of blood cells in exposure to local vibration]. AB - The physiological features of the blood cells have been studied in the workers, exposed to a long-term local vibration. The summary peroxidase activity of the blood cells, the levels of the phagocytic response as well as of the alkaline and acid phosphatases in the neutrophiles, the glycogen content in the neutrophiles and lymphocytes have been evaluated. The alterations associated with the decrease in the functional-metabolic parameters in dependence on the contact duration with the vibration-induced tools and on the severity of the clinical symptomatics have been revealed. The different declinations revealed in the character of the cellular responsiveness may display peculiarities in the mechanisms of adaptive regulation. PMID- 23101246 TI - [Effects of dehydroepiandrosteron sulfat on induced apoptosis of lymphocytes in healthy persons]. AB - Effects of dehydroepiandrosteron sulfate on oxidative stress- and ethanol-induced morphological changes and level of apoptotic enzymes (Bcl-2 and caspase-3) of lymphocytes in healthy persons have been studied. This study showed that hydroperoxide induces apoptotic changes in lymphocytes. Ethanol did not change the basal concentration of apoptotic enzyme. Dehydroepiandrosteron sulfate prevented the augmentation of apoptosis in hydroperoxide-treated lymphocytes. PMID- 23101247 TI - [The influence of level of arterial pressure on regulatory-adaptive status]. AB - People with increased arterial pressure have more low regulatory-adaptive abilities than people with normal arterial pressure. The achievement of target blood pressure level with antihypertensive drugs is accompanied by normalization the regulatory-adaptive abilities. It is true only for people who had arterial hypertension less than 160/90 mm Hg until treatment. PMID- 23101248 TI - [Characteristics of oxidative stress in mental maladaptation]. AB - Changes in the balance of pro and antioxidant systems were studied in persons in state of mental maladaptation, developed under the influence of emotional stress. Activation of lipid peroxidation has been revealed associated with increase of amount of malondialdehyde in erythrocytes and blood serum in persons surveyed. Activity of catalase and glutathione peroxidase in erythrocytes in persons in state of mental stress was increased and glutathione preductase, glutathione-S transferase and glucose-6-phosphate dehydrogenase has been reliably reduced as compared with group of healthy people. Comparative chemiluminiscent analysis of common antioxidant properties of serum of blood of studied groups has also revealed decrease of antioxidant properties of blood under influence of mental stress. PMID- 23101249 TI - [Sauna effect on blood oxygen transport function and proxidant/antioxidant balance in youths]. AB - There was investigated sauna effect on blood oxygen transport function and proxidant/antioxidant balance in 18 to 22 years old males. Subjects being tested underwent thermal exposure once per week over a period of 5 months (20 procedures). There were two exposure over the course of sauna bathing (temperature 85-90 degrees C, humidity 10-15%): the first exposure lasted for 5 minutes and the second one for 10 minutes. Dry air sauna in youth's leads to respiratory alkalosis, increases pO2, decreases haemoglobin binding capacity to venous blood oxygen thus facilitating oxygen transport into body tissues. Single sauna visit results in oxidative stress (augmentation of free radical processes and deterioration of antioxidant defence mechanisms), while its manifestations being diminished after multiple thermal exposures. Increase in nitrogen monoxide formation being observed might matter for the modification of the oxygen dependent processes of the human body. PMID- 23101250 TI - [Intensity of lipid peroxidation and antioxidant protection system indices in the course of a 3-day "dry" immersion experiment]. AB - In the course of a 3-day "dry" immersion experiment involving participation of five male test volunteers aged 25 to 40, in the blood serum of participants were determined the content of LPO (lipid peroxidation) products, namely diene conjugates, malon dialdehyde, shiffbases, as well as the values of the antioxidant protection system (AOP) indices - the concentration of tocopherol as the main lipid antioxidant and the level of general antioxidant activity. During the immersion action no deviations of indices under study from the background values were revealed, with the exception of a certain increase in tocopherol concentration within two hours after experiment beginning. At the restoring period after two hours upon immersion completion a reliable increase of lipid peroxidation products, particularly diene conjugates in participants' blood serum was made evident. At this, the tocopherol content was significantly below the background values. It is therefore concluded that the test participants' adaptation to the simulated weightlessness conditions shows no pronounced stress component, whereas bringing back to normal vital functions after exposure to immersion occurs with significantly pronounced stress reaction development, as demonstrated by considerable growth of LPO processes against the background of AOP system functional activity reducing. PMID- 23101251 TI - [Preservation of leukocytes at moderately low temperature]. AB - It was shown that the use of little toxic cold-protective containing the glycerol protector endocellular action, HES--protector exocellular action, and "restored" component of the succinate 3-hydroxy-6-methyl-2- ethylpyridine preserves nuclear blood cells in a viable condition at -40 degrees C. PMID- 23101252 TI - [Physiological basis of survival and rehabilitation of the residents of blockaded Leningrad]. AB - The authors attribute survival of certain residents of blockaded Leningrad under conditions ofcomplete starvation to activation of natural sanologic mechanisms of the body. Physiological psychoemotional stress is supposed to contribute to the formation of prerequisites for survival during subsequent starvation. Also, the survival is believed to be related to selected activation of apoptosis of renewable cells and utilization of their constituents in endogenous nutrition. The role of priority energetic and trophic support of brain and kidneys and the contribution of the psychosomatic factor are postulated. The mechanisms of rehabilitation after upset of vital activity involve partial reversibility of atrophic and metabolic processes and neural regulation of organs and their systems. The importance of the study of activation of natural sanologic mechanisms in extreme conditions is discussed PMID- 23101253 TI - [Ulcer disease: challenging problems of etiology, pathogenesis, differential treatment]. AB - This review summarizes the data of Russian and foreign authors as well as the results of original studies on etiology pathogenesis, and differential treatment of ulcer disease (UD). The author's original concepts of UD pathogenesis and relations between man and Helicobacter pylori are discussed. The pathogenetic role of disturbances in the system of gastroduodental self-regulatory function and psychosomatic mechanisms as well as immune deficiency and impaired antioxidatve protection is considered. Peculiarities and results of UD eradication therapy intended to eliminate H. pylori infection are described. The importance of the choice of the UD treatment strategy on an individual basis is emphasized as opposed to the use of universal standards and therapeutic modalities influencing only local pathogenic factors, such as acidopeptic ones and H. pylori infection. PMID- 23101254 TI - [Plastic surgery of the mitral valve in patients with coronary heart disease]. AB - Modern approaches to cardiosurgical plastic intervention on the mitral valve in case of its ischemic insufficiency are discussed. Etiology of this condition, indications for surgery, and the history of such operations are described. It is concluded that plastic surgery of the mitral valve is the method of choice for the treatment of patients with coronary heart disease. PMID- 23101255 TI - [True polycythemia: current views of pathogenesis, diagnostics and treatment]. AB - Current concepts of true polycythemia are reviewed. Results of numerous epidemiological studies on the prevalence of this form of myeloproliferative neoplasms are presented with special reference to recent findings concerning its pathogenesis and the role of JAK2V617F mutation that occurs in the majority of patients. The clinical picture and new diagnostic criteria are discussed The data on the incidence and prevalence of the disease and its complications are considered including venous and/or arterial thrombosis, transformation into post polycythemic myelofibrosis and acute myeloleucosis. An algorithm for the treatment of patients with erythremia is proposed along with recommendations on the use of aspirin, hydroxyurea, alpha-interpheron, and imatinib. The prospects for clinical application of selective JAK2 inhibitors are discussed. PMID- 23101256 TI - [Quantitative characteristic of the regulatory and adaptive status for the estimation of severity of chronic cardiac failure]. AB - A method for the estimation of severity of chronic cardiac failure (CCF) based on the quantitative evaluation of the regulatory and adaptive status (RAS) of the organism. Patients with FC I-III HCF concomitant with grade I-III hypertensive disease and/or coronary heart disease underwent cardiorespiratory synchronism test for the quantitative estimation of RAS (6 min walk), echocardiography, treadmill measuring maximum oxygen consumption (VO2max), measurement of plasma N terminal precursor of brain natriuretic peptide. The lowering of RAS was especially pronounced when HCF FC changed from I to III, in agreement with results of traditional instrumental and laboratory tests. Specifically, left ventricle systolic and diastolic function was impaired, tolerance of physical exercise decreased while neurohumoral regulation was activated. There was positive correlation between RAS indices at HCF CF I and II for left ventricular ejection fraction, maximum physical load, VO2max and negative correlation for N terminal precursor of brain natriuretic hormone. At HCF FC II and III, positive correlation was documented for left ventricular ejection fraction, maximum physical load, VO2max and negative correlation for the N-terminal precursor of brain natriuretic hormone. It means that the qualitative estimate of RAS obtained in the cardiorespiratory synchronism test can be used to assess severity of HCF in patients with hypertensive disease and/or coronary heart disease. PMID- 23101257 TI - [The impact of antihypertensive therapy on cerebral hemodynamics in patients with metabolic syndrome]. AB - The aim of this work was the scintigraphic study of brain perfusion and the elucidation of the relationship between daily variations of arterial pressure (AP) and the results of single photon emission computed tomography (SPCT) of the brain in patients with metabolic syndrome (MS). The secondary objective was to estimate effect of combined antihypertensive therapy on cerebral circulation. 24 patients with MS underwent SPCT with 99mTc HMPOA and 24 hr AP monitoring before and 6 mo after therapy with long-acting verapamil combined with slow-release indapamide or enalapril. It was shown that all the patients suffered disturbances of regional cerebral blood flow even in the absence of focal neurological symptoms. Perfusion was especially impaired in the temporal, occipital and superior frontal lobes. The degree of the night-time fall in AP was related to the level of perfusion in the right temporal region (r = -0.5; p = 0.04) which confirms the danger of extreme AD decrease in hypertonics during sleep. Combined antihypertensive therapy has positive influence on cerebral perfusion. Verapamil plus enalapril has more pronounced effect than verapamil plus indapamide on cerebral blood flow in many brain regions. PMID- 23101258 TI - [Peculiarities of the clinical course of viral hepatitis B in Tadzhikistan]. AB - 12 (53%) patients with genotype A and 4 (50%) with genotype D of hepatitis virus B (HBV) had HbeAg-negative phenotype of HBV. Patients with genotypes C and D were characterized by a milder clinical course of hepatitis; liver cirrhosis progressed only in one of them. Patients infected with HBC of genotype A suffered more severe condition and earlier development of cirrhosis. PMID- 23101259 TI - [Diagnostic significance of different apolipoprotein levels during hypertriglyceridemia]. AB - Active receptor-mediated uptake of fatty acids (as lipids in VLDLP and LDLP) involves dynamic apolipoproteins apoE and apoC-III. Modern methods allow apoB-100 and apoA-1 to be determined both separately and together in HDLP and VLDLP+LDLP. We estimated diagnostic significance of simultaneous apoE and apoC-III determination in the serum and two LP classes in the patients having either physiological levels of triglycerides or moderate and pronounced hypertriglyceridemia. Serum apoE and apoC-III increased with increasing triglyceride levels and percent of prebeta-LP fractions in electrophoresis. There was significant correlation between apoE and apoC-II content in the sera and in apoB-100 LP. It precludes using measurements of apoproteins for differential assessment of VLDLP and LDLP uptake by the cells or differential diagnostics of primary phenotypes and secondary hyperlipoproteinemias. The apoE content in LDLP was increased only in 1/5 of the patients with marked hyertriglyceridemia. The ApoE an apoC-III content in lipoproteins is of no diagnostic value; it is enough to determine serum apoprotein levels. Significant correlation between HDLP cholesterol and apoA-1 and between LDLP and apoB-100 questions the necessity of measuring serum apoA-1 and apoB. PMID- 23101260 TI - [Adaptive systems of the body in metabolic syndrome]. AB - The aim of the work was to study the state of adaptive systems in patients with metabolic syndrome. This cross-sectional randomized trial included 99 women and 32 men. The measured variables were blood levels of dehydroepiandrosterone sulfate (DGEAS), cortisol, total T3 and T4, lymphocyte count, and muscle endurance (number of squats/min). 43 patients presented with metabolic syndrome (MS) and 88 without it. MS was associated with decreased blood DGEAS and T3 levels, increased lymphocyte count, reduced activity of sympathetic nervous system and muscle endurance. PMID- 23101261 TI - [The balance of markers of regulation vascular tone and fibrinogen in the prognosis of hemorrhagic transformation and fatal outcome in the acute period of ischemic stroke]. AB - The markers of regulation vascular tone, such as rennin, endothelin-1, and C-type natriuretic peptide, are of great value for prognosis of hemorrhagic transformation and fatal outcome of ischemic stroke. A change in the vascular tone in case of hemorrhagic transformation at the affected site precedes activation of the coagulation component of hemostasis as a mechanism preventing blood loss and increasing fibrinogen level. This work was aimed to study the balance of the above markers and fibrinogen in the prognosis of hemorrhagic transformation and fatal outcome in the acute period of ischemic stroke. It included 62 patients receiving no thrombolytic therapy. It was shown that symptomatic hemorrhagic transformation was associated with elevated rennin levels without a marked fall in the level of C-type natriuretic peptide and asymptomatic hemorrhagic transformation with elevated endothelin-1 levels and decreased concentration of natriuretic peptide. Fibrinogen level on day 4 of the observation proved to be a reliable predictor of negative prognosis. Asymptomatic hemorrhagic transformation without fatal outcome was associated with systemic and local vasoconstriction and inhibition of local vasodilation. Symptomatic hemorrhagic transformation with the fatal outcome was accompanied by dysregulation of vascular tone in the form of activation of systemic and local vasoconstriction, insufficient inhibition of local vasodilation and compensatory reaction in the form of activation of hemostatic mechanisms manifest as elevated fibrinogen levels on day 4. The lethal outcome without hemorrhagic transformation was associated with systemic vasoconstriction, activation of local vasodilation and vasoconstriction leading to local "biochemical paralysis" of vascular tone regulation. PMID- 23101262 TI - [Herpetic infection in patients with psoriasis: the improvement of therapy]. AB - The aim of the study was to estimate the efficacy of liniment cycloferon included in combined therapy of herpetic infection in 30 patients with psoriasis divided into 2 groups. Combined treatment of patients with recurrent herpetic infection promoted elimination of general infection syndrome, shortened duration of eruption and local inflammation, accelerated epithelization of herpetic erosion, and decreased the frequency of relapses during the follow-up. PMID- 23101263 TI - [Diagnostics and treatment of polyglandular syndrome of adults]. AB - Autoimmune polyendocrine syndromes (APS) are rare endocrinopathies characterized by the coexistence of at least two glandular autoimmune diseases. APS comprise a wide spectrum of autoimmune disorders and are divided into a very rare juvenile (APS type 1) and a more common adult type with (APS 2) or without adrenal failure (APS 3). The first clinical manifestations of APS 1 usually occur in childhood whereas APS 2 mostly occurs during the third and fourth decades of life. The third type has been described in adults that, contrary to types 1 and 2, does not involve the adrenal cortex. No clinical differences between types 2 and 3 have been described except the absence of adrenal failure. Type 4 APS is a rare syndrome characterized by the combination of autoimmune conditions not falling into the above categories. It consists of adrenal failure with one or more minor autoimmune disorders barring major components of type 1 and 2 APS. Usually, autoimmune polyendocrine syndrome of adults manifests itself as one of the major autoimmune diseases (such as adrenal failure, Grave's disease, or type 1 diabetes) and minor autoimmune disorders (vitiligo, alopecia) preceding the development of autoimmune deficiency of major endocrine glands. This article describes a patient with type 3 APS, who developed type 1 diabetes. Grave's disease and vitiligo. The development of the syndrome started from vitiligo in the chidhood. Moreover, the patient suffered primary sterility and presented with progressive diabetic nephropathy of autoimmune origin. It is concluded that patients with a single autoimmune component of polyendocrine syndrome should be screened to exclude other autoimmune endocrine disorders. PMID- 23101264 TI - [Resolution of postanoxic encephalopathy in postreanimation disease following pulmonary thromboembolism]. AB - Diagnostics of massive and submassive pumonary thromboembolism sometimes encounters difficulty arising from polymorphism of clinical manifestations, transience of clinical symptoms, severe complications leading to exsanguination of organs and systems, anoxic and dysmetabolic disturbances thereof. The authors report a case of successful resolution of posthypoxic encephalopathy after circulatory, arrest for over 3 minutes with the functional recovery in the late period of postreanimation disease in the absence of an apparent deficit. PMID- 23101265 TI - [Bioethics or medical (deontological) ethics? Main principles of medical ethics]. PMID- 23101266 TI - [Chronomedicine, circadian rhythms. Who may be interested?]. PMID- 23101267 TI - CD200/CD200R paired potent inhibitory molecules regulating immune and inflammatory responses; Part II: CD200/CD200R potential clinical applications. AB - SUMMARY: CD200 and its receptor were recognized as having the multiple immunoregulatory functions. Their immunoregulatory, suppressive, and tolerogenic potentials could be very effectively exploited in the treatment of many diseases, e.g. Alzheimer disease, rheumatoid arthritis, and allergy to name only some. Many research projects are aimed to develop clinically valuable methods being based on the structure and function of these paired molecules. In this review, we would like to introduce CD200/CD200R functions in a clinical context. PMID- 23101268 TI - Radio-sensitization of human leukaemic molt-4 cells by DNA-dependent protein kinase inhibitor, NU7026. AB - In this paper we describe the influence of NU7026, a specific inhibitor of DNA dependent protein kinase, phosphoinositide 3-kinase, and ATM-kinase on molecular and cellular mechanisms triggered by ionising irradiation in human T-lymphocyte leukaemic MOLT-4 cells. We studied the effect of this inhibitor (10 1microM) combined with gamma-radiation (1 Gy) leading to DNA damage response and induction of apoptosis. We used methods for apoptosis assessment (cell viability count and flow-cytometric analysis) and cell cycle analysis (DNA content measurement) and we detected expression and post-translational modifications (Western blotting) of proteins involved in DNA repair signalling pathways. Pre-treatment with NU7026 resulted into decreased activation of checkpoint kinase-2 (Thr68), p53 (Ser15 and Ser392), and histone H2A.X (Ser139) 2 hours after irradiation. Subsequently, combination of radiation and inhibitor led to decreased amount of cells in G2 phase arrest and into increased apoptosis after 72 hours. Our results indicate that in leukaemic cells the pre-incubation with inhibitor NU7026 followed by low doses of ionising radiation results in radio-sensitising of MOLT-4 cells via diminished DNA repair and delayed but pronounced apoptosis. This novel approach might offer new strategies in combined treatment of leukaemia diseases. PMID- 23101269 TI - Preoperative serum levels of soluble endoglin for prediction of recurrence in stage III colorectal cancer patients. AB - BACKGROUND: To evaluate the clinical usefulness of serum levels of soluble form of endoglin in stage III colorectal adenocarcinomas (CRC) patients for detection of recurrence. METHODS: The case-control study consisted of 80 stage III CRC patients who underwent surgery with curative intent and 70 age-and sex-matched healthy volunteers. Serum levels of soluble form of endoglin (sol-end) were measured in both groups. Also, predictive factors of recurrence were evaluated using multivariate analyses. RESULTS: Serum levels of sol-end in stage III CRC patients were significantly higher than those in controls. There was not a significant association between serum levels of sol-end and clinicopathological features in CRC patients. Multivariate regression analysis showed the LNR (hazard ratio, 2.54; 95% CI, 1.46-4.34; p < 0.001), to be significant independent factors to estimate local recurrence in stage III CRC patients. CONCLUSION: Preoperative serum levels of sol-end do not seem useful as a marker for detection of recurrence in stage III CRC patients. PMID- 23101270 TI - Venous thromboembolism in adolescents. AB - The incidence of venous thromboembolism (VTE) during childhood is low with two peaks - neonatal and adolescent age. This retrospective study is focused on clinical characteristics ofVTE during adolescence. The main goals are to assess the most frequent inherited and acquired risk factors and to evaluate the benefit of D-dimers in diagnostics of venous thromboemblism. The data of 18 adolescents were analysed--16 girls (88.9%), 2 boys (11.1%). In 9 patients (50%) thrombosis of the lower limb deep veins was diagnosed, six patients (33.3%) suffered from symptomatic pulmonary embolism (PE) and 3 patients (16.7%) from thrombosis at unusual sites. One patient had an idiopathic VTE, the mean number of the inherited and acquired risk factors was 2.6. The most frequent inherited risk factor was Leiden mutation of factor V (27.8%). The most frequent acquired risk factor was oral contraception (OC) in 12 out of 16 girls (75%). All of our patients on oral contraception had one or more additional risk factors. 10 out of 18 (55.6%) patients with VTE had elevated activity of factor VIII. The sensitivity of D-dimers was low (50%) in patients with distal lower limb thrombosis, but very high (100%) in patients with PE. PMID- 23101271 TI - Quantitative analysis of cerebrospinal fluid brain derived neurotrophic factor in the patients with multiple sclerosis. AB - Multiple sclerosis (MS) is the most common cause ofnontraumatic neurological disability in Europe and North America. Growth factor expression could participate in the repair process of the demyelinating disease. Among growth factors, brain derived neurotrophic factors (BDNF) has been demonstrated to play an important role in neuronal and axonal survival. In the central nervous system (CNS), neurons are the main source of BDNF. Another potential source are activated astrocytes, which are present in inflamed areas in the CNS as shown in MS. In this study, total protein concentration (TPC) and BDNF levels in the cerebrospinal fluid (CSF) samples from the patients with MS (n = 48) and control subjects (n = 53) were measured using a Bio-Rad protein assay and enzyme linked immunosorbent assay (ELISA). No significant change in the CSF TPC of patients with MS was seen as compared to normal CSF. The presence of BDNF in the CSF samples was shown by Western blot. Using ELISA, it was shown that the level of BDNF in the MS CSF is higher than in normal CSF. It is concluded that BDNF is a constant component of human CSF. Moreover, it could be implicated in the pathophysiology of MS. PMID- 23101272 TI - Serum homocysteine levels in Czech children and adolescents. AB - AIM: The principal aim was to establish reference paediatric data for the serum homocysteine levels in Czech children and adolescents. METHODS AND RESULTS: 144 children either healthy or not sufferig from acute or chronic inflammation, autoimmune disorders including rheumatic diseases, inflammatory musculoskeletal disorders, inflammatory bowel disease, diabetes mellitus, hypercholesterolemia, epilepsy, chronic renal failure, aged 0-19.9 years (0-6.9 years, n = 40; 7-10.9 y, n = 28; 11-15.9 y, n = 45; 16-19.9 y, n = 31) had their blood samples collected and the serum homocysteine level (S-homocysteine) was evaluated by chemiluminescence. A significant age dependence of the S-homocysteine levels was observed (R = 0.35, p < 0.01); with highest values of upper reference range in the 11-15.9 and 16-19.9 years' group, respectively. CONCLUSION: The establishment of S-homocysteine reference Czech pediatric values is a potentially useful tool for proper evaluation of elevated homocysteine levels and corresponding risks in childhood. PMID- 23101273 TI - The number of immunoregulatory T cells is increased in patients with psoriasis after Goeckerman therapy. AB - Regulatory T cells (Treg) are a specialized subpopulation of T cells that act to suppress inadequate immune response. Psoriasis is recognized as a T-cell driven immune-mediated systemic inflammatory disease with skin manifestation. Effective therapeutical approach to treat psoriasis is Goeckerman therapy (GT). The aim of this study was to compare the number of Treg in the peripheral blood of 27 psoriatic patients and 19 controls and to evaluate the influence of GT on Treg population in peripheral blood of patients with psoriasis. There was no significant difference in the relative number of Treg cells in the peripheral blood of healthy blood donors and patients with psoriasis before initiation of GT (P = 0.2668). In contrary, the relative number of Treg cells in peripheral blood of patients with psoriasis after GT was significantly higher than those found in healthy blood donors (P = 0.0019). Moreover, the relative number of Treg is significantly increased in psoriatic patients after Goeckerman therapy compared to the pre-treatment level (P = 0.0042). In conclusion, this significant increase in Treg count after GT is probably associated with amelioration of inflammation by GT, as disease activity expressed as PASI decreased in our patients by GT (P = 0.0001). PMID- 23101274 TI - Role of electrophysiological study and catheter ablation for recurrent ventricular tachycardia complicating myocarditis. AB - Here we report the case of a 31-year-old man admitted to our hospital with echocardiografic and Cardiac Magnetic Resonance signs of myocarditis complicated by ventricular tachycardia, initially resolved with direct current shock. After the recurrence of ventricular tachycardia the patient was submitted to electrophysiological study revealing a re-entrant circuit at the level of the medium segment of interventricular septum, successfully treated with transcatheter ablation. This case highlights how the presence of recurrent ventricular arrhythmias at the onset of acute myocarditis, suspected or proven, could be associated with a pre-existing arrhythmogenic substrate, therefore these patients should be submitted to electrophysiological study in order to rule out the presence of arrhythmogenic focuses that can be treated with transcatheter ablation. PMID- 23101275 TI - Unexpected finding in ocular surface trauma: a large intraorbital foreign body (bullet). AB - Sometimes intraorbital foreign bodies lead to unexpected findings. A 16-year old boy was referred due to ocular surface trauma. A conjunctival laceration was detected at the level of the left caruncle with associated left exotropia, reduced adduction as well as a preretinal hemorrhage along the nasal periphery of the fundus. A blow-out fracture of the medial orbital wall was suspected and a CT scan of the orbits was scheduled which revealed the presence of a large intraorbital foreign body. The removal of the intraorbital foreign body (which proved to be a bullet) and precautionary laser photocoagulation along the nasal periphery of the left eye were performed. Ocular surface trauma may reveal unexpected findings, such as an intraorbital foreign body, requiring investigation by a CT scan. PMID- 23101276 TI - Recalcitrant pruritus as primary manifestation of synchronous Hodgkins lymphoma and Langerhans cell histiocytosis. AB - We present a 73 year old female with intractable pruritus and nonspecific cutaneous rash for a period of 9 months. She had recieved symptomatic therapy with no improvement. A complete examination revealed axillary and abdominal lymphadenopathy. A biopsy confirmed the diagnosis of Hodgkins lymphoma with Langerhans cell histiocytosis. She received 5 cycles of chemotherapy with resolution of pruritus and reduction in axillary and abdominal lymphadenopathy. The patient presented 6 months later with relapse and succumbed to the illness. Simultaneous occurrence of Langerhans cell histiocytosis and Hodgkins lymphoma may lead to misdiagnosis. The awareness of such an association is important to make an accurate diagnosis and guide appropriate therapy. PMID- 23101277 TI - Rapidly progrediating aortic valve infective endocarditis in an intravenous drug user treated by antibiotics and surgery. AB - We report the case of a 22-year old male, a self-confessed recreational drug user who developed cardiogenic shock because of severe destruction of the aortic valve by rapidly progressive aortic valve endocarditis. The disease progression was acute; in a matter of days, the clinical manifestations were life-threatening necessitating urgent aortic valve replacement surgery. Cultivation revealed Streptococcus viridans as the microbial agent. Subsequent recovery with antibiotic treatment was without complication. This case report shows that immediately performed transoesophageal echocardiography and early consultation with a cardiac surgeon has fundamental importance in diagnosis and management of acute infective endocarditis in haemodynamically instable patients. PMID- 23101278 TI - Non-pharmacological methods in the treatment of resistant hypertension. AB - INTRODUCTION: Arterial hypertension is the most common chronic cardiovascular disease affecting about 25% of the adult population. Meta-analyses have demonstrated a linear relationship between blood pressure and the risk of cardiovascular events. Resistant hypertension defined as failure to reach blood pressure targets despite treatment with three antihypertensive drugs including a diuretic represents a serious clinical problem. It has been estimated that it affects between 8.9% and 12.8% of all treated hypertensive subjects. In resistant hypertension the optimal blood pressure is illusive despite very well tailored therapy. OBJECTIVE: Management of resistant hypertension is exactly the field where blood pressure-controlling non-pharmacological methods fit best. The present article aims at throwing light on these methods' principles of action, on who the target patient groups are and the respective results. Two methods are especially reviewed here: the carotid baroreflex stimulation and the transcatheter renal sympathetic denervation. Current results from the use of renal denervation suggest stable efficiency of the method, the results becoming significant 6 months after the procedure is applied and sustained for two years in the follow-up. As much as 90% of the treated patients respond to the procedure. The transcatheter renal denervation is associated with only 2.61% of procedural complications. The baroreflex carotid stimulation, too, is known to produce a stable effect on blood pressure: the effect become obvious at 12 months in 88% of the treated subjects. The neurologic complications associated with the procedure are reported to occur in 4.4% of cases. CONCLUSION: The present review article clearly demonstrates that non-pharmacological methods for treatment of resistant hypertension show great promise despite some open questions concerning their long term effects and procedural safety. PMID- 23101279 TI - Epigenetic aspects in schizophrenia etiology and pathogenesis. AB - Epidemiological evidence suggests that etiology of schizophrenia may involve both the influence of genetic factors specific for the individual and the impact of the environment. It is quite likely that a crucial role in the disease development is played by molecular mechanisms mediating the interaction between genes and environment. Modern research have shown that epigenetic mechanisms or chemical modifications of deoxyribonucleic acids (DNA) and histone proteins remain unstable throughout life and can be changed by environmental factors. Thus the epigenetic mechanisms outline an attractive molecular hypothesis of the environment modelling role and the environmental contribution to schizophrenia progression. We give in the present study a general outline of schizophrenia as a pathological entity and discuss the role and involvement of environment versus genetic determinant (nature versus nurture) in the pathophysiolgical processes. Additionally, we focus on DNA methylation discussing the evidence for the role of that process in schizophrenia. Thirdly, we review the post-translational histone modifications and their role in schizophrenia. These investigations might surely lead further to the development of epigenetic therapy that looks promising in regard to symptom alleviation and the disease-associated cognitive deficit. PMID- 23101280 TI - Size of tumour as a risk factor for malignancy in patients with peripheral pulmonary nodules. AB - Peripheral pulmonary tumours are often quite difficult to diagnose and treat. Their detection brings immediately the problem of whether clinicians should just wait and observe or operate the patients. The aim of this study was to determine if there is a direct correlation between tumour size and the risk for malignancy and whether the tumor size should be considered a risk factor for malignancy. PATIENTS AND METHODS: Between 1997 and 2009, 145 patients with peripheral pulmonary tumours of less than 3 cm in diameter underwent video-assisted thoracoscopic (VATS) resection for the purpose of histologic examination of the tumor. RESULTS: The mean age of the patients was 62.60 +/- 0.95 years. The youngest patient was 17 years old and the oldest--82. The study sample included 61 women and 84 men; the men were statistically significantly more than the women (57.3% and 42.07%, respectively) (t = 2.74, P < 0.01). The total number of patients we operated were 145 with 198 resected tumours. The diameter of the lesions ranged between 0.30 cm and 3 cm (mean 1.41 +/- 0.06 cm). We found that 108 (54.55%) of the tumours were malignant, and 90 (45.45%) were benign, the difference between them failing to reach statistical significance (t = 1.82, P > 0.05). The mean size of malignant lesions was statistically significantly greater than that of benign tumours (1.62 +/- 0.08 cm vs 1.15 +/- 0.06 cm). CONCLUSION: The results of this study suggest that the bigger the diameter of the nodule, the greater the percentage share of malignant tumours, which means that the size of the tumour is an important risk factor for malignancy. PMID- 23101281 TI - Repeat transrectal prostate biopsies in diagnosing prostate cancer. AB - Patients with negative prostate biopsy and persistent suspicion of prostate cancer (PCa) can pose a serious diagnostic problem. The AIM of our study was to determine the frequency of PCa found on repeat prostate biopsy and the factors leading to higher possibility of cancer positive histological result. PATIENTS AND METHODS: We studied retrospectively 113 patients (82 from University Clinic, Jena, Germany and 31 from Department of Urology, Plovdiv, Bulgaria) with initial negative biopsy for cancer who underwent repeat biopsies. The patients were examined between January 1999 and May 2010. The target group included patients with Prostate Specific Antigen (PSA) level lower than 12.5 ng/ml and without suspicious finding on digital rectal examination (DRE). Different biopsy schemes were used in the initial and the following biopsies, depending on patient age and total prostate volume. RESULTS: Overall PCa detection rate was 22.1% (25 of 113). The repeat biopsy found PCa in 15.9% (18 of 113). In patients with 3 biopsies the PCa detection rate was considerably lower--only 8.6% (3 of 35). PCa was found in only 1 patient of 18 (5.5%) who underwent four or more biopsies. Transurethral resection of the prostate (TURP) was performed in 15 patients with at least two previously negative biopsies. The pathohistological examination of the resected tissue showed PCa in 3 of the patients (20%). CONCLUSION: The interval between biopsies is not a significant predictive factor for positive prostate biopsy. The chance for detecting PCa after the second negative transrectal biopsy procedure is low. Therefore, TURP can be used as an alternative procedure to harvest adequate tissue material for pathologic examination, especially in patients with obstructive voiding symptoms. PMID- 23101282 TI - Effect of selective beta-blockade with bisoprolol in the treatment of recent onset atrial fibrillation. AB - The incidence of atrial fibrillation has been rapidly increasing in recent years. The increased tonus of the sympathetic nervous system is related to the development of atrial fibrillation. OBJECTIVE: TO study the effect of bisoprolol, a highly selective beta-blocker, on patients with recent-onset atrial fibrillation (< 48 hours) for regularization of the rhythm using propafenone. PATIENTS AND METHODS: The study includes 164 patients (81 women, 83 men, age 59.09 +/- 10.81) with successfully restored sinus rhythm in recent-onset atrial fibrillation. The patients received either propafenone (group A, n = 82) or a combination of propafenone and bisoprolol (group B, n = 82). The studied patients were randomly allocated to the groups. Propafenone was administered intravenously as a 2 mg/kg bolus followed by infusion of 0.0078 mg/kg/min for 120 min and orally in dosage of 300 mg three times every 8 hours if arrhythmia persisted. Bisoprolol was administered in a single dose at the very beginning of propafenone treatment and only in patients from group B at a dose of 5 or 10 mg. Regularization of the rhythm was assessed at the 3rd, 6th, 12th and 24th hour. RESULTS: In the initial stages of regularization the combined therapy restored the sinus rhythm in a greater number of patients in comparison with the monotherapy (at the 6th hour 67.07% in group B versus 48.78% in group A, P < 0.05; at the 12th hour it was 87.80% versus 75.60%, respectively, P < 0.05). CONCLUSION: Early regularization of rhythm in patients with recent-onset atrial fibrillation reduces the likelihood of recurrent episodes of arrhythmia. This makes the application of selective beta-blockade clinically significant. PMID- 23101283 TI - Association of physical activity with insulin resistance, subclinical inflammation, coagulation, and fibrinolytic biomarkers among population at high risk for type 2 diabetes. AB - OBJECTIVE: TO investigate the association of physical activity with insulin resistance and biomarkers of inflammation, coagulation, and fibrinolysis in a population at high risk for type 2 diabetes. PATIENTS AND METHODS: A total of 778 subjects from the Risk factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes (RIAD) study aged 40-70 years were included in the present cross sectional analysis. RESULTS: Participants classified as having low physical activity (PA) were more insulin resistant in comparison to participants with medium (P = 0.042) and high PA (P = 0.015). Individuals with high physical activity had a significantly lower leucocytes count than individuals with low PA (P = 0.027) and significantly lower hs-CRP and fibrinogen concentrations than individuals with medium (P = 0.011 and P = 0.021) and low physical activity (P = 0.04 and P = 0.007). Although a trend towards a decrease in plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) levels with increasing physical activity was present, significant differences were observed only between subjects with high and medium physical activity (P = 0.045 and P = 0.033). In multivariate regression analyses physical activity was an independent determinant of insulin resistance, leucocytes count, hs-CRP, and fibrinogen concentrations. CONCLUSIONS: Physical activity was independently associated with insulin resistance and biomarkers of inflammation, whereas only a tendency towards decreased concentrations of coagulation and fibrinolytic biomarkers with increasing physical activity was observed. PMID- 23101284 TI - Somatotype characteristics of male patients with type 2 diabetes mellitus. AB - INTRODUCTION: Type 2 diabetes is a metabolic disorder and as such it no doubt affects the components of somatotype of diabetics. AIM: The aim of this study was to determine the somatotype of males with type 2 diabetes. PATIENTS AND METHODS: In the study we assessed anthropometrically 169 male patients with type 2 diabetes. The patients were Bulgarian; they were allocated into two age groups: group 1 included 40-60-year-old patients and group 2--61-80-year olds. Healthy Bulgarian men without any history of metabolic, neoplastic, or other diseases were used as controls divided into age matched groups. Measurements obtained directly were height, body weight, biepicondylar breadth of humerus, biepicondylar breadth of femur, relaxed upper arm circumference, contracted upper arm circumference, forearm circumference, waist circumference, hip circumference, thigh circumference, calf circumference. Skin folds: subscapular, over rib 10, suprailiac, over abdomen, triceps, biceps, forearm, thigh, calf. Calculated parameters: Heath-Carter anthropometric somatotype components. RESULTS: Mean somatotype of 40-60-year-old male diabetics was endomorphic mesomorph (endo mesomorph), (endo 5.03; meso 6.57; ecto 2.01). Mean somatotype 61-80-year-old diabetic males was endomorphic mesomorph (endo-mesomorph), (endo 4.14; meso 5.88; ecto 1.64). The between-age comparison showed the somatotype in both age groups of diabetic males to be endomorphic mesomorph. The mesomorphy was dominant, followed by endomorphy and ectomorphy was far behind. The differences in the ratings of the somatotype components were of high statistical significance (P < 0.001). The mesomorphy and endomorphy ratings in patients with type 2 diabetes aged 40-60 years were greater than those of patients aged 61-80 years with the difference reaching statistical significance (P < 0.001). CONCLUSIONS: Both age groups of male diabetics presented with endomorphic mesomorph somatotype. Mesomorphy was the highest, followed by endomorphy. Ectomorphy lagged substantially behind, leading to a shift in the somatoplot upward to mesomorphy and leftward to endomorphy. Unlike the findings of studies in foreign countries presenting markedly dominating endomorphy, in our study Bulgarian diabetic males presented with dominating mesomorphy. This can be regarded as a characteristic feature of Bulgarian diabetic patients. This could be accounted for by the role played by factors such as lifestyle, habits, environment, diet, methods of treatment, etc. The somatotype of Bulgarian diabetic males (endomorphic mesomorph) is more favourable with regard to the risk, course and prognosis of the disease. PMID- 23101285 TI - Correlation between salivary alpha-amylase and stress-related anxiety. AB - Salivary alpha-amylase is a useful biomarker that can be used in assessing human psychobiological and social behavioural processes. Studying it opens up possibilities for the creation of novel concepts concerning the interaction of biological and social processes and their impact on health and behaviour. MATERIALS AND METHODS: The levels of salivary alpha-amylase and situation anxiety self-assessment using Spielberger test were measured twice in 30 individuals aged 21.37 +/- 0.96 yrs (18 females and 12 males): once during stressful situation (prior to examination) and, again a month later, in stress-free environment (during a training session). Salivary alpha-amylase was measured using kinetic reaction kit Salimetrics LLC--USA. RESULTS: The mean level of salivary alpha amylase measured during the first measurement 156.0 +/- 93.33 U/ml. During the second measurement in the absence of intense stress, the levels were two times lower - 74.03 +/- 58.06 U/ml and the differences were statistically significant (P < 0.001). We found a statistically significant correlation between the levels of salivary alpha-amylase in both measurements (P < 0.01). The correlation coefficient was r = 0.472 (P < 0.01). CONCLUSIONS: The adapted version of the State-Trait Anxiety Inventory score (STAI) created by Spielberger is appropriate for assessment of stress-related anxiety in young individuals. Salivary alpha amylase may be used as a biomarker for objective evaluation of the psychosomatic state of individuals in a stressful environment. The combination of psychological test and objective indicator such as salivary alpha-amylase is an excellent tool for objective evaluation of individual's state in stressful environment. Similar tests may be used in assessment of patients' behaviours at dental treatment that may be considered a stressor in most patients. PMID- 23101286 TI - Perceived sources of stress in fifth year dental students--a comparative study. AB - INTRODUCTION: The term "stress" refers to the effect of certain external factors (physical or mental) on the individual's physical and psychological health. Stress is very high in dental medicine. It may well be generated by the process of training in dentistry. During their training dental students express high levels of stress and considerable stress-related symptoms such as physical problems, depression, obsessive-compulsive and personality disorders. The perceived stress can be dependent on socio-cultural factors. The type of personality, gender, emotional intelligence and other individual characteristics may also influence the stress effects. AIM: To determine the main sources of stress in students during their dental training and compare the level of stress fifth-year dental students experience in the Faculty of Dental Medicine, Plovdiv, Bulgaria and the Faculty of Dentistry in Montpellier, France. METHODS: We recruited in the study fifth-year students from the Faculty of Dental Medicine in Plovdiv, Bulgaria and the Faculty of Dentistry in Montpellier, France. The modified Dental Environment Stress (DES) questionnaire was used to assess the effect of the various stressors. The questionnaire survey was conducted between February and March 2008. RESULTS: The living arrangements domain indicates higher levels of stress in Bulgarian students compared to their French counterparts with significant statistical difference for all factors. In personal factors the highest levels of stress were found with respect to the reduced holidays during school year and financial problems. Exams were the highest stressor in academic work domain and for the survey as a whole. In educational environment factors the stressors with the highest significance were the interactions with patients, academic environment (for French students) and risk of cross transmitted infections (for Bulgarian students). The high stress during clinical work is related to completing the assigned clinical workload quota and the shortage of time for clinical work. CONCLUSIONS: The students from both faculties report the highest mean levels of stress are related to examinations and clinical factors. Bulgarian students experienced higher mean levels of stress compared to their French colleges. The differences in mean stress levels are associated with socio cultural factors and variations in educational curriculums at both dental faculties. PMID- 23101288 TI - Stories of achievement that will inspire others. PMID- 23101287 TI - Functional reconstruction of subtotal glossectomy defects with radial forearm free flap: case report and review of literature. AB - Adequate reconstruction of defects that are consequences of glossectomy is of primary importance for achieving satisfactory functional results and improving the quality of life. AIM: The aim of this study was to report a case of free flap reconstruction of a subtotal glossectomy defect and discuss it in relation to other available methods. CASE REPORT: A 48-year-old woman was operated on for a T4N0M0 squamous cell carcinoma of the tongue. A subtotal glossectomy via mandibular swing procedure with bilateral supraomohyoid neck dissection and reconstruction with a radial forearm free flap (RFFF) was performed. Surgery was followed by adjuvant radiotherapy. RESULTS: The post-operative period was uneventful. The patient resumed intelligible speech evaluated as "excellent" and oral feeding. The donor site morbidity was acceptable. Present reconstructive options of the tongue include two categories: to maintain mobility or to provide bulk. In glossectomy with 30 to 50 percent preservation of the original musculature, maintaining the mobility of the remaining tongue by a thin, pliable flap is preferred. This can be achieved by infrahyoid myofascial, medial sural artery perforator flap, RFFF, anterolateral thigh and ulnar forearm flap. When the post-resectional volume is less than 30 percent of the original tongue, the reconstruction shifts to restoration of bulk to facilitate swallowing by providing contact of the neotongue with the palate. Flaps providing bulk include the free TRAM flap, latissimus dorsi myocutaneous free flap, pectoralis major musculocutaneous flap and trapezius island flap. CONCLUSION: Surgical treatment of advanced tongue cancer requires adequate reconstruction with restoration of speech, swallowing and oral feeding. Free tissue transfer seems to achieve superior functional results with acceptable donor site morbidity when indicated. PMID- 23101289 TI - Chief nursing officer sets out her vision for the profession's future. PMID- 23101290 TI - Survey reveals students rate their courses and placements highly. PMID- 23101291 TI - Trust 'cartel' hoards millions while still looking to cut staff pay. PMID- 23101293 TI - 'I will repeal the act and restore the 'N' in the NHS,' says Burnham. PMID- 23101292 TI - Professions team up in a bid to eradicate hospital-acquired VTE. PMID- 23101294 TI - Integrated islands. AB - NHS Orkney is pioneering a programme to integrate health and social care services. Integration puts the patient at the centre of services, but the process can be difficult for staff and there is a risk of inadvertently creating new barriers. PMID- 23101295 TI - A will to make it happen. AB - During her long career as an army nurse, Pauline MacDonald became an expert in infection control. Today she helps to look after the people of Dudley in her day job, while also advising the government on national policy around vaccinations. PMID- 23101296 TI - Thinking outside the box. AB - People with dementia can spend almost all their time indoors, despite the fact that exposure to sunlight and access to outdoor spaces is important to their physical and mental wellbeing. Nurses are becoming involved in specialised building and garden design, allowing people with dementia to enjoy outdoor spaces. PMID- 23101297 TI - Acute oncological emergencies. AB - The number of people receiving systemic anti-cancer treatment and presenting at emergency departments with treatment-related problems is rising. Nurses will be the first point of contact for most patients and need to be able to recognise oncological emergencies to initiate urgent assessment of patients and referral to the acute oncology team so that the most appropriate care can be delivered promptly. This article discusses the role of acute oncology services, and provides an overview of the most common acute oncological emergencies. PMID- 23101298 TI - Benefits of telemonitoring in the care of patients with heart failure. AB - Telemonitoring involves remotely monitoring patients' vital signs. It is an innovative and promising development in the care of people with heart failure that may reduce hospital admissions and the burden on the NHS, as well as improve patients' quality of life and clinical outcomes. This article describes what telemonitoring is and explores the evidence base for its use. The role of the nurse in telemonitoring is also discussed, with particular reference to dealing with and responding to alerts. The development and implementation of new technology is essential to improve the delivery of healthcare and optimise patient outcomes, and telemonitoring may play an important role in the future of heart failure services. PMID- 23101299 TI - Safeguarding vulnerable older people in hospital. AB - Safeguarding vulnerable older people is the responsibility of all healthcare professionals, but what this means in reality and how it can be achieved in practice is not always well understood. This article provides guidance on how government initiatives can be used by nurses to improve the care of older people. The article identifies criteria for determining when a concern should be raised as a safeguarding alert and when neglect may be occurring. A positive culture encompassing zero tolerance of poor care in the hospital setting is advocated. PMID- 23101300 TI - Chronic fatigue syndrome. PMID- 23101301 TI - A flair for organisation. PMID- 23101302 TI - The motherhood career slide. PMID- 23101303 TI - Attention, courtesy and patience: how to talk to patients effectively. PMID- 23101304 TI - 'Balancing demands is strenuous'. PMID- 23101305 TI - Stressed? You're not alone... PMID- 23101306 TI - Latex allergy: Position Paper. AB - Correct management of latex allergy is essential to ensure adequate care of patients who are allergic to latex, which is ubiquitous in the health care setting. In this Position Paper, the Latex Committee of the Spanish Society of Allergology and Clinical Immunology provides guidelines for the management of latex allergy. PMID- 23101307 TI - Genetic association study in nasal polyposis. AB - BACKGROUND AND OBJECTIVES: Nasal polyposis (NP) is a chronic inflammatory disease of the upper airways with a variable clinical course and unknown pathogenesis that often coexists with other conditions. Considering the possibility of genetic predisposition, we decided to analyze whether polymorphisms in LTC4S, CYSLTR1, PTGDR, and NOS2A were associated with NP. METHODS: The study population comprised 486 Caucasian individuals. Polyposis and aspirin intolerance were diagnosed following the recommendations of the European Position Paper on Rhinosinusitis and Nasal Polyps. Genotypes were determined using polymerase chain reaction amplification and direct sequencing. RESULTS: The -444A > C LTC4S polymorphism was significantly associated with NP and atopy (P = .033) and with NP and atopic asthma, (P =.012). In addition, a significant association was found when the (CCTTT) repetition of the NOS2A gene was present more than 14 times in patients with NP and asthma (P = .034), in patients with polyposis and intolerance to nonsteroidal anti-inflammatory drugs (P = .009), and in patients with the aspirin triad (P = .005). The PTGDR diplotype CCCT/CCCC (-613CC, -549CC, -441CC and 197TC) was more frequent in patients with NP (P = .043), NP with asthma (P = .013), and the aspirin triad (P = .041). CONCLUSIONS: NP was associated with specific polymorphisms only when it occurred with related phenotypes. Our results suggest that this genetic background plays a more relevant role in the development of the associated clinical features of nasal polyposis than in simple polyposis. PMID- 23101308 TI - Trace element levels in children with atopic dermatitis. AB - BACKGROUND: Trace elements are micronutrients that are present in small amounts in the body and are essential for normal functioning of the immune and antioxidant systems. Inflammation and oxidative stress are major pathogenic mechanisms in the development of atopic dermatitis (AD). The role of micronutrients in AD has been investigated in a limited number of studies, although the results are contradictory. OBJECTIVES: In this study, we examined the levels of iron, copper, and magnesium in serum and the level of zinc in erythrocytes in children with AD. We compared our findings with those of a healthy control group. METHOD: The study population comprised 92 AD patients and 70 controls. We performed a complete blood count and measured levels of iron, copper, and magnesium in serum and levels of zinc in erythrocytes. RESULTS: We found that serum magnesium and erythrocyte zinc levels were lower in children with AD than in the control group; levels of copper and iron did not differ between the groups. The levels of micronutrients studied were not correlated with disease severity. CONCLUSION: Evaluation of zinc and magnesium levels in children with AD could prove useful. The role of micronutrients in the pathogenesis and course of AD warrants further study. PMID- 23101309 TI - Goji berries (Lycium barbarum): risk of allergic reactions in individuals with food allergy. AB - BACKGROUND: New foods are frequently introduced in Western diets for their healthy properties; however, they may produce adverse effects. OBJECTIVE: After attending a patient who experienced an allergic reaction to Goji berries, we evaluated the allergenic potential of this food in plant food-allergic individuals, a group that is considered to be at high risk of experiencing a reaction. METHODS: We recruited 30 additional plant food-allergic individuals in Spain during 3 months in 2010. Four patients reported symptoms on intake, 6 tolerated the berries, and 20 had never tried Goji berries. Patients underwent skin prick tests with Goji berries, as well as with peach peel and plant food panallergens as markers of cross-reactivity between unrelated foods. We carried out in vitro tests in symptomatic patients. RESULTS: Skin tests to Goji berries were positive in 24 patients (77%): 5 symptomatic patients and 19 asymptomatic patients. Positivity to Goji berries was associated with positivity to peach peel and to the panallergen nonspecific lipid transfer protein (LTP). Nearly half of the patients reported symptoms (45%), but 89% of the skin test-positive patients had never eaten Goji berries. We detected specific immunoglobulin E to Goji berries in all cases, and several individuals recognized 2 protein bands in the immunoblot. Addition of LTP to sera mostly inhibited immunoglobulin E binding to an LTP-like band, suggesting a role for this panallergen in sensitization to Goji berries. CONCLUSIONS: Our results demonstrate the allergenic potential of Goji berries in high-risk individuals, which is probably due to cross-reactivity with LTP from other foods. The risks of Goji berries should be taken into consideration in individuals with food allergy, especially those who are allergic to LTP. PMID- 23101310 TI - Nasal and bronchial inflammation after nasal allergen challenge: assessment using noninvasive methods. AB - BACKGROUND: Links between the upper and lower airways have been demonstrated in recent years. However, few studies have evaluated inflammation using noninvasive methods. METHODS: A nasal allergen challenge was performed with pollen outside the pollen season in 30 patients with allergic rhinitis due to pollen but no asthma. Clinical and inflammatory nasal and bronchial responses to nasal allergen challenge were evaluated using the nasal symptoms score (NSS), visual analog scale (VAS), nasal geometry (volume between 2 and 5 cm [Vol2-5]) by acoustic rhinometry, lung function by spirometry, nasal nitric oxide (nNO), and exhaled nitric oxide (eNO). Values were recorded at baseline, 15 minutes, and 2 and 24 hours after challenge. Nasal lavage and exhaled breath condensate (EBC) samples were collected at 2 and 24 hours to assess 8-isoprostane, cys-leukotrienes, eosinophil cationic protein (ECP), tryptase, granulocyte-macrophage colony stimulating factor, and interleukin (IL) 5. RESULTS: NSS and VAS increased significantly at 15 minutes and 2 and 24 hours after challenge. Vol2-5 decreased significantly at 15 minutes and 2 hours, while nNO decreased at 15 minutes. All inflammatory mediators except ECP increased significantly at 2 hours in nasal lavage samples, while ECP, 8-isoprostane, and cys-leukotrienes increased at 24 hours (P < .01). In EBC, 8-isoprostane and cys-leukotrienes increased at 2 and 24 hours (P < .01). No significant changes were found at any time in lung function or eNO. CONCLUSION: Nasal allergen challenge induces clinical and inflammatory responses in the nose and bronchi that can be assessed using noninvasive methods such as nasal lavage, EBC, and nNO. PMID- 23101311 TI - Self-reported drug allergy in health care workers in conservative and surgical medicine departments. AB - BACKGROUND: Drug allergy comprises 10% to 30% of all adverse drug reactions, and according to data from the literature, sensitivity to drug allergens is 2 to 3 times more common in health care workers than in the general population. OBJECTIVE: The aims of this study were to estimate the prevalence of self reported drug allergy in health care workers and compare the data obtained between doctors and nurses from conservative medicine (CM) and surgical medicine (SM) departments. METHODS: This was an analytic questionnaire-based survey conducted using the European Network of Drug Allergy questionnaire adapted to the Lithuanian population. The questionnaires were completed by 346 individuals. RESULTS: Nurses from SM departments reported allergy symptoms more frequently than doctors from the same departments (38.1% vs. 16.7%, P = .01) and nurses from the CM departments (38.1% vs. 18%; P = .02). The most common drugs reported to cause hypersensitivity symptoms were similar in the CM and SM departments: antibiotics (8.8% and 12.7%), local anesthetics (2.9% and 6.9%), and group B vitamins (1.2% and 2.1%). Skin damage was indicated as the most common clinical manifestation. CONCLUSIONS: Based on the data reported by the questionnaire respondents, drug allergy was most prevalent among nurses from the SM departments, and antibiotics and local anesthetics were the most common substances that induced the symptoms. PMID- 23101312 TI - Drug hypersensitivity reactions: response patterns, drug involved, and temporal variations in a large series of patients. AB - BACKGROUND: Drug hypersensitivity reactions (DHRs) are among the most frequent reasons for consultation in allergy departments, and are becoming more common due to increasing prevalence and case complexity. OBJECTIVE: To study the clinical characteristics, drugs involved, diagnostic methods, and temporal variation of DHRs in a large series of patients over a 6-year period. METHODS: We included all patients attending our department between 2005 and 2010. The diagnosis was performed by in vivo and/or in vitro tests (basophil activation test and specific immunoglobulin [Ig] E in serum and drug provocation testing [DPT]) when indicated. RESULTS: We evaluated 4460 patients who reported 4994 episodes (mean [SD] of 1.13 [0.36] [range, 1-3] episodes per patient). Based on clinical history, 37% of the episodes were attributed to nonsteroidal anti-inflammatory drugs (NSAIDs), 29.4% to beta-lactam antibiotics (BLs), 15% to non-BLs, and 18.4% to other drugs.Analysis of the 1683 patients (37.45%) finally confirmed as allergic showed the most frequent diagnosis to be hypersensitivity to multiple NSAIDs (47.29%), followed by immediate reactions to BLs (18.12%). There was an increase in reactions to non-BLs (from 21.2% to 31.9%; P < .03) over the study period, mainly due to an increase in allergy to quinolones (from 0.5% to 6.8%; P < .02); 44% of patients were diagnosed by clinical history, 14.6% by skin tests, 10.4% by in vitro tests, and 30.8% by DPT. CONCLUSIONS: NSAIDs were the drugs most frequently involved in DHRs and the most common diagnosis was urticaria/angioedema with cross intolerance. Reactions to emerging drugs such as quinolone derivatives and radiocontrast media are becoming more common. PMID- 23101313 TI - A delayed reaction to oxaliplatin. PMID- 23101314 TI - Urticaria due to an intradermal test with articaine hydrochloride. PMID- 23101315 TI - Specific immunoglobulin E to Echinococcus granulosus in children allergic to cow's milk proteins. PMID- 23101316 TI - Ibuprofen-induced exudative erythema multiforme after 1 week of continued therapy following oral challenge. PMID- 23101317 TI - Report from the Hymenoptera Committee of the Spanish Society of Allergology and Clinical Immunology: immunotherapy with bumblebee venom. PMID- 23101318 TI - Anaphylaxis due to sulpiride and sensitization to metamizole. PMID- 23101319 TI - DRESS syndrome in a 19-year-old patient following the administration of first line antituberculosis drugs. PMID- 23101320 TI - Severe reaction following sugammadex injection: hypersensitivity? PMID- 23101321 TI - Occupational asthma caused by the inhalation of Tyrophagus putrescentiae allergens in a dry-cured ham transporter allergic to shrimp. PMID- 23101322 TI - Hypersensitivity to cassava: an allergen-based assessment. PMID- 23101323 TI - Quantitative measurement of allergen-specific immunoglobulin E levels in mass units (ng/mL): an interlaboratory comparison. PMID- 23101324 TI - Erythema and hand edema due to flavoxate. PMID- 23101325 TI - Food protein-induced enterocolitis syndrome (FPIES) to corn: a case report. PMID- 23101326 TI - Immunological features in influenza A H1N1 pneumonitis. PMID- 23101327 TI - [Veterinarians important in battling undesirable dog trafficking]. PMID- 23101328 TI - [District court rabbit]. PMID- 23101329 TI - [Secretary of State Henk Bleker: 'veterinarian has landed on the political agenda']. PMID- 23101330 TI - [Trends from the GD monitoring]. PMID- 23101331 TI - [Practical guidelines for the treatment of cases of adder envenomation in dogs]. AB - Every year, dogs are presented to veterinary clinics in the Netherlands after having been bitten by a viper. The viper is the only venomous snake native to the Netherlands. Clinical signs after an acquired viper bite can range from none (after a 'dry' bite) to very mild up to life threatening following a 'wet' bite. To prevent mortality it is important to monitor the animals for a period of time and provide adequate treatment. Clotting disorders and multiple organ failure can occur several days to a week after the viper bite, appropriate follow up is therefore important. In the Netherlands, a specific antiserum is available for veterinarians. The use of this antiserum is strongly recommended in severe cases of viper envenomation. PMID- 23101332 TI - [Gastro-intestinal lymphocytic and sclerosing leiomyositis (pseudoobstruction) in a dog]. AB - The clinical, ultrasonographic and radiologic aspects and the pathology of gastro intestinal lymphocytic and sclerosing leiomyositis (pseudoobstruction) are described in a 14 month old, male American Staffordshire terrier. PMID- 23101333 TI - [Prostasomes are of interest in fertility problems in the horse and prostate neoplasms in people]. PMID- 23101334 TI - [The cat with months of misery...]. PMID- 23101335 TI - [When it comes to rabbits]. PMID- 23101336 TI - [The misunderstood animal]. PMID- 23101337 TI - [Gate keeper as gate closer?]. PMID- 23101339 TI - [Almost retired]. PMID- 23101338 TI - [Pain and discomfort during calving]. PMID- 23101340 TI - [Subclinical ketosis: frequent and an expensive problem]. PMID- 23101341 TI - [On the road to integration of theory and practice in education]. PMID- 23101342 TI - [Henk Schoenmaker: clinician in hart and soul]. PMID- 23101343 TI - [Heart for people and animals]. PMID- 23101344 TI - Clinical simulation in health care--contemporary learning for safety and practice. PMID- 23101345 TI - Providing simulation experiences for large cohorts of 1st year nursing students: evaluating quality and impact. AB - To provide each student within a large cohort the opportunity to participate in a small group simulation that meets recognised quality indicators is a challenge for Bachelor of Nursing programmes in Australia. This paper, as part of a larger longitudinal study, describes one approach used to manage a simulation for 375 1st year nursing students and to report on the quality of the experience from the student's perspective. To ensure quality was maintained within the large cohort, aspects of the simulation were assessed against the following indicators: alignment with curriculum pedagogy and goals; preparation of students and staff; fidelity; and debriefing. Data obtained from a student focus group were analysed in the context of the quality indicators. The following themes emerged from the data: knowing what to expect; assuming roles for the simulation; authenticity and thinking on your feet; feeling the RN role; and, preparation for clinical practice. This paper demonstrates it is possible to provide students in large cohorts with active participatory roles in simulations whilst maintaining quality indicators. PMID- 23101346 TI - Patient deterioration simulation experiences: impact on teaching and learning. AB - Early recognition and management of patient deterioration are essential nursing skills, and can be improved through education and experience. However, both nursing students and registered nurses may have few opportunities to develop and maintain the emergency management skills necessary to ensure patient safety. Using both theory and empirical evidence, we have developed a simulation-based educational model, 'FIRST2ACT' (Feedback Incorporating Review and Simulation Techniques to Act on Clinical Trends), to provide nurses with a high-fidelity learning experience. The model has been tested in three different settings: it is highly acceptable to learners, adaptable to different training needs, and shows promise in improving actual clinical performance. PMID- 23101347 TI - An evaluation of a complex simulated scenario with final year undergraduate children's nursing students. AB - The last decade has witnessed the emergence of simulation as a useful, but sometimes challenging teaching methodology. This is supported by a number of sources of evidence, which focus strongly upon student evaluation of the learning experience. The challenges are equally worth consideration. These include issues such as the commissioning of space, staff expertise in resourcing and creating a situation which is as close to real practice as possible. It is against this backdrop, following a number of years developing innovative clinical simulation at Cardiff University; children's nursing students were exposed to a complex simulated clinical shift. The activities included: managing the clinical area; the transfer of a sick child; managing a medication error; subsequent discussion with the parents; and prioritising and organising care. The use of role-play was utilised throughout, to create a realistic experience and the simulation activity took place in two settings to enable the transfer from one area to another. The simulation experience was undertaken at the end of the third year undergraduate program by three cohorts of students (n = 41). Following the experience, data were collected through a post-simulation de-briefing and a Likert style questionnaire, enabling the collection of qualitative and quantitative data concerned with the student's experience of the simulation. Overwhelmingly, the results showed that this was a positive experience for the students, demonstrating a number of perceived improvements in the application of their clinical skills. These included: development of specific management skills; enhanced confidence; development of self-awareness; and the transferability of skills to practice. Students also demonstrated strong agreement in terms of the realism of the experience. PMID- 23101348 TI - High fidelity simulation in critical care: a Canadian perspective. AB - The use of high fidelity human simulation has exploded into the nursing education context over the last decade. In Ontario, Canada an innovative Critical Care e learning program was established in 2007 to create accessible critical care education for nurses across Ontario and Canada. The program has a three-pronged approach including online, simulation and practicum components. The purpose of this paper is to present lessons learned during the last five years of development and growth of this program. The paper will focus on the use of simulation to build confidence and prepare registered nurses for critical care nursing practice. In addition, subsequent development of a network of ten simulation partners that deliver critical care simulation will be discussed. High fidelity simulation delivery in the critical care context will be explored and the use of summative or 'high stakes' simulation competency evaluation will be elaborated on. PMID- 23101349 TI - Interdisciplinary collisions: bringing healthcare professionals together. AB - Since the publication of its reports, Health professions education: A bridge to quality (2003) and To err is human: Building a safer health system (2000), the Institute of Medicine has continued to emphasize interprofessional education (IPE), founded on quality improvement and informatics, as a better way to prepare healthcare professionals for practice. As this trend continues, healthcare education will need to implement administrative and educational processes that encourage different professions to collaborate and share resources. With greater numbers of students enrolled in health professional programs, combined with ethical imperatives for learning and reduced access to quality clinical experiences, medical and nursing education increasingly rely on simulation education to implement interdisciplinary patient safety initiatives. In this article, the authors describe one approach, based on the Core Competencies for Interprofessional Collaborative Practice released by the Interprofessional Education Collaborative (2011), toward providing IPE to an audience of diverse healthcare professionals in academia and clinical practice. This approach combines professional standards with the authors' practical experience serving on a key operations committee, comprising members from a school of medicine, a school of nursing, and a large healthcare system, to design and implement a new state-of-the-art simulation center and its IPE-centered curriculum. PMID- 23101350 TI - A review of undergraduate interprofessional simulation-based education (IPSE). AB - Interprofessional simulation-based education (IPSE) is becoming an increasingly popular educational strategy worldwide within undergraduate healthcare curricular. The purpose of the literature review was to examine qualitative, quantitative and mixed/multi-method research studies featuring undergraduate IPSE. A literature review was conducted using CINAHL, MEDLINE, and PsycINFO databases from January 1999 to September 2011 and pre-set criteria. The criteria used to screen all 120 abstracts included: (a) the article pertained to both simulation and undergraduate IPE and (b) the article reported a research study. Eighteen articles which met the pre-set criteria were included in the literature review. All studies featured outcome measures; many were purposely designed and lacked psychometric development and evaluation. Key IPSE drivers included capacity planning, preparedness for disaster management and improving patient care through the evaluation of teambuilding, teamwork skills or communicating within inter-disciplinary teams. Studies evaluated/explored either student or teacher perspectives of learning within the context of IPSE or both. The IPSE learning processes varied considerably in relation to duration, fidelity and professions involved. The scenarios ranged from managing adults admitted to hospital settings, mass casualty/mock disaster patient management to the use of training wards. The majority of the articles identified common IPSE outcomes relating to increased confidence, knowledge, leadership, teamwork, and communication skills. Based on the findings of this review, the authors suggest that further multi-site, longitudinal research studies are required to provide evidence of the transferability of skills developed during IPSE and their overall impact on both undergraduate education and healthcare. PMID- 23101351 TI - Advanced practice nursing students: pilot test of a simulation scenario. AB - In the current educational environment, increasing numbers of advanced practice nursing (APN) students compete for decreasing numbers of clinical sites where patient safety is paramount. Clinical simulations with high-fidelity human patient simulators provide APN students opportunities to demonstrate clinical skills and judgment in a safe supportive environment. Development, implementation, and preliminary evaluation of a scenario for APN students are discussed. Faculty and student evaluations are reviewed as well as recommendations for future simulations. PMID- 23101352 TI - Clinical simulation in Australia and New Zealand: through the lens of an advisory group. AB - Across Australia, innovations in simulation to enhance learning in nursing have been occurring for three decades and nursing is, and needs to be, a leading player in simulation knowledge diffusion. However, expertise is unevenly distributed across health services and education providers. Rather than build on the expertise and achievements of others, there is a tendency for resource duplication and for trial and error problem solving, in part related to a failure to communicate achievements for the benefits of the professional collective. For nursing to become a Leader in the use of simulation and drive ongoing development, as well as conducting high quality research and evaluation, academics need to collaborate, aggregate best practice in simulation learning, and disseminate that knowledge to educators working in health services and higher education sectors across the whole of Australia and New Zealand. To achieve this strategic intent, capacity development principles and committed action are necessary. In mid 2010 the opportunity to bring together nurse educators with simulation learning expertise within Australia and New Zealand became a reality. The Council of Deans of Nursing and Midwifery (CDNM) Australia and New Zealand decided to establish an expert reference group to reflect on the state of Australian nursing simulation, to pool expertise and to plan ways to share best practice knowledge on simulation more widely. This paper reflects on the achievements of the first 18 months since the group's establishment and considers future directions for the enhancement of simulation learning practice, research and development in Australian nursing. PMID- 23101353 TI - Your time has come. PMID- 23101354 TI - Experiences of military nurses in the Iraq and Afghanistan wars: review of research report. AB - Scannell-Desch and Doherty's (2010) research study findings are important to evidence-based nursing practice experiences of United States military nurses in the Iraq and Afghanistan wars to expand the research research findings identified common experiences and reoccurring stories and struggles of nurses pre, during, and postemployment in the Iraq and Afghanistan wars. These findings can be used for the education of future deploying military nurses and set the groundwork for further in-depth research studies on military nursing. One suggestion for future research would be a more in-depth study on the challenges faced by military nurses postemployment and interventions to assist in overcoming these challenges. PMID- 23101355 TI - Taking the plunge into doctoral education. PMID- 23101356 TI - Challenges in recruitment of African Americans with type 2 diabetes in rural settings. AB - Recruitment of African Americans to participate in research studies is challenging, however creativity in study design and attention to the community can overcome many barriers. Community based partnerships to assist African Americans in managing their disease and preventing complications. PMID- 23101357 TI - International educational experiences for rural nursing students in Kentucky. PMID- 23101358 TI - New report finds that sequester of Medicare spending could lead to more than 750,000 jobs lost. PMID- 23101359 TI - [The role of vestibular afferentation in the system cooperation's of cortical field's human brain]. AB - For the purpose of studying of a role vestibular afftrentation in the organization of system interaction of cortical fields of a brain of the person dynamics of inter-regional cortical interactions at patients by a cervical dystonia in the course of their treatment by a method transtimpanal chemical vestibular dereception was investigated. It is shown, what even at unilateral vestibular dereception deep reorganization of system interaction distance the separated cortical areas, mentioning, first of all, back and forward associative zones of both hemispheres is observed. The laws specifying for an organizing role vestibular afftrentation in the organization of integrative activity of a brain that confirms its system value are revealed. PMID- 23101360 TI - [The comparative analysis of changes of short pieces of EEG at perception of music on the basis of the event-related synchronization/desynchronization and wavelet-synchrony]. AB - The going of present pilot study is an analysis of features changes of EEG short pieces registered from 32 sites, at perception of musical melodies healthy examinees depending on logic (cognizance) and emotional (it was pleasant it was not pleasant) melody estimations. For this purpose changes of event-related synchronization/desynchronization, and also wavelet-synchrony of EEG-responses at 31 healthy examinees at the age from 18 till 60 years were compared. It is shown that at a logic estimation of music the melody cognizance is accompanied the event-related desynchronization in the left fronto-parietal-temporal area. At an emotional estimation of a melody the event-related synchronization in left fronto - temporal area for the pleasant melodies, desynchronization in temporal area for not pleasant and desynchronization in occipital area for the melodies which are not causing the emotional response is typical. At the analysis of wavelet synchrony of EEG characterizing jet changes of interaction of cortical zones, it is revealed that the most distinct topographical distinctions concern type of processing of the heard music: logic (has learned-hasn't learned) or emotional (it was pleasant-it was not pleasant). If at an emotional estimation changes interhemispheric communications between associative cortical zones (central, frontal, temporal), are more expressed at logic - between inter - and intrahemispheric communications of projective zones of the acoustic analyzer (temporal area). It is supposed that the revealed event-related synchronization/desynhronization reflects, most likely, an activation component of an estimation of musical fragments whereas the wavelet-analysis provides guidance on character of processing of musical stimulus. PMID- 23101361 TI - [Influence of music on a decision of mathematical logic tasks]. AB - Accompaniment of a decision of mathematical logical tasks by music (different style and power) influenced on the time of the decision. Classical music 35 and 65 dB and roc-music 65 and 85 dB decreased the time of the decision. More powerful classical music (85 dB) did not effect like that. The decision without the musical accompaniment led to increasing of coherent values especially in beta1, beta2, gamma frequency ranges in EEG of occipital cortex. The intrahemispheric and the interhemispheric coherences of frontal EEG increased and EEG asymmetry (in a number of Coh-connections in left and right hemispheres) arose during the tasks decision accompanied by music. Application of classical music 35 and 65 dB caused left-side asymmetry in EEG. Using of more powerful classical or rock music led to prevalence of quantity of Coh-connections in a right hemisphere. PMID- 23101362 TI - [Gender differences in emotion regulation in response to texts with violent content]. AB - We investigated gender differences in emotion regulation depending on the cognitive disclosure of negative emotive content of 3 different texts after their presentations. For the purposes of the study we varied order between (i) completing of special checklists, created for specification of emotive and arousing attributes of the text contents and (ii) readings of autonomic activity. Results suggested that completing of the checklists increased engagement in processing of the most arousing text's content in men, while no effect was found in women, who were proposed to be engaged in content processing already during the text presentation. Results of the present study are discussed in the context of the recent findings on the emotional regulation. PMID- 23101363 TI - [Gender differences of dynamic changes of anterior cortical activity under negative emotional strain]. AB - Dynamic changes of anterior cortical areas activity under negative emotional strain at male and female teenage examinees were investigated. Dependence of anterior cortical activity changes on gender and initial conflictness level of examinees is determined, which is also confirmed by detected shifts in phychoemotional sphere. PMID- 23101364 TI - [Features of dual--postural and calculation--task performance in patients with consequences of traumatic brain injury]. AB - Dual tasks with voluntary postural control and calculation have been done by 14 patients (25.7 +/- 4.7 yo.) after traumatic brain injury and 40 healthy volunteers (29.8 +/- 2.5 y.o.). Complex clinical (MMSE, FIM, MPAI-3 and Berg scales) and stabilographic evaluation has been performed. According to clinical evaluation 8 patients were included into group 1 with less severe functional deficit and 6 patients formed group 2 with more severe deficit. Parameters of motor and especially cognitive sub-tasks in patients were lower than in healthy subjects in both separate and dual tasks. In group 2 these parameters were lower than in group 1. Certain types of dual task where the quality of sub-tasks, especially of the motor-one increased in healthy subjects and patients of the first group were revealed. The complex of stabilographic parameters which could be used for estimation of quality of sub-tasks performance has been revealed. Dual tasks could be an additional method of evaluation of patients' adaptive possibilities and certain type of dual task could become a promising approach to recovery at late period of rehabilitation. PMID- 23101365 TI - [Oscillatory structure of parameters of pulse signal of a beam artery]. AB - The typological analysis of curves of spectral density of the dynamic numbers formed of various indicators of individual fluctuations pulse of a signal is realized. The formalized classification (typology) of spectral curve parameters in space - mutual parities of peak values of spectral density of slow waves VLF, LF, HF is spent. Criteria of reference of curve spectral density to this or that type which characterize degree of expressiveness of these oscillatory a component are defined. Researches are spent on the basis of the experimental material received during inspection of children and teenagers on revealing of an early stage of an arterial hypertensia. Distribution of objects on types of spectral density for various parameters of individual fluctuation pulse a signal is analysed. Results of the comparative analysis of distribution of types of a spectrum for various parameters pulse a signal the carried out analysis are resulted has allowed to reveal the spectral parameters possessing greatest informtiveness for differential diagnostics of two classes of diseases (1st class -a primary arterial hypertensia, 2nd class--various functional pathologies at normal arterial pressure). It is shown that with reference to a problem of revealing of signs of an arterial hypertensia at children's age of the greatest informtiveness the indicators defined by oscillatory components of time parameter of a dicrotic wave pulse of a signal possess. PMID- 23101366 TI - [The capnography parameters in healthy adults and patients with psychogenic dyspnea]. AB - A comparison is made the end-tidal fractional concentration of carbon dioxide (FetCO2) and breathing frequency (f) obtained by capnography between 106 healthy persons (H-group) and 30 persons with a psychogenic dyspnea (P-group). The structure of a respiratory cycle was estimated by parameter R(CO2). It was calculated by relation of time of an exhalation to time of all respiratory cycle. Degree of "breath arrhythmia" was estimated by means of parameter CVR(CO2). It was the coefficient of variation (CV) for R(CO2) recorded during the 5-min capnography. The groups was differed for all parameters (p < 0.01), except for R(CO)2 (structures of a respiratory cycle). FetCO2 at H-group was 5.24 +/- 0.36%, at P-group 4.07 +/- 0.47. The breathing frequency at H-group was 14.3 +/- 3.7 br/min, at P-group 17.9 +/- 4.5 and CVR(CO2) at H-group was 8.9 +/- 2.7%, at P group 12.7 +/- 3.1. We conclude that the most informative indicator of a psychogenic dyspnea is the complex of parameters taking into account all three characteristics of a pattern of breath: decrease FetCO2, increase f, and rhythm of breath. PMID- 23101367 TI - [Noninvasive estimation of human tissue respiration with wavelet-analysis of oxygen saturation and blood flow oscillations in microvessels]. AB - Laser Doppler flowmetry, laser spectrophotometry of oxygen saturation and fluorescence determination of NAD-H/FAD ratio were carried out at 30 humans in the upper extremity skin zones with and without arteriole-venule anastomoses (AVA). For the first time it was shown that wavelet-analysis of oxygen saturation and microvascular blood flow oscillations was an effective approach to noninvasive estimation of skin oxygen extraction (OE) and oxygen consumption rate (OC). OE = (SaO2--SvO2)/SaO2, where SaO2 (%) and SvO2(%) are the oxygen saturation of arterial and venular blood, correspondingly. If the ratio between amplitudes of cardiac rhythm (Ac, p.u.) and respiratory rhythm (Ar, p.u.) Ac/Ar < or = 1, SvO2 = SO2. In the case of Ac/Ar >1, SvO2 = SO2/(Ac/Ar). OC = Mnutr x (SaO2-SvO2) in p.u. x %O2, where Mnutr--value of nutritive perfusion (p.u.). Mnutr = M/SI, where SI--shunting index of blood flow in microvessels. The values of perfusion, OE and OC were higher in the skin with AVA than in the skin without AVA. The values of perfusion and oxygen saturation were more variable in the skin with AVA. The greatest significance for tissue metabolism have the oxygen diffused from the smallest arterioles and capillaries. The contribution increased to tissue metabolism of total perfusion and of oxygen diffused from arterioles in the conditions of tissue ischemia. PMID- 23101368 TI - [Metabolic states at athletes in the strenuous muscular activity of variable character]. AB - Investigated dynamics of metabolic conditions at athletes in strenuous muscular activity of variable character. The sportsmen of high qualification specializing in bicycle and skating sports, performed in vitro work on a bicycle ergometer at level of critical power at the maximum consumption of oxygen. In two additional series of experiences each of examinees has performed work on critical power by the initial accelerations making 28% from limiting duration of exercise of 45 and 108 seconds. At work on critical power on a course of performance of exercise consecutive change of metabolic conditions with a phase initial a log-period, fast exponential increase to level of the critical power, the subsequent maintenance of critical power and final dissociation of functions of an aerobic metabolism at increase of local exhaustion was traced. It is established that the most effective concerning work maintenance at level of critical power are short term (no more than 10 s) initial accelerations on the power corresponding to 45 second limiting exercises: these accelerations stimulate development of functions of an aerobic metabolism and don't lead to exhaustion anaerobic resources and to development of the expressed local exhaustion in the end of work. PMID- 23101369 TI - [The features of cardio-respiratory system and autonomic regulation in parasportsmen with spinal injury]. AB - A comprehensive study of the functional state of basketball athletes in wheelchairs with spinal cord injuries in the T6-T10 and paraplegia (n = 9, mean age 26.6 +/- 1.7 years) was held. As a control, we used disability groups with a similar injury, leading an active life (n = 13, mean age 44.5 +/- 2.6 years), athletes ( = 14, mean age 24.6 +/- 1.3 years) and healthy physically active men (n = 15, the average age of 24.9 +/- 0.6 years). In the athletes in wheelchairs it was revealed an increase in the length of the body in a sitting position, the increase in tidal volume and increasing in the effectiveness of the functional respiratory tests. These changes in the state of the musculoskeletal system and autonomic systems to ensure physical activity classified as adaptive and due to sports training. In the state of the cardiovascular system and its autonomic regulation parasportsmen showed a reduction in trauma-induced increase in diastolic blood pressure and increase in the magnitude of arterial baroreflex sensitivity, decreased due to spinal injury. These data indicate availability of compensatory processes aimed at optimizing the cardiovascular system through the mechanisms of baroreflex regulation. PMID- 23101370 TI - [Influence of the initial vegetative tone on the condition of haemodynamics of younger schoolboys]. AB - The comparative analysis of the functional condition of cardiovascular system and their reaction to the local isometric exercise for the 7-8-year-old boys, who are practically healthy, and in relation ship with the initial tone of the vegetative nervous system is given in the article. By means of variation pulsometer analysis, as well as by means of tetrapolar breast rheography it is found that children with sympathetic influences on heart rate (67.00%-55.55% out of all the studied) in comparison with those, who are normal or vagotonic show the higher activity of neuromediator link in sympathoadrenal system, as well as the increased stroke and minute blood volume on aveioge tachycardia background. With sympathotonic boys it is found that the leadiry link in the mechanism of urgent adaptation of the cardiovascular system to local static exercise there may be the spastic reactions of bloodstream, which allows us to distinguish such-like schoolchildren as a high-risk group in terms of appearance of vegetative dystonia with hypertensire vascular syndrome. PMID- 23101371 TI - [Adaptive changes lipid peroxidation (LPO)--antioxidative defence (AOD) of children having a different level of motion activity during school study]. AB - Parameters of systems of lipid peroxidation-antioxidative protection of the pupils of the 1-11th grade of general Chelyabinsk schools, having a different level of motion activity were studied and analyzed with purpose to reveal possible interrelation between these parameters and the level of motion activity of children. PMID- 23101372 TI - [Antifibrillatory activity of dipeptide antagonist of nerve growth factor]. AB - In experiments on anesthetized rats were assessed antifibrillatoty action of dipeptide GK-1. This compound is the fragment of fourth loop of nerve growth factor (NGF) and manifests antagonistic activity in respect to TrkA receptor, that specified for NGF. It is shown that this compound is able to significantly increase the threshold of electrical fibrillation of the heart and its effectiveness is not inferior to the reference antiarrhythmics I and III class on Vaughan Williams classification. However, unlike the latter, antifibrillatory action of dipeptide GK-1 was delayed and realized within 40-60 minutes after its administration. It is discussed possible mechanisms underlying antifibrillatory action of dipeptide GK-1, that, to some extent, may be associated with its ability to change the reactivity of beta-adrenergic structures of the heart. PMID- 23101373 TI - [Functional state of the liver at modeling hemodynamic effects of the weightlessness in human organism]. AB - The radioisotope researches (RR) ofcholeresis function of a liver, the ultrasonic researches (USR) of a liver, the contractile gallbladder function (GF) and the gastroduodenoscopy (GDS) were carried out at 8 men after 24 hour duration of stay in antiorthostatic position--12 degrees (AOP), simulating arising in weightlessness of hemodynamics changes in abdominal cavity. The dynamic difficulty of venous blood outflow from a liver at simulated in antiorthostatic position changes of activation choleresis on an empty stomach was produced, by increase of a zone central perfusion of a liver parenchyma, biliary ductules dilation and of a gallbladder reduction, and were accompanied by choleresis in duodenum. The activation choleresis in a liver was accompanied by of reduction of the area of radioactive marker distribution in a liver, the decrease of hepatocytes metabolic activity and concentration function ofbiliary excretion system. Specificity of a functional condition of a liver within AOP reflects reaction caused by plethoric changes induced by body position, which is negative to vector of gravity. The mechanism of the revealed changes includes occurrence dynamic venous plethora in a liver, centralization hepatic blood flow with activation choleresis activity against the background tissual blood flow depletion in peripheral zones, reduction of hepatocytes metabolic activity and concentration function biliary excretion system. PMID- 23101374 TI - [Role of shedding in the activity of immunocompetent cells with reagin protection mechanism]. AB - In work the data on studying of a parity of the maintenance of the soluble and membrane form of antigen CD23 at almost healthy faces is cited. To the specified sign 3 groups are allocated: in parallel low maintenance membrane and free CD23 (1 group), simultaneous increase of their concentration (2 group) and increase CD23 against significant decrease in concentration sCD23 (3 group). The conclusion becomes that photolytic shedding CD23 is made by the activated cells at increase in the maintenance of phenotypes of lymphocytes CD23+. Increase of expression CD23 by lymphocytes is associated with concentration increase of cytokines IL-6 and IFN-gamma, and a natural mitogen an alpha-fetoprotein. Abscission of cells CD23 and increase of concentration sCD23 occurs at excessive increase in maintenance IgE and anti-inflammatory ofcytokine IL-10. The parity of membrane and free forms CD23 is defined by activity of an expression, shedding and an educational level association. PMID- 23101375 TI - [The impact of oxygen tension in physiological regulation of human multipotent mesenchymal stromal cell functions]. AB - The significant progress in the clarification of cellular mechanisms governing tissue homeostasis and physiological remodeling was achieved in recent decades. Undifferentiated cells such as multipotent mesenchymal stromal (stem) cells (MMSCs) play an important role in these processes. MMSCs reside in virtually all postnatal organs and tissues occupying a specific tissue niche associated with the perivascular spaces. The most important property of MMSCs is, on the one hand, their ability to provide structural integrity of tissues and on the other - to respond on paracrine stimuli and migrate into the site of injury, promoting the tissue repair. The main feature of the MMSC physiological and regenerative milieu is a low oxygen tension, which can significantly modify the properties ofstromal cells. This review is concerned with analysis of the recent data on the MMSC tissue niches in terms of integration of these cells into the comprehensive physiological and reparative tissue remodeling and the role of the partial oxygen pressure in the realization of MMSCs. PMID- 23101376 TI - [Activity of the skeletal muscle proteolytic systems during functional unloading]. AB - The recovery of the skeletal muscle structure and function after prolonged disuse is the problem of the rehabilitation and space medicine great concern. Hypokinesia affects mainly the postural muscles responsible for the support reaction. Atrophy developed under disuse is the result of the protein synthesis and proteolysis balance shift. Several signaling systems regulating proteolysis are known now, though only recently researchers paid attention to the question whether these systems work identically in the muscles atrophied under different stimuli (denervation, starvation etc.). In this review we aimed to summarize and analyze cumulative data concerning the work of the different proteolytic systems during the atrophy caused by hypokinesia and/or hypogravity. Also we discuss here the latest data about the interconnection of the signaling systems regulating the structural and functional muscle proteins degradation and synthesis under disuse. PMID- 23101377 TI - [Endogenous cannabinoid system in the brain: role in regulation of seizure activity]. AB - In overview one can find up-today data on endogenous cannabinoids (EC), their role in brain functioning. Interest in EC in recent years has significantly increased. Despite the fact that existence of EC-system among mammals was identified in nineties of the twenties century, deciphering the mechanisms of its functioning both in healthy brain as well in various pathologies, is far from final stage. The main function of EC in brain is implementation of the retrograde synaptic function of communication and neuromodulation. In overview one can see data on localization and functions of cannabinoids receptors and its endogenous ligands in CMS, as well as on EC-system participation in epileptiform activity modulation. Special focus on the analysis of works, where the projection revealed the role of EC in experimental modeling of the temporal epilepsy with animals, as well as for diseases in humans epilepsy. Set out the estimated survival mechanisms of cells and their repair provided by cannabinoid system in the generation of seizure activity; also provides information about the neurotoxic effects of EC. Possible reasons of contradictions are being discussed, that exist in the literature regarding the functions of EC in the brain. PMID- 23101378 TI - [Dynamic hierarchy of regulatory peptides. Structure of the induction relations of regulators as the target for therapeutic agents]. AB - Based on the database information (literature period 1970-2010 gg.) on the effects of regulatory peptides (RP) and non-peptide neurotransmitters (dopamine, serotonin, norepi-nephrine, acetylcholine) it was analyzed of possible cascade processes of endogenous regulators. It was found that the entire continuum of RP and mediators is a chaotic soup of the ordered three-level compartments. Such a dynamic functional hierarchy of endogenous regulators allows to create start-up and corrective tasks for a variety of physiological functions. Some examples of static and dynamic patterns of induction processes of RP and mediators (that regulate the states of anxiety, depression, learning and memory, feeding behavior, reproductive processes, etc.) are considered. PMID- 23101379 TI - [Physiological and cytological bases of cellular regulation of angiogenesis]. AB - One of the major directions of development of cell therapy is a therapeutic angiogenesis. Progress in this area is associated with the discovery of endothelial progenitor cells, which play an important role in neovascularization of adult tissues. The list of candidate cells for the regeneration of the cardiovascular system is constantly updated. Nevertheless, these preclinical and clinical studies to assess the possibility of using cells for therapy, isolated from different sources are contradictory. For urgent issues in the research of cell therapy include lack of uniform nomenclature, as well as the lack of functional characteristics expected of stem/progenitor cells. Given the controversial results of initial clinical trials, require more accurate knowledge of the biological properties of cells used for transplantation. PMID- 23101380 TI - [The physiological role of nitric oxide in infectious process]. AB - This review presents the recent data on the physiological role of the molecule nitric oxide (NO) and its derivatives in the pathogenesis of bacterial and viral infection. Indicated that the effect of NO on individual cells involved in inflammation and immune regulation may be ambiguous, and depends on the cellular environment on the concentration NO and other factors. Thus, the interaction between reactive oxygen and NO derivatives provides a molecular basis for synergy between the respiratory burst and synthesis of NO, which leads to the formation of peroxynitrite, which has powerful bactericidal potential. At the same time production of NO can counteract the oxidant damage to cell membranes by blocking the oxidation of lipids and protect cells from damage, for example, by inhibiting the respiratory burst. Thus, nitrate and oxidative stress observed in pathophysiological states, has a modulating effect on the function of cells and tissues of various organs. PMID- 23101381 TI - [Pineal hormone melatonin is an universal adaptogenic agent]. AB - Pineal hormone melatonin is an universal chronobiotic with adaptogenic propertied which showed stabilized action on pathologically changed fluctuations of any physiological functions, protects a brain and an internal peripheral tissues from emotional and oxidant stress. It also produced hypnotic and anxiolytic effects, normalised function of cadriovascular system and immunological reactions. These properties can be used for treatment of various psychosomatic diseases. PMID- 23101382 TI - [Fisiological aspects of host--microorganisms interreaction: the role of neurotransmitter amines]. AB - Ability to use catecholamines as a stimulus for growth and pathogenic activity realization is widespread among bacteria. In the review numerous facts testifying the ability of these substances to stimulate pathogenic microflora development are systematized and mechanisms of growth stimulation and change of genes expression of microorganisms by catecholamines are considered. The microbial endocrinology role in shaping integrative physiological concepts is discussed. PMID- 23101383 TI - [Biogas production from cellulose-containing substrates: a review]. AB - Anaerobic microbial conversion of organic substrates to various biofuels is one of the alternative energy sources attracting the greatest attention of scientists. The advantages of biogas production over other technologies are the ability of methanogenic communities to degrade a broad range of substrates and concomitant benefits: neutralization of organic waste, reduction of greenhouse gas emission, and fertilizer production. Cellulose-containing materials are a good substrate, but their full-scale utilization encounters a number of problems, including improvement of the quality and amount ofbiogas produced and maintenance of the stability and high efficiency of microbial communities. We review data on microorganisms that form methanogenic cellulolytic communities, enzyme complexes of anaerobes essential for cellulose fiber degradation, and feedstock pretreatment, as biodegradation is hindered in the presence of lignin. Methods for improving biogas production by optimization of microbial growth conditions are considered on the examples of biogas formation from various types of plant and paper materials: writing paper and cardboard. PMID- 23101384 TI - [Catalytic properties of a nitrile hydratase immobilized on activated chitosan]. AB - The catalytic properties of a nitrile hydratase, isolated from a strain of Rhodococcus ruber gt1 and immobilized by covalent cross-linking with chitosan activated with 0.1% benzoquinone solution, have been investigated. The kinetic parameters ofacrylonitrile hydration catalyzed by immobilized nitrile hydratase and the enzyme in a solution have been determined. It is found that the immobilization does not lead to a decrease in the maximum reaction rate (Vmax), whereas the Michaelis constant (K(M)) is reduced by a factor of 2.4. The possibility of reusing an immobilized enzyme for 50 consecutive cycles of acrylonitrile transformation was shown, and the nitrile hydratase activity in the 50th cycle exceeded that in the first cycle by 3.5 times. It is shown that the effect of temperature on activity depended on the concentration of the enzyme, which confirms the dissociative nature of nitrile hydratase inactivation. It was found that immobilized nitrile hydratases remain active at pH 3.0-4.0, whereas the enzyme is inactivated in a solution under these conditions. The resulting biocatalyst can be effectively used to receive acrylamide from acrylonitrile. PMID- 23101385 TI - Production of cellulase by immobilized whole cells of Haloarcula. AB - Halophilic Archaea are adapted to a life in the extreme conditions and some of them are capable of growth on cellulosic waste as carbon and energy source by producing cellulase enzyme. The production of cellulase using free and immobilized cells of halophilic archaeal strain Haloarcula 2TK2 isolated from Tuzkoy Salt Mine and capable of producing cellulose was studied. The cells were cultured in a liquid medium containing 2.5 M NaCl to obtain the maximum cellulase activity and immobilized on agarose or polyacrylamide or alginate. Optimal salt dependence of free and immobilized cells of Haloarcula 2TK2 was established and the effects of pH and temperature were investigated. Immobilization to Na alginate enhanced the enzymatic activity of the haloarchaeal cells when compared to free cells and other polymeric supports. From the results obtained it is reasonable to infer that decomposition of plant polymers into simpler end products does occur at high salinities and cellulase producing haloarchael cells may be potentially utilized for the treatment of hypersaline waste water to remove cellulose. PMID- 23101386 TI - Fructose 6-phosphate phosphoketolase activity in wild-type strains of Lactobacillus, isolated from the intestinal tract of pigs. AB - Phosphoketolases are key enzymes of the phosphoketolase pathway of heterofermentative lactic acid bacteria, which include lactobacilli. In heterofermentative lactobacilli xylulose 5-phosphate phosphoketolase (X5PPK) is the main enzyme of the phosphoketolase pathway. However, activity of fructose 6 phosphate phosphoketolase (F6PPK) has always been considered absent in lactic acid bacteria. In this study, the F6PPK activity was detected in 24 porcine wild type strains of Lactobacillus reuteri and Lactobacillus mucosae, but not in the Lactobacillus salivarius or in L. reuteri ATCC strains. The activity of F6PPK increased after treatment of the culture at low-pH and diminished after porcine bile-salts stress conditions in wild-type strains of L. reuteri. Colorimetric quantification at 505 nm allowed to differentiate between microbial strains with low activity and without the activity of F6PPK. Additionally, activity of F6PPK and the X5PPK gene expression levels were evaluated by real time PCR, under stress and nonstress conditions, in 3 L. reuteri strains. Although an exact correlation, between enzyme activity and gene expression was not obtained, it remains possible that the xpk gene codes for a phosphoketolase with dual substrate, at least in the analyzed strains of L. reuteri. PMID- 23101387 TI - [Effect of cultivation conditions on the adhesive activity of rhodococci towards n-hexadecane]. AB - The effect of cultivation conditions (the composition, acidity, and salinity of the cultivation medium; temperature; and the hydrodynamic conditions of cultivation) on the adhesion of actinobacteria of the genus Rhodococcus to n hexadecane has been investigated. A study performed showed that the adhesive activity of rhodococci depends on the composition of the cultivation medium and on the cultivation temperature. The possible mechanisms underlying the effect of growth conditions on the adhesion ofrhodococci to liquid hydrocarbons and involving changes in the cell lipid content or the zeta potential of cells are addressed. Rhodococcal strains displaying high adhesive activity (80-90%) at a low temperature (18 degrees C), high salinity (5.0% NaCl), and acidity (pH 6.0) of the cultivation medium have been selected as a result of the present work; these strains have a considerable potential for use in bioremediation of soil and water contaminated by hydrocarbons. PMID- 23101388 TI - Degradation of nicosulfuron by Bacillus subtilis YB1 and Aspergillus niger YF1. AB - The optimal degrading conditions for the nicosulfuron degradation by Bacillus subtilis YB1 and Aspergillus niger YF1, and site of their action on nicosulfuron were studied. The results showed that the degradation efficiency of free cells of B. subtilis YB1 and A. niger YF1 was respectively 87.9 and 98.8% in basic medium III containing 2 mg/l of nicosulfuron after inoculation with 1 ml of culture containing 2.3 x 10(7) CFU ml(-1) and incubation for 5 days at 35 degrees C. Moreover, the degradation rate of nicosulfuron by the mixture of microorganisms was much higher than for every of them taken separately in the same conditions. The mass spectrometric analysis of the products degraded by B. subtilis YB1 revealed that the sulfonylurea bridge in nicosulfuron molecule had been broken. Extracellular (EXF) and endocellular (ENF) fractions obtained from bacterium and fungus were tested for the ability to degrade nicosulfuron. The degradation efficiency of fractions extracted from B. subtilis YBI was 66.8% by EXF and 15.8% by ENF, but neither EXF nor ENF extracted from A. niger YFI had the activity of degrading nicosulfuron. PMID- 23101389 TI - [Functional analysis of the genome fragment involved in aerobic dichloromethane degradation by methylobacterium dichloromethanicum DM4]. AB - The hypothetical genes of Methylobacterium dichloromethanicum DM4, METDI 2671 (bioD2), and METDI 2680 located within the chromosomal fragment (126 kb) associated with dichloromethane (DCM) degradation have been studied. The reverse transcription polymerase chain reaction method (RT-PCR) showed the presence of transcripts of both genes in cells grown on DCM and methanol. The mobilized suicidal vector pK18mob was used to obtain knockout mutants in these genes. The BIO mutant (with an insertion in the bioD2 gene) after cultivation on methanol was characterized by a lower growth rate on DCM compared to the wild-type DM4 strain, while the MT mutant (with an insertion in the METDI 2680 gene) did not differ from the initial strain in respect of these characteristics. The results demonstrate the involvement of the bioD2 gene in biotin biosynthesis coupled with DCM degradation. PMID- 23101390 TI - Cloning and bioinformatic analysis of an acidophilic beta-mannanase gene, Anman5A, from Aspergillus niger LW-1. AB - Using 3' and 5' rapid amplification of cDNA ends (RACE) techniques, the full length cDNA sequence of the AnmanSA, a gene that encodes an acidophilic beta mannanase of Aspergillus niger LW-1 (abbreviated to AnMan5A), was identified from the total RNA. The cDNA sequence was 1417 bp in length, harboring 5'- and 3' untranslated regions, as well as an open reading frame (ORF) which encodes a 21 aa signal peptide, a 17-aa propeptide and a 345-aa mature peptide. Based on the topology of the phylogenetic tree of beta3-mannanases from glycoside hydrolase (GH) family 5, the AnMan5A belongs to the subfamily 7 of the GH family 5. Its 3D structure was modeled by the bitemplate-based method using both MODELLER 9.9 and SALIGN programs, based on the known beta-mannanase crystal structures of Trichoderma reesei (1QNO) and Lycopersicon esculentum (1RH9) from the GH family 5. In addition, the complete DNA sequence of the Anman5A was amplified from the genomic DNA using the pUCm-T vector-mediated PCR and conventional PCR methods. The DNA sequence was 1825 bp in length, containing a 5'-flanking regulatory region, 2 introns and 3 exons when compared with the full-length cDNA. PMID- 23101391 TI - Production of poly(3-hydroxybutyrate-co-3-hydroxyvalerate) depolymerase from Aspergillus sp. NA-25. AB - Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) degrading thermophilic fungus was isolated from soil sample collected from waste disposal site, Islamabad, Pakistan. It was able to grow efficiently on a medium containing PHBV as a sole source of carbon and has been identified as Aspergillus sp. NA-25 by 18S rRNA. Using 9% of inoculum maximum production of PHBV depolymerase was observed at 45 degrees C, pH 7.0 in the presence of 0.2% lactose as an additional carbon source. PHBV depolymerase was purified by precipitation with 80% ammonium sulfate and gel filtration chromatography on Sephadex G-75. The four enzyme forms obtained after gel filtration were analyzed on SDS-PAGE and their molecular weights (36, 68, 72 and 90 kDa) were determined. They were characterized on the basis of effect of different temperatures, pH, metal ions and different reagents on the PHBV activity and stability. It is obvious that the fungal strain Aspergillus sp. NA 25 is capable of degrading PHBV with the help of different types of depolymerases. PMID- 23101392 TI - [Aspergillus ochraceus myxomycetes produce extracellular proteinases--protein C activators of blood plasma]. AB - Natural isolates of Aspergillus ochraceus myxomycetes from soil and plant remains from various regions have been screened. The isolated strains were characterized by similar cultural and morphological features and an identical nucleotide sequence in the ITS1-5,8S-ITS2 region of rDNA. The ability of the extracellular proteinases of A. ochraceus myxomycetes to activate protein C of blood plasma has been established. Differences are revealed in the accumulation of proteinases activating protein C and proteinases with thrombin- and plasmin-like activities in the growth dynamics of producers. PMID- 23101393 TI - [Development of complex enzymatic preparations of pactinases and celulases for sugar beet marc digestion]. AB - Complex enzymatic preparations demonstrating activities homologous to pectinlyase A and heterologous to endo-1,4-beta-glucanase from Penicilliumverruculosum and beta-glycosidase from Aspergillusniger have been obtained on the basis of recombinant strains of the fungus Penicilliumcanescens. Two approaches were utilized: development of an enzymatic preparation on the basis of a new strain, which produced all three enzymes, and development of an enzymatic preparation via combined cultivation of three strains, each of which produced one of the enzymes. PMID- 23101394 TI - [Induction of heat resistance in wheat coleoptiles by salicylic and succinic acids: connection of the effect with the generation and neutralization of active oxygen forms]. AB - The influence of salicylic (SaA) and succinic (SuA) acids on the generation of active oxygen forms (AOFs) and the heat resistance of wheat (Triticum aestivum L.) coleoptiles has been studied. The treatment of coleoptiles with 10 microM SaA or SuA results in the accumulation of hydrogen peroxide and enhanced formation of a superoxide anion radical. This effect is partially suppressed by both alpha naphthol (the NADPH oxidase inhibitor) and salicylhydroxamic acid (peroxidase inhibitor). SaA and SuA cause an increase in the activity of antioxidant enzymes, such as superoxide dismutase, catalase, and soluble peroxidase, and improve the heat resistance ofcoleoptiles. Antioxidant ionol and compounds, which inhibit the NADPH oxidase and peroxidase, significantly reduce the positive influence of SaA and SuA on the heat resistance of wheat coleoptiles. AOFs are considered to be intermediates for heat resistance induction in coleoptiles, treated with SaA and SuA; enhanced AOF generation can be caused by an increased activity of the NADPH oxidase and peroxidase. PMID- 23101395 TI - [Effect of conditions of monoclonal antibody adsorption on antigen-binding activity]. AB - The dependence of the antigen-binding activity of immobilized antibodies on pH of a saturating buffer has been investigated. We analyzed 28 monoclonal antibodies (MCAs) produced by various hybridomas to three virus antigens, i.e., the nuclear p23 protein of hepatitis C virus (C core protein p23), p24 protein of HIV 1, and the surface antigen of hepatitis B virus (HBsAg). Antibodies were adsorbed on the surfaces of immune plates in acidic (pH 2.8), neutral (pH 7.5), and alkaline (pH 9.5) buffers. The binding of labeled antigens, i.e., biotinylated or conjugated with horseradish peroxidase, with immobilized antigens was tested. It was shown that 10 out of 28 analyzed MCAs (36%) considerably better preserved their antigen binding activity if their passive adsorption was carried out on the surface of polystyrene plates in an acidic buffer (pH 2.8). This approach allowed constructing a highly sensitive sandwich method for HBsAg assay with a minimal reliably determined antigen concentration of 0.013-0.017 ng/ml. The described approach may be recommended for the optimization of sandwich methods and solid phase competitive methods. PMID- 23101396 TI - [Comparison of the antiradical activity of ionol, components of fresh ginger, and its extracts]. AB - The antiradical properties of three samples of ginger (Zingiber officinale R.) juice from fresh rhizome, essential oil, and extracts (oleoresin)-were studied and compared with the properties of synthetic antioxidant ionol (butylatedhydroxy toluene, BHT). Reaction antioxidants with stable free 2,2-diphenyl-1 picrylhydrozyl radicals were used as model systems. DPPH equivalents per gram of ginger sample, EC50, and antiradical efficiency (AE) were determined. The EC50 and AE values for ginger oleoresin and BHT were similar. They were the same as those of highly active natural antioxidants, and the values for essential oil and ginger juice were lower by two orders of magnitude. On the base of kinetic parameters, the ginger samples may belong to antiradical compounds with prolonged action. PMID- 23101397 TI - [Receptor elements for biosensors in two ways of methylotrophic yeast immobilization]. AB - Receptor elements for biosensors based on Hansenula polymorpha NCYC 495 In yeast cells for ethanol assay were developed using two ways of cell immobilization, i.e., physical adsorption on a glass fiber membrane and covalent binding on a modified nitrocellulose membrane. The linear diapason of ethanol assays for a biosensor based on yeast cells adsorbed on glass fiber was 0.05-1.18; for a biosensor based on yeasts immobilized on a nitrocellulose membrane, 0.2-1.53 mM. Receptor elements based on sorbed cells possessed 2.5 times higher long-term stability. The time response was 1.5 times less for cells immobilized using DEAE dextran and benzochinone. The results of ethyl alcohol assays using biosensors based on cells immobilized via adsorption and covalent binding, as well as using the standard areometric method, had high correlation coefficients (0.998 and 0.997, respectively, for the two ways of immobilization). The results indicate the possibility to consider the described models of receptor elements for biosensors as prototypes for experimental samples for practical use. PMID- 23101398 TI - [The increase of variability in animal behavior due to autocorrelations]. AB - We consider a simple kind of variability in animal instinctive behavior. It is comprised of switching between alternative actions. It consists also of variations in intensity of consecutive actions. This variability is not related to ambient stimuli or needs of organism--it is spontaneous and generated by nervous system itself. At the same time, the variability is not completely random. For example, autocorrelations are observed in variations of animal's consecutive actions. An interaction of autocorrelations with random influences results in an increase of behavioral variability. The increased variability is a property of mechanism controlling instinctive behavior. This does mean that an instinctive behavior is not entirely preprogrammed. One could assert that the instinct is a mechanism for generation of behavioral variations that are not preprogrammed. PMID- 23101399 TI - [Interrelationship between the level of chromosomal aberrations and demographic parameters]. AB - The interrelationship between the level of chromosomal abnormalities and demographic parameters has been studied using individuals from the natural population of bank vole (Clethrionomys glareolus) from a locality within the Middle Ural, of the southern taiga subzone (57 degrees 15' N, 58 degrees 44' E). Routine methods of cytogenetic analysis are applied to examination of variability in the frequency of structural chromosomal aberrations, gaps and changes in number of chromosomes in bank voles' bone marrow cells. Influence of demographic parameters, namely population density, age, sex, and reproductive status, on cytogenetic characteristics is estimated with the help of log-linear analysis. It is shown that population increasing in size leads to a decrease in the share of individuals characterized by higher frequency of cells with structural chromosomal abnormalities and gaps. This outcome appears to be in concordance with the notion of less amount of mutations in somatic cells to be favorable for organisms' survival rate. Such a pattern could emerge as a consequence of natural selection causing reorganization of genetic structure of a population. Alternatively, these changes may be a by-product of other processes accompanying population dynamics. High population density results in an increase of a share of individuals among young-of-the-years with higher frequency of cells subjected to abnormalities in chromosome number. Similar effects are possible as a result of asymmetric interference competition of adults in relation to younglings. Our data indicate that the share of animals having higher frequency of somatic cells with structual chromosomal aberrations and numerical chromosomal abnormalities is essentially increased by age, which is in accordance to theoretical concepts and experimental data. Gender and participation in reproduction do not render significant influence on the level of cytogenetic instability. PMID- 23101400 TI - [Taxonomic theory for non-classical systematics]. AB - Outlined briefly are basic principles of construing general taxonomic theory for biological systematics considered in the context of non-classical scientific paradigm. The necessity of such kind of theory is substantiated, and some key points of its elaboration are exposed: its interpretation as a framework concept for the partial taxonomic theories in various schools of systematics; elaboration of idea of cognitive situation including three interrelated components, namely subject, object, and epistemic ones; its construing as a content-wisely interpreted quasi-axiomatics, with strong structuring of its conceptual space including demarcation between axioms and inferring rules; its construing as a "conceptual pyramid" of concepts of various levels of generality; inclusion of a basic model into definition of the taxonomic system (classification) regulating its content. Two problems are indicated as fundamental: definition of taxonomic diversity as a subject domain for the systematics as a whole; definition of onto epistemological status of taxonomic system (classification) in general and of taxa in particular. PMID- 23101401 TI - [Contribution of syntaxonomy to the study of vegetation dynamics]. AB - Of late decades, numerous studies on vegetation dynamics have been carried out and the spectrum of studied objects extended. However, syntaxonomy, while is capable to reveal patterns in vegetation changes, is virtually not used in analysis of succession. Prospects of syntaxonomy application to the study of vegetation dynamics are demonstrated by the example of succession analyses of pasture digression, vegetation changes under influence of recreation, progressive succession at the place of deserted settlements. The special role played by the analysis of syntaxonomic spectre of serial plant communities is discussed. The analysis makes it possible to estimate the serial status of communities by the ratio in their floral composition of species from cenofloras of classes that represent different serial stages of vegetation. PMID- 23101402 TI - [Autocenosis and democenosis as symbiotic systems and biological notions]. AB - Contemporary data and concepts about the role of symbiogenesis in organization, functioning, and evolution of biosystems at different organizational levels allow to contemplate the forming of a symbiotic approach to solving theoretical and practical problems in biology. According to the author's concept, at the organismic level, the basic unit should be considered as not being an individual, but autocenosis, i.e., a self-regulating system of "host-symbionts" type. Then, democenosis, being a system of autocenoses, would correspond to the population level, and speciocenosis, being a system of democenoses, would correspond to the species level. Within democenoses, not individuals, but autocenoses are subject to natural selection. Different links in trophic chains and webs are not "individuals" or "populations" but auto- and democenoses. However, symbiotic approach does not leave out the population paradigm and should develop in parallel with it. Novel concepts in the field of symbiology are indicative of this point of view. PMID- 23101403 TI - [Mechanisms of reproductive behavior in humans: olfactory markers of males' attractiveness]. AB - The present work represents a pilot study in the area of olfactory communication in humans. On the basis of experiments, it is demonstrated that women are able to detect, by means of smell, a number of morphological and psychological characteristics of men. The samples of sweat from 29 young men were collected, as well as anthropometry measurements (interpupillary distance, height and width of the lower jaw, and so forth) and behavioral characteristics (personality questionnaire NEO, risk-taking questionnaire, Sandra Bem masculinity and femininity indices, a self-rating on aggression Buss-Perry questionnaire). Data on hormonal status of all males were collected (testosterone and cortisol). It is demonstrated that women are able to detect both morphological (masculinity, physical health) and psychological characteristics (aggression, risk taking, neuroticism, extraversion, cooperation, etc.). The smell of men rating high on cortisol is estimated as the least attractive. On the contrary, the sweat of men with combination of high level of testosterone and low level of cortisol is considered the most attractive. Females rating of male's smell differed depending on a phase of a monthly cycle. The data obtained are discussed in the light of evolutionary basis of permanent partner choice. PMID- 23101404 TI - [Coats of preimplantation mammalian embryos as a target of reproductive technologies]. AB - The structure and function of the mammalian oocyte and preimplantation embryo coverings are described in this review. The integrity of embryonic coverings is the main prerequisite for the success of such technology as preimplantation embryo freezing and, especially, for successful rederivation. On the other hand, results of in vitro fertilization and, sometimes, the results of embryo freezing are improved after perforation of the oocyte/embryonic coverings. Modern reproductive technologies focusing on oocyte/embryonic coverings, such as preimplantation embryo freezing/cryopreservation, in vitro fertilization, intracytoplasmic sperm injection, assisted hatching, immunocontraception, and rederivation, are reviewed. Application of these technologies to different mammalian species is discussed with a special emphasis on the oocytes/preimplantation embryos coverings. PMID- 23101405 TI - [Developmental stability of a leaf of Pisum sativum L. under the influence of formaldehyde in a wide range of doses]. AB - The influence of formaldehyde in a wide range of doses on the stability of development of the third leaf of pea (Pisum sativum L.) was studied. The developmental stability of the leaf was assessed by the change in the value of the directional asymmetry of the right and left leaflets caused by the fluctuating asymmetry of these morphological structures. When subjected to a toxic agent, the studied parameter exhibited a paradoxical effect. In minimum studied concentrations, formaldehyde disturbed stability of leaf development, which was manifested in an increase in the asymmetry of the right and left leaflets. At medium concentrations of the toxicant, the asymmetry was less than the control level, which indicated an increase in the developmental stability of the pea leaf. Maximum studied concentrations of formaldehyde, close to sublethal, again reduced the stability of development of the pea leaf and led to an increase in the asymmetry of its leaflets compared with the controls. PMID- 23101406 TI - [Study of intracellular localization of the proteolytic enzyme complex and its protein inhibitors in bombyx grain]. AB - Intracellular localization of serine, cysteine and aspartate proteases, as well as their protein inhibitors, in bombyx grain in the postdiapause period of embryogenesis has been studied. Proteolytic activity of aspartate and cysteine proteases was found in lysosomal, mitochondrial, and nuclear fractions of grains. Serine protease activity was not observed in subcellular fractions of grains of the fourth day of postdiapause development. It has been shown that activities of protein inhibitors and certain peptide hydrolases in subcellular fractions provide consistent functioning and fine regulation of the proteolytic enzyme complex. PMID- 23101407 TI - [On some features of embryonic development and metamorphosis of Aurelia aurita (Cindaria, Scyphozoa)]. AB - Aurelia aurita is a cosmopolite species of scyphomedusae. Its major structural patterns and life cycle are well investigated. This work provides a detailed study on development and structure of the planula in A. aurita until it completes its metamorphosis. Lifetime observations and histological study performed during the settlement and metamorphosis of the planulae demonstrated that the inner manibrium linen of primary polyp (gastroderm) develops from the ectoderm of the planula posterior end. The spatial and temporal dynamics of serotonergic cells from the early embryonic stages until the formation of the primary polyp were studied for the first time. In addition, the distribution oftyrosinated tubulin and neuropeptide RFamide at different stages ofA. aurita development were studied. PMID- 23101408 TI - [Growth and development peculiarities of testicles in inbred mice lines PT and CBA/Lac]. AB - The goal of this study is to perform a comparative genetic investigation of testicle development during the postpubescence period (from days 70 to 90 of life) in the inbred mice lines PT and CBA/Lac. Interlinear differences in the body and testicular weight, serum testosterone concentration, number of epididymal spermatozoa, area of testicular epithelium, semeniferous tubule lumen, and insulae of Leydig cells were analyzed. It was found that the morphological and histomorphometric parameters of testicles in males from the PT line compared to the males of the CBA/Lac line did not reach a definitive stage with the end of the postpubescence period and kept on developing until day 90 of life. Therefore, genetic differences remain in the postpubertal testicular development of laboratory mice. PMID- 23101409 TI - [Reproductive success of males of the ICR outbred line during propagation against the background of antigenic stimulation]. AB - Diversity of viruses, bacteria, microscopic fungi, and endo- and ectoparasites is an inevitable environmental factor that influences the host reproduction and that is determined not only by negative effects of infectious diseases but also by activation of protective mechanisms, which provide a confrontation to the pressure of parasites. In the present work, hemocyanin was injected into males of the ICR outbred line in order to study reproductive consequences of antigenic stimulation of males. Intact females were added to control and antigen-stimulated males at the initial stage of antibody formation. During 6 days of combined keeping, a significantly greater amount of ovulated egg cells and living embryos were registered in the females added to males that were injected with hemocyanin compared with that theoretically expected for equal reproductive yield. Females covered by antigen-stimulated males bred larger embryos compared with those in the control. Indices of female fertility depended on prevalence of cellular (Th1) or humoral (Th2) immune responses in antigen-stimulated males. Shift of Th1/Th2 balance resulted in higher preimplantation embryonic losses in females covered by males with a prevalence of cellular immune response; however, they bred larger embryos. Thus, it was established that activation of the immune system in males does not influence their reproductive abilities. This allows us, on the one hand, to explain the contribution of protective reactions of the organism in the increase in fertility of the mammals that inhabit territories with high specific abundance of parasites; on the other hand, it demonstrates new ways of the management of the reproduction of animals bred under human control. PMID- 23101410 TI - [Recovery of genomic regions affecting lawc/Trf2 expression during Drosophila melanogaster development]. AB - Leg-arista-wing complex (lawc) mutations affect the expression of D. melanogaster proteins homologous to a human basic transcription factor, TBP (TATA-box binding protein) Related Factor 2 (TRF2), specifically involved in development. The paper for the first time reports the application of genetic screens for various genomic regions to recover genetic interactions between the lawc/Trf2 gene and other genes and genetic loci by using Deficiency Kit lines with small deletions in total providing maximal coverage of the genome. The deletion mapping allowed us to recover 26 genomic regions that, when deleted, are lethal or modify the mutant phenotype due to a decreased TRF2 expression level. These deletions could be useful in identifying both novel TRF2 targets and its positive and negative regulators. There is evidence that TRF2 can be a component of high molecular DNA Replication-related Element Factor (DREF)- and Nucleosome Remodeling Factor (NURF)-containing complexes. The present study for the first time reports new genetic interactions of lawc/Trf2 with genes that encode basic and specific transcription factors. In most cases, if mutated, those genes caused developmental defects or death of progeny. However, in the case of the e(y) 1 gene, coding for the Taf9 transcription factor, only the male reproductive system is impaired when the lawc/Trf2 phenotype is associated with a e(y)l gene mutation. Mutant lawc(p1)e(y)1(u1) males become infertile due to primary spermatocyte maturation arrest and impaired premeiotic chromosome condensation in germ cells. PMID- 23101411 TI - In remembrance of the victims of Nazi medicine Nuremberg, May 2012. PMID- 23101412 TI - Comment on the German Medical Association declaratiion. PMID- 23101413 TI - Reflections on the Nuremberg declaration of the German medical assembly. PMID- 23101414 TI - Quo vadis, bioethics. AB - The recent paper by Giubilini and Minerva suggesting the ethical permissibility of infanticide of normal newborns, calling it "postbirth abortion," represents a dangerous deterioration of generally accepted ethical norms. Their proposal represents a clear example of the so-called slippery slope and we caution against abandoning the age-old traditions of the medical profession assigning intrinsic value to human life from birth. This article discusses the proposed concept, makes comparisons with earlier similar trends of thought, and highlights the dangers of the proposal. PMID- 23101415 TI - Compliance for genetic screening in the Arab population in Israel. AB - BACKGROUND: Genetic screening tests for cystic fibrosis (CF), fragile X (FRAX) and spinal muscular atrophy (SMA) have been offered to the entire Arab population of Israel in the last few years. Since 2008, screening for CF is provided free of charge, but for FRAX and SMA the screening is privately funded with partial coverage by complementary health insurance programs. OBJECTIVES: To assess the compliance of Arab couples with regard to genetic screening tests, and the factors that affect their decisions. METHODS: We analyzed compliance for genetic screening tests at the Emek Medical Center Genetic Institute, and in outreach clinics in four Arab villages. We enquired about the reasons individuals gave for deciding not to undergo testing. We also assessed the compliance of these individuals for the triple test (a screening test for Down syndrome). RESULTS: Of the 167 individuals included in our study, 24 (14%) decided not to be tested at all. Of the 143 (86%) who decided to be tested, 109 were tested for CF only (65%) and 34 (20%) for SMA and FRAX (as well as CF). The compliance rate for the triple test was 87%. Technical reasons, mainly financial issues, were the most significant factor for not undergoing all three tests. CONCLUSIONS: The compliance of the Arab community for genetic testing for SMA and FRAX is extremely low. We believe that this low utilization of screening is due to economic reasons, especiallywhen a complementary health plan has not been acquired, and largely reflects the perception that these tests are less important since they are privately funded. PMID- 23101416 TI - Optical coherence tomography characteristics of eyes with acute anterior uveitis. AB - BACKGROUND: Acute, as opposed to chronic, anterior uveitis is rarely associated with macular or optic nerve edema. Nevertheless, mild changes may not be visible on examination. OBJECTIVE: To implement non-invasive ocular coherence tomography (OCT) for obtaining quantitative and qualitative data in the assessment of changes in macular morphology and peripapillary retinal nerve fiber layers in eyes with acute anterior uveitis. METHODS: This retrospective case-control study was conducted in patients with unilateral acute anterior uveitis lasting for up to one month. Patients with evidence of other ocular disease or who had undergone intraocular surgery were excluded. We reviewed the charts of 14 consecutive patients who were diagnosed with acute unilateral anterior uveitis between 2007 and 2008 at the Tel Aviv Medical Center. Data on demographic details, ophthalmic examination, macular thickness and peripapillary retinal nerve fiber layer (RNFL) thickness (as demonstrated by OCT) were retrieved. Retinal and RNFL thickness was compared between the healthy fellow eye (control) and the uveitic eye in the central and four perifoveal quadrant regions, and RNFL thickness was compared in the mean and four quadrant values by Student's t-test. RESULTS: We evaluated 28 eyes of7 males and 7 females (mean age 37.7 years, range 20-65). The diagnoses were: idiopathic in five patients, ankylosing spondylitis in five, Crohn's disease in one patient and reactive arthritis in one. Nine patients were HLA-B27 positive. The retina and the peripapillary NFL in each area were thicker in the uveitic eyes compared to the controls. The difference was statistically significant. There was no correlation between the differences in OCT values and patients' demographic characteristics. CONCLUSIONS: OCT demonstrated that eyes with acute anterior uveitis had thicker maculae and thicker peripapillary RNFL than controls. This finding suggests that even milder anterior uveitis may be associated with some degree of posterior segment manifestations. PMID- 23101417 TI - Acute meningitis among infants and toddlers with febrile seizures: time for a reappraisal of the value of a lumbar puncture. AB - BACKGROUND: Since clinical signs of meningeal irritation in infants may be absent or misleading, the American Academy of Pediatrics in 1996 recommended that a lumbar puncture be performed in young children following a febrile seizure. Recent evidence supports a conservative approach in children who do not look ill at the time of the physician's assessment. Moreover, seizures as the presenting or sole symptom of bacterial meningitis are very rare. OBJECTIVES: To assess physicians' compliance with the Academy's recommendations and to determine the incidence of meningitis among febrile seizure patients, including those who did not undergo the puncture. METHODS: We conducted a retrospective analysis of the number of punctures obtained in febrile seizure patients aged 6-24 months, focusing on the clinician's indications for performing the procedure and on the clinical course of children who did not undergo the puncture. RESULTS: Among 278 patients (84% simple febrile seizure), 52 (18.7%) underwent the procedure. It was performed in 38% of 45 complex febrile seizure cases and in 48% of 91 infants younger than 12 months of age. Aseptic meningitis occurred in two infants, both with post-ictal apathy. Bacterial meningitis was not found and in none of the patients who did not undergo the puncture was meningitis later diagnosed. CONCLUSIONS: Compliance with the Academy's recommendations was low, as emergency room physicians based their decision whether to obtain a lumbar puncture solely on clinical grounds. No case of bacterial meningitis was detected among 278 young children with a febrile seizure, including those who did not undergo the puncture. PMID- 23101418 TI - Breast-conserving surgery and intraoperative electron radiotherapy in early breast cancer: experience at the Rambam Health Care Campus. AB - BACKGROUND: Local recurrences after breast-conserving surgery occur mostly at the site of the primary carcinoma. The main objective of postoperative radiotherapy is sterilization of residual cancer cells. Whole-breast radiotherapy is the standard of care, but its utility has recently been challenged in favor of radiotherapy limited to the area at highest risk of recurrence. Intraoperative electron radiotherapy (IOeRT) is an innovative technique for accelerated partial breast irradiation (APBI) that is applied to selected patients affected by early breast cancer. OBJECTIVES: To describe our experience with IOeRT at the Rambam Health Care Campus in Haifa since we began utilizing this modality in 2006. METHODS: From April 2006 to September 2010, 31 patients affected by unifocal invasive duct breast carcinoma < or = 2 cm diameter received wide local resection followed by intraoperative radiotherapy with electrons. Patients were evaluated for early and late complications, and other events, 1 month after surgery and every 3 months thereafter for the duration of the first 2 years. RESULTS: After a mean follow-up of 36 months, seven patients developed mild breast fibrosis and three suffered from mild postoperative infection. Rib fractures were observed in four patients before routine lead shielding was initiated. Additional whole breast irradiation was given to four patients. None of the patients developed local recurrences or other ipsilateral cancers. Similarly, no contralateral cancers or distant metastases were observed. CONCLUSIONS: Intraoperative electron radiotherapy may be an alternative to external beam radiation therapy in an appropriate selected group of early-stage breast cancer patients. However, long term results of clinical trials are required to better evaluate the indications and utility of this technique in the management of breast cancer. PMID- 23101419 TI - Fatigue as a first-time presenting symptom: management by family doctors and one year follow-up. AB - BACKGROUND: Fatigue is a common complaint in primary care and has a broad differential diagnosis, making the approach complex and often ineffective. OBJECTIVES: To follow the course of adults without a significant known background disease who complain of fatigue for the first time, and to characterize the family physician's approach. METHODS: The study population comprised a random sample of 299 patients aged 18-45 who presented with fatigue as a first-time single complaint to their family physician. Excluded were patients with chronic diseases or states that may include signs of fatigue. We analyzed the index encounter data, the diagnostic and laboratory tests, the medications prescribed and the one year clinical outcome. RESULTS: Seventy percent were women, average age 30.5 years, and 69% had no known co-morbidities; 57% of the patients were physically examined at the first visit and most (78.6%) were sent for laboratory analysis. Five percent of laboratory tests were positive. Eighty patients (26.8%) were given a specific diagnosis, with the leading diagnoses being anemia and infectious diseases; 18.7% were given sick leave at the first visit. Fatigue was more common in early summer. CONCLUSIONS: The majority of young healthy patients complaining of fatigue are not diagnosed with an organic physiological disorder. Many of the study patients were sent for laboratory tests but in most cases these tests were not contributory to the diagnosis or management. It seems likely that the most efficient strategy would be watchful follow-up with a minimum of testing. PMID- 23101420 TI - Continued progression of asbestos-related respiratory disease after more than 15 years of non-exposure. AB - BACKGROUND: Most studies on asbestos-related diseases describe the associations between exposure and disease and the factors influencing that association. It is recognized that there is a long latency period between exposure and disease, but the health status of affected individuals after long-term non-exposure is uncertain. OBJECTIVES: To describe the changes in pulmonary function tests (PFTs) and computed tomographic imaging of the thorax over a 15 year period after cessation of exposure to asbestos in a cohort of Israeli power plant workers. METHODS: Israeli power plant workers whose PFTs and thoracic CT imaging between 1993 and 1998 revealed asbestos-related disease underwent a second clinical, functional and imaging evaluation up to 15 years later. The two sets of results were compared. RESULTS: Of the original cohort of 59 males, 35 were still alive and 18 of them agreed to take part in the current study. The mean length of their exposure was 30 +/- 10.06 years (range 7-43 years). Comparison of the initial and follow-up examination findings revealed a significant increase in calcification of the pleural plaques (from 37% to 66%, P = 0.008) and a deterioration in PFT results (P= 0.04). Of the 24 men who died, malignant disease was the cause of death in 53%, mostly in sites other than the respiratory system. CONCLUSIONS: PFTs declined and CT findings worsened in subjects who were formerly exposed to asbestos and had not been exposed to it for over a decade. Continued monitoring of individuals exposed to asbestos, even decades after the cessation of exposure, is recommended. PMID- 23101421 TI - Is it tiring to deal with fatigue? PMID- 23101422 TI - The beneficial effects of intravenous immunoglobulin for antineutrophil cytoplasmic antibody-positive vasculitis. PMID- 23101423 TI - The cardiorenal syndrome: a mutual approach to concomitant cardiac and renal failure. AB - Heart failure (HF) accompanied by renal failure, termed cardiorenal syndrome (CRS), encompasses both the development and worsening of renal insufficiency secondary to HF as well as the harmful effects of impaired renal function on the cardiovascular system, and remains a universalclinical challenge. CRS was recently classified into subtypes depending on the etiologic and chronologic interactions between cardiac and renal dysfunctions. The mechanisms underlying the CRS are multifactorial, including hemodynamic alterations, neurohormonal effects, and inflammatory components. However, despite enhanced understanding and awareness of CRS, further elucidation of the mechanisms involved and the appropriate treatment approaches are clearly warranted. CRS is a difficult condition to manage, as treatment to relieve congestive symptoms of HF is limited by a further decline in renal functions, itself a major independent predictor of long-term cardiac morbidity. In order to perform a proper clinical investigation and implement appropriate treatmentthat will minimize subsequent progression of heart and kidney injury, a comprehensive approach to these two pathologies is crucial. In the present review we discuss current theories behind the mechanistic evolution of the CRS as well as therapeutic issues regarding this multifaceted condition. PMID- 23101424 TI - Drug reaction with eosinophilia and systemic symptoms (DRESS): a complex interaction of drugs, viruses and the immune system. AB - The DRESS syndrome (drug reaction with eosinophilia and systemic symptoms), also known as DIHS (drug-induced hypersensitivity syndrome), presents clinically as an extensive mucocutaneous rash, accompanied by fever, lymphadenopathy, hepatitis, hematologic abnormalities with eosinophilia and atypical lymphocytes, and may involve other organs with eosinophilic infiltration, producing damage in several systems, especially kidney, heart, lungs, and pancreas. The pathogenesis is related to specific drugs (especially the aromatic anticonvulsants), altered immune response, sequential reactivation of herpes virus, and association with some HLA alleles. Glucocorticoids are the basis for the treatment of the syndrome, which may be given with intravenous immunoglobulin and, in selected cases, ganciclovir. This article reviews current concepts regarding the interaction of drugs, viruses and immune responses during this complex adverse drug reaction. PMID- 23101425 TI - Churg-Strauss syndrome with neurologic manifestations: successful treatment with intravenous immunoglobulins. PMID- 23101426 TI - Clostridium difficile infection and partial membrane cofactor protein (CD46) deficiency. PMID- 23101427 TI - Gastrointestinal stromal tumor of the ampulla of Vater. PMID- 23101428 TI - Optimal time needed for weaning of mechanical ventilation in COPD: still looking for the lost golden hour. PMID- 23101429 TI - Direct observation of beamed Raman scattering. AB - Appropriately designed surface plasmon nanostructures enable the emission patterns of surface-enhanced Raman scattering to be modified to facilitate efficient collection, an effect sometimes termed "beamed Raman scattering". Here, we demonstrate the direct and unambiguous observation of this phenomenon by separating the Raman emission pattern from the luminescent background using energy momentum spectroscopy. We observe beamed Raman scattering from two types of optical antennas: the first are Yagi-Uda optical antennas, and the second are optical dimer antennas formed above a plasmonic substrate consisting of a gold film integrated with a one-dimensional array of gold stripes. For both antenna types, the emission patterns from different Raman lines are simultaneously measured. For the second antenna type, the emission patterns show signatures stemming from the bandstructure of the plasmonic substrate. PMID- 23101430 TI - Two-layer architecture using atom transfer radical polymerization for enhanced sensing and detection in complex media. AB - A novel, two-layer hierarchical architecture based on surface-initiated atom transfer radical polymerization was investigated. It combines a thin and highly dense first layer, for nonfouling properties, with a loose second layer for high immobilization levels of active biomolecules. Sodium azide treatment, to reduce the concentration of macroinitiators on the first layer for reinitiation, and by controlling the polydispersity allowed one to achieve three polymer architectures with low, moderate, or high azide substitution. Moderate substitution enabled the highest immobilization levels with a nonfouling background. Integration with dual functional zwitterionic poly(carboxybetaine) made this platform suitable for applications in undiluted complex media such as blood. It was demonstrated via a surface plasmon resonance biosensor that antigen accessibility and antibody loading were greatly improved. These results indicate the two-layer strategy as a generic concept suitable for applications from diagnostics to medical coatings in order to maximize and minimize specific and nonspecific responses, respectively. PMID- 23101431 TI - Prognostic value of semi-quantitative bacteruria counts in the diagnosis of group B streptococcus urinary tract infection: a 4-year retrospective study in adult patients. AB - BACKGROUND: Semi-quantitative bacteruria counts (s-QBC) are important in the diagnosis of urinary tract infection (UTI) due to most uropathogens. The prognostic value of s-QBC for diagnosis of UTI due to group B streptococcus (GBS) is unknown. In this study, we assessed the value of s-QBC for differentiating acute GBS UTI from asymptomatic bacteruria (ABU), independent of other potential prognostic indicators. METHODS: Medical record review and urinalysis (UA) values for 1593 patients who had urinary GBS isolated (103 to >=105 CFU/ml) during a four-year period were analyzed using binary logistic regression to determine the predictive values of s-QBC, age, and gender for infection category (acute UTI, ABU) based on the clinical diagnosis. RESULTS: s-QBC alone had a strong predictive value for infection category but only for ABU. Multivariate logistic regression showed similar predictive power of s-QBC for infection category using age as a co-predictor, which was also independently associated with infection category. Typical s-QBC cut-off values that are commonly used in diagnostic settings had no significant power in predicting infection category. Among other UA measures, proteinuria and hematuria were significantly associated with acute infection. CONCLUSIONS: Together, these data show that s-QBC is not useful in the differential diagnosis of GBS UTI. Among the patients in this study, age was an equally effective prognostic indicator compared to s-QBC for identifying high- and low-risk patients for acute GBS UTI. Collectively, these findings indicate that age-based associations may be equally as useful as s-QBC for predicting infection category in the setting of adult patients with GBS-positive urine cultures. PMID- 23101432 TI - Gold nanorods for ovarian cancer detection with photoacoustic imaging and resection guidance via Raman imaging in living mice. AB - Improved imaging approaches are needed for ovarian cancer screening, diagnosis, staging, and resection guidance. Here, we propose a combined photoacoustic (PA)/Raman approach using gold nanorods (GNRs) as a passively targeted molecular imaging agent. GNRs with three different aspect ratios were studied. Those with an aspect ratio of 3.5 were selected for their highest ex vivo and in vivo PA signal and used to image subcutaneous xenografts of the 2008, HEY, and SKOV3 ovarian cancer cell lines in living mice. Maximum PA signal was observed within 3 h for all three lines tested and increased signal persisted for at least two days postadministration. There was a linear relationship (R(2) = 0.95) between the PA signal and the concentration of injected molecular imaging agent with a calculated limit of detection of 0.40 nM GNRs in the 2008 cell line. The same molecular imaging agent could be used for clear visualization of the margin between tumor and normal tissue and tumor debulking via surface-enhanced Raman spectroscopy (SERS) imaging. Finally, we validated the imaging findings with biodistribution data and elemental analysis. To the best of our knowledge, this is the first report of in vivo imaging of ovarian cancer tumors with a photoacoustic and Raman imaging agent. PMID- 23101434 TI - Growth trends in boys and girls (10-17 years-old) from autonomous region of Madeira, Portugal between 1996-1998 and 2007-2009. AB - BACKGROUND: Growth trends have never been studied in adolescents of the Autonomous Region of Madeira, Portugal. AIMS: To analyse growth trends in weight, height, body mass index (BMI), waist circumference (WC), mid-upper arm circumference (MUAC) and triceps skin-fold thickness (TST) of adolescents (10-17 years old) of the Autonomous Region of Madeira between 1996-1998 and 2007-2009. SUBJECTS AND METHODS: A cross-sectional study was carried out between 2007-2009, including 4314 adolescents, 2237 girls and 2077 boys (10-17 years old). To study secular growth trends, data were compared with a sample from 1996-1998, comparing the means for each anthropometric variable by age and sex using the independent sample t-test. RESULTS: An average increase was found in weight of 5.8 kg in boys and 6.3 kg in girls; in height of 3.0 cm in boys and 3.7 cm in girls; in BMI of 1.5 kg/m(2) in boys and 1.7 kg/m(2) in girls; in WC a difference of 5.6 cm and 4.9 cm for boys and girls, respectively, and for MUAC a difference of 2.7 cm in boys and 2.0 cm in girls. No differences were found in TST in boys, but in girls an increase of 1.2 mm was observed. CONCLUSIONS: A general increase in anthropometric measurements, more marked in weight, BMI, WC and MUAC and at younger ages, was observed. PMID- 23101437 TI - Dynamics of the translocation step measured in individual DNA polymerase complexes. AB - Complexes formed between the bacteriophage phi29 DNA polymerase (DNAP) and DNA fluctuate between the pre-translocation and post-translocation states on the millisecond time scale. These fluctuations can be directly observed with single nucleotide precision in real-time ionic current traces when individual complexes are captured atop the alpha-hemolysin nanopore in an applied electric field. We recently quantified the equilibrium across the translocation step as a function of applied force (voltage), active-site proximal DNA sequences, and the binding of complementary dNTP. To gain insight into the mechanism of this step in the DNAP catalytic cycle, in this study, we have examined the stochastic dynamics of the translocation step. The survival probability of complexes in each of the two states decayed at a single exponential rate, indicating that the observed fluctuations are between two discrete states. We used a robust mathematical formulation based on the autocorrelation function to extract the forward and reverse rates of the transitions between the pre-translocation state and the post translocation state from ionic current traces of captured phi29 DNAP-DNA binary complexes. We evaluated each transition rate as a function of applied voltage to examine the energy landscape of the phi29 DNAP translocation step. The analysis reveals that active-site proximal DNA sequences influence the depth of the pre translocation and post-translocation state energy wells and affect the location of the transition state along the direction of the translocation. PMID- 23101438 TI - Bone marrow abnormalities in systemic lupus erythematosus with peripheral cytopenia. AB - OBJECTIVES: Peripheral cytopenia is frequently found among patients with systemic lupus erythematosus (SLE). Bone marrow examination is usually considered in most cases; however, the incidence and association between cytopenia and disorders of the bone marrow remain unclear. We therefore conducted a prospective, cross sectional, analytical study among patients with SLE and peripheral cytopenia to determine the incidence of bone marrow abnormalities and to find predictive factors for bone marrow examination. RESULTS: Of the 41 patients, 20 had bone marrow abnormalities that could be categorised into six groups: hypocellularity (50%), plasmacytosis (35%), haemophagocytosis (30%), dyserythropoiesis (10%), aplastic marrow (10%) and myelofibrosis (5%). Most of the patients (75.6%) had moderate to severe, active disease and recovery from the cytopenia occurred after treatment of the SLE. None of the clinical factors was statistically proven to be associated with bone marrow abnormalities; however, 3 factors indicated an active disease status including (a) the SLEDAI score (b) the number of organs involved and (c) previous immunosuppressive drug therapy. All of these are potentially predictive factors of bone marrow abnormalities. CONCLUSIONS: The incidence of bone marrow abnormalities is high among patients with SLE and peripheral cytopenia. Bone marrow may be one of the common targets of organs affected by immune mechanisms in active SLE. Peripheral cytopenia can be subsequently improved after treatment of the disease; therefore, bone marrow examination should be recommended among patients whose cytopenia does not recover after conventional therapy. PMID- 23101439 TI - Qualitative studies of patients' perceptions of loss of teeth, the edentulous state and prosthetic rehabilitation: a systematic review with meta-synthesis. AB - OBJECTIVE: To conduct a systematic review and meta-synthesis of qualitative studies addressing patients' perceptions of loss of teeth, edentulism and oral rehabilitation. BACKGROUND: Qualitative studies can complement quantitative studies by achieving deep understanding of patients' subjective experiences of losing teeth and coping with edentulism. They can also explore the perception that the benefits of prosthetic rehabilitation extend far beyond primary clinical treatment goals of restoration of oral function. MATERIALS AND METHODS: The major data bases were searched extensively for relevant qualitative and quantitative studies, followed by manual searching of the reference lists of included publications. Two authors independently read all abstracts. Relevant papers were retrieved in full-text and included or excluded according to a specially designed protocol. The included articles were then appraised and rated for quality: high, moderate or low. Articles of low quality were excluded. RESULTS: The database search yielded 36 abstracts of qualitative studies; manual search disclosed one further article. All were read in full-text by two independent authors: 28 were excluded. Of the remaining nine, two (assessed as of low quality) were excluded for further analysis. Meta-synthesis, based on seven studies, disclosed two major themes: loss of quality-of-life associated with losing teeth and restored quality of-life after oral rehabilitation. CONCLUSIONS: In this relatively new field of research, there are few published papers. Nevertheless, the studies to date show that loss of teeth is associated not only with compromised oral function, but also loss of social status and diminished self-esteem. Oral rehabilitation has broad positive implications, restoring quality of life and self-worth. PMID- 23101440 TI - Lanthanide complexes of the Klaui metalloligand, CpCo(P?O(OR)2)3: an examination of ligand exchange kinetics between isotopomers by electrospray mass spectrometry. AB - A series of lanthanide complexes, {[CpCo(P?O(OR)2)3]2Ln(H2O)x}(+)Cl(-) (Ln = Nd, 3; Eu, 4; Tb, 5; Yb, 6; R = Et, a; R = Ph, b) bearing two cobalt metalloligands were prepared. Electrospray mass spectrometry and thermogravimetric analysis suggest that the cations are either solvent-free or contain very weakly bound water molecules. The related complex {[CpCo(P?O(OPh)2)3]2Yb}(+) [CoCl3(THF)](-), 7, was crystallographically characterized, and the cation in this case was confirmed to be 6-coordinate and solvent-free. Ligand exchange rates between the d0- and d60-isotopomers of 3a-6a and 5b were determined in acetonitrile by electrospray mass spectrometry. The ligand exchange rate was found to increase by almost 4 orders of magnitude from the smallest (Yb, 6a, k = 0.3 M(-1) s(-1)) to largest ion (Nd, 3a, >2500 M(-1) s(-1)) in acetonitrile. Additionally, the ligand exchange rate increased rapidly for 5a (Tb) with increasing water concentration from 30 M(-1) s(-1) in pure acetonitrile to 268 M(-1) s(-1) in 50:50 (v/v) acetonitrile/water. Changing the phosphite substituent had no significant impact on the rate of ligand exchange for 5b (R = Ph) relative to 5a (R = Et). PMID- 23101441 TI - Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma. AB - The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma. PMID- 23101442 TI - Epilepsy surgery. PMID- 23101436 TI - Chronic obstructive pulmonary disease and glucose metabolism: a bitter sweet symphony. AB - Chronic obstructive pulmonary disease, metabolic syndrome and diabetes mellitus are common and underdiagnosed medical conditions. It was predicted that chronic obstructive pulmonary disease will be the third leading cause of death worldwide by 2020. The healthcare burden of this disease is even greater if we consider the significant impact of chronic obstructive pulmonary disease on the cardiovascular morbidity and mortality. Chronic obstructive pulmonary disease may be considered as a novel risk factor for new onset type 2 diabetes mellitus via multiple pathophysiological alterations such as: inflammation and oxidative stress, insulin resistance, weight gain and alterations in metabolism of adipokines. On the other hand, diabetes may act as an independent factor, negatively affecting pulmonary structure and function. Diabetes is associated with an increased risk of pulmonary infections, disease exacerbations and worsened COPD outcomes. On the top of that, coexistent OSA may increase the risk for type 2 DM in some individuals. The current scientific data necessitate a greater outlook on chronic obstructive pulmonary disease and chronic obstructive pulmonary disease may be viewed as a risk factor for the new onset type 2 diabetes mellitus. Conversely, both types of diabetes mellitus should be viewed as strong contributing factors for the development of obstructive lung disease. Such approach can potentially improve the outcomes and medical control for both conditions, and, thus, decrease the healthcare burden of these major medical problems. PMID- 23101443 TI - Role of resection of malignant peripheral nerve sheath tumors in patients with neurofibromatosis type 1. AB - OBJECT: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that often arise from major peripheral nerves. Approximately half of MPNSTs arise in patients with neurofibromatosis Type 1 (NF1) who, in comparison with patients without NF1, present at younger ages and with larger tumors that are commonly associated with extensive plexiform neurofibromas. These tumors therefore pose a particularly difficult treatment challenge because of the morbidity often associated with attempted gross-total resection (GTR). Here, the authors aim to examine what role the extent of resection and other covariates play in the long term survival of patients with NF1 in the setting of MPNST. METHODS: The authors retrospectively reviewed the records of 23 adult patients with NF1 who underwent surgery for MPNSTs at their institution between 1991 and 2008. The primary end points of the study were mortality, local recurrence, and metastasis. Kaplan Meier survival curves were evaluated for all patients. Differences for each of the primary end points were evaluated based on cause-specific covariates, which included tiered tumor size, tumor location, grade, resection margin status, postoperative weakness, and use of chemotherapy and radiation therapy. Multivariate analysis was performed using Cox proportional hazards models. RESULTS: Gross-total resection (p = 0.01) and surgical margin status (p = 0.034) had a statistically important role in prolonging overall survival in patients with NF1 by univariate analysis. When tumor size, location, grade, postoperative weakness, and radiation therapy were also taken into account using multivariate analysis, GTR continued to be a significant prognostic factor (p = 0.035). CONCLUSIONS: These findings suggest that GTR offers significant long-term benefit on survival in patients with NF1. Benefit on survival occurred independently of all other covariates, suggesting that complete resection should be the principal goal of treatment in this patient population. PMID- 23101444 TI - Letter to the editor: Deep brain stimulation and general anesthesia. PMID- 23101445 TI - Meningeal management for optimal revascularization from middle meningeal artery. AB - Numerous surgical techniques have been developed and refined for the treatment of moyamoya disease. Among the indirect techniques of revascularization, encephaloduroarteriosynangiosis has been recognized as effective in promoting revascularization and reversing symptomatology. Neovascularization occurs between the donor artery, either the superficial temporal artery or the occipital artery, and the underlying ischemic cortex. Additionally, the middle meningeal artery and its dural branches have also been shown to contribute to collateral blood supply. In this report the authors describe an integrated management of the meninges for optimal revascularization. They emphasize the importance of recognizing the 3 major layers of the dura and describe a technique of dural splitting at the locus minoris resistentiae between the dura mater's vascular (middle) layer and internal median layer. Applying the dura's vascular layer to the surface of the brain after opening of the arachnoid is designed to optimize dural-pial synangiosis related to middle meningeal artery branches. PMID- 23101446 TI - Long-term hearing outcomes following stereotactic radiosurgery for vestibular schwannoma: patterns of hearing loss and variables influencing audiometric decline. AB - OBJECT: The goals of this retrospective cohort study were as follows: 1) to describe the long-term prevalence and timing of hearing deterioration following low-dose (12- to 13-Gy marginal dose) stereotactic radiosurgery (SRS) for vestibular schwannoma (VS); and 2) to identify clinical variables associated with long-term preservation of useful hearing following treatment. METHODS: Patients with serviceable hearing who underwent SRS for VS between 1997 and 2002 were studied. Data including radiosurgery treatment plans, tumor characteristics, pre- and posttreatment pure tone average, speech discrimination scores, and American Academy of Otolaryngology-Head and Neck Surgery hearing class were collected. Time to nonserviceable hearing was estimated using the Kaplan-Meier method. Univariate and multivariate associations with time to nonserviceable hearing were evaluated using Cox proportional hazards regression models. RESULTS: Forty-four patients met the study criteria and were included. The median duration of audiometric follow-up was 9.3 years. Thirty-six patients developed nonserviceable hearing at a mean of 4.2 years following SRS. The Kaplan-Meier estimated rates of serviceable hearing at 1, 3, 5, 7, and 10 years following SRS were 80%, 55%, 48%, 38%, and 23%, respectively. Multivariate analysis revealed that pretreatment ipsilateral pure tone average (p < 0.001) and tumor size (p = 0.009) were statistically significantly associated with time to nonserviceable hearing. CONCLUSIONS: Durable hearing preservation a decade after low-dose SRS for VS occurs in less than one-fourth of patients. Variables including preoperative hearing capacity and tumor size may be used to predict hearing outcomes following treatment. These findings may assist in pretreatment risk disclosure. Furthermore, these data demonstrate the importance of long-term follow-up when reporting audiometric outcomes following SRS for VS. PMID- 23101447 TI - Nervus intermedius dysfunction following Gamma Knife surgery for vestibular schwannoma. AB - OBJECT: The purpose of this study was to evaluate the function of the nervus intermedius, the nonmotor component of the facial nerve, following modern Gamma Knife surgery (GKS) for the treatment of vestibular schwannoma. METHODS: Sixty five consecutive patients at our center underwent GKS as a primary treatment option for vestibular schwannoma between 2005 and 2010. The authors interviewed patients with a functional questionnaire to evaluate the function of the nervus intermedius before and after radiosurgery from their subjective point of view. Data from 50 patients treated using GKS for a unilateral vestibular schwannoma were obtained. RESULTS: Nine (18%) of 50 patients presented with at least one preradiosurgical disturbance of the nervus intermedius caused by the vestibular schwannoma itself, with dysfunctions of lacrimation, salivation, nasal secretion, and taste. Of the 41 patients without preradiosurgical disturbances, 9 (22%) experienced the onset of at least one new disturbance after GKS. Specifically for each dysfunction, of the 45 patients without a lacrimal disturbance before GKS, 5 (11.1%) had a new lacrimal disturbance after GKS. New onset of a salivary disturbance after GKS was reported in 3 (6.2%) of 48 patients. In 1 patient (2%), increased nasal secretion was noted 1 year after GKS. Five (10.6%) of 47 patients without a preradiosurgical taste disturbance experienced the symptom after GKS. No facial palsy developed in any patient before or after GKS. There was no significant correlation between postradiosurgical nervus intermedius dysfunction and tumor size, margin dose, or patient age. CONCLUSIONS: The authors demonstrated that 22% of patients undergoing modern GKS for vestibular schwannoma experience various disturbances of nonmotor components of the facial nerve as a result of the radiosurgery. Through this study, we can provide useful information about the likelihood of certain postradiosurgical symptoms for vestibular schwannoma. PMID- 23101449 TI - Malignant nerve sheath tumors. PMID- 23101448 TI - Exogenous hormone use, reproductive factors, and risk of intracranial meningioma in females. AB - OBJECT: The 2-fold higher incidence of meningioma in women compared with men has long suggested a role for hormonally mediated risk factors, but specific mechanisms remain elusive. METHODS: The study included data obtained in 1127 women 29-79 years of age with intracranial meningioma diagnosed among residents of Connecticut, Massachusetts, North Carolina, the San Francisco Bay Area, and 8 Texas counties between May 1, 2006, and October 6, 2011, and data obtained in 1092 control individuals who were frequency matched for age group and geography with meningioma patients. RESULTS: No association was observed for age at menarche, age at menopause, or parity and meningioma risk. Women who reported breastfeeding for at least 6 months were at reduced risk of meningioma (OR 0.78, 95% CI 0.63-0.96). A significant positive association existed between meningioma risk and increased body mass index (p < 0.01) while a significant negative association existed between meningioma risk and current smoking (p < 0.01). Among premenopausal women, current use of oral contraceptives was associated with an increased risk of meningiomas (OR 1.8, 95% CI 1.1-2.9), while current use of hormone replacement therapy among postmenopausal women was not associated with a significant elevation in risk (OR 1.1, 95% CI 0.74-1.67). There was no association between use of fertility medications and meningioma risk. CONCLUSIONS: The authors' study confirms associations for body mass index, breastfeeding, and cigarette smoking but provides little evidence for associations of reproductive and menstrual factors with meningioma risk. The relationship between current use of exogenous hormones and meningioma remains unclear, limited by the small numbers of patients currently on oral hormone medications and a lack of hormone receptor data for meningioma tumors. PMID- 23101450 TI - Navigated transcranial magnetic stimulation for preoperative language mapping in a patient with a left frontoopercular glioblastoma. AB - Up to now, navigated transcranial magnetic stimulation (nTMS) has been used for motor mapping in the vicinity of rolandic brain lesions. Recently, nTMS has also been suggested to be useful in mapping human language areas. The authors describe the case of a left-handed patient with a left-side glioblastoma within the opercular inferior frontal gyrus who presented with severe motor aphasia. Preoperative functional MRI (fMRI) indicated speech dominance of the right hemisphere and did not show any language-related activation in the vicinity of the tumor. Navigated TMS, however, showed a significantly higher rate of induced speech arrests for the left than for the right. Left-side direct cortical stimulation induced clear speech arrests during awake surgery. This case suggests that nTMS may be useful for preoperative speech mapping in tumors affecting the anatomy, vasculature, and brain oxygen levels and therefore impairing fMRI reliability. PMID- 23101452 TI - Hemihypoglossal nerve transfer for acute facial paralysis. AB - OBJECT: The authors have developed a technique for the treatment of facial paralysis that utilizes anastomosis of the split hypoglossal and facial nerve. Here, they document improvements in the procedure and experimental evidence supporting the approach. METHODS: They analyzed outcomes in 36 patients who underwent the procedure, all of whom had suffered from facial paralysis following the removal of large vestibular schwannomas. The average period of paralysis was 6.2 months. The authors used 5 different variations of a procedure for selecting the split nerve, including evaluation of the split nerve using recordings of evoked potentials in the tongue. RESULTS: Successful facial reanimation was achieved in 16 of 17 patients using the cephalad side of the split hypoglossal nerve and in 15 of 15 patients using the caudal side. The single unsuccessful case using the cephalad side of the split nerve resulted from severe infection of the cheek. Procedures using the ansa cervicalis branch yielded poor success rates (2 of 4 cases). Some tongue atrophy was observed in all variants of the procedure, with 17 cases of minimal atrophy and 14 cases of moderate atrophy. No procedure led to severe atrophy causing functional deficits of the tongue. CONCLUSIONS: The split hypoglossal-facial nerve anastomosis procedure consistently leads to good facial reanimation, and the use of either half of the split hypoglossal nerve results in facial reanimation and moderate tongue atrophy. PMID- 23101451 TI - Surgical results of the Carotid Occlusion Surgery Study. AB - OBJECT: The Carotid Occlusion Surgery Study (COSS) was conducted to determine if superficial temporal artery-middle cerebral artery (STA-MCA) bypass, when added to the best medical therapy, would reduce subsequent ipsilateral stroke in patients with complete internal carotid artery (ICA) occlusion and an elevated oxygen extraction fraction (OEF) in the cerebral hemisphere distal to the occlusion. A recent publication documented the methodology of the COSS in detail and briefly outlined the major findings of the trial. The surgical results of the COSS are described in detail in this report. METHODS: The COSS was a prospective, parallel-group, 1:1 randomized, open-label, blinded-adjudication treatment trial. Participants, who had angiographically demonstrated complete occlusion of the ICA causing either a transient ischemic attack or ischemic stroke within 120 days and hemodynamic cerebral ischemia indicated by an increased OEF measured by PET, were randomized to either surgical or medical treatment. One hundred ninety-five patients were randomized: 97 to the surgical group and 98 to the medical group. The surgical patients underwent an STA-MCA cortical branch anastomosis. RESULTS: In the intention-to-treat analysis, the 2-year rates for the primary end point were 21% for the surgical group and 22.7% for the medical group (p = 0.78, log rank test). Fourteen (15%) of the 93 patients who had undergone an arterial bypass had a primary end point ipsilateral hemispheric stroke in the 30-day postoperative period, 12 within 2 days after surgery. The STA-MCA arterial bypass patency rate was 98% at the 30-day postoperative visit and 96% at the last follow up examination. The STA-MCA arterial bypass markedly improved, although it did not normalize, the level of elevated OEF in the symptomatic cerebral hemisphere. Five surgically treated and 1 nonsurgically treated patients in the surgical group had a primary end point ipsilateral hemispheric stroke after the 30-day postoperative period. No baseline characteristics or intraoperative variables revealed those who would experience a procedure-related stroke. CONCLUSIONS: Despite excellent bypass graft patency and improved cerebral hemodynamics, STA MCA anastomosis did not provide an overall benefit regarding ipsilateral 2-year stroke recurrence, mainly because of a much better than expected stroke recurrence rate (22.7%) in the medical group, but also because of a significant postoperative stroke rate (15%). Clinical trial registration no.: NCT00029146. PMID- 23101453 TI - Relationship between hospital surgical volume, lobectomy rates, and adverse perioperative events at US epilepsy centers. AB - OBJECT: Epilepsy surgery remains significantly underutilized. The authors recently reported that the number of lobectomies for localized intractable epilepsy in the US has not changed despite the implementation of clear evidence based guidelines 10 years ago supporting early referral for surgery. To better understand why epilepsy surgery continues to be underused, the authors' objective was to carefully examine hospital-related factors related to the following: 1) where patients are being admitted for the evaluation of epilepsy, 2) rates of utilization for surgery across hospitals, and 3) perioperative morbidity between hospitals with low versus high volumes of epilepsy surgery. METHODS: The authors performed a population-based cohort study of US hospitals between 1990 and 2008 using the Nationwide Inpatient Sample (NIS), stratifying epilepsy surgery rates and trends as well as perioperative morbidity rates by hospital surgical volume. RESULTS: The number of lobectomies for epilepsy performed at high-volume centers (> 15 lobectomies/year) significantly decreased between 1990 and 2008 (F = 20.4, p < 0.001), while significantly more procedures were performed at middle-volume hospitals (5-15 lobectomies/year) over time (F = 16.1, p < 0.001). No time trend was observed for hospitals performing fewer than 5 procedures per year. However, patients admitted to high-volume centers were significantly more likely to receive lobectomy than those at low-volume hospitals (relative risk 1.05, 95% CI 1.03-1.08, p < 0.001). Also, the incidence of perioperative adverse events was significantly higher at low-volume hospitals (12.9%) than at high-volume centers (6.1%) (relative risk 1.08, 95% CI 1.03-1.07, p < 0.001). CONCLUSIONS: Hospital volume is an important predictor of epilepsy surgery utilization and perioperative morbidity. Patients with medically refractory epilepsy should be referred to a comprehensive epilepsy treatment center for surgical evaluation by an experienced clinical team. PMID- 23101454 TI - Carotid occlusion. PMID- 23101455 TI - Interleukin-6 as a therapy target in oral squamous carcinoma. AB - INTRODUCTION: Interleukin-6 (IL-6) is a multifunctional cytokine which is implicated in the regulation of immune responses and cellular events. It may activate signaling pathways of Janus kinase/signal transducer and activator of transcription (JAK/STAT) factors, mitogen-activated protein kinases, and Akt. IL 6 could exert pleiotropic effects in a variety of cancers. AREAS COVERED: Oral squamous cell carcinoma epidemiology, pathology, regulation by IL-6, and experimental therapy. EXPERT OPINION: Oral squamous cell carcinoma development is in part facilitated by chronic epithelial irritations and this tumor is more frequent in smokers or individuals who consume excessive amounts of alcohol. IL-6 levels are elevated in this neoplasm and IL-6 is considered a bad prognostic factor in oral cancer. IL-6 secretion in oral squamous cancer is facilitated by the microenvironment, in particular by stromal derived factor-1. IL-6 function in non-malignant and malignant diseases is controlled by endogenous inhibitors of cytokine signaling. IL-6 action in oral squamous cancer is largely mediated by the JAK/STAT3 pathway and may lead to epithelial to mesenchymal transition, thus contributing to tumor progression. IL-6 also enhances angiogenesis and lymphangiogenesis through regulation of vascular endothelial growth factor. In addition, experimental anti-IL-6/anti-IL-6 receptor-targeted therapies in oral cancer have been proposed. PMID- 23101456 TI - A systematic review of behavioural weight-loss interventions involving primary care physicians in overweight and obese primary-care patients (1999-2011). AB - OBJECTIVE: The present review aimed to examine the effectiveness of behavioural weight-loss interventions involving primary-care physicians in producing weight loss in overweight and obese primary-care patients. DESIGN: A systematic review was conducted by searching online databases (MEDLINE, EMBASE, Cochrane, PsycINFO and SCOPUS) from January 1999 to December 2011. All abstracts were screened and coded for eligibility. The Cochrane Effective Practice and Organisation of Care Group quality criteria were used to assess the methodological adequacy of included studies. Information related to study design, population characteristics and intervention details was extracted. SETTING: Primary care. SUBJECTS: Overweight or obese (defined as having a BMI > or = 25.0 kg/m2) primary care patients. RESULTS: Sixteen different studies were included. Of these, six assessed primary care physicians' delivery of weight-loss counselling; nine assessed weight-loss counselling delivered by non-physician personnel with monitoring by primary care physicians; and one assessed a multi-component intervention. Overall, high intensity weight-loss counselling by primary-care physicians resulted in moderate but not clinically significant weight loss. High intensity weight-loss counselling delivered by non-physicians, meal replacements delivered in conjunction with dietitian counselling and referral to commercial weight-loss centre programmes accompanied by regular monitoring by a primary-care physician were effective in producing clinically significant weight loss. Dietitian-delivered care appeared effective in producing weight loss regardless of level of intervention intensity. CONCLUSIONS: Overall, there were few studies on this topic and the methodological rigour of some included studies was poor. Additional studies assessing the effectiveness and acceptability of potential interventions are needed to confirm these findings. PMID- 23101457 TI - Use of randomisation in clinical trials: a survey of UK practice. AB - BACKGROUND: In healthcare research the randomised controlled trial is seen as the gold standard because it ensures selection bias is minimised. However, there is uncertainty as to which is the most preferred method of randomisation in any given setting and to what extent more complex methods are actually being implemented in the field. METHODS: In this paper we describe the results of a survey of UK academics and publicly funded researchers to examine the extent of the use of various methods of randomisation in clinical trials. RESULTS: Trialists reported using simple randomisation, permuted blocks and stratification more often than more complex methods such as minimisation. Most trialists believed that simple randomisation is suitable for larger trials but there is a high probability of possible imbalance between treatment groups in small trials. It was thought that groups should be balanced at baseline to avoid imbalance and help face-validity. However, very few respondents considered that more complex methods offer any advantages. CONCLUSIONS: This paper demonstrates that for most UK trialists the preferred method of randomisation is using permuted blocks of varying random length within strata. This method eliminates the problem of predictability while maintaining balance across combinations of factors. If the number of prognostic factors is large, then minimisation can be used to provide treatment balance as well as balance over these factors. However, only those factors known to affect outcome should be considered. PMID- 23101459 TI - Proteomics reveals the effects of salicylic acid on growth and tolerance to subsequent drought stress in wheat. AB - Pretreatment with 0.5 mM salicylic acid (SA) for 3 days significantly enhanced the growth and tolerance to subsequent drought stress (PEG-6000, 15%) in wheat seedlings, manifesting as increased shoot and root dry weights, and decreased lipid peroxidation. Total proteins from wheat leaves exposed to (i) 0.5 mM SA pretreatment, (ii) drought stress, and (iii) 0.5 mM SA treatment plus drought stress treatments were analyzed using a proteomics method. Eighty-two stress responsive protein spots showed significant changes, of which 76 were successfully identified by MALDI-TOF-TOF. Analysis of protein expression patterns revealed that proteins associated with signal transduction, stress defense, photosynthesis, carbohydrate metabolism, protein metabolism, and energy production could by involved in SA-induced growth and drought tolerance in wheat seedlings. Furthermore, the SA-responsive protein interaction network revealed 35 key proteins, suggesting that these proteins are critical for SA-induced tolerance. PMID- 23101460 TI - Clinical significance of coexisting antitopoisomerase I and anticentromere antibodies in patients with systemic sclerosis: a EUSTAR group-based study. AB - OBJECTIVES: To determine the clinical characteristics of simultaneous occurrence of antitopoisomerase (ATA) and anticentromere (ACA) autoantibodies in systemic sclerosis (SSc). METHODS: Data of patients (n=4,687) fulfilling the ACR criteria for SSc and followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. Sera from patients with simultaneous ATA and ACA were reanalyzed centrally by indirect immunofluorescence, enzyme immunoassay, and immunoblot to confirm antibody status. RESULTS: A total of 29 patients (0.6%) had been documented double-positive for both ATA and ACA in the EUSTAR database. Sera of 14 cases were available for central analysis, of which 8 were confirmed to unequivocally contain both antibodies. The double-positive patients were on average 52.4 years of age, 87.5% were female, and 62.5% had diffuse cutaneous (dc) SSc. Compared with matched ACA single-positive disease, cutaneous and visceral complications were more prevalent in double-positive cases, but this prevalence did not differ significantly in comparison to ATA single-positives. CONCLUSIONS: Coexistence of ATA and ACA can be found at low prevalence in SSc. The clinical features of double-positive patients are not clearly dissimilar to those of patients harbouring only ATA. The data do not support a direct involvement of these antibodies in the pathogenesis of established SSc, but may lack statistical power. PMID- 23101462 TI - Contribution of a new generation field-emission scanning electron microscope in the understanding of a 2099 Al-Li alloy. AB - Aluminum-lithium alloys are widespread in the aerospace industry. The new 2099 and 2199 alloys provide improved properties, but their microstructure and texture are not well known. This article describes how state-of-the-art field-emission scanning electron microscopy (FE-SEM) can contribute to the characterization of the 2099 aluminum-lithium alloy and metallic alloys in general. Investigations were carried out on bulk and thinned samples. Backscattered electron imaging at 3 kV and scanning transmission electron microscope imaging at 30 kV along with highly efficient microanalysis permitted correlation of experimental and expected structures. Although our results confirm previous studies, this work points out possible substitutions of Mg and Zn with Li, Al, and Cu in the T1 precipitates. Zinc and magnesium are also present in "rice grain"-shaped precipitates at the grain boundaries. The versatility of the FE-SEM is highlighted as it provides information in the macro- and microscales with relevant details. Its ability to probe the distribution of precipitates from nano- to microsizes throughout the matrix makes FE-SEM an essential technique for the characterization of metallic alloys. PMID- 23101461 TI - Spuriously low IgG levels in lupus-associated mixed cryoglobulinaemia type II complicated by iatrogenic immunoglobulin-induced immune complex vasculitis. PMID- 23101463 TI - Streptococcal lung abscesses from a dental focus following tocilizumab: a case report. AB - Patients suffering from dental infections and concurrently using immunosuppressive medication are at increased risk of developing systemic streptococcal infections. Tocilizumab is a novel therapeutic agent targeting interleukin-6. We describe a case of streptococcal lung abscesses from a dental focus after use of tocilizumab for treatment of Takayasu arteritis. PMID- 23101465 TI - Optimal harvesting in forestry: steady-state analysis and climate change impact. AB - We perform the steady-state analysis of a nonlinear partial differential equation model that describes the dynamics of a managed size-structured forest. The harvesting policy is to maximize the net benefits from timber production over an infinite planning horizon. The existence and uniqueness of the steady-state trajectories are analysed. Closed-form steady states are obtained in meaningful special cases and are used to estimate how climate change affects the optimal harvesting regime, diameter of cut trees, number of logged trees, and net benefits in the long run. PMID- 23101466 TI - Rapid decline in HIV viral load when introducing raltegravir-containing antiretroviral treatment late in pregnancy. AB - Antenatal screening program for HIV has been in use in Sweden since 1987 with a 95-98% acceptance rate. Screening is performed during gestational week 10-12 and antiretroviral treatment (ART) to prevent mother-to-child transmission (MTCT) is initiated at gestational week 14-18. However, some women present with HIV in late pregnancy and additional treatment are wanted to achieve viral suppression before delivery. The integrase inhibitor raltegravir has a favorable pharmacokinetic profile and a capacity to rapidly decrease the viral load (VL). We describe four women presenting as HIV positive late in pregnancy, their ART, and outcome for the mother and child. Four women were discovered as HIV positive late in pregnancy, of 7 discovered in the antenatal screening programme in Stockholm County Council during 2011. Raltegravir was added to standard ART. The mean VL at presentation was 217,000 copies per milliliter (range, 65,000-637,000). A rapid decline of HIV RNA was observed in all cases, one woman treated with ART for only 8 days prior to delivery. The mean VL decline per week was 1.12 log (range, 0.94 1.22), which is estimated to occur (based on literature) after 1-2 months with standard ART. No side effects due to raltegravir were observed in mothers or infants. Caesarean section was performed in all cases, and the women did not breastfeed. No infant was infected. This report suggests that raltegravir added to standard antiretroviral treatment would be an option for women presenting with HIV in late pregnancy. PMID- 23101464 TI - Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states. AB - Synthetic kappa-opioid receptor (KOR) agonists induce dysphoric and pro depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects. PMID- 23101467 TI - High level of distress in long-term survivors of thyroid carcinoma: results of rapid screening using the distress thermometer. AB - CONTEXT: Cancer patients are at increased risk for distress. The Distress Thermometer (DT) and problem list (PL) are short-tools validated and recommended for distress screening in cancer patients. OBJECTIVE: To investigate the level of distress and problems experienced by survivors of differentiated non-medullary thyroid carcinoma (DTC), using the DT and PL and whether this correlates with clinical and demographical variables. PARTICIPANTS, DESIGN AND SETTING: All 205 DTC patients, under follow-up at the outpatient clinic of our university hospital, were asked to fill in the DT and PL, hospital anxiety and depression scale (HADS), illness cognition questionnaire (ICQ) and an ad hoc questionnaire. Receiver Operator Characteristic analysis (ROC) was used to establish the optimal DT cut-off score according to HADS. Correlations of questionnaires scores with data on diagnosis, treatment and follow-up collected from medical records were analyzed. RESULTS: Of the 159 respondents, 145 agreed to participate [118 in remission, median follow-up 7.2 years (range 3 months-41 years)]. Of these, 34.3% rated their distress score >=5, indicating clinically relevant distress according to ROC analysis. Patients reported physical (86%) over emotional problems (76%) as sources of distress. DT scores correlated with HADS scores and ICQ subscales. No significant correlations were found between DT scores and clinical or demographical characteristics except for employment status. CONCLUSION: Prevalence of distress is high among patients with DTC even after long-term remission and cannot be predicted by clinical and demographical characteristics. DT and PL are useful screening instruments for distress in DTC patients and could easily be incorporated into daily practice. PMID- 23101468 TI - Excess mortality after curative surgery for colorectal cancer changes over time and differs for patients with colon versus rectal cancer. AB - BACKGROUND: Improved management of colorectal cancer patients has resulted in better five-year survival for rectal cancer compared with colon cancer. We compared excess mortality rates in various time intervals after surgery in patients with colon and rectal cancer. MATERIAL AND METHODS: We analysed all patients with curative resection of colorectal cancers reported in the Cancer Registry of Norway before (1994-1996) and after (2001-2003) national treatment guidelines were introduced. Excess mortality was analysed in different postoperative time intervals within the five-year follow-up periods for patients treated in 1994-1996 vs. 2001-2003. RESULTS: A total of 11 437 patients that underwent curative resection were included. For patients treated from 1994 to 1996, excess mortality was similar in colon and rectal cancer patients in all time intervals. For those treated from 2001 to 2003, excess mortality was significantly lower in rectal cancer patients than in colon cancer patients perioperatively (in the first 60 days: excess mortality ratio = 0.46, p = 0.007) and during the first two postoperative years (2-12 months: excess mortality ratio = 0.54, p = 0.010; 1-2 years: excess mortality ratio = 0.60, p = 0.009). Excess mortality in rectal cancer patients was significantly greater than in colon cancer patients 4-5 years postoperatively (excess mortality ratio = 2.18, p = 0.003). CONCLUSION: Excess mortality for colon and rectal cancer changed substantially after the introduction of national treatment guidelines. Short-term excess mortality rates was higher in colon cancer compared to rectal cancer for patients treated in 2001-2003, while excess mortality rates for rectal cancer patients was significantly higher later in the follow-up period. This suggests that future research should focus on these differences of excess mortality in patients curatively treated for cancer of the colon and rectum. PMID- 23101469 TI - Longitudinal pain reports in a palliative care population. AB - BACKGROUND: The experiences of people with pain under palliative care is not well documented longitudinally. This work aims to describe the prevalence, intensity, progression, and associations of self-reported pain scores of people under a community palliative care service, by retrospectively examining how routinely collected pain scores changed over time. METHODS: Pain was subcategorized depending on intensity, allowing group differences to be explored using analysis of variance. Bivariate analysis was used to explore the relationship between pain scores and other symptoms using Spearman's Rho correlation. RESULTS: Over two years, 3027 patients were seen, with data collected an average of 17.3 times (52,387 data points). At referral, 50% (n=1402) were pain free. Of those with pain, mean score was 2 (range 0-10). The majority had cancer (90%), with no significant difference between the severity of reported pain scores between cancer and nonmalignant diagnoses (P=0.27). A significant gender difference was noted, with females statistically more likely to report severe pain (chi(2) (3026)=5.61, p=0.018). Similarly, those <60 years were more likely to report pain chi(2)(3025)=3.07; p=0.022). Longitudinal changes in pain revealed the pain scores of people admitted with pain <7 always reported lower pain scores than those with severe pain on admission (90 days, F(1, 654)=55.72, p<0.001; 60 days, F(1, 1008)=48.62, p<0.001; 30 days, F(1, 1522)=60.36, p<0.001; 7 days, F(1, 1897)=15.4, p<0.001). However, pain scores of those with pain <7 on admission rose as death approached compared with those who reported severe pain. CONCLUSION: Even in the context of expert delivery of palliative care where pain is most likely to be optimally managed, pain continues to be a problem. Work such as this suggests that the different mechanisms that contribute to pain may influence patients' experiences even when analgesia is optimized in a specialist setting. Particular attention is needed in the future to explore the relationship between severe pain and mobility. PMID- 23101470 TI - A Chinese version of the Spiritual Needs Assessment for patients survey instrument. AB - CONTEXT: Unmet spiritual needs have been associated with decreased patient ratings of quality of care, satisfaction, and quality of life. Few instruments exist to measure spiritual needs particularly among non-English speaking patients in the U.S. OBJECTIVE: To develop an internally consistent and reliable Chinese version of the Spiritual Needs Assessment for Patients (SNAP). METHODS: The SNAP consists of 23 total items in 3 domains: psychosocial (n=5), spiritual (n=13), and religious (n=5). The Chinese SNAP was developed through a translation-back translation process followed by cognitive pre-testing. The instrument was then administered to a convenience sample of 30 ambulatory predominantly Mandarin speaking cancer patients in New York. We tested for internal consistency, test retest reliability, and degree of association with the question "Have your spiritual needs been met?" RESULTS: Mean participant age was 56 years, 70% had less than a high school education. Twenty three percent were Buddhist, 63% identified no religious affiliation, 83% described themselves as spiritual but not religious, 33% reported unmet spiritual needs, and 60% wanted help meeting their spiritual needs. The Cronbach's alpha for the total SNAP was 0.89. Test retest correlation coefficient for the total SNAP=0.75. Unmet spiritual needs, as assessed through a single-item question, were not associated with higher SNAP scores in contrast to results of the English SNAP. CONCLUSION: The Chinese SNAP is an internally consistent and reliable instrument for measuring spiritual needs. The apparent lack of correlation between the SNAP score and the question on unmet spiritual needs may suggest that the SNAP captures patient needs considered by Westerners to be spiritual but that Chinese patients might not readily describe as spiritual. PMID- 23101471 TI - The relationships among hope, pain, psychological distress, and spiritual well being in oncology outpatients. AB - OBJECTIVE: Limited research in Taiwan and Europe suggest that hope is inversely correlated with certain dimensions of the pain experience. However, the relationship between hope and pain among oncology outpatients in the United States has not been evaluated. The aims of this study were to investigate the relationship between hope and cancer pain, after accounting for key psychological, demographic, and clinical characteristics. DESIGN: We enrolled a convenience sample of 78 patients who were receiving concurrent oncologic and symptom-focused care in a comprehensive cancer center. Patient demographic and clinical information was obtained from patient report and medical record review. Patients completed the Herth Hope Index, the Brief Pain Inventory, the Hospital Anxiety and Depression Scale, and the Steinhauser Spiritual Concern Probe. RESULTS: Levels of hope were not associated with age, gender, or the presence of metastatic disease. Herth Hope Index scores were negatively correlated with average pain intensity (p=0.02), worst pain intensity (p<0.01), pain interference with function (p<0.05), anxiety (p<0.01), and depression (p<0.01), and were positively correlated with spiritual well-being scores (p<0.01). However, after controlling for depression and spiritual well-being with regression analysis, the relationship between pain intensity and hope was no longer significant. CONCLUSIONS: While an association exists between the patients' experience of pain and levels of hope in this study, adjustment for depression and spiritual well being eliminates the relationship initially observed. Although the causal relationships have yet to be determined, in our study hope had a stronger connection to psycho-spiritual factors, than to pain experiences or severity. PMID- 23101473 TI - Quantiferon TB Gold and tuberculin skin tests for the detection of latent tuberculosis infection in patients treated with tumour necrosis factor alpha blocking agents. AB - OBJECTIVES: The risk of activation of latent tuberculosis infection (LTBI) is increased in patients treated with anti-TNF-alpha drugs. Tuberculin skin test (TST) and Quantiferon-TB Gold test (QFT) are used to detect LTBI before and during anti-TNF-alpha treatment. We describe here a relation of these tests at various timepoints and also longitudinal QFT data. METHODS: Study group consisted of 305 patients with several rheumatic inflammatory diseases treated and/or scheduled for anti-TNF-alpha drugs. The QFT was performed in 303 patients during therapy and in 177 patients also during screening. The TST was used in 284 patients. Both tests simultaneously were utilised in 360 instances. RESULTS: Twenty-two patients were QFT positive; 3.9% before and 5.9% during anti-TNF-alpha treatment. Two patients who became QFT positive developed active tuberculosis. The TST was positive in 42% and 38% of patients before and during treatment, respectively. There was poor agreement between the two tests. Patients on glucocorticoids had a negative TST more frequently. The IFN-gamma response to mycobacterial antigens significantly increased after application of tuberculin, but never reached the positive threshold. There was a significant increase in mitogen-induced IFN-gamma production after initiation of anti-TNF-alpha therapy. CONCLUSIONS: Poor correlation between the QFT and TST renders the TST non specific for LTBI. QFT is more specific to detect LTBI and conversion to a positive result may predict active TB. An increase in IFN-gamma production in response to mycobacterial antigens is seen when the TST is performed before the QFT. Mitogen-induced IFN-gamma production increases after initiation of anti-TNF alpha therapy. PMID- 23101474 TI - The Project TALENT Twin and Sibling Study. AB - Project TALENT is a US national longitudinal study of about 377,000 individuals born in 1942-1946, first assessed in 1960. Students in about 1,200 schools participated in a 2-day battery covering aptitudes, abilities, interests, and individual and family characteristics (Flanagan, 1962; www.projectTALENT.org). Follow-up assessments 1, 5, and 11 years later assessed educational and occupational outcomes. The sample includes approximately 92,000 siblings from 40,000 families, including 2,500 twin pairs and 1,200 other siblings of twins. Until recently, almost no behavior genetic research has been conducted with the sample. In the original data collection information was not collected with the intent to link family members. Recently, we developed algorithms using names, addresses, birthdates, and information about family structure to link siblings and identify twins. We are testing several methods to determine zygosity, including use of yearbook photographs. In this paper, we summarize the design and measures in Project TALENT, describe the Twin and Sibling sample, and present our twin-sib-classmate model. In most twin and family designs, the 'shared environment' includes factors specific to the family combined with between-family differences associated with macro-level variables such as socioeconomic status. The school-based sampling design used in Project TALENT provides a unique opportunity to partition the shared environment into variation shared by siblings, specific to twins, and associated with school- and community-level factors. The availability of many measured characteristics on the family, schools, and neighborhoods enhances the ability to study the impact of specific factors on behavioral variation. PMID- 23101477 TI - Solution and solid-state structural chemistry of actinide hydrates and their hydrolysis and condensation products. PMID- 23101472 TI - Therapeutic opportunities for targeting the ubiquitous cell surface receptor CD47. AB - INTRODUCTION: CD47 is a ubiquitously expressed cell surface receptor that serves as a counter-receptor for SIRPalpha in recognition of self by the innate immune system. Independently, CD47 also functions as an important signaling receptor for regulating cell responses to stress. AREAS COVERED: We review the expression, molecular interactions, and pathophysiological functions of CD47 in the cardiovascular and immune systems. CD47 was first identified as a potential tumor marker, and we examine recent evidence that its dysregulation contributes to cancer progression and evasion of anti-tumor immunity. We further discuss therapeutic strategies for enhancing or inhibiting CD47 signaling and applications of such agents in preclinical models of ischemia and ischemia/reperfusion injuries, organ transplantation, pulmonary hypertension, radioprotection, and cancer. EXPERT OPINION: Ongoing studies are revealing a central role of CD47 for conveying signals from the extracellular microenvironment that limit cell and tissue survival upon exposure to various types of stress. Based on this key function, therapeutics targeting CD47 or its ligands thrombospondin-1 and SIRPalpha could have broad applications spanning reconstructive surgery, engineering of tissues and biocompatible surfaces, vascular diseases, diabetes, organ transplantation, radiation injuries, inflammatory diseases, and cancer. PMID- 23101475 TI - Direct optical imaging of graphene in vitro by nonlinear femtosecond laser spectral reshaping. AB - Nonlinear optical microscopy, based on femtosecond laser spectral reshaping, characterized and imaged graphene samples made from different methods, both on slides and in a biological environment. This technique clearly discriminates between graphene flakes with different numbers of layers and reveals the distinct nonlinear optical properties of reduced graphene oxide as compared to mechanically exfoliated or chemical vapor deposition grown graphene. The nonlinearity makes it applicable to scattering samples (such as tissue) as opposed to previous methods, such as transmission. This was demonstrated by high resolution imaging of breast cancer cells incubated with graphene flakes. PMID- 23101478 TI - Single nucleotide polymorphisms (SNPs) involved in insulin resistance, weight regulation, lipid metabolism and inflammation in relation to metabolic syndrome: an epidemiological study. AB - BACKGROUND: Mechanisms involved in metabolic syndrome (MetS) development include insulin resistance, weight regulation, inflammation and lipid metabolism. Aim of this study is to investigate the association of single nucleotide polymorphisms (SNPs) involved in these mechanisms with MetS. METHODS: In a random sample of the EPIC-NL study (n = 1886), 38 SNPs associated with waist circumference, insulin resistance, triglycerides, HDL cholesterol and inflammation in genome wide association studies (GWAS) were selected from the 50K IBC array and one additional SNP was measured with KASPar chemistry. The five groups of SNPs, each belonging to one of the metabolic endpoints mentioned above, were associated with MetS and MetS-score using Goeman's global test. For groups of SNPs significantly associated with the presence of MetS or MetS-score, further analyses were conducted. RESULTS: The group of waist circumference SNPs was associated with waist circumference (P=0.03) and presence of MetS (P=0.03). Furthermore, the group of SNPs related to insulin resistance was associated with MetS score (P<0.01), HDL cholesterol (P<0.01), triglycerides (P<0.01) and HbA1C (P=0.04). Subsequent analyses showed that MC4R rs17782312, involved in weight regulation, and IRS1 rs2943634, related to insulin resistance were associated with MetS (OR 1.16, 95%CI 1.02-1.32 and OR 0.88, 95% CI 0.79; 0.97, respectively). The groups of inflammation and lipid SNPs were neither associated with presence of MetS nor with MetS score. CONCLUSIONS: In this study we found support for the hypothesis that weight regulation and insulin metabolism are involved in MetS development.MC4R rs17782312 and IRS1 rs2943634 may explain part of the genetic variation in MetS. PMID- 23101479 TI - Association between XRCC1 polymorphism 399 G->A and glioma among Caucasians: a systematic review and meta-analysis. AB - BACKGROUND: The x-ray cross complementing group 1 gene (XRCC1) is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G -> A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest. METHODS: A systematic literature review and meta-analysis was conducted to explore the association between XRCC1 399 G -> A and glioma. Subgroup analyses by grade, gender, genotyping method, country in which study was conducted, and study size were conducted when data were available and validity of the results were assessed by influence analyses and exploration of potential publication bias. RESULTS: Six studies were eligible for meta-analysis including data on 2,362 Caucasian glioma cases and 3,085 Caucasian controls. Pooled analysis yielded a significant association between the variant of interest and risk of glioma (OR = 1.17, 95% CI: 1.05-1.30) which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma (OR = 1.10, 95% CI: 0.98-1.23), and no evidence of publication bias. CONCLUSIONS: This meta-analysis does not suggest a major role of the XRCC1 399 G -> A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene. PMID- 23101481 TI - Oxygen radical functionalization of boron nitride nanosheets. AB - The covalent chemical functionalization of exfoliated hexagonal boron-nitride nanosheets (BNNSs) is achieved by the solution-phase oxygen radical functionalization of boron atoms in the h-BN lattice. This involves a two-step procedure to initially covalently graft alkoxy groups to boron atoms and the subsequent hydrolytic defunctionalization of the groups to yield hydroxyl functionalized BNNSs (OH-BNNSs). Characterization of the functionalized-BNNSs using HR-TEM, Raman, UV-vis, FTIR, NMR, and TGA was performed to investigate both the structure of the BNNSs and the covalent functionalization methodology. OH BNNSs were used to prepare polymer nanocomposites and their mechanical properties analyzed. The influence of the functional groups grafted to the surface of the BNNSs is investigated by demonstrating the impact on mechanical properties of both noncovalent and covalent bonding at the interface between the nanofiller and polymer matrixes. PMID- 23101480 TI - Rationale and design of the RIACT-study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial. AB - BACKGROUND: Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. METHODS/DESIGN: The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. DISCUSSION: It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. TRIAL REGISTRATION: Clinical trials gov. number: NCT01117662. PMID- 23101482 TI - Teleconcussion: an innovative approach to screening, diagnosis, and management of mild traumatic brain injury. AB - Concussion awareness and management in sports have gained a great deal of attention in light of research illustrating the potentially devastating consequences of repeated traumatic brain injuries. In order to address this public health crisis, numerous states have passed legislation that mandates medical clearance before being eligible to return to play of concussed athletes by a qualified healthcare provider. As the number of qualified healthcare providers with expertise in the diagnosis and management of concussions remains very small, patient safety and the ability to fulfill these legislative return-to play requirements present unique problems to rural communities without easy access to subspecialty care. Telemedicine is a possible means by which to address the needs of the rural student-athlete. PMID- 23101483 TI - Remote diagnosis of congenital heart disease in southern Arizona: comparison between tele-echocardiography and videotapes. AB - OBJECTIVE: We report our experience with tele-echocardiography and echocardiograms recorded digitally or on videotape (recorded-echos) at The University of Arizona from August 2006 to December 2010 and compare their quality and diagnostic accuracy. MATERIALS AND METHODS: Tele-echocardiograms (tele-echos) were transmitted from the Yuma Regional Medical Center to The University of Arizona via a T-1 and aT-3 line at a bandwidth of 768 kilobits per second. Recorded-echos were shipped for interpretation to The University of Arizona by overnight mail. Diagnostic accuracy was assessed by comparing tele- and recorded echos with electrocardiograms performed by a pediatric cardiologist (PedsCard echos). RESULTS: Three hundred forty-six tele-echos in 260 patients and 455 recorded-echos in 406 patients were performed (median age, 6 and 8 days, respectively). Indications included possible congenital heart disease (CHD), patent ductus arteriosus (PDA), and persistent pulmonary hypertension of the newborn. Diagnostic categories included complex CHD, non-critical disease, PDA, and other. PedsCard-echos were available for 27% of the tele-echo and 30% of the recorded-echo patients. Comparisons between tele- and PedsCard-echo yielded no discrepancies in 12 (23%), expected resolution of condition in 26 (49%), and minor in 14 (26%). One (2%) major discrepancy was detected. Comparisons between recorded- and PedsCard-echo showed no discrepancies in 28 (40%), expected resolution of condition in 14 (20%), and minor discrepancies in 28 (40%) patients. No significant difference with respect to discrepancies was detected between tele- and recorded-echos. There was significant (p<0.01) improvement in tele- and recorded-echo study quality by 2010. CONCLUSIONS: (1) Tele echocardiography can be performed successfully with excellent accuracy. (2) The quality of tele- and recorded-echo studies improved toward the end of the analysis period. (3) Although initially tele-echo studies were more accurate than recorded-echo studies, there was no difference between these two types of studies by the fourth year of the study. (4) Both tele- and recorded-echos were indispensible in the remote diagnosis of CHD. PMID- 23101484 TI - Just-in-time cost-effective off-the-shelf remote telementoring of paramedical personnel in bedside lung sonography-a technical case study. AB - PURPOSE: Remote telementored ultrasound (RTMUS) is a new discipline that allows a remote expert to guide variably experienced clinical responders through focused ultrasound examinations. We used the examination of the pleural spaces after tube thoracostomy (TT) removal by a nurse with no prior ultrasound experience as an illustrative but highly accurate example of the technique using a simple cost effective system. MATERIALS AND METHODS: The image outputs of a handheld ultrasound machine and a head-mounted Web camera were input into a customized graphical user interface and streamed over a freely available voice over Internet protocol system that allowed two-way audio and visual communication between the novice examiner and the remote expert. The bedside nurse was then guided to examine the anterior chest of a patient who had recently had bilateral TTs removed. The team sought to determine the presence or absence of any recurrent pneumothoraces using the standard criteria for the ultrasound diagnosis of post removal pneumothorax (PTXs). An upright chest radiograph (CXR) was obtained immediately after the RTMUS examination. RESULTS: The RTMUS system enabled the novice user to learn how to hold the ultrasound probe, where to place it on the chest, and thereafter to diagnose a subtle unilateral PTX characterized as "tiny" on the subsequent formal CXR report. CONCLUSIONS: As ultrasound has almost limitless clinical utility, using simple but advanced informatics and communication technologies has potential to improve worldwide healthcare delivery. RTMUS could be used both to enhance the information content as well as to digitally document important physiologic findings in any clinical encounter wherever a portable ultrasound and Internet connectivity are available. PMID- 23101485 TI - Weighing risks and benefits of stress ulcer prophylaxis in critically ill patients. AB - BACKGROUND: Recent observational studies suggest that bleeding from stress ulceration is extremely uncommon in intensive care unit patients. Furthermore, the risk of bleeding may not be altered by the use of acid suppressive therapy. Early enteral tube feeding (initiated within 48 h of intensive care unit admission) may account for this observation. Stress ulcer prophylaxis may, however, increase the risk of hospital-acquired pneumonia and Clostridia difficile infection. METHODS: Objective: A systematic review of the literature to determine the benefit and risks of stress ulcer prophylaxis and the moderating effect of enteral nutrition. Design: Data Sources: MEDLINE, Embase, Cochrane Register of Controlled Trials, and citation review of relevant primary and review articles. Study selection: Randomized, controlled studies that evaluated the association between stress ulcer prophylaxis and gastro intestinal bleeding. The authors included only those studies that compared a histamine-2 receptor blocker with a placebo. Data extraction: Data were abstracted on study design, study size, study setting, patient population, histamine-2 receptor blocker and dosage used, incidence of clinically significant gastrointestinal bleeding, hospital acquired pneumonia, mortality, and the use of enteral nutrition. RESULTS: Seventeen studies (which enrolled 1836 patients) met the inclusion criteria. Patients received adequate enteral nutrition in three of the studies. Overall, stress ulcer prophylaxis with a histamine-2 receptor blocker reduced the risk of gastrointestinal bleeding (odds ratio 0.47; 95% confidence interval, 0.29-0.76; P < 0.002; Heterogeneity [I2] = 44%); however, the treatment effect was noted only in the subgroup of patients who did not receive enteral nutrition. In those patients who were fed enterally, stress ulcer prophylaxis did not alter the risk of gastrointestinal bleeding (odds ratio 1.26; 95% confidence interval, 0.43 3.7). Overall histamine-2 receptor blockers did not increase the risk of hospital acquired pneumonia (odds ratio 1.53; 95% confidence interval, 0.89-2.61; P = 0.12; I2 = 41%); however, this complication was increased in the subgroup of patients who were fed enterally (odds ratio 2.81; 95% confidence interval, 1.20 6.56; P = 0.02; I2 = 0%). Overall, stress ulcer prophylaxis had no effect on hospital mortality (odds ratio 1.03; 95% confidence interval, 0.78-1.37; P = 0.82). The hospital mortality was, however, higher in those studies (n = 2) in which patients were fed enterally and received a histamine-2 receptor blocker (odds ratio 1.89; 95% confidence interval, 1.04-3.44; P = 0.04, I2 = 0%). Sensitivity analysis and metaregression demonstrated no relationship between the treatment effect (risk of gastrointestinal bleeding) and the classification used to define gastrointestinal bleeding, the Jadad quality score or the year the study was reported. CONCLUSIONS: The results of this meta-analysis suggest that, in those patients receiving enteral nutrition, stress ulcer prophylaxis may not be required and, indeed, such therapy may increase the risk of pneumonia and death. However, because no clinical study has prospectively tested the influence of enteral nutrition on the risk of stress ulcer prophylaxis, those findings should be considered exploratory and interpreted with some caution. PMID- 23101487 TI - Lochia patterns among normal women: a systematic review. AB - BACKGROUND: We conducted a systematic review of the literature to determine the amount and duration of blood loss 24 hours to 12 weeks after delivery. METHODS: We searched MEDLINE, CINAHL, and PubMed for studies between the years 1950 and 2011 that prospectively evaluated the amount and duration of blood loss from 24 hours to 12 weeks after delivery. Excluded were those that were only case studies, retrospective studies, studies not published in English, studies outside of the time frame, and studies that included only subjects from special populations. RESULTS: From the 333 identified studies, 18 met inclusion criteria. There was variability in how the amount of blood loss was determined, ranging from subject self-assessment to objective measures, such as pad weight and spectrophotometric readings of hematin concentration. The reported duration of normal blood loss after delivery varied among the studies. Whereas the average duration of blood loss in these studies ranged from 24 to 36 days, in only 1 study was bleeding followed to cessation. CONCLUSIONS: An understanding of bleeding patterns after delivery is important for clinicians to recognize deviations from normal, identify women at risk for delayed postpartum hemorrhage, and limit unnecessary interventions, yet studies reveal significant variability in amount and duration of normal lochial blood loss and methods of assessment that are inconsistent. This review draws attention to the need for the establishment of valid, reliable, and feasible methods to quantify normal and abnormal postpartum blood loss. PMID- 23101486 TI - Systems of career influences: a conceptual model for evaluating the professional development of women in academic medicine. AB - BACKGROUND: Surprisingly little research is available to explain the well documented organizational and societal influences on persistent inequities in advancement of women faculty. METHODS: The Systems of Career Influences Model is a framework for exploring factors influencing women's progression to advanced academic rank, executive positions, and informal leadership roles in academic medicine. The model situates faculty as agents within a complex adaptive system consisting of a trajectory of career advancement with opportunities for formal professional development programming; a dynamic system of influences of organizational policies, practices, and culture; and a dynamic system of individual choices and decisions. These systems of influence may promote or inhibit career advancement. Within this system, women weigh competing influences to make career advancement decisions, and leaders of academic health centers prioritize limited resources to support the school's mission. RESULTS AND CONCLUSIONS: The Systems of Career Influences Model proved useful to identify key research questions. We used the model to probe how research in academic career development might be applied to content and methods of formal professional development programs. We generated a series of questions and hypotheses about how professional development programs might influence professional development of health science faculty members. Using the model as a guide, we developed a study using a quantitative and qualitative design. These analyses should provide insight into what works in recruiting and supporting productive men and women faculty in academic medical centers. PMID- 23101488 TI - Second-hand exposure to tobacco smoke and its effect on disease activity in Swedish rheumatoid arthritis patients. Data from BARFOT, a multicenter study of RA. AB - OBJECTIVES: We studied the prevalence and effect on disease activity of ever having had second-hand exposure to tobacco smoke in Swedish rheumatoid arthritis (RA) patients who had never smoked. METHODS: Between 1992 and 2005, 2,800 patients were included in the BARFOT early-RA study in Sweden. Disease Activity Score 28 joints (DAS28), C-reactive protein (CRP), Health Assessment Questionnaire (HAQ), rheumatoid factor (RF), general health and pain visual analogue scales (VAS), and drug treatment were registered at inclusion and at follow-up at 3, 6, and 12 months and 2 and 5 years. EULAR response criteria were applied at the same follow-up points. In 2010, a self-completion postal questionnaire was sent to 2,102 patients in the BARFOT study enquiring about lifestyle habits such as whether they had ever been exposed to tobacco smoke as a result of someone else smoking. RESULTS: A total of 963/1,421 patients (68%) had had second-hand exposure to tobacco smoke. At 3, 6, and 12 months, at 2 years, and at 5 years of follow-up, there were no differences in EULAR response between patients who had never smoked and who had been exposed or had not been exposed second-hand to tobacco smoke (p=0.91, p=0.88, p=0.84, p=0.61 and p=0.85, respectively). CONCLUSIONS: We did not find any association between second-hand exposure to tobacco smoke and disease activity in RA. PMID- 23101489 TI - The East Flanders Prospective Twin Survey (EFPTS): an actual perception. AB - The East Flanders Prospective Twin Survey (EFPTS) is a prospective, population based registry of multiple births in the province of East-Flanders, Belgium. EFPTS has several unique features: it is population-based and prospective, with the possibility of long-term follow-up; the twins (and higher order multiple births) are recruited at birth; basic perinatal data recorded; chorion type and zygosity established; and since 1969 placental biopsies have been taken and frozen at -20 degrees C for later determination of genetic markers. The EFPTS is the only large register that includes placental data and allows differentiation of three subtypes of monozygotic (MZ) twins based on the time of the initial zygotic division: the dichorionic-diamnionic pairs (early, with splitting before the fourth day after fertilization), the monochorionic-diamnionic pairs (intermediate, splitting between the fourth and the seventh day post fertilization), and the monochorionic-monoamnionic pairs (late, splitting after the eighth day post-fertilization). Studies can be initiated taking into account primary biases, those originating 'in utero'. Such studies could throw new light on the controversy over the validity of the classic twin method, the consequences of early embryological events, and the gene-environment interactions as far as periconceptional and intrauterine environment are concerned. PMID- 23101490 TI - Self-assembly of conjugated polymer on hybrid nanospheres for cellular imaging applications. AB - A new kind of hybrid core-shell nanosphere was fabricated by combining the in situ formation of Au nanoparticles and covalent cross-linking of biocompatible carboxymethyl starch dialdehyde (CMSD) and chitosan (CTS). When the fluorescent dye poly[9,9'-bis(6"-(N,N,N-trimethylammonium)-hexyl)fluorene-2,7-ylenevinylene co-alt-1,4-phenylene dibromide] (PFV) was assembled on the surface of the hybrid nanospheres through electrostatic attraction, these biocompatible hybrid nanospheres exhibited metal-enhanced fluorescence effects. The fluorescence intensity of (CTS-Au)@CMSD/PFV hybrid nanosphere is 1.43 times that of CTS CMSD/PFV hybrid nanospheres lacking Au nanoparticle. In addition, the (CTS Au)@CMSD/PFV hybrid nanospheres exhibit excellent biodegradability upon exposure to enzymatic aqueous solution and good biocompatibility when cocultured with HeLa cervical carcinoma cells; these advantages make them attractive for cellular imaging and biological analysis and detection. PMID- 23101491 TI - Pd-catalyzed tandem cyclization of ethyl glyoxalate and amines: rapid assembly of highly substituted cyclic dehydro-alpha-amino acid derivatives. AB - A novel cascade cyclization of ethyl glyoxalate and amines proceeds in the presence of Pd(TFA)(2) (5 mol %) to give the cyclic dehydro-alpha-amino acid derivatives. This method provides a fast and simple access to highly substituted dihydro-pyrrol-2-ones in good yields. PMID- 23101494 TI - Adolescents with lesbian mothers describe their own lives. AB - Empirical research on the everyday life experiences of adolescents reared by lesbian mothers is limited. The current study gathered self-report descriptive data from 78 adolescents enrolled in the largest, longest-running, prospective longitudinal study of planned lesbian families, with a 93% retention rate to date. Results revealed that the 17-year-old adolescents were academically successful in supportive school environments. They had active social networks and close family bonds. Nearly all considered their mothers good role models. The adolescents rated their overall wellbeing an average of 8.14 on a 10-point maximum scale. The implications of these findings for research and practice are discussed. PMID- 23101492 TI - In vivo susceptibility of Plasmodium falciparum to artesunate in Binh Phuoc Province, Vietnam. AB - BACKGROUND: By 2009, there were worrying signs from western Cambodia that parasitological responses to artesunate-containing treatment regimens for uncomplicated Plasmodium falciparum malaria were slower than elsewhere which suggested the emergence of artemisinin resistance. Vietnam shares a long land border with Cambodia with a large number of migrants crossing it on a daily basis. Therefore, there is an urgent need to investigate whether there is any evidence of a change in the parasitological response to the artemisinin derivatives in Vietnam. METHODS: From August 2010 to May 2011, a randomized controlled clinical trial in uncomplicated falciparum malaria was conducted to compare two doses of artesunate (AS) (2mg/kg/day versus 4 mg/kg/day for three days) followed by dihydroartemisinin-piperaquine (DHA-PPQ) and a control arm of DHA-PPQ. The goal was characterization of the current efficacy of artesunate in southern Vietnam. The primary endpoint of this study was the parasite clearance half-life; secondary endpoints included the parasite reduction ratios at 24 and 48 hours and the parasite clearance time. RESULTS: 166 patients were recruited into the study. The median parasite clearance half-lives were 3.54 (AS 2mg/kg), 2.72 (AS 4mg/kg), and 2.98 hours (DHA-PPQ) (p=0.19). The median parasite reduction ratio at 24 hours was 48 in the AS 2mg/kg group compared with 212 and 113 in the other two groups, respectively (p=0.02). The proportions of patients with a parasite clearance time of >72 hours for AS 2mg/kg, AS 4mg/kg and DHA-PPQ were 27%, 27%, and 22%, respectively. Early treatment failure occurred in two (4%) and late clinical failure occurred in one (2%) of the 55 patients in the AS 2mg/kg group, as compared with none in the other two study arms. The PCR corrected adequate clinical and parasitological response (APCR) rates in the three groups were 94%, 100%, and 100% (p=0.04). CONCLUSIONS: This study demonstrated faster P. falciparum parasite clearance in southern Vietnam than in western Cambodia but slower clearance in comparison with historical data from Vietnam. Further studies to determine whether this represents the emergence of artemisinin resistance in this area are needed. Currently, the therapeutic response to DHA-PPQ remains satisfactory in southern Vietnam. TRIAL REGISTRATION: NTC01165372. PMID- 23101495 TI - Marriage and the homosexual body: it's about race. AB - Any analogy between race and homosexuality cannot erase the fact that skin color has marked and continues to mark bodies for special punishment and necessary protection. Yet, the analogy has also been forged in the struggles against sexual discrimination and in the courts to recognize same-sex marriage as a basic civil right. My purposes here are, first, to review the role the race-sexual orientation analogy has played in same-sex marriage debates, second to examine the analogy within the context of race and queer theories and, finally, to suggest a racial dimension to sexuality that marks the homosexual body. PMID- 23101496 TI - The relationship between socioeconomic factors, wellbeing, and homosexuality in the theatrical profession. AB - This article relates to the theory suggesting that there is a prevalence of male homosexuality within the theatrical profession that can be explained through male performers becoming homosexual due to their low socioeconomic position. In a questionnaire-based study, the socioeconomic status (SES) is measured of 121 homosexual performers who considered themselves to have been heterosexual at the time of joining the profession, and results are compared with a control group of 121 heterosexual male performers. The experimental group was chosen in this way due to the suggestion of the hypothesis that the change in sexual orientation occurs after the man begins performing professionally. Results were not significant and little difference was noted in any of the parameters of SES, including annual earnings and home ownership. However, a marginal though insignificant increase in SES was noted in the experimental group of homosexual men. Consequently, existing theories for homosexuality and possible reasons for the high prevalence within the performing profession are discussed; the notions of adult performing and creativity being extensions of childhood gender atypical behavior are considered and possible links between sexual orientation and these traits. Elements of genetic heritability of homosexuality are likewise implicated. PMID- 23101497 TI - A scale on beliefs about children's adjustment in same-sex families: reliability and validity. AB - In this study, we developed a new instrument named Scale Beliefs about Children's Adjustment on Same-Sex Families (SBCASSF). The scale was developed to assess of the adults' beliefs about negative impacts on children who are raised by same-sex parents. An initial pool of 95 items was generated by the authors based on a review of the literature on homophobia and feedback from several focus groups. Research findings, based on a sample of 212 university students (mean age 22 years, SD = 8.28), supported the reliability and validity of the scale. The final versions of the SBCASSF included items reflecting the following two factors: individual opposition (alpha = .87) and normative opposition (alpha = .88). Convergent validity of the scale is demonstrated by predictable correlations with beliefs about the cause of same-sex sexual orientation and the support for gay and lesbian rights. Our study reveals a strong positive association between high scores on SBCASSF and beliefs that the origin of same-sex sexual orientation is learned and opposition to gay and lesbian rights. PMID- 23101498 TI - Analysis of GLBTQ youth community-based programs in the United States. AB - Gay, lesbian, bisexual, transgender, and queer/questioning (GLBTQ) youth face oppression despite some increases in cultural support for GLBTQ individuals. Research has revealed the psychological and social distress associated with oppression and the benefits of peer social support programs. This study was conducted to analyze the types and frequency of services, age of participants, and organizational structures of the 116 GLBTQ community-based programs operating in the United States. Using an Internet survey, information from 61 of the programs was secured. The results revealed the community-based youth programs provide critical and unique programs and services that can promote the mental and physical health of GLBTQ youth. PMID- 23101499 TI - Growing support for gay and lesbian equality since 1990. AB - Since 1991, public acceptance of gays and lesbians has grown dramatically. We use two approaches to examine changing attitudes in U.S. survey data. First, we conduct cohort analyses showing that both generational replacement and period effects are having impacts. Since 1991, older, less accepting generations of Americans have been dying and being replaced by younger, more tolerant Americans, and all age groups have been becoming more tolerant. Second, we pool cross sectional, time series survey data to show that there has been a broad, dramatic increase in virtually every group's acceptance of gays and lesbians over time. PMID- 23101501 TI - Mechanistic studies on Lewis acid catalyzed Biginelli reactions in ionic liquids: evidence for the reactive intermediates and the role of the reagents. AB - This paper describes the use of common Lewis acids supported in imidazolium-based ionic liquids as the catalysts to promote the Biginelli reaction. The ionic liquid effect and the reaction mechanism are discussed on the basis of nuclear magnetic resonance (NMR), electrospray ionization mass spectrometry (ESI-MS), and theoretical calculations. Indeed, the results showed that the ionic medium plays a fundamental role in the synthesis of biologically active dihydropyrimidinones due to the stabilization of the charged intermediates proposed in the mechanism. When conducted in an ionic liquid as solvent, the reaction mechanism is more complex than in other Lewis acid catalyzed Biginelli reactions. PMID- 23101500 TI - Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions. AB - BACKGROUND: Neurofibromatosis type-1 (NF1) is caused by mutations of the NF1 gene at 17q11.2. In 95% of non-founder NF1 patients, NF1 mutations are identifiable by means of a comprehensive mutation analysis. 5-10% of these patients harbour microdeletions encompassing the NF1 gene and its flanking regions. NF1 is characterised by tumours of the peripheral nerve sheaths, the pathognomonic neurofibromas. Considerable inter- and intra-familial variation in expressivity of the disease has been observed which is influenced by genetic modifiers unrelated to the constitutional NF1 mutation. The number of plexiform neurofibromas (PNF) in NF1 patients is a highly heritable genetic trait. Recently, SNP rs2151280 located within the non-coding RNA gene ANRIL at 9p21.3, was identified as being strongly associated with PNF number in a family-based association study. The T-allele of rs2151280, which correlates with reduced ANRIL expression, appears to be associated with higher PNF number. ANRIL directly binds to the SUZ12 protein, an essential component of polycomb repressive complex 2, and is required for SUZ12 occupancy of the CDKN2A/CDKN2B tumour suppressor genes as well as for their epigenetic silencing. METHODS: Here, we explored a potential association of PNF number and PNF volume with SNP rs2151280 in 29 patients with constitutional NF1 microdeletions using the exact Cochran-Armitage test for trends and the exact Mann-Whitney-Wilcoxon test. Both the PNF number and total tumour volume in these 29 NF1 patients were assessed by whole-body MRI. The NF1 microdeletions observed in these 29 patients encompassed the NF1 gene as well as its flanking regions, including the SUZ12 gene. RESULTS: In the 29 microdeletion patients investigated, neither the PNF number nor PNF volume was found to be associated with the T-allele of rs2151280. CONCLUSION: Our findings imply that, at least in patients with NF1 microdeletions, PNF susceptibility is not associated with rs2151280. Although somatic inactivation of the NF1 wild-type allele is considered to be the PNF-initiating event in NF1 patients with intragenic mutations and patients with NF1 microdeletions, both patient groups may differ with regard to tumour progression because of the heterozygous constitutional deletion of SUZ12 present only in patients with NF1 microdeletions. PMID- 23101502 TI - Smaller sulfur molecules promise better lithium-sulfur batteries. AB - The lithium-sulfur battery holds a high theoretical energy density, 4-5 times that of today's lithium-ion batteries, yet its applications have been hindered by poor electronic conductivity of the sulfur cathode and, most importantly, the rapid fading of its capacity due to the formation of soluble polysulfide intermediates (Li(2)S(n), n = 4-8). Despite numerous efforts concerning this issue, combatting sulfur loss remains one of the greatest challenges. Here we show that this problem can be effectively diminished by controlling the sulfur as smaller allotropes. Metastable small sulfur molecules of S(2-4) were synthesized in the confined space of a conductive microporous carbon matrix. The confined S(2 4) as a new cathode material can totally avoid the unfavorable transition between the commonly used large S(8) and S(4)(2-). Li-S batteries based on this concept exhibit unprecedented electrochemical behavior with high specific capacity, good cycling stability, and superior rate capability, which promise a practicable battery with high energy density for applications in portable electronics, electric vehicles, and large-scale energy storage systems. PMID- 23101503 TI - The diagnosis and surgical treatment of occult otogenic CSF leakage. AB - CONCLUSIONS: The diagnosis of occult otogenic cerebrospinal fluid (CSF) leakage is challenging and it can easily be misdiagnosed. Some characteristics of clinical presentation can supply important clues and confirmed diagnosis should be obtained according to these clues and suitable imaging studies before meningitis develops. Different surgical techniques should be adopted to treat the CSF leakage according to different leakage etiologies, and good results can be obtained. OBJECTIVE: The aim of the study was to evaluate the diagnosis and surgical treatment of occult otogenic CSF leakage, including the characteristics of clinical presentation, imaging studies, and operation methods in order to decrease the rate of misdiagnosis and obtain a good curative effect. METHODS: We performed a retrospective review of 11 cases of CSF leakage that were all misdiagnosed and accompanied by meningitis, operated in our department from 2007 to 2012 after a mean follow-up of 3 years. In this context, the characteristics of clinical presentation, imaging studies, and management of CSF leakage were studied. RESULTS: The CSF leakage had arisen traumatically (n = 9) or congenitally (n = 2). The medical history and special clinical presentation such as repeated otorrhea or rhinorrhea, fever, headache, and unilateral deafness can supply important diagnostic clues. Imaging studies including high-resolution noncontrast CT (HRCT), CT cisternography, and magnetic resonance imaging (MRI) are very important diagnostic methods. The surgical repairs were performed via a transmastoid approach (n = 8), packing the vestibule (n = 1) or a translabyrithine approach (n = 2). Recurrent leakage did not occur. PMID- 23101505 TI - Bioinformatics: living on the edge. AB - A report on the 11th European Conference on Computational Biology (ECCB), Basel, Switzerland, September 9-12, 2012. PMID- 23101504 TI - Factors influencing the implementation of a lifestyle counseling program in patients with venous leg ulcers: a multiple case study. AB - BACKGROUND: Implementation of lifestyle interventions in patient care is a major challenge. Understanding factors that influence implementation is a first step in programs to enhance uptake of these interventions. A lifestyle-counseling intervention, Lively Legs, delivered by trained nurses, can effectively improve the lifestyle in patients with venous leg ulcers. The aim of this study was to identify factors that hindered or facilitated implementation of this intervention in outpatient dermatology clinics and in home care. METHODS: A mixed-methods multiple case study in five purposefully selected healthcare settings in the Netherlands was conducted. Measurements to identify influencing factors before and after implementation of Lively Legs included interviews, focus groups, questionnaires, and nurses' registration. Analyses focused on qualitative data as the main data source. All data were compared across multiple cases to draw conclusions from the study as a whole. RESULTS: A total of 53 patients enrolled in the Lively Legs program, which was delivered by 12 trained nurses. Barriers for implementation were mainly organizational. It was difficult to effectively organize reaching and recruiting patients for the program, especially in home care. Main barriers were a lack of a standardized healthcare delivery process, insufficient nursing time, and a lack of motivated nurses to deliver the program. Facilitating factors were nurse-driven coordination of care and a standardized care process to tie Lively Legs into, as this resulted in better patient recruitment and better program implementation. CONCLUSIONS: This study identified a range of factors influencing the implementation of a lifestyle-counseling program, mainly related to the organization of healthcare. Using a case study method proved valuable in obtaining insight into influencing factors for implementation. This study also shed light on a more general issue, which is that leg ulcer care is often fragmented, indicating that quality improvement is needed. PMID- 23101506 TI - The West Japan Twins and Higher Order Multiple Births Registry. AB - The West Japan Twins and Higher Order Multiple Births Registry was established in the 1990s by recruiting young twins and multiples and through referrals from public health centers. To date, over 7,000 twins and 4,300 higher order multiple births and their families have been registered in the survey, and it includes one of the largest triplet samples in the world. Follow-up questionnaires are also mailed every 2 to 3 years as part of longitudinal survey studies. This article describes the goals of the registry, the recruitment of multiples, and the overall focus of the study. The goals of the registry are not only to provide data for research on human genetics and maternal and child health, but also to provide appropriate information for families with multiples. PMID- 23101507 TI - Body fluid identification in forensics. AB - Determination of the type and origin of the body fluids found at a crime scene can give important insights into crime scene reconstruction by supporting a link between sample donors and actual criminal acts. For more than a century, numerous types of body fluid identification methods have been developed, such as chemical tests, immunological tests, protein catalytic activity tests, spectroscopic methods and microscopy. However, these conventional body fluid identification methods are mostly presumptive, and are carried out for only one body fluid at a time. Therefore, the use of a molecular genetics-based approach using RNA profiling or DNA methylation detection has been recently proposed to supplant conventional body fluid identification methods. Several RNA markers and tDMRs (tissue-specific differentially methylated regions) which are specific to forensically relevant body fluids have been identified, and their specificities and sensitivities have been tested using various samples. In this review, we provide an overview of the present knowledge and the most recent developments in forensic body fluid identification and discuss its possible practical application to forensic casework. PMID- 23101508 TI - Physiological roles of N-acetylglucosaminyltransferase V(GnT-V) in mice. AB - Oligosaccharide modification by N-acetylglucosaminyltransferase- V (GnT-V), a glycosyltransferase encoded by the Mgat5 gene that catalyzes the formation of beta1,6GlcNAc (N-acetylglucosamine) branches on N-glycans, is thought to be associated with cancer growth and metastasis. Overexpression of GnT-V in cancer cells enhances the signaling of growth factors such as epidermal growth factor by increasing galectin-3 binding to polylactosamine structures on receptor N glycans. In contrast, GnT-V deficient mice are born healthy and lack beta1,6GlcNAc branches on N-glycans, but develop immunological disorders due to T cell dysfunction at 12-20 months of age. We have developed Mgat5 transgenic (Tg) mice (GnT-V Tg mice) using a beta-actin promoter and found characteristic phenotypes in skin, liver, and T cells in the mice. Although the GnT-V Tg mice do not develop spontaneous cancers in any organs, there are differences in the response to external stimuli between wild-type and GnT-V Tg mice. These changes are similar to those seen in cancer progression but are unexpected in some aspects. In this review, we summarize what is known about GnT-V functions in skin and liver cells as a means to understand the physiological roles of GnT-V in mice. PMID- 23101509 TI - Peroxiredoxin I deficiency attenuates phagocytic capacity of macrophage in clearance of the red blood cells damaged by oxidative stress. AB - The role of peroxiredoxin (Prx) I as an erythrocyte antioxidant defense in red blood cells (RBCs) is controversial. Here we investigated the function of Prx I by using Prx I(-/-) and Prx I/II(-/-) mice. Prx I(-/-) mice exhibited a normal blood profile. However, Prx I/II(-/-) mice showed more significantly increased Heinz body formation as compared with Prx II(-/-) mice. The clearance rate of Heinz body-containing RBCs in Prx I(-/-) mice decreased significantly through the treatment of aniline hydrochloride (AH) compared with wild-type mice. Prx I deficiency decreased the phagocytic capacity of macrophage in clearing Heinz body containing RBCs. Our data demonstrate that Prx I deficiency did not cause hemolytic anemia, but showed that further increased hemolytic anemia symptoms in Prx II(-/-) mice by attenuating phagocytic capacity of macrophage in oxidative stress damaged RBCs, suggesting a novel role of Prx I in phagocytosis of macrophage. PMID- 23101510 TI - 1,8-cineole protected human lipoproteins from modification by oxidation and glycation and exhibited serum lipid-lowering and anti-inflammatory activity in zebrafish. AB - We recently reported that a water extract of laurel or turmeric, 1,8-cineole enriched fractions, showed hypolipidemic activity in the zebrafish model. Therefore, the present study investigated the cineole's anti-oxidant and anti inflammatory activities in lipoprotein metabolism in vitro and in vivo. Cineole had inhibitory effects on cupric ion-mediated oxidation of lipoproteins in general, while simultaneously enhancing ferric ion removal ability in high density lipoprotein (HDL). Hypercholesterolemia was induced in zebrafish using cholesterol-feeding treatment, 4% cholesterol, for 3 weeks. After feeding with or without the addition of cineole, the results revealed that cineole possessed lipid-lowering and anti-inflammatory activities in hypercholesterolemic zebrafish. In addition, serum amyloid A and interleukin-6 levels were lowered and lipid accumulation was decreased in the liver. Conclusively, 1,8-cineole was found to have anti-oxidant activities in lipoprotein metabolism both in vitro and in vivo with simultaneous reduction of lipid accumulation in the liver of zebrafish. PMID- 23101511 TI - X-ray radiation at low doses stimulates differentiation and mineralization of mouse calvarial osteoblasts. AB - Radiotherapy is considered to cause detrimental effects on bone tissue eventually increasing bone loss and fracture risk. However, there is a great controversy on the real effects of irradiation itself on osteoblasts, and the mechanisms by which irradiation affects osteoblast differentiation and mineralization are not completely understood. We explored how X-ray radiation influences differentiation and bone-specific gene expression in mouse calvarial osteoblasts. Irradiation at 2 Gy not only increased differentiation and mineralization of the cells, but also upregulated the expression of alkaline phosphatase, type I collagen, osteopontin, and osteocalcin at early stages of differentiation. However, irradiation at higher doses (>2 Gy) did not stimulate osteoblast differentiation, rather it suppressed DNA synthesis by the cells without a toxic effect. Additional experiments suggested that transforming growth factor-beta 1 and runt transcription factor 2 play important roles in irradiation- stimulated bone differentiation by acting as upstream regulators of bone-specific markers. PMID- 23101512 TI - Mesodermal repression of single-minded in Drosophila embryo is mediated by a cluster of Snail-binding sites proximal to the early promoter. AB - single-minded (sim) is a master regulatory gene that directs differentiation in the central nervous system during Drosophila embryogenesis. Recent identification of the mesectoderm enhancer (MSE) of sim has led to the hypothesis that two Snail (Sna)-binding sites in the MSE may repress sim expression in the presumptive mesoderm. We provide evidence here that three Sna-binding sites proximal to the sim promoter, but not those of the MSE, are responsible for the mesodermal repression of sim in vivo. Using transgenic embryos injected with lacZ transgenes, we showed that sim repression in the mesoderm requires the three promoter-proximal Sna-binding sites. These results suggest that Sna represses the mesectodermal expression of sim by directly repressing the nearby promoter, and not by quenching adjacent transcriptional activators in the MSE. These data also showed how the MSE, lacking the three proximal Sna-binding sites, reproduced the endogenous pattern of sim expression in transgenic embryos. PMID- 23101513 TI - c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) are involved in Mycobacterium tuberculosis-induced expression of Leukotactin-1. AB - Leukotactin(Lkn)-1 is a CC chemokine and is upregulated in macrophages in response to Mycobacterium tuberculosis (MTB) infection. We investigated whether mitogen-activated protein kinases (MAPKs) are involved in MTB-induced expression of Lkn-1. The up-regulation of Lkn-1 by infection with MTB was inhibited in cells treated with inhibitors specific for JNK (SP600125) or p38 MAPK (SB202190). Since the up-regulation of Lkn-1 by MTB has been reported to be mediated by the PI3 K/PDK1/Akt signaling, we examined whether JNK and/or p38 MAPK are also involved in this signal pathway. MTB-induced Akt phosphorylation was blocked by treatment with JNK- or p38 MAPK-specific inhibitors implying that p38 and JNK are upstream of Akt. In addition, treatment with the PI3-K-specific inhibitor inhibited MTB stimulated activation of JNK or p38 MAPK implying that PI3-K is upstream of JNK and p38 MAPK. These results collectively suggest that JNK and p38 MAPK are involved in the signal pathway responsible for MTB-induced up-regulation of Lkn 1. PMID- 23101514 TI - Production of taxadiene from cultured ginseng roots transformed with taxadiene synthase gene. AB - Paclitaxel is produced by various species of yew trees and has been extensively used to treat tumors. In our research, a taxadiene synthase (TS) gene from Taxus brevifolia was used to transform the roots of cultured ginseng (Panax ginseng C.A. Meyer) to produce taxadiene, the unique skeletal precursor to taxol. The TS gene was successfully introduced into the ginseng genome, and the de novo formation of taxadiene was identified by mass spectroscopy profiling. Without any change in phenotypes or growth difference in a TS-transgenic ginseng line, the transgenic TSS3-2 line accumulated 9.1 MUg taxadiene per gram of dry weight. In response to the treatment of methyl jasmonate for 3 or 6 days, the accumulation was 14.6 and 15.9 MUg per g of dry weight, respectively. This is the first report of the production of taxadiene by engineering ginseng roots with a taxadiene synthase gene. PMID- 23101515 TI - The World Report on Disability as a blueprint for international, national, and local aphasia services. AB - This commentary aims to extend the debate of the lead article authors (Wylie, McAllister, Davidson, and Marshall, 2013) by translating the nine recommendations of the World Report on Disability into a plan of action for the aphasia community. Solutions for the advancement of aphasia science and services are presented at international (macro), national (meso), and local (micro) levels. Implications for speech-language pathologists and aphasia service delivery are discussed. An overarching call to action is the need for speech-language pathologists to support a strong and vibrant aphasia community at all levels, so that the voices of people with aphasia can be heard. PMID- 23101516 TI - Nano-Fe0 encapsulated in microcarbon spheres: synthesis, characterization, and environmental applications. AB - Nanoscaled zerovalent iron (ZVI) encapsulated in carbon spheres (nano-Fe0@CS) were prepared via a hydrothermal carbonization method, using glucose and iron(III) nitrate as precursors. The properties of the nano-Fe0@CS were investigated by X-ray diffraction (XRD), thermogravimetric analysis-differential scanning calorimetry (TGA-DSC), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and nitrogen adsorption/desorption isotherms. Nano-Fe0@CS was demonstrated, for the first time, as an effective material in activating Oxone (peroxymonosulfate, PMS) for the oxidation of organic pollutants. It was found that the efficiency of nano Fe0@CS was higher than ZVI particles, iron ions, iron oxides, and a cobalt oxide. The mechanism of the high performance was discussed. The structure of the nano Fe0@CS not only leads to high efficiency in the activation of PMS, but also good stability. This study extended the application of ZVI from reductive destruction of organics to oxidative degradation of organics by providing a green material for environmental remediation. PMID- 23101517 TI - Scaphotrapeziotrapezoid arthrodesis and lunate excision for advanced Kienbock disease. AB - PURPOSE: To analyze the outcomes of lunate excision combined with scaphotrapeziotrapezoid arthrodesis for the treatment of advanced Kienbock disease. METHODS: Sixteen patients with Lichtman stage IIIB Kienbock disease were treated with scaphotrapeziotrapezoid arthrodesis and lunate excision and were followed for a mean of 67 months (range, 49 to 108 mo). The indications for lunate excision included pain and limited motion associated with a collapsed lunate. Clinical evaluation included range of motion, grip strength, and modified Mayo wrist score. Based on plain radiographs, the carpal height ratio, ulnar carpal distance ratio, scaphoid translation ratio, and radioscaphoid angle were measured and any presence of degenerative changes was assessed. To investigate the effects of lunate excision on the radiologic results, we compared 12 patients with stage IIIB Kienbock disease who had only scaphotrapeziotrapezoid arthrodesis as the control group. RESULTS: Range of motion tended to be preserved, with a trend toward an increase in extension after surgery. Grip strength and modified Mayo score improved significantly. Fourteen patients with lunate excision demonstrated radiographic ulnar translation of the scaphoid beyond the scapholunate ridge, and radioscaphoid arthritis was observed in 4 patients. Compared to initial postoperative radiographs, the scaphoid translation ratio was significantly decreased, but neither ulnar carpal distance ratio nor radioscaphoid angle showed significant differences. In the control group, neither ulnar translation of the scaphoid nor significant changes of radiologic parameters was found between initial postoperative and final radiographs. CONCLUSIONS: Scaphotrapeziotrapezoid arthrodesis with lunate excision for advanced Kienbock disease provided favorable clinical results in terms of pain relief and functional improvement. With the absence of the lunate, however, the scaphoid had a tendency to shift toward the lunate fossa. This study suggests the risk of early development of radioscaphoid arthritis as a negative effect of lunate excision. PMID- 23101518 TI - Results after radioscapholunate arthrodesis with or without resection of the distal scaphoid pole. AB - PURPOSE: To evaluate the differences between radioscapholunate (RSL) arthrodesis alone versus RSL arthrodesis with additional distal scaphoidectomy. METHODS: We retrospectively evaluated 61 patients who were treated with RSL arthrodesis for painful posttraumatic osteoarthritis. Thirty patients had an RSL arthrodesis with additional resection of the distal scaphoid pole (group A), and 31 had RSL arthrodesis alone (group B). Six patients in group A and 8 in group B had the RSL arthrodesis converted to a complete wrist arthrodesis during follow-up. Those patients were excluded from the survey. Of the remaining 47 patients, 35 (20 from group A, 15 from group B) returned for a clinical and radiological examination at an average of 28 (range, 10-47) months after the index surgery. The results were rated by the Disabilities of the Arm, Shoulder, and Hand score and the modified Mayo Wrist Score. The patients' outcomes after RSL arthrodesis with or without distal scaphoidectomy were compared for pain, wrist motion, grip strength, nonunion rate, osteoarthritis of the adjacent joints, the Disabilities of the Arm, Shoulder, and Hand score and the modified Mayo Wrist Score. RESULTS: Three patients with RSL arthrodesis alone showed a radioscaphoid nonunion. All arthrodeses in group A healed. In the clinical evaluation, there was no significant difference between groups A and B in the Disabilities of the Arm, Shoulder, and Hand score, the modified Mayo Wrist Score, grip strength, pain, or wrist motion. Assuming that wrist motion might be better in patients with a nonunion, the average wrist motion was recalculated after eliminating 3 patients with a radioscaphoid nonunion from group B. Radial deviation was then found to be significantly better in group A. CONCLUSIONS: Additional distal scaphoidectomy with RSL arthrodesis seems to improve postoperative radial deviation of the wrist. The radioscaphoid nonunion rate is high with RSL arthrodesis alone. Distal scaphoidectomy appeared to increase the successful fusion rate of RSL arthrodeses. No significant effect on wrist extension, flexion, ulnar deviation, pain level, restriction in activities of daily living, or grip strength was noted. PMID- 23101519 TI - Four-corner arthrodesis concentrator of nickel-titanium memory alloy for carpal collapse: a report on 18 cases. AB - PURPOSE: To evaluate the treatment of carpal collapse using a four-corner arthrodesis concentrator of nickel-titanium memory alloy. METHODS: From August 2006 to August 2010, 18 patients with carpal collapse had scaphoid excision and four-corner (capitate, lunate, triquetrum, and hamate) arthrodesis using a nickel titanium memory alloy four-corner arthrodesis concentrator. The mean follow-up time was 30 months (range, 12-48). Various wrist parameters, including grip strength, wrist motion, and degree of pain were recorded and compared before and after surgery. RESULTS: The average fusion time was 2.3 months (range, 2-4). Neither nonunion nor wound infection was found in any of the patients. At one year follow-up, the grip strength had reached 80% of that of the healthy side, whereas the range of motion was greater than 50% of the contralateral side. After the surgery, the mean pain scores were improved. CONCLUSIONS: Four-corner arthrodesis using a nickel-titanium memory alloy four-corner arthrodesis concentrator effectively treated carpal collapse and preserved most wrist function. PMID- 23101520 TI - Interobserver variability among radiologists for diagnosis of scaphoid fractures by computed tomography. AB - PURPOSE: To determine the interobserver variability among radiologists for computed tomography (CT) diagnosis of scaphoid fractures. METHODS: Four specialized musculoskeletal radiologists evaluated the CT scans of 150 consecutive patients who were clinically suspected of having sustained a scaphoid fracture but whose scaphoid-specific radiographs were normal. The radiologists were asked to determine the presence or absence of a scaphoid fracture and to localize the fracture. Interobserver agreement was calculated using the kappa statistic. RESULTS: The radiologists diagnosed between 11 (7%) and 22 (15%) scaphoid fractures; the kappa value was 0.51. CONCLUSION: Agreement on the presence of a scaphoid fracture and its location on a CT scan was moderate among the 4 radiologists. This finding raises the question as to whether scaphoid fractures could be under- or overdiagnosed in daily practice when CT is used to exclude or confirm a fracture. This should be kept in mind when interpreting clinical and radiological results in patients with suspected scaphoid fractures. PMID- 23101521 TI - In vivo changes in contact regions of the radiocarpal joint during wrist hyperextension. AB - PURPOSE: Distal radius and scaphoid fractures commonly occur after a fall with the hand outstretched and wrist hyperextended. We investigated contact characteristics of the radiocarpal joint in neutral position, hyperextension, and hyperextension combined with radial deviation in vivo. METHODS: Eight volunteers without a known history of wrist injury were enrolled. We obtained computed tomography scans with 3-dimensional reconstructions of the subjects' right wrists in neutral, hyperextension, and hyperextension with 10 degrees of radial deviation. The contact regions of the radiocarpal joint were mapped. The direction and distance of changes in the contact region centers were recorded and analyzed. RESULTS: From neutral position to hyperextension, the contact of the scaphoid substantially shifted from the middle to the dorsal part of the articular surface of the radius in 5 of the 8 wrists. With these wrists further deviated radially, the contact shifted to the surface over the radial styloid. In the other wrists, the contact of the scaphoid remained in the center of the radial articular surface. In all wrists, the contact of the radius on the scaphoid shifted from the proximal lateral surface of the scaphoid to the proximal dorsal surface of the scaphoid, and the contact of the radius on the lunate shifted dorsally. CONCLUSIONS: During wrist hyperextension, the contact of the scaphoid on the distal radius exhibited 2 possible types of changes: either shifting from the mid-portion to the dorsal ridge of the articular surface of the radius or remaining at the center of the articular surface. Combined wrist hyperextension with radial deviation caused the scaphoid to contact the radius over the radial styloid. The contact of the radius on the scaphoid shifted from proximal lateral to proximal dorsal scaphoid, and that on the lunate shifted dorsally. CLINICAL RELEVANCE: This study provided in vivo mechanical findings to improve our understanding of the mechanism of hyperextension injuries of carpus. PMID- 23101522 TI - Fractional Fowler tenotomy for chronic mallet finger: a cadaveric biomechanical study. AB - PURPOSE: The Fowler tenotomy, adjusting the balance of the extensor mechanism by central slip and lateral band detachment, is a common surgical technique for chronic mallet finger. The purpose of this study was to determine how much tendon to detach from the middle phalanx by measuring the extensor lag of the distal interphalangeal (DIP) joint following the procedure and to quantify how often a boutonniere deformity occurred as a consequence of the procedure. METHODS: Sixteen fingers were obtained from 8 fresh-frozen cadaver hands. We made mallet finger deformity models by terminal tendon elongation. We detached the central slip and lateral band from the middle phalanx by one-third, one-half, and two thirds of the phalangeal length and measured extensor lag of the DIP and proximal interphalangeal joints before and after this procedure. RESULTS: In these models, the average extensor lag of the DIP joint was 44 degrees (range, 40 degrees to 50 degrees ). After central slip and lateral band detachment over one-third of the phalangeal length, the average residual extensor lag of the DIP joint was 19 degrees (range, 0 degrees to 40 degrees ). With one-half detachment, the average lag was 13 degrees (range, 0 degrees to 35 degrees ), and with two thirds detachment, the average lag was 6 degrees (range, 0 degrees to 15 degrees ). Extensor lag at the proximal interphalangeal joint occurred in 4 fingers, with an average lag of 8 degrees (range, 5 degrees to 15 degrees ). CONCLUSIONS: In the Fowler tenotomy models, detachment of the central slip and lateral band from the middle phalanx reduced extensor lag of the DIP joint. Detachment of up to two-thirds of the phalangeal length was effective in this model and did not cause any boutonniere deformity. CLINICAL RELEVANCE: Controlled clinical application of our cadaveric results might yield improved active motion for chronic mallet extensor lag. PMID- 23101523 TI - Resection of the flexor digitorum superficialis for trigger finger with proximal interphalangeal joint positional contracture. AB - PURPOSE: Open release of the A1 pulley is a widely known procedure for the treatment of trigger finger. A subset of patients presents with both trigger finger and a positional contracture of the proximal interphalangeal (PIP) joint. These patients usually have a long history of trigger finger or have already undergone a surgical release of the annular pulley. This study is a retrospective review of the outcomes of resection of the flexor digitorum superficialis (FDS) for patients whose trigger finger was associated with a positional contracture of the PIP joint. METHODS: Thirty-six patients (39 fingers) were treated by resection of the FDS after section of the A1 pulley. The mean age of the patients was 63 years (range, 45-90 y). Seven patients (19 %) had previously undergone an open release of the A1 pulley and had developed a positional contracture of the PIP joint 2 to 5 months afterward. We performed a retrospective review with a mean follow-up of 30 months (range, 12-60 mo). No patient was lost to follow-up. The active range of motion was recorded at the PIP joint before and after surgery. RESULTS: The mean preoperative positional contracture of the PIP joint was 24 degrees (range, 15 degrees -30 degrees ). The mean postoperative positional contracture of the PIP joint was 4 degrees (range, 0 degrees -10 degrees ). The most commonly affected digit was the middle finger (26 fingers, 67%). In 28 fingers (72%), full extension was achieved following only the surgical procedure. The remaining 11 fingers (28%) had a postoperative residual positional contracture (range, 5 degrees -10 degrees ). However, all fingers achieved a full range of motion after physical therapy and an injection of betamethasone. All of the resected tendons had histological damage. CONCLUSIONS: This technique is a useful treatment for selected patients whose trigger finger is associated with a positional contracture. PMID- 23101525 TI - Varied anatomy of the thumb pulley system: implications for successful trigger thumb release. AB - PURPOSE: The anatomical arrangement of the thumb pulley system continues to be revised through ongoing investigative research, changing our previous assumptions. This study demonstrates the components and anatomical features of this pulley system in an effort to improve surgical outcomes and to clarify current misconceptions. METHODS: Researchers procured 75 hand specimens from 41 adult cadavers through our institution's anatomical donations program. Dissections of the thumb and thenar compartment identified the various pulleys. A detailed analysis of the thumb pulleys was performed through various measurements. RESULTS: Four different pulley categories were identified: type I (n = 5), type II (n = 29), type III (n = 29), and type IV (n = 12). The variable annular pulley was present in 70 of 75 hands (93%) in 1 of 3 arrangements: transverse, oblique, or fused with the A1 pulley. CONCLUSIONS: The pulley system of the thumb is composed of 4 components, as opposed to the traditional view of only 3. Along with the A1 pulley, the additional variable annular pulley might contribute to stenosis in trigger thumb. This might necessitate a more extensive surgical incision and its partial release to relieve triggering. CLINICAL RELEVANCE: Understanding the anatomical configuration of the thumb pulley system will aid in the surgical attempt to resolve triggering while avoiding complications such as bowstringing of the flexor pollicis longus tendon and iatrogenic nerve injury. PMID- 23101524 TI - Percutaneous release of the A1 pulley: a cadaver study. AB - PURPOSE: Percutaneous release of the A1 pulley has been used for treatment of trigger fingers with success. However, lack of direct visualization raises concerns about the completeness of the release and about potential injury to the tendons or neurovascular structures. The purpose of this study was to assess the efficacy and safety of percutaneous release of the A1 pulley in a cadaveric model using a commonly available instrument, a #15 scalpel blade. METHODS: Fourteen fresh frozen cadaveric hands (54 fingers, thumbs excluded) were used. Landmarks were established for the A1 pulley based upon cutaneous features. Percutaneous release was performed using a #15 blade. The specimens were then dissected and examined for any tendon or neurovascular injury, and completeness of A1 pulley release was evaluated. RESULTS: There were 39 (72%) complete releases of the A1 pulley with 14 partial and 1 missed (failed) release. There was a 22% incidence of release of the proximal edge of the A2 pulley. However, there was no case of release of more than 25% of the A2 pulley length, nor was bowstringing of flexor tendons seen in these specimens. Eleven digits showed longitudinal scoring of the flexor tendons and 3 had partial tendon lacerations. No neurovascular injuries were noted. CONCLUSIONS: Percutaneous release of the A1 pulley using a #15 blade was associated with good efficacy and an acceptable margin of safety in this series. CLINICAL RELEVANCE: Percutaneous release of trigger digits may assume a greater role in the treatment of patients with trigger finger because of cost containment pressures. The data from this study suggest that the technique used in this study is both safe and effective. With use of proper anatomical guidelines, risk to neurovascular structures is low, although longitudinal scoring of the tendon can occur. PMID- 23101526 TI - Focal fibrocartilaginous dysplasia in the ulna: report on 3 cases. AB - Focal fibrocartilaginous dysplasia is an uncommon, benign bone lesion that causes deformity in young children. It is most commonly encountered in the proximal tibia, with few cases documented in the upper extremity. We report 3 cases affecting the ulna. In each case, the fibrous tissue appeared to anchor itself in the ulnar diaphysis, behaving as a tether that retards growth. All 3 patients had excision of the fibrous tissue. There was concern for radial head subluxation before surgical intervention, but all patients maintained a congruent radiocapitellar articulation. The visible deformity improved in all 3 patients, although the limbs remained shorter than the contralateral side. In our limited series, we believe that early excision of the fibrous tissue tether can prevent radiocapitellar joint dislocation in patients with focal fibrocartilaginous dysplasia of the ulna. PMID- 23101527 TI - Contribution of flexor pollicis longus to pinch strength: an in vivo study. AB - PURPOSE: To estimate the contribution of the flexor pollicis longus (FPL) to key pinch strength. Secondary outcomes include tip pinch, 3-point chuck pinch, and grip strength. METHODS: Eleven healthy volunteers consented to participate in the study. We recorded baseline measures for key, 3-point chuck, and tip pinch and for grip strength. In order to control for instability of the interphalangeal (IP) joint after FPL paralysis, pinch measurements were repeated after immobilizing the thumb IP joint. Measures were repeated after subjects underwent electromyography-guided lidocaine blockade of the FPL muscle. Nerve conduction studies and clinical examinations were used to confirm FPL blockade and to rule out median nerve blockade. Paired t-tests were used to compare pre- and postblock means for both unsplinted and splinted measures. The difference in means was used to estimate the contribution of FPL to pinch strength. RESULTS: All 3 types of pinch strength showed a significant decrease between pre- and postblock measurements. The relative contribution of FPL for each pinch type was 56%, 44%, and 43% for key, chuck, and tip pinch, respectively. Mean grip strength did not decrease significantly. Splinting of the IP joint had no significant effect on pinch measurements. CONCLUSIONS: FPL paralysis resulted in a statistically significant decrease in pinch strength. IP joint immobilization to simulate IP joint fusion did not affect results. CLINICAL RELEVANCE: Reconstruction after acute or chronic loss of FPL function should be considered when restoration of pinch strength is important. PMID- 23101528 TI - Radiographic early to midterm results of distraction osteogenesis in radial longitudinal deficiency. AB - PURPOSE: To analyze early to midterm radiographic results after forearm lengthening in children with radial longitudinal deficiency. METHODS: We conducted a retrospective chart review of patients with radial longitudinal deficiency undergoing distraction osteogenesis with an Ilizarov device. We retrospectively reviewed 8 lengthening procedures in 6 children with respect to distraction details and assessed anteroposterior and lateral radiographs of the hand and forearm of the preoperative and postoperative follow-up investigations. RESULTS: The mean age at time of ulna lengthening was 9.9 years (range, 6.3-14.0 y). The mean follow-up period was 4.7 years (range, 1.0-8.5 y). Mean lengthening of the ulna was 7.0 cm (range, 3.5-8.7 cm), and the mean length gain of the ulna compared with its preoperative length was 75% (range, 42% to 103%). The mean ulna bowing was 25 degrees preoperatively (range, 7 degrees to 42 degrees ), 6 degrees after forearm distraction (range, 0 degrees to 14 degrees ), and 17 degrees at latest follow-up (range, 0 degrees to 45 degrees ). The mean hand forearm angle was 25 degrees of radial deviation preoperatively (range, 15 degrees ulnar to 60 degrees radial deviation), 11 degrees of radial deviation after distraction (range, 0 degrees to 41 degrees ), and 23 degrees at latest follow-up (range, 0 degrees to 45 degrees ). We encountered 2 major complications: 1 ulna fracture after removal of the Ilizarov device and 1 insufficient bone regenerate during lengthening. CONCLUSIONS: We achieved both deformity correction and improvement of limb length after distraction osteogenesis with an Ilizarov device. However, some of the deformity-in particular, ulnar bowing and radial deviation of the hand-recurred at midterm follow-up. PMID- 23101529 TI - A radiographic method for evaluation of the index-hypoplastic thumb angle. AB - PURPOSE: Thumb metacarpophalangeal joint radial instability occurs during the pinch motion in patients with hypoplastic thumb because of thumb-index web narrowing. We devised a radiographic technique to measure the thumb-index angle, applied while the patient holds a styrene foam cone, to evaluate the relationship between the thumb and the index finger. We used this technique to compare different types of thumb hypoplasia and the groups before and after surgery. METHODS: Twenty patients with hypoplastic thumbs held the styrene foam cone. The average age of the patients was 6.5 years (range, 1.6 to 12.0 y). We obtained an overhead radiograph while the patient held the cone and evaluated the apparent thumb-index web angle, the thumb to index finger metacarpal angle (1-2MCA), and the first metacarpophalangeal angle (1MPA). RESULTS: In the 9 unilateral cases, no significant difference was detected between the unaffected side and the affected side in terms of thumb-index web angle, but the data showed meaningful differences in terms of 1-2MCA and 1MPA. In addition, the data showed meaningful differences between the groups before surgery and 2 years after surgery in terms of 1-2MCA and 1MPA. CONCLUSIONS: Measuring both 1-2MCA and 1MPA enables evaluation of the severity of the deformity, and these parameters allowed for comparative evaluation of the severity of preoperative and postoperative narrowing of thumb-index web space and the radial instability of the thumb metacarpophalangeal joint. By focusing on these characteristics, we devised a novel approach for imaging of the thumb-index web space. PMID- 23101530 TI - Arthroscopic repair of ulnar-sided triangular fibrocartilage complex (Palmer Type 1B) tears: a comparison between short- and midterm results. AB - PURPOSE: To compare short- and midterm functional and subjective outcomes of arthroscopically repaired Palmer 1B tears. METHODS: At 2 time points, we evaluated 49 patients with Palmer 1B tears who underwent arthroscopic repair. We examined 46 patients (23 males and 23 females) in the short-term at an average of 11 months (range, 6-23 mo) postoperatively. In a second midterm follow-up, we examined 40 patients (20 males and 20 females) an average of 4.8 years (range, 4.2-5.9 y) after repair. Between short- and midterm follow-ups, 6 patients underwent an ulnar-shortening osteotomy to alleviate persistent ulnar-sided symptoms. Objective and subjective evaluation included the determination of range of motion, grip strength, pain, and wrist scores (modified Mayo wrist score and Disabilities of Arm, Shoulder, and Hand score). RESULTS: Compared with short-term repair results, midterm outcomes showed a further improvement in pain, wrist scores, grip strength, and motion. Neither static nor dynamic ulnar variance was correlated to preoperative and postoperative Disabilities of the Arm, Shoulder, and Hand scores, short-term modified Mayo wrist scores, or need for ulnar shortening osteotomy. Five patients improved only after having received an ulnar shortening osteotomy. CONCLUSIONS: After repair of Palmer 1B lesions, patients continued to improve in function and comfort at least into the second year, although some needed to have the ulna shortened to achieve this result. PMID- 23101531 TI - Assessment of velocity, range, and smoothness of wrist circumduction using flexible electrogoniometry. AB - PURPOSE: To quantify the range, velocity, and smoothness of wrist circumduction, to explore the oblique functional plane of wrist circumduction, and to establish the reproducibility and reliability of these measures. METHODS: Forty healthy subjects with a mean age of 43 years and without a history of wrist pathology or pain participated in this study. We used a flexible electrogoniometer with a twin axis sensor to measure the relative angles between the 2 end blocks while the subject performed maximum excursion of flexion-extension, radioulnar deviation, and circumduction of the wrist held in a standardized, fully pronated position. A software package was used to further analyze the characteristics of the circumduction curve or oval such as the mean area (designated as degree-degree or oo) shape, size, rate, smoothness, and orientation. RESULTS: The mean area of circumduction (4729 [degree-degree]) and circumference (265 degrees ) of the circumduction curve indicated the total range of circumduction. The velocity of circumduction (mean 179 degrees /s) and the time (1.6 second) taken to complete 1 cycle of circumduction were similar in both hands. The 4 quadrants for the velocity of circumduction showed that the velocity was faster in the radioulnar deviation quadrants compared with flexion and extension. Quadrant analysis showed the smoothness was greater in the radioulnar deviation quadrants than in the flexion and extension quadrants. The oblique planes of the circumduction curves of all the normal wrists lie in ulnopalmar and radiodorsal direction with a mean angle of 28 degrees to the vertical flexion and extension plane. CONCLUSIONS: This technique was accurate and reliable in measuring the velocity, range, and smoothness of wrist circumduction. PMID- 23101532 TI - Functional outcome following nerve repair in the upper extremity using processed nerve allograft. AB - PURPOSE: Reconstruction of peripheral nerve discontinuities with processed nerve allograft has become increasingly relevant. The RANGER Study registry was initiated in 2007 to study the use of processed nerve allografts in contemporary clinical practice. We undertook this study to analyze outcomes for upper extremity nerve repairs contained in the registry database. METHODS: We identified an upper extremity-specific population within the RANGER Study registry database consisting of 71 nerves repaired with processed nerve allograft. This group was composed of 56 subjects with a mean age of 40 +/- 17 years (range, 18-86 y). We analyzed data to determine the safety and efficacy of processed nerve allograft. Quantitative data were available on 51 subjects with 35 sensory, 13 mixed, and 3 motor nerves. The mean gap length was 23 +/- 12 mm (range, 5-50 mm). We performed an analysis to evaluate response-to-treatment and to examine sensory and motor recovery according to the international standards for motor and sensory nerve recovery. RESULTS: There were no reported implant complications, tissue rejections, or adverse experiences related to the use of the processed nerve allografts. Overall recovery, S3 or M4 and above, was achieved in 86% of the procedures. Subgroup analysis demonstrated meaningful levels of recovery in sensory, mixed, and motor nerve repairs with graft lengths between 5 and 50 mm. The study also found meaningful levels of recovery in 89% of digital nerve repairs, 75% of median nerve repairs, and 67% of ulnar nerve repairs. CONCLUSIONS: Our data suggest that processed nerve allografts offer a safe and effective method of reconstructing peripheral nerve gaps from 5 to 50 mm in length. These outcomes compare favorably with those reported in the literature for nerve autograft, and exceed those reported for tube conduits. PMID- 23101533 TI - A modification of the palmaris longus-to-extensor pollicis longus transfer for radial nerve palsy. AB - PURPOSE: The standard palmaris longus (PL)-to-rerouted extensor pollicis longus (EPL) transfer was modified by taking the PL with an extension of the palmar aponeurosis (PA) and performing the transfer at the level of the thumb metacarpal. Our purpose was to evaluate whether this modified transfer could restore both the extension and the radial abduction of the thumb without rerouting the EPL. METHODS: We restored thumb function of 5 patients with unrecovered radial nerve palsy (4 men and 1 women; mean age at surgery, 47 years; mean duration between onset of palsy and surgery, 13 months; and mean follow-up period after surgery, 17 months). The PA was dissected in continuity with the PL (PA/PL) tendon, as is done in Camitz thumb opponensplasty. Another skin incision was made on the dorsal side of the thumb metacarpal, and the EPL tendon was exposed. The PA/PL tendon was drawn into this skin incision, passing under the abductor pollicis longus and extensor pollicis brevis tendons. The PA/PL tendon was woven into the undivided EPL tendon and immobilized for 3 weeks. RESULTS: The mean values of active hyperextension and flexion of the interphalangeal joint, radial abduction, palmar abduction of the thumb, grip strength, and tip pinch strength of the involved/contralateral sides were 3 degrees /7 degrees , 41 degrees /49 degrees , 59 degrees /65 degrees , 65 degrees /70 degrees , 37 kg/47 kg, and 4.0 kg/5.2 kg, respectively. DISCUSSION: We used the PA to lengthen the PL tendon, to transfer it to the EPL at a level distal to the Lister tubercle. Because our procedure is based on the concept of standard transfer, it should yield similar long-term results. Our procedure should be a good alternative, especially in cases of closed radial nerve injury, because it preserves the paralyzed EPL for possible future recovery. PMID- 23101534 TI - Optimal Jamar dynamometer handle position to assess maximal isometric hand grip strength in epidemiological studies. AB - PURPOSE: Hand grip strength is an indicator of general muscle strength that is measured using a hand dynamometer. In some studies, a subject's grip strength is taken to be the maximal grip strength achieved from measurements taken at several different dynamometer handle positions. However, little is known about the influence of these different positions on the measured grip strength. The aim of the study was to identify one standard handle position that could be used to assess the grip strength of all subjects. METHODS: Grip strength was assessed with a hand dynamometer (Jamar Plus+; Sammons Preston, Rolyon, Bolingbrook, IL). Each participant's grip strength was measured 3 times in each of 5 different handle positions with each hand. The best position for each participant was defined as the position at which they achieved maximal grip strength. RESULTS: The mean (+/- standard deviation) age of the 50 participants was 41 (+/- 13) years. Maximal grip strength was 43.7 (+/- 12.4) kg for all participants; 55.0 (+/- 10.2) kg for men and 35.4 (+/- 5.2) kg for women. Handle position 2 was the best position for 70% of participants. The mean difference between the grip strength achieved by each participant at handle position 2 and that achieved at each participant's best position was 0.8 (+/- 1.78) kg. CONCLUSIONS: Our results show that measurements taken at a single standard handle position are sufficiently accurate to assess grip strengths for all subjects. We therefore recommend handle position 2 as the standard position for measuring grip strength with the Jamar Plus+ hand dynamometer. CLINICAL RELEVANCE: The assessment of grip strength with the Jamar Plus+ dynamometer is easier and faster if a single, standard handle position is used rather than multiple different positions. As well as providing accurate results, a single, standard handle position also reduces fatigue and increases the comparability of results between subjects. PMID- 23101535 TI - Survey of hand surgeons regarding their perceived needs for an expanded upper extremity fellowship. AB - PURPOSE: To survey practicing hand surgeons regarding their perceived need for an expanded upper extremity fellowship. METHODS: Electronic surveys were sent to 248 surgeons who had completed a hand surgery fellowship between 2008 and 2010. The survey was structured to ascertain whether there was a need for expanded education encompassing the entire upper extremity. Four separate mailings were made. Of the 248 surgeons who were sent the survey, 131 (53%) responded. Of the respondents, 74% (97) were trained in orthopedics, 16% (21) in plastic surgery, and 10% (13) in general surgery. RESULTS: Of the 131 respondents, 7% (9) felt that 1 year of specialty training was insufficient, 48% (63) had sought shoulder and elbow training in their fellowship, and 52% (68) did not have dedicated plastic surgery rotations. Microsurgical experience was variable: 8% (10) of respondents had not been exposed to replantation, 23% (30) had not been exposed to free flap surgery, 32% (42) had not participated in brachial plexus surgery, and 17% (22) had not done a vascularized bone graft. Fifty-six percent (73) of respondents had not had dedicated time for research during their fellowship. Eleven percent (15) had obtained additional training after their fellowship, including shoulder and elbow, microsurgery, pediatrics, and peripheral nerve surgery. When asked if they would have applied to a 2-year hand and upper extremity fellowship, 60% (79) of respondents would have applied. CONCLUSIONS: Based on the results of this survey, 1 year of hand fellowship training has been perceived as inadequate by 7% (9) of respondents, with exposure insufficient in shoulder and elbow, microsurgery, pediatrics, and clinical research. Further critical review of hand fellowship education should be considered, with the availability of extended fellowship tracks for those requesting an increased breadth of upper extremity surgical training. PMID- 23101536 TI - Early experience with (dry) arthroscopic 4-corner arthrodesis: from a 4-hour operation to a tourniquet time. AB - PURPOSE: Scaphoidectomy and 4-corner arthrodesis (4CA) is an effective procedure for treating several degenerative conditions of the wrist. Recently, the arthroscopic approach to this operation was described. Although it is conceptually appealing, certain aspects make its application difficult. We present our technique for dry arthroscopic scaphoidectomy and 4CA, which reduces the operative time to less than 2 hours. METHODS: Four consecutive patients underwent scaphoidectomy and 4CA. In each case, we performed the operation with a dry arthroscopic technique using cannulated screws for rigid fixation. We performed bone grafting from the distal radius in 2 patients and from the scaphoid itself in the other two. The relevant operative details are the use of a scapholunate portal, the resection of the scaphoid with a pituitary rongeur, and the placement of bone graft in a dry arthroscopic environment. Range of motion exercises are started 2 to 3 weeks after the operation. RESULTS: The first operation took 4 hours. The last 2 were completed in 1 hour 45 minutes and 1 hour 55 minutes, respectively. No complications occurred. No operations were converted to an open procedure. CONCLUSIONS: Although the operation has a steep learning curve, it is conceptually appealing. It is too early to prove that the arthroscopic procedure has better results than the open 4CA; nevertheless, in our opinion it represents the future of wrist surgery. PMID- 23101537 TI - Technique of forearm osteotomy for pediatric problems. AB - Correction of a rigid forearm deformity in children is often desired in congenital radioulnar synostosis, brachial plexus palsy, cerebral palsy, or posttraumatic torsional deformity. Osteotomies at the diaphyseal level present difficulties with maintenance of reduction, whether or not internal or pin fixation is used. The stabilizing and healing potential of the periosteum in these cases can be used to advantage in the correction of these deformities. PMID- 23101538 TI - Coronal shear fractures of the distal humerus. AB - Management of coronal shear fractures of the distal humerus has evolved considerably over the past 3 decades, with an increased appreciation of the complexity of these fractures, improvements in internal fixation techniques, and the use of more extensile exposures. Nearly all of these fractures are displaced, given the paucity of soft tissue attachments and correspondingly, nonsurgical management is fraught with complications including chronic pain, mechanical symptoms, and instability and is not recommended. Good to excellent outcomes can be achieved in the majority of patients with open reduction internal fixation, particularly when the fracture is limited to the radiocapitellar joint. Outcomes are worst for those with considerable medial extension or comminution. Computed tomography is highly recommended to guide surgical planning. The presence of posterior comminution or extension to the medial column might require more extensile exposures and supplemental fixation for adequate stability. Arthroscopic reduction and fixation techniques have been described for the simple fracture. Those not amenable to fixation might do better with total elbow arthroplasty in a select population. Long-term data demonstrate the durability of these elbows following open reduction internal fixation. Complications other than stiffness are rare. Radiographic avascular necrosis does not appear to affect outcome. Radiographic mild to moderate arthritis was observed in half of patients at 17-year follow-up. PMID- 23101539 TI - Coronoid fractures. AB - Coronoid fractures are rarely isolated injuries; they are most commonly encountered in association with other elbow injuries as part of 3 major instability patterns. Type 1 fractures are usually associated with terrible triad injuries. Type 2 fractures are associated with varus posteromedial rotatory instability. Type III fractures are associated with transolecranon fracture dislocations. Current recommendations are to repair all coronoid fractures associated with elbow instability, regardless of fragment size. Surgical techniques are described in detail. PMID- 23101540 TI - Letter regarding "Adverse events of open A1 pulley release for idiopathic trigger finger". PMID- 23101542 TI - Steroid injections in combination with needle aponeurotomy as a treatment method for Dupuytren disease: suggestions for increasing the research evidence. PMID- 23101544 TI - Evaluation of gas chromatography-combustion-isotope ratio mass spectrometry (GC-C IRMS) for the quality assessment of citrus liqueurs. AB - Citrus liqueurs are alcoholic beverages obtained by maceration. The European Parliament protects these alcoholic beverages, forbidding the addition of nature identical flavoring substances. However, for economical and technological reasons, producers often add natural and/or synthetic flavors to the alcoholic syrup, obtaining artificial spirit drinks. The aim of this study is to investigate the authenticity of Italian liqueurs, of lemon, bergamot, and mandarin (locally known as "limoncello", "bargamino", and "mandarinetto"), comparing the carbon isotope ratios with values determined in genuine cold pressed peel oils. Authenticity assessment was performed using headspace-solid phase microextraction coupled to gas chromatography-combustion-isotope ratio mass spectrometry. Additional analyses were performed by direct enantioselective gas chromatography to determine the enantiomeric distribution of selected chiral volatiles and by gas chromatography-mass spectrometry for the qualitative analyses of the samples. The method allowed confirmation of genuineness. Enantioselective gas chromatography analyses confirmed the results, demonstrating the reliability of the method. PMID- 23101546 TI - Distress screening: an opportunity for enhancing quality cancer care and promoting the oncology social work profession. AB - Throughout its history, social work has played a critical role in major client/patient care initiatives because of its unique perspective, wisdom, and skills. The new screening standards set forth by the American College of Surgeons' Commission on Cancer place oncology social workers at the forefront of developing and implementing procedures for distress screening. Our profession is again challenged to work across disciplines and change systems of care to improve the health and welfare of patients with cancer and their families. Indeed, emerging research suggests that the use of psychosocial screening instruments results in reductions in emotional distress, better quality of life, and improved patient-provider communication. As an introduction to this special issue on distress screening, this article offers a brief overview of issues related to distress screening that are covered by papers authored in this special issue by Association of Oncology Social Work members. Topics addressed include a review of the historical context driving distress screening implementation, barriers and challenges to oncology social workers trying to implement distress screening, statistical and cultural considerations for selecting screening tools, best practice models, and future considerations. This special issue is intended to be a primer and serves to promote oncology social workers' involvement and leadership in the development and implementation of distress screening. PMID- 23101547 TI - The history of psychosocial screening among cancer patients. AB - Over the past ten years, the concept of psychosocial screening has received a great deal of attention. Guidelines, recommendations, and standards have been developed to encourage or require that all patients be screened for their distress at the time of diagnosis or when patients commence care in a cancer center for the first time. However, the concept of psychosocial screening has long history in the cancer literature. PMID- 23101545 TI - Synbiotic therapy decreases microbial translocation and inflammation and improves immunological status in HIV-infected patients: a double-blind randomized controlled pilot trial. AB - BACKGROUND: HIV-infection results in damage and dysfunction of the gastrointestinal system. HIV enteropathy includes pronounced CD4+ T-cell loss, increased intestinal permeability, and microbial translocation that promotes systemic immune activation, which is implicated in disease progression. A synbiotic is the combination of probiotics and prebiotics that could improve gut barrier function. Our study goal was to determine whether the use of a synbiotic, probiotics or a prebiotic can recover immunological parameters in HIV-infected subjects through of a reduction of microbial translocation and pro-inflammatory cytokine production. METHODS: A randomized, double-blind controlled study was performed; twenty Antiretroviral treatment-naive HIV-infected subjects were subgrouped and assigned to receive a synbiotic, probiotics, a prebiotic, or a placebo throughout 16 weeks. RESULTS: We had no reports of serious adverse events. From baseline to week 16, the synbiotic group showed a reduction in bacterial DNA concentrations in plasma (p = 0.048). Moreover, the probiotic and synbiotic groups demonstrated a decrease in total bacterial load in feces (p = 0.05). The probiotic group exhibited a significant increment of beneficial bacteria load (such as Bifidobacterium; p = 0.05) and a decrease in harmful bacteria load (such as Clostridium; p = 0.063). In the synbiotic group, the CD4+ T-cells count increased (median: +102 cells/MUL; p = 0.05) and the level of Interleukin 6 cytokine decreased significantly (p = 0.016). CONCLUSIONS: Our study showed a significant increase in CD4+ T lymphocyte levels in the synbiotic group, which could delay the initiation of antiretroviral therapy and decrease costs in countries with limited resources. PMID- 23101548 TI - An analysis of Social Work Oncology Network Listserv Postings on the Commission of Cancer's distress screening guidelines. AB - This is a qualitative study of listserv postings by members of the Social Work Oncology Network (SWON) in response to the Commission on Cancer's 2011 guidelines for distress screening of cancer patients. Archived listserv postings for the period of December 2010 to November 2011 were deidentified and a sample was derived by a list of keywords for the analysis. Aims of the study included describing the general categories and themes of the postings devoted to the new distress screening standard and examining the process of facilitation of mutual support and information exchange by oncology social workers in response to the new screening standards. During the 12-month timeframe there were 242 unique listserv postings sampled for the analysis. Oncology social worker (OSW) discussion of the distress screening guidelines remained a constant topic over the 12 months, and major themes that emerged from the data included processes of implementation of distress screening in cancer centers, screening policies and protocols, screening tool choice, and oncology social worker professional identity. The SWON listserv members used the listserv as a mechanism to post their requests for information on screening, to share their experiences in the beginning stages of implementing the guidelines, and to build support for legitimizing oncology social workers as the lead profession in the implementation of the guidelines in member cancer centers. PMID- 23101549 TI - Distress screening: experiences of oncology social workers. AB - The purpose of this pilot study was to explore oncology social workers experiences with the introduction and use of distress screening tools with patients who are diagnosed with cancer. Focus groups were conducted with 15 oncology social workers, who were primarily employed in large hospitals or cancer centers. The results fell into three broad areas: initiating distress screening, adapting distress screening to the setting, and evaluating distress screening. Findings revealed that social workers face many decisions as they adapt distress screening to their settings, including when and how to measure distress, and how to refer patients to services. Social workers were concerned about being overwhelmed with referrals and sought to manage the screening to better identify those who are likely to benefit from services. This research suggests a need for further study, the development of practice guidelines, and training of oncology social workers. PMID- 23101550 TI - Removing the stress from selecting instruments: arming social workers to take leadership in routine distress screening implementation. AB - Quality cancer care requires identifying and addressing the psychosocial needs of cancer patients. Oncology social workers have long been on the forefront of this endeavor. Although there has been longstanding interest in screening cancer patients for distress, it has recently been included as a quality of care metric in institutions accredited by the American College of Surgeons. Implementing routine screening for distress in oncology settings requires thoughtful planning, including assessing various screening instruments and considering a host of variables within each practice setting. Oncology social workers are best positioned to provide leadership in operationalizing this mandate and to lead their team in the choice of a distress measure for compliance with the screening guideline. This article highlights the most popular distress screening measures used in oncology and their psychometric properties. PMID- 23101551 TI - No patients left behind: a systematic review of the cultural equivalence of distress screening instruments. AB - Despite the widespread use of distress screening instruments in cancer care, the reliability and validity of these instruments for a diverse population of cancer patients have not been well established. This is a systematic review of the conceptual and statistical equivalence of screening instruments of 148 psycho oncology studies that included distress screening instruments. The findings indicate that screening measures of distress have comparable reliability, sensitivity, and specificity for White, Latino, and Asian samples. However, it is unclear if equivalent psychometrics are found among minority ethnic groups (e.g., African American) and immigrants within countries. Given the ethnic diversity among cancer patients and the lack of representation of this diversity in the current research, it is critical that researchers begin to include cancer patients of minority ethnic/racial groups in their samples so that health care providers can screen for distress with cultural sensitivity. PMID- 23101552 TI - From distress guidelines to developing models of psychosocial care: current best practices. AB - Psychological distress has been recognized as having a significant effect upon cognitive and emotional functioning, quality of life, and in some populations increased costs of care. Screening for distress and provision of psychosocial care in oncology treatment settings has been identified as a future accreditation standard by the American College of Surgeons Commission on Cancer (CoC). Because there are few available models of programs of distress screening and referral to inform oncology social workers and other members of the psychosocial support team with planning their own programs, this article seeks to provide exemplars of best practices that are currently in place in four different settings where psychosocial support is provided to people living with cancer and their families. Each program will provide an overview of how it was successfully established and its contribution toward evolving evidence-informed best practices. PMID- 23101553 TI - Now what? Toward an integrated research and practice agenda in distress screening. AB - Significant gains have been made in the detection and treatment of cancer, contributing to increased survival, but a cancer diagnosis and treatment may be accompanied by physical and psychosocial after-effects. Distress screening has been championed as a mechanism to identify patients with high levels of psychosocial morbidity for subsequent assessment and psychosocial care delivery. However, implementation of distress screening has been variable, in scope and in the consistency and quality of metrics and methods used. This capstone article identifies challenges in the measurement and implementation of distress screening and examines future opportunities for research and implementation. PMID- 23101555 TI - A novel syndrome of lethal familial hyperekplexia associated with brain malformation. AB - BACKGROUND: Hyperekplexia (HPX) is a rare non-epileptic disorder manifesting immediately after birth with exaggerated persistent startle reaction to unexpected auditory, somatosensory and visual stimuli, and non-habituating generalized flexor spasm in response to tapping of the nasal bridge (glabellar tap) which forms its clinical hallmark. The course of the disease is usually benign with spontaneous amelioration with age. The disorder results from aberrant glycinergic neurotransmission, and several mutations were reported in the genes encoding glycine receptor (GlyR) alpha1 and beta subunits, glycine transporter GlyT2 as well as two other proteins involved in glycinergic neurotransmission gephyrin and collybistin. METHODS: The phenotype of six newborns, belonging to Saudi Arabian kindred with close consanguineous marriages, who presented with hyperekplexia associated with severe brain malformation, is described. DNA samples were available from two patients, and homozygosity scan to determine overlap with known hyperkplexia genes was performed. RESULTS: The kindred consisted of two brothers married to their cousin sisters, each with three affected children who presented antenatally with excessive fetal movements. Postnatally, they were found to have microcephaly, severe hyperekplexia and gross brain malformation characterized by severe simplified gyral pattern and cerebellar underdevelopment. The EEG was normal and they responded to clonazepam. All of the six patients died within six weeks. Laboratory investigations, including metabolic screen, were unremarkable. None of the known hyperkplexia genes were present within the overlapping regions of homozygosity between the two patients for whom DNA samples were available. CONCLUSIONS: We present these cases as a novel syndrome of lethal familial autosomal recessive hyperekplexia associated with microcephaly and severe brain malformation. PMID- 23101556 TI - Symptomatic postsurgical cerebrospinal fluid leak treated by aspiration and epidural blood patch under ultrasound guidance in 2 adolescents. AB - Cerebrospinal fluid leakage causing a pseudomeningocele is a well-recognized complication after spine surgery. The repair of pseudomeningocele in a symptomatic patient is usually accomplished with direct open surgical repair of the durotomy, prolonged lumbar drainage, and/or placement of an epidural blood patch. The authors highlight a unique method of pseudomeningocele repair by presenting 2 cases of adolescent girls with symptomatic lumbar pseudomeningoceles. In both cases ultrasound was used to guide the aspiration of CSF from each pseudomeningocele and to apply the epidural blood patch. Both patients had complete and immediate resolution of symptoms. The authors found ultrasound to be a useful tool to assess the extent of the CSF leakage, to determine the degree of aspiration of the extradural CSF, and to confirm the injection of the blood into the epidural space and the space created by the pseudomeningocele. PMID- 23101557 TI - Revision rate of pediatric ventriculoperitoneal shunts after 15 years. AB - OBJECT: Ventriculoperitoneal (VP) shunt placement remains the mainstay treatment for pediatric hydrocephalus. These devices have a relatively high complication and failure rate, often requiring multiple revisions. The authors present a single institution's experience of pediatric patients treated with VP shunts. With an average follow-up time of 20 years, this study is among the longest reports of VP shunt revision in the literature to date. Hydrocephalus origins, shunt revision rates, and causes of shunt failure are described. Patients who underwent their first shunt revision more than 10 years after initial shunt placement were also explored. METHODS: A retrospective chart review was performed on all pediatric patients who underwent VP shunt placement from January 1990 through November 1996 at the University of Rochester Medical Center. Only patients who had at least 15 years of follow-up since their initial shunting procedure were included. RESULTS: A total of 234 procedures were performed on 64 patients, with a mean follow-up of 19.9 years. Patients ranged from a few days to 17.2 years old when they received their original shunt, with a median age of 4 months; 84.5% of the patients required 1 or more shunt revisions and 4.7% required 10 or more. Congenital defects, Chiari Type II malformations, tumors, and intraventricular hemorrhage were the most common causes of hydrocephalus. Overall, patients averaged 2.66 revisions, with proximal (27%) and distal (15%) catheter occlusion, disconnection (11%), and infection (9%) comprising the most common reasons for shunt malfunction. Notably, 12.5% of patients did not require their first shunt revision until more than 10 years after initial device placement, a previously undescribed finding due to the short follow-up duration in previous studies. CONCLUSIONS: This long-term retrospective analysis of pediatric VP shunt placement revealed a relatively high rate of complications with need for shunt revision as late as 17 years after initial placement. Catheter occlusion represented a significant percentage of shunt failures. Cerebrospinal fluid shunting has a propensity for mechanical failure and patients with VP shunts should receive follow-up through the transition to adulthood. PMID- 23101558 TI - Posthemorrhagic hydrocephalus and shunts: what are the predictors of multiple revision surgeries? AB - OBJECT: Cerebrospinal fluid shunts in patients with posthemorrhagic hydrocephalus are prone to failure, with some patients at risk for multiple failures. The objective of this study was to identify factors leading to multiple failures. METHODS: The authors performed a retrospective analysis of cases of posthemorrhagic hydrocephalus requiring neurosurgical intervention between 1982 and 2010. RESULTS: In the 109 cases analyzed, 54% of the patients were male, their mean birth weight was 1223 g, and their mean head circumference 25.75 cm. The mean duration of follow-up was 6 years, and 9 patients died. Grade III intraventricular hemorrhage was seen in 47.7% and Grade IV in 43.1%. Initial use of a ventricular access device was needed in 65 patients (59.6%), but permanent CSF shunting was needed in 104 (95.4%). A total of 454 surgical procedures were performed, including 304 shunt revisions in 78 patients (71.6%). Detailed surgical notes were available for 261 of these procedures, and of these, 51% were proximal revisions, 13% distal revisions, and 17% total shunt revisions. Revision rates were not affected by catheter type, patient sex, presence of congenital anomalies, or type of hydrocephalus. Age of less than 30 days at the initial procedure was associated with decreased survival of the first shunt. Regression analysis revealed that lower estimated gestational age (EGA) and obstructive hydrocephalus were significant predictors of multiple shunt revisions. CONCLUSIONS: We found a high rate of need for permanent CSF shunts (95.4%) in patients with posthemorrhagic hydrocephalus. Shunt revision was required in 71.6% of patients, with those with lower birth weight and EGA at a higher risk for revisions. PMID- 23101559 TI - UCP2 I/D modulated change in BMI during a lifestyle modification intervention study in Japanese subjects. AB - AIM: Polymorphisms in uncoupling protein (UCP) genes have been strongly associated with energy expenditure and obesity. This study aimed at investigating the effects of UCP gene polymorphisms (UCP1 -3826A/G, UCP2A/V, UCP2 I/D, and UCP3 -55C/T) on change in body mass index (BMI) during a lifestyle modification program in Japanese subjects. RESULTS: Intervention induced a significant decrease in energy intake (-8.6% +/- 17.0%) and a significant increase in energy expenditure (7.7% +/- 7.4%). As a result, participants experienced a significant decrease in their BMI of -1.8% +/- 2.7%. In a multivariate regression analysis, only UCP2 D/I among the selected UCP gene polymorphisms was associated with a change in BMI independent of the effects of gender, age, baseline BMI, changes in energy intake, and expenditure. Further regression analysis revealed that, in contrast to the DD genotype group, the DI+II genotype group showed no significant association between weight loss and change in energy expenditure suggesting this polymorphism altered the effects of this parameter on change in BMI. CONCLUSION: The study found UCP2 D/I to be associated with change in BMI by altering the effect of change in energy expenditure on change in BMI. PMID- 23101560 TI - A real-time polymerase chain reaction-based protocol for low/medium-throughput Y chromosome microdeletions analysis. AB - PURPOSE: We describe a real-time polymerase chain reaction (PCR) protocol based on the fluorescent molecule SYBR Green chemistry, for a low- to medium-throughput analysis of Y-chromosome microdeletions, optimized according to the European guidelines and aimed at making the protocol faster, avoiding post-PCR processing, and simplifying the results interpretation. METHODS: We screened 156 men from the Assisted Reproduction Unit, Department of Obstetrics and Gynecology, Institute for Maternal and Child Health IRCCS Burlo Garofolo (Trieste, Italy), 150 not presenting Y-chromosome microdeletion, and 6 with microdeletions in different azoospermic factor (AZF) regions. For each sample, the Zinc finger Y-chromosomal protein (ZFY), sex-determining region Y (SRY), sY84, sY86, sY127, sY134, sY254, and sY255 loci were analyzed by performing one reaction for each locus. RESULTS: AZF microdeletions were successfully detected in six individuals, confirming the results obtained with commercial kits. CONCLUSION: Our real-time PCR protocol proved to be a rapid, safe, and relatively cheap method that was suitable for a low- to medium-throughput diagnosis of Y-chromosome microdeletion, which allows an analysis of approximately 10 samples (with the addition of positive and negative controls) in a 96-well plate format, or approximately 46 samples in a 384-well plate for all markers simultaneously, in less than 2 h without the need of post-PCR manipulation. PMID- 23101562 TI - Direct conversion of indoles to 3,3-difluoro-2-oxindoles via electrophilic fluorination. AB - 3,3-Difluoro-2-oxindoles can be obtained directly from indoles in moderate yields via electrophilic fluorination using N-fluorobenzenesulfonimide as a mild fluorinating reagent. The presence of tert-butyl hydroperoxide during the reaction, together with additional heating after quenching the reaction with triethylamine, is beneficial to the formation of the desired product. PMID- 23101561 TI - Compromised quality of life in adult patients who have received a radiation dose towards the basal part of the brain. A case-control study in long-term survivors from cancer in the head and neck region. AB - BACKGROUND: Adult patients with hypothalamic-pituitary disorders have compromised quality of life (QoL). Whether this is due to their endocrine consequences (hypopituitarism), their underlying hypothalamic-pituitary disorder or both is still under debate. The aim of this trial was to measure quality of life (QoL) in long-term cancer survivors who have received a radiation dose to the basal part of the brain and the pituitary. METHODS: Consecutive patients (n=101) treated for oropharyngeal or epipharyngeal cancer with radiotherapy followed free of cancer for a period of 4 to10 years were identified. Fifteen patients (median age 56 years) with no concomitant illness and no hypopituitarism after careful endocrine evaluation were included in a case-control study with matched healthy controls. Doses to the hypothalamic-pituitary region were calculated. QoL was assessed using the Symptom check list (SCL)-90, Nottingham Health Profile (NHP), and Psychological Well Being (PGWB) questionnaires. Level of physical activity was assessed using the Baecke questionnaire. RESULTS: The median accumulated dose was 1.9 Gy (1.5-2.2 Gy) to the hypothalamus and 2.4 Gy (1.8-3.3 Gy) to the pituitary gland in patients with oropharyngeal cancer and 6.0-9.3 Gy and 33.5-46.1 Gy, respectively in patients with epipharyngeal cancer (n=2). The patients showed significantly more anxiety and depressiveness, and lower vitality, than their matched controls. CONCLUSION: In a group of long time survivors of head and neck cancer who hade received a low radiation dose to the hypothalamic-pituitary region and who had no endocrine consequences of disease or its treatment QoL was compromised as compared with well matched healthy controls. PMID- 23101563 TI - Carbanion-accelerated Claisen rearrangements: asymmetric induction with chiral phosphorus-stabilized anions. AB - The carbanion-accelerated Claisen rearrangement has been extended to include phosphorus carbanion-stabilizing groups. The appropriately substituted allyl vinyl ethers are synthesized by the nucleophilic addition of allyl oxides to phosphorus-substituted allenes, which are obtained in one step from simple starting materials. The phosphorus-stabilized, carbanion-accelerated Claisen rearrangements proceed rapidly at room temperature in high yield, and the rearrangements are highly site- and stereoselective. The first examples of asymmetric induction in the Claisen rearrangement with chiral, phosphorus, anion stabilizing groups are described. The observed asymmetric induction is highly dependent on the structure of the auxiliary and the metal counterion involved. Both internal and relative diastereoselectivity are high. A model for the observed sense of internal diastereoselectivity is proposed that is founded in the current understanding of the structure of phosphorus-stabilized anions. PMID- 23101564 TI - [Tackling the risk of alcohol consumption from primary care]. PMID- 23101565 TI - [Optimising the use of exercise for the treatment of fibromyalgia]. PMID- 23101566 TI - On the relationship between peptide adsorption resistance and surface contact angle: a combined experimental and simulation single-molecule study. AB - The force-induced desorption of single peptide chains from mixed OH/CH(3) terminated self-assembled monolayers is studied in closely matched molecular dynamics simulations and atomic force microscopy experiments with the goal to gain microscopic understanding of the transition between peptide adsorption and adsorption resistance as the surface contact angle is varied. In both simulations and experiments, the surfaces become adsorption resistant against hydrophilic as well as hydrophobic peptides when their contact angle decreases below theta ~ 50 degrees -60 degrees , thus confirming the so-called Berg limit established in the context of protein and cell adsorption. Entropy/enthalpy decomposition of the simulation results reveals that the key discriminator between the adsorption of different residues on a hydrophobic monolayer is of entropic nature and thus is suggested to be linked to the hydrophobic effect. By pushing a polyalanine peptide onto a polar surface, simulations reveal that the peptide adsorption resistance is caused by the strongly bound water hydration layer and characterized by the simultaneous gain of both total entropy in the system and total number of hydrogen bonds between water, peptide, and surface. This mechanistic insight into peptide adsorption resistance might help to refine design principles for anti-fouling surfaces. PMID- 23101568 TI - Possible neoplastic effects of acrylamide on rat exocrine pancreas. AB - We investigated whether the acrylamide formed during cooking carbohydrate-rich foods at high temperatures causes neoplastic changes in rat pancreas. Azaserine, which is an amino acid derivative that has the ability to initiate neoplastic changes in rat pancreas, was injected into 14-day-old male rats once a week for three weeks. Acrylamide was given to both azaserine-injected and non-injected rats at doses of 5 and 10 mg/kg/day in drinking water for 16 weeks after which tissue slides were prepared from the pancreata. Pancreas weights and body weights of rats treated with azaserine and acrylamide together increased significantly compared to the other groups. Moreover, the size, average diameter and volume of atypical acinar cell foci that developed in the pancreata of rats treated with azaserine and acrylamide together increased significantly compared to rats treated with either azaserine or acrylamide alone and control groups. Atypical acinar cell adenoma or adenocarcinoma was not observed in the pancreata of rats in any group. PMID- 23101567 TI - The Michigan State University Twin Registry (MSUTR): an update. AB - The primary aim of the Michigan State University Twin Registry (MSUTR) is on understanding developmental changes in genetic, environmental, and neurobiological influences on internalizing and externalizing disorders, with antisocial behavior and disordered eating representing our particular areas of interest. The MSUTR has two broad components: a large-scale, population-based registry of child, adolescent, and adult twins and their families (current N ~20,000) and a series of more focused and in-depth studies drawn from the registry (current N ~4,000). Participants in the population-based registry complete a family health and demographic questionnaire via mail. Families are then recruited for one or more of the intensive, in-person studies from the population-based registry based on their answers to relevant items in the registry questionnaire. These in-person assessments target a variety of biological, genetic, and environmental phenotypes, including multi-informant measures of psychiatric and behavioral phenotypes, census and neighborhood informant reports of twin neighborhood characteristics, buccal swab and salivary DNA samples, assays of adolescent and adult steroid hormone levels, and/or videotaped interactions of child twin families. This article provides an overview of the MSUTR and describes current and future research directions. PMID- 23101569 TI - Management of mild traumatic brain injury in the emergency department. AB - With over 1.7 million people in the United States seeking medical attention for head injury each year, emergency clinicians are challenged daily to screen quickly for the small subset of patients who harbor a potentially lethal intracranial lesion while minimizing excessive cost, unnecessary diagnostic testing, radiation exposure, and admissions. Whether working at a small, rural hospital or a large inner-city public hospital, emergency clinicians play a critical role in the diagnosis and management of mild traumatic brain injury. This review assesses the burgeoning research in the field and reviews current clinical guidelines and decision rules on mild traumatic brain injury, addressing the concept of serial examinations to identify clinically significant intracranial injury, the approach to pediatric and elderly patients, and the management of patients who are on anticoagulants or antiplatelet agents or have bleeding disorders. The evidence on sports-related concussion and postconcussive syndrome is reviewed, and tools for assessments and discharge are included. PMID- 23101570 TI - Epidemiology of arrhythmias and conduction disorders in older adults. AB - Normal aging is associated with a multitude of changes in the cardiovascular system, including decreased compliance of blood vessels, mild concentric left ventricular hypertrophy, an increased contribution of atrial contraction to left ventricular filling, and a higher incidence of many cardiac arrhythmias, both bradyarrhythmias and tachyarrhythmias. Conduction disorders also become more common with age, and may either be asymptomatic, or cause hemodynamic changes requiring treatment. The epidemiology of common arrhythmias and conduction disorders in the elderly is reviewed. PMID- 23101572 TI - Pharmacology of antiarrhythmic drugs in elderly patients. AB - Bradyarrhythmias and tachyarrhythmias are common in elderly patients as a result of aging and acquired cardiac disease. Antiarrhythmic drugs are effective in elderly patients for the management of supraventricular and ventricular arrhythmias; however, dosing of drugs must be performed with care because of age related changes in drug pharmacokinetics, the presence of concomitant disease, and frequent drug-drug interactions. Despite the large number of antiarrhythmic drugs having different electrophysiologic actions, as described in this article, only the beta-blockers have been shown to be effective in reducing mortality and to lack proarrhythmic actions. PMID- 23101573 TI - Atrial fibrillation: stroke prevention in older adults. AB - Atrial fibrillation (AF) is an increasingly prevalent disease in the elderly. Patients with AF are at increased risk of ischemic stroke, resulting in significant morbidity and mortality. Warfarin is highly effective at reducing stroke risk, with a net clinical benefit favoring treatment in older individuals. The advent of newer oral anticoagulants provides promising alternatives to warfarin. Appropriate risk stratification for stroke should be performed for all patients with AF to guide antithrombotic therapy. For patients at lower stroke risk, bleeding risk stratification tools can also be used when the benefit of anticoagulant therapy is unclear. PMID- 23101574 TI - Atrial fibrillation and atrial flutter: medical management. AB - Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac arrhythmias in older adults. Medical management focuses on rate and rhythm control of AF and AFL to promote symptomatic relief and avoid tachycardia-mediated cardiomyopathy. Pharmacologic treatment of AF and AFL is especially challenging in the elderly because of the presence of comorbidities that may affect drug kinetics, and polypharmacy, which may lead to drug interactions. The potential for complications from medications and procedures required to achieve and maintain sinus rhythm must be carefully balanced against the benefits of therapy. This article reviews medical management of AF and AFL specifically relating to rate and rhythm control. The controversy of rate versus rhythm control is also discussed. PMID- 23101575 TI - Atrial fibrillation and atrial flutter: nonpharmacologic therapy. AB - As elderly patients present significant challenges for long-term pharmacologic management, nonpharmacologic treatment of atrial fibrillation (AF) will continue to be a vital option in improving the quality of life and function of these patients. This review discusses nonpharmacologic approaches for AF in the elderly. Observational studies of catheter ablation suggest similar long-term efficacy and safety rates in elderly and younger groups. Minimally invasive surgical approaches have distinct advantages in certain populations. Further research, adequately powered to assess age-related differences, is needed to confirm the findings of observational studies of elderly patients who have undergone nonpharmacologic approaches to rhythm control. PMID- 23101571 TI - Mechanisms of arrhythmias and conduction disorders in older adults. AB - Aging is associated with an increased prevalence of cardiac arrhythmias, which contribute to higher morbidity and mortality in the elderly. The frequency of cardiac arrhythmias, particularly atrial fibrillation and ventricular tachyarrhythmia, is projected to increase as the population ages, greatly impacting health care resource utilization. Several clinical factors associated with the risk of arrhythmias have been identified in the population, yet the molecular bases for the increased predisposition to arrhythmogenesis in the elderly are not fully understood. This review highlights the epidemiology of cardiac dysrhythmias, changes in cardiac structure and function associated with aging, and the basis for arrhythmogenesis in the elderly. PMID- 23101576 TI - Ventricular arrhythmias in the elderly: evaluation and medical management. AB - Ventricular arrhythmias constitute the main cause of sudden cardiac death. In the elderly, their presentation may be manifested by intermittent confusion or unexplained falls. In some cases, they may also be asymptomatic. The primary management goals are to identify and treat the underlying cause and prevent recurrence. With the exception of beta-blockers, none of the other antiarrhythmic drugs available reduce mortality associated with ventricular arrhythmias. In the elderly, these drugs are associated with a higher risk of adverse events. In this article, the authors review the data available regarding evaluation and management of ventricular arrhythmias in the elderly. PMID- 23101577 TI - Ventricular arrhythmias: device therapy and ablation. AB - There are few randomized, well-controlled studies to guide decision making with respect to the treatment of ventricular arrhythmias in the elderly treated with either device implantation or catheter ablation. Although some data are conflicting, the elderly appear to have a greater degree of risk related to treatment compared with younger ones; however, this increased risk is in part a consequence of age itself and comorbid conditions. Conversely, in terms of benefit, although the data may again be mixed, there is ample information indicating that age should not contraindicate aggressive treatment when accepted indications for intervention exist. PMID- 23101578 TI - Quality of life and end-of-life issues for older patients with implanted cardiac rhythm devices. AB - This article provides an overview of quality of life (QOL) and end-of-life issues that pertain to older patients with implanted cardiac rhythm devices. Most patients with implantable cardioverter-defibrillators (ICDs) enjoy similar QOL to that of other patients with cardiac diseases, especially in the absence of ICD shocks. Conventional pacemakers, as well as devices incorporating cardiac resynchronization, can improve QOL in appropriately selected patients regardless of age. In patients approaching the end of life, all devices, but especially ICDs, can adversely impact QOL in patients and families. All patients should have the opportunity to discuss the option of device deactivation. PMID- 23101579 TI - Bradyarrhythmias in the elderly. AB - Over the next decade, there will be a dramatic increase in the number of elderly people in the United States and in most parts of the world. With this increase, there will be an accompanying increase in patients with sinus node dysfunction and atrioventricular block; therefore, it will be essential for health care personnel to have a basic knowledge of bradyarrhythmias and the considerations required for managing these rhythms in elderly patients. In particular, comprehensive assessment before decisions on medical and device-based management is critical and must take into account social issues and the presence of comorbid conditions. PMID- 23101580 TI - Syncope: evaluation and management in the geriatric patient. AB - Syncope is a common clinical problem accounting for 3% of all emergency room visits and 1% to 6% of all hospital admissions. Both a sign and a symptom, syncope can be caused by a wide variety of conditions. Syncope in the geriatric patient can be a particularly challenging problem because of the coexistence of multiple possible causative pathologic conditions in the same individual. This article reviews the causes, evaluation, and management of syncope in the elderly. PMID- 23101581 TI - Management of arrhythmias in the perioperative setting. AB - Perioperative arrhythmias are a common complication of surgery, with incidence ranging from 4% to 20% for noncardiothoracic procedures, depending on the type of surgery performed. The immediate postoperative period is a dynamic time and is associated with many conditions conducive to the development of postoperative arrhythmias. The presence of postoperative atrial fibrillation is associated with increased morbidity, ICU stay, length of hospitalization, and hospital costs. The associated burdens are expected to rise in the future, given that the population undergoing cardiac surgery is getting older and sicker. Thousands of patients undergo major surgery each year and a major complication of these procedures is the occurrence of perioperative arrhythmia. It is imperative for clinicians to be up-to-date on current management of these arrhythmias. PMID- 23101582 TI - Cardiac rhythm disorders in older adults. PMID- 23101583 TI - Systematic approach for structure elucidation of polyphenolic compounds using a bottom-up approach combining ion trap experiments and accurate mass measurements. AB - Polyphenols are a group of plant secondary metabolites with a wide range of structural differences. In many cases, in vitro and in vivo studies of polyphenols revealed beneficial health effects. The mass spectrometric characterization of polyphenols can be the key to understanding the metabolism and resorption of this group of substances. For structure elucidation of polyphenolic compounds nuclear magnectic resonance spectroscopy is the method of choice. Due to the broad structure variability and the sometimes relatively low concentrations of polyphenols and/or their metabolites in foods as well as physiological samples, mass spectrometry could be an alternative for structure elucidation. Especially high-resolution mass spectrometry, for example, Fourier transformation mass spectrometry (FTMS), is a valuable tool. Using a FTMS system, a systematic approach to the fragmentation behavior of phenolic and polyphenolic compounds was chosen to verify the influence of the structure on the fragmentation pattern of the different substances. Depending on the structure, specific fragment ions could be detected. Therefore, it is possible to gain reliable information about the structure of the pseudomolecular ion from its fragmentation spectrum, which is of great aid in the structure elucidation of unknown polyphenols and/or their metabolites. PMID- 23101585 TI - Isotope Coded Protein Labeling analysis of plasma specimens from acute severe dengue fever patients. AB - BACKGROUND: Dengue fever is the most important arthropod born viral disease of public health significance. Although most patients suffer only from flu-like symptoms, a small group of patient experiences more severe forms of the disease. To contribute to a better understanding of its pathogenesis this study aims to identify proteins differentially expressed in a pool of five viremic plasma from severe dengue patients relative to a pool of five non-severe dengue patients. RESULTS: The use of Isotope Coded Protein Labeling (ICPLTM) to analyze plasma depleted of twenty high-abundance proteins allowed for the identification of 51 differentially expressed proteins, which were characterized by mass spectrometry. Using quantitative ELISA, three of these proteins (Leucine-rich glycoprotein 1, Vitamin D binding-protein and Ferritin) were confirmed as having an increased expression in a panel of severe dengue plasma. The proteins identified as overexpressed by ICPLTM in severe dengue plasma involve in clear up action after cell injury, tissue coherence and immune defense. CONCLUSION: This ICPLTM study evaluating differences between acute severe dengue plasmas and acute non-severe dengue plasmas suggests that the three proteins identified are overexpressed early in the course of the disease. Their possible use as biomarkers for the prognostic of disease severity is discussed. PMID- 23101584 TI - Identification of estrogen responsive genes using esophageal squamous cell carcinoma (ESCC) as a model. AB - BACKGROUND: Estrogen therapy has positively impact the treatment of several cancers, such as prostate, lung and breast cancers. Moreover, several groups have reported the importance of estrogen induced gene regulation in esophageal cancer (EC). This suggests that there could be a potential for estrogen therapy for EC. The efficient design of estrogen therapies requires as complete as possible list of genes responsive to estrogen. Our study develops a systems biology methodology using esophageal squamous cell carcinoma (ESCC) as a model to identify estrogen responsive genes. These genes, on the other hand, could be affected by estrogen therapy in ESCC. RESULTS: Based on different sources of information we identified 418 genes implicated in ESCC. Putative estrogen responsive elements (EREs) mapped to the promoter region of the ESCC genes were used to initially identify candidate estrogen responsive genes. EREs mapped to the promoter sequence of 30.62% (128/418) of ESCC genes of which 43.75% (56/128) are known to be estrogen responsive, while 56.25% (72/128) are new candidate estrogen responsive genes. EREs did not map to 290 ESCC genes. Of these 290 genes, 50.34% (146/290) are known to be estrogen responsive. By analyzing transcription factor binding sites (TFBSs) in the promoters of the 202 (56+146) known estrogen responsive ESCC genes under study, we found that their regulatory potential may be characterized by 44 significantly over-represented co-localized TFBSs (cTFBSs). We were able to map these cTFBSs to promoters of 32 of the 72 new candidate estrogen responsive ESCC genes, thereby increasing confidence that these 32 ESCC genes are responsive to estrogen since their promoters contain both: a/mapped EREs, and b/at least four cTFBSs characteristic of ESCC genes that are responsive to estrogen. Recent publications confirm that 47% (15/32) of these 32 predicted genes are indeed responsive to estrogen. CONCLUSION: To the best of our knowledge our study is the first to use a cancer disease model as the framework to identify hormone responsive genes. Although we used ESCC as the disease model and estrogen as the hormone, the methodology can be extended analogously to other diseases as the model and other hormones. We believe that our results provide useful information for those interested in genes responsive to hormones and in the design of hormone based therapies. PMID- 23101587 TI - Intramolecular Schmidt reaction of acyl chlorides with alkyl azides: rapid access to fused polycyclic nitrogen-containing heterocycles via a multistep one-pot transformation. AB - The first intramolecular Schmidt reaction of acyl chlorides with alkyl azides has been developed. In this one-pot conversion, an omega-azido hydrocinnamic acid is converted to a tricyclic lactam. The most important feature of the process is the efficiency in bond formation (one bond broken and three new bonds created) and ring construction (two new rings formed). PMID- 23101586 TI - Erlotinib binds both inactive and active conformations of the EGFR tyrosine kinase domain. AB - Erlotinib and gefitinib, tyrosine kinase inhibitors used to block EGFR (epidermal growth factor receptor) signalling in cancer, are thought to bind only the active conformation of the EGFR-TKD (tyrosine kinase domain). Through parallel computational and crystallographic studies, we show in the present study that erlotinib also binds the inactive EGFR-TKD conformation, which may have significant implications for its use in EGFR-mutated cancers. PMID- 23101588 TI - The theory and practice of hyperpolarization in magnetic resonance using parahydrogen. PMID- 23101589 TI - The determination of accurate nuclear magnetic dipole moments and direct measurement of NMR shielding constants. PMID- 23101590 TI - Splenic marginal zone lymphoma: a population-based study on the 2001-2008 incidence and survival in the United States. AB - The epidemiology of splenic marginal zone lymphoma (SMZL) in the United States has not been addressed. Eight years of data (2001-2008) from 17 registries of the Surveillance, Epidemiology and End Results (SEER) program were used for this study. Of the 116,411 cases of non-Hodgkin lymphoma (NHL) in the registries, 763 (0.6%) were SMZL. The overall annual age-adjusted incidence was 0.13 per 100,000 persons per year. The annual percent change in age-adjusted incidence was 4.81% overall (p < 0.05), and significantly increasing trends were found for patients who were white, male or aged 70 years and older (p < 0.05). The relative 5-year overall survival rate for patients with SMZL was 81% (95% confidence interval 75 86%). The incidence of SMZL was highest among whites, males and older patients. A steadily increasing trend in incidence was observed for SMZL. The relative 5-year overall survival rate was high. PMID- 23101591 TI - From base Pairs to bedside...and beyond. PMID- 23101592 TI - Comparison between the polymerase chain reaction-based screening and the Southern blot methods for identification of fragile X syndrome. AB - The fragile X syndrome (FXS), the most common cause of hereditary mental retardation, is caused by expansions of CGG repeats in the FMR1 gene. The gold standard method to diagnose FXS is the Southern blot (SB). Because SB is laborious and costly, some adaptations in the polymerase chain reaction (PCR) method have been utilized for FXS screening. A previous PCR-based screening method for FXS identification utilizing small amounts of DNA was reported as simple and efficient. The aim of this study was to reproduce the mentioned PCR based screening method for identification of expanded alleles of the FMR1 gene in Brazilian individuals and to investigate the efficiency of this method in comparison with SB. Utilizing the enzyme Expand Long Template PCR System, 78 individuals were investigated by that PCR-based screening method for FXS identification. Conclusive results were obtained for 75 samples. Considering all the allelic forms of FXS (normal [NL], premutation [PM], and full-mutation [FM]), the comparison of the PCR-based screening method with SB demonstrated 100% of accuracy, sensitivity, and specificity. However, when the PM and the FM were analyzed separately from each other, but together with the NL allele, the accuracy, sensitivity, and specificity decreased (to 42.9%-97.4%). We concluded that the PCR-based screening method was reproducible and capable of identifying all different FXS alleles, but because the differentiation between the PM and the FM alleles was not accurate, SB is still the gold-standard method for the molecular diagnosis of FXS. PMID- 23101593 TI - Why does ingroup essentialism increase prejudice against minority members? AB - A study with British participants (N = 90) tested a potential mediator of the effect of essentialist beliefs about the national ingroup on prejudice against immigrants. Essentialist beliefs were defined as beliefs in genetic determinism, a basic assumption that group membership is "written in the blood" and that the groups' boundaries and characteristics are determined by genetic and/or biological factors. Essentialist beliefs were expected to play an important role in the formation of prejudice. They were predicted to be associated with a reduction in the perceived possibility of immigrants' adopting the mainstream culture. Further, it was expected that essentialist beliefs would be positively associated with perceptions of intergroup threat, which in turn would be associated with a stronger demand for immigrants adopting the mainstream culture. Taken together, essentialist beliefs were predicted to be associated with a greater discrepancy between the demand for and perceived feasibility of culture adoption. This discrepancy was hypothesized to mediate the effect of essentialist beliefs on prejudice against immigrants. Structural equation modeling analysis and mediation analysis supported the hypotheses, showing that essentialism attributed to the national ingroup results in people demanding something seemingly impossible from immigrants, and that this situation in which immigrants have little chance of fulfilling majority members' expectations results in prejudice against them. Thus, results show that perceptions of the ingroup are associated with attitudes to the outgroup, and they outline an explanatory mechanism for the positive correlation between essentialism and prejudice which has been found in previous research. Theoretical and applied implications are discussed. PMID- 23101594 TI - Turkish twin study: an initial step. AB - In this article we introduce the first twin study in Turkey with the future plan to register all twins born in Turkey for research purposes. The Turkish twin study will illuminate the etiology of health problems in the context of cultural differences, owing to the rich cultural diversity in Turkey. As a first step, we selected a sample of 618 twin individuals from 302 pairs and 14 singletons living in the Kirikkale and Ankara regions of Turkey and administered a questionnaire with items about nicotine use, psychiatric disorders, and information about the family, in addition to zygosity items. Our study provides valuable information regarding factors related to nicotine dependence, age, gender, social situation, and family structure. PMID- 23101595 TI - An inventory of Canadian pregnancy and birth cohort studies: research in progress. AB - BACKGROUND: A web-based inventory was developed as a voluntary registry of Canadian pregnancy and birth cohort studies, with the objective to foster collaboration and sharing of research tools among cohort study groups as a means to enrich research in maternal and child health across Canada. DESCRIPTION: Information on existing birth cohort studies conducted in Canada exclusively or as part of broader international initiatives was accessed by searching the literature in PubMed and PsychInfo databases. Additional studies were identified by enquiring about the research activities of researchers at Canadian universities or working in affiliated hospitals or research centres or institutes. Of the fifty-eight birth cohort studies initially identified, forty six were incorporated into the inventory if they were of a retrospective and/or prospective longitudinal design and with a minimum of two phases of data collection, with the first period having occurred before, during, or shortly after pregnancy and had an initial study sample size of a minimum of 200 participants.Information collected from each study was organized into four main categories: basic information, data source and period of collection, exposures, and outcome measures and was coded and entered into an Excel spreadsheet. The information incorporated into the Excel spreadsheet was double checked, completed when necessary, and verified for completeness and accuracy by contacting the principal investigator or research coordinator. All data collected were then uploaded onto the website of the Institute of Human Development Child and Youth Health of the Canadian Institutes of Health Research. Subsequently, the database was updated and developed as an online searchable inventory on the website of the Maternal, Infant, Child and Youth Research Network. CONCLUSIONS: This inventory is unique, as it represents detailed information assembled for the first time on a large number of Canadian birth cohort studies. Such information provides a valuable resource for investigators in the planning stages of cohort studies and identifying current research gaps. PMID- 23101596 TI - Bone graft substitutes. AB - Replacement of missing bone stock is a reconstructive challenge to upper extremity surgeons and decision-making with regards to available choices remains difficult. Preference is often given to autograft in the form of cancellous, cortical, or corticocancellous grafts from donor sites. However, the available volume from such donor sites is limited and fraught with potential complications. Advances in surgical management and medical research have produced a wide array of potential substances that can be used for bone graft substitute. Considerations in selecting bone grafts and substitutes include characteristic capabilities, availability, patient morbidity, immunogenicity, potential disease transmission, and cost variability. PMID- 23101597 TI - Reverse total shoulder arthroplasty: early results of forty-one cases and a review of the literature. AB - Reverse total shoulder arthroplasty was officially approved for use in the United States in 2003. The procedure is proving to be one of the most exciting advances in upper extremity surgery in the past quarter-century. The prosthesis is used to salvage the arthritic, unstable, rotator cuff-deficient shoulder and allow patients to obtain nearly pain-free overhead motion of the upper limb. This article reviews the previous literature and the results of 41 reverse shoulder arthroplasties implanted in 39 patients by a single orthopedically trained hand and upper extremity surgeon at a single institution from November 2004 until July 2011. PMID- 23101598 TI - Platelet-rich plasma and the upper extremity. AB - Platelet-rich plasma (PRP) is a fraction of whole blood containing powerful growth factors and cytokines. Preclinical studies suggest PRP may be useful for tendon repair or regeneration. Clinical investigations have focused on the treatment of chronic lateral epicondylar tendinopathy and rotator cuff pathology. Multiple controlled studies support the use of PRP for chronic tennis elbow. Rotator cuff studies, however, have produced conflicting results based on PRP formulation, surgical technique, and size of tendon tear. This article explores the scientific rational for using PRP, its various formulations, and the emerging clinical data. Future potential applications are also explored. PMID- 23101599 TI - Free vascularized medial femoral condyle autograft for challenging upper extremity nonunions. AB - Free vascularized bone grafts from the medial femoral condyle have increasingly demonstrated utility in the successful treatment of challenging nonunions and bony defects. The consistent, robust vascular anatomy and the versatility to function as either a thin, flexible periosteal or corticoperiosteal graft or as a structural corticocancellous graft have made this graft a valuable option for addressing recalcitrant nonunions. The rationale, indications, vascular anatomy, and surgical technique of harvesting these grafts from the medial femoral condyle are presented. PMID- 23101600 TI - Allograft tendon for second-stage tendon reconstruction. AB - Tendons are made of compact dense collagen fibers with only sparse cellularity and naturally low immunogenicity. Allogenic tendons may be preserved through deep freezing methods and retain excellent mechanical properties after revitalization. Allogenic tendons were used in 22 patients (30 tendons) for second-stage tendon reconstruction in the hand. Preliminary results indicate no observable adverse tissue reactions, and functional recovery after tendon grafting does not seem different from reconstruction using tendon autografts. This type of allogenic graft does not seem to produce serious concern as a foreign tissue in the body, at least in the short term. PMID- 23101601 TI - Use of suture anchors and new suture materials in the upper extremity. AB - Suture anchors are an important tool in the orthopedist's armamentarium. Their use is prevalent in surgery of the entire upper limb. Suture anchors have mostly obviated the need for multiple drill holes when striving for secure fixation of soft tissue to bone. As with most other orthopedic products, the designs of these anchors and the materials used to fabricate them have evolved as their use increased and their applications became more widespread. It is ultimately the surgeon's responsibility to be familiar with these rapidly evolving technologies and to use the most appropriate anchor for any given surgery. PMID- 23101602 TI - Advances in treating skin defects of the hand: skin substitutes and negative pressure wound therapy. AB - Surgeons and scientists have been developing alternative methods of hand reconstruction that may play an adjunctive role to, or completely supplant, more traditional reconstructive modalities. This article provides an overview of these emerging techniques, with an emphasis on skin substitutes and negative-pressure wound therapy as they apply to the treatment of soft tissue defects of the hand. The indications, contraindications, and relative advantages and disadvantages of these techniques are discussed in detail. PMID- 23101603 TI - Nerve glue for upper extremity reconstruction. AB - Nerve glue is an attractive alternative to sutures to improve the results of nerve repair. Improved axon alignment, reduced scar and inflammation, greater and faster reinnervation, and better functional results have been reported with the use of nerve glue. The different types of nerve glue and the evidence to support or oppose their use are reviewed. Although the ideal nerve glue has yet to be developed, fibrin sealants can be used as nerve glue in select clinical situations. Technology to allow suture-free nerve repair is one development that can potentially improve functional nerve recovery and the outcomes of upper extremity reconstruction. PMID- 23101604 TI - Advanced imaging and arthroscopic management of shoulder contracture after birth palsy. AB - Modern imaging techniques applied to the pediatric glenohumeral joint have advanced understanding of the anatomic changes that occur secondary to muscular imbalance after brachial plexus birth palsy. A better understanding of the progression and timing of glenohumeral dysplasia has also increased awareness and vigilance of this problem. Early detection of glenohumeral joint subluxation is now possible, allowing for prompt treatment with closed, arthroscopic, or open joint reduction with and without tendon transfers. Dynamic ultrasound imaging, Botox, and arthroscopic techniques have expanded treatment options, providing minimally invasive methods to successfully manage glenohumeral joint dysplasia. PMID- 23101605 TI - Advances in the management of Dupuytren disease: collagenase. AB - Dupuytren disease (DD) is a benign, generally painless connective tissue disorder affecting the palmar fascia that leads to progressive hand contractures. Mediated by myofibroblasts, the disease most commonly begins as a nodule in the palm or finger, and can progress where pathologic cords form leading to progressive flexion deformity of the involved fingers. The palmar skin overlying the cords may become excessively calloused and contracted and involved joints may develop periarticular fibrosis. Although there is no cure, the sequellae of this affliction can be corrected. This article focuses on the role of collagen in DD and the development of a collagen-specific enzymatic treatment for DD contractures. PMID- 23101606 TI - Modern tendon repair techniques. AB - Digital tendon repair is one of the most common issues in hand surgery and also one of the most vexing. A repair must withstand the forces imparted on it during early motion. Common clinical scenarios that challenge the hand surgeon are flexor tendon injuries in zone II, zone I, and extensor tendons. Repair of tendons that have flat morphology present a particular challenge to achieving a strong repair while maintaining the native tendon shape. This article evaluates modern tendon repair techniques. Early clinical experience using such methods have shown clinical success of improved motion and no known ruptures. PMID- 23101607 TI - Nerve transfers. AB - Nerve transfers have been performed for many years, but the technique is further developing and gaining increased recognition as a time-tested procedure. The original operations are continually modified to treat a wide variety of peripheral nerve injuries, and yield reliable results. In addition, nerve transfers can be used in conjunction with tendon transfers or nerve grafts in order to best treat a specific patient's set of deficits. This review of nerve transfers briefly discusses the evolution of the technique, general principles, some specific transfers, post-operative rehabilitation, and their place on the reconstructive ladder. PMID- 23101608 TI - Suture-button suspensionplasty for the treatment of thumb carpometacarpal joint arthritis. AB - Trapeziectomy has been regaining popularity in treatment of thumb carpometacarpal (CMC). Current approaches to trapeziectomy use Kirschner wire fixation to prevent subsidence of the thumb metacarpal into the newly created trapeziectomy space. This fixation method requires at least 4 weeks of strict immobilization of the thumb. A technique using a suture-button device to suspend the thumb allows for earlier mobilization of the thumb and potentially leads to a faster overall recovery. Preliminary results are promising, but further studies must be conducted to confirm the long-term efficacy of this suture-button suspensionplasty. PMID- 23101609 TI - Advances in upper extremity prosthetics. AB - Until recently, upper extremity prostheses had changed little since World War II. In 2006, the Defense Advanced Research Projects Agency responded to an increasing number of military amputees with the Revolutionizing Prosthetics program. The program has yielded several breakthroughs both in the engineering of new prosthetic arms and in the control of those arms. Direct brain-wave control of a limb with 22 degrees of freedom may be within reach. In the meantime, advances such as individually powered digits have opened the door to multifunctional full and partial hand prostheses. Restoring sensation to the prosthetic limb remains a major challenge to full integration of the limb into a patient's self-image. PMID- 23101610 TI - Total wrist arthroplasty. AB - This article reviews the history of total wrist arthroplasty as a treatment option for painful, nonfunctional wrists in disease states. Technologic advances in materials, wear properties, and manufacturing now account for increased implant longevity. They may also improve total wrist replacement design, survival, and hence patient function. Also, alternative surgical treatments such as distal radius hemiarthroplasty may serve as a treatment option for patients with higher activity levels and diffuse arthritis. With careful patient selection, soft tissue considerations, and novel implant designs, TWA may become a viable treatment staple for patients with functional wrist disability. PMID- 23101611 TI - Distal ulna arthroplasties. AB - The distal radioulnar joint (DRUJ) is the distal link between the radius and the ulna, and forms a pivot for forearm pronation and supination. As well as being susceptible to idiopathic arthritis, any injury or deformity of the DRUJ involving the radius or ulna can alter the function of this joint. Treatment options for irreparable destruction of this joint have ranged from fusion of the DRUJ joint to a variety of excision techniques with soft-tissue reconstructions, and are ever evolving. Understanding the distal ulnar anatomy is key to success. PMID- 23101612 TI - New and emerging technology in the treatment of the upper extremity. PMID- 23101613 TI - Site-specific coupling of hydration water and protein flexibility studied in solution with ultrafast 2D-IR spectroscopy. AB - There is considerable evidence for the slaving of biomolecular dynamics to the motions of the surrounding solvent environment, but to date there have been few direct experimental measurements capable of site-selectively probing both the dynamics of the water and the protein with ultrafast time resolution. Here, two dimensional infrared spectroscopy (2D-IR) is used to study the ultrafast hydration and protein dynamics sensed by a metal carbonyl vibrational probe covalently attached to the surface of hen egg white lysozyme dissolved in D(2)O/glycerol solutions. Surface labeling provides direct access to the dynamics at the protein-water interface, where both the hydration and the protein dynamics can be observed simultaneously through the vibrational probe's frequency frequency correlation function. In pure D(2)O, the correlation function shows a fast initial 3 ps decay corresponding to fluctuations of the hydration water, followed by a significant static offset attributed to fluctuations of the protein that are not sampled within the <20 ps experimental window. Adding glycerol increases the bulk solvent viscosity while leaving the protein structurally intact and hydrated. The hydration dynamics exhibit a greater than 3-fold slowdown between 0 and 80% glycerol (v/v), and the contribution from the protein's dynamics is found to slow in a nearly identical fashion. In addition, the magnitude of the dynamic slowdown associated with hydrophobic hydration is directly measured and shows quantitative agreement with predictions from molecular dynamics simulations. PMID- 23101614 TI - Evidence for an enhancing effect of alginate on iron availability in Caco-2 cells. AB - The potential use of alginates as a vehicle for water-soluble (bioavailable) iron for fortifying food products was examined using a Caco-2 cell model system. Cell monolayers were exposed to alginates with various mannuronic to guluronic acid ratios at three different concentrations, and cellular ferritin was measured as a surrogate marker of iron uptake into the cell. Ferritin concentrations were significantly higher when the cells were treated with ferric ammonium citrate and 0.5 and 1% w/v (but not 0.1%) alginate, but were unaffected by mannuronic/guluronic acid ratios. The enhancing effect of ascorbic acid was maintained with 0.1% alginate and significantly increased with 0.5 and 1% alginate, whereas the inhibitory effect of tannic acid was significantly reduced with 0.5% alginate. Alginate beads delivered available iron to Caco-2 cells, indicating that they are a promising vehicle for soluble iron with potential use in food fortification programs. PMID- 23101615 TI - Application of binding pancreatogastrostomy in laparoscopic central pancreatectomy. AB - BACKGROUND: The feasibility of binding pancreaticogastrostomy in laparoscopic central pancreatectomy is not known. METHODS: In October 2011, a female patient with a pancreatic neck mass received laparoscopic central pancreatectomy with binding pancreaticogastrostomy. RESULTS: The operation was successful. No complications occurred. The operative time was 210 min. Blood loss was 120 ml. On day 11 after the operation, the patient was discharged. The postoperative pathological result showed a 2 * 2 * 2-cm solid pseudopapillary tumor of the pancreas with intrapancreatic infiltration. The surgical margin was negative. CONCLUSIONS: Laparoscopic central pancreatectomy with binding pancreaticogastrostomy might be feasible, facilitating further study in laparoscopic pancreatoduodenectomy. TRIAL REGISTRATION: This study was waived from trial registration because it is a retrospective analysis of medical records. PMID- 23101616 TI - Enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block. AB - A brief, enantioselective synthesis of a hydroxymethyl-cis-1,3-cyclopentenediol building block is presented. This scaffold allows access to the cis-1,3 cyclopentanediol fragments found in a variety of biologically active natural and non-natural products. This rapid and efficient synthesis is highlighted by the utilization of the palladium-catalyzed enantioselective allylic alkylation of dioxanone substrates to prepare tertiary alcohols. PMID- 23101617 TI - A missing link in genotype-directed cancer therapy. AB - Genotype-directed therapy holds great promise for the treatment of cancer, but crosstalk between signaling pathways often confounds simple genotype-drug response relationships. To deliver on the promise of precision medicine, a coordinated effort is needed to make a comprehensive inventory of the many signaling feedback circuits that exist in cancer cells. PMID- 23101618 TI - Macrolides: the plug is out. AB - Macrolide antibiotics are thought to clog up the ribosomal tunnel and thereby block general protein synthesis. By using a combination of elegant in vivo and in vitro approaches, Kannan et al. show that the inhibitory action of these drugs on bacterial protein synthesis is selective rather than global. PMID- 23101619 TI - "Transflammation": when innate immunity meets induced pluripotency. AB - A surprising link between innate immunity and nuclear reprogramming is reported by Lee et al.; this discovery may boost the efficiency of stem cell production. PMID- 23101620 TI - A tollgate for typhoid. AB - Humans are uniquely susceptible to typhoid fever caused by infection with Salmonella enterica serovar Typhi. Mathur et al. now report that mice lacking Toll-like receptor 11, which is absent in humans, can be lethally infected with S. Typhi, a breakthrough that promises to speed the development of better vaccines. PMID- 23101621 TI - Revisiting global gene expression analysis. AB - Gene expression analysis is a widely used and powerful method for investigating the transcriptional behavior of biological systems, for classifying cell states in disease, and for many other purposes. Recent studies indicate that common assumptions currently embedded in experimental and analytical practices can lead to misinterpretation of global gene expression data. We discuss these assumptions and describe solutions that should minimize erroneous interpretation of gene expression data from multiple analysis platforms. PMID- 23101622 TI - Single-neuron sequencing analysis of L1 retrotransposition and somatic mutation in the human brain. AB - A major unanswered question in neuroscience is whether there exists genomic variability between individual neurons of the brain, contributing to functional diversity or to an unexplained burden of neurological disease. To address this question, we developed a method to amplify genomes of single neurons from human brains. Because recent reports suggest frequent LINE-1 (L1) retrotransposition in human brains, we performed genome-wide L1 insertion profiling of 300 single neurons from cerebral cortex and caudate nucleus of three normal individuals, recovering >80% of germline insertions from single neurons. While we find somatic L1 insertions, we estimate <0.6 unique somatic insertions per neuron, and most neurons lack detectable somatic insertions, suggesting that L1 is not a major generator of neuronal diversity in cortex and caudate. We then genotyped single cortical cells to characterize the mosaicism of a somatic AKT3 mutation identified in a child with hemimegalencephaly. Single-neuron sequencing allows systematic assessment of genomic diversity in the human brain. PMID- 23101623 TI - Visualizing group II intron catalysis through the stages of splicing. AB - Group II introns are self-splicing ribozymes that share a reaction mechanism and a common ancestor with the eukaryotic spliceosome, thereby providing a model system for understanding the chemistry of pre-mRNA splicing. Here we report 14 crystal structures of a group II intron at different stages of catalysis. We provide a detailed mechanism for the first step of splicing, we describe a reversible conformational change between the first and the second steps of splicing, and we present the ligand-free intron structure after splicing in an active state that corresponds to the retrotransposable form of the intron. During each reaction, the reactants are aligned and activated by a heteronuclear four metal-ion center that contains a metal cluster and obligate monovalent cations, and they adopt a structural arrangement similar to that of protein endonucleases. Based on our data, we propose a model for the splicing cycle and show that it is applicable to the eukaryotic spliceosome. PMID- 23101624 TI - Selective protein synthesis by ribosomes with a drug-obstructed exit tunnel. AB - The polypeptide exit tunnel is an important functional compartment of the ribosome where the newly synthesized proteins are surveyed. The tunnel is the target of clinically important macrolide antibiotics. Macrolides plug the tunnel and are believed to stop production of all proteins. Contrary to this view, we show that drug-bound ribosomes can synthesize a distinct subset of cellular polypeptides. The structure of a protein defines its ability to thread through the antibiotic-obstructed tunnel. Synthesis of certain polypeptides that initially bypass translational arrest can be stopped at later stages of elongation while translation of some proteins goes to completion. Our findings reveal that small-molecule effectors can accentuate the discriminatory properties of the ribosomal exit tunnel and that macrolide antibiotics reshape the cellular proteome rather than block global protein synthesis. PMID- 23101625 TI - Activation of innate immunity is required for efficient nuclear reprogramming. AB - Retroviral overexpression of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) generates induced pluripotent stem cells (iPSCs). However, the integration of foreign DNA could induce genomic dysregulation. Cell-permeant proteins (CPPs) could overcome this limitation. To date, this approach has proved exceedingly inefficient. We discovered a striking difference in the pattern of gene expression induced by viral versus CPP-based delivery of the reprogramming factors, suggesting that a signaling pathway required for efficient nuclear reprogramming was activated by the retroviral, but not CPP approach. In gain- and loss-of-function studies, we find that the toll-like receptor 3 (TLR3) pathway enables efficient induction of pluripotency by viral or mmRNA approaches. Stimulation of TLR3 causes rapid and global changes in the expression of epigenetic modifiers to enhance chromatin remodeling and nuclear reprogramming. Activation of inflammatory pathways are required for efficient nuclear reprogramming in the induction of pluripotency. PMID- 23101627 TI - A mouse model of Salmonella typhi infection. AB - Salmonella spp. are gram-negative flagellated bacteria that can cause food- and waterborne gastroenteritis and typhoid fever in humans. We now report that flagellin from Salmonella spp. is recognized in mouse intestine by Toll-like receptor 11 (TLR11). Absence of TLR11 renders mice more susceptible to infection by S. Typhimurium, with increased dissemination of the bacteria and enhanced lethality. Unlike S. Typhimurium, S. Typhi, a human obligatory pathogen that causes typhoid fever, is normally unable to infect mice. TLR11 is expressed in mice, but not in humans, and remarkably, we find that tlr11(-/-) mice are efficiently infected with orally administered S. Typhi. We also find that tlr11( /-) mice can be immunized against S. Typhi. Therefore, tlr11(-/-) mice represent a small-animal model for the study of the immune response to S. Typhi and for the development of vaccines against this important human pathogen. PMID- 23101626 TI - Regulation of pluripotency and self- renewal of ESCs through epigenetic-threshold modulation and mRNA pruning. AB - Embryonic stem cell (ESC) pluripotency requires bivalent epigenetic modifications of key developmental genes regulated by various transcription factors and chromatin-modifying enzymes. How these factors coordinate with one another to maintain the bivalent chromatin state so that ESCs can undergo rapid self-renewal while retaining pluripotency is poorly understood. We report that Utf1, a target of Oct4 and Sox2, is a bivalent chromatin component that buffers poised states of bivalent genes. By limiting PRC2 loading and histone 3 lysine-27 trimethylation, Utf1 sets proper activation thresholds for bivalent genes. It also promotes nuclear tagging of messenger RNAs (mRNAs) transcribed from insufficiently silenced bivalent genes for cytoplasmic degradation through mRNA decapping. These opposing functions of Utf1 promote coordinated differentiation. The mRNA degradation function also ensures rapid cell proliferation by blocking the Myc Arf feedback control. Thus, Utf1 couples the core pluripotency factors with Myc and PRC2 networks to promote the pluripotency and proliferation of ESCs. PMID- 23101628 TI - Meiotic prophase requires proteolysis of M phase regulators mediated by the meiosis-specific APC/CAma1. AB - Whereas proliferating cells enter M phase shortly after DNA replication, the first M phase of meiosis is preceded by an extended prophase in which homologous chromosomes undergo recombination. Exit from prophase I is controlled by the recombination checkpoint (RC), which, in yeast, represses the meiosis-specific transcription factor Ndt80 required for the expression of B-type cyclins and other M phase regulators. We show that an extended prophase I additionally requires the suppression of latent, mitotic cell-cycle controls by the anaphase promoting complex (APC/C) and its meiosis-specific activator Ama1, which trigger the degradation of M phase regulators and Ndd1, a subunit of a mitotic transcription factor. ama1Delta mutants exit from prophase I prematurely and independently of the RC, which results in recombination defects and chromosome missegregation. Thus, control of prophase I by meiotic mechanisms depends on the suppression of the alternative, mitotic mechanisms by a meiosis-specific form of the APC/C. PMID- 23101629 TI - Membrane shape at the edge of the dynamin helix sets location and duration of the fission reaction. AB - The GTPase dynamin polymerizes into a helical coat that constricts membrane necks of endocytic pits to promote their fission. However, the dynamin mechanism is still debated because constriction is necessary but not sufficient for fission. Here, we show that fission occurs at the interface between the dynamin coat and the uncoated membrane. At this location, the considerable change in membrane curvature increases the local membrane elastic energy, reducing the energy barrier for fission. Fission kinetics depends on tension, bending rigidity, and the dynamin constriction torque. Indeed, we experimentally find that the fission rate depends on membrane tension in vitro and during endocytosis in vivo. By estimating the energy barrier from the increased elastic energy at the edge of dynamin and measuring the dynamin torque, we show that the mechanical energy spent on dynamin constriction can reduce the energy barrier for fission sufficiently to promote spontaneous fission. : PMID- 23101630 TI - MICU1 is an essential gatekeeper for MCU-mediated mitochondrial Ca(2+) uptake that regulates cell survival. AB - Mitochondrial Ca(2+) (Ca(2+)(m)) uptake is mediated by an inner membrane Ca(2+) channel called the uniporter. Ca(2+) uptake is driven by the considerable voltage present across the inner membrane (DeltaPsi(m)) generated by proton pumping by the respiratory chain. Mitochondrial matrix Ca(2+) concentration is maintained five to six orders of magnitude lower than its equilibrium level, but the molecular mechanisms for how this is achieved are not clear. Here, we demonstrate that the mitochondrial protein MICU1 is required to preserve normal [Ca(2+)](m) under basal conditions. In its absence, mitochondria become constitutively loaded with Ca(2+), triggering excessive reactive oxygen species generation and sensitivity to apoptotic stress. MICU1 interacts with the uniporter pore-forming subunit MCU and sets a Ca(2+) threshold for Ca(2+)(m) uptake without affecting the kinetic properties of MCU-mediated Ca(2+) uptake. Thus, MICU1 is a gatekeeper of MCU-mediated Ca(2+)(m) uptake that is essential to prevent [Ca(2+)](m) overload and associated stress. PMID- 23101631 TI - GABAergic RIP-Cre neurons in the arcuate nucleus selectively regulate energy expenditure. AB - Neural regulation of energy expenditure is incompletely understood. By genetically disrupting GABAergic transmission in a cell-specific fashion, and by combining this with selective pharmacogenetic activation and optogenetic mapping techniques, we have uncovered an arcuate-based circuit that selectively drives energy expenditure. Specifically, mice lacking synaptic GABA release from RIP-Cre neurons have reduced energy expenditure, become obese and are extremely sensitive to high-fat diet-induced obesity, the latter due to defective diet-induced thermogenesis. Leptin's ability to stimulate thermogenesis, but not to reduce feeding, is markedly attenuated. Acute, selective activation of arcuate GABAergic RIP-Cre neurons, which monosynaptically innervate PVH neurons projecting to the NTS, rapidly stimulates brown fat and increases energy expenditure but does not affect feeding. Importantly, this response is dependent upon GABA release from RIP-Cre neurons. Thus, GABAergic RIP-Cre neurons in the arcuate selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity. PMID- 23101632 TI - Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. AB - Many common diseases have an important inflammatory component mediated in part by macrophages. Here we used a systems genetics strategy to examine the role of common genetic variation in macrophage responses to inflammatory stimuli. We examined genome-wide transcript levels in macrophages from 92 strains of the Hybrid Mouse Diversity Panel. We exposed macrophages to control media, bacterial lipopolysaccharide (LPS), or oxidized phospholipids. We performed association mapping under each condition and identified several thousand expression quantitative trait loci (eQTL), gene-by-environment interactions, and eQTL "hot spots" that specifically control LPS responses. We used siRNA knockdown of candidate genes to validate an eQTL hot spot in chromosome 8 and identified the gene 2310061C15Rik as a regulator of inflammatory responses in macrophages. We have created a public database where the data presented here can be used as a resource for understanding many common inflammatory traits that are modeled in the mouse and for the dissection of regulatory relationships between genes. PMID- 23101634 TI - SnapShot: Bone Metastasis. PMID- 23101633 TI - Quantitative analysis of fission yeast transcriptomes and proteomes in proliferating and quiescent cells. AB - Data on absolute molecule numbers will empower the modeling, understanding, and comparison of cellular functions and biological systems. We quantified transcriptomes and proteomes in fission yeast during cellular proliferation and quiescence. This rich resource provides the first comprehensive reference for all RNA and most protein concentrations in a eukaryote under two key physiological conditions. The integrated data set supports quantitative biology and affords unique insights into cell regulation. Although mRNAs are typically expressed in a narrow range above 1 copy/cell, most long, noncoding RNAs, except for a distinct subset, are tightly repressed below 1 copy/cell. Cell-cycle-regulated transcription tunes mRNA numbers to phase-specific requirements but can also bring about more switch-like expression. Proteins greatly exceed mRNAs in abundance and dynamic range, and concentrations are regulated to functional demands. Upon transition to quiescence, the proteome changes substantially, but, in stark contrast to mRNAs, proteins do not uniformly decrease but scale with cell volume. PMID- 23101635 TI - [Physiology: from the birth of life to its fulfillment . . . A semantic journey to the source of nature]. PMID- 23101636 TI - [Pathophysiology of pulmonary hypertension: advances and prospects]. PMID- 23101637 TI - [Home-related hypersensitivity pneumonitis]. PMID- 23101638 TI - [Pulmonary hypertension: from molecular pathophysiology to haemodynamic abnormalities]. AB - Pulmonary hypertension (PH) is a complex disorder resulting from many etiologies that cause disturbances of normal pulmonary haemodynamics. Recent breakthroughs have led to a better understanding of the pathophysiology of the disease. In PH, haemodynamic disturbances are closely linked to structural changes and excessive remodeling of pulmonary vessels, leading to progressive narrowing of the pulmonary vascular lumen. Imbalances between pulmonary vasoconstrictors and vasodilators on the one hand, and factors favoring cell proliferation and apoptosis on the other hand, probably account for most cases of PH. This review aims to update readers with the current knowledge on the molecular physiopathology of PH and how this can progress the therapeutic of this disorder. PMID- 23101639 TI - [Domestic hypersensitivity pneumonitis]. AB - INTRODUCTION: Domestic hypersensitivity pneumonitis (HP) cases are relatively widespread, with an overall annual incidence of approximately 1/100,000 reported in a British study covering several million patients. All-causes mortality is three times higher within HP-affected patients than amongst the general population. STATE OF THE ART: Cases of HP are usually diagnosed as 'farmer's lung' (FL) and 'bird fancier's lung' (BFL) diseases, however we suggest that other domestic causes, such as humidifier lung, hot tub pneumonitis, feather duvet and domestic exposure to moulds may be more frequent than widely suggested. Usually, the diagnosis is established on the basis of characteristic clinical, functional, radiological and broncho-alveolar lavage findings or recurrence of respiratory symptoms after returning home. PERSPECTIVES: In the absence of a common cause (FL or BFL), physicians must have a high index of clinical suspicion and should consider an environmental antigen source. Detailed questioning of HP patients on their living conditions and, where appropriate, a home inspection conducted by an environmental health expert are necessary for identifying causative antigens. CONCLUSION: The cornerstone of therapy is antigen avoidance. PMID- 23101640 TI - [Smoking and active tuberculosis]. AB - The link between tuberculosis and HIV infection has long been established but the link between tuberculosis and smoking is not well understood. However, many patients with tuberculosis are smokers and an increasing proportion of them live in developing countries where there is a high incidence of the disease. Smoking increases the risk of tuberculosis and of subsequent death from the disease. Henceforth, smoking cessation will become a way of controlling the tuberculosis epidemic in developing nations. This evidence must be used to mobilize an international effort to deal with these two major public health issues. PMID- 23101641 TI - [Non-invasive ventilation era: is there still a place for long-term tracheostomy?]. AB - INTRODUCTION: At a time when non-invasive ventilation (NIV) is commonly used in acute as well as chronic respiratory failure, it is important to consider the current place, if any, of long-term tracheostomy. BACKGROUND: Except in emergency situations where tracheostomy is mandatory to ensure safe access to the airway, long-term ventilation with tracheostomy (LTVT) is generally considered in the case of inability to wean from NIV after an episode of acute respiratory failure requiring endotracheal ventilation or because of the development of bulbar signs (swallowing, phonation) in advanced neuromuscular disease. It is also appropriate when ventilatory dependence on NIV exceeds 20 hours per day. Historical retrospective studies confirmed the feasibility of LTVT, but this has to be seen in perspective with the results obtained 20 years later with NIV. VIEWPOINT AND CONCLUSION: Even if the indications for LTVT have diminished considerably since the emergence of NIV, tracheostomy remains mandatory in some situations of respiratory distress and it should be considered as a potential resource, possibly temporary in some cases in the light of recent work on the possibility of decanulation after LTVT. PMID- 23101642 TI - [Tobacco smoking and latent tuberculous infection]. AB - Tobacco smoking has a significant impact on the risk of tuberculosis and the mortality of the disease. There is a strong dose-response relationship both in terms of quantity and duration of smoking. Latent tuberculous infection and tuberculosis disease are different stages of the same infectious process but the relation between smoking and the risk of being infected with Mycobacterium tuberculosis is less well understood. The aim of this review is to describe the relationship between tobacco consumption and tuberculous infection and the mechanism by which smoking increases the risk. It outlines the public health consequences of the increased risk of latent tuberculous infection due to active and passive smoking. This justifies promotion of smoking cessation as a way of limiting the epidemic of tuberculosis in developing countries. PMID- 23101643 TI - [Pulmonary and alveolar ventilation, gas exchanges and arterial blood gases during ramp exercise]. AB - In response to ramp exercise, changes in ventilation, gas exchange and arterial blood gases, which are closely interrelated, reflect the two roles of ventilation: 1) providing O(2) and eliminating metabolic CO(2) (from rest to maximal exercise); and 2) contributing to acid-base balance by eliminating non metabolic CO(2) from the alkaline reserve (from the first ventilatory threshold [VT(1)] to maximal exercise). Hyperpnea before VT(1) increases gas exchanges as needed for aerobic metabolism without large changes in ventilatory equivalent of O(2) and CO(2) (VE/V(O2) or VE/V(CO2)), in P(O2) and P(CO2) in alveoli or arterial blood (except for a small widening of alveolo-arterial P(O2) gradient), and in bicarbonate concentration. In contrast, above VT(1), CO(2) is washed-out from the alkaline reserve due to the combined effect of the fall in PA(CO2) (because of hyperventilation) and in pH, and this helps maintaining acid-base balance. Pa(CO2) and bicarbonate concentration decrease while PA(O2) and VE/V(O2) increase, and V(CO2), which follows VE, becomes higher than V(O2). In healthy young subjects, but very seldom in patients, the end of exercise can occur after a second ventilatory threshold (VT(2)), which is the zone where the increase in V(CO2) fails to follow that in VE in spite of hyperventilation and acidosis because of the progressive depletion of the alkaline reserve. PMID- 23101644 TI - [The different pleuro-pulmonary pathologies related to asbestos: definitions, epidemiology and evolution]. AB - Pleural plaques (fibrosis of the parietal pleura) are sometimes seen following light exposure. Their prevalence may reach 70% in heavily exposed populations. Fibrosis of the visceral pleura is much less common and it is not specifically related to asbestos. The incidence of asbestosis (pulmonary fibrosis induced by asbestos exposure) is diminishing in France. According to the data of the National Programme for the Surveillance of Mesothelioma, the annual number of cases of pleural mesothelioma varied from 646 to 800 for the period 1998-2003. Primary lung cancer due to asbestos does not have specific clinical, radiological or anatomical-pathological features. The number of cases attributable to asbestos has been estimated as between 2086 and 4172 for 1999. A report of the National Academy of Medicine, the Academy of Sciences and the International Centre of Cancer Research has calculated the incidence of primary lung cancer due to asbestos in 2000 as 969 for men and 133 for women. The risk of primary lung cancer is increased in populations exposed to asbestos even in the absence of radiological signs of pulmonary fibrosis. For an identical total exposure, asbestosis increases the risk of primary lung cancer. On the basis of radiological studies, pleural plaques are associated with an increased risk of lung cancer and mesothelioma. For identical levels of total asbestos exposure, it has not been established that the presence of pleural plaques increases the risk of developing thoracic cancer. PMID- 23101645 TI - [Asthmatic emergencies: a psychosocial approach to behaviour of asthmatics]. AB - Emergency department admissions for acute asthma often show that patients have failed to manage their disease well. Such admissions may reflect poor asthma control, as defined in the literature, often due to a lack of education and medical follow-up. If patient-centred education has been recognised as effective, what are the best locations and the best moments in the patient's disease history to provide this education? The French Guidelines (HAS) on therapeutic education suggested that education should take place in the emergency department. Moreover, the emergency department is a unique healthcare situation and opportunity for therapeutic education. In the emergency department, a better analysis and understanding of an asthmatic's health orientated behaviour by a psychosocial interview may improve the patient's decision making and lead to an appropriate education programme. PMID- 23101646 TI - [Bacterial pneumonia in HIV-infected patients (excluding mycobacterial infection)]. AB - Respiratory infections are the most common complications in HIV patients, regardless of the degree of immunosuppression. Even though antiretroviral therapy has a protective effect on the risk of bacterial pneumonia, this still remains high (including those with CD(4)>500/mm(3)). The most frequently isolated bacteria are Streptococcus pneumoniae and Haemophilus influenzae. The clinical and radiological presentations of lower respiratory tract infections in HIV patients are quite variable. The clinical presentation is more severe and the radiological presentation is more atypical if the immunosuppression is severe. The first-line antibiotic therapy is an injectable third-generation cephalosporin (ceftriaxone or cefotaxime) or co-amoxiclav. Pneumococcal vaccination (as well as influenza vaccine) is recommended. Although rare, Nocardia spp. and Rhodococcus equi seem more common among AIDS patients. PMID- 23101647 TI - Large-scale prediction of drug-target interactions using protein sequences and drug topological structures. AB - The identification of interactions between drugs and target proteins plays a key role in the process of genomic drug discovery. It is both consuming and costly to determine drug-target interactions by experiments alone. Therefore, there is an urgent need to develop new in silico prediction approaches capable of identifying these potential drug-target interactions in a timely manner. In this article, we aim at extending current structure-activity relationship (SAR) methodology to fulfill such requirements. In some sense, a drug-target interaction can be regarded as an event or property triggered by many influence factors from drugs and target proteins. Thus, each interaction pair can be represented theoretically by using these factors which are based on the structural and physicochemical properties simultaneously from drugs and proteins. To realize this, drug molecules are encoded with MACCS substructure fingerings representing existence of certain functional groups or fragments; and proteins are encoded with some biochemical and physicochemical properties. Four classes of drug-target interaction networks in humans involving enzymes, ion channels, G-protein-coupled receptors (GPCRs) and nuclear receptors, are independently used for establishing predictive models with support vector machines (SVMs). The SVM models gave prediction accuracy of 90.31%, 88.91%, 84.68% and 83.74% for four datasets, respectively. In conclusion, the results demonstrate the ability of our proposed method to predict the drug-target interactions, and show a general compatibility between the new scheme and current SAR methodology. They open the way to a host of new investigations on the diversity analysis and prediction of drug-target interactions. PMID- 23101648 TI - An overview of the analytical methods for the determination of organic ultraviolet filters in biological fluids and tissues. AB - Organic UV filters are chemical compounds added to cosmetic sunscreen products in order to protect users from UV solar radiation. The need of broad-spectrum protection to avoid the deleterious effects of solar radiation has triggered a trend in the cosmetic market of including these compounds not only in those exclusively designed for sun protection but also in all types of cosmetic products. Different studies have shown that organic UV filters can be absorbed through the skin after topical application, further metabolized in the body and eventually excreted or bioaccumulated. These percutaneous absorption processes may result in various adverse health effects, such as genotoxicity caused by the generation of free radicals, which can even lead to mutagenic or carcinogenic effects, and estrogenicity, which is associated with the endocrine disruption activity caused by some of these compounds. Due to the absence of official monitoring protocols, there is a demand for analytical methods that enable the determination of UV filters in biological fluids and tissues in order to retrieve more information regarding their behavior in the human body and thus encourage the development of safer cosmetic formulations. In view of this demand, there has recently been a noticeable increase in the development of sensitive and selective analytical methods for the determination of UV filters and their metabolites in biological fluids (i.e., urine, plasma, breast milk and semen) and tissues. The complexity of the biological matrix and the low concentration levels of these compounds inevitably impose sample treatment processes that afford both sample clean-up to remove potentially interfering matrix components as well as the enrichment of analytes in order to achieve their determination at very low concentration levels. The aim of this review is to provide a comprehensive overview of the recent developments in the determination of UV filters in biological fluids and tissues, with special emphasis on the elucidation of new metabolites, sample preparation and analytical techniques as well as occurrence levels. PMID- 23101649 TI - An advanced multivariate approach for processing X-ray fluorescence spectral and hyperspectral data from non-invasive in situ analyses on painted surfaces. AB - In the last decades, in situ non-invasive analytical techniques have been widely used for the analysis of paintings. These techniques are useful to extensively map the surface in a non-invasive way, in order to identify the most representative areas to be sampled. When spectroscopic investigations, such as X ray fluorescence (XRF), are conducted, they usually imply the acquisition of a huge amount of measurements. Subsequently, all these data should be processed in situ, in order to immediately support the sampling strategies. To this aim, an appropriate and fast strategy for multivariate treatment of XRF spectral and hyperspectral data sets is presented, able to account for inter-correlation among variables, which is an issue of high importance for elemental analyses. The main advantage of the approach is that XRF spectral profiles are analysed directly, without computation of derived parameters, by means of principal component analysis (PCA). This procedure allows a fast interpretation of results that can be accomplished in situ. Particular attention was paid to the selection of proper spectral pre-treatments to be applied on data together with the use of several chemometric tools (peak alignment, spectra normalisation and exploratory analysis) aimed at improving the interpretation of XRF results. In addition, the application of multivariate exploratory analysis on XRF hyperspectral maps was studied by using an interactive brushing procedure. The multivariate approach was validated on data obtained from the analysis of the famous Renaissance panel painting "The Ideal City", exhibited in Palazzo Ducale of Urbino, Italy. PMID- 23101650 TI - Electrochemical deoxyribonucleic acid biosensor based on carboxyl functionalized graphene oxide and poly-L-lysine modified electrode for the detection of tlh gene sequence related to vibrio parahaemolyticus. AB - A carboxyl functionalized graphene oxide (GO-COOH) and electropolymerized poly-l lysine (PLLy) modified glassy carbon electrode (GCE) was fabricated and used for the construction of an electrochemical deoxyribonucleic acid (DNA) biosensor. The NH(2) modified probe ssDNA sequences were immobilized on the surface of GO COOH/PLLy/GCE by covalent linking with the formation of amide bonds, which was stable and further hybridized with the target ssDNA sequence. Differential pulse voltammetry (DPV) was used to monitor the hybridization events with methylene blue as electrochemical indicator, which gave a sensitive reduction peak at 0.287 V (vs. SCE). Under the optimal conditions the reduction peak current was proportional to the concentration of tlh gene sequence in the range from 1.0*10( 12) to 1.0*10(-6) mol L(-1) with a detection limit as 1.69*10(-13) mol L(-1) (3sigma). The polymerase chain reaction products of tlh gene from oyster samples were detected with satisfactory results, indicating the potential application of this electrochemical DNA sensor. PMID- 23101651 TI - Electrochemical study of nitrobenzene reduction using novel Pt nanoparticles/macroporous carbon hybrid nanocomposites. AB - Novel Pt nanoparticles (PN) ensemble on macroporous carbon (MPC) hybrid nanocomposites (PNMPC) were prepared through a rapidly and simple one-step microwave-assisted heating procedure. The obtained PNMPC was characterized by transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA) and electrochemical methods. The electrochemical reduction of nitrobenzene (NB) was thoroughly investigated at the PNMPC modified glassy carbon (GC) electrode, and the catalytic rate constant was calculated to be 3.14*10(4) M(-1) s(-1) for NB. A sensitive NB sensor was developed based on the PNMPC/GC electrode, which showed a wide linear range (1-200 MUM), low detection limit (50 nM), high sensitivity (6.93 MUA MUM(-1)), excellent anti interference ability and good stability. And moreover, the electrode was successfully applied to the determination of NB in real samples. PMID- 23101652 TI - Ultrasound-assisted matrix solid-phase dispersive liquid extraction for the determination of intermediates in hair dyes with ion chromatography. AB - A novel one-step sample preparation technique called ultrasound-assisted matrix solid-phase dispersive liquid extraction was developed. After sample matrices being dispersed, target analytes were extracted into acid solutions and fat and lipin were dissolved in n-hexane while the interfering components were retained by dispersing sorbent. The extraction process could be rapidly accomplished within 9 min with high sample throughput under the synergistic effects of vibration, ultrasound action and heating. The extraction efficiency of approach was demonstrated for the determination of intermediates in commercial hair dyes with ion chromatography. Linearity ranges of 0.2-100 mg L(-1) and detection limits varying from 0.019 to 0.048 mg L(-1) were achieved. The recoveries ranged from 85.7 to 107.0% with the relative standard deviations (RSDs) of 0.31-3.7%. These results showed that the method was simple, time-saving, reliable and suitable for the routine analysis of intermediates in large numbers of hair dyes. PMID- 23101653 TI - Enantiomer-specific determination of hexabromocyclododecane in fish by supramolecular solvent-based single-step sample treatment and liquid chromatography-tandem mass spectrometry. AB - A single-step, environmentally friendly sample treatment was developed and used in combination with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the quantitation of hexabromocyclododecane (HBCD) stereoisomers in fish. It was based on the microextraction of the stereoisomers with a supramolecular solvent (SUPRAS) made up of reverse aggregates of decanoic acid (DeA). The procedure involved the stirring of the fish sample (750 mg) with 600 MUL of SUPRAS for five minutes, subsequent centrifugation for extract separation from matrix components and direct analysis of the extract after dilution 1:1 with methanol. Individual enantiomers of alpha-, beta- and gamma-HBCD were separated on a chiral stationary phase of beta-cyclodextrin and quantified by monitoring of the [M-H](-)->Br(-) transition at m/z 640.9->80.9. Driving forces for the microextraction of HBCD in the SUPRAS involved both dispersion and dipole-dipole interactions. Quantitation limits for the determination of individual HBCD enantiomers in hake, cod, sole, panga, whiting and sea bass were within the intervals 0.5-3.4 ng g(-1), 0.9-2.5 ng g(-1), 0.6-1.4 ng g(-1), 1.0-5.6 ng g(-1), 0.8-1.3 ng g(-1) and 0.5-3.5 ng g( 1), respectively. Recoveries for fish samples fortified at the ng g(-1) level ranged between 87 and 114% with relative standard deviations from 1 to 10%. The sample treatment proposed greatly simplifies current procedures for extraction of HBCD stereoisomers and is a useful tool for the development of a large scale database for their presence in fish. PMID- 23101654 TI - Rapid quality assessment of Radix Aconiti Preparata using direct analysis in real time mass spectrometry. AB - This study presents a novel and rapid method to identify chemical markers for the quality control of Radix Aconiti Preparata, a world widely used traditional herbal medicine. In the method, the samples with a fast extraction procedure were analyzed using direct analysis in real time mass spectrometry (DART MS) combined with multivariate data analysis. At present, the quality assessment approach of Radix Aconiti Preparata was based on the two processing methods recorded in Chinese Pharmacopoeia for the purpose of reducing the toxicity of Radix Aconiti and ensuring its clinical therapeutic efficacy. In order to ensure the safety and effectivity in clinical use, the processing degree of Radix Aconiti should be well controlled and assessed. In the paper, hierarchical cluster analysis and principal component analysis were performed to evaluate the DART MS data of Radix Aconiti Preparata samples in different processing times. The results showed that the well processed Radix Aconiti Preparata, unqualified processed and the raw Radix Aconiti could be clustered reasonably corresponding to their constituents. The loading plot shows that the main chemical markers having the most influence on the discrimination amongst the qualified and unqualified samples were mainly some monoester diterpenoid aconitines and diester diterpenoid aconitines, i.e. benzoylmesaconine, hypaconitine, mesaconitine, neoline, benzoylhypaconine, benzoylaconine, fuziline, aconitine and 10-OH-mesaconitine. The established DART MS approach in combination with multivariate data analysis provides a very flexible and reliable method for quality assessment of toxic herbal medicine. PMID- 23101655 TI - Determination of cyromazine and melamine in chicken eggs using quick, easy, cheap, effective, rugged and safe (QuEChERS) extraction coupled with liquid chromatography-tandem mass spectrometry. AB - A rapid and sensitive method has been developed for the simultaneous detection of cyromazine and melamine in chicken eggs using the quick, easy, cheap, effective, rugged and safe (QuEChERS) method coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The optimal extraction solvent for the liquid-liquid extraction was 5 mL of acetonitrile with a 0.1 M hydrochloric acid aqueous solution (99.5:0.5, v/v). The extract was cleaned with 0.5 g of anhydrous magnesium sulfate and 10 mg of graphitized carbon black. The analysis of cyromazine and melamine was accomplished by combining the use of an anion exchange LC column with tandem mass spectrometry in the positive electrospray ionization mode with selected reaction monitoring mode (SRM). The detection limits were 1.6 ng g(-1) for cyromazine and 8 ng g(-1) for melamine, and the quantitation limits were 5.5 ng g(-1) for cyromazine and 25 ng g(-1) for melamine. The recoveries of cyromazine and melamine in the spiked egg samples were 83.2% and 104.6%, respectively, with an relative standard deviation (RSD) of less than 18.1%. The intra-day and inter-day precisions, represented by the RSD, ranged from 1.5% to 8.8% and 6.8% to 14.3%, respectively. The proposed method was tested by analyzing chicken eggs from the markets and from the veterinary medicine laboratory. The concentrations of cyromazine and melamine detected in these samples were in the range of 20-94 ng g(-1). The results demonstrated that the QuEChERS method combined with LC-MS/MS is a simple, rapid and inexpensive method for the analysis of cyromazine and melamine in eggs. PMID- 23101656 TI - Inverse opal pH sensors with various protic monomers copolymerized with polyhydroxyethylmethacrylate hydrogel. AB - pH sensitive inverse opal sensors were synthesized using various vinyl monomers containing acidic or basic substituents. Acrylic acid (AA), vinylphosphonic acid (VPA), vinylimidazole (VI), and dimethylaminoethylmethacrylic acid (DMAEMA) were respectively copolymerized with hydroxyethylmethacrylate (HEMA), the building block monomer of the hydrogel via UV-initiated photopolymerization. Opal templating and subsequent template removal enabled the fabrication of four inverse opal (IO) hydrogel colorimetric sensors, which responded to pH in different fashions. pH-dependent swelling of the IO hydrogel induced the red shift of the diffracted color. The sensors containing AA or VPA, the proton donating monomers showed the color shifts from green to red with pH increase due to the increased concentration of carboxylate anions bound to the hydrogel. Diprotic VPA sensor exhibited two-step increases of diffracted wavelengths at its pK(a1) and pK(a2) respectively. The sensors containing proton acceptors, VI and DMAEMA showed the pH-dependent color changes in an opposite way to the AA sensor and the VPA sensor since their ionizations take place by lowering pH due to the protonation at the amino groups. The shapes of pH response curves of VI and DMAEMA sensors were similar but pK(b)s were different from each other. Optical diffraction responses of four sensors were compared with the calculated concentration ratios of the ionized species to the total monomer with pH variation, and a deswelling effect in the vicinities of pK(a)s of phosphate buffer on the swelling response could be explained by shrinkage of PHEMA hydrogel under high ionic environment. In addition, copolymerization of AA, VPA and HEMA was carried out which resulted in a pH sensor exhibiting a wider range of pH for color change. PMID- 23101657 TI - Poly(alizarin red)/graphene modified glassy carbon electrode for simultaneous determination of purine and pyrimidine. AB - In this work, a poly(alizarin red)/Graphene composite film modified glassy carbon electrode (PAR/Graphene/GCE) was prepared for simultaneous determination of four DNA bases (guanine, adenine, thymine and cytosine) without any pretreatment. The morphology and interface property of PAR/Graphene films were examined by scanning electron microscopy and electrochemical impedance spectroscopy. The PAR/Graphene/GCE exhibited excellent electrocatalytic activity toward purine (guanine and adenine) and pyrimidine (thymine and cytosine) in 0.1 M phosphate buffer solution (pH 7.4). Under optimum conditions, differential pulse voltammetry was used to detect the oxidation of purine and pyrimidine. The results showed that PAR/Graphene/GCE exhibited well-separated peaks, low detection limit, high sensitivity and wide linear range for simultaneous detection of purine and pyrimidine. The proposed sensor also has good stability and reproducibility. Furthermore, the modified electrode was applied for the detection of DNA bases in a fish sperm DNA sample with satisfactory results. PMID- 23101658 TI - Ultrathin CdSe nanosheets: synthesis and application in simultaneous determination of catechol and hydroquinone. AB - Ultrathin crystalline CdSe nanosheets have been synthesized through a facile solution processes. Their application to simultaneous electrochemical determination of catechol and hydroquinone is demonstrated. The few-layer single crystalline CdSe modified electrode exhibits strong electrocatalytic activity toward the oxidation of a mixture of catechol and hydroquinone. The excellent analytical performance makes the ultrathin CdSe nanomaterials promising for the development of electrochemical sensors for potential applications in medicine, biotechnology and environmental chemistry. PMID- 23101659 TI - A micro trapping system coupled with a high performance liquid chromatography procedure for methylamine determination in both tissue and cigarette smoke. AB - Both endogenous and exogenous methylamine have been found to be involved in many human disorders. The quantitative assessment of methylamine has drawn considerable interest in recent years. Although there have been many papers about the determination of methylamine, only a few of them involved cigarette smoke or mammalian tissue analysis. The major hurdles of the determination of methylamine are the collection of methylamine from samples and the differentiation of methylamine from the background compounds, e.g., biogenic amines. We have solved this problem using a micro trapping system coupled with an HPLC procedure. The interference from other biogenic amines has been avoided. The high selectivity of this method was achieved using four techniques: distillation, trapping, HPLC separation and selective detection. The chromatograms of both mouse tissues and cigarette smoke are simple, with only a few peaks. The method is easy and efficient and it has been validated and applied to the determination of methylamine in tissues of normal CD 1 mice and cigarette smoke. The methylamine contents were determined to be approximately 268.3 ng g(-1) in the liver, 429.5 ng g(-1) in the kidney and 547.4 ng g(-1) in the brain respectively. The methylamine in the cigarette smoke was approximately 213 ng to 413 ng per cigarette. These results in tissues and in cigarette smoke were found to be consistent with the data in the previous literature. To the best of our knowledge, this is the first report on a method suitable for methylamine analysis in both mammalian tissue and cigarette smoke. PMID- 23101661 TI - Risk of second malignant neoplasms after cyclophosphamide-based chemotherapy with or without radiotherapy for non-Hodgkin lymphoma. AB - Relatively little information is available on quantitative risks of therapy induced second malignant neoplasm (SMN) in patients with non-Hodgkin lymphoma (NHL). A nested case-control study was conducted in a cohort of 3412 patients treated for NHL between 1990 and 2006, including 118 patients with SMN and 472 controls. Risks of leukemia/lung/breast/colorectal and bladder cancer were higher in NHL compared with the general population. A higher risk of leukemia was restricted to patients given a cumulative dose of cyclophosphamide more than 11 250 mg/m(2). However, no significant association was found between SMN risk with rituximab, fludarabine, anthracyclines, epipodophyllotoxins and platinum, respectively. In combined modality treatment, involved-field radiation therapy (IFRT) had a higher risk for second solid cancers as compared to involved-nodal radiation therapy (INRT). For patients receiving radiation doses exceeding 40 Gy, the risk of lung cancer and breast cancer was increased. In conclusion, we found that cyclophosphamide-based therapy increased the risk of SMN in NHL. Leukemia risk was linked with high-dose cyclophosphamide. A received larger radiation field or higher radiation dose also could be an important risk factor for the development of SMN. PMID- 23101660 TI - Immunization with the immunodominant Helicobacter suis urease subunit B induces partial protection against H. suis infection in a mouse model. AB - Helicobacter (H.) suis is a porcine and human gastric pathogen. Previous studies in mice showed that an H. suis infection does not result in protective immunity, whereas immunization with H. suis whole-cell lysate (lysate) protects against a subsequent experimental infection. Therefore, two-dimensional gel electrophoresis of H. suis proteins was performed followed by immunoblotting with pooled sera from H. suis- infected mice or mice immunized with lysate. Weak reactivity against H. suis proteins was observed in post-infection sera. Sera from lysate immunized mice, however, showed immunoreactivity against a total of 19 protein spots which were identified using LC-MS/MS. The H. suis urease subunit B (UreB) showed most pronounced reactivity against sera from lysate-immunized mice and was not detected with sera from infected mice. None of the pooled sera detected H. suis neutrophil-activating protein A (NapA). The protective efficacy of intranasal vaccination of BALB/c mice with H. suis UreB and NapA, both recombinantly expressed in Escherichia coli (rUreB and rNapA, respectively), was compared with that of H. suis lysate. All vaccines contained choleratoxin as adjuvant. Immunization of mice with rUreB and lysate induced a significant reduction of H. suis colonization compared to non-vaccinated H. suis-infected controls, whereas rNapA had no significant protective effect. Probably, a combination of local Th1 and Th17 responses, complemented by antibody responses play a role in the protective immunity against H. suis infections. PMID- 23101662 TI - Robust synchronization control scheme of a population of nonlinear stochastic synthetic genetic oscillators under intrinsic and extrinsic molecular noise via quorum sensing. AB - BACKGROUND: Collective rhythms of gene regulatory networks have been a subject of considerable interest for biologists and theoreticians, in particular the synchronization of dynamic cells mediated by intercellular communication. Synchronization of a population of synthetic genetic oscillators is an important design in practical applications, because such a population distributed over different host cells needs to exploit molecular phenomena simultaneously in order to emerge a biological phenomenon. However, this synchronization may be corrupted by intrinsic kinetic parameter fluctuations and extrinsic environmental molecular noise. Therefore, robust synchronization is an important design topic in nonlinear stochastic coupled synthetic genetic oscillators with intrinsic kinetic parameter fluctuations and extrinsic molecular noise. RESULTS: Initially, the condition for robust synchronization of synthetic genetic oscillators was derived based on Hamilton Jacobi inequality (HJI). We found that if the synchronization robustness can confer enough intrinsic robustness to tolerate intrinsic parameter fluctuation and extrinsic robustness to filter the environmental noise, then robust synchronization of coupled synthetic genetic oscillators is guaranteed. If the synchronization robustness of a population of nonlinear stochastic coupled synthetic genetic oscillators distributed over different host cells could not be maintained, then robust synchronization could be enhanced by external control input through quorum sensing molecules. In order to simplify the analysis and design of robust synchronization of nonlinear stochastic synthetic genetic oscillators, the fuzzy interpolation method was employed to interpolate several local linear stochastic coupled systems to approximate the nonlinear stochastic coupled system so that the HJI-based synchronization design problem could be replaced by a simple linear matrix inequality (LMI)-based design problem, which could be solved with the help of LMI toolbox in MATLAB easily. CONCLUSION: If the synchronization robustness criterion, i.e. the synchronization robustness >= intrinsic robustness + extrinsic robustness, then the stochastic coupled synthetic oscillators can be robustly synchronized in spite of intrinsic parameter fluctuation and extrinsic noise. If the synchronization robustness criterion is violated, external control scheme by adding inducer can be designed to improve synchronization robustness of coupled synthetic genetic oscillators. The investigated robust synchronization criteria and proposed external control method are useful for a population of coupled synthetic networks with emergent synchronization behavior, especially for multi-cellular, engineered networks. PMID- 23101663 TI - System design for integrated comprehensive and multidimensional gas chromatography with mass spectrometry and olfactometry. AB - An integrated system having the combined capability to perform gas chromatography (GC), comprehensive two-dimensional GC (GC * GC), and target heart-cut multidimensional GC (MDGC) using olfactometry (O), flame ionization (FID), and/or mass spectrometry (MS) detection is described. This combines a number of contemporary GC methods into a single instrument to provide very high resolution profiling of a sample. This provides initial assessment of volatile compound composition through GC * GC analysis with FID, which can be correlated with GC analysis using parallel O and FID detection. Subsequent microfluidic (Deans) switching selects regions (heart-cuts) of the chromatographic elution from the first dimension ((1)D) column for further resolution on a long second dimension ((2)D(L)) column for parallel detection of O and MS. Various (2)D(L) operational conditions, as well as the effect of different heart-cut (H/C) duration, were compared. The favored mode involves cryotrapping of heart-cuts, cooling the oven, and reducing carrier flow to offer greater efficiency. An analytical strategy that incorporates GC-FID/O, GC * GC-FID, and MDGC-MS/O analyses with cumulative solid phase microextraction (SPME) sampling for volatile sample enrichment is presented in this work. Excellent qualitative and quantitative performance was demonstrated with a Shiraz wine sample and an allergens mixture, with tentative identification of acetic acid, octen-3-ol, and ethyl octanoate as aroma contributors in Shiraz wine and determination of beta-damascenone (floral odor) well separated from hexanoic acid (sweaty odor). A novel approach to obtain (2)D retention indices is reported, allowing matching of mass spectral, (1)I (retention index in (1)D) and (2)I (retention index in (2)D) data. The method employs the same olfactory detector at the end of the (1)D and (2)D(L) columns. PMID- 23101664 TI - Microsatellite and single nucleotide polymorphisms in the beta-globin locus control region-hypersensitive Site 2: SPECIFICITY of Tunisian betas chromosomes. AB - The diversity of sickle cell disease severity is attributed to several cis acting factors, among them the single nucleotide polymorphisms (SNPs) and (AT) rich region in the beta-locus control region (beta-LCR). This contains five DNase I hypersensitive sites (HS) located 6 to 22 kb upstream to the epsilon gene. The most important of these is the HS2 (5' beta-LCR-HS2), characterized by the presence of three different SNPs and a microsatellite region known to be in association with beta(S) chromosomes in various populations. The aim of this study was to present the molecular investigation of the 5' beta-LCR-HS2 site in normal and sickle cell disease individuals in order to determine if there is any correlation or specificity between these molecular markers, the beta(S) Tunisian chromosomes and phenotypical expression of sickle cell disease. One hundred and twenty-four chromosomes from Tunisian individuals (49 beta(S) carriers and 13 normal individuals) were screened by polymerase chain reaction (PCR) and sequencing for the polymorphic short tandem microsatellite repeats (AT)(X)N(12)(AT)(Y) and the three SNPs (rs7119428, rs9736333 and rs60240093) of the 5' beta-LCR-HS2. Twelve configurations of the microsatellite motif were found with an ancestral configuration elaborated by ClustalW software. Normal and mutated alleles were observed at the homozygous and heterozygous states for the three SNPs. Correlation between microsatellites and SNPs suggests that mutant SNP alleles were mainly associated, in the homozygous sickle cell disease phenotype, with the (AT)(8)N(12)GT(AT)(7) configuration, whereas, normal SNP alleles were associated with the (AT)(X)N(12)(AT)(11) configurations in normal beta(A) chromosomes. The correlation of these various configurations with Hb F expression was also investigated. The principal component analysis (PCA) showed the correlation between the homozygous sickle cell disease phenotype, mutated SNP alleles and the Benin microsatellite configuration (AT)(8)N(12)GT(AT)(7), which confirmed the specificity of this configuration to the beta(S) chromosomes. In addition, the observed high level of Hb F (14.6%) could play a protective role against Hb S to justify the modulation of sickle cell disease severity within the Benin haplotype compared to the other haplotypes. This study highlights the fact that the beta-LCR-HS2 could be a genetic marker to identify the ethnic Tunisian beta(S) chromosomes and facilitate the molecular diagnosis of sickle cell disease. PMID- 23101665 TI - Altered sequence of the ETS1 transcription factor may predispose to rheumatoid arthritis susceptibility. AB - OBJECTIVE: ETS1 belongs to the ETS family of transcription factors that regulate the expression of various immune-related genes. The aim of this study was to identify whether the ETS1 single nucleotide polymorphism (SNP) rs11221332, described in Caucasian subjects, plays a role in rheumatoid arthritis (RA) susceptibility. METHODS: We genotyped this polymorphism in 136 unrelated patients with RA and 147 healthy individuals with no history of autoimmune disease. Genotyping was performed with a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and the data were analysed using SPSS statistical software. RESULTS: A statistically significant difference was observed in the distribution of the rs11221332 genotypes between RA patients and controls (p = 0.041). Comparing the distribution of rs11221332 alleles between the groups studied, a greater difference was found [odds ratio (OR) 1.504, 95% confidence interval (CI) 1.036-2.183; p = 0.039]. CONCLUSIONS: The present study revealed, for first time, the positive association of a polymorphism in the sequence of the ETS1 transcription factor with RA susceptibility. Further studies in other ethnic groups of patients are needed to confirm the results of the present genetic association study related to ETS1, a widely used transcription factor in the regulation of the expression of various genes. PMID- 23101667 TI - Field necropsy of cattle and diagnostic sample submission. AB - Field necropsies can provide a wealth of information that can help guide production management decisions. Techniques outlined can allow a veterinary practitioner to complete a thorough necropsy of a bovine, including examination of the brain when indicated, in less than 20 minutes. An observation and history collection system using form templates and photographs is outlined that improves efficiency of recording necropsy results. One key to necropsy efficiency, speed, and enjoyment is having sharp knives. The first part of the article includes tips for sharpening knives. The article also includes detailed information on appropriate diagnostic specimen handling, packaging, and shipping. PMID- 23101666 TI - Systematic review with meta-analysis of the epidemiological evidence relating FEV1 decline to lung cancer risk. AB - BACKGROUND: Reduced FEV1 is known to predict increased lung cancer risk, but previous reviews are limited. To quantify this relationship more precisely, and study heterogeneity, we derived estimates of beta for the relationship RR(diff) = exp(betadiff), where diff is the reduction in FEV1 expressed as a percentage of predicted (FEV1%P) and RR(diff) the associated relative risk. We used results reported directly as beta, and as grouped levels of RR in terms of FEV1%P and of associated measures (e.g. FEV1/FVC). METHODS: Papers describing cohort studies involving at least three years follow-up which recorded FEV1 at baseline and presented results relating lung cancer to FEV1 or associated measures were sought from Medline and other sources. Data were recorded on study design and quality and, for each data block identified, on details of the results, including population characteristics, adjustment factors, lung function measure, and analysis type. Regression estimates were converted to beta estimates where appropriate. For results reported by grouped levels, we used the NHANES III dataset to estimate mean FEV1%P values for each level, regardless of the measure used, then derived beta using regression analysis which accounted for non independence of the RR estimates. Goodness-of-fit was tested by comparing observed and predicted lung cancer cases for each level. Inverse-variance weighted meta-analysis allowed derivation of overall beta estimates and testing for heterogeneity by factors including sex, age, location, timing, duration, study quality, smoking adjustment, measure of FEV1 reported, and inverse-variance weight of beta. RESULTS: Thirty-three publications satisfying the inclusion/exclusion criteria were identified, seven being rejected as not allowing estimation of beta. The remaining 26 described 22 distinct studies, from which 32 independent beta estimates were derived. Goodness-of-fit was satisfactory, and exp(beta), the RR increase per one unit FEV1%P decrease, was estimated as 1.019 (95%CI 1.016-1.021). The estimates were quite consistent (I2 =29.6%). Mean age was the only independent source of heterogeneity, exp(beta) being higher for age <50 years (1.024, 1.020-1.028). CONCLUSIONS: Although the source papers present results in various ways, complicating meta-analysis, they are very consistent. A decrease in FEV1%P of 10% is associated with a 20% (95%CI 17%-23%) increase in lung cancer risk. PMID- 23101668 TI - Ruminant abortion diagnostics. AB - Successful abortion diagnosis in ruminants involves input from the producer, practitioner, and diagnostician. Unfortunately, despite best efforts, many investigations still result in a diagnosis of idiopathic abortion. If this diagnosis is made after a complete and systematic investigation of appropriate and reasonably preserved samples, some comfort can be taken that practitioners and diagnosticians did their best for the benefit of the producer. As new diagnostic technology is developed for abortion diseases, hopefully this best will only get better. PMID- 23101669 TI - Laboratory and postmortem diagnosis of bovine respiratory disease. AB - Pathologic and laboratory investigations are essential when identification of the specific cause of bovine respiratory disease is needed. Considerations for planning a diagnostic investigation include the goals of the inquiry, the potential impact of the diagnosis, the plausible causes based on the clinical and epidemiologic appearance, and the relative merits of the available diagnostic strategies. This review uses 4 cases to outline different approaches to laboratory diagnosis. The postmortem examination is described, along with the patterns and gross appearance of lesions, considerations for effective sampling from appropriately selected animals, and reasons for discrepant or negative laboratory test results. PMID- 23101670 TI - Diagnostics of dairy and beef cattle diarrhea. AB - Calf diarrhea is a multifactorial disease related to a combination of host and pathogen factors. The most common pathogens found in diarrheic calves are cryptosporidium, rotavirus, coronavirus, Salmonella, attaching and effacing E coli and F5 (K99) Escherichia coli. Increased mortality and morbidity are often due to the presence of more than one pathogen. This article includes a discussion of key information to obtain a clinical history, the pathogens, pathology findings, and diagnostic methods. PMID- 23101671 TI - Field disease diagnostic investigation of neonatal calf diarrhea. AB - Diarrhea is a leading cause of sickness and death of beef and dairy calves in their first month of life. Field investigations of outbreaks of neonatal calf diarrhea should be conducted for the purposes of (1) reducing the losses associated with existing cases and (2) preventing new cases from occurring. The appropriate corrective actions are determined by taking a population approach to diagnostics and prevention. It can be difficult to provide solutions to disease outbreaks, but success is more likely if an organized, epidemiologic approach to outbreak investigation is followed. PMID- 23101672 TI - Gross lesions of alimentary disease in adult cattle. AB - The purpose of the gross necropsy examination of the gastrointestinal tract is to recognize the presence of lesions, thus requiring a basic understanding of its normal appearance and anatomy. This article highlights gross changes to the gastrointestinal tract of adult cattle that help place the disease processes into broad categories. Although few gross lesions reach the zenith of pathognomonic, there are numerous lesions that, when considered in aggregate with history (eg, number of animals affected, environment, duration of signs, time of onset relative to management changes, previous management) and clinical signs, can help narrow the spectrum of causes, provide a basis for a strong presumptive diagnosis, and focus diagnostic test selection. PMID- 23101673 TI - Neuropathology and diagnostics in food animals. AB - Diseases of the central nervous system (CNS) are relatively common in food animals. Potential causes include infectious agents, nutritional deficiencies, metabolic disorders, genetic defects, toxins, and idiopathic causes. Determining the correct etiologic diagnosis often depends on a thorough postmortem examination and collection of samples. This article reviews some of the steps and procedures necessary to collect the necessary information on CNS diseases in food animals. Techniques for the examination of the CNS are briefly described, and some of the gross pathology likely to be encountered in a food animal practice is reviewed. PMID- 23101674 TI - Clinical diagnosis of foot and leg lameness in cattle. AB - The causes of lameness in cattle are multifactorial and involve a combination of housing, management, and environmental factors and a variety of infectious agents. Arriving at a cause can often require concerted efforts. Diagnosis of lameness is often based mainly on clinical observations. A detailed record of those observations with time and among several animals within a herd can provide valuable information toward solving lameness problems. Advances in computer hardware and software help facilitate more detailed data collection and analysis. PMID- 23101675 TI - Ruminant toxicology diagnostics. AB - The most common sources of ruminant poisoning are feed and water. Diagnoses are based on history, clinical signs, lesions, laboratory examinations, and analytical chemistry. A complete history is necessary for developing the scheme of laboratory investigation and may be valuable in case of litigation. This article outlines the toxicology involved, as well as the procedures and analytic capability of the tests used for differential diagnosis in these cases. PMID- 23101676 TI - Molecular diagnostics applied to mastitis problems on dairy farms. AB - Mastitis in dairy cows is among the most important diseases of dairy cattle worldwide. Mastitis is most often the response of the host to an intramammary infection. Accurate and cost-effective methods of identifying mastitis pathogens are important for the diagnosis, surveillance, and control of this economically important disease. Rapid identification methods have the potential to be extremely specific and can also discriminate among closely related organisms. A wide range of phenotyping and genotyping methods have been developed or implemented to study mastitis-causing bacteria of dairy cattle at the species and subspecies level. This article provides the basis for evaluating molecular diagnostic technologies as a routine tool in diagnosing mastitis pathogens. PMID- 23101677 TI - Diagnostic sampling and gross pathology of New World camelids. AB - This article provides an overview of tests and appropriate samples to send to a Veterinary Diagnostic Laboratory for the diagnosis of common diseases of New World Camelids (NWC) such as abortions, congenital anomalies, anemia, enteritis, endoparasitism, gastric ulcer, hepatic lipidosis, encephalitis, pneumonia, dermatosis, neoplasia and cryptococcosis. Unique anatomic features of NWC and common findings encountered during gross necropsy examination are briefly reviewed. PMID- 23101678 TI - Diagnostic pathology. PMID- 23101679 TI - Plants as biofactories: glyphosate-induced production of shikimic acid and phenolic antioxidants in wounded carrot tissue. AB - The use of plants to produce chemical compounds with pharmaceutical and nutraceutical applications has intensified in recent years. In this regard, genetic engineering is the most commonly used tool to generate crop lines with enhanced concentrations of desirable chemicals. However, growing genetically modified plants is still limited because they are perceived as potential biological hazards that can create an ecological imbalance. The application of postharvest abiotic stresses on plants induces the accumulation of secondary metabolites and thus can be used as an alternative to genetic modification. The present project evaluated the feasibility of producing shikimic acid (SA) and phenolic compounds (PC) in wounded carrots ( Daucus carota ) treated with glyphosate. The spray application of a concentrated glyphosate solution on wounded carrot tissue increased the concentrations of SA and chlorogenic acid by ~1735 and ~5700%, respectively. The results presented herein demonstrate the potential of stressed carrot tissue as a biofactory of SA and PC. PMID- 23101680 TI - Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin 2. AB - Synthesis of the C1-C26 hexacyclic subunit of pectenotoxin-2 (PTX-2) is described that features a stereoselective annulation to generate the C-ring by triple asymmetric Nozaki-Hiyama-Kishi coupling followed by oxidative cyclization. Preparation of the C1-C14 AB spriroketal-containing subunit employs a recently developed metallacycle-mediated reductive cross-coupling between a TMS-alkyne and a terminal alkene. PMID- 23101682 TI - The correct structure of aquatolide-experimental validation of a theoretically predicted structural revision. AB - Aquatolide has been reisolated from its natural source, and its structure has been revised on the basis of quantum-chemical NMR calculations, extensive experimental NMR analysis, and crystallography. PMID- 23101681 TI - Prognostic significance of muc4 expression in gallbladder carcinoma. AB - BACKGROUND: Mucins are high molecular glycoproteins and play protective and lubricating roles in various epithelial tissues. Deregulated expression of mucins is involved in carcinogenesis and tumor invasion. MUC4 expression has been identified as a poor prognostic factor in pancreatobiliary carcinomas. To date, the relation between MUC4 expression and prognosis in gallbladder carcinoma remains to be determined. Authors examined MUC4 expression in gallbladder carcinoma and investigated its impact on prognosis. METHODS: The expression profiles of MUC4, MUC1, MUC2 mucins in gallbladder carcinoma tissues from 63 patients were investigated using immunohistochemical staining. RESULTS: For gallbladder carcinoma, positive staining of MUC4, MUC1, and MUC2 was 55.6%, 81.0%, 28.6%, respectively. There was a significant correlation between the expression of MUC4 and the expression of MUC1 or MUC2 (p = 0.004, p = 0.009, respectively). Univariate analysis showed that MUC4 expression (p = 0.047), differentiation (p < 0.05), T-stage (p < 0.05) and lymph node metastasis (p < 0.001) were significantly associated with poor survival. Expression of MUC1 and MUC2 was not correlated to survival. The backward stepwise multivariate analysis showed that MUC4 expression (p = 0.039) and lymph node metastasis (p = 0.001) were significant independent risk factors. In combined assessment of MUC4 and MUC2 expression, MUC4 positive and MUC2 negative group showed a significantly worse outcome than MUC4 negative groups(MUC4-/MUC2+ and MUC4-/MUC2-) and MUC4/MUC2 co-expression group(MUC4+/MUC2+) (p < 0.05). CONCLUSIONS: MUC4 expression in gallbladder carcinoma is an independent poor prognostic factor. Therefore, MUC4 expression may be a useful marker to predict the outcome of patients with surgically resected gallbladder carcinoma. MUC2 expression may have prognostic value when combined with MUC4 expression. PMID- 23101683 TI - Early development of intestinal microbiota: implications for future health. AB - Gut microbiota constitute a highly complex ecosystem that interacts with the host and profoundly affects gastrointestinal and systemic immunologic functions. Specific microbial patterns are associated with healthy children and adults, and these patterns are greatly related to the early acquisition of microbes by the newborn and the development of gut microbial communities in the perinatal period. Although direct causation must be firmly established and mechanisms fully elucidated, strong and increasing evidence shows that the early acquisition, development, and maintenance of specific bacterial populations are critical to human health, and a better understanding of these offers great opportunities for intervention. PMID- 23101684 TI - Treatment of necrotizing enterocolitis with probiotics. AB - Necrotizing enterocolitis (NEC) is a devastating condition characterized by diffuse intestinal inflammation and necrosis in preterm infants. It is the most common gastrointestinal emergency in the neonatal intensive care unit and is associated with significant morbidity and mortality. Primary risk factors include prematurity and low birth weight. Although the pathogenesis of NEC is complex and not entirely understood, it is known that an interplay between immature intestinal immune responses and the process of bacterial colonization is required for the development of this disease. PMID- 23101685 TI - Probiotics in the development and treatment of allergic disease. AB - Gut microbiota composition can discriminate between allergic and healthy children, and the distinction may precede clinical manifestations of disease. The mother provides the first inoculum of bacteria, which influences the risk of becoming allergic later in life. Bifidobacterium species are major determinants of disease risk. Specific probiotics may modulate early microbial colonization, which represents the first intervention target in allergic disease, together with their ability to reverse the increased intestinal permeability characteristic of children with atopic eczema and food allergy. Probiotics also enhance gut specific IgA responses, which are frequently defective in children with food allergy. In addition, probiotics have the potential to alleviate allergic inflammation locally and systemically. PMID- 23101686 TI - The role of probiotics in the prevention and treatment of antibiotic-associated diarrhea and Clostridium difficile colitis. AB - Clostridium difficile colitis is the most common gastrointestinal infection, exceeding all other gastrointestinal infections combined. There has been a dramatic increase in Clostridium difficile infection (CDI) worldwide during the past decade. Antibiotic therapy is a trigger precipitating antibiotic-associated diarrhea (AAD), which may lead to CDI. The antibiotic alters the protective, diverse bacteria allowing pathogenic bacteria to cause disease. Probiotics have been effective in reducing AAD and preventing CDI. PMID- 23101687 TI - Fecal microbiota transplantation: techniques, applications, and issues. AB - Fecal microbiota transplantation (FMT) has gained widespread recognition in light of the recent Clostridium difficile infection (CDI) epidemic, responsible for almost 110,000 deaths per year. The procedure's success rate has caused experts to reflect on what other conditions may benefit. This article provides an overview of (1) description and history of FMT, (2) FMT publications in CDI, (3) the concept of the gut microbiota as a virtual organ, (4) rationale for FMT use, (5) FMT use in inflammatory bowel disease, (6) emerging FMT applications, (7) how FMT is currently performed, and (8) how FMT may be performed in the future. PMID- 23101688 TI - Probiotics in the management of functional bowel disorders: promise fulfilled? AB - Irritable bowel syndrome (IBS) and chronic constipation (CC) are common problems worldwide and are associated with significant impact on activities of daily living and quality of life. Recent interest, in IBS in particular, has focused on the potential roles of the microbiota and its interaction with the host's immune system. Recently, high-quality clinical trials have been performed on prebiotics and probiotics in IBS or CC. Although strategies that seek to modify the microbiota, such as the use of probiotics, offer much promise in IBS and CC, more high-quality trials and, studies of longer duration are required. PMID- 23101689 TI - Probiotic bacteria in the prevention and the treatment of inflammatory bowel disease. AB - Definitive curative strategies for inflammatory bowel disease remain challenging for physicians and patients. For decades, probiotic organisms have been used in various gastrointestinal diseases. Only recently has comprehension of the pathophysiology of inflammatory bowel disease developed to the point where the significance of the host gastrointestinal microbial population is seen to have marked influence on the initiation and ongoing inflammatory processes of Crohn disease and ulcerative colitis. Well-designed, large randomized controlled trials using probiotics in patients with inflammatory bowel disease are required for probiotics to become mainstream therapy. PMID- 23101690 TI - Probiotics, prebiotics, energy balance, and obesity: mechanistic insights and therapeutic implications. AB - Obesity-related disorders derive from a combination of genetic susceptibility and environmental factors. Recent evidence supports the role of gut microbiota in the pathogenesis of obesity, type 2 diabetes mellitus, and insulin resistance by increasing energy harvest from diet and by inducing chronic, low-grade inflammation. Several studies describe characteristic differences between composition and activity of gut microbiota of lean individuals and those with obesity. Despite this evidence, some pathophysiological mechanisms remain to be clarified. This article discusses mechanisms connecting gut microbiota to obesity and fat storage and the potential therapeutic role of probiotics and prebiotics. PMID- 23101691 TI - Nucleic acid-based methods to assess the composition and function of the bowel microbiota. AB - This article describes nucleic acid-based methods to assess the composition and function of the bowel microbiota. The methods range from the relatively simple (polymerase chain reaction) to the technically sophisticated (metatranscriptomics). Not all are accessible to the majority of laboratories, but a core of validated (used in more than 1 study) tools is readily available to most researchers. Reliance on a single methodology per human study is not recommended. Generally, a study could commence with a screening of samples to determine whether it will be worthwhile expending further time and money on an in depth analysis. PMID- 23101692 TI - A commentary on the safety of probiotics. AB - Probiotics have a long record of safety, which relates primarily to lactobacilli and bifidobacteria. Experience with other forms of probiotic is more limited. There is no such thing as zero risk, particularly in the context of certain forms of host susceptibility. There is poor public understanding of the concept of risk, in general, and risk/benefit analysis, in particular. Uncertainty persists regarding the potential for transfer of antibiotic resistance with probiotics, but the risk seems to be low with currently available probiotic products. As with other forms of therapeutics, the safety of probiotics should be considered on a strain-by-strain basis. PMID- 23101693 TI - Preface: clinical applications of probiotics in gastroenterology: questions and answers. PMID- 23101694 TI - Free light chain assay: doing a "good job" in Job's syndrome. PMID- 23101695 TI - Molecularly imprinted electrochemical luminescence sensor based on signal amplification for selective determination of trace gibberellin A3. AB - A new molecularly imprinted electrochemical luminescence (MIP-ECL) sensor was developed for Gibberellin A3 (GA3) determination. This sensor is based on competitive binding between the GA3 and the Rhodamine B (RhB)-labeled GA3 (RhB GA3) to the MIP film. After the competitive binding, the residual RhB-GA3 on the MIP was electro-oxidized to produce RhB oxide, which could greatly amplify the weak electrochemiluminescence (ECL) signal of luminol. The ECL intensity decreased when the RhB-GA3 was replaced by GA3 molecules in the samples. Accordingly, GA3 was determined in the concentration range from 1 * 10(-11) to 3 * 10(-9) mol/L with a detection limit of 3.45 * 10(-12) mol/L. The sensor shows high sensitivity and selectivity, wide response range, good accuracy, and fast response. Beer samples were assayed by using the sensors, and the recoveries ranging from 96.0% to 103.2% were obtained. PMID- 23101696 TI - Linking avian communities and avian influenza ecology in southern Africa using epidemiological functional groups. AB - The ecology of pathogens, and particularly their emergence in multi-host systems, is complex. New approaches are needed to reduce superficial complexities to a level that still allows scientists to analyse underlying and more fundamental processes. One promising approach for simplification is to use an epidemiological function classification to describe ecological diversity in a way that relates directly to pathogen dynamics. In this article, we develop and apply the epidemiological functional group (EFG) concept to explore the relationships between wild bird communities and avian influenza virus (AIV) in three ecosystems in southern Africa. Using a two year dataset that combined bird counts and bimonthly sampling for AIV, we allocated each bird species to a set of EFGs that captured two overarching epidemiological functions: the capacity of species to maintain AIV in the system, and their potential to introduce the virus. Comparing AIV prevalence between EFGs suggested that the hypothesis that anseriforms (ducks) and charadriiforms (waders) drive AIV epidemiology cannot entirely explain the high prevalence observed in some EFGs. If anseriforms do play an important role in AIV dynamics in each of the three ecosystems, the role of other species in the local maintenance of AIV cannot be ruled out. The EFG concept thus helped us to identify gaps in knowledge and to highlight understudied bird groups that might play a role in AIV epidemiology. In general, the use of EFGs has potential for generating a range of valuable insights in epidemiology, just as functional group approaches have done in ecology. PMID- 23101697 TI - Line tension and line activity in mixed monolayers composed of aliphatic and terphenyl-containing surfactants. AB - Custom-designed surfactants, known as "linactants", have the ability to reduce the line tension between coexisting phases within mixed monolayers of chemically dissimilar compounds at the air-water interface. Thus far, linactants have been successfully identified for only one type of chemical dissimilarity, involving mixed monolayers of hydrocarbon and fluorocarbon surfactants. In the present work, we have pursued a more general interpretation of linactant compounds by extending the concept to a new system that is comprised of a mixture of aliphatic (pentadecanoic acid) and aromatic (p-terphenyl carboxylic acid) compounds. We found that the "bare" line tension between phases of this mixed monolayer was ~4 pN, and within the same order of magnitude as our previous measurement in mixed monolayers containing hydrocarbons and fluorocarbons. Furthermore, we examined a homologous series of potential linactant compounds possessing an aliphatic tail of variable length and a p-terphenyl block. We determined that linactants with longer tails were able to reduce the line tension more efficiently and effectively. In particular, the addition of only 0.14% of a linactant with an 11 carbon chain reduced the line tension by more than a factor of 2. We hypothesize that the efficiency of this particular linactant is associated with its long tail; this creates strong van der Waals interactions with the aliphatic chains and enables the tail to adopt conformations that facilitate pi-stacking interactions with the aromatic compounds within the monolayer. PMID- 23101698 TI - Promoting research integrity: a new global effort. PMID- 23101699 TI - Cardiac arrhythmias revisited. PMID- 23101700 TI - Sex workers, HIV, and the law in Asia Pacific. PMID- 23101701 TI - The EU Tobacco Products Directive must not be derailed. PMID- 23101702 TI - Cardiac arrhythmias--trials and tribulations. PMID- 23101704 TI - Andrew Grace: tackling the rising tide of arrhythmia. PMID- 23101705 TI - Antiarrhythmic drug treatment after cardioversion of atrial fibrillation. PMID- 23101706 TI - Antiarrhythmic drug treatment after cardioversion of atrial fibrillation. PMID- 23101707 TI - Antiarrhythmic drug treatment after cardioversion of atrial fibrillation. PMID- 23101709 TI - Reconstructive surgery after female genital mutilation. PMID- 23101711 TI - Reconstructive surgery after female genital mutilation. PMID- 23101712 TI - Dementia incidence in middle-income countries. PMID- 23101713 TI - Dementia incidence in middle-income countries. PMID- 23101714 TI - Hypertension in developing countries. PMID- 23101715 TI - Hypertension in developing countries. PMID- 23101716 TI - Apologising for Nazi medicine: too little too late. PMID- 23101718 TI - Catheter ablation of atrial arrhythmias: state of the art. AB - Catheter ablation is at the forefront of the management of a range of atrial arrhythmias. In this Series paper, we discuss the underlying mechanisms and the current role of catheter ablation for the three most common atrial arrhythmias encountered in clinical practice: focal atrial tachycardia, atrial flutter, and atrial fibrillation. The mechanisms of focal atrial tachycardia and atrial flutter are well understood, and these arrhythmias are amenable to curative catheter ablation with high success rates. In most cases, paroxysmal atrial fibrillation is initiated by triggers located within pulmonary vein musculature. Circumferential ablation to isolate this musculature is associated with high success rates for elimination of paroxysmal atrial fibrillation in selected populations. Because of the problem of recurrent pulmonary vein connection, more than one procedure will be needed in about 30% of patients, and new technologies are being developed to reduce this occurrence. The mechanisms that sustain persistent atrial fibrillation are not well understood and are the subject of continuing investigation. As such, ablation approaches and technologies for this arrhythmia are still evolving. PMID- 23101719 TI - Ventricular arrhythmias and sudden cardiac death. AB - Management strategies for ventricular arrhythmias are guided by the risk of sudden death and severity of symptoms. Patients with a substantial risk of sudden death usually need an implantable cardioverter defibrillator (ICD). Although ICDs effectively end most episodes of ventricular tachycardia or ventricular fibrillation and decrease mortality in specific populations of patients, they have inherent risks and limitations. Generally, antiarrhythmic drugs do not provide sufficient protection from sudden death, but do have a role in reducing arrhythmias that cause symptoms. Catheter ablation is likewise important for reducing the frequency of spontaneous arrhythmias and is curative for some patients, usually those with idiopathic arrhythmias and no heart disease. Arrhythmia surgery is now infrequent, offered by only a few specialised centres for refractory arrhythmias. Advances in understanding of genetic arrhythmia syndromes and in technology for mapping and ablation of ventricular arrhythmias, and enhanced algorithms in implantable devices for rhythm management, have contributed to improved outcomes. PMID- 23101717 TI - Systems biology and cardiac arrhythmias. AB - During the past few years, the development of effective, empirical technologies for treatment of cardiac arrhythmias has exceeded the pace at which detailed knowledge of the underlying biology has accumulated. As a result, although some clinical arrhythmias can be cured with techniques such as catheter ablation, drug treatment and prediction of the risk of sudden death remain fairly primitive. The identification of key candidate genes for monogenic arrhythmia syndromes shows that to bring basic biology to the clinic is a powerful approach. Increasingly sophisticated experimental models and methods of measurement, including stem cell based models of human cardiac arrhythmias, are being deployed to study how perturbations in several biologic pathways can result in an arrhythmia-prone heart. The biology of arrhythmia is largely quantifiable, which allows for systematic analysis that could transform treatment strategies that are often still empirical into management based on molecular evidence. PMID- 23101720 TI - Keeping abreast of axillary masses. PMID- 23101721 TI - The Narcissistic Personality Inventory: a useful tool for assessing pathological narcissism? Evidence from patients with Narcissistic Personality Disorder. AB - The Narcissistic Personality Inventory (NPI) has dominated research on narcissism in the field of social and personality psychology. Surprisingly, it is unclear whether the NPI is useful for identifying pathological narcissism in patients with Narcissistic Personality Disorder (NPD). The goal of this study was to close this research gap. We used an extreme-group approach by including NPD patients and healthy controls and comparing their narcissism scores. We further investigated whether explicit self-esteem (assessed with the Rosenberg Self Esteem Scale) suppressed the relationship between group membership and NPI narcissism. According to our results, NPD patients do not score higher on the NPI in comparison to healthy controls. Analysis of indirect effects revealed that differences in NPI scores are suppressed by NPD patients' low self-esteem. Our results indicate that the NPI is not a valid indicator of NPD, unless one controls for self-esteem. Implications for future research are discussed. PMID- 23101722 TI - Elevated levels of interleukin-27 and effect on production of interferon-gamma and interleukin-17 in patients with Behcet's disease. AB - OBJECTIVES: To measure the levels of interleukin (IL)-27, interferon (IFN)-gamma, and IL-17 in serum and supernatants of stimulated peripheral blood mononuclear cells (PBMCs) of patients with Behcet's disease (BD) compared with healthy subjects, and to evaluate the effect of recombinant human IL-27 (rhIL-27) on IFN gamma and IL-17 production by PBMCs. METHODS: Forty-three patients with BD and 40 healthy controls were included in this study. The serum levels of IL-27, IFN gamma, and IL-17 and their production by PBMCs were measured by enzyme-linked immunosorbent assay (ELISA), together with the effects of levels of rhIL-27 on IFN-gamma and IL-17 production by PBMCs. RESULTS: There were significantly higher levels of IL-27, IFN-gamma, and IL-17 in sera of patients with BD compared with the controls. Levels of IL-27, IFN-gamma, and IL-17 in BD patients with active uveitis were significantly higher than in those without. Moreover, IL-27, IFN gamma, and IL-17 production by stimulated PBMCs was increased in BD patients compared to controls. In the presence of rhIL-27, stimulation of PBMCs from BD patients resulted in decreased production of IL-17 but increased production of IFN-gamma. CONCLUSIONS: These findings suggest that IL-27, IFN-gamma, and IL-17 play a role in the pathogenesis of BD. PMID- 23101723 TI - Palladium-catalyzed synthesis of isocoumarins and phthalides via tert-butyl isocyanide insertion. AB - A novel and highly efficient strategy for the synthesis of isocoumarins and phthalides through a palladium(0)-catalyzed reaction incorporating tert-butyl isocyanide has been developed. This process, providing one of the simplest methods for the synthesis of this class of valuable lactones, involves two steps including cyclization reaction and simple acid hydrolysis. The methodology is tolerant of a wide range of substrates and applicable to library synthesis. PMID- 23101724 TI - Sickness certificates in Sweden: did the new guidelines improve their quality? AB - BACKGROUND: Long-term sickness absence is high in many Western countries. In Sweden and many other countries, decisions on entitlement to sickness benefits and return to work measures are based on information provided by physicians in sickness certificates. The quality demands, as stressed by the Swedish sick leave guidelines from 2008, included accurate sickness certificates with assessment of functioning clearly documented. This study aims to compare quality of sickness certificates between 2007 and 2009 in Ostergotland County, Sweden. Quality is defined in terms of descriptions of functioning with the use of activity and participation according to WHO's International Classification of Functioning, Disability and Health (ICF), and in prescriptions of early rehabilitation. METHODS: During two weeks in 2007 and four weeks in 2009, all certificates had been collected upon arrival to the social insurance office in Ostergotland County, Sweden. Four hundred seventy-five new certificates were included in 2007 and 501 in 2009. Prolongations of sick leave were included until the last date of sick listing. Free text on functioning was analysed deductively using the ICF framework, and placed into categories (body functions/structures, activity, participation, no description) for statistical analysis. RESULTS: The majority of the certificates were issued for musculoskeletal diseases or mental disorders. Text on functioning could be classified into the components of ICF in 65% and 78% of sickness certificates issued in 2007 and 2009, respectively. Descriptions according to body components such as "sensations of pain" or "emotional functions" were given in 58% of the certificates from 2007 and in 65% from 2009. The activity component, for example "walking" or "handling stress", was more frequent in certificates issued in 2009 compared with 2007 (33% versus 26%). Prescriptions of early rehabilitation increased from 27% in 2007 to 35% in 2009, primarily due to more counseling. CONCLUSIONS: An improvement of the quality between certificates collected in 2007 and 2009 was demonstrated in Ostergotland County, Sweden. The certificates from 2009 provided more information linkable to ICF and incorporated an increased use of activity limitations when describing patients' functioning. Still, activity limitations and prescriptions of early rehabilitation were only present in one-third of the sickness certificates. PMID- 23101725 TI - Fast responsive, optical trace level ammonia sensor for environmental monitoring. AB - BACKGROUND: Ammonia is a ubiquitous chemical substance which is created in technical and biological processes and harmful to many different organisms. One specific problem is the toxicity of ammonia in fish at levels of 25 MUg/l - a very common issue in today's aqua culture. In this study we report a development of a fast responsive, optical ammonia sensor for trace concentrations. RESULTS: Different hydrogels have been investigated as host polymers for a pH based sensing mechanism based on fluorescent dyes. A porous hydrophobic fluoropolymer membrane was used as an ion barrier cover layer to achieve a good ammonia permeability. The sensor's sensitivity towards ammonia as well as crosssensitivity towards pH-value and salinity, and the temperature dependency have been determined. Two different methods to reference fluorescence signals have been employed to eliminate intensity-based measurement drawbacks. CONCLUSION: The presented sensor features high sensitivity and a fast response even at concentrations near 1 ppb. No cross sensitivity towards pH and salinity could be observed and temperature dependency was determined as compensateable. Both referencing approaches prove themselves to be able to provide a simple use of the sensor for in-field applications. PMID- 23101726 TI - Neurocognitive functioning in children with obstructive sleep apnea syndrome: a pilot study of positive airway pressure therapy. AB - Studies of individuals with obstructive sleep apnea syndrome (OSAS) have shown impairment in neurocognitive function. This study investigated the neurocognitive function in children with OSAS before and after positive airway pressure (PAP) therapy. Twenty-one participants with suspected/documented OSAS were recruited, completing the Epworth Sleepiness Scale (ESS), the Child Sleep Habit Questionnaire (CSHQ), and/or the Pittsburgh Sleep Quality Index. Participants were administered sections of the Wechsler Intelligence Scale for Children-IV, the Delis Kaplan Executive Functioning Scales, the Test of Everyday Attention for Children, and the Wide Range Assessment of Memory and Learning--2nd Edition to assess neurocognitive function. The ESS and the CSHQ indicate that many participants had excessive daytime sleepiness and increased sleep-disordered breathing. Participants before therapy reflected neurocognitive deficiencies in all areas. Of the original 21 children, 4 completed the full PAP treatment and were reevaluated, demonstrating improvements in memory and motor speed. Children with OSAS reported sleep-disordered breathing, increased daytime sleepiness, and deficiencies in neurocognitive measures. Correcting these sleep impairments appeared to reduce global neurocognitive deficits while improving memory and processing speed. PMID- 23101727 TI - Caregiver perspectives on unintentional injury risk in children with an autism spectrum disorder. AB - Unintentional injury risk research for children with an autism spectrum disorder (ASD) is currently limited. This article presents findings from a two-phase investigation of caregiver perspectives regarding unintentional injury risk in children with an ASD. Results indicate that children with an ASD exhibit elevated rates of risk-taking behaviors compared with peers, which increases the likelihood of more frequent and severe injuries. In addition, although ASD symptom severity positively correlated with risk-taking behavior and frequency of injury, children with an ASD were rarely rated as high risks for injury by caregivers. Implications are discussed in the context of pediatric health service provision. PMID- 23101728 TI - Explicating caregiving by mothers of children with complex needs in ireland: a phenomenological study. AB - This qualitative phenomenological study explored mothers' experiences of caring for a child with complex needs. After ethical approval was obtained, data were collected through 11 diaries and 48 interviews with 17 mothers in Ireland. Caring for a child with complex needs involves the delivery of care in an inside world of the home, the world outside the home, and a "going-between" world. Caregiving, 1 of 8 closely linked dimensions, is presented, including its 4 categories. These are normal mothering, technical caregiving, preemptive caregiving, and individualized caregiving. Professionals require a greater understanding of the experiences of mothers caring for children with complex needs at home. PMID- 23101729 TI - Ultrafast photoinduced processes in subphthalocyanine electron donor-acceptor conjugates linked by a single B-N bond. AB - We have prepared two different subphthalocyanine conjugates by linking these macrocycles either to an electron-accepting perylene diimide or to an electron donating phenothiazine through a single B-N covalent bond. The short spacing between the two active building blocks results in ultrafast photoinduced electron transfer reactions. PMID- 23101730 TI - Preparation of polyclonal antibodies and development of a direct competitive enzyme-linked immunosorbent assay to detect residues of phenylethanolamine A in urine samples. AB - Phenylethanolamine A (PEAA) is a phenethanolamine member of the family of beta adrenergic agonists (beta-agonists) compounds. To determine PEAA residues, we established a rapid direct competitive enzyme-linked immunosorbent assay (ELISA) using a polyclonal antibody produced with the immunogen PEAA-HSA conjugate. The antibody showed high sensitivity, where IC(50) and the limit of detection were 0.3 and 0.02 MUg/L, respectively. The specificity of the assay was evaluated by the measurement of cross-reactivity of the antibody with 15 beta-agonists compounds. The data demonstrated that the antibody was highly specific for PEAA, with negligible cross-reactivity (CR) with other beta-agonists compounds (CR < 0.1%) including ractopamine (CR is 0.3%). Recovery rates ranged from 81% to 110%, indicating relatively good parallelism and accuracy of the assay when applied to real samples. The detection limit in blank urine samples was 0.5 MUg/L. The coefficient of variation was below 18% and 20% for intra-assay and inter-assay, respectively, demonstrating an acceptable level of precision. Largely consistent results were obtained for the urine samples by ELISA and UPLC-MS/MS methods. From a practical point of view, the prototype kit could be advantageously used for the screening of large groups of urine samples, and the kit employed has reliability even in routine application for the control of the illegal use of the drug. PMID- 23101732 TI - Enhanced thermal decomposition of nitromethane on functionalized graphene sheets: ab initio molecular dynamics simulations. AB - The burning rate of the monopropellant nitromethane (NM) has been observed to increase by adding and dispersing small amounts of functionalized graphene sheets (FGSs) in liquid NM. Until now, no plausible mechanisms for FGSs acting as combustion catalysts have been presented. Here, we report ab initio molecular dynamics simulations showing that carbon vacancy defects within the plane of the FGSs, functionalized with oxygen-containing groups, greatly accelerate the thermal decomposition of NM and its derivatives. This occurs through reaction pathways involving the exchange of protons or oxygens between the oxygen containing functional groups and NM and its derivatives. FGS initiates and promotes the decomposition of the monopropellant and its derivatives, ultimately forming H(2)O, CO(2), and N(2). Concomitantly, oxygen-containing functional groups on the FGSs are consumed and regenerated without significantly changing the FGSs in accordance with experiments indicating that the FGSs are not consumed during combustion. PMID- 23101731 TI - Roles of prostaglandin F2alpha and hydrogen peroxide in the regulation of Copper/Zinc superoxide dismutase in bovine corpus luteum and luteal endothelial cells. AB - BACKGROUND: Prostaglandin F2alpha (PGF) induces luteolysis in cow by inducing a rapid reduction in progesterone production (functional luteolysis) followed by tissue degeneration (structural luteolysis). However the mechanisms of action of PGF remain unclear. Reactive oxygen species (ROS) play important roles in regulating the luteolytic action of PGF. The local concentration of ROS is controlled by superoxide dismutase (SOD), the main enzyme involved in the control of intraluteal ROS. Thus SOD seems to be involved in luteolysis process induced by PGF in cow. METHODS: To determine the dynamic relationship between PGF and ROS in bovine corpus luteum (CL) during luteolysis, we determined the time-dependent change of Copper/Zinc SOD (SOD1) in CL tissues after PGF treatment in vivo. We also investigated whether PGF and hydrogen peroxide (H2O2) modulates SOD1 expression and SOD activity in cultured bovine luteal endothelial cells (LECs) in vitro. RESULTS: Following administration of a luteolytic dose of PGF analogue (0 h) to cows at the mid-luteal stage, the expression of SOD1 mRNA and protein, and total SOD activity in CL tissues increased between 0.5 and 2 h, but fell below the initial (0 h) level at 24 h post-treatment. In cultured LECs, the expression of SOD1 mRNA was stimulated by PGF (1-10 microM) and H2O2 (10-100 microM) at 2 h (P<0.05). PGF and H2O2 increased SOD1 protein expression and total SOD activity at 2 h (P<0.05), whereas PGF and H2O2 inhibited SOD1 protein expressions and total SOD activity at 24 h (P<0.05). In addition, H2O2 stimulated PGF biosynthesis at 2 and 24 h in bovine LECs. Overall results indicate that, SOD is regulated by PGF and ROS in bovine LECs. SOD may play a role in controlling intraluteal PGF and ROS action during functional and structural luteolysis in cows. PMID- 23101733 TI - Negotiating old and new ways: contextualizing adapted health care-seeking behaviors of Korean immigrants in Hawaii. AB - OBJECTIVE: Korean immigrants have been identified as one of the most disadvantaged ethnic groups in terms of health insurance coverage and health care access in the U.S.A. Korean immigrants enjoyed access to primary and preventive care services in their home country. This study explores how Korean immigrants' health-seeking behaviors are reconstructed by contextualizing their health care experience and adaptation process in Hawaii. DESIGN: Face-to-face individual in depth interviews were conducted with 20 recently arrived Korean immigrant adults in Hawaii, who were selected by a purposive sampling method. RESULTS: A diminution of seeking professional health care services after immigration was the prominent change in their health care behaviors. They delayed seeking primary care, underused preventive care, extended self-diagnosis and self-treatment, and practiced more treatment- and emergency-oriented care. New immigrants also adopted ethnic enclave health care and transnational health care as alternative strategies to meet their health care needs given the structural and cultural constraints. Sociocultural contexts of both home and host countries shaped the behavioral changes and adoption of alternative health care strategies, interplaying with an individual's characteristics. Lack of health insurance and unfamiliarity with the health care system were the most important factors in the decision whether to and when to seek professional health care, while the lack of English proficiency and cultural concerns were the major determinants of where to get health care. CONCLUSIONS: The study suggested that efforts should be concentrated to minimize structural barriers to health insurance and to improve health care access through policy interventions. Ethnic networks and ethnic media could be used as an effective informational reservoir for introducing various health care resources, disseminating information, and navigating new immigrants to the health system and services. Utilizing ethnic health care facilities and professionals would foster the promotion of immigrant health care without language and cultural challenges. PMID- 23101735 TI - Princess by proxy: what child beauty pageants teach girls about self-worth and what we can do about it. PMID- 23101736 TI - Into, and out, of the "Valley of Death": research in autism spectrum disorders. PMID- 23101737 TI - Evidence-based integrated treatment in autism spectrum disorders. PMID- 23101738 TI - Attention-deficit/hyperactivity disorder and the battle for control of attention. PMID- 23101739 TI - The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward. AB - OBJECTIVE: First, we give an overview of child psychiatric research in the Generation R Study, a population-based cohort from fetal life forward. Second, we examine within Generation R whether the functional polymorphism (5-HTTLPR) in the promoter of the serotonin transporter gene interacts with prenatal maternal chronic difficulties, prenatal maternal anxiety or postnatal maternal anxiety to influence child emotional development. METHOD: A total of 2,136 northern European children were genotyped for 5-HTTLPR and rs25531. Mothers reported chronic difficulties and anxiety symptoms at 20 weeks' pregnancy and when the child was 3 years old. Child emotion recognition was observed at 3 years, and child emotional problems were assessed with the CBCL/11/2-5 at 5 years. RESULTS: There were consistent main effects of maternal difficulties and anxiety on child emotional problems, but no main effect of 5-HTTLPR. Moreover, children with the s allele were at increased risk for emotional problems if their mothers reported prenatal anxiety symptoms (beta = 2.02, p < .001) or postnatal anxiety symptoms (beta = 1.64, p < 0.001). Also, in children of mothers with prenatal anxiety symptoms, the s allele was associated with less accurate emotion-matching (beta = -0.11, p = .004). CONCLUSIONS: This population-based study shows that vulnerability due to 5-HTTLPR is not specific for certain adverse exposures or severe events, but suggests that the small effects of gene-environment interaction on emotional development become manifest early in life. PMID- 23101740 TI - Findings from the Pittsburgh Youth Study: cognitive impulsivity and intelligence as predictors of the age-crime curve. AB - OBJECTIVE: This article first summarizes key research findings from the Pittsburgh Youth Study from 1987 to the present, and focuses on delinquency in 1,517 young men who have been followed up from late childhood into their 20s. Second, the article addresses how indicators of self-control prospectively predict later offending, and whether the prediction shows individual difference in the age-crime curve, particularly the up-slope, peak, and down-slope of that curve. METHOD: Longitudinal analyses were conducted on a sample of boys in the middle sample of the Pittsburgh Youth Study (n = 422), whose cognitive impulsivity and intelligence were assessed at about age 12 years. Criminal records on the sample were until age 28. RESULTS: The results show that cognitive impulsivity and intelligence, measured between ages 12 and 13 by means of psychometric tests, predicted the age-crime curve. The age-arrest curve was substantially higher in boys with high cognitive impulsivity and in boys with low IQ. However, there was a significant interaction between cognitive impulsivity and intelligence. For boys with high IQ, cognitive impulsivity was associated with a greater escalation in the prevalence of offending during early adolescence, followed by a more rapid decline in offending as boys entered early adulthood with a slight subsequent increase in criminal offending then occurring late 20. In contrast, there was no evidence that cognitive impulsivity independently influenced criminal offending at any developmental period for boys with low IQ. CONCLUSIONS: The results are discussed in terms of interventions to reduce individuals' delinquency from childhood through early adulthood and lower the age-crime curve for populations. However, the association was complex because it was moderated by both age and intelligence. PMID- 23101741 TI - Early behavioral intervention is associated with normalized brain activity in young children with autism. AB - OBJECTIVE: A previously published randomized clinical trial indicated that a developmental behavioral intervention, the Early Start Denver Model (ESDM), resulted in gains in IQ, language, and adaptive behavior of children with autism spectrum disorder. This report describes a secondary outcome measurement from this trial, EEG activity. METHOD: Forty-eight 18- to 30-month-old children with autism spectrum disorder were randomized to receive the ESDM or referral to community intervention for 2 years. After the intervention (age 48 to 77 months), EEG activity (event-related potentials and spectral power) was measured during the presentation of faces versus objects. Age-matched typical children were also assessed. RESULTS: The ESDM group exhibited greater improvements in autism symptoms, IQ, language, and adaptive and social behaviors than the community intervention group. The ESDM group and typical children showed a shorter Nc latency and increased cortical activation (decreased alpha power and increased theta power) when viewing faces, whereas the community intervention group showed the opposite pattern (shorter latency event-related potential [ERP] and greater cortical activation when viewing objects). Greater cortical activation while viewing faces was associated with improved social behavior. CONCLUSIONS: This was the first trial to demonstrate that early behavioral intervention is associated with normalized patterns of brain activity, which is associated with improvements in social behavior, in young children with autism spectrum disorder. PMID- 23101742 TI - Are autism spectrum disorder and attention-deficit/hyperactivity disorder different manifestations of one overarching disorder? Cognitive and symptom evidence from a clinical and population-based sample. AB - OBJECTIVE: Autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. Given the heterogeneity of both disorders, several more homogeneous ASD-ADHD comorbidity subgroups may exist. The current study examined whether such subgroups exist, and whether their overlap or distinctiveness in associated comorbid symptoms and cognitive profiles gives support for a gradient overarching disorder hypothesis or a separate disorders hypothesis. METHOD: Latent class analysis was performed on Social Communication Questionnaire (SCQ) and Conners' Parent Rating Scale (CPRS-R:L) data for 644 children and adolescents (5 through 17 years of age). Classes were compared for comorbid symptoms and cognitive profiles of motor speed and variability, executive functioning, attention, emotion recognition, and detail-focused processing style. RESULTS: Latent class analysis revealed five classes: two without behavioral problems, one with only ADHD behavior, and two with both clinical symptom levels of ASD and ADHD but with one domain more prominent than the other (ADHD[+ASD] and ASD[+ADHD]). In accordance with the gradient overarching disorder hypothesis were the presence of an ADHD class without ASD symptoms and the absence of an ASD class without ADHD symptoms, as well as cognitive functioning of the simple ADHD class being less impaired than that of both comorbid classes. In conflict with this hypothesis was that there was some specificity of cognitive deficits across classes. CONCLUSIONS: The overlapping cognitive deficits may be used to further unravel the shared etiological underpinnings of ASD and ADHD, and the nonoverlapping deficits may indicate why some children develop ADHD despite their enhanced risk for ASD. The two subtypes of children with both ASD and ADHD behavior will most likely benefit from different clinical approaches. PMID- 23101743 TI - Research Units of Pediatric Psychopharmacology (RUPP) autism network randomized clinical trial of parent training and medication: one-year follow-up. AB - OBJECTIVE: To follow up on a three-site, 24-week randomized clinical trial (N = 124) comparing antipsychotic medication alone (MED) with antipsychotic medication plus parent training in the behavior management (COMB) of children with autism spectrum disorders and severe behavior problems. The COMB treatment had shown a significant advantage for child behavioral noncompliance (p = .006, d = 0.34), irritability (p = .01, d = 0.48), and hyperactivity/noncompliance (p = .04, d = 0.55) with a lower medication dose. METHOD: One year after each participant's termination, the authors mailed an assessment packet with a return-addressed envelope; a telephone call alerted the family. Failure to return packets within 1 month elicited another contact and offers to resend. RESULTS: Eighty-seven of 124 families (70.2%) participated in the follow-up. The improvement difference between treatments attenuated from after treatment to follow-up for noncompliance (d = 0.32 to 0.12) and irritability (d = 0.46 to 0.03). The follow-up differences were nonsignificant (the noncompliance difference also was nonsignificant after treatment for these 87 families). Sixty-seven percent of the COMB group and 53% of the MED group were still taking risperidone, the original study medication. Most needed dose adjustments or additional medication, and the COMB group no longer had a significantly lower dose. All COMB families but only 39% of MED families reported seeking parent training after treatment. Improvements in daily living skills during treatment predicted noncompliance improvement at follow-up for the COMB children, but noncompliance deterioration and especially hyperactivity/noncompliance deterioration for the MED children. CONCLUSIONS: The study treatment experience/familiarity greatly influenced the follow-up treatment: those who had received parent training reported seeking it, whereas those who had not received it tended not to seek it. The superiority of COMB over MED after treatment attenuated by more than half at follow-up. PMID- 23101744 TI - Children of treatment-seeking depressed mothers: a comparison with the sequenced treatment alternatives to relieve depression (STAR*D) child study. AB - OBJECTIVE: To estimate the prevalence of current psychiatric disorders among children and adolescents (collectively called children) of mothers entering treatment for depression; to examine maternal predictors of child psychopathology among children of depressed mothers; and to determine consistency of findings with a similar child study ancillary to Sequenced Treatment Alternatives to Reduce Depression (STAR*D) from seven United States sites (STAR*D-Child). METHOD: Mothers (N = 82) with major depressive disorder (MDD) enrolled in a treatment study in Ottawa (Ontario, Canada) or New York City, and their eligible children (N = 145) (aged 7 through 17 years) were assessed independently when the mother enrolled. RESULTS: Among the children of depressed mothers, 42% had at least one current psychiatric diagnosis, including affective (15%), anxiety (19%), behavioral (23%), and/or substance use (2%) disorders. In all, 40% of the children were rated as impaired by clinical assessors. Mothers' comorbid anxiety disorders predicted the highest rates of current disorders in the child in both studies. The severity of the mother's depression predicted behavioral problems in the child. The current and lifetime rates of psychiatric disorders in the children of depressed mothers were compared to rates found in STAR*D Child and findings were consistent. Both studies used similar diagnostic assessments. CONCLUSION: Given the high prevalence of offspring psychiatric disorders, inquiring about the mental health of the children when a depressed mother comes for treatment, and referring children for treatment when appropriate, are important. PMID- 23101747 TI - On "Your child does NOT have bipolar disorder". PMID- 23101745 TI - Atypical pulvinar-cortical pathways during sustained attention performance in children with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: The neurobiological basis of inattentiveness, a core feature of attention-deficit/hyperactivity disorder (ADHD), is not yet well understood. Structural abnormalities in thalamus, especially the pulvinar nuclei, have recently been reported in ADHD. Pulvinar nuclei maintain reciprocal connections with cortical/subcortical areas, and play a central coordinating role during visual attention processing. The objective of this study was to test the hypothesis that children and young adolescents with ADHD would show atypical pulvinar-cortical functional pathways during sustained attention performance, and that these functional abnormalities would be associated with the inattentive symptoms of the disorder. METHOD: Visual attention task-based functional magnetic resonance imaging (fMRI) data from 22 children and young adolescents with ADHD and 22 demographically matched, normal control subjects were analyzed. Cortical activation maps and temporal correlations of activity patterns between pulvinar nuclei and the remainder of brain were constructed for each participant. Correlations between activation magnitude of pulvinar and diagnostic measures were calculated in subjects with ADHD. RESULTS: Compared to controls, subjects with ADHD showed significantly reduced pulvinar activations bilaterally, significantly decreased functional connectivity between bilateral pulvinar and right prefrontal regions, and significantly increased connectivity between the right pulvinar and bilateral occipital regions. In addition, the activation magnitude in the left pulvinar was negatively correlated with the DSM-IV inattentive index in ADHD group. CONCLUSIONS: Allied with previous evidence of structural abnormalities in pulvinar, the current data suggest that inappropriate development of pulvinar may lead to disrupted functional circuits for visual attention processing, and that these disruptions contribute significantly to the pathophysiological mechanisms of the inattentiveness symptoms in ADHD. PMID- 23101748 TI - To the editor: the reviewed book, "Your child does NOT have bipolar disorder". PMID- 23101746 TI - Neuroimaging correlates of novel psychiatric disorders after pediatric traumatic brain injury. AB - OBJECTIVE: To study magnetic resonance imaging (MRI) correlates of novel (new onset) psychiatric disorders (NPD) after traumatic brain injury (TBI) and orthopedic injury (OI). METHOD: Participants were 7 to 17 years of age at the time of hospitalization for either TBI or OI. The study used a prospective, longitudinal, controlled design with standardized psychiatric assessments conducted at baseline (reflecting pre-injury function) and 3 months post-injury. MRI assessments including diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), volumetric measures of gray and white matter regions, volumetric measures of lesions, and cortical thickness were conducted. Injury severity was assessed by standard clinical scales. The outcome measure was the presence of an NPD identified during the first 3 months after injury. RESULTS: There were 88 participants (TBI, 44; OI, 44). NPD occurred more frequently in the TBI (21/44; 48%) versus the OI (6/44; 14%) group (Fisher's exact test, p = .001). NPD in TBI participants was not related to injury severity. Multivariate analysis of covariance of the relationship between FA in hypothesized regions of interest (bilateral frontal and temporal lobes, bilateral centrum semiovale, bilateral uncinate fasciculi) and NPD and group (TBI versus OI) was significant, and both variables (NPD, p < .05; group, p < .001) were jointly significantly related to FA. NPD was not significantly related to volumetric measures of white or gray matter structures, volumetric measures of lesions, or cortical thickness measures. CONCLUSIONS: Lowered white matter integrity may be more important in the pathophysiology of NPD than indices of gray matter or white matter atrophic changes, macroscopic lesions, and injury severity. PMID- 23101749 TI - Drs. Althoff and Williamson reply. PMID- 23101751 TI - Specific immune responses against epitopes derived from Aurora kinase A and B in acute myeloid leukemia. AB - Aurora kinases are serine/threonine kinases which play an important role in the process of mitosis and cell cycle regulation. Aurora kinase inhibitors are described to sensitize malignant cells to cytosine arabinoside and specific antibodies by mediating apoptosis. Aurora kinases are overexpressed in most acute leukemias but also in solid tumors. In this study we investigated whether epitopes derived from Aurora kinase A and B are able to elicit cellular immune responses in patients with acute myeloid leukemia (AML) to investigate their role as potential targets for specific immunotherapy. Samples of eight patients with AML were analyzed in enzyme-linked immunosorbent spot (ELISpot) assays and compared with immune responses of nine healthy volunteers (HVs). Specific CD8 + T cell responses were detected against the epitopes Aura A1, A2, B1, B2, B3, B4 and B5. Immune responses for epitopes derived from Aura B were induced more frequently compared to Aura A. The antigens with the most frequent cytotoxic T lymphocyte (CTL) responses were Aura B3, B4 and B5, although the number of patients tested for these antigens was low. Aura B5 did not elicit specific CTL responses in HVs. For epitope Aura B6 no immune response was detected in HVs or patients. Taken together, with the combination of Aurora kinase inhibitors and an immunotherapeutic approach, an effective blast and minimal residual disease elimination might be achieved. PMID- 23101752 TI - Cladribine therapy in adults with advanced Langerhans cell histiocytosis. PMID- 23101753 TI - Optimized loading and sustained release of hydrophilic proteins from internally nanostructured particles. AB - In this study, we demonstrate that emulsified microemulsions and micellar cubosomes are suitable as sustained delivery vehicles for water-soluble proteins. Through structural modifications, the loading efficiency of two model proteins, namely bovine serum albumin (BSA) and cytochrome c could be remarkably increased. A procedure for preparing these particles loaded with optimized amounts of sensitive substances is presented. Loading and dispersion at low temperatures is performed in two successive steps. First, a water-in-oil microemulsion is loaded with the proteins. Subsequently, this phase is dispersed in water resulting in particles with microemulsion and micellar cubic internal structure and a size of approximately 620 nm. This two-step method ensures optimal loading of the particles with the proteins. These nanostructured particles are able to sustain the release of the water-soluble BSA and cytochrome c. Within one day, less than 10% of BSA and 15% of cytochrome c are released. The release rate of cytochrome c is influenced by the nanostructure of the particles. PMID- 23101754 TI - Daily dietary energy and macronutrient intake and anthropometric measurements of the peritoneal dialysis patients. AB - INTRODUCTION: This study was planned to investigate the relation between dietary macronutrient status and anthropometric measurements in peritoneal dialysis (PD) patients. MATERIALS AND METHODS: A total of 28 clinically stable patients were enrolled in this study. All patients were taken a dietary therapy according to the guidelines of the American Journal of Kidney Foundation for 12 weeks. The anthropometric measurements were taken by bioelectrical impedance analyzer. The daily macronutrient intakes of the patients were calculated by the food consumption records. RESULTS: The mean age was 48.3 +/- 13.10 years [56.3 +/- 7.41 years for males (n = 14) and 40.3 +/- 12.84 years for females (n = 14)]. There were significant changes in fat percentage (%), total body water (TBW; %, L), extracellular water (ECW; %, L), basal metabolic rate over body weight (BMR/BW), and body fat mass index (BMFI) in males (p < 0.05), but there was no change in females (p > 0.05). The daily dietary energy and protein intakes were under the recommended level in the study period. CONCLUSION: Patients undergoing PD frequently have low intakes of protein and energy. It is recommended that individuals undergoing PD periodically maintain 3-day dietary records followed by dietary interviews conducted by a dietitian. PMID- 23101755 TI - Enzyme mimics of Au/Ag nanoparticles for fluorescent detection of acetylcholine. AB - We have developed a highly sensitive and selective fluorescent assay for the detection of acetylcholine (ACh) based on enzyme mimics of Au/Ag nanoparticles (NPs). These NPs were prepared via a one-step solution phase reaction between 13 nm Au NPs and Ag(+) ions in the presence of stabilizing agents such as adenosine triphosphate (ATP) and polyethylene glycol (PEG). Our sensing strategy involves reacting ACh with acetylcholinesterase (AChE) to form choline that is in turn oxidized by choline oxidase (ChOx) to produce betaine and H(2)O(2), which reacts with Amplex UltraRed (AUR) in the presence of bimetallic NPs catalyst to form a fluorescent product. The fluorescence intensity (excitation/emission wavelengths of 540/592 nm) is proportional to the concentration of ACh over a range of 1-100 nM (R(2) = 0.998), with a limit of detection of 0.21 nM (signal/noise = 3). When compared with Au NPs and horseradish peroxidase, the Au/Ag NPs provide 150- and 115-fold higher catalytic activity toward the H(2)O(2)-mediated AUR reaction. The practicality of the assay has been validated by determining the concentrations of ACh in plasma and blood samples, with results of 2.69 +/- 0.84 nM (n = 5) and 6.75 +/- 1.42 nM (n = 5), respectively. Thus, the present assay holds great potential for the analysis of ACh in biological samples. PMID- 23101756 TI - Raman spectroscopy of oral buccal mucosa: a study on age-related physiological changes and tobacco-related pathological changes. AB - Biophysical techniques play an important role in detecting physiological alterations during pathogenesis. Raman spectroscopy has shown immense potential in identifying several diseased conditions, including oral cancers. Classification of normal, inflammatory, premalignant and malignant conditions has been demonstrated using ex vivo Raman spectroscopy. Feasibility of recording in vivo spectra in clinically implementable time has also been shown. Translation of this technology to clinics requires extensive validation of methodologies, building of robust models and testing the same under stringent conditions as well as on diverse populations. In this context, the ability of Raman spectroscopy in identifying subtle changes in oral mucosa with increasing age, and the influence of these aging related changes on classification with tobacco-related pathological changes was evaluated. A total of 451 spectra from 62 subjects were recorded from buccal mucosa of healthy subjects of 4 different age groups (aged 20-60 years). Also, 478 spectra from 85 subjects belonging to 4 different categories, tobacco exposed mucosa, contralateral normal (opposite side of tumor), premalignant patches and tumors on buccal mucosa were recorded using fiber optic probe-coupled commercial Raman spectrometer. Differences in spectra were explored by unsupervised Principal Component Analysis (PCA) and supervised Linear Discriminant Analysis (LDA), followed by Leave one out cross validation. Results indicate feasibility of classifying early and late age groups. Also, clear classification is observed between healthy and pathological groups, thus inherent heterogeneity in healthy groups seems to have no bearing on classification of normal with abnormal conditions. Findings of the study indicate high sensitivity of Raman spectroscopy in detecting subtle mucosal changes, further supporting efficacy of Raman spectroscopic approaches in oral cancer applications. Prospectively, more vigorous validation studies of Raman methodology would enable routine clinical applications. PMID- 23101757 TI - Expression and cellular localization of metalloproteases ADAMs in high graded carotid artery lesions. AB - Metalloproteases with a disintegrin domain (ADAM) has already been implicated in various cellular processes such as cytokine and growth factor shedding, proliferation, migration, and degradation of extracellular matrix. Their role in the development and progression of atherosclerosis in carotid lesions is however unknown. The aim of the study was to analyze expression of proteolytic ADAMs (8, 9, 10, 12, 15, 17) and their inhibitors TIMP-1, -3 in patients with high-graded carotid artery stenosis. Atherosclerotic plaques were obtained from 44 patients undergoing carotid endarterectomy (CEA) and analyzed by histochemistry, immunohistochemistry, and SYBR green-based real-time PCR. All ADAMs analyzed in our study were expressed in early as well as in advanced atherosclerotic carotid lesions. The highest expression within the plaque was observed for ADAM15 followed by ADAM8. Furthermore, a significant increase was observed in the expression of ADAM10 and ADAM12 in unstable plaques compared to unstable lesions (p = 0.05 and p = 0.036, respectively). In contrast, expression of TIMP-1 was significantly reduced in the same lesions (p = 0.020). Macrophages and smooth muscle cells showed the highest staining intensity and were positive for all ADAMs and TIMPs tested, with the exception of ADAM9. Endothelial cells at the lumen side were positive for ADAM 15 and TIMP-1, neovessels were positive also for ADAM12. In conclusion, the ADAM family of proteases seems to play an important role in the maintenance of proper vessel physiology and some ADAMs such as ADAM10 and ADAM12 might also contribute to the progression of atherosclerosis. PMID- 23101758 TI - Highly ordered nanorod assemblies extending over device scale areas and in controlled multilayers by electrophoretic deposition. AB - Here we describe the formation of vertically aligned nanorod assemblies over several multilayers using CdS and CdSe nanorods by electrophoretic deposition. The presence of both charge and dipole on the rods allows both field driven deposition and orientational order to form close packed arrays where each rod is vertically aligned. Comparing assembly formation in electrophoresis to spontaneous assembly in solution gives important insights into nanorod organization by these different mechanisms. We show the influence of ligand environment on net charge (zeta potential) and its influence on assembly formation in CdSe nanorods that have long chain alkyl ligands (low charge) or pyridine ligands (high charge). The experimental observations show that highly charged rods deposit too quickly to allow close-packing to occur with perpendicular alignment only occurring with a lower net charge. This is supported by simulation predicting a lower energy configuration with a preference for perpendicular alignment as the charge state decreases. The resolute order that is retained over device scale areas and over several multilayers combined with inherent scalability of electrophoretic deposition makes this approach highly attractive for large scale nanorod integration in electronic, photonic, or photovoltaic devices. PMID- 23101759 TI - Multiple chronic conditions among adults aged 45 and over: trends over the past 10 years. AB - Studies suggest that the presence of multiple chronic conditions (MCC) adds a layer of complexity to disease management (1-6); recently the U.S. Department of Health and Human Services established a strategic framework for improving the health of this population (2). This report presents estimates of the population aged 45 and over with two or more of nine self-reported chronic conditions, using a definition of MCC that was consistent in the National Health Interview Survey (NHIS) over the recent 10-year period: hypertension, heart disease, diabetes, cancer, stroke, chronic bronchitis, emphysema, current asthma, and kidney disease. Examining trends in the prevalence of MCC informs policy on chronic disease management and prevention, and helps to predict future health care needs and use for Medicare and other payers. PMID- 23101760 TI - The validity of the Personality Diagnostic Questionnaire-4 Narcissistic Personality Disorder scale for assessing pathological grandiosity. AB - Although controversy surrounds the definition and measurement of narcissism, the claim that pathological grandiosity is central to the construct generates little disagreement. Yet representations of pathological grandiosity vary across measures of narcissism, leading to conceptual confusion in the literature. The validity of a DSM-based measure of pathological narcissism, the Personality Diagnostic Questionnaire-4 Narcissistic Personality Disorder scale (PDQ-4 NPD), was evaluated in 1 clinical and 3 nonclinical samples (total N=2,391) for its ability to measure pathological grandiosity. Findings were generally supportive: average scores were higher in the clinical than nonclinical samples and the PDQ-4 NPD scale correlated most strongly with (a) other measures of NPD; (b) other DSM Cluster B personality disorders; (c) traits involving antagonism, hostility, and assertiveness; and (d) interpersonal distress and disaffiliative dominance. However, the low internal consistency of the PDQ-4 NPD scale and unexpected associations with Cluster A and obsessive-compulsive features point to potential psychometric weaknesses with this instrument. These findings are useful for evaluating the PDQ-4 NPD scale and for informing ongoing debates regarding how to define and assess pathological narcissism. PMID- 23101761 TI - Switching diastereoselectivity in proline-catalyzed aldol reactions. AB - The choice of the anion of an achiral TBD-derived guanidinium salt, used as cocatalyst for proline, allows reacting cycloketones with aromatic aldehydes and preparing either anti- or syn-aldol adducts with very high enantioselectivity. As a proof of principle, we show how the judicious choice of an additive allows individual access to all possible products, thus controlling the stereochemical outcome of the asymmetric aldol reaction. The origin of the syn diastereoselectivity unfolds from an unusual equilibrium process coupled to the enamine-based catalytic cycle standard for proline. PMID- 23101762 TI - Proanthocyanidin composition and antioxidant potential of the stem winemaking byproducts from 10 different grape varieties (Vitis vinifera L.). AB - Stem byproducts from 10 different grape (Vitis vinifera L.) varieties were evaluated in terms of their total phenolic and total proanthocyanidin contents, flavan-3-ol and proanthocyanidin profiles, and antioxidant capacity measured by ABTS, CUPRAC, FRAP, and ORAC assays, with a view to the recovery of their natural bioactive compounds. Stems from Callet, Syrah, Premsal Blanc, Parellada, and Manto Negro varieties yielded the highest total phenolic and total proanthocyanidin contents and showed the greatest antioxidant capacities, whereas Chardonnay and Merlot stems presented the lowest values. Varieties differed significantly (p<0.05) with regard to both the phenolic composition and antioxidant capacity of their stems. However, no significant differences (p>0.05) were observed when stems from red and white varieties were considered separately. For the 10 grape varieties investigated, this is the first study presenting a detailed description of their stem flavan-3-ol composition determined by HPLC-UV fluo. All of the analyses confirmed the stem byproducts as a potential polyphenol rich source, especially promising in the case of the Callet variety. PMID- 23101763 TI - Mixed methods evaluation of targeted case finding for cardiovascular disease prevention using a stepped wedged cluster RCT. AB - BACKGROUND: A pilot project cardiovascular prevention was implemented in Sandwell (West Midlands, UK). This used electronic primary care records to identify untreated patients at high risk of cardiovascular disease then invited these high risk patients for assessment by a nurse in their own general practice. Those found to be eligible for treatment were offered treatment. During the pilot a higher proportion of high risk patients were started on treatment in the intervention practices than in control practices. Following the apparent success of the prevention project, it was intended to extend the service to all practices across the Sandwell area. However the pilot project was not a robust evaluation. There was a need for an efficient evaluation that would not disrupt the planned rollout of the project. METHODS/DESIGN: Project nurses will sequentially implement targeted cardiovascular case finding in a phased way across all general practices, with the sequence of general practices determined randomly. This is a stepped wedge randomised controlled trial design. The target population is patients aged 35 to 74, without diabetes or cardiovascular disease whose ten-year cardiovascular risk, (determined from data in their electronic records) is >= 20%. The primary outcome is the number of high risk patients started on treatment, because these data could be efficiently obtained from electronic primary care records. From this we can determine the effects of the case finding programme on the proportion of high risk patients started on treatment in practices before and after implementation of targeted case finding. Cost effectiveness will be modelled from the predicted effects of treatments on cardiovascular events and associated health service costs. Alongside the implementation it is intended to interview clinical staff and patients who participated in the programme in order to determine acceptability to patients and clinicians. Practical considerations meant that 26 practices in Sandwell could be randomised, including about 6,250 patients at high risk of cardiovascular disease. This gives sufficient power for evaluation. DISCUSSION: It is possible to design a stepped wedge randomised controlled trial using routine data to determine the primary outcome to evaluate implementation of a cardiovascular prevention programme. PMID- 23101764 TI - Synthesis of hapten and preparation of specific polyclonal antibody with high affinity for lenalidomide, the potent drug for treatment of multiple myeloma. AB - BACKGROUND: For therapeutic monitoring and pharmacokinetic studies of lenalidomide (LND), the potent drug for treatment of multiple myeloma (MM), a specific antibody was required for the development of a sensitive immunoassay system for the accurate determination of LND in plasma. RESULTS: In this study, a hapten of LND (N-glutaryl-LND) was synthesized by introducing the glutaryl moiety, as a spacer, into the primary aromatic amine site of the LND molecular structure. The structure of the hapten (G-LND) was confirmed by mass, 1H-NMR, and 13C spectrometric techniques. G-LND was coupled to each of bovine serum albumin (BSA) and keyhole limpet hemocyanin (KLH) proteins by ethyl-3-(3 dimethylaminopropyl) carbodiimide as a coupling reagent. LND-KLH conjugate was used as an immunogen. Four female 2-3 months old New Zealand white rabbits were immunized with an emulsion of LND-KLH with Freund's adjuvant. The immune response of the rabbits was monitored by direct enzyme-linked immunosorbent assay (ELISA) using LND-BSA immobilized onto microwell plates as a solid phase. The rabbit that showed the highest antibody titer and affinity to LND was scarified and its sera were collected. The IgG fraction was isolated and purified by affinity chromatography on protein A column. The specificity of the purified antibody for LND was evaluated by indirect competitive ELISA using dexamethasone as a competitor as it is used with LND in a combination therapy. CONCLUSIONS: The high affinity of the antibody (IC50 = 10 ng/mL) will be useful in the development of an immunoassay system for the determination of plasma LND concentrations. Current research is going to optimize the assay conditions and validate the procedures for the routine application in clinical laboratories. PMID- 23101765 TI - Remnant fragments within an agricultural matrix enhance conditions for a rodent host and its fleas. AB - Habitat fragmentation can adversely impact biodiversity, although where remnant fragments of natural vegetation provide favourable conditions the negative effects of fragmentation may be mitigated. Host-parasite systems in fragmented areas have only recently been examined, with parasites generally showing higher prevalence and richness in fragments, mediated by changes in host density. However, the effect of fragmentation on parasite body size and fecundity remains poorly investigated. Thus, here we compared the body size and condition of a generalist rodent host, Rhabdomys pumilio and the body size of 2 common flea species between pristine natural areas and remnant fragments within agriculture areas. Host body length, weight and body condition values were significantly larger in fragments than in pristine natural vegetation. Listropsylla agrippinae fleas showed the same pattern, being significantly larger in fragments, while Chiastopsylla rossi fleas did not differ in size between fragments and natural areas. The differential response of the 2 flea species may reflect the strength of association between the host and parasite, with the former spending a greater proportion of its lifespan on the host. Therefore, in this study agriculture fragments provide better conditions for both an opportunistic rodent and a closely associated flea species. PMID- 23101766 TI - Controllable self-assembling of gold nanorods via on and off supramolecular noncovalent interactions. AB - 5,15-Bis(4-sulfonatophenyl)porphyrin (DPPS) with a planar conjugated system and two negative charges was found to be able to engender the self-assembling of CTAB GNRs due to the electrostatic interaction between DPPS and CTAB together with the pi-pi intermolecular interaction of DPPS, while its bulky supramolecular pseudo[3]rotaxane included by beta-cyclodextrin prevented such self-assembling due to the interruption of the above noncovalent interactions. PMID- 23101767 TI - Prolonged sedentary time and physical activity in workplace and non-work contexts: a cross-sectional study of office, customer service and call centre employees. AB - BACKGROUND: To examine sedentary time, prolonged sedentary bouts and physical activity in Australian employees from different workplace settings, within work and non-work contexts. METHODS: A convenience sample of 193 employees working in offices (131), call centres (36) and customer service (26) was recruited. Actigraph GT1M accelerometers were used to derive percentages of time spent sedentary (<100 counts per minute; cpm), in prolonged sedentary bouts (>=20 minutes or >=30 minutes), light-intensity activity (100-1951 cpm) and moderate-to vigorous physical activity (MVPA; >=1952 cpm). Using mixed models adjusted for confounders, these were compared for: work days versus non-work days; work hours versus non-work hours (work days only); and, across workplace settings. RESULTS: Working hours were mostly spent sedentary (77.0%, 95%CI: 76.3, 77.6), with approximately half of this time accumulated in prolonged bouts of 20 minutes or more. There were significant (p<0.05) differences in all outcomes between workdays and non-work days, and, on workdays, between work- versus non-work hours. Results consistently showed "work" was more sedentary and had less light intensity activity, than "non-work". The period immediately after work appeared important for MVPA. There were significant (p<0.05) differences in all sedentary and activity outcomes occurring during work hours across the workplace settings. Call-centre workers were generally the most sedentary and least physically active at work; customer service workers were typically the least sedentary and the most active at work. CONCLUSION: The workplace is a key setting for prolonged sedentary time, especially for some occupational groups, and the potential health risk burden attached requires investigation. Future workplace regulations and health promotion initiatives for sedentary occupations to reduce prolonged sitting time should be considered. PMID- 23101768 TI - Metabolism of growth hormone releasing peptides. AB - New, potentially performance enhancing compounds have frequently been introduced to licit and illicit markets and rapidly distributed via worldwide operating Internet platforms. Developing fast analytical strategies to follow these new trends is one the most challenging issues for modern doping control analysis. Even if reference compounds for the active drugs are readily obtained, their unknown metabolism complicates effective testing strategies. Recently, a new class of small C-terminally amidated peptides comprising four to seven amino acid residues received considerable attention of sports drug testing authorities due to their ability to stimulate growth hormone release from the pituitary. The most promising candidates are the growth hormone releasing peptide (GHRP)-1, -2, -4, 5, -6, hexarelin, alexamorelin, and ipamorelin. With the exemption of GHRP-2, the entity of these peptides represents nonapproved pharmaceuticals; however, via Internet providers, all compounds are readily available. To date, only limited information on the metabolism of these substances is available and merely one metabolite for GHRP-2 is established. Therefore, a comprehensive in vivo (po and iv administration in rats) and in vitro (with human serum and recombinant amidase) study was performed in order to generate information on urinary metabolites potentially useful for routine doping controls. The urine samples from the in vivo experiments were purified by mixed-mode cation-exchange solid phase extraction and analyzed by ultrahigh-performance liquid chromatography (UHPLC) separation followed by high-resolution/high-accuracy mass spectrometry. Combining the high resolution power of a benchtop Orbitrap mass analyzer for the first metabolite screening and the speed of a quadrupole/time-of-flight (Q-TOF) instrument for identification, urinary metabolites were screened by means of a sensitive full scan analysis and subsequently confirmed by high-accuracy product ion scan experiments. Two deuterium-labeled internal standards (triply deuterated GHRP-4 and GHRP-2 metabolite) were used to optimize the extraction and analysis procedure. Overall, 28 metabolites (at least three for each GHRP) were identified from the in vivo samples and main metabolites were confirmed by the human in vitro model. All identified metabolites were formed due to exopeptidase- (amino- or carboxy-), amidase-, or endopeptidase activity. PMID- 23101769 TI - Infection after urogynecologic surgery with the use of dexamethasone for nausea prophylaxis. AB - STUDY OBJECTIVE: To determine if a single perioperative dose of dexamethasone increases the risk of infection after urogynecologic surgery. DESIGN: Retrospective chart review (2004 - 2006) of patient records from the preoperative period to follow-up of 6 weeks from procedure. SETTING: University-affiliated tertiary-care hospital. MEASUREMENTS: The records of 574 ASA physical status 1, 2, and 3 women who had undergone urogynecologic surgery and who consented to have their information utilized for research were studied. The perioperative course of those who did and did not receive single-dose dexamethasone (4-8 mg) for postoperative nausea and vomiting prophylaxis was compared. Data collected included dexamethasone use, patient age, body mass index, ASA physical status, preexisting cardiovascular or respiratory disease, diabetes mellitus, type of surgery (vaginal vs abdominal), type of anesthesia (general vs regional, or combination), and duration of surgery. Postoperative infectious complications, including urinary tract infection (UTI), wound infection, other infections, and other complications, were noted. MAIN RESULTS: Univariate and multivariable analysis found no significant association between single-dose dexamethasone use and perioperative complications, including wound infection and UTI. There was an increased incidence of UTI with vaginal versus abdominal procedures, and longer duration of surgery. CONCLUSIONS: There was no significant association between single-dose dexamethasone and perioperative infectious complications. PMID- 23101770 TI - Prevention of central venous catheter-related bloodstream infections: is it time to add simulation training to the prevention bundle? AB - STUDY OBJECTIVE: To study the impact of adding simulation-based education to the pre-intervention mandatory hospital efforts aimed at decreasing central venous catheter-related blood stream infections (CRBSI) in intensive care units (ICU). DESIGN: Pre- and post-intervention retrospective observational investigation. SETTING: 24-bed ICU and a 562-bed university-affiliated, urban teaching hospital. PATIENTS: ICU patients July 2004-June 2008 were studied for the development of central venous catheter related blood stream infections (CRBSI). MEASUREMENTS: ICU patients from July 2004-June 2008 were studied for the development of central venous catheter-related blood stream infections (CRBSI). PRE-INTERVENTION: mandatory staff and physician education began in 2004 to reduce CRBSI. The CRBSI prevention program included online and didactic courses, and a pre- and post test. Elements in the pre-intervention efforts included hand hygiene, full barrier precautions, use of Chlorhexidine skin preparation, and mask, gown, gloves, and hat protection for operators. A catheter-insertion cart containing all supplies and checklist were was a mandatory element of this program; a nurse was empowered to stop the procedure for non-performance of checklist items. INTERVENTION: As of July 1, 2006, a mandatory simulation-based program for all intern, resident, and fellow physicians was added to teach central venous catheter (CVC) insertion. MEASUREMENTS: Data collected pre- and post-intervention were CRBSI incidence, number of ICU catheter days, mortality, laboratory pathogen results, and costs. MAIN RESULTS: The pre-intervention CRBSI incidence of 6.47/1,000 catheter days was reduced significantly to 2.44/1,000 catheter days post-intervention (58%; P < 0.05), resulting in a $539,902 savings (USD; 47%), and was attributed to shorter ICU and hospital lengths of stay. CONCLUSIONS: Following simulation-based CVC program implementation, CRBSI incidence and costs were significantly reduced for two years post-intervention. PMID- 23101771 TI - Comparison of the Pentax-AWS airway scope with the Macintosh laryngoscope for nasotracheal intubation: a randomized, prospective study. AB - STUDY OBJECTIVE: To evaluate the effectiveness of the Pentax-AWS Airway Scope (AWS) in comparison to the Macintosh laryngoscope during nasotracheal intubation. DESIGN: Prospective randomized study. SETTING: Operating room of a university affiliated hospital. PATIENTS: 90 ASA physical status 1 and 2 adults, aged 18 to 72 years, scheduled for orthodontia surgery requiring nasotracheal intubation. INTERVENTIONS: Patients were randomly assigned to three groups to undergo tracheal intubation with a Macintosh laryngoscope (Group Mac; n = 30), AWS with its tip inserted into the vallecula for indirect elevation of the epiglottis (Group AWS-I; n = 30), or AWS with its tip positioned posterior to the epiglottis for direct elevation of the epiglottis (Group AWS-D; n = 30). MEASUREMENTS: Percentage of glottic opening (POGO) score at the time of laryngeal exposure, time required for intubation, and intubation difficulty scale (IDS) were measured. The frequency of postoperative sore throat and hoarseness also were noted. MAIN RESULTS: Patient demographics did not differ among the groups. In Groups AWS-I and AWS-D, IDS scores were reduced significantly, and the percentages of glottic opening were significantly improved, compared with the Macintosh group. Time to place the endotracheal tube was significantly shortest in Group AWS-I. In one case from each group, intubation within two attempts failed and a different approach was required. CONCLUSION: The AWS offers better intubation conditions than the Macintosh laryngoscope during nasotracheal intubation. The AWS may be used to elevate the epiglottis both directly and indirectly for nasotracheal intubation. PMID- 23101772 TI - Anesthesiology resident personality type correlates with faculty assessment of resident performance. AB - STUDY OBJECTIVE: To study the association between anesthesiology residents' personality preference types, faculty evaluations of residents' performance, and knowledge. DESIGN: Convenience sample and prospective study. SETTING: Academic department of anesthesiology. SUBJECTS: Consenting anesthesiology residents (n = 36). INTERVENTIONS: All participants completed the Myers Briggs Type Indicator(r) (MBTI(r)). MEASUREMENTS: All residents' 6-month summation of daily focal evaluations completed by faculty [daily performance score (DPS); 1 = unsatisfactory, 2 = needs improvement, 3 = meets expectations, 4 = exceeds expectations], as well as a global assessment of performance (GAP) score based on placement of each resident into perceived quartile compared with their peers (ie,1 = first, or top, quartile) by senior faculty (n = 7) who also completed the MBTI, were obtained. The resident MBTI personality preferences were compared with the DPS and GAP scores, the United States Medical Licensing Examination (USMLE) I and II scores, and faculty MBTI personality type. MAIN RESULTS: There was no association between personality preference type and performance on standardized examinations (USMLE I, II). The mean GAP score was better (higher quartile score) for Extraverts than Introverts (median 2.0 vs 2.6, P = 0.0047) and for Sensing versus Intuition (median 2.0 vs 2.6, P = 0.0206) preference. Faculty evaluator MBTI preference type did not influence the GAP scores they assigned residents. Like GAP, the DPS was better for residents with Sensing versus Intuition preference (median 3.5 vs 3.3, P = 0.0111). No difference in DPS was noted between Extraverts and Introverts. CONCLUSIONS: Personality preference type was not associated with resident performance on standardized examinations, but it was associated with faculty evaluations of resident performance. Residents with Sensing personality preference were evaluated more favorably on global and focal faculty evaluations than those residents who chose the Intuition preference. Extraverted residents were evaluated more favorably on global but not focal assessment of performance. PMID- 23101773 TI - Mechanical airway obstruction due to dislodged spinal hardware. AB - A difficult airway caused by mechanical obstruction from dislodged spinal hardware in a patient undergoing revision surgery for a cervical chordoma is presented. Due to the logical, sequential multidisciplinary airway and patient management by the anesthesiology, neurosurgery, and otolaryngology teams working together in an environment of clear communication, a potential life-threatening crisis was averted with successful outcome for the patient. PMID- 23101774 TI - Massive pulmonary embolism in a patient undergoing Cesarean delivery. AB - A case of a 40 year old, 86 kg, G7P1 woman with a history of hypercoagulability, at 39.1 weeks' gestation, who presented for elective Cesarean section during spinal anesthesia, is presented. During closure of the uterus, she became unresponsive and went into asystolic cardiac arrest. During resuscitation, clinical signs suggested pulmonary embolism, as confirmed by transesophageal echocardiogram. She was anticoagulated and taken to the Cardiac Catheterization Laboratory; there, clot lysis was performed, resulting in massive bleeding. Embolization of the uterine arteries was attempted and was only partially successful in reducing the bleeding. She then underwent Cesarean hysterectomy to control the bleeding. She had a full recovery and was discharged on the sixth postoperative day. PMID- 23101775 TI - Case report of a parturient with cyanotic congenital heart disease palliated with a Glenn procedure. AB - As the prevalence of adults with palliated congenital heart disease continues to increase, so, too, does the number of these patients who will become pregnant. Practicing physicians need to be familiar with the impact that normal physiologic changes associated with pregnancy and delivery has on patients with palliated congenital heart disease. The physiologic impact of pregnancy on a patient with palliated cyanotic congenital heart disease and the management of her delivery are presented. PMID- 23101776 TI - Anatomic changes in the inguinal region after hip arthroscopy: implications for femoral nerve block. AB - Patients may experience significant pain after hip arthroscopy. Two patients who experienced severe pain after arthroscopic hip surgery, despite receiving multimodal pharmacologic therapy, are presented. In both cases, ultrasound-guided femoral nerve block provided excellent analgesia. However, during ultrasound, significant anatomic changes were noted in the inguinal region. In this report, we describe anatomic changes in the inguinal region that are visible with ultrasound after hip arthroscopy. PMID- 23101777 TI - Videolaryngoscopy: should it replace direct laryngoscopy? a pro-con debate. AB - Although it is universally recognized that the advent of videolaryngoscopy has revolutionized airway management, there is considerable disagreement over the future role of direct laryngoscopy and whether direct laryngoscopy should be relegated to a legacy technique. Arguments against the continued relevance of traditional intubation methods include increased success and decreased complications when videolaryngoscopy is utilized, as well as the fact that videolaryngoscopy enhances the performance of nonanesthesia providers. However, proponents of direct laryngoscopy cite technical issues, as well as instances in which intubation by videolaryngoscopy fails despite successful visualization. This argument serves as the rationale for the continued use of direct laryngoscopy, particularly for airway management experts. PMID- 23101778 TI - Unanticipated motor block with brachial plexus analgesia after increasing dilute ropivacaine infusion. PMID- 23101779 TI - Wiggle technique for orbital block. PMID- 23101780 TI - An unusual cause of nasotracheal tube cuff equipment failure. PMID- 23101781 TI - Ketamine and postoperative nausea and vomiting: role of the morphine-sparing effect. PMID- 23101782 TI - Intravenous macrolide use: a reminder of the dangers of rapid infusion rates. PMID- 23101783 TI - Discounted cash flow of anesthesia information management systems. PMID- 23101784 TI - A novel way of anesthetizing and maintaining airway/ventilation in an ultra morbidly obese patient presenting for upper GI endoscopy. PMID- 23101785 TI - A venipuncture needle exchange device designed for central venous catheterization. PMID- 23101786 TI - Locally learning biomedical data using diffusion frames. AB - Diffusion geometry techniques are useful to classify patterns and visualize high dimensional datasets. Building upon ideas from diffusion geometry, we outline our mathematical foundations for learning a function on high-dimension biomedical data in a local fashion from training data. Our approach is based on a localized summation kernel, and we verify the computational performance by means of exact approximation rates. After these theoretical results, we apply our scheme to learn early disease stages in standard and new biomedical datasets. PMID- 23101787 TI - Electrostatically guided dynamics--the root of fidelity in a promiscuous terpene synthase? AB - Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of more than 60,000 known natural products. This abundance of compounds is generated using a very limited pool of substrates based on linear isoprenoids. The astounding chemodiversity obtained by terpene cyclases suggests a tremendous catalytic challenge to these often promiscuous enzymes. In the current study we present a detailed mechanistic view of the biosynthesis of the monoterpene bornyl diphosphate (BPP) from geranyl diphosphate by BPP synthase using state of the art simulation methods. We identify the bornyl cation as an enzyme-induced bifurcation point on the multidimensional free energy surface, connecting between the product BPP and the side product camphene. Chemical dynamics simulations suggest that the active site diphosphate moiety steers reaction trajectories toward product formation. Nonetheless, chemical dynamics is not precise enough for exclusive product formation, providing a rationale for the lack of fidelity in this promiscuous terpene cyclase. PMID- 23101788 TI - The relationships between serum sTWEAK, FGF-23 levels, and carotid atherosclerosis in renal transplant patients. AB - BACKGROUND: Cardiovascular disease is the main cause of mortality after renal transplantation. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and fibroblast growth factor-23 (FGF-23) are two novel molecules that have been associated with atherosclerosis in different populations. In this cross sectional study, we investigated the associations between sTWEAK, FGF-23, and carotid artery intima-media thickness (CA-IMT) in renal transplant patients. METHODS: A total of 117 renal transplant patients were studied. CA-IMT was determined by B-mode Doppler ultrasonography. Serum sTWEAK and FGF-23 were measured by a commercially available enzyme-linked immunosorbent assay (ELISA). RESULTS: Mean age was 39.6 +/- 9.6 years and 51% of the patients were male. Mean sTWEAK level was 595 +/- 225 pg/mL (158-1140), FGF-23 level was 92 +/- 123 RU/mL (9.6-1006), and CA-IMT level was 0.62 +/- 0.11 mm (0.40-0.98). sTWEAK level was positively correlated with CA-IMT. There was no association between sTWEAK and FGF-23 levels. FGF-23 was also associated with CA-IMT. In adjusted models using linear regression analysis, only age and serum TWEAK levels were predictors for CA-IMT. CONCLUSION: There is a positive correlation between CA-IMT and sTWEAK, but not with FGF-23 levels in renal transplant patients. PMID- 23101789 TI - The health of male veterans and nonveterans aged 25-64: United States, 2007-2010. AB - The well-being of military personnel and their families is a topic of growing concern in public health. The effects of military service on physical and psychological health, especially after extended overseas deployments, are complex. There may also be long-term consequences of military service for the health and health care utilization of veterans as they age (1). Today, over 12 million men aged 25-64 in the United States are veterans, representing 15% of the total U.S. male population at those ages (2). More attention is now being paid to gathering accurate data to help veterans readjust to civilian life (3). Many studies of veterans only use information from military or veteran databases, which limits the ability to make comparisons with the overall population. This report uses data from the 2007-2010 National Health Interview Survey (NHIS) to describe the health status of community-dwelling male veterans aged 25-64. It directly compares the health status of veterans with nonveterans on a variety of measures. PMID- 23101790 TI - Denaturation and preservation of globular proteins: the role of DMSO. AB - The thermal denaturation of hen egg white lysozyme (HEWL) in D(2)O was followed by IR absorption after addition of dimethyl sulfoxide (DMSO) at different molar fractions. Amide I intensity and position revealed that DMSO reduces the thermal stability of the native protein and favors the formation of ordered aggregates. The comparison with ethanol/water solutions evidenced that ethanol (partially deuterated ethanol EtOD) has a stronger effect on the thermal stability of HEWL: the same down-shift of melting temperature was measured at 0.18 and 0.30 molar fraction of ethanol and DMSO, respectively. This is probably due to lower polarity of EtOD/D(2)O with respect to DMSO/D(2)O solutions. A kinetic study of protein assembling at 0.30 DMSO molar fraction, was also performed at different temperatures. The high viscosity of the solvent was observed to cause a sensitive slowing down of aggregation rate in comparison to that of water/alcohol solutions. The evidence of a retarded self-assembling put forward a possible explanation for the use of dimethyl sulfoxide as a protectant of protein structure. In fact, for both organic solvents a nonspecific interaction with the protein and a water-mediated action is deduced, but the addition of DMSO reduces the irreversible denaturation due to kinetic effects and this can be exploited for lessening one of the main degradation routes of globular proteins during freezing-thawing cycles. PMID- 23101791 TI - Laparoscopic resection of hilar cholangiocarcinoma. AB - BACKGROUND: Surgical resection is the only curative treatment for hilar cholangiocarcinoma. Laparoscopic hepatectomy has been used to treat several types of liver neoplasms. However, technical issues have limited the adoption of laparoscopy for the treatment of hilar cholangiocarcinoma. To date there is only one report of minimally invasive procedure for hilar cholangiocarcinoma in the literature. The present video-assisted procedure shows a laparoscopic resection of hilar cholangiocarcinoma. PATIENT AND METHODS: A 43-year-old woman with progressive jaundice due to left-sided hilar cholangiocarcinoma was referred for treatment. The decision was to perform a laparoscopic left hepatectomy with lymphadenectomy and resection of extrahepatic bile ducts. Biliary reconstruction was performed using the hybrid method. RESULTS: Operative time was 300 minutes with minimum blood loss and no need for blood transfusion. Recovery was uneventful, and the patient was discharged on postoperative Day 7. Pathology revealed a well-differentiated cholangiocarcinoma with negative lymph nodes and clear surgical margins. The patient is well with no signs of the disease 18 months after the procedure. CONCLUSIONS: Laparoscopic left hepatectomy with lymphadenectomy is safe and feasible in selected patients and when performed by surgeons with expertise in liver surgery and minimally invasive techniques. The use of a hybrid method may be needed for biliary reconstruction, especially in cases where position and size of remnant bile ducts may jeopardize the anastomosis. Further studies are still needed to confirm the benefit of this approach over conventional surgery for hilar cholangiocarcinoma. PMID- 23101792 TI - Comparison of surgical and functional outcomes of minimally invasive and open pyeloplasty. AB - OBJECTIVE: To compare the surgical and functional outcomes of minimally invasive pyeloplasty versus open pyeloplasty. SUBJECTS AND METHODS: Between 2008 and 2010, 20 patients underwent transperitoneal minimally invasive (13 robot-assisted and 7 laparoscopic) pyeloplasty, and 22 patients underwent conventional open pyeloplasty. Operative and functional outcomes were compared between the minimally invasive and open pyeloplasty groups. The statistical analysis was performed using Fisher's exact test, unpaired t test, and Mann-Whitney U test. RESULTS: The mean age was 31 years in the minimally invasive group and 27 years in the open group. The mean operative time was 131 minutes in the minimally invasive group and 128 minutes in the open group (P=.71). The estimated blood loss was 30 mL in the minimally invasive group and 108 mL in the open group (P=.001). The drain was removed after 1.75 days and 4.48 days in the minimally invasive and open groups, respectively (P=.001). The mean hospital stay was 1.94 days and 4.19 days in the minimally invasive and open groups, respectively (P=.001). Crossing vessels were observed in 21% of all patients, and the transposition of the ureter was performed in all patients with an anterior crossing vessel. One patient in each group had symptomatic and radiographic recurrence and persistently obstructed drainage pattern on diuretic renography. The radiographic and symptomatic success rate was 95% in the minimally invasive group and 95.5% in the open group. CONCLUSIONS: Minimally invasive pyeloplasty has low morbidity, short length of stay, and less blood loss compared with open surgical repair. It is an effective and feasible minimally invasive treatment modality for ureteropelvic junction obstruction. PMID- 23101793 TI - Single-incision versus conventional three-incision laparoscopic appendectomy: a single-center experience. PMID- 23101794 TI - Evaluating mental workload of two-dimensional and three-dimensional visualization for anatomical structure localization. AB - Visualization of medical data in three-dimensional (3D) or two-dimensional (2D) views is a complex area of research. In many fields 3D views are used to understand the shape of an object, and 2D views are used to understand spatial relationships. It is unclear how 2D/3D views play a role in the medical field. Using 3D views can potentially decrease the learning curve experienced with traditional 2D views by providing a whole representation of the patient's anatomy. However, there are challenges with 3D views compared with 2D. This current study expands on a previous study to evaluate the mental workload associated with both 2D and 3D views. Twenty-five first-year medical students were asked to localize three anatomical structures--gallbladder, celiac trunk, and superior mesenteric artery--in either 2D or 3D environments. Accuracy and time were taken as the objective measures for mental workload. The NASA Task Load Index (NASA-TLX) was used as a subjective measure for mental workload. Results showed that participants viewing in 3D had higher localization accuracy and a lower subjective measure of mental workload, specifically, the mental demand component of the NASA-TLX. Results from this study may prove useful for designing curricula in anatomy education and improving training procedures for surgeons. PMID- 23101795 TI - Laparoscopic versus conventional Kasai portoenterostomy. PMID- 23101796 TI - Laparoscopy can aggravate the severity of pancreatitis in an experimental rat model. AB - PURPOSE: Over the past decade, laparoscopic techniques have markedly evolved, and it has been shown that minimally invasive surgery can provide a safe, effective, and less traumatic management of various surgical diseases. Additionally, it is well known that pancreatitis itself also produced severe oxidative tissue injury by increasing levels of reactive oxygen species. This study therefore aimed to investigate the effects of pneumoperitoneum on the severity of pancreatitis in a rat model of acute pancreatitis induced by cerulein. MATERIALS AND METHODS: Thirty-five Wistar albino rats were divided into five groups with seven rats in each. Experimental pancreatitis was induced using intraperitoneal injection of cerulein. The first group received open laparotomy. Groups 2-5 were treated with 5, 10, 15, and 20 mm Hg, respectively, achieved by applying pressure and waiting for 60 minutes. After this waiting interval, all of the rats were sacrificed; blood samples were taken by intracardiac puncture for biochemical assays, and pancreatic tissue samples were taken for light microscope analysis. Histopathology was scored according to edema, granulation, polymorphonuclear leukocytes, and mononuclear cells in all groups. RESULTS: Great increases in malondialdehyde and reduced glutathione levels were seen in all of the groups in which pancreatitis was induced. In Group 2-5, more significant increases were detected than in the open laparotomy group (P<.005). In the histopathological examination, Groups 2-5 showed more inflammatory cell infiltration, edema, and granulation tissue than the open laparotomy group (P<.005). CONCLUSIONS: It is useful to remember the parameters of the medical treatment of pancreatitis. While surgical treatment is being decided, we think that the process of all kinds of surgery, including laparoscopic surgery, can increase the severity of pancreatitis. PMID- 23101866 TI - Effect of tissue-engineered chitosan-poly(vinyl alcohol) nanofibrous scaffolds on healing of burn wounds of rat skin. AB - Chitosan-poly(vinyl alcohol) (Cs:PVA) nanofibrous scaffolds were electrospun from 2:3 (wt/wt) Cs:PVA solution dissolved in 80% acetic acid. In vivo study was carried out on the dorsum skin of rat which burnt with a hot brass cylinder. The scaffolds were applied in two forms, that is, acellular (n=6) and cell-seeded with mesenchymal stem cells (n=6). Macroscopic measurements of wound area showed good aspect healing effect of scaffolds in comparison with control wounds specially in 15 days post operating. Pathological studies were done on the wounds to investigate the healing effects. The healing process of the wound covered with Cs/PVA nanofibrous scaffolds was much rapid compared to untreated wounds. However, the presence of stem cells on this scaffolds accelerated the wound healing process owing to their ability of collagen regeneration. PMID- 23101867 TI - Hybrid polymer-metal nanospheres based on highly branched gold nanoparticles for potential medical applications. AB - Hybrid polymer-metal nanospheres are potential nano-sized medical devices that can provide multi-functions such as medical imaging and drug/biomolecule delivery. Gold nanoparticle-based hybrid nanospheres are particularly attractive owing to the unique optical and electronic properties that they possess. The polymer in hybrid nanospheres can be tasked for cancer cell targeting, DNA delivering etc. In the current investigation, a simple one-pot synthesis method was developed for producing folic acid-chitosan-capped gold (Au@CS-FA) nanospheres. These nanospheres consisted of a flower-like gold nanoparticle core and a cross-linked folic acid (FA)-conjugated chitosan shell. During the synthesis of Au@CS-FA nanospheres, FA-conjugated chitosan molecules acted as a reductant for gold and also as a structure-directing agent for the formation of highly branched gold nanoparticles. The evolution of Au@CS-FA nanospheres during their manufacture was studied using various analytical techniques and the mechanism of formation and growth was proposed. The Au@CS-FA nanospheres exhibited high-surface-enhanced Raman scattering which could be utilised for imaging at the single molecule level. The biopolymer shell was functionalised with -NH(2) and -COOH groups, which could be readily conjugated with macromolecules, peptides, nucleotides etc. for potentially wide applications of Au@CS-FA nanospheres in the medical field. PMID- 23101868 TI - Functional analysis of single Poly(methyl-methacrylate)-based submicron pore electrophoretic flow detectors via translocation of differently sized silica nanoparticles. AB - Detection and discrimination of nanoparticles is a vital step in several analytical and diagnostic procedures. Towards this, the authors present in the current study, for the first time, an all poly(methyl-methacrylate) (PMMA) polymer membrane-based solid-state sensor capable of detecting single silica nanoparticles. The sensor is based on a single cylindrical submicron pore of 450 nm in diameter and 1 [micro sign]m in length, patterned by electron beam lithography in a PMMA membrane. It was subsequently integrated into a PMMA-based electrophoretic flow detector system containing two electrolyte reservoirs. Silica nanoparticles of 100 nm in diameter were dispersed in an electrolyte and detected as they temporarily block the current flow during translocation through the submicron pore, driven by an electric field. The submicron pore was highly stable, and able to not only detect but also discriminate between silica nanoparticles of different dimensions recognised by different amounts of current blockade produced as they translocated through the pore. The translocations of individual 100 and 150 nm diameter silica nanoparticles through the single submicron pore, and thus the amounts of current blockade they produce, were shown in very close agreement with the results evaluated mathematically using the model presented in this study. PMID- 23101869 TI - Influence of hybrid inorganic/organic mesoporous and nanostructured materials on the cephalosporins' efficacy on different bacterial strains. AB - The aim of this study was to investigate the effect of different hybrid inorganic organic micro- and nanomaterials (Fe(3)O(4)/PEG(600), Fe(3)O(4)/C(12), ZSM-5) on the antibacterial activity of different cephalosporins against Gram-positive and Gram-negative bacterial strains. The synergic effect of the studied materials was demonstrated by the increase in the growth inhibition zones diameter. All tested hybrid micro- and nanomaterials increased the activity of cefotaxime against Staphylococcus aureus. ZSM-5 increased the activity of cefotaxime and ceftriaxone and Fe(3)O(4)/C(12) that of ceftriaxone against Pseudomonas aeruginosa and S. aureus. The anti-Pseudomonas, anti-Klebsiella pneumoniae and anti-Bacillus subtilis activity of cefoperazone was increased by Fe(3)O(4)/C(12) nanoparticles, while the ZSM-5 improved its anti-Escherichia coli, K. pneumoniae, S. aureus and B. subtilis activity, whereas Fe(3)O(4)/PEG(600) against K. pneumoniae. The anti K. pneumoniae activity of cefepime was increased by all tested nanoparticles, whereas its anti-B. subtilis and anti-E. coli activity was improved by Fe(3)O(4)/C(12) and Fe(3)O(4)/PEG(600) nanoparticles. In conclusion, both magnetic Fe(3)O(4) nanoparticles, charged outside as extra-shell with the antibiotic as well as ZSM-5 microparticles carrying the antibiotic inside the pores, significantly and specifically improved cephalosporin efficacy. A probable explanation for the increase in the antibiotic efficiency is the better penetration through the cellular wall of the antibiotic charged nanoparticles. PMID- 23101870 TI - Comparison of statistical and optimisation-based methods for data-driven network reconstruction of biochemical systems. AB - Data-driven reconstruction of biological networks is a crucial step towards making sense of large volumes of biological data. Although several methods have been developed recently to reconstruct biological networks, there are few systematic and comprehensive studies that compare different methods in terms of their ability to handle incomplete datasets, high data dimensions and noisy data. The authors use experimentally measured and synthetic datasets to compare three popular methods - principal component regression (PCR), linear matrix inequalities (LMI) and least absolute shrinkage and selection operator (LASSO) - in terms of root-mean-squared error (RMSE), average fractional error in the value of the coefficients, accuracy, sensitivity, specificity and the geometric mean of sensitivity and specificity. This comparison enables the authors to establish criteria for selection of an appropriate approach for network reconstruction based on a priori properties of experimental data. For instance, although PCR is the fastest method, LASSO and LMI perform better in terms of accuracy, sensitivity and specificity. Both PCR and LASSO are better than LMI in terms of fractional error in the values of the computed coefficients. Trade-offs such as these suggest that more than one aspect of each method needs to be taken into account when designing strategies for network reconstruction. PMID- 23101871 TI - Building blocks of biological networks: a review on major network motif discovery algorithms. AB - In recent years, there has been a great interest in studying different aspects of complex networks in a range of fields. One important local property of networks is network motifs, recurrent and statistically significant sub-graphs or patterns, which assists researchers in the identification of functional units in the networks. Although network motifs may provide a deep insight into the network's functional abilities, their detection is computationally challenging. Therefore several algorithms have been introduced to resolve this computationally hard problem. These algorithms can be classified under various paradigms such as exact counting methods, sampling methods, pattern growth methods and so on. Here, the authors will give a review on computational aspects of major algorithms and enumerate their related benefits and drawbacks from an algorithmic perspective. PMID- 23101872 TI - Identifying similar functional modules by a new hybrid spectral clustering method. AB - Recently, a large number of researches have focused on finding cellular modules within protein-protein interaction networks. Until now, most of the works have concentrated on finding small modules and protein complexes. The authors have extended the concept of functional module and have identified larger functional modules which are the most similar to the entire network. To this end, a new hybrid spectral-based method is proposed here. First, the original graph is transformed into a line graph. Next, the nodes of the new graph are represented in the Euclidean space by using spectral methods and finally, a self-organising map is applied to the points in the new feature space. The experimental results show that similar modules, obtained from the proposed method, have own local hubs and lots of significant functional subunits concerning each other. These modules not only detect general biological processes that each protein is involved in, but also due to great similarities to the original network, it can be used as significant subnetworks for predicting protein function as detailed as possible. Some interesting properties of these modules are also investigated in this research. PMID- 23101873 TI - Systemic modelling of human bioenergetics and blood circulation. AB - This work reviews the main aspects of human bioenergetics and the dynamics of the cardiovascular system, with emphasis on modelling their physiological characteristics. The methods used to study human bioenergetics and circulation dynamics, including the use of mathematical models, are summarised. The main characteristics of human bioenergetics, including mitochondrial metabolism and global energy balance, are first described, and the systemic aspects of blood circulation and related physiological issues are introduced. The authors also discuss the present status of studies of human bioenergetics and blood circulation. Then, the limitations of the existing studies are described in an effort to identify directions for future research towards integrated and comprehensive modelling. This review emphasises that a multi-scale and multi physical approach to bioenergetics and blood circulation that considers multiple scales and physiological factors are necessary for the appropriate clinical application of computational models. PMID- 23101874 TI - Analysis of a bio-dynamic model via Lyapunov principle and small-world network for tuberculosis. AB - The study will apply Lyapunov principle to construct a dynamic model for tuberculosis (TB). The Lyapunov principle is commonly used to examine and determine the stability of a dynamic system. To simulate the transmissions of vector-borne diseases and discuss the related health policies effects on vector borne diseases, the authors combine the multi-agent-based system, social network and compartmental model to develop an epidemic simulation model. In the identity level, the authors use the multi-agent-based system and the mirror identity concept to describe identities with social network features such as daily visits, long-distance movement, high degree of clustering, low degree of separation and local clustering. The research will analyse the complex dynamic mathematic model of TB epidemic and determine its stability property by using the popular Matlab/Simulink software and relative software packages. Facing the current TB epidemic situation, the development of TB and its developing trend through constructing a dynamic bio-mathematical system model of TB is investigated. After simulating the development of epidemic situation with the solution of the SMIR epidemic model, the authors will come up with a good scheme to control epidemic situation to analyse the parameter values of a model that influence epidemic situation evolved. The authors will try to find the quarantining parameters that are the most important factors to control epidemic situation. The SMIR epidemic model and the results via numerical analysis may offer effective prevention with reference to controlling epidemic situation of TB. PMID- 23101875 TI - Successful conservative management of a colorenal fistula complicating percutaneous cryoablation of renal tumors: a case report. AB - INTRODUCTION: Colorenal fistula is a rare phenomenon and may complicate percutaneous cryoablation of renal cell carcinoma. Treatment remains controversial. CASE PRESENTATION: A 62-year-old Caucasian man presented with pneumaturia and left flank pain six weeks following ultrasound-guided percutaneous cryoablation of two recurrent lesions in the left kidney 14 years after partial left nephrectomy for a left renal cell carcinoma. A computed tomography scan eight weeks after cryoablation revealed a cryoablated mass with adjacent stranding and adherent descending colon as well as bubbles of gas in the area of stranding, the left collecting system, and the bladder. These features were consistent with a colorenal fistula at the site of previous ablation. Successful resolution of the fistula, both clinical and radiological, was achieved following a complete conservative non-interventional out-patient approach. No ureteric stent or surgical intervention was employed. CONCLUSIONS: In the absence of severe symptoms or sepsis, complete conservative management of a colorenal fistula complicating percutaneous cryoablation of renal tumors should be considered prior to interventional stenting or resectional surgery. PMID- 23101876 TI - Psychosocial workload and stress in the workers' representative. AB - BACKGROUND: Using a data set of works councils of trade union IG Metal, this paper investigates psychosocial stress and strain on this specific group in comparison to employees working in administration in general (leadership and non leadership-role) and a national reference value. METHODS: For assessing psychosocial work factors on works councils within the sector represented by the trade union IG Metal in Germany, a research by using the German standard version of COPSOQ (Copenhagen Psychosocial Questionnaire) was performed. The instrument includes 87 single items forming 25 aspects of strain and stress. Results from the study group of works councils were compared to those from employees working in administration and to the general population mean (COPSOQ database). Statistical analysis included t-tests, analysis of variance and multiple comparisons of means. To be significant in terms of statistics, p<0.05 (two tailed) and a minimum deviation of 5 or more points between groups' mean values identify the relevant values. RESULTS: All in all, 309 works councils from a national survey of the German chemical and metalworking industries took part in the study. 113 were full-time works council members (exempted from the duty to perform their regular work), 196 were voluntary members (acting as employee representatives on an honorary basis alongside their normal duties). Comparison between works councils and employees working in administration (leadership roles (N=1810) and non-leadership roles (N=2970)) and for employees in general (N=35.000) showed unfavourable values for works councils for most scales. Significantly higher values indicating higher strain and stress were found for the scales: emotional demands, work-privacy conflict, role conflicts, mobbing, cognitive stress symptoms and burnout. Unfavourable results were obtained for the aspects: quality of leadership, social support, sense of community and general health. Favourable findings were found on the scales: influence at work, quantity of social relations and the partly positive values for quantitative demands and commitment to the workplace. CONCLUSION: Compared to the reference groups, works council members perceive the psychosocial demands of working life as more exhausting for the majority of aspects. This allows several conclusions. One reason may be the extended tasks employee representatives face, an other may be that the education of most works council members does not seem appropriate to the high demands of their managerial and executive tasks. PMID- 23101877 TI - The meaning of a positive client-nurse relationship for senior home care clients with chronic disease. AB - This study explored the meaning of a positive client-nurse relationship for seniors with chronic disease receiving in-home care. In this phenomenological study, eight participants aged 65 to 86 were purposefully selected from the Southwest Community Care Access Centre (SW-CCAC) in London, Ontario. Narrative data were collected through audiotaped, in-depth interviews using a semi structured interview guide. The analysis and interpretation of the interviews revealed that the meaning of a positive client-nurse relationship for these seniors encompassed two patterns of the meaning: having comfort and being connected within this relationship. These two patterns were contextualized by being a senior with chronic disease and were socially constructed through the relational experience of co-creating a positive relationship. Although further research is needed, the insights gained add to what is known about the theory and practice of relational health promotion for seniors living with chronic disease receiving in-home care. PMID- 23101878 TI - Synthesis, structure and metal binding property of internally 1,3-arylene-bridged azacalix[6]aromatics. AB - Three internally 1,3-arylene-bridged azacalix[6]aromatics 1-3 were synthesized by the Pd-catalyzed macrocyclic fragment coupling reaction between a stellated dibrominated pentamer and N(2),N(6)-dimethylpyridine-2,6-diamine or N(1),N(3) dimethylbenzene-1,3-diamine. Single-crystal X-ray analysis revealed that these bimacrocyclic compounds all adopt a triply pillared groove-shaped conformation, conceptually being derived from the fusion of two 1,3-alternate macrocycles. Four host/metal discrete complexes of the all-pyridine host 1, {Co(1)(CH(3)OH)(2)}(CoCl(4)).3(CH(3)OH), {Ni(1)(CH(3)OH)(2)}(NiCl(4)), {Ni(1)(CH(3)OH)(2)}(ClO(4))(2).CH(3)OH and {Cd(2)(1)(CH(3)CN)(4)(H(2)O)(4)}(ClO(4))(4), have been structurally characterized by X-ray crystallographic analysis, exploring two different metal binding modes. The metal complexation property of the host 1 in solution was then investigated by the UV-vis and NMR titration. With variation of the radii of the tested metal ions (Mn(2+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), and Hg(2+)), the host 1 can trap one or two metal ions via four different modes by using its two coordination cavities or two marginal pyridine rings. Such metal binding diversity of internally bridged heteracalixaromatics spotlights their potential applications in metal ion transport, ion channel, and metallo-enzyme mimics. PMID- 23101879 TI - Mechanisms of gas permeation through single layer graphene membranes. AB - Graphene has enormous potential as a unique molecular barrier material with atomic layer thickness, enabling new types of membranes for separation and manipulation. However, the conventional analysis of diffusive transport through a membrane fails in the case of single layer graphene (SLG) and other 2D atomically thin membranes. In this work, analytical expressions are derived for gas permeation through such atomically thin membranes in various limits of gas diffusion, surface adsorption, or pore translocation as the rate-limiting step. Gas permeation can proceed via direct gas-phase interaction with the pore, or interaction via the adsorbed phase on the membrane exterior surface. A series of van der Waals force fields allows for the estimation of the energy barriers present for various types of graphene nanopores. These analytical models will assist in the understanding of molecular dynamics and experimental studies of such membranes. PMID- 23101880 TI - Volumetric motion quantification by 3D tissue phase mapped CMR. AB - BACKGROUND: The objective of this study was the quantification of myocardial motion from 3D tissue phase mapped (TPM) CMR. Recent work on myocardial motion quantification by TPM has been focussed on multi-slice 2D acquisitions thus excluding motion information from large regions of the left ventricle. Volumetric motion assessment appears an important next step towards the understanding of the volumetric myocardial motion and hence may further improve diagnosis and treatments in patients with myocardial motion abnormalities. METHODS: Volumetric motion quantification of the complete left ventricle was performed in 12 healthy volunteers and two patients applying a black-blood 3D TPM sequence. The resulting motion field was analysed regarding motion pattern differences between apical and basal locations as well as for asynchronous motion pattern between different myocardial segments in one or more slices. Motion quantification included velocity, torsion, rotation angle and strain derived parameters. RESULTS: All investigated motion quantification parameters could be calculated from the 3D-TPM data. Parameters quantifying hypokinetic or asynchronous motion demonstrated differences between motion impaired and healthy myocardium. CONCLUSIONS: 3D-TPM enables the gapless volumetric quantification of motion abnormalities of the left ventricle, which can be applied in future application as additional information to provide a more detailed analysis of the left ventricular function. PMID- 23101881 TI - Proteomic identification and analysis of K63-linked ubiquitin conjugates. AB - Post-translational modification of proteins by covalent attachment of ubiquitin or a polyubiquitin chain is involved in myriad of processes in eukaryotic cells. The particular outcome of ubiquitination is directed by the length of the ubiquitin conjugate and its linkage composition. Among seven possible isopeptide linkage sites in ubiquitin, K48 and K63 occur most commonly and act as distinct cellular signals. Strategies are reported here for analysis of linkage sites and complexity of K63-linked polyubiquitin chains, based on rapid chemical proteolysis at aspartate residues combined with immunoprecipitation and mass spectrometry. Rapid chemical proteolysis at aspartate residues results in K63 linked peptides with truncated branches, which enable identification and characterization of stretches of consecutive K63 linkages on generally available instruments. A characteristic cleavage pattern and a characteristic fragmentation pattern allow recognition of K63 oligomers in proteolytic mixtures. Engineered K63-linked polyubiquitin chains of defined lengths were used to evaluate and demonstrate the method. In-gel microwave-supported acid hydrolysis was used to observe peptides specific to K63-linked ubiquitin dimers and trimers. Acid hydrolysis in solution, used in conjunction with linkage-specific immunoprecipitation, allowed more complex K63-linked branches to be characterized. Finally, a substrate protein, UbcH5b, was conjugated to monoubiquitin and to polyubiquitin chains containing only K63 linkages, and the sites of conjugation and chain lengths were characterized. PMID- 23101882 TI - Enhancement of volatile aglycone recovery facilitated by acid hydrolysis of glucosides from Nicotiana flower species. AB - Four different Nicotiana flowers (Nicotiana alata (alata), Nicotiana sylvestris (Sy), Nicotiana suaveolens (Su), and Nicotiana tabacum cv. Flue-Cured (FC)) from farms in Virginia and North Carolina were harvested and promptly quenched with liquid nitrogen and hand-ground prior to analysis. Each Nicotiana flower was pre extracted with hexane to remove unbound volatiles. Fifteen standard compounds that were thought to be in the pre-extract were employed to aid in GC-MS identification and quantification. Glucosides were then chromatographically isolated and next hydrolyzed via 2 M sulfuric acid for 24 h at 75 degrees C. For each flower, the products of hydrolysis were extracted in tandem with hexane and dichloromethane (DCM) prior to analysis by GC-MS. The mixture of hexane and DCM extracts of the flowers after hydrolysis were then analyzed for each of 15 external standards via GC-MS to determine the concentration of any isolated flower-derived aglycone. Quantitative results for each of the possible 15 free volatile compounds extracted before and after hydrolysis were compared. Benzyl alcohol, phenethyl alcohol, and cis-3-hexenol were found in all Nicotiana both before and after acid hydrolysis. Enormous increases in the mass of benzyl alcohol and phenethyl alcohol were obtained with all flowers as a result of acid hydrolysis. With selected Nicotiana flowers, significant increases were observed for eugenol and cinnamaldehyde. The significant increases observed in cinnamaldehyde and eugenol upon mild acid hydrolysis strongly indicate that this approach could be a viable alternative process for the production scale isolation of these important natural flavor compounds. PMID- 23101883 TI - Rhenium solubility in borosilicate nuclear waste glass: implications for the processing and immobilization of technetium-99. AB - The immobilization of technetium-99 ((99)Tc) in a suitable host matrix has proven to be a challenging task for researchers in the nuclear waste community around the world. In this context, the present work reports on the solubility and retention of rhenium, a nonradioactive surrogate for (99)Tc, in a sodium borosilicate glass. Glasses containing target Re concentrations from 0 to 10,000 ppm [by mass, added as KReO(4) (Re(7+))] were synthesized in vacuum-sealed quartz ampules to minimize the loss of Re from volatilization during melting at 1000 degrees C. The rhenium was found as Re(7+) in all of the glasses as observed by X ray absorption near-edge structure. The solubility of Re in borosilicate glasses was determined to be ~3000 ppm (by mass) using inductively coupled plasma optical emission spectroscopy. At higher rhenium concentrations, additional rhenium was retained in the glasses as crystalline inclusions of alkali perrhenates detected with X-ray diffraction. Since (99)Tc concentrations in a glass waste form are predicted to be <10 ppm (by mass), these Re results implied that the solubility should not be a limiting factor in processing radioactive wastes, assuming Tc as Tc(7+) and similarities between Re(7+) and Tc(7+) behavior in this glass system. PMID- 23101884 TI - An examination of behavioral antecedents to individuals' participation in a social mentoring network from a protege's perspective. AB - The present study seeks to identify the behavioral antecedents to individuals' participation as protege in a social mentoring network (SMN). It draws on social psychology and vocational literature and applies the Theory of Planned Behavior (TPB) to understand and predict the specific behavioral context. A SMN was operationally defined as a special case of informal mentoring coupled with a social networking platform. Two additional variables--similarity and self disclosure--were incorporated into the standard TPB model to improve its predictive power. A total of 376 respondents completed their first- and second wave questionnaires in a 2-week-longitudinal survey design. Two hierarchical multiple regressions were performed to determine the unique contributions made by the extended TPB model to the variance in behavioral intention and behavior. The results indicate that intention was demonstrated as a single significant variable in determining the behavior. Furthermore, intention was significantly influenced by respondents' attitudinal and normative beliefs toward the behavior, weighted by their internal mechanism that establishes the importance of necessary preconditions for the development of successful mentoring relationship. These preconditions include proteges' need for similarity with their mentor as well as willingness to self-disclose themselves to the SMN. PMID- 23101885 TI - Dynamical stability and assembly cooperativity of beta-sheet amyloid oligomers- effect of polarization. AB - The soluble intermediate oligomers of amyloidogenic proteins are suspected to be more cytotoxic than the mature fibrils in neurodegenerative disorders. Here, the dynamic stability and assembly cooperativity of a model oligomer of human islet amyloid polypeptide (hIAPP) segments were explored by means of all-atom molecular dynamics (MD) simulations under different force fields including AMBER99SB, OPLS, and polarized protein-specific charge (PPC) model. Simulation results show that the dynamic stability of beta-sheet oligomers is seriously impacted by electrostatic polarization. Without inclusion of polarization (simulation under standard AMBER and OPLS force field), the beta-sheet oligomers are dynamically unstable during MD simulation. For comparison, simulation results under PPC give significantly more stable dynamical structures of the oligomers. Furthermore, calculation of electrostatic interaction energy between the neighboring beta strands with an approximate polarizable method produces energetic evidence for cooperative assembly of beta-strand oligomers. This result supports a picture of downhill-like cooperative assembly of beta strands during fibrillation process. The present study demonstrates the critical role of polarization in dynamic stability and assembly cooperativity of beta-sheet-rich amyloid oligomers. PMID- 23101886 TI - Wait time for treatment in hospital emergency departments: 2009. AB - From 1999 through 2009, the number of visits to emergency departments (EDs) increased 32%, from 102.8 million visits in 1999 to 136.1 million visits in 2009 (1,2). In some hospitals, increased ED visit volume has resulted in ED crowding and increased wait times for minor and sometimes serious problems, such as myocardial infarction (3-7). This report describes the recent trend in wait times for treatment in EDs, and focuses on how wait times for treatment varied by two ED crowding measures: ambulance diversions and boarding of admitted patients. PMID- 23101887 TI - The mannan of Candida albicans lacking beta-1,2-linked oligomannosides increases the production of inflammatory cytokines by dendritic cells. AB - Mannans are mannose polymers attached to cell wall proteins in all Candida species, including the pathogenic fungus Candida albicans. Mannans are sensed by pattern recognition receptors expressed on innate immune cells. However, the detailed structural patterns affecting immune sensing are not fully understood because mannans have a complex structure that includes alpha- and beta-mannosyl linkages. In this study, we focused on the beta-1,2-mannosides of N-linked mannan in C. albicans because this moiety is not present in the non-pathogenic yeast Saccharomyces cerevisiae. To investigate the impact of beta-1,2-mannosides on immune sensing, we constructed a C. albicans ?mnn4/?bmt1 double deletant. Thin layer chromatography and nuclear magnetic resonance analyses revealed that the deletant lacked beta-1,2-mannosides in N-linked mannan. Mannans lacking the beta 1,2-mannosides induced the production of higher levels of inflammatory cytokines, including IL-6, IL-12p40 and TNF-alpha, in mice dendritic cells compared to wild type mannan. Our data show that beta-1,2-mannosides in N-linked mannan reduce the production of inflammatory cytokines by dendritic cells. PMID- 23101888 TI - Aqueous self-assembly of an electroluminescent double-helical metallopolymer. AB - A new type of water-soluble copper-containing polymer has been synthesized using the technique of subcomponent self-assembly. Copper(I)-directed imine bond formation between triethylene glycol functionalized 1,2-phenylenediamine and 2,9 diformylphenanthroline subcomponents resulted in the formation of a chain in which two conjugated helical ligand strands wrap around a linear array of metal ions. Characterization data from a variety of analytical methods are consistent with our formulation of this material. After purification by dialysis, the polymer was shown to possess several properties of conceptual and practical interest. (1) Individual double-helical strands appear to further aggregate through entanglement of their side chains to form well-defined superstructures such as nanoscale bow ties and macrocycles, which can be imaged on a surface. (2) The material's copper(I) ions underwent reversible electrochemical oxidation in solution, whereas analogous model compounds were observed to decompose upon oxidation: the polymer's greater length appeared to stabilize oxidized states through delocalization or entrapment. (3) Photophysical measurements reveal this material to be photo- and electroluminescent. It has been successfully used for the fabrication of electroluminescent devices and shows a weak emission of white blue light with CIE coordinates of (0.337, 0.359). This study further demonstrates the utility of the technique of subcomponent self-assembly for the straightforward generation of materials with useful properties. PMID- 23101889 TI - [Statistics in clinical and experimental medicine]. AB - The paper presents a brief overview of statistical methods used in clinical and experimental medicine, ranging from basic indicators and parameters of descriptive statistics and hypotheses testing (parametric as well as non parametric methods) to a description of the most frequently used multivariate methods in medical scientific publications, to logistic regression. The paper also describes Principle Component Analysis (PCA), which is one of the methods used to decrease a data dimensionality. The proper use of statistical methods is demonstrated on specific clinical cases. PMID- 23101891 TI - [Weight changes of patients in methadone maintenance treatment during four years period]. AB - BACKGROUND: Besides significant reduction in heroin consumption, weight gain is an accompanying phenomenon during methadone maintenance treatment. Priority of this on-going study was to find out, if it is stable, or transitory. We were also interested in possible contribution of pharmacological and socio-cultural factors on body weight changes. METHODS AND RESULTS: It was a longitudinal, clinical, observational study. The sample consisted of 42 patients from methadone maintenance treatment program (MMTP) from the Centre for Treatment of Drug Dependencies in Bratislava. Their average age was 28.6 years (SD +/- 6.0); 67 % were males. The weight (kg) and body mass index (BMI) were monitored in the series of five measurements during four years period in MMTP: at treatment entry after one year, after two, after three and after four years in the program. Relationship was also explored between daily dose of methadone and BMI. The average weight of the patients and their BMI were: before the entry into MMTP 65.2 kg (SD +/- 13.9) and 22.2 (SD +/- 3.9); after one year 72.7 kg (SD +/- 15.3) and 24.7 (SD +/- 4.1); after two 75.2 kg (SD +/- 16.7) and 25.6 (SD +/- 4.4); after three 74.2 kg (SD +/- 17.1) and 25.1 (SD +/- 4.5); after four years 75.0 kg (SD +/- 16.5) and 25.2 (SD +/- 4.2). Significant increase of BMI was detected after one year (t = 5.03; p < 0.001) and less significant between one and two years (t = 2.5; p < 0.05) in MMTP. Significant difference was also found between proportional distributions of the patients according to BMI categories: underweight, norm, overweight, obesity; at the time of entry to MMTP and after one year in it (chi2 = 13.6; p < 0.01). No any other statistically significant changes were found later on, after 1 - 4 years from the entry to the treatment. The correlation between daily dose of methadone and BMI (r = 0.273) was not significant after four years in MMTP. CONCLUSIONS: The weight of the patients in MMTP has increased significantly after one year in the treatment, but remained stable from the second year. No substantial correlation was detected between methadone dose and BMI. PMID- 23101893 TI - [The transrectal ultrasonography of prostate in men with congenital hypogonadism treated by long term testosterone replacement therapy]. AB - BACKGROUND: The aim of the study was to evaluate prostate transrectal ultrasonography findings in men with congenital hypogonadism treated by long term testosterone replacement therapy. METHODS: We have gradually included 31 men with congenital hypogonadism in period of 2001-2011. The average follow-up was 7.3 years (2 months - 10.8 years). We have used Sustanon(r) 250 i.m. every 3 weeks or Nebido(r) i.m. every 3 months for continual testosterone replacement therapy. We performed to all patients the transrectal ultrasonography of prostate and seminal vesicles by biplanar rectal probe every 6 months. RESULTS: During the transrectal ultrasonography we observed in 22 (71.0 %) patients changes in prostatic tissue. In case of 12 patients were diagnosed asymptomatic prostatic cysts, in 9 patients prostatolithiasis and in 5 patients changes in echogenity of prostatic tissue. In 2 patients was found simultaneous occurrence of prostatic cyst and prostolithiasis, in further 2 patients simultaneous occurrence of hyperechogenic prostatic lesion and prostatolithiasis. The above described findings were diagnosed in 5 patients in the treatment lasting from 3 to 5 years, for the other 17 men with hormone replacement therapy longer than 5 years. CONCLUSIONS: The study presents long term results of complex treatment in patients with disorders of sexual development, onset and progress of puberty. The long term treatment of these patients in interdisciplinary cooperation of endocrinologist and andrologist may significantly contribute to clarify an impact of testosterone replacement therapy on prostate development. PMID- 23101894 TI - [Evaluation of malnutrition of hospitalized children by the Screening Tool for the Assessment of Malnutrition in Paediatrics]. AB - BACKGROUND: Among the major tasks of medical and nursing care during child hospitalization belong nutritional risk screening and identification of patients requiring nutritional support. The main objective of the study was to verify the usefulness of rating scale The Screening Tool for the Assessment of Malnutrition in Paediatrics (STAMP) to assess the risk of development of malnutrition in hospitalized children. METHODS: To compare results of risk of development of child malnutrition was used the score of Paediatric nutritional risk. The sample consisted of 130 respondents (73 boys, 57 girls) aged 2 months to 18 years (average 8 years), who were hospitalized at the University Hospital of Ostrava- at the Department of Paediatrics. RESULTS: A difference was found in detection of risk of development of malnutrition though STAMP scale between children with different medical diagnoses (p=0.000) and in different age categories (p=0.0418). No difference was found in detection of malnutrition among the sexes. A significant difference was found in detecting risk of malnutrition between the scales (p=0.000). The overall consensus of risk of formation of malnutrition between the two scales was 46.9%. A higher number of high risk of development of malnutrition was found by the STAMP scale. CONCLUSION: Screening of malnutrition through the STAMP scale can identify paediatric patients who suffer from malnutrition or are threatened with its development. PMID- 23101906 TI - [Nobel Prize Laureates]. PMID- 23101907 TI - Contribution of education level and dairy fat sources to serum cholesterol in Russian and Finnish Karelia: results from four cross-sectional risk factor surveys in 1992-2007. AB - BACKGROUND: Food habits vary by socio-economic group and geographic area. Data on socio-economic differences in food habits and in serum total cholesterol concentration from Russia are scarce. Our aim was to examine changes and educational differences in serum total cholesterol and in the consumption of major sources of saturated fat in two geographically neighbouring areas, Russian and Finnish Karelia, and to examine whether the foods associated with serum total cholesterol are different in the two areas. METHODS: Data from cross-sectional risk factor surveys from years 1992, 1997, 2002 and 2007 in the district of Pitkaranta, the Republic of Karelia, Russia (n = 2672), and North Karelia, Finland (n = 5437), were used. The analyses included two phases. 1) To examine the differences in cholesterol by education, the means and 95% confidence intervals for education groups were calculated for each study year. 2) Multivariate linear regression analysis was employed to examine the role of butter in cooking, butter on bread, fat-containing milk and cheese in explaining serum total cholesterol. In these analyses, the data for all four study years were combined. RESULTS: In Pitkaranta, serum total cholesterol fluctuated during the study period (1992-2007), whereas in North Karelia cholesterol levels declined consistently. No apparent differences in cholesterol levels by education were observed in Pitkaranta. In North Karelia, cholesterol was lower among subjects in the highest education tertile compared to the lowest education tertile in 1992 and 2002. In Pitkaranta, consumption of fat-containing milk was most strongly associated with cholesterol (beta=0.19, 95% CI 0.10, 0.28) adjusted for sex, age, education and study year. In North Karelia, using butter in cooking (beta=0.09, 95% CI 0.04, 0.15) and using butter on bread (beta=0.09, 95% CI 0.02, 0.15) had a significant positive association with cholesterol. CONCLUSIONS: In the two geographically neighbouring areas, the key foods influencing serum cholesterol levels varied considerably. Assessment and regular monitoring of food habits are essential to plan nutrition education messages that are individually tailored for the target area and time. PMID- 23101908 TI - Visible-light-mediated alpha-arylation of enol acetates using aryl diazonium salts. AB - Visible light mediates efficiently the alpha-arylation of enol acetates by aryl diazonium salts under mild conditions using [Ru(bpy)(3)]Cl(2) as a photoredox catalyst. The broad scope of the reaction toward various diazonium salts and enol acetates was explored. The application of this reaction in the concise synthesis of 2-substituted indoles was demonstrated. PMID- 23101910 TI - Systemic lupus erythematosus associated with sickle-cell disease: a case report and literature review. AB - INTRODUCTION: The occurrence of systemic lupus erythematosus has been only rarely reported in patients with sickle-cell disease. CASE PRESENTATION: We describe the case of a 23-year-old North-African woman with sickle-cell disease and systemic lupus erythematosus, and discuss the pointers to the diagnosis of this combination of conditions and also present a review of literature. The diagnosis of systemic lupus erythematosus was delayed because our patient's symptoms were initially attributed to sickle-cell disease. CONCLUSIONS: Physicians should be alerted to the possible association of sickle-cell disease and systemic lupus erythematosus so as not to delay correct diagnosis and initiation of appropriate treatment. PMID- 23101911 TI - Temperature-dependent Raman investigation of rolled up InGaAs/GaAs microtubes. AB - Large arrays of multifunctional rolled-up semiconductors can be mass-produced with precisely controlled size and composition, making them of great technological interest for micro- and nano-scale device fabrication. The microtube behavior at different temperatures is a key factor towards further engineering their functionality, as well as for characterizing strain, defects, and temperature-dependent properties of the structures. For this purpose, we probe optical phonons of GaAs/InGaAs rolled-up microtubes using Raman spectroscopy on defect-rich (faulty) and defect-free microtubes. The microtubes are fabricated by selectively etching an AlAs sacrificial layer in order to release the strained InGaAs/GaAs bilayer, all grown by molecular beam epitaxy. Pristine microtubes show homogeneity of the GaAs and InGaAs peak positions and intensities along the tube, which indicates a defect-free rolling up process, while for a cone-like microtube, a downward shift of the GaAs LO phonon peak along the cone is observed. Formation of other type of defects, including partially unfolded microtubes, can also be related to a high Raman intensity of the TO phonon in GaAs. We argue that the appearance of the TO phonon mode is a consequence of further relaxation of the selection rules due to the defects on the tubes, which makes this phonon useful for failure detection/prediction in such rolled up systems. In order to systematically characterize the temperature stability of the rolled up microtubes, Raman spectra were acquired as a function of sample temperature up to 300 degrees C. The reversibility of the changes in the Raman spectra of the tubes within this temperature range is demonstrated. PMID- 23101909 TI - Exclusion of aldose reductase as a mediator of ERG deficits in a mouse model of diabetic eye disease. AB - Streptozotocin (STZ)-induced diabetes is associated with reductions in the electrical response of the outer retina and retinal pigment epithelium (RPE) to light. Aldose reductase (AR) is the first enzyme required in the polyol-mediated metabolism of glucose, and AR inhibitors have been shown to improve diabetes induced electroretinogram (ERG) defects. Here, we used control and AR -/- mice to determine if genetic inactivation of this enzyme likewise inhibits retinal electrophysiological defects observed in a mouse model of type 1 diabetes. STZ was used to induce hyperglycemia and type 1 diabetes. Diabetic and age-matched nondiabetic controls of each genotype were maintained for 22 weeks, after which ERGs were used to measure the light-evoked components of the RPE (dc-ERG) and the neural retina (a-wave, b-wave). In comparison to their nondiabetic controls, wildtype (WT) and AR -/- diabetic mice displayed significant decreases in the c wave, fast oscillation, and off response components of the dc-ERG but not in the light peak response. Nondiabetic AR -/- mice displayed larger ERG component amplitudes than did nondiabetic WT mice; however, the amplitude of dc-ERG components in diabetic AR -/- animals were similar to WT diabetics. ERG a-wave amplitudes were not reduced in either diabetic group, but b-wave amplitudes were lower in WT and AR -/-diabetic mice. These findings demonstrate that the light induced responses of the RPE and outer retina are disrupted in diabetic mice, but these defects are not due to photoreceptor dysfunction, nor are they ameliorated by deletion of AR. This latter finding suggests that benefits observed in other studies utilizing pharmacological inhibitors of AR might have been secondary to off-target effects of the drugs. PMID- 23101912 TI - Quality improvement guidelines for pediatric abscess and fluid drainage. AB - Image-guided drainage of abscesses and fluid collections is a valuable tool in the treatment of pediatric patients. It may obviate surgery or optimize the child's clinical condition for subsequent surgery. Compared with adults, several differences exist in terms of etiology, risks (especially radiation exposure), preprocedural imaging and planning, technical considerations, support issues such as sedation, and complications. Knowledge of these differences is important in the planning and treatment of these patients. In addition, a quality improvement plan can be used to assess practice performance. PMID- 23101913 TI - Prostatic arterial supply: anatomic and imaging findings relevant for selective arterial embolization. AB - PURPOSE: To describe the anatomy and imaging findings of the prostatic arteries (PAs) on multirow-detector pelvic computed tomographic (CT) angiography and digital subtraction angiography (DSA) before embolization for symptomatic benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In a retrospective study from May 2010 to June 2011, 75 men (150 pelvic sides) underwent pelvic CT angiography and selective pelvic DSA before PA embolization for BPH. Each pelvic side was evaluated regarding the number of independent PAs and their origin, trajectory, termination, and anastomoses with adjacent arteries. RESULTS: A total of 57% of pelvic sides (n = 86) had only one PA, and 43% (n = 64) had two independent PAs identified (mean PA diameter, 1.6 mm +/- 0.3). PAs originated from the internal pudendal artery in 34.1% of pelvic sides (n = 73), from a common trunk with the superior vesical artery in 20.1% (n = 43), from the anterior common gluteal pudendal trunk in 17.8% (n = 38), from the obturator artery in 12.6% (n = 27), and from a common trunk with rectal branches in 8.4% (n = 18). In 57% of pelvic sides (n = 86), anastomoses to adjacent arteries were documented. There were 30 pelvic sides (20%) with accessory pudendal arteries in close relationship with the PAs. No correlations were found between PA diameter and patient age, prostate volume, or prostate-specific antigen values on multivariate analysis with logistic regression. CONCLUSIONS: PAs have highly variable origins between the left and right sides and between patients, and most frequently arise from the internal pudendal artery. PMID- 23101914 TI - Percutaneous vertebroplasty and kyphoplasty for pathologic vertebral fractures in the Medicare population: safer and less expensive than open surgery. AB - PURPOSE: To compare cost and outcomes of surgical and percutaneous treatments of pathologic vertebral fractures. MATERIALS AND METHODS: Standard Medicare 5% anonymized inpatient files (1999-2009) were retrospectively reviewed. Patients with a diagnosis of vertebral fracture without spinal cord injury and primary or metastatic bony malignancy were divided into percutaneous or surgical groups based on whether they received vertebroplasty/kyphoplasty or surgical treatment. Patients who had no intervention or both interventions were excluded. Cost, length of stay, and type of discharge were examined while controlling for demographic and comorbidity variables. RESULTS: A total of 451 patients were included; 52% received percutaneous treatment and 48% received surgery. Patients treated percutaneously were older (P < .001) and more likely to be female (P = .04). Percutaneous therapy predicted $14,862 less Medicare cost and $13,565 less overall cost (P < .001 for both), and 4.1 fewer inpatient days (P < .001). Patients who underwent surgery had higher odds of death (odds ratio = 3.38, P = .016), discharge to a rehabilitation facility (odds ratio = 3.3, P = .003), and transfer to another inpatient facility (odds ratio = 8.53, P < .001), and lower odds of discharge to home (odds ratio = 0.42, P < .001) and hospice (odds ratio = 0.08, P = .002). CONCLUSIONS: In a Medicare population with bony malignancy and vertebral fractures, percutaneous therapy predicted significantly reduced cost and length of stay versus surgery. Patients who underwent percutaneous therapy were significantly less likely to die, be transferred, or be discharged to rehabilitation facilities, and were more likely to be discharged to home or hospice. PMID- 23101915 TI - Percutaneous treatment of lumbar compression fracture with canal stenosis and neurogenic intermittent claudication: combining kyphoplasty and interspinous spacer. AB - Vertebral compression fractures (VCFs) can cause symptomatic spinal canal stenosis secondary to posterior wall retropulsion. This report describes four patients with VCF and lumbar stenosis secondary to posterior wall retropulsion who were treated with combined kyphoplasty and percutaneous interspinous spacer (IS) placement. Clinical and imaging follow-up ranged from 12-36 months. Outcomes were favorable. Combined kyphoplasty and percutaneous IS implant represents a minimally invasive, safe, and efficient option to treat VCF with symptomatic spinal stenosis. PMID- 23101916 TI - Early outcomes of empiric embolization of tumor-related gastrointestinal hemorrhage in patients with advanced malignancy. AB - PURPOSE: To report short-term results of empiric transcatheter embolization for patients with advanced malignancy and gastrointestinal (GI) hemorrhage directly from a tumor invading the GI tract wall. MATERIALS AND METHODS: Between 2005 and 2011, 37 mesenteric angiograms were obtained in 26 patients with advanced malignancy (20 men, six women; mean age, 56.2 y) with endoscopically confirmed symptomatic GI hemorrhage from a tumor invading the GI tract wall. Angiographic findings and clinical outcomes were retrospectively evaluated. Clinical success was defined as absence of signs and symptoms of hemorrhage for at least 30 day following embolization. RESULTS: Active extravasation was demonstrated in three cases. Angiographic abnormalities related to a GI tract tumor were identified on 35 of 37 angiograms, including tumor neovascularity (n = 21), tumor enhancement (n = 24), and luminal irregularity (n = 5). In the absence of active extravasation, empiric embolization with particles and/or coils was performed in 25 procedures. Cessation of hemorrhage (ie, clinical success) occurred more frequently when empiric embolization was performed (17 of 25 procedures; 68%) than when embolization was not performed (two of nine; 22%; P = .03). Empiric embolization resulted in clinical success in 10 of 11 patients with acute GI bleeding (91%), compared with seven of 14 patients (50%) with chronic GI bleeding (P = .04). No ischemic complications were encountered. CONCLUSIONS: In patients with advanced malignancy, in the absence of active extravasation, empiric transcatheter arterial embolization for treatment of GI hemorrhage from a direct tumor source demonstrated a 68% short-term success rate, without any ischemic complications. PMID- 23101917 TI - Carbon dioxide (CO2) vs iodinated contrast digital subtraction angiography during balloon-occluded retrograde transvenous obliteration (BRTO) using foam sclerosant for gastric varices. AB - PURPOSE: To compare the visualization of the target gastric varices (GV) on balloon-occluded retrograde transvenous venography (BRTV) using iodinated contrast material vs carbon dioxide (CO(2)) in preparation for subsequent balloon occluded retrograde transvenous obliteration (BRTO) using foam sclerotherapy. MATERIALS AND METHODS: In 16 consecutive patients with nonruptured GV, BRTV was performed first using iodinated contrast material and then with CO(2). BRTV was repeated whenever there were changes in the catheter or patient position or when coil embolization of collaterals was needed. Each visualization grade of GV (grade 1 = GV only; grade 2 = GV > collaterals; 3 = GV < collaterals; grades 4-5 = collaterals only) was determined by two observers in consensus. During foam BRTO, the GV visualization grade was recorded again and confirmed by C-arm computed tomography (CT). RESULTS: In 38 pairs of BRTV, GV grades were significantly (P < .0001) lower (ie, favoring BRTO) on CO(2) BRTV (mean +/- standard deviation, 1.8 +/- 0.8) than on iodine BRTV (3.4 +/- 0.8). GV grades on foam BRTO (1.4 +/- 0.7) were similar to the grades obtained on the most recent CO(2) BRTV (1.3 +/- 0.5) but were significantly smaller (P < .0001) than on iodinated BRTV (3.1 +/- 0.9). GV were opacified by foam on initial C-arm CT in 14 patients (87.5%), and complete thrombosis of GV was obtained without any complication in all 16 patients (100%). CO(2) reached the GV even when iodinated contrast material could not (grade 4) in seven of our 16 patients (43.8%), leading to successful BRTO. CONCLUSIONS: CO(2) BRTV visualized GV better than did iodine BRTV and changed the management of more than 40% of patients by enabling successful foam BRTO in patients in which conventional liquid BRTO could not be performed. PMID- 23101918 TI - Ultrasound-accelerated vs standard catheter-directed thrombolysis--a comparative study in patients with iliofemoral deep vein thrombosis. AB - PURPOSE: To compare the thrombolytic efficacy and safety of standard catheter directed thrombolysis (CDT) and ultrasound (US)-accelerated thrombolysis (UAT) for the treatment of iliofemoral deep vein thrombosis (DVT). MATERIALS AND METHODS: All medical records of patients who underwent CDT or UAT for DVT between June 2004 and October 2011 at a single tertiary care center were reviewed. Target vein patency was graded according to a reporting standard by an independent interventional radiologist. RESULTS: CDT was performed in 19 patients and UAT in 64 patients. The baseline parameters and DVT characteristics, including the duration of symptoms, the location, and the extension did not differ significantly between groups. Both treatment modalities were associated with a similar substantial resolution of thrombus load (CDT = 89%; interquartile range [IQR], 70%-100%; UAT = 82%; IQR, 55%-92% (P = .560). No significant differences in the lytic drug infusion rates, the total lytic doses, the total infusion time, and the use of adjunctive procedures were observed between groups. Major and minor bleeding complications were observed in 8.4% and 4.8% of the patients, with no difference between the treatment groups (P = .709 and P = .918, respectively). During a median follow-up of 35 months (20-55 months), three deaths and 16 cases of repeated thrombosis were observed. The estimated mean event-free survival time was longer after CDT (69 mo) compared with UAT (33 mo) (log-rank test P = .310). CONCLUSIONS: The present study failed to prove any substantial clinical benefit provided by UAT with regard to effectiveness or safety compared with standard CDT. Given the added costs of the US delivery device, prospective randomized data are needed to justify its widespread use for DVT treatment. PMID- 23101919 TI - Correlation of the diameter of the left common iliac vein with the risk of lower extremity deep venous thrombosis. AB - PURPOSE: Compression of the left common iliac vein (CIV; LCIV) is a known risk factor for lower-extremity deep vein thrombosis (DVT). This study was performed to model the probability of DVT based on LCIV diameter and apply this to a quantitative DVT risk factor scoring system. MATERIALS AND METHODS: Medical records were used to identify female patients younger than 45 years of age who were diagnosed with lower-extremity DVT (n = 21) and age-matched control subjects (n = 26) who presented to the emergency department with abdominal pain. Minimum CIV diameters were measured on computed tomography. Based on published reporting standards, 13 risk factors were scored for patients diagnosed with left-sided DVT and for control subjects. The association between vein diameter and DVT was examined by Mann-Whitney test. Odds of DVT based on vein diameter was assessed by logistic regression. RESULTS: Mean minimum LCIV diameters were 4.0 mm for patients with DVT and 6.5 mm for patients without DVT (P = .001). The odds of left DVT increased by a factor of 1.68 for each millimeter decrease in LCIV diameter (odds ratio = 1.68; P = .006; 95% confidence interval, 1.16-2.43). As the risk factor score increased, the relationship between diameter and risk for DVT became stronger; identical LCIV diameters were associated wtih a higher probability of developing DVT if the risk factor score was higher. CONCLUSIONS: Stenosis of the LCIV was found to be a strong independent risk factor for development of DVT. Moreover, each millimeter decrease in CIV diameter increased the odds of DVT by a factor of 1.68. PMID- 23101920 TI - Stent placement for treatment of long segment (>=80 mm) carotid artery stenosis in patients with Takayasu disease. AB - PURPOSE: To evaluate the effectiveness and safety of carotid artery stent (CAS) placement for treatment of long segment stenosis in patients with Takayasu arteritis. MATERIALS AND METHODS: Between January 2002 and February 2012, all patients with Takayasu arteritis found to have long segment (>=80 mm) carotid artery stenoses at a single institution were retrospectively analyzed. Five patients treated by CAS placement with either long or multiple self-expandable stents were included. All patients had focal neurologic symptoms, including three strokes and two transient ischemic attacks (TIAs). Six self-expanding stents were used in five patients. The mean follow-up period was 19.2 months (range, 6-30 mo); all patients had clinical evaluation, laboratory examination, and vascular imaging follow-up. RESULTS: Improvement in clinical symptoms was shown after successful angioplasty. There were no perioperative or in-hospital deaths. Four patients exhibited persistent relief, and repeated angiography or computed tomography (CT) angiography showed normal flow. One patient stopped taking her medications after CAS placement and became symptomatic 8 months later as a result of a severe in-stent stenosis. CONCLUSIONS: CAS placement was shown to be a feasible option for treating long segment (>=80 mm) stenosis of carotid arteries in patients with Takayasu arteritis with encouraging results. PMID- 23101921 TI - Predictive factors for response of peripheral arteriovenous malformations to embolization therapy: analysis of clinical data and imaging findings. AB - PURPOSE: To find a significant predictive factor for the efficacy of endovascular treatment of peripheral arteriovenous malformations (AVMs). MATERIALS AND METHODS: One hundred seventy-six patients (73 male patients and 103 female patients; mean age, 29.4 y) who underwent treatment for AVMs in the body or extremities were included. Per Schobinger classification, lesions in 31 patients (18%) were stage II, those in 136 (77%) were stage III, and those in nine (5%) were stage IV. AVMs were located in the extremities in 130 patients (74%) and in the trunk in 46 patients (26%). AVMs were angiographically classified as type I (n = 1), type II (n = 36), type IIIa (n = 6), type IIIb (n = 9 1), or complex type (n = 42). Demographic factors, clinical data, and imaging data were analyzed to determine a statistically significant relationship with overall clinical outcomes. RESULTS: Overall, 68 patients (39%) were cured, 91 patients (52%) showed a partial response, nine patients (5%) showed no response, treatment failed in seven patients (4%), and treatment aggravated the condition in one patient (1%). The overall complication rate was 45% (79 of 176 patients). Minor complications developed in 62 patients (35%) and major complications developed in 17 (10%). Statistically, the extent of AVMs (odds ratio, 0.199) and angiographic classification (odds ratio, 0.162) were significant predictive factors for overall clinical outcome. CONCLUSIONS: Endovascular treatment of peripheral AVMs, planned with consideration of anatomic extent and angiographic subtypes, is likely to yield good clinical results with low complication rates. PMID- 23101922 TI - Effects of antiangiogenic therapy. PMID- 23101923 TI - Back again to vasopressin? PMID- 23101924 TI - Basic study of a mixture of N-butyl cyanoacrylate, ethanol, and lipiodol as a new embolic material. AB - PURPOSE: To clarify the configuration change of N-butyl cyanoacrylate (NBCA) polymerization with increasing proportion of ethanol, the properties of a mixture of NBCA with lipiodol plus ethanol (NLE), and the feasibility of use of NLE for aneurysm packing in a swine model. MATERIALS AND METHODS: The polymerization configuration of NLE was explored using ratios of 1-4 parts NBCA and 1-3 parts ethanol per 1 part of lipiodol; a 1:1 ratio of NBCA to lipiodol (NLE110) was used as a control. The distance that NLE migrated into saline flowing in a tube was measured. A carotid artery aneurysm was created in each of 18 swine. Aneurysmal packing with three configurations--NLE110, NLE at a ratio of 1:1:2 (NLE112), and NLE at a ratio of 1:1:3 (NLE113)--was attempted in six swine for each configuration. RESULTS: Regardless of NBCA composition, medium-sized droplets, a single large droplet, and a noodle-shaped extrusion were observed in NLE with lipiodol versus ethanol ratios of 1:1, 1:2, and 1:3. NLE110 migrated as viscous fluid to 190 cm from the injection site, whereas NLE112 migrated for 81 cm +/- 11 and NLE113 migrated for 74 cm +/- 9. Instant outflow of NLE110 from the six aneurysms caused occlusion of the parent artery, with adhesion to the microcatheter. Packing was achieved with minimal adhesion for all six of the aneurysms packed with NLE112 or with NLE113. CONCLUSIONS: With high ratios of ethanol, the NLE polymerization configuration acquired solid-like properties with potent occlusive ability and negligible adhesion to the microcatheter, suggesting its feasibility for packing of aneurysms. PMID- 23101925 TI - Radiofrequency coil for the creation of large ablations: ex vivo and in vivo testing. AB - PURPOSE: Various radiofrequency (RF) ablation electrode designs have been developed to increase ablation volume. Multiple heating cycles and electrode positions are often required, thereby increasing treatment time. The objective of this study was to evaluate the performance of a high-frequency monopolar induction coil designed to produce large thermal lesions (>3 cm) with a single electrode insertion in a treatment time of less than 10 minutes. MATERIALS AND METHODS: A monopolar nitinol interstitial coil operated at 27.12 MHz and 200 W was evaluated. Ex vivo performance was tested in excised bovine liver (n = 22). In vivo testing (n = 10) was conducted in livers of seven Yorkshire pigs. Visual inspection, contrast-enhanced computed tomography (CT), and pathologic evaluation of ablation zones were performed. RESULTS: Average ablation volumes in ex vivo and in vivo tests were 60.5 cm(3) +/- 14.1 (5.9 * 4.4 * 4.4 cm) and 57.1cm(3) +/- 13.8 (6.1 * 4.5 * 4.1cm), with average treatment times of 9.0 minutes +/- 3.0 and 8.4 minutes +/- 2.7, respectively. Contrast-enhanced CT ablation volume measurements corresponded with findings of gross inspection. Pathologic analysis showed morphologic and enzymatic changes suggestive of tissue death within the ablation zones. CONCLUSIONS: The RF ablation coil device successfully produced large, uniform ablation volumes in ex vivo and in vivo settings in treatment times of less than 10 minutes. Ex vivo and in vivo lesion sizes were not significantly different (P = .53), suggesting that the heating efficiency of this higher-frequency coil device may help to minimize the heat-sink effect of perfusion. PMID- 23101926 TI - A novel in vivo rabbit model of abdominal aortic aneurysm induced by periarterial incubation of papain. AB - PURPOSE: The objective of this study was to determine the possibility of creating a novel animal model of abdominal aortic aneurysm (AAA) in rabbits by the periarterial application of papain. MATERIALS AND METHODS: Twelve New Zealand white rabbits were randomized into two groups: (1) the papain group, which received 2mg of papain (n = 8) and (2) the control group, which received physiologic saline solution (n = 4). A 1-cm aortic segment proximal to the bifurcation was isolated, and its adventitia was incubated with papain for 20 minutes. The rabbits underwent intravenous digital subtraction angiography (IVDSA) 5 and 21 days after the operation. The animals were then humanely killed for histomorphometric and immunohistochemical studies. RESULTS: All animals in the papain group developed AAA, with an average aneurysm diameter of 4.0 +/- 0.6 and 4.1 +/- 0.4 mm on days 5 and 21, respectively. No aneurysms were seen in the control group. On day 5, the papain-incubated aortas exhibited thinned and disorganized aortic walls, with decreased smooth muscle cells (SMCs) and fragmented and almost nonexistent elastic lamella. Media thickening, intimal hyperplasia, and smooth muscle cell regeneration were obvious on day 21. Immunostaining of matrix metalloproteinase (MMP)-9 and RAM11 showed strong expression in the papain group. On the contrary, the control group did not present histologic alterations and showed almost no expression of MMP-9 and RAM11. CONCLUSIONS: A novel in vivo rabbit model of AAA can be induced through periarterial application of papain for 20 minutes. This model is similar to an elastase-induced aneurysm model and could be useful to clarify AAA pathogenesis and endovascular treatment intervention. PMID- 23101927 TI - Real-time MR imaging guidance for percutaneous core biopsy of US- and CT-negative lesion. AB - Biopsies traditionally are performed under ultrasound (US), computed tomography (CT), or fluoroscopic guidance. In situations in which lesions are difficult to visualize with US or CT guidance, magnetic resonance (MR) imaging often can provide better imaging results. The authors describe a case in which a recurrent calf mass not well visualized under fluoroscopy, CT, or US was identified on MR imaging. In the absence of real-time needle visualization, percutaneous interventions under MR guidance have been limited by prohibitively long imaging times. A novel guidance system providing real-time MR guidance of needle position was used to procure a core biopsy specimen of the lesion. PMID- 23101928 TI - Spinal cord needle tract following epidural steroid injection. PMID- 23101929 TI - Endoleak mimic on CT angiography following endograft repair of abdominal aortic aneurysms with Endologix stent-grafts. PMID- 23101931 TI - Toll-like receptor-based immuno-analysis of pathogenic microorganisms. AB - In this study, a novel mammalian cell receptor-based immuno-analytical method was developed for the detection of food-poisoning microorganisms by employing toll like receptors (TLRs) as sensing elements. Upon infection with bacterium, the host cells respond by expressing TLRs, particularly TLR1, TLR2, and TLR4, on the outer membrane surfaces. To demonstrate the potential of using this method for detection of foodborne bacteria, we initially selected two model sensing systems, expression of TLR1 on a cell line, A549, for Escherichia coli and TLR2 on a cell line, RAW264.7, for Shigella sonnei (S. sonnei). Each TLR was detected using antibodies specific to the respective marker. We also found that the addition of immunoassay for the pathogen captured by the TLRs on the mammalian cells significantly enhanced the detection capability. A dual-analytical system for S. sonnei was constructed and successfully detected an extremely low number (about 3.2 CFU per well) of the pathogenic bacterium 5.1 h after infection. This detection time was 2.5 h earlier than the time required for detection using the conventional immunoassay. To endow the specificity of detection, the target bacterium was immuno-magnetically concentrated by a factor of 50 prior to infection. This further shortened the response to approximately 3.4 h, which was less than half of the time needed when the conventional method was used. Such enhanced performance could basically result from synergistic effects of bacterial dose increase and subsequent autocrine signaling on TLRs' up-regulation upon infection with live bacterium. This TLR-based immuno-sensing approach may also be expanded to monitor infection of the body, provided scanning of the signal is feasible. PMID- 23101930 TI - Surface-grafted polysarcosine as a peptoid antifouling polymer brush. AB - Poly(N-substituted glycine) "peptoids" are a class of peptidomimetic molecules receiving significant interest as engineered biomolecules. Sarcosine (i.e., poly(N-methyl glycine)) has the simplest side chain chemical structure of this family. In this Article, we demonstrate that surface-grafted polysarcosine (PSAR) brushes exhibit excellent resistance to nonspecific protein adsorption and cell attachment. Polysarcosine was coupled to a mussel adhesive protein-inspired DOPA Lys pentapeptide, which enabled solution grafting and control of the surface chain density of the PSAR brushes. Protein adsorption was found to decrease monotonically with increasing grafted chain densities, and protein adsorption could be completely inhibited above certain critical chain densities specific to different polysarcosine chain lengths. The dependence of protein adsorption on chain length and density was also investigated by a molecular theory. PSAR brushes at high chain length and density were shown to resist fibroblast cell attachment over a 7 week period, as well as resist the attachment of some clinically relevant bacterial strains. The excellent antifouling performance of PSAR may be related to the highly hydrophilic character of polysarcosine, which was evident from high-pressure liquid chromatography measurements of polysarcosine and water contact angle measurements of the PSAR brushes. Peptoids have been shown to resist proteolytic degradation, and polysarcosine could be produced in large quantities by N-carboxy anhydride polymerization. In summary, surface-grafted polysarcosine peptoid brushes hold great promise for antifouling applications. PMID- 23101932 TI - Facebook and romantic relationships: intimacy and couple satisfaction associated with online social network use. AB - Online social networks, such as Facebook, have gained immense popularity and potentially affect the way people build and maintain interpersonal relationships. The present study sought to examine time spent on online social networks, as it relates to intimacy and relationship satisfaction experienced in romantic relationships. Results did not find relationships between an individual's usage of online social networks and his/her perception of relationship satisfaction and intimacy. However, the study found a negative relationship between intimacy and the perception of a romantic partner's use of online social networks. This finding may allude to an attributional bias in which individuals are more likely to perceive a partner's usage as negative compared to their own usage. Additionally, it was found that intimacy mediates the relationship between online social network usage and overall relationship satisfaction, which suggests that the level of intimacy experienced in a relationship may serve as a buffer that protects the overall level of satisfaction. PMID- 23101933 TI - Prevalence of uncontrolled risk factors for cardiovascular disease: United States, 1999-2010. AB - Heart disease is the leading cause of death in the United States (1). High blood pressure, high cholesterol, and smoking are all risk factors that could lead to cardiovascular disease (CVD) and stroke. The recently announced Million Hearts Initiative is aimed at preventing 1 million heart attacks and strokes over the next 5 years (2-4). This report expands on results previously published (2) by presenting the most recent prevalence estimates and trends of uncontrolled high blood pressure, uncontrolled high levels of low-density lipoproteins cholesterol (LDL-C), and current cigarette smoking among adults aged 20 and over. PMID- 23101934 TI - The effect of oxygen heteroatoms on the single molecule conductance of saturated chains. AB - Single molecule conductance measurements on alkanedithiols and alkoxydithiols (dithiolated oligoethers) were performed using the STM-controlled break junction method in order to ascertain how the oxygen heteroatoms in saturated linear chains impact the molecular conductance. The experimental results show that the difference in conductance increases with chain length, over the range studied. Comparisons with electronic structure calculations and previous work on alkanes indicate that the conductance of the oligoethers is lower than that of alkane chains with the same length. Electronic structure calculations allow the difference in the conductance of these two families of molecules to be traced to differences in the spatial distribution of the molecular orbitals that contribute most to the conductance. A pathway analysis of the electronic coupling through the chain is used to explain how the difference in conductance between the alkane and oligoether molecules depends on the chain length. PMID- 23101936 TI - Physicochemical characterization and in vivo evaluation of solid self nanoemulsifying drug delivery system for oral administration of docetaxel. AB - To formulate a self-nanoemulsifying drug delivery system (SNEDDS) for the oral administration of docetaxel as an alternative to commercial docetaxel-loaded injectable products, it was prepared by spray-drying an aqueous solution containing liquid SNEDDS and colloidal silica. Its physicochemical properties and oral bioavailability were investigated compared to a clear docetaxel solution administered intravenously or orally to rats. In the docetaxel-loaded solid SNEDDS prepared with colloidal silica, the liquid SNEDDS composed of Capryol 90, Cremophore EL and Transcutol HP (45/35/20, volume ratio) was absorbed inside the pores of carriers, and docetaxel was present in a changed amorphous state. The solid SNEDDS with 3.3% (w/v) docetaxel produced nanoemulsions, and showed about 12.5% absolute bioavailability in rats. Thus, this solid SNEDDS may be a potential candidate for oral pharmaceutical product with improved oral bioavailability of docetaxel. PMID- 23101935 TI - Human DNA polymerase beta, but not lambda, can bypass a 2-deoxyribonolactone lesion together with proliferating cell nuclear antigen. AB - The C1'-oxidized lesion 2-deoxyribonolactone (L) is induced by free radical attack of DNA. This lesion is mutagenic, inhibits base excision repair, and can lead to strand scission. In double-stranded DNA L is repaired by long-patch base excision repair, but it induces replication fork arrest in a single-strand template. Translesion synthesis requires a specialized DNA polymerase (Pol). In E. coli, Pol V is responsible for bypassing L, whereas in yeast Pol zeta has been shown to be required for efficient bypass. Very little is known about the identity of human Pols capable of bypassing L. For instance, the activity of family X enzymes has never been investigated. We examined the ability of different family X Pols: Pols beta, lambda, and TdT from human cells and Pol IV from S. cerevisiae to act on DNA containing an isolated 2-deoxyribonolactone, as well as when the lesion comprises the 5'-component of a tandem lesion. We show that Pol beta, but not Pol lambda, can bypass a single L lesion in the template, and its activity is increased by the auxiliary protein proliferating cell nuclear antigen (PCNA), whereas both enzymes were completely blocked by a tandem lesion. Yeast Pol IV was able to bypass the single L and the tandem lesion but with little nucleotide insertion specificity. Finally, L did not affect the polymerization activity of the template-independent enzyme TdT. PMID- 23101938 TI - Adjunctive use of rifampicin pre-operation can reduce infections in orthopaedic surgery? PMID- 23101937 TI - Designing two self-assembly mechanisms into one viral capsid protein. AB - ELP-CP, a structural fusion protein of the thermally responsive elastin-like polypeptide (ELP) and a viral capsid protein (CP), was designed, and its assembly properties were investigated. Interestingly, this protein-based block copolymer could be self-assembled via two mechanisms into two different, well-defined nanocapsules: (1) pH-induced assembly yielded 28 nm virus-like particles, and (2) ELP-induced assembly yielded 18 nm virus-like particles. The latter were a result of the emergent properties of the fusion protein. This work shows the feasibility of creating a self-assembly system with new properties by combining two structural protein elements. PMID- 23101939 TI - Active bleeding from a periampullary duodenal diverticulum that was difficult to diagnose but successfully treated using hemostatic forceps: a case report. AB - INTRODUCTION: Although duodenal diverticula are common, periampullary duodenal diverticula are rare. Periampullary duodenal diverticula are usually asymptomatic and may be difficult to diagnose and treat. However, they may present with massive bleeding, requiring prompt diagnosis. CASE PRESENTATION: We report the case of a 71-year-old Asian woman with bleeding from a periampullary duodenal diverticulum. She presented with severe anemia and tarry stools. Two examinations using a forward-viewing endoscope did not identify the source of the bleeding. However, examination using a side-viewing endoscope found an exposed bleeding vessel overlying the bile duct within a periampullary diverticulum of the descending part of the duodenum. The bleeding was successfully controlled by using hemostatic forceps. CONCLUSIONS: Bleeding periampullary duodenal diverticula are rare, and a bleeding point in the mucosa overlying the bile duct within a large periampullary duodenal diverticulum is very rare. Identification of a bleeding point within a duodenal diverticulum often requires repeated examination and may require the use of a side-viewing endoscope. Use of hemostatic forceps to control bleeding from a periampullary duodenal diverticulum is very rare but, for bleeding lesions overlying the bile duct within a periampullary duodenal diverticulum, is the best way to prevent obstructive jaundice. PMID- 23101940 TI - Highly ordered Fe-Au heterostructured nanorod arrays and their exceptional near infrared plasmonic signature. AB - The potential of highly ordered array nanostructures in sensing applications is well recognized, particularly with the ability to define the structural composition and arrangement of the individual nanorods accurately. The use of heterogeneous nanostructures generates an additional degree of freedom, which can be used to tailor the optical response of such arrays. In this article, we report on the fabrication and characterization of well-defined Fe-Au bisegmented nanorod arrays in a repeating hexagonal arrangement. Through an asymmetric etching method, free-standing Fe-Au nanorod arrays on a gold-coated substrate were produced with an inter-rod spacing of 26 nm. This separation distance renders the array capable of sustaining resonant electromagnetic wave coupling between individual rods. Owing to this coupling, the subwavelength arrangement, and the structural heterogeneity, the nanorod arrays exhibit unique plasmonic responses in the near-infrared (NIR) range. Enhanced sensitivity in this spectral region has not been identified for gold-only nanorods of equivalent dimensions. The NIR response offers confirmation of the potential of these highly ordered, high density arrays for biomedical relevant applications, such as subcutaneous spectroscopy and biosensing. PMID- 23101941 TI - Unbinding pathways of GW4064 from human farnesoid X receptor as revealed by molecular dynamics simulations. AB - Farnesoid X receptor (FXR, NR1H4) is a member of a nuclear receptor superfamily, which plays important roles in bile acid homeostasis, lipoprotein and glucose metabolism, and hepatic regeneration. GW4064 is a potent and selective FXR agonist and has become a tool compound to probe the physiological functions of FXR. Until now, the mechanism of GW4064 entering and leaving the FXR pocket is still poorly understood. Here, we report a computational study of GW4064 unbinding pathways from FXR by using several molecular dynamics (MD) simulation techniques. Based on the crystal structure of FXR in complex with GW4064, conventional MD was first used to refine the binding and check the stability of GW4064 in the FXR pocket. Random acceleration MD simulations were then performed to explore the possible unbinding pathways of GW4064 from FXR. Four main pathway clusters were found, among which three subpathways, namely Paths 2A, 2B, and 1B, were observed most frequently. Multiple steered MD simulations were further employed to estimate the maximum rupture force and the sum of the forces and to characterize the intermediate states of the ligand unbinding process. By comparing the average force profiles and structural changes, Paths 2A and 2B were identified to be the most favorable unbinding pathways. The former is located between the H1-H2 loop and the H5-H6 loop, and the latter is located in the cleft formed by the H5-H6 loop, H6, and H7. Moreover, the residues lining the pathways were analyzed for their roles in ligand unbinding. Based on our results, the possible structural modification strategies on GW4064 were also proposed. PMID- 23101943 TI - Multiscale model to investigate the effect of graphene on the fracture characteristics of graphene/polymer nanocomposites. AB - In this theoretical research work, the fracture characteristics of graphene modified polymer nanocomposites were studied. A three-dimensional representative volume element-based multiscale model was developed in a finite element environment. Graphene sheets were modeled in an atomistic state, whereas the polymer matrix was modeled as a continuum. Van der Waals interactions between the matrix and graphene sheets were simulated employing truss elements. Fracture characteristics of graphene/polymer nanocomposites were investigated in conjunction with the virtual crack closure technique. The results demonstrate that fracture characteristics in terms of the strain energy release rate were affected for a crack lying in a polymer reinforced with graphene. A shielding effect from the crack driving forces is considered to be the reason for enhanced fracture resistance in graphene-modified polymer nanocomposites. PMID- 23101942 TI - Trends in educational inequalities in old age mortality in Norway 1961-2009: a prospective register based population study. AB - BACKGROUND: The vast majority of deaths occur in older adults. Paradoxically, knowledge on long-term trends in mortality inequalities among the aged, and particularly for those aged 80 years and over, is sparse. The historical trends in size and impact of socioeconomic inequalities on old age mortality are important to monitor because they may give an indication on future burden of inequalities. We investigated trends in absolute and relative educational inequalities in old age mortality in Norway between 1961 and 2009. METHODS: We did a register-based population study covering the entire Norwegian population aged 65-94 in the years 1961-2009 (1,534,513 deaths and 29,312,351 person years at risk). By examining 1-year mortality rates by gender, age and educational level we estimated trends in mortality rate ratios and rate differences. RESULTS: On average, age-standardised absolute inequalities increased by 0.17 deaths per 1000 person-years per year in men (P<0.001), and declined by 0.07 deaths per 1000 person-years per year in women (P<0.001). Trends in rate differences were largest in men aged 75-84 years, but differed in direction by age group in women. The corresponding mean increase in age-standardised relative inequalities was 0.4% and 0.1% per year in men and women, respectively (P<0.001). Trends in rate ratios were largest in the youngest age groups for both genders and negligible among women aged 85-94 years. CONCLUSIONS: While relative educational inequalities in old age mortality increased for both genders, absolute educational inequalities increased only temporarily in men and changed little among women. Our study show the importance of including absolute measures in inequality research in order to present a more complete picture of the burden of inequalities to policy makers. As even in older ages, inequalities represent an unexploited potential to public health, old age inequalities will become increasingly important as many countries are facing aging populations. PMID- 23101944 TI - Improvement of sagittal balance and lumbar lordosis following less invasive adult spinal deformity surgery with expandable cages and percutaneous instrumentation. AB - OBJECT: The treatment of adult spinal deformity (ASD) remains a challenge for the spine surgeon. While minimally invasive surgery (MIS) has many favorable attributes that would be of great benefit for the ASD population, improvements in lordosis and sagittal balance have remained elusive in cases involving the MIS approach. This report describes the evolution of an MIS method for treating ASD with attention to sagittal correction. METHODS: Over an 18-month period 25 patients with thoracolumbar scoliosis were treated surgically. The mean patient age was 72 years, and 68% of the population was female. Patients were treated with multilevel facet osteotomies and interbody fusion in which expandable cages (mean 3.2 levels) were placed and percutaneous screw fixation (mean 5.3 levels) was performed. Seven patients underwent supplemental percutaneous iliac fixation. RESULTS: All patients underwent MIS without conversion to a traditional open procedure. The mean operative time was 273 mins and the mean blood loss was 416 ml. There were no intraoperative complications. The Cobb angle over the scoliotic deformity improved from a mean of 29.2 degrees to that of 9.0 degrees (p < 0.001). Lumbar lordosis between L-1 and S-1 improved from a mean of 27.8 degrees to one of 42.6 degrees (p < 0.001). Sagittal vertical axis improved from 7.4 cm to 4.3 cm (p = 0.001). Numeric pain scale scores improved as well, an average of 3.3 and 4.2 for the leg and back, respectively. A mean improvement of 20.8 points on the Oswestry Disability Index was seen at 12 months. Complications included: two cases requiring hardware repositioning, one case of screw pullout, one asymptomatic pedicle screw breach, prolonged hospitalization from constipation, and one acute coronary syndrome developing 3 days after surgery without myocardial damage. CONCLUSIONS: An expanding body of evidence suggests that sagittal balance remains a keystone for good outcomes after ASD surgery. Minimally invasive surgery that involves a combination of osteotomies, interbody height restoration, and advanced fixation techniques may achieve this goal in patients with less severe deformities. While feasibility will have to be proven with larger series and improved surgical methods, the present technique holds promise as a means of reducing the significant morbidity associated with surgery in the ASD population. PMID- 23101946 TI - Delivering a third course of radiation to spine metastases using image-guided, intensity-modulated radiation therapy. AB - OBJECT: The objective of this study was to investigate the feasibility and safety of delivering a third course of radiation to patients with multiply recurrent metastatic disease to the spine. METHODS: Between 2009 and 2011, 10 patients received a third course of radiation to spinal metastases at Memorial Sloan Kettering Cancer Center using image-guided intensity-modulated radiation therapy (IMRT). Patient and tumor characteristics, dosimetry details, and outcomes were obtained using retrospective chart review. Spinal imaging was performed prior to treatment and at regular follow-up intervals. The cumulative biologically effective dose (BED) to the spinal cord and cauda equina was calculated and was normalized to 2 Gy equivalents (Gy(2/2)). Toxicity and local control were assessed. RESULTS: The median time between the first and second courses of radiation was 18.5 months and the median time between the second and third courses was 11.5 months. The median follow-up from the third course of radiation was 12 months and the median overall survival was 13 months. Pain or neurological symptoms were improved in 80% of patients. The median spinal cord maximum dose normalized BED (nBED) for the whole cohort was 70.73 Gy(2/2) (range 51.9-101.7 Gy(2/2)). The median dose to 5% of the spinal cord D(05) nBED for the entire cohort was 59.4 Gy(2/2). Acute toxicity was most commonly fatigue and dermatitis, with 1 patient experiencing Grade 3 fatigue and 1 patient Grade 3 dermatitis. Late toxicity was limited to 2 cases of Grade 1 dysphagia. There was 1 case of Grade 1 neuropathy and 1 case of Grade 2 neuropathy. The crude rate of local control was 80% with 1 in-field failure and 1 marginal failure. CONCLUSIONS: In this cohort of patients, a third course of IMRT to the spine was well tolerated with no significant late toxicities. Used as salvage therapy for select patients, a third course of radiation is a safe and effective treatment strategy. PMID- 23101947 TI - Comparison of a novel pedicle subtraction osteotomy model using the traditional American Society of Testing and Materials standard for spinal biomechanics fatigue testing [RETRACTED]. AB - OBJECT: There is currently an internationally recognized standard (F1717) provided by the American Society of Testing and Materials (ASTM) for fatigue testing of spinal fixation constructs, assuming relatively straight posterior rods between 2 vertebral segments. However, there is currently no standard that effectively describes the changes in forces and moments for procedures that induce more drastic curvatures, such as pedicle subtraction osteotomies (PSOs). In this study, the author proposes a modified version of the ASTM F1717 standard to compensate for changes in loading conditions for PSO constructs. METHODS: Twelve specimens were divided into 2 groups: 6 modeled after the original ASTM standard and 6 after the modified version. Three specimens each from the 2 groups had rods contoured to corresponding PSO angles of 20 degrees and 60 degrees , respectively. Specimens were cycled at 4 Hz at a 400 N/40 N or 700 N/70 N load ratio until failure was observed or run-out (testing cycle end point) was reached at 2,000,000 cycles. Cox proportional hazards regression was used to analyze the effect of rod curvature on the fatigue strength of the 2 different models. RESULTS: Results indicated that contouring rods from a PSO angle of 20 degrees to 60 degrees significantly increased the fatigue life of the screw-rod construct (hazard ratio [HR] 1.57, p = 0.0144) for the original model, but had the opposite effect of decreasing the fatigue life for the modified model (HR 0.64, p = 0.0144). CONCLUSIONS: Because there is extensive data showing that contouring rods to more extreme angles significantly lowers their fatigue life, the modified ASTM model may be more accurate for simulating constructs that assume insignificant rod bending. PMID- 23101948 TI - Editorial: minimally invasive spinal deformity surgery. PMID- 23101949 TI - Improvement in sensory function via granulocyte-macrophage colony-stimulating factor in rat spinal cord injury models. AB - OBJECT: The aim in this study was to determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF) leads to sensory improvement in rat spinal cord injury (SCI) models. METHODS: Thirty male Sprague-Dawley rats were included in this study: 10 in the sham group (laminectomy alone without SCI), 10 in the SCI group (SCI treated with phosphate-buffered saline), and 10 in the GM-CSF treatment group (SCI treated with GM-CSF). A locomotor function test and pain sensitivity test were conducted weekly for 9 weeks after SCI or sham injury. Spinal tissue samples from all rats were immunohistochemically examined for the expression of calcitonin gene-related peptide (CGRP) and abnormal sprouting at Week 9 post-SCI. RESULTS: Granulocyte-macrophage colony-stimulating factor treatment improves functional recovery after SCI. In the tactile withdrawal threshold and frequency of the hindlimb paw, the GM-CSF group always responded with a statistically significant lower threshold than the SCI group 9 weeks after SCI (p < 0.05). The response of the forelimb and hindlimb paws to cold in the GM CSF group always reflected a statistically significant lower threshold than in the SCI group 9 weeks after injury (p < 0.05). Decreased CGRP expression, observed by density and distribution area, was noted in the GM-CSF group (optical density 113.5 +/- 20.4) compared with the SCI group (optical density 143.1 +/- 18.7; p < 0.05). CONCLUSIONS: Treatment with GM-CSF results in functional recovery, improving tactile and cold sense recovery in a rat SCI model. Granulocyte-macrophage colony-stimulating factor also minimizes abnormal sprouting of sensory nerves after SCI. PMID- 23101950 TI - Biosimilar insulins: how will this story evolve? PMID- 23101951 TI - Rate of hypoglycemia in insulin-treated patients with type 2 diabetes can be predicted from glycemic variability data. AB - BACKGROUND: We set out to study the relationship between different measures of glycemic variability and the rate of hypoglycemia in patients with type 2 diabetes. SUBJECTS AND METHODS: Data were pooled from three 24-week insulin trials including patients on twice-daily (BID) insulin lispro mix 75/25 (75% insulin lispro protamine suspension, 25% insulin lispro) (n=805), daily (QD) insulin glargine (n=1,019), insulin lispro protamine suspension (n=353) (QD or BID), and insulin detemir (n=166) (QD or BID), all with continuation of prestudy oral antihyperglycemic medications. Glycemic variability measures were derived from seven-point self-monitored blood glucose profiles. RESULTS: At baseline, mean (+/-SD) age was 56.9+/-9.7 years, duration of type 2 diabetes was 9.5+/-6.1 years, hemoglobin A1c (HbA1c) was 8.9+/-1.1%, and 51.9% were male. Intra-day glucose coefficient of variation (CV), fasting blood glucose, intra-day minimum glucose and inter-day glucose CV at 24 weeks, and intra-day glucose CV at baseline were significantly correlated with the rate of hypoglycemia events between Weeks 12 to 24 (P<0.05 for all measures). CONCLUSIONS: Intra-day and inter-day glycemic variability is significantly associated with the risk of hypoglycemia in insulin-treated patients with type 2 diabetes, even after adjusting for mean glucose and HbA1c. The intra-day glycemic variability before starting insulin is significantly associated with the risk of hypoglycemia during insulin treatment, which points at treatment- and patient-related factors mediating this relationship. PMID- 23101952 TI - Influence of local skin temperature and choice of insulin analog on catheter occlusion rates during continuous insulin infusion: an exploratory study. AB - AIMS: The aim of this study was to determine whether changes in local skin temperature over which the infusion catheters pass when using insulin pump therapy and the choice of rapid-acting insulin analog influence the risk of catheter occlusion. SUBJECTS AND METHODS: Twenty healthy volunteers were assigned to wear insulin pumps primed with insulin glulisine and insulin aspart in a randomized order each for a duration of 5 days and a temperature probe (taped to the skin near the insulin catheter). To reproduce the effect of subcutaneous infusion, the insulin catheter was inserted into an absorbent sponge in a plastic bag strapped to the subject's abdomen. Basal infusion rates were programmed at 0.2 IU/h, and 2-IU boluses were given three times a day with meals. RESULTS: Average skin temperature ranged between 33.5 degrees C and 36.68 degrees C for insulin glulisine and 32.35 degrees C and 35.28 degrees C for insulin aspart, with no difference in skin temperature between treatments or between the first and second week of the study. Nine occlusions were seen in eight subjects with an overall rate of occlusion of 22.5% (95% confidence interval, 21.9-61.3%) and were more likely to occur in the second week. On an individual level the risk of occlusion was similar for insulin glulisine and insulin aspart (odds ratio, 0.87%; P=0.6). CONCLUSIONS: Overall, in this small study simulating subcutaneous insulin infusion, the rate of catheter occlusion was low and unaffected by local fluctuations in ambient skin temperature. There was no significant difference between the two rapid-acting insulin analogs tested. Where occlusions occurred, they were more likely to happen beyond the manufacturer's recommended 72-h limit for catheter use. PMID- 23101953 TI - Carbohydrate-to-insulin ratio is estimated from 300-400 divided by total daily insulin dose in type 1 diabetes patients who use the insulin pump. AB - BACKGROUND: To optimize insulin dose using insulin pump, basal and bolus insulin doses are widely calculated from total daily insulin dose (TDD). It is recommended that total daily basal insulin dose (TBD) is 50% of TDD and that the carbohydrate-to-insulin ratio (CIR) equals 500 divided by TDD. We recently reported that basal insulin requirement is approximately 30% of TDD. We therefore investigated CIR after adjustment of the proper basal insulin rate. SUBJECTS AND METHODS: Forty-five Japanese patients with type 1 diabetes were investigated during several weeks of hospitalization. The patients were served standard diabetes meals (25-30 kcal/kg of ideal body weight). Each meal omission was done to confirm basal insulin rate. Target blood glucose level was set at 100 and 150 mg/dL before and 2 h after each meal, respectively. After the basal insulin rate was fixed and target blood glucose levels were achieved, TBD, CIR, TDD, and their products were determined. RESULTS: Mean (+/-SD) blood glucose levels before and 2 h after meals were 121+/-47 and 150+/-61 mg/dL, respectively. TDD was 31.5+/-9.0 U, and TBD was 27.0+/-6.5% of TDD. CIR*TDD of breakfast was significantly lower than those of lunch and supper (288+/-73 vs. 408+/-92 and 387+/-83, respectively; P<0.01). CONCLUSIONS: CIR has diurnal variance and is estimated from the formula CIR=300/TDD at breakfast or CIR=400/TDD at lunch and supper in type 1 diabetes patients. These results indicate that the insulin dose has been underestimated by using previously established calculations. PMID- 23101954 TI - Sample preparation-free, real-time detection of microRNA in human serum using piezoelectric cantilever biosensors at attomole level. AB - A sensitive, selective, sample preparation-free method for near real-time detection of microRNA in buffer and human serum is given using gold (Au)-coated dynamic piezoelectric cantilever sensors. Sensor response to thiolated DNA probe chemisorption, hsa-let-7a hybridization, labeled-DNA hybridization, and Au nanoparticle-functionalized DNA hybridization was monitored continuously in flowing liquid samples using custom flow-cells. The assay showed successful detection of target let-7a with a dynamic range spanning 6 orders of magnitude (10 fM-1 nM) with a limit of detection of less than 10 attomoles (~4 fM). The serum background had negligible effect on sensitivity relative to the results obtained in the buffer due to reduction in nonspecific binding caused by continuous sensor vibration. Both hybridization and nonspecific binding reduction were confirmed using fluorescence-based assays to support sensor-based results. The sensor-based method demonstrated excellent selectivity for the microRNA target in comparison with similar microRNA differing by only a single nucleotide (hsa-let-7c) and random microRNA sequences. Au nanoparticle-based amplification of sensor response was investigated and led to an order of magnitude improvement in the detection limit and a 128% amplification of sensor response over the entire dynamic range. Au nanoparticle amplification was verified by scanning electron microscopy. The cantilever sensor-based microRNA assay provides competitive sensitivity with current microRNA detection methods and has the advantage of requiring no sample preparation, even when working with biological samples that contain a complex background. PMID- 23101955 TI - Photoinduced electron transfer in a chromophore-catalyst assembly anchored to TiO2. AB - Photoinduced formation, separation, and buildup of multiple redox equivalents are an integral part of cycles for producing solar fuels in dye-sensitized photoelectrosynthesis cells (DSPECs). Excitation wavelength-dependent electron injection, intra-assembly electron transfer, and pH-dependent back electron transfer on TiO(2) were investigated for the molecular assembly [((PO(3)H(2) CH(2))-bpy)(2)Ru(a)(bpy-NH-CO-trpy)Ru(b)(bpy)(OH(2))](4+) ([TiO(2)-Ru(a)(II) Ru(b)(II)-OH(2)](4+); ((PO(3)H(2)-CH(2))(2)-bpy = ([2,2'-bipyridine]-4,4' diylbis(methylene))diphosphonic acid); bpy-ph-NH-CO-trpy = 4-([2,2':6',2" terpyridin]-4'-yl)-N-((4'-methyl-[2,2'-bipyridin]-4-yl)methyl) benzamide); bpy = 2,2'-bipyridine). This assembly combines a light-harvesting chromophore and a water oxidation catalyst linked by a synthetically flexible saturated bridge designed to enable long-lived charge-separated states. Following excitation of the chromophore, rapid electron injection into TiO(2) and intra-assembly electron transfer occur on the subnanosecond time scale followed by microsecond millisecond back electron transfer from the semiconductor to the oxidized catalyst, [TiO(2)(e(-))-Ru(a)(II)-Ru(b)(III)-OH(2)](4+)->[TiO(2)-Ru(a)(II) Ru(b)(II)-OH(2)](4+). PMID- 23101956 TI - [Conservative management of urothelial carcinomas of the upper urinary tract]. AB - Urothelial carcinomas of the upper urinary tract (UUT-UCs) are rare and represent about 5% of all urothelial carcinomas. The standard treatment is still open radical nephroureterectomy. Low-grade and non-invasive UUT-UCs have a favourable outcome as non-muscle invasive bladder carcinomas (80% specific - survival rate at 5 years). First-line conservative treatment is being increasingly performed in patients with a normal controlateral kidney for surgical management of UUT-UCs. Conservative surgical management allows for kidney preservation contingent upon it is technically feasible to achieve. Conservative procedures (i.e., flexible ureteroscopy or open conservative surgery) for the treatment of superficial or low grade UUT-UCs have good outcomes and are therefore an alternative to open radical surgery. The important cost of the endoscopic techniques remains currently a limiting factor for the spread of the technique in France. PMID- 23101957 TI - [Radioprotection in endo urology]. AB - The aim of radioprotection is to protect people against harmful effects of radiation; those radiations come from electromagnetic wave or radioactivity that can be natural or related to human activity. Radiation risk is dose related and biological dose is expressed in millisievert (mSv). Mean dose received from natural radioactivity is about 3 mSv, which is a low and non-dangerous dose. Total annual biological dose received should not exceed 20 mSv a year. In endo urology image intensifier is the main source of irradiation in operating theatre. Rules for utilisation are detailed. PMID- 23101958 TI - [Management of acute pyelonephritis]. AB - Pyelonephritis is a bacterial infection of the upper urinary tract and renal parenchyma. Infection occurs primarily by urinary contamination upward and backward from the intestinal flora, and genital skin, explaining that the seeds are most commonly encountered Gram-Negative bacilli (GNB), Escherichia coli in mind. The peak incidence is among women aged 15 to 65, but pyelonephritis may include subjects of all ages and both sexes. The diagnosis is usually straightforward and based on a combination of fever, unilateral flank pain and a positive urine culture. Biology and imaging aim to seek any form of pyelonephritis complicated, especially due to the obstructive form a barrier (usually a calculation) of the urinary tract and is a surgical emergency. Support depends on the existence of signs of severity or complications. Treatment consists of antibiotics, to begin immediately, initially probabilistic and secondarily adapted to the antibiogram. Patients hospitalized in the urology will be those with complicated pyelonephritis (urinary obstruction, abscess, sepsis, renal insufficiency, solitary kidney, comorbidity). PMID- 23101959 TI - [Urolithiasis: metabolic evaluation and prevention]. PMID- 23101960 TI - [Hormone replacement therapy in prostate cancer: side effects and their management]. AB - Hormone replacement therapy in prostate cancer is androgen deprivation. This deprivation causes side effects that are well known. The most frequent complications are hot flashes, erectile dysfunction and libido disorders. These complications have a strong impact on the quality of life of the patient. The other side effects, namely metabolic syndrome and osteopenia, are less frequent, but have a worse prognosis due to their significant impact on patients' survival. The metabolic syndrome results in dyslipidaemia and insulin resistance. Patients under hormone therapy must have an initial evaluation and a subsequent close monitoring. Screening for these side effects and their specific management must be essential during the monitoring of long-term hormone therapy. PMID- 23101961 TI - [Female stress incontinence treatment: urethral slings]. AB - Female stress incontinence is often the consequences of obstetrical traumatisms. They are responsible of a weakness of perineal musculoaponevrotic structures. Until 1996, the reference treatment of this pathology was the "Burch" colposuspension, by laparotomy, then laparoscopic way. After 1996, a new procedure was developped by Ulmten, reproducible, easy, safe and mini-invasive: the tension free-vaginal-tape (TVT) followed by the trans-obturator-tape (TOT). This therapeutic tool has become the reference for the treatment of the female stress incontinence. There are now 15 years from the beginning of this procedure and still 80% of the patients are improved. PMID- 23101962 TI - [Botulinum toxin injections: a new therapeutic avenue in urology]. PMID- 23101963 TI - [Urology and ambulatory surgery]. AB - The ambulatory surgery is the realization of a surgical act with entrance and taken out the same day. The evolution of the surgery in traditional hospitalization towards the ambulatory is a cultural revolution. The function care and accommodation of our establishments of health are disconnected. The ambulatory surgery is source of progress for the surgery, the anesthesia, our organizations. She corresponds to a demand of the public. She is ethical. There is an institutional will shared by all the actors of health today. The AFU measured its delay and has the objective to facilitate to the urologic community this mode of taken care. Learned recommendations are going to be produced in association with the HAS. The role of the IDE of urology is specified there. PMID- 23101964 TI - Anthranilate phosphoribosyl transferase (TrpD) generates phosphoribosylamine for thiamine synthesis from enamines and phosphoribosyl pyrophosphate. AB - Anthranilate phosphoribosyl transferase (TrpD) has been well characterized for its role in the tryptophan biosynthetic pathway. Here, we characterized a new reaction catalyzed by TrpD that resulted in the formation of the purine/thiamine intermediate metabolite phosphoribosylamine (PRA). The data showed that 4- and 5 carbon enamines served as substrates for TrpD, and the reaction product was predicted to be a phosphoribosyl-enamine adduct. Isotopic labeling data indicated that the TrpD reaction product was hydrolyzed to PRA. Variants of TrpD that were proficient for tryptophan synthesis were unable to support PRA formation in vivo in Salmonella enterica. These protein variants had substitutions at residues that contributed to binding substrates anthranilate or phosphoribosyl pyrophosphate (PRPP). Taken together the data herein identified a new reaction catalyzed by a well-characterized biosynthetic enzyme, and both illustrated the robustness of the metabolic network and identified a role for an enamine that accumulates in the absence of reactive intermediate deaminase RidA. PMID- 23101965 TI - Effect of insulin-like growth factor I on functional parameters of ram cooled stored spermatozoa. AB - The aim of the study was to examine the effects of insulin-like growth factor I (IGF-I) on ram sperm traits after hypothermic storage. Sperm ejaculates from Lacaune rams were diluted in a Tris extender, pooled, divided into groups of IGF I doses tested (0, 10, 100 or 200 ng.ml-1) and stored (0-5 degrees C) for 96 h. IGF-I elevated whole sperm motility as measured by a Computer-assisted Sperm Analyser (CASA) system, by 24 h (10 ng.ml-1) and 48 h (200 ng.ml-1) of storage, and by progressive movement on each day of storage. After 72 h the sperm samples were analysed for plasma membrane integrity (peanut agglutinin-fluorescein isothiocyanate), membrane stability (annexin V-Fluos) and apoptosis (Yo-Pro(r)-1) using fluorescence microscopy. The addition of IGF-I (at 100 or 200 ng.ml-1) reduced the ratio of sperm with disrupted membranes and the ratio of annexin V labelled sperm. The ratio of apoptotic sperm was reduced by IGF-I given at 10 or 100 ng.ml-1 compared with control. Sperm fertilizing ability, determined at 48 h by an in vitro fertilization (IVF) test on bovine oocytes, was increased by IGF-I given at 100 ng.ml-1 from 47.0 to 67.7%. In conclusion, IGF-I maintained ram sperm functions following cooling storage and its effects were reflected in sperm fertilizing ability in vitro. PMID- 23101967 TI - Available, intuitive and free! Building e-learning modules using web 2.0 services. AB - BACKGROUND: E-learning is part of the mainstream in medical education and often provides the most efficient and effective means of engaging learners in a particular topic. However, translating design and content ideas into a useable product can be technically challenging, especially in the absence of information technology (IT) support. There is little published literature on the use of web 2.0 services to build e-learning activities. AIM: To describe the web 2.0 tools and solutions employed to build the GP Synergy evidence-based medicine and critical appraisal online course. METHODS: We used and integrated a number of free web 2.0 services including: Prezi, a web-based presentation platform; YouTube, a video sharing service; Google Docs, a online document platform; Tiny.cc, a URL shortening service; and Wordpress, a blogging platform. RESULTS: The course consisting of five multimedia-rich, tutorial-like modules was built without IT specialist assistance or specialised software. The web 2.0 services used were free. The course can be accessed with a modern web browser. CONCLUSIONS: Modern web 2.0 services remove many of the technical barriers for creating and sharing content on the internet. When used synergistically, these services can be a flexible and low-cost platform for building e-learning activities. They were a pragmatic solution in our context. PMID- 23101966 TI - The successful experimental induction of necrotic enteritis in chickens by Clostridium perfringens: a critical review. AB - Necrotic enteritis (NE) is one of the most important enteric diseases in poultry and is a high cost to the industry worldwide. It is caused by avian-specific, Necrotic Enteritis Beta toxin (NetB)-producing, strains of Clostridium perfringens that also possess in common other virulence-associated genes. In Europe the disease incidence has increased since the ban on in-feed "growth promoting" antibiotics. Because of this, many recent studies of NE have focused on finding different ways to control the disease, and on understanding its pathogenesis. Frustratingly, reproduction of the disease has proven impossible for some researchers. This review describes and discusses factors known to be important in reproducing the disease experimentally, as well as other considerations in reproducing the disease. The critical bacterial factor is the use of virulent, netB-positive, strains; virulence can be enhanced by using tpeL- positive strains and by the use of young rather than old broth cultures to increase toxin expression. Intestinal damaging factors, notably the use of concurrent or preceding coccidial infection, or administration of coccidial vaccines, combined with netB-positive C. perfringens administration, can also be used to induce NE. Nutritional factors, particularly feeding high percentage of cereals containing non-starch polysaccharides (NSP) (wheat, rye, and barley) enhance disease by increasing digesta viscosity, mucus production and bacterial growth. Animal proteins, especially fish meal, enhance C. perfringens proliferation and toxin production. Other factors are discussed that may affect outcome but for which evidence of their importance is lacking. The review compares the different challenge approaches; depending on the aim of particular studies, the different critical factors can be adjusted to affect the severity of the lesions induced. A standardized scoring system is proposed for international adoption based on gross rather than histopathological lesions; if universally adopted this will allow better comparison between studies done by different researchers. Also a scoring system is provided to assist decisions on humane euthanasia of sick birds. PMID- 23101968 TI - Oral health disparities as determined by selected healthy people 2020 oral health objectives for the United States, 2009-2010. AB - The Healthy People 2020 initiative contains over 1,200 objectives that serve as a roadmap for tracking the nation's health (1). Oral health is 1 of 42 Healthy People topic areas comprising 33 objectives ranging from dental caries and periodontal disease, to access to preventive dental services and program infrastructure. One important activity of Healthy People is to monitor health disparities. Influential sociodemographic indicators for oral health disparities in the United States include poverty status and race and ethnicity (2). This report focuses on key Healthy People objectives covering select age groups by race and ethnicity and poverty status from 2009 to 2010. PMID- 23101970 TI - Importance of following published protocol. PMID- 23101971 TI - Can quality of care indicators measure quality of care? PMID- 23101974 TI - Molecular insight into the hydrogen bonding and micro-segregation of a cryoprotectant molecule. AB - Glycerol-water liquid mixtures are intriguing hydrogen-bonded systems and essential in many fields of chemistry, ranging from basic molecular research to widespread use in industrial and biomedical applications as cryoprotective solutions. Despite much research on these mixtures, the details of their microscopic structure are still not understood. One common notion is that glycerol acts to diminish the hydrogen bonding ability of water, a recurring hypothesis that remains untested by direct experimental approaches. The present work characterizes the structure of glycerol-water mixtures, across the concentration range, using a combination of neutron diffraction experiments and computational modeling. Contrary to previous expectations, we show that the hydrogen bonding ability of water is not diminished in the presence of glycerol. We show that glycerol-water hydrogen bonds effectively take the place of water water hydrogen bonds, allowing water to maintain its full hydrogen bonding capacity regardless of the quantity of glycerol in the environment. We provide a quantitative measurement of all hydrogen bonding in the system and reveal a concentration range where a microsegregated, bipercolating liquid mixture exists in coexistence with a considerable interface region. This work highlights the role of hydrogen bonding connectivity rather than water structuring/destructuring effects in these important cryoprotective systems. PMID- 23101975 TI - Prevalence and natural history of alcoholic liver disease. AB - Alcoholic liver disease is a major cause of morbidity and mortality among people who drink excessive amounts of alcohol. There is a spectrum of liver injury that ranges from steatosis to varying stages of hepatic fibrosis and cirrhosis, with subsequent risk for hepatocellular carcinoma. Steatohepatitis can occur at any stage of disease. PMID- 23101977 TI - Immunology in alcoholic liver disease. AB - Hepatic fibrosis is a known consequence of long-term use of alcohol and is regarded as a turning point in alcohol-induced liver disease because it can lead to cirrhosis. The mechanisms of injury are not well understood, but recent studies have helped advance the understanding of the earliest events in the process that eventually leads to hepatic injury and, in some cases, fibrosis. It is hoped that increasing understanding of the role played by the immune system in the process will lead to the development of new therapies for these patients. PMID- 23101976 TI - Alcohol metabolism. AB - This article describes the pathways and factors that modulate blood alcohol levels and metabolism and describes how the body disposes of alcohol. The various factors that play a role in the distribution of alcohol in the body, influence the absorption of alcohol, and contribute to first-pass metabolism of alcohol are described. Most alcohol is oxidized in the liver, and general principles and overall mechanisms for alcohol oxidation are summarized. The kinetics of alcohol elimination in-vivo and the various genetic and environmental factors that can modify the rate of alcohol metabolism are discussed. PMID- 23101978 TI - Histologic findings in alcoholic liver disease. AB - The necessity of the liver being the organ responsible for metabolism of alcohol exposes it to many untoward toxic side effects. In the first instance of hepatic steatosis, fibrosis may occur indolently over years, slowly converting a greasy, steatotic liver into a cirrhotic liver. In the case of alcoholic hepatitis, brisk sinusoidal fibrosis may lead to more rapid development of cirrhosis, with the liver extensively subdivided by sublobular fibrous septa developing in the midst of extensive ongoing inflammation and hepatocellular destruction. Continued destruction of the parenchyma after cirrhosis has developed may produce a densely fibrotic organ with little remaining parenchyma. PMID- 23101979 TI - Diagnosis and management of alcoholic hepatitis. AB - Alcoholic hepatitis is a form of severe, cholestatic liver disease that results from consumption of large amount of alcohol during a sustained period of time in a subset of alcoholics. Symptoms could be mild and nonspecific to more severe. The diagnosis of alcoholic hepatitis can be made with a thorough history, physical examination, and review of laboratory results. Liver biopsy is confirmatory but generally not indicated for the diagnosis. Abstinence is the key form of therapeutic intervention. Despite variable results in clinical trials, corticosteroids and pentoxifylline seem to provide moderate survival benefit. Liver transplantation in acute alcoholic hepatitis is contentious. PMID- 23101980 TI - Management of alcohol abuse. AB - This article reviews the spectrum of alcohol use disorders. The pharmacologic properties of ethanol and its metabolism, and the historical, physical, and laboratory elements that may help diagnose an alcohol use disorder are examined. The concepts of motivational interviewing and stages of change are mentioned, along with the American Society of Addiction Medicine patient placement criteria, to determine the best level of treatment for alcoholism. Various therapeutic management options are reviewed, including psychological, pharmacologic, and complementary/alternative choices. This article provides a basic understanding of available tools to diagnose and treat this cunning and baffling brain and multisystem disease. PMID- 23101981 TI - Long-term management of alcoholic liver disease. AB - Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Patients with cirrhosis caused by alcohol are at risk for developing complications associated with a failing liver. The long-term management of alcoholic liver disease stresses the following: (1) Abstinence of alcohol (Grade 1A), with referral to an alcoholic rehabilitation program; (2) Adequate nutritional support (Grade 1B), emphasizing multiple feedings and a referral to a nutritionist; (3) Routine screening in alcoholic cirrhosis to prevent complications; (4) Timely referral to a liver transplant program for those with decompensated cirrhosis; (5) Avoid pharmacologic therapies, as these medications have shown no benefit. PMID- 23101982 TI - Infections in alcoholic liver disease. AB - Alcoholic individuals are at increased risk of infection in general, in part because of immune defects. In addition, associated situations, such as depressed mental status, increase risk to specific syndromes such as lung abscess related to depressed consciousness and aspiration. Social factors related to hygiene and living situations are also linked to specific microorganisms, such as Mycobacteria tuberculosis, Bartonella quintana, Vibrio vulnificus, and Capnocytophaga canimorus.. PMID- 23101983 TI - Nutrition in alcoholic liver disease. AB - The liver plays an important role in the metabolism, synthesis, storage, and absorption of nutrients. Patients with cirrhosis are prone to nutritional deficiencies and malnutrition, with a higher prevalence among patients with decompensated disease. Mechanisms of nutritional deficiencies in patients with liver disease are not completely understood and probably multifactorial. Malnutrition among patients with cirrhosis or alcoholic liver disease correlates with poor quality of life, increased risk of infections, frequent hospitalizations, complications, mortality, poor graft and patient survival after liver transplantation, and economic burden. Physicians, including gastroenterologists and hepatologists, should be conversant with assessment and management of malnutrition and nutritional supplementation. PMID- 23101984 TI - Alcohol's effect on other chronic liver diseases. AB - In addition to directly causing liver disease, alcohol consumption is a common comorbid condition with other chronic liver diseases and may exacerbate liver injury, particularly in nonalcoholic fatty liver disease, chronic viral hepatitis, hereditary hemochromatosis, and autoimmune liver diseases. This synergism can result in increased hepatic inflammation and accelerated rates of fibrosis, with more rapid and earlier development of cirrhosis, and also increase the risk for liver cancer and death from liver disease. PMID- 23101985 TI - Liver cancer and alcohol. AB - Annually, hepatocellular carcinoma is diagnosed in approximately a half-million people worldwide. Based on the association of alcohol with cancer, a International Agency for Research on Cancer working group recently deemed alcoholic beverages "carcinogenic to humans," causally related to occurrence of malignant tumors of the oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast. Alcohol metabolism in the liver leads to reactive oxygen species production, induction of activity of cytochrome P450s, and reduction of antioxidants. This review analyzes the epidemiology and pathogenesis of alcohol in hepatocellular cancer. PMID- 23101986 TI - Evaluation and selection of the patient with alcoholic liver disease for liver transplant. AB - Alcoholic liver cirrhosis is the second most common indication for liver transplantation in the United States. Studies have shown that these patients do as well as those transplanted for nonalcoholic liver disease. Recently, transplantation of patients with alcoholic liver disease has come under closer scrutiny following an article in the New England Journal of Medicine demonstrating comparable outcomes and survival in patients transplanted for acute alcoholic hepatitis. This article reviews the literature and data on the evaluation and selection of patients with alcoholic cirrhosis for liver transplant, and discusses the most recent indication (once a contraindication), acute alcoholic hepatitis. PMID- 23101987 TI - Complications in patients with alcohol-associated liver disease who undergo liver transplantation. AB - Cirrhosis caused by alcohol-associated liver disease is a common indication for liver transplantation worldwide. Patients with alcohol-associated liver disease who undergo liver transplantation face multiple challenging comorbid medical issues that enhance the potential for perioperative and postoperative complications. Awareness of these issues and appropriate therapeutic intervention may minimize the negative effect of these complications on posttransplantation survival. This article reviews important posttransplantation problems in patients transplanted for alcohol-associated liver disease. PMID- 23101988 TI - Alcoholic liver disease. PMID- 23101989 TI - Structural determinants for the membrane insertion of the transmembrane peptide of hemagglutinin from influenza virus. AB - Membrane fusion is a process involved in a high range of biological functions, going from viral infections to neurotransmitter release. Fusogenic proteins increase the slow rate of fusion by coupling energetically downhill conformational changes of the protein to the kinetically unfavorable fusion of the membrane lipid bilayers. Hemagglutinin is an example of a fusogenic protein, which promotes the fusion of the membrane of the influenza virus with the membrane of the target cell. The N-terminus of the HA2 subunit of this protein contains a fusion domain described to act as a destabilizer of the target membrane bilayers, leading eventually to a full fusion of the two membranes. On the other hand, the C-terminus of the same subunit contains a helical transmembrane domain which was initially described to act as the anchor of the protein to the membrane of the virus. However, in recent years the study of this peptide segment has been gaining more attention since it has also been described to be involved in the membrane fusion process. Yet, the structural characterization of the interaction of such a protein domain with membrane lipids is still very limited. Therefore, in this work, we present a study of this transmembrane peptide domain in the presence of DMPC membrane bilayers, and we evaluate the effect of several mutations, and the effect of peptide oligomerization in this interaction process. Our results allowed us to identify and confirm amino acid residue motifs that seem to regulate the interaction between the segment peptide and membrane bilayers. Besides these sequence requirements, we have also identified length and tilt requirements that ultimately contribute to the hydrophobic matching between the peptide and the membrane. Additionally, we looked at the association of several transmembrane peptide segments and evaluated their direct interaction and stability inside a membrane bilayer. From our results we could conclude that three independent TM peptide segments arrange themselves in a parallel arrangement, very similarly to what is observed for the C-terminal regions of the hemagglutinin crystallographic structure of the protein, to where the segments are attached. PMID- 23101990 TI - Enhanced avoidance learning in behaviorally inhibited young men and women. AB - Behavioral inhibition (BI) is a temperamental tendency to avoid or withdraw from novel social and nonsocial situations, and has been shown to predispose individuals to anxiety disorders. However, adequate means to assess individual differences in avoidance learning in humans are presently limited. Here, we tested whether individuals with high self-reported BI show faster associative learning on a purely cognitive task and whether such inhibited individuals are more prone to avoid aversive outcomes. In Experiment 1, we tested 74 healthy undergraduate students (mean age 19.5 years; 55.4% female) on a computer-based probabilistic classification task, where participants were asked to classify four distinct visual stimuli into two categories. Two stimuli were associated with reward (point gain) and two were associated with punishment (point loss). In Experiment 2, 79 participants from the same population (mean age 19.8 years; 62% female) were tested on a novel modification of the same task, where they also had the option to opt out of responding on each trial, thus avoiding any chance of being punished (or rewarded) on that trial. Results show that inhibited participants demonstrated better associative learning in Experiment 1, while exhibiting a greater tendency to opt out in Experiment 2 (repeated-measures analysis of variance, main effects of BI, both p < 0.05). These results indicate that the facilitated classically conditioned learning previously observed in inhibited individuals can be extended to a cognitive task, and also highlight a specific preference in inhibited individuals for withdrawal ("opting out") as a response strategy, when multiple strategies are available to avoid punishment. PMID- 23101991 TI - Fabrication and spectroscopic investigation of branched silver nanowires and nanomeshworks. AB - Wide wavelength ranges of light localization and scattering characteristics can be attributed to shape-dependent longitude surface plasmon resonance in complicated nanostructures. We have studied this phenomenon by spectroscopic measurement and a three-dimensional numerical simulation, for the first time, on the high-density branched silver nanowires and nanomeshworks at room temperature. These nanostructures were fabricated with simple light-induced colloidal method. In the range from the visible to the near-infrared wavelengths, light has been found effectively trapped in those trapping sites which were randomly distributed at the corners, the branches, and the junctions of the nanostructures in those nanostructures in three dimensions. The broadened bandwidth electromagnetic field enhancement property makes these branched nanostructures useful in optical processing and photovoltaic applications. PMID- 23101992 TI - Significant variation in the concentration of carcinogenic polycyclic aromatic hydrocarbons in yerba mate samples by brand, batch, and processing method. AB - Drinking mate, common in southern South America, may increase the risk of esophageal squamous cell carcinoma (ESCC). In 2006, we found high but variable polycyclic aromatic hydrocarbon (PAH) content in commercial yerba mate samples from eight Brazilian brands. The PAH content of new samples from the same brands, purchased in 2008, and four brands from a single manufacturer processed in different ways, obtained in 2010, were quantified to determine whether PAH concentration was still high, whether PAH content variation was brand specific, and whether processing method affects PAH content of commercial yerba mate. Concentrations of individual PAHs were quantified using gas chromatography/mass spectrometry with deuterated PAHs as internal standards. Median total PAH concentration was 1500 ng/g (range: 625-3710 ng/g) and 1090 ng/g (621-1990 ng/g) in 2008 and 2010 samples, respectively. Comparing 2006 and 2008 samples, some brands had high PAH concentrations in both years, while PAH concentration changed considerably in others. Benzo[a]pyrene concentrations ranged from 11.9 to 99.3 ng/g and 5.11 to 21.0 ng/g in 2008 and 2010 samples, respectively. The 2010 sample processed without touching smoke had the lowest benzo[a]pyrene content. These results support previous findings of very high total and carcinogenic PAH concentrations in yerba mate, perhaps contributing to the high incidence of ESCC in southern South America. The large PAH content variation by brand, batch, and processing method suggests it may be possible to reduce the content of carcinogenic PAHs in commercial yerba mate, making it a healthier beverage. PMID- 23101993 TI - Iatrogenic esophageal injuries: evidence-based management for diagnosis and timing of contrast studies after repair. AB - Leakage from gastroesophageal repair is considered a major complication and is often associated with increased hospital stay, morbidity, and mortality. Management of these patients is variable among surgeons. Cases managed by the thoracic surgical service from March 1, 2010 to March 1, 2011 were retrospectively reviewed. Eight patients met criteria for inclusion: 4 were repaired primarily, 2 by debridement with diversion, and 2 by Ivor-Lewis resection and reconstruction. Esophograms were completed between 1 and 7 days postoperatively. Of the 8 patients treated, there was 1 mortality (12%) due to fungal mediastinitis. Soluble contrast imaging revealed 2 leaks (25%), 1 contained and 1 diffuse, which was the only mortality. Changes in clinical status, even minor, require contrast imaging of the esophagus to assess repair integrity. Timing of contrast study is variable in the literature, averaging 5 to 14 days. A conservative time frame is 7 days, unless any clinical suspicion of an esophageal leak exists. PMID- 23101994 TI - Successful combination therapy of radical liver resection with 5 fluorouracil/leucovorin, oxaliplatin, plus bevacizumab for ascending colon cancer with pulmonary and 43 liver metastases: report of a case. AB - At the time of diagnosis, 20% to 25% of patients with colorectal cancer already have liver metastases, the presence of which is a most important prognostic factor. A 64-year-old man was admitted to our hospital for investigation of anemia and multiple liver tumors. Examinations revealed ascending colon carcinoma with more than 40 liver metastases and 2 lung metastases. We performed right hemicolectomy with lymph node dissection, which was followed by 5 fluorouracil/leucovorin, oxaliplatin, plus bevacizumab (FOLFOX-BV). After 4 courses of chemotherapy, the lung metastases were in complete remission and the liver metastases had shrunk. We suggested the option of radical liver resection, but the patient declined initially as he had not suffered any severe side effects of FOLFOX-BV. After 23 courses of the chemotherapy, he agreed to undergo hepatectomy. We performed extended right lobectomy with partial left and caudal lobe resection. All of the macroscopic metastatic lesions were resected. Histopathologically, viable cancer cells were recognized in 7 of the 43 liver metastatic lesions. Postoperatively, FOLFOX-BV was restarted and continued for 10 months. At the time of writing, 15 months after the hepatectomy, the patient was well without evidence of recurrence of the cancer. PMID- 23101995 TI - Colonic perforation in graft versus host disease: a case report. AB - Graft versus host disease (GVHD) is a phenomenon that occurs after allogeneic bone marrow transplants. Gastrointestinal (GI) manifestations of acute GVHD are common, but severe GI GVHD complications, such as bowel perforation, occur rarely and necessitate surgical intervention. To our knowledge, there are no recorded cases of colonic perforation resulting from GVHD with negative cultures for infectious agents such as cytomegalovirus. We present a case of large bowel perforation due to GVHD. PMID- 23101996 TI - Primary hepatic cancers with multiple pathologic features in a patient with hepatitis C: report of a case. AB - We report a case of multiple primary hepatic cancers exhibiting different pathologic features coexisting in a patient with chronic hepatitis C. Computed tomography showed 2 tumors in segment 8, 20 mm (S8-A) and 5 mm (S8-B) in diameter, and a 10-mm tumor in segment 6 (S6). Based on the images, the S8-A lesion was diagnosed as cholangiocellular carcinoma or combined hepatocellular carcinoma and cholangiocarcinoma (combined HCC-CC). The other 2 tumors were diagnosed as HCC. The patient underwent partial resections of segments 6 and 8. We found 2 more tumors (S8-C was 6 mm in diameter and S8-D was 4 mm) in the resected segment 8 specimen. Histopathologic examination revealed that the S8-A and S8-C tumors were combined HCC-CC, the S8-B and S6 lesions were scirrhous HCC, and the S8-D tumor was an early HCC. This is a very rare case in which different hepatic cancers with multiple pathologic features coexisted. PMID- 23101997 TI - Unusual location of hydatid cysts: a case report and literature review. AB - Hydatid cysts develop most frequently in the liver and lungs, but they are occasionally found in other organs. Hydatid cysts in the axillary space are an extremely rare event in areas where the disease is endemic, and are still common in many countries, including Turkey. A 73-year-old man presented to our clinic with a painful axillary mass. Thoracoabdominal computed tomography revealed multilocular cystic masses localized in the left axillary space, with minimal invasion of the peripheral soft tissue and no pulmonary or hepatic involvement. An echinococcal indirect hemagglutination test was negative. The masses were dissected through their stalks and removed completely. Macroscopic and microscopic examination of the specimens confirmed hydatid cysts. This case report demonstrates that hydatid cysts should be considered as a possible cause for palpable lesions in the axillary region or chest wall, especially in endemic locations. PMID- 23101998 TI - Thoracic disk herniation, a not infrequent cause of chronic abdominal pain. AB - This study assesses the proportion of patients presenting with nonvisceral chronic abdominal pain who have thoracic disk herniation as a possible cause. We designed a descriptive transversal study of patients attending our offices between February 2009 and October 2010, with a complaint of chronic abdominal pain of suspected abdominal wall source (positive Carnett sign). Nuclear magnetic resonance (NMR) of the spinal column was performed on all patients. When the NMR showed thoracic disk herniation the patients were treated according to their etiology. We also evaluated the symptoms in patients with thoracic disk herniation and their response to the applied treatment. Twenty-seven patients with chronic abdominal pain were evaluated. The NMR results in 18 of these 27 patients (66.66%) showed evidence of disk herniation. We report on the results of these 18 patients, emphasizing that the symptoms are florid and varied. Many patients had been previously diagnosed with irritable bowel syndrome. Thoracic disk herniation may account for chronic abdominal pain in many patients who remain undiagnosed or are diagnosed with irritable bowel syndrome. Thus, this possibility needs to be taken into account to achieve a correct diagnosis and a suitable mode of treatment. PMID- 23101999 TI - The effect of antifibrinolytic prophylaxis on postoperative outcomes in patients undergoing cardiac operations. AB - Antifibrinolytic agents such as aprotinin and epsilon aminocaproic acid limit postoperative bleeding and blood transfusion in patients undergoing cardiac operations using cardiopulmonary bypass (CPB). Recent evidence suggests that these agents have adverse side effects that influence operative mortality and morbidity. We studied postoperative bleeding, transfusion rates, and operative outcomes in our patients in order to assess the efficacy of these agents during cardiac operations requiring CPB. We reviewed records of 520 patients undergoing a variety of cardiac operations between January 2005 and May 2009. We measured multiple variables including pre-operative risk factors, antifibrinolytic agent used, and outcomes of operation, such as measures of bleeding and blood transfusion, as well as serious operative morbidity and mortality. Postoperative bleeding rates varied significantly between patients receiving aprotinin and those receiving aminocaproic acid (P < 0.05). There was an associated 12% decrease in operative site bleeding in aprotinin-treated patients compared with aminocaproic acid. There was no significant difference in the transfusion rates of packed red blood cells between patients receiving aminocaproic acid or aprotinin (P > 0.05), though individuals in the aprotinin group did receive FFP more frequently than patients in the aminocaproic acid group (P < 0.05). There was no significant difference in morbidity and mortality rates between patients in either drug group (P > 0.05). Our study shows that aprotinin is more effective at controlling operative site bleeding than aminocaproic acid. Reduced operative site bleeding did not portend better outcome or differences in transfusion requirements. Aminocaproic acid remains a safe and cost-effective option for antifibrinolytic prophylaxis because of unavailability of aprotinin. PMID- 23102000 TI - Transesophageal echocardiography for the noncardiac surgical patient. AB - Transesophageal echocardiography (TEE) has been established as a very valuable asset for patient monitoring during cardiac surgery. The value of perioperative TEE for patients undergoing noncardiac surgery is less clear. This article reviews the technical aspects of TEE and comments on the potential benefit of using TEE as a monitoring modality apart from cardiac surgery. Based on patient's comorbidities and/or injury pattern, TEE is a fast and minimally invasive approach to obtain important hemodynamic information, especially useful in a hemodynamically unstable patient. However, certain requirements for the use of the technique are necessary, most important the development of sufficient echocardiographic skills by the anesthesiologists. Indications, skill requirements, and possible complications of the technique are reviewed. PMID- 23102001 TI - Hybrid endarterectomy and endovascular therapy in multilevel lower extremity arterial disease involving the femoral artery bifurcation. AB - The objective of this study was to evaluate the feasibility and efficacy of hybrid therapy (combined endarterectomy-endovascular) in patients with complex peripheral multifocal steno-obstructive vascular disease involving the femoral artery bifurcation. Forty-one combined procedures were performed on 40 patients. Although the common femoral artery was usually treated with endarterectomy, endoluminal procedures were performed proximally in 12 patients (group 1), distally in 18 patients (group 2), and both upward and downward in 11 patients (group 3). Patients underwent clinical assessment and ankle-brachial index measurement thereafter. Primary, assisted-primary, and secondary patency rates at 24 months were 59%, 66%, and 72%, respectively. Primary patency rates were lower in group 3 compared with groups 1 and 2 (P = 0.015). The limb salvage rate was 86.4% at the end of the follow-up period. Hybrid procedures provide feasible and effective treatment management of selected patients with multilevel lower extremity arterial disease involving the femoral artery bifurcation. PMID- 23102002 TI - Three-dimensional stereoscopic volume rendering of malignant pleural mesothelioma. AB - Our objective was to investigate the application of three-dimensional (3D) stereoscopic volume rendering with perceptual colorization on preoperative imaging for malignant pleural mesothelioma. At present, we have prospectively enrolled 6 patients being considered for resection of malignant pleural mesothelioma that have undergone a multidetector-row computed tomography (CT) scan of the chest. The CT data sets were volume rendered without preprocessing. The resultant 3D rendering was displayed stereoscopically and used to provide information regarding tumor extent, morphology, and anatomic involvement. To demonstrate this technique, this information was compared with the corresponding two-dimensional CT grayscale axial images from two of these patients. Three dimensional stereoscopic reconstructions of the CT data sets provided detailed information regarding the local extent of tumor that could be used for preoperative surgical planning. Three-dimensional stereoscopic volume rendering for malignant pleural mesothelioma is a novel approach. Combined with our innovative perceptual colorization algorithm, stereoscopic volumetric analysis potentially allows for the accurate determination of the extent of pleural mesothelioma with results difficult to duplicate using grayscale, multiplanar CT images. PMID- 23102003 TI - Giant neurofibroma in the right lower limb of a 26-year-old woman: report of a case. AB - Neurofibromatosis (NF) is a genetically inherited, autosomal-dominant disease with an incidence of 1 in 3000 live births. There are two types of NF, NF 1 and NF 2, and NF 1 is the most common. This study reports on the diagnosis, treatment, and related family medical history of a rare case with NF-1 in the right lower limb. PMID- 23102004 TI - Instrumented outpatient anterior cervical discectomy and fusion: is it safe? AB - Anterior cervical discectomy and fusion procedures are one of the most common procedures performed in spinal surgery. Increasingly they are being performed on an outpatient basis. The primary impetus for performing procedures as an outpatient is potential cost savings. However, there are few studies discussing the safety of performing the procedure in an ambulatory setting. This is a retrospective review of our initial experience in performing anterior cervical discectomy and fusion procedures with instrumentation (ACDFI) in an ambulatory surgery center dedicated to spine surgery. Patients were selected for outpatient surgery if they had limited co-morbidities and the surgery involved only 1 or 2 levels. One hundred fifty-two patients underwent outpatient ACDFI during the study period (2007-2009). Six patients returned to the hospital emergency room after discharge. The reasons for evaluation included 2 for neck pain, 1 for dysphagia, 1 for vocal cord paralysis and dysphagia, 1 for nausea, and 1 for cervical swelling. Only 1 of the 6 patients required admission to the hospital. None of the 6 suffered any long-term sequelae. The overall complication rate was 3.9%. A self-reported survey was completed by 75 patients within 6 months of surgery, and there was a 100% satisfaction rate among responders. ACDFI can be performed safely on an outpatient in selected patients with a high degree of patient satisfaction. Our experience is consistent with those of previous investigators. PMID- 23102005 TI - Electrocoagulative surgical procedure for treatment of conjunctivochalasis. AB - The purpose of this study was to present a new procedure to treat symptomatic conjunctivochalasis (CCh) and to evaluate its efficacy. Forty-two patients with symptomatic CCh refractory to medical management were included on this study. Twenty-two patients (n = 32, eyes; n = 14 women and n = 8 men) underwent the new electrocoagulation procedure (group I). Twenty patients (n = 27 eyes; n = 11 women and n = 9 men) underwent crescent-shaped conjunctiva resection (group II). Ocular surface disease index (OSDI) was used to evaluate ocular symptoms. There was a significant difference in mean and SD operation time between group I (8.67 +/- 2.07 minutes) and group II (20.45 +/- 3.98 minutes; P < 0.0001). OSDI scores (mean +/- SD) were significantly lower in group I (28.38 +/- 3.14) than group II (31.62 +/- 3.17) at postoperative week 2 (P = 0.0004). No differences in OSDI scores were found between the 2 groups at postoperative week 4 (P = 0.1749) or 8 (P = 0.1483). OSDI scores were significantly lower at postoperative week 8 than at baseline in both group I (P = 0.0002) and group II (P = 0.0011). Electrocoagulation of the conjunctiva can successfully treat symptomatic CCh with earlier symptomatic attenuation and less operation time than traditional conjunctiva resection. PMID- 23102007 TI - Porcine oocyte vitrification in optimized low toxicity solution with open pulled straws. AB - One of the greatest challenges for reproductive cryobiologists today is to develop an efficient cryopreservation method for human and domestic animal oocytes. The objective of the present study was to optimize a low toxicity solution called VM3 to vitrify porcine oocytes using an open pulled straw (OPS) device and to evaluate the effects on viability, chromosomal organization and cortical granules distribution. Two experiments were conducted in this study. Firstly, we determined the minimum concentration of cryoprotectant present in the VM3 solution required (7.6 M) for vitrification using an OPS device. The appearance of opacity was observed when using a cooling solution at -196 degrees C; no observable opacity was noted as vitrification. In addition, the ultrastructure of oocytes in VM3 or VM3 optimized solution was examined using cryo-scanning electron microscopy. The minimum total cryoprotectant concentration present in VM3 solution necessary for apparent vitrification was 5.6 M when combined with use of an OPS device. Use of both vitrification solutions showed a characteristic plasticized surface. In the second experiment, the relative cytotoxicity of vitrification solutions (VM3 and VM3 optimized) was studied. Oocyte viability, chromosomal organization and the cortical granules distribution were assessed by fluorescent stain. After warming, oocyte survival rate was similar to that of fresh oocytes. The vitrification process significantly reduced correct chromosomal organization and cortical granules distribution rates compared with the fresh oocytes group. However, correct chromosomal organization and cortical granules distribution rates did not differ among oocytes placed in different vitrification solutions. In conclusion, our data demonstrated that the VM3 solution can be optimized and that reduction in concentration to 5.6 M enabled vitrification of oocytes with an OPS device, however use of the VM3 optimised solution had no beneficial effect on vitrification of porcine oocytes. PMID- 23102008 TI - Socioeconomic inequalities in risk factors for non communicable diseases in low income and middle-income countries: results from the World Health Survey. AB - BACKGROUND: Monitoring inequalities in non communicable disease risk factor prevalence can help to inform and target effective interventions. The prevalence of current daily smoking, low fruit and vegetable consumption, physical inactivity, and heavy episodic alcohol drinking were quantified and compared across wealth and education levels in low- and middle-income country groups. METHODS: This study included self-reported data from 232,056 adult participants in 48 countries, derived from the 2002-2004 World Health Survey. Data were stratified by sex and low- or middle-income country status. The main outcome measurements were risk factor prevalence rates reported by wealth quintile and five levels of educational attainment. Socioeconomic inequalities were measured using the slope index of inequality, reflecting differences in prevalence rates, and the relative index of inequality, reflecting the prevalence ratio between the two extremes of wealth or education accounting for the entire distribution. Data were adjusted for confounding factors: sex, age, marital status, area of residence, and country of residence. RESULTS: Smoking and low fruit and vegetable consumption were significantly higher among lower socioeconomic groups. The highest wealth-related absolute inequality was seen in smoking among men of low- income country group (slope index of inequality 23.0 percentage points; 95% confidence interval 19.6, 26.4). The slope index of inequality for low fruit and vegetable consumption across the entire distribution of education was around 8 percentage points in both sexes and both country income groups. Physical inactivity was less prevalent in populations of low socioeconomic status, especially in low-income countries (relative index of inequality: (men) 0.46, 95% confidence interval 0.33, 0.64; (women) 0.52, 95% confidence interval 0.42, 0.65). Mixed patterns were found for heavy drinking. CONCLUSIONS: Disaggregated analysis of the prevalence of non-communicable disease risk factors demonstrated different patterns and varying degrees of socioeconomic inequalities across low- and middle-income settings. Interventions should aim to reach and achieve sustained benefits for high-risk populations. PMID- 23102009 TI - Copper-promoted sulfenylation of sp2 C-H bonds. AB - An auxiliary-assisted, copper catalyzed or promoted sulfenylation of benzoic acid derivative beta-C-H bonds and benzylamine derivative gamma-C-H bonds has been developed. The method employs disulfide reagents, copper(II) acetate, and DMSO solvent at 90-130 degrees C. Application of this methodology to the direct trifluoromethylsulfenylation of C-H bonds was demonstrated. PMID- 23102010 TI - Production of four Neurospora crassa lytic polysaccharide monooxygenases in Pichia pastoris monitored by a fluorimetric assay. AB - BACKGROUND: Recent studies demonstrate that enzymes from the glycosyl hydrolase family 61 (GH61) show lytic polysaccharide monooxygenase (PMO) activity. Together with cellobiose dehydrogenase (CDH) an enzymatic system capable of oxidative cellulose cleavage is formed, which increases the efficiency of cellulases and put PMOs at focus of biofuel research. Large amounts of purified PMOs, which are difficult to obtain from the native fungal producers, are needed to study their reaction kinetics, structure and industrial application. In addition, a fast and robust enzymatic assay is necessary to monitor enzyme production and purification. RESULTS: Four pmo genes from Neurospora crassa were expressed in P. pastoris under control of the AOX1 promoter. High yields were obtained for the glycosylated gene products PMO-01867, PMO-02916 and PMO-08760 (>300 mg L-1), whereas the yield of non-glycosylated PMO-03328 was moderate (~45 mg L-1). The production and purification of all four enzymes was specifically followed by a newly developed, fast assay based on a side reaction of PMO: the production of H2O2 in the presence of reductants. While ascorbate is a suitable reductant for homogeneous PMO preparations, fermentation samples require the specific electron donor CDH. CONCLUSIONS: P. pastoris is a high performing expression host for N. crassa PMOs. The pmo genes under control of the native signal sequence are correctly processed and active. The novel CDH-based enzyme assay allows fast determination of PMO activity in fermentation samples and is robust against interfering matrix components. PMID- 23102011 TI - Eudragit: a technology evaluation. AB - INTRODUCTION: Eudragit is the brand name for a diverse range of polymethacrylate based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacrylic/acrylic esters or their derivatives. AREAS COVERED: In this review, the physicochemical characteristics and applications of different grades of Eudragit in colon-specific/enteric-coated/sustained release drug delivery and taste masking have been addressed. EXPERT OPINION: Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150(o)C. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Studies in human volunteers have confirmed that pH drops from 7.0 at terminal ileum to 6.0 at ascending colon, and Eudragit S based systems sometimes fail to release the drug. To overcome the shortcoming, combination of Eudragit S and Eudragit L which ensures drug release at pH < 7 has been advocated. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH >= 5, can prevent drug release in saliva and finds application in taste masking. PMID- 23102012 TI - [MRI-guided targeted prostate biopsies in the diagnosis of prostate cancer: a systematic literature review]. AB - INTRODUCTION: Advances in MRI technology for detection of prostate cancer allow targeted biopsies of suspicious areas. MATERIAL AND METHODS: A systematic literature review was performed on Medline((r)) with the keywords "targeted", "prostate biopsy" and related articles. We studied 65 abstracts and 102 related abstracts, read 38 articles and selected 27 articles. RESULTS: Mental reconstruction gives way for targeted biopsies by direct MRI guidance inside the MRI, and MRI-TRUS fusion. The first option offers high precision targeting but is limited by the accessibility, cost and duration of the procedure. MRI-TRUS image fusion is a promising compromise. Cancer detection rates vary from 15 to 64 %. CONCLUSION: Biopsies targeting suspicious areas on MRI are promising to improve the sensitivity and performance of prostate biopsies. PMID- 23102013 TI - [Aetiology and management of iatrogenic injury of the ureter: a review]. AB - OBJECTIVE: Ureteric injuries (IU) are common complications occurring during abdomino-pelvic surgical procedures. Our aim was to review risk factors, treatment and methods of prevention of these iatrogenic UI. MATERIAL AND METHODS: A literature review in English and French by Medline((r)) was performed using the keywords: ureter; iatrogenic; injury; ureteroscopy; morbidity and endoscopy. RESULTS: The analysis of the epidemiology of IU shows that the first two causes are gynecological and urological surgery. In 80% of cases, the pelvic ureter was concerned. Mechanisms of injury were essentially ligation, section and ischemia by altering the ureteral vasculature. The main risk factors found were pelvic inflammation (endometriosis, radiation...) and the occurrence of bleeding during surgery. In the presence of risk factors, placing a double J stent or a CT may be useful preoperatively. The choice of reparation technique depended on the location of the PU, the circumstances of the occurrence and experience of the surgical team. CONCLUSION: Pelvic surgery is a provider of iatrogenic PU. Knowledge of the management of PU once occurred must be mastered before carrying out any risk surgery. PMID- 23102014 TI - [Guidelines for good practice of intravesical instillations of BCG and mitomycin C from the French national cancer committee (CC-AFU) for non-muscle invasive bladder cancer]. AB - INTRODUCTION: Intravesical BCG immunotherapy and mitomycin C are considered as the standard treatment for non-muscle invasive bladder cancer. These guidelines aim to describe the optimal condition to perform intravesical instillation of BCG or mitomycin C in order to increase its oncologic efficiency and to decrease its morbidity. METHODS: Online systematic literature search was performed on PubMed((r)) until April 2010. Regulation texts, published guidelines and results of recent urologists practice study were taken into consideration. Level of evidence was assigned to each recommendation. A bibliographic research in French and English using Medline((r)) and Embase((r)) with the keywords "BCG", "mitomycin C", "bladder", "complication", "toxicity", "adverse reaction", "prevention" and "treatment" was performed. RESULTS: Patient information must be prior to the first intravesical instillation and should be given through a medical exam by the physician performing the procedure. The check for formal contra-indication to BCG is systematically mandatory by the physician during the medical exam. Intravesical instillation must be realized in a health center where urologic endoscopic procedures are made frequently. A recent urine culture has to be checked systematically before any instillation done either by the urologist or a specialized nurse. Contingent upon a bladder catheter has been inserted in the bladder without any injury of the lower urinary tract, the instillation can be done. The pharmaceutical agent needs to be kept two hours in the bladder. After instillation, the patient must be seated to void and also has to keep in mind that he needs to drink at least 2 liters of water per day for 2 days. CONCLUSION: To improve the oncologic performance and to reduce the risk of complication and adverse event, achievement of intravesical instillations of BCG and/or mitomycin C should follow a standardized procedure. PMID- 23102015 TI - [Xp11.2 translocation renal carcinoma in adults over 50 years of age: about four cases]. AB - OBJECTIVE: To describe demographic, therapeutic and follow-up data of four cases of renal cell carcinoma with Xp11.2 translocation in adults older than 50 years of age. PATIENTS AND METHODS: Between January 2008 and December 2011, 170 patients underwent surgery for renal cell carcinoma in our center. Systematic histopathologic analysis of specimen removed was performed. Complementary immunohistochemical analysis was performed only in cases with uncertain diagnosis or in patients younger than 40 years of age. RESULTS: Among these 170 patients with a median age of 59years old (21-89), immunohistochemistry helped find a TFE3 translocation in four cases (2.4%). There were three women and one man of 53, 71, 75 and 86years old respectively. One patient was metastatic at diagnosis. Radical nephrectomy was first performed in all cases. TNM staging was T3aN2R0, T3bN0R0, T2N2R0 and T3aN2R2, with a Furhman grade of 4. Two patients progressed with metastasis 5 and 7months after surgery, and two with lymphatic invasion 2 and 9months after nephrectomy. One patient died during follow-up. CONCLUSION: Xp11.2 translocation renal cell carcinoma was uncommon after 50years of age in our series, but probably under estimated. It seemed to be associated with a poor prognosis. Larger studies must be performed to optimize its specific treatment. PMID- 23102016 TI - [Stone composition in the central coast Tunisian population]. AB - BACKGROUND: Studies that evaluated the effect of age and gender on the stone composition were scarce. The aim of this study was to identify the stone composition in Tunisian patients and to highlight their modification according to patients' sex and age. PATIENTS AND METHODS: We studied 1200 urolithiasic patients, from the urologic and the pediatric surgery departments, ranging from six months to 92years old and known as having urinary stones (729 males and 471 females). Stone analysis was performed respectively using a stereomicroscope and infrared spectroscopy to determine, respectively, the morphological type and the molecular composition of each. RESULTS: Kidney stones were encountered in 48.6% of calculi. Children and old men were more affected by bladder stone. Whewellite was the main component in 51.8% of the stones and 39.6% of the stone core, its frequency fell according to age from 61.4% in young adults to 47.7% in elderly in favor of the increase of uric acid stones, from 16.4% in young adults to 35.6% in elderly (P<0,02). Struvite stones were rare (3.2%) and more frequent in boys. CONCLUSION: The analysis of these data shows that urinary stones in Tunisia were tending to evolve in the same direction as in industrialized countries. PMID- 23102017 TI - [Urinary continence following laparoscopic radical prostatectomy: qualitative analysis]. AB - PURPOSE: The main purpose of this study was to report urinary continence after laparoscopic radical prostatectomy (LRP) for localised prostate cancer and the return to baseline rate for urinary continence. The minor purpose was to determine the risk factors, which influence return to baseline urinary continence after radical prostatectomy. METHODS: Prospective evaluation of urinary continence with self-administered questionnaire in 300 consecutive LRP for localized prostate cancer. RESULTS: After LRP, at 3, 6 and 12 months, respectively 12.5%, 23% and 33.7% of patients recover baseline urinary continence. Fifty-four percent, 72.3% and 78.4% of patients did not wear pads 3, 6 and 12 months after LRP. In patients without pad, 43 % recovered baseline continence one year after radical prostatectomy. In univariate analysis, age older than 60 years (P=0.003, P=0.003, P=0.02, 3, 6 and 12 months after LRP) and no sparing of neurovascular bundles (P=0.01, P=0.08 at 3 and 6 months after LRP) were risks factors of urinary incontinence. In multivariate analysis, only age older than 60 years (P=0.018, P=0.01 and P=0.01 at 3, 6 and 12 months after LRP) was a risk factor of urinary incontinence. CONCLUSION: One year after LRP, 66.3% of patients had urinary incontinence according to our evaluation using stringent criteria, i.e. return to baseline continence status. However, only 21.6% of patients wore pads and less than 2% wore more than two pads per day. PMID- 23102018 TI - [Radiotherapy with androgen deprivation in high-risk prostate cancer: what outcomes on a Caribbean population?]. AB - OBJECTIVE: To analyze in a Caribbean population at 90% of African descent, the results of radiotherapy with androgen deprivation (AD) in high-risk prostate cancer (PCa). PATIENTS AND METHODS: Fifty-nine consecutive patients with a high risk PCa as defined by the D'AMICO classification and treated by radiotherapy with AD between January 2003 and April 2009 in our center were analyzed. The median dose of radiation and the median duration of AD were 70Gy and 37months respectively. Biochemical recurrence (BF), as primary outcome was defined according to the PHOENIX criteria (nadir PSA+2ng/mL). Multivariate analysis was performed to identify predictive factors of BF. The median follow-up was 47months. RESULTS: Eight (13.6%) patients had BF and four (6.8%) developed metastases. Six (10.2%) died during the follow-up. The 5years acturial biochemical disease-free survival was 79.7%. Multivariate analyses have shown that Gleason sum (GS) superior to 7 (P=0.029), AD duration less than 24months (P=0.004) and the rate of Nadir PSA greater or equal to 0.5ng/mL (P=0.011) were independent predictive factors of BF. CONCLUSION: This study was the first to our knowledge, to provide that radiotherapy associate with AD for HRPC among Caribbean men is effective as observed in other populations. Patients with GS superior to 7 could be considered for more aggressive treatments in clinical trials. PMID- 23102019 TI - [Transurethral resection (TUR) in saline plasma vaporization of the prostate versus standard TUR of the prostate: an economic evaluation]. AB - OBJECTIVE: To evaluate and compare the hospital costs of the transurethral resection in saline plasma vaporization of the prostate (TURis-PVP) and the standard TUR of the prostate (TURP). BACKGROUND: their efficiency and short terms outcomes are similar. PATIENTS AND METHODS: In an observational retrospective and monocentric study, 86 consecutive patients with benign prostatic enlargement (BPE) secondary to benign prostatic hyperplasia (BPH) were enrolled in two non randomized groups. TURP was performed in 44 cases and TURis-PVP in 42 cases. Patients with prostate cancer, urethral stenosis or bladder neck stenosis were not included. Hospital costs with a 3-month follow-up were measured using the database and hospital cost accounting system of the Medical Information Department. RESULTS: Patients from both series had similar preoperative characteristics concerning the age, ASA score, urologic history, and antithrombosis treatments. Catheterization period, complications and rehospitalisation rates were similar. With TURis-PVP, prostatic volume was larger (60+/-24mL vs. 42+/-16mL; P<0.05), hospital stay was shorter (4.0+/-2.8days vs. 4.4+/-2.1days; P<0.05), single-used materials costs were higher (332+/-64? vs. 40+/-18?; P<0.05). The costs of the first hospitalization were 3721+/-843? with TURis-PVP and were 3712+/-880? with TURP (P=0.14). Global costs with a 3-month follow-up were 3867+/-1104? with TURis-PVP and were 4074+/-1624? with TURP (P=0.53). CONCLUSION: In this study, the costs for the hospital are lightly higher in TURis-PVP, due to single use systems, but there is no significant difference for global costs between TURP and TURis-PVP with a 3-month follow-up difference for the health care system. PMID- 23102020 TI - [Malakoplakia involving kidney, both ureters and bladder: a case report and review of the literature]. AB - Malakoplakia is an unusual chronic inflammation characterized macroscopically by pseudotumoral lesions and histologically by the presence of "Michaelis-Gutman" bodies in macrophages. It affects principally the urinary tract and is probably secondary to an unusual macrophagic reaction to recurrent urinary tract infections. If the bladder is the most frequent site of occurrence, the ureters can very rarely be affected resulting in urinary tract obstruction. We presented here a unique presentation of renal, bilateral ureteral and bladder malakoplakia. PMID- 23102021 TI - [Comment to intra-prostatic UroLift((r)) implants for benign prostatic hyperplasia]. PMID- 23102023 TI - Twelve tips for junior doctors interested in a career in medical education. AB - BACKGROUND: As with the many specialities within medicine, the expanding field of medical education is becoming a more formal and professionalised arena. AIM: This article aims to assist junior doctors wishing to pursue formal educational roles in their future careers. METHODS: We offer twelve tips for junior doctors with these aspirations in mind, exploring a range of potential roles, resources and opportunities available. RESULTS: Twelve practical suggestions on how junior doctors can nurture their portfolios of evidence and subsequent future careers in medical education. CONCLUSIONS: The developing world of medical education is becoming evermore structured and professionalised. Educators of the future will need to demonstrate evidence of their knowledge, skills and experience in the field in order to effectively assume and perform educational roles. PMID- 23102022 TI - Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3 carboxylate (CXL017): a novel scaffold that resensitizes multidrug resistant leukemia cells to chemotherapy. AB - Multidrug resistance (MDR) is a major hurdle in the treatment of cancer, and there is a pressing need for new therapies. We have recently developed ethyl 2 amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017), derived from a dual inhibitor of Bcl-2 and SERCA proteins, sHA 14-1, with selective cytotoxicity toward MDR cancer cell lines in vitro. In this study, we present new evidence for its therapeutic potential in treatment of MDR cancers and offer mechanistic insights toward its preferential targeting of drug resistant cancer. CXL017 selectively suppressed the growth of tumors derived from the MDR cancer cell line, HL60/MX2, in vivo. In addition, even after chronic exposure to CXL017, HL60/MX2 failed to develop stable resistance to CXL017, whereas it acquired >2000-fold resistance to cytarabine (Ara-C), the major first line chemotherapy for the treatment of acute myeloid leukemia (AML). Remarkably, instead of acquiring further cross-resistance, HL60/MX2 cells exposed to CXL017 were resensitized to standard therapies (10- to 100-fold). Western blotting analyses revealed that CXL017 exposure significantly down-regulated Mcl-1 and Bax and up-regulated Noxa, Bim, Bcl-X(L), SERCA2, and SERCA3 proteins, along with a reduction in endoplasmic reticulum (ER) calcium content. Given the well established functions of Bcl-2 family proteins and ER calcium in drug resistance, our results suggest that the down-regulation of Mcl-1 and the up-regulation of Noxa and Bim along with the decrease in ER calcium content are likely responsible for CXL017-induced resensitization of MDR cancer cells. These data also demonstrate the unique potential of CXL017 to overcome MDR in cancer treatment. PMID- 23102024 TI - Baeyer-Villiger C-C bond cleavage reaction in gilvocarcin and jadomycin biosynthesis. AB - GilOII has been unambiguously identified as the key enzyme performing the crucial C-C bond cleavage reaction responsible for the unique rearrangement of a benz[a]anthracene skeleton to the benzo[d]naphthopyranone backbone typical of the gilvocarcin-type natural anticancer antibiotics. Further investigations of this enzyme led to the isolation of a hydroxyoxepinone intermediate, leading to important conclusions regarding the cleavage mechanism. PMID- 23102025 TI - A quantitative genetic and epigenetic model of complex traits. AB - BACKGROUND: Despite our increasing recognition of the mechanisms that specify and propagate epigenetic states of gene expression, the pattern of how epigenetic modifications contribute to the overall genetic variation of a phenotypic trait remains largely elusive. RESULTS: We construct a quantitative model to explore the effect of epigenetic modifications that occur at specific rates on the genome. This model, derived from, but beyond, the traditional quantitative genetic theory that is founded on Mendel's laws, allows questions concerning the prevalence and importance of epigenetic variation to be incorporated and addressed. CONCLUSIONS: It provides a new avenue for bringing chromatin inheritance into the realm of complex traits, facilitating our understanding of the means by which phenotypic variation is generated. PMID- 23102026 TI - Glycosaminoglycan-mediated selective changes in the aggregation states, zeta potentials, and intrinsic stability of liposomes. AB - Though the aggregation of glycosaminoglycans (GAGs) in the presence of liposomes and divalent cations has been previously reported, the effects of different GAG species and minor changes in GAG composition on the aggregates that are formed are yet unknown. If minor changes in GAG composition produce observable changes in the liposome aggregate diameter or zeta potential, such a phenomenon may be used to detect potentially dangerous oversulfated contaminants in heparin. We studied the mechanism of the interactions between heparin and its oversulfated glycosaminoglycan contaminants with liposomes. Herein, we demonstrate that Mg(2+) acts to shield the incoming glycosaminoglycans from the negatively charged phosphate groups of the phospholipids and that changes in the aggregate diameter and zeta potential are a function of the glycosaminoglycan species and concentration as well as the liposome bilayer composition. These observations are supported by TEM studies. We have shown that the organizational states of the liposome bilayers are influenced by the presence of GAG and excess Mg(2+), resulting in a stabilizing effect that increases the T(m) value of DSPC liposomes; the magnitude of this effect is also dependent on the GAG species and concentration present. There is an inverse relationship between the percent change in aggregate diameter and the percent change in aggregate zeta potential as a function of GAG concentration in solution. Finally, we demonstrate that the diameter and zeta potential changes in POPC liposome aggregates in the presence of different oversulfated heparin contaminants at low concentrations allow for an accurate detection of oversulfated chondroitin sulfate at concentrations of as low as 1 mol %. PMID- 23102027 TI - T-wave axis deviation, metabolic syndrome and cardiovascular risk: results from the MOLI-SANI study. AB - Early recognition of patients at increased cardiovascular risk is a major challenge. The surface electrocardiogram provides a useful platform and it has been used to propose several indexes. T wave axis abnormality is associated with an increased risk of cardiovascular mortality, independently of other risk factors and can be associated with the presence of the metabolic syndrome (MetS). We assessed the prevalence of T axis abnormalities and its relationship with MetS and its components in a large population of Italian adults. Data concerning 11,143 women (54 +/- 11 years) and 9742 men (55 +/- 11 years) randomly recruited from a general population (Moli-sani cohort) were analyzed. After excluding subjects with incomplete data and with history of cardiac disease or left ventricular hypertrophy, T-wave axis was normal in 74.5% of men and 80.9% of women, borderline in 23.6% and 17.3% and abnormal in 1.9% and 1.8%. In subjects with MetS, the prevalence of borderline or abnormal T-wave axis deviation was higher than in subjects without MetS (in men: 26.6% vs. 22.1% and 2.5% vs. 1.7%; in women: 25% vs. 15% and 2.4% vs. 1.6%, respectively for borderline and abnormal levels, p<0.0001). Each component of MetS increased the odds of having borderline or abnormal T-wave axis deviation by 1.21 in men and 1.31 in women. T wave axis deviation is associated with MetS and its individual components. These findings confirm previous reported results, expanding them to a large and representative sample of European population of Caucasian ethnicity. PMID- 23102028 TI - Transforming the emergency department observation unit: a look into the future. AB - Many institutions have developed outpatient observation units as an alternative to short-stay inpatient admissions. In this article, we highlight evidence to support the efficacy of EDOU care for chest pain and identify areas in which additional research is needed. Evidence-based protocols and collaborative approaches to care have potential to achieve similar clinical and improved economic outcomes compared with hospital admission. The potential for the EDOU to provide the right care for the right patient at the right time is only beginning to be realized, with significant advances in health care delivery anticipated in the near future. PMID- 23102029 TI - Is it prime time for "rapid comprehensive cardiopulmonary imaging" in the emergency department? AB - Reducing hospital admissions through improved risk stratification of patients with potential acute coronary syndrome represents a critical focus for reducing health care expenditure. Coronary computed tomographic angiography (CTA) has been used with increasing frequency as part of the evaluation of chest pain in the Emergency Department. In the appropriate group of patients at low to intermediate risk CTA appears to be an excellent evaluation strategy, safely and efficiently allowing for the rapid discharge of patients home. PMID- 23102030 TI - Hypertension crisis in the emergency department. AB - Hypertensive crises, which include hypertensive emergencies and urgencies, are frequently encountered in the emergency department, and require immediate attention as they can lead to irreversible end-organ damage. Normal blood pressure (BP) regulation is altered during acute rises in BP, leading to end organ damage. Multiple organs can be injured. Special considerations should be given to hypertensive pregnant patients and patients with postoperative hypertension. Treatment should be individualized to each patient based on the type and extent of end-organ damage, degree of BP elevation, and the specific side effects that each medication could have on a patient's preexisting comorbidities. PMID- 23102031 TI - Blunt cardiac injury. AB - Blunt chest trauma represents a spectrum of injuries to the heart and aorta that vary markedly in character and severity. The setting, signs, and symptoms of chest trauma are often nonspecific, which represents a challenge to emergency providers. Individuals with suspected blunt chest trauma who have only mild or no symptoms, a normal electrocardiogram (ECG), and are hemodynamically stable typically have a benign course and rarely require further diagnostic testing or long periods of close observation. Individuals with pain, ECG abnormalities, or hemodynamic instability may require rapid evaluation of the heart by echocardiography and the great vessels by advanced imaging. PMID- 23102032 TI - I passed out: now what?: general approach to the patient with syncope. AB - Syncope is the transient loss of consciousness and postural tone caused by transient cerebral hypoperfusion. It is a common problem that is often alarming to patients and their families. The differential diagnosis of the patient with transient loss of consciousness is broad and workup may be expensive. It is important to identify patients with life-threatening conditions and those with red flags indicating an increased risk of sudden death. An initial approach consisting of a careful history, physical examination, and electrocardiograms is essential. This review covers the general diagnostic approach to the patient with syncope. PMID- 23102033 TI - Acute management of atrial fibrillation: from emergency department to cardiac care unit. AB - Atrial fibrillation (AF) is the most common tachyarrhythmia encountered in clinical practice. One-third of hospitalizations in the United States are attributed to AF, with increasing rates in the past decade. Significant morbidity and mortality, including ~15% to 20% of all ischemic strokes, result from AF. AF is associated with many causes and comorbidities. Hallmarks of acute AF management are accurate diagnosis, clinical stabilization, symptom relief through rate or rhythm control, thromboembolic stroke risk modification, and treatment of underlying causes. Meticulous and individualized acute evaluation based on these goals facilitates successful transition to long-term collaborative optimization of outcomes. PMID- 23102034 TI - Novel patterns of ischemia and STEMI equivalents. AB - Diagnosis of ST-segment elevation myocardial infarction has long been considered time sensitive. Several other electrocardiogram abnormalities, sometimes referred to as "STEMI-equivalents", should also alert the clinician to conditions similarly requiring aggressive intervention. The de Winter/ST/T complex, ST segment elevation in lead aVR, Wellens' phenomenon, posterior wall myocardial infarction, and pathologic ST changes in the presence of left bundle branch block and pacemakers are all discussed in this article. PMID- 23102035 TI - Electrocardiographic patterns mimicking ST segment elevation myocardial infarction. AB - The 12-lead electrocardiogram (ECG) remains the cornerstone of prompt diagnosis of STEMI; Furthermore, the 12-lead ECG provides the primary indication for emergent reperfuison therapy in the STEMI patient. In certain cases, a patient's ECG can resemble STEMI yet manifest ST-segment elevation from a non-coronary based syndrome; these entities are termed the STEMI mimics and include benign early repolarization, acute pericarditis, and left ventricular aneurysm, to name only a few. In other situations, the patient's ECG makes it difficult or impossible to determine whether STEMI is present, the so-called STEMI confounders and include left bundle branch block pattern, left ventricular hypertrophypattern, and the ventricular paced pattern. The goal with STEMI mimics and confounders is to maximize rapid, accurate diagnosis while avoiding delays in treatment of alternative causes of ST-segment elevation. PMID- 23102036 TI - Acute coronary syndromes: from the emergency department to the cardiac care unit. AB - Acute coronary syndromes result in a significant burden of morbidity and mortality in the United States. This spectrum of acute coronary thrombosis (including unstable angina, non-ST-segment elevation myocardial infarction, and ST-elevation myocardial infarction) has been well studied in large clinical trials. This review details the initial management of patients presenting with possible acute coronary syndromes in the context of care from the emergency department to the cardiac care unit. The importance of a rapid and focused evaluation, risk stratification, and appropriate therapies are discussed. PMID- 23102037 TI - Reperfusion strategies and systems of care in ST-elevation myocardial infarction. AB - Approximately 330,000 ST-elevation myocardial infarctions (STEMI) occur yearly in the United States. Emergent reperfusion is the cornerstone of STEMI therapy and the key to restoration of coronary blood flow in an infarct-related vessel. Reperfusion methods include thrombolysis, primary percutaneous coronary intervention, or both methods combined. Selection of the appropriate reperfusion strategy is essential, along with having an efficient system of care capable of delivering these therapies. Timely reperfusion is highly dependent on a well structured care system designed to meet the needs of each individual community. This article reviews the data behind different reperfusion strategies and introduces successful systems-of-care models. PMID- 23102038 TI - Cooling the fire: resuscitated sudden death. AB - Care of the patient with return of spontaneous circulation following sudden cardiac death is complex and challenging. A systematic and comprehensive approach can increase the chances of meaningful recovery of the postarrest patient. This article focuses on a systematic approach to the postarrest patient, which includes optimizing oxygenation and ventilation, maintaining adequate perfusion pressure, monitoring oxygen delivery, initiating and maintaining therapeutic hypothermia, and identifying patients appropriate for emergent cardiac catheterization. Using this approach, providers treating the postarrest patient can maximize the chance that a patient walks out of the hospital neurologically intact. PMID- 23102039 TI - Assessment and management of cardiogenic shock in the emergency department. AB - Cardiogenic shock remains a major cause of morbidity and mortality in patients hospitalized with myocardial infarction, severe valvular disease, and other causes of cardiomyopathy. Emergency physicians play a pivotal role in the initial management of these patients, as they are most often the point of first contact with the medical system. This review discusses the initial assessment and management of cardiogenic shock, emphasizing the importance and role of the emergency physician. PMID- 23102040 TI - Acute decompensated heart failure. AB - Acute decompensated heart failure (ADHF) is the most common cause of cardiovascular hospital admission; 1 in 4 patients with heart failure is readmitted within 30 days of being discharged, and ADHF consumes 1% to 2% of the total health care resources. The most effective approach for preventing heart failure hospitalizations is a combination of improvement in management of patients while they are in the hospital and comprehensive post hospitalization care. Decreasing the length of hospitalization can increase readmission rate, so optimization of inpatient and outpatient care is essential. PMID- 23102041 TI - Management of implantable assisted circulation devices: emergency issues. AB - As the prevalence of systolic heart failure increases, the population of patients in need of advanced therapies becomes larger. As the number of transplants performed each year plateaus, the prevalence of community-dwelling patients with ventricular assist devices (VADs) increases. A broad range of physicians, including emergency physicians, general cardiologists, and generalists, will be exposed to these patients, and must be informed on the disease processes and complications specific to these devices. With an understanding of up-front evaluation and management, these patients may be triaged and stabilized, and will benefit before referral for definitive care by a VAD specialist. PMID- 23102042 TI - Emergency cardiovascular care. PMID- 23102043 TI - Emergency cardiovascular care: from ED to CCU and beyond. PMID- 23102044 TI - Accurate stabilities of laccase mutants predicted with a modified FoldX protocol. AB - Fungal laccases are multicopper enzymes of industrial importance due to their high stability, multifunctionality, and oxidizing power. This paper reports computational protocols that quantify the relative stability (DeltaDeltaG of folding) of mutants of high-redox-potential laccases (TvLIIIb and PM1L) with up to 11 simultaneously mutated sites with good correlation against experimental stability trends. Molecular dynamics simulations of the two laccases show that FoldX is very structure-sensitive, since all mutants and the wild type must share structural configuration to avoid artifacts of local sampling. However, using the average of 50 MD snapshots of the equilibrated trajectories restores correlation (r ~ 0.7-0.9, r(2) ~ 0.49-0.81) and provides a root-mean-square accuracy of ~1.2 kcal/mol for DeltaDeltaG or 3.5 degrees C for T(50), suggesting that the time average of the crystal structure is recovered. MD-averaged input also reduces the spread in DeltaDeltaG, suggesting that local FoldX sampling overestimates free energy changes because of neglected protein relaxation. FoldX can be viewed as a simple "linear interaction energy" method using sampling of the wild type and mutant and a parametrized relative free energy function: Thus, we show in this work that a substantial "hysteresis" of ~1 kcal/mol applies to FoldX, and that an improved protocol that reverses calculations and uses the average obtained DeltaDeltaG enhances correlation with the experimental data. As glycosylation is ignored in FoldX, its effect on DeltaDeltaG must be additive to the amino acid mutations. Quantitative structure-property relationships of the FoldX energy components produced a substantially improved laccase stability predictor with errors of ~1 degrees C for T(50), vs 3-5 degrees C for a standard FoldX protocol. The developed model provides insight into the physical forces governing the high stability of fungal laccases, most notably the hydrophobic and van der Waals interactions in the folded state, which provide most of the predictive power. PMID- 23102046 TI - The behavior of acoustic bubbles in aqueous solutions containing soluble polymers. AB - The effects of the water-soluble polymer polyvinylpyrrolidone (PVP) on the multibubble sonoluminescence (MBSL) intensity generated in aqueous solutions exposed to ultrasound at the two ultrasound frequencies of 20 and 363 kHz have been examined. In both cases, the presence of PVP, at concentrations of up to 2 g/100 mL, was found to enhance the MBSL intensity emitted from the solutions. On the basis of the intensity behavior of the SL observed from aqueous solutions containing PVP/surfactant and PVP/alcohol mixtures, it is suggested that PVP enhances MBSL by increasing the number of active bubbles in the system by hindering bubble-bubble coalescence processes and probably also by changing the structure of the bubble "clouds" formed at the acoustic antinodes in solution. The influence of PVP on bubble-bubble coalescence rates was also measured to support the interpretation of the MBSL emission experiments. PMID- 23102047 TI - Generalist and specialty physicians: supply and access, 2009-2010. AB - As the overall population ages, policy makers are focusing on the current and growing shortage of the primary care workforce (1-3), particularly as provisions of the 2010 Patient Protection and Affordable Care Act (PPACA) expand health insurance coverage. This report presents selected trends in physician shortage measures and access to care measures for generalist physicians and specialists. Generalists are those in the specialties of family practice, general practice, internal medicine, and pediatrics, whereas specialists comprise all other specialties. Estimates are based on physicians who participated in the National Ambulatory Medical Care Survey (NAMCS) by providing data on visits. PMID- 23102048 TI - In vitro detection of adrenocorticotropic hormone levels by fluorescence correlation spectroscopy immunoassay for mathematical modeling of glucocorticoid mediated feedback mechanisms. AB - Performing quantitative, highly sensitive measurements at a single molecule level is often necessary to address specific issues related to complex molecular and biochemical systems. For that purpose, we present a technique exploiting both the flexibility of immunoassays as well as the low operating costs and high throughput rates of the fluorescence correlation spectroscopy (FCS) method. That way we have established a quantitative measurement technique providing accurate and flexibly time resolved data of single molecules. Nanomolar changes in adrenocorticotropic hormone (ACTH) levels have been detected in a short time frame that are caused by fast feedback actions in AtT-20 anterior pituitary glands in vitro. Especially with respect to clinical diagnostic or mathematical modeling this improved FCS setup may be of high relevance in order to accurately quantify the amounts of peptide hormones-such as ACTH-as well as signaling molecules, transcription factors, etc., being involved in intra- and extracellular reaction networks. PMID- 23102049 TI - Effect of surface charge on the uptake and distribution of gold nanoparticles in four plant species. AB - Small (6-10 nm) functionalized gold nanoparticles (AuNPs) featuring different, well-defined surface charges were used to probe the uptake and distribution of nanomaterials in terrestrial plants, including rice, radish, pumpkin, and perennial ryegrass. Exposure of the AuNPs to plant seedlings under hydroponic conditions for a 5-day period was investigated. Results from these studies indicate that AuNP uptake and distribution depend on both nanoparticle surface charge and plant species. The experiments show that positively charged AuNPs are most readily taken up by plant roots, while negatively charged AuNPs are most efficiently translocated into plant shoots (including stems and leaves) from the roots. Radish and ryegrass roots generally accumulated higher amounts of the AuNPs (14-900 ng/mg) than rice and pumpkin roots (7-59 ng/mg). Each of the AuNPs used in this study were found to accumulate to statistically significant extents in rice shoots (1.1-2.9 ng/mg), while none of the AuNPs accumulated in the shoots of radishes and pumpkins. PMID- 23102050 TI - What is the role of eye movements in eye movement desensitization and reprocessing (EMDR) for post-traumatic stress disorder (PTSD)? a review. AB - BACKGROUND: Controversy continues to exist regarding how EMDR works and whether its mechanisms differ from those at work in standard exposure techniques. AIMS: To investigate first whether eye movement bilateral stimulation is an essential component of EMDR and, second, the current status of its theoretical basis. METHOD: A systematic search for relevant articles was conducted in databases using standard methodology. RESULTS: Clinical research evidence is contradictory as to how essential EMs are in PTSD treatment. More positive support is provided by analogue studies. With regards to potential theoretical support, some evidence was found suggesting bilateral stimulation first increases access to episodic memories; and second that it could act on components of working memory which makes focusing on the traumatic memories less unpleasant and thereby improves access to these memories. CONCLUSIONS: The results suggest support for the contention that EMs are essential to this therapy and that a theoretical rationale exists for their use. Choice of EMDR over trauma-focused CBT should therefore remain a matter of patient choice and clinician expertise; it is suggested, however, that EMs may be more effective at reducing distress, and thereby allow other components of treatment to take place. PMID- 23102051 TI - Intimate partner violence and use of reproductive health services among married women: evidence from a national Bangladeshi sample. AB - BACKGROUND: Data from a statewide survey in India and clinic-based studies in developed settings have previously suggested an association between maternal physical intimate partner violence (IPV) experiences and the low use of antenatal care (ANC). This study aimed to explore the association between maternal experiences of physical and sexual IPV and the use of reproductive health care services, using a large nationally representative data set from Bangladesh. METHODS: This paper used data from the 2007 Bangladesh Demographic Health Survey. The analyses were based on the responses of 2001currently married women living with at least one child younger than 5 years. Exposure was determined from maternal reports of physical and sexual IPV. The utilization of ANC according to amount and type of provider and utilization of delivery assistance according to provider type were used as proxy outcome variables for reproductive health care utilization. Descriptive statistics and multivariate logistic regression analysis used in the study. RESULTS: Approximately two out of four (48.2%) respondents had experienced physical IPV. Maternal experience of physical IPV was associated with low use of receiving sufficient ANC (adjusted odds ratio [AOR] 0.69; 95% confidence interval [CI] 0.49-0.96), lower likelihood of receiving ANC (AOR 0.69; 95% CI 0.53-0.89), and assisted deliveries from skilled provider (AOR 0.54; 95% CI 0.37-0.78). Women who had been sexually abused were significantly less likely to have visited a skilled ANC and delivery care provider. Furthermore, severity of physical IPV appeared to have more profound consequences on the outcome measured. CONCLUSIONS: The association between exposure to IPV and use of reproductive health care services suggests that partner violence plays a significant role in lower utilization of reproductive health services among women in Bangladesh. Our findings suggest that, in addition to a wide range of socio demographic factors, preventing maternal physical and sexual IPV need to be considered as an important psychosocial determinates for the higher utilization of reproductive health care services in Bangladesh. PMID- 23102052 TI - Melt sonocrystallized piroxicam for oral delivery: particle characterization, solid state analysis, and pharmacokinetics. AB - OBJECTIVES: The present study investigates the effect of particle engineering technique on powder properties and pharmacokinetics of piroxicam (PXM). METHODS: PXM was subjected to melt sonocrystallization to obtain product designated as MSCPXM and characterized for various pharmacotechnical parameters, performance characteristics and pharmacokinetic evaluation. RESULTS: Micromeritic and rheological properties were found to be superior to the original form (OFPXM). On melt sonocrystallization, solubility and intrinsic dissolution rate were enhanced by 76.45% and 33.33%, respectively. Solid state evaluation by DSC and XRPD ruled out possibilities of polymorph formation but confirmed decreased crystallinity index. SEM analysis revealed uniformly shaped smaller drug particles of MSCPXM as compared to PXM. The thermodynamic stability of MSCPXM was monitored by XRPD and the sample was stable even after 3 months of storage at 40 +/- 2 degrees C and 75 +/- 5% RH. The MSCPXM was formulated as immediate release tablets (F1 - F4) and evaluated with reference tablets of OFPXM (F0). F2 was identified as best formulation with suitable tablet characteristics and in-vitro drug release profile. Pharmacokinetic evaluation of F2 in rats supported the in-vitro data with 2.08-fold increase in bioavailability achieved at 4.8 +/- 1.7 h with MSCPXM as compared to OFPXM. CONCLUSIONS: Conclusively, melt sonocrystallization offered an efficient, solvent-free technique that can be exploited for particle designing of drugs with favorable pharmaceutical properties. PMID- 23102053 TI - Noble metal nanowires: from plasmon waveguides to passive and active devices. AB - Using chemical synthesis, researchers can produce noble metal nanowires with highly regular, crystalline properties unachievable by alternative, top-down nanofabrication methods. Sitting at the intersection of nanochemistry and nanooptics, noble metal nanowires have generated intense and growing research interest. These nanostructures combine subwavelength transverse dimensions (50 100 nm) and longitudinal dimensions that can reach tens of micrometers or more, which makes them an ideal platform to launch surface plasmon waves by direct illumination of one end of the structure. Because of this property, researchers are using noble metal nanowires as a tool for fundamental studies of subwavelength plasmon-based optics and the properties of surface plasmon guided wave propagation in highly confined geometries below the classical optical diffraction limit. In this Account, we review some of the recent developments in plasmonic nanowire fabrication, nanowire plasmon imaging, and nanowire optical components and devices. The addition of an adjacent nanowire, substrate, or other symmetry-breaking defect can enable the direct coupling of light to and from free space to the guided waves on a nanowire structure. Such structures lead to more complex nanowire-based geometries with multiple optical inputs and outputs. Additional nanowire imaging methods are also possible: plasmon propagation on nanowires produces intense near-field diffraction, which can induce fluorescence in nearby quantum dots or photobleach adjacent molecules. When the nanowire is deposited on a dielectric substrate, the plasmon propagation along chemically synthesized nanowires exceeds 10 MUm, which makes these structures useful in nonlocal applications such as remote surface-enhanced Raman spectroscopy (SERS) sensing. Nanowires can be used as passive optical devices, which include, for example, polarization manipulators, linear polarization rotators, or even broadband linear-to-circular polarization converters, an optical function not yet achievable with conventional diffraction-limited optical components. Nanowires can also serve as highly directional broadband optical antennas. When assembled into networks, plasmonic nanowires can be used to create optical devices, such as interferometric logic gates. Individual nanowires function as multiple input and output terminals in branched network geometries, where light incident on one wire can turn the emission from one or more output wires on or off. Nanowire-based devices that could exploit this effect include nanoscale routers and multiplexers, light modulators, and a complete set of Boolean logic functions. PMID- 23102055 TI - Competency-based education in family medicine. AB - BACKGROUND: As a way of demonstrating an objective assessment of trainee competence, the College of Family Physicians of Canada has recently approved a competency-based framework known as CanMEDS-FM. All training programs in family medicine in Canada will be required to demonstrate the development of curriculum and evaluation methods based on the roles defined by the framework. AIM: This article describes the rationale and the approach used to develop a competency based education curriculum in the postgraduate family medicine program at the University of Toronto. METHOD: The authors describe a systematic approach to curriculum development which includes the formation of a central steering committee, content development by faculty experts, mapping of curriculum to an accreditation framework, and a faculty consensus exercise. We discuss challenges to development and implementation of a competency-based framework as well as areas that require further work and development. CONCLUSIONS: The competency based curriculum is both a new method of learning for residents and, a new method of teaching for faculty. While there are many potential benefits and challenges, this article focuses on the model's utility in terms of flexible learner-centered educational design, as well as its ability to identify learners' strengths and needs. PMID- 23102054 TI - Synthesis and evaluation of the aldolase antibody-derived chemical-antibodies targeting alpha5beta1 integrin. AB - Integrin alpha5beta1 is an important therapeutic target that can be inhibited using an aldolase antibody (Ab)-derived chemical-Ab (chem-Ab) for the treatment of multiple human diseases, including cancers. A fairly optimized anti-integrin alpha5beta1 chem-Ab 38C2-4e was obtained using an in situ convergent chemical programming (CP) approach, which minimized the time and effort needed to develop a chem-Ab. Multiple Ab-programming agents (PAs) 4a-e could be prepared rapidly using the Cu-catalyzed alkyne-azide coupling (Cu-AAC) reaction of an alpha5beta1 inhibitor 2 with multiple linkers 3a-e, either before or after conjugating the linkers into Ab 38C2 binding sites. In these two-steps processes, the products after step 1 can be used in the next step without performing an extensive purification or analysis of the Ab-PAs or Ab-linker conjugates affording chem-Abs 38C2-(4a-e). Flow cytometry assay was used to determine the binding of the chem Abs to U87 human glioblastoma cells expressing alpha5beta1 integrin and identify 38C2-3e as the strongest binder. Further studies revealed that 38C2-3e strongly inhibited proliferation of U87 cells and tube formation of HUVEC in the matrigel assay, as well as tumor growth and metastasis of 4T1 cells in vivo. PMID- 23102056 TI - The application of wiki technology in medical education. AB - BACKGROUND, AIMS AND METHODS: Recent years have seen the introduction of web based technologies such as the 'wiki', which is a webpage whose content can be edited in real time using a web browser. This article reviews the current state of knowledge about the use of wikis in education, and considers whether wiki technology has features that might prove useful in medical education. RESULTS: Advantages and challenges of the technology are discussed, and recommendations for use are provided. We believe that wiki technology offers a number of potential benefits for administrators, students and instructors, including the ability to share information online, to construct knowledge together, to facilitate collaboration and to enable social learning and peer feedback. CONCLUSIONS: We believe that with proper planning and instructional design, wiki technology can be usefully employed in medical education. We intend to continue to study the impact of wiki technology in our own programme, and we encourage others to evaluate the application of wiki technology in other areas of medical education. PMID- 23102057 TI - Developing a multisource feedback tool for postgraduate medical educational supervisors. AB - PURPOSE: Supervisors play a key role in the development of postgraduate medical trainees both in the oversight of their day-to-day clinical practice but also in the support of their learning experiences. In the UK, there has been a clear distinction made between these two activities. In this article, we report on the development of a web-based multisource feedback (MSF) tool for educational supervisors in the London Deanery, an organisation responsible for 20% of the UK's doctors and dentists in training. METHODS: A narrative review of the literature generated a question framework for a series of focus groups. Data were analysed using an interpretative thematic approach and the resulting instrument piloted online. Instrument performance was analysed using a variety of tools including factor analysis, generalisability theory and analysis of performance in the first year of implementation. RESULTS: Two factors were initially identified. Three questions performed inadequately and were subsequently discarded. Educational supervisors scored well, generally rating themselves lower than they were by their trainees. The instrument was launched in July 2010, requiring five respondents to generate a summated report, with further validity evidence collated over the first year if implementation. CONCLUSIONS: Arising out of a robust development process, the London Deanery MSF instrument for educational supervisors is a tool that demonstrates considerable evidence of validity and can provide supervisors with useful evidence of their effectiveness. PMID- 23102058 TI - Theoretical investigations on decomposition of HCOOH catalyzed by Pd7 cluster. AB - Density functional theory based calculations have been performed to investigate decomposition of HCOOH on a Pd(7) cluster in vacuum and solution. The adsorption of HCOOH on Pd(7) cluster occurs on a layer-by-layer quasi-planar conformation of Pd(7) with 4 atoms on top and 3 atoms below. Possible reaction pathways for the decomposition of HCOOH adsorbed on Pd(7) cluster in vacuum and solution are located and compared in terms of the reaction enengies and barriers. Formic acid prefers to decompose through dehydrogenation rather than dehydrate under the significant effect of solvent. The toxic species, CO generated on Pt surface, could not possibly appear in the catalytic decomposition of formic acid on Pd(7) cluster due to high reaction barrier, thus no poisoning of catalyst would occur on Pd surface. The Pd(7) cluster model rationalizes experimental observation, and the predictions are in good agreement with the ones based on the surface model. PMID- 23102059 TI - Combing the hairball with BioFabric: a new approach for visualization of large networks. AB - BACKGROUND: The analysis of large, complex networks is an important aspect of ongoing biological research. Yet there is a need for entirely new, scalable approaches for network visualization that can provide more insight into the structure and function of these complex networks. RESULTS: To address this need, we have developed a software tool named BioFabric, which uses a novel network visualization technique that depicts nodes as one-dimensional horizontal lines arranged in unique rows. This is in distinct contrast to the traditional approach that represents nodes as discrete symbols that behave essentially as zero dimensional points. BioFabric then depicts each edge in the network using a vertical line assigned to its own unique column, which spans between the source and target rows, i.e. nodes. This method of displaying the network allows a full scale view to be organized in a rational fashion; interesting network structures, such as sets of nodes with similar connectivity, can be quickly scanned and visually identified in the full network view, even in networks with well over 100,000 edges. This approach means that the network is being represented as a fundamentally linear, sequential entity, where the horizontal scroll bar provides the basic navigation tool for browsing the entire network. CONCLUSIONS: BioFabric provides a novel and powerful way of looking at any size of network, including very large networks, using horizontal lines to represent nodes and vertical lines to represent edges. It is freely available as an open-source Java application. PMID- 23102061 TI - A clinical approach to diffuse parenchymal lung disease. AB - The diffuse parenchymal lung diseases (DPLDs) are a group of more than 200 diverse conditions; therefore achieving an exact diagnosis is frequently challenging. However, with the advent of novel, disease-specific therapies, an accurate diagnosis in DPLD is of growing importance. The recognition that many of the DPLDs have distinctive high-resolution computed tomography appearances has greatly reduced the need for biopsy, although in cases of uncertainty, histologic assessment remains an important tool. Ultimately, the diagnostic assessment of DPLD is best undertaken through an interstitial lung disease multidisciplinary team meeting that brings together physicians, thoracic radiologists, and pathologists. PMID- 23102060 TI - Simple neck pain questions used in surveys, evaluated in relation to health outcomes: a cohort study. AB - BACKGROUND: The high prevalence of pain reported in many epidemiological studies, and the degree to which this prevalence reflects severe pain is under discussion in the literature. The aim of the present study was to evaluate use of the simple neck pain questions commonly included in large epidemiological survey studies with respect to aspects of health. We investigated if and how an increase in number of days with pain is associated with reduction in health outcomes. METHODS: A cohort of university students (baseline age 19-25 years) were recruited in 2002 and followed annually for 4 years. The baseline response rate was 69% which resulted in 1200 respondents (627 women, 573 men). Participants were asked about present and past pain and perceptions of their general health, sleep disturbance, stress and energy levels, and general performance. The data were analyzed using a mixed model for repeated measurements and a random intercept logistic model. RESULTS: When reporting present pain, participants also reported lower prevalence of very good health, higher stress and sleep disturbance scores and lower energy score. Among those with current neck pain, additional questions characterizing the pain such as duration (categorized), additional pain sites and decreased general performance were associated with lower probability of very good health and higher amounts of sleep disturbance. Knowing about the presence or not of pain explains more of the variation in health between individuals, than within individuals. CONCLUSION: This study of young university students has demonstrated that simple neck pain survey questions capture features of pain that affect aspects of health such as perceived general health, sleep disturbance, mood in terms of stress and energy. Simple pain questions are more useful for group descriptions than for describing or following pain in an individual. PMID- 23102062 TI - Idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause characterized by progressive scarring of the lung parenchyma and relentless loss of lung function. The diagnosis depends on close collaboration between clinicians, radiologists, and pathologists. No therapies approved by the Food and Drug Administration are available for IPF, and an analysis of completed clinical trials has demonstrated that the clinical course of IPF is largely unpredictable. Until therapies that improve survival become available, measures to preserve function and quality of life should be considered, and gastroesophageal reflux should be treated aggressively. PMID- 23102063 TI - Sarcoidosis. AB - Sarcoidosis is a multisystem granulomatous syndrome with a vast range of clinical manifestations. Since the first description of sarcoidosis in 1869, it has simultaneously intrigued and perplexed generations of physicians. Because sarcoidosis can occur variably in any organ and does not always adhere to classic descriptions, both diagnosis of sarcoidosis and attribution of symptoms can be extremely challenging. The management of sarcoidosis requires consideration of the expected course. Medication is considered when there is risk of irreversible vital organ damage, substantial progression, or symptoms that are affecting quality of life. Recently, a range of steroid-sparing therapies have been adopted for sarcoidosis. PMID- 23102064 TI - Connective tissue disease-associated lung disease. AB - This article provides a broad overview of the complex intersection between the connective tissue diseases (CTDs) and their pulmonary manifestations. Indirect pulmonary complications - such as respiratory infection and medication-induced lung toxicity - are briefly discussed, and the importance of a comprehensive assessment of the patient with CTD with respiratory symptoms is emphasized. A concise review of the many pulmonary manifestations of each specific CTD is provided, and particular emphasis is placed on CTD-associated interstitial lung disease. PMID- 23102065 TI - Hypersensitivity pneumonitis. AB - Clinical manifestations of hypersensitivity pneumonitis may closely mimic other interstitial lung diseases, and the disease onset is usually insidious. High resolution computed tomography and bronchoalveolar lavage are the sensitive and characteristic diagnostic tests for hypersensitivity pneumonitis. The relevant antigen to hypersensitivity pneumonitis cannot be identified in up to 20% to 30% of patients. Clinicians should be aware that hypersensitivity pneumonitis must be considered in all cases of interstitial lung disease, and a detailed environmental exposure history is mandatory. PMID- 23102066 TI - Eosinophilic lung diseases. AB - Eosinophilic lung diseases comprise eosinophilic pneumonia, which may present with chronic or acute onset, or as Loffler syndrome. The diagnosis of eosinophilic pneumonia relies on clinical imaging and the demonstration of alveolar eosinophilia. Lung biopsy is generally not necessary. Peripheral blood eosinophilia is common but may be absent at presentation in idiopathic acute eosinophilic pneumonia, which may be misdiagnosed as severe infectious pneumonia. Extra-thoracic manifestations should raise the suspicion of Churg-Strauss syndrome. All possible causes of eosinophilia (especially fungus infection or drug or toxic exposure) must be thoroughly investigated before the diagnosis of idiopathic disease is made. PMID- 23102068 TI - Bronchiolitis. AB - Bronchiolitis is a disease of the small airways accompanied by progressive and often irreversible airflow obstruction. Bronchiolitis can have several causes such as infection, toxic exposure, collagen vascular disease, post lung and stem cell transplant, and idiopathic etiology. Symptoms of cough and sputum production are often mistaken for chronic obstructive pulmonary disease or asthma, leading to a delay in diagnosis. Unfortunately, many types of bronchiolitis do not improve with therapy. Bronchiolitis following lung and stem cell transplant are the most common types seen in adults, and provide important insights into its pathogenesis. PMID- 23102067 TI - Update on diffuse alveolar hemorrhage and pulmonary vasculitis. AB - Diffuse alveolar hemorrhage is a clinical syndrome that can be a manifestation of multiple different causes. Identification of the underlying etiology is of utmost importance and dictates treatment. Pulmonary vasculitis including antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a common cause of diffuse alveolar hemorrhage. For AAV, treatment includes induction followed by maintenance therapy. Rituximab has an increasing role in the treatment of AAV. PMID- 23102069 TI - Granulomatous lymphocytic interstitial lung disease. AB - As the use of high-dose intravenous gamma globulin and available antimicrobials expands, the incidence of noninfectious common variable immunodeficiency-related disorders, such as granulomatous-lymphocytic interstitial lung disease (GLILD), is likely to increase. A thorough clinical evaluation using a multidisciplinary care model is recommended to achieve accurate diagnosis of GLILD. Enough progress has been made in the understanding of GLILD over the last decade that clinicians are now poised to conduct therapeutic trials. Data from large registries and population-based studies of GLILD are needed to better understand the disease trends and burden. This article focuses on the diagnosis and management of GLILD. PMID- 23102070 TI - Immunosuppressive therapy for autoimmune lung diseases. AB - This article focuses on issues of safety and monitoring when immunosuppressive pharmacologic therapies are prescribed for the treatment of connective tissue disease (CTD)-associated interstitial pneumonias, vasculitides, and bronchiolitis. Prospective, randomized placebo-controlled clinical trials have yet to be performed to evaluate the efficacy and safety of various immunosuppressive agents used to treat patients with CTD-interstitial lung disease or idiopathic interstitial pneumonias other than idiopathic pulmonary fibrosis (idiopathic usual interstitial pneumonia) that are not associated with the presence of CTD. Knowledge of their potential toxicities and interactions with other drugs combined with the adoption of a systematic approach to monitoring therapy can minimize life-threatening reactions. PMID- 23102071 TI - Interstitial lung disease and autoimmune lung diseases. Preface. PMID- 23102072 TI - Interstitial lung diseases. Foreword. PMID- 23102073 TI - Malignant phyllodes tumors of the breast: a study in clinical practice. AB - Malignant phyllodes tumors are an uncommon breast tumor in clinical practice of surgery. The study population consisted of five consecutive patients. Each patient had complete clinical follow-up with annual mammograms and physical examination in a specialized breast clinic. They were surgically treated for with malignant phyllodes tumor of the breast. All patients are alive and well with a complete follow-up. The first 2 patients had a fine needle aspiration cytology and were surgically treated by a simple mastectomy. The remaining 3 patients were preoperatively diagnosed with core needle biopsy. These 3 patients were treated with a wide excision of the phyllodes tumor with at least a 1-cm margin of normal breast tissue. Mammography was 100% accurate in demonstrating a dense breast mass. In each patient ultrasound suggested heterogeneous internal echoes present in each malignant phyllodes tumor. Fine needle aspiration cytology was of no value in the diagnosis of a phyllodes tumor. Core needle biopsy is highly reliable in establishing a preoperative diagnosis. The most helpful clinical observation of a malignant phyllodes tumor was rapid growth and enlargement, which is frequently noted by the patient. PMID- 23102074 TI - Could the eZ-SCOPE AN gamma camera replace intraoperative measurement of iPTH for PHPT? AB - Intraoperative intact parathyroid hormone (iPTH) measurements have been proposed as an effective assay in surgery for primary hyperparathyroidism (PHPT). We have demonstrated the efficiency of the use of a hand-held gamma camera, eZ-SCOPE AN, with technetium-99m sestamibi (Tc-MIBI) scintigraphy for navigation surgery for PHPT. The aim of this preliminary study was to assess the possibility that the eZ SCOPE AN can replace the measurement of intraoperative iPTH in surgery for PHPT. Sixteen consecutive patients with documented primary hyperparathyroidism underwent surgery using this compact camera. iPTH was routinely measured preoperatively and 10 minutes after the complete removal of adenoma. All patients had a well-defined parathyroid lesion identified on preoperative Tc-MIBI. The eZ SCOPE revealed hyperfunctioning parathyroid glands in all cases. iPTH levels were decreased in all cases after the removal of adenomas. Our results suggest that this gamma camera is useful for confirming complete resection of endocrinologically active tissue in surgery for PHPT. In selective patients with scan-positive cases identified by preoperative Tc-MIBI, the eZ-SCOPE may replace the intraoperative iPTH assay in surgery for PHPT. PMID- 23102075 TI - Predictors of successful outcome after adrenalectomy for primary aldosteronism. AB - The underlying cause of resistant hypertension after adrenalectomy for primary hyperaldosteronism remains controversial. The objective of this study was to identify preoperative factors predictive of resistant hypertension in patients after undergoing retroperitoneoscopic adrenalectomy. Between 2003 and 2009, 124 patients with unilateral aldosterone-producing adenoma or unilateral adrenal hyperplasia underwent retroperitoneoscopic adrenalectomy at our institution. Clinical and biochemical data were reviewed retrospectively at baseline and after a median follow-up time of 59.2 +/- 37.2 months. Adrenalectomy cured hypertension in 68 patients (54.8%) and 43 (34.8%) had persistent hypertension that was much easier to control after surgery, whereas 13 patients (10.4%) had continued hypertension and poor blood pressure control. Multivariate regression analysis revealed that the main determinants of postoperative cure were duration of hypertension less than 5 years [odds ratio (OR): 6.515, 95% confidence interval (CI) 2.278-10.293), number of antihypertensive medications <=2 (OR: 2.939, 95% CI 1.254-5.235), preoperative response to spironolactone (OR: 3.405, 95% CI 1.681 6.985), the TT genotype of the CYP11B2 gene (344 C/T) (OR: 2.765, 95% CI 1.221 4.986), and the presence of adenoma rather than hyperplasia (OR: 5.274, 95% CI 2.150-8.141). The main determinants of surgical cure or control of hypertension in patients with primary hyperaldosteronism were duration of hypertension, number of antihypertensive medications, preoperative response to spironolactone, the presence of adenoma, and CYP11B2 (344 C/T) genotype. Consideration of these factors may help in the evaluation of patients for surgery and for the identification of patients with continued postoperative hypertension that may require more long-term monitoring and treatment. PMID- 23102076 TI - Glyceryl trinitrate ointment did not reduce pain after stapled hemorrhoidectomy: a randomized controlled trial. AB - Medications, including topical 0.2% glyceryl trinitrate (GTN), can reduce anal spasm and pain after excisional hemorrhoidectomy. GTN after stapled hemorrhoidopexy was compared with routine postoperative management. Patients with symptomatic grade 3/4 hemorrhoids were recruited. After stapled hemorrhoidopexy, residual perianal skin tags were excised as appropriate. Those requiring double purse-string mucosectomy were excluded. Postoperative pain, pain duration, and complications were assessed. One hundred ten patients (74 men; mean age 50.6 years) were enrolled in the control group and 100 patients (57 men; mean age 49.8 years) in the GTN group. Maximum pain was higher in the GTN group (P = 0.015). There were no differences between the two groups in residual perianal skin tags requiring excision, postoperative complications, recurrence rates, follow-up period, average pain, duration of pain, or satisfaction scores. Sixteen GTN patients were noncompliant due to side effects. None had persistent perianal skin tags. GTN did not reduce postoperative pain after stapled hemorrhoidectomy. PMID- 23102077 TI - Difference in recurrence patterns between anastomosis and strictureplasty after surgical treatment for crohn disease. AB - This study aimed to investigate whether the initial indication for surgery or type of surgery (strictureplasty or resection) performed determines recurrence patterns in patients with Crohn disease. Recurrence patterns of 41 patients (31 patients: only resection and anastomosis of the intestine, and 10 patients: strictureplasty with/without resection and anastomosis) who underwent operation for recurrent Crohn disease (June 2002-December 2010) were evaluated. Strictureplasty for nonperforating disease was performed at 17 sites, and reoperation was required at 11 sites (10 sites for nonperforating disease and 1 site for perforating disease). There was a significant difference in the recurrence pattern in patients who underwent resection and anastomosis (P < 0.01) and in patients who underwent strictureplasty with resection and anastomosis (P < 0.05) between sites at which resection and anastomosis was performed for nonperforating and for perforating disease. Initial indication for surgery, but not the type of surgery, appeared to determine recurrence patterns. PMID- 23102078 TI - Postoperative course after emergency colorectal surgery for secondary peritonitis in the elderly is often complicated by delirium. AB - Postoperative delirium, morbidity, and mortality in our elderly patients with secondary perionitis of colorectal origin is described. This is a chart-based retrospective analysis of 63 patients who were operated on at the University Hospital Basel from April 2001 to May 2004. Postoperative delirium occurred in 33%. Overall morbidity was 71.4%. Surgery-related morbidity was 43.4%. Mortality was 14.4%. There was no statistical significance between delirium, morbidity and mortality (P = 0.279 and P = 0.364). There was no statistically significant correlation between the analyzed scores (American Society of Anesthesiologists classification, Mannheimer Peritonitis Index, Acute Physiology and Chronic Health Evaluation score II, physiological and operative surgical severity and enumeration of morbidity and mortality score' or short 'cr-POSSUM') and postoperative delirium, morbidity or mortality. Postoperative delirium occurred in one-third of the patients, who seem to have a trend to higher morbidity. Even if the different scores already had proven to be predictive in terms of morbidity and mortality, they do not help the risk stratification of postoperative delirium, morbidity, or mortality in our collective population. PMID- 23102079 TI - Laparoscopic trocar port site endometriosis: a case report and brief literature review. AB - Endometriosis is defined as the presence of ectopic endometrial tissue outside the lining of the uterine cavity. It occurs most commonly in pelvic sites such as ovaries, cul-de-sac, and fallopian tubes but also can be found associated with the lungs, bowel, ureter, brain, and abdominal wall. Abdominal wall endometriosis, also known as scar endometriosis, is extremely rare and mainly occurs at surgical scar sites. Although many cases of scar endometriosis have been reported after a cesarean section, some cases of scar endometriosis have been reported after an episiotomy, hysterectomy, appendectomy, and laparoscopic trocar port tracts. To our knowledge, 14 case reports related to trocar site endometriosis have been published in the English language literature to date. Herein, we present the case of a 20-year-old woman (who had been previously operated on for left ovarian endometrioma 1.5 years ago by laparoscopy) with the complaint of a painful mass at the periumbilical trocar site with cyclic pattern. Consequently, although rare, if a painful mass in the surgical scar, such as the trocar site, is found in women of reproductive age with a history of pelvic or obstetric surgery, the physician should consider endometriosis. PMID- 23102080 TI - Hemobilia due to cystic artery stump pseudoaneurysm following laparoscopic cholecystectomy: case presentation and literature review. AB - Hemobilia is the process of bleeding into the biliary tree and is an unusual cause of upper gastrointestinal hemorrhage. When this event results from a cystic artery pseudoaneurysm, it is a particularly rare phenomenon; fewer than 20 cases are described in the literature. Alongside the literature review, we report a case of a 34-year-old woman presenting 3 months post laparoscopic cholecystectomy with hematemesis. Computed tomography (CT) angiography revealed a cystic artery pseudoaneurysm. Following an ineffective hyperselective arterial embolization, the patient was successfully treated by surgical ligation of the right hepatic artery. Even though this complication is uncommon, all surgeons need to be aware of its presentation and of available therapeutic options. PMID- 23102081 TI - Deep venous thrombosis in spine surgery patients: incidence and hematoma formation. AB - Deep venous thrombosis (DVT) is a significant health care problem; a variety of factors place spinal surgery patients at high risk for DVT. Our aim is to define the incidence of DVT occurrence in spite of prophylactic measures (mechanical and chemoprophylaxis), and the development of spinal epidural hematoma as a complication of chemoprophylaxis. In a single-center prospective study, 158 patients who underwent spinal surgical procedures were evaluated by clinical evaluation and lower limb Doppler ultrasonography imaging. Only one patient (0.6%) developed DVT; this patient was treated successfully without thrombus progression, with full recanalization. Three patients (1.8%) developed spinal epidural hematoma, but only one required surgical evacuation, and none sustained neurologic deficit. Careful evaluation for DVT risk on an individual basis and good prophylaxis helps to minimize the risk of DVT. The neurosurgeon is thus left to weigh the risks of postoperative hematoma formation against the benefits of protecting against DVT. PMID- 23102082 TI - Cost analysis of establishing a relationship between a surgical program in the US and Vietnam. AB - "Twinning" refers to a constructive partnership between hospitals in developed and developing nations. Such an effort may contribute immensely to capacity building for the developing nation, but one of the reasons given for the lack of sustainability is cost. We share a detailed operating cost analysis of our recent experience with an institution in Vietnam. We were awarded a 1-year $54,000 grant from the Vietnam Education Foundation (VEF) to conduct a live tele-video conferencing course on the "Fundamentals of Clinical Surgery" with Thai Binh Medical University (TBMU). In-country lectures as well as an assessment of the needs at TBMU were performed. Total financial assistance and expenditures were tabulated to assess up-front infrastructure investment and annual cost required to sustain the program. The total amount of direct money ($66,686) and in-kind services ($70,276) was $136,962. The initial infrastructure cost was $41,085, which represented 62% of the direct money received. The annual cost to sustain the program was approximately $11,948. We concluded that the annual cost to maintain a "twinning" program was relatively low, and the efforts to sustain a "twinning" program were financially feasible and worthwhile endeavors. "Twinning" should be a critical part of the surgical humanitarian volunteerism effort. PMID- 23102083 TI - Abdominal trauma in durban, South Africa: factors influencing outcome. AB - Abdominal injury as a result of both blunt and penetrating trauma has an appreciable mortality rate from hemorrhage and sepsis. In this article, we present our experience with the management of abdominal trauma in Durban and investigate factors that influence outcome. We performed a prospective study of patients with abdominal trauma in one surgical ward at King Edward VIII Hospital in Durban over a period of 7 years, from 1998 through 2004. Demographic details, cause of injury, delay before surgery, clinical presentation, findings at surgery, management and outcome were documented. There were 488 patients with abdominal trauma with a mean age of 29.2 +/- 10.7 years. There were 440 penetrating injuries (240 firearm wounds; 200 stab wounds) and 48 blunt injuries. The mean delay before surgery was 11.7 +/- 16.4 hours, and 55 patients (11%) presented in shock. Four hundred and forty patients underwent laparotomy, and 48 were managed nonoperatively. The Injury Severity Score was 11.1 +/- 6.7, and the New Injury Severity Score was 17.1 +/- 11.1. One hundred and thirty-seven patients (28%) were admitted to the intensive care unit (ICU), with a mean ICU stay of 3.6 +/- 5.5 days. One hundred and thirty-two patients developed complications (28%), and 52 (11%) died. Shock, acidosis, increased transfusion requirements, number of organs injured, and injury severity were all associated with higher mortality. Delay before surgery had no influence on outcome. Hospital stay was 9.2 +/- 10.8 days. The majority of abdominal injuries in our environment are due to firearms. Physiological instability, mechanism of injury, severity of injury, and the number of organs injured influence outcome. PMID- 23102084 TI - A prospective randomized study to assess the optimal duration of intravenous antimicrobial prophylaxis in elective gastric cancer surgery. AB - The duration of antimicrobial prophylaxis in gastric cancer surgery is not yet established. This prospective randomized study was performed to confirm the noninferiority of single-dose versus multiple-dose antimicrobial prophylaxis in terms of the incidence of surgical-site infection in gastric cancer surgery. Three hundred twenty-five patients undergoing elective resection for gastric cancer were randomized to receive only single-dose cefazolin (1 g) during surgery (single-dose group) or an additional 5 doses every 12 hours postoperatively (multiple-dose group). The overall incidence of surgical-site infections was 9.1% in the single-dose group and 6.2% in the multiple-dose group [difference (95% confidence interval): -2.9% (-5.9%-0.0%)]. Multivariate logistic regression analysis identified blood loss, being overweight, and advanced age as significant independent risk factors for surgical-site infection. Single-dose antimicrobial prophylaxis seemed to be acceptable, and choosing multiple-dose prophylaxis may have little impact on the prevention of surgical-site infections in elective gastric cancer surgery. PMID- 23102085 TI - The value of immunohistochemistry in diagnosing primary renal synovial sarcoma: a case report and literature review. AB - Primary synovial sarcoma of the kidney is rare and difficult to diagnose with 100% accuracy without the use of up-to-date histopathologic methods. Immunohistochemical procedures are well established and are continuously expanding and improving. Currently, these methods are successful in up to 90% of tumor identification. The remaining cases will ultimately benefit by combining immunohistochemistry with tumor-specific genetic marker identifiers, the latter of which are increasing in availability for tumor diagnosis. The principal immunohistochemical methods enlisted in establishing a diagnosis of primary renal synovial sarcoma are summarized. PMID- 23102086 TI - Ultrasonography-guided percutaneous nephrolithotomy for the treatment of urolithiasis in patients with scoliosis. AB - We examined the surgical outcomes of minimally invasive percutaneous nephrolithotomy (MPCNL) in scoliotic patients with complicating urolithiasis. Two patients with scoliosis were hospitalized for MPNCL due to upper tract urolithiasis. Calyx puncture was performed in the prone position under ultrasonographic guidance. The renal access route was established using a set of 8F to 16F dilators, and a transpyelic ballistic lithotriptor was used to fragment the calculi. The stone burdens in the 2 patients were 410 mm(2) and 500 mm(2). The entire operative time was 40 to 70 minutes, and the mean time of establishing percutaneous access was 20 minutes. The calculi were completely removed by single session pneumatic lithotripsy. The 2 patients recovered from MPCNL uneventfully, and the follow-up radiologic examinations identified no stone residual or recurrence. MPCNL is a minimally invasive modality that is effective and safe for the treatment of urolithiasis in patients with scoliosis. PMID- 23102087 TI - 21st century technology and online publishing. PMID- 23102088 TI - The reaction mechanism of the enantioselective Tsuji allylation: inner-sphere and outer-sphere pathways, internal rearrangements, and asymmetric C-C bond formation. AB - We use first principles quantum mechanics (density functional theory) to report a detailed reaction mechanism of the asymmetric Tsuji allylation involving prochiral nucleophiles and nonprochiral allyl fragments, which is consistent with experimental findings. The observed enantioselectivity is best explained with an inner-sphere mechanism involving the formation of a 5-coordinate Pd species that undergoes a ligand rearrangement, which is selective with regard to the prochiral faces of the intermediate enolate. Subsequent reductive elimination generates the product and a Pd(0) complex. The reductive elimination occurs via an unconventional seven-centered transition state that contrasts dramatically with the standard three-centered C-C reductive elimination mechanism. Although limitations in the present theory prevent the conclusive identification of the enantioselective step, we note that three different computational schemes using different levels of theory all find that inner-sphere pathways are lower in energy than outer-sphere pathways. This result qualitatively contrasts with established allylation reaction mechanisms involving prochiral nucleophiles and prochiral allyl fragments. Energetic profiles of all reaction pathways are presented in detail. PMID- 23102089 TI - Contrasting effects of vasculogenic induction upon biaxial bioreactor stimulation of mesenchymal stem cells and endothelial progenitor cells cocultures in three dimensional scaffolds under in vitro and in vivo paradigms for vascularized bone tissue engineering. AB - Clinical translation of bone tissue engineering approaches for fracture repair has been hampered by inadequate vascularization required for maintaining cell survival, skeletal regeneration, and remodeling. The potential of vasculature formation within tissue-engineered grafts depends on various factors, including an appropriate choice of scaffold and its microarchitectural design for the support of tissue ingrowth and vessel infiltration, vasculogenic potential of cell types and mechanostimulation on cells to enhance cytokine expression. Here, we demonstrated the effect of biomechanical stimulation on vasculogenic and bone forming capacity of umbilical-cord-blood endothelial progenitor cells (UCB-EPC) and human fetal bone marrow-derived mesenchymal stem cell (hfMSC) seeded within macroporous scaffolds and cocultured dynamically in a biaxial bioreactor. Dynamically cultured EPC/hfMSC constructs generated greater mineralization and calcium deposition consistently over 14 days of culture (1.7-fold on day 14; p<0.05). However, in vitro vessel formation was not observed as compared to an extensive EPC-vessel network formed under static culture on day 7. Subsequent subcutaneous implantations in NOD/SCID mice showed 1.4-fold higher human:mouse cell chimerism (p<0.001), with a more even cellular distribution throughout the dynamically cultured scaffolds. In addition, there was earlier evidence of vessel infiltration into the scaffold and a trend toward increased ectopic bone formation, suggesting improved efficacy and cellular survival through early vascularization upon biomechanical stimulation. The integrative use of bioreactor culture systems with macroporous scaffolds and cocultured osteogenic and vasculogenic cells promotes maturation of EPC/hfMSC-scaffold grafts necessary for vascularized bone tissue engineering applications. PMID- 23102091 TI - Prevalence of obesity among older adults in the United States, 2007-2010. AB - By 2050, the number of U.S. older adults, defined as persons aged 65 and over, is expected to more than double, rising from 40.2 million to 88.5 million (1). Both aging and obesity contribute to increased health care service use (2,3). Consequently, an increase in the proportion of older adults who are obese may compound health care spending. Given the demographic changes forecasted and the potential health care costs of obesity, it is important to track the prevalence of obesity among older adults (2,3). This report presents the most recent national estimates of obesity in older adults, by sex, age, race and ethnicity, and educational attainment, and examines changes in the prevalence of obesity between 1999 and 2010. PMID- 23102090 TI - A spruce gene map infers ancient plant genome reshuffling and subsequent slow evolution in the gymnosperm lineage leading to extant conifers. AB - BACKGROUND: Seed plants are composed of angiosperms and gymnosperms, which diverged from each other around 300 million years ago. While much light has been shed on the mechanisms and rate of genome evolution in flowering plants, such knowledge remains conspicuously meagre for the gymnosperms. Conifers are key representatives of gymnosperms and the sheer size of their genomes represents a significant challenge for characterization, sequencing and assembling. RESULTS: To gain insight into the macro-organisation and long-term evolution of the conifer genome, we developed a genetic map involving 1,801 spruce genes. We designed a statistical approach based on kernel density estimation to analyse gene density and identified seven gene-rich isochors. Groups of co-localizing genes were also found that were transcriptionally co-regulated, indicative of functional clusters. Phylogenetic analyses of 157 gene families for which at least two duplicates were mapped on the spruce genome indicated that ancient gene duplicates shared by angiosperms and gymnosperms outnumbered conifer-specific duplicates by a ratio of eight to one. Ancient duplicates were much more translocated within and among spruce chromosomes than conifer-specific duplicates, which were mostly organised in tandem arrays. Both high synteny and collinearity were also observed between the genomes of spruce and pine, two conifers that diverged more than 100 million years ago. CONCLUSIONS: Taken together, these results indicate that much genomic evolution has occurred in the seed plant lineage before the split between gymnosperms and angiosperms, and that the pace of evolution of the genome macro-structure has been much slower in the gymnosperm lineage leading to extent conifers than that seen for the same period of time in flowering plants. This trend is largely congruent with the contrasted rates of diversification and morphological evolution observed between these two groups of seed plants. PMID- 23102092 TI - Molecular dynamics study of the role of the spine of hydration in DNA A-tracts in determining nucleosome occupancy. AB - A-tracts in DNA are generally associated with reduced nucleosome occupancy relative to other sequences, such that the longer the A-tract, the less likely that nucleosomes are found. In this paper, we use molecular dynamics methods to study the structural properties of A-tracts, and in particular the role that the spine of hydration in A-tracts plays in allowing DNA to distort to the highly bent structure needed to form nucleosomes. This study includes a careful assessment of the ability of the Amber (parmbsc0), CHARMM27, and BMS force fields to describe these structural waters for the AAATTT sequence (here capped with CGC and GCG), including comparisons with X-ray results. All three force fields show a spine of hydration, but BMS and Amber show better correlation with measured properties, such as in narrowing of the minor groove width associated with the A tract. We have used Amber to study the spine properties for several 6 and 14 base pair A-tracts (all capped with CGC and GCG). These calculations show that the structural waters are tightly bound for "pure" A-tracts that allow for A-water-T links, and for AT steps that allow for a T-water-T link, but other sequences disfavor structural water, especially those that lead to A-water-A, G-water-G, and C-water-A structures. In addition, we show that pure A-tracts favor roll values close to the Watson-Crick value for linear DNA, while A-tract sequences containing embedded T's, C's, or G's that are less favorable to structural water are more flexible. This implies the essential role of the spine of hydration in disfavoring nucleosome formation. PMID- 23102093 TI - Exceptionally high serum concentrations of perfluorohexanesulfonate in a Canadian family are linked to home carpet treatment applications. AB - Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) are normally the dominant perfluoroalkyl substances (PFASs) in human serum, but here a Canadian family of seven was identified with particularly high exposure to perfluorohexanesulfonate (PFHxS). Disproportionately high serum PFHxS concentrations (range 27.5-423 ng/mL) and moderately high PFOS (range 15.2-108 ng/mL) and PFOA (range 2.40-9.23 ng/mL) concentrations were detected in the family members, with all three chemicals being highest in the youngest children. We therefore sought to identify the source(s) and pathway(s) of this unusual exposure, and to study the excretion of PFASs for this family. Serum, urine, and stool were sampled from family members, carpet, dust, and air were sampled in the home, and a questionnaire was administered. Over 15 years, the family's household carpets were treated 8 times with Scotchgard formulations. Elevated concentrations of PFHxS were detected in household dust (2780 ng/g dust) and in family room carpet (2880 ng/g carpet), and the primary mode of excretion for the major PFASs was through urine. The high PFHxS and moderately high PFOS concentrations in serum and household samples are consistent with the known PFAS content of certain Scotchgard formulations, and exposure was likely through dust ingestion and/or inhalation. PMID- 23102095 TI - Worry and rumination in anorexia nervosa. AB - BACKGROUND: Difficulties with comprehending and managing emotions are core features of the pathology of anorexia nervosa (AN). Advancements in understanding aetiology and treatment have been made within other clinical domains by targeting worry and rumination. However, worry and rumination have been given minimal consideration in AN. AIMS: This study is the largest to date of worry and rumination in AN. METHOD: Sixty-two outpatients with a diagnosis of AN took part. Measures of worry, rumination, core AN pathology and neuropsychological correlates were administered. RESULTS: Findings suggest that worry and rumination are elevated in AN patients compared with both healthy controls and anxiety disorder comparison groups. Regression analyses indicated that worry and rumination were significant predictors of eating disorder symptomatology, over and above the effects of anxiety and depression. Worry and rumination were not associated with neuropsychological measures of set-shifting and focus on detail. CONCLUSIONS: The data suggest that worry and rumination are major concerns for this group and warrant further study. PMID- 23102096 TI - Ladderphanes: a new type of duplex polymers. AB - A polymeric ladderphane is a step-like structure comprising multiple layers of linkers covalently connected to two or more polymeric backbones. The linkers can be planar aromatic, macrocyclic metal complexes, or three-dimensional organic or organometallic moieties. Structurally, a DNA molecule is a special kind of ladderphane, where the cofacially aligned base-pair pendants are linked through hydrogen bonding. A greater understanding of this class of molecules could help researchers develop new synthetic molecules capable of a similar transfer of chemical information. In this Account, we summarize our studies of the strategy, design, synthesis, characterization, replications, chemical and photophysical properties, and assembly of a range of double-stranded ladderphanes with many fascinating structures. We employed two norbornene moieties fused with N arylpyrrolidine to connect covalently with a range of relatively rigid linkers. Ring opening metathesis polymerizations (ROMP) of these bis-norbornenes using the first-generation Grubbs ruthenium-benzylidene catalyst produced the corresponding symmetrical double-stranded ladderphanes. The N-arylpyrrolidene moiety in the linker controls the isotactic selectivity and the trans configuration for all double bonds in both single- and double-stranded polynorbornenes. The pi-pi interactions between these aryl pendants may contribute to the high stereoselectivity in the ROMP of these substrates. We synthesized chiral helical ladderphanes by incorporating asymmetric center(s) in the linkers. Replication protocols and sequential polymerization of a monomer that includes two different polymerizable groups offer methods for producing unsymmetical ladderphanes. These routes furnish template synthesis of daughter polymers with well-controlled chain lengths and polydispersities. The linkers in these ladderphanes are well aligned in the center along the longitudinal axis of the polymer. Fluorescence quenching, excimer formation, or Soret band splitting experiments suggest that strong interactions take place between the linkers. The antiferromagnetism of the oxidized ferrocene-based ladderphanes further indicates strong coupling between linkers in these ladderphanes. These polynorbornene-based ladderphanes can easily aggregate to form a two-dimensional, highly ordered array on the graphite surface with areas that can reach the submicrometer range. These morphological patterns result from interactions between vinyl and styryl end groups via pi-pi stacking along the longitudinal axis of the polymer and van der Waals interaction between backbones of polymers. Such assembly orients planar arene moieties cofacially, and polynorbornene backbones insulate each linear array of arenes from the adjacent arrays. Dihydroxylation converts the double bonds in polynorbornene backbones of ladderphanes into more hydrophilic polyols. Hydrogen bonding between these polyol molecules leads to self-assembly and produces structures with longitudinally staggered morphologies on the graphite surface. PMID- 23102097 TI - Effects of high tidal volume mechanical ventilation on production of cytokines, iNOS, and MIP-1beta proteins in pigs. AB - The aim of this study was to investigate longitudinal changes of the pulmonary inflammatory process as a result of mechanical stress due to mechanical ventilation. The concentrations of IL-8, TNF-alpha, MIP-1beta, nitrites/nitrates, and inducible nitric oxide synthases (iNOS) were investigated indicate in bronchoalveolar lavage (BAL). Twenty-three piglets were divided into three groups. Group I: animals breathing spontaneously; group II: mechanical ventilation (tidal volume (TV) = 7 mL/kg, PEEP = 5 cmH(2)O); group III: mechanical ventilation (TV = 15 mL/kg, PEEP = 0 cmH(2)0). Concentrations of BAL nitrites/nitrates from groups II and III increased during the first hour of mechanical ventilation (P = .03 and .02, respectively). The highest expression of iNOS was observed during the first hour in groups II and III. IL-8 concentration increased significantly in groups II and III. Production of TNF-alpha increased significantly in group III during the second and third hour (P = .01). Concentration of MIP-1beta was significantly increased in groups II and III after the first hour (P = .012 and P = .008, respectively). PMID- 23102099 TI - N-myristoylation of the Rpt2 subunit regulates intracellular localization of the yeast 26S proteasome. AB - The 26S proteasome is a large, complex multisubunit protease involved in protein quality control and other critical processes in eukaryotes. More than 110 post translational modification (PTM) sites have been identified by a mass spectrometry of the 26S proteasome of Saccharomyces cerevisiae and are predicted to be implicated in the dynamic regulation of proteasomal functions. Here, we report that the N-myristoylation of the Rpt2 subunit controls the intracellular localization of the 26S proteasome. While proteasomes were mainly localized in the nucleus in normal cells, mutation of the N-myristoylation site of Rpt2 caused diffusion of the nuclear proteasome into the cytoplasm, where it formed aggregates. In mutant cells, the level of accumulation of cytoplasmic proteasomes was significantly increased in the nonproliferating state. Although the molecular assembly and peptidase activity of the 26S proteasome were totally unchanged in the nonmyristoylated mutants of Rpt2, an increased level of accumulation of polyubiquitinated proteins and a severe growth defect were observed in mutant cells induced for protein misfolding. In addition, polyubiquitinated protein and the nuclear protein Gcn4 tended not to colocalize with the proteasome in normal and mutant cells. Our results suggest that N-myristoylation is involved in regulating the proper intracellular distribution of proteasome activity by controlling the nuclear localization of the 26S proteasome. PMID- 23102098 TI - Influence of statins locally applied from orthopedic implants on osseous integration. AB - BACKGROUND: Simvastatin increases the expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts, therefore it is important to investigate the influence of statins on bone formation, fracture healing and implant integration. The aim of the present study was to investigate the effect of simvastatin, locally applied from intramedullary coated and bioactive implants, on bone integration using biomechanical and histomorphometrical analyses. METHODS: Eighty rats received retrograde nailing of the femur with titanium implants: uncoated vs. polymer-only (poly(D,L-lactide)) vs. polymer plus drug coated (either simvastatin low- or high dosed; "SIM low/ high"). Femurs were harvested after 56 days for radiographic and histomorphometric or biomechanical analysis (push-out). RESULTS: Radiographic analysis revealed no pathological findings for animals of the control and SIM low dose group. However, n=2/10 animals of the SIM high group showed osteolysis next to the implant without evidence of bacterial infection determined by microbiological analysis. Biomechanical results showed a significant decrease in fixation strength for SIM high coated implants vs. the control groups (uncoated and PDLLA). Histomorphometry revealed a significantly reduced total as well as direct bone/implant contact for SIM high- implants vs. controls (uncoated and PDLLA-groups). Total contact was reduced for SIM low vs. uncoated controls. Significantly reduced new bone formation was measured around SIM high coated implants vs. both control groups. CONCLUSIONS: This animal study suggests impaired implant integration with local application of simvastatin from intramedullary titanium implants after 8 weeks when compared to uncoated or carrier-only coated controls. PMID- 23102100 TI - Characterization of the dispersion interactions and an ab initio study of van der Waals potential energy parameters for coinage metal clusters. AB - Dispersion interactions and van der Waals C(6) coefficients are studied in small model systems involving copper, silver, and gold atoms. We investigate a novel method where the intermolecular dispersion interactions are characterized by interatomic C(6) coefficients that can be used to formulate the dispersion energy as a separate contribution to the total interaction energy at long distances. We obtain the C(6) coefficients from a least-squares fit to the interaction energy surface. Other significant effects to the long-range interaction energy such as multipole-multipole and induction energy are explicitly taken into account. The electronic structure calculations are performed at the coupled cluster level including single, double, and perturbative triple excitations (CCSD(T) level) with triple-zeta basis sets. PMID- 23102101 TI - Peer review: an effective approach to cultivating lecturing virtuosity. AB - BACKGROUND: Most university faculty members are expected to teach. Many would benefit from instruction designed to improve lecturing. AIMS: To explore the impact of a program in which video-recorded lectures were critiqued by peers. METHOD: Sixteen lecturers participated in this qualitative study. Four agreed to have an undergraduate lecture video-recorded for peer review. Twelve participated in review sessions wherein the lecturer and three peers viewed and critiqued the recorded lecture. All discussions were recorded and transcribed for thematic analysis. Subsequently, semi-structured interviews were conducted with each lecturer and all 12 peer reviewers. Three pairs of research team members independently conducted thematic analyses of the discussion transcripts and the interviews; then all members met to develop consensus on major emergent themes. RESULTS: Six themes were identified: (1) the benefits of peer review; (2) the components of successful peer review; (3) the value of reflection on teaching experiences; (4) the inherent stress in peer evaluations; (5) the elements of successful lecturing; (6) lecturing as performance. CONCLUSIONS: The benefits of peer assessment of lecturing (PAL) were enthusiastically endorsed by all 16 participants. The PAL program is now supported by the McGill Faculty Development Committee and plans to implement regular PAL sessions in place. PMID- 23102102 TI - Postgraduate clinical teaching. PMID- 23102103 TI - Relationship between medical student perceptions of mistreatment and mistreatment sensitivity. AB - BACKGROUND: National statistics reveal that efforts to reduce medical student mistreatment have been largely ineffective. Some hypothesize that as supervisors gain skills in professionalism, medical students become more sensitive. AIMS: The purpose of this study was to determine if medical student perceptions of mistreatment are correlated with mistreatment sensitivity. METHOD: At the end of their third year, 175 medical students completed an Abuse Sensitivity Questionnaire, focused on student assessment of hypothetical scenarios which might be perceived as abusive, and the annual Well-Being Survey, which includes measurement of incident rates of mistreatment. It was hypothesized that those students who identified the scenarios as abusive would also be more likely to perceive that they had been mistreated. RESULTS: Student perceptions of mistreatment were not statistically correlated with individual's responses to the scenarios or to a statistically derived abuse sensitivity variable. There were no differences in abuse sensitivity by student age or ethnicity. Women were more likely than men to consider it "harsh" to be called incompetent during rounds (p < 0.0005). CONCLUSION: This study provides preliminary evidence that challenges the hypothesis that medical students who perceive mistreatment by their superiors are simply more sensitive. PMID- 23102104 TI - Demographic attributes and knowledge acquisition among graduate-entry medical students. AB - BACKGROUND: Recent changes to undergraduate (basic) medical education in Ireland have linked an expansion of student numbers with wide-ranging reforms. Medical schools have broadened access by admitting more mature students from diverse backgrounds and have increased their international student numbers. This has resulted in major changes to the demographic profile of students at Irish medical schools. AIM: To determine whether the demographic characteristics of students impact on their academic performance and specifically on their rate of knowledge acquisition. METHODS: As a formative assessment exercise, we administered a progress test to all students twice each year during a 4 year graduate-entry medical programme. We compared scores over time between students from different age cohorts, of different gender, of different nationalities and from different academic backgrounds. RESULTS: In the 1143 tests taken by 285 students to date, there were no significant differences in the rate of knowledge acquisition between the various groups. Early in the course, students from a non-biological science background performed less well than others but outperformed their peers by the time of graduation. CONCLUSION: Neither age, gender, nationality nor academic background impacts on the rate of knowledge acquisition among graduate entry medical students. PMID- 23102105 TI - Promoting self-directed learning through portfolios in undergraduate medical education: the mentors' perspective. AB - BACKGROUND: Medical students need to acquire self-directed learning (SDL) skills for effective lifelong learning. Portfolios allow learners to reflect on their progress, diagnose learning needs and create learning plans, all elements of SDL. While mentorship is deemed to be essential for successful portfolio use, it is not known what constitutes effective mentorship in this process. In-depth understanding of the SDL construct seems a prerequisite. AIMS: The aim of this study was to examine how portfolio mentors perceive and approach SDL. METHODS: Interviews with faculty members who mentored medical students in portfolio were audio-recorded, transcribed and analysed for themes. RESULTS: Eight mentors participated. Qualitative analysis revealed six major themes around mentors' definitions of SDL, their perception of innate SDL abilities of medical students, their own approach to SDL, their understanding of the value of learning plans, their perceptions of students' engagement with the portfolio and the impact of the portfolio process on the mentoring relationship. CONCLUSIONS: This study revealed tensions between mentors' beliefs regarding the importance of SDL, their own approach to SDL and their perceptions of students' SDL skills. Based on our analysis of these tensions, we recommend both explicit faculty development and institutional culture change for successful integration of SDL in medical education. PMID- 23102106 TI - A novel approach to assess the impact of changes in admission criteria. PMID- 23102107 TI - Mucin (Muc) expression during pancreatic cancer progression in spontaneous mouse model: potential implications for diagnosis and therapy. AB - BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients. METHODS: In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (Kras(G12D);Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) by immunohistochemistry and quantitative real-time PCR. RESULTS: In agreement with previous studies on human PC, we observed a progressive increase in the expression of mucins particularly Muc1, Muc4 and Muc5AC in the pancreas of KC (as early as PanIN I) mice with advancement of PanIN lesions and PDAC both at mRNA and protein levels. Additionally, mucin expression correlated with the increased expression of inflammatory cytokines IFN-gamma (p < 0.0062), CXCL1 (p < 0.00014) and CXCL2 (p < 0.08) in the pancreas of KC mice, which are known to induce mucin expression. Further, we also observed progressive increase in inflammation in pancreas of KC mice from 10 to 50 weeks of age as indicated by the increase in the macrophage infiltration. Overall, this study corroborates with previous human studies that indicated the aberrant overexpression of MUC1, MUC4 and MUC5AC mucins during the progression of PC. CONCLUSIONS: Our study reinforces the potential utility of the KC murine model for determining the functional role of mucins in PC pathogenesis by crossing KC mice with corresponding mucin knockout mice and evaluating mucin based diagnostic and therapeutic approaches for lethal PC. PMID- 23102109 TI - "The National Institute of Nursing Research: Delivering on the promise". PMID- 23102108 TI - Coral: an integrated suite of visualizations for comparing clusterings. AB - BACKGROUND: Clustering has become a standard analysis for many types of biological data (e.g interaction networks, gene expression, metagenomic abundance). In practice, it is possible to obtain a large number of contradictory clusterings by varying which clustering algorithm is used, which data attributes are considered, how algorithmic parameters are set, and which near-optimal clusterings are chosen. It is a difficult task to sift though such a large collection of varied clusterings to determine which clustering features are affected by parameter settings or are artifacts of particular algorithms and which represent meaningful patterns. Knowing which items are often clustered together helps to improve our understanding of the underlying data and to increase our confidence about generated modules. RESULTS: We present Coral, an application for interactive exploration of large ensembles of clusterings. Coral makes all-to-all clustering comparison easy, supports exploration of individual clusterings, allows tracking modules across clusterings, and supports identification of core and peripheral items in modules. We discuss how each visual component in Coral tackles a specific question related to clustering comparison and provide examples of their use. We also show how Coral could be used to visually and quantitatively compare clusterings with a ground truth clustering. CONCLUSION: As a case study, we compare clusterings of a recently published protein interaction network of Arabidopsis thaliana. We use several popular algorithms to generate the network's clusterings. We find that the clusterings vary significantly and that few proteins are consistently co clustered in all clusterings. This is evidence that several clusterings should typically be considered when evaluating modules of genes, proteins, or sequences, and Coral can be used to perform a comprehensive analysis of these clustering ensembles. PMID- 23102110 TI - Kidney organ donation knowledge and attitudes among health care professionals: findings from a Greek general hospital. AB - Identified barriers of organ donation advancement include lack of knowledge, personal beliefs, and a negative attitude from health professionals. This article reports on current knowledge and attitudes toward kidney donation among nurses and physicians in a Greek general hospital. A previously used questionnaire was applied. More physicians than nurses were donor card holders, with registration rates being lower than expected. Over half of the participants did not consider themselves well informed about registering as a kidney donor. Older nurses differed significantly from younger ones in their willingness to become live donors if an adult required a kidney. Nurses who were blood donors had higher odds ratio of feeling well informed when compared with nurses who were not blood donors. Integrating organ donation issues into undergraduate health science curricula and continuous education interdisciplinary programs is essential in increasing awareness, eradicating negativism, and reversing inertia. PMID- 23102111 TI - Phosphorus-containing fluorinated organics: polyfluoroalkyl phosphoric acid diesters (diPAPs), perfluorophosphonates (PFPAs), and perfluorophosphinates (PFPIAs) in residential indoor dust. AB - Indoor dust is thought to be a source of human exposure to perfluorocarboxylates (PFCAs) and perfluorosulfonates (PFSAs), but exposures to emerging organofluorine compounds, including precursors to PFCAs and PFSAs via indoor dust, remain unknown. We report an analytical method for measuring several groups of emerging phosphorus-containing fluorinated compounds, including polyfluoroalkyl phosphoric acid diesters (diPAP), perfluorophosphonates (PFPA), and perfluorophosphinates (PFPIA), as well as perfluoroethylcyclohexane sulfonate (PFECHS) in indoor dust. This method was used to analyze diPAP, PFPA, and PFPIA levels in 102 residential dust samples collected in 2007-2008 from Vancouver, Canada. The results indicated a predominant and ubiquitous presence of diPAPs (frequency of detection 100%, mean and median SigmadiPAPs 7637 and 2215 ng/g). Previously measured median concentrations of perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and fluorotelomer alcohols (FTOHs) in the same samples were 14-74 times lower than SigmadiPAP levels, i.e. 71 ng/g PFOS, 30 ng/g PFOA, and 152 ng/g SigmaFTOHs. PFPAs and PFPIAs were detected in 62% and 85% of samples, respectively, at concentrations nearly 3 orders of magnitude lower than diPAPs (median 2.3 ng/g SigmaPFPAs and 2.3 ng/g SigmaPFPIAs). PFECHS was detected in only 8% of dust samples. To the best of our knowledge, this is the first report of these compounds in indoor dust. In this study, diPAP concentrations represented 98% +/- 7% of the total measured analytes in the dust samples. Detection of diPAPs at such high concentrations in indoor dust may represent an important and as-yet unrecognized indirect source of PFCA exposure in humans, given the identified biotransformation pathways. Identifying the sources of diPAPs to the indoor environment is a priority for future research to improve air quality in households. PMID- 23102112 TI - The NiCEST approach: nickel(II) paraCEST MRI contrast agents. AB - Paramagnetic Ni(II) complexes are shown here to form paraCEST MRI contrast agents (paraCEST = paramagnetic chemical exchange saturation transfer; NiCEST = Ni(II) based CEST agents). Three azamacrocycles with amide pendent groups bind Ni(II) to form stable NiCEST contrast agents including 1,4,7-tris(carbamoylmethyl)-1,4,7 triazacyclononane (L1), 1,4,8,11-tetrakis(carbamoylmethyl)-1,4,8,11 tetraazacyclotetradecane (L2), and 7,13-bis(carbamoylmethyl)-1,4,10-trioxa-7,13 diazacyclopentadecane (L3). [Ni(L3)](2+), [Ni(L1)](2+), and [Ni(L2)](2+) have CEST peaks attributed to amide protons that are shifted 72, 76, and 76 ppm from the bulk water resonance, respectively. Both CEST MR images and CEST spectroscopy show that [Ni(L3)](2+) has the largest CEST effect in 100 mM NaCl, 20 mM HEPES pH 7.4 at 37 degrees C. This larger CEST effect is attributed to the sharper proton resonances of the complex which arise from a rigid structure and low relaxivity. PMID- 23102113 TI - Dendritic cell CNS recruitment correlates with disease severity in EAE via CCL2 chemotaxis at the blood-brain barrier through paracellular transmigration and ERK activation. AB - BACKGROUND: Transmigration of circulating dendritic cells (DCs) into the central nervous system (CNS) across the blood-brain barrier (BBB) has not thus far been investigated. An increase in immune cell infiltration across the BBB, uncontrolled activation and antigen presentation are influenced by chemokines. Chemokine ligand 2 (CCL2) is a potent chemoattractant known to be secreted by the BBB but has not been implicated in the recruitment of DCs specifically at the BBB. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by injection of MOG35-55 peptide and pertussis toxin intraperitoneally. Animals with increasing degree of EAE score were sacrificed and subjected to near-infrared and fluorescence imaging analysis to detect and localize the accumulation of CD11c+-labeled DCs with respect to CCL2 expression. To further characterize the direct effect of CCL2 in DC trafficking at the BBB, we utilized an in vitro BBB model consisting of human brain microvascular endothelial cells to compare migratory patterns of monocyte-derived dendritic cells, CD4+ and CD8+ T cells. Further, this model was used to image transmigration using fluorescence microcopy and to assess specific molecular signaling pathways involved in transmigration. RESULTS: Near-infrared imaging of DC transmigration correlated with the severity of inflammation during EAE. Ex vivo histology confirmed the presence of CCL2 in EAE lesions, with DCs emerging from perivascular spaces. DCs exhibited more efficient transmigration than T cells in BBB model studies. These observations correlated with transwell imaging, which indicated a paracellular versus transcellular pattern of migration by DCs and T cells. Moreover, at the molecular level, CCL2 seems to facilitate DC transmigration in an ERK1/2-dependent manner. CONCLUSION: CNS recruitment of DCs correlates with disease severity in EAE via CCL2 chemotaxis and paracellular transmigration across the BBB, which is facilitated by ERK activation. Overall, these comprehensive studies provide a state-of-the-art view of DCs within the CNS, elucidate their path across the BBB, and highlight potential mechanisms involved in CCL2-mediated DC trafficking. PMID- 23102115 TI - Hypertension among adults in the United States, 2009-2010. AB - Significant increases have been seen over the past 10 years in hypertension awareness, treatment, and control among adults with hypertension. However, less than 50% of adults with hypertension controlled their blood pressure (BP) in 2007 2008 (1). The high prevalence of undiagnosed and uncontrolled hypertension, especially among minority groups, remains a challenge (2,3). A recent prediction model showed that every 10% increase in hypertension treatment could prevent an additional 14,000 deaths per year in the adult population ages 25-79 (4). This report examines the most recent national data on hypertension prevalence, awareness, treatment, and control. PMID- 23102116 TI - The spread of nucleation temperatures of a sample of supercooled liquid is independent of the average nucleation temperature. AB - The stochastic nature of the nucleation of a supercooled solution is not always realized or well-defined. There exists an inherent spread of nucleation temperatures of any given sample which is repeatedly supercooled, frozen, and then thawed, in the same container, even when the nucleation is occurring at the same site. Classical nucleation theory predicts such a spread but does not provide any molecular level interpretation for the value of the spread and thus it has been the subject of some speculation. This report shows that there is a lower limit to the value of the spread which is related neither to the efficiency of the best nucleation site nor the number of times the sample is cooled and the nucleation temperature measured. PMID- 23102114 TI - A novel internal fixator device for peripheral nerve regeneration. AB - Recovery from peripheral nerve damage, especially for a transected nerve, is rarely complete, resulting in impaired motor function, sensory loss, and chronic pain with inappropriate autonomic responses that seriously impair quality of life. In consequence, strategies for enhancing peripheral nerve repair are of high clinical importance. Tension is a key determinant of neuronal growth and function. In vitro and in vivo experiments have shown that moderate levels of imposed tension (strain) can encourage axonal outgrowth; however, few strategies of peripheral nerve repair emphasize the mechanical environment of the injured nerve. Toward the development of more effective nerve regeneration strategies, we demonstrate the design, fabrication, and implementation of a novel, modular nerve lengthening device, which allows the imposition of moderate tensile loads in parallel with existing scaffold-based tissue engineering strategies for nerve repair. This concept would enable nerve regeneration in two superposed regimes of nerve extension--traditional extension through axonal outgrowth into a scaffold and extension in intact regions of the proximal nerve, such as that occurring during growth or limb-lengthening. Self-sizing silicone nerve cuffs were fabricated to grip nerve stumps without slippage, and nerves were deformed by actuating a telescoping internal fixator. Poly(lactic co-glycolic) acid (PLGA) constructs mounted on the telescoping rods were apposed to the nerve stumps to guide axonal outgrowth. Neuronal cells were exposed to PLGA using direct contact and extract methods, and they exhibited no signs of cytotoxic effects in terms of cell morphology and viability. We confirmed the feasibility of implanting and actuating our device within a sciatic nerve gap and observed axonal outgrowth following device implantation. The successful fabrication and implementation of our device provides a novel method for examining mechanical influences on nerve regeneration. PMID- 23102117 TI - The value of high-frequency and color Doppler ultrasonography in diagnosing congenital muscular torticollis. AB - BACKGROUND: Congenital muscular torticollis (CMT) is a relatively common neck deformity in infancy. The aim of our research was to determine the value of high frequency and color Doppler ultrasonography in diagnosing CMT. METHODS: Patients with a clinical suspicion of CMT underwent an ultrasound examination before diagnosis, and the sonographic characteristics were analyzed and compared with the clinical findings. RESULTS: The sensitivity and specificity of an ultrasound diagnosis for CMT was 95.83% and 83.33%, respectively. The patients were divided into 2 groups based on the stage of the disease: the early-stage group (age <1 year) and the late-stage group(age >=1 year). Differences existed between the two groups with respect to sonographic findings and clinical characteristics. The sonographic characteristics of the early-stage group included local thickening of the sternocleidomastoid muscle (SCM), weak or uneven echoes, and blood flow signals around or inside most of the lesions. The sonographic characteristics of the late-stage group included diffusely hyperechoic, or cord-like hyperechoic signals inside the muscle layer without significant blood flow signals. CONCLUSIONS: Different stage of CMT patients had different sonographic characteristics. High-frequency and color Doppler ultrasonography can serve as adjunct confirmation tool for the diagnosis of CMT. PMID- 23102118 TI - Cardiovascular risk factors, cortisol, and amyloid-beta deposition in Alzheimer's Disease Neuroimaging Initiative. AB - BACKGROUND: There is epidemiological evidence that cardiovascular risk factors (CVRF) also are risk factors for Alzheimer's disease, but there is limited information on this from neuropathological studies, and even less from in vivo studies. Therefore, we examined the relationship between CVRF and amyloid-beta (Abeta) brain burden measured by Pittsburgh Compound B-positron emission tomography (PiB-PET) studies in the Alzheimer's Disease Neuroimaging Initiative. METHODS: Ninety-nine subjects from the Alzheimer's Disease Neuroimaging Initiative cohort who had a PiB-PET study measure, apolipoprotein E genotyping data, and information available on CVRF (body mass index [BMI], systolic blood pressure, diastolic blood pressure [DBP], and cholesterol and fasting glucose test results) were included. Eighty-one subjects also had plasma cortisol, C reactive protein, and superoxide dismutase 1 measurements. Stepwise regression models were used to assess the relation between the CVRF and the composite PiB PET score. RESULTS: The first model included the following as baseline variables: age, clinical diagnosis, number of apolipoprotein E4 alleles, BMI (P = .023), and DBP (P = .012). BMI showed an inverse relation with PiB-PET score, and DBP had a positive relation with PiB-PET score. In the second adjusted model, cortisol plasma levels were also associated with PiB-PET score (P = .004). Systolic blood pressure, cholesterol, or impaired fasting glucose were not found to be associated with PiB-PET values. CONCLUSION: In this cross-sectional study, we found an association between Abeta brain burden measured in vivo and DBP and cortisol, indicating a possible link between these CVRF and Abeta burden measured by PiB-PET. These findings highlight the utility of biomarkers to explore potential pathways linking diverse Alzheimer's disease risk factors. PMID- 23102119 TI - Longitudinal modeling of cognitive aging and the TOMM40 effect. AB - BACKGROUND: TOMM40 (translocase of the outer mitochondrial membrane pore subunit) is in linkage disequilibrium with apolipoprotein E (APOE). APOE e4 is linked to long (L; 21-29 T residues) poly-T variants within intron 6 of TOMM40, whereas APOE e3 can be associated with either a short (S; <21 T residues) or very long (VL; >29 T residues) variant. To assess the possible contribution of TOMM40 to Alzheimer's disease onset, we compared the effects of TOMM40 and APOE genotype on preclinical longitudinal memory decline. METHODS: An APOE e4-enriched cohort of 639 cognitively normal individuals aged 21 to 97 years with known TOMM40 genotype underwent longitudinal neuropsychological testing every 2 years. We estimated the longitudinal effect of age on memory using statistical models that simultaneously modeled cross-sectional and longitudinal effects of age on the Auditory Verbal Learning Test Long-Term Memory score by APOE, TOMM40, and the interaction between the two. RESULTS: There were significant effects overall for both TOMM40 (linear effect, P = .04; quadratic effect, P = .03) and APOE (linear effect, P = .06; quadratic effect, P = .008), with no significant interaction (P = .63). In a piecewise model, there was a significant TOMM40 effect before age 60 years (P = .009), characterized by flattened test-retest improvement (VL/VL subgroup only) but no significant APOE effect, and a significant APOE effect after age 60 years (P = .006), characterized by accelerated memory decline (e4 carriers) but no significant TOMM40 effect. CONCLUSION: Both TOMM40 and APOE significantly influence age-related memory performance, but they appear to do so independently of each other. PMID- 23102120 TI - Imaging brain amyloid in nondemented young adults with Down syndrome using Pittsburgh compound B. AB - Down syndrome (DS) is one of the most common causes of intellectual disability. Although DS accounts for only 15% of all individuals with intellectual disabilities, adults with DS account for approximately 60% of individuals with intellectual disabilities and Alzheimer's disease. This is thought to be because of overproduction of the beta-amyloid (Abeta) protein due to trisomy for the Abeta precursor protein gene on chromosome 21. Pittsburgh compound B (PiB) is a noninvasive in vivo positron emission tomography tracer used to image amyloid deposition in living humans. Studies using PiB have shown an age-dependent asymptomatic amyloid deposition in more than 20% of the cognitively normal elderly population. Presymptomatic carriers of presenilin (PS-1) and Abeta precursor protein gene mutations who are destined to develop Alzheimer's disease also show preclinical amyloid deposition. This report describes a pilot study involving the use of PiB in seven adults with DS (age: 20-44 years). Compared with objective cutoffs for amyloid positivity in older non-DS cognitively normal control subjects, only two of the seven DS subjects (age: 38 and 44 years) showed increased PiB retention. The remaining five subjects aged between 20 and 35 years showed no detectable increase in PiB retention. Interestingly, the two subjects who showed elevated PiB retention showed a striatal-predominant pattern similar to that previously reported for PS-1 mutation carriers. These results demonstrate the feasibility of conducting PiB positron emission tomography scanning in this special population, and suggest a link between Abeta overproduction and early striatal deposition of fibrillar Abeta. PMID- 23102122 TI - Differential prediction of vascular dementia and Alzheimer's disease in nondemented older adults within 5 years of initial testing. AB - OBJECTIVE: To determine whether neuropsychological tests and the Hachinski Ischemic Score (HIS) can differentiate incident vascular dementia (VaD) from Alzheimer's disease (AD) in nondemented older adults within 5 years of initial testing. METHODS: The Canadian Study of Health and Aging (CSHA) included three waves: CSHA-1 (1991-1992), CSHA-2 (1996-1997), and CSHA-3 (2001-2002). This analysis included participants of the CSHA who (a) underwent neuropsychological testing and clinical assessment at CSHA-2 and were determined to be nondemented, and (b) underwent diagnostic assessment at CSHA-3. The outcome measure was CSHA-3 diagnosis, classified as VaD (n = 22), probable or possible AD (n = 65), and all other diagnostic outcomes (n = 417). CSHA-3 diagnosticians were blinded to CSHA-2 test scores and diagnoses. Multinomial logistic regression with forward selection was used to determine the ability of the HIS and 15 CSHA-2 neuropsychological tests to predict CSHA-3 diagnostic outcome. The analysis was repeated after removing 15 AD cases with coexisting vascular disease. RESULTS: The HIS and four neuropsychological tests were significant predictors of CSHA-3 diagnostic outcome (chi2 (14) = 149.59, P < .001, R2 = 0.38). Relative to developing VaD, higher HIS (odds ratio [OR]: 0.70; 95% confidence interval [CI]: 0.57-0.86) and Rey Auditory Verbal Learning Test immediate verbal recall scores (OR: 0.77; 95% CI: 0.62-0.97) were associated with lowered odds of developing AD, whereas higher phonemic fluency scores (OR: 1.21; 95% CI: 1.02-1.17) were associated with increased odds of developing AD. Removing AD cases with vascular disease did not affect results. CONCLUSIONS: In an epidemiological sample of nondemented participants, the HIS and two neuropsychological tests contributed to the differential prediction of VaD and AD within 5 years of initial measurement. PMID- 23102121 TI - Greater regional brain atrophy rate in healthy elderly subjects with a history of cigarette smoking. AB - BACKGROUND: Little is known about the effects of cigarette smoking on longitudinal brain morphological changes in the elderly. This study investigated the effects of a history of cigarette smoking on changes in regional brain volumes over 2 years in healthy, cognitively intact elderly individuals. We predicted that individuals with a history of cigarette smoking, compared with never smokers, demonstrate greater rate of atrophy over 2 years in regions that manifest morphological abnormalities in the early stages of Alzheimer's disease (AD), as well as in the extended brain reward/executive oversight system (BREOS), which is implicated in the development and maintenance of substance use disorders. METHODS: Participants were healthy, cognitively normal elderly control subjects (75.9 +/- 4.8 years of age) with any lifetime history of cigarette smoking (n = 68) or no history of smoking (n = 118). Data were obtained through the Alzheimer Disease Neuroimaging Initiative from 2005 to 2010. Participants completed four magnetic resonance scans over 2 years. A standardized protocol using high-resolution three-dimensional T1-weighted sequences at 1.5 T was used for structural imaging and regional brain volumetric analyses. RESULTS: Smokers demonstrated a significantly greater atrophy rate over 2 years than nonsmokers in multiple brain regions associated with the early stages of AD, as well as in the BREOS system. Groups did not differ on the rate of global cortical atrophy. CONCLUSIONS: A history of cigarette smoking in this healthy elderly cohort was associated with decreased structural integrity of multiple brain regions, which manifested as a greater rate of atrophy over 2 years in regions specifically affected by incipient AD as well as chronic substance abuse. PMID- 23102123 TI - A new informant-based questionnaire for instrumental activities of daily living in dementia. AB - BACKGROUND: Interference in everyday functioning is part of the diagnostic criteria for dementia. Questionnaires measuring "instrumental activities of daily living" (IADL) are used to measure this interference, but the psychometric quality of these questionnaires is often questioned. In addition, these questionnaires are less suited for early-onset patients. This is problematic, given the high frequency of relatively young patients in memory clinics. In this article, we describe the development and psychometric properties of a new informant-based IADL questionnaire aimed at detecting incipient dementia and appropriate for a broad age range. METHODS: We defined IADL in consensus with experts and constructed items based on existing items and suggestions from experts and informants. Informants of subjects (n = 206) who visited the Alzheimer Center of the VU University Medical Center completed the questionnaire. Factor structure was investigated using classical exploratory factor analysis and item response theory. We assessed test-retest reliability in 73 informants using weighted kappa values. RESULTS: The questionnaire consisted of 75 items and was computerized to enhance ease of administration. Exploratory factor analysis supported a single-factor model, with 48.3% of the variance being explained by the first factor. We removed five items, as they did not fit the model. High internal consistency was demonstrated. Test-retest reliability showed that the majority of items (87.9%) had substantial-to-almost perfect kappa values. CONCLUSION: The Amsterdam IADL Questionnaire (Amsterdam IADL questionnaire is a registered trademark of Alzheimer Center VU University Medical Center, Amsterdam, The Netherlands) is a 70-item informant-based computerized questionnaire aimed at detecting early dementia and early-onset dementia. Initial results show that this questionnaire is a promising new tool. PMID- 23102124 TI - Computer-related self-efficacy and anxiety in older adults with and without mild cognitive impairment. AB - BACKGROUND: This study examines differences in computer-related self-efficacy and anxiety in subgroups of older adults, and changes in those measures after exposure to a systematic training program and subsequent computer use. METHODS: Participants were volunteers in the Intelligent Systems for Assessment of Aging Changes study (ISAAC) carried out by the Oregon Center for Aging and Technology. Participants were administered two questionnaires before training and again 1 year later, which were related to computer self-efficacy and anxiety. Continuous recording of computer use was also assessed for a subset of participants. RESULTS: Baseline comparisons by sex, age, education, living arrangement, and computer proficiency, but not cognitive status, yielded significant differences in confidence and anxiety related to specific aspects of computer use. At 1-year follow-up, participants reported less anxiety and greater confidence. However, the benefits of training and exposure varied by group and task. Comparisons based on cognitive status showed that the cognitively intact participants benefited more from training and/or experience with computers than did participants with mild cognitive impairment (MCI), who after 1 year continued to report less confidence and more anxiety regarding certain aspects of computer use. CONCLUSION: After 1 year of consistent computer use, cognitively intact participants in this study reported reduced levels of anxiety and increased self confidence in their ability to perform specific computer tasks. Participants with MCI at baseline were less likely to demonstrate increased efficacy or confidence than their cognitively intact counterparts. PMID- 23102125 TI - Predictive validity and diagnostic stability of mild cognitive impairment subtypes. AB - BACKGROUND: Mild cognitive impairment (MCI) is subclassified into four subtypes by the presence of impairment in the memory domain (amnestic vs. nonamnestic) and the number of impaired cognitive domains (single vs multiple). However, predictive validity for outcomes of these criteria and the diagnostic stability of the subtypes are questionable. METHODS: We investigated the outcomes of 140 patients with MCI who participated in the baseline study of the Korean Longitudinal Study on Health and Aging and completed the 18-month follow-up evaluation (mean duration of follow-up = 1.57 +/- 0.24 years). We evaluated the predictive validity of the criteria using multinomial logistic regression analyses, and the diagnostic stability of MCI subtypes using annual conversion rates between subtypes. RESULTS: Compared with the single-domain type (MCIs), the multiple-domain type (MCIm) had a lower chance of reversion to normal cognition (MCIm = 10.94%, MCIs = 43.42%) and higher risk of conversion to dementia (MCIm = 23.44%, MCIs = 5.26%). The difference in the reversion rate between the multiple- and single-domain type was statistically significant (odds ratio = 0.233, 95% confidence interval = 0.070-0.771, P = .017). However, neither the chance of reversion nor the risk of conversion was different between amnestic and nonamnestic subtypes. Among the 81 participants who neither converted to dementia nor reverted to normal cognition, 39 converted to different subtype (annual conversion rate = 17.74%). CONCLUSIONS: The number of impaired cognitive domains, but not the presence of memory impairment, predicted poor outcomes in people with MCI. However, MCI subtype was diagnostically unstable. PMID- 23102126 TI - Comparison of International Working Group criteria and National Institute on Aging-Alzheimer's Association criteria for Alzheimer's disease. AB - Two sets of research criteria for Alzheimer's disease are now available: those published by an International Working Group in 2007, and the recommendations published by the National Institute on Aging and the Alzheimer's Association (NIA AA) in 2011. They both provide guidelines for the diagnosis of asymptomatic and symptomatic Alzheimer's disease. The coexistence of two sets of criteria for the same disorder raises the question of which set of criteria should be preferred. A comparison of the criteria revealed differences in approach, terminology, and use of cognitive markers and biomarkers. Most persons who meet the International Working Group criteria will also meet the NIA-AA criteria and vice versa. However, the NIA-AA criteria allow for a subclassification of persons based on biomarker results within each diagnostic category. Further research is needed to validate the criteria. Modifications are likely to be made before the criteria can be used in daily practice. PMID- 23102127 TI - A model for improving the treatment and care of Alzheimer's disease patients through interdisciplinary research. AB - The emerging global epidemic of Alzheimer's disease (AD) demands novel paradigms to address the two unmet needs of the field: (a) cost-effective health care delivery programs/services, and (b) clinical and basic research to accelerate therapy discovery/development. This report outlines a model demonstration project, the Marian S. Ware Alzheimer Program at the University of Pennsylvania, which was designed to achieve four specific aims: (1) improve the integration and continuity of AD care; (2) identify biomarkers that detect the earliest presence of AD and related neurodegenerative cognitive disorders; (3) enhance both the design and conduct of clinical trials as well as review their results to more effectively test new AD therapies and translate valuable therapies into clinical practice; and (4) discover and develop novel disease-modifying small molecule treatments for AD. The "Ware-UPenn" program has been presented in this report as a useful prototype for partnerships between private philanthropy and academia in planning and developing programs to address a major national public health problem. PMID- 23102129 TI - Robotic intracorporeal urinary diversion: ileal conduit. AB - Radical cystectomy is considered the standard of care for muscle-invasive bladder cancer. The use of minimally invasive techniques, particularly robot-assisted radical cystectomy, is steadily increasing with an acceptable learning curve, adequate lymph node yield, and acceptable perioperative complications. Longer term follow-up is necessary to confirm oncologic efficacy, but early data are encouraging. While the majority of urinary diversions are performed extracorporeally, several recent small case studies have reported successful totally intracorporeal diversions, including both ileal conduit and orthotopic neobladder creation. Operative and short-term clinical outcomes have thus far been comparable to those of previously reported extracorporeal techniques. As surgeons gain experience with the robotic techniques needed for radical cystectomy, the frequency of intracorporeal urinary diversions will similarly increase. In this article, we describe the stepwise surgical procedure and perioperative management of the robot-assisted laparoscopic intracorporeal ileal conduit. PMID- 23102128 TI - Review of selected databases of longitudinal aging studies. AB - One of the recommendations of the 2010 Leon Thal Symposium, organized to develop strategies to prevent Alzheimer's disease, was to build a global database of longitudinal aging studies. Although several databases of longitudinal aging studies exist, none of these are comprehensive or complete. In this article, we review selected databases of longitudinal aging studies. We also make recommendations on future steps to create a comprehensive database. Additionally, we discuss issues related to data harmonization. PMID- 23102130 TI - [Updated view of fibromyalgia]. AB - Fibromyalgia is a chronic syndrome characterized by dysfunction of pain processing and regulation. Although the definite etiology has not been recognized yet, the key role in the pathogenesis of this syndrome probably plays the central sensitization process with the development of chronic (central) pain and other associated symptoms (fatigue, stiffness, sleep disorders, cognitive and vegetative disturbance). The absence of objective diagnostic tests often results in delayed diagnosis and patient fluctuation among a number of specialists with uncertainty and fear of a serious disease. The treatment is based on the individually adjusted and multidisciplinary approach to the patient, combining pharmacological and non-pharmacological therapy. New drugs introduced to the therapy in the recent years can have positive effect on symptom reduction and improvement of patients quality of life. Key words: fibromyalgia, chronic pain, fatigue, central sensitization. PMID- 23102131 TI - [General psychopathology--the basis for objective psychiatric findings]. AB - General psychopathology is an integral part of psychiatry; without knowledge of it we would be unable to describe an objective clinical psychiatric finding and set the diagnosis. It is dealing with not only description of single psychopathologic terms but also studies its connection with pathophysiology, genetics, biochemistry, psychology and sociology. The grounds of psychopathology were given by Karl Jaspers who devoted much attention to the problem of subjective and objective; it happens quite often that subjective symptoms may bear a character of objective signs. In spite of serious importance of general psychopathology these facts have been grossly neglected during the last several decades. Key words: general psychopathology, psychopathologic terms, their subjective and objective character. PMID- 23102133 TI - [Phytotherapy of skin wounds - overview of experimental and clinical studies in the first decennium of the 21st century]. AB - Delayed wound healing presents a significant burden for the patient and healthcare system. One of many possibilities how to improve the process of wound healing and to prevent development of unwanted complications is the use of herbal substances which are still commonly used in folk medicine. This review gives an overview of experimental and clinical studies related to phytotherapeutic approaches of skin wound healing which have during the 21st century been indexed by the largest biomedical database NCBI - PubMed. PMID- 23102134 TI - [The importance of DNA analysis of C282Y, H63D and S65C mutations in the HFE gene]. AB - BACKGROUND: Hereditary hemochromatosis is a relatively common genetic disease characterized by increased iron absorption and deposition in major organs of the body. The aim of this study was to determine the prevalence of C282Y, H63D and S65C mutations in the HFE gene in patients suspected of hereditary hemochromatosis and to compare it with healthy subjects (control group). MATERIAL AND METHODS: The group of patients consisted of 95 males and 45 females (median age 55 years, range 20 to 83 years). The control group was represented by 167 volunteers of Caucasian origin (65 males and 102 females, median age 25 years, range 18 to 62 years). The PCR/RFLP genetic analysis was used to detect mutations in the HFE gene. RESULTS: Allelic frequencies of C282Y, H63D, and S65C in the groups of patients were 18.2 %, 17.5 %, and 1.8 %, respectively. The frequencies of the alleles in the control group were 5.7 % (C282Y), 12.3 % (H63D), and 0.6 % (S65C). CONCLUSIONS: Our results show significant differences in the frequency of C282Y mutation between the patients suspected of hereditary hemochromatosis and the control group (18.2 % vs. 5.7 %). The prevalence of H63D and S65C mutations in both groups was not statistically significant. PMID- 23102135 TI - [Treatment of tobacco dependence - improving availability in the clinical practice]. AB - Tobacco dependence is a disease that causes dozens of illnesses and premature deaths. Effective treatment exists and should be available to all smokers in frame of the local health care service. The Czech Republic is not the only country missing the full availability. A worldwide project "Global Bridges: Healthcare Alliance for Tobacco Dependence Treatment" is trying to improve the situation. As we can see from the website globalbridges.org, the project focuses on different geographical regions of the world - even if comparisons between countries are difficult due to the different health care systems including their financing. The European Globalbridges group met in June 2012 in Birmingham at the occasion of the UK National Smoking Cessation Conference. The entire interconnected system of thousands of people involved in smoking cessation in UK, including research support, is truly impressive and may be an example to other countries not only in Europe. PMID- 23102147 TI - Ab initio calculations of the interaction between CO2 and the acetate ion. AB - A series of ab initio calculations designed to investigate the interaction of CO(2) with acetate are presented. The lowest energy structure, AC-CO(2)-eta(2), is predicted by CCSD(T)/aVTZ to be bound by -10.6 kcal/mol. Six of the bound complexes have binding energies on the order of -8 kcal/mol, but analysis shows that the eta(1)-CT complex is fundamentally different from the others. The eta(1) CT complex is characterized by geometric distortion, large polarization and induction effects and charge transfer whereas the other five complexes have little geometric distortion and negligible charge transfer. The amount of charge that is transferred from the anion to the CO(2) in the eta(1)-CT complex is estimated to be about half an electron by NPA, DMA, CHELPG, and Mulliken analyses, whereas the EDA-ALMO-CTA (B3LYP) approach predicts a charge transfer of 75 me(-). However, the transfer of this small amount of charge leads to an energy lowering of -56 kcal/mol, without which the complex would not be bound. The RI MP2 geometries closely approximate those resulting from the CCSD optimizations, and the optimized second-order opposite spin (O2) method performs well for all the complexes except for the eta(1)-CT complex. DFT methods do not reproduce all the ab initio geometries, binding energies and/or energy ordering of these complexes although the range-separated hybrid meta-GGA (M11) and nonlocal (VV10 and vdwDF10) functionals are shown to yield results significantly better than other functionals considered for this system. The fact that there is such variation among DFT methods has implications for DFT-based ab initio molecular dynamics simulations and for the parametrization of classical force fields based on DFT calculations. PMID- 23102146 TI - HIRA dependent H3.3 deposition is required for transcriptional reprogramming following nuclear transfer to Xenopus oocytes. AB - BACKGROUND: Nuclear reprogramming is potentially important as a route to cell replacement and drug discovery, but little is known about its mechanism. Nuclear transfer to eggs and oocytes attempts to identify the mechanism of this direct route towards reprogramming by natural components. Here we analyze how the reprogramming of nuclei transplanted to Xenopus oocytes exploits the incorporation of the histone variant H3.3. RESULTS: After nuclear transplantation, oocyte-derived H3.3 but not H3.2, is deposited on several regions of the genome including rDNA, major satellite repeats, and the regulatory regions of Oct4. This major H3.3 deposition occurs in absence of DNA replication, and is HIRA-and transcription-dependent. It is necessary for the shift from a somatic- to an oocyte-type of transcription after nuclear transfer. CONCLUSIONS: This study demonstrates that the incorporation of histone H3.3 is an early and necessary step in the direct reprogramming of somatic cell nuclei by oocyte. It suggests that the incorporation of histone H3.3 is necessary during global changes in transcription that accompany changes in cell fate. PMID- 23102148 TI - Molecular subdivision of the marine diatom Thalassiosira rotula in relation to geographic distribution, genome size, and physiology. AB - BACKGROUND: Marine phytoplankton drift passively with currents, have high dispersal potentials and can be comprised of morphologically cryptic species. To examine molecular subdivision in the marine diatom Thalassiosira rotula, variations in rDNA sequence, genome size, and growth rate were examined among isolates collected from the Atlantic and Pacific Ocean basins. Analyses of rDNA included T. gravida because morphological studies have argued that T. rotula and T. gravida are conspecific. RESULTS: Culture collection isolates of T. gravida and T. rotula diverged by 7.0 +/- 0.3% at the ITS1 and by 0.8 +/- 0.03% at the 28S. Within T. rotula, field and culture collection isolates were subdivided into three lineages that diverged by 0.6 +/- 0.3% at the ITS1 and 0% at the 28S. The predicted ITS1 secondary structure revealed no compensatory base pair changes among lineages. Differences in genome size were observed among isolates, but were not correlated with ITS1 lineages. Maximum acclimated growth rates of isolates revealed genotype by environment effects, but these were also not correlated with ITS1 lineages. In contrast, intra-individual variation in the multi-copy ITS1 revealed no evidence of recombination amongst lineages, and molecular clock estimates indicated that lineages diverged 0.68 Mya. The three lineages exhibited different geographic distributions and, with one exception, each field sample was dominated by a single lineage. CONCLUSIONS: The degree of inter- and intra specific divergence between T. gravida and T. rotula suggests they should continue to be treated as separate species. The phylogenetic distinction of the three closely-related T. rotula lineages was unclear. On the one hand, the lineages showed no physiological differences, no consistent genome size differences and no significant changes in the ITS1 secondary structure, suggesting there are no barriers to interbreeding among lineages. In contrast, analysis of intra-individual variation in the multicopy ITS1 as well as molecular clock estimates of divergence suggest these lineages have not interbred for significant periods of time. Given the current data, these lineages should be considered a single species. Furthermore, these T. rotula lineages may be ecologically relevant, given their differential abundance over large spatial scales. PMID- 23102150 TI - A call for reflection: medical student driven effort to foster empathy and compassion. PMID- 23102151 TI - Top five flashpoints in the assessment of teaching effectiveness. AB - BACKGROUND: Despite thousands of publications over the past 90 years on the assessment of teaching effectiveness, there is still confusion, misunderstanding, and hand-to-hand combat on several topics that seem to pop up over and over again on listservs, blogs, articles, books, and medical education/teaching conference programs. If you are measuring teaching performance in face-to-face, blended/hybrid, or online courses, then you are probably struggling with one or more of these topics or flashpoints. AIM: To decrease the popping and struggling by providing a state-of-the-art update of research and practices and a "consumer's guide to trouble-shooting these flashpoints." METHODS: Five flashpoints are defined, the salient issues and research described, and, finally, specific, concrete recommendations for moving forward are proffered. Those flashpoints are: (1) student ratings vs. multiple sources of evidence; (2) sources of evidence vs. decisions: which come first?' (3) quality of "home-grown" rating scales vs. commercially-developed scales; (4) paper-and-pencil vs. online scale administration; and (5) standardized vs. unstandardized online scale administrations. The first three relate to the sources of evidence chosen and the last two pertain to online administration issues. RESULTS: Many medical schools/colleges and higher education in general fall far short of their potential and the available technology to comprehensively assess teaching effectiveness. Specific recommendations were given to improve the quality and variety of the sources of evidence used for formative and summative decisions and their administration procedures. CONCLUSIONS: Multiple sources of evidence collected through online administration, when possible, can furnish a solid foundation from which to infer teaching effectiveness and contribute to fair and equitable decisions about faculty contract renewal, merit pay, and promotion and tenure. PMID- 23102152 TI - How useful are structured electronic portfolio templates to encourage reflective practice? AB - BACKGROUND: Some specialties in the U.K. use structured templates in electronic (e) Portfolios to encourage reflective practice. This study looked at completion of an 11-field template by U.K. Paediatric specialty trainees. METHODS: A reflective ePortfolio log from all paediatric specialty trainees in one large U.K. deanery was assessed by two medical educators. The consultant supervisors' opinion of the trainee's standard of reflective practice and outcome of annual review of competence progression was noted. RESULTS: If the 115 trainees, 10 had no reflective logs and 105 had reflective logs ranging in number from 1 to -18 (mean of 5). The structured template was poorly completed by trainees especially sections on what could be done differently and outcomes for the trainee, parents and others. Discrepancy between the evidence of reflection in ePortfolio and trainers assessment of reflective practice was noted. CONCLUSION: An 11-field structured template for reflective practice was not completed well. We suggest four fields as a maximum so as to enable trainees to reflect and note their personal key learning points. There needs to be an emphasis on quality rather than quantity of ePortfolio reflective logs, both in number and length of log aiming for 1-2 well completed reflections per post. PMID- 23102149 TI - Concentrations of bisphenol A and seven other phenols in pooled sera from 3-11 year old children: 2001-2002 National Health and Nutrition Examination Survey. AB - Concerns exist regarding children's exposure to bisphenol A (BPA) and other phenols because of the higher sensitivity, compared to adults, of children's developing organs to endocrine disruptors. Several studies reported the urinary concentrations of these phenols in children, but data on levels of these compounds in children's serum are limited. We present here the total (free plus conjugated) and free concentrations of BPA and seven other phenols in 24 pooled serum samples prepared from individual specimens collected from 936 children 3-11 years old who participated in the 2001-2002 National Health and Nutrition Examination Survey. We detected benzophenone-3, triclosan, 2,4-dichlorophenol, 2,5- dichlorophenol, and three parabens in at least 60% of the pools suggesting children's exposure to these compounds or their precursors. Conjugated phenols were the major species. However, although many previous studies have shown widespread detection of BPA in children's urine, we only detected total or free BPA in 3 and 2 pooled serum samples, respectively, at concentrations of 0.1-0.2 MUg/L. The nonpersistent nature of BPA and the phenols examined and the likely episodic nature of the exposures to these compounds (or their precursors) suggest that for general population biomonitoring of these nonpersistent phenols, urine, not serum or plasma, is the preferred matrix. PMID- 23102153 TI - Psychostimulant drug abuse and personality factors in medical students. AB - BACKGROUND: Psychostimulants have a high abuse potential and are appealing to college students for enhancing their examination performance. AIM: This study was designed to examine the prevalence of psychostimulant drug abuse among medical students and to test the hypothesis that medical students who use psychostimulant drugs for non-medical reasons are characterized by a sensation seeking and aggressive-hostility personality and exhibit lower empathy. METHODS: The Zuckerman-Kuhlman personality questionnaire and the Jefferson scale of empathy were completed anonymously on-line by 321 medical students in 2010-2011 academic year. RESULTS: A total of 45 students (14%) reported that they had abused psychostimulant medications either before or during medical school. RESULTS of multivariate analysis of variance provided support for one of our research hypothesis: students who reported using psychostimulant compared to the rest, obtained a significantly higher average score on the aggressive-hostility personality factor. No other significant differences were observed. CONCLUSION: Further research is needed to confirm the rate of psychostimulant drug abusers among medical students in other medical schools. In particular, it is desirable to examine if such psychostimulant drug abusers are likely to abuse other substances in medical school and later in their professional career. PMID- 23102154 TI - How we make good doctors into good teachers: a short course to support busy clinicians to improve their teaching skills. AB - BACKGROUND: Doctors are expected to teach but many are reluctant through lack of training. Busy clinicians have little time to attend faculty development initiatives. We wanted to increase clinical teaching capacity locally. WHAT WE DID: In response to requests from doctors lacking confidence in their teaching skills, we developed a programme tailored to the needs of working clinical teachers. The emphasis is on teaching effectively in a busy clinical environment. There are five 90 min modules: bedside teaching, effective supervision and feedback, teaching physical examination and procedures, effective lectures and facilitating development of clinical reasoning skills. The course is practical, interactive and takes place in a supportive learning environment adjacent to the workplace. A total of 81 clinicians participated in the course. EVALUATION: The main outcomes were increased confidence in bedside teaching, teaching more effectively on ward rounds and reduction in need for support with teaching. Participants reported a better understanding of basic educational theory and its relevance to clinical teaching. There is increased activity in clinical teaching among past participants. CONCLUSIONS: All clinical teachers require guidance and encouragement in developing their teaching skills. An accessible, practical focused teaching course run locally by colleagues with education expertise can improve clinicians' skills and motivation to teach. PMID- 23102155 TI - Project-based faculty development by international health professions educators: practical strategies. AB - BACKGROUND: Project design and implementation, applied to real life situations, is emerging as an educational strategy for application of health professions faculty development learning within a supportive environment. AIM: We conducted a retrospective analysis of project evolution to identify common experiences, challenges, and successful strategies of 54 mid-career faculty members from 18 developing countries who attended the Foundation for the Advancement of International Medical Education and Research Institute between 2001 and 2006 and designed, conducted, and evaluated education innovations at their home institutions. METHODS: Chronological analysis of the evolution of 54 projects over the initial 16-18 months of the 2-year Fellowship was based on an iterative qualitative analysis of 324 reports and individual interview transcripts collected over 6 years. RESULTS: Useful skill areas for project implementation included educational methods, leadership and management, and relationships/collaboration. Common challenges included competing responsibilities, lack of protected time, and limited resources. Themes identified with the evolution and success of education innovation projects included leadership and organization, collaboration, personal professional growth, and awareness of the relevant societal context. CONCLUSIONS: Common challenges and success factors in project-based faculty development were identified. Twelve practical strategies to promote successful project-based faculty development emerged that can be generalized for faculty development. PMID- 23102156 TI - Sharing methodology: a worked example of theoretical integration with qualitative data to clarify practical understanding of learning and generate new theoretical development. AB - BACKGROUND: Theoretical integration is a necessary element of study design if clarification of experiential learning is to be achieved. There are few published examples demonstrating how this can be achieved. AIMS: This methodological article provides a worked example of research methodology that achieved clarification of authentic early experiences (AEEs) through a bi-directional approach to theory and data. METHODS: Bi-directional refers to our simultaneous use of theory to guide and interrogate empirical data and the use of empirical data to refine theory. We explain the five steps of our methodological approach: (1) understanding the context; (2) critique on existing applications of socio cultural models to inform study design; (3) data generation; (4) analysis and interpretation and (5) theoretical development through a novel application of Metis. RESULTS: These steps resulted in understanding of how and why different outcomes arose from students participating in AEE. Our approach offers a mechanism for clarification without which evidence-based effective ways to maximise constructive learning cannot be developed. In our example it also contributed to greater theoretical understanding of the influence of social interactions. CONCLUSION: By sharing this example of research undertaken to develop both theory and educational practice we hope to assist others seeking to conduct similar research. PMID- 23102157 TI - Factors influencing the EBM behaviour of GP trainers: a mixed method study. AB - BACKGROUND: General practitioner (GP) trainees state that their trainers are not consistent in using evidence-based medicine (EBM) or are even dismissive of it. As trainers are important role models in the Dutch GP training system this could have a large influence on the EBM training of GP trainees. AIM: To establish the motivations and barriers of Dutch GP trainers in using EBM. METHODS: A questionnaire on personal characteristics, knowledge, skills (Berlin, score 0-15) and attitude (McColl, VAS score 0-100), and statements about EBM barriers were presented to 106 GP trainers. Additionally, three focus group sessions with trainers (n = 30) were held. RESULTS: Knowledge and skills were less than half correct (mean 6.1, standard deviation (SD) 2.9); the overall score on attitude was 58.8 (SD 9.4). Factor analysis showed four categories of barriers: EBM competence (mean 3.5 (SD 0.8)), search activities (mean 3.5 (SD 0.8)), motivation (mean 3.8 (SD 0.7)) and time (mean 2.5 (SD 0.9)). After analysis of the focus group sessions, five categories of motivations and barriers predominated: EBM competence, attitude and behaviour, sources, time and logistics. CONCLUSION: GP trainers experience motivations in EBM; however, these motivations can also be barriers, depending on the trainer's level of knowledge and attitude. PMID- 23102158 TI - How we teach ethics and communication during a Canadian neonatal perinatal medicine residency: an interactive experience. AB - BACKGROUND: Ethically challenging clinical situations frequently confront health care professionals in neonatology. These situations require neonatologists to exercise professionalism by communicating effectively throughout evolving physician-parent relationships in order to arrive at shared decisions for care that are in the best interest of the neonate and grounded solidly in ethical precepts. AIM: This article describes the process by which a well-delineated, interactive program to teach ethical reasoning and skillful communication with parents was implemented at the University of Ottawa, Canada. METHODS: A revised ethics program implemented in 2009 identified competencies that should be demonstrated at the end of the Neonatal-Perinatal Medicine (NPM) residency. Several seminars were refined while new workshops, problem-based learning in ethics, and a personal portfolio were added. RESULTS: All teaching strategies were well received based on the average level of satisfaction (5.8 out of 7, SD 0.4). We are now moving forward by formally assessing our program including the impact on knowledge acquisition and behavior. CONCLUSION: A dedicated, interactive competency-based neonatal ethics teaching program is vital to support NPM trainees in learning how to integrate ethical thinking with competencies in communication. PMID- 23102159 TI - Fostering students' reflection about bias in healthcare: cognitive dissonance and the role of personal and normative standards. AB - BACKGROUND: To reduce cognitive dissonance about one's beliefs or behavior, individuals may compare their behavior to personal and/or normative standards. The details of this reflection process are unclear. AIMS: We examined how medical students compare their behavior or beliefs to standards in discussions about implicit bias, and explored if and how different reflective pathways (preserving vs. reconciling) are associated with each standard. METHODS: Third-year students engaged in a small-group discussion about bias. Some students and group facilitators also participated in a debriefing about the experience. Using qualitative methods, the transcripts from these 11 sessions were analyzed for evidence of student comparison to a standard and of reflection pathways. RESULTS: Of 557 text units, 75.8% could be coded with a standard and/or a path of reflection. Students referenced personal and normative standards about equally, and preserved or reconciled existing beliefs about equally. Uses of normative standards were associated with preservation-type reflection, and uses of personal standards with reconciliation-type reflection. CONCLUSIONS: Normative expectations of physicians are sometimes used to provoke students' consideration of implicit biases about patients. To encourage critical reflection and reconciliation of biased beliefs or behavior, educators should frame reflective activities as a personal exercise rather than as a requirement. PMID- 23102160 TI - How we created a peer-designed specialty-specific selective for medical student career exploration. AB - BACKGROUND: In recent years, medical students have recognized and advocated for opportunities to explore various specialties earlier in their medical education. A brief literature review, however, reveals little consensus on the best approach to introduce students to different fields during their preclinical years. AIM: We present one of the first reports of a student-led effort to design and implement a preclinical specialty-specific elective. METHODS: At Mayo Medical School, for two consecutive years the student president of the Pediatric Interest Group has created a peer-designed weeklong group elective ("selective") experience consisting of workshops, faculty and resident panel discussions, and clinical shadowing experiences based on a student needs assessment. RESULTS: Each year, more than 25% of the first- and second-year medical student body participated. The majority of students who completed the selective agreed that this experience heightened their interests and expanded their knowledge about pediatrics. CONCLUSIONS: The pediatric group selective has provided students with important resources for their medical education and future careers. Students found the group selective beneficial to their learning experience and recommend continuing to offer it in the future. PMID- 23102161 TI - The obligation of debriefing in global health education. AB - BACKGROUND: An outcome of globalization and internationalization in higher education in the health professions has been increasing global health placements. There is, however, a lack of literature on debriefing and support following these placements. The authors undertook a participatory project to develop peer support and debriefing in a global health nursing elective, during which this gap in literature was addressed. AIMS: The purpose of the project was to develop a peer support component of the course and revise the debriefing component based on results of a previous course evaluation. METHODS: The methods were guided by a participatory approach involving course alumni and included a scoping review and focus groups. RESULTS: The project resulted in development of: (1) a peer support statement and (2) a debriefing framework. CONCLUSIONS: Key lessons about the obligation of appropriate debriefing for students returning from global health placements include importance of affective learning, a pedagogy of discomfort, and global health ethics. PMID- 23102162 TI - Measuring social accountability in health professional education: development and international pilot testing of an evaluation framework. AB - BACKGROUND: Health professional schools are responsible for producing graduates with competencies and attitudes to address health inequities and respond to priority health needs. Health professional schools striving towards social accountability founded the Training for Health Equity Network (THEnet). AIM: This article describes the development of THEnet evaluation framework for socially accountable health professional education, presents the framework to be used as a tool by other schools and discusses the findings of pilot implementation at five schools. METHODS: The framework was designed collaboratively and built on Boelen and Woollard's conceptualization, production and usability model. It includes key components, linked to aspirational statements, indicators and suggested measurement tools. Five schools completed pilot implementation, involving workshops, document/data review and focus group discussions with faculty, students and community members. RESULTS: Three sections of the framework consider: How does our school work?; What do we do? and What difference do we make? Pilot testing proved that the evaluation framework was acceptable and feasible across contexts and produced findings useful at school level and to compare schools. The framework is designed as a formative exercise to help schools take a critical look at their performance and progress towards social accountability. Initiatives to implement the framework more widely are underway. The framework effectively aids in identifying strengths, weaknesses and gaps, with a view to schools striving for continuous self-improvement. CONCLUSION: THEnet evaluation framework is applicable and useful across contexts. It is possible and desirable to assess progress towards social accountability in health professional schools and this is an important step in producing health professionals with knowledge, attitudes, and skills to meet the challenges of priority health needs of underserved populations. PMID- 23102163 TI - What is the value of global health electives during medical school? AB - PURPOSE: To determine whether global health (GH) electives enhanced the development of medical students and to examine the influence on host communities. METHODS: A retrospective survey study was conducted with Queen's University undergraduate medical students who had participated in a GH elective. Participants rated the influence of their elective on the aspects of their professional and personal development and their perceived community impact on a scale of 0-5. RESULTS: The highest rated statements focused on the students' personal development and whether the elective provided a valuable learning experience (4.39 and 4.07, respectively). Students also reported a heightened level of awareness of social determinants of health (mean rating of 3.98). The statements with the lowest mean ratings involved students' perceptions of their impact on the communities. Overall, 73.5% of participants agreed or strongly agreed that GH electives are valuable to medical education. CONCLUSION: GH electives benefit the professional and personal development of medical students. Although students gain significantly from their experience, they are unable to assess the impact of their work on the community. Thus, there is a need to assess the effect from both the perspective of the students and of the community members. PMID- 23102164 TI - Senior medical students as peer examiners in an OSCE. AB - BACKGROUND: At Sydney Medical School, we have recently introduced a practice objective structured clinical examination (OSCE) where our junior medical students are assessed by the senior peers. AIM: We sought to evaluate the efficacy of the programme. METHODS: The study took place in 2010 and 2011, with two cohorts of final-year students participating. A total of 40/98 (41%) of final year students chose to participate as examiners. Following the completion of standardised marking sheets by the student examiners, the marking sheets were reviewed by a senior academic examiner, and the 'global' mark was adjusted in accordance with the marking criteria. Student examiners also completed an open and closed-ended questionnaire regarding their experience as an examiner. A total of 105/115 (91%) of year 2 medical students were examined in the OSCE over the two-year period. RESULTS: The senior academic changed a total of 94 'global' marks, reducing the majority (55%) from 'satisfactory' to 'borderline'; 12% were reduced from 'satisfactory' to 'not satisfactory' and 33% from 'borderline' to 'not satisfactory'. Student questionnaire results showed a high level of engagement with their examiner experience overall, and it was regarded as a useful learning experience. CONCLUSION: Student examiners found peer assessment to be a very useful learning activity. However, our students need further training in how to globally assess a fellow student's overall performance objectively and to provide accurate feedback. PMID- 23102165 TI - Water structure, dynamics, and spectral signatures: changes upon model cavity ligand recognition. AB - It is becoming increasingly evident that water plays an active role in noncovalent receptor-ligand association. In this study, hydrophobic cavity-ligand association in a model system is characterized through the analysis of the structure, dynamics, and corresponding spectral signatures of water at different stages of the binding process. Molecular dynamics simulations reveal that the reorientation of the water molecules around the ligand becomes faster as the receptor-ligand distance reduces, which is correlated with the decrease in number of water-water hydrogen bonds within the ligand hydration shells. Prompted by the need for calculating physical quantities that can be amenable to experimental validation, the changes in the spectroscopic features upon cavity-ligand binding are investigated. The analysis of both linear and nonlinear infrared spectra allows direct insight into the evolution of water structure and dynamics around the ligand. In particular, characteristic spectroscopic features emerge at key stages of the binding process, which are related to changes in the hydrogen-bond topology of water around the ligand. This study demonstrates that computer simulations and vibrational spectroscopy could be integrated to facilitate the direct study of solvent effects in biomolecular association. PMID- 23102166 TI - Demand for long acting and permanent methods of contraceptives and factors for non-use among married women of Goba Town, Bale Zone, South East Ethiopia. AB - BACKGROUND: Contraceptive use including short acting, long acting and permanent methods positively influence the socio-economic development of a nation by allowing families to space and limit their family size to their economic capacity. Demand for LAPMs of contraception as detrmined by utilization and unmet need for LAPMs of contraception can provide realiable information for providers. OBJECTIVE: To determine the utilization of long acting and permanent contraception and its associated factors among married women of Goba town, South East Ethiopia. METHODS: A cross sectional community based study was conducted among 734 systematically selected married women of reproductive age in Goba town in September/ 2009. A structured and pretested, interview questionaire was used to collect data on socio-demographic, behavioral factors and data related to demand for LAPMs of contraception. Data were analyzed using EPI INFO and SPSS version 16. RESULT: The demand for Long Acting and Permanent Methods (LAPMs) of contraception was 18.1%. Utilization of LAPMs of contraception in the town was 64 (8.7%) and the unmet need for LAPMs was 69 (9.4%). Information on LAPMs in the town was 636 (86.6%). Media (radio and television) was the major sources of information 641 (87.3%). The use of LAPMs was significatly associated with ever use AOR[17.43, 95% CI:9.19, 33.03], number of times discussions made on methods AOR[4.6, 95% CI: 1.72,12.17] and main decider of using methods AOR[ 2.2, 95% CI:1.03, 4.65]. It was not associated with socio-demographic variables. CONCLUSION AND RECOMMENDATION: The utilization of LAPMs in the town was less although higher than the Ethiopian demographic and health survey 2005 result. Moreover, there was a considerable unmet need. Increase the method mix of LAPMs by incorporating varaies of implnats in order to increase utilization. Proper counseling of client and partners discussion were some of the recommendation forwarded. PMID- 23102167 TI - Chondrogenic differentiation of immortalized human mesenchymal stem cells on zirconia microwell substrata. AB - Human mesenchymal stem cells (hMSCs) that can differentiate into chondrocytes are a potential autologous cell source for repair of damaged tissue. Current methods usually induce the formation of all three chondrocyte phenotypes, hyaline, fibrous, and elastic, without the ability to selectively induce only one of them. By controlling the size of hMSC cell clusters, it may be possible to direct differentiation more uniformly toward hyaline chondrocytes. We designed new cell culture platforms containing microwells of different diameters. The platforms and wells were composed of a zirconia ceramics substratum. hMSCs briefly adhered to the substratum before releasing and entering the microwells. The physical restraints imposed by the microwells enabled hMSC clusters to homogenously differentiate into hyaline chondrocyte-like cells. Chondrogenic aggregates in microwells expressed the hyaline chondrocyte-specific genes Col II, aggrecan (ACAN), and cartilage oligomeric protein (COMP). The cultures also produced hyaline chondrocyte-specific matrix proteins Col II and ACAN homogenously throughout the aggregates. In contrast, chondrogenesis in pellet cultures was heterogeneous with the expression of nonhyaline chondrocyte genes CD105, Col X, and Col I. In these pellet cultures, hyaline and nonhyaline chondrocyte-specific matrix proteins were distributed heterogeneously. Thus, this novel ceramic microwell substratum technology efficiently directed the differentiation of hyaline chondrocyte-like cells from hMSCs. These results indicate that there is a close relationship between hMSC cluster size regulation in the microwells and differentiation tendency. This microwell culture differentiation method will provide a valuable experimental system for both experimental and potential clinical studies. PMID- 23102168 TI - Diabetes, diet, and dietitians: an urgent public health problem requiring multi disciplinary decisions. PMID- 23102169 TI - Translating science into action. PMID- 23102170 TI - The great migration: opportunities and obstacles await those advancing toward electronic health record adoption. PMID- 23102171 TI - Legal risks of social media: what dietetics practitioners need to know. PMID- 23102172 TI - Medical nutrition therapy for youth with type 1 diabetes mellitus: more than carbohydrate counting. PMID- 23102174 TI - Achievable cost saving and cost-effective thresholds for diabetes prevention lifestyle interventions in people aged 65 years and older: a single-payer perspective. AB - BACKGROUND: More than 75% of people older than 65 years of age in the United States have prediabetes or diabetes. Diabetes is a burden on Medicare, the US health care payer. Intensive lifestyle interventions have successfully prevented diabetes cases, and medical nutrition therapy has also significantly reduced diabetes risk factors. Including medical nutrition therapy coverage for prediabetes is a policy decision to be made by Medicare, and cost-effectiveness data must support that decision. OBJECTIVE: The aims of this study were to determine the thresholds of diabetes cases that need to be averted by prediabetes lifestyle interventions in order to be cost saving and/or cost-effective to a single health care insurance payer, such as Medicare; and to compare those thresholds with published intervention data to determine the feasibility of cost savings and/or cost-effectiveness. DESIGN: This analysis used standard methods of cost-effectiveness and cost saving analysis. A health system perspective was used. Cost estimates for diabetes treatment and lifestyle interventions were based on published data. Costs for 3-, 6-, and 10-year lifestyle interventions were calculated. Sensitivity analyses were performed using least and most conservative published data for health care and intervention costs. RESULTS: The number of cases averted needed for base-case cost savings ranged from 882,883 to 2,443,686, and in sensitivity analysis from 394,148 to 6,738,678. Cost savings are likely in the base and least-conservative scenarios. The number of cases averted needed for base-case cost-effectiveness ranged from 454,755 to 1,258,692, and in sensitivity analysis from 212,225 to 4,843,262. Cost-effectiveness is likely in all interventions, except the 10-year interventions in the most conservative scenario. CONCLUSIONS: Prediabetes lifestyle interventions for people aged 65 years or older are highly cost-effective and possibly cost saving to a health care insurance payer such as Medicare. It is likely that medical nutrition therapy could be even more cost saving and/or cost-effective than intensive lifestyle interventions. These results suggest that Medicare would receive financial benefit from providing coverage for these services. PMID- 23102173 TI - Multiple indicators of poor diet quality in children and adolescents with type 1 diabetes are associated with higher body mass index percentile but not glycemic control. AB - BACKGROUND: Diet is a cornerstone of type 1 diabetes treatment, and poor diet quality may affect glycemic control and other health outcomes. Yet diet quality in children and adolescents with type 1 diabetes remains understudied. OBJECTIVE: To evaluate multiple indicators of diet quality in children and adolescents with type 1 diabetes and their associations with hemoglobin A1c and body mass index percentile. DESIGN: In this cross-sectional study, participants completed 3-day diet records, and data were abstracted from participants' medical records. Diet quality indicators included servings of fruit, vegetables, and whole grains; Healthy Eating Index-2005 (HEI-2005) score; Nutrient Rich Foods 9.3 score (NRF 9.3); and glycemic index. PARTICIPANTS/SETTING: Children and adolescents with type 1 diabetes >= 1 year, aged 8 to 18 years, were recruited at routine clinic visits. Of 291 families enrolled, 252 provided diet data. STATISTICAL ANALYSES: Associations of diet quality indicators to HbA1c and body mass index percentile were examined using analysis of covariance and multiple linear regression. RESULTS: Participants demonstrated low adherence to dietary guidelines; mean HEI 2005 score was 53.4 +/- 11.0 (range = 26.7 to 81.2). Intake of fruit, vegetables, and whole grains was less than half the recommended amount. Almost half of the participants' daily energy intake was derived from refined-grain products, desserts, chips, and sweetened beverages. Higher fruit (P = 0.04) and whole-grain (P = 0.03) intake were associated with lower HbA1c in unadjusted, but not adjusted analyses; vegetable intake, HEI-2005 score, NRF 9.3 score, and glycemic index were not associated with HbA1c. Higher fruit (P = 0.01) and whole-grain (P = 0.04) intake and NRF 9.3 score (P = 0.02), but not other diet quality indicators, were associated with lower body mass index percentile in adjusted analyses. CONCLUSIONS: Data demonstrate poor diet quality in youth with type 1 diabetes and provide support for the importance of diet quality for weight management. Future research on determinants of dietary intake and methods to promote improved diet quality would be useful to inform clinical care. PMID- 23102175 TI - The influence of home-delivered dietary approaches to stop hypertension meals on body mass index, energy intake, and percent of energy needs consumed among older adults with hypertension and/or hyperlipidemia. AB - BACKGROUND: It is unclear whether participation in home-delivered meal programs similar to the Older Americans Act home-delivered meals program influence weight status among older adults with hypertension and/or hyperlipidemia. OBJECTIVE: To examine the influence of a home-delivered Dietary Approaches to Stop Hypertension (DASH) meal intervention on body mass index (BMI), energy consumed, and percent of energy needs consumed. DESIGN: A 1-year randomized control trial of home delivered DASH meals and medical nutrition therapy conducted from 2003 through 2005. Participants who received DASH meals were compared with those who did not receive meals. Data were collected in participants' homes at baseline, 6 months, and 12 months. PARTICIPANTS/SETTING: The study sample was composed of 298 adults aged >60 years with hypertension and/or hyperlipidemia residing in a county in the southeastern part of North Carolina. INTERVENTION: Participants in the meals intervention group received seven frozen meals per week for 1 year. The meals were designed to meet one third of participants' energy and nutrient needs and to comply with the DASH diet. MAIN OUTCOME MEASURES: Change in BMI, energy consumed, and percent of energy needs consumed. STATISTICAL ANALYSES PERFORMED: Difference in-differences models were used to estimate the effects of the meal intervention on BMI, energy consumed, and percent of daily energy needs consumed. Analyses were conducted among the full sample and by subgroup (ie, race, income, and baseline obesity status). RESULTS: In the full sample, receipt of meals did not have a significant effect on BMI, energy consumed, or percent of daily energy needs consumed. Among those living at or above the 165% poverty threshold, receipt of home-delivered meals was significantly associated with a decrease in energy consumed and, therefore, percent of daily energy needs consumed. CONCLUSIONS: Participation in a home-delivered DASH meal program did not lead to weight gain or weight loss in a group of mostly overweight or obese older adults with hypertension and/or hyperlidemia. PMID- 23102176 TI - Qualitative application of the theory of planned behavior to understand beverage consumption behaviors among adults. AB - Despite strong scientific data indicating associations among sugar-sweetened beverages (SSB) and numerous adverse health outcomes, little is known about culturally specific beliefs and potential individual-level behavioral strategies to reduce SSB intake. The primary objective of this formative study targeting adults residing in rural southwest Virginia was to apply the Theory of Planned Behavior to investigate culturally specific attitudes, subjective norms, and perceived behavioral control constructs related to the consumption of SSB, water, and artificially sweetened beverages. Using a homogenous sampling strategy, eight focus groups were conducted with 54 adult participants who exceeded recommendations of <1 cup of SSB/day. An experienced moderator and co-moderator utilized a semi-structured script, grounded in the Theory of Planned Behavior, to execute the focus group. All focus groups were audiotaped and transcribed verbatim. Three researchers independently coded meaning units to the major themes and subsequently met to gain consensus in coding. Important beverage-specific themes emerged for attitudes, subjective norms, perceived behavioral control, and intentions. Across all beverages, the most notable themes included taste (n=161 meaning units), availability/convenience (n=95 meaning units), habit/addiction (n=57 meaning units), and cost (n=28 meaning units). Health consequences associated with beverages and water-quality issues also surfaced, as well as normative beliefs, including the influence of doctors and peers. The identified themes and subthemes provide critical insight into understanding culturally relevant context and beliefs associated with beverage consumption behaviors and helps inform the development and evaluation of future intervention efforts targeting SSB consumption in the health disparate region of southwest Virginia. PMID- 23102177 TI - Partial sleep deprivation and energy balance in adults: an emerging issue for consideration by dietetics practitioners. AB - During the past 30 years, rates of partial sleep deprivation and obesity have increased in the United States. Evidence linking partial sleep deprivation, defined as sleeping <6 hours per night, to energy imbalance is relevant to weight gain prevention and weight loss promotion. With a majority of Americans overweight or obese, weight loss is a recommended strategy for reducing comorbid conditions. Our purpose was to review the literature regarding the role of partial sleep deprivation on energy balance and weight regulation. An inverse relationship between obesity and sleep duration has been demonstrated in cross sectional and prospective studies. Several intervention studies have tested mechanisms by which partial sleep deprivation affects energy balance. Reduced sleep may disrupt appetitive hormone regulation, specifically increasing ghrelin and decreasing leptin and, thereby, influence energy intake. Increased wakefulness also may promote food intake episodes and energy imbalance. Energy expenditure may not be greatly affected by partial sleep deprivation, although additional and more accurate methods of measurements may be necessary to detect subtle changes in energy expenditure. Body weight loss achieved by reduced energy intake and/or increased energy expenditure combined with partial sleep deprivation may contribute to undesirable body composition change with proportionately more fat-free soft tissue mass lost compared with fat mass. Evaluating sleep patterns and recommending regular, sufficient sleep for individuals striving to manage weight may be prudent. PMID- 23102178 TI - Consistency with the dietary approaches to stop hypertension diet among adults with diabetes. AB - Few studies have documented whether the dietary patterns of adults with diabetes are similar to the Dietary Approaches to Stop Hypertension (DASH) diet. Our objective was to determine differences in the degree of consistency with the DASH diet among adults with self-reported diabetes (with and without self-reported high blood pressure) compared with those without either disease. It was a cross sectional study using data from 5,867 nonpregnant, noninstitutionalized adults aged >= 20 years with two reliable 24-hour recall dietary interviews in the National Health and Nutrition Examination Survey during 2003-2004 and 2005-2006. Diabetes and hypertension status were obtained from a questionnaire, and degree of consistency with the DASH diet was calculated based on nine nutrient targets (0- to 9-point DASH score). Multiple linear regression (adjusting for age, energy intake, and other covariates such as education, race, and body mass index) was performed to compare mean DASH scores and mean nutrient intakes among adults with diabetes, with and without high blood pressure, to those without either disease. No statistically significant differences were seen in mean DASH score among the three groups in the unadjusted or fully adjusted multivariable models. Compared with adults without either disease, those with only diabetes had higher intakes of fiber (8.1 g/1,000 kcal vs 7.6 g/1,000 kcal; P=0.02) and total fat as a percentage of total energy (35.3% vs 34.1%; P=0.006), and those with both diabetes and hypertension had higher sodium intake (153.0% of DASH target vs 146.6%; P=0.04). This information about individual nutrients could help guide the development of education programs. PMID- 23102179 TI - Effect of ground cinnamon on postprandial blood glucose concentration in normal weight and obese adults. AB - In healthy normal-weight adults, cinnamon reduces blood glucose concentration and enhances insulin sensitivity. Insulin resistance, resulting in increased fasting and postprandial blood glucose and insulin levels, is commonly observed in obese individuals. The objective of the study was to compare declines in postprandial glycemic response in normal-weight and obese subjects with ingestion of 6 g ground cinnamon. In a crossover study, subjects consumed 50 g available carbohydrate in instant farina cereal, served plain or with 6 g ground cinnamon. Blood glucose concentration, the main outcome measure, was assessed at minutes 0, 15, 30, 45, 60, 90, and 120. Repeated-measures analysis of variance evaluated the effects of body mass index (BMI) group, dietary condition, and time on blood glucose. Paired t-test assessed blood glucose at individual time points and glucose area under the curve (AUC) between dietary conditions. Thirty subjects between the ages of 18 and 30 years, 15 with BMIs between 18.5 and 24.9 and 15 with BMIs of 30.0 or more, completed the study. There was no significant difference in blood glucose between the two BMI groups at any time point. However, in a combined analysis of all subjects, the addition of cinnamon to the cereal significantly reduced 120-minute glucose AUC (P=0.008) and blood glucose at 15 (P=0.001), 30 (P<0.001), 45 (P<0.001), and 60 (P=0.001) minutes. At 120 minutes, blood glucose was significantly higher with cinnamon consumption (P<0.001). These results suggest cinnamon may be effective in moderating postprandial glucose response in normal weight and obese adults. PMID- 23102180 TI - Disordered eating behaviors are associated with poorer diet quality in adolescents with type 1 diabetes. AB - Disordered eating behaviors may pose a risk for poor long-term health outcomes in patients with type 1 diabetes. This cross-sectional study examined associations of disordered eating behaviors with diet quality, diet-related attitudes, and diabetes management in adolescents with type 1 diabetes (N=151, 48% female). Participants, recruited July 2008 through February 2009, completed 3-day diet records and survey measures, including the Diabetes Eating Problem Survey (DEPS) and measures of eating-related attitudes. Biomedical data were obtained from medical records. Participants scoring more than 1 standard deviation above the mean DEPS were classified as at risk for disordered eating. The Healthy Eating Index-2005 was calculated to assess diet quality. Analysis of covariance was used to test for differences between risk groups in diet quality, eating attitudes, and diabetes management, controlling for age, sex, and body mass index (BMI) percentile. Youth at risk for disordered eating were more likely to be overweight/obese than those at low risk (59.1% vs 31.8%, P=0.01). The at-risk group had poorer diet quality (P=0.003) as well as higher intake of total fat (P=0.01) and saturated fat (P=0.007) compared with the low-risk group. The at risk group reported lower self-efficacy (P=0.005), greater barriers (P<0.001), and more negative outcome expectations (P<0.001) for healthful eating, as well as worse dietary satisfaction (P=0.004). The at-risk group had lower diabetes adherence (P<0.01), less-frequent blood glucose monitoring (P<0.002), and higher hemoglobin A1c (P<0.001). The constellation of excess weight, poorer dietary intake, and poorer diabetes management associated with youth at risk for disordered eating suggests potential risk of future poor health outcomes. Attention should be given to healthful weight management, especially among overweight youth with type 1 diabetes. PMID- 23102181 TI - Dietary intake and cardiometabolic risk in ethnically diverse urban schoolchildren. AB - Dietary factors vary widely among ethnic groups. However, the effect of specific nutrients on cardiometabolic risk is not well understood, especially in children. Four dietary factors known to influence cardiometabolic risk (ie, carbohydrate, saturated, monounsaturated, and polyunsaturated fat intake) were assessed by the Block Kids 2004 Food Frequency Questionnaire in a cross-sectional sample of racially diverse fourth- through eighth-grade students (n=148) in a Boston-area school district studied between January and April 2010. Fasting total cholesterol, low-density lipoprotein, high-density lipoprotein (HDL) cholesterol, triglyceride, C-reactive protein (CRP), and interleukin-6 (IL-6) levels, and body mass index z scores were measured. Differences in dietary factors and cardiometabolic risk factors were examined among the following racial/ethnic groups: white (39%), Hispanic (32%), black (8%), Asian (10%), and multiracial/other (11%). In bivariate analyses, total, saturated, and polyunsaturated fat intakes differed by race/ethnicity (P<0.05), with white and black children reporting saturated fat intakes above the recommended level. Forty seven percent of children had at least one suboptimal cardiometabolic risk factor. HDL cholesterol, triglyceride, and IL-6 concentrations differed by race/ethnicity (P<0.05, P<0.01, and P<0.01, respectively), with Hispanics having low HDL cholesterol levels and high triglyceride levels, whereas Asians had high IL-6 levels. In multivariate analyses controlling for demographic characteristics, none of the dietary factors examined explained racial/ethnic differences in lipid profiles or inflammatory markers. Body mass index z score was associated with lower HDL cholesterol, higher triglyceride, higher CRP, and higher IL-6 levels (P<0.0001). Further research is warranted to determine the influence of dietary recommendations at a young age among different racial/ethnic groups on cardiometabolic health. PMID- 23102182 TI - Use of caloric and noncaloric sweeteners in US consumer packaged foods, 2005 2009. AB - Our understanding of the use of caloric and noncaloric sweeteners in the US food supply is limited. This study uses full ingredient list and Nutrition Facts label data from Gladson Nutrition Database and nationally representative purchases of consumer packaged foods from Nielsen Homescan in 2005 through 2009 to understand the use of caloric sweeteners (including fruit juice concentrate) and noncaloric sweeteners in consumer packaged foods. Of the 85,451 uniquely formulated foods purchased during 2005 through 2009, 75% contain sweeteners (68% with caloric sweetener only, 1% with noncaloric sweetener only, 6% with both caloric and noncaloric sweeteners). Caloric sweetener are in >95% of cakes/cookies/pies, granola/protein/energy bars, ready-to-eat cereals, sweet snacks, and sugar sweetened beverages. Noncaloric sweetener are in >33% of yogurts and sport/energy drinks, 42% of waters (plain or flavored), and most dietetic sweetened beverages. Across unique products, corn syrup is the most commonly listed sweetener, followed by sorghum, cane sugar, high-fructose corn syrup, and fruit juice concentrate. Also, 77% of all calories purchased in the United States in 2005 2009 contained caloric sweeteners and 3% contained noncaloric sweeteners, and 73% of the volume of foods purchased contained caloric sweetener and 15% contained noncaloric sweetener. Trends during this period suggest a shift toward the purchase of noncaloric sweetener-containing products. Our study poses a challenge toward monitoring sweetener consumption in the United States by discussing the need and options available to improve measures of caloric sweetener and noncaloric sweetener and additional requirements on Nutrition Facts labels on consumer packaged foods. PMID- 23102183 TI - Comparative effectiveness of a mindful eating intervention to a diabetes self management intervention among adults with type 2 diabetes: a pilot study. AB - Mindful eating offers promise as an effective approach for weight management and glycemic control in people with diabetes. Diabetes self-management education (DSME) is an essential component of effective self-care. Yet, little research has compared the effect of mindful eating to DSME-based treatment. This study compared the impact of these two interventions in adults with type 2 diabetes mellitus. A prospective randomized controlled trial with two parallel interventions was used. Participants included adults age 35 to 65 years with type 2 diabetes mellitus for 1 year or more, body mass index (BMI) of 27 or more, and hemoglobin A1c (HbA1c) of 7% or more who were randomly assigned to a 3-month mindful eating (MB-EAT-D; n=27) or Smart Choices (SC) DSME-based (n=25) intervention. Follow-up occurred 3 months after intervention completion. Dietary intake, physical activity, weight, HbA1c and fasting plasma glucose, and fasting insulin were assessed using repeated measures analysis of variance with contrast analysis. There was no significant difference between groups in the change in weight or glycemia at study end. Significant difference occurred between groups in the change in dietary intake/1,000 kcal of trans fats, total fiber, and sugars (all P<0.05). Mean (+/- standard error) reduction in weight (-2.92 +/- 0.54 kg for SC vs -1.53 +/- 0.54 kg for MB-EAT-D) and HbA1c (-0.67 +/- 0.24% for SC and 0.83 +/- 0.24% for MB-EAT-D) were significant (P<0.01). Significant reduction in energy intake and glycemic load occurred (all P<0.0001) for both groups. Training in mindful eating and diabetes self-management facilitate improvement in dietary intake, modest weight loss, and glycemic control. The availability of effective treatments gives patients with diabetes choices in meeting their self-care needs. PMID- 23102186 TI - Burning brightly into the 21st Century: the academy's history from 1990-present. PMID- 23102184 TI - Methodology for adding glycemic index to the National Health and Nutrition Examination Survey nutrient database. AB - Generating valid estimates of dietary glycemic index (GI) and glycemic load (GL) has been a challenge in nutritional epidemiology. The methodologic issues may have contributed to the wide variation of GI/GL associations with health outcomes observed in existing literature. We describe a standardized methodology for assigning GI values to items in the National Health and Nutrition Examination Survey (NHANES) nutrient database using the new International Tables to develop research-driven, systematic procedures and strategies to estimate dietary GI/GL exposures of a nationally representative population sample. Nutrient databases for NHANES 2003-2006 contain information on 3,155 unique foods derived from the US Department of Agriculture National Nutrient Database for Standard Reference versions 18 and 20. Assignment of GI values were made to a subset of 2,078 carbohydrate-containing foods using systematic food item matching procedures applied to 2008 international GI tables and online data sources. Matching protocols indicated that 45.4% of foods had identical matches with existing data sources, 31.9% had similar matches, 2.5% derived GI values calculated with the formula for combination foods, 13.6% were assigned a default GI value based on low carbohydrate content, and 6.7% of GI values were based on data extrapolation. Most GI values were derived from international sources; 36.1% were from North American product information. To confirm data assignments, dietary GI and GL intakes of the NHANES 2003-2006 adult participants were estimated from two 24 hour recalls and compared with published studies. Among the 3,689 men and 4,112 women studied, mean dietary GI was 56.2 (men 56.9, women 55.5), mean dietary GL was 138.1 (men 162.1, women 116.4); the distribution of dietary GI was approximately normal. Estimates of population GI and GL compare favorably with other published literature. This methodology of adding GI values to an existing population nutrient database utilized systematic matching protocols and the latest comprehensive data sources on food composition. The database can be applied in clinical and survey research settings where there is interest in estimating individual and population dietary exposures and relating them to health outcomes. PMID- 23102187 TI - The academy's governance and practice: restructuring for the challenges of the turn of the 21st Century. PMID- 23102188 TI - What role does nutrition play in the prevention or treatment of childhood lead poisoning? PMID- 23102189 TI - Fluticasone/formoterol combination therapy versus budesonide/formoterol for the treatment of asthma: a randomized, controlled, non-inferiority trial of efficacy and safety. AB - OBJECTIVES: The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting beta2 agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform((r))). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort((r)) Turbohaler((r))). METHODS: A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7 (+/- 3) day screening, 2-4-week run-in, and 12-week treatment periods. Patients aged >= 12 years with moderate to severe persistent asthma for >= 6 months before screening and forced expiratory volume in one second (FEV1) 50-80% predicted and >= 15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 MUg twice daily (n = 140) or budesonide/formoterol 400/12 MUg twice daily (n = 139). RESULTS: Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. The LS mean treatment difference was -0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non inferiority limit of -0.2 L (95% CI: -0.130, 0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV1 from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol. CONCLUSIONS: This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints. PMID- 23102190 TI - Hospitalization for congestive heart failure: United States, 2000-2010. AB - Congestive heart failure (CHF) is a serious medical condition in which the heart cannot pump enough blood to meet the body's needs. CHF is often caused by hypertension, diabetes, or coronary heart disease. It is estimated that 5.8 million people in the United States have CHF (1). CHF is one of the most common reasons those aged 65 and over are hospitalized (2). This report presents National Hospital Discharge Survey (NHDS) data from 2000 through 2010 on hospitalizations for CHF. PMID- 23102191 TI - Parallel divergent adaptation along replicated altitudinal gradients in Alpine trout. AB - BACKGROUND: The European trout (Salmo trutta species complex) occurs across a very wide altitudinal range from lowland rivers to alpine streams. Historically, the major European river systems contained different, evolutionarily distinct trout lineages, and some of this genetic diversity has persisted in spite of extensive human-mediated translocations. We used AFLP-based genome scans to investigate the extent of potentially adaptive divergence among major drainages and along altitudinal gradients replicated in several rivers. RESULTS: The proportion of loci showing evidence of divergent selection was larger between drainages than along altitudinal transects within drainages. This suggests divergent selection is stronger between drainages, or adaptive divergence is constrained by gene flow among populations within drainages, although the latter could not be confirmed at a more local scale. Still, altitudinal divergence occurred and, at approximately 2% of the markers, parallel changes of the AFLP band frequencies with altitude were observed suggesting that altitude may well be an important source of divergent selection within rivers. CONCLUSIONS: Our results indicate that adaptive genetic divergence is common both between major European river systems and along altitudinal gradients within drainages. Alpine trout appear to be a promising model system to investigate the relative roles of divergent selection and gene flow in promoting or preventing adaptation to climate gradients. PMID- 23102192 TI - [BRAF mutation: a novel approach in targeted melanoma therapy]. AB - The incidence of malignant melanoma is increasing worldwide, despite our best efforts in prevention and early detection. The locally advanced disease may be treated surgically with good results, however, metastatic melanoma is considered to be one of the most therapeutically challenging malignancies. The increasing knowledge of molecular changes in melanoma may change this picture. Malignant melanoma is not a singular, homogeneous disease but rather a mixture of subtypes characterized by specific mutations. Tumors with C-KIT mutation respond to therapy with C-KIT kinase inhibitor imatinib and the ones characterized by BRAF mutations respond to BRAF kinase inhibitor vemurafenib. Vemurafenib was approved by US FDA in 2011 and EMA in 2012 for therapy of patients with advanced melanoma, harboring mutation in BRAFV600E gene. Ipilimumab, an antibody to cytotoxic T lymphocyte antigen 4 (CTLA-4), was registered in 2011 by both US FDA and European Medicines Agency for treatment of metastatic melanoma. This therapy promotes the anti-tumor T-cell activity by blocking a CTLA-4 antigen, a key negative regulator of immune response. PMID- 23102193 TI - [The substance of genetic information--nucleic acids]. AB - If we look at the history of our knowledge of nucleic acids, we would see in the distant past of 140 years Friedrich Miescher who had identified the acidic substance within the cell nucleus, which he called nuclein. About 70 years after his initial observation, this substance was connected with genetic information. This very substantial finding happened during the World War II. This was the impulse that research of nucleic acids received to speed up continuously growing mountain of information, which is more and more difficult to understand. Another eruption of new information about our genome was the result of ten years of intensive cooperation of many manufacturers divided into two competitive blocks which offered us knowledge of nucleotide sequence of all 46 DNA molecules. The year 2000 became the landmark marking the start of the postgenomic era. It did not mean that human genome was totally explored, but the cornerstone has been settled. Since then, we could concentrate our efforts on variability; use of the project of 1,000 genomes brought many important findings, eg. copy number variability (CNV) exceeds the single nucleotide polymophisms (SNP). Also intergenomic relationships, studies on function and pathways began to be much more understandable by elucidation of the genome primary structure. NGS as a tool also accelerated the epigenetic research. All this improved molecular diagnostics by discovering many new markers playing their role in disease and treatment and allowed us to enter the field of multifactorial illnesses including cancer. The progress in diagnostic technologies which has happened during the last decade forced our research teams to include other professions - eg. bioinformatics. PMID- 23102194 TI - [Dabrafenib: the new inhibitor of hyperactive B-RAF kinase]. AB - The B-RAF kinase is among major targets of biological therapy of cancer. B-RAF acts in the MAP kinase pathway, being activated by any of the RAS G-proteins. Hyperactive B-RAF is typically detected in chemoresistant and radioresistant malignant metastatic melanoma. In this study, we focus on the reversible ATP competitive inhibitor dabrafenib (GSK-2118436), which is now in phase III clinical trial for use in subjects with various cancers expressing hyperactive B RAF. Dabrafenib is selective for B-RAFV600E and B-RAFV600K (less for B-RAFV600D) over wild-type B-RAF. Thus, similarly to vemurafenib (Zelboraf), suggested is mandatory pre-screening for activating B-RAF mutations in the cancer tissue of each subject. Dabrafenib inhibits neoplastic growth at concentrations 53.8 nM in plasma, which corresponds to 30 mg/kg qd p.o., or to --- 3 mg/kg qd i.v. Most of the cancers expressing hyperactive B-RAF respond to dabrafenib treatment, but the complete response is only rarely achieved. Toxic side effects include skin lesions, pyrexia, frequent fatigue, nausea and pain. Resistance to dabrafenib is frequently developed via de novo RAS mutations, leading to the disease relapse. The RAS G-protein is capable of signaling downstream not only through B-RAF, but also through closely related C-RAF, which circumvents the effects of the B-RAF inhibitor. Thus, dabrafenib should not be prescribed to subjects with neoplasias that are positive for activating RAS mutations. Since B-RAF mutations alone cause only the formation of benign naevi, since the tumors frequently and quickly acquire resistance to B-RAF inhibitors, and because the B-RAF-inhibitor-mediated treatment outcomes are severely affected by changes in the activity and expression of a number of signaling molecules (among them PI3K/mTOR, PTEN, AKT, MEK, PDGFRbeta), it can be anticipated that dabrafenib treatment should be suggested only as a part of combined therapy targeting simultaneously the other pathways responsible for cancer onset and progression. PMID- 23102195 TI - [Uterine Sarcomas - a review]. AB - Uterine sarcomas are a heterogeneous group, which constitutes about 8% of malignant uterine tumors. This heterogeneousness and rare occurrence were the main cause of non-uniform therapeutical management. In previously published papers, there were mainly retrospective assessments of the experience of individual centres. The basis of relevant conclusions of the studies, beside their prospectiveness, is the use of unified classification criteria. Currently, a completely new classification of uterine sarcomas is being used, which consists of leiomyosarcoma, endometrial stromal sarcomas and adenosarcomas. For classification of carcinosarcomas, there are valid new criteria of endometrial cancer classification. The basic therapeutic approach of leiomyosarcoma and endometrial stromal sarcomas is a surgical intervention. The gold standard is hysterectomy and salpingooophorectomy. Justifiability of lymphadenectomy is being discussed. For carcinosarcomas, the same recommendations as for the surgical treatment of prognostically unfavourable endometrial carcinoma are valid - hysterectomy, salpingooophorectomy, pelvic and paraaortal lymph node dissection and omentectomy. It is necessary to implement the new classification into clinical practice, to publish and evaluate existing papers, which take into account their basic thesis. Only then it will be possible to create unified therapies. They should be aimed to improve patients survival. PMID- 23102196 TI - [Analysis of prognostic factors in osteosarcoma adult patients, a single institution experience]. AB - BACKGROUND: The objective of this report was to estimate long-term outcome and prognostic factors in adult patients with high-grade osteosarcoma. The intended therapeutic strategy included preoperative and/or postoperative chemotherapy as well as surgery of all operable lesions. PATIENTS AND METHODS: We reviewed the clinical data of 36 newly diagnosed adult patients (aged 19-82, average 37.5, median 28.5 years) with high-grade osteosarcoma of the trunk or limbs evaluated by a multidisciplinary team and treated between 1999 and 2010 in Brno. Forty-five percent of patients were over thirty, more than 36% over forty. Thirty-one percent of patients had metastasis at the time of diagnosis. Demographic parameters, tumor-related and treatment-related variables included possible prognostic factors and their impact on response, overall survival (OS) and event free survival (EFS) were analyzed. RESULTS: All the patients were followed up after treatment. Seventy-three percent of patients were poor responders to chemotherapy. Sixteen patients are alive, and twenty patients died. The survival time ranged from 2 to 177 months (average 45 months, median survival 23 months). The 5-year OS of all patients was 52.4%. OS of patients without metastasis was 68.12%, while 2-year OS with metastasis was 26% only. 5-year EFS was 38.7%. Univariate analysis revealed that the prognosis of adult osteosarcoma patients was significantly related to distant metastasis (p = 0.006), surgical stage (p = 0.00582), serum alkaline phosphatase (ALP) level (p = 0.00841) and serum lactatdehydrogenase (LD) level (p = 0.047). The other analyzed prognostic factors including age had no statistically significant influence on outcome of osteosarcoma in adult patients. CONCLUSION: The prognosis of osteosarcoma in adult patients was significantly correlated to surgical stage, distant metastasis, serum ALP and LD. PMID- 23102197 TI - [Neoplastic effect of indomethacin in N-methyl-N-nitrosourea induced mammary carcinogenesis in female rats]. AB - BACKGROUND: High levels of prostaglandins found in many neoplastic tissues, especially in colon cancer and breast cancer, suggest a role of cyclooxygenase in the process of carcinogenesis. MATERIAL AND METHODS: The aim of this study was to analyse the chemopreventive potential of non-steroidal inflammatory drug indomethacin and its combination with pineal hormone melatonin in rat mammary carcinogenesis induced by N-methyl-N-nitrosourea. Indomethacin was administered 3 times a week and melatonin 4 times a week, both substances in a concentration of 20 ug/ml of drinking water. Chemoprevention began approximately 2 weeks before carcinogen administration and lasted until the end of the experiment 25 weeks later. RESULTS: Indomethacin administered alone and in combination with melatonin stimulated the growth of mammary tumors. We found a significant increase in the average tumor volume caused by indomethacin alone by 126%, and in combination with melatonin by 104% compared to the control group. Indomethacin administered alone increased the incidence of tumors by 21.5% (also in combination with melatonin) and reduced the tumor latency by 17 days compared to controls. Melatonin alone significantly reduced tumor volume in comparison with control animals. During the long-term administration, both substances were well tolerated by animals. CONCLUSION: Indomethacin, a predominant cyclooxygenase inhibitor-1, showed significant neoplastic effects in the prevention of N-methyl-N-nitrosourea induced rat mammary carcinogenesis. This finding is in strong contrast to our previous experiment, where indomethacin in 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinogenesis revealed marked antineoplastic effects. PMID- 23102198 TI - Preoperative radiotherapy of locally advanced rectal cancer: clinical outcome of short-course and long-course treatment with or without concomitant chemotherapy. AB - BACKGROUND: Preoperative radiotherapy is considered to be standard treatment for locally advanced rectal cancer. The timing and dosage of radiotherapy with or without preoperative chemotherapy remain controversial issues. The objective of this study was to evaluate relevant clinical outcomes of two preoperative radiotherapy regimens - the short-course and -long-course radiotherapy with or without chemotherapy for patients with locally advanced rectal cancer. PATIENTS AND METHODS: 151 patients with stage II-III rectal cancer (103 males and 48 females) treated with preoperative radiotherapy between 01/1999 and 01/2008 were involved in this study. Analysed patterns included sphincter preservation, tumor down-staging, pathological complete remission, frequency of local recurrence, acute and late toxicity, peri-operative complications, overall survival and disease-free survival. RESULTS: Tumor downstaging has been achieved by long course radiotherapy alone (46%) or in combination with chemotherapy (5-FU or capecitabine, 61%). Pathological complete remission has also been achieved only in the group with long-course radiotherapy (13%). Long-course radiotherapy combined with chemotherapy significantly decreased post treatment local recurrence rates (5% versus 15% in the group after long-course radiotherapy alone, p = 0.0132). Statistically significant difference was confirmed in overall survival of patients treated with long-course radiotherapy combined with chemotherapy vs long-course radiotherapy alone (p = 0.015). Significant difference between the rate of perioperative complications, of acute and late toxicity, 3 and 5 years disease-free survival of treated patients after short course radiotherapy and long-course radiotherapy was not confirmed. CONCLUSION: Our findings provide convincing evidence that in comparison to preoperative short course radiotherapy, the preoperative long-course radiotherapy in combination with chemotherapy is the most effective treatment modality for patients with operable locally advanced rectal cancer in terms downstaging and pathologic complete response. Increase in overall survival time as well as lower local recurrence rate makes this modality superior to other preoperative radiotherapy alternatives. PMID- 23102199 TI - [Importance of expression of DNA repair proteins in non-small-cell lung cancer]. AB - BACKGROUND: Proteins XRCC1 and ERCC1 are involved in DNA repair. XRCC1 plays a role in DNA base excision repair and ERCC1 in nucleotide excision repair pathway. Higher expression profile of both proteins in cancer cells may contribute to development of drug resistance. ERCC1 is involved in removal of platinum adducts and might be a potential predictive and prognostic marker in NSCLC (non-small cell lung cancer) treated with a cisplatin-based regimen. The purpose of study was determination of XRCC1 and ERCC1 levels and their correlation with basic clini-copathological parameters in NSCLC. PATIENTS AND METHODS: In this study, 107 tumor samples diagnosed as NSCLC were immunohistochemically examined for expression of XRCC1 and ERCC1 proteins. Our results were compared to basic clinicopathological parameters: type of tumor, tumor grade and stage of disease. For statistical analysis, the chi-square test was used. RESULTS: In squamous cell carcinoma and large cell carcinoma samples, the XRCC1 protein level was twofold higher (60% of positive samples) than in adenocarcinoma samples (35.5% of positive samples). We have found statistical correlation between XRCC1 protein expression and type of tumor (p = 0.0306). On the other hand, the statistical importance between the protein level versus grade and stage was not found. In the case of the ERCC1 protein, we observed the highest protein level in adenocarcinoma (64.5%) and squamous cell carcinoma (62.5%) samples. Next, we determined a significant difference in content of XRCC1 versus ERCC1 (35.5% vs 64.5%) in adenocarcinoma samples. Statistical chi-square test did not reveal any correlation between ERCC1 status and clinicopathological parameters. CONCLUSION: According to our results, XRCC1 represents an important mechanism of DNA repair in squamous cell and large cell carcinomas. Besides that, expression of XRCC1 was in correlation with type of tumor. In patients with adenocarcinoma and squamous cell carcinoma, we could assume increased resistance to platinum-based therapy because of high expectation of ERCC1 protein expression. However, its levels did not correlate with monitored clinicopathological parameters. The ERCC1 protein will be possibly an independent prognostic factor in NSCLC. To prove a true survival benefit of patients with expression of ERCC1, prospective validation of ERCC1 before clinical implication is needed in the future. PMID- 23102200 TI - [Bloodstream infections of the intravascular access devices - case reports and review of the literature]. AB - Long-term access devices (VAD) in oncology patients are the elemental procedure of contemporary treatment. Apart from their indisputable benefit they are linked with an increased risk of infectious complications, ranging between simple colonisation of a device to catheter related bloodstream infections. The decision to salvage or extract the VAD in case of bloodstream infection depends on patient's clinical state, localisation of infection (site of insertion, catheter or pocket), casual agent and complications (e.g. endocarditis, septic embolization, osteomyelitis and so on). Authors present 5 case reports of portacath sepsis in their oncology department in 2011 (i.e. 4.46% of 112 inserted ports). In the second part of the article they review current literature data about prevention and treatment of infectious complications of vascular devices in cancer patients. PMID- 23102201 TI - [The TULUNG clinical registry]. PMID- 23102202 TI - [Another positive study of ovarian carcinoma]. PMID- 23102203 TI - [Oncology in images: generalized Kaposi sarcoma]. PMID- 23102204 TI - Partitioning of neutral organic compounds to structural proteins. AB - Protein-water partition coefficients (K(pw)) of neutral organic chemicals were measured using muscle proteins (from chicken, fish, and pig), collagen and gelatin. K(pw) values for these structural proteins were consistently lower than those of bovine serum albumin (BSA), indicating that the use of BSA as a model protein leads to an overestimation of K(pw) for structural proteins. Differences in K(pw) between chicken, fish, and pig muscle proteins were small. Across the structural proteins, K(pw) values were often in the order: muscle proteins > collagen >= gelatin. Differences in K(pw) between the structural proteins were relatively large (<2 log units) for nonpolar compounds, and much smaller or insignificant for polar compounds. There were correlations between log K(pw) of muscle proteins and log K(ow) (R(2) = 0.83-0.86, SD: 0.35-0.40, n = 45-46). The polyparameter linear free energy relationship (PP-LFER) models fit even better to the data (R(2) = 0.95, SD: 0.22). The good model fitting suggests that the reversible binding to muscle proteins can be considered to be nonspecific binding. There was an indication that some chemicals may sorb irreversibly to muscle proteins, which needs further research. We found that the partitioning to muscle protein is typically weaker than that to lipids, but that the protein partitioning of an H-bond donor compound can be as strong as the storage lipid partitioning. PMID- 23102205 TI - Dental care and treatments provided under general anaesthesia in the Helsinki Public Dental Service. AB - BACKGROUND: Dental general anaesthesia (DGA) is a very efficient treatment modality, but is considered only in the last resort because of the risks posed by general anaesthesia to patients' overall health. Health services and their treatment policies regarding DGA vary from country to country. The aims of this work were to determine the reasons for DGA in the Helsinki Public Dental Service (PDS) and to assess the role of patient characteristics in the variation in reasons and in the treatments given with special focus on preventive care. METHODS: The data covered all DGA patients treated in the PDS in Helsinki in 2010. The data were collected from patient documents and included personal background: age (<6, 6-12, 13-17, 18-68), gender, immigration, previous conscious sedation and previous DGA; medical background; reasons for DGA and treatments provided. Chi-square tests, Fisher's exact test, and logistic regression modelling were employed in the statistical analyses. RESULTS: The DGA patients (n=349) were aged 2.3 to 67.2 years. Immigrants predominated in the youngest age group (p<0.001) and medically compromised patients among the adults (p<0.001) relative to the other age groups. The main reason for DGA was extreme non cooperation (65%) followed by dental fear (37%) and an excessive need for treatment (26%). In total, 3435 treatments were performed under DGA, 57% of which were restorations, 24% tooth extractions, 5% preventive measures, 5% radiography, 4% endodontics and the remaining 5% periodontics, surgical procedures and miscellaneous. The reasons for DGA and the treatments provided varied according to age, immigration, previous sedation and DGA and medical background. The logistic regression model showed that previous sedation (OR 2.3; 95%CI 1.3-4.1; p=0.005) and extreme non-cooperation (OR 1.7; 95%CI 0.9-3.2; p=0.103) were most indicative of preventive measures given. CONCLUSIONS: Extreme non-cooperation, dental fear and an excessive need for treatment were the main reasons for the use of comprehensive, conservative DGA in the Helsinki PDS. The reasons for the use of DGA and the treatments provided varied according to personal and medical background, and immigration status with no gender-differences. Preventive measures formed only a minor part of the dental care given under DGA. PMID- 23102206 TI - Determinants of suboptimal breast-feeding practices in Pakistan. AB - OBJECTIVE: Exclusive breast-feeding is estimated to reduce infant mortality in low-income countries by up to 13 %. The aim of the present study was to determine the risk factors associated with suboptimal breast-feeding practices in Pakistan. DESIGN: A cross-sectional study using data extracted from the multistage cluster sample survey of the Pakistan Demographic and Health Survey 2006-2007. SETTING: A nationally representative sample of households. SUBJECTS: Last-born alive children aged 0-23 months (total weighted sample size 3103). RESULTS: The prevalences of timely initiation of breast-feeding, bottle-feeding in children aged 0-23 months, exclusive breast-feeding and predominant breast-feeding in infants aged 0-5 months were 27.3 %, 32.1 %, 37.1 % and 18.7 %, respectively. Multivariate analysis indicated that working mothers (OR = 1.48, 95 % CI 1.16, 1.87; P = 0.001) and mothers who delivered by Caesarean section (OR = 1.95, 95 % CI 1.30, 2.90; P = 0.001) had significantly higher odds for no timely initiation of breast-feeding. Mothers from North West Frontier Province were significantly less likely (OR = 0.37, 95 % CI 0.23, 0.59; P < 0.001) not to breast-feed their babies exclusively. Mothers delivered by traditional birth attendants had significantly higher odds to predominantly breast-feed their babies (OR = 1.96, 95 % CI 1.18, 3.24; P = 0.009). The odds of being bottle-fed was significantly higher in infants whose mothers had four or more antenatal clinic visits (OR = 1.93, 95 % CI 1.46, 2.55; P < 0.001) and belonged to the richest wealth quintile (OR = 2.41, 95 % CI 1.62, 3.58; P < 0.001). CONCLUSIONS: The majority of Pakistani mothers have suboptimal breast-feeding practices. To gain the full benefits of breast-feeding for child health and nutrition, there is an urgent need to develop interventions to improve the rates of exclusive breast-feeding. PMID- 23102208 TI - The administration of renoprotective agents extends warm ischemia in a rat model. AB - BACKGROUND AND PURPOSE: Extended warm ischemia time during partial nephrectomy leads to considerable renal injury. Using a rat model of renal ischemia, we examined the ability of a unique renoprotective cocktail to ameliorate warm ischemia-reperfusion injury and extend warm ischemia time. MATERIALS AND METHODS: A warm renal ischemia model was developed using Sprague-Dawley rats, clamping the left renal artery for 40, 50, 60, and 70 minutes, followed by 48 hours of reperfusion. An improved renoprotective cocktail referred to as I-GPM (a mixture of specific renoprotective growth factors, porphyrins, and mitochondria protecting amino acids) was administered -24 hours, 0 hours, and +24 hours after surgery. At 48 hours, both kidneys were harvested and examined with hematoxylin and eosin and periodic acid-Schiff stains for the analysis of renal tubular necrosis. Creatinine, protein, and gene expression levels were also analyzed to evaluate several ischemia-specific and antioxidant response markers. RESULTS: I GPM treated kidneys showed significant reversal of morphologic changes and a significant reduction in specific ischemic markers lipocalin-2, galectin-3, GRP 78, and HMGB1 compared with ischemic controls. These experiments also showed an upregulation of the stress response protein, heat shock protein (HSP)-70, as well as the phosphorylated active form of the transcription factor, heat shock factor (HSF)-1. In addition, quantitative RT-PCR analyses revealed a robust upregulation of several antioxidant pathway response genes in I-GPM treated animals. CONCLUSIONS: By histopathologic and several molecular measures, our unique renoprotective cocktail mitigated ischemia-reperfusion injury. Our cocktail minimized oxidative stress in an ischemic kidney rat model while at the same time protecting the global parenchymal function during extended periods of ischemia. PMID- 23102207 TI - Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers. AB - The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the structure affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to an increase of both the affinity and selectivity for 5-HT(4)R, suggesting the design of the antagonist 4v, exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8 amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R. PMID- 23102209 TI - In vitro nanoparticle toxicity to rat alveolar cells and coelomocytes from the earthworm Lumbricus rubellus. AB - Sensitivity of immune cells (coelomocytes) of Lumbricus rubellus earthworms was investigated for exposure to selected nanoparticles, in order to obtain further insight in mechanisms of effects observed after in vivo C60 exposure. In the in vivo study, tissue damage appeared to occur without accompanying increased immune responses. Coelomocytes exposed in vitro to C60 showed no decrease of their cellular viability, but demonstrated a decrease in gene expression of the cytokine-like protein CCF-1, indicating immunosuppression. Experiments with NR8383 rat macrophage cells and tri-block copolymer nanoparticles were used to compare sensitivity and to demonstrate the usefulness of coelomocytes as a test system for nano-immunotoxicity, respectively. Overall, the results imply that sensitivity towards nanoparticles differs between cell types and nanoparticles. Moreover, this study indicates that injuries in absence of an immune response, observed after in vivo C60 exposure in our earlier work, are caused by immunosuppression rather than coelomocyte mortality. PMID- 23102210 TI - Near-infrared surface-enhanced Raman spectroscopy (NIR-SERS) for the identification of eosin Y: theoretical calculations and evaluation of two different nanoplasmonic substrates. AB - This work demonstrates the development of near-infrared surface-enhanced Raman spectroscopy (NIR-SERS) for the identification of eosin Y, an important historical dye. NIR-SERS benefits from the absence of some common sources of SERS signal loss including photobleaching and plasmonic heating, as well as an advantageous reduction in fluorescence, which is beneficial for art applications. This work also represents the first rigorous comparison of the enhancement factors and the relative merits of two plasmonic substrates utilized in art applications; namely, citrate-reduced silver colloids and metal film over nanosphere (FON) substrates. Experimental spectra are correlated in detail with theoretical absorption and Raman spectra calculated using time-dependent density functional theory (TDDFT) in order to elucidate molecular structural information and avoid relying on pigment spectral libraries for dye identification. PMID- 23102211 TI - Stem cells from fat bulge their way into clinical trials. PMID- 23102212 TI - Revisiting the specificity of small molecule inhibitors: the example of stattic in dendritic cells. PMID- 23102214 TI - Controlling radicals in the powerhouse: development of MitoSOD. AB - Investigators in the redox biology field have long recognized the unique role mitochondrial superoxide generation plays in physiological signaling and in dysregulated bioenergetic dysfunction. Pharmacological manipulation has been challenging, and in this issue of Chemistry & Biology, Kelso and colleagues present the synthesis and characterization of a novel mitochondrial-targeted SOD mimetic, MitoSOD. PMID- 23102215 TI - Prospecting for aptamers in the human genome. AB - Aptamers are RNA molecules that bind small molecules. They were originally isolated from random libraries and then found in bacteria. In this issue of Chemistry & Biology, Vu et al. demonstrate that a motif for an adenosine aptamer occurs in human and bacterial genomes and binds AMP and ATP in vitro. PMID- 23102216 TI - Mining the antibiotic resistome. AB - Antibiotic-producing microoganisms are a reservoir of drug resistance genes. Studies of the "antibiotic resistome" can inform antimicrobial drug discovery and explain the emergence of multidrug resistant pathogens. In this issue of Chemistry & Biology, Westman and colleagues take an alternative look at the resistome and identify genes that could be used to detoxify the anticancer compound, doxorubicin. PMID- 23102218 TI - A mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic. AB - Superoxide (O(2)(.-)) is the proximal mitochondrial reactive oxygen species underlying pathology and redox signaling. This central role prioritizes development of a mitochondria-targeted reagent selective for controlling O(2)(. ). We have conjugated a mitochondria-targeting triphenylphosphonium (TPP) cation to a O(2)(.-)-selective pentaaza macrocyclic Mn(II) superoxide dismutase (SOD) mimetic to make MitoSOD, a mitochondria-targeted SOD mimetic. MitoSOD showed rapid and extensive membrane potential-dependent uptake into mitochondria without loss of Mn and retained SOD activity. Pulse radiolysis measurements confirmed that MitoSOD was a very effective catalytic SOD mimetic. MitoSOD also catalyzes the ascorbate-dependent reduction of O(2)(.-). The combination of mitochondrial uptake and O(2)(.-) scavenging by MitoSOD decreased inactivation of the matrix enzyme aconitase caused by O(2)(.-). MitoSOD is an effective mitochondria targeted macrocyclic SOD mimetic that selectively protects mitochondria from O(2)(.-) damage. PMID- 23102217 TI - AMP-activated protein kinase: a target for drugs both ancient and modern. AB - The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. It is activated, by a mechanism requiring the tumor suppressor LKB1, by metabolic stresses that increase cellular ADP:ATP and/or AMP:ATP ratios. Once activated, it switches on catabolic pathways that generate ATP, while switching off biosynthetic pathways and cell-cycle progress. These effects suggest that AMPK activators might be useful for treatment and/or prevention of type 2 diabetes and cancer. Indeed, AMPK is activated by the drugs metformin and salicylate, the latter being the major breakdown product of aspirin. Metformin is widely used to treat diabetes, while there is epidemiological evidence that both metformin and aspirin provide protection against cancer. We review the mechanisms of AMPK activation by these and other drugs, and by natural products derived from traditional herbal medicines. PMID- 23102220 TI - Bacterial inactivation of the anticancer drug doxorubicin. AB - Microbes are exposed to compounds produced by members of their ecological niche, including molecules with antibiotic or antineoplastic activities. As a result, even bacteria that do not produce such compounds can harbor the genetic machinery to inactivate or degrade these molecules. Here, we investigated environmental actinomycetes for their ability to inactivate doxorubicin, an aminoglycosylated anthracycline anticancer drug. One strain, Streptomyces WAC04685, inactivates doxorubicin via a deglycosylation mechanism. Activity-based purification of the enzymes responsible for drug inactivation identified the NADH dehydrogenase component of respiratory electron transport complex I, which was confirmed by gene inactivation studies. A mechanism where reduction of the quinone ring of the anthracycline by NADH dehydrogenase leads to deglycosylation is proposed. This work adds anticancer drug inactivation to the enzymatic inactivation portfolio of actinomycetes and offers possibilities for novel applications in drug detoxification. PMID- 23102221 TI - Orthogonal ubiquitin transfer through engineered E1-E2 cascades for protein ubiquitination. AB - Protein modification by ubiquitin (UB) controls diverse cellular processes. UB is conjugated to cellular proteins by sequential transfer through an E1-E2-E3 enzymatic cascade. The cross-activities of 2 E1s, 50 E2s and thousands of E3s encoded by the human genome make it difficult to identify the substrate proteins of a specific E3 enzyme in the cell. One way to solve this problem is to engineer an orthogonal UB transfer (OUT) cascade in which the engineered UB (xUB) is relayed by engineered E1, E2 and E3 enzymes (xE1, xE2, xE3) to modify the substrate proteins of a specific E3. Here, we use phage display and mutagenesis to construct xUB-xE1 and xE1-xE2 pairs that are orthogonal to the native E1 and E2 enzymes. Our work on engineering the UB transfer cascades will enable us to use OUT to map the signal transduction networks mediated by protein ubiquitination. PMID- 23102219 TI - Convergent evolution of adenosine aptamers spanning bacterial, human, and random sequences revealed by structure-based bioinformatics and genomic SELEX. AB - Aptamers are structured macromolecules in vitro evolved to bind molecular targets, whereas in nature they form the ligand-binding domains of riboswitches. Adenosine aptamers of a single structural family were isolated several times from random pools, but they have not been identified in genomic sequences. We used two unbiased methods, structure-based bioinformatics and human genome-based in vitro selection, to identify aptamers that form the same adenosine-binding structure in a bacterium, and several vertebrates, including humans. Two of the human aptamers map to introns of RAB3C and FGD3 genes. The RAB3C aptamer binds ATP with dissociation constants about 10 times lower than physiological ATP concentration, while the minimal FGD3 aptamer binds ATP only cotranscriptionally. PMID- 23102222 TI - Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP. AB - Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, deconvolution identified the latonduines as F508del-CFTR trafficking correctors that give functional correction in vivo. Using a biotinylated azido derivative of latonduine, we identified the poly(ADP-ribose) polymerase (PARP) family as latonduine target proteins. We show that latonduine binds to PARPs 1, 2, 3, 4, 5a, and 5b and inhibits PARP activity, especially PARP-3. Thus, latonduine corrects F508del-CFTR trafficking by modulating PARP activity. Latonduines represent pharmacologic agents for F508del-CFTR correction, and PARP-3 is a pathway for the development of CF treatments. PMID- 23102224 TI - Quartromicin biosynthesis: two alternative polyketide chains produced by one polyketide synthase assembly line. AB - The antiviral compounds quartromicins represent unique members of a family of spirotetronate natural products. In this study, a biosynthetic gene cluster of quartromicins was identified by degenerate primer PCR amplification of specific genes involved in the biosynthesis of the tetronate moiety. The biochemical results confirmed that 1,3-bisphosphoglycerate was incorporated into the tetronate ring, and the intermediates of this ring were also reconstructed in vitro. The data also suggested a module skipping strategy for the production of two alternative polyketide chains by the same polyketide synthase assembly line. These findings set the stage for further investigations of the stereodivergent intermolecular cyclization mechanism, and highlight how nature has constructed this type of C2 symmetric molecule through intermolecular dimerization. PMID- 23102223 TI - Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1alpha protein-protein interface. AB - Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1alpha interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed. PMID- 23102225 TI - Synthetic evolving systems that implement a user-specified genetic code of arbitrary design. AB - A synthetic genetic system, based on cross-replicating RNA enzymes, provides a means to evaluate alternative genetic codes that relate heritable information to corresponding molecular function. A special implementation of encoded combinatorial chemistry was used to construct complex populations of cross replicating RNA enzymes in accordance with a user-specified code that relates genotype and phenotype on a molecule-by-molecule basis. The replicating enzymes were made to undergo self-sustained Darwinian evolution, resulting in the emergence of the most advantageous variants. These included both highly active enzymes that sustained the population as a whole and poorly active enzymes that survived as parasites of the active molecules. This evolutionary outcome was a consequence of the information capacity and fidelity of the genetic code, suggesting how these parameters should be adjusted to implement codes tailored to particular applications. PMID- 23102226 TI - A genetically encoded metabolite sensor for malonyl-CoA. AB - Malonyl-CoA is the rate-determining metabolite for long chain de novo fatty acid synthesis and allosterically inhibits the rate-setting step in long chain fatty acid beta-oxidation. We developed a cell-based genetically encoded biosensor based on the malonyl-CoA responsive Bacillus subtilis transcriptional repressor, FapR, for living mammalian cells. Here, we show that fluctuations in malonyl-CoA, in mammalian cells, can regulate the transcription of a FapR-based malonyl-CoA biosensor. The biosensor reflects changes in malonyl-CoA flux regulated by malonyl-CoA decarboxylase and AMP-activated protein kinase in a concentration dependent manner. To gain further insight into the regulatory mechanisms that affect fatty acid metabolism, we used the malonyl-CoA sensor to screen and identify several kinases. LIMK1 was identified and its expression was shown to alter both fatty acid synthesis and oxidation rates. This simple genetically encoded biosensor can be used to study the metabolic properties of live mammalian cells and enable screens for novel metabolic regulators. PMID- 23102229 TI - Cardiovascular preventing effects of dipeptidyl peptidase-4 inhibitors: beyond glucagon-like peptide-1. PMID- 23102227 TI - Selective positive modulator of calcium-activated potassium channels exerts beneficial effects in a mouse model of spinocerebellar ataxia type 2. AB - Spinocerebellar ataxia type 2 (SCA2) is a neurodegenerative disorder caused by a polyglutamine expansion within the Ataxin-2 (Atxn2) protein. Purkinje cells (PC) of the cerebellum fire irregularly and eventually die in SCA2. We show here that the type 2 small conductance calcium-activated potassium channel (SK2) play a key role in control of normal PC activity. Using cerebellar slices from transgenic SCA2 mice we demonstrate that SK channel modulators restore regular pacemaker activity of SCA2 PCs. Furthermore, we also show that oral delivery of a more selective positive modulator of SK2/3 channels (NS13001) alleviates behavioral and neuropathological phenotypes of aging SCA2 transgenic mice. We conclude that SK2 channels constitute a therapeutic target for SCA2 treatment and that the developed selective SK2/3 modulator NS13001 holds promise as a potential therapeutic agent for treatment of SCA2 and possibly other cerebellar ataxias. PMID- 23102228 TI - Targeting adipose tissue. AB - Two different types of adipose tissues can be found in humans enabling them to respond to starvation and cold: white adipose tissue (WAT) is generally known and stores excess energy in the form of triacylglycerol (TG), insulates against cold, and serves as a mechanical cushion. Brown adipose tissue (BAT) helps newborns to cope with cold. BAT has the capacity to uncouple the mitochondrial respiratory chain, thereby generating heat rather than adenosine triphosphate (ATP). The previously widely held view was that BAT disappears rapidly after birth and is no longer present in adult humans. Using positron emission tomography (PET), however, it was recently shown that metabolically active BAT occurs in defined regions and scattered in WAT of the adult and possibly has an influence on whole body energy homeostasis. In obese individuals adipose tissue is at the center of metabolic syndrome. Targeting of WAT by thiazolidinediones (TZDs), activators of peroxisome proliferator-activated receptor gamma (PPARgamma) a 'master' regulator of fat cell biology, is a current therapy for the treatment of type 2 diabetes. Since its unique capacity to increase energy consumption of the body and to dissipate surplus energy as heat, BAT offers new perspectives as a therapeutic target for the treatment of obesity and associated diseases such as type 2 diabetes and metabolic syndrome. Recent discoveries of new signaling pathways of BAT development give rise to new therapeutic possibilities in order to influence BAT content and activity. PMID- 23102231 TI - Weight loss surgery, left ventricular mass and repolarization. PMID- 23102232 TI - Side effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists: are we facing a new syndrome. PMID- 23102233 TI - Statin therapy for secondary prevention: is there a gender difference? Test for interaction in meta-analysis revisited. PMID- 23102234 TI - Three-dimensional printing of soy protein scaffolds for tissue regeneration. AB - Fabricating three-dimensional (3D) porous scaffolds with controlled structure and geometry is crucial for tissue regeneration. To date, exploration in printing 3D natural protein scaffolds is limited. In this study, soy protein slurry was successfully printed using the 3D Bioplotter to form scaffolds. A method to verify the structural integrity of resulting scaffolds during printing was developed. This process involved measuring the mass extrusion flow rate of the slurry from the instrument, which was directly affected by the extrusion pressure and the soy protein slurry properties. The optimal mass flow rate for printing soy slurry at 27 degrees C was 0.0072+/-0.0002 g/s. The addition of dithiothreitol to soy slurries demonstrated the importance of disulfide bonds in forming solid structures upon printing. Resulting Bioplotted soy protein scaffolds were cured using 95% ethanol and post-treated using dehydrothermal treatment (DHT), a combination of freeze-drying and DHT, and chemical crosslinking using 1-ethyl-3-(3 dimethylaminopropyl)carbodiimide (EDC) chemistry. Surface morphologies of the different treatment groups were characterized using scanning electron microscopy. Scaffold properties, including relative crosslink density, mass loss upon rinsing, and compressive modulus revealed that EDC crosslinked scaffolds were the most robust with moduli of approximately 4 kPa. Scaffold geometry (45 degrees and 90 degrees layer rotations) affected the mechanical properties for DHT and EDC crosslinked scaffolds. Seeding efficiency of human mesenchymal stem cells (hMSC) was highest for nontreated and thermally treated scaffolds, and all scaffolds supported hMSC viability over time. PMID- 23102235 TI - Consumption of diet drinks in the United States, 2009-2010. AB - Sugar drinks are a major source of added sugars in the diets of Americans (1). Several recent studies have described factors associated with sugar-drink consumption (2,3); however, the consumption of diet drinks among the U.S. population has not been as well-characterized. This report describes the consumption of diet beverages among the U.S. population during 2009-2010 by sex, age, race and ethnicity, and income, and details trends in diet drink consumption from 1999-2000 through 2009-2010. PMID- 23102236 TI - Euchromatin islands in large heterochromatin domains are enriched for CTCF binding and differentially DNA-methylated regions. AB - BACKGROUND: The organization of higher order chromatin is an emerging epigenetic mechanism for understanding development and disease. We and others have previously observed dynamic changes during differentiation and oncogenesis in large heterochromatin domains such as Large Organized Chromatin K (lysine) modifications (LOCKs), of histone H3 lysine-9 dimethylation (H3K9me2) or other repressive histone posttranslational modifications. The microstructure of these regions has not previously been explored. RESULTS: We analyzed the genome-wide distribution of H3K9me2 in two human pluripotent stem cell lines and three differentiated cells lines. We identified > 2,500 small regions with very low H3K9me2 signals in the body of LOCKs, which were termed as euchromatin islands (EIs). EIs are 6.5-fold enriched for DNase I Hypersensitive Sites and 8-fold enriched for the binding of CTCF, the major organizer of higher-order chromatin. Furthermore, EIs are 2-6 fold enriched for differentially DNA-methylated regions associated with tissue types (T-DMRs), reprogramming (R-DMRs) and cancer (C DMRs). Gene ontology (GO) analysis suggests that EI-associated genes are functionally related to organ system development, cell adhesion and cell differentiation. CONCLUSIONS: We identify the existence of EIs as a finer layer of epigenomic architecture within large heterochromatin domains. Their enrichment for CTCF sites and DNAse hypersensitive sites, as well as association with DMRs, suggest that EIs play an important role in normal epigenomic architecture and its disruption in disease. PMID- 23102238 TI - Zero-field splitting in a series of structurally related mononuclear Ni(II) bispidine complexes. AB - The synthesis, single-crystal X-ray structures, electronic absorption spectra, and magnetic properties of six Ni(II) complexes with a tetradentate (L(1)) and three pentadentate (L(2), L(3), L(4)) bispidine ligands (3,7 diazabicyclo[3.3.1]nonane derivatives), Ni(L(1).H2O)(OH2)2](PF6)2, [Ni(L(1).H2O)(O2NO)]NO3, [Ni(L(1).H2O)(OOCCH3)]PF6, [Ni(L(2).H2O)NCMe](PF6)2, [Ni(L(3).H2O)OH2](PF6)2, and [Ni(L(4).H2O)NCMe](PF6)2 are reported. The Ni-donor bonding to pyridine and tertiary amine groups and oxygen- or nitrogen-bound coligands, completing the octahedral coordination sphere of Ni(II), is analyzed using a combination of ab initio electronic structure calculations (complete active space self-consistent field, CASSCF, followed by N-electron valence perturbation theory, NEVPT2) and angular overlap ligand field analysis. Magnetic properties are rationalized with an analysis of the magnetic anisotropy in terms of zero-field splitting and g-tensor parameters, obtained from first principles, and their correlation with the Ni(II)-donor bonding parameters from the ligand field analysis of the ab initio results. A two-dimensional spectrochemical series of the ligands considered, according to their sigma and pi bonding to Ni(II), is also derived. PMID- 23102239 TI - Trends of asthma mortality in Galicia from 1993 to 2007. AB - INTRODUCTION: In the past few years, deaths due to asthma appear to decrease at least in Western countries; but there are significant variations between populations. The aim of this study is to describe the trends in deaths due to asthma between 1993 and 2007 in our community and to analyze any factors associated with this. METHODS: All cases, which had asthma as a cause of death, were included in the study. The mortality data were obtained from the official death certificate from the Deaths Register. Mortality relative risk, based on the calendar year, sociodemographic variables (age and gender), seasons, and days of the week, were estimated using a Poisson generalized linear model with a log link. RESULTS: In the 15 years of the study period, a total of 1180 people had died due to asthma, mainly in winter (34.5%), women (64.5%), and advanced age (65 years or above; 84.6%). A tendency of decreased mortality in all age groups was observed during the period of the study, which was significant in both the sexes in the 35- to 64-year-old age group, and in males above 65 years. CONCLUSION: Death due to asthma is changing favorably in our community, with a tendency to decrease in the past few years. Advanced age, being female, and the winter period are associated with a higher mortality rate due to asthma. PMID- 23102240 TI - Gastric cancer prevention through eradication of helicobacter pylori infection: feasibility and pitfalls. PMID- 23102241 TI - Precancerous conditions after H. pylori eradication: a randomized double blind study in first degree relatives of gastric cancer patients. AB - BACKGROUND: Regression of precancerous lesions after H. pylori eradication remains controversial. This study evaluates the change and topography in first degree relatives (FDR) of gastric cancer (GC) patients following H. pylori eradication. METHODS: Participants underwent endoscopy with antrum and corpus histological examinations. Subjects with pangastritis were randomly allocated to placebo or eradication therapy and followed over 41/2 years. RESULTS: Among 989 evaluated FDR, we excluded 468 patients as follows: 108 had macroscopic lesions, 243 had no evidence of any H. pylori infection, and 117 were excluded for other reasons. The remaining subjects (n = 521) were allocated to therapy (group A, n = 261) or placebo (group B, n = 260) groups. Interim analysis of 403 subjects (201 placebo, 202 therapy) showed regression of atrophy (60 out of 97 in the antrum and 37 out of 104 in the corpus) in H.pylori-eradicated versus regression of atrophy (57 out of 184 in the antrum and 23 out of 173 in the corpus) in non H.pylori-eradicated cases over 21/2 years (P < 0.0001). No regression of intestinal metaplasia (IM) occurred in the antrum and corpus of treated subjects over 41/2 years. However, progression of IM occurred in the antrum in 17 out of 90 patients in the non-H. pylori-eradicated versus 4 out of 68 H. pylori eradicated subjects after 41/2 years (P < 0.05). CONCLUSION: Eradication of H. pylori is associated with regression of gastric atrophy but not IM, even in its early stages. Gastric atrophy and IM in the antrum have shown more rapid progression in cases not treated for H. pylori infection (over 41/2 years follow up) compared to H. pylori-eradicated cases. PMID- 23102237 TI - The role of infections and coinfections with newly identified and emerging respiratory viruses in children. AB - Acute respiratory infections are a major cause of morbidity in children both in developed and developing countries. A wide range of respiratory viruses, including respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza viruses (PIVs), adenovirus, rhinovirus (HRV), have repeatedly been detected in acute lower respiratory tract infections (LRTI) in children in the past decades. However, in the last ten years thanks to progress in molecular technologies, newly discovered viruses have been identified including human Metapneumovirus (hMPV), coronaviruses NL63 (HcoV-NL63) and HKU1 (HcoV-HKU1), human Bocavirus (HBoV), new enterovirus (HEV), parechovirus (HpeV) and rhinovirus (HRV) strains, polyomaviruses WU (WUPyV) and KI (KIPyV) and the pandemic H1N1v influenza A virus. These discoveries have heavily modified previous knowledge on respiratory infections mainly highlighting that pediatric population is exposed to a variety of viruses with similar seasonal patterns. In this context establishing a causal link between a newly identified virus and the disease as well as an association between mixed infections and an increase in disease severity can be challenging. This review will present an overview of newly recognized as well as the main emerging respiratory viruses and seek to focus on the their contribution to infection and co-infection in LRTIs in childhood. PMID- 23102242 TI - Detection of vim- and ipm-type metallo-beta-lactamases in Pseudomonas aeruginosa clinical isolates. AB - BACKGROUND: Pseudomonas aeruginosa is the most important bacterium isolated from burn wounds, and its resistance to imipenem due to metallo-beta-lactamases is increasing. This study was designed to detect vim1, vim2, ipm1 and ipm2 metallo beta-lactamases genes between Pseudomonas aeruginosa isolates isolated from Shahid Motahari Burns Hospital, Iran. METHODS: To that end, we isolated 483 nonduplicate consecutive isolates of P. aeruginosa from burn infections; and after biochemical confirmation, we examined the imipenem susceptibility via the Kirby-Bauer method. All the imipenem-resistant and imipenem-intermediate isolates were screened for vim1, vim2, ipm1 and ipm2 genes through the PCR method. RESULTS: From the 483 isolates, 272 (56%) and 63 (13%) isolates had resistant and intermediate zones in their imipenem antibiogram pattern, respectively. Fifty four (16.1%), 7 (2.1%), 22 (6.6%), and 11 (3.3%) of the resistant and intermediate isolates had vim1, vim2, ipm1 and ipm2 genes in their PCR results, respectively. CONCLUSION: MBL-mediated imipenem resistance in P. aeruginosa is a cause for concern in the treatment of infective burn patients. The rate of imipenem resistance due to MBL was increased dramatically and newer versions of MBL families were detected for the first time. These results suggest that an effective method should be provided to fight MBL production in clinical isolates. PMID- 23102243 TI - Potential protective effect of honey against paracetamol-induced hepatotoxicity. AB - BACKGROUND: Paracetamol overdose causes severe hepatotoxicity that leads to liver failure in both humans and experimental animals. The present study investigates the protective effect of honey against paracetamol-induced hepatotoxicity in Wistar albino rats. We have used silymarin as a standard reference hepatoprotective drug. METHODS: Hepatoprotective activity was assessed by measuring biochemical parameters such as the liver function enzymes, serum alanine aminotransferase (ALT) and serum aspartate aminotransferase (AST). Equally, comparative effects of honey on oxidative stress biomarkers such as malondialdyhyde (MDA), reduced glutathione (GSH) and glutathione peroxidase (GPx) were also evaluated in the rat liver homogenates. We estimated the effect of honey on serum levels and hepatic content of interleukin-1beta (IL-1beta) because the initial event in paracetamol-induced hepatotoxicity has been shown to be a toxic-metabolic injury that leads to hepatocyte death, activation of the innate immune response and upregulation of inflammatory cytokines. RESULTS: Paracetamol caused marked liver damage as noted by significant increased activities of serum AST and ALT as well as the level of Il-1beta. Paracetamol also resulted in a significant decrease in liver GSH content and GPx activity which paralleled an increase in Il-1beta and MDA levels. Pretreatment with honey and silymarin prior to the administration of paracetamol significantly prevented the increase in the serum levels of hepatic enzyme markers, and reduced both oxidative stress and inflammatory cytokines. Histopathological evaluation of the livers also revealed that honey reduced the incidence of paracetamol-induced liver lesions. CONCLUSION: Honey can be used as an effective hepatoprotective agent against paracetamol-induced liver damage. PMID- 23102244 TI - Accuracy of energy intake reporting: comparison of energy intake and resting metabolic rate and their relation to anthropometric and sociodemographic factors among Iranian women. AB - BACKGROUND: This study assesses the accuracy of energy intake (EI) reporting and its relation to anthropometric characteristics and sociodemographic factors. In addition, we attempt to identify foods for which under- or over-reporting is more prevalent. METHODS: EI was assessed for 187 women using a semi-quantitative 168 item food frequency questionnaire (FFQ). Resting metabolic rate (RMR) was measured with an indirect calorimeter. We calculated the EI/RMR ratio to assess the accuracy of EI reporting. This study defined under-reporters as those with an EI/RMR of <= 1.34 and over-reporters as those with an EI/RMR of >= 2.4. We measured anthropometric characteristics and collected sociodemographic information. The chi-square test, ANOVA and multiple linear regressions were used for statistical analyses. RESULTS: Among participants, the under-reporting rate was 35.5% and the over-reporting rate was 7.5%. The EI/RMR ratio was significantly higher for younger women compared to older women (P < 0.04). Under reporters had higher weight, waist circumference (WC), body mass index (BMI) and resting metabolism compared to accurate reporters (P < 0.05). Resting metabolism was significantly lower among over-reporters than accurate reporters. After adjusting for energy, the consumption of fish, high-fat dairy products, hydrogenated oil, sweets and coffee was lower, whereas consumption of unsaturated oils, tea, salt and yellow vegetables was higher among under-reporters compared to accurate reporters. CONCLUSION: Under-reporting of EI is more frequent than over-reporting among Iranian women. Among various factors that may affect the accuracy of EI reporting, age and anthropometric characteristics might have a significant effect. PMID- 23102245 TI - Elevated serum visfatin levels in patients with acute myocardial infarction. AB - BACKGROUND: Visfatin, a novel adiopocytokine, has been proven to be a proinflammatory mediator involved in the process of atherosclerosis. Visfatin has been shown to play a role in plaque destabilization as it is found abundantly in foam cell macrophages within unstable atherosclerotic plaques. The present study is designed to investigate the potential association between serum vistafin levels and the risk of acute myocardial infarction (AMI). METHODS: There were 72 patients (mean age: 61.57 +/- 11.40 years) as cases who presented with first-time AMI that were assessed 8 hours after the incident. The control group consisted of 83 healthy volunteers (mean age: 60.30 +/- 8.32 years). Plasma visfatin levels were measured using enzyme immunoassay in both groups. Biochemical parameters were analyzed. Blood pressure, body mass index (BMI), waist circumference, diabetes, and hypertension were recorded. RESULTS: Serum visfatin levels were significantly higher in patients with AMI (12.77 +/- 8.06 ng/ml) compared to controls (6.57 +/- 2.96 ng/ml, P <= 0.001). We found that a visfatin level > 7.244 ng/ml (log visfatin > 0.86) had a sensitivity of 70% and a specificity of 75% for predicting AMI. CONCLUSION: We have detected high levels of visfatin in patients with AMI. It can be concluded that proinflammatory cytokines such as visfatin may play a role in the development of atherosclerosis as well as destabilization of the atherosclerotic plaque. PMID- 23102246 TI - Percutaneous device closure for secundum-type atrial septal defect: short and intermediate-term results. AB - BACKGROUND: Device closure of an isolated secundum type atrial septal defect (ASD) has been used as an alternative method for open surgical closure with comparable success and lower morbidity. In this study we evaluated the procedural success and mid-term follow-up results of percutaneous closure of secundum ASD with an AmplatzerTMSeptal Occluder(ASO) device or a Figula ASD occluder device. METHODS: From June 2001 to January 2009, 74 consecutive patients were scheduled for percutaneous device closure in two centers in Tehran, Iran. All patients had a stretched defect diameter of 30mm or less. After using a sizing balloon to measure the stop-flow diameter, device implantation was performed under the guidance of a trans-esophageal echocardiography (TEE).The size was generally 1 - 2 mm larger than the stretched diameter. Patients were followed for an average of 11 +/-4 months. RESULTS: The median stretched diameter of the defect was 20.7+/ 4.8 mm (range: 8 - 30 mm).A total of 73 devices were used in this study. Device closure was successful in 72 (97.2%) out of 74 patients. Repositioning of the device was required in one patient. Major complications(including significant residual shunt and device embolization) occurred in 3 (4%) patients.There was no procedure-related mortality in our patients. Mild-to-moderate residual shunt was detectable in 10 (13.7%) patients immediately following the procedure and in 5 (6.7%) patients 24 hours after the procedure. None had residual flow across the device at the end of the follow-up period. CONCLUSION: Device closure of ASD has a safety profile comparable to open surgical repair and can effectively close the defect with excellent procedural and mid-term results. PMID- 23102247 TI - Cytotoxic effect of ICD-85 (venom-derived peptides) on HeLa cancer cell line and normal LK cells using MTT Assay. AB - BACKGROUND: Cancer is the fifth leading cause of death worldwide. There are considerable efforts to identify naturally occurring substances for use as new drugs in cancer therapy. Some components of animal venoms have been identified that possess substantial anticancer properties. In our previous studies, the cytotoxic effects of ICD-85 (venom-derived peptides) have been reported on HL-60 and MDA-MB231 cell lines. This has prompted us to investigate the comparative cytotoxic effects of ICD-85 on the HeLa cell line and normal lamb kidney (LK) cells. METHODS: Cells were exposed to various concentrations (8 * 10-4 to 5.6 * 10 ug/ml) of ICD-85 at various incubation times (24, 48 and 72 hours). Cell viability was measured by the MTT assay. A morphological study was also carried out using an inverted microscope. Caspase-8 activity was assayed by the Caspase-8 Colorimetric Assay Kit in HeLa cells that were exposed to ICD-85 for 48 hours. RESULTS: Data analysis showed that ICD-85 has a dose-dependent cytotoxic effect on HeLa cells with an inhibitory concentration 50% (IC50) of 26.62 +/- 2.13 ug/ml at 24 hours, 27.33 +/- 2.35 ug/ml at 48 hours, and 28.13 +/- 2.52 ug/ml at 72 hours. Results also indicated that the cytotoxic effect of ICD-85, at 48 and 72 hours incubation times did not show significant alteration compared to 24 hours of exposure. Interestingly, the minimum concentration of ICD-85 which showed a cytotoxic effect on LK cells was found to be 3500-fold less than the minimum concentration that showed a cytotoxic effect on the HeLa cancer cells. While morphological analysis revealed a significant difference that included the characteristic rounding of dying cells by treatment with ICD-85 compared with untreated HeLa cells, this difference was not observed in normal cells. ICD-85 increased caspase-8 activity in HeLa cells after 48 hours of exposure. DISCUSSION: ICD-85 has a dose-dependent cytotoxic effect on HeLa cancer cells in contrast with its negligible effect on normal LK cells. PMID- 23102248 TI - Monosymptomatic and non-monosymptomatic nocturnal enuresis: a clinical evaluation. AB - BACKGROUND: Nocturnal enuresis is divided into monosymptomatic nocturnal enuresis (MNE) and non-monosymptomatic nocturnal enuresis (NMNE). This study reviews clinical and ultrasonography (US) findings in enuretic children, and compares the organic and functional pathologies of the lower urinary tract (LUT) in children with MNE to those who have NMNE. METHODS: We enrolled 111 neurologically normal children with chief complaints of enuresis in this study. Participants included 60 boys and 51 girls, aged 5 - 17 years. There were 43 (38.8%) patients diagnosed with MNE and 68(61.2)% with NMNE. Urine analysis, urine culture and kidney bladder US were performed for patients. Some patients underwent a voiding cystoureterography (VCUG), urodynamic study (UDS), or both. RESULTS: Patients were divided into three groups: i) MNE, ii) NMNE without daytime incontinence (NMNE - daytime incontinence), and iii) NMNE plus daytime incontinence (NMNE + daytime incontinence). Constipation (P = 0.011), encopresis (P = 0.003) and urge incontinence (P = 0.001) were significantly more frequent in patients with NMNE +daytime incontinence. Bladder wall thickness (BWT) was the most common US finding. One patient with MNE and 9 with NMNE+ daytime incontinence had vesicoureteral reflux (VUR; P = 0.016). Posterior urethral valve (PUV) was reported in one patient with NMNE. Evidence of bladder dysfunction was noted in about half of the patients who underwent UDS, with a higher prevalence in cases that had NMNE +daytime incontinence (P = 0.297). Bowel symptoms and VUR were significantly more prevalent in cases with NMNE + daytime incontinence. CONCLUSION: We recommend VCUG in enuretic children who have daytime incontinence. In addition our study has revealed that symptoms suggestive of an overactive bladder (OAB) are not good indicators for bladder dysfunction. PMID- 23102249 TI - Expression and clinical significance of CD82/KAI1 and E-cadherin in non-small cell lung cancer. AB - BACKGROUND: This study investigates the expression of CD82/KAI1 and epithelial cadherin (E-cad) in non-small cell lung cancer (NSCLC). METHODS: Tissues of resected primary NSCLC and normal lung tissue were investigated. Protein expression was detected with immunohistochemical staining. mRNA expression levels of CD82/KAI1 and E-cad were determined by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) after mRNA extraction. RESULTS: The expression of CD82/KAI1 and E-cad was significantly lower in NSCLC compared to normal lung tissue (P < 0.01). CD82/KAI1 and E-cad mRNA and protein expression were found to be in close relationship with the grade of differentiation, lymph node metastasis and pathologic tumor-node-metastasis (pTNM) stages, and survival in NSCLC (P < 0.01), but no relationship was observed with gender, diameter, type, histological type and age (P > 0.05). Expression of mRNA CD82/KAI1 and E-cad were consistent with their proteins (P < 0.01), and there was a significant relationship between expression of CD82/KAI1 and E-cad. The survival rate of the CD82/KAI1-positive and CD82/KAI1-negative groups was significantly different (P < 0.01). In addition, the survival rate was significantly different between the E-cad positive and E-cad-negative groups. pTNM stages and positive expression of CD82/KAI1 and E-cad were independent prognostic factors of NSCLC (P < 0.05). CONCLUSION: Lower expression of CD82/KAI1 and E-cad was found in NSCLC compared to normal lung tissue. Decreased expression of CD82/KAI1 and E-cad was closely related to cellular differentiation, pTNM stages, invasion and metastasis. PMID- 23102251 TI - Brucellar psychosis. AB - Brucellosis is the most common worldwide zoonotic infection of which psychosis is a rare feature of this disease. Brucellar psychosis should be considered in a patient with unexplained, nonspecific psychological complaints. Its timely diagnosis relies on special attention to the epidemiologic profile of the patient for a possible exposure to the brucella species. This article has presented three cases of brucellar psychosis initially misdiagnosed because the risk factors which made them at risk for the disease were ignored. PMID- 23102252 TI - 19-year survival in a patient with rectosigmoid liver metastasis. AB - We present the case of an 82-year-old man diagnosed with rectosigmoid cancer and liver metastasis who survived for 19 years following treatment. At the age of 64, the patient twice experienced mucus excretion for which he underwent a colonoscopy that resulted in a diagnosis of rectosigmoid cancer the patient underwent surgery for resection of the tumor and liver metastasis. Histopathology was notable for a diagnosis of rectal adenocarcinoma that infiltrated the entire thickness of the wall, with metastasis to the liver and no lymph node involvement. Post-operative chemotherapy was administered for about four months. The patient remained asymptomatic for 19 years which at that time he presented with liver metastasis, ascites and renal failure. PMID- 23102253 TI - Neonatal atypical hemolytic uremic syndrome may cause prenatal asphyxia. AB - Microthrombi formation and hemolytic anemia are signs of hemolytic-uremic syndrome (HUS) that result from platelet consumption and red blood cell (RBC) destruction due to vascular damage. HUS manifests as a triad of signs: micro angiopathic hemolytic anemia, thrombocytopenia, and uremia. Prenatal asphyxia (PA) also leads to renal insufficiency and vascular damage. There is an overlap between the clinical presentation of PA and neonatal atypical HUS. We have reported the case of a neonate with a primary diagnosis of PA and clinical presentation of acute renal failure (ARF), anemia (Hb = 10 g/dl) and thrombocytopenia (Plt = 80000). His APGAR scores were 1 (1 minute), 3 (5 minutes), and 7 (10 minutes). A peripheral blood smear (PBS) was performed, which contained schistocytes (32%) with helmet and burr cells. The neonate's cord blood gas values were: pH of 7.07, HCO3 = 11mmol/L, and CO2 = 57mmHg. The first two days of life, he was anuric with elevated BUN and Cr (2.1mg/dL) levels. Complement (C3) was within normal limits at 0.65 g/L (0.89 - 1.87 g/L), however C4 was below the lower limit of normal at 0.14 g/L (0.16 - 0.38 g/L). We ruled out other causes of PA such as maternal illness, placenta abnormalities and infections (TORCH). We hypothesized that atypical neonatal HUS can progress to PA because of the presence of severe anemia and microthrombi formation. PMID- 23102250 TI - Polycyclic aromatic hydrocarbons and esophageal squamous cell carcinoma. AB - Esophageal cancer (EC) is the 8th most common cancer and the 6th most frequent cause of cancer mortality worldwide. Esophageal squamous cell carcinoma (ESCC) is the most common type of EC. Exposure to polycyclic aromatic hydrocarbons (PAHs) has been suggested as a risk factor for developing ESCC. In this paper we will review different aspects of the relationship between PAH exposure and ESCC. PAHs are a group of compounds that are formed by incomplete combustion of organic matter. Studies in humans have shown an association between PAH exposure and development of ESCC in many populations. The results of a recent case-control study in a high risk population in northeastern Iran showed a dramatic dose response relationship between PAH content in non-tumor esophageal tissue (the target tissue for esophageal carcinogenesis) and ESCC case status, consistent with a causal role for PAH exposure in the pathogenesis of ESCC. Identifying the main sources of exposure to PAHs may be the first and most important step in designing appropriate PAH-reduction interventions for controlling ESCC, especially in high risk areas. Coal smoke and drinking mate have been suggested as important modifiable sources of PAH exposure in China and Brazil, respectively. But the primary source of exposure to PAHs in other high risk areas for ESCC, such as northeastern Iran, has not yet been identified. Thus, environmental studies to determining important sources of PAH exposure should be considered as a high priority in future research projects in these areas. PMID- 23102255 TI - In memory of professor Ali Mohammad Handjani (1925 - 2012). PMID- 23102254 TI - Photoclinic. PMID- 23102256 TI - Photophysical and DFT characterization of novel Pt(II)-coupled 2,5-diaryloxazoles for nonlinear optical absorption. AB - Several new bis-phosphine platinum(II) complexes with 2,5-diaryl-substituted oxazole-containing alkyne ligands have been synthesized and optically characterized in solution. Measurements of nonlinear absorption showed strong attenuation of laser light at 532 and 600 nm. The light absorption of the Pt complexes was shifted from the near-UV region for the ground state to the red region for the excited triplet state, and was associated with large extinction coefficients. The optical limiting effect can be explained by triplet-triplet excited state absorption in conjunction with fast excited singlet-to-triplet intersystem crossing and slow triplet-to-ground-state decay, in comparison with the pulse length of the laser. DFT calculations show good predictability of the S(0)-S(1) and S(0)-T(1) energy gaps and offer insight into the interaction strength between Pt and the alkyne ligands. The use of this type of ligand, with weak absorption for the Pt(II) complexes in the visual wavelength range as a key feature, enables the possibility to further improve these molecular systems for nonlinear absorption applications. PMID- 23102257 TI - Intakes of milk and alternatives among on-reserve First Nations youth in northern and southern Ontario, Canada. AB - OBJECTIVE: To assess the adequacy of milk and alternatives, Ca and vitamin D intakes in First Nations (FN) youth in Ontario, Canada. Intakes were compared with the general population and dietary standards. Variation in intakes by community (proxy for remoteness) and BMI was examined. DESIGN: Data were collected by 24 h recall between November 2003 and June 2010. Intakes were analysed descriptively. Variation in intakes, by community and BMI category, was assessed using ANOVA. SETTING: Five remote FN communities of the Mushkegowuk Territory (northern Ontario, Canada) and two less-remote southern Ontario FN communities. SUBJECTS: Schoolchildren (n 457) in grades 6 to 12. RESULTS: Compared with Canada's Food Guide recommendations, 72.6 to 84.7% had an inadequate intake of milk and alternatives depending on age and sex group; 86.2% of individuals fell below the RDA for Ca; 96.4% fell below the RDA for vitamin D. Community variation in intakes was detected, although in all cases Fort Albany had higher intakes, even when it was the more northern (remote) community. A BMI * sex interaction was found for intake of milk and alternatives (P = 0.041): an inverse relationship between intake and BMI was seen in females; in males, those who were overweight had the highest intake, followed by normal-weight and obese youth. CONCLUSIONS: The nutritional inadequacies parallel the results of other Canadian studies of Aboriginal populations. Population health interventions to improve intakes are warranted. Moreover, community variation in intakes exists among FN youth in the present study (Fort Albany pairs only), but results were not as expected. PMID- 23102258 TI - Incorporation of a 3-(2,2,2-trifluoroethyl)-gamma-hydroxy-gamma-lactam motif in the side chain of 4-aminoquinolines. Syntheses and antimalarial activities. AB - In this paper we report the synthesis and antimalarial properties of two series of fluoroalkylated gamma-lactams derived from 4-aminoquinoline as potent chemotherapeutic agents for malaria treatment. These molecules obtained in several steps resulted in the identification of very potent structures with in vitro activity against Plasmodium falciparum clones of variable sensitivity (3D7 and W2) in the range of 19-50 nM with resistance indices in the range of 1.0-2.5. In addition, selected molecules (50, 51, 58, 60, 63, 70, 72, 74, 78, 81, 84, and 87) that are representative of the two series of compounds did not show cytotoxicity in vitro when tested against human umbilical vein endothelial cells up to a concentration of 100 MUM. The most promising compounds (82 and 84) showed significant IC50 values close to 26 and 19 nM against the chloroquino-sensitive strain 3D7 and 49 and 42 nM against the multi-drug-resistant strain W2. Furthermore, two model compounds (50 and 70) were found to be quite stable over 48 h at pH 7.4 and 5.2. Overall, our preliminary data indicate that this class of structures contains promising candidates for further study. PMID- 23102259 TI - Development, validation and operating room-transfer of a six-step laparoscopic training program for the vesicourethral anastomosis. AB - PURPOSE: Development and full validation of a laparoscopic training program for stepwise learning of a reproducible application of a standardized laparoscopic anastomosis technique and integration into the clinical course. MATERIALS AND METHODS: The training of vesicourethral anastomosis (VUA) was divided into six simple standardized steps. To fix the objective criteria, four experienced surgeons performed the stepwise training protocol. Thirty-eight participants with no previous laparoscopic experience were investigated in their training performance. The times needed to manage each training step and the total training time were recorded. The integration into the clinical course was investigated. The training results and the corresponding steps during laparoscopic radical prostatectomy (LRP) were analyzed. Data analysis of corresponding operating room (OR) sections of 793 LRP was performed. Based on the validity, criteria were determined. RESULTS: In the laboratory section, a significant reduction of OR time for every step was seen in all participants. Coordination: 62%; longitudinal incision: 52%; inverted U-shape incision: 43%; plexus: 47%. Anastomosis catheter model: 38%. VUA: 38%. The laboratory section required a total time of 29 hours (minimum: 16 hours; maximum: 42 hours). All participants had shorter execution times in the laboratory than under real conditions. The best match was found within the VUA model. To perform an anastomosis under real conditions, 25% more time was needed. By using the training protocol, the performance of the VUA is comparable to that of an surgeon with experience of about 50 laparoscopic VUA. Data analysis proved content, construct, and prognostic validity. CONCLUSIONS: The use of stepwise training approaches enables a surgeon to learn and reproduce complex reconstructive surgical tasks: eg, the VUA in a safe environment. The validity of the designed system is given at all levels and should be used as a standard in the clinical surgical training in laparoscopic reconstructive urology. PMID- 23102260 TI - Electrostatic optimization of the conformational energy landscape in a metamorphic protein. AB - The equilibrium unfolding reaction of Ltn, a metamorphic C-class chemokine, was monitored by tryptophan fluorescence to determine unfolding free energies. Measurements revealed that addition of 150 mM NaCl stabilized the Ltn chemokine fold by approximately 1 kcal/mol. Specific mutations involving Arg23 and Arg43 also increased the stability by 1 kcal/mol, suggesting their involvement in chloride ion coordination. This interaction was confirmed by nuclear magnetic resonance (NMR) salt titration studies that revealed chemical shift perturbations localized to these residues and backbone amides within the proximal 40s loop. The effects of NaCl on the free energy landscape were further verified by ZZ-exchange NMR spectroscopy. Our results suggest that changes in the electrostatic environment modulate the Gibbs free energy of folding and alter the forward and reverse rates of interconversion. These results demonstrate how solution ions can promote metamorphic folding by adjusting the relative stabilities of two unrelated Ltn native-state structures. PMID- 23102261 TI - The effect of intellectual ability on functional activation in a neurodevelopmental disorder: preliminary evidence from multiple fMRI studies in Williams syndrome. AB - BACKGROUND: Williams syndrome (WS) is a rare genetic disorder caused by the deletion of approximately 25 genes at 7q11.23 that involves mild to moderate intellectual disability (ID). When using functional magnetic resonance imaging (fMRI) to compare individuals with ID to typically developing individuals, there is a possibility that differences in IQ contribute to between-group differences in BOLD signal. If IQ is correlated with BOLD signal, then group-level analyses should adjust for IQ, or else IQ should be matched between groups. If, however, IQ is not correlated with BOLD signal, no such adjustment or criteria for matching (and exclusion) based on IQ is necessary. METHODS: In this study, we aimed to test this hypothesis systematically using four extant fMRI datasets in WS. Participants included 29 adult subjects with WS (17 men) demonstrating a wide range of standardized IQ scores (composite IQ mean = 67, SD = 17.2). We extracted average BOLD activation for both cognitive and task-specific anatomically defined regions of interest (ROIs) in each individual and correlated BOLD with composite IQ scores, verbal IQ scores and non-verbal IQ scores in Spearman rank correlation tests. RESULTS: Of the 312 correlations performed, only six correlations (2%) in four ROIs reached statistical significance at a P value < 0.01, but none survived correction for multiple testing. All six correlations were positive. Therefore, none supports the hypothesis that IQ is negatively correlated with BOLD response. CONCLUSIONS: These data suggest that the inclusion of subjects with below normal IQ does not introduce a confounding factor, at least for some types of fMRI studies with low cognitive load. By including subjects who are representative of IQ range for the targeted disorder, findings are more likely to generalize to that population. PMID- 23102262 TI - Pulmonary instillation of multi-walled carbon nanotubes promotes coronary vasoconstriction and exacerbates injury in isolated hearts. AB - The growing use of multi-walled carbon nanotubes (MWCNTs) across industry has increased human exposures. We tested the hypothesis that pulmonary instillation of MWCNTs would exacerbate cardiac ischaemia/reperfusion (I/R) injury. One day following intratracheal instillation of 1, 10 or 100 MUg MWCNT in Sprague-Dawley rats, we used a Langendorff isolated heart model to examine cardiac I/R injury. In the 100 MUg MWCNT group we report increased premature ventricular contractions at baseline and increased myocardial infarction. This was associated with increased endothelin-1 (ET-1) release and depression of coronary flow during early reperfusion. We also tested if isolated coronary vascular responses were affected by MWCNT instillation and found trends for enhanced coronary tone, which were dependent on ET-1, cyclooxygenase, thromboxane and Rho-kinase. We concluded that instillation of MWCNTs promoted cardiac injury and depressed coronary flow by invoking vasoconstrictive mechanisms involving ET-1, cyclooxygenase, thromboxane and Rho-kinase. PMID- 23102263 TI - Dental treatment needs in the Canadian population: analysis of a nationwide cross sectional survey. AB - BACKGROUND: Nationally representative clinical data on the oral health needs of Canadians has not been available since the 1970s. The purpose of this study was to determine the normative treatment needs of a nationally representative sample of Canadians and describe how these needs were distributed. METHODS: A secondary analysis of data collected through the Canadian Health Measures Survey (CHMS) was undertaken. Sampling and bootstrap weights were applied to make the data nationally representative. Descriptive frequencies were used to examine the sample characteristics and to examine the treatment type(s) needed by the population. Bivariate logistic regressions were used to see if any characteristics were predictive of having an unmet dental treatment need, and of having specific treatment needs. Lastly, multivariate logistic regression was used to identify the strongest predictors of having an unmet dental treatment need. RESULTS: Most of the population had no treatment needs and of the 34.2% who did, most needed restorative (20.4%) and preventive (13.7%) care. The strongest predictors of need were having poor oral health, reporting a self-perceived need for treatment and visiting the dentist infrequently. CONCLUSIONS: It is estimated that roughly 12 million Canadians have at least one unmet dental treatment need. Policymakers now have information by which to assess if programs match the dental treatment needs of Canadians and of particular subgroups experiencing excess risk. PMID- 23102264 TI - Structure by sequencing: discovery of hidden messages in the noncoding RNA fraction. AB - A lack of tools has hampered the search for the potential functions of the abundant noncoding RNA (ncRNA) portion of the genome. Wan et al. (2012) report a new sequencing-based method for determining ncRNA secondary structure termed PARTE, promising to accelerate ncRNA studies. PMID- 23102265 TI - Long noncoding RNAs as sinks in Prader-Willi syndrome. AB - In this issue of Molecular Cell, Yin et al. (2012) identify a class of long noncoding RNAs (lncRNAs) and propose a new mechanism as to how they contribute to the pathogenesis of Prader-Willi syndrome. PMID- 23102267 TI - Electronically nonalloyed state of a statistical single atomic layer semiconductor alloy. AB - Using atomically and momentum resolved scanning tunneling microscopy and spectroscopy, we demonstrate that a two-dimensional (2D) ?3 * ?3 semiconducting Ga-Si single atomic alloy layer exhibits an electronic structure with atomic localization and which is different at the Si and Ga atom sites. No indication of an interaction or an electronic intermixing and formation of a new alloy band structure is present, as if no alloying happened. The electronic localization is traced back to the lack of intra alloy bonds due to the 2D atomically confined structure of the alloy overlayer. PMID- 23102268 TI - Mass production of nanofibrous extracellular matrix with controlled 3D morphology for large-scale soft tissue regeneration. AB - AIM: Biomaterials that mimic the nanofibrous architecture of the natural extracellular matrix (ECM) are in the focus for stem cell hosting or delivery in tissue engineering of multilayered soft tissues such as skin, mucosa, or retina. Synthetic nanofibers for such ECM are usually produced by single-syringe electrospinning with only one needle-jet at very low production rates of 0.005 0.008 g.min-1. The aim of this study was to utilize a novel industrial needle free multijet electrospinning device with the potential for mass production of nanofibrous ECM (NF-ECM) exhibiting a controlled three-dimensional (3D) morphology for large-scale applications such as large area skin regeneration in patients with burns. METHODS: The novel NanoSpiderTM NS200, an industrial apparatus originally designed for electrospinning of nanofibrous textile meshes, was used to fabricate 3D NF-ECMs of the following synthetic and natural biopolymers: collagen, gelatin, poly(caprolactone) (PCL), and poly(L-lactide-co glycolide) (PLGA). Different concentrations of Gelatin polymer solution were electrospun under varying processing conditions, namely speed of spinning electrode rotation (u) and electric field intensity (E) by altering applied voltage (v) or the distance between electrodes (h) to achieve homogeneous desirable 3D morphology. Nanofiber diameters were assessed by scanning electron microscopy (SEM). Biocompatibility was tested by WST-1 (water-soluble tetrazolium salt) proliferation assay of seeded human mesenchymal stem cells (HMSCs). Biological performance of HMSCs on 3D PLGA NF-ECM was compared to two-dimensional (2D) PLGA film controls via SEM and confocal microscopy. Western blotting addressed the expression of surface adhesion proteins; focal adhesion kinase (FAK), phosphorylated FAK (pY397), alpha-tubulin, paxillin, vinculin. and integrin subunits; alpha5, alphav, and beta1 proteins. RESULTS: Large-scale mass production of NF-ECM membranes with a highly homogenous nanofiber morphology and 3D architecture could be produced with an extremely high production rate of 0.394+/-0.013 g.min-1.m-1 when compared to standard procedures. This was achieved by electrospinning a 20% (wt)/v gelatin solution, in an electric field intensity of 0.381 kV.mm-1. The nanofibers possessed diameters of around 180+/-40 nm with 28% deviation. HSMCs proliferation was significantly improved on NF-ECMs derived from collagen, gelatin, and PLGA when compared to PCL or flat coverglass controls (p<0.01). PLGA NF-ECM in 3D nanofibrous architecture possessed significantly superior biocompatibility when compared to flat 2D PLGA film (p<0.05). Furthermore, on 3D PLGA NF-ECMs, HSMCs expressed a higher amount of alpha-tubulin and paxillin compared to the HMSCs cultured on a 2D PLGA film (p<0.05). HMSCs exhibited a complex multifaceted morphology on all NF-ECMs, where cells appeared to be integrated into the 3D NF-ECMs niches with complex cell filopodia extending into to all directions. In contrast, HMSCs on flat 2D films of the same materials or on coverglass displayed a simple flattened, monolayered structure. CONCLUSION: Needle-free multijet electrospinning can be used to mass produce artificial ECMs with intrinsic biocompatibility and desirable integration of stem cells for large scale applications. PMID- 23102266 TI - Physiological roles of mitochondrial reactive oxygen species. AB - Historically, mitochondrial reactive oxygen species (mROS) were thought to exclusively cause cellular damage and lack a physiological function. Accumulation of ROS and oxidative damage have been linked to multiple pathologies, including neurodegenerative diseases, diabetes, cancer, and premature aging. Thus, mROS were originally envisioned as a necessary evil of oxidative metabolism, a product of an imperfect system. Yet few biological systems possess such flagrant imperfections, thanks to the persistent optimization of evolution, and it appears that oxidative metabolism is no different. More and more evidence suggests that mROS are critical for healthy cell function. In this Review, we discuss this evidence following some background on the generation and regulation of mROS. PMID- 23102270 TI - Multimass velocity-map imaging with the Pixel Imaging Mass Spectrometry (PImMS) sensor: an ultra-fast event-triggered camera for particle imaging. AB - We present the first multimass velocity-map imaging data acquired using a new ultrafast camera designed for time-resolved particle imaging. The PImMS (Pixel Imaging Mass Spectrometry) sensor allows particle events to be imaged with time resolution as high as 25 ns over data acquisition times of more than 100 MUs. In photofragment imaging studies, this allows velocity-map images to be acquired for multiple fragment masses on each time-of-flight cycle. We describe the sensor architecture and present bench-testing data and multimass velocity-map images for photofragments formed in the UV photolysis of two test molecules: Br(2) and N,N dimethylformamide. PMID- 23102269 TI - Quantitative GPCR and ion channel transcriptomics in primary alveolar macrophages and macrophage surrogates. AB - BACKGROUND: Alveolar macrophages are one of the first lines of defence against invading pathogens and play a central role in modulating both the innate and acquired immune systems. By responding to endogenous stimuli within the lung, alveolar macrophages contribute towards the regulation of the local inflammatory microenvironment, the initiation of wound healing and the pathogenesis of viral and bacterial infections. Despite the availability of protocols for isolating primary alveolar macrophages from the lung these cells remain recalcitrant to expansion in-vitro and therefore surrogate cell types, such as monocyte derived macrophages and phorbol ester-differentiated cell lines (e.g. U937, THP-1, HL60) are frequently used to model macrophage function. METHODS: The availability of high throughput gene expression technologies for accurate quantification of transcript levels enables the re-evaluation of these surrogate cell types for use as cellular models of the alveolar macrophage. Utilising high-throughput TaqMan arrays and focussing on dynamically regulated families of integral membrane proteins, we explore the similarities and differences in G-protein coupled receptor (GPCR) and ion channel expression in alveolar macrophages and their widely used surrogates. RESULTS: The complete non-sensory GPCR and ion channel transcriptome is described for primary alveolar macrophages and macrophage surrogates. The expression of numerous GPCRs and ion channels whose expression were hitherto not described in human alveolar macrophages are compared across primary macrophages and commonly used macrophage cell models. Several membrane proteins known to have critical roles in regulating macrophage function, including CXCR6, CCR8 and TRPV4, were found to be highly expressed in macrophages but not expressed in PMA-differentiated surrogates. CONCLUSIONS: The data described in this report provides insight into the appropriate choice of cell models for investigating macrophage biology and highlights the importance of confirming experimental data in primary alveolar macrophages. PMID- 23102271 TI - Rational design of single-ion magnets and spin qubits based on mononuclear lanthanoid complexes. AB - Here we develop a general approach to calculating the energy spectrum and the wave functions of the low-lying magnetic levels of a lanthanoid ion submitted to the crystal field created by the surrounding ligands. This model allows us to propose general criteria for the rational design of new mononuclear lanthanoid complexes behaving as single-molecule magnets (SMMs) or acting as robust spin qubits. Three typical environments exhibited by these metal complexes are considered, namely, (a) square antiprism, (b) triangular dodecahedron, and (c) trigonal prism. The developed model is used to explain the properties of some representative examples showing these geometries. Key questions in this area, such as the chemical tailoring of the superparamagnetic energy barrier, tunneling gap, or spin relaxation time, are discussed. Finally, in order to take into account delocalization and/or covalent effects of the ligands, this point-charge model is complemented with ab initio calculations, which provide accurate information on the charge distribution around the metal, allowing for an explanation of the SMM behavior displayed by some sandwich-type organometallic compounds. PMID- 23102272 TI - Glucose Tolerance in Mice is Linked to the Dose of the p53 Transactivation Domain. AB - Aim. To test the transactivation domain-mediated control of glucose homeostasis by the tumor suppressor p53. Background. The tumor suppressor p53 has a critical role in maintenance of glucose homeostasis. Phosphorylation of Ser18 in the transaction domain of p53 controls the expression of Zpf385a, a zinc finger protein that regulates adipogenesis and adipose function. This results suggest that the transactivation domain of p53 is essential to the control of glucose homeostasis. Materials and Methods. Mice with mutations in the p53 transactivation domain were examined for glucose homeostasis as well as various metabolic parameters. Glucose tolerance and insulin tolerance tests were performed on age matched wild type and mutant animals. In addition, mice expressing increased dosage of p53 were also examined. Results. Mice with a mutation in p53Ser18 exhibit reduced Zpf385a expression in adipose tissue, adipose tissue-specific insulin resistance, and glucose intolerance. Mice with relative deficits in the transactivation domain of p53 exhibit similar defects in glucose homeostasis, while "Super p53" mice with an increased dosage of p53 exhibit improved glucose tolerance. Conclusion. These data support the role of an ATM-p53 cellular stress axis that helps combat glucose intolerance and insulin resistance and regulates glucose homeostasis. PMID- 23102274 TI - A healthy trend: less food used in fundraising and as rewards and incentives in Minnesota middle and high schools. AB - OBJECTIVE: To assess change in the 4-year prevalence (2006-2009) of the use of food in school fundraising and as rewards and incentives for students, following implementation of federal legislation in the USA in 2006. DESIGN: Serial cross sectional design using trend analysis to assess school-level data collected over four consecutive years from 2006/2007 to 2009/2010. SETTING: Minneapolis/St. Paul, MN. SUBJECTS: Convenience sample of middle and high schools participating in two longitudinal, aetiological studies that examined youth, their environment and obesity-related factors. RESULTS: A significant and sustained decrease was demonstrated in the use of low-nutrient, energy-dense foods in school fundraising activities and the use of food and food coupons as rewards and incentives by teachers and school staff. CONCLUSIONS: Results support the utility of policy and legislative action as a tool for creating healthy, sustainable environmental change. PMID- 23102273 TI - Variation of the net charge, lipophilicity, and side chain flexibility in Dmt(1) DALDA: Effect on Opioid Activity and Biodistribution. AB - The influence of the side chain charges of the second and fourth amino acid residues in the peptidic MU opioid lead agonist Dmt-d-Arg-Phe-Lys-NH(2) ([Dmt(1)] DALDA) was examined. Additionally, to increase the overall lipophilicity of [Dmt(1)]-DALDA and to investigate the Phe(3) side chain flexibility, the final amide bond was N-methylated and Phe(3) was replaced by a constrained aminobenzazepine analogue. The in vitro receptor binding and activity of the peptides, as well as their in vivo transport (brain in- and efflux and tissue biodistribution) and antinociceptive properties after peripheral administration (ip and sc) in mice were determined. The structural modifications result in significant shifts of receptor binding, activity, and transport properties. Strikingly, while [Dmt(1)]-DALDA and its N-methyl analogue, Dmt-d-Arg-Phe-NMeLys NH(2), showed a long-lasting antinociceptive effect (>7 h), the peptides with d Cit(2) generate potent antinociception more rapidly (maximal effect at 1h postinjection) but also lose their analgesic activity faster when compared to [Dmt(1)]-DALDA and [Dmt(1),NMeLys(4)]-DALDA. PMID- 23102275 TI - Seroepidemiology of human enterovirus71 and coxsackievirusA16 in Jiangsu province, China. AB - BACKGROUND: The major etiology of hand, foot and mouth disease (HFMD) is infection with human enterovirus A (HEV-A). Among subtypes of HEV-A, coxsackievirusA16 (CoxA16) and enterovirus 71 (EV71) are major causes for recurrent HFMD among infants and children in Jiangsu Province, mainland China. Here, we analyzed maternal antibodies between prenatal women and their neonates, to determine age-specific seroprevalence of human EV71 and CoxA16 infections in infants and children aged 0 to 15 years. The results may facilitate the development of immunization against HFMD. METHODS: This study used cross-section of 40 pairs of pregnant women and neonates and 800 subjects aged 1 month to 15 years old. Micro-dose cytopathogenic effects measured neutralizing antibodies against EV71 and CoxA16. Chi-square test compared seroprevalence rates between age groups and McNemar test, paired-Samples t-test and independent-samples t-test analyzed differences of geometric mean titers. RESULTS: A strong correlation between titers of neutralizing antibody against EV71 and CoxA16 in prenatal women and neonates was observed (rEV71 = 0.67, rCoxA16 = 0.56, respectively, p < 0.05). Seroprevalence rates of anti-EV71 antibody gradually decreased with age between 0 to 6 months old, remained low between 7 to 11 months (5.0-10.0%), and increased between 1 and 4 years (22.5-87.5%). Age-specific seroprevalence rates of anti EV71 antibody stabilized in >80% of children between 5 to 15 years of age. However, seroprevalence rates of anti-CoxA16 antibody were very low (0.0-13.0%) between 0 to 6 months of age, gradually increased between 7 months to 4 years (15.0-70.0%), and stabilized at 54.0% (108/200) between 5 to 15 years. Seroprevalence rates against EV71 and CoxA16 were low under 1 year (0.0-10.0%), and showed an age dependent increase with high seroprevalence (52.5-62.5%) between 4 and 10 years of age. CONCLUSIONS: Concomitant infection of EV71 and CoxA16 was common in Jiangsu Province. Therefore, development of bivalent vaccine against both EV71 and CoxA16 is critical. The optimal schedule for vaccination may be 4 to11 months of age. PMID- 23102277 TI - State-independent experimental test of quantum contextuality in an indivisible system. AB - We report the first state-independent experimental test of quantum contextuality on a single photonic qutrit (three-dimensional system), based on a recent theoretical proposal [Phys. Rev. Lett. 108, 030402 (2012)]. Our experiment spotlights quantum contextuality in its most basic form, in a way that is independent of either the state or the tensor product structure of the system. PMID- 23102278 TI - Balance between information gain and reversibility in weak measurement. AB - We derive a tight bound between the quality of estimating a quantum state by measurement and the success probability of undoing the measurement in arbitrary dimensional systems, which completely describes the tradeoff relation between the information gain and reversibility. In this formulation, it is clearly shown that the information extracted from a weak measurement is erased through the reversing process. Our result broadens the information-theoretic perspective on quantum measurement as well as provides a standard tool to characterize weak measurements and reversals. PMID- 23102276 TI - A role for G-proteins in directing G-protein-coupled receptor-caveolae localization. AB - Caveolae are membrane domains that may influence cell signaling by sequestering specific proteins such as G-protein-coupled receptors (GPCRs). While previous reports largely show that Galpha(q) subunits, but not other G-proteins, interact strongly with the caveolae protein, Caveolin-1 (Cav1), the inclusion of GPCRs in caveolae is controversial. Here, we have used fluorescence methods to determine the effect of caveolae on the physical and functional properties of two GPCRs that have been reported to reside in caveolae, bradykinin receptor type 2 (B(2)R), which is coupled to Galpha(q), and the MU-opioid receptor (MUOR), which is coupled to Galpha(i). While caveolae do not affect cAMP signals mediated by MUOR, they prolong Ca(2+) signals mediated by B(2)R. In A10 cells that endogenously express B(2)R and Cav1, downregulation of Cav1 ablates the prolonged recovery seen upon bradykinin stimulation in accord with the idea that the presence of caveolae prolongs Galpha(q) activation. Immunofluorescence and Forster resonance energy transfer (FRET) studies show that a significant fraction of B(2)R resides at or close to caveolae domains while none or very little MUOR resides in caveolae domains. The level of FRET between B(2)R and caveolae is reduced by downregulation of Galpha(q) or by addition of a peptide that interferes with Galpha(q)-Caveolin-1 interactions, suggesting that Galpha(q) promotes localization of B(2)R to caveolae domains. Our results lead to the suggestion that Galpha(q) can localize its associated receptors to caveolae domains to enhance their signals. PMID- 23102279 TI - Observation of the emergence of multipartite entanglement between a bipartite system and its environment. AB - The dynamics of the environment is usually experimentally inaccessible and hence ignored for open systems. Here we overcome this limitation by using an interferometric setup that allows the implementation of several decoherence channels and full access to all environmental degrees of freedom. We show that when a qubit from an entangled pair interacts with the environment, the initial bipartite entanglement gets redistributed into bipartite and genuine multipartite entanglements involving the two qubits and the environment. This is yet another trait of the subtle behavior of entangled open systems. PMID- 23102280 TI - Distinct quantum states can be compatible with a single state of reality. AB - Perhaps the quantum state represents information about reality, and not reality directly. Wave function collapse is then possibly no more mysterious than a Bayesian update of a probability distribution given new data. We consider models for quantum systems with measurement outcomes determined by an underlying physical state of the system but where several quantum states are consistent with a single underlying state-i.e., probability distributions for distinct quantum states overlap. Significantly, we demonstrate by example that additional assumptions are always necessary to rule out such a model. PMID- 23102281 TI - Stimulation of the fluctuation superconductivity by PT symmetry. AB - We discuss fluctuations near the second-order phase transition where the free energy has an additional non-Hermitian term. The spectrum of the fluctuations changes when the odd-parity potential amplitude exceeds the critical value corresponding to the PT-symmetry breakdown in the topological structure of the Hilbert space of the effective non-Hermitian Hamiltonian. We calculate the fluctuation contribution to the differential resistance of a superconducting weak link and find the manifestation of the PT-symmetry breaking in its temperature evolution. We successfully validate our theory by carrying out measurements of far from equilibrium transport in mesoscale-patterned superconducting wires. PMID- 23102282 TI - Quantum catastrophes and ergodicity in the dynamics of bosonic Josephson junctions. AB - We study rainbow (fold) and cusp catastrophes that form in Fock space following a quench in a Bose Josephson junction. In the Gross-Pitaevskii mean-field theory, the rainbows are singular caustics, but in the second-quantized theory a Poisson resummation of the wave function shows that they are described by well-behaved Airy functions. The structural stability of these Fock space caustics against variations in the initial conditions and Hamiltonian evolution is guaranteed by catastrophe theory. We also show that the long-time dynamics are ergodic. Our results are relevant to the question posed by Berry [M. V. Berry, Nonlinearity 21, T19 (2008)]: Are there circumstances when it is necessary to second quantize wave theory in order to avoid singularities? PMID- 23102283 TI - Observing trajectories with weak measurements in quantum systems in the semiclassical regime. AB - We propose a scheme allowing us to observe the evolution of a quantum system in the semiclassical regime along the paths generated by the propagator. The scheme relies on performing consecutive weak measurements of the position. We show how "weak trajectories" can be extracted from the pointers of a series of devices having weakly interacted with the system. The properties of these weak trajectories are investigated and illustrated in the case of a time-dependent model system. PMID- 23102284 TI - Topological invariants for spin-orbit coupled superconductor nanowires. AB - We show that the Hamiltonian of a multiband spin-orbit coupled semiconductor nanowire with Zeeman splitting and s-wave superconductivity is approximately chiral symmetric. The chiral symmetry becomes exact when only one pair of confinement bands is occupied and the Zeeman splitting is parallel to the nanowire. In this idealized case the Hamiltonian is in the BDI symmetry class of the topological classification of band Hamiltonians, allowing an arbitrary integer number of zero-energy Majorana fermion modes at each end. In the realistic case of multiband wires (Zeeman splitting still parallel to the length) the chiral symmetry is approximate and results in multiple near-zero-energy end states with increasing Zeeman splitting. The existence of such low energy end states implies the vanishing of the minigap with increased Zeeman splitting which can only be restored by breaking the approximate chiral symmetry by a second Zeeman field. PMID- 23102285 TI - Penrose-Onsager criterion validation in a one-dimensional polariton condensate. AB - We perform quantum tomography on one-dimensional polariton condensates, spontaneously occurring in linear disorder valleys in a CdTe planar microcavity sample. By the use of optical interferometric techniques, we determine the first order coherence function and the amplitude and phase of the order parameter of the condensate, providing a full reconstruction of the single particle density matrix for the polariton system. The experimental data are used as input to theoretically test the consistency of the Penrose-Onsager criterion for Bose Einstein condensation in the framework of nonequilibrium polariton condensates. The results confirm the pertinence and validity of the criterion for a nonequilibrium condensed gas. PMID- 23102286 TI - Zeno dynamics, indistinguishability of state, and entanglement. AB - According to the quantum Zeno effect (QZ), frequent observations of a system can dramatically slow down its dynamical evolution. We show that the QZ is a physical consequence of the statistical indistinguishability of neighboring quantum states. The time scale of the problem is expressed in terms of the Fisher information and we demonstrate that the Zeno dynamics of particle entangled states might require quite smaller measurement intervals than classically correlated states. We propose an interferometric experiment to test the prediction. PMID- 23102287 TI - Quantum walks with encrypted data. AB - In the setting of networked computation, data security can be a significant concern. Here we consider the problem of allowing a server to remotely manipulate client supplied data, in such a way that both the information obtained by the client about the server's operation and the information obtained by the server about the client's data are significantly limited. We present a protocol for achieving such functionality in two closely related models of restricted quantum computation-the boson sampling and quantum walk models. Because of the limited technological requirements of the boson scattering model, small scale implementations of this technique are feasible with present-day technology. PMID- 23102288 TI - Polarization-entangled light pulses of 10(5) photons. AB - We experimentally demonstrate polarization entanglement for squeezed vacuum pulses containing more than 10(5) photons. We also study photon-number entanglement by calculating the Schmidt number and measuring its operational counterpart. Theoretically, our pulses are the more entangled the brighter they are. This promises important applications in quantum technologies, especially photonic quantum gates and quantum memories. PMID- 23102289 TI - Absolute transition rates for rare events from dynamical decoupling of reaction variables. AB - We introduce a new approach to evaluate transition rates for rare events in complex many-particle systems. Building on a path-integral representation of transition probabilities for Markov processes, the rate is first expressed in terms of a free energy in the transition-path ensemble. We then define an auxiliary process where a suitably defined reaction variable is dynamically decoupled from all the others, whose dynamics is left unchanged. For this system the transition rates coincide with those of a unidimensional process whose only coordinate is the reaction variable. The free-energy difference between the auxiliary and the physical transition-path ensembles is finally evaluated using standard techniques. The efficiency of this method is deemed to be optimal because the physical and auxiliary dynamics differ by one degree of freedom only at any system size. Our method is demonstrated numerically on a simple model of Lennard-Jones particles ruled by the overdamped Langevin equation. PMID- 23102290 TI - Exploring the nuclear pasta phase in core-collapse supernova matter. AB - The core-collapse supernova phenomenon, one of the most explosive events in the Universe, presents a challenge to theoretical astrophysics. Of the large variety of forms of matter present in core-collapse supernova, we focus on the transitional region between homogeneous (uniform) and inhomogeneous (pasta) phases. A three-dimensional, finite temperature Skyrme-Hartree-Fock (3D-SHF)+BCS calculation yields, for the first time fully self-consistently, the critical density and temperature of both the onset of the pasta in inhomogeneous matter, consisting of neutron-rich heavy nuclei and a free neutron and electron gas, and its dissolution to a homogeneous neutron, proton, and electron liquid. We also identify density regions for different pasta formations between the two limits. We employ four different forms of the Skyrme interaction, SkM*, SLy4, NRAPR, and SQMC700 and find subtle variations in the low density and high density transitions into and out of the pasta phase. One new stable pasta shape has been identified, in addition to the classic ones, on the grid of densities and temperatures used in this work. Our results are critically compared to recent calculations of pasta formation in the quantum molecular dynamics approach and Thomas-Fermi and coexisting phase approximations to relativistic mean-field models. PMID- 23102291 TI - Flat-space chiral gravity. AB - We provide the first evidence for a holographic correspondence between a gravitational theory in flat space and a specific unitary field theory in one dimension lower. The gravitational theory is a flat-space limit of topologically massive gravity in three dimensions at a Chern-Simons level of k=1. The field theory is a chiral two-dimensional conformal field theory with a central charge of c=24. PMID- 23102292 TI - Polyakov loop and the hadron resonance gas model. AB - The Polyakov loop has been used repeatedly as an order parameter in the deconfinement phase transition in QCD. We argue that, in the confined phase, its expectation value can be represented in terms of hadronic states, similarly to the hadron resonance gas model for the pressure. Specifically, L(T)~1/2[?(alpha)g(alpha)e(-Delta(alpha)/T), where g(alpha) are the degeneracies and Delta(alpha) are the masses of hadrons with exactly one heavy quark (the mass of the heavy quark itself being subtracted). We show that this approximate sum rule gives a fair description of available lattice data with N(f)=2+1 for temperatures in the range 150 MeV1s(2)(1)S(0)) x-ray resonance line transition energy in heliumlike titanium. This measurement is one of few sensitive to two-electron QED contributions. Systematic errors such as Doppler shifts are minimized in our experiment by trapping and stripping Ti atoms in an electron beam ion trap and by applying absolute wavelength standards to calibrate the dispersion function of a curved crystal spectrometer. We also report a more general systematic discrepancy between QED theory and experiment for the w transition energy in heliumlike ions for Z>20. When all of the data available in the literature for Z=16-92 are taken into account, the divergence is seen to grow as approximately Z(3) with a statistical significance on the coefficient that rises to the level of 5 standard deviations. Our result for titanium alone, 4749.85(7) eV for the w line, deviates from the most recent ab initio prediction by 3 times our experimental uncertainty and by more than 10 times the currently estimated uncertainty in the theoretical prediction. PMID- 23102305 TI - Measurement-induced qubit state mixing in circuit QED from up-converted dephasing noise. AB - We observe measurement-induced qubit state mixing in a transmon qubit dispersively coupled to a planar readout cavity. Our results indicate that dephasing noise at the qubit-readout detuning frequency is up-converted by readout photons to cause spurious qubit state transitions, thus limiting the nondemolition character of the readout. Furthermore, we use the qubit transition rate as a tool to extract an equivalent flux noise spectral density at f~1 GHz and find agreement with values extrapolated from a 1/f(alpha) fit to the measured flux noise spectral density below 1 Hz. PMID- 23102296 TI - Precision top-quark mass measurement at CDF. AB - We present a precision measurement of the top-quark mass using the full sample of Tevatron ?s = 1.96 TeV proton-antiproton collisions collected by the CDF II detector, corresponding to an integrated luminosity of 8.7 fb(-1). Using a sample of tt- candidate events decaying into the lepton+jets channel, we obtain distributions of the top-quark masses and the invariant mass of two jets from the W boson decays from data. We then compare these distributions to templates derived from signal and background samples to extract the top-quark mass and the energy scale of the calorimeter jets with in situ calibration. The likelihood fit of the templates from signal and background events to the data yields the single most-precise measurement of the top-quark mass, M(top)=172.85+/-0.71(stat)+/ 0.85(syst) GeV/c(2). PMID- 23102299 TI - Evolution of pi(0) suppression in Au+Au collisions from ?(s(NN))=39 to 200 GeV. AB - Neutral-pion pi(0) spectra were measured at midrapidity (|y|<0.35) in Au+Au collisions at ?(s(NN))=39 and 62.4 GeV and compared with earlier measurements at 200 GeV in a transverse-momentum range of 1J/psif(0)(980) is measured using 1.0 fb(-1) of data collected in pp collisions at ?s=7 TeV with the LHCb detector. The result is 1.700+/-0.040+/-0.026 ps, where the first uncertainty is statistical and the second systematic. As the final state is CP-odd, and CP violation in this mode is measured to be small, the lifetime measurement can be translated into a measurement of the decay width of the heavy B-(s)(0) mass eigenstate, Gamma(H)=0.588+/-0.014+/-0.009 ps(-1). PMID- 23102311 TI - Tunneling effect and the natural boundary of invariant tori. AB - The invariant torus of nonintegrable systems breaks up in complexified phase space. The breaking border is expected to form a natural boundary (NB) along which singularities are densely condensed. The NB cuts off the instanton orbit controlling the tunneling transport from a quantized invariant torus, which might result in a serious effect on the tunneling process. In the present Letter, we provide clear evidence showing that the presence of the NB is observable as an anomalous enhancement of the tunneling wave amplitude in the immediate outer side of the NB. PMID- 23102313 TI - Electric-field-induced friction reduction and control. AB - Friction is always present when surfaces in contact are set in motion. In this work I describe how a precise, active control of the global friction is possible by adjusting the local molecular conformation of a polyelectrolyte coating via the application of an alternating electric field. The intensity of the applied field determines the degree of interpenetration between polymer brushes in contact, regulating chain stretching while sliding, which is the process at the origin of the global friction. The dynamics of the problem is controlled by the relaxation times of the polyelectrolyte. PMID- 23102312 TI - Effect of boundary layers asymmetry on heat transfer efficiency in turbulent Rayleigh-Benard convection at very high Rayleigh numbers [corrected]. AB - The heat transfer efficiency in turbulent Rayleigh-Benard convection is investigated experimentally, in a cylindrical cell of height 0.3 m, diameter 0.3 m. We show that for Rayleigh numbers 10(12) < or approximately equal to Ra < or approximately equal to 10(15) the Nusselt number closely follows Nu is proportional to Ra(1/3 if the mean temperature of the working fluid-cryogenic helium gas-is measured by small sensors directly inside the cell at about half of its height. In contrast, if the mean temperature is determined in a conventional way, as an arithmetic mean of the bottom and top plate temperatures, the Nu(Ra) is proportional to Ra(gamma) displays spurious crossover to higher gamma that might be misinterpreted as a transition to the ultimate Kraichnan regime. PMID- 23102314 TI - Beyond Tanner's law: crossover between spreading regimes of a viscous droplet on an identical film. AB - We present results on the leveling of polymer microdroplets on thin films prepared from the same material. In particular, we explore the crossover from a droplet spreading on an infinitesimally thin film (Tanner's law regime) to that of a droplet leveling on a film thicker than the droplet itself. In both regimes, the droplet's excess surface area decreases towards the equilibrium configuration of a flat liquid film, but with a different power law in time. Additionally, the characteristic leveling time depends on molecular properties, the size of the droplet, and the thickness of the underlying film. Flow within the film makes this system fundamentally different from a droplet spreading on a solid surface. We thus develop a theoretical model based on thin film hydrodynamics that quantitatively describes the observed crossover between the two leveling regimes. PMID- 23102315 TI - Spontaneous symmetry breaking of a hinged flapping filament generates lift. AB - Elastic filamentous structures found on swimming and flying organisms are versatile in function, rendering their precise contribution to locomotion difficult to assess. We show in this Letter that a single passive filament hinged on the rear of a bluff body placed in a stream can generate a net lift force without increasing the mean drag force on the body. This is a consequence of spontaneous symmetry breaking in the filament's flapping dynamics. The phenomenon is related to a resonance between the frequency associated with the von Karman vortex street developing behind the bluff body and the natural frequency of the free bending vibrations of the filament. PMID- 23102316 TI - Observation of dynamic interactions between fundamental and second-harmonic modes in a high-power sub-terahertz gyrotron operating in regimes of soft and hard self excitation. AB - Dynamic mode interaction between fundamental and second-harmonic modes has been observed in high-power sub-terahertz gyrotrons [T. Notake et al., Phys. Rev. Lett. 103, 225002 (2009); T. Saito et al. Phys. Plasmas 19, 063106 (2012)]. Interaction takes place between a parasitic fundamental or first-harmonic (FH) mode and an operating second-harmonic (SH) mode, as well as among SH modes. In particular, nonlinear excitation of the parasitic FH mode in the hard self excitation regime with assistance of a SH mode in the soft self-excitation regime was clearly observed. Moreover, both cases of stable two-mode oscillation and oscillation of the FH mode only were observed. These observations and theoretical analyses of the dynamic behavior of the mode interaction verify the nonlinear hard self-excitation of the FH mode. PMID- 23102317 TI - Investigation of high-temperature bright plasma X-ray sources produced in 5-MA X pinch experiments. AB - Using solid, machined X-pinch targets driven by currents rising from 0 to 5-6 MA in 60 ns, we observed bright spots of 5-9-keV continuum radiation from 5+/-2-MUm diameter regions. The >6-keV radiation is emitted in about 0.4 ns, and the bright spots are roughly 75 times brighter than the bright spots measured at 1 MA. A total x-ray power of 10 TW peak and yields of 165+/-20 kJ were emitted from a 3 mm height. The 3-5-keV continuum radiation had a 50-90-GW peak power and 0.15 0.35-kJ yield. The continuum is plausibly from a 1275+/-75-eV blackbody or alternatively from a 3500+/-500-eV bremsstrahlung source. PMID- 23102318 TI - Magnetizing a complex plasma without a magnetic field. AB - We propose and demonstrate a concept that mimics the magnetization of the heavy dust particles in a complex plasma while leaving the properties of the light species practically unaffected. It makes use of the frictional coupling between a complex plasma and the neutral gas, which allows us to transfer angular momentum from a rotating gas column to a well-controlled rotation of the dust cloud. This induces a Coriolis force that acts exactly as the Lorentz force in a magnetic field. Experimental normal mode measurements for a small dust cluster with four particles show excellent agreement with theoretical predictions for a magnetized plasma. PMID- 23102320 TI - Coupling between whistler waves and ion-scale solitary waves: cluster measurements in the magnetotail during a substorm. AB - We present a new model of self-consistent coupling between low frequency, ion scale coherent structures with high frequency whistler waves in order to interpret Cluster data. The idea relies on the possibility of trapping whistler waves by inhomogeneous external fields where they can be spatially confined and propagate for times much longer than their characteristic electronic time scale. Here we take the example of a slow magnetosonic soliton acting as a wave guide in analogy with the ducting properties of an inhomogeneous plasma. The soliton is characterized by a magnetic dip and density hump that traps and advects high frequency waves over many ion times. The model represents a new possible way of explaining space measurements often detecting the presence of whistler waves in correspondence to magnetic depressions and density humps. This approach, here given by means of slow solitons, but more general than that, is alternative to the standard approach of considering whistler wave packets as associated with nonpropagating magnetic holes resulting from a mirror-type instability. PMID- 23102321 TI - Effect of sheared flow on the growth rate and turbulence decorrelation. AB - The effect of a large scale flow shear on a linearly unstable turbulent system is considered. A cubic equation describing the effective growth rate is obtained, which is shown to reduce to well-known forms in weak and strong shear limits. A shear suppression rule is derived which corresponds to the point where the effective growth rate becomes negative. The effect of flow shear on nonlinear mode coupling of drift or Rossby waves is also considered, and it is shown that the resonance manifold shrinks and weakens as the vortices are sheared. This leads to a reduction of the efficiency of three-wave interactions. Tilted eddies can then only couple to the large scale sheared flows, because the resonance condition for that interaction is trivially satisfied. It is argued that this leads to absorbtion of the sheared vortices by large scale flow structures. Studying the form of the effective growth rate for weak shear, it was shown that in addition to reducing the overall growth rate, a weak flow shear also reduces the wave number where the fluctuations are most unstable. PMID- 23102319 TI - Validation of a turbulent Kelvin-Helmholtz shear layer model using a high-energy density OMEGA laser experiment. AB - Following the successful demonstration of an OMEGA laser-driven platform for generating and studying nearly two-dimensional unstable plasma shear layers [Hurricane et al., Phys. Plasmas 16, 056305 (2009); Harding et al., Phys. Rev. Lett. 103, 045005 (2009)], this Letter reports on the first quantitative measurement of turbulent mixing in a high-energy-density plasma. As a blast wave moves parallel to an unperturbed interface between a low-density foam and a high density plastic, baroclinic vorticity is deposited at the interface and a Kelvin Helmholtz instability-driven turbulent mixing layer is created in the postshock flow due to surface roughness. The spatial scale and density profile of the turbulent layer are diagnosed using x-ray radiography with sufficiently small uncertainty so that the data can be used to ~0.17 MUm) in the postshock plasma flow are consistent with an "inertial subrange," within which a Kolmogorov turbulent energy cascade can be active. An illustration of comparing the data set with the predictions of a two-equation turbulence model in the ares radiation hydrodynamics code is also presented. PMID- 23102322 TI - Experimental validation of the two-plasmon-decay common-wave process. AB - The energy in hot electrons produced by the two plasmon decay instability, in planar targets, is measured to be the same when driven by one or two laser beams and significantly reduced with four for a constant overlapped intensity on the OMEGA EP. This is caused by multiple beams sharing the same common electron plasma wave. A model, consistent with the experimental results, predicts that multiple laser beams can only drive a resonant common two plasmon decay electron plasma wave in the region of wave numbers bisecting the beams. In this region, the gain is proportional to the overlapped laser beam intensity. PMID- 23102323 TI - Absence of supersolidity in solid helium in porous Vycor glass. AB - In 2004, Kim and Chan carried out torsional oscillator measurements of solid helium confined in porous Vycor glass and found an abrupt drop in the resonant period below 200 mK. The period drop was interpreted as probable experimental evidence of nonclassical rotational inertia. This experiment sparked considerable activities in the studies of superfluidity in solid helium. More recent ultrasound and torsional oscillator studies, however, found evidence that shear modulus stiffening is responsible for at least a fraction of the period drop found in bulk solid helium samples. The experimental configuration of Kim and Chan makes it unavoidable to have a small amount of bulk solid inside the torsion cell containing the Vycor disk. We report here the results of a new helium in Vycor experiment with a design that is completely free from any bulk solid shear modulus stiffening effect. We found no measurable period drop that can be attributed to nonclassical rotational inertia. PMID- 23102324 TI - Anisotropic excitation spectrum of a dipolar quantum Bose gas. AB - We measure the excitation spectrum of a dipolar chromium Bose-Einstein condensate with Raman-Bragg spectroscopy. The energy spectrum depends on the orientation of the dipoles with respect to the excitation momentum, demonstrating an anisotropy that originates from the dipole-dipole interactions between the atoms. We compare our results with the Bogoliubov theory based on the local density approximation and, at large excitation wavelengths, with the numerical simulations of the time dependent Gross-Pitaevskii equation. Our results show an anisotropy of the speed of sound. PMID- 23102325 TI - Strong isotope effect in phase II of dense solid hydrogen and deuterium. AB - Quantum nuclear zero-point motions in solid H(2) and D(2) under pressure are investigated at 80 K up to 160 GPa by first-principles path-integral molecular dynamics calculations. Molecular orientations are well defined in phase II of D(2), while solid H(2) exhibits large and very asymmetric angular quantum fluctuations in this phase, with possible rotation in the (bc) plane, making it difficult to associate a well-identified single classical structure. The mechanism for the transition to phase III is also described. Existing structural data support this microscopic interpretation. PMID- 23102326 TI - Triplet pair correlations in s-wave superfluids as a signature of the Fulde Ferrell-Larkin-Ovchinnikov state. AB - We show that antiparallel triplet pairing correlations are generated in superfluids with purely s-wave interactions whenever population imbalance enforces anisotropic Fulde-Ferrell (FF) or inhomogeneous Larkin-Ovchinikov (LO) states. These triplet correlations appear in the Cooper pair wave function, while the triplet part of the gap remains zero. The same set of quasiparticle states contributes to the triplet component and to the polarization, thus spatially correlating them. In the LO case, this set forms a narrow band of Andreev states centered on the nodes of the s-wave order parameter. This picture naturally provides a unifying explanation of previous findings that attractive p-wave interaction stabilizes FFLO states. We also study a similar triplet mixing which occurs when a balanced two-component system displays FFLO-type oscillations due to a spin-dependent optical lattice. We discuss how this triplet component can be measured in systems of ultracold atoms using a rapid ramp across a p-wave Feshbach resonance. This should provide a smoking gun signature of FFLO states. PMID- 23102327 TI - Roton-phonon interactions in superfluid 4He. AB - High-resolution neutron resonance spin-echo measurements of superfluid 4He show that the roton energy does not have the same temperature dependence as the inverse lifetime. Diagrammatic analysis attributes this to the interaction of rotons with thermally excited phonons via both four- and three-particle processes, the latter being allowed by the broken gauge symmetry of the Bose condensate. The distinct temperature dependence of the roton energy at low temperatures suggests that the net roton-phonon interaction is repulsive. PMID- 23102328 TI - Anderson localization of pairs in bichromatic optical lattices. AB - We investigate the formation of bound states made of two interacting atoms moving in a one dimensional (1D) quasiperiodic optical lattice. We derive the quantum phase diagram for Anderson localization of both attractively and repulsively bound pairs. We calculate the pair binding energy and show analytically that its behavior as a function of the interaction strength depends crucially on the nature-extended, multifractal, localized-of the single-particle atomic states. Experimental implications of our results are discussed. PMID- 23102329 TI - Reduced step edges on rutile TiO2(110) as competing defects to oxygen vacancies on the terraces and reactive sites for ethanol dissociation. AB - The rutile TiO2(110) surface is the most studied surface of titania and considered as a prototype of transition metal oxide surfaces. Reactions on flat TiO2(110)-(1*1) surfaces are well studied, but the processes occurring on the step edges have barely been considered. Based on scanning tunneling microscopy studies, we here present experimental evidence for the existence of O vacancies along the [11-1](R) step edges (O(S) vac.'s) on rutile TiO(2)(110). Both the distribution of bridging O vacancies on the terraces and temperature-programed reaction experiments of ethanol-covered TiO(2)(110) point to the existence of the O(S) vac.'s. Based on experiments and density functional theory calculations, we show that O(S) vac.'s are reactive sites for ethanol dissociation via O-H bond scission. Implications of these findings are discussed. PMID- 23102330 TI - Control of nanoscale friction on gold in an ionic liquid by a potential-dependent ionic lubricant layer. AB - The lubricating properties of an ionic liquid on gold surfaces can be controlled through application of an electric potential to the sliding contact. A nanotribology approach has been used to study the frictional behavior of 1-butyl 1-methylpyrrolidinium tris(pentafluoroethyl) trifluorophosphate ([Py(1,4)]FAP) confined between silica colloid probes or sharp silica tips and a Au(111) substrate using atomic force microscopy. Friction forces vary with potential because the composition of a confined ion layer between the two surfaces changes from cation-enriched (at negative potentials) to anion-enriched (at positive potentials). This offers a new approach to tuning frictional forces reversibly at the molecular level without changing the substrates, employing a self replenishing boundary lubricant of low vapor pressure. PMID- 23102331 TI - Nanostructure and nanomechanics of cement: polydisperse colloidal packing. AB - Cement setting and cohesion are governed by the precipitation and growth of calcium-silicate-hydrate, through a complex evolution of microstructure. A colloidal model to describe nucleation, packing, and rigidity of calcium-silicate hydrate aggregates is proposed. Polydispersity and particle size dependent cohesion strength combine to produce a spectrum of packing fractions and of corresponding elastic properties that can be tested against nanoindentation experiments. Implications regarding plastic deformations and reconciling current structural characterizations are discussed. PMID- 23102332 TI - Dynamic hysteresis in cyclic deformation of crystalline solids. AB - The hysteresis or internal friction in the deformation of crystalline solids stressed cyclically is studied from the viewpoint of collective dislocation dynamics. Stress-controlled simulations of a dislocation dynamics model at various loading frequencies and amplitudes are performed to study the stress strain rate hysteresis. The hysteresis loop areas exhibit a maximum at a characteristic frequency and a power law frequency dependence in the low frequency limit, with the power law exponent exhibiting two regimes, corresponding to the jammed and the yielding or moving phases of the system, respectively. The first of these phases of the system exhibits nontrivial critical-like viscoelastic dynamics, crossing over to intermittent viscoplastic deformation for higher stress amplitudes. PMID- 23102333 TI - Bond disorder induced criticality of the three-color Ashkin-Teller model. AB - An intriguing result of statistical mechanics is that a first-order phase transition can be rounded by disorder coupled to energylike variables. In fact, even more intriguing is that the rounding may manifest itself as a critical point, quantum or classical. In general, it is not known, however, what universality classes, if any, such criticalities belong to. In order to shed light on this question we examine in detail the disordered three-color Ashkin Teller model by Monte Carlo methods. Extensive analyses indicate that the critical exponents define a new universality class. We show that the rounding of the first-order transition of the pure model due to the impurities is manifested as criticality. However, the magnetization critical exponent, beta, and the correlation length critical exponent, nu, are found to vary with disorder and the four-spin coupling strength, and we conclusively rule out that the model belongs to the universality class of the two-dimensional Ising model. PMID- 23102334 TI - Modification of late-time phase structure by quantum quenches. AB - The consequences of the sudden change in the coupling constants (quenches) on the phase structure of the theory at late times are explored. We study in detail the three-dimensional phi6 model in the large-N limit and show that the phi6 coupling enjoys a widened range of stability compared to the static scenario. Moreover, a new massive phase emerges, which for sufficiently large coupling becomes the dominant vacuum. We argue that these novel phenomena cannot be described by a simple thermalization effect or the emergence of a single effective temperature. PMID- 23102335 TI - Unbinding of giant vortices in states of competing order. AB - We consider a two-dimensional system with two order parameters, one with O(2) symmetry and one with O(M), near a point in parameter space where they couple to become a single O(2+M) order. While the O(2) sector supports vortex excitations, these vortices must somehow disappear as the high symmetry point is approached. We develop a variational argument which shows that the size of the vortex cores diverges as 1/?Delta and the Berezinskii-Kosterlitz-Thouless transition temperature of the O(2) order vanishes as 1/ln(1/Delta), where Delta denotes the distance from the high-symmetry point. Our physical picture is confirmed by a renormalization group analysis which gives further logarithmic corrections, and demonstrates full symmetry restoration within the cores. PMID- 23102336 TI - Effect of polydispersity on diffusion in random obstacle matrices. AB - The dynamics of tracers in disordered matrices is of interest in a number of diverse areas of physics such as the biophysics of crowding in cells and cell membranes, and the diffusion of fluids in porous media. To a good approximation the matrices can be modeled as a collection of spatially frozen particles. In this Letter, we consider the effect of polydispersity (in size) of the matrix particles on the dynamics of tracers. We study a two dimensional system of hard disks diffusing in a sea of hard disk obstacles, for different values of the polydispersity of the matrix. We find that for a given average size and area fraction, the diffusion of tracers is very sensitive to the polydispersity. We calculate the pore percolation threshold using Apollonius diagrams. The diffusion constant, D, follows a scaling relation D~(phi(c)-phi(m))(MU-beta) for all values of the polydispersity, where phi(m) is the area fraction and phi(c) is the value of phi(m) at the percolation threshold. PMID- 23102337 TI - Anomalous smoothing preceding island formation during growth on patterned substrates. AB - We show that on suitably pit-patterned Si(001), deposition of just a few atomic layers of Ge can trigger a far larger flow of Si into the pits. This surprising effect results in anomalous smoothing of the substrate preceding island formation in the pits. We show that the effect naturally arises in continuum simulations of growth, and we identify its physical origin in the composition dependence of the surface diffusivity. Our interpretation suggests that anomalous smoothing is likely to also occur in other technologically relevant heteroepitaxial systems. PMID- 23102338 TI - Mixing-induced anisotropic correlations in molecular crystalline systems. AB - We investigate the structure of mixed thin films composed of pentacene and diindenoperylene using x-ray reflectivity and grazing incidence x-ray diffraction. For equimolar mixtures we observe vanishing in-plane order coexisting with an excellent out-of-plane order, a yet unreported disordering behavior in binary mixtures of organic semiconductors, which are crystalline in their pure form. One approach to rationalize our findings is to introduce an anisotropic interaction parameter in the framework of a mean field model. By comparing the structural properties with those of other mixed systems, we discuss the effects of sterical compatibility and chemical composition on the mixing behavior, which adds to the general understanding of interactions in molecular mixtures. PMID- 23102339 TI - Thermodynamic relation between voltage-concentration dependence and salt adsorption in electrochemical cells. AB - Electrochemical cells containing two electrodes dipped in an ionic solution are widely used as charge accumulators, either with polarizable (supercapacitor) or nonpolarizable (battery) electrodes. Recent applications include desalination ("capacitive deionization") and energy extraction from salinity differences ("capacitive mixing"). In this Letter, we analyze a general relation between the variation of the electric potential as a function of the concentration and the salt adsorption. This relation comes from the evaluation of the electrical and mechanical energy exchange along a reversible cycle, which involves salt adsorption and release by the electrodes. The obtained relation thus describes a connection between capacitive deionization and capacitive mixing. We check this relation with experimental data already reported in the literature, and moreover by some classical physical models for electrodes, including polarizable and nonpolarizable electrodes. The generality of the relation makes it very useful in the study of the properties of the electric double layer. PMID- 23102340 TI - Tuning the area percentage of reactive surface of TiO2 by strain engineering. AB - Surfaces with high reactivity usually have a low area percentage, which greatly limits the efficiency of surface reactivity. In this Letter we demonstrate a generic way of increasing the percentage of the highly reactive surface by using external strain. Bulk and surface elastic properties of TiO2 are studied via density functional theory calculations. The equilibrium shape of anatase TiO2 under applied strain is discussed based on the elastic properties. We find that when 5% compressive strain is applied biaxially along [100] and [010]; directions, the area percentage of the anatase (001) surface can be increased by ~5 times in comparison with the case when no strain is applied. Since the moderate strain does not introduce extrinsic defects into the material, we propose that it is an ideal way to increase the reactivity of titanium dioxide crystallites by applying biaxial compressive external strain along the a axis. PMID- 23102341 TI - Scanning tunneling microscopy contrast mechanisms for TiO2. AB - Controlled dual mode scanning tunneling microscopy (STM) experiments and first principles simulations show that the tunneling conditions can significantly alter the positive-bias topographic contrast of geometrically corrugated titania surfaces such as rutile TiO2(011)-(2*1). Depending on the tip-surface distance, two different contrasts can be reversibly imaged. STM simulations which either include or neglect the tip-electronic structure, carried out at three density functional theory levels of increasing accuracy, allow assignment of both contrasts on the basis of the TiO2(011)-(2*1) structure proposed by Torrelles et al. [Phys. Rev. Lett. 101, 185501 (2008)]. Finally, the mechanisms of contrast formation are elucidated in terms of the subtle balance between the surface geometry and the different vacuum decay lengths of the topmost Ti(3d) and O(2p) states probed by the STM-tip apex. PMID- 23102342 TI - Spin-flip transitions induced by time-dependent electric fields in surfaces with strong spin-orbit interaction. AB - We present a comprehensive theoretical investigation of the light absorption rate at a Pb/Ge(111)-beta?3 * ?3R30 degrees surface with strong spin-orbit coupling. Our calculations show that electron spin-flip transitions cause as much as 6% of the total light absorption, representing 1 order of magnitude enhancement over Rashba-like systems. Thus, we demonstrate that a substantial part of the light irradiating this nominally nonmagnetic surface is attenuated in spin-flip processes. Remarkably, the spin-flip transition probability is structured in well defined hot spots within the Brillouin zone, where the electron spin experiences a sudden 90 degrees rotation. This mechanism offers the possibility of an experimental approach to the spin-orbit phenomena by optical means. PMID- 23102343 TI - Site-selective Mott transition in rare-earth-element nickelates. AB - A combination of density functional and dynamical mean field theory calculations are used to show that the remarkable metal-insulator transition in the rare-earth element nickelate perovskites arises from a site-selective Mott phase, in which the d electrons on half of the Ni ions are localized to form a fluctuating moment while the d electrons on other Ni ions form a singlet with holes on the surrounding oxygen ions. The calculation reproduces key features observed in the nickelate materials, including an insulating gap in the paramagnetic state, a strong variation of static magnetic moments among Ni sites and an absence of charge order. A connection between structure and insulating behavior is documented. The site-selective Mott transition may be a more broadly applicable concept in the description of correlated materials. PMID- 23102344 TI - Conductivity close to antiferromagnetic criticality. AB - We study the conductivity of a three-dimensional disordered metal close to antiferromagnetic instability within the framework of the spin-fermion model using the diagrammatic technique. We calculate the interaction correction deltasigma(omega,T) to the conductivity, assuming that the latter is dominated by the disorder scattering, and the interaction is weak. Although the fermionic scattering rate shows critical behavior on the entire Fermi surface, the interaction correction is dominated by the processes near the hot spots, narrow regions of the Fermi surface corresponding to the strongest spin-fermion scattering. Exactly at the critical point deltasigma is proportional to [max(omega,T)](3/2). At sufficiently large frequencies omega the conductivity is independent of the temperature, and deltasigma is proportional to (tau(-1) iomega)(-2), tau being the elastic scattering time. In a certain intermediate frequency range deltasigma(omega) is proportional to iomega(tau(-1)-iomega)(-2). PMID- 23102345 TI - Nonequilibrium propagation and decay of a bound pair in driven t-J models. AB - We perform an accurate time-dependent numerical study of an out-of-equilibrium response of a bound state within t-J systems on a two-leg ladder and a square lattice. We show that the bound hole pair decays with the onset of finite steady current if both mechanisms for binding and the dissipation share matching degrees of freedom. Moreover, by investigating the mechanism of decay on the square lattice we find that the dynamics is governed by the decay in the direction perpendicular to the electric field, leading to much shorter decay times in comparison to the ladder where such dynamics is topologically restricted. PMID- 23102346 TI - Thermoelectric response near a quantum critical point of beta-YbAlB4 and YbRh2Si2: a comparative study. AB - The thermoelectric coefficients have been measured down to a very low temperature for the Yb-based heavy-fermion compounds beta-YbAlB4 and YbRh2Si2, often considered as model systems for the local quantum criticality case. We observe a striking difference in the behavior of the Seebeck coefficient S in the vicinity of their respective quantum critical point (QCP). Approaching the critical field, S/T is enhanced in beta-YbAlB4, but drastically reduced in YbRh2Si2. The ratio of thermopower to specific heat remains constant for beta-YbAlB4, but it is significantly reduced near the QCP in YbRh2Si2. In both systems, on the other hand, the Nernst coefficient shows a diverging behavior near the QCP. The interplay between valence and magnetic quantum criticality and the additional possibility of a Lifshitz transition crossing the critical field under magnetic field are discussed as the origin of the different behaviors of these compounds. PMID- 23102347 TI - Enhanced screening in chemically functionalized graphene. AB - Resonant scatterers such as hydrogen adatoms can strongly enhance the low-energy density of states in graphene. Here, we study the impact of these impurities on electronic screening. We find a two-faced behavior: Kubo formula calculations reveal an increased dielectric function epsilon upon creation of midgap states but no metallic divergence of the static epsilon at small momentum transfer q->0. This bad metal behavior manifests also in the dynamic polarization function and can be directly measured by means of electron energy loss spectroscopy. A new length scale l(c) beyond which screening is suppressed emerges, which we identify with the Anderson localization length. PMID- 23102348 TI - Giant spin Hall effect induced by skew scattering from bismuth impurities inside thin film CuBi alloys. AB - We demonstrate that a giant spin Hall effect (SHE) can be induced by introducing a small amount of Bi impurities in Cu. Our analysis, based on a new three dimensional finite element treatment of spin transport, shows that the sign of the SHE induced by the Bi impurities is negative and its spin Hall (SH) angle amounts to -0.24. Such a negative large SH angle in CuBi alloys can be explained by applying the resonant scattering model proposed by Fert and Levy [Phys. Rev. Lett. 106, 157208 (2011)] to 6p impurities. PMID- 23102349 TI - Spontaneous quantum Hall effect via a thermally induced quadratic Fermi point. AB - Gapless electronic systems containing topologically nontrivial Fermi points are sources of various topological insulators. Whereas, most of these special band crossing points are built in the electronic structure of the noninteracting lattice models, we show that a quadratic Fermi point characterized by a nonzero winding number emerges with a collinear triple-Q spin-density-wave state that arises from a perfectly nested but topologically trivial Fermi surface. We obtain a universal low-energy Hamiltonian for the quadratic Fermi point and show that such collinear orderings are unstable against the onset of scalar spin chirality that opens a gap and induces a spontaneous quantum Hall insulator as the temperature tends to zero. PMID- 23102350 TI - Coupling of Josephson currents in quantum Hall bilayers. AB - We study ring-shaped (Corbino) devices made of bilayer two-dimensional electron gases in the total filling factor one quantized Hall phase, which is considered to be a coherent Bardeen-Cooper-Schrieffer-like state of interlayer excitons. Identical Josephson currents are observed at the two edges while only a negligible conductance between them is found. The maximum Josephson current observed at either edge can be controlled by passing a second interlayer Josephson current at the other edge. Because of the large electric resistance between the two edges, the interaction between them can only be mediated by the neutral interlayer excitonic ground state. PMID- 23102351 TI - Topological Kondo effect with Majorana fermions. AB - The Kondo effect is a striking consequence of the coupling of itinerant electrons to a quantum spin with degenerate energy levels. While degeneracies are commonly thought to arise from symmetries or fine-tuning of parameters, the recent emergence of Majorana fermions has brought to the fore an entirely different possibility: a topological degeneracy that arises from the nonlocal character of Majorana fermions. Here we show that nonlocal quantum spins formed from these degrees of freedom give rise to a novel topological Kondo effect. This leads to a robust non-Fermi liquid behavior, known to be difficult to achieve in the conventional Kondo context. Focusing on mesoscopic superconductor devices, we predict several unique transport signatures of this Kondo effect, which would demonstrate the nonlocal quantum dynamics of Majorana fermions and validate their potential for topological quantum computation. PMID- 23102352 TI - Tunable Kondo physics in a carbon nanotube double quantum dot. AB - We investigate a tunable two-impurity Kondo system in a strongly correlated carbon nanotube double quantum dot, accessing the full range of charge regimes. In the regime where both dots contain an unpaired electron, the system approaches the two-impurity Kondo model. At zero magnetic field the interdot coupling disrupts the Kondo physics and a local singlet state arises, but we are able to tune the crossover to a Kondo screened phase by application of a magnetic field. All results show good agreement with a numerical renormalization group study of the device. PMID- 23102353 TI - High-Tc nodeless s+/--wave superconductivity in (Y,La)FeAsO(1-y) with Tc=50 K:75As-NMR study. AB - We report on an (75)As-NMR study on the Fe-pnictide high-T(c) superconductor Y(0.95)La(0.05)FeAsO(1-y) (Y(0.95)La(0.05)1111) with T(c)=50 K that includes no magnetic rare-earth elements. The measurement of the nuclear-spin lattice relaxation rate (75)(1/T(1)) has revealed that the nodeless bulk superconductivity takes place at T(c)=50 K while antiferromagnetic spin fluctuations develop moderately in the normal state. These features are consistently described by the multiple fully gapped s(+/-)-wave model based on the Fermi-surface nesting. Incorporating the theory based on band calculations, we propose that the reason that T(c)=50 K in Y(0.95)La(0.05)1111 is larger than T(c)=28 K in La1111 is that the Fermi-surface multiplicity is maximized, and hence the Fermi-surface nesting condition is better than that in La1111. PMID- 23102354 TI - Near-unity Cooper pair splitting efficiency. AB - The two electrons of a Cooper pair in a conventional superconductor form a spin singlet and therefore a maximally entangled state. Recently, it was demonstrated that the two particles can be extracted from the superconductor into two spatially separated contacts via two quantum dots in a process called Cooper pair splitting (CPS). Competing transport processes, however, limit the efficiency of this process. Here we demonstrate efficiencies up to 90%, significantly larger than required to demonstrate interaction-dominated CPS, and on the right order to test Bell's inequality with electrons. We compare the CPS currents through both quantum dots, for which large apparent discrepancies are possible. The latter we explain intuitively and in a semiclassical master equation model. Large efficiencies are required to detect electron entanglement and for prospective electronics-based quantum information technologies. PMID- 23102355 TI - Magnetic ordering and structural phase transitions in a strained ultrathin SrRuO3/SrTiO3 superlattice. AB - Ruthenium-based perovskite systems are attractive because their structural, electronic, and magnetic properties can be systematically engineered. The SrRuO3/SrTiO3 superlattice, with its period consisting of one unit cell each, is very sensitive to strain change. Our first-principles simulations reveal that, in the high tensile strain region, it transits from a ferromagnetic metal to an antiferromagnetic insulator with clear tilted octahedra, while in the low strain region, it is a ferromagnetic metal without octahedra tilting. Detailed analyses of three spin-down Ru-t(2g) orbitals just below the Fermi level reveal that the splitting of these orbitals underlies these dramatic phase transitions, with the rotational force constant of RuO(6) octahedron high up to 16 meV/Deg(2), 4 times larger than that of TiO(6). Differently from nearly all the previous studies, these transitions can be probed optically through the diagonal and off-diagonal dielectric tensor elements. For a 1% change in strain, our experimental spin moment change is -0.14+/-0.06 MU(B), quantitatively consistent with our theoretical value of -0.1 MU(B). PMID- 23102356 TI - Predicted suppression of the superconducting transition of new high-pressure yttrium phases with increasing pressure from first-principles calculations. AB - Structure searches for new high-pressure phases of Y metal have been performed by using evolutionary algorithms in conjunction with a first-principles, pseudopotential plane-wave method based on density functional theory. The oF16 Fddd and hP3-P3(1)21 phases are predicted to be energetically favorable at pressures over 97 GPa. These two phases are shown to be dynamically stable by computing their phonon dispersions. We thus propose that oF16-Fddd and hP3 P3(1)21 are the most probable crystal structures Y may take in the 97-206 GPa range. The superconducting critical temperatures (T(c)) of the new phases are estimated using the Allen-Dynes formula. The T(c) is predicted to decrease with increasing pressure over about 100 GPa, in sharp contrast to its observed monotonic increase under lower pressure. The electronic origins of the stabilities of the proposed high-pressure phases have also been investigated. PMID- 23102357 TI - Internal loss of superconducting resonators induced by interacting two-level systems. AB - In a number of recent experiments with microwave high quality superconducting coplanar waveguide resonators an anomalously weak power dependence of the quality factor has been observed. We argue that this observation implies that the monochromatic radiation does not saturate the two level systems (TLS) located at the interface oxide surfaces of the resonator and suggests the importance of their interactions. We estimate the microwave loss due to interacting TLS and show that the interactions between TLS lead to a drift of their energies that result in a much slower, logarithmic dependence of their absorption on the radiation power in agreement with the data. PMID- 23102358 TI - Anomalous upper critical field in CeCoIn5/YbCoIn5 superlattices with a Rashba type heavy Fermion interface. AB - We report a highly unusual angular variation of the upper critical field (H(c2)) in epitaxial superlattices CeCoIn(5)(n)/YbCoIn(5)(5), formed by alternating layers of n and a 5 unit-cell thick heavy-fermion superconductor CeCoIn(5) with a strong Pauli effect and normal metal YbCoIn(5), respectively. For the n=3 superlattice, H(c2)(theta) changes smoothly as a function of the field angle theta. However, close to the superconducting transition temperature, H(c2)(theta) exhibits a cusp near the parallel field (theta=0 degrees ). This cusp behavior disappears for n=4 and 5 superlattices. This sudden disappearance suggests the relative dominance of the orbital depairing effect in the n=3 superlattice, which may be due to the suppression of the Pauli effect in a system with local inversion symmetry breaking. Taking into account the temperature dependence of H(c2)(theta) as well, our results suggest that some exotic superconducting states, including a helical superconducting state, might be realized at high magnetic fields. PMID- 23102359 TI - Microscopic model for ultrafast remagnetization dynamics. AB - In this Letter, we provide a microscopic model for the ultrafast remagnetization of atomic moments already quenched above the Stoner-Curie temperature by a strong laser fluence. Combining first-principles density functional theory, atomistic spin dynamics utilizing the Landau-Lifshitz-Gilbert equation, and a three temperature model, we analyze the temporal evolution of atomic moments as well as the macroscopic magnetization of bcc Fe and hcp Co covering a broad time scale, ranging from femtoseconds to picoseconds. Our simulations show a variety of complex temporal behavior of the magnetic properties resulting from an interplay between electron, spin, and lattice subsystems, which causes an intricate time evolution of the atomic moment, where longitudinal and transversal fluctuations result in a macrospin moment that evolves highly nonmonotonically. PMID- 23102360 TI - Tuning the disorder in superglasses. AB - We study the interplay of superfluidity, glassy, and magnetic orders in the XXZ model with random Ising interactions on a three dimensional cubic lattice. In the classical limit, this model reduces to a +/-J Edwards-Anderson Ising model with concentration p of ferromagnetic bonds, which hosts a glassy-ferromagnetic transition at a critical concentration p(c)(cl)~0.77. Our quantum Monte Carlo simulation results show that quantum fluctuations stabilize the coexistence of superfluidity and glassy order (superglass), and shift the (super)glassy ferromagnetic transition to p(c)>p(c)(cl). In contrast, antiferromagnetic order coexists with superfluidity to form a supersolid, and the transition to the glassy phase occurs at a higher p. PMID- 23102361 TI - Imprinting magnetic information in manganites with x rays. AB - The effect of x rays on an orbital and charge ordered epitaxial film of a Pr0.5Ca0.5MnO3 is presented. As the film is exposed to x rays, the antiferromagnetic response increases and concomitantly the conductivity of the film improve. These results are discussed in terms of a persistent x-ray induced doping, leading to a modification of the magnetic structure. This effect allows writing electronic and magnetic information in the film and represents a novel way of manipulating magnetism. PMID- 23102362 TI - Evolution of magnetic oxygen states in Sr-doped LaCoO3. AB - Magnetism in La(1-x)Sr(x)CoO(3) as a function of doping is investigated with x ray absorption spectroscopy and x-ray magnetic circular dicrhoism at the O K edge, and corresponding first principles electronic structure calculations. For small x, the spectra are consistent with the formation of ferromagnetic clusters occurring within a nonmagnetic insulating matrix. Sr-induced, magnetic O-hole states form just above E(F) and grow with increasing Sr doping. Density functional calculations for x=0 yield a nonmagnetic ground state with the observed rhombohedral distortion and indicates that doping introduces holes at the Fermi level in magnetic states with significant O 2p and Co t(2g) character for the undistorted pseudocubic structure. Supercell calculations show stronger magnetism on oxygen atoms having more Sr neighbors. PMID- 23102363 TI - Super-rough glassy phase of the random field XY model in two dimensions. AB - We study both analytically, using the renormalization group (RG) to two loop order, and numerically, using an exact polynomial algorithm, the disorder-induced glass phase of the two-dimensional XY model with quenched random symmetry breaking fields and without vortices. In the super-rough glassy phase, i.e., below the critical temperature T(c), the disorder and thermally averaged correlation function B(r) of the phase field theta(x), B(r)=([theta(x) theta(x+r)](2)) behaves, for r >> a, as B(r) is approximately equal to A(tau)ln(2)(r/a) where r=|r| and a is a microscopic length scale. We derive the RG equations up to cubic order in tau=(T(c)-T)/T(c) and predict the universal amplitude A(tau)=2tau(2)-2tau(3)+O(tau(4)). The universality of A(tau) results from nontrivial cancellations between nonuniversal constants of RG equations. Using an exact polynomial algorithm on an equivalent dimer version of the model we compute A(tau) numerically and obtain a remarkable agreement with our analytical prediction, up to tau~0.5. PMID- 23102364 TI - Magnetism in parent iron chalcogenides: quantum fluctuations select plaquette order. AB - We analyze magnetic order in Fe chalcogenide Fe(1+y)Te, the parent compound of the high-temperature superconductor Fe(1+y)Te(1-x)Se(x). Experiments show that magnetic order in this material contains components with momentum Q(1)=(pi/2,pi/2) and Q(2)=(pi/2,-pi/2) in the Fe only Brillouin zone. The actual spin order depends on the interplay between these two components. Previous works assumed that the ordered state has a single Q (either Q(1) or Q(2)). In such a state, spins form double stripes along one of the diagonals breaking the rotational C(4) symmetry. We show that quantum fluctuations actually select another order-a double Q plaquette state with equal weight of Q(1) and Q(2) components, which preserves C(4) symmetry. We argue that the order in Fe(1+y)Te is determined by the competition between quantum fluctuations and magnetoelastic coupling. PMID- 23102365 TI - High-temperature magnetic insulating phase in ultrathin La0.67Sr0.33MnO3 films. AB - We present a study of the thickness dependence of magnetism and electrical conductivity in ultrathin La0.67Sr0.33MnO3 films grown on SrTiO3 (110) substrates. We found a critical thickness of 10 unit cells below which the conductivity of the films disappeared and simultaneously the Curie temperature increased, indicating a magnetic insulating phase at room temperature. These samples have a Curie temperature of about 560 K with a significant saturation magnetization of 1.2+/-0.2MU(B)/Mn. The canted antiferromagnetic insulating phase in ultra thin films of n<10 coincides with the occurrence of a higher symmetry structural phase with a different oxygen octahedra rotation pattern. Such a strain engineered phase is an interesting candidate for an insulating tunneling barrier in room temperature spin polarized tunneling devices. PMID- 23102366 TI - Testing the validity of the strong spin-orbit-coupling limit for octahedrally coordinated iridate compounds in a model system Sr3CuIrO6. AB - The electronic structure of Sr3CuIrO6, a model system for the 5d Ir ion in an octahedral environment, is studied through a combination of resonant inelastic x ray scattering and theoretical calculations. Resonant inelastic x-ray scattering spectra at the Ir L3 edge reveal an Ir t(2g) manifold that is split into three levels, in contrast to the expectations of the strong spin-orbit-coupling limit. Effective Hamiltonian and ab inito quantum chemistry calculations find a strikingly large noncubic crystal field splitting comparable to the spin-orbit coupling, which results in a strong mixing of the j(eff)=1/2 and j(eff)=3/2 states and modifies the isotropic wave functions on which many theoretical models are based. PMID- 23102367 TI - Large spin-wave energy gap in the bilayer iridate Sr3Ir2O7: evidence for enhanced dipolar interactions near the mott metal-insulator transition. AB - Using resonant inelastic x-ray scattering, we observe in the bilayer iridate Sr3Ir2O7, a spin-orbit coupling driven magnetic insulator with a small charge gap, a magnon gap of ~92 meV for both acoustic and optical branches. This exceptionally large magnon gap exceeds the total magnon bandwidth of ~70 meV and implies a marked departure from the Heisenberg model, in stark contrast to the case of the single-layer iridate Sr2IrO4. Analyzing the origin of these observations, we find that the giant magnon gap results from bond-directional pseudodipolar interactions that are strongly enhanced near the metal-insulator transition boundary. This suggests that novel magnetism, such as that inspired by the Kitaev model built on the pseudodipolar interactions, may emerge in small charge-gap iridates. PMID- 23102368 TI - Magnetic-field control of photon echo from the electron-trion system in a CdTe quantum well: shuffling coherence between optically accessible and inaccessible states. AB - We report on magnetic field-induced oscillations of the photon echo signal from negatively charged excitons in a CdTe/(Cd,Mg)Te semiconductor quantum well. The oscillatory signal is due to Larmor precession of the electron spin about a transverse magnetic field and depends sensitively on the polarization configuration of the exciting and refocusing pulses. The echo amplitude can be fully tuned from the maximum down to zero depending on the time delay between the two pulses and the magnetic-field strength. The results are explained in terms of the optical Bloch equations accounting for the spin level structure of electrons and trions. PMID- 23102369 TI - Optical generation of collective plasmon modes in small gold chains induced by doping transition-metal impurities. AB - Our examination of the optical properties of small gold chains containing up to 24 atoms doped with a transition metal (TM) atom (Ni, Rh, Fe), using the time dependent density functional theory, show the splitting of the collective plasmon peak. We associate the additional peak with a local plasmonic mode which corresponds to charge oscillations around the potential created by the d orbitals of the impurity atoms. The effect is almost independent of the position of the TM atom in the chain, as long as it is not at the chain edge. This behavior is opposite to that of larger noble-metal-TM clusters (radius >1 nm), in which doping with TM atoms does not lead to generation of new modes, and often produces a suppression of the main plasmon peak. PMID- 23102370 TI - Twisting transition between crystalline and fibrillar phases of aggregated peptides. AB - We study two distinctly ordered condensed phases of polypeptide molecules, amyloid fibrils and amyloidlike microcrystals, and the first-order twisting phase transition between these two states. We derive a single free-energy form which connects both phases. Our model identifies relevant degrees of freedom for describing the collective behavior of supramolecular polypeptide structures, reproduces accurately the results from molecular dynamics simulations as well as from experiments, and sheds light on the uniform nature of the dimensions of different peptide fibrils. PMID- 23102371 TI - Ultrasound induces aging in granular materials. AB - Aging and rejuvenation have been identified as the general mechanisms that rule the time evolution of granular materials subjected to some external confinement pressure. In creep experiments performed in a triaxial configuration, we obtained evidence that relatively high intensity ultrasound waves propagating through the material induce both weakening and significant plasticity. In the framework of glassy materials, it is shown that the effect of ultrasound can be simply accounted for by a general variable, the fluidity, whose dynamics are described by an effective aging parameter that strongly decreases with sound amplitude and vanishes at the yield stress limit. The response from step perturbations in ultrasound intensity provided a method to assess the effective-viscosity jumps which are direct evidence of acoustic fluidization. PMID- 23102372 TI - Autonomous motility of active filaments due to spontaneous flow-symmetry breaking. AB - We simulate the nonlocal Stokesian hydrodynamics of an elastic filament which is active due a permanent distribution of stresslets along its contour. A bending instability of an initially straight filament spontaneously breaks flow symmetry and leads to autonomous filament motion which, depending on conformational symmetry, can be translational or rotational. At high ratios of activity to elasticity, the linear instability develops into nonlinear fluctuating states with large amplitude deformations. The dynamics of these states can be qualitatively understood as a superposition of translational and rotational motion associated with filament conformational modes of opposite symmetry. Our results can be tested in molecular-motor filament mixtures, synthetic chains of autocatalytic particles, or other linearly connected systems where chemical energy is converted to mechanical energy in a fluid environment. PMID- 23102373 TI - From networks to time series. AB - In this Letter, we propose a framework to transform a complex network to a time series. The transformation from complex networks to time series is realized by the classical multidimensional scaling. Applying the transformation method to a model proposed by Watts and Strogatz [Nature (London) 393, 440 (1998)], we show that ring lattices are transformed to periodic time series, small-world networks to noisy periodic time series, and random networks to random time series. We also show that these relationships are analytically held by using the circulant-matrix theory and the perturbation theory of linear operators. The results are generalized to several high-dimensional lattices. PMID- 23102374 TI - Calpain 1 knockdown improves tissue sparing and functional outcomes after spinal cord injury in rats. AB - To evaluate the hypothesis that calpain 1 knockdown would reduce pathological damage and functional deficits after spinal cord injury (SCI), we developed lentiviral vectors encoding calpain 1 shRNA and eGFP as a reporter (LV-CAPN1 shRNA). The ability of LV-CAPN1 shRNA to knockdown calpain 1 was confirmed in rat NRK cells using Northern and Western blot analysis. To investigate the effects on spinal cord injury, LV-CAPN1shRNA or LV-mismatch control shRNA (LV-control shRNA) were administered by convection enhanced diffusion at spinal cord level T10 in Long-Evans female rats (200-250 g) 1 week before contusion SCI, 180 kdyn force, or sham surgery at the same thoracic level. Intraspinal administration of the lentiviral particles resulted in transgene expression, visualized by eGFP, in spinal tissue at 2 weeks after infection. Calpain 1 protein levels were reduced by 54% at T10 2 weeks after shRNA-mediated knockdown (p<0.05, compared with the LV-control group, n=3 per group) while calpain 2 levels were unchanged. Intraspinal administration of LV-CAPN1shRNA 1 week before contusion SCI resulted in a significant improvement in locomotor function over 6 weeks postinjury, compared with LV-control administration (p<0.05, n=10 per group). Histological analysis of spinal cord sections indicated that pre-injury intraspinal administration of LV-CAPN1shRNA significantly reduced spinal lesion volume and improved total tissue sparing, white matter sparing, and gray matter sparing (p<0.05, n=10 per group). Together, results support the hypothesis that calpain 1 activation contributes to the tissue damage and impaired locomotor function after SCI, and that calpain1 represents a potential therapeutic target. PMID- 23102375 TI - Effects of ginsenoside Re on LPS-induced inflammatory mediators in BV2 microglial cells. AB - BACKGROUND: Microglial activation plays an important role in neurodegenerative diseases by producing several pro-inflammatory enzymes and pro-inflammatory cytokines. Lipopolysaccharide (LPS)-induced inflammation leads to the activation of microglial cells in the central nervous system (CNS) and is associated with the pathological mechanisms of neurodegenerative diseases, including PD, AD, and ALS. Ginseng is a natural antioxidant used in herbal medicine and contains ginsenosides (Rb1, Rg1, Rg3, Re, and Rd), which have anti-neoplastic and anti stress properties.This study demonstrates the involvement of the anti inflammatory signaling pathway, ginsenoside-Re (G-Re), which is one of the ginsenosides mediated by LPS-induced neuroinflammation in BV2 microglial cells. METHODS: BV2 microglial cells were pretreated with 2 MUg/ml G-Re and stimulated with 1 MUg/ml LPS to induce neuroinflammation. To investigate the effect of G-Re on LPS-induced cell signaling, we performed western blotting and immunofluorescence using specific antibodies, such as phospho-p38, COX2, and iNOS. RESULTS: Pretreatment with 2 MUg/ml G-Re was neuroprotective against 1 MUg/ml LPS-treated microglial cells. The neuroprotective events induced by G-Re treatment in neuroinflammation occurred via the phospho-p38, iNOS, and COX2 signaling pathways in BV2 cells. CONCLUSION: Taken together, we suggest that G-Re exerts a beneficial effect on neuroinflammatory events in neurodegenerative diseases. PMID- 23102377 TI - Theoretical study of the binding of silane (SiH4) with borane (BH3), diborane (B2H6), and boron trichloride (BCl3): the role of core-electron correlation. AB - Equilibrium structures and energies of gas-phase molecular complexes SiH(4)...BH(3), SiH(4)...B(2)H(6), and SiH(4)...BCl(3) were determined using second-order Moller-Plesset perturbation theory (MP2) and the aug-cc-pVTZ basis set, with and without explicit core electron correlation. Single-point energies were calculated for the MP2-optimized structures using MP2 with the aug-cc-pVQZ basis set and using coupled cluster theory (CCSD(T)) with both the aug-cc-pVTZ and the aug-cc-pVQZ basis sets to extrapolate to the complete basis set (CBS). Partition functions were calculated using the harmonic oscillator/rigid rotorapproximation at the MP2/aug-cc-pVTZ level of theory. The explicit core electron correlation is demonstrated to have significant impact on the structures and binding energies and binding enthalpies of these complexes. The binding enthalpies were obtained at various temperatures ranging from 0 K to the dissociation temperatures of the complexes. The potential energy surfaces of the three complexes were explored, and no transition states were found along the pathways from separated species to the complexes. PMID- 23102376 TI - Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer. AB - INTRODUCTION: Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and phosphorylated ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer. METHODS: Primary tumors were collected from 190 patients with Stage I to III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays. Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed. RESULTS: High eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node positivity. Median follow-up for living patients was 96 months. CONCLUSIONS: Increased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer, suggesting their role as prognostic markers and therapeutic targets. PMID- 23102379 TI - Population-based versus high-risk strategies for the prevention of cardiovascular diseases in low- and middle-income countries. AB - Cardiovascular diseases (CVD) are now the number one cause of death in low- and middle-income countries (LMIC), such as those in South East Asia (SEA). It is projected that SEA countries will have the greatest total number of deaths due to non-communicable diseases (NCDs) by 2020. In low resource countries, the rising burden of CVDs imposes severe economic consequences that range from impoverishment of families to high health system costs and the weakening of country economies. There are two possible options to be considered for addressing this issue: a "population-based strategy" and/or a "high risk" strategy. The question is, what is the optimal way to reduce the excessive burden of these diseases in the LMICs. We believe that by applying systematic policy and smoking cessation programs with proven effectiveness, there is a chance that the high smoking prevalence, particularly among SEA. PMID- 23102380 TI - Safety and efficacy of bivalirudin with glycoprotein IIb/IIIa for high-risk percutaneous coronary intervention. AB - AIMS: The aim of the study was to assess the safety and efficacy of bivalirudin + glycoprotein (Gp) IIb/IIIa inhibitor as compared to unfractionated heparin (UFH) + Gp IIb/IIIa inhibitor in high risk patients undergoing elective percutaneous coronary intervention (PCI). The primary end point was time to sheath removal and ambulation where as peri-procedure myocardial damage, access site bleeding and major adverse cardiac events (MACE) rates were secondary end points. METHODS: One hundred and one high risk patients undergoing elective PCI were randomly assigned to either bivalirudin + GpIIb/IIIa inhibitor or UFH + Gp IIb/IIIa inhibitor. PCI was performed by standard technique and activated clotting time was monitored immediately on arrival to recovery area and every 60 min thereafter. Sheath were pulled out once ACT was below 150 seconds and patients were mobilized 6hrs after sheath were removed. Peri-procedure myocardial damage was assessed by serial Trop I levels. RESULTS: Patient assigned to bivalirudin + tirofiban has significantly reduced time to sheath removal and ambulation as compared to those who received UFH + tirofiban (p < 0.0001) although peak Act did not differ in the groups. Peak Trop I levels were significantly lower in bivalirudin + tirofiban group (p = 0.023) and peri-procedure Trop I elevation occurred in significantly lower number of patients treated with bivalirudin + tirofiban (p = 0.029). CONCLUSIONS: The combination of bivalirudin + tirofiban was safe and effective as compared to UFH + tirofiban in high risk patients undergoing elective PCI. PMID- 23102381 TI - Bivalirudin: the relevance in today's interventional practice. PMID- 23102382 TI - The 'all comer' Coroflex Please drug-eluting stent registry in Europe and Asia - an overall and transcontinental assessment of the 10-month major adverse cardiac events. AB - BACKGROUND: Randomized trials assess the potential of a medical device in well defined indications while "all comer studies" reveal the device performance in the real clinical environment. AIMS: This 'all comers' registry assessed the 10 month outcome of the Coroflex((r)) Please drug-eluting stent in Europe and Asia by clinically driven major adverse cardiac events. METHODS: The Coroflex((r)) Please Registry was an international, prospective, multicenter registry enrolling patients with symptomatic ischemic heart disease. The primary endpoint was clinically driven target lesion revascularization (TLR) at 9 months. Secondary endpoints were technical success, in-hospital outcomes, definite stent thrombosis and major adverse cardiac events (death, myocardial infarction, or TLR) for subgroup analyses. RESULTS: Of the enrolled 1230 patients (63.6 +/- 11.2 years, 33.9% diabetics), 339 (27.6%) had an acute coronary syndrome, 148 (12.1%) STEMI and 191 (15.6%) NSTEMI. After 10.5 +/- 3.8 months (follow-up rate 92.8%), the target lesion revascularization rate (TLR) was 7.8% overall, 8.3% in STEMI, and 11.3% in NSTEMI patients. Total MACE was 11.1% and significantly higher in ACS with either diabetes mellitus (22.9%, p = 0.017) or age >=75 years (25.4%, p = 0.026). In European and Asian patients MI rates (5.2% vs 3.1%, p = 0.135) and cardiac death rates (1.6% vs 0.9%, p = 0.414) were similar. The MACE rate was higher in Europe (13.6% vs 4.7%, p < 0.001) driven by a six times higher TLR rate. CONCLUSIONS: TLR and MACE occurred within the range of previously published data. The incidence of MI and cardiac death were not different between Europe and Asia. MACE were higher in Europe driven by target lesion revascularization. PMID- 23102383 TI - Effect of percutaneous mitral balloon valvuloplasty on left atrial appendage function: transesophageal echo study. AB - BACKGROUND: To compare left atrial appendage (LAA) function by Doppler and Doppler tissue imaging (DTI) before and after percutaneous balloon mitral valvuloplasty (PBMV). MATERIALS AND METHODS: Fifty-nine patients with symptomatic rheumatic mitral stenosis who underwent PBMV were included in this study. LAA function was measured before and after PBMV. To study LAA function, LAA late emptying (LAALE) velocity, LAA late filling (LAALF) velocity, and LAA area change percentage (LAAAC %) were measured. In the DTI study, tissue Doppler velocities of the LAA, including peak early diastolic (E(LAA)), peak late diastolic (A(LAA)), and peak systolic (S(LAA)), were measured. RESULTS: There was significant increase in LAALE velocity, LAALF velocity, E(LAA), A(LAA), S(LAA) waves measured by Doppler and DTI after PBMV compared with baseline (p < 0.001) but there was no significant change in LAAAC% (p = not significant). Spontaneous echo contrast was present in 10 of the 59 patients before the procedure. It completely disappeared (6 patients) or decreased (4 patients) after PBMV. CONCLUSIONS: Our results suggest that PBMV improves LAA function and, thereby, may have a favorable influence on future thromboembolic complications. PMID- 23102384 TI - Echocardiography for left atrial appendage structure and function. PMID- 23102385 TI - Atrial fibrillation in a tertiary care institute - a prospective study. AB - OBJECTIVE: Atrial fibrillation is the commonest sustained arrhythmia. In western countries the common causes of atrial fibrillation are hypertensive heart disease, dilated cardiomyopathy, and coronary heart disease. Rheumatic heart disease being still common in India, we studied its contribution to atrial fibrillation. MATERIAL AND METHODS: 137 consecutive patients of atrial fibrillation coming to our hospital were subjected to echocardiography to determine the cause. RESULTS: Out of 137 patients with atrial fibrillation, 76 were female (55.47%) and 61 were male (44.43%). Mean age was 51.24+/-15.36 years. Commonest cause of AF was rheumatic heart disease found in 84 (61.31%) patients. Next common causes were hypertensive heart disease in 14 (10.2%) patients and chronic obstructive pulmonary disease (COPD) in 14 (10.2%) patients. Mean left atrial size was 47.8+/-12.25mm. CONCLUSION: In our study of patients coming from a rural back ground of North India, more than 60% patients of AF are due to RHD. Hypertensive heart disease and COPD are the next common causes. PMID- 23102386 TI - Is cardiac biomarkers and left ventricular function affected by chronic kidney disease? AB - BACKGROUND: Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). These patients may have high level of cardiac troponins in their serum irrelevant to acute coronary syndrome (ACS) that could have profound impact on patient's morbidity and mortality. OBJECTIVES: The aim of this study was to assess the relation between level of serum creatinine (Cr) and cardiac troponins T and I, and left ventricular (LV) function (as defined by LV ejection fraction) in non-dialysis and non-acute coronary syndrome CKD patients. MATERIALS AND METHODS: This is a prospective cross sectional study that includes 150 non-dialysis CKD patients without history of ACS in at least 1 month before the beginning of the study. Patients with history of CKD (serum Cr >=1.5 mg/dl) of more than 6 months were selected. Patients with advanced multi-organ disease (lung disease, liver disease, cerebrovascular disease and peripheral vascular disease) and history of dialysis were excluded from the study. In each patient blood sample was obtained for analyzing serum Cr and cardiac troponin T and I (cTnT and cTnI). Also LV ejection fraction (LVEF) was measured by echocardiography in the same session. RESULT: There was a positive non-parametric relation between serum Cr and cTnT (p = 0.028). However there were no relation between serum Cr, cTnI (p = 0.57) and LVEF (p = 0.188). CONCLUSION: In patients with CKD, serum Cr level has an impact on cTnT, but has no impact on cTnI and LVEF. PMID- 23102387 TI - Risk factors for contrast induced nephropathy: a study among Italian patients. AB - This study aimed to make a profile of patients at highest risk of developing contrast induced nephropathy (CIN) in order to take appropriate prevention measures. 591 patients undergoing coronary procedures were divided into two groups: patients with (CIN-group) and without (no-CIN) an increase in creatinine level equal or more than 25% from baseline values within 24-48 h after the coronary procedure. All patients underwent an accurate anamnesis, objective exam, hematochemical measurements, and diagnostic exams. The results of this study while confirming that, average age (p = 0.01), diabetes mellitus (p < 0.0001), base line renal insufficiency (p = 0.0001), diuretic therapy (p = 0.002), higher contrast doses (p = 0.01), are associated with a higher risk of contrast-induced nephropathy, also demonstrated that both clinical (p = 0.01) and subclinical (p < 0.0001) atherosclerosis, and higher preprocedural high sensitive C-reactive protein levels (hs- CRP) (p = 0.02) are risk factors for CIN. PMID- 23102388 TI - Cardiac tumours in infancy. AB - Cardiac tumours in infancy are rare and are mostly benign with rhabdomyomas, fibromas and teratomas accounting for the majority. The presentation depends on size and location of the mass as they tend to cause cavity obstruction or arrhythmias. Most rhabdomyomas tend to regress spontaneously but fibromas and teratomas generally require surgical intervention for severe haemodynamic or arrhythmic complications. Other relatively rare cardiac tumours too are discussed along with an Indian perspective. PMID- 23102389 TI - Ticagrelor: molecular discovery to clinical evidence: ticagrelor: a novel antiplatelet agent. AB - Cardiovascular (CV) deaths are one of the leading cause of death, both in developed and developing countries, with acute coronary syndrome (ACS) accounting for about 50% of all CV deaths. Atherothrombosis formation is the prime reason behind ACS and platelets play a central role in formation of thrombus. Antiplatelet drugs, particularly dual antiplatelet therapy (DAPT) with Aspirin and Clopidogrel play a vital role and are widely used in the management of ACS for the past decade. However in spite of currently available options for antiplatelet therapy there remains a significant risk of arterial thrombosis and post ACS mortality grows over a period of time. Thus, there is a need for novel antiplatelet agents which can overcome some limitations of current antiplatelet therapies. Ticagrelor is a novel antiplatelet agent which has a faster onset of action, produces high level of platelet inhibition with minimal inter patient variability. This review summarizes the pharmacokinetic, pharmacodynamic characteristics and clinical evidence of ticagrelor in the management of ACS. PMID- 23102390 TI - Role of omega-3 ethyl ester concentrate in reducing sudden cardiac death following myocardial infarction and in management of hypertriglyceridemia: an Indian consensus statement. AB - INTRODUCTION: Sudden cardiac death (SCD) is the most lethal manifestation of heart disease. In an Indian study the SCDs contribute about 10% of the total mortality and SCD post ST elevation myocardial infarction (MI) constitutes for about half of total deaths. OBJECTIVE: Given the limitations of existing therapy there is a need for an effective, easy to use, broadly applicable and affordable intervention to prevent SCD post MI. Leading cardiologists from all over India came together to discuss the potential role of n-3 acid ethyl esters (90%) of eicosapentaenoic acid (EPA) 460 mg & docosahexaenoic acid (DHA) 380 mg in the management of post MI patients and those with hypertriglyceridemia. RECOMMENDATIONS: Highly purified & concentrated omega-3 ethyl esters (90%) of EPA (460 mg) & DHA (380 mg) has clinically proven benefits in improving post MI outcomes (significant 15% risk reduction for all-cause mortality, 20% risk reduction for CVD and 45% risk reduction in SCD in GISSI-Prevenzione trial) and in reducing hypertriglyceridemia, and hence, represent an interesting option adding to the treatment armamentarium in the secondary prevention after MI based on its anti-arrhythmogenic effects and also in reducing hypertriglyceridemia. PMID- 23102391 TI - Cardiac rhabdomyoma with LVOT obstruction and anorectal malformation in a neonate: a rare association. AB - Cardiac rhabdomyomas are described as sporadic as well as associated with tuberous sclerosis. Association with LVOT obstruction with anorectal malformation or imperforate anus has not been reported so far in published literature. In this case report we describe one such case. PMID- 23102392 TI - An uncommon presentation of a rare disease - high-degree AV block with takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy is a type of non-ischemic cardiomyopathy in which there is sudden temporary left ventricular dysfunction. High-degree AV block and takotsubo cardiomyopathy have been reported together rarely in medical literature. Here we discuss a case of takotsubo cardiomyopathy presenting with complete heart block. A 72-year-old female presented with retrosternal chest pain. Electrocardiogram showed complete heart block without any significant ST-T changes. Echocardiogram revealed regional wall motion abnormality not consistent with coronary artery disease and was suggestive of apical ballooning. Coronary angiogram showed no significant coronary artery lesion. LV angiogram showed apical ballooning and LV systolic dysfunction. Patient underwent temporary pacemaker implantation. Since the complete heart block did not revert even after 18 days, she underwent a permanent pacemaker implantation. PMID- 23102393 TI - Symptomatic complete heart block leading to a diagnosis of Kearns-Sayre syndrome. AB - Kearns-Sayre syndrome (KSS) is a rare syndrome characterized by the triad of progressive external ophthalmoplegia, pigmentary retinopathy and cardiac conduction system disturbances; it is a mitochondrial encephalomyopathy with which usually presents before the patient reaches the age of 20. Here we present a case report of a patient with KSS who presented with symptomatic complete heart block. PMID- 23102394 TI - Longitudinal deformation - price we pay for better deliverability of coronary stent platforms. AB - Coronary stents, especially drug eluting stents (DES), have revolutionized the practice of interventional cardiology. Newer stents are manufactured by altering basic design characteristics to tackle complex coronary morphologies more effectively. Alteration in one particular attribute might affect other attributes adversely. Even though, reduction in the number and alteration of the orientation of the connectors improves the stent flexibility and deliverability, it adversely decreases the axial strength of the stent with resulting longitudinal stent deformation. A 67 year old female underwent percutaneous coronary intervention for a mid left anterior descending artery stenosis with a 2.75 * 16 mm Promus Element stent (Boston Scientific, Natick, Massachusetts). The stent got longitudinally distorted during post-stent balloon dilatation which was effectively managed with further dilatation with non-compliant balloon. PMID- 23102395 TI - Transcatheter closure of a residual aortopulmonary window through internal jugular vein access. AB - The use of Amplatzer septal occluder for closing a residual aortopulmonary defect has been described. This is usually performed by femoral access. We report closure of a residual aortopulmonary defect using right internal jugular vein access in a patient who had no femoral access as a result of previous cannulation for surgical repair. The 1 cm defect was closed successfully using a 10 mm Amplatzer septal occluder. Technical difficulty anticipated was unfounded although it was more cumbersome than femoral access. Left to right cardiac defects including PDA and AP window are amenable to transcatheter closure through internal jugular vein access. PMID- 23102396 TI - Tracking the path traversed by temporary pacing lead. AB - Persistent left superior vena cava (PLSVC) results from abnormal development of the sinus venosus in the early stages of fetal life. Though there are numerous reports of successful permanent pacemaker implants in such cases, placement of permanent pacing leads in such cases is technically challenging, often requiring shaping of stylets and considerable lead maneuvering. We describe an interesting case wherein a temporary pacemaker lead after entering the PLSVC followed an unusual fluoroscopic course with demonstrable pacing in right ventricle (RV), right atrium (RA) and the left ventricle (LV). Interventional cardiologists and intensivists performing pacing procedures need to be aware that one may rarely encounter such interesting radiographic and electrocardiographic patterns in these cases with anomalous systemic venous drainage. PMID- 23102397 TI - Two pacing spikes on the QRS complex in a single-chamber pacemaker. AB - AutoCapture algorithm helps the pacemakers to automatically adjust output close to the pacing threshold. This algorithm monitors the evoked response signal of myocardial depolarization, and delivers a high output back-up pulse if there is a loss of capture. This case, with two pacemaker spikes on the QRS complexes in a patient with VVI pacemaker, simulating a sensing failure, demands clear understanding of AutoCapture function before labeling the pacemaker malfunction. PMID- 23102301 TI - Measurement of the pseudorapidity and centrality dependence of the transverse energy density in Pb-Pb collisions at ?(s(NN))=2.76 TeV. AB - The transverse energy (E(T)) in Pb-Pb collisions at 2.76 TeV nucleon-nucleon center-of-mass energy (?(s(NN)) has been measured over a broad range of pseudorapidity (eta) and collision centrality by using the CMS detector at the LHC. The transverse energy density per unit pseudorapidity (dE(T)/deta) increases faster with collision energy than the charged particle multiplicity. This implies that the mean energy per particle is increasing with collision energy. At all pseudorapidities, the transverse energy per participating nucleon increases with the centrality of the collision. The ratio of transverse energy per unit pseudorapidity in peripheral to central collisions varies significantly as the pseudorapidity increases from eta=0 to |eta|=5.0. For the 5% most central collisions, the energy density per unit volume is estimated to be about 14 GeV/fm(3) at a time of 1 fm/c after the collision. This is about 100 times larger than normal nuclear matter density and a factor of 2.6 times higher than the energy density reported at ?(s(NN))=200 GeV at the Relativistic Heavy Ion Collider. PMID- 23102398 TI - ST-segment elevation after abdominal aortic aneurysm repair. AB - We describe a case of post-operative inferior myocardial infarction after abdominal aortic aneurysm repair due to compromise of a gastroepiploic coronary arterial graft. PMID- 23102399 TI - Assessment of left ventricular systolic function by vector velocity imaging. PMID- 23102402 TI - Cationic iridium complexes with intramolecular pi-pi interaction and enhanced steric hindrance for solid-state light-emitting electrochemical cells. AB - Cationic iridium complexes incorporated 4,5-diaza-9,9'-spirobifluorene as N(?)N ancillary ligands, in which one (2) or two (3) phenyl groups were introduced onto 4,5-diazafluorene to afford intraligand pi-pi interactions. The X-ray crystal structures of complexes 2 and 3 show that the pendant phenyl ring forms strong intramolecular face-to-face pi-stacking with the difluorophenyl ring of the cyclometalated ligand with distances of 3.38 A for complex 2 and 3.40 and 3.46 A for complex 3. This pi-pi stacking interaction minimizes the expansion of the metal-ligand bonds in the excited state, resulting in a longer device lifetime in the light-emitting electrochemical cell (LEC) devices. PMID- 23102401 TI - Arrays of aligned supramolecular wires by macroscopic orientation of columnar discotic mesophases. AB - Structure formation, phase behavior, and dynamics of mono-bromo hexa-peri hexabenzocoronene (HBC-Br) are strongly affected by the confinement of cylindrical nanopores with rigid walls. Using self-ordered nanoporous anodic aluminum oxide (AAO)-containing arrays of aligned nanopores with narrow size distribution as a confining matrix, pronounced alignment of the HBC-Br columns along the nanopore axes was found to be independent of the pore diameter. Hence, arrays of one-dimensional supramolecular HBC-Br wires with the columns uniformly oriented along the wire axes on a macroscopic scale were obtained, unlike with discotics bearing smaller cores. The formation of the crystalline herringbone structure is shifted to lower temperatures in nanopores with diameters of a few hundred nanometers, whereas the formation of this low-temperature phase is completely suppressed when the pore diameter is below 20 lattice parameters. Moreover, the cylindrical confinement affects the disk axial dynamics as well as the distribution of relaxation times. PMID- 23102404 TI - Risk factors associated with patient and visitor violence in general hospitals: results of a multiple regression analysis. AB - BACKGROUND: Patient and visitor violence (PVV) is the most dangerous occupational hazard that health professionals must contend with. Staff training is recommended to prevent and manage PVV. There is minimal research focusing on risk factors associated with PVV in general hospital settings. Therefore, staff training is mostly based upon expert knowledge and knowledge from psychiatric and emergency settings. OBJECTIVES: This study investigates health professionals' experiences with PVV in order to describe risk factors related to PVV that occur in general hospital settings. DESIGN: A retrospective cross-sectional survey was conducted in 2007. SETTING: A university general hospital in Switzerland. PARTICIPANTS: 2495 out of 4845 health professionals participated (58.0% nurses & midwives, 19.2% medical doctors, 3.6% physical therapists, occupational therapists & nutritionists, 6.1% ward secretaries, medical & radiology assistants, 6.3% nursing assistants or less qualified nursing staff and 5.1% other staff). All had direct patient contact and 82% were female. METHODS: Data were collected via questionnaires using the Survey of Violence Experienced by Staff German-Version Revised, the German version of the shortened Perception of Aggression Scale and the Perception of Importance of Intervention Skills Scale. Descriptive statistics and multiple logistic regression analyses were used. RESULTS: Risk factors associated with PVV depend upon the form of violence. Those trained in aggression management and/or those who work predominantly with patients over 65 years of age experience twice as much PVV as others. Health professionals working in emergency rooms, outpatient units, intensive care units, recovery rooms, anesthesia, intermediate care and step-down units also experience PVV more often. When health professionals are older in age, are from the medical profession, are students, or when they have an attitude rating preventive measures as being less important and aggression as emotionally letting off steam, they experience less PVV. CONCLUSION: Training could change the perception and the recognition of PVV, and could therefore increase the risk of experiencing PVV. The health professionals' specific occupation along with attitude and age, the patients' age, the communication and the workplace are all relevant risk factors. Further studies should investigate the impact of aggression management training and other measures that would reduce PVV. PMID- 23102403 TI - Amniotic fluid soluble Toll-like receptor 2 in pregnancies complicated by preterm prelabor rupture of membranes. AB - OBJECTIVE: To determine amniotic fluid soluble Toll-like receptor 2 (sTLR2) levels in PPROM according to the presence of microbial invasion of the amniotic cavity (MIAC), histological chorioamnionitis (HCA), and both these conditions. To test the cutoff level of 222.7 ng/mL, as proposed in our previous study, in order to distinguish women with both MIAC and HCA. METHODS: 169 women with a gestational age between 24+0 and 36+6 weeks were included in a prospective cohort study. Amniocenteses were performed, and sTLR2 in the amniotic fluid were determined using ELISA. RESULTS: Women with MIAC had higher sTLR2 levels (median 113.2 ng/mL) than those without MIAC (median 47.1 ng/mL; p < 0.0001). Women with HCA did not have a higher sTLR2 level (median 52.6 ng/mL) compared with women without HCA (median 47.1 ng/mL; p = 0.23). Women with both MIAC and HCA had higher sTLR2 levels (median: 311.3 ng/mL) than other women (17.5 ng/mL; p < 0.0001). The cutoff level 222.7 ng/mL had a sensitivity of 63%, a specificity of 98%, and a likelihood ratio of 40.3 for the prediction of both MIAC and HCA. CONCLUSIONS: Amniotic fluid sTLR2 is a promising predictor of both MIAC and HCA with high specificity in PPROM. PMID- 23102405 TI - Chronic self-administration of alcohol results in elevated DeltaFosB: comparison of hybrid mice with distinct drinking patterns. AB - BACKGROUND: The inability to reduce or regulate alcohol intake is a hallmark symptom for alcohol use disorders. Research on novel behavioral and genetic models of experience-induced changes in drinking will further our knowledge on alcohol use disorders. Distinct alcohol self-administration behaviors were previously observed when comparing two F1 hybrid strains of mice: C57BL/6J x NZB/B1NJ (BxN) show reduced alcohol preference after experience with high concentrations of alcohol and periods of abstinence while C57BL/6J x FVB/NJ (BxF) show sustained alcohol preference. These phenotypes are interesting because these hybrids demonstrate the occurrence of genetic additivity (BxN) and overdominance (BxF) in ethanol intake in an experience dependent manner. Specifically, BxF exhibit sustained alcohol preference and BxN exhibit reduced alcohol preference after experience with high ethanol concentrations; however, experience with low ethanol concentrations produce sustained alcohol preference for both hybrids. In the present study, we tested the hypothesis that these phenotypes are represented by differential production of the inducible transcription factor, DeltaFosB, in reward, aversion, and stress related brain regions. RESULTS: Changes in neuronal plasticity (as measured by DeltaFosB levels) were experience dependent, as well as brain region and genotype specific, further supporting that neuronal circuitry underlies motivational aspects of ethanol consumption. BxN mice exhibiting reduced alcohol preference had lower DeltaFosB levels in the Edinger-Westphal nucleus than mice exhibiting sustained alcohol preference, and increased DeltaFosB levels in central medial amygdala as compared with control mice. BxN mice showing sustained alcohol preference exhibited higher DeltaFosB levels in the ventral tegmental area, Edinger-Westphal nucleus, and amygdala (central and lateral divisions). Moreover, in BxN mice DeltaFosB levels in the Edinger Westphal nucleus and ventral tegmental regions significantly positively correlated with ethanol preference and intake. Additionally, hierarchical clustering analysis revealed that many ethanol-naive mice with overall low DeltaFosB levels are in a cluster, whereas many mice displaying sustained alcohol preference with overall high DeltaFosB levels are in a cluster together. CONCLUSIONS: By comparing and contrasting two alcohol phenotypes, this study demonstrates that the reward- and stress-related circuits (including the Edinger Westphal nucleus, ventral tegmental area, amygdala) undergo significant plasticity that manifests as reduced alcohol preference. PMID- 23102407 TI - Whole grains and health: attitudes to whole grains against a prevailing background of increased marketing and promotion. AB - OBJECTIVE: To explore current awareness and perceptions of whole grain foods and perceived barriers and facilitators of whole grain consumption. DESIGN: Focus groups were conducted to investigate consumer attitudes to whole grains. Discussions were transcribed verbatim and analysed thematically. SETTING: Discussions were held throughout Northern Ireland with adults who were at least partly responsible for food shopping. SUBJECTS: Seven focus groups were held (n 43; thirty-three females, ten males). RESULTS: All participants were aware of the term 'whole grain' and had a basic level of awareness of their health benefits. Prominent barriers and facilitators of whole grain intake were related to perceptions of the sensory properties (most dominant factor) of whole grains; knowledge of how to locate, identify and use whole grains; and awareness of the health benefits, perceived cost and family influences. Parents of young children appeared to be altruistically motivated with many stating they wanted to ensure their children consumed whole grains in order to establish good eating habits. CONCLUSIONS: Participants were generally aware of the term 'whole grain'; however, even against a background of increased availability and promotion of whole grain foods, many key barriers to whole grain consumption were still evident. Alongside general education efforts, opportunities and challenges exist for the food industry to develop novel, but affordable, food products that are able to deliver whole grains in a wide variety of forms, including whole grains 'in disguise' for those who are most resistant to change. PMID- 23102408 TI - Perceptions of primary care professionals on quality of services in rural Greece: a qualitative study. AB - INTRODUCTION: Greece is striving to limit its health expenditure to essential needs. General practice and the provision of Primary Health Care (PHC) mainly take place in rural settings, where approximately 200 Primary Health Care Centres (PHCCs) have been established. In order to determine how to optimize the effectiveness and efficiency of PHC services, it is important to first gain insights into the providers' perspectives. The aim of the study was to assess the perceptions of General Practitioners (GPs) and the directors of PHCCs regarding the effectiveness of available PHC services, and to elicit suggestions on how current services could be improved. METHODS: This qualitative study was based on semi-structured interviews. The setting was 21 PHCCs in the Epirus and Crete regions of Greece. Twenty-nine physicians were interviewed on aspects of capacity, resources, performance and quality of PHC services. Discussions were digitally recorded and transcribed verbatim. The transcriptions were then analysed using thematic content analysis. RESULTS: The main identified barriers to providing high-quality PHC services were: PHC service shortages in workforce and equipment; inadequate GP and paramedic training; the absence of position/job descriptions or duty statements for GPs and other PHC personnel; and limited public awareness about the role of GPs. Suggestions for remodelling the current PHC system included: the introduction of new technologies; GP empowerment; leadership reforms; and mechanisms for evaluating of the quality of services. Finally, areas of concern regarding future development and utilisation of private PHC infrastructure and services were highlighted. CONCLUSION: The methodology of this study and the results regarding remodelling the current PHC system could be used to inform policy-making in Greece, particularly in the current period of severe economic crisis; they may also be of relevance to other European countries facing similar challenges in allocating resources and reforming PHC. PMID- 23102406 TI - Secretagogin is expressed in sensory CGRP neurons and in spinal cord of mouse and complements other calcium-binding proteins, with a note on rat and human. AB - BACKGROUND: Secretagogin (Scgn), a member of the EF-hand calcium-binding protein (CaBP) superfamily, has recently been found in subsets of developing and adult neurons. Here, we have analyzed the expression of Scgn in dorsal root ganglia (DRGs) and trigeminal ganglia (TGs), and in spinal cord of mouse at the mRNA and protein levels, and in comparison to the well-known CaBPs, calbindin D-28k, parvalbumin and calretinin. Rat DRGs, TGs and spinal cord, as well as human DRGs and spinal cord were used to reveal phylogenetic variations. RESULTS: We found Scgn mRNA expressed in mouse and human DRGs and in mouse ventral spinal cord. Our immunohistochemical data showed a complementary distribution of Scgn and the three CaBPs in mouse DRG neurons and spinal cord. Scgn was expressed in ~7% of all mouse DRG neuron profiles, mainly small ones and almost exclusively co localized with calcitonin gene-related peptide (CGRP). This co-localization was also seen in human, but not in rat DRGs. Scgn could be detected in the mouse sciatic nerve and accumulated proximal to its constriction. In mouse spinal cord, Scgn-positive neuronal cell bodies and fibers were found in gray matter, especially in the dorsal horn, with particularly high concentrations of fibers in the superficial laminae, as well as in cell bodies in inner lamina II and in some other laminae. A dense Scgn-positive fiber network and some small cell bodies were also found in the superficial dorsal horn of humans. In the ventral horn, a small number of neurons were Scgn-positive in mouse but not rat, confirming mRNA distribution. Both in mouse and rat, a subset of TG neurons contained Scgn. Dorsal rhizotomy strongly reduced Scgn fiber staining in the dorsal horn. Peripheral axotomy did not clearly affect Scgn expression in DRGs, dorsal horn or ventral horn neurons in mouse. CONCLUSIONS: Scgn is a CaBP expressed in a subpopulation of nociceptive DRG neurons and their processes in the dorsal horn of mouse, human and rat, the former two co-expressing CGRP, as well as in dorsal horn neurons in all three species. Functional implications of these findings include the cellular refinement of sensory information, in particular during the processing of pain. PMID- 23102410 TI - Neomaclafungins A-I: oligomycin-class macrolides from a marine-derived actinomycete. AB - Nine new 26-membered macrolides of the oligomycin subfamily, neomaclafungins A-I, were isolated from the fermentation broth of Actinoalloteichus sp. NPS702, which was isolated from marine sediment collected from Usa Bay, Kochi Prefecture, Japan. Their structures were identified through mass spectrometry and NMR experiments. They belong to the oligomycin class and have several distinct features including the presence of alkane or alkanol branches. Neomaclafungins A I exhibited significant antifungal activity in vitro against Trichophyton mentagrophytes (ATCC 9533), showing MIC values between 1 and 3 MUg/mL. PMID- 23102409 TI - Building better systems of care for Aboriginal and Torres Strait Islander people: findings from the Kanyini health systems assessment. AB - BACKGROUND: Australian federal and jurisdictional governments are implementing ambitious policy initiatives intended to improve health care access and outcomes for Aboriginal and Torres Strait Islander people. In this qualitative study we explored Aboriginal Medical Service (AMS) staff views on factors needed to improve chronic care systems and assessed their relevance to the new policy environment. METHODS: Two theories informed the study: (1) 'candidacy', which explores "the ways in which people's eligibility for care is jointly negotiated between individuals and health services"; and (2) kanyini or 'holding', a Central Australian philosophy which describes the principle and obligations of nurturing and protecting others. A structured health systems assessment, locally adapted from Chronic Care Model domains, was administered via group interviews with 37 health staff in six AMSs and one government Indigenous-led health service. Data were thematically analysed. RESULTS: Staff emphasised AMS health care was different to private general practices. Consistent with kanyini, community governance and leadership, community representation among staff, and commitment to community development were important organisational features to retain and nurture both staff and patients. This was undermined, however, by constant fear of government funding for AMSs being withheld. Staff resourcing, information systems and high-level leadership were perceived to be key drivers of health care quality. On-site specialist services, managed by AMS staff, were considered an enabling strategy to increase specialist access. Candidacy theory suggests the above factors influence whether a service is 'tractable' and 'navigable' to its users. Staff also described entrenched patient discrimination in hospitals and the need to expend considerable effort to reinstate care. This suggests that Aboriginal and Torres Strait Islander people are still constructed as 'non-ideal users' and are denied from being 'held' by hospital staff. CONCLUSIONS: Some new policy initiatives (workforce capacity strengthening, improving chronic care delivery systems and increasing specialist access) have potential to address barriers highlighted in this study. Few of these initiatives, however, capitalise on the unique mechanisms by which AMSs 'hold' their users and enhance their candidacy to health care. Kanyini and candidacy are promising and complementary theories for conceptualising health care access and provide a potential framework for improving systems of care. PMID- 23102411 TI - Tough and catalytically active hybrid biofibers wet-spun from nanochitin hydrogels. AB - Sustainable alternatives for high-performance and functional materials based on renewable resources are intensely needed as future alternatives for present-day, fossil-based materials. Nanochitin represents an emerging class of highly crystalline bionanoparticles with high intrinsic mechanical properties and the ability for conjugation into functional materials owing to reactive amine and hydroxyl groups. Herein we demonstrate that hydrogels containing surface deacetylated chitin nanofibrils of micrometer length and average diameters of 9 nm, as imaged by cryogenic transmission electron microscopy, can be wet-spun into macrofibers via extrusion in a coagulation bath, a simple low energy and large scale processing route. The resulting biofibers display attractive mechanical properties with a large plastic region of about 12% in strain, in which frictional sliding of nanofibrils allows dissipation of fracture energy and enables a high work-of-fracture of near 10 MJ/m3. We further show how to add functionality to these macrofibers by exploiting the amine functions of the surface chitosan groups to host catalytically active noble metal nanoparticles, furnishing biobased, renewable catalytic hybrids. These inorganic/organic macrofibers can be used repeatedly for fast catalytic reductions of model compounds without loss of activity, rendering the concept of hybridized chitin materials interesting as novel bioderived supports for nanoparticle catalysts. PMID- 23102413 TI - Potential for overuse of corticosteroids and vasopressin in septic shock. PMID- 23102414 TI - Super-resolution optical measurement of nanoscale photoacid distribution in lithographic materials. AB - We demonstrate a method using photoactivation localization microscopy (PALM) in a soft-material system, with a rhodamine-lactam dye that is activated by both ultraviolet light and protonation, to reveal the nanoscale photoacid distribution in a model photoresist. Chemically amplified resists are the principal lithographic materials used in the semiconductor industry. The photoacid distribution generated upon exposure and its subsequent evolution during post exposure bake is a major limiting factor in determining the resolution and lithographic quality of the final developed resist image. Our PALM data sets resolve the acid distribution in a latent image with subdiffraction limit accuracy. Our overall accuracy is currently limited by residual mechanical drift. PMID- 23102412 TI - Engineering Escherichia coli to synthesize free fatty acids. AB - Fatty acid metabolism has received significant attention as a route for producing high-energy density, liquid transportation fuels and high-value oleochemicals from renewable feedstocks. If microbes can be engineered to produce these compounds at yields that approach the theoretical limits of 0.3-0.4 g/g glucose, then processes can be developed to replace current petrochemical technologies. Here, we review recent metabolic engineering efforts to maximize production of free fatty acids (FFA) in Escherichia coli, the first step towards production of downstream products. To date, metabolic engineers have succeeded in achieving higher yields of FFA than any downstream products. Regulation of fatty acid metabolism and the physiological effects of fatty acid production will also be reviewed from the perspective of identifying future engineering targets. PMID- 23102415 TI - Is socioeconomic status a risk factor for stiffness after total knee arthroplasty? A multicenter case-control study. AB - Socioeconomic factors may play a role in the development of arthrofibrosis following total knee arthroplasty. Using manipulation following total knee arthroplasty as a surrogate for stiffness, this multicenter case-control study found that African American and young patients (<45 years of age) had twice the odds for manipulation compared with Caucasian and older-age patients. PMID- 23102416 TI - Comparative analysis of periarticular osteolysis in modern total hip bearings: a minimum 5-year study. AB - The best bearing to use in the young active population remains unknown because there are currently no evidence-based data to rely on. This article compares the prevalence of periacetabular osteolysis using computerized tomography in patients with metal-on-metal, ceramic-on-ceramic, and metal-on-cross-linked bearings at a minimum 5-year follow-up. PMID- 23102417 TI - Patient-specific instrumentation for total knee arthroplasty: a review. AB - Patient-specific instrumentation is a new technology that offers increased surgical accuracy, which could decrease outliers, increased efficiency, involving fewer steps and shorter surgical times, and has the potential for cost effectiveness, if overall surgical volume can be increased and future revision rates can be decreased. As with all technology, further studies are necessary, but there is much interest in this technology as medicine enters the age of increased patient burden and an increased emphasis on efficiency. PMID- 23102418 TI - The importance of acetabular component position in total hip arthroplasty. AB - Correct acetabular cup position is critical to successful total hip replacement. Unfortunately, malposition of acetabular cups is common and leads to increased rates of dislocation, wear, and ion toxicity. Despite the popularity of Lewinnek's safe zone, the exact target of acetabular abduction and version remains elusive. Differences in functional pelvic position, surgical approach, and femoral anteversion affect the optimal cup position for individual patients. Surgeons need to be aware of pelvic position changes from the supine to lateral decubitus position. PMID- 23102419 TI - Highly cross-linked polyethylene in posterior stabilized total knee arthroplasty: early results. AB - This article examines whether any new complications were associated with highly cross-linked polyethylene in posterior stabilized total knee arthroplasty (TKA) due to its altered mechanical properties. Average preoperative Knee Society Scores (KSS) were 49.7 and 51.5, with a range of movement (ROM) of 3 degrees to 116 degrees , and average postoperative KSS were 87.7 clinical and 89.7, with ROM of 0 degrees to 123 degrees . Postoperative alignment averaged 3.8 degrees of valgus. There were no cases of polyethylene or post failure. Short-term results of posterior stabilized TKAs using highly cross-linked polyethylene show good functional outcomes with no evidence of loosening or tibial post failure. PMID- 23102420 TI - Retrieval analysis of nonmodular constrained tibial inserts after primary total knee replacement. AB - Large angular deformities can be a challenge when performing primary total knee replacement. Some investigators have advocated the use of increased component constraint in these settings. The goal of this study was to determine the location and extent of damage to a consecutive series of retrieved constrained tibial inserts used in primary arthroplasty. There was significant post and articular damage in retrieved implants. Reliance on the polyethylene post for implant stability was associated with post and articular surface damage and may be a potential source of failure. Attempts to achieve implant stability using soft tissue techniques seem justified. PMID- 23102421 TI - Blood loss and transfusion rates following patellofemoral arthroplasty. AB - Patellofemoral arthroplasty (PFA) is a viable treatment option of the patient with isolated patellofemoral arthritis. Some of the purported advantages of PFA compared with total knee arthroplasty (TKA) include less invasive approach, less bone resection and tissue destruction, decreased operative time, shorter rehabilitation, better knee kinematics, and decreased blood loss. This study compared the blood loss associated with PFA with that of a cohort of patients with TKA. A proposed benefit of partial knee arthroplasty is less blood loss. Patellofemoral replacement seems not to have this benefit and blood loss prevention initiatives similar to those of TKA should be maintained. PMID- 23102422 TI - Difference in hip prosthesis femoral offset affects hip abductor strength and gait characteristics during obstacle crossing. AB - The purpose of this article is to determine if individuals with high rather than low femoral offset of a total hip arthroplasty achieve improved hip abductor muscle strength and thus improved their ability to step over an obstacle safely. These outcomes will help surgeons decide whether increasing the femoral offset helps a patient's physical function. PMID- 23102423 TI - Bilateral pseudogout 8 years after bilateral total knee arthroplasty. AB - This article presents the clinical features of crystal arthropathy after knee replacement. The current literature on pseudogout and gout after both total and partial knee replacement is summarized. A case of bilateral pseudogout 8 years after initial total knee arthroplasty (TKA) is used to highlight the clinical characteristics and treatment options for this underrecognized condition. Presentation mimicked a late septic joint arthroplasty with sudden onset of pain and effusion. The patient was treated successfully with an arthrotomy, debridement, synovectomy, polyethylene insert exchange, oral steroids, and nonsteroidal anti-inflammatories. There are no other reported cases of bilateral pseudogout after bilateral TKA. PMID- 23102424 TI - Catastrophic wear in total hip arthroplasty. Complete wear-through of a metal backed acetabular component: case report. AB - A unique case of catastrophic wear of a total hip arthroplasty is presented. This brief report demonstrates the presentation of catastrophic wear of a modular acetabular component with protrusion of the femoral head through a modular metal backed titanium cup. During the revision surgery, the polyethylene was found to have disengaged from the cup, and the cup was pistoning on the femoral neck. Significant metallosis and bone loss was found. The presence of severe metallosis mimicked bone on the preoperative radiograph and obscured the severity of the osteolysis seen on imaging. PMID- 23102425 TI - Hip resurfacing is less painful at 24 hours than hip replacement. AB - This article quantifies pain differences in the immediate postoperative period between patients undergoing total hip arthroplasty (THA) and metal-on-metal hip resurfacing (MoMHR). Patients less than 65 years old indicated for either a primary MoMHR or THA were screened for consent. A total of 51 patients completed the study. Controlling for confounding factors, patients having MoMHR experienced significantly less pain at 24 hours than patients having THA. The MoMHR cohort experienced a significantly shorter length of stay than the THA cohort. MoMHR shows a significantly lower pain level at 24 hours than THA and a significantly earlier discharge. PMID- 23102426 TI - Evidence for the existence of terminal scandium imidos: mechanistic studies involving imido-scandium bond formation and C-H activation reactions. AB - The anilide-methyl complex (PNP)Sc(NH[DIPP])(CH(3)) (1) [PNP(-) = bis(2 diisopropylphosphino-4-tolyl)amide, DIPP = 2,6-diisopropylphenyl] eliminates methane (k(avg) = 5.13 * 10(-4) M(-1) s(-1) at 50 degrees C) in the presence of pyridine to generate the transient scandium imido (PNP)Sc?N[DIPP](NC(5)H(5)) (A py), which rapidly activates the C-H bond of pyridine in 1,2-addition fashion to form the stable pyridyl complex (PNP)Sc(NH[DIPP])(eta(2)-NC(5)H(4)) (2). Mechanistic studies suggest the C-H activation process to be second order overall: first order in scandium and first order in substrate (pyridine). Pyridine binding precedes elimination of methane, and alpha-hydrogen abstraction is overall-rate-determining [the kinetic isotope effect (KIE) for 1-d(1) conversion to 2 was 5.37(6) at 35 degrees C and 4.9(14) at 50 degrees C] with activation parameters DeltaH(?) = 17.9(9) kcal/mol and DeltaS(?) = -18(3) cal/(mol K), consistent with an associative-type mechanism. No KIE or exchange with the anilide proton was observed when 1-d(3) was treated with pyridine or thermolyzed at 35 or 50 degrees C. The post-rate-determining step, C-H bond activation of pyridine, revealed a primary KIE of 1.1(2) at 35 degrees C for the intermolecular C-H activation reaction in pyridine versus pyridine-d(5). Complex 2 equilibrated back to the imide A-py slowly, as the isotopomer (PNP)Sc(ND[DIPP])(eta(2)-NC(5)H(4)) (2-d(1)) converted to (PNP)Sc(NH[DIPP])(eta(2)-NC(5)H(3)D) over 9 days at 60 degrees C. Molecular orbital analysis of A-py suggested that this species possesses a fairly linear scandium imido motif (169.7 degrees ) with a very short Sc-N distance of 1.84 A. Substituted pyridines can also be activated, with the rates of C-H activation depending on both the steric and electronic properties of the substrate. PMID- 23102427 TI - Head drop in progressive supranuclear palsy: an unusual association with amyotrophic lateral sclerosis. PMID- 23102428 TI - Force field for monovalent, divalent, and trivalent cations developed under the solvent boundary potential. AB - Presented are parameters for mono-, di-, and trivalent cations compatible with the CHARMM additive force field and the TIP3P water model. Thermodynamic perturbation molecular dynamics simulations were performed for the cations located at the center of a TIP3P water sphere under a solvent boundary potential. A series of perturbations generated free energies of hydration indexed by the two Lennard-Jones parameters, epsilon and R(min). Interpolating the experimental free energies of hydration showed that multiple combinations of epsilon and R(min) values reproduced the free energies of hydration for each ion. To overcome this nonunique parameter problem, the hydration shell model in combination with an empirical scaling parameter was applied to assign values for each ion. R(min) values were then identified via interpolation of the calculated free energies of hydration. The presented parameters are anticipated to be of utility for simulations of ions, including ions complexed to proteins. PMID- 23102429 TI - [Group A streptococcal meningitis]. AB - An increased incidence and severity of invasive group A streptococcus (GAS) infections over the past decade have been reported by several authors, but GAS remains an uncommon cause of bacterial meningitis. The aim of this study was to describe and analyze the clinical and biological data of GAS meningitis by reporting 10 new cases of pediatric GAS meningitis and making a literature review. The mean age of patients, seven girls and three boys, was 3 years. There was a history of preexisting or concomitant community-acquired infection in five patients over 10. The outcome was fatal in two cases. All patients received an initial empirical antimicrobial therapy with a third generation cephalosporin switched in six cases to amoxicillin. The prognosis for this type of streptococcal meningitis is usually good, but death may occur even in children without any identified risk factor for severe infection. PMID- 23102430 TI - Sensitive photoluminescent detection of Cu2+ in real samples using CdS quantum dots in combination with a Cu(2+)-reducing reaction. AB - By reducing free and/or weakly complexed Cu(2+) with a Cu(2+)-reducing agent (ascorbic acid in the present study) and detecting the photoluminescence peak of Cu(2)S-covered CdS quantum dots (QDs) at 650 nm, Cu(2+) concentrations ranging from 1 nM to 1 MUM can be readily determined. Unlike other related reports, the present method takes advantage of the more efficient chemical reduction of Cu(2+) to Cu(+) (with respect to the photochemical reduction inherent in CdS QDs) and the facile deposition of Cu(2)S. As a result, a detection limit of 0.5 nM was achieved, which is at least 2-3 orders of magnitude lower than QD-based detection methods. In contrast with other methods requiring sample pretreatment or Cu(2+) specific ligands capping QDs, the selectivity of the method towards Cu(2+) is excellent. Among a number of metal ions examined, only Cu(2+) causes the red shift of the CdS photoluminescence. A process causing the shift of the CdS photoluminescence was investigated and described. The matrix effect on the photoluminescent behavior of CdS QDs and the amenability of this method for real samples were also studied. Analyses of Cu(2+) in a river water sample and Cu(2+) complexed by amino acids and proteins in cerebrospinal fluids were performed. The latter analysis reveals that our method can differentiate weakly complexed Cu(2+) ions from the more strongly bound ones. This simple method was also demonstrated to be highly sensitive, accurate and reproducible. PMID- 23102431 TI - Ru(II) encapsulated phosphorylate-terminated silica nanoparticles-based electrochemiluminescent strategy for label-free assay of protein kinase activity and inhibition. AB - A highly sensitive and simple label-free electrochemiluminescent (ECL) sensing strategy has been developed for assay of protein kinase A (PKA) activity and inhibition by taking advantage of zirconium cation (Zr(4+)) mediated signal transition and signal amplification of Ru(II) encapsulated phosphorylate terminated silica nanoparticles (R-PSiNPs). In the protocol, an N-terminally cysteine-containing peptide (S-peptide) is self-assembled onto the gold electrode via Au-S bonding and used as substrate for PKA. The R-PSiNPs are chosen as the signal indicator by virtue of the intrinsic phosphate groups on the surface of the silica nanoparticles and the high loading of Ru(II) markers for ECL signal generation and amplification. The substrate peptide on the electrode is phosphorylated by PKA in the presence of ATP. The phosphorylated peptide (P peptide) is subsequently linked with the R-PSiNPs by Zr(4+). The R-PSiNPs then can be grafted to the surface of Au electrode and generate high ECL signal. The ECL intensity is proportional to the activity of PKA. Due to the high loading of Ru(II) markers in a single phosphorylate-terminated silica nanoparticle, this strategy can be employed to assay PKA activity with a low detection limit of 0.005 U/mL. The linear range of the assay for PKA was 0.01 U/mL to 1 U/mL. Furthermore, the interferences experiments of CK2 and PKA inhibition have been also studied by using this strategy. This selective and sensitive method does not require labeling of the substrate peptide with ECL molecules, which provides a diversified platform for kinase activity and inhibition assay. PMID- 23102432 TI - AlGaN/GaN high electron mobility transistors for protein-peptide binding affinity study. AB - Antibody-immobilized AlGaN/GaN high electron mobility transistors (HEMTs) were used to detect a short peptide consisting of 20 amino acids. One-binding-site model and two-binding-site model were used for the analysis of the electrical signals, revealing the number of binding sites on an antibody and the dissociation constants between the antibody and the short peptide. In the binding site models, the surface coverage ratio of the short peptide on the sensor surface is relevant to the electrical signals resulted from the peptide-antibody binding on the HEMTs. Two binding sites on an antibody were observed and two dissociation constants, 4.404*10(-11) M and 1.596*10(-9) M, were extracted from the binding-site model through the analysis of the surface coverage ratio of the short peptide on the sensor surface. We have also shown that the conventional method to extract the dissociation constant from the linear regression of curve fitting with Langmuir isotherm equation may lead to an incorrect information if the receptor has more than one binding site for the ligand. The limit of detection (LOD) of the sensor observed in the experimental result (~10 pM of the short peptide) is very close to the LOD (around 2.7-3.4 pM) predicted from the value of the smallest dissociation constants. The sensitivity of the sensor is not only dependent on the transistors, but also highly relies on the affinity of the ligand-receptor pair. The results demonstrate that the AlGaN/GaN HEMTs cannot only be used for biosensors, but also for the biological affinity study. PMID- 23102433 TI - Development and validation of an ultrasensitive fluorescence planar waveguide biosensor for the detection of paralytic shellfish toxins in marine algae. AB - Marine dinoflagellates of the genera Alexandrium are well known producers of the potent neurotoxic paralytic shellfish toxins that can enter the food web and ultimately present a serious risk to public health in addition to causing huge economic losses. Direct coastal monitoring of Alexandrium spp. can provide early warning of potential shellfish contamination and risks to consumers and so a rapid, sensitive, portable and easy-to-use assay has been developed for this purpose using an innovative planar waveguide device. The disposable planar waveguide is comprised of a transparent substrate onto which an array of toxin protein conjugates is deposited, assembled in a cartridge allowing the introduction of sample, and detection reagents. The competitive assay format uses a high affinity antibody to paralytic shellfish toxins with a detection signal generated via a fluorescently labelled secondary antibody. The waveguide cartridge is analysed by a simple reader device and results are displayed on a laptop computer. Assay speed has been optimised to enable measurement within 15 min. A rapid, portable sample preparation technique was developed for Alexandrium spp. in seawater to ensure analysis was completed within a short period of time. The assay was validated and the LOD and CCbeta were determined as 12 pg/mL and 20 pg/mL respectively with an intra-assay CV of 11.3% at the CCbeta and an average recovery of 106%. The highly innovative assay was proven to accurately detect toxin presence in algae sampled from the US and European waters at an unprecedented cell density of 10 cells/L. PMID- 23102434 TI - Selective and sensitive turn-on detection of adenosine triphosphate and thrombin based on bifunctional fluorescent oligonucleotide probe. AB - A bifunctional fluorescent oligonucleotide probe for small molecules and protein detection has been developed based on turn on fluorescence response via the target induced structure-switching of molecular beacon. The two loops of this molecular beacon are designed in such a manner that they consist of thrombin (Tmb) aptamer sequence and adenosine triphosphate (ATP) aptamer sequence, respectively, which are utilized to sense thrombin and ATP. The oligonucleotide forms double stem-loops in the absence of targets, yielding no fluorescence emission because of the FRET from the excited fluorophore to the proximal quencher. Upon addition of the target, the ATP or Tmb, its specific interaction with loop sequence of the hairpin structure induce the separation of reporter fluorophore and the fluorescence quencher of the molecular beacon, resulting in an increase of fluorescence response. Hence, the separate analysis of ATP and Tmb could be realized through only one designed molecular beacon. The detection limits were estimated to be 25 nM for ATP and 12 nM for Tmb, respectively. The results of this study should substantially broaden the perspective for future development of oligonucleotide probe for analysis of other analytes. PMID- 23102435 TI - Porokeratosis of Mibelli: a new indication for photodynamic therapy? PMID- 23102436 TI - Communicating bad news during an office visit. PMID- 23102438 TI - Granulomatosis and testicular germ cell tumors. AB - OBJECTIVE: To determine the cumulative incidence of granulomatous disease among patients with testicular germ cell tumor (GCT) at the University of Pennsylvania and to describe these patients' characteristics and disease outcomes. MATERIALS AND METHODS: A computerized search of a large electronic medical database at the University of Pennsylvania was conducted to identify all patients from 1997 to 2012 with a diagnosis of granulomatous disease and GCT. RESULTS: A total of 14 patients were identified. The median age at the diagnosis of GCT was 32.5 years, and the median age at the diagnosis of granulomatous disease was 31 years. Most patients were diagnosed with granulomatous disease either concomitantly or after their diagnosis of GCT. The estimated cumulative incidence of granulomatous disease in patients with GCT at the University of Pennsylvania from 1997 to 2012 was 168.7/100,000. CONCLUSION: These data suggest a strong association between granulomatous disease and GCTs. The observed incidence of granulomatous disease among patients with GCT represents a 10-fold increase compared with the general population. Additional investigation is needed to elucidate the true nature of this association. PMID- 23102437 TI - Plant plasma membrane-bound staphylococcal-like DNases as a novel class of eukaryotic nucleases. AB - BACKGROUND: The activity of degradative nucleases responsible for genomic DNA digestion has been observed in all kingdoms of life. It is believed that the main function of DNA degradation occurring during plant programmed cell death is redistribution of nucleic acid derived products such as nitrogen, phosphorus and nucleotide bases. Plant degradative nucleases that have been studied so far belong mainly to the S1-type family and were identified in cellular compartments containing nucleic acids or in the organelles where they are stored before final application. However, the explanation of how degraded DNA components are exported from the dying cells for further reutilization remains open. RESULTS: Bioinformatic and experimental data presented in this paper indicate that two Arabidopsis staphylococcal-like nucleases, named CAN1 and CAN2, are anchored to the cell membrane via N-terminal myristoylation and palmitoylation modifications. Both proteins possess a unique hybrid structure in their catalytic domain consisting of staphylococcal nuclease-like and tRNA synthetase anticodon binding like motifs. They are neutral, Ca2+-dependent nucleaces showing a different specificity toward the ssDNA, dsDNA and RNA substrates. A study of microarray experiments and endogenous nuclease activity revealed that expression of CAN1 gene correlates with different forms of programmed cell death, while the CAN2 gene is constitutively expressed. CONCLUSIONS: In this paper we present evidence showing that two plant staphylococcal-like nucleases belong to a new, as yet unidentified class of eukaryotic nucleases, characterized by unique plasma membrane localization. The identification of this class of nucleases indicates that plant cells possess additional, so far uncharacterized, mechanisms responsible for DNA and RNA degradation. The potential functions of these nucleases in relation to their unique intracellular location are discussed. PMID- 23102439 TI - Gas-containing renal stones: findings from five consecutive patients. AB - OBJECTIVE: To describe the clinical course, microbiology, and metabolic findings of 5 patients presenting to our institution with gas-containing renal stones. MATERIALS AND METHODS: During a 20-month period beginning in 2009, 5 patients were identified by computed tomography scanning to harbor gas-containing renal calculi. Despite similar imaging and referral practice patterns, no such cases had been seen at our institution in the preceding 20 years. The records of these patients were reviewed to better characterize this unique condition. RESULTS: All 5 subjects were premenopausal women. One patient presented with urosepsis and 4 presented with flank pain. All had urinary tract infections, and Escherichia coli was isolated from a voided urine specimen in 3. Stone culture was positive in 2 and was concordant with the voided specimen in 1. The stones were solitary in 4 and multiple in 1 patient. All the stones were composed of calcium phosphate. Of the 5 patients, 3 had pure calcium phosphate stones and 2 had stones with calcium oxalate monohydrate components. Also, 3 subjects had diabetes mellitus, 3 had hypertension, and 1 had a history of gout. Two subjects underwent 24-hour urine metabolic testing, and abnormalities were identified in both. All patients were rendered stone free: 4 with percutaneous nephrostolithotomy and 1 using robotic pyelolithotomy. CONCLUSION: Gas-containing renal stones are rare but might be increasing in prevalence. The pathophysiology is unknown but is most likely influenced by a combination of metabolic and infectious factors. PMID- 23102440 TI - Critical analysis of outcome after open dismembered pyeloplasty in ectopic pelvic kidneys in a pediatric cohort. AB - OBJECTIVE: To evaluate the functional and morphologic outcome after open pyeloplasty for ureteropelvic junction obstruction (UPJO) in ectopic pelvic kidneys. MATERIALS AND METHODS: A retrospective review of all patients who underwent open pyeloplasty in ectopic pelvic kidneys was conducted. Records were evaluated with respect to age at presentation, preoperative imaging, surgical details, and postoperative course. Patients were followed up regularly for functional and morphologic outcome. Success was defined as symptomatic relief and radiographic improvement of obstruction at the last follow-up. RESULTS: Between 1995 and 2010, 680 patients with primary UPJO underwent open dismembered pyeloplasty at our center. Of these patients, 43 (6.3%) had UPJO in ectopic pelvic kidneys. No perioperative complications were encountered in the study group. Mean follow-up was 42 months (range, 18-90 months), and 5 patients were lost to follow-up. The overall success rate was 82.6%. Postoperative hydronephrosis was improved in 20 (52.6%), stable in 11 (29%), and worsened in 7 (18.4%). Postoperative renal function was improved in 12 (31.6%), stable in 19 (50%), and deteriorated in 7 (18.4%). Redo pyeloplasty was required in 4 patients and secondary nephrectomy in 3. Preoperative differential renal function and surgeon experience were statistically significant predictors of improvement in renal function after pyeloplasty. CONCLUSION: Open pyeloplasty for UPJO in ectopic pelvic kidneys is feasible, but varying degrees of hydronephrosis and radiologic obstruction persist after pyeloplasty that could be attributed to anatomy-related pelvocaliectasis, and so regular follow-up is warranted in this subpopulation. PMID- 23102441 TI - The natural history of penile length after radical prostatectomy: a long-term prospective study. AB - OBJECTIVE: To describe the penile length after radical prostatectomy (RP) in a long-term follow-up. MATERIALS AND METHODS: We evaluated prospectively the penile length of 105 patients with localized prostate cancer treated by open RP. Participants using therapy for penile rehabilitation were excluded from statistical analysis. Measurements of the stretched penis were taken preoperatively and at 3, 6, 12, 24, 36, 48, and 60 months postoperatively. The International Index of Erectile Function-Erectile Function (IIEF-EF) questionnaire was used to evaluate erectile function. The penile anthropometric measure used was the stretched length of the flaccid penis, from the pubopenile skin angle to the end of the glans, after the prepubic fat was depressed under maximum manual traction. RESULTS: The mean stretched penile length 3 months after RP decreased an average of 1 cm from baseline (P <.001). This mean difference persisted until 24 months. At 36 months, the penile length differed 0.6 cm. At 48 months (-0.3 cm) and 60 months (+0.4 cm), the mean differences in penile length before and after RP were not significant (P = .080 and P = .065, respectively). Erectile function was a predictor for early return of penile length. CONCLUSION: Nearly 1 cm of penile shortening after RP may be expected up to 12 months. However, a trend toward recovery of penile length occurs after 24 months of follow-up and is completely re-established after 48 months. The preserved erectile function after RP is a predictor for penile length recovery. PMID- 23102442 TI - Extremely delayed presentation of an enterocutaneous fistula after Marshall Marchetti-Krantz procedure. AB - A 77-year-old woman with a history of urinary stress incontinence, who underwent urethral suspension surgery (Marshall-Marchetti-Krantz procedure) 10 years earlier, presented with a suprapubic abdominal wall abscess. She was found to have an enterocutaneous fistula. The patient underwent an exploratory laparoscopy. The involved bowel segment was resected. A unique feature of the present case is the formation of an enterocutaneous fistula with an extremely long latency, which has not been previously reported in the literature. PMID- 23102443 TI - Autonomic nervous system dysfunction in lifelong premature ejaculation: analysis of heart rate variability. AB - OBJECTIVE: To identify autonomic nervous dysfunction in patients with lifelong premature ejaculation. METHODS: The study participants were 25 men with lifelong premature ejaculation and 25 healthy controls. The parameters of 24-hour heart rate variability that are influenced by the autonomic nervous system were compared between the men with lifelong premature ejaculation and the healthy controls. RESULTS: The laboratory results of all patients were within normal limits, and no significant differences were found between the patients and the controls in age, body weight, and body mass index. A low-frequency signal that is influenced by the sympathetic system was increased in the patients (P = .026). Furthermore, a high-frequency signal that is influenced by the parasympathetic system was decreased in the patients (P = .011). Finally, the low frequency-to high frequency ratio, an indicator of the balance between the two components of the autonomic nervous system, was increased in the patients (P = .002). CONCLUSION: To our knowledge, no study has investigated the influence of the autonomic nervous system on 24-hour heart rate variability in premature ejaculation. In the present study, sympathetic activity was increased in men with lifelong premature ejaculation; this overactivity might lead to lifelong premature ejaculation. Additional studies are required to reveal the possible alteration of the autonomic nervous system in premature ejaculation. PMID- 23102444 TI - Editorial comment. PMID- 23102445 TI - The use of tramadol "on-demand" for premature ejaculation: a systematic review. AB - OBJECTIVE: To determine the efficacy and safety of tramadol in the treatment of premature ejaculation (PE) by systematically reviewing the results of randomized controlled trials. MATERIALS AND METHODS: All studies evaluating the efficacy of tramadol for the treatment of PE published in peer reviewed medical journals between 2006 and March 2012 were identified by searching for the keywords "premature ejaculation" and "tramadol" in the PubMed database. Only randomized controlled trials published in the English language were included. RESULTS: A total of 5 articles, comprising 823 patients, met the inclusion criteria for further analysis. Overall, tramadol on-demand results in a significant improvement in mean intravaginal ejaculatory latency time and symptom scores compared with placebo and in an improvement in partner sexual satisfaction scores. The rate of short-term adverse effects is low. CONCLUSION: Tramadol is an effective treatment for patients with PE and represents a promising alternative to the currently used oral pharmacologic agents. Longer-term safety studies, and those comparing tramadol with the selective serotonin receptor inhibitors, are essential to determine the place of tramadol in the treatment of this distressing condition. PMID- 23102447 TI - Editorial comment. PMID- 23102446 TI - Out-of-pocket expenses and treatment choice for men with prostate cancer. AB - OBJECTIVE: To describe the knowledge of, and attitudes toward, out-of-pocket expenses (OOPE) associated with prostate cancer treatment and the influence of OOPE on the treatment choices of patients with prostate cancer. MATERIALS AND METHODS: We undertook a qualitative research study for which we recruited patients with clinically localized prostate cancer. Patients answered a series of open-ended questions during a semistructured interview and completed a questionnaire about the physician's role in discussing OOPE, the burden of OOPE, the effect of OOPE on treatment decisions, and previous knowledge of OOPE. RESULTS: A total of 41 (26 white and 15 black) eligible patients were enrolled from the urology and radiation oncology practices of the University of Pennsylvania. Qualitative assessment revealed 5 major themes: (a) "my insurance takes care of it"; (b) "health is more important than cost"; (c) "I did not look into it"; (d) "I cannot afford it but would have chosen the same treatment"; and (e) "It is not my doctor's business." Most patients (38 of 41, 93%) reported that they would not have chosen a different treatment even if they had known the actual OOPE of their treatment. Patients who reported feeling burdened by OOPE were socioeconomically heterogeneous, and their treatment choices remained unaffected. Only 2 patients stated they knew "a lot" about the likely OOPE for different prostate cancer treatments before choosing their treatment. CONCLUSION: Among insured patients with prostate cancer treated at a large academic medical center, few had knowledge of OOPE before making treatment choices. PMID- 23102448 TI - Physical activity modifies the associations between genetic variants and hypertension in the Chinese children. AB - BACKGROUND: Childhood hypertension is a complex disease influenced by both genetic and environmental factors. We aimed to examine the effect of interactions of five polymorphisms with physical activity on blood pressure (BP)/hypertension in the Chinese children. METHODS AND RESULTS: A population-based case-control study was carried out in Beijing of China in 2004, which included 619 hypertensive cases and 2458 normal BP controls. Physical activity information was collected through the use of a validated questionnaire, and five polymorphisms were genotyped using TaqMan. In active group, there was no significant association of five polymorphisms and genetic risk score with systolic/diastolic BP (SBP/DBP) and risk of hypertension (all p > 0.05). In contrast, in inactive group, two polymorphisms and genetic risk score were significantly associated with SBP (rs17249754: beta = 1.26, 95% confidence interval (CI) 0.61-1.90, p < 0.001; rs1004467: beta = 0.68, 95%CI 0.03-1.32, p = 0.039; genetic risk score: beta = 1.54, 95%CI 0.74-2.33, p < 0.001); three polymorphisms and genetic risk score were significantly associated with hypertension (rs17249754: odds ratio (OR) = 1.27, 95%CI 1.08-1.49, p = 0.004; rs1378942: OR = 1.25, 95%CI 1.00-1.57, p = 0.050 (marginally significant); rs16998073: OR = 1.17, 95%CI 1.01-1.37, p = 0.044; genetic risk score: OR = 1.38, 95%CI 1.13-1.68, p = 0.001). CONCLUSIONS: The present study provides evidence that interactions between recently identified variants and physical activity play important roles in the regulation of BP and development of hypertension. Physical activity should be prescribed for hypertensive children, especially for those with high risk genetic alleles. PMID- 23102449 TI - Endothelial function and cardiovascular risk in patients with idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: To evaluate cardiovascular risk factors and pre-clinical atherosclerosis in subjects affected by idiopathic sudden sensorineural hearing loss (ISSHL). METHODS: In this study, 29 ISSHL patients and 29 healthy controls were evaluated. All of the patients underwent a complete audiovestibular and clinical evaluation. Carotid intima-media thickness (C-IMT) and flow-mediated dilation (FMD) of the brachial artery were assessed as early markers of atherosclerosis. RESULTS: Our results showed that FMD was significantly lower in the ISSHL patients than in the controls (5.6 +/- 1.6% vs. 7.7 +/- 3.7%, p < 0.01). Moreover, the total cholesterol and low density lipoprotein cholesterol were significantly higher in the ISSHL patients than in the controls (p < 0.05). The two groups did not differ with regards to C-IMT and other cardiovascular risk factors. Vestibular involvement was shown to be associated with lower FMD values (4.1 +/- 1.7% vs. 5.8 +/- 1.5%, p < 0.05). No relationship was found between C IMT and vestibular involvement. Finally, multiple logistic regression highlighted the finding that only FMD values seemed to predispose individuals to developing ISSHL (p = 0.03, OR: 1.4). CONCLUSIONS: ISSHL seemed to be associated with vascular endothelial dysfunction and an increased cardiovascular risk, which supports the hypothesis of a vascular aetiology for this disease. PMID- 23102450 TI - A high CHA(2)DS(2)-VASc score is associated with a high risk for critical limb ischemia in peripheral arterial occlusive disease patients. AB - BACKGROUND: The CHA(2)DS(2)-VASc (congestive heart failure, hypertension, age >= 75 years (doubled), type 2 diabetes, previous stroke, transient ischemic attack, or thromboembolism (doubled), vascular disease, age 65-75 years, and sex category) score was published as a predictive scoring model for stroke in atrial fibrillation patients. As multiple vascular risk factors are included in this score we evaluated the occurrence of critical limb ischemia (CLI) in peripheral arterial occlusive disease (PAOD) patients according to their CHA(2)DS(2)-VASc score independent of a coexisting atrial fibrillation. METHODS: We evaluated 2237 PAOD patients treated at our institution from 2005 to 2010. CHA(2)DS(2)-VASc score was calculated and the occurrence of CLI was investigated. Furthermore all constituents of the score were investigated concerning association with CLI. RESULTS: Frequency of CLI was higher in patients with a high CHA(2)DS(2)-VASc score. Age >= 75 years was associated with an increased risk for CLI (OR 3.0), as was age 65-75 years (OR 1.8), type 2 diabetes (OR 2.8), and the factor previous stroke, transient ischemic attack, or thromboembolism (OR 1.4). The occurrence of arterial hypertension was protective for CLI (OR 0.6). Sex and congestive heart failure were not associated with an increased CLI risk. CONCLUSION: High CHA(2)DS(2)-VASc score is associated with a high CLI risk. As not all constituents are equally associated with CLI and some are even protective, a new score including only some of the factors should be evaluated for the prediction of CLI. PMID- 23102454 TI - Achieving universal health care coverage: Current debates in Ghana on covering those outside the formal sector. AB - BACKGROUND: Globally, extending financial protection and equitable access to health services to those outside the formal sector employment is a major challenge for achieving universal coverage. While some favour contributory schemes, others have embraced tax-funded health service cover for those outside the formal sector. This paper critically examines the issue of how to cover those outside the formal sector through the lens of stakeholder views on the proposed one-time premium payment (OTPP) policy in Ghana. DISCUSSION: Ghana in 2004 implemented a National Health Insurance Scheme, based on a contributory model where service benefits are restricted to those who contribute (with some groups exempted from contributing), as the policy direction for moving towards universal coverage. In 2008, the OTPP system was proposed as an alternative way of ensuring coverage for those outside formal sector employment. There are divergent stakeholder views with regard to the meaning of the one-time premium and how it will be financed and sustained. Our stakeholder interviews indicate that the underlying issue being debated is whether the current contributory NHIS model for those outside the formal employment sector should be maintained or whether services for this group should be tax funded. However, the advantages and disadvantages of these alternatives are not being explored in an explicit or systematic way and are obscured by the considerable confusion about the likely design of the OTPP policy. We attempt to contribute to the broader debate about how best to fund coverage for those outside the formal sector by unpacking some of these issues and pointing to the empirical evidence needed to shed even further light on appropriate funding mechanisms for universal health systems. SUMMARY: The Ghanaian debate on OTPP is related to one of the most important challenges facing low- and middle-income countries seeking to achieve a universal health care system. It is critical that there is more extensive debate on the advantages and disadvantages of alternative funding mechanisms, supported by a solid evidence base, and with the policy objective of universal coverage providing the guiding light. PMID- 23102455 TI - Association of family income with BMI from childhood to adult life: a birth cohort study. AB - OBJECTIVE: To investigate the association of family income at birth with BMI among young adults who have been followed since birth. DESIGN: A birth cohort study. SETTING: In 1982, all children born in Pelotas, southern Brazil, were included in a perinatal survey and visited at ages 1, 2, 4, 15, 18-19 and 23 years. SUBJECTS: Cohort members (n 4297) were traced and interviewed in 2004 2005. In all follow-ups, participants were weighed and measured, and BMI and prevalence of obesity were calculated for each age. Family income was obtained in minimum wages in 1982 and as a continuous variable, in reais, in later follow ups. Skin colour was self-reported in 2004-2005. RESULTS: Mean BMI and prevalence of obesity differed between males and females. In males, a direct relationship was found throughout life and among females this relationship was modified by age. During childhood, BMI was higher among girls from higher income groups and this association was inversed at age 23 years. At this same age, mean BMI among black women was 1.3 kg/m2 higher than among white women, even after adjustment for current family income. CONCLUSIONS: The findings show in men that the relationship between income and BMI is similar to that seen in less developed areas, whereas among adult women the relationship is similar to that observed in developed countries. In addition to the effect of socio-economic status, skin colour also has an influence on the BMI of adult women. PMID- 23102456 TI - Identification of oxytocin receptor in the dorsal horn and nociceptive dorsal root ganglion neurons. AB - Oxytocin (OT) secreted by the hypothalamo-spinal projection exerts antinociceptive effects in the dorsal horn. Electrophysiological evidence indicates that OT could exert these effects by activating OT receptors (OTR) directly on dorsal horn neurons and/or primary nociceptive afferents in the dorsal root ganglia (DRG). However, little is known about the identity of the dorsal horn and DRG neurons that express the OTR. In the dorsal horn, we found that the OTR is expressed principally in neurons cell bodies. However, neither spino-thalamic dorsal horn neurons projecting to the contralateral thalamic ventral posterolateral nucleus (VPL) and posterior nuclear group (Po) nor GABaergic dorsal horn neurons express the OTR. The OTR is not expressed in skin nociceptive terminals or in dorsal horn nociceptive fibers. In the DRG, however, the OTR is expressed predominantly in non-peptidergic C-fiber cell bodies, but not in peptidergic or mechanoreceptor afferents or in skin nociceptive terminals. Our results suggest that the antinociceptive effects of OT are mediated by direct activation of dorsal horn neurons and peripheral actions on nociceptive, non peptidergic C-afferents in the DRG. PMID- 23102457 TI - Myosin-driven intercellular transportation of wheat germ agglutinin mediated by membrane nanotubes between human lung cancer cells. AB - Membrane nanotubes can facilitate direct intercellular communication between cells and provide a unique channel for intercellular transfer of cellular contents. However, the transport mechanisms of membrane nanotubes remain poorly understood between cancer cells. Also largely unknown is the transport pattern mediated by membrane nanotubes. In this work, wheat germ agglutinin (WGA), a widely used drug carrier and potential antineoplastic drug, was labeled with quantum dots (QDs-WGA) as a model for exploring the intercellular transportation via membrane nanotubes. We found that membrane nanotubes allowed effective transfer of QDs-WGA. Long-term single-particle tracking indicated that the movements of QDs-WGA exhibited a slow and directed motion pattern in nanotubes. Significantly, the transport of QDs-WGA was driven by myosin molecular motors in an active and unidirectional manner. These results contribute to a better understanding of cell-to-cell communication for cancer research. PMID- 23102458 TI - [Science, citation culture, and money]. PMID- 23102459 TI - In vivo cell aggregations of a recent swine biofilm-forming isolate of Leptospira interrogans strain from Argentina. AB - Leptospirosis is a zoonosis of ubiquitous distribution caused by spirochetes. Leptospires exist either as saprophytic water-associated organisms or as animal pathogens that can survive in water. Previous works have demonstrated that both saprophytic and pathogenic leptospires are able to produce functional biofilms, which consist of a community of bacteria embedded in an extracellular matrix attached to a surface. This structure is believed to provide protection from environmental aggressiveness. In the present study, we analyzed the capacity of biofilm formation both of a a recent field isolate of Leptospira interrogans serovar Pomona obtained from an aborted swine fetus and of the saprophytic Leptospira biflexa serovar Patoc. We used light microscopy, immunofluorescence, and scanning electron microscopic examinations on glass and polystyrene plate models to evaluate the process in vitro. The ability to form bacterial aggregations in vivo was tested using pregnant guinea pigs infected with both strains. We obtained biofilms both on glass and plastic surfaces. Scanning electron microscopic analysis showed differences in the biofilm structure formed by both strains. L. interrogans serovar Pomona cell aggregations were observed in placental tissues by light microscopy. Biofilms and cell aggregations are consistent with the life of saprophytic strains in water and could help pathogenic strains to colonize the host and lead to abortion in pregnant animals. PMID- 23102460 TI - [Comparison of nucleic acid extraction efficiency using different commercial kits and qPCR. Effect of inhibitors]. AB - The detection of specific nucleic acid (NA) sequences by PCR has revolutionized the biological and medical sciences. Real-time PCR (qPCR) opened up the possibility of obtaining quantitative results. NA extraction is a decisive step prior to qPCR since it may produce either the removal or co-extraction of inhibitory substances of the enzymatic reaction, which in turn affects the amplification efficiency. In the present work we compared the commercial NA extraction kits from Qiagen, Invitrogen and Macherey-Nagel, which were used to extract DNA from mice blood artificially infected with Trypanosoma cruzi and PP7 RNA, Pseudomonas aeruginosa bacteriophage, in spiked aqueous matrices. NA recovery efficiency in samples without inhibitors was similar for the three extraction kits. However, the Invitrogen kit was the only one that remained unaffected in the presence of inhibitors in the samples. PMID- 23102461 TI - Siderophores of Stenotrophomonas maltophilia: detection and determination of their chemical nature. AB - Stenotrophomonas maltophilia is an emerging nosocomial pathogen. Despite the broad spectrum of syndromes associated with S. maltophilia infections, little is known about its virulence factors, including siderophore production. The aims of this work were to detect S. maltophilia siderophores and to determine their chemical nature. We studied 31 S. maltophilia isolates from device-associated infections, recovered over the period 2006-2011 at Hospital de Clinicas Jose de San Martin, Buenos Aires, Argentina, and the strain K279a, whose genome has been fully sequenced. The production of siderophores was screened by the chrome azurol S (CAS) agar assay, previously modified to detect siderophores in this species. When grown on modified CAS agar plates, all the clinical isolates and K279a were CAS-positive for siderophore production. In order to determine the chemical nature of siderophores, the Csaky (hydroxamate-type) and Arnow (catechol-type) assays were used. All S. maltophilia isolates produced catechol-type siderophores, but hydroxamate-type siderophores were not detected. PMID- 23102462 TI - [Production and evaluation of a purified protein derivative from an Argentine strain of Mycobacterium avium subsp. paratuberculosis]. AB - Purified Protein Derivatives (PPDs) are non-defined antigens prepared from mycobacteria cultures. They are usually employed to evaluate the specific cellular immune response both in animals and humans. Bovine and avian PPDs are usually employed as antigens in mycobacterial infections such as tuberculosis and paratuberculosis. Nevertheless, PPD from Mycobacterium avium subsp. paratuberculosis, (PPDj) is neither commonly used nor frequently available. However, PPD from Mycobacterium avium subsp. avium is in fact used. We aimed to obtain and evaluate the performance of a PPDj from a local isolate of MAP using the aInterferon-release assay. The stimulation of aInterferon-release was significantly different between infected and control cattle when this antigen, named PPDj-IB, was used. Stimulation in the infected animals was similar with both antigens (PPDa and PPDj-IB). However, some animals were positively stimulated with PPDj-IB and not with PPDa. We demonstrated by Western blot that two antigenic molecules, lipoarabinoman and APA/ModD antigen were differentially represented in both PPDs. This could explain the difference in stimulation induction of yIFN observed at individual level. Although PPDj-IB could not improve PPDa performance, we could easily produce an effective purified protein derivative for in vitro assays. PMID- 23102463 TI - [Evaluation of direct susceptibility testing from blood culture bottles. Clinical usefulness]. AB - A prospective observational study was conducted in two hospitals of Buenos Aires city (Argentina); 191 clinically significant monomicrobial gram-negative bloodstream infections were included in the study, which combined the Bact-Alert System Blood culture machine and the Vitek 2C System. Organism identification and susceptibility results directly from blood culture bottles were compared with those obtained from cards inoculated with a standardized bacterial suspension obtained following subculture on agar. By comparing the results obtained from pure cultures with those by the Vitek 2C System as reference method, the agreement between the reference method and the direct identification from positive blood cultures was 99 %. By antimicrobial susceptibility testing, the overall categorical accuracy was 99 % (0.22 %, very major errors, 0.17 %, major errors and 0.61 %, minor errors). One hundred and eight (56,8 %) bloodstream infections were treated empirically with adequate antibiotics. After the results obtained directly from the bottles were reported, antimicrobial therapy was changed in 116 (60.7 %) of the episodes. PMID- 23102464 TI - [Fatal bacteremia related to Capnocytophaga sputigena in a hematological patient with type T non-Hodgkin lymphoma. Diagnosis by 16S rRNA gene sequencing]. AB - We described a case of fatal bacteremia related to Capnocytophaga sputigena in a hematological patient. The strain was identified by 16S rRNA gene sequencing. PMID- 23102465 TI - Utilization of bacteriological culture for increased diagnostic performance at a tuberculosis reference center hospital. AB - The purpose of this study was to assess the increase in positive results of bacteriological diagnostic tests for tuberculosis with the utilization of culture at a referral hospital for tuberculosis (TB). A retrospective analysis was conducted based on the positive bacteriological results obtained at the Julia Kubistchek Hospital. The number of bacteriological diagnoses was increased by 24.6 % with the utilization of culture of sputum samples and by 56.1% of bronchoalveolar lavage samples. With regard to pleural fluid, all six positive cultures were negative for bacilloscopy. Mycobacterium tuberculosis was isolated in 59.6 % of positive cultures. Since mycobacterial culture was not undertaken for all clinical samples, this procedure is an important laboratory routine at the Julia Kubistchek Hospital in order to learn the real TB prevalence. PMID- 23102466 TI - [Immunoenzymatic evaluation of the recombinant SAPA protein of Trypanosoma cruzi in naturally infected dogs]. AB - We evaluated the recombinant antigen SAPA (Shed Acute Phase Antigen) for the detection of Trypanosoma cruzi antibodies in sera from naturally infected dogs. The technique used was ELISA and the antigens were a homogenate of parasite T. cruzi (ELISA-H) and the recombinant SAPA (ELISA-SAPA). We analyzed 93 sera from dogs by ELISA-H and ELISA-SAPA, which were grouped as follows: G1: 11 negative control sera from the city of Salta, G2: 11 positive control sera from dogs naturally infected with T. cruzi and G3: 71 samples of dogs belonging to a Chagas disease-endemic area. The sensitivity and specificity of ELISA-SAPA were 100 %. The kappa index between ELISA-H and ELISA-SAPA was 0,85. These results confirm the use of SAPA antigen in the diagnosis of infection with T. cruzi in dogs. PMID- 23102468 TI - Association between milking practices and psychrotrophic bacterial counts in bulk tank milk. AB - The objective of this work was to determine on-farm risk factors for psychrotrophic bacterial counts in bulk tank milk from dairy farms in Argentina. Raw milk samples from bulk tanks of 27 dairy farms were examined for total psychrotrophic counts (TPC), proteolytic psychrotrophic counts (PPC) and lipolytic psychrotrophic counts (LPC) (dependent or outcome variables). A survey recording infrastructure conditions, milking equipment and milking management (independent variables) was performed. Bivariate association proofs and logistic regression analyses were used to determine association between independent variables and psychrotrophic bacterial counts. Milk cooled in plate heat exchangers or barrel tanks were 16.39 and 10.52 times more likely to yield TPC and PPC above the standard established for high quality milk compared with milk cooled in bulk tanks, respectively. Periodic cleaning of cooling tanks (3 times a week or daily) was associated with lower TPC (approximately 1.5 log CFU/ml) than weekly cleaning frequency and farms where milkers did not wash their hands during milking time were 7.81 times more likely to have higher PPC. No association was found between LPC and any of the independent variables. The only variable associated with TPC and PPC in a logistic regression model was the refrigeration system used on the farm. Dairy farms that possessed bulk milk cooling tanks yielded the lowest bacterial counts. Results of this study highlight the importance of both the type of cooling system used on the farm and its adequate hygienic maintenance for obtaining low pshychrotrophic counts at dairy farm. PMID- 23102467 TI - Plasmid-Encoded AmpC (pAmpC) in Enterobacteriaceae: epidemiology of microorganisms and resistance markers. AB - CMY-2 Beta-lactamase is an important cause of Beta-lactam resistance in Enterobacteriaceae and constitutes the most widespread pAmpC. Although CMY-2 has been previously recognized in our region, the real prevalence and epidemiology of this resistance marker was uncertain. During August-October 2009, we conducted a multicenter, prospective study to determine pAmpC prevalence and to characterize CMY-2 producing Escherichia coli associated plasmids. Plasmid-encoded AmpC prevalence was 0.9 % in enterobacteria in this period, being CMY-2 prevalent and to a lesser extent DHA. Molecular typing of CMY-2- producing Escherichia coli isolates showed several lineages. Moreover, replicon typing of cmy-2- containing plasmids displayed a broad diversity in Inc/cmy-2 links. Therefore, association of cmy-2 with specific transposon elements may be responsible for the spread of this resistance marker in Enterobacteriaceae. PMID- 23102469 TI - Characterization of Listeria monocytogenes isolates from cattle and ground beef by pulsed-field gel electrophoresis. AB - The aims of this study were to determine the occurrence of Listeria monocytogenes in cattle feces and ground beef, to characterize these strains by pulsed-field gel electrophoresis and to compare them to three listeria strains found in humans. Cattle from different origins (n = 250) and ground beef obtained from supermarkets (n = 40) were sampled. The results show low occurrence in cattle feces (0.4 %) but a higher presence in ground beef (37 %). An important part of the ground beef strains (80 %) had > 95 % similarity with a strain isolated from a human sporadic case and the ATCC 19115 used as control. The strain isolated from cattle feces had 93 % similarity to clone 009, previously associated with a listeriosis outbreak related to cheese. Cattle and ground beef can harbor virulent L. monocytogenes strains. Further studies in animals and animal products are needed to improve listeriosis control. PMID- 23102470 TI - Bovine paratuberculosis: a review of the advantages and disadvantages of different diagnostic tests. AB - Paratuberculosis (PTB), or Johne's disease, is a chronic infectious granulomatous enteritis of ruminants, caused by Mycobacterium avium subspecies paratuberculosis (Map). It is characterized by diarrhea and progressive cachexia, which may cause the death of the animal. Calves are the most susceptible to infection. Infected animals excrete Map mainly by the feces. PTB is endemic worldwide, with high prevalence levels, strong economic impact and public health relevance because of its possible association with Crohn's disease. Although the current reference diagnostic test is identification of Map in the bacterial culture, there are different diagnostic tests to identify infected individuals and/or herds. The sensitivity and specificity of these tests vary according to the stage of the disease in the animals to be evaluated. The correct choice and application of each of these diagnostic tests will ensure their success and may allow to establish a control program. The aim of this work is to review and discuss the different diagnostic tests used in the detection of Map-infected animals, focusing on their advantages and disadvantages. PMID- 23102471 TI - [Advances in the development of vaccines for bovine neosporosis]. AB - Neosporosis, a disease caused by the obligate intracellular protozoan Neospora caninum, produces abortions in cattle. The severe economic losses in cattle industry justify the need to develop control measures for preventing bovine abortion. Apicomplexan parasitic resistance is associated with T helper 1 immune response mediated by CD4 cytotoxic T lymphocytes, the production of interferon gamma, interleukin-12, tumor necrosis factor and immunoglobulin G2. The reduction of vertical transmission in subsequent pregnancies and the low levels of abortion repetition suggests the existence of protective immune mechanisms. Inoculation with live tachyzoites before mating protects against infection and abortion. Antecedents of the development of live vaccines against other protozoa stimulate research to develop a live vaccine against N. caninum. On the other hand, an inactivated vaccine with low efficacy against neosporosis is useful in the prevention of abortion in farms with epizootic disease. A neosporosis vaccine should avoid abortion, transplacental transmission and infection persistence. In the present work, advances in vaccine development including lysate of tachyzoites, live parasites, recombinant antigens and vaccine vectors are reviewed. PMID- 23102472 TI - [Trichosporon asahii]. PMID- 23102473 TI - A lipid mediator controls neutrophil recruitment in acute lung injury--should we really be surprised? AB - New therapeutic approaches are sorely needed for acute lung injury. Neutrophil recruitment is a pathological hallmark of this syndrome, and is mainly regulated by CXC chemokine receptor 2 and its ligand CXC ligand 1. Rossaint and colleagues have described a new mechanism for regulation of this axis by 12/15-lipoxygenase products. This work opens the door for new therapeutic approaches and highlights the crucial interplay between lipid mediators and chemokines, a time-honored but often-ignored concept. PMID- 23102474 TI - Role of serial quantitative assessment of right ventricular function by strain in pulmonary arterial hypertension. AB - The aim of this study was to assess whether serial quantitative assessment of right ventricular (RV) function by speckle-based strain imaging is affected by pulmonary hypertension-specific therapies and whether there is a correlation between serial changes in RV strain and clinical status. RV longitudinal systolic function was assessed using speckle-tracking echocardiography in 50 patients with pulmonary arterial hypertension (PAH) before and after the initiation of therapy. The mean interval to follow-up was 6 +/- 2 months. Subsequent survival was assessed over 4 years. Patients demonstrated a mean increase in RV systolic strain from -15 +/- 5 before to -20 +/- 7% (p = 0.0001) after PAH treatment. Persistence of or progression to a severe reduction in free wall systolic strain (<-12.5%) at 6 months was associated with greater disease severity (100% were in functional class III or IV vs 42%, p = 0.005), greater diuretic use (86% vs 40%, p = 0.02), higher mean pulmonary artery pressure (67 +/- 20 vs 46 +/- 17 mm Hg, p = 0.006), and poorer survival (4-year mortality 43% vs 23%, p = 0.002). After adjusting for age, functional class, and RV strain at baseline, patients with >= 5% improvement in RV free wall systolic strain had a greater than sevenfold lower mortality risk at 4 years (hazard ratio 0.13, 95% confidence interval 0.03 to 0.50, p = 0.003). In conclusion, serial echocardiographic assessment of RV longitudinal systolic function by quantitative strain imaging independently predicts clinical deterioration and mortality in patients with PAH after the institution of medical therapy. PMID- 23102475 TI - Patent foramen ovale screening by ear oximetry in divers. AB - The aim of this study was to test the hypothesis that ear oximetry immediately after the release of a sustained Valsalva maneuver accurately detects patent foramen ovale (PFO). One hundred sixty-five scuba divers underwent transesophageal echocardiography (TEE; reference method) for PFO assessment. Ear oximetry of the right earlobe was performed in a different room within a time frame of 2 hours before or after TEE. The subject and the oximetry operator were unaware of the results of TEE. Oxygen saturation (SO(2)) measurements were obtained at baseline and during the release phase of 4 Valsalva maneuvers within 10 minutes, and the average SO(2) change (SO(2) at baseline minus SO(2) at Valsalva release) was determined as the primary study end point. One hundred seventeen divers had no PFO, and 48 (29%) had PFO by TEE (mean age 39 +/- 8 years). The average SO(2) change was 0.79 +/- 1.13% (i.e., a slight absolute SO(2) decrease in response to the Valsalva maneuver) in the group without PFO and 1.67 +/- 1.19% in the PFO group (p <0.0001). Using receiver-operating characteristic curve analysis, a PFO as defined by TEE could be detected at a threshold of a Valsalva-induced decrease in SO(2) of >=0.825 percentage points in comparison to baseline (sensitivity 0.756, specificity 0.706, area under the receiver-operating characteristic curve 0.763, p <0.0001, negative predictive value 0.882). In conclusion, the entirely noninvasive method of ear oximetry in response to repetitive Valsalva maneuvers is accurate and useful as a screening method for the detection of a PFO, as shown in this study of divers. PMID- 23102476 TI - Infectious disease emergencies: frontline clinical pearls. AB - This article reviews various infectious disease emergencies from an internist's perspective. Key epidemiologic, diagnostic, and therapeutic points are reviewed with an emphasis on timely and appropriate initial management. The content serves to highlight essential points that are discussed in subsequent articles in this issue and to elucidate pearls that may facilitate timely and appropriate management. PMID- 23102477 TI - Role of molecular diagnostics in the management of infectious disease emergencies. AB - In the setting of infectious disease emergencies, rapid and accurate identification of the causative agent is critical to optimizing antimicrobial therapy in a timely manner. It is clearly evident that the age of molecular diagnostics is now upon us, with real-time PCR becoming the standard of diagnosis for many infectious disease emergencies in either monoplex or multiplex format. Other molecular techniques such as whole or partial genome sequencing, microarrays, broad-range PCR, restriction fragment length polymorphisms, and molecular typing are also being used. However, for most small clinical laboratories, implementation of these advanced molecular techniques is not feasible owing to the high cost of instrumentation and reagents. If these tests are not available in-house, samples can be sent to national reference laboratories (eg, Mayo Medical Laboratories and Quest Diagnostics) for real-time PCR assays that can be completed in 1 day. It is anticipated that over time commercial real-time PCR tests and instrumentation will become more standardized and affordable, allowing individual laboratories to conduct tests locally, thus further reducing turnaround time. Although real-time PCR has been proved to expand our diagnostic capability, it must be stressed that such molecular methodology constitutes only an additional tool in the diagnosis of infectious diseases in emergency situations. Phenotypic methodologies (staining, cultures, biochemical tests, and serology) still play a critical role in identifying, confirming, and providing antibiotic susceptibility testing for many microbial pathogens. As multiplex assays become increasingly available, there will be even greater temptation for taking a "shotgun" approach to diagnostic testing. These new technologies will not substitute for a proper history and physical examination leading to a thoughtful differential diagnosis. None the less, these new molecular tests increase the capability of the diagnostician to rapidly identify the microbiological etiology of an infection. An added advantage of rapid diagnostic tests often not emphasized is the capability to rule out certain diagnoses for which unnecessary antimicrobial therapy may otherwise be instituted and/or continued. PMID- 23102478 TI - Choosing optimal antimicrobial therapies. AB - Life-threatening infectious disease emergencies require immediate, aggressive parenteral administration of antimicrobial agents to ensure high bactericidal concentrations of drug at the site of infection. Usually initial treatment is empiric until culture results and antimicrobial sensitivities are reported. This approach necessitates the use of broad-spectrum bactericidal agents that will eradicate the presumed infecting organism(s), which potentially could be multidrug resistant. For infections potentially attributable to gram-positive bacteria, vancomycin is commonly used because it will be effective for highly resistant strains such as MRSA and multidrug-resistant S pneumoniae. For gram negative infections, broad-spectrum beta-lactams, such as ceftriaxone, piperacillin-tazobactam, and the carbapenems, are commonly chosen. Excellent alternatives include the fluoroquinolone antibiotics. For nosocomial infections whereby P aeruginosa and other highly resistant organisms may be the cause, antipseudomonal beta-lactams such as cefepime, ceftazidime, piperacillin tazobactam, or doripenem may be used as well as the fluoroquinolone, ciprofloxacin. For anaerobic infections, it is usually necessary to add either metronidazole or clindamycin. Once an infection is under control and the culture and sensitivity results are reported, it is important to switch to the most narrow-spectrum agent possible. Taking this action will decrease the potential for adverse drug effects and the risk of development of antibiotic-induced resistance. PMID- 23102479 TI - Endocrine and metabolic changes during sepsis: an update. AB - The authors have reviewed the most recent and relevant literature from which reasonable conclusions may be drawn. This article highlights important endocrine and metabolic changes, and provides possible explanations for observed perturbations. Obviously infectious disease specialists are not charged with the primary responsibility of addressing these issues, which have largely remained the domain of endocrinologists and intensivists. However, infectious disease specialists use a variety of drugs that can contribute to these abnormalities. Therefore, a constant dialogue between specialists would enhance the quality of care and also contribute immensely to favorable outcomes. PMID- 23102480 TI - Head and neck emergencies: bacterial meningitis, encephalitis, brain abscess, upper airway obstruction, and jugular septic thrombophlebitis. AB - Head and neck infectious disease emergencies can be rapidly fatal without prompt recognition and treatment. Empiric intravenous (IV) antibiotics should be initiated immediately in any patient with suspected bacterial meningitis, and IV acyclovir in any patient with suspected encephalitis. Surgical intervention is often necessary for brain abscesses, epiglottitis, and Ludwig's angina. A high index of suspicion is often needed to diagnose epiglottitis, Ludwig's angina, and Lemierre's syndrome. Brain infections can have high morbidity among survivors. In this article, the causes, diagnostic tests, treatment, and prognosis are reviewed for some of the more common head and neck infectious disease emergencies. PMID- 23102481 TI - Pulmonary emergencies: pneumonia, acute respiratory distress syndrome, lung abscess, and empyema. AB - This article describes the clinical presentation of pneumonia, acute respiratory distress syndrome, lung abscess, and empyema: life-threatening infections of the pulmonary system. The etiology and risk factors for each of these conditions are described, diagnostic approaches are discussed, and evidence-based management options are reviewed. PMID- 23102482 TI - Cardiac emergencies: infective endocarditis, pericarditis, and myocarditis. AB - Cardiac infections presenting as emergencies include complications of infective endocarditis, including congestive heart failure, chordae tendinae rupture, cardiac arrhythmias, and embolic phenomenon; acute pericarditis, including cardiac tamponade; and acute myocarditis presenting with malignant cardiac arrhythmias or congestive heart failure. Most of these emergent infectious disease manifestations of the cardiovascular system have a good prognosis if diagnosed early and managed appropriately. Newer diagnostic modalities and combined treatment guidelines are available from the European Society of Cardiology and the American Heart Association. PMID- 23102483 TI - Intra-abdominal and pelvic emergencies. AB - The diversity in intra-abdominal/pelvic infections is more than any other organ system. Several clinical scenarios can end up in intra-abdominal infections. The common causes include penetrating abdominal trauma, abdominal surgery, diverticulitis, appendicitis, pancreatitis, biliary disease, perforated viscus, and primary peritonitis. Intra-abdominal infections can masquerade as fever of obscure origin or as dysfunction of neighboring organs, such as lower lobe pneumonia related to a subphrenic abscess or an abscess causing small bowel obstruction. An urgent surgical intervention is the mainstay of the management of serious intra-abdominal infections. PMID- 23102484 TI - Necrotizing soft-tissue infections. AB - NSTI is a life-threatening, surgical, and medical emergency. Clinical presentation, at least in the initial phase, can be misleading. Various studies have shown that delay in surgical debridement is associated with increased mortality. A high index of suspicion is important in early recognition and in instituting prompt therapy without delay. Early diagnosis, aggressive surgical debridement, aggressive supportive care, and optimal presumptive antibiotic therapy significantly improve morbidity and mortality associated with NSTIs. PMID- 23102485 TI - Sepsis syndrome, bloodstream infections, and device-related infections. AB - The diagnosis of sepsis is challenging given the lack of appropriate diagnostic methods and the inaccuracy of diagnostic criteria. Early resuscitation, intravenous antibiotics, and source control are crucial in the management of septic patients. The treatment of catheter-related bloodstream infection (CRBSI) often comprises 1 to 2 weeks of intravenous antibiotics plus catheter removal. Infections related to surgical devices are more difficult to manage because they require longer duration of therapy and possibly multiple surgical procedures. This review represents an update on the diagnosis and management of sepsis, catheter-related blood stream infections and some clinically important device related infections. PMID- 23102486 TI - Infectious disease emergencies in returning travelers: special reference to malaria, dengue fever, and chikungunya. AB - This review article discusses important infectious illnesses, namely malaria, dengue, and chikungunya, in travelers returning from endemic areas. Malaria and dengue are two of the most common systemic illnesses reported in returning travelers. Because chikungunya is gaining importance, it is also briefly discussed. The clinical significance of these diseases is mainly due to the possibility of sudden deterioration with high mortality in clinically healthy looking patients. The key clinical features, their diagnosis, and treatment algorithms are discussed in detail to help in early diagnosis and appropriate clinical management of such travelers presenting in emergency departments. PMID- 23102487 TI - Medical Clinics of North America. Interventions in infectious disease emergencies. Preface. PMID- 23102488 TI - Imaging of nonthrombotic pulmonary embolism: biological materials, nonbiological materials, and foreign bodies. AB - Nonthrombotic pulmonary embolism is defined as embolization to the pulmonary circulation caused by a wide range of substances of endogenous and exogenous biological and nonbiological origin and foreign bodies. It is an underestimated cause of acute and chronic embolism. Symptoms cover the entire spectrum from asymptomatic patients to sudden death. In addition to obstruction of the pulmonary vasculature there may be an inflammatory cascade that deteriorates vascular, pulmonary and cardiac function. In most cases the patient history and radiological imaging reveals the true nature of the patient's condition. The purpose of this article is to give the reader a survey on pathophysiology, typical clinical and radiological findings in different forms of nonthrombotic pulmonary embolism. The spectrum of forms presented here includes pulmonary embolism with biological materials (amniotic fluid, trophoblast material, endogenous tissue like bone and brain, fat, Echinococcus granulosus, septic emboli and tumor cells); nonbiological materials (cement, gas, iodinated oil, glue, metallic mercury, radiotracer, silicone, talc, cotton, and hyaluronic acid); and foreign bodies (lost intravascular objects, bullets, catheter fragments, intraoperative material, radioactive seeds, and ventriculoperitoneal shunts). PMID- 23102489 TI - Environmental factors influencing the efficacy of probiotic bacteria. AB - Probiotic bacteria are not typical ingredients but rather living cells that can rapidly respond and adapt to changing conditions in their environment. Numerous factors from culture preparation and preservation, conditions in consumer product matrices, and genetic, dietary, cultural, and health differences between consumers can affect probiotic cell activity and probably influence the specific host-microbe interactions required for probiotic effects in the digestive tract. Understanding the impact of these factors on probiotic efficacy will aid in elucidating the molecular mechanisms of probiotic function, improve the design of probiotic-containing consumer products, and guide the establishment of standardized procedures for clinical studies intended to evaluate probiotic effects. PMID- 23102490 TI - In situ treatment of PCBs by anaerobic microbial dechlorination in aquatic sediment: are we there yet? AB - The remediation of polychlorinated biphenyls (PCBs) in soils and sediments remains a particularly difficult problem to solve. The possibility of in situ degradation by microorganisms has been pursued for many years since this approach has the potential to provide a cost-effective and environmentally sustainable alternative to dredging for treatment of PCB impacted sites. Being hydrophobic, PCBs partition into organic material and accumulate in anoxic environments well poised to support anaerobic dechlorination of highly chlorinated congeners; products of which are susceptible to complete aerobic degradation. Laboratory research over the past 25 years is now leading to new microbial technologies that could soon be tested for treatment of PCB impacted sediments in the field. PMID- 23102491 TI - pH-responsive bioactive glycopolypeptides with enhanced helicity and solubility in aqueous solution. AB - Copolypeptides of L-glutamate and glucosylated L-/DL-allyl- or DL propargylglycine were synthesized by ring-opening polymerization and thiol ene/yne photochemistry in aqueous solution, allowing the mild introduction of sugar units (here, glucose) in the final step. The glucosylated and non glucosylated samples adopt a random-coil conformation in neutral and basic media and an alpha-helical conformation in acidic media, the helical content depending on the number and configuration of allyl-/propargylglycine units. The glucocopolypeptides unveil enhanced helical stability and solubility down to pH 3.5. Turbidity assays proved the selective binding of the polymers to the plant lectin concanavalin A. PMID- 23102492 TI - Clinical validation of S100B use in management of mild head injury. AB - BACKGROUND: Despite validated guidelines, management of mild head injury (MHI) is still associated with excessive computed tomography (CT) scanning. Reports concerning serum levels of S100B have shown promise concerning safe reduction in CT scanning but clinical validation and actual impact on patient management is unclear. In 2007, S100B was introduced into emergency department (ED) clinical management routines in Halmstad, Sweden. MHI patients with low (<0.10 mikrogram/L) levels of S100B could be discharged without CT. Our aim was to examine the clinical impact and performance of S100B in clinical use for MHI patients. METHODS: Adult ([>=]18 years) patients with MHI (GCS 14-15, loss of consciousness and/or amnesia and no additional risk factors) and S100B sampling within 3 hours were prospectively included in this validation study. Patients were managed according to the adapted guidelines and management was documented. Outcome was determined with a questionnaire 3 months post-trauma and medical records to identify significant intracranial complications such as new neuroimaging, neurosurgery and/or death related to the trauma. RESULTS: 512 patients were included. 24 (4.7%) showed traumatic abnormalities on CT and 1 patient died (0.2%). 138 patients (27%) had normal S100B levels and 374 patients (73%) showed elevated S100B levels. No patients with a normal S100B level showed significant intracranial complication. 44 patients (32%) were managed with CT despite the guidelines recommending discharge (all these CT scans were normal) and 28 patients (7%) were discharged despite a CT recommendation (follow-up was normal in all these patients). S100B had a sensitivity of 100% (95% CI 83-100%) and a specificity of 28% (95% CI 24-33%) for significant intracranial complications. CONCLUSION: The clinical use of S100B within our existing guidelines for management of MHI is safe and effective. Adult MHI patients, without additional risk factors and with normal S100B levels within 3 hours of injury, can safely be discharged from the hospital. PMID- 23102494 TI - Vascular endothelial growth factor family gene polymorphisms in preeclampsia in Sinhalese women in Sri-Lanka. AB - OBJECTIVE: To investigate the association of polymorphisms in the vascular endothelial growth factor (VEGF) family genes (VEGFA rs699947, VEGFA rs3025039, PGF rs1042886, KDR rs2071559 and KDR rs2305948) with preeclampsia in Sinhalese women in Sri-Lanka. METHODS: We conducted a case-control study where 175 nulliparous Sinhalese women with preeclampsia and 171 normotensive women matched for age, ethnicity, parity and BMI were recruited in tertiary care maternity hospitals in Sri-Lanka. Preeclampsia was diagnosed using international guidelines. DNA extracted from peripheral venous blood and was genotyped using the Sequenom MassARRAY system. chi(2)-test was used to compare the distribution of allele and genotype frequencies between the cases and the control subjects. RESULTS: The frequency of PGF rs1042886 variant allele (odds ratio (OR) 1.5, 95% confidence interval (CI) 1.1-2.1) and dominant genotype model (aOR 1.6, 95% CI 1.0-2.4) were increased in preeclamptic women compared to controls. VEGFA rs699947, VEGFA rs3025039, KDR rs2071559, and KDR rs2305948 polymorphisms were not associated with preeclampsia. CONCLUSION: Maternal PGF rs1042886 polymorphism is associated with preeclampsia in Sinhalese women in Sri-Lanka. PMID- 23102493 TI - Diurnal variations in articular cartilage thickness and strain in the human knee. AB - Due to the biphasic viscoelastic nature of cartilage, joint loading may result in deformations that require times on the order of hours to fully recover. Thus, cartilaginous tissues may exhibit cumulative strain over the course of each day. The goal of this study was to assess the magnitude and spatial distribution of strain in the articular cartilage of the knee with daily activity. Magnetic resonance (MR) images of 10 asymptomatic subjects (six males and four females) with mean age of 29 years were obtained at 8:00 AM and 4:00 PM on the same day using a 3T magnet. These images were used to create 3D models of the femur, tibia, and patella from which cartilage thickness distributions were quantified. Cartilage thickness generally decreased from AM to PM in all areas except the patellofemoral groove and was associated with significant compressive strains in the medial condyle and tibial plateau. From AM to PM, cartilage of the medial tibial plateau exhibited a compressive strain of -5.1+/-1.0% (mean+/-SEM) averaged over all locations, while strains in the lateral plateau were slightly lower (-3.1+/-0.6%). Femoral cartilage showed an average strain of -1.9+/-0.6%. The findings of this study show that human knee cartilage undergoes diurnal changes in strain that vary with site in the joint. Since abnormal joint loading can be detrimental to cartilage homeostasis, these data provide a baseline for future studies investigating the effects of altered biomechanics on diurnal cartilage strains and cartilage physiology. PMID- 23102496 TI - Clinical characteristics and prognostic factors of primary pulmonary vein stenosis or atresia in children. AB - BACKGROUND: Primary pulmonary vein stenosis or atresia (PVS/A) is a rare entity with a high mortality rate. The aim of this study was to elucidate the clinical characteristics, progression, and prognostic factors of primary PVS/A in children. METHODS: We reviewed the medical records of patients who had primary PVS/A with normally connected pulmonary veins (PVs) at five pediatric cardiology centers in Korea between 1995 and 2010. RESULTS: A total of 34 cases were identified. The median age at diagnosis was 12.0 months. During the follow-up period (median, 18 months; range, 2 to 185 months), PVS/A progressed to previously uninvolved veins in 9 patients. Surgical interventions were performed on 29 patients (venoplasty on 25 and pneumonectomy on 4). Nineteen of the patients who underwent venoplasty had restenosis after a median of 2 months. The sutureless technique did not reduce the rate of restenosis, progression of the disease to previously uninvolved PVs, or mortality rate. The mortality rate was 46.7%, the median age of death was 10.8 months, and the median interval between diagnosis and death was 3.0 months. In univariate analysis, predictors of death included involvement of at least three PVs, bilateral PV involvement, infancy onset PVS/A, restenosis after surgery, and progression to previously uninvolved PVs. In multivariate analysis, significant risk factors for death were involvement of at least three PVs (hazard ratio, 8.8; p < 0.0001) and progression to uninvolved PVs (hazard ratio, 4.2; p = 0.014). CONCLUSIONS: Primary PVS/A may carry a significant risk of recurrent and progressive PV obstruction or death even after surgical venoplasty. PMID- 23102495 TI - Medical versus medical and surgical treatment for brucella endocarditis. AB - This review was undertaken to determine the role of surgery in the treatment of brucella endocarditis. All English and French articles reporting brucella endocarditis (1966 to 2011) in PubMed, Google, and Scopus were reviewed. In all, 308 cases were identified, and linear and logistic regression was performed. Surgery improved outcomes by decreasing mortality from 32.7% in the medical treatment only group to 6.7% in the combined surgical and medical treatment group (p<0.001). This association was still significant while controlling for other contributing factors. In the absence of a controlled trial, we recommend the utmost vigilance and consideration of surgical management in treating such patients. PMID- 23102497 TI - Deficient mismatch repair phenotype is a prognostic factor for colorectal cancer in elderly patients. AB - OBJECTIVE: About 15% of colorectal adenocarcinomas have a deficient DNA mismatch repair phenotype. The frequency of deficient DNA mismatch repair tumours increases with age due to the hypermethylation of hMLH1 promoter. The study aimed to determine the prognostic value of deficient DNA mismatch repair phenotype in elderly patients. DESIGN: Mismatch repair phenotype was retrospectively determined by molecular analysis in consecutive resected colorectal adenocarcinoma specimens from patients over 75 years of age from 4 Oncology centres. RESULTS: 231 patients (median age: 81, range: 75-100) were enrolled from 2005 to 2008. Mean prevalence of deficient DNA mismatch repair phenotype was 22.5%, and 36% for patients over 85 years. Deficient DNA mismatch repair status was significantly associated with older age, female sex, proximal colon primary and high grade tumour. For stage II tumours no deficient DNA mismatch repair tumours had a recurrence at end of follow-up compared to 17% for tumours with proficient phenotype. The proficient phenotype status was significantly associated with worse age-adjusted overall survival [HR 2.60; 95% CI 1.05-6.44; p=0.039]. For stage III tumours a trend for less recurrence was observed for deficient DNA mismatch repair phenotype (16%) compared to proficient phenotype (36%). CONCLUSION: deficient DNA mismatch repair phenotype is a prognostic factor in stage II colorectal tumour in elderly patients. Our results suggest that mismatch repair phenotype should be taken in consideration for adjuvant chemotherapy decision in elderly patients. PMID- 23102498 TI - Futility of antiviral treatments for hepatitis C: an evolving concept entering the direct antiviral agents era. AB - Two first-generation non-specific protein 3/4A protease inhibitors (Boceprevir and Telaprevir) have been approved in the U.S. and in Europe in combination with the standard of care for treatment of both previously untreated and prior non responder genotype 1 chronic hepatitis C, based on the results of 5 large phase III trials. With these drugs, futility-stopping rules at weeks 4, 8 and 12 have been provided in order to avoid ineffective therapy and dangerous adverse events. However, despite several guidelines that have been published, a main question remains: how we can identify patients in whom triple therapy will be useless or ineffective? Based on the available data, this review proposes three algorithms to optimize triple antiviral therapy for chronic hepatitis C, to aid physicians avoid prescription of unnecessary treatment, given its substantial side effects and costs. PMID- 23102499 TI - Early-stage gastric cancers represented as dysplasia in a previous forceps biopsy: the importance of clinical management. AB - BACKGROUND AND AIMS: Because histological examination of gastric lesions by forceps biopsy is of limited accuracy, management on the basis of histological results is occasionally controversial. We examined the characteristics of early gastric cancers that presented as dysplasia resulting from a previous forceps biopsy. PATIENTS AND METHODS: Between April 2007 and December 2010, 341 gastric adenocarcinoma lesions from 330 patients previously diagnosed histologically via endoscopic submucosal dissection were examined. We retrospectively assessed the characteristics of early gastric cancer according to their initial forceps biopsy results. RESULTS: In total, 183 EGCs were diagnosed as dysplasia (53.7%; 89 low grade and 94 high-grade) and 158 (46.3%) as carcinoma by forceps biopsy before endoscopic submucosal dissection. Significant differences were noted with respect to histologic differentiation of carcinomas, Lauren histologic type, depth of invasion, lymphovascular invasion, and en bloc resection between the dysplastic group and carcinoma group, based on forceps biopsy results. CONCLUSION: A forceps biopsy result is not fully representative of the entire lesion and, thus, endoscopic submucosal dissection should be considered for lesions diagnosed as dysplasia via forceps biopsy in order to avoid the risk of missed carcinomas. PMID- 23102500 TI - Tailored synthesis of intelligent polymer nanocapsules: an investigation of controlled permeability and pH-dependent degradability. AB - In this study, we present a new route to synthesize an intelligent polymer nanocapsule with an ultrathin membrane based on surface-initiated reversible addition-fragmentation chain-transfer polymerization. The key concept of our report is to use pH-responsive polydiethylaminoethylmethacrylate as a main membrane-generating component and a degradable disulfide bond to cross-link the membrane. The permeability of membrane, tuned by adjusting pH and using different lengths of the cross-linkers, was proven by showing a dramatic swelling behavior of the nanocapsules with the longest cross-linker from 560 nm at pH 8.0 to 780 nm at pH 4.0. Also, due to the disulfide cross-linker, degradation of the capsules using GSH as reducing agent was achieved which is further significantly promoted at pH 4.0. Using a rather long-chain dithiol cross-linker, the synthesized nanocapsules demonstrated a good permeability allowing that an enzyme myoglobin can be postencapsulated, where the pH controlled enzyme activity by switching membrane permeability was also shown. PMID- 23102501 TI - Depression among caregivers of children with asthma and its impact on communication with health care providers. AB - BACKGROUND: Caregiver depression is common, can negatively influence one's ability to communicate with health care providers, and may hinder appropriate care for children with asthma. OBJECTIVE: To evaluate the impact of caregiver depression on communication and self-efficacy in interactions about asthma with their child's physician. STUDY DESIGN: Cross sectional analysis using data from the Prompting Asthma Intervention in Rochester-Uniting Parents and Providers study. METHODS: We enrolled caregivers of children (2-12 yrs) with persistent asthma prior to their health care visit. Caregivers were interviewed via telephone after the visit to assess depression, self-efficacy, and provider communication at the visit. Caregiver depression was measured using the Kessler Psychological Distress scale. We assessed caregiver self-efficacy using items from the Perceived Efficacy in Patient-Physician Interactions scale; caregivers rated their confidence for each item (range 0-10). We also inquired about how well the provider communicated regarding the child's asthma care. Bivariate and multivariate analyses were used. RESULTS: We interviewed 195 caregivers (response rate 78%; 41% Black, 37% Hispanic), and 30% had depressive symptoms. Caregiver rating of provider communication did not differ by depression. Most caregivers reported high self-efficacy in their interactions with providers; however depressed caregivers had lower scores (8.7 vs. 9.4, p = .001) than non-depressed caregivers. Further, depressed caregivers were less likely to be satisfied with the visit (66% vs. 83%, p = .014), and to feel all of their needs were met (66% vs. 85%, p = .007). In multivariate analyses, depressed caregivers were >2* more likely to be unsatisfied with the visit and to have unmet needs compared to non depressed caregivers. CONCLUSIONS: Depressed caregivers of children with asthma report lower confidence in interactions with providers about asthma and are less likely to feel that their needs are met at a visit. Further study is needed to determine the best methods to communicate with and meet the needs of these caregivers. PMID- 23102502 TI - Physical and structural properties of [Cu(BOT1)Cl]Cl, a fluorescent imaging probe for HNO. AB - Nitroxyl, or HNO, is involved in a number of important physiological processes, such as vascular relaxation and neuroregulation. Effective imaging tools are required in order to gain a deeper understanding of the in vivo mechanisms of these processes and to identify the endogenous sources of HNO. Here, we further investigate the physical properties of our previously reported fluorescent nitroxyl sensor, [Cu(BOT1)Cl]Cl (J. Am. Chem. Soc.2010, 132, 5536; BOT1=BODIPY.triazole, a tetradentate ligand). A new high-yielding synthetic procedure for BOT1 is reported. The X-ray crystal structures of two Cu(II) complexes of BOT1 are described. These structural studies show that the BOT1 ligand can form Cu(II) coordination complexes of both square-pyramidal and trigonal-bipyramidal geometries. Cyclic voltammograms of [Cu(BOT1)Cl]Cl were acquired, revealing the presence of a quasi-reversible feature at 130 mV (vs the ferrocene/ferrocenium couple) in MeCN and at -40 mV (vs Ag/AgCl) in aqueous buffer, which is assigned to the Cu(II)/Cu(I) couple. The reactivity of [Cu(BOT1)Cl]Cl with Angeli's salt, a stable source of HNO, was further investigated. A 1000-fold excess of Angeli's salt elicits an immediate 10-fold emission turn-on response of the sensor, consistent with our previous report. A new observation, reported here, is that the intensity of this turn-on emission diminishes at longer incubation times. Fluorescent imaging of nitroxyl by [Cu(BOT1)Cl]Cl in HeLa cells was carried out. Upon treatment of the cells with Angeli's salt, there was a modest 2-fold intracellular turn-on in emission intensity. PMID- 23102503 TI - A comparison of the chemistry associated with the biological signaling and actions of nitroxyl (HNO) and nitric oxide (NO). AB - Nitric oxide (NO) and nitroxyl (HNO) are reported to have numerous biological activities with significant therapeutic potential. Many of these activities are overlapping. The chemistry by which these two species act is likely to be distinct in spite of their apparent close structural similarities. Discussed in this review is the chemistry of NO and HNO with their likely biological targets - thiolproteins, metalloproteins (more specifically iron heme proteins) and free radical processes. Based on the chemistry discussed, it can be concluded that the biological actions of NO are likely due primarily to its interactions with metal centers and reaction with radical species. The likely biological targets for HNO are, similarly, metal centers and radical species (albeit with different chemistry compared to NO). HNO is also particularly good at directly modifying thiols while NO-mediated thiol modification requires other reactants to be present and is not as facile. Thus, a fundamental difference between NO and HNO that likely distinguishes them with regards to their biological activity is the greater propensity for HNO to react with thiols compared to NO. PMID- 23102504 TI - Day-to-day care in palliative sedation: survey of nurses' experiences with decision-making and performance. AB - CONTEXT: Continuous palliative sedation has been the focus of extensive international debates in the field of end-of-life decision making. Although nurses may be important participants in the performance of continuous palliative sedation, research has focused primarily on the role and experience of physicians. Nurses' experiences differ from that of physicians; they more often describe that continuous palliative sedation is used with the intention of hastening death and to have experienced serious emotional burden. Therefore, it is important to understand the experience of nurses in continuous palliative sedation. OBJECTIVE: To describe nurses' experiences with the decision-making and performance of continuous palliative sedation in terminally ill patients. METHODS: Cross-sectional study. In 2008, a structured questionnaire was sent to 576 nurses in six professional home care organizations, ten units for palliative care in nursing homes and in-patient hospices and seven hospitals in the western region of the Netherlands. Respondents provided information about the last patient receiving continuous palliative sedation whom they had cared for. RESULTS: Two-hundred seventy-seven questionnaires were returned and 199 (71.84%) reported a case of continuous palliative sedation. Nurses felt involved in the decision to use sedation in 84% of cases, albeit to a lesser extent in home care (68.75%, p=0.002). They agreed with the performance of continuous palliative sedation in 95.97% of cases and they proposed the use of continuous palliative sedation in 16.16%. Nurses were present at the start of sedation in 81.40% of cases and reported physicians to be present in 45.22%. In 72.77%, arrangements had been made among caregivers about the coordination of health care regarding the sedation. CONCLUSION: Nurses seem to play an important role in the use of continuous sedation. This role is mainly supportive toward physicians and patients during the decision-making process, but shifts to an active performance of sedation, particularly in settings where they explicitly participate as members of a team. Nurses could develop the practice of palliative sedation by anticipating procedural obstacles in the performance of continuous palliative sedation. We recommend them to become more active participants in the decision making to improve the care of patients receiving continuous palliative sedation. PMID- 23102505 TI - Is venous foot pump effective in prevention of thromboembolic disease after joint arthroplasty: a meta-analysis. AB - The goal of this meta-analysis was to evaluate the efficacy of venous foot pumps in prevention of venous thromboembolism following joint arthroplasty. Using different databases, we found 13 prospective clinical trials published meeting our inclusion criteria. In total, 1514 patients were included in the final analysis. Venous foot pump devices are effective in prevention of venous thromboembolic disease after total hip and knee arthroplasty compared to chemoprophylaxis. This was especially significant in prevention of major deep vein thrombosis and pulmonary emboli rate. The use of mechanical devices like venous calf or foot pump, either alone or in combination with less potent chemical prophylaxis, on the other hand can reduce the rate of venous thromboembolism and complications of potent chemoprophylaxis like wound hematoma. PMID- 23102506 TI - Serum dehydroepiandrosterone (DHEA) and DHEA-sulfate (S) levels in medicated patients with major depressive disorder compared with controls. AB - BACKGROUND: There is accumulating evidence regarding gender differences in clinical symptoms or response to antidepressants in patients with depression. However, less attention has been given to sex differences in the underlying biological mechanisms of depression. The adrenal androgens, dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S), play a critical role in controlling affect, mood, and anxiety. Changes in serum adrenal androgen levels have been reported in conditions pertaining to stress as well as in psychiatric disorders. The objective of the present study was to investigate differences in serum levels of adrenal androgens in male and female patients with major depressive disorder (MDD). METHODS: Participants included 90 inpatients with MDD at the psychiatric ward of Juntendo University Koshigaya Hospital who were receiving antidepressants. Serum levels of DHEA and DHEA-S were assessed at the time of admission. Matched controls (based on sex and age) included 128 healthy individuals. First, data from male and female MDD patients and controls were compared. Second, correlations between serum hormone levels and scores on the Hamilton Rating Scale for Depression (HAM-D) of patients with MDD were assessed by gender. In addition, effects of various factors on adrenal androgens were analyzed using multiple regression analysis. RESULTS: Serum DHEA levels were significantly increased in both male and female MDD patients compared with controls. Serum levels of DHEA-S in male patients were significantly decreased compared with male controls, whereas no significant differences were seen in female patients and controls. No significant correlations among adrenal androgens were observed in male patients with MDD, whereas significant positive correlations were found in both male and female controls. No significant correlations were seen between adrenal androgens and HAM-D scores in male or female patients. Multiple regression analysis showed that both hormones were affected by the age at onset of depression. LIMITATIONS: All subjects in the present study were on antidepressant medications. CONCLUSIONS: Elevated levels of serum DHEA may be associated with the biological pathophysiology of depression, as DHEA administration has been found to be effective for the treatment of depression. Findings of differential changes in DHEA-S levels in men compared with women may suggest distinct characteristics of these hormones between men and women with depression. However, DHEA/DHEA-S may be a poor indicator for evaluating severity of depression. PMID- 23102507 TI - Experimental model for reproduction of canine visceral leishmaniosis by Leishmania infantum. AB - In this report an experimental model of Leishmania infantum (L. infantum) infection in dogs is described. The data presented are derived from an overall and comparative analysis of the clinical outcomes of three groups of dogs intravenously infected with 500,000 promastigotes on different dates (2003, 2006 and 2008). The parasites used for challenge were isolated from a dog having a patent form of leishmaniosis, classified as MCAN/ES/1996/BCN150 zymodeme MON-1. Late-log-phase promastigote forms derived from cultured amastigotes obtained from the spleen of the heavily infected hamsters were used for infection. Only one single infective dose was administered to each dog. After challenge, the animals were monitored for 12 months. To analyze the disease outcome, several biopathological, immunological and parasitological end-points were considered. The analysis of the infected dogs indicated that the development of the clinical disease was very similar in the three experimental challenges, as shown by the immune response, the parasite load and the clinical and histopathological lesions detected at necropsy. A high similarity was also observed between the disease development after the experimental challenge and the one reported to occur in endemic natural infection areas, as various degrees of susceptibility to the disease and even resistance were observed in the experimentally infected animals. We believe that this challenge model faithfully reproduces and mimics the course of a natural infection and that it could be used as a suitable tool for analyzing the efficacy of anti-Leishmania drugs and vaccines. PMID- 23102508 TI - Enzyme kinetic and molecular docking studies for the inhibitions of miltirone on major human cytochrome P450 isozymes. AB - Previous studies have shown that major tanshinones isolated from Danshen (Salvia miltiorrhiza) inhibited human and rat CYP450 enzymes-mediated metabolism of model probe substrates, with potential in causing herb-drug interactions. Miltirone, another abietane type-diterpene quinone isolated from Danshen, has been reported for its anti-oxidative, anxiolytic and anti-cancer effects. The aim of this study was to study the effect of miltirone on the metabolism of model probe substrates of CYP1A2, 2C9, 2D6 and 3A4 in pooled human liver microsomes. Miltirone showed moderate inhibition on CYP1A2 (IC(50)=1.73 MUM) and CYP2C9 (IC(50)=8.61 MUM), and weak inhibition on CYP2D6 (IC(50)=30.20 MUM) and CYP3A4 (IC(50)=33.88 MUM). Enzyme kinetic studies showed that miltirone competitively inhibited CYP2C9 (K(i)=1.48 MUM), and displayed mixed type inhibitions on CYP1A2, CYP2D6 and CYP3A4 with K(i) values of 3.17 MUM, 24.25 MUM and 35.09 MUM, respectively. Molecular docking study further confirmed the ligand-binding conformations of miltirone in the active sites of these human CYP450 isoforms, and provided some information on structure-activity relationships for the CYPs inhibition by tanshinones. Taken together, CYPs inhibitions of miltirone were weaker than dihydrotanshinone, but stronger than cryptotanshinone, tanshinone I and tanshinone IIA. PMID- 23102509 TI - Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats. AB - Asiatic acid (AA), a triterpenoid derivative of Centella asiatica, has shown significant biological effects of antioxidant and anti-inflammatory activities. Aim of this investigation was to evaluate the antihyperglycemic effect of AA on the activities of hepatic enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. To induce diabetes mellitus, rats were injected with streptozotocin intraperitoneally at a single dose of 40 mg/kg b.w. Diabetic rats showed significant (p<0.05) increased in plasma glucose, glycosylated hemoglobin and significant (p<0.05) decreased in circulating insulin and hemoglobin. The altered activities of key enzymes such as glucose-6-phosphatase and fructose-1,6 bisphosphatase of carbohydrate metabolism significantly (p<0.05) increased whereas hexokinase, pyruvate kinase, glucose-6-phosphate dehydrogenase and glycogen content significantly (p<0.05) decreased in the liver of diabetic rats and also increased activities of aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP). Oral administration of AA (5, 10 and 20 mg/kg b.w.) and glibenclamide (600 MUg/kg b.w.) to diabetic rats for 45 days prevented the above alteration and reverted to near normalcy. Protection of body weight loss of diabetic rats by AA was also observed. No significant effect was observed in normal rats treated with AA (20 mg/kg b.w.). In this search, AA found to be potential bioactive compound to regulate the carbohydrate metabolism by modulating the key regulatory enzymes in diabetic rats. These findings merit further research in this field. PMID- 23102510 TI - Percutaneous repair of Achilles tendon ruptures with Tenolig: quantitative analysis of postural control and gait pattern. AB - BACKGROUND: Surgical approach in Achilles tendon's rupture involved during the last years has becoming safer and less invasive as possible. Lots of study investigate the outcomes of the mini-invasive technique with Tenolig proving its good results, but never in the long-term. OBJECTIVES: Our study want to emphasize the effectiveness of this treatment exploring the postural and gait patterns in a 24-month follow up. METHOD: Patients did self-training exercises without specific supervision, instead of a particular postoperative rehabilitation protocol. We compared 21 patients to a control group of 19 health subjects using a clinical examination, a podobarometric and an optokinetic analysis. RESULTS: Data shows no differences in time-distance parameters, despite a reduction of propulsion phase data, confirmed also by kinetic analysis. Podobarometric results show only a decrease in the anterior pressure of the injured limb (p=0.09). In standing an increase of anterior-posterior oscillation of the COP (center of pressure) (p=0.03). CONCLUSIONS: The results underline the long-term outcome effectiveness of the technique but some functional alterations remain. This could be the reason of the weakness, which always affected the patients. Reduction of the triceps elongation and restoration of strength during the propulsion phase should be the key points in postoperative physiotherapy. PMID- 23102511 TI - Postoperative costs associated with outcomes after cardiac surgery with extracorporeal circulation: role of antithrombin levels. AB - OBJECTIVE: To study the impact on postoperative costs of a patient's antithrombin levels associated with outcomes after cardiac surgery with extracorporeal circulation. DESIGN: An analytic decision model was designed to estimate costs and clinical outcomes after cardiac surgery in a typical patient with low antithrombin levels (<63.7%) compared with a patient with normal antithrombin levels (>=63.7%). The data used in the model were obtained from a literature review and subsequently validated by a panel of experts in cardiothoracic anesthesiology. SETTING: Multi-institutional (14 Spanish hospitals). PARTICIPANTS: Consultant anesthesiologists. MEASUREMENTS AND MAIN RESULTS: A sensitivity analysis of extreme scenarios was carried out to assess the impact of the major variables in the model results. The average cost per patient was ?18,772 for a typical patient with low antithrombin levels and ?13,881 for a typical patient with normal antithrombin levels. The difference in cost was due mainly to the longer hospital stay of a patient with low antithrombin levels compared with a patient with normal levels (13 v 10 days, respectively, representing a ?4,596 higher cost) rather than to costs related to the management of postoperative complications (?215, mostly owing to transfusions). Sensitivity analysis showed a high variability range of approximately +/-55% of the base case cost between the minimum and maximum scenarios, with the hospital stay contributing more significantly to the variation. CONCLUSIONS: Based on this analytic decision model, there could be a marked increase in the postoperative costs of patients with low antithrombin activity levels at the end of cardiac surgery, mainly ascribed to a longer hospitalization. PMID- 23102513 TI - [Anaphylactic shock from an iodine contrast medium: role of the allergy check-up in one case]. AB - Anaphylactoid reactions to iodine contrast media are rare but serious, possibly life-threatening and calling an appropriate and urgent care. The physiopathological mechanism of these reactions remains to be fully elucidated. This reaction is still mostly called "pseudoallergic" in the literature. However, recent papers emphasise that a true allergic process is more frequent than previously expected. They also insist on the interest of running allergy tests including skin testing. We report the case of an anaphylactic shock to iodine contrast media, occurring during coronary angiography. We performed an allergy check-up and found the culprit allergen. We also evidenced a cross-reaction to another contrast media from the similar group. On the other hand, there was no reaction to contrast media of other types. With these results, another coronary angiography could be performed without any adverse event. When hypersensitivity reactions to iodine contrast media occur, it is mandatory to perform a complete allergy check-up. This will help determine the precise mechanism of the reaction and find the culprit allergen. PMID- 23102512 TI - Neural correlates of conceptual object priming in young and older adults: an event-related functional magnetic resonance imaging study. AB - In this event-related functional magnetic resonance imaging study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded "living/nonliving" classification task with 3 repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidenced repetition-related activation reductions in fusiform gyrus, superior occipital, middle, and inferior temporal cortex, and inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, and neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation and in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which might be a form of compensatory neural activity. PMID- 23102514 TI - Challenges in the care for consanguineous couples: an exploratory interview study among general practitioners and midwives. AB - BACKGROUND: It is often suggested that an effort must be made to increase awareness among consanguineous couples of their reproductive risk, and to refer them for genetic counseling if needed. Primary care professionals are considered most appropriate for addressing the subject and identifying couples at risk during consultations in their practice. This Dutch study aims to explore the experiences, attitudes and beliefs of such professionals regarding their care for consanguineous couples. METHODS: Sixteen semi-structured interviews were conducted with midwives and general practitioners. RESULTS: Although most primary care professionals considered it their task to inform couples about the risks of consanguinity, during consultations the topic was generally only briefly touched upon and quickly abandoned. Important reasons for this were professionals' beliefs about religious and social values of couples, their low perception of the couples' reproductive risk and expected limited feasibility of referral. Feelings of embarrassment regarding addressing consanguinity did not seem to play a significant role. CONCLUSIONS: Primary care professional beliefs about their clients' religious and social values, their attitudes toward the risk, and perceived limited options for referral seem to conflict with the professional norm to address the topic of consanguinity. PMID- 23102515 TI - Landing and catalytic characterization of individual nanoparticles on electrode surfaces. AB - We demonstrate a novel and versatile pipet-based approach to study the landing of individual nanoparticles (NPs) on various electrode materials without any need for encapsulation or fabrication of complex substrate electrode structures, providing great flexibility with respect to electrode materials. Because of the small electrode area defined by the pipet dimensions, the background current is low, allowing for the detection of minute current signals with good time resolution. This approach was used to characterize the potential-dependent activity of Au NPs and to measure the catalytic activity of a single NP on a TEM grid, combining electrochemical and physical characterization at the single NP level for the first time. Such measurements open up the possibility of studying the relation between the size, structure and activity of catalyst particles unambiguously. PMID- 23102516 TI - Determination of essential and toxic elements in Cordyceps kyushuensis Kawam by inductively coupled plasma mass spectrometry. AB - In this study, a total of 20 elements (essential, non-essential and toxic): lithium (Li), sodium (Na), potassium (K), gallium (Ga), magnesium (Mg), zinc (Zn), iron (Fe), copper (Cu), manganese (Mn), vanadium (V), chromium (Cr), nickel (Ni), cobalt (Co), molybdenum (Mo), selenium (Se), barium (Ba), tin (Sn), arsenic (As), lead (Pb) cadmium (Cd) and mercury (Hg) in natural and cultured Cordyceps kyushuensis have been determined by means of inductively coupled plasma mass spectrometry (ICP-MS). Cultured stroma, natural stroma and natural worm were digested by microwave-assisted method before analysis. The proposed ICP-MS method was validated by analyzing a certified reference material (CRM) GBW10015 (spinach). The results of one-way analysis of variance (ANOVA) revealed that the element concentrations in the three kinds of samples were significantly different (p<0.05). Except for Mg, Zn, Cu, the values of other elemental contents were the highest in the stroma of natural C. kyushuensis. In comparison with the worm, the concentrations of determined elements in wild stroma were higher. The remarkable difference of elemental contents between cultured and natural stroma may be caused by distinct growing environment. This finding highlighted the usefulness of ICP-MS elemental analysis and enhanced the value of C. kyushuensis as a candidate for nourishing food based on its composition. PMID- 23102517 TI - [Diffuse cystic lung disease as a manifestation of neurofibromatosis]. PMID- 23102518 TI - Proton pump inhibitors have no measurable effect on calcium and bone metabolism in healthy young males: a prospective matched controlled study. AB - OBJECTIVES: Proton pump inhibitors (PPIs) are associated with an increased risk of bone fractures. This study sought to evaluate the effect of PPIs on biochemical markers of calcium and bone metabolism. METHODS: Prospective matched controlled study involving healthy adult males (age 18-50years) suffering from frequent heartburn. Patients received standard-dose PPI for 12weeks and were matched by age with healthy controls. Blood studies were taken at 0, 1 and 3months for biochemical markers of mineral and bone metabolism. Two-way (time and PPI treatment) repeated measures analysis of variance (RM-ANOVA) and multiple linear regression were used for analysis. RESULTS: A total of 58 participants (29 per group) completed the study. Mean age of participants was 33.2+/-7.5years. Baseline characteristics and biomarkers were similar for both groups except for higher BMI (28.6 vs. 25.6kg/m(2), p=0.008) and serum C-terminal cross linked telopeptides of type I collagen [CrossLaps, (300 vs. 228pg/ml, p=0.028)] in the PPI group. There was no difference in parathormone (PTH), ionized calcium, vitamin D, osteocalcin and CrossLaps between the PPI and control subjects (all non-significant; 2-way RM-ANOVA). Multiple linear regression modeling showed no effect of PPIs on any of the studied calcium or bone metabolism biomarkers. CONCLUSION: PPI intake for 12weeks has no measurable effect on calcium or bone metabolism in healthy young males. PMID- 23102519 TI - Gd complexes of diethylenetriaminepentaacetic acid conjugates of low-molecular weight chitosan oligosaccharide as a new liver-specific MRI contrast agent. AB - This study was to describe the synthesis of complexes of gadolinium diethylenetriaminepentaacetic acid conjugates of low-molecular-weight chitosan oligosaccharide Gd-DTPA-CSn (n=6, 8, 11) as a new class of contrast agent as well as its magnetic property in a pilot magnetic resonance imaging. The efficacy of the contrast agent was assessed by measuring the longitudinal relaxivity (r1), FLASH imaging in phantoms in vitro and signal intensity in vivo of the rat abdominal axial imaging. The r1 of Gd-DTPA-CS11 was up to 11.65 mM(-1).s(-1), which was 3 times higher than that of the analogous MRI contrast agent Gd-DTPA in commercial use. In vivo MR images of rat obtained with Gd-DTPA-CS11 showed strong signal enhancement in liver and the vessels of the liver parenchyma during the extended period of time. The present study suggests that the new synthesized gadolinium complexes can be used as a new class of practical liver-specific MRI contrast agent because of its superior performance compared with Gd-DTPA. PMID- 23102520 TI - Current questions for the treatment of advanced gastric cancer. AB - BACKGROUND: Gastric cancer remains a major health problem worldwide. Treatment of advanced gastric cancer is controversial and there is no standard regimen for first- or second-line chemotherapy (CT). This review aims to give an overview of the hot topics concerning treatment, prognostic factors and new strategies in advanced gastric cancer. MATERIAL AND METHODS: Seven questions of special clinical interest have been formulated previously to the literature review. With the aim of answering each of these questions, a specific search of the relevant trials and meta-analyses published or communicated from 1990 to date was performed. RESULTS: Patients treated with CT have a survival benefit over those treated with only best supportive care (BSC). Such active cytotoxic drugs as cisplatin or docetaxel and targeted agents as trastuzumab showed superiority in randomized trials. Other agents such as oxaliplatin, oral fluoropyrimidines and irinotecan showed non-inferiority or less toxic results, positioning them as valuable alternatives to classical schedules. Combination regimens seem to be an improvement over single agent therapy. However, increased toxicity of some regimens makes their general use difficult. Second-line CT is of value for selected patients with good performance status. Trastuzumab is the only targeted agent showing better survival when added to chemotherapy in HER2-driven tumors. CONCLUSIONS: With the introduction of new agents, management of advanced gastric cancer has experienced important changes. First and second-line CT improve survival in patients with good performance status. Future trials should address how to better select patients for new, targeted agents, based upon validated predictive biomarkers. PMID- 23102521 TI - Acupuncture for irritable bowel syndrome: diagnosis and treatment of patients in a pragmatic trial. AB - OBJECTIVE: The aim of this study was to evaluate the treatments delivered during a pragmatic effectiveness study of acupuncture for irritable bowel syndrome (IBS) and to explore the roles of Traditional Chinese Medicine (TCM) diagnoses and preferences of the acupuncturists in treatment design. METHODS: Patients allocated to an acupuncture arm of a study were offered up to ten sessions of acupuncture over 3 months. Acupuncturists followed a flexible treatment protocol that allowed for treatment individualization, use of additional therapies such as moxa, and provision of lifestyle advice. All treatments were recorded in logbooks and analyzed by content analysis. RESULTS: Seven primary and eight secondary TCM patterns were identified among the 113 patients with IBS, and were combined in various ways to produce unique diagnoses for 84% patients. Liver Qi Stagnation and Damp Heat were the most commonly reported patterns. Of the 126 acupuncture points used, a distinct core and supporting group of points was associated with each primary pattern. Each practitioner also utilized a distinct core and supporting group of points that reflected his/her preferences. Use of additional therapies (e.g., moxa) and provision of lifestyle advice (e.g., diet) were generally consistent with a particular practitioner. CONCLUSIONS: Data suggest that a patient's TCM diagnosis, the practitioner's preferences, and a patient's individual characteristics beyond his/her diagnosis influence treatment delivery. In particular, TCM diagnoses appear to influence the acupuncture (i.e., point selection) aspect of treatment more than the selection of additional therapies and lifestyle advice. From another perspective, the treatments incorporated pragmatic, individualized, and disease-specific approaches with combinations that produced both treatment commonalities and diversities. PMID- 23102522 TI - An experimental study on the ergonomics indices of partial pressure suits. AB - Partial pressure suits (PPSs) are used under high altitude, low-pressure conditions to protect the pilots. However, the suit often limits pilot's mobility and work efficiency. The lack of ergonomic data on the effects of PPSs on mobility and performance creates difficulties for human factor engineers and cockpit layout specialists. This study investigated the effects of PPSs on different ergonomic mobility and performance indices in order to evaluate the suit's impact on pilot's body mobility and work efficiency. Three types of ergonomics indices were studied: the manipulative mission, operational reach and operational strength. Research results indicated that a PPS significantly affects the mobility and operational performance of the wearers. The results may provide mission planners and human factors engineers with better insight into the understanding of pilots' operational function, mobility and strength capabilities when wearing PPS. PMID- 23102523 TI - Experimental and theoretical studies on the enantioselectivity of molecularly imprinted polymers prepared with a chiral functional monomer. AB - A comprehensive study on the enantioseparation of racemic bis[1-phenylethyl]amine (PEA) on a series of molecularly imprinted polymers (MIPs) prepared using the chiral functional monomer (S)-2-(2-methyl-acryloylamino)-3-phenyl propionic acid (MAPP) is reported. MIP-R, MIP-S and MIP-RS, were synthesized separately by imprinting the pure enantiomers (R-, S-PEA) and racemic PEA, respectively, MAPP, EDGMA as crosslinker and chloroform as the porogen. It was found that all MIPs prepared were able to resolve the PEA racemate. Residence times (t(r)) and enantioselectivity factors (alpha) were estimated from typical elution chromatography experiments. Frontal chromatography experiments were conducted to acquire the adsorption isotherms for both enantiomers on the different MIPs (and on the non-imprinted polymer, NIP). The adsorption isotherms were analyzed using the affinity spectrum (AS) and the expectation-maximization (EM) methods. The study also involved the theoretical evaluation of the MAPP/enantiomers interactions in the pre-polymer mixture. The EM method predicts mono- and bimodal distribution of affinity binding sites depending upon the polymer analyzed. Apparently, the enantioseparation process depends on relatively small differences in the stabilization of the diasteroisomeric ion-pairs PEA/MAPP complexes on the surface of the polymers. PMID- 23102524 TI - High-throughput simultaneous analysis of pesticides by supercritical fluid chromatography/tandem mass spectrometry. AB - Combination techniques such as gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) are commonly used for pesticide residue analysis, but there is no reported method for the simultaneous analysis of multiple pesticides in a sample using a single instrument. Supercritical fluid chromatography (SFC) offers high resolution at high flow rates and various separation modes and hence may aid the rapid simultaneous analysis of pesticide. We developed an SFC/MS/MS method and analyzed 17 pesticides with a wide range of polarities (logP(ow)=-4.6 to 7.05) and molecular weights (112.1-888.6) within 11min using a polar-embedded reversed-phase column. To the best of our knowledge, there is no previous report on the SFC analysis of a wide variety of compounds, including highly hydrophilic ones. By SFC, diquat dibromide (logP(ow)=-4.6), together with cypermethrin (logP(ow)=6.6) and tralomethrin (logP(ow)=5.05), could be detected in the presence of various other pesticides using a single mobile phase. SFC/MS allows for the rapid and simultaneous analysis of low concentrations (ng/L levels) of pesticides that typically need to be analyzed by GC/MS and LC/MS separately. PMID- 23102525 TI - Multiple automated headspace in-tube extraction for the accurate analysis of relevant wine aroma compounds and for the estimation of their relative liquid-gas transfer rates. AB - An automated headspace in-tube extraction (ITEX) method combined with multiple headspace extraction (MHE) has been developed to provide simultaneously information about the accurate wine content in 20 relevant aroma compounds and about their relative transfer rates to the headspace and hence about the relative strength of their interactions with the matrix. In the method, 5 MUL (for alcohols, acetates and carbonyl alcohols) or 200 MUL (for ethyl esters) of wine sample were introduced in a 2 mL vial, heated at 35 degrees C and extracted with 32 (for alcohols, acetates and carbonyl alcohols) or 16 (for ethyl esters) 0.5 mL pumping strokes in four consecutive extraction and analysis cycles. The application of the classical theory of Multiple Extractions makes it possible to obtain a highly reliable estimate of the total amount of volatile compound present in the sample and a second parameter, beta, which is simply the proportion of volatile not transferred to the trap in one extraction cycle, but that seems to be a reliable indicator of the actual volatility of the compound in that particular wine. A study with 20 wines of different types and 1 synthetic sample has revealed the existence of significant differences in the relative volatility of 15 out of 20 odorants. Differences are particularly intense for acetaldehyde and other carbonyls, but are also notable for alcohols and long chain fatty acid ethyl esters. It is expected that these differences, linked likely to sulphur dioxide and some unknown specific compositional aspects of the wine matrix, can be responsible for relevant sensory changes, and may even be the cause explaining why the same aroma composition can produce different aroma perceptions in two different wines. PMID- 23102526 TI - Being overweight or obese is associated with decreased mortality in critically ill patients: a retrospective analysis of a large regional Italian multicenter cohort. AB - PURPOSE: To describe the epidemiology of obesity in a large cohort of intensive care unit (ICU) patients and study its impact on outcomes. METHODS: All 3902 patients admitted to one of 24 ICUs in the Piedmont region of Italy from April 3 to September 29, 2006, were included in this retrospective analysis of data from a prospective, multicenter study. RESULTS: Mean body mass index (BMI) was 26.0 +/ 5.4 kg/m(2): 32.8% of patients had a normal BMI, 2.6% were underweight, 45.1% overweight, 16.5% obese, and 2.9% morbidly obese. ICU mortality was significantly (P < .05) lower in overweight (18.8%) and obese (17.5%) patients than in those of normal BMI (22%). In multivariate logistic regression analysis, being overweight (OR = 0.73; 95%CI: 0.58-0.91, P = .007) or obese (OR = 0.62; 95%CI: 50.45-0.85, P = .003) was associated with a reduced risk of ICU death. Being morbidly obese was independently associated with an increased risk of death in elective surgery patients whereas being underweight was independently associated with an increased risk of death in patients admitted for short-term monitoring and after elective surgery. CONCLUSIONS: In this cohort, overweight and obese patients had a reduced risk of ICU death. Being underweight or morbidly obese was associated with an increased risk of death in some subgroups of patients. PMID- 23102527 TI - Predictors of mortality of mechanically ventilated patients in internal medicine wards. AB - PURPOSE: Budget restrictions have led to shortage of intensive care unit (ICU) beds in several countries. Consequently, ventilated patients are often kept on the wards. This study examined survival likelihood among patients ventilated on the wards and the predictive value of commonly used severity-of-illness scores. METHODS: This study is a prospective observation and characterization of consecutive, mechanically ventilated patients in 3 internal medicine wards of a single hospital who were denied ICU admission. Outcome measures are as follows: 28-day mortality, survival to hospital discharge, and 3 months postdischarge. RESULTS: Eighty-six patients were examined. The patients were 78.9 +/- 8.9 years old; 53% were independent preadmission. Respiratory insufficiency due to infection was the main reason for mechanical ventilation (58%). Charlson and acute physiology scores (APS) averaged 4 +/- 2.2 and 91.8 +/- 26.7, respectively. Twenty-eight-day mortality was 71%, whereas in-hospital mortality was 74% and 3 months postdischarge mortality was 79%. Survivors were significantly younger than nonsurvivors (74.4 +/- 8.5 years vs 80.4 +/- 8.6 years, P < .01), were more likely to be ventilated for cardiac causes (41% vs 11%, P = .04), and had significantly higher initial mean blood pressure (79.4 mm Hg vs 58.2 mm Hg, P = .02) and blood albumin levels (29.8 g/L vs 25.7 g/L, P = .05). Death rate was 10 times more likely, with an APS greater than 90 on the day of intubation as compared with an APS less than 90. CONCLUSION: Mortality in patients ventilated on the ward was high, especially in the subgroup of patients with an APS score greater than 90. The early calculation of APS may assist in focusing therapeutic efforts on patients with better survival chances. PMID- 23102528 TI - Use of a protocolized approach to the management of sepsis can improve time to first dose of antibiotics. AB - PURPOSE: The Surviving Sepsis Guidelines established recommendations for early recognition and rapid treatment of patients with sepsis. Recognizing systemic difficulties that delayed the application of early goal-directed therapy, the Emergency Department and Critical Care leadership instituted a sepsis protocol to identify patients with sepsis and expedite antibiotic delivery. We aimed to determine if the sepsis protocol improved the time to first dose of antibiotics in patients diagnosed with sepsis. MATERIALS AND METHODS: We performed a retrospective chart review of patients with sepsis comparing the time from antibiotic order placement to the first dose of antibiotic therapy over a 3-year period. Patients who received vancomycin and ciprofloxacin underwent additional subgroup analysis, as these antibiotics were made available by protocol for use without infectious disease consultation. RESULTS: The average time to first dose of antibiotics for the presepsis protocol group was 160 minutes, and the average time for the sepsis protocol group was 99 minutes. Fifty-eight patients received vancomycin, and 30 received ciprofloxacin, with a decrease in time of 65 minutes and 41 minutes, respectively. CONCLUSIONS: Initiation of a sepsis protocol, which emphasizes early goal-directed therapy, can improve time to administration of first dose of antibiotics. PMID- 23102529 TI - Configuration of the circle of Willis is associated with less symptomatic intracerebral hemorrhage in ischemic stroke patients treated with intravenous thrombolysis. AB - BACKGROUNDS: The circle of Willis (CoW) is a primary collateral pathway that compensates quickly for a drop in cerebral blood flow. Using the complete CoW as a surrogate marker for good collateral circulation, its prognostic value after intravenous thrombolysis was examined. METHODS: We prospectively studied 64 consecutive patients with acute ischemic stroke treated with tissue plasminogen activator within 3 hours of stroke onset between October 2005 and June 2012 in our hospital. The study protocol was based on standard guidelines for intravenous thrombolysis. On computed tomographic angiography 24 hours after thrombolysis, the CoW was complete in 21 (32.8%) cases and incomplete in 43 (67.2%). RESULTS: Patients with complete CoW were more likely to have early improvement in National Institute of Health Stroke Scale (NIHSS) score (median improvement 2 vs 0 at 2 hours; 4 vs 1 at 24 hours), be independent at 3 months (42% vs 19%). In the incomplete CoW group, the rate of symptomatic intracerebral haemorrhage (SICH) according to the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) definition was almost 3 times higher. Complete CoW was one of the strongest predictors of good functional outcome at 3 months (odds ratio 2.32; P = .01). CONCLUSIONS: Complete CoW independently predicted functional independence and survival. PMID- 23102530 TI - End-expiratory lung volume recovers more slowly after closed endotracheal suctioning than after open suctioning: a randomized crossover study. AB - PURPOSE: Endotracheal suctioning causes significant lung derecruitment. Closed suction (CS) minimizes lung volume loss during suction, and therefore, volumes are presumed to recover more quickly postsuctioning. Conflicting evidence exists regarding this. We examined the effects of open suction (OS) and CS on lung volume loss during suctioning, and recovery of end-expiratory lung volume (EELV) up to 30 minutes postsuction. MATERIAL AND METHODS: Randomized crossover study examining 20 patients postcardiac surgery. CS and OS were performed in random order, 30 minutes apart. Lung impedance was measured during suction, and end expiratory lung impedance was measured at baseline and postsuctioning using electrical impedance tomography. Oximetry, partial pressure of oxygen in the alveoli/fraction of inspired oxygen ratio and compliance were collected. RESULTS: Reductions in lung impedance during suctioning were less for CS than for OS (mean difference, -905 impedance units; 95% confidence interval [CI], -1234 to -587; P < .001). However, at all points postsuctioning, EELV recovered more slowly after CS than after OS. There were no statistically significant differences in the other respiratory parameters. CONCLUSIONS: Closed suctioning minimized lung volume loss during suctioning but, counterintuitively, resulted in slower recovery of EELV postsuction compared with OS. Therefore, the use of CS cannot be assumed to be protective of lung volumes postsuctioning. Consideration should be given to restoring EELV after either suction method via a recruitment maneuver. PMID- 23102531 TI - Assessment of the safety and feasibility of administering antipyretic therapy in critically ill adults: a pilot randomized clinical trial. AB - PURPOSE: To assess the safety and feasibility of treating critically ill adults with different fever control strategies. METHODS: This was a pilot, open-label clinical trial (ClinicalTrials.gov, number NCT01173367) that randomized febrile patients to an aggressive or permissive fever control strategy. For the aggressive and permissive groups, antipyretic therapy (acetaminophen, physical cooling) was administered when the temperature was >= 38.3 degrees C and >= 40.0 degrees C respectively. The primary outcome was 28-day mortality. RESULTS: Two hundred patients experienced a fever (31% of the originally projected estimate), among which 26 were randomized to the aggressive (n = 14) or permissive (n = 12) arm. The aggressive group received a greater dose of acetaminophen (2275 mg vs 0 mg, P = .0001), and more frequently received physical cooling than patients in the permissive group (57% vs 8%, P = .01). The mean daily temperature was lower in the aggressive group (37.8 degrees C vs 38.0 degrees C, P = .02). There was no difference in the primary outcome (21% vs 17%, P = 1.0) or in any safety outcome between the treatment groups. CONCLUSIONS: This study demonstrated the safety and feasibility of administering antipyretic therapy in critically ill adults. The key finding was a lower than expected incidence of fever. PMID- 23102532 TI - Muscle strength measurement in the intensive care unit: not everything that can be counted counts. PMID- 23102533 TI - Circuit lifespan during continuous renal replacement therapy for combined liver and kidney failure. AB - PURPOSE: To evaluate circuit lifespan (CL) and bleeding risk during continuous renal replacement therapy (CRRT), in combined liver and renal failure. METHODS: Single-center retrospective analysis of adults with acute liver failure or decompensated cirrhosis who received CRRT, without anticoagulation or with heparinization in intensive care unit. RESULTS: Seventy-one patients with 539 CRRT circuits were evaluated. Median overall CL was 9 (6-16) hours. CL was 12 (7 24) hours in 51 patients never anticoagulated for CRRT. In 20 patients who subsequently received heparinization, CL was 7 (5-11) hours without anticoagulation, which did not improve with systemic or regional heparinization (P = .231), despite higher peri-circuit activated partial thromboplastin time (APTT) and heparin dose. Using multivariate linear regression, patients with higher baseline APTT or serum bilirubin, or who were not mechanically ventilated, had longer CL (P < .05). Additionally, peri-circuit thrombocytopenia (P < .0001) or higher international normalized ratio (P < .05) predicted longer CL. Of 71 patients, 33 had significant bleeding events. Using multivariate logistic regression, patients with higher baseline APTT, vasoactive drug use >24 hours, or thrombocytopenia, had more bleeding complications (P < .05). Decreasing platelet counts (especially <50 * 10(9)/mm(3)) had an incremental effect on CL (P < .0001). CONCLUSION: CRRT CL is short in patients with liver failure despite apparent coagulopathy. Thrombocytopenia predicts longer CL and bleeding complications. PMID- 23102534 TI - Use of 2-hour creatinine clearance to guide cessation of continuous renal replacement therapy. AB - PURPOSE: A simple test that could guide successful cessation of continuous renal replacement therapy (CRRT) in critically ill patients would be clinically useful. This study aimed to investigate whether a 2-hour creatinine clearance (2h-CrCl) measurement could more accurately predict successful cessation of CRRT than serum creatinine or urine output alone. MATERIALS AND METHODS: This retrospective study identified all patients admitted to a university teaching hospital intensive care unit who received CRRT and had a 2h-CrCl measurement performed in the 12 hours preceding CRRT cessation. The ability of 2h-CrCl to predict successful discontinuation of CRRT was compared to other renal indices. RESULTS: Of 85 patients who had 2h-CrCl performed prior to CRRT cessation 53 (62.4%)(success group) remained dialysis free 7 days after CRRT cessation. 2h-CrCl was a better predictor of remaining CRRT free at day 7 (OR, 1.108 [1.05-1.17] per 1 mL/min increase in 2 hours CrCl, P < .001) than urine output, serum creatinine or age. A 2h-CrCl value of 23 mL/min had a sensitivity, specificity and positive predictive value for remaining CRRT free at day 7 of 75.5%, 84.4%, and 88.8%, respectively. CONCLUSION: 2h-CrCl may be a useful measurement to help guide discontinuation from CRRT. PMID- 23102535 TI - On-demand nanodevice with electrical and neuromorphic multifunction realized by local ion migration. AB - A potential route to extend Moore's law beyond the physical limits of existing materials and device architectures is to achieve nanotechnology breakthroughs in materials and device concepts. Here, we discuss an on-demand WO(3-x)-based nanoionic device where electrical and neuromorphic multifunctions are realized through externally induced local migration of oxygen ions. The device is found to possess a wide range of time scales of memorization, resistance switching, and rectification varying from volatile to permanent in a single device, and these can furthermore be realizable in both two- or three-terminal systems. The gradually changing volatile and nonvolatile resistance states are experimentally demonstrated to mimic the human brain's forgetting process for short-term memory and long-term memory.We propose this nanoionic device with its on-demand electrical and neuromorphic multifunction has a unique paradigm shifting potential for the fabrication of configurable circuits, analog memories, digital neural fused networks, and more in one device architecture. PMID- 23102536 TI - A kinematic analysis of manual aiming control on euthymic bipolar disorder. AB - Motor deficits in tasks that require force steadiness or scaling of movement velocity have been found in bipolar disorder (BD). A potential explanation for these results is the abnormal functioning of the frontostriatal circuitry. We designed this study to investigate the possible impairments in a manual aiming task. Participants comprised 15 euthymic BD patients and 15 healthy controls, who performed 100 trials of a goal-directed manual movement with a non-inking pen on a digitizing tablet. Four different conditions of execution were required. The control condition appeared on the computer screen in 70% of the trials, and the other three conditions, (a) distractor, (b) inhibition of response and (c) higher index of difficulty, each appeared in 10% of the trials. Compared to the controls, the BD patients were less fluent in their movements, relied more heavily on visual feedback to control their manual movements and presented a lower spatial accuracy. We found that motor deficits in euthymic BD were observed in the kinematic analysis of manual aiming. Our findings are consistent with the hypothesis of abnormal functioning of the frontostriatal circuitry in euthymic BD. PMID- 23102537 TI - Executive attention deficits in schizophrenia: putative mandatory and differential cognitive pathology domains in medicated schizophrenia patients. AB - Executive attention (EA) is a core-construct of working memory (WM) capacity. EA performance is directly related to dorsolateral prefrontal cortex (DLPFC) activation, a neural mechanism that is dysfunctional in schizophrenia. We examined the differences in particular types of EA failure in schizophrenia patients and healthy controls. We evaluated executive attention in 60 medicated schizophrenia patients and 60 matched healthy individuals. We used a standard WM task, a verbal n-Back task, to measure executive attention (WM accuracy). Our standard-version WM task (control block, 10min long) was designed to examine baseline executive attention function and was followed by one out of three different experimental blocks (revised n-Back tasks). Baseline executive attention performance was significantly related to psychosis severity and functional capacity in the psychiatric group. In both healthy and psychiatric groups, experimental-block conditions revealed that domain-general recall had a differential effect on WM scores, and was related to the patient's clinical condition. Only in the psychiatric group domain-specific recall impairments were mandatory, most severe, and independent of baseline WM scores. The results revealed the importance of domain-general recall WM scores in the evaluation of executive attention deficits in patients and controls. Disruption in domain specific recall may represent a specifier of cognitive impairment in schizophrenia spectrum disorders. PMID- 23102538 TI - Design and synthesis of new agents for neuronal nicotinic acetylcholine receptor (nAChRs) imaging. AB - INTRODUCTION: The most abundant subtype of cerebral nicotinic acetylcholine receptors (nAChR), alpha4beta2, plays a critical role in various brain functions and pathological states. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer aided drug design (CADD) plays a more and more important role in today's drug discovery. METHODS: Two novel 3-pyridyl ether nicotinic ligands-3-((pyridine-2-yl)methoxy)-5 iodopyridine, and 3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy) methyl)pyridine were designed and synthesized and radiolabeled with I-125 based on our 3D-QSAR models reported previously. Their ability to label high-affinity brain nicotinic acetylcholine receptors (nAChRs) was evaluated. RESULTS: [125I]3 ((pyridin-2-yl)methoxy)-5-iodopyridine shows rapid accumulation and elimination with peak (1.86%ID/g) at 5 min post injection, but has high blood uptake. [125I]3 (((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine entered the brain with maximal uptake value 3.01%ID/g at 15 min after injection, and showed approximately 27% inhibition of radioactivity uptake in thalamus in mice pretreated with nicotine. CONCLUSIONS: The results of this preliminary study show that [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5-((4-iodobenzyloxy)methyl)pyridine shows relatively high uptake to the brain, however, since the in vivo selectivity for alpha4beta2 nAChRs was not enough, [125I]3-(((S)-pyrrolidin-2-yl)methoxy)-5 ((4-iodobenzyloxy)methyl)pyridine does not have the required properties for imaging nAChRs using SPECT. Structure optimization is needed for specific visualization of brain alpha4beta2 nAChRs in vivo. PMID- 23102539 TI - PET quantification of pancreatic VMAT 2 binding using (+) and (-) enantiomers of [18F]FP-DTBZ in baboons. AB - OBJECTIVES: The exact cause(s) of apparent overestimation of beta cell mass (BCM) with vesicular monoamine transporter type 2 (VMAT2) PET imaging in type 1 diabetes (T1D) is unknown. The objectives were to estimate in baboons non displaceable binding of [18F]fluoropropyl (FP)-(+)-dihydrotetrabenazine (DTBZ) with its inactive enantiomer, [18F]FP-(-)-DTBZ, to validate the use of the reference tissue (renal cortex or spleen) in VMAT2 quantification; and also to compare specific pancreatic VMAT2 binding with that of the striatum in the same baboon brains because high specific binding signal for the pancreas would be desirable for its accurate quantification. METHODS: Baboons (Papio ursinus) had multiple dynamic abdominal and brain PET scans each for 2 h with (+) and (-) enantiomers on separate occasions. Data were analyzed by compartmental models to estimate non-displaceable (V(ND)) and specific (V(S)) VMAT2 binding in respective organs. RESULTS: [18F]FP-DTBZ PET showed excellent target tissue signal and specific VMAT2 binding in the pancreas (Vs =41+/-11 mL/cm3) at nearly 80% that of the striatum. Directly estimated non-displaceable binding in the pancreas (V(ND) =12+/-1 mL/cm3) was similar to that of the renal cortex, spleen or cerebellum. CONCLUSION: 18FFP-DTBZ PET shows excellent specific VMAT2 binding in both the pancreas and striatum in baboons. The renal cortex or spleen as the reference tissue in VMAT2 quantification appears supported. However further studies appear warranted to directly estimate pancreatic non-displaceable binding in humans including T1D patients and also to clarify the cause of the apparent overestimation of BCM in T1D. PMID- 23102540 TI - [68Ga]NS3-RGD and [68Ga] Oxo-DO3A-RGD for imaging alpha(v)beta3 integrin expression: synthesis, evaluation, and comparison. AB - INTRODUCTION: 68Ga-labeled RGD peptides in combination with PET allow non invasive determination of alpha(v)beta3 integrin expression which is highly increased during tumor-induced angiogenesis. The aim of this study was to synthesize and evaluate two RGD peptides containing alternative chelating systems, namely [68Ga]NS3-RGD-RGD and [68Ga]Oxo-DO3A-RGD and to compare their in vitro and in vivo properties with [68Ga]DOTA- and [68Ga]NODAGA-RGD. METHODS: Syntheses of both radiotracers followed standard SPPS protocols. For in vitro characterization distribution coefficients, protein binding abilities, serum stabilities, and alpha(v)beta3 integrin binding affinities were determined. For in vitro tests as well as for the biodistribution assay alpha(v)beta3 positive human melanoma M21 and alpha(v)beta3 negative M21-L cells were used. RESULTS: 68Ga-labeling of NS3-RGD resulted in good radiochemical purity, whereas HPLC analysis showed two peaks with a ratio of 1:6 for [68Ga]Oxo-DO3A-RGD. Distribution coefficients were -3.4 for [68Ga]Oxo-DO3A-RGD and -2.9 for [68Ga]NS3 RGD. Both radiotracers were stable in PBS solution at 37 degrees C for 2 h but lack stability in human serum. Protein binding was approximately 40% of the total activity for [68Ga]NS3-RGD and 70% for [68Ga]Oxo-DO3A-RGD, respectively, resulting in high blood pool activities. Biodistribution assays confirmed these findings and showed an additional high uptake in liver and kidneys, especially for [68Ga]NS3-RGD. Furthermore, [68Ga]Oxo-DO3A-RGD showed nearly the same activity concentrations in alpha(v)beta3 positive and alpha(v)beta3 negative tumors. CONCLUSIONS: [68Ga]Oxo-DO3A-RGD and [68Ga]NS3-RGD have inferior characteristics compared to already existing 68Ga-labeled RGD peptides and thus, both are not suited to image alpha(v)beta3 integrin expression. Of all our tested RGD peptides, [68Ga]NODAGA-RGD still possesses the most favorable imaging properties. Moreover this study shows that the use of appropriate chelators to achieve good targeting properties of 68Ga-labeled biomolecules and careful in vitro and in vivo evaluation including comparative studies of different strategies are essential components in designing an effective imaging agent for PET. PMID- 23102541 TI - [National prostate cancer registry 2010 in Spain]. AB - OBJECTIVES: To estimate the 2010 incidence of PCa in Spain and describe the clinical profile of newly-diagnosed cases using a nationwide hospital-based registry. MATERIAL AND METHODS: National epidemiological study in 25 public hospitals with a specific reference population according to the National Health System. Sociodemographic and clinical variables of all newly diagnosed, histopathological confirmed PCa cases were collected in 2010, in the area of influence of each centre. The age-standardised PCa incidence was determined based on the age distribution of the Spanish population in Spain and in 3 regions: Andalusia, Catalonia and Region of Madrid. RESULTS: 4,087 new cases of PCa were diagnosed for a reference population of 4,933,940 men (21.8% of the Spanish male population). The estimated age-standardised PCa incidence was 82.27 cases per 100,000 men in Spain, 70,38 in Andalusia, 85,70 in Catalonia and 92,29 in the Region of Madrid. Mean age at diagnosis was 69 years. Median PSA was 8 ng/ml. Gleason score was <=6 in 56.5%, 7 in 26.7% and >7 in 16.8% of patients. At diagnosis, 90% had localised disease. CONCLUSIONS: In the 3 Regions analyzed, around 80-90% of the cases are diagnosed in a clinical localised stage. The incidence rates in Andalusia, Catalonia and Region of Madrid show a great difference between them due to several factors. PMID- 23102542 TI - Structural insights into nonsense-mediated mRNA decay (NMD) by electron microscopy. PMID- 23102543 TI - A Survey of Internists and Cardiologists: Are Discoveries in Fatty Acids Truly being translated into Clinical Practice? PMID- 23102544 TI - Alternative treatment options in colorectal cancer patients with 5-fluorouracil- or capecitabine-induced cardiotoxicity. AB - Most chemotherapy regimens in colorectal cancer treatment are 5-fluorouracil (5 FU)/leucovorin or capecitabine-based. Cardiotoxicity is a less common but potentially lethal complication of 5-FU or capecitabine treatment, and some physicians might be unfamiliar with treatment alternatives. Rechallenging should be avoided because it carries a high risk of recurrence of the cardiac symptoms and prophylactic treatment is not always protective. Possible alternative treatment options to be considered are to replace the oral capecitabine or intravenous 5-FU by a 5-FU bolus regimen, by uracil-tegafur or tegafur/gimeracil/oteracil, both oral fluoropyrimidines combining a 5-FU prodrug with a dihydropyrimidine dehydrogenase (DPD) inhibitor, or by raltitrexed, a thymidilate synthase inhibitor whose metabolism is independent of DPD. Patients with advanced colorectal cancer and fluoropyrimidine-induced cardiotoxicity can be treated with other non-fluoropyrimidine related chemotherapy, either as a single agent, combined, or in combination with biological agents. In this report we discuss the different alternative treatment options. PMID- 23102545 TI - Body size over-estimation in women with anorexia nervosa is not qualitatively different from female controls. AB - Over-estimation of body size is a cardinal feature of anorexia nervosa (AN), usually revealed by comparing individuals who have AN with non-AN individuals, the inference being that over-estimation is pathological. We show that the same result can be reproduced by sampling selectively from a single distribution of performance in body size judgement by comparing low BMI individuals with normal BMI individuals. Over-estimation of body size in AN is not necessarily pathological and can be predicted by normal psychophysical biases in magnitude estimation. We confirm this prediction in a dataset from a morphing study in which 30 women with AN and 137 control women altered a photograph of themselves to estimate their actual body size. We further investigated the relative contributions of sensory and attitudinal factors to body-size overestimation in a sample of 166 women. Our results suggest that both factors play a role, but their relative importance is task dependent. PMID- 23102546 TI - Anaphylaxis to cow's milk formula containing short-chain galacto-oligosaccharide. AB - BACKGROUND: On the basis of the proven prebiotic effects of oligosaccharides in cow's milk formula (CMF) in infants, CMFs are supplemented with oligosaccharides. OBJECTIVE: We present a series of 5 cases of cow's milk-tolerant but atopic patients with a history of respiratory allergies. All had anaphylaxis after the ingestion of CMF supplemented with short-chain galacto-oligosaccharide (scGOS). The allergen trigger was investigated. METHODS: Clinical histories were collated. Skin prick tests (SPTs) and basophil activation tests (BATs) were carried out with the eliciting CMF that triggered anaphylaxis, with or without supplemented prebiotics (scGOS) and with scGOS fractions containing oligosaccharides of different chain lengths. RESULTS: The median age of presentation was 6 years (range, 5-38 years). Anaphylaxis occurred within 30 minutes of the first known exposure to CMF supplemented with prebiotics in all patients. Only 1 patient was subjected to oral challenge, which resulted in an anaphylactic reaction. All patients demonstrated IgE sensitization through SPTs and BATs to scGOS and fractions of scGOS containing 3 sugar units or greater but not to cow's milk or long-chain fructo-oligosaccharide. Eight child control subjects tolerant to regular ingestion of scGOS-supplemented CMF and 1 adult volunteer were found to have negative results to scGOS through SPTs and BATs. In addition, in vitro BATs with donor basophils sensitized with sera from 2 of the 3 reported cases showed reactions to scGOS. The scGOS-induced basophil activation was inhibited in the presence of wortmannin, a phosphatidylinositol 3-kinase inhibitor. CONCLUSIONS: This study describes an unusual form of IgE-mediated anaphylaxis triggered by low molecular-weight oligosaccharides in scGOS. The primary sensitizer for this phenomenon requires further investigation. PMID- 23102547 TI - Prevalence and genetic diversity of enteropathogenic Yersinia spp. in pigs at farms and slaughter in Lithuania. AB - The prevalence of enteropathogenic Yersinia spp. in pigs at farms and slaughter in relation to potential farming risk factors in Lithuania was examined. Pig faeces and carcase swab samples from 11 farms were studied at slaughterhouses. Nine of the 11 farms were visited again 3-5 months later, and pooled feacal samples and environmental samples were collected. Pathogenic Yersinia enterocolitica was found in 64% and Yersinia pseudotuberculosis in 45% of the sampled pig farms. All obtained isolates belonged to bioserotypes 4/O:3 and 2/O:3, respectively. Low biosecurity level was associated with a high prevalence of Y. enterocolitica on farms. Characterization with PFGE of 64 Y. enterocolitica and 27 Y. pseudotuberculosis isolates revealed seven and two different genotypes, respectively. Dominant enteropathogenic Yersinia spp. genotypes were obtained in both pig feacal and carcase samples. The high contamination of pig carcases (25%) with enteropathogenic Yersinia spp. may be an important factor contributing to the high incidence of human yersiniosis in Lithuania. PMID- 23102548 TI - Role of secondary level laboratories in strengthening quality at primary level health facilities' laboratories: an innovative approach to ensure accurate HIV, tuberculosis, and malaria test results in resource-limited settings. AB - Providing regular external quality assessment of primary level laboratories and timely feedback is crucial to ensure the reliability of testing capacity of the whole laboratory network. This study was aimed to assess the diagnostic performances of primary level laboratories in Southwest Showa Zone in Ethiopia. An external quality assessment protocol was devised whereby from among all the samples collected on-site at 4 health centers (HCs), each HC sent to a district hospital (DH) on a weekly basis 2 TB slides (1 Ziehl-Neelsen stained and another unstained), 2 malaria slides (1 Giemsa stained and another unstained), and 2 blood samples for HIV testing (1 whole blood and another plasma) for a comparative analysis. Similarly, the DH preserved the same amount and type of specimens to send to each HC for retesting. From October to November 2011, 192 single-blinded specimens were rechecked: 64 TB slides, 64 malaria slides, and 64 blood specimens for HIV testing. The analyses demonstrated an overall agreement of 95.3% (183/192) between the test and the retest, and 98.4% (63/64), 92.2% (59/64,) and 95.3% (61/64) for TB microscopy, malaria microscopy, and HIV rapid testing, respectively. Of the total TB slides tested positive, 20/23 (87%) were quantified similar in both laboratories. The agreement on HIV rapid testing was 100% (32/32) when plasma samples were tested either at HC (16/16) or at DH (16/16), while when whole blood specimens were tested, the agreement was 87.5% (14/16) and 93.8% (15/16) for samples prepared by HCs and DH, respectively. Results of this new approach proved that secondary laboratories could play a vital role in assuring laboratory qualities at primary level HCs, without depending on remotely located national and regional laboratories to provide this support. PMID- 23102549 TI - IRIS iQ200 workstation as a screen for performing urine culture. AB - We cultured 1000 urines and tested them with the iQ200 Workstation (Iris Diagnostics, Chatsworth, CA, and Arkray, Edina, MN, USA) for leukocyte esterase and nitrite (LE/N), white blood cells (WBC), all small particles (ASP), bacteria, and yeast. Positive culture grew >= 10(4) CFU/mL of 1 or 2 uropathogens. Method A assessed LE/N, WBCs >= 6/MUL, and bacteria/yeast. Method B assessed WBCs >= 6/MUL, bacteria/yeast, and ASP >= 10,000. Each was compared to culture results, clinician's diagnosis (CD), or expert review (ER). Sensitivities by culture were 88.7% (Method A) and 88.3% (Method B), with negative predictive values (NPVs) of 94.4% and 94.2%, respectively. Sensitivity and NPV increased for comparison to the CD (99.6%) and NPVs of 99.0% and 99.3% compared to ER. ASP did not enhance specificity, sensitivity, or NPV. The iQ200 Workstation performed well by any standard, thus providing a reliable system by which to improve the use of laboratory resources. PMID- 23102550 TI - Interferon gamma mRNA quantitative real-time polymerase chain reaction for the diagnosis of latent tuberculosis: a novel interferon gamma release assay. AB - The interferon gamma (IFN-gamma) release assay (IGRA) is widely used as a diagnostic method for latent tuberculosis infection (LTBI). The QuantiFERON-TB Gold and QuantiFERON-TB Gold In-tube (QFT-IT) tests measure plasma IFN-gamma levels using enzyme-linked immunosorbent assay (ELISA), and T-SPOT.TB counts IFN gamma-producing cells using enzyme-linked immunosorbent spot assay. IFN-gamma mRNA was evaluated as an indicator of IGRA in comparison with QFT-IT IFN-gamma ELISA in 46 subjects with active TB and in 73 at low risk for TB. Significant IFN gamma mRNA expression was detected from 30 min and peaked 4 h after stimulation with MTB antigens or mitogen. This was defined as the optimal time point for IFN gamma mRNA real-time polymerase chain reaction (PCR). The sensitivities of IFN gamma mRNA real-time PCR and IFN-gamma ELISA were 84.8% (39/46) and 89.1% (41/46), respectively (no significant difference). Although the specificities of IFN-gamma ELISA was 4.1% higher than that of IFN-gamma mRNA real-time PCR (60.3% versus 56.2%), the difference was not statistically significant. The overall agreement between IFN-gamma mRNA real-time PCR and IFN-gamma ELISA was 79.8% (kappa = 0.475). Whilst there was no difference in the performance of IFN-gamma mRNA real-time PCR and IFN-gamma ELISA, IFN-gamma mRNA real-time PCR was superior to IFN-gamma ELISA in terms of the time required for detection of MTB infection. PMID- 23102551 TI - Assessment of the effect of low-energy diode laser irradiation on gamma irradiated rats' mandibles. AB - OBJECTIVE: The purpose of the present study was to evaluate the biostimulative and regenerative effects of low intensity laser irradiation (LILT) (applied before or after initiation of radiotherapy) on gamma irradiated rats' jaw bones. METHODS: Forty eight male Albino rats were equally divided into two groups: group 1, in which the left side of the mandible was subjected to three successive sessions of laser (LILT) prior to whole body gamma radiation (2Gy/3 fractions/week) and group 2, received whole body gamma radiation (2Gy/3 fractions/week) prior to three successive sessions of laser applied to left side. The right side of both groups was used as gamma irradiated non-lased control group. Each group was then subdivided into four equal subgroups (a, b, c, d) according to the time of scarification (3, 7, 14, 21 days respectively). Specimens were subjected to histological, histomorphometric and scanning electron microscopic examinations. RESULTS: Thin irregular bone trabeculae and widened marrow spaces were identified in the control group. The lased sides of groups 1 and 2 demonstrated regular, thick and continuous bone trabeculae. Ultrastructurally, collagen fibres of the control group appeared irregularly arranged and more spaced compared to groups 1 and 2. Normal-sized osteocytic lacunae were seen in the lased groups, as compared to the wide lacunar spaces noted in the control group. Histomorphometric analysis showed a significant increase in the area of bone trabeculae, as well as the width of compact bone, for the lased groups. CONCLUSIONS: LILT seemed to attenuate the radiation-related damage in alveolar bones. PMID- 23102553 TI - Transfer of object category knowledge across visual and haptic modalities: experimental and computational studies. AB - We study people's abilities to transfer object category knowledge across visual and haptic domains. If a person learns to categorize objects based on inputs from one sensory modality, can the person categorize these same objects when the objects are perceived through another modality? Can the person categorize novel objects from the same categories when these objects are, again, perceived through another modality? Our work makes three contributions. First, by fabricating Fribbles (3-D, multi-part objects with a categorical structure), we developed visual-haptic stimuli that are highly complex and realistic, and thus more ecologically valid than objects that are typically used in haptic or visual haptic experiments. Based on these stimuli, we developed the See and Grasp data set, a data set containing both visual and haptic features of the Fribbles, and are making this data set freely available on the world wide web. Second, complementary to previous research such as studies asking if people transfer knowledge of object identity across visual and haptic domains, we conducted an experiment evaluating whether people transfer object category knowledge across these domains. Our data clearly indicate that we do. Third, we developed a computational model that learns multisensory representations of prototypical 3-D shape. Similar to previous work, the model uses shape primitives to represent parts, and spatial relations among primitives to represent multi-part objects. However, it is distinct in its use of a Bayesian inference algorithm allowing it to acquire multisensory representations, and sensory-specific forward models allowing it to predict visual or haptic features from multisensory representations. The model provides an excellent qualitative account of our experimental data, thereby illustrating the potential importance of multisensory representations and sensory-specific forward models to multisensory perception. PMID- 23102552 TI - Regional variation in IIM myosin heavy chain expression in the temporalis muscle of female and male baboons (Papio anubis). AB - OBJECTIVE: The purpose of this study was to determine whether high amounts of fast/type II myosin heavy chain (MyHC) in the superficial as compared to the deep temporalis muscle of adult female and male baboons (Papio anubis) correlates with published data on muscle function during chewing. Electromyographic (EMG) data show a regional specialization in activation from low to high amplitude activity during hard/tough object chewing cycles in the baboon superficial temporalis.(48,49) A positive correlation between fast/type II MyHC amount and EMG activity will support the high occlusal force hypothesis. DESIGN: Deep anterior temporalis (DAT), superficial anterior temporalis (SAT), and superficial posterior temporalis (SPT) muscle samples were analyzed using SDS-PAGE gel electrophoresis to test the prediction that SAT and SPT will show high amounts of fast/type II MyHC compared to DAT. Serial muscle sections were incubated against NOQ7.5.4D and MY32 antibodies to determine the breadth of slow/type I versus fast/type II expression within each section. RESULTS: Type I and type IIM MyHCs comprise nearly 100% of the MyHCs in the temporalis muscle. IIM MyHC was the overwhelmingly predominant fast MyHC, though there was a small amount of type IIA MyHC (<=5%) in DAT in two individuals. SAT and SPT exhibited a fast/type II phenotype and contained large amounts of IIM MyHC whereas DAT exhibited a type I/type II (hybrid) phenotype and contained a significantly greater proportion of MyHC-I. MyHC-I expression in DAT was sexually dimorphic as it was more abundant in females. CONCLUSIONS: The link between the distribution of IIM MyHC and high relative EMG amplitudes in SAT and SPT during hard/tough object chewing cycles is evidence of regional specialization in fibre type to generate high occlusal forces during chewing. The high proportion of MyHC-I in DAT of females may be related to a high frequency of individual fibre recruitment in comparison to males. PMID- 23102554 TI - Interplay between mechanical, electrical, and thermal relaxations in nanocomposite proton conducting membranes based on Nafion and a [(ZrO2).(Ta2O5)(0.119)] core-shell nanofiller. AB - The thermal, mechanical, and electric properties of hybrid membranes based on Nafion that contain a [(ZrO(2)).(Ta(2)O(5))(0.119)] "core-shell" nanofiller are elucidated. DSC investigations reveal the presence of four endothermic transitions between 50 and 300 degrees C. The DMA results indicate improved mechanical stability of the hybrid materials. The DSC and DMA results are consistent with our previous suggestion of dynamic R-SO(3)H...[ZrTa] cross-links in the material. These increase the thermal stability of the -SO(3)H groups and the temperature of thermal relaxation events occurring in hydrophobic domains of Nafion. The broadband electrical spectroscopic analysis reveals two electric relaxations associated with the material's interfacial (sigma(IP)) and bulk proton conductivities (sigma(EP)). The wet [Nafion/(ZrTa)(1.042)] membrane has a conductivity of 7.0 * 10(-2) S cm(-1) at 115 degrees C, while Nafion has a conductivity of 3.3 * 10(-2) S cm(-1) at the same temperature and humidification conditions. sigma(EP) shows VTF behavior, suggesting that the long-range conductivity is closely related to the segmental motion of the Nafion host matrix. Long-range conduction (sigma(EP)) occurs when the dynamics of the fluorocarbon matrix induces contact between different delocalization bodies (DB), which results in proton exchange processes between these DBs. PMID- 23102555 TI - Antifungal effect of ophthalmic preservatives phenylmercuric nitrate and benzalkonium chloride on ocular pathogenic filamentous fungi. AB - In the present study, the antifungal effects of phenylmercuric nitrate and benzalkonium chloride versus those of natamycin and ketoconazole were assessed against 216 filamentous fungi isolates from cases of fungal keratitis. They included 112 Fusarium isolates, 94 Aspergillus isolates, and 10 Alternaria alternata isolates. The strains were tested by broth dilution antifungal susceptibility testing of filamentous fungi approved by the Clinical and Laboratory Standards Institute M38-A document. The results showed that the MIC(50) values of phenylmercuric nitrate were 0.0156, 0.0156, and 0.0313 MUg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC(90) values of phenylmercuric nitrate were 0.0313, 0.0313, and 0.0313 MUg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC(50) values of benzalkonium chloride were 16, 32, and 8 MUg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The MIC(90) values of benzalkonium chloride were 32, 32, and 16 MUg/mL for Fusarium spp., Aspergillus spp., and A. alternata, respectively. The study indicates that phenylmercuric nitrate has considerable antifungal activity and its effect is significantly superior to those of benzalkonium chloride, natamycin, and ketoconazole against ocular pathogenic filamentous fungi in vitro, deserving further investigation for treating fungal keratitis as a main drug. PMID- 23102556 TI - Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance(r)) registry, 2004-2008. AB - This analysis describes the epidemiology and outcomes of candidemia in patients enrolled in the Prospective Antifungal Therapy Alliance (PATH Alliance(r)) registry from 2004 to 2008. Overall, 4067 Candida isolates were identified from 3648 patients. The most common Candida spp. were C. albicans (42.1%), C. glabrata (26.7%), C. parapsilosis (15.9%), C. tropicalis (8.7%), and C. krusei (3.4%). The proportion of candidemia caused by non-albicans Candida spp. (57.9%) was higher than that caused by C. albicans (42.1%). Infections with C. albicans were most common in neonatal intensive care unit (54.8%). In total, 3342 patients received antifungal therapy; fluconazole (66.0%) and echinocandins (50.5%) were most frequently administered. The 90-day survival rate for all patients was 61.3%. Among the most common Candida spp., the highest 90-day survival rate was observed for C. parapsilosis (70.0%) and the lowest for C. krusei (53.6%). In conclusion, this study expands the current knowledge of the epidemiology and outcomes of candidemia. PMID- 23102557 TI - Assessment of microbiota and peptidoglycan in perianal fistulas. AB - Transanal advancement flap repair has been advocated as the treatment of choice for high transsphincteric perianal fistulas, but fails in 1 of every 3 patients. Persistence of the fistula after flap repair might be the result of ongoing disease in the remaining fistula tract. In 10 specimens of the distal part of the fistula, microbiota was assessed by means of conventional microbiological culture and 16S rRNA gene sequencing. Proinflammatory bacterial peptidoglycan and recognition proteins were assessed by immunohistochemistry. Bacterial species were bowel derived, skin derived, or a combination of both. No mycobacterium species were identified. 16S rRNA gene sequencing failed to identify bacteria in all but 1 specimen, most likely as a result of low numbers of organisms. Peptidoglycan was detected in 90% of the patients, and a host response to peptidoglycan in 60%. Therefore, we suggest that peptidoglycan might play a role in the ongoing inflammation in perianal fistulas. PMID- 23102558 TI - Use of a surfactant (polysorbate 80) to improve MIC susceptibility testing results for polymyxin B and colistin. AB - Accurate determination of in vitro activity for polymyxin class agents has consistently been a problem due to their physical-chemical characteristics that can be influenced by the constituents of reference and/or standardized susceptibility testing methods. We evaluated the impact of using polysorbate 80 (P-80), a surfactant, in reference broth microdilution (BMD) methods when testing polymyxin B and colistin against 247 clinical strains of Enterobacteriaceae (124 strains), Acinetobacter spp. (60 strains), and Pseudomonas aeruginosa (63 strains). All testing was performed in frozen-form BMD panels with and without 0.002% P-80. MIC results for both polymyxins were generally 4- to 8-fold lower when P-80 was added to the testing broth compared to Mueller-Hinton broth without the surfactant. Decreases were greatest in organisms having MIC values at <=2 MUg/mL and among Acinetobacter spp. Polymyxins should be tested with P-80 to more accurately assess the potencies of these agents necessary to treat multidrug resistant Gram-negative bacilli. PMID- 23102559 TI - Evaluation of hepatitis C virus RNA stability in room temperature and multiple freeze-thaw cycles by COBAS AmpliPrep/COBAS TaqMan HCV. AB - To assess the stability of various sample types and storage conditions for quantitative detectability of hepatitis C virus (HCV) RNA viral loads, we studied serum and EDTA/citrate plasma samples obtained from 10 patients known to be positive for HCV RNA. Samples were subjected to the following conditions: 1) 10 freeze-thaw (FT) cycles, and 2) storage at room temperature for 24, 48, and 72 h. Detection of HCV RNA was performed by COBAS AmpliPrep/COBAS TaqMan HCV. The following conclusions were reached: 1) no significantly different viral loads were observed in different blood compartments; 2) no significantly different viral loads were observed after 24, 48, and 72 h at room temperature; 3) no significantly different viral loads were observed after 10 FT cycles in serum and plasma samples; and 4) HCV RNA is quite stable in serum and plasma (EDTA/citrate) samples. PMID- 23102560 TI - Factors that affect quality of dying and death in terminal cancer patients on inpatient palliative care units: perspectives of bereaved family caregivers. AB - CONTEXT: There is an increasing use of palliative care units (PCUs) for the treatment of terminally ill cancer patients. Thus, it is important to evaluate the care and quality of life of terminally ill cancer patients treated in PCUs so that improvements can be made. Limited research has investigated the quality of dying and death in PCUs. OBJECTIVES: The aim of this study was to identify factors associated with the quality of dying and death for terminally ill cancer patients in PCUs. METHODS: Data were collected from 570 bereaved family caregivers of terminally ill cancer patients. All patients were registered and died in one of the 40 inpatient PCUs designated by the Korean Ministry of Health and Welfare. We assessed the perceived timing of referral to a PCU; the quality of end-of-life cancer care with the Care Evaluation Scale; and the quality of dying and death with the Good Death Inventory. RESULTS: The perception of appropriate timing of referral, use of a community-based PCU, and higher quality of cancer care as assessed by the Care Evaluation Scale were associated with good dying and death in all domains of the Good Death Inventory. CONCLUSION: The good quality of end-of-life care in a PCU improves the quality of dying in terminally ill cancer patients. The data have the potential to guide the development of interventions aimed at achieving a good quality of dying for patients with terminal cancer. PMID- 23102561 TI - Opioid switching in patients with advanced cancer followed at home. A retrospective analysis. AB - CONTEXT: Opioid switching has been found to improve opioid responsiveness in different conditions. However, data on opioid switching performed at home are almost nonexistent, despite the fact that most patients are followed at home. OBJECTIVES: The aim of this retrospective survey was to determine frequency, indications, usefulness, and safety of opioid switching when treating advanced cancer-related pain in patients followed at home. METHODS: A retrospective review of data from patients with advanced cancer followed at home by three home care teams for a period of two years was performed. Patients who had their opioids switched were selected. Reasons for switching opioid doses and routes of administration and outcomes were collected. RESULTS: Two hundred one (17%) of 1141 patients receiving "strong" opioids were switched. The mean Karnofsky Performance Status score was 35.6, and the median survival was 30 days. The most frequent reason to switch was for convenience, and the most frequent switch was to parenteral morphine. In most patients, a better analgesic response was observed. Patients who were switched to parenteral morphine had a shorter survival in comparison with other opioid sequences (P<0.0005). After switching, opioid doses were increased by 23% and 41%, after a week and at time of death, respectively. CONCLUSION: Opioid switching was useful for most patients in the home environment, at least in less complex circumstances, when done by experienced home care teams. Prospective studies are needed to provide information about the decision to admit to hospital for this purpose and the predictive factors that may relatively contraindicate transportation to a facility in severely ill patients. PMID- 23102563 TI - The effect of severe androgen deficiency on physical function in male patients with cancer. AB - CONTEXT: Low circulating testosterone concentrations are commonly observed in male patients with cancer and have been shown to be associated with weight loss and increased severity of many symptoms, including fatigue and weakness. OBJECTIVES: The aim of the present study was to determine the extent to which testosterone deficiency is associated with poor physical function in male patients with nonhormonal cancers. METHODS: We measured serum free testosterone concentration in 101 male patients with cancer evaluated at a nutrition rehabilitation clinic and performed univariate and multivariate linear regression analyses to assess the effect of a free testosterone concentration in the lowest quartile on six-minute walk distance (6-MWD) (n=100) and maximal gait speed (n=49). RESULTS: In the univariate analyses, patients in the lowest free testosterone quartile had a 6-MWD that was 96 m (95% CI 51, 141) less and a maximal gait speed that was 0.26 m/second (95% CI 0.06, 0.47) slower on average than patients in the upper three free testosterone quartiles. When controlling for other demographic, clinical, and biological factors, a free testosterone concentration in the lowest quartile was associated, on average, with a 51 m (95% CI 44, 97) lower 6-MWD but did not affect maximal gait speed. CONCLUSION: The present study shows that in male patients with cancer, an extremely low serum free testosterone concentration is independently associated with 6-MWD but not maximal gait speed. Hence, a severe testosterone deficiency may impair their ability to perform sustained activity, but to a lesser degree, short bursts of activity. PMID- 23102564 TI - Extraoral vertical subcondylar osteotomy with rigid fixation for correction of mandibular prognathism. Comparison with bilateral sagittal split osteotomy and surgical technique. AB - PURPOSE: The aim was to compare outcome after extraoral vertical subcondylar osteotomy (EVSO) with rigid fixation and bilateral sagittal split osteotomy (BSSO) for correction of mandibular prognathism. The objectives were to examine treatment factors, postoperative results, and long-term stability. The surgical technique for EVSO is presented in detail. SUBJECTS AND METHODS: Lateral cephalograms and information from patient files of 65 consecutively operated patients with EVSO and 65 matching patients operated with BSSO were analyzed preoperatively, postoperatively, after 6 months and 3 years. RESULTS: No clinically significant differences were observed in long-term stability. The retromandibular scar inferior to the earlobe after EVSO was on average 25 mm long and 1 mm wide, and was of no concern for most of the patients. Normal or near normal sensation to the lower lip/chin was reported by half of the BSSO patients at the 3-year follow-up. CONCLUSION: Because no major differences in outcome were observed, EVSO with rigid fixation may be considered as a viable alternative if it is important to avoid alterations in sensation, whereas BSSO may be preferred if retromandibular scar is of concern. PMID- 23102562 TI - Alteration in pain modulation in women with persistent pain after lumpectomy: influence of catastrophizing. AB - CONTEXT: Persistent pain is common after surgical treatment of breast cancer, but fairly little is known about the changes in sensory processing that accompany such pain syndromes. OBJECTIVES: This study used quantitative sensory testing to compare psychophysical responses to standardized noxious stimulation in two groups of women who had previously undergone breast cancer surgery: women with (n=37) and without (n=34) persistent postoperative pain. METHODS: Participants underwent a single testing session in which responses to a variety of noxious stimuli were assessed. RESULTS: Findings suggested that women with chronic pain after breast cancer surgery display enhanced temporal summation of mechanical pain, deficits in endogenous pain inhibition, and more intense painful aftersensations compared with those without long-term pain. Some of these group differences were mediated by higher levels of pain catastrophizing in the group of women with persistent pain. CONCLUSION: These findings suggest that persistent postoperative pain is associated with alterations in central nervous system pain modulatory processes. Future treatment studies might benefit from targeting these pain-modulatory systems, and additional studies using functional neuroimaging methods might provide further valuable information about the pathophysiology of long-term postsurgical pain in women treated for breast cancer. PMID- 23102565 TI - Avian lipocalin expression in chickens following Escherichia coli infection and inhibition of avian pathogenic Escherichia coli growth by Ex-FABP. AB - Avian pathogenic Escherichia coli (APEC) causes respiratory disease and sepsis in poultry. To persist in its host, E. coli requires essential nutrients including iron. Since iron is limited in extra-intestinal tissues, E. coli produces siderophores, small molecules with high affinity for ferric iron, to sequester this essential nutrient. To counter bacterial siderophore systems, mammalian hosts secrete siderocalin (also called lipocalin 2 or NGAL), which binds ferric siderophore complexes rendering them unavailable to bacteria. In humans and mice, siderocalin is known to play a role in primary defense against bacterial infections. In poultry, 4 proteins display homology to the human NGAL (CALbeta, CALgamma, Ggal-C8GC and Ex-FABP). The function and expression of the genes coding for these 4 proteins during infection by APEC is still unknown. Expression levels of these genes were determined by quantitative RT-PCR using RNA extracted from lungs, livers and spleens of healthy 3-week-old chickens and chickens infected with APEC. The gene coding for Ex-FABP was overexpressed in all organs tested. It was significantly more overexpressed in the lungs and liver than in the spleen (37.3 and 27.3 times versus 11.5 times, respectively). The genes coding for Calbeta and Calgamma were also found significantly overexpressed in the liver (27 and 8.2 times, respectively). To confirm the function of Ex-FABP as a siderocalin, the gene coding for this protein was cloned in an expression vector and the protein was purified. In vitro growth inhibition of E. coli strains by Ex FABP was assayed in parallel with growth inhibition caused by human siderocalin. Purified Ex-FABP inhibited growth of E. coli K-12, which only produces the siderophore enterobactin. However, E. coli strains producing pathogen-associated siderophores including salmochelins (glucosylated enterobactin), aerobactin and yersiniabactin grew normally in the presence of Ex-FABP. These results indicate that Ex-FABP is an avian siderocalin with a siderophore-binding activity similar to that of human siderocalin and that pathogen-specific siderophores are required by APEC to overcome this innate defense protein in poultry. PMID- 23102566 TI - Snow ball earth and the split of Streptophyta and Chlorophyta. AB - About 700 million years ago (Mya), the ancestor of all green plants evolved into two major groups: the Chlorophyta (many green algae) and the Streptophyta (some green algae and land plants = embryophytes). Both groups are separated by several morphological, physiological, and molecular characteristics, including different photorespiration pathways. The Chloropyhta/Streptophyta split was probably very important for the colonization of the terrestrial habitat because embryophytes, the descendants of streptophyte algae, today completely dominate the macrophyte flora of the terrestrial habitats. By contrast, in aquatic ecosystems macrophytes from brown, red, and green algae compete with embryophytes. In this opinion article, I argue that the Chlorophyta/Streptophyta split is related to glaciation events (snow ball earth states) in the Neoproterozoic and provide an explanation for the different photorespiration pathways. PMID- 23102567 TI - Did early land plants use carbon-concentrating mechanisms? AB - Carbon-concentrating mechanisms (CCMs) in plants involve actively increasing CO2 concentrations near ribulose-1,5-bisphosphate carboxylase oxygenase (RuBisCO). The assumption has been that terrestrial plants did not evolve CCMs for well over 300 million years, yet most marine plants probably evolved CCMs at the time when oxygenic photosynthesis first occurred in the Paleozoic. One primary reason for this assumption is that analysis of genetic mutations for phosphoenolpyruvate carboxylase (PEPc; an enzyme required for C4 and CAM photosynthesis) indicate a molecular age of no more than 65 Ma. Could the evolutionary response of both RuBisCO and PEPc to varying concentrations of atmospheric CO2 and O2 over geological time have obscured the real time when land plants first used PEPc during photosynthesis? PMID- 23102568 TI - Quality of life in coeliac patients: Italian validation of a coeliac questionnaire. AB - BACKGROUND: Coeliac disease (CD) is a chronic condition requiring a gluten-free diet, which is a very demanding diet to maintain on a life-long basis. For this reason it is a condition that can have serious repercussions on the quality of life (QOL). Therefore the need to elaborate a questionnaire on QOL specifically for patients with CD (CDQ): its original language is German, and the translation/validation process represents a considerable challenge involving not only a translation into Italian but also an adaptation to the country's specific cultural differences. METHODS: The questionnaire has been translated according to a "German -> Italian -> Italian -> German" algorithm with reconciliation of the differences. Scores for CDQ are computed overall and over four areas of four items each: emotion, gastrointestinal symptoms, gastrointestinal worries, social problems. RESULTS: CDQ was administered to 171 coeliacs (F 132, mean age 38 yrs +/- 14). Completeness was optimal. Item internal consistency was satisfied for 100% and 97% of patients for the specific and generic part, respectively. Cronbach's alpha coefficient was 0.7 for all scales. The general CDQ was higher in patients reporting subjective well-being (discriminant validity). CONCLUSIONS: The Italian translation of CDQ sounds natural, is easy to understand and reduces possible cultural biases to a minimum. A field test gave results comparable to the original validation, supporting the use of CDQ in cross-national surveys. PMID- 23102569 TI - Serological markers of erosive hand osteoarthritis. AB - This review focuses on biomarkers in erosive hand osteoarthritis (EHOA), a subset of hand osteoarthritis (HOA), that primarily affects interphalangeal joints and is characterized by abrupt onset, severe pain and functional impairment, as well as signs of inflammation, in particular stiffness, swelling, erythema, paraesthesiae, and worse outcome. Inflammatory features and radiographic erosions are the main diagnostic hallmarks of this particular disease subset. As in other fields of OA, EHOA biomarkers can be classified as dry and soluble. Soluble biomarkers which are found in serum, synovial fluid and urine can be specific indicators of joint inflammation and degradation. With regard to inflammatory markers, C-reactive protein and myeloperoxidase have been found to be increased in EHOA, with respect to non-erosive HOA. All these markers have, moreover, been found to be correlated with disease activity. Another interesting marker linked to inflammation is hyaluronic acid, considered to be a marker of synovitis, which is frequently found in EHOA. The most useful cartilage markers in both erosive and non-erosive HOA, seems to be collagen (Coll) 2-1, Coll 2-1NO(2) and Col2 3/4C(short). Immunogenetic markers were also determined and an association between EHOA and a single nucleotide polymorphism on the gene encoding interleukin-1beta was found in HLA and there was an increased frequency of HLA B44 and HLA-DRB1*07 in EHOA. PMID- 23102570 TI - Energy drinks and chemotherapy: can these products cause detrimental effects in cancer patients receiving chemotherapy? PMID- 23102571 TI - Methylation matters? Decreased methylation status of genomic DNA in the blood of schizophrenic twins. AB - Studies of schizophrenia inheritance in identical twins show a concordance of about 50%, which supports an epigenetic model. In our present study we investigated methylation of genomic DNA and promoter methylation of Reelin and SOX10 genes in peripheral blood of twins suffering from schizophrenia. Global DNA methylation was reduced (52.3%) in schizophrenic twins if compared with healthy control twins (65.7%). The reduced methylation was significant in males only. We also found a similar hypomethylation in the non-affected twins of discordant pairs and a mixed group of psychiatric controls. In discordant twins there was a relative hypermethylation of the SOX10 promoter. Within-pair-difference of methylation of Reelin promoter was significantly lower in monozygotic twins than in dizygotic twins. PMID- 23102572 TI - [Gastric cancer in a Spanish hospital: Segovia General Hospital (2005-2008)]. AB - OBJECTIVE: To estimate the incidence, pathological characteristics, treatment patterns, survival and mortality of gastric cancer in Segovia from 2005-2008. METHODS: We conducted a retrospective, descriptive study of 163 patients diagnosed with gastric cancer at the Segovia General Hospital during the study period. RESULTS: We estimated a gastric cancer incidence of 25 cases/100,000 inhabitants. The ratio of men to women was 1.6:1. The mean age was 72 years. The most important findings were diagnosis in stages III and IV (64.5%), the high frequency of intestinal carcinoma (56.4%) and the gastric antrum as the most frequent localization (48.8%). At the end of the study, 54.2% of patients had died and the median overall survival was 19 months. The main factors for an unfavorable prognosis were advanced tumoral stage (III and IV), the number of nodes involved, and diffuse histological type. Despite surgical treatment with curative intent, 63.2% of tumors at early stages (I and II) recurred during the study. CONCLUSIONS: The risk of gastric cancer in Segovia is higher in men aged over 70 years. Most tumors are diagnosed at advanced stages and recurrences are common, limiting the possibility of cure. Early diagnosis of this entity and improved treatments are required. PMID- 23102573 TI - [Significance of free perigastric fluid detected by echoendoscopy in patients with gastric cancer]. AB - OBJECTIVES: To determine the diagnostic value of free perigastric fluid identified by echoendoscopy in patients with gastric cancer and to establish the factors related to the presence of peritoneal carcinomatosis in these patients. MATERIAL AND METHODS: We retrospectively included 100 patients with a histological diagnosis of gastric adenocarcinoma referred for echoendoscopy. A positive result was defined as the echoendoscopic identification of free perigastric fluid. This result was compared with the final study based on exploratory laparoscopy-laparotomy. The histological and endoscopic characteristics were compared with the final result. RESULTS: Free perigastric fluid was found in 21 patients (21%). Among these, 15 (71%) showed peritoneal carcinomatosis, confirmed by laparoscopy (12 patients) or echoendoscopy-guided fine-needle-aspiration biopsy (three patients). In seven of the 79 patients (8%) not showing the presence of ascites, peritoneal implants were identified by exploratory laparoscopy-laparotomy. The sensitivity, specificity, positive predictive value and diagnostic accuracy of free fluid in the diagnosis of carcinomatosis was 68%, 92%, 71%, 91% and 87%, respectively. No histologic or endoscopic factors related to the malignancy of echoendoscopically-detected fluid were identified. CONCLUSION: In patients with gastric cancer, free perigastric fluid identified by echoendoscopy is an important predictive factor of peritoneal carcinomatosis and may have significant implications in the management of these patients. PMID- 23102574 TI - [Estimation of fetal weight by external abdominal measurements and fundal height measurement near term for the detection of intra-uterine growth retardation]. AB - OBJECTIVES: To evaluate the estimation of fetal weight by external abdominal measurements, alone or associated with fundal height measurement and/or ultrasonographic exams near 32 weeks, to detect intra-uterine growth retardation (IUGR) near term. PATIENTS AND METHODS: A retrospective cohort study included all women who delivered a small-for-gestational-age infant less than 37 weeks gestation during 2008-2009. We analyzed the sensitivity of estimation of fetal weight by external abdominal measurements and the others different routine exams during third trimester, and compared them to detect IUGR near term. RESULTS: The estimation of fetal weight by external abdominal measurements was used in 263 pregnant patients. External abdominal measurements and fundal height measurement were not statistically different and were better tests than ultrasonographic exams at 32 weeks to detect IUGR near term (sensitivity: 41.4%, 42.2% and 22.8%, respectively; P<0.05). External abdominal measurements associated with regular ultrasonographic examination at 32 weeks of gestation significantly increased the sensitivity to detect IUGR near term (42.9% vs. 22.8%; P<0.05). But, the association of external abdominal measurements and fundal height measurement did not increase the rate of detection (47.9% vs. 42.2%; P=0.22). DISCUSSION AND CONCLUSION: The present findings confirm that the use of the estimation of fetal weight by external abdominal measurements to detect intra-uterine growth retardation is effective. Measures to improve the learning of this technique and its reproducibility are recommended. PMID- 23102575 TI - [Typology of various researches and implications of the Jarde law on resident's work]. PMID- 23102576 TI - [Male gamete...spermatozoon or spermatid?]. AB - Normal spermatogenesis results from a balance between process of cell proliferation, cell differentiation and apoptosis that concern somatic cells and germ cells. Dysfunction of spermatogenesis may be the result of constitutional or acquired abnormalities of spermatogonia stem cells or somatic cells. To overcome these problems, it seems necessary to implement preventive measures for germ stem cell preservation or substitute measures to replace them, the objective being to replicate in vivo or in vitro the process of spermatozoa production. This article will discuss the different experimental strategies for considering the in vivo or in vitro production of spermatozoa, outside the physiological process. PMID- 23102577 TI - [External cephalic version in case of persisting breech presentation at term: motivations and women's experience of the intervention]. AB - OBJECTIVES: To evaluate the efficacy and acceptability of external cephalic version (ECV). MATERIALS AND METHOD: From 2004 to 2008, 212 pregnant women between 34-37 weeks of gestation with fetus in breech presentation were included in a randomized clinical trial and 125 externals cephalic versions were studied. RESULTS: A success rate of 37.6%t was recorded. At 34 weeks of gestation, 80.6% of women were considering an ECV in the event of persistent breech position at 37 weeks. These women expressed the desire to give birth vaginally (52% versus 24.4%, P<0.001). In contrast, others women preferred an elective cesarean section to avoid the risk of a breech vaginal delivery. Women felt pain during the ECV and scored 60 on average using the analogical visual scale. Women rated on a verbal rating scale the ECV as severely painful to unbearable (68%), and as stressful (70%). Despite this, the majority of women would recommend ECV to their friends or would be willing to repeat it for themselves. DISCUSSION AND CONCLUSION: ECV remains a scary and painful medical procedure. More research is needed to reduce the impact. The use of analgesic medication for this indication is controversial. Hypnosis could be an alternative to evaluate. PMID- 23102578 TI - Low diphoterine provision in UK industrial chemical manufacturing plants highlights the need for new research. PMID- 23102579 TI - Functional late outgrowth endothelial progenitors isolated from peripheral blood of burned patients. AB - BACKGROUND: Bioengineered skin substitutes are increasingly considered as a useful option for the treatment of full thickness burn injury. Their viability following grafting can be enhanced by seeding the skin substitute with late outgrowth endothelial progenitor cells (EPCs). However, it is not known whether autologous EPCs can be obtained from burned patients shortly after injury. METHODS: Late outgrowth EPCs were isolated from peripheral blood sampled obtained from 10 burned patients (extent 19.6+/-10.3% TBSA) within the first 24h of hospital admission, and from 7 healthy subjects. Late outgrowth EPCs were phenotyped in vitro. RESULTS: In comparison with similar cells obtained from healthy subjects, growing colonies from burned patients yielded a higher percentage of EPC clones (46 versus 17%, p=0.013). Furthermore, EPCs from burned patients secreted more vascular endothelial growth factor (VEGF) into the culture medium than did their counterparts from healthy subjects (85.8+/-56.2 versus 17.6+/-14pg/mg protein, p=0.018). When injected to athymic nude mice 6h after unilateral ligation of the femoral artery, EPCs from both groups of subjects greatly accelerated the reperfusion of the ischaemic hindlimb and increased the number of vascular smooth muscle cells. CONCLUSIONS: The present study supports that, in patients with burns of moderate extension, it is feasible to obtain functional autologous late outgrowth EPCs from peripheral blood. These results constitute a strong incentive to pursue approaches based on using autotransplantation of these cells to improve the therapy of full thickness burns. PMID- 23102581 TI - GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. AB - Male sex determination in mammals is induced by Sry, a gene whose regulation is poorly understood. Here we show that mice mutant for the stress-response gene Gadd45g display complete male-to-female sex reversal. Gadd45g and Sry have a strikingly similar expression pattern in the genital ridge, and they are coexpressed in gonadal somatic cells. In Gadd45g mutants, Sry expression is delayed and reduced, and yet Sry seemed to remain poised for expression, because its promoter is demethylated on schedule and is occupied by active histone marks. Instead, p38 MAPK signaling is impaired in Gadd45g mutants. Moreover, the transcription factor GATA4, which is required for Sry expression, binds to the Sry promoter in vivo in a MAPK-dependent manner. The results suggest that a signaling cascade, involving GADD45G -> p38 MAPK -> GATA4 -> SRY, regulates male sex determination. PMID- 23102580 TI - Gadd45gamma and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. AB - Loss of the kinase MAP3K4 causes mouse embryonic gonadal sex reversal due to reduced expression of the testis-determining gene, Sry. However, because of widespread expression of MAP3K4, the cellular basis of this misregulation was unclear. Here, we show that mice lacking Gadd45gamma also exhibit XY gonadal sex reversal caused by disruption to Sry expression. Gadd45gamma is expressed in a dynamic fashion in somatic cells of the developing gonads from 10.5 days postcoitum (dpc) to 12.5 dpc. Gadd45gamma and Map3k4 genetically interact during sex determination, and transgenic overexpression of Map3k4 rescues gonadal defects in Gadd45gamma-deficient embryos. Sex reversal in both mutants is associated with reduced phosphorylation of p38 MAPK and GATA4. In addition, embryos lacking both p38alpha and p38beta also exhibit XY gonadal sex reversal. Taken together, our data suggest a requirement for GADD45gamma in promoting MAP3K4-mediated activation of p38 MAPK signaling in embryonic gonadal somatic cells for testis determination in the mouse. PMID- 23102582 TI - Preoperatively evaluating the correlation between pathological grades and blood oxygenation level-dependent MRI in clear cell renal cell carcinomas. AB - RATIONALE AND OBJECTIVES: To assess whether r(2)* values can be used to determine the nuclear grade of clear cell renal cell carcinomas (CRCC). MATERIALS AND METHODS: A total of 26 patients with pathologically proven CRCCs underwent blood oxygen level-dependent magnetic resonance imaging. r(2)* values were determined for the solid components of CRCC lesions. Histological nuclear grade was determined for each lesion. All patients were divided into low- and high-grade groups. r(2)* values were compared between different grades and between low- and high- grade groups. Receiver operating characteristic curve was drawn to establish the cutoff point for r(2)* values. The correlation between r(2)* values and pathological groups was assessed. RESULTS: Low-grade group (grades I + II) contained 17 cases and high-grade group (grades III + IV) contained nine cases. The intraclass correlation coefficient for r(2)* values was 0.89. Significant difference was seen between different grades (P < .005). r(2)* values of the high grade group were higher than the low-grade group (P < .005). A sensitivity of 78% and a specificity of 100% were achieved with a cutoff of 31.87 seconds(-1). r(2)* values directly correlated with pathological groups (P < .005). CONCLUSION: r(2)* values of CRCCs could be employed as a noninvasive biomarker to help classify the nuclear grade of CRCC. PMID- 23102583 TI - Deciphering the transcriptional cis-regulatory code. AB - Information about developmental gene expression resides in defined regulatory elements, called enhancers, in the non-coding part of the genome. Although cells reliably utilize enhancers to orchestrate gene expression, a cis-regulatory code that would allow their interpretation has remained one of the greatest challenges of modern biology. In this review, we summarize studies from the past three decades that describe progress towards revealing the properties of enhancers and discuss how recent approaches are providing unprecedented insights into regulatory elements in animal genomes. Over the next years, we believe that the functional characterization of regulatory sequences in entire genomes, combined with recent computational methods, will provide a comprehensive view of genomic regulatory elements and their building blocks and will enable researchers to begin to understand the sequence basis of the cis-regulatory code. PMID- 23102584 TI - Can we deconstruct cancer, one patient at a time? AB - Patients with cancer face an ever-widening gap between the exponential rate at which technology improves and the linear rate at which these advances are translated into clinical practice. Closing this gap will require the establishment of learning loops that intimately link lab and clinic and enable the immediate transfer of knowledge, thereby engaging highly motivated patients with cancer as true partners in research. Here, we discuss the goal of creating a distributed network that aims to place world-class resources at the disposal of select patients with cancer and their oncologists, and then use these intensively monitored individual patient experiences to improve collective understanding of how cancer works. PMID- 23102585 TI - Innovative financing for health: what is truly innovative? AB - Development assistance for health has increased every year between 2000 and 2010, particularly for HIV/AIDS, tuberculosis, and malaria, to reach US$26.66 billion in 2010. The continued global economic crisis means that increased external financing from traditional donors is unlikely in the near term. Hence, new funding has to be sought from innovative financing sources to sustain the gains made in global health, to achieve the health Millennium Development Goals, and to address the emerging burden from non-communicable diseases. We use the value chain approach to conceptualise innovative financing. With this framework, we identify three integrated innovative financing mechanisms-GAVI, Global Fund, and UNITAID-that have reached a global scale. These three financing mechanisms have innovated along each step of the innovative finance value chain-namely resource mobilisation, pooling, channelling, resource allocation, and implementation-and integrated these steps to channel large amounts of funding rapidly to low-income and middle-income countries to address HIV/AIDS, malaria, tuberculosis, and vaccine-preventable diseases. However, resources mobilised from international innovative financing sources are relatively modest compared with donor assistance from traditional sources. Instead, the real innovation has been establishment of new organisational forms as integrated financing mechanisms that link elements of the financing value chain to more effectively and efficiently mobilise, pool, allocate, and channel financial resources to low-income and middle-income countries and to create incentives to improve implementation and performance of national programmes. These mechanisms provide platforms for health funding in the future, especially as efforts to grow innovative financing have faltered. The lessons learnt from these mechanisms can be used to develop and expand innovative financing from international sources to address health needs in low-income and middle-income countries. PMID- 23102586 TI - The association of body mass index and biochemical hyperandrogenaemia in women with and without polycystic ovary syndrome. AB - OBJECTIVE: To investigate the association between BMI and different androgen parameters in women with PCOS and normal ovulatory women. STUDY DESIGN: A cross sectional, observational study was carried out. A total of 286 patients aged 20 44years were recruited. One hundred and sixty-five women had a diagnosis of PCOS and 121 women were ovulatory with no clinical or biochemical or ultrasound evidence of PCOS. The PCOS and non-PCOS groups were sub-divided into two subgroups based on BMI (BMI<=30kg/m(2) and BMI>30kg/m(2)). Androgen parameters measured were testosterone, androstenedione, free androgen index and sex hormone binding globulin (SHBG). Testosterone and androstenedione were measured using tandem mass spectrometry. Free androgen index (FAI) was calculated using the formula: (testosterone/SHBG)*100. Spearman rank correlations were used to determine relationship between BMI and androgens. RESULTS: The PCOS group had a higher BMI compared with the non-PCOS group (28.9+/-5.8, 24.5+/-4.1). Total testosterone, androstenedione, and FAI were significantly higher while SHBG was lower in the PCOS group. A correlation between BMI and total testosterone was not observed in either group. Positive correlations were observed between BMI and FAI in both PCOS (p<0.001) and non-PCOS groups (p=0.02) while a positive correlation was observed between BMI and androstenedione in the PCOS group (p=0.001). SHBG correlated negatively with BMI in both groups. CONCLUSION: A strong correlation exists between BMI and FAI but not with total testosterone, possibly due to the mediation of SHBG. Hyperandrogenaemia in the form of androstenedione seems to be augmented in PCOS with increasing BMI. A direct causal relationship between BMI and androgenaemia was not established. PMID- 23102587 TI - Effects of melatonin on ovarian follicles. AB - OBJECTIVE: To evaluate the histomorphometry and expression of Ki-67 and c-kit in ovarian follicles of pinealectomized or melatonin-treated pinealectomized rats. STUDY DESIGN: Forty adult rats were randomly divided into four groups of 10 animals: Group I - control; Group II - sham-pinealectomized; Group III - pinealectomized (Px), and Group IV - Px treated with melatonin (10MUg/night, per animal). After two months' treatment, on the night of proestrous, the animals were placed in metabolic cages for night urine collection and subsequent measurement of 6-sulfatoxymelatonin (6-SMT). The rats were anesthetized, blood samples were taken for estrogen and progesterone determinations, and they were then euthanized. The ovaries were dissected out for further histological and immunohistochemical analyses. Data were first submitted to analysis of variance (ANOVA) complemented with the Tukey-Kramer test for multiple comparisons (P<0.05). RESULTS: The urinary levels of 6-SMT and serum progesterone were lower in the Px group (GIII). Exogenous melatonin treatment restored both blood melatonin and 6-SMT urinary levels. The histomorphometric data in Group III revealed a significant increase of degenerating antral and non-antral follicles with regard to the other groups. In addition no corpora lutea were observed in this group. No significant differences were noticed regarding the number of corpora lutea among the other groups (I, II and IV), but the number of cells and the thickness of the theca interna of Px animals (Group III) were higher than in the other groups. Conversely, the density of progesterone receptors (fmol/g) in the ovaries of Group III was significantly lower than in the other groups. CONCLUSION: Our data indicate that melatonin exerts a role on the maintenance of a proper follicular function, and is thus important for ovulation and progesterone production. PMID- 23102588 TI - Lung transplantation in cystic fibrosis normalizes essential fatty acid profiles. AB - BACKGROUND: Cystic fibrosis (CF) can be a devastating disease. Disorders in essential fatty acid state are increasingly reported and various supplementation trials have been performed in an attempt to improve outcomes. However, the mechanisms leading to these disturbances remain elusive. We wanted to investigate the role of the diseased CF lung on fatty acid profiles. METHODS: We compared fatty acid profiles in patients with CF after lung transplantation (n=11) to age matched healthy controls and homozygous F508del patients (n=22 each). RESULTS: Compared to healthy controls, in patients with CF, there are decreased levels of docosahexaenoic, linoleic and arachidonic acid and increased levels of mead acid. In patients that underwent a lung transplantation, levels of docosahexaenoic, linoleic and arachidonic acid were normal. Mead acid did not decrease significantly. CONCLUSIONS: The diseased CFTR deficient lung is a major determinant in the disturbed fatty acid profile in CF. PMID- 23102589 TI - Continuous renal replacement therapy for children <=10 kg: a report from the prospective pediatric continuous renal replacement therapy registry. AB - OBJECTIVE: To report circuit characteristics and survival analysis in children weighing <=10 kg enrolled in the Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry. STUDY DESIGN: We conducted prospective cohort analysis of the ppCRRT Registry to: (1) evaluate survival differences in children <=10 kg compared with other children; (2) determine demographic and clinical differences between surviving and non-surviving children <=10 kg; and (3) describe continuous renal replacement therapy (CRRT) circuit characteristics differences in children <=5 kg versus 5-10 kg. RESULTS: The ppCRRT enrolled 84 children <=10 kg between January 2001 and August 2005 from 13 US tertiary centers. Children <=10 kg had lower survival rates than children >10 kg (36/84 [43%] versus 166/260 [64%]; P < .001). In children <=10 kg, survivors were more likely to have fewer days in intensive care unit prior to CRRT, lower Pediatric Risk of Mortality 2 scores at intensive care unit admission and lower mean airway pressure (P(aw)), higher urine output, and lower percent fluid overload (FO) at CRRT initiation. Adjusted regression analysis revealed that Pediatric Risk of Mortality 2 scores, FO, and decreased urine output were associated with mortality. Compared with circuits from children 5-10 kg at CRRT initiation, circuits from children <=5 kg more commonly used blood priming for initiation, heparin anticoagulation, and higher blood flows/effluent flows for body weight. CONCLUSION: Mortality is more common in children who are <=10 kg at the time of CRRT initiation. Like other CRRT populations, urine output and FO at CRRT initiation are independently associated with mortality. CRRT prescription differs in small children. PMID- 23102590 TI - Effects of immediate telephone follow-up with providers on sweat chloride test timing after cystic fibrosis newborn screening identifies a single mutation. AB - OBJECTIVE: To assess whether reporting "possible cystic fibrosis (CF)" newborn screening (NBS) results via fax plus simultaneous telephone contact with primary care providers (PCPs) versus fax alone influenced 3 outcomes: undergoing a sweat chloride test, age at sweat chloride testing, and undergoing sweat testing before age 8 weeks. STUDY DESIGN: This was a retrospective cohort comparison of infants born in Wisconsin whose PCP received a telephone intervention (n = 301) versus recent historical controls whose PCP did not (n = 355). Intervention data were collected during a longitudinal research and quality improvement effort; deidentified comparison data were constructed from auxiliary NBS tracking information. Parametric and nonparametric statistical analyses were performed for group differences. RESULTS: Most infants (92%) with "possible CF" NBS results whose PCP lacked telephone intervention ultimately underwent sweat testing, underlining efficacy for fax-only reporting. Telephone intervention was significantly associated with improvements in the infants undergoing sweat testing at age <=6 weeks and <8 weeks and a slight, statistically nonsignificant 3.5-day reduction in the infants' age at sweat testing. The effect of telephone intervention was greater for PCPs whose patients underwent sweat testing at community-affiliated medical centers versus those whose patients did so at academic medical centers (P = .008). CONCLUSION: Reporting "possible CF" NBS results via fax plus simultaneous telephone follow-up with PCPs increases the rate of sweat chloride testing before 8 weeks of age, when affected infants are more likely to receive full benefits of early diagnosis and treatment. PMID- 23102591 TI - Inflammation or infection at the time of second trimester induced abortion. AB - BACKGROUND: Induced abortion via dilation and evacuation (D&E) typically involves cervical preparation. Some clinicians also induce fetal death in the second trimester. We designed this study to determine if the combination of intra amniotic digoxin and osmotic dilators induced intrauterine inflammatory changes. STUDY DESIGN: Twenty-two women requesting abortion at 19-23 weeks gestation had amniotic fluid sent for measurement of interleukin-6 (IL-6), interleukin-8 (IL 8), tumor necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count and anaerobic and aerobic cultures on day 1, before dilators and digoxin amnioinjection. Sampling was repeated on Day 2, prior to D&E. RESULTS: All subjects had significantly elevated IL-6, IL-8 and TNF-alpha in the amniotic fluid on Day 2. The median difference for IL-6 was 19,893.4 pg/mL (p<.0001), 7040.7 pg/mL (p<.0001) for IL-8 and 181.0 pg/mL (p<.0001) for TNF-alpha. There was no significant difference in WBC count. There were no clinically significant positive cultures and no clinical infections. CONCLUSION: The administration of intra-amniotic digoxin and the placement of osmotic dilators prior to D&E create an intrauterine inflammatory response. PMID- 23102592 TI - [Peripheral blocks in one-day surgery; contribution of ultrasound]. PMID- 23102593 TI - Chlamydia and gonorrhea screening in United States emergency departments. AB - BACKGROUND: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are the most commonly reported notifiable diseases in the United States, with annual reported cases exceeding 1.2 million and estimated costs exceeding $1.2 billion. Reported Emergency Department (ED) prevalence rates for CT and GC for adolescents and young adults range from 0.9% to 8.1%. OBJECTIVE: Our aim was to evaluate the burden of CT/GC infection in ED patients, assess the extent of associated under- and overtreatment, and investigate mechanisms whereby ED screening can be feasible. METHODS: We performed a systematic review of the time period from 1995 to 2010. DISCUSSION: Positivity rates for ED patients are comparable with other high-risk populations, and sufficient for selected screening to be cost effective. Unfortunately, ED patient follow-up is notoriously difficult, and clinicians frequently must choose to either delay treatment until laboratory confirmation or presumptively treat based on presenting symptoms and clinical diagnosis. This results in high rates of both undertreatment (i.e., not treating those infected) and overtreatment (i.e., treating those who are infection-free). Incorrect on-the-spot treatment decisions can result in potentially infected future partners and lack of follow-up treatment, or unnecessary treatment and personal stress associated with improper diagnosis. CONCLUSIONS: ED clinician activities are frequently symptom-driven, and screening nonsymptomatic patients presents a major barrier. Educating ED clinicians on the topics of CT/GC epidemiology, sample collection, and analysis will enable them to address the risks in their presenting populations. Collaboration with health department partners for sample analysis, cost-sharing, and patient follow-up can make routine screening feasible and enable EDs to become more important partners in intervention programs. PMID- 23102594 TI - An Emergency Department-initiated, web-based, multidisciplinary approach to decreasing emergency department visits by the top frequent visitors using patient care plans. AB - BACKGROUND: Many patients present to the Emergency Department (ED) for multiple visits. Whatever the cause, assuring the highest quality of care is difficult in the ED. OBJECTIVES: We sought to implement a web-based, ED-initiated, multidisciplinary program to improve patient care and reduce frequent visits to the ED. METHODS: The top 50 ED frequent visitors were identified and care plans were constructed. Care plans consist primarily of a summary of the patient's pertinent history and any psychosocial issues that can contribute to frequent use of the ED, and recommend treatment plans for these patients. RESULTS: During the study period, ED visits by the top 50 chronic frequent visitors ranged from 88 to 98 visits/month and 28 to 31 admissions/month. As of January 2007, the top 50 frequent visitors had 94 ED visits/month (1,129 visits/year) for 2.2% of the total census, and 31 admissions/month (372 admissions per year) for approximately 3.3% of the total admissions. Each frequent visitor has approximately 22.6 visits/year (range from 11 to 41) and 7.3 admissions/year (range from 0 to 20). By May 2008, the top 50 frequent visitors had a decrease to 88 visits/month (1,059 visits/year) and 28 admissions/month (340 admissions/year), with each frequent visitor having 21.2 visits/year and 6.8 admissions/year. Social determinants included psychiatric disease (36%), substance abuse (22%), malingering (20%), medication noncompliance (16%), and unstable housing (10%). CONCLUSIONS: There was a trend toward a decrease of monthly ED visits by the top 50 ED frequent visitors, but no effect on the rate of admissions. Based on these preliminary data and the relative ease of integration into the system, this project shows the potential to begin to address the problem of chronic ED use with patient care plans. PMID- 23102595 TI - High expression of P53-induced Ring-h2 protein is associated with poor prognosis in clear cell renal cell carcinoma. AB - PURPOSE: This study was carried out to examine P53-induced Ring-h2 protein (Pirh2) expression and investigate its clinical and prognostic significance in patients with clear cell renal cell carcinoma (ccRCC). METHODS: Pirh2 mRNA and protein expressions were detected by quantitative reverse-transcription polymerase chain reaction (Q-RT PCR) and Western blotting in 35 frozen renal cancer tissue specimens and 35 adjacent normal renal tissue specimens of the same patients. Pirh2 protein expression was assessed by immunohistochemical analysis in 92 paraffin-embedded specimens of human ccRCC and 30 specimens of adjacent normal renal tissue. Correlations between Pirh2 and clinicopathologic features and prognosis were analyzed statistically. RESULTS: Pirh2 mRNA and protein levels in ccRCC samples were increased significantly as compared with the adjacent normal renal tissues (P < 0.001). Pirh2 mRNA overexpression correlated with high stage and grade of the renal cancer (P < 0.001 and P < 0.001 respectively). Pirh2 protein expression was negative in most normal renal tissue specimens (23/30) but positive in 52.2% (48/92) of ccRCC specimens (P = 0.006). Pirh2 protein expression correlated with tumor grade and stage (P < 0.001 and P < 0.001 respectively). The median follow-up interval was 42.0 months. Overexpression of Pirh2 protein in ccRCC was significantly associated with shorter overall survival and recurrence-free survival (P = 0.001 and P = 0.003, respectively). Multivariate analysis showed that Pirh2 expression was an independent prognostic factor for ccRCC patients (P = 0.037). CONCLUSIONS: Pirh2 was up-regulated in ccRCC at both transcriptional and translational levels compared with normal renal tissues, suggesting that Pirh2 may be a potential prognostic marker for ccRCC. PMID- 23102596 TI - Characterization of the plastidial geraniol synthase from Madagascar periwinkle which initiates the monoterpenoid branch of the alkaloid pathway in internal phloem associated parenchyma. AB - Madagascar periwinkle (Catharanthus roseus [L.] G. Don, Apocynaceae) produces monoterpene indole alkaloids (MIAs), secondary metabolites of high interest due to their therapeutic value. A key step in the biosynthesis is the generation of geraniol from geranyl diphosphate (GPP) in the monoterpenoid branch of the MIA pathway. Here we report on the cloning and functional characterization of C. roseus geraniol synthase (CrGES). The full-length CrGES was over-expressed in Escherichia coli and the purified recombinant protein catalyzed the conversion of GPP into geraniol with a K(m) value of 58.5 MUM for GPP. In vivo CrGES activity was evaluated by heterologous expression in a Saccharomyces cerevisiae strain mutated in the farnesyl diphosphate synthase gene. Analysis of culture extracts by gas chromatography-mass spectrometry confirmed the excretion of geraniol into the growth medium. Transient transformation of C. roseus cells with a Yellow Fluorescent Protein-fusion construct revealed that CrGES is localized in plastid stroma and stromules. In aerial plant organs, RNA in situ hybridization showed specific labeling of CrGES transcripts in the internal phloem associated parenchyma as observed for other characterized genes involved in the early steps of MIA biosynthesis. Finally, when cultures of Catharanthus cells were treated with the alkaloid-inducing hormone methyl jasmonate, an increase in CrGES transcript levels was observed. This observation coupled with the tissue-specific expression and the subcellular compartmentalization support the idea that CrGES initiates the monoterpenoid branch of the MIA biosynthetic pathway. PMID- 23102598 TI - Guidelines on CVD prevention: confusing or complementary? PMID- 23102597 TI - Impact of long-term measures of glucose and blood pressure on the retinal microvasculature. AB - OBJECTIVE: Retinopathy and retinal microvascular abnormalities are common in adult populations, yet few long-term predictors have been identified. We therefore examined the association between systolic blood pressure (SBP) and fasting plasma glucose, assessed over 18 years, with retinopathy and retinal vascular caliber in 2066 Carotid MRI participants, an Atherosclerosis Risk in Communities ancillary study. METHODS: Retinopathy and retinal vascular caliber were assessed by retinal photography. Confounder-adjusted weighted regression models were used to examine exposures defined as cumulative, long-term prospective, concurrent, and 18-year change. RESULTS: Long-term prospective (prevalence odds ratio (POR) per 10 mm Hg: 1.14 (95% CI: 1.01, 1.30)) and cumulative (POR per 10 mm Hg: 1.30 (95% CI: 1.09, 1.56) effects spanning approximately 18 years were found for SBP and retinopathy. The strongest long term prospective association for plasma glucose and retinopathy was identified at the baseline visit (POR per 10 mg/dl: 1.26 (95% CI: 1.16, 1.38)); sustained glucose elevations over 18 years were also associated with prevalent retinopathy (POR per 10 mg/dl: 1.33 (95% CI: 1.24, 1.43)). Results were robust to the exclusion of participants with diabetes. CONCLUSIONS: Modest and sustained long term elevations in glucose and blood pressure are associated with retinopathy and retinal vascular caliber. PMID- 23102599 TI - Antibodies to malondialdehyde oxidized low-density lipoproteins predict long term cardiovascular mortality in high risk patients. AB - AIMS: Antibodies to oxidized low-density lipoproteins (oxLDLAbs) are detectable in the serum of patients with and without atherosclerosis, but it is unclear if they play a pathogenic or a protective role in atherogenesis or if they are simply a marker of atherosclerosis. Therefore, in a prospective cohort study we investigated if oxLDLAbs titer predicts cardiovascular (CV) events in high-risk coronary artery disease patients. METHODS AND RESULTS: The titer of IgG antibodies to malondialdehyde modified oxidized low-density lipoproteins was measured in 748 randomly selected patients of the GENICA study who underwent coronary angiography and assessment of incident CV events at follow-up. Patients were classified by oxLDLAbs into a low and a high titer group, corresponding to the first three and the last quartile, respectively. Cardiovascular event-free survival was compared between oxLDLAbs groups by Kaplan-Meier and multivariate technique including propensity score matching analysis. During long-term follow up (median 7.2 years) CV deaths were observed in 65 patients (11.6%), more commonly in the high than in the low oxLDLAbs group (patients free from CV death 83.1% vs. 89% respectively, p=0.025). The incidence of CV events was also higher in the former than in latter (event-free survival 69.2% vs. 77.7% respectively, p=0.030). CONCLUSIONS: An oxLDLAbs titer above the 75th percentile is a marker of LDL oxidation which predicts a worse CV prognosis at long term follow-up in high risk Caucasian patients referred for coronary angiography. PMID- 23102600 TI - Association between obesity and infarct size: insight into the obesity paradox. PMID- 23102601 TI - Cardiac magnetic resonance myocardial perfusion imaging for detection of functionally significant obstructive coronary artery disease: a prospective study. AB - BACKGROUND: Cardiac magnetic resonance myocardial perfusion imaging (CMR-MPI) is considered a state of the art non-invasive modality for the detection of reversible ischemia. Recent studies have shown its utility in the diagnosis of coronary artery disease (CAD) and superiority over other established techniques. However, only a few studies compared CMR-MPI against the invasive standard including fractional flow reserve (FFR) and clinical validation in non specialized centers is scarce. The aim of this study was to validate CMR-MPI in a real-world clinical environment and to test its diagnostic accuracy in symptomatic patients with suspected CAD versus FFR as the reference standard of functionally significant disease. METHODS AND RESULTS: 103 symptomatic consecutive patients (62 +/- 8.0 years, 66% males) with suspected CAD and intermediate or high probability of disease underwent sequential CMR and invasive coronary angiography (XA). The CMR protocol included stress-rest adenosine perfusion, SSFP cine imaging and late-enhancement imaging. Functionally significant CAD was defined as occlusive/sub-occlusive stenoses on XA or non occlusive stenoses with a FFR measurement of <0.80 in vessels >2mm. On a patient based model, CMR-MPI had sensitivity, specificity, positive and negative predictive values of 89%, 88%, 85%, and 91%, respectively, with a global accuracy of 88%. On a vessel-based analysis, these values were 80%, 93%, 79% and 94%, respectively, with a global accuracy of 90%. CONCLUSIONS: CMR-MPI had a very high accuracy for detection of functionally significant CAD as assessed by FFR in patients with intermediate to high pretest probability. PMID- 23102602 TI - Inflammatory activation is related to glucose impairment in diabetics with acute myocardial infarction. PMID- 23102603 TI - Does linear ablation and defragmentation really improve the success rate of persistent AF? Follow-up results and electrophysiological findings from 169 consecutive patients. AB - BACKGROUND: Catheter ablation of persistent atrial fibrillation (AF) has been performed with varying results using a combination of different techniques. We sought to evaluate the efficacy of additional linear lesion and defragmentation of left atrium (LA). METHODS: A cohort of 169 patients with persistent AF was studied. Ablation was performed following a sequential strategy consisted of circumferential pulmonary vein isolation (CPVI), LA roof linear ablation, posterior mitral area, coronary sinus and cavotricuspid isthmus, and complex fractionated electrograms ablation. RESULTS: During a mean follow-up of 15 +/- 8 months after a single procedure, 84 (50%) patients were in sinus rhythm, 34 (20%) had an AF recurrence and 51(30%) developed atrial tachycardias (ATs). Repeat procedures were performed in 24 recurrent AF and 46 AT patients. A total of 81 different ATs were mapped and ablated in 46 AT patients, characterized as focal for 45 and macroreentry for 36 ATs. Most of the ATs were likely to be attributed to the previous lesions by an analysis of substrate and activation mapping in the redo procedure and a review of the lesions placed in the initial procedure. Overall, 75 (93%) ATs were ablated successfully. Procedural complications occurred in 11 of the 239 procedures. After a mean follow-up of 20 +/- 9 months, 128 (76%) patients were free of arrhythmias after the final procedure. CONCLUSIONS: CPVI supplemented by linear ablation and defragmentation does not seem to improve the overall success rate of persistent AF. The efficacy of linear ablation and defragmentation might be diluted by their proarrhythmic effects. PMID- 23102604 TI - Scar imaging using multislice computed tomography versus metabolic imaging by F 18 FDG positron emission tomography: a pilot study. AB - INTRODUCTION: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) FDG PET is an established metabolic imaging technique to assess myocardial viability. Delayed iodinated contrast enhancement (DE) of myocardium on computed tomography (CT) has also been shown to be an anatomical marker of nonviable myocardium. A pilot study was undertaken to determine quantitative and qualitative agreement between metabolic viability imaging and scar imaging using FDG PET and multislice CT respectively. METHODS: Fifteen patients with coronary artery disease and left ventricular dysfunction were recruited in the study. All patients underwent same day FDG PET and DECT to evaluate myocardial viability. The images were analyzed quantitatively and qualitatively using a 17 segment model. RESULTS: DECT diagnosed viability in 57% (146/255) whilst PET in 51% (129/255) of segments. The per-segment agreement between DECT and FDG PET on qualitative analysis was 70% (Kappa: 0.40). The agreement in quantitative measurements between the two techniques for viability showed modest correlation [Pearson rho: 0.63; P<0.0001] on scatter plot and the Passing-Bablok regression analysis. Higher agreement (70 vs 77%; P=0.051; Kappa: 0.40 vs 0.53) was obtained with quantitative compared to qualitative DECT. CONCLUSIONS: DECT may be useful in characterizing myocardial scar, and preliminary results correlate modestly with metabolic FDG PET, both qualitatively and quantitatively. Although in our study quantitative analysis offered superior agreement compared to qualitative with DECT, further studies are needed to determine its incremental value. PMID- 23102605 TI - Paracardiac mass on chest X-ray in a patient with Eisenmenger syndrome. PMID- 23102606 TI - Effect of oral ALA supplementation on oxidative stress and insulin sensitivity among overweight/obese adults: a double-blinded, randomized, controlled, cross over intervention trial. PMID- 23102607 TI - Current role of glycoprotein IIb/IIIa receptor inhibitors in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention after pretreatment with loading dose thienopyridines. PMID- 23102609 TI - Infraareolar pectoralis major myocutaneous island flap as treatment of first choice for deep sternal wound infection. AB - Deep sternal wound infection (DSWI) is a grave complication of median sternotomy, associated with high morbidity, mortality and escalating treatment costs. There is general consensus that optimal treatment comprises radical debridement followed by coverage with a vascularised flap. However, there is ongoing debate regarding the ideal operative procedure. We present our experience with the infraareolar pectoralis major island myocutaneous flap (PEC-MI flap) as treatment of first choice in DSWI. Following a retrospective chart review, data pertaining to patient demographics, type of cardiac surgery performed, prevalence of known DSWI risk factors, identified pathogens, duration of surgery, flap-related complications, duration of hospital stay and antibiotic therapy, as well as mortality were noted. Additionally, we describe the operative technique and review the relevant literature. Twenty-five patients underwent coverage with the PEC-MI flap in our department. The average age was 69.2 years. Nineteen patients underwent coronary artery bypass surgery, 10 valve replacement, two aortic replacement surgery and one pericardiectomy. In six cases, no internal mammary artery was used in cardiac surgery, in 11 cases one and in seven cases both internal mammary arteries were used. The average duration of surgery was 154.2 min and the average hospital stay was 28.4 days. Complications which required revision surgery were haematoma in three cases, one wound dehiscence and one recurrent infection. Two cases required coverage with an additional regional flap. The PEC-MI flap has been used as flap of first choice in our clinic for treatment of DSWI. It is sufficient to raise the flap unilaterally, and it does not require skin grafting. The combination of immunocompetent bulky muscle tissue used to obliterate the sternal cavity and the large skin paddle enabling a low tension skin closure allows reliable and efficient treatment of this severe complication. PMID- 23102608 TI - Epstein-Barr virus-induced gene 3 negatively regulates neuroinflammation and T cell activation following coronavirus-induced encephalomyelitis. AB - Epstein-Barr virus-induced gene 3 (EBI3) associates with p28 and p35 to form the immunomodulatory cytokines IL-27 and IL-35, respectively. Infection of EBI3-/- mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) resulted in increased mortality that was not associated with impaired ability to control viral replication but enhanced T cell and macrophage infiltration into the CNS. IFN-gamma secretion from virus-specific CD4+ and CD8+ T cells isolated from infected EBI3-/- mice was augmented while IL-10 expression muted in comparison to infected WT mice. These data demonstrate a regulatory role for EBI3-associated cytokines in controlling host responses following CNS viral infection. PMID- 23102610 TI - The reoperation cascade after breast augmentation with implants: what the patient needs to know. AB - Breast augmentation with implants is the most commonly performed aesthetic surgical procedure. However, the risk of complications requiring revision surgery with unsatisfactory final results is often underestimated. In a 10-year retrospective study, patients receiving implant exchange or implant removal after breast augmentation were reviewed with regards to surgical technique, implant type and position, complications and follow-up interventions. As many as 230 patients were included with a mean age of 40.23 years. A total of 192 (83.5%) had primary augmentation for aesthetic reasons, 24 (10.4%) patients were transsexuals and 14 (6.1%) were treated for malformations. The median primary implant size was 260, 224 and 327 g for aesthetic, malformation and transsexual patients, respectively. Capsular contracture was the leading cause for revision in aesthetic patients whereas size and shape were the main reasons for reoperation in transsexual and malformation patients, respectively. As many as 25% of patients required more than one revision procedure. The time between operations in aesthetic augmentation patients was significantly shorter for the second revision procedure (106.2 months vs. 11.4 months, p<0.0001). The cumulative risk for needing a second revision procedure in aesthetic patients at 12 months was 24.5%. There was no correlation between implant site, size, position or type of complication and the number of revision procedures. Our data highlight the high complication rate of revision surgery involving implant removal or replacement. We conclude that patients must be routinely informed of the high risk and arduous consequences of revision surgery, which should be stated as such in the written consent for the procedure. PMID- 23102611 TI - Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naive patients. AB - The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage II) chronic obstructive pulmonary disease (COPD) and those naive to maintenance respiratory therapy in the 1-year Prevention Of Exacerbations with Tiotropium in COPD (POET-COPD((r))) trial (NCT00563381). Time to first exacerbation (primary endpoint) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression (adjusting for time on treatment). Of 7376 randomized patients, 3614 were GOLD stage II (tiotropium n = 1781; salmeterol n = 1833) and 1343 were maintenance therapy naive (tiotropium n = 672; salmeterol n = 671). Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients (hazard ratio [HR], 0.88; 95% confidence interval [CI]: 0.79-0.99; p = 0.028) and maintenance therapy naive patients (HR, 0.79; 95% CI, 0.65-0.97; p = 0.028). Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naive subgroup compared with salmeterol (rate ratio [RR], 0.77; 95% CI, 0.63-0.94; p = 0.012). In the GOLD stage II subgroup, the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol (RR, 0.70; 95% CI, 0.57-0.85; p < 0.001); tiotropium also significantly prolonged time to first hospitalized exacerbation versus salmeterol in this subgroup (HR, 0.66; 95% CI, 0.48-0.91; p = 0.012). In conclusion, results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD. PMID- 23102612 TI - Impaired endothelium-dependent vasodilator response in patients with pulmonary fibrosis. AB - BACKGROUND: Recent epidemiological evidence indicates an association between cardiovascular diseases and pulmonary fibrosis. The vascular endothelium acts to maintain vascular homeostasis through multiple mechanisms and impaired endothelial function can contribute to the development, progression and clinical expression of atherosclerosis. METHODS: We consecutively recruited 39 newly diagnosed chronic interstitial pneumonitis/fibrosis patients without any specific etiology. We assessed endothelium-dependent vasodilator response of patients using digital pulse amplitude tonometry and compared the reactive hyperemia index (RHI) with age-, sex- and body mass index-matched control subjects (n = 30). We further investigated the relationships between RHI and clinical characteristics, laboratory cardiovascular risk factors, disease-related factors and circulating levels of inflammatory biomarkers. RESULTS: RHI was significantly lower in patients with chronic interstitial pneumonitis/fibrosis than in control subjects (p = 0.02). While circulating levels of total cholesterol, triglycerides, HbA1c and fasting glucose did not differ significantly between groups, patients with chronic interstitial pneumonitis/fibrosis had significantly lower high density lipoprotein levels and higher low density lipoprotein levels as compared with control subjects. Regarding disease-related factors, RHI was significantly associated with the diffusing capacity for carbon monoxide, alveolar-arterial oxygen pressure difference, 6-min walk distance and end-exercise oxygen saturation. Additionally, circulating levels of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were inversely correlated with RHI. CONCLUSIONS: We confirmed a possible link between pulmonary fibrosis and cardiovascular disease by demonstrating an impairment of endothelium-dependent vasodilator response, which was significantly associated with the severity of pulmonary fibrosis and circulating levels of adhesion molecules. PMID- 23102613 TI - [Comparison between immunological and molecular techniques for the diagnosis of Chagas disease]. AB - INTRODUCTION: Chagas disease is caused by the parasite Trypanosoma cruzi. The disease involves an acute and chronic phases. The diagnosis has limitations, both in parasitological and immunological techniques. Molecular assays are an alternative, but these must be evaluated to determine its diagnostic usefulness. The aim of this study was to compare the effectiveness of immunological techniques with molecular assays in the diagnosis of Chagas disease in its different phases. METHODS: The immunological techniques used were ELISA, HAI and IFI and the molecular techniques used were PCR for amplification of kinetoplast minicircles, and satellite DNA of T. cruzi. Thirty-nine blood samples from patients in the acute phase of Chagas disease, and 42 samples from patients in the chronic phase were evaluated. In addition, 20 samples from healthy individuals and 10 patients with other diseases were also studied. RESULTS: With immunological techniques were positive, 69.2% of samples from patients in the acute phase, while in the chronic phase were positive 95.2%. Using molecular techniques 79.5% of samples from patients in the acute phase were positive, while 23.8% of the samples from patients in the chronic phase were positive. None of the samples from healthy individuals was positive for any technique, while two samples from patients with other diseases were positive by the immunological assays. CONCLUSIONS: The diagnostic efficacy of molecular techniques is high in the acute phase of Chagas disease, while in the chronic phase the immunological techniques are more effective. PMID- 23102614 TI - The development of endocrine therapy for women with breast cancer. AB - The development of endocrine therapies has transformed the treatment of patients with breast cancer. The shift from ablative surgery and aggressive chemotherapies to more targeted, better tolerated therapy has improved both mortality and quality of life for patients with hormone-responsive disease. During the 1970s, the selective oestrogen-receptor modulator, tamoxifen, emerged as a new treatment for women with advanced breast cancer. The subsequent development of numerous and diverse selective endocrine therapies such as luteinising hormone-releasing hormone agonists, aromatase inhibitors and oestrogen-receptor antagonists have added further treatment options. Furthermore, with well-tolerated and effective endocrine therapy, adjuvant treatment became an option for patients with early breast cancer. Tamoxifen emerged as the gold standard adjuvant therapy in the 1980s; however, later trials in postmenopausal women showed the aromatase inhibitors offer advantages over tamoxifen. In addition to AIs being indicated as adjuvant therapy, some are also being evaluated for use as a preventative measure in high-risk women. This chronological account outlines key milestones in the evolution of endocrine therapies over the last 40 years, highlighting each class of agent and the key trials that have led to changes in clinical practice. The advances in endocrine therapies outlined here, coupled with advances in breast cancer management and diagnostics, will likely lead to more patient-tailored therapy, resulting in greater clinical benefits and more cost-effective treatment strategies. PMID- 23102615 TI - Clinicopathological factors impact the survival outcome following the resection of combined hepatocellular carcinoma and cholangiocarcinoma. AB - Studies have demonstrated poor survival outcomes for patients with resected combined hepatocellular carcinoma-cholangiocarcinoma tumours (CHCC-CC). Our objectives are to report on our institutional experience regarding the clinico pathological and prognostic features of CHCC-CC and to compare our results with published series. The clinico-pathological features and outcomes of 11 patients with CHCC-CC who had a complete surgical resection for primary liver cancer were reviewed. There were 8 male and 3 female patients. The overall median age was 61 years. Active hepatitis B and hepatitis C infections were present in 6 (54%) and 2 (18%) patients, respectively. Alcoholism was present in one case. Cirrhosis was present in 8 (72%) cases. There were no causative factors identified in 2 patients with non-cirrhotic livers. The median AFP value was 30.56 ng/ml. A single mass located in the right lobe and a single mass located in the left lobe of the liver was noted in 6 (54%) and 4 (36%) patients, respectively. Bilobar involvement was observed in one case. Major and minor resections were performed in 2 (18%) and 9 (81%) cases, respectively. The median tumour size was 3 cm. Tumours measuring >5 cm were identified in only 2 (18%) cases. The majority of the cases were classified as stage I (54%) and stage II (36%). Four patients died 11-50 months after the surgery. Postoperative tumour recurrences were observed in 5 (45.45%) patients within 4 years of surgical resection. The overall 1- and 3 year survival rates in this series were 80% and 69.3%. Our series demonstrated cases of CHCC-CC with more favourable pathological traits and survival outcomes compared with similar studies. PMID- 23102616 TI - The influence of gender on phenotype and disease progression in patients with Huntington's disease. AB - INTRODUCTION: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. The aim of this study is to determine whether gender plays a role in the phenotypic expression and progression of HD. METHODS: 1267 patients with HD (636 women) from the Registry project of the EHDN were included. A cross-sectional analysis (ANCOVA) controlling for differences in age at onset, disease burden, disease duration, smoking status, alcohol abuse, depression and the number of years of education, was performed to evaluate if there were differences between men and women in UHDRS motor, function and cognitive scores. Additionally, analyses on follow-up data using linear mixed models with the same covariates were performed to test for gender-related differences in progression. RESULTS: Baseline features did not differ between genders, with the exception of a higher frequency of past and current depression among women, and a higher number of years of education as well as more frequent alcohol abuse and smoking among men. In the cross-sectional ANCOVA analyses of patients with a mid-age HD onset, women showed worse scores than men in the functional domain (TFC, P = 0.001; UHDRS functional, P = 0.033), UHDRS motor (P = 0.033). The longitudinal analyses showed a faster rate of progression in women in the functional assessment (P = 0.025), the motor assessment (P = 0.032) and the independence scale (P = 0.008). CONCLUSIONS: These results suggest a complex gender effect on the phenotypical presentation and the rate of disease progression in HD, with slightly more severe phenotype and faster rate of progression in women in especially the motor and functional domains. PMID- 23102617 TI - Self-regulatory practices of drivers with Parkinson's disease: accuracy of patient reports. AB - BACKGROUND: Studies suggest that drivers with Parkinson's disease (PD) are more likely than controls to restrict their exposure and avoid challenging situations possibly to compensate for declining abilities; however it is questionable whether patient reports should be taken at face value. To address this issue, this study examined agreement between self-reported and actual driving practices in drivers with and without PD. METHODS: Two electronic devices (one with GPS) were installed in the vehicles of 26 drivers with PD (mean age 71.5 +/- 6.8, 77% men) and 20 controls (mean age 70.6 +/- 7.9, 80% men) for two weeks. Participants completed a questionnaire on usual driving patterns, scales on Situational Driving Frequency (SDF) and Avoidance (SDA), the MoCA and an interview. RESULTS: Self-estimates of distance driven (km) over the two weeks were inaccurate in both groups; however the tendency to under-estimate was more pronounced in PD drivers. Drivers with PD reported more self-restrictions (higher SDA scores, p < .01; lower SDF scores, p < .05), yet drove more at night, in bad weather, in rush hour and on highways than they reported. Drivers with PD had significantly lower MoCA scores overall (p < .01) and on the memory subtest (p < .05), however, MoCA scores were not correlated with self-reported restrictions, or actual driving distance in either group. CONCLUSIONS: These findings indicate that patient reports of driving behavior should not be taken at face value by researchers or clinicians. Patients with PD may be more likely than drivers in general to have problems with recall and possibly less awareness of their driving practices. PMID- 23102618 TI - mTOR regulates cellular iron homeostasis through tristetraprolin. AB - Iron is an essential cofactor with unique redox properties. Iron-regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron requiring genes in both mammalian and yeast cells, and modulates survival in low iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron-regulatory pathways, and point toward the existence of a yeast-like TTP-mediated iron conservation program in mammals. PMID- 23102620 TI - Concurrent ranavirus and Batrachochytrium dendrobatidis infection in captive frogs (Phyllobates and Dendrobates species), The Netherlands, 2012: a first report. AB - A ranavirus infection with concurrent Batrachochytrium dendrobatidis infection and mortality in captive Phyllobates and Dendrobates species is reported. Greyish skin with hepato- and reno-megaly were evident. Microscopically, Batrachochytrium dendrobatidis was present in the stratum corneum of the hyperkeratotic skin. Intracytoplasmic inclusion bodies were present in erythrocytes and multiple organs. All samples examined tested positive using PCR for the major capsid protein (MCP) gene of ranavirus and the ITS-1-5.8S region of B. dendrobatidis. The sequence obtained showed a 99% identity with the deposited sequence of the MCP gene of the common midwife toad virus (CMTV). This is the first report of mortality in captivity in poison dart frogs caused by a ranavirus, CMTV or like virus, and Batrachochytrium dendrobatidis infection. PMID- 23102619 TI - Resveratrol supplementation does not improve metabolic function in nonobese women with normal glucose tolerance. AB - Resveratrol has been reported to improve metabolic function in metabolically abnormal rodents and humans, but it has not been studied in nonobese people with normal glucose tolerance. We conducted a randomized, double-blind, placebo controlled trial to evaluate the metabolic effects of 12 weeks of resveratrol supplementation (75 mg/day) in nonobese, postmenopausal women with normal glucose tolerance. Although resveratrol supplementation increased plasma resveratrol concentration, it did not change body composition, resting metabolic rate, plasma lipids, or inflammatory markers. A two-stage hyperinsulinemic-euglycemic clamp procedure, in conjunction with stable isotopically labeled tracer infusions, demonstrated that resveratrol did not increase liver, skeletal muscle, or adipose tissue insulin sensitivity. Consistent with the absence of in vivo metabolic effects, resveratrol did not affect its putative molecular targets, including AMPK, SIRT1, NAMPT, and PPARGC1A, in either skeletal muscle or adipose tissue. These findings demonstrate that resveratrol supplementation does not have beneficial metabolic effects in nonobese, postmenopausal women with normal glucose tolerance. PMID- 23102621 TI - Noncovalenly PEGylated CTGF siRNA/PDMAEMA complex for pulmonary treatment of bleomycin-induced lung fibrosis. AB - On the basis of wide biomedical applications of methacrylate polymers, we previously developed noncovalently post-PEGylated ternary complex of siRNA using poly(dimethylamino)ethylmethacrylate (PDMAEMA) and its copolymer with poly(alpha methylether-omega-methacrylate-ethyleneglycol) [PMAPEG]. In this work, we investigated the antifibrotic effect of connective tissue growth factor siRNA (siCTGF)/PDMAEMA/PDMAEMA-b-PMAPEG complex for the treatment of bleomycin-induced pulmonary fibrosis. After orotracheal administration to fibrotic Sprague Dawley (SD) model rats, FAM-labeled siCTGF complex was effectively delivered to the cells in the lung. The siCTGF ternary complex resulted in a significant reduction in target gene expression, collagen deposition, inflammatory cytokines production, and drastic attenuation of pulmonary fibrosis in pathophysiological analysis. Furthermore, the survival rate was remarkably increased to the statistically significant level in comparison with the scrambled siCTGF treatment group. PMID- 23102622 TI - pH-sensitive poly(histidine)-PEG/DSPE-PEG co-polymer micelles for cytosolic drug delivery. AB - To introduce pH sensitivity into the DSPE-PEG-based micellar system and achieve the quick intracellular drug release in response to the acidity in endosomes, a mixed polymeric micelle was developed based on three grafted copolymers, including 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol 2000(DSPE-PEG(2000)), antinucleosome antibody (mAb 2C5)-modified DSPE-PEG(3400) (DSPE-PEG(3400)-2C5), and poly(ethylene glycol)-coupled poly(L-histidine) (PHIS PEG(2000)). The structure of PHIS-PEG(2000) was confirmed by (1)H NMR spectroscopy. The mixed micelles with the diameter ranging from 110 to 135 nm were prepared using a dialysis method against pH 7.6 PBS. Paclitaxel (PCT) was used as a model drug, the encapsulation efficiency and loading content of PCT were 88% and 5%, respectively. The mixed micelles composed with 50 wt% of PHIS PEG(2000) showed the desired pH-dependent drug release property with much faster drug release than micelles without PHIS-PEG(2000). At pH around 5.5, about 75-95% of the loaded drug was released within 2 h. The MTT assay showed PCT-loaded mixed micelles had higher cytotoxicity at pH 5.8 than that at pH 7.4. Further modification of the mixed micelles with anti-cancer nucleosome-specific monoclonal antibody 2C5 significantly increased their cellular uptake efficiency and cytotoxicity. Thus, the low pH in endosomes could trigger the PCT release from the pH-sensitive mixed micelles after 2C5-mediated endocytosis. The results of this study suggest that the mixed micelles (DSPE-PEG(2000)/DSPE-PEG(3400) 2C5/PHIS-PEG(2000)) could enhance the tumor cell-specific internalization and trigger the quick drug release, resulting in the improved anti-cancer efficacy. PMID- 23102624 TI - Twelve-lead electrocardiography in the young: physiologic and pathologic abnormalities. AB - BACKGROUND/ OBJECTIVE: The purpose of the present study was to analyze the prevalence of physiologic and pathologic ECG abnormalities in a cohort of young conscripts that represents the whole young generation of today. METHODS: ECGs of all Swiss citizens who underwent conscription for the army during a 29-month period were analyzed manually. RESULTS: ECGs of 43,401 conscripts (mean age 19.2 +/- 1.1 years) were analyzed; 158 conscripts were female. Incomplete right bundle branch block was found in 5870 (13.5%) and left anterior fascicular block in 360 (0.83%). First-degree AV block was present in 329 (0.8%) and Mobitz type I (Wenckebach) second-degree AV block in 3 (0.01%). Early repolarization was observed in 1035 (2.4%), T-wave inversion in 39 (0.09%), and minor T-wave changes in 182 (0.42%). Brugada-like abnormalities were observed in 6 (0.01%). None of the conscripts had atrial fibrillation or flutter. CONCLUSION: ECG abnormalities can be found in a relatively large proportion of young individuals. Incomplete right bundle branch block, left fascicular block, and first-degree AV block are the most frequent findings. No conscript presented with atrial fibrillation or flutter. PMID- 23102623 TI - The effect of substrate modulus on the growth and function of matrix-embedded endothelial cells. AB - Endothelial cells (EC) are potent bioregulatory cells, modulating thrombosis, inflammation and control over mural smooth muscle cells and vascular health. The biochemical roles of EC are retained when cells are embedded within three dimensional (3D) denatured collagen matrices. Though substrate mechanics have long been known to affect cellular morphology and function and 3D-EC systems are increasingly used as therapeutic modalities little is known about the effect of substrate mechanics on EC in these 3D systems. In this work, we examined the effect of isolated changes in modulus on EC growth and morphology, extracellular matrix gene expression, modulation of smooth muscle cell growth, and immunogenicity. EC growth, but not morphology was dependent on scaffold modulus. Increased scaffold modulus reduced secretion of smooth muscle cell growth inhibiting heparan sulfate proteoglycans (HSPGs), but had no effect on secreted growth factors, resulting in a loss of smooth muscle cell growth inhibition by EC on high modulus scaffolds. Expression of ICAM-1, VCAM-1 and induction of CD4(+) T cell proliferation was reduced by increased scaffold modulus, and correlated with changes in integrin alpha5 expression. Expression of several common ECM proteins by EC on stiffer substrates dropped, including collagen IV(alpha1), collagen IV(alpha5), fibronectin, HSPGs (perlecan and biglycan). In contrast, expression of elastin and TIMPs were increased. This work shows even modest changes in substrate modulus can have a significant impact on EC function in three dimensional systems. The mechanism of these changes is not clear, but the data presented here within suggests a model wherein EC attempt to neutralize changes in environmental force balance by altering ECM and integrin expression, leading to changes in effects on downstream signaling and function. PMID- 23102625 TI - When genetic screening for your patient with long QT syndrome comes back negative, don't always take a no for a no. PMID- 23102626 TI - Effect of radiation therapy on permanent pacemaker and implantable cardioverter defibrillator function. AB - BACKGROUND: Radiation therapy's (RT's) effects on cardiac implantable electronic devices (CIEDs) such as implantable cardioverter-defibrillators (ICDs) and pacemakers (PMs) are not well established, leading to device removal or relocation in preparation for RT. OBJECTIVE: To determine the effect of scattered RT on CIED performance. METHODS: We analyzed 69 patients--50 (72%) with PMs and 19 (28%) with ICDs--receiving RT at the University of Michigan. Collected data included device model, anatomic location, and treatment beam energies, treatment type, and estimated dose to the device. Patients were treated with either high energy (16-MV) and/or low-energy (6 MV) photon beams with or without electron beams (6-16 MeV). The devices were interrogated with pre- and post-RT and/or weekly with either in-treatment or home interrogation, depending on the patient's dependence on the device and the estimated or measured delivered dose. Outcomes analyzed were inappropriate ICD therapies, device malfunctions, or device-related clinical events. RESULTS: The PMs were exposed to 84.4 +/- 99.7 cGy of radiation, and the ICDs were exposed to 92.1 +/- 72.6 cGy of radiation. Two patients with ICDs experienced a partial reset of the ICD with the loss of historic diagnostic data after receiving 123 and 4 cGy, respectively. No device malfunction or premature battery depletion was observed at 6-month follow-up from RT completion. CONCLUSIONS: CIED malfunction due to indirect RT exposure is uncommon. Regular in treatment or home interrogation should be done to detect and treat these events and to ensure that diagnostic data are preserved. PMID- 23102627 TI - Ablation-induced epsilon wave. PMID- 23102629 TI - Family history of schizophrenia as a risk factor for axis I psychiatric conditions. AB - People with first-degree relatives with schizophrenia are at an elevated risk of developing the disorder themselves. High rates of psychotic symptoms in non psychotic disorders, high rates of comorbidity in psychotic disorders, and diversity of outcomes following psychosis-risk states together suggest that this vulnerability may be for psychiatric conditions in general, not limited to schizophrenia. In this study, data from the National Survey of American Life (NSAL) were used to examine the association between having a first-degree relative with schizophrenia and the lifetime development of a range of non psychotic axis I psychiatric disorders using adjusted odds ratios. Having a relative with schizophrenia was associated with increased risk for most non psychotic psychiatric conditions examined, including those expected to be associated with schizophrenia (affective, anxiety, and substance use disorders) and those not expected (bulimia, disorders of childhood onset), excluding respondents with lifetime psychotic symptoms and controlling for demographic factors. Family history of schizophrenia among this predominantly African American and Afro-Caribbean sample appears to be a risk factor for a range of axis I diagnoses, supporting a continuous rather than categorical nature of psychiatric vulnerability. Future studies should examine whether these associations are due to genetic or environmental factors, or both. PMID- 23102630 TI - Diagnostic accuracy of serum brain derived neurotrophic factor concentration in antidepressant naive patients with first major depression episode. AB - Diagnosing major depressive disorder (MDD) continues to be based on meeting phenomenological and descriptive criteria. As of yet, there is still no non invasive, peripheral biomarker that would allow for a certain diagnosis of MDD. The objective of this paper is to use the receiver operating characteristic (ROC) analysis to test the diagnostic value of serum concentrations of brain derived neurotrophic factor (BDNF) in diagnosing the first episode of MDD. Among 1014 patients admitted for an initial psychiatric evaluation, antidepressant naive patients diagnosed with first episode MDD were separated into the test group. Only patients signing an informed consent form were included in the study. Using DSM-IV-TR diagnostic criteria, those patients meeting the MDD criteria (N = 122) and patients not meeting MDD or other psychiatric disorder criteria (N = 142) were differentiated. Subjects with repeated episode MDD (N = 121) and other psychiatric comorbid illnesses (N = 138) in the MDD group were excluded from the study. In the group without MDD or other psychiatric illnesses, patients with physical comorbidities (N = 59) were excluded. The serum concentration of BDNF was determined in all patients using the ELISA assay. Subjects with first episode MDD showed differences in serum BDNF concentrations (ng/mL) in comparison to the control group of patients not meeting the criteria for first episode MDD (mean +/ SD; 37.5 +/- 13.3 vs. 56.8 +/- 6.3; t = 1.372; df = 262; p < 0.01). The ROC analysis established a discriminant diagnostic value of serum BDNF in diagnosing MDD. The area under the curve (AUC) was 0.892 with a 95% confidence level (0.826 0.939), which was statistically significant at p < 0.01. The serum BDNF had a high diagnostic sensitivity of 83.9% and a specificity of 93%. Serum BDNF concentrations appear to be a promising tool in discriminating subjects with MDD from those without MDD. PMID- 23102628 TI - Lifetime history of traumatic events in an American Indian community sample: heritability and relation to substance dependence, affective disorder, conduct disorder and PTSD. AB - American Indians appear to experience a higher rate of traumatic events than what has been reported in general population surveys. American Indians also suffer higher alcohol related death rates than any other ethnic group in the U.S. population. Therefore efforts to delineate factors which may uniquely contribute to increased likelihood of trauma, post traumatic stress disorder (PTSD), and substance use disorders (SUD) over the lifetime in American Indians are important because of the high burden of morbidity and mortality that they pose to American Indian communities. Participants were American Indians recruited from reservations that were assessed with the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA), family history assessment and the stressful-life events scale. Of the 309 participants, equivalent numbers of men and women (94%) reported experiencing traumas; however, a larger proportion of women received a PTSD diagnosis (38%) than men (29%). Having experienced multiple trauma and sexual abuse were most highly associated with PTSD. Having experienced assaultive trauma and having PTSD symptoms were both found to be moderately heritable (30 50%). Logistic regression revealed that having an anxiety and/or affective disorder and having a substance dependent diagnosis, but not having antisocial personality disorder/conduct disorder, were significantly correlated with having a diagnosis of PTSD. These studies suggest that trauma is highly prevalent in this American Indian community, it is heritable, is associated with PTSD, affective/anxiety disorders and substance dependence. Additionally, trauma, PTSD and substance dependence appear to all co-emerge in early adulthood in this high risk population. PMID- 23102631 TI - A screening model analysis of mercury sources, fate and bioaccumulation in the Gulf of Mexico. AB - A mass balance model of mercury (Hg) cycling and bioaccumulation was applied to the Gulf of Mexico (Gulf), coupled with outputs from hydrodynamic and atmospheric Hg deposition models. The dominant overall source of Hg to the Gulf is the Atlantic Ocean. Gulf waters do not mix fully however, resulting in predicted spatial differences in the relative importance of external Hg sources to Hg levels in water, sediments and biota. Direct atmospheric Hg deposition, riverine inputs, and Atlantic inputs were each predicted to be the most important source of Hg to at least one of the modeled regions in the Gulf. While incomplete, mixing of Gulf waters is predicted to be sufficient that fish Hg levels in any given location are affected by Hg entering other regions of the Gulf. This suggests that a Gulf-wide approach is warranted to reduce Hg loading and elevated Hg concentrations currently observed in some fish species. Basic data to characterize Hg concentrations and cycling in the Gulf are lacking but needed to adequately understand the relationship between Hg sources and fish Hg concentrations. PMID- 23102632 TI - Development, optimization and validation of a sub-minute analytical enantioselective high performance liquid chromatographic separation for a folic acid precursor in normal phase mode. AB - A sub-minute enantioselective normal phase high performance liquid chromatographic (HPLC) method for the analysis of a chiral precursor molecule employed frequently in folic acid syntheses was developed, optimized and successfully validated according to ICH-guidelines. It could be shown that ultra high performance chromatography (UHPLC) can give significant advantages compared to traditional HPLC not only in reversed phase HPLC, but also for enantioselective separations in normal phase mode. Novel 3 MUm-particle sizes allow developing analytical chromatographic methods completely resolving two enantiomers in the shortest time possible while preserving high efficiency and low detection limits. By offering increased resolution, sensitivity and speed, enantioselective UHPLC (eUHPLC) improves sample throughput, productivity and provides considerably faster access to information on enantiomeric purity also under non-aqueous conditions. PMID- 23102633 TI - Compensation for matrix effects in the gas chromatography-mass spectrometry analysis of 186 pesticides in tea matrices using analyte protectants. AB - A gas chromatography-mass spectrometry (GC-MS) analytical method was developed for simultaneously determining 186 pesticides in tea matrices using analyte protectants to counteract the matrix-induced effect. The matrix effects were evaluated for green, oolong and black tea, representing unfermented, partially fermented and completely fermented teas respectively and depending on the type of tea, 72%, 94% and 94% of the pesticides presented strong response enhancement effect. Several analyte protectants as well as certain combinations of these protectants were evaluated to check their compensation effects. A mixture of triglycerol and d-ribonic acid-gamma-lactone (both at 2mg/mL in the injected samples) was found to be the most effective in improving the chromatographic behavior of the 186 pesticides. More than 96% of the 186 pesticides achieved recoveries within the range of 70-120% when using the selected mixture of analyte protectants. The simple addition of analyte protectants offers a more convenient solution to overcome matrix effects, results in less active sites compared to matrix-matched standardization and can be an effective approach to compensate for matrix effects in the GC-MS analysis of pesticide residues. PMID- 23102634 TI - Sirtuins: NAD(+)-dependent deacetylase mechanism and regulation. AB - Sirtuins are NAD(+)-dependent deacetylases involved in chemical reversal of acetyllysine modifications of cellular proteins. Deacetylation catalyzed by sirtuins is implicated in regulating diverse biological processes, including energy homeostasis. The mechanism of NAD(+)-dependent deacetylation is proposed to occur via an ADPR-peptidyl-imidate intermediate, resulting from reaction of NAD(+) and an acetyllysine residue. This mechanism enables sirtuins to respond dynamically to intracellular fluctuations of NAD(+) and nicotinamide. Chemical probes such as nicotinamide antagonists and thioacetyl compounds provide key support for the imidate mechanism of sirtuin deacetylation catalysis. Novel new directions include chemical probes to study sirtuins in cells, and the discovery of novel post-translational modifications besides acetyl, such as succinyl and malonyl, that are regulated by sirtuins. PMID- 23102635 TI - Practice patterns and job satisfaction in fellowship-trained endocrine surgeons. AB - BACKGROUND: Debates about the difficult job market for young endocrine surgeons are ongoing. This study aimed to analyze the practice patterns and work-related satisfaction levels of recently trained endocrine surgeons. METHODS: An anonymous survey was utilized. Participants were divided into 3 groups: "Young" (<3 years in practice), "middle" (3-5 years), and "older" (>5 years). RESULTS: Fifty-six of 78 surgeons (72%) responded to the survey. Time in practice ranged from 1 to 9 years (mean, 3.9 +/- 0.28). Forty-five (80%) described their practice as academic. Participants performed 244.1 +/- 17.8 operations within the last year; 75.4 +/- 3.3% were endocrine cases. More surgeons in the "young" group have academic practices (92%) and joined established endocrine surgery groups (54%) versus older surgeons (67% and 42%; P = .05). Of surgeons in the "young" group, 4% started their own practice versus 33% in the "older" group (P = .04). Level of satisfaction with financial compensation (3.2 on a 4-point scale versus 2.9) and lifestyle (3.6 vs 3.1) was also higher in the younger group (P = .009). CONCLUSION: Despite widespread speculation about scarcity of academic jobs after fellowship, recently trained endocrine surgeons are more likely to practice in academic settings and join established endocrine surgery practices when compared with older surgeons. Overall satisfaction level is higher among recently trained surgeons. PMID- 23102636 TI - Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma. AB - BACKGROUND: Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors. We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma (ACC). METHODS: We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells. The effects of monotherapy and strategic combination regimens were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium (ie, MTS) assay. RESULTS: The minimum inhibitory concentrations (IC(min)) of sunitinib quenched its primary targets: FLT-3, VEGFR-2, and RET. In contrast, ERK, HCK, Chk2, YES, CREB, MEK, MSK, p38, FGR, and AXL were hyperactivated. Monotherapy with sunitinib or PD98059 at their IC(min) reduced proliferation by 23% and 19%, respectively, in H295R cells and by 25% and 24%, respectively, in SW13 cells. Sunitinib and PD98059 in combination decreased proliferation by 68% and 64% in H295R and in SW13 cells, respectively (P < .05 versus monotherapy). The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone. CONCLUSION: We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC. Because many tyrosine kinase inhibitors are readily available, this model can be immediately tested in clinical trials for patients with advanced ACC. PMID- 23102638 TI - AJPM childhood obesity challenge. PMID- 23102637 TI - Variation in susceptibility of human malignant melanomas to oncolytic vesicular stomatitis virus. AB - BACKGROUND: Vesicular stomatitis virus (VSV) is a novel, anti-cancer therapy that targets cancer cells selectively with defective antiviral responses; however, not all malignant cells are sensitive to the oncolytic effects of VSV. Herein, we have explored the mechanistic determinants of mutant M protein VSV (M51R-VSV) susceptibility in malignant melanoma cells. METHODS: Cell viability after VSV infection was measured by the 3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) viability assay in a panel of melanoma cell lines. VSV infectability, viral protein synthesis, and viral progeny production were quantified by flow cytometry, (35)S-methionine electrophoresis, and viral plaque assays, respectively. Interferon (IFN) responsiveness was determined using MTS assay after beta-IFN pretreatment. Xenografts were established in athymic nude mice and treated with intratumoral M51R-VSV. RESULTS: Cell viability after M51R-VSV infection at a multiplicity of infection of 10 pfu/mL, 48 hours postinfection) ranged between 0 +/- 1% and 59 +/ 9% (mean +/- standard deviation). Sensitive cell lines supported VSV infection, viral protein synthesis, and viral progeny production. In addition, when pretreated with beta-IFN, sensitive cells became resistant to M51R-VSV, suggesting that IFN-mediated antiviral signaling is defective in these cells. In contrast, resistant melanoma cells do not support VSV infection, viral protein synthesis, or viral replication, indicating that antiviral defenses remain intact. In a murine xenograft model, intratumoral M51R-VSV treatment decreased tumor growth relative to controls after 26 days in SK-Mel 5 (-21 +/- 19% vs. 2,100 +/- 770%; P < .0001) and in SK-Mel 3 (2,000 +/- 810% vs. 7,000 +/- 3,000%; P = .008) established tumors. CONCLUSION: M51R-VSV is a viable anti-cancer therapy, but susceptibility varies among melanomas. Future work will exploit specific mechanisms of resistance to expand the therapeutic efficacy of M51R-VSV. PMID- 23102639 TI - Post-mortem modelling of pH and temperature in related lamb carcases. AB - Exponential decay models have been used to model pH and temperature decline in lamb carcases post mortem. Such models, once fitted to carcase data, can then be used to predict a carcase's pH at a temperature of 18 degrees C and its temperature when the pH equals 6. Unfortunately, these models frequently fail when fitted to limited pH/temperature data, because of either insufficient data or inappropriateness of the exponential decay model. To overcome these problems an alternative though similar modelling approach is proposed. This alternative approach replaces the exponential decay model with a more flexible spline modelling approach for the average trend and includes in the model, as random effects, individual deviations from average trend. Including the individual deviations from average trend as random effects in the model allows information on individual carcases to be shared across carcases. PMID- 23102641 TI - Aggregate material formulated with MSWI bottom ash and APC fly ash for use as secondary building material. AB - The main goal of this paper is to obtain a granular material formulated with Municipal Solid Waste Incineration (MSWI) bottom ash (BA) and air pollution control (APC) fly ash to be used as secondary building material. Previously, an optimum concrete mixture using both MSWI residues as aggregates was formulated. A compromise between the environmental behavior whilst maximizing the reuse of APC fly ash was considered and assessed. Unconfined compressive strength and abrasion resistance values were measured in order to evaluate the mechanical properties. From these results, the granular mixture was not suited for certain applications owing to the high BA/APC fly ash content and low cement percentages used to reduce the costs of the final product. Nevertheless, the leaching test performed showed that the concentrations of all heavy metals were below the limits established by the current Catalan legislation for their reutilization. Therefore, the material studied might be mainly used in embankments, where high mechanical properties are not needed and environmental safety is assured. PMID- 23102642 TI - [Association of renovascular hypertension and primary aldosteronism]. AB - INTRODUCTION: Renal artery stenosis is rarely associated with Conn adenoma. CASE REPORT: We report a 27-year-old male patient who presented in 2001 with a severe high blood pressure associated with hypokaliemia. Radiologic investigations showed a left renal artery stenosis with agenesis of left kidney. A left nephrectomy was performed and blood pressure returned to normal with a single antihypertensive drug. Five years later, the patient again presented with severe high blood pressure. Laboratory studies revealed a low serum potassium level at 2.8 mmol/L associated with high urinary potassium excretion (84 mmol/24h) and a very high aldosterone/renin ratio (>462). Abdominal CT scan demonstrated a right adrenal mass. The patient underwent a right adrenalectomy (adenoma). Blood pressure returned to normal with a single antihypertensive. Serum potassium levels as well as aldosterone/renin ratio normalized. CONCLUSION: We discussed whether the association between these two entities is merely fortuitous or conversely based on a causal relationship. PMID- 23102643 TI - Effects of organic matter and submerged macrophytes on variations of alkaline phosphatase activity and phosphorus fractions in lake sediment. AB - Organic matter and submerged plants may affect internal phosphate loading in lake sediment. In this study, we investigated the changes of alkaline phosphatase activity (APA) and phosphorus (P) fractions in lake sediment by adding organic matter (0.0%, 0.5% and 1.0% of dry weight) and plant submerged plants under experimental conditions. Results indicated that the APA in sediments significant increased after 50 days incubation than at 7 days. The APA in the treatments by adding organic matter and submerged plants increased by 26.37%-61.78% than that of control after 7 days incubation, and increased by 1.00%-29.51% at 50 days, indicating both organic matter and submerged plants may remarkable affect APA in sediment, especially for the early stage of incubation. In addition, the soluble reactive P (SRP) concentrations of the overlying water increased significantly with increasing sediment organic matter, possibly related to increase of APA in sediment. However, the release of SRP was obvious restrained due to absorption of submerged plant. TP and P fraction in sediment decreased with increasing incubation time, but the decrease of TP content in sediment was mainly from NaOH P and OP sources, but not from HCl-P and IP. Effects of organic matter and submerged plants on P fractions in sediment mainly occurred in NaOH-P and OP fractions. At the end of experiments, the contents of NaOH-P and OP in the treatments by adding organic matter and submerged plant decreased by 5.46%-20.47% and 7.87%-21.46%, respectively. These results indicated that the relative importance of organic matter and submerged plants during the release and transformation of P in lake sediment. PMID- 23102644 TI - Determination of octanol-air partition coefficients of organochlorine pesticides (OCPs) as a function of temperature: application to air-soil exchange. AB - Octanol-air partition coefficients (K(OA)) for 7 organochlorine pesticides (OCPs) were determined as a function of temperature using the GC retention time method. Log K(OA) values at 25 degrees C ranged over two orders of magnitude, between 8.32 (chlorpyrifos) and 10.48 (methoxychlor). The determined K(OA) values were within a factor of 0.5 (endosulfan sulfate) to 7.9 (endrin aldehyde) for values calculated as the ratio of octanol-water partition coefficient to dimensionless Henry's law constant. The internal energies of phase transfer between octanol and air (DeltaU(OA)) ranged between 71.8 and 95.4 kJ mol(-1) and they were within the reported range for OCPs (55.8-105 kJ mol(-1)). Atmospheric and soil OCP concentrations were also measured in Izmir, Turkey, and data used to investigate the soil-air gas exchange. Net soil-air gas exchange fluxes of OCPs ranged from 0.01 (volatilization, cis-nonachlor) to 56.4 ng m(-2) day(-1) (deposition, chlorpyrifos) in winter, while in summer they ranged from -0.03 (trans-nonachlor) to 329 ng m(-2) day(-1) (endosulfan I). In both sampling periods, endosulfan I and II, trans-nonachlor, p,p'-DDD and p,p'-DDT were generally deposited to the soil while gamma-HCH and heptachlor epoxide mostly volatilized. Fluxes of other OCPs were variable (volatilization or absorption) due to their largely fluctuating ambient air concentrations. Calculated dry deposition and recently measured wet deposition fluxes were used to estimate the relative importance of different mechanisms (i.e., dry deposition, wet deposition, gas absorption, and volatilization) to the local soil pollutant inventory. Generally, all mechanisms contributed significantly to the soil OCP inventory. Volatilization fluxes were generally much lower than the sum of input fluxes (dry deposition, wet deposition and gas absorption) for most of the OCPs indicating a net deposition to the soil. PMID- 23102645 TI - Pattern recognition receptors--molecular orchestrators of inflammation in inflammatory bowel disease. AB - Pattern recognition receptors (PRRs) are a family of germline encoded receptors responsible for the detection of "pathogen associated molecular patterns" (PAMPs) or host derived "damage associated molecular patterns" (DAMPs) which induce innate immune signalling to generate a pro-inflammatory profile within the host. Four main classes of PRRs are recognised, Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like receptors (RLRs) and C-type lectin receptors (CLRs). Abnormal activation of PRRs has been implicated in various autoimmune and inflammatory conditions including rheumatoid arthritis and asthma. Recent growing evidence has implicated these PRRs as contributory elements to the pathogenesis of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Here, the current literature which implicates PRRs in IBD and CAC is comprehensively reviewed. PMID- 23102647 TI - Effects of EPA and DHA on lipid droplet accumulation and mRNA abundance of PAT proteins in caprine monocytes. AB - The present study investigated the in vitro effects on caprine monocytes of two omega-3 PUFAs, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on lipid droplet formation, an emerging process of fundamental importance in innate immunity regulation. The mRNA abundance of PAT protein family (PLIN1, PLIN2 and PLIN3), involved in the formation and trafficking of the droplets, was also assessed. The effects of EPA and DHA on monocyte apoptosis were studied as well. The number of lipid droplets per cell was found to be dependent on both type and concentration of fatty acid. omega-3 PUFAs upregulated PLIN3 and PLIN2 gene expression, as well as apoptosis rate. The present findings suggest that PUFA might modify innate immune functions of goat monocytes by interfering with the formation of lipid droplets and by upregulating proteins belonging to PAT protein family. PMID- 23102646 TI - Snail/Gfi-1 (SNAG) family zinc finger proteins in transcription regulation, chromatin dynamics, cell signaling, development, and disease. AB - The Snail/Gfi-1 (SNAG) family of zinc finger proteins is a group of transcriptional repressors that have been intensively studied in mammals. SNAG family members are similarly structured with an N-terminal SNAG repression domain and a C-terminal zinc finger DNA binding domain, however, the spectrum of target genes they regulate and the ranges of biological functions they govern vary widely between them. They play active roles in transcriptional regulation, formation of repressive chromatin structure, cellular signaling and developmental processes. They can also result in disease states due to deregulation. We have performed a thorough investigation of the relevant literature and present a comprehensive mini-review. Based on the available information, we also propose a mechanism by which SNAG family members may function. PMID- 23102648 TI - Persistent efficacy of 3.5% doramectin compared to 3.15% ivermectin against gastrointestinal nematodes in experimentally-infected cattle in Brazil. AB - The present study aimed to evaluate the persistent efficacy of a 3.5% doramectin(*) (700 MUg/kg) formulation compared to 3.15% ivermectin(**) (630 MUg/kg) treatment, administered subcutaneously at a dose of 1 mL/50 kg body weight in cattle experimentally infected with gastrointestinal nematodes. Seventy two male crossbred Holstein cattle that were negative for helminth infection were divided into nine groups. Treatments of 3.5% doramectin (Groups 2, 4, 6 and 8) and 3.15% ivermectin (Groups 3, 5, 7 and 9) were administered on days 49, 42, 35 and 28 prior to challenge with infectious nematode larvae (L3). Animals in the control group (Group 1) received saline solution on day 49 before challenge. Beginning on day zero, each animal received 50 mL orally of a mixed culture containing approximately 3,000 third stage larvae (L3) of Haemonchus (60%), Oesophagostomum (20%), Cooperia (15%) and Trichostrongylus (5%) for seven consecutive days, resulting in a total challenge of 21,000 larvae/animal. Due to the large number of cattle, autopsies were performed between days 28 and 35 after the last day of inoculation. The formulation containing doramectin (700 mcg/kg) achieved persistent efficacy against H. placei and C. punctata for 49 and 35 days, respectively. The persistent efficacy of ivermectin (630 mcg/kg) against H. placei lasted for 49 days, but this treatment was ineffective against C. punctata. Both formulations demonstrated persistent efficacy against T. axei for 49 days. The persistent efficacy of doramectin (700 mcg/kg) and ivermectin (630 mcg/kg) lasted for 49 and 42 days against O. radiatum, respectively. PMID- 23102649 TI - Serum sickness-like reaction due to Infliximab reintroduction during pregnancy. PMID- 23102650 TI - Homing marker expression on circulating dendritic cells correlates with different phenotypes of Crohn's disease. PMID- 23102651 TI - Pediatric pulmonary Crohn's disease: more frequent than expected. PMID- 23102652 TI - Treatment of depression in people with lung cancer: a systematic review. AB - Lung cancer commonly occurs in older adults who live in deprived areas and have multiple medical comorbidities. As well as suffering severe physical deterioration they are aware of their poor prognosis. It is therefore unsurprising that people with lung cancer have a high rate of depression. Whilst there are effective treatments for depression in people who do not have cancer, it is uncertain which treatments, if any, are effective in depressed cancer patients; the special characteristics of the condition only increase that uncertainty for people with lung cancer. We therefore conducted a systematic review of relevant randomised controlled trials to determine which, if any, treatments have been found to be effective for depression in patients with lung cancer. Surprisingly, we found no completed trials of treatments in patients selected for having depression and no trials that had evaluated treatments known to be effective for depression in the general population. We did, however, find six trials of interventions intended to improve quality of life in unselected patients with lung cancer. These suggested that enhanced care is more effective in reducing depressive symptoms than standard care. Whilst it may be reasonable to treat depression in individuals with lung cancer with standard treatments until more specific evidence is available, clinicians should be aware that the effectiveness and potential adverse effects of these treatments remain unknown in this patient group. Evidence from randomised trials is urgently required. PMID- 23102653 TI - Synthesis and glycosidase inhibitory activity of novel (2-phenyl-4H benzopyrimedo[2,1-b]-thiazol-4-yliden)acetonitrile derivatives. AB - A series of (2-phenyl-4H-benzopyrimodo[2,1-b][1,3]thiazol-4-yliden-4 yliden)acetonitrile derivatives have been prepared by ring transformation reaction of 4-(methylthio)-2-oxo-6-aryl-2H-pyrane-3-carbonitriles. The yield of ring transformation product is moderate to good. Furthermore the glycosidase inhibitory activities were tested by using alpha-amylase and alpha-glucosidase pancreatic, intestinal and liver enzymes, responsible for hyperglycemia in type II diabetes. The results revealed that all compounds exhibit significant glycosidase inhibitory activity. PMID- 23102654 TI - Inhibition of monoamine oxidase by derivatives of piperine, an alkaloid from the pepper plant Piper nigrum, for possible use in Parkinson's disease. AB - A series of compounds related to piperine and antiepilepsirine was screened in a monoamine oxidase A and B assay. Piperine is an alkaloid from the source plant of both black and white pepper grains, Piper nigrum. Piperine has been shown to have a wide range of activity, including MAO inhibitory activity. The z-factor for the screening assay was found to be greater than 0.8 for both assays. Notably, the compounds tested were selective towards MAO-B, with the most potent compound having an IC(50) of 498 nM. To estimate blood-brain barrier (BBB) permeability, we used a PAMPA assay, which suggested that the compounds are likely to penetrate the BBB. A fluorescent bovine serum albumin (BSA) high-throughput screening (HTS) binding assay showed an affinity of 8 MUM for piperine, with more modest binding for other test compounds. Taken together, the data described here may be useful in gaining insight towards the design of selective MAO-B inhibitory compounds devoid of MAO-A activity. PMID- 23102655 TI - The ever growing complexity of placental epigenetics - role in adverse pregnancy outcomes and fetal programming. AB - As the primary interface between maternal and fetal circulations, the placenta is subject to a myriad of environmental exposures with the capacity to alter placental function and fetal development. Many of these effects are likely to be mediated by epigenetic ('above DNA') change, which is also in turn regulated by maternal and fetal genetic factors. Linking specific environmental exposures, genetic, and epigenetic variation to maternal and fetal outcomes may provide valuable mechanistic insights into the role of placental dysfunction in pregnancy associated disease and later health. The complexities are manifold but are rapidly being overcome by technological advances and emerging analytical approaches. Although focussing on recent genome-scale and gene-specific DNA methylation studies in the human placenta, this review also discusses the potential of a future broader exploration of combined environmental, genetic and epigenomic approaches, encompassing higher order epigenetic modifications, for unravelling the molecular mechanisms underlying gene-environment interaction at the fetomaternal interface. PMID- 23102657 TI - Fusobacterium necrophorum mastoiditis in children - emerging pathogen in an old disease. AB - BACKGROUND: Anaerobic bacteria are uncommon etiologic agents of acute mastoiditis in children. However, recent studies suggest an increase in the incidence of Fusobacterium necrophorum mastoid infections in the last two decades. METHODS: A surveillance study performed over 3.5 years in a tertiary pediatric medical center identified 7 children with acute F. necrophorum mastoiditis. Clinical, laboratory, and treatment data were collected by file review. RESULTS: Five of the 7 children presented in the last year of the study. All 7 children were less than 26 months old on admission, and none had a history of otogenic infections. All cases were characterized by significantly elevated levels of inflammatory markers. All were diagnosed as complicated mastoiditis with abscess formation. Four children had an epidural abscess, three children had evidence of osteomyelitis beyond the mastoid bone, and four children had imaging evidence of sinus vein thrombosis. All seven children required cortical mastoidectomy with ventilatory tubes insertion and two children required more than one surgical intervention. During follow-up, two children had recurrent episodes of mastoiditis due to other pathogens. CONCLUSION: Our data support the literature suggesting that the occurrence of F. necrophorum mastoiditis among children is rising. Acute coalescent mastoiditis due to F. necrophorum is associated with a complicated course and warrants particular attention by pediatricians, infectious disease experts, and ear, nose and throat specialists. PMID- 23102656 TI - Effect of repetitive daily ethanol intoxication on adult rat brain: significant changes in phospholipase A2 enzyme levels in association with increased PARP-1 indicate neuroinflammatory pathway activation. AB - Collaborating on studies of subchronic daily intoxication in juvenile and adult rats, we examined whether the repetitive ethanol treatments at these two life stages altered levels of key neuroinflammation-associated proteins-aquaporin-4 (AQP4), certain phospholipase A2 (PLA2) enzymes, PARP-1 and caspase-3-in hippocampus (HC) and entorhinal cortex (EC). Significant changes in the proteins could implicate activation of specific neuroinflammatory signaling pathways in these rats as well as in severely binge-intoxicated adult animals that are reported to incur degeneration of vulnerable neurons in HC and EC. Male Wistar rats, ethanol-intoxicated (3 g/kg i.p.) once daily for 6 days over an 8-day interval beginning at 37 days old and repeated at age 68-75 days, were sacrificed 1 h after the day 75 dose (blood ethanol, 200- 230 mg/dl). Analysis of HC with an immunoblot technique showed that AQP4, Ca(+2)-dependent PLA2 (cPLA2 IVA), phosphorylated (activated) p-cPLA2, cleaved (89 kD) PARP (c-PARP), and caspase-3 levels were significantly elevated over controls, whereas Ca(+2)-independent PLA2 (iPLA2 VIA) was reduced ~70%; however, cleaved caspase-3 was undetectable. In the EC, AQP4 was unchanged, but cPLA2 and p-cPLA2 were significantly increased while iPLA2 levels were diminished (~40%) similar to HC, although just outside statistical significance (p = 0.06). In addition, EC levels of PARP-1 and c-PARP were significantly increased. The ethanol-induced activation of cPLA2 in association with reduced iPLA2 mirrors PLA2 changes in reports of neurotrauma and also of dietary omega-3 fatty acid depletion. Furthermore, the robust PARP-1 elevations accompanied by negligible caspase-3 activation indicate that repetitive ethanol intoxication may be potentiating non-apoptotic neurodegenerative processes such as parthanatos. Overall, the repetitive ethanol treatments appeared to instigate previously unappreciated neuroinflammatory pathways in vivo. The data provide insights into mechanisms of binge ethanol abuse that might suggest new therapeutic approaches to counter neurodegeneration and dementia. PMID- 23102658 TI - Cost-effective production of bacterial cellulose in static cultures using distillery wastewater. AB - Thin stillage (TS), wastewater from rice wine distillery, was used as a cost-free feedstock to replace the costly traditional Hestrin and Schramm (HS) medium for BC production by Gluconacetobacter xylinus. Due to the rich organic acids and amino acids content in TS, BC production was significantly enhanced as 50 (v/v) % of HS medium was replaced with TS. In the 50/50 TS-HS medium, BC concentration of 6.26 g/l could be obtained after 7 days static cultivation which is approximately 50% higher than that could be produced in HS-only medium. The BC produced by TS containing medium had slightly denser reticulated structures and higher crystallinity index values but with lower water holding capacities than that obtained from HS medium. Based on the 50% cost-free TS, the 50/50 TS-HS medium had a BC production feedstock cost about 67% lower than that of traditional HS medium. The employment of cost-free TS to replace a portion of HS medium to achieve a higher BC production not only can reduce the BC production cost but also solve the wastewater disposal problem of winery industry. PMID- 23102659 TI - Outpatient cardiac telemetry detects a high rate of atrial fibrillation in cryptogenic stroke. AB - BACKGROUND: The etiology of cerebral ischemia is undetermined in one-third of patients upon discharge. Occult paroxysmal atrial fibrillation (PAF) is considered a potential etiology. A high rate of PAF detection with 21-day mobile cardiac outpatient telemetry (MCOT) has been reported in two small studies. Optimal monitoring duration and factors predicting PAF have not been adequately defined. METHODS: We performed a retrospective analysis on patients evaluated by MCOT monitoring within 6 months of a cryptogenic stroke or TIA. Multivariate analysis with survival regression methods was performed using baseline characteristics to determine predictive risk factors for detection of PAF. Kaplan Meier estimates were computed for 21-day PAF rates. RESULTS: We analyzed 156 records; PAF occurred in 27 of 156 (17.3%) patients during MCOT monitoring of up to 30 days. The rate of PAF detection significantly increased from 3.9% in the initial 48 h, to 9.2% at 7 days, 15.1% at 14 days, and 19.5% by 21 days (p<0.05). Female gender, premature atrial complex on ECG, increased left atrial diameter, reduced left ventricular ejection fraction and greater stroke severity were independent predictors of PAF detection on multivariate analysis with strongest correlation seen for premature atrial complex on ECG (HR 13.7, p=0.001). CONCLUSION: MCOT frequently detects PAF in patients with cryptogenic stroke and TIA. Length of monitoring is strongly associated with detection of PAF, with an optimal monitoring period of at least 21 days. Of the predictors of PAF detection, the presence of premature atrial complexes on ECG held the strongest correlation with PAF. PMID- 23102660 TI - Oxfordshire Community Stroke Project classification but not NIHSS predicts symptomatic intracerebral hemorrhage following thrombolysis. AB - BACKGROUND: The Oxfordshire Community Stroke Project (OCSP) classification is a simple tool to categorize clinical stroke syndromes. We compared the outcomes of stroke patients after intravenous thrombolysis stratified by the baseline National Institutes of Health Stroke Scale (NIHSS) score or by the OCSP classification. METHODS: We assessed the safety of thrombolysis in consecutive stroke patients who received intravenous thrombolysis within 3h after onset. The patients were grouped by the NIHSS score into mild to moderate stroke (<= 20) and severe stroke (>20), and also by the OCSP classification as having total anterior circulation infarcts (TACI), partial anterior circulation infarcts (PACI), posterior circulation infarcts (POCI), or lacunar infarcts (LACI). Symptomatic intracerebral hemorrhage (SICH) was used as the primary outcome. RESULTS: Of the 145 patients included in the study, 45 had a baseline NIHSS score>20. Their stroke syndromes were as follows: 78 with TACI, 29 with PACI, 16 with POCI, and 22 with LACI. The proportion of SICH was comparable between patients with high or low NIHSS score (11.1% vs. 9.0%, P=0.690). The chance of SICH was highest in patients with TACI (15.4%), followed by LACI (4.5%), PACI (3.4%), and POCI (0%). After adjustment for age, baseline glucose, and use of antiplatelet agents before admission, SICH was significantly increased in patients with TACI relative to those with non-TACI (odds ratio 5.92; 95% confidence interval 1.24-28.33, P=0.026). CONCLUSIONS: The OCSP clinical classification may help clinicians evaluate the risk of SICH following intravenous thrombolysis. PMID- 23102661 TI - Lactococcus lactis subsp. cremoris FC triggers IFN-gamma production from NK and T cells via IL-12 and IL-18. AB - Lactic acid bacteria (LAB) benefit health as probiotics in a strain-dependent way. In this study, we investigated the immunomodulatory effects of Lactococcus lactis subsp. cremoris FC (LcFC) on dendritic cells (DCs), natural killer (NK) cells and T cells. LcFC induced the production of cytokines such as IL-10, IL-12, IL-6 and TNF-alpha from murine bone marrow DCs (BMDCs) via MyD88-dependent pathway. In comparison with the type strain L. lactis subsp. cremoris ATCC 19257, LcFC induced particularly high production of IL-12 while induction of IL-6 was moderate. Consequently, LcFC triggered IFN-gamma production in splenic NK, CD8(+), and CD4(+) cells. Most prominent effect of LcFC on IFN-gamma production was observed in NK cells, followed by CD8(+) cells, which was completely inhibited by combination of neutralizing anti-IL-12 and anti-IL-18 mAbs. Moreover, oral administration of LcFC enhanced the production of IFN-gamma and IL 10 from splenocytes of treated mice. These findings suggest that this LAB strain is an efficient activator of protective cellular immunity via stimulation of myeloid cells including DCs. PMID- 23102662 TI - Cordycepin suppresses TNF-alpha-induced NF-kappaB activation by reducing p65 transcriptional activity, inhibiting IkappaBalpha phosphorylation, and blocking IKKgamma ubiquitination. AB - Cordycepin is reported to participate in multiple pharmacological activities including anti-tumor and anti-inflammation, and is involved in the regulation of NF-kappaB signaling pathway. However, the detailed molecular mechanism of cordycepin in suppression of NF-kappaB signaling pathway remains ambiguous. In this study, we first analyzed the effect of cordycepin on NF-kappaB activity in HEK-293T cells, and found that cordycepin resulted in a dose-dependent reduction in TNF-alpha-induced NF-kappaB activation. Although cordycepin did not block TNF alpha-induced nuclear translocation of p65, high concentration of cordycepin reduced the DNA-binding and transcriptional activities of NF-kappaB. Moreover, cordycepin also inhibited IkappaBalpha phosphorylation so as to suppress the degradation of IkappaBalpha. Further investigation revealed that cordycepin suppressed IKKs-mediated NF-kappaB activation and inhibited the ubiquitination of IKKgamma. In conclusion, cordycepin effectively inhibits NF-kappaB signaling through suppressing the activities of NF-kappaB, IkappaB and IKK. Thus, cordycepin may provide some potential therapeutic application in inflammation associated disorders and cancer. PMID- 23102663 TI - Triptolide attenuates idiopathic pneumonia syndrome in a mouse bone marrow transplantation model by down-regulation of IL-17. AB - Idiopathic pneumonia syndrome (IPS) accounts for significant morbidity and mortality in patients following bone marrow transplantation (BMT). However, no effective therapy has been identified to reliably treat IPS. Previous studies using mouse BMT models suggest that the pathology of IPS in IFN-gamma deficient host involves increased IL-17 levels along with recruitment of donor T cells into lung. Triptolide is a potent immunosuppressive compound isolated from an anti inflammatory Chinese herbal medicine. Triptolide can significantly inhibit generation of IL-17 by T cells and mediate immunosuppressive effect on autoimmune disease. In the present study, we used a specific murine BMT model (IFN-gamma deficient B6 to wildtype B6D2F1) to assess the protective effect of Triptolide on the development of IPS. We observed that IL-17 levels were significantly decreased in the lung after triptolide treatment compared with vehicle group. Furthermore, decreased number of Th17 cells in lung was found to be associated with amelioration of lung histological injury and pulmonary dysfunction. Additionally, neutralization of IL-17 also significantly reduced IPS pathology. Our study implied that triptolide could significantly inhibit donor T cell recruitment into lung, and thus prevent lung dysfunction after BMT usefully and effectively. Our study may shed some light on searching for proper strategies to prevent IL-17 mediated IPS and other Th17 cell-mediated immune pathologies. PMID- 23102664 TI - Anti-inflammatory effects of dehydrogeijerin in LPS-stimulated murine macrophages. AB - In this study, we investigated whether Heracleum (H) moellendorffii Hance-derived dehydrogeijerin and geijerin could be used to suppress lipopolysaccharide (LPS) induced inflammatory responses in murine macrophage cell lines, Raw 264.7 cells. Dehydrogeijerin reduced nitric oxide (NO) and inducible nitric oxide synthase (iNOS) production from LPS-stimulated Raw 264.7 cells, but on the other hand, geijerin did not reduce NO production. Dehydrogeijerin, unlike geijerin, has a double bond at C2'-C3' with an oxo function at C1'. Pre-treatment of Raw 264.7 cells with dehydrogeijerin reduced the production of cyclooxigenase-2 (COX-2) and pro-inflammatory cytokines. These inhibitory effects were associated with decreases in the phosphorylation of mitogen-activated protein (MAP) kinases. Our results indicate that dehydrogeijerin significantly inhibits the inflammatory activity of activated macrophages, suggesting that dehydrogeijerin could be a potential candidate for the treatment of inflammatory disease. PMID- 23102665 TI - Trigonelline ameliorates diabetic hypertensive nephropathy by suppression of oxidative stress in kidney and reduction in renal cell apoptosis and fibrosis in streptozotocin induced neonatal diabetic (nSTZ) rats. AB - Oxidative stress and apoptotic cell death in kidney have been suggested as contributing factors in the development and complication of diabetes especially in diabetic nephropathy (DN). This study investigated the effects of trigonelline (TG) on the renal functional, morphological changes and renal apoptosis in neonatal diabetic rats, a model of non-insulin-dependent diabetes mellitus. Diabetes mellitus was induced in one day old neonatal Wistar rat pups by an intraperitoneal (i.p.) injection of streptozotocin (STZ) (50mg/kg) and monitored for 16 weeks thereafter. The diabetic rats were divided as follows: the nSTZ diabetic group, the TG (50mg/kg) treated diabetic group, and the TG (100mg/kg) treated diabetic group. The age matched nondiabetic group received an injection of citrate buffer (0.1M, pH4.5). At the end kidney samples were taken for light microscopic examinations. The levels of serum creatinine and BUN were significantly low in TG (100mg/kg) treated diabetic rats. Glomerular filtration rate was improved in TG treated rats. The activities of antioxidant enzyme and membrane bound enzyme were decreased and the levels of tumor necrotic factor (TNF alpha) and hydroxyproline content were increased in renal tissues of the diabetic group. TG (100mg/kg/day) treatment for a period of 4 weeks showed significant ameliorative effects on all the biochemical parameters studied. Biochemical findings were supported by histological studies. The degenerative changes in kidney tissue and fibrosis were alleviated in the TG treated groups. These results suggested that TG might have a significant role in alleviating kidney damage in nSTZ-diabetic rats. PMID- 23102666 TI - Characterization of immunologically active drugs in a novel organotypic co culture model of the human gut and whole blood. AB - The human immune system represents a highly complex multicellular network that protects the organism against the environment and pathogens. Within this system, different immune cells communicate with each other, as well as with adjacent organs and tissues, using an impressive network of regulatory signals. This inherent complexity makes it rather difficult to mimic these processes in vitro. Unpredictable drug-induced side effects can be the consequence when moving from preclinical animal models into clinical phase. Therefore, there is a demand for more elaborate in vivo like human cell culture models. In this study, an in vitro co-culture model consisting of Caco-2 human gut epithelial cells and human whole blood representing the immune system is applied to investigate the intestinal absorption of anti-inflammatory drugs and the subsequent modulation of the immunoregulatory signaling processes. By using blood of different donors, the individuality of the immune system is integrated into the overall analysis. The anti-inflammatory drugs prednisolone and ibuprofen were applied on top of the Caco-2 epithelial cells and alterations in the extracellular communication via cytokines and chemokines were visualized using miniaturized multiplexed sandwich immunoassays. Optionally, pretreatment of the Caco-2 epithelial cells with pro inflammatory mediators can be used to modulate the epithelial barrier function similar to the situation observed during inflammatory conditions of the gut. The presented translational test system, consisting of differentiated Caco-2 intestinal epithelial cells and whole blood substantially improves preclinical screening of immunologically active drugs with respect to an approximation of the human "in vivo" conditions. PMID- 23102667 TI - Association between ADIPOQ SNPs with plasma adiponectin and glucose homeostasis and adiposity phenotypes in the IRAS Family Study. AB - CONTEXT: Adiponectin is an adipocytokine associated with a variety of metabolic traits. These associations in human studies, in conjunction with functional studies in model systems, have implicated adiponectin in multiple metabolic processes. OBJECTIVE: We hypothesize that genetic variants associated with plasma adiponectin would also be associated with glucose homeostasis and adiposity phenotypes. DESIGN AND SETTING: The Insulin Resistance Atherosclerosis Family Study was designed to identify the genetic and environmental basis of insulin resistance and adiposity in the Hispanic- (n=1,424) and African-American (n=604) population. MAIN OUTCOME MEASURES: High quality metabolic phenotypes, e.g. insulin sensitivity (S(I)), acute insulin response (AIR), disposition index (DI), fasting glucose, body mass index (BMI), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), and waist circumference, were explored. RESULTS: Based on association analysis of more than 40 genetic polymorphisms in the adiponectin gene (ADIPOQ), we found no consistent association of ADIPOQ variants with plasma adiponectin levels and adiposity phenotypes. However, there were two promoter variants, rs17300539 and rs822387, associated with plasma adiponectin levels (P=0.0079 and 0.021, respectively) in the Hispanic-American cohort that were also associated with S(I) (P=0.0067 and 0.013, respectively). In contrast, there was only a single promoter SNP, rs17300539, associated with plasma adiponectin levels (P=0.0018) and fasting glucose (P=0.042) in the African American cohort. Strikingly, high impact coding variants did not show evidence of association. CONCLUSIONS: The lack of consistent patterns of association between variants, adiponectin levels, glucose homeostasis, and adiposity phenotypes suggests a reassessment of the influence of adiponectin in these pathways. PMID- 23102668 TI - Speech characteristics of 8-year-old children: findings from a prospective population study. AB - Speech disorder that continues into middle childhood is rarely studied compared with speech disorder in the early years. Speech production in single words, connected speech and nonword repetition was assessed for 7390 eight-year-old children within the Avon Longitudinal Study of Parents and Children (ALSPAC). The majority (n=6399) had typical speech and 50 of these children served as controls. The remainder were categorised as using common clinical distortions only (CCD, n=582) or speech difficulties (SDiff, n=409). The samples from the CCD children were not analysed further. Speech samples from the SDiff and the control children were transcribed and analysed in terms of percentage consonants correct, error type and syllable structure. Findings were compared with those from children in the Shriberg et al. (1997) lifespan database (n=25). The 8-year-old children from ALSPAC in the SDiff and control groups achieved similar speech accuracy scores to the 8-year-old children in the lifespan database. The SDiff group had consistently lower scores than the ALSPAC control group, with the following measures most clearly differentiating the groups: single word task (percentage of substitutions and distortions), connected speech task (percentage of vowels correct (PVC), percentage of omission of singletons and entire clusters, and stress pattern matches), nonword repetition task (PVC, percentage of entire clusters omitted, percentage of distortions, and percentage of stress pattern matches). Connected speech and nonword samples provide useful supplementary data for identifying older children with atypical speech. LEARNING OUTCOMES: The reader will recognize the methods used to identify speech characteristics in a large scale population study. They will describe how measures of speech accuracy in connected speech compare with the Shriberg et al. (1997) lifespan database. The reader will also recall information on how typically and atypically developing children differ on a range of measures across different types of speech sample. PMID- 23102670 TI - Optical coherence tomography imaging in asymptomatic patients with carotid artery stenosis. AB - Assessment and treatment plan for asymptomatic patients with carotid stenosis are based on angiography at the present time. However, angiography or other imaging modalities are limited with their resolution to detect high-risk plaque features. Intravascular optical coherence tomography (IVOCT) recently emerged as a novel imaging modality with a unique resolution to identify vulnerable plaque characteristics. We report use of IVOCT in two separate asymptomatic patients with carotid stenosis with two different plaque types. PMID- 23102671 TI - Outcomes and revision rate after bone-patellar tendon-bone allograft versus autograft anterior cruciate ligament reconstruction in patients aged 18 years or younger with closed physes. AB - PURPOSE: The purpose of this study was to compare revision rates and outcomes after anterior cruciate ligament (ACL) reconstruction with bone-patellar tendon bone (BPTB) autografts versus BPTB allografts in patients aged 18 years or younger with closed physes. METHODS: Institutional review board approval was obtained for this study. This study included 90 consecutive patients aged 18 years or younger with closed physes who underwent primary ACL reconstruction by a single surgeon between 1998 and 2009, with either BPTB autograft (n = 70) or BPTB allograft (n = 20). Patients who had concomitant ligament injuries were excluded. Outcome measures included the Lysholm score, Tegner activity scale, and patient satisfaction (0, very unsatisfied; 10, very satisfied). Failures were defined as cases requiring ACL revision surgery. RESULTS: Of the 90 patients, 79 (88%) were contacted (20 of 20 with allografts and 59 of 70 with autografts). Of these 79 patients, 9 (11%) required revision ACL reconstruction. In the autograft group, 3% (2 of 59) required revision ACL reconstruction at a mean of 15.4 months (range, 13.0 to 17.7 months) after the index procedure. In the allograft group, 35% (7 of 20) required revision ACL reconstruction at a mean of 9.1 months (range, 5.3 to 12.0 months) after the index procedure. The allograft group was 15 (95% confidence interval [CI], 2 to 123) times more likely to require revision reconstruction than the autograft group (P = .001). The mean Lysholm score at follow-up was 85 (95% CI, 80.4 to 90.3) for the autograft group and 91 (95% CI, 88.1 to 97.3) for the allograft group (P = .46). The median Tegner activity scale was 7.0 (95% CI, 6.9 to 8.0) for autograft group and 6.5 (95% CI, 4.9 to 8.4) for the allograft group (P = .27). Median patient satisfaction score was 10 of 10 in both cohorts. No failures were seen in either group at 2 years postoperatively. Five of seven allograft failures occurred because of a premature return to sports. CONCLUSIONS: No significant differences in function, activity, or satisfaction were found between allograft and autograft reconstructions in this patient population. The allograft group had a failure rate 15 times greater than that in the autograft group, with all failures occurring within the first year after reconstruction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 23102672 TI - Influence of ankle plantarflexor fatigue on postural sway, lower limb articular angles, and postural strategies during unipedal quiet standing. AB - The purpose of this study was to investigate the changes in postural control and in posture induced by ankle plantarflexor fatigue during a unipedal stance task. We also studied the postural strategies in the antero-posterior and medio-lateral planes used by participants to maintain balance. Thirteen young adults were asked to stand barefoot on their preferred leg as still as possible for 30s with vision or without vision. Participants performed postural trials before and after a fatigue protocol that consisted of standing on toes until exhaustion. Centre of pressure (COP) displacements were measured with a force platform and electrogoniometers were placed at the ankle, knee and hip joints of the support leg to monitor articular angles. Relationships between changes in articular angles and displacements of the COP in the antero-posterior and medio-lateral planes were tested using cross-correlations. Sway area and velocity increased with fatigue, but only without vision. A posterior shift of the mean COP position was also observed after fatigue. Ankle and hip joints were more flexed after fatigue. Moderate to good relationships between COP displacements and ankle angles were observed before and after fatigue in both planes whereas these relationships were low for hip and knee joints. Ankle plantarflexors fatigue induced impairment in postural control and changes in posture. To compensate for the effects of fatigue, participants increased the flexion of the ankle and/or the hip joints but conserved the ankle strategy as the dominant postural strategy in both planes. PMID- 23102673 TI - Plantar pressure trigger for reliable nerve stimulus application during dynamic H reflex measurements. AB - In dynamic H-reflex measurements, the standardisation of the nerve stimulation to the gait cycle is crucial to avoid misinterpretation due to altered pre-synaptic inhibition. In this pilot study, a plantar pressure sole was used to trigger the stimulation of the tibialis nerve with respect to the gait cycle. Consequently, the intersession reliability of the soleus muscle H-reflex during treadmill walking was investigated. Seven young participants performed walking trials on a treadmill at 5 km/h. The stimulating electrode was placed on the tibial nerve in the popliteal fossa. An EMG was recorded from the soleus muscle. To synchronize the stimulus to the gait cycle, initial heel strike was detected with a plantar pressure sole. Maximum H-reflex amplitude and M-wave amplitude were obtained and the Hmax/Mmax ratio was calculated. Data reveals excellent reliability, ICC=0.89. Test-retest variability was 13.0% (+/-11.8). The Bland-Altman analysis showed a systematic error of 2.4%. The plantar pressure sole was capable of triggering the stimulation of the tibialis nerve in a reliable way and offers a simple technique for the evaluation of reflex activity during walking. PMID- 23102675 TI - Midterm results from an international multicentre randomised controlled trial comparing bipolar with monopolar transurethral resection of the prostate. AB - BACKGROUND: Pooled data from randomised controlled trials (RCTs) with short-term follow-up have shown a safety advantage for bipolar transurethral resection of the prostate (B-TURP) compared with monopolar TURP (M-TURP). However, RCTs with follow-up >12 mo are scarce. OBJECTIVE: To compare the midterm safety/efficacy of B-TURP versus M-TURP. DESIGN, SETTING, AND PARTICIPANTS: From July 2006 to June 2009, TURP candidates with benign prostatic obstruction were consecutively recruited in four centres, randomised 1:1 into the M-TURP or the B-TURP arm and regularly followed up to 36 mo postoperatively. A total of 295 patients were enrolled. INTERVENTION: M-TURP or B-TURP using the AUTOCON II 400 electrosurgical unit. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Safety was estimated by complication rates with a special emphasis on urethral strictures (US) and bladder neck contractures (BNCs) recorded during the short-term (up to 12 mo) and midterm (up to 36 mo) follow-up. Efficacy quantified by changes in maximum urine flow rate, postvoid residual urine volume, and International Prostate Symptom Score was compared with baseline, and reintervention rates in each arm were also evaluated. RESULTS AND LIMITATIONS: A total of 279 patients received treatment after allocation. Mean follow-up was 28.8 mo. A total of 186 of 279 patients (66.7%) completed the 36-mo follow-up. Posttreatment withdrawal rates did not differ significantly between arms. Safety was assessed in 230 patients (82.4%) at a mean follow-up of 33.4 mo. Ten US cases were seen in each arm (M-TURP vs B TURP: 9.3% vs 8.2%; p=0.959); two versus eight BNC cases (M-TURP vs B-TURP: 1.9% vs 6.6%; p=0.108) were collectively detected at the midterm follow-up. Resection type was not a significant predictor of the risk of US/BNC formation. Efficacy was similar between arms and durable. A total of 10 of 230 patients (4.3%) experienced failure to cure and needed reintervention without significant differences between arms. High overall reintervention rates, withdrawal rates, and sample size determination not based on US/BNC rates represent potential limitations. CONCLUSIONS: The midterm safety and efficacy of B-TURP and M-TURP are comparable. TRIAL REGISTRATION: Netherlands Trial Register, NTR703 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=703). PMID- 23102676 TI - Peripancreatic schwannoma. AB - BACKGROUND: The extrapancreatic nerve plexus may give rise to schwannomas. The aim of this study was to define the clinicopathologic features of peripancreatic schwannoma and to allow improved diagnosis and treatment for this condition. METHODS: A retrospective analysis was performed on 17 patients with pathologically proven peripancreatic schwannoma (defined as schwannoma in anatomic proximity to the pancreas) treated at our hospital between 1995 and 2011. RESULTS: The patient group included 9 men and 8 women between the ages of 26 and 67 years. The tumor size ranged from 2.5 to 13 cm. Tumor locations were the pancreatic head plexus in 5 patients, the superior mesenteric plexus in 3, the pancreatic head and superior mesenteric plexus in 2, the celiac plexus in 4, and the splenic plexus in 3. The main symptoms were vague abdominal pain (n = 5; 29.4%) and abdominal mass (n = 2; 11.8%). A correct preoperative diagnosis was made in 12 patients by either computed tomography (CT) or magnetic resonance imaging (MRI). Sixteen patients (94.1%) underwent total resection and 1 patient (5.9%) underwent subtotal resection. Three patients underwent concomitant pancreatectomy. No recurrences were noted in the 16 patients who underwent total tumor resection. CONCLUSION: Most peripancreatic schwannomas are benign. Peripancreatic schwannoma may often be accurately diagnosed before surgery by its typical location and CT or MRI findings. Total resection is important for treatment, and no recurrences are seen when resection is complete. Prognosis after total resection is extremely good. PMID- 23102669 TI - MicroRNA and cancer. AB - With the advent of next generation sequencing techniques a previously unknown world of non-coding RNA molecules have been discovered. Non-coding RNA transcripts likely outnumber the group of protein coding sequences and hold promise of many new discoveries and mechanistic explanations for essential biological phenomena and pathologies. The best characterized non-coding RNA family consists in humans of about 1400 microRNAs for which abundant evidence have demonstrated fundamental importance in normal development, differentiation, growth control and in human diseases such as cancer. In this review, we summarize the current knowledge and concepts concerning the involvement of microRNAs in cancer, which have emerged from the study of cell culture and animal model systems, including the regulation of key cancer-related pathways, such as cell cycle control and the DNA damage response. Importantly, microRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents. PMID- 23102677 TI - Calculating an individual maxPTH to aid diagnosis of normocalemic primary hyperparathyroidism. AB - BACKGROUND: We aimed to validate a nomogram for diagnosing primary hyperparathyroidism (PHP), particularly when normocalcemic PHP and vitamin D (VitD25) deficiency coexist. METHODS: The nomogram calculates maximal upper limit of normal PTH unique for each person by maxPTH = 120 - [6*calcium] - [1/2*VitD25] + [1/4*age]. PHP is suspected when serum PTH exceeds maxPTH. Normocalcemic PHP (NCPHP) was defined as always normal serum calcium (8.5-10.5 mg/dL) with PTH >60 pg/mL preoperatively and VitD25 deficiency as <31 ng/mL. RESULTS: A total of 477 patients had operatively and histologically proven PHP. Overall and including those with classical presentation (high serum levels of calcium and PTH), the nomogram predicted PHP in 97% patients. A total of 66 had NCPHP: 47 with low VitD25 levels (20 +/- 0.4 ng/mL) made initial PHP diagnosis challenging; 19 had normal VitD25 status. Although the level of serum calcium concentrations were equivalent in these 2 groups (10.1 +/- 0.4 mg/dL), PTH was greater in patients with concurrent VitD25 deficiency (129 vs 97 pg/mL, P = .04). However, when used to calculate maxPTH, the nomogram predicted PHP correctly in all 66 NCPHP patients (100%). CONCLUSION: The maxPTH nomogram functions as expected to classify patients with PHP and may aid in the diagnosis of NCPHP regardless of vitamin D status and repletion, reassuring primary providers and surgeons alike to embark on appropriate and timely PHP management. PMID- 23102678 TI - Neurokinin A levels predict survival in patients with stage IV well differentiated small bowel neuroendocrine neoplasms. AB - BACKGROUND: Recent European investigations have shown that persistently elevated (>50 pg/mL) plasma neurokinin A levels are associated with poor short-term survival in patients with midgut neuroendocrine neoplasms. We hypothesized that American patients with persistently elevated plasma neurokinin A levels (>50 pg/mL) will also have a poor short-term survival. METHODS: Serial plasma neurokinin A levels were collected from the charts of 180 patients with metastatic midgut neuroendocrine neoplasms. Patients were grouped according to their plasma neurokinin A values, and survival rates were calculated. Group 1 had plasma neurokinin A levels <50 pg/mL. Group 2 at one point had plasma neurokinin A levels >50 pg/mL, but are currently <50 pg/mL. Group 3 had plasma neurokinin A values consistently >50 pg/mL. RESULTS: Group 1 patients (n = 143) have not reached their median survival and have a 24-month survival of 93%. Thirteen of 14 (93%) group 2 patients are currently alive. Group 3 patients (n = 23) had a median survival of 20 months and a 24-month survival of 48%. CONCLUSION: Patients with midgut neuroendocrine neoplasms who have serial plasma neurokinin A levels <50 pg/mL have an excellent short-term prognosis, while patients with plasma neurokinin A levels >50 pg/mL have a poor short-term prognosis. PMID- 23102679 TI - Small, nonfunctioning, asymptomatic pancreatic neuroendocrine tumors (PNETs): role for nonoperative management. AB - BACKGROUND: Controversy exists regarding the optimal management of incidentally discovered, small pancreatic neuroendocrine tumors (PNETs). Our aim was to review the outcomes of patients who underwent nonoperative and operative management. METHODS: We retrospectively reviewed patients with nonfunctioning PNETs at our institution from January 1, 2000 to June 30, 2011. Patients were included if the tumor was sporadic and <4 cm without radiographic evidence of local invasion or metastases. RESULTS: Nonoperative patients (n = 77, median age, 67 years; range, 31-94) had a median tumor size of 1.0 cm (range, 0.3-3.2). Mean follow-up (F/U) was 45 months (max. 153 months). Median tumor size did not change throughout F/U; there was no disease progression or disease specific mortality. In the operative group (n = 56, median age, 60 years; range, 27-82), median neoplasm size was 1.8 cm (range, 0.5-3.6). Mean F/U was 52 months (max. 138 months). A total of 46% of the operative patients had some type of complication, more than half due to a clinically significant pancreatic leak. No recurrence or disease specific mortality was seen in the operative group, including 5 patients with positive lymph nodes. CONCLUSION: Small nonfunctioning PNETs usually exhibit minimal or no growth over many years. Nonoperative management may be advocated when serial imaging demonstrates minimal or no growth without suspicious features. PMID- 23102680 TI - Pasireotide (SOM230) is effective for the treatment of pancreatic neuroendocrine tumors (PNETs) in a multiple endocrine neoplasia type 1 (MEN1) conditional knockout mouse model. AB - BACKGROUND: Pasireotide (SOM230), a long-acting somatostatin analogue (LAR), has improved agonist activity at somatostatin receptors. We tested the effect of SOM230 on insulin secretion, serum glucose concentrations, tumor growth, and survival using an MEN1 transgenic mouse model. METHODS: Eight 12-month-old conditional Men1 knockout mice with insulinoma were assessed. The treatment (n = 4) and control groups (n = 4) received monthly subcutaneous injections of SOM230 or PBS. Serum insulin and glucose levels were determined by enzyme-linked immunosorbent assay and enzymatic colorimetric assay, respectively. Tumor activity, growth, and apoptosis were determined by microPET/CT scan and histologic analysis. RESULTS: On day 7, there was a decrease in serum insulin levels from 1.06 +/- 0.28 MUg/L to 0.37 +/- 0.17 MUg/L (P = .0128) and a significant increase in serum glucose from 4.2 +/- 0.45 mmol/L to 7.12 +/- 1.06 mmol/L (P = .0075) in the treatment group but no change in the control group. Tumor size was less in the treatment group (2,098 +/- 388 MUm(2)) compared with the control group (7,067 +/- 955 MUm(2); P = .0024). Furthermore, apoptosis was increased in the treatment group (6.9 +/- 1.23%) compared with the control group (0.29 +/- 0.103%; P = .002). CONCLUSION: SOM230 demonstrates antisecretory, antiproliferative, and proapoptotic activity in our MEN1 model of insulinoma. Further studies of the effects of SOM230 in PNET patients with MEN1 mutations are warranted. PMID- 23102682 TI - Are surgeons ethically obligated to treat Medicare patients despite substantial reductions in reimbursement? Introduction. PMID- 23102683 TI - Feasibility of creating a novel animal heart model to test transcatheter techniques for a cavocaval connection that mimics a Fontan completion. AB - OBJECTIVE: The objective of this study was to create a novel animal model to foster the future development of interventional techniques for a cavocaval connection that mimics a Fontan completion. METHODS: Ten sheep were studied. All had the superior vena cava-right atrium junction closed using a polytetrafluoroethylene membrane. A valveless Gore-Tex conduit connecting the terminal portion of the superior vena cava to the right atrium was used to bypass the polytetrafluoroethylene occlusion and to allow normal venous drainage through the right atrium. Radio-opaque nitinol rings were placed around the inferior vena cava near its entry in the right atrium to allow better fluoroscopic visualization and to enhance stent stability during transcatheter cavocaval connection. RESULTS: The first 3 animals died during the learning curve as a result of technical issues. The subsequent 7 surviving sheep showed good flow dynamics on cardiac catheterization. Transcatheter cavocaval connection was performed successfully performed in 6 sheep at 0 to 9 months after the initial surgery. Sacrifice was done electively in all animals at 1 to 9 months per protocol. One animal was euthanized early because of an untreatable infection. One sheep was observed as a control without a transcatheter cavocaval connection and was sacrificed at 12 months. CONCLUSIONS: A novel, chronic ovine model to foster development of transcatheter techniques for cavocaval connection to mimic a Fontan completion was created. The successful model is easily reproducible after a short learning curve and shows good survival. PMID- 23102681 TI - Are unreliable release mechanisms conserved from NMJ to CNS? AB - The frog neuromuscular junction (NMJ) is a strong and reliable synapse because, during activation, sufficient neurotransmitter is released to trigger a postsynaptic action potential (AP). Recent evidence supports the hypothesis that this reliability emerges from the assembly of thousands of unreliable single vesicle release sites. The mechanisms that govern this unreliability include a paucity of voltage-gated calcium channels, a low probability of calcium channel opening during an AP, and the rare triggering of synaptic vesicle fusion even when a calcium channel does open and allows calcium flux. Here, we discuss the evidence that these unreliable single vesicle release sites may be the fundamental building blocks of many types of synapses in both the peripheral and central nervous system (PNS and CNS, respectively). PMID- 23102684 TI - Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm. AB - OBJECTIVES: Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction. METHODS: All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence. RESULTS: Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13 families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm. CONCLUSIONS: These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management. PMID- 23102685 TI - Risk factors for surgical site infection in pediatric cardiac surgery patients undergoing delayed sternal closure. AB - OBJECTIVES: To determine the incidence of surgical site infections (SSIs) in congenital heart surgery (CHS) patients undergoing delayed sternal closure (DSC) and to evaluate risk factors for SSI. METHODS: A nested case-control study was performed within a cohort of CHS patients undergoing DSC at our institution between 2005 and 2009. Cases met 2008 Centers for Disease Control and Prevention criteria for SSI; control subjects were matched based on year of surgery. Uni- and multivariate logistic regressions were performed to identify SSI risk factors. RESULTS: Of 375 patients who underwent DSC, 43 (11%) developed an SSI. The analysis included 172 patients (43 cases, 129 controls); 118 (69%) were neonates, 80 (47%) had undergone Norwood procedure, and 150 (87%) had DSC initiated in the operating room. Case and control subjects were similar based on pre- and intraoperative characteristics. Duration of mechanical ventilation, intensive care unit and hospital length of stay, and mortality were significantly greater in patients with an SSI. Multiple periods of DSC, longer duration of DSC, greater dependence on parenteral nutrition, and extracorporeal membrane oxygenation were significantly associated with SSI in univariate analyses. Multivariate analysis demonstrated that multiple periods of DSC (adjusted odds ratio, 5.9; 95% confidence interval, 1.7-20.1) and extracorporeal membrane oxygenation (adjusted odds ratio, 2.9; 95% confidence interval, 1.1-7.6) remained independent risk factors for SSI. CONCLUSIONS: For CHS patients undergoing DSC, extracorporeal membrane oxygenation and multiple periods of DSC are independent risk factors for SSI. New strategies for prevention and prophylaxis of SSI may be indicated for these high-risk patients who have worse outcomes and greater health care resource utilization. PMID- 23102687 TI - Time in the stair-climbing test as a predictor of thoracotomy postoperative complications. AB - OBJECTIVES: The stair-climbing test as measured in meters or number of steps has been proposed to predict the risk of postoperative complications. The study objective was to determine whether the stair-climbing time can predict the risk of postoperative complications. METHODS: Patients aged more than 18 years with a recommendation of thoracotomy for lung resection were included in the study. Spirometry was performed according to the criteria by the American Thoracic Society. The stair-climbing test was performed on shaded stairs with a total of 12.16 m in height, and the stair-climbing time in seconds elapsed during the climb of the total height was measured. The accuracy test was applied to obtain stair-climbing time predictive values, and the receiver operating characteristic curve was calculated. Variables were tested for association with postoperative cardiopulmonary complications using the Student t test for independent populations, the Mann-Whitney test, and the chi-square or Fisher exact test. Logistic regression analysis was performed. RESULTS: Ninety-eight patients were evaluated. Of these, 27 showed postoperative complications. Differences were found between the groups for age and attributes obtained from the stair-climbing test. The cutoff point for stair-climbing time obtained from the receiver operating characteristic curve was 37.5 seconds. No differences were found between the groups for forced expiratory volume in 1 second. In the logistic regression, stair-climbing time was the only variable associated with postoperative complications, suggesting that the risk of postoperative complications increases with increased stair-climbing time. CONCLUSIONS: The only variable showing association with complications, according to multivariate analysis, was stair-climbing time. PMID- 23102686 TI - Erythropoietin neuroprotection in neonatal cardiac surgery: a phase I/II safety and efficacy trial. AB - OBJECTIVES: Neonates undergoing complex congenital heart surgery have a significant incidence of neurologic problems. Erythropoietin has antiapoptotic, antiexcitatory, and anti-inflammatory properties to prevent neuronal cell death in animal models, and improves neurodevelopmental outcomes in full-term neonates with hypoxic ischemic encephalopathy. We designed a prospective phase I/II trial of erythropoietin neuroprotection in neonatal cardiac surgery to assess safety and indicate efficacy. METHODS: Neonates undergoing surgery for D-transposition of the great vessels, hypoplastic left heart syndrome, or aortic arch reconstruction were randomized to 3 perioperative doses of erythropoietin or placebo. Neurodevelopmental testing using the Bayley Scales of Infant and Toddler Development III was performed at age 12 months. RESULTS: Fifty-nine patients received the study drug. Safety profile, including magnetic resonance imaging brain injury, clinical events, and death, was not different between groups. Three patients in each group died. Forty-two patients (22 in the erythropoietin group and 20 in the placebo group; 79% of survivors) returned for 12-month follow-up. In the group receiving erythropoietin, mean Cognitive Scale scores were 101.1 +/- 13.6, Language Scale scores were 88.5 +/- 12.8, and Motor Scale scores were 89.9 +/- 12.3. In the group receiving placebo, Cognitive Scale scores were 106.3 +/- 10.8 (P = .19), Language Scores were 92.4 +/- 12.4 (P = .33), and Motor Scale scores were 92.6 +/- 14.1 (P = .51). CONCLUSIONS: Safety profile for erythropoietin administration was not different than placebo. Neurodevelopmental outcomes were not different between groups; however, this pilot study was not powered to definitively address this outcome. Lessons learned suggest optimized study design features for a larger prospective trial to definitively address the utility of erythropoietin for neuroprotection in this population. PMID- 23102688 TI - Hybrid approach to HeartMate II left ventricular assist device exchange. PMID- 23102689 TI - Reduced absorption of long-chain fatty acids during methotrexate-induced gastrointestinal mucositis in the rat. AB - BACKGROUND & AIMS: Patients with chemotherapy-induced gastrointestinal mucositis suffer from weight loss and possibly malabsorption. Since long-chain fatty acids serve important functions in the body, we aimed to determine the intestinal capacity of fat absorption in rats with and without methotrexate-induced mucositis. METHODS: Four days after intravenous injection with methotrexate (60 mg/kg) or saline, rats received saturated ([U-(13)C]palmitic acid) and unsaturated ([U-(13)C]linoleic acid) fatty acids dissolved in oil, either as a single bolus by oral gavage or by continuous intraduodenal infusion. We determined plasma and liver label concentrations at specific time points. RESULTS: We confirmed methotrexate-induced mucositis by villus atrophy using microscopy. Methotrexate treatment severely reduced the appearance of [U (13)C]palmitic- and [U-(13)C]linoleic acid in plasma and liver, compared to controls, either when administered as a bolus or continuously (all at least -63%, P < 0.05). Liver [U-(13)C]palmitic acid appearance was higher than [U (13)C]linoleic acid appearance, either when administered as a bolus (2.8-fold, P < 0.01) or continuously (5.7-fold, P < 0.01). CONCLUSIONS: The intestinal capacity to absorb long-chain fatty acids is severely reduced in rats with methotrexate-induced mucositis. Continuous administration does not overcome this impairment. The liver takes up and/or retains mainly saturated fatty acids during mucositis. PMID- 23102690 TI - Oxytocin mediates rodent social memory within the lateral septum and the medial amygdala depending on the relevance of the social stimulus: male juvenile versus female adult conspecifics. AB - Brain oxytocin (OXT) plays an important role in short-term social memory in laboratory rodents. Here we monitored local release of OXT and its functional involvement in the maintenance and retrieval of social memory during the social discrimination test. We further assessed, if the local effects of OXT within the medial amygdala (MeA) and lateral septum (LS) on social discrimination abilities were dependent on the biological relevance of the social stimulus, thus comparing male juvenile versus adult female conspecifics. OXT release was increased in the LS of male rats during the retrieval, but not during the acquisition or maintenance, of social memory for male juvenile stimuli. Blockade of OXT activity by intracerebroventricular (ICV) administration of a specific OXT receptor antagonist (OXTR-A, rats: 0.75 MUg/5 MUl, mice: 2 MUg/2 MUl) immediately after acquisition of social memory impaired the maintenance of social memory, and consequently discrimination abilities during retrieval of social memory. In contrast, ICV OXTR-A was without effect when administered 20 min prior to retrieval of social memory in both species. Non-social memory measured in the object discrimination test was not affected by ICV OXTR-A in male mice, indicating that brain OXT is mainly required for memory formation in a social context. The biological relevance of the social stimulus seems to importantly determine social memory abilities, as male rats recognized a previously encountered female adult stimulus for at least 2h (versus 60 min for male juveniles), with a region-dependent contribution of endogenous OXT; while bilateral administration of OXTR-A into the MeA (0.1 MUg/1 MUl) impaired social memory for adult females only, administration of OXTR-A into the LS via retrodialysis (10 MUg/ml, 1.0 MUl/min) impaired social memory for both male juveniles and female adults. Overall, these results indicate that brain OXT is a critical mediator of social memory in male rodents and that, depending on the biological relevance of the social stimulus, distinct brain regions are recruited to mediate its effects. PMID- 23102691 TI - Effects of cognitive remediation on neurocognitive functions and psychiatric symptoms in schizophrenia inpatients. AB - OBJECTIVE: Many individuals diagnosed with schizophrenia have significant neurocognitive deficits, especially in the areas of attention, memory, and executive function. These deficits may exacerbate patients' psychiatric symptoms. Cognitive remediation has shown efficacy in improving neurocognitive functioning and may lead to amelioration of psychiatric symptoms in persons with schizophrenia. METHOD: Forty-two schizophrenic inpatients were randomly assigned to either a cognitive remediation group (n=21) or a control group (n=21) and were assessed using a neuropsychological battery and symptom scales for depression, anxiety, and positive and negative symptoms of schizophrenia at baseline and after two months of participation in a cognitive remediation program. RESULTS: The intervention group showed significant improvements in neuropsychological functioning, depression and negative symptoms of schizophrenia after the intervention compared to the control group. CONCLUSION: Results of the study provide support for cognitive remediation as an efficacious intervention to improve neurocognitive functioning and decrease psychiatric symptoms of schizophrenia. PMID- 23102692 TI - Executive function in early- and adult onset schizophrenia. AB - BACKGROUND: The goal of this study was to investigate differences in executive functioning between patients with early-onset and adult-onset schizophrenia spectrum psychoses at the time of first treatment. METHODS: Neuropsychological tests covering executive functioning domains were performed for 20 adolescents with early-onset schizophrenia (EOS) close to first treatment and 90 first episode patients with adult onset schizophrenia (AOS) in addition to 66 adolescent- and 127 adult age and gender matched healthy controls. RESULTS: Both EOS and AOS patients had significantly poorer executive performance than their age- and gender matched healthy counterparts. Both healthy adolescent controls and EOS patients had poorer executive performance than their adult counterparts. However, there were no differences in executive functioning between EOS and AOS patients after controlling for the levels of their age matched healthy control groups. Substituting EOS/AOS status with other age-at-onset thresholds had no effect. CONCLUSIONS: We find the same relative levels of executive dysfunction in EOS- and AOS groups at the time of first treatment. This does not necessarily contradict previous findings of more severe dysfunction in EOS patients over time, but indicates an interaction between the disorder and the maturational processes that only can be investigated through longitudinal studies. PMID- 23102693 TI - Meta-analysis and brain imaging data support the involvement of VRK2 (rs2312147) in schizophrenia susceptibility. AB - Recent genome-wide association studies have reported a set of schizophrenia susceptibility genes, but many of them await further replications in additional samples. Here we analyzed 5 genome-wide supported variants in a Han Chinese sample, and the variant rs2312147 at VRK2 showed significant association, which was confirmed in the meta-analysis combining multiple Asian and European samples (P=3.17*10(-4), N=7498). Rs2312147 is also associated with brain structure in healthy subjects, including the total brain volume and the white matter volume. Gene expression analyses indicated an up-regulation of VRK2 in schizophrenia patients. Our data provide further evidence for the contribution of VRK2 to schizophrenia. PMID- 23102694 TI - Anaortic, total-arterial, off-pump coronary artery bypass surgery: why bother? AB - Coronary artery bypass grafting (CABG) remains the standard of care for multi vessel coronary disease. However, the increased rate of peri-operative stroke reported after surgery compared to percutaneous coronary intervention (PCI) remains of concern. Anaortic, total-arterial, off-pump coronary artery bypass (OPCAB) grafting is a technique that offers the main advantages of surgical revascularisation with a rate of stroke that is equivalent to that of PCI. Some recent trials comparing conventional on-pump CABG with OPCAB have questioned the efficacy of the off-pump technique - these are most often performed with manipulation of the ascending aorta. We review the potential benefits of the anaortic, total-arterial OPCAB technique to explain why it is being employed by an increasing number of surgeons. PMID- 23102696 TI - Distributions and sea-to-air fluxes of volatile halocarbons in the East China Sea in early winter. AB - The concentrations of six volatile halogenated organic compounds (VHOC) chloroform (CHCl(3)), trichloroethylene (C(2)HCl(3)), tetrachloroethylene (C(2)Cl(4)), carbon tetrachloride (CCl(4)), methylchloroform (CH(3)CCl(3)), and bromoform (CHBr(3)) in the East China Sea (ECS) in November and December 2010 were measured by a purge and trap system coupled to a gas chromatograph with an electron capture detection (ECD). Mean (range) concentrations of CHCl(3), C(2)HCl(3), C(2)Cl(4), CH(3)CCl(3), CCl(4) and CHBr(3) in the surface water were 16.90 (0.40-62.92), 16.27 (2.78-83.33), 2.40 (0.39-9.33), 32.29 (19.72-57.68), 1.70 (0.39-8.73) and 17.11 (4.33-34.46) pM, respectively. With the exception of C(2)HCl(3), the concentrations of other five kinds of VHOC generally exhibited a decreasing trend with distance from the coast, with the low values found in the open sea. The anthropogenic sources contributed to the elevated levels of CCl(4) and CH(3)CCl(3), whereas a combination of the anthropogenic and biogenic sources might be responsible for the elevated levels of CHCl(3), C(2)HCl(3), C(2)Cl(4) and CHBr(3). In the depth profiles, vertical distributions of the six VHOC in the water column were complicated, with the maxima occurring at 0-100 m depths. The mean sea-to-air fluxes of CHCl(3), C(2)HCl(3), C(2)Cl(4) and CHBr(3) were estimated to be 21.08, 29.94, 2.05 and 35.50 nmol m(-2) d(-1), respectively, indicating that the ECS was a source for the four VHOC in the atmosphere. PMID- 23102695 TI - Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship. AB - Rapid innovations in radiation therapy techniques have resulted in an urgent need for risk projection models for second cancer risks from high-dose radiation exposure, because direct observation of the late effects of newer treatments will require patient follow-up for a decade or more. However, the patterns of cancer risk after fractionated high-dose radiation are much less well understood than those after lower-dose exposures (0.1-5 Gy). In particular, there is uncertainty about the shape of the dose-response curve at high doses and about the magnitude of the second cancer risk per unit dose. We reviewed the available evidence from epidemiologic studies of second solid cancers in organs that received high-dose exposure (>5 Gy) from radiation therapy where dose-response curves were estimated from individual organ-specific doses. We included 28 eligible studies with 3434 second cancer patients across 11 second solid cancers. Overall, there was little evidence that the dose-response curve was nonlinear in the direction of a downturn in risk, even at organ doses of >=60 Gy. Thyroid cancer was the only exception, with evidence of a downturn after 20 Gy. Generally the excess relative risk per Gray, taking account of age and sex, was 5 to 10 times lower than the risk from acute exposures of <2 Gy among the Japanese atomic bomb survivors. However, the magnitude of the reduction in risk varied according to the second cancer. The results of our review provide insights into radiation carcinogenesis from fractionated high-dose exposures and are generally consistent with current theoretical models. The results can be used to refine the development of second solid cancer risk projection models for novel radiation therapy techniques. PMID- 23102697 TI - Anaerobic abiotic transformations of cis-1,2-dichloroethene in fractured sandstone. AB - A fractured sandstone aquifer at an industrial site is contaminated with trichloroethene to depths greater than 244 m. Field data indicate that trichloroethene is undergoing reduction to cis-1,2-dichloroethene (cDCE); vinyl chloride and ethene are present at much lower concentrations. Transformation of cDCE by pathways other than reductive dechlorination (abiotic and/or biotic) is of interest. Pyrite, which has been linked to abiotic transformation of chlorinated ethenes, is present at varying levels in the sandstone. To evaluate the possible role of pyrite in transforming cDCE, microcosms were prepared with groundwater, ~40 mg L(-1) cDCE+[(14)C]cDCE, and crushed solids (pure pyrite, pyrite-rich sandstone, or typical sandstone). During 120 d of incubation, the highest level of cDCE transformation occurred with typical sandstone (11-14% (14)CO(2), 1-3% (14)C-soluble products), followed by pyrite-rich sandstone (2-4% (14)CO(2), 1% (14)C-soluble products) and even lesser amounts with pure pyrite. These results indicate pyrite is not likely the mineral involved in transforming cDCE. A separate experiment using only typical sandstone compared the rate of cDCE transformation in non-sterilized, autoclaved, and propylene-oxide sterilized treatments, with pseudo-first order rate constants of 8.7, 5.4, and 1.0 yr(-1), respectively; however, transformation stopped after several months of incubation. Autoclaving increased the volume of pores, adsorption pore diameter, and surface area in comparison to non-sterilized typical sandstone. Nevertheless, autoclaving was less disruptive than chemical sterilization. The results provide definitive experimental evidence that cDCE undergoes anaerobic abiotic and biotic transformation in typical sandstone, with formation of CO(2) and soluble products. PMID- 23102698 TI - Remediation of DDTs contaminated soil in a novel Fenton-like system with zero valent iron. AB - Application of a novel Fenton-like system with zero-valent iron, EDTA and Air (ZVI/EDTA/Air) was investigated to degrade dichlorodiphenyltrichloroethane (DDT), dichlorodiphenyldichloroethane, and dichlorodiphenyldichloroethylene (DDE) in the actual contaminated soil from an organochlorine pesticide site. It was found DDTs in the soil were effectively degraded by the system at room temperature, ambient atmosphere pressure and near neutral pH. The dosages of EDTA and ZVI were the dominant factors influencing the removal of contaminants. An increase of EDTA from 0.05 to 0.2 mM and ZVI from 1 to 5 g L(-1) improved the removal of the contaminants significantly. However, excessive amount of EDTA led to a negative effect on the degradation process. Meanwhile, EDTA was simultaneously degraded so as to avoid the secondary pollution risk on soil remediation. Only a small amount of 4,4'-DDE and 2,2-bis(4-chlorophenyl)-1-chloroethylene (4,4'-DDMU) generated as the intermediates of DDT degradation during the process. Our investigation suggests that the Fenton-like system is a promising alternative for remediation of organochlorine pesticides contaminated soils. PMID- 23102699 TI - Poly (ADP-ribose) glycohydrolase regulates retinoic acid receptor-mediated gene expression. AB - Poly-(ADP-ribose) glycohydrolase (PARG) is a catabolic enzyme that cleaves ADP ribose polymers synthesized by poly-(ADP-ribose) polymerases. Here, transcriptome profiling and differentiation assay revealed a requirement of PARG for retinoic acid receptor (RAR)-mediated transcription. Mechanistically, PARG accumulates early at promoters of RAR-responsive genes upon retinoic acid treatment to promote the formation of an appropriate chromatin environment suitable for transcription. Silencing of PARG or knockout of its enzymatic activity maintains the H3K9me2 mark at the promoter of the RAR-dependent genes, leading to the absence of preinitiation complex formation. In the absence of PARG, we found that the H3K9 demethylase KDM4D/JMJD2D became PARsylated. Mutation of two glutamic acids located in the Jumonji N domain of KDM4D inhibited PARsylation. PARG becomes dispensable for ligand-dependent transcription when either a PARP inhibitor or a non-PARsylable KDM4D/JMJD2D mutant is used. Our results define PARG as a coactivator regulating chromatin remodeling during RA-dependent gene expression. PMID- 23102700 TI - The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5. AB - Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H(2)O(2)-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5. PMID- 23102702 TI - A novel treatment strategy targeting shugoshin 1 in hematological malignancies. AB - Shugoshin 1 (SGOL1), a centromeric protein, plays an important role in mitosis. This study explored the levels of SGOL1 in hematological malignancies and found that SGOL1 was aberrantly expressed in various human leukemia cell lines (n=10, e.g., HL60, U937, MOLM-13, K562, EOL-1, etc.) and freshly isolated leukemia cells from individuals with acute myelogenous leukemia (AML, n=43, p<0.001) compared with bone marrow mononuclear cells isolated from healthy volunteers (n=9), as measured by real-time RT-PCR. Forced expression of SGOL1 in hematopoietic stem/progenitor cells (HSPCs) significantly increased colony numbers for CFU-M and CFU-GM compared with control vector transduced infected HSPCs, suggesting that SGOL1 might act as an oncogene in hematopoietic cells. In addition, we found that repression of SGOL1 by small interfering RNA (siRNA) slowed the proliferation of NB4, EOL-1 and U937 cells compared with the control siRNA transfected cells, in parallel with the appearance of precocious dissociation of centromeric cohesion and separation of sister chromatids in these cells. Furthermore, we found that repression of SGOL1 by siRNA accumulated EOL-1 and U937 cells in the G2/M phase of the cell cycle, in conjunction with up-regulation of the spindle checkpoint protein BubR1, followed by apoptosis via caspase pathways. Thus, SGOL1 might be a promising molecular target for treating individuals with AML. PMID- 23102701 TI - Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes. AB - The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3sigma) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well characterized oncogenic properties of Nup98 fusion proteins. PMID- 23102704 TI - Smoking and risk of meningioma: a meta-analysis. AB - OBJECTIVE: The relationship between smoking and the development of meningioma has been investigated in several epidemiological studies. However, the results of these studies are inconsistent. We conducted a meta-analysis in order to identify any potential association. METHODS: PubMed, the Cochrane Library, and EMBASE databases were searched to identify relevant articles that investigated the risk of meningioma following cigarette smoking. Two researchers evaluated study eligibility and extracted the data independently, and disagreements were resolved by discussion. The variables used to estimate the pooled risk of smoking in meningioma development were the multivariate-adjusted risk estimates presented in the literature. RESULTS: Seven case-control and two cohort studies were included in this meta-analysis. The pooled estimated risks associated with ever smoking for meningioma were 1.02 (95% confidence interval (CI): 0.85-1.21) in the case control studies, 0.93 (95% CI: 0.83-1.04) in the cohort studies and 0.95 (95% CI: 0.87-1.05, P = 0.32) in all studies when the cohort and case-control data were combined. Subgroup analyses suggested that the risk estimates were 1.49 (95% CI: 1.06-2.09, P = 0.02), 0.86 (95% CI: 0.65-1.13), 0.79 (95% CI: 0.50-1.25) and 0.84 (95% CI: 0.69-1.03) for men, women, current and past smoking respectively. Sensitivity analyses restricted to studies with different adjustments for confounders yielded similar results. No evidence of publication bias was observed. CONCLUSION: Our meta-analysis suggests that there is no association between ever smoking and the risk of meningioma. However, a small but significant risk elevation is present among men smokers. PMID- 23102703 TI - Acute myeloid leukemia with translocation t(8;16) presents with features which mimic acute promyelocytic leukemia and is associated with poor prognosis. AB - Previous small series have suggested that acute myeloid leukemia with t(8;16) is a distinct morphologic and clinical entity associated with poor prognosis. We describe 18 patients with t(8;16) AML, including their clinical, cytomorphologic, immunophenotypic and cytogenetic features. Half of the patients had extramedullary disease, most commonly leukemia cutis, which often preceded bone marrow involvement and six had therapy-related AML. Patients with t(8;16) AML commonly present with clinical and pathological features that mimic APL, with promyelocytes and promyeloblast-like cells and coagulopathy in most patients. Several patients also presented with marrow histiocytes with hemophagocytosis and erythrophagocytosis. Comprehensive molecular analysis for co-occurring genetic alterations revealed a somatic mutation in RUNX1 in 1 of 6 t(8;16) patients with no known AML mutation in the remaining five t(8;16) patients. This suggests that the t(8;16) translocation could be sufficient to induce hematopoietic cell transformation to AML without acquiring other genetic alteration. These data further support classifying t(8;16) AML as a clinically and molecularly defined subtype of AML marked by characteristic clinical and cytomorphologic features that mimic APL, and is associated with very poor survival. PMID- 23102705 TI - Focusing on desired outcomes of care after colon cancer resections; hospital variations in 'textbook outcome'. AB - AIMS: We propose a summarizing measure for outcome indicators, representing the proportion of patients for whom all desired short-term outcomes of care (a 'textbook outcome') is realized. The aim of this study was to investigate hospital variation in the proportion of patients with a 'textbook outcome' after colon cancer resections in the Netherlands. METHODS: Patients who underwent a colon cancer resection in 2010 in the Netherlands were included in the Dutch Surgical Colorectal Audit. A textbook outcome was defined as hospital survival, radical resection, no reintervention, no ostomy, no adverse outcome and a hospital stay < 14 days. We calculated the number of hospitals with a significantly higher (positive outlier) or lower (negative outlier) Observed/Expected (O/E) textbook outcome than average. As quality measures may be more discriminative in a low-risk population, analyses were repeated for low-risk patients only. RESULTS: A total of 5582 patients, treated in 82 hospitals were included. Average textbook outcome was 49% (range 26-71%). Eight hospitals were identified as negative outliers. In these hospitals a 'textbook outcome' was realized in 35% vs. 52% in average hospitals (p < 0.01). In a sub-analysis for low-risk patients, only one additional negative outlier was identified. CONCLUSIONS: The textbook outcome, representing the proportion of patients with a perfect hospitalization, gives a simple comprehensive summary of hospital performance, while preventing indicator driven practice. Therewith the 'textbook outcome' is meaningful for patients, providers, insurance companies and healthcare inspectorate. PMID- 23102706 TI - S-nitrosylation of Mycobacterium tuberculosis tyrosine phosphatase A (PtpA) induces its structural instability. AB - S-nitrosylation is associated with signal transduction and microbicidal activity of nitric oxide (NO). We have recently described the S-nitrosylation of Mycobacterium tuberculosis protein tyrosine phosphatase A, PtpA, an enzyme that plays an important role in mycobacteria survival inside macrophages. This post translational modification decreases the activity of the enzyme upon modification of a single Cys residue, C53. The aim of the present work was the investigation of the effect of S-nitrosylation in PtpA kinetic parameters, thermal stability and structure. It was observed that the K(M) of nitrosylated PtpA was similar to its unmodified form, but the V(max) was significantly reduced. In contrast, treatment of PtpA C53A with GSNO, did not alter either K(M) or V(max). These results confirmed that PtpA S-nitrosylation occurs specifically in the non catalytic C53 and that this modification does not affect substrate affinity. Using circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy techniques it was shown that PtpA S-nitrosylation decreased protein thermal stability and promoted a local effect in the surroundings of the C53 residue, which interfered in both protein stability and function. PMID- 23102707 TI - Protein enrichment and digestion improvement of napiergrass and pangolagrass with solid-state fermentation. AB - BACKGROUND AND PURPOSE: Napiergrass (Pennisetum purpureum Schumacher) and pangolagrass (Digitaria decumbens Stent) are two major forage grasses for cow feeding. They possess high yields and high regeneration properties. Inoculation of cellulolytic microbes on herbage could enhance the protein content of herbage and promote digestibility in chickens. METHODS: Cellulolytic microbes were isolated from various sources and cultivated on napiergrass and pangolagrass with solid-state fermentation for protein enrichment and in vitro digestion improvement.The fermented napiergrass and pangolagrass were used as the main protein source in chicken diets to assess the feasibility for non-ruminants feed. RESULTS: After a 42-day fermentation period, napiergrass showed higher protein contents (13.4-13.9%) than those of pangolagrass(11.1-11.7%). The in vitro digestibility of pangolagrass increased from 5.29% to 20.4%, whereas that of napiergrass increased from 5.29% to 19.0%. The average feed conversion efficiencies of chickens were close to the traditional fodder using corn as the main ingredient. CONCLUSION: Inoculation of appropriate cellulolytic microbes to enrich protein content and improve in vitro digestibility of herbage with solid state fermentation for chicken feed is the prospective technique for agriculture, animal husbandry, and substantial management. PMID- 23102708 TI - Report of a 63-case series of Candida empyema thoracis: 9-year experience of two medical centers in central Taiwan. AB - BACKGROUND: Candida empyema thoracis is a serious complication of invasive candidiasis with high mortality. However, the treatment for Candida empyema remains controversial. We conducted a 9-year retrospective study to analyze the treatments and factors associated with the mortality of patients with Candida empyema thoracis in two medical centers in central Taiwan. METHODS: The medical records of all patients with positive Candida culture from pleural effusion between October 2002 and September 2011 were reviewed. The demographic data, treatment regimens, and factors associated with mortality were analyzed. RESULTS: During the period of this study, 102 patients were identified. Sixty-three of these patients fulfilled the enrollment criteria, and their data were analyzed. Three-quarters of these patients were male, and the median age of these patients was 69. Thirty-five (55.6%) patients had contiguous infection. The crude mortality rate was 61.9%. Candida albicans was the most common isolate, and malignancy was the most common underlying disease. Patients with advanced age, a higher Charlson's score, shock status, respiratory failure, and noncontiguous infection had a higher mortality rate. Those who had received surgical intervention had a better outcome. In multivariate analysis, the shock status, respiratory failure, and noncontiguous infection source were associated with a higher mortality risk. CONCLUSION: Candida empyema thoracis is a severe invasive candidiasis with high mortality rate. Shock status, respiratory failure, and noncontiguous infection were factors associated with a higher mortality rate. Surgical intervention or drainage may improve the treatment outcome, especially in patients with contiguous infection. PMID- 23102710 TI - Experimental and numerical study of evanescent waves in the mini stopband of a 1D phononic crystal. AB - This paper deals with the analysis of the guided evanescent waves in stopbands of a 1D phononic crystal (PC). A new numerical implementation is shown in order to get the complex values of the wavenumbers in a frequency range where a gap occurs. The considered phononic system is an aluminum plate with a one dimensional sinusoidal grating. For this structure a mode-gap (mini stopband) occurs at low frequency: it involves the two fundamental Lamb modes A(0) and S(0). The numerical study is performed by using a finite element method (ATILA code). The experiments deal with a finite length grating and evanescent waves are characterized at the vicinity of the mini stopband. PMID- 23102709 TI - Relative contributions of biomarkers in Alzheimer's disease. AB - PURPOSE: To assess relationships between biomarkers for Alzheimer's disease (AD) and their potential contributions to AD. METHODS: Biomarkers and cognitive evaluations were assessed longitudinally in 179 patients with mild cognitive impairment, from the Alzheimer's Disease Neuroimaging Initiative from 2003 to 2006, and were used to examine, at any given time, the joint contributions of hippocampal volume, whole brain volume, and brain glucose metabolism on clinical AD progression, using the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Marginal structural models were applied, and an inverse-probability of treatment weight estimation was used to account for time-dependent confounding between study variables. RESULTS: At any given time, population-level differences (e.g., 1-standard deviation [SD] increase) in brain glucose metabolism (-1.036; 95% confidence interval [95% CI], -1.608, -0.464) and hippocampal volume (-1.537; 95% CI, -2.399, -0.674) independently reduced mean (ADAS-Cog), whereas a 1-SD increase in whole brain volume did not (0.372; 95% CI, -0.283, 1.027). The effects of brain glucose metabolism differed in subgroups defined by baseline covariates (e.g., age), but no subgroup effects were observed for hippocampal volume and brain volume. CONCLUSIONS: Brain glucose metabolism and hippocampal volume represent relevant biological markers in subjects at risk for AD. PMID- 23102711 TI - Delivery strategies to optimize resource utilization and performance status for patients with advanced life-limiting illness: results from the "palliative care trial" [ISRCTN 81117481]. AB - CONTEXT: Evidence-based approaches are needed to improve the delivery of specialized palliative care. OBJECTIVES: The aim of this trial was to improve on current models of service provision. METHODS: This 2*2*2 factorial cluster randomized controlled trial was conducted at an Australian community-based palliative care service, allowing three simultaneous comparative effectiveness studies. Participating patients were newly referred adults, experiencing pain, and who were expected to live >48 hours. Patients enrolled with their general practitioners (GPs) and were randomized three times: 1) individualized interdisciplinary case conference including their GP vs. control, 2) educational outreach visiting for GPs about pain management vs. control, and 3) structured educational visiting for patients/caregivers about pain management vs. control. The control condition was current palliative care. Outcomes included Australia modified Karnofsky Performance Status (AKPS) and pain from 60 days after randomization and hospitalizations. RESULTS: There were 461 participants: mean age 71 years, 50% male, 91% with cancer, median survival 179 days, and median baseline AKPS 60. Only 47% of individuals randomized to the case conferencing intervention received it; based on a priori-defined analyses, 32% of participants were included in final analyses. Case conferencing reduced hospitalizations by 26% (least squares means hospitalizations per patient: case conference 1.26 [SE 0.10] vs. control 1.70 [SE 0.13], P=0.0069) and better maintained performance status (AKPS case conferences 57.3 [SE 1.5] vs. control 51.7 [SE 2.3], P=0.0368). Among patients with declining function (AKPS <70), case conferencing and patient/caregiver education better maintained performance status (AKPS case conferences 55.0 [SE 2.1] vs. control 46.5 [SE 2.9], P=0.0143; patient/caregiver education 54.7 [SE 2.8] vs. control 46.8 [SE 2.1], P=0.0206). Pain was unchanged. GP education did not change outcomes. CONCLUSION: A single case conference added to current specialized community-based palliative care reduced hospitalizations and better maintained performance status. Comparatively, patient/caregiver education was less effective; GP education was not effective. PMID- 23102712 TI - Medicare payments for outpatient urological surgery by location of care. AB - PURPOSE: The cost implications associated with offloading outpatient surgery from hospitals to ambulatory surgery centers and the physician office remain poorly defined. Therefore, we determined whether payments for outpatient surgery vary by location of care. MATERIALS AND METHODS: Using national Medicare claims from 1998 to 2006, we identified elderly patients who underwent 1 of 22 common outpatient urological procedures. For each procedure we measured all relevant payments (in United States dollars) made during the 30-day claims window that encompassed the procedure date. We then categorized payment types (hospital, physician and outpatient facility). Finally, we used multivariable regression to compare price standardized payments across hospitals, ambulatory surgery centers and the physician office. RESULTS: Average total payments for outpatient surgery episodes varied widely from $200 for urethral dilation in the physician office to $5,688 for hospital based shock wave lithotripsy. For all but 2 procedure groups, ambulatory surgery centers and physician offices were associated with lower overall episode payments than hospitals. For instance, average total payments for urodynamic procedures performed at ambulatory surgery centers were less than a third of those done at hospitals (p <0.001). Compared to hospitals, office based prostate biopsies were nearly 75% less costly (p <0.001). Outpatient facility payments were the biggest driver of these differences. CONCLUSIONS: These data support policies that encourage the provision of outpatient surgery in less resource intensive settings. PMID- 23102713 TI - Intravenous immunoglobulin treatment recovers the down-regulated levels of Th1 cytokines in the sera and skin of scleroderma patients. PMID- 23102714 TI - Arbuscular mycorrhizal fungi in arsenic-contaminated areas in Brazil. AB - Arbuscular mycorrhizal fungi (AMF) are ubiquitous and establish important symbiotic relationships with the majority of the plants, even in soils contaminated with arsenic (As). In order to better understand the ecological relationships of these fungi with excess As in soils and their effects on plants in tropical conditions, occurrence and diversity of AMF were evaluated in areas affected by gold mining activity in Minas Gerais State, Brazil. Soils of four areas with different As concentrations (mg dm(-3)) were sampled: reference Area (10); B1 (subsuperficial layer) (396); barren material (573), and mine waste (1046). Soil sampling was carried out in rainy and dry seasons, including six composite samples per area (n = 24). AMF occurred widespread in all areas, being influenced by As concentrations and sampling periods. A total of 23 species were identified, belonging to the following genus: Acaulospora (10 species), Scutellospora (4 species), Racocetra (3 species), Glomus (4 species), Gigaspora (1 species) and Paraglomus (1 species). The most frequent species occurring in all areas were Paraglomus occultum, Acaulospora morrowiae and Glomus clarum. The predominance of these species indicates their high tolerance to excess As. Although arsenic contamination reduced AMF species richness, presence of host plants tended to counterbalance this reduction. PMID- 23102715 TI - Study on the aerobic biodegradability and degradation kinetics of 3-NP; 2,4-DNP and 2,6-DNP. AB - Four biodegradability tests (BOD(5)/COD ratio, production of carbon dioxide, relative oxygen uptake rate and relative enzymatic activity) were used to determine the aerobic biodegradability of 3-nitrophenol (3-NP), 2,4-dinitrophenol (2,4-DNP) and 2,6-dinitrophenol (2,6-DNP). Furthermore, biodegradation kinetics of the compounds was investigated in sequencing batch reactors both in the presence of glucose (co-substrate) and with nitrophenol as the sole carbon source. Among the three tested compounds, 3-NP showed the best biodegradability while 2,6-DNP was the most difficult to be biodegraded. The Haldane equation was applied to the kinetic test data of the nitrophenols. The kinetic constants are as follows: the maximum specific degradation rate (K(max)), the saturation constants (K(S)) and the inhibition constants (K(I)) were in the range of 0.005 2.98 mg(mgSS d)(-1), 1.5-51.9 mg L(-1) and 1.8-95.8 mg L(-1), respectively. The presence of glucose enhanced the degradation of the nitrophenols at low glucose concentrations. The degradation of 3-NP was found to be accelerated with the increasing of glucose concentrations from 0 to 660 mg L(-1). At high (1320-2000 mg L(-1)) glucose concentrations, the degradation rate of 3-NP was reduced and the K(max) of 3-NP was even lower than the value obtained in the absence of glucose, suggesting that high concentrations of co-substrate could inhibit 3-NP biodegradation. At 2,4-DNP concentration of 30 mg L(-1), the K(max) of 2,4-DNP with glucose as co-substrate was about 30 times the value with 2,4-DNP as sole substrate. 2,6-DNP preformed high toxicity in the case of sole carbon source degradation and the kinetic data was hardly obtained. PMID- 23102716 TI - Whole-body vibration during passive standing in individuals with spinal cord injury: effects of plate choice, frequency, amplitude, and subject's posture on vibration propagation. AB - BACKGROUND: To date, few pharmacologic or rehabilitation interventions for sublesional osteoporosis (SLOP) or low bone mass of the hip and knee regions after spinal cord injury (SCI) have produced significant or sustained increases in lower extremity bone mineral density. Whole body vibration (WBV) is a potential intervention for the prevention and/or treatment of SLOP. OBJECTIVE: To identify the optimal WBV conditions (ie, plate, frequency, amplitude, and subject posture) among men with chronic SCI during passive standing and facilitate the implementation and future evaluation of the efficacy of WBV and passive standing for prevention and treatment of SLOP in men with SCI. DESIGN: This phase 0 device development study assessed the lower extremity propagation characteristics of WBV in men with and without SCI by using a variety of a priori specified plates, frequencies, amplitudes, and postures that facilitate lower extremity vibration absorption while minimizing vibration propagation to the head. SETTING: A tertiary SCI rehabilitation center in Toronto, Canada. PARTICIPANTS: Healthy men with chronic paraplegia (n = 5) and those without SCI (n = 7), ages 20-50 years, weight 68-113 kg, and height 168-188 cm. INTERVENTIONS: An EasyStand standing frame (Altimate Medical Inc, Morton, MN) was fitted onto 2 commercially available vibration platforms: WAVE (WAVE Manufacturing Inc, Windsor, Ontario, Canada) and Juvent (Juvent Medical Inc, Somerset, NJ). Accelerometers were attached to the participants' forehead, hip, knee, and ankle to measure vibration propagation. Vibration parameters evaluated were posture (knee angles of 140 degrees , 160 degrees , and 180 degrees [180 degrees for Juvent only]), vibration frequency (25 Hz, 35 Hz, and 45 Hz), and vibration amplitude (0.6 mm and 1.2 mm [WAVE only]). The subjects were exposed to all combinations of posture, frequencies, and amplitudes during the experiments (total parameter combinations: 12 WAVE and 9 Juvent). MAIN OUTCOME MEASUREMENTS: Peak-to-peak vibration and transmissibility of vibration were recorded and computed for each accelerometer at the tested locations. RESULTS: Variations in frequency generated the most noticeable changes in propagation characteristics, followed by variations in knee angle and amplitude. CONCLUSIONS: WBV therapy delivered with use of the WAVE platform with a knee angle of 140 degrees , plate frequency of 45 Hz, and amplitude of 1.2 mm met our a priori criteria for the "optimal WBV condition." Future studies should evaluate the therapeutic efficacy of the WAVE platform by using these parameters to maintain or augment bone mass among persons with SCI and SLOP. PMID- 23102717 TI - Acute subarachnoid haemorrhage: is a negative CT angiogram enough? AB - AIM: To determine the negative predictive value of 16 channel multisection computed tomography angiography (CTA) for detecting aneurysms in spontaneous subarachnoid haemorrhage (SAH), using digital subtraction angiography (DSA) as the reference standard. MATERIALS AND METHODS: The prospectively collected cerebral angiogram database of Department of Neuroradiology, Atkinson Morley Regional Neuroscience Centre was used to identify 200 consecutive patients who had undergone DSA for SAH. Of these, 176 had undergone CTA prior to DSA. Clinical details and radiology reports were correlated and images of positive investigations reviewed. RESULTS: DSA showed one or more cerebral aneurysms in 105 (60%) patients. These were correctly reported on CTA in 100. CTA was reported negative for aneurysms in 74 patients. Of these five were false negative and had aneurysms detected on DSA. In the CTA/DSA negative group, 11 (16%) patients had classical perimesencephalic clinical syndrome and blood distribution. There were two false positives at CTA. For ruptured cerebral aneurysms, CTA had 95.2% sensitivity, 97.2% specificity, 98.1% positive predictive value, and 93.2% negative predictive value. CONCLUSION: The sensitivity and negative predictive value of CTA for ruptured aneurysms remains imperfect. Continued use of DSA is recommended in most patients with a negative CTA after acute SAH. Confirmation of a negative CTA result with DSA may not be routinely required in patients with perimesencephalic syndrome. PMID- 23102718 TI - [Red-blood-cell allo-immunization]. AB - Red blood cell allo-immunization is the immune response of an individual to foreign red blood cell antigens not present on the surface of their own cells. The aim of that paper is to clarify the different factors influencing the antibody response against red blood cell antigens. PMID- 23102719 TI - Gestrinone inhibits growth of human uterine leiomyoma may relate to activity regulation of ERalpha, Src and P38 MAPK. AB - The study was to investigate the effect of gestrinone on the growth of human uterine leiomyoma cells and on the levels and activity of p38, Src and estrogen receptor alpha (ERalpha). Human uterine leiomyoma cells were cultured and treated with dimethylsulfoxide (DMSO) or a gestrinone concentration gradient. Morphological changes were observed and apoptosis was evaluated. Levels of p38 and phosphorylated-p38 (pp38) were assayed by enzyme-linked immunosorbent assay (ELISA). Levels of ERalpha and Src were analyzed using real-time RT-PCR and Western blotting. The result showed that gestrinone significantly inhibited the growth of cultured human uterine leiomyoma cells in a concentration- and time dependent manner, with a 50% inhibitory concentration (IC(50)) value and corresponding 95% confidence intervals (CI) of 43.67 (23.46~81.32), 27.78 (12.51~61.68) and 15.25 (7.17~32.43) MUmol/L at 20, 40 and 60h, respectively. Compared with control-treated leiomyoma cells, gestrinone significantly reduced both the expression of ERalpha (P<0.05) and the levels of phospho-Ser167-ERalpha (P<0.05). Gestrinone also markedly suppressed the level of phospho-Tyr416-Src (P<0.05). Moreover, gestrinone significantly increased the ratio of phospho p38/p38 mitogen-activated protein kinase (MAPK) (P<0.05). However, no significant increase in apoptosis or cell cycle arrest was observed (P>0.05) in response to the tested concentrations of 0.1 to 3.0MUmol/L. As a conclusion, gestrinone suppresses the proliferation of uterine leiomyoma cells mainly by regulating the activity of ERalpha/Src/p38 MAPK in a concentration-dependent manner at a low concentration of 0.1~3.0MUM, but not significantly regulating apoptosis. Gestrinone opposes the growth of uterine leiomyoma through multiple genes. PMID- 23102720 TI - Systems, strategies, and interventions for sustainable long-term care and protection of children with a history of living outside of family care. AB - OBJECTIVES: This article reviews the available evidence regarding the efficacy, effectiveness, ethics, and sustainability of approaches to strengthen systems to care for and protect children living outside family care in low- and middle income countries. METHOD: For trafficked children, children of and on the street, children of conflict/disaster, and institutionalized children, a systems framework approach was used to organize the topic of sustainable approaches in low- and middle-income countries and addresses the following: legislation, policies, and regulations; system structures and functions (formal and informal); and continuum of care and services. The article draws on the findings of a focal group convened by the U.S. Government Evidence Summit: Protecting Children Outside of Family Care (December 12-13, 2011, Washington, DC), tasked with reviewing the literature on systems, strategies, and interventions for sustainable long-term care and protection of children with a history of living outside of family care in low- and middle-income country contexts. The specific methodology for the review is described in the commentary paper (Higgs, Zlidar, & Balster, 2012) that accompanies these papers. RESULTS: For the most part, the evidence base in support of sustainable long-term care for the populations of interest is relatively weak, with some stronger but unreplicated studies. Some populations have been studied more thoroughly than others, and there are many gaps. Most of the existing studies identify population characteristics, needs, and consequences of a lack of systemic services to promote family-like care. There is some evidence of the effectiveness of laws and policies, as well as some evidence of service effectiveness, in improving outcomes for children outside of family care. CONCLUSIONS: Despite the weaknesses and gaps of the existing research, there is a foundation of research for going forward, which should focus on developing and implementing systems for these most vulnerable children. The evidence reviewed indicates that child protection systems should aim for appropriate, permanent family care (including reunification, adoption, kinship care, or kafalah) for children in order to secure the best environment for a child's developmental prospects. Evidence also suggests that the quality and duration of care, including both permanent family care and alternative care, are important regardless of setting. The diversity of political, socioeconomic, historical, regional, community, and cultural contexts in which child protection systems operate need to be taken into account during programming and research design. PMID- 23102721 TI - The relationship between depressive symptoms and health service utilization for elderly people in Taiwan. AB - OBJECTIVE: This study analyzes the relationship between depressive symptoms and the utilization of medical services for elderly people in Taiwan. METHODS: Because depressive symptoms and physical health may have a reciprocal relationship, a simultaneous equations model was used by performing a 3-stage least squares (3SLS) regression. The data in this study were obtained from the 2003 Survey of Health and Living Status of the Elderly in Taiwan (SHLSE). RESULTS: The findings show that depressive symptoms have a significantly negative effect on the utilization of outpatient, inpatient, and emergency services. Furthermore, the magnitude of the 3SLS estimates of physical health status in relation to health service utilization is substantially greater than that in the OLS estimates. The results may reveal that people with depressive symptoms may seek healthcare services because of physical discomfort. CONCLUSIONS: Those with depressive symptoms may not seek specialty mental treatments, suggesting that policy interventions to monitor the need to care for elderly people with depressive symptoms through primary care services are important in screening and maintaining the mental health of elderly people. PMID- 23102722 TI - Kinetic and product study of the heterogeneous reactions of NO3 radicals with suspended resmethrin, phenothrin, and fenvalerate particles. AB - Resmethrin, phenothrin, and fenvalerate are the synthetic pyrethroids that have been used widely against groundling or flying insect pests both indoors and outdoors. In this study, the heterogeneous reactions of the three pyrethroid particles with NO(3) radicals are investigated with a mixed-phase relative rate method. The reactions are performed in a reaction chamber equipped with a vacuum ultraviolet photoionization aerosol time-of-flight mass spectrometer (VUV-ATOFMS) and an atmospheric gas analysis mass spectrometer. The uptake coefficients of NO(3) radicals on resmethrin, phenothrin, and fenvalerate particles are ~0.20, 0.04, and 0.03 respectively, calculated with a spherical shell model. And the atmospheric lifetimes of the three pyrethroid particles toward NO(3) radicals are estimated to be ~2.6, 7.5, and 9.3 h, respectively. The molecular structures of reaction products and the reaction pathways are suggested based on the measurements of VUV-ATOFMS and off-line GC-MS. PMID- 23102723 TI - Soil test phosphorus dynamics in animal waste amended soils: using P mass balance approach. AB - Soil test phosphorus (STP) is commonly used for phosphorus (P) fertilizer recommendations in agriculture and in risk assessment of offsite P movement from environmental perspectives. Present guidelines do not differentiate between the P sources and assume that P added to the soil would behave alike. The objective of this study was to understand the influence of different animal P sources applied at three different rates on changes in STP in many different soils using P mass balance approach. Six P sources consisting of three types of monogastric, two ruminant and triple super phosphate (TSP) applied at 0, 50, and 150 mg P kg(-1) in six different soils. Corn (Zea mays L.) was used to remove P and total of seven harvests were achieved. The STP (Bray 1P) was monitored at T(0) and after each harvest and relationship was developed between STP and net P addition/removal to compute the slope. Prior to crop P removal, the Turkey (Meleagris gallopava) litter (TL) produced the smallest slope at both rates and across all soils. Most P sources resulted large slope values in the Woodson soil. The slope value progressively decreased from higher rate to lower rate to the control treatment in P mass balance study. Soil clay content, initial STP, soil pH, and soil organic matter levels were involved in explaining variations in slope value in TL, while initial STP and clay content in Hog (Sus scrofa) manure (HM) and biosolid (SS) amended soils in net P addition/removal study. PMID- 23102724 TI - Fate of atrazine in switchgrass-soil column system. AB - Atrazine, a broad-leaf herbicide, has been used widely to control weeds in corn and other crops for several decades and its extensive used has led to widespread contamination of soils and water bodies. Phytoremediation with switchgrass and other native prairie grasses is one strategy that has been suggested to lessen the impact of atrazine in the environment. The goal of this study is to characterize: (1) the uptake of atrazine into above-ground switchgrass biomass; and (2) the degradation and transformation of atrazine over time. A fate study was performed using mature switchgrass columns treated with an artificially created agricultural runoff containing 16 ppm atrazine. Soil samples and above ground biomass samples were taken from each column and analyzed for the presence of atrazine and its chlorinated metabolites. Levels of atrazine in both soil and plant material were detectable through the first 2 weeks of the experiment but were below the limit of detection by Day 21. Levels of deethylatrazine (DEA) and didealkylatrazine (DDA) were detected in soil and plant tissue intermittently over the course of the study, deisopropylatrazine (DIA) was not detected at any time point. A radiolabel study using [(14)C]atrazine was undertaken to observe uptake and degradation of atrazine with more sensitivity. Switchgrass columns were treated with a 4 ppm atrazine solution, and above-ground biomass samples were collected and analyzed using HPLC and liquid scintillation counting. Atrazine, DEA, and DIA were detected as soon as 1d following treatment. Two other metabolites, DDA and cyanuric acid, were detected at later time points, while hydroxyatrazine was not detected at all. The percentage of atrazine was observed to decrease over the course of the study while the percentages of the metabolites increased. Switchgrass plants appeared to exhibit a threshold in regard to the amount of atrazine taken up by the plants; levels of atrazine in leaf material peaked between Days 3 and 4 in both studies. PMID- 23102725 TI - Degradation of metaflumizone in soil: impact of varying moisture, light, temperature, atmospheric CO2 level, soil type and soil sterilization. AB - Soil is a major sink for the bulk of globally used pesticides. Hence, fate of pesticides in soil under the influence of various biotic and abiotic factors becomes important for evaluation of stability and safety. This paper presents the impact of varying moisture, light, temperature, atmospheric CO(2) level, soil type and soil sterilization on degradation of metaflumizone, a newly registered insecticide in India. Degradation of metaflumizone in soil followed the first order reaction kinetics and its half life values varied from ~20 to 150 d. Under anaerobic condition, degradation of metaflumizone was faster (t(1/2) 33.4 d) compared to aerobic condition (t(1/2) 50.1 d) and dry soil (t(1/2) 150.4 d). Under different light exposures, degradation was the fastest under UV light (t(1/2) 27.3 d) followed by Xenon light (t(1/2) 43 d) and dark condition (t(1/2) 50.1 d). Degradation rate of metaflumizone increased with temperature and its half life values ranged from 30.1 to 100.3d. Elevated atmospheric CO(2) level increased the degradation in soil (t(1/2) 20.1-50.1 d). However, overall degradation rate was the fastest at 550 ppm atmospheric CO(2) level, followed by 750 ppm and ambient level (375 ppm). Degradation of metaflumizone was faster in Oxisol (pH 5.2, Total Organic Carbon 1.2%) compared to Inceptisol (pH 8.15, TOC 0.36%). In sterile soil, only 5% dissipation of initial concentration was observed after 90 d of sampling. Under various conditions, 4-cyanobenzoic acid (0.22-1.86 mg kg(-1)) and 4-trifluoromethoxy aniline (0.21-1.23 mg kg(-1)) were detected as major degradation products. PMID- 23102726 TI - 137Cs in fungal sporocarps in relation to vegetation in a bog, pine swamp and forest along a transect. AB - In this study, we estimated the relative importance of vegetation and fungi for radiocesium uptake and biological retention in adjacent bog, pine swamp, and forest. The measurements for (137)Cs activity concentration in sporocarps (i.e. fruitbodies of fungi) and vegetation along a bog to forest transect were combined with complementary published data to calculate estimates. Aboveground vegetation comprised 17.7% of the total fallout-derived radiocesium in the system in bog, 16.5% in pine swamp, and 40.6% in forest. In fungal sporocarps grown along a gradient, (137)Cs activity comprised <0.001% of the total radiocesium for peat bog, <0.02% for pine swamp, and 0.11% for forest. Total (137)Cs activity in sporocarps increased along the gradient due to increased production of sporocarps in the presence of trees from 0.006 (bog), 0.097 (pine swamp) and 0.67 (forest) g dwt m(-2). Based on calculation of the total vegetation biomass and through relationships between fungal biomass in sporocarps and as mycelia in soil, the total (137)Cs activity located in fungi was estimated as 0.1% in bog, 2% in pine swamp, and 11% in forest. An analysis of the time-dependency of (137)Cs in the sporocarps in forest between 1990 and 2011 suggested an ecological half-life for (137)Cs between 8 and 13 years. Although fungi comprised a relatively small fraction of the total radiocesium in the systems, its activity decreased slowly with time, and ecological residence time for (137)Cs in sporocarps of fungi was long, suggesting they will continue to contribute to the accumulation and cycling of this radionuclide in forest. PMID- 23102727 TI - Photorefractive keratectomy in patients with suspected keratoconus: five-year follow-up. AB - PURPOSE: To assess the long-range outcomes of photorefractive keratectomy (PRK) using functional and topographic criteria in myopic eyes with suspected keratoconus. SETTING: Rothschild Foundation, Paris, France. DESIGN: Retrospective interventional case series. METHODS: Eyes of patients classified as keratoconus suspects or keratoconus by the Corneal Navigator software of the OPD-Scan II device were included. They were treated with myopic PRK using an EC-5000 excimer laser between 2004 and 2007. The main outcome measures were refractive stability, mean corneal keratometry, mean central pachymetry, mean thinnest point value, and the occurrence of postoperative complications such as corneal ectasia. RESULTS: The study evaluated 62 eyes of 42 patients. The mean patient age was 34.6 years +/- 15.1 (SD) and the mean spherical equivalent (SE), -3.96 +/- 3.05 diopters (D). The mean central pachymetry was 529.4 +/- 32.8 MUm and the mean simulated keratometry, 45.75 +/- 1.75 D. The percentage of similarity to keratoconus suspects or keratoconus was positive in all 62 eyes and exceeded a 50% similarity score in 30 eyes (48.4%). The mean follow-up was 4.8 +/- 1.4 years. The mean magnitude of the SE was -0.53 +/- 1.35 D over the follow-up. Two patients required glasses postoperatively because of significant myopic regression. No case of corneal ectasia was reported. CONCLUSION: Photorefractive keratectomy in eyes with suspected keratoconus based on a Placido neural network may be safe and effective for myopia and astigmatism in carefully selected patients. PMID- 23102729 TI - Impact of panic disorder on quality of life among veterans in a primary care pilot study. AB - Panic disorder is a debilitating and costly mental health condition which commonly presents in primary care settings; however, little is known about the impact of panic disorder on quality of life and health utility valuations among Veterans in primary care. A cross-sectional investigation of quality of life was conducted in a sample of 21 Veterans with panic disorder in a VA primary care clinic. Health utilities were determined using an algorithm based upon the Medical Outcomes Study Short-Form 36 Health Survey (SF-36). Veterans in the current sample reported significantly greater impairment on all eight of the SF 36 subscales in comparison to published norms. Veterans with panic and comorbid mood disorders reported significantly greater impairment on the Vitality, Social Functioning, and Mental Health subscales, while Veterans with panic and comorbid anxiety disorders reported significantly greater impairment on the Physical Functioning and Bodily pain subscales. Health utilities for the current sample were comparable to previous reports of Veterans with PTSD and depression, as well as health utilities of persons with chronic pulmonary disease and irritable bowel syndrome. The findings from this study highlight the devastating nature of panic disorder and reflect the need for increased attention to the identification and treatment of panic disorder in VA primary care settings. PMID- 23102728 TI - MEK inhibitors reverse resistance in epidermal growth factor receptor mutation lung cancer cells with acquired resistance to gefitinib. AB - Lung adenocarcinoma cells harboring epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs), including gefitinib. Acquired resistance to EGFR-TKIs develops after prolonged treatments. The study was prompt to explore effective strategies against resistance to EGFR TKIs. We established gefitinib resistant PC-9 cells which harbor EGFR exon 19 deletion. Known mechanisms for intrinsic or acquired EGFR-TKI resistance, including KRAS mutation, HER2 mutation, EGFR T790M mutation and MET gene amplification, were studied, and we did not observe any known mechanisms for intrinsic or acquired resistance to EGFR-TKIs in the resistant cells. In the parental PC-9 cells, labeled as PC-9/wt, gefitinib completely inhibited EGF induced phosphorylation of EGFR, AKT and ERK. Gefitinib inhibited EGFR phosphorylation, but was unable to block EGF-induced phosphorylation of ERK in resistant cells, labeled as PC-9/gef cells, including PC-9/gefB4, PC-9/gefE3, and PC-9/gefE7 subclones. We detected NRAS Q61K mutation in the PC-9/gef cells but not the PC-9/wt cells. MEK inhibitors, either AZD6244 or CI1040, inhibited ERK phosphorylation and sensitized gefitinib-induced cytotoxicity in PC-9/gef cells. Whereas MEK inhibitors or gefitinib alone did not activate caspases in PC-9/gef cells, combination of gefitinib and AZD6244 or CI1040 induced apoptosis. Our in vivo studies showed that gefitinib inhibited growth of PC-9/wt xenografts but not PC-9/gef xenografts. Furthermore, combination of a MEK inhibitor and gefitinib inhibited growth of both PC-9/wt xenografts and PC-9/gefB4 xenografts. To conclude, persistent activation of ERK pathway contributes to the acquired gefitinib-resistance. Combined treatment of gefitinib and MEK inhibitors may be therapeutically useful for acquired gefitinib-resistance lung adenocarcinoma cells harboring EGFR mutations. PMID- 23102730 TI - The influence of Debaryomyces hansenii, Candida deformans and Candida zeylanoides on the aroma formation of dry-cured "lacon". AB - The volatile profile of dry-cured "lacon" that has been inoculated with three different yeasts were determined and compared with a non-inoculated dry-cured "lacon". Yeasts (Debaryomyces hansenii, Candida deformans and Candida zeylanoides) that were used as starter cultures in the present study were selected among yeasts that were isolated from native dry-cured "lacon" at different stages of ripening process. These starters were spread on dry-cured "lacon" surface in order to test their capacity to contribute on the generation of volatile compounds. A total of forty two volatile compounds were detected by dynamic headspace sampling followed by gas chromatography-mass spectrometry analysis. Significant differences (P<0.001) on the volatile profiles of different batches were found in comparison with non-inoculated samples, showing the highest total area values for the inoculated ones. Esters were the most abundant chemical family in all batches studied except for C. zeylanoides batch, which showed greater amount of hydrocarbons than esters. The second more abundant family was hydrocarbons for control and C. deformans batches (147.6 and 445.24 * 10(6) area units, respectively), alcohols for D. hansenii (363.77 * 10(6) area units) and esters for C. zeylanoides (248.33 * 10(6) area units). However, the aldehyde compound group in control batch samples was found to be significantly higher than in the inoculated ones (P<0.001). Among inoculated batches, D. hansenii batch showed the lowest hexanal content (14.42 * 10(6) area units) in comparison with non-inoculated batch (105.99 * 10(6) area units). Among all batches studied, D. hansenii batch presented the highest area values for esters, alcohols, linear hydrocarbons, ketones, acids and furans; control batch for aldehydes and C. zeylanoides batch for branched hydrocarbons. Therefore, the study showed that every yeast strain produced a specific volatile profile which was also different from that of the control dry-cured "lacon". PMID- 23102731 TI - The triggering effect of alcohol and illicit drugs on violent crime in a remand prison population: a case crossover study. AB - BACKGROUND: The association between substance abuse, particularly alcohol abuse, and violence has been well established. However, since substance abuse co-occurs with several other risk factors for violence, the causal link between substance abuse and violence and the extent to which the acute influence of alcohol, illicit drugs, benzodiazepines, and anabolic androgenic steroids have a triggering effect on violent behavior are more uncertain. METHODS: Case-crossover design was used based on data from structured face to face interviews with remand prisoners (n=194; 172 men, 22 women) suspected of violent crimes. MAIN OUTCOME MEASURE: odds ratio (OR 95% CI) for a violent crime, 24h after exposure to different substances, compared to periods of no exposure was calculated using conditional logistic regression and a Mantel-Haenszel estimator with confidence intervals for sparse data. RESULTS: Intake of alcohol (OR 6.41 CI 4.24-9.67) and large doses of benzodiazepines (OR 36.32 CI 7.14-183.65) triggered interpersonal violence. Stratified analyses of possible effect modifiers were sex, conduct/behavioral problems, trauma experiences; psychiatric vulnerability did not reveal any substantial differences. CONCLUSION: Influences of alcohol and unusually high doses of benzodiazepines are proximal risk factors for violent crime. Improved knowledge of short-term (and dose-related) risk factors may contribute to treatment planning and risk assessment of violence. PMID- 23102732 TI - CKD-mineral and bone disorder management in kidney transplant recipients. AB - Kidney transplantation, the most effective treatment for the metabolic abnormalities of chronic kidney disease (CKD), only partially corrects CKD mineral and bone disorders. Posttransplantation bone disease, one of the major complications of kidney transplantation, is characterized by accelerated loss of bone mineral density and increased risk of fractures and osteonecrosis. The pathogenesis of posttransplantation bone disease is multifactorial and includes the persistent manifestations of pretransplantation CKD-mineral and bone disorder, peritransplantation changes in the fibroblast growth factor 23 parathyroid hormone-vitamin D axis, metabolic perturbations such as persistent hypophosphatemia and hypercalcemia, and the effects of immunosuppressive therapies. Posttransplantation fractures occur more commonly at peripheral than central sites. Although there is significant loss of bone density after transplantation, the evidence linking posttransplantation bone loss and subsequent fracture risk is circumstantial. Presently, there are no prospective clinical trials that define the optimal therapy for posttransplantation bone disease. Combined pharmacologic therapy that targets multiple components of the disordered pathways has been used. Although bisphosphonate or calcitriol therapy can preserve bone mineral density after transplantation, there is no evidence that these agents decrease fracture risk. Moreover, bisphosphonates pose potential risks for adynamic bone disease. PMID- 23102733 TI - Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. AB - Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis. PMID- 23102734 TI - A novel RUNX1-C11orf41 fusion gene in a case of acute myeloid leukemia with a t(11;21)(p14;q22). AB - The RUNX1 locus, which encodes a transcription factor that is essential for normal hematopoiesis, is a frequent location of chromosomal rearrangements in human hematological malignancies. We report the case of a 78-year-old man with acute myeloid leukemia (AML), M1 subtype (French-American-British classification), with a t(11;21)(p14;q22). Fluorescence in situ hybridization showed a split signal for RUNX1, which indicated that RUNX1 was involved in this translocation. Using 3'-rapid amplification of cDNA ends and reverse transcription-polymerase chain reaction analyses, we found that RUNX1 was fused to C11orf41 on 11p14 and detected two in-frame C11orf41-RUNX1 fusion transcripts. One was a fusion between exon 5 of RUNX1 and exon 13 of C11orf41, and the other was between exon 6 of RUNX1 and exon 13 of C11orf41. This suggested that the RUNX1 breakpoint was in intron 6 and had generated alternative fusion splice variants. A reciprocal C11orf41-RUNX1 fusion was not detected. Thus, we identified C11orf41 as a novel fusion partner of RUNX1 in AML. PMID- 23102735 TI - Effect of inhaled endotoxin on regional particle deposition in patients with mild asthma. PMID- 23102736 TI - Time, trust and reflection: three aspects of precepting in clinical nursing education. PMID- 23102737 TI - [Prenatal diethylstilbestrol exposure and breast cancer]. AB - Diethylstilbestrol (DES) is a synthetic estrogen prescribed to prevent miscarriages until 1977. Its role in the development of vaginal adenocarcinoma and cervical dysplasia is known and screening codified. Recent cohort studies show that exposure to DES in utero increases breast cancer risk especially after 40 years. This article reports the observation of a breast cancer of exceptional gravity in a patient exposed to DES in utero. It details the risk of breast cancer for "DES daughters" and support possible screening modalities. PMID- 23102738 TI - Autogenous impaction grafting in total hip arthroplasty with developmental dysplasia of the hip. AB - Autogenous impaction grafting was performed to improve acetabular cup coverage in 68 patients (78 hips) with developmental dysplasia of the hip (DDH) after total hip arthroplasty, and the patients were then monitored for a mean duration of 5.5years. No cup revisions were required, and there was no radiographic loosening. The host-graft interface became indistinct by 6weeks after surgery, trabecular bone formation was seen by 12weeks, and definite trabecular reorientation was seen by 20months. At the last follow-up examination, the mean cup coverage was 97.7%, whereas mean coverage by bone grafting was 27.9%. Among 12 patients with most of the bone graft placed at the absolutely protruded area of the cup, the cup coverage provided by the bone graft decreased from 95.4% immediately after surgery to 20.7% by the final follow-up examination. Bone particle grafting can provide a satisfactory integration speed and a low incidence of displacement and ectopic ossification. PMID- 23102739 TI - Forensic psychiatry in Chile. AB - Mental disorders are among the most prevalent of chronic disorders, and a high prevalence of these disorders has been consistently found in jails and prisons. This study was a retrospective case series that described the population of adults charged with a criminal offense who were court ordered to undergo a psychiatric assessment within the Medical Legal Service in Santiago, Chile from 2005 to 2006. Characteristics were explored in order to better understand this population in light of the recent reforms in the judicial and health systems of Chile. Ninety percent of sampled individuals were male, primarily between the ages of 18-39 years. Seventy percent of the evaluations came from the pre reformed judicial system and 30% were from the reformed system. Approximately 63% of evaluated offenders were considered to have a psychiatric pathology, the most common being the personality disorders. Of the evaluated offenders, approximately 84% were considered by a psychiatrist to be criminally responsible for their crime, 7% were regarded as having diminished criminal responsibility, 4% were considered to be not criminally responsible for their crime, and 4% were cases where criminal responsibility was not applicable. Profession status, municipality of residence, type of residence, ICD-10 diagnosis, treatment recommendation, and criminal responsibility were found to be significantly different between male and female evaluated offenders. Results from this investigation will contribute to knowledge about forensic psychiatry and mental health in Latin America, and will hopefully pave the way for more research and international comparisons. PMID- 23102740 TI - Health status and associated factors among the community-dwelling elderly in China. AB - The objective of this study was to evaluate the health status and associated factors of the elderly Chinese population. A cross-sectional survey was administered to 849 elderly people aged 60 years and over living in a certain district of Nanjing, China. A health rating scale based on the characteristics of the elderly in China was used. The difference of self-rated health between different groups was tested using an ANOVA, and the associated factors were tested using an ordinal logistic regression. The results showed that the general health of the elderly Chinese people studied was not good. The scores of body function, self-care ability, and physical health decreased gradually with age. The scores of men were higher than those of women in terms of emotional personality. The factors associated with the health status of the elderly were education, living mode and marital status. The health status of the elderly Chinese and the associated factors highlighted in this study demonstrated that emotional and social support were more important than financial support for promoting the mental health of the elderly. These findings will provide a basis for the development of programmes promoting the health management and healthy ageing of the elderly in China. PMID- 23102741 TI - The iScore predicts efficacy and risk of bleeding in the National Institute of Neurological disorders and Stroke Tissue Plasminogen Activator Stroke Trial. AB - The iScore is a validated tool to estimate outcomes after an acute ischemic stroke. A previous study showed the iScore can predict clinical response and risk of intracerebral hemorrhage (ICH) after administration of tissue plasminogen activator (tPA). We applied the iScore (www.sorcan.ca/iscore) to participants in the National Institute of Neurological Disorders and Stroke tPA stroke trials to evaluate its ability to estimate clinical response and risk of ICH after thrombolysis. Based on results from our previous study, patients were stratified a priori into iScore <200 and iScore >= 200. The main outcome measure was ICH. Secondary outcomes included favorable composite outcome (defined as a modified Rankin Scale score of 0 or 1, National Institutes of Health Stroke Scale score <= 1, Barthel Index >= 95, or Glasgow Outcome Scale <1 at 3 months) and functional outcomes. The iScore was calculated in all 624 patients enrolled in the trial. The cohort comprised 507 patients (81%) with an iScore <200 and 117 (19%) with an iScore >= 200. An iScore >= 200 was associated with greater risk of symptomatic ICH in the tPA group compared with the placebo group (15.4% v 3.9%; P = .04). Similar findings were found for ICH of any type (30.8% v 11.5%; P = .014), with higher ICH mortality (69.2% v 23.8%; P < .001). Despite the higher favorable composite outcome of tPA therapy in patients with an iScore <200 (58.7% v 41.9%; P < .001), this therapy had no benefit in patients with an iScore >= 200 (15.4% v 13.4%; P = .77). In patients receiving tPA in the National Institute of Neurological Disorders and Stroke trial, the iScore estimated the clinical response and risk of hemorrhagic complications. Further prospective studies are needed before a change in practice can be recommended. PMID- 23102742 TI - Recovery of swallowing after dysphagic stroke: an analysis of prognostic factors. AB - BACKGROUND: Dysphagia is a major complication of stroke, but factors influencing its recovery are incompletely understood. The goal of this study was to identify important prognostic variables affecting swallowing recovery after acute ischemic stroke. METHODS: We retrospectively reviewed our patient database to identify acute ischemic stroke patients who developed dysphagia after stroke but were free of other confounding conditions affecting swallowing. Of the 1774 patients screened, 323 met the study criteria. We assessed the effect of age, sex, baseline National Institutes of Health Stroke Scale (NIHSS) score, level of consciousness (LOC), facial weakness, dysarthria, neglect, bihemispheric infarcts, right hemispheric infarcts, brainstem infarcts, intubation, aspiration, acute stroke therapies, occurrence of symptomatic hemorrhagic transformation, seizures, pneumonia, and length of hospitalization (LOH) on persistence of dysphagia at hospital discharge in a logistic regression analysis. RESULTS: The mean age and NIHSS scores (mean +/- standard deviation) were 75.9 +/- 13.6 years and 13.5 +/- 6.9, respectively; 58.5% were women. In a multivariate analysis, aspiration detected on a clinical swallowing evaluation (odds ratio [OR] 21.83; 95% confidence interval [CI] 8.16-58.42; P < .0001), aspiration on videofluoroscopic swallowing study (OR 10.50; 95% CI 3.35-32.96; P < .0001), bihemispheric infarcts (OR 3.72; 95% CI 1.33-10.43; P = .0123), dysarthria (OR 3.4; 95% CI 1.57-7.35; P = .0019), intubation (OR 2.86; 95% CI 1.10-7.39; P = .0301), NIHSS score >=12 (OR 2.51; 95% CI 1.19-5.23; P = .0157) were significant predictors of persistent dysphagia. The area under the curve and Somer's Dxy statistics of the model were 0.8918 and 0.78, respectively, indicating good calibration and discriminative power. CONCLUSIONS: Prognostic factors affecting swallowing recovery identified in this study can help advance dysphagia research methodologies and the clinical care of stroke patients. PMID- 23102743 TI - Neural correlates of delayed visual-motor performance in children treated for brain tumours. AB - Both structural and functional neural integrity is critical for healthy cognitive function and performance. Across studies, it is evident that children who are affected by neurological insult commonly demonstrate impaired cognitive abilities. Children treated with cranial radiation for brain tumours suffer substantial structural damage and exhibit a particularly high correlation between the degree of neural injury and cognitive deficits. However the pathophysiology underlying impaired cognitive performance in this population, and many other paediatric populations affected by neurological injury or disease, is unknown. We wished to investigate the characteristics of neuronal function during visual motor task performance in a group of children who were treated with cranial radiation for brain tumours. We used Magnetoencephalography to investigate neural function during visual-motor reaction time (RT) task performance in 15 children treated with cranial radiation for Posterior Fossa malignant brain tumours and 17 healthy controls. We found that, relative to controls, the patient group showed: 1) delayed latencies for neural activation in both visual and motor cortices; 2) muted motor responses in the alpha (8-12Hz) and beta (13-29Hz) bandwidths, and 3) potentiated visual and motor responses in the gamma (30-100Hz) bandwidth. Collectively these observations indicate impaired neural processing during visual motor RT performance in this population and that delays in the speed of visual and motor neuronal processing both contribute to the delays in the behavioural response. As increases in gamma activity are often observed with increases in attention and effort, increased gamma activities in the patient group may reflect compensatory neural activity during task performance. This is the first study to investigate neural function in real-time during cognitive performance in paediatric brain tumour patients. PMID- 23102749 TI - A network meta-analysis of antibiotics for treatment of hospitalised patients with suspected or proven meticillin-resistant Staphylococcus aureus infection. AB - Infections due to meticillin-resistant Staphylococcus aureus (MRSA) pose a serious health risk. Novel methods for assessing comparative effectiveness and safety may provide valuable insights into therapeutic choices. We did a systematic review searching electronic databases including the archives of FDA/CDER and performed a Bayesian network meta-analysis to compare parenteral antibiotics used for treating hospitalised adults with complicated skin and soft tissue infections (cSSTIs) or hospital-acquired or ventilator-associated pneumonia (HAP/VAP). Models were adjusted for clinical heterogeneity due to between-arm differences in the proportion of patients with diabetes (for cSSTI) and in those requiring mechanical ventilation (for pneumonia). Treatments were ranked on efficacy, defined as clinical success in the modified intention-to treat population (MITT) and in the MITT population with MRSA at baseline (MRSA m MITT), on all-cause mortality (in pneumonia only), and on serious adverse events and withdrawals due to adverse events. We identified 24 randomised controlled trials (17 for cSSTI and 10 for HAP/VAP) comparing one of six antibiotics with vancomycin. The network meta-analysis indicated that vancomycin ranked third (of six antibiotics) in cSSTI and second (of four) in pneumonia on both efficacy and safety. However, direct pairwise meta-analyses remained inconclusive as evidenced by the adjusted median odds ratios (ORs) and their 95% credible intervals. In cSSTI, linezolid and ceftaroline were non-significantly more effective than vancomycin. Linezolid ORs were 1.15 (0.74-1.71) and 1.01 (0.42-2.14) and ceftaroline ORs were 1.12 (0.78-1.64) and 1.59 (0.68-3.74) in the MITT and MRSA m MITT populations, respectively. For HAP/VAP, linezolid was non-significantly better than vancomycin, with ORs of 1.05 (0.72-1.57) and 1.32 (0.71-2.48) in the MITT and MRSA m-MITT populations, respectively. We suspect performance and detection bias in cSSTI trials involving linezolid, but regression methods could not adjust for this potential bias. In these clinical trials, the preferred agents for treating serious MRSA infections were ceftaroline (for cSSTI, not studied in HAP/VAP) and linezolid. However, translation of these findings into practice should consider the small size of the evidence networks and the consequent uncertainty associated with the parameter estimates, the lack of evidence for ceftaroline in patients with severe renal impairment, and the lower internal validity of some of the linezolid trials. PMID- 23102750 TI - An ensemble system for automatic sleep stage classification using single channel EEG signal. AB - The present work aims at automatic identification of various sleep stages like, sleep stages 1, 2, slow wave sleep (sleep stages 3 and 4), REM sleep and wakefulness from single channel EEG signal. Automatic scoring of sleep stages was performed with the help of pattern recognition technique which involves feature extraction, selection and finally classification. Total 39 numbers of features from time domain, frequency domain and from non-linear analysis were extracted. After extraction of features, SVM based recursive feature elimination (RFE) technique was used to find the optimum number of feature subset which can provide significant classification performance with reduced number of features for the five different sleep stages. Finally for classification, binary SVMs were combined with one-against-all (OAA) strategy. Careful extraction and selection of optimum feature subset helped to reduce the classification error to 8.9% for training dataset, validated by k-fold cross-validation (CV) technique and 10.61% in the case of independent testing dataset. Agreement of the estimated sleep stages with those obtained by expert scoring for all sleep stages of training dataset was 0.877 and for independent testing dataset it was 0.8572. The proposed ensemble SVM-based method could be used as an efficient and cost-effective method for sleep staging with the advantage of reducing stress and burden imposed on subjects. PMID- 23102751 TI - The contribution of MRI in the diagnosis of acute myocarditis following a spider bite: a case report. PMID- 23102752 TI - The emotional overlay: older person and carer perspectives on negotiating aging and care in rural Ontario. AB - This paper extends the burgeoning interest in emotion, health and place by investigating the emotionally complex experiences of aging and care in rural settings. Featuring a thematic analysis of 44 semi-structured interviews and two focus groups with older people and their carers in rural Ontario (Canada) we examine the importance and implications of emotions within and across multiple scales at which care relationships, expectations and responsibilities are negotiated. With the aim of broadening the discussion surrounding geographical dimensions of ethical care, our approach draws on feminist care ethics to understand the multifaceted ways in which emotions shape and are shaped by experiences of aging and caring at the interpersonal, household and community scales. The findings reveal how emotions are central, yet often-overlooked and even hidden within care relationships among older rural people and their carers. We argue that ethical care is contingent on recognizing and valuing the situated emotions involved in doing care work, sustaining care relationships and asking for care. In doing so, we demonstrate how qualitative research on the emotional geographies of care can contribute to the development of informed policies that are contextually sensitive and, ultimately, have the potential to build more ethical rural conditions of care. PMID- 23102753 TI - "Pay them if it works": discrete choice experiments on the acceptability of financial incentives to change health related behaviour. AB - The use of financial incentives to change health-related behaviour is often opposed by members of the public. We investigated whether the acceptability of incentives is influenced by their effectiveness, the form the incentive takes, and the particular behaviour targeted. We conducted discrete choice experiments, in 2010 with two samples (n = 81 and n = 101) from a self-selected online panel, and in 2011 with an offline general population sample (n = 450) of UK participants to assess the acceptability of incentive-based treatments for smoking cessation and weight loss. We focused on the extent to which this varied with the type of incentive (cash, vouchers for luxury items, or vouchers for healthy groceries) and its effectiveness (ranging from 5% to 40% compared to a standard treatment with effectiveness fixed at 10%). The acceptability of financial incentives increased with effectiveness. Even a small increase in effectiveness from 10% to 11% increased the proportion favouring incentives from 46% to 55%. Grocery vouchers were more acceptable than cash or vouchers for luxury items (about a 20% difference), and incentives were more acceptable for weight loss than for smoking cessation (60% vs. 40%). The acceptability of financial incentives to change behaviour is not necessarily negative but rather is contingent on their effectiveness, the type of incentive and the target behaviour. PMID- 23102754 TI - Medical professionalism among clinical physicians in two tertiary hospitals, China. AB - In order to investigate medical professional attitudes and behaviors in China and explore the influencing factors with a focus on hospital internal management, we developed a 13-item professional attitudes and 11-item behaviors inventory. Self administered questionnaires were distributed to 390 physicians mainly in four specialties in two tertiary Chinese hospitals in 2011. 306 completed questionnaires were collected. More than 90% of respondents agreed with at least nine of the 13 specific statements about principles. However, responses on behaviors were not necessarily consistent with those on attitudes. 80.3% of respondents reported that they usually or always participated in quality improvement activities and 48.2% reported that they usually or always participated in peer evaluations of colleagues' quality of care. Some 47.8% had encountered incompetent colleagues and 17.7% had encountered significant medical errors caused by colleagues. Among those who had encountered incompetence or significant medical errors, almost two thirds had never reported their concerns to the hospital or other relevant authorities. Half of the physicians did not obtain enough continuing medical education credits. Physicians' professional reported behaviors were influenced by their personal and professional characteristics, professional attitudes, and assessment of hospital internal management constitutions. For example, participation in decision-making had a significant role in professional reported behaviors of protecting patient confidentiality, improving quality of care, and self-regulation, with those sometimes or often participating in decision-making indicating higher levels of reported behaviors than those who seldom participated (odds ratios: 1.84; 4.31, 2.44; 3.31). The results showed Chinese physicians demonstrated positive attitudes to professionalism principles. However, their reported behaviors were at times inconsistent with their attitudes, especially in the areas of competence, quality improvement, and self-regulation. One of effective strategies to facilitate Chinese physicians' professionalism may be to improving hospital management. PMID- 23102755 TI - Association between body image dissatisfaction and weight loss among patients with advanced cancer and their caregivers: a preliminary report. AB - CONTEXT: No prospective studies have dealt with the impact of cachexia-related weight loss on patients' body image as well as the impact of patients' body image changes on the level of patient and family distress. OBJECTIVES: Our aim was to examine associations between body mass index (BMI), weight loss, symptom distress, and body image for patients with advanced cancer and their caregivers. METHODS: Outpatients with advanced cancer and different levels of BMI, along with their caregivers, were recruited. Patient assessments included BMI, precancer weight, Body Image Scale (BIS; 0-30), Edmonton Symptom Assessment System (ESAS), Hospital Anxiety and Depression Scale (HADS), and sexual interest and enjoyment as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Head and Neck Cancer Module 35. Caregivers were asked to assess the patient's body image, using the BIS; rate their own quality of life, using the Caregiver Quality of Life Index-Cancer; and rate their overall distress and distress regarding the patient's weight, using the Distress Thermometer (DT). RESULTS: We included 81 patients and 30 caregivers. Forty-eight patients (59%) experienced weight loss of at least 10%. The mean BIS score was 11.23 (SD = 7.24). Body image dissatisfaction was correlated with weight loss (r = 0.31, P = 0.006), anxiety (HADS-A; r = 0.39, P < 0.001), depression (HADS-D; r = 0.46, P < 0.001), decreased sexual interest (r = 0.37, P = 0.001), decreased sexual enjoyment (r = 0.33, P = 0.004), ESAS score for pain (r = 0.25, P = 0.026), fatigue (r = 0.28, P = 0.014), drowsiness (r = 0.28, P = 0.014), shortness of breath (r = 0.27, P = 0.016), sleep disorders (r = 0.24, P = 0.036), and well-being (r = 0.29, P = 0.011). We found a significant association between the caregivers' evaluation of patients' body image dissatisfaction and patients' BIS score (r = 0.37, P = 0.049) and caregivers' distress regarding the patients' weight (DT; r = 0.58; P = 0.001). CONCLUSION: Body image dissatisfaction was strongly associated with patients' weight loss and with psychosocial distress among patients and their caregivers. More research is necessary to better understand the association between the severity of body image dissatisfaction and the severity of other problems in patients with cancer. PMID- 23102756 TI - The development and validation of a shorter version of the Canadian Health Care Evaluation Project Questionnaire (CANHELP Lite): a novel tool to measure patient and family satisfaction with end-of-life care. AB - CONTEXT: The recently developed Canadian Health Care Evaluation Project (CANHELP) questionnaire, which can be used to assess both patient and family satisfaction with end-of-life care, takes 40-60 minutes to complete. The length of the interview may limit its uptake and clinical utility; a shorter version would make its use more feasible. OBJECTIVES: The purpose of this study was to develop and validate a shorter version of the CANHELP questionnaire. METHODS: Data were collected using a cross-sectional survey of patients with advanced medical diseases and their family members. Participants completed the long version of CANHELP, a global rating of satisfaction with care (GRS), the FAMCARE scale (family members only), and a quality-of-life (QOL) questionnaire. We reduced the items on the long version based on their relationship to the GRS, the frequency of missing data, the distribution of responses, the redundancy of the items, and focus groups with frontline users. With the remaining items, we assessed internal consistency using Cronbach's alpha, and evaluated construct validity by describing the correlation of the new CANHELP Lite with the full version of CANHELP, GRS, FAMCARE, and the QOL questionnaire scores. RESULTS: A total of 363 patients and 193 family members participated in this study. The patient version was reduced from 37 items to 20 items and the caregiver version was reduced from 38 items to 21 items. Cronbach's alphas ranged from 0.68 to 0.93 for all domains of both the patient and caregiver questionnaires. We observed a high degree of correlation between CANHELP Lite domains and overall scores and the same domains and overall scores for the full version of CANHELP. In addition, we observed moderate to strong correlation between the CANHELP Lite overall satisfaction scores and the GRS questions. There was moderate correlation between the overall family member CANHELP Lite score and overall FAMCARE score (r = 0.45) and this was similar to the correlation between the full version of CANHELP and FAMCARE scores (r = 0.41). CANHELP Lite correlated more strongly with the QOL subscale on health care than the other QOL subscales. CONCLUSION: The CANHELP Lite questionnaire is a valid and internally consistent instrument to measure satisfaction with end-of-life care. PMID- 23102757 TI - Long-term control of refractory hemorrhagic radiation proctitis with ozone therapy. AB - CONTEXT: Persistent or severe hemorrhagic radiation proctitis (HRP) has limited therapeutic options. OBJECTIVES: To describe our experience with ozone therapy (O3T) in the management of refractory HRP. METHODS: Patients (n=17; median age 69 years [range 42-80 years]) previously irradiated for prostate or uterine cancer and suffering persistent or severe HRP without response to conventional treatment were enrolled to receive an O3/O2 gas mixture via rectal insufflations and topical application of ozonized oil. Most of the patients (83%) had Grade 3 or Grade 4 toxicity. Median follow-up post-O3T was 40 months (range 3-56 months). RESULTS: Endoscopic treatments required were: 43 (median 1; range 0-10) pre-O3T; 17 (median 0; range 0-8; P=0.063) during O3T; and five (median 0; range 0-2; P=0.008) during follow-up. Hemoglobin levels were 10.35g/dL (7-14g/dL) pre-O3T and 13g/dL (9-15g/dL) (P=0.001) post-O3T. Median toxicity grades were 3 (range 2 4) pre-O3T, 1 (range 0-2; P<0.001) at the end of O3T, and 0 (range 0-1; P<0.001) at the last follow-up. CONCLUSION: Persistent advanced HRP was significantly improved with O3T. The addition of O3T can be useful as a complementary treatment in the long-term management of HRP and, as such, merits further evaluation. PMID- 23102758 TI - Missing data from missing participants. PMID- 23102760 TI - Detection of Neospora caninum in wild carnivorans in Great Britain. AB - Samples of brain and other tissues were collected from 99 ferrets (Mustela furo), 83 red foxes (Vulpes vulpes), 70 European polecats (Mustela putorius), 65 American mink (Neovison vison), 64 Eurasian badgers (Meles meles) and 9 stoats (Mustela erminea), from around Great Britain. DNA was extracted from approximately 1g of tissue and tested by specific nested ITS1 PCR for Neospora caninum. The results from the PCR demonstrated that Neospora specific DNA was detected in all species of wild carnivorans with the exception of the stoats (0/9). Neospora DNA positive samples were detected in: polecats 18.6% (13/70), badgers 10.9% (7/64), ferrets 10.1% (10/99), foxes 4.8% (4/83) and mink 4.6% (3/65). In the badgers N. caninum DNA positive samples were found in brain (n=2), liver (n=2) and neck muscle (n=3). Selected positive ITS1 DNA sequences were submitted to Genbank. Sequence UKwildlife1 (accession number JX857862) was found in two badgers, whilst UKwildlife2 and UKwildlife3 (accession numbers JX857863 and JX857864 respectively) were found in ferrets, all three sequences demonstrated point mutations at a single base, while sequence UKwildlife4 (accession number JX857865) was found in all the species that tested positive and showed complete identity when compared against published reference sequences for: N. caninum (Nc Liverpool isolate, EU564166). Our data shows that almost all the wild carnivoran mammal species tested are intermediate hosts for N. caninum and are therefore capable of acting as reservoirs of infection for other species. These species could also act as useful sentinel species, demonstrating the presence of the parasite in particular geographical and environmental locations. PMID- 23102761 TI - Anthelmintic effect of plant extracts containing condensed and hydrolyzable tannins on Caenorhabditis elegans, and their antioxidant capacity. AB - Although tannin-rich forages are known to increase protein uptake and to reduce gastrointestinal nematode infections in grazing ruminants, most published research involves forages with condensed tannins (CT), while published literature lacks information on the anthelmintic capacity, nutritional benefits, and antioxidant capacity of alternative forages containing hydrolyzable tannins (HT). We evaluated the anthelmintic activity and the antioxidant capacity of plant extracts containing either mostly CT, mostly HT, or both CT and HT. Extracts were prepared with 70% acetone, lyophilized, redissolved to doses ranging from 1.0mg/mL to 25mg/mL, and tested against adult Caenorhabditis elegans as a test model. The extract concentrations that killed 50% (LC(50)) or 90% (LC(90)) of the nematodes in 24h were determined and compared to the veterinary anthelmintic levamisole (8 mg/mL). Extracts were quantified for CT by the acid butanol assay, for HT (based on gallic acid and ellagic acid) by high-performance liquid chromatography (HPLC) and total phenolics, and for their antioxidant activity by the oxygen radical absorbance capacity (ORAC) assay. Extracts with mostly CT were Lespedeza cuneata, Salix X sepulcralis, and Robinia pseudoacacia. Extracts rich in HT were Acer rubrum, Rosa multiflora, and Quercus alba, while Rhus typhina had both HT and CT. The extracts with the lowest LC(50) and LC(90) concentrations, respectively, in the C. elegans assay were Q. alba (0.75 and 1.06 mg/mL), R. typhina collected in 2007 (0.65 and 2.74 mg/mL), A. rubrum (1.03 and 5.54 mg/mL), and R. multiflora (2.14 and 8.70 mg/mL). At the doses of 20 and 25mg/mL, HT-rich, or both CT- and HT-rich, extracts were significantly more lethal to adult C. elegans than extracts containing only CT. All extracts were high in antioxidant capacity, with ORAC values ranging from 1800 MUmoles to 4651 MUmoles of trolox equivalents/g, but ORAC did not correlate with anthelmintic activity. The total phenolics test had a positive and highly significant (r=0.826, p <= 0.01) correlation with total hydrolyzable tannins. Plants used in this research are naturalized to the Appalachian edaphoclimatic conditions, but occur in temperate climate areas worldwide. They represent a rich, renewable, and unexplored source of tannins and antioxidants for grazing ruminants, whereas conventional CT-rich forages, such as L. cuneata, may be hard to establish and adapt to areas with temperate climate. Due to their high in vitro anthelmintic activity, antioxidant capacity, and their adaptability to non-arable lands, Q. alba, R. typhina, A. rubrum, and R. multiflora have a high potential to improve the health of grazing animals and must have their anthelmintic effects confirmed in vivo in both sheep and goats. PMID- 23102762 TI - Expression, purification and antigenicity of Neospora caninum-antigens using silkworm larvae targeting for subunit vaccines. AB - Infection of Neospora caninum causes abortion in cattle, which has a serious worldwide impact on the economic performance of the dairy and beef industries. Now, inexpensive and efficacious vaccines are required to protect cattle from neosporosis in livestock industry. In this study, N. caninum surface antigen 1 (SAG1) and SAG1-related sequence 2 (SRS2) were expressed in hemolymph of silkworm larvae as a soluble form. Expressed SAG1 and SRS2 clearly showed antigenicity against N. caninum-positive sera of cow. SAG1 and SRS2 were purified to near homogeneity from hemolymph of silkworm larvae using anti-FLAG M2 antibody agarose: approximately 1.7 mg of SAG1 from 10 silkworm larvae and 370 MUg of SRS2 from 17 silkworm larvae. Mice that were injected by antigens induced antibodies against SAG1 and SRS2. This study indicates that it is possible that this silkworm expression system leads to a large-scale production of N. caninum antigens with biological function and low production cost. Bombyx mori nucleopolyhedrovirus (BmNPV) bacmid expression system paves the way to produce largely and rapidly these recombinant antigens for its application to subunit vaccines against neosporosis in cattle. PMID- 23102759 TI - Transfusion-associated microchimerism: the hybrid within. AB - Microchimerism, the coexistence of genetically disparate populations of cells in a receptive host, is well described in both clinical and physiological settings, including transplantation and pregnancy. Microchimerism can also occur after allogeneic blood transfusion in traumatically injured patients, where donor cells have been observed decades after transfusion. To date, transfusion-associated microchimerism (TA-MC) appears confined to this clinical subset, most likely due to the immune perturbations that occur after severe trauma that allow foreign donor cells to survive. Transfusion-associated microchimerism appears to be unaffected by leukoreduction and has been documented after transfusion with an array of blood products. The only significant predictor of TA-MC to date is the age of red cells, with fresher units associated with higher risk. Thus far, no adverse clinical effect has been observed in limited studies of TA-MC. There are, however, hypothesized links to transfusion-associated graft vs host disease that may be unrecognized and consequently underreported. Microchimerism in other settings has gained increasing attention owing to a plausible link to autoimmune diseases, as well as its diagnostic and therapeutic potential vis-a-vis antenatal testing and adoptive immunotherapy, respectively. Furthermore, microchimerism provides a tool to further our understanding of immune tolerance and regulation. PMID- 23102763 TI - Clinical application of the thoracodorsal artery perforator flaps. AB - BACKGROUND: Thoracodorsal artery perforator (TAP) flaps without latissimus dorsi muscle - have been used for reconstruction of the extremities, head and neck as free style flaps, and as pedicled flaps for reconstruction of the chest wall and axillary wounds. This retrospective study aimed to analyse the clinical applications and relevant anatomic findings of TAP flaps. METHODS: From April 2007 to August 2011, 67 free or pedicled TAP flaps were transferred in 67 patients for reconstruction of wounds of the extremities, chest wall and axilla. Eight were used as free flaps for reconstruction of extremities, and 59 used as pedicled flaps for reconstruction of axillary or chest wounds. Patient ages ranged from 7 to 55 years (26.04+/-12.83). Perforator arteries were detected and identified with a hand-held Doppler. The size of flaps ranged from 6 by 9 to 14 by 18 cm ((8.66+/-2.05) by (12.62+/-2.03)). Flaps were designed with the perforator artery included, with all flaps based on one or two perforator arteries. RESULTS: All of the flaps survived. There were no problems with vascular spasm or occlusion. Significant venous congestion was not observed in any of the cases. Two cases developed minor wound dehiscence but healed with conservative therapy. None of the donor sites developed seromas. CONCLUSIONS: The thoracodorsal artery flap without associated latissimus dorsi muscle can provide a thin, large and reliable flap with robust blood supply. The TAP flap can significantly reduce donor site morbidity. PMID- 23102764 TI - A comparison of perioperative complications following transfer of fibular and scapular flaps for immediate mandibular reconstruction. AB - BACKGROUND: The fibular flap and the scapular flap are widely used for immediate reconstruction after segmental mandibulectomy. The aim of this study was to compare perioperative complications between the fibular flap and the scapular flap in immediate mandibular reconstruction. METHODS: Data were retrospectively collected on 56 patients who had undergone immediate mandibular reconstruction with a fibular flap (38 patients) or a scapular flap (18 patients) after segmental mandibulectomy from 2005 to 2011. The rates of perioperative recipient site and donor-site complications were compared between the groups. RESULTS: The overall rate of recipient-site complications did not differ significantly between the fibula group and the scapula flap. However, the rate of donor-site complications was significantly higher in the fibula group than in the scapula group. Partial skin-graft loss in the fibula group occurred in as high as 13 out of 38 patients. DISCUSSION: For immediate mandibular reconstruction, a scapular flap provides short-term results equivalent to those with a fibular flap but with less donor-site morbidity. The major drawbacks of the fibular flap include prolonged healing of the donor site and the delayed mobilisation of patients. Although our first choice of vascularised bone graft is the fibular flap, the scapular flap in an alternative for those patients, especially elderly patients, in whom fibula harvest can result in significant morbidity. PMID- 23102765 TI - Time course of hydronephrotic changes following unilateral pyeloplasty. AB - OBJECTIVES: The temporal pattern of hydronephrotic change following pyeloplasty has not been well defined. To address this issue, 23 years of postpyeloplasty follow-up data from a single surgeon were analyzed. PATIENTS AND METHODS: Records of dismembered pyeloplasty from 1986 to 2004 were retrospectively reviewed. Ultrasound follow-ups were conducted at 3-6-month intervals after surgery for up to 3 years, and were then extended to either annually or biannually until the completion of puberty. Overall outcome of hydronephrosis (HN), timing of initial improvement and normalization were determined. Factors associated with these changes were examined. RESULTS: Of 215 patients who completed follow-up of at least 5 years, about 80% experienced either normalization or improvement. Once they had shown improvement of HN during follow-up, no recurrence was observed. The median time for recognition of initial improvement and normalization of HN was 8 months and 41 months after surgery, respectively. Multivariate analysis revealed that the presence of immediate postoperative obstruction was a negative factor for initial improvement. Symptomatic presentation and no initial improvement until 6 months after pyeloplasty turned out to be negative factors for normalization. CONCLUSIONS: The results confirm the excellent long-term outcome of pyeloplasty, and highlight the importance of frequent ultrasound until initial improvement of HN, when subsequent ultrasound follow-ups may be safely omitted to focus on follow-up of renal function, proteinuria and hypertension. PMID- 23102766 TI - Loss of anatomical landmarks with eutectic mixture of local anesthetic cream for neonatal male circumcision. AB - We report two cases of newborns who developed marked local edema after application of a eutectic mixture of local anesthetic (EMLA) topical anesthetic cream for neonatal male circumcision (NMC). Although local edema and erythema are known potential side effects of EMLA cream, a common anesthetic used for NMC, the loss of landmarks precluding safe NMC has not previously been reported, and is described here. Although we cannot recommend an alternate local anesthetic for neonates with this reaction to EMLA, based on a review of the published data we think that serious systemic adverse events related to EMLA are extremely rare. PMID- 23102767 TI - Cutaneous multicentric Castleman's disease mimicking IgG4-related disease. AB - Castleman's disease, an uncommon lymphoproliferative disorder, can be difficult to differentiate from immunoglobulin (Ig) G4-related disease. The latter is typically characterized by elevated serum IgG4 levels and abundant IgG4-positive cells. However, multicentric Castleman's disease can also have elevated serum IgG4 levels and even fulfill the histological diagnostic criteria for IgG4 related disease. We present a case of cutaneous multicentric Castleman's disease mimicking IgG4-related disease. A 55-year-old Japanese woman developed erythematous and brown plaques on her back. Skin biopsy revealed regressive follicles with interfollicular plasmacytosis, and many plasma cells were positive for IgG4 (mean 263.67+/-79.19, range 214-355 per high power field). The IgG4-/IgG positive cell ratios were 35.6%, 36.2%, and 48.4%, respectively, with an average of 40.6%, thus fulfilling the histological diagnostic criteria for IgG4-related disease. Furthermore, serum IgG4 level was significantly elevated (1490 mg/dl; normal range: 4.8-105 mg/dl). However, laboratory findings of anemia, hypoalbuminemia, polyclonal gammaglobulinemia, high C-reactive protein level, and elevated serum interleukin-6 level were consistent with hyper-IL-6 syndrome. Hence, the diagnosis of cutaneous multicentric Castleman's disease was made. In conclusion, IgG4-related disease cannot be differentiated from hyper-IL-6 syndromes on histology alone. Instead, laboratory analyses are necessary to distinguish between the two diseases. PMID- 23102768 TI - The inactivation kinetics of polyphenol oxidase in mushroom (Agaricus bisporus) during thermal and thermosonic treatments. AB - The effect of thermal and thermosonic treatments on the inactivation kinetics of polyphenol oxidase (PPO) in mushroom (Agaricus bisporus) was studied in 55-75 degrees C temperature range. In both the processes, the inactivation kinetics of PPO followed a first-order kinetics (R(2)=0.941-0.989). The D values during thermal inactivation varied from 112+/-8.4min to 1.2+/-0.07min while they varied from 57.8+/-6.1min to 0.88+/-0.05min during thermosonic inactivation at the same temperature range. The activation energy during thermal inactivation was found to be 214+/-17kJ/mol, while it was 183+/-32kJ/mol during thermosonic inactivation. The inactivating effect of combined ultrasound and heat was found to synergistically enhance the inactivation kinetics of PPO. The D values of PPO decreased by 1.3-3 times during thermosonic inactivation compared to the D values of PPO during thermal inactivation at the temperature range. Therefore, thermosonication can be further developed as an alternative to "hot break" process of mushroom. PMID- 23102769 TI - Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. AB - OBJECTIVES: We sought to characterize a new category of autoinflammatory disease associated with nucleotide-binding oligomerization domain 2 (NOD2) gene mutations. METHODS: A total of 22 patients were identified, inclusive of those reported previously. All had autoinflammatory phenotypes and NOD2 gene mutations that were prospectively studied between January 2009 and February 2012. RESULTS: All 22 patients were non-Jewish whites (13 women and 9 men). The mean age at diagnosis was 40.1 years (range 17-72), with a mean disease duration of 4.7 years (range 1-13). Three female patients were siblings. Common clinical features were weight loss (13/22), episodic self-limiting fever (13/22), dermatitis (19/22), and inflammatory polyarthritis/polyarthralgia (20/22). Gastrointestinal symptoms occurred in 13 patients, sicca-like symptoms in 9, and recurrent chest pain in 5. All patients carried the NOD2 gene mutations, with the intervening sequence 8(+158) variant in 21 and the R702W variant in 8. LIMITATIONS: The NOD2 allelic frequency may need to be examined in a larger population with systemic autoimmune diseases. CONCLUSIONS: The characteristic clinical phenotype, notably dermatitis, coupled with certain NOD2 variants constitutes a new autoinflammatory disease entity, which we have named as NOD2-associated autoinflammatory disease. PMID- 23102770 TI - A systematic review of patient-reported outcome instruments of nonmelanoma skin cancer in the dermatologic population. AB - BACKGROUND: Treatment of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) has traditionally focused on minimizing recurrence and complication rates. However, the assessment of patient satisfaction and quality of life (QOL) is also important. These outcomes are best assessed by patient-reported outcome (PRO) instruments. OBJECTIVES: We sought to conduct a systematic review of published PRO instruments purporting to measure aspects associated with QOL and/or patient satisfaction in the dermatologic BCC/SCC population and evaluate their development, content, and psychometric properties. METHODS: PubMed, Embase, Cochrane via Wiley, PsycINFO, CINAHL, and HaPI from inception to April 2011 were searched. Articles that discussed the instrument development and validation process were included. RESULTS: A total of 2212 articles were identified. Twenty met our inclusion criteria resulting in 6 PRO instruments: 3 general dermatology (Skindex, Dermatology Life Quality Index, dermatology quality of life scales), 1 general plastic surgery (Patient Outcomes of Surgery-Head/Neck), and 2 skin cancer-specific (Skin Cancer Index, disease-specific questionnaire). The 6 instruments all underwent some degree of formal development and validation, however, only the Skin Cancer Index was developed and validated in the BCC/SCC population. LIMITATIONS: The review may not have included all relevant PRO instruments. CONCLUSIONS: The Skin Cancer Index demonstrates the most evidence of its usefulness in patients with BCC/SCC. The Skindex-16, Dermatology QOL Scales, and Dermatology Life Quality Index target different aspects of QOL and should be used depending on the specific question being investigated. The Patient Outcomes of Surgery-Head/Neck may be beneficial to assess perceptions in appearance before and after surgical intervention. PMID- 23102771 TI - Food patch testing for irritable bowel syndrome. AB - BACKGROUND: The traditional classification of irritable bowel syndrome (IBS) as a functional disorder has been challenged in recent years by evidence of ongoing low-grade gastrointestinal tract inflammation. Inflammation may alter gastrointestinal motility and thus be central to the pathogenesis of IBS. Many foods and food additives are known to cause allergic contact dermatitis. We hypothesize that allergenic foods and food additives may elicit a similar allergic reaction in the gastrointestinal tract, giving rise to symptoms suggestive of IBS. OBJECTIVE: We sought to determine whether skin patch testing to a panel of foods and food additives may identify food allergens that may be responsible for symptoms of IBS. METHODS: We performed skin patch testing to common allergenic foods and food additives on individuals with a history of or symptoms suggestive of IBS. We used patch test-guided avoidance diets to determine whether avoidance alleviates IBS symptoms. RESULTS: Thirty of the 51 study participants showed at least 1 doubtful or positive patch test result. Fourteen of the participants reported symptomatic improvement, ranging from slight to great, upon avoidance of the foods/food additives to which they reacted. LIMITATIONS: Double-blind study design, inclusion of only patients with active IBS, larger sample size, more balanced gender distribution, testing of more foods/food additives, and longer duration of and more precise quantification of response to dietary avoidance are suggested for future studies. CONCLUSION: Allergic contact enteritis to ingested foods, food additives, or both may contribute to IBS symptoms. Patch testing may be useful in identifying the causative foods. PMID- 23102772 TI - Oxidation of N-hydroxy-l-arginine by hypochlorous acid to form nitroxyl (HNO). AB - Recent research has shown that nitroxyl (HNO) has important and unique biological activity, especially as a potential alternative to current treatments of cardiac failure. HNO is a reactive molecule that undergoes efficient dimerization and subsequent dehydration to form nitrous oxide (N(2)O), making its detection in solution or biologically relevant preparations difficult. Due to this limitation, HNO has not yet been observed in vivo, though several pathways for its endogenous generation have been postulated. Here, we investigate the oxidation of N-hydroxy l-arginine (NOHA) by hypochlorous acid (HOCl), which is generated in vivo from hydrogen peroxide and chloride by the heme enzyme, myeloperoxidase. NOHA is an intermediate in the enzymatic production of nitric oxide (NO) by NO synthases, and has been shown previously to be chemically oxidized to either HNO or NO, depending on the oxidant employed. Using membrane inlet mass spectrometry and standard N(2)O analysis by gas chromatography, we find that NOHA is oxidized by excess HOCl to form HNO-derived N(2)O. In addition, we also observe the analogous production of HNO from the HOCl oxidation of hydroxylamine, hydroxyurea, and (to a lesser extent) acetohydroxamic acid. PMID- 23102773 TI - Single turnover studies of oxidative halophenol dehalogenation by horseradish peroxidase reveal a mechanism involving two consecutive one electron steps: toward a functional halophenol bioremediation catalyst. AB - Horseradish peroxidase (HRP) catalyzes the oxidative para-dechlorination of the environmental pollutant/carcinogen 2,4,6-trichlorophenol (2,4,6-TCP). A possible mechanism for this reaction is a direct oxygen atom transfer from HRP compound I (HRP I) to trichlorophenol to generate 2,6-dichloro 1,4-benzoquinone, a two electron transfer process. An alternative mechanism involves two consecutive one electron transfer steps in which HRP I is reduced to compound II (HRP II) and then to the ferric enzyme as first proposed by Wiese et al. [F.W. Wiese, H.C. Chang, R.V. Lloyd, J.P. Freeman, V.M. Samokyszyn, Arch. Environ. Contam. Toxicol. 34 (1998) 217-222]. To probe the mechanism of oxidative halophenol dehalogenation, the reactions between 2,4,6-TCP and HRP compounds I or II have been investigated under single turnover conditions (i.e., without excess H(2)O(2)) using rapid scan stopped-flow spectroscopy. Addition of 2,4,6-TCP to HRP I leads rapidly to HRP II and then more slowly to the ferric resting state, consistent with a mechanism involving two consecutive one-electron oxidations of the substrate via a phenoxy radical intermediate. HRP II can also directly dechlorinate 2,4,6-TCP as judged by rapid scan stopped-flow and mass spectrometry. This observation is particularly significant since HRP II can only carry out one-electron oxidations. A more detailed understanding of the mechanism of oxidative halophenol dehalogenation will facilitate the use of HRP as a halophenol bioremediation catalyst. PMID- 23102774 TI - Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2. PMID- 23102775 TI - Mediterranean diet: natural salicylates and other secrets of the pyramid. PMID- 23102776 TI - Pediatric prostatic abscess. AB - Prostatic abscesses are an increasingly rare clinical entity. They are commonly caused by spread of a gram-negative urinary tract infection. Most cases reported in urologic studies have occurred in older men and are the result of bladder outlet obstruction. To date, very few cases of pediatric prostatic abscesses have been reported in published studies, and most of these occurred in neonates. We present a case of methicillin-resistant Staphylococcus aureus prostatic abscess in an adolescent and review the related data for this unusual process. PMID- 23102777 TI - Editorial comment. PMID- 23102778 TI - Polymorphism in the SCN9A voltage-gated sodium channel gene associated with interstitial cystitis/bladder pain syndrome. AB - OBJECTIVE: To determine whether an association exists between interstitial cystitis/bladder pain syndrome (IC/BPS) and a nonsynonymous single nucleotide polymorphism in the SCN9A voltage-gated sodium channel gene previously associated with other chronic pain syndromes. MATERIALS AND METHODS: Germline deoxyribonucleic acid was sampled from archived bladder biopsy specimens from patients with a documented diagnosis of IC/BPS. Deoxyribonucleic acid from hysterectomy specimens was obtained as a control population. The genotype of single nucleotide polymorphism rs6746030 was determined by deoxyribonucleic acid sequencing after polymerase chain reaction amplification. Contingency analysis of genotypes was performed using Pearson's chi-square test and Fisher's exact test. RESULTS: Polymerase chain reaction product was obtained from 26 of 31 control specimens and from 53 of 57 IC/BPS biopsy specimens. Of the 26 control subjects, 3 (11.5%) were genotype AG and 23 were GG. In contrast, AA or AG genotypes were present in 21 of 53 (39.6%) patients with IC/BPS, a statistically significant difference compared with the controls (Pearson's chi-square, P=.036). Similarly, the A allele was at a greater frequency in the IC/BPS group using Fisher's exact test (P=.009). CONCLUSION: These data strongly suggest that pain perception in at least a subset of patients with IC/BPS is influenced by this polymorphism in the SCN9A voltage-gated sodium channel. PMID- 23102779 TI - Antitumor effects of exogenous ganglioside GM3 on bladder cancer in an orthotopic cancer model. AB - OBJECTIVE: To investigate the therapeutic effects of exogenous gangliosides GM3 on human bladder cancer cell lines and the severe combined immunodeficiency mouse model of orthotopic bladder cancer. MATERIALS AND METHODS: Human bladder cancer cell lines YTS-1, T24, 5637, and KK47 were used in the study. In vitro cytotoxicity of GM3 was assessed using the cell counting kit-8. Cell adhesion was determined using a spreading assay. Phosphorylation of epidermal growth factor receptor was determined by Western blotting. In vivo, the orthotopic bladder cancer model was established using severe combined immunodeficiency mice and GM3 was administered intravesically by way of a transurethral catheter. RESULTS: GM3 inhibited the proliferation of all the bladder cancer cell lines tested. The addition of GM3 decreased cell adhesion and epidermal growth factor-dependent phosphorylation of epidermal growth factor receptor. Direct instillation of GM3 into the bladder of the orthotopic model significantly inhibited tumor growth. CONCLUSION: Our results suggest exogenous GM3 as a potential therapeutic agent for treating bladder cancer. PMID- 23102780 TI - [3.0T MRI with a high resolution protocol for the study of benign disease of the anus and rectum. Part 2: Anorectal inflammatory disease. Postsurgical anatomy and complications after treatment]. AB - Benign anorectal disease comprises a broad group of processes with very diverse origins; these processes may be congenital or acquired as well as inflammatory or tumor related. However, benign anorectal disease has received less attention in the scientific literature than malignant disease. In this second part of this image-based review of benign anorectal disease, we describe the most common inflammatory and fistulous diseases, the postsurgical anatomy, and complications that can occur after surgical treatment or radiotherapy for anorectal disease. PMID- 23102781 TI - [Appendicular mucocele simulating an adnexal mass]. PMID- 23102782 TI - Effects of chemokine-like factor 1 on vascular smooth muscle cell migration and proliferation in vascular inflammation. AB - OBJECTIVE: Vascular smooth muscle cell (VSMC) migration and proliferation are key components of vascular inflammation that may lead to atherosclerosis and restenosis, in which cytokines are considered as pivotal factors regarding recruitment of VSMC. A member of recently described family of chemokines, chemokine-like factor 1 (CKLF1), displays a wide spectrum of chemotaxis. This study investigated the role of CKLF1 in VSMC migration and proliferation during the process of vascular inflammation. METHODS AND RESULTS: : The effects of CKLF1 on migration, proliferation and neointimal formation were investigated in cultured VSMCs, rat balloon injured arteries and human atherosclerotic plaques. CKLF1 overexpression greatly enhanced, whereas shRNA knockdown markedly retarded, VSMC migration and proliferation in vitro. In addition, CKLF1 protein accumulated preferentially in neointima of the injured rat arteries in vivo. CKLF1 overexpression resulted in a 2.5-fold increase in intimal thickness. In contrast, shRNA-mediated CKLF1 knockdown significantly suppressed neointima formation by 70% compared that in control group. Intriguingly, besides animal model, higher level of CKLF1 was observed in human atherosclerotic plaques than that in normal arteries. CONCLUSION: CKLF1 plays an essential role in migration and proliferation of VSMCs, which in turn facilitated neointimal hyperplasia and atherosclerosis. Inhibition of CKLF1 activity provides a potential target for the prevention of atherosclerosis and restenosis. PMID- 23102783 TI - Modulation of atherogenic lipidome by cigarette smoke in apolipoprotein E deficient mice. AB - OBJECTIVE: Although relationships between smoking and cardiovascular diseases (CVD), and between CVD and lipids are established, the direct impact of smoking on lipidomes is not well understood. We investigated the effect of mainstream cigarette smoke (CS) exposure on plasma, liver, and aorta molecular lipid profiles, and liver transcriptome in the ApoE(-/-) mouse, a well-established mouse model for human atherogenesis. METHODS: Plasma, liver, and aorta samples from ApoE(-/-) mice exposed to CS or fresh air (sham) for six months were extracted for lipids using robotic-assisted method and analyzed by mass spectrometry. Gene expression in the liver was obtained on microarrays. Development of atherosclerosis in the aorta was further assessed by plaque size in the aortic arch and lipoprotein concentration in plasma and plaque. RESULTS: CS increased most lipid classes and molecular lipid species. In plasma, free cholesterol, ceramides, cerebrosides, and most phospholipids were increased in CS exposed mice. In the liver, several lipid species including free and esterified cholesterol, triacylglycerols, phospholipids, sphingomyelins, and ceramides were elevated. In the aorta, more than 2-fold higher cholesteryl ester (CE), lysophosphatidylcholine, and glucosyl/galactosylceramide levels were seen. Moreover, CS exposure induced a significant decrease in several plasma CE and phosphatidylcholine species that contained polyunsaturated fatty acids. Genes involved in amino acid and lipid metabolism showed perturbed transcription profiles in the liver. CONCLUSION: We have quantified some of the molecular changes that accompany the increase of plaque size that is accelerated by CS exposure in the aortae of ApoE(-/-) mice. These results suggest that specific changes in the lipidome and transcriptome, for example in ceramide and polyunsaturated fatty acid species, may be associated with atherosclerosis. PMID- 23102784 TI - Mutations in the SORT1 gene are unlikely to cause autosomal dominant hypercholesterolemia. AB - OBJECTIVE: To study whether mutations in the SORT1 gene could be a cause of autosomal dominant hypercholesterolemia and to study the effect of sortilin on the binding and internalization of low density lipoprotein (LDL). METHODS: 842 unrelated hypercholesterolemic subjects without mutations in genes known to cause autosomal dominant hypercholesterolemia, were screened for mutations in the SORT1 gene by DNA sequencing. Transfections of wild-type or mutant SORT1 plasmids in HeLa T-REx cells and the use of siRNA were used to study the effect of sortilin on the number of cell-surface LDL receptors and on the binding and internalization of LDL. RESULTS: A total of 45 mutations in the SORT1 gene were identified of which 15 were missense mutations. Eight of these were selected for in vitro studies, of which none had a major impact on the amount of LDL bound to the cell surface. There was a positive correlation between the amount of sortilin on the cell surface and the amount of LDL bound. The observation that a mutant sortilin which is predominantly found on the cell surface rather than in post Golgi compartments, bound very high amounts of LDL, indicates that sortilin does not increase the binding of LDL through an intracellular mechanism. Rather, our data indicate that sortilin binds LDL on the cell surface. CONCLUSION: Even though sortilin binds and internalizes LDL by receptor-mediated endocytosis, mutations in the SORT1 gene are unlikely to cause autosomal dominant hypercholesterolemia and may only have a marginal effect on plasma LDL cholesterol levels. PMID- 23102787 TI - Unanswered questions in including HDL-cholesterol in the cardiovascular risk estimation. Is time still on our side? PMID- 23102785 TI - The relationship between sex hormones, sex hormone binding globulin and peripheral artery disease in older persons. AB - OBJECTIVE: The prevalence of peripheral artery disease (PAD) increases with aging and is higher in persons with metabolic syndrome and diabetes. PAD is associated with adverse outcomes, including frailty and disability. The protective effect of testosterone and sex hormone binding globulin (SHBG) for diabetes in men suggests that the biological activity of sex hormones may affect PAD, especially in older populations. METHODS: Nine hundred and twenty-one elderly subjects with data on SHBG, testosterone (T), estradiol (E2) were selected from InCHIANTI study. PAD was defined as an Ankle-Brachial Index (ABI) < 0.90. Logistic regression models adjusted for age (Model 1), age, BMI, insulin, interleukin-6, physical activity, smoking, chronic diseases including metabolic syndrome (Model 2), and a final model including also sex hormones (Model 3) were performed to test the relationship between SHBG, sex hormones and PAD. RESULTS: The mean age (+/-SD) of the 419 men and 502 women was 75.0 +/- 6.8 years. Sixty two participants (41 men, 21 women) had ABI < 0.90. Men with PAD had SHBG levels lower than men without PAD (p = 0.03). SHBG was negatively and independently associated with PAD in men (p = 0.028) but not in women. The relationship was however attenuated after adjusting for sex hormones (p = 0.07). The E2 was not significantly associated with PAD in both men and women. In women, but not in men, T was positively associated with PAD, even after adjusting for multiple confounders, including E2 (p = 0.01). CONCLUSIONS: Low SHBG and high T levels are significantly and independently associated with the presence of PAD in older men and women, respectively. PMID- 23102786 TI - Regulation of endothelial lipase and systemic HDL cholesterol levels by SREBPs and VEGF-A. AB - OBJECTIVE: Endothelial lipase (EL) regulates HDL cholesterol levels and in inflammatory states, like atherosclerosis, EL expression is increased contributing to low HDL cholesterol. The regulation of EL expression is poorly understood and has mainly been attributed to inflammatory stimuli. As sterol regulatory element binding proteins (SREBPs) are regulators of genes involved in lipid metabolism, we hypothesized that EL is regulated by SREBPs and that EL expression is modified by the SREBP activator vascular endothelial growth factor A (VEGF-A). METHODS: and results: Quantitative PCR and Western blot results demonstrated that starvation increased EL expression in human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs). Also, 25 hydroxycholesterol (25HC), an inhibitor of SREBP activation inhibited EL expression. With siRNA-mediated inhibition of SREBPs the effect of starvation was shown to be SREBP-2 dependent. VEGF-A decreased EL expression in both endothelial cell lines used, most likely via inhibition of SREBP-2 binding determined by chromatin immunoprecipitation (ChIP). Furthermore, in atherosclerosis prone LDLR( /-)ApoB(100/100) mice, systemic adenoviral gene transfer with human VEGF-A decreased EL mRNA in peripheral tissues and increased plasma HDL cholesterol. CONCLUSIONS: These results identify SREBPs as novel regulators of EL expression. VEGF-A as an endogenous EL inhibitor could be therapeutically relevant in atherosclerosis by increasing systemic HDL cholesterol levels. PMID- 23102788 TI - ABO gene variants and increased risk of atherosclerosis. PMID- 23102789 TI - Nocturnal sleep measured by actigraphy in children with Prader-Willi syndrome. AB - OBJECTIVE: To assess nocturnal sleep duration by actigraphy in children with Prader-Willi syndrome (PWS). STUDY DESIGN: Baseline measurements including height, weight, and body mass index (BMI) were collected on 8 children with PWS (6 boys) with each subject age- and sex-matched to 2 control children. From 7 consecutive nights of actigraphy data, values for total sleep time (TST), sleep efficiency, sleep latency (SL), number of awakenings after sleep onset, and duration of awakenings after sleep onset (WASO) were extracted. Parents also completed a sleep diary and questionnaire during this period. RESULTS: Subjects with PWS ranged from 4.2 to 15.4 years, and they had a lower height z score and higher BMI z score compared with controls. The PWS group had a shorter SL (P = .0007), longer WASO (P = .009), and higher daytime sleepiness score. TST, sleep efficiency, and number of awakenings after sleep onset were not significantly different between the groups, and subjects with PWS did not wake earlier than controls. There was no correlation between WASO and BMI or between WASO and sleepiness score. CONCLUSION: Children with PWS appear to have a shorter SL but more time awake in the night than normal children and have similar TST and morning wake time compared with controls. PMID- 23102790 TI - Acute necrotizing pancreatitis in children. AB - OBJECTIVE: To describe the etiologic factors, course, and outcome of acute necrotizing pancreatitis in children. STUDY DESIGN: We performed a retrospective study of children with necrotizing pancreatitis diagnosed during the last 21 years at Yale-New Haven Children's Hospital. Computed tomography (CT) criteria were used to diagnose necrotizing pancreatitis and to assess severity index. Charts were reviewed to collect demographics, etiology, details of hospital stay, complications, and outcome. RESULTS: Seven children (mean age, 11.6 years; range, 4-17.8 years) had necrotizing pancreatitis. Etiologic factors were medications, diabetes, and gallstones. All had prolonged hospitalization (9-40 days; mean, 20 days) and 5 patients required admission to the pediatric intensive care unit. During the hospital stay, patients developed complications involving the respiratory, hematologic, renal, metabolic, and circulatory systems. All patients had aggressive supportive medical therapy, and none required surgery. There were no deaths attributable to pancreatitis. Late complications after hospital discharge occurred in 5 patients and included pseudocysts, transient hyperglycemia, diabetes, and pancreatic exocrine insufficiency. The CT severity index correlated with the risk of complications. CONCLUSIONS: A cute necrotizing pancreatitis has a variable etiology in children. CT scan is useful in the diagnosis and assessment of severity. Necrotizing pancreatitis in children is associated with severe acute and late complications and requires intensive medical therapy. PMID- 23102791 TI - Coarctation of the aorta in late adolescence. PMID- 23102792 TI - Effect of nasal continuous and biphasic positive airway pressure on lung volume in preterm infants. AB - OBJECTIVE: To monitor regional changes in end-expiratory lung volume (EELV), tidal volumes, and their ventilation distribution during different levels of nasal continuous positive airway pressure (nCPAP) and nasal biphasic positive airway pressure (BiPAP) in stable preterm infants. STUDY DESIGN: By using electrical impedance tomography and respiratory inductive plethysmography, we measured changes in EELV and tidal volumes in 22 preterm infants (gestational age 29.7 +/- 1.5 weeks) during 3 nCPAP levels (2, 4, and 6 cmH2O) and unsynchronized BiPAP (nCPAP = 6 cmH2O; pressure amplitude = 3 cmH2O; frequency = 50/min; inspiration time = 0.5 seconds) at 10-minute intervals. We assessed the distribution of these volumes in ventral and dorsal chest regions by using electrical impedance tomography. RESULTS: EELV increased with increasing nCPAP with no difference between the ventral and dorsal lung regions. Tidal volume also increased, and a decrease in phase angle and respiratory rate was noted by respiratory induction plethysmography. At the regional level, electrical impedance tomography data showed a more dorsally oriented ventilation distribution. BiPAP resulted in a small increase in EELV but without changes in tidal volume or its regional distribution. CONCLUSION: Increasing nCPAP in the range of 2 to 6 cmH2O results in a homogeneous increase in EELV and an increase in tidal volume in preterm infants with a more physiologic ventilation distribution. Unsynchronized BiPAP does not improve tidal volume compared with nCPAP. PMID- 23102793 TI - Evaluating manual inflations and breathing during mask ventilation in preterm infants at birth. AB - OBJECTIVE: To investigate inflations (initial sustained inflations and consecutive inflations) and breathing during mask ventilation in preterm infants at birth. STUDY DESIGN: Resuscitation of infants <32 weeks' gestation receiving mask ventilation at birth were recorded. Recorded waveforms were divided into inflations (sustained and consecutive inflations), breaths in between inflations, breaths coinciding with an inflation, and breaths on continuous positive airway pressure (during evaluation moments in between and after ventilation) and expiratory tidal volume (V(Te)) was compared. Inflations were analyzed for leak, low V(Te) (<2.5 mL/kg), high V(Te) (>15 mL/kg in sustained inflations, >10 mL/kg in consecutive inflations), and airway obstruction. RESULTS: In 27 infants, we analyzed 1643 inflations, 110 breaths in between inflations, 133 breaths coinciding with an inflation, and 1676 breaths on continuous positive airway pressure. A large mask leak frequently resulted in low V(Te). Breathing during positive pressure ventilation occurred in 24 of 27 infants (89%). Median (IQR) V(Te) of inflations, breaths in between inflations, and breaths coinciding with an inflation were 0.8 mL/kg (0.0-5.6 mL/kg), 2.8 mL/kg (0.7-4.6 mL/kg), and 3.9 mL/kg (0.0-7.7 mL/kg) during sustained inflations and 3.7 mL/kg (1.4-6.7 mL/kg), 3.3 mL/kg (2.1-6.6 mL/kg), and 4.6 mL/kg (2.1-7.8 mL/kg) during consecutive inflations, respectively. The V(Te) of breaths were significantly lower than the V(Te) of inflations or breaths coinciding with an inflation. CONCLUSIONS: We often observed large leak and low V(Te), especially during sustained inflations. Most preterm infants breathe when receiving mask ventilation and this probably contributed to the stabilization of the infants after birth. PMID- 23102794 TI - Prader-Willi syndrome and growth hormone therapy: take a deep breath and weigh the data. PMID- 23102795 TI - Gastroesophageal reflux, esophageal function, gastric emptying, and the relationship to dysphagia before and after antireflux surgery in children. AB - OBJECTIVES: To assess gastroesophageal reflux (GER), esophageal motility, and gastric emptying in children before and after laparoscopic fundoplication and to identify functional measures associated with postoperative dysphagia. STUDY DESIGN: Combined impedance-manometry, 24-hour pH-impedance, and gastric-emptying breath tests were performed before and after laparoscopic anterior partial fundoplication. Impedance-manometry studies were analyzed with the use of conventional analysis methods and a novel automated impedance manometry (AIM) analysis. RESULTS: Children with therapy resistent GER disease (n = 25) were assessed before fundoplication, of whom 10 (median age 6.4 years; range, 1.1-17.1 years; 7 male; 4 with neurologic impairment) underwent fundoplication. GER episodes reduced from 97 (69-172) to 66 (18-87)/24 hours (P = .012). Peristaltic contractions were unaltered. Complete lower esophageal sphincter relaxations decreased after fundoplication (92% [76%-100%] vs 65% [29%-91%], P = .038). Four (40%) patients developed postoperative dysphagia, which was transient in 2. In those patients, preoperative gastric emptying was delayed compared with patients without postoperative dysphagia, 96 minutes (71-104 minutes) versus 48 minutes (26-68 minutes), P = .032, and AIM analysis derived dysphagia risk index was greater (56 [15-105] vs 2 [2-6] P = .016). Two patients underwent a repeat fundoplication. DISCUSSION: Fundoplication in children reduced GER without altering esophageal motility. Four patients who developed dysphagia demonstrated slower gastric emptying and greater dysplasia risk index preoperatively. AIM analysis may allow detection of subtle esophageal abnormalities potentially leading to postoperative dysphagia. PMID- 23102796 TI - Activities of doripenem against nosocomial bacteremic drug-resistant Gram negative bacteria in a medical center in Taiwan. AB - BACKGROUND: The majority of nosocomial infections in Taiwan hospitals are caused by drug-resistant Gram-negative bacteria (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, and various species of Enterobacteriaceae. Carbapenems are important agents for treating infections caused by these GNB. Recently, doripenem was approved for use in Taiwan in August 2009. However, data on its in vitro activity against nosocomial GNB isolated from Taiwan remain limited. The study was designed to look into this clinical issue. METHODS: A total of 400 nonduplicated nosocomial blood isolates isolated in 2009, inclusive of P. aeruginosa (n = 100), A. baumannii (n = 100), and Enterobacteriaceae (n = 200), were randomly selected from the bacterial bank preserved at National Taiwan University Hospital. Susceptibilities of these 400 isolates to various antibiotics, including doripenem, imipenem, meropenem, ceftazidime, amikacin, ciprofloxacin, colistin, and tigecycline were determined by using Etest. RESULTS: Doripenem demonstrated similar in vitro activity to imipenem and meropenem against P. aeruginosa (87%, vs. 85% and 89%), A. baumannii (56%, vs. 60% and 60%), and Enterobacteriaceae (100%, vs. 98.5% and 99.5%). The prevalence of carbapenem-resistant (any one of three tested carbapenems) P. aeruginosa, A. baumannii, and Enterobacteriaceae isolates was 15%, 44%, and 0.5%, respectively. CONCLUSIONS: Doripenem was as effective as imipenem and meropenem in our study. However, there was a significant proportion of carbapenem resistance among the tested isolates. Hence, longitudinal surveillance is necessary to monitor the resistance trend. PMID- 23102797 TI - A randomized clinical trial comparing the short-term side effects of sublingual and buccal routes of misoprostol administration for medical abortions up to 63 days' gestation. AB - BACKGROUND: Buccal misoprostol 800 mcg and sublingual misoprostol 800 mcg show high efficacy when used with 200 mg mifepristone for early pregnancy termination but have different side effect profiles. This is the first double-blind randomized trial comparing the side effect profiles of these two routes of administration of misoprostol when used with mifepristone for termination of pregnancies up to 63 days' gestation. STUDY DESIGN: Eligible women (n=90) who requested legal termination of pregnancy up to 63 days' gestation were randomized to two groups and given 200 mg of oral mifepristone followed 48 h later by 800 mcg of either sublingual (n=45) or buccal (n=45) misoprostol. RESULTS: Most of the side effects including fever were more common in the sublingual group, but only the incidence of chills was significantly higher in the sublingual group (55.6% vs 91.1%, p=.0001). Complete abortion occurred in 95.4% [95% confidence interval (CI): 84.9-99.5] of women in the buccal group and 97.8% (95% CI: 88.2 99.9) in the sublingual group. CONCLUSIONS: When combined with mifepristone for termination of pregnancy up to 63 days, both the buccal and sublingual routes are effective routes of administration. The sublingual route tended to be associated with more side effects. PMID- 23102798 TI - Effects of combined oral contraceptives containing levonorgestrel or chlormadinone on the endothelium. AB - BACKGROUND: Although the use of combined oral contraceptives (COCs) is associated with an increased risk of arterial and venous thromboembolic events, less is known about the impact of COCs on endothelial function. The present study evaluated the effects on the endothelium of healthy women of combinations of 30 mcg ethinylestradiol (EE)/2 mg chlormadinone acetate (CMA) and 30 mcg EE/150 mcg levonorgestrel (LNG). STUDY DESIGN: Sixty-four healthy women were evaluated, 21 using a nonhormonal contraceptive method (control) and 43 using COCs, randomized to EE 30 mcg /CMA 2 mg or to EE 30 mcg/LNG 150 mcg. Anthropometric parameters, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), ultrasound markers of endothelial function, flow-mediated dilation (FMD) of the brachial artery, intima-media thickness (IMT) and common carotid artery stiffness were measured at randomization and 6 months later. RESULTS: Relative to baseline, EE/CMA users showed a significant reduction in mean DAP at 6 months (p=.02), and EE/LNG users showed a significant increase in mean IMT (p=.02) and a significant reduction in mean FMD (p=.01) at 6 months. DAP at 6 months was significantly lower in COC users than in controls (p=.01). Intergroup evaluations showed that, at 6 months, mean SAP (p=.02) was significantly lower in EE/LNG users than in controls (p=.02) and that mean DAP was significantly lower in EE/CMA (p<.01) and EE/LNG (p=.01) users than in controls. EE/LNG users experienced a mean FMD reduction almost threefold greater than that of EE/CMA users. Compared to controls, EE/LNG users experienced a 7.5-fold greater reduction in mean FMD. CONCLUSIONS: COC containing LNG is associated with more pronounced changes in the FMD and IMT of healthy women than a COC containing CMA and nonhormonal contraception. Further studies are needed to determine whether these differences may lead to higher risk of arterial thromboembolic events. PMID- 23102799 TI - Complex regional pain syndrome following trigeminal nerve injury: report of 2 cases. AB - Complex regional pain syndrome (CRPS) is a debilitating neuropathic pain condition that has been extensively reported in the extremities following variable degrees of nerve trauma. CRPS has rarely been reported in the orofacial region. We report 2 orofacial pain patients whose clinical phenotypes fit the criteria for CRPS. Two cases of orofacial complex regional pain syndrome (CRPS) are described, both of which began following trigeminal nerve trauma. In case 1 the patient presented with redness of the ipsilateral ear during painful episodes, pain that extended into the ipsilateral arm and was associated with variations in the appearance of the ipsilateral hand. Symptoms also included "electric-burning pain" of the right side of the head, including the ear, teeth, jaw, eye, neck, and cheek. In case 2 the patient presented with intractable pain of the upper left face, head, and neck accompanied by color changes in the painful areas, which increased with exposure to cold. PMID- 23102800 TI - Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience. AB - Cleidocranial dysplasia (CCD) is an uncommon but well-known genetic skeletal condition. Several hundred affected persons are members of a large extended family in the Cape Town Mixed Ancestry community of South Africa. The clinical manifestations are often innocuous, but hyperdontia and other developmental abnormalities of the teeth are a major feature and may require special dental management. Over the past 40 years, the authors have encountered more than 100 affected persons in Cape Town. Emphasis has been on dental management, but medical, genetic, and social problems have also been addressed. In this article, we have reviewed the manifestations of the disorder in the light of our own experience, and performed a literature search with emphasis on the various approaches to dental management and treatment options in CCD. Advances in the understanding of the biomolecular pathogenesis of CCD are outlined and the international and local history of the disorder is documented. PMID- 23102801 TI - Detection of vertical root fractures by cone-beam computerized tomography in endodontically treated teeth with fiber-resin and titanium posts: an in vitro study. AB - OBJECTIVE: The aim of this study was to assess the performance of 2 cone-beam computerized tomography (CBCT) systems for detecting vertical fractures in root filled teeth with fiber-resin or titanium posts. STUDY DESIGN: CBCT images acquired with the use of Scanora 3D and i-CAT of roots with fiber-resin (n = 30) or titanium (n = 29) posts, before and after the induction of fractures, were assessed by 6 radiologists using Ondemand 3D software. Interobserver agreement was analyzed using kappa statistics. Sensitivity, specificity, accuracy, and positive and negative predictive values were compared with analysis of variance/Student-Newman-Keuls test. RESULTS: Interobserver agreement for fiber resin posts ranged from 0.5 to 0.7 (Scanora 3D) and 0.35-0.76 (i-CAT). For titanium posts, ranged from 0.42 to 0.80 (Scanora 3D) and 0.31-0.73 (i-CAT). Higher sensitivity (0.85; P < .05) and negative predictive values (0.88; P < .001) were observed for i-CAT in roots with fiber-resin posts than with other combinations. CONCLUSIONS: The diagnostic performance for detecting vertical fractures was higher for roots with fiber-resin than with titanium posts. PMID- 23102802 TI - Topical tacrolimus with custom trays in the treatment of severe oral chronic graft-versus-host disease refractory to a potent topical steroid therapy: a case report. AB - BACKGROUND: The authors present a case demonstrating the success of topical tacrolimus (TAC) therapy with custom trays in the treatment of oral chronic graft versus-host disease (cGVHD). The 41-year-old male patient initially responded to topical steroid therapy (clobetasol propionate 0.05% ointment) applied both topically and with flexible carrier trays, but later became refractory to this potent topical agent. Topical TAC therapy with flexible carrier trays and systemic prednisone therapy was initiated. RESULTS: The patient responded favorably with the change to topical TAC therapy with custom trays (and oral prednisone). His oral cGVHD lesions resolved within a period of 4 weeks. The improvement has remained stable at 14 months of follow-up. CLINICAL IMPLICATIONS: This is the first case reported with regard to the successful resolution of steroid recalcitrant cGVHD successfully treated with topical TAC with custom trays. PMID- 23102803 TI - Intracranial arachnoid cyst on dental radiography: a diagnostic challenge. AB - Intracranial arachnoid cysts (IACs) can present as congenital asymptomatic lesions that may predispose them to present as an incidental finding during radiographic examination. On the other hand, IACs may also give rise to a series of neurologic symptoms depending on their size and location, such as vomiting, seizures, headache, and ataxia. Skull deformities, including macrocephaly, may occur and become remarkable on dental radiology. We report 2 patients who were identified with IAC before orthodontic treatment. The dental radiologic appearance of IAC is discussed and may constitute a diagnostic challenge to both the dentist and radiologist. PMID- 23102804 TI - Recommendations for matching pediatric nurse practitioner education and certification to pediatric acute care populations. PMID- 23102805 TI - Relationship between monoclonal gammopathy and cardiac amyloid type. AB - BACKGROUND: Proper identification of cardiac amyloid type is essential for patient management, and has historically relied upon immunohistochemical- or immunofluorescence-based methods, often correlated with serum and urine protein electrophoresis (SPEP and UPEP) with immunofixation electrophoresis (IFE), and/or free light chain immunoassay (FLC). The recent implementation of mass spectrometry-based proteomic analysis for clinical amyloid typing allows us to determine the validity of these tests to predict amyloid type. Validity of SPEP/UPEP/IFE and FLC assays in cardiac amyloid prediction was examined. METHODS: Retrospective analysis of two tertiary care populations (n=143, 2001-2010), of cardiac biopsy-proven amyloidosis, was performed. RESULTS: Amyloid of transthyretin (ATTR) type was found in 81 (57%) of 143 patients and immunoglobulin light chain amyloid was found in the remaining 62 (43%). SPEP/UPEP/IFE detected a monoclonal gammopathy in 76 individuals, 56 with AL and 20 with ATTR amyloid and was overall a poor predictor of AL amyloid in this patient population: specificity (75%; 95% CI, 65-83%) and positive predictive value (PPV 74%; 95% CI, 63-82%). The FLC assay detected an abnormal kappa/lambda ratio in 61 patients, 53 with AL and 8 with ATTR amyloid and was a better predictor of AL amyloid type in this patient population: specificity (90%, 95% CI, 82-95%) and PPV (87%, 95% CI, 76-93%). CONCLUSIONS: ATTR was the predominant amyloid type in this large cohort of endomyocardial biopsies characterized by mass spectrometry. Although FLC performs better than SPEP/UPEP/IFE, the performance of blood and urine studies for monoclonal proteins are not adequate to classify amyloid type. SUMMARY: This large-scale retrospective analysis of cardiac amyloidosis shows that blood and urine monoclonal protein studies are not, by themselves, robust predictors of cardiac amyloid type in patients undergoing endomyocardial biopsy. PMID- 23102806 TI - Within-day and between-day variability of transthoracic anatomic M-mode echocardiography in the awake bottlenose dolphin (Tursiops truncatus). AB - The use of transthoracic echocardiography in dolphins has been limited so far owing to technical and anatomical specificities. Anatomic M-mode (AMM) is a postprocessing echocardiographic technique generating M-mode studies from two dimensional (2D) cineloops independently of the ultrasound beam orientation. The aim of the present study was to determine the within-day (repeatability) and between-day (reproducibility) variability of AMM echocardiography in awake healthy bottlenose dolphins (BN, Tursiops truncatus). Four adult BN trained to lie in left recumbency at the water surface were involved in the protocol. A total of 96 echocardiographic examinations were performed on 4 different days by a trained observer examining each BN 6 times per day. Video clips of 2D left parasternal long-axis views showing the left ventricle (LV) ventrally and the aortic root dorsally were recorded at each examination and analyzed for AMM measurements in a random order. A general linear model was used to determine the within-day and between-day coefficients of variation (CV). All examinations were interpretable allowing calculation of 10 AMM variables (i.e., end-diastolic and end-systolic ventral and dorsal LV myocardial wall thicknesses as well as LV and aortic diameters, mean aortic diameter, and LV shortening fraction). Most within- and between-day CV values (18/20) were <15%, the lowest being observed for the end-diastolic LV diameter (1.6%). In conclusion, AMM provides a simple non invasive evaluation of heart morphology and function in the awake BN with good repeatability and reproducibility of the measurements. Further studies are required to determine the corresponding reference intervals. PMID- 23102807 TI - GRM7 variants associated with age-related hearing loss based on auditory perception. AB - Age-related hearing impairment (ARHI), or presbycusis, is a common condition of the elderly that results in significant communication difficulties in daily life. Clinically, it has been defined as a progressive loss of sensitivity to sound, starting at the high frequencies, inability to understand speech, lengthening of the minimum discernable temporal gap in sounds, and a decrease in the ability to filter out background noise. The causes of presbycusis are likely a combination of environmental and genetic factors. Previous research into the genetics of presbycusis has focused solely on hearing as measured by pure-tone thresholds. A few loci have been identified, based on a best ear pure-tone average phenotype, as having a likely role in susceptibility to this type of hearing loss; and GRM7 is the only gene that has achieved genome-wide significance. We examined the association of GRM7 variants identified from the previous study, which used an European cohort with Z-scores based on pure-tone thresholds, in a European American population from Rochester, NY (N = 687), and used novel phenotypes of presbycusis. In the present study mixed modeling analyses were used to explore the relationship of GRM7 haplotype and SNP genotypes with various measures of auditory perception. Here we show that GRM7 alleles are associated primarily with peripheral measures of hearing loss, and particularly with speech detection in older adults. PMID- 23102808 TI - Potential reliability and validity of a modified version of the Unified Parkinson's Disease Rating Scale that could be administered remotely. AB - BACKGROUND: By permitting remote assessments of patients and research participants, telemedicine has the potential to reshape clinical care and clinical trials for Parkinson disease. While the majority of the motor Unified Parkinson's Disease Rating Scale (UPDRS) items can be conducted visually, rigidity and retropulsion pull testing require hands-on assessment by the rater and are less feasible to perform remotely in patients' homes. METHODS: In a secondary data analysis of the Comparison of the Agonist pramipexole vs. Levodopa on Motor complications in Parkinson's Disease (CALM-PD) study, a randomized clinical trial, we assessed the cross-sectional (baseline and 2 years) and longitudinal (change from baseline to 2 years) reliability of a modified motor UPDRS (removing rigidity and retropulsion items) compared to the standard motor UPDRS (all items) using intraclass correlation coefficients (ICC), stratified by treatment group. Internal consistency of the modified UPDRS (mUPDRS) was measured using Cronbach's alpha, and concurrent validity was assessed using Pearson's correlation coefficient (r) between the standard motor UPDRS and mUPDRS. RESULTS: The mUPDRS versus standard motor UPDRS is cross-sectionally (ICC >= 0.92) and longitudinally (ICC >= 0.92) reliable for both treatment groups. High internal consistencies were also observed (alpha >= 0.96). The mUPDRS had high concurrent validity with the standard UPDRS at both time points and longitudinally (r >= 0.93, p < 0.0001). CONCLUSIONS: A modified version of the motor UPDRS without rigidity and retropulsion pull testing is reliable and valid and may lay the foundation for its use in remote assessments of patients and research participants. PMID- 23102809 TI - Comparison of the larynx-associated lymphoid tissue in the false vocal cords and subglottis in pediatric autopsies. AB - The aim this work was to compare the distribution of cellular phenotypes of the LF in the FVC to the ones in the subglottic region in pediatric autopsy, relating this distribution to age and different causes of death. We analyzed 60 larynges of newborns and children autopsied in the period from 1993 to 2003. The fragments were prepared in order to perform histochemical and immunohistochemical techniques. The morphological analysis showed cases that presented LF only in FVC (35%), LF only in the subglottic region (20%), lack of LF in FVC (30%) and lymphoid aggregates, which did not characterize an LF (15%). The cases of LF in the subglottic region were significantly younger compared to the ones that presented LF in the FVC (p=0.017). The LF in the subglottic region was bigger than the LF in the FVC (p=0.020). There was no significant difference between the cause of death and cellular phenotype for both FVC and the subglottic region. In conclusion, the cells that make up the LF in the FVC in newborns and children younger than one year have functional characteristics similar to LF cells in the subglottic region, suggesting that there are similarities with LALT. PMID- 23102810 TI - Sarcomatous evolution of oligodendroglioma ("oligosarcoma"): confirmatory report of an uncommon pattern of malignant progression in oligodendroglial tumors. AB - By analogy to gliosarcoma, the neologism "oligosarcoma" is to describe an uncommon form of biphasic central nervous system tumor composed of contiguous neuroepithelial and mesenchymal elements, each of which individually meet the criteria of oligodendroglioma and sarcoma, respectively. By virtue of its distinctive genotype (codeletion 1p/19q), oligodendroglioma is a particularly inviting paradigm to test the assumption that such mixed tumors are clonally derived from a glial primary. We observed this constellation in a 41-year-old male who underwent two resection procedures for a recurring right frontal tumor at five years' interval. On imaging, both lesions were contrast-enhancing, and measured 7 cm * 7 cm * 6.8 cm and 7 cm * 6.5 cm * 4cm, respectively. Following the first operation, temozolomide monotherapy was administered. Whereas initial histology showed conventional anaplastic oligodendroglioma, the recurrence consisted mostly of a fibrosarcoma-like, fascicular neoplasm that was immunoreactive for vimentin, smooth muscle actin, S100 protein, and focally epithelial membrane antigen. In between, a subset of otherwise indistinguishable spindle cells expressed GFAP, and focally merged with residues of oligodendroglioma. Molecular testing for loss of heterozygosity confirmed codeletion of 1p/19q in both the primary tumor and the sarcomatous recurrence. Similarly, generalized immunoreactivity for the mutant R132H form of isocitrate dehydrogenase in both lesions indicated an identical mutation of the IDH1 gene. By the above standards, biologically consistent "oligosarcomas" are felt to be exceedingly rare, and possibly participate of a nosologically heterogeneous group of combined glial/mesenchymal lesions that may also include iatrogenically induced second malignancies as well as true collision tumors. PMID- 23102811 TI - Erlotinib and bevacizumab in newly diagnosed performance status 2 or elderly patients with nonsquamous non-small-cell lung cancer, a phase II study of the Hoosier Oncology Group: LUN04-77. AB - BACKGROUND: Poor PS is a negative prognostic factor for survival and a risk factor for treatment-related toxicity with standard platinum-doublet chemotherapy for advanced NSCLC. A phase II study combining erlotinib and bevacizumab for treatment of recurrent NSCLC showed encouraging efficacy and acceptable toxicity. PATIENTS AND METHODS: This single-arm phase II study evaluated erlotinib and bevacizumab as first-line therapy for newly diagnosed nonsquamous advanced NSCLC patients with Eastern Cooperative Oncology Group PS >= 2 or age 70 or older. Only patients eligible for bevacizumab per label were enrolled. Patients received erlotinib 150 mg orally daily and bevacizumab 15 mg/kg intravenously on day 1 every 21 days for up to 6 cycles. The primary end point was the rate of nonprogressive disease at 4 months (alternative hypothesis > 60%). RESULTS: Twenty-five patients were enrolled, with median age 77 years (range, 52-90 years), 44% female, 20% never- or remote-smokers. Ninety-two percent of patients enrolled had PS of 2 per investigator assessment. The rate of nonprogressive disease at 4 months was 28%. There were no complete responses, 1 patient achieved a partial response, and 11 patients (44%) experienced stable disease as best response. Rash, fatigue, and diarrhea were the most common toxicities. CONCLUSION: The combination of erlotinib and bevacizumab had insufficient activity in the absence of known activating epidermal growth factor receptor gene mutations to warrant study in newly diagnosed elderly or poor PS patients with nonsquamous NSCLC. PMID- 23102812 TI - Cytotoxicity testing of methyl and ethyl 2-cyanoacrylate using direct contact assay on osteoblast cell cultures. AB - PURPOSE: Cyanoacrylate has been used as a commercial tissue adhesive. Recently, ethyl 2-cyanoacrylate has been suggested for the fixation of onlay autogenous bone graft. However, ethyl 2-cyanoacrylate must be biocompatible with bone tissue. This study evaluated the cytotoxicity of cyanoacrylate adhesives using a direct contact assay on human oral osteoblast cells. MATERIALS AND METHODS: Osteoblastic cells derived from human alveolar bone of the mandible were cultured with or without cyanoacrylate. The CA1 group contained methyl 2-cyanoacrylate, the CA2 group contained ethyl 2-cyanoacrylate, and the CA3 group did not contain cyanoacrylate (control). This study investigated cell morphology, which included the inhibition zone, and cytotoxicity was evaluated using the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which was measured as optical density. Data from the MTT assay were tested statistically using SigmaStat 3.5. RESULTS: Dead cells found around the CA1- and CA2-treated cells constituted inhibitory zones that varied from 200 to 500 MUm. There was no inhibitory zone in the CA3 group. Cell viability evaluated by the MTT assay showed that the CA2 and CA3 optical densities were not significantly different. The CA1 optical densities differed significantly from the CA3 optical densities. CONCLUSIONS: Within the limits of this study, the MTT method supported the conclusion that ethyl 2-cyanoacrylate is biocompatible according to a direct contact assay on human osteoblast cell cultures and suggests its usefulness in bone graft fixation. PMID- 23102813 TI - LIN28A is a suppressor of ER-associated translation in embryonic stem cells. AB - LIN28 plays a critical role in developmental transition, glucose metabolism, and tumorigenesis. At the molecular level, LIN28 is known to repress maturation of let-7 microRNAs and enhance translation of certain mRNAs. In this study, we obtain a genome-wide view of the molecular function of LIN28A in mouse embryonic stem cells by carrying out RNA crosslinking-immunoprecipitation-sequencing (CLIP seq) and ribosome footprinting. We find that, in addition to let-7 precursors, LIN28A binds to a large number of spliced mRNAs. LIN28A recognizes AAGNNG, AAGNG, and less frequently UGUG, which are located in the terminal loop of a small hairpin. LIN28A is localized to the periendoplasmic reticulum (ER) area and inhibits translation of mRNAs that are destined for the ER, reducing the synthesis of transmembrane proteins, ER or Golgi lumen proteins, and secretory proteins. Our study suggests a selective regulatory mechanism for ER-associated translation and reveals an unexpected role of LIN28A as a global suppressor of genes in the secretory pathway. PMID- 23102814 TI - Clonal spread and patient risk factors for acquisition of extensively drug resistant Acinetobacter baumannii in a neonatal intensive care unit in Italy. AB - AIM: To report an outbreak of extensively drug-resistant (XDR) Acinetobacter baumannii in the neonatal intensive care unit (NICU) of an Italian university hospital. Patient risk profiles for acquisition of A. baumannii and measures used to control the outbreak are described. METHODS: Antibiotic susceptibility of strains was evaluated by microdilution. Genotyping was performed by pulsed-field gel electrophoresis (PFGE) and multi-locus sequence typing. Carbapenemase genes were analysed by polymerase chain reaction and DNA sequencing. A case-control study was designed to identify risk factors for acquisition of A. baumannii. FINDINGS: A. baumannii was isolated from 22 neonates, six of whom were infected. One major PFGE type was identified, assigned to sequence type (ST) 2, corresponding to International Clone II; this was indistinguishable from isolates from the adult ICU in the same hospital. A. baumannii isolates were resistant to aminoglycosides, quinolones and classes of beta-lactam antibiotics, but were susceptible to tigecycline and colistin. Carbapenem resistance was associated with the presence of transposon Tn2006 carrying the bla(OxA-23) gene. Length of NICU stay, length of exposure to A. baumannii, gestational age, use of invasive devices and length of exposure to invasive devices were significantly associated with acquisition of A. baumannii on univariate analysis, while length of exposure to central venous catheters and assisted ventilation were the only independent risk factors after multi-variate analysis. CONCLUSIONS: This XDR A. baumannii outbreak in an NICU was probably caused by intrahospital transfer of bacteria via a colonized neonate whose mother was admitted to the adult ICU. Strengthened infection control measures were necessary to control the outbreak. PMID- 23102815 TI - Control of multi-drug-resistant Acinetobacter baumannii outbreaks in an intensive care unit: feasibility and economic impact of rapid unit closure. AB - From January to May 2006, a nosocomial outbreak caused by a multi-drug-resistant strain of Acinetobacter baumannii (MDRAB) occurred in a multi-specialty surgical ICU (SICU). During this episode, 20 patients were colonized by an identical MDRAB strain. Despite introduction of control measures, the outbreak was only stopped after complete closure of the unit. When a second MDRAB outbreak was confirmed in the same unit in January 2009, the SICU was closed as soon as possible. This measure allowed faster control of the outbreak, which only involved seven patients and lasted for 25 days. The economic impact of the outbreak was also considerably lower; estimated costs were ?202,214 in 2009 compared with ?539,325 in 2006. This study found that rapid closure of the SICU, with patients cohorted elsewhere, was a cost-effective way of controlling an MDRAB outbreak. PMID- 23102816 TI - Pre-incision antibiotic prophylaxis reduces the incidence of post-caesarean surgical site infection. AB - A two-part prospective study was conducted to assess rates of surgical site infection (SSI) following caesarean section in a large Australian regional hospital before and after a change of timing of antibiotic prophylaxis from after cord clamping to pre-incision. SSI rates dropped from 10.8% in 2010 to 2.8% in 2011 with no adverse neonatal consequences, providing further evidence that antibiotic prophylaxis should be given pre-incision for caesarean section in hospitals in Australia and New Zealand, as is now accepted practice elsewhere. PMID- 23102817 TI - Three years' experience of screening for meticillin-resistant Staphylococcus aureus in obstetrics. AB - There are few data on meticillin-resistant Staphylococcus aureus (MRSA) screening in obstetrics, a largely healthy population that should be at lower risk for MRSA than most hospitalized populations. From January 2009 to December 2011 nose swabs were screened from 5548 of 21,770 (25.5%) women who delivered at Birmingham Women's Hospital. Only 29 (0.5%) were MRSA positive: MRSA infections occurred later in three cases. MRSA infections occurred in a further 13 mother-infant pairs, including six cases where mothers were MRSA screen negative. Seventeen mothers had risk factors for MRSA. MRSA is not widespread in obstetrics, and large-scale screening of nasal swabs is of limited value in preventing MRSA related morbidity in this population. PMID- 23102818 TI - Feasibility and effectiveness of an electronic hand hygiene feedback device targeted to improve rates of hand hygiene. AB - Various electronic tools have been developed to monitor hand hygiene compliance (HHC). A prospective, investigator-blinded, pilot study was conducted to evaluate the feasibility and effectiveness of an electronic hand hygiene feedback device to improve rates of hand hygiene. The first month of participation provided baseline rates of HHC (37%). During months 2-5, mean HHC rates were 43%, 44%, 45%, and 49% respectively (P < 0.001). Implementing this electronic device was feasible and showed a modest improvement in rates of HHC. Subsequent studies are warranted to validate the impact of such electronic devices on a larger scale. PMID- 23102819 TI - Invasive aspergillosis: drug-dispensing systems as a source of filamentous fungal contamination in high-risk units? AB - High-risk units with air-control measures at Grenoble University Hospital are equipped with automated dispensing systems that are filled daily using drug trolleys routed from the pharmacy to the ward. The aim of this study was to evaluate the level of filamentous fungi (FF) contamination present in trolleys under usual conditions and after cleaning with Aniosurf((r)) (fungicidal disinfectant). FF were detected in all samples, and 83.3% of samples were contaminated with Aspergillus fumigatus. Cleaning trolleys with Aniosurf((r)) decreased the level of FF significantly, but contamination re-appeared within 24 h due to storage in a non-controlled environment. PMID- 23102820 TI - A new type of scale for determining remission from depression: the Remission from Depression Questionnaire. AB - Current standards for treating major depressive disorder (MDD) recommend that achieving remission should be considered the principal goal of treatment. Recent research suggests that the symptom-based definitions of remission used in efficacy studies do not adequately reflect the perspective of depressed patients receiving treatment in routine clinical settings. We developed the Remission from Depression Questionnaire (RDQ) to capture the broader array of domains considered by patients to be relevant to the construct of remission--symptoms of depression, nondepressive symptoms, features of positive mental health, coping ability, functioning, life satisfaction and a general sense of well-being. The current report is the first study of the reliability and validity of the RDQ. The test retest reliability of the RDQ was studied in 60 depressed outpatients in ongoing treatment. The convergent and discriminant validity of the RDQ was studied in 274 depressed outpatients who were rated on the 17-item Hamilton Depression Scale (HAM-D) and who completed several self-report scales including the Quick Inventory of Depressive Symptomatology (QIDS). The RDQ demonstrated excellent internal consistency, with a Cronbach's alpha of .97 for the total scale and above .80 for each of the 7 subscales. The test-retest reliability of the total scale was .85 and above .60 for each subscale. Both the RDQ and QIDS were significantly associated with patients' self-reported remission status. However, the RDQ remained significantly associated with remission status after controlling for QIDS scores (r = -.32, p < .001) whereas the QIDS was not associated with remission status after controlling for RDQ scores (r = -.06). The RDQ is a reliable and valid measure that evaluates the multiple domains that depressed patients consider important in determining remission. The results are consistent with prior research suggesting that depressed patients' perspective of remission goes beyond symptom resolution. PMID- 23102822 TI - Membrane tension of red blood cells pairwisely interacting in simple shear flow. AB - Flow-induced membrane tension contributes to the release of molecules by red blood cells (RBCs), and extremely high tension may cause haemolysis. Here, we investigated the membrane tension of RBCs during pairwise interactions in simple shear flow, given that pairwise interactions form the basis of many-body interactions. RBCs were modelled as capsules with a two-dimensional hyperelastic membrane, and large deformations were solved by the finite element method. Due to the small size of the RBCs, surrounding fluid motion was estimated as a Stokes flow and solved by the boundary element method. The results showed that the maximum isotropic tension appeared around the dimple of the biconcave surface and not around the rim. A comparison of the results with solitary cases indicated that the maximum principal tension and isotropic tension were significantly increased by cell-cell interaction effects. As the volume fraction of RBCs is large under physiological conditions, as well as in blood flow in vitro, cell cell interactions must be analysed carefully when considering mechanotransduction and haemolysis in blood flow. PMID- 23102823 TI - [Presurgical fasting and pharmacological aspects of bronchoaspiration]. PMID- 23102821 TI - Dysfunctional attitudes as a moderator of pharmacotherapy and psychotherapy for chronic depression. AB - OBJECTIVE: Individuals with chronic depression exhibit heterogeneous responses to treatment. Important individual differences may therefore exist within this particularly difficult to treat population that act as moderators of treatment response. METHOD: The present study examined whether pretreatment levels of dysfunctional attitudes (DA) moderated treatment response in a large sample of chronically depressed individuals. Data were taken from the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) treatment study--a multi-site treatment and augmentation study of 808 chronically depressed individuals. REVAMP comprised two phases: 1) a 12-week open-label antidepressant trial and 2), a subsequent phase, in which phase 1 non-remitters (N = 491) were randomized to either receive an ongoing medication algorithm alone, medication plus cognitive behavioral analysis system of psychotherapy, or medication plus brief supportive psychotherapy. RESULT: In phase 1, compared to the pharmacotherapy response of patients with lower DA scores, the response for patients with higher DA scores was steeper, but leveled off toward the end of the phase. In phase 2, DA predicted a differential response in the medication only arm, but not in the two psychotherapy + medication conditions. Specifically, in the phase 2 medication only condition, patients with higher DA improved while those with lower DA scores did not. CONCLUSION: These results indicate that the relation between DA and treatment response in chronic depression is complex, but suggest that greater DA may be associated with a steeper reduction and/or better response to pharmacotherapy. PMID- 23102824 TI - Photoangiolytic laser treatment of recurrent respiratory papillomatosis: a scaled assessment. AB - OBJECTIVES: To investigate the effectiveness of unsedated office-based photoangiolytic laser surgery (UOLS) for treating recurrent respiratory papillomatosis (RRP) using the Derkay severity scale, Voice Handicap Index-10 (VHI-10), and Grade, Roughness, Breathiness, Asthenia, Strain (GRBAS) scale. Although previous studies examined the effect of UOLS on voice quality, few studies evaluated the effect on disease regression or used accepted and validated scales as outcome measures. STUDY DESIGN: Retrospective case series. METHODS: Charts were reviewed for patients who underwent UOLS for RRP (2007-2010). Twenty one patients met the inclusion criteria. Nineteen patients underwent treatment with a 532-nm potassium titanyl phosphate laser and two with a 585-nm pulsed dye laser. The Derkay, VHI-10, and GRBAS scores of posttreatment findings were compared with those of the pretreatment findings. RESULTS: Twenty-one patients underwent 81 office procedures. Mean follow-up was 18 months. From baseline to latest follow-up, there was significant improvement in the mean Derkay score from 6.1 to 3.0 (P=0.001), VHI-10 score from 24.5 to 15.9 (P=0.04), and GRBAS score from 8.6 to 4.9 (P=0.004). CONCLUSIONS: UOLS results in patient benefit from disease regression, reduced voice handicap, and improved voice quality without the risks associated with direct laryngoscopy and general anesthesia. UOLS is an effective, safe, nonexperimental treatment modality for RRP that has shifted the therapeutic paradigm while decreasing patient morbidity. PMID- 23102825 TI - Defining the lived experience of older adults with voice disorders. AB - OBJECTIVES: The purpose of this qualitative phenomenological study was to gather rich thick descriptive data regarding the lived experiences of older adults seeking treatment for a voice disorder. DESIGN: Using qualitative methodologies, participants completed semi-structured interviews with trained investigators to detail their thoughts, beliefs, feelings, and experiences of living with a voice disorder. Using a process of horizontalization, themes were identified that described the experiences of older adults with voice disorders. SETTING: Research was conducted at four clinical voice centers in Kentucky, Wisconsin, and Ohio. Data were analyzed in the Laryngeal and Speech Dynamics Lab at the University of Kentucky. PARTICIPANTS: A total of 28 adults (aged 65-90 years) with voice disorders were recruited for this study. RESULTS AND CONCLUSIONS: Aging adults demonstrated a strong urge to communicate; however, they tended to describe their voice quality in negative terms and were emotionally impacted by these associations. They admitted to withdrawing from some activity or social event because their voice did not meet their expectations or voice needs; thought their voice quality was part of normal aging; and had resigned to accept their current voice. PMID- 23102826 TI - Isolated myoclonus of the vocal folds. AB - OBJECTIVE: Laryngeal manifestations of stroke play a significant role in the morbidity and mortality among affected patients. The objective of this article was to describe unique myoclonic vocal fold movement disorder, which is an unusual post-stroke manifestation. STUDY DESIGN: A retrospective case study. SETTING: The study group included post-stroke patients with dysphagia who were referred to the Swallowing Clinic at Edith Wolfson Medical Center. SUBJECTS AND METHODS: All patients underwent flexible laryngoscopy and flexible endoscopic evaluation of swallowing with sensory testing. The vocal fold movement was analyzed with the Sisson-Ammons video analysis system. RESULTS: Three post pontine stroke patients presented with vocal fold myoclonus (VFM). The myoclonus was spontaneous, unintentional, and irregular (19-420 jerks per minute). Two patients presented with unilateral myoclonus, ipsilateral to the brainstem stroke. One patient, who experienced subsequent pontine strokes, presented with bilateral VFM. When patients were asked to swallow or phonate, the myoclonus disappeared. CONCLUSION: Isolated VFM is an unusual manifestation of pontine injury, resulting in a sudden, involuntary, and non-rhythmic vocal fold movement. This laryngeal pathology is not associated with either dyspnea or dysphonia and most likely not with inefficient swallowing. PMID- 23102827 TI - Tuberculosis in patients with systemic lupus erythematosus: Spain's situation. AB - There has recently been an increase in the incidence of patients with systemic lupus erythematosus (SLE) due mainly to earlier diagnosis, and increased survival. Tuberculosis in our country is one of the most prevalent infectious diseases, and one of the underlying causes would be HIV infection and increased immigration from areas with high tuberculosis prevalence; this phenomenon is truly important in patients with autoimmune diseases, as clinical presentation, severity and prognosis of tuberculosis are often different to that of immunocompetent patients. Studies of tuberculosis in patients with SLE are scarce and inconclusive, with many doubts existing about the performance or non tuberculous prophylaxis in this population and the absence of a protocol due to lack of conclusive studies. New techniques for diagnosis of tuberculosis (IGRAs) may be useful in this population due to higher sensitivity than Mantoux, helping avoid false negatives. PMID- 23102828 TI - Are spondyloarthropathies adequately referred from primary care to specialized care? AB - OBJECTIVE: To evaluate the degree of agreement between primary care physicians and rheumatologists when evaluating the referral criteria in patients with suspected early spondyloarthropathy (Spa). MATERIAL AND METHODS: Patients with suspected early Spa (according to predefined clinical referral criteria) were sent by primary care physicians to early Spa units (where a rheumatologist evaluated the same criteria and confirmed the diagnosis) through an on-line platform. We assessed the agreement between primary care physicians and rheumatologists regarding the predefined clinical referral criteria among patients with definitive Spa using the kappa index (k). RESULTS: Eight hundred and two patients were analysed, 8.31% of whom were incorrectly referred to the rheumatologist. The degree of agreement regarding the predefined clinical referral criteria was poor for inflammatory back pain (k=0,16; 95% confidence interval [95% CI] 0,09-0,23), radiographic sacroiliitis (k=0,31; 95% CI 0,211 0,428), back or joint pain (k=0,21; 95% CI 0,14-0,29); mild for asymmetric arthritis (k=0,51; 95% CI 0,43-0,59), positive HLA B27 (k=0,59; 95% CI 0,52-0,67) and family history (k=0,50; 95% CI 0,415-0,604); and it was good or very good for anterior uveitis (k=0,81; 95% CI 0,68-0,93), inflammatory bowel disease (k=0,87; 95% CI 0,79-0,96) and psoriasis (k=0,73; 95% CI 0,65-0,81),. CONCLUSIONS: The degree of agreement between primary care physicians and rheumatologists regarding the predefined clinical referral criteria was variable. Agreement was very poor for variables like inflammatory back pain, which are crucial for the diagnosis of Spa. Training programs for primary care physicians are important in order for them to correctly identify early Spa patients. PMID- 23102829 TI - Characterization of the role of Fhit in suppression of DNA damage. AB - The fragile histidine triad protein, Fhit, has a number of reported tumor suppressive functions which include signaling of apoptosis in cancer cells in vitro and in vivo, modulation of the DNA damage response, down-regulation of target oncogene expression, suppression of tumor growth in vivo, and suppression of cancer cell invasion and metastasis. Most of these functions of Fhit have been observed on exogenous re-expression of Fhit in Fhit-negative cancer cells. However, little is known about the tumorigenic changes that occur in normal or precancerous cells following loss of Fhit expression. Recently, we have shown that shortly after loss of Fhit expression, cells exhibit signs of DNA replication stress-induced DNA damage and develop genomic instability. Here, we extend these findings through investigation of different factors that affect Fhit function to prevent DNA damage. We found that Fhit activity is dependent upon a functional HIT domain and the tyrosine-114 residue, previously shown to be required for tumor suppression by Fhit. Furthermore, Fhit function was shown to be independent of exogenous and endogenous sources of oxidative stress. Finally, Fhit function was shown to be dependent upon Chk1 kinase activity, but independent of Atr or Atm kinases. Evidence suggests that Fhit and Chk1 kinase cooperate to prevent replication stress-induced DNA damage. These findings provide important and unexpected insights into the mechanism whereby loss of Fhit expression contributes to cell transformation. PMID- 23102830 TI - An electrochemical sensor based on label-free functional allosteric molecular beacons for detection target DNA/miRNA. AB - We report two novel electrochemical sensors (E-sensors) for the detection of target DNA and miRNA. The E-sensors were fabricated using label-free functional allosteric molecular beacons (aMBs), which can form streptavidin aptamers to bind to streptavidin peroxidase polymer and so generate catalytic currents in the presence of the targets. These E-sensors eliminate the antigen antibody interactions which require sophisticated DNA modification. During the experiment, we found a pair of CV peaks located at around 0.17 V. These peaks contributed to the redox reaction between TMB and TMB(+), and the adsorption-desorption process of TMB(+) to the negative aMB backbone. When the E-sensor was hybridized with the complement of the aMB sequence, a pair of CV peaks were found at around 0.47 V which were related to the redox reaction between TMB(+) and TMB(2+), and the process of intercalation of the planar structure of TMB(2+) to dsDNA. The RSV-aMB E-sensor could detect 44 amol RSV DNA in the 4 MUL sample and performed well in complicated biological environments. The let-7a-aMB E-sensor reached a detection limit of 13.6 amol let-7a miRNA in the 4 MUL sample and showed good selectivity for one base mismatched miRNA. PMID- 23102831 TI - Signal-amplified platform for electrochemical immunosensor based on TiO2 nanotube arrays using a HRP tagged antibody-Au nanoparticles as probe. AB - In this study, a novel signal-amplified electrochemical immunosensor was proposed by using TiO(2) nanotube (TiNT) arrays as the platform. Due to the distinct tubular features-large surface area, high pore volume and good electrochemical conductivity, the TiNT based electrodes exhibited excellent signal-amplified effects. gold nanoparticle (AuNP) was further utilized to bind horseradish peroxidase (HRP) tagged antibodies as recognition elements. Compared to the immunosensor based on either flat electrode, the immunosensors using TiNT layer as electrode showed higher amplified electrochemical signals from the catalytic reaction of HRP relative to hydrogen peroxide (H(2)O(2)). Under optimal conditions, the proposed immunosensor exhibited a good electrochemical behavior to antigen in a concentration range from 0.1 ng mL(-1) to 10(5) ng mL(-1) with a detection limit of 0.01 ng mL(-1). The results showed that the TiNT-based electrochemical immunosensing platform could provide a great potential in clinical application for detection of low-abundant proteins. PMID- 23102832 TI - Electromyographic and mechanomyographic responses across repeated maximal isometric and concentric muscle actions of the leg extensors. AB - The purpose of the present study was to examine the patterns of responses for torque, electromyographic (EMG) amplitude, EMG mean power frequency (MPF), mechanomyographic (MMG) amplitude, and MMG MPF across 30 repeated maximal isometric (ISO) and concentric (CON) muscle actions of the leg extensors. Twelve female subjects (21.1+/-1.4yrs; 63.3+/-7.4kg) performed ISO and CON fatigue protocols with EMG and MMG signals recorded from the vastus lateralis. The relationships for torque, EMG amplitude, EMG MPF, MMG amplitude, and MMG MPF versus repetition number were examined using polynomial regression. The results indicated there were decreases (p<0.05) across the ISO muscle actions for torque (r(2)=0.95), EMG amplitude (R(2)=0.44), EMG MPF (r(2)=0.62), and MMG MPF (r(2)=0.48), but no change in MMG amplitude (r(2)=0.07). In addition, there were decreases across the CON muscle actions for torque (R(2)=0.97), EMG amplitude (R(2)=0.46), EMG MPF (R(2)=0.86), MMG amplitude (R(2)=0.44), and MMG MPF (R(2)=0.80). Thus, the current findings suggested that the mechanisms of fatigue and motor control strategies used to modulate torque production were similar between maximal ISO and CON muscle actions. PMID- 23102833 TI - Reduction of STAT3 expression induces mitochondrial dysfunction and autophagy in cardiac HL-1 cells. AB - Signal transducer and activator of transcription 3 (STAT3) is an important mediator of cardiac survival pathways. Reduced levels of STAT3 in patients with end-stage heart failure suggest a clinical relevance of STAT3 deficiency for cardiac disease. The recent identification of STAT3 as a mitochondrial protein which is important for full activity of mitochondrial complex I has opened a new field for the investigation of how STAT3 functions in cardioprotection. The goal of this study was to establish a cell culture model with a reduced STAT3 expression, and to use this model for the investigation of mitochondrial and mitochondrial-associated functions under STAT3 deficiency. In the murine cardiomyogenic cell line HL-1, the expression of STAT3 was silenced by lentiviral transduction with anti-STAT3 shRNA (STAT3 KD cells). STAT3 mRNA and protein levels were significantly reduced in HL-1 STAT3 KD cells compared to HL-1 cells transduced with a control shRNA. Spectrophotometric and polarographic assays with mitochondrial enriched fractions and intact cells showed reduced activities of respiratory chain complexes I, II, III and IV in HL-1 STAT3 KD cells. At ultrastructural level, a severe damage of mitochondrial integrity was observed, combined with a significant increase in autophagolysosomes in STAT3-deficient HL 1 cells. Our results demonstrate that the HL-1 STAT3 KD cell line is a good model to study cellular consequences of STAT3 deficiency. Moreover, this is the first study to show that STAT3 deficiency leads to a disruption of mitochondrial ultrastructure and increased autophagy. PMID- 23102834 TI - Epilepsy health consumer groups and charities; how representative of patients are they? The results of a pilot study. AB - PURPOSE: In the United Kingdom all health care providers are encouraged to consult with user groups. The submissions of charities and patient advocacy groups to NICE and SIGN are considered reflective of the patient groups they purport to represent, yet little is known about how representative they are. This pilot study was designed to ascertain how many patients attending a hospital based epilepsy clinic were members of such advocacy groups. METHODS: Patients were asked to complete a brief 9-question questionnaire before they left the clinic. RESULTS: One hundred and twenty-five questionnaires were distributed, of which 101 were returned. Seventeen percent of patients were members of advocacy groups, with several being members of more than one charity/group. Only seven percent of the respondents had ever been contacted by an advocacy group to canvass their opinions. Seventy percent of patients questioned stated they thought a frank discussion with their physician, or specialist nurse was more likely to influence patient services. Patients with long duration of disease and taking multiple anti-epileptic drugs were more likely to be members of charity/advocacy groups. CONCLUSIONS: As patient charities in the U.K. are often in receipt of public funds, and actively seek to influence public policy this raises the question of whether they should be required to consult more widely with the people they claim to represent. PMID- 23102835 TI - Adalimumab levels in an infant. PMID- 23102836 TI - Two-dimensional longitudinal strain assessment in the presence of myocardial contrast agents is only feasible with speckle-tracking after microbubble destruction. AB - BACKGROUND: Longitudinal strain (LS) imaging is an important tool for the quantification of left ventricular function and deformation, but its assessment is challenging in the presence of echocardiographic contrast agents (CAs). The aim of this study was to test the hypothesis that destruction of microbubbles using high mechanical index (MI) could allow the measurement of LS. METHODS: LS was measured using speckle strain (speckle-tracking LS [STLS]) and Velocity Vector Imaging (VVI) before and after CA administration in 30 consecutive patients. Low MI was used for left ventricular opacification and three dimensional high MI for microbubble destruction. Four different settings were tested over 60 sec: (1) baseline LS without contrast, (2) LS after CA administration with low MI (0.3), (3) LS after CA administration with high MI (0.9), and (4) LS after microbubble destruction with high MI and three dimensional imaging. RESULTS: Baseline feasibility of LS assessment (99.3% and 98.2% with STLS and VVI, respectively) was reduced after CA administration using STLS at low (69%, P < .0001) and high (95.4%, P = .0002) MI as well as with VVI (93.8%, P = .004, and 84.7%, P < .0001, respectively). STLS assessment was feasible with high MI after microbubble destruction (1.7% of uninterpretable segments vs 0.7%, P = .26) but not using VVI (7.2% vs 1.8%, P < .001). Regardless of which microbubbles or image settings were used, VVI was associated with significant variability and overestimation of global LS (for low MI, +4.7%, P < .01; for high MI, +3.3%, P < .001; for high MI after microbubble destruction, +1.3%, P = .04). CONCLUSIONS: LS assessment is most feasible without contrast. If a CA is necessary, the calculation of LS is feasible using the speckle-tracking method, if three-dimensional imaging is used as a tool for microbubble destruction 1 min after CA administration. PMID- 23102837 TI - PSA response to neoadjuvant androgen deprivation therapy is a strong independent predictor of survival in high-risk prostate cancer in the dose-escalated radiation therapy era. AB - PURPOSE: The aim of the study was to evaluate the prognostic value of prostate specific antigen (PSA) response to neoadjuvant androgen deprivation therapy (ADT) prior to dose-escalated radiation therapy (RT) and long-term ADT in high-risk prostate cancer. METHODS AND MATERIALS: We reviewed the charts of all patients diagnosed with high-risk prostate cancer and treated with a combination of long term ADT (median, 24 months) and dose-escalated (median, 75.6 Gy) RT between 1990 and 2007. The associations among patient, tumor, and treatment characteristics with biochemical response to neoadjuvant ADT and their effects on failure-free survival (FFS), time to distant metastasis (TDM), prostate cancer-specific mortality (PCSM) and overall survival (OS) were examined. RESULTS: A total of 196 patients met criteria for inclusion. Median follow-up time for patients alive at last contact was 7.0 years (range, 0.5-18.1 years). Multivariate analysis identified the pre-RT PSA concentration (<0.5 vs >=0.5 ng/mL) as a significant independent predictor of FFS (P=.021), TDM (P=.009), PCSM (P=.039), and OS (P=.037). On multivariate analysis, pretreatment PSA (iPSA) and African-American race were significantly associated with failure to achieve a pre-RT PSA of <0.5 ng/mL. CONCLUSIONS: For high-risk prostate cancer patients treated with long-term ADT and dose-escalated RT, a pre-RT PSA level>=0.5 ng/mL after neoadjuvant ADT predicts for worse survival measures. Both elevated iPSA and African-American race are associated with increased risk of having a pre-RT PSA level>=0.5 ng/mL. These patients should be considered for clinical trials that test newer, more potent androgen-depleting therapies such as abiraterone and MDV3100 in combination with radiation. PMID- 23102838 TI - Acceptable toxicity after stereotactic body radiation therapy for liver tumors adjacent to the central biliary system. AB - PURPOSE: To evaluate biliary toxicity after stereotactic body radiation therapy (SBRT) for liver tumors. METHODS AND MATERIALS: Among 297 consecutive patients with liver tumors treated with SBRT of 35 to 50 Gy in 5 fractions, patients who were irradiated with >20 Gy to the central biliary system (CBS), including the gallbladder, and had follow-up times >6 months were retrospectively analyzed. Toxicity profiles, such as clinical symptoms and laboratory and radiologic data especially for obstructive jaundice and biliary infection, were investigated in relation to the dose volume and length relationship for each biliary organ. RESULTS: Fifty patients with 55 tumors were irradiated with >20 Gy to the CBS. The median follow-up period was 18.2 months (range, 6.0-80.5 months). In the dose length analysis, 39, 34, 14, and 2 patients were irradiated with >20 Gy, >30 Gy, >40 Gy, and >50 Gy, respectively, to >1 cm of the biliary tract. Seven patients were irradiated with >20 Gy to >20% of the gallbladder. Only 2 patients experienced asymptomatic bile duct stenosis. One patient, metachronously treated twice with SBRT for tumors adjacent to each other, had a transient increase in hepatic and biliary enzymes 12 months after the second treatment. The high-dose area >80 Gy corresponded to the biliary stenosis region. The other patient experienced biliary stenosis 5 months after SBRT and had no laboratory changes. The biliary tract irradiated with >20 Gy was 7 mm and did not correspond to the bile duct stenosis region. No obstructive jaundice or biliary infection was found in any patient. CONCLUSIONS: SBRT for liver tumors adjacent to the CBS was feasible with minimal biliary toxicity. Only 1 patient had exceptional radiation induced bile duct stenosis. For liver tumors adjacent to the CBS without other effective treatment options, SBRT at a dose of 40 Gy in 5 fractions is a safe treatment with regard to biliary toxicity. PMID- 23102839 TI - Incidence of leukoencephalopathy after whole-brain radiation therapy for brain metastases. AB - PURPOSE: To evaluate the incidence of leukoencephalopathy after whole-brain radiation therapy (WBRT) in patients with brain metastases. METHODS AND MATERIALS: We retrospectively reviewed 111 patients who underwent WBRT for brain metastases from April 2001 through March 2008 and had evaluable computed tomography (CT) and/or magnetic resonance imaging (MRI) at least 1 month after completion of WBRT. We evaluated the leukoencephalopathy according to the Common Terminology Criteria for Adverse Events, version 3.0. The patients who had brain tumor recurrence after WBRT were censored at the last follow-up CT or MRI without recurrence. To evaluate the risk factors for leukoencephalopathy, bivariate analysis was performed using a logistic regression analysis adjusted for follow up time. Factors included in the analysis were age, gender, dose fractionation, 5 fluorouracil, methotrexate, cisplatin, and other chemotherapeutic agents. RESULTS: The median age of the 111 patients was 60.0 years (range, 23-89 years). The median follow-up was 3.8 months (range, 1.0-38.1 months). Leukoencephalopathy developed in 23 of the 111 patients. Grades 1, 2, and 3 were observed in 8, 7, and 8 patients, respectively. The incidence was 34.4% (11 of 32), 42.9% (6 of 14), 66.7% (2 of 3), and 100% (2 of 2) of the patients who were followed up for >=6, >=12, >=24, and >=36 months, respectively. In the bivariate analysis, older age (>=65 years) was significantly correlated with higher risk of leukoencephalopathy (odds ratio 3.31; 95% confidence interval 1.15-9.50; P=.03). CONCLUSIONS: The incidence of leukoencephalopathy after WBRT was 34.4% with >=6 months follow-up, and increased with longer follow-up. Older age was a significant risk factor. The schedule of WBRT for patients with brain metastases should be carefully determined, especially for favorable patients. PMID- 23102840 TI - Planning 4-dimensional computed tomography (4DCT) cannot adequately represent daily intrafractional motion of abdominal tumors. AB - PURPOSE: To evaluate whether planning 4-dimensional computed tomography (4DCT) can adequately represent daily motion of abdominal tumors in regularly fractionated and stereotactic body radiation therapy (SBRT) patients. METHODS AND MATERIALS: Intrafractional tumor motion of 10 patients with abdominal tumors (4 pancreas-fractionated and 6 liver-stereotactic patients) with implanted fiducials was measured based on daily orthogonal fluoroscopic movies over 38 treatment fractions. The needed internal margin for at least 90% of tumor coverage was calculated based on a 95th and fifth percentile of daily 3-dimensional tumor motion. The planning internal margin was generated by fusing 4DCT motion from all phase bins. The disagreement between needed and planning internal margin was analyzed fraction by fraction in 3 motion axes (superior-inferior [SI], anterior posterior [AP], and left-right [LR]). The 4DCT margin was considered as an overestimation/underestimation of daily motion when disagreement exceeded at least 3 mm in the SI axis and/or 1.2 mm in the AP and LR axes (4DCT image resolution). The underlying reasons for this disagreement were evaluated based on interfractional and intrafractional breathing variation. RESULTS: The 4DCT overestimated daily 3-dimensional motion in 39% of the fractions in 7 of 10 patients and underestimated it in 53% of the fractions in 8 of 10 patients. Median underestimation was 3.9 mm, 3.0 mm, and 1.7 mm in the SI axis, AP axis, and LR axis, respectively. The 4DCT was found to capture irregular deep breaths in 3 of 10 patients, with 4DCT motion larger than mean daily amplitude by 18 to 21 mm. The breathing pattern varied from breath to breath and day to day. The intrafractional variation of amplitude was significantly larger than intrafractional variation (2.7 mm vs 1.3 mm) in the primary motion axis (ie, SI axis). The SBRT patients showed significantly larger intrafractional amplitude variation than fractionated patients (3.0 mm vs 2.1 mm, P<.05). CONCLUSIONS: It may not be appropriate to use 4DCT without monitoring of patient motion on a regular basis for patients with abdominal tumors, especially SBRT patients. PMID- 23102841 TI - UbcH10 overexpression in human lung carcinomas and its correlation with EGFR and p53 mutational status. AB - INTRODUCTION: UbcH10 codes for the cancer related E2 Ubiquitin Conjugating Enzyme, an enzymatic molecule with a key role in the ubiquitin-proteasome pathway. Current studies have suggested a critical role of UbcH10 in a variety of malignancies, including human thyroid, breast, ovarian and colorectal carcinomas. The aim of this study has been to extend the analysis of UbcH10 expression to lung cancer. This neoplasia represents one of the leading cause of cancer mortality worldwide, and new tools for an accurate diagnosis/prognosis are needed. METHODS: The expression levels of UbcH10 were analysed in human non-small cell lung carcinoma (NSCLC) by quantitative RT-PCR and tissue microarray immunohistochemistry, and these values were correlated with the clinicopathological features of the patients affected by NSCLC. RESULTS: Our results demonstrate that UbcH10 is overexpressed in NSCLC compared to the normal lung tissue. Moreover, UbcH10 expression is significantly higher in squamous cell and large cell carcinomas than in adenocarcinomas, and directly and inversely correlated with the mutational status of p53 and EGFR, respectively. The suppression of UbcH10 expression by RNAi resulted in a drastic reduction of proliferation and migration abilities of lung carcinoma cell lines. CONCLUSION: These results, taken together, indicate that UbcH10 overexpression has a critical role in lung carcinogenesis, and the evaluation of UbcH10 expression levels may be a new tool for the characterisation of NSCLC. PMID- 23102842 TI - Accuracy and reliability of coronal and sagittal spinal curvature data based on patient-specific three-dimensional models created by the EOS 2D/3D imaging system. AB - BACKGROUND CONTEXT: Three-dimensional (3D) deformations of the spine are predominantly characterized by two-dimensional (2D) angulation measurements in coronal and sagittal planes, using anteroposterior and lateral X-ray images. For coronal curves, a method originally described by Cobb and for sagittal curves a modified Cobb method are most widely used in practice, and these methods have been shown to exhibit good-to-excellent reliability and reproducibility, carried out either manually or by computer-based tools. Recently, an ultralow radiation dose-integrated radioimaging solution was introduced with special software for realistic 3D visualization and parametric characterization of the spinal column. PURPOSE: Comparison of accuracy, correlation of measurement values, intraobserver and interrater reliability of methods by conventional manual 2D and sterEOS 3D measurements in a routine clinical setting. STUDY DESIGN/SETTING: Retrospective nonrandomized study of diagnostic X-ray images created as part of a routine clinical protocol of eligible patients examined at our clinic during a 30-month period between July 2007 and December 2009. PATIENT SAMPLE: In total, 201 individuals (170 females, 31 males; mean age, 19.88 years) including 10 healthy athletes with normal spine and patients with adolescent idiopathic scoliosis (175 cases), adult degenerative scoliosis (11 cases), and Scheuermann hyperkyphosis (5 cases). Overall range of coronal curves was between 2.4 degrees and 117.5 degrees . Analysis of accuracy and reliability of measurements were carried out on a group of all patients and in subgroups based on coronal plane deviation: 0 degrees to 10 degrees (Group 1, n=36), 10 degrees to 25 degrees (Group 2, n=25), 25 degrees to 50 degrees (Group 3, n=69), 50 degrees to 75 degrees (Group 4, n=49), and more than 75 degrees (Group 5, n=22). METHODS: Coronal and sagittal curvature measurements were determined by three experienced examiners, using either traditional 2D methods or automatic measurements based on sterEOS 3D reconstructions. Manual measurements were performed three times, and sterEOS 3D reconstructions and automatic measurements were performed two times by each examiner. Means comparison t test, Pearson bivariate correlation analysis, reliability analysis by intraclass correlation coefficients for intraobserver reproducibility and interrater reliability were performed using SPSS v16.0 software (IBM Corp., Armonk, NY, USA). No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this article. RESULTS: In comparison with manual 2D methods, only small and nonsignificant differences were detectable in sterEOS 3D-based curvature data. Intraobserver reliability was excellent for both methods, and interrater reproducibility was consistently higher for sterEOS 3D methods that was found to be unaffected by the magnitude of coronal curves or sagittal plane deviations. CONCLUSIONS: This is the first clinical report on EOS 2D/3D system (EOS Imaging, Paris, France) and its sterEOS 3D software, documenting an excellent capability for accurate, reliable, and reproducible spinal curvature measurements. PMID- 23102843 TI - Regulation of sheep oocyte maturation using cAMP modulators. AB - Physical removal of mammalian cumulus-oocyte complexes (COCs) from ovarian follicles results in spontaneous resumption of meiosis, largely because of a decrease in cAMP concentrations, causing asynchrony between cytoplasmic and nuclear maturation and decreased oocyte developmental competence. The aim of this study was to modulate cAMP concentrations within ovine COCs to delay spontaneous nuclear maturation and improve developmental competence. Abattoir-derived sheep COCs were cultured for 2 hours (pre-IVM) in 100 MUM forskolin (FSK) plus 500 MUM 3-isobutyl-1-methylxanthine (IBMX). Pre-IVM (100 MUM FSK and 500 MUM IBMX) culture increased COC cAMP concentrations 10-fold compared with controls (P < 0.05). With regard to nuclear maturation, with FSK and IBMX and/or with FSH and cilostamide delayed completion of meiosis (metaphase II) by 3 to 4 hours compared with standard IVM (FSH-stimulated induction of meiosis). In this study, pre-IVM (with FSK and IBMX) followed by IVM (with FSH and cilostamide), increased ovine COC cAMP concentrations and delayed, but did not inhibit, completion of nuclear maturation. This did not affect embryo development rates, but increased total cell number of blastocysts compared with IVM with FSH alone (103 +/- 6 vs. 66 +/- 4 cells, respectively; mean +/- SEM; P < 0.05). We inferred that regulation of ovine oocyte cAMP concentrations during IVM improved embryo quality compared with embryos produced by standard IVM methods. PMID- 23102844 TI - Elevation of serum thymidine kinase 1 in a bacterial infection: canine pyometra. AB - Pyometra is a bacterial infection of the uterus that is common in dogs and is potentially life-threatening if delayed in diagnosis and/or treatment. Thymidine kinase 1 (TK1) is a cytosolic enzyme involved in DNA precursor synthesis, and it is also present in serum from patients with malignant diseases. TK1 has been used as a cell proliferation biomarker for many years in human medicine and recently in dogs. However, little is known regarding serum TK1 levels in individuals with bacterial infection. The objective of this study was to determine the activity of serum TK1 in dogs with pyometra and compare it with hematologic and biochemical parameters, e.g., acute phase proteins and inflammatory mediators such as C reactive protein and Prostaglandin F(2alpha). Serum and plasma TK1 activity of 40 healthy female dogs and 54 dogs with pyometra were analyzed using an optimized [(3)H]-thymidine phosphorylation assay. TK1 activities in serum or plasma were significantly higher in dogs with pyometra as compared with healthy female dogs (mean +/- SD: 4.0 +/- 7.3 pmol/min/mL in the pyometra group and 1.07 +/- 0.34 pmol/min/mL in healthy control group). However, there was no difference in TK1 activity between systemic inflammatory response syndrome (SIRS) positive (n = 38) and SIRS negative (n = 16) pyometra cases. Furthermore, the plasma TK1 activity decreased in six and increased in one pyometra patients (n = 10), 24 h after ovariohysterectomy. No significant correlations (P > 0.05) were found between TK1 activity and hematological or other biochemical parameters. In conclusion, the TK1 activity was significantly elevated in dogs with pyometra. Further studies are needed to evaluate the mechanism and role of serum TK1 activity in bacterial infections and its possible diagnostic or prognostic value. PMID- 23102845 TI - Superovulation in waptiti (Cervus elaphus) during the anovulatory season. AB - The objective was to evaluate the efficacy of three previously unreported ovarian superovulatory treatment protocols in wapiti. Protocols were initiated specifically at the time of ovarian follicular wave emergence, and intended to enable determination of the effects of frequency of treatment (i.e., animal handling) and LH supplementation on ovarian response. Thirteen parous wapiti hinds, 2 to 4 y of age, were used late in the anovulatory season (July). The ovaries were examined daily by transrectal ultrasonography. Hinds were given 5 mg estradiol 17-beta im (day of treatment designated as Day 0) to induce a new wave of ovarian follicular development. On the expected day of wave emergence (Day 3), hinds were assigned randomly to three treatment groups and given: (1) 100 mg FSH im once a day for 4 days (N = 5); (2) 200 mg FSH sc on Day 3 and Day 5 (N = 4); or (3) 200 mg FSH plus 2.5 mg LH sc on Day 3 and Day 5 (N = 4). All hinds were given 10 mg LH im on Day 6 to induce ovulation. The mean (+/- SEM) number of ovulations per animal in the respective groups was 6.2 +/- 2.0, 15.5 +/- 5.9, and 14.8 +/- 2.7. In conclusion, the technique of inducing follicular wave emergence to initiate superovulatory treatment at the time of wave emergence was effective in wapiti during the anovulatory season. The most efficient and effective method of ovarian superovulation in this study involved administration of estradiol 17 beta on Day 0, followed by 200 mg FSH sc on Days 3 and 5, and induction of ovulation (10 mg of LH) on the evening of Day 6. Compared with conventional methods that require 14 days and handling the hinds six times, the protocol used herein reduced the treatment period to 8 days and the number of animal handlings to four. PMID- 23102846 TI - Comparative metabolic pathway analysis with special reference to nucleotide metabolism-related genes in chicken primordial germ cells. AB - Metabolism provides energy and nutrients required for the cellular growth, maintenance, and reproduction. When compared with genomics and proteomics, metabolism studies provide novel findings in terms of cellular functions. In this study, we examined significant and differentially expressed genes in primordial germ cells (PGCs), gonadal stromal cells, and chicken embryonic fibroblasts compared with blastoderms using microarray. All upregulated genes (1001, 1118, and 974, respectively) and downregulated genes (504, 627, and 1317, respectively) in three test samples were categorized into functional groups according to gene ontology. Then all selected genes were tested to examine their involvement in metabolic pathways through Kyoto Encyclopedia of Genes and Genomes pathway database using overrepresentation analysis. In our results, most of the upregulated and downregulated genes were involved in at least one subcategory of seven major metabolic pathways. The main objective of this study is to compare the PGC expressed genes and their metabolic pathways with blastoderms, gonadal stromal cells, and chicken embryonic fibroblasts. Among the genes involved in metabolic pathways, a higher number of PGC upregulated genes were identified in retinol metabolism, and a higher number of PGC downregulated genes were identified in sphingolipid metabolism. In terms of the fold change, acyl-CoA synthetase medium-chain family member 3 (ACSM3), which is involved in butanoate metabolism, and N-acetyltransferase, pineal gland isozyme NAT-10 (PNAT10), which is involved in energy metabolism, showed higher expression in PGCs. To validate these gene changes, the expression of 12 nucleotide metabolism-related genes in chicken PGCs was examined by real-time polymerase chain reaction. The results of this study provide new information on the expression of genes associated with metabolism function of PGCs and will facilitate more basic research on animal PGC differentiation and function. PMID- 23102847 TI - Effect of pH and cation concentrations on spermatozoan motility of sea trout (Salmo trutta m. trutta L.). AB - Environmental conditions during external fertilization in fish have a significant effect on spermatozoan motility (MOT) and fertilization ability. Even in the same family of fish, spermatozoa might differ in sensitivity to ions present in the external medium. Elucidation of such differences within a species would help to understand spermatozoan biology and to determine external conditions that would optimize spermatozoan MOT and successful fertilization. Objectives of the current study were to determine the effects of pH and of sodium, potassium, and calcium ion concentrations in the activation solution on sea trout spermatozoan MOT. Six parameters characterizing MOT (MOT, curvilinear velocity [VCL], linearity, amplitude of lateral head displacement, beat cross frequency, and duration of MOT) in spermatozoa activated in prepared buffers were traced by computer assisted sperm analysis. Sea trout spermatozoa were motile over a wide range of pH values, and increasing pH did influence MOT, VCL, linearity, amplitude of lateral head displacement, and MOT duration. The optimum pH for sperm MOT was established at approximately 10. Increasing K(+) ion concentration within the observed range caused a decrease in MOT and VCL. Spermatozoan movement ceased at 8 mM KCl concentrations. In Ca(2+) buffers, sperm were motile within the range of 0 to 70 mM CaCl(2) concentration; although beyond 8 mM concentration, VCL and MOT gradually declined. Spermatozoan aggregation was observed at the highest ion concentrations tested. Increasing CaCl(2) concentration affected MOT pattern from initiation to termination of spermatozoan movement in a similar manner as changes associated with increasing pH. At concentrations of CaCl(2) higher than 0.5 mM and in buffers with pH values 10 to 11, movement of spermatozoa was characterized by high initial linearity followed by its gradual reduction. In contrast to the effects of KCl and CaCl(2), increasing NaCl concentration up to 90 mM Na(+) concentration prolonged the duration of spermatozoan movement and, up to 60 mM Na(+) concentration, slightly increased sperm velocity as well. Above the concentration of 90 mM NaCl, these parameters decreased; and at 240 mM of Na(+), spermatozoa did not activate. PMID- 23102848 TI - Steroid hormones, boar taint compounds, and reproductive organs in pigs according to the delay between immunocastration and slaughter. AB - The producer of vaccine against GnRH recommends that immunocastrated pigs are to be slaughtered within 4 to 6 weeks after the second vaccination (V2). The objective of the study was to examine the effect of shorter or longer delay on steroid hormones, boar taint compounds, and morphologic and histologic traits of reproductive organs. Forty male pigs (individually housed and fed a commercial diet) were assigned within litter to four treatment groups, 10 pigs were left entire (EM27) and the others were vaccinated against GnRH (Improvac, Pfizer Animal Health) at the age of 12 and 19 weeks. Pigs were slaughtered at 21 (IC21), 24 (IC24), and 27 (IC27 and EM27) weeks of age. Two EM27 pigs died during the experiment, one IC21 pig was excluded because of illness, one IC27 pig was a nonresponder, and two pigs (IC24 and IC27) were hermaphrodites. To assess the effect on steroid hormones, blood was taken at 12, 15, 19, 21, and 24 weeks of age. Subcutaneous fat and reproductive organs were sampled after slaughter for determination of androstenone, skatole, morphologic, and histologic measurements. Immmunocastration interrupted the rise of estrogen and caused a substantial fall of testosterone in IC21, IC24, and IC27 pigs. As a result, androstenone and skatole levels were successfully reduced regardless of the time elapsed from V2. The weight of the reproductive organs was also drastically reduced, the shrinkage being proportional to the length of the interval between V2 and slaughter and was the most evident for vesicular glands, followed by bulbourethral glands, and testes. Corresponding changes were observed also on a histologic level with a progressive decrease in the size and number of Leydig cells, a diminishing immunoreactivity of 3beta-hydroxysteroid dehydrogenase/Delta-5-4 isomerase, and luteinizing hormone receptor, along with a shrinkage of tubuli seminiferi, atrophy of seminiferous epithelium, and a loss of germ cells, indicating a disruption in testicular spermatogenetic function. Regression of the glandular tissue with a decreasing amount of secreta was also observed for bulbourethral and vesicular glands. The investigated physiologic, morphologic, and histologic traits were progressive with the increasing delay to slaughter (clearly seen already 2 weeks after V2), though no signs of functional or morphological restoration was observed within 8 weeks after V2. PMID- 23102849 TI - Different swimming behaviors of sterlet (Acipenser ruthenus) spermatozoa close to solid and free surfaces. AB - Spermatozoa tend to swim near surfaces. Such attraction toward surface vicinity was approximated by the force-dipole theoretical approach and hydrodynamic modeling, but the physical parameters of surfaces have not usually been included in these models and their effect on sperm mobility remains unknown. In spermatozoa, changes in wave parameters, together with rotation around their longitudinal axis and circling appear when movement takes place close to surfaces. Here we show, by analysis of microscopy images (including high-speed video), a strong influence of the liquid-solid interface on sterlet spermatozoa motility characteristics compared with motility near the liquid-gas interface. Sperm cells swam at 16% lower velocity near a liquid-solid interface, rotating at a stable frequency of 25 Hz, each 180 degrees rotation corresponding to one beat cycle and circling clockwise (when observed from top). In case of spermatozoa close to a water-air interface, rotation and circling were sporadic and irregular. Sterlet spermatozoa movement near a surface affects their velocity and possibly causes rotation. These behaviors are highly dependent on the level of suppleness of the interface, as has been previously predicted by modeling. Our results enhance the understanding of how surfaces influence fish spermatozoa motility. These insights on the effects of surfaces on fish spermatozoa motility imply that widely used methods rating sperm motility, such as computer-assisted sperm analysis, might lead to erroneous results. Further study of sperm motility near surfaces is urgently needed to correct our rating methods and better understand sperm behavior in natural conditions. Improved evaluation of sperm motility behavior near surfaces could be used to determine physical properties of aquatic interfaces with various surfaces composed of different materials. PMID- 23102850 TI - Retinoic acid signaling biomarkers after treatment with retinoic acid and retinoic acid receptor alpha antagonist (Ro 41-5253) in canine testis: an in vitro organ culture study. AB - Retinoic acid (RA) is an essential component for development and maintenance of the male genital tract and for spermatogenesis. Aldehyde dehydrogenase (ALDH)1, cytochrome P450 (CYP)26b1, RA receptor (RAR)alpha, cellular RA-binding protein (CRAB)II, and stimulated by RA gene (STRA)8 are involved in synthesis, metabolism signaling pathways, and as downstream effectors of RA. The objective was to elucidate the effects of exogenous RA and a RARalpha antagonist on gene expression of ALDH1, CYP26b1, RARalpha, cellular RA-binding protein II, and STRA8 in an in vitro organ culture model of canine testis. Testicular tissues from medium-sized mixed breed dogs (N = 5; age 8 +/- 0.17 mo) were subjected to exogenous all trans-RA (final concentrations of 1, 2, and 10 MUM, and DMSO as control) for 24 h. Similarly, testicular tissues were treated with Ro 41-5253 (RARalpha antagonist), at 1, 10, and 50 MUM final concentrations (DMSO as control) for 24 h. Exogenous RA or the RARalpha antagonist decreased (P < 0.05) mRNA abundance of ALDH1 in a dose-dependent manner compared with control. The CRABII mRNA abundance was greater after RA treatment compared with control (P < 0.01), but only 50 MUM Ro 41-5253 effectively decreased CRABII mRNA abundance compared with control (P < 0.01). Although RA did not affect RARalpha mRNA abundance, the RARalpha antagonist treatment lowered RARalpha mRNA abundance compared with control (P < 0.05). Abundance of CYP26b1and STRA8 mRNA were greater (P < 0.05) after RA treatment, but lower (P < 0.05) after RARalpha antagonist treatment compared with control. In conclusion, exogenous RA decreased mRNA abundance of ALDH1 and increased mRNA abundance of RA signaling molecules and its downstream effectors (CYP26b1, CRABII, and STRA8), whereas treatment with a RARalpha antagonist effectively decreased RARalpha and RA metabolism molecules and its downstream effectors in canine testis. Perhaps pharmacological intervention via the RA pathway would enable canine male contraception or treatment of testicular pathology. PMID- 23102851 TI - Nonmotor symptoms more closely related to Parkinson's disease: comparison with normal elderly. AB - Nonmotor symptoms (NMSs) commonly occur in Parkinson's disease (PD). This study sought to explore the domains of NMSs that are more closely related to PD using nonmotor symptoms scale (NMSS), through a quantitative comparison of NMSs' prevalence and NMSS scores of PD patients with normal controls, and clinical implications. We performed a prospective case-control study on PD patients (n=131) and age- and gender-matched normal controls (n=129). We compared NMSs' prevalence and NMSS scores of the PD patients with those of normal controls, and obtained the ratio to identify the domains that were more closely related to PD than normal aging using the NMSS. NMSs are very common among normal elderly as well as PD patients. The domains with the highest ratio of NMSs' prevalence and NMSS scores between the patient and control groups were the miscellaneous, perceptual problems/hallucinations, and sexual function. These three domains were found to be most closely related to PD. NMSs with higher prevalence in PD patients do not always relate more to PD. As NMSs in PD can also commonly occur among the normal elderly, the NMS prevalence should be interpreted with extreme caution. To properly manage the NMSs in PD, it should be kept in mind that avoiding the overestimation of NMSs as part of PD is as important as their early recognition in PD. PMID- 23102852 TI - What is the accuracy of screening instruments for alcohol and cannabis misuse disorders among adolescents and young adults in the emergency department? PMID- 23102853 TI - Format and readability of an enhanced invitation letter did not affect participation rates in a cancer registry-based study: a randomized controlled trial. AB - OBJECTIVES: To assess the effectiveness of an "enhanced" invitation letter in increasing participation in an Australian cancer registry-based study and assess the representativeness of the study sample. STUDY DESIGN AND SETTING: Eight hundred hematological cancer survivors, diagnosed within the last 3 years and aged 18-80 years at recruitment, were selected from one Australian state-based cancer registry. Half were randomly allocated to receive the standard invitation letter (control group). The remaining half received a modified invitation letter, incorporating content and design characteristics recommended to improve written communication (intervention group). RESULTS: Of the 732 eligible survivors, 268 (37%) returned a completed survey. There was no difference in participation between the intervention (n = 131, 36%) and control groups (n = 137, 38%; P = 0.53). Participants were representative of the population for characteristics assessed, except for age group at diagnosis. Survivors 50 years or older at diagnosis had higher odds of returning a completed survey, 50-59 (odds ratio [OR]: 2.53; 95% confidence interval [CI]: 1.47, 4.35), 60-69 (OR: 2.69; 95% CI: 1.58-4.58), and 70-80 (OR: 1.90; 95% CI: 1.07-3.35), than survivors aged 15-39 years at diagnosis. CONCLUSION: An enhanced invitation letter was not effective in increasing participation of hematological cancer survivors in an Australian cancer registry study. The study sample was moderately representative on variables assessed, with age group at diagnosis the only variable associated with participation. Research should evaluate strategies to increase participation in registry studies and focus on tailoring techniques to patient's age. PMID- 23102854 TI - The anterior recurrent peroneal nerve entrapment syndrome: a patellar tendinopathy differential diagnosis case report. AB - Patellar tendinopathy which is a cause of pain in the inferior patellar region is a relatively common pathology among sports enthusiasts. This paper describes a new pain syndrome identified from clinical observations which is a differential diagnosis to patellar tendinopathy. The pattern is specific and recognizable among many individuals, and it should be considered as its own entity. The new syndrome is discussed in terms of the pain experienced, the diagnostic criteria, treatment and the rationale to explain it. As it is a differential diagnosis to patellar tendinopathy, many sports enthusiasts might benefit from this diagnosis. If identified correctly, treatment might be directed to the correct structures and with the appropriate modalities, ensuring the patients a fast return to their past occupations without pain and without unwarranted treatments. PMID- 23102855 TI - [What can be able to expect in stillbirth registration in Hospital Discharge Data System? A feedback from Armand-Trousseau Hospital (Paris)]. PMID- 23102856 TI - The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. AB - OBJECTIVE: To compare the accuracy and reproducibility of the endometrial receptivity array (ERA) versus standard histologic methods. DESIGN: A comparative prospective study (May 2008-May 2012). SETTING: University-affiliated infertility clinic. PATIENT(S): Eighty-six healthy oocyte donors, regularly cycling, aged 20 34 years with a body mass index (BMI) of 19-25 kg/m(2). INTERVENTION(S): Endometrial biopsies were collected throughout the menstrual cycle. For the accuracy study, 79 samples were grouped into two cohorts: the training set (n = 79) for ERA machine-learning training and dating, and a dating subset (n = 49) for comparison between histologic and ERA dating. For the reproducibility study, seven women underwent ERA testing and it was repeated in the same patients on the same day of their cycle 29-40 months later. MAIN OUTCOME MEASURE(S): Concordance of histologic and ERA dating related to LH as a reference, and interobserver variability between pathologists were statistically analyzed by the quadratic weighted Kappa index. The ERA reproducibility was tested and its gene expression visualized by principal component analysis. RESULT(S): For each pathologist, concordance against LH peak yielded values of 0.618 (0.446-0.791) and 0.685 (0.545-0.824). Interobserver variability between pathologists yielded a Kappa index of 0.622 (0.435-0.839). Concordance for ERA dating against LH peak showed a value of 0.922 (0.815-1.000). Reproducibility of the ERA test was 100% consistent. CONCLUSION(S): The ERA is more accurate than histologic dating and is a completely reproducible method for the diagnosis of endometrial dating and receptivity status. PMID- 23102857 TI - Best practices of ASRM and ESHRE: a journey through reproductive medicine. AB - BACKGROUND: The American Society for Reproductive Medicine (ASRM) and the European Society of Human Reproduction and Embryology (ESHRE) are the two largest societies in the world whose members comprise the major experts and professionals working in the field of reproductive medicine and embryology. These societies have never before had a joint scientific meeting. METHOD(S): A 3-day meeting was planned and took place in March of 2012. The goal was to present and debate key topics, as well as modes of practice in reproductive medicine and to discuss recent developments in the field. RESULT(S): Presentations by members of ASRM and ESHRE were of three types: 'state of the art' lectures, 'back-to-back' presentations of two points of view and debates. CONCLUSION(S): For the first time, ASRM and ESHRE held a joint meeting where a special emphasis was given to presentations on the hottest topics in the field. Although different opinions and approaches sometimes exist on the two sides of the Atlantic, an appreciation and acceptance of these differences was evident, and there was more commonality than divergence of opinion. PMID- 23102858 TI - Effect of vitrification on human oocytes: a metabolic profiling study. AB - OBJECTIVE: To evaluate the effect of oocyte vitrification in the metabolomic profile of embryos developed from vitrified and fresh oocytes in our ovum donation program. DESIGN: Analysis of the metabolic profiles of spent culture medium samples corresponding to embryos developed from vitrified and fresh oocytes. SETTING: In vitro fertilization (IVF) unit/metabolomic facility. PATIENT(S): Oocyte donors between the ages of 18 and 35 years. INTERVENTION(S): Metabolomic profile liquid chromatography coupled with mass spectrometry (LC-MS) of spent media samples. MAIN OUTCOME MEASURE(S): Identification of spent media components and metabolites present and absent in vitrified and fresh day-3 embryos. RESULT(S): We obtained a total of 190 spent media samples: vitrification group (65), fresh group (59), and a matched control media group (66). Multivariate data analysis was performed after global metabolomic and amino acid profiles did not reveal any statistically significant differences in day-3 embryos derived from fresh and vitrified oocytes, indicating that other metabolic differences between the samples (e.g., patient-to-patient variability, analytical variation) are greater than those between the vitrified and fresh sample groups. Univariate statistical analysis revealed a series of possible biomarkers, such as tryptophan, phenylalanine, and 2,5,7,8-tetramethyl-2-(2'-carboxyethyl)-6 hydroxychroman (alpha-CEHC), although only alpha-CEHC was statistically significant after correction for multiple testing. CONCLUSION(S): Multivariate data analysis did not reveal statistically significant differences between the analyzed groups, suggesting that oocyte vitrification does not disturb embryonic metabolomic profiles. PMID- 23102859 TI - Diagnosis and treatment of diminished ovarian reserve in assisted reproductive technology cycles of women up to age 40 years: the role of insurance mandates. AB - OBJECTIVE: To explore correlates of diminished ovarian reserve (DOR) and predictors of assisted reproductive technologies (ART) treatment outcome in DOR cycles using the Society for Assisted Reproductive Technologies-Clinical Outcomes Reporting System (SART-CORS) database; we hypothesized that mandated state insurance coverage for ART is associated with the prevalence of DOR diagnosis in ART cycles and with treatment outcomes in DOR cycles. DESIGN: Cross-sectional study using ART cycles between 2004 and 2007. SETTING: Not applicable. PATIENT(S): A total of 182,779 fresh, nondonor, initial ART cycles in women up to age 40 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Prevalence of DOR and elevated FSH, odds ratio of DOR and elevated FSH in ART mandated vs. nonmandated states, live birth rates. RESULT(S): Compared with cycles performed in states with mandated ART coverage, cycles in states with no ART mandate were more likely to have DOR (adjusted odds ratio 1.43, 95% confidence interval 1.37 1.5) or elevated FSH (adjusted odds ratio 1.69, 95% confidence interval 1.56 1.85) as the sole reason for treatment. Lack of mandated ART coverage was associated with increased live birth rates in cycles diagnosed as DOR, but not in cycles characterized only by an elevated FSH. CONCLUSION(S): A significant association was observed between lack of mandated insurance for ART and the proportion of cycles treating DOR or elevated FSH. The presence or absence of state-mandated ART coverage could impact access to care and the mix of patients that pursue and initiate ART cycles in ways that influence these proportions. Additional studies are needed that consider the coalescence of insurance mandates, patient and provider factors, and state-level variables on the odds of specific infertility diagnoses and treatment prognosis. PMID- 23102860 TI - Live birth after orthotopic grafting of autologous cryopreserved ovarian tissue and spontaneous conception in Italy. AB - OBJECTIVE: To describe a live birth obtained in Italy after autologous orthotopic transplantation of cryopreserved ovarian cortical tissue. DESIGN: Case report. SETTING: University department of gynecology and obstetrics, reproductive medicine and IVF unit. PATIENT(S): A 29-year-old patient affected by beta thalassemia (intermedia phenotype) who underwent chemotherapy and bone marrow transplantation at age 21 years, resulting in a complete precocious ovarian failure. INTERVENTION(S): Before being treated with chemotherapy (busulfan, cyclophosphamide, and cyclosporine) for bone marrow transplantation, the patient underwent laparoscopic sampling of ovarian cortical tissue that was frozen and cryopreserved in liquid nitrogen. Eight years later, the ovarian tissue was thawed and grafted during laparoscopy at an orthotopic site. MAIN OUTCOME MEASURE(S): Ultrasound and endocrine monitoring of the postgrafting restoration of ovarian function; conception, pregnancy, and live birth. RESULT(S): Three months after grafting, the decrease of circulating FSH levels and the parallel increase of E(2) levels demonstrated ovarian function restoration, which was confirmed by bidimensional ultrasound and color Doppler examinations. After some ovulatory cycles, the patient spontaneously conceived 16 months after transplantation. After 39 weeks of uneventful gestation, a healthy girl weighing 3,970 g was born. CONCLUSION(S): Autologous grafting of cryopreserved ovarian cortex at an orthotopic site may allow ovarian function restoration, spontaneous conception, and birth of a healthy baby. PMID- 23102861 TI - Intranuclear rods myopathy with autonomic dysfunction. AB - Intranuclear rods myopathy (IRM), a variant of nemaline myopathy (NM), is characterized by rod structure in the myonuclei. Patients with IRM present with similar symptoms to those of severe infantile-type NM but have worse outcome. Several extramuscular manifestations have been reported in NM but no dysautonomia. We herein report a 2-year-old girl with IRM and a heterozygous mutation, c.430C>T (p.L144F) in ACTA1. During the infancy, the patient showed severe diaphoresis and facial flushing. Arrhythmia and hypertension with the precipitating factors of feeding, defecation, and urination were observed. Sympathetic antagonist was prescribed and showed some effectiveness. Our report may widen the clinical spectrum of IRM. It also reminds clinicians that autonomic dysfunction may occur in patients with IRM or other actinopathies and appropriate treatment may be necessary. PMID- 23102862 TI - Cognitive correlates of serious suicidal ideation in a community sample of adolescents. AB - BACKGROUND: Studies indicate that a dysfunctional attributional style, problem solving deficits and hopelessness place youths at risk of developing suicidal thoughts and engaging in suicidal behaviour. However, in the realm of suicidality in adolescent, no study has examined the linkages between these three cognitive variables and suicidal ideation in non-clinical samples while taking into account the moderating role of gender on the relationships and controlling for depression. METHODS: In this community study of 712 adolescents 14-18 years of age, through a multivariate approach, the interaction between the cognitive variables, depression and gender was examined with depression controlled in the analyses. RESULTS: Problem-solving deficits and hopelessness proved predictive of such ideation whether or not depressive symptoms were controlled in the analyses. Negative problem orientation/avoidant style was more predictive of ideation in boys than in girls. On the other hand, hopelessness was more predictive for girls than boys. LIMITATIONS: Results were based on a convenience community sample of adolescents and a cross-sectional survey. CONCLUSIONS: Results suggest that a unique explanatory model of the suicide process in adolescence that fails to take account of gender would be ill informed. Suicide prevention strategies should be differentiated according to gender with a stronger emphasis in hopelessness in female adolescents, and problem-solving deficits in male adolescents. PMID- 23102863 TI - Outcomes of induction chemotherapy followed by concurrent chemoradiation for nasopharyngeal carcinoma. AB - PURPOSE: Current standard therapy for nasopharyngeal carcinoma (NPC) is concurrent chemoradiation based on randomized data. However, limited randomized data exist to support the addition of induction chemotherapy (ICT). METHODS: 58 Patients with NPC were treated from 1990 to 2010. All patients received platinum based ICT. All 58 patients were treated with chemoradiation, 57 in a week-on/week off (WOWO) fashion. Concurrent chemotherapy included hydroxyurea/5-fluorouracil for all patients. Median radiation dose was 70 Gy. No patient received adjuvant chemotherapy. RESULTS: AJCC 2009 stage was II=13, III=21, IVa=13, and IVb=11. Median follow-up for surviving patients was 66 months. Response to ICT was complete response (CR) 17% and partial response (PR) 64%. The CR rate after chemoradiation was 96%. Five-year actuarial freedom from local failure (FFLF), freedom from distant failure (FFDF), cause-specific survival (CSS), and overall survival (OS) was 98%, 90%, 90%, and 76%, respectively. Analysis of pediatric patients (n=9) demonstrated 5-year actuarial FFLF, FFDF, CSS, and OS of 100%, 88%, 80%, and 80%, respectively. CONCLUSIONS: ICT followed by concurrent chemoradiation demonstrates excellent FFLF, FFDF, CSS, and OS with tolerable toxicity. Induction chemotherapy followed by concurrent chemoradiation for patients with NPC should be explored further in a randomized setting. PMID- 23102864 TI - Metabolomics platforms for genome wide association studies--linking the genome to the metabolome. AB - Genome-wide association studies (GWAS) reveal links between genetic variance and predisposition to disease. With the advent of modern 'omics-technologies', GWAS can now identify the genetic factors that influence intermediate traits on pathways to disease, such as blood concentrations of carbohydrates, lipids, amino acids, and secondary metabolites, hormones and signal molecules. At the example of recent GWAS with metabolic traits (mGWAS) we review the high-throughput screening approaches that are available to further advance the field. PMID- 23102865 TI - Engineering specialized metabolic pathways--is there a room for enzyme improvements? AB - Recent advances in enzyme engineering enable dramatic improvements in catalytic efficiency and/or selectivity, as well as de novo engineering of enzymes to catalyze reactions where natural enzymes are not available. Can these capabilities be utilized to transform biosynthesis pathways? Metabolic engineering is traditionally based on combining existing enzymes to give new, or modified, pathways, within a new context and/or organism. How efficient, however, are the individual enzyme components? Is there room to improve pathway performance by enzyme engineering? We discuss the differences between enzymes in central versus specialized, or secondary metabolism and highlight unique features of specialized metabolism enzymes participating in the synthesis of natural products. We argue that, for the purpose of metabolic engineering, the catalytic efficiency and selectivity of many enzymes can be improved with the aim of achieving higher rates, yields and product purities. We also note the relative abundance of spontaneous reactions in specialized metabolism, and the potential advantage of engineering enzymes that will catalyze these steps. Specialized metabolism therefore offers new opportunities to integrate enzyme and pathway engineering, thereby achieving higher metabolic efficiencies, enhanced production rates and improved product purities. PMID- 23102866 TI - A systems biology approach to studying the role of microbes in human health. AB - Host-microbe interactions play a crucial role in human health and disease. Of the various systems biology approaches, reconstruction of genome-scale metabolic networks combined with constraint-based modeling has been particularly successful at in silico predicting the phenotypic characteristics of single organisms. Here, we summarize recent studies, which have applied this approach to investigate microbe-microbe and host-microbe metabolic interactions. This approach can be also expanded to investigate the properties of an entire microbial community, as well as single organisms within the community. We illustrate that the constraint based modeling approach is suitable to model host-microbe interactions at molecular resolution and will enable systematic investigation of metabolic links between the human host and its microbes. Such host-microbe models, combined with experimental data, will ultimately further our understanding of how microbes influence human health. PMID- 23102867 TI - The association of living conditions and lifestyle factors with burden of cysts among neurocysticercosis patients in Ecuador. AB - We used baseline data on 154 symptomatic neurocysticercosis (NCC) patients in Ecuador to identify predictors of the burden of cysts. We ran logistic regression models with the burden of cysts as the outcome, defined as the number of cysts in the brain (1 vs >1), and having cysts in all 3 phases of evolution (active, transitional and calcifications) vs <3. These two outcomes are thought to be indicators of exposure dose and/or repeated exposure over time. The predictors examined were: living in a rural area, living on a dirt road, living in an adobe or wood house (vs brick/cement), no running water in the house, no bathroom in the house, having a domestic employee cook in the home, eating most meals at restaurants or street vendors, working in a manual labour job. We found that the odds of having multiple NCC cysts was higher among those working in manual labour (OR=3.5, p=0.004), and those who ate most meals outside the home had higher odds of having cysts in all 3 phases (OR=5.0, p=0.007). Burden of cysts may be a useful outcome when looking to identify exposure risk factors in the absence of an uninfected control group. PMID- 23102868 TI - The treatment of visceral leishmaniasis (kala-azar) in India: no obvious signs of long-term success. AB - In India, the eastern state of Bihar is particularly badly affected by visceral leishmaniasis (VL). It was in Bihar in the 1980s that the first clear signs of resistance to pentavalent antimonials, which had then been the standard antileishmanial treatment for several decades, were observed. New drugs and new formulations of old drugs have since been developed for the treatment of VL. However, despite some initial signs of benefit after each major revision in the method of treatment of VL in India, the VL-related case fatality rates recorded in India since the 1970s show no clear evidence of long-term success. In fact, the most recent data indicate that such rates have stabilised or even increased, probably because of the continued usage of sodium stibogluconate in northern Bihar. PMID- 23102869 TI - Chromatographic lipophilicity determination using large volume injections of the solvents non-miscible with the mobile phase. AB - A new perspective in the lipophilicity evaluation through RP-HPLC is permitted by analysis of the retention factor (k) obtained by injecting large volumes of test samples prepared in solvents immiscible with mobile phase. The experiment is carried out on representative groups of compounds with increased toxicity (mycotoxins and alkaloids) and amines with important biological activity (naturally occurring monoamine compounds and related drugs), which are covering a large interval of lipophilicity. The stock solution of each compound was prepared in hexane and the used mobile phases were mixtures of methanol or acetonitrile and water, in suited volume ratio. The injected volume was between 10 and 100 MUL, while the used stationary phases were RP-18 and RP-8. On both reverse stationary phases the retention factors were linearly decreasing while the injection volume was increasing. In all cases, the linear models were highly statistically significant. On the basis of the obtained results new lipophilicity indices were purposed and discussed. The developed lipophilicity indices and the computationally expressed ones are correlated at a high level of statistical significance. PMID- 23102870 TI - Renal dietitians lack time and resources to follow the NKF KDOQI guidelines for frequency and method of diet assessment: results of a survey. AB - OBJECTIVE: This study was conducted to determine how often renal dietitians assess patients' diets and what methods they use to collect and analyze the data. DESIGN AND METHODS: Data were collected through an anonymous online survey. The survey was distributed to renal dietitians during the winter of 2012. SUBJECTS: Currently practicing renal dietitian members of the International Society for Renal Nutrition and Metabolism, the National Kidney Foundation Council on Renal Nutrition, the Academy of Nutrition and Dietetics Renal Practice Group, and the RenalRD listserve were invited to participate. Of 599 usable responses received, 91% worked in the United States. The main outcome measure was dietitian compliance with Kidney Disease Outcomes Quality Initiative (KDOQI) nutrition assessment guidelines. RESULTS: Most dietitians collect dietary intake data when certain laboratory results are abnormal (70%) whereas 6.5% biannually collect dietary intake data (recommended by KDOQI). The most common reasons for not collecting dietary intake data more frequently were lack of time (42%) and software (25%). Most dietitians determine the frequency of dietary intake assessment on their own (60%) whereas 10% follow the KDOQI guidelines. The most common method of dietary intake data collection was a typical day recall (50%), although 8% reported using a 3-day food record as recommended by KDOQI. The most common method for analyzing dietary intake data was "estimate in my head" (62%) followed by calculate by hand (24.5%). CONCLUSION: Renal dietitians do not follow the KDOQI guidelines for diet assessment because of time constraints. Research must explore which nutrition assessment tools may improve patient outcomes and can also be completed within the time allotted for nutrition care. PMID- 23102871 TI - Ischaemic time and fat necrosis in breast reconstruction with a free deep inferior epigastric perforator flap. AB - PURPOSE: Fat tissue can be injured by ischaemia in free flap surgeries, leading to the development of fat necrosis. The aim of this study was to evaluate the association between ischaemic time and fat necrosis in microsurgical breast reconstruction using a deep inferior epigastric perforator (DIEP) flap. METHODS: A retrospective chart review was performed for patients who underwent breast reconstruction with free DIEP flaps between June 2009 and November 2011. Data regarding patient demographics, potential risk factors and fat necrosis were collected. Fat necrosis was diagnosed with ultrasound imaging between 3 and 6 months postoperatively. Univariate and multivariate analyses were used to assess the correlation between ischaemic time and fat necrosis rate. Receiver operating characteristic curve analysis was used to determine a cut-off value for the ischaemic time at which differential fat necrosis rates were maximal. RESULTS: A total of 86 patients were included in this study. The mean ischaemic time was 89 min, and fat necrosis was diagnosed in 15 patients (17.4%). A significant association was found between ischaemic time and fat necrosis rate on univariate (p-value=0.001) and multivariate analyses (p-value=0.017). The trend analysis of ischaemic time as a categorical variable relative to fat necrosis rate was also significant (p-value<0.001). A threshold value was found whereby patients with an ischaemic time longer than 99.5 min appeared to experience a significantly higher fat necrosis rate than patients with shorter times (p-value=0.005, odds ratio=9.449). CONCLUSION: Ischaemic time appears to be significantly associated with increased fat necrosis rate in breast reconstruction using DIEP flaps. A long ischaemia time may be a risk factor for the development of fat necrosis. PMID- 23102872 TI - Early prediction of anastomotic leakage after free jejunal flap reconstruction of circumferential pharyngeal defects. AB - BACKGROUND: Anastomotic leakage from the free jejunal flap, if diagnosed late, can result in catastrophes. Our study aims to look for clinical parameters that allow early identification of leakage so that appropriate interventions can be taken. METHOD: Between 1980 and 2011, consecutive patients with free jejunal flap reconstruction of circumferential pharyngeal defects were included. A retrospective chart review was then performed comparing the clinical parameters (body temperature, heart rate, serum albumin, haemoglobin and white cell count) between patients with no leakage and those with clinical and radiological leakage. LEVEL OF EVIDENCE: 4. RESULTS: Ninety-six patients were included in the study. The median age was 62 years. Majority (69.8%) of the defects were created after resection of tumours in the hypopharynx. Five (5.2%) patients had clinical leakage and 12 (12.5%) had radiological leakage. There was no significant difference in body temperature, heart rate, incidence of atrial fibrillation and haemoglobin level between those with and without leakage. The serum white cell count was higher in the patients who leaked, but it became statistically significant only after day 7 postoperatively. The serum albumin level was significantly lower in patients with anastomotic leakage starting as early as day 3 after surgery, and the difference persisted until the leak was controlled. However, there was no significant difference in the plasma albumin level between those with clinical or radiological leak. CONCLUSION: Both serum albumin level and white cell count identified the presence of anastomotic leakage from the free jejunal flap. Serum albumin allows early prediction of leakage so that early interventions can be taken to avoid the damage resulting from the delay in diagnosis. PMID- 23102873 TI - Use of botulinum toxin type A to improve treatment of facial wounds: a prospective randomised study. AB - BACKGROUND: The tension vectors acting on the wound edges are transmitted to immature collagen fibres synthesised during the normal healing phase. This accounts for scar widening as well as hypertrophic and hyperpigmented scars. The aim of our study was to evaluate whether early injections of botulinum toxin type A (BTA), which induces temporary muscular paralysis, decreases tension vectors on wound edges and enhances scarring of facial wounds. PATIENTS AND METHODS: Thirty patients with facial wounds were enrolled in this study and randomised into two groups with or without injection of BTA within 72 h postoperatively. BTA was injected into the facial muscles directly or indirectly involved in scar widening. Scars were assessed at a 1-year follow-up visit by patients using the Patient Scar Assessment Scale (PSAS) scale, by an independent evaluator using the Observer Scar Assessment Scale (OSAS) and the Vancouver Scar Scale (VSS), and by a board of six experienced medical specialists using the Visual Analogue Scale (VAS) with standardised photographs. RESULTS: At the 1-year visit, 24 patients were reviewed and six patients were lost to follow-up. No statistically significant differences were found between the two groups for the PSAS, OSAS and VSS scores. However, the median VAS rated by the six evaluators was 8.25 for the botulinum toxin-treated group compared with 6.35 for the control group. This result was statistically different, demonstrating improved scarring with BTA. CONCLUSIONS: Thanks to chemoimmobilisation, injections of BTA appear to improve cosmesis of facial wounds. Accordingly, they would be beneficial for use in young patients for wounds without tissue loss, lying perpendicular to the reduced tension lines of the skin of the face. PMID- 23102874 TI - Role of cellular allograft containing mesenchymal stem cells in high-risk foot and ankle reconstructions. AB - The use of cellular allograft containing mesenchymal stem cells is gaining popularity as an augmentation to foot and ankle arthrodesis. Those with underlying comorbidities (diabetes mellitus, Charcot osteoarthropathy, smoking, suppressive medication, increased body mass index) are more likely to require surgical revision procedures and typically have a greater rate of nonunion than their healthy counterparts. We believe that the use of a mesenchymal stem cell graft will increase the likelihood of a successful fusion during the primary procedure. The present study reviewed the use of stem cell grafting in hindfoot and ankle surgery and the healing times in high-risk patients. Successful fusion was defined as bridging across 3 cortices. In this patient group, the average interval to radiologic union was 11.1 +/- 2.0 (range 8 to 15) weeks. The interval to partial weightbearing was 5.5 +/- 1.8 (range 3 to 12) weeks, to full weightbearing was 8.4 +/- 1.9 (range 5 to 14) weeks, and to shoe wearing was 13.6 +/- 3.0 (range 10 to 20) weeks. PMID- 23102875 TI - Coronatine, a more powerful elicitor for inducing taxane biosynthesis in Taxus media cell cultures than methyl jasmonate. AB - Coronatine is a toxin produced by the pathogen Pseudomonas syringae. This compound has received much attention recently for its potential to act as a plant growth regulator and elicitor of plant secondary metabolism. To gain more insight into the mechanism by which elicitors can affect the biosynthesis of paclitaxel (Px) and related taxanes, the effect of coronatine (Cor) and methyl jasmonate (MeJA) on Taxus media cell cultures has been studied. For this study, a two-stage cell culture was established, in which cells were first cultured for 14 days in a medium optimised for growth, after which the cells were transferred to medium optimised for secondary metabolite production. The two elicitors were added to the medium at the beginning of the second stage. Total taxane production in the cell suspension was significantly enhanced by both elicitors, increasing from a maximum level of 8.14mg/L in control conditions to 21.48mg/L (day 12) with MeJA and 77.46mg/L (day 16) with Cor. Expression analysis indicated that the txs, t13oh, t2oh, t7oh, dbat, pam, bata and dbtnbt genes were variably induced by the presence of the elicitors. Genes encoding enzymes involved in the formation of the polihydroxylated hypothetical intermediate (TXS, T13OH, T2OH, T7OH) and the phenylalanoil CoA chain (PAM) were stronger induced than those encoding enzymes catalysing the last steps of the Px biosynthetic pathway (DBAT, BAPT and DBTNBT). Notably, although taxane accumulation differed qualitatively and quantitatively following MeJA- or Cor-elicitation, gene expression induction patterns were similar, inferring that both elicitors may involve distinct but yet uncharacterised regulatory mechanisms. PMID- 23102876 TI - Arbuscular mycorrhizal symbiosis influences strigolactone production under salinity and alleviates salt stress in lettuce plants. AB - Arbuscular mycorrhizal (AM) symbiosis can alleviate salt stress in plants. However the intimate mechanisms involved, as well as the effect of salinity on the production of signalling molecules associated to the host plant-AM fungus interaction remains largely unknown. In the present work, we have investigated the effects of salinity on lettuce plant performance and production of strigolactones, and assessed its influence on mycorrhizal root colonization. Three different salt concentrations were applied to mycorrhizal and non mycorrhizal plants, and their effects, over time, analyzed. Plant biomass, stomatal conductance, efficiency of photosystem II, as well as ABA content and strigolactone production were assessed. The expression of ABA biosynthesis genes was also analyzed. AM plants showed improved growth rates and a better performance of physiological parameters such as stomatal conductance and efficiency of photosystem II than non-mycorrhizal plants under salt stress since very early stages - 3 weeks - of plant colonization. Moreover, ABA levels were lower in those plants, suggesting that they were less stressed than non-colonized plants. On the other hand, we show that both AM symbiosis and salinity influence strigolactone production, although in a different way in AM and non-AM plants. The results suggest that AM symbiosis alleviates salt stress by altering the hormonal profiles and affecting plant physiology in the host plant. Moreover, a correlation between strigolactone production, ABA content, AM root colonization and salinity level is shown. We propose here that under these unfavourable conditions, plants increase strigolactone production in order to promote symbiosis establishment to cope with salt stress. PMID- 23102877 TI - Prognostic value of total bilirubin in patients with ST-segment elevation acute myocardial infarction undergoing primary coronary intervention. AB - Previous studies have shown that the serum total bilirubin (TB) concentration was inversely related with stable coronary artery disease, diabetes mellitus, hypertension, and metabolic syndromes. The relation between TB levels and in hospital and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI) is not known. Data from 1,624 consecutive patients with STEMI who underwent primary PCI were evaluated. TB was measured after primary PCI, and the study population was divided into tertiles. The high TB group (n = 450) was defined as a value in the upper third tertile (>0.9 mg/dl) and the low TB group (n = 1,174) as any value in the lower 2 tertiles (<=0.9 mg/dl). The in-hospital mortality rate was significantly greater in the high TB group than in the low TB group (4% vs 1.5%, p = 0.003). In the multivariate analyses, a significant association was noted between high TB levels and the adjusted risk of in-hospital cardiovascular mortality (odds ratio 3.24, 95% confidence interval 1.27 to 8.27, p = 0.014). In the receiver operating characteristic curve analysis, TB >0.90 mg/dl was identified as an effective cutpoint in patients with STEMI for in-hospital cardiovascular mortality (area under the curve 0.66, 95% confidence interval 0.55 to 0.76, p = 0.001). The mean follow-up period was 26.2 months. No differences were seen in the long-term mortality rates between the 2 groups. In conclusion, high TB is independently associated with in-hospital adverse outcomes in patients with STEMI who undergo primary PCI. However, no association was found with long term mortality. PMID- 23102878 TI - Utility of combination of cardiac magnetic resonance imaging and high-sensitivity cardiac troponin T assay in diagnosis of inflammatory cardiomyopathy. AB - We evaluated the clinical utility of cardiac magnetic resonance imaging (CMR) combined with a novel high-sensitivity troponin T assay (hs-cTnT) in the diagnosis of inflammatory cardiomyopathy. CMR, measurement of hs-cTnT, and endomyocardial biopsy were performed in 42 patients with dilated cardiomyopathy and a short-term history of heart failure (median 2 months, interquartile range 1 to 3.5). The patients were followed up for 25 +/- 9 months for events. Endomyocardial biopsy revealed myocarditis in 15 subjects (36%). The sensitivity, specificity, and diagnostic accuracy of the individual CMR tissue parameters for myocardial inflammation was 40%, 96%, and 76% for early gadolinium enhancement, 87%, 44%, and 60% for late gadolinium enhancement, 47%, 89%, and 74% for pericardial effusion, and 67%, 85%, and 79% for any 2 of the criteria simultaneously, respectively. An assessment of myocardial edema on T(2)-weighted imaging and/or hs-cTnT assay were inadequate for the diagnosis. The extent of late gadolinium enhancement and increased hs-cTnT concentration were significant predictors of a composite end point of cardiac death, urgent heart transplantation, and hospitalization for worsening heart failure (hazard ratio 1.1, 95% confidence interval 1.0 to 1.2, per percentage of left ventricular mass; and hazard ratio 2.2, 95% confidence interval 1.4 to 3.5, per ln ng/L; p = 0.008 and p = 0.001, respectively). In conclusion, the results of the present study have demonstrated a modest performance for CMR and a limited use of the hs-cTnT assay in the diagnosis of inflammatory cardiomyopathy. Nonetheless, in these patients, CMR and/or hs-cTnT assessment seems to be useful for the prediction of the clinical outcome. PMID- 23102879 TI - Effect of body mass index on short- and long-term outcomes after transcatheter aortic valve implantation. AB - Better outcomes have been reported after percutaneous cardiac intervention in obese patients ("obesity paradox"). However, limited information is available on the effect of the body mass index on the outcomes after transcatheter aortic valve implantation (TAVI). We, therefore, sought to determine the effect of the body mass index on the short- and long-term outcomes in patients who underwent TAVI. The population consisted of 940 patients, of whom 25 (2.7%) were underweight, 384 had a (40.9%) normal weight, 372 (39.6%) were overweight, and 159 (16.9%) were obese. Overall, the obese patients were younger (79.7 +/- 6.4 years vs 81.7 +/- 7.3 and 80.8 +/- 7.0 years, p = 0.008) and had a greater prevalence of preserved left ventricular and renal function. On univariate analysis, obese patients had a greater incidence of minor stroke (1.3% vs 0 and 0.3%, p = 0.03), minor vascular complications (15.7% vs 9.1% and 11.6%, p = 0.028) and acute kidney injury stage I (23.3% vs 10.7% and 16.1%, p <0.001). After adjustment, body mass index, as a continuous variable, was associated with a lower risk of mortality at 30 days (odds ratio 0.93, 95% confidence interval 0.86 to 0.98, p = 0.023) and no effect on survival after discharge (hazard ratio 1.01, 95% confidence interval 0.96 to 1.07, p = 0.73). In conclusion, obesity was associated with a greater incidence of minor, but no major, perioperative complications after TAVI. After adjustment, obesity was associated with a lower risk of 30-day mortality and had no adverse effect on mortality after discharge, underscoring the "obesity paradox" in patients undergoing TAVI. PMID- 23102880 TI - Mean platelet volume and long-term mortality in patients undergoing percutaneous coronary intervention. AB - Increased platelet activity is associated with adverse cardiovascular events. The mean platelet volume (MPV) correlates with platelet activity; however, the relation between the MPV and long-term mortality in patients undergoing percutaneous coronary intervention (PCI) is not well established. Furthermore, the role of change in the MPV over time has not been previously evaluated. We evaluated the MPV at baseline, 30 days, 60 days, 90 days, 1 year, 2 years, and 3 years after the procedure in 1,512 patients who underwent PCI. The speed of change in the MPV was estimated using the slope of linear regression. Mortality was determined by query of the Social Security Death Index. During a median of 8.7 years, mortality was 49.3% after PCI. No significant difference was seen in mortality when stratified by MPV quartile (first quartile, 50.1%; second quartile, 47.7%; third quartile, 51.3%; fourth quartile, 48.3%; p = 0.74). For the 839 patients with available data to determine a change in the MPV over time after PCI, mortality was 49.1% and was significantly greater in patients with an increase (52.9%) than in those with a decrease (44.2%) or no change (49.1%) in the MPV over time (p <0.0001). In conclusion, no association was found between the baseline MPV and long-term mortality in patients undergoing PCI. However, increased mortality was found when the MPV increased over time after PCI. Monitoring the MPV after coronary revascularization might play a role in risk stratification. PMID- 23102881 TI - Effect of macroscopic-positive thrombus retrieval during primary percutaneous coronary intervention with thrombus aspiration on myocardial infarct size and microvascular obstruction. AB - Adjunctive thrombus aspiration (TA) during primary percutaneous coronary intervention improves myocardial perfusion and survival; however, the effect of effective thrombus retrieval remains unclear. We evaluated whether macroscopic positive TA in patients with ST-segment elevation myocardial infarction would reduce the infarct size (IS) and microvascular obstruction (MVO), as assessed by contrast-enhanced magnetic resonance imaging. A total of 88 patients with ST segment elevation myocardial infarction were prospectively recruited and assigned to the TA-positive group (n = 38) or TA-negative group (n = 50) according to whether macroscopic aspirate thrombus was visible to the naked eye. The primary end points were the extent of early and late MVO as assessed by contrast-enhanced magnetic resonance imaging performed during in-hospital stay and IS evaluated in the acute phase and at 6 months of follow-up. The incidence of early and late MVO and IS in the acute phase was lower in the TA-positive group than in the TA negative group (early MVO 3.8 +/- 1.1% vs 7.6 +/- 2.1%, respectively, p = 0.003; late MVO 2.1 +/- 0.9% vs 5.4 +/- 2.9%, p = 0.006; and IS 14.9 +/- 8.7% vs 28.2 +/ 15.8%, p = 0.004). At the 6-month contrast-enhanced magnetic resonance imaging study, the final IS was significantly lower in the TA-positive group (12.0 +/- 8.3% vs 22.3 +/- 14.3%, respectively) than in the TA-negative group (p = 0.002). After multivariate adjustment, macroscopic-positive TA represented an independent predictor of final IS (odds ratio 0.34, 95% confidence interval 0.03 to 0.71, p = 0.01). In conclusion, effective macroscopic thrombus retrieval before stenting during percutaneous coronary intervention for ST-segment elevation myocardial infarction is associated with an improvement in myocardial reperfusion, as documented by a clear reduction in the MVO extent and IS. PMID- 23102882 TI - Prehospitalization antiplatelet therapy and outcomes after saphenous vein graft intervention. AB - Antiplatelet therapy is recommended after coronary artery bypass grafting, because it improves saphenous vein graft (SVG) patency and clinical outcomes. We investigated the association between prehospital antiplatelet regimens and outcomes after SVG intervention. Patients who underwent SVG intervention from 2003 to 2008 were divided into 3 groups: (1) no antiplatelet therapy, (2) the use of aspirin or clopidogrel, and (3) the use of dual antiplatelet therapy (DAPT) at admission. Clinical follow-up examinations were performed at 30 days and 1 year. The primary outcome was the composite of all-cause mortality, myocardial infarction, the need for revascularization, and stroke at 30 days. The relation between antiplatelet therapy and outcomes was adjusted for factors associated with the outcomes. A total of 225 patients underwent SVG intervention, 87% were men, and the mean age was 70 years. Of the 225 patients, 21 (9.4%) were not receiving antiplatelet therapy, 102 (45.3%) were receiving aspirin/clopidogrel, and 102 (45.3%) were receiving DAPT. The patients without antiplatelet therapy were more frequently women, had presented earlier after coronary artery bypass grafting, and were less frequently taking other cardiac-related medications. The patients taking aspirin or DAPT were more often smokers and had a greater peripheral vascular burden. The incidence of the 30-day and 1-year primary outcomes was greater in patients without preadmission antiplatelet use (38.1% vs 14.9% and 13.9%, overall p = 0.01; 52.4% vs 29.5% and 28.3%, overall p = 0.03). After adjustment, antiplatelet use remained associated with the primary outcome. In conclusion, prehospital use of antiplatelet therapy was associated with a lower occurrence of major adverse cardiac events after SVG intervention. We did not find that DAPT improved outcomes compared to single antiplatelet therapy. PMID- 23102883 TI - Prognostic utility of BCIS myocardial jeopardy score for classification of coronary disease burden and completeness of revascularization. AB - Several coronary disease scoring systems have been developed to predict procedural risk during revascularization. Many vary in complexity, do not specifically account for myocardium at risk, and are not applicable across all patient subsets. The British Cardiovascular Intervention Society myocardial jeopardy score (BCIS-JS) addresses these limitations and is applicable to all patients, including those with coronary artery bypass grafts or left main stem disease. We assessed the prognostic relevance of the BCIS-JS in patients undergoing percutaneous coronary intervention (PCI). A total of 663 patients who underwent PCI with previous left ventricular function assessment were retrospectively assessed for inclusion, incorporating 221 with previous coronary artery bypass grafting. Blinded observers calculated the BCIS-JS, before (BCIS JS(PRE)) and after (BCIS-JS(POST)) PCI, using the revascularization index (RI) (RI = [BCIS-JS(PRE) - BCIS-JS(POST)]/BCIS-JS(PRE)), quantifying the extent of revascularization, 1 indicating full revascularization and 0 indicating no revascularization. The primary end point all-cause mortality, tracked via the Office of National Statistics. A total of 660 patients were included (66 +/- 10.7 years), with 43 deaths (6.5%) occurring during 2.6 +/- 1.1 years after PCI. All cause mortality was directly related to BCIS-JS(PRE) (hazard ratio [HR] 2.96, 95% confidence interval [CI] 1.71 to 5.15, p = 0.001) and BCIS-JS(POST) (HR 4.02, 95% CI 2.41 to 6.68, p = 0.001). A RI of <0.67 was associated with increased mortality compared to a RI of >=0.67 (HR 4.13, 95% CI 1.91 to 8.91, p = 0.0001). On multivariate analysis, a RI <0.67 (HR 1.99, 95% CI 1.03 to 3.87, p = 0.04), left ventricular dysfunction (HR 2.03, 95% CI 1.25 to 3.30, p = 0.004) and renal impairment (HR 3.75, 95% CI 1.48 to 8.64, p = 0.005) were independent predictors of mortality. In conclusion, the BCIS-JS predicts mortality after PCI and can assess the degree of revascularization, with more complete revascularization conferring a survival advantage in the medium term. PMID- 23102885 TI - Moderate pulmonary embolism treated with thrombolysis (from the "MOPETT" Trial). AB - The role of low-dose thrombolysis in the reduction of pulmonary artery pressure in moderate pulmonary embolism (PE) has not been investigated. Because the lungs are very sensitive to thrombolysis, we postulated that effective and safe thrombolysis might be achieved by a lower dose of tissue plasminogen activator. The purpose of the present study was to evaluate the role of this "safe dose" thrombolysis in the reduction of pulmonary artery pressure in moderate PE. During a 22-month period, 121 patients with moderate PE were randomized to receive a "safe dose" of tissue plasminogen activator plus anticoagulation (thrombolysis group [TG], n = 61 patients) or anticoagulation alone (control group [CG], n = 60). The primary end points consisted of pulmonary hypertension and the composite end point of pulmonary hypertension and recurrent PE at 28 months. Pulmonary hypertension and the composite end point developed in 9 of 58 patients (16%) in the TG and 32 of 56 patients (57%) in the CG (p <0.001) and 9 of 58 patients (16%) in the TG and 35 of 56 patients (63%) in the CG (p <0.001), respectively. The secondary end points were total mortality, the duration of hospital stay, bleeding at the index hospitalization, recurrent PE, and the combination of mortality and recurrent PE. The duration of hospitalization was 2.2 +/- 0.5 days in the TG and 4.9 +/- 0.8 days in the CG (p <0.001). The combination of death plus recurrent PE was 1 (1.6%) in TG and 6 (10%) in the CG (p = 0.0489). No bleeding occurred in any group, and despite a positive trend in favor of a "safe dose" thrombolysis, no significant difference was noted in the rate of individual outcomes of death and recurrent PE when assessed independently. In conclusion, the results from the present prospective randomized trial suggests that "safe dose" thrombolysis is safe and effective in the treatment of moderate PE, with a significant immediate reduction in the pulmonary artery pressure that was maintained at 28 months. PMID- 23102884 TI - Left ventricular diastolic function in children and young adults with congenital aortic valve disease. AB - Young patients with congenital aortic valve disease are at risk of left ventricular (LV) diastolic dysfunction (DD). We evaluated LV remodeling and the prevalence of, and risk factors for, DD in patients with aortic stenosis (AS), pure aortic regurgitation (AR), and AS+AR. Patients aged 8 to 39 years with congenital AS (n = 103), AR (n = 36), or AS+AR (n = 107) were identified. Cross sectional assessment of the LV remodeling pattern and diastolic function was performed. A diastolic function score (DFS; range 0 to 4) was assigned to each patient, with 1 point for an abnormal value in each of 4 categories: mitral inflow (E/A and E-wave deceleration time), tissue Doppler E', E/E', and left atrial volume. Patients with a DFS of >=2 were compared to those with a DFS <2. Concentric hypertrophy was the most common remodeling pattern in those with AS (51%), mixed/physiologic hypertrophy in those with AS+AR (48%) and eccentric hypertrophy in those with AR (49%) predominated. In the entire cohort, 91 patients (37%) had a DFS of >=2. Patients with AS or AS+AR had greater DFS than those with pure AR (p <0.001). On multivariate analysis, a greater LV mass z score and previous aortic valve balloon dilation were associated with a DFS of >=2. In patients with catheterization data (n = 65), E/E' correlated with LV end diastolic pressure. Those with a DFS of >=2 had a greater LV end-diastolic pressure and mean pulmonary artery pressure than those with a DFS <2. In conclusion, DD is common in young patients with AS and AS+AR but not in those with pure AR. A greater LV mass and previous aortic valve dilation were associated with DD. PMID- 23102886 TI - Pneumomediastinum and subcutaneous emphysema from bronchial foreign body aspiration. AB - Pneumomediastinum and subcutaneous emphysema are rare presentations of an airway foreign body. Only a handful of other cases have been reported in the English literature. We present a case of a 2 year old female who presented with wheezing and a dry cough. Following a breathing treatment with a non-rebreather mask, she developed right sided facial subcutaneous emphysema. The following day, after an episode of crying, the subcutaneous emphysema rapidly progressed to involve the anterior chest wall, shoulders, neck and face. Rigid bronchoscopy was emergently performed and a ball-valving, soft foreign body was removed from the right bronchus. A chest tube was placed, and the patient was successfully extubated the following day. When faced with a pediatric patient presenting with subcutaneous emphysema or pneumomediastinum of unknown origin, the pediatrician and otolaryngologist should consider the possibility of an airway foreign body. Management involves emergent airway evaluation in the operating room, removal of the foreign body, placement of a chest tube if pneumomediastinum is present, and supportive care with reflux medications and intravenous steroids. PMID- 23102887 TI - The learning curve in revision cholesteatoma surgery. AB - OBJECTIVE: To review the results of revision surgery for cholesteatoma. STUDY DESIGN: Retrospective review of patient's records. SETTING: Tertiary referral center. PATIENTS: A retrospective study of patients operated for acquired middle ear cholesteatoma during the period 1990-2002 was performed. A total of 758 patients were divided into two groups according to surgical experience, and followed during short-term and long-term period. The cholesteatoma was divided according to location, age of patients, status of auditory ossicles, and bilaterality of disease. INTERVENTIONS: The patients were treated with single canal wall up or wall down, according to the propagation of disease and condition of middle ear. The indications for the reoperations were: recurrent or residual cholesteatoma, resuppuration, and AB gap more than 20 dB. MAIN OUTCOME MEASURES: Type of surgical therapy, localization of cholesteatoma, age of patients, revisions, bilaterality of disease, damage of auditory ossicles and learning curve were analyzed. RESULTS: The number of revision operations was reduced in the second period (from totally 24.3% to 16.4%). Closed technique gave a significantly lower rate of failure. For attic cholesteatoma, adults, bilateral disease, and ossicular damage the rate of revisions was significantly lower with surgical experience. CONCLUSION: Surgical experience was important for reduction of reoperation rate for attic and sinus cholesteatoma, adults, bilateral cholesteatoma, and when closed technique is used. PMID- 23102888 TI - Stearidonic acid as a supplemental source of omega-3 polyunsaturated fatty acids to enhance status for improved human health. AB - There is substantial evidence to show that consumption and increased blood levels of the very long-chain (VLC) omega-3 polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with health benefits. The consumption of oily fish is an effective way of increasing EPA and DHA intake and status, but intake in most Western countries remains below the levels recommended for optimal health. The reasons for this include not liking the taste, a concern about sustainability of fish supplies, or potential chemical and heavy metal contamination. Alternative dietary sources of omega-3 fatty acids to enhance EPA and DHA status in the body would therefore be beneficial. There are many non-fish food sources of the essential plant-derived omega-3 fatty acid alpha-linolenic acid, but conversion from this to longer-chain EPA and especially to DHA is poor. Stearidonic acid (SDA) is an intermediate fatty acid in the biosynthetic pathway from alpha-linolenic acid to VLC omega-3 PUFAs and the conversion from SDA is more efficient than from alpha-linolenic acid. However, there are few food sources rich in SDA. Oil crops naturally rich in SDA or enriched through genetic modification may offer an alternative supplemental oil to boost the population status of VLC omega-3 PUFAs. This review discusses the currently available evidence that increased SDA consumption can increase red blood cell EPA content, although this is less than the effect of supplementation directly with EPA. There is now a need for trials specifically designed to assess whether an increased SDA consumption would translate into improved human health outcomes. PMID- 23102889 TI - Synthesis and antibacterial activity of new fluoroquinolones containing a cis- or trans-cyclohexane moiety. AB - New quinolone derivatives bearing a cis- or trans-cyclohexane side chain at the C 7 position have been synthesized and evaluated for their antibacterial activities against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa using the agar dilution method. The activities of compound 53 against these three bacteria were superior to those of the reference drug lomefloxacin. Compounds bearing a cis-cyclohexane side chain generally exhibited greater antibacterial activity than their corresponding trans-isomers. PMID- 23102890 TI - Microwave-assisted synthesis and in vitro antibacterial activity of novel steroidal thiosemicarbazone derivatives. AB - Herein, we reported the synthesis of 16 novel steroidal thiosemicarbazone derivatives via the condensation of steroidal ketones and substituted thiosemicarbazides under solvent-free conditions using microwave irradiation. The yields obtained are in the range of 84-96% using microwave method and 46-62% using conventional method. All the synthesized compounds (7a-p) have been characterized by (1)H NMR, ESI-MS, IR and elemental analyses. All the series compounds (7a-p) were evaluated for their antibacterial activity against and the results were compared with the standard drug Amoxicillin. Some of the compounds from the series like 7c, 7o and 7p were equipotent with Amoxicillin against Pseudomonas aeruginosa. Also compound 7h was better than Amoxicillin against Staphylococcus aureus and Bacillus subtilis. PMID- 23102891 TI - Synthesis and structure-activity relationships of fibrate-based analogues inside PPARs. AB - In an effort to develop safe and efficacious compounds for the treatment of metabolic disorders, new compounds based on a combination of clofibric acid, the active metabolite of clofibrate, and lipophilic groups derived from natural products chalcone and stilbene were synthesised. Some of them were found to be active at micromolar concentrations only on PPARalpha or PPARgamma, while others were identified as dual agonists PPARalpha/gamma. PMID- 23102892 TI - Synthesis of chiral hydroxylated enones as potential anti-tumor agents. AB - A series of chiral hydroxylated enones were synthesized as COTC ether analogues to investigate the structural features required for optimal and selective anti tumor activity. The cytotoxicity of the seven COTC ether analogues against WRL-68 normal and HepG2, HL-60 cancer cell lines were measured. C-4 ether analogues with an aliphatic chain substituent were found to be more favorable than their aromatic counterparts. Inversion of the configuration at C-4 in 5e to give 5f only resulted in reduced selectivity towards cancer cells. These results show that 4-O-pentyl-gabosine D (5e) has optimum selectivity and cytotoxicity towards two cancer cell lines. PMID- 23102893 TI - Design and one-pot synthesis of new 7-acyl camptothecin derivatives as potent cytotoxic agents. AB - New 7-acyl camptothecin derivatives were designed and synthesized from camptothecin in a one-pot reaction through a Minisci type-reaction and were evaluated for cytotoxicity against four tumor cell lines, A-549, DU-145, KB, and KB-vin. All of the new compounds showed significant inhibition of human tumor cell growth, with IC(50) values ranging from 0.01538 to 13.342 MUM. Most of the derivatives were more cytotoxic than irinotecan, and the (7a) and 7-propionyl (7b) analogs exhibited the highest cytotoxic activity against the tumor cell lines tested. This compound class merits further development as anticancer clinical trial candidates. PMID- 23102894 TI - Phase I - II study to assess the feasibility and activity of the triple combination of 5-fluorouracil/folinic acid, carboplatin and irinotecan (CPT-11) administered by chronomodulated infusion for the treatment of advanced colorectal cancer. Final report of the BE-1603 study. AB - Thirty-six metastatic colorectal cancer patients received every 2 weeks, as first (17) or second-line (19) treatment a combined chronotherapy with CPT-11 (infused at day 1 from 2 to 8 a.m.; peak at 5 a.m.), given with 5FU (700 mg/m(2) per day; days 2-5) and folinic acid (300 mg/m(2) per day; days 2-5) both infused from 10 p.m. to 10 a.m. with a peak at 4 a.m., and carboplatin (40 mg/m(2) per day; days 2-5; infused from 10 a.m. to 10 p.m.; peak at 4 p.m.). The doses of CPT11 could be easily pushed from 120 to 180 mg/m(2) in successive cohorts in the phase I part of the study (11 cases). Twenty-five patients were then treated in the phase II of the trial. The overall toxicity was mild leading to dose-reductions in only 11-13% courses. The tumoral activity was interesting with 81% responses and 94% tumour control. Also prolonged survivals were recorded with 8.8 months of progression free and 15.6 months overall survivals. More prolonged survivals were observed in chemotherapy naive patients. Seven patients (19%) could be reoperated from their residual disease. PMID- 23102895 TI - Evaluation of biological rhythms in elderly cancer patients. A complementary translational research within the frame of the trans-hospital pilot program of oncogeriatrics launched at CHC-Liege. AB - Thanks to the sponsoring of Belgian Cancer Plan, we have launched a trans hospital project of oncogeriatrics implying any concerned actors from medical (oncology, geriatrics, various specialties) and paramedical staffs (nurses, physiotherapists, ergotherapists, dieteticians, social workers, psychologists...). We aim to recruit 300 consecutive patients aged over 70 and presenting with a new diagnosed cancer. They will benefit from both detailed Comprehensive Geriatrical (CGA) and Oncological (COA) assessments. A multidisciplinary concertation will try to define for each patient an individualized treatment planning taking into account CGA, CGO, co-morbidities, predictive indexes of chemotherapy toxicity (MAX2, i.e.). Detailed records will be obtained in collaboration with the data-management staff. Furthermore, a complementary translational research will include patients for a simple evaluation of their circadian rhythmicities through cortisol titration at 8a.m. and 4p.m. and actometry recordings of the rest-activity rhythms. Future steps could be developed aiming at the restoration of circadian structure disturbances with revalidation (physical exercise, tai-chi, yoga) and resynchronization (melatonin, hydrocortisone, bright light...) programs. PMID- 23102896 TI - Targeted therapy for metastatic colorectal cancer: role of aflibercept. AB - Worldwide, colorectal cancer (CRC) is the third most commonly diagnosed cancer in male individuals and the second most commonly diagnosed cancer in female individuals. Survival outcomes are less than optimal for patients with metastatic disease, with a 5-year survival in the 5% to 8% range. The development of new chemotherapeutic agents and effective combination regimens for metastatic colorectal cancer (mCRC) has increased median overall survival (OS) to the 24- to 28-month range. Because of the recognition that vascular endothelial growth factors (VEGFs) and their receptors are primary regulators of physiologic and pathologic angiogenesis and lymphangiogenesis, leading to neovascularization and tumor growth, the targeting of the angiogenic pathway has become a focus of key therapeutic strategies in mCRC. Therapeutic regimens that include bevacizumab, an inhibitor of VEGF-A, in combination with cytotoxic chemotherapy, have resulted in improved response rate (RR) and survival in mCRC. However, the effects of VEGF-A inhibition are often temporary, with resistance and disease progression developing in most patients. Proposed models include intrinsic and adaptive resistance, mediated by factors other than VEGF-A. Aflibercept (known as ziv aflibercept in the United States; Zaltrap(r), Regeneron Pharmaceuticals; sanofi aventis), a novel recombinant fusion protein, is an angiogenic factor trap that blocks the binding of VEGF-A, VEGF-B, and placental growth factor. Phase I/II clinical trials have demonstrated effective activity in mCRC, with acceptable safety and tolerability. A recent phase III randomized double-blind trial in patients previously treated with oxaliplatin reported significant improvement in OS, progression-free survival (PFS), and RR with aflibercept compared with placebo when administered in combination with irinotecan and fluorouracil. Adverse events were consistent with anti-VEGF therapy. Thus aflibercept represents a potential new treatment option for patients with mCRC. PMID- 23102897 TI - Safety and effectiveness of oxaliplatin-based chemotherapy regimens in adults 75 years and older with colorectal cancer. AB - Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults > 75 years of age enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. In this comparative effectiveness study, we note that older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin-based chemotherapy regimens comparable to that of younger adults. BACKGROUND: Although the safety and efficacy of oxaliplatin-based chemotherapy regimens for colorectal cancer (CRC) have been demonstrated in adults >= 75 years of age who are enrolled in clinical trials, safety and effectiveness outside the trial setting are less established. METHODS: We retrospectively collected cases of patients >= 75 years of age who were diagnosed with stage III and metastatic CRC and initiated treatment between January 2000 and January 2007 at 2 academic hospitals in Boston, MA. Cases were matched in a 1:2 ratio to controls who were < 75 years of age by hospital site, stage of disease (stage III vs. metastatic) and line of therapy (first- or second line or beyond). The primary study endpoints were grade >= 3 treatment-associated toxicities and intolerance (number of dose delays/reductions and hospital/facility admissions during treatment). The secondary endpoint was overall survival. RESULTS: We identified 84 patients >= 75 years of age (25% >= 80 years) and 168 controls. In the cohort, 77% had colon cancer, 75% had metastatic disease, and 60% were receiving oxaliplatin as first-line therapy. There was no significant difference in grade >= 3 treatment-associated toxicities between the patients and the controls (71.4% vs. 68.5%, respectively; P = .63). Further there was no statistically significant difference between patients and controls for combined endpoints of any grade >= 3 toxicity or hospital/facility admission (P = .92). With a median follow-up of 52 months, 2-year overall survival was similar between patients and controls (43% vs. 52%, respectively; P = .87). CONCLUSION: Older adults with stage III and metastatic CRC treated outside of a clinical trial experienced safety and effectiveness of oxaliplatin based chemotherapy regimens that was comparable to that of younger adults. PMID- 23102898 TI - Intact discourse cohesion and coherence following bilateral ventromedial prefrontal cortex. AB - Discourse cohesion and coherence give communication its continuity providing the grammatical and lexical links that hold an utterance or text together and give it meaning. Researchers often link cohesion and coherence deficits to the frontal lobes by drawing attention to frontal lobe dysfunction in populations where discourse cohesion and coherence deficits are reported and through attribution of these deficits to underlying cognitive impairments putatively associated with the frontal lobes. We examined the distinct contribution of a region of the frontal lobes, the ventromedial prefrontal cortex (vmPFC), to discourse cohesion and coherence across a range of discourse tasks. We found that bilateral vmPFC damage does not impair cohesion and coherence in spoken discourse. This study provides insights into the contribution of the major anatomical subdivisions of the frontal lobes to language use and furthers our understanding of the neural and cognitive underpinnings of discourse cohesion and coherence. PMID- 23102899 TI - Pipestem capillaries in necrotizing myopathy revisited. AB - Pipestem-capillaries in necrotizing myopathy, have been reported as a feature of a distinct type of myopathy. Here, we analyze four muscle biopsy specimens from patients exhibiting endomysial fibrosis associated with pipestem capillaries using histological and electronmicroscopic techniques. However, only one case displayed all of the originally described features, including necrotic fibres, capillary thickening and lack of a significant lymphocytic inflammation, while one case exhibited striking capillary pathology with minimal necrosis and absence of inflammation, and the other two cases were accompanied by additional pathological features. These data support the existence of a microangiopathy with pipestem capillaries as a characteristic and distinct histopathological pattern, and indicate that it occurs in the context of a variety of muscular disorders broader than initially suspected. Furthermore, we show that the pipestem capillary associated decrease in fibre size is at least in part a result of hypoxic changes. PMID- 23102900 TI - Bisphosphonate duration of therapy for management of osteoporosis. PMID- 23102901 TI - Interforaminal implant placement in oral cancer patients: during ablative surgery or delayed? A 5-year retrospective study. AB - In a retrospective study, two mandibular prosthetic rehabilitation strategies supported by implants in oral cancer patients were evaluated: implants placed in the non-resected edentulous symphyseal area during ablative surgery (DAS implants); or at a later stage (postponed (P) implants). Medical files of patients from two head-neck oncology groups from 2000 to 2005 were screened for study inclusion. DAS protocol was used in one group and P protocol in the other. After a 5 year follow-up of 261 edentulous patients with oral cancer in the second group, P implants were placed in 27 patients to support an overdenture. Of the 249 edentulous patients in the first group, 82 patients were given an implant supported overdenture using the DAS implant protocol. Regarding implant loss, no statistically significant differences were seen between the DAS and P implants. In the DAS group, more patients benefited from an implant-supported lower overdenture (39 versus 11%, respectively), and they received their overdenture on average 20.0 months sooner (sd=11.01, p<0.001) after ablative surgery. 17.1% of DAS implants and 4.6% of P implants were never loaded due to tumour and patient related factors including unfavourable implant soft tissue, tumour recurrence near the implant, or radiotherapy induced trismus. PMID- 23102903 TI - Preoperative antithrombin supplementation in cardiac surgery: a randomized controlled trial. AB - OBJECTIVES: Purified antithrombin supplementation in cardiac surgery has been suggested for the treatment of heparin resistance and the prevention of thromboembolic complications. This study is a randomized controlled trial of preoperative purified antithrombin supplementation, with the primary end point of avoiding low (<58%) postoperative antithrombin activity levels and secondary end points including avoidance of heparin resistance, clinical outcome, and safety end points. METHODS: Two hundred patients were randomly allocated to the antithrombin group and the control group. Patients in the antithrombin group received a dose of purified antithrombin to reach an antithrombin activity value of 120%, whereas patients in the control group did not receive antithrombin. RESULTS: The antithrombin activity values were significantly higher in the antithrombin group at all postoperative determinations until discharge. Antithrombin activity levels <58% at admission to the intensive care unit were found in 26.6% of patients in the control group versus none in the antithrombin group (P = .001). Heparin resistance rate was significantly (P = .001) higher in the control group (38.2%) versus the antithrombin group (17%). Patients in the antithrombin group had a significant but clinically irrelevant (8 mL/hour) higher postoperative bleeding, with no differences in transfusion rates. No differences were found for clinical outcomes, and no safety issues were identified. CONCLUSIONS: Preoperative antithrombin supplementation prevents heparin resistance and avoids excessive postoperative decrease of antithrombin activity. PMID- 23102902 TI - Mercury in Arctic marine ecosystems: sources, pathways and exposure. AB - Mercury in the Arctic is an important environmental and human health issue. The reliance of Northern Peoples on traditional foods, such as marine mammals, for subsistence means that they are particularly at risk from mercury exposure. The cycling of mercury in Arctic marine systems is reviewed here, with emphasis placed on the key sources, pathways and processes which regulate mercury levels in marine food webs and ultimately the exposure of human populations to this contaminant. While many knowledge gaps exist limiting our ability to make strong conclusions, it appears that the long-range transport of mercury from Asian emissions is an important source of atmospheric Hg to the Arctic and that mercury methylation resulting in monomethylmercury production (an organic form of mercury which is both toxic and bioaccumulated) in Arctic marine waters is the principal source of mercury incorporated into food webs. Mercury concentrations in biological organisms have increased since the onset of the industrial age and are controlled by a combination of abiotic factors (e.g., monomethylmercury supply), food web dynamics and structure, and animal behavior (e.g., habitat selection and feeding behavior). Finally, although some Northern Peoples have high mercury concentrations of mercury in their blood and hair, harvesting and consuming traditional foods have many nutritional, social, cultural and physical health benefits which must be considered in risk management and communication. PMID- 23102906 TI - Foot pressure distribution variation in pre-obese and non-obese adult subject while standing. AB - BACKGROUND: To investigate foot pressure distribution parameter-power ratio (PR) difference between pre-obese and non-obese adults subjects during standing and show the correlation between body mass index (BMI) and PR value. METHODS: We examined 22 healthy adult subjects aged from 20 to 45 years were classified into two groups according to their BMI values, as 11 non-obese and 11 pre-obese subjects. Foot pressure distribution image during standing was obtained using PedoPowerGraph system. Pedopowergraphic parameters such as percentage medial impulse, forefoot to hind foot pressure distribution ratio and PR were evaluated and compared between the groups. Correlation between BMI value and PR value was assessed. RESULTS: Our result shows significant change in contact area between the groups in mid foot regions. Also we found significant differences in mid foot PR values (p<0.05) between the groups, but no significant differences in hind foot and forefoot PR values. In addition BMI value was found to have positive correlation with right and left mid foot PR value (r=0.60 & 0.61) for all the subjects. CONCLUSION: This study provides for the first time new insights into foot pressure distribution difference in mid foot among pre-obese subjects as compared to non-obese adult subject while standing. Hence knowledge of high mid foot PR value among pre-obese subjects can provide suitable guidelines for designing orthotic devices. PMID- 23102905 TI - Differential membrane type 1 matrix metalloproteinase substrate processing with ischemia-reperfusion: relationship to interstitial microRNA dynamics and myocardial function. AB - OBJECTIVES: Membrane type 1 matrix metalloproteinase (MT1-MMP) is critical to a number of proteolytic and profibrotic events. However, upstream regulation of MT1 MMP with myocardial ischemia-reperfusion remains poorly understood. MicroRNAs regulate post-transcriptional events, and in silico mapping has identified a conserved sequence in MT1-MMP for microRNA-133a. This study tested the hypothesis that changes in microRNA-133a regulation occur with myocardial ischemia reperfusion, which contributes to time- and region-dependent changes in MT1-MMP activity and processing of MT1-MMP substrates. METHODS: Yorkshire pigs (n = 12) underwent ischemia-reperfusion (90 minutes ischemia and 120 minutes reperfusion), where regional preload recruitable stroke work (sonomicrometry), interstitial MT1 MMP activity (microdialysis), Smad2 abundance (immunoblotting), and interstitial microRNA-133a (polymerase chain reaction) were determined within the ischemia reperfusion and remote regions. Human left ventricular fibroblasts were transduced with microRNA-133a and anti-microRNA-133a (lentivirus) to determine the effects on MT1-MMP protein abundance. RESULTS: With ischemia-reperfusion, regional preload recruitable stroke work decreased from steady state (139 +/- 20 mm Hg to 44 +/- 11 mm Hg, P < .05) within the ischemia-reperfusion region. MT1 MMP activity increased in both regions. Phosphorylated Smad2 increased within the ischemia-reperfusion region. Both in vitro and in vivo interstitial levels of microRNA-133a decreased with ischemia and returned to steady-state levels with reperfusion. In vitro transduction of microRNA-133a in left ventricular fibroblasts decreased MT1-MMP levels. CONCLUSIONS: Modulation of MT1-MMP activity and microRNA-133a exportation into the myocardial interstitium occurred in the setting of acute myocardial ischemia-reperfusion. In addition, changes in microRNA-133a expression in left ventricular fibroblasts resulted in an inverse modulation of MT1-MMP abundance. Therefore, targeting of microRNA-133a represents a potentially novel means for regulating the cascade of profibrotic events after ischemia-reperfusion. PMID- 23102907 TI - Effect of Fe3O4 addition on removal of ammonium by zeolite NaA. AB - Magnetic zeolite NaA with different Fe(3)O(4) loadings was prepared by hydrothermal synthesis based on metakaolin and Fe(3)O(4). The effect of added Fe(3)O(4) on the removal of ammonium by zeolite NaA was investigated by varying the Fe(3)O(4) loading, pH, adsorption temperature, initial concentration, adsorption time. Langmuir, Freundlich, and pseudo-second-order modeling were used to describe the nature and mechanism of ammonium ion exchange using both zeolite and magnetic zeolite. Thermodynamic parameters such as change in Gibbs free energy, enthalpy and entropy were calculated. The results show that all the selected factors affect the ammonium ion exchange by zeolite and magnetic zeolite, however, the added Fe(3)O(4) apparently does not affect the ion exchange performance of zeolite to the ammonium ion. Freundlich model provides a better description of the adsorption process than Langmuir model. Moreover, kinetic analysis indicates the exchange of ammonium on the two materials follows a pseudo second-order model. Thermodynamic analysis makes it clear that the adsorption process of ammonium is spontaneous and exothermic. Regardless of kinetic or thermodynamic analysis, all the results suggest that no considerable effect on the adsorption of the ammonium ion by zeolite is found after the addition of Fe(3)O(4). According to the results, magnetic zeolite NaA can be used for the removal of ammonium due to the good adsorption performance and easy separation method from aqueous solution. PMID- 23102908 TI - Temperature response of luminescent tris(bipyridine)ruthenium(II)-doped silica nanoparticles. AB - Nanoparticle-based temperature imaging is an emerging field of advanced applications. Herein, the sensitivity of the phosphorescence of tris(bipyridine)ruthenium(II)-doped silica nanoparticles towards temperature is studied. 130 nm size particles were prepared by a modification of Stober's method, that allows the incorporation of Ru[(bpy)(3)](2+) into the outer particle shell. The entrapped Ru[(bpy)(3)](2+) retains its photophysical properties, yet the emission of the particles is not affected by the presence of O(2), neither by anionic quenchers; quenching by MV(2+), on the other hand, is strongly dependent on pH. Between 20 and 60 degrees C, the steady-state emission of the particles decreases linearly with increasing temperature. The slope of the straight line diminishes slightly on thermal cycling, but soon stabilizes. Fluorescence measurements by scanning confocal microscopy indicate that the silica nanoparticles doped with Ru[(bpy)(3)](2+) can indeed be employed to probe thermal processes in micro-environments. PMID- 23102909 TI - Electric-field-enhanced oriented cobalt coordinated peptide monolayer and its electrochemical properties. AB - The monolayer composed of cobalt coordinated peptides having lipoic acid at the amino terminals was fabricated on gold substrate by a self-assembly method under the electric field. For comparison, the self-assembled peptide monolayer was also prepared without applying a voltage. A leucine-rich hexadecapeptide, Leu(2)HisLeu(6)HisLeu(6), was chosen as the cobalt coordinated peptide. Histidines, His, were introduced as metal ligands for cobalt to the sequential peptide. The complexation between the cobalt and imidazole groups of His residues formed a stable alpha-helical peptide bundle, which oriented perpendicularly to the substrate surface. In the case of the self-assembled peptide monolayer (SAM), which was fabricated under the electric field, the peptide macro-dipole moments aligned unidirectionally along to the direction of the electric field, and the cobalt complexes were fixed in the monolayer to form the ordered arrangement. On the other hand, the SAM prepared without applying the voltage formed the mixture of parallel and antiparallel packing owing to the dipole-dipole interaction. As the result, the efficient non-linear electron flow through the SAM, which was fabricated under the electric field, was achieved by the regular alignment of the peptide macro-dipole moment and the cobalt complexes. This result implied that the self-assembly under the electric field is an efficient method to obtain stable oriented alpha-helical peptide monolayers. This method may be useful for the fabrication of the nano-devices capable of transferring information. PMID- 23102910 TI - Graft-specific immune cells communicate inflammatory immune responses after brain death. AB - BACKGROUND: Donor brain death (BD) triggers inflammatory graft activation that leads to impaired graft quality and outcome. We used a mouse BD model to investigate graft inflammation in cardiac transplants from immune-competent and immune-deficient donor animals. Effects of donor T-cell depletion were tested in an additional group of cardiac transplant recipients. METHODS: We analyzed systemic and graft-specific inflammatory activation after BD in donors and in syngeneic recipients of hearts retrieved from BD donors. To dissect the role of donor-specific immune cells in communicating BD-triggered inflammation, immune deficient T-cell-, B-cell-, and natural killer cell-deficient Rag2/double knockout mice and naive C57BL6 treated with anti-thymocyte globulin (Thymoglobulin; Genzyme Transplant, Cambridge, MA) were observed. RESULTS: Donor BD boosted lymphocyte activation in donors and recipients of syngeneic BD grafts. Lymphocyte activation was mitigated in recipients of immune-deficient and Thymoglobulin-treated BD donor grafts. Likewise, systemic and intra-graft levels of inflammatory cytokines interleukin -1, interleukin-6, interferon-gamma, and tumor necrosis factor-alpha were significantly reduced in immune-deficient and anti-thymocyte globulin-treated recipients. Dense lymphocyte infiltrates were detected in the hearts from untreated BD donors; in contrast, the hearts from donors treated with Thymoglobulin demonstrated a preserved structure with minimal infiltrates comparable with naive controls. CONCLUSION: BD triggers inflammatory graft activation communicated through intra-graft immune cells. Donor treatment with Thymoglobulin prevented inflammatory immune activation and improved graft quality to levels comparable to living donor organs. PMID- 23102911 TI - Central aortic stiffness, hypertension, and coronary allograft vasculopathy in children. PMID- 23102912 TI - Successful management of severe liver failure on venoarterial extracorporeal membrane oxygenation using molecular adsorbent recirculating systeme. PMID- 23102913 TI - Decline in 25% to 75% forced expiratory flow as an early predictor of chronic airway rejection in pediatric lung transplant recipients. AB - BACKGROUND: Bronchiolitis obliterans (BO) is the major obstacle to long-term lung allograft viability. Its clinical correlate, BO syndrome (BOS), is defined as a decline of at least 20% in forced expiratory volume in 1 second (FEV(1)) from baseline. BOS is often diagnosed after significant organ dysfunction has occurred. Because BO is a small-airways disease, we hypothesized that a 20% decline in the 25% to 75% forced expiratory flow (FEF(25-75)) from baseline should occur before a decline in FEV(1) and should predict progression to BOS with high sensitivity and specificity. METHODS: Pulmonary function tests and records of pediatric lung transplantation patients at Texas Children's Hospital from 2002 to 2007 were reviewed. Declines in FEV(1) and FEF(25-75) from the best post-transplant baseline values were recorded and analyzed. Sensitivity, specificity, and positive and negative predictive values were calculated. RESULTS: Thirty-one patients were eligible for the study. In 11 BOS patients, the mean+/-standard deviation number of days from transplant until a 20% decline in FEV(1) was 896.5+/-400 compared with 728.0+/-475 (p = 0.022) until a 20% decline in FEF(25-75) was reached. The sensitivity, specificity, and positive predictive and negative predictive values of a 20% reduction in FEF(25-75) in determining BOS were 100%, 90.0%, 84.6%, and 100%, respectively. CONCLUSIONS: All patients who developed BOS had a decline in FEF(25-75) at or before the decline in FEV(1). The reduction in FEF(25-75) occurred statistically significantly earlier than the decline in FEV(1), by an average of 168.5 days. This decline in FEF(25-75) was also highly sensitive and specific for the diagnosis of BOS. PMID- 23102914 TI - [Transtibial amputation salvage with a cutaneous flap based on posterior tibial perforators]. AB - When performing an amputation of the lower limb, the preservation of the knee joint is important to obtain an optimal functional outcome. Many reconstruction procedures are available to cover the amputation defect in order to preserve a sufficient length of the stump, so a prosthesis could be put in place with the best functional results. Local musculocutaneous flaps or free flaps are conventionally described with their advantages and disadvantages. In this report, we describe our experience with a transtibial amputation and stump covering using a fasciocutaneous flap based on tibial posterior perforators. An extensive tibial bone exposure with only posterior skin was viable. It is an efficient and reliable solution for covering tibial stump without microvascular anastomosis. PMID- 23102915 TI - The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression. AB - Diabetic nephropathy, a progressive kidney disease that develops secondary to diabetes, is the major cause of chronic kidney disease in developed countries, and contributes significantly to increased morbidity and mortality among individuals with diabetes. Although the causes of diabetic nephropathy are not fully understood, recent studies demonstrate a role for epigenetic factors in the development of the disease. For example, non-coding RNA (ncRNA) molecules, including microRNAs (miRNAs), have been shown to be functionally important in modulating renal response to hyperglycemia and progression of diabetic nephropathy. Characterization of miRNA expression in diabetic nephropathy from studies of animal models of diabetes, and in vitro investigations using different types of kidney cells also support this role. The goal of this review, therefore, is to summarize the current state of knowledge of specific ncRNAs involved in the development of diabetic nephropathy, with a focus on the potential role of miRNAs to serve as sensitive, non-invasive biomarkers of kidney disease and progression. Non-coding RNAs are currently recognized as potentially important regulators of genes involved in processes related to the development of diabetic nephropathy, and as such, represent viable targets for both clinical diagnostic strategies and therapeutic intervention. PMID- 23102916 TI - C-reactive protein and procalcitonin for the early detection of anastomotic leakage after elective colorectal surgery: pilot study in 100 patients. AB - INTRODUCTION: Anastomotic leakage is the most important complication after colorectal surgery. Its prognosis depends on its early diagnosis. C-reactive protein (CRP) has already shown its usefulness for the early detection of anastomotic leaks. Procalcitonin (PCT) is widely used in intensive care units and is more expensive, but its usefulness in the postoperative period of digestive surgery is not well established. PATIENTS AND METHODS: Between May 2010 and June 2011, 100 patients undergoing elective colorectal surgery were prospectively included in a database. CRP and PCT were measured before surgery and daily until postoperative day 4. All intraabdominal infections were considered as anastomotic leaks, regardless of their clinical impact and their management. The kinetics of PCT and CRP were recorded, as well as their accuracy for the detection of anastomotic fistula. RESULTS: The incidence of fistula was 13% and the overall mortality rate was 2%. Both CRP and PCT were significantly higher in patients with leakage. Areas under the receiver-operating characteristics (ROC) for CRP were higher than those for PCT each day. The best accuracy was obtained for CRP on postoperative day 4 (areas under the ROC curve were 0.869 for CRP and 0.750 for PCT). CONCLUSION: Procalcitonin is neither earlier nor more accurate than CRP for the detection of anastomotic leakage after elective colorectal surgery. PMID- 23102917 TI - Implications of England's four-hour target for quality of care and resource use in the emergency department. AB - STUDY OBJECTIVE: In 2005, England implemented a controversial target limiting patient stays in the emergency department (ED) to 4 hours. We determine the effect of the "4-hour target" on quality of care and resource use. METHODS: This was a retrospective study of 15 purposively sampled EDs in England, representing a range of performance on the target. The EDs provided administrative data on all visits for May and June, 2003 to 2006. These years spanned the period before the target until more than a year after full implementation. We assessed changes in admission rate, investigations, deaths in the ED, and return visits within 1 week for all patients and separately for those aged 65 years or older. Regression analyses adjusted for clustering at the hospital level and changes in acuity reflected by ambulance arrivals. Results are expressed as the estimated annual change in the percentage of patients experiencing the outcome, with 95% confidence intervals (CIs). RESULTS: A total of 772,525 ED visits were analyzed; visits increased 19% during the 4-year period. Between 2003 and 2006, the percentage of patients arriving by ambulance decreased from 27.8% to 25.8% (annual change from 2003 -0.80%; 95% CI for change: -1.48% to -0.12%). Visits by individuals aged 65 years or older were stable (19.9% to 19.1%; annual change 0.19%; 95% CI for change -0.44% to 0.06%). Between 2003 and 2006, admissions from the ED were unchanged, at 23% (95% CI for change -0.43% to 1.11%). The percentage of patients receiving blood tests increased from 13.8% to 19.8% (annual change 1.00%; 95% CI for change -0.09% to 2.08%). Frequency of radiologic studies decreased slightly, from 38.0% to 35.7% (annual change -0.60%; 95% CI -1.58% to 0.37%). Deaths in the ED and return ED visits within 1 week were unchanged. Return visits resulting in hospital admission increased initially and then returned to 2003 levels (annual change -3.10%; 95% CI -7.32% to 1.11%). CONCLUSION: England's 4-hour target did not appear to have a negative effect on quality or safety of ED care and had little effect on test use. PMID- 23102918 TI - Enhanced production of CCL18 by tolerogenic dendritic cells is associated with inhibition of allergic airway reactivity. AB - BACKGROUND: IL-10-treated dendritic cells (DCs) have been shown to inhibit T-cell responses through induction of anergy and regulatory T cells in various model systems, including allergic inflammation, but the factors being involved in this inhibition are still unclear. OBJECTIVE: This study set out to analyze such factors produced or induced by IL-10-treated DCs by using gene expression profiling and to explore their function. METHODS: CD4(+) T cells from allergic donors were stimulated with autologous monocyte-derived allergen-pulsed mature DCs or IL-10-treated DCs. After 24 hours, the transcriptional profile was analyzed by using Affymetrix technology. Results were validated by using quantitative real-time PCR, protein expression, and functional in vitro and in vivo studies. RESULTS: In CD4(+) T-cell/IL-10-treated DC cocultures the expression of several known genes, such as IL13, IL5 and OX40, was suppressed. Interestingly, there was only one factor that was strongly upregulated: the DC derived chemokine CCL18. In vitro addition of CCL18 to cocultures of CD4(+) T cells and allergen-pulsed DCs resulted in a similar inhibition of T(H)2 cytokine production as induced by allergen-pulsed IL-10-treated DCs without exogenous CCL18, whereas T(H)1 cytokine production, IL-10 production, and proliferation were not affected. Furthermore, in a humanized mouse model of allergy using PBMC engrafted NOD-scid-gammac(-/-) mice, CCL18, but not another T(H)2-associated chemokine, CCL17, inhibited airway reactivity and lung inflammation. Chemotaxis assays revealed that CCL18 preferentially attracted regulatory T cells and, less efficiently, T(H)2 cells. CONCLUSION: These data demonstrate that CCL18 might represent a molecule of significant importance in immunoregulation and might be a therapeutic target in patients with allergic airway diseases. PMID- 23102919 TI - Infant acetaminophen use associates with early asthmatic symptoms independently of respiratory tract infections: the Copenhagen Prospective Study on Asthma in Childhood 2000 (COPSAC(2000)) cohort. PMID- 23102920 TI - Interruption of CD28-mediated costimulation during allergen challenge protects mice from allergic airway disease. AB - BACKGROUND: Allergic asthma is a T(H)2-promoted hyperreactivity with an immediate, IgE, and mast cell-dependent response followed by eosinophil-dominated inflammation and airway obstruction. OBJECTIVE: Because costimulation by CD28 is essential for T(H)2 but not T(H)1 responses, we investigated the effect of selective interference with this pathway in mice using the models of ovalbumin and house dust mite-induced airway inflammation. METHODS: To study the role of CD28 in the effector phase of allergic airway inflammation, we developed an inducibly CD28-deleting mouse strain or alternatively used a CD28 ligand-binding site-specific mouse anti-mouse mAb blocking CD28 engagement. RESULTS: We show that even after systemic sensitization to the allergen, interruption of CD28 mediated costimulation is highly effective in preventing airway inflammation during challenge. In addition to improving airway resistance and histopathologic presentation and reducing inflammatory infiltrates, antibody treatment during allergen challenge resulted in a marked relative increase in regulatory T-cell numbers among the CD4 T-cell subset of the challenged lung. CONCLUSION: Selective interference with CD28-mediated costimulation during allergen exposure might be an attractive therapeutic concept for allergic asthma. PMID- 23102921 TI - Healthcare providers attitudes and perceptions of 'inappropriate attendance' in the Emergency Department. AB - Emergency Departments (EDs) worldwide are facing a crisis from overcrowding and a common perception exists that inappropriate use of the ED is a major contributing factor. Patients, who attend the ED with non-urgent problems, could be dealt with by a General Practitioner; such patients use time and resources that would otherwise be used for patients with more appropriate needs. STUDY AIM: To explore attitudes and perceptions of healthcare providers regarding 'inappropriate attendance' in the ED. STUDY DESIGN: Using a survey questionnaire, this descriptive quantitative study included ED nurses, doctors and paramedics from three regional hospitals in the Republic of Ireland. RESULTS: A total of 163 surveys were returned (59% response rate). There was an overwhelming agreement among respondents that inappropriate attendance in Irish ED exists and poses a considerable challenge for healthcare providers. Results suggest differences of opinion on what represents inappropriate ED use. Potential solutions to address the issue of inappropriate ED attendance include General Practitioners and Advanced Nurse Practitioners practicing within the ED setting; education and greater public awareness and faster access to a specialist opinion in the Out Patient Department. PMID- 23102922 TI - Impact of COMT genotype on cognition in schizophrenia spectrum patients and their relatives. AB - Cognitive impairment in schizophrenia is a core feature and seems to be related mainly to dopaminergic dysfunction in the prefrontal cortex (PFC). The functional polymorphism Val158Met of the COMT (catechol-O-methyltransferase) gene could mediate the relationship between cognition and dopamine activity in PFC. The present study tested the influence of this polymorphism on the cognitive performance of schizophrenia spectrum patients and their relatives, using some subtests of the neuropsychological battery, the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery, and evaluated the impact of this polymorphism on a specific prefrontal cognitive function using a cognitive neuroscience paradigm. A Group of 74 schizophrenia spectrum disorder patients, 48 relatives and 67 controls performed some subtests of the MATRICS Consensus Cognitive Battery. In addition, 40 schizophrenia spectrum disorder patients, 26 relatives and 63 controls performed the Dot Pattern Expectancy Task (DPX) to study context processing. For the neuropsychological battery, no differences in any of the cognitive domains were found according to genotype. The DPX task was sensitive to genotype effects in patients as well as in relatives. Context processing deficits in schizophrenia patients and their relatives may be mediated by COMT genotype. The influence of the COMT genotype on cognition is more relevant in specific cognitive tasks related to prefrontal function. These results should be replicated in larger samples. PMID- 23102923 TI - Skeletal and dental indicators of health in the late mediaeval (12-15th century) population from Nin, southern Croatia. AB - A comprehensive bioarchaeological study of the late mediaeval (12-15th century) skeletal sample from Nin was carried out in order to test the historically documented hypothesis that during the late mediaeval period Nin sustained a period of rapid development that resulted in it becoming one of the major urban centres on the eastern Adriatic coast. The analysed pathological changes (alveolar bone disease, dental caries, dental enamel hypoplasia, cribra orbitalia, periostitis, tuberculosis, Schmorl's nodes, vertebral osteoarthritis, and bone fractures) indicate a relatively good quality of life for the majority of the population from this late mediaeval site. A low prevalence of dental pathologies suggests an adequate diet while a low frequency of long bone trauma testifies to a relatively peaceful life for the inhabitants of mediaeval Nin. Increased urban development during this period resulted in a worsening of sanitary conditions most likely caused by overcrowding, which is reflected in the presence of tuberculosis and the relatively high frequencies of dental enamel hypoplasia and cribra orbitalia. An additional health concern for the late mediaeval inhabitants of Nin may have been the presence of malaria, as recorded in numerous historical sources. Comparison with other Croatian mediaeval skeletal samples suggests that the inhabitants of late mediaeval Nin experienced somewhat better living conditions than their contemporaries from other parts of Croatia. PMID- 23102924 TI - Single-image super-resolution of brain MR images using overcomplete dictionaries. AB - Resolution in Magnetic Resonance (MR) is limited by diverse physical, technological and economical considerations. In conventional medical practice, resolution enhancement is usually performed with bicubic or B-spline interpolations, strongly affecting the accuracy of subsequent processing steps such as segmentation or registration. This paper presents a sparse-based super resolution method, adapted for easily including prior knowledge, which couples up high and low frequency information so that a high-resolution version of a low resolution brain MR image is generated. The proposed approach includes a whole image multi-scale edge analysis and a dimensionality reduction scheme, which results in a remarkable improvement of the computational speed and accuracy, taking nearly 26 min to generate a complete 3D high-resolution reconstruction. The method was validated by comparing interpolated and reconstructed versions of 29 MR brain volumes with the original images, acquired in a 3T scanner, obtaining a reduction of 70% in the root mean squared error, an increment of 10.3 dB in the peak signal-to-noise ratio, and an agreement of 85% in the binary gray matter segmentations. The proposed method is shown to outperform a recent state-of-the art algorithm, suggesting a substantial impact in voxel-based morphometry studies. PMID- 23102925 TI - Intrapulmonary lymph nodes: computed tomography findings with histopathologic correlations. AB - We retrospectively assessed the computed tomography (CT) features of 31 intrapulmonary lymph nodes (IPLNs) with histopathologic correlations. CT scans revealed that the IPLNs are located in the subpleural region, frequently below the level of the carina, and angular in shape. Most of the IPLNs are solid in texture but occasionally present with a ground-glass appearance. For pleura attached and pleura-separated IPLNs, one or more and 3 or more linear opacities extending from the nodules can be identified, respectively. Histologically, the IPLNs are located either at the junction of the pleura and lung lobules or at the junction of adjacent lung lobules. PMID- 23102926 TI - Acute irradiation injury of canine brain with pathology control is detected by diffusion-weighted imaging of MRI. AB - To investigate the pathological changes of canine brain after irradiation and evaluate the effect of diffusion-weighted imaging (DWI), 25 healthy dogs were treated with 70 Gy (60)Cogamma-ray irradiation on right temporal brain. Respectively, the apparent diffusion coefficient (ADC) values of canine alba and ectocinerea were measured by MRI T1 weighted imaging (T1WI), T2 weighted imaging (T2WI), and DWI. Compared with the control group, at every time point after irradiation, the ADC values of canine brain tissue were decreased significantly (P<.05). DWI is a very sensitive imaging technology that detects the changes of water molecule diffusion and microscopic pathological changes after canine brain irradiation. PMID- 23102927 TI - Transoral ultrasonography in the diagnosis and treatment of peritonsillar abscess. AB - PURPOSE: To evaluate the contribution of transoral ultrasonography (TUS) in the diagnosis and treatment of peritonsillar abscess. METHODS: We assessed the records of the patients who underwent TUS for suspected peritonsillar abscess. RESULTS: We identified a total of 26 patients with a prediagnosis of peritonsillar abscess. Following TUS examination, while the diagnosis was confirmed for 23 of the 26 patients (88.46%), the remaining 3 (11.53%) were diagnosed as having peritonsillar cellulitis. CONCLUSION: TUS allows the differentiation of peritonsillar abscess from cellulitis, hence to avoid an unnecessary invasive procedure in the case of a peritonsillar cellulitis. PMID- 23102928 TI - Renal cyst pseudoenhancement at 16- and 64-dector row MDCT. AB - OBJECTIVE: To evaluate the presence of renal cyst pseudoenhancement at 16- and 64 row multidetector computed tomography (MDCT) in patients. METHODS: MDCT images from 90 patients with renal cysts >1 cm in diameter (n=122) were retrospectively analyzed for the presence and predictors of cyst pseudoenhancement. RESULTS: Fifty-three percent of cysts 1-2 cm demonstrated pseudoenhancement (ranged from 11 to 35 HU). Cyst pseudoenhancement was more pronounced when imaged with 64-row CTs compared to 16-row CT. Cyst size, postcontrast renal parenchymal density, and number of scanner detector rows were independent predictors of pseudoenhancement. CONCLUSION: Pseudoenhancement occurs most frequently in patients with renal cysts <2 cm imaged with 64-detector-row MDCT. PMID- 23102929 TI - Evaluation of the left renal vein variations and inferior vena cava variations by means of helical computed tomography. AB - PURPOSE: To evaluate the percentages of the left renal vein (LRV) variations and inferior vena cava (IVC) variations as well as the effect of gender on their frequencies. MATERIALS AND METHODS: Contrast-enhanced abdominal helical computed tomography (CT) examinations of 1204 patients were retrospectively evaluated. RESULTS: The correspondent percentages of the total LRV variations, retroaortic left renal vein (RLRV), and circumaortic LRV were 5.2%, 3.1%, and 2.1%, respectively. A statistically significant correlation was found between RLRV variation and gender (P=.036). CONCLUSIONS: Helical CT is an efficient, fast, easily applicable, and reliable imaging modality in demonstration of LRV variations and IVC variations. PMID- 23102930 TI - Discordant computed tomography and histopathological findings in acute appendicitis: really a radiological "error?". PMID- 23102931 TI - Are caudate-right lobe ratio and splenic size correlated with the MELD score in cirrhotic patients? AB - AIM: To determine the relationship between caudate-right lobe ratio (C/R) and model for end-stage liver disease (MELD) score. METHODS: The study included 50 patients with cirrhosis and a control group of 20 patients. C/R was measured as described by Harbin et al. The size of the spleen was measured on coronal images. The Organ Procurement and Transplantation Network Web site was used for MELD score calculation. Aspartate to alanine aminotranferase (AST/ALT) ratio was calculated. RESULTS: There was statistically significant difference between the two groups. C/R, the size of the spleen, and AST/ALT values were significantly correlated with MELD score. CONCLUSIONS: There is a significant relationship between the C/R and MELD score. PMID- 23102932 TI - Tc-99m sestamibi parathyroid gland scintigraphy: added value of Tc-99m pertechnetate thyroid imaging for increasing interpretation confidence and avoiding additional testing. AB - PURPOSE: To evaluate the benefit of adding a pertechnetate parathyroid scan (dual isotope imaging) in the interpretation of sestamibi dual-phase parathyroid scintigraphy. MATERIAL AND METHODS: One hundred and sixteen dual Tc-99m sestamibi (MIBI) and Tc-99m pertechnetate subtraction parathyroid studies, performed between January 2000 and February 2006, were retrospectively reviewed. Dual-phase technetium sestamibi examinations were initially interpreted, with blinding to the technetium pertechnetate findings. Subsequently, technetium pertechnetate scan findings were added, and changes in interpretation were recorded. RESULTS: By adding Tc-99m pertechnetate imaging, the interpretation of 17 scans (17/116=14.6%) was substantially altered. This included 5 scans (4%) that changed from negative to positive and 9 scans (8%) that changed from equivocal to positive, excluding ectopic tissue and directing minimally invasive surgery, without the need for further imaging, such as ultrasound, in 12% of cases. One examination changed from positive to negative. In addition, 2 scans changed from equivocal to negative, necessitating further preoperative imaging for the evaluation of additional pathology such as thyroid nodules and lymph nodes and the consideration of hyperplasia. Among the remaining 99 patients, Tc-99m pertechnetate scans may also have contributed to the diagnosis in the 66 positive Tc-99m MIBI scans by increasing confidence in the interpretation and obviating additional imaging. Ten cases remained equivocal. CONCLUSION: By adding Tc-99m pertechnetate imaging, scan interpretation was changed in 14.6% of cases, and interpretation confidence was enhanced in all but 10 remaining equivocal cases. The addition of a dual-isotope subtraction also eliminated the need for additional testing, such as ultrasound, in 12% of our cases. Increased confidence in interpretation that comes with dual-isotope subtraction may come at the cost of slight lengthening of imaging time but likely simplifies preoperative localization and decreases intraoperative time for many patients with primary hyperparathyroidism. PMID- 23102933 TI - Evaluation of metabolic risk in prepubertal girls versus boys in relation to fitness and physical activity. AB - BACKGROUND: Low levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a risk of the development of metabolic syndrome. Contradictory findings are reported in the literature regarding the influence of sex and CRF and PA on metabolic changes. OBJECTIVE: The aim of this study was to analyze the effects of CRF and PA on lipid and carbohydrate metabolism biomarkers in boys and girls. METHODS: A total of 82 prepubertal boys and 55 girls (7-12 years of age) were classified according to sex, low or high CRF, and performance or nonperformance of PA. Anthropometric and blood pressure (BP) measurements, plasma lipid profile values, glucose and insulin levels, and homeostasis model assessment for insulin resistance were analyzed. RESULTS: The percentage of boys with high CRF and performance of PA was higher than that of girls (P < 0.05). When children of the same sex were compared, higher values for body mass index and waist circumference z-scores were found for boys with low CRF compared with boys with high CRF (P < 0.001) without differences between girls, and in all groups classified by PA. Systolic and diastolic BPs were higher in boys than in girls, in both CRF and PA groups (P < 0.05). In the low CRF and no PA groups, girls had higher plasma glucose, total cholesterol, and low-density lipoprotein cholesterol levels than boys, with higher high-density lipoprotein cholesterol and apolipoprotein A levels (P < 0.05). CONCLUSIONS: Sex in relation to CRF and PA could affect the plasma lipid profile. These changes in girls are associated with low CRF and low levels of PA. Considering these results, we suggest the need to improve CRF and promote PA, especially in girls, to reduce metabolic risk. PMID- 23102934 TI - Family violence assessment practices of pediatric ED nurses and physicians. AB - BACKGROUND: Recommendations by the ENA and other professional organizations have not resulted in widespread adoption of routine assessment for family violence such as child abuse and intimate partner violence. The aim of this qualitative study was to use a theory-driven approach to explore the salient beliefs and attitudes of nurses and physicians related to routine assessment of child abuse and intimate partner violence in the pediatric emergency department. METHODS: Nurse and physician participants from a large Midwestern pediatric trauma center responded to a series of open-ended questions designed to identify positive or negative attitudes toward family violence assessment, approving or disapproving beliefs about family violence assessment, and the perception of ease or difficulty in performing family violence assessment. RESULTS: Respondents valued early identification and the associated health benefits of keeping pediatric patients safe, as well as linking at-risk families to community resources. They believe that victims, health care organizations, and some providers approve of routine family violence assessment but also believe that some providers and families who value privacy disapprove. Previously identified barriers and facilitators to family violence assessment were confirmed by participants. A finding unique to this study was that participants expressed the belief that routine family violence assessment offers more complete health care to children. DISCUSSION: Participants viewed child abuse and intimate partner violence as an event in a child's life that affects the child's health. Participants valued the benefits of routine family violence assessment; however, translating these value beliefs into practice remains elusive. A theoretical framework may provide insight into yet unidentified aspects of known barriers and facilitators. PMID- 23102935 TI - Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. AB - Pathogenic mutations of the APP gene, leading to early-onset Alzheimer's disease (AD) have been known for more than 20 years. Recently, it was discovered that APP mutations might also be protective. A rare variant A673T reportedly protects against AD and age-related cognitive impairment and might functionally inhibit proteolytic cleavage at the beta-secretase site of APP. We sequenced APP exon 16 in a population-based sample of 515 Finnish subjects aged 85 or older. Neuropathologic data were available in 274. We found the A673T variant in 1 subject (0.2%), who lived until age 104.8 years (second highest age-at-death in the cohort). Neuropathologic analysis showed little beta-amyloid pathology (Consortium to Establish a Registry for Alzheimer's Disease score 0). Some vascular amyloid was detected in meningeal arteries suggesting that vascular beta amyloid accumulation might be less inhibited than the parenchymal. She was demented at the age of 104, most likely because of hippocampal sclerosis. The low amount of parenchymal beta-amyloid pathology at the age of 104.8 years supports the concept that the A673T variant protects the brain against beta-amyloid pathology and AD. PMID- 23102936 TI - Screening of VCP mutations in Chinese amyotrophic lateral sclerosis patients. AB - Mutations in valosin-containing protein (VCP) gene have been recently found in familial and sporadic amyotrophic lateral sclerosis (ALS). To define the frequency of VCP mutations in ALS patients in Chinese population, we sequenced all 17 exons of the VCP gene in a cohort of both familial and sporadic ALS patients of Chinese origin. No nonsynonymous coding variants were identified. This indicates that VCP mutations are not a common cause of familial or sporadic ALS in Chinese population. PMID- 23102937 TI - Importance of circulating IGF-1 for normal cardiac morphology, function and post infarction remodeling. AB - IGF-1 plays an important role in cardiovascular homeostasis, and plasma levels of IGF-1 correlate inversely with systolic function in heart failure. It is not known to what extent circulating IGF-1 secreted by the liver and local autocrine/paracrine IGF-1 expressed in the myocardium contribute to these beneficial effects on cardiac function and morphology. In the present study, we used a mouse model of liver-specific inducible deletion of the IGF-1 gene (LI-IGF 1 -/- mouse) in an attempt to evaluate the importance of circulating IGF-I on cardiac morphology and function under normal and pathological conditions, with an emphasis on its regulatory role in myocardial phosphocreatine metabolism. Echocardiography was performed in LI-IGF-1 -/- and control mice at rest and during dobutamine stress, both at baseline and post myocardial infarction (MI). High-energy phosphate metabolites were compared between LI-IGF-1 -/- and control mice at 4 weeks post MI. We found that LI-IGF-1 -/- mice had significantly greater left ventricular dimensions at baseline and showed a greater relative increase in cardiac dimensions, as well as deterioration of cardiac function, post MI. Myocardial creatine content was 17.9% lower in LI-IGF-1 -/- mice, whereas there was no detectable difference in high-energy nucleotides. These findings indicate an important role of circulating IGF-1 in preserving cardiac structure and function both in physiological settings and post MI. PMID- 23102938 TI - Scaling of an information system in a public healthcare market--infrastructuring from the vendor's perspective. AB - PURPOSE: The purpose of this paper is to explore the making and scaling of information infrastructures, as well as how the conditions for scaling a component may change for the vendor. The first research question is how the making and scaling of a healthcare information infrastructure can be done and by whom. The second question is what scope for manoeuvre there might be for vendors aiming to expand their market. METHOD: This case study is based on an interpretive approach, whereby data is gathered through participant observation and semi-structured interviews. RESULTS: A case study of the making and scaling of an electronic system for general practitioners ordering laboratory services from hospitals is described as comprising two distinct phases. The first may be characterized as an evolving phase, when development, integration and implementation were achieved in small steps, and the vendor, together with end users, had considerable freedom to create the solution according to the users' needs. The second phase was characterized by a large-scale procurement process over which regional healthcare authorities exercised much more control and the needs of groups other than the end users influenced the design. CONCLUSION: The making and scaling of healthcare information infrastructures is not simply a process of evolution, in which the end users use and change the technology. It also consists of large steps, during which different actors, including vendors and healthcare authorities, may make substantial contributions. This process requires work, negotiation and strategies. The conditions for the vendor may change dramatically, from considerable freedom and close relationships with users and customers in the small-scale development, to losing control of the product and being required to engage in more formal relations with customers in the wider public healthcare market. Onerous procurement processes may be one of the reasons why large-scale implementation of information projects in healthcare is difficult and slow. PMID- 23102939 TI - Loco-regional therapy and breast cancer survival: searching for a link. AB - OBJECTIVE: The relationship between loco-regional (LR) control and breast cancer survival was investigated with the intention of generating a new biological hypothesis to explain some of the paradoxes unaccounted for by the prevailing conceptual model of the disease. BACKGROUND: The progressive reduction of surgical aggressiveness has been accompanied by an increase of breast cancer survival mainly attributed to the adoption of adjuvant systemic therapies. More recently, it has been recognized that effective LR control may prolong the survival of breast cancer patients, although the reasons for this improvement have not yet been clearly defined. METHODS: The literature (PubMed) was reviewed for publications related to breast cancer LR treatments using the following key words: breast cancer surgery, breast cancer radiotherapy, breast cancer loco regional control, breast cancer survival. RESULTS: Although breast cancer is frequently a multifocal disease, neither mastectomy nor whole breast irradiation are always mandatory to obtain adequate local control. Conversely, selected groups of patients carry a particularly elevated risk of LR relapse and require more effective treatments to be developed. True LR recurrences are associated with a decreased overall survival and this may be related to a complex relationship between circulating tumor cells, re-seeding of the primary tumor site and several metabolic effects linked to the act of surgery. CONCLUSION: The prevention of LR recurrences is a major goal of breast cancer care, which requires a better understanding of the complex relationships between the primary tumor and its metastatic process. PMID- 23102940 TI - Phonetic measures of reduced tongue movement correlate with negative symptom severity in hospitalized patients with first-episode schizophrenia-spectrum disorders. AB - BACKGROUND: Aprosody, or flattened speech intonation, is a recognized negative symptom of schizophrenia, though it has rarely been studied from a linguistic/phonological perspective. To bring the latest advances in computational linguistics to the phenomenology of schizophrenia and related psychotic disorders, a clinical first-episode psychosis research team joined with a phonetics/computational linguistics team to conduct a preliminary, proof-of concept study. METHODS: Video recordings from a semi-structured clinical research interview were available from 47 first-episode psychosis patients. Audio tracks of the video recordings were extracted, and after review of quality, 25 recordings were available for phonetic analysis. These files were de-noised and a trained phonologist extracted a 1-minute sample of each patient's speech. WaveSurfer 1.8.5 was used to create, from each speech sample, a file of formant values (F0, F1, F2, where F0 is the fundamental frequency and F1 and F2 are resonance bands indicating the moment-by-moment shape of the oral cavity). Variability in these phonetic indices was correlated with severity of Positive and Negative Syndrome Scale negative symptom scores using Pearson correlations. RESULTS: A measure of variability of tongue front-to-back position-the standard deviation of F2-was statistically significantly correlated with the severity of negative symptoms (r=-0.446, p=0.03). CONCLUSION: This study demonstrates a statistically significant and meaningful correlation between negative symptom severity and phonetically measured reductions in tongue movements during speech in a sample of first-episode patients just initiating treatment. Further studies of negative symptoms, applying computational linguistics methods, are warranted. PMID- 23102941 TI - [Role of new oral anticoagulants in interventional cardiology]. AB - New oral anticoagulants constitute an important breakthrough for cardiologists and their patients. After reviewing their mechanism of action, their role in the context of interventional cardiology, particularly for patients with acute coronary syndromes, is discussed. PMID- 23102942 TI - 7T MUMRI of mesenteric venous ischemia in a rat model: timing of the appearance of findings. AB - OBJECTIVES: The aim of this study is to analyze the chronological development of macroscopic, microscopic and magnetic resonance imaging (MRI) findings in a rat model of Superior Mesenteric Venous (SMV) ligation, and to evaluate the role of MRI in the diagnosis of mesenteric venous thrombosis. METHODS: Thirty adult Sprague-Dawley rats were used and divided in two different groups that underwent a different surgical model and a different monitoring of ischemic damage. Group I underwent macroscopical and histological observation; Group II underwent 7T MUMRI evaluation and histological analysis. RESULTS: The first alterations occurred 30 min after SMV ligation and progressively worsened until the eighth hour. The morphological and MRI findings showed the same course. CONCLUSIONS: This study provides a systematic evaluation of early anatomopathological and MRI findings following the SMV ligation. MRI allows to identify the early pathological findings of venous mesenteric ischemia and allows to correlate those to the histopathological features. Our data suggest a relevant role of MRI in the diagnostic management of mesenteric venous thrombosis, allowing to non-invasively identify and characterize the histopathologic findings. So, thanks to these skills, its future application in early diagnosis of human mesenteric venous ischemia is supposable. PMID- 23102943 TI - Intravoxel incoherent motion imaging of the kidney: alterations in diffusion and perfusion in patients with renal dysfunction. AB - PURPOSE: To investigate the relationship between estimated glomerular filtration rate (eGFR) and parameters calculated using intravoxel incoherent motion (IVIM) imaging of the kidneys. MATERIALS AND METHODS: We studied 365 patients, divided into 4 groups based on eGFR levels (mL/min/1.73m(2)): group 1, eGFR>=80(n=80); group 2, eGFR 60-80 (n=156); group 3, eGFR 30-60 (n=114); and group 4 ,eGFR<30 (n=15). IVIM imaging was used to acquire diffusion-weighted images at 12 b values. The diffusion coefficient of pure molecular diffusion (D), the diffusion coefficient of microcirculation or perfusion (D*), and perfusion fraction (f) were compared among the groups using group 1 as control. RESULTS: In the renal cortex, D* values were significantly lower in groups 2, 3, and 4 than in group 1. The D value of renal cortex was significantly low in only group 3. In the renal medulla, the D* and D values were significantly lower only in groups 2 and 3, respectively. CONCLUSION: As renal dysfunction progresses, renal perfusion might be reduced earlier and affected more than molecular diffusion in the renal cortex. These changes are effectively detected by IVIM MR imaging. PMID- 23102944 TI - Usefulness of the navigator-echo triggering technique for free-breathing three dimensional magnetic resonance cholangiopancreatography. AB - PURPOSE: To prospectively compare the navigator-echo triggering technique (navigator technique) and the conventional respiratory triggering technique using bellows (bellows technique) for free-breathing three-dimensional (3D) magnetic resonance cholangiopancreatography (MRCP) under clinical conditions. MATERIALS AND METHODS: Forty patients referred for evaluation of biliary or pancreatic diseases underwent 3D MRCP examination using both navigator and bellows techniques. Two independent radiologists visually evaluated the image quality of 12 segments of the pancreaticobiliary tree in a blinded manner. In addition, the clarity of the lesion was compared between the two techniques in a side-by-side manner. RESULT: MRCP images were successfully acquired using both techniques in all patients. No significant difference in acquisition time was found between the two techniques. The image quality was significantly better using the navigator technique than using the bellows technique for the following seven segments: the head, body, and tail of the pancreatic duct; right hepatic duct; anterior and posterior segments of the right hepatic duct; and cystic duct. The other segments (common hepatic and bile duct, left hepatic duct, medial and lateral segments of left hepatic duct, gallbladder) showed no significant difference. The clarity of lesion depiction was significantly better using the navigator technique than using the bellows technique. CONCLUSION: Respiratory-triggered 3D MRCP using the navigator technique was shown to be feasible in routine clinical practice. The navigator technique improved the image quality of free-breathing 3D MRCP compared with the bellows technique. The clarity of lesion visualization was also better using the navigator technique than using the bellows technique. PMID- 23102945 TI - Measurement of T1 of human arterial and venous blood at 7T. AB - Techniques for measuring cerebral perfusion require accurate longitudinal relaxation (T1) of blood, an MRI parameter that is field dependent. T1 of arterial and venous human blood was measured at 7T using three different sources pathology laboratory, blood bank and in vivo. The T1 of venous blood was measured from sealed samples from a pathology lab and in vivo. Samples from a blood bank were oxygenated and mixed to obtain different physiological concentrations of hematocrit and oxygenation. T1 relaxation times were estimated using a three-point fit to a simple inversion recovery equation. At 37 degrees C, the T1 of blood at arterial pO2 was 2.29+/-0.1s and 2.07+/-0.12 at venous pO2. The in vivo T1 of venous blood, in three subjects, was slightly longer at 2.45+/ 0.11s. T1 of arterial and venous blood at 7T was measured and found to be significantly different. The T1 values were longer in vivo than in vitro. While the exact cause for the discrepancy is unknown, the additives in the blood samples, degradation during experiment, oxygenation differences, and the non stagnant nature of blood in vivo could be potential contributors to the lower values of T1 in the venous samples. PMID- 23102947 TI - Non-convex algorithm for sparse and low-rank recovery: application to dynamic MRI reconstruction. AB - In this work we exploit two assumed properties of dynamic MRI in order to reconstruct the images from under-sampled K-space samples. The first property assumes the signal is sparse in the x-f space and the second property assumes the signal is rank-deficient in the x-t space. These assumptions lead to an optimization problem that requires minimizing a combined lp-norm and Schatten-p norm. We propose a novel FOCUSS based approach to solve the optimization problem. Our proposed method is compared with state-of-the-art techniques in dynamic MRI reconstruction. Experimental evaluation carried out on three real datasets shows that for all these datasets, our method yields better reconstruction both in quantitative and qualitative evaluation. PMID- 23102946 TI - Empirical mathematical model for dynamic manganese-enhanced MRI of the murine pancreas for assessment of beta-cell function. AB - Autoimmune ablation of pancreatic beta-cells and alteration of its microvasculature may be a predictor of Type I diabetes development. A dynamic manganese-enhanced MRI (MEMRI) approach and an empirical mathematical model were developed to monitor whole pancreatic beta-cell function and vasculature modifications in mice. Normal and streptozotocin-induced diabetic FVB/N mice were imaged on a 9.4T MRI system using a 3D magnetization prepared rapid acquisition gradient echo pulse sequence to characterize low dose manganese kinetics in the pancreas head, body and tail. Average signal enhancement in the pancreas (head, body, and tail) as a function of time was fit by a novel empirical mathematical model characterizing contrast uptake/washout rates and yielding parameters describing peak signal, initial slope, and initial area under the curve. Signal enhancement from glucose-induced manganese uptake was fit by a linear function. The results demonstrated that the diabetic pancreatic tail had a significantly lower contrast uptake rate, smaller initial slope/initial area under the curve, and a smaller rate of Mn uptake following glucose activation (p<0.05) compared to the normal pancreatic tail. These observations parallel known patterns of beta cell loss and alteration in supportive vasculature associated with diabetes. Dynamic MEMRI is a promising technique for assessing beta-cell functionality and vascular perfusion with potential applications for monitoring diabetes progression and/or therapy. PMID- 23102948 TI - Spatio-temporal anomalous diffusion imaging: results in controlled phantoms and in excised human meningiomas. AB - Recently, we measured two anomalous diffusion (AD) parameters: the spatial and the temporal AD indices, called gamma and alpha, respectively, by using spectroscopic pulse gradient field methods. We showed that gamma quantifies pseudo-superdiffusion processes, while alpha quantifies subdiffusion processes. Here, we propose gamma and alpha maps obtained in a controlled heterogeneous phantom, comprised of packed micro-beads in water and in excised human meningiomas. In few words, alpha maps represent the multi-scale spatial distribution of the disorder degree in the system, while gamma maps are influenced by local internal gradients, thus highlighting the interface between compartments characterized by different magnetic susceptibility. gamma maps were already obtained by means of AD stretched exponential imaging and alpha-type maps have been recently achieved for fixed rat brain with the aim of highlighting the fractal dimension of specific brain regions. However, to our knowledge, the maps representative of the spatial distribution of alpha and gamma obtained on the same controlled sample and in the same excised tissue have never been compared. Moreover, we show here, for the first time, that alpha maps are representative of the spatial distribution of the disorder degree of the system. In a first phase, gamma and alpha maps of controlled phantom characterized by an ordered and a disordered rearrangement of packed micro-beads of different sizes in water and by different magnetic susceptibility (Deltachi) between beads and water were obtained. In a second phase, we investigated excised human meningiomas of different consistency. Results reported here, obtained at 9.4T, show that alpha and gamma maps are characterized by a different image contrast. Indeed, unlike gamma maps, alpha maps are insensible to (Deltachi) and they are sensible to the disorder degree of the microstructural rearrangement. These observations strongly suggest that AD indices alpha and gamma reflect some additional microstructural information which cannot be obtained using conventional diffusion methods based on Gaussian diffusion. Moreover, alpha and gamma maps obtained in excised meningiomas seem to provide more microstructural details above those obtained with conventional DTI analysis, which could be used to improve the classification of meningiomas based on their consistency. PMID- 23102949 TI - A systematic approach to magnetic resonance imaging evaluation of epiphyseal lesions. AB - Magnetic Resonance Imaging (MRI) is the preferred modality of choice to image epiphyseal lesions. It provides excellent soft tissue resolution and extent of disease. A wide spectrum of tumor and tumor like lesions can involve the epiphysis. Early and accurate diagnosis as well as appropriate management of epiphyseal lesions is critical as these conditions may lead to disabling complications such as, limb length discrepancy, angular or joint surface deformities and secondary osteoarthritis. In this article, we discuss the role of conventional sequences, such as T1W, fluid sensitive T2W and intravenous (IV) Gadolinium enhanced sequences as well as the additional value of problem solving MRI sequences such as, chemical shift and diffusion weighted imaging. Based on the imaging findings on various MRI sequences and lesion characteristics, a systematic approach directed to the diagnoses of epiphyseal lesions is presented and discussed. MRI features of clinically and biopsy proven examples of the epiphyseal lesions, such as osteomyelitis, intra-osseous abscess, infiltrative malignancy, metastases, transient osteoporosis, subchondral insufficiency fracture, avascular necrosis, osteochondral fracture, osteochondritis dissecans, eosinophilic granuloma and geode are demonstrated. Using this systematic approach, the reader will be able to better characterize epiphyseal lesions with a potential to positively affect patient management. PMID- 23102950 TI - Hepatic sarcoidosis: MR appearances in patients with chronic liver disease. AB - PURPOSE: To describe the MR appearances of hepatic sarcoidosis in patients with chronic liver disease and correlate the results with clinical stage of disease as measured with the Mayo end-stage liver disease (MELD) score. MATERIALS AND METHODS: Twenty patients with chronic liver disease and histopathological diagnosis of hepatic sarcoidosis who underwent MR imaging were included in this study. Two abdominal radiologists retrospectively reviewed all images for the presence of cirrhosis, imaging pattern of the liver, intrahepatic biliary dilatation, presence of areas of parenchymal atrophy, presence of splenic nodules and lymphadenopathy. Imaging findings were correlated with the MELD score. RESULTS: Of the patients, 14/20 had imaging findings of cirrhosis, 9/20 had a large macronodular pattern of liver cirrhosis and 5/20 had a diffuse pattern of liver cirrhosis. Peripheral wedge-shaped areas of parenchymal atrophy were observed in 10 patients. The combination of a central macronodular pattern and peripheral atrophy was observed in 9/20 patients. The pattern of cirrhosis had statistically significant correlation with the presence of wedge-shaped areas of parenchymal atrophy (p<0.005). No statistically significant difference was revealed between the clinical score of patients who had imaging findings consistent with cirrhosis and those who did not. CONCLUSION: MR imaging appearances of chronic sarcoid liver disease are diverse and do not appear to correlate with severity of clinical disease. Large central regenerative nodules and wedge-shaped areas of peripheral parenchymal atrophy are frequent findings and may help to suggest the diagnosis. PMID- 23102951 TI - Measuring small compartments with relatively weak gradients by angular double pulsed-field-gradient NMR. AB - NMR diffusion-diffraction patterns observed in compartments in which restricted diffusion occurs are a useful tool for direct extraction of compartment sizes. Such diffusion-diffraction patterns may be observed when the signal intensity E(q,?) is plotted against the wave-vector q (when q=(2pi)(-1)gammadeltaG). However, the smaller the compartment sizes are, the higher are the q-values needed to observe such diffractions. Moreover, these q-values should be achieved using short gradient pulses requiring extremely strong gradient systems. The angular double-pulsed-field gradient (d-PFG) NMR methodology has been proposed as a tool to extract compartment sizes using relatively low q-values. In this study, we have used single-PFG (s-PFG) NMR and angular d-PFG NMR to characterize the size of microcapillaries of about 2+/-1MUm in diameter. We found that these microcapillaries are characterized by relatively strong background gradients that completely masked the effects of the microscopic anisotropy (MUA) of the sample, resulting in a completely unexpected E(phi) profile in the angular d-PFG NMR experiments. We also show that bipolar angular d-PFG NMR experiments can largely suppress the effect of these background gradients resulting in the expected E(phi) profile from which the compartment dimensions could be obtained with relatively weak gradient pulses. These results demonstrate that the above methodology provides a quick, reliable, non-invasive means for estimating small pore sizes with relatively weak gradients in the presence of large magnetic susceptibility. PMID- 23102952 TI - Timing of supplementation alters grazing behavior and milk production response in dairy cows. AB - Offering feed supplements to grazing dairy cows results in substitution of pasture; however, previous data indicate that the time at which concentrate supplements are offered might affect the level of substitution. These data indicated that cows grazed more intensely presunset, regardless of the amount of supplement offered. It was, therefore, hypothesized that substitution rate would be less, and response to supplement greater if cows received their supplement at the p.m. rather than the a.m. milking. Forty-eight multiparous, nonpregnant, Holstein-Friesian cows, approximately 60 d in milk, were randomly allocated to 1 of 3 treatments in an incomplete crossover arrangement. Treatments were pasture only, pasture + 3 kg of concentrate supplement dry matter (DM) offered during the a.m. milking (AM-SUP), and pasture + 3 kg of concentrate supplement DM offered during the p.m. milking (PM-SUP). Time spent grazing and calculated pasture DM intake did not differ between the AM-SUP and PM-SUP cows. However, a tendency (0.18 kg of milk/kg of concentrate DM) was observed for an increased marginal milk response (kg of milk/kg of DM supplement) for the AM-SUP cows when compared with PM-SUP cows. Irrespective of when supplements were offered, supplementation reduced total grazing time by a similar amount, and the reduction in time spent grazing was evident throughout the day. Cows in the PM-SUP group ruminated for longer and cows in the AM-SUP group spent more time idle compared with the pasture only groups. Cows in the AM-SUP group grazed for less time during the major a.m. grazing bout following a.m. milking compared with PM-SUP cows; in comparison, the major p.m. grazing bout following p.m. milking was unaffected by supplementation. The results indicated possible improvements in marginal milk response to supplements from altering the timing of delivery. PMID- 23102953 TI - The gradient boosting algorithm and random boosting for genome-assisted evaluation in large data sets. AB - In the next few years, with the advent of high-density single nucleotide polymorphism (SNP) arrays and genome sequencing, genomic evaluation methods will need to deal with a large number of genetic variants and an increasing sample size. The boosting algorithm is a machine-learning technique that may alleviate the drawbacks of dealing with such large data sets. This algorithm combines different predictors in a sequential manner with some shrinkage on them; each predictor is applied consecutively to the residuals from the committee formed by the previous ones to form a final prediction based on a subset of covariates. Here, a detailed description is provided and examples using a toy data set are included. A modification of the algorithm called "random boosting" was proposed to increase predictive ability and decrease computation time of genome-assisted evaluation in large data sets. Random boosting uses a random selection of markers to add a subsequent weak learner to the predictive model. These modifications were applied to a real data set composed of 1,797 bulls genotyped for 39,714 SNP. Deregressed proofs of 4 yield traits and 1 type trait from January 2009 routine evaluations were used as dependent variables. A 2-fold cross-validation scenario was implemented. Sires born before 2005 were used as a training sample (1,576 and 1,562 for production and type traits, respectively), whereas younger sires were used as a testing sample to evaluate predictive ability of the algorithm on yet to-be-observed phenotypes. Comparison with the original algorithm was provided. The predictive ability of the algorithm was measured as Pearson correlations between observed and predicted responses. Further, estimated bias was computed as the average difference between observed and predicted phenotypes. The results showed that the modification of the original boosting algorithm could be run in 1% of the time used with the original algorithm and with negligible differences in accuracy and bias. This modification may be used to speed the calculus of genome-assisted evaluation in large data sets such us those obtained from consortiums. PMID- 23102954 TI - The use of equine chorionic gonadotropin in the treatment of anestrous dairy cows in gonadotropin-releasing hormone/progesterone protocols of 6 or 7 days. AB - In seasonally calving, pasture-based dairy farm systems, the interval from calving to first estrus is a critical factor affecting reproductive efficiency. This study evaluated the effects of equine chorionic gonadotropin (eCG) on the reproductive response of lactating, seasonally calving dairy cows diagnosed with anovulatory anestrus by rectal palpation. Cows on 15 commercial dairy farms were selected for initial inclusion based on nonobserved estrus by 7 d before the planned start of mating. All cows were palpated rectally and evaluated for body condition score and ovary score, and were included for treatment according to the trial protocol if diagnosed with anovulatory anestrus. All cows received a standard anestrous treatment protocol consisting of insertion of a progesterone device, injection of 100 ug of GnRH at the time of device insertion, and injection of PGF(2alpha) at device removal (GPG/P4). Cows were randomly assigned to 1 of 2 groups (6 d or 7 d) for duration of progesterone device insertion. Within each of these groups, cows were further randomly assigned to receive either 400 IU of eCG at device removal or to remain untreated as controls, resulting in a 2*2 arrangement of treatment groups: (1) 6-d device and no eCG (n=484); (2) 6-d device and eCG (n=462); (3) 7-d device and no eCG (n=546); and (4) 7-d device and eCG (n=499). Cows were detected for estrus from the time of progesterone device removal and were inseminated; those not detected in estrus within 60 h after progesterone device removal received 100 ug of GnRH and were inseminated at 72 h. The primary outcomes considered were proportion of cows conceiving within 7 d of the beginning of breeding (7-d conception rate; 7-d CR), proportion pregnant within 28 d (28-d in calf rate; 28-d ICR), and days to conception (DTC). We found no significant differences between the 6- and 7-d insertion periods and found no 6- or 7-d insertion period * eCG treatment interactions. Inclusion of eCG into either length of GPG/P4 protocol increased 7 d CR (36.0 vs. 30.6%) and 28-d ICR (58.6 vs. 52.3%) and decreased median days to conception. The use of eCG in GPG/P4 breeding protocols will improve reproductive efficiency in seasonally calving, anestrous dairy cattle. PMID- 23102955 TI - Comparison of methods for the implementation of genome-assisted evaluation of Spanish dairy cattle. AB - The aim of this study was to evaluate methods for genomic evaluation of the Spanish Holstein population as an initial step toward the implementation of routine genomic evaluations. This study provides a description of the population structure of progeny tested bulls in Spain at the genomic level and compares different genomic evaluation methods with regard to accuracy and bias. Two bayesian linear regression models, Bayes-A and Bayesian-LASSO (B-LASSO), as well as a machine learning algorithm, Random-Boosting (R-Boost), and BLUP using a realized genomic relationship matrix (G-BLUP), were compared. Five traits that are currently under selection in the Spanish Holstein population were used: milk yield, fat yield, protein yield, fat percentage, and udder depth. In total, genotypes from 1859 progeny tested bulls were used. The training sets were composed of bulls born before 2005; including 1601 bulls for production and 1574 bulls for type, whereas the testing sets contained 258 and 235 bulls born in 2005 or later for production and type, respectively. Deregressed proofs (DRP) from January 2009 Interbull (Uppsala, Sweden) evaluation were used as the dependent variables for bulls in the training sets, whereas DRP from the December 2011 DRPs Interbull evaluation were used to compare genomic predictions with progeny test results for bulls in the testing set. Genomic predictions were more accurate than traditional pedigree indices for predicting future progeny test results of young bulls. The gain in accuracy, due to inclusion of genomic data varied by trait and ranged from 0.04 to 0.42 Pearson correlation units. Results averaged across traits showed that B-LASSO had the highest accuracy with an advantage of 0.01, 0.03 and 0.03 points in Pearson correlation compared with R-Boost, Bayes-A, and G BLUP, respectively. The B-LASSO predictions also showed the least bias (0.02, 0.03 and 0.10 SD units less than Bayes-A, R-Boost and G-BLUP, respectively) as measured by mean difference between genomic predictions and progeny test results. The R-Boosting algorithm provided genomic predictions with regression coefficients closer to unity, which is an alternative measure of bias, for 4 out of 5 traits and also resulted in mean squared errors estimates that were 2%, 10%, and 12% smaller than B-LASSO, Bayes-A, and G-BLUP, respectively. The observed prediction accuracy obtained with these methods was within the range of values expected for a population of similar size, suggesting that the prediction method and reference population described herein are appropriate for implementation of routine genome-assisted evaluations in Spanish dairy cattle. R-Boost is a competitive marker regression methodology in terms of predictive ability that can accommodate large data sets. PMID- 23102956 TI - Development of probiotic dairy beverages: rheological properties and application of mathematical models in sensory evaluation. AB - Strawberry-flavored probiotic dairy beverages (2% vol/vol Lactobacillus acidophilus) were produced using 0, 20, 35, 50, 65, and 80% (vol/vol) whey in their formulations. Mathematical models (survival analysis, minimal significant difference, and mean global acceptance) were used to identify the optimal (sensorially) whey concentration in probiotic beverages. Fifty-five consumers evaluated acceptance of the beverages using hybrid 9-point hedonic scales. In addition, Lb. acidophilus were enumerated and pH was determined. Rheological behavior is an important characteristic for the processing and sensory acceptance of dairy beverages, varying with the presence of additives, fermentation process (time, bacterial strain), and whey concentrations used. All beverages presented minimal counts of 8 log cfu/mL of Lb. acidophilus, and pH ranged from 4.09 to 4.14. Increasing the whey content increased the fragility of the gel structure, probably because of the replacement of casein by whey proteins, once the concentrations of other ingredients in formulation were fixed. Whey content had a significant effect on acceptance of the probiotic dairy beverages; beverages with whey contents greater than 65% resulted in lower acceptance by consumers. The model of mean global acceptance presented 2 solutions with high sensory scores: beverages with 12 and 65% whey, the latter being of interest because it allows greater use of the whey by-product. The Weibull distribution presented a prediction of whey concentration of 49%, with higher sensory acceptance. The methodologies used in this research were shown to be useful in determining the constituents of food formulations, especially for whey-based probiotic beverages. PMID- 23102957 TI - Regulation of lipid synthesis by liver X receptor alpha and sterol regulatory element-binding protein 1 in mammary epithelial cells. AB - The objectives of this experiment were to characterize the roles of the transcription factors liver X receptor alpha (LXRalpha) and sterol regulatory element-binding protein 1 (SREBP1) in the transcriptional regulation of lipid synthesis in a bovine mammary epithelial cell line. Whereas many lipid synthesis genes contain a response element in their promoters for SREBP1, a few also contain a response element for LXR, suggesting that both transcription factors could directly regulate transcription of these genes. However, the promoter of SREBP1 contains a response element for LXR, indicating the additional potential for indirect transcriptional regulation by LXR, through SREBP1, on lipogenic genes. To characterize these effects, small interfering RNA (siRNA) directed against LXRalpha and SREBP1 were used to knockdown gene expression, and then, in the presence of SREBP1 siRNA, T 4506585 (T09) was used to specifically activate LXRalpha. Reducing LXRalpha mRNA abundance in mammary alveolar T cells did not alter mRNA abundance of genes involved in de novo lipogenesis or the rate of de novo lipogenesis, suggesting that LXRalpha is not required for basal transcription of genes required for fatty acid synthesis. Knockdown of SREBP1 reduced the mRNA abundance of acetyl-coenzyme A (CoA) carboxylase, fatty acid synthase, diacylglycerol acyltransferase, and stearoyl-CoA desaturase-1, indicating that these genes are regulated in part by SREBP1. When SREBP1 was reduced, T09 increased the mRNA abundance of acetyl-CoA carboxylase, fatty acid synthase, and diacylglycerol acyltransferase, potentially indicating that these genes are directly regulated by LXR. The results of the present study provide insight into the transcriptional regulatory mechanisms involved in lipid synthesis by mammary epithelial cells, and suggest that several transcription factors may be required for full lipogenic activation. PMID- 23102958 TI - In vitro gastric digestion of heat-induced aggregates of beta-lactoglobulin. AB - In vitro gastric digestion of heat-induced aggregates of beta-lactoglobulin (beta LG) in simulated gastric fluid was investigated using sodium dodecyl sulfate-PAGE (under nonreducing and reducing conditions), native PAGE, 2-dimensional electrophoresis, and size exclusion chromatography. Heating at 90 degrees C significantly increased the digestibility of beta-LG, with a high initial digestion rate followed by a relatively constant rate of digestion at a high enzyme:substrate (E:S) ratio of 3:1. At a low E:S ratio (1:6), the rate of digestion of beta-LG was slower, and intermediate- and low-molecular-weight species could be seen. The high-molecular-weight nonnative aggregates (e.g., pentamers, tetramers, and trimers) were digested relatively rapidly, whereas some of the nonnative dimers were resistant to digestion and others were digested rapidly. The intermediate-molecular-weight species (21 to 23 kDa) were digested slowly. The digestibility of nonnative beta-LG aggregates varied significantly depending on the E:S ratio and the types of aggregate. Further investigation is necessary to identify and characterize slowly digested dimers and species of intermediate molecular weight. PMID- 23102959 TI - Relationships between bovine hoof disorders, body condition traits, and test-day yields. AB - A designed field study was conducted on 1,962 first-lactation Holstein cows kept on 7 large-scale dairy farms in Germany, in loose-housing systems on standard slatted flooring. Records of hoof disorders at trimming composed of subclinical as well as clinical cases were combined with body measurements and body condition scores, test-day records, and further individual cow data. The 6 most frequent disorders were laminitis, also known as sole hemorrhage (57.3% of all cows), dermatitis digitalis (17.0%), dermatitis interdigitalis (7.9%), white line disease (12.6%), sole ulcer (7.1%), and interdigital hyperplasia (5.5%). The most important environmental effects were herd-visit date and stage of lactation. Heifers between 50 and 99 d in milk had the highest frequencies for laminitis. Lighter cows were less susceptible to laminitis and white line disease, but had a higher prevalence of interdigital hyperplasia. Relationships between stature and white line disease as well as relationships between body condition score and dermatitis digitalis were nonlinear, resulting in an improved disorder status of cows with an intermediate condition score and average stature. Increased biomechanical stress caused by different factors (weight, social rank, standing time) is a presumed effect that leads to an increased susceptibility for hoof diseases. From a management perspective, under- and overconditioning should be avoided. Milk production traits differed between cows with and without laminitis related claw horn lesions. Fat percentage and fat-to-protein ratio in the first month before trimming were significantly decreased for cows with a positive laminitis status. Hence, this finding points to metabolic disorders being associated with a higher risk for hoof diseases. Estimates of heritabilities for laminitis, dermatitis digitalis, dermatitis interdigitalis, white line disease, and sole ulcer were 0.09, 0.14, 0.10, 0.11, and 0.06 when applying a threshold model with a probit link function. PMID- 23102960 TI - A survey of management practices that influence production and welfare of dairy cattle on family farms in southern Brazil. AB - A survey on dairy production in family dairy farms in the northwest of Santa Catarina, Brazil, was carried out to assess husbandry practices and elements of the living environment that may influence animal welfare and productivity. Three farm systems common in the region were compared: extensive, pasture-based, and semi-intensive. Data were collected through face-to-face interviews with farmers, followed by an inspection of the production environment and of dairy cows on 124 dairy farms. Some welfare and production problems were common to the 3 systems, mainly subclinical mastitis and tick infestations, which affected one-third of cows, deficiencies in the provision of drinking water and shade, and poor hygiene practices during milking. Some problems were specific to farming systems, such as lameness and hock injuries on the semi-intensive farms, and inadequate milking infrastructure and greater frequencies of cows with low body condition scores on extensive and pasture-based farms. A greater proportion of farms in the semi intensive group had modern, herringbone-type milking parlors, applied the California Mastitis Test, and followed teat disinfection practices, and more pasture-based farms provided shade in the paddocks. The widespread use of pasture and adapted genotypes and individual identification of animals were positive aspects present in all systems. The absence of health and production records in more than half of the farms may prevent farmers from recognizing certain problems. Results of this survey may guide public policies aiming to improve milk productivity and quality with sustainable and low-cost production practices. PMID- 23102961 TI - Dry period and parturient predictors of early lactation hyperketonemia in dairy cattle. AB - The purpose was to determine important dry and calving period predictors of (1) a cow developing hyperketonemia at any time between 3 and 16 d in milk (DIM) and (2) a cow having hyperketonemia at her first beta-hydroxybutyrate (BHBA) test after calving (between 3 and 5 DIM). Cows from 4 freestall dairy herds [2 in New York (NY) and 2 in Wisconsin] were enrolled at 266 d carried calf. Precalving data included body condition score, locomotion score, and blood nonesterified fatty acids (NEFA) concentration; calving-associated data included previous days carried calf, calving ease, calf sex, twins, stillbirth, and parity. Cows were each tested 6 times for hyperketonemia from 3 to 16 DIM on Mondays, Wednesdays, and Fridays using the Precision Xtra meter (Abbott Laboratories, Abbott Park, IL). Hyperketonemia was defined as a blood BHBA concentration of >=1.2 mmol/L. Multivariable fixed-effects Poisson regression models were developed to predict the probability of a cow developing hyperketonemia between either 3 and 16 DIM or at her first BHBA test. As only the NY herds had precalving NEFA data, each prediction model was developed twice: once with data from all 4 herds (n=1,672) and once with data from only the NY herds (n=544). For the models with data from all 4 herds, increased body condition score group and an interaction between advanced parity and herd were important predictors of hyperketonemia development at any time from 3 to 16 DIM; calf sex (male), herd, and an advanced parity by increased body condition score group interaction were important predictors of hyperketonemia development between 3 and 5 DIM. The 4-herd models had a 64 and 78% predictive concordance for hyperketonemia between 3 and 16 DIM and at first BHBA test, respectively. For the models with data from the NY herds only, increased NEFA, calf sex (male), advanced parity, and herd were found to be important predictors of hyperketonemia development at any time from 3 to 16 DIM; increased NEFA, calf sex (male), decreased calving ease, stillbirth, and advanced parity were important predictors of having hyperketonemia at first BHBA test. The NY models had a 69 and 87% predictive concordance, respectively. These results may help identify at-risk animals and improve dry-cow management strategies before hyperketonemia develops. PMID- 23102962 TI - DNA-based identification of novel bovine casein gene variants. AB - In cattle, at least 39 variants of the 4 casein proteins (alpha(S1)-, beta-, alpha(S2)- and kappa-casein) have been described to date. Many of these variants are known to affect milk-production traits, cheese-processing properties, and the nutritive value of milk. They also provide valuable information for phylogenetic studies. So far, the majority of studies exploring the genetic variability of bovine caseins considered European taurine cattle breeds and were carried out at the protein level by electrophoretic techniques. This only allows the identification of variants that, due to amino acid exchanges, differ in their electric charge, molecular weight, or isoelectric point. In this study, the open reading frames of the casein genes CSN1S1, CSN2, CSN1S2, and CSN3 of 356 animals belonging to 14 taurine and 3 indicine cattle breeds were sequenced. With this approach, we identified 23 alleles, including 5 new DNA sequence variants, with a predicted effect on the protein sequence. The new variants were only found in indicine breeds and in one local Iranian breed, which has been phenotypically classified as a taurine breed. A multidimensional scaling approach based on available SNP chip data, however, revealed an admixture of taurine and indicine populations in this breed as well as in the local Iranian breed Golpayegani. Specific indicine casein alleles were also identified in a few European taurine breeds, indicating the introgression of indicine breeds into these populations. This study shows the existence of substantial undiscovered genetic variability of bovine casein loci, especially in indicine cattle breeds. The identification of new variants is a valuable tool for phylogenetic studies and investigations into the evolution of the milk protein genes. PMID- 23102963 TI - Sampling behavior of dairy cattle: effects of variation in dietary energy density on behavior at the feed bunk. AB - Factors affecting sampling behavior of cattle are poorly understood. The objectives of this study were to measure the effects of variation in feed quality on the feeding behavior of Holstein dairy heifers. Thirty-two heifers were housed in 4 groups of 8. Each group pen had 8 distinct feeding stations. The total mixed ration (TMR) provided was low energy (TMR-L), moderate energy (TMR-M), or high energy (TMR-H). During trial 1 (d 1 to 8), heifers were offered a uniform baseline diet (TMR-M in all 8 feeding stations) interspaced with 2 uniform test diets on d 3 and 6 (TMR-L or TMR-H in all 8 feeding stations). During trial 2 (d 9 to 17) heifers were offered a nonuniform baseline diet (7 feeding stations with TMR-L and 1 feeding station with TMR-H) interspaced with 3 uniform test diets on d 11, 14, and 17 (TMR-L, TMR-M, or TMR-H in all 8 feeding stations). Heifers were observed in pairs (n=16) for 15 min following delivery of fresh feed. Relative to the uniform baseline period of trial 1, 31% fewer switches occurred between feeding stations when offered TMR-H and 51% more switches when offered TMR-L. Relative to the nonuniform baseline of trial 2, 49% fewer, 27% fewer, and 25% more switches occurred during the TMR-H, TMR-M, and TMR-L treatments, respectively. In general, when heifers were offered a diet that was lower in energy density than that previously experienced, they spent less time at each feeding station and when offered a higher energy diet, heifers spent more time at each feeding station. The greater the contrast in energy density between the test and baseline diets, the greater the change in the behavioral response. Competitive interactions at the feed bunk were most frequent when TMR quality varied among the 8 feeding stations; during the nonuniform baseline period of trial 2, the number of competitive interactions was over 3.5 times higher than during all uniform dietary treatments. In summary, dairy heifers sample feed quality by changing feeding locations at the feed bunk and this sampling behavior is affected by variation in diet quality along the feed bunk and across days. PMID- 23102964 TI - In-Office Jones tube exchange using the Seldinger technique. AB - Conjunctivodacryocystorhinostomy (CDCR) with Jones tube placement is usually performed as a primary procedure for severe stenosis or obstruction of both upper and lower canaliculi of the lacrimal drainage pathway, or occasionally, after unsuccessful dacryocystorhinostomy (DCR). Jones tube obstruction is quite common, and often requires removal of the obstructed tube and replacement or exchange of the tube in the operating room. This procedure is typically performed under general anesthesia, and is associated with the risks of general anesthesia, a significant investment of time, and the cost of the operating suite. Recently, there has been a movement toward in-office procedures in otolaryngology and ophthalmology due to greater patient satisfaction and savings in time and money for patients and physicians. In this report, we describe a novel in-office method to exchange an obstructed Jones tube that provides the aforementioned benefits while preserving patient comfort. No similar case has been previously reported in the literature. PMID- 23102965 TI - Bilateral parotitis as the initial presentation of childhood sarcoidosis. AB - The differential diagnosis of bilateral parotid gland enlargement in children includes infectious, inflammatory, and neoplastic disorders. We present the case of a 13-year-old male who presented with a 5-week history of bilateral parotid swelling. On exam, both parotid glands were nontender, smooth, and diffusely enlarged. He had slightly elevated inflammatory markers, but other lab results were normal. A neck CT revealed symmetric enlargement of the parotid, submandibular, and sublingual glands. A chest CT revealed scattered peripheral pulmonary nodules and bilateral hilar adenopathy. A parotid gland biopsy showed multiple noncaseating granulomas with multinucleated giant cells surrounded by lymphocytes, consistent with the diagnosis of sarcoidosis. Special stains for acid-fast and fungal organisms were negative. Using this illustrative case, we discuss the differential diagnosis of bilateral salivary gland enlargement in children and review the etiology, diagnosis, clinical manifestations, and treatment of pediatric sarcoidosis. PMID- 23102966 TI - Thyroid carcinoma uptake of 18F-fluorodeoxyglucose in patients with elevated serum thyroglobulin and negative 131I scintigraphy. AB - PURPOSE: To determine if FDG-PET results can predict for outcome in thyroid cancer patients with elevated Tg and negative I-131 imaging. MATERIALS AND METHODS: We conducted a retrospective review of 76 patients who had elevated serum Tg and negative (131)I scintigraphy and who underwent FDG-PET. After FDG PET, patients underwent neck dissection or radiation. RESULTS: The 51 patients with positive FDG-PET had a 5-year survival of 63% compared to 100% (p<0.049) for the 25 patients with negative PET. Patients with FDG-avid disease isolated to the lymph nodes had 5-year CSS of 91% compared to 32% (p=0.0033) for those with disease outside the regional lymph nodes. Twenty-nine patients with disease isolated to the regional lymph nodes underwent salvage neck dissection and 22 remain NED after 28 months. CONCLUSIONS: Negative FDG-PET with elevated Tg predicts an excellent outcome. FDG-avid disease isolated to the regional lymph nodes had a low likelihood of death due to thyroid cancer. PMID- 23102967 TI - High-resolution computed tomography analysis of the frontal sinus ostium: a pilot study. AB - PURPOSE: Identification and exposure of the frontal sinus recess (FSR) during endoscopic sinus surgery (ESS) are challenging due to the variable anatomy, the narrow opening of the frontal sinus ostium (FSO), and the proximity of vital anatomic structures. Hence, a strong understanding of frontal sinus anatomy is required to prevent intracranial entry. Consistent and easily identifiable landmarks and measurements could assist safe entry into the FSO. In this study, we determine the distances from the columella and anterior nasal spine (ANS) to the nasofrontal beak (NFB) and anterior skull base (ASB) using high-resolution computed tomography (HRCT) scans. METHODS: A radiographic analysis was performed at a tertiary care medical center. Measurements from the ANS to the NFB and ASB, and from the columella to the NFB and ASB were made using sagittal HRCT. Thirty two HRCT scans were analyzed by three observers, and the mean distances and standard deviations were calculated. RESULTS: The mean distance from the ANS to the NFB was 52.3+/-3.4mm in men and 47.7+/-3.5mm in women (p<0.0001). Mean distance from the ANS to the ASB was 61.8+/-4.1mm in men and 56.5+/-4.1mm in women (p<0.0001). Mean distance from the columella to the NFB was 58.9+/-2.3mm in men and 53.0+/-3.3mm in women (p<0.0001), and from the columella to the ASB was 67.9+/-3.7 mm in men and 61.3+/-4.1mm in women (p<0.0001). CONCLUSION: While performing FSR exposure in ESS, it is recommended to stay a distance of less than 66.9 mm in men and 60.6mm in women from the columella to minimize intracranial complications. PMID- 23102968 TI - Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. AB - The genomic diversity of 99 T4-like coliphages was investigated by sequencing an equimolar mixture with Illumina technology and screening them against different databases for horizontal gene transfer and undesired genes. A 9-phage cocktail was given to 15 healthy adults from Bangladesh at a dose of 3*10(9) and 3*10(7) plaque-forming units and placebo respectively. Phages were detected in 64% of the stool samples when subjects were treated with higher titer phage, compared to 30% and 28% with lower-titer phage and placebo, respectively. No Escherichia coli was present in initial stool samples, and no amplification of phage was observed. One percent of the administered oral phage was recovered from the feces. No adverse events were observed by self-report, clinical examination, or from laboratory tests for liver, kidney, and hematology function. No impact of oral phage was seen on the fecal microbiota composition with respect to bacterial 16S rRNA from stool. PMID- 23102970 TI - Neurogenetics of birdsong. AB - Songbirds are a productive model organism to study the neural basis of auditory guided vocal motor learning. Like human babies, juvenile songbirds learn many of their vocalizations by imitating an adult conspecific. This process is a product of genetic predispositions and the individual's life experience and has been investigated mainly by neuroanatomical, physiological and behavioral methods. Results have revealed general principles governing vertebrate motor behavior, sensitive periods, sexual dimorphism, social behavior regulation and adult neurogenesis. More recently, the emerging field of birdsong neurogenetics has advanced the way we think about genetic contributions to communication, mechanistically and conceptually. PMID- 23102969 TI - P-body components LSM1, GW182, DDX3, DDX6 and XRN1 are recruited to WNV replication sites and positively regulate viral replication. AB - In mammalian cells, proteins involved in mRNA silencing and degradation localize to discrete cytoplasmic foci called processing or P-bodies. Here we show that microscopically visible P-bodies are greatly diminished following West Nile viral infection, but the component proteins are not depleted. On the other hand, many P body components including LSM1, GW182, DDX3, DDX6 and XRN1, but not others like DCP1a and EDC4 are recruited to the viral replication sites, as evidenced by their colocalization at perinuclear region with viral NS3. Kinetic studies suggest that the component proteins are first released from P-bodies in response to WNV infection within 12 h post-infection, followed by recruitment to the viral replication sites by 24-36 h post-infection. Silencing of the recruited proteins individually with siRNA interfered with viral replication to varying extents suggesting that the recruited proteins are required for efficient viral replication. Thus, the P-body proteins might provide novel drug targets for inhibiting viral infection. PMID- 23102971 TI - Timing and quantifying Aphanomyces astaci sporulation from the noble crayfish suffering from the crayfish plague. AB - Aphanomyces astaci sporulation is crucial for the spreading potential of this disease agent. For the first time, we are reporting timing and quantity of A. astaci spores released from noble crayfish (Astacus astacus) suffering from crayfish plague under practical aquatic conditions. We infected nine noble crayfish with A. astaci PsI-genotype and maintained them in individual 8L tanks. Spores (zoospores and cysts) were quantified from water samples (3 * 1 mL) taken every 12h over 10 d using A. astaci specific qPCR. A clear sporulation trend was found, together with a high individual spore estimate variation. The median spore counts from two days before death to 12h post mortem were from ~500 to ~2000 spores L(-1). A significant sporulation increase occurred after 24h post mortem (~12,000 spores L(-1)) and reached a peak after two days (~65,000 spores L(-1)) before declining to or below pre mortem levels from the fourth day. The single most sporulating crayfish released from ~75,000 to ~400,000 spores L(-1) during the mass sporulating period, yielding a maximum estimate of ~3,200,000 spores released from a single crayfish if we assume homogeneous spore distribution. The results confirm a mass A. astaci spore release from moribund and recently dead infected noble crayfish, with a sporulation peak one to three days post mortem. The acute crayfish mortality only three days after zoospore exposure confirm the lethal potential of the PsI-genotype. The powerful sporulation potential observed here may be one of the key virulence factors of this genotype. PMID- 23102972 TI - French experience in the management of hemorrhoids by HALTM Doppler. AB - OBJECTIVE: The goal of this study was to prospectively evaluate the surgical management of hemorrhoids by Doppler-guided hemorrhoidal artery ligation (Doppler HALTM). PATIENTS AND METHODS: This study was conducted between April 2008 and September 2009. The Doppler HALTM technique was performed in patients with grades II to IV, irrespective of whether they had previously undergone medical or instrumental management or not. The other demographics of the studied population, the operative and post-operative results as well as the functional outcome at one month and at one year were recorded prospectively and analyzed retrospectively. RESULTS: Sixty-one consecutive patients (mean age 45 [range 28-85]) underwent Doppler HALTM. The mean duration of operation was 26minutes [range 18-45]. The average number of ligations per patient was seven. Three patients left the hospital the same day, 51 patients were discharged on day 1 and five patients on day 2. Post-operative mortality was nil. The post-operative morbidity rate was 4.9%. Functional results evaluated at one month and one year showed that initial symptoms had disappeared in more than 78% of patients. The recurrence rate for hemorrhoidal related disease was 10.5% during the first year. CONCLUSION: Surgical treatment of hemorrhoids by the Doppler-guided hemorrhoidal artery ligation technique is mini-invasive, with low morbidity, and satisfactory short and medium term functional results. This technique represents a reliable surgical alternative to classical hemorrhoidectomy and hemorrhoidopexy in the therapeutic strategy of hemorrhoidal disease. PMID- 23102973 TI - Individual-, family- and community-level determinants of full vaccination coverage among children aged 12-23 months in western Kenya. AB - To identify individual-, family-, and community-level determinants of full vaccination status at most challenging areas in Kenya, we conducted a cross sectional study among children aged 12-23 months and their mothers. 1965 children were involved in this research and their mothers completed a questionnaire. Middle or high knowledge of vaccination schedule (Adjusted Odds Ratio (AOR)=2.69, 95%CI: 2.01-3.60 or AOR=8.12, 95%CI:5.50-11.97), medium/long birth interval or first birth (AOR=2.46, 95%CI: 1.29-4.69 or AOR=1.84, 95%CI:1.10-3.09 or AOR=2.14, 95%CI: 1.20-3.84), less than 5 children under five years old (AOR=1.39, 95%CI: 1.04-1.88) and highest community health worker's (CHWs) performance (AOR=2.20, 95%CI: 1.39-3.47) were significantly associated with complete vaccination status in the final multiple regression model. In addition, a interaction between literacy and wealth was significantly related in full vaccination status (AOR=1.38, 95%CI: 1.08-1.75). Increased frequency and quality of CHW visits could be effective intervention to enhance vaccination coverage. Future interventions focusing on vaccination coverage should be given more attention especially to high risk group identified in this study. PMID- 23102974 TI - Alum-adjuvanted H5N1 whole virion inactivated vaccine (WIV) induced IgG1 and IgG4 antibody responses in young children. AB - IgG subclass antibody responses are not fully understood. Alum-adjuvanted H5N1whole virion inactivated vaccine (WIV), a genetically reassortant vaccine seed strain originating from H5N1/A/Vietnam/1194/2004 and PR-8, induced significantly stronger antibody responses in neutralizing antibodies in children. In this report, IgG subclass antibody responses were investigated, and most serum samples were positive for IgG1 antibody before immunization. A significant response (more than 4-fold increase) of IgG1 antibody was observed in 67/193 (34.7%) and that of gG4 antibodies in 42/193(21.8%). Children <4 years of age showed a significant increase in IgG subclass antibodies but those >=4 years showed lower responses. Alum- adjuvanted H5N1WIV induced an efficient immune response in young children especially <4 years. PMID- 23102975 TI - Re-emergence of diphtheria and pertussis: implications for Nigeria. AB - In the prevaccine era pertussis and diphtheria were responsible for significant morbidity and mortality in children. In the United States of America more than 125,000 cases of diphtheria with 10,000 deaths were reported annually in the 1920s. In the same period about 1.7 million cases of pertussis with 73,000 deaths were also reported. Vaccination against these two diseases has caused remarkable reduction in the morbidity and mortality from these diseases both in developed and developing countries. The initial vaccines were the combined diphtheria toxoid and whole cell pertussis vaccine. The recent reported increases in the incidence of these two diseases in countries, which maintain high childhood vaccination coverage is a source of concern not only to these countries but also for developing countries with weak immunization programmes. Nigeria for example reported 11,281 cases of pertussis, the second highest number of cases worldwide in 2009. Waning immunity in adult and adolescent populations has been reported and epidemiologically, more cases are being reported in adults and adolescents. Also a high proportion of pertussis cases are being reported in infants and most of these infant cases are linked to adult/adolescent sources. Recent approaches to control of these diseases include booster doses of combined diphtheria, tetanus and acellular pertussis vaccine while the cocooning strategy (which is immunizing every person who is likely to have contact with a given infant such as mother, father, grandparents and health care workers) is being used in a number of countries. For developing countries including Nigeria where the capacity for making the diagnosis of both diseases is limited, strengthening of routine immunization as well as diagnostic capacity is imperative. Research to determine current levels of immunity in children, adolescents and adults is required. This will enable the determination of the need for booster doses and the age at which such boosters should be administered. Improved surveillance will be needed to delineate current epidemiological profiles of both diseases. PMID- 23102976 TI - Conservation of HIV-1 T cell epitopes across time and clades: validation of immunogenic HLA-A2 epitopes selected for the GAIA HIV vaccine. AB - HIV genomic sequence variability has complicated efforts to generate an effective globally relevant vaccine. Regions of the viral genome conserved in sequence and across time may represent the "Achilles' heel" of HIV. In this study, highly conserved T-cell epitopes were selected using immunoinformatics tools combining HLA-A2 supertype binding predictions with relative global conservation. Analysis performed in 2002 on 10,803 HIV-1 sequences, and again in 2009, on 43,822 sequences, yielded 38 HLA-A2 epitopes. These epitopes were experimentally validated for HLA binding and immunogenicity with PBMCs from HIV-infected patients in Providence, Rhode Island, and/or Bamako, Mali. Thirty-five (92%) stimulated an IFNgamma response in PBMCs from at least one subject. Eleven of fourteen peptides (79%) were confirmed as HLA-A2 epitopes in both locations. Validation of these HLA-A2 epitopes conserved across time, clades, and geography supports the hypothesis that such epitopes could provide effective coverage of virus diversity and would be appropriate for inclusion in a globally relevant HIV vaccine. PMID- 23102978 TI - [Rhabdomyolysis following the coprescription of atorvastatin and fusidic acid]. AB - INTRODUCTION: The incidence of rhabdomyolysis associated with statin therapy is underestimated, especially when they are coprescribed with other drugs. CASE REPORT: We report a 68-year-old man who presented with rhabdomyolysis causing muscle weakness that occurred seven months after fusidic acid was coprescribed with atorvastatin. A literature review identified eight additional cases of rhabdomyolysis with fusidic acid and atorvastatin and six with fusidic acid and simvastatin. The risk of rhabdomyolysis associated with statin therapy is dependent of the extent to which an individual statin is metabolized by P450 3A4 isoenzyme and to the degree of inhibition of this isoenzyme activity by some antimicrobial. CONCLUSION: Our case report highlights the importance of the close monitoring of patients on statins, especially when new drugs are started or if patients become symptomatic, with testing for occurrence of muscle weakness and creatine kinase serum level. PMID- 23102977 TI - Musical training during early childhood enhances the neural encoding of speech in noise. AB - For children, learning often occurs in the presence of background noise. As such, there is growing desire to improve a child's access to a target signal in noise. Given adult musicians' perceptual and neural speech-in-noise enhancements, we asked whether similar effects are present in musically-trained children. We assessed the perception and subcortical processing of speech in noise and related cognitive abilities in musician and nonmusician children that were matched for a variety of overarching factors. Outcomes reveal that musicians' advantages for processing speech in noise are present during pivotal developmental years. Supported by correlations between auditory working memory and attention and auditory brainstem response properties, we propose that musicians' perceptual and neural enhancements are driven in a top-down manner by strengthened cognitive abilities with training. Our results may be considered by professionals involved in the remediation of language-based learning deficits, which are often characterized by poor speech perception in noise. PMID- 23102979 TI - Effectiveness of antidementia drugs in delaying Alzheimer's disease progression. AB - BACKGROUND: Randomized controlled trials (RCTs) provide safety and efficacy data for regulatory approval of antidementia drugs, but offer limited data regarding real-world effectiveness. Long-term observational controlled studies (LTOCs) extend our understanding by providing longitudinal data across multiple stages of Alzheimer's disease (AD). METHODS: Comparisons of strengths, limitations, evidence level, and results for monotherapy (cholinesterase inhibitors) and combination therapy (cholinesterase inhibitors + memantine) in RCTs versus LTOCs were made. RESULTS: Similar to RCTs, LTOCs have shown that both monotherapy and combination therapy are associated with slower cognitive and functional decline. Combination therapy is associated with better cognitive outcomes and greater delays in time to nursing home admission versus monotherapy or no treatment. Persistent antidementia drug treatment is associated with slower decline in cognition, daily function, and global severity, even in patients with advanced disease. CONCLUSIONS: LTOCs provide complementary evidence regarding effectiveness of antidementia therapy over many years, a time course relevant to AD management. These findings also provide compelling arguments in favor of using LTOCs to estimate effectiveness, risk-benefit, and costs of AD treatments. PMID- 23102980 TI - Microsurgical management of non-neurofibromatosis spinal schwannoma. AB - INTRODUCTION: The aim of this study is to assess the clinical properties and surgical results of patients diagnosed with spinal schwannomas without neurofibromatosis (NF) properties. PATIENTS AND METHODS: The data obtained from 35 patients who underwent resection of spinal schwannomas were analyzed. All cases with neurofibromas and those with a known diagnosis of NF Type 1 or 2 were excluded. 35 patients underwent surgery for spinal schwannoma at our institution between January 1997 and 2010. The data were gathered retrospectively from medical records and included clinical presentation, tumor location and post operative complications. All cases were surgically excised, and they were confirmed to be schwannomas by pathologists with histopathological sections in paraffin stained with hematoxylin-eosin. RESULT: We treated 35 (20 males and 15 females) patients with spinal schwannomas. The mean age of the patients was 47.2 (between 13 and 76) years. Of the cases, six schwannomas were located in the cervical spine, four in the thoracic spine, two in cervico-thoracic area, 10 in the thoraco-lumbar area and 13 in the lumbar spine. Two patients had malignant schwannomas that were recurrent. Of the 35 cases, the schwannomas were intradural extramedullary in 30 cases (86%), intradural-intramedullar in 2 cases (6%), and extradural in 3 cases (9%). CONCLUSION: Spinal schwannomas may occur at any level of the spinal axis and are most frequently intradural-extramedullary. The most common clinical presentation is pain. Most of the spinal schwannomas in non-NF patients can be resected completely without or with minor post-operative deficits. This knowledge may help us to create a strategy for total resection of a spinal schwannomas. PMID- 23102981 TI - Risk factors for surgical site infection after delayed sternal closure. AB - We examined the rates and risk factors for surgical site infections (SSIs) following delayed sternal closure after pediatric cardiac surgery by way of retrospective review of prospectively collected infection control data. Of 130 patients, 13.7% developed an SSI, and 6.9% developed mediastinitis following delayed sternal closure. There was a trend toward increased SSIs in patients undergoing delayed sternal closure in beds in the open bay of a pediatric intensive care unit. PMID- 23102982 TI - Support for mandatory health care worker influenza vaccination among allied health professionals, technical staff, and medical students. AB - Although policies mandating annual influenza vaccination among health care workers (HCWs) are recommended, little is known about which HCWs support mandatory vaccination. We surveyed non-physician, non-nursing HCWs to identify beliefs associated with supporting mandatory HCW vaccination. Although similarities were identified, some beliefs and concerns associated with supporting mandatory vaccination differed among HCW groups. Policy makers should understand these differences and address beliefs and concerns of all HCW groups when attempting to implement a mandatory influenza vaccination policy. PMID- 23102983 TI - Assessment of the burden of mandatory reporting of health care-associated infection using the National Healthcare Safety Network in Massachusetts. AB - An online survey was sent to 73 facilities in December 2010 to assess the time commitment, staff involvement, and methods used in reporting health care associated infection (HAI) events through the National Healthcare Safety Network in Massachusetts. Of the 65 respondents, 45% reported electronically importing at least a portion of their data. Facilities that reported using electronic import spent fewer hours per week on data collection and entry than those performing manual data entry. Although not all facilities found electronic import easy to use, nearly all found it to be helpful. Allocating financial and information technology resources to allow for electronic import may ease the burden of HAI reporting to the National Healthcare Safety Network. PMID- 23102984 TI - Ineffectiveness of a quaternary ammonium salt and povidone-iodine for the inactivation of Ascaris suum eggs. AB - Two commonly used disinfectants, a quaternary ammonium salt and povidone-iodine, were tested for effectiveness against unembryonated Ascaris suum eggs. The quaternary ammonium salt (alkyl dimethyl benzyl ammonium chloride) had no effect on the Ascaris eggs (10 minutes and 22 degrees C) when compared with the controls in water with egg viabilities of 88.8% +/- 3.3% and 86.9% +/- 6.2%, respectively. An additional quaternary ammonium salt, 2.5% benzethonium chloride, also had no effect. Phenol (5%) and cresol (3%) completely inactivated the eggs. Povidone iodine at 100%, 50%, 10%, and 1% had no effect on the eggs at exposures of 5, 15, 30, 60, or 120 minutes (22 degrees C) compared with the water controls. PMID- 23102985 TI - Zeroing in on methicillin-resistant Staphylococcus aureus: US Department of Veterans Affairs' MRSA Prevention Initiative. AB - Implementation of a methicillin-resistant Staphylococcus aureus (MRSA) Prevention Initiative within US Department of Veterans Affairs medical facilities was associated with a significant reduction in MRSA health care-associated infection (HAI) rates nationwide. The first 36 months of data from the Initiative were analyzed to determine how many facilities reported zero MRSA HAIs each month. From October 2007 through September 2010, there was a 37.6% increase nationwide in the number of facilities achieving zero MRSA HAIs each month. PMID- 23102986 TI - Temporal changes in pulsed-field gel electrophoresis banding in vancomycin resistant Enterococcus faecium and implications for outbreak investigations. AB - BACKGROUND: Patients are often screened with surveillance cultures to discern transmissions vs transformation of an isolate to vancomycin-resistant Enterococcus faecium. To determine the amount of time between which isolates could be considered genetically similar by pulsed-field gel electrophoresis, isolate change over time within single patients was studied. METHODS: A minimum of 4 isolates per patient, separated by at least 2 months, were collected from previously frozen stores. Visual comparison of banding patterns was conducted, and percent relatedness was calculated. RESULTS: Twenty-eight isolates from 6 patients were studied. No isolate differed by more than 3 bands before 150 days, and the average percent difference per band was 3.7%. The isolates diverged genetically as a linear function of number of bands over time (good model fit intrapatient r(2) = 0.42; poor model fit interpatient r(2) = 0.0062). CONCLUSION: Trajectory of genetic variation appears to be isolate/patient specific; however, commonalities exist and tested isolates were relatively stable out to 150 days. PMID- 23102987 TI - Effectiveness of a Protective Environment implementation for cancer patients with chemotherapy-induced neutropenia on fever and mortality incidence. AB - In a quasiexperimental study conducted to evaluate the impact of a Protective Environment implementation, febrile neutropenia (P = .009), overall mortality (P = .001), and 30-day adjusted mortality (P = .02) were reduced in cancer patients with chemotherapy-induced neutropenia. Our study highlights the potential success of a set of prevention measures mainly designed to reduce invasive environmental fungal infections in allogeneic hematopoietic stem cell transplant patients, in reducing fever and mortality among neutropenic cancer patients. PMID- 23102988 TI - Evaluating infection control: a review of implementation of an infection prevention and control program in a low-income country setting. AB - BACKGROUND: This study was conducted to review the status of the comprehensive infection prevention and control program (IPCP) established in the Republic of Kiribati in 2005, and to identify opportunities to continue and expand the integration of the IPCP into health service delivery. METHODS: The review was conducted in 2010 using 2 empirical tools: a pilot IPCP evaluation (IPCPE) tool that evaluated the activities of the program and its implementation, and a previously validated self-administered survey that assessed health care worker (HCW) knowledge, application, and confidence in infection control principles and practice. The survey was given to all 186 clinicians at Tungaru Central Hospital; the response rate was 59.7%. RESULTS: The Kiribati IPCP demonstrated a minimum level of compliance (75%) with the activity standards set out in the IPCPE tool. The mean scores on the HCW survey were 62% for knowledge, 63% for application, and 79% for confidence. Significant correlations were found among knowledge, application, and confidence. CONCLUSIONS: This evaluation of the Kiribati IPCP with our IPCPE tool provides valuable insight into the status of a recently adopted comprehensive program and how it has translated into the knowledge, application, and confidence of HCWs in their clinical practice. The HCW survey provides evidence that the IPCP has translated into confidence and ability in the application of infection prevention practices. PMID- 23102989 TI - Molecular prophage typing of avian pathogenic Escherichia coli. AB - Escherichia coli prophages confer virulence and resistance to physico-chemical, nutritional, and antibiotic stresses on their hosts, and they enhance the evolution of E. coli. Thus, studies on profiles of E. coli prophages are valuable to understand the population structure and evolution of E. coli pathogenicity. Large terminase genes participate in phage genome packaging and are one of the cornerstones for the identification of prophages. Thus, we designed primers to detect 16 types of large terminase genes and analyzed the genomes of 48 E. coli and Shigella reference strains for the prophage markers. We also investigated the distribution of the 16 prophage markers among 92 avian pathogenic E. coli (APEC) strains. APEC strains were classified into 61 prophage types (PPTs). Each strain was different from the reference strains as measured by the PPTs and from the frequency of each prophage marker. Investigation of the distribution of prophage related serum resistance (bor), toxin (stx1 and cdtI), and T3SS effector (lom, espK, sopE, nleB, and ospG) genes revealed the presence of bor (44.1%), lom (95.5%) and cdtI (9.1%) in APEC strains with related prophages. Therefore, the molecular prophage typing method may be useful to understand population structure and evolution of E. coli pathogenicity, and further studies on the mobility of the prophages and the roles of virulence genes in APEC pathogenicity may be valuable. PMID- 23102990 TI - Control of the formation of vascular networks in 3D tissue engineered constructs. AB - Construction of bio-mimetic well-organized three-dimensional (3D) tissue with various cells in vitro is one of the ultimate goals of tissue engineering. In particular, fabrication of vasculature in 3D tissue is one of the most important tasks in tissue engineering, because a vascular network is indispensable for almost every tissue in our body. Here, we sandwiched stripe patterned endothelial cells by randomly cultured fibroblast sheets to control the formation of vasculature in the tissue. The endothelial cells left the original pattern and formed a random network between the two sheets, but, where fibroblasts were focally oriented, some endothelial cells changed their orientation to the same direction as the surrounding fibroblasts. Based on this phenomenon, we sandwiched stripe-patterned endothelial cells between parallel-oriented fibroblast sheets to construct a continuous pre-vascular structure. In the tissue, endothelial cells maintained the shape of their original pattern. On the other hand, stripe patterned endothelial cells that were vertically sandwiched between oriented fibroblast sheets diverged from the original pattern at right angles, so that they were aligned with the surrounding fibroblasts. These data indicates that, 3D design with consideration of cell-to-cell interaction is critical to fabricate a specific 3D tissue structure. The 3D-designed tissue will become a powerful tool for the study of pharmacology and biology, the substitution of animal models and the fabrication of vascularized tissue grafts. PMID- 23102991 TI - Proteomic analysis of a decellularized human vocal fold mucosa scaffold using 2D electrophoresis and high-resolution mass spectrometry. AB - Natural biologic scaffolds for tissue engineering are commonly generated by decellularization of tissues and organs. Despite some preclinical and clinical success, in vivo scaffold remodeling and functional outcomes remain variable, presumably due to the influence of unidentified bioactive molecules on the scaffold-host interaction. Here, we used 2D electrophoresis and high-resolution mass spectrometry-based proteomic analyses to evaluate decellularization effectiveness and identify potentially bioactive protein remnants in a human vocal fold mucosa model. We noted proteome, phosphoproteome and O-glycoproteome depletion post-decellularization, and identified >200 unique protein species within the decellularized scaffold. Gene ontology-based enrichment analysis revealed a dominant set of functionally-related ontology terms associated with extracellular matrix assembly, organization, morphology and patterning, consistent with preservation of a tissue-specific niche for later cell seeding and infiltration. We further identified a subset of ontology terms associated with bioactive (some of which are antigenic) cellular proteins, despite histological and immunohistochemical data indicating complete decellularization. These findings demonstrate the value of mass spectrometry-based proteomics in identifying agents potentially responsible for variation in host response to engineered tissues derived from decellularized scaffolds. This work has implications for the manufacturing of biologic scaffolds from any tissue or organ, as well as for prediction and monitoring of the scaffold-host interaction in vivo. PMID- 23102992 TI - Mucosal priming of the murine immune system against enterohemorrhagic Escherichia coli O157:H7 using Lactococcus lactis expressing the type III secretion system protein EspB. AB - Enterohemorrhagic Escherichia coli (EHEC), particularly E. coli serotype O157:H7, has been responsible for multiple human outbreaks of hemorrhagic colitis and hemolytic uremic syndrome worldwide. Humans become infected by direct or indirect contact with faeces of asymptomatic EHEC shedding ruminants. Currently there is no human or animal vaccine available against EHEC infection. EHEC use a type III secretion system (T3SS) to colonize the intestine and therefore eliciting mucosal immunity against T3SS proteins could be a potential vaccination strategy. To develop such a mucosal vaccine, EspB - a significant member of the T3SS - was intracellularly expressed in Lactococcus lactis (LL-EspB) and this strain was used to immunize BALB/c mice orally. Ten days post-immunization, no specific antibody response was detected in serum or faeces of immunized mice. However, statistically significant (P<0.0001) levels of specific serum Ig and faecal IgA were detected after intraperitoneal boosting of the orally immunized mice with recombinant EspB. Our results show that oral administration of LL-EspB resulted in mucosal priming of BALB/c mice against the EHEC T3SS protein, EspB. Nevertheless, an optimized EspB expression in L. lactis may be required to improve the mucosal immune response. PMID- 23102993 TI - Structure-activity relationship studies of naphthol AS-E and its derivatives as anticancer agents by inhibiting CREB-mediated gene transcription. AB - CREB (cyclic AMP-response element binding protein) is a downstream transcription factor of a multitude of signaling pathways emanating from receptor tyrosine kinases or G-protein coupled receptors. CREB is not activated until it is phosphorylated at Ser133 and its subsequent binding to CREB-binding protein (CBP) through kinase-inducible domain (KID) in CREB and KID-interacting (KIX) domain in CBP. Tumor tissues from various organs present higher level of expression and activation of CREB. Thus CREB has been proposed as a promising cancer drug target. We previously described naphthol AS-E (1a) as a small molecule inhibitor of CREB-mediated gene transcription in living cells. Here we report the structure activity relationship (SAR) studies of 1a by modifying the appendant phenyl ring. All the compounds were evaluated for in vitro inhibition of KIX-KID interaction, cellular inhibition of CREB-mediated gene transcription and inhibition of proliferation of four cancer cell lines (A549, MCF-7, MDA-MB-231 and MDA-MB-468). SAR indicated that a small and electron-withdrawing group was preferred at the para-position for KIX-KID interaction inhibition. Compound 1a was selected for further biological characterization and it was found that 1a down-regulated the expression of endogenous CREB target genes. Expression of a constitutively active CREB mutant, VP16-CREB in MCF-7 cells rendered the cells resistant to 1a, suggesting that CREB was critical in mediating its anticancer activity. Furthermore, 1a was not toxic to normal human cells. Collectively, these data support that 1a represents a structural template for further development into potential cancer therapeutics with a novel mechanism of action. PMID- 23102994 TI - Changes in constraint of proximal segments effects time to task failure and activity of proximal muscles in knee position-control tasks. AB - OBJECTIVE: Maintenance of a limb position against external load (position control) fails earlier (time to task failure: TTF) than maintenance of identical force against rigid restraint (force-control). Although possibly explained by physiological differences between contractions, we investigated whether less constraint of movements in other planes and proximal segments (commonly less in position-control tasks) shortens TTF. METHODS: Seventeen adults (32+/-7 years) contracted knee extensor muscles to task failure in a position-control task, with and without constraint of motion in other planes and proximal segments, and a force-control task with constraints. Electromyography of knee extensors, their antagonist and hip muscles was recorded with force/position. RESULTS: TTF was shorter for position-control without (161+/-55 s) than with constraint (184+/-51 s). Despite identical constraint, TTF was shorter in position- than force-control (216+/-56 s). Muscle activity and position variability at failure was greater without constraint. CONCLUSION: Constraint of motion of proximal segments and other planes increases position-control TTF with less muscle activity and variability. As TTF differed between force- and position-control, despite equivalent constraint, other factors contribute to shorter position-control TTF. SIGNIFICANCE: Results clarify that differences in the TTF between position- and force-control tasks are partly explained by unmatched restriction of motion in other planes and proximal segments. PMID- 23102995 TI - Differential blood pressure reductions by angiotensin receptor blocker plus calcium channel blocker or diuretic in elderly hypertension with or without obesity. AB - We conducted the Miyazaki Olmesartan Therapy for Hypertension in the EldeRly (MOTHER) study, which suggested that there are preferable effects of an angiotensin receptor blocker (ARB), olmesartan, plus a calcium channel blocker (CCB) over the ARB plus a diuretic, in elderly patients with hypertension. In this subanalysis, we examined whether obesity influences the efficacies of these combination therapies. The study subjects were 58 hypertensive patients ages 65 to 85, who had been randomly assigned to either group treated with olmesartan plus a CCB or a diuretic and completed the treatment for 6 months. Systolic and diastolic blood pressures were reduced following these combination treatments in nonobese and obese patients. In the CCB combination, blood pressure reductions in nonobese patients were larger than in obese patients at 1 and 3 months, and serum creatinine remained unchanged despite the greater reduction of blood pressure. Meanwhile, such differences were not noted in the diuretic groups. Plasma aldosterone was significantly reduced in nonobese patients of two combination groups, but not in those with obesity. ARB plus CCB combination therapy might be preferably chosen for nonobese elderly patients, whereas the influence of obesity seems smaller in the efficacy of ARB plus a diuretic. PMID- 23102996 TI - Evaluation of a rapid lateral flow immunoassay for Staphylococcus aureus detection in respiratory samples. AB - Rapid point-of-care pathogen detection remains a challenge in routine diagnostics. A Staphylococcus aureus-specific lateral flow immunochromatography (LFI) test has been developed using a specific monoclonal antibody to the S. aureus cell-wall peptidoglycan. The LFI test was shown to be specific for S. aureus with no signal development for other Staphylococcal species or common respiratory pathogens. Evaluation of S. aureus isolates spiked into induced sputum and bronchoalveolar lavage samples derived from severe asthmatic patients showed a detection limit of 10(6) CFU/mL for the LFI. The test was also shown to successfully detect S. aureus in 1 sample independently determined to be S. aureus positive by quantitative polymerase chain reaction. The ability of the LFI test to rapidly detect S. aureus in clinical respiratory samples suggests that it might be a useful platform for further development of point-of-care diagnostic applications. PMID- 23102997 TI - Direct mecA polymerase chain reaction testing of blood culture bottles growing Gram-positive cocci and the clinical potential in optimizing antibiotic therapy for staphylococcal bacteremia. AB - This study evaluated the performance of direct mecA polymerase chain reaction (PCR) from blood culture bottles growing Gram-positive cocci in clusters and its role in optimization of antibiotic therapy. A total of 266 blood cultures including 121 methicillin-resistant and 122 methicillin-susceptible Staphylococci were tested for mecA. Compared to phenotypic testing, the overall performance of direct mecA PCR was 99% for sensitivity, specificity, positive predictive value, and negative predictive value, respectively. Assessment of antibiotic therapy upon microbiology reporting of direct mecA PCR results from 38 patients prior to (phase I) and 48 patients after implementation of testing and reporting (phase II) showed that the mean time to antibiotic optimization in phase II (0.9 +/- 0.9 day) was significantly shorter than that in phase I (2.2 +/- 3.2 days) (P < 0.05). Methicillin-susceptible staphylococcal bacteremias had significantly higher frequency of antibiotic adjustment upon direct mecA reporting, compared to methicillin-resistant staphylococcal bacteremias. Our study indicated that direct mecA PCR improved timely antibiotic optimization. PMID- 23102998 TI - The sigma-1 receptor: roles in neuronal plasticity and disease. AB - Sigma-1 receptors (Sig-1Rs) have been implicated in many neurological and psychiatric conditions. Sig-1Rs are intracellular chaperones that reside specifically at the endoplasmic reticulum (ER)-mitochondrion interface, referred to as the mitochondrion-associated ER membrane (MAM). Here, Sig-1Rs regulate ER mitochondrion Ca(2+) signaling. In this review, we discuss the current understanding of Sig-1R functions. Based on this, we suggest that the key cellular mechanisms linking Sig-1Rs to neurological disorders involve the translocation of Sig-1Rs from the MAM to other parts of the cell, whereby Sig-1Rs bind and modulate the activities of various ion channels, receptors, or kinases. Thus, Sig-1Rs and their associated ligands may represent new avenues for treating aspects of neurological and psychiatric diseases. PMID- 23102999 TI - Live-cell imaging shows apoptosis initiates locally and propagates as a wave throughout syncytiotrophoblasts in primary cultures of human placental villous trophoblasts. AB - Human placental villi are surfaced by the syncytiotrophoblast, a multinucleated, epithelial-cell layer that functions in maternal-fetal exchange. Mononucleated cytotrophoblasts are subjacent to the syncytiotrophoblast. Using confocal fluorescence microscopy of third-trimester villi, we previously found that cytotrophoblasts are often interdigitated into the syncytiotrophoblast, that cytotrophoblasts undergo caspase-mediated apoptosis, and that apoptosis is much lower, and perhaps completely inhibited, in intact syncytiotrophoblast lacking fibrin-type fibrinoid. Previous analysis of primary cultures of human trophoblasts also indicated lower levels of apoptosis in syncytiotrophoblast compared to cytotrophoblasts. Here, using confocal microscopy we find that cultured cytotrophoblasts and syncytiotrophoblasts display complex structural relationships, as in vivo, and that apoptosis of a cytotrophoblast or syncytiotrophoblast does not induce apoptosis of adjacent trophoblasts. Using live-cell imaging of mitochondrial depolarization and nuclear condensation in cultured syncytiotrophoblasts, we show apoptosis initiates in a localized region and propagates radially at ~5 MUm/min with no loss of velocity until the entire syncytium has undergone apoptosis. The rate of propagation is similar in cases of spontaneous apoptosis and in apoptosis that occurs in the presence of cobalt chloride or rotenone, two inducers of apoptosis. We suggest that inhibition of syncytiotrophoblast apoptosis in vivo is important to prevent widespread syncytiotrophoblast death, which would result in placental dysfunction and contribute to poor pregnancy outcomes. PMID- 23103000 TI - Impact of lung function changes after induction radiochemotherapy on resected T4 non-small cell lung cancer outcome. AB - BACKGROUND: Induction radiochemotherapy, followed by resection, for T4 non-small cell lung cancer, has shown promising long-term survival but may be associated with increased postoperative morbidity and death, depending on patient selection. Here, we determined the effect of induction radiochemotherapy on pulmonary function and whether postinduction pulmonary function changes predict hospital morbidity and death and long-term survival. METHODS: A consecutive prospective cohort of 72 patients with T4 N0-2 M0 non-small cell lung cancer managed by radiochemotherapy, followed by resection, is reported. All patients underwent thoracoabdominal computed tomography or fusion positron emission tomography computed tomography, brain imaging, mediastinoscopy, echocardiography, ventilation-perfusion scintigraphy, and pulmonary function testing before and after induction therapy. Resection was performed if the postoperative forced expiratory volume in 1 second and diffusion capacity of the lung for carbon monoxide exceeded 30% predicted and if the postoperative maximum oxygen consumption exceeded 10 mL/kg/min. RESULTS: The postoperative 90-day mortality rate was 8% (lobectomy, 2%; pneumonectomy, 21%; p=0.01). All deaths after pneumonectomy occurred after right-sided procedures. The 3-year and 5-year survival was 50% (95% confidence interval, 36% to 62%) and 45% (95% confidence interval, 31% to 57%) and was significantly associated with completeness of resection (p=0.004) and resection type (pneumonectomy vs lobectomy, p=0.01). There was no correlation between postinduction pulmonary function changes and postoperative morbidity or death or long-term survival in patients managed by lobectomy or pneumonectomy. CONCLUSIONS: In properly selected patients with T4 N0 2 M0 non-small cell lung cancer, resection after induction radiochemotherapy can be performed with a reasonable postoperative mortality rate and long-term survival, provided the resection is complete and a right-sided pneumonectomy is avoided. Postinduction pulmonary function changes did not correlate with postoperative morbidity or death or with long-term outcome. PMID- 23103001 TI - Adjuvant chemotherapy and age-related biases in non-small cell lung cancer. AB - BACKGROUND: Five-year survival for early-stage lung cancer despite complete surgical resection is approximately 50%. Adjuvant chemotherapy has been shown to improve survival in some patients. Older cancer patients do not always receive standard therapy. The purpose of this study was to determine if there were age related biases concerning the use of adjuvant chemotherapy after lobectomy for elderly patients with non-small cell lung cancer (NSCLC). METHODS: A prospective lung cancer outcomes database was queried for all patients undergoing lobectomy for NSCLC pathologic stage IB and higher between April 2006 and October 2010. Patients who received neoadjuvant treatment or who died within 30 days of operation were excluded. Ninety-nine patients met the inclusion criteria. Patients were divided into 2 groups based on age (<70 or >=70 years). The use of adjuvant chemotherapy was compared between groups. RESULTS: Sixty-nine patients (70%) were younger than 70 years and 30 (30%) were 70 years or older. There was a significant difference in the use of adjuvant chemotherapy between the 2 groups, with 46 (66.7%) of the younger patients and 7 (25%) of the elderly patients receiving adjuvant treatment (p<0.01). The difference persisted when analyzed by stage, with older patients less likely to receive chemotherapy among all patients with stage IB disease, stage II or more advanced disease, and stage IB lesions greater than or equal to 4 cm plus stage II or more advanced disease. In multivariate analysis of preoperative and postoperative factors, age remained the only independent predictor of chemotherapy use. CONCLUSIONS: Patients undergoing lobectomy who were 70 years of age or older received adjuvant chemotherapy less often than did younger patients. PMID- 23103002 TI - The risk and outcomes of reoperative tricuspid valve surgery. AB - BACKGROUND: Outcomes after tricuspid valve reoperation have not been published before. This study examines our 32-year experience in this cohort of patients. METHODS: Between May 1979 and January 2011, a total of 68 patients who had previous tricuspid valve surgery (49 repairs and 19 replacements) had reoperations on their tricuspid valves. The median age was 60 years (19 to 75). Redo tricuspid valve pathologies included 18 functional and 50 organic. Follow-up was 100% complete, with a mean follow-up of 87 months (5 to 248). RESULTS: Re repair of the tricuspid valve was feasible in 26 patients (16 of 18 [89%] functional and 10 of 31 [32%] organic, p < 0.001). In-hospital mortality was 13.2%. Factors related to early mortality were nonelective surgery, New York Heart Association (NYHA) functional class III/IV, left ventricle ejection fraction less than 0.40, cardiopulmonary bypass time greater than 136 minutes, and postoperative low cardiac output syndrome (p < 0.05). Postoperative complications included 9 reoperations for bleeding, 11 postoperative low cardiac output syndrome, 5 renal failure requiring dialysis, 3 strokes, and 13 pacemaker implantation. Factors related to late mortality were age greater than 60 years, male sex, ventilation time greater than 24 hours, cardiopulmonary bypass time greater than 136 minutes, and postoperative low cardiac output syndrome (p < 0.05). Survivors had 5-, 10-, and 15-year survival rates of 86%, 64%, and 33%, respectively. Functional class improved in hospital survivors; NYHA class I/II 80.6% compared with preoperative NYHA class III/IV of 90% (p = 0.001). CONCLUSIONS: Redo tricuspid valve surgery is associated with high operative mortality and morbidity; however, survivors benefited from reasonable survival rates. Re-repair of the tricuspid valve is feasible in the majority of patients with functional tricuspid valve pathology, while the majority of patients with underlying organic pathology required a valve replacement. PMID- 23103003 TI - Hybrid coronary revascularization using robotic totally endoscopic surgery: perioperative outcomes and 5-year results. AB - BACKGROUND: Hybrid coronary revascularization combines minimally invasive coronary artery bypass grafting and catheter-based interventions. This treatment option represents a viable alternative to both open multivessel coronary bypass surgery through sternotomy and multivessel percutaneous coronary intervention. The surgical component of hybrid coronary intervention can be offered in a completely endoscopic fashion using robotic technology. We report on one of the largest series to date. METHODS: From 2001 to 2011, 226 patients (age, 61 years [range, 31 to 90 years]; 77.0% male; EuroSCORE, 2 [range, 0 to 13]) underwent hybrid coronary interventions on an intention-to-treat basis. Robotically assisted procedures were performed using the daVinci, daVinci S, and daVinci Si surgical telemanipulation systems (Intuitive Surgical, Inc, Sunnyvale, CA) and included 147 single, 72 double, and 7 triple endoscopic coronary artery bypass grafting procedures. Surgery was carried out first in 160 cases (70.8%), percutaneous coronary intervention was carried out first in 38 cases (16.8%), and 28 patients underwent simultaneous operations in a hybrid operating room (12.4%). Drug-eluting stents were used in 70.0% of the patients. RESULTS: Hospital mortality was 3 of 226 patients (1.3%), and hospital stay averaged 6 days (range, 3 to 54 days). Patients walked outside 7 days (range, 3 to 97 days) postoperatively and performed general household work 14 days (range, 7 to 180 days) postoperatively. Full activity was resumed at 42 days (range, 7 to 720 days). Five-year survival was 92.9%, and 5-year freedom from major adverse cardiac and cerebral events was 75.2%. At 5 years, 2.7% of bypass grafts and 14.2% of percutaneous coronary intervention targets needed reintervention. CONCLUSIONS: Robotically assisted hybrid coronary intervention enables surgical treatment of multivessel coronary artery disease with minimal trauma. Perioperative results and intermediate-term outcomes meet the standards of open coronary artery bypass grafting. Recovery time is short, and reintervention rates are acceptable. PMID- 23103004 TI - Expanding indications for valve-sparing aortic root reconstruction: early and midterm results. AB - BACKGROUND: Valve-sparing aortic root reconstruction (VSRR) is an accepted method to treat patients with aortic root dilation. The role of the VSRR is less well defined for patients with bicuspid aortic valve, severe aortic valve insufficiency, congenital heart defects, and type A aortic dissection. We studied the clinical outcome of patients who underwent VSRR for expanded indications. METHODS: Seventy-eight patients underwent VSRR between the 2005 and 2012. Seventy two patients (92%) underwent reimplantation and 6 patients (8%) were operated on with the remodeling technique. The mean age was 51 +/- 12 years (range 24 to 73). For 71 patients (91%), the operation was elective, and for 7 (9%; all with type A aortic dissection), on an emergency basis. Preoperatively, the degree of aortic insufficiency was graded as 2+ or greater for 27 patients (35%). Connective tissue disorder (Marfan or Loeys-Dietz), bicuspid aortic valve, or congenital heart disease was present in 15 (19%), 15 (19%), and 7 patients (9%), respectively. Concomitant aortic valve leaflet repair was performed for 39 patients (50%). The mean follow-up time was 2.4 +/- 1.7 years (range, 0.1 to 7.0). RESULTS: Thirty-day mortality was zero. The rate of postoperative complications was low: stroke 3%, renal failure 3%, prosthesis infection 1%, and low cardiac output syndrome 1%. Survival was 100% at 1 year and 97% at 5 years. Freedom from recurrent aortic valve insufficiency (>=2+) during the follow-up was 94%. CONCLUSIONS: The midterm results of VSRR in terms of survival, freedom from recurrent aortic valve insufficiency, and the need for reoperation are excellent, even for high-risk patients. PMID- 23103006 TI - Late development of a gigantic aneurysm of the neoaorta after Norwood palliation. PMID- 23103005 TI - Dynamic 3-dimensional echocardiographic assessment of mitral annular geometry in patients with functional mitral regurgitation. AB - BACKGROUND: Mitral valve (MV) annular dynamics have been well described in animal models of functional mitral regurgitation (FMR). Despite this, little if any data exist regarding the dynamic MV annular geometry in humans with FMR. In the current study we hypothesized that 3-dimensional (3D) echocardiography, in conjunction with commercially available software, could be used to quantify the dynamic changes in MV annular geometry associated with FMR. METHODS: Intraoperative 3D transesophageal echocardiographic data obtained from 34 patients with FMR and 15 controls undergoing cardiac operations were dynamically analyzed for differences in mitral annular geometry with TomTec 4D MV Assessment 2.0 software (TomTec Imaging Systems GmbH, Munich, Germany). RESULTS: In patients with FMR, the mean mitral annular area (14.6 cm(2) versus 9.6 cm(2)), circumference (14.1 cm versus 11.4 cm), anteroposterior (4.0 cm versus 3.0 cm) and anterolateral-posteromedial (4.3 cm versus 3.6 cm) diameters, tenting volume (6.2 mm(3) versus 3.5 mm(3)) and nonplanarity angle (NPA) (154 degrees +/- 15 versus 136 degrees +/- 11) were greater at all points during systole compared with controls (p < 0.01). Vertical mitral annular displacement (5.8 mm versus 8.3 mm) was reduced in FMR compared with controls (p < 0.01). CONCLUSIONS: There are significant differences in dynamic mitral annular geometry between patients with FMR and those without. We were able to analyze these changes in a clinically feasible fashion. Ready availability of this information has the potential to aid comprehensive quantification of mitral annular function and possibly assist in both clinical decision making and annuloplasty ring selection. PMID- 23103007 TI - Nitinol flexigrip sternal closure system and chest wound infections: insight from a comparative analysis of complications and costs. AB - BACKGROUND: We sought to assess the efficiency of two different sternal closure techniques in preventing sternal wound complications (SWC). A cost analysis was also considered. METHODS: Between January 2008 and April 2010, 1,644 consecutive cardiac surgery patients who underwent cardiac surgery in our institute were prospectively collected. A total of 1,072 patients received a standard parasternal wiring technique (group A), and 572 patients received a new method of sternal closure based on the use of thermoreactive nitillium clips (Flexigrip; Praesidia SRL, Bologna, Italy [group B]). We investigated, by a propensity matched analysis, whether the use of standard or nitinol clip closure would impact on sternal wound outcome. RESULTS: In all, 464 patients of each group were matched for 17 available risk factors. Overall incidence of SWC was significantly higher in group A (4.1% versus 1.7%; p=0.03). Sternal surgical revision to treat a thoracic instability was required in a significantly higher number of patients in group A (9 patients, 1.9%) and in none of group B (p=0.004). The incidence of sternal instability, secondary to wound infection, was significantly lower in group B (p=0.05). Overall costs were ?7,407,296 and ?6,896,432 in group A and group B, respectively. Thus, nitinol clip closure technique offered a ?510,864 cost saving compared with standard steel wiring technique. CONCLUSIONS: The Flexigrip assured a lower incidence of SWC. The use of the nitinol clip favored an improved sternal closure technique preventing mediastinitis. Additionally, the nitinol clip system proved to be cost effective in cardiac surgery. PMID- 23103008 TI - Robotic posterior mitral leaflet repair: neochordal versus resectional techniques. AB - BACKGROUND: Resectional techniques are the established method of posterior mitral valve leaflet repair for degenerative disease; however, use of neochordae in a robotically assisted approach is gaining acceptance because of its versatility for difficult multisegment disease. The purposes of this study were to compare the versatility, safety, and effectiveness of neochordal versus resectional techniques for robotic posterior mitral leaflet repair. METHODS: From December 2007 to July 2010, 334 patients underwent robotic posterior mitral leaflet repair for degenerative disease by a resectional (n = 248) or neochordal (n = 86) technique. Outcomes were compared both unadjusted and after propensity score matching. RESULTS: Neochordae were more likely to be used than resection in patients with two (28% versus 13%; p = 0.002) or three (3.7% versus 0.87%; p = 0.08) diseased posterior leaflet segments. Three resection patients (0.98%) but no neochordal patient required reoperation for hemodynamically significant systolic anterior motion. Residual mitral regurgitation (MR) at hospital discharge was similar for matched neochordal versus resection patients (MR 0+, 82% versus 89%; MR 1+, 14% versus 8.2%; MR 2+, 2.3% versus 2.6%; 1 neochordal patient had 4+ MR and underwent reoperation; p = 0.14). Among matched patients, postoperative mortality and morbidity were similarly low. CONCLUSIONS: Compared with a resectional technique, robotic posterior mitral leaflet repair with neochordae is associated with shorter operative times and no occurrence of systolic anterior motion. The versatility, effectiveness, and safety of this repair make it a good choice for patients with advanced multisegment disease. PMID- 23103009 TI - Preclinical study of near-infrared-guided sentinel lymph node mapping of the porcine lung. AB - BACKGROUND: The presence of lymph node metastasis is the most important prognostic factor in early non-small cell lung cancer. Our objective was to develop a rapid, simple, and reliable method for thoracic sentinel lymph node (SLN) identification using near-infrared fluorescence imaging and clinically available contrast agents. METHODS: Indocyanine green (ICG) reconstituted in saline, human serum albumin, human fresh frozen plasma, and autologous porcine plasma was evaluated for optimal formulation and dosing for SLN within porcine lungs. Animals were imaged using the fluorescence-assisted resection and exploration for surgery imaging system. The SLN identification rate, time to identification and fluorescence intensity of the SLN, bronchus, and background were measured. RESULTS: The SLN identification rates varied widely, ranging from 33% to 100% as a function of the carrier used for ICG reconstitution. No significant difference was noted in SLN fluorescence intensity; however, bronchial intensity was significantly higher with ICG: albumin, which resulted in the lowest rate of SLN identification. Subsequent evaluation with 125 MUM and 250 MUM ICG:porcine plasma resulted in identification of strongly fluorescent SLNs, with identification rates of 93% and 100% and median signal-to-background ratios of 8.5 and 12.15, respectively, in less than 2 minutes in situ. CONCLUSIONS: Near infrared fluorescence imaging with ICG is a reliable method for SLN mapping in the lung with high sensitivity. Mixing of ICG with plasma resulted in strong SLN fluorescence signal with reliable identification rates. PMID- 23103010 TI - Sternal closure with rigid plate fixation versus wire closure: a randomized controlled multicenter trial. AB - BACKGROUND: Rigid bone fixation is the standard of care for all bone reconstructions except that after sternotomy. Sternal reconstruction after median sternotomy using rigid fixation with plates may improve bone healing and reduce pain when compared with wire cerclage. METHODS: One-hundred forty patients at six centers who were determined preoperatively to be at high risk for sternal wound complications were randomly assigned to sternal closure with rigid plate fixation (n=70) or wire cerclage (n=70). Sternal healing was evaluated at 3 or 6 months by a core laboratory using computed tomography. Pain and function were evaluated at postoperative day 3 through discharge, 3 weeks, 6 weeks, 3 months, and 6 months. RESULTS: Sternal healing was superior in rigid plate fixation patients at both 3 and 6 months. Mean computed tomography scores in the rigid plate fixation and wire cerclage groups at 3 months were 1.7+/-1.1 and 0.9+/-0.8 (p=0.003). At 6 months, the scores were 3.2+/-1.6 and 2.2+/-1.1, respectively (p=0.01). At 6 months, 70% of rigid plate fixation patients had achieved sternal union, compared with 24% of conventional wire cerclage patients (p=0.003). Pain scores and narcotic usage were lower in rigid plate fixation patients. Significant differences in pain scores were observed at 3 weeks for total pain (p=0.020) and pain with coughing (p=0.0084) or sneezing (p=0.030). Complication rates were similar in both groups. CONCLUSIONS: Sternal reconstruction using rigid fixation with plates improved bone healing and reduced early postoperative pain compared with wire cerclage. PMID- 23103011 TI - The Ross-Konno is a high-risk procedure when compared with the Ross operation in children. AB - BACKGROUND: For children who require aortic valve replacement, the pulmonary autograft (Ross procedure) may be the ideal substitute. However, performing a modified Konno procedure at the time of autograft implantation (Ross-Konno) may be associated with significant morbidity and mortality. A retrospective study was undertaken to compare the outcomes of Ross-Konno (RK) and the Ross (R) procedures including the need for reinterventions and long-term survival. METHODS: Between 1993 and 2011, 78 children (mean age, 11.1 +/- 5.6 years; range, 1 week to 18 years) underwent the Ross procedure. Modified Konno-type enlargement of the left ventricular outflow tract was performed in 18 of those patients. RESULTS: There was no statistically significant difference between the groups with respect to pathologic process, sex, concomitant procedures, and aortic gradient. Our data demonstrate that mean age (R, 12.9 years versus RK, 5.3 years; p < 0.001), mean size of allograft (R, 23.3 mm versus RK, 20.1 mm; p < 0.001), previous surgery (R, 51% versus RK, 83%; p = 0.05), and postoperative morbidity (R, 3% versus RK, 28%; p = 0.003) were significantly different between the groups. There were 3 hospital deaths (all RK with mitral valve anomalies). Actuarial survival at 10 years was significantly better for Ross patients than Ross-Konno (R, 96% versus RK, 72%; p = 0.001). Freedom from autograft, right ventricular outflow tract obstruction, and cumulative reoperations at 10 years were not significantly different between groups. CONCLUSIONS: The risk of death and postoperative complications after the Ross-Konno procedure is higher than for the Ross procedure. Preoperative complexity (including mitral valve anomalies) is associated with significantly higher morbidity and mortality. Autograft insufficiency and right ventricular outflow tract obstruction are common postoperative complications, requiring reoperation in one quarter of patients, but these were not significantly different between the groups. PMID- 23103012 TI - Significance of postoperative acute renal failure after continuous-flow left ventricular assist device implantation. AB - BACKGROUND: Deteriorating renal function is common in patients with advanced heart failure and is associated with poor outcomes. The relationship between renal function and left ventricular assist device (LVAD) implantation is complex and has been explored in multiple studies with contradictory results. The aim of our study is to examine the significance of postoperative renal failure after implantation of a continuous-flow LVAD and its relationship to outcomes. METHODS: From March 2006 to July 2011, 100 patients underwent implantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) or HeartWare (Heart International, Inc, Framingham, MA) LVAD at our institution. Patients were stratified based on postoperative development of acute renal failure (ARF). Variables were compared using 2-sided t tests, chi(2) tests, Cox proportional hazards models, and log rank tests to determine whether there was a difference between the 2 groups and whether postoperative renal failure was a significant independent predictor of outcome. RESULTS: We identified 28 patients (28%) with postoperative ARF and 72 patients (72%) without postoperative ARF. The 2 groups were similar with regard to demographics and comorbidities. The patients with ARF were more likely to be intubated preoperatively (14.3% versus 1.4%; p = 0.021) and had higher preoperative central venous pressure (CVP) (14.3 mm Hg versus 10.7 mm Hg; p = 0.015). Postoperatively patients with ARF had a longer hospital stay (32.4 versus 18.7; p = 0.05), were more likely to experience right ventricular (RV) failure (25% versus 5.6%; p = 0.01) and ventilator-dependent respiratory failure (VDRF) (28.6% versus 6.9%; p = 0.007). There was a significant difference when comparing the ARF and non-ARF groups for 30-day (17.9% versus 0%; p < 0.001), 180-day (28.6% versus 2.8%; p < 0.001), and 360-day mortality (28.6% versus 6.9%; p = 0.012). CONCLUSIONS: Patients in whom ARF developed after LVAD implantation had a higher rate of VDRF and RV failure and a longer length of stay (LOS). Postoperative ARF was associated with higher mortality at the 30-day, 180-day, and 360-day intervals. ARF after LVAD may be an early marker of poor outcome, particularly RV failure, and may be an opportunity for early intervention and rescue. PMID- 23103013 TI - The poxvirus C7L host range factor superfamily. AB - Host range factors, expressed by the poxvirus family, determine the host tropism of species, tissue, and cell specificity. C7L family members exist in the genomes of most sequenced mammalian poxviruses, suggesting an evolutionarily conserved effort adapting to the hosts. In general, C7L orthologs influence the host tropism in mammalian cell culture, and for some poxviruses it is essential for the complete viral life cycle in vitro and in vivo. The C7L family members lack obvious sequence homology with any other known viral or cellular proteins. Here we review recent findings from an evolutionary perspective and summarize recent progress that broadens our view on the role of C7L family members in mediating poxvirus host range and antagonizing the host defense system. PMID- 23103014 TI - In vivo and in vitro expression of the plasminogen activators and urokinase type plasminogen activator receptor (u-PAR) in the pig oviduct. AB - Plasminogen activator activities have previously been reported in oviductal fluid. At present the question was whether the source of these activities is molecules come from blood plasma or if these activators are synthesized by the oviduct. Gene expression and protein synthesis of urokinase type (u-PA) and tissue type (t-PA) occur in different regions of the pig oviduct. Their relative concentrations do not vary between the ampulla and isthmus regions and are similar throughout the estrous cycle. However, while relative amounts of t-PA mRNA were not different between the different stages of the estrous cycle, u-PA mRNA was greater after ovulation (P<0.05). Regarding the function of u-PA, its receptor (u-PAR) was distinguished by immunohistochemistry at the apical region of the epithelial cells and was more noticeable in the isthmus. Expression of u PA, t-PA, u-PAR and PAI-1 genes in primary oviductal epithelial cell cultures was studied under 17-beta-estradiol (100 pg/ml) and progesterone (100 ng/ml). u-PA mRNA increased in the presence of progesterone (P<0.05), but not by action of 17 beta-estradiol. t-PA, PAI-1 and u-PAR were similar when cultured with the hormones. These results suggest that u-PA could be regulated by progesterone at a transcriptional level, by the balance of their activity for PAI-1 or at the epithelial surface through the binding of u-PAR. In conclusion, plasminogen activation system components might cooperate in the oviductal lumen to control plasmin generation. PMID- 23103015 TI - Gene expression analysis of epidermolysis bullosa simplex with mottled pigmentation. PMID- 23103016 TI - Aromatase inhibitors for male infertility. AB - Some men with severely defective sperm production commonly have excess aromatase activity, reflected by low serum testosterone and relatively elevated estradiol levels. Aromatase inhibitors can increase endogenous testosterone production and serum testosterone levels. Treatment of infertile males with the aromatase inhibitors testolactone, anastrazole, and letrozole has been associated with increased sperm production and return of sperm to the ejaculate in men with non obstructive azoospermia. Use of the aromatase inhibitors anastrazole (1 mg/day) and letrozole (2.5 mg/day) represent off-label use of these agents for impaired spermatogenesis in men with excess aromatase activity (abnormal testosterone/estradiol [T/E] ratios). Side effects have rarely been reported. Randomized controlled trials are needed to define the magnitude of benefit of aromatase inhibitor treatment for infertile men. PMID- 23103017 TI - Dietary fish oil supplementation inhibits formation of endometriosis-associated adhesions in a chimeric mouse model. AB - OBJECTIVE: To examine whether dietary fish oil supplementation reduces development of spontaneous endometriosis-associated adhesions using an established model. DESIGN: Laboratory-based study. SETTING: Medical center research laboratory. PATIENT(S)/ANIMAL(S): Disease-free women of reproductive age and nude mice. INTERVENTION(S): Women were not provided any intervention. Mice were randomized to receive fish oil supplementation or control diet. MAIN OUTCOME MEASURE(S): Experimental endometriosis was established in mice via injection of human endometrial tissue within 16 hours of ovariectomy. Mice were provided standard or menhaden fish oil-supplemented diets for >= 2 weeks before initiation of experimental endometriosis and until killing them 1 week later. At necropsy, mice were examined for the presence and extent of adhesions and endometriotic like lesions. Tissues were excised and morphologically characterized. RESULT(S): Adhesions/lesions were reduced in mice provided with dietary fish oil compared with control animals. Leukocytes were more numerous within the adhesions/lesions of the mice maintained on the standard diet compared with animals provided with fish oil. As indicated by staining intensity, collagen deposition was greater at adhesion sites within control mice compared with fish oil-supplemented animals. CONCLUSION(S): Wound-healing associated with surgery created an inflammatory peritoneal microenvironment that promoted the development of both experimental endometriosis and adhesions in a murine model. Targeting excessive inflammation with fish oil may be an effective adjuvant therapy to reduce the development of postsurgical adhesions related to endometriosis. PMID- 23103018 TI - Subclinical hypothyroidism in young women with polycystic ovary syndrome: an analysis of clinical, hormonal, and metabolic parameters. AB - OBJECTIVE: To analyze the relationship between selected clinical and metabolic parameters in young women with polycystic ovary syndrome (PCOS) and normal thyroid function or subclinical hypothyroidism (SCH). DESIGN: A cross-sectional cohort study. SETTING: Tertiary care clinic. PATIENT(S): Women diagnosed with PCOS according to the Rotterdam criteria (n = 168). INTERVENTION(S): Clinical, hormonal, and metabolic parameters were evaluated. SCH was defined as TSH levels of 4.5-10 mIU/L. MAIN OUTCOME MEASURE(S): Separately, PCOS and SCH exert adverse effects on metabolic parameters; however, in conjunction their effect is unclear. This study evaluated whether SCH in women with PCOS affects clinical, hormonal, and metabolic parameters. RESULT(S): The mean age of the 168 women was 24 +/- 5.8 years. Mean body mass index was 33.4 +/- 8.2 kg/m(2). Thyroid function was normal in 149 women, and 19 had SCH. Only serum low-density lipoprotein cholesterol and PRL levels were significantly higher in the women with SCH (122.6 +/- 25.6 mg/dL and 17.7 +/- 7.7 ng/mL, respectively) compared with those with normal thyroid function (105.6 +/- 33 mg/dL and 14 +/- 10.3 ng/mL, respectively). CONCLUSION(S): In young women with PCOS, SCH is associated with higher low-density lipoprotein cholesterol levels, albeit with no changes in other lipid profile parameters, insulin resistance, or phenotypic manifestations. This study adds to current evidence supporting an association between PCOS and SCH. PMID- 23103019 TI - Some criticism about postoperative pain after adnexal surgery performed by single port versus standard laparoscopy. PMID- 23103020 TI - Raw and test-thaw semen parameters after cryopreservation among men with newly diagnosed cancer. AB - OBJECTIVE: To characterize sperm parameters from thawed semen samples of men with different cancers who cryopreserved semen before oncologic therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary academic medical center. PATIENT(S): 1,010 semen samples collected between 1994 to 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Mean total motile count (TMC), change in percentage motility and percentage survival (100 * [postthaw % motility/raw % motility]) for each cancer compared with data from samples of men without cancer (the "procreative management" group), and proportion of postthaw samples with TMC >5 * 10(6). RESULT(S): The procreative management group had the best raw and postthaw semen quality. The best raw and postthaw semen quality for cancer patients occurred in those with prostate cancer (TMC of 155.1 and 53.2 * 10(6), respectively) and the worst in those with leukemias. Lymphoid leukemias demonstrated the worst raw TMC (26.8 * 10(6)), but myeloid leukemias displayed the worst postthaw TMC (6.9 * 10(6)). The testicular cancer group was the only group with a statistically significantly lower chance of having TMC >5 * 10(6). CONCLUSION(S): Men with testicular cancer were most commonly referred for sperm cryopreservation and were the only group that was statistically significantly less likely to have TMC >5 * 10(6) on postthaw semen analysis. The most severe reduction in TMC was seen in the myeloid leukemia group, suggesting that these patients along with men with testis cancer and those with lymphoid leukemia should be counseled to provide increased numbers of specimens for fertility preservation. PMID- 23103021 TI - Peripheral blood stem cell transplants do not result in endometrial stromal engraftment. AB - OBJECTIVE: To determine whether peripheral blood stem cell transplant (PBSCT) result in engraftment of donor stem cells in the recipient uterus. DESIGN: Prospective clinical and laboratory research. SETTING: Translational medicine research hospital. PATIENT(S)/ANIMAL(S): Macaque and human bone marrow transplant recipients. INTERVENTION(S): Rhesus macaques received autologous transduced immunoselected cytokine-mobilized CD34+ cells after total body irradiation. Vector constructs expressed green fluorescent protein. In the human subjects, prior PBSCT subjects underwent endometrial biopsy and bone marrow aspiration. Macaque and human endometrial and bone marrow cells were isolated and cultured. Fluorescent microscopy, flow cytometry, and polymerase chain reaction (PCR) were used to evaluate for the presence of donor-derived cells. MAIN OUTCOME MEASURE(S): Presence of donor cells in recipient endometrium and bone marrow stroma. RESULT(S): The macaque endometrial cells did not exhibit evidence of green fluorescent protein labeling. Human endometrial cells were cultured and the absence of donor blood contamination was verified. The PCR evaluation of the human endometrial cells did not demonstrate evidence of donor short tandem repeats. CONCLUSION(S): The PBSCT did not result in engraftment of donor-derived cells in the endometrium. PMID- 23103022 TI - Reply of the authors. PMID- 23103023 TI - How next-generation sequencing is transforming complex disease genetics. AB - Progress in understanding the genetics of human disease is closely tied to technological developments in DNA sequencing. Recently, next-generation technology has transformed the scale of sequencing; compared to the methods used in the Human Genome Project, modern sequencers are 50000-fold faster. Complex disease genetics presents an immediate opportunity to use this technology to move from approaches using only partial information (linkage and genome-wide association studies, GWAS) to complete analysis of the relationship between genomic variation and phenotype. We first describe sequence-based improvements to existing study designs, followed by prioritization of both samples and genomic regions to be sequenced, and then address the ultimate goal of analyzing thousands of whole-genome sequences. Finally, we discuss how the same technology will also fundamentally change the way we understand the biological mechanisms underlying disease associations discovered through sequencing. PMID- 23103024 TI - Vagal projections to the pylorus in the domestic pig (Sus scrofa domestica). AB - The goal of the present study was to examine the precise localization of the brainstem motor and primary sensory (nodose ganglion) vagal perikarya supplying the pylorus in the domestic pig. Using the Fast Blue retrograde tracing technique it has been established that all the vagal motor neurons projecting to the pylorus (about 337 +/- 59 cells per animal) were localized bilaterally in the dorsal motor nucleus of the vagus nerve (DMX, 171 - left; 167 - right) and all other regions of the porcine brainstem were devoid of labeled neurons. The vagal perikarya supplying the porcine pylorus were dispersed throughout the whole rostro-caudal extent of the DMX and no somatotopic organization of these neurons was observed. The labeled neurons occurred individually or in groups up to five cell bodies per nuclear transverse cross section area (in the middle part of the nucleus). An immunocytochemical staining procedure disclosed that all Fast Blue labeled motor neurons were choline acetyltransferase (ChAT) immunoreactive, however some differences in immunofluorescence intensity occurred. The primary sensory vagal neurons were observed within the left (215+/-37 cells/animal) and right (148+/-21 cells/animal) nodose ganglion. The traced neurons were dispersed throughout the ganglia and no characteristic arrangement of these neurons was observed. The present experiment precisely indicates the sources of origin of the vagal motor and primary sensory neurons supplying the pyloric region in the pig, the animal of an increasing significance in biomedical research. PMID- 23103025 TI - Variations in the anatomical dimensions of the mandibular ramus and the presence of third molars: its effect on the sagittal split ramus osteotomy. AB - The authors undertook a prospective study to evaluate the influence that the anatomical dimensions of the ramus of the mandible and the presence of lower third molar teeth may have on the sagittal split ramus osteotomy. The anatomical dimensions measured included the width of the anterior mandibular ramus, the height of the corpus posterior to the second mandibular molar and the antero posterior anatomical position of the lingual. The influence that these dimensions of the mandible may have on the successful splitting of the mandibular ramus was investigated. The effect that the presence of wisdom teeth had on the difficulty of the procedure was also investigated. This study found that, unlike the presence of third molars, there was no single anatomical measurement that contributed to the level of difficulty of the sagittal split osteotomy. For descriptive purposes the authors proposes a classification of the four typical patterns of unfavourable splits. PMID- 23103026 TI - Is meconium stained amniotic fluid related to occult myocardial injury in term low risk pregnancies? AB - AIM: The present study aimed to compare Troponin T (Tp T) levels of infants born with meconium stained amniotic fluid (MSAF) to those with clear amniotic fluid. STUDY DESIGN: Case-control study SUBJECTS: Thirty-five women who had delivery complicated by MSAF between 37 and 41weeks of gestation were defined as the study group and women with healthy uncomplicated pregnancies with clear amniotic fluid who were matched for age, parity, and gestational age were defined as the control group. OUTCOME MEASURES: Cord blood Tp T level, gas analysis and neonatal outcomes were compared between groups. RESULTS: Tp T levels of the study and control groups were 0.026+/-0.013ng/ml and 0.031+/-0.016ng/ml, respectively. The difference was not statistically significant (p=0.132). On the other hand, the study group had a statistically lower HCO(3) level (21.80 vs 23.60mmol/l ) and higher rate of base deficit (4.85 vs 3.25mmol/l) than the control group. CONCLUSION: The presence of meconium during labor is not related to occult myocardial injury in low-risk term pregnancies. PMID- 23103027 TI - The twists and turns of neonatal oxygen therapy. AB - Although supplemental oxygen is one of the commonest treatments in neonatal medicine, the evidence base for deciding which newborns need it, and what is the appropriate dose remains weak. Clinical research in this area is difficult because it requires clinicians to depart from established practice and, in the case of oxygen therapy, the stakes seem far higher to them than for other investigational treatments. Consequently, beyond the knowledge that extreme hyperoxia and hypoxia are harmful, the middle ground remains uncertain for both preterm and term infants. PMID- 23103028 TI - Benthic infauna variability in relation to environmental factors and organic pollutants in tropical coastal lagoons from the northern Yucatan Peninsula. AB - We examine the abundance and species composition variability of benthic infauna from tropical coastal lagoons in relation to environmental factors and organic pollutants. Sediment samples were collected at 40 sites in four lagoons in the northern Yucatan Peninsula. A total of 7985 individuals belonging to 173 species were sampled. While the eastern lagoons were dominated by polychaetes, the western ones were dominated by crustaceans. Overall, polychaetes had the highest abundance (48%), followed by crustaceans (42%). According to canonical correspondence analysis, species attributes were correlated with water salinity, pH and temperature, but also with sediment pentachlorobenzene, trichlorobenzene, and low molecular weight polycyclic aromatic hydrocarbons. Some pollutants exceeded sediment quality guidelines, representing a potential environmental risk to benthic infauna. Together, environmental factors and pollutants explained 52% of the variance in abundance and species composition among sites. PMID- 23103029 TI - Evaluation of the ecotoxicity and biological efficacy of ship's ballast water treatment based on hydroxyl radicals technique. AB - Ballast water has been identified as one of the key pathways for the movement of species between different ecosystems. The purpose of this study is to evaluate the biological efficacy and the potential toxicological impact of a proposed ballast water treatment using hydroxyl radicals as the main active substances. Living biomass of organisms kept in treated water for 2 days met the requirement stated in the International Maritime Organization (IMO) Ballast Water Convention (Regulation D-2), and no re-growth was observed over a period of 5 days. Aquatic toxicity tests of three trophic levels for the treated ballast water were performed. The results indicated that the toxicological risk of the discharge water to the receiving environment was not significant. PMID- 23103030 TI - A pilot study to assess the effectiveness of orthotic insoles on the reduction of plantar soft tissue strain. AB - BACKGROUND: Plantar ulcers pose a frequent serious complication in the neuropathic foot. Previous studies suggested that ulcer initiation occurs within the plantar soft tissue rather than on the plantar surface. This study investigated the effectiveness of different shaped silicone insoles on the reduction of both plantar soft tissue strain and pressure. The authors have found no previous experimental studies on the effectiveness of insole shape on reducing plantar soft tissue strain during standing. METHODS: A custom molded silicone insole which allowed passage of ultrasound to the plantar surface of the foot was prototyped for this study. Soft tissue strain was computed from soft tissue thickness measured using ultrasound in five conditions: unloaded, barefoot, wearing a prefabricated silicone insole, wearing the custom molded silicone insole alone then with a metatarsal pad. Plantar pressure was measured for the same conditions. FINDINGS: The custom molded insole was found to significantly reduce soft tissue strain and plantar pressure relative to both the barefoot condition and the prefabricated insole under the second and third metatarsal heads. The metatarsal pad was found to significantly reduce soft tissue strain but not significantly affect plantar pressure. INTERPRETATION: A custom molded silicone insole can effectively reduce both soft tissue strain and plantar pressure and is thus preferable to a prefabricated insole. It is suggested that quantifying the reduction of soft tissue strain is an essential design requirement for orthotic insoles since plantar pressure may not be a sufficient indicator of the effectiveness of an insole in preventing ulcer initiation. PMID- 23103031 TI - A psychophysical account of patient non-adherence to medical prescriptions. The case of insulin dose adjustment. AB - AIM: Diabetic patients often do not adjust their insulin doses using the algorithms that they have been taught. While this behavior may intuitively have a number of causes, such as the complexity of the decision or the fear of hypoglycaemia, we propose in this article a more general, "psychophysical", explanation based on behavioral economics concepts used to describe decisions made under uncertainty and risk. The concepts discussed herein may not be familiar to clinicians, who will find here an introduction to theories that may be helpful in understanding some aspects of non-adherence to medical prescriptions. RESULTS: 1) The Prospect Theory of Kahneman and Tversky proposes that choices made in the context of risk are subject to loss aversion. 2) Decisions under uncertainty use mental short cuts called "heuristics", which can lead to biases; for instance, overestimating the probability of the risk. 3) To understand the very concept of risk, emotions must be considered with a special focus on anticipated regret. 4) Finally, selection difficulty is an important determinant of the preference for the status quo. CONCLUSION: These concepts may be relevant for understanding a preference for the status quo in decisions made in a context of uncertainty and risk, such as insulin dose adjustment. We suggest that these mental mechanisms may also be involved in other aspects of patients' non-adherence. As other common human behaviors, non-adherence may actually often be a consequence of biases resulting from our ways of thinking, being both cognitive and emotional, and, according to Kahneman, more often "fast" than "slow". Empirical studies are needed to support this hypothesis. PMID- 23103033 TI - Prospective, Randomized, Multicenter Evaluation of a Polyethylene Terephthalate Micronet Mesh-Covered Stent (MGuard) in ST-Segment Elevation Myocardial Infarction: The MASTER Trial. AB - OBJECTIVES: This study sought to evaluate the potential utility of a novel polyethylene terephthalate micronet mesh-covered stent (MGuard) in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Suboptimal myocardial reperfusion after PCI in STEMI is common and results in increased infarct size and mortality. The MGuard is a novel thin-strut metal stent with a polyethylene terephthalate micronet covering designed to trap and exclude thrombus and friable atheromatous debris to prevent distal embolization. METHODS: A total of 433 patients with STEMI presenting within 12 h of symptom onset undergoing PCI were randomized at 50 sites in 9 countries to the MGuard (n = 217) or commercially available bare metal or drug-eluting stents (n = 216). The primary endpoint was the rate of complete (>=70%) ST-segment resolution measured 60 to 90 min post-procedure. RESULTS: Baseline characteristics were well matched between the groups. The primary endpoint of post-procedure complete ST-segment resolution was significantly improved in patients randomized to the MGuard stent compared with control patients (57.8% vs. 44.7%; difference: 13.2%; 95% confidence interval: 3.1% to 23.3%; p = 0.008). By core laboratory analysis, the MGuard stent compared with control stents also resulted in superior rates of Thrombolysis In Myocardial Infarction 3 flow (91.7% vs. 82.9%, p = 0.006) with comparable rates of myocardial blush grade 2 or 3 (83.9% vs. 84.7%, p = 0.81). Mortality (0% vs. 1.9%, p = 0.06) and major adverse cardiac events (1.8% vs. 2.3%, p = 0.75) at 30 days were not significantly different between patients randomized to the MGuard stent and control stent, respectively. CONCLUSIONS: Among patients with acute STEMI undergoing emergent PCI, the MGuard micronet mesh-covered stent compared with conventional metal stents resulted in superior rates of epicardial coronary flow and complete ST-segment resolution. A larger randomized trial is warranted to determine whether these benefits result in reduced infarct size and/or improved clinical outcomes. (Safety and Efficacy Study of MGuard Stent After a Heart Attack [MASTER]; NCT01368471). PMID- 23103034 TI - Chronic air pollution exposure and endothelial dysfunction: what you can't see- can harm you. PMID- 23103036 TI - Effects of radial versus femoral artery access in patients with acute coronary syndromes with or without ST-segment elevation. AB - OBJECTIVES: The purpose of this study was to determine the consistency of the effects of radial artery access in patients with ST-segment elevation myocardial infarction (STEMI) and in those with non-ST-segment elevation acute coronary syndrome (NSTEACS). BACKGROUND: The safety associated with radial access may translate into mortality benefit in higher-risk patients, such as those with STEMI. METHODS: We compared efficacy and bleeding outcomes in patients randomized to radial versus femoral access in RIVAL (RadIal Vs femorAL access for coronary intervention trial) (N = 7,021) separately in those with STEMI (n = 1,958) and NSTEACS (n = 5,063). Interaction tests between access site and acute coronary syndrome type were performed. RESULTS: Baseline characteristics were well matched between radial and femoral groups. There were significant interactions for the primary outcome of death/myocardial infarction/stroke/non-coronary artery bypass graft-related major bleeding (p = 0.025), the secondary outcome of death/myocardial infarction/stroke (p = 0.011) and mortality (p = 0.001). In STEMI patients, radial access reduced the primary outcome compared with femoral access (3.1% vs. 5.2%; hazard ratio [HR]: 0.60; p = 0.026). For NSTEACS, the rates were 3.8% and 3.5%, respectively (p = 0.49). In STEMI patients, death/myocardial infarction/stroke were also reduced with radial access (2.7% vs. 4.6%; HR 0.59; p = 0.031), as was all-cause mortality (1.3% vs. 3.2%; HR: 0.39; p = 0.006), with no difference in NSTEACS patients. Operator radial experience was greater in STEMI versus NSTEACS patients (400 vs. 326 cases/year, p < 0.0001). In primary PCI, mortality was reduced with radial access (1.4% vs. 3.1%; HR: 0.46; p = 0.041). CONCLUSIONS: In patients with STEMI, radial artery access reduced the primary outcome and mortality. No such benefit was observed in patients with NSTEACS. The radial approach may be preferred in STEMI patients when the operator has considerable radial experience. (A Trial of Trans-radial Versus Trans-femoral Percutaneous Coronary Intervention (PCI) Access Site Approach in Patients With Unstable Angina or Myocardial Infarction Managed With an Invasive Strategy [RIVAL]; NCT01014273). PMID- 23103037 TI - The year in non-ST-segment elevation acute coronary syndrome. PMID- 23103035 TI - Vascular responses to long- and short-term exposure to fine particulate matter: MESA Air (Multi-Ethnic Study of Atherosclerosis and Air Pollution). AB - OBJECTIVES: This study evaluated the association of long- and short-term air pollutant exposures with flow-mediated dilation (FMD) and baseline arterial diameter (BAD) of the brachial artery using ultrasound in a large multicity cohort. BACKGROUND: Exposures to ambient air pollution, especially long-term exposure to particulate matter <2.5 MUm in aerodynamic diameter (PM(2.5)), are linked with cardiovascular mortality. Short-term exposure to PM(2.5) has been associated with decreased FMD and vasoconstriction, suggesting that adverse effects of PM(2.5) may involve endothelial dysfunction. However, long-term effects of PM(2.5) on endothelial dysfunction have not been investigated. METHODS: FMD and BAD were measured by brachial artery ultrasound at the initial examination of the Multi-Ethnic Study of Atherosclerosis. Long-term PM(2.5) concentrations were estimated for the year 2000 at each participant's residence (n = 3,040) using a spatio-temporal model informed by cohort-specific monitoring. Short-term PM(2.5) concentrations were based on daily central-site monitoring in each of the 6 cities. RESULTS: An interquartile increase in long-term PM(2.5) concentration (3 MUg/m(3)) was associated with a 0.3% decrease in FMD (95% confidence interval [CI] of difference: -0.6 to -0.03; p = 0.03), adjusting for demographic characteristics, traditional risk factors, sonographers, and 1/BAD. Women, nonsmokers, younger participants, and those with hypertension seemed to show a greater association of PM(2.5) with FMD. FMD was not significantly associated with short-term variation in PM(2.5) (-0.1% per 12 MUg/m(3) daily increase [95% CI: -0.2 to 0.04] on the day before examination). CONCLUSIONS: Long term PM(2.5) exposure was significantly associated with decreased endothelial function according to brachial ultrasound results. These findings may elucidate an important pathway linking air pollution and cardiovascular mortality. PMID- 23103038 TI - Improving the odds in the evaluation of chest pain. PMID- 23103039 TI - Prognostic value of multidetector coronary computed tomography angiography in relation to exercise electrocardiogram in patients with suspected coronary artery disease. AB - OBJECTIVES: This study was designed to determine the prognostic value of multidetector coronary computed tomography angiography (CTA) in relation to exercise electrocardiography (XECG) findings. BACKGROUND: The prognostic usefulness of coronary CTA findings of coronary artery disease in relation to XECG findings has not been explored systematically. METHODS: Patients with suspected coronary artery disease who had undergone both coronary CTA and XECG (<90 days between tests) from 2003 through 2009 were enrolled retrospectively. Coronary CTA results were classified according to the severity of maximal stenosis (normal, mild: <40% of luminal stenosis, moderate: 40% to 69%, severe: >=70%), XECG results were categorized as positive and negative, and Duke XECG score was calculated. Clinical follow-up data were collected for major adverse cardiac events (MACE): cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, and revascularization after 90 days from index coronary CTA. C-statistics were calculated to compare discriminatory values of each test. RESULTS: Among the 2,977 (58 +/- 10 years) study patients, 12% demonstrated positive XECG results. By coronary CTA, patients were categorized as normal (56%) or having mild (26%), moderate (13%), or severe (5%) disease. During a median follow-up of 3.3 years (interquartile range: 2.3 to 4.6), 97 MACE were observed and the 5-year cumulative event rate was 3.6% (95% confidence interval: 3.0 to 4.3). Although both XECG (C-statistic: 0.790) and coronary CTA (C statistic: 0.908) improved risk stratification beyond clinical risk factors (C statistic: 0.746, p < 0.05 for all), XECG in addition to coronary CTA (C statistic: 0.907) did not provide better discrimination than coronary CTA alone (p = 0.389). In subgroup analyses, coronary CTA stratified risk of MACE in groups with both positive and negative XECG results (all p < 0.001 for trend). However, positive XECG results predicted risk of MACE on coronary CTA only in the moderate stenosis group (hazard ratio: 2.58, 95% confidence interval: 1.29 to 5.19, p = 0.008) and severe stenosis group (hazard ratio: 2.28, 95% confidence interval: 1.19 to 4.38, p = 0.013). CONCLUSIONS: In patients with suspected coronary artery disease, coronary CTA discriminates future risk of MACE in patients independent of XECG results. Compared with coronary CTA, XECG has an additive prognostic value only in patients with moderate to severe stenosis on coronary CTA. PMID- 23103040 TI - Temporal trends and geographic variation of lower-extremity amputation in patients with peripheral artery disease: results from U.S. Medicare 2000-2008. AB - OBJECTIVES: This study sought to characterize temporal trends, patient-specific factors, and geographic variation associated with amputation in patients with lower-extremity peripheral artery disease (LE PAD) during the study period. BACKGROUND: Amputation represents the end-stage failure for those with LE PAD, and little is known about the rates and geographic variation in the use of LE amputation. METHODS: By using data from the Centers for Medicare & Medicaid Services (CMS) from January 1, 2000, to December 31, 2008, we examined national patterns of LE amputation among patients age 65 years or more with PAD. Multivariable logistic regression was used to adjust regional results for other patient demographic and clinical factors. RESULTS: Among 2,730,742 older patients with identified PAD, the overall rate of LE amputation decreased from 7,258 per 100,000 patients with PAD to 5,790 per 100,000 (p < 0.001 for trend). Male sex, black race, diabetes mellitus, and renal disease were all independent predictors of LE amputation. The adjusted odds ratio of LE amputation per year between 2000 and 2008 was 0.95 (95% CI: 0.95-0.95, p < 0.001). CONCLUSIONS: From 2000 to 2008, LE amputation rates decreased significantly among patients with PAD. However, there remains significant patient and geographic variation in amputation rates across the United States. PMID- 23103041 TI - Intravenous iron alone is equally effective with the combination of iron and erythropoietin for the treatment of iron-deficiency anemia in advanced heart failure. PMID- 23103042 TI - Atrioventricular valve annular remodeling with a bioabsorbable ring in young children. PMID- 23103043 TI - Increased arterial wave reflection magnitude: a novel form of stage B heart failure? PMID- 23103044 TI - Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). AB - OBJECTIVES: This study sought to assess the relationship between central pressure profiles and cardiovascular events (CVEs) in a large community-based sample. BACKGROUND: Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear. METHODS: Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 5,960 participants in the Multiethnic Study of Atherosclerosis. The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM = [Reflected/Forward wave amplitude] * 100), augmentation index ([Second/First systolic peak] * 100) and pulse pressure amplification ([Radial/aortic pulse pressure] * 100) were assessed as predictors of CVEs and congestive heart failure (CHF) during a median follow up of 7.61 years. RESULTS: After adjustment for established risk factors, aortic AIx independently predicted hard CVEs (hazard ratio [HR] per 10% increase: 1.08; 95% confidence interval [CI]: 1.01 to 1.14; p = 0.016), whereas PPA independently predicted all CVEs (HR per 10% increase: 0.82; 95% CI: 0.70 to 0.96; p = 0.012). RM was independently predictive of all CVEs (HR per 10% increase: 1.34; 95% CI: 1.08 to 1.67; p = 0.009) and hard CVEs (HR per 10% increase: 1.46; 95% CI: 1.12 to 1.90; p = 0.006) and was strongly predictive of new-onset CHF (HR per 10% increase: 2.69; 95% CI: 1.79 to 4.04; p < 0.0001), comparing favorably to other risk factors for CHF as per various measures of model performance, reclassification, and discrimination. In a fully adjusted model, compared to nonhypertensive subjects with low RM, the HRs (95% CI) for hypertensive subjects with low RM, nonhypertensive subjects with high RM, and hypertensive subjects with high RM were 1.81 (0.85 to 3.86), 2.16 (1.07 to 5.01), and 3.98 (1.96 to 8.05), respectively. CONCLUSIONS: Arterial wave reflections represent a novel strong risk factor for CHF in the general population. PMID- 23103045 TI - New unipolar electrogram criteria to identify irreversibility of nonischemic left ventricular cardiomyopathy. AB - OBJECTIVES: This study sought to assess the value of left ventricular (LV) endocardial unipolar electroanatomical mapping (EAM) in identifying irreversibility of LV systolic dysfunction in patients with left ventricular nonischemic cardiomyopathy (LVCM). BACKGROUND: Identifying irreversibility of LVCM would be helpful but cannot be reliably accomplished by bipolar EAM or cardiac magnetic resonance identification of macroscopic scar. METHODS: Detailed endocardial LV EAM was performed in 3 groups: 1) 24 patients with irreversible LVCM (I-LVCM) but with no or minimal macroscopic scar (<15% LV surface) evidenced on bipolar voltage EAM and/or cardiac magnetic resonance; 2) 14 patients with reversible ventricular premature depolarization-mediated LVCM (R-LVCM); and 3) 17 patients with structurally normal hearts. LV endocardial unipolar electrogram amplitude and area of unipolar amplitude abnormality were defined after excluding macroscopic scar. RESULTS: Unipolar amplitude differed in the 3 groups: median of 7.6 (interquartile range [IQR]: 5.5 to 9.7) mV in I-LVCM group, 13.2 (IQR: 10.4 to 16.2) mV in R-LVCM group, and 16.3 (IQR: 13.6 to 19.8) mV in structurally normal hearts group (p < 0.001). Areas of unipolar abnormality represented a large proportion of total LV surface in I-LVCM, 64.7% (IQR: 47.5% to 75.9%) compared with R-LVCM, 5.2% (IQR: 0.0% to 19.1%) and structurally normal hearts, 0.1% (IQR: 0.0% to 0.9%), groups (p < 0.001). A unipolar abnormality area cutoff of 32% of total LV surface was 96% sensitive and 100% specific in identifying irreversible cardiomyopathy among patients with LV dysfunction (I-LVCM and R LVCM), p < 0.001. CONCLUSIONS: Detailed unipolar voltage mapping can identify irreversible myocardial dysfunction consistent with fibrosis, even in the absence of bipolar EAM or cardiac magnetic resonance abnormalities, and may serve as valuable prognostic tool in patients presenting with LVCM to facilitate clinical decision making. PMID- 23103046 TI - Hospital-acquired symptomatic urinary tract infection in patients admitted to an academic stroke center affects discharge disposition. AB - OBJECTIVE: To test the role of hospital-acquired symptomatic urinary tract infection (SUTI) as an independent predictor of discharge disposition in the acute stroke patient. STUDY DESIGN: A retrospective study of data collected from a stroke registry service. The registry is maintained by the Specialized Programs of Translational Research in Acute Stroke Data Core. The Specialized Programs of Translational Research in Acute Stroke is a national network of 8 centers that perform early phase clinical projects, share data, and promote new approaches to therapy for acute stroke. SETTING: A single university-based hospital. PARTICIPANTS: We performed a data query of the fields of interest from our university-based stroke registry, a collection of 200 variables collected prospectively for each patient admitted to the stroke service between July 2004 and October 2009, with discharge disposition of home, inpatient rehabilitation, skilled nursing facility, or long-term acute care. MAIN OUTCOME MEASURES: Baseline demographics, including age, gender, ethnicity, and National Institutes of Health Stroke Scale (NIHSS) score, were collected. Cerebrovascular disease risk factors were used for independent risk assessment. Interaction terms were created between SUTI and known covariates, such as age, NIHSS, serum creatinine level, history of stroke, and urinary incontinence. Because patients who share discharge disposition tend to have similar length of hospitalization, we analyzed the effect of SUTI on the median length of stay for a correlation. Days in the intensive care unit and death were used to evaluate morbidity and mortality. By using multivariate logistic regression, the data were analyzed for differences in poststroke disposition among patients with SUTI. RESULTS: Of 4971 patients admitted to the University of Texas at Houston Stroke Service, 2089 were discharged to home, 1029 to inpatient rehabilitation, 659 to a skilled nursing facility, and 226 to a long-term acute care facility. Patients with an SUTI were 57% less likely to be discharged home compared with the other levels of care (P < .0001; odds ratio 0.430 [95% confidence interval 0.303-0.609]). When considering inpatient rehabilitation versus skilled nursing facility, patients with SUTI were 38% less likely to be discharged to inpatient rehabilitation (P < .0058; odds ratio 0.626 [95% confidence interval, 0.449-0.873]). We performed interaction analyses for SUTI and age, NIHSS, urinary incontinence, serum creatinine level, and history of stroke. We noted an interaction between SUTI and NIHSS for discharge disposition to a skilled nursing facility versus a long-term acute care facility. For patients with SUTI, a 1-unit increase in NIHSS results in a 10.6% increase in the likelihood of stroke rehabilitation in a long-term acute care facility compared with 5.6% increased likelihood for patients without SUTI (P = .0370). CONCLUSIONS: Acute stroke patients with hospital-acquired SUTI are less likely to be discharged home. In our analysis, if poststroke care is necessary, then patients with SUTI are more likely to receive inpatient stroke rehabilitation at the level of care suggestive of lower functional status. For every point increase in NIHSS, stroke patients with SUTI are 10.6% more likely to require continued rehabilitation care in a long-term acute care facility versus a skilled nursing facility compared with 5.6% for patients without SUTI. The combination of premorbid urinary incontinence and urinary tract infection has no additional impact on discharge disposition. This study is limited by its retrospective nature and the undetermined role of psychosocial factors related to discharge. Prospective studies are warranted on the efficacy of early catheter discontinuation, identification of new-onset urinary incontinence, use of genitourinary barriers, and catheter care every shift as variables that can decrease the risk of infection. The information obtained from prospective studies will have an impact on resource use that is of prime importance in the current health care climate. PMID- 23103047 TI - Decline in macrolide-resistant Streptococcus pyogenes isolates from French children. AB - We studied the macrolide resistance and serotypes of 585 group A streptococcus (GAS) isolates collected from French children with pharyngitis. Nineteen isolates (3.2%) were erythromycin-resistant and harbored the following resistance genes: 31.6% mef(A), 15.8% erm(A), and 52.6% erm(B). The 19 isolates included 7 different emm types (4, 1, 11, 2, 28, 12, and 77) and 7 corresponding multilocus sequence types. The current fall in macrolide consumption has led to a very low rate of GAS macrolide resistance. PMID- 23103048 TI - Cytotoxic effects of polycarbonate-based orthodontic brackets by activation of mitochondrial apoptotic mechanisms. AB - OBJECTIVES: The aim of the study was to evaluate the biological effects of water eluents from polycarbonate based esthetic orthodontic brackets. METHODS: The composite polycarbonate brackets tested were Silkon Plus (SL, fiber-glass reinforced), Elan ME (EL, ceramic particle-reinforced) and Elegance (EG, fiber glass-reinforced). An unfilled polyoxymethylene bracket (Brilliant, BR) was used as control. The brackets' composition was analyzed by ATR-FTIR spectrometry. The cytotoxicity and estrogenicity of the eluents obtained after 3 months storage of the brackets in water (37 degrees C) were investigated in murine fibroblasts (NIH 3T3), breast (MCF-7) and cervical cancer (CCl-2/Hela) cell lines. RESULTS: SL and EG were based on aromatic-polycarbonate matrix, whereas EL consisted of an aromatic polycarbonate-polyethylene terepthalate copolymer. A significant induction of cell death and a concurrent decrease in cell proliferation was noted in the EG eluent-treated cells. Moreover, EG eluent significantly reduced the levels of the estrogen signaling associated gene pS2, specifically in MCF7 cells, suggesting that cell death induced by this material is associated with downregulation of estrogen signaling pathways. Even though oxidative stress mechanisms were equally activated by all eluents, the EG eluents induced expression of apoptosis inducing factor (AIF) and reduced Bcl-xL protein levels. SIGNIFICANCE: Some polycarbonate-based composite brackets when exposed to water release substances than activate mitochondrial apoptosis. PMID- 23103049 TI - Online prediction model based on the SVD-KPCA method. AB - This paper proposes a new method for online identification of a nonlinear system modelled on Reproducing Kernel Hilbert Space (RKHS). The proposed SVD-KPCA method uses the Singular Value Decomposition (SVD) technique to update the principal components. Then we use the Reduced Kernel Principal Component Analysis (RKPCA) to approach the principal components which represent the observations selected by the KPCA method. PMID- 23103050 TI - Thermographic visualization of leaf response in cucumber plants infected with the soil-borne pathogen Fusarium oxysporum f. sp. cucumerinum. AB - Infection with the soil-borne pathogen Fusarium oxysporum f. sp. cucumerinum (FOC), which causes Fusarium wilt of cucumber plants, might result in changes in plant transpiration and water status within leaves. To monitor leaf response in cucumber infected with FOC, digital infrared thermography (DIT) was employed to detect changes in leaf temperature. During the early stages of FOC infection, stomata closure was induced by ABA in leaves, resulting in a decreased transpiration rate and increased leaf temperature. Subsequently, cell death occurred, accompanied by water loss, resulting in a little decrease in leaf temperature. A negative correlation between transpiration rate and leaf temperature was existed. But leaf temperature exhibited a special pattern with different disease severity on light-dark cycle. Lightly wilted leaves had a higher temperature in light and a lower temperature in dark than did in healthy leaves. We identified that the water loss from wilted leaves was regulated not by stomata but rather by cells damage caused by pathogen infection. Finally, water balance in infected plants became disordered and dead tissue was dehydrated, so leaf temperature increased again. These data suggest that membrane injury caused by FOC infection induces uncontrolled water loss from damaged cells and an imbalance in leaf water status, and ultimately accelerate plant wilting. Combining detection of the temperature response of leaves to light-dark conditions, DIT not only permits noninvasive detection and indirect visualization of the development of the soil-borne disease Fusarium wilt, but also demonstrates certain internal metabolic processes correlative with water status. PMID- 23103051 TI - Neandertal diet, voracious bacteria and the hunger for knowledge: reply to Tomczyk's comments. PMID- 23103052 TI - Spectrum of gluten-sensitive enteropathy in patients with dysmotility-like dyspepsia. AB - BACKGROUND: Dysmotility-like dyspepsia symptoms are frequent in patients with gluten-sensitive enteropathy (GSE). Current data suggest that patients with mild enteropathy may be present with gluten-sensitive symptoms and complications. AIM: To investigate the prevalence of GSE, including mild enteropathy, in patients with dysmotility-like dyspepsia symptoms. METHODS: We retrospectively studied 142 patients who presented dysmotility-like dyspepsia symptoms and normal upper gastrointestinal endoscopy. Endoscopic duodenal biopsies were taken and processed using hematoxylin-eosin staining and CD3 immunophenotyping. In patients with enteropathy (number of intraepithelial lymphocytes greater than 25 per 100 enterocytes) we also performed coeliac serology (anti-tissue transglutaminase IgA) and HLA-DQ2/DQ8 genotyping. A gluten-free diet was offered if one of these markers was positive. The final GSE diagnosis was established based on clinical and histopathological response to the gluten-free diet after 18 months of follow up. RESULTS: Fifty-one patients (35.9%) had enteropathy; 4 (2.8%) Marsh type 3b, 24 (16.9%) Marsh type 3a, 3 (2.1%) Marsh type 2, and 20 (14.1%) Marsh type 1. A positive serology result was extremely low (6.7%) in mild enteropathy (Marsh type 1-3a) in contrast with Marsh type 3b patients (50%). Most patients with enteropathy had positive HLA DQ2 or -DQ8 genotyping (84.1%). Out of the 37 patients who started a gluten-free diet, 34 (91.9%) improved their symptoms, and 28 of 32 (87.5%) had a histopathological or serological response. A final GSE diagnosis was established in 28 of the 142 patients (19.7%). CONCLUSION: Gluten sensitive enteropathy can be a frequent and unsuspected cause of dysmotility-like dyspepsia. PMID- 23103053 TI - Global transcriptome analysis of Atlantic cod (Gadus morhua) liver after in vivo methylmercury exposure suggests effects on energy metabolism pathways. AB - Methylmercury (MeHg) is a widely distributed contaminant polluting many aquatic environments, with health risks to humans exposed mainly through consumption of seafood. The mechanisms of toxicity of MeHg are not completely understood. In order to map the range of molecular targets and gain better insights into the mechanisms of toxicity, we prepared Atlantic cod (Gadus morhua) 135k oligonucleotide arrays and performed global analysis of transcriptional changes in the liver of fish treated with MeHg (0.5 and 2 mg/kg of body weight) for 14 days. Inferring from the observed transcriptional changes, the main pathways significantly affected by the treatment were energy metabolism, oxidative stress response, immune response and cytoskeleton remodeling. Consistent with known effects of MeHg, many transcripts for genes in oxidative stress pathways such as glutathione metabolism and Nrf2 regulation of oxidative stress response were differentially regulated. Among the differentially regulated genes, there were disproportionate numbers of genes coding for enzymes involved in metabolism of amino acids, fatty acids and glucose. In particular, many genes coding for enzymes of fatty acid beta-oxidation were up-regulated. The coordinated effects observed on many transcripts coding for enzymes of energy pathways may suggest disruption of nutrient metabolism by MeHg. Many transcripts for genes coding for enzymes in the synthetic pathways of sulphur containing amino acids were also up regulated, suggesting adaptive responses to MeHg toxicity. By this toxicogenomics approach, we were also able to identify many potential biomarker candidate genes for monitoring environmental MeHg pollution. These results based on changes on transcript levels, however, need to be confirmed by other methods such as proteomics. PMID- 23103055 TI - Subtherapeutic itraconazole and voriconazole levels in children with cystic fibrosis. PMID- 23103054 TI - Regulation of pluripotency and cellular reprogramming by the ubiquitin-proteasome system. AB - Although transcriptional regulation of stem cell pluripotency and differentiation has been extensively studied, only a small number of studies have addressed the roles for posttranslational modifications in these processes. A key mechanism of posttranslational modification is ubiquitination by the ubiquitin-proteasome system (UPS). Here, using shotgun proteomics, we map the ubiquitinated protein landscape during embryonic stem cell (ESC) differentiation and induced pluripotency. Moreover, using UPS-targeted RNAi screens, we identify additional regulators of pluripotency and differentiation. We focus on two of these proteins, the deubiquitinating enzyme Psmd14 and the E3 ligase Fbxw7, and characterize their importance in ESC pluripotency and cellular reprogramming. This global characterization of the UPS as a key regulator of stem cell pluripotency opens the way for future studies that focus on specific UPS enzymes or ubiquitinated substrates. PMID- 23103057 TI - Chronic administration of the Y2 receptor antagonist, JNJ-31020028, induced anti depressant like-behaviors in olfactory bulbectomized rat. AB - Recent studies from our groups have shown that BIIE0246, a Y2 receptor antagonist, has antidepressant effect in olfactory bulbectomized (OBX) rat. However, its complex structure and high molecular weight limit its usefulness as an in vivo pharmacological tool. Alternatively, the novel and brain penetrant Y2 receptor antagonist, JNJ-31020028 is a useful tool to investigate the in vivo function of the Y2 receptor. In the present study, we evaluated the effect of chronic intracerebroventricular (icv) administration of JNJ-31020028 in a battery of behavioral tests in an animal model that mimics several deficits observed in the human depression, the OBX rat. Chronic administration of JNJ-31020028 induced a decrease in immobility time in the forced swim test in OBX while had no effect in control animals. Additionally, it decreased number of grooming events in OBX animals, but had no effects on some other behavioral deficits observed such as rearing and hyperlocomotion. Furthermore, JNJ-31020028 had no effect on behavior tests that are commonly used to evaluate anxiety, namely the social interaction test in both OBX and control animals. These data indicate that similar to BIIE0246, JNJ-31020028 also has antidepressant like effects in the OBX model. PMID- 23103058 TI - Forward osmosis desalination using polymer hydrogels as a draw agent: influence of draw agent, feed solution and membrane on process performance. AB - We have previously reported the use of hydrogel particles as the draw agent for forward osmosis desalination. In the present work, the effects of draw agent, feed concentration and membrane on the process performance were systematically examined. Our results showed that the incorporation of carbon filler particles in polymer hydrogels led to enhanced swelling ratios of the draw agents and thus higher water fluxes in the FO process. The composite polymer hydrogel particles of sizes ranging from 100 MUm to 200 MUm as draw agents induced greater water fluxes in FO desalination as compared with those with larger particle sizes (500 700 MUm). Similar to other types of draw solutes, as the salt concentration in the feed increased, the water flux created by the polymer hydrogel draw agent decreased; the use of a cellulose triacetate forward osmosis membrane resulted in higher water flux compared with the use of a polyamide composite reverse osmosis membrane. PMID- 23103056 TI - Cohort study for prevention of atopic dermatitis using hair mineral contents. AB - We undertook a cohort study to determine the association between hair mineral content and the onset of atopic dermatitis (AD) in infants. Eight hundred and thirty-four mother-infant pairs, who donated hair samples during one and ten month health checkups, had their samples analyzed by proton induced X-ray emission (PIXE) for 32 mineral concentrations, and these mineral concentration data together with their AD family history were statistically examined for any relationships between them. Results indicated that of all minerals, only selenium (Se) and strontium (Sr) showed statistically significant associations for infants, while the same two elements were only marginally significant for mothers. Se deficiency in either infant or mother increased the AD risk. A Sr deficiency in infants increased AD risk, while the same deficiency in mothers decreased the risk. To predict the probability of AD development using this data, we performed logistic regression analysis, which provided a sensitivity of 65.9%, a specificity of 70.5%, a positive predictive value (PPV) of 10.3%, a negative predictive value (NPV) of 97.6% and a relative risk (RR) of 4.2, all far better than any corresponding figures explicitly mentioned in previously published papers. PMID- 23103059 TI - Developmental changes in resting gamma power from age three to adulthood. PMID- 23103060 TI - The serum zinc, copper, iron, and chromium concentrations in epileptic children. AB - To assess whether epileptic children have abnormal values of some trace elements, the aim of this preliminary study was to assess the serum zinc (Zn), copper (Cu), iron (Fe), and chromium (Cr) concentrations in 23 children with initial recognition of epilepsy before beginning of pharmacological therapy in comparison with a healthy control group of 25 children, according to the gender. The study demonstrated that epilepsy decreases levels of Zn and Cr concentrations in all patients, and Fe level in girls, and increases level of Cu in all patients. The frequency distribution of these metals was significantly different in epileptic patients than in healthy subjects. There is a conclusion that status of trace elements in epileptic children needs to be monitored. PMID- 23103061 TI - Cost-effectiveness analysis for the use of serum antiepileptic drug level monitoring in children diagnosed with structural-metabolic epilepsy. AB - Treatment with antiepileptic drugs is commonly guided by serum level monitoring. Such monitoring requires expensive laboratory equipment and products. However, well-conducted studies on the cost-effectiveness of therapeutic drug monitoring for antiepileptic drugs are lacking particularly in patients with structural metabolic epilepsy. The study aims to assess the cost-effectiveness of serum level monitoring services in the management of children with structural-metabolic epilepsy during the first year of diagnosis. A retrospective cost-effectiveness analysis was conducted from the provider perspective. It included patients attended a paediatric neurology clinic. The effectiveness measures used in this analysis were the number of patients that achieved >=50% reduction in seizure frequency, and the number of patients with 3-month seizure free. Medical records of the patients were reviewed for the required information. Medical chart/billing data obtained from the hospital were collected to estimate the resources used (One Malaysian Ringgit MYR is equivalent to 0.31 USD). The recruited children were followed for one year following their first visit. The average cost effectiveness ratio for the monitored patients (MYR 2735 per patient that achieved a >=50% reduction in seizure frequency) was lower than that for non monitored patients (MYR 2921 per patients that achieved a >=50% reduction in seizure frequency), with incremental cost-effectiveness ratio of MYR 2357 per one additional patient that achieved a >=50% reduction in seizure frequency. The average cost effectiveness ratios for monitored and non-monitored group were MYR 8279 and MYR 6433 per patient with a 3-month seizure-free period, respectively, with incremental cost-effectiveness ratio of MYR 29,666 per one additional patient with a 3-month seizure-free period. In terms of the effectiveness measures used, serum level monitoring of antiepileptic drugs was found to be cost effective. However, the incremental cost-effectiveness ratio was found to be sensitive to the cost of management. PMID- 23103062 TI - Deficiency of selenium and zinc as a causative factor for idiopathic intractable epilepsy. AB - PURPOSE: The accumulation of free radicals may lead to seizures and increase the risk of their recurrence. Glutathione peroxidase and superoxide dismutase are 2 major enzymes that are involved in antioxidative defense mechanisms. Selenium (Se), zinc (Zn), and copper (Cu) are important trace elements that participate in the structure of these enzymes. The purpose of this study was to evaluate the possible associations between trace elements and idiopathic intractable epilepsy (IIE) by comparing the levels of Se, Zn, and Cu between patients with IIE and healthy children. METHODS: Our study was designed as a case-control study with 70 IIE patients and 60 healthy children who were matched for age, ethnicity, and socioeconomic status. The levels of serum Se, Zn, and Cu were measured with an atomic absorption spectrophotometer. The results were statistically analyzed with SPSS version 16.0. KEY FINDINGS: We found that the patients with IIE had significantly decreased levels of serum Se and Zn compared to those of the control group (p<0.05). SIGNIFICANCE: We believe that this study presents the first reports of decreased levels of Se and Zn in patients with IIE. These results may provide new insights for delineating the etiological basis of IIE and its potential therapeutic options. PMID- 23103063 TI - Chronic pain, impact of pain and pain severity with physical disability in older people--is there a gender difference? AB - OBJECTIVE: To establish if there is any gender difference in associations between chronic pain, impact of pain and pain severity with physical disability. METHODS: Data from the New South Wales Older People's Health Survey (OPHS), a population based survey of 8881 older people aged 65 years and above were used in the analysis. Chronic pain, pain with interference and pain severity and outcome variable of physical disability were all measured and determined by self report. RESULTS: Physical disability were more frequent in respondents reporting chronic pain, pain that interferes with activities and pain that was of moderate and strong to severe severity. Chronic pain was significantly associated with physical disability among men with adjusted prevalence ratio (PR) 1.31 (95% CI 1.19, 1.43) and women with adjusted prevalence ratio (PR) 1.34 (95% CI 1.28, 1.42). The relationships between pain with interference and pain severity with physical disability were similar in older men and older women. However, adjustment for psychological distress and self-rated health led to greater reductions in prevalence ratios for older men than women for all associations. CONCLUSION: There is no gender difference in associations between pain and physical disability among older people. However, psychological distress accounted for more pain-related physical disability in men than in women. PMID- 23103064 TI - Predictive factors of successful telephone-assisted cardiopulmonary resuscitation. AB - BACKGROUND: Our emergency medical service developed a telephone (phone)-assisted cardiopulmonary resuscitation (PACPR) procedure. OBJECTIVES: To describe this procedure and study the factors modulating its implementation. METHODS: We conducted a single-center prospective study of telephone calls to our emergency medical communication center for cardiac arrest, for which PACPR was initiated. RESULTS: Thirty-eight patients were included in the study. In six cases, cardiopulmonary resuscitation (CPR) had been started before the call. When PACPR was initiated, CPR was performed until the rescue team arrived in 27 cases. One third (n = 9) of the bystanders in these cases knew first-aid interventions, and all of these bystanders continued CPR until the rescue team arrived. The absence of a familial relationship between bystander and patient facilitated the continuation of CPR (100% vs. 37% with family ties, p = 0.01). CPR was continued more often if the bystander immediately agreed to PACPR than when he or she did not agree at first (88% vs. 45%, respectively, p = 0.01). When an obstacle to performing CPR was encountered, CPR was then performed in 57% of cases vs. 100% of cases with no obstacle (p = 0.003). These obstacles were associated with either the bystander (panic, apprehension, feelings of inadequacy, physical inability, indirect witness, tiredness) or the victim (morphotype, physical position). The presence of an obstacle, compared to no obstacle, associated with the bystander lowered the CPR performance rate (58% vs. 94%, respectively, p = 0.01). The presence of an obstacle, compared to no obstacle, associated with the victim also lowered CPR performance rate (50% vs. 85%, respectively, p = 0.04). CONCLUSION: Our study demonstrates the feasibility of PACPR. The results may lead to a better understanding of facilitating factors and obstacles to telephone assisted CPR, with the goal of improving its implementation. Good command of communication tools, identification of an appropriate bystander, and appropriate victim positioning are three fundamental factors of success. PMID- 23103065 TI - The association between self-reported exercise intensity and acute coronary syndrome in emergency department chest pain patients. AB - BACKGROUND: Regular exercise is thought to be protective against coronary artery disease. As a result, some physicians believe that the likelihood of acute coronary syndrome (ACS) in patients with acute chest pain is reduced in those who exercise regularly. We studied the association between self-reported frequency of exercising and the likelihood of ACS in patients presenting to the Emergency Department (ED) with chest pain. METHODS: A multi-center prospective, descriptive, cohort study design was used in ED patients to determine whether the risk of ACS was reduced in patients who self-reported regular exercise. RESULTS: There were 1093 patients enrolled. Median (interquartile range) age was 57 (48 67) years; 506 (45.7%) were female. ACS was diagnosed in 248 (22.7%) patients. Patients who did not exercise at least monthly were more likely to be diagnosed with ACS than those who did (129/466 [27.7%] vs. 119/627 [19.0%]; odds ratio 1.63, 95% CI 1.23-2.17). After adjusting for age, gender, body mass index, smoking, and prior history, limited exercise was still associated with ACS (adjusted odds ratio 1.52, 95% CI 1.10-2.10). There was no apparent association between frequency and intensity of exercise and risk of ACS. CONCLUSION: Although self-reported frequency of exercise was significantly associated with a decrease in ACS in ED patients with chest pain, it should not be used to exclude ACS in symptomatic ED patients. PMID- 23103066 TI - Eosinophilia and rash. PMID- 23103067 TI - Single-operator ultrasound-guided intravenous line placement by emergency nurses reduces the need for physician intervention in patients with difficult-to establish intravenous access. AB - BACKGROUND: Emergency physicians (EPs) have become facile with ultrasound-guided intravenous line (USIV) placement in patients for whom access is difficult to achieve, though the procedure can distract the EP from other patient care activities. OBJECTIVES: We hypothesize that adequately trained Emergency Nurses (ENs) can effectively perform single-operator USIV placement with less physician intervention than is required with blind techniques. METHODS: This was a prospective multicenter pilot study. Interested ENs received a 2-h tutorial from an experienced EP. Patients were eligible for inclusion if they had either two failed blind peripheral intravenous (i.v.) attempts, or if they reported or had a known history of difficult i.v. placement. Consenting patients were assigned to have either EN USIV placement or standard of care (SOC). RESULTS: Fifty patients were enrolled, of which 29 were assigned to USIV and 21 to SOC. There were no significant differences in age, race, gender, or reason for inclusion. Physicians were called to assist in 11/21 (52.4%) of SOC cases and 7/29 (24.1%) of USIV cases (p = 0.04). Mean time to i.v. placement (USIV 27.6 vs. SOC 26.4 minutes, p = 0.88) and the number of skin punctures (USIV 2.0 vs. SOC 2.1, p = 0.70) were not significantly different. Patient satisfaction was higher in the USIV group, though the difference did not reach statistical significance (USIV 86.2% vs. SOC 63.2%, p = 0.06). Patient perception of pain on a 10-point scale was also similar (USIV 4.9 vs. SOC 5.5, p = 0.50). CONCLUSIONS: ENs performing single-operator USIV placement in patients with difficult-to-establish i.v. access reduces the need for EP intervention. PMID- 23103068 TI - Eating a larger number of high-salt foods is not associated with short-term risk of acute decompensation in patients with chronic heart failure. AB - BACKGROUND: Risk factors for exacerbation of congestive heart failure have not been consistently validated. OBJECTIVE: Our objective was to examine the role of short-term dietary sodium intake in acute decompensated heart failure. METHODS: Patients with chronic congestive heart failure presenting to the Emergency Department for either acute decompensated heart failure (cases) or for other reasons (controls) were included in a case-control study. Cases and controls were compared with respect to age, smoking, recent sodium intake, medication nonadherence, coronary artery disease, and hypertension. A food frequency questionnaire was utilized to estimate recent sodium intake, defined as the number of food types consumed in the previous 3 days from the 12 highest-sodium food categories. RESULTS: There were 182 patients enrolled. One patient was excluded due to uncertainty about the primary diagnosis. When adjusted for age, smoking, medication nonadherence, coronary artery disease, and hypertension, acute decompensated heart failure was not associated with short-term dietary sodium intake. The odds ratio for acute decompensated heart failure for each increase in the number of high-sodium food types consumed was 1.1 (95% confidence interval 0.9-1.3; p = 0.3). Acute decompensated heart failure was associated with medication nonadherence, with an odds ratio for decompensation of 2.5 (95% confidence interval 1.2-5.1; p = 0.01). CONCLUSIONS: Patients with chronic congestive heart failure who presented to the Emergency Department with acute decompensated heart failure were no more likely to report consuming a greater number of high-sodium foods in the 3 days before than were patients with chronic congestive heart failure who presented with unrelated symptoms. On the other hand, those who presented with acute decompensated heart failure were significantly more likely to report nonadherence with medications. PMID- 23103069 TI - Successful resuscitation after multiple injuries in the wilderness. AB - BACKGROUND: Survival of blunt trauma associated with hypothermic and hemorrhagic cardiac arrest in wilderness areas is extremely rare. CASE REPORT: We describe a case of a 19-year-old female college sophomore who, while glissading down Mt. Adams, had a 400-pound boulder strike her back and left pelvis, propelling her 40 feet down the mountain to land face down in the snow at 7000 feet. It took 4 h from the time of injury until the arrival of the helicopter at our Emergency Department and Trauma Center. The patient lost vital signs en route and had no CO(2) production. A cardiothoracic surgeon was the trauma surgeon on call. The patient was taken directly from the helipad to the operating room, where cutdowns enabled initial intravenous access, median sternotomy and pericardiotomy open heart massage, massive transfusion, chest and abdominal cavity irrigations with warm saline, correction of acid base imbalances and coagulopathies, and epicardial pacing that led to a successful reanimation of the patient. The patient was rewarmed without extracorporeal membrane oxygenation or heat exchangers. The ensuing multiple organ failures (heart, lungs, kidneys, intestines, brain, and immune system) and rhabdomyolysis led to a 2-month intensive care unit stay. She received over 120 units of blood and blood products. The patient regained cognitive function, mobility, and overcame multiple organ failure. CONCLUSION: This report is presented to increase awareness of the potential survivability in hypothermia, and to recognize the heroic efforts of the emergency services personnel whose efforts saved the patient's life. PMID- 23103070 TI - A huge aortic root pseudoaneurysm. PMID- 23103071 TI - Isolated tricuspid valve surgery: predictors of adverse outcome and survival. AB - BACKGROUND: Isolated tricuspid valve surgery is a rare operation, for which outcomes are not well defined. We describe a single-centre experience with isolated tricuspid surgery, and an analysis of risk factors for adverse outcome and predictors of survival. METHODS: Retrospective analysis of 56 consecutive adult patients undergoing isolated tricuspid valve surgery between November 1998 and November 2010 was performed. RESULTS: Eight patients died in hospital (early mortality 14.2%). In comparison with tricuspid repair patients, tricuspid replacement patients required more intraoperative red cell blood transfusion (RBC>1 unit: p=0.033), platelet transfusion (p=0.051), and more postoperative ventilator support (p=0.023). Predictors of early (in hospital) mortality include advanced age (p=0.019) higher euroSCORE (p<0.001), transfusion of intraoperative red blood cells (p=0.005), and cryoprecipitate (p=0.014). Twenty-five patients (44.6%) reached the end-point of death. There was no statistical difference in early and late survival rates between repair and replacement groups. CONCLUSIONS: Patients with isolated tricuspid valve surgery continue to be a high-risk group in cardiac surgery with unacceptable operative mortality and limited survival. There were no statistical differences in early and late outcomes between the isolated tricuspid valve repair versus replacement surgery. Timely referral to surgery before the onset of class 3 heart failure, malnutrition, renal dysfunction and age>60 years is recommended. PMID- 23103072 TI - Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer. AB - INTRODUCTION: The development of anaplastic lymphoma kinase (ALK) inhibitor has just followed the recent discovery of ALK rearrangement in lung cancer, therefore not much is yet known about the clinical course and treatment outcomes to chemotherapy in ALK-positive patients. The purpose of this study was to investigate the clinical characteristics and treatment outcomes in patients with ALK-positive NSCLC treated with conventional chemotherapy during pre-ALK inhibitor period. PATIENTS AND METHODS: We retrospectively screened 381 consecutive NSCLC patients without known epidermal growth factor receptor (EGFR) or KRAS mutation who were diagnosed between 2007 and 2008 at a single center, and identified ALK rearrangements by fluorescence in situ hybridization. Additional 44 ALK-positive patients who were identified since 2009 by central lab for participation on clinical trial were included for the analysis of clinical outcomes. RESULTS: Of the 381 tumors screened, 21 (5.6%) showed ALK rearrangements, with twenty adenocarcinomas and one pleomorphic carcinoma. Of 65 ALK-positive patients including additional 44 ALK-positive patients, 32 patients received pemetrexed as a second- or further-line therapy, in whom the response rate was 34.4% (11/32), median progression-free survival (PFS) was 4.0 months (range: 0-22.0 months) and median overall survival (OS) was 50.8 months (95% confidence interval [CI]: 38.7-62.8). CONCLUSIONS: The prevalence of ALK rearrangement was 5.6% among EGFR and/or KRAS wild-type/unknown NSCLC population. Pemetrexed, given as a second- or further-line therapy, showed favorable clinical outcomes in ALK-positive NSCLC patients. PMID- 23103073 TI - Provider incentives and access to dental care: evaluating NHS reforms in England. AB - Changes were made to the management and delivery of primary dental care in the NHS in England in 2006 aimed at improving access to NHS dental services among populations with low use. These included: (i) commissioning of NHS dental services by primary care trusts (ii) replacing item of service patient charges by Course of Treatment cost bands and (iii) changing the remuneration of dentists providing NHS dental care. Using longitudinal data from the 1991-2008 waves of the British Household Panel Survey, we estimate the effects of these changes on the levels and distribution of dental care in the population and on the public private mix of primary dental care services in England using dynamic probit models. We find evidence of a decrease in NHS use, driven by reductions in use among populations with previously good access to care and a positive effect of the reforms on consumer transitions from NHS to private practice. Our results highlight the potential (unintended) consequences of reforming public health care systems. It appears that contrary to expanding NHS access, the dental reforms contracted NHS use amongst those with previously good access. This contraction relied upon the ability of the private sector to absorb this group. PMID- 23103074 TI - Household-based cash transfer targeting strategies in Zimbabwe: are we reaching the most vulnerable children? AB - Census data, collected in July 2009, from 27,672 children were used to compare the effectiveness, coverage and efficacy of three household-based methods for targeting cash transfers to vulnerable children in eastern Zimbabwe: targeting the poorest households using a wealth index; targeting HIV-affected households using socio-demographic information (households caring for orphans, chronically ill or disabled members; child-headed households); and targeting labour constrained households using dependency ratios. All three methods failed to identify large numbers of children with poor social and educational outcomes. The wealth index approach was the most efficient at reaching children with poor outcomes whilst socio-demographic targeting reached more vulnerable children but was less efficient. PMID- 23103075 TI - Effects of different consolidation periods on bone formation and implant success in alveolar distraction osteogenesis: a clinical study. AB - PURPOSE: The aims of this study were to compare the consolidation periods in alveolar distraction osteogenesis and evaluate the effects of this condition on bone formation, bone relapse and implant success in reconstruction of resorbed edentulous mandibles. PATIENTS AND METHODS: Eighteen patients were underwent vertical alveolar distraction osteogenesis under the same distraction protocol, except for variations in consolidation time. After a consolidation period of 5 weeks for Group 1 and 14 weeks for Group 2, 36 implants were placed to support their dentures. Bone height and relapse were evaluated using digital orthopantomographic radiographs. RESULTS: The radiological findings showed that the mean distraction was 6.968 mm in Group 1 and 7.031 mm in Group 2. At the end of the consolidation period, the mean bone relapse was 0.832 +/- 0.135 mm in Group 1 and 0.738 +/- 0.135 mm in Group 2. At the end of 6 months, the mean bone relapse was 1.380 +/- 0.144 mm in Group 1 and 1.112 +/- 0.144 mm in Group 2. No significant difference existed between the two groups at any time. CONCLUSION: Consolidation periods may be reduced in alveolar distraction osteogenesis to enable more patient comfort by providing dentures early. PMID- 23103076 TI - Relative strength of tailor's bunion osteotomies and fixation techniques. AB - A paucity of data is available on the mechanical strength of fifth metatarsal osteotomies. The present study was designed to provide that information. Five osteotomies were mechanically tested to failure using a materials testing machine and compared with an intact fifth metatarsal using a hollow saw bone model with a sample size of 10 for each construct. The osteotomies tested were the distal reverse chevron fixated with a Kirschner wire, the long plantar reverse chevron osteotomy fixated with 2 screws, a mid-diaphyseal sagittal plane osteotomy fixated with 2 screws, the mid-diaphyseal sagittal plane osteotomy fixated with 2 screws, and an additional cerclage wire and a transverse closing wedge osteotomy fixated with a box wire technique. Analysis of variance was performed, resulting in a statistically significant difference among the data at p <.0001. The Tukey Kramer honestly significant difference with least significant differences was performed post hoc to separate out the pairs at a minimum alpha of 0.05. The chevron was statistically the strongest construct at 130 N, followed by the long plantar osteotomy at 78 N. The chevron compared well with the control at 114 N, and they both fractured at the proximal model to fixture interface. The other osteotomies were statistically and significantly weaker than both the chevron and the long plantar constructs, with no statistically significant difference among them at 36, 39, and 48 N. In conclusion, the chevron osteotomy was superior in strength to the sagittal and transverse plane osteotomies and similar in strength and failure to the intact model. PMID- 23103077 TI - Computational investigations of HNO in biology. AB - HNO (nitroxyl) has been found to have many physiological effects in numerous biological processes. Computational investigations have been employed to help understand the structural properties of HNO complexes and HNO reactivities in some interesting biologically relevant systems. The following computational aspects were reviewed in this work: 1) structural and energetic properties of HNO isomers; 2) interactions between HNO and non-metal molecules; 3) structural and spectroscopic properties of HNO metal complexes; 4) HNO reactions with biologically important non-metal systems; 5) involvement of HNO in reactions of metal complexes and metalloproteins. Results indicate that computational investigations are very helpful to elucidate interesting experimental phenomena and provide new insights into unique structural, spectroscopic, and mechanistic properties of HNO involvement in biology. PMID- 23103078 TI - Computational insights on the possibility of tri-coordinated cisplatinated adducts with protein models. AB - In the organism, cisplatin binds to numerous proteins. These interactions can ultimately lead to the emergence of resistance and side effects. Little is known on these recognition processes with only few crystallographic structures of cisplatinated proteins released so far. Some of them, like the monoadduct of cisplatin with the hen egg white lysozyme, display unexpected structural features. Instead of the usual square planar configuration of the metal, an apparent T-shaped geometry is observed. This tri-coordinated structure could be a consequence of some crystallographic limitations. However, the increasing reports of tri-coordinated Pt(II) organometallic complexes questions whether it could also have some physiological relevance. Here, we present a computational study allying pure quantum mechanical and hybrid quantum mechanical/molecular mechanics methodologies to shed light on this particular question. Calculations on monoadducts of cis-diamminediaquo-platinum(II) with protein models show that square planar geometries are, as expected, the most stable ones. Dehydrations leading to trigonal geometries have Gibbs energies ranging from 8 to 31 kcal/mol and indicate that some of them may be possible in a proteic environment. Nonetheless, we also observed that such conditions are not afforded in the hen egg white lysozyme adduct. PMID- 23103079 TI - Antithrombotic effect of taurine in healthy Japanese people may be related to an increased endogenous thrombolytic activity. AB - INTRODUCTION: Prevention of arterial thrombotic diseases has high priority in developed countries. Taurine (2-aminomethylsulfonic acid), which is rich in sea foods, showed antithrombotic effect in animal models of thrombosis. The present study aimed to investigate such effect in healthy human volunteers. METHODS AND RESULTS: In 101 healthy Japanese people the overall thrombotic status was accessed from non-anticoagulated blood sample by the Global Thrombosis Test (GTT). There was no significant correlation between taurine concentration in urine samples and GTT-Occlusion Times (OT; mainly reactivity of platelets). In contrast, a significant inverse correlation was demonstrated between urine taurine concentrations and GTT-Lysis Times (LT; showing spontaneous thrombolytic activity). CONCLUSIONS: Our findings suggest that taurine enhances endogenous thrombolytic activity which could be a mechanism of the earlier observed cardioprotective and antithrombotic effect. PMID- 23103080 TI - IL1 blockade in crystal-induced arthritis: impact of disease duration and the inflammatory syndrome. Comments on the article by Couderc M. et al. "Efficacy of anakinra in articular chondrocalcinosis". PMID- 23103081 TI - Operative techniques in pancreatic trauma--a heuristic approach. PMID- 23103082 TI - Psychological distress after physical injury: a one-year follow-up study of conscious hospitalised patients. AB - BACKGROUND: Acute physical injury may lead to psychological distress. The relationship between peritraumatic responses, injury severity, the personality trait of optimism/pessimism and psychological distress is not fully understood. In addition, the development of post-traumatic stress symptoms may differ in subgroups. METHODS: One hundred and eighty-one patients (18-65 years) completed questionnaires 1 (baseline), 3 and 12 months after first admission for acute physical injury. All patients were conscious on arrival. Scores on the Casualty Chain Inventory (CCI) for peritraumatic responses, the Impact of Event Scale (IES), the Hospital Anxiety and Depression Scale (HADS), the Life Orientation Test-Revised (LOT-R), trauma-related variables (ISS, Abbreviated Injury Scale [AIS], Glasgow Coma Scale [GCS]), and background variables were assessed. RESULTS: Mean IES scores were 21.5 (95% CI: 19.0-24.0) at baseline and 15.8 (13.5 18.1) at 12 months (p<0.001). One subgroup (delayed onset, 12.2%) had an increase of at least 10 points in the IES score and another subgroup (chronic, 13.3%) had high and persistent post-traumatic stress symptoms during the follow-up period. At baseline, 45.3% had an IES score >= 20, indicating possible clinical case levels, compared with 33.1% at 12 months. Accordingly, 14% had anxiety symptoms and 10.8% had depression symptoms at a case level (HADS >= 8) at one-year follow up. Mutually independent predictors of post-traumatic stress symptoms at 12 months were dissociation (OR 1.3, 95% CI: 1.1-1.6) and perception (OR 1.1, 95% CI: 1.0-1.3) measured by the CCI. Being in work before injury (OR 0.1, 95% CI: 0.02-0.4) and higher educational level (OR 0.3, 95% CI: 0.1-0.7) were associated with fewer IES symptoms. Dissociation and having a pessimistic trait predicted anxiety and depression at 12 months. Previous psychiatric problems predicted anxiety symptoms, and high educational level predicted less depression symptoms. CONCLUSION: One-third of conscious physical injured patients had post-traumatic stress symptoms at a possible clinical case level one year after the traumatic event, and one-third of these had delayed onset. Symptoms of peritraumatic dissociation and perception were mutually independent predictors of psychological distress. PMID- 23103083 TI - Lenalidomide is effective for the treatment of bortezomib-resistant extramedullary disease in patients with multiple myeloma: report of 2 cases. PMID- 23103084 TI - Visceral varicella in a patient with chronic lymphocytic leukemia treated with fludarabine: a case report. PMID- 23103086 TI - Paraneoplastic nephrotic syndrome and inflammatory arthritis at diagnosis in Hodgkin lymphoma. PMID- 23103085 TI - Current practices in the management of chronic myeloid leukemia. AB - BACKGROUND: A previous survey of physician self-reported practice patterns in the management of CML was conducted in 2005. The National Comprehensive Cancer Network and European LeukemiaNet guidelines now include nilotinib and dasatinib in their treatment algorithms for CML. To assess these new guidelines, a cross sectional survey of US hematologists and/or oncologists was conducted in December 2010 through an online survey. MATERIALS AND METHODS: The survey had 43 questions consisting of items updated from the 2005 survey to reflect changes in clinical practice, tyrosine kinase inhibitor therapy, and current guidelines. RESULTS: Analysis of the responses from 507 board certified medical oncologists/hematologists suggests that the use of imatinib 400 mg as an initial treatment option had decreased from 62% in 2005 to 52% in the 2010 survey. Currently, nearly 40% of physicians would choose either nilotinib or dasatinib as first-line treatment. From the surveyed physicians, achievement of at least a major molecular response (MMR) is the predominant treatment goal in chronic phase CML. CONCLUSION: This survey emphasizes the need for continued updates and education regarding optimal therapy, monitoring practices, and therapeutic end points in CML. PMID- 23103087 TI - Desensitization to lenalidomide in a patient with relapsed multiple myeloma. PMID- 23103088 TI - Sickle-cell disorders: limits of descriptive epidemiology. PMID- 23103089 TI - Global epidemiology of sickle haemoglobin in neonates: a contemporary geostatistical model-based map and population estimates. AB - BACKGROUND: Reliable estimates of populations affected by diseases are necessary to guide efficient allocation of public health resources. Sickle haemoglobin (HbS) is the most common and clinically significant haemoglobin structural variant, but no contemporary estimates exist of the global populations affected. Moreover, the precision of available national estimates of heterozygous (AS) and homozygous (SS) neonates is unknown. We aimed to provide evidence-based estimates at various scales, with uncertainty measures. METHODS: Using a database of sickle haemoglobin surveys, we created a contemporary global map of HbS allele frequency distribution within a Bayesian geostatistical model. The pairing of this map with demographic data enabled calculation of global, regional, and national estimates of the annual number of AS and SS neonates. Subnational estimates were also calculated in data-rich areas. FINDINGS: Our map shows subnational spatial heterogeneities and high allele frequencies across most of sub-Saharan Africa, the Middle East, and India, as well as gene flow following migrations to western Europe and the eastern coast of the Americas. Accounting for local heterogeneities and demographic factors, we estimated that the global number of neonates affected by HbS in 2010 included 5,476,000 (IQR 5,291,000-5,679,000) AS neonates and 312,000 (294,000-330,000) SS neonates. These global estimates are higher than previous conservative estimates. Important differences predicted at the national level are discussed. INTERPRETATION: HbS will have an increasing effect on public health systems. Our estimates can help countries and the international community gauge the need for appropriate diagnoses and genetic counselling to reduce the number of neonates affected. Similar mapping and modelling methods could be used for other inherited disorders. FUNDING: The Wellcome Trust. PMID- 23103090 TI - Is increased red cell distribution width (RDW) indicating the inflammation in Alzheimer's disease (AD)? AB - Increasing evidence indicates that inflammation has a substantial role in the pathogenesis and progression of AD. RDW, a measure of heterogeneity in the size of circulating erythrocytes, is associated with inflammatory markers in many numerous diseases. Present study was undertaken to assess the interrelationships between RDW and AD. A total of 197 patients with AD (male/female: 96/101, mean age 76.2 +/- 6.9) and 133 patients as controls with normal cognitive function (male/female: 72/61, mean age 71.68 +/- 5.3) were enrolled in this cross sectional study. RDW values of all participants were measured. Mini-Mental State Examination (MMSE) and clock drawing tests were performed for cognitive assessment. DSM-IV and NINCDS-ADRDA criteria were used for diagnosis of AD. The mean RDW values were significantly higher in AD group (13.93 +/- 1.1 vs. 13.24 +/ 1.2; p<0.001) and also a negative moderate correlation between RDW and MMSE was identified (r: -0.453; p<0.001). After adjusting for confounders, RDW has the strongest association with AD (odd ratio (OR) 1.51, CI=1.10-2.07). In present study RDW levels were significantly increased in patients with AD. Whereas elevated RDW value is usually considered as a novel biomarker of inflammation, the results of our study may support the role of inflammation in pathophysiology of AD. Furthermore the correlation of RDW with poorer cognition status suggests that it may be used as a marker of AD severity. PMID- 23103091 TI - Associations between sex hormones and cognitive and neuropsychiatric manifestations in vascular dementia (VaD). AB - Although numerous studies have been carried out to determine the effects of sex hormones on Alzheimer's disease (AD), little is known about the associations between sex hormones and VaD. The aim of this study was to compare serum sex hormone levels between VaD patients and normal controls, and to further determine the link between sex hormones and cognitive and neuropsychiatric manifestations of VaD. Serum levels of total estradiol (TE2), total testosterone (TT), luteinizing hormone (LH), and sex hormone binding globulin (SHBG) were measured in 87 VaD patients and 110 cognitive normal controls. The levels of bioavailable estradiol (BE2) and bioavailable testosterone (BT) were calculated. The VaD patients underwent the tests of global cognitive function, verbal memory, and visuospatial, and executive ability. The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Compared to controls, the testosterone and SHBG levels were lower in male VaD patients, and the estradiol levels were higher in female VaD patients. The hormones levels were not correlated with cognitive functions among either male or female VaD patients. There were no associations between hormone levels and neuropsychiatric symptoms among male patients, while the TE2 and TT levels were positively associated with apathy and anxiety, respectively among female patients. Our findings suggested there were sex hormone level changes in VaD patients in comparison with cognitive normal controls. Sex hormones were associated with neuropsychiatric symptoms among female but not male VaD patients. PMID- 23103092 TI - [Determinants of participation among primiparous women in a prenatal education program]. AB - OBJECTIVES: To determine the factors associated with participation in a prenatal education program among primiparous mothers. METHODS: A multicenter observational study was carried out in four Andalusian hospitals (Spain) in primiparous women in 2010. Sociodemographic characteristics, obstetric history, and previous diseases were collected through an interview and from the clinical charts. Crude and adjusted odds ratios were calculated. RESULTS: The study population consisted of 520 women. According to multivariate analysis, the factors associated with participation in the program were educational level (p <0.001), higher income levels (p <0.001), birth in Spain (p <0.001) and viewing the program as useful (p <0.001). After adjusting for these variables, no other variable was related to participation. The main reason given by women for not attending prenatal education was lack of an invitation to attend. CONCLUSIONS: Participation in the prenatal education program was favored by a higher educational level and income, birth in Spain, and viewing the program as useful. PMID- 23103093 TI - [Validity of the international physical activity questionnaire in the Catalan population (Spain)]. AB - OBJECTIVES: To validate the short form of the International Physical Activity Questionnaire in the population of Catalonia (Spain). METHODS: A convenience sample wore a uniaxial accelerometer (MTI Actigraph, Computer Science and Application's Inc.) for 7 days and completed the questionnaire, translated to Catalan. The sensitivity and specificity of the questionnaire in measuring adherence to physical activity recommendations were also tested. RESULTS: Valid data were obtained from 55 participants (29 women). The mean age was 40.5 years. Moderate correlations were found for total physical activity (r=0.27; p<0.05) and the time spent in vigorous activity (r=0.38; p<0.01). Sensitivity was 75% and specificity was 75% (kappa=0.33). CONCLUSION: The short Catalan version of the International Physical Activity Questionnaire had acceptable validity for the measurement of total and vigorous physical activity. This questionnaire can be used to identify adherence to physical activity recommendations in the Catalan population. PMID- 23103094 TI - Essential structure of opioid kappa receptor agonist nalfurafine for binding to the kappa receptor 3: synthesis of decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position and their pharmacologies. AB - To clarify the essential structures of an opioid kappa receptor selective agonist, nalfurafine, for binding to the kappa receptor, we designed and synthesized the decahydro(iminoethano)phenanthrene derivatives with an oxygen functionality at the 3-position. The introduction of a hydroxy group to the derivatives increased the affinity and selectivity to the kappa receptor regardless of the configuration at the 3-position. However, their affinities were lower than those of nalfurafine with the phenolic hydroxy group. The results suggested that the acidity of the hydroxy group would play an important role in the interaction with the opioid receptor. The low affinities of the 3-keto derivatives indicated that the 3-hydroxy group may participate in the hydrogen bonding with the receptor site not as a hydrogen acceptor but as a hydrogen donor. This is the first experimental evidence for a role as a hydrogen donor for the 3-hydroxy group in morphinans. Furthermore, the kappa selectivities in these derivatives with the 6alpha-amide side chain were affected by the the 3-hydroxy group. The obtained structure-activity relationship information is expected to be useful for the design of more selective ligands for the kappa receptor. PMID- 23103095 TI - Hit to Lead optimization of a novel class of squarate-containing polo-like kinases inhibitors. AB - A high throughput screening (HTS) hit, 1 (Plk1 K(i)=2.2 MUM) was optimized and evaluated for the enzymatic inhibition of Plk-1 kinase. Molecular modeling suggested the importance of adding a hydrophobic aromatic amine side chain in order to improve the potency by a classic kinase H-donor-acceptor binding mode. Extensive SAR studies led to the discovery of 49 (Plk1 K(i)=5 nM; EC(50)=1.05 MUM), which demonstrated moderate efficacy at 100 mpk in a MiaPaCa tumor model, with no overt toxicity. PMID- 23103096 TI - Facile synthesis and anticancer activity of C-10 non-acetal deoxoartemisinin dimers. AB - In this research, N-(2-aminoethyl)glycine-linked C-10 non-acetal deoxoartemisinin dimers were synthesized by using solution phase peptide synthesis approach. In addition, chemical modification of the C-10 non-acetal deoxoartemisinin monomers and dimers by adding a lysine unit to the N-terminus has been performed. The biological activities of all synthesized compounds were evaluated against the colon cancer cell line (Caco-2). The non-acetal deoxoartemisinin monomers 12a, 15a-c and dimers 13a, 16a-c were active against Caco-2 cells and more potent than dihydroartemisinin. PMID- 23103097 TI - Synthesis and biological evaluation of colchicine C-ring analogues tethered with aliphatic linkers suitable for prodrug derivatisation. AB - Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III beta-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor selective delivery. PMID- 23103098 TI - (R)- and (S)-4-Amino-3-(trimethylsilyl)methylbutanoic acids ameliorate neuropathic pain without central nervous system-related side effects. AB - Neuropathic pain is a chronic pain condition resulting from neuronal damage, and is usually treated with pregabalin or gabapentin, which are structurally related to gamma-aminobutyric acid (GABA) and are originally developed as anticonvulsant drugs. Here, we report the synthesis and pharmacology of (R)- and (S)-4-amino-3 (trimethylsilyl)methylbutanoic acids (1a and 1b), which showed analgesic activity as potent as that of pregabalin in the Chung spinal nerve ligation model. However, unlike pregabalin, 1a and 1b do not have antiepileptic effects, and they are therefore promising candidates for selective therapeutic agents to treat neuropathic pain without central nervous system-related side effects. PMID- 23103099 TI - Docosahexaenoic acid in translational medicine: the Tenth Fatty Acids and Cell Signaling meeting (FACS-10). PMID- 23103100 TI - In vitro infection of human cells with Mycobacterium tuberculosis. AB - It has been estimated that approximately 50% of individuals exposed to Mycobacterium tuberculosis never become tuberculin skin test positive, which may indicate that successful human immunological responses are able not only to inhibit mycobacterial growth, but also to kill the bacteria. Nevertheless, it has been extremely difficult to reproduce this effect in vitro and the ability of human phagocytes to eliminate the bacteria is controversial. This is one of the reasons why we do not fully understand either tuberculosis resistance or susceptibility. Nowadays there is a pressing need in tuberculosis vaccine research to find biomarkers of successful responses to tuberculosis and the use of in vitro models may allow the identification of the immunological mechanisms responsible for the mycobacterial killing that could be tested in clinical settings. Besides biosafety concerns, the manipulation of mycobacteria is technically very demanding, and the optimization of in vitro infection protocols have been difficult. As a result, there are a large number of variations in the methodology that make arduous the comparison of results obtained in different research groups. In this review an overview of the mycobacterial and human cellular models most frequently studied are presented, together with a description of several of the modifications tried in infection protocols, from the preparation of the inoculum to the quantification of surviving mycobacteria after infection. A comment about statistical methods that may improve the detection of relevant biological effects is also included. PMID- 23103101 TI - [Optimization of the medical treatment for acromegaly]. AB - Somatostatin analogues are the cornerstone in the first-line and adjuvant (postsurgical) therapy in patients with acromegaly. These drugs highly effectively decrease serum concentrations of growth hormone (GH) and insulin-like growth factor type I (IGF-I), as well as pituitary adenoma size. However, in approximately one third of patients response to these agents is unsatisfactory. The optimization of the medical therapy for acromegaly can be accomplished by modifying the dose or the interval of administration of somatostatin analogues or by combining other pharmacological agents. Increasing the dose or frequency of administration is followed by an additional decrease in GH and IGF-I levels in a significant percentage of patients. These changes are not accompanied by a relevant increase in the number or severity of adverse events. Combined treatment with somatostatin analogues and pegvisomant has been shown to significantly reduce serum IGF-I levels in patients with inadequate control of disease activity. The addition of cabergoline to somatostatin analogue therapy is accompanied by a further decrease in IGF-I levels that is independent of serum prolactin concentrations. PMID- 23103102 TI - [Bisphosphonate related osteonecrosis of the jaw and infection with Actinomyces]. AB - BACKGROUND AND OBJECTIVE: Bisphosphonate related osteonecrosis of the jaw (BRONJ) has raised considerable interest since its recent description. Its pathogenesis is not yet clarified; formerly it has been considered a non-infectious complication, but recent studies seem to implicate bacteria of the genus Actinomyces. The objective of this study is to analyze the cases of BRONJ in our institution. PATIENTS AND METHODS: Review of medical records of patients diagnosed of BRONJ in the Maxillofacial Surgery Unit of our hospital. RESULTS: We have found 11 cases of BRONJ in our hospital: 4 women taking oral alendronate or risendronate for osteoporosis and 7 cancer patients treated with intravenous zolendronic acid. All of them showed bone invasion by bacteria of the genus Actinomyces. Nine patients underwent prolonged treatment with amoxicillin with favourable clinical outcome in all of them, but 3 died of their malignancy. By contrast, one patient with beta-lactamic allergy and irregular treatment with erythromycin and tetracycline had a chronic evolution of the lesions. There was no information for other patient. CONCLUSIONS: Actinomyces play an important role in the development of BRONJ and specific antibiotic treatment improves the prognosis of this process. PMID- 23103103 TI - [Clinical factors associated with invasive pulmonary aspergillosis in patients with chronic pneumopathies and respiratory isolation of Aspergillus spp]. AB - BACKGROUND AND OBJETIVE: To determine clinical variables to distinguish invasive pulmonary aspergillosis (IPA) from colonization in patients with chronic pneumopathies with positive culture of Aspergillus spp. in respiratory samples. PATIENTS AND METHODS: Retrospective cohort study including patients with respiratory isolations of Aspergillus spp. during a period of 10 years. IPA was evaluated according to the Bulpa criteria. Clinical variables were collected and a multiple logistic regression analysis was carried out. RESULTS: Eighty-three patients with isolation of Aspergillus spp. from respiratory samples were included; 68.7% (n=57) of the patients had chronic obstructive pulmonary disease, 18% (n=15) pulmonary fibrosis and 13.3% (n=11) bronchial asthma. Twenty-two patients (26.6%) had IPA. The use of fluconazole (OR 4.49; CI 95% 1.5-13.4; P=.007), severe respiratory failure (OR 4.64; CI 95% 1.46-14.72; P=.009) and hospitalization time (OR 1.05; CI 95% 1.01-1.1; P=.006) were associated with IPA. CONCLUSIONS: Prior use of fluconazole, severe respiratory failure and hospitalization time are associated with IPA in patients with chronic pneumopathies with respiratory isolation of Aspergillus spp. PMID- 23103104 TI - [Comments to the study DIABES]. PMID- 23103105 TI - [Bisphosphonate-associated jaw osteonecrosis]. PMID- 23103106 TI - [3'UTR +62G>A polymorphism of the RETN gene coding resistin and its association with metabolic syndrome components]. AB - BACKGROUND AND OBJECTIVE: The polymorphism of the resistin gene (RETN/RSTN) has been associated with metabolic alterations. In this study the association between the 3'UTR +62G>A polymorphism and metabolic syndrome components was evaluated. SUBJECTS AND METHODS: The population (n=218) was distributed in 3 groups: the control group with no metabolic alterations (n=77), nSMA group with isolated metabolic alterations (n=94) and MS group with metabolic syndrome (n=47). The 3'UTR +62G>A polymorphism was analyzed by PCR-RFLP. RESULTS: Central obesity was the most frequent alteration in both nSMA (56.4%) and MS (91.5%) groups followed by low c-HDL levels in the nSMA group (42.6%) and arterial hypertension in the MS group (85%). The frequency of the +62G/A genotype was 20.2% in the population. The G/A genotype was more frequently found in the MS (38.3%) and nSMA (17%) groups than in the control group (13%). The allelic distribution between the control group (+62G=0.94, +62A=0.06) and MS group (+62G=0.81, +62A=0.19) was significantly different (P=.0001). Significant associations between the G/A genotype and high values of abdominal circumference (P=.047), basal glycemia (P=.02) and systolic arterial pressure (P=.003) were found. CONCLUSION: The findings suggest the association between the G/A genotype and high values of systolic arterial pressure, basal glycemia and abdominal circumference. This association was independent of the metabolic syndrome context. PMID- 23103107 TI - [Calcified uterine leiomyoma]. PMID- 23103108 TI - [Early evaluation of anaemia in patients with acute gastrointestinal bleeding: venous blood gas analysis compared to conventional laboratory]. AB - BACKGROUND AND OBJECTIVE: Evaluation of patients with acute gastrointestinal bleeding (AGB) requires early clinical evaluation and analysis. The aim of this study is to evaluate early concordance of hemoglobin (Hb) and hematocrit (HTC) levels determined by conventional venous blood gas analysis (VBG) and by conventional Laboratory in Emergencies (LAB). PATIENTS AND METHODS: Observational and prospective study of patients admitted in the Gastrointestinal Haemorrhage Unit with both high and low AGB. Demographic and clinical variables and simultaneous venous blood samples were obtained to determine Hb and HTC by VBG and LAB. Concordance in both methods was analysed by intra-class correlation coefficient (ICC) and Bland-Altman analysis. RESULTS: One hundred and thirty-two patients were included: 87 (65.9%) males, average age 66.8 years. VBG overestimated Hb in 0.49 g/dl (95% confidence interval: 0.21-0.76) with respect to LAB. Concordance was very high in Hb (ICC 0.931) and high in HTC (0.899), with the Bland-Altman graphs showing both concordance and overestimation of Hb levels determined by VBG. In 19 patients (14.39%), Hb by VBG exceeded in more than 1g/dL the final determination obtained by LAB. CONCLUSIONS: Early determination of Hb and HTC in patients with AGB by VBG provides reliable results in the initial evaluation of anaemia. VBG systematically overestimates Hb values by less than 0.5 g/dl, and therefore clinical and hemodynamic evaluation of the bleeding patient should prevail over analytical results. PMID- 23103109 TI - [Protection of ideas and research results]. PMID- 23103110 TI - [Identification of people with chronic advanced diseases and need of palliative care in sociosanitary services: elaboration of the NECPAL CCOMS-ICO(c) tool]. AB - BACKGROUND AND OBJECTIVE: Around 75% of the population in our country will die as a consequence of chronic advanced diseases. Advanced chronic care is one of the major challenges for public health systems. This study describes the development of a tool to identify patients with advanced chronic diseases and life limited prognosis that might require some type of palliative intervention in our health and social environment. MATERIAL AND METHODS: Spanish translation of PIG/GSF, cultural and clinical adaptation, identification of indicators of severity and progression -general and specific-; study of content validity and pre-test. RESULTS: The NECPAL CCOMS-ICO((c)) tool proposes a quantitative-qualitative, multifactorial, indicative and not dichotomous evaluation combining subjective perception assessment (surprise question) with demand and perceived needs; parameters of severity and progression, geriatric syndromes, emotional aspects, comorbidity and use of resources; and indicators for selected pathologies. CONCLUSIONS: The NECPAL CCOMS-ICO((c)) tool, feasible and easy to use, would identify patients with advanced chronic palliative needs of any cause, early and in all resources. PMID- 23103112 TI - Cholesterol metabolism and cancer: the good, the bad and the ugly. PMID- 23103111 TI - Report of a novel OCA2 gene mutation and an investigation of OCA2 variants on melanoma risk in a familial melanoma pedigree. AB - BACKGROUND: Oculocutaneous albinism type 2 (OCA2) is caused by mutations of the OCA2 gene. Individuals affected by OCA2 as well as other types of albinism are at a significantly increased risk for sun-induced skin-cancers, including malignant melanoma (MM). OBJECTIVE: To identify the molecular etiology of oculocutaneous albinism in a previously uncharacterized melanoma pedigree and to investigate the relationship between two OCA2 variants and melanoma predisposition in this pedigree. METHODS: DNA and RNA were isolated from the peripheral blood of seven patients in a familial melanoma pedigree. Electron microscopy was performed on the individual with clinical oculocutaneous albinism. OCA2, TYRP1, MC1R, CDKN2A/p16, CDKN2A/p19ARF, and CDK4 genes were sequenced in affected individuals. The relationship between OCA2 variants and melanoma was assessed using a pedigree likelihood-based method. RESULTS: The proband was determined to be an OCA2 compound heterozygous mutation carrier with a previously reported conservative missense mutation (V443I) and a novel non-conservative missense mutation (L734R). The pedigree contained individuals diagnosed with both cutaneous and iris melanoma. Based on co-segregation analysis, the odds of these OCA2 variants being high penetrance loci for melanoma was: 1.3-to-1 if we include the iris melanoma as affected and 6.5-to-1 if we only consider cutaneous melanoma as affected. CONCLUSION: The discovery of this novel OCA2 variant adds to the body of evidence on the detrimental effects of OCA2 gene mutations on pigmentation, supports existing GWAS data on the relevance of the OCA2 gene in melanoma predisposition, and may ultimately assist in the development of targeted molecular therapies in the treatment of OCA and melanoma. PMID- 23103113 TI - Periprosthetic fractures around hip hemiarthroplasty performed for hip fracture. AB - Hip fracture is associated with considerable morbidity and mortality and occurs in an elderly and infirm group of patients. Periprosthetic fracture after hip hemiarthroplasty is a serious complication. In this study, we have reviewed our experience of this injury. The outcome measures used were fracture union, mortality, infection and requirement for further surgery. METHOD: We identified a cohort of 79 patients who sustained periprosthetic fractures after hip hemiarthroplasty from a prospective hip fracture database of 8354 patients (3611 were treated with hemiarthroplasty). Seventy-two percent were female and the mean age was 86 years at time of periprosthetic fracture. RESULTS: Sixty-two fractures occurred around uncemented prostheses (Austin Moore n=61); the remainder occurred around cemented prostheses. The mean time from hip fracture surgery to periprosthetic fracture was 35 months (median time 5 months). Fractures were classified according to the Vancouver system. Fifteen percent (n=12) were type A fractures, 26% (n=21) were type B1 fractures, 41% (n=32) were type B2 fractures, 9% (n=7) were type B3 fractures and 9% (n=7) were type C fractures. Twenty-eight patients underwent open reduction internal fixation (ORIF), 36 required revision surgery, one required fixation and simultaneous revision and 14 were treated non operatively. Eleven percent (n=9) died within 1 month of periprosthetic fracture, 23% had died by 3 months, 34% by 1 year and 49% by 2 years. Nineteen patients (24%) died before fracture union had occurred. Fracture union occurred in 97% of the remaining cases (58/60). Two patients developed nonunion requiring revision surgery (3%), and three patients developed deep infection requiring debridement (4%), one patient had an infection at the time of the periprosthetic fracture requiring a planned two-stage revision, one patient sustained a second periprosthetic fracture and two patients underwent superficial wound debridement (3%). The incidence of periprosthetic fracture at our institution since 1999 is 1.7% (62 of 3611 patients). The incidence rate after uncemented Austin Moore stem was 2.3% (54/2378) and cemented Exeter stem was 0.5% (4/812); Fisher's exact test p=0.004. CONCLUSIONS: This article reports satisfactory outcomes in this complex group of patients. We have established the incidence of 1.7%, with relatively low rates of nonunion, infection and other complications. The mortality rate has been established, and survivorship analysis has identified an increased rate of fracture around the Austin Moore prosthesis. PMID- 23103114 TI - The metabolic effects of feeding and fasting in beluga Huso huso. AB - A six week-study was conducted to determine the effect of starvation and feeding on growth, hematology and biochemical variables in sub-yearling beluga. Fish were placed on six feeding strategies: i) starved condition for 6 weeks, ii) a 2-week starvation, 2-week feeding and 2-week starvation, iii) a 2-week feeding, 2-week starvation and 2-week feeding, iv) a 3-week starvation followed by a 3-week feeding, v) a 3-week feeding with following 3-week starvation, and vi) fed throughout the 6 weeks. After 6 weeks, hematology, triacylglycerol, cholesterol, total protein, HSI, VSI, crude fat in muscle, final weight, feed conversion, specific growth rate, and condition factor were significantly affected by feeding strategies. The results suggested that most of the growth and physiological variables responded to a short period of starvation or re-feeding. These findings indicated that beluga could partially recover in weight and some physiological indices from periods of starvation when provided subsequently ad libitum feeding. PMID- 23103115 TI - Repeatability of oral fluid collection methods for THC measurement. AB - STUDY OBJECTIVES: To determine the influence of sample collection for two different collection methods on THC concentrations and to compare THC concentrations collected by both methods. METHODS: A total of 136 pairs of oral fluid samples from subjects who had recently smoked Cannabis were obtained by the non-acidic Statsure oral fluid collection device and by ordinary spit tubes. Oral fluid was analyzed for THC by LC-MS/MS. Bland-Altman plots were used for the quantitative analysis of repeatability, whereas Cohen's kappa was used for qualitative analysis to determine the consistency of the results with regard to the Belgian legal limit. RESULTS: Repeatability of both sampling methods was very low. The Statsure device had a better rate of agreement when compared with the Belgian legal limit than the spitting method. THC concentrations of samples collected by spit tubes were on average a factor 5.9 higher than the corresponding concentrations in samples collected by the Statsure device. CONCLUSIONS: The repeatability of both the Statsure collection method and the ordinary spit tubes was low when applied to subjects who had consumed Cannabis very recently. Furthermore, THC concentrations were higher in samples obtained by spitting than samples collected with Statsure. These results may have implications for confirmation analysis in oral fluid, when applied for legal purposes. PMID- 23103116 TI - Affect of impact angle variations on area of origin determination in bloodstain pattern analysis. AB - The estimation of the location of the area of origin of a blood source is of major importance within bloodstain pattern analysis. Given this, it is particularly important to establish the accuracy of such estimations. This study examines error rates by investigation of alpha angle inaccuracies of upward directional stains and compares a virtual bloodstain pattern model to real bloodstain patterns. It was found that the size of the area of origin influences the level of accuracy required in alpha angle estimations: larger areas of origin tolerated larger errors. Practical applications of the virtual model using real bloodstain patterns demonstrated that alpha angle measurements may show an inaccuracy of approximately 0-12 degrees within a single pattern. The averaging process that occurs in estimating the area of origin lessens the influence of a few large variations, such that, there is no significant change in the area of origin estimation. The virtual model was validated as a conservative indicator, by means of overestimation, of the influence of alpha angle inaccuracy on area of origin. The study confirms that with proper stain selection, straight-line trajectories to estimate area of origin are valid and reliable. PMID- 23103117 TI - Neoadjuvant treatment improves capsular integrity and the width of the fibrous capsule of high-grade soft-tissue sarcomas. AB - BACKGROUND: Neoadjuvant treatment is thought to improve resection with margin negative surgery in locally advanced soft-tissue sarcomas (STS). Treatment induced alterations of the tumor peripheryhave not yet been microscopically evaluated. OBJECTIVE: This histopathological study compared limb STS with primary resection and those that had undergone neoadjuvant treatment, emphasizing microscopic changes of the fibrous capsule (FC) and reactive zone (RZ) after neoadjuvant treatment. PATIENTS AND METHODS: Patients with primary high-grade limb sarcomas (N = 76) which have not previously been treated were included. Of those, 37 were primarily resected and 39 were treated with one of the following neoadjuvant treatment modalities: 7x chemotherapy (CTX), 3x radiotherapy (RT), 15x isolated limb perfusion (ILP), 8x CTX + RT, and 6x CTX + ILP. Sizes of the FC and RZ were microscopically measured, and FC-integrity was documented. Histopathologic regression was expressed as a percent. RESULTS: Only 35.1% of untreated sarcomas showed an intact FC. We observed significantly higher capsular integrity after treatment (76.9%). Additionally, the average width of the FC (0.21 mm vs. 0.61 mm) and RZ (0.67 mm vs. 1.48 mm) increased significantly. The extent of histopathologic regression showed a correlation with capsular integrity and width. The combination of two treatment modalities (CTX + RT or ILP) showed strongest effects at the tumor periphery. CONCLUSIONS: Neoadjuvant treatment stabilizes the tumor periphery in STS (e.g., the capsule). Concerning local treatment strategies, these novel histopathologic insights might significantly influence the decision as to whether primary resection is advisable in advanced local soft-tissue sarcoma. PMID- 23103118 TI - Ectodermal dysplasias: a clinical and molecular review. AB - The ectodermal dysplasias are a large group of hereditary disorders characterized by alterations of structures of ectodermal origin. Although some syndromes can have specific features, many of them share common clinical characteristics. Two main groups of ectodermal dysplasias can be distinguished. One group is characterized by aplasia or hypoplasia of ectodermal tissues, which fail to develop and differentiate because of a lack of reciprocal signaling between ectoderm and mesoderm, the other has palmoplantar keratoderma as its most striking feature, with additional manifestations when other highly specialized epithelia are also involved. In recent decades, the genes responsible for at least 30 different types of ectodermal dysplasia have been identified, throwing light on the pathogenic mechanisms involved and their correlation with clinical findings. PMID- 23103120 TI - Oxalosis and livedo reticularis. AB - Oxalosis is a disease caused by the deposition of calcium oxalate in extrarenal tissues, most commonly bone, myocardium, retina, blood vessels, and skin, causing the clinical manifestations of the disease. Involvement of the blood vessels of the skin can give rise to livedo reticularis, acrocyanosis, ulcers, and gangrene. We present the case of a 60-year-old woman with a history of recurrent renal lithiasis that had led to terminal renal failure requiring hemodialysis and, subsequently, peritoneal dialysis. The patient developed tender red-violaceous skin discoloration of sudden onset, consistent with livedo reticularis; the lesions progressed to form ulcers. Skin biopsy revealed oxalate vasculopathy. In this article we describe the characteristics of this rare disorder, its differentiation from calciphylaxis, and the therapeutic options. PMID- 23103121 TI - Development and evaluation of a SYBR Green real-time RT-PCR assay for evaluation of cytokine gene expression in horse. AB - Cytokine secretion is one of the main mechanisms by which the immune system is regulated in response to pathogens. Therefore, the measurement of cytokine expression is fundamental to characterizing the immune response to infections. Real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR) is widely used to measure cytokine mRNA levels, but assay conditions should be properly evaluated before analyzing important equine infections through relative quantification of gene expression. The aim of this study was to develop and evaluate a set of RT-qPCR assays for a panel of the most common cytokines in horses involved in innate and adaptive immune responses. Eight cytokines (interleukin (IL)-1beta, IL-2, IL-4, IL-10, IL-12, TNFalpha, IFNbeta and IFNgamma) and a housekeeping gene (beta-actin) were detected and amplified with the same annealing temperature in a SYBR Green RT-qPCR assay of samples of mitogen-stimulated peripheral blood mononuclear cells from a healthy horse and whole blood from a horse infected with African horse sickness virus. The method gave good efficiency for all genes tested, allowing quantification of relative expression levels. These SYBR Green RT-qPCR assays may be useful for examining cytokine gene expression in horses in response to exposure to economically important pathogens. PMID- 23103122 TI - Calcitriol downregulates TNF-alpha and IL-6 expression in cultured placental cells from preeclamptic women. AB - Placenta is an important source and target of hormones that contribute to immunological tolerance and maintenance of pregnancy. In preeclampsia (PE), placental calcitriol synthesis is low; whereas pro-inflammatory cytokines levels are increased, threatening pregnancy outcome. Previously, we showed that calcitriol inhibits Th-1 cytokines under experimental inflammatory conditions in normal trophoblasts. However, a study of the regulation of inflammatory cytokines by calcitriol in trophoblasts from a natural inflammatory condition, such as PE, is still lacking. Therefore, the aim of the present study was to investigate calcitriol effects upon TNF-alpha, IFN-gamma, IL-6 and IL-1beta in cultured placental cells from preeclamptic women by using qPCR and ELISA. Placentas were collected after cesarean section from preeclamptic women and enriched trophoblastic preparations were cultured in the absence or presence of different calcitriol concentrations during 24h. In these cell cultures, pro-inflammatory cytokines TNF-alpha and IL-6 secretion and mRNA expression were downregulated by calcitriol (P<0.05). No significant effects of calcitriol upon IFN-gamma and IL 1beta were observed. In addition, basal expression of TNF-alpha, IL-6 and IL 1beta decreased as the cells formed syncytia. Our study supports an important autocrine/paracrine role of placental calcitriol in controlling adverse immunological responses at the feto-maternal interface, particularly in gestational pathologies associated with exacerbated inflammatory responses such as preeclampsia. PMID- 23103123 TI - Life, death, and the metabolically controlled protein acetylome. AB - The complex signaling pathways that control cellular fate can be intimately influenced by metabolic status. Although the ability of nutrients to influence intracellular decisions has been appreciated for some time, the complex signaling mechanisms linking metabolic inputs to cell proliferation and death are not fully understood. An emerging theme in the literature is that intracellular metabolite levels can directly influence cell fate decisions through modulation of nutrient derived protein modifications. It appears that varying the level of intracellular metabolites can alter the abundance of post-translational modifications, both by altering the availability of donor substrates and changing the activity of the nutrient-sensitive enzymes regulating these reactions. We focus here on protein acetylation, a modification that can modulate both cell proliferation and cell death in response to changes in extracellular nutrient supply. PMID- 23103124 TI - [Myelodysplastic syndromes]. PMID- 23103125 TI - Modelling of living systems: comment on "Thermostatted kinetic equations as models for complex systems in physics and life sciences" by C. Bianca. PMID- 23103126 TI - [Prenatal analysis of primary sulci by ultrasonography and MRI]. AB - Gyration abnormalities often reflect severe neurological diseases. Their diagnosis is impeded by our limited knowledge about normal sulci anatomy throughout fetal brain development. Primary sulci appears in a specific chronology which is unchanged among all fetuses. We think it is interesting to remind of sulci anatomy and then to depict sulci MRI and ultrasonography appearance at 22, 27 and 32 weeks of gestation. We pay particular attention to the lateral sulcus, also called Sylvian fissure. PMID- 23103128 TI - The Kyoto Protocol: beyond the limit of histochemistry. PMID- 23103127 TI - Indoleamine 2,3 dioxygenase and metabolic control of immune responses. AB - Sustained access to nutrients is a fundamental biological need, especially for proliferating cells, and controlling nutrient supply is an ancient strategy to regulate cellular responses to stimuli. By catabolizing the essential amino acid TRP, cells expressing the enzyme indoleamine 2,3 dioxygenase (IDO) can mediate potent local effects on innate and adaptive immune responses to inflammatory insults. Here, we discuss recent progress in elucidating how IDO activity promotes local metabolic changes that impact cellular and systemic responses to inflammatory and immunological signals. These recent developments identify potential new targets for therapy in a range of clinical settings, including cancer, chronic infections, autoimmune and allergic syndromes, and transplantation. PMID- 23103129 TI - A rare case of inguinolabial lipoblastoma in a 13-month-old female. AB - Lipoblastoma is a rare, rapidly growing, benign mesenchymal tumor composed of various stages of maturing adipocytes that most often occurs in children under the age of 3. The common locations are the extremities and the trunk. Presentation in the genitoinguinal area is rare. We report a case of a 13-month old female infant with a 4-month history of a progressively enlarging left labial mass that encompassed her left labium majora and inguinal region. Pelvic MRI confirmed growth from previous ultrasound size of 3 * 2 * 1 cm to 7 * 2 * 2 cm. Composition was suggestive of adipose tissue. The mass was excised through a left inguinal incision. The final pathology results described a lipoblastoma. Six year follow-up has not revealed any signs or symptoms of recurrence. Circumscribed lipoblastomas should be distinguished from their infiltrative counterpart, diffuse lipoblastoma or lipoblastomatosis, which can be more difficult to excise and thus, more likely to recur. Lipoblastoma should also be distinguished from myxoid liposarcoma, which has malignant features, carries a high risk of recurrence, and requires a more aggressive management protocol. Although rare, lipoblastoma should be considered as part of the differential diagnosis of a rapidly growing vulvar mass in prepubertal children. PMID- 23103130 TI - Single trocar retroperitoneoscopic nephrectomy for dysplastic poorly functioning kidney with ectopic ureter in children. AB - This is the first report of a single trocar nephrectomy for poorly functioning dysplastic kidney and ectopic ureter, performed in 5 patients from 2010 to 2011. The mean operative time was 63 min and mean postoperative hospital stay was 31 h. There were no perioperative complications. The single trocar nephrectomy is a feasible and safe procedure for patients with dysplastic kidney and ectopic ureter. PMID- 23103131 TI - Congenital prepubic sinus: a variant of epispadiac dorsal urethral duplication. AB - Congenital prepubic sinus is a tract originating in the skin overlying the base of the penis. Its embryologic basis is still debated. We present a 9-month-old boy with a recurrent muco-purulent discharge from a tiny opening in the midline prepubic area on the base of the penis. Examination revealed a ventrally hooded prepuce, dorsal chordee, penile torsion to the left, and a 3-mm-diameter prepubic sinus 1 cm from the base of the penis. Histology of the excised tract showed a transitional epithelium. We believe our case is an epispadiac variant of dorsal urethral duplication. PMID- 23103133 TI - A prognostic tool to predict fatigue in women with early-stage breast cancer undergoing radiotherapy. AB - BACKGROUND: Fatigue during and after radiotherapy impacts negatively on normal functioning and quality of life. A pre-treatment estimate of the risk of fatigue would facilitate the targeting of timely interventions to limit consequential behavioural symptoms arising. We have developed a prognostic tool to predict the risk of fatigue in women with early-stage breast cancer undergoing radiotherapy. METHODS: Socio-demographic, clinical and self-reported characteristics were recorded for 100 women prescribed adjuvant radiotherapy for stages Tis-T2N1 breast cancer. Multiple logistic regression was used to develop a parsimonious prognostic model. The performance of the model when predicting fatigue for individuals not in the study was estimated by a leave-one-out cross-validation. A statistical weighting was assigned to the model variables to render a Fatigue Propensity Score of between 0 and 15. The ability of the Propensity Score to discriminate fatigued participants was estimated via receiver operating characteristic curve analysis. RESULTS: 38% of participants reported significant fatigue during radiotherapy. Fatigue risk was predicted by elevated pre-treatment fatigue and anxiety, and diagnoses other than invasive ductal carcinoma (ductal carcinoma in-situ, invasive lobular and rarer carcinoma subtypes). The positive predictive value of the prognostic model was 80%. A Propensity Score threshold of >=6 corresponded to a specificity of 90.3% and a sensitivity of 76.3%. The area under the receiver operating characteristic curve was 0.83 for the cross validation sample. CONCLUSIONS: Application of the Fatigue Propensity Score in the patient pathway can help direct fatigue management resources at those patients most likely to benefit. PMID- 23103134 TI - Lp-PLA2--a novel marker of atherosclerosis: to treat or not to treat? PMID- 23103132 TI - The TCF-1 and LEF-1 transcription factors have cooperative and opposing roles in T cell development and malignancy. AB - The TCF-1 and LEF-1 transcription factors are known to play critical roles in normal thymocyte development. Unexpectedly, we found that TCF-1-deficient (Tcf7( /-)) mice developed aggressive T cell malignancy, resembling human T cell acute lymphoblastic leukemia (T-ALL). LEF-1 was aberrantly upregulated in premalignant Tcf7(-/-) early thymocytes and lymphoma cells. We further demonstrated that TCF-1 directly repressed LEF-1 expression in early thymocytes and that conditional inactivation of Lef1 greatly delayed or prevented T cell malignancy in Tcf7(-/-) mice. In human T-ALLs, an early thymic progenitor (ETP) subtype was associated with diminished TCF7 expression, and two of the ETP-ALL cases harbored TCF7 gene deletions. We also showed that TCF-1 and LEF-1 were dispensable for T cell lineage commitment but instead were required for early thymocytes to mature beyond the CD4(-)CD8(-) stage. TCF-1 thus has dual roles, i.e., acting cooperatively with LEF-1 to promote thymocyte maturation while restraining LEF-1 expression to prevent malignant transformation of developing thymocytes. PMID- 23103135 TI - Interpretation of lipoprotein-associated phospholipase A2 levels is influenced by cardiac disease, comorbidities, extension of atherosclerosis and treatments. AB - PURPOSE: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory biomarker secreted in the atherosclerotic plaque. Blood levels of Lp-PLA2 predict future cardiovascular events in patients with ischemic disease and heart failure. This association seems to be independent of traditional cardiovascular risk factors. The aims of our study were (1) to assess relationships between Lp-PLA2 levels, cardiac disease and treatments; (2) to evaluate the association of Lp PLA2 level with the severity of angiographic coronary artery disease (CAD) and the extracoronary atherosclerosis. METHODS: Between December 2009 and June 2010, 494 subjects were recruited from a population scheduled for diagnostic coronary angiography. Routine clinical (age, gender, BMI and treatment), cardiac (echocardiography, coronarography, carotid ultrasonography) and biochemical parameters were recorded for all patients. Lp-PLA2 mass concentration was assessed in serum with a Plac(r)-test turbidimetric immunoassay. Control Lp-PLA2 values were specifically obtained in 61 healthy subjects aged 44.5 +/- 17.6 years (range: 25 to 59 years) without known cardiovascular risk factors (diabetes, smoking, hypertension, dyslipidemia) or cardiac treatment. RESULTS: In healthy controls, mean Lp-PLA2 level was 163 +/- 43 MUg/L (166 +/- 45 MUg/L in men and 159 +/- 39 MUg/L in women, non significant difference). In our cohort of 494 patients (69.8% men) aged 64.2 +/- 16.7 years, the main etiologies of cardiomyopathies were ischemic (40%), valvular (22%), cardiac failure with left ventricular (LV) dysfunction (14%), infection (5%) and aortic aneurysm (7%). Mean Lp-PLA2 levels were 216 +/- 17 MUg/L. Lp-PLA2 correlated with age, BMI, current smoking, history of hypertension but not with diabetes and gender. The bivariate analysis showed a significant correlation between Lp-PLA2, and BMI (p=0.001) but no correlation with serum creatinine or NYHA status. A multivariate correlation showed that Lp-PLA2 was associated with total cholesterol, LDL-cholesterol and apoB (r=0.95, p<0.0001) but not with Lp(a). We observed that Lp-PLA2 was significantly associated with treatments such as statins and ACEi/ARA2 but not with beta-blockers, antiaggregant drugs or diuretics. Lp-PLA2 levels were significantly higher in patients with CAD than in patients without CAD (223 +/- 54 vs. 208 +/- 52 MUg/L, respectively; p<0.007). Moreover, Lp-PLA2 levels were significantly higher in patients with the most extensive angiographic CAD [single (n=24)=215.2 +/- 52 MUg/L; two (n=55)=222 +/- 53 MUg/L and three vessels (n=140)=251.9 +/- 53.7 MUg/L, respectively; p<0.0001]. Patients with heart failure, sepsis or aortic aneurysm had increased Lp-PLA2 levels: 256.2 +/- 46.8; 226.7 +/- 47.3; 218.1 +/- 38.9 MUg/L, respectively, as compared to controls (p<0.0001). In patients with carotid artery disease, Lp-PLA2 significantly increased with the severity of atherosclerosis. Mean Lp-PLA2 levels were 218.8 +/ 51 MUg/L in the group without any stenosis (n=108), 224 +/- 51 MUg/L in the group with mild stenosis (n=101), and 231 +/- 46 MUg/L in the group with severe stenosis (n=22); p=0.004. CONCLUSION: This study clearly shows that interpretation of Lp-PLA2 levels needs a good assessment of cardiac parameters and treatments, especially statins and ACEi/ARA2. Lp-PLA2 levels are significantly associated with coronary heart disease and with the extension of extra coronary disease after adjustment for age and gender. PMID- 23103136 TI - The obesity paradox of mortality in patients with coronary artery disease undergoing percutaneous coronary intervention. PMID- 23103137 TI - Reliability revisited: autonomic responses in the context of everyday well-being. PMID- 23103138 TI - Review: the physiological and computational approaches for atherosclerosis treatment. AB - The cardiovascular disease has long been an issue that causes severe loss in population, especially those conditions associated with arterial malfunction, being attributable to atherosclerosis and subsequent thrombotic formation. This article reviews the physiological mechanisms that underline the transition from plaque formation in atherosclerotic process to platelet aggregation and eventually thrombosis. The physiological and computational approaches, such as percutaneous coronary intervention and stent design modeling, to detect, evaluate and mitigate this malicious progression were also discussed. PMID- 23103139 TI - Objective cardiac markers in dementia: results from the Kerala-Einstein study. PMID- 23103140 TI - Physical activity is associated with improved subclinical atherosclerosis in spinal cord injury subjects independent of variation in traditional risk factors. PMID- 23103141 TI - The relationship between cardiac autonomic functions and left ventricular diastolic dysfunctions in metabolic syndrome. PMID- 23103142 TI - Untreated obstructive sleep apnea as a differential diagnosis in young woman with aortic dissection. PMID- 23103143 TI - Gender-related differences of diabetic patients undergoing percutaneous coronary intervention with drug-eluting stents: a real-life multicenter experience. AB - BACKGROUND: Gender-based differences in diabetic patients are understudied in the field of percutaneous coronary intervention (PCI) with drug-eluting stents. METHODS: Data were obtained from a multicenter registry of 2420 consecutive patients with diabetes mellitus (DM) who underwent PCI with paclitaxel- or sirolimus-eluting stents between 2003 and 2009. Among them, 679 (28.1%) women were compared to 1741 (71.9%) men in terms of clinical aspects and major adverse cardiac events (MACE), including all-cause death, myocardial infarction (MI) and target lesion revascularization (TLR). Target vessel revascularization (TVR) and any revascularization were also reported. RESULTS: Women were less numerous, older, used more insulin and showed more tortuous coronary arteries, while men were more frequently smokers and received larger stents. At the median follow-up of 24.3 months (interquartile range 12.3-39.7), MACE, TVR and any revascularization did not significantly differ between females and males (19.9% vs 18.7%, 12.2% vs 13.4%, 14.1% vs 15.1%, respectively). At multivariable analysis of the overall cohort, female gender was not a predictor of MACE (hazard ratio [HR] 1.02, 95% confidence interval [CI] 0.92-2.36, p=0.11), death (HR 1.04, 95% CI 0.84-1.24, p=0.86), MI (HR 1.48, 95% CI 0.92-2.36, p=0.11), and TLR (HR 1.14, 95% CI 0.85-1.52, p=0.38). CONCLUSION: In this registry of diabetic patients treated by drug-eluting stents, women were less represented, older and needed more insulin compared to men who, on the other hand, received larger stents. Gender-related outcomes were similar and female sex did not predict MACE. PMID- 23103144 TI - Features of left ventricular noncompaction in peripartum cardiomyopathy: a case series. PMID- 23103145 TI - Cardiovascular health status in Chinese adults in urban areas: analysis of the Chinese Health Examination Database 2010. AB - BACKGROUND: The American Heart Association (AHA) recently developed definitions of cardiovascular health for adults and children based on 7 cardiovascular disease risk factors or health behaviors. We applied this new construct to examine the cardiovascular health status in adult Chinese urban residents. METHODS: Data of 1,012,418 subjects aged 20-65 years (55% were men; mean age, 42.4 years) who received health examination at 58 health examination centers across China was analyzed. The AHA ideal health behaviors index and ideal health factor index were evaluated among the subjects. RESULTS: Only 0.6% of male and 2.6% of female subjects met all 7 health components, and only 39.1% of the subjects met 5 or more components of ideal cardiovascular health. The prevalence of "ideal", "intermediate" and "poor" cardiovascular health was 1.5%, 33.9% and 64.6%, respectively. CONCLUSION: About two-thirds of the adult Chinese urban population has "poor" cardiovascular health. Comprehensive individual and population-based interventions must be developed to improve cardiovascular health status in China. PMID- 23103146 TI - Stroke risk and suboptimal thromboprophylaxis in Chinese patients with atrial fibrillation: would the novel oral anticoagulants have an impact? AB - BACKGROUND: The risk of stroke associated with atrial fibrillation (AF) is higher in Far Eastern population than in Western population, and warfarin use suboptimal. There is uncertainty whether the novel oral anticoagulants (NOACs) would have a major impact on stroke prevention in Far Eastern populations with AF. OBJECTIVES: We investigated current antithrombotic therapy use on stroke and bleeding risk, determinants of warfarin use and performed a modeling analysis of the net clinical benefit of the NOACs (apixaban, dabigatran) in a large cohort of Chinese patients with AF. METHODS: We studied 1034 Chinese patients (27.1% female, median age 75 years, interquartile range [IQR]: 63-83) with AF who were followed-up for an average of 1.9 years (IQR: 1.43-2.64). Stroke/thromboembolism (TE), and major bleeding associated to antithrombotic treatment were investigated. A modeling analysis was performed for the net clinical benefit balancing major bleeding against stroke/TE for dabigatran 110 mg bid, dabigatran 150 mg bid and apixaban, using their respective recent clinical trial outcome data. RESULTS: Using a Cox proportional hazard model, the Hazard Ratio [HR (95% confidence interval, CI)] for stroke/TE compared to no-antithrombotic therapy (no ATT) was 1.27 (0.65-2.50) on aspirin, 1.40 (0.35-3.57) on clopidogrel, 1.52 (0.72 3.23) on dual antiplatelets and 1.65 (0.76-3.57) on warfarin. The risk for major bleeding was 0.35 (0.14-0.85) on aspirin, 0.74 (0.24-2.29) on clopidogrel, 0.35 (0.11-1.10) on dual antiplatelets, and 0.88 (0.36-2.17) on warfarin. Binary logistic regression analysis showed persistent/permanent AF (Odds Ratio, OR, 2.03 [95%CI 1.05-3.92], p=0.035) was associated with warfarin use, but age >=75 years (0.26 [0.16-0.42], p<0.001), aspirin (0.18 [0.12-0.27], p<0.001) and clopidogrel (0.17 [0.08-0.33], p<0.001) were independent determinants of non-use of warfarin. On modeling net clinical benefit (per 100 person-years [95% CI]), apixaban use compared to antiplatelet agents or no ATT was 3.29 (2.15-4.30) using Singer's method and 2.08 (1.18-3.21) with Connolly's method amongst high-risk patients. The use of dabigatran 110 mg bid and 150 mg bid compared to antiplatelet agents could reduce an additional 18.1 stroke/TE and 24.3 stroke/TE events, respectively. Compared to warfarin, dabigatran 150 mg bid had the best net clinical benefit. CONCLUSIONS: There was suboptimal stroke prevention with no difference between antiplatelet and OAC treated patients, perhaps reflecting an inappropriate Target INR range. On modeling analyses, the use of the NOACs (apixaban and dabigatran) could provide better stroke prevention compared to antiplatelet (or warfarin) use in this Chinese AF population, with a positive net clinical benefit. PMID- 23103147 TI - Acute myocardial infarction without cardiogenic shock does not affect serum prostate specific antigen levels: a case control study. PMID- 23103148 TI - The importance of L-arginine metabolism modulation in diabetic patients with distal symmetric polyneuropathy. AB - BACKGROUND: Micro and macrovascular disease is the most frequent cause of morbidity and mortality of the patients with diabetes mellitus. The recent investigations have pointed out the relationship between endothelial dysfunction and the progression of these diabetic complications, suggesting the crucial role of nitric oxide, vasodilator molecule of endothelial origin, in these events, including diabetic symmetric polyneuropathy. MATERIAL AND METHODS: The present study encompassed 100 individuals with diabetes mellitus type II and diabetic distal symmetric polyneuropathy (DSP). Nitrate+nitrite concentration, 3 nitrotyrosine, S-nitrosothiols, ADMA and SDMA levels and arginase activity were determined compared to the control group consisted of 50 age and sex matched voluntary blood donors. RESULTS: NO(2)+NO(3) concentrations, as well as 3 nitrotyrosine, S-nitrosothiol, ADMA and SDMA levels were significantly higher in patients with DSP compared to the control group. Plasma arginase activity in the patients with diabetic DSP was significantly lower compared to the values in plasma of control subjects. CONCLUSION: The obtained results confirmed that nitrate+nitrite, 3-nitrotyrosine, S-nitrosothiols, ADMA, SDMA and arginase activity determination in plasma of patients with diabetic DSP could be useful in monitoring the disease development and in assesing the therapy effects. PMID- 23103149 TI - Nourishment practices on Australian sandy beaches: a review. AB - It is predicted that the coastal zone will be among the environments worst affected by projected climate change. Projected losses in beach area will negatively impact on coastal infrastructure and continued recreational use of beaches. Beach nourishment practices such as artificial nourishment, replenishment and scraping are increasingly used to combat beach erosion but the extent and scale of projects is poorly documented in large areas of the world. Through a survey of beach managers of Local Government Areas and a comprehensive search of peer reviewed and grey literature, we assessed the extent of nourishment practices in Australia. The study identified 130 beaches in Australia that were subject to nourishment practices between 2001 and 2011. Compared to projects elsewhere, most Australian projects were small in scale but frequent. Exceptions were nine bypass projects which utilised large volumes of sediment. Most artificial nourishment, replenishment and beach scraping occurred in highly urbanised areas and were most frequently initiated in spring during periods favourable to accretion and outside of the summer season of peak beach use. Projects were generally a response to extreme weather events, and utilised sand from the same coastal compartment as the site of erosion. Management was planned on a regional scale by Local Government Authorities, with little monitoring of efficacy or biological impact. As rising sea levels and growing coastal populations continue to put pressure on beaches a more integrated approach to management is required, that documents the extent of projects in a central repository, and mandates physical and biological monitoring to help ensure the engineering is sustainable and effective at meeting goals. PMID- 23103150 TI - Optokinetic stimulation can break Listing's law without induction of eye movement. AB - OBJECTIVE: Pseudo-images of three-dimensional eye movements captured on an infrared video oculogram can be translated onto a rotational expression around axial vector. This provides a subject's Listing's plane, which moves according to the head's orientation relative to gravity. Optokinetically induced changes in the cognitive gravitational reference frame will affect the context of Listing's plane. The purpose of this study was to estimate the effect of OKS on Listing's plane. METHODS: In this study, we presented vertical optokinetic visual stimulation with fixation targets, which are thought to induce pseudo-inclination of the head, and evaluated changes in the subjects' Listing's plane. RESULTS: We observed no stimulus-induced movement of Listing's plane that corresponded to the assumed pseudo-recognition of a change in verticality. On the other hand, we did observe vergence movement of Listing's plane (in the yaw plane), which corresponded to exposure to diminished and increased gravitational circumstance. In addition, the thickness of Listing's plane significantly increased with the load of each stimulation. CONCLUSION: Vertical OKS leads to a rotation of Listing's plane mainly around a vertical axis. This may represent false exhibition of central compensatory re-weighting with respect to inherent otoconial mass asymmetry resulting from the OKS-mediated loss of the gravity reference. In addition, a OKS-mediated thickening of Listing's plane suggests to us that confusing visual input can reduce the stability of the internal model, which would likely manifest itself as a thickening of Listing's plane. In other words, fluctuation between the build-up and drop-out of vection induced by optokinetic stimulation will cause a thickening of Listing's plane. The thickness of Listing's plane could be a novel clinical parameter for quantitatively evaluating static vestibular function and accuracy of the internal model. PMID- 23103151 TI - Evaluation of cytologically benign solitary thyroid nodules by ultrasonography: a retrospective analysis of 1877 cases. AB - OBJECTIVE: The purpose of this study is to evaluate the role of ultrasonography (US) in the management of thyroid nodules when the cytology is benign tumor on fine needle aspiration biopsy (FNAB). METHODS: Between 2006 and 2011, we investigated 13,972 patients who had solitary thyroid nodule with cytological findings of benign. Surgery was performed according to our criteria for surgical indication. Of these patients, 1877 (13%) patients who underwent surgery were enrolled in this study. We compared the results of clinical findings including US classification and final histopathological diagnosis. RESULTS: One hundred seven (6%) after surgery were diagnosed as malignancy pathologically. Large nodule or high serum thyroglobulin level were not associated with an increased risk of malignancy. Ultrasonographic evaluation as malignancy was directly linked to pathological diagnosis as thyroid carcinoma (p<0.001). CONCLUSION: US may help to play a role in deciding whether surgical treatment is necessary for cytologically benign thyroid nodules. PMID- 23103152 TI - Application of distortion product otoacoustic emissions to inflation of the eustachian tube in low frequency tinnitus with normal hearing. AB - OBJECTIVE: This study was designed to investigate the applications of distortion product otoacoustic emissions to assess the efficacy of eustachian tube inflation on low frequency tinnitus with normal hearing. METHODS: Ninety-four patients (155 ears) suffering from subjective tinnitus with normal hearing sensitivity participated in this study. Control group consists of fifty volunteers (100 ears) without tinnitus. They were subjected to full history taking, otoscopy, basic audiologic evaluation and distortion product otoacoustic emissions (DPOAE). As for the patients with decreased DPOAE amplitude over a limited frequency range from 0.5 to 1kHz, we offered nose dropping and tubal inflation for a week and DPOAE was preformed again. The patients were followed up for a month. RESULTS: 34.8% DPOAE-gram showed decreased amplitude at the frequencies from 0.5 to 1kHz in tinnitus group and "the ring" is mostly lower in pitch. Among the patients accepted the treatment of eustachian tube inflation, 16.7% the tinnitus disappeared, no recurrence within one month; 66.67% the tinnitus reduced within one month. 95.5% the amplitude of DPOAE showed improved over the limited frequency. 16.7% the tinnitus still existed. CONCLUSION: The changes of the mechanical properties of ossicular chain or the tympanic membrane influenced by tympanum pressure may cause tinnitus, which is sub-clinical prior to the changes of audiometry and tympanometry. The low frequency tinnitus may gain transitory relief from ringing with the tubal inflation. DPOAE was proved to be a useful tool in the evaluation of the efficacy of tubal inflation on low frequency tinnitus with normal hearing. PMID- 23103153 TI - Intracochlear schwannoma extending to vestibule. AB - Intralabyrinthine schwannomas are benign tumors arising de novo from the perineural Schwann cell sheath of the intralabyrinthine branches of the vestibulocochlear nerve. The development of magnetic resonance imaging (MRI) has significantly increased the diagnosis of these tumors. Intralabyrinthine schwannomas can be sub-classified into seven groups according to the structures of the inner ear that are affected. The management strategy for intralabyrinthine schwannoma is regular monitoring with MRI, as the tumor grows slowly. In cases where the tumor growth is documented on serial MRI or disturbing vestibular symptoms are present, surgical removal can be considered. The surgical approach varies based on tumor location and size. We report a case of intravestibulocochlear schwannoma causing vertigo that developed from an intracochlear tumor during MRI. We successfully removed the tumor via the transotic approach. PMID- 23103154 TI - Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment. AB - While human bone morphogenetic protein-2 (rhBMP-2) is a promising growth factor for bone regeneration, its clinical efficacy has recently shown to be below expectation. In order to improve the clinical translation of rhBMP-2, there exists strong motivation to engineer better delivery systems. Hyaluronic acid (HA) hydrogel is a suitable carrier for the delivery of rhBMP-2, but a major limitation of this scaffold is its low cell adhesive properties. In this study, we have determined whether covalent grafting of an integrin-specific ligands into HA hydrogel could improve cell attachment and further enhance the osteogenic potential of rhBMP-2. A structurally stabilized fibronectin (FN) fragment containing the major integrin-binding domain of full-length FN (FN III9*-10) was engineered, in order to be incorporated into HA hydrogel. Compared to non functionalized HA hydrogel, HA-FN hydrogel remarkably improved the capacity of the material to support mesenchymal stem cell attachment and spreading. In an ectopic bone formation model in the rat, delivery of rhBMP-2 with HA-FN hydrogel resulted in the formation of twice as much bone with better organization of collagen fibers compared to delivering the growth factor in non-functionalized HA hydrogel. This engineered hydrogel carrier for rhBMP-2 can be relevant in clinical bone repair. PMID- 23103155 TI - Effects of pH on molecular mechanisms of chitosan-integrin interactions and resulting tight-junction disruptions. AB - Chitosan (CS) is a potential paracellular permeation enhancer for trans epithelial drug delivery; however, its ability to enhance epithelial permeability in a pH-dependent manner remains unclear. This study was designed to explore the underlying molecular mechanisms with regard to the effect of CS on tight junction (TJ) disruption at different pH environments in Caco-2 cell monolayers. The experimental results revealed that the direct interaction between CS and integrin alpha(V)beta(3) on cell surfaces has a crucial role in CS-induced TJ opening, an indication of receptor activation. The mechanism of action appeared to be the electrostatic interaction between the positively-charged CS and the negatively charged integrin alpha(V)beta(3). This electrostatic interaction led to the conformation change of integrin alpha(V)beta(3) and its clustering along the cell border, F-actin reorganization, and CLDN4 down-regulation, eventually resulting in the disruption of TJs and an increase in paracellular permeability. The above observations were all in a pH-dependent manner. As pH increased, CS became less positively charged, thereby losing its capability to interact with integrin alpha(V)beta(3) and failing to induce the TJ opening. These consequences might help to better understand the molecular mechanism of TJ opening mediated by CS, thereby facilitating the use of CS for trans-epithelial drug delivery. PMID- 23103156 TI - Transferrin receptor specific nanocarriers conjugated with functional 7peptide for oral drug delivery. AB - In an attempt to increase the interaction of a nanocarrier system with gastrointestinal epithelial cells, a transferrin receptor (TfR) specific 7peptide was conjugated to PEG-b-PCL copolymer and the functional nanocarriers were constructed and characterized. The endocytosis, intracellular trafficking and transcytosis of such nanocarriers loaded with coumarin 6 (7pep-M-C6) in a human colon carcinoma cell line (Caco-2) were investigated, followed by the in vivo intestine distribution study. The real-time imaging of live cell, three dimensional reconstruction of confocal image, quantitative colocalization analysis and other techniques were applied. First, the TfR expression was confirmed in Caco-2. Then, 7pep-M-C6 exhibited higher intracellular uptake compared with unmodified nanocarriers. In a live cell study, 7pep-M-C6 demonstrated faster uptake kinetics especially in the surface of cells. Together with a competition study using TfR antibody, it was proved that the increased cellular uptake was due to a receptor-mediated mechanism. Besides the unspecific endocytosis pathway, 7pep-M-C6 was found to enter the cells through a specific clathrin-mediated mechanism, related to the expression of TfR on Caco-2 cells. Possibly for this reason, 7pep-M-C6 tended to colocalize more with late endosomes and lysosomes than the control micelles. Also for the same mechanism, the increased transport of 7pep-M-C6 across Caco-2 monolayer was found, through a transcellular but not a paracellular pathway, while an increased in vivo intestinal distribution of 7pep-M-C6 was observed. In conclusion, the functional nanocarriers could specifically interact with gastrointestinal endothelial cells, increase their transport and alter their pathway as a result. PMID- 23103158 TI - Generation of human secondary cardiospheres as a potent cell processing strategy for cell-based cardiac repair. AB - Cell therapy is a promising approach for repairing damaged heart. However, there are large rooms to be improved in therapeutic efficacy. We cultured a small quantity (5-10 mg) of heart biopsy tissues from 16 patients who received heart transplantation. We produced primary and secondary cardiospheres (CSs) using repeated three-dimensional culture strategy and characterized the cells. Approximately 5000 secondary CSs were acquired after 45 days. Genetic analysis confirmed that the progenitor cells in the secondary CSs originated from the innate heart, but not from extra-cardiac organs. The expressions of Oct4 and Nanog were significantly induced in secondary CSs compared with adherent cells derived from primary CSs. Those expressions in secondary CSs were higher in a cytokine-deprived medium than in a cytokine-supplemented one, suggesting that formation of the three-dimensional structure was important to enhance stemness whereas supplementation with various cytokines was not essential. Signal blocking experiments showed that the ERK and VEGF pathways are indispensable for sphere formation. To optimize cell processing, we compared four different methods of generating spheres. Method based on the hanging-drop or AggreWellTM was superior to that based on the poly-d-lysine-coated dish or Petri dish with respect to homogeneity of the product, cellular potency and overall simplicity of the process. When transplanted into the ischemic myocardium of immunocompromised mice, human secondary CSs differentiated into cardiomyocytes and endothelial cells. These results demonstrate that generation of secondary CSs from a small quantity of adult human cardiac tissue is a feasible and effective cell processing strategy to improve the therapeutic efficacy of cell therapy. PMID- 23103157 TI - Mitigation of diabetes-related complications in implanted collagen and elastin scaffolds using matrix-binding polyphenol. AB - There is a major need for scaffold-based tissue engineered vascular grafts and heart valves with long-term patency and durability to be used in diabetic cardiovascular patients. We hypothesized that diabetes, by virtue of glycoxidation reactions, can directly crosslink implanted scaffolds, drastically altering their properties. In order to investigate the fate of tissue engineered scaffolds in diabetic conditions, we prepared valvular collagen scaffolds and arterial elastin scaffolds by decellularization and implanted them subdermally in diabetic rats. Both types of scaffolds exhibited significant levels of advanced glycation end products (AGEs), chemical crosslinking and stiffening -alterations which are not favorable for cardiovascular tissue engineering. Pre-implantation treatment of collagen and elastin scaffolds with penta-galloyl glucose (PGG), an antioxidant and matrix-binding polyphenol, chemically stabilized the scaffolds, reduced their enzymatic degradation, and protected them from diabetes-related complications by reduction of scaffold-bound AGE levels. PGG-treated scaffolds resisted diabetes-induced crosslinking and stiffening, were protected from calcification, and exhibited controlled remodeling in vivo, thereby supporting future use of diabetes-resistant scaffolds for cardiovascular tissue engineering in patients with diabetes. PMID- 23103160 TI - Intrinsic catalytic activity of Au nanoparticles with respect to hydrogen peroxide decomposition and superoxide scavenging. AB - Gold nanoparticles have received a great deal of interest due to their unique optical and catalytic properties and biomedical applications. Developing applications as well as assessing associated risks requires an understanding of the interactions between Au nanoparticles (NPs) and biologically active substances. In this paper, electron spin resonance spectroscopy (ESR) was used to investigate the catalytic activity of Au NPs in biologically relevant reactions. We report here that Au NPs can catalyze the rapid decomposition of hydrogen peroxide. Decomposition of hydrogen peroxide is accompanied by the formation of hydroxyl radicals at lower pH and oxygen at higher pH. In addition, we found that, mimicking SOD, Au NPs efficiently catalyze the decomposition of superoxide. These results demonstrate that Au NPs can act as SOD and catalase mimetics. Since reactive oxygen species are biologically relevant products being continuously generated in cells, these results obtained under conditions resembling different biological microenvironments may provide insights for evaluating risks associated with Au NPs. PMID- 23103159 TI - The induction of cytokines by polycation containing microspheres by a complement dependent mechanism. AB - The cytokine-inducing potential of various microspheres were evaluated in a short time screening assay of lepirudin-anticoagulated human whole blood utilizing the Bio-Plex Human cytokine 27-plex system. The inflammatory cytokines IL-1beta, TNF and IL-6; the anti-inflammatory mediators IL-1ra and IL-10; the chemokines IL-8, MIP-1alpha and MCP-1; and the growth factor VEGF were induced by polycation (poly l-lysine or poly(methylene-co-guanidine)) containing microspheres. Alginate microspheres without polycations did not induce the corresponding cytokine panel, nor did soluble alginate. By inhibiting complement C3 using compstatin analog CP20, a total inhibition of complement activation as well as the inflammatory mediators was achieved, indicating that complement activation alone was responsible for the induced cytokines. A strong deposition of C3c on the poly-l lysine containing surface, while not on the microspheres lacking polycations, also points to the formation of C3 convertase as involved in the biomaterial induced cytokine induction. These results show that complement is responsible for the induction of cytokines by polycation containing microspheres. We point to complement as an important initiator of inflammatory responses to biomaterials and the lepirudin anticoagulated whole blood assay as an important tool to identify the most tolerable and safe materials for implantation to humans. PMID- 23103161 TI - Buckle up: non-seat belt use and antisocial behavior in the United States. AB - OBJECTIVE: To compare persons who report that they never wear a seat belt while driving or as a passenger with those who do in a nationally representative sample in the United States. Our guiding hypothesis is that failure to wear a seat belt is part of an antisocial behavior spectrum. METHODS: Using public-use data from the 2010 National Survey on Drug Use and Health, this study employed binary logistic regression with adjustments for complex survey sampling to assess relationships between never wearing a seat belt and sociodemographic variables, antisocial behaviors, substance abuse and co-occurring problems, and criminal justice system contact. RESULTS: Individuals who do not wear seat belts are younger, more likely to be male, less likely to be African American or Hispanic, have incomes of less than $75,000, and be a high school or college graduate. After controlling for the effects of age, gender, race, income, education, and population density, individuals reporting that they never wear a seat belt while driving or as a passenger are more likely to report using alcohol and drugs (adjusted odds, 1.61-2.56), committing antisocial behaviors including felony offenses (adjusted odds, 2.13-3.57), and possess a dual diagnosis (adjusted odds, 1.62-1.73). CONCLUSIONS: Findings indicate that non-seat belt use is convergent with a spectrum of serious antisocial behavior and comorbid psychological distress. Importantly, results suggest that standard seat belt use policies and campaigns may not be effective for non-seat belt using individuals and a targeted approach may be needed. PMID- 23103162 TI - Cardiovascular protection by ApoE and ApoE-HDL linked to suppression of ECM gene expression and arterial stiffening. AB - Arterial stiffening is a risk factor for cardiovascular disease, but how arteries stay supple is unknown. Here, we show that apolipoprotein E (apoE) and apoE containing high-density lipoprotein (apoE-HDL) maintain arterial elasticity by suppressing the expression of extracellular matrix genes. ApoE interrupts a mechanically driven feed-forward loop that increases the expression of collagen I, fibronectin, and lysyl oxidase in response to substratum stiffening. These effects are independent of the apoE lipid-binding domain and transduced by Cox2 and miR-145. Arterial stiffness is increased in apoE null mice. This stiffening can be reduced by administration of the lysyl oxidase inhibitor BAPN, and BAPN treatment attenuates atherosclerosis despite highly elevated cholesterol. Macrophage abundance in lesions is reduced by BAPN in vivo, and monocyte/macrophage adhesion is reduced by substratum softening in vitro. We conclude that apoE and apoE-containing HDL promote healthy arterial biomechanics and that this confers protection from cardiovascular disease independent of the established apoE-HDL effect on cholesterol. PMID- 23103163 TI - Removal of Polycomb repressive complex 2 makes C. elegans germ cells susceptible to direct conversion into specific somatic cell types. AB - How specific cell types can be directly converted into other distinct cell types is a matter of intense investigation with wide-ranging basic and biomedical implications. Here, we show that removal of the histone 3 lysine 27 (H3K27) methyltransferase Polycomb repressor complex 2 (PRC2) permits ectopically expressed, neuron-type-specific transcription factors ("terminal selectors") to convert Caenorhabditis elegans germ cells directly into specific neuron types. Terminal-selector-induced germ-cell-to-neuron conversion can be observed not only upon genome-wide loss of H3K27 methylation in PRC2(-) animals but also upon genome-wide redistribution of H3K27 methylation patterns in animals that lack the H3K36 methyltransferase MES-4. Manipulation of the H3K27 methylation status not only permits conversion of germ cells into neurons but also permits hlh-1/MyoD dependent conversion of germ cells into muscle cells, indicating that PRC2 protects the germline from the aberrant execution of multiple distinct somatic differentiation programs. Taken together, our findings demonstrate that the normally multistep process of development from a germ cell via a zygote to a terminally differentiated somatic cell type can be short-cut by providing an appropriate terminal selector transcription factor and manipulating histone methylation patterns. PMID- 23103164 TI - A small molecule that promotes cardiac differentiation of human pluripotent stem cells under defined, cytokine- and xeno-free conditions. AB - Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, are potentially useful in regenerative therapies for heart disease. For medical applications, clinical-grade cardiac cells must be produced from hPSCs in a defined, cost-effective manner. Cell-based screening led to the discovery of KY02111, a small molecule that promotes differentiation of hPSCs to cardiomyocytes. Although the direct target of KY02111 remains unknown, results of the present study suggest that KY02111 promotes differentiation by inhibiting WNT signaling in hPSCs but in a manner that is distinct from that of previously studied WNT inhibitors. Combined use of KY02111 and WNT signaling modulators produced robust cardiac differentiation of hPSCs in a xeno-free, defined medium, devoid of serum and any kind of recombinant cytokines and hormones, such as BMP4, Activin A, or insulin. The methodology has potential as a means for the practical production of human cardiomyocytes for regeneration therapies. PMID- 23103165 TI - SAP102 mediates synaptic clearance of NMDA receptors. AB - Membrane-associated guanylate kinases (MAGUKs) are the major family of scaffolding proteins at the postsynaptic density. The PSD-MAGUK subfamily, which includes PSD-95, PSD-93, SAP97, and SAP102, is well accepted to be primarily involved in the synaptic anchoring of numerous proteins, including N-methyl-D aspartate receptors (NMDARs). Notably, the synaptic targeting of NMDARs depends on the binding of the PDZ ligand on the GluN2B subunit to MAGUK PDZ domains, as disruption of this interaction dramatically decreases NMDAR surface and synaptic expression. We recently reported a secondary interaction between SAP102 and GluN2B, in addition to the PDZ interaction. Here, we identify two critical residues on GluN2B responsible for the non-PDZ binding to SAP102. Strikingly, either mutation of these critical residues or knockdown of endogenous SAP102 can rescue the defective surface expression and synaptic localization of PDZ binding deficient GluN2B. These data reveal an unexpected, nonscaffolding role for SAP102 in the synaptic clearance of GluN2B-containing NMDARs. PMID- 23103166 TI - The transporter Spns2 is required for secretion of lymph but not plasma sphingosine-1-phosphate. AB - Plasma sphingosine-1-phosphate (S1P) regulates vascular permeability, and plasma and lymph S1P guide lymphocyte egress from lymphoid organs. S1P is made intracellularly, and little is known about how S1P is delivered into circulatory fluids. Here, we find that mice without the major facilitator superfamily transporter Spns2 have a profound reduction in lymph S1P, but only a minor decrease in plasma S1P. Spns2-deficient mice have a redistribution of lymphocytes from the spleen to lymph nodes and a loss of circulating lymphocytes, consistent with normal egress from the spleen directed by plasma S1P and blocked egress from lymph nodes directed by lymph S1P. Spns2 is needed in endothelial cells to supply lymph S1P and support lymphocyte circulation. As a differential requirement for lymph and blood S1P, Spns2 may be an attractive target for immune suppressive drugs. PMID- 23103167 TI - Dynamics of intracellular clathrin/AP1- and clathrin/AP3-containing carriers. AB - Clathrin/AP1- and clathrin/AP3-coated vesicular carriers originate from endosomes and the trans-Golgi network. Here, we report the real-time visualization of these structures in living cells reliably tracked by rapid, three-dimensional imaging with the use of a spinning-disk confocal microscope. We imaged relatively sparse, diffraction-limited, fluorescent objects containing chimeric fluorescent protein (clathrin light chain, sigma adaptor subunits, or dynamin2) with a spatial precision of up to ~30 nm and a temporal resolution of ~1 s. The dynamic characteristics of the intracellular clathrin/AP1 and clathrin/AP3 carriers are similar to those of endocytic clathrin/AP2 pits and vesicles; the clathrin/AP1 coats are, on average, slightly shorter-lived than their AP2 and AP3 counterparts. We confirmed that although dynamin2 is recruited as a burst to clathrin/AP2 pits immediately before their budding from the plasma membrane, we found no evidence supporting a similar association of dynamin2 with clathrin/AP1 or clathrin/AP3 carriers at any stage during their lifetime. We found no effects of chemical inhibitors of dynamin function or the K44A dominant-negative mutant of dynamin on AP1 and AP3 dynamics. This observation suggests that an alternative budding mechanism, yet to be discovered, is responsible for the scission step of clathrin/AP1 and clathrin/AP3 carriers. PMID- 23103168 TI - The H3K27 demethylase JMJD3 is required for maintenance of the embryonic respiratory neuronal network, neonatal breathing, and survival. AB - JMJD3 (KDM6B) antagonizes Polycomb silencing by demethylating lysine 27 on histone H3. The interplay of methyltransferases and demethylases at this residue is thought to underlie critical cell fate transitions, and the dynamics of H3K27me3 during neurogenesis posited for JMJD3 a critical role in the acquisition of neural fate. Despite evidence of its involvement in early neural commitment, however, its role in the emergence and maturation of the mammalian CNS remains unknown. Here, we inactivated Jmjd3 in the mouse and found that its loss causes perinatal lethality with the complete and selective disruption of the pre Botzinger complex (PBC), the pacemaker of the respiratory rhythm generator. Through genetic and electrophysiological approaches, we show that the enzymatic activity of JMJD3 is selectively required for the maintenance of the PBC and controls critical regulators of PBC activity, uncovering an unanticipated role of this enzyme in the late structuring and function of neuronal networks. PMID- 23103169 TI - The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast. AB - Antagonistic pleiotropy (AP), or genetic tradeoff, is an important concept that is frequently invoked in theories of aging, cancer, genetic disease, and other common phenomena. However, the prevalence of AP, which genes are subject to AP, and to what extent and how AP may be resolved remain unclear. By measuring the fitness difference between the wild-type and null alleles of ~5,000 nonessential genes in yeast, we found that in any given environment, yeast expresses hundreds of genes that harm rather than benefit the organism, demonstrating widespread AP. Nonetheless, under sufficient selection, AP is often resolvable through regulatory evolution, primarily by trans-acting changes, although in one case we also detected a cis-acting change and localized its causal mutation. However, AP is resolved more slowly in smaller populations, predicting more unresolved AP in multicellular organisms than in yeast. These findings provide an empirical foundation for AP-dependent theories and have broad biomedical and evolutionary implications. PMID- 23103170 TI - Large-scale functional organization of long-range chromatin interaction networks. AB - Chromatin interactions play important roles in transcription regulation. To better understand the underlying evolutionary and functional constraints of these interactions, we implemented a systems approach to examine RNA polymerase-II associated chromatin interactions in human cells. We found that 40% of the total genomic elements involved in chromatin interactions converged to a giant, scale free-like, hierarchical network organized into chromatin communities. The communities were enriched in specific functions and were syntenic through evolution. Disease-associated SNPs from genome-wide association studies were enriched among the nodes with fewer interactions, implying their selection against deleterious interactions by limiting the total number of interactions, a model that we further reconciled using somatic and germline cancer mutation data. The hubs lacked disease-associated SNPs, constituted a nonrandomly interconnected core of key cellular functions, and exhibited lethality in mouse mutants, supporting an evolutionary selection that favored the nonrandom spatial clustering of the least-evolving key genomic domains against random genetic or transcriptional errors in the genome. Altogether, our analyses reveal a systems level evolutionary framework that shapes functionally compartmentalized and error tolerant transcriptional regulation of human genome in three dimensions. PMID- 23103173 TI - Surviving sepsis: a systems issue. PMID- 23103171 TI - Antagonism between MES-4 and Polycomb repressive complex 2 promotes appropriate gene expression in C. elegans germ cells. AB - The Caenorhabditis elegans MES proteins are key chromatin regulators of the germline. MES-2, MES-3, and MES-6 form the C. elegans Polycomb repressive complex 2 and generate repressive H3K27me3. MES-4 generates H3K36me3 on germline expressed genes. Transcript profiling of dissected mutant germlines revealed that MES-2/3/6 and MES-4 cooperate to promote the expression of germline genes and repress the X chromosomes and somatic genes. Results from genome-wide chromatin immunoprecipitation showed that H3K27me3 and H3K36me3 occupy mutually exclusive domains on the autosomes and that H3K27me3 is enriched on the X. Loss of MES-4 from germline genes causes H3K27me3 to spread to germline genes, resulting in reduced H3K27me3 elsewhere on the autosomes and especially on the X. Our findings support a model in which H3K36me3 repels H3K27me3 from germline genes and concentrates it on other regions of the genome. This antagonism ensures proper patterns of gene expression for germ cells, which includes repression of somatic genes and the X chromosomes. PMID- 23103172 TI - The role of the Panton-Valentine leucocidin toxin in staphylococcal disease: a systematic review and meta-analysis. AB - BACKGROUND: Invasive community-onset staphylococcal disease has emerged worldwide associated with Panton-Valentine leucocidin (PVL) toxin. Whether PVL is pathogenic or an epidemiological marker is unclear. We investigate the role of PVL in disease, colonisation, and clinical outcome. METHODS: We searched Medline and Embase for original research reporting the prevalence of PVL genes among Staphylococcus aureus pneumonia, bacteraemia, musculoskeletal infection, skin and soft-tissue infection, or colonisation published before Oct 1, 2011. We calculated odds ratios (ORs) to compare patients with PVL-positive colonisation and each infection relative to the odds of PVL-positive skin and soft-tissue infection. We did meta-analyses to estimate odds of infection or colonisation with a PVL-positive strain with fixed-effects or random-effects models, depending on the results of tests for heterogeneity. RESULTS: Of 509 articles identified by our search strategy, 76 studies from 31 countries met our inclusion criteria. PVL strains are strongly associated with skin and soft-tissue infections, but are comparatively rare in pneumonia (OR 0.37, 95% CI 0.22-0.63), musculoskeletal infections (0.44, 0.19-0.99), bacteraemias (0.10, 0.06-0.18), and colonising strains (0.07, 0.01-0.31). PVL-positive skin and soft-tissue infections are more likely to be treated surgically than are PVL-negative infections, and children with PVL-positive musculoskeletal disease might have increased morbidity. For other forms of disease we identified no evidence that PVL affects outcome. INTERPRETATION: PVL genes are consistently associated with skin and soft-tissue infections and are comparatively rare in invasive disease. This finding challenges the view that PVL mainly causes invasive disease with poor prognosis. Population-based studies are needed to define the role of PVL in mild, moderate, and severe disease and to inform control strategies. FUNDING: None. PMID- 23103174 TI - Panton-Valentine leucocidin and staphylococcal disease. PMID- 23103175 TI - Outcomes of the Surviving Sepsis Campaign in intensive care units in the USA and Europe: a prospective cohort study. AB - BACKGROUND: Mortality from severe sepsis and septic shock differs across continents, countries, and regions. We aimed to use data from the Surviving Sepsis Campaign (SSC) to compare models of care and outcomes for patients with severe sepsis and septic shock in the USA and Europe. METHODS: The SSC was introduced into more than 200 sites in Europe and the USA. All patients identified with severe sepsis and septic shock in emergency departments or hospital wards and admitted to intensive care units (ICUs), and those with sepsis in ICUs were entered into the SSC database. Patients entered into the database from its launch in January, 2005, through January, 2010, in units with at least 20 patients and 3 months of enrolment of patients were included in this analysis. Patients included in the cohort were limited to those entered in the first 4 years at every site. We used random-effects logistic regression to estimate the hospital mortality odds ratio (OR) for Europe relative to the USA. We used random effects linear regression to find the relation between lengths of stay in hospital and ICU and geographic region. FINDINGS: 25 375 patients were included in the cohort. The USA included 107 sites with 18 766 (74%) patients, and Europe included 79 hospital sites with 6609 (26%) patients. In the USA, 12 218 (65.1%) were admitted to the ICU from the emergency department whereas in Europe, 3405 (51.5%) were admitted from the wards. The median stay on the hospital wards before ICU admission was longer in Europe than in the USA (1.0 vs 0.1 days, difference 0.9, 95% CI 0.8-0.9). Raw hospital mortality was higher in Europe than in the USA (41.1%vs 28.3%, difference 12.8, 95% CI 11.5-14.7). The median length of stay in ICU (7.8 vs 4.2 days, 3.6, 3.3-3.7) and hospital (22.8 vs 10.5 days, 12.3, 11.9-12.8) was longer in Europe than in the USA. Adjusted mortality in Europe was not significantly higher than that in the USA (32.3%vs 31.3%, 1.0, 1.7 to 3.7, p=0.468). Complete compliance with all applicable elements of the sepsis resuscitation bundle was higher in the USA than in Europe (21.6%vs 18.4%, 3.2, 2.2-4.4). INTERPRETATION: The significant difference in unadjusted mortality and the fact that this difference disappears with severity adjustment raise important questions about the effect of the approach to critical care in Europe compared with that in the USA. The effect of ICU bed availability on outcomes in patients with severe sepsis and septic shock requires further investigation. PMID- 23103176 TI - Intensified intravenous rifampicin in tuberculous meningitis. PMID- 23103177 TI - Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. AB - BACKGROUND: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. METHODS: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. FINDINGS: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78.7 mg.h/L [95% CI 71.0-87.3] vs 26.0 mg.h/L [19.0-35.6]), maximum plasma concentrations (C(max); 22.1 mg/L [19.9-24.6] vs 6.3 mg/L [4.9 8.3]), and concentrations in cerebrospinal fluid (0.60 mg/L [0.46-0.78] vs 0.21 mg/L [0.16-0.27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31.5 mg.h/L [24.1-41.1] vs 15.1 mg.h/L [12.8-17.7]), C(max) (7.4 mg/L [5.6-9.6] vs 3.9 mg/L [3.2-4.8]), and drug concentrations in the cerebrospinal fluid (2.43 mg/L [1.81-3.27] vs 1.52 mg/L [1.28-1.82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0.42; 95% CI 0.20-0.91; p=0.03). INTERPRETATION: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. FUNDING: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia. PMID- 23103178 TI - Fixing latent fingermarks developed by iodine fuming: a new method. AB - The latent fingermarks developed with iodine fumes are not permanent due to the sublimation of iodine. In this paper a new method has been proposed to fix the latent fingermarks developed with iodine fumes. Latent fingermarks were developed on both porous as well as non-porous substrates which were subsequently fixed by treating them with brucine based reagent. The fingermarks fixed with this method were not only permanent but also without any background coloration. Adsorption of the brucine over the iodine has been found to be a possible reason for permanency of iodine developed fingermarks. This research has successfully demonstrated the first use of the brucine solution for fixing latent fingermarks on porous and as well as on non porous substrates. PMID- 23103180 TI - European nursing students' academic success or failure: a post-Bologna Declaration systematic review. AB - OBJECTIVES: The aim of this systematic review is to synthesise the available evidence in the European scientific literature produced after the Bologna Declaration and to evaluate studies that quantify and examine the factors associated with the academic success or failure of nursing students. DESIGN: A systematic review of the literature was conducted. DATA SOURCES: Major health literature databases were searched for studies published from 2000 to 2011. REVIEW METHODS: This review includes only European observational studies that were submitted to a quality assessment by two researchers before inclusion. RESULTS: Only five studies were included in this review. There are discordant results regarding the predictors of success or failure, which were common objects of study (gender, age, qualification on entry, ethnic group). other factors were studied individually (student personality, gendered view of nursing careers, intention to leave, family commitments, working while on course, student performance, clinical learning environment) need to be confirmed in additional studies. Although the predictors may be relevant at the local level, given their low external validity and the conflicting results, it is not possible to state with certainty that these factors are effectively predictive of success or failure in the context of post-Bologna Declaration Europe. CONCLUSIONS: This review showed that over the last ten years, in the European context, only a few high-quality observational studies have been performed. In this regard, given the small number and heterogeneity of the available studies, there is little useful evidence available for Higher Education Institutions (HEIs) to effectively address the problem. In the future, European researchers should focus not only on the documentation of the predictors but also on the documentation of the outcomes produced by the HEI strategies that have been implemented to prevent avoidable academic failure and contain physiological academic failure. PMID- 23103181 TI - Student scientists learn about energy balance through science museum-academic partnership. PMID- 23103182 TI - Use of technology to reach families with young children with food safety information. PMID- 23103183 TI - [Paediatric anaesthesia: what are we really doing?]. PMID- 23103184 TI - Satisfaction of search from detection of pulmonary nodules in computed tomography of the chest. AB - RATIONALE AND OBJECTIVES: We tested whether satisfaction of search (SOS) effects that occur in computed tomography (CT) examination of the chest on detection of native abnormalities are produced by the addition of simulated pulmonary nodules. MATERIALS AND METHODS: Two experiments were conducted. In the first experiment, 70 CT examinations, half that demonstrated diverse, subtle abnormalities and half that demonstrated no native lesions, were read by 18 radiology residents and fellows under two experimental conditions: presented with and without pulmonary nodules. In a second experiment, many of the examinations were replaced to include more salient native abnormalities. This set was read by 14 additional radiology residents and fellows. In both experiments, detection of the natural abnormalities was studied. Receiver operating characteristic (ROC) curve areas for each reader-treatment combination were estimated using empirical and proper ROC models. Additional analyses focused on decision thresholds and visual search time on abnormality-free CT slice ranges. Institutional review board approval and informed consent from 32 participants were obtained. RESULTS: Observers more often missed diverse native abnormalities when pulmonary nodules were added, but also made fewer false-positive responses. There was no change in ROC area, but decision criteria grew more conservative. The SOS effect on decision thresholds was accompanied by a reduction in search time on abnormality-free CT slice ranges. CONCLUSION: The SOS effect in CT examination of the chest is similar to that found in contrast examination of the abdomen, involving induced visual neglect. PMID- 23103185 TI - Unbiased review of digital diagnostic images in practice: informatics prototype and pilot study. AB - RATIONALE AND OBJECTIVES: Clinical and contextual information associated with images may influence how radiologists draw diagnostic inferences, highlighting the need to control multiple sources of bias in the methodologic design of investigations involving radiologic interpretation. In the past, manual control methods to mask review films presented in practice have been used to reduce potential interpretive bias associated with differences between viewing images for patient care and reviewing images for the purposes of research, education, and quality improvement. These manual precedents from the film era raise the question whether similar methods to reduce bias can be implemented in the modern digital environment. MATERIALS AND METHODS: A prototype application, CreateAPatient, was built for masking review case presentations within one institution's production radiology information system and picture archiving and communication system. To test whether CreateAPatient could be used to mask review images presented in practice, six board-certified radiologists participated in a pilot study. During pilot testing, seven digital chest radiographs, known to contain lung nodules and associated with fictitious patient identifiers, were mixed into the routine workloads of the participating radiologists while they covered general evening call shifts. The aim was to test whether it was possible to mask the presentation of these review cases, both by probing the interpreting radiologists to report detection and by conducting a forced-choice experiment on a separate cohort of 20 radiologists and information technology professionals. RESULTS: None of the participating radiologists reported awareness of review activity, and forced-choice detection was less than predicted at chance, suggesting that radiologists were effectively blinded. In addition, no evidence was identified of review reports unsafely propagating beyond their intended scope or otherwise interfering with patient care, despite integration of these records within production electronic work flow systems. CONCLUSIONS: Information technology can facilitate the design of unbiased methods involving professional review of digital diagnostic images. PMID- 23103179 TI - Trials with 'epigenetic' drugs: an update. AB - Epigenetic inactivation of pivotal genes involved in correct cell growth is a hallmark of human pathologies, in particular cancer. These epigenetic mechanisms, including crosstalk between DNA methylation, histone modifications and non-coding RNAs, affect gene expression and are associated with disease progression. In contrast to genetic mutations, epigenetic changes are potentially reversible. Re expression of genes epigenetically inactivated can result in the suppression of disease state or sensitization to specific therapies. Small molecules that reverse epigenetic inactivation, so-called epi-drugs, are now undergoing clinical trials. Accordingly, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for cancer treatment have approved some of these drugs. Here, we focus on the biological features of epigenetic molecules, analyzing the mechanism(s) of action and their current use in clinical practice. PMID- 23103186 TI - Diagnostic performance of contrast enhanced ultrasound in patients with prostate cancer: a meta-analysis. AB - RATIONALE AND OBJECTIVES: We aimed to do a meta-analysis of the existing literature to assess the accuracy of prostate cancer (PCa) studies that use contrast-enhanced ultrasound (CEUS) as a diagnostic tool. MATERIALS AND METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched for relevant original articles published up to August 2012. Characteristics of Included studies were recorded. Methodological quality was assessed by using the quality assessment of diagnostic studies tool. Pooled weighted estimates of diagnostic odds ratio (DOR), sensitivity, specificity, and positive and negative likelihood ratio (LR) were calculated. A summary receiver operator characteristic (SROC) curve was constructed to calculate the area under the curve (AUC). Publication bias analysis was also performed. RESULTS: Sixteen studies (2624 patients) were included in the meta-analysis. Various contrast agents and imaging modes were applied. The independent random-effects summary showed a variation in diagnostic values. The summary estimates of sensitivity, specificity, and DOR were 0.70, 0.74, and 9.09, respectively. The weighted positive and negative LR were 2.81 and 0.35, with statistically significant between-study heterogeneity (P < .001). Sensitivity was better in positive patient studies than positive biopsy cores ones (0.78 vs. 0.64). SROC plot displayed value for AUC (0.82). Begg's test (P = .822) and Egger's test (P = .198) did not show evidence of publication bias. CONCLUSION: CEUS is a promising tool in the detection of PCa, but it cannot completely replace systematic biopsy under the present circumstances. It is necessary to standardize imaging techniques, contrast agents and diagnostic criteria. Large samples, multi-center studies and high-quality prospective trials are necessary to assess its clinical value. PMID- 23103187 TI - Substrate-borne vibratory communication during courtship in Drosophila melanogaster. AB - Courtship in Drosophila melanogaster has become an iconic example of an innate and interactive series of behaviors. The female signals her acceptance of copulation by becoming immobile in response to a male's display of stereotyped actions. The male and female communicate via vision, air-borne sounds, and pheromones, but what triggers the female's immobility is undetermined. Here, we describe an overlooked and important component of Drosophila courtship. Video recordings and laser vibrometry show that the male abdomen shakes ("quivers"), generating substrate-borne vibrations at about six pulses per second. We present evidence that the female becomes receptive and stops walking because she senses these vibrations, rather than as a response to air-borne songs produced by the male fluttering the wings. We also present evidence that the neural circuits expressing the sex-determination genes fruitless and doublesex drive quivering behavior. These abdominal quivers and associated vibrations, as well as their effect on female receptivity, are conserved in other Drosophila species. Substrate-borne vibrations are an ancient form of communication that is widespread in animals. Our findings in Drosophila open a door to study the neuromuscular circuitry responsible for these signals and the sensory systems needed for their reception. PMID- 23103188 TI - Phenotypic engineering unveils the function of genital morphology. AB - The rapidly evolving and often extraordinarily complex appearance of male genital morphology of internally fertilizing animals has been recognized for centuries. Postcopulatory sexual selection is regarded as the likely evolutionary engine of this diversity, but direct support for this hypothesis is limited. We used two complementary approaches, evolution through artificial selection and microscale laser surgery, to experimentally manipulate genital morphology in an insect model system. We then assessed the competitive fertilization success of these phenotypically manipulated males and studied the fate of their ejaculate in females using high-resolution radioisotopic labeling of ejaculates. Males with longer genital spines were more successful in gaining fertilizations, providing experimental evidence that male genital morphology influences success in postcopulatory reproductive competition. Furthermore, a larger proportion of the ejaculate moved from the reproductive tract into the female body following mating with males with longer spines, suggesting that genital spines increase the rate at which seminal fluid passes into the female hemolymph. Our results show that genital morphology affects male competitive fertilization success and imply that sexual selection on genital morphology may be mediated in part through seminal fluid. PMID- 23103190 TI - Deuterostomic development in the protostome Priapulus caudatus. AB - The fate of the blastopore during development in the bilaterian ancestor is currently not well understood. In deuterostomes, the blastopore forms the anus, but its fate in protostome groups is variable. This variability, combined with an absence of information from key taxa, hampers the reconstruction of the ancestral developmental mode of the Protostomia and the Bilateria. The blastopore fate of the bilaterian ancestor plays a crucial role in understanding the transition from radial to bilateral symmetric organisms. Priapulids have a conservative morphology, an abundant Cambrian fossil record, and a phylogenetic position that make them a key group in understanding protostome evolution. Here, we characterize gastrulation and the embryonic expression of genes involved in bilaterian foregut and hindgut patterning in Priapulus caudatus. We show that the blastopore gives rise to the anus at the vegetal pole and that the hindgut markers brachyury and caudal are expressed in the blastopore and anus, whereas the foregut markers foxA and goosecoid are expressed in the mouth in the animal hemisphere. Thereby, gastrulation in the conservatively evolving protostome P. caudatus follows strictly a deuterostomic pattern. These results are more compatible with a deuterostomic rather than protostomic (blastopore forms the mouth) or amphistomic (mouth and anus are formed simultaneously) mode of development in the last common bilaterian ancestor. PMID- 23103189 TI - Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis. AB - BACKGROUND: Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. RESULTS: Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. CONCLUSIONS: Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. PMID- 23103191 TI - Simplification and desexualization of gene expression in self-fertile nematodes. AB - Evolutionary transitions between sexual modes could be potent forces in genome evolution. Several Caenorhabditis nematode species have evolved self-fertile hermaphrodites from the obligately outcrossing females of their ancestors. We explored the relationship between sexual mode and global gene expression by comparing two selfing species, C. elegans and C. briggsae, with three phylogenetically informative outcrossing relatives, C. remanei, C. brenneri, and C. japonica. Adult transcriptome assemblies from the selfing species are consistently and strikingly smaller than those of the outcrossing species. Against this background of overall simplification, genes conserved in multiple outcrossing species with strong sex-biased expression are even more likely to be missing from the genomes of the selfing species. In addition, the sexual regulation of remaining transcripts has diverged markedly from the ancestral pattern in both selfing lineages, though in distinct ways. Thus, both the complexity and the sexual specialization of transciptomes are rapidly altered in response to the evolution of self-fertility. These changes may result from the combination of relaxed sexual selection and a recently reported genetic mechanism favoring genome shrinkage in partial selfers. PMID- 23103192 TI - Dendritic filopodia, Ripped Pocket, NOMPC, and NMDARs contribute to the sense of touch in Drosophila larvae. AB - BACKGROUND: Among the Aristotelian senses, the subcellular and molecular mechanisms involved in the sense of touch are the most poorly understood. RESULTS: We demonstrate that specialized sensory neurons, the class II and class III multidendritic (md) neurons, are gentle touch sensors of Drosophila larvae. Genetic silencing of these cells significantly impairs gentle touch responses, optogenetic activation of these cells triggers behavioral touch-like responses, and optical recordings from these neurons show that they respond to force. The class III neurons possess highly dynamic dendritic protrusions rich in F-actin. Genetic manipulations that alter actin dynamics indicate that the actin-rich protrusions (termed sensory filopodia) on the class III neurons are required for behavioral sensitivity to gentle touch. Through a genome-wide RNAi screen of ion channels, we identified Ripped Pocket (rpk), No Mechanoreceptor Potential C (nompC), and NMDA Receptors 1 and 2 (Nmdars) as playing critical roles in both behavioral responses to touch and in the formation of the actin-rich sensory filopodia. Consistent with this requirement, reporters for rpk and nompC show expression in the class III neurons. A genetic null allele of rpk confirms its critical role in touch responses. CONCLUSIONS: Output from class II and class III md neurons of the Drosophila larvae is necessary and sufficient for eliciting behavioral touch responses. These cells show physiological responses to force. Ion channels in several force-sensing gene families are required for behavioral sensitivity to touch and for the formation of the actin-rich sensory filopodia. PMID- 23103193 TI - Exact alpha-error determination for two-stage sampling strategies to substantiate freedom from disease. AB - Sampling strategies to substantiate freedom from disease are important when it comes to the trade of animals and animal products. When considering imperfect tests and finite populations, sample size calculation can, however, be a challenging task. The generalized hypergeometric formula developed by Cameron and Baldock (1998a) offers a framework that can elegantly be extended to multi-stage sampling strategies, which are widely used to account for disease clustering at herd-level. The achieved alpha-error of such surveys, however, typically depends on the realization of the sample and can differ from the pre-calculated value. In this paper, we introduce a new formula to evaluate the exact alpha-error induced by a specific sample. We further give a numerically viable approximation formula and analyze its properties using a data example of Brucella melitensis in the Austrian sheep population. PMID- 23103194 TI - Rubella control in Papua New Guinea: age-specific immunity informs strategies for introduction of rubella vaccine. AB - AIM: To determine the age specific immunity profile for rubella from three discrete study populations in Papua New Guinea, and to inform policy regarding the possible introduction of rubella vaccine. BACKGROUND: In 2005, the Western Pacific Region (WPR), of which Papua New Guinea (PNG) is a member state, declared the goal of regional measles elimination by 2012. Recently, WPR has incorporated an accelerated control goal for rubella and congenital rubella syndrome (CRS). PNG currently recommends two doses of measles vaccination at 6 and 9 months of age with a monovalent measles vaccine, which does not include rubella vaccine. METHODS: Convenience samples were collected from 1326 eligible participants in PNG and assessed for rubella immunity using the Dade Behring EnzygnostTM Anti Rubella-Virus enzyme immunoassay. Nearly 34% were collected during an age stratified prospective survey of febrile patients in Madang Province; approximately 49% were collected from women of childbearing age in East Sepik and Milne Bay Provinces. Remaining specimens were collected from 6 to 7-month-old infants in Port Moresby prior to receiving the first dose of measles vaccine. FINDINGS: Of all samples tested, 65.2% (95% confidence interval (CI): 62.6-67.8) had evidence of immunity to rubella infection. Of women more than 15 years of age, 91.6% (95% CI: 89.4-93.5) were immune. The force of infection was highest between 5 and 19 years of age. CONCLUSIONS: Although a population-based sample was not used, our multi-centre study of the population immunity profile suggests that immunity against rubella is extremely high in most women of childbearing age, but women who become pregnant at an early age may be at high risk of rubella infection during pregnancy and potential delivery of an infant with CRS. Routine measles vaccine coverage, a proxy for measles-rubella vaccine coverage, as measured in recently published studies, is well below the WHO target of 80% coverage. Introduction of a child or infant dose of rubella vaccine requires caution and further study. PMID- 23103195 TI - Effect of two injections of non-adjuvanted influenza A H1N1pdm2009 vaccine in renal transplant recipients: INSERM C09-32 TRANSFLUVAC trial. AB - BACKGROUND: Enhancing vaccine immunogenicity in kidney transplant recipients, particularly against influenza, is required since the immunosuppression used to prevent graft rejection limits vaccine immunogenicity. We therefore investigated the immunogenicity and safety of a double dose non-adjuvanted vaccination regimen against influenza H1N1pdm2009 in kidney transplant adult recipients. METHODS: A prospective single-arm study was conducted including 121 renal transplant recipients under triple immunosuppressive regimen. Patients received 2 injections (day 0, day 21) of an inactivated, non-adjuvanted H1N1pdm2009 vaccine. Immunogenicity (hemagglutination-inhibition [HI] antibodies and anti-hemagglutin [HA] specific T cells) was evaluated after one and two injections (day 21, day 42) and at 6 months (day 182). RESULTS: The seroprotection rate (HI antibody titer>=1/40) was 19% at day 0 (n=119), 53% at day 21 (n=118), 60% at day 42 (n=116) (p=0.013; day 42 vs. day 21) and 56% at day 182 (n=113). The seroconversion rate was 24% and 32%, the geometric mean fold rise was 3.7 and 4.6 after the first and second injections, respectively. T-cell immunity to the H1N1pdm2009 vaccine showed a two-fold increase from baseline, though not statistically significant, in H1N1pdm2009-HA-specific CD4+ and CD8+ T cells in 34% and 48% of cases, respectively. No rejection episodes related to vaccination were observed while the donor-specific antibodies and creatinine clearance remained unchanged throughout the study. CONCLUSION: Administration of two doses of the non-adjuvanted influenza H1N1pdm2009 vaccine in renal transplant patients is safe and induces a significant seroprotection, not strong enough yet to meet European or US requirements for adults below 60 years, but comparable to seroprotection levels usually observed in the non immunosuppressed elderly population or conferred by a single dose of adjuvanted vaccine in solid organ transplant recipients. These results provide useful indications for future strategies required to improve immunogenicity of vaccines against influenza in transplanted patients. PMID- 23103196 TI - Rotavirus vaccination effectiveness: a case-case study in the EDICS project, Castellon (Spain). AB - In Spain, in 2006, two oral live-attenuated vaccines against rotavirus disease were licensed for infants up to 6 months. Recent data suggest that vaccine efficacy may vary by region. This makes the real-life postmarketing monitoring of rotavirus vaccination effectiveness an important aspect of rotavirus epidemiologic surveillance. We carried out a case-case study to assess the rotavirus vaccination effectiveness in children from 2 to 35 months of age during the year 2009 in Castellon. As a second- and counterfactual objective to evaluate the possible selection bias and the specificity of the association, we evaluated the "effectiveness" of pneumococcal vaccination against rotavirus diarrhea. Cases were 71 children with confirmed rotavirus gastroenteritis, and controls were 261 children with positive results to any other organism that was not rotavirus. The immunization status of each child, the number of doses and dates of vaccination were assessed by consulting the Regional Immunization Registry. The lowest proportion of vaccinated cases was observed among rotavirus diarrhea (2.8%). The proportion of vaccinated children among the control group was 21.8%. The effectiveness of vaccination with at least one dose of vaccine against rotavirus was 87.7% (45.5-99.7%). If we restrict the analysis to non-hospitalized children, this figure was slightly lower, 83.5% (25.4-96.3%). As expected, pneumococcal vaccination was not protective against rotavirus infection showing the specificity of the association found. The immunization information systems in combination with population-based studies of the incidence of infectious gastroenteritis, such as EDICS offer appropriate conditions for postmarketing monitoring of vaccine effectiveness. PMID- 23103197 TI - Technology transfer of oil-in-water emulsion adjuvant manufacturing for pandemic influenza vaccine production in Romania. AB - Many developing countries lack or have inadequate pandemic influenza vaccine manufacturing capacity. In the 2009 H1N1 pandemic, this led to delayed and inadequate vaccine coverage in the developing world. Thus, bolstering developing country influenza vaccine manufacturing capacity is urgently needed. The Cantacuzino Institute in Bucharest, Romania has been producing seasonal influenza vaccine since the 1970s, and has the capacity to produce ~5 million doses of monovalent vaccine in the event of an influenza pandemic. Inclusion of an adjuvant in the vaccine could enable antigen dose sparing, expanding vaccine coverage and potentially allowing universal vaccination of the Romanian population and possibly neighboring countries. However, adjuvant formulation and manufacturing know-how are difficult to access. This manuscript describes the successful transfer of oil-in-water emulsion adjuvant manufacturing and quality control technologies from the Infectious Disease Research Institute in Seattle, USA to the Cantacuzino Institute. By describing the challenges and accomplishments of the project, it is hoped that the knowledge and experience gained will benefit other institutes involved in similar technology transfer projects designed to facilitate increased vaccine manufacturing capacity in developing countries. PMID- 23103198 TI - The efficacy of HSV-2 vaccines based on gD and gB is enhanced by the addition of ICP27. AB - DNA vaccines expressing HSV-2 gD, gB, ICP27, VP22 and VP13/14 were shown to be immunogenic in mice; gD and gB elicited neutralising antibody, and all five antigens induced T cell responses measured by IFNgamma ELISPOT. In murine HSV-2 challenge studies, gD and gB provided moderate to high levels of protection while ICP27 provided a lower level of protection depending on the model (intravaginal or intranasal) and the challenge dose. Combining vaccines expressing gB or gD with vaccines expressing ICP27 provided greater protection than any antigen alone. We conclude that the addition of ICP27 to enhance the anti-viral T cell response can improve the efficacy of gD- and gB-based vaccines. PMID- 23103199 TI - Nanoparticle size influences the magnitude and quality of mucosal immune responses after intranasal immunization. AB - BACKGROUND: The development of nanoparticulate antigen-delivery systems is an important emerging area of vaccinology, being sought to amplify immune responses to recombinant antigens that are poorly immunogenic. Nanoparticle size may play an important role in influencing the activity of such particulate-based adjuvants. METHODS: To explore how the size of nanoparticles that are in the range of many common viruses can modulate the magnitude and quality of mucosal immune responses, the model antigen ovalbumin (OVA) was conjugated to 30 nm or 200 nm polypropylene sulfide nanoparticles (NPs) and administered intranasally to C57BL/6 mice. RESULTS: We show that by increasing the size of the NPs from 30 to 200 nm, OVA was more effectively delivered into both MHC class I and MHC class II presentation pathways. Intranasal immunization with the 200 nm NPs increased the magnitude of CD4(+) T cell responses in the lungs, as well as systemic and mucosal humoral responses. Most importantly, 200 nm NPs increased the proportion of antigen-specific polyfunctional CD4(+) T cells as compared to 30 nm NPs. CONCLUSIONS: The 200 nm NPs are a very interesting antigen nanocarrier for prophylactic vaccines against mucosal pathogens that require multifunctional CD4(+) T cells for protection. These results contribute to our understanding of how the size of an antigen-conjugated nanoparticle modulates mucosal immune responses to a protein antigen and may be useful to engineer subunit vaccines able to elicit appropriate mucosal immune responses that correlate with protection. PMID- 23103200 TI - Usefulness of inducible ventricular tachycardia to predict long-term adverse outcomes in arrhythmogenic right ventricular cardiomyopathy. AB - The role of the electrophysiologic (EP) study for risk stratification in patients with arrhythmogenic right ventricular cardiomyopathy is controversial. We investigated the role of inducible sustained monomorphic ventricular tachycardia (SMVT) for the prediction of an adverse outcome (AO), defined as the occurrence of cardiac death, heart transplantation, sudden cardiac death, ventricular fibrillation, ventricular tachycardia with hemodynamic compromise or syncope. Of 62 patients who fulfilled the 2010 Arrhythmogenic Right Ventricular Cardiomyopathy Task Force criteria and underwent an EP study, 30 (48%) experienced an adverse outcome during a median follow-up of 9.8 years. SMVT was inducible in 34 patients (55%), 22 (65%) of whom had an adverse outcome. In contrast, in 28 patients without inducible SMVT, 8 (29%) had an adverse outcome. Kaplan-Meier analysis showed an event-free survival benefit for patients without inducible SMVT (log-rank p = 0.008) with a cumulative survival free of an adverse outcome of 72% (95% confidence interval [CI] 56% to 92%) in the group without inducible SMVT compared to 26% (95% CI 14% to 50%) in the other group after 10 years. The inducibility of SMVT during the EP study (hazard ratio [HR] 2.99, 95% CI 1.23 to 7.27), nonadherence (HR 2.74, 95% CI 1.3 to 5.77), and heart failure New York Heart Association functional class II and III (HR 2.25, 95% CI 1.04 to 4.87) were associated with an adverse outcome on univariate Cox regression analysis. The inducibility of SMVT (HR 2.52, 95% CI 1.03 to 6.16, p = 0.043) and nonadherence (HR 2.34, 95% CI 1.1 to 4.99, p = 0.028) remained as significant predictors on multivariate analysis. This long-term observational data suggest that SMVT inducibility during EP study might predict an adverse outcome in patients with arrhythmogenic right ventricular cardiomyopathy, advocating a role for EP study in risk stratification. PMID- 23103201 TI - Tobacco smoking and dermatologic surgery. AB - BACKGROUND: Cigarette smoking is the leading cause of preventable death and a major public health concern. Numerous clinical and experimental studies have examined the effect of nicotine on wound healing and surgical procedures, but there are limited published reports in the dermatologic surgery literature. OBJECTIVE: This article seeks to develop evidence-based recommendations regarding the effect of tobacco use in patients undergoing dermatologic surgery procedures. METHODS: This article reviews the existing published English-language literature pertaining to the effects of tobacco on wound healing and surgical complications. RESULTS: Tobacco use is associated with a higher incidence of postoperative complications including wound dehiscence, flap or graft necrosis, prolonged healing time, and infections. LIMITATIONS: This review article only summarizes past reports and studies. CONCLUSION: Recommendations for smoking cessation before dermatologic surgery are provided based on the available data. PMID- 23103202 TI - Response to ethanol induced ataxia between C57BL/6J and 129X1/SvJ mouse strains using a treadmill based assay. AB - More sensitive assays of mouse motor ataxia may provide a better understanding of the pathological profile. Treadmill gait analysis using ventral imaging allows for unhindered access to the ambulating mouse. In contrast to genetic mutations or exogenous brain injury, ethanol (EtOH) allows for the detection of dose dependent changes in motor behavior, which can be used to assess an assay's detection sensitivity. EtOH induced ataxia was assessed in C57BL/6J (B6) and 129X1/SvJ (129) mice using the DigiGait imaging system. Gait was analyzed across EtOH dosage (1.75, 2.25 and 2.75 g/kg) in each strain using a linear mixed effects model. Overall, 129 mice displayed greater susceptibility to EtOH ataxia than their B6 counterparts. In both strains, hind paws exhibited greater sensitivity to EtOH dosage than fore paws. Across most variables analyzed, only a modest EtOH-induced change in motor behavior was observed in each strain with the 1.75 g/kg EtOH doses failing to elicit significant change. These data indicate the ability to detect motor differences between strains, yet only moderate ability to detect change across EtOH dosage using the automated treadmill. Rotarod assays, however, were able to detect motor impairment at lower doses of EtOH. The significant, but opposite changes in paw placement with increasing EtOH doses highlight strain-specific differences in biophysical adaptations in response to acute EtOH intoxication. PMID- 23103203 TI - Lesion of olfactory epithelium attenuates expression of morphine-induced behavioral sensitization and reinstatement of drug-primed conditioned place preference in mice. AB - Previous studies have shown that olfactory impairment by disrupting the olfactory epithelium prior to morphine administration attenuated the development addiction related behaviors. However, it is unclear whether olfactory impairment will affect the expression of already established addiction-related behaviors. To address this issue, mice were conditioned with morphine to induce behavioral sensitization and condition placed preference (CPP). After an abstinence period, the animals were subjected to either an intranasal ZnSO(4) effusion (ZnE) or sham treatment with saline. Behavioral sensitization and CPP reinstatement were evaluated 24h later, as well as the expression of c-Fos protein, a marker of activated neural sites, in brain regions of interest. It was found that ZnE treatment attenuated morphine-induced behavioral sensitization and reinstatement of CPP. Compared to the saline-treated ones, the ZnE-treated animals showed reduced c-Fos expression in the nucleus accumbens (NAc) associated with behavioral sensitization, and in the NAc, cingulate cortex, dentate gyrus, amygdala, lateral hypothalamus and ventral tegmental area associated with CPP reinstatement. Together, these results demonstrated that acute olfactory impairment could attenuate already established addiction-related behaviors and expression of c-Fos in drug addiction related brain regions, perhaps by affecting the coordination between reward and motivational systems in the brain. PMID- 23103204 TI - Abnormal regulation for progesterone production in placenta with prenatal cocaine exposure in rats. AB - Cocaine abuse in pregnant women is currently a significant public hygiene problem and is tightly associated with elevated risk for preterm delivery. Placental steroidogenesis especially progesterone production was essential for success and maintenance of pregnancy in humans and rodents. In the present study, we determined the impact of prenatal cocaine exposure on pathways of placental progesterone synthesis in rats. Pregnant rats were treated cocaine twice daily (15 mg/kg/day) during the third trimester, and the maternal and fetal plasma progesterone and pregnenolone concentrations were detected. We also examined both the protein and mRNA expression of some key enzymes and regulators for progesterone production in placenta. Results showed that, after maternal cocaine use during pregnancy, progesterone and pregnenolone concentrations in both maternal and fetal rats were significantly decreased. Although prenatal cocaine exposure had no effects on placental 3beta-hydroxysteroid dehydrogenase type 1 (3betaHSD1) expression, protein and mRNA expression of the cholesterol side-chain cleavage enzyme (P450scc/CYP11a) in placenta was significantly inhibited. Moreover, protein and mRNA expressions of MLN64 that regulating cholesterol transport and activating protein 2gamma (AP2gamma/Tfap2c) that controlling P450scc/CYP11a gene expression in placenta were both decreased following maternal cocaine use in pregnancy. Collectively, this study suggested that prenatal cocaine exposure could insult the placental progesterone production in rats possibly associated with the high risk for preterm delivery. PMID- 23103205 TI - Enhanced xylitol production through simultaneous co-utilization of cellobiose and xylose by engineered Saccharomyces cerevisiae. AB - As Saccharomyces cerevisiae cannot utilize xylose as a carbon source, expression of XYL1 coding for xylose reductase (XR) from Scheffersomyces (Pichia) stipitis enabled production of xylitol from xylose with a high yield. However, insufficient supply of NAD(P)H for XR and inhibition of xylose uptake by glucose are identified as major constraints for achieving high xylitol productivity. To overcome these problems, we engineered S. cerevisiae capable of converting xylose into xylitol through simultaneous utilization of xylose and cellobiose. An engineered S. cerevisiae (D-10-BT) expressing XR, cellodextrin transporter (cdt 1) and intracellular beta-glucosidase (gh1-1) produced xylitol via simultaneous utilization of cellobiose and xylose. The D-10-BT strain exhibited 40% higher volumetric xylitol productivity with co-consumption of cellobiose and xylose compared to sequential utilization of glucose and xylose. Furthermore, the overexpression of S. cerevisiae ALD6, IDP2, or S. stipitis ZWF1 coding for cytosolic NADP(+)-dependent dehydrogenases increased the intracellular NADPH availability of the D-10-BT strain, which resulted in a 37-63% improvement in xylitol productivity when cellobiose and xylose were co-consumed. These results suggest that co-utilization of cellobiose and xylose can lead to improved xylitol production through enhanced xylose uptake and efficient cofactor regeneration. PMID- 23103206 TI - The regulatory domain stabilizes the p53 tetramer by intersubunit contacts with the DNA binding domain. AB - The tumor suppressor protein p53 is often referred to as the guardian of the genome. In the past, controversial findings have been presented for the role of the C-terminal regulatory domain (RD) of p53 as both a negative regulator and a positive regulator of p53 activity. However, the underlying mechanism remained enigmatic. To understand the function of the RD and of a dominant phosphorylation site within the RD, we analyzed p53 variants in vivo and in vitro. Our experiments revealed, surprisingly, that the p53 RD of one subunit interacts with the DNA binding domain of an adjacent subunit in the tetramer. This leads to the formation of intersubunit contacts that stabilize the tetrameric state of p53 and enhance its transcriptional activity in a cooperative manner. These effects are further modulated by phosphorylation of a conserved serine within the RD. PMID- 23103207 TI - Prediction of scar integrity and vaginal birth after caesarean delivery. AB - A statistically significant association with uterine rupture during a trial of labour after caesarean delivery was found in at least two studies for the following variables: inter-delivery interval (higher risk with short interval), birth weight (higher risk if 4000 g or over), induction of labour (higher risk), oxytocin dose (higher risk with higher doses), and previous vaginal delivery (lower risk). However, no clinically useful risk estimation model that includes clinical variables has been published. A thin lower uterine segment at 35-40 weeks, as measured by ultrasound in women with a caesarean hysterotomy scar, increases the risk of uterine rupture or dehiscence. No cut-off for lower uterine segment thickness, however, can be suggested because of study heterogeneity, and because prospective validation is lacking. Large caesarean hysterotomy scar defects in non-pregnant women seen at ultrasound examination increase the risk of uterine rupture or dehiscence in subsequent pregnancy, but the strength of the association is unknown. To sum up, we currently lack a method that can provide a reliable estimate of the risk of uterine rupture or dehiscence during a trial of labour in women with caesarean hysterotomy scar(s). PMID- 23103208 TI - Acute abdominal pain in a teenager with anorexia nervosa. PMID- 23103209 TI - End-binding proteins and Ase1/PRC1 define local functionality of structurally distinct parts of the microtubule cytoskeleton. AB - The microtubule cytoskeleton is crucial for the intracellular organization of eukaryotic cells. It is a dynamic scaffold that has to perform a variety of very different functions. This multitasking is achieved through the activity of numerous microtubule-associated proteins. Two prominent classes of proteins are central to the selective recognition of distinct transiently existing structural features of the microtubule cytoskeleton. They define local functionality through tightly regulated protein recruitment. Here we summarize the recent developments in elucidating the molecular mechanism underlying the action of microtubule end binding proteins (EBs) and antiparallel microtubule crosslinkers of the Ase1/PRC1 family that represent the core of these two recruitment modules. Despite their fundamentally different activities, these conserved families share several common features. PMID- 23103210 TI - Establishing a database of radionuclide transfer parameters for freshwater wildlife. AB - Environmental assessments to evaluate potentials risks to humans and wildlife often involve modelling to predict contaminant exposure through key pathways. Such models require input of parameter values, including concentration ratios, to estimate contaminant concentrations in biota based on measurements or estimates of concentrations in environmental media, such as water. Due to the diversity of species and the range in physicochemical conditions in natural ecosystems, concentration ratios can vary by orders of magnitude, even within similar species. Therefore, to improve model input parameter values for application in aquatic systems, freshwater concentration ratios were collated or calculated from national grey literature, Russian language publications, and refereed papers. Collated data were then input into an international database that is being established by the International Atomic Energy Agency. The freshwater database enables entry of information for all radionuclides listed in ICRP (1983), in addition to the corresponding stable elements, and comprises a total of more than 16,500 concentration ratio (CRwo-water) values. Although data were available for all broad wildlife groups (with the exception of birds), data were sparse for many organism types. For example, zooplankton, crustaceans, insects and insect larvae, amphibians, and mammals, for which there were CRwo-water values for less than eight elements. Coverage was most comprehensive for fish, vascular plants, and molluscs. To our knowledge, the freshwater database that has now been established represents the most comprehensive set of CRwo-water values for freshwater species currently available for use in radiological environmental assessments. PMID- 23103211 TI - Anterior vesical hitch--a step to enhance safety of percutaneous access to bladder. AB - PURPOSE: To describe the novel technique of anterior vesical hitch to enhance the efficacy and safety of percutaneous bladder surgery. MATERIALS AND METHODS: The anterior bladder wall is anchored to the anterior abdominal wall with the help of a prolene suture passed slightly lateral to the midline midway between the pubic symphysis and umbilicus. Percutaneous cystolitholapaxy and antegrade posterior urethral valve ablation were performed after anterior vesical hitch in five pediatric male patients. Data collected included operative parameters and complications related to the technique. RESULTS: Mean patient age was 2.9 years (range 1.5-6 years). Three patients had bladder stones and two had posterior urethral valves. Mean time to achieve bilateral parietal fixation of the bladder was 7 min 20 s. There was no intraoperative slippage of Amplatz sheath or suture cut through. No bleeding from the puncture site was encountered. No postoperative complication related to the percutaneous access tract was noted in any patient. CONCLUSIONS: The anterior vesical hitch procedure is safe and easy. It prevents slippage of Amplatz sheath during percutaneous access to the bladder lumen. PMID- 23103212 TI - Early spread of hyperexcitability to caudal dorsal horn networks after a chemically-induced lesion of the rat spinal cord in vitro. AB - Hyperexcitability of dorsal horn neurons has been shown to play a key role in neuropathic pain following chronic experimental spinal cord injury. With a neonatal in vitro spinal cord injury model, we show that a chemically-induced lesion leads to rapid gain-of-function of sublesional dorsal horn networks biased to hyperexcitation. The expression of the GABA synthetic enzyme GAD65 was significantly reduced at the same level of the spinal cord, suggesting a compromised inhibitory system. We propose that our model could be useful to test early approaches to contrast spinal cord injury-induced central sensitization of dorsal horn circuits. PMID- 23103214 TI - Cortical current density oscillations in the motor cortex are correlated with muscular activity during pedaling exercise. AB - Despite modern imaging techniques, assessing and localizing changes in brain activity during whole-body exercise is still challenging. Using an active electroencephalography (EEG) system in combination with source localization algorithms, this study aimed to localize brain cortical oscillations patterns in the motor cortex and to correlate these with surface electromyography (EMG) detected muscular activity during pedaling exercise. Eight subjects performed 2 min isokinetic (90 rpm) cycling bouts at intensities ranging from 1 to 5 Wkg(-1) body mass on a cycle ergometer. These bouts were interspersed by a minimum of 2 min of passive rest to limit to development of peripheral muscle fatigue. Brain cortical activity within the motor cortex was analyzed using a 32-channel active EEG system combined with source localization algorithms. EMG activity was recorded from seven muscles on each lower limb. EEG and EMG activity revealed comparatively stable oscillations across the different exercise intensities. More importantly, the oscillations in cortical activity within the motor cortex were significantly correlated with EMG activity during the high-intensity cycling bouts. This study demonstrates that it is possible to localize oscillations in brain cortical activity during moderate- to high-intensity cycling exercise using EEG in combination with source localization algorithms, and that these oscillations match the activity of the active muscles in time and amplitude. Results of this study might help to further evaluate the effects of central vs. peripheral fatigue during exercise. PMID- 23103213 TI - Brain-derived neurotrophic factor and androgen interactions in spinal neuromuscular systems. AB - Neurotrophic factors and steroid hormones interact to regulate a variety of neuronal processes such as neurite outgrowth, differentiation, and neuroprotection. The coexpression of steroid hormone and neurotrophin receptor mRNAs and proteins, as well as their reciprocal regulation provides the necessary substrates for such interactions to occur. This review will focus on androgen brain-derived neurotrophic factor (BDNF) interactions in the spinal cord, describing androgen regulation of BDNF in neuromuscular systems following castration, androgen manipulation, and injury. Androgens interact with BDNF during development to regulate normally-occurring motoneuron death, and in adulthood, androgen-BDNF interactions are involved in the maintenance of several features of neuromuscular systems. Androgens regulate BDNF and trkB expression in spinal motoneurons. Androgens also regulate BDNF levels in the target musculature, and androgenic action at the muscle regulates BDNF levels in motoneurons. These interactions have important implications for the maintenance of motoneuron morphology. Finally, androgens interact with BDNF after injury, influencing soma size, dendritic morphology, and axon regeneration. Together, these findings provide further insight into the development and maintenance of neuromuscular systems and have implications for the neurotherapeutic/neuroprotective roles of androgens and trophic factors in the treatment of motoneuron disease and recovery from injury. PMID- 23103215 TI - The puerperium alters spinal cord plasticity following peripheral nerve injury. AB - Tissue and nerve damage can result in chronic pain. Yet, chronic pain after cesarean delivery is remarkably rare in women and hypersensitivity from peripheral nerve injury in rats resolves rapidly if the injury occurs in the puerperium. Little is known regarding the mechanisms of this protection except for a reliance on central nervous system oxytocin signaling. Here we show that the density of inhibitory noradrenergic fibers in the spinal cord is greater when nerve injury is performed in rats during the puerperium, whereas the expression of the excitatory regulators dynorphin A and neuregulin-1 in the spinal cord is reduced. The puerperium did not alter spinal cord microgial and astrocyte activation. Astrocyte activation, as measured by glial fibrillary acidic protein (GFAP) expression, was not evident in female rats with injury, regardless of delivery status suggesting sex differences in spinal astrocyte activation after injury. These results suggest a change in the descending inhibitory/facilitating balance on spinal nociception neurotransmission during the puerperium, as mechanisms for its protective effect against injury-induced hypersensitivity. PMID- 23103217 TI - Augmented reality intravenous injection simulator based 3D medical imaging for veterinary medicine. AB - Augmented reality (AR) is a technology which enables users to see the real world, with virtual objects superimposed upon or composited with it. AR simulators have been developed and used in human medicine, but not in veterinary medicine. The aim of this study was to develop an AR intravenous (IV) injection simulator to train veterinary and pre-veterinary students to perform canine venipuncture. Computed tomographic (CT) images of a beagle dog were scanned using a 64-channel multidetector. The CT images were transformed into volumetric data sets using an image segmentation method and were converted into a stereolithography format for creating 3D models. An AR-based interface was developed for an AR simulator for IV injection. Veterinary and pre-veterinary student volunteers were randomly assigned to an AR-trained group or a control group trained using more traditional methods (n = 20/group; n = 8 pre-veterinary students and n = 12 veterinary students in each group) and their proficiency at IV injection technique in live dogs was assessed after training was completed. Students were also asked to complete a questionnaire which was administered after using the simulator. The group that was trained using an AR simulator were more proficient at IV injection technique using real dogs than the control group (P <= 0.01). The students agreed that they learned the IV injection technique through the AR simulator. Although the system used in this study needs to be modified before it can be adopted for veterinary educational use, AR simulation has been shown to be a very effective tool for training medical personnel. Using the technology reported here, veterinary AR simulators could be developed for future use in veterinary education. PMID- 23103216 TI - Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton. AB - Estrogen's acute, facilitatory effects on glutamatergic transmission and long term potentiation (LTP) provide a potential explanation for the steroid's considerable influence on behavior. Recent work has identified mechanisms underlying these synaptic actions. Brief infusion of 17beta-estradiol (E2) into adult male rat hippocampal slices triggers actin polymerization within dendritic spines via a signaling cascade beginning with the GTPase RhoA and ending with inactivation of the filament-severing protein cofilin. Blocking this sequence, or actin polymerization itself, eliminates E2's effects on synaptic physiology. Notably, the theta burst stimulation used to induce LTP activates the same signaling pathway as E2 plus events that stabilize the reorganization of the sub synaptic cytoskeleton. These observations suggest that E2 elicits a partial form of LTP, resulting in an increase of fast excitatory postsynaptic potentials (EPSPs) and a reduction in the threshold for lasting synaptic changes. While E2's effects on the cytoskeleton could be direct, results described here indicate that the hormone activates synaptic tropomyosin-related kinase B (TrkB) receptors for brain-derived neurotrophic factor (BDNF), a releasable neurotrophin that stimulates the RhoA to cofilin pathway. It is therefore possible that E2 acts via transactivation of neighboring receptors to modify the composition and structure of excitatory contacts. Finally, there is the question of whether a loss of acute synaptic actions contributes to the memory problems associated with estrogen depletion. Initial tests found that ovariectomy in middle-aged rats disrupts RhoA signaling, actin polymerization, and LTP consolidation. Acute applications of E2 reversed these defects, a result consistent with the idea that disturbances to actin management are one cause of behavioral effects that emerge with reductions in steroid levels. PMID- 23103218 TI - Natural IgG antibodies in normal rabbit serum are involved in killing of the ompP2 mutant of Haemophilus parasuis SC096 strain via the classical complement pathway. AB - Serum resistance in Haemophilus parasuis strain SC096 has been shown to be dependent on expression of the outer membrane protein P2 (OmpP2) and loss of the ompP2 gene results in significantly greater sensitivity to both porcine and rabbit sera. However, the mechanism of complement activation by the serum sensitive DeltaompP2 strain is unknown. In this study, the classical complement pathway is demonstrated to be the main pathway for killing the H. parasuis DeltaompP2 strain, and not the mannan-binding lectin (MBL) or alternative pathway. In addition, absorption of antibodies against DeltaompP2 strain or depletion of IgGs from serum inhibited serum killing activity, which could be restored by addition of heat-inactivated serum or purified IgGs. Western blot analysis indicated that the OmpP2 mutant could bind significantly more IgGs than the wild type strain SC096 when incubated with serum. Finally, IgGs in normal rabbit serum targeted to the OMPs, but not lipooligosaccharide (LOS) in the OmpP2 mutant strain were found to be involved in bacterial killing indicating that the bactericidal epitope(s) is in the outer membrane proteins. PMID- 23103219 TI - Bioexclusion of diseases from dairy and beef farms: risks of introducing infectious agents and risk reduction strategies. AB - Infectious disease represents a major threat to the productivity and welfare of cattle herds throughout the world. The introduction of infectious agents into dairy and beef farms may be through direct transmission (purchased cattle, reintroduced resident cattle and contact with contiguous cattle) or indirect transmission (fomites, visitors, other species, and biological materials) and this article reviews the evidence supporting these transmission routes. In the absence of eradication programmes for many endemic infectious diseases, bioexclusion is the key management process for risk reduction. Various ameliorative bioexclusion strategies have been recommended and the evidence supporting these protocols is considered. PMID- 23103220 TI - Comparative assessment of 2-dimensional echocardiography vs cardiac magnetic resonance imaging in measuring left ventricular mass in patients with and without end-stage renal disease. AB - BACKGROUND: While echocardiography (ECHO)-measured left ventricular mass (LVM) predicts adverse cardiovascular events that are common in hemodialysis (HD) recipients, cardiac magnetic resonance imaging (CMR) is now considered the reference standard for determination of LVM. This study aimed to evaluate concordance between LVM measurements across ECHO and CMR among chronic HD recipients and matched controls. METHODS: A single-centre, cross-sectional study of 41 chronic HD patients and 41 matched controls with normal kidney function was performed to compare LVM measurements and left ventricular hypertrophy (LVH) designation by ECHO and CMR. RESULTS: In both groups, ECHO, compared with CMR, overestimated LVM. Bland-Altman analysis demonstrated wider agreement limits in LVM measurements by ECHO and CMR in the chronic HD group (mean difference, 60.8 g; limits -23 g to 144.6 g) than in the group with normal renal function (mean difference, 51.4 g; limits -10.5 g to 113.3 g). LVH prevalence by ECHO and CMR in the chronic HD group was 37.5% and 22.5%, respectively, while 17.5% and 12.5% had LVH by ECHO and CMR, respectively, in the normal kidney function group. Intermodality agreement in the designation of LVH was modest in the chronic HD patients (kappa = 0.42, P = 0.005) but strong (kappa = 0.81, P < 0.001) in the patients with preserved kidney function. Agreement was strong in assessing LVH by ECHO and CMR only in those with normal kidney function. CONCLUSIONS: Our results suggest that the limitations of LVM measurement by ECHO may be more pronounced in patients receiving HD, and provide additional support for the use of CMR in research and clinical practice when rigourous assessment of LVM is essential. PMID- 23103221 TI - MR grading system of osteochondritis dissecans lesions: comparison with arthroscopy. AB - OBJECTIVE: To assess the diagnostic performance of combined three-dimensional (3D) gradient-echo (GRE) T1-weighted and routine MR imaging protocol for the evaluation of osteochondritis dissecans (OCD). MATERIALS AND METHODS: This prospective study was approved by our institutional review board and all patients gave informed consent. Three-dimensional GRE MR sequence was added to the routine protocol performed on 40 consecutive patients (35 men, 5 women; age range, 12-57 years; mean age, 20 years) with 17 juvenile and 24 adult OCD lesions (27 in knees; 14 in elbows) which were confirmed by arthroscopy. Two independent musculoskeletal radiologists reviewed all MR images. The OCD lesions were classified into five stages by assessing the signal intensity of fragment-bone interface and the integrity of articular cartilage on MR images. Stage-IV and -V lesions were considered as unstable. The sensitivity, specificity, accuracy, and interobserver agreement (kappa statistics) were calculated. RESULTS: The sensitivity, specificity, and accuracy for detection of OCD instability were 100% (11 of 11), 100% (6 of 6), and 100% (17 of 17) in juvenile lesions; and 93% (14 of 15), 100% (9 of 9), and 96% (23 of 24) in adult lesions. The overall accuracy of MR findings in determining the staging was 90% (37 of 41) for reader 1 and 83% (34 of 41) for reader 2. Agreement between readers was substantial with a kappa value of 0.75 for MR staging of OCD lesions. CONCLUSIONS: Three-dimensional GRE T1-weighted MR imaging combined with the routine sequences demonstrates excellent diagnostic capabilities in detecting unstable OCD lesions. PMID- 23103222 TI - Selective estrogen receptor modulators inhibit hepatitis C virus infection at multiple steps of the virus life cycle. AB - We screened for hepatitis C virus (HCV) inhibitors using the JFH-1 viral culture system and found that selective estrogen receptor modulators (SERMs), such as tamoxifen, clomifene, raloxifene, and other estrogen receptor alpha (ERalpha) antagonists, inhibited HCV infection. Treatment with SERMs for the first 2 h and treatment 2-24 h after viral inoculation reduced the production of HCV RNA. Treating persistently JFH-1 infected cells with SERMs resulted in a preferential inhibition of extracellular HCV RNA compared to intracellular HCV RNA. When we treated two subgenomic replicon cells, which harbor HCV genome genotype 2a (JFH 1) or genotype 1b, SERMs reduced HCV genome copies and viral protein NS5A. SERMs inhibited the entry of HCV pseudo-particle (HCVpp) genotypes 1a, 1b, 2a, 2b and 4 but did not inhibit vesicular stomatitis virus (VSV) entry. Further experiment using HCVpp indicated that tamoxifen affected both viral binding to cell and post binding events including endocytosis. Taken together, SERMs seemed to target multiple steps of HCV viral life cycle: attachment, entry, replication, and post replication events. SERMs may be potential candidates for the treatment of HCV infection. PMID- 23103223 TI - Acceptability of standing workstations in elementary schools: a pilot study. AB - OBJECTIVE: To examine the acceptability of introducing standing workstations in elementary-school classrooms; and to quantify changes in children's time spent sitting, standing, and walking; step counts; sit-to-stand transitions; and musculoskeletal discomfort. METHODS: A controlled trial was conducted in two elementary schools in Auckland, New Zealand (March-May 2012). Participants were 30 third and fourth graders (n = 23 intervention, n = 7 control). Intervention classes received standing workstations; control class retained usual sitting desks. Children wore ActivPAL monitors over 7 days at baseline and during the fourth week of the intervention. RESULTS: Children spoke enthusiastically of the standing workstations. School staffs were supportive of the standing workstations because they offered "flexibility in learning". Overall, children in the intervention group sat less (intervention: 8.27 (1.45), mean (SD); control: 9.00 (0.80) h/day), stood longer (3.75 (0.88); 2.85 (0.30) h/day), and engaged in fewer transitions from sitting to standing (93 (17); 98 (26) counts) compared to the control group. Effect size ranged from small-large (-0.49; 95% confidence limits (0.64)%, 0.71; (0.48), -0.96; (0.54)% respectively). Results for time spent stepping and step counts were unclear. CONCLUSION: Standing workstations can be successfully integrated in classroom environments and appear to decrease overall sedentariness. PMID- 23103224 TI - Mitochondrial fusion: a mechanism of cisplatin-induced resistance in neuroblastoma cells? AB - Cisplatin induces apoptosis through different pathways. The intrinsic apoptotic pathway is mediated by mitochondria, which, as a result of cisplatin treatment, undergo morphological alterations. The aim of this study was to investigate cisplatin-induced mitochondrial functional and morphological long-term effects in neuroblastoma B50 rat cells. To this purpose, we followed evaluated different several apoptotic markers by means of flow cytometry, confocal and electron microscopy and western blotting techniques. We applied different treatment protocols based on the incubation of the neuroblastoma B50 rat cells with 40 MUM cisplatin: (i) for 48 h and harvesting of the cells at the end of the treatment; (ii) further recovery in drug-free medium for 7 days post-treatment; (iii) conditions as in (ii) followed by re-seeding in normal medium and growth for a further 4 days. We observed apoptosis induction after the first treatment and after the recovery from cell death after long-term culture in drug-free medium. Interestingly, the latter phenomenon was characterized by mitochondrial elongation and mitochondrial protein rearrangement. In recovered and re-seeded cells, mitochondrial equilibrium moved toward fusion, possibly protecting cells from apoptosis. PMID- 23103225 TI - Comparative proteomic analysis for assessment of the ecological significance of maize and peanut intercropping. AB - Intercropping is an important and sustainable cropping practice in agroecosystems. Peanut/maize intercropping is known to improve the iron (Fe) content of peanuts in calcareous soils. In this study, a proteomic approach was used to uncover the ecological significance of peanut/maize intercropping at the molecular level. We demonstrate that photosynthesis-related proteins accumulated in intercropped peanut leaves, suggesting that the intercropped peanuts had a stronger photosynthetic efficiency. Moreover, stress-response proteins displayed elevated expression levels in both peanut and maize in a monocropping system. This indicated that intercropping contributes to resistance to stress conditions. Allene oxide synthase and 12-oxo-phytodienoic acid reductase, two key enzymes in jasmonate (JA) biosynthesis, increased in abundance in the maize roots of the intercropping system, consistent with the upregulation of JA-induced proteins shown by microarray analysis. These results imply that JA may act as a signaling molecule, playing an important role in intercropping through rhizosphere interaction. This study suggests that peanut/maize intercropping results in high Fe availability in the rhizosphere, leading to variation in the proteins related to carbon and nitrogen metabolism. The advantages of intercropping systems may improve the ecological adaptation of plants to environmental stress. PMID- 23103226 TI - Detecting and estimating contamination of human DNA samples in sequencing and array-based genotype data. AB - DNA sample contamination is a serious problem in DNA sequencing studies and may result in systematic genotype misclassification and false positive associations. Although methods exist to detect and filter out cross-species contamination, few methods to detect within-species sample contamination are available. In this paper, we describe methods to identify within-species DNA sample contamination based on (1) a combination of sequencing reads and array-based genotype data, (2) sequence reads alone, and (3) array-based genotype data alone. Analysis of sequencing reads allows contamination detection after sequence data is generated but prior to variant calling; analysis of array-based genotype data allows contamination detection prior to generation of costly sequence data. Through a combination of analysis of in silico and experimentally contaminated samples, we show that our methods can reliably detect and estimate levels of contamination as low as 1%. We evaluate the impact of DNA contamination on genotype accuracy and propose effective strategies to screen for and prevent DNA contamination in sequencing studies. PMID- 23103227 TI - Genetic variants at 6p21.1 and 7p15.3 are associated with risk of multiple cancers in Han Chinese. AB - Cancer susceptibility loci identified in reported genome-wide association studies (GWAS) are often tumor-specific; however, evidence of pleiotropy of some genes/loci has also been observed and biologically plausible. We hypothesized that there are important regions in the genome harboring genetic variants associated with risk of multiple types of cancer. In the current study, we attempted to map genetic variants that have consistent effects on risk of multiple cancers using our existing genome-wide scan data of lung cancer, noncardia gastric cancer, and esophageal squamous-cell carcinoma with overall 5,368 cases and 4,006 controls (GWAS stage), followed by a further evaluation in additional 9,001 cases with one of these cancer types and 11,436 controls (replication stage). Five variants satisfying the criteria of pleiotropy with p values from 1.10 * 10(-8) to 8.96 * 10(-6) for genome-wide scans of three cancer types were further evaluated in the replication stage. We found consistent associations of rs2494938 at 6p21.1 and rs2285947 at 7p15.3 with these three cancers in both GWAS and replication stages. In combined samples of GWAS and replication stages, the minor alleles of rs2494938 and rs2285947 were significantly associated with an increased risk of the cancers (odds ratio [OR] = 1.15, 95% confidence interval [CI], 1.10-1.19 and OR = 1.17, 95% CI, 1.12-1.21), with the p values being 1.20 * 10(-12) and 1.26 * 10(-16), respectively, which are at a genome-wide significance level. Our findings highlight the potential importance of variants at 6p21.1 and 7p15.3 in the susceptibility to multiple cancers. PMID- 23103228 TI - Identification of IL18RAP/IL18R1 and IL12B as leprosy risk genes demonstrates shared pathogenesis between inflammation and infectious diseases. AB - Of eight leprosy susceptibility loci identified by genome-wide association studies, five have been implicated in Crohn disease, suggesting a common genetic fingerprint between leprosy and inflammatory bowel disease (IBD). Here, we conducted a multiple-stage genetic association study of 133 IBD susceptibility loci in multiple leprosy samples (totaling 4,971 leprosy cases and 5,503 controls) from a Chinese population and discovered two associations at rs2058660 on 2q12.1 (p = 4.57 * 10(-19); odds ratio [OR] = 1.30) and rs6871626 on 5q33.3 (p = 3.95 * 10(-18); OR = 0.75), implicating IL18RAP/IL18R1 and IL12B as susceptibility genes for leprosy. Our study reveals the important role of IL12/IL18-mediated transcriptional regulation of IFN-gamma production in leprosy, and together with previous findings, it demonstrates the shared genetic susceptibility between infectious and inflammatory diseases. PMID- 23103229 TI - Exploring population admixture dynamics via empirical and simulated genome-wide distribution of ancestral chromosomal segments. AB - The processes of genetic admixture determine the haplotype structure and linkage disequilibrium patterns of the admixed population, which is important for medical and evolutionary studies. However, most previous studies do not consider the inherent complexity of admixture processes. Here we proposed two approaches to explore population admixture dynamics, and we demonstrated, by analyzing genome wide empirical and simulated data, that the approach based on the distribution of chromosomal segments of distinct ancestry (CSDAs) was more powerful than that based on the distribution of individual ancestry proportions. Analysis of 1,890 African Americans showed that a continuous gene flow model, in which the African American population continuously received gene flow from European populations over about 14 generations, best explained the admixture dynamics of African Americans among several putative models. Interestingly, we observed that some African Americans had much more European ancestry than the simulated samples, indicating substructures of local ancestries in African Americans that could have been caused by individuals from some particular lineages having repeatedly admixed with people of European ancestry. In contrast, the admixture dynamics of Mexicans could be explained by a gradual admixture model in which the Mexican population continuously received gene flow from both European and Amerindian populations over about 24 generations. Our results also indicated that recent gene flows from Sub-Saharan Africans have contributed to the gene pool of Middle Eastern populations such as Mozabite, Bedouin, and Palestinian. In summary, this study not only provides approaches to explore population admixture dynamics, but also advances our understanding on population history of African Americans, Mexicans, and Middle Eastern populations. PMID- 23103230 TI - In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. AB - Shprintzen-Goldberg syndrome (SGS) is characterized by severe marfanoid habitus, intellectual disability, camptodactyly, typical facial dysmorphism, and craniosynostosis. Using family-based exome sequencing, we identified a dominantly inherited heterozygous in-frame deletion in exon 1 of SKI. Direct sequencing of SKI further identified one overlapping heterozygous in-frame deletion and ten heterozygous missense mutations affecting recurrent residues in 18 of the 19 individuals screened for SGS; these individuals included one family affected by somatic mosaicism. All mutations were located in a restricted area of exon 1, within the R-SMAD binding domain of SKI. No mutation was found in a cohort of 11 individuals with other marfanoid-craniosynostosis phenotypes. The interaction between SKI and Smad2/3 and Smad 4 regulates TGF-beta signaling, and the pattern of anomalies in Ski-deficient mice corresponds to the clinical manifestations of SGS. These findings define SGS as a member of the family of diseases associated with the TGF-beta-signaling pathway. PMID- 23103232 TI - AZFc deletions and spermatogenic failure: a population-based survey of 20,000 Y chromosomes. AB - Deletions involving the Y chromosome's AZFc region are the most common known genetic cause of severe spermatogenic failure (SSF). Six recurrent interstitial deletions affecting the region have been reported, but their population genetics are largely unexplored. We assessed the deletions' prevalence in 20,884 men in five populations and found four of the six deletions (presented here in descending order of prevalence): gr/gr, b2/b3, b1/b3, and b2/b4. One of every 27 men carried one of these four deletions. The 1.6 Mb gr/gr deletion, found in one of every 41 men, almost doubles the risk of SSF and accounts for ~2% of SSF, although <2% of men with the deletion are affected. The 1.8 Mb b2/b3 deletion, found in one of every 90 men, does not appear to be a risk factor for SSF. The 1.6 Mb b1/b3 deletion, found in one of every 994 men, appears to increase the risk of SSF by a factor of 2.5, although <2% of men with the deletion are affected, and it accounts for only 0.15% of SSF. The 3.5 Mb b2/b4 deletion, found in one of every 2,320 men, increases the risk of SSF 145 times and accounts for ~6% of SSF; the observed prevalence should approximate the rate at which the deletion arises anew in each generation. We conclude that a single rare variant of major effect (the b2/b4 deletion) and a single common variant of modest effect (the gr/gr deletion) are largely responsible for the AZFc region's contribution to SSF in the population. PMID- 23103231 TI - Imputation of exome sequence variants into population- based samples and blood cell-trait-associated loci in African Americans: NHLBI GO Exome Sequencing Project. AB - Researchers have successfully applied exome sequencing to discover causal variants in selected individuals with familial, highly penetrant disorders. We demonstrate the utility of exome sequencing followed by imputation for discovering low-frequency variants associated with complex quantitative traits. We performed exome sequencing in a reference panel of 761 African Americans and then imputed newly discovered variants into a larger sample of more than 13,000 African Americans for association testing with the blood cell traits hemoglobin, hematocrit, white blood count, and platelet count. First, we illustrate the feasibility of our approach by demonstrating genome-wide-significant associations for variants that are not covered by conventional genotyping arrays; for example, one such association is that between higher platelet count and an MPL c.117G>T (p.Lys39Asn) variant encoding a p.Lys39Asn amino acid substitution of the thrombopoietin receptor gene (p = 1.5 * 10(-11)). Second, we identified an association between missense variants of LCT and higher white blood count (p = 4 * 10(-13)). Third, we identified low-frequency coding variants that might account for allelic heterogeneity at several known blood cell-associated loci: MPL c.754T>C (p.Tyr252His) was associated with higher platelet count; CD36 c.975T>G (p.Tyr325(*)) was associated with lower platelet count; and several missense variants at the alpha-globin gene locus were associated with lower hemoglobin. By identifying low-frequency missense variants associated with blood cell traits not previously reported by genome-wide association studies, we establish that exome sequencing followed by imputation is a powerful approach to dissecting complex, genetically heterogeneous traits in large population-based studies. PMID- 23103233 TI - Length distributions of identity by descent reveal fine-scale demographic history. AB - Data-driven studies of identity by descent (IBD) were recently enabled by high resolution genomic data from large cohorts and scalable algorithms for IBD detection. Yet, haplotype sharing currently represents an underutilized source of information for population-genetics research. We present analytical results on the relationship between haplotype sharing across purportedly unrelated individuals and a population's demographic history. We express the distribution of IBD sharing across pairs of individuals for segments of arbitrary length as a function of the population's demography, and we derive an inference procedure to reconstruct such demographic history. The accuracy of the proposed reconstruction methodology was extensively tested on simulated data. We applied this methodology to two densely typed data sets: 500 Ashkenazi Jewish (AJ) individuals and 56 Kenyan Maasai (MKK) individuals (HapMap 3 data set). Reconstructing the demographic history of the AJ cohort, we recovered two subsequent population expansions, separated by a severe founder event, consistent with previous analysis of lower-throughput genetic data and historical accounts of AJ history. In the MKK cohort, high levels of cryptic relatedness were detected. The spectrum of IBD sharing is consistent with a demographic model in which several small sized demes intermix through high migration rates and result in enrichment of shared long-range haplotypes. This scenario of historically structured demographies might explain the unexpected abundance of runs of homozygosity within several populations. PMID- 23103234 TI - The effects of positive patient testimonials on PTSD treatment choice. AB - Despite the existence of effective treatment options for PTSD, these treatments are failing to reach those that stand to benefit from PTSD treatment. Understanding the processes underlying an individual's treatment seeking behavior holds the potential for reducing treatment-seeking barriers. The current study investigates the effects that positive treatment testimonials have on decisions regarding PTSD treatment. An undergraduate (N = 439) and a trauma-exposed community (N = 203) sample were provided with videotaped treatment rationales for prolonged exposure (PE) and sertraline treatments of PTSD. Half of each sample also viewed testimonials, detailing a fictional patient's treatment experience. All participants then chose among treatment options and rated the credibility of and personal reactions toward - those options. Among treatment naive undergraduates, testimonials increased the proportion choosing PE alone; and among treatment naive members of the trauma-exposed community sample, testimonials increased the proportion choosing a combined PE plus sertraline treatment. These effects were not observed for those with prior history of either psychotherapeutic or pharmacological treatment. Major barriers exist that prevent individuals with PTSD from seeking treatment. For a critical unreached treatment sample, those who are treatment naive, positive patient testimonials offer a mechanism in which to make effective treatments more appealing and accessible. PMID- 23103235 TI - 25-Year disease-free survival rate after irradiation for prostate cancer calculated with the prostate specific antigen definition of recurrence used for radical prostatectomy. AB - PURPOSE: We addressed whether there is durable control of prostate cancer, defined as a prostate specific antigen cutoff of less than 0.2 ng/ml, greater than 20 years after irradiation for this disease. We also evaluated late recurrence, defined as recurrence after 10-year followup. MATERIALS AND METHODS: A total of 3,546 consecutive hormone naive men were treated with a (125)I prostate implant (retropubic and later transperineal), followed by external beam irradiation, from 1984 to 2000. Recurrence was defined as a prostate specific antigen increase of greater than 0.20 ng/ml or a prostate specific antigen nadir of greater than 0.20 ng/ml. Median followup was 11 years (range 3 months to 26 years). RESULTS: In all men 10, 15, 20 and 25-year disease-free survival rates were 75%, 73%, 73% and 73%, respectively. Longest time to recurrence was at the 15.5-year followup. In 313 men with recurrence who were treated 16 to 25 years ago 5% of recurrences were late. In men implanted by the transperineal method since 1995 the 15-year disease-free survival rate was 79%. CONCLUSIONS: With this irradiation program cancer control, defined using the recurrence definition for radical prostatectomy, was durable with no further recurrence between 15.5 and 25 years of followup. This study also suggests that at least 15 years of followup are necessary to fully evaluate any prostate cancer treatment. Furthermore, if prostate specific antigen is less than 0.20 ng/ml 15 years after treatment, later recurrence should be unlikely. PMID- 23103236 TI - Characteristics of lower urinary tract dysfunction and bladder afferent nerve properties in type 2 diabetic goto-kakizaki rats. AB - PURPOSE: We investigated longitudinal changes in lower urinary tract function, especially sensory function, in the type 2 diabetes mellitus model of Goto Kakizaki rats. MATERIALS AND METHODS: We used 16 Wistar and 16 Goto-Kakizaki rats. Body weight, blood glucose, 24-hour voiding frequency-volume data and cardiovascular system data were measured every 3 weeks starting at age 5 weeks until age 14 weeks and then every 6 weeks until age 44 weeks. At ages 10 and 46 weeks conscious cystometry was done, pelvic afferent nerve fiber conduction velocity was measured using urethane anesthesia and isolated detrusor smooth muscle function was determined. RESULTS: Goto-Kakizaki rats showed lower body weight, higher blood glucose and mean voided volume, and less voiding frequency than Wistar rats throughout the observation period. In 46-week-old Goto-Kakizaki rats lower peak micturition pressure, larger bladder capacity and higher bladder compliance were noted on cystometry, while slower conduction velocity and a lesser proportion of Adelta fibers were observed on conduction velocity measurement. Goto-Kakizaki rats showed a lower contractile response to carbachol but not to electrical field stimulation or high K(+) in isolated detrusor smooth muscle. These differences between the 2 groups of rats at age 46 weeks were not noted at age 10 weeks. Cardiovascular system results did not differ between the 2 groups. CONCLUSIONS: The results of this longitudinal study in Goto-Kakizaki rats indicate that type 2 diabetes induces bladder sensory dysfunction, manifesting as slower bladder afferent conduction velocity, larger bladder capacity and greater hypocontractility to acetylcholine. PMID- 23103237 TI - About the article "Exploring the impact of climate on human longevity" (Exp. Geront. 47, 660-671, 2012). PMID- 23103239 TI - Incidence of salivary gland neoplasms in a defined UK population. AB - To establish a true prevalence of salivary gland tumours in a fixed population in the United Kingdom (UK), we searched the unified computerised pathology records of two teaching hospitals, including two private hospitals, for all salivary gland neoplasms (benign and malignant) over two 10-year periods (January 1988 December 1997, and January 1998-December 2007). Reports included needle biopsy, open biopsy, or excision biopsy. Equivocal results were checked by review of the medical notes. Patients referred from outside the catchment area were excluded. Both series combined showed that all neoplasms confirmed the 10:1:1 rule of distribution, but the benign to malignant ratio did not conform to standard teaching. The data suggest that 70-75 benign, and 8-14 malignant neoplasms present annually/million population, which is consistent with established patterns. However, this points towards a lower incidence of cancer in the major salivary glands than was traditionally thought. PMID- 23103238 TI - Fatigability and recovery of arm muscles with advanced age for dynamic and isometric contractions. AB - This study determined whether age-related mechanisms can increase fatigue of arm muscles during maximal velocity dynamic contractions, as it occurs in the lower limb. We compared elbow flexor fatigue of young (n=10, 20.8+/-2.7 years) and old men (n=16, 73.8+/-6.1 years) during and in recovery from a dynamic and an isometric postural fatiguing task. Each task was maintained until failure while supporting a load equivalent to 20% of maximal voluntary isometric contraction (MVIC) torque. Transcranial magnetic stimulation (TMS) was used to assess supraspinal fatigue (superimposed twitch, SIT) and muscle relaxation. Time to failure was longer for the old men than for the young men for the isometric task (9.5+/-3.1 vs. 17.2+/-7.0 min, P=0.01) but similar for the dynamic task (6.3+/ 2.4 min vs. 6.0+/-2.0 min, P=0.73). Initial peak rate of relaxation was slower for the old men than for the young men, and was associated with a longer time to failure for both tasks (P<0.05). Low initial power during elbow flexion was associated with the greatest difference (reduction) in time to failure between the isometric task and the dynamic task (r=-0.54, P=0.015). SIT declined after both fatigue tasks similarly with age, although the recovery of SIT was associated with MVIC recovery for the old (both sessions) but not for the young men. Biceps brachii and brachioradialis EMG activity (% MVIC) of the old men were greater than that of the young men during the dynamic fatiguing task (P<0.05), but were similar during the isometric task. Muscular mechanisms and greater relative muscle activity (EMG activity) explain the greater fatigue during the dynamic task for the old men compared with the young men in the elbow flexor muscles. Recovery of MVC torque however relies more on the recovery of supraspinal fatigue among the old men than among the young men. PMID- 23103240 TI - Ultrasound of the abdominal wall and groin. PMID- 23103241 TI - Recognition and treatment of craniocervical vascular complications encountered during diagnostic and interventional cerebral angiography. PMID- 23103242 TI - Is gait variability reliable in older adults and Parkinson's disease? Towards an optimal testing protocol. AB - BACKGROUND: Despite the widespread use of gait variability in research and clinical studies, testing protocols designed to optimise its reliability have not been established. This study evaluates the impact of testing protocol and pathology on the reliability of gait variability. OBJECTIVE: To (i) estimate the reliability of gait variability during continuous and intermittent walking protocols in older adults and people with Parkinson's disease (PD), (ii) determine optimal number of steps for acceptable levels of reliability of gait variability and (iii) provide sample size estimates for use in clinical trials. METHODS: Gait variability was measured twice, one week apart, in 27 older adults and 25 PD participants. Participants walked at their preferred pace during: (i) a continuous 2 min walk and (ii) 3 intermittent walks over a 12 m walkway. Gait variability was calculated as the within-person standard deviation for step velocity, length and width, and step, stance and swing duration. RESULTS: Reliability of gait variability ranged from poor to excellent (intra class correlations .041-.860; relative limits of agreement 34-89%). Gait variability was more reliable during continuous walks. Control and PD participants demonstrated similar reliability. Increasing the number of steps improved reliability, with most improvement seen across the first 30 steps. CONCLUSIONS: In this study, we identified testing protocols that improve the reliability of measuring gait variability. We recommend using a continuous walking protocol and to collect no fewer than 30 steps. Early PD does not appear to impact negatively on the reliability of gait variability. PMID- 23103243 TI - The influence of body mass index and velocity on knee biomechanics during walking. AB - Obesity has been associated with both the development and progression of knee osteoarthritis. Being overweight or obese from a young age is likely to decrease the age of onset for co-morbidities of obesity such as osteoarthritis. However, research on osteoarthritis has thus far focused on older adults. Therefore, the purpose of this study was to determine whether young adults who are overweight or obese exhibit biomechanical risk factors for knee osteoarthritis at either their preferred walking velocity or at 1m/s, which was slower than the preferred velocity. Thirty healthy young adults formed three equal groups according to body mass index. Three dimensional kinetics and kinematics were collected while participants walked overground at both velocities. Joint moments were normalized to fat free weight and height. The preferred walking velocity of obese participants was slower than that of normal weight individuals. There were no differences in knee flexion excursion, peak knee flexion angle, normalized peak knee flexion moment or normalized peak knee adduction moment among groups. Obese participants walked with lower peak knee adduction angle than both overweight and normal body mass index participants and several shifted towards knee abduction. All groups had smaller knee flexion excursion, peak knee flexion angle, peak knee flexion moment and peak knee adduction moment at 1m/s compared to preferred walking velocity. Overall, young and otherwise healthy overweight and obese participants have knee biomechanics during gait at preferred and slow walking velocities that are comparable to normal weight adults. PMID- 23103244 TI - A hairy tale: successful patient education strategies to reduce prehospital hair removal by patients undergoing elective caesarean section. AB - Inappropriate hair removal is a risk factor for postoperative surgical site infections (SSIs). A series of obstetric patient awareness interventions were introduced regarding hair self-removal before presentation at hospital. Active inpatient and outpatient surveillance of SSIs following caesarean section was undertaken prospectively. The rate of hair self-removal decreased significantly from 41% (2008) to 27% (2011) after implementation of posters and enhanced prenatal education (P = 0.048). Concurrently, a 51% reduction was seen in the SSI rate following caesarean section. This multi-faceted strategy proved successful in reducing prehospital hair self-removal overall, particularly shaving. Other simultaneous SSI prevention interventions are also likely to have contributed to the reduction in SSI rate. PMID- 23103245 TI - Significant reduction in vancomycin-resistant enterococcus colonization and bacteraemia after introduction of a bleach-based cleaning-disinfection programme. AB - BACKGROUND: Vancomycin-resistant enterococcus (VRE) colonization and infection have increased at our hospital, despite adherence to standard VRE control guidelines. AIM: We implemented a multi-modal, hospital-wide improvement programme including a bleach-based cleaning-disinfection programme ('Bleach Clean'). VRE colonization, infection and environmental contamination were compared pre and post implementation. METHODS: The programme included a new product (sodium hypochlorite 1000 ppm + detergent), standardized cleaning disinfection practices, employment of cleaning supervisors, and modified protocols to rely on alcohol-based hand hygiene and sleeveless aprons instead of long-sleeved gowns and gloves. VRE was isolated using chromogenic agar and/or routine laboratory methods. Outcomes were assessed during the 6 months pre and 12 months post implementation, including proportions (per 100 patients screened) of VRE colonization in high-risk wards (HRWs: intensive care, liver transplant, renal, haematology/oncology); proportions of environmental contamination; and episodes of VRE bacteraemia throughout the entire hospital. FINDINGS: Significant reductions in newly recognized VRE colonizations (208/1948 patients screened vs 324/4035, a 24.8% reduction, P = 0.001) and environmental contamination (66.4% reduction, P = 0.012) were observed, but the proportion of patients colonized on admission was stable. The total burden of inpatients with VRE in the HRWs also declined (median percentage of colonized inpatients per week, 19.4% vs 17.3%, P = 0.016). Hospital-wide VRE bacteraemia declined from 14/2935 patients investigated to 5/6194 (83.1% reduction; P < 0.001), but there was no change in vancomycin susceptible enterococcal bacteraemia (P = 0.54). CONCLUSION: The Bleach-Clean programme was associated with marked reductions in new VRE colonizations in high risk patients, and VRE bacteraemia across the entire hospital. These findings have important implications for VRE control in endemic healthcare settings. PMID- 23103246 TI - Outbreak of Pseudomonas fluorescens bloodstream infection in a coronary care unit. AB - An outbreak of Pseudomonas fluorescens infection in six patients in a coronary care unit was associated with a source not previously reported, namely the ice bath used for cardiac output determinations. Outbreaks of pseudobacteraemia caused by P. fluorescens and occasional blood transfusion-associated bloodstream infection (BSI) have been described. However, during the last two decades, two outbreaks of P. fluorescens BSI have been described and this article reports a third. Isolation of P. fluorescens in blood cultures must alert clinicians to the possibility of contamination of infusate, lock solutions or catheter flush. PMID- 23103247 TI - Use of microbial sealant to prevent surgical site infections. PMID- 23103248 TI - Improving infection prevention practice in primary and community care. AB - In March 2012, the National Institute for Health and Clinical Excellence (NICE) published an update of the 2003 guideline that addressed infection prevention and control of healthcare-associated infection in primary and community care settings. In the development of the guideline little high-quality evidence from randomized controlled trials was found. This is an area where high-quality research would impact on future updates of NICE guidance and more robust recommendations could then be made. This article summarizes the main research recommendations made in the guideline and describes the process of making research recommendations when evidence from systematic reviews is lacking. PMID- 23103249 TI - Multidrug-resistant bacteria in travellers hospitalized abroad: prevalence, characteristics, and influence on clinical outcome. AB - BACKGROUND: Worldwide, the burden of multidrug-resistant bacteria (MDR) is increasing, especially in the hospital setting. AIM: To explore characteristics and clinical relevance of MDR obtained from travellers transferred from hospitals abroad. METHODS: This retrospective study included patients transferred from hospitals abroad to the University Hospital Zurich, Switzerland, who routinely underwent admission screening for possible colonization with meticillin-resistant Staphylococcus aureus (MRSA), extended-spectrum beta-lactamase-producing bacteria (ESBL) and multidrug-resistant Gram-negative bacteria (MR Gram negative). FINDINGS: Forty-six (17%) of 259 subjects were found to be colonized with MDR and nine (3.5%) patients to be infected. Thirty-three (12%) patients were colonized with one bacterial species, 12 (4.6%) with two, and three (1.2%) were colonized with three different bacterial species. In total, 36 ESBL, 21 MR Gram-negative and three MRSA isolates were detected. Escherichia coli (N = 18, 30%), Klebsiella pneumoniae (N = 14, 23%) and Acinetobacter baumannii (N = 14, 23%) were most frequently isolated. The most common sites of detection were skin (97%) and respiratory tract (41%). Being colonized contributed to an increased length of ICU stay [median (range): 8 (1-35) vs 3.5 (1-78) days; P = 0.011]. In-hospital mortality in patients colonized with MDR (10.9%) was higher than in uncolonized patients (2.3%, P = 0.018). Being colonized with MDR was associated with death (adjusted odds ratio: 5.176; 95% confidence interval: 1.325-20.218). CONCLUSIONS: A substantial proportion of patients transferred from abroad are colonized with MDR, a fact which is associated with poor clinical outcome. PMID- 23103250 TI - Decreasing time trend in SSI incidence for orthopaedic procedures: surveillance matters! AB - BACKGROUND: Infection is the most common reason for early revision after hip and knee arthroplasty, and the revision rate is increasing. Surgical site infection (SSI) surveillance data are important to assess the true infection rate. There is little information regarding the potential time trend in SSI incidence following orthopaedic surgery. AIM: To evaluate whether a time trend exists in SSI incidence due to surveillance following orthopaedic surgery. METHODS: The SSI rates after hip and knee replacements and osteosynthesis of trochanteric femoral fractures and ankle fractures were recorded prospectively from May 1998 to October 2008 according to the criteria of the US Centers for Disease Control and Prevention. In total, 4177 procedures were analysed, 65.8% of which were performed on female patients. Linear regression was used to analyse trends in SSI rates. FINDINGS: SSI incidence decreased significantly from 7% in the first year to 3% in the last year; a 57% relative reduction. The duration of surgery was the only significant predictor for infection (P < 0.001) in a logistic regression model that also included age, American Society of Anesthesiologists' score and level of emergency. CONCLUSION: Surveillance following orthopaedic procedures showed a significant decrease in SSI incidence over the 11-year surveillance period. The causality between surveillance and SSI incidence is difficult to prove, but surveillance with feedback probably influences several procedures that affect the quality of health care, even if duration of surgery is the only significant predictor of this effect. PMID- 23103251 TI - Virological screening in cases of ALI/ARDS. PMID- 23103252 TI - A role for H2B ubiquitylation in DNA replication. AB - The monoubiquitylation of histone H2B plays an important role in gene expression by contributing to the regulation of transcription elongation and mRNA processing and export. We explored additional cellular functions of this histone modification by investigating its localization to intergenic regions. H2B ubiquitylation is present in chromatin around origins of DNA replication in budding yeast, and as DNA is replicated its levels are maintained on daughter strands by the Bre1 ubiquitin ligase. In the absence of H2B ubiquitylation, the prereplication complex is formed and activated, but replication fork progression is slowed down and the replisome becomes unstable in the presence of hydroxyurea. H2B ubiquitylation promotes the assembly or stability of nucleosomes on newly replicated DNA, and this function is postulated to contribute to fork progression and replisome stability. PMID- 23103254 TI - Distinct single-cell morphological dynamics under beta-lactam antibiotics. AB - The bacterial cell wall is conserved in prokaryotes, stabilizing cells against osmotic stress. Beta-lactams inhibit cell-wall synthesis and induce lysis through a bulge-mediated mechanism; however, little is known about the formation dynamics and stability of these bulges. To capture processes of different timescales, we developed an imaging platform combining automated image analysis with live-cell microscopy at high time resolution. Beta-lactam killing of Escherichia coli cells proceeded through four stages: elongation, bulge formation, bulge stagnation, and lysis. Both the cell wall and outer membrane (OM) affect the observed dynamics; damaging the cell wall with different beta-lactams and compromising OM integrity cause different modes and rates of lysis. Our results show that the bulge formation dynamics are determined by how the cell wall is perturbed. The OM plays an independent role in stabilizing the bulge once it is formed. The stabilized bulge delays lysis and allows recovery upon drug removal. PMID- 23103255 TI - Texting for health: the use of participatory methods to develop healthy lifestyle messages for teens. AB - OBJECTIVE: To develop and test messages and a mobile phone delivery protocol designed to influence the nutrition and physical activity knowledge, attitudes, and behavior of adolescents. DESIGN: Nine focus groups, 4 classroom discussions, and an 8-week pilot study exploring message content, format, origin, and message delivery were conducted over 12 months using a multistage, youth-participatory approach. SETTING: Youth programs at 11 locations in Arizona. PARTICIPANTS: Recruitment was coordinated through youth educators and leaders. Eligible teens were 12-18 years old and enrolled in youth programs between fall 2009 and 2010. PHENOMENON OF INTEREST: Adolescent preferences for messages and delivery of messages. ANALYSIS: Qualitative data analysis procedures to generate themes from field notes. RESULTS: One hundred seventy-seven adolescents participated in focus groups (n = 59), discussions (n = 86), and a pilot study (n = 32). Youth preferred messages with an active voice that referenced teens and recommended specific, achievable behaviors; messages should come from nutrition professionals delivered as a text message, at a frequency of <= 2 messages/day. CONCLUSIONS AND IMPLICATIONS: More than 300 messages and a delivery protocol were successfully developed and tested in partnership with adolescents. Future research should address scalability of texting interventions; explore dose associated with changes in knowledge, attitudes, and behaviors; and offer customized message subscription options. PMID- 23103253 TI - HIF2alpha acts as an mTORC1 activator through the amino acid carrier SLC7A5. AB - The mammalian target of rapamycin (mTOR) pathway, which is essential for cell proliferation, is repressed in certain cell types in hypoxia. However, hypoxia inducible factor 2alpha (HIF2alpha) can act as a proliferation-promoting factor in some biological settings. This paradoxical situation led us to study whether HIF2alpha has a specific effect on mTORC1 regulation. Here we show that activation of the HIF2alpha pathway increases mTORC1 activity by upregulating expression of the amino acid carrier SLC7A5. At the molecular level we also show that HIF2alpha binds to the Slc7a5 proximal promoter. Our findings identify a link between the oxygen-sensing HIF2alpha pathway and mTORC1 regulation, revealing the molecular basis of the tumor-promoting properties of HIF2alpha in von Hippel-Lindau-deficient cells. We also describe relevant physiological scenarios, including those that occur in liver and lung tissue, wherein HIF2alpha or low-oxygen tension drive mTORC1 activity and SLC7A5 expression. PMID- 23103256 TI - Examining the diet of post-migrant Hispanic males using the precede-proceed model: predisposing, reinforcing, and enabling dietary factors. AB - OBJECTIVE: To examine socio-environmental, behavioral, and predisposing, reinforcing, and enabling (PRE) factors contributing to post-migration dietary behavior change among a sample of traditional Hispanic males. DESIGN: In this descriptive study, semistructured interviews, a group interview, and photovoice, followed by group interviews, were used to examine dietary change and contributing factors. The behavioral, environmental, organizational, and educational assessment phases of the PRECEDE-PROCEED model guided the organization of dietary contributing factors for development of a nutrition intervention. SETTING: The southern region of Mississippi. PARTICIPANTS: Traditional Hispanic males (n = 19) were identified from 35 Hispanic males who participated in a larger study. The traditional Hispanic males were identified by the Acculturation Rating Scale for Mexican Americans-II and the Marginality Scale. ANALYSIS: Using the Grounded Theory approach to data analysis, themes and core categories relating to dietary behavior were identified and defined during the analysis process. The constant comparison method was used to identify key themes among coders. RESULTS: Cultural gender role and living structure, as socio environmental factors, influenced the PRE dietary factors. CONCLUSIONS AND IMPLICATIONS: Multiple factors influence dietary behavior in the target population. The identified socio-environmental factors underlie the PRE factors and, therefore, must first be addressed in nutrition interventions. PMID- 23103257 TI - Cervical orthoses after atlantoaxial fixation: who are we treating, the patient or ourselves? PMID- 23103258 TI - Posterior atlantoaxial fixation with screw-rod constructs: safety, advantages, and shortcomings. PMID- 23103259 TI - Neuroendoscopic training by low-priced universal serial bus endoscopes. PMID- 23103260 TI - Pictorial review of in vivo human brain: from anatomy to molecular imaging. AB - Recent advances in neuroimaging demonstrated many markedly improved images hitherto unavailable, specifically the areas that lie deep in the brain. The anatomic images of the deep brain structure taken in vivo using 7.0 T magnetic resonance imaging (MRI) and the molecular images using high resolution research tomography positron emission tomography, as well as the fusion images using state of-art neuroimaging techniques can contribute to the noninvasive treatment of neurologic and psychiatric diseases. We present a pictorial review with selected brain images obtained from 7.0 T MRI, and the images of brain metabolic function accompanied with high resolution anatomic information obtained using the positron emission tomography-MRI fusion technique. In addition, we present some recent results of the cerebral microvasculature and diffusion tractography imaging for the deep brain areas acquired with 7.0 T MRI. PMID- 23103262 TI - Transsphenoidal surgery: a journey of 50 years. PMID- 23103263 TI - Neurosurgical implications of dabigatran-associated intracerebral hemorrhage. PMID- 23103261 TI - Rapid and progressive venous thrombosis after occlusion of high-flow arteriovenous fistula. AB - BACKGROUND: Cerebral venous thrombosis developing after surgical or endovascular obliteration of arteriovenous fistula (AVF) is a rare but devastating complication that has not been adequately reported. CASE DESCRIPTION: Two patients presenting with AVF (1 pial, 1 dural) and large venous pouches were successfully treated by surgical and endovascular means and were neurologically intact postoperatively. Rapid neurologic deterioration was seen on postoperative day 5 in the first patient and postoperative day 2 in the second patient. Both patients had massive cerebral venous thromboses on brain imaging and surgical exploration. One patient died and the other was severely disabled. CONCLUSION: Rapid occlusion of a high-flow AVF resulting in significant venous stasis can precipitate thrombosis of the venous system distal to the fistulous point. In the presence of large venous pouches and significant venous stasis, strict therapeutic anticoagulation may be required to prevent cerebral venous thrombosis. Therapeutic anticoagulation, though feasible following endovascular treatment, may prove particularly challenging after open surgical interventions given the risk of hemorrhagic complications. PMID- 23103264 TI - The creator invented spinal fluid to annoy neurosurgeons. PMID- 23103265 TI - Whether subarachnoid hemorrhage depends on the weather? PMID- 23103266 TI - "Eyeing" the skull base. PMID- 23103267 TI - Oops, I did it again... PMID- 23103268 TI - A plea to pay more attention on anatomo-functional connectivity in surgical management of brain cavernomas. PMID- 23103269 TI - Lessons from the DECRA study. PMID- 23103270 TI - Navigation for spinal surgery: why hasn't it become the accepted standard? PMID- 23103271 TI - To screen or not to screen: vertebral artery injuries in blunt cervical spine trauma. PMID- 23103272 TI - Treatment of incidentally discovered low-grade gliomas: "watch-and-wait" or not? PMID- 23103273 TI - Endoscopy or microsurgery: is the never-ending debate concerning the choice of surgical strategy for colloid cysts of the third ventricle still a topical issue or has it been resolved? PMID- 23103274 TI - Cervical spine injuries: how much imaging is necessary? PMID- 23103275 TI - Angioplasty alone versus angioplasty and stenting for acute cervical carotid occlusions: technical and antiplatelet considerations. PMID- 23103276 TI - Can the hype of "endoscope" become a reality for colloid cyst surgery? PMID- 23103277 TI - Trigeminal neuralgia without evidence of neurovascular conflict: microvascular compression or route entry zone exploration? PMID- 23103278 TI - When blood tickles the brain: where is the argument? PMID- 23103279 TI - Cortisol levels as predictors of short- and long-term adrenal function after endonasal transsphenoidal surgery for pituitary adenomas and Rathke's cleft cyst. PMID- 23103281 TI - Schizanthus grahamii and Schizanthus hookeri. Is there any relationship between their anthocyanin compositions and their different pollination syndromes? AB - Three different pollination syndromes (bee, hummingbird and moth-pollination syndromes) have been described for the different species of the genus Schizanthus Ruiz & Pav. (Solanaceae). Two closely related species from a phylogenetic point of view, Schizanthus grahamii and Schizanthus hookeri, show hummingbird and bee pollination syndromes, respectively. One of the traits used to assign these pollination syndromes is the colour of the petals, which is red in S. grahamii and bluish-pink in S. hookeri. The objective of this work was to establish the differences in the anthocyanin composition of these two Schizanthus species that contribute to the different pollination syndrome. Identification of the pigments was carried out from the chromatographic and spectral data supplied by the HPLC DAD-MS(n) analyses of the samples. Alkaline and acid hydrolyses were also performed in the extracts and in some isolated compounds in order to confirm the identities. First difference between these two species was found in the total anthocyanin content, which was about 13-fold higher in S. grahamii than in S. hookeri. Furthermore, the major peak was also different in both cases, thus explaining quantitative and qualitative colour differences between species. Delphinidin 3-O-rutinoside represented ca. 72% of the total area in S. grahamii and petanin (Petunidin 3-O-p-coumaroylrutinoside-5-O-glucoside) accounted for almost 62% of the total area in S. hookeri. The presence of the p coumaroylrutinosyl moiety in the petanin makes the intramolecular copigmentation possible, thus conferring the bluish-pink hue to the petals of S. hookeri. Delphinidin 3-O-rutinoside is in turn responsible for the red colour exhibited by the petals of S. grahamii and along with other floral traits, responsible for the attraction of hummingbirds to the plant. Pigments structurally related to petanin, which have been often detected in other genus of Solanaceae, were detected in both species and in similar contents, supporting results from previous studies that pointed to a bee-pollinated common ancestor for both species that further specialised acquiring traits attractive to hummingbirds and among them, red colour of the petals which is mainly supplied by delphinidin 3-O rutinoside. PMID- 23103282 TI - Social networks, web-based tools and diseases: implications for biomedical research. AB - Advances in information technology have improved our ability to gather, collect and analyze information from individuals online. Social networks can be seen as a nonlinear superposition of a multitude of complex connections between people where the nodes represent individuals and the links between them capture a variety of different social interactions. The emergence of different types of social networks has fostered connections between individuals, thus facilitating data exchange in a variety of fields. Therefore, the question posed now is "can these same tools be applied to life sciences in order to improve scientific and medical research?" In this article, I will review how social networks and other web-based tools are changing the way we approach and track diseases in biomedical research. PMID- 23103283 TI - Mancozeb-induced behavioral deficits precede structural neural degeneration. AB - Manganese-containing fungicides like Mancozeb have been associated with neurodegenerative conditions like Parkinson's disease. We examined the behavioral damage and differential neuronal vulnerability resulting from Mancozeb exposure using Caenorhabditis elegans, an important mid-trophic level soil organism that is also a powerful model for studying mechanisms of environmental pollutant induced neurodegenerative disease. The dopamine-mediated swim to crawl locomotory transition behavior is exquisitely vulnerable to Mancozeb, with functional impairment preceding markers of neuronal structural damage. The damage is partially rescued in mutants lacking the divalent metal transporter, SMF-1, demonstrating that some, but not all, of the damage is mediated by manganese. Increasing concentrations of Mancozeb recruit additional behavioral dysfunction, notably serotonin-mediated egg-laying behavior, but without evident serotonergic neuronal structural damage. Thus, measurements of behavioral dysfunction are a sensitive early marker of fungicide toxicity that could be exploited to examine further mechanisms of neuron damage and possible therapeutic interventions. These results also provide important insight into the consequences of fungicide use on the ecological behavior of nematodes. PMID- 23103284 TI - TLR9-signaling is required for turning retinoic acid into a potent stimulator of RP105 (CD180)-mediated proliferation and IgG synthesis in human memory B cells. AB - The role of vitamin A in the various parts of the immune system remains elusive. Toll-like receptors (TLRs) are involved in innate polyclonal activation of B cells, and as such they are important for maintaining long-lasting first line defense against pathogens. Here we explore the impact of all-trans retinoic acid (RA) on B cell responses mediated via the TLR homolog RP105 (CD180). We show that RA slightly reduces the proliferation and IgG production in CD27+ memory B cells stimulated by anti-RP105 alone. However, co-stimulation with the TLR9-ligand CpG results in turning RA into a potent stimulator of RP105-induced proliferation and IgG synthesis in memory B cells. The results emphasize the important role of RA in stimulating TLR-mediated polyclonal activation and differentiation of B cells, and reveal the complex interplay between various TLRs that may underlie the ability of RA to fight pathogens. PMID- 23103285 TI - Risk factors for and prevention of human papillomaviruses (HPV), genital warts and cervical cancer. AB - Genital HPV infection is associated with development of cervical cancer, cervical neoplasia, anogenital warts, and other anogenital cancers. A number of reviews have primarily addressed the role of HPV infection in cervical carcinogenesis, and differences in human papillomavirus (HPV) subtypes found in cervical cancer cases by histology and geographical region. This review provides an informative summary of the broad body of literature on the burden of HPV, the risk factors for HPV infection, genital warts and cervical cancer, and preventive measures against these conditions in females. Studies have identified the main risk factors for genital HPV infection in females as follows: acquisition of new male partners; an increasing number of lifetime sexual partners both in females and their male partners; and having non-monogamous male partners. Cervical cancer screening and HPV vaccination are the primary measures currently recommended to prevent cervical cancer. There is also an ongoing debate and conflicting findings on whether male circumcision and condom use protect against HPV infection and subsequent development of HPV-related illnesses in females. PMID- 23103286 TI - Immunity to measles, diphtheria and tetanus in residents of homeless shelters in Marseilles, France. PMID- 23103287 TI - IL28B polymorphisms are associated with severity of liver disease in human immunodeficiency virus (HIV) patients coinfected with hepatitis C virus. AB - OBJECTIVE: To evaluate the association of IL28B polymorphisms and severity of liver disease among human immunodeficiency virus (HIV)/hepatitis C virus (HCV) coinfected patients. METHODS: We carried out a cross-sectional study on 223 patients. Liver biopsies were evaluated according to Metavir score. IL28B polymorphisms (rs12980275, rs8099917, rs7248668, and rs11881222) were genotyped using GoldenGate((r)) assay. RESULTS: IL28B polymorphisms were in strong linkage disequilibrium, especially the couples rs12980275/rs11881222 and rs8099917/rs7248668. For all patients, the rs12980275 A allele increased the odds for significant fibrosis (F >= 2) odds ratio (OR) = 1.68; p = 0.018) and more rapid fibrosis progression (FPR >= 0.075 fibrosis units/year) (OR = 1.64; p = 0.035), and decreased the odds for liver steatosis (OR = 0.61; p = 0.046). Furthermore, the rs8099917 T allele increased the odds for F >= 2 (OR = 1.93; p = 0.020), FPR >= 0.075 (OR = 2.08; p = 0.021), and elevated ALT (>=80 IU/l) (OR = 1.78; p = 0.048). For HCV-genotype 1 patients, rs12980275 A and rs8099917 T alleles decreased the odds for liver steatosis (OR = 0.22; p < 0.001 and OR = 0.39; p = 0.048; respectively). For HCV-genotype 3 patients, the rs12980275 A allele increased the odds for F >= 2 ((OR = 6.30; p = 0.012), FPR >= 0.075 (OR = 6.40; p = 0.025), and elevated ALT (OR = 4.12; p = 0.037); and the rs8099917 T allele also increased the odds for F >= 2 (OR = 7.56; p = 0.027), FPR >= 0.075 (OR = 50.8; p = 0.012), and elevated ALT (OR = 5.39; p = 0.043). However, we did not find significant trends in patients infected with HCV-genotype 4. CONCLUSION: The major alleles of IL28B (rs12980275 A, rs11881222 A, rs8099917 T, and rs7248668 G) are associated with increased odds of liver disease severity in HIV patients infected with HCV-genotype 3. In contrast, HCV-genotype 1 patients carrying the major alleles of IL28B polymorphisms had lower odds for liver steatosis. PMID- 23103288 TI - Stochastic modelling of intra-household transmission of hepatitis C virus: evidence for substantial non-sexual infection. AB - OBJECTIVE: To simulate the probability of HCV transmission from an HCV seropositive index patient to susceptible household contacts through non-sexual exposures. METHODS: A modified Reed-Frost stochastic simulation model was used to assess the probability of HCV transmission from an HCV seropositive index patient to susceptible household contacts through non-sexual exposures. This mathematical model does not require the specification of infection onset times for individual, nor is it necessary to identify the chains of household infections. Therefore, this model can be used with serologic data on detected asymptomatic infections. The HCV serological data on 341 non-sexual household contacts of 86 HCV seropositive index patients were used in this simulation study. The frequency distribution of HCV infection of susceptibles for each household size of 4-8 initial susceptibles was calculated. A maximum likelihood procedure was used to estimate the non-sexual household transmission parameter for HCV infection for the range of household sizes studied and was used in 1000 stochastic iterations. The goodness-of-fit test was carried out to compare the observed proportions of households where HCV transmission occurred to one or more initial susceptible with mean expected simulated proportions of such households with varying sizes ranging from 4 to 8 initial susceptibles. RESULTS: The maximum likelihood estimates (90% probability interval (PI)) of binomial probability of HCV transmission within households with varying number of initial susceptible non sexual household contacts ranged from 0.248 (90%PI: 0.031, 0.560) to 0.164 (90%PI: 0.011, 0.440) for household size of 4 and 8 respectively. The chi(2) goodness-of-fit test of observed and mean expected simulated proportions of households wherein at least one of the susceptibles was infected revealed good fit for households of all sizes examined (P >= 0.96). In a household, the probability of HCV transmission from the index HCV seropositive patient to susceptible via non-sexual contacts tended to decrease linearly as the household size increased from four to seven. CONCLUSION: Intra-household HCV transmission through non-sexual contacts may have substantial impact on HCV transmission and needs to be considered in an HCV control program. PMID- 23103289 TI - Implications of HIV diversity for the HIV-1 pandemic. AB - HIV-1 genetic variability within individuals and populations plays a central role in the HIV pandemic. Multiple zoonotic transmissions of SIV to humans have resulted in distinct HIV lineages in humans which have further diversified within the population over time. High rates of mutation and recombination during HIV reverse transcription create a genetic diversity in the host which is subject to selection pressures by the immune response and antiretroviral treatment. The global distribution of HIV genetic variants and the impact of HIV diversity on pathogenesis, transmission and clinical management are reviewed. Finally, the key role of escape mutations in the immune response to HIV is discussed as well as the major challenge which HIV-1 diversity poses to HIV vaccine development. PMID- 23103290 TI - Changing epidemiology of community-onset Staphylococcus aureus bacteremia over nine years in an emergency department in Taiwan. PMID- 23103291 TI - Mortality and hospital stay related to coagulase-negative Staphylococci bacteremia in non-critical patients. AB - OBJECTIVES: To describe the morbidity and mortality related to coagulase-negative Staphylococci (CNS) bacteremia in non-critical patients. METHODS: Prospective, matched case-control study nested in a cohort. Patients with CNS bacteremia and no other isolate in blood cultures during their admission were defined as cases. Each case was matched by age, sex and area of hospitalization to one control. A 30-day follow-up was performed. Mortality and hospital stay were defined as endpoints. RESULTS: 105 cases and 105 controls were included. All cases carried intravascular catheters at the time of inclusion. Cases presented higher mortality compared to controls (14.3% vs. 4.8%), although this association was not independent in a multivariate analysis (p = 0.11). CNS bacteremia was independently associated with longer hospital stay (mean 12 vs. 8.5 days, p = 0.008). Moreover, when patients with CNS bacteremia were specifically analyzed, the persistence of fever (p = 0.005) and inappropriate empirical treatment (p = 0.04) were independently related to mortality. CONCLUSION: We did not observe increased mortality attributable to CNS bacteremia, although it was associated with longer hospitalizations. Early appropriate empirical antibiotic therapy pending blood culture results might improve the outcome of patients with CNS bacteremia. Close follow-up is recommended if fever persists beyond 72 h. PMID- 23103292 TI - Antibodies against dengue virus nonstructural protein-1 induce heme oxygenase-1 via a redox-dependent pathway in human endothelial cells. AB - Heme oxygenase (HO)-1, the inducible isoform of the first and rate-limiting enzyme of heme degradation, affords anti-inflammatory protection via its cell type-specific effects in endothelial cells (ECs). In dengue hemorrhagic fever (DHF), which is the life-threatening form of dengue virus (DV) infection, endothelial interactions of cross-reactive antibodies against the DV nonstructural glycoprotein-1 (NS1) are associated with endothelial dysfunction. In this study, we investigated whether anti-NS1 antibodies might regulate HO-1 gene expression in human ECs. Serum from DHF patients with high anti-NS1 titers and a monoclonal anti-NS1 antibody upregulated HO-1 gene expression in human umbilical vein ECs, which was blocked by purified NS1 antigen. Immunoprecipitation studies showed that anti-NS1 antibodies specifically bound to the oxidoreductase protein disulfide isomerase (PDI) on ECs. Moreover, anti-NS1 mediated HO-1 induction was reduced by inhibition of PDI enzyme activity. Reactive oxygen species, which were generated by NADPH oxidase and in turn activated the phosphatidylinositol 3-kinase (PI3K)/Akt cascade, were involved in this upregulation of HO-1 gene expression. Finally, apoptosis of ECs caused by anti-NS1 antibodies was increased by pharmacological inhibition of HO-1 enzyme activity. In conclusion, HO-1 gene expression is upregulated by anti-NS1 antibodies via activation of a redox-dependent PDI/PI3K/Akt-mediated pathway in human ECs. PMID- 23103293 TI - The increased use of computed tomography scanning for diagnosing superficial soft tissue infections: a disturbing trend of increased radiation with no benefit. AB - BACKGROUND: Soft tissue infections have historically been diagnosed on the basis of clinical signs and symptoms. A trend toward the increased use of computed tomographic (CT) imaging in their evaluation has been noted. METHODS: A retrospective review was performed of soft tissue infection admissions in 2003 and 2004 and in 2009 and 2010. Intracavitary abscesses (eg, intra-abdominal, pelvic) that would not be evident on physical examination were excluded. Demographic and outcome variables, number of CT scans by body region, and total effective radiation dose were recorded. Radiation exposure was stratified into low, moderate, high, and very high categories. RESULTS: There was a significant increase in the number of patients receiving >=1 CT scan for initial diagnosis, from 36.7% in the early cohort to 50% in the later cohort (P < .001). The mean cumulative effective dose increased from 5.46 to 7.82 mSv (P = .007). Greater proportions of patients fell into the moderate (32.9% vs 24.5%) and high (6.8% vs 10.6%) radiation exposure categories. CONCLUSIONS: CT scans are increasingly used in the evaluation of soft tissue infections, with resultant increase in radiation exposure. PMID- 23103294 TI - Bioactive phenolics and terpenoids from Manglietia insignis. AB - Four new compounds, maninsigins A-D (1-4), including two new neolignans (1-2) and two new sesquiterpenes (3-4), as well as ten known compounds (5-14), were isolated from the leaves and stems of Manglietia insignis. Their structures were established on the basis of extensive spectroscopic analyses. In addition, some compounds were tested for their cytotoxic and neurite outgrowth-promoting activities, as well as their antagonistic activity toward FXR ligand. PMID- 23103295 TI - Anti-neuroinflammatory constituents from Asparagus cochinchinensis. AB - Three new pregnane glycosides, aspacochinosides N (1), O (2), and P (3) were isolated from the roots of Asparagus cochinchinensis, together with four known furostanol glycosides. Their structures were determined by chemical methods and NMR spectral analysis, including extensive 1D and 2D NMR experiments. Compounds 1 7 were evaluated for their anti-neuroinflammatory activity in LPS-induced BV-2 microglial cells. Compounds 2, 3, and 4 showed significant inhibition on NO production in LPS-induced BV-2 microglial cells with IC(50) values of 13.51, 4.72, and 63.57MUM, respectively. PMID- 23103296 TI - In vitro metabolism, permeation, and brain availability of six major boswellic acids from Boswellia serrata gum resins. AB - Boswellia serrata gum resin extracts (BSE) revealed potent anti-inflammatory actions in preclinical and clinical studies. In 2002 BSE was assigned an orphan drug status by the European Medicines Agency (EMA) for the treatment of peritumoral edema. In the past pharmacological effects of BSE were mainly attributed to 11-keto-beta-boswellic acid (KBA) and 3-acetyl-11-keto-beta boswellic acid (AKBA). Therefore pharmacokinetic and pharmacodynamic studies focused mainly on these two boswellic acids (BAs). However, other BAs, like beta boswellic acid (betaBA), might also contribute to the anti-inflammatory actions of BSE. Here, we determined the metabolic stability, permeability and brain availability of six major BAs, that is, KBA, AKBA, betaBA, 3-acetyl-beta boswellic acid (AbetaBA), alpha-boswellic acid (alphaBA), and 3-acetyl-alpha boswellic acid (AalphaBA). For permeability studies, the Caco-2 model was adapted to physiological conditions by the addition of bovine serum albumin (BSA) to the basolateral side and the use of modified fasted state simulated intestinal fluid (FaSSIF) on the apical side. Under these conditions the four BAs lacking the 11 keto moiety revealed moderate permeability. Furthermore the permeability of AKBA and KBA was improved compared to earlier studies. In contrast to Aalpha- and AbetaBA, betaBA and alphaBA were intensively metabolized after incubation with human and rat liver microsomes. Finally, the availability of all six major BAs could be confirmed in rat brain 8h after oral administration of 240mg/kg BSE to rats showing mean concentrations of 11.6ng/g for KBA, 37.5ng/g for AKBA, 485.1ng/g for alphaBA, 1066.6ng/g for betaBA, 43.0ng/g for AalphaBA and 163.7ng/g for AbetaBA. PMID- 23103297 TI - (-)-Carvone: antispasmodic effect and mode of action. AB - (-)-Carvone is a monoterpene ketone found in spearmint (Mentha spicata var. crispa) essential oil that is widely used as an odor and flavor additive. An intestinal antispasmodic effect was recently reported for (-)-carvone, and it has been shown to be more potent than its (+)-antipode. The mechanism of (-)-carvone action in the intestines has not been investigated. To gain a better understanding of the (-)-carvone antispasmodic effect, we investigated its pharmacological effects in the guinea pig ileum. Terminal portions of the ileum were mounted for isotonic contraction recordings. The effect of (-)-carvone was compared with that of the classical calcium channel blocker (CCB) verapamil. In isolated ileal smooth muscle, (-)-carvone did not produce direct contractile or relaxation responses and did not modify electrically elicited contractions or low K(+)-evoked contractions. The submaximal contractions induced by histamine (p<0.001), BaCl2 (p<0.05), and carbachol (p<0.01) were significantly reduced by ( )-carvone. The contractile response elicited by high concentrations of carbachol was reduced but not abolished by (-)-carvone. No additive action was detected with co-incubation of (-)-carvone and verapamil on carbachol-induced contraction. (-)-Carvone reduced the contraction induced by high K(+) and was almost 100 times more potent than verapamil. Thus, (-)-carvone showed a typical and potent CCB like action. Many effects described for both (-)-carvone and spearmint oil can be explained as a CCB-like mode of action. PMID- 23103298 TI - Possible ways of fagopyrin biosynthesis and production in buckwheat plants. AB - The present work extends knowledge about possible biosynthesis of fagopyrin in buckwheat plants by providing possible candidate genes for its biosynthesis and the role of type III polyketide synthases (PKSs). Moreover, new information is presented about the possible connection between naphthodianthrones and phenolic biosynthesis. Possible regulation of fagopyrin biosynthesis and production under different growth conditions is also discussed. PMID- 23103299 TI - A multistage-polyepitope vaccine protects against Mycobacterium tuberculosis infection in HLA-DR3 transgenic mice. AB - Mycobacterium tuberculosis (Mtb) is responsible for almost 2 million deaths annually. BCG, currently the only TB vaccine, induces variable protection and does not protect against reactivation of latent TB. Thus, efficient vaccines to supplement BCG are required urgently. Since Mtb's proteome differs qualitatively and quantitatively during bacterial replication stages from that expressed during dormancy, improved TB vaccines should drive immune responses to Mtb antigens expressed during multiple stages of infection. Consequently, such "multistage" vaccines should be composed of (immunodominant) antigens expressed during different phases of Mtb infection. As a concept multistage vaccine, we constructed a polyepitope by fusing five HLA-DR3-restricted T-cell epitopes derived from different Mtb proteins either expressed highly by replicating bacteria (Ag85B, hsp65, 19 kDa lipoprotein), or abundantly expressed by dormant bacilli and recognized preferentially by TST(+) individuals (hsp16, Rv1733c). PBMC of HLA-DR3(+) but not HLA-DR3(-) cured TB patients and TST(+) individuals responded well to the multistage-polyepitope in vitro. The in vivo immunogenicity and protective efficacy of the multistage-polyepitope were analyzed using HLA-DR3 transgenic mice lacking endogenous murine class II as a model. Immunization with the multistage-polyepitope adjuvanted with CpG generated high IgG levels as well as polyfunctional CD4(+) T-cells producing IFN-gamma, TNF and IL-2, specific for these HLA-DR3-restricted epitopes. Importantly, multistage-polyepitope immunization reduced the number of bacilli in the lungs after Mtb challenge when administered as prophylactic vaccine. Given the extensive repertoire of potential Mtb antigens available for immune recognition, the data of our model demonstrate the potential of multistage-polyepitope vaccines to protect against TB. PMID- 23103300 TI - Stochastic disease dynamics of a hospital infection model. AB - A stochastic model for hospital infection incorporating both direct transmission and indirect transmission via free-living bacteria in the environment is investigated. We examine the long term behavior of the model by calculating a stationary distribution and normal approximation of the distribution. The quasi stationary distribution of the model is studied to investigate the models' behavior before extinction and the time to extinction. Numerical results show agreement between the calculated distributions and results of event-driven simulations. Hand hygiene of volunteers is more effective in terms of reducing the mean (or standard deviation) of the stationary distribution of colonized patients and the expected time to extinction compared to hand hygiene of health care workers (HCWs), on the basis of our parameter values. However, the indirect (or direct) transmission rate can lead to either increase or decrease in the standard deviation of the stationary distribution, but the impact of the indirect transmission is much greater than that of the direct transmission. The findings suggest that isolation of new admitted colonized patients is most effective in reducing both the mean and standard deviation of the stationary distribution and measures related to indirect transmission are secondary in their effects compared to other interventions. PMID- 23103301 TI - The vascular anastomoses in monochorionic twin pregnancies and their clinical consequences. AB - Monochorionic twin pregnancies are at increased risk of adverse outcome because of the vascular anastomoses that connect the 2 fetal circulation systems. The shared circulation is responsible for some unique complications in monochorionic twins, such as the twin-to-twin transfusion syndrome, the twin anemia polycythemia sequence, the twin reversed arterial perfusion sequence, and monoamniotic twinning. Another consequence of the shared circulation is that the well-being of one twin critically depends on that of the other. In this review, we will describe the technique of placental injection. Further, we will discuss the role of the vascular anastomoses in each of the complications described above and provide an update on their management. PMID- 23103302 TI - An unnatural attachment: a young woman experienced gynecologic effects of chronic graft-vs-host disease. PMID- 23103303 TI - Melatonin secretion in children with epilepsy. AB - This study examined melatonin (MLT) system in children with epilepsy. Diurnal patterns of salivary MLT, urinary metabolite 6-sulphatoxymelatonin, core body temperature, pulse and blood pressure were measured in 51 children with epilepsy (6.6-17.9 years) and 29 comparison children (5.5-17.3 years). The children with epilepsy preserved MLT and other circadian rhythms. In nine children with epilepsy (17.6%), peak salivary MLT concentrations were very high. There were no associations between MLT secretion/excretion parameters (diurnal profile, peak nocturnal concentrations, area under the time curve, duration of elevated concentrations, acrophase) and seizure characteristics (time, type of seizures, antiepileptic medications). The study observations are important for understanding of the MLT system in epilepsy and for exploring the potential for seizure treatment with melatonin. PMID- 23103304 TI - A strength exercise program in rats with epilepsy is protective against seizures. AB - The beneficial effects of physical exercise on epilepsy, such as a decreased seizure frequency, have been observed following aerobic exercise programs in both clinical and experimental studies. However, it is not well clarified whether other types of exercise, including strength exercise, can provide similar benefits for epilepsy. Forty four animals with epilepsy were continuously monitored 24 h a day for 60 days and divided into two periods of 30 days. The first period was used to determine the number of seizures before beginning the physical exercise program, and the second period was utilized to determine the number of seizures during the strength training. The mean frequency of seizures in the control and SHAM groups increased significantly from period 1 to period 2. Although the frequency of seizures did not change significantly between the two periods of 30 days of observation in the strength exercise group, a significant reduction in the seizure frequency was observed compared with the control and SHAM groups in period 2. Our study demonstrated that a strength exercise program exerted a significant influence on the seizure frequency in animals with epilepsy and strengthens the observed beneficial effect of exercise on epilepsy that has been demonstrated in animal studies. The finding of this nonclinical study can open a new window to verify the beneficial contribution of strength exercise in epilepsy. Further experimental and clinical investigations are necessary to explore the extent to which strength exercise interferes with the epileptic condition. PMID- 23103305 TI - Acute lorazepam effects on neurocognitive performance. AB - A double-blind, placebo-controlled, crossover design was employed to determine whether acute lorazepam (2 mg orally) cognitive side effects would emerge in a differential age-dependent fashion in 15 young (mean age=22 years) and 12 older (mean age=64 years) subjects. Acute use of lorazepam is frequently the initial treatment choice for convulsive status epilepticus or repetitive seizure clusters. Cognitive assessment was performed during drug and placebo conditions using a computerized battery of cognitive tests. With the exception of performance on the reasoning composite score, significant drug effects were present on all primary cognitive domain measures. However, the only significant drug-by-age interaction effect was seen for dual-task performance. The relationship between test performance and plasma lorazepam concentrations was generally modest and non-significant, suggesting that individual differences in pharmacokinetics are not a major factor contributing to the emergence of cognitive side effects. Despite robust lorazepam effects on multiple measures of neurocognitive function, differential age effects are largely restricted to dual task performance. These results indicate that with the exception of dual-task performance, older individuals in the age range of this study do not appear to be at increased risk for the emergence of cognitive side effects following a single 2-mg dose of lorazepam. PMID- 23103306 TI - A critical and descriptive approach to interictal behavior with the Neurobehavior Inventory (NBI). AB - PURPOSE: The purpose of this study was to test the psychometric properties of the Neurobehavior Inventory (NBI) in a group of temporal lobe epilepsy (TLE) patients from a tertiary care center, correlating its scores with the presence of psychiatric symptoms. METHODS: Clinical and sociodemographic data from ninety-six TLE outpatients were collected, and a neuropsychiatric evaluation was performed with the following instruments: Mini-Mental State Examination (MMSE), structured psychiatric interview (MINI-PLUS), Neurobehavior Inventory (NBI), and Hamilton Depression Rating Scale (HAM-D). RESULTS: Some traits evaluated by the NBI showed adequate internal consistency (mean inter-item correlation between 0.2 and 0.4) and were frequent, such as religiosity (74%) and repetitiveness (60.4%). Principal component analysis showed three factors, named here as emotions (Factor 1), hyposexuality (Factor 2), and unusual ideas (Factor 3). Depressive symptoms on HAM-D showed a strong association with emotions and hyposexuality factors. When patients with left TLE and right TLE were compared, the former exhibited more sadness (p=0.017), and the latter, a greater tendency toward sense of personal destiny (p=0.028). CONCLUSION: Depression influences NBI scoring, mainly emotionality and hyposexuality traits. Neurobehavior Inventory subscales can be better interpreted with an appropriate evaluation of comorbid mood and anxiety disorders. Compromise in left temporal mesial structures is associated with increased tendency toward sad affect, whereas right temporal pathology is associated with increased beliefs in personal destiny. PMID- 23103307 TI - Reasons for uncontrolled seizures in children: the impact of pseudointractability. AB - PURPOSE: We investigated the various possible reasons for uncontrolled seizures in patients under 18 years of age to determine the impact of pseudointractability. We also investigated the various forms of pseudointractability in children with uncontrolled seizures. METHODS: In this cross-sectional retrospective chart review study, all patients under 18 years of age with their first seizure occurring at least 6 months prior to the referral date, taking at least one antiepileptic drug (AED), and having at least one seizure in the past 3 months were studied. The presumed reason for uncontrolled seizures was arbitrarily considered to be one of these five categories: poor adherence; wrong medication; wrong dose of the correct medication; diagnosis other than epilepsy; and finally, medically refractory epilepsy. Statistical analyses were performed using Chi-square and Fisher's Exact tests to determine potentially significant differences, and a P value less than 0.05 was considered significant. RESULTS: During the study period, 198 patients were referred to us due to uncontrolled seizures. Ninety patients (45%) were taking one AED, 55 (28%) were taking two AEDs, and 53 (27%) patients were taking more than two AEDs at the time of referral. Four percent of these patients did not have epilepsy. Forty seven percent of the children with uncontrolled seizures had medically refractory epilepsy; 37% were taking the wrong AEDs; 10% were taking suboptimal doses of AEDs; and 2% had poor drug adherence. CONCLUSION: Uncontrolled seizures in children are a commonly encountered problem, particularly at epilepsy clinics. One should consider all possible reasons for these uncontrolled seizures, including non-epileptic seizures, pseudointractability, and medically refractory epilepsy. The mainstay for making a correct diagnosis is a detailed clinical history. PMID- 23103308 TI - Psychiatric comorbidity in veterans with psychogenic seizures. AB - Psychogenic non-epileptic seizures (PNES) are frequently encountered in epilepsy monitoring units (EMU) at Veterans Affairs Medical Centers (VAMCs) and cause significant long-term disability. An understanding of psychiatric factors associated with PNES could aid in earlier diagnosis and treatment. We studied 50 consecutive veterans diagnosed with PNES and 37 veterans diagnosed with epileptic seizures (ES), evaluated at a VAMC EMU. We reviewed all available mental health evaluations prior to EMU evaluation. Univariate comparisons included axis I diagnoses, axis II diagnoses, and psychiatric hospitalizations. Predictive models of seizure classification were evaluated by logistic regression. A diagnosis of post-traumatic stress disorder (PTSD) preceded the diagnosis of PNES in 58% of patients and the diagnosis of ES in 13.5% (p<0.001). On logistic regression, PTSD was the only significant psychiatric diagnosis (odds ratio 9.2). Major depression and alcohol abuse were common diagnoses but did not differentiate PNES and ES groups. PMID- 23103310 TI - Psychogenic non-epileptic seizures: predisposing factors to diminished quality of life. AB - OBJECTIVE: The objective of this study was to examine the factors that contribute to the reports of diminished quality of life (QOL) in patients with psychogenic non-epileptic seizures (PNES). METHODS: We assessed 62 patients with PNES for quality of life, anger expression and personality, and psychiatric, social and medical histories. RESULTS: Diagnosis of depression, pain syndromes, older age of onset and shorter duration of PNES correlated with poorer quality of life. Elevated anger state, trait and total anger scores correlated with worse quality of life and with Quality of Life in Epilepsy 31 subscales of emotional well being, medication, cognitive and social effects, seizure worry, and fatigue. CONCLUSION: Our study verifies reported correlations between depression and somatic symptoms and quality of life. A novel finding is that of a relationship between quality of life in PNES and anger expression. This result has important implications for psychotherapeutic treatment of PNES in that it provides a potentially modifiable target. PMID- 23103309 TI - Effect of lateralized temporal lobe epilepsy on the default mode network. AB - The default mode network (DMN) is composed of cerebral regions involved in conscious, resting state cognition. The hippocampus is an essential component of this network. Here, the DMN in TLE is compared to control subjects to better understand its involvement in TLE. We performed resting state connectivity analysis using regions of interest (ROIs) in the retrosplenium/precuneus (Rsp/PCUN) and the ventro-medial pre-frontal cortex (vmPFC) in 36 subjects (11 with right TLE, 12 with left TLE, 13 controls) to delineate the posterior and anterior DMN regions respectively. We found reduced connectivity of the posterior to the anterior DMN in patients with both right and left TLE. However, the posterior and anterior networks were found to be individually preserved. Lateralization of TLE affects the DMN with left TLE demonstrating more extensive networks. These DMN changes may be relevant to altered cognition and memory in TLE and may be relevant to right vs. left TLE differences in cognitive involvement. PMID- 23103311 TI - Sleep apnea and epilepsy: who's at risk? AB - Obstructive sleep apnea (OSA) is highly prevalent, affecting 25% of men and 10% of women. Treatment reduces seizures in some patients. Awareness of the comorbidity of sleep disturbances in epilepsy has been increasing. No study has explored OSA predictors in patients unselected for epilepsy severity and sleep disorder symptoms. We assessed cross-sectional OSA prevalence and predictors (apnea-hypopnea index [AHI] >=10) in 130 consecutive adults using structured interview, subjective assessments, and polysomnography. Obstructive sleep apnea prevalence was 30%, 16% having moderate-severe disease, rates that markedly exceed general population estimates. Obstructive sleep apnea predictors in multivariate modeling included age, dental problems, and standardized AED dose. Male gender, older age, higher BMI, hypertension, and dental problems were associated with higher AHI. Adults with epilepsy appear at increased risk for OSA, increasing with age and AED load, regardless of gender, BMI, and seizure frequency. These findings support the implementation of routine OSA screening in adult epilepsy clinics. PMID- 23103312 TI - Interaction profile of Zizyphus jujuba with phenytoin, phenobarbitone, and carbamazepine in maximal electroshock-induced seizures in rats. AB - The antiepileptic effect of hydroalcoholic extract of Zizyphus jujuba (HEZJ) in experimental seizures was demonstrated earlier. The present study aimed to evaluate the pharmacokinetic and pharmacodynamic interactions of HEZJ with phenytoin (PHT), phenobarbitone (PB), and carbamazepine (CBZ) in maximal electroshock (MES)-induced seizures in male Wistar rats. Maximal electroshock (70 mA, 9 ms pulse width, 0.2 s) was used to induce seizures. Blood samples were collected at two time points for estimation of serum PHT, PB, and CBZ levels using high-pressure liquid chromatography (HPLC). Co-administration of HEZJ with the sub-therapeutic doses of PHT, PB, and CBZ exhibited 66.7, 66.7, and 50.0% protection against tonic hind limb extension as compared to 33.3, 33.3, and 50% protection respectively, in the groups treated with PHT, PB, and CBZ alone in their sub-therapeutic doses. Co-administration of HEZJ with the sub-therapeutic doses of these antiepileptic drugs (AEDs) showed significant improvement in cognitive functions as compared to MES group as well as these AEDs alone. A significant increase in glutathione levels and decrease in malondialdehyde levels were observed with pretreatment of HEZJ with the sub-therapeutic doses of these AEDs. Co-administration of HEZJ with PHT, PB, and CBZ did not cause any significant changes in the serum concentrations of these AEDs. The results of the present study indicate that the co-administration of HEZJ with sub-therapeutic doses of PHT and PB potentiated the antiepileptic effect of PHT and PB in MES induced seizures with no change found in the antiepileptic effect of CBZ. PMID- 23103313 TI - Sexual desire and satisfaction after resective surgery in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. AB - Utilizing a questionnaire, we inquired about the self-perceived sexual behavior of 50 married males with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) before and after anterior temporal lobectomy (ATL) and compared the results with those of 50 age-matched healthy married males. The sexual desire and satisfaction of the patients were poor when compared to the controls. Although a majority of the sexual domains improved following ATL, even after a median duration of five years, the sexual status of the patients did not match with that of the controls. Those who, after ATL, were seizure free, had one or no antiepileptic drug (AED) and had an EEG without epileptiform abnormalities achieved a better sexual outcome. We conclude that sexual dysfunction is frequent in male patients with MTLE-HS. They require preoperative assessment to identify their sexual inadequacies as well as counseling about the expected post-ATL sexual outcome. Discontinuation of enzyme-inducing AEDs facilitates post-ATL improvement in sexual function. PMID- 23103314 TI - Neurocognitive and neurobehavioral disabilities in Epilepsy with Electrical Status Epilepticus in slow sleep (ESES) and related syndromes. AB - AIM: The aims of this study were to assess the cognitive and behavioral problems of patients with Epilepsy with Electrical Status Epilepticus in slow sleep (ESES) and related syndromes and to review their EEG (electroencephalography) findings and treatment options. RESULTS: Fourteen patients with ESES were evaluated and treated in 2010. Nine children had continuous spike and wave during slow-wave sleep (CSWS)/ESES syndrome, 3 had Atypical BECTS (benign epilepsy with centrotemporal spikes), 1 had Opercular syndrome, and 1 had Landau-Kleffner syndrome. The duration of ESES ranged from 6 to 52 months. Eleven (91%) children had behavioral issues, most prominent being hyperactivity. Seven of the 13 children (53%) showed evidence of borderline to moderate cognitive impairment. A total of 28 EEG findings of ESES were analyzed for SWI (spike-wave index). Antiepileptic drugs received by the patients included valproate, clobazam, levetiracetam, and others. Eleven patients had been treated with oral steroids and it was found to be efficacious in seven (63%). CONCLUSION: Disabilities caused by ESES affect multiple domains. Patients with an SWI>50% should be followed up frequently with neuropsychological assessments. Steroids appear to be effective, although there is a need to standardize the dose and duration of treatment. PMID- 23103315 TI - Abdominal auras in patients with mesial temporal sclerosis. AB - To better clarify abdominal auras and their clinical correlates, we enrolled 331 temporal lobe epilepsy patients who received surgical treatment. Detailed descriptions of their auras were obtained before surgery and reconfirmed during postoperative outpatient follow-ups. Pathology revealed mesial temporal sclerosis (MTS) in 256 patients (77.3%) and 75 non-MTS. Of 214 MTS patients with auras, 78 (36.4%) reported abdominal auras (vs. 30.4% in non-MTS, p=0.439): 42 with left sided seizure onset, and 36 with right-sided seizure onset. Moreover, 49 of the 78 MTS patients had abdominal auras accompanied by rising sensations (vs. 2 of 14 in non-MTS group, p=0.004). The "rising air" was initially described to locate to the epigastric (47.8%) or periumbilical area (45.7%) and mostly reached the chest (40.4%) or remained in the abdominal region (27.1%). An epigastric location of "rising air" favored a left-sided seizure onset, and non-epigastric areas favored right-sided seizure onset (p=0.018). Finally, we found that abdominal auras with or without rising sensations did not predict postoperative seizure outcomes. PMID- 23103316 TI - Interrelationship of sleep and juvenile myoclonic epilepsy (JME): a sleep questionnaire-, EEG-, and polysomnography (PSG)-based prospective case-control study. AB - We studied the effects of 'epilepsy on sleep and its architecture' and 'sleep on the occurrence and distribution of interictal epileptiform discharges (ED)' using 'sleep questionnaires', 'EEG', and 'PSG' in patients with JME. Forty patients with JME [20 on valproate (Group I - 20.8+/-4.0 years; M: F=9:11) and 20 drug naive (Group II - 24.4+/-6.7 years; M: F=9:11)] and 20 controls (M: F=9:11; age: 23.5+/-4.7 years) underwent assessment with Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), overnight PSG, and scalp-EEG. Epileptiform discharges (EDs) were quantified in different sleep stages. The 'ED Index' was derived as number of EDs/min per stage. Statistical Package for the Social Sciences (SPSS) vs. 11 was used for statistical analysis. A 'p' <0.05 was considered as statistically significant. There was poor sleep quality in patients compared to controls (p=0.02), while there was no significant difference in ESS scores between the groups. The PSG parameters were comparable in both groups. Routine EEG revealed EDs in 22/40 (Group I: 7 and Group II: 15) patients. Thirty five patients had EDs in various sleep stages during PSG (Group I: 17 and Group II: 18): N1 - Group I: 9 and Group II: 14, N2 - Group I: 14 and Group II: 14, N3 Group I: 14 and Group II: 10, and REM - Group I: 9 and Group II: 11. The ED Index was higher during N2/N3 in Group I and N1/REM in Group II. The epileptiform discharges were frequently associated with arousals in N1/REM and K-complexes in N2. There was no other significant difference between Groups I and II. In conclusion, there was poor sleep quality in patients with JME compared to controls, especially those on valproate who had altered sleep architecture. Epileptiform activity was observed more often in sleep than wakefulness. Sleep stages had variable effect on epileptiform discharges with light sleep having a facilitatory effect in the drug-naive group and slow wave sleep having a facilitatory effect in the valproate group. PMID- 23103317 TI - Spasticity as an ictal pattern due to excitotoxic upper motor neuron damage. AB - We describe the case of a man who presented with spasticity and aphasia related to continuous electroencephalographic epileptic activity in the left frontal temporal regions. Magnetic resonance imaging (MRI) documented in diffusion weighted images (DWI) two areas of restricted diffusion in the left frontal and temporal cortex. After starting treatment with levetiracetam 3000 mg/day there was progressive recovery of the clinical picture as well as the gradual disappearance of the electroencephalographic seizure activity and the vanishing of areas of restricted diffusion in brain MRI. Based on the clinical, EEG and MRI data, we hypothesized that both aphasia and spasticity represented ictal signs. To our knowledge, this is the first case report of ictal spasticity. PMID- 23103318 TI - The sitting position and the patent foramen ovale. Commentary: "A streamlined protocol for the use of the semi-sitting position in neurosurgery". PMID- 23103319 TI - Gestational weight gain within recommended ranges in consecutive pregnancies: a retrospective cohort study. AB - OBJECTIVE: to examine whether, among parous women, adherence to gestational weight gain (GWG) recommendations in the most recent previous pregnancy is associated with adherence to GWG recommendations in the current pregnancy. DESIGN: retrospective cohort study. SETTING: review of labour and delivery records from a Massachusetts tertiary-care centre. PARTICIPANTS: 1,325 women who delivered two consecutive singletons from April 2006 to March 2010. MEASUREMENTS: pre-pregnancy weight status and adherence to GWG recommendations were categorised using 1990 Institute of Medicine (IOM) guidelines. Analyses were stratified by weight status before the second pregnancy. FINDINGS: 56% and 46% of women gained more than 1990 IOM recommendations during the first and second of consecutive pregnancies; 57% gained within the same adherence category in both pregnancies. Excessive GWG during the first pregnancy was strongly associated with excessive gain during the second pregnancy (adjusted odds ratio [AOR]=5.4 [95% CI: 1.7 16.4] for underweight, 3.7 [95% CI: 2.4-5.5] for normal weight, 3.0 [95% CI: 1.2 7.6] for overweight, and 5.3 [95% CI: 2.4-11.7] for obese women). Inadequate gain in the first of consecutive pregnancies was strongly associated with subsequent inadequate GWG for underweight women (AOR=13.7; 95% CI: 3.9-48.0), normal weight women (AOR=2.9; 95% CI: 1.7-5.1), and obese women (AOR=3.6; 95% CI: 1.4-9.3). Results were similar in sensitivity analyses using IOM 2009 guidelines. KEY CONCLUSIONS: adherence to GWG recommendations in consecutive pregnancies is highly concordant. IMPLICATIONS FOR PRACTICE: consideration of GWG during previous pregnancies may facilitate discussions about GWG during prenatal care. PMID- 23103320 TI - Patterns of gestational weight gain in healthy, low-risk pregnant women without co-morbidities. AB - BACKGROUND: little is known of the impact of gestational weight gain (GWG) in relation to Body Mass Index (BMI) classification on perinatal outcomes in healthy pregnant women without co-morbidities. As a first step, the prevalence of obesity and the distribution of GWG in relation to the Institute of Medicine (IOM) 2009 guidelines for GWG were examined. METHODS: data from a prospective cohort study of - a priori - low risk, pregnant women from five midwife-led practices (n=1449) were analysed. Weight was measured at 12, 24 and 36 weeks. FINDINGS: at 12 weeks, 1.4% of the women were underweight, 53.8% had a normal weight, 29.6% were overweight, and 15.1% were obese according to the WHO classification of BMI. In our study population, 60% of the women did not meet the IOM recommendations: 33.4% had insufficient GWG and 26.7% gained too much weight. Although BMI was negatively correlated to total GWG (p<.001), overweight and obese women class I had a significant higher risk of exceeding the IOM guidelines. Normal weight women had a significantly higher risk of gaining less weight than recommended. Obese women classes II and III were at risk in both over- and undergaining. CONCLUSIONS: our data showed that the majority of women were unable to stay within recommended GWG ranges without additional interventions. The effects on pregnancy and health outcomes of falling out the IOM guidelines remain unclear for - a priori - low risk women. Since interventions to control GWG would have considerable impact on women and caregivers, harms and benefits should be well considered before implementation. PMID- 23103321 TI - Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): sensitivity to TCP parameters. AB - The aim of this investigation was to explore the potential of biological optimization in the case of simultaneous integrated boost on intra-prostatic dominant lesions (DIL) and evaluating the impact of TCP parameters uncertainty. Different combination of TCP parameters (TD50 and gamma50 in the Poisson-like model), were considered for DILs and the prostate outside DILs (CTV) for 7 intermediate/high-risk prostate patients. The aim was to maximize TCP while constraining NTCPs below 5% for all organs at risk. TCP values were highly depending on the parameters used and ranged between 38.4% and 99.9%; the optimized median physical doses were in the range 94-116 Gy and 69-77 Gy for DIL and CTV respectively. TCP values were correlated with the overlap PTV-rectum and the minimum distance between rectum and DIL. In conclusion, biological optimization for selective dose escalation is feasible and suggests prescribed dose around 90-120 Gy to the DILs. The obtained result is critically depending on the assumptions concerning the higher radioresistence in the DILs. In case of very resistant clonogens into the DIL, it may be difficult to maximize TCP to acceptable levels without violating NTCP constraints. PMID- 23103322 TI - Congruence of disposition after emergency department intubation in the National Hospital Ambulatory Medical Care Survey. AB - STUDY OBJECTIVE: The National Hospital Ambulatory Medical Care Survey (NHAMCS) includes a large nationally representative sample of emergency department (ED) visits that is widely used for research. This study investigates the frequency of apparent NHAMCS disposition discrepancies for visits with intubation. METHODS: Using 10 years' worth of NHAMCS data composed of 348,367 ED visits, those recorded as including intubation were evaluated for congruence of disposition, which was expected to be either death or admission to a critical care unit. RESULTS: Of the 875 ED patients recorded as having intubation performed, 27% had incompatible dispositions: 81 (9%) were recorded as discharged and 153 (17%) as admitted to a non-critical care unit. Cross-reference with free text chief complaint descriptions and International Classification of Diseases, Ninth Revision diagnoses codes indicated errors in recording both intubation and admission. CONCLUSION: One fourth of NHAMCS ED visits with intubation have an ED disposition incompatible with this procedure. PMID- 23103323 TI - Unraveling the genetics of common epilepsies: approaches, platforms, and caveats. AB - With no known intervention to prevent or cure epilepsy, treatment is primarily symptomatic and requires long-term administration of medications to suppress seizure occurrence. Current antiepileptic drugs (AEDs) are ineffective in one third of patients (Kwan and Brodie, 2000). Such therapeutic inadequacy is largely due to our insufficient understanding of the basic molecular pathophysiological processes that underlie epileptogenesis. Breakthroughs are needed in the identification of new molecular targets that will translate to novel intervention approaches. Discovering genetic variants that increase the susceptibility to disease is a promising avenue to identifying such targets. However, early candidate gene-based studies in epilepsy proved ineffective in identifying genetic risk factors for the non-Mendelian, complex epilepsies, which represent >95% of clinically encountered epilepsy. Furthermore, genome-wide association studies (GWAS) of epilepsy patients have been largely negative, with the exception of several putative susceptibility loci discovered in Han Chinese focal epilepsy and European Caucasian GGE patients (Kasperaviciute et al., 2010; Guo et al., 2012; Consortium et al., 2012). Results of these GWAS suggest that, similar to other common diseases, associations with common single nucleotide variants (SNV) appear likely to account for a small fraction of the heritability of epilepsy, thus fuelling the effort to also search for alternative genetic contributors, with a recent increased emphasis on rare variants with larger effects (Manolio et al., 2009). It is possible that both common and rare variants contribute to an increased susceptibility to common epilepsy syndromes (Mulley et al., 2005). We review the approaches that have been taken to identify genetic risk markers of the common epilepsy syndromes, the experimental platforms, and their caveats. We discuss current technologies and analytical frameworks that might expedite the discovery of these variants by leveraging advances in microarray-based, high-throughput, genotyping technology, and complementary interdisciplinary expertise of study teams including the need for meta-analyses under global collaborative frameworks. We briefly discuss the analytical options made available through rapid advances in sequencing and other genomic technologies. PMID- 23103324 TI - No benefit of covered vs uncovered self-expandable metal stents in patients with malignant distal biliary obstruction: a meta-analysis. AB - BACKGROUND & AIMS: Self-expandable metal stents (SEMS) are used in patients with malignant distal biliary obstruction; trials that compared covered and uncovered SEMS reported different results because of heterogeneous designs and patient populations. These studies compared patency of uncovered SEMS and covered SEMS, along with rates of pancreatitis, cholecystitis, cholangitis, SEMS migration, bleeding, perforation, and recurrent biliary obstruction. METHODS: We performed a meta-analysis to compare the effects of covered and uncovered SEMS in patients with malignant distal biliary obstruction. We identified randomized controlled trials by using a literature search from 1980 through March 2012. We evaluated data from 5 full articles and 4 abstracts, comprising 1061 patients, and assessed statistical heterogeneity and publication bias. RESULTS: The weighted mean difference in the stent patency duration could only be calculated on the basis of 2 studies, but it was 67.9 days longer for covered SEMS than for uncovered SEMS (95% confidence interval [CI], 60.3-75.5). A summary analysis of data from 4 trials demonstrated no differences in patency of covered vs uncovered SEMS after 6 months (odds ratio [OR], 1.82; 95% CI, 0.62-5.25) or 12 months (OR, 1.25; 95% CI, 0.65-2.39). There were also no differences in the rates of pancreatitis, cholecystitis, perforation, bleeding, or cholangitis; length of hospital stay; or number of recurrent biliary obstructions. However, covered SEMS had a higher migration rate (OR, 7.13; 95% CI, 2.29-22.21). Patients with covered SEMS had a lower rate of tumor ingrowth (OR, 0.19; 95% CI, 0.07-0.55) but a higher rate of tumor overgrowth (OR, 1.88; 95% CI, 1.02-3.45). No summary calculations could be completed to confidently assess patient survival. CONCLUSIONS: The use of covered SEMS, compared with uncovered SEMS, in patients with distal malignant biliary obstruction is of unclear benefit; covered SEMS have a higher rate of migration and do not appear to have longer patency. PMID- 23103325 TI - Interobserver variability of ultrasound elastography in transplant kidneys: correlations with clinical-Doppler parameters. AB - Real-time sonoelastography (RSE) is a relatively new imaging technique that visualizes relative difference in tissue hardness by evaluating changes in local strain in response to external stress. Our aim was to evaluate the ability of investigators to use sonoelastography to detect differences in renal cortical stiffness and assess the relationship between stiffness and clinical-Doppler parameters. In 42 adult renal transplant recipients, sonoelastography of kidney was performed to calculate the strain ratio (SR) of the central echo complex to the renal parenchyma. Resistive index (RI) and pulsatility index (PI) were also measured. Estimated glomerular filtration rate (eGFR) was calculated. Parenchymal stiffness showed significant positive correlation with RI and PI (r: 0.41 p = 0.007 and r: 0.48 p = 0.001, respectively). Parenchymal stiffness and eGFR did not have a significant correlation (p = 0.42). Interobserver agreement, expressed as intraclass correlation coeffiicient was 0.47 (95% CI: 0.05-0.70). Parenchymal stiffness (SR) showed significant positive correlation with RI and PI but sonoelastography has also wide range intra- and low interobserver agreement in renal transplants. Further studies are warranted in larger patient groups to determine the reliability of sonoelastography in renal transplants. PMID- 23103327 TI - Elemental analysis of Anethum gravedlens, Sismbrium Irio Linn and Veronia Anthelmintica seeds by instrumental neutron activation analysis. AB - Instrumental neutron activation analysis has been used to characterize As, Ba, Br, Ce, Cl, Co, Cr, Cs, Eu, Fe, Hg, K, Mn, Na, Rb, Sb, Se and Zn, and Sc in seeds of Anethum graveolens (Dill), Sisymbrium irio Linn. (Wild Mustard) and Vernonia anthelmintica (Iron Weed). Dill seed was found to contain high K while Wild Mustard has high Fe, Mn and Na levels. Iron Weed has highest Cl, Co, Cr and Zn content with least concentration of Fe. PMID- 23103328 TI - Biologically active equine estrogens and sulfate conjugates labelled with tritium at high specific activity. AB - Methods are presented to tritiate and characterize the steroid equilin as well as a structurally related 17-alpha alcohol metabolite and several 3-position sulfate conjugates. PMID- 23103329 TI - Risk factors for falls in a longitudinal population-based cohort study of Japanese men and women: the ROAD Study. AB - The objective of this study was to clarify the associations of physical performance and bone and joint diseases with single and multiple falls in Japanese men and women using a population-based longitudinal cohort study known as Research on Osteoarthritis/osteoporosis Against Disability (ROAD). A total of 452 men and 896 women were analyzed in the present study (mean age, 63.9 years). A questionnaire was used to assess the number of falls during the 3-year follow up. Grip strength, 6-m walking time, and chair stand time were measured at baseline. Knee osteoarthritis (OA) and lumbar spondylosis were defined as Kellgren Lawrence=2, 3 or 4. Vertebral fracture (VFx) was assessed with the Japanese Society of Bone and Mineral Research criteria. Osteoporosis was defined by bone mineral density using dual energy X-ray absorptiometry based on World Health Organization criteria. Knee and lower back pain were estimated by an interview. During a 3-year follow-up, 79 (17.4%) men and 216 (24.1%) women reported at least one fall, and 54 (11.9%) men and 111 (12.4%) women reported multiple falls. Knee pain was a risk factor for multiple falls in women, but not in men. VFx tended to be associated with multiple falls in women, but not in men. A longer 6-m walking time was a risk factor for multiple falls in women, whereas a longer chair stand time was a risk factor for multiple falls in men. We found gender differences in risk factors for falls. PMID- 23103326 TI - Memory in aged mice is rescued by enhanced expression of the GluN2B subunit of the NMDA receptor. AB - The GluN2B subunit of the N-methyl-d-aspartate (NMDA) receptor shows age-related declines in expression across the frontal cortex and hippocampus. This decline is strongly correlated to age-related memory declines. This study was designed to determine if increasing GluN2B subunit expression in the frontal lobe or hippocampus would improve memory in aged mice. Mice were injected bilaterally with either the GluN2B vector, containing cDNA specific for the GluN2B subunit and enhanced green fluorescent protein (eGFP); a control vector or vehicle. Spatial memory, cognitive flexibility, and associative memory were assessed using the Morris water maze. Aged mice, with increased GluN2B subunit expression, exhibited improved long-term spatial memory, comparable to young mice. However, memory was rescued on different days in the Morris water maze; early for hippocampal GluN2B subunit enrichment and later for the frontal lobe. A higher concentration of the GluN2B antagonist, Ro 25-6981, was required to impair long term spatial memory in aged mice with enhanced GluN2B expression, as compared to aged controls, suggesting there was an increase in the number of GluN2B containing NMDA receptors. In addition, hippocampal slices from aged mice with increased GluN2B subunit expression exhibited enhanced NMDA receptor-mediated excitatory post-synaptic potentials (EPSP). Treatment with Ro 25-6981 showed that a greater proportion of the NMDA receptor-mediated EPSP was due to the GluN2B subunit in these animals, as compared to aged controls. These results suggest that increasing the production of the GluN2B subunit in aged animals enhances memory and synaptic transmission. Therapies that enhance GluN2B subunit expression within the aged brain may be useful for ameliorating age-related memory declines. PMID- 23103330 TI - The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: findings from a pQCT case-control study. AB - High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans. pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls. HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm(3)), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p<0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p<0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p<0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p<0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p<0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted beta -0.01 [-0.02, 0.01], p=0.41), but declined in family controls ( 0.05 [-0.03, -0.07], p<0.001) interaction p=0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD. HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype. PMID- 23103331 TI - Duration of membrane rupture and risk of perinatal transmission of HIV-1 in the era of combination antiretroviral therapy. AB - OBJECTIVE: The objective of the study was to determine whether the duration of membrane rupture of 4 or more hours is a significant risk factor for perinatal transmission of human immunodeficiency virus (HIV) in the era of combination antiretroviral therapy (ART). STUDY DESIGN: This was a prospective cohort study of 717 HIV-infected pregnant women-infant pairs with a delivery viral load available who received prenatal care and delivered at our institution during the interval 1996-2008. RESULTS: The cohort comprised 707 women receiving ART who delivered during this interval. The perinatal transmission rate was 1% in women with membranes ruptured for less than 4 hours and 1.9% when ruptured for 4 or more hours. For 493 women with a delivery viral load less than 1000 copies/mL receiving combination ART in pregnancy, there were no cases of perinatal transmission identified up to 25 hours of membrane rupture. Logistic regression demonstrated only a viral load above 10,000 copies/mL as an independent risk factor for perinatal transmission. CONCLUSION: Duration of membrane rupture of 4 or more hours is not a risk factor for perinatal transmission of HIV in women with a viral load less than 1000 copies/mL receiving combination ART. PMID- 23103332 TI - Immune aspects of the pathogenesis of inflammatory bowel disease. AB - Although the precise etiologies of inflammatory bowel disease (IBD) (ulcerative colitis and Crohn's disease) remain obscure, several reports have indicated that dysfunction of the mucosal immune system plays an important role in its pathogenesis. Recent progress with genome-wide association studies has identified many IBD susceptibility genes. In individuals with genetic risk, abnormal interactions between the host immune system and gut flora, and dysregulation of cellular responses such as autophagy and ER stress, induce an abnormal host immune response in the gut resulting in intestinal inflammation. Research progress animal models in IBD, and in human IBD, has identified several key molecules in IBD pathogenesis such as TNFalpha and adhesion molecules, and molecular targeting therapies based on these molecules have been developed. Here, we review immunological aspects in IBD pathogenesis and the development of immunoregulatory therapy. PMID- 23103333 TI - Dengue virus therapeutic intervention strategies based on viral, vector and host factors involved in disease pathogenesis. AB - Dengue virus (DV) is the most widespread arbovirus, being endemic in over 100 countries, and is estimated to cause 50 million infections annually. Viral factors, such as the genetic composition of the virus strain can play a role in determining the virus virulence and subsequent clinical disease severity. Virus vector competence plays an integral role in virus transmission and is a critical factor in determining the severity and impact of DV outbreaks. Host genetic variations in immune-related genes, including the human leukocyte antigen, have also been shown to correlate with clinical disease and thus may play a role in regulating disease severity. The host's immune system, however, appears to be the primary factor in DV pathogenesis with the delicate interplay of innate and acquired immunity playing a crucial role. Although current research of DV pathogenesis has been limited by the lack of an appropriate animal model, the development of DV therapeutics has been a primary focus of research groups around the world. In the past decade advances in both the development of vaccines and anti-virals have increased in dramatically. This review summarises the current understanding of viral, vector and host factors which contribute to dengue virus pathogenesis and how this knowledge is critically important in the development of pharmaceutical interventions. PMID- 23103334 TI - Neglected but amazingly diverse type IVb pili. AB - This review provides an overview of current knowledge concerning type IVb pili in Gram-negative bacteria. The number of these pili identified is steadily increasing with genome sequencing and mining studies, but studies of these pili are somewhat uneven, because their expression is tightly regulated and the signals or regulators controlling expression need to be identified. However, as illustrated here, they have a number of interesting functional, assembly-related and regulatory features. PMID- 23103335 TI - Physics of bacterial near-surface motility using flagella and type IV pili: implications for biofilm formation. AB - We review physically-motivated studies of bacterial near-surface motility driven by flagella and type IV pili (TfP) in the context of biofilm formation. We describe the motility mechanisms that individual bacteria deploying flagella and TfP use to move on and near surfaces, and discuss how the interactions of motility appendages with fluid and surfaces promote motility, attachment and dispersal of bacteria on surfaces prior to biofilm formation. PMID- 23103336 TI - Identification of five novel tectiviruses in Bacillus strains: analysis of a highly variable region generating genetic diversity. AB - Our biosphere is abundant with unique and small genes for which no homologs are known. These genes, often referred to as orphans or ORFans, are commonly found in bacteriophage genomes but their origins remain unclear. We discovered five novel tectivirus-like genetic elements by screening more than five-hundred Bacillus strains. A highly variable region (HVR) of these viruses was shown to harbor ORFans in most of these otherwise well-conserved bacteriophages. Previous studies demonstrated that mutations close to this region dramatically alter bacteriophage gene regulation, suggesting that the acquisition of those ORFans may provide a source of genetic diversity that is then subject to genetic selection during bacteriophage evolution. PMID- 23103337 TI - Surgical techniques for unclippable fusiform A2-anterior cerebral artery aneurysms and description of a frontopolar-to-A2 bypass. AB - BACKGROUND: Fusiform aneurysms involving the A2 or distal A1-A2 segment of the anterior cerebral artery are uncommon and difficult to manage surgically with simple coiling or clipping. METHODS: We illustrate four technical strategies to achieve complete obliteration of such complex aneurysms based on individual clinical conditions and imaging characteristics. Such treatments included combined open and endovascular techniques. RESULTS: The techniques described include simultaneous clipping and wrap reinforcement of the aneurysm (clip wrapping), flow reversal with A3-to-A3 bypass, trapping with A3-to-A3 bypass, and the use of an ipsilateral frontopolar-to-contralateral A2 bypass after resection of the aneurysm. CONCLUSIONS: These techniques may involve endovascular and surgical options in an attempt to obtain the best overall outcome. Bypasses in the interhemispheric fissure, while difficult, are important, even necessary, adjuncts to treatment of these complex lesions. PMID- 23103338 TI - Reactive oxygen species mediated DNA damage in human lung alveolar epithelial (A549) cells from exposure to non-cytotoxic MFI-type zeolite nanoparticles. AB - Increasing utilization of engineered nanoparticles in the field of electronics and biomedical applications demands an assessment of risk associated with deliberate or accidental exposure. Metal based nanoparticles are potentially most important of all the nanoparticles in terms of health risks. Microporous alumino silicates and pure silicates named as zeolites and zeo-type materials with variety of structures, chemical compositions, particle sizes and morphologies have a significant number of industrial uses such as in catalysis, sorption and ion-exchange processes. In particular, the nanosized particles due to their unique properties are used in hybrid organic-inorganic materials for photography, photonics, electronics, labeling, imaging, and sensing. The aim of the current study is to investigate pure silica MFI-type zeolites nanoparticles with sizes of 50nm and 100nm (samples MFI-50 and MFI-100) under suspended conditions and their toxicological effects on human lung alveolar (A549) cells under in vitro conditions. Live cell imaging showed that the nanoparticles precipitated from the colloidal suspension of cell culture media as large agglomerates, coming in contact with the cell surface through sedimentation. A cellular proliferative capacity test showed the zeolite nanoparticles to exhibit no significant cytotoxicity below a concentration of 100MUg/ml. However, both the MFI-50 and MFI 100 nanoparticles induced high intracellular reactive oxygen species (ROS) generation and elevated mitochondrial membrane potential in the A549 cells over the measured time period of 12h and at concentrations up to <=50MUg/ml. DNA fragmentation analysis using the comet assay showed that the MFI-50 and MFI-100 nanoparticles cause genotoxicity in a concentration dependent manner. Furthermore, the rate at which maximum genomic damage was caused by MFI-100 nanoparticles in the A549 cells was found to be high as compared to the MFI-50 nanoparticles. However, the damage caused by the MFI-50 nanoparticles was found to accumulate over a longer period of time as compared to MFI-100 nanoparticles. The study therefore points towards the capability of the non-cytotoxic zeolite nanoparticles to induce oxidative stress resulting in short-term altered cellular metabolism up-regulation and genomic instability. Although the damage was found to be short-lived, its persistence over longer durations, or stabilization cannot be neglected. Further studies are in progress to yield a better understanding of the mechanisms for oxidative stress and resulting cascade of events leading to genetic damage in the human lung alveolar epithelial cells following exposure to zeolite nanoparticles of different sizes. PMID- 23103339 TI - Quantitative single-nucleotide polymorphism analysis in secondary-structured DNA by affinity capillary electrophoresis using a polyethylene glycol-peptide nucleic acid block copolymer. AB - To estimate allele frequency of single-nucleotide polymorphisms (SNPs) in pooled DNAs with secondary structures, an affinity capillary electrophoresis was developed using an allele-specific peptide nucleic acid probe modified with polyethylene glycol. This probe disrupted secondary structures of DNA analytes and hybridized to them during electrophoresis. Such DNA-binding capability allowed separation of the folded analytes with a single-base difference within 20 min. The feed ratio of the target allele was evaluated by calculating the peak area ratio. The averaged difference between the feed and observed ratio was 1.5%. This method should be of general applicability to quantitative SNP analyses. PMID- 23103340 TI - A highly efficient, high-throughput lipidomics platform for the quantitative detection of eicosanoids in human whole blood. AB - We have developed an ultra-performance liquid chromatography-multiple reaction monitoring/mass spectrometry (UPLC-MRM/MS)-based, high-content, high-throughput platform that enables simultaneous profiling of multiple lipids produced ex vivo in human whole blood (HWB) on treatment with calcium ionophore and its modulation with pharmacological agents. HWB samples were processed in a 96-well plate format compatible with high-throughput sample processing instrumentation. We employed a scheduled MRM (sMRM) method, with a triple-quadrupole mass spectrometer coupled to a UPLC system, to measure absolute amounts of 122 distinct eicosanoids using deuterated internal standards. In a 6.5-min run, we resolved and detected with high sensitivity (lower limit of quantification in the range of 0.4-460 pg) all targeted analytes from a very small HWB sample (2.5 MUl). Approximately 90% of the analytes exhibited a dynamic range exceeding 1000. We also developed a tailored software package that dramatically sped up the overall data quantification and analysis process with superior consistency and accuracy. Matrix effects from HWB and precision of the calibration curve were evaluated using this newly developed automation tool. This platform was successfully applied to the global quantification of changes on all 122 eicosanoids in HWB samples from healthy donors in response to calcium ionophore stimulation. PMID- 23103341 TI - DNA from oral bacteria by sodium hydroxide-paper method suitable for polymerase chain reaction. AB - In the oral cavity, we can find a complex mixture of microorganisms, commensals, and pathogens. The studies of normal oral microbiota, as well as the studies of much oral pathology (e.g., caries, periodontitis), involve the isolation and cultivation of these microorganisms and their molecular analysis. The aim of this study was to validate a quick, easy, efficient, and inexpensive DNA extraction method for the recovery of genomic DNA from gram-positive and gram-negative oral bacteria to be used in polymerase chain reaction amplification. This method worked great with all samples analyzed, providing an approach to extract DNA for different microorganisms. PMID- 23103342 TI - Multiplexed infectious protein microarray immunoassay suitable for the study of the specificity of monoclonal immunoglobulins. AB - Enzyme-linked immunosorbent assays (ELISAs) used to detect antibodies specific for common infectious agents such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), Toxoplasma gondii (T. gondii), and hepatitis C virus (HCV) are time consuming and require large volumes of samples, which restrict their use. We propose a new assay based on a multiplexed infectious protein (MIP) microarray combining different epitopes representative of the four germs. Antigens and lysates were printed on nitrocellulose slides to constitute the microarray. First, the microarray was incubated with human serum samples. Then, the suitability of the microarray for analysis of the specificity of purified monoclonal immunoglobulin (mc Ig) was assessed using serum and mc Ig of HCV positive patients. Bound human immunoglobulin G (IgG) was detected using fluorescently labeled secondary antibodies, and the signals were quantified. Results obtained in serum samples with the new MIP microarray immunoassay were compared with ELISAs; we observed concordances of 95% for EBV, 93% for CMV, 91% for T. gondii, and 100% for HCV. Regarding purified mc Ig of HCV-positive patients, 3 of 3 recognized antigens printed on the microarray. Hence, the novel EBV/CMV/T. gondii/HCV MIP microarray allows simultaneous diagnosis of polyclonal and monoclonal immune response to infectious diseases using very small volume samples. PMID- 23103343 TI - Fibroid tumors are not a risk factor for adverse outcomes in twin pregnancies. AB - OBJECTIVE: Uterine fibroid tumors have been associated with adverse outcomes in singleton pregnancies. We aimed to estimate risk for adverse obstetric outcomes that are associated with fibroid tumors in twin pregnancies. STUDY DESIGN: A retrospective cohort study of twin pregnancies with >=1 fibroid tumor on second trimester ultrasound examination. Outcomes included small-for-gestational-age fetal growth, preterm delivery, preterm rupture of membranes, abruption, preeclampsia, and intrauterine fetal death. Univariable and multivariable analyses were used to evaluate the impact of fibroid tumors on outcomes in twin pregnancies compared with twin pregnancies without fibroid tumors. RESULTS: Of 2378 nonanomalous twin pregnancies, 2.3% had fibroid tumors. Twin pregnancies with fibroid tumors were no more likely to have small-for-gestational-age growth (40.0% vs. 36.0%; adjusted odds ratio, 1.1; 95% confidence interval, 0.7-2.0) or preterm delivery at <34 weeks' gestation (25.0% vs. 24.0%; adjusted odds ratio, 1.0; 95% confidence interval, 0.5-1.9) than twin pregnancies without fibroid tumors. Other adverse outcomes were no more likely to occur in twin pregnancies with fibroid tumors than in twin pregnancies without fibroid tumors. Post hoc power calculations suggested >97% power to detect 2-fold differences in small for gestational age and preterm delivery at <34 weeks' gestation. CONCLUSION: In contrast to data that suggest an increased risk for adverse outcomes in singleton pregnancies with fibroid tumors, twin pregnancies with fibroid tumors do not appear to be at increased risk for complications compared with those pregnancies without fibroid tumors. PMID- 23103344 TI - Validity of perceived weight gain in women using long-acting reversible contraception and depot medroxyprogesterone acetate. AB - OBJECTIVE: The objective of the study was to evaluate perceived weight gain in women using contraception and determine the validity of self-reported weight gain. STUDY DESIGN: We analyzed data from new contraceptive method users who self reported a weight change at 3, 6, and 12 months after enrollment. We examined a subgroup of participants with objective weight measurements at baseline and 12 months to test the validity of self-reported weight gain. RESULTS: Thirty-four percent of participants (1407 of 4133) perceived weight gain. Compared with copper intrauterine device users, implant users (relative risk, 1.29; 95% confidence interval, 1.10-1.51) and depot medroxyprogesterone acetate users (relative risk, 1.37; 95% confidence interval, 1.14-1.64) were more likely to report perceived weight gain. Women who perceived weight gain experienced a mean weight gain of 10.3 pounds. The sensitivity and specificity of perceived weight gain were 74.6% and 84.4%, respectively. CONCLUSION: In most women, perceived weight gain represents true weight gain. Implant and depot medroxyprogesterone acetate users are more likely to perceive weight gain among contraception users. PMID- 23103345 TI - Impact of childbirth and mode of delivery on vaginal resting pressure and on pelvic floor muscle strength and endurance. AB - OBJECTIVE: We sought to study impact of delivery mode on vaginal resting pressure (VRP) and on pelvic floor muscle (PFM) strength and endurance, and whether these measurements differed in women with and without urinary incontinence. STUDY DESIGN: We conducted a cohort study following 277 nulliparous women from midpregnancy to 6 weeks postpartum. Manometer was used for PFM measurements; differences were analyzed by t test (within groups) and analysis of variance (between groups). RESULTS: Only VRP changed significantly (10% reduction, P = .001) after emergency cesarean section. After normal and instrumental vaginal delivery, VRP was reduced by 29% and 30%; PFM strength by 54% and 66%; and endurance by 53% and 65%, respectively. Significant differences for all PFM measures (P < .001) were found when comparing cesarean vs normal and instrumental vaginal delivery, respectively. Urinary continent women at both time points had significantly higher PFM strength and endurance than incontinent counterparts (P < .05). CONCLUSION: Pronounced reductions in VRP and in PFM strength and endurance were found after vaginal delivery. Continent women were stronger than incontinent counterparts. PMID- 23103346 TI - Clinical outcomes after arthroscopic treatment of knee osteoarthritis. AB - PURPOSE: The aim of this study was to describe the clinical outcomes of patients with knee osteoarthritis (OA) treated with arthroscopic surgery, documenting the associated injuries and defining the type of treatment selected for OA patients with different symptoms. HYPOTHESIS: Knee arthroscopy is effective for treating patients with symptomatic OA and mechanical symptoms. METHODS: This was a prospective, consecutive series of 100 patients with a clinical and radiological diagnosis of OA who were treated with knee arthroscopy. The average follow-up time was 35.9months (25-71), and the average age was 60.1years (50-83). INCLUSION CRITERIA: >50years of age, a clinical imaging diagnosis of knee OA with an Ahlback I-III classification. EXCLUSION CRITERIA: <50years of age, Ahlback IV, pathologic lower limb mechanical axis and inflammatory joint diseases. The IKDC and Lysholm scores were assessed before and after surgery. RESULTS: The preoperative average scores were as follows: Lysholm, 56.9+/-13.5 points (22-71); IKDC, 59.4+/-21.7 points (45-80). The postoperative average scores were as follows: Lysholm, 86.9 points (22-87); IKDC, 79.5 points (45-100). Regarding the Lysholm scores, 76% were good and excellent results and 24% were moderate (p=0.045). The associated injuries included 48% of chondral and 36% of unstable meniscal injuries. Good or excellent results were observed in 76% of the meniscal injury cases according to the Lysholm scores, while only 84.6% of the cases with unstable chondral lesions had good or excellent results (p=0.035). CONCLUSION: Most patients with knee OA associated with unstable cartilage or meniscal injuries reported good-to-excellent symptomatic results at the short- and mid term follow-ups. LEVEL OF EVIDENCE: III. PMID- 23103349 TI - Affordability as a discursive accomplishment in a changing National Health Service. AB - Health systems worldwide face the challenges of rationing. The English National Health Service (NHS) was founded on three core principles: universality, comprehensiveness, and free at the point of delivery. Yet patients are increasingly hearing that some treatments are unaffordable on the NHS. We considered affordability as a social accomplishment and sought to explore how those charged with allocating NHS resources achieved this in practice. We undertook a linguistic ethnography to examine the work practices of resource allocation committees in three Primary Care Trusts (PCTs) in England between 2005 and 2012, specifically deliberations over 'individual funding requests' (IFRs)- requests by patients and their doctors for the PCT to support a treatment not routinely funded. We collected and analysed a diverse dataset comprising policy documents, legal judgements, audio recordings, ethnographic field notes and emails from PCT committee meetings, interviews and a focus group with committee members. We found that the fundamental values of universality and comprehensiveness strongly influenced the culture of these NHS organisations, and that in this context, accomplishing affordability was not easy. Four discursive practices served to confer legitimacy on affordability as a guiding value of NHS health care: (1) categorising certain treatments as only eligible for NHS funding if patients could prove 'exceptional' circumstances; (2) representing resource allocation decisions as being not (primarily) about money; (3) indexical labelling of affordability as an ethical principle, and (4) recontextualising legal judgements supporting refusal of NHS treatment on affordability grounds as 'rational'. The overall effect of these discursive practices was that denying treatment to patients became reasonable and rational for an organisation even while it continued to espouse traditional NHS values. We conclude that deliberations about the funding of treatments at the margins of NHS care have powerful consequences both for patients and for redrawing the ideological landscape of NHS care. PMID- 23103350 TI - Essential drugs policy in three rural counties in China: what does a complexity lens add? AB - In 2009 the government of China identified an essential drugs policy as one of five priority areas for health system reform. Since then, a national essential drugs policy has been defined, along with plans to implement it. As a large scale social intervention, the policy will have a significant impact on various local health actors. This paper uses the lens of complex adaptive systems to examine how the policy has been implemented in three rural Chinese counties. Using material gathered from interviews with key actors in county health bureaus and township health centers, we illustrate how a single policy can lead to multiple unanticipated outcomes. The complexity lens applied to the material gathered in interviews helps to identify relevant actors, their different relationships and policy responses and a new framework to better understand heterogeneous pathways and outcomes. Decision-makers and policy implementers are advised to embrace the complex and dynamic realities of policy implementation. This involves developing mechanisms to monitor different behaviors of key actors as well as the intended outcomes and unintended consequences of the policy. PMID- 23103351 TI - Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique. AB - The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism. Data on viability, correlation between apparent permeability coefficients (P(app)) and fraction absorbed (f(a)) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors. Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally. Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER). Intestinal metabolism was studied using testosterone and midazolam as probe substrates. There was a steep sigmoidal correlation between P(app) in the Ussing chamber, using jejunal segments, and oral f(a) in humans, for a set of 25 drugs (R(2): 0.85, p<0.01). A clear sigmoidal relationship was also obtained between P(app) in colonic segments and f(a) after colonic administration in humans for a set of 10 drugs (R(2): 0.93, p<0.05). Regional permeability data showed a tendency for highly permeable compounds to have higher or similar P(app) in colon as in the small intestinal segments, while the colonic regions showed a lower P(app) for more polar compounds as well as for d-glucose and l-leucine. Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux- and uptake asymmetry. Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam. In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (f(a)), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man. Furthermore, a sigmoidal relationship of P(app) vs. f(a) was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R(2): 0.83, p<0.01). The correlation curve reported can be used by any laboratory for predictions of human permeability and f(a)(.) In addition, for the first time a correlation curve between colonic P(app) and human colonic f(a) is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates. PMID- 23103347 TI - Adolescent male rats are less sensitive than adults to the anxiogenic and serotonin-releasing effects of fenfluramine. AB - Risk taking behavior increases during adolescence, which is also a critical period for the onset of drug abuse. The central serotonergic system matures during the adolescent period, and its immaturity during early adolescence may contribute to adolescent risk taking, as deficits in central serotonergic function have been associated with impulsivity, aggression, and risk taking. We investigated serotonergic modulation of behavior and presynaptic serotonergic function in adult (67-74 days old) and adolescent (28-34 days old) male rats. Fenfluramine (2 mg/kg, i.p.) produced greater anxiogenic effects in adult rats in both the light/dark and elevated plus maze tests for anxiety-like behavior, and stimulated greater increases in extracellular serotonin in the adult medial prefrontal cortex (mPFC) (1, 2.5, and 10 mg/kg, i.p.). Local infusion of 100 mM potassium chloride into the mPFC also stimulated greater serotonin efflux in adult rats. Adult rats had higher tissue serotonin content than adolescents in the prefrontal cortex, amygdala, and hippocampus, but the rate of serotonin synthesis was similar between age groups. Serotonin transporter (SERT) immunoreactivity and SERT radioligand binding were comparable between age groups in all three brain regions. These data suggest that lower tissue serotonin stores in adolescents limit fenfluramine-stimulated serotonin release and so contribute to the lesser anxiogenic effects of fenfluramine. PMID- 23103352 TI - Clinical significance of zoledronic acid and strontium-89 in patients with asymptomatic bone metastases from non-small-cell lung cancer. AB - BACKGROUND: The purpose of this study was to clarify the treatment value of zoledronic acid (ZA) and/or strontium-89 (Sr-89) in patients with non-small-cell lung cancer (NSCLC) with asymptomatic bone metastases (BMs). PATIENTS AND METHODS: Eligible patients were those with resectable NSCLC and asymptomatic BMs. These candidates were randomized into 4 groups: group A was treated with ZA and Sr-89 simultaneously, group B was treated with ZA, group C was treated with Sr 89, and group D was untreated. Patients were monitored and analyzed for the first skeletal-related event (SRE), overall survival (OS), and annual incidence of SREs. RESULTS: One hundred eighty patients were enrolled. Time to first SRE in group A was 15 months (95% confidence interval [CI], 14.0-16.0 months), in group B it was 12 months (95% CI, 11.1-13.0 months), in group C it was 9 months (95% CI, 8.5-9.5 months), and in group D it was 8 months (95% CI, 7.1-8.9 months) (P = .000). The overall survival (OS) in group A was 17 months (95% CI, 16.0-18.1 months); in group B, it was 16 months (95% CI, 14.2-17.8 months); in group C, it was 12 months (95% CI, 11.1-12.9 months); and in group D, it was 12 months (95% CI, 10.8-13.2 months). The annual incidence of SREs in group A was 24.4%; in group B, it was 55.6%; in group C, it was 75.6%; in group D, it was 91.1% (P = .000). CONCLUSIONS: Treatment with ZA and/or Sr-89 significantly extended the time to first SRE as well as survival time and reduced the annual incidence of SREs. Treatment with the combined use of ZA and Sr-89 was safe and well tolerated and achieved the best effect on asymptomatic BMs of NSCLC. PMID- 23103353 TI - Conservative management of upper tract urothelial carcinoma in France: a 2004 2011 national practice report. PMID- 23103354 TI - [Cranial fasciitis: a case report and review of the literature]. AB - Cranial fasciitis is an uncommon, rapidly-growing, benign, non-tumoural, myofibroblastic lesion of the skull, found mainly among young children in their first year of life. It is histologically similar to nodular fasciitis and pseudosarcomatous fasciitis. It may mimic more aggressive pathologies, such as sarcomatosis or histiocytosis, due to its rapid, nodular growth in subcutaneous tissue. Complete resection is considered curative and, therefore, entails a low risk of metastases or malignant recurrences. We present the clinical, radiological and pathological findings in a 4-year-old boy with cranial fasciitis in the deep, subcutaneous, soft tissue, with erosion of the outer table of the cranium, which also produced periosteal reaction, while respecting the inner table and meninges. The objective of this article is to highlight the absence of radiotherapeutic or chemotherapeutic adjuvant treatment. In addition, an exhaustive review of the literature is also presented. PMID- 23103355 TI - Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. AB - Cannabinoids-endocannaboids are possible preventatives of common diseases including cancers. Cannabinoid receptors (CB(1/2), TRPV1) are central components of the system. Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways. Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals. They signal through p38, MAPK, JUN, PI3, AKT, ceramide, caspases, MMPs, PPARs, VEGF, NF-kappaB, p8, CHOP, TRB3 and pro-apoptotic oncogenes (p53,p21 waf1/cip1) to induce cell cycle arrest, autophagy, apoptosis and tumour inhibition. Paradoxically they are pro-proliferative and anti-apoptotic in some cancers. Differences in receptor expression and concentrations of cannabinoids in cancer and immune cells can elicit anti- or pro-cancer effects through different signal cascades (p38MAPK or PI3/AKT). Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways. Evidence in vivo and in vitro shows EPA and DHA can form endocannabinoids that: (i) are ligands for CB(1/2) receptors and possibly TRPV-1, (ii) have non-receptor mediated bioactivity, (iii) induce cell cycle arrest, (iii) increase autophagy and apoptosis, and (iv) augment chemotherapeutic actions in vitro. They can also form bioactive, eicosanoid-like products that appear to be non-CBR ligands but have effects on PPARs and NF-kB transcription factors. The use of cannabinoids in cancer treatment is currently limited to chemo- and radio therapy-associated nausea and cancer-associated pain apart from one trial on brain tumours in patients. Further clinical studies are urgently required to determine the true potential of these intriguing, low toxicity compounds in cancer therapy. Particularly in view of their synergistic effects with chemotherapeutic agents similar to that observed for n-3 LCPUFA. PMID- 23103356 TI - Arabidopsis cuticular waxes: advances in synthesis, export and regulation. AB - Cuticular waxes and cutin form the cuticle, a hydrophobic layer covering the aerial surfaces of land plants and acting as a protective barrier against environmental stresses. Very-long-chain fatty acid derived compounds that compose the cuticular waxes are produced in the endoplasmic reticulum of epidermal cells before being exported to the environmental face of the epidermis. Twenty years of genetic studies on Arabidopsis thaliana have led to the molecular characterization of enzymes catalyzing major steps in fatty acid elongation and wax biosynthesis. Although transporters required for wax export from the plasma membrane have been identified, intracellular and extracellular traffic remains largely unknown. In accordance with its major function in producing an active waterproof barrier, wax metabolism is up-regulated at the transcriptional level in response to water deficiency. However its developmental regulation is still poorly described. Here, we discuss the present knowledge of wax functions, biosynthesis and transport as well as the regulation of these processes. PMID- 23103357 TI - Nervous system metastases from malignant mesothelioma. PMID- 23103359 TI - Computing life: Add logos to biology and bios to physics. AB - This paper discusses the interrelations between physics and biology. Particularly, we analyse the approaches for reconstructing the emergent properties of physical or biological systems. We propose approaches to scale emergence according to the degree of state-dependency of the system's component properties. Since the component properties of biological systems are state dependent to a high extent, biological emergence should be considered as very strong emergence - i.e. its reconstruction would require a lot of information about state-dependency of its component properties. However, due to its complexity and volume, this information cannot be handled in the naked human brain, or on the back of an envelope. To solve this problem, biological emergence can be reconstructed in silico based on experimentally determined rate laws and parameter values of the living cell. According to some rough calculations, the silicon human might comprise the mathematical descriptions of around 10(5) interactions. This is not a small number, but taking into account the exponentially increase of computational power, it should not prove to be our principal limitation. The bigger challenges will be located in different areas. For example they may be related to the observer effect - the limitation to measuring a system's component properties without affecting the system. Another obstacle may be hidden in the tradition of "shaving away" all "unnecessary" assumptions (the so-called Occam's razor) that, in fact, reflects the intention to model the system as simply as possible and thus to deem the emergence to be less strong than it possibly is. We argue here that that Occam's razor should be replaced with the law of completeness. PMID- 23103358 TI - Measurement of the phospholipase activity of endothelial lipase in mouse plasma. AB - Endothelial lipase (EL) is a major negative regulator of plasma HDL levels in mice, rabbits, and most probably, humans. Although this regulatory function is critically dependent on EL's hydrolysis of HDL phospholipids, as yet there is no phospholipase assay specific for EL in plasma. We developed such an assay for the mouse enzyme using a commercially available phospholipid-like fluorescent substrate in combination with an EL neutralizing antibody. The specificity of the assay was established using EL knockout mice and its utility demonstrated by detection of an increase in plasma EL phospholipase activity following exposure of wild-type mice to lipopolysaccharide. The assay revealed that murine pre heparin plasma does not contain measurable EL activity, indicating that the hydrolysis of HDL phospholipids by EL in vivo likely occurs on the cell surface. PMID- 23103360 TI - Intershell spacing changes in MWCNT induced by metal-CNT interactions. AB - The intershell spacing in different regions of a multi-walled carbon nanotube (MWCNT) was determined by analysis of high resolution transmission electron (HR TEM) micrographs. Three general effects can be pointed out, (1) the regular intershell spacing of a CNT is bigger than that in a graphitic carbon because the curvature generates geometrical and electronic deformations which increase repulsion forces between the graphene sheets, (2) when an extra curvature appears, e.g. at the tip of a closed CNT or in a bamboo-like structure, the intershell spacing is expanded due to the extra repulsion caused by the combination of pentagonal and heptagonal rings imbibed in the hexagonal lattice, and (3) when a metal particle interacts with a CNT, the intershell spacing is compressed due to strong metal-CNT interactions. PMID- 23103362 TI - Maturation of auditory event-related potentials across adolescence. AB - Adolescence is a time of great change in the brain in terms of structure and function. It is possible to track the development of neural function across adolescence using auditory event-related potentials (ERPs). We measured passive auditory ERPs to pure tones and consonant-vowel (CV) syllables in 90 children and adolescents aged 10-18 years, as well as 10 adults. With one exception, the pattern of results were the same for tones and speech: Across adolescence, the P1 ERP peak decreased in size and latency, the N1 increased in size and decreased in latency, the P2 remained constant in size, and the N2 decreased in size but remained stable across adolescence. The exception was P2 latency, which increased for speech but remained stable for tones. Interesting step-like changes were observed for N1 latency for both tones and speech stimuli in 15- to 16-year-olds. These may stem from rapid hormonal changes that affect neurotransmitter activity of the ERP-generating neurons. PMID- 23103361 TI - Biochemical and biophysical characterization of recombinant rat apolipoprotein E: similarities to human apolipoprotein E3. AB - Apolipoprotein E (apoE) is an anti-atherogenic protein that plays a critical role in maintaining plasma cholesterol and triglyceride homeostasis by virtue of its ability to act as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins. In this study, we characterized the biochemical and biophysical features of recombinant rat apoE, in comparison with those of human apoE3. Rat apoE was overexpressed in Escherichia coli using a codon optimized system and purified by affinity chromatography. SDS-PAGE and RP-HPLC of rat apoE confirmed the purity, while immunoblot verified the identity and cross-reactivity with the LDLr-binding region of apoE3. The alpha-helical content was calculated to be ~45% by circular dichroism spectroscopy. The protein exists in a predominantly tetrameric form in lipid-free state. Chemical denaturation studies reveal that the unfolding pattern is biphasic with mid points of denaturation corresponding to 0.8 and 2.2 M guanidine hydrochloride, suggesting the presence of two domains. Rat apoE converts DMPC vesicles to smaller DMPC/apoE complexes with a first order rate constant of 0.12 min(-1). It has the ability to bind the LDLr and to heparin. Our studies indicate that although its sequence resembles apoE4, an isoform of apoE3, rat apoE displays the biophysical behavior of apoE3. PMID- 23103363 TI - Prognostic factors for triple-negative breast cancer patients receiving preoperative systemic chemotherapy. AB - BACKGROUND: Triple-negative breast cancer patients are more likely to achieve a pathologic complete response after preoperative chemotherapy but they have still poor prognosis. The aim of this study was to identify prognostic factors in triple-negative breast cancer patients receiving preoperative chemotherapy. PATIENTS AND METHODS: Triple-negative breast cancer patients who underwent preoperative chemotherapy were retrospectively analyzed. Significant prognostic factors among clinical and pathologic variables were investigated with Kaplan Meier analysis and Cox proportional hazards modeling for disease-free survival and overall survival. RESULTS: Among the 135 triple-negative breast cancer patients, the median age was 54 years, median tumor diameter on palpation was 4.5 cm, and there were 62 clinically node positive patients. The clinical response rate was 76% (103 patients) and pathologic complete response rate was 21% (29 patients). Median disease-free survival was 44.4 months and median overall survival was 49.2 months. Univariate and multivariate analysis showed that that completion of chemotherapy, better clinical response, fewer positive nodes, and lower histologic grades were significant factors associated with both disease free and overall survival. CONCLUSIONS: Our data demonstrated that clinical response of preoperative systemic chemotherapy is an important independent favorable prognostic factor for triple-negative breast cancer. PMID- 23103364 TI - Epidemiologic study of radiotherapy use in China in patients with breast cancer between 1999 and 2008. AB - BACKGROUND: To investigate the use of radiotherapy (RT) in China in patients with breast cancer over a 10-year period. A hospital-based, nationwide, multicenter, retrospective epidemiologic study of women with primary breast cancer was conducted. PATIENTS AND METHODS: Patients were selected randomly in 7 hospitals from 1999 to 2008. Data on overall RT, postmastectomy RT (PMRT), RT after conservative breast surgery (PBRT) and palliative RT (PRT) were recorded. RT use was analyzed, and differences were compared by using the Cochran-Armitage trend test and the chi(2) test. A total of 3732 patients were included: 1009 (27%) received RT, including 688 (18.4%) PMRT, 170 (4.6%) PBRT, 86 (2.3%) PRT, 47 (1.3%) both PMRT and PRT, and 18 (0.5%) other RT. RESULTS: Overall use of RT increased significantly from 1999 to 2008 (2P < .001). There was a slight but significant increase in PMRT (2P = .012) and a 10-fold increase in PBRT (2P < .001); use of PRT was relatively constant (2P = .777). There was a significant difference among regions in the use of RT, PMRT, PBRT, and PRT (2P < .01). Of patients with stage III disease, 51.6% and of those with node-positive stage II disease treated by radical mastectomy, 21% had received PMRT. In patients treated by using breast conservative surgery, 83.7% received PBRT, which was not affected by stage. CONCLUSION: In summary, in China, the overall use of RT in patients with breast cancer was quite low, but there was an increasing trend in those treated between 1999 and 2008. PMID- 23103365 TI - Five-year outcomes and toxicities using 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation. AB - BACKGROUND: Limited 5-year data exist on clinical outcomes and toxicities for patients undergoing 3-dimensional conformal radiation therapy (3D-CRT) APBI. PATIENTS AND METHODS: Two hundred five patients were treated with 3D-CRT APBI between August, 2000 and December, 2011. Cases with > 1 year of follow-up were analyzed for cosmesis, chronic toxicities, and clinical outcomes. Outcome by American Society for Radiation Oncology (ASTRO) Consensus Panel (CP) group were also compared. Rates of excellent and good cosmesis for 3D-CRT were evaluated over time for stability. RESULTS: One hundred ninety-two patients were evaluated; median follow-up was 4.8 years (range, 1.0-11.2 years). Seventy-two patients (37.5%) were categorized as ASTRO CP subgroup 'suitable,' 89 (46.4%) 'cautionary,' and 31 (16.1%) 'unsuitable.' At 5 years, the rate of IBTR, regional recurrence, distant metastases, cause-specific survival, and overall survival were 0%, 0%, 2%, 99%, and 92%, respectively. Thirty-seven percent of patients had excellent cosmesis, 44% good cosmesis, 15% fair cosmesis, and 4% poor cosmesis. No statistically significant differences in excellent (37% vs. 37%; P = .99) or good (49% vs. 37%; P = .28) cosmesis were noted between patients with < 5 years follow-up and those with >= 5 years follow-up. The rates of grade III fibrosis and telangiectasia were 7.5% and 7.6%, respectively. CONCLUSION: In the largest group of patients published to date using 3D-CRT to deliver APBI, no local recurrences were noted at 5 years. More than 80% of patients had excellent or good cosmesis. PMID- 23103366 TI - Association of the Arg194Trp and the Arg399Gln polymorphisms of the XRCC1 gene with risk occurrence and the response to adjuvant therapy among Polish women with breast cancer. AB - BACKGROUND: The XRCC1 gene encoding the X-ray cross-complementing group 1 protein (XRCC1) is involved in the base excision repair (BER) pathway. METHODS: The aim of this study was to investigate an association of the Arg194Trp and Arg399Gln polymorphisms of the XRCC1 gene with a risk of breast cancer occurrence and the response to adjuvant treatment among Polish women. Overall survival (OS) and disease-free survival (DFS) were investigated in groups of patients with breast cancer treated with (1) all types of adjuvant therapy, (2) concomitant radiotherapy and chemotherapy, (3) chemotherapy alone, or (4) radiotherapy alone. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used to evaluate the genotype distribution of the XRCC1 gene among 185 patients with breast cancer and 205 female controls. RESULTS: We showed a higher risk of breast cancer occurrence for the Trp allele and the Arg194Trp genotype of the XRCC1 gene. However there was no significant difference in distribution of the Arg399Gln genotype of XRCC1 between patients and the control group. In the patient subgroup treated with adjuvant therapy, Kaplan-Meier survival analysis showed a significantly higher OS as well as DFS for carriers of the Gln399Gln genotype when compared with carriers of the Arg399Gln and Arg399Arg genotypes. The Gln399Gln genotype was associated with a significantly higher DFS in the subgroup of patients treated with chemotherapy alone or with concomitant radiotherapy and chemotherapy. CONCLUSION: We suggest that the polymorphism of the XRCC1 gene may be considered a predictive factor associated with the risk of occurrence and the survival outcome in breast cancer among Polish women. PMID- 23103367 TI - Oncoplastic surgery in surgical treatment of breast cancer: is the timing of adjuvant treatment affected? AB - INTRODUCTION: With the results of studies on the timing of adjuvant treatment, it currently appears that adjuvant treatment should be initiated as soon as possible. Breast conserving surgery and oncoplastic surgery is being used with increasing frequency. Therefore, studies about whether or not these applications delay the adjuvant treatment are needed. The aim of this study was to determine the time period needed for adjuvant chemotherapy and radiotherapy of the patients with breast cancer and to reveal associated factors related to the patient, tumor, and surgical technique. PATIENTS AND METHODS: Two hundred eighty patients with breast cancer who had surgery and were given adjuvant treatments in our clinic were included in the study. Age, body mass index, concomitant diseases, smoking habits, menopausal status, neoadjuvant treatments, tumor characteristics, surgical technique, and surgical complications were recorded. The time period between surgery and initiation of chemotherapy and radiotherapy, the number of chemotherapy cycles, and the duration of chemotherapy and radiotherapy were calculated. RESULTS: The numbers of patients who had modified radical mastectomy, breast conserving surgery, and oncoplastic surgery were 155 (55%), 47 (16.8%), and 78 (27.9%), respectively. The mean (SD) time period needed for chemotherapy administration was 19.5 +/- 4.2 days (range, 13-41 days) and 3.9 +/- 0.9 months for radiotherapy. Early wound complication of breast surgery was the only factor that delayed the adjuvant chemotherapy (P = .001). DISCUSSION: It has been well known that the time period between surgical treatment of breast cancer and adjuvant treatment affects survival. In our study, it has been shown that the surgical techniques used in breast and axillary surgery do not delay the initiation of adjuvant treatments. The adjuvant treatments of the patients who had oncoplastic surgery and breast conserving surgery were not delayed. The cooperation between the disciplines for the initiation of adjuvant treatments is important. PMID- 23103368 TI - Influence of neoadjuvant chemotherapy on HER2/neu status in invasive breast cancer. AB - INTRODUCTION: Reliably estimating HER2/neu expression in breast cancer is important for predicting patient prognosis and optimizing adjuvant therapeutic strategies. In this retrospective cohort study, effects of NAC on HER2/neu status in invasive breast cancer were evaluated, and the related factors were analyzed. PATIENTS AND METHODS: One hundred thirty-one patients with primary breast cancer were treated with anthracycline- and/or taxane-based NAC. HER2/neu status was evaluated by IHC on core needle biopsies of primary tumors before NAC and surgical resection specimens of post-NAC residual breast cancers or tumor positive axillary lymph nodes. Thirty-two pairs of specimens with discordant HER2/neu IHC scores were analyzed by fluorescence in situ hybridization (FISH). RESULTS: A significant difference in HER2/neu status by IHC between core needle biopsies and surgical resection specimens in patients receiving NAC was observed. After NAC, 23.4% (29 of 124) of tumors showed downregulated HER2/neu expression by IHC. Alterations of HER2/neu IHC scores did not significantly correlate with tumor subtype, pathologic response to NAC, adjuvant regimen, or time interval from the last chemotherapy to surgery. HER2/neu protein overexpression level was associated with favorable pathologic response to anthracycline and taxane-based chemotherapy. However, tumors with altered HER2/neu IHC scores after NAC revealed stable HER2/neu gene amplification/nonamplification by FISH analysis. CONCLUSION: Neoadjuvant chemotherapy for breast carcinoma resulted in the HER2/neu status alteration by IHC, but they have stable gene amplification status by FISH. HER2/neu protein overexpression indicated greater sensitivity to neoadjuvant anthracycline- and taxane-based chemotherapy. Thus, retesting HER2/neu IHC status in residual tumors after NAC should be considered in order to optimize adjuvant systemic therapy. PMID- 23103370 TI - High Court overturns two GMC judgments and sends them back to be heard by new panels. PMID- 23103369 TI - Vaccination of risk groups in England using the 13 valent pneumococcal conjugate vaccine: economic analysis. AB - OBJECTIVE: To estimate the cost effectiveness of vaccinating people with high risk conditions against invasive pneumococcal disease using the 13 valent pneumococcal conjugate vaccine. DESIGN: Economic evaluation using a cohort model from the perspective of healthcare providers. SETTING: England. PARTICIPANTS: People aged 2 years and older at increased risk of invasive pneumococcal disease due to chronic kidney disease; splenic dysfunction; HIV infection; a compromised immune system; chronic heart, liver, or respiratory disease; or diabetes. MAIN OUTCOME MEASURES: Costs, gains in life years and quality adjusted life years (QALYs), and incremental cost effectiveness ratios. RESULTS: Increasing indirect protection resulting from the vaccination programme of infants using the 13 valent pneumococcal conjugate vaccine means that the burden of disease preventable by targeting high risk groups will diminish in time. Under base case assumptions--that is, no overall impact on non bacteraemic pneumonia in high risk groups and assuming the high risk vaccination programme would be launched two to three years after the infant programme--the incremental cost effectiveness ratio was estimated to be more than L30,000 (?37,216; $48,210) per QALY gained for most risk groups. If, however, the vaccine does not offer protection against non bacteraemic pneumococcal pneumonia or the vaccine was introduced concomitantly with the infant 13 valent pneumococcal conjugate vaccination programme then vaccinating high risk people would (more) likely be cost effective. Sensitivity analyses showed that the cost effectiveness was particularly sensitive to assumed herd benefits and vaccine efficacy estimates. CONCLUSION: Under base case assumptions it is unlikely that a pneumococcal vaccination programme aimed at risk groups could be considered cost effective. Uncertainty could be substantially reduced by establishing the effectiveness of the 13 valent pneumococcal conjugate vaccine against non-bacteraemic pneumococcal pneumonia, particularly in at risk groups. PMID- 23103371 TI - Is the evidence strong enough to change the diagnostic criteria for gestational diabetes now? AB - The International Association of the Diabetes and Pregnancy Study Groups has proposed new thresholds for oral glucose tolerance tests that are based on the large observational Hyperglycemia and Adverse Pregnancy Outcomes study. By using these criteria about 18% of pregnant women will be diagnosed as having gestational diabetes mellitus. The question arises if we are ready for such an enormous increase in gestational diabetes mellitus patients, if outcome would really improve by using these criteria, and if additional studies are necessary before deciding on new diagnostic thresholds. In this clinical opinion, the pros and cons will be discussed. PMID- 23103372 TI - Robust in vitro affinity maturation strategy based on interface-focused high throughput mutational scanning. AB - Development of protein therapeutics or biosensors often requires in vitro affinity maturation. Here we report a robust affinity engineering strategy using a custom designed library. The strategy consists of two steps beginning with identification of beneficial single amino acid substitutions then combination. A high quality combinatorial library specifically customized to a given binding interface can be rapidly designed by high-throughput mutational scanning of single substitution libraries. When applied to the optimization of a model antibody Fab fragment, the strategy created a diverse panel of high affinity variants. The most potent variant achieved 2110-fold affinity improvement to an equilibrium dissociation constant (Kd) of 3.45 pM with only 7 amino acid substitutions. The method should facilitate affinity engineering of a wide variety of protein-protein interactions due to its context-dependent library design strategy. PMID- 23103373 TI - Heterologous expression of C. elegans fat-1 decreases the n-6/n-3 fatty acid ratio and inhibits adipogenesis in 3T3-L1 cells. AB - In general, a diet enriched in polyunsaturated fatty acids (PUFAs) inhibits the development of obesity and decreases adipose tissue. The specific impacts of n-3 and n-6 PUFAs on adipogenesis, however, have not been definitively determined. Traditional in vivo and in vitro supplementation studies have yielded inconsistent or even contradictory results, which likely reflect insufficiently controlled experimental systems. Caenorhabditiselegans fat-1 gene encodes an n-3 fatty acid desaturase, and its heterologous expression represents an effective method both for altering the n-6/n-3 PUFA ratio and for evaluating the biological effects of n-3 and n-6 PUFAs. We sought to determine whether a reduced n-6/n-3 ratio could influence adipogenesis in 3T3-L1 cells. Lentivirus-mediated introduction of the fat-1 gene into 3T3-L1 preadipocytes significantly reduced the n-6/n-3 ratio and inhibited preadipocyte proliferation and differentiation. In mature adipocytes, fat-1 expression reduced lipid deposition, as measured by Oil Red O staining, and induced apoptosis. Our results indicate that a reduced n 6/n-3 ratio inhibits adipogenesis through several mechanisms and that n-3 PUFAs more effectively inhibit adipogenesis (but not lipogenesis) than do n-6 PUFAs. PMID- 23103374 TI - Effect of zonisamide co-administration with levodopa on global gene expression in the striata of rats with Parkinson's disease. AB - The anti-epileptic drug zonisamide is reported to exert beneficial effects in patients with Parkinson's disease. To elucidate the pathophysiological mechanisms underlying the anti-parkinsonism effects of zonisamide, we examined the effect of zonisamide co-administered with levodopa in the striata of rats with 6 hydoroxydopamine hemiparkinsonism by using a DNA microarray for genome-wide gene expression profiling. We found that the expression of some genes related to metabolism and nervous system development and function were upregulated by zonisamide; expression of these genes was downregulated by levodopa. Furthermore, many genes related to the immune system and inflammation were downregulated by zonisamide, and their expression was upregulated by levodopa. These results indicate that zonisamide has a protective effect when co-administered with levodopa. PMID- 23103375 TI - MicroRNA functions in insects. AB - MicroRNAs (miRNAs) are small non-coding RNAs that are generated in all eukaryotes and viruses. Their role as master regulators of gene expression in various biological processes has only been fully appreciated over the last decade. Accumulating evidence suggests that alterations in the expression of miRNAs may lead to disorders, including developmental defects, diseases and cancer. Here, I review what is currently known about miRNA functions in insects to provide an insight into their diverse roles in insect biology. PMID- 23103376 TI - A novel ring electrode setup for the recording of somatosensory evoked potentials during transcranial direct current stimulation (tDCS). AB - Transcranial direct current stimulation (tDCS) modulates cortical excitability thereby influencing behavior and learning. While previous studies focused on tDCS after-effects, limited information about "online" tDCS effects is available. This in turn is an important prerequisite to better characterize and/or optimize tDCS effects. Here, we aimed to explore the feasibility of recording low-artifact somatosensory evoked potentials (SEPs) during tDCS using a novel ring electrode setup. We recorded SEP before, during and after 10 min of anodal or sham tDCS using a full-band direct current (DC) EEG system in a total number of 3 subjects. SEPs were recorded in the bore of the tDCS ring electrode. Using this approach, no tDCS-induced artifacts could be observed after the application of a standard EEG filter. This new setup might help to better characterize how tDCS alters evoked brain responses thus providing novel insight into underlying physiological effects during stimulation. PMID- 23103377 TI - Multivalent glycopeptide dendrimers for the targeted delivery of antigens to dendritic cells. AB - Dendritic cells are the most powerful type of antigen presenting cells. Current immunotherapies targeting dendritic cells have shown a relative degree of success but still require further improvement. One of the most important issues to solve is the efficiency of antigen delivery to dendritic cells in order to achieve an appropriate uptake, processing, and presentation to Ag-specific T cells. C-type lectins have shown to be ideal receptors for the targeting of antigens to dendritic cells and allow the use of their natural ligands - glycans - instead of antibodies. Amongst them, dendritic cell-specific ICAM-3-grabbing non-integrin (DC-SIGN) is an interesting candidate due to its biological properties and the availability of its natural carbohydrate ligands. Using Le(b)-conjugated poly(amido amine) (PAMAM) dendrimers we aimed to characterize the optimal level of multivalency necessary to achieve the desired internalization, lysosomal delivery, Ag-specific T cell proliferation, and cytokine response. Increasing DC SIGN ligand multivalency directly translated in an enhanced binding, which might also be interesting for blocking purposes. Internalization, routing to lysosomal compartments, antigen presentation and cytokine response could be optimally achieved with glycopeptide dendrimers carrying 16-32 glycan units. This report provides the basis for the design of efficient targeting of peptide antigens for the immunotherapy of cancer, autoimmunity and infectious diseases. PMID- 23103378 TI - Role of HLA-B alpha-3 domain amino acid position 194 in HIV disease progression. AB - HLA class I molecules play a role in the regulation of innate immune response. Therefore, the interaction of HLA class I molecules with different activating and inhibitory receptors leads to balancing the immune response. Among the different family of receptors, NK receptors KIR3DL1/S1 and LIR1, play a major role. Aim of this study was to evaluate the role of amino acid polymorphic positions of HLA class I molecules interacting with NK receptors in HIV progression. In order to minimize the influence of viral variability, a cohort of children with a nosocomial monophyletic HIV-1 infection from the Benghazi Children Hospital has been evaluated. To assess the role of single amino acid positions, we translated all HLA alleles in the different amino acid position polymorphisms. Interestingly, the polymorphism Val 194 located in the alpha3-domain of HLA-B, resulted associated with LTNP (LTNP=73.08%, FP=34.78%; P<0.02). When Val is present at position 194, HLA-B is known to interact with the receptor LIR1 (ILT2/LILRB1/CD85j). Therefore, we analyzed the role of the polymorphism in position 194 in HLA-B/LIR1 interaction by homology molecular modeling. The change Val to Ile at position 194 alters significantly the network of interaction between the amino acid residues of HLA-B and LIR1. In conclusion, considering the limitation of the small population evaluated, polymorphisms outside the peptide binding region of the HLA class I molecule can play a key role in HIV progression through interaction with other immune-relevant receptors. PMID- 23103379 TI - Expression of the calcium sensing receptor in human peripheral blood T lymphocyte and its contribution to cytokine secretion through MAPKs or NF-kappaB pathways. AB - The calcium-sensing receptor (CaSR) has been reported to play an important role in many tissues and organs. However, studies about the expression and function of CaSR in T lymphocytes are still not very lucid. In this study, we investigated the above-mentioned issues using RT-PCR, immunofluorescence staining, Western blotting, and the ELISA techniques. We found that the CaSR protein was expressed, and mainly located in the membrane in the normal human peripheral blood T lymphocytes. GdCl(3) (an agonist of CaSR) increased the dose-dependency of the CaSR expression, which was abolished by NPS2390 (an inhibitor of CaSR). GdCl(3) and Ca(2+) increased the phosphorylation of extracellular signal-regulated kinase (ERK)1/2 (one subgroup of MAPKs) and P65 (subunit of NF-kappaB),but, they had no significant effects on the JNK and P38 subgroups of MAPKs. Meantime, GdCl(3) and Ca(2+) stimulated both the IL-6 and TNF-beta releases and their mRNA expressions. However, these effects of GdCl(3) and Ca(2+) were inhibited by NPS2390, U0126 (MAPKs pathway inhibitor) or Bay-11-7082 (NF-kappaB pathway inhibitor). These results suggested that CaSR was functionally expressed in the T cells, and the activated CaSR contributed to the cytokine secretion through the partial MAPK and NF-kappaB pathways. PMID- 23103380 TI - Identification of binding sites of Lactobacillus plantarum enolase involved in the interaction with human plasminogen. AB - The enolase EnoA1 of Lactobacillus plantarum is here shown to interact with human plasminogen (Plg). By sequence alignment of EnoA1 with Streptococcus pneumoniae and Bifidobacterium lactis enolases, we identified BS1 and BS2 Plg-binding sites. A structure prediction of EnoA1 showed lysine residues in position 255 (BS2), and 422 (BS1) exposed on protein surface. A lysine residue in position 259 was as well identified as surface-exposed amino acid. The enoA1 gene was site directed mutagenized to generate four mutated proteins, carrying K255A, K259A, K422A and K259A/K422A substitutions. The functional role of these lysine residues was assessed evaluating specific Plg-binding activity of the mutated proteins. While the binding activity of the mutated proteins was drastically reduced, the residual enzymatic activity was more than 50% of EnoA1. Our results show that L. plantarum EnoA1 exhibits the Plg-BS1, and the Plg-BS2 extending up to the lysine residue in position 259, therefore consisting of 12-aa residues instead of 9-aa residues described in S. pneumoniae. A test performed on whole cells of L. plantarum, demonstrated that after inducing conversion of the cell-bound plasminogen to plasmin, this was released into the medium, unlike the mechanism reported for most pathogens, that retained plasmin bound to the cell surface. PMID- 23103381 TI - Does life satisfaction change in old age: results from an 8-year longitudinal study. AB - OBJECTIVES: The unexpected positive relationship between aging and happiness was called "the paradox of well-being," which is still a matter of debate. This study examined longitudinal change in life satisfaction (LS) in older adults. METHODS: LS was assessed with the satisfaction with life scale, in a sample of individuals (N = 899; aged 62-95 years, at first occasion; M = 72.73, SD = 5.68) for a period of 8 years (5 waves of data). A multiple indicator (e.g., second order) growth modeling was used to assess change in LS. RESULTS: Findings from both unconditional and conditional model (in which time-invariant, i.e., age, gender, and education, and time-varying, i.e., self-perceived health, covariates were incorporated in the model) indicated a linear increase in LS for the 8-year period. As expected, the results showed significant random variation in both intercept and slope, indicating that participants start at different levels and change at different rates. DISCUSSION: Our findings contribute to the debate concerning the paradox of well-being, which calls for explanation. There are few theories that provide some explanation (e.g., the socioemotional selectivity theory). However, to enhance researchers' understanding of developmental changes that contribute to the paradox of well-being, a more integrative theoretical model is needed. PMID- 23103382 TI - Predictors of successful communication with interactive voice response systems in older people. AB - OBJECTIVES: Interactive voice response (IVR) systems are computer programs that can interact with people to provide a number of services from business to health care. However, surveys examining people's attitudes toward these systems have consistently found that people in general and older people in particular strongly dislike these systems. We wanted to determine the memory and cognitive abilities that predict successful IVR interactions for older people. METHOD: We compared the performance of 185 older adults (aged 65 and older) on normed cognitive tests (the Wechsler Adult Intelligence Scale fourth edition and the Wechsler Memory Scale fourth edition) with their performance on 4 real-life IVR systems that included fact-finding at governmental agencies and plane ticket reservation. RESULTS: The results indicated that adults aged 65 and older experience significant difficulties in interacting with IVR systems. A significant number of people (20.5%) could not complete any of the tasks. Participants who could not complete any task were older and had the lowest full-scale IQ. However, there was little difference between the age of participants who completed 1, 2, 3, or 4 tasks. Rather, auditory memory and working memory were the best overall predictors for success in IVR tasks. DISCUSSION: The impact of poorer auditory memory and working memory is compounded by programming practices that increase the demand on these abilities and create unnecessary difficulties. Successful use of IVR systems could eventually complement in person health services. PMID- 23103383 TI - Diminished but not forgotten: effects of aging on magnitude of spacing effect benefits. AB - OBJECTIVES: Age-related changes in memory performance are common in paired associate episodic memory tasks, although the deficit can be ameliorated with distributed practice. Benefits of learning episode spacing in older adults have been shown in single-session studies with spaced presentations of items followed by a test. This study examined the magnitude of the spacing effect benefit in older adults relative to younger adults when given a multiday spacing effect paradigm. METHOD: We examined the impact of spacing gap (~15min vs. 24hr) in younger (N = 51, Mage = 19 years, SD = 0.6) and older (N = 54, Mage = 65 years, SD = 8.8) adults with a 10-day retention interval. RESULTS: Spacing of learning episodes benefited both younger and older adults. There was an age-related difference in the magnitude of this benefit that has not been observed in earlier studies. DISCUSSION: These results suggest that spacing benefited the long-term memory of older adults, however the effect was diminished and qualitatively different from that of younger adults. PMID- 23103384 TI - Quantification of ER/PR expression in ovarian low-grade serous carcinoma. AB - OBJECTIVE: Case reports suggest that hormonal therapy may be a useful treatment option for low-grade serous carcinomas (LGSC) but the clinical value remains uncertain. We hypothesized that LGSCs show a constitutive high hormone receptor expression and that type diagnosis may be sufficient to initiate hormonal therapy. METHODS: We assessed ER and PR expression on 27 LGSC, 69 high-grade serous carcinomas (HGSC), 36 serous borderline tumors (SBOT), and five normal fallopian tubes using three different platforms/antibodies on tissue microarrays. Staining from the Leica Bond Max and DAKO PharmDx platforms was evaluated using the Allred score. Quantitative fluorescence immunohistochemistry was performed using the HistoRx AQUAnalysis platform. A second cohort of 12 LGSC and 183 HGSC was assessed using the HistoRx AQUAnalysis platform. Welch ANOVA or Fisher's Exact Test was used to compare differences in the histological types for each platform. Nonparametric bivariate density plots were used to graphically demonstrate the relationship between ER and PR for the various histological types. RESULTS: LGSC have higher ER and PR expression compared to HGSC but significantly less than FT and SBOT. Nonparametric bivariate density revealed two populations of LGSC: one fifth of LGSC are ER high/PR high expressers similar to SBOT but the majority show low ER/PR expression more like HGSC. CONCLUSIONS: Quantitative assessment of ER/PR expression using the HistoRx AQUAnalysis platform may be useful as a predictive diagnostic for hormonal therapy in LGSC, assuming that only the fraction of double high expressers benefit from hormonal treatment. PMID- 23103385 TI - Water oxidation mechanism in photosystem II, including oxidations, proton release pathways, O-O bond formation and O2 release. AB - The present status of DFT studies on water oxidation in photosystem II is described. It is argued that a full understanding of all steps is close. In each S-transition, the manganese that is oxidized and the proton released are strongly implicated, and structures of all intermediates have been determined. For the S2 state, recent important experimental findings support key elements of the structure and the mechanism. In this mechanism, the O-O bond is formed between an oxyl radical in the center of the cluster and an Mn-bridging MU-oxo ligand, which was suggested already in 2006. The DFT structure of the oxygen evolving complex, suggested in 2008, is very similar to the recent high-resolution X-ray structure. Some new aspects of the interaction between P680 and the OEC are suggested. This article is part of a Special Issue entitled: Metals in Bioenergetics and Biomimetics Systems. PMID- 23103386 TI - True wild type and recombinant wild type cytochrome c oxidase from Paracoccus denitrificans show a 20-fold difference in their catalase activity. AB - The four subunit (SU) aa(3) cytochrome c oxidase (CcO) from Paracoccus denitrificans is one of the terminal enzymes of the respiratory chain. Its binuclear active center, residing in SU I, contains heme a(3) and Cu(B). Apart from its oxygen reductase activity, the protein possesses a peroxidase and a catalase activity. To compare variants and the wild type (WT) protein in a more stringent way, a recombinant (rec.) WT strain was constructed, carrying the gene for SU I on a low copy number plasmid. This rec. WT showed no difference in oxygen reductase activity compared to the American Type Culture Collection (ATCC) WT CcO but surprisingly its catalase activity was increased by a factor of 20. The potential over-production of SU I might impair the correct insertion of heme a(3) and Cu(B) because of a deficiency in metal inserting chaperones. An altered distance between heme a(3) and Cu(B) and variations in protein structure are possible reasons for the observed increased catalase activity. The availability of chaperones was improved by cloning the genes ctaG and surf1c on the same plasmid as the SU I gene. The new rec. WT CcO showed in fact a reduced catalase activity. Using differential scanning calorimetry no significant difference in thermal stability between the ATCC WT CcO and the rec. WT CcO was detected. However, upon aging the thermal stability of the rec. WT CcO was reduced compared to that of the ATCC WT CcO pointing to a decreased structural stability of the rec. WT CcO. PMID- 23103387 TI - Does acetogenesis really require especially low reduction potential? AB - Acetogenesis is one of the oldest metabolic processes on Earth, and still has a major global significance. In this process, acetate is produced via the reduction and condensation of two carbon dioxide molecules. It has long been assumed that acetogenesis requires ferredoxin with an exceptionally low reduction potential of ~-500mV in order to drive CO(2) reduction to CO and the reductive carboxylation of acetyl-CoA to pyruvate. However, no other metabolic pathway requires electron donors with such low reduction potential. Is acetogenesis a special case, necessitating unique cellular conditions? In this paper, I suggest that it is not. Rather, by keeping CO as a bound metabolite, the CO-dehydrogenase-acetyl-CoA synthase complex can couple the unfavorable CO(2) reduction to CO with the favorable acetyl-CoA synthesis, thus enabling the former process to proceed using ferredoxin of moderate reduction potential of -400mV. I further show that pyruvate synthesis can also take place using the same ferredoxins. In fact, the synthesis of pyruvate from CO(2), methylated-protein-carrier and -400mV ferredoxins is an energy-neutral process. These findings suggest that acetogenesis can take place at normal cellular redox state. Mechanistic coupling of reactions as suggested here can flatten energetic landscapes and diminish thermodynamic barriers and can be another role for enzymatic complexes common in nature and a useful tool for metabolic engineering. PMID- 23103388 TI - Severe fever with thrombocytopenia syndrome bunyavirus (SFTSV) infections in Zhejiang Province, China. PMID- 23103389 TI - Local and global interpretations of a disease-causing mutation near the ligand entry path in hyperpolarization-activated cAMP-gated channel. AB - Hyperpolarization-activated, cAMP-gated (HCN) channels sense membrane potential and intracellular cAMP levels. A mutation identified in the cAMP binding domain (CNBD) of the human HCN4 channel, S672R, severely reduces the heart rate, but the molecular mechanism has been unclear. Our biochemical binding assays on isolated CNBD and patch-clamp recordings on the functional channel show that S672R reduces cAMP binding. The crystal structure of the mutant CNBD revealed no global changes except a disordered loop on the cAMP entry path. To address this localized structural perturbation at a whole protein level, we studied the activity dependent dynamic interaction between cAMP and the functional channel using the patch-clamp fluorometry technique. S672R reduces the binding of cAMP to the channels in the resting state and significantly increases the unbinding rate during channel deactivation. This study on a disease-causing mutation illustrates the important roles played by the structural elements on the ligand entry-exit path in stabilizing the bound ligand in the binding pocket. PMID- 23103391 TI - The stress of aging. AB - Although the evolutionary theories of aging are quite well established, our knowledge about how we age is still very limited. The abundance and heterogeneity of available mechanistic theories of aging implicitly suggest that this phenomenon is overly complex and unlikely to be explained by a single pathway. Moreover, although aging remains a unique process, it is characterized by heterogeneous manifestations, not only determining inter-individual variations, but even intra-individual diversities. Such heterogeneity renders the inner nature of the aging process of difficult evaluation in older persons due to the potential biases introduced by multiple age-related social, biological, and clinical factors (and responsible for the evidence-based issue in geriatrics). Moving from the difficulties in translating anti-aging preclinical interventions into clinical trials, an alternative approach is illustrated. We encourage moving to a holistic evaluation of aging by adopting specific and consequent modifications in the design and conduction of clinical research. Such approach is today commonly applied in the clinical setting where the complexity of older patients often requires multidimensional interventions to adequately target the geriatric syndromes. Consistently, interventions targeting the aging process may result ineffective if too focused on a single underlying causal mechanism and/or failing to capture the complexity of the phenomenon. In this context, frailty (a geriatric syndrome characterized by age-related declines occurring across multiple physiologic systems) may indeed represent a clinically relevant threshold throughout the continuum of the aging process and a promising benchmark to test multidomain interventions against age-related conditions. PMID- 23103390 TI - Targeting the cell wall of Mycobacterium tuberculosis: structure and mechanism of L,D-transpeptidase 2. AB - With multidrug-resistant cases of tuberculosis increasing globally, better antibiotic drugs and novel drug targets are becoming an urgent need. Traditional beta-lactam antibiotics that inhibit D,D-transpeptidases are not effective against mycobacteria, in part because mycobacteria rely mostly on L,D transpeptidases for biosynthesis and maintenance of their peptidoglycan layer. This reliance plays a major role in drug resistance and persistence of Mycobacterium tuberculosis (Mtb) infections. The crystal structure at 1.7 A resolution of the Mtb L,D-transpeptidase Ldt(Mt2) containing a bound peptidoglycan fragment, reported here, provides information about catalytic site organization as well as substrate recognition by the enzyme. Based on our structural, kinetic, and calorimetric data, we propose a catalytic mechanism for Ldt(Mt2) in which both acyl-acceptor and acyl-donor substrates reach the catalytic site from the same, rather than different, entrances. Together, this information provides vital insights to facilitate development of drugs targeting this validated yet unexploited enzyme. PMID- 23103392 TI - On the spin order transfer from parahydrogen to another nucleus. AB - The hyperpolarization of nuclear spins holds great potential e.g. for biomedical research. Strong signal enhancements have been demonstrated e.g. by transforming the spin order of parahydrogen (pH(2)) to net polarization of a third nucleus (e.g. (13)C) by means of a spin-order-transfer (SOT) sequence. The polarization achieved is vitally dependent on the sequence intervals, which are a function of the J-coupling constants of the molecule to be polarized. How to derive the SOT sequence intervals, the actual values for molecules as well as the (theoretical) polarization yield and robustness, however, are not fully described. In this paper, (a) we provide the methods to obtain the SOT intervals for a given set of J-coupling constants (i.e. of a new hyperpolarization agent); (b) exemplify these methods on molecules from literature, providing the hitherto missing intervals and simulated polarization yield; and (c) assess the robustness of the sequences towards B(1) and J-coupling errors. Close to unity polarization is obtained for all molecules and sequences. Furthermore, the loss of polarization caused by erroneous B(1) and J-coupling constants is reduced by choosing the channel and phase of some pulses in the SOT sequences appropriately. PMID- 23103393 TI - Research review of nongovernmental organizations' security policies for humanitarian programs in war, conflict, and postconflict environments. AB - OBJECTIVES: To identify the most and least commonly cited security management messages that nongovernmental organizations (NGOs) are communicating to their field staff, to determine the types of documentation that NGOs most often use to communicate key security messages, and to distinguish the points of commonality and divergence across organizations in the content of key security messages. METHODS: The authors undertook a systematic review of available security policies, manuals, and training materials from 20 international humanitarian NGOs using the InterAction Minimum Operating Security Standards as the basis for a review framework. RESULTS: The most commonly cited standards include analytical security issues such as threat and risk assessment processes and guidance on acceptance, protection, and deterrence approaches. Among the least commonly cited standards were considering security threats to national staff during staffing decision processes, incorporating security awareness into job descriptions, and ensuring that national staff security issues are addressed in trainings. NGO staff receive security-related messages through multiple document types, but only 12 of the 20 organizations have a distinct security policy document. Points of convergence across organizations in the content of commonly cited standards were found in many areas, but differences in security risk and threat assessment guidance may undermine communication between aid workers about changes in local security environments. CONCLUSIONS: Although the humanitarian community has experienced significant progress in the development of practical staff security guidance during the past 10 years, gaps remain that can hinder efforts to garner needed resources, clarify security responsibilities, and ensure that the distinct needs of national staff are recognized and addressed. PMID- 23103394 TI - Information for action? Analysis of 2005 South Asian earthquake reports posted on Reliefweb. AB - OBJECTIVE: Following a sudden-onset disaster (SOD), rapid information is needed. We assessed the relevance of information available for relief planning on a main Internet portal following a major SOD. METHODS: We reviewed all information posted on the Reliefweb Web site in the first 7 days following the 2005 South Asian earthquake using a predeveloped registration form focusing on essential indicators. These data were compared with Pakistani government figures posted by the Centre for Research on the Epidemiology of Disasters. RESULTS: A total of 820 reports were reviewed. More reports came from nongovernmental organizations (NGOs; 35%) than any other source. A total of 42% of reports addressed only national level information, while 32% specified information at the provincial level. Fewer than 12% of all reports discussed the earthquake at the more local division and district levels. Only 13 reports provided pre-earthquake estimates of the number of people living in the affected areas. A third of all reports cited a common figure of 2.5 million made homeless. These were lower than official figures of 5 million homeless. A total of 43% reported on the estimated number of deaths. The estimated number peaked on day 4 at 40 000. All of these reports were lower than official data, which reported 73 000 deaths in total. CONCLUSION: Early reports heavily underestimated the number of affected, homeless, injured, and dead. Many reports repeated information provided from previous unnamed sources rather than providing unique contributions from eyewitness reports or from contextual information based on previous work in the area. Better information on predisaster essential indicators should be available and used in combination with post-SOD information to better adapt humanitarian relief and funding according to needs. PMID- 23103396 TI - Mitigating the risk of late-life mental health problems for veterans: contributions of the life course perspective to emergency management. PMID- 23103395 TI - Planning for chronic disease medications in disaster: perspectives from patients, physicians, pharmacists, and insurers. AB - BACKGROUND: Recent US disasters highlight the current imbalance between the high proportion of chronically ill Americans who depend on prescription medications and their lack of medication reserves for disaster preparedness. We examined barriers that Los Angeles County residents with chronic illness experience within the prescription drug procurement system to achieve recommended medication reserves. METHODS: A mixed methods design included evaluation of insurance pharmacy benefits, focus group interviews with patients, and key informant interviews with physicians, pharmacists, and insurers. RESULTS AND DISCUSSION: Most prescriptions are dispensed as 30-day units through retail pharmacies with refills available after 75% of use, leaving a monthly medication reserve of 7 days. For patients to acquire 14- to 30-day disaster medication reserves, health professionals interviewed supported 60- to 100-day dispensing units. Barriers included restrictive insurance benefits, patients' resistance to mail order, and higher copay-ments. Physicians, pharmacists, and insurers also varied widely in their preparedness planning and collective mutual-aid plans, and most believed pharmacists had the primary responsibility for patients' medication continuity during a disaster. CONCLUSIONS: To strengthen prescription drug continuity in disasters, recommendations include the following: (1) creating flexible drug dispensing policies to help patients build reserves, (2) training professionals to inform patients about disaster planning, and (3) building collaborative partnerships among system stakeholders. PMID- 23103397 TI - Monitoring of the human serum albumin carbonylation level through determination of guanidino group content. AB - Carbonylation of the protein amino, guanidine, and thiol groups with alpha oxoaldehydes (which are produced in higher quantities in diabetes, uremia, oxidative stress, aging, and inflammation) is one of the important causes of vascular complications. For monitoring of the human serum albumin (HSA) carbonylation level, a spectrophotometric method based on the formation of colored adduct between guanidine group and thymol-sodium hypobromite reagent in the alkaline medium was investigated. Beer's law is obeyed in the concentration range of Arg and protein guanidine groups from 1 to 40 mM. Precision of the method (relative standard deviation) was in the range of 0.9 to 2%. Accuracy was examined by the standard addition method (recovery ~100%). The method was applied for monitoring of the carbonylation level of HSA with methylglyoxal in vitro and of HSA isolated (using affinity chromatography) from sera of 21 patients with type 2 diabetes and 12 healthy persons. The content of guanidine groups in HSA isolated from diabetics (19.64 +/- 1.07 mM/mM albumin) was significantly lower (P < 0.001) in comparison with a control group (21.87 +/- 1.02 mM/mM albumin). The method is simple and fast, has good accuracy and precision, and is suitable for clinical practice as well for in vitro protein carbonylation experiments. PMID- 23103398 TI - Fluorescent primer-based in vitro transcription system of viral RNA-dependent RNA polymerases. AB - Viral infection is a leading cause of disease and death. Although vaccines are the most effective method of controlling viral infections, antiviral drugs are also important. Here, we established an in vitro transcription system by using fluorescein isothiocyanate-conjugated primers for RNA polymerases of viruses that are important disease-causing human pathogens (influenza, hepatitis C, Japanese encephalitis viruses, and enterovirus 71). This technology will allow us to analyze RNA polymerase activity without using radioisotopes. PMID- 23103399 TI - An acrylamide biosensor based on immobilization of hemoglobin onto multiwalled carbon nanotube/copper nanoparticles/polyaniline hybrid film. AB - A method is described for the construction of a highly sensitive electrochemical biosensor for the detection of acrylamide, based on covalent immobilization of hemoglobin (Hb) onto carboxylated multiwalled carbon nanotube/copper nanoparticle/polyaniline (c-MWCNT/CuNP/PANI) composite electrodeposited onto pencil graphite (PG) electrode. The enzyme electrode was characterized by cyclic voltammetry (CV), scanning electron microscopy (SEM), X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, and electrochemical impedance spectroscopy (EIS). The biosensor showed an optimal response at pH 5.5 (0.1 M sodium acetate buffer) and 35 degrees C when operated at 20 mV s(-1). The biosensor exhibited low detection limit (0.2 nM) with high sensitivity (72.5 MUA/nM/cm(2)), fast response time (<2 s), and wide linear range (5 nM to 75 mM). Analytical recovery of added acrylamide was 95.40 to 97.56%. Within- and between-batch coefficients of variation were 2.35 and 4.50%, respectively. The enzyme electrode was used 120 times over a period of 100 days, when stored at 4 degrees C. PMID- 23103400 TI - Deficiency of ubiquitin A20 promotes antigen transport across airway epithelial cells via a transcellular pathway. AB - The epithelial barrier dysfunction is associated with the pathogenesis of a number of diseases. Ubiquitin E3 ligase A20 (A20) plays a critical role in maintaining the homeostasis in the body. This study aimed to investigate the role of A20 in the degradation of endocytic antigens in airway epithelial cells. The expression of A20 in the human nasal epithelial cell line, RPMI 2650 cells (Rpcs), was evaluated. The role of A20 in maintaining the intracellular permeability in Rpc monolayers was assessed in Transwells. The endosome/lysosome fusion in epithelial cells was observed by immunocytochemistry. On the absorption of antigen, the expression of A20 was increased in Rpcs. The knockdown of the A20 gene in Rpcs increased the amounts of the endocytic antigens across the Rpc monolayers. A20 was required in the process of the endosome/lysosome fusion. The antigens transported to the basal compartment by A20-deficient Rpc monolayers still kept strong antigenicity. The nasal epithelial cell line, Rpcs, expresses A20 that facilitates the degradation of endocytic antigens in Rpcs by facilitating the endosome/lysosome fusion. PMID- 23103401 TI - Social isolation induces deficit of latent learning performance in mice: a putative animal model of attention deficit/hyperactivity disorder. AB - Social isolation of rodents (SI) elicits a variety of stress responses such as increased aggressiveness, hyper-locomotion, and reduced susceptibility to pentobarbital. To obtain a better understanding of the relevance of SI-induced behavioral abnormalities to psychiatric disorders, we examined the effect of SI on latent learning as an index of spatial attention, and discussed the availability of SI as an epigenetic model of attention deficit hyperactivity disorder (ADHD). Except in specially stated cases, 4-week-old male mice were housed in a group or socially isolated for 3-70 days before experiments. The animals socially isolated for 1 week or more exhibited spatial attention deficit in the water-finding test. Re-socialized rearing for 5 weeks after 1-week SI failed to attenuate the spatial attention deficit. The effect of SI on spatial attention showed no gender difference or correlation with increased aggressive behavior. Moreover, SI had no effect on cognitive performance elucidated in a modified Y-maze or an object recognition test, but it significantly impaired contextual and conditional fear memory elucidated in the fear-conditioning test. Drugs used for ADHD therapy, methylphenidate (1-10 mg/kg, i.p.) and caffeine (0.5 1 mg/kg, i.p.), improved SI-induced latent learning deficit in a manner reversible with cholinergic but not dopaminergic antagonists. Considering the behavioral features of SI mice together with their susceptibility to ADHD drugs, the present findings suggest that SI provides an epigenetic animal model of ADHD and that central cholinergic systems play a role in the effect of methylphenidate on SI-induced spatial attention deficit. PMID- 23103402 TI - Perirhinal cortex lesions produce retrograde but not anterograde amnesia for allocentric spatial information: within-subjects examination. AB - Using a reference spatial memory task sensitive to hippocampal lesions, the same groups of rats were subjected to four successive experimental phases to investigate which aspects of spatial cognition are perirhinal cortex dependent. Results showed that the perirhinal cortex is not necessary for acquisition or for long-term spatial memory retention. However, the perirhinal cortex was differentially involved in spatial memory expression depending on whether the original learning took place in an intact brain or in a perirhinal damaged brain. Specifically, only when the lesions were made after learning was a profound impairment in the expression of preoperatively acquired spatial information observed. These results suggest that, in a normal brain, the perirhinal cortex plays an essential role in the expression of spatial information during the post learning period. PMID- 23103403 TI - Daily treadmill exercise attenuates cocaine cue-induced reinstatement and cocaine induced locomotor response but increases cocaine-primed reinstatement. AB - Exercise affects neuroplasticity and neurotransmission including dopamine (DA), which modulates drug-taking behavior. Previous research in rodents has shown that exercise may attenuate the rewarding effects of drugs of abuse. The present study examined the effects of high and low exercise on cocaine responses in male Wistar rats that had been trained to self-administer and were compared to a group of sedentary rats. High exercise rats (HE) ran daily on a treadmill for 2h and low exercise (LE) ran daily for 1h. After 6 weeks of this exercise regimen, rats were tested over 2 days for reinstatement (day 1: cue-induced reinstatement; day 2: cocaine-primed reinstatement). During cue-induced reinstatement, the sedentary rats showed the expected increase in active lever responses when compared to maintenance, whereas these increased responses were inhibited in the exercised rats (HE and LE). During cocaine-primed reinstatement, however, there was a significant increase in active lever presses when compared to maintenance only in the HE group. This data suggests that chronic exercise during abstinence attenuates the cue-induced reinstatement seen in the sedentary rats by 26% (LE) and 21% (HE). In contrast, only the high exercise rats exhibited sensitized cocaine-seeking behavior (active lever presses) following cocaine-primed reinstatement. Finally, while sedentary rats increased locomotor activity during cocaine-primed reinstatement over that seen with cocaine during maintenance, this was not observed in the exercised rats, suggesting that exercise may interfere with the sensitized locomotor response during cocaine reinstatement. PMID- 23103405 TI - Social modulation in extinction of aversive memories. AB - Return of fear after extinction is a considerable challenge for the efficacy of exposure-based therapies. Fear recovery is most often modeled in the laboratory by changing the experimental context and studied in isolated animals. Since social context is an important factor affecting behavior, the question arises how it influences the recovery of extinguished fear. Here we present two novel behavioral models that allow studying social modulation of extinction memory retrieval. We show that the presence of a fearful cage mate results in a robust renewal of freezing as well as avoidance responses that were previously successfully extinguished. PMID- 23103404 TI - Alterations in ethanol seeking and self-administration following yohimbine in selectively bred alcohol-preferring (P) and high alcohol drinking (HAD-2) rats. AB - Evidence suggests that stress increases alcohol drinking and promotes relapse in humans. Animal models that assess related behaviors include the sipper tube ethanol self-administration and the stress-induced reinstatement paradigms. While selectively bred for the same high-ethanol-drinking behavior, alcohol-preferring P rats appear to show greater sensitivity to ethanol reinforcement than high alcohol-drinking HAD rats. The present experiment tested the effects of the pharmacological stressor, yohimbine, on the motivation to seek and consume ethanol implementing a combined sipper tube/reinstatement model using male P and HAD-2 rats. Following training to self-administer ethanol using the sipper tube procedure, rats were tested for the effects of yohimbine (0.625-2.5 mg/kg) on ethanol drinking. Subsequently, rats were tested for the effects of 1.25 mg/kg yohimbine on reinstatement of ethanol seeking. Yohimbine (0.625 and 1.25 mg/kg) increased ethanol self-administration, and the latter dose also decreased latency to complete the response requirement. Yohimbine elicited reinstatement of ethanol seeking in both lines. HAD-2 rats drank more ethanol, but showed similar responding on the ethanol-associated lever compared to P rats. These findings extend both the reinstatement and sipper tube models and justify further exploration of this unique combined paradigm. Despite prior evidence suggesting that P rats are more motivated to seek and consume ethanol, differences in these behaviors between P and HAD-2 rats were not systematic in the present experiment. Further investigation may elucidate whether either selected line may be more sensitive than other selectively bred or outbred rats to stress-related changes in ethanol's reinforcing effects. PMID- 23103406 TI - Serotonin (2C) receptor regulation of cocaine-induced conditioned place preference and locomotor sensitization. AB - Previous studies have identified an inhibitory regulatory role of the 5-HT(2C) receptor in serotonin and dopamine neurotransmission. As cocaine is known to enhance serotonin and dopamine transmission, the ability of 5-HT(2C) receptors to modulate cocaine-induced behaviors was investigated. Alterations in cocaine reward behavior were assessed in the conditioned place preference (CPP) paradigm. Mice were injected with a selective 5-HT(2C) receptor agonist, Ro 60-0175 (0, 1, 3, 10 mg/kg, i.p.) prior to cocaine administration (10 mg/kg, i.p.) on cocaine conditioning days. Administration of Ro 60-0175(10 mg/kg) prior to cocaine attenuated the development of cocaine place preference. To assess the potential of the 5-HT(2C) receptor to influence cocaine-induced behavioral sensitization, mice were pretreated with either saline or Ro 60-0175 (10 mg/kg, i.p.) and 30 min later, administered cocaine (20 mg/kg, i.p.) or saline once daily for 5 days. Locomotor activity was measured daily following cocaine administration. After a 10-day drug-free period, locomotor activity was measured on day 16 following a challenge injection of cocaine (20 mg/kg, i.p.). Pharmacological activation of 5 HT(2C) receptors with Ro 60-0175 attenuated acute cocaine-induced activity on days 1-5, as well as the development of long-term cocaine-induced locomotor sensitization. Thus, activation of 5-HT(2C) receptors attenuated the rewarding and locomotor-stimulating effects of cocaine, as well as inhibited the development of sensitization. The current study shows that 5-HT(2C) receptor activity exerts an inhibitory influence on the short-term and long-term behavioral responses to cocaine. PMID- 23103407 TI - Reducing subsidence risk by using rapid manufactured patient-specific intervertebral disc implants. AB - BACKGROUND CONTEXT: Intervertebral disc implant size, shape, and position during total disc replacement have been shown to affect the risk of implant subsidence or vertebral fracture. Rapid manufacturing has been successfully applied to produce patient-specific implants for craniomaxillofacial, dental, hip, and knee requirements, but very little has been published on its application for spinal implants. PURPOSE: This research was undertaken to investigate the improved load distribution and stiffness that can be achieved when using implants with matching bone interface geometry as opposed to implants with flat end plate geometries. STUDY DESIGN: The study design comprises a biomechanical investigation and comparison of compressive loads applied to cadaveric vertebrae when using two different end plate designs. METHODS: Four spines from male cadavers (ages 45-65 years, average 52 years), which had a total of n=88 vertebrae (C3-L5), were considered during this study. Bone mineral density scans on each spine revealed only one to be eligible for this study. Twenty remaining vertebrae (C3-L3) were potted and subjected to nondestructive compression tests followed by destructive compression tests. Custom-made nonfunctional implants were designed for this experiment. Ten implants were designed with matching end plate-to-bone interface geometry, whereas the other 10 were designed with flat end plates. Testing did not incorporate the use of a keel in either design type. I-Scan pressure sensors (Tekscan, Inc., MA, USA) were used during the nondestructive tests to assess the load distribution and percentage surface contact. RESULTS: Average percent contact area measured during nondestructive tests was 45.27% and 10.49% for conformal and flat implants, respectively-a difference that is statistically significant (p<.001). A higher percent contact area was especially observed for cervical vertebrae because of their pronounced end plate concavity. During destructive compression tests, conformal implants achieved higher failure loads than flat implants. Conformal implants also performed significantly better when stiffness values were compared (p<.0001). CONCLUSIONS: One of the main expected benefits from customizing the end plate geometry of disc implants is the reduced risk and potential for subsidence into the vertebral bone end plate. Subsidence depends in part on the stiffness of the implant-bone construct, and with a 137% increase in stiffness, the results of this study show that there are indeed significant potential benefits that can be achieved through the use of customization during the design and manufacture of intervertebral disc implants. PMID- 23103408 TI - Temperature dependent empirical pseudopotential theory for self-assembled quantum dots. AB - We develop a temperature dependent empirical pseudopotential theory to study the electronic and optical properties of self-assembled quantum dots (QDs) at finite temperature. The theory takes the effects of both lattice expansion and lattice vibration into account. We apply the theory to InAs/GaAs QDs. For the unstrained InAs/GaAs heterostructure, the conduction band offset increases whereas the valence band offset decreases with increasing temperature, and there is a type-I to type-II transition at approximately 135 K. Yet, for InAs/GaAs QDs, the holes are still localized in the QDs even at room temperature, because the large lattice mismatch between InAs and GaAs greatly enhances the valence band offset. The single-particle energy levels in the QDs show a strong temperature dependence due to the change of confinement potentials. Because of the changes of the band offsets, the electron wavefunctions confined in QDs increase by about 1-5%, whereas the hole wavefunctions decrease by about 30-40% when the temperature increases from 0 to 300 K. The calculated recombination energies of excitons, biexcitons and charged excitons show red shifts with increasing temperature which are in excellent agreement with available experimental data. PMID- 23103410 TI - Distinct neural correlates for pragmatic and semantic meaning processing: an event-related potential investigation of scalar implicature processing using picture-sentence verification. AB - The present study examines the brain-level representation and composition of meaning in scalar quantifiers (e.g., some), which have both a semantic meaning (at least one) and a pragmatic meaning (not all). We adopted a picture-sentence verification design to examine event-related potential (ERP) effects of reading infelicitous quantifiers for which the semantic meaning was correct with respect to the context but the pragmatic meaning was not, compared to quantifiers for which the semantic meaning was inconsistent with the context and no additional pragmatic meaning is available. In the first experiment, only pragmatically inconsistent quantifiers, not semantically inconsistent quantifiers, elicited a sustained posterior negative component. This late negativity contrasts with the N400 effect typically elicited by nouns that are incongruent with their context, suggesting that the recognition of scalar implicature errors elicits a qualitatively different ERP signature than the recognition of lexico-semantic errors. We hypothesize that the sustained negativity reflects cancellation of the pragmatic inference and retrieval of the semantic meaning. In our second experiment, we found that the process of re-interpreting the quantifier was independent from lexico-semantic processing: the N400 elicited by lexico-semantic violations was not modulated by the presence of a pragmatic inconsistency. These findings suggest that inferential pragmatic aspects of meaning are processed using different mechanisms than lexical or combinatorial semantic aspects of meaning, that inferential pragmatic meaning can be realized rapidly, and that the computation of meaning involves continuous negotiation between different aspects of meaning. PMID- 23103409 TI - Behavioral and electrophysiological outcomes of tissue-specific Smn knockdown in Drosophila melanogaster. AB - Severe reduction in Survival Motor Neuron 1 (SMN1) protein in humans causes Spinal Muscular Atrophy (SMA), a debilitating childhood disease that leads to progressive impairment of the neuro-muscular system. Although previous studies have attempted to identify the tissue(s) in which SMN1 loss most critically leads to disease, tissue-specific functions for this widely expressed protein still remain unclear. Here, we have leveraged RNA interference methods to manipulate SMN function selectively in Drosophila neurons or muscles followed by behavioral and electrophysiological analysis. High resolution measurement of motor performance shows profound alterations in locomotor patterns following pan neuronal knockdown of SMN. Further, locomotor phenotypes can be elicited by SMN knockdown in motor neurons, supporting previous demonstrations of motor neuron specific SMN function in mice. Electrophysiologically, SMN modulation in muscles reveals largely normal synaptic transmission, quantal release and trans-synaptic homeostatic compensation at the larval neuro-muscular junction. Neuronal SMN knockdown does not alter baseline synaptic transmission, the dynamics of synaptic depletion or acute homeostatic compensation. However, chronic glutamate receptor dependent developmental homeostasis at the neuro-muscular junction is strongly attenuated following reduction of SMN in neurons. Together, these results support a distributed model of SMN function with distinct neuron-specific roles that are likely to be compromised following global loss of SMN in patients. While complementary to, and in broad agreement with, recent mouse studies that suggest a strong necessity for SMN in neurons, our results uncover a hitherto under appreciated role for SMN in homeostatic regulatory mechanisms at motor synapses. PMID- 23103411 TI - Novel odors affect gene expression for cytokines and proteinases in the rat amygdala and hippocampus. AB - Olfaction in rodents provides an excellent modality for the study of cellular mechanisms of information processing and storage, since a single occurrence of precisely timed stimuli has high survival value. We have followed up preliminary evidence of cytokine and proteinase involvement in normal (as opposed to pathologically-induced) brain plasticity by surveying for the presence of these factors in the olfactory circuitry of the rat. Genes for 25-30 common cytokines and their receptors, and over 30 cell matrix and adhesion molecules were found to be expressed across the olfactory bulb, insular cortex, amygdala, and dorsal hippocampus. We then measured by real-time PCR the transcriptional expression of seven of these genes following a one-time exposure to the novel odor of blueberry bars or cornnuts, in contrast to presentation of the familiar odor of lab chow. In the amygdala significant up-regulation of interleukin-1 receptor 1 (IL1r1), interleukin-4 receptor (IL4r), fibroblast growth factor 13 (FGF13), and cathepsin H (CtsH) was observed in males in response to the odor of cornnuts only. Changes were less consistent and widespread in the hippocampus, but were again sex specific for three genes: cathepsin-L (CtsL), matrix metalloproteinase-14 (MMP 14) and MMP-16. Our results show that transcription for several specific cytokines, growth factors, and proteinases responds to a one-time exposure to a novel odor, in a manner that tends to be region- and sex-specific. This suggests considerable variation in the way that olfactory information is processed at the cellular level in different brain regions and by the two sexes. PMID- 23103412 TI - Modulation of diazepam-insensitive GABA(A) receptors by micromolar concentrations of thyroxine and related compounds in vitro. AB - The effects of thyroxine and its related compounds on the benzodiazepine insensitive gamma-aminobutyric acid type A (GABA(A)) receptors were studied. Thyroxine at micromolar concentrations potentiated the (3)H-Ro15-4513 binding to rat brain membranes in-vitro in the thalamus, striatum, cortex and hippocampus, but not in cerebellum. In the thalamus, the rank order of potency was the following: 3,3',5,5'-tetraiodothyroacetic acid (TETRAC)>L-thyroxine>3,5-diiodo-l thyronine (3,5-T2). TETRAC induced a slight potentiation of flumazenil binding to diazepam-sensitive GABA(A) receptors in the thalamus and striatum while no effect was found in cortex and hippocampus. Consequently, we examined whether these compounds could exert their modulatory effect on the currents mediated by benzodiazepine-insensitive GABA(A) receptors. The diazepam-insensitive GABA(A) receptor-mediated currents were recorded from acutely isolated rat ventrobasal thalamic neurons by applying low concentrations of 4,5,6,7 tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP). TETRAC and thyroxine at low MUM concentrations potentiated the THIP-evoked currents, although 3,5-T2 had no effect on the THIP-induced currents. Ethanol had no effect on the enhancing effects of TETRAC. TETRAC itself evoked GABA(A) receptor-mediated currents at high concentrations beyond 30 MUM. Although the effects of TETRAC and thyroxine were observed at non-physiological concentrations of hormones, the present results might lead to new lead structures with specificity to diazepam insensitive GABA(A) receptor subtypes. PMID- 23103413 TI - Investigation of the performance of PEG-PEI/ROCK-II-siRNA complexes for Alzheimer's disease in vitro. AB - Recent studies have showed inhibiting ROCK promoted axonal regeneration and suppressing ROCK-II decreased Abeta formation, suggesting ROCK is a potential target for the treatment of Alzheimer's disease. Because ROCK-II mRNA is abundantly expressed in brain, we targeted ROCK-II mRNA using a siRNA approach. To suppress ROCK-II mRNA expression, we synthesized PEG-PEI/ROCK-II-siRNA complexes and transfected C17.2 neural stem cells in vitro. The characteristics of the complexes were tested using a gel retardation assay. Particle size and zeta potential were examined using dynamic light scattering and the morphology of the complexes were observed by transmission electron microscopy. The toxicity was detected by an MTT assay and transfection efficiency was determined by flow cytometry. Laser confocal microscopy was employed to investigate the cell uptake of the complexes. RT-PCR and western blotting were used to verify the effect of gene silencing. Our results indicated that the characteristics of the complexes depended on the N/P ratios. At a high N/P ratio, PEG-PEI could completely condense the siRNA into small-sized uniform particles. However, high N/P ratios are accompanied with high cytotoxicity. Because of high transfection efficiency and low cytotoxicity, N/P=50 was chosen to transfect C17.2 cells in vitro. Laser confocal microscopy showed that ROCK-II-siRNA with green fluorescence was mainly distributed in the cytoplasm and synapses. Moreover, ROCK-II-siRNA was successfully released from the lysosome. RT-PCR and western blotting demonstrated effective gene silencing. These results indicated that PEG-PEI/ROCK-II-siRNA complexes effectively suppressed ROCK-II mRNA expression, providing the basis for future research in vivo. PMID- 23103414 TI - Incorporating waste into an experimental school prototype: lessons regarding materials reclamation opportunities. AB - This article presents lessons learned from a design project that explored the possibility of incorporating waste into the design of a school prototype. The authors worked with professional architects, a waste artist, environmental scientists and local waste operators to uncover new uses and applications for discarded items. As a result, bottles, aluminium cans, reclaimed doors, crushed concrete and second-hand bricks, etc. were identified, explored and integrated into the architectural design. This article serves as a catalyst that advocates the use of reclaimed materials in the field of design and planning. In particular, it highlights the challenges and issues that need to be addressed in carrying out design work with waste. Designers and practitioners interested in minimizing waste generation by proposing the use of reclaimed materials will find this article useful. PMID- 23103415 TI - A novel four-dimensional radiotherapy planning strategy from a tumor-tracking beam's eye view. AB - To investigate the feasibility of four-dimensional radiotherapy (4DRT) planning from a tumor-tracking beam's eye view (ttBEV) with reliable gross tumor volume (GTV) delineation, realistic normal tissue representation, high planning accuracy and low clinical workload, we propose and validate a novel 4D conformal planning strategy based on a synthesized 3.5D computed tomographic (3.5DCT) image with a motion-compensated tumor. To recreate patient anatomy from a ttBEV in the moving tumor coordinate system for 4DRT planning (or 4D planning), the centers of delineated GTVs in all phase CT images of 4DCT were aligned, and then the aligned CTs were averaged to produce a new 3.5DCT image. This GTV-motion-compensated CT contains a motionless target (with motion artifacts minimized) and motion-blurred normal tissues (with a realistic temporal density average). Semi-automatic threshold-based segmentation of the tumor, lung and body was applied, while manual delineation was used for other organs at risk (OARs). To validate this 3.5DCT-based 4D planning strategy, five patients with peripheral lung lesions of small size (<5 cm(3)) and large motion range (1.2-3.5 cm) were retrospectively studied for stereotactic body radiotherapy (SBRT) using 3D conformal radiotherapy planning tools. The 3.5DCT-based 4D plan (3.5DCT plan) with 9-10 conformal beams was compared with the 4DCT-based 4D plan (4DCT plan). The 4DCT plan was derived from multiple 3D plans based on all phase CT images, each of which used the same conformal beam configuration but with an isocenter shift to aim at the moving tumor and a minor beam aperture and weighting adjustment to maintain plan conformality. The dose-volume histogram (DVH) of the 4DCT plan was created with two methods: one is an integrated DVH (iDVH(4D)), which is defined as the temporal average of all 3D-phase-plan DVHs, and the other (DVH(4D)) is based on the dose distribution in a reference phase CT image by dose warping from all phase plans using the displacement vector field (DVF) from a free-form deformable image registration (DIR). The DVH(3.5D) (for the 3.5DCT plan) was compared with both iDVH(4D) and DVH(4D). To quantify the DVH difference between the 3.5DCT plan and the 4DCT plan, two methods were used: relative difference (%) of the areas underneath the DVH curves and the volumes receiving more than 20% (V20) and 50% (V50) of prescribed dose of these 4D plans. The volume of the delineated GTV from different phase CTs varied dramatically from 24% to 112% among the five patients, whereas the GTV from 3.5DCT deviated from the averaged GTV in 4DCT by only -6%+/ 6%. For planning tumor volume (PTV) coverage, the difference between the DVH(3.5D) and iDVH(4D) was negligible (<1% area), whereas the DVH(3.5D) and DVH(4D) were quite different, due to DIR uncertainty (~2 mm), which propagates to PTV dose coverage with a pronounced uncertainty for small tumors (0.3-4.0 cm(3)) in stereotactic plans with sharp dose falloff around PTV. For OARs, such as the lung, heart, cord and esophagus, the three DVH curves (DVH(3.5D), DVH(4D) and iDVH(4D)) were found to be almost identical for the same patients, especially in high-dose regions. For the tumor-containing lung, the relative difference of the areas underneath the DVH curves was found to be small (5.3% area on average), of which 65% resulted from the low-dose region (D < 20%). The averaged V20 difference between the two 4D plans was 1.2% +/- 0.8%. For the mean lung dose (MLD), the 3.5DCT plan differed from the 4DCT plan by -1.1%+/-1.3%. GTV-motion compensated CT (3.5DCT) produces an accurate and reliable GTV delineation, which is close to the mean GTV from 4DCT. The 3.5DCT plan is equivalent to the 4DCT plan with <1% dose difference to the PTV and negligible dose difference in OARs. The 3.5DCT approach simplifies 4D planning and provides accurate dose calculation without a substantial increase of clinical workload for motion-tracking delivery to treat small peripheral lung tumors with large motion. PMID- 23103416 TI - Changes in task-extrinsic context do not affect the persistence of long-term cumulative structural priming. AB - We present two experiments exploring the role of extrinsic memory factors (i.e., factors that are extrinsic to the primary task that is being performed) and intrinsic memory factors (i.e., factors that are intrinsic to the primary task being completed) in the persistence of cumulative structural priming effects. Participants completed a two-phase experiment, where the first phase established a bias toward producing either the double object or prepositional object construction, and the second phase assessed the effects of this bias. Extrinsic memory factors were manipulated by having participants complete the two phases of the study in the same or different locations (physical context change) or while watching the same or different videos (video context change). Participants completed the second phase of the study 10 min after the first phase of the study in Experiment 1, and after a delay of 1 week in Experiment 2. Results suggest that the observed structural priming effects were not affected by manipulations of extrinsic memory factors. These data suggest that explicit memory does not play a large role in the long-term persistence of cumulative structural priming effects. PMID- 23103417 TI - Thrombin regulation of synaptic transmission: implications for seizure onset. AB - Seizures are a common outcome of cerebrovascular events as well as of traumatic brain injuries. Thrombin, a protease-activated receptor (PAR) agonist, has been implicated in the onset of seizures in these settings, yet its mode of action is not entirely clear. In this study, the effect of thrombin and a PAR-1 agonist on neuronal excitability and synaptic currents was assessed by whole cell-patch recordings of pyramidal neurons in rat hippocampal slices. In addition, PAR-1 distribution in different hippocampal regions was assessed using immunohistochemistry. We found that thrombin caused an increase in spontaneous action potential discharges of CA3 but not of CA1 pyramidal neurons. When excitatory synaptic activity was blocked, thrombin caused a marked reduction in spontaneous IPSCs in CA3 neurons and a marked increase in the frequency of IPSCs in CA1 neurons. These effects are likely to be local, as they were reproduced in TTX-treated slices. In parallel, thrombin increased both the frequency and the amplitude of mEPSCs only in CA3 neurons. These effects were blocked by a selective PAR-1 antagonist. The higher expression of PAR-1 in stratum lucidum of CA3 is correlated with the effects of thrombin in this region. These results suggest that thrombin triggers the generation of epileptic seizures by reducing the inhibitory and increasing the excitatory tone in CA3 neurons, providing a novel insight to the pathophysiology of seizures following cerebrovascular events and present new avenues for therapeutic intervention. PMID- 23103419 TI - CACNA1A variants may modify the epileptic phenotype of Dravet syndrome. AB - Dravet syndrome is an intractable epileptic syndrome beginning in the first year of life. De novo mutations of SCN1A, which encode the Na(v)1.1 neuronal voltage gated sodium channel, are considered the major cause of Dravet syndrome. In this study, we investigated genetic modifiers of this syndrome. We performed a mutational analysis of all coding exons of CACNA1A in 48 subjects with Dravet syndrome. To assess the effects of CACNA1A variants on the epileptic phenotypes of Dravet syndrome, we compared clinical features in two genotype groups: 1) subjects harboring SCN1A mutations but no CACNA1A variants (n=20) and 2) subjects with SCN1A mutations plus CACNA1A variants (n=20). CACNA1A variants detected in patients were studied using heterologous expression of recombinant human Ca(v)2.1 in HEK 293 cells and whole-cell patch-clamp recording. Nine CACNA1A variants, including six novel ones, were detected in 21 of the 48 subjects (43.8%). Based on the incidence of variants in healthy controls, most of the variants seemed to be common polymorphisms. However, the subjects harboring SCN1A mutations and CACNA1A variants had absence seizures more frequently than the patients with only SCN1A mutations (8/20 vs. 0/20, p=0.002). Moreover, the former group of subjects exhibited earlier onset of seizures and more frequent prolonged seizures before one year of age, compared to the latter group of subjects. The electrophysiological properties of four of the five novel Ca(v)2.1 variants exhibited biophysical changes consistent with gain-of-function. We conclude that CACNA1A variants in some persons with Dravet syndrome may modify the epileptic phenotypes. PMID- 23103418 TI - Role of glutamic acid decarboxylase 67 in regulating cortical parvalbumin and GABA membrane transporter 1 expression: implications for schizophrenia. AB - Markers of GABA neurotransmission are altered in multiple regions of the neocortex in individuals with schizophrenia. Lower levels of glutamic acid decarboxylase 67 (GAD67) mRNA and protein, which is responsible for most cortical GABA synthesis, are accompanied by lower levels of GABA membrane transporter 1 (GAT1) mRNA. These alterations are thought to be most prominent in the parvalbumin (PV)-containing subclass of interneurons, which also contain lower levels of PV mRNA. Since GAT1 and PV each reduce the availability of GABA at postsynaptic receptors, lower levels of GAT1 and PV mRNAs have been hypothesized to represent compensatory responses to an upstream reduction in cortical GABA synthesis in schizophrenia. However, such cause-and-effect hypotheses cannot be directly tested in a human illness. Consequently, we used two mouse models with reduced GAD67 expression specifically in PV neurons (PV(GAD67+/-)) or in all interneurons (GABA(GAD67+/-)) and quantified GAD67, GAT1 and PV mRNA levels using methods identical to those employed in studies of schizophrenia. Cortical levels of PV or GAT1 mRNAs were not altered in PV(GAD67+/-) mice during postnatal development or in adulthood. Furthermore, cellular analyses confirmed the predicted reduction in GAD67 mRNA, but failed to show a deficit in PV mRNA in these animals. Levels of PV and GAT1 mRNAs were also unaltered in GABA(GAD67+/-) mice. Thus, mouse lines with cortical reductions in GAD67 mRNA that match or exceed those present in schizophrenia, and that differ in the developmental timing and cell type-specificity of the GAD67 deficit, failed to provide proof-of concept evidence that lower PV and GAT1 expression in schizophrenia are a consequence of lower GAD67 expression. Together, these findings suggest that the correlated decrements in cortical GAD67, PV and GAT1 mRNAs in schizophrenia may be a common consequence of some other upstream factor. PMID- 23103420 TI - High t-PA release by neonate brain microvascular endothelial cells under glutamate exposure affects neuronal fate. AB - Glutamate excitotoxicity is a consolidated hypothesis in neonatal brain injuries and tissue plasminogen activator (t-PA) participates in the processes through proteolytic and receptor mediated effects. In brain microvascular endothelial cell (nBMEC) cultures from neonates, t-PA content and release upon glutamate are higher than in adult (aBMECs) cultures. Owing to the variety of t-PA substrates and receptor targets, the study was aimed at determining the putative roles of endothelial t-PA in the neonatal brain parenchyma under glutamate challenge. Basal t-PA release was 4.4 fold higher in nBMECs vs aBMECs and glutamate was 20 fold more potent to allow Evans blue vascular permeability in neonate microvessels indicating that, under noxious glutamate (50 MUM) exposure, high amounts of endothelial t-PA stores may be mobilized and may access the nervous parenchyma. Culture media from nBMECS or aBMECs challenged by excitotoxic glutamate were applied to neuron cultures at DIV 11. While media from adult cells did not evoke more LDH release in neuronal cultures that under glutamate alone, media from nBMECs enhanced 2.2 fold LDH release. This effect was not observed with media from t-PA(-/-) nBMECs and was inhibited by hr-PAI-1. In Cortical slices from 10 day-old mice, hrt-PA associated with glutamate evoked neuronal necrosis in deeper (more mature) layers, an effect reversed by NMDA receptor GluN1 amino-terminal domain antibody capable of inhibiting t-PA potentiation of the receptor. In superficial layers (less mature), hrt-PA alone inhibited apoptosis, an effect reversed by the EGF receptor antagonist AG1478. Applied to immature neurons in culture (DIV5), media from nBMEC rescued 85.1% of neurons from cell death induced by serum deprivation. In cortical slices, the anti apoptotic effect of t-PA fitted with age dependent localization of less mature neurons. These data suggest that in the immature brain, propensity of vessels to release high amounts of t-PA may not only impact vascular integrity but may also influence neuronal fate, via regulation of apoptosis in immature cells and, as in adult by potentiating glutamate toxicity in mature neurons. The data point out putative implication of microvessels in glutamate neurotoxicity in the development, and justify research towards vessel oriented neuroprotection strategies in neonates. PMID- 23103421 TI - Extravascular hemolysis mimicking severe obstructive jaundice. PMID- 23103422 TI - [Errors of red cell concentrates recipients: method of analysis using the adverse events notified to the hemovigilance network in 2009]. AB - CONTEXT: Among the adverse events in the blood transfusion process, transfusion to a "wrong" patient is potentially dangerous, as it can lead to an adverse reaction at least in case of ABO incompatible red cell concentrate. MATERIAL AND METHODS: The "Root Cause Analysis" working party of the National Hemovigilance Commission developed a tool to collect this type of adverse event, and tested it on a sample of 43 cases involving red cell concentrates notified between March, 2009 and February, 2010. RESULTS: One hundred and nine failures of a step in the transfusion process were observed, i.e. 2.5 failures per adverse event. Failures may occur early in the process. However, they are mainly found at the time of issuing of the blood component, and further, in the clinical ward. How the failure is eventually detected is not always described when the blood component has been fully transfused, in contrast with the cases where actual transfusion to the wrong patient has been prevented. Knowing the way of failure detection enables an objective approach of the efficacy of the numerous existing safety measures. In this sample, bedside controls (documents check as well as the use of anti-A and anti-B reagents with patient's blood and red cell concentrates) detected the failure in three cases out of 34, which were not detected before, showing an efficacy similar to the administrative control done at reception in the clinical ward. CONCLUSION: The document, set up to analyse step by step these cases of patient errors, will be used in the future to analyse all similar cases, not only with red cell concentrates, but also with platelet concentrates and fresh frozen plasma, ultimately in order to improve their prevention. PMID- 23103423 TI - [Prevalence of platelet-specific antibodies in the recipients of platelet units with transfusion adverse event]. AB - PURPOSE OF THE STUDY: In practice, platelet transfusions are frequently performed in patients with haematologic and/or oncologic diseases. Subsequent to these transfusions, platelet specific antibodies may develop and could induce adverse events, such as platelet transfusion refractoriness or post-transfusion purpura. In order to evaluate the prevalence of platelet specific antibodies in these recipients, adverse events with a request for platelet specific antibodies testing, were studied. PATIENTS AND METHODS: Recipients of platelet units with adverse event, excluding platelet transfusion refractoriness or post-transfusion purpura, were evaluated. RESULTS: From January 1st 2009 to October 31st 2011, 125 adverse events with platelet specific antibodies screening, corresponding to 116 recipients (64 females, 52 males) were included. The main aetiology of the adverse event was a febrile non-haemolytic transfusion reaction in 62 cases (49.6%) and allergy in 40 (32.0%). Most samples tested were post-transfusion solely (101 adverse events, 80.8%). Seven of these samples had free platelet specific antibodies, including four anti-HPA-5b, one anti-HPA-2a and two anti GPIaIIa. In the cross-match test, platelet specific antibodies were found in two pre-transfusion samples (anti-GP IaIIa) and in five post-transfusion samples (anti-GPIaIIa, three cases; anti-GP IbIX, one case; anti-GP IIbIIIa and -GPIbIX, one case). CONCLUSION: According to this study on platelet transfusion related adverse event, few platelet specific antibodies were detected on pre- and post transfusion samples. The implementation of platelet specific antibodies testing before transfusion would give more accurate data and help prevent adverse events as typed platelets would be given when platelet specific antibodies were found. PMID- 23103424 TI - [Red blood cell immunization in haemoglobinopathie: about 84 cases]. AB - AIMS: To estimate the rate of red cell immunization in hemoglobinopathies. PATIENTS AND METHODS: Prospective study (1990-2009) about 84 patients: 44 homozygous sickle cell anemia, one heterozygous sickle cell anemia S/C, 30 thalassemia and nine sickle cell anemia-thalassemia. The mean age was 10.13 years (extremes: 1-45). The red cell units transfused were ABORH1 compatible, then RH KELL phenotyped after 2006 and phenocompatible after alloimmunisation. The cross match was realized using indirect antiglobuline test. Irregular red cell antibody screening was realized before every transfusional episode and the direct antiglobuline test was done when there was a poor transfusional efficiency. RESULTS: The number of red blood cells units transfused was 3545 (42.2/patient). The number of red cell antibody screening and the number of direct antiglobulin test were respectively 1474 (17.5/patient) and 272 (3.2/patient). Twenty-seven antibodies were identified (32.1%): 14 alloantibodies (16.6%, 16.6% in sickle cell disease, 16.6% in thalassemia, P=1), 16 antoantibodies (19.04%, 11.1% in sickle cell disease, 33.3% in thalassemia, P=0.018). There were three cases of association of allo- and autoantibodies. The most frequent alloantibodies were anti-RH3 and anti-KEL1 and were developed after transfusion of standard red cell units. There was no significant relation, neither between sex and risk of immunization, nor between the number of red cell units transfused and alloimmunization. On the other hand, there was a significant relation between autoimmunization and the number of red cell units transfused in thalassemia (P<0.001). CONCLUSION: This study proves the interest of using RH-KELL red cell units compatible in patients with hemoglobinopathies in order to reduce alloimmunisation rates. PMID- 23103425 TI - A model-based approach to select case sites for walkability audits. AB - Walkability audits provide valuable information about pedestrian environments, but are time-consuming and can be expensive to implement. In this paper, we propose a model-based approach to select sites for conducting walkability audits. The key idea is to estimate a model of travel behavior at the meso-scale level, which can be examined to identify locations where the behavior is under- and over estimated. We conjecture that systematic under- and over-estimation can be caused by micro-level factors that influence the behavior. The results can be used to identify sites for walkability audits. The approach is demonstrated with a case study in Hamilton, Canada. A model of walk shares forms the basis of the site selection procedure. After identifying areas with higher and lower shares than predicted by the model we select a sample of neighborhoods for audits. Analysis of the results reveals elements of the local environment that associate with greater-than-expected walk shares. The case study demonstrates that the proposed model-based strategy can be used to better target limited resources, and produce valuable insights into micro-level factors that affect travel behavior. PMID- 23103426 TI - Mitochondrial electron transfer chain complexes inhibition by different organochalcogens. AB - Mitochondrial dysfunction plays a pivotal role in the cell toxicology and death decision. The aim of the present study was to investigate the effect of three organocompounds (ebselen [Ebs], diphenyl diselenide [(PhSe)(2)] and diphenyl ditelluride [(PhTe)(2)]) on mitochondrial complexes (I, II, I-III, II-III and IV) activity from rat liver and kidney to determine their potential role as molecular targets of organochalcogens. All studied organochalcogens caused a statistically significant inhibition of the mitochondrial complex I activity. Ebs and (PhTe)(2) caused a statistically significant inhibition of the mitochondrial complex II activity in both hepatic and renal membranes. Hepatic mitochondrial complex II activity was practically unchanged by (PhSe)(2), whereas it significantly inhibited renal complex II activity. Mitochondrial complex IV activity was practically unchanged by the organochalcogens. Furthermore, organochalcogens inhibited the mitochondrial respiration supported by complex I or complex II substrates. The inhibitory effect of Ebs, (PhSe)(2) and (PhTe)(2) on mitochondrial complex I was prevented by NADH, but it was not prevented by catalase (CAT) and/or superoxide dismutase (SOD). Additionally, the organochalcogens-induced inhibition of complex I and II was completely reversed by reduced glutathione (GSH). In conclusion, Ebs, (PhSe)(2) and (PhTe)(2) were more effective inhibitors of renal and hepatic mitochondrial complex I than complex II, whereas complexes III and IV were little modified by these compounds. Taking into account the presented results, we suggest that organochalcogen induced mitochondrial complexes I and II inhibition can be mediated by their thiol oxidation activity, i.e., Ebs, (PhSe)(2) and (PhTe)(2) can oxidize critical thiol groups from mitochondrial complexes I and II. So, mitochondrial dysfunction can be considered an important factor in the toxicity of Ebs, (PhSe)(2) and (PhTe)(2). PMID- 23103427 TI - RAGE in tissue homeostasis, repair and regeneration. AB - RAGE (receptor for advanced glycation end-products) is a multiligand receptor of the immunoglobulin superfamily involved in inflammation, diabetes, atherosclerosis, nephropathy, neurodegeneration, and cancer. Advanced glycation end-products, high mobility group box-1 (amphoterin), beta-amyloid fibrils, certain S100 proteins, and DNA and RNA are RAGE ligands. Upon RAGE ligation, adaptor proteins (i.e., diaphanous-1, TIRAP, MyD88 and/or other as yet unidentified adaptors) associate with RAGE cytoplasmic domain resulting in signaling. However, RAGE activation may not be restricted to pathological statuses, the receptor being involved in tissue homeostasis and regeneration/repair upon acute injury, and in resolution of inflammation. RAGE effects are strongly dependent on the cell type and the context, which may condition therapeutic strategies aimed at reducing RAGE signaling. PMID- 23103428 TI - Characterization of a chimeric antimicrobial peptide uncovers evolutionary significance of exon-shuffling. AB - The abaecin family comprises a class of proline-rich antimicrobial peptides (AMPs) with restricted distribution in hymenopteran insects. Intriguingly, in the parasitic wasp Nasonia vitripennis its members (termed nabaecin-1 to -3) have gained a carboxyl terminal glycine-rich antimicrobial unit through exon shuffling. Here, we describe cDNA cloning of nabaecin-3 and the donor gene (navitripenicin) of the shuffling, and structural and functional features of nabaecin-3 and its two domains (respectively called amino-terminal abaecin unit (NtAU) and carboxyl-terminal navitripenicin unit (CtNU)). Nabaecin-3 and navitripenicin were found to be transcriptionally up-regulated in response to bacterial challenge. By using recombinant expression and chemical synthesis techniques, we produced nabaecin-3, NtAU and CtNU. Circular dichroism (CD) analyses show that these peptides remarkably differ in their structures. Functionally, nabaecin-3 displayed a wide spectrum of antimicrobial activity against an array of bacteria, yeasts and fungi at micromolar concentrations, while CtNU only had a weak antibacterial activity and NtAU completely lacked activity. Our results indicate that in Nasonia the antimicrobial function of abaecin depends on the combination of NtAU with CtNU and thus suggest a new role of exon-shuffling in buffering loss-of-function mutation of a gene. PMID- 23103429 TI - Reported eating ability of young children with cerebral palsy: is there an association with gross motor function? AB - OBJECTIVE: To examine the association between parent-reported ability of young children with cerebral palsy (CP) to eat different food textures and gross motor functional abilities. DESIGN: Prospective, longitudinal, representative cohort study. SETTING: Community and tertiary pediatric hospital settings. PARTICIPANTS: Children (N=170; 110 boys [65%]) were assessed on 396 occasions (range, 1-4 occasions), including 67 at 1 year 6 months (49 boys), 99 at 2 years (66 boys), 111 at 2 years 6 months (71 boys), and 119 at 3 years (64 boys). INTERVENTIONS: Not applicable MAIN OUTCOME MEASURES: Gross motor function was determined using the Gross Motor Function Classification System (GMFCS). Parent-reported eating ability was determined using 4 items of the Pediatric Evaluation of Disability Inventory. The association between capability to eat food textures and GMFCS level was examined using generalized estimating equations. RESULTS: The distribution of GMFCS levels at initial presentation was as follows: I, n=62; II, n=32; III, n=24; IV, n=22; and V, n=30. Reported capability to eat cut-up/chunky and "all textures" of table foods decreased significantly as GMFCS level increased. A decreased capability to eat pureed/blended and ground/lumpy foods compared with GMFCS I was significantly associated with GMFCS levels IV and V only. CONCLUSIONS: Reported attainment of eating skills was closely associated with GMFCS level in young children with CP across age levels. These results emphasize the need for early oral-motor and feeding screening in young children with CP across gross motor functional abilities. PMID- 23103430 TI - Effect of singing on respiratory function, voice, and mood after quadriplegia: a randomized controlled trial. AB - OBJECTIVE: To explore the effects of singing training on respiratory function, voice, mood, and quality of life for people with quadriplegia. DESIGN: Randomized controlled trial. SETTING: Large, university-affiliated public hospital, Victoria, Australia. PARTICIPANTS: Participants (N=24) with chronic quadriplegia (C4-8, American Spinal Injury Association grades A and B). INTERVENTIONS: The experimental group (n=13) received group singing training 3 times weekly for 12 weeks. The control group (n=11) received group music appreciation and relaxation for 12 weeks. Assessments were conducted pre, mid-, immediately post-, and 6 months postintervention. MAIN OUTCOME MEASURES: Standard respiratory function testing, surface electromyographic activity from accessory respiratory muscles, sound pressure levels during vocal tasks, assessments of voice quality (Perceptual Voice Profile, Multidimensional Voice Profile), and Voice Handicap Index, Profile of Mood States, and Assessment of Quality of Life instruments. RESULTS: The singing group increased projected speech intensity (P=.028) and maximum phonation length (P=.007) significantly more than the control group. Trends for improvements in respiratory function, muscle strength, and recruitment were also evident for the singing group. These effects were limited by small sample sizes with large intersubject variability. Both groups demonstrated an improvement in mood (P=.002), which was maintained in the music appreciation and relaxation group after 6 months (P=.017). CONCLUSIONS: Group music therapy can have a positive effect on not only physical outcomes, but also can improve mood, energy, social participation, and quality of life for an at-risk population, such as those with quadriplegia. Specific singing therapy can augment these general improvements by improving vocal intensity. PMID- 23103431 TI - Preliminary prediction model for fear-induced activity limitation after total knee arthroplasty in people 60 years and older: prospective cohort study. AB - OBJECTIVES: To assess the presence of fear-induced activity limitation (FIAL) in a sample of patients 1 year after total knee arthroplasty (TKA), and to develop a preliminary prediction model to predict the risk of FIAL. DESIGN: Prospective cohort study. SETTING: A tertiary teaching hospital. PARTICIPANTS: Patients (N=72; mean age, 70+/-6y) undergoing primary, unilateral TKA participated. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Preoperative candidate predictors were age, sex, body mass index, previous falls history, number of comorbidities, self-report physical function, gait speed, knee range of motion, knee pain, and standing balance. Outcome measure at 1-year follow-up was the level of FIAL, measured by the Survey of Activities and Fear of Falling in the Elderly. RESULTS: Thirty-one patients (41%; 95% confidence interval, .31-.55) had FIAL, of whom 15 had moderate to severe FIAL. Multivariable predictors of FIAL included preoperative habitual gait speed and velocity of postural sway in the anterior-posterior axis. A 2-variable nomogram-based prediction model was constructed, and this model showed moderately good discrimination (optimism corrected c-index, .76) and adequate calibration. CONCLUSIONS: In our sample of patients with TKA, FIAL is common, and early identification of patients at risk of FIAL would bring them into appropriate modes of preventive care. Our prediction model shows some promise in identifying patients with FIAL, but prospective validation studies are needed. PMID- 23103432 TI - Demand on Medicaid slows in 2012 as economy improves. PMID- 23103433 TI - Structure-dependent interatomic dispersion coefficients in oxides with maximally localized Wannier functions. AB - The interatomic C(6) dispersion coefficients in crystalline and amorphous SiO(2) and ZrO(2) structures were obtained with the approach proposed by Silvestrelli (2008 Phys. Rev. Lett. 100 053002) and based on the use of maximally localized Wannier functions (MLWFs) for partitioning the electron density. Localization of Wannier functions close to the nuclei in oxide systems makes it possible to assign the MLWFs to the atoms in an unambiguous way and then to compute the C(6) coefficients in an atom pairwise manner. A modification of the method is suggested in which the MLWFs are condensed to effective orbitals centred on the atoms and parameters of these effective orbitals are used for computing the interatomic dispersion coefficients. The obtained values of the dispersion coefficients were found to vary not only from one oxide to another, but also between different modifications of the same compound. The oxygen-oxygen coefficient C6(OO) reveals the largest variation and its value in ZrO(2) structures is twice as large as that in SiO(2) ones. Atomic characteristics obtained in the frame of the effective orbital method, such as the self-atom dispersion coefficient, and the oxide ion polarizability were found to correlate with the metal-oxygen bond length and the oxygen coordination number in the systems. This behaviour is attributed to the confinement of electrons by the electrostatic potential. The values of the coefficient and of the polarizability were related to charges of the oxygen atoms. In all studied systems the oxygen atoms having larger absolute values of charge were found to be less polarizable because of a stronger confinement effect. The obtained results can be used in the development of polarizable force fields for the atomistic modelling of oxide materials. PMID- 23103434 TI - Success, failure, and putative mechanisms in hypothalamic stimulation for drug resistant chronic cluster headache. AB - Drug-resistant chronic cluster headache (CH) is an unremitting illness with excruciatingly severe headaches that occur several times daily. Starting in 2000, a total of 19 patients with long-lasting chronic CH, with multiple daily attacks unresponsive to all known prophylactics, received stimulation of the posterior inferior hypothalamic area ipsilateral to the pain as treatment. We report long term follow-up (median 8.7 years, range 6-12 years) in 17 patients. Long-lasting improvement occurred in 70% (12 of 17): 6 are persistently almost pain-free; another 6 no longer experience daily attacks but rather episodic CH interspersed with long-lasting remissions. In 5 of 6 almost pain-free patients, the stimulators have been off for a median of 3 years (range 3-4 years). Five patients did not improve: 4 had bilateral CH, and 3 developed tolerance after experiencing relief for 1-2 years. Adverse events are electrode displacement (n=2), infection (electrode n=3; generator n=1), electrode malpositioning (n=1), transient nonsymptomatic third ventricle hemorrhage (n=1), persistent slight muscle weakness on one side (n=1), and seizure (n=1). This exceptionally long follow-up shows that hypothalamic stimulation for intractable chronic CH produces long-lasting improvement in many patients. Previous experience was limited to a median of 16 months. Important new findings are as follows: stimulation is well tolerated for many years after implantation; after several years during which stimulation was necessary for relief, a persistent almost pain-free condition can be maintained when stimulation is off, suggesting that hypothalamic stimulation can change disease course; tolerance can occur after marked long-lasting improvement; and bilateral chronic CH seems to predict poor response to hypothalamic stimulation. PMID- 23103435 TI - A longitudinal analysis of the development of infant facial expressions in response to acute pain: immediate and regulatory expressions. AB - Facial expressions during infancy are important to examine, as infants do not have the language skills to describe their experiences. This is particularly vital in the context of pain, where infants depend solely on their caregivers for relief. The objective of the current study was to investigate the development of negative infant facial expressions in response to immunization pain over the first year of life. Infant facial expressions were examined longitudinally using a subsample of 100 infants that were each videotaped during their 2-, 4-, 6-, and 12-month routine immunization appointments. Infant facial expressions were coded using BabyFACS (facial action coding system) for the first minute after a painful needle prick. Facial expressions were examined with a catalogue of the most commonly occurring facial expressions. Results demonstrated that clear differences were seen over ages. Infants display a variety of facial expressions with some of the components of adult pain expressions immediately after the needle and they abate shortly after. However, infants did not display adult expressions of discrete negative emotions. Instead, infants displayed a variety of generalized pain and distress faces aimed at gaining caregiver aid. The development of nonverbal communication in infants, particularly facial expressions, remains an important area of inquiry. Further study into accurately measuring infant negative emotions, pain, and distress is warranted. PMID- 23103436 TI - Resident glial cell activation in response to perispinal inflammation leads to acute changes in nociceptive sensitivity: implications for the generation of neuropathic pain. AB - Injury or disease affecting the spinal cord is often accompanied by abnormal, chronic pain. Recent estimates suggest that approximately 60% of patients with multiple sclerosis are affected by significant changes in pain sensitivity or experience ongoing neuropathic pain of unknown etiology. Chronic pain is also a significant concern after direct spinal cord trauma. Inflammatory events and the changes in astrocyte and microglia reactivity at the spinal level in response to injury or disease are now recognized as important processes that can initiate pain hypersensitivity. Changes in the structural integrity or permeability of the blood-brain barrier/blood-spinal cord barrier (BBB/BSCB) can facilitate the inflammatory events that result in these abnormal pain states. It remains unclear, however, whether chronic pain in these disorders is dependent on the influx of peripheral leukocytes or whether changes in the reactivity of resident glial cells within the central nervous system alone are sufficient. To address this question, we generated a model of perispinal inflammation that resulted in significant changes in the reactivity of resident astrocytes and microglia within the spinal cord but maintained the integrity of the BSCB. A number of similar changes at the behavioural and cellular level occur in this model that mimic the responses seen in animal models of multiple sclerosis or spinal cord injury (SCI). However, these changes are short lived and resolve over the course of a 2 week observation period. Our findings suggest that the chronicity of pain after injury or disease in the nervous system is dependent on the integrity of the BBB/BSCB. PMID- 23103437 TI - Significant correlation of P-wave parameters with left atrial volume index and left ventricular diastolic function. AB - BACKGROUND: The 12-lead electrocardiogram (ECG) is a commonly used tool to access left atrial enlargement, which is a marker of left ventricular diastolic dysfunction (LVDD). The aim of this study was to evaluate any association of the P-wave measurements in ECG with left atrial volume (LAV) index and LVDD. METHODS: This study enrolled 270 patients. In this study, 4 ECG P-wave parameters corrected by heart rate, that is, corrected P-wave maximum duration (PWdurMaxC), corrected P-wave dispersion (PWdisperC), corrected P-wave area (PWareaC) and corrected mean P-wave duration (meanPWdurC), were measured. LAV and left ventricular diastolic parameters were measured from echocardiography. LVDD was defined as a pseudonormal or restrictive mitral inflow pattern. RESULTS: The 4 P wave parameters were significantly correlated with the LAV index after adjusting for age, sex, diabetes, hypertension, coronary artery disease, body mass index and diastolic blood pressure in multivariate analysis. The standardized beta coefficients of PWdurMaxC, PWdisperC, meanPWdurC and PWareaC were 0.338, 0.298, 0.215 and 0.296, respectively. The 4 P-wave parameters were also significantly correlated with LVDD after multivariate logistic regression analysis. The odds ratios (95% confidence intervals) of PWdurMaxC, PWdisperC, meanPWdurC and PWareaC were 1.03 (1.01-1.04), 1.02 (1.04-1.04), 1.04 (1.02-1.07) and 1.01 (1.00-1.02), respectively. CONCLUSIONS: This study demonstrated that PWdurMaxC, PWdisperC, meanPWdurC and PWareaC were important determinants of the LAV index and LVDD. Therefore, screening patients by means of the 12-lead ECG may be helpful in identifying a high-risk group of increased LAV index and LVDD. PMID- 23103438 TI - Sudden cardiac arrest in a patient on chronic methadone after the addition of azithromycin. AB - Corrected QT-interval (QTc) prolongation with increased risk of fatal arrhythmia is a well-established toxicity of methadone. In this study, a case of sudden cardiac arrest in a patient on chronic methadone therapy is presented. A 47-year old man presented unresponsive to the emergency department after pulseless arrest at his home. The patient's wife revealed he was taking methadone as part of an ongoing opioid dependency treatment and that he was prescribed azithromycin for an upper respiratory tract infection 3 days before his presentation. A 12-lead electrocardiogram at the time of presentation showed sinus tachycardia and a QTc of 490 milliseconds. It was concluded that the patient experienced a fatal arrhythmia because of QTc prolongation, precipitated by azithromycin in the setting of ongoing methadone use. PMID- 23103439 TI - Detection of anti-PLA2R autoantibodies and IgG subclasses in post-allogeneic hematopoietic stem cell transplantation membranous nephropathy. AB - BACKGROUND: Membranous nephropathy (MN) is the most common glomerular disease of post-allogeneic hematopoietic stem cell transplantation (HSCT). Although this condition is now considered a renal complication of chronic graft-versus-host disease (cGVHD), the pathogenesis of this disease is not well established. METHODS: Five patients with post-HSCT MN diagnosed by renal biopsy were selected for this study. The clinical and renal pathological data of these patients were analyzed, and anti-PLA2R (M-type phospholipase A2 receptor) autoantibodies and IgG subclasses were detected in the serum samples from the patients. RESULTS: None of the 5 patients had a history of kidney disease. All the patients had a combination of cGVHD and proteinuria, which was in remission after an effective anti-graft-versus-host disease treatment. The immunofluorescent detection showed that IgG4 was the predominant IgG subclass, and the distribution of IgG4 was the same as that of nephrin. The anti-PLA2R autoantibodies were negative in 4 patients and positive in 1 patient. The levels of IgG2, IgG3 and IgG4 increased in the majority of the patients. CONCLUSIONS: Our data showed that the clinical course of post-HSCT MN patients was closely related to that of cGVHD. Although the renal pathology was similar to idiopathic MN, the negative result for the anti-PLA2R autoantibodies in the majority of the patients suggested that the formation of an immune complex occurs differently between these 2 diseases. PMID- 23103440 TI - Risk of vancomycin-induced nephrotoxicity in the population with chronic kidney disease. AB - The antibiotic vancomycin has been available since the 1950s but has been used more commonly since the early 1980s because of the widespread appearance of methicillin-resistant Staphylococcus aureus. Infectious Diseases Society of America guidelines recommend achieving vancomycin trough levels of 10 to 20 MUg/mL. Usage of vancomycin in high dosages especially >= 4 g/d has led to an increase in the incidence of vancomycin-induced nephrotoxicity, particularly in patients with chronic kidney disease (CKD). This review focuses on the impact of vancomycin-induced nephrotoxicity in patients with CKD. Patients with CKD are at increased risk of developing acute kidney injury and subsequently requiring renal replacement therapy. There is substantial need for vancomycin pharmacokinetic studies to be performed in the population with CKD to develop an optimum vancomycin nomogram in these patients. At present, tight monitoring of vancomycin trough levels in the population with CKD is recommended to help prevent acute kidney injury and its associated high morbidity, mortality and health care costs. PMID- 23103441 TI - One decade of salivary proteomics: current approaches and outstanding challenges. AB - Efforts have been made in the last decade towards the complete characterization of saliva proteome using gel-based and gel-free approaches. The combination of these strategies resulted in the increment of the dynamic range of saliva proteome, which yield in the identification of more than 3,000 different protein species. Comparative protein profiling using isotope labeling and label free approaches has been used for the identification of novel biomarkers for oral and related diseases. Although progresses have been made in saliva proteome characterization, the comparative profiling in different pathophysiological conditions is still at the beginning if compared to other bodily fluids. The potential biomarkers identified so far lack specificity once common differentially expressed proteins were detected in the saliva of patients with distinct diseases. In addition, recent research works focused on saliva peptidome profiling already allowed a better understanding of peptides' physiological role in oral cavity. This review provides an overview of the major achievements in saliva proteomics giving emphasis to methodological concerns related with saliva collection, treatment and analysis, as well as the main advantages and pitfalls underlying salivary proteomic strategies and potential clinical outcomes. PMID- 23103442 TI - Spectral differences in 6 MV beams with matched PDDs and the effect on chamber response. AB - The Australian Radiation Protection and Nuclear Safety Agency (ARPANSA) has installed an Elekta Synergy platform linac to establish a direct megavoltage primary standard calibration service, instead of relying on calibrations derived from (60)Co. One of the 6 MV beams of the ARPANSA linac has been approximately matched to the Varian high energy platform 6 MV photon beam. The electron beam energy was adjusted to match the percentage depth dose (PDD) curve and TPR(20,10). This work calculates the error introduced when using a calibration factor from this Elekta Synergy Platform linac on a Varian high-energy platform beam at 6 MV. Monte Carlo models of the Varian and matched Elekta accelerator accurately predict the measured PDDs and profiles, but show significantly different energy spectra, resulting mainly from differences in target thickness between the two accelerators. Monte Carlo modelling of the energy correction factor k(Q) of a secondary standard NE2561 chamber shows a difference of 0.4% between the Varian and the Varian-matched Elekta beams. Although small, this is a significant discrepancy for primary standard calibrations. Similar variations are expected for chambers of similar construction, and additional variations may occur with other linac manufacturers. The work has also investigated the design of a custom flattening filter to precisely match the energy spectrum of the Varian beam on the Elekta platform. PMID- 23103443 TI - The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses following stressor exposure. AB - Exposure to stressors or trauma in the absence of pathogenic challenge can stimulate a systemic sterile inflammatory response characterized by high concentrations of blood and tissue cytokines, chemokines, and danger associated molecular patterns (DAMPs) such as heat shock protein-72 (Hsp72), and uric acid. The signaling pathways responsible for these responses remain unclear, however, the inflammasome may play a role. In vitro, DAMPs are known to stimulate the inflammasome in the presence of LPS to activate caspase-1 which cleaves immature precursors of interleukin (IL)-1beta and IL-18 into their mature releasable forms. Furthermore, in vivo neutralization of the LPS selectively attenuates the stress-induced increase in the inflammasome-dependent cytokines IL-1beta and IL 18. Thus, the current experiments tested the hypothesis that inflammasome mediated processes are necessary for a systemic stress-induced inflammatory response to an acute stressor. The data presented (1) establish that male F344 rats exposed to an acute severe stressor (100 tail shocks) have elevated plasma concentrations of inflammatory proteins (IL-1beta, IL-18, IL-6, IL-10, and monocyte chemotactic protein (MCP)-1), and DAMPs (uric acid and Hsp72); (2) demonstrate that inhibiting caspase-1 in vivo, using the caspase-1 inhibitor ac YVAD-cmk, attenuates stress-induced production of IL-1beta, IL-18, and IL-6 in both the circulation and peripheral tissues; and (3) implicates the DAMPs uric acid and Hsp72 as important signals contributing to inflammasome-dependent inflammatory responses using a stepwise multiple regression. The results increase our mechanistic understanding of systemic sterile inflammatory responses, and provide novel evidence that the inflammasome may be an important pharmacological target for treatment of these conditions. PMID- 23103444 TI - MMP-8 overexpression and persistence of neutrophils relate to stress-impaired healing and poor collagen architecture in mice. AB - Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) are critical for tissue remodeling during wound repair. Psychological stress has been found to impair wound healing in humans and animals. The objective of this study was to assess MMP and TIMP gene expression during stress impaired healing. Female SKH-1 mice (n=299) were divided into control and stress groups (13h restraint/day for 3days prior to and 5days post-wounding). Two 3.5mm cutaneous full-thickness wounds were placed on the dorsum of each mouse and wound measurements were performed daily. RT-PCR for gene expression of MMP-2, MMP-8, MMP-9, TIMP-1 and TIMP-2 was performed at days 1, 3 and 5. Immunohistochemical analyses of the healed wounds were performed at days 15 and 28. As expected, wounds healed more slowly in restraint-stressed mice compared to controls. Stressed mice exhibited MMP-8 overexpression and lower TIMP-1 levels during healing, and poorer collagen organization once healed. MMP-8 overexpression may have stemmed from a higher level of neutrophils, observed in wound tissue on days 3 and 5. These findings implicate higher neutrophil numbers, MMP-8 overexpression, and TIMP-1 under-expression, as mechanisms that may compromise wound outcomes such as scarring under conditions of stress. PMID- 23103445 TI - Placenta-derived adherent cells attenuate hyperalgesia and neuroinflammatory response associated with perineural inflammation in rats. AB - Neuropathic pain is a debilitating condition of the somatosensory system caused by pathology of the nervous system. Current drugs treat symptoms but largely fail to target the underlying mechanisms responsible for the pathological changes seen in the central or peripheral nervous system. We investigated the therapeutic effects of PDA-001, a culture expanded placenta-derived adherent cell, in the rat neuritis model. Pain is induced in the model by applying carrageenan to the sciatic nerve trunk, causing perineural inflammation of the sciatic nerve. PDA 001, at doses ranging from 0.4*10(6) to 4*10(6) cells/animal, or vehicle control was intravenously administrated to assess the biological activity of the cells. A dose-dependent effect of PDA-001 on pain relief was demonstrated. PDA-001 at doses of 1*10(6) and 4*10(6), but not 0.4*10(6), reduced mechanical hyperalgesia within 24h following treatment and through day 8 after induction of neuritis. The mechanism underlying PDA-001-mediated reduction of neuroinflammatory pain was also explored. Ex vivo tissue analyses demonstrated that PDA-001 suppressed homing, maturation and differentiation of dendritic cells, thus inhibiting T-cell priming and activation in draining lymph nodes. PDA-001 also reduced interferon gamma and IL-17 in draining lymph nodes and in the ispilateral sciatic nerve, and increased the levels of IL-10 in draining lymph nodes and plasma, pointing to T cell modulation as a possible mechanism mediating the observed anti-hyperalgesic effects. Furthermore, in the ipsilateral sciatic nerve, significantly less leukocyte infiltration was observed in PDA-001-treated animals. The results suggest that PDA-001may provide a novel therapeutic approach in the management of inflammatory neuropathic pain and similar conditions. PMID- 23103446 TI - Can P-glycoprotein mediate resistance to nilotinib in human leukaemia cells? AB - The effect of P-glycoprotein (P-gp, ABCB1, MDR1) expression on cell resistance to nilotinib was studied in human leukaemia cells. We used K562/Dox cells overexpressing P-gp and their variants (subclones) with a gradually decreased P gp expression. These subclones were established by stable transfection of K562/Dox cells with a plasmid vector expressing shRNA targeting the ABCB1 gene. Functional analysis of P-gp using a specific fluorescent probe indicated gradually decreased dye efflux which was proportional to the P-gp expression. We observed that K562/Dox cells overexpressing P-gp contained a significantly reduced intracellular level of nilotinib when compared to their counter partner K562 cells, which do not express P-gp. This effect was accompanied by a decreased sensitivity of the K562/Dox cells to nilotinib. Importantly, cells with downregulated expression of P-gp gradually lost their ability to decrease the intracellular level of nilotinib although they still significantly decreased the intracellular level of daunorubicin (DNR). Accordingly, cells with the reduced expression of P-gp concomitantly failed to provide resistance to nilotinib, however, they exhibited a significant resistance to DNR. Taken together, we demonstrated that the conclusion as to whether P-gp is involved in nilotinib resistance or not strongly depends on its expression at protein level. PMID- 23103447 TI - [Long-term results of exclusive radiotherapy and brachytherapy of breast cancer]. AB - PURPOSE: To report retrospective long-term results of historical experience of breast radiotherapy (RT) including external beam radiotherapy (EBRT) followed by low dose rate (LDR) brachytherapy. PATIENTS AND METHODS: Between 1971 and 1983, at our service 474 breast cancer patients underwent exclusive conserving radiotherapy treatment. The RT included an initial external irradiation followed by interstitial LDR brachytherapy (37Gy) to the residual tumour. The local regional nodes received 47.5Gy followed by a 15Gy boost delivered to the mammary nodes internal (IMN) and 25Gy axilla. RESULTS: Median follow-up was 139months (8 342). There were 40 T1, 356 T2, and 78 T3. Local recurrences (LR) were observed in 20% of cases. The rate of recurrences free at 5, 10, 15 and 20years were 86%, 77%, 73% and 67% respectively. At 5, 10, 15 and 20-year, the disease-free survival rates were 63%, 42%, 32% and 24%. Overall survival rates at 5, 10, 15 and 20-years were 75%, 53%, 34% and 25% respectively. CONCLUSION: Although the historical retrospective character of these series, it is interesting to have this experience and to analyse it according to our new knowledge and advances. The described technique was a standard for many years and could be still used in some cases. PMID- 23103448 TI - Characterization of the Type III sulfide:quinone oxidoreductase from Caldivirga maquilingensis and its membrane binding. AB - Sulfide:quinone oxidoreductases (SQRs) are ubiquitous enzymes which have multiple roles: sulfide detoxification, energy generation by providing electrons to respiratory or photosynthetic electron transfer chains, and sulfide homeostasis. A recent structure-based classification defines 6 groups of putative SQRs (I-VI), and representatives of all but group III have been confirmed to have sulfide oxidase activity. In the current work, we report the first characterization of a predicted group III SQR from Caldivirga maquilingensis, and confirm that this protein is a sulfide oxidase. The gene encoding the enzyme was cloned, and the protein was expressed in E. coli and purified. The enzyme oxidizes sulfide using decylubiquinone as an electron acceptor, and is inhibited by aurachin C and iodoacetamide. Analysis of the amino acid sequence indicates that the C. maquilingensis SQR has two amphiphilic helices at the C-terminus but lacks any transmembrane helices. This suggests that C. maquilingensis SQR interacts with the membrane surface and that the interactions are mediated by the C-terminal amphiphilic helices. Mutations within the last C-terminal amphiphilic helix resulted in a water-soluble form of the enzyme which, remarkably, retains full SQR activity using decylubiquinone as the electron acceptor. Mutations at one position, L379, also located in the C-terminal amphiphilic helix, inactivated the enzyme by preventing the interaction with decylubiquinone. It is concluded that the C-terminal amphiphilic helix is important for membrane binding and for forming part of the pathway providing access of the quinone substrate to the protein-bound flavin at the enzyme active site. PMID- 23103449 TI - Effects of dehydration on light-induced conformational changes in bacterial photosynthetic reaction centers probed by optical and differential FTIR spectroscopy. AB - Following light-induced electron transfer between the primary donor (P) and quinone acceptor (Q(A)) the bacterial photosynthetic reaction center (RC) undergoes conformational relaxations which stabilize the primary charge separated state P(+)Q(A)(-). Dehydration of RCs from Rhodobacter sphaeroides hinders these conformational dynamics, leading to acceleration of P(+)Q(A)(-) recombination kinetics [Malferrari et al., J. Phys. Chem. B 115 (2011) 14732-14750]. To clarify the structural basis of the conformational relaxations and the involvement of bound water molecules, we analyzed light-induced P(+)Q(A)(-)/PQ(A) difference FTIR spectra of RC films at two hydration levels (relative humidity r=76% and r=11%). Dehydration reduced the amplitude of bands in the 3700-3550cm(-1) region, attributed to water molecules hydrogen bonded to the RC, previously proposed to stabilize the charge separation by dielectric screening [Iwata et al., Biochemistry 48 (2009) 1220-1229]. Other features of the FTIR difference spectrum were affected by partial depletion of the hydration shell (r=11%), including contributions from modes of P (9-keto groups), and from NH or OH stretching modes of amino acidic residues, absorbing in the 3550-3150cm(-1) range, a region so far not examined in detail for bacterial RCs. To probe in parallel the effects of dehydration on the RC conformational relaxations, we analyzed by optical absorption spectroscopy the kinetics of P(+)Q(A)(-) recombination following the same photoexcitation used in FTIR measurements (20s continuous illumination). The results suggest a correlation between the observed FTIR spectral changes and the conformational rearrangements which, in the hydrated system, strongly stabilize the P(+)Q(A)(-) charge separated state over the second time scale. PMID- 23103450 TI - Arsenic trioxide-induced hERG K(+) channel deficiency can be rescued by matrine and oxymatrine through up-regulating transcription factor Sp1 expression. AB - The human ether-a-go-go-related gene (hERG) encodes the rapidly activating, delayed rectifier potassium channel (IKr) important for cardiac repolarization. Dysfunction of the hERG channel can cause Long QT Syndrome (LQTS). A wide variety of structurally diverse therapeutic compounds reduce the hERG current by acute direct inhibition of the hERG current or/and selective disruption of hERG protein expression. Arsenic trioxide (As(2)O(3)), which is used to treat acute promyelocytic leukemia, can cause LQTS type 2 (LQT2) by reducing the hERG current through the diversion of hERG trafficking to the cytoplasmic membrane. This cardiotoxicity limits its clinical applications. Our aim was to develop cardioprotective agents to decrease As(2)O(3)-induced cardiotoxicity. We reported that superfusion of hERG-expressing HEK293 (hERG-HEK) cells with matrine (1, 10 MUM) increased the hERG current by promoting hERG channel activation. Long-term treatment with 1 MUM matrine or oxymatrine increased expression of the hERG protein and rescued the hERG surface expression disrupted by As(2)O(3). In addition, Matrine and oxymatrine significantly shortened action potential duration prolonged by As(2)O(3) in guinea pig ventricular myocytes. These results were ascribed to the up-regulation of hERG at both mRNA and protein levels via an increase in the expression of transcription factor Sp1, an established transactivator of the hERG gene. Therefore, matrine and oxymatrine may have the potential to cure LQT2 as a potassium channel activator by promoting hERG channel activation and increasing hERG channel expression. PMID- 23103451 TI - Correlates of subjective health across the aging lifespan: understanding self rated health in the oldest old. AB - OBJECTIVES: To examine the determinants of self-rated health (SRH) in different age groups of older adults, including the oldest old. METHODS: Variables assessing physical health, difficulty with self-care, depressive symptoms, and cognitive impairment were pooled and harmonized from three Australian longitudinal studies of ageing (N = 5,222). The association of these with SRH was examined in older adults aged 60 to 64 years, 65 to 74 years, 75 to 84 years, and 85 years and older. RESULTS: SRH was not associated with cognitive impairment or difficulty with self-care in the oldest old, and its association with physical health was diminished compared with younger groups. Depression showed a significant relationship in all age groups, conferring an approximately fourfold increase in the likelihood of poorer SRH. DISCUSSION: As old age progresses, self reports of poor health become most closely related to psychological symptoms. This explains some of the paradoxes of past literature and offers important insights for health professionals working with the oldest old. PMID- 23103452 TI - Memory training in the ACTIVE study: how much is needed and who benefits? AB - OBJECTIVE AND METHOD: Data from the memory training arm (n = 629) of the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) trial were examined to characterize change in memory performance through 5 years of follow-up as a function of memory training, booster training, adherence to training, and other characteristics. RESULTS: Latent growth model analyses revealed that memory training was associated with improved memory performance through Year 5 but that neither booster training nor training adherence significantly influenced this effect. Baseline age was associated with change in memory performance attributable to the passage of time alone (i.e., to aging). Higher education and better self-rated health were associated with greater change in memory performance after training. DISCUSSION: These findings confirm that memory training can aid in maintaining long-term improvements in memory performance. Booster training and adherence to training do not appear to attenuate rates of normal age-related memory decline. PMID- 23103454 TI - Reducing health care costs for dementia patients: estimating savings from a caregiver support program. AB - OBJECTIVE: Estimating cost savings based on limited health care events within a short time span for a dementia care program. METHOD: Data on health care utilization of persons with dementia (PWDs) and caregivers were gathered in the Dementia Care Services Program in North Dakota from January 2010 to January 2012. Data were aggregated into 3-month intervals and compared to 3 months before program intervention. Paired and cross-time models were used to estimate cost savings. RESULTS: Health care cost savings for PWDs were estimated at US$143,118 to US$180,102 during the first 3 months after intervention, then decreased over time. Only the first 9 months could be used in the paired model due to small N and low power. DISCUSSION: For programs with short time spans and limited health care events, a cross-time model can be used to estimate cost savings while producing results similar to paired models. PMID- 23103453 TI - The ACTIVE cognitive training interventions and trajectories of performance among older adults. AB - OBJECTIVES: Salthouse illustrated that among Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) participants, cognitive change accelerated following training. Our goal was to determine if this finding persists net of practice, training, and loss of training gains effects. METHODS: We evaluated change over 5 years following cognitive training among older adults (N = 1,659, age 65 to 94). RESULTS: Reasoning training, but not memory or speed, attenuated aging-related change. Memory gains were maintained, but about half of reasoning and speed gains were lost. Performance differences at the end of the follow-up were equivalent to about 6, 4, and 8 years of aging for memory, reasoning, and speed training, respectively. DISCUSSION: Training can appear to accelerate age related change, because change over time is coupled with loss of training gains. Our analysis is limited by follow-up that is short for precisely characterizing aging-related change. PMID- 23103456 TI - Transition moment directions and selected spectroscopic properties of Ivabradine. AB - Based on the Kawski-Gryczynski method the value of angle beta=38 degrees between absorption and fluorescence transition moments of Ivabradine was determined. Such a high value of beta is responsible for low emission anisotropy of Ivabradine in a rigid polyvinyl alcohol matrix and in anhydrous glycerol despite the elongated shape of the fluorophore. Selected steady-state and time-resolved spectroscopic results support the analysis. PMID- 23103455 TI - Mathematical modeling of drug delivery from autocatalytically degradable PLGA microspheres--a review. AB - PLGA microspheres are widely studied for controlled release drug delivery applications, and many models have been proposed to describe PLGA degradation and erosion and drug release from the bulk polymer. Autocatalysis is known to have a complex role in the dynamics of PLGA erosion and drug transport and can lead to size-dependent heterogeneities in otherwise uniformly bulk-eroding polymer microspheres. The aim of this review is to highlight mechanistic, mathematical models for drug release from PLGA microspheres that specifically address interactions between phenomena generally attributed to autocatalytic hydrolysis and mass transfer limitation effects. Predictions of drug release profiles by mechanistic models are useful for understanding mechanisms and designing drug release particles. PMID- 23103457 TI - Competition of hydrogen, halogen, and pnicogen bonds in the complexes of HArF with XH2P (X=F, Cl, and Br). AB - A theoretical study of the complexes formed between HArF and XH2P (X=F, Cl, and Br) has been carried out using ab initio methods (MP2/aug-cc-pVDZ, MP2/aug-cc pVTZ, and CCSD(T)/aug-cc-pVTZ). Three minima were found, which correspond to a hydrogen-bonded complex (I), a pnicogen-bonded complex (II), and a halogen-bonded complex (III). The pnicogen-bonded complex is the most stable, followed by the hydrogen-bonded complex, and the halogen-bonded complex is the least stable. The Ar-H bond is enhanced in FH2P-HArF-I complex and exhibits a blue shift, while it is weakened in ClH2P-HArF-I and BrH2P-HArF-I complexes and shows a red shift. A blue shift is also found for the distant Ar-H bond in the halogen-bonded and pnicogen-bonded complexes. These complexes have been understood with the electrostatic potentials and symmetry adapted perturbation theory (SAPT) method. PMID- 23103458 TI - Synthesis, structural, spectroscopic and optical studies of charge transfer complex salts. AB - New charge transfer molecular complex adducts of picric acid (C6H3N3O7) with triethylamine (C6H15N) and dimethylformamide (HCON(CH3)2) were synthesized successfully for the first time. Chemical composition and stoichiometry of the synthesized complex salts were verified by CHN elemental analysis. Solubility of the complex salts have been determined by gravimetric method and single crystals of two new salts were grown by low temperature solution growth technique. Crystal system, crystalline nature and cell parameters of the grown crystals were determined by single crystal X-ray diffraction (SXRD) and powder X-ray diffraction (PXRD) analyses. The formations of the charge-transfer complex, functional groups and the modes of vibrations have been confirmed by Fourier transform infrared (FTIR) spectroscopy. In order to know the linear and nonlinear optical suitability for device fabrication, UV-Vis (UV) spectral analysis and relative second harmonic generation (SHG) efficiency test were performed for the grown crystals. PMID- 23103459 TI - Synthesis of monodispersed silver nanoparticles using Hibiscus cannabinus leaf extract and its antimicrobial activity. AB - Synthesis of silver nanoparticles using leaf extract of Hibiscus cannabinus has been investigated. The influences of different concentration of H. cannabinus leaf extract, different metal ion concentration and different reaction time on the above cases on the synthesis of nanoparticles were evaluated. The synthesized nanoparticles were characterized using UV-vis spectroscopy, Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD) and Transmission Electron Microscopy (TEM). The prepared silver nanoparticles were monodispersed, spherical in shape with the average particle size of 9 nm and shows surface plasmon peak at 446 nm. The study also reveals that the ascorbic acid present in H. cannabinus leaf extract has been used as reducing agent. The prepared silver nanoparticle shows good antimicrobial activity against Escherichia coli, Proteus mirabilis and Shigella flexneri. PMID- 23103460 TI - A DFT/TDDFT study on the excited-state hydrogen bonding dynamics of 6 aminocoumarin in water solution. AB - Intermolecular hydrogen bonding, as a site-specific solute-solvent interaction, plays an extremely important role on the spectra of chemical and biological molecules. A detailed theoretical study on the hydrogen bonds is extremely necessary for understanding the unusual spectra blue-shift for some molecules. In the present paper, the hydrogen bonding dynamics of 6-aminocoumarin (6AC) in the water was investigated by the time-dependent density functional theory (TDDFT) and density functional theory (DFT) methods. According to our results, it is demonstrated that C6-N1?H9 bond (AHB) is the strongest hydrogen bonds among three ones formed between 6AC and water molecules in the ground state. Upon the photoexcitation, due the photo-induced charge transfer from N1 to C6, AHB is proved to be extremely weakened which is significantly greater than the strengthening of C9=O2?H11 bond (BHB) and N1-H6?O5 bond (CHB) in S1 states. This is expected to be theoretical explanation for the unusual blue-shift of a long wavelength band in absorption spectra for 6AC in the water observed in the experiment. PMID- 23103461 TI - Molecular structure of 4-hidroxy-3-(3-methyl-2-butenyl) acetophenone, a plant antifungal, by X-ray diffraction, DFT calculation, and NMR and FTIR spectroscopy. AB - The molecular structure of two mixed and closely related conformers of the title compound, C13H16O2, found in the solid with unequal occupancies has been determined by X-ray diffraction methods. The substance crystallizes in the monoclinic Pca2(1) space group with a=17.279(2), b=5.1716(7), c=12.549(2)A, and Z=4 molecules per unit cell. The structure was solved from 1314 reflections with I>2sigmaI and refined to an agreement R1-factor of 0.049. The minor conformer (34.7%) is nearly mirror-related to and extensively overlapped with the major one. The skeleton of the 4-hydroxyacetophenone molecular fragment and the prenyl group, (CH2)(CH)C(CH3)2, pendant arm attached to it are both planar and perpendicular to each other. A strong intermolecular O-H?O bond links neighboring molecules in the lattice to produce a polymeric structure. The conformational structures of the compound in the gas phase have been calculated by the DFT method and the geometrical results have been compared with the X-ray data. These data allow a complete assignment of vibration modes in the solid state FTIR and Raman spectra. The calculated 1H and 13C chemicals shifts are in good agreement with the corresponding experimental NMR spectra of the compound in solution. PMID- 23103462 TI - Ab initio HF, DFT and experimental (FT-IR) investigation of vibrational spectroscopy of 3-(2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)-6-(4 methoxybenzoyl)benzo[d]thiazol-2(3H)-one. AB - FT-IR spectra was recorded for 3-(2-(4-isopropylpiperazin-1-yl)-2-oxoethyl)-6-(4 methoxybenzoyl)benzo[d]thiazol-2(3H)-one molecule (abbreviated as IOMBT) sample in solid state. Conformational analysis of IOMBT was performed to determine the most stable conformer. Potential energy curves of IOMBT were obtained performing a relaxed scan of D1-7 dihedral angels at B3LYP/6-311++G(d,p) level of theory. Geometrical parameters of these structures were optimized by using the same method. The molecular geometry of IOMBT was reoptimized at DFT(B3LYP) and HF methods using 6-311++G(d,p), 6-311+G(d), 6-311G(d,p), 6-311G(d) and 6-31++G(d,p) basis sets for the lowest energy conformer. The vibrational frequencies, IR intensities were calculated at DFT(B3LYP) and HF methods. The thermodynamic parameters (such as zero-point vibrational energy, EHOMO, ELUMO, thermal corrections to energy, enthalpy and Gibbs free energy, and entropy) have also been computed. The LUMO-HOMO energy gap of IOMBT shows that the energy gap reflects the chemical reactivity and the level of conductivity of the molecule. PMID- 23103463 TI - 1-(3-methyl-3-mesityl)-cyclobutyl-2-(5-pyridin-4-yl-2H-[1,2,4]triazol-3 ylsulfanyl)-ethanone: X-ray structure, spectroscopic characterization and DFT studies. AB - The triazole compound 1-(3-Methyl-3-mesityl)-cyclobutyl-2-(5-pyridin-4-yl-2H [1,2,4]triazol-3-ylsulfanyl)-ethanone, (C23H26N4OS), was characterized by X-ray single crystal diffraction technique, IR NMR spectroscopy and quantum chemical computational methods as both experimental and theoretically. The compound crystallizes in the monoclinic space group P2(1)/c with Z=4. The molecular geometry was also optimized using density functional theory (DFT/B3LYP) method with the 6-311G(d,p) basis set in ground state and compared with the experimental data. The computed vibrational frequencies are used to determine the types of molecular motions associated with each of the experimental bands observed. The results of the calculations were applied to simulate spectra of the title compound, which show excellent agreement with observed spectra. Data of the title compound display significant structure correlation and provide the basis for future design of efficient materials having the derivatives of 1,2,4-triazole. From the optimized geometry of the molecule, vibrational frequencies, gauge independent atomic orbital (GIAO) 1H and 13C NMR chemical shift values, molecular electrostatic potential (MEP) distribution, non-linear optical properties and frontier molecular orbitals (FMOs) of the title compound were performed at B3LYP/6-311G(d,p). On the basis of theoretical vibrational analyses, the thermodynamic properties (standard heat capacities, standard entropies, and standard enthalpy changes) of the title compound at different temperatures have been calculated, revealing the correlations between Cp,m0, Sm0, DeltaHm0 and temperatures. The predicted non-linear optical properties of the title compound are much greater than those of urea. Data of the title compound display significant structure-correlation and provide the basis for future design of efficient materials having the derivatives of 1,2,4-triazole. PMID- 23103464 TI - The analytical application and spectral investigation of DNA-CPB-emodin and sensitive determination of DNA by resonance Rayleigh light scattering technique. AB - A new sensitive DNA probe containing cetylpyridinium bromide (CPB) and emodin (an effective component of Chinese herbal medicine) was developed using the resonance Rayleigh light scattering (RLS) technique. A novel assay was first developed to detect DNA at nanogram level based on the ternary system of DNA-CPB-emodin. The RLS signal of DNA was enhanced remarkably in the presence of emodin-CPB, and the enhanced RLS intensity at 340.0 nm was in direct proportion to DNA concentration in the range of 0.01-2.72 MUg mL(-1) with a good linear relationship. The detection limit was 1.5 ng mL(-1). Three synthetic DNA samples were measured obtaining satisfactory results, the recovery was 97.6-107.3%. PMID- 23103465 TI - Solvent-free synthesis, spectral correlations and antimicrobial activities of some aryl imines. AB - A series of aryl imines have been synthesized by Fly-ash: H2SO4 catalyzed microwave assisted process under solvent-free conditions. The yields of the imines have been found to be more than 87%. The purity of all imines has been checked using their physical constants and spectral data as published earlier in literature. The UV lambdamaxCN(nm), infrared nuCN(cm(-1)), NMR delta(ppm) of CH and CN spectral data have been correlated with Hammett substituent constants and F and R parameters using single and multi-linear regression analysis. From the results of statistical analysis, the effect of substituents on the above spectral data has been studied. The antimicrobial activities of All synthesised imines have been studied using Bauer-Kirby method. PMID- 23103466 TI - Physico-chemical studies of fused phenanthrimidazole derivative as sensitive NLO material. AB - Heterocyclic phenanthrimidazole derivative, 2-(4-fluorophenyl)-1-p-tolyl-1H imidazo[4,5-f] [1,10] phenanthroline (FPTIP) has been synthesized and characterised by NMR, mass and CHN analysis. The FPTIP was evaluated concerning their solvatochromic properties and molecular optical nonlinearities. Their electric dipole moment (MU), polarizability (alpha) and hyperpolarizability (beta) have been calculated theoretically and the results indicate that the extension of the pi-framework of the ligands has an effect on the NLO properties. The energies of the HOMO and LUMO levels and the molecular electrostatic potential (MEP) energy surface studies have exploited the existence of intramolecular charge transfer (ICT) within the molecule. PMID- 23103467 TI - An efficient one pot syntheses of aryl-3,3'-bis(indolyl)methanes and studies on their spectral characteristics, DPPH radical scavenging-, antimicrobial-, cytotoxicity-, and antituberculosis activity. AB - An efficient one-pot syntheses of aryl-3,3'-bis(indolyl)methanes (BIMs) from indole/2-methylindole and formylphenoxyaliphatic acid(s) is described. Esterification of carboxylic acid and aromatic electrophilic substitution reactions are achieved simultaneous in the presence of potash alum as a catalyst. This catalyst could be recovered and reused without substantial loss in its catalytic activity and the methodology could be applied on a range of closely related substrates. The solvation characteristics in ground and excited states of the compounds by monitoring the absorbance and fluorescence band maxima have been studied. The fluorescence studies in protic and aprotic solvents were rationalized on the basis of solute-solvent interaction and substituents effect on these photophysical processes analyzed. The compounds prepared showed efficient antimicrobial effect against human pathogens, cytotoxicity against A431 cell line, and DPPH radical scavenging effect. Single crystal XRD studies have been carried out for a few compounds synthesized in this work. PMID- 23103468 TI - Synthesis, spectral characterization and antioxidant activity studies of a bidentate Schiff base, 5-methyl thiophene-2-carboxaldehyde-carbohydrazone and its Cd(II), Cu(II), Ni(II) and Zn(II) complexes. AB - A new Schiff base bidentate ligand (L), 5-methyl thiophene-2-carboxaldehyde carbohydrazone and its metal (Cu(II), Cd(II), Ni(II) and Zn(II)) complexes with general stoichiometry [M(L)2X2] (where X=Cl) were synthesized. The ligand and its metal complexes were characterized by elemental analyses, IR, 1H NMR, ESR spectral analyses, and molar conductance studies. The molar conductance data revealed that all the metal chelates are non-electrolytes. IR spectra showed that ligand (L) is coordinated to the metal ions in a bidentate manner with N and O donor sites of the azomethine-N, and carbonyl-O. ESR and UV-Vis spectral data showed that the geometrical structure of the complexes are Orthorhombic. Furthermore, the antioxidant activity of the ligand and its complexes was determined by hydroxyl radical scavenging, DPPH, NO, reducing power methods in vitro. The obtained IC50 value of the DPPH activity for the copper complex (IC50=66.4 MUm) was higher than other compounds. Microbial assay of the above complexes against Staphylococcus aureus, Escherichia coli, Rhizocotonia bataticola and Alternaria alternata showed that copper complex exhibited higher activity than the other complexes. PMID- 23103469 TI - Vibrational spectroscopic and DFT calculation studies of cobalt(II) complexes with 3-hydroxypicolinic acid. AB - Two cobalt(II) complexes with 3-hydroxypicolinic acid (3-hydroxypyridine-2 carboxylic acid, 3-OHpicH), trans-[Co(3-OHpic)2(py)2] (2) and cis-[Co(3-OHpic)2(4 pic)2] (3) (py=pyridine; 4-pic=4-picoline or 4-methylpyridine), previously synthesized and characterized by X-ray diffraction, are here studied by Raman and mid-infrared spectroscopy with the help from the corresponding DFT vibrational calculations using B3LYP/6-311G(d,p) computational model. Intramolecular O-H?O hydrogen bond appears in both complexes 2 and 3, while weak C-H?O hydrogen bonds assemble molecules of 2 or 3 into 3D architecture. A complete presentation of all Raman, infrared and theoretical results is given for complex 3. The measured spectra are shown, relative intensities and bandwidths are discussed and the assignment of vibrational bands is given on the basis of the DFT calculations. The calculated spectra agree very well with the presented experimental findings, thanks to the suitable grouping of modes. The same vibrational calculations also reveal insignificant influence of H->CH3 substitution for the spectroscopic characterization of the complex. A careful study of differences between calculated and observed wavenumbers suggests that modified single-factor scaling is actually better than the classic multi-factor scaling approach. PMID- 23103470 TI - Large-scale development of cost-effective single-nucleotide polymorphism marker assays for genetic mapping in pigeonpea and comparative mapping in legumes. AB - Single-nucleotide polymorphisms (SNPs, >2000) were discovered by using RNA-seq and allele-specific sequencing approaches in pigeonpea (Cajanus cajan). For making the SNP genotyping cost-effective, successful competitive allele-specific polymerase chain reaction (KASPar) assays were developed for 1616 SNPs and referred to as PKAMs (pigeonpea KASPar assay markers). Screening of PKAMs on 24 genotypes [23 from cultivated species and 1 wild species (Cajanus scarabaeoides)] defined a set of 1154 polymorphic markers (77.4%) with a polymorphism information content (PIC) value from 0.04 to 0.38. One thousand and ninety-four PKAMs showed polymorphisms between parental lines of the reference mapping population (C. cajan ICP 28 * C. scarabaeoides ICPW 94). By using high-quality marker genotyping data on 167 F(2) lines from the population, a comprehensive genetic map comprising 875 PKAMs with an average inter-marker distance of 1.11 cM was developed. Previously mapped 35 simple sequence repeat markers were integrated into the PKAM map and an integrated genetic map of 996.21 cM was constructed. Mapped PKAMs showed a higher degree of synteny with the genome of Glycine max followed by Medicago truncatula and Lotus japonicus and least with Vigna unguiculata. These PKAMs will be useful for genetics research and breeding applications in pigeonpea and for utilizing genome information from other legume species. PMID- 23103471 TI - Genome-wide analysis of bZIP-encoding genes in maize. AB - In plants, basic leucine zipper (bZIP) proteins regulate numerous biological processes such as seed maturation, flower and vascular development, stress signalling and pathogen defence. We have carried out a genome-wide identification and analysis of 125 bZIP genes that exist in the maize genome, encoding 170 distinct bZIP proteins. This family can be divided into 11 groups according to the phylogenetic relationship among the maize bZIP proteins and those in Arabidopsis and rice. Six kinds of intron patterns (a-f) within the basic and hinge regions are defined. The additional conserved motifs have been identified and present the group specificity. Detailed three-dimensional structure analysis has been done to display the sequence conservation and potential distribution of the bZIP domain. Further, we predict the DNA-binding pattern and the dimerization property on the basis of the characteristic features in the basic and hinge regions and the leucine zipper, respectively, which supports our classification greatly and helps to classify 26 distinct subfamilies. The chromosome distribution and the genetic analysis reveal that 58 ZmbZIP genes are located in the segmental duplicate regions in the maize genome, suggesting that the segment chromosomal duplications contribute greatly to the expansion of the maize bZIP family. Across the 60 different developmental stages of 11 organs, three apparent clusters formed represent three kinds of different expression patterns among the ZmbZIP gene family in maize development. A similar but slightly different expression pattern of bZIPs in two inbred lines displays that 22 detected ZmbZIP genes might be involved in drought stress. Thirteen pairs and 143 pairs of ZmbZIP genes show strongly negative and positive correlations in the four distinct fungal infections, respectively, based on the expression profile and Pearson's correlation coefficient analysis. PMID- 23103472 TI - ABCA1-dependent serum cholesterol efflux capacity inversely correlates with pulse wave velocity in healthy subjects. AB - The capacity of HDL to induce cell cholesterol efflux is considered one of its main antiatherogenic properties. Little is known about the impact of such HDL function on vascular physiology. We investigated the relationship between ABCA1 dependent serum cholesterol efflux capacity (CEC), an HDL functionality indicator, and pulse wave velocity (PWV), an indicator of arterial stiffness. Serum of 167 healthy subjects was used to conduct CEC measurement, and carotid femoral PWV was measured with a high-fidelity tonometer. J774 macrophages, labeled with [(3)H]cholesterol and stimulated to express ABCA1, were exposed to sera; the difference between cholesterol efflux from stimulated and unstimulated cells provided specific ABCA1-mediated CEC. PWV is inversely correlated with ABCA1-dependent CEC (r = -0.183; P = 0.018). Moreover, controlling for age, sex, body mass index, mean arterial pressure, serum LDL, HDL-cholesterol, and fasting plasma glucose, PWV displays a significant negative regression on ABCA1-dependent CEC (beta = -0.204; 95% confidence interval, -0.371 to -0.037). The finding that ABCA1-dependent CEC, but not serum HDL cholesterol level (r = -0.002; P = 0.985), is a significant predictor of PWV in healthy subjects points to the relevance of HDL function in vascular physiology and arterial stiffness prevention. PMID- 23103473 TI - Nicotinic acid and DP1 blockade: studies in mouse models of atherosclerosis. AB - The use of nicotinic acid to treat dyslipidemia is limited by induction of a "flushing" response, mediated in part by the interaction of prostaglandin D(2) (PGD(2)) with its G-protein coupled receptor, DP1 (Ptgdr). The impact of DP1 blockade (genetic or pharmacologic) was assessed in experimental murine models of atherosclerosis. In Ptgdr(-/-)ApoE(-/-) mice versus ApoE(-/-) mice, both fed a high-fat diet, aortic cholesterol content was modestly higher (1.3- to 1.5-fold, P < 0.05) in Ptgdr(-/-)ApoE(-/-) mice at 16 and 24 weeks of age, but not at 32 weeks. In multiple ApoE(-/-) mouse studies, a DP1-specific antagonist, L-655, generally had a neutral to beneficial effect on aortic lipids in the presence or absence of nicotinic acid treatment. In a separate study, a modest increase in some atherosclerotic measures was observed with L-655 treatment in Ldlr(-/-) mice fed a high-fat diet for 8 weeks; however, this effect was not sustained for 16 or 24 weeks. In the same study, treatment with nicotinic acid alone generally decreased plasma and/or aortic lipids, and addition of L-655 did not negate those beneficial effects. These studies demonstrate that inhibition of DP1, with or without nicotinic acid treatment, does not lead to consistent or sustained effects on plaque burden in mouse atherosclerotic models. PMID- 23103475 TI - Coronary Artery RIsk MAnagement Programme (CARIMAP) delivered by a rehabilitation day-hospital: impact on patients with coronary artery disease. AB - PURPOSE: Previous studies have shown that correct management of different coronary risk factors can reduce coronary event rates. However, significant undertreatment of hyperlipidemia, diabetes, and hypertension is still found during clinical practice. The purpose of this study was to evaluate the effectiveness of an individualized management program to modify coronary disease risk profile. METHODS: One hundred sixty-eight patients discharged from a cardiac rehabilitation department after acute coronary events were prospectively randomized into 2 management strategies: 84 started usual community care and 84 entered a Coronary Artery RIsk MAnagement Programme (CARIMAP) delivered by the rehabilitation day-hospital. Coronary risk profile, optimized therapy, and management were evaluated after the acute event and again after a followup of 9 +/- 4 months in both groups. RESULTS: Patients accessed the day-hospital an average of 4 +/- 1 months (range, 1-13 months) after the acute event. The duration of the CARIMAP was 5 +/- 2 months and the individual number of accesses to the day-hospital was 4 +/- 3.8. After the CARIMAP, patients received better optimized therapy (beta-blockers 57% vs 85%, P < .0001; angiotensin-converting enzyme inhibitors 54% vs 84%, P < .00001; statins 38% vs 78%, P < .0001; and amlodipine 22% vs 51%, P < .0001) and had a better risk profile (low-density lipoprotein-cholesterol < 100 mg/dL 30% vs 42%, P < .0001; blood pressure < 140/90 mmHg 63% vs 88%, P < .00001). CONCLUSION: The CARIMAP of secondary prevention delivered by a rehabilitation day-hospital to patients who had undergone an acute coronary event, enabled individually titrated therapy and better control of coronary artery risk factors. PMID- 23103476 TI - Aerobic exercise intensity assessment and prescription in cardiac rehabilitation: a joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation, and the Canadian Association of Cardiac Rehabilitation. AB - Aerobic exercise intensity prescription is a key issue in cardiac rehabilitation, being directly linked to both the amount of improvement in exercise capacity and the risk of adverse events during exercise. This joint position statement aims to provide professionals with up-to-date information regarding the identification of different exercise intensity domains, the methods of direct and indirect determination of exercise intensity for both continuous and interval aerobic training, the effects of the use of different exercise protocols on exercise intensity prescription and the indications for recommended exercise training prescription in specific cardiac patients' groups. The importance of functional evaluation through exercise testing prior to starting an aerobic training program is strongly emphasized, and ramp incremental cardiopulmonary exercise test, when available, is proposed as the gold standard for a physiologically comprehensive exercise intensity assessment and prescription. This may allow a shift from a 'range-based' to a 'threshold-based' aerobic exercise intensity prescription, which, combined with thorough clinical evaluation and exercise-related risk assessment, could maximize the benefits obtainable by the use of aerobic exercise training in cardiac rehabilitation. PMID- 23103474 TI - Influence of dietary saturated fat content on adiposity, macrophage behavior, inflammation, and metabolism: composition matters. AB - We examined the effects of three high-fat diets (HFD), differing in the percentage of total calories from saturated fat (SF) (6%, 12%, and 24%) but identical in total fat (40%), on body composition, macrophage behavior, inflammation, and metabolic dysfunction in mice. Diets were administered for 16 weeks. Body composition and metabolism [glucose, insulin, triglycerides, LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C), total cholesterol (TC)] were examined monthly. Adipose tissue (AT) expression of marker genes for M1 and M2 macrophages and inflammatory mediators [Toll-like receptor (TLR)-2, TLR-4, MCP-1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10, suppressor of cytokine signaling (SOCS)1, IFN-gamma] was measured along with activation of nuclear factor kappa-B (NFkappaB), c-Jun N-terminal kinase (JNK), and p38- mitogen-activated protein kinase (MAPK). AT macrophage infiltration was examined using immunohistochemistry. Circulating MCP-1, IL-6, adiponectin, and leptin were also measured. SF content, independent of total fat, can profoundly affect adiposity, macrophage behavior, inflammation, and metabolic dysfunction. In general, the 12%-SF diet, most closely mimicking the standard American diet, led to the greatest adiposity, macrophage infiltration, and insulin resistance (IR), whereas the 6%-SF and 24%-SF diets produced lower levels of these variables, with the 24%-SF diet resulting in the least degree of IR and the highest TC/HDL-C ratio. Macrophage behavior, inflammation, and IR following HFD are heavily influenced by dietary SF content; however, these responses are not necessarily proportional to the SF percentage. PMID- 23103477 TI - Monte Carlo-based correction factors for ion chamber dosimetry in heterogeneous phantoms for megavoltage photon beams. AB - The purpose of this study was to investigate the perturbation correction factors and inhomogeneity correction factors (ICFs) for a thin-walled cylindrical ion chamber in a heterogeneous phantom including solid water, lung and bone plastic materials. The perturbation factors due to the replacement of the air cavity, non water equivalence of the wall and the stem, non-air equivalence of the central electrode and the overall perturbation factor, P(Q), for a cylindrical chamber, in the heterogeneous phantom were calculated with the EGSnrc/Cavity Monte Carlo code for 6 and 15 MV photon beams. The PTW31010 (0.125 cm(3)) chamber was modeled with Monte Carlo simulations, and was used for measurements and calculations of percentage depth ionization (PDI) or percentage depth dose (PDD). ICFs were calculated from the ratio of the product of the stopping power ratios (SPRs) and P(Q) of lung or bone to solid water. Finally, the measured PDIs were converted to PDDs by using ICFs and were compared with those calculated by the Monte Carlo method. The perturbation effect for the ion chamber in lung material is insignificant at 5 * 5 and 10 * 10 cm(2) fields, but the effect needs to be considered under conditions of lateral electron disequilibrium with a 3 * 3 cm(2) field. ICFs in lung varied up to 2% and 4% depending on the field size for 6 and 15 MV, respectively. For bone material, the perturbation effects due to the chamber wall and the stem were more significant at up to 3.5% and 1.6% for 6 MV, respectively. ICFs for bone material were approximately 0.945 and 0.940 for 6 and 15 MV, respectively. The converted PDDs by using ICFs were in good agreement with Monte Carlo calculated PDDs. The chamber perturbation correction and SPRs should strictly be considered for ion chamber dosimetry in heterogeneous media. This is more important for small field dosimetry in lung and bone materials. PMID- 23103478 TI - Tunable band gap of boron nitride interfaces under uniaxial pressure. AB - In this work we show, by means of a density functional theory formalism, that the interaction between hydrogen terminated boron nitride surfaces gives rise to a metallic interface with free carriers of opposite sign at each surface. A band gap can be induced by decreasing the surface separation. The size of the band gap changes continuously from zero up to 4.4 eV with decreasing separation, which is understood in terms of the interaction between surface states. Due to the high thermal conductivity of cubic boron nitride and the coupling between band gap and applied pressure, such tunable band gap interfaces may be used in highly stable electronic and electromechanical devices. In addition, the spatial separation of charge carriers at the interface may lead to photovoltaic applications. PMID- 23103479 TI - For the write reason. AB - In between editing the JWC this month, I have been preparing to give a talk on writing for publication, so this topic that has been very much on my mind recently. One interesting question keeps coming up, and I feel it is quite possibly the most important place to begin. Simply put: why do we publish? PMID- 23103480 TI - Case series of sural island flaps used for soft-tissue defects of the distal third lower extremity. AB - OBJECTIVE: To establish the sural island fasciocutaneous flap as an initial consideration for distal third lower-extremity soft tissue coverage and to provide non-plastic surgeons with a procedure they can perform on their own. METHOD: Literature on reverse sural island fasciocutaneous flaps was reviewed and summarised. We then assessed our care series of sural island flaps from 2008-2011 and looked to provide our operative technique and patient outcomes. RESULTS: Nine patients, aged 12-70 years old, with greater than 1 year follow-up, were reviewed. Five patients had diabetes, peripheral vascular disease, or smoked tobacco. All patients healed their soft tissue coverage with minimal complication and were able to accommodate normal footwear. CONCLUSION: Reverse sural island flaps are resilient flaps that should be considered as an alternative to free muscle transfer, for distal third lower extremity coverage. DECLARATION OF INTEREST: There were no external sources of funding for this study. The authors have no conflicts of interest to declare. PMID- 23103481 TI - Porcine urinary bladder matrix: a retrospective study and establishment of protocol. AB - OBJECTIVE: To summarise our experience with porcine urinary bladder matrix extracellular matrix (UBM) for the treatment of diabetic, venous, ischaemic or decubitus ulcerations and to outline appropriate protocol for its application. METHOD: A retrospective review was also conducted on all patients who received UBM (MatriStem; A Cell, Inc.) from January to December 201 I. Information regarding patient demographics, wound aetiology and location, as well as any prior treatments and follow-up data,were collected and reviewed from patients' medical records. RESULTS: Thirty-four patients were evaluated for this study. Mean patient age was 62.4 + 13.4 years (range 29-88 years) and 76% (n = 26) were male.The most common comorbidities were peripheral neuropathy (n = 20), diabetes mellitus type 2 (n = 19) and hypertension (n= 13). Mean wound duration prior to UBM application was 25.5 43.5 weeks, and mean time to healing following initial application was 9.8 9.3 weeks. All patients treated with UBM progressed to full healing. CONCLUSION: After addressing modifiable risk factors, our study suggests UBM is effective in the treatment of acute and recalcitrant diabetic or venous ulcerations when applied correctly with an appropriate dressing. DECLARATION OF INTEREST: There were no external sources of funding for this study.The authors have no conflicts of interest to declare. PMID- 23103482 TI - Risk of diabetic foot ulceration during treatment with insulin glargine and NPH insulin. AB - OBJECTIVE: To evaluate the effect of the long-acting basal insulin analog glargine compared with neutral protamine Hagedorn (NPH) insulin on the incidence of diabetic foot ulceration (DFU) in patients with diabetes in Germany. METHOD: A retrospective cohort study was performed using a representative German database (IMS Disease Analyzer) of patients with type 2 diabetes, who started a basal insulin therapy with either insulin glargine or NPH insulin, between July 2000 and September 2007, and continued this therapy for at least 24 months, and whose data were continuously documented.The occurrence of DFU was recorded beginning in the third year after therapy initiation and Kaplan-Meier curves were generated and compared using log-rank tests. Cox proportional hazard models were used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI) for the incidence of DFU. RESULTS: Patients who fulfilled the inclusion criteria (n=23 395) had started either on insulin glargine (n=9638) or on NPH insulin (n= 13 757).After adjustment for demographic and clinical variables, it was demonstrated that the relative risk to diabetes patients of developing DFS is 64% lower with insulin glargine than with NPH insulin therapy (HR=0.6 I; p=0.0405). CONCLUSION: The results suggest that, compared with NPH insulin, insulin glargine therapy significantly reduces the risk of DFS in patients with diabetes under real life conditions. Prospective long-term trials are needed to confirm these secondary data analysis results. DECLARATION OF INTEREST: There were no external sources of funding for this study.The authors have no conflicts of interest to declare. PMID- 23103483 TI - The psychological impact of split-thickness skin grafts. AB - OBJECTIVE: To measure the psychological distress associated with a split thickness skin graft (STSG). METHOD: A retrospective postal questionnaire survey of 102 patients who had undergone a STSG procedure within the last 3.5 years. Outcomes measures included the Hospital Anxiety and Depression Scale (HADS), Derriford Appearance Scale (DAS-59) and subjective rating scales (SRS) of noticeability and worry about the grafted and donor area. RESUTLS: Scores on the SRS correlated positively with HADS and DAS-59 scores. Rates of anxiety were higher than depression (19% vs 13%, respectively). Greater than 10% of the sample experienced significant appearance-related distress when compared to standardised test norms. Concerns about the grafted area were higher than for the donor site, but those concerned about the graft were also likely to be concerned about the donor area. Aged (< 60 years) and reason for surgery (trauma as opposed to cancer) were associated with significantly higher scores on appearance measures. CONCLUSION: STSG is not associated with high levels of psychological distress, However, there is a small but significant monitory who experience appearance related distress, low mood and anxiety who would benefit from targeted psychological intervention, Demographic factors, such as age or gender, and length of time since surgery, are not useful discriminators in identifying vulnerable individuals. Simple SRS of visibility and worry correlate significantly with standardised psychological measures. These can be used as a short and effective screening tool to identify individuals who would benefit from postoperative psychological input. DECLARATION OF INTERNET: There were no external sources sources of funding for this study. The authors have no conflicts of interest to declare. PMID- 23103484 TI - Accidental radiation exposure leading to non-healing ulcers. AB - Two patients with accidental radiation injury presented at the Sir Ganga Ram Hospital. The first patient, a 41-year-old male, presented with a large necrotic patch on his right gluteal region, which was debrided. Due to the progressive nature of the injury, he developed further necrosis and a non-healing ulcer over the right gluteal region, which was further debrided and covered with a tensor fascia lata flap. Further necrosis over the ischial region was debrided and covered with a pedicled gracilis muscle flap, following which he again required debridement and flap cover for the residual area, which then finally healed. The second patient had a history of radiation exposure followed by a non-healing ulcer on right arm. He was managed by debridement and flap coverage in a single sitting. These two cases suggest that wide excision, thorough debridement and coverage with vascularised tissue are effective in treating radiation ulcers and emphasise that all radiation sources and their management should be strictly controlled. PMID- 23103485 TI - Randomised, controlled pilot to compare collagen and foam in stagnating pressure ulcers. AB - OBJECTIVE: To compare the clinical efficacy of a collagen dressing covered with a foam dressing with the same foam used as a primary dressing in stagnating granulating pressure ulcer patients. METHOD: Patients were randomised to receive either a foam dressing (Suprasorb P; Lohmann & Rauscher) as a primary dressing (group A), or a combination of a collagen dressing (Suprasorb C; Lohmann & Rauscher) covered with the same foam dressing (group B).Wound fluid was collected and evaluated prior to treatment (day 0), and on days 3,7, 14 and 21 .The level and expression of matrix metalloproteinases (MMPs) MMP-2 and MMP-9, and tissue inhibitors of metalloproteinases (TIMPs) TIMP- I and TIMP-2,as well as elastase content in wound fluid and angiogenesis,were evaluated, comparing results on day 0 and day 2 I.Time to ulcer healing, reduction in ulcer area, safety of treatment, patient-reported ulcer pain and comfort of the dressing regimen were evaluated as secondary outcomes. Patients received standard preventive measures, in line with the pressure ulcer prevention guidelines. RESULTS: Ten patients were included in the pilot; five were treated with the foam dressing (group A) and five patients received the collagen dressing, using the foam as a secondary dressing (group B).Wound fluid from group B displayed a significant positive effect on angiogenesis (p < 0.05) compared with group A. In the collagen and foam groupTIMP- I and -2 increased faster and levels were higher than in group A. Furthermore, MMP-2, MMP-9 (p < 0.04) and elastase in group B showed faster and greater decrease in levels, compared with group A, indicating a faster and superior reduction of inflammation. In both groups the ulcers started to heal, with a faster onset of healing for group B. CONCLUSION: The results of this pilot support published data on the use of collagen dressings compared with foam for stagnating wounds, shown in clinical studies. DECLARATION OF INTEREST: This study was supported with an educational grant by Lohmann & Rauscher GmbH.Apart from DrAbel, the sponsors had no role in the design or conduct of the study, in the collection, analysis and interpretation of the data, or in the preparation, review or approval of the manuscript. DrAbel gave input to the study design from a scientific perspective. None of the authors received administrative, technical or material support for the conduct of this study.The authors have no other relevant financial interests to declare. PMID- 23103486 TI - Pediatric Arm Function Test: reliability and validity for assessing more-affected arm motor capacity in children with cerebral palsy. AB - OBJECTIVE: Although there are several validated upper-extremity measures in young children with cerebral palsy, none of these primarily assess the capacity to carry out actions and tasks with the more-affected arm. To address this need, we developed the Pediatric Arm Function Test (PAFT), which involves the behavioral observation of how children use their more-affected arm during structured play in a laboratory or clinic. This article evaluates the reliability and validity of the PAFT Functional Ability scale. DESIGN: In study 1, a total of 20 children between 2 and 8 yrs old with a wide range of upper-extremity hemiparesis caused by cerebral palsy completed the PAFT on two occasions separated by 3 wks. In study 2, a total of 41 children between 2 and 6 yrs old with similar characteristics completed the PAFT and received a grade reflecting the severity of more-affected arm motor impairment. RESULTS: In study 1, the PAFT test-retest reliability correlation coefficient was 0.74. In study 2, convergent validity was supported by a strong inverse correlation (r = -0.6, P < 0.001) between the PAFT scores and the grade of impairment. CONCLUSIONS: The PAFT Functional Ability scale is a reliable and valid measure of more-affected arm motor capacity in children between 2 and 6 yrs old with cerebral palsy. It can be used to measure upper-extremity neurorehabilitation outcome. PMID- 23103487 TI - The impact of pregnancy on the HIV-1-specific T cell function in infected pregnant women. AB - Evidences indicate that pregnancy can alter the Ag-specific T-cell responses. This work aims to evaluate the impact of pregnancy on the in vitro HIV-1-specific immune response. As compared with non-pregnant patients, lower T-cell proliferation and higher IL-10 production were observed in T-cell cultures from pregnant patients following addition of either mitogens or HIV-1 antigens. In our system, the main T lymphocyte subset involved in producing IL-10 was CD4(+)FoxP3( ). Depletion of CD4(+) cells elevated TNF-alpha and IFN-gamma production. Interestingly, the in vitro HIV-1 replication was lower in cell cultures from pregnant patients, and it was inversely related to IL-10 production. In these cultures, the neutralization of IL-10 by anti-IL-10 mAb elevated TNF-alpha release and HIV-1 replication. In conclusion, our results reveal that pregnancy related events should favor the expansion of HIV-1-specific IL-10-secreting CD4(+) T-cells in HIV-1-infected women, which should, in the scenario of pregnancy, help to reduce the risk of vertical HIV-1 transmission. PMID- 23103488 TI - Phosphorus limitation increases attachment in Agrobacterium tumefaciens and reveals a conditional functional redundancy in adhesin biosynthesis. AB - Bacterial responses to phosphorus limitation, commonly inorganic phosphate (P(i)), are important survival mechanisms in a variety of environments. The two component sensor kinase PhoR and its cognate response regulator PhoB are central to the P(i) limitation response of many bacteria and control the large Pho regulon. Limitation for P(i) significantly increased attachment and biofilm formation by the plant pathogen Agrobacterium tumefaciens, and this was driven by PhoB. Surprisingly, it was also found that both phoR and phoB were essential in A. tumefaciens. Expression of a plasmid-borne copy of the low affinity P(i) transporter (pit) from Sinorhizobium meliloti in A. tumefaciens abolished the phoB and phoR essentiality in A. tumefaciens and allowed direct demonstration of the requirement for this regulatory system in the biofilm response. Increased attachment under P(i) limitation required a unipolar polysaccharide (UPP) adhesin. Mutation of a polyisoprenylphosphate hexose-1-phosphate transferase (PHPT) called uppE abolished UPP production and prevented surface attachment under P(i)-replete conditions, but this was rescued under P(i) limitation, and this rescue required phoB. In low P(i) conditions, either uppE or a paralogous gene Atu0102 is functionally redundant, but only uppE functions in UPP synthesis and attachment when P(i) is replete. This conditional functional redundancy illustrates the influence of phosphorus availability on A. tumefaciens surface colonization. PMID- 23103489 TI - Carotid atherosclerosis and prospective risk of dementia. AB - BACKGROUND AND PURPOSE: Although vascular risk factors have been implicated in the development of all-cause dementia and Alzheimer disease (AD), few studies have examined the association between subclinical atherosclerosis and prospective risk of dementia. METHODS: Participants from the Baltimore Longitudinal Study of Aging (n=364; age, 60-95 years; median age, 73; 60% male; 82% white) underwent initial carotid atherosclerosis assessment and subsequently were assessed for dementia and AD annually for up to 14 years (median, 7.0). Cox proportional hazards models predicting all-cause dementia and AD were adjusted for age, sex, race, education, blood pressure, cholesterol, cardiovascular disease, diabetes mellitus, and smoking. RESULTS: Sixty participants developed dementia, with 53 diagnosed as AD. Raw rates of future dementia and AD among individuals initially in the upper quintile of carotid intimal medial thickness or with bilateral carotid plaque were generally double the rates of individuals with intimal medial thickness in the lower quintiles or no plaque at baseline. Adjusted proportional hazards models revealed >2.5-fold increased risk of dementia and AD among individuals in the upper quintile of carotid intimal medial thickness, and approximately 2.0-fold increased risk of dementia among individuals with bilateral plaque. CONCLUSIONS: Multiple measures of carotid atherosclerosis are associated with prospective risk of dementia. Individuals in the upper quintile of carotid intimal medial thickness or bilateral carotid plaque were at greatest risk. These findings underscore the possibility that early intervention to reduce atherosclerosis may help delay or prevent onset of dementia and AD. PMID- 23103490 TI - Interobserver agreement of ASPECT score distribution for noncontrast CT, CT angiography, and CT perfusion in acute stroke. AB - BACKGROUND AND PURPOSE: The Alberta Stroke program early CT score (ASPECTS) is a semiquantative scale for estimating extent and distribution of early ischemic changes within the MCA territory in the acute stroke setting. Good interobserver agreement of total ASPECTS is demonstrated for noncontrast CT (NCCT) and other imaging modalities. Our purpose is to assess interobserver agreement for individual ASPECTS regions for different imaging modalities. METHODS: One hundred and eighty-one consecutive patients presenting with acute stroke symptoms within 4.5 hours of onset were included. Four readers assigned total and individual ASPECTS for NCCT, CT angiography source images (CTA-SI), and CTP maps of cerebral blood volume (CTP-CBV). Interobserver agreement was assessed by measuring internal consistency and concordance of total and individual ASPECTS using Cronbach's alpha and intraclass correlation coefficient, respectively. RESULTS: Total ASPECTS demonstrated very good concordance and internal consistency for all 3 modalities. Intraclass correlation coefficient and Cronbach's alpha were 0.834 and 0.859 for NCCT, 0.876 and 0.894 for CTA, and 0.903 and 0.911 for CTP-CBV, respectively. Performance for individual ASPECTS regions was inferior to total ASPECTS, but incremental improvement in interobserver reliability was demonstrated for NCCT, CTA-SI, and CTP-CBV, respectively. Highest concordance was shown for caudate, lentiform, and M1-M3, whereas performance for internal capsule and M4-M6 was poorer. CONCLUSIONS: CTP-CBV demonstrates the highest interobserver agreement for individual ASPECTS regions. PMID- 23103491 TI - Baseline smoking status and the long-term risk of death or nonfatal vascular event in people with stroke: a 10-year survival analysis. AB - BACKGROUND AND PURPOSE: Smoking may exacerbate the risk of death or further vascular events in those with stroke, but data are limited. METHODS: 1589 cases of first-ever and recurrent stroke were recruited between 1996 and 1999 from a defined geographical region in North East Melbourne. Both hospital and nonhospital cases were included. Over a 10-year period, all deaths, recurrent stroke events, and acute myocardial infarctions that were reported at follow-up interviews were validated using medical records. Cox proportional hazards regression was used to assess the association between baseline smoking status (never, ex, and current) and outcome (death, acute myocardial infarction, or recurrent stroke). RESULTS: Patients who were current smokers (Hazard Ratio [HR], 1.30; 95% Confidence Interval [CI], 1.06-1.60; P=0.012) at the time of their stroke had poorer outcome when compared with those who had never smoked. Among those who survived the first 28 days of stroke, current smokers (HR, 1.42; 95% CI, 1.13-1.78; P<0.003) and ex-smokers (HR, 1.18; 95% CI, 1.01-1.39; P=0.039) at baseline had poorer outcome than those who had never smoked. Current smokers also had a greater risk of recurrent events than past smokers (HR, 1.23; 95% CI, 1.00 1.50; P=0.050). CONCLUSIONS: Patients who smoked at the time of their stroke or had smoked before their stroke had greater risk of death or recurrent vascular events when compared with patients who were never smokers. There are benefits of smoking cessation, with ex-smokers appearing to have a lesser risk of recurrent vascular events than current smokers. PMID- 23103492 TI - Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes. AB - Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 MUg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemia-reperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX. PMID- 23103493 TI - Marine n3 polyunsaturated fatty acids enhance resistance to mitochondrial permeability transition in heart failure but do not improve survival. AB - Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether they prolong survival in heart failure. Male delta sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA, or a 1:1 mixture of DHA + EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298 +/- 15 days in untreated hamsters and 335 +/- 17, 328 +/- 14, and 311 +/- 15 days with DHA, EPA, and DHA + EPA, respectively (n = 27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters but does not prolong survival or improve cardiac function. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure. PMID- 23103494 TI - Taming the "sleeping giant": the role of endothelin-1 in the regulation of skeletal muscle blood flow and arterial blood pressure during exercise. AB - The cardiovascular response to exercise is governed by a combination of vasodilating and vasoconstricting influences that optimize exercising muscle perfusion while protecting mean arterial pressure (MAP). The degree to which endogenous endothelin (ET)-1, the body's most potent vasoconstrictor, participates in this response is unknown. Thus, in eight young (24 +/- 2 yr), healthy volunteers, we examined leg blood flow, MAP, tissue oxygenation, heart rate, leg arterial-venous O(2) difference, leg O(2) consumption, pH, and net ET-1 and lactate release at rest and during knee extensor exercise (0, 5, 10, 15, 20, and 30 W) before and after an intra-arterial infusion of BQ-123 [ET subtype A (ET(A)) receptor antagonist]. At rest, BQ-123 did not evoke a change in leg blood flow or MAP. During exercise, net ET-1 release across the exercising leg increased approximately threefold. BQ-123 increased leg blood flow by ~20% across all work rates (changes of 113 +/- 76, 176 +/- 83, 304 +/- 108, 364 +/- 130, 502 +/- 117, and 570 +/- 178 ml/min at 0, 5, 10, 15, 20, and 30 W, respectively) and attenuated the exercise-induced increase in MAP by ~6%. The increase in leg blood flow was accompanied by a ~9% increase in leg O(2) consumption with an unchanged arterial-venous O(2) difference and deoxyhemoglobin, suggesting a decline in intramuscular efficiency after ET(A) receptor blockade. Together, these findings identify a significant role of the ET-1 pathway in the cardiovascular response to exercise, implicating vasoconstriction via the ET(A) receptor as an important mechanism for both the restraint of blood flow in the exercising limb and maintenance of MAP in healthy, young adults. PMID- 23103495 TI - Identification of L- and T-type Ca2+ channels in rat cerebral arteries: role in myogenic tone development. AB - L-type Ca(2+) channels are broadly expressed in arterial smooth muscle cells, and their voltage-dependent properties are important in tone development. Recent studies have noted that these Ca(2+) channels are not singularly expressed in vascular tissue and that other subtypes are likely present. In this study, we ascertained which voltage-gated Ca(2+) channels are expressed in rat cerebral arterial smooth muscle and determined their contribution to the myogenic response. mRNA analysis revealed that the alpha(1)-subunit of L-type (Ca(v)1.2) and T-type (Ca(v)3.1 and Ca(v)3.2) Ca(2+) channels are present in isolated smooth muscle cells. Western blot analysis subsequently confirmed protein expression in whole arteries. With the use of patch clamp electrophysiology, nifedipine sensitive and -insensitive Ba(2+) currents were isolated and each were shown to retain electrical characteristics consistent with L- and T-type Ca(2+) channels. The nifedipine-insensitive Ba(2+) current was blocked by mibefradil, kurtoxin, and efonidpine, T-type Ca(2+) channel inhibitors. Pressure myography revealed that L-type Ca(2+) channel inhibition reduced tone at 20 and 80 mmHg, with the greatest effect at high pressure when the vessel is depolarized. In comparison, the effect of T-type Ca(2+) channel blockade on myogenic tone was more limited, with their greatest effect at low pressure where vessels are hyperpolarized. Blood flow modeling revealed that the vasomotor responses induced by T-type Ca(2+) blockade could alter arterial flow by ~20-50%. Overall, our findings indicate that L- and T-type Ca(2+) channels are expressed in cerebral arterial smooth muscle and can be electrically isolated from one another. Both conductances contribute to myogenic tone, although their overall contribution is unequal. PMID- 23103498 TI - Role of endothelin-A receptors in optic nerve head red cell flux regulation during isometric exercise in healthy humans. AB - Endothelin-1 (ET-1) is an important regulator of vascular tone in the eye. It appears to play a role in ocular disease because of its strong vasoconstrictor action, its role in intraocular pressure homeostasis, and its neurotoxic potential. We have previously shown that ET-1 is involved in choroidal red cell flux (RCF) regulation during isometric exercise in healthy humans. In the present study we hypothesized that ET-1 also plays a role in optic nerve head (ONH) RCF regulation during isometric exercise. To test this hypothesis, we performed a randomized, double-masked, placebo-controlled, two-way crossover study in 15 healthy volunteers. Subjects were randomized to receive intravenous infusions of the specific endothelin type A receptor antagonist BQ-123 and placebo on two different study days. During these infusion periods, subjects performed squatting for 6 min to increase ocular perfusion pressure (OPP). ONH RCF was assessed with laser-Doppler flowmetry, and OPP was calculated from mean arterial pressure and intraocular pressure. BQ-123 did not change OPP or ONH RCF at baseline. The relative increase in OPP during isometric exercise was comparable between both groups (between 84 and 88%, P = 0.76 between groups; P < 0.001 vs. baseline). Isometric exercise increased ONH RCF during placebo and BQ-123, but the increase was more pronounced when the endothelin type-A receptor antagonist was administered (placebo, 27.3 +/- 5.4%; and BQ-123, 39.2 +/- 4.4%; P = 0.007 between groups). The present data indicate that ET-1 regulates red cell flux in the ONH beyond the autoregulatory range. PMID- 23103497 TI - Chronic hypoxia decreases arterial and venous compliance in isolated perfused rat lungs: an effect that is reversed by exogenous L-arginine. AB - Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (C(a)) in right ventricular work, a decrease in C(a) would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from L-arginine (L-Arg). However, little is known of the effect of L-Arg on vascular compliance (C(v)) in the lung. We hypothesized that exposure to CH would decrease C(a) and that this effect would be reversed by exogenous L-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R(0)). Hypoxia resulted in the expected increase in arterial resistance (R(a)) as well as a decrease in both C(a) and C(v). L-Arg had little effect on R(a), C(a), or C(v) in isolated lungs from normoxic animals. L-Arg decreased R(a) in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R(0), and L-Arg reversed this increase in R(0). L-Arg increased exhaled NO, and inhibition of L-Arg uptake attenuated the L-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in C(a) was reversed by L-Arg, suggesting that L-Arg may improve CH-induced right ventricular dysfunction. PMID- 23103500 TI - High-throughput screening of drug-binding dynamics to HERG improves early drug safety assessment. AB - The use of computational models to predict drug-induced changes in the action potential (AP) is a promising approach to reduce drug safety attrition but requires a better representation of more complex drug-target interactions to improve the quantitative prediction. The blockade of the human ether-a-go-go related gene (HERG) channel is a major concern for QT prolongation and Torsade de Pointes risk. We aim to develop quantitative in-silico AP predictions based on a new electrophysiological protocol (suitable for high-throughput HERG screening) and mathematical modeling of ionic currents. Electrophysiological recordings using the IonWorks device were made from HERG channels stably expressed in Chinese hamster ovary cells. A new protocol that delineates inhibition over time was applied to assess dofetilide, cisapride, and almokalant effects. Dynamic effects displayed distinct profiles for these drugs compared with concentration effects curves. Binding kinetics to specific states were identified using a new HERG Markov model. The model was then modified to represent the canine rapid delayed rectifier K(+) current at 37 degrees C and carry out AP predictions. Predictions were compared with a simpler model based on conductance reduction and were found to be much closer to experimental data. Improved sensitivity to concentration and pacing frequency variables was obtained when including binding kinetics. Our new electrophysiological protocol is suitable for high-throughput screening and is able to distinguish drug-binding kinetics. The association of this protocol with our modeling approach indicates that quantitative predictions of AP modulation can be obtained, which is a significant improvement compared with traditional conductance reduction methods. PMID- 23103501 TI - Thermodynamically unfavorable DNA hybridizations can be made to occur by a water to ice phase change. AB - In an apparent contradiction to Debye-Huckel theory, it was possible to hybridize DNA in solutions of Milli-Q water (resistivity>18MOmegacm(-1)) containing no added ions. This was demonstrated by hybridizing four bi-complementary DNA sequences to form an 'X' shape, as indicated by acrylamide gel electrophoresis. The requirement for hybridization was that a water-to-ice phase change should occur. Comparative experiments, using freezing by liquid nitrogen and thawing at different temperatures, showed that hybridization could take place during either the freezing or thawing process provided either was slow enough. We speculate that the low solubility of DNA in ice creates liquid inclusions of extremely high DNA and counter-ion concentration prior to complete freezing, and that hence in these inclusions hybridization was actually in accordance with Debye-Huckel theory. PMID- 23103499 TI - Pkd2 mesenteric vessels exhibit a primary defect in endothelium-dependent vasodilatation restored by rosiglitazone. AB - Patients with autosomal dominant polycystic kidney disease have a high prevalence of hypertension and structural vascular abnormalities, such as intracranial aneurysms. Hypertension can develop in childhood and often precedes a significant reduction in the glomerular filtration rate. The major aim of this study was to investigate whether a primary endothelial defect or a vascular smooth muscle (VSM) defect was present in murine polycystic kidney disease (Pkd)2 heterozygous mesenteric vessels before the development of renal failure or hypertension. Using pressure myography, we observed a marked defect in ACh-stimulated endothelium dependent vasodilatation in Pkd2 arterioles. In contrast, Pkd2 vessels responded normally to sodium nitroprusside, phenylephrine, KCl, and pressure, indicating unaltered VSM-dependent responses. Pretreatment with the peroxisome proliferator activated receptor-gamma agonist rosiglitazone significantly restored ACh dependent vasodilation in Pkd2 mice. Isolated heterozygous Pkd2 endothelial cells displayed normal ACh-stimulated Ca(2+) and nitric oxide production. However, isolated Pkd2 heterozygous VSM cells displayed basal increases in superoxide and sodium nitroprusside-stimulated peroxynitrite formation, which were both suppressed by rosiglitazone. Furthermore, we observed a defective response of Pkd2 mesenteric venules to ACh in vivo, which was more marked after ischemia reperfusion injury. In conclusion, the results of our study suggest that the defect in vasodilatation in Pkd2 heterozygous vessels is primarily due to a reduction in nitric bioavailability secondary to increased vascular oxidative stress. The ability of rosiglitazone to correct this phenotype suggests that this defect is potentially reversible in patients with autosomal dominant polycystic kidney disease. PMID- 23103502 TI - Herkinorin dilates cerebral vessels via kappa opioid receptor and cyclic adenosine monophosphate (cAMP) in a piglet model. AB - Since herkinorin is the first non-opioid mu agonist derived from salvinorin A that has the ability to induce cerebral vascular dilatation, we hypothesized that herkinorin could have similar vascular dilatation effect via the mu and kappa opioid receptors and the cAMP pathway. The binding affinities of herkinorin to kappa and mu opioid receptors were determined by in-vitro competition binding assays. The cerebral arteries were monitored in piglets equipped with a closed cranial window and the artery responses were recorded before and every 30s after injection of artificial cerebrospinal fluid (CSF) in the presence or absence of the investigated drugs: herkinorion, norbinaltorphimine (NTP), a kappa opioid receptor antagonist, beta-funaltrexamine (beta-FNA), a mu opioid receptor antagonist, or Rp-8-Br-cAMPS (Rp-cAMPS), an inhibitor of protein kinase A (PKA). CSF samples were collected before and 10 min after herkinorin and NTP administration for the measurement of cAMP levels. Data were analyzed by repeated measures analysis of variance. Our results show that herkinorin binds to both kappa and mu opioid receptors. Its vasodilation effect is totally abolished by NTP, but is not affected by beta-FNA. The levels of cAMP in the CSF elevate after herkinorin administration, but are abolished with NTP administration. The cerebral vasodilative effect of herkinorin is also blunted by Rp-cAMPS. In conclusion, as a non-opioid kappa and mu opioid receptor agonist, herkinorin exhibits cerebral vascular dilatation effect. The dilatation is mediated though the kappa opioid receptor rather than the mu opioid receptor. cAMP signaling also plays an important role in this process. PMID- 23103504 TI - Complex modulation of the expression of PKC isoforms in the rat brain during chronic type 1 diabetes mellitus. AB - We previously demonstrated that chronic hyperglycemia has a detrimental influence on neurovascular coupling in the brain-an effect linked to an alteration in the protein kinase C (PKC)-mediated phosphorylation pattern. Moreover, the activity of PKC was increased, in diabetic rat brain, in a tissue fraction composed primarily of the superficial glia limitans and pial vessels, but trended toward a decrease in cerebral cortical gray matter. However, that study did not examine the expression patterns of PKC isoforms in the rat brain. Thus, in a rat model of streptozotocin (STZ)-induced chronic type 1 diabetes mellitus (T1DM), and in non diabetic (ND) controls, two hypotheses were addressed. First, chronic T1DM is accompanied by changes in the expression of PKC-alpha, betaII, gamma, delta, and epsilon Second, those changes differ when comparing cerebral cortex and glio-pial tissue. In addition, we analyzed the expression of a form of PKC-gamma, phosphorylated on threonine 514 (pT514-PKC-gamma), as well as the receptor for activated C kinase 1 (RACK1). The expression pattern of different PKC isoforms was altered in a complex and tissue-specific manner during chronic hyperglycemia. Notably, in the gray matter, PKC-alpha expression significantly decreased, while pT514-PKC-gamma expression increased. However, PKC-betaII, -gamma, -delta, epsilon, and RACK1 expressions did not change. Conversely, in glio-pial tissue, PKC-alpha and RACK1 were upregulated, whereas PKC-gamma, pT514-PKC-gamma, and PKC epsilon were downregulated. PKC-betaII, and PKC-delta, were unchanged. These findings suggest that the PKC activity increase previously seen in the glio-pial tissue of diabetic rats may be due to the selective upregulation of PKC-alpha, and ultimately lead to the impairment of neurovascular coupling. PMID- 23103503 TI - Presenilin-null cells have altered two-pore calcium channel expression and lysosomal calcium: implications for lysosomal function. AB - Presenilins are necessary for calcium homeostasis and also for efficient proteolysis through the autophagy/lysosome system. Presenilin regulates both endoplasmic reticulum calcium stores and autophagic proteolysis in a gamma secretase independent fashion. The endo-lysosome system can also act as a calcium store, with calcium efflux channels being recently identified as two-pore channels 1 and 2. Here we investigated lysosomal calcium content and the channels that mediate calcium release from these acidic stores in presenilin knockout cells. We report that presenilin loss leads to a lower total lysosomal calcium store despite the buildup of lysosomes found in these cells. Additionally, we find alterations in two-pore calcium channel protein expression, with loss of presenilin preventing the formation of a high molecular weight species of TPC1 and TPC2. Finally, we find that treatments that disturb lysosomal calcium release lead to a reduction in autophagy function yet lysosomal inhibitors do not alter two-pore calcium channel expression. These data indicate that alterations in lysosomal calcium in the absence of presenilins might be leading to disruptions in autophagy. PMID- 23103505 TI - The toll-like receptor 4-mediated signaling pathway is activated following optic nerve injury in mice. AB - Toll-like receptor 4 (TLR4) has been demonstrated to play an important role during aseptic inflammation caused by nervous system diseases. The purpose of this study was to explore the underlying mechanism(s) regulating TLR4-mediated signaling and aseptic inflammatory responses following optic nerve injury in mice. We successfully generated an optic nerve crush model in mice in which the optic nerve upregulated TLR4 following injury. The protein expression levels of TLR4, Mac1, MyD88, NF-kappaB, IL-6 and TNF-alpha were significantly increased after optic nerve injury. Moreover, the expression levels of TLR4, NF-kappaB and TNF-alpha were robust at 2 weeks following injury; however, TRIF protein expression levels were low. In addition, we found that the mRNA transcript levels of MyD88 were higher than TRIF. IL-6 and TNF-alpha exhibited a statistically significant increase in their expression at 1 day, 1 week, 2 weeks and 3 weeks after optic nerve injury, compared with the normal and sham control groups (p value <0.05). Therefore, the TLR4-mediated signaling pathway is activated following optic nerve injury in mice. We found that TLR4-MyD88-NF-kappaB signaling is the main signaling pathway activated in TLR4-mediated inflammation. Our results suggest this pathway may be a main pathway mediating inflammatory responses following optic nerve injury. This may provide insight into novel regenerative targets for the treatment of nerve injury. PMID- 23103506 TI - Nanoencapsulation of quercetin and resveratrol into elastic liposomes. AB - Based on the fact that quercetin (QUE) and resveratrol (RES) induce a synergic inhibition of the adipogenesis and increase apoptosis in adipocytes, and that sodium deoxycholate (SDC) has necrotic effects, the nanoencapsulation of QUE and RES into SDC-elastic liposomes is proposed as a new approach for dissolving the subcutaneous fat. The concentration of constituents and the effect of the drug incorporation into cyclodextrin inclusion complexes on the stability of QUE/RES loaded liposomes were studied. The best liposomal formulation reduced the use of phosphatidylcholine and cholesterol in 17.7% and 68.4%, respectively. Liposomes presented a mean diameter of 149nm with a polydispersion index of 0.3. The zeta potential of liposomes was slightly negative (-13.3mV) due to the presence of SDC in the phospholipid bilayer. Encapsulation efficiency of QUE and RES into liposomes was almost 97%. To summarize, QUE/RES-loaded elastic liposomes are stable and suitable for subcutaneous injection, thereby providing a new strategy for reducing subcutaneous fat. PMID- 23103507 TI - A lipid-dependent link between activity and oligomerization state of the M. tuberculosis SMR protein TBsmr. AB - TBsmr is a secondary active multidrug transporter from Mycobacterium tuberculosis that transports a plethora of compounds including antibiotics and fluorescent dyes. It belongs to the small multidrug resistance (SMR) superfamily and is structurally and functionally related to E. coli EmrE. Of particular importance is the link between protein function, oligomeric state and lipid composition. By freeze fracture EM, we found three different size distributions in three different lipid environments for TBsmr indicating different oligomeric states. The link of these states with protein activity has been probed by fluorescence spectroscopy revealing significant differences. The drug binding site has been probed further by (19)F-MAS NMR through chemical labeling of native cysteine residues showing a water accessible environment in agreement with the alternating access model. PMID- 23103508 TI - Model for beta-1,6-N-acetylglucosamine oligomer hydrolysis catalysed by DispersinB, a biofilm degrading enzyme. AB - DispersinB (DspB), a member of beta-1,6-N-acetylglucosaminidase group of GH 20 glycoside hydrolases, catalyses the biofilm degradation of several human pathogenic microorganisms. DspB is a (beta/alpha)(8) barrel protein, showing retaining cleavage mechanism towards oligomer and polymer substrates. A chromophore containing oligomer substrate series was used to study the DspB's mode of action. The hydrolysis reaction of beta(1,6)-linked N-acetylglucosamine thiophenyl glycosides with degree of polymerisation of 2, 3, 4 and 5 was followed by reversed phase HPLC and progress curves were determined and analysed. Based on the analysis of process curves obtained from prolonged hydrolysis we assumed the presence of more productive binding modes resulting in parallel reactions followed by consecutive reaction steps. Strictly nonreducing-end specificity was observed, the presence of monomer, dimer and trimer nonreducing-end products was verified by MALDI-TOF MS. Another cleavage was suggested after the first glycosidic attack in the case of trimer, while two and three consecutive steps were possible in tetramer and pentamer hydrolyses, respectively. Chain lengthening increased catalytic efficiency (2.1->8.6M(-1)s(-1)) and calculated kinetic constants showed a similarly increasing tendency (1.0->6.7 * 10(-3) min( 1)). PMID- 23103509 TI - Revisit of the phenol O-glycosylation with glycosyl imidates, BF3.OEt2 is a better catalyst than TMSOTf. AB - With BF(3).OEt(2) as the catalyst, the glycosylation of phenols with glycosyl trichloroacetimidates (or N-phenyl trifluoroacetimidates) bearing 2-O participating groups leads to the desired 1,2-trans-O-glycosides in generally excellent yields without formation of the 1,2-cis-anomers. However, with TMSOTf as the catalyst, the outcomes of the corresponding phenol O-glycosylation are highly dependent on the nucleophilicity of the phenols; less nucleophilic is the phenol, higher amounts of the 1,2-cis-O-glycoside together with more side products are generated. 1,2-Orthoesters have been found to be the major products at a low temperature (<-70 degrees C) in all these phenol O-glycosylation reactions, which are transformed into the final products at a higher temperature. BF(3).OEt(2) is an effective catalyst to promote the conversion of 1,2 orthoesters into the corresponding 1,2-trans-O-glycosides. However, the 1,2 orthoesters could be converted into the dioxolenium triflate and glycosyl triflate in the presence of TMSOTf, these intermediates which might be in equilibrium with the glycosyl oxocarbenium related species lead to the final mixture of the alpha/beta-O-glycosides and side-products. PMID- 23103511 TI - Occurrence and structure of cyclic Enterobacterial Common Antigen in Escherichia coli O157:H-. AB - Two cyclic forms of the Enterobacterial Common Antigen were isolated from Escherichia coli O157:H(-). These antigenic determinants were purified from the biomass through extensive chemical, enzymatic and chromatographic procedures whereas MALDI MS spectrometry indicated their cyclic nature with a polymerization degree of 4 or 5. The two species, denoted as ECA(CYC-4) and ECA(CYC-5), were assigned by NMR and showed no further substitution with other appendages such as acetyl groups as usually described for similar cyclic antigens from other Enterobacteriaceae. PMID- 23103510 TI - Detailed structural analysis of the O-polysaccharide expressed by Burkholderia thailandensis E264. AB - O-polysaccharide (OPS) was isolated from purified Burkholderia thailandensis E264 lipopolysaccharide by mild-acid hydrolysis and gel-permeation chromatography. Glycosyl composition and methylation analyses along with 1D and 2D (1)H and (13)C NMR spectroscopy experiments revealed that the OPS antigen was an unbranched heteropolymer with the following structure: [structure: see text] Collectively, these results suggest that B. thailandensis OPS is structurally more complex than B. pseudomallei OPS and provide evidence of the signal used by B. thailandensis to terminate chain elongation. PMID- 23103512 TI - Amino acids interference on the quantification of reducing sugars by the 3,5 dinitrosalicylic acid assay mislead carbohydrase activity measurements. AB - This study evaluated the interference of the amino acids tryptophan, cysteine, histidine, tyrosine, hydroxyproline, leucine, proline, serine, glycine, valine, glutamic acid, phenylalanine, and methionine on the measurement of reducing sugars using a phenol-free 3,5-dinitrosalicylic acid (DNS) reagent. It was found that in reaction mixtures containing 20mM of either tryptophan, cysteine, histidine, tyrosine, or hydroxyproline the measurement of 3.7 mM glucose was overestimated by 76%, 50%, 35%, 18%, and 10%, respectively. The amino acids valine, glutamic acid, and phenylalanine did not affect the DNS reaction, while methionine decreased the color development by 5%. The measurement of glucose, xylose, arabinose, and cellobiose at the 3.7-12.4 mM range in the presence of 20 mM cysteine resulted in an overestimated concentration of 34.8-50%. Enzymatic assays for measuring xylanolytic and filter paper activity (FPAse) were conducted in the presence of 20-60 mM cysteine, and compared to cysteine-free assays. In the presence of cysteine, the measured xylanase activity increased threefold and the FPAse activity increased twofold due to the overestimation of the reducing sugar concentrations in the assays. The interference from cysteine was reduced to a maximum of 8.6% when a DNS reagent containing phenol was used. PMID- 23103515 TI - Calcium/calmodulin-dependent protein kinase IV (CaMKIV) enhances osteoclast differentiation via the up-regulation of Notch1 protein stability. AB - The Notch signaling pathway plays a crucial role in the regulation of cell fate decision, and is also a key regulator of cell differentiation, including bone homeostasis, in a variety of contexts. However, the role of Notch1 signaling in osteoclast differentiation is still controversial. In this study, we show that Receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation is promoted by the Notch1 intracellular domain (Notch1-IC) and Ca(2+)/Calmodulin dependent protein kinase IV (CaMKIV) signaling. Notch1-IC protein level was augmented by CaMKIV through escape from ubiquitin dependent protein degradation. In addition, CaMKIV remarkably increased Notch1-IC stability, and the kinase activity of CaMKIV was essential for facilitating Notch1 signaling. CaMKIV directly interacted with Notch1-IC and phosphorylates Notch1-IC, thereby decreasing proteasomal protein degradation through F-box and WD repeat domain-containing 7 (Fbw7). We also found that Notch1-IC prevented inhibition of osteoclast differentiation by KN-93 but not the phosphorylation deficient form of Notch1-IC. These results suggest that phosphorylated Notch1-IC by CaMKIV increases Notch1-IC stability, which enhances osteoclast differentiation. PMID- 23103514 TI - A divalent interaction between HPS1 and HPS4 is required for the formation of the biogenesis of lysosome-related organelle complex-3 (BLOC-3). AB - Hermansky-Pudlak syndrome (HPS) is a group of rare autosomal recessive disorders characterized by oculocutaneous albinism, a bleeding tendency, and sporadic pulmonary fibrosis, granulomatous colitis or infections. Nine HPS-causing genes have been identified in humans. HPS-1 is the most severe subtype with a prevalence of ~1/1800 in northwest Puerto Rico due to a founder mutation in the HPS1 gene. Mutations in HPS genes affect the biogenesis of lysosome-related organelles such as melanosomes in melanocytes and platelet dense granules. Two of these genes (HPS1 and HPS4) encode the HPS1 and HPS4 proteins, which assemble to form a complex known as Biogenesis of Lysosome-related Organelle Complex 3 (BLOC 3). We report the identification of the interacting regions in HPS1 and HPS4 required for the formation of this complex. Two regions in HPS1, spanning amino acids 1-249 and 506-700 are required for binding to HPS4; the middle portion of HPS1 (residues 250-505) is not required for this interaction. Further interaction studies showed that the N-termini of HPS1 and HPS4 interact with each other and that a discrete region of HPS4 (residues 340-528) interacts with both the N- and C-termini of the HPS1 protein. Several missense mutations found in HPS-1 patients did not affect interaction with HPS4, but some mutations involving regions interacting with HPS4 caused instability of HPS1. These observations extend our understanding of BLOC-3 assembly and represent an important first step in the identification of domains responsible for the biogenesis of lysosome-related organelles. PMID- 23103516 TI - GM-CSF promotes inflammatory dendritic cell formation but does not contribute to disease progression in experimental autoimmune myocarditis. AB - BACKGROUND: Granulocyte macrophage-colony stimulating factor (GM-CSF) is critically required for the induction of experimental autoimmune myocarditis (EAM), a model of post-inflammatory dilated cardiomyopathy. Its specific role in the progression of myocarditis into end stage heart failure is not known. METHODS AND RESULTS: BALB/c mice were immunized with myosin peptide and complete Freund's adjuvant at days 0 and 7. Heart-infiltrating inflammatory CD133(+) progenitors were isolated from inflamed hearts at the peak of inflammation (day 21). In the presence of GM-CSF, inflammatory CD133(+) progenitors up-regulated integrin, alpha X (CD11c), class II major histocompatibility complex, CD80 and CD86 co stimulatory molecules reflecting an inflammatory dendritic cell (DC) phenotype. Inflammatory DCs stimulated antigen-specific CD4(+) T cell proliferation and induced myocarditis after myosin peptide loading and adoptive transfer in healthy mice. Moreover, GM-CSF treatment of mice after the peak of disease, between days 21 and 29 of EAM, transiently increased accumulation of inflammatory DCs in the myocardium. Importantly, bone marrow-derived CD11b(+) monocytes, rather than inflammatory CD133(+) progenitors represent the dominant cellular source of heart infiltrating inflammatory DCs in EAM. In contrast, GM-CSF treatment neither affected numbers of heart-infiltrating CD45(+) and CD3(+) T cells nor the development of post-inflammatory fibrosis. CONCLUSIONS: GM-CSF treatment promotes formation of inflammatory DCs in EAM. In contrast to the active roles of GM-CSF and DCs in EAM induction, GM-CSF-induced inflammatory DCs neither prevent resolution of active inflammation, nor contribute to post-inflammatory cardiac remodelling. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID- 23103517 TI - Towards a neural circuit model of verbal humor processing: an fMRI study of the neural substrates of incongruity detection and resolution. AB - The present study builds on our previous study within the framework of Wyer and Collin's comprehension-elaboration theory of humor processing. In this study, an attempt is made to segregate the neural substrates of incongruity detection and incongruity resolution during the comprehension of verbal jokes. Although a number of fMRI studies have investigated the incongruity-resolution process, the differential neurological substrates of comprehension are still not fully understood. The present study utilized an event-related fMRI design incorporating three conditions (unfunny, nonsensical and funny) to examine distinct brain regions associated with the detection and resolution of incongruities. Stimuli in the unfunny condition contained no incongruities; stimuli in the nonsensical condition contained irresolvable incongruities; and stimuli in the funny condition contained resolvable incongruities. The results showed that the detection of incongruities was associated with greater activation in the right middle temporal gyrus and right medial frontal gyrus, and the resolution of incongruities with greater activation in the left superior frontal gyrus and left inferior parietal lobule. Further analysis based on participants' rating scores provided converging results. Our findings suggest a three-stage neural circuit model of verbal humor processing: incongruity detection and incongruity resolution during humor comprehension and inducement of the feeling of amusement during humor elaboration. PMID- 23103513 TI - Multilayered regulation of cardiac ion channels. AB - Essential to beat-to-beat heart function is the ability for cardiomyocytes to propagate electrical excitation and generate contractile force. Both excitation and contractility depend on specific ventricular ion channels, which include the L-type calcium channel (LTCC) and the connexin 43 (Cx43) gap junction. Each of these two channels is localized to a distinct subdomain of the cardiomyocyte plasma membrane. In this review, we focus on regulatory mechanisms that govern the lifecycles of LTCC and Cx43, from their biogenesis in the nucleus to directed delivery to T-tubules and intercalated discs, respectively. We discuss recent findings on how alternative promoter usage, tissue-specific transcription, and alternative splicing determine precise ion channel expression levels within a cardiomyocyte. Moreover, recent work on microtubule and actin-dependent trafficking for Cx43 and LTCC are introduced. Lastly, we discuss how human cardiac disease phenotypes can be attributed to defects in distinct mechanisms of channel regulation at the level of gene expression and channel trafficking. This article is part of a Special Issue entitled: Cardiomyocyte Biology: Cardiac Pathways of Differentiation, Metabolism and Contraction. PMID- 23103518 TI - Preparatory patterns of neural activity predict visual category search speed. AB - Rapidly detecting target object categories when objects are embedded in naturalistic scenes is facilitated by preparatory baseline signal changes. However, it is unclear as to what information most strongly predicts perceptual speed in terms of the minimal exposure duration required for accurate detection. Using novel surface-based spatiotemporal pattern classification, we found that while category-specific biases resulting from merely providing a category name can be detected in multiple cortical areas, only biases in lateral occipital complex predicted perceptual speed. These biases likely carry visual semantic information regarding multiple object categories placed in familiar scene contexts. Discriminatory voxels during the preparatory period showed congruent category-selectivity during visual stimulation. PMID- 23103519 TI - Long-term electrical resistivity monitoring of recharge-induced contaminant plume behavior. AB - Geophysical measurements, and electrical resistivity tomography (ERT) data in particular, are sensitive to properties that are related (directly or indirectly) to hydrological processes. The challenge is in extracting information from geophysical data at a relevant scale that can be used to gain insight about subsurface behavior and to parameterize or validate flow and transport models. Here, we consider the use of ERT data for examining the impact of recharge on subsurface contamination at the S-3 ponds of the Oak Ridge Integrated Field Research Challenge (IFRC) site in Tennessee. A large dataset of time-lapse cross well and surface ERT data, collected at the site over a period of 12 months, is used to study time variations in resistivity due to changes in total dissolved solids (primarily nitrate). The electrical resistivity distributions recovered from cross-well and surface ERT data agrees well, and both of these datasets can be used to interpret spatiotemporal variations in subsurface nitrate concentrations due to rainfall, although the sensitivity of the electrical resistivity response to dilution varies with nitrate concentration. Using the time-lapse surface ERT data interpreted in terms of nitrate concentrations, we find that the subsurface nitrate concentration at this site varies as a function of spatial position, episodic heavy rainstorms (versus seasonal and annual fluctuations), and antecedent rainfall history. These results suggest that the surface ERT monitoring approach is potentially useful for examining subsurface plume responses to recharge over field-relevant scales. PMID- 23103520 TI - Gaps, disconnections, and discontinuities--the role of information exchange in the delivery of quality long-term care. AB - PURPOSE OF THE STUDY: The smart use of information and communication technologies (ICT) is widely seen as a means of enhancing the quality of aged care services. One of the barriers to ICT diffusion in aged care is the failure to cater for the complex and interdisciplinary requirements of the aged care environment. The aim of this qualitative study was to identify the layers of information exchange and communication and produce a conceptual model that can help to inform decisions related to the design, implementation, and sustainability of ICT. DESIGN AND METHODS: A qualitative study conducted in 2010 within seven Australian residential aged care facilities. It included 11 focus groups involving 47 staff and 54 individual interviews and observation sessions. RESULTS: The analysis of work processes identified key information exchange components related to the type of information (residential, clinical, and administrative) that is collected, stored, and communicated. This information relies on a diverse number of internal and external communication channels that are important for the organization of care. IMPLICATIONS: The findings highlight potential areas of communication dysfunction as a consequence of structural holes, fragmentation, or disconnections that can adversely affect the continuity and coordination of care, its safety, and quality. PMID- 23103521 TI - Modeling causes of aggressive behavior in patients with dementia. AB - PURPOSE OF THE STUDY: To examine factors predicting development of aggression in patients with dementia as a step toward developing preventive strategies and nonpharmacologic therapies. DESIGN AND METHODS: Study participants were 171 nonaggressive, community-residing VA patients aged more than 60, newly diagnosed with dementia. Patients and caregivers were assessed at baseline and at months 5, 9, 13, 17, 21, and 25. Aggression was evaluated using the Cohen-Mansfield Agitation Inventory. Survival models incorporating direct and indirect effects were conducted to estimate associations between psychosocial factors (baseline and change measures of dementia severity, pain, depression, caregiver burden, patient-caregiver relationship, and nonaggressive physical agitation) and time to aggression onset. RESULTS: Higher levels of baseline caregiver burden, worst pain, declining patient-caregiver relationship, and increasing nonaggressive physical agitation predicted increased risk of aggression. Baseline dementia severity and depression were indirectly related to onset of aggression. The association between increasing nonaggressive physical agitation and time to aggression onset was independent of the associations between our psychosocial measures and time to aggression onset. IMPLICATIONS: Potentially mutable factors were associated with development of aggression. The longitudinal design of this study and its sample of newly diagnosed, previously nonaggressive dementia patients strengthen prior findings in the literature. PMID- 23103522 TI - Temporal horizons in pain management: understanding the perspectives of physicians, physical therapists, and their middle-aged and older adult patients. AB - PURPOSE: The management of chronic noncancer pain (CNCP) involves trade-offs between immediate and delayed consequences of various treatments. Temporal trade offs may be particularly salient for older adults because of age-related differences in prognosis and perceptions of future time. This study examined how perceptions of time influence the management of CNCP among patients and providers with particular emphasis on age differences. DESIGN AND METHODS: Focus groups were conducted with 28 CNCP patients (5 groups), 21 physicians (4 groups), and 23 physical therapists (3 groups). Audiotapes were transcribed and analyzed using standard qualitative methods. RESULTS: Analyses identified multiple aspects of time perceptions that are relevant to the management of CNCP: the long-term prognosis, the time horizon used for concrete treatment planning, and concerns about future side effects. Although there was some overlap, these aspects showed divergent patterns across age groups and between patients and providers. Patients and providers agreed that pain is more stable and chronic in older adults. Time horizons in treatment planning differed between patients who were present-focused and providers who were focused on longer term effects, but treatment horizons did not differ by patient age. Finally, although providers were more concerned about future side effects in older people, patients' concerns did not differ by age. IMPLICATIONS: Time horizons have practical implications for the quality of the patient-provider relationship and self-management of CNCP. A better understanding of the underlying mechanisms could inform interventions to reduce age disparities in pain care. PMID- 23103523 TI - Associations among indicators of depression in Medicaid-eligible community dwelling older adults. AB - PURPOSE: The purpose of this research was to examine associations among 2 separate Minimum Data Set-Home Care (MDS-HC) depression measures (the Depression Rating Scale [DRS] and medical diagnosis of depression) with billed antidepressant medications in Medicaid paid claim files. DESIGN AND METHODS: The sample for this cross-sectional research included 3,041 Medicaid-eligible older adult participants in a Home and Community Based Waiver Program and used data from the MDS-HC, Version 1 and Medicaid Paid Claim Files. Sensitivity and specificity analyses, receiver operating characteristic (ROC) curve analysis, and t tests were utilized. RESULTS: DRS scoring indicated that 15.4% of participants had behaviors indicative of depression, whereas 42% had a medical diagnosis of depression noted in the MDS-HC. Of those with a medical diagnosis of depression, 51% had a prescribed antidepressant medication. ROC analysis suggested that the DRS was a poor distinguisher of participants with and without a medical diagnosis of depression or prescribed antidepressant medications. IMPLICATIONS: Approximately half of Medicaid-eligible older adults medically diagnosed with depression were treated pharmacologically. Longitudinal research is recommended to assess responsiveness of the DRS over time to pharmacological and psychotherapeutic interventions for depression. PMID- 23103524 TI - Structural and functional interaction of (+/-)-2-(N-tert-butylamino)-3'-iodo-4' azidopropiophenone, a photoreactive bupropion derivative, with nicotinic acetylcholine receptors. AB - The pharmacological properties of (+/-)-2-(N-tert-butylamino)-3'-iodo-4' azidopropiophenone [(+/-)-SADU-3-72], a photoreactive analog of bupropion (BP), were characterized at different muscle nicotinic acetylcholine receptors (AChRs) by functional and structural approaches. Ca2+ influx results indicate that (+/-) SADU-3-72 is 17- and 6-fold more potent than BP in inhibiting human (h) embryonic (halpha1beta1gammadelta) and adult (halpha1beta1epsilondelta) muscle AChRs, respectively. (+/-)-SADU-3-72 binds with high affinity to the [3H]TCP site within the resting or desensitized Torpedo AChR ion channel, whereas BP has higher affinity for desensitized AChRs. Molecular docking results indicate that both SADU-3-72 enantiomers interact with the valine (position 13') and serine (position 6') rings. However, an additional domain, between the outer (position 20') and valine rings, is observed in Torpedo AChR ion channels. Our results indicate that the azido group of (+/-)-SADU-3-72 may enhance its interaction with polar groups and the formation of hydrogen bonds at AChRs, thus supporting the observed higher potency and affinity of (+/-)-SADU-3-72 compared to BP. Collectively our results are consistent with a model where BP/SADU-3-72 and TCP bind to overlapping sites within the lumen of muscle AChR ion channels. Based on these results, we believe that (+/-)-SADU-3-72 is a promising photoprobe for mapping the BP binding site, especially within the resting AChR ion channel. PMID- 23103525 TI - Structural, biological, and pharmacological strategies for the inhibition of nerve growth factor. AB - Nerve growth factor (NGF) is critical for the development and maintenance of sympathetic and sensory neurons in the developing nervous system, including nociceptors. In the adult nervous system, NGF is known to produce significant pain signals by binding to the TrkA and p75NTR receptors. Several pathological pain disorders are associated with nerve growth factor dysregulation, including neuropathic pain, osteoarthritic pain, and hyperalgesia. Currently, clinical management of these pathologies has relied on the use of opioid and non-steroidal anti-inflammatory drugs (NSAID). However, several chronic pain conditions demonstrate insensitivity to NSAID treatment or the development of detrimental opioid-related side effects, including addiction. As NGF plays an important role in pain generation; antibodies, small molecules and peptides have been designed to antagonize NGF. In this review, we discuss the structural biology of NGF ligand/receptor interaction, and we review current biological and pharmacological strategies to modulate NGF-related pathologies. PMID- 23103526 TI - Feasibility of using PRESAGE(r) for relative 3D dosimetry of small proton fields. AB - Small field dosimetry is challenging due to the finite size of the conventional detectors that underestimate the dose distribution. With the fast development of the dynamic proton beam delivery system, it is essential to find a dosimeter which can be used for 3D dosimetry of small proton fields. We investigated the feasibility of using a proton formula PRESAGE(r) for 3D dosimetry of small fields in a uniform scanning proton beam delivery system with dose layer stacking technology. The relationship between optical density and the absorbed dose was found to be linear through small volume cuvette studies for both photon and proton irradiation. Two circular fields and three patient-specific fields were used for proton treatment planning calculation and beam delivery. The measured results were compared with the calculated results in the form of lateral dose profiles, depth dose, isodose plots and gamma index analysis. For the circular field study, lateral dose profile comparison showed that the relative PRESAGE(r) profile falls within +/- 5% from the calculated profile for most of the spatial range. For unmodulated depth dose comparison, the agreement between the measured and calculated results was within 3% in the beam entrance region before the Bragg peak. However, at the Bragg peak, there was about 20% underestimation of the absorbed dose from PRESAGE(r). For patient-specific field 3D dosimetry, most of the data points within the target volume passed gamma analysis for 3% relative dose difference and 3 mm distance to agreement criteria. Our results suggest that this proton formula PRESAGE(r) dosimeter has the potential for 3D dosimetry of small fields in proton therapy, but further investigation is needed to improve the dose under-response of the PRESAGE(r) in the Bragg peak region. PMID- 23103527 TI - Efficacy and safety of local versus general anesthesia in stereotactic biopsies: a matched-pairs cohort study. AB - BACKGROUND: Frame-based stereotactic biopsies remain the gold standard for the diagnosis of intracerebral lesions. A major advantage is the ability to perform these procedures under local anesthesia (LA). However, there is no consensus on whether or when to use LA or general anesthesia (GA). It has been postulated that the use of LA may reduce the risk of complications. This study aims to objectify the efficacy and safety of stereotactic biopsies under LA versus GA by analyzing a prospective registry for stereotactic biopsies. METHODS: A prospective registry for stereotactic procedures was analyzed for the activities performed between May 2009 and August 2011. Inclusion criteria were patients undergoing a stereotactic biopsy. Patients with functional stereotactic procedures, cyst or abscess evacuation, and children were excluded. Of the remaining 274 patients, 204 could be randomly matched considering sex, age, American Society of Anesthesiologists (ASA) classification, and type of hospitalization. The primary endpoint was the diagnostic yield. Secondary endpoints were safety and procedural time intervals. RESULTS: Ninety-six percent of diagnosis was achieved in the LA group and 94% within the GA group. There was no significant difference in the overall complication rate. However, the rate of pulmonary complications was higher in the GA group (P=0.059). The rate of bleeding was significantly higher in the LA group (P=0.003) intraoperatively. However, no significant difference was found clinically or on routine postoperative computed tomography scan reports. There was a significant reduction in the time spent in the operating room within the LA group (P<0.001). CONCLUSIONS: The type of anesthesia may not interfere with the diagnostic yield in stereotactic biopsies. Patients operated under LA are less likely to suffer pulmonary complications. Furthermore, LA could spare hospital resources in this setting. PMID- 23103528 TI - Some historical notes on hyperosmolar therapy. PMID- 23103529 TI - Identification of novel bacterial M.SssI DNA methyltransferase inhibitors. AB - DNA methylation is an important epigenetic regulator of gene expression. Abnormalities in DNA methylation patterns have been associated with various developmental and proliferative diseases, particularly cancer. Targeting DNA methyltransferases (DNMTs) represents a promising strategy for the treatment of such diseases. Current DNMT inhibitors suffer important drawbacks with respect to their efficacy, specificity, and toxicity. In this study, we have set up a robust in vitro bacterial M.SssI DNMT activity assay to systematically screen a collection of 26 240 compounds that were predicted to compete with the S-adenosyl L-methionine (SAM) substrate of DNMT. This resulted in the identification of a novel set of structurally distinct inhibitors of M.SssI DNMT activity. Although molecular docking studies using an M.SssI homology model suggest that these compounds might compete with SAM binding, mode of activity (MoA) assays are still needed to confirm this hypothesis. Our set of novel M.SssI DNMT inhibitors, once confirmed in an orthogonal DNMT assay, may thus serve as a starting point to identify and characterize suitable lead candidates for further drug optimization. PMID- 23103530 TI - New bioactive alkyl sulfates from Mediterranean tunicates. AB - Chemical investigation of two species of marine ascidians, Aplidium elegans and Ciona edwardsii, collected in Mediterranean area, led to isolation of a series of alkyl sulfates (compounds 1-5) including three new molecules 1-3. Structures of the new metabolites have been elucidated by spectroscopic analysis. Based on previously reported cytotoxic activity of these type of molecules, compounds 1-3 have been tested for their effects on the growth of two cell lines, J774A.1 (BALB/c murine macrophages) and C6 (rat glioma) in vitro. Compounds 1 and 2 induced selective concentration-dependent mortality on J774A.1 cells. PMID- 23103531 TI - Two new glycosides from the fruits of Morinda citrifolia L. AB - To study the chemical constituents of the fruits of noni (Morinda citrifolia L.), and find novel compounds, an n-butanol extract of the ethanol soluble fraction was subjected to repeated silica gel and ODS column chromatography and HPLC. Two new glycosides were isolated and their structures elucidated by NMR and HRFAB-MS spectrometry as (2E,4E,7Z)-deca-2,4,7-trienoate-2-O-beta-D-glucopyranosyl-beta-D glucopyranoside and amyl-1-O-beta-D-apio-furanosyl-1,6-O-beta-D-glucopyranoside, respectively. PMID- 23103532 TI - Antioxidant interactions between major phenolic compounds found in 'Ataulfo' mango pulp: chlorogenic, gallic, protocatechuic and vanillic acids. AB - Phenolic compounds are known to have antioxidant capacity; however, there is little information about molecular interactions between particular phenolics found in fruits at different developmental stages. Therefore, the total antioxidant capacity of the phenolic compounds of a fruit may not correspond to the sum of individual antioxidant capacity given by antioxidants from that tissue. In this study, individual antioxidant capacity and the interactions of four major phenolic compounds (chlorogenic, gallic, protocatechuic and vanillic acid) found in 'Ataulfo' mango pulp were tested using the DPPH assay. Significant synergism was found in the majority of the all combinations, as well as the combination of the four phenolics. However, antagonism was also observed between some molecules. This work demonstrated particular interactions that may occur in a complex environment within the complex framework of a natural food. The present results may also assist in the future design of functional foods or ingredients based on their antioxidant activity and their synergistic or antagonist interactions. PMID- 23103533 TI - Chemical architecture and applications of nucleic acid derivatives containing 1,2,3-triazole functionalities synthesized via click chemistry. AB - There is considerable attention directed at chemically modifying nucleic acids with robust functional groups in order to alter their properties. Since the breakthrough of copper-assisted azide-alkyne cycloadditions (CuAAC), there have been several reports describing the synthesis and properties of novel triazole modified nucleic acid derivatives for potential downstream DNA- and RNA-based applications. This review will focus on highlighting representative novel nucleic acid molecular structures that have been synthesized via the “click” azide-alkyne cycloaddition. Many of these derivatives show compatibility for various applications that involve enzymatic transformation, nucleic acid hybridization, molecular tagging and purification, and gene silencing. The details of these applications are discussed. In conclusion, the future of nucleic acid analogues functionalized with triazoles is promising. PMID- 23103534 TI - An efficient synthesis of novel dispirooxindole derivatives via one-pot three component 1,3-dipolar cycloaddition reactions. AB - A series of novel dispirooxindoles have been synthesized through three-component 1,3-dipolar cycloaddition of azomethine ylides generated in situ by the decarboxylative condensation of isatin and an alpha-amino acid with the dipolarophile 5-benzylidene-1,3-dimethylpyrimidine-2,4,6-trione. This method has the advantages of mild reaction conditions, high atom economy, excellent yields, and high regio- and stereo-selectivity. PMID- 23103535 TI - 17O-Dynamic NMR and DFT investigation of bis(acyloxy)iodoarenes. AB - Bis(acetoxy)iodobenzene and related acyloxy derivatives of hypervalent I(III) were studied by variable temperature solution-state 17O-NMR and DFT calculations. The 17O-NMR spectra reveal a dynamic process that interchanges the oxygen atoms of the acyloxy groups. For the first time, coalescence events could be detected for such compounds, allowing the determination of activation free energy data which are found to range between 44 and 47 kJ/mol. The analysis of the 17O linewidth measured for bis(acetoxy)iodobenzene indicates that the activation entropy is negligible. DFT calculations show that the oxygen atom exchange arises as a consequence of the [1,3]-sigmatropic shift of iodine. The calculated activation barriers are in excellent agreement with the experimental results. Both the 17O-NMR and DFT studies show that the solvent and chemical alterations, such as modification of the acyl groups or para- substitution of the benzene ring, hardly affect the energetics of the dynamic process. The low I-O Wiberg bond index (0.41-0.42) indicates a possible explanation of the invariance of both the energy barrier and the 17O chemical shift with para-substitution. PMID- 23103537 TI - Screening utility of the "attended alone" sign for subjective memory impairment. AB - As awareness of dementia as a major public health issue grows, increasing numbers of individuals with subjective memory impairment (SMI) are presenting to memory services. Many with SMI are cognitively healthy and require only reassurance. In the absence of reliable and easily available biomarkers of dementia, clinical signs may be the most effective way of differentiating cognitively healthy SMI individuals from those with underlying brain disease. Collateral history is important in the assessment of memory complaints, so patients are routinely instructed to bring a relative, friend, or a carer to clinic with them. Attending the clinic alone despite these instructions, the "attended alone" sign, is shown in this study to be not only a robust marker of absence of dementia but also of cognitively healthy individuals with SMI. PMID- 23103536 TI - Preparation, characterization and efficacy evaluation of synthetic biocompatible polymers linking natural antioxidants. AB - The purpose of this work was the synthesis, characterization and efficacy evaluation of new biocompatible antioxidant polymers linking trans-ferulic acid or a-lipoic acid. In particular, ferulic or lipoic acid were introduced in the preformed polymeric backbone. The new antioxidant biopolymers were characterized by Fourier transform infrared spectroscopy and gel permeation chromatography. The degree of functionalization (moles of antioxidant per gram of polymer) was determined by the Gaur-Gupta method for free amino group determination and by the Folin method for the phenolic groups. Their ability to inhibit lipid peroxidation were estimated in rat liver microsomal membranes induced in vitro by tert-BOOH (tert-butyl hydroperoxide), as a source of free radicals. The DPPH (1,1 diphenyl-2-picrylhydrazyl) radical-scavenging effect was also evaluated. The obtained systems, with different solubility, showed strong antioxidant and antiradical activities, suggesting potential use as packaging materials for foods, cosmetics, pharmaceuticals and personal care products. Moreover, the cytotoxicity of the synthesized polymers was also evaluated on Caco-2 cell cultures in order to verify their biocompatibility when exposed to an absorptive epithelial cell line. PMID- 23103538 TI - The phase transition and elastic and optical properties of polymorphs of CuI. AB - The high-pressure polymorphs of CuI have attracted much attention due to the somewhat contradictory identification of their structures by means of x-ray diffraction measurements and theoretical calculations. In this paper, we report the results of a theoretical investigation of polymorphs of CuI including zinc blende, rhombohedral, tetragonal, rocksalt and orthorhombic phases. We find that CuI follows the high-pressure transition path from the zinc-blende phase to the orthorhombic phase via the tetragonal phase, and the rhombohedral phase shows mechanical instability under high pressure. The bulk moduli are almost isotropic but the shear moduli show large anisotropy in these polymorphs. A relatively strong hybridization of I p and Cu d states appears to determine the electronic properties of the CuI polymorphs. The zinc-blende and tetragonal CuI are direct gap semiconductors and their optical properties are similar, whereas the orthorhombic CuI is metallic. PMID- 23103539 TI - Glycine ameliorates liver injury and vitamin D deficiency induced by bile duct ligation. AB - BACKGROUND: Patients with chronic liver disease had lower serum concentrations 25 hydroxyvitamin D (25OHD). Glycine, a nonessential amino acid, exerts anti inflammatory, cytoprotective, and immunomodulatory properties. This study aimed to establish a tandem mass spectrometry assay to measure 25OHD in guinea pigs serum and to investigate the effects of glycine against the liver damage induced by bile duct ligation (BDL). METHODS: BDL was performed on male guinea pigs. Glycine, alanine, serine or tyrosine was given by intraperitoneal injection. The animals were sacrificed and examined at 7 and 14 days after BDL. Serum concentrations of total bilirubin and aminotransferase were measured. Serum concentrations of 25OHD2 and 25OHD3 were measured by API 5000 mass spectrometer. In addition, oxidative stress was assessed by serum ischemia-modified albumin (IMA) and hepatic malondialdehyde (MDA), and apoptosis by hepatic caspase 3 activities. RESULTS: Serum 25OHD concentrations were decreased around 50% in the BDL group at days 7 and 14 post ligation, compared to sham (mean 65.3 ng/ml, p<0.005). Glycine but not other amino acid treatment blunted the reduced serum 25OHD (52.6 ng/ml, p<0.05) resulting from BDL. The concentrations of 25OHD were negatively associated with concentrations of IMA (r=-0.305, p<0.05) and caspase 3 (r=-0.562, p<0.0001). At day-14 post ligation, glycine treatment also ameliorated liver damage indicated by serum AST (p<0.005), ALT (p<0.05) and hepatic caspase 3 activities (p<0.05) and oxidative stress. CONCLUSION: Our results indicate that glycine may protect against BDL-induced liver injury through attenuation of oxidative stress, apoptosis and the vitamin D deficiency. PMID- 23103540 TI - Epileptic seizures, movement disorders, and breathing disturbances in Rett syndrome: diagnostic relevance of video-polygraphy. AB - Epileptic seizures, movement disorders and breathing disturbances may be observed in Rett syndrome, and correct diagnosis is mandatory for the management. We evaluated the usefulness of video-polygraphy in the differential diagnosis between epileptic and non-epileptic paroxysmal events in eight patients with Rett syndrome. Based on video analysis, myoclonic seizures were usually misdiagnosed as movement disorders and stereotypies; the events identified by parents as generalized tonic-clonic seizures included episodes of motor activity and breathing abnormality. Myoclonic seizures aggravated by inappropriate treatment were evident in four patients; hyperventilation and apnea during wakefulness were present in all patients, while central sleep apneas were present in one patient; sinus tachycardia and cardiac arrhythmias emerged in six patients; cortical myoclonus was disclosed in five patients. In Rett syndrome, video-polygraphy is essential in characterizing the clinical features of paroxysmal events, determining autonomic dysfunctions, documenting myoclonic motor phenomena, and evaluating the responses to the treatment of epilepsy. PMID- 23103541 TI - Regulation of feeding by Neuropeptide F in the desert locust, Schistocerca gregaria. AB - Our knowledge on the physiological function of the insect Neuropeptide F (NPF) mostly comes from studies in the fruit fly, Drosophila melanogaster, where NPF was shown to regulate diverse processes, such as feeding, learning and responding to stress. In the desert locust, Schistocerca gregaria, only a truncated form of the "full-length" NPF (the biologically active "trNPF") has been isolated. In this study, we investigated whether this peptide is involved in the regulation of feeding in this orthopteran species. In the S. gregaria EST-database, an NPF precursor encoding transcript was found. Alignment with other insect NPF precursors showed relatively highest sequence conservation within the trNPF region (and the flanking dibasic cleavage site), as compared to other regions of the NPF-precursor. Quantitative real-time RT-PCR revealed that the Schgr-NPF precursor encoding transcript occurs throughout the central nervous system with relatively high transcript levels in the brain, optic lobes and suboesophageal ganglion. It was also detected at relatively high levels in the midgut, which suggests that the encoded peptide also functions in the digestive system. Moreover, Schgr-NPF-transcript levels were notably higher in starved animals than in animals fed ad libitum, while transcript levels were also shown to be regulated after the consumption of a meal. Injection of locust trNPF in adults stimulated food intake, while RNAi knockdown reduced food intake. Furthermore, injection of trNPF in adults stimulated weight increase, while RNAi knockdown reduced weight gain. This effect of trNPF on body weight gain may result from its stimulatory effect on food intake. Taken together, we provide clear evidence for an important role of trNPF in the regulation of feeding in the desert locust, S. gregaria. PMID- 23103542 TI - Differential response of epithelial stem cell populations in hair follicles to TGF-beta signaling. AB - Epidermal stem cells residing in different locations in the skin continuously self-renew and differentiate into distinct cell lineages to maintain skin homeostasis during postnatal life. Murine epidermal stem cells located at the bulge region are responsible for replenishing the hair lineage, while the stem cells at the isthmus regenerate interfollicular epidermis and sebaceous glands. In vitro cell culture and in vivo animal studies have implicated TGF-beta signaling in the maintenance of epidermal and hair cycle homeostasis. Here, we employed a triple transgenic animal model that utilizes a combined Cre/loxP and rtTA/TRE system to allow inducible and reversible inhibition of TGF-beta signaling in hair follicle lineages and suprabasal layer of the epidermis. Using this animal model, we have analyzed the role of TGF-beta signaling in distinct phases of the hair cycle. Transient abrogation of TGF-beta signaling does not prevent catagen progression; however, it induces aberrant proliferation and differentiation of isthmus stem cells to epidermis and sebocyte lineages and a blockade in anagen re-entry as well as results in an incomplete hair shaft development. Moreover, ablation of TGF-beta signaling during anagen leads to increased apoptosis in the secondary hair germ and bulb matrix cells. Blocking of TGF-beta signaling in bulge stem cell cultures abolishes their colony-forming ability, suggesting that TGF-beta signaling is required for the maintenance of bulge stem cells. At the molecular level, inhibition of TGF-beta signaling results in a decrease in both Lrig1-expressing isthmus stem cells and Lrg5 expressing bulge stem cells, which may account for the phenotypes seen in our animal model. These data strongly suggest that TGF-beta signaling plays an important role in regulating the proliferation, differentiation, and apoptosis of distinct epithelial stem cell populations in hair follicles. PMID- 23103543 TI - Mitsugumin 53 attenuates the activity of sarcoplasmic reticulum Ca(2+)-ATPase 1a (SERCA1a) in skeletal muscle. AB - Mitsugumin 53 (MG53) is a member of the membrane repair system in skeletal muscle. However, the roles of MG53 in the unique functions of skeletal muscle have not been addressed, although it is known that MG53 is expressed only in skeletal and cardiac muscle. In the present study, MG53-binding proteins were examined along with proteins that mediate skeletal muscle contraction and relaxation using the binding assays of various MG53 domains and quadrupole time of-flight mass spectrometry. MG53 binds to sarcoplasmic reticulum Ca(2+)-ATPase 1a (SERCA1a) via its tripartite motif (TRIM) and PRY domains. The binding was confirmed in rabbit skeletal muscle and mouse primary skeletal myotubes by co immunoprecipitation and immunocytochemistry. MG53 knockdown in mouse primary skeletal myotubes increased Ca(2+)-uptake through SERCA1a (more than 35%) at micromolar Ca(2+) but not at nanomolar Ca(2+), suggesting that MG53 attenuates SERCA1a activity possibly during skeletal muscle contraction or relaxation but not during the resting state of skeletal muscle. Therefore MG53 could be a new candidate for the diagnosis and treatment of patients with Brody syndrome, which is not related to the mutations in the gene coding for SERCA1a, but still accompanies exercise-induced muscle stiffness and delayed muscle relaxation due to a reduction in SERCA1a activity. PMID- 23103544 TI - L-Arginine ameliorates cardiac left ventricular oxidative stress by upregulating eNOS and Nrf2 target genes in alloxan-induced hyperglycemic rats. AB - Hyperglycemia is independently related with excessive morbidity and mortality in cardiovascular disorders. L-Arginine-nitric oxide (NO) pathway and the involvement of NO in modulating nuclear factor-E2-related factor-2 (Nrf2) signaling were well established. In the present study we investigated, whether L arginine supplementation would improve the myocardial antioxidant defense under hyperglycemia through activation of Nrf2 signaling. Diabetes was induced by alloxan monohydrate (90 mg kg(-1) body weight) in rats. Both non-diabetic and diabetic group of rats were divided into three subgroups and they were administered either with L-arginine (2.25%) or L-NAME (0.01%) in drinking water for 12 days. Results showed that L-arginine treatment reduced the metabolic disturbances in diabetic rats. Antioxidant enzymes and glutathione levels were found to be increased in heart left ventricles, thereby reduction of lipid peroxidation by L-arginine treatment. Heart histopathological analysis further validates the reversal of typical diabetic characteristics consisting of alterations in myofibers and myofibrillary degeneration. qRT-PCR studies revealed that L-arginine treatment upregulated the transcription of Akt and downregulated NF-kappaB. Notably, transcription of eNOS and Nrf2 target genes was also upregulated, which were accompanied by enhanced expression of Nrf2 in left ventricular tissue from diabetic and control rats. Under these findings, we suggest that targeting of eNOS and Nrf2 signaling by L-arginine supplementation could be used as a potential treatment method to alleviate the late diabetic complications. PMID- 23103545 TI - Energy status determines the distinct biochemical and physiological behavior of interfibrillar and sub-sarcolemmal mitochondria. AB - Reports about the effect of ischemia and reperfusion on specific activities of the respiratory chain are often discrepant. One of the factors that govern this discrepancy is that typical mechanical procedures for mitochondrial isolation yield largely sub-sarcolemmal mitochondria (SSM), while the interfibrillar mitochondria (IFM), which provide most of the energy for the contractile apparatus, are under-represented. Here we investigated the impact of myocardial ischemia and reperfusion on SSM and IFM separately. Thirty-two Wister rats were randomly divided into four groups: control groups, ischemia groups, reperfusion groups and precondition groups. SSM and IFM were isolated from the rats' hearts from all the groups. The mitochondrial membrane potential (Deltapsi) and swelling were assessed at energized (using either 5mM succinate or 5mM glutamate and 5mM malate (GM) as a substrate) and non-energized conditions, where IFM showed better resistance to change in both conditions. Results showed that IFM have a higher coupling efficiency than SSM when energized by GM, but lower than SSM when energized with succinate. Preconditioning the rats' hearts prior to ischemia or reperfusion preserved the physiological and biochemical functions of both IFM and SSM and are energy dependent. The distinct physiological-biochemical functions of the mitochondrial sub-populations during ischemia and reperfusion depend on the overall energy status of the mitochondrial sub-population. PMID- 23103546 TI - Nanosecond pulsed electric fields activate AMP-activated protein kinase: implications for calcium-mediated activation of cellular signaling. AB - Nanosecond pulsed electric fields (nsPEFs) are increasingly being recognized as a potential tool for use in the life sciences. Exposure of human cells to nsPEFs elicits the formation of small membrane pores, intracellular Ca(2+) mobilization, signaling pathway activation, and apoptosis. Here we report the activation of AMP activated protein kinase (AMPK) by nsPEFs. AMPK activation is generally achieved by the phosphorylation of AMPK in response to changes in cellular energy status and is mediated by two protein kinases, LKB1 and CaMKK. Exposure to nsPEFs rapidly induced phosphorylation of AMPK and its downstream target ACC in both LKB1-proficient and LKB1-deficient cells. In LKB1-deficient cells, AMPK activation by nsPEFs was mediated by CaMKK and required extracellular Ca(2+), which suggested the occurrence of Ca(2+) mobilization and its participation in AMPK activation by nsPEFs. Our results provide experimental evidence for a direct link between activated cellular signaling and Ca(2+) mobilization in nsPEF exposed cells. PMID- 23103547 TI - Positive selection-guided mutational analysis revealing two key functional sites of scorpion ERG K(+) channel toxins. AB - Scorpion gamma-KTx toxins are important molecular tools for studying physiological and pharmacological functions of human ether-a-go-go related gene (hERG) K(+) channels. To pinpoint functional residues of this class of toxins involved in channel binding, we employed a combined approach that integrates evolutionary information and site-directed mutagenesis. Among three positively selected sites (PSSs) identified here, two (Gln18 and Met35) were found to be associated with the toxin's function because their changes significantly decreased the potency of ErgTx1 (also called CnErg1) on hERG1 channel. On the contrary, no potency alteration was observed at the third PSS (Ala42) when the mutation was introduced, which could be due to its location far from the functional surface of the toxin. Our strategy will accelerate the research of structure-function relationship of scorpion K(+) channel toxins. PMID- 23103548 TI - Body change techniques in Iranian adolescents. Relationship to sex and body weight status. AB - OBJECTIVE: Several studies indicated that techniques to change body weight and appearance were prevalent and different among adolescents. The aim of the study, therefore, was to assess differences in frequency and type of body change techniques used among adolescents by sex and body weight status. METHODS: A sample of 758 adolescents aged 12-18 years were recruited from private and public schools in Tehran. Information about socio-demographic background and body change techniques were collected via a self-administered questionnaire. RESULTS: A high percentage of adolescents used body change techniques frequently to alter their body appearance. Girls changed normal eating pattern significantly (p=0.007) to lose weight more frequently than boys while boys used this method significantly (p=0.01) to gain weight more frequently than girls. Overweight/obese adolescents exercised significantly to change muscle size (p=0.03) and changed normal diet to lose weight (p<0.001) more frequently than normal weight adolescents. The relation between sex and body weight status with body change techniques (p<0.0) implied that male and female adolescents especially overweight/obese adolescents were frequently trying to change their body appearance. CONCLUSION: Significant differences existed in using body change techniques according to sex and body weight status and these should be considered in obesity prevention programs for adolescents. PMID- 23103549 TI - BDNF Val66Met and DRD2 Taq1A polymorphisms interact to influence PTSD symptom severity: a preliminary investigation in a South African population. AB - BACKGROUND: We evaluated the role that selected variants in serotonin transporter (5-HTT), dopamine receptor 2 (DRD2) and brain-derived neurotrophic factor (BDNF) genes play in PTSD symptom severity in an at-risk population. We also investigated the interaction between the genetic variants to determine whether these variables and the interactions between the variables influenced the severity of PTSD symptoms. METHODS: PTSD symptoms were quantitatively assessed using the Davidson Trauma Scale (DTS) in 150 participants from an at-risk South African population. All participants were genotyped for the 5-HTTLPR, DRD2 Taq1A and BDNF Val66Met polymorphisms. Gene-gene interactions were investigated using various linear models. All analyses were adjusted for age, gender, major depressive disorder diagnosis, level of resilience, level of social support and alcohol dependence. RESULTS: A significant interaction effect between DRD2 Taq1A and BDNF Val66Met variants on DTS score was observed. On the background of the BDNF Val66Val genotype, DTS score increased significantly with the addition of a DRD2 Taq1A A1 allele. However, on the BDNF Met66 allele background, the addition of an A1 allele was found to reduce total DTS score. CONCLUSIONS: This study provides preliminary evidence for an epistatic interaction between BDNF Val66Met and DRD2 Taq1A polymorphisms on the severity of PTSD symptoms, where both too little and too much dopamine can result in increased PTSD symptom severity. PMID- 23103550 TI - Different patterns of administration modulate propensity of methadone and buprenorphine to promote locomotor sensitization in mice. AB - Following chronic administration of morphine a locomotor sensitization is usually observed. This behavioral sensitization is influenced by numerous factors including the administration pattern. While methadone and buprenorphine are the two main treatments for opioid dependence, literature about their ability to promote long-term sensitization after chronic exposure/withdrawal are scarce considering the long-term treatments used in patients. In this study we investigated the propensity of these two opioids to promote behavioral sensitization using different patterns of administration. Mice were treated with escalating doses of methadone or buprenorphine during 5 days given either once (binge) or three times a day (TTD). After 1-, 7-, 14- and 35-days washout period, animals were challenged with either morphine or the opioid used for the chronic treatment to evaluate heterologous or homologous sensitization, respectively. While methadone produced homologous and heterologous sensitization either with the binge or the TTD regimen over the whole period studied, buprenorphine induced a transient heterologous locomotor sensitization on day 14 only with the binge administration. Our data evidenced a different ability of methadone and buprenorphine to produce behavioral sensitization and that the pattern of drug exposure determined the expression of this phenomenon. PMID- 23103551 TI - Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome. AB - The present study aimed to examine the long-term efficacy and safety of rotigotine treatment for restless legs syndrome (RLS), as well as the rate of clinically significant augmentation, in a 1-year open-label study of Japanese subjects. Japanese patients with RLS who had been treated with rotigotine or placebo in a double-blind trial were enrolled in a 1-year, open-label, uncontrolled extension study and treated with rotigotine at a dose of up to 3 mg/24 h after an 8-week titration phase. Outcomes included International Restless Legs Syndrome Study Group rating scale (IRLS scale), Pittsburgh Sleep Quality Index (PSQI), safety, and investigator-/expert panel-assessed augmentation (including Augmentation Severity Rating Scale). Overall, 185 patients entered the open-label study and 133 completed the study. IRLS and PSQI total scores improved throughout the 52-week treatment period (IRLS, from 23.2+/-5.1 to 7.8+/-7.6 and PSQI, from 8.0+/-3.1 to 5.0+/-2.9). Treatment-emergent adverse events were mild to moderate in severity, and included application site reactions (52.4%) and nausea (28.6%). Clinically significant augmentation occurred in five patients (2.7%). These results indicate a good long-term efficacy of rotigotine for treating RLS, with a relatively low risk of clinically significant augmentation. PMID- 23103553 TI - Side effects and complication of Port-A-Cath. AB - Central venous catheter techniques find at present use for administering of NPT, for the drug injection ( especially chemiotherapeutic drugs) because of the possible damage of a few substances when perfused in a peripheral way. At present port-a-cath find their most extensive use: these are systems which can be set up and tolerated for many months. For the access to subclavian vein must be necessary put in supine decubitus, with light Trendelenburg position, with the opposite arm along the body and the head turned on the opposite side. In this way the clavicle is in perpendicular position with regard to the sternal handlebar, except for patient affected with bpco, kypho-scoliosis, scapular-homeral arthrosis. In these patients the clavicle can put on a particular course, oblique and upper as to the sternal articular face. So there is a serious obstacle to the passage to the metal needle under the clavicle. KEY WORDS: Chemiotherapy, CVC, NPT, Port-a-Cath. PMID- 23103552 TI - Transcriptional dysregulation and impairment of PHOX2B auto-regulatory mechanism induced by polyalanine expansion mutations associated with congenital central hypoventilation syndrome. AB - The PHOX2B transcription factor plays a crucial role in autonomic nervous system development. In humans, heterozygous mutations of the PHOX2B gene lead to congenital central hypoventilation syndrome (CCHS), a rare disorder characterized by a broad variety of symptoms of autonomic nervous system dysfunction including inadequate control of breathing. The vast majority of patients with CCHS are heterozygous for a polyalanine repeat expansion mutation involving a polyalanine tract of twenty residues in the C-terminus of PHOX2B. Although several lines of evidence support a dominant-negative mechanism for PHOX2B mutations in CCHS, the molecular effects of PHOX2B mutant proteins on the transcriptional activity of the wild-type protein have not yet been elucidated. As one of the targets of PHOX2B is the PHOX2B gene itself, we tested the transcriptional activity of wild type and mutant proteins on the PHOX2B gene promoter, and found that the transactivation ability of proteins with polyalanine expansions decreased as a function of the length of the expansion, whereas DNA binding was severely affected only in the case of the mutant with the longest polyalanine tract (+13 alanine). Co-transfection experiments using equimolar amounts of PHOX2B wild-type and mutant proteins in order to simulate a heterozygous state in vitro and four different PHOX2B target gene regulatory regions (PHOX2B, PHOX2A, DBH, TLX2) clearly showed that the polyalanine expanded proteins alter the transcriptional activity of wild-type protein in a promoter-specific manner, without any clear correlation with the length of the expansion. Moreover, although reduced transactivation may be caused by retention of the wild-type protein in the cytoplasm or in nuclear aggregates, this mechanism can only be partially responsible for the pathogenesis of CCHS because of the reduction in cytoplasmic and nuclear accumulation when the +13 alanine mutant is co-expressed with wild type protein, and the fact that the shortest polyalanine expansions do not form visible cytoplasmic aggregates. Deletion of the C-terminal of PHOX2B leads to a protein that correctly localizes in the nucleus but impairs PHOX2B wild-type transcriptional activity, thus suggesting that protein mislocalization is not the only mechanism leading to CCHS. The results of this study provide novel in vitro experimental evidence of a transcriptional dominant-negative effect of PHOX2B polyalanine mutant proteins on wild-type protein on two different PHOX2B target genes. PMID- 23103554 TI - Direct electrochemistry of Penicillium chrysogenum catalase adsorbed on spectroscopic graphite. AB - The voltammetric studies of Penicillium chrysogenum catalase (PcCAT) adsorbed on spectroscopic graphite, showed direct electron transfer (DET) between its active site and the electrode surface. Analogous tests performed with the commercially available bovine catalase revealed that mammalian enzyme is much less efficient in the DET process. Both catalases were found capable to catalyse the electrooxidation of phenol, but differed in the specifics of catalytic action. At an applied potential of 0.45V the non-linear regression showed the kinetics of the bioelectrochemical oxidation catalysed by the PcCAT obeyed the Hill equation with a binding constant K=0.034+/-0.002 M(2) (Hill's coefficient n=2.097+/-0.083, R(2)=0.997), whilst the catalytic action of the bovine catalase was described by the Michaelis-Menten kinetic model with the following parameters: V(max,app)=7.780+/-0.509 MUA, and K(M,app)=0.068+/-0.070 mol L(-1). The performance of the electrode reaction was affected by the electrode potential, the pH, and temperature. Based on the effect of pH and temperature on the electrode response in presence of phenol a tentative reaction pathway of its bioelectrocatalytic oxidation has been hypothesised. The possible application of these findings in biosensing phenol up to concentration 30 mM at pHs below 7 and in absence of oxidising agents (oxygen or H(2)O(2)) was considered. PMID- 23103555 TI - Gauge approach to the 'pseudogap' phenomenology of the spectral weight in high Tc cuprates. AB - We assume the t-t'-J model to describe the CuO(2) planes of hole-doped cuprates and we adapt the spin-charge gauge approach, previously developed for the t-J model, to describe the holes in terms of a spinless fermion carrying the charge (holon) and a neutral boson carrying spin 1/2 (spinon), coupled by a slave particle gauge field. In this framework we consider the effects of a finite density of incoherent holon pairs in the normal state. Below a crossover temperature, identified as the experimental 'upper pseudogap', the scattering of the 'quanta' of the phase of the holon-pair field against holons reproduces the phenomenology of nodal Fermi arcs coexisting with a gap in the antinodal region. We thus obtain a microscopic derivation of the main features of the hole spectra due to the pseudogap. This result is obtained through a holon Green function which follows naturally from the formalism and analytically interpolates between a Fermi liquid-like and a d-wave superconductor behaviour as the coherence length of the holon-pair order parameter increases. By inserting the gauge coupling with the spinon we construct explicitly the hole Green function and calculate its spectral weight and the corresponding density of states. So we prove that the formation of holon pairs induces a depletion of states on the hole Fermi surface. We compare our results with ARPES and tunnelling experimental data. In our approach the hole preserves a finite Fermi surface until the superconducting transition, where it reduces to four nodes. Therefore we propose that the gap seen in the normal phase of cuprates is due to the thermal broadening of the SC-like peaks masking the Fermi-liquid peak in the spectral weight. The Fermi arcs then correspond to the region of the Fermi surface where the Fermi-liquid peak is unmasked. PMID- 23103556 TI - Characterization of RSF-1, the Caenorhabditis elegans homolog of the Ras association domain family protein 1. AB - Mammals have 10 RASSF proteins, which are characterized by the Ras-association (RA) domain. Among them, RASSF1 to RASSF6 have the Salvador/RASSF/Hippo (SARAH) domain and form the subclass C-terminal RASSF proteins. Drosophila genome has a single C-terminal RASSF, dRASSF. All these RASSF proteins are related to the tumor suppressive Hippo pathway, and are considered to function as tumor suppressors. Caenorhabditis elegans T24F1.3 encodes a protein with the RA and the SARAH domains. The amino acid sequences are 40% and 55% similar to those of RASSF1 in the RA and the SARAH domains, respectively. We have characterized T24F1.3 gene product and named it RSF-1 as RASSF1 homolog. RSF-1 is widely expressed in epithelial cells. About 14% rsf-1 mutants exhibit defects in embryonal morphogenesis and the actin disorganization. The combinatorial synthetic lethal analysis demonstrates that the lethality is enhanced to more than 80% in rsf-1 mutants with the WASP-family verprolin homologous protein complex-related gene depletions and corroborates the implication of RSF-1 in the regulation of actin cytoskeleton. In rsf-1 mutants, the structures of muscle actin are preserved, but the swimming ability is impaired. Although we could not detect the direct physical interaction of LET-60 with RSF-1, rsf-1 mutants suppress the multivulva phenotype of the active let-60 mutants, suggesting that rsf-1 genetically interacts with the Ras signaling. PMID- 23103557 TI - Epileptogenic effect of sevoflurane: determination of the minimal alveolar concentration of sevoflurane associated with major epileptoid signs in children. AB - BACKGROUND: Sevoflurane has become the gold standard for inhalation induction in children. However in children as in adults, epileptiform electroencephalographic signs have been described under high concentrations of sevoflurane. The aim of this study was to determine the minimal alveolar concentration (MAC) of sevoflurane associated with the occurrence of major epileptiform signs (MES) in 50% children under steady-state conditions. The MAC of MES (MAC MES) was determined in 100% oxygen and with the addition of 50% nitrous oxide or after the injection of alfentanil (ALFENTA). METHODS: Seventy-nine children (3-11 yr), undergoing elective surgery and premedicated with hydroxyzine were included. After induction by inhalation and tracheal intubation, a 10-min period with a stable expired fraction of sevoflurane was obtained. The MES were defined as rhythmic polyspikes or epileptiform discharges. Electroencephalographic recordings were blindly analyzed by two independent experts. The MAC MES were determined by the Dixon method: the concentration of sevoflurane was determined by the result from the previous patient: increase of 0.2% if MES were absent or decrease of 0.2% if MES were present. Three consecutive series were performed: (1) in 100% oxygen (MAC MESO2); (2) in 50% oxygen and 50% nitrous oxide (MAC MESN2O); and (3) in 100% oxygen with a bolus of alfentanil (MAC MESALFENTA). RESULTS: The MAC MESO2 was 4.3+/-0.1% (mean+/-SD), the MAC MESN2O and the MAC MESALFENTA were higher, respectively: 4.6+/-0.2% (P=0.01) and 4.6+/-0.2% (P=0.02). CONCLUSIONS: In children premedicated with hydroxyzine, the MAC MES of sevoflurane calculated in 100% O2 corresponded to 1.75 surgical MAC. In addition, our results have demonstrated a moderate effect of nitrous oxide and alfentanil in raising the threshold of MES. PMID- 23103558 TI - Ultrasound-guided tracheal intubation: a novel intubation technique. PMID- 23103559 TI - Intraoperative non-record-keeping usage of anesthesia information management system workstations and associated hemodynamic variability and aberrancies. AB - BACKGROUND: Anesthesia information management system workstations in the anesthesia workspace that allow usage of non-record-keeping applications could lead to distraction from patient care. We evaluated whether non-record-keeping usage of the computer workstation was associated with hemodynamic variability and aberrancies. METHODS: Auditing data were collected on eight anesthesia information management system workstations and linked to their corresponding electronic anesthesia records to identify which application was active at any given time during the case. For each case, the periods spent using the anesthesia information management system record-keeping module were separated from those spent using non-record-keeping applications. The variability of heart rate and blood pressure were also calculated, as were the incidence of hypotension, hypertension, and tachycardia. Analysis was performed to identify whether non record-keeping activity was a significant predictor of these hemodynamic outcomes. RESULTS: Data were analyzed for 1,061 cases performed by 171 clinicians. Median (interquartile range) non-record-keeping activity time was 14 (1, 38) min, representing 16 (3, 33)% of a median 80 (39, 143) min of procedure time. Variables associated with greater non-record-keeping activity included attending anesthesiologists working unassisted, longer case duration, lower American Society of Anesthesiologists status, and general anesthesia. Overall, there was no independent association between non-record-keeping workstation use and hemodynamic variability or aberrancies during anesthesia either between cases or within cases. CONCLUSION: Anesthesia providers spent sizable portions of case time performing non-record-keeping applications on anesthesia information management system workstations. This use, however, was not independently associated with greater hemodynamic variability or aberrancies in patients during maintenance of general anesthesia for predominantly general surgical and gynecologic procedures. PMID- 23103560 TI - Atorvastatin decreases Toll-like receptor 4 expression and downstream signaling in human monocytic leukemia cells. AB - PURPOSE: We aim to evaluate the effects of atorvastatin on the expression of Toll like receptor (TLR4) protein and mRNA, and to explore their effects on TLR4 dependent downstream signaling in human monocytic leukemia (THP-1) cells. METHODS: TLR4 protein and mRNA expression, levels of NF-kappaB protein, and expression of TNF-alpha, IL-6, and IL-1beta in lipopolysaccharide-induced THP-1 cells after incubation with different concentrations of atorvastatin (0.1, 1, 10, 20MUM) were quantified via flow-cytometry, quantitative RT-PCR, western blotting, and ELSIA kits. RESULTS: Atorvastatin incubation resulted in significant decreases in the levels of TLR4 protein and mRNA, NF-kappaB expression, and levels of TNF-alpha, IL-6, and IL-1beta in LPS-induced THP-1 cells (P<0.01). However, compared with the untreated control, the expression of these were significantly increased (P<0.01). CONCLUSIONS: Atorvastatin could inhibit the TLR4 expression and TLR4-dependent downstream signaling in THP-1 cells. These observations imply that the interactions with innate immunity may serve as one of the pleiotropic mechanisms of atorvastatin. PMID- 23103562 TI - TNF-alpha-mediated NF-kappaB survival signaling impairment by cisplatin enhances JNK activation allowing synergistic apoptosis of renal proximal tubular cells. AB - Cisplatin-induced nephrotoxicity is an important limiting factor for cisplatin use. Tumor necrosis factor-alpha (TNF-alpha) is known to contribute to cisplatin induced nephrotoxicity by inducing an inflammatory process aggravating the primary injury, thereby resulting in acute kidney injury (AKI). The present study investigates the pathways synergistically activated by cisplatin and TNF-alpha responsible for TNF-alpha-enhanced cisplatin-induced renal cell injury. To do so, immortalized renal proximal tubular epithelial cells (IM-PTECs) were co-treated with TNF-alpha and cisplatin. Under these conditions, cisplatin induced dose dependent apoptosis in IM-PTECs, which was significantly enhanced by TNF-alpha. Transcriptomic analysis revealed that cisplatin inhibited the typical TNF-alpha response and cisplatin/TNF-alpha treatment up-regulated cell death pathways while it down-regulated survival pathways compared to cisplatin alone. In concordance, the gene expression levels of kidney injury markers combined with activation of specific inflammatory mediators were enhanced by cisplatin/TNF-alpha treatment, resembling the in vivo cisplatin-induced nephrotoxicity response. Furthermore, combined cisplatin/TNF-alpha treatment inhibited NF-kappaB nuclear translocation and NF-kappaB-mediated gene transcription leading to enhanced and prolonged JNK and c-Jun phosphorylation. JNK sustained activation further inhibited NF-kappaB signaling via a feedback loop mechanism. This led to an alteration in the transcription of the NF-kappaB-induced anti-apoptotic genes c-IAP2, Bcl-XL, Bruce and Bcl2 and pro-apoptotic genes Bfk and Xaf1 and consequently to sensitization of the IM-PTECs toward cisplatin/TNF-alpha-induced toxicity. In conclusion, our findings support a model whereby renal cells exposed to both cisplatin and TNF alpha switch into a more pro-apoptotic and inflammatory program by altering their NF-kappaB/JNK/c-Jun balance. PMID- 23103561 TI - AMP kinase activation improves angiogenesis in pulmonary artery endothelial cells with in utero pulmonary hypertension. AB - Pulmonary artery endothelial cells (PAEC) isolated from fetal lambs with in utero pulmonary hypertension (IPH) have phenotypical changes that lead to increased reactive oxygen species (ROS) formation and impaired angiogenesis. AMP-activated protein kinase (AMPK) is known to be activated by ROS, which is expected to help angiogenesis in IPH-PAEC. The objectives of this study were to investigate AMPK responses in IPH and its role in angiogenesis. We observed that, compared with control PAEC, IPH-PAEC have decreased phosphorylation of AMPKalpha catalytic subunit and AMPK downstream enzymes, indicating a decrease in AMPK activity. In addition, the expression of AMPK kinases is decreased, and protein phosphatase 2 is increased in IPH-PAEC, potentially contributing to the decreased AMPK activation. Metformin, an AMPK activator, improved IPH-PAEC angiogenesis while increasing endothelial NO synthase (eNOS) serine(1179) phosphorylation and decreasing the eNOS-caveolin-1 association. Metformin also increased MnSOD activity and the expression of both eNOS and MnSOD. The increase in angiogenesis by Metformin is abolished by pretreatment with AMPK inhibitor, Compound C. Expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor beta (PDGFbeta) are decreased in IPH-PAEC compared with control PAEC and were not altered by Metformin. These data indicate that Metformin improves angiogenesis through mechanisms independent of these angiogenic factors. In conclusion, activation of AMPK restores angiogenesis and increases the bioavailability of nitric oxide in IPH. Whether Metformin is beneficial in the management of pulmonary hypertension requires further investigation. PMID- 23103564 TI - Interorgan metabolism of ornithine phenylacetate (OP)--a novel strategy for treatment of hyperammonemia. AB - Combined administration of ornithine and phenylacetate (OP) is proposed as a novel treatment of hyperammonemia and hepatic encephalopathy. Ornithine is believed to increase ammonia fixation into glutamine in muscle tissue and glutamine is subsequently thought to react with phenylacetate forming phenylacetylglutamine (PAGN) which is excreted in urine. The aim of the present study was to elucidate the interorgan metabolism of ornithine and ammonia in cirrhotic rats treated with OP in order to obtain an understanding of the underlying mechanisms of the beneficial effect of the treatment, which are largely unknown. Bile duct ligated cirrhotic rats and SHAM rats were treated with OP or saline for five days. [2,5-(15)N]Ornithine or (15)NH(4)(+) were administered intravenously and the incorporation of (15)N in amino acids as well as the content of the amino acids were subsequently determined in plasma, skeletal muscle, liver and kidney. In BDL rats, OP treatment reduced arterial ammonia concentration and increased that of glutamine 30 min after the treatment but not after 15 h. OP treatment did not increase (15)N labeling in glutamine from [2,5-(15)N]ornithine and (15)NH(4)(+) in skeletal muscle or liver. However, the extent of glutamine labeling from [2,5-(15)N]ornithine or (15)NH(4)(+) was similar in arterial blood and liver and higher than that in skeletal muscle. These findings suggest that the effect of OP was related to hepatic metabolism of ornithine. PAGN could not be detected in urine or blood in any of the rats which may explain why OP treatment only reduced arterial ammonia transiently. PMID- 23103563 TI - Ibandronate increases the expression of the pro-apoptotic gene FAS by epigenetic mechanisms in tumor cells. AB - There is growing evidence that aminobisphosphonates like ibandronate show anticancer activity by an unknown mechanism. Biochemically, they prevent posttranslational isoprenylation of small GTPases, thus inhibiting their activity. In tumor cells, activated RAS-GTPase, the founding member of the gene family, down-regulates the expression of the pro-apoptotic gene FAS via epigenetic DNA-methylation by DNMT1. We compared ibandronate treatment in neoplastic human U-2 osteosarcoma and in mouse CCL-51 breast cancer cells as well as in the immortalized non-neoplastic MC3T3-E1 osteoblastic cells. Ibandronate attenuated cell proliferation in all cell lines tested. In the neoplastic cells we found up-regulation of caspases suggesting apoptosis. Further we found stimulation of FAS-expression as a result of epigenetic DNA demethylation that was due to down-regulation of DNMT1, which was rescued by re-isoprenylation by both geranylgeranyl-pyrophosphate and farnesylpyrophosphate. In contrast, ibandronate did not affect FAS and DNMT1 expression in MC3T3-E1 non-neoplastic cells. Data suggest that bisphosphonates via modulation of the activity of small GTPases induce apoptosis in neoplastic cells by DNA-CpG-demethylation and stimulation of FAS-expression. In conclusion the shown epigenetic mechanism underlying the anti-neoplastic activity of farnesyl-transferase-inhibition, also explains the clinical success of other drugs, which target this pathway. PMID- 23103565 TI - Platelet-derived growth factor triggers PKA-mediated signalling by a redox dependent mechanism in rat renal mesangial cells. AB - Inflammatory glomerular kidney diseases are often accompanied with a massive production of reactive oxygen species (ROS) that affect the function of the glomerular filtration barrier and contribute to mesangiolysis via the induction of cell death in mesangial cells. Intriguingly, ROS also trigger fine-tuned signalling processes that affect gene expression and cell proliferation or migration. To define such redox-driven signalling devices, a proteomics approach was performed to identify the formation of protein complexes induced by ROS. To this end, protein lysates of human podocytes were treated with or without hydrogen peroxide (250 MUM). Thereafter cell lysates were subjected to diagonal 2D gel electrophoresis and putative redox-affected proteins were analysed by MS/MS analysis. Among others, the regulatory subunit of protein kinase A (PKA) could be identified that forms homodimers under oxidative conditions. To evaluate whether ROS dependent dimerization of PKA also occurs in a more physiological setting, rat mesangial cells were treated with platelet-derived growth factor-BB (PDGF-BB) to induce ROS formation. This regimen resulted in a redox dependent dimerization of the R-subunits of PKA. To demonstrate whether PDGF-BB induced ROS formation affects PKA dependent pathways, the effects of PDGF-BB on phosphorylation of serine 157 of vasodilator stimulated protein (VASP) a classical target of PKA were analysed. Interestingly PDGF-BB induced VASP phosphorylation in a ROS dependent manner but independent of changes in cAMP levels. Taken together, we demonstrate a redox-mediated activation of PKA by PDGF BB thus highlighting a physiological role of ROS as regulator of PKA activity in rat mesangial cells. PMID- 23103566 TI - Reversal of the deleterious effects of chronic dietary HFCS-55 intake by PPAR delta agonism correlates with impaired NLRP3 inflammasome activation. AB - Although high-fructose corn syrup (HFCS-55) is the major sweetener in foods and soft-drinks, its potential role in the pathophysiology of diabetes and obesity ("diabesity") remains unclear. Peroxisome-proliferator activated receptor (PPAR) delta agonists have never been tested in models of sugar-induced metabolic abnormalities. This study was designed to evaluate (i) the metabolic and renal consequences of HFCS-55 administration (15% wt/vol in drinking water) for 30 weeks on male C57Bl6/J mice and (ii) the effects of the selective PPAR-delta agonist GW0742 (1 mg/kg/day for 16 weeks) in this condition. HFCS-55 caused (i) hyperlipidemia, (ii) insulin resistance, and (iii) renal injury/inflammation. In the liver, HFCS-55 enhanced the expression of fructokinase resulting in hyperuricemia and caused abnormalities in known insulin-driven signaling events. In the kidney, HFCS-55 enhanced the expression of the NLRP3 (nucleotide-binding domain and leucine-rich-repeat-protein 3) inflammasome complex, resulting in caspase-1 activation and interleukin-1beta production. All of the above effects of HFCS-55 were attenuated by the specific PPAR-delta agonist GW0742. Thus, we demonstrate for the first time that the specific PPAR-delta agonist GW0742 attenuates the metabolic abnormalities and the renal dysfunction/inflammation caused by chronic HFCS-55 exposure by preventing upregulation of fructokinase (liver) and activation of the NLRP3 inflammasome (kidney). PMID- 23103567 TI - Targeting FOXM1 in cancer. AB - Oncogenic transcription factor FOXM1 is overexpressed in the majority of human cancers. In addition, FOXM1 has been implicated in cell migration, invasion, angiogenesis and metastasis. The important role of FOXM1 in cancer affirms its significance for therapeutic intervention. Current data suggest that targeting FOXM1 in mono- or combination therapy may have promising therapeutic benefits for the treatment of cancer. However, challenges with the delivery of anti-FOXM1 siRNA to tumors and the absence of small molecules, which specifically inhibit FOXM1, are delaying the development of FOXM1 inhibitors as feasible anticancer drugs. In this review, we describe and summarize the efforts that have been made to target FOXM1 in cancer and the consequences of FOXM1 suppression in human cancer cells. PMID- 23103568 TI - Estrogen receptor signaling as a target for novel breast cancer therapeutics. AB - In breast cancer (BC) epithelial cells, the mitogenic action of estradiol is transduced through binding to two receptors, ERalpha and ERbeta, which act as transcription factors. Anti-estrogens (AEs) and aromatase inhibitors (AIs) are used clinically to arrest the estrogen-dependent growth of BC. In the case of AE or AI resistance, Herceptin or lapatinib may be used to inhibit growth factors. Estrogen effects are mediated not only through nuclear ERs but also through cytoplasmic/membrane ERs and G-protein-coupled ERs. These estrogen-binding systems associate with various proteins that direct cell cycle signaling, proliferation and survival. The partners of nuclear ER include SRC1-3, HDACs and ERbeta itself as well as newly identified proteins, such as E6-AP, LKB1, PELP1, PAX-2 and FOXA1. The partners of extra-nuclear ERalpha include PI3K and the tyrosine kinase Src. These various factors are all potential targets for therapeutic intervention. In addition, BC proliferation is enhanced by insulin and EGF, which stimulate signaling through the MAPK and PI3K/AKT pathways by activation of the IGF-1R and EGFR axes, respectively. These pathways are tightly interconnected with ER-activated signaling, and membrane ERalpha forms complexes with Src and PI3K. Chemokine-mediated signaling also modulates the estrogen response. Inhibiting these pathways with specific inhibitors or activating some of the pathways by gene manipulation may be therapeutically valuable for arresting BC cell cycle progression and for inducing apoptosis to antagonize hormone-resistance. Here, we review some newly identified putatively targetable ER partners and highlight the need to develop tumor-targeting drug carrier systems affecting both the tumor cells and the tumor environment. PMID- 23103570 TI - A phylogenetic blueprint for a modern whale. AB - The emergence of Cetacea in the Paleogene represents one of the most profound macroevolutionary transitions within Mammalia. The move from a terrestrial habitat to a committed aquatic lifestyle engendered wholesale changes in anatomy, physiology, and behavior. The results of this remarkable transformation are extant whales that include the largest, biggest brained, fastest swimming, loudest, deepest diving mammals, some of which can detect prey with a sophisticated echolocation system (Odontoceti - toothed whales), and others that batch feed using racks of baleen (Mysticeti - baleen whales). A broad-scale reconstruction of the evolutionary remodeling that culminated in extant cetaceans has not yet been based on integration of genomic and paleontological information. Here, we first place Cetacea relative to extant mammalian diversity, and assess the distribution of support among molecular datasets for relationships within Artiodactyla (even-toed ungulates, including Cetacea). We then merge trees derived from three large concatenations of molecular and fossil data to yield a composite hypothesis that encompasses many critical events in the evolutionary history of Cetacea. By combining diverse evidence, we infer a phylogenetic blueprint that outlines the stepwise evolutionary development of modern whales. This hypothesis represents a starting point for more detailed, comprehensive phylogenetic reconstructions in the future, and also highlights the synergistic interaction between modern (genomic) and traditional (morphological+paleontological) approaches that ultimately must be exploited to provide a rich understanding of evolutionary history across the entire tree of Life. PMID- 23103571 TI - Phylogeny and historical demography of Cynops pyrrhogaster (Amphibia: Urodela): taxonomic relationships and distributional changes associated with climatic oscillations. AB - We investigated the phylogenetic relationships and estimated the historical demography of the Japanese fire-bellied newt, Cynops pyrrhogaster, from Japanese mainlands using 1407-bp sequences of the mitochondrial DNA (NADH6, tRNAglu, cyt b) and 1208-bp sequences of nuclear DNA (Rag-1) genes. Phylogenetic trees based on mitochondrial DNA revealed four major haplotype clades (NORTHERN, CENTRAL, WESTERN, and SOUTHERN clades) within this species. Degree of genetic differentiation among major haplotype clades was very large for intraspecific variation, suggesting this species to be composed of four species lineages that replace each other geographically. Nuclear genetic variation presented no obvious patterns of geographic structure except for the distinctness of populations diagnosed by NORTHERN clade of mitochondrial haplotypes, suggesting results of incomplete lineage sorting. Current distribution and estimated divergence times for the genus Cynops suggest that the common ancestor of two Japanese species (C. pyrrhogaster and C. ensicauda from the Ryukyu Islands) had diverged at the edge of the continent corresponding to the present East China Sea and Central Ryukyus. Subsequent range expansion to Japanese mainland seems to have occurred in the middle Miocene. Population-genetic analyses indicated that all species lineages, except for the SOUTHERN one, experienced geographic population reductions and expansions associated with glacial and postglacial climatic oscillations. PMID- 23103569 TI - Biology and therapeutic potential of hydrogen sulfide and hydrogen sulfide releasing chimeras. AB - Hydrogen sulfide, H2S, is a colorless gas with a strong odor that until recently was only considered to be a toxic environmental pollutant with little or no physiological significance. However, the past few years have demonstrated its role in many biological systems and it is becoming increasingly clear that H2S is likely to join nitric oxide (NO) and carbon monoxide (CO) as a major player in mammalian biology. In this review, we have provided an overview of the chemistry and biology of H2S and have summarized the chemistry and biological activity of some natural and synthetic H2S-donating compounds. The naturally occurring compounds discussed include, garlic, sulforaphane, erucin, and iberin. The synthetic H2S donors reviewed include, GYY4137; cysteine analogs; S-propyl cysteine, S-allyl cysteine, S-propargyl cysteine, and N-acetyl cysteine. Dithiolethione and its NSAID and other chimeras such as, L-DOPA, sildenafil, aspirin, diclofenac, naproxen, ibuprofen, indomethacin, and mesalamine have also been reviewed in detail. The newly reported NOSH-aspirin that releases both NO and H2S has also been discussed. PMID- 23103572 TI - Mass attenuation coefficients of soil and sediment samples using gamma energies from 46.5 to 1332 keV. AB - Mass attenuation coefficients of various soil and sediment samples (density range between 1.0 and 1.7 g cm(-3)) collected from 60 sites distributed in Syrian land have been determined for gamma lines of 46.5, 59.5, 88, 122, 165, 392, 661, 1173, and 1332 keV using gamma spectrometry and simulation software program X-com. The average mass attenuation coefficients for the studied samples were found to be 0.513, 0.316, 0.195, 0.155, 0.134, 0.096, 0.077, 0.058, and 0.055 cm(2) g(-1) at previous energies, respectively. The results have shown that Ca and Fe contents of the samples have strong effect on the mass attenuation coefficient at lower energies. In addition, self-attenuation correction factors determined using mass attenuation coefficient was in good agreement with addition spiked reference material method provided that the sample thickness is 2.7 cm. However, mass attenuation coefficients determined in this study can be used for determination of gamma emitters at energy ranges from 46.5 to 1332 keV in any soil and sediment samples having density of 1.0-1.7 g cm(-3). PMID- 23103573 TI - 210Po, 210Pb, 40K and 137Cs in edible wild berries and mushrooms and ingestion doses to man from high consumption rates of these wild foods. AB - This paper discusses activity concentrations of (210)Po, (210)Pb, (40)K and (137)Cs in edible wild berries and mushrooms collected from Ovre Dividalen national park, Northern Norway and derives committed effective ingestion doses to man based on high consumption rates of these wild foods. Edible wild berries and mushrooms accumulated similar levels of (210)Pb, but mushrooms accumulated higher levels of (210)Po and (40)K than berries. There appears to be a clear difference in the ability of Leccinum spp. of fungi to accumulate (210)Po and/or translocate (210)Po to mushrooms compared to Russula spp. of fungi. Activity concentrations of (137)Cs in edible wild berries and mushrooms from Ovre Dividalen national park reflected the lower levels of fallout of this radionuclide in Northern Norway compared to more central areas following the Chernobyl accident. For mushrooms, ingestion doses are dominated by (210)Po, while for berries, (40)K is typically the main contributor to dose. Based on high consumption rates, ingestion doses arising from the combination of (210)Po, (210)Pb and (40)K were up to 0.05 mSv/a for berries and 0.50 mSv/a for mushrooms. Consumption of such wild foods may result in a significant contribution to total annual doses when consumed in large quantities, particularly when selecting mushrooms species that accumulate high activity concentrations of (210)Po. PMID- 23103574 TI - Long-term variations in the surface air 7Be concentration and climatic changes. AB - We have used EML Surface Air Sampling Program (SASP) data to analyze the long term trend in (7)Be surface concentration and address possible correlation between this long-term trend and climatic changes, namely changes in precipitation patterns and temperature. In this paper we present (7)Be concentration data from 23 sites, spanning over 25 years, all over the world, and extract long-term trend parameter using two independent techniques. The (7)Be concentrations in most stations show a pronounced decreasing trend, potentially corresponding to statistically significant changes in transporting (7)Be from upper atmosphere source to these sites. Weak negative correlation between (7)Be concentration and amount of precipitation was also observed. However, more data from more representative sites around the world are needed the statistical robustness of this trend. PMID- 23103575 TI - Impact of the geological substrate on the radiological content of Galician waters. AB - Galicia (NW of Spain) is home to a highly-fractured soil rich in (238)U minerals, being the widest radon-prone area of the Iberian Peninsula. High precipitation levels confer a rich variety and abundance of both surface and groundwaters, which are extensively used for human consumption. Nevertheless, there exists no comprehensive body of information about the impact of the high environmental radioactivity on the radiological content of Galician waters. Measurements of (222)Rn, gross alpha/beta, (226, 224)Ra and (3)H activity were undertaken over a significant range of traditional springs, waters for spas and bottling plant wells. A seasonal survey was also performed for five network water suppliers to the largest Galician cities. The main outcome of this study has been the determination of statistical correlations between the water's radiological content and different environmental factors. Water measured at bottling plants reveal radiological values exceeding the U.E. limits, however this is eliminated in the industrial bottling process before reaching the consumer. Neither significant values nor seasonal variations were obtained for network waters. PMID- 23103576 TI - 236U/238U and 240Pu/239Pu isotopic ratios in small (2 L) sea and river water samples. AB - Accelerator Mass Spectrometry (AMS) and alpha spectrometry were used to determine uranium ((236)U, (238)U, (234)U) and plutonium isotopes ((239)Pu, (240)Pu) in sea and river water samples. Plutonium was separated by Dowex((r)) 1 * 8 resin and UTEVA((r)) resin was used for uranium purification. The measured (236)U/(238)U isotopic ratios for surface water from the Atlantic Ocean, the Pacific Ocean and the Black Sea were in the order of 10(-9), while values for river water were in the order of 10(-8). These contaminations may be attributed to global fallout. A sample of the reference material IAEA-443, collected from the Irish Sea, showed, in accordance to the reference value, a ratio that was 10(3) times higher due to effluents from the reprocessing plant at Sellafield. These results underline the good suitability of (236)U/(238)U as a tracer for hydrology and oceanography, and show that relatively small water samples are sufficient for the determination of (236)U by AMS, which is not the case for plutonium with present techniques. The plutonium concentrations in our water samples could only be measured with large uncertainties and were in the order of 10(-3) mBq/L (with the exception of the Irish Sea sample). PMID- 23103577 TI - Paddy-field contamination with 134Cs and 137Cs due to Fukushima Dai-ichi Nuclear Power Plant accident and soil-to-rice transfer coefficients. AB - The transfer coefficient (TF) from soil to rice plants of (134)Cs and (137)Cs in the form of radioactive deposition from the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident in March 2011 was investigated in three rice paddy fields in Minami-Soma City. Rice crops were planted in the following May and harvested at the end of September. Soil cores of 30-cm depth were sampled from rice-planted paddy fields to measure (134)Cs and (137)Cs radioactivity at 5-cm intervals. (134)Cs and (137)Cs radioactivity was also measured in rice ears (rice with chaff), straws and roots. The rice ears were subdivided into chaff, brown rice, polished rice and rice bran, and the (134)Cs and (137)Cs radioactivity concentration of each plant part was measured to calculate the respective TF from the soil. The TF of roots was highest at 0.48 +/- 0.10 in the field where the (40)K concentration in the soil core was relatively low, in comparison with TF values of 0.31 and 0.38 in other fields. Similar trends could be found for the TF of whole rice plants, excluding roots. The TF of rice ears was relatively low at 0.019-0.026. The TF of chaff, rice bran, brown rice and polished rice was estimated to be 0.049, 0.10-0.16, 0.013-0.017 and 0.005-0.013, respectively. PMID- 23103578 TI - Tracking suspended particle transport via radium isotopes ((226)Ra and (228)Ra) through the Apalachicola-Chattahoochee-Flint River system. AB - Suspended particles in rivers can carry metals, nutrients, and pollutants downstream which can become bioactive in estuaries and coastal marine waters. In river systems with multiple sources of both suspended particles and contamination sources, it is important to assess the hydrologic conditions under which contaminated particles can be delivered to downstream ecosystems. The Apalachicola-Chattahoochee-Flint (ACF) River system in the southeastern United States represents an ideal system to study these hydrologic impacts on particle transport through a heavily-impacted river (the Chattahoochee River) and one much less impacted by anthropogenic activities (the Flint River). We demonstrate here the utility of natural radioisotopes as tracers of suspended particles through the ACF system, where particles contaminated with arsenic (As) and antimony (Sb) have been shown to be contributed from coal-fired power plants along the Chattahoochee River, and have elevated concentrations in the surficial sediments of the Apalachicola Bay Delta. Radium isotopes ((228)Ra and (226)Ra) on suspended particles should vary throughout the different geologic provinces of this river system, allowing differentiation of the relative contributions of the Chattahoochee and Flint Rivers to the suspended load delivered to Lake Seminole, the Apalachicola River, and ultimately to Apalachicola Bay. We also use various geochemical proxies ((40)K, organic carbon, and calcium) to assess the relative composition of suspended particles (lithogenic, organic, and carbonate fractions, respectively) under a range of hydrologic conditions. During low (base) flow conditions, the Flint River contributed 70% of the suspended particle load to both the Apalachicola River and the bay, whereas the Chattahoochee River became the dominant source during higher discharge, contributing 80% of the suspended load to the Apalachicola River and 62% of the particles entering the estuary. Neither of these hydrologic scenarios, which were moderately low flow regimes, appeared to transport particles contaminated with arsenic and antimony to Apalachicola Bay. PMID- 23103579 TI - Colloid-associated plutonium transport in the vadose zone sediments at Lop Nor. AB - A framework to describe the characteristics of pore water in unsaturated media was established in order to study transport of colloid-associated (239)Pu (i.e., colloidal Pu) through the vadose sediments. Effluent concentrations and recoveries of Pu were found to decrease with increasing ionic strength. However, they would remain approximately constant at a critical value of 0.0289 M (Na(+)) though ionic strengths were further increased. Fast deposition rate coefficient (k(fast)) was thus experimentally determined. To our knowledge, this relationship between the mobility of colloidal Pu and the critical ionic strength was the first time observed. On the other hand, significant detachment of colloidal Pu once retained in the sediments was not observed during the subsequent chemical and physical perturbations. But slow release and transport could persist as long as flow continued. The threshold infiltration intensity (0.166 cm/min) revealed a nonmonotonic dependence of the cumulative amount of detached colloidal Pu on the intensity. PMID- 23103580 TI - Database of meteorological and radiation measurements made in Belarus during the first three months following the Chernobyl accident. AB - Results of all available meteorological and radiation measurements that were performed in Belarus during the first three months after the Chernobyl accident were collected from various sources and incorporated into a single database. Meteorological information such as precipitation, wind speed and direction, and temperature in localities were obtained from meteorological station facilities. Radiation measurements include gamma-exposure rate in air, daily fallout, concentration of different radionuclides in soil, grass, cow's milk and water as well as total beta-activity in cow's milk. Considerable efforts were made to evaluate the reliability of the measurements that were collected. The electronic database can be searched according to type of measurement, date, and location. The main purpose of the database is to provide reliable data that can be used in the reconstruction of thyroid doses resulting from the Chernobyl accident. PMID- 23103581 TI - Discharges of nuclear medicine radioisotopes in Spanish hospitals. AB - Given the increasing use of radiopharmaceuticals in medicine, the aim of this paper is to determine radioactivity levels in the effluents of hospitals with Nuclear Medicine Departments. The radiological study of hospital discharges was carried out by gamma spectrometry, and liquid scintillation spectrometry to determine (14)C and (3)H contents. On March 9th and April 19th, 2010, daily radioactivity levels were monitored from 8:30 a.m. to 7:30 p.m. Each sample was collected at a specific control point of two major public hospitals in Granada (Spain). The analytical results show the presence of radionuclides such as (99m)Tc, (131)I, (67)Ga, and (111)In.They are frequently used in nuclear medicine for diagnostic and/or therapeutic purposes. This study shows the differences between direct and after-storage discharges and also justifies the need of storage tanks in hospitals with nuclear medicine departments. Moreover, monitoring of (99m)Tc released at hospital control points can be a useful tool for optimizing the safety conditions of storage tanks and discharge of radionuclides. PMID- 23103582 TI - Various consequences regarding hypothetical dispersion of airborne radioactivity in a city center. AB - In case of dispersion of airborne radioactive material in a city center a number of questions will prompt for an answer. While many questions can get their answers in due course of time based on results of tests and sampling, a good understanding of the quantitative effect of dispersion will be very helpful to rescue staff, in particular in the early stage. In the following dose and dose rate estimates are presented for three scenarios including dispersion of radioactivity in a city center. In one case the activity is released in an open place, in another from a roof and in the third case from a source on a street where the wind is blowing along the street. In each case, at specific positions, estimates are made of dose from inhalation, and dose rates for contamination on skin as well as from radioactive particles deposited onto ground, walls and roofs (external exposure) in the city center. It should be noted that the deposition pattern in urban areas varies greatly which means that the consequences are difficult to predict. The dispersion is influenced by recirculation behind tall buildings and diverted flow close to street-ends, which have significant effects on the deposit pattern. Regarding the relative importance of contributions to total dose it is found that inhalation could play a major role for long term effects while dose to skin might dominate acute effects. PMID- 23103583 TI - Atmospheric fluxes of (7)Be and (210)Pb on monthly time-scales and during rainfall events at Stony Brook, New York (USA). AB - The particle-reactive radionuclides (7)Be and (210)Pb have been employed extensively as tracers and chronometers for a variety of aquatic and terrestrial processes. Both radionuclides are delivered to the Earth's surface from the atmosphere, and in order to use them effectively as natural tracers, an understanding of variations in atmospheric fluxes of these radionuclides due to latitudinal differences and storm events is required. The monthly atmospheric fluxes of (7)Be and (210)Pb, measured from April-2008 to December-2009 at Stony Brook, NY, ranged from 67 to 385 Bq m(-2) and 6.7 to 16.7 Bq m(-2), respectively. Composite annual atmospheric fluxes over the sampling period were 3110 +/- 1200 Bq m(-2) y(-1) for (7)Be and 146 +/- 50 Bq m(-2) y(-1) for (210)Pb and were similar to geographically comparable sites. The monthly atmospheric fluxes of (7)Be and (210)Pb were significantly correlated with rainfall. The (7)Be/(210)Pb ratio in the monthly samples varied seasonally, with values of ~10-11 during the winter months and ~20-28 during the spring - fall. The pattern of seasonal variation in (7)Be fluxes and (7)Be/(210)Pb ratios is most consistent with that observed in surface air at continental sites in which more frequent deep convective storms occur during the summer and therefore result in an increased transport of (7)Be from the upper troposphere to the Earth's surface. An additional factor may be that the winds at Stony Brook were dominantly from the northwest during the winter of 2009 and so were characterized by low (7)Be/(210)Pb ratios while in the spring, winds from the southwest brought marine air with higher (7)Be/(210)Pb ratios to the sampling site. Fluxes of (7)Be and (210)Pb also were measured over two long (16-24 h) and two short (~1 h) intense periods of rainfall in June and July 2009. Fluxes of (7)Be and (210)Pb continued throughout the short events, but the two radionuclides showed different patterns during the long events. While the entirety of the (210)Pb flux accumulated during the first ~1 h, (7)Be continued to be accumulated over the course of both long events. The (7)Be/(210)Pb ratio ranged from 20 to ~300 during the events and, in general, was considerably greater than the ratios measured in the monthly samples. Radar image snapshots taken during the events show cloud heights of 7 10.5 km, and the (7)Be/(210)Pb ratios measured in the precipitation are consistent with previous model estimates of (7)Be/(210)Pb ratios in aerosols at altitudes of 5-10 km (latitude 40 degrees N). The data suggest that (210)Pb can be effectively stripped from the lower troposphere early in a rainfall event, but intense convective mixing and scavenging of (7)Be from the upper troposphere results in a continuous flux of (7)Be and elevated (7)Be/(210)Pb ratios as the event progresses. PMID- 23103584 TI - VEGF-mediated phosphorylation of eNOS regulates angioblast and embryonic endothelial cell proliferation. AB - To evaluate potential roles of nitric oxide (NO) in the regulation of the endothelial lineage and neovascular processes (vasculogenesis and angiogenesis) we evaluated endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p eNOS) expression in 7.2-8.5 days post-coitum (dpc) mouse embryos. Analysis revealed that p-eNOS((S1177)) but not P-eNOS((S617)) or P-eNOS((T495)) was expressed in a subpopulation of angioblasts (TAL-1(+)/Flk-1(+)/CD31(-)/CD34(-)/VE Cadherin(-)) at 7.2 dpc. A role of the VEGF/Akt1/eNOS signaling pathway in the regulation of the endothelial cell (EC) lineage was suggested by the strong correlation observed between cell division and p-eNOS((S1177)) expression in both angioblasts and embryonic endothelial cells (EECs, TAL-1(+)/Flk 1(+)/CD31(+)/CD34(+)/VE-Cadherin(+)). Our studies using Akt1 null mouse embryos show a reduction in p-eNOS((S1177)) expression in angioblast and EECs that is correlated with a decrease in endothelial cell proliferation and results in changes in VEGF-induced vascular patterning. Further, we show that VEGF-mediated cell proliferation in Flk-1(+) cells in allantoic cultures is decreased by pharmacological inhibitors of the VEGF/Akt1/eNOS signaling pathways. Taken together, our findings suggest that VEGF-mediated eNOS phosphorylation on Ser1177 regulates angioblast and EEC division, which underlies the formation of blood vessels and vascular networks. PMID- 23103585 TI - Muscle and connective tissue progenitor populations show distinct Twist1 and Twist3 expression profiles during axolotl limb regeneration. AB - Limb regeneration involves re-establishing a limb development program from cells within adult tissues. Identifying molecular handles that provide insight into the relationship between cell differentiation status and cell lineage is an important step to study limb blastema cell formation. Here, using single cell PCR, focusing on newly isolated Twist1 sequences, we molecularly profile axolotl limb blastema cells using several progenitor cell markers. We link their molecular expression profile to their embryonic lineage via cell tracking experiments. We use in situ hybridization to determine the spatial localization and extent of overlap of different markers and cell types. Finally, we show by single cell PCR that the mature axolotl limb harbors a small but significant population of Twist1(+) cells. PMID- 23103587 TI - A novel cysteine-rich antimicrobial peptide from the mucus of the snail of Achatina fulica. AB - Antimicrobial peptides (AMPs) are important components of the innate immunity. Many antimicrobial peptides have been found from marine mollusks. Little information about AMPs of mollusks living on land is available. A novel cysteine rich antimicrobial peptide (mytimacin-AF) belonging to the peptide family of mytimacins was purified and characterized from the mucus of the snail of Achatina fulica. Its cDNA was also cloned from the cDNA library. Mytimacin-AF is composed of 80 amino acid residues including 10 cysteines. Mytimacin-AF showed potent antimicrobial activity against Gram-negative and Gram-positive bacteria and the fungus Candida albicans. Among tested microorganisms, it exerted strongest antimicrobial activity against Staphylococcus aureus with a minimal peptide concentration (MIC) of 1.9 MUg/ml. Mytimacin-AF had little hemolytic activity against human blood red cells. The current work confirmed the presence of mytimacin-like antimicrobial peptide in land-living mollusks. PMID- 23103588 TI - Steviol glycoside safety: is the genotoxicity database sufficient? AB - The safety of steviol glycoside sweeteners has been extensively reviewed in the literature. National and international food safety agencies and approximately 20 expert panels have concluded that steviol glycosides, including the widely used sweeteners stevioside and rebaudioside A, are not genotoxic. However, concern has been expressed in recent publications that steviol glycosides may be mutagenic based on select studies representing a small fraction of the overall database, and it has been suggested that further in vivo genotoxicity studies are required to complete their safety profiles. To address the utility of conducting additional in vivo genotoxicity studies, this review evaluates the specific genotoxicity studies that are the sources of concern, and evaluates the adequacy of the database including more recent genotoxicity data not mentioned in those publications. The current database of in vitro and in vivo studies for steviol glycosides is robust and does not indicate that either stevioside or rebaudioside A are genotoxic. This, combined with a lack of evidence for neoplasm development in rat bioassays, establish the safety of all steviol glycosides with respect to their genotoxic/carcinogenic potential. PMID- 23103586 TI - BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. AB - Bone morphogenetic proteins (BMPs) are involved in embryonic mammary gland (MG) development and can be dysregulated in breast cancer. However, the role BMPs play in the postnatal MG remains virtually unknown. BMPs are potent morphogens that are involved in cell fate determination, proliferation, apoptosis and adult tissue homeostasis. Twisted gastrulation (TWSG1) is a secreted BMP binding protein that modulates BMP ligand availability in the extracellular space. Here we investigate the consequences of TWSG1 deletion on development of the postnatal MG. At puberty, Twsg1 is expressed in the myoepithelium and in a subset of body cells of the terminal end buds. In the mature duct, Twsg1 expression is primarily restricted to the myoepithelial layer. Global deletion of Twsg1 leads to a delay in ductal elongation, reduced secondary branching, enlarged terminal end buds, and occluded lumens. This is associated with an increase in luminal epithelial cell number and a decrease in apoptosis. In the MG, pSMAD1/5/8 level and the expression of BMP target genes are reduced, consistent with a decrease in BMP signaling. GATA-3, which is required for luminal identity, is reduced in Twsg1(-/ ) MGs, which may explain why K14 positive cells, which are normally restricted to the myoepithelial layer, are found within the luminal compartment and shed into the lumen. In summary, regulation of BMP signaling by TWSG1 is required for normal ductal elongation, branching of the ductal tree, lumen formation, and myoepithelial compartmentalization in the postnatal MG. PMID- 23103590 TI - Using supermatrices for phylogenetic inquiry: an example using the sedges. AB - In this article, we use supermatrix data-mining methods to reconstruct a large, highly inclusive phylogeny of Cyperaceae from nucleotide data available on GenBank. We explore the properties of these trees and their utility for phylogenetic inference, and show that even the highly incomplete alignments characteristic of supermatrix approaches may yield very good estimates of phylogeny. We present a novel pipeline for filtering sparse alignments to improve their phylogenetic utility by maximizing the partial decisiveness of the matrices themselves through a technique we call "phylogenetic scaffolding," and we present a new method of scoring tip instability (i.e. "rogue taxa") based on the I statistic implemented in the software Mesquite. The modified statistic, which we call I(S), is somewhat more straightforward to interpret than similar statistics, and our implementation of it may be applied to large sets of large trees. The largest sedge trees presented here contain more than 1500 tips (about one quarter of all sedge species) and are based on multigene alignments with more than 20 000 sites and more than 90% missing data. These trees match well with previously supported phylogenetic hypotheses, but have lower overall support values and less resolution than more heavily filtered trees. Our best-resolved trees are characterized by stronger support values than any previously published sedge phylogenies, and show some relationships that are incongruous with previous studies. Overall, we show that supermatrix methods offer powerful means of pursuing phylogenetic study and these tools have high potential value for many systematic biologists. PMID- 23103589 TI - Estimating speciation and extinction rates for phylogenies of higher taxa. AB - Speciation and extinction rates can be estimated from molecular phylogenies. Recently, a number of methods have been published showing that these rates can be estimated even if the phylogeny is incomplete, that is, if not all extant species are included. We show that the accuracy of such methods strongly depends on making the correct assumptions about how the sampling process was performed. We focus on phylogenies that are incomplete because some subclades (e.g., genera and families) are each represented as a single lineage. We show that previous methods implicitly assumed that such subclades are defined by randomly (or in an extreme deterministic way) choosing the edges that define the subclades from the complete species phylogeny. We show that these methods produce biased results if higher taxa are defined in a different manner. We introduce strict higher level phylogenies where subclades are defined so that the phylogeny is fully resolved from its origin to time x(cut), and fully unresolved thereafter, so that for all subclades, stem age > x(cut) > crown age. We present estimates of speciation and extinction rates from a phylogeny of birds in which this subclade definition was applied. However, for most higher level phylogenies in the literature, it is unclear how higher taxa were defined, but often such phylogenies can be easily transformed into strict higher level phylogenies, as we illustrate by estimating speciation and extinction rates from a near-complete but only partly resolved species-level phylogeny of mammals. The accuracy of our methods is verified using simulations. PMID- 23103591 TI - Metrorrhagia in a child with an endodermal sinus tumor of the vagina: a case report. AB - In a female child presenting with vaginal bleeding or a mass protruding through the vagina, it is mandatory to perform an endoscopic and laparoscopic examination and biopsy to establish the correct diagnosis and precise extent of the lesion. An endodermal sinus tumor (EST) of the vagina is a rare, malignant germ cell tumor that occurs primarily in infants. Clearly, the vagina is a critical site for treatment, and the surgeon should seek to preserve the reproductive and sexual function, if possible. We report our experience of a case of EST of the vagina in a 9-month-old female with a history of metrorrhagia. We employed minimally invasive procedures for diagnosis and then, after the administration of platinum- based chemotherapy (PEB regimen), removed a residual lesion during follow-up. These procedures resulted in tumor regression. At follow-up, after two years, the patient is alive and disease-free. PMID- 23103592 TI - Applying comparative effectiveness research to integrative oncology. PMID- 23103593 TI - Preventive medicine in 2030. AB - This invited commentary imagines two futures for preventive medicine and public health in the Year 2030. Using satire, the commentary describes one future in which large corporations control public health and another where a robust public sector plays the leading role. PMID- 23103594 TI - Reno-protective effects of epigallocatechingallate in a small piglet model of extracorporeal circulation. AB - Cardiopulmonary bypass still often is a necessary tool in cardiac surgery in particular in the correction of congenital heart defects in small infants. Nevertheless, among the complications linked to extracorporeal circulation (ECC) with cardiopulmonary bypass (CPB) in both infants and adults one of the most serious problems is renal impairment. Since this might be caused by ischemia/reperfusion injury and accumulation of free radicals, we used (-) epigallocatechin-3-gallate (EGCG), a derivate from green tea, which is known to possess antioxidant, antiapoptotic and NO-scavenging properties in order to find out whether EGCG may protect the kidney. 23 four-week-old Angler Sattelschwein piglets (8-15 kg) were divided into three groups: control-group (n=7), ECC-group (n=10), EGCG-group (n=6). The ECC- and EGCG-group were thoracotomized and underwent CPB for 120 min followed by a 90-min recovery-time. The EGCG-group received 10 mg/kg EGCG before and after CPB. Histology revealed that CPB led to widening of Bowman's capsule, and to vacuolization of proximal tubular cells (p<0.05) which could be prevented by EGCG (p<0.05). Using immunohistology, we found significant nuclear translocation of hypoxia-inducible-factor-1-alpha (HIF 1-alpha) and increased nitrotyrosine formation in the ECC-group. Both were significantly (p<0.05) inhibited by EGCG. ECC-induced loss of energy-rich phosphates was prevented by EGCG. In blood samples we found that CPB resulted in increases in creatinine and urea (in serum) and led to loss of total protein (p<0.05), which all was not present in EGCG-treated animals. We conclude that CPB causes damage in the kidney which can be attenuated by EGCG. PMID- 23103595 TI - Development of a high-throughput electrophysiological assay for the human ether-a go-go related potassium channel hERG. AB - INTRODUCTION: Drug-induced prolongation of the QT interval via block of the hERG potassium channel is a major cause of attrition in drug development. The advent of automated electrophysiology systems has enabled the detection of hERG block earlier in drug discovery. In this study, we have evaluated the suitability of a second generation automated patch clamp instrument, the IonWorks Barracuda, for the characterization of hERG biophysics and pharmacology. METHODS: All experiments were conducted with cells stably expressing hERG. Recordings were made in perforated patch mode either on a conventional patch clamp setup or on the IonWorks Barracuda. On the latter, all recordings were population recordings in 384-well patch plates. RESULTS: HERG channels activated with a V(1/2)=-3.2+/ 1.6mV (n=178) on the IonWorks Barracuda versus -11.2+/-6.1mV (n=9) by manual patch clamp. On the IonWorks Barracuda, seal resistances and currents were stable (<30% change) with up to six cumulative drug additions and 1-min incubations per addition. Over 27 experiments, an average of 338 concentration-response curves were obtained per experiment (96% of the 352 test wells on each plate). HERG pharmacology was examined with a set of 353 compounds that included well characterized hERG blockers. Astemizole, terfenadine and quinidine inhibited hERG currents with IC(50) values of 159nM, 224nM and 2MUM, respectively (n=51, 10 and 18). This set of compounds was also tested on the PatchXpress automated electrophysiology system. We determined through statistical methods that the two automated systems provided equivalent results. DISCUSSION: Evaluating drug effects on hERG channels is best performed by electrophysiological methods. HERG activation and pharmacology on the IonWorks Barracuda automated electrophysiology platform were in good agreement with published electrophysiology results. Therefore, the IonWorks Barracuda provides an efficient way to study hERG biophysics and pharmacology. PMID- 23103597 TI - TTAS a new stilbene derivative that induces apoptosis in Leishmania infantum. AB - Leishmania parasites are able to undergo apoptosis (programmed cell death), similarly to mammalian cells. Recently it was demonstrated in vitro the anti leishmanial effect of some natural and synthetic stilbenoids including resveratrol and piceatannol. In this study we evaluated the Leishmanicidal activity of a pool of stilbene derivatives which had previously shown high apoptotic efficacy against neoplastic cells. All the compounds tested were capable to decrease the parasite viability in a dose-dependent manner. Trans stilbenes proved to be markedly more effective than cis-isomers. This was different from that observed in tumor cells in which cis-stilbenes were more potent cytotoxic agents. Trans-3,4',5-trimethoxy-3'-amino-stilbene (TTAS) was the most active stilbene showing in Leishmania infantum a LD(50) value of 2.6 MUg/mL. In contrast TTAS showed a low toxicity when tested on normal hemopoietic cells. This compound induced apoptosis in parasites by disrupting the mitochondrial membrane potential. Moreover it shows the ability to block Leishmania parasites in G(2)-M phase of cell cycle in agreement with the data obtained by affinity chromatography that identify tubulin as the putative target of TTAS. In conclusion, our results indicate that some stilbene derivatives are highly effective as anti-leishmanial agents and TTAS represents a pro-apoptotic agent in Leishmania parasites that merit further in vivo investigation. PMID- 23103598 TI - Induction of microRNA resistance and secretion in differentiating human endometrial stromal cells. PMID- 23103599 TI - Functional and structural characterization of DNMT2 from Spodoptera frugiperda. PMID- 23103596 TI - Safety and efficacy of tramadol hydrochloride on treatment of premature ejaculation. AB - Premature ejaculation (PE) is the most common sexual disorder. It affects 20%-30% of adult men; the aetiology of this condition has not yet been elucidated. The aim of this study is to evaluate the efficacy, safety, tolerability, undesirable effects and improved satisfaction with sexual intercourse with tramadol hydrochloride at different dosages for the treatment of PE. A total of 300 patients who presented with lifelong (primary) PE were included in this study. The study was performed for 28 weeks, in which placebo (starch tablet) was given for 4 weeks, and active ingredient (tramadol hydrochloride) was administered at different therapeutic dosages for 24 weeks. Patients were divided into three equal groups, each consisting of 100 patients. The first group (A) was given tramadol hydrochloride capsule 25 mg. The second group (B) was given tramadol hydrochloride capsule 50 mg. The third group (C) was given tramadol hydrochloride capsule 100 mg. All of the 300 participants included completed the study voluntarily. The age of the patients varied from 25 to 50 years. After the treatment period, the recorded data were collected for each group and analysed. The results showed a highly significant increase in the mean intravaginal ejaculatory latency time (IELT) in all groups compared to baseline data (P<0.0001). We concluded that using tramadol hydrochloride at different doses on demand for the treatment of PE is effective, safe and tolerable, with minimal undesirable effects, and approval for this indication should be sought. PMID- 23103600 TI - The diversity of microbial aldo/keto reductases from Escherichia coli K12. AB - The genome of Escherichia coli K12 contains 9 open reading frames encoding aldo/keto reductases (AKRs) that are differentially regulated and sequence diverse. A significant amount of data is available for the E. coli AKRs through the availability of gene knockouts and gene expression studies, which adds to the biochemical and kinetic data. This together with the availability of crystal structures for nearly half of the E. coli AKRs and homologues of several others provides an opportunity to look at the diversity of these representative bacterial AKRs. Based around the common AKR fold of (beta/alpha)8 barrel with two additional alpha-helices, the E. coli AKRs have a loop structure that is more diverse than their mammalian counterparts, creating a variety of active site architectures. Nearly half of the AKRs are expected to be monomeric, but there are examples of dimeric, trimeric and octameric enzymes, as well as diversity in specificity for NAD as well as NADP as a cofactor. However in functional assignments and characterisation of enzyme activities there is a paucity of data when compared to the mammalian AKR enzymes. PMID- 23103601 TI - Specific heat versus field for LiFe(1-x)Cu(x)As. AB - LiFeAs is one of the new class of iron superconductors with a bulk [Formula: see text] in the 15-17 K range. We report on the specific heat characterization of single crystal material prepared by self-flux growth techniques with significantly improved properties, including a much decreased residual gamma, gamma(r) (=C/T as T -> 0), in the superconducting state. Thus, in contrast to previous explanations of a finite gamma(r) in LiFeAs being due to intrinsic states in the superconducting gap, the present work shows that such a finite residual gamma in LiFeAs is instead a function of sample quality. Further, since LiFeAs has been characterized as nodeless with multiple superconducting gaps, we report here on its specific heat properties in zero and applied magnetic fields, to compare to similar results on nodal iron superconductors. For comparison, we also investigate LiFe(0.98)Cu(0.02)As, which has the reduced T(c) of ~9 K and an H(c2) of 15 T. Interestingly, although presumably both LiFeAs and LiFe(0.98)Cu(0.02)As are nodeless, they clearly show a non-linear dependence of the electronic density of states (is proportional to specific heat gamma) at the Fermi energy in the mixed state with the applied field, similar to the Volovik effect for nodal superconductors. However, rather than indicating nodal behavior, the satisfactory comparison with a recent theory for gamma(H) for a superconductor with two isotropic gaps in the presence of impurities argues for nodeless behavior. Thus, in terms of specific heat in a magnetic field, LiFeAs can serve as the prototypical multiband, nodeless iron superconductor. PMID- 23103602 TI - Development of a cancer-based chronic inhalation reference value for hexavalent chromium based on a nonlinear-threshold carcinogenic assessment. AB - The carcinogenicity of hexavalent chromium(CrVI) is of significant interest to regulatory agencies for the protection of public health and to industry. Additionally, the mode of action (MOA) and conditions under which CrVI may induce carcinogenicity (e.g., reductive capacity considerations) have recently been the subject of significant scientific debate. Epidemiological data supported by data relevant to the carcinogenic MOA support considering nonlinear-threshold carcinogenic assessments for comparison to default linear low-dose extrapolation approaches. This study reviews epidemiological studies available in the scientific literature and conducts additional statistical dose-response analyses to identify potential carcinogenic thresholds and points of departure (PODs) in the context of supportive MOA information for a nonlinear-threshold inhalation carcinogenic assessment. Dosimetric adjustments and application of appropriate uncertainty factors (total UF of 30) to the selected cumulative exposure POD results in a cancer-based chronic inhalation reference value (ReV) of 0.24 MUgCrVI/m(3). This chronic ReV is 300 times higher than the 1 in 100,000 excess cancer risk air concentration of 8E-04 MUg/m(3) based on USEPA's unit risk factor. PMID- 23103603 TI - Laparoscopic splenectomy for splenic hamartoma in elderly patien Case report and review of the literature. AB - AIM: We proved the feasibility and the safety of the laparoscopic splenectomy for splenic hamartoma in elderly patients. MATERIAL AND METHODS: We present the first case of laparoscopic splenectomy for splenic hamartoma in elderly patients and we reviewed the English literature regarding the laparoscopic approach. RESULTS: A 74-year-old man with a 6-month history of left upper quadrant abdominal and back pain was referred to our hospital for the evaluation of a splenic mass detected by ultrasonography. Computerized tomography scan (CT) revealed the presence of a solid tumor in the upper pole of the spleen (size 5.3 x 4.5 cm). The diagnosis of a malignant tumor was not excluded completely and because of increasing severe left upper quadrant pain, after three days the patient underwent laparoscopic splenectomy and the final pathological diagnosis was splenic hamartoma. The patient's postoperative course was uneventful and the patient was discharged by the sixth postoperative day. CONCLUSIONS: Splenectomy is still necessary for diagnostic and therapeutic purposes and mini-invasive surgical technique today represents the standard procedure for the management of any space-occupying lesions of the spleen also in elderly patients. KEY WORDS: Elderly patients, Hamartoma, Laparoscopic splenectomy, Management. PMID- 23103605 TI - Health service use in adults 20-64 years with traumatic brain injury, spinal cord injury or pelvic fracture. A cohort study with 9-year follow-up. AB - OBJECTIVES: To estimate the health service use over 9 years after the injury year for patients with traumatic brain injury (TBI), spinal cord injury (SCI) and pelvic fracture (PF), and compare with non-injured. DESIGN: A register-based cohort design with a 9-year follow-up period. SETTING: The Danish population. PARTICIPANTS: The study included 434, 100 and 278 hospital-treated incident patients with TBI, SCI and PF, respectively, among 20-year-olds to 64-year-olds identified using the National Patient Register. Controls for each patient group were drawn from the population register, matched by age, sex and health service use during 1995. All were followed during 1996-2005 by linkage to national health registers. The observations were excluded when the patients left Denmark or died. OUTCOME MEASURES: The use of hospital treatments, contacts with general practitioners and the use of physiotherapy. RESULTS: Compared to the controls, more patients with TBI and SCI were hospital admitted all 9 years after the injury year, on average 0.36 and 0.50 times annually, respectively. For patients with PF hospital admissions returned to baseline year 2 after the injury year. For patients with SCI the use of general practitioner services remained at an increased level year 9 after the injury year, while it returned to baseline level year 4 after the injury year for patients with TBI and year 2 for patients with PF. For patients with SCI physiotherapy use remained increased over 9 years after the injury year, while it returned to baseline the fifth year for patients with TBI and the third year after for patients with PF. CONCLUSIONS: TBI and SCI increase the use of health services over 9 years after the injury year, while most health service use after PF returned to baseline 2 years after the injury year. PMID- 23103604 TI - Adverse events related to intravenous antibiotic therapy: a prospective observational study in the treatment of infective endocarditis. AB - OBJECTIVE: The goal of this prospective observational study was to identify adverse events (AEs) related to the use of intravenous access sites used for infective endocarditis (IE) treatment in a tertiary care hospital. DESIGN: This is an observational, analytical and prospective study on AEs resulting from the use of intravenous access sites in patients under antimicrobial treatment for IE. Patients enrolled in the International Collaboration on Endocarditis (ICE) study had their peripheral, short-term central catheters (CVC) and peripherally inserted central catheters (PICC) monitored for AEs. SETTING: Tertiary care hospital for cardiac surgery in Rio de Janeiro, Brazil. PATIENTS: Patients over 14 years of age, hospitalised in 2009 and 2010 with possible or definite criteria for IE by the modified Duke criteria were included. MAIN OUTCOME MEASURES: AEs related to intravenous catheters: erythema and infiltration, fever, obstruction, externalisation and blood stream infection. RESULTS: Thirty-seven episodes of IE in 35 patients were studied. Mean patient age was 44.32+/-15.2 years; 22 (63%) were men. The number of vascular catheters studied were 253, 148 of which were peripheral, 85 CVC (21 of which for haemodialysis) and 20 PICC. The most frequent AEs were 'erythema' and 'infiltration' for peripheral catheters, 'fever' for CVCs and 'obstruction' and 'externalisation' for PICCs. The number of catheter-days was 360 for peripheral catheters, 1.156 for CVC and 420 for PICC. Kaplan-Meier curves for CVC and PICC showed statistical difference for obstruction (p<0.001) in PICCs. More bacteraemia occurred in CVC compared with PICC. CONCLUSIONS: The choice of intravenous access sites is critical in the treatment of IE. Close observation for AEs and stricter implementation of infection control measures and better manipulation of catheters are suggested. PMID- 23103606 TI - Utilisation of a thoracic oncology database to capture radiological and pathological images for evaluation of response to chemotherapy in patients with malignant pleural mesothelioma. AB - OBJECTIVE: An area of need in cancer informatics is the ability to store images in a comprehensive database as part of translational cancer research. To meet this need, we have implemented a novel tandem database infrastructure that facilitates image storage and utilisation. BACKGROUND: We had previously implemented the Thoracic Oncology Program Database Project (TOPDP) database for our translational cancer research needs. While useful for many research endeavours, it is unable to store images, hence our need to implement an imaging database which could communicate easily with the TOPDP database. METHODS: The Thoracic Oncology Research Program (TORP) imaging database was designed using the Research Electronic Data Capture (REDCap) platform, which was developed by Vanderbilt University. To demonstrate proof of principle and evaluate utility, we performed a retrospective investigation into tumour response for malignant pleural mesothelioma (MPM) patients treated at the University of Chicago Medical Center with either of two analogous chemotherapy regimens and consented to at least one of two UCMC IRB protocols, 9571 and 13473A. RESULTS: A cohort of 22 MPM patients was identified using clinical data in the TOPDP database. After measurements were acquired, two representative CT images and 0-35 histological images per patient were successfully stored in the TORP database, along with clinical and demographic data. DISCUSSION: We implemented the TORP imaging database to be used in conjunction with our comprehensive TOPDP database. While it requires an additional effort to use two databases, our database infrastructure facilitates more comprehensive translational research. CONCLUSIONS: The investigation described herein demonstrates the successful implementation of this novel tandem imaging database infrastructure, as well as the potential utility of investigations enabled by it. The data model presented here can be utilised as the basis for further development of other larger, more streamlined databases in the future. PMID- 23103607 TI - Evaluation of the self-inflating bag-valve-mask and non-rebreather mask as preoxygenation devices in volunteers. AB - OBJECTIVE: To evaluate and compare the effectiveness and tolerability of preoxygenation with the self-inflating bag-valve-mask (BVM) and non-rebreather mask (NRM) as are used before emergency anaesthesia. DESIGN: Device performance evaluation. SETTING: Experimental study. PARTICIPANTS: 12 male and 12 female healthy volunteers (age range 24-47) with no history of clinically significant respiratory disease. INTERVENTIONS: End-expiration oxygen measurements (F(E)O(2)) after 3 min of preoxygenation with BVM (without mechanical assistance) and NRM devices. Mask pressures were measured and subjective difficulty of breathing was also assessed with a visual analogue score (VAS). PRIMARY AND SECONDARY OUTCOME MEASURES: The final F(E)O(2) achieved was 58.0% (SD 7.3%) for the NRM compared to 53.1% (SD 13.4%) for the BVM (p=0.072). Preoxygenation was associated with small increases in F(E)CO(2) that were greater for the BVM (0.50%; 95% CI 0.48 to 0.52) than the NRM (0.29%; 95% CI 0.31 to 0.28); this difference was statistically significant (p=0.028). Both devices were well tolerated on VAS assessment of difficulty of breathing although this was higher for the BVM than the NRM (median VAS 1.85/10 compared to 1.1/10; p=0.041). Inspiratory and expiratory mask pressures were higher for the BVM. CONCLUSIONS: In healthy volunteers, the NRM performs comparably to the BVM in terms of the degree of denitrogenation achieved although neither performed well. Although it was well tolerated, the BVM was subjectively more difficult to breathe through and was associated with greater mask pressures and a small increase in F(E)CO(2) consistent with hypoventilation or rebreathing. Our results suggest that preoxygenation with the NRM may be a preferable approach in spontaneously breathing patients. PMID- 23103608 TI - The impact of drug eluting stents availability on the treatment choice among medical therapy, percutaneous or surgical revascularisation and on 4-year clinical outcome in patients with coronary artery disease: a cohort study. AB - OBJECTIVE: To investigate the influence of the availability of drug eluting stents (DES) on treatment choice (TC) among medical therapy (MT), coronary by pass surgery (CABG) or percutaneous coronary interventions (PCI) and the consequent clinical outcomes in patients hospitalised because of coronary artery disease (CAD). DESIGN: Observational study comparing two cohorts hospitalised immediately before, and 3 years after DES availability. SETTING: Thirteen hospitals with cardiology facilities. PATIENTS: 2131 consecutive patients with at least one coronary stenosis >50% at coronary angiography (CA) after exclusion of those with acute myocardial infarction or previous CABG or associated relevant valvular disease. MAIN OUTCOME MEASURES: Treatment choice after CA and 4-year clinical outcomes. RESULTS: TC among MT (27% vs 29.2%), PCI (58.6% vs 55.5%) and CABG (14.5% vs 15.3%) was similar in the DES and bare metal stent (BMS) periods (p = 0.51). At least one DES was implanted in 57% of patients treated with PCI in 2005. After 4 years, no difference in mortality (13.8% vs 13.2%, p = 0.72), hospital admissions for myocardial infarction (6.6% vs 5.2%, p = 0.26), stroke (2.2% vs 1.7%, p = 0.49) and further revascularisations (22.3% vs 19.7%, p = 0.25) were observed in patients enrolled in the DES and BMS periods. Only in patients with Syntax score 23-32 a significant change of TC (p = 0.0002) occurred in the DES versus BMS period: MT in 17.4% vs 31%, PCI in 62.2% vs 35.8%, CABG in 20.3% vs 33.2%, with similar 4-year combined end-point of mortality, stroke, myocardial infarction and further revascularisations (45.3% vs 34.2%, p = 0.087). CONCLUSIONS: Three years after DES availability, the TC in patients with CAD has not changed significantly as well as the 4-year incidence of death, myocardial infarction, stroke and further revascularisations. In subgroup with Syntax score 23-32, a significant increase of indications to PCI was observed in the DES period, without any improvement of the 4-year clinical outcome. PMID- 23103609 TI - Applying the RE-AIM framework to the Alberta's Caring for Diabetes Project: a protocol for a comprehensive evaluation of primary care quality improvement interventions. AB - INTRODUCTION: Diabetes represents a major public health and health system burden. As part of the Alberta's Caring for Diabetes (ABCD) Project, two quality improvement interventions are being piloted in four Primary Care Networks in Alberta. Gaps between health research, policy and practice have been documented and the need to evaluate the impact of public health interventions in real-world settings to inform decision-making and clinical practice is paramount. In this article, we describe the application of the RE-AIM framework to evaluate the interventions beyond effectiveness. METHODS AND ANALYSIS: Two quality-improvement interventions were implemented, based on previously proven effective models of care and are directed at improving the physical and mental health of patients with type-2 diabetes. Our goal is to adapt and apply the RE-AIM framework, using a mixed-methods approach, to understand the impact of the interventions to inform policy and clinical decision-making. We present the proposed measures, data sources and data management and analysis strategies used to evaluate the interventions by RE-AIM dimension. ETHICS AND DISSEMINATION: Ethics approval for the ABCD Project has been granted from the Health Research Ethics Board (HREB #PRO00012663) at the University of Alberta. The RE-AIM framework will be used to structure our dissemination activities by dimension. RESULTS: It will be presented at relevant conferences and prepared for publication in peer-reviewed journals. Various products, such as presentations, briefing reports and webinars, will be developed to inform key stakeholders of the findings. Presentation of findings by RE-AIM dimension will facilitate discussion regarding the public health impact of the two interventions within the primary care context of Alberta and lessons learned to be used in programme planning and care delivery for patients with type-2 diabetes. It will also promote the application of evaluation models to better assess the impact of community-based primary healthcare interventions through our dissemination activities. PMID- 23103611 TI - Cytoplasmic mislocalization of overexpressed FOXF1 is associated with the malignancy and metastasis of colorectal adenocarcinomas. AB - Our previous studies have revealed that the human FOXF1 gene, encoding a transcription factor member of the forkhead box (FOX) family, functions as a tumor suppressor and its expression is frequently silenced in breast cancer via DNA hypermethylation. Moreover, we recently reported that FOXF1 expression is preferentially silenced in colorectal cancer cell lines with inactive p53 and knockdown of FOXF1 caused genomic instability in FOXF1-expressing colorectal cancer cells with a defect in the p53-p21(WAF1) checkpoint, suggesting that FOXF1 plays a key role in colorectal tumorigenesis. Given that the in vivo role of FOXF1 in colorectal cancer remains unknown, the study here was aimed at delineating the clinical relevance of FOXF1 in colorectal adenocarcinomas. To characterize FOXF1 protein expression in colorectal cancer, designed tissue microarrays, comprising 50 cases of primary colorectal adenocarcinoma paired with matched adjacent normal tissue, were utilized in the immunohistochemistry (IHC) study. The IHC results showed that for adjacent normal colorectal tissue, the FOXF1 protein was only detected in stroma, not in epithelium, with either cytoplasmic staining (70% of total cases) or a mix of cytoplasmic and nuclear staining (6%). In contrast, for colorectal adenocarcinomas, FOXF1 staining was predominately identified in the cytoplasm of tumor epithelial cells (40% of total cases) and tumor-associated stromal cells of some cases (10%) also exhibited FOXF1 positivity in their cytoplasm. Cytoplasmic FOXF1 protein expression in tumor epithelial cells positively correlated with the histologic grade, depth of invasion, stage and lymphatic metastasis of colorectal adenocarcinomas (p<0.05). Moreover, in silico meta-analysis of Oncomine's cancer microarray database indicates that FOXF1 mRNA is overexpressed in a significant subset of colorectal adenocarcinoma tumors compared with normal colorectal tissue and other types of cancers. Our findings for the first time have revealed that the FOXF1 protein is overexpressed as well as mislocalized in cancerous epithelial cells and underexpressed/lost in tumor-associated stromal fibroblasts of colorectal adenocarcinomas, and suggest that FOXF1 is a potential prognostic marker due to its association with the malignancy and metastasis of colorectal cancer. PMID- 23103610 TI - Obesity pharmacotherapy: what is next? AB - The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development. PMID- 23103613 TI - Chloroacetic acid induced neuronal cells death through oxidative stress-mediated p38-MAPK activation pathway regulated mitochondria-dependent apoptotic signals. AB - Chloroacetic acid (CA), a toxic chlorinated analog of acetic acid, is widely used in chemical industries as an herbicide, detergent, and disinfectant, and chemical intermediates that are formed during the synthesis of various products. In addition, CA has been found as a by-product of chlorination disinfection of drinking water. However, there is little known about neurotoxic injuries of CA on the mammalian, the toxic effects and molecular mechanisms of CA-induced neuronal cell injury are mostly unknown. In this study, we examined the cytotoxicity of CA on cultured Neuro-2a cells and investigated the possible mechanisms of CA-induced neurotoxicity. Treatment of Neuro-2a cells with CA significantly reduced the number of viable cells (in a dose-dependent manner with a range from 0.1 to 3mM), increased the generation of ROS, and reduced the intracellular levels of glutathione depletion. CA also increased the number of sub-G1 hypodiploid cells; increased mitochondrial dysfunction (loss of MMP, cytochrome c release, and accompanied by Bcl-2 and Mcl-1 down-regulation and Bax up-regulation), and activated the caspase cascades activations, which displayed features of mitochondria-dependent apoptosis pathway. These CA-induced apoptosis-related signals were markedly prevented by the antioxidant N-acetylcysteine (NAC). Moreover, CA activated the JNK and p38-MAPK pathways, but did not that ERK1/2 pathway, in treated Neuro-2a cells. Pretreatment with NAC and specific p38-MAPK inhibitor (SB203580), but not JNK inhibitor (SP600125) effectively abrogated the phosphorylation of p38-MAPK and attenuated the apoptotic signals (including: decrease in cytotoxicity, caspase-3/-7 activation, the cytosolic cytochrome c release, and the reversed alteration of Bcl-2 and Bax mRNA) in CA-treated Neuro 2a cells. Taken together, these data suggest that oxidative stress-induced p38 MAPK activated pathway-regulated mitochondria-dependent apoptosis plays an important role in CA-caused neuronal cell death. PMID- 23103612 TI - Classical and alternative activation of rat hepatic sinusoidal endothelial cells by inflammatory stimuli. AB - The ability of rat hepatic sinusoidal endothelial cells (HSEC) to become activated in response to diverse inflammatory stimuli was analyzed. Whereas the classical macrophage activators, IFNgamma and/or LPS upregulated expression of iNOS in HSEC, the alternative macrophage activators, IL-10 or IL-4+IL-13 upregulated arginase-1 and mannose receptor. Similar upregulation of iNOS and arginase-1 was observed in classically and alternatively activated Kupffer cells, respectively. Removal of inducing stimuli from the cells had no effect on expression of these markers, demonstrating that activation is persistent. Washing and incubation of IFNgamma treated cells with IL-4+IL-13 resulted in decreased iNOS and increased arginase-1 expression, while washing and incubation of IL-4+IL 13 treated cells with IFNgamma resulted in decreased arginase-1 and increased iNOS, indicating that classical and alternative activation of the cells is reversible. HSEC were more sensitive to phenotypic switching than Kupffer cells, suggesting greater functional plasticity. Hepatocyte viability and expression of PCNA, beta-catenin and MMP-9 increased in the presence of alternatively activated HSEC. In contrast, the viability of hepatocytes pretreated for 2 h with 5 mM acetaminophen decreased in the presence of classically activated HSEC. These data demonstrate that activated HSEC can modulate hepatocyte responses following injury. The ability of hepatocytes to activate HSEC was also investigated. Co culture of HSEC with acetaminophen-injured hepatocytes, but not control hepatocytes, increased the sensitivity of HSEC to classical and alternative activating stimuli. The capacity of HSEC to respond to phenotypic activators may represent an important mechanism by which they participate in inflammatory responses associated with hepatotoxicity. PMID- 23103614 TI - Blocking the natural killer cell inhibitory receptor NKG2A increases activity of human natural killer cells and clears hepatitis B virus infection in mice. AB - BACKGROUND & AIMS: We studied the functions of natural killer (NK) cells and the role of the NK cell inhibitory receptor (NKG2A) during hepatitis B virus (HBV) infection in patients and mice. METHODS: We analyzed levels of NKG2A on peripheral blood NK cells from 42 patients with active chronic hepatitis B (CHB), 31 patients with inactive CHB, and 35 healthy volunteers (controls). Five patients with CHB treated with antiviral therapy were also included to evaluate changes in NK cells after HBV titers decreased. We examined the effects of blocking antibodies against NKG2A or its ligand Qa-1 (equivalent to HLA-E in humans) in immunocompetent mice that express HBV from a plasmid and are positive for serum hepatitis B surface antigen (a mouse model of HBV infection). RESULTS: A higher percentage of NK cells from patients with active CHB were positive for NKG2A (38.47%) than from patients with inactive CHB (19.33%; P < .01) or controls (27.96%; P < .05). The percentage of NKG2A(+) cells correlated with serum viral load (r = 0.5457; P < .001). The percentage of NKG2A(+) cells decreased along with HBV load in patients that received antiviral therapy (P < .05). Blocking NKG2A interaction with HLA-E in peripheral NK cells from patients with active CHB increased their cytotoxicity in vitro. NK cells of HBV carrier mice also had higher percentages of NK cells that expressed NKG2A compared with control mice; NKG2A was likely to be up-regulated by production of interleukin-10 by hepatic regulatory CD4(+)CD25(+) T cells. Blocking Qa-1 in these mice promoted viral clearance in an NK cell-dependent manner. CONCLUSIONS: Infection with HBV increases levels of the inhibitory receptor NKG2A on NK cells in mice and humans, and reduces their ability to clear HBV. Reagents designed to block the interaction between NKG2A and HLA-E might be developed to treat CHB infection. PMID- 23103615 TI - Regional variation in anesthesia assistance during outpatient colonoscopy is not associated with differences in polyp detection or complication rates. AB - BACKGROUND & AIMS: We investigated the rate and predictors of anesthesia assistance during outpatient colonoscopy and whether anesthesia assistance is associated with colonoscopy interventions and outcomes. METHODS: We performed a retrospective cohort study using a 20% sample of Medicare administrative claims submitted during the 2003 calendar year. We analyzed data from 328,177 adults, 66 years old or older, who underwent outpatient colonoscopy examinations. RESULTS: Overall, 8.7% of outpatient colonoscopies were performed with anesthesia assistance. In multivariate analysis, independent predictors of anesthesia assistance included black race, female sex, and a nonscreening indication; anesthesia assistance increased with median income and comorbidities. General and colorectal surgeons, fewer years in their practice, and nonhospital site of service were also significantly associated with anesthesia assistance. The strongest predictor of anesthesia assistance was the Medicare carrier, with odds ratios ranging from 0.22 (95% confidence interval: 0.12-0.43) for the Arkansas carrier (crude rate 0.9%) to 9.90 (95% confidence interval: 7.92-12.39) for the Empire carrier in New York area (crude rate 35.3%) compared with the Wisconsin carrier (crude rate 4.3%). There was also considerable variation among endoscopists; 75% of providers had no colonoscopies with anesthesia assistance recorded in their dataset, and 4.5% of providers had anesthesia assistance in at least three quarters of their examinations. Anesthesia assistance was not associated with the diagnosis of polyps, the performance of biopsy or polypectomy, or complications in multivariate analyses. CONCLUSIONS: There are significant variations among regions and sites of service in anesthesia assistance during outpatient colonoscopies of Medicare beneficiaries. Although this variation has considerable economic implications, it was not associated with measures of patient risk or outcomes, such as polyp detection or procedure related complications. PMID- 23103616 TI - Declarative interference affects off-line processing of motor imagery learning during both sleep and wakefulness. AB - Retroactive interference from a declarative memory can prevent the consolidation of motor skill memories over wakefulness, but not over a night of sleep. Recently, motor imagery (MI) learning has been showed to allow for a stronger resistance against procedural interference rather than physical practice, but whether declarative interference might impact sleep-dependent consolidation process of an explicit finger tapping task learned with MI remains unknown. To address this issue, 57 subjects mentally rehearsed an explicit finger tapping sequence, and half of them were then requested to practice an interferential declarative task. All participants were re-tested on the initial procedural task either after a night of sleep or a similar daytime interval. The main findings provided evidence that declarative interference affected MI consolidation both over the night- and wakefulness intervals. These results extend our previous findings by underlying that declarative interference might impact more strongly explicit MI practice than physical practice, hence suggesting that MI might rely on declarative memory rather than exclusively on procedural memory system. The relationship between declarative and procedural memories during MI practice, as well as during off-line consolidation, is discussed. PMID- 23103618 TI - Population pharmacokinetics of modafinil acid and estimation of the metabolic conversion of modafinil into modafinil acid in 5 major ethnic groups of China. AB - AIM: To describe the population pharmacokinetic profile of modafinil acid and to compare the extent of metabolism of modafinil into modafinil acid in 5 major ethnic groups (Han, Mongolian, Korean, Uygur, and Hui) of China. METHODS: In a multi-center, open-label, single dose clinical trial, 49 healthy volunteers from the 5 ethnic groups received 200 mg of modafinil orally. Blood samples for pharmacokinetic evaluation of modafinil and modafinil acid were drawn before and at different time after the administration. Systematic population pharmacokinetic (PopPK) modeling for modafinil acid was conducted, integrating with our previous PopPK model for modafinil. The influence of ethnicity, gender, height, body weight and body mass index (BMI) was estimated. The extent of metabolism of modafinil into modafinil acid, expressed as the relative conversion fraction, was estimated and compared among the 5 ethnic groups. RESULTS: When combined with the PopPK model of modafinil, the concentration of modafinil acid versus time profile was best described with a one-compartment model. The typical clearance and volume of distribution for modafinil acid were 4.94 (l/h) and 2.73 (l), respectively. The Korean group had 25% higher clearance, and the Uygur and Hui groups had 12% higher clearance than the Han group. The median for the relative conversion fraction was 0.53 for Koreans, and 0.24 for the other 4 ethnicities. CONCLUSION: Ethnicity has significant influence on the clearance of modafinil acid. When patients in the 5 ethnic groups are administered drugs or prodrugs catalyzed by esterases and/or amidases, the variability in the extent of drug metabolism should be considered. PMID- 23103619 TI - A single-dose toxicity study on non-radioactive iodinated hypericin for a targeted anticancer therapy in mice. AB - AIM: Hypericin (Hyp) and its radio-derivatives have been investigated in animal models with ischemic heart diseases and malignancies for diagnostic and therapeutic purposes. Before radioiodinated Hyp ((123)I-Hyp or (131)I-Hyp) can be considered as a clinically useful drug, vigorous evaluations on its chemotoxicity are necessary. In the present study, we examined the toxicity of a single dose of non-radioactive (127)I-Hyp in normal mice for 24 h and 14 d. METHODS: Studies were performed on 132 normal mice. (127)I -Hyp at a clinically relevant dose of 0.1 mg/kg body weight and a 100-times higher dose of 10 mg/kg was intravenously injected into 40 mice. The safety aspects of clinical manifestations, serological biochemistry, and histopathology were assessed. In another 72 mice, (127)I-Hyp was administered intravenously at assumed values to bracket the value of LD(50). The rest 20 mice were used in the control groups. RESULTS: At 24 h and 14 d following the injection of (127)I -Hyp at either 0.1 or 10 mg/kg, all mice tolerated well without mortality or any observable treatment-related symptoms. No significant differences were found in blood biochemical parameters between the test and control groups. All organs presented normal appearances upon histopathological inspection. The value of LD(50) of (127)I-Hyp in mice through intravenous injection was 20.26 mg/kg, with the 95% confidence interval between 18.90 and 21.55 mg/kg. CONCLUSION: The current study reveals a broad safety range of (127)I-Hyp, which not only supports the use of (123)I-Hyp or (131)I-Hyp in the necrosis targeting theragnostic strategy, but also serves as a valuable reference for exploring other possible applications for iodinated Hyp. PMID- 23103617 TI - Chloride channels in stroke. AB - Vascular remodeling of cerebral arterioles, including proliferation, migration, and apoptosis of vascular smooth muscle cells (VSMCs), is the major cause of changes in the cross-sectional area and diameter of the arteries and sudden interruption of blood flow or hemorrhage in the brain, ie, stroke. Accumulating evidence strongly supports an important role for chloride (Cl(-)) channels in vascular remodeling and stroke. At least three Cl(-) channel genes are expressed in VSMCs: 1) the TMEM16A (or Ano1), which may encode the calcium-activated Cl(-) channels (CACCs); 2) the CLC-3 Cl(-) channel and Cl(-)/H(+) antiporter, which is closely related to the volume-regulated Cl(-) channels (VRCCs); and 3) the cystic fibrosis transmembrane conductance regulator (CFTR), which encodes the PKA- and PKC-activated Cl(-) channels. Activation of the CACCs by agonist-induced increase in intracellular Ca(2+) causes membrane depolarization, vasoconstriction, and inhibition of VSMC proliferation. Activation of VRCCs by cell volume increase or membrane stretch promotes the production of reactive oxygen species, induces proliferation and inhibits apoptosis of VSMCs. Activation of CFTR inhibits oxidative stress and may prevent the development of hypertension. In addition, Cl(-) current mediated by gamma-aminobutyric acid (GABA) receptor has also been implicated a role in ischemic neuron death. This review focuses on the functional roles of Cl(-) channels in the development of stroke and provides a perspective on the future directions for research and the potential to develop Cl(-) channels as new targets for the prevention and treatment of stroke. PMID- 23103620 TI - Population pharmacokinetics of lamotrigine in Chinese children with epilepsy. AB - AIM: To establish a population pharmacokinetics (PPK) model for lamotrigine (LTG) in Chinese children with epilepsy in order to formulate an individualized dosage guideline. METHODS: LTG steady-state plasma concentration data from therapeutic drug monitoring (TDM) were collected retrospectively from 284 patients, with a total of 404 plasma drug concentrations. LTG concentrations were determined using a HPLC method. The patients were divided into 2 groups: PPK model group (n=116) and PPK valid group (n=168). A PPK model of LTG was established with NONMEM based on the data from PPK model group according to a one-compartment model with first order absorption and elimination. To validate the basic and final model, the plasma drug concentrations of the patients in PPK model group and PPK valid group were predicted by the two models. RESULTS: The final regression model for LTG was as follows: CL (L/h)=1.01*(TBW/27.87)(0.635)*e( 0.753*VPA)*e(0.868*CBZ)*e(0.633*PB), Vd (L)= 16.7*(TBW/27.87). The final PPK model was demonstrated to be stable and effective in the prediction of serum LTG concentrations by an internal and external approach validation. CONCLUSION: A PPK model of LTG in Chinese children with epilepsy was successfully established with NONMEM. LTG concentrations can be predicted accurately by this model. The model may be very useful for establishing initial LTG dosage guidelines. PMID- 23103621 TI - The effect of poor compliance on the pharmacokinetics of carbamazepine and its epoxide metabolite using Monte Carlo simulation. AB - AIM: To study the effects of delayed and missed doses (poor compliance) on the pharmacokinetics of carbamazepine (CBZ) and its main active metabolite carbamazepine-10,11-epoxide (CBZE) in Chinese epilepsy patients using Monte Carlo simulation. METHODS: CBZ and CBZE time-concentration profiles in various scenarios were generated based on a population pharmacokinetic study in Chinese epilepsy patients using Monte Carlo simulation. The scenarios included patients given multiple doses of CBZ that ranged from 100 to 300 mg three times daily or from 200 to 300 mg every 12 h. The therapeutic range of CBZ and CBZE for each scenario was estimated to assess the effect of delayed or missed doses and to design corresponding rescue regimens. Moreover, the impact of body weight, absorption rate and co-therapy with other antiepileptic drugs (phenytoin, phenobarbital and valproic acid) on the dosage recommendation was investigated in the event of poor compliance. RESULTS: The risk for a sub-therapeutic range of CBZ and CBZE was increased in a dose-dependent manner in both two and three times daily regimens when delayed or missed doses occurred. The effects of poor compliance was less prominent on the lower daily doses compared with those on the higher daily doses. The dose recommendations, in the event of poor compliance, were time related and dose dependent. Patient body weight, absorption rate and co therapy with phenytoin, phenobarbital and valproic acid had no significant impact on the dose recommendation. CONCLUSION: Patients with epilepsy should take the delayed doses as soon as they remember, and partial missed doses may need to be taken near or at the next scheduled time. PMID- 23103623 TI - Astragalus polysaccharide stimulates glucose uptake in L6 myotubes through AMPK activation and AS160/TBC1D4 phosphorylation. AB - AIM: To establish the mechanism responsible for the stimulation of glucose uptake by Astragalus polysaccharide (APS), extracted from Astragalus membranaceus Bunge, in L6 myotubes in vitro. METHODS: APS-stimulated glucose uptake in L6 myotubes was measured using the 2-deoxy-[(3)H]-D-glucose method. The adenine nucleotide contents in the cells were measured by HPLC. The phosphorylation of AMP-activated protein kinase (AMPK) and Akt substrate of 160 kDa (AS160) was examined using Western blot analysis. The cells transfected with 4P mutant AS160 (AS160-4P) were constructed using gene transfer approach. RESULTS: Treatment of L6 myotubes with APS (100-1600 MUg/mL) significantly increased glucose uptake in time- and concentration-dependent manners. The maximal glucose uptake was reached in the cells treated with APS (400 MUg/mL) for 36 h. The APS-stimulated glucose uptake was significantly attenuated by pretreatment with Compound C, a selective AMPK inhibitor or in the cells overexpressing AS160-4P. Treatment of L6 myotubes with APS strongly promoted the activation of AMPK. We further demonstrated that either Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta) or liver kinase B1 (LKB1) mediated APS-induced activation of AMPK in L6 myotubes, and the increased cellular AMP: ATP ratio was also involved. Treatment of L6 myotubes with APS robustly enhanced the phosphorylation of AS160, which was significantly attenuated by pretreatment with Compound C. CONCLUSION: Our results demonstrate that APS stimulates glucose uptake in L6 myotubes through the AMP-AMPK-AS160 pathway, which may contribute to its hypoglycemic effect. PMID- 23103622 TI - Loss of endoplasmic reticulum Ca2+ homeostasis: contribution to neuronal cell death during cerebral ischemia. AB - The loss of Ca(2+) homeostasis during cerebral ischemia is a hallmark of impending neuronal demise. Accordingly, considerable cellular resources are expended in maintaining low resting cytosolic levels of Ca(2+). These include contributions by a host of proteins involved in the sequestration and transport of Ca(2+), many of which are expressed within intracellular organelles, including lysosomes, mitochondria as well as the endoplasmic reticulum (ER). Ca(2+) sequestration by the ER contributes to cytosolic Ca(2+) dynamics and homeostasis. Furthermore, within the ER Ca(2+) plays a central role in regulating a host of physiological processes. Conversely, impaired ER Ca(2+) homeostasis is an important trigger of pathological processes. Here we review a growing body of evidence suggesting that ER dysfunction is an important factor contributing to neuronal injury and loss post-ischemia. Specifically, the contribution of the ER to cytosolic Ca(2+) elevations during ischemia will be considered, as will the signalling cascades recruited as a consequence of disrupting ER homeostasis and function. PMID- 23103625 TI - Telmisartan attenuates hepatic fibrosis in bile duct-ligated rats. AB - AIM: To evaluate the antifibrotic effect of telmisartan, an angiotensin II receptor blocker, in bile duct-ligated rats. METHODS: Adult Sprague-Dawley rats were allocated to 3 groups: sham-operated rats, model rats underwent common bile duct ligation (BDL), and BDL rats treated with telmisartan (8 mg/kg, po, for 4 weeks). The animals were sacrificed on d 29, and liver histology was examined, the Knodell and Ishak scores were assigned, and the expression of angiotensin converting enzyme (ACE) and ACE2 was evaluated with immunohistochemical staining. The mRNAs and proteins associated with liver fibrosis were evaluated using RTQ PCR and Western blot, respectively. RESULTS: The mean fibrosis score of BDL rats treated with telmisartan was significantly lower than that of the model rats (1.66+/-0.87 vs 2.13+/-0.35, P=0.015). However, there was no significant difference in inflammation between the two groups, both of which showed moderate inflammation. Histologically, treatment with telmisartan significantly ameliorated BDL-caused the hepatic fibrosis. Treatment with telmisartan significantly upregulated the mRNA levels of ACE2 and MAS, and decreased the mRNA levels of ACE, angiotensin II type 1 receptor (AT1-R), collagen type III, and transforming growth factor beta1 (TGF-beta1). Moreover, treatment with telmisartan significantly increased the expression levels of ACE2 and MAS proteins, and inhibited the expression levels of ACE and AT1-R protein. CONCLUSION: Telmisartan attenuates liver fibrosis in bile duct-ligated rats via increasing ACE2 expression level. PMID- 23103624 TI - A novel approach to induction and rehabilitation of deficits in forelimb function in a rat model of ischemic stroke. AB - AIM: Constraint-induced movement therapy (CIMT), which forces use of the impaired arm following unilateral stroke, promotes functional recovery in the clinic but animal models of CIMT have yielded mixed results. The aim of this study is to develop a refined endothelin-1 (ET-1) model of focal ischemic injury in rats that resulted in reproducible, well-defined lesions and reliable upper extremity impairments, and to determine if an appetitively motivated form of rehabilitation (voluntary forced use movement therapy; FUMT) would accelerate post-ischemic motor recovery. METHODS: Male Sprague Dawley rats (3 months old) were given multiple intracerebral microinjections of ET-1 into the sensorimotor cortex and dorsolateral striatum. Sham-operated rats received the same surgical procedure up to but not including the drill holes on the skull. Functional deficits were assessed using two tests of forelimb placing, a forelimb postural reflex test, a forelimb asymmetry test, and a horizontal ladder test. In a separate experiment ET-1 stroke rats were subjected to daily rehabilitation with FUMT or with a control therapy beginning on post-surgery d 5. Performance and post-mortem analysis of lesion volume and regional BDNF expression were measured. RESULTS: Following microinjections of ET-1 animals exhibited significant deficits in contralateral forelimb function on a variety of tests compared with the sham group. These deficits persisted for up to 20 d with no mortality and were associated with consistent lesion volumes. FUMT therapy resulted in a modest but significantly accelerated recovery in the forelimb function as compared with the control therapy, but did not affect lesion size or BDNF expression in the ipsilesional hemisphere. CONCLUSION: We conclude that refined ET-1 microinjection protocols and forcing use of the impaired forelimb in an appetitively motivated paradigm may prove useful in developing strategies to study post-ischemic rehabilitation and neuroplasticity. PMID- 23103627 TI - Multifocal hepatic cystic mass as first manifestation of metastatic spinal hemangiopericytoma. AB - INTRODUCTION: Hemangiopericytomas (HPCs) are rare vascular tumors with a high malignant potential. Hepatic metastases from HPC are very infrequent and usually show a distinctive solid aspect with a surrounding pseudocapsule. PRESENTATION OF CASE: A 37-year-old man with a previous medical history of recurrent spinal hemangiopericytoma with a 9cm*7cm cystic hepatic mass detected on follow-up. Contrast enhanced US and MRI confirmed the presence the lesion showing mixed (solid and cystic) content. Parasitic and viral serology plus serum tumoral markers (CEA, ca 19.9, ca 125, AFP) tests, upper and lower endoscopy and general laboratory tests were normal and extended left lobectomy was performed. Histopathologic study confirmed the diagnosis of multifocal metastasic hemangiopericytoma with moderate CD-34, CD-99 and Bcl-2 positivity after immunohistochemical staining. After 1-year follow-up the patient does not present any evidence of abdominal recurrence but a skull base recurrence has been detected. DISCUSSION: Liver metastasis from spinal HPC are uncommon and do not have cystic appearance so radiologic diagnosis can be challenging. In spite of the presence of previously diagnosed HPC context, the presence of a liver cystic mass in a young patient makes necessary to discard a number much more frequent benign and malignant diagnosis before metastatic disease can be confirmed. CONCLUSION: The presence of a cystic hepatic mass makes it mandatory to rule out a number neoplasms other than metastasic HPC before a definitive diagnosis is made. In addition to local radiotherapy and antiangiogenic agents, surgery can be useful to treat liver dissemination. PMID- 23103626 TI - Galectin-3 gene silencing inhibits migration and invasion of human tongue cancer cells in vitro via downregulating beta-catenin. AB - AIM: Galectin-3 (Gal-3) is a member of the carbohydrate-binding protein family that contributes to neoplastic transformation, tumor survival, angiogenesis, and metastasis. The aim of this study is to investigate the role of Gal-3 in human tongue cancer progression. METHODS: Human tongue cancer cell lines (SCC-4 and CAL27) were transfected with a small-interfering RNA against Gal-3 (Gal-3-siRNA). The migration and invasion of the cells were examined using a scratch assay and BD BioCoat Matrigel Invasion Chamber, respectively. The mRNA and protein levels of beta-catenin, Akt/pAkt, GSK-3beta/pGSK-3beta, MMP-9 in the cells were measured using RT-PCR and Western blotting, respectively. RESULTS: Transient silencing of Gal-3 gene for 48 h significantly suppressed the migration and invasion of both SCC-4 and CAL27 cells. Silencing of Gal-3 gene significantly decreased the protein level of beta-catenin, leaving the mRNA level of beta-catenin unaffected. Furthermore, silencing Gal-3 gene significantly decreased the levels of phosphorylated Akt and GSK-3beta, and suppressed the mRNA and protein levels of MMP-9 in the cells. CONCLUSION: Our data suggest that Gal-3 mediates the migration and invasion of tongue cancer cells in vitro via regulating the Wnt/beta-catenin signaling pathway and Akt phosphorylation. PMID- 23103628 TI - Castleman's disease in the pelvic retroperitoneum: A case report and review of the Japanese literature. AB - INTRODUCTION: Castleman's disease is a fairly rare benign tumor of lymphoid origin. It can develop anywhere lymphoid tissue is found, but the expected origin is mediastinum and rarely pelvic retroperitoneum. PRESENTATION OF CASE: A 22-year old woman was admitted to our hospital for a mass in the pelvic retroperitoneum that was detected incidentally on an ultrasonography during a routine medical checkup with no signs of symptoms. After laboratory examination, ultrasonography, and magnetic resonance imaging (MRI), surgical resection was performed successfully through a lower midline incision. But the patient was needed transfusion because of massive bleeding. Postoperative histopathological diagnosis was hyaline-vascular type of Castleman's disease. The patient is leading an active social life without any signs of sequelae or recurrence. DISCUSSION: Through the review of Japanese literature on Castleman's disease in the retroperitoneum, the characteristics of preoperative imaging findings are studied. Castleman's disease is easily misdiagnosed clinically because of its scarcity and no specific imaging findings. And the embolization via angiography should be considered in the hypervasular tumors such as in this case to prevent massive bleeding and transfusion. CONCLUSION: Although Castleman's disease is uncommon, it should always be included in the differential diagnosis of pelvic retroperitoneal tumors. A better knowledge of this disease would help surgeon to avoid unnecessarily extensive resection and massive bleeding for transfusion when dealing with retroperitoneal tumors. PMID- 23103629 TI - Abdominal aorta as a recipient artery: Using a free latissimus dorsi myocutaneous flap to close hip and pelvic defects. AB - INTRODUCTION: Free tissue transfer (FTT) is now a common procedure in many surgical centres around the world and it has shown well established results especially in the field of reconstructive surgery. The choice of FTT depends on the size of defect, nature of tissue, length of pedicle and donor site morbidity. Notwithstanding, FTT is complex and always depending on a sufficient recipient vessel. PRESENTATION OF CASE: Herein, we report a case in which the abdominal aorta was used as arterial recipient vessel for microvascular transfer of a free latissimus dorsi myocutaneous flap. It was utilized to reconstruct an extensive pelvic and hip defect following a massive gas gangrene with a prior debridement of other potential recipient vessels. DISCUSSION: In this case, the patient had a large defect that demanded a choice of a large flap such as the free latissimus dorsi myocutaneous flap. The iliac system has been sacrificed during the debridement procedure together with other potential recipient vessels. In the presented case, arterial anastomosis of the free latissimus dorsi myocutaneous flap was performed to the distal part of the aorta without complications. CONCLUSION: Using the abdominal aorta as a recipient arterial vessel seems to be a reliable alternative that should be considered in difficult reconstructive scenarios such as the "vessel-depleted" pelvis. PMID- 23103630 TI - Traumatic abdominal wall hernia: Delayed repair: Advantageous or taxing. AB - INTRODUCTION: Traumatic abdominal wall hernia (TAWH) is a rare entity. Most cases occur in children, following an injury from the bicycle handle bar. In adults, it usually results from road traffic accidents (RTA). We present one of the largest reported cases of TAWH following RTA managed by delayed mesh repair. PRESENTATION OF CASE: A 35yr old obese male with RTA was diagnosed with TAWH with 19cm*15cm defect in left flank. As there were no intra abdominal injuries and overlying skin was abraded, he was planned for elective repair after 6 months. On exploration a defect of 30cm*45cm was found extending from midline anteriorly to 8cm short of midline posteriorly in transverse axis and costal margin to iliac crest in craniocaudal axis. After restoration of bowel into abdominal cavity, primary closure or even approximation of muscular defect was not possible thus a mesh closure using 60cm*60cm prolene mesh in subcutaneous plane was done. After 4 months follow up, patient is healthy and has no recurrence. DISCUSSION: Emergent surgical management of TAWH is usually favoured due to high incidence of associated intra abdominal injuries. Delayed repair may be undertaken in selected cases. CONCLUSION: TAWH, although rare, should be suspected in cases of RTA with abdominal wall swellings. With time, the hernia defect may enlarge and muscles may undergo atrophy making delayed repair difficult. PMID- 23103631 TI - Brain activity and human unilateral chewing: an FMRI study. AB - Brain mechanisms underlying mastication have been studied in non-human mammals but less so in humans. We used functional magnetic resonance imaging (fMRI) to evaluate brain activity in humans during gum chewing. Chewing was associated with activations in the cerebellum, motor cortex and caudate, cingulate, and brainstem. We also divided the 25-second chew-blocks into 5 segments of equal 5 second durations and evaluated activations within and between each of the 5 segments. This analysis revealed activation clusters unique to the initial segment, which may indicate brain regions involved with initiating chewing. Several clusters were uniquely activated during the last segment as well, which may represent brain regions involved with anticipatory or motor events associated with the end of the chew-block. In conclusion, this study provided evidence for specific brain areas associated with chewing in humans and demonstrated that brain activation patterns may dynamically change over the course of chewing sequences. PMID- 23103632 TI - Gene expression dynamics during diabetic periodontitis. AB - Diabetes impairs the resolution of periodontal inflammation. We explored pathways altered by inflammation in the diabetic periodontium by using ligatures to induce periodontitis in type-2 diabetic Goto-Kakizaki rats. Ligatures were removed after 7 days, and rats were then treated with TNF inhibitor (pegsunercept) or vehicle alone and euthanized 4 days later. RNA was extracted from periodontal tissue, examined by mRNA profiling, and further analyzed by functional criteria. We found that 1,754 genes were significantly up-regulated and 1,243 were down-regulated by pegsunercept (p < 0.05). Functional analysis revealed up-regulation of neuron associated and retina-associated gene clusters as well as those related to cell activity and signaling. Others were down-regulated by TNF inhibition and included genes associated with host defense, apoptosis, cell signaling and activity, and coagulation/hemostasis/complement. For selected genes, findings with microarray and rt-PCR agreed. PPAR-alpha was investigated further by immunohistochemistry due to its anti-inflammatory function and was found to be up-regulated in the gingiva during the resolution of periodontal inflammation and suppressed by diabetes. The results indicate that diabetes-enhanced inflammation both up- and down-regulates genes involved in cellular activity and cell signaling, while it predominantly up-regulates genes involved in the host response, apoptosis, and coagulation/homeostasis/complement and down-regulates mRNA levels of neuron, retina, and energy/metabolism-associated genes. PMID- 23103633 TI - Influence of S. mutans on base-metal dental casting alloy toxicity. AB - We have highlighted that exposure of base-metal dental casting alloys to the acidogenic bacterium Streptococcus mutans significantly increases cellular toxicity following exposure to immortalized human TR146 oral keratinocytes. With Inductively Coupled Plasma-Mass Spectrometry (ICP-MS), S. mutans-treated nickel based (Ni-based) and cobalt-chromium-based (Co-Cr-based) dental casting alloys were shown to leach elevated levels of metal ions compared with untreated dental casting alloys. We targeted several biological parameters: cell morphology, viable cell counts, cell metabolic activity, cell toxicity, and inflammatory cytokine expression. S. mutans-treated dental casting alloys disrupted cell morphology, elicited significantly decreased viable cell counts (p < 0.0001) and cell metabolic activity (p < 0.0001), and significantly increased cell toxicity (p < 0.0001) and inflammatory cytokine expression (p < 0.0001). S. mutans-treated Ni-based dental casting alloys induced elevated levels of cellular toxicity compared with S. mutans-treated Co-Cr-based dental casting alloys. While our findings indicated that the exacerbated release of metal ions from S. mutans treated base-metal dental casting alloys was the likely result of the pH reduction during S. mutans growth, the exact nature of mechanisms leading to accelerated dissolution of alloy-discs is not yet fully understood. Given the predominance of S. mutans oral carriage and the exacerbated cytotoxicity observed in TR146 cells following exposure to S. mutans-treated base-metal dental casting alloys, the implications for the long-term stability of base-metal dental restorations in the oral cavity are a cause for concern. PMID- 23103634 TI - Effect of phosphoric acid on the degradation of human dentin matrix. AB - This study determined if dentin proteases are denatured by phosphoric acid (PA) used in etch-and-rinse dentin adhesives. Dentin beams were completely demineralized with EDTA for 30 days. We "acid-etched" experimental groups by exposing the demineralized dentin beams to 1, 10, or 37 mass% PA for 15 sec or 15 min. Control beams were not exposed to PA but were incubated in simulated body fluid for 3 days to assay their total endogenous telopeptidase activity, by their ability to solubilize C-terminal crosslinked telopeptides ICTP and CTX from insoluble dentin collagen. Control beams released 6.1 +/- 0.8 ng ICTP and 0.6 +/- 0.1 ng CTX/mg dry-wt/3 days. Positive control beams pre-incubated in p aminophenylmercuric acetate, a compound known to activate proMMPs, released about the same amount of ICTP peptides, but released significantly less CTX. Beams immersed in 1, 10, or 37 mass% PA for 15 sec or 15 min released amounts of ICTP and CTX similar to that released by the controls (p > 0.05). Beams incubated in galardin, an MMP inhibitor, or E-64, a cathepsin inhibitor, blocked most of the release of ICTP and CTX, respectively. It is concluded that PA does not denature endogenous MMP and cathepsin activities of dentin matrices. PMID- 23103635 TI - Identification and expression analysis of two Toll-like receptor genes from sea cucumber (Apostichopus japonicus). AB - Toll-like receptors (TLRs) are a family of type I integral membrane glycoproteins which play pivotal roles in innate immunity. In this study, two TLRs named AjTLR3 and AjToll were cloned from sea cucumber (Apostichopus japonicus). The full length cDNA sequences of AjTLR3 and AjToll are 3484 bp and 4211 bp, with an open reading frame (ORF) of 2679 bp and 2853 bp, encoding 892 and 950 amino acids, respectively. Both AjTLR3 and AjToll are composed of a leucine-rich repeat (LRR) domain, a transmembrane (TM) domain and an intracellular Toll/interleukin-1 receptor (TIR) domain. Evolution analysis revealed that AjTLR3 and AjToll were clustered with the vertebrate-like TLRs (V-TLRs) and the protostome-like TLRs (P TLRs), respectively. These two genes were widely expressed in all five tested tissues (body wall, coelomocytes, tube feet, intestine and respiratory tree), but showed different expression patterns. The significantly up-regulated expressions of AjTLR3 and AjToll after peptidoglycan (PGN), lipopolysaccharides (LPS), Zymosan A and polyinosinic-polycytidylic acid (PolyI:C) challenges suggested that they were functionally involved in the immune responses to the Cram-positive bacteria, Gram-negative bacteria, fungi and double-stranded RNA (dsRNA) viruses, respectively. PMID- 23103638 TI - An inguinal bladder diverticulum Case report of a rare finding in a recurrent inguinal hernia. AB - We report a rare case of recurrent right inguinal hernia with bladder diverticulum incarcerated in a 63 years old male. Patient complained of painful swelling in inguinoscrotal region associated with urinary discomfort. Preoperatively diagnosis was made possible by ultrasound and urography imaging. Surgical treatment was achieved, by infra-umbilical incision, a reduction of the herniated and fixed diverticulum followed by a mesh repair of the wall defect. Patient was discharged five days after surgery and became free of symptomatology soon after surgical procedure. Bladder diverticulum involvement in a direct inguinal hernia is rare finding and define a potential pitfall for surgeon if not diagnosed preoperatively. There are no other cases of incarcerated bladder diverticulum incarcerated in a recurrent inguinal hernia described in Literature. KEY WORDS: Bladder diverticulum, Bladder hernia, Inguinal hernia. PMID- 23103639 TI - Antiferro- and ferromagnetic ordering in a PrGe single crystal. AB - An equiatomic PrGe single crystal was grown by the Czochralski pulling method. The grown single crystal was found to have CrB-type orthorhombic crystal structure with the space group Cmcm (no. 63). Transport and magnetization data reveal large anisotropy in the electrical resistivity, magnetic susceptibility and magnetization. PrGe was found to exhibit two consecutive magnetic orderings at 44 K and 41.5 K, respectively. The magnetic susceptibility measurement along the three principal directions in low applied fields revealed a cusp-like behaviour at 44 K while at 41.5 K a ferromagnetic-like increase was observed. The hysteretic behaviour in the magnetization measurement at 1.8 K confirmed the ferromagnetic nature of PrGe at low temperatures. The heat capacity data clearly revealed the bulk nature of two magnetic transitions by the presence of two sharp peaks attaining values exceeding 40 J K(-1) mol(-1) at the respective temperatures. The absence of a Schottky contribution in the magnetic part of the heat capacity indicates a quasi-ninefold degenerate J = 4 magnetic ground state in this system. The low temperature data of electrical resistivity and the magnetic part of the heat capacity show the existence of a gap in the spin-wave spectrum. PMID- 23103637 TI - Detection of autoantibodies against platelet glycoproteins in patients with immune thrombocytopenic purpura by flow cytometric immunobead array. AB - BACKGROUND: The goal of this study is to develop a flow cytometric immunobead array (FCIA) assay to detect platelet autoantibodies commonly present in bleeding patients with immune thrombocytopenic purpura (ITP). METHODS: Polystyrene microbeads coated with antibodies against human platelet glycoproteins (GPs) IX (SZ1), Ib (SZ2), IIIa (SZ21), IIb (SZ22), and P-selectin (SZ51) were incubated with platelet lysate from 50 ITP patients and 86 controls. The platelet antigen autoantibody complexes were detected by flow cytometry using an FITC-labeled antibody. The results were compared with that of a monoclonal antibody immobilization of platelet antigen (MAIPA) assay. RESULTS: By FCIA, platelet autoantibodies against GPIb, GPIIb, GPIIIa, GPIX and P-selectin were detected in ITP patients. Mean fluorescent intensity values with antibodies SZ1, SZ2, SZ21, SZ22 and SZ51 were all higher in ITP patients than controls (p values<0.01). In ROC analysis, values of the area under the curve were 0.89, 0.82, 0.93, 0.94 and 0.95, respectively. In ITP diagnosis, the FCIA assay with these five antibodies had better sensitivity and accuracy than the MAIPA assay (96% vs. 44% in sensitivity; 80.9% vs. 64.7% in accuracy, p<0.01). CONCLUSION: FCIA assays with multiple antibodies against platelet GPs may be used to improve the diagnosis of ITP in hospitals. PMID- 23103640 TI - Immunohistochemistry and ultrastructural characteristics of nerve endings in the oral mucosa of rat. AB - The sensory nerve endings of the rat tongue, cheek and palate were studied using immunohistochemical staining and transmission electron microscopy analysis. The specimens were fixed in modified Karnovsky solution and embedded in Spurr resin. Substance P, calcitonin gene-related peptide (CGRP)- and protein gene product 9.5 (PGP b9.5)-containing nerve fibers in the rat tongue, cheek and palate were examined by electronic microscopical analysis and immunohistochemical localization. These fibers run very close to the basal lamina of the epithelium and extend into the filliform and fungiform papillae. Numerous plexiform fibers immunoreactive for substance P, CGRP and PGP 9.5 were found in the connective tissue of mucosa. Electron microscopic observations showed clearly immunostained nerve fibers, which are located very close to the basal lamina of epithelial cells. Some electron-dense granules may be observed in the axoplasms of both substance P and CGRP immunoreactive fibers. Several lamellar corpuscles into the subepithelial connective tissue papillae, Merkel corpuscles and numerous thin unmyelinated and myelinated axons were observed. The terminal axons revealed numerous mitochondria, neurofilaments, microtubules and clear vesicles in the base of axoplasmic protrusions. The lamellar cells showed caveolae and interlamelar spaces filled by amorphous substance. Between the lamellar cells and axoplasmic membrane, and in the adjacent lamellae region, desmosome-type junctions were observed. The quantitative and morphometric analysis showed nerve endings with an average area of 4.83 +/- 3.4 MUm(2) and 19.4 internal mitochondria in this site and the organized corpuscles with an average area of 79.24 +/- 27.24 MUm(2) and 24.23 internal mitochondria in this place. All the structures observed are involved in the transmission of pain and mechanoreceptors stimulus of these oral mucosae. PMID- 23103636 TI - The ageing ovary and uterus: new biological insights. AB - BACKGROUND Advanced maternal age is associated with reduced fertility and adverse pregnancy outcomes. This review details recent developments in our understanding of the biology and mechanisms underlying reproductive ageing in women and the implications for fertility and pregnancy. METHODS Sociological online libraries (IBSS, SocINDEX), PubMed and Google Scholar were searched for relevant demographic, epidemiological, clinical and biological studies, using key words and hierarchical MeSH terms. From this, we identified and focused on key topics where it was judged that there had been clinically relevant advances in the understanding of ovarian and uterine ageing with implications for improved diagnostics and novel interventions. RESULTS Mapping of the ovarian reserve, follicular dynamics and associated biomarkers, across the reproductive lifespan has recently been performed. This now allows an assessment of the effects of environmental, lifestyle and prenatal exposures on follicular dynamics and the identification of their impact during periods of germ cell vulnerability and may also facilitate early identification of individuals with shorter reproductive lifespans. If women choose to time their family based on their ovarian reserve this would redefine the meaning of family planning. Despite recent reports of the potential existence of stem cells which may be used to restore the primordial follicle and thereby the oocyte pool, therapeutic interventions in female reproductive ageing at present remain limited. Maternal ageing has detrimental effects on decidual and placental development, which may be related to repeated exposure to sex steroids and underlie the association of ageing with adverse perinatal outcomes. CONCLUSIONS Ageing has incontrovertible detrimental effects on the ovary and the uterus. Our enhanced understanding of ovarian ageing will facilitate early identification of individuals at greatest risk, and novel therapeutic interventions. Changes in both ovary and uterus are in addition to age-related co-morbidities, which together have synergistic effects on reducing the probability of a successful pregnancy outcome. PMID- 23103641 TI - Research progress reported at the 50th Anniversary of the Discovery of Congenital Sucrase-Isomaltase Deficiency Workshop. PMID- 23103642 TI - Introduction to the 8th Starch Digestion Consortium Workshop. PMID- 23103643 TI - Congenital sucrase-isomaltase deficiency: heterogeneity of inheritance, trafficking, and function of an intestinal enzyme complex. PMID- 23103644 TI - 50 years of progress since congenital sucrase-isomaltase deficiency recognition. PMID- 23103645 TI - Investigations of the structures and inhibitory properties of intestinal maltase glucoamylase and sucrase isomaltase. PMID- 23103646 TI - Starch digestion and patients with congenital sucrase-isomaltase deficiency. PMID- 23103647 TI - Frequency of sucrase deficiency in mucosal biopsies. PMID- 23103648 TI - Phenotypic observations by the CSID Dietary and Medical Support Group. PMID- 23103649 TI - Poor starch digestion in children with CSID and recurrent abdominal pain. PMID- 23103650 TI - Four mutations in the SI gene are responsible for the majority of clinical symptoms of CSID. PMID- 23103652 TI - Congenital sucrase-isomaltase deficiency: diet assessment and education guidelines. PMID- 23103651 TI - Congenital sucrase-isomaltase deficiency: summary of an evaluation in one family. PMID- 23103653 TI - Transient sucrose and starch intolerance. PMID- 23103654 TI - Dietary issues in recurrent abdominal pain. PMID- 23103655 TI - The nature of raw starch digestion. PMID- 23103656 TI - Direct starch digestion by sucrase-isomaltase and maltase-glucoamylase. PMID- 23103658 TI - Clinical aspects and treatment of congenital sucrase-isomaltase deficiency. PMID- 23103657 TI - Inhibition of maltase-glucoamylase activity to hydrolyze alpha-1,4 linkages by the presence of undigested sucrose. PMID- 23103659 TI - Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach. AB - AIMS: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (FerahemeTM, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. METHODS AND RESULTS: Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14 22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. CONCLUSION: We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO. PMID- 23103660 TI - Long-term prognostic value of residual pulmonary vascular obstruction at discharge in patients with intermediate- to high-risk pulmonary embolism. AB - BACKGROUND: We evaluated prognostic value at 6 months of residual pulmonary vascular obstruction (RPVO) measured before discharge in patients with intermediate- or high-risk pulmonary embolism (PE). METHODS AND RESULTS: Prospective registry including 416 consecutive patients with intermediate- or high-risk PE who survived the acute phase. Patients with previous cardiopulmonary disease were excluded. Perfusion lung scans were performed within 6-8 days after the onset of treatment. Residual pulmonary vascular obstruction was graded as the proportion of the lung not perfused. Primary objective was a combined endpoint at 6 months, including death, recurrent PE, and appearance of signs of heart failure. At 6 months, 32 patients (7.7%) had at least one adverse event: 12 deaths (2.9%), 12 recurrent PE (2.9%), and 14 (3.4%) heart failure. Independent predictors of combined endpoint were: cancer [odds ratio (OR) 3.07 (1.22-7.85)]; renal insufficiency at admission [OR: 2.53 (1.17-5.8)]; persistent signs of right ventricular dysfunction at 48 h echography [OR: 3.99 (1.36-11.3)]. The severity of RPVO at discharge was significantly associated with an unfavourable outcome [OR: 2.66 (1.58-3.93)]. The incremental prognostic value of RPVO information was confirmed by significantly improved goodness-of-fit. Threshold RPVO for predicting adverse events was estimated at 35% [area under the curve = 0.76 (0.73 0.82)]. Patients with RPVO greater than threshold at discharge had a significantly higher risk of death at 6 months (P = 0.01). CONCLUSIONS: Residual pulmonary vascular obstruction evaluated before hospital discharge in patients with intermediate- to high-risk PE is a powerful prognostic factor for a 6-month outcome. RPVO >=35% is associated with an increased risk of adverse events at 6 months. PMID- 23103661 TI - Chronic heart failure: a look through the rear view mirror. PMID- 23103662 TI - Smoking, birthweight, and mortality across generations. PMID- 23103663 TI - Incidence and multivariable correlates of long-term mortality in patients treated with surgical or percutaneous revascularization in the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) trial. AB - AIMS: The aim of this investigation was to determine the incidence and multivariable correlates of long-term (4-year) mortality in patients treated with surgical or percutaneous revascularization in the synergy between percutaneous coronary intervention (PCI) with TAXUS Express and Cardiac Surgery (SYNTAX) trial. METHODS AND RESULTS: A total of 1800 patients were randomized to undergo coronary artery bypass graft (CABG) surgery (n = 897) or PCI (n = 903). Prospectively collected baseline and peri- and post-procedural data were used to determine independent correlates of 4-year all-cause death in the CABG and the PCI arms (Cox proportional hazards model). Four-year mortality rates in the CABG and the PCI arms were 9.0% [74 deaths (12 in-hospital)] and 11.8% [104 deaths (16 in-hospital)], respectively (log-rank P-value = 0.063). Censored data comprised 78 patients (8.7%) in the CABG arm, and 24 patients (2.7%) in the PCI arm (log rank P-value < 0.001). Within the CABG arm, the strongest independent correlates of 4-year mortality were lack of discharge aspirin [hazard ratio (HR) 3.56; 95% CI: 2.04, 6.21; P < 0.001], peripheral vascular disease (PVD) (HR: 2.65; 95% CI: 1.49, 4.72; P = 0.001), chronic obstructive pulmonary disease, age, and serum creatinine. Within the PCI arm, the strongest independent correlate of 4-year mortality was lack of post-procedural anti-platelet therapy (HR: 152.16; 95% CI: 53.57, 432.22; P < 0.001), with 10 reported early (within 45 days) in-hospital deaths secondary to multifactorial causes precluding administration of anti platelet therapy. Other independent correlates of mortality in the PCI arm included amiodarone therapy on discharge, pre-procedural poor left ventricular ejection fraction, a 'history of gastrointestinal bleeding or peptic ulcer disease', PVD (HR: 2.13; 95% CI: 1.26, 3.60; P = 0.005), age, female gender (HR: 1.60; 95% CI: 1.01, 2.56; P = 0.048), and the SYNTAX score (Per increase in 10 points: HR: 1.25; 95% CI: 1.06, 1.47; P = 0.007). CONCLUSION: Independent correlates of 4-year mortality in the SYNTAX trial were multifactorial. Lack of discharge aspirin and lack of post-procedural anti-platelet therapy were the strongest independent correlates of mortality in the CABG and the PCI arms, respectively. Peripheral vascular disease is a common independent correlate of 4 year mortality and may be a marker of the severity of baseline coronary disease and risk of future native coronary disease (and extra-cardiac disease) progression. PMID- 23103664 TI - Murine and human pluripotent stem cell-derived cardiac bodies form contractile myocardial tissue in vitro. AB - AIMS: We explored the use of highly purified murine and human pluripotent stem cell (PSC)-derived cardiomyocytes (CMs) to generate functional bioartificial cardiac tissue (BCT) and investigated the role of fibroblasts, ascorbic acid (AA), and mechanical stimuli on tissue formation, maturation, and functionality. METHODS AND RESULTS: Murine and human embryonic/induced PSC-derived CMs were genetically enriched to generate three-dimensional CM aggregates, termed cardiac bodies (CBs). Addressing the critical limitation of major CM loss after single cell dissociation, non-dissociated CBs were used for BCT generation, which resulted in a structurally and functionally homogenous syncytium. Continuous in situ characterization of BCTs, for 21 days, revealed that three critical factors cooperatively improve BCT formation and function: both (i) addition of fibroblasts and (ii) ascorbic acid supplementation support extracellular matrix remodelling and CB fusion, and (iii) increasing static stretch supports sarcomere alignment and CM coupling. All factors together considerably enhanced the contractility of murine and human BCTs, leading to a so far unparalleled active tension of 4.4 mN/mm(2) in human BCTs using optimized conditions. Finally, advanced protocols were implemented for the generation of human PSC-derived cardiac tissue using a defined animal-free matrix composition. CONCLUSION: BCT with contractile forces comparable with native myocardium can be generated from enriched, PSC-derived CMs, based on a novel concept of tissue formation from non dissociated cardiac cell aggregates. In combination with the successful generation of tissue using a defined animal-free matrix, this represents a major step towards clinical applicability of stem cell-based heart tissue for myocardial repair. PMID- 23103665 TI - Electronic ward round: finding time for the inpatient with Clostridium difficile infection. PMID- 23103666 TI - Clostridium difficile: a European perspective. AB - Clostridium difficile infection is the leading cause of diarrhoea in the industrialised world. First identified in 1935, our knowledge about the clonal population structure, toxins and PCR ribotypes is still increasing. New PCR ribotypes and sequence types are frequently added. In the last decade hypervirulent strains have emerged and been associated with increased severity of disease, high recurrence and significant mortality. Although previously a primarily hospital- or health-care acquired infection, since the 1990's C. difficile infections that are community-acquired have been increasingly reported. Risk factors include hospitalisation, advancing age and prior antibiotic use. The ubiquitous presence of C. difficile in the environment and asymptomatic intestinal colonisation may be important reservoirs for infection and the changing epidemiology of C. difficile infection. Although surveillance in Europe is now a requirement of the European Commission, reporting is not standardised or mandatory. Here we review the current literature, guidelines on diagnosis and treatment and conclude by highlighting a number of areas where further research would increase our understanding. PMID- 23103667 TI - Serial QuantiFERON TB-gold in-tube testing during LTBI therapy in candidates for TNFi treatment. AB - OBJECTIVES: To evaluate the T-cell interferon (IFN)-gamma response to Mycobacterium tuberculosis-specific antigens during latent tuberculosis infection (LTBI) therapy in candidates for tumor necrosis factor-alpha inhibitors (TNFi). METHODS: 1490 Patients were screened for LTBI. One-hundred and sixty-six of them were treated for LTBI and followed-up with QuantiFERON-TB Gold (QFT-IT) testing at baseline (T0) and therapy completion (T1); 92 subjects were also tested 3-6 months after therapy completion (T2). RESULTS: At T1 the QFT-IT reversion and conversion rates were 24% (27/111) and 18% (10/55), respectively. By multivariate analysis, the likelihood of reversion significantly decreased with older age (>50 60), larger TST size (>15 mm) and higher IFN-gamma value at T0 (>1 IU/ml); the likelihood of conversion increased with higher IFN-gamma levels at T0 (1 IU/ml) and in female patients. Quantitative data among those who scored QFT-IT-positive at T0 showed a decreasing trend of IFN-gamma levels between T0 and T1 that reached statistical significance when T0 was compared to T2, and T1 to T2. CONCLUSIONS: The data confirm the difficulty of interpreting the modulation of IFN-gamma levels during LTBI therapy. Currently, there is no evidence to support the use of QFT-IT in the clinical practice of monitoring LTBI treatment in candidates for TNFi. PMID- 23103668 TI - Prolonged stimulation with thyrotropin-releasing hormone and pituitary adenylate cyclase-activating polypeptide desensitize their receptor functions in prolactin producing GH3 cells. AB - We used somatolactotroph GH3 cells to examine changes in response to stimulation with thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase activating polypeptide (PACAP) after sustained treatment with these peptides. TRH and PACAP increased prolactin promoter activity in mock- and PACAP type 1 receptor (PAC1R)-transfected cells. When the cells were pretreated with TRH for 48 h, the response of the prolactin promoter to both TRH and PACAP was diminished. Similarly, in PAC1R-transfected GH3 cells pretreated with PACAP, the effects of TRH and PACAP on the prolactin promoter were eliminated. The stimulation of prolactin mRNA expression by TRH and PACAP was eliminated by prolonged pretreatment with these peptides in PAC1R-transfected cells. Both the serum response element (SRE) promoters and cAMP response element (CRE) promoters were activated by TRH and PACAP in either mock- or PAC1R-transfected cells. Pretreatment for 48 h with TRH also eliminated the effects of TRH and PACAP on the SRE and CRE promoters, and pretreatment of PAC1R-transfected cells with PACAP for 48 h reduced the responses of the SRE and CRE promoters to TRH and PACAP. These observations demonstrated that sustained stimulation with TRH and PACAP desensitizes their own and each other's receptors. PMID- 23103670 TI - Genetic differences in yolk testosterone levels influence maternal hormone deposition in the second laying cycle in Japanese quails. AB - Maternally-derived yolk androgens exhibit distinct among- and within-female variations but limited data refer to inter-seasonal changes of maternal hormones in the yolk. We investigated the deposition of yolk testosterone (T) across two laying cycles in Japanese quail. To test how genetically-determined differences influence between cycle variations in yolk androgens we compared females from low (LET) and high (HET) egg T lines at the end of the first and at the beginning of the second laying cycle after an induced moult. Line differences in yolk T levels exhibited high consistency exceeding two reproductive cycles. Yolk T concentrations increased in the second laying cycle in HET but not in LET females. Plasma T levels did not differ between cycles in both lines and no line differences were found either before or after the moult indicating the presence of mechanisms limiting the increase of T concentrations in the circulation. Differences in the yolk T levels were not accompanied by changes in the egg and yolk mass. The HET quail laid eggs with heavier eggshell than the LET quail. Our results demonstrate different abilities of mothers to deposit T in their eggs over two reproductive seasons with expected consequences on the development of their progeny. PMID- 23103671 TI - Fibre digestibility in large herbivores as related to digestion type and body mass--an in vitro approach. AB - The coexistence of different ungulate species in a given ecosystem has been the focus of many studies. Differences between ruminant foregut fermenters and hindgut fermenters were remarkable for example in the way they ingest and digest high fibre diets. Digestion trials based on total collections are difficult to conduct or are sometimes even not possible for wild animals in the field or in zoos. To gain information on the fibre digestion achieved by these animals and the influence of body mass (BM) thereon, a method using spot sampling is desirable. In this study, in vitro fermentation of faecal neutral detergent fibre (NDF) was used as a measure of fibre digestion in large ungulates. Food and faecal samples of 10 ruminant foregut fermenting and 7 hindgut fermenting species/breeds were collected. All animals received 100% grass hay with ad libitum access. The NDF of food and faeces was fermented in vitro in a Hohenheim gas test (HGT) for 96 h. The digestion type generally had an effect on the gas production (GP) of faecal NDF in the HGT with hindgut fermenters showing higher values than ruminant foregut fermenters. At any time interval of incubation, BM had no influence on GP. The results are in accordance with both findings that ruminant foregut fermenters have longer mean retention times and more comprehensive particle reduction and findings of a lack of influence of BM on digesta mean retention time. It can be stated that the HGT (96 h) is a useful and quick method to show also small differences within groups in fibre digestion. PMID- 23103672 TI - Osmoregulatory and metabolic costs of salt excretion in the Rufous-collared sparrow Zonotrichia capensis. AB - Recent experiments on shorebirds have demonstrated that maintaining an active osmoregulatory machinery is energetically expensive. This may, in part, explain diet and habitat selection in birds with salt glands. However little is known about the osmoregulatory costs in birds lacking functional salt glands. In these birds, osmotic work is done almost exclusively by the kidneys. We investigated the osmoregulatory cost in a bird species lacking functional salt glands, the passerine Zonotrichia capensis. After 20 days of acclimation to fresh water (FW) and salt water (200 mM NaCl, SW), SW birds tended to be heavier than FW birds. However, this difference was not statistically significant. Total basal metabolic rate was higher in SW birds as compared with FW birds. Renal and heart masses were also higher in the SW group. We also found greater medullary development and an increase in urine osmolality in the SW group. In spite of Z. capensis' ability to tolerate a moderate salt load in the laboratory, we hypothesize that increased cost of maintenance produced by salt consumption may significantly affect energy budget, dietary, and habitat choices in the field. PMID- 23103669 TI - The protein pheromone Er-1 of the ciliate Euplotes raikovi stimulates human T cell activity: involvement of interleukin-2 system. AB - Water-soluble protein signals (pheromones) of the ciliate Euplotes have been supposed to be functional precursors of growth factors and cytokines that regulate cell-cell interaction in multi-cellular eukaryotes. This work provides evidence that native preparations of the Euplotes raikovi pheromone Er-1 (a helical protein of 40 amino acids) specifically increases viability, DNA synthesis, proliferation, and the production of interferon-gamma, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-2, and IL-13 in human Jurkat T-cells. Also, Er-1 significantly decreases the mRNA levels of the beta and gamma subunits of IL-2 receptor (IL-2R), while the mRNA levels of the alpha subunit appeared to be not affected. Jurkat T-cell treatments with Er-1 induced the down-regulation of the IL-2Ralpha subunit by a reversible and time-dependent endocytosis, and increased the levels of phosphorylation of the extracellular signal-regulated kinases (ERK). The cell-type specificity of these effects was supported by the finding that Er-1, although unable to directly influence the growth of human glioma U-373 cells, induced Jurkat cells to synthesize and release factors that, in turn, inhibited the U-373 cell proliferation. Overall, these findings imply that Er-1 coupling to IL-2R and ERK immuno-enhances T-cell activity, and that this effect likely translates to an inhibition of glioma cell growth. PMID- 23103673 TI - Cloning of the crustacean hyperglycemic hormone and evidence for molt-inhibiting hormone within the central nervous system of the blue crab Portunus pelagicus. AB - The crustacean X-organ-sinus gland (XO-SG) complex controls molt-inhibiting hormone (MIH) production, although extra expression sites for MIH have been postulated. Therefore, to explore the expression of MIH and distinguish between the crustacean hyperglycemic hormone (CHH) superfamily, and MIH immunoreactive sites (ir) in the central nervous system (CNS), we cloned a CHH gene sequence for the crab Portunus pelagicus (Ppel-CHH), and compared it with crab CHH-type I and II peptides. Employing multiple sequence alignments and phylogenic analysis, the mature Ppel-CHH peptide exhibited residues common to both CHH-type I and II peptides, and a high degree of identity to the type-I group, but little homology between Ppel-CHH and Ppel-MIH (a type II peptide). This sequence identification then allowed for the use of MIH antisera to further confirm the identity and existence of a MIH-ir 9kDa protein in all neural organs tested by Western blotting, and through immunohistochemistry, MIH-ir in the XO, optic nerve, neuronal cluster 17 of the supraesophageal ganglion, the ventral nerve cord, and cell cluster 22 of the thoracic ganglion. The presence of MIH protein within such a diversity of sites in the CNS, and external to the XO-SG, raises new questions concerning the established mode of MIH action. PMID- 23103674 TI - Impact of lymphocyte and monocyte recovery on the outcomes of allogeneic hematopoietic SCT with fludarabine and melphalan conditioning. AB - We have recently shown that lymphocyte and monocyte recovery by day +100 are associated with survival post myeloablative allogeneic hematopoietic transplant for acute leukemia. We hypothesized that lymphocyte and monocyte recovery would have a similar impact on survival in the reduced intensity setting. To test this hypothesis, we analyzed clinical data from 118 consecutive fludarabine/melphalan conditioned patients by correlating peripheral blood absolute lymphocyte counts and monocyte counts (ALC and AMC, respectively) at days +15, +30, +60 and +100 with the outcomes. Multivariate analysis revealed that day +100 AMC (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.07-0.73, P=0.01) and mild chronic GVHD (RR 0.09, 95% CI 0.005-0.43, P=0.008) were independently associated with survival. To explore whether the patterns of lymphocyte and monocyte recovery had a prognostic value, we performed unsupervised hierarchical clustering on the studied hematopoietic parameters and identified three patient clusters, A-C. Patient clusters A and B both had improved OS compared with cluster C (77.8 months vs not reached vs 22.3 months, respectively, P<0.001). No patient in cluster C had a day +100 AMC >300. Both severe acute GVHD and relapse occurred more frequently in cluster C. Our data suggest that patients with low AMC by day +100 post fludarabine/melphalan-conditioned allogeneic hematopoietic SCT may be at risk for poor outcomes. PMID- 23103675 TI - Light-chain amyloidosis: SCT, novel agents and beyond. AB - Light-chain amyloidosis is a plasma cell dyscrasia characterized by the production of fibrillar proteins comprised of monoclonal light chains, which deposit in tissues causing multiorgan dysfunction and death. The diagnosis is challenging and requires a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains, which improve organ function and extend survival. Standard treatment approaches have included high-dose melphalan followed by autologous hematopoietic SCT or oral melphalan with dexamethasone. The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk-adapted approach to SCT followed by novel agents as consolidation, reduces treatment related mortality with promising activity. Immunotherapy targeting pathologic plasma cells and amyloid fibrils is being developed and could potentially eliminate visceral amyloid deposits. Improved understanding of the biology that renders light-chains amyloidogenic and a commitment to refer patients to specialized centers conducting well-designed clinical trials is essential to improve patient outcomes. PMID- 23103676 TI - Communicating cancer risk from radiation exposures: nuclear accidents, total body radiation and diagnostic procedures. PMID- 23103677 TI - Long-term survival after allogeneic-matched sibling PBSC transplantation with conditioning consisting of low-dose busilvex and fludarabine in a 3-year-old boy with ataxia-telangiectasia syndrome and ALL. PMID- 23103679 TI - Trimming the fat: obesity and hematopoietic cell transplantation. AB - Obesity, increasing worldwide, is common in patients undergoing hematopoietic cell transplantation (HCT). This complex physiological state may alter the outcome of cancer therapies by many mechanisms including direct effects on pathogenesis, host responses to disease and altered pharmacology of chemotherapy. Obesity has been associated with multiple adverse health outcomes. Reports of obese patients undergoing HCT are challenging to interpret because of the heterogeneity of obesity definitions, underlying diseases, graft sources and chemotherapy regimens employed. Compared with normal-weight patients, it appears that obese patients undergoing allogeneic HCT have a higher risk of non-relapse mortality and inferior survival whereas those receiving autologous HCT appear to have equivalent outcomes. These findings are also difficult to interpret because there is no consistent standard for calculating chemotherapy dose in this group and future studies on specific regimens in this population are urgently needed. Patients who have undergone bariatric surgery may be at risk for unexpected events because of impaired nutritional state and altered pharmacokinetics of oral drugs. We recommend that future studies utilize more consistent and biologically relevant definitions of obesity and that the pharmacokinetics and pharmacodynamics of specific conditioning regimens be studied. Until more evidence is available, a rationale is presented for dosing based on adjusted body weight. Moreover, recommendations are provided to guide future research efforts based on more definitive measurements of body fat and its distribution available through modern quantitative imaging techniques using dual energy X-ray absorptiometry or magnetic resonance imaging scanning. PMID- 23103680 TI - Long-term outcome of childhood aplastic anemia patients who underwent allogeneic hematopoietic SCT from an HLA-matched sibling donor in Japan. AB - We report long-term outcomes of 329 childhood severe aplastic anemia (SAA) patients who underwent hematopoietic SCT (HSCT) from an HLA-matched sibling donor in the Japanese Hematopoietic Cell Transplantation Registry. OS and EFS at 10 years were as high as 89.7+/-1.7% and 85.5+/-2.0%, respectively. Five cases of late malignancies (LM) were identified (malignant peripheral nerve sheath tumor, thyroid carcinoma, colon carcinoma, MDS and hepatoblastoma). Cumulative incidence of LM was 0.8% at 10 years and 2.5% at 20 years, respectively, which was lower than that in previous reports. This low incidence is in keeping with the low occurrence of skin cancer in Japanese population and of acute GVHD in our study group. Radiation-containing conditioning was not significantly associated with the incidence of LM after HSCT probably because of absolute low patient number who developed LM in our series. In terms of LM development after HSCT, low-dose TBI in HSCT for SAA to avoid graft rejection, which is commonly used in Japan, might be tolerable in the Japanese population because of its low incidence. PMID- 23103681 TI - Validating the positive impact of in-hospital lay care-partner support on patient survival in allogeneic BMT: a prospective study. AB - This prospective study validates the finding from retrospective research that having an inpatient lay care-partner (CP) is associated with better survival following allogeneic BMT. Compared with patients without a CP (n=76), patients with a CP (n=88) have significantly better OS (P=0.017) and relapse-free survival (RFS) (P=0.020). Four-year and median survivals were 42% and 36 months among patients with CPs, compared with 26% and 10 months among those without CPs. Four year survival and median RFS were 39% and 25 months among those with CPs, compared with 23% and 7 months among those without CPs. Further, better survival and RFS were associated with CP visit duration of >3 h per day (P=0.005 and P=0.007, respectively) and with CP frequency of visits >75% of inpatient days (P=0.004 and P=0.010, respectively). A CP support program should encourage not only presence of a CP but also duration and frequency of CP visits associated with better patient survival. PMID- 23103678 TI - Allo-SCT using BU, CY and melphalan for children with AML in second CR. AB - Based on the results from the AML-BFM 98 trial, hematopoietic SCT (HSCT) is recommended for children with AML in second CR only. Here, we retrospectively analyze interphase data of children who underwent HSCT after myeloablative conditioning with BU, CY, and melphalan (BuCyMel) for AML in second remission (CR2) between 1998 and 2009. Out of 152 children, transplant data were available on 109 individuals. Sixty out of 109 children (55%) received BuCyMel. Median age at HSCT was 12.2 years (range 3.0; 18.3). GVHD prophylaxis mostly consisted of CsA and short term MTX with or without antithymocyte globulin. Matched-sibling donors were used for 6/60 analyzed recipients, the remainder either received grafts from matched unrelated (30/60) or mismatched donors. OS after 5 years was 62% (s.e. 6%), relapse incidence 35% (18/60 children) and treatment-related mortality accounted for 12% (7/60) of fatal events. In conclusion, even taking into account possible selection bias in this retrospective analysis, HSCT in CR2 using BuCyMel resulted in a respectable OS. Based on this data the prospective, controlled and centrally monitored AML SCT-BFM 2007 trial has started to recruit patients in January 2010 aiming to generate valid outcome data for further strategy decisions. PMID- 23103682 TI - Recipient seropositivity for adenovirus type 11 (AdV11) is a highly predictive factor for the development of AdV11-induced hemorrhagic cystitis after allogeneic hematopoietic SCT. PMID- 23103683 TI - Tunable bandgap energy of fluorinated nanocrystals for flash memory applications produced by low-damage plasma treatment. AB - A plasma system with a complementary filter to shield samples from damage during tetrafluoromethane (CF(4)) plasma treatment was proposed in order to incorporate fluorine atoms into gadolinium oxide nanocrystals (Gd(2)O(3)-NCs) for flash memory applications. X-ray photoelectron spectroscopy confirmed that fluorine atoms were successfully introduced into the Gd(2)O(3)-NCs despite the use of a filter in the plasma-enhanced chemical vapour deposition system to shield against several potentially damaging species. The number of incorporated fluorine atoms can be controlled by varying the treatment time. The optimized memory window of the resulting flash memory devices was twice that of devices treated by a filterless system because more fluorine atoms were incorporated into the Gd(2)O(3)-NCs film with very little damage. This enlarged the bandgap energy from 5.48 to 6.83 eV, as observed by ultraviolet absorption measurements. This bandgap expansion can provide a large built-in electric field that allows more charges to be stored in the Gd(2)O(3)-NCs. The maximum improvement in the retention characteristic was >60%. Because plasma damage during treatment is minimal, maximum fluorination can be achieved. The concept of simply adding a filter to a plasma system to prevent plasma damage exhibits great promise for functionalization or modification of nanomaterials for advanced nanoelectronics while introducing minimal defects. PMID- 23103685 TI - Molecular cloning of the cDNAs encoding three somatostatin variants in the dogfish (Scylorhinus canicula). AB - It has been recently shown that the somatostatin gene family was likely composed of at least three paralogous genes in the common ancestor of all extant jawed vertebrates. These three genes, namely SS1, SS2 and SS5, are thought to have been generated through the two rounds of whole-genome duplications (2R) that took place early during the vertebrate evolution. In the present study, we report the cloning of three distinct somatostatin cDNAs from the dogfish Scylorhinus canicula, a member of the group of cartilaginous fish. We decided to call these cDNAs, at least provisionally, SSa, SSb and SSc, respectively. Two of them, SSa and SSb, encode proteins that both contain the same tetradecapeptide sequence at their C-terminal extremity (AGCKNFFWKTFTSC). This putative peptide is identical to that generated by the SS1 gene in other vertebrate species. The last cDNA, SSc, encodes a protein that contains at its C-terminal extremity the same peptide sequence as that generated by the SS2 gene in teleosts (APCKNFFWKTFTSC). Phylogenetic analysis showed that the SSa and SSc genes likely correspond to the dogfish counterparts of the SS1 and SS2 genes, respectively. In contrast, the phylogenetic status of the SSb gene is less clear. Several lines of evidence suggest that it could correspond to the SS5 gene, but this view will need to be confirmed, for example by synteny analysis. Finally, RT-PCR analysis revealed that SSa, SSb and SSc genes are differentially expressed in dogfish tissues, suggesting that the corresponding peptides may exert distinct functions. PMID- 23103684 TI - Litter box preference in domestic cats: covered versus uncovered. AB - Feline inappropriate elimination (periuria and/or perichezia) remains a very common behavioral complaint of cat owners. Treatment recommendations often include improving the attractiveness of the litter boxes available to the cat. One frequent recommendation is to avoid covered litter boxes, although this has not previously been tested experimentally. The goal of this study was to assess whether, all else being equal, cats preferentially used uncovered litter boxes over covered litter boxes. Twenty-eight cats were enrolled in the study and offered the choice of a covered or uncovered box. Waste was scooped daily from each box, and the weight of waste in the different box styles was compared and evaluated using paired t-tests and chi(2) analyses. Overall, there was no significant difference between use of the two box styles. Eight individual cats did exhibit a preference (four for covered, four for uncovered), but individual preference results are not evenly distributed, with more cats than expected showing no preference between litter box types. We postulate that, if boxes are kept sufficiently clean (ie, once daily minimum cleaning), most cats will not show a preference for either box type. The observation that a minority of cats in the study exhibited a preference supports the recommendation of providing individual cats with a 'cafeteria' of litter box styles, including a covered box, to determine whether such a preference exists. These findings add to existing literature on the topic of feline inappropriate elimination and provide additional information for clinicians recommending treatment options for cats exhibiting this behavior. PMID- 23103686 TI - Functional imaging of brain responses to different outcomes of hypothesis testing: revealed in a category induction task. AB - Functional magnetic resonance imaging (fMRI) was used to examine differences in brain activation that occur when a person receives the different outcomes of hypothesis testing (HT). Participants were provided with a series of images of batteries and were asked to learn a rule governing what kinds of batteries were charged. Within each trial, the first two charged batteries were sequentially displayed, and participants would generate a preliminary hypothesis based on the perceptual comparison. Next, a third battery that served to strengthen, reject, or was irrelevant to the preliminary hypothesis was displayed. The fMRI results revealed that (1) no significant differences in brain activation were found between the 2 hypothesis-maintain conditions (i.e., strengthen and irrelevant conditions); and (2) compared with the hypothesis-maintain conditions, the hypothesis-reject condition activated the left medial frontal cortex, bilateral putamen, left parietal cortex, and right cerebellum. These findings are discussed in terms of the neural correlates of the subcomponents of HT and working memory manipulation. PMID- 23103687 TI - Resting-state EEG power predicts conflict-related brain activity in internally guided but not in externally guided decision-making. AB - Most experimental studies of decision-making have specifically examined situations in which a single correct answer exists (externally guided decision making). Along with such externally guided decision-making, there are instances of decision-making in which no correct answer based on external circumstances is available for the subject (internally guided decision-making, e.g. preference judgment). We compared these two different types of decision-making in terms of conflict-monitoring and their relation with resting-state brain activity. Current electroencephalography (EEG) data demonstrated that conflict-related N2 amplitudes (i.e., difference between large-conflict and small-conflict conditions) in externally guided decision-making were modulated by the type of external stimulus (i.e., large-conflict stimulus pair or small-conflict stimulus pair) but were not found to be correlated with resting-state brain activity (i.e. resting-state EEG power). In contrast, conflict-related N2 amplitudes in internally guided decision-making were found to be correlated with resting-state brain activity, but were not found to be modulated by the type of stimulus itself: the degree to which the type of external stimulus modulates the conflict during stimulus encoding varies according to individual differences in intrinsic brain activity. Considering those results comprehensively, we demonstrate for the first time resting-state and stimulus-related differences between externally and internally guided decision-making. PMID- 23103688 TI - Statistical localization of human olfactory cortex. AB - Functional neuroimaging methods have been used extensively during the last decades to explore the neural substrates of olfactory processing. While a general consensus on the functional anatomy of olfactory cortex is beginning to emerge, the mechanisms behind the functions of individual processing nodes still remain debated. Further, it remains unclear to which extent divergent findings result from differences in methodological approaches. Using Activation Likelihood Estimation (ALE), the aim of the present study was to statistically combine all published data on functional neuroimaging of olfaction to provide a probability map reflecting the state of the field to date. Additionally, we grouped studies according to various methodological approaches to investigate whether these systematically affected the reported findings. A total of 45 studies (69 contrasts, 594 foci) met our inclusion criteria. Significant ALE peaks for odor against baseline were observed in areas commonly labeled as primary and secondary olfactory cortex, such as the piriform and orbitofrontal cortex, amygdala, anterior insula, and ventral putamen. In addition, differences were observed in the extent to which different methods were able to induce activation in these different nodes of the olfactory network. PMID- 23103689 TI - Coevolution of brain structures in amnestic mild cognitive impairment. AB - Network accounts of the progression of Alzheimer's disease (AD), based on cross sectional brain imaging observations, postulate that the biological course of the disease is characterized by coordinated spatial patterns of brain change to distributed cognitive networks. This study tests this conjecture by quantifying inter-regional covariance in cortical gray matter atrophy rates in 317 Alzheimer's Disease Neuroimaging Initiative participants who were clinically diagnosed with amnestic mild cognitive impairment at baseline and underwent serial MRI at 6-month intervals over the course of 2years. A factor analysis model identified five factors (i.e. groupings of regions) that exhibited highly correlated rates of atrophy. Four groupings approximately corresponded to coordinated change within the posterior default mode network, prefrontal cortex, medial temporal lobe, and regions largely spared by the early pathological course of AD (i.e., sensorimotor and occipital cortex), while the fifth grouping represented diffuse, global atrophy. The data-driven observation of "frontal aging" superimposed upon medial temporal atrophy typical of early AD and default mode network changes supports the view that in individuals at high risk of eventual clinical AD, multiple patterns of distributed neuronal death corresponding to multiple biological substrates may be active. PMID- 23103691 TI - The neural mechanisms of semantic and response conflicts: an fMRI study of practice-related effects in the Stroop task. AB - Previous studies have demonstrated that there are separate neural mechanisms underlying semantic and response conflicts in the Stroop task. However, the practice effects of these conflicts need to be elucidated and the possible involvements of common neural mechanisms are yet to be established. We employed functional magnetic resonance imaging (fMRI) in a 4-2 mapping practice-related Stroop task to determine the neural substrates under these conflicts. Results showed that different patterns of brain activations are associated with practice in the attentional networks (e.g., dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and posterior parietal cortex (PPC)) for both conflicts, response control regions (e.g., inferior frontal junction (IFJ), inferior frontal gyrus (IFG)/insula, and pre-supplementary motor areas (pre-SMA)) for semantic conflict, and posterior cortex for response conflict. We also found areas of common activation in the left hemisphere within the attentional networks, for the early practice stage in semantic conflict and the late stage in "pure" response conflict using conjunction analysis. The different practice effects indicate that there are distinct mechanisms underlying these two conflict types: semantic conflict practice effects are attributable to the automation of stimulus processing, conflict and response control; response conflict practice effects are attributable to the proportional increase of conflict-related cognitive resources. In addition, the areas of common activation suggest that the semantic conflict effect may contain a partial response conflict effect, particularly at the beginning of the task. These findings indicate that there are two kinds of response conflicts contained in the key-pressing Stroop task: the vocal-level (mainly in the early stage) and key-pressing (mainly in the late stage) response conflicts; thus, the use of the subtraction method for the exploration of semantic and response conflicts may need to be further examined. PMID- 23103690 TI - Functional connectivity in obesity during reward processing. AB - Obesity is a health problem that has become a major focus of attention in recent years. There is growing evidence of an association between obesity and differences in reward processing. However, it is not known at present whether these differences are linked exclusively to food, or whether they can be detected in other rewarding stimuli. We compared responses to food, rewarding non-food and neutral pictures in 18 young adults with obesity and 19 normal-weight subjects using independent component analysis. Both groups modulated task-related activity in a plausible way. However, in response to both food and non-food rewarding stimuli, participants with obesity showed weaker connectivity in a network involving activation of frontal and occipital areas and deactivation of the posterior part of the default mode network. In addition, obesity was related with weaker activation of the default mode network and deactivation of frontal and occipital areas while viewing neutral stimuli. Together, our findings suggest that obesity is related to a different allocation of cognitive resources in a fronto-occipital network and in the default mode network. PMID- 23103692 TI - Neuropeptide S receptor gene: fear-specific modulations of prefrontal activation. AB - Since central administration of neuropeptide S (NPS) has been shown to exert anxiolytic effects on rodent behavior in a number of studies, genetic variants of its cognate G-protein coupled receptor (NPSR1) became the focus of several recent human studies on anxiety and anxiety disorders. The T allele of rs324981, which goes along with enhanced receptor function, was associated with panic disorder, increased anxiety sensitivity in healthy subjects, attenuated prefrontal brain activation and elevated amygdala responses to fear-relevant stimuli. To investigate whether prefrontal attenuations in rs324981 T allele carriers are specific to fear-relevant stimulus content and cannot be attributed to a generally higher interference of emotional stimuli, 92 subjects performed a combined cognitive and emotional Stroop task while oxygenation changes in the prefrontal cortex were recorded using functional near-infrared spectroscopy. Results showed a specific NPSR1 gene activation modulation in response to fear relevant word stimuli. Only A-homozygotes displayed an emotional Stroop effect in terms of increased activation to fear-relevant stimuli in medial and dorsolateral prefrontal cortex. Specifically, activation in the fear-relevant condition was higher in A-homozygotes as compared to T allele carriers while no group differences were found during neutral, congruent or highly interfering incongruent color word presentation. The current results are in line with earlier imaging genetic studies and suggest a potential protective function of the NPSR1 rs324981 A/A genotype against pathologically enhanced anxiety that might be explained by stronger reflective prefrontal regulation over the subcortical fear response. PMID- 23103693 TI - Can learning to interpret pump messages help lead to an early diagnosis of HeartWare ventricular assist device thrombosis? AB - Left ventricular assist device thrombosis is a detrimental complication that, if not properly diagnosed and treated, can lead to low output syndrome and death. When ongoing thrombus formation is caused by inappropriate anticoagulation, timely identification is possible, and could perhaps be the key to successful treatment. PMID- 23103694 TI - Design and in vitro assessment of an improved, low-resistance compliant thoracic artificial lung. AB - Current thoracic artificial lungs (TALs) have blood flow impedances greater than the natural lungs, which can result in abnormal pulmonary hemodynamics. This study investigated the impedance and gas transfer performance of a compliant TAL (cTAL). Fluid-structure interaction analysis was performed using ADINA (ADINA R&D Inc., Watertown, MA) to examine the effect of the inlet and outlet expansion angle, theta, on device impedance and blood flow patterns. Based on the results, the theta = 45 degrees model was chosen for prototyping and in vitro testing. Glycerol was pumped through this cTAL at 2, 4, and 6 L/min at 80 and 100 beats/min, and the zeroth and first harmonic impedance moduli, Z(0) and Z(1), were calculated. Gas transfer testing was conducted at blood flow rates of 3, 5, and 7 L/min. Fluid-structure interaction results indicated that the 45 degrees model had an ideal combination of low impedance and even blood flow patterns and was thus chosen for prototyping. In vitro, Z(0) = 0.53 +/- 0.06 mm Hg/(L/min) and Z(1) = 0.86 +/- 0.08 mm Hg/(L/min) at 4 L/min and 100 beats/min. Outlet PO(2) and SO(2) values were above 200 mm Hg and 99.5%, respectively, at each flow rate. Thus, the cTAL had lower impedance than hard shell TALs and excellent gas transfer. PMID- 23103695 TI - Will we see nuclear-powered ventricular assist devices? PMID- 23103696 TI - Left ventricular reverse remodeling with a continuous flow left ventricular assist device measured by left ventricular end-diastolic dimensions and severity of mitral regurgitation. AB - Pulsatile flow left ventricular assist devices (LVADs) maximally unload the left ventricle (LV), leading to reverse remodeling of the myopathic LV that manifests as decreased LV end-diastolic dimension (LVEDD) and decreased severity of mitral regurgitation (MR). There is a paucity of data, however, regarding the ability of continuous flow (CF) pumps to adequately decompress the LV to induce similar reverse remodeling. We sought to evaluate the effects of CF-LVADs on LV reverse remodeling. From March 2006 through July 2011, one hundred patients with chronic heart failure underwent implantation of CF-LVAD (93 HeartMate II LVADs and seven HeartWare LVADs) as bridge-to-transplant (n = 68) and destination therapies (n = 32). Echocardiograms and right heart catheterizations were reviewed preoperatively and at 1 and 6 months post-LVAD implantation. Mean age was 52.1 +/ 12.1 years; etiology of heart failure was ischemic cardiomyopathy in 34 patients and nonischemic dilated cardiomyopathy in 66 patients. Median LVAD support time was 378.3 days; 371.5 days for patients who received bridge-to-transplant therapy and 422.2 days for patients who underwent destination therapy. Left ventricular end-diastolic dimension significantly decreased at 1 month post-LVAD implantation from 71.6 +/- 12.4 to 58.3 +/- 13.8 mm (p < 0.001). Severity of MR also significantly decreased from 76.0% of patients having moderate or severe MR preoperatively to 8.0% with moderate or severe MR at 1 month post-LVAD (p < 0.001). These reductions were maintained at 6 months. These data demonstrate the ability of a CF-LVAD to significantly decompress the LV, leading to significant reductions in LVEDD and severity of MR. This reverse remodeling was apparent in the early postoperative period and was sustained at 6 months. Further studies are warranted to investigate whether this correlates with clinical LV recovery. PMID- 23103697 TI - Insertion of bicaval dual-lumen cannula via the left internal jugular vein for extracorporeal membrane oxygenation. AB - Venovenous extracorporeal membrane oxygenation (ECMO) can support gas exchange in patients with primary respiratory failure. Venovenous ECMO can be initiated through a single-site, dual-lumen cannula designed for insertion in the right internal jugular vein. We describe four cases of hypercapnic or hypoxemic respiratory failure, in which we performed single-site cannulation of the left internal jugular vein with 23 Fr or 27 Fr bicaval dual-lumen catheters when the right internal jugular vein was inaccessible because of either stenosis or thrombosis. The surgical approach for left-sided access is similar to the approach used for the right internal jugular vein. The left-sided approach resulted in equivalent blood flow and gas exchange compared with our previous experience with right-sided cannulation. This case series demonstrates the feasibility of placing a bicaval dual-lumen catheter in the left internal jugular vein for the initiation of venovenous ECMO when the right internal jugular vein is inaccessible. PMID- 23103698 TI - Evaluation of a ventricular assist device system: stability in a proton beam therapy. AB - Inadequate research exists regarding testing of a ventricular assist device (VAD) for susceptibility to radiation damage. Specifically, minimal data are available to radiation oncologists prescribing treatment plans for patients with an implanted VAD. As the number of implanted devices increases, patients requiring radiation at tissue sites near or at the device will increase. The purpose of this study is to provide the first analysis of radiation effects of proton beams on VADs. Five left VAD (LVAD) pumps (HeartWare Inc., Miami Lakes, FL) were exposed to proton beam radiation at a calibrated dose rate of 5 Gy/min up to a cumulative dose of 70 Gy. The Heartware LVAD pump recorded parameters including power (W), speed (revolutions/min), and estimated flow (L/min). Analysis of collected data after each irradiation found no deviation in pump parameters from baseline values. The Heartware LVAD pump exhibited no change in device function when directly irradiated by a high energy proton beam. Secondary neutron fluence created in the proton beam during irradiation had no effect on external components including the system controller and batteries powering the Heartware LVAD. PMID- 23103699 TI - Pump exchange for cable damage in patients supported with HeartMate II left ventricular assist device. AB - Implantable continuous flow pumps are a routine treatment for end-stage heart failure. The waiting time for heart transplantation is increasing, and more and more patients receive the pump for permanent support. We retrospectively analyzed our database of patients supported with the HeartMate II left ventricular assist device to identify instances of cable damage. Between May 9, 2006 and May 9, 2012, 161 patients were supported with the HeartMate II. There were 187 cumulative years of HeartMate II support. The documented cable damage occurred in 12 patients (7.5%), requiring pump exchange in five patients after a mean time of 706 days on support. There was no perioperative mortality. The damage occurred typically at the "weak" place-the feedthrough of the driveline to the pump body. In some cases, the device alarm history and x-ray may allow diagnosis before pump stop occurs. However, since the most recent changes in the design of the connection and modifications made in the implantation technique, no instance of cable damage has been registered. PMID- 23103700 TI - Inferior vena cava filter placement before ECMO decannulation. AB - Venous thromboembolism (VTE), particularly thrombi in the inferior vena cava (IVC) and pulmonary embolism, can occur after successful extracorporeal membrane oxygenation (ECMO) and can be associated with adverse outcomes including death. VTE is related to the presence of a venous cannula and in some cases inadequate anticoagulation caused by clinical bleeding. We have developed a simple method for guidewire exchange of the femoral venous ECMO cannula to a working catheter for intravascular ultrasound (IVUS) IVC filter placement, and describe the specific methodology. PMID- 23103701 TI - Modified central closure technique for treatment of aortic insufficiency in patients on left ventricular assist device support. AB - Development of aortic insufficiency (AI) in a patient with a continuous flow left ventricular assist device (CF-LVAD) represents a serious complication. The circulatory loop that is created by the AI can lead to cardiogenic shock, malperfusion, and multisystem organ failure. The central closure technique has been well described and is a popular method of repairing the aortic valve in CF LVAD patients with AI. Because of an early failure using this technique, we developed a modification of this technique that we describe in this report that can be particularly useful when the aortic valve leaflet tissue is relatively normal or thin, as opposed to thickened/fibrosed, as the strength of the repair is not solely provided by the central coaptation point of the leaflets, but is rather, distributed more diffusely across the leaflets. PMID- 23103702 TI - Successful treatment of a continuous flow left ventricular assist device thrombosis with eptifibatide. AB - Left ventricular assist device thrombosis is a rare but potentially lethal complication of mechanical circulatory support. Here, we present a case of successful treatment of a suspected HeartMate II thrombosis with the glycoprotein IIb/IIIa inhibitor, eptifibatide. The patient presented with signs and symptoms of heart failure, along with acute kidney injury and hemolytic anemia that did not respond to diuresis, inotrope support, or anticoagulation. Treatment with eptifibatide resulted in marked clinical and hemodynamic improvement within 24 hrs. The patient was transitioned to clopidogrel and discharged without further incident. Eptifibatide may represent a potential therapeutic option for patients with device thrombosis. PMID- 23103703 TI - Allosensitization in cardiac transplantation: shooting at a moving target. PMID- 23103705 TI - Neopterin levels are independently associated with cardiac remodeling in patients with chronic heart failure. AB - OBJECTIVES: Neopterin, a marker of inflammation and monocyte activation, is found increased in patients with heart failure (HF). This study investigates whether neopterin levels correlate with left ventricular (LV) remodeling and brain natriuretic peptide (BNP), a marker of cardiac stress, in chronic HF (CHF) patients with different severity of disease. DESIGN AND METHODS: The relationship between neopterin and LV dimensions, NT-proBNP, and pro-inflammatory cytokines were studied in 98 CHF patients, while nineteen healthy subjects were enrolled as controls. Nineteen (19%) patients were in NYHA class I, 38 (39%) in NYHA class II, 27 (28%) in NYHA class III, and 14 (14%) in NYHA class IV. RESULTS: Neopterin levels were higher in CHF patients than in age- and gender-matched healthy controls, and related with indexed LV end-diastolic volume (LVEDVi). Prospectively CHF patients were separated into tertiles of low, medium and high neopterin levels. Among patients, male gender, LVEDVi, diuretic treatment, NYHA class I, NT-proBNP and IL-8 levels were significant determinants of urine neopterin levels by bivariate analysis. Neopterin levels were associated only to LV remodeling, as assessed by LVEDVi, and IL-8 levels, a crucial monocyte chemoattractant, by multivariate ordinal regression analysis. CONCLUSIONS: The relationship between elevated neopterin levels and LV enlargement in CHF patients suggests a crucial role of monocyte activation in the development of cardiac dysfunction in CHF patients. Assessment of neopterin levels is a potential biomarker to evaluate the progression of LV remodeling in CHF patients. PMID- 23103704 TI - Mass spectrometry-based quantification. AB - OBJECTIVE: This review describes the most common methods currently used for mass spectrometry-based quantification in proteomic applications. DESIGN AND METHODS: Quantification can be performed using either labeled or unlabeled approaches. Labeled approaches rely on mass-tagging of peptide reference standards either by direct synthesis or through chemical or metabolic means. Following labeling, samples are pooled and analyzed as one, thereby circumventing any potential error that could result from run-to-run variability. Unlabeled approaches rely on run to-run comparisons between test and reference samples and assume a highly reproducible separation and similar sample compositions. RESULTS: A number of commercial labeling reagents are now available and each of these are described along with their strengths and limitations. CONCLUSIONS: The choice of method will ultimately depend, not just on financial considerations, but also on the context of the experiment. PMID- 23103706 TI - Discordance between urine pH measured by dipstick and pH meter: implications for methotrexate administration protocols. AB - OBJECTIVES: To minimize toxicity of high-dose methotrexate (MTX) therapy, urinary alkalinization with frequent monitoring of urine pH is required. Urine pH is usually assessed by fast and convenient dipstick methods. When urine color interferes with dipstick measurement, as occurs in patients receiving MTX, alternative methods such as pH meters are used. Nursing staff caring for patients on high-dose MTX reported that urine pH results from dipstick and pH analyzers were often clinically discordant. As a result urine pH by dipstick and pH meter were compared in patients on high-dose MTX therapy and patients with normal colored urine samples. DESIGN AND METHODS: We measured urine pH by dipstick and pH meter in 116 urine samples from 4 patients receiving high-dose MTX therapy, and in 50 normal-colored urine samples from 50 patients not on MTX therapy. RESULTS: In patients on MTX therapy the mean (+/-standard deviation) bias between dipstick and pH meter urine pH was 0.7+/-0.4, compared to 0.4+/-0.3 in patients not on MTX. For patients on MTX clinical concordance between dipstick and pH meter urine results was poor around a clinical cut-off of pH 8.0. Of the 92 samples with a meter urine pH<=8.0, 72 had a discordant value by dipstick (pH>8). CONCLUSIONS: Urine pH readings by dipstick and pH meter are not equivalent, and the bias between them is exacerbated in patients on MTX. Institutions with high dose MTX therapy protocols should not alternate between dipstick and pH meter urine pH monitoring. PMID- 23103707 TI - Erythrocyte caspase-3 levels in children with chronic kidney disease. AB - OBJECTIVES: In chronic kidney disease (CKD), a number of intra- and extracellular factors, e.g., uremic toxins, mechanic, oxidative or osmotic stress - induce changes (rearrangements) in the structure of cytoplasmatic membrane, while also simultaneously deregulating blood cell metabolism and, in consequence, contributing to preliminary ageing and suicidal death of red blood cells (RBCs).The aim of the reported study was an evaluation of caspase-3 and lactate dehydrogenase activities and of ATP concentrations in erythrocytes as cellular responses to CKD progress. DESIGN AND METHODS: Conservatively treated sixty (60) CKD children were enrolled into the study and divided, according to CKD progression (stage I-IV). The control group consisted of twenty-five (25) healthy children. The activity of caspase-3 (Casp-3) and lactate dehydrogenase (LDH) were spectrophotometrically assayed in haemolysed erythrocytes. Adenosine triphosphate (ATP(e)) concentrations were measured by means of a luciferin-luciferase kit. RESULTS: A gradual increase of LDH and ATP levels was observed in transition from CKD stage I to stage III. In Group IV, the levels of those parameters were statistically significantly lower than in the control group. The activity of Casp 3 in Group I was comparable to that in healthy children. The highest activity of Casp-3 was observed in Group III. CONCLUSIONS: 1. The activity of caspase-3 in RBCs of CKD children grows with progression of the disease. 2. The lower LDH activities and the ATP concentration drop below the values characteristic for the control group, as observed in stage IV of CKD, indicate a compromised energy balance. PMID- 23103708 TI - Possible relationship between Al/ferritin complex and Alzheimer's disease. AB - OBJECTIVES: Ferritin is the main iron-storage protein capable of containing thousands of iron atoms. However, ferritin can bind in vitro other atoms such as aluminum and it has been shown that also in vivo atoms other than iron, as aluminum and zinc, are present in large amounts in ferritin. Since aluminum appears to be involved in the development of Alzheimer's disease, in the present study the specific content of aluminum in ferritin of Alzheimer's patients was analyzed and compared with other control groups. DESIGN AND METHODS: The content of Fe, Al and Zn of blood ferritin was measured by mass spectrometry in patients with Alzheimer's disease and compared with other clinical and control groups. RESULTS: The results obtained confirm the hypothesis of a functional role of ferritin as a regulatory protein of toxic metals and clearly indicate that ferritin from Alzheimer's patients has a content of aluminum higher than that of controls. CONCLUSIONS: The specific aluminum content of ferritin seems to be related to different disease stages of Alzheimer's disease. This result confirms the hypothesis of aluminum as a possible factor inducing the Alzheimer's disease and opens the ways to possible new diagnostic tests. PMID- 23103709 TI - A study on serum advanced glycation end products and its association with oxidative stress and paraoxonase activity in type 2 diabetic patients with vascular complications. AB - OBJECTIVES: Enhanced formation of advanced glycation end products (AGEs) formed secondary to hyperglycemic conditions has been linked to diabetes mellitus (DM) associated complications. We investigated the clinical relevance of estimating AGEs and their relationship with oxidative stress (OS) and paraoxonase (PON1) activity in type 2 DM (T2DM) in relation to development of vascular complications. DESIGN AND METHODS: Serum AGEs along with PON1 activity, protein carbonyl (PCO), advanced oxidation protein products (AOPP), lipid peroxidation (MDA), and total thiol (T-SH) were determined in 157 T2DM patients (DM without complications n=57, DM micro-vascular complications n=53, DM macro-vascular complications n=47) and 40 healthy controls. RESULTS: Serum AGE level increased significantly in various study groups in following manner: healthy control 0.05 chi2 test). Also, no association was found between the RV/LV ratio and the VOI and PESI (P-value > 0.05 chi2 test). PESI is an accurate tool for pulmonary embolism prognostic stratification. It safely discriminates low-risk from high-risk patients regarding death outcome. We were unable to demonstrate an association between image scores and mortality. PMID- 23103728 TI - Successful use of recombinant factor VIIa in a child with Schoenlein-Henoch purpura presenting with compartment syndrome and severe factor XIII deficiency. AB - In this article, we present a 7-year-old boy with Schoenlein-Henoch purpura (HSP) presented with compartment syndrome and factor XIII deficiency and treated with recombinant factor VIIa and fasciotomy. Treatment decisions for patients with HSP presenting with compartment syndrome should be made on a case-by-case basis. Factor XIII deficiency should be in mind in these patients. The use of recombinant factor VIIa might be effective and well tolerated for treating hemorrhage in patients with HSP and compartment syndrome. Surgical treatment should be preferred in patients with compartment syndrome. However, in patients who have a coagulation defect, the first priority is to correct the clotting deficiency. The use of recombinant factor VIIa is a treatment option for children who develop compartment syndrome due to a coagulation defect. PMID- 23103723 TI - Diabetic nephropathy and extracellular matrix. AB - Diabetic nephropathy (DN) is a serious complication in diabetes. Major typical morphological changes are the result of changes in the extracellular matrix (ECM). Thus, basement membranes are thickened and the glomerular mesangial matrix and the tubulointerstitial space are expanded, due to increased amounts of ECM. One important ECM component, the proteoglycans (PGs), shows a more complex pattern of changes in DN. PGs in basement membranes are decreased but increased in the mesangium and the tubulointerstitial space. The amounts and structures of heparan sulfate chains are changed, and such changes affect levels of growth factors regulating cell proliferation and ECM synthesis, with cell attachment affecting endothelial cells and podocytes. Enzymes modulating heparan sulfate structures, such as heparanase and sulfatases, are implicated in DN. Other enzyme classes also modulate ECM proteins and PGs, such as matrix metalloproteinases (MMPs) and serine proteases, such as plasminogen activator, as well as their corresponding inhibitors. The levels of these enzymes and inhibitors are changed in plasma and in the kidneys in DN. Several growth factors, signaling pathways, and hyperglycemia per se affect ECM synthesis and turnover in DN. Whether ECM components can be used as markers for early kidney changes is an important research topic, whereas at present, the clinical use remains to be established. PMID- 23103729 TI - Comparison of empirical estimate of clinical pretest probability with the Wells score for diagnosis of deep vein thrombosis. AB - Wells score has been validated for estimation of pretest probability in patients with suspected deep vein thrombosis (DVT). In clinical practice, many clinicians prefer to use empirical estimation rather than Wells score. However, which method is better to increase the accuracy of clinical evaluation is not well understood. Our present study compared empirical estimation of pretest probability with the Wells score to investigate the efficiency of empirical estimation in the diagnostic process of DVT. Five hundred and fifty-five patients were enrolled in this study. One hundred and fifty patients were assigned to examine the interobserver agreement for Wells score between emergency and vascular clinicians. The other 405 patients were assigned to evaluate the pretest probability of DVT on the basis of the empirical estimation and Wells score, respectively, and plasma D-dimer levels were then determined in the low-risk patients. All patients underwent venous duplex scans and had a 45-day follow up. Weighted Cohen's kappa value for interobserver agreement between emergency and vascular clinicians of the Wells score was 0.836. Compared with Wells score evaluation, empirical assessment increased the sensitivity, specificity, Youden's index, positive likelihood ratio, and positive and negative predictive values, but decreased negative likelihood ratio. In addition, the appropriate D-dimer cutoff value based on Wells score was 175 MUg/l and 108 patients were excluded. Empirical assessment increased the appropriate D-dimer cutoff point to 225 MUg/l and 162 patients were ruled out. Our findings indicated that empirical estimation not only improves D-dimer assay efficiency for exclusion of DVT but also increases clinical judgement accuracy in the diagnosis of DVT. PMID- 23103730 TI - Midgut proteins released by microapocrine secretion in Spodoptera frugiperda. AB - Microapocrine vesicles bud from the lepidopteran midgut microvilli as double membrane vesicles. To identify the proteins secreted by this process, antibodies raised against isolated microapocrine vesicles from Spodoptera frugiperda were used for screening a midgut cDNA expression library. Positive clones were sequenced, assembled and N blasted against S. frugiperda sequences obtained by pyrosequencing midgut mRNA. This procedure led to the extension of microapocrine sequences that were annotated. A similar procedure was used to identify midgut microvillar proteins that necessarily are part of the microapocrine vesicle. Forty-eight proteins were associated with microvillar membranes. They pertain to 8 functional groups: digestive enzymes, peritrophic membrane, protection, transporters, receptors, secretory machinery, cytoskeleton and signaling, and unknown. Twenty-eight proteins are putatively secreted by microapocrine secretion. Most of them are digestive enzymes, but the list also includes proteins involved in protection and in peritrophic membrane formation. Among the identified digestive enzymes, aminopeptidases are typically microvillar and group into the classes 1, 2, 3, 5, and 6. There are two amylases secreted by microapocrine secretion: one is a digestive enzyme and the other is a transporter like amylase with no clear function. One lipase has a predicted transmembrane loop, whereas the others are supposed to be secreted by microapocrine secretion and be digestive. Trypsin is membrane bound and is delivered by microapocrine secretion, but has no predicted features to bind membranes. It may remain bound through the signal peptide till be delivered into the midgut lumen. Proteins supposed to be involved in the microapocrine secretory machinery were: calmodulin, annexin, myosin 7a, and gelsolin 1. Their putative roles are discussed, but more research is necessary to settle this subject. PMID- 23103731 TI - Severe degenerative prolapse hiding a double-orifice mitral valve. PMID- 23103732 TI - Aortic arch replacement in an elderly patient with dextrocardia and situs inversus. PMID- 23103733 TI - Monitoring of the respiratory muscles in the critically ill. AB - Evidence has accumulated that respiratory muscle dysfunction develops in critically ill patients and contributes to prolonged weaning from mechanical ventilation. Accordingly, it seems highly appropriate to monitor the respiratory muscles in these patients. Today, we are only at the beginning of routinely monitoring respiratory muscle function. Indeed, most clinicians do not evaluate respiratory muscle function in critically ill patients at all. In our opinion, however, practical issues and the absence of sound scientific data for clinical benefit should not discourage clinicians from having a closer look at respiratory muscle function in critically ill patients. This perspective discusses the latest developments in the field of respiratory muscle monitoring and possible implications of monitoring respiratory muscle function in critically ill patients. PMID- 23103734 TI - Test variability of the QuantiFERON-TB gold in-tube assay in clinical practice. AB - RATIONALE: Although IFN-gamma release assays (IGRAs) are widely used to screen for Mycobacterium tuberculosis infection in high-income countries, published data on repeatability are limited. OBJECTIVES: To determine IGRA repeatability. METHODS: The study population included consecutive patients referred to The Methodist Hospital (Houston, TX) between August 1, 2010 and July 31, 2011 for latent tuberculosis (TB) infection screening with an IGRA (QuantiFERON-TB Gold In Tube; Cellestis, Carnegie, Australia). We performed multiple IGRA tests using leftover stimulated plasma according to a prospectively formulated quality control protocol. We analyzed agreement in interpretation of test results classified according to manufacturer-recommended criteria and repeatability of quantitative TB response. MEASUREMENTS AND MAIN RESULTS: During the study period, 1,086 test results were obtained from 543 subjects. Per the manufacturer's cut point, the result of the second test was discordant from that of the first in 28 (8%) of 366 patients with valid test results, including 13 with an initial negative result and 15 with an initial positive result. Although agreement between repeat test results was high (kappa = 0.84; 95% confidence interval, 0.79 0.90), the normal expected range of within-subject variability in TB response on retesting included differences of +/- 0.60 IU/ml for all individuals (coefficient of variation, 14%), and +/- 0.24 IU/ml (coefficient of variation, 27%) for individuals whose initial TB response was between 0.25 and 0.80 IU/ml. CONCLUSIONS: There is substantial variability in TB response when IGRAs are repeated using the same patient sample. IGRA results should be interpreted cautiously when TB response is near interpretation cut-points. PMID- 23103735 TI - Traffic-related air pollution and lung function in children at 8 years of age: a birth cohort study. AB - RATIONALE: Long-term exposure to air pollution has been related to lung function decrements in children, but the role of timing of exposure remains unknown. OBJECTIVES: To assess the role of long-term exposure to air pollution on lung function in school-age children. METHODS: More than 1,900 children in the Swedish birth cohort BAMSE were followed with repeated questionnaires, dynamic spirometry, and IgE measurements until 8 years of age. Outdoor concentrations of particulate matter with an aerodynamic diameter less than 10 MUm (PM(10)) from road traffic were estimated for residential, day care, and school addresses from birth and onward using dispersion modeling. The relationship between time weighted average exposure during different time windows and FEV at 8 years was analyzed by linear regression, adjusting for potential confounding factors, including short-term exposure to air pollution. MEASUREMENTS AND MAIN RESULTS: A 5th to 95th percentile difference in time-weighted average particulate matter less than 10 MUm in aerodynamic diameter exposure during the first year of life was associated with a reduced FEV(1) of -59.3 ml (95% confidence interval, -113 to -5.6) at 8 years of age. The negative association was particularly pronounced in children concomitantly sensitized to common inhalant or food allergens (-136.9 ml; 95% confidence interval, -224.1 to -49.7). Exposure after the first year of life seemed to have less impact on lung function at 8 years. CONCLUSIONS: Our results indicate that exposure to traffic-related air pollution during infancy affects lung function in children up to 8 years of age and particularly in those sensitized to common inhalant or food allergens. PMID- 23103736 TI - Noninvasive ventilation in acute hypercapnic respiratory failure caused by obesity hypoventilation syndrome and chronic obstructive pulmonary disease. AB - RATIONALE: Noninvasive ventilation (NIV) is widely used in episodes of acute hypercapnic respiratory failure (AHRF) in patients with chronic obstructive pulmonary disease (COPD). However, there is no evidence on the efficacy of NIV during similar episodes in obesity hypoventilation syndrome (OHS). OBJECTIVES: To compare the efficacy of NIV in episodes of AHRF caused by OHS and COPD. METHODS: We prospectively assessed 716 consecutive patients (173 with OHS and 543 with COPD) with AHRF (arterial pH < 7.35 and Pa(CO(2)) > 45 mm Hg) treated with a similar protocol of NIV. We defined successful NIV as avoidance of intubation and intensive care unit survival at least 24 hours in the ward. Hospital survivors were followed for 1 year to assess hospital readmission and survival. MEASUREMENTS AND MAIN RESULTS: Both groups had similar (mean +/- SD) baseline respiratory acidosis (arterial pH, 7.22 +/- 0.08; Pa(CO(2)), 86 +/- 21 mm Hg). Patients with OHS were older (74 +/- 11 vs. 71 +/- 10 yr; P < 0.001); were more frequently female (134, 77% vs. 66, 12%; P < 0.001); had less late NIV failure (12, 7% vs. 67, 13%; P = 0.037); had lower hospital mortality (10, 6% vs. 96, 18%; P < 0.001); and had higher 1-year survival (odds ratio, 1.83; 95% confidence interval, 1.24-2.69; P = 0.002). However, survival adjusted for confounders (adjusted odds ratio, 1.41; 95% confidence interval, 0.70-2.83; P = 0.34), NIV failure (11, 6% vs. 59, 11%; P = 0.11), length of stay, and hospital readmission were similar in both groups. Among patients with COPD, obesity was associated with less late NIV failure and hospital readmission. CONCLUSIONS: Patients with OHS can be treated with NIV during an episode of AHRF with similar efficacy and better outcomes than patients with COPD. PMID- 23103738 TI - A comparative analysis of the aggregation behavior of amyloid-beta peptide variants. AB - Aggregated forms of the amyloid-beta peptide are hypothesized to act as the prime toxic agents in Alzheimer disease (AD). The in vivo amyloid-beta peptide pool consists of both C- and N-terminally truncated or mutated peptides, and the composition thereof significantly determines AD risk. Other variations, such as biotinylation, are introduced as molecular tools to aid the understanding of disease mechanisms. Since these modifications have the potential to alter key aggregation properties of the amyloid-beta peptide, we present a comparative study of the aggregation of a substantial set of the most common in vivo identified and in vitro produced amyloid-beta peptides. PMID- 23103737 TI - High-altitude medicine. AB - Medical problems occur at high altitude because of the low inspired Po(2), which is caused by the reduced barometric pressure. The classical physiological responses to high altitude include hyperventilation, polycythemia, hypoxic pulmonary vasoconstriction-increased intracellular oxidative enzymes, and increased capillary density in muscle. However, with the discovery of hypoxia inducible factors (HIFs), it is apparent that there is a multitude of responses to cellular hypoxia. HIFs constitute a master switch determining the general response of the body to oxygen deprivation. The recent discovery of genetic changes in Tibetans has opened up an exciting area of research. The two major human populations that have adapted well to high altitude, the Tibetans and Andeans, have strikingly different phenotypes. Diseases of lowlanders going to high altitude include acute mountain sickness, high-altitude pulmonary edema, and high-altitude cerebral edema. Diseases affecting permanent residents or highlanders include chronic mountain sickness and high-altitude pulmonary hypertension. Important recent advances have been made on mitigation of the effects of the hypoxic environment. Oxygen enrichment of room air is very powerful. Every 1% increase in oxygen concentration reduces the equivalent altitude by about 300 m. This procedure is used in numerous facilities at high altitude and in a Chinese train to Lhasa. An alternative strategy is to increase the barometric pressure as in aircraft cabins. A hybrid approach combining both strategies shows promise but has never been used. Mines that are being developed at increasingly high altitudes pose great medical problems. PMID- 23103739 TI - MiR-34a is involved in Tat-induced HIV-1 long terminal repeat (LTR) transactivation through the SIRT1/NFkappaB pathway. AB - MicroRNAs (miRNAs) regulate gene expression and may contribute to HIV-1 infection. In this study, our goal was to investigate the mechanisms by which miR 34a influenced Tat-induced HIV-1 transactivation through the SIRT1/NFkappaB pathway. We showed that Tat induced up-regulation of miR-34a expression in TZM-bl cells. MiR-34a significantly inhibited SIRT1 expression. Overexpression of miR 34a increased Tat-induced LTR transactivation. Forced expression of miR-34a decreased SIRT1 protein expression and consequently diminished Tat-induced acetylation of p65, while treatment with a miR-34a inhibitor had the opposite effect. These results suggest that regulating SIRT1 by down-regulation of miR-34a levels may be a therapeutic strategy against HIV-1 replication. PMID- 23103740 TI - The PGM3 gene encodes the major phosphoribomutase in the yeast Saccharomyces cerevisiae. AB - The phosphoglucomutases (PGM) Pgm1, Pgm2, and Pgm3 of the yeast Saccharomyces cerevisiae were tested for their ability to interconvert ribose-1-phosphate and ribose-5-phosphate. The purified proteins were studied in vitro with regard to their kinetic properties on glucose-1-phosphate and ribose-1-phosphate. All tested enzymes were active on both substrates with Pgm1 exhibiting only residual activity on ribose-1-phosphate. The Pgm2 and Pgm3 proteins had almost equal kinetic properties on ribose-1-phosphate, but Pgm2 had a 2000 times higher preference for glucose-1-phosphate when compared to Pgm3. The in vivo function of the PGMs was characterized by monitoring ribose-1-phosphate kinetics following a perturbation of the purine nucleotide balance. Only mutants with a deletion of PGM3 hyper-accumulated ribose-1-phosphate. We conclude that Pgm3 functions as the major phosphoribomutase in vivo. PMID- 23103741 TI - [Oral antidiabetic drugs in chronic renal disease]. AB - Decline in renal function may increase plasma concentration of several drugs - including oral antidiabetics - with a possible need for dose adjustment in this patient population. In this review, the pathophysiology and progression of diabetic kidney diseases is summarized. Guidance is given about appropriate administration of oral antidiabetic drugs in chronic kidney diseases, based on approved product label information. In addition to pioglitazon, recent availability of the new dipeptidyl peptidase-4 inhibitor linagliptin provides another option for diabetic patients with renal impairment without the need for dose reduction due to its predominant enterohepatic elimination. PMID- 23103742 TI - [The prognostic value of smudge cells (Gumprecht shadows) in chronic lymphocytic leukaemia]. AB - INTRODUCTION: Smudge cells (Gumprecht shadows) are chronic lymphocytic leukaemic cells ruptured during peripheral blood smear preparation. It has been demonstrated to be linked to reduced expression of the cytoskeletal protein vimentin and its inverse correlation with the clinical outcome of the disease. AIMS: Investigation of the percentage of smudge cells, CD38-, ZAP-70-positive cells and the time to treatment in patients with chronic lymphocytic leukaemia. METHODS: Authors investigated the percentage of smudge cells, CD38- and ZAP-70 positive cells in the peripheral blood of 50 patients with chronic lymphocytic leukaemia and their correlation with the time to treatment. RESULTS: 21 patients required treatment in the follow-up period. Their median smudge cell percentage was 9.9%, while it was 26.8% in the non-treated group. The cut-off value of smudge cell positivity was set to 20%. 59.3% of the patients with less than cut off had to be treated in the follow-up time compared to 21.7% of patients with more smudge cells. These findings were similar to the prognostic value of CD38 and ZAP-70. The necessity of treatment increased to 75-77.8% with the combination of investigated markers. The time to treatment was 19 months when smudge cells were less than 20%, but above 20% it was 36.15 months. In case of low smudge cell percentage and CD38 positivity the time to treatment was 14.14 months and in case of high smudge cell percentage and CD38 negativity it was 32.92 months. In discordant cases the time to treatment was 18.43 months. The authors also present a case report that demonstrates the relationship between the percentage of smudge cells and apoptotic cells with annexin V and 7-AAD staining. CONCLUSIONS: Estimation of smudge cells on a blood smear could be a simple and cheap prognostic test in chronic lymphocytic leukaemia with sensitivity similar to CD38 and ZAP-70 estimation. Combination of these tests raised the sensitivity of their prognostic value. PMID- 23103743 TI - [Perspectives of studies about physicians and medical students]. AB - INTRODUCTION: The fundamental purpose of sociological studies is to explore social problems which should be also in focus when examining doctors and medical students. In addition to fact findings, published reports may raise awareness toward these issues. AIM: The authors formulate a possible change of the research approach exploring possibilities to move forward with special focus on the health status among doctors, the role-conflict among female doctors and the professional socialisation among medical students. METHODS: Secondary analysis of published studies among health care professionals. RESULTS: Almost all published papers convey the conflict of being a physician in some aspect, but they fail to explore issues related to professional success, protective factors, resources and conflict management modes. CONCLUSION: In addition to exploration of risk factors, future studies should promote medical identity, should call attention to existing positive examples and should provide hints to cope with challenging issues in order to achieve a successful medical career. PMID- 23103744 TI - [Correlations between malignant breast cancer and breast screening in Hungary, based on the National Health Insurance Fund database]. AB - The effectiveness of different screening programs can be characterized by the number of subjects taking part in the programs and the number of persons found positive. In this study the outcome of mammographic screening in Hungary was examined using data obtained from the National Health Insurance Fund database. The author posed questions whether breast cancer patients participated in screening before the discovery of their disease and, if yes, what was its outcome. It was also examined whether the disease had been discovered by screening or not. The results indicated that the willingness of subjects with breast cancer to participate in breast cancer screening was 38.8%, and this percentage did not significantly differ from that found in the average population. Because the percentage of screened subjects was less than the originally planned 60%, more efforts to increase willingness for mammographic screening should be invested. Data analysis also points out that providers do not always report correct ICD codes to health insurance authorities. PMID- 23103745 TI - [History of the endemic cretinism in Csallokoz, Hungary]. PMID- 23103748 TI - Synthesis, copolymerization and peptide-modification of carboxylic acid functionalized 3,4-ethylenedioxythiophene (EDOTacid) for neural electrode interfaces. AB - BACKGROUND: Conjugated polymers have been developed as effective materials for interfacing prosthetic device electrodes with neural tissue. Recent focus has been on the development of conjugated polymers that contain biological components in order to improve the tissue response upon implantation of these electrodes. METHODS: Carboxylic acid-functionalized 3,4-ethylenedioxythiophene (EDOTacid) monomer was synthesized in order to covalently bind peptides to the surface of conjugated polymer films. EDOTacid was copolymerized with EDOT monomer to form stable, electrically conductive copolymer films referred to as PEDOT-PEDOTacid. The peptide GGGGRGDS was bound to PEDOT-PEDOTacid to create peptide functionalized PEDOT films. RESULTS: The PEDOT-PEDOTacid-peptide films increased the adhesion of primary rat motor neurons between 3 and 9 times higher than controls, thus demonstrating that the peptide maintained its biological activity. CONCLUSIONS: The EDOT-acid monomer can be used to create functionalized PEDOT PEDOTacid copolymer films that can have controlled bioactivity. GENERAL SIGNIFICANCE: PEDOT-PEDOTacid-peptide films have the potential to control the behavior of neurons and vastly improve the performance of implanted electrodes. This article is part of a Special Issue entitled Organic Bioelectronics-Novel Applications in Biomedicine. PMID- 23103749 TI - Medial arch supports do not significantly alter the knee adduction moment in people with knee osteoarthritis. AB - OBJECTIVE: This study aimed to evaluate the immediate effects of medial arch supports on indices of medial knee joint load (the peak external knee adduction moment (KAM) and knee adduction angular (KAA) impulse) and knee pain during walking in people with medial knee osteoarthritis (OA). DESIGN: Twenty-one people with medial compartment OA underwent gait analysis in standardised athletic shoes wearing (1) no medial arch supports and (2) prefabricated medial arch supports, in random order. Outcomes were the first and second peaks in the external KAM, the KAA impulse and severity of knee pain during testing. Outcomes were compared across conditions using paired t tests (gait data) and Wilcoxon Signed Ranks test (pain data). RESULTS: There were no significant changes in either first or second peak KAM, or in the KAA impulse, with the addition of medial arch supports (all P > 0.05). Considerable individual variation in response to the arch supports was observed across participants. There was no immediate change in knee pain during walking when medial arch supports were worn (P = 0.56). CONCLUSIONS: This study showed no mean change in any of the measured indices of medial knee load with medial arch supports. No immediate changes in knee pain were evident. PMID- 23103750 TI - Rapid manufacturing of low-noise membranes for nanopore sensors by trans-chip illumination lithography. AB - In recent years, the concept of nanopore sensing has matured from a proof-of principle method to a widespread, versatile technique for the study of biomolecular properties and interactions. While traditional nanopore devices based on a nanopore in a single layer membrane supported on a silicon chip can be rapidly fabricated using standard microfabrication methods, chips with additional insulating layers beyond the membrane region can provide significantly lower noise levels, but at the expense of requiring more costly and time-consuming fabrication steps. Here we present a novel fabrication protocol that overcomes this issue by enabling rapid and reproducible manufacturing of low-noise membranes for nanopore experiments. The fabrication protocol, termed trans-chip illumination lithography, is based on illuminating a membrane-containing wafer from its backside such that a photoresist (applied on the wafer's top side) is exposed exclusively in the membrane regions. Trans-chip illumination lithography permits the local modification of membrane regions and hence the fabrication of nanopore chips containing locally patterned insulating layers. This is achieved while maintaining a well-defined area containing a single thin membrane for nanopore drilling. The trans-chip illumination lithography method achieves this without relying on separate masks, thereby eliminating time-consuming alignment steps as well as the need for a mask aligner. Using the presented approach, we demonstrate rapid and reproducible fabrication of nanopore chips that contain small (12 MUm * 12 MUm) free-standing silicon nitride membranes surrounded by insulating layers. The electrical noise characteristics of these nanopore chips are shown to be superior to those of simpler designs without insulating layers and comparable in quality to more complex designs that are more challenging to fabricate. PMID- 23103752 TI - Is menopause a harbinger of physical disability? PMID- 23103751 TI - Mood and the aging ovary. PMID- 23103753 TI - Revisiting the prevention of bone loss at menopause. PMID- 23103755 TI - Phosphorylation and nitration of tyrosine residues affect functional properties of Synaptophysin and Dynamin I, two proteins involved in exo-endocytosis of synaptic vesicles. AB - Phosphorylation and nitration of protein tyrosine residues are thought to play a role in signaling pathways at the nerve terminal and to affect functional properties of proteins involved in the synaptic vesicle (SV) exo-endocytotic cycle. We previously demonstrated that the tyrosine residues in the C-terminal domain of the SV protein Synaptophysin (SYP) are targets of peroxynitrite (PN). Here, we have characterized the association between SYP and c-src tyrosine kinase demonstrating that phosphorylation of Tyr(273) in the C-terminal domain of SYP is crucial in mediating SYP binding to and activation of c-src. SYP forms a complex with Dynamin I (DynI), a GTPase required for SV endocytosis, which may be regulated by tyrosine phosphorylation of SYP. We here report that, in rat brain synaptosomes treated with PN, the formation of SYP/DynI complex was impaired. Noteworthy, we found that DynI was also modified by PN. DynI tyrosine phosphorylation was down-regulated in a dose-dependent manner, while DynI tyrosine nitration increased. Using mass spectrometry analysis, we identified Tyr(354) as one nitration site in DynI. In addition, we tested DynI self-assembly and GTPase activity, which are enhanced by c-src-dependent tyrosine phosphorylation of DynI, and found that both were inhibited by PN. Our results suggest that the site-specific tyrosine residue modifications may modulate the association properties of SV proteins and serve as a regulator of DynI function via control of self-assembly, thus influencing the physiology of the exo endocytotic cycle. PMID- 23103754 TI - Effects of bazedoxifene acetate with and without conjugated equine estrogens on the breast of postmenopausal monkeys. AB - OBJECTIVE: Concerns about increased breast cancer risk with estrogen and progestin therapy have led to an increased interest in progestin alternatives. The main objective of this study was to determine if bazedoxifene acetate (BZA), a new selective estrogen receptor modulator, will antagonize the proliferative and transcriptional effects of conjugated equine estrogens (CEE) in the breast. METHODS: As part of a 20-month preclinical trial, 95 ovariectomized cynomolgus macaques (Macaca fascicularis) were randomized to receive no treatment or treatment with BZA (20 mg/d), CEE (0.45 mg/d), or BZA and CEE in combination (women's daily equivalent doses). The data presented here include breast effects after 6 months of treatment. Endpoints included histomorphometry, histopathological evaluations, gene microarray assays, polymerase chain reaction quantification of specific estrogen receptor alpha (ER-alpha) activity markers, and immunohistochemical detection of sex steroid receptors, and the proliferation marker Ki67. RESULTS: BZA + CEE and BZA resulted in significantly less total epithelial density, lobular enlargement, and Ki67 immunolabeling in the terminal ducts compared with CEE alone (P < 0.05 for all). The addition of BZA to CEE antagonized the expression of ER-alpha-regulated genes such as GREB1 and TFF1 (P < 0.01 for both), whereas BZA alone had minimal effects on ER-alpha-mediated transcriptional activity. BZA and BZA + CEE did not significantly up-regulate genes related to cell cycle progression and proliferation. BZA with and without CEE also resulted in less lobular and terminal duct ER-alpha immunolabeling compared with control and CEE (P < 0.0001 for all). CONCLUSIONS: These findings demonstrate that BZA given at a clinically relevant dose is an estrogen antagonist in the breast, supporting the idea that CEE + BZA may provide a lower breast cancer risk profile compared with traditional estrogen + progestin therapies. PMID- 23103756 TI - Gene function hypotheses for the Campylobacter jejuni glycome generated by a logic-based approach. AB - Increasingly, experimental data on biological systems are obtained from several sources and computational approaches are required to integrate this information and derive models for the function of the system. Here, we demonstrate the power of a logic-based machine learning approach to propose hypotheses for gene function integrating information from two diverse experimental approaches. Specifically, we use inductive logic programming that automatically proposes hypotheses explaining the empirical data with respect to logically encoded background knowledge. We study the capsular polysaccharide biosynthetic pathway of the major human gastrointestinal pathogen Campylobacter jejuni. We consider several key steps in the formation of capsular polysaccharide consisting of 15 genes of which 8 have assigned function, and we explore the extent to which functions can be hypothesised for the remaining 7. Two sources of experimental data provide the information for learning-the results of knockout experiments on the genes involved in capsule formation and the absence/presence of capsule genes in a multitude of strains of different serotypes. The machine learning uses the pathway structure as background knowledge. We propose assignments of specific genes to five previously unassigned reaction steps. For four of these steps, there was an unambiguous optimal assignment of gene to reaction, and to the fifth, there were three candidate genes. Several of these assignments were consistent with additional experimental results. We therefore show that the logic based methodology provides a robust strategy to integrate results from different experimental approaches and propose hypotheses for the behaviour of a biological system. PMID- 23103747 TI - Mammalian P4-ATPases and ABC transporters and their role in phospholipid transport. AB - Transport of phospholipids across cell membranes plays a key role in a wide variety of biological processes. These include membrane biosynthesis, generation and maintenance of membrane asymmetry, cell and organelle shape determination, phagocytosis, vesicle trafficking, blood coagulation, lipid homeostasis, regulation of membrane protein function, apoptosis, etc. P(4)-ATPases and ATP binding cassette (ABC) transporters are the two principal classes of membrane proteins that actively transport phospholipids across cellular membranes. P(4) ATPases utilize the energy from ATP hydrolysis to flip aminophospholipids from the exocytoplasmic (extracellular/lumen) to the cytoplasmic leaflet of cell membranes generating membrane lipid asymmetry and lipid imbalance which can induce membrane curvature. Many ABC transporters play crucial roles in lipid homeostasis by actively transporting phospholipids from the cytoplasmic to the exocytoplasmic leaflet of cell membranes or exporting phospholipids to protein acceptors or micelles. Recent studies indicate that some ABC proteins can also transport phospholipids in the opposite direction. The importance of P(4)-ATPases and ABC transporters is evident from the findings that mutations in many of these transporters are responsible for severe human genetic diseases linked to defective phospholipid transport. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID- 23103757 TI - Intraluminal migration of a surgical drain. Report of a very rare complication and literature review. AB - INTRODUCTION: Gastric or intestinal foreign bodies may cause heterogeneous symptoms ranging from asymptomatic conditions to chronic pain and, in some cases, occlusion and/or perforation. There are sporadic reports of intraluminal migration of medical devices. Most commonly they are sponges, hernia meshes, gastrotomy tubes, while surgical drains are very rarely reported. METHODS: A 79 year-old female who consulted our department in May 2009 for abdominal pain and constipation. Her symptomatology started in 2006 some months after an anterior resection for sigmoid diverticulitis associated to obstructed incisional hernia. The symptoms had begun a few months after the operation and were progressively increased month by month. An abdominal CT- scan showed the presence of an intra peritoneal foreign body and at laparotomy a drain fragment was found inside a small bowel loop and pulled out through a small enterotomy. RESULTS: Post operative course was regular and the patient was discharged at 7th day. DISCUSSION: The observation of this case and a literature review led us to analyze the origin and the clinical problems of this very rare complication. Incidence, symptomatology, diagnosis and treatment were analysed. CONCLUSIONS: The intraluminal migration of a surgical drain is very rare. The diagnosis is easy by abdominal plan radiogram or CT-scan, but it is casually achieved, because, as it almost always occurs in case of intra-peritoneal foreign bodies, the clinical suspicion is focused on other conditions that most frequently cause abdominal symptoms. When a foreign body is found in intraluminal position and its endoscopic removal is not feasible, then surgery is mandatory and resolutive. PMID- 23103758 TI - Reperfusion therapies reduce ischemic mitral regurgitation following inferoposterior ST-segment elevation myocardial infarction. AB - BACKGROUND: The presence of ischemic mitral regurgitation (IMR) after ST-segment elevation myocardial infarction (STEMI) portends a poorer prognosis. The possible influence of reperfusion therapy in restoring mitral valve competence in inferoposterior STEMI has not been well elucidated. METHODS AND RESULTS: We studied 423 consecutive patients with a first inferoposterior STEMI and determined the presence of IMR in patients treated with reperfusion therapy versus medical therapy. A primary percutaneous coronary intervention (PCI) was performed in 186 patients; 74 patients underwent thrombolysis, 63 patients had rescue PCI whereas 54 patients were treated medically. The mean time interval between STEMI presentation and echocardiography was 14 +/- 27 days. Patients receiving reperfusion therapy had less moderate or severe IMR (2.5 vs. 11.1%, P=0.001). The presence of IMR between the primary PCI and the thrombolytic groups was similar (52.2 vs. 60.8%, P=NS). Left ventricular ejection fraction (47.7 +/- 10.3 vs. 53.1 +/- 11.4%, P<0.001) and infarct size (mean CK-MB) (271 +/- 168 vs. 222 +/- 151 U/l, P<0.001) were significantly worse in patients with IMR. Dominance of the coronary artery system, involvement of the right or the left coronary arteries, and the presence of triple-vessel disease did not correlate with the presence of IMR. After adjustment for age and left ventricular ejection fraction, there was a trend toward poorer survival and recurrent admission for heart failure at 1 year in patients with IMR (hazard ratio=2.4, 95% confidence interval 0.91-6.2, P=0.08). CONCLUSION: Both thrombolytic therapy and primary PCI were associated with decreased incidences of IMR following inferoposterior STEMI. PMID- 23103759 TI - Soil acidification occurs under ambient conditions but is retarded by repeated drought: results of a field-scale climate manipulation experiment. AB - Acid atmospheric emissions within Europe and North America have decreased strongly since 1985 and most recent acidification studies have focused on the changes occurring within ecosystems as a result of this decreased deposition. This current study documents a soil acidification trend under ambient N deposition conditions over a 13 year period, suggesting that acidification continues to be a process of concern at this Calluna vulgaris dominated heathland with an acidic sandy soil. The annual manipulation of climatic conditions on this heathland simulated the predicted summer rainfall reduction (drought) and resulted in a long term retardation of the soil acidification trend. The pH of the soil solution significantly decreased over the course of the trial for both treatments, however, in the final 2 years the decline continued only in the Control treatment. This retardation is primarily associated with the reduction in rainfall leading to lower drainage rates, reduced loss of cations and therefore reduced lowering of the soil acid neutralizing capacity (ANC). However, a change in the underlying mechanisms also indicated that N transformations became less important in the Drought treatment. This change corresponded to an increase in groundcover of an air-pollution tolerant moss species and it is hypothesized that this increasing moss cover filtered an increasing quantity of deposited N, thus reducing the N available for transformation. A soil acidification lag time is expected to increase between the two treatments due to the cumulative disparity in cation retention and rates of proton formation. To the authors' knowledge, this is the first study in which such acidification trends have been demonstrated in a field-scale climate manipulation experiment. PMID- 23103760 TI - MiniSipper: a new in situ water sampler for high-resolution, long-duration acid mine drainage monitoring. AB - Abandoned hard-rock mines can be a significant source of acid mine drainage (AMD) and toxic metal pollution to watersheds. In Colorado, USA, abandoned mines are often located in remote, high elevation areas that are snowbound for 7-8 months of the year. The difficulty in accessing these remote sites, especially during winter, creates challenging water sampling problems and major hydrologic and toxic metal loading events are often under sampled. Currently available automated water samplers are not well suited for sampling remote snowbound areas so the U.S. Geological Survey (USGS) has developed a new water sampler, the MiniSipper, to provide long-duration, high-resolution water sampling in remote areas. The MiniSipper is a small, portable sampler that uses gas bubbles to separate up to 250 five milliliter acidified samples in a long tubing coil. The MiniSipper operates for over 8 months unattended in water under snow/ice, reduces field work costs, and greatly increases sampling resolution, especially during inaccessible times. MiniSippers were deployed in support of an U.S. Environmental Protection Agency (EPA) project evaluating acid mine drainage inputs from the Pennsylvania Mine to the Snake River watershed in Summit County, CO, USA. MiniSipper metal results agree within 10% of EPA-USGS hand collected grab sample results. Our high resolution results reveal very strong correlations (R(2)>0.9) between potentially toxic metals (Cd, Cu, and Zn) and specific conductivity at the Pennsylvania Mine site. The large number of samples collected by the MiniSipper over the entire water year provides a detailed look at the effects of major hydrologic events such as snowmelt runoff and rainstorms on metal loading from the Pennsylvania Mine. MiniSipper results will help guide EPA sampling strategy and remediation efforts in the Snake River watershed. PMID- 23103761 TI - Intransitivity and coexistence in four species cyclic games. AB - Intransitivity is a property of connected, oriented graphs representing species interactions that may drive their coexistence even in the presence of competition, the standard example being the three species Rock-Paper-Scissors game. We consider here a generalization with four species, the minimum number of species allowing other interactions beyond the single loop (one predator, one prey). We show that, contrary to the mean field prediction, on a square lattice the model presents a transition, as the parameter setting the rate at which one species invades another changes, from a coexistence to a state in which one species gets extinct. Such a dependence on the invasion rates shows that the interaction graph structure alone is not enough to predict the outcome of such models. In addition, different invasion rates permit to tune the level of transitiveness, indicating that for the coexistence of all species to persist, there must be a minimum amount of intransitivity. PMID- 23103762 TI - Evidence of disruption in estrogen-associated signaling in the liver transcriptome of in-migrating sockeye salmon of British Columbia, Canada. AB - The health of sockeye (Oncorhynchus nerka) salmon stocks is of increasing concern; reflecting both a sentinel of human-impacted aquatic environments and as a key fishery for British Columbia, Canada. The spawning migration of Pacific sockeye salmon represents a critical life stage where significant demands are made on animal biology and important BC fisheries are linked to this migration in the Skeena and Fraser River watersheds. These watersheds present very different environments; the former being sparsely populated with little industrial impact, while the latter flows through highly-populated areas. The present study used quantitative real-time PCR analysis of adult sockeye salmon from four 2008 stocks [Fulton River and Pinkut Creek (Skeena) and Weaver Creek and Harrison River (Fraser)] to evaluate ten hepatic gene transcripts associated with reproduction, stress, energy metabolism, and exposure to environmental contaminants. Dynamic changes in mRNA abundance were observed in Fulton River stock animals from the Skeena River mouth to the spawning ground which reflect the physiological demands of in-river migration and reproductive maturation. Inter-stock comparisons of migrants at spawning grounds demonstrated a marked difference in the sex-specific gene hepatic gene expression profiles. Our original hypothesis was that a greater diversity in mRNA profiles is associated with watersheds with higher human impact. However, our observations contradict this posit. Skeena males and females displayed poor definition in their molecular profiles between sexes while the Fraser River fish had very distinctive sex differences that were consistent with the previous year's migration. The genetic sex distribution and ratio of milt versus roe production did not differ between the Skeena and Fraser River spawning site fish. However, a significant percentage of Skeena animals displayed marked discordance of these characteristics with gender-specific hepatic mRNA profiles implying that an alteration in estrogen-mediated signaling has occurred. Continued geospatial and longitudinal assessments will help determine to what extent the dynamic molecular biology of late life-stage sockeye salmon reflects natural variation or modulation by anthropogenic causative agents. PMID- 23103763 TI - Reciprocal expression of MRTF-A and myocardin is crucial for pathological vascular remodelling in mice. AB - Myocardin-related transcription factor (MRTF)-A is a Rho signalling-responsive co activator of serum response factor (SRF). Here, we show that induction of MRTF-A expression is key to pathological vascular remodelling. MRTF-A expression was significantly higher in the wire-injured femoral arteries of wild-type mice and in the atherosclerotic aortic tissues of ApoE(-/-) mice than in healthy control tissues, whereas myocardin expression was significantly lower. Both neointima formation in wire-injured femoral arteries in MRTF-A knockout (Mkl1(-/-)) mice and atherosclerotic lesions in Mkl1(-/-); ApoE(-/-) mice were significantly attenuated. Expression of vinculin, matrix metallopeptidase 9 (MMP-9) and integrin beta1, three SRF targets and key regulators of cell migration, in injured arteries was significantly weaker in Mkl1(-/-) mice than in wild-type mice. In cultured vascular smooth muscle cells (VSMCs), knocking down MRTF-A reduced expression of these genes and significantly impaired cell migration. Underlying the increased MRTF-A expression in dedifferentiated VSMCs was the downregulation of microRNA-1. Moreover, the MRTF-A inhibitor CCG1423 significantly reduced neointima formation following wire injury in mice. MRTF-A could thus be a novel therapeutic target for the treatment of vascular diseases. PMID- 23103764 TI - Nucleosome positioning and transcription: fission yeast CHD remodellers make their move. AB - Regularly positioned nucleosomes are a common feature of 5' ends of most eukaryotic genes. A series of three studies, Shim et al (2012) and Pointner et al (2012) in this issue of The EMBO Journal and Hennig et al (2012) in EMBO Reports, now show that in the fission yeast Schizosaccharomyces pombe this intragenic nucleosome positioning mostly requires two ATP-dependent remodellers of the CHD family, Hrp1 and Hrp3. Moreover, they suggest that Hrp1- and Hrp3-dependent nucleosome spacing contributes to the silencing of cryptic antisense transcription. PMID- 23103765 TI - CHD1 remodelers regulate nucleosome spacing in vitro and align nucleosomal arrays over gene coding regions in S. pombe. AB - Nucleosome positioning governs access to eukaryotic genomes. Many genes show a stereotypic organisation at their 5'end: a nucleosome free region just upstream of the transcription start site (TSS) followed by a regular nucleosomal array over the coding region. The determinants for this pattern are unclear, but nucleosome remodelers are likely critical. Here we study the role of remodelers in global nucleosome positioning in S. pombe and the corresponding changes in expression. We find a striking evolutionary shift in remodeler usage between budding and fission yeast. The S. pombe RSC complex does not seem to be involved in nucleosome positioning, despite its prominent role in S. cerevisiae. While S. pombe lacks ISWI-type remodelers, it has two CHD1-type ATPases, Hrp1 and Hrp3. We demonstrate nucleosome spacing activity for Hrp1 and Hrp3 in vitro, and that together they are essential for linking regular genic arrays to most TSSs in vivo. Impaired arrays in the absence of either or both remodelers may lead to increased cryptic antisense transcription, but overall gene expression levels are only mildly affected. PMID- 23103766 TI - Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance. AB - Histone deacetylase 7 (HDAC7) is a T-cell receptor (TCR) signal-dependent regulator of differentiation that is highly expressed in CD4/CD8 double-positive (DP) thymocytes. Here, we examine the effect of blocking TCR-dependent nuclear export of HDAC7 during thymic selection, through expression of a signal-resistant mutant of HDAC7 (HDAC7-DeltaP) in thymocytes. We find that HDAC7-DeltaP transgenic thymocytes exhibit a profound block in negative thymic selection, but can still undergo positive selection, resulting in the escape of autoreactive T cells into the periphery. Gene expression profiling reveals a comprehensive suppression of the negative selection-associated gene expression programme in DP thymocytes, associated with a defect in the activation of MAP kinase pathways by TCR signals. The consequence of this block in vivo is a lethal autoimmune syndrome involving the exocrine pancreas and other abdominal organs. These experiments establish a novel molecular model of autoimmunity and cast new light on the relationship between thymic selection and immune self-tolerance. PMID- 23103767 TI - TNFalpha signals through specialized factories where responsive coding and miRNA genes are transcribed. AB - Tumour necrosis factor alpha (TNFalpha) is a potent cytokine that signals through nuclear factor kappa B (NFkappaB) to activate a subset of human genes. It is usually assumed that this involves RNA polymerases transcribing responsive genes wherever they might be in the nucleus. Using primary human endothelial cells, variants of chromosome conformation capture (including 4C and chromatin interaction analysis with paired-end tag sequencing), and fluorescence in situ hybridization to detect single nascent transcripts, we show that TNFalpha induces responsive genes to congregate in discrete 'NFkappaB factories'. Some factories further specialize in transcribing responsive genes encoding micro-RNAs that target downregulated mRNAs. We expect all signalling pathways to contain this extra leg, where responding genes are transcribed in analogous specialized factories. PMID- 23103768 TI - Long non-coding RNA gadd7 interacts with TDP-43 and regulates Cdk6 mRNA decay. AB - Long non-coding RNAs (lncRNAs) transcribed extensively from the genome have been proposed to be key regulators of diverse biological processes. However, little is known about the role of lncRNAs in regulation of the cell-cycle G1/S checkpoint following DNA damage, a key step in the maintenance of genomic fidelity. Here we show that growth-arrested DNA damage-inducible gene 7 (gadd7), a DNA damage inducible lncRNA, regulates the G1/S checkpoint in response to UV irradiation. Interestingly, UV-induced gadd7 directly binds to TAR DNA-binding protein (TDP 43) and interferes with the interaction between TDP-43 and cyclin-dependent kinase 6 (Cdk6) mRNA, resulting in Cdk6 mRNA degradation. These findings demonstrate a role for gadd7 in controlling cell-cycle progression and define a novel mechanism by which lncRNAs modulate mRNA expression at the post transcriptional level by altering mRNA stability. PMID- 23103770 TI - Potential role of signal transducer and activator of transcription (STAT)3 signaling pathway in inflammation, survival, proliferation and invasion of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, and is also the fourth most common cancer worldwide with around 700,000 new cases each year. Currently, first line chemotherapeutic drugs used for HCC include fluorouracil, cisplatin, doxorubicin, paclitaxel and mitomycin, but most of these are non-selective cytotoxic molecules with significant side effects. Sorafenib is the only approved targeted therapy by the U.S. Food and Drug Administration for HCC treatment, but patients suffer from various kinds of adverse effects, including hypertension. The signal-transducer-and-activator-of-transcription 3 (STAT3) protein, one of the members of STATs transcription factor family, has been implicated in signal transduction by different cytokines, growth factors and oncogenes. In normal cells, STAT3 activation is tightly controlled to prevent dysregulated gene transcription, whereas constitutively activated STAT3 plays an important role in tumorigenesis through the upregulation of genes involved in anti-apoptosis, proliferation and angiogenesis. Thus, pharmacologically safe and effective agents that can block STAT3 activation have the potential both for the prevention and treatment of HCC. In the present review, we discuss the possible role of STAT3 signaling cascade and its interacting partners in the initiation of HCC and also analyze the role of various STAT3 regulated genes in HCC progression, inflammation, survival, invasion and angiogenesis. PMID- 23103769 TI - Effects of oxidative alcohol metabolism on the mitochondrial permeability transition pore and necrosis in a mouse model of alcoholic pancreatitis. AB - BACKGROUND & AIMS: Opening of the mitochondrial permeability transition pore (MPTP) causes loss of the mitochondrial membrane potential (DeltaPsim) and, ultimately, adenosine triphosphate depletion and necrosis. Cells deficient in cyclophilin D (CypD), a component of the MPTP, are resistant to MPTP opening, loss of DeltaPsim, and necrosis. Alcohol abuse is a major risk factor for pancreatitis and is believed to sensitize the pancreas to stressors, by poorly understood mechanisms. We investigated the effects of ethanol on the pancreatic MPTP, the mechanisms of these effects, and their role in pancreatitis. METHODS: We measured DeltaPsim in mouse pancreatic acinar cells incubated with ethanol alone and in combination with physiologic and pathologic concentrations of cholecystokinin-8 (CCK). To examine the role of MPTP, we used ex vivo and in vivo models of pancreatitis, induced in wild-type and CypD(-/-) mice by a combination of ethanol and CCK. RESULTS: Ethanol reduced basal DeltaPsim and converted a transient depolarization, induced by physiologic concentrations of CCK, into a sustained decrease in DeltaPsim, resulting in reduced cellular adenosine triphosphate and increased necrosis. The effects of ethanol and CCK were mediated by MPTP because they were not observed in CypD(-/-) acinar cells. Ethanol and CCK activated MPTP through different mechanisms-ethanol by reducing the ratio of oxidized nicotinamide adenine dinucleotide to reduced nicotinamide adenine dinucleotide, as a result of oxidative metabolism, and CCK by increasing cytosolic Ca(2+). CypD(-/-) mice developed a less-severe form of pancreatitis after administration of ethanol and CCK. CONCLUSIONS: Oxidative metabolism of ethanol sensitizes pancreatic mitochondria to activate MPTP, leading to mitochondrial failure; this makes the pancreas susceptible to necrotizing pancreatitis. PMID- 23103772 TI - Trading public goods stabilizes interspecific mutualism. AB - The existence of cooperation between species raises a fundamental problem for evolutionary theory. Why provide costly services to another species if the feedback of this provision also happens to benefit intra-specific competitors that provide no service? Rewarding cooperators and punishing defectors can help maintain mutualism; this is not possible, however, when one can only respond to the collective action of one's partners, which is likely to be the case in many common symbioses. We show how the theory of public goods can explain the stability of mutualism when discrimination between cooperators and defectors is not possible: if two groups of individuals trade goods that are non-linear, increasing functions of the number of contributions, their mutualistic interaction is maintained by the exchange of these public goods, even when it is not possible to punish defectors, which can persist at relatively high frequencies. This provides a theoretical justification and testable predictions for the evolution of mutualism in the absence of discrimination mechanisms. PMID- 23103771 TI - Economic evaluation of internet-based interventions for harmful alcohol use alongside a pragmatic randomized controlled trial. AB - BACKGROUND: Internet interventions with and without therapist support have been found to be effective treatment options for harmful alcohol users. Internet-based therapy (IT) leads to larger and longer-lasting positive effects than Internet based self-help (IS), but it is also more costly to provide. OBJECTIVE: To evaluate the cost effectiveness and cost utility of Internet-based interventions for harmful use of alcohol through the assessment of the incremental cost effectiveness of IT compared with IS. METHODS: This study was performed in a substance abuse treatment center in Amsterdam, the Netherlands. We collected data over the years 2008-2009. A total of 136 participants were included, 70 (51%) were female, and mean age was 41.5 (SD 9.83) years. Reported alcohol consumption and Alcohol Use Disorders Identification Test (AUDIT) scores indicated harmful drinking behavior at baseline. We collected self-reported outcome data prospectively at baseline and 6 months after randomization. Cost data were extracted from the treatment center's cost records, and sex- and age-specific mean productivity cost data for the Netherlands. RESULTS: The median incremental cost-effectiveness ratio was estimated at ?3683 per additional treatment responder and ?14,710 per quality-adjusted life-year (QALY) gained. At a willingness to pay ?20,000 for 1 additional QALY, IT had a 60% likelihood of being more cost effective than IS. Sensitivity analyses attested to the robustness of the findings. CONCLUSIONS: IT offers better value for money than IS and might therefore be considered as a treatment option, either as first-line treatment in a matched-care approach or as a second-line treatment in the context of a stepped-care approach. TRIAL REGISTRATION: Netherlands Trial Register NTR TC1155; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1155 (Archived by WebCite at http://www.webcitation.org/6AqnV4eTU). PMID- 23103773 TI - Spatial memory deficits and motor coordination facilitation in cGMP-dependent protein kinase type II-deficient mice. AB - Activity-dependent trafficking of AMPA receptors to synapses regulates synaptic strength. Activation of the NMDA receptor induces several second messenger pathways that contribute to receptor trafficking-dependent plasticity, including the NO pathway, which elevates cGMP. In turn, cGMP activates the cGMP-dependent protein kinase type II (cGKII), which phosphorylates the AMPA receptor subunit GluA1 at serine 845, a critical step facilitating synaptic delivery in the mechanism of activity-dependent synaptic potentiation. Since cGKII is expressed in the striatum, amygdala, cerebral cortex, and hippocampus, it has been proposed that mice lacking cGKII may present phenotypic differences compared to their wild type littermates in emotion-dependent tasks, learning and memory, and drug reward salience. Previous studies have shown that cGKII KO mice ingest higher amounts of ethanol as well as exhibit elevated anxiety levels compared to wild-type (WT) littermates. Here, we show that cGKII KO mice are significantly deficient in spatial learning while exhibiting facilitated motor coordination, demonstrating a clear dependence of memory-based tasks on cGKII. We also show diminished GluA1 phosphorylation in the postsynaptic density (PSD) of cGKII KO prefrontal cortex while in hippocampal PSD fractions, phosphorylation was not significantly altered. These data suggest that the role of cGKII may be more robust in particular brain regions, thereby impacting complex behaviors dependent on these regions differently. PMID- 23103775 TI - Comparison of propofol and fentanyl administered at the end of anaesthesia for prevention of emergence agitation after sevoflurane anaesthesia in children. AB - BACKGROUND: Propofol and fentanyl can be administered at the end of sevoflurane anaesthesia to decrease the incidence and severity of emergence agitation (EA), although it has not been determined which agent has superior efficacy. The purpose of this study was to compare the effects of propofol and fentanyl on EA. METHODS: In this prospective, randomized, double-blind study, 222 children, 18-72 months of age, undergoing sevoflurane anaesthesia were randomly assigned to one of the three groups receiving either propofol 1 mg kg(-1) (Group P), fentanyl 1 ug kg(-1) (Group F), or saline (Group S) at the end of anaesthesia. The incidence and severity of EA were evaluated with the paediatric anaesthesia emergence delirium (PAED) scale. Time to recovery and incidence of nausea/vomiting were assessed. RESULTS: The mean PAED score was 4.3 in Group P and 4.9 in Group F (P=0.682), which were lower than 9.0 in Group S (P<0.001). Nausea and vomiting were significantly more frequent in Group F than Groups P and S (adjusted P=0.003 and adjusted P<0.001). Group F had also longer stay in the post-anaesthesia care unit (PACU) than Group S (P<0.001), while Group P did not. However, the differences in PACU stays between the P and F groups were considered clinically insignificant. CONCLUSION: Small doses of propofol or fentanyl at the end of sevoflurane anaesthesia comparably reduced EA. Propofol was better than fentanyl due to a lower incidence of nausea and vomiting. PMID- 23103774 TI - Critical role of NMDA but not opioid receptors in the acquisition of fat conditioned flavor preferences in rats. AB - Animals learn to prefer flavors associated with the intake of dietary fats such as corn oil (CO) solutions. We previously reported that fat-conditioned flavor preferences in rats were relatively unaffected by systemic treatment with dopamine D1 and D2 antagonsits. The present study examined whether systemic opioid (naltrexone, NTX) or NMDA (MK-801) receptor antagonists altered the acquisition and/or expression of CO-CFP. The CFP was produced by training rats to drink one novel flavor (CS+, e.g., cherry) mixed in a 3.5% CO solution and another flavor (CS-, e.g., grape) in a 0.9% CO solution. In expression studies, food-restricted rats drank these solutions in one-bottle sessions (2 h) over 10 d. Subsequent two-bottle tests with the CS+ and CS- flavors mixed in 0.9% CO solutions occurred 0.5h after systemic administration of vehicle (VEH), NTX (0.1 5 mg/kg) or MK-801 (50-200 MUg/kg). Rats displayed a robust CS+ preference following VEH treatment (85-88%) which was significantly though moderately attenuated by NTX (69-70%). The lower doses of MK-801 slightly reduced the CS+ preference; the high dose blocked the CS+ preference (49%) but also markedly reduced overall CS intake. In separate acquisition studies, rats received VEH or NTX (0.1, 0.5, 1mg/kg) or MK-801 (100 MUg/kg) 0.5h prior to 1-bottle training trials with CS+/3.5% CO and CS-/0.9% CO training solutions. Additional Limited VEH groups were trained with intakes limited to that of the NTX and MK-801 groups. Subsequent two-bottle CS+ vs. CS- tests were conducted without injections. Significant and persistent CS+ preferences were observed in VEH (77 84%) and Limited VEH (88%) groups. NTX treatment during training failed to block the acquisition of CO-CFP although the magnitude of the CS+ preference was reduced by 0.5 (70%) and 1.0 (72%) mg/kg doses relative to the Limited VEH treatment (88%). In contrast, MK-801 (100 MUg/kg) treatment during training blocked the acquisition of the CO-CFP. These data suggest a critical role for NMDA, but not opioid receptor signaling in the acquisition of a fat conditioned flavor preferences, and at best limited involvement of NMDA and opioid receptors in the expression of a previously learned preference. PMID- 23103776 TI - Transmission of arterial oxygen partial pressure oscillations to the cerebral microcirculation in a porcine model of acute lung injury caused by cyclic recruitment and derecruitment. AB - BACKGROUND: Cyclic recruitment and derecruitment (R/D) play a key role in the pathomechanism of acute lung injury (ALI) leading to respiration-dependent oscillations of arterial partial pressure of oxygen (Pa(O(2))). These Pa(O(2)) oscillations could also be forwarded to the cerebral microcirculation. METHODS: In 12 pigs, partial pressure of oxygen was measured in the thoracic aorta (Pa(O(2))) and subcortical cerebral tissue (Pbr(O(2))). Cerebral cortical haemoglobin oxygen saturation (Sbr(O(2))), cerebral blood flow (CBF), and peripheral haemoglobin saturation (Sp(O(2))) were assessed by spectroscopy and laser Doppler flowmetry. Measurements at different fractions of inspired oxygen (F(I(O(2)))) were performed at baseline and during cyclic R/D. STATISTICS: frequency domain analysis, the Mann-Whitney test, linear models to test the influence of Pa(O(2)) and systolic arterial pressure (SAP) oscillations on cerebral measurements. RESULTS: Parameters [mean (SD)] remained stable during baseline. Pa(O(2)) oscillations [10.6 (8) kPa, phase(reference)], systemic arterial pressure (SAP) oscillations [20 (9) mm Hg, phase(Pa(O(2))-SAP) -33 (72) degrees ], and Sp(O(2))oscillations [1.9 (1.7)%, phase(Pa(O(2))-Sp(O(2))) 264 (72) degrees ] were detected during lung R/D at 1.0. Pa(O(2)) oscillations decreased [2.7 (3.5) kPa, P=0.0008] and Sp(O(2)) oscillations increased [6.8 (3.9)%, P=0.0014] at F(I(O(2))) 0.3. In the brain, synchronized Pbr(O(2)) oscillations [0.6 (0.4) kPa, phase(Pa(O(2))-Pbr(O(2))) 90 (39) degrees ], Sbr(O(2)) oscillations [4.1 (1.5)%, phase(Pa(O(2))-Sbr(O(2))) 182 (54) degrees ], and CBF oscillations [198 (176) AU, phase(Pa(O(2))-CBF) 201 (63) degrees ] occurred that were dependent on Pa(O(2)) and SAP oscillations. CONCLUSIONS: Pa(O(2)) oscillations caused by cyclic R/D are transmitted to the cerebral microcirculation in a porcine model of ALI. These cyclic oxygen alterations could play a role in the crosstalk of acute lung and brain injury. PMID- 23103777 TI - Pleth variability index is a weak predictor of fluid responsiveness in patients receiving norepinephrine. AB - BACKGROUND: In patients receiving an infusion of norepinephrine, the relationship between the amplitude of the oximeter plethysmographic waveform and stroke volume may be variable and quality of the waveform might be reduced, compared with patients not receiving norepinephrine. We assessed the reliability of the pleth variability index (PVI), an automatic measurement of the respiratory variation of the plethysmographic waveform, for predicting fluid responsiveness in patients receiving norepinephrine infusions. METHODS: We measured the response of cardiac index (transpulmonary thermodilution) to i.v. fluid administration in 42 critically ill patients receiving norepinephrine. Patients with arrhythmias, spontaneous breathing, tidal volume <8 ml kg(-1), and respiratory system compliance <30 ml cm H(2)O(-1) were excluded. Before fluid administration, we recorded the arterial pulse pressure variation (PPV) and pulse contour analysis derived stroke volume variation (SVV, PiCCO2) and PVI (Masimo Radical-7). RESULTS: In seven patients, the plethysmographic signal could not be obtained. Among the 35 remaining patients [mean SAPS II score=77 (sd=17)], i.v. fluid increased cardiac index >=15% in 15 'responders'. A baseline PVI >=16% predicted fluid responsiveness with a sensitivity of 47 (inter-quartile range=21-73)% and a specificity of 90 (68-99)%. The area under the receiver operating characteristic curve was significantly lower for PVI [0.68 (0.09)] than for PPV and SVV [0.93 (0.06) and 0.89 (0.07), respectively]. Considering all pairs of measurements, PVI was correlated with PPV (r(2)=0.27). The fluid-induced changes in PVI and PPV were not significantly correlated. CONCLUSIONS: PVI was less reliable than PPV and SVV for predicting fluid responsiveness in critically ill patients receiving norepinephrine. In addition, PVI could not be measured in a significant proportion of patients. This suggests that PVI is not useful in patients receiving norepinephrine. PMID- 23103778 TI - Relation between mixed venous oxygen saturation and cerebral oxygen saturation measured by absolute and relative near-infrared spectroscopy during off-pump coronary artery bypass grafting. AB - BACKGROUND: We hypothesized that previously reported contradictory results regarding the equivalence of mixed venous (Smv(O(2))) and cerebral (rS(c)O(2)) oxygen saturation might be related to time delay issues and to measurement technology. In order to explore these two factors, we designed a prospective clinical study comparing with relative (INVOS((r))) and absolute (Foresight((r))) rS(c)O(2) measurements. METHODS: Forty-two consenting patients undergoing elective off-pump coronary artery bypass grafting were included. Two INVOS and two Foresight sensors continuously registered rS(c)O(2). Smv(O(2)) was measured continuously via a pulmonary artery catheter. Data were assessed by within- and between-group comparisons and correlation analysis. RESULTS: A similar time delay of 19 (4) and 18 (4) s was found for compared with rS(c)O(2) measurements by Foresight and INVOS, respectively, during haemodynamic changes. After adjusting for this time delay, the correlation between Smv(O(2)) and rS(c)O(2) increased from r=0.25 to 0.75 (P<0.001) for Foresight, and from r=0.28 to 0.73 (P<0.001) for INVOS. Comparison of Foresight and INVOS revealed significant differences in absolute rS(c)O(2) values (range 58-89% for Foresight and 28-95% for INVOS). Changes in rS(c)O(2) in response to acute haemodynamic alterations were significantly more pronounced with INVOS compared with Foresight (P<0.001). CONCLUSIONS: Considering the important time delay with Smv(O(2)), rS(c)O(2) seems to reflect more appropriately acute haemodynamic alterations. This might suggest its use as a valid alternative to invasive monitoring of tissue oxygen saturation. Relative and absolute rS(c)O(2) measurements demonstrated significant differences in measured rS(c)O(2) values and in the magnitude of rS(c)O(2) changes during haemodynamic alterations. PMID- 23103779 TI - Editorial: Molecular Endocrinology articles in the spotlight for November 2012. PMID- 23103781 TI - Stable lithium-ion cathodes from nanocomposites of VO2 nanowires and CNTs. AB - A VO(2)(B) nanowire/CNT nanocomposite was fabricated with a stable lithium storage performance resulting in an interpenetrating porous network. This material demonstrated an enhanced Li-ion storage capacity with a significantly improved cycling stability. The capacity of the composite faded by only 6% after 100 cycles at 1 C, suggesting great promise for better lithium-ion cathodes. These results demonstrated that the CNT's network could effectively harvest the charges during the reaction. Moreover, these further prove a general approach to achieve high-capacity electrode materials with long-term cycling stability using intertwined network structures. PMID- 23103782 TI - The effects of wedged footwear on lower limb frontal plane biomechanics during running. AB - OBJECTIVE: Patellofemoral pain syndrome (PFPS), the most common running injury, has been associated with increased internal knee abduction angular impulses (KAAI). Wedged footwear can reduce these impulses during walking, but their effects during running are not well understood. The purpose of this study was to identify the effects of wedged footwear on KAAIs and describe the mechanism by which wedged footwear alters KAAIs during running. DESIGN: Controlled laboratory study. SETTING: Motion analysis laboratory. PARTICIPANTS: Nine healthy male subjects. INTERVENTIONS: Participants ran at a speed of 4 m/s with 7 different footwear conditions (3-, 6-, and 9-mm lateral wedges; 3-, 6-, and 9-mm medial wedges; neutral). MAIN OUTCOME MEASURES: Knee abduction angular impulses and 8 predictor variables were measured and compared by 1-way repeated measures analysis of variance (alpha = 0.05) with Bonferroni-adjusted 2-tailed paired t tests for post hoc analysis (alpha = 0.002). Correlation (alpha = 0.05) was used to determine the relationship between the mediolateral center of pressure to ankle joint center (COP-AJC) lever arm length and KAAIs. RESULTS: Laterally wedged conditions produced significantly lower KAAIs (P = 0.001) than medial wedge conditions. Peak knee abduction moments decreased (P = 0.001), whereas ankle inversion moments (P = 0.041) and the COP-AJC lever arms increased (P < 0.001) as wedges progressed from medial to lateral. KAAIs were negatively correlated with COP-AJC lever arm length (r = -0.50, P < 0.001). CONCLUSIONS: KAAIs are reduced with laterally wedged footwear because of lateral shifts in the center of pressure beneath the foot, which then increases ankle inversion moments and decreases peak knee abduction moments. Laterally wedged footwear may therefore offer greater relief to runners with PFPS than medially wedged footwear by reducing KAAIs. PMID- 23103783 TI - Induced anterior knee pain immediately reduces involuntary and voluntary quadriceps activation. AB - OBJECTIVE: To examine the immediate effects of experimentally induced anterior knee pain (AKP) on involuntary and voluntary quadriceps strength and activation. DESIGN: Crossover 3 * 3 randomized controlled laboratory study with repeated measures. SETTING: Human Performance Research Center, Brigham Young University. PARTICIPANTS: Thirteen neurologically sound volunteers (age, 21.9 +/- 3.2 years). INTERVENTIONS: Subjects underwent 3 different conditions (pain, sham, and control). To induce AKP and sham condition, 5% sodium chloride and 0.9% sodium chloride (total volume of 1.0 mL for each condition), respectively, were injected into the infrapatellar fat pad on the dominant leg. No injection was performed for the control condition. MAIN OUTCOME MEASURES: The vastus medialis peak Hoffmann reflex normalized by the peak motor response (H:M ratio) was used to measure involuntary quadriceps activation. Quadriceps central activation ratio (CAR) using maximal isometric knee extension torque (N.m) was calculated to assess voluntary quadriceps activation. The visual analog scale was used to measure pain perception. RESULTS: Our pain model increased perceived pain immediately after the 5% hypertonic saline injection and pain lasted for 12 minutes on average (F40,743 = 16.85, P < 0.001). During the pain condition, subjects showed a 12% decrease in H:M ratio (F2,59 = 8.64, P < 0.001), a 34% decrease in maximal isometric knee extension torque (F2,59 = 5.89, P < 0.01), and a 5% decrease in CAR (F2,59 = 3.83, P = 0.03). CONCLUSIONS: Our data showed that joint pain may be an independent factor to alter function of the muscles surrounding the painful joint. Both involuntary and voluntary inhibitory pathways may play a role in an immediate reduction of muscle activation. PMID- 23103784 TI - The perception of injury risk and safety in triathlon competition: an exploratory focus group study. AB - OBJECTIVE: To explore stakeholder perceptions of triathlon competition safety and injury risk. DESIGN: Qualitative focus group study. SETTING: Triathlon stakeholders from Melbourne, Australia. PARTICIPANTS: Competition organizers, coaches, and competitors of various skill levels, age, gender, and experience (n = 18). INTERVENTIONS: Focus groups were conducted, recorded, and transcribed for analysis. MAIN OUTCOME MEASURES: Key themes were identified using content analysis. RESULTS: The perceived risk of serious injury was highest for cycling. Running was most commonly linked to minor injuries. Physical and environmental factors, including course turning points, funneling of competitors into narrow sections, and the weather, were perceived as contributing to injury. Experience, skill level, feelings of vulnerability, personal awareness, club culture, and gender issues were perceived as the competitor-related factors potentially contributing to injury. The cycling mount/dismount area, cycling, and swim legs were the race sections perceived as the riskiest for competitors. Competition organizers were considered to generally have the competitors' best interest as a priority. Triathlons were acknowledged as risky activities and individual competitors accepted this risk. CONCLUSIONS: This study has highlighted the main risks and concerns perceived by triathlon competitors, coaches, and competition organizers, which will help identify potential, context-relevant intervention strategies to reduce injury risk. PMID- 23103785 TI - Tears of pectoralis major in steer wrestlers: a novel repair technique using the EndoButton. AB - This case report describes the unique surgical management of a pectoralis major tendon rupture in a professional steer wrestler using intramedullary EndoButton fixation. PMID- 23103786 TI - Targeted molecular imaging of vascular inflammation in cardiovascular disease using nano- and micro-sized agents. AB - Molecular imaging is emerging as a key experimental tool for the identification of inflammatory cellular and molecular processes involved in the development of cardiovascular disease. This review summarises current molecular imaging approaches for the detection of vascular inflammation using a range of nano- and micro-sized contrast agents. We highlight strategies for detection of cell adhesion molecules, which are key regulators of endothelial activation and leukocyte recruitment in atherogenesis and ischaemia-reperfusion in jury. In particular, we address the properties of targeted microparticles of iron oxide (MPIO) for MRI detection of endothelial cell-specific activation of adhesion molecules in experimental models of atherosclerosis, acute vascular inflammation and ischaemia-reperfusion injury, which are otherwise undetectable by conventional imaging modalities. The ability of targeted MPIO to detect endothelial activation could enable early subclinical disease detection and development of novel therapeutic strategies. We discuss opportunities for further development and potential translation of targeted MPIO for clinical imaging of cardiovascular disease. PMID- 23103787 TI - Dual antiplatelet treatment in patients candidates for abdominal surgery. AB - With the increasing diffusion of percutaneous interventions (PCI), surgeons are often faced with the problem of operating on patients under dual antiplatelet treatment. Replacing dual antiplatelet regiment with low molecular weight heparin may expose to the abrupt thrombosis of coronary stent and massive myocardial infarction. The purpose of this study was to test the hypothesis that abdominal operations can be safely performed under dual antiplatelet treatment. Eleven patients underwent 5 colectomies, 3 nefrectomies, 2 gastrectomies and 1 hysterectomy under aspirin and plavix without any significant perioperative hemorrhage. These preliminary results show that abdominal operations can be safely performed under dual antiplatelet regimen. KEY WORDS: Abdominal surgery, Dual antiplatelet treatment. PMID- 23103788 TI - Role of glucocorticoid in developmental programming: evidence from zebrafish. AB - The vertebrate corticosteroid stress response is highly conserved and a key function is to restore homeostasis by mobilizing and reallocating energy stores. This process is primarily initiated by activation of the hypothalamus-pituitary adrenal axis, leading to the release of corticosteroids into the circulation. In teleosts, cortisol is the primary corticosteroid that is released into the circulation in response to stress. This steroid activates corticosteroid receptors that are ligand-bound transcription factors, modulating downstream gene expression in target tissues. Recent research in zebrafish (Danio rerio) has identified novel roles for cortisol in early developmental processes, including organogenesis and mesoderm formation. As cortisol biosynthesis commences only around the time of hatch in teleosts, the early developmental events are orchestrated by cortisol that is maternally deposited prior to fertilization. This review will highlight the molecular events leading to the development of the corticosteroid stress axis, and the possible role of cortisol in the developmental programming of stress axis function. Use of zebrafish as a model may lead to significant insights into the conserved role of glucocorticoids during early development with potential implications in biomedical research, including fetal stress syndromes in humans. PMID- 23103790 TI - Feasibility of a wiki as a participatory tool for patients in clinical guideline development. AB - BACKGROUND: Patient participation is essential in developing high-quality guidelines but faces practical challenges. Evidence on timing, methods, evaluations, and outcomes of methodologies for patient participation in guideline development is lacking. OBJECTIVE: To assess the feasibility of a wiki as a participatory tool for patients in the development of a guideline on infertility determined by (1) use of the wiki (number of page views and visitors), (2) benefits of the wiki (ie, number, content, and eligibility of the recommendations to be integrated into the guideline), and (3) patients' facilitators of and barriers to adoption, and the potential challenges to be overcome in improving this wiki. METHODS: To obtain initial content for the wiki, we conducted in-depth interviews (n = 12) with infertile patients. Transcripts from the interviews were translated into 90 draft recommendations. These were presented on a wiki. Over 7 months, infertile patients were invited through advertisements or mailings to formulate new or modify existing recommendations. After modifying the recommendations, we asked patients to select their top 5 or top 3 recommendations for each of 5 sections on fertility care. Finally, the guideline development group assessed the eligibility of the final set of recommendations within the scope of the guideline. We used a multimethod evaluation strategy to assess the feasibility of the wiki as a participatory tool for patients in guideline development. RESULTS: The wiki attracted 298 unique visitors, yielding 289 recommendations. We assessed the 21 recommendations ranked as the top 5 or top 3 for their eligibility for being integrated into the clinical practice guideline. The evaluation identified some challenges needed to be met to improve the wiki tool, concerning its ease of use, website content and layout, and characteristics of the wiki tool. CONCLUSIONS: The wiki is a promising and feasible participatory tool for patients in guideline development. A modified version of this tool including new modalities (eg, automatically limiting the number and length of recommendations, using a fixed format for recommendations, including a motivation page, and adding a continuous prioritization system) should be developed and evaluated in a patient-centered design. PMID- 23103791 TI - Double gene therapy with granulocyte colony-stimulating factor and vascular endothelial growth factor acts synergistically to improve nerve regeneration and functional outcome after sciatic nerve injury in mice. AB - Peripheral-nerve injuries are a common clinical problem and often result in long term functional deficits. Reconstruction of peripheral-nerve defects is currently undertaken with nerve autografts. However, there is a limited availability of nerves that can be sacrificed and the functional recovery is never 100% satisfactory. We have previously shown that gene therapy with vascular endothelial growth factor (VEGF) significantly improved nerve regeneration, neuronal survival, and muscle activity. Our hypothesis is that granulocyte colony stimulating factor (G-CSF) synergizes with VEGF to improve the functional outcome after sciatic nerve transection. The left sciatic nerves and the adjacent muscle groups of adult mice were exposed, and 50 or 100 MUg (in 50 MUl PBS) of VEGF and/or G-CSF genes was injected locally, just below the sciatic nerve, and transferred by electroporation. The sciatic nerves were transected and placed in an empty polycaprolactone (PCL) nerve guide, leaving a 3-mm gap to challenge nerve regeneration. After 6 weeks, the mice were perfused and the sciatic nerve, the dorsal root ganglion (DRG), the spinal cord and the gastrocnemius muscle were processed for light and transmission electron microscopy. Treated animals showed significant improvement in functional and histological analyses compared with the control group. However, the best results were obtained with the G-CSF+VEGF treated animals: quantitative analysis of regenerated nerves showed a significant increase in the number of myelinated fibers and blood vessels, and the number of neurons in the DRG and motoneurons in the spinal cord was significantly higher. Motor function also showed that functional recovery occurred earlier in animals receiving G-CSF+VEGF-treatment. The gastrocnemius muscle showed an increase in weight and in the levels of creatine phosphokinase, suggesting an improvement of reinnervation and muscle activity. These results suggest that these two factors acted synergistically and optimized the nerve repair potential, improving regeneration after a transection lesion. PMID- 23103789 TI - 1 Hz rTMS of the left posterior parietal cortex (PPC) modifies sensorimotor timing. AB - In order to investigate the relevance of the left posterior parietal cortex (PPC) for precise sensorimotor timing we applied 1 Hz repetitive transcranial magnetic stimulation (rTMS) over left PPC, right PPC and visual cortex of healthy participants for 10 min, respectively. The impact on sensorimotor timing of the right hand was assessed using a synchronization task that required subjects to synchronize their right index finger taps with respect to constant auditory, visual or auditory-visual pacing. Our results reveal reduced negative tap-to pacer asynchronies following rTMS of the left PPC in all pacing conditions. This effect lasted for about 5 min after cessation of rTMS. Right PPC and visual cortex stimulation did not yield any significant behavioural effects. Since suppression of left PPC modified right-hand synchronization accuracy independent of the pacing signal's modality, the present data support the significance of left PPC for anticipatory motor control over a primary role in multisensory integration. The present data suggest that 1 Hz rTMS might interrupt a matching process of anticipated and real sensorimotor feedback within PPC. Alternatively, downregulation of left PPC activity may affect M1 excitability via functional connections leading to a delay in motor output and, thus, smaller tap-to-pacer asynchronies. PMID- 23103793 TI - Differential firing pattern and response to lighting conditions of rat intergeniculate leaflet neurons projecting to suprachiasmatic nucleus or contralateral intergeniculate leaflet. AB - The intergeniculate leaflet (IGL) of the lateral geniculate body in the rat is a population of GABAergic neurons that can be divided into two, anatomically and neurochemically distinct populations. One population comprises neuropeptide-Y (NPY)-positive neurons that form the geniculohypothalamic tract innervating the suprachiasmatic nuclei (SCN) and the other population comprises enkephalin positive (ENK) neurons giving rise to the geniculo-geniculate tract innervating the contralateral IGL (cIGL). Previous electrophysiological studies have observed various patterns of firing and different responses to changes in lighting conditions of IGL neurons in vitro and in vivo. The aim of the present study was to determine if these distinct properties could be ascribed to differentially projecting IGL neurons. Neuron activity was recorded extracellularly in the IGL of anaesthetised rats under different lighting conditions (i.e. light/dark). Antidromic activation was used to identify recorded cells as projecting to the SCN or the contralateral IGL. All IGL neurons identified as projecting to the contralateral IGL displayed infra-slow oscillatory activity (ISO; i.e. slow rhythmic bursts of action potentials). ISO of these neurons was sustained in the light and was diminished in the darkness. In contrast, all IGL neurons identified as projecting to the SCN displayed a low level of firing in the light and a majority of these cells increased firing in the darkness. All IGL neurons projecting to the SCN were characterised by an irregular pattern of firing in the light and dark. These data are the first to demonstrate that differentially projecting rat intergeniculate leaflet neurons are characterised by distinct firing patterns and opposite responses to light and dark conditions. PMID- 23103792 TI - Noradrenergic innervation of pyramidal cells in the rat basolateral amygdala. AB - The basolateral nuclear complex of the amygdala (BLC) receives dense noradrenergic/norepinephrine (NE) inputs from the locus coeruleus that play a key role in modulating emotional memory consolidation. Knowledge of the extent of synapse formation by NE inputs to the BLC, as well as the cell types innervated, would contribute to an understanding of how NE modulates the activity of the BLC. To gain a better understanding of NE circuits in the BLC, dual-label immunohistochemistry was used at the light and electron microscopic levels in the present study to analyze NE axons and their innervation of pyramidal cells in the anterior subdivision of the basolateral amygdalar nucleus (BLa). NE axons and BLa pyramidal cells were labeled using antibodies to the norepinephrine transporter (NET) and Ca(2+)/calmodulin-dependent protein kinase (CaMK), respectively. Dual localization studies using antibodies to NET and dopamine-beta-hydroxylase (DBH) revealed that virtually all NE axons and varicosities expressed both proteins. The BLa exhibited a medium density of NET+ fibers. Ultrastructural analysis of serial section reconstructions of NET+ axons revealed that only about half of NET+ terminals formed synapses. The main postsynaptic targets were small-caliber CAMK+ dendritic shafts and spines of pyramidal cells. A smaller number of NET+ terminals formed synapses with unlabeled cell bodies and dendrites. These findings indicate that the distal dendritic domain of BLa pyramidal cells is the major target of NE terminals in the BLa, and the relatively low synaptic incidence suggests that diffusion from non-synaptic terminals may be important for noradrenergic modulation of the BLa. PMID- 23103794 TI - The incretin analogue D-Ala2GIP reduces plaque load, astrogliosis and oxidative stress in an APP/PS1 mouse model of Alzheimer's disease. AB - Type 2 diabetes mellitus has been identified as a risk factor for Alzheimer's disease (AD). Insulin is a neuroprotective growth factor, and an impairment of insulin signalling has been found in AD brains. Glucose-dependent insulinotropic polypeptide (GIP), an incretin hormone, normalises insulin signalling and also acts as a neuroprotective growth factor. GIP plays an important role in memory formation, synaptic plasticity and cell proliferation. We have shown previously that the long-lasting incretin hormone analogue D-Ala(2)GIP protects memory formation and synaptic plasticity, reduces plaques, normalises the proliferation of stem cells, reduces the activation of microglia, and prevents the loss of synapses in the cortex of the APPswe/PS1deltaE9 mouse model of Alzheimer's disease. D-Ala(2)GIP was injected for 35 days at 25 nmol/kg i.p. once daily in APP/PS1 male mice and wild-type (WT) littermates aged 6, 12 and 19 months. In a follow-up study, we analysed plaque load, the activation of astrocytes as a means of chronic inflammation in the brain, and oxidative stress in the brains of these mice (8-oxoguanine levels). D-Ala(2)GIP reduced the amyloid plaque load in 12- and 19-month-old mice, and the inflammation response as shown in the reduction of activated astrocytes in 12- and 19-month old APP/PS1 mice. Chronic oxidative stress in the brain was reduced in 12- and 19-month-old mice as shown in the reduction of 8-oxoguanine levels in the cortex of D-Ala(2)GIP-injected APP/PS1 mice. The results demonstrate that D-Ala(2)GIP has neuroprotective properties on key markers found in Alzheimer's disease. This finding shows that novel GIP analogues have the potential to be developed as novel therapeutics for Alzheimer's disease. PMID- 23103795 TI - Neuroprotective effect of naringenin is mediated through suppression of NF-kappaB signaling pathway in experimental stroke. AB - Oxidative stress and inflammation play an integral role in the pathogenesis of cerebral ischemia that leads to a cascade of events culminating in the death of neurons and their supporting structures. The signaling pathways that link these events are not fully understood. Recent studies have demonstrated a close link between the nuclear factor-kappaB (NF-kappaB) signaling pathway and cerebral ischemia/reperfusion (I/R)-induced inflammation. Flavonoids have been suggested to exert human health benefits by anti-oxidant and anti-inflammatory mechanisms. In this study we undertook a pharmacological approach to investigate the ability of naringenin, a potent flavonoid, to prevent oxidative stress and NF-kappaB mediated inflammatory brain damage in the rat model of focal cerebral I/R injury. To test this hypothesis, male Wistar rats were pretreated with naringenin once daily for 21 days and then subjected to 1h of middle cerebral artery occlusion followed by 23 h of reperfusion. Naringenin treatment successfully upregulates the antioxidant status, decreases the infarct size and lowers the levels of myeloperoxidase, nitric oxide and cytokines, besides functional recovery returned close to the baseline. Moreover, immunohistochemical and Western blot analyses clearly demonstrated that naringenin treatment limits glial activation and downregulates the NF-kappaB expression level and their target genes. These results show, prophylactic treatment with naringenin improved functional outcomes and abrogated the ischemic brain injury by suppressing NF-kappaB-mediated neuroinflammation. The present study suggests that naringenin may be used as a potential neuroprotectant in patients at high risk of ischemic stroke. PMID- 23103796 TI - Pre- and post-synaptic switches of GABA actions associated with Cl- homeostatic changes are induced in the spinal nucleus of the trigeminal nerve in a rat model of trigeminal neuropathic pain. AB - Although trigeminal neuropathic pain is one of the most common chronic pain syndromes, the etiology is still unknown. Here, a rat model was generated using chronic constrictive injury (CCI) with ligation of the infraorbital nerve to test the hypothesis that collapse of chloride homeostasis in trigeminal neurons causes impairment of gamma-aminobutyric acid-ergic (GABAergic) inhibition and induces trigeminal allodynia. Rats showed a reduction and increase in pain threshold and pain response scores, respectively, to mechanical stimulation, 1 and 3weeks after CCI. In situ hybridization and immunohistochemical analysis showed that inward directed Na(+), K(+)-2Cl(-) cotransporter (NKCC1) mRNA and protein were upregulated in the small-sized and large-sized primary neurons in the injured side of the trigeminal ganglion and in the peripherin-positive terminal, respectively, for the first 2weeks, while outward-directed K(+)-Cl(-) cotransporter (KCC2) mRNA and protein were downregulated in secondary relay neurons on the injured side of the spinal trigeminal nucleus caudalis (Sp5C). Optical imaging of evoked synaptic responses using a voltage-sensitive dye revealed that pre- and post-synaptic GABA actions were disinhibited and excitatory in the injured side, respectively, but inhibited in the sham-operated side of the Sp5C. This downregulation of KCC2 in the Sp5C may result in an excitatory switch by impairing postsynaptic GABA inhibition. GABA-mediated presynaptic disinhibition was attenuated by bumetanide, suggesting that NKCC1 upregulation in primary neurons may facilitate pain transmission by presynaptic GABAergic depolarization. Such Cl(-) homeostatic disruption resulting in perturbation of the inhibitory system possibly increases pain transmission, which may underlie the pathophysiology of trigeminal neuropathic pain. PMID- 23103797 TI - Fundamental interstrain differences in cortical activity between Wistar and Sprague-Dawley rats during global ischemia. AB - Four-vessel occlusion (4VO), a frequently used model of global cerebral ischemia in rats, results in a dysfunction in wide brain areas, including the cerebral cortex and hippocampus. However, there are pronounced differences in response to global ischemia between the laboratory rat strains used in these studies. In the present work, the immediate acute effects of 4VO-induced global ischemia on the spontaneous electrocorticogram (ECoG) signals were analyzed in Wistar and Sprague Dawley rats. The ECoG was isoelectric during the 10 min of global cerebral ischemia in Wistar rats and the first burst (FB) was seen 10-13 min after the start of reperfusion. In Sprague-Dawley rats, the FB was detected immediately after the start of 4VO or a few seconds later. The burst suppression ratio (BSR) in Wistar rats decreased to 45% in 5 min after FB, and after 25 min it was approximately 40%. In Sprague-Dawley rats, the BSR was 55% immediately after the FB and it decreased steeply to reach 0% by 10 min. There was also a significant difference between the two strains in the frequency composition of the ECoG pattern. The power spectral densities of the two strains differed virtually throughout the post-ischemic state. The histological results (Evans Blue, Cresyl Violet and Fluoro Jade C stainings) supplemented the electrophysiological data: the neuronal damage in the CA1 pyramids in Wistar rats was severe, whereas in the Sprague-Dawley animals it was only partial. These observations clearly demonstrate that the use of different rat strains (e.g. Wistar vs. Sprague Dawley) can be a source of considerable variability in the results of acute experiments on global ischemia and it is important that the laboratory rats used in such experiments should be carefully chosen. PMID- 23103798 TI - Role of posterior tibial nerve stimulation in the treatment of refractory monosymptomatic nocturnal enuresis: a pilot study. AB - PURPOSE: We evaluated the early clinical and urodynamic results of posterior tibial nerve stimulation in patients with refractory monosymptomatic nocturnal enuresis. MATERIALS AND METHODS: We randomly assigned 28 patients with refractory monosymptomatic nocturnal enuresis to 2 equal groups. Group 1 received a weekly session of posterior tibial nerve stimulation for 12 weeks and group 2 was the placebo group. Evaluation was performed in each group at baseline and after posterior tibial nerve stimulation to compare clinical and urodynamic findings. Another clinical assessment was done 3 months after the first followup. RESULTS: The 2 groups were comparable in baseline clinical and urodynamic data. Overall, 13 patients (46.4%) had detrusor overactivity and 14 (50%) had decreased bladder capacity. After treatment 11 group 1 patients (78.6%) had a partial or full response to posterior tibial nerve stimulation but only 2 (14.3%) in group 2 had a partial response (p = 0.002). Also, the average number of wet nights in group 1 was significantly lower than at baseline (p = 0.002). All urodynamic parameters significantly improved in group 1. In contrast, the number of wet nights and urodynamic parameters did not change significantly in group 2. At 3-month followup the number of patients with a partial or full response in group 1 had decreased from 11 (78.6%) to 6 (42.9%). No change was evident in group 2. CONCLUSIONS: Posterior tibial nerve stimulation can be a viable treatment option in some patients with refractory monosymptomatic nocturnal enuresis. However, deterioration in some responders with time suggests the need for maintenance protocols. PMID- 23103799 TI - Re: editorial comment on LHRH antagonist cetrorelix reduces prostate size and gene expression of proinflammatory cytokines and growth factors in a rat model of benign prostatic hyperplasia (Prostate 2011; 71: 736-747). PMID- 23103800 TI - Development and initial validation of a scoring system to diagnose testicular torsion in children. AB - PURPOSE: Testicular torsion is a surgical emergency requiring prompt intervention. Although clinical diagnosis is recommended, scrotal ultrasound is frequently ordered, delaying treatment. We created a scoring system to diagnose testicular torsion, decreasing the indication for ultrasound. MATERIALS AND METHODS: We prospectively evaluated 338 patients with acute scrotum, of whom 51 had testicular torsion. Physical examination was performed by a urologist, and all patients underwent scrotal ultrasound. Univariate analysis and logistic regression were performed, and a scoring system for risk stratification of torsion was created. Retrospective validation was performed with 2 independent data sets. RESULTS: The scoring system consisted of testicular swelling (2 points), hard testicle (2), absent cremasteric reflex (1), nausea/vomiting (1) and high riding testis (1). Cutoffs for low and high risk were 2 and 5 points, respectively. Ultrasound would be indicated only for the intermediate risk group. In the prospective data set 69% of patients had low, 19% intermediate and 11.5% high risk. Negative and positive predictive values were 100% for cutoffs of 2 and 5, respectively (specificity 81%, sensitivity 76%). Retrospective validation in 1 data set showed 66% of patients at low, 16% intermediate and 17% high risk. Negative and positive predictive values for cutoffs of 2 and 5 were 100% (specificity 97%, sensitivity 54%). The second retrospective data set included only torsion cases, none of which was misdiagnosed by the scoring system. CONCLUSIONS: This scoring system can potentially diagnose or rule out testicular torsion in 80% of cases, with high positive and negative predictive values for selected cutoffs. Ultrasound orders would be decreased to 20% of acute scrotum cases. Prospective validation of this scoring system is necessary. PMID- 23103801 TI - Impact of obesity on urinary storage symptoms: results from the FINNO study. AB - PURPOSE: Urinary storage symptoms are the most common and most bothersome urinary symptoms. Many studies on the relation between body weight and urinary symptoms have focused on urinary incontinence in women. We evaluated the association of obesity with urinary storage symptoms in a population based study of men and women age 18 to 79 years old. MATERIALS AND METHODS: Questionnaires were mailed to 6,000 adults randomly identified from the Finnish Population Register. Self reported height and weight were used to calculate body mass index. Urinary frequency, nocturia, urgency, stress urinary incontinence and urgency urinary incontinence were assessed using validated instruments. Multivariate logistic regression analyses (adjusted for age, comorbidity and medications, and sociodemographic, lifestyle and reproductive factors) were performed to evaluate associations between body mass index and each symptom. RESULTS: Of the 6,000 individuals approached 3,727 participated (62.4% response, 53.7% women). In men and women obesity was associated with nocturia (adjusted OR 2.0, 95% CI 1.2-3.3 for men; OR 2.4, 95% CI 1.5-3.8 for women) but not with urgency (adjusted OR 1.2, 95% CI 0.7-2.3 for men; OR 1.2, 95% CI 0.7-2.1 for women). In men obesity was also associated with urinary frequency (OR 2.0, 95% CI 1.0-3.9), and in women it was associated with stress urinary incontinence (OR 1.9, 95% CI 1.2-3.0) and urgency urinary incontinence (OR 3.0, 95% CI 1.2-7.4). However, the number of men with stress urinary incontinence or urgency urinary incontinence was insufficient for precise analyses. CONCLUSIONS: This study extends previous research by providing symptom specific associations between obesity and urinary storage symptoms in a population based sample of men and women. Obesity impacts individual urinary storage symptoms differently and these associations may be influenced by gender. PMID- 23103803 TI - Potential for airway smooth muscle as therapeutic target is reflected in the breadth of expertise of next generation scientists. PMID- 23103802 TI - Prediction of cancer specific survival after radical nephroureterectomy for upper tract urothelial carcinoma: development of an optimized postoperative nomogram using decision curve analysis. AB - PURPOSE: We conceived and proposed a unique and optimized nomogram to predict cancer specific survival after radical nephroureterectomy in patients with upper tract urothelial carcinoma by merging the 2 largest multicenter data sets reported in this population. MATERIALS AND METHODS: The international and the French national collaborative groups on upper tract urothelial carcinoma pooled data on 3,387 patients treated with radical nephroureterectomy for whom full data for nomogram development were available. The merged study population was randomly split into the development cohort (2,371) and the external validation cohort (1,016). Cox regressions were used for univariable and multivariable analyses, and to build different models. The ultimate reduced nomogram was assessed using Harrell's concordance index (c-index) and decision curve analysis. RESULTS: Of the 2,371 patients in the nomogram development cohort 510 (21.5%) died of upper tract urothelial carcinoma during followup. The actuarial cancer specific survival probability at 5 years was 73.7% (95% CI 71.9-75.6). Decision curve analysis revealed that the use of the best model was associated with benefit gains relative to the prediction of cancer specific survival. The optimized nomogram included only 5 variables associated with cancer specific survival on multivariable analysis, those of age (p = 0.001), T stage (p <0.001), N stage (p = 0.001), architecture (p = 0.02) and lymphovascular invasion (p = 0.001). The discriminative accuracy of the nomogram was 0.8 (95% CI 0.77-0.86). CONCLUSIONS: Using standard pathological features obtained from the largest data set of upper tract urothelial carcinomas worldwide, we devised and validated an accurate and ultimate nomogram, superior to any single clinical variable, for predicting cancer specific survival after radical nephroureterectomy. PMID- 23103805 TI - Quantification of the surface stress in microcantilever biosensors: revisiting Stoney's equation. AB - Microcantilever biosensors in the static operation mode translate molecular recognition into a surface stress signal. Surface stress is derived from the nanomechanical cantilever bending by applying Stoney's equation, derived more than 100 years ago. This equation ignores the clamping effect on the cantilever deformation, which induces significant errors in the quantification of the biosensing response. This leads to discrepancies in the surface stress induced by biomolecular interactions in measurements with cantilevers with different sizes and geometries. So far, more accurate solutions have been precluded by the formidable complexity of the theoretical problem that involves solving the two dimensional biharmonic equation. In this paper, we present an accurate and simple analytical expression to quantify the response of microcantilever biosensors. The equation exhibits an excellent agreement with finite element simulations and DNA immobilization experiments on gold-coated microcantilevers. PMID- 23103806 TI - The hygiene hypothesis in allergy and asthma: an update. AB - PURPOSE OF REVIEW: It has been hypothesized that increased cleanliness, reduced family size, and subsequent decreased microbial exposure could explain the increases in global asthma prevalence. This review considers the recent evidence for and against the 'hygiene hypothesis'. RECENT FINDINGS: Recent evidence does not provide unequivocal support for the hygiene hypothesis: the hygiene hypothesis specifically relates to atopic asthma, but some of the protective effects (e.g. farm exposures) appear to apply to both atopic and nonatopic asthma; asthma prevalence has begun to decline in some western countries, but there is little evidence that they have become less clean; Latin American countries with high infection rates have high asthma prevalence and the hygiene hypothesis relates to early-life exposures, but exposures throughout life may be important. SUMMARY: There is a considerable body of evidence which warrants scepticism about the hygiene hypothesis. However, these anomalies contradict the 'narrow' version of it in which microbial pressure early in life protects against atopic asthma by suppressing T-helper 2 immune responses. It is possible that a more general version of the hygiene hypothesis is still valid, but the aetiologic mechanisms involved are currently unclear. PMID- 23103807 TI - [Osteoimmunology-overview]. AB - The immune and skeletal systems are closely related through a number of shared regulatory molecules including cytokines. Studies on bone destruction associated rheumatoid arthritis (RA) as well as identification of the various bone phenotypes found in immune-compromised genetically modified mice have highlighted the importance of the interplay between the two systems, and promoted the new interdisciplinary field of "osteoimmunology" . Accumulating evidence has indicated that bone destruction associated with RA is caused by the enhanced activity of osteoclasts, resulting from the activation of a unique helper T cell subset, "Th17 cells" . The osteoimmunological insight is of growing importance in clinical applications. Furthermore, recent studies has suggested the relationship between bone cells and hematopoietic stem cells in bone marrow. Various cell types in bone marrow are expected to control bone homeostasis, calcium metabolism and hematopoiesis by mutually affecting each other. Osteoimmunology becomes the viewpoint indispensable for not only bone and mineral research but also immunological research. PMID- 23103808 TI - [Regulation of osteoclast development by immunoglobulin-like receptors]. AB - Immunoglobulin-like receptors (IgLR) , expressed in a wide range of cells in immune system, provide a positive and negative regulation of immune responses. Activation signals initiated by activating IgLR associating with ITAM-containing adapter proteins DAP12 and FcRgamma are indispensable for the development of osteoclasts. On the other hand, ITIM signals induced by inhibitory IgLR regulate osteoclast development and activation. Thus, ITAM and ITIM play important roles in the maintenance of bone homeostasis. PMID- 23103809 TI - [Bone and marrow niches for hematopoiesis]. AB - Hematopoietic stem cells (HSCs) and their progeny are thought to be regulated by special microenvironments, termed niches in the bone marrow during homeostasis. However, the identity and function of these hematopoietic niches remains unclear. It has been reported that HSCs are in contact with osteoblasts lining the bone surface and osteoblasts act as niches for HSCs (endosteal niche) ; however, other studies suggest that few HSCs reside in the endosteal niche. In contrast, most HSCs are shown to be in contact with endothelial cells (vascular niches) and/or primitive mesenchymal cells, including CXCL12-abundant reticular (CAR) cells or Nestin-expressing cells, which have ability to differentiate into adipocytes as well as osteoblasts. Recent in vivo studies revealed that CAR cells acted as niches for hematopoietic stem and progenitor cells (HSPCs) and that endothelial cells and Nestin-expressing cells acted as niches for HSCs. In addition, marrow nonmyelinating schwann cells might be involved in the maintenance of HSCs. Here we review candidate niches for HSCs and hematopoiesis in the marrow. PMID- 23103810 TI - [Regulation of bone metabolism by Eph-ephrin family members]. AB - Eph receptors and ephrin ligands mediate cell-cell communication during development of various tissues including the nervous system, vasculature, and skeletal system. During bone remodeling in adult mice, Eph-ephrin bidirectional signaling regulates differentiation and function of bone cells such as osteoclasts and osteoblasts. When expressed in osteoclasts, ephrinB2 and ephrinA2 act as a coupling stimulator and a coupling inhibitor, respectively, thus enhancing or suppressing osteoblast differentiation. In neurons and endothelial cells, signaling downstream of Eph-ephrin interaction often controls the actin cytoskeleton and dynamic alterations in the topology of lipid bilayers associated with endocytosis, axon guidance and angiogenesis, and mediates the switch from cell attraction to repulsion through activation of multiple effectors such as Rho family small GTPases. Here we review similarities and differences between downstream events of Eph-ephrin signaling in bone cells compared to other cell types. PMID- 23103811 TI - [BMP signaling and bone formation]. AB - Bone morphogenetic proteins (BMPs) bind to two types of membrane receptors. Type II receptor phosphorylates type I receptor, then the phosphorylated type I receptor phosphorylates downstream effectors, such as Smads. Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by progressive heterotopic ossification in skeletal muscle tissue. ALK2, a BMP type I receptor has been mutated in patients with FOP. The mutant ALK2 phosphorylates Smads in the absence of BMPs. In FOP, muscle injury may enhance BMP signaling via Smads to induce acute heterotopic ossification. Inhibitors of the BMP-Smad pathway will be useful to develop novel treatments for FOP. PMID- 23103812 TI - [Mechanisms for bone resorption induced by periodontal pathogens]. AB - Periodontitis is the inflammatory disease caused by periodontal pathogens in dental plaque, and progression of this pathological condition is also considered as a major cause of alveolar bone resorption and subsequent tooth depletion. LPS and several kinds of proteinases produced by periodontal pathogens directly destroy periodontal tissues. On the other hand, host defense systems existing in the periodontal tissues exert essential roles in protection of periodontal tissues from bacterial invasion. Immune system divides broadly into 2 categories, innate immune and acquired immune systems. The former is the first defensive barrier against infectious diseases of pathogens, and phagocytic cells including macrophages and neutrophils are involved in this immune system as innate immune function. The latter is the secondary immune system that antigen-presenting cells such as dendritic cells detect smaller pathogens or intracellular pathogens, and antigens which retain as intact proteins on the surfaces of these cells activate T cells and B cells. However, once inflammation becomes persistent with bacteria, these biological defective mechanisms causes breakdown of host innate and acquired immune systems, and subsequent destruction of periodontal tissues. Here we review the mechanisms by which periodontal pathogens cause bone resorption. PMID- 23103813 TI - [The regulatory mechanisms of bone metabolism by semaphorin]. AB - Bone is continuously remodeled by osteoclastic bone resorption and osteoblastic bone formation to maintain the structural integrity and mineral homeostasis. This process is called "bone remodeling" . These bone cells are regulated by mechanical stimulation and systemic (hormonal) factors in addition to autocrine, paracrine factors and cell-cell interactions. Recently, we reported that two semaphorin molecules Sema4D and Sema3A have a crucial role in the regulation of bone remodeling. Sema4D derived from osteoclasts inhibits osteoblast differentiation not to hamper osteoclastic bone resorption. Sema3A derived from osteoblast lineage cells inhibits osteoclast differentiation and promotes osteoblast differentiation synchronously to increase bone mass. These studies provide a scientific basis for future therapeutic approaches to bone diseases. PMID- 23103814 TI - [Roles of Wnt signaling in bone metabolism]. AB - Wnts, palmitoylated and glycosylated molecules play a central role in the early development of organs and tissues. Wnts bind to receptor complexes of frizzled and low density lipoprotein-related protein 5/6, which in turn, activate thebeta catenin-dependent canonical pathway. Wnt5a, a typical non-canonical ligand, activates thebeta-catenin-independent noncanonical pathways such as the Wnt/Ca pathway and the Wnt/planar cell polarity pathway. Recent studies have established that Wnt-mediated signals are crucial for bone formation and resorption. This review summarizes the current knowledge of the roles of Wnt signaling in bone formation and resorption. PMID- 23103815 TI - [Zinc signaling : a novel regulatory system on bone homeostasis, and immune and allergic responses]. AB - Zinc (Zn) is an essential trace element that is required for proliferation, differentiation, and variety of cellular functions, and unbalanced homeostasis of Zn ion (Zn(2 + )) results in health problems such as abnormal bone formation and immunodeficiency. Recent studies have shed light on important roles of Zn(2 + )as a signaling mediator, called Zn signal. Zn(2 + )homeostasis is regulated through Zn transporters and cation channels. Advances of genetic and molecular approaches have revealed that Zn signal regulates mammalian physiology and pathogenesis. We will address that Zn signal undoubtedly contributes to our health, by highlighting it in bone homeostasis and immune regulation, and discuss that the "Zn signal axis" selectively controls intracellular signal transduction to fine tune cellular functions. PMID- 23103816 TI - [Genomic approach to pathophysiology of rheumatoid arthritis]. AB - Genetic studies identified multiple genes and polymorphisms that increase risk to develop rheumatoid arthritis. Genomic approach is characterized with its integrative style using mathematical and statistical models. Its main targets include (1)combinatorial effect of multiple genetic and environmental factors, (2)heterogeneity of pathological states and its individuality, and (3)their chronological heterogeneity. Genomic approach will clarify pathophysiology of various diseases along with the progresses in molecular biology and other researches on individual molecules. PMID- 23103817 TI - [Inflammatory cytokines in rheumatoid arthritis]. AB - Dysregulation of cytokines, including tumor necrosis factor (TNF) and interleukin 6 (IL-6) , is involved in joint destruction in rheumatoid arthritis (RA) . TNF and IL-6 induce the differentiation and activation of osteoclasts. They also provide the formation of pannus through the synthesis of vascular endothelial growth factor (VEGF) . In addition, they contribute to the production of matrix metalloproteinases which digest collagen and proteoglycan of cartilage and bone. Biologic agents targeting these cytokines have provided beneficial outcomes, such as achievement of clinical remission, protective effects against joint destruction, and improvement in quality of life (QOL) in RA patients. PMID- 23103818 TI - [Progress in the treatment targeting intracellular signaling in the context of osteoimmunology]. AB - The appropriate intracellular signaling pathways are activated via binding of receptors on the cell surface to ligands such as cytokines and cell surface antigens. The tyrosine kinase transduce the first "outside to in" signals to be phosphorylated following receptor binding to its ligand. Among them, members of Janus kinase (Jak) family and Spleen tyrosine kinase (Syk) family are essential for the signaling pathways of various cytokines and are implicated in the pathogenesis of autoimmune inflammatory disease. The development of low molecular weight kinase inhibitors targeting Jak and Syk appears to be successful for the treatment of rheumatoid arthritis, a representative inflammatory disease. These inhibitors also succeed to regulate joint destruction. On the other hand, calcineurin inhibitors such as tacrolimus and vitamin D are also effective for immune regulation as well as bone metabolism through the inhibition of nuclear factors. Taken together, regulation of cellular signals functioning on immunity as well as bone metabolism may have a potential to approach to the treatment of osteo-immune diseases. PMID- 23103819 TI - Effects of discontinuing anti-tumor necrosis factor therapy during pregnancy on the course of inflammatory bowel disease and neonatal exposure. AB - BACKGROUND & AIMS: We assessed the course of inflammatory bowel disease (IBD) among pregnant women who stopped taking anti-tumor necrosis factor (TNF) agents. We also analyzed levels of anti-TNF agents in cord blood samples. METHODS: We followed 31 pregnancies in 28 women with IBD between April 2006 and April 2011 who were treated with anti-TNF agents (18 received infliximab, and 13 received adalimumab) during pregnancy. We used enzyme-linked immunosorbent assays to measure levels of anti-TNF agents in cord blood collected from 18 newborns (12 whose mothers took infliximab, and 6 whose mothers took adalimumab). RESULTS: Among the patients taking infliximab, 12 (71%) discontinued treatment before gestational week 30; all patients remained in remission. All the patients taking adalimumab discontinued treatment before gestational week 30; two patients had relapses of IBD. There were 28 live births, 1 miscarriage among patients taking infliximab (at gestational week 6), and 2 miscarriages among patients taking adalimumab (at weeks 6 and 8); there were no congenital malformations. The mean cord blood level of infliximab was 6.4 +/- 1.6 MUg/mL; it was significantly lower among women who received the drug 10 weeks or less before delivery (2.8 +/- 1.1 MUg/mL) than those who received infliximab closer to delivery (10 +/- 2.3 MUg/mL; P = .02). Adalimumab was detected in 5 samples of cord blood (mean concentration, 1.7 +/- 0.4 MUg/mL); 1 cord blood sample from a woman who discontinued the treatment at gestational week 22 had an undetectable level of the drug. CONCLUSIONS: Discontinuation of anti-TNF therapy appears to be safe for pregnant women with quiescent IBD. However, these drugs are still detected in cord blood samples. PMID- 23103820 TI - Effects of a multimodal management strategy for acute mesenteric ischemia on survival and intestinal failure. AB - BACKGROUND & AIMS: Acute mesenteric ischemia (AMI) is an emergency with a high mortality rate; survivors have high rates of intestinal failure. We performed a prospective study to assess a multidisciplinary and multimodal management approach, focused on intestinal viability. METHODS: In an Intestinal Stroke Center, we developed a multimodal management strategy involving gastroenterologists, vascular and abdominal surgeons, radiologists, and intensive care specialists; it was tested in a pilot study on 18 consecutive patients with occlusive AMI, admitted to a tertiary center from July 2009 to November 2011. Patients with left ischemic colitis, nonocclusive AMI, chronic mesenteric ischemia, and other emergencies were excluded. Patients received specific medical management: revascularization of viable small bowel and/or resection of nonviable small bowel; 12 patients received arterial revascularization. We evaluated the percentages of patients who survived for 30 days or 2 years, the number with permanent intestinal failure, and morbidity. Lengths and rates of intestinal resection were compared with or without revascularization, and in patients with early or late-stage disease. RESULTS: Patients were followed up for a mean of 497 days (range, 7-2085 d); 95% survived for 30 days, 89% survived for 2 years, and 28% had morbidities within 30 days. Intestinal resection was necessary for 7 cases (39%), with mean lengths of intestinal resection of 30 cm and 207 cm, with or without revascularization, respectively (P = .03). Among patients with early or late-stage AMI, rates of resection were 18% and 71%, respectively (P = .049). Patients with early stage disease had shorter lengths of intestinal resection than those with late-stage disease (7 vs 94 cm; P = .02), and spent less time in intensive care (2.5 vs 49.8; P = .02). CONCLUSIONS: A multidisciplinary and multimodal management approach might increase survival of patients with AMI and prevent intestinal failure. PMID- 23103821 TI - Inflammatory bowel disease has a small effect on bone mineral density and risk for osteoporosis. AB - BACKGROUND & AIMS: A high prevalence of osteoporosis has been reported among individuals with inflammatory bowel disease (IBD). We performed a population based analysis to determine whether IBD is itself a risk factor for low bone mineral density (BMD) or whether low BMD results from other factors associated with IBD. METHODS: We identified 1230 subjects with IBD in the Manitoba BMD Database, which contains results of BMD tests performed on all Manitobans since 1997 (n = 45,714). BMD was assessed at the lumbar spine (mean value, L1-L4), hip (total), femoral neck, and trochanter. Multivariate linear and logistic regression analyses were performed to determine the independent effects of IBD, Crohn's disease (CD), or ulcerative colitis (UC) on T score and the presence of osteoporosis (a low T score was equal to or less than -2.5) at any site; we controlled for age, sex, body mass index, hormone replacement therapy, osteoprotective medications, and corticosteroid use. We also performed regression analysis within the IBD population to determine the effect of IBD-specific factors on T score and osteoporosis. RESULTS: IBD was associated with a statistically significant but small effect on T score; IBD did not increase the risk for osteoporosis at any site measured. CD was associated with an increased risk of osteoporosis at the lumbar spine and trochanter, but UC was not associated with an increased risk of osteoporosis or low T score. No IBD-specific variables were associated with increased risk of osteoporosis or low T score. CONCLUSIONS: IBD has a small effect on BMD; CD poses a greater risk than UC. The risk of osteoporosis in patients with IBD appears to be related to other known osteoporosis risk factors. PMID- 23103822 TI - Defining thresholds of antibody levels improves diagnosis of celiac disease. AB - BACKGROUND & AIMS: The European Society for Pediatric Gastroenterology and Nutrition proposed guidelines for the diagnosis of celiac disease, stating that duodenal biopsy is no longer needed if patients have symptoms and levels of immunoglobulin A anti-tissue transglutaminase (IgA anti-tTG) more than 10-fold the cut-off value. We evaluated the accuracy of this guideline in a well characterized population using different commercial assays. METHODS: We analyzed levels of IgA anti-tTG in serum samples from 104 consecutive pediatric and adult patients who were not deficient in IgA and were diagnosed with celiac disease from August 1, 2000, to December 31, 2009. We also analyzed serum samples from 537 consecutive patients without celiac disease (controls), collected from May 1, 2004, to October 12, 2006, who underwent intestinal biopsy analysis. Serum levels of antibodies were quantified using assays from Bio-Rad, INOVA, Genesis, and Thermo Fisher. RESULTS: The likelihood ratio (probability of a specific result in patients divided by the probability of the same result in controls) for celiac disease increased with levels of IgA anti-tTG in all assays. Depending on the assay, the likelihood ratio for levels greater than 10-fold the cut-off value ranged from 111 to 294. The percentage of patients with celiac disease with levels of IgA anti-tTG greater than 10-fold the cut-off value ranged from 41% to 61%, depending on the assay. For levels of anti-tTG greater than 10-fold the cut off value, the post-test probabilities for celiac disease (probability of disease, based on pretest probability and test result) were, depending on the assay, 89%-96% and 53%-75% for pretest probabilities (probability of disease depending on symptoms) of 7% and 1%, respectively. CONCLUSIONS: To diagnose celiac disease based on serologic factors, it might be best to define thresholds for levels of IgA anti-tTG based on a predefined likelihood ratio or post-test probability, instead of a multiple of a cut-off value. Patients with a high pretest probability and levels of anti-tTG greater than 10-fold the cut-off value have a high probability for having celiac disease, aiding clinical decision making. PMID- 23103823 TI - A model to determine absolute risk for esophageal adenocarcinoma. AB - BACKGROUND & AIMS: Esophageal adenocarcinoma (EAC) develops rapidly and has a high mortality rate. We aimed to develop a prediction model to estimate the absolute 5-year risks, based on different profiles of factors, for developing EAC. METHODS: We derived a risk model using epidemiologic data from 364 patients with incident EAC and 1580 population controls. Significant risk factors were fitted into an unconditional multiple logistic regression model. The final model was combined with age- and sex-specific EAC incidence data to estimate absolute 5 year risks for EAC. We performed a 10-fold cross-validation of the data to assess the relative performance of the model. RESULTS: The final risk model included terms for highest level of education, body mass index, smoking status, frequency of gastroesophageal reflux symptoms and/or use of acid-suppressant medications, and frequency of nonsteroidal anti-inflammatory drug use. The population attributable risk for the model was 0.92. A 10-fold cross-validation produced an area under the receiver operating characteristic curve statistic of 0.75 (95% confidence interval, 0.66-0.84), indicating good discrimination. Adding data on alarm symptoms, frequency of symptoms of dysphagia, and unexplained weight loss to the model significantly improved discrimination (area under the receiver operating characteristic curve, 0.85; 95% confidence interval, 0.78-0.91). CONCLUSIONS: Risk models can be used to identify people with a higher than average risk for developing EAC; these individuals might benefit from targeted cancer-prevention strategies. PMID- 23103824 TI - Safety and efficacy of endoscopic mucosal therapy with radiofrequency ablation for patients with neoplastic Barrett's esophagus. AB - BACKGROUND & AIMS: The goal of radiofrequency ablation (RFA) for patients with Barrett's esophagus (BE) is to eliminate dysplasia and metaplasia. The efficacy and safety of RFA for patients with BE and neoplasia are characterized incompletely. METHODS: We performed a retrospective study of 244 patients treated with RFA for BE with dysplasia or intramucosal carcinoma. Efficacy outcomes were complete eradication of intestinal metaplasia (CEIM), complete eradication of dysplasia, total treatments, and RFA sessions. Safety outcomes included death, perforation, stricture, bleeding, and hospitalization. We identified factors associated with incomplete EIM and stricture formation. RESULTS: CEIM was achieved in 80% of patients, and complete eradication of dysplasia was achieved in 87%; disease progressed in 4 patients. A higher percentage of patients with incomplete EIM were female (40%) than those with CEIM (20%; P = .045); patients with incomplete EIM also had a longer segment of BE (5.5 vs 4.0 cm; P = .03), had incomplete healing between treatment sessions (45% vs 15%; P = 0.004), and underwent more treatment sessions (4 vs 3; P = .007). Incomplete healing was associated independently with incomplete EIM. Twenty-three patients (9.4%) had a treatment-related complication during 777 treatment sessions (3.0%), including strictures (8.2%), postprocedural hemorrhages (1.6%), and hospitalizations (1.6%). Patients who developed strictures were more likely to use nonsteroidal anti-inflammatory drugs than those without strictures (70% vs 45%; P = .04), have undergone antireflux surgery (15% vs 3%; P = .04), or had erosive esophagitis (35% vs 12%; P = .01). CONCLUSIONS: RFA is highly effective and safe for treatment of BE with dysplasia or early stage cancer. Strictures were the most common complications. Incomplete healing between treatment sessions was associated with incomplete EIM. Nonsteroidal anti-inflammatory drug use, prior antireflux surgery, and a history of erosive esophagitis predicted stricture formation. PMID- 23103825 TI - Dyspnea and shoulder pain in a patient with hepatocellular carcinoma. PMID- 23103826 TI - Burden of illness in irritable bowel syndrome: looking beyond the patient. PMID- 23103827 TI - Pro-apoptotic effect of anti-beta1-adrenergic receptor antibodies in periodontitis patients. AB - An anti-beta(1)-adrenergic antibody from the sera of periodontitis patients (anti beta(1)-AR IgG) against the second extracellular loop of the human beta(1) adrenoceptor (beta(1)-AR) has been shown to cause rat atria apoptosis. The anti beta(1)-AR IgG binds and activates atria beta(1)-AR, increasing the intracellular calcium concentration, which, in turn, activates caspases-3, -8, and -9. The beta(1)-AR and the post-receptor activation of calcium/calmodulin (CaM) lead to increased inducible nitric oxide synthase (iNOS) activity, with an increase in cyclic GMP (cGMP) accumulation as well as increased JNK phosphorylation and cyclic AMP (cAMP) production. We also observed an apoptotic effect of anti beta(1)-AR IgG, with increased generation of PGE(2). Comparatively, xamoterol, an authentic beta(1)-AR agonist, mimicked the autoantibody effect on rat atria beta(1)-AR apoptosis. Our results suggest that autoantibodies from the sera of periodontitis patients bind and interact with rat atria beta(1)-AR, provoking apoptosis. This implicates a series of modulatory cardiac signaling events that could alter normal heart function and may occur with chronic stimulation of the atria beta(1)-AR, which could lead to heart failure. These results suggest an important link between periodontitis and cardiovascular disease. PMID- 23103828 TI - Expression of trisomic proteins in Down syndrome model systems. AB - Down syndrome (DS) is the most common genetic aberration leading to intellectual disability. DS results from an extra copy of the long arm of human chromosome 21 (HSA21) and the increased expression of trisomic genes due to gene dosage. While expression in DS and DS models has been studied extensively at the RNA level, much less is known about expression of trisomic genes at the protein level. We have used quantitative Western blotting with antibodies to 20 proteins encoded by HSA21 to assess trisomic protein expression in lymphoblastoid cell lines (LCLs) from patients with DS and in brains from two mouse models of DS. These antibodies have recently become available and the 20 proteins largely have not been investigated previously for their potential contributions to the phenotypic features of DS. Twelve proteins had detectable expression in LCLs and three, CCT8, MX1 and PWP2, showed elevated levels in LCLs derived from patients with DS compared with controls. Antibodies against 15 proteins detected bands of appropriate sizes in lysates from mouse brain cortex. Genes for 12 of these proteins are trisomic in the Tc1 mouse model of DS, but only SIM2 and ZNF295 showed elevated expression in Tc1 cortex when compared with controls. Genes for eight of the 15 proteins are trisomic in the Ts65Dn mouse model of DS, but only ZNF294 was over expressed in cortex. Comparison of trisomic gene expression at the protein level with previous reports at the mRNA level showed many inconsistencies. These may be caused by natural inter-individual variability, differences in the age of mice analyzed, or post-transcriptional regulation of gene dosage effects. These antibodies provide resources for further investigation of the molecular basis of intellectual disability in DS. PMID- 23103829 TI - Differentially expressed miRNAs in retinoblastoma. AB - MicroRNAs (miRNAs) are short non-coding RNA transcripts that have the ability to regulate the expression of target genes, and have been shown to influence the development of various tumors. The purpose of our study is to identify aberrantly expressed miRNAs in retinoblastoma for the discovery of potential therapeutic targets for this disease, and to gain a greater understanding of the mechanisms driving retinoblastoma progression. We report 41 differentially expressed miRNAs (p<0.05) in 12 retinoblastomas as compared to three normal human retinae. Of these miRNAs, many are newly identified as being differentially expressed in retinoblastoma. Further, we report the validations of five of the most downregulated miRNAs in primary human retinoblastomas (p<0.05), human retinoblastoma cell lines, and mouse retinoblastoma cell lines. This serves as the largest and most comprehensive retinoblastoma miRNA analysis to date with corresponding clinical and pathological characteristics. This is an essential step in the discovery of miRNAs associated with retinoblastoma progression, and in the identification of potential therapeutic targets for this disease. PMID- 23103830 TI - Identification of one novel causative mutation in exon 4 of WFS1 gene in two Italian siblings with classical DIDMOAD syndrome phenotype. AB - The aim of the present paper is to describe a novel missense mutation (G107R) of WFS1 gene that was unexpectedly detected, in two siblings from Southern Italy, outside exon 8; a very unusual finding which has previously been reported only twice in Italian patients with Wolfram syndrome (WS). Although in Spanish pedigrees' WFS1 mutations are frequently located in exon 4, this finding is very infrequent in other pedigrees, particularly in Italian patients. CONCLUSIONS: a) our report of two siblings with one novel WSF1 mutation (G107R) expands the molecular spectrum of WS; b) this is the 3rd report of Italian patients harbouring one mutation outside exon 8 and the 2nd with one mutation in exon 4; c) on the basis of the present observations, and literature data we can infer that mutation locations outside exon 8 do not seem to be clearly associated with peculiar phenotype expressions of WFS1 gene. PMID- 23103831 TI - VDR TaqI is associated with obesity in the Greek population. AB - The prevalence of obesity has increased dramatically during the last thirty years in western countries with severe complications for health and economy. Obesity is the outcome of the strong interplay between genetic and environmental factors and is therefore widely expected that the discovery of the many genetic factors underlying the heritable risk of obesity will contribute critically to our basic knowledge of the disease etiopathogenesis and the identification of new targets for therapeutic intervention. The aim of the present study was to assess the genetic contribution of known polymorphisms in two genes that are linked to the pathogenetic mechanism of obesity. Analysis of vitamin D receptor (VDR) TaqI (rs731236; T/C) and fat mass and obesity-associated (FTO) (rs9939609; A/T) [corrected] polymorphisms in 82 obesity subjects and 102 controls showed significant association for VDR TaqI 'T' allele and obesity (OR: 2.07; 1.123 3.816; P=0.019), contributing to an elevated BMI of 3kg/m(2) per risk allele. No association was observed for the FTO polymorphism. These results further support a role for VDR as risk factor for obesity and suggest its further validation in larger independent populations as well as highlight a target for functional analysis towards therapeutic intervention in obese individuals. PMID- 23103832 TI - The context of transcription start site regions is crucial for transcription of a plant tRNA(Lys)(UUU) gene group both in vitro and in vivo. AB - Nuclear tRNA genes are transcribed by RNA polymerase III. The A- and B-boxes located within the transcribed regions are essential promoter elements for nuclear tRNA gene transcription. The Arabidopsis genome contains ten annotated genes encoding identical tRNA(Lys)(UUU) molecules, which are scattered on the five chromosomes. In this study, we prepared ten tDNA constructs including each of the tRNA(Lys)(UUU) coding sequences with their individual 5' and 3' flanking sequences, and assayed tRNA expression using an in vitro RNA polymerase III dependent transcription system. Transcription levels differed significantly among the ten genes and two of the tRNA genes were transcribed at a very low level, despite possessing A- and B-boxes identical to those of the other tRNA genes. To examine whether the in vitro results were reproducible in vivo, the 5' flanking sequence of an amber suppressor tRNA gene was then replaced with those of the ten tRNA(Lys) genes. An in vivo experiment based on an amber suppressor tRNA that mediates suppression of a premature amber codon in a beta-glucuronidase (GUS) reporter gene in plant tissues generated nearly identical results to those obtained in vitro. Analysis of mutated versions of the amber suppressor tRNA gene, which contained base substitutions around the transcription start site (TSS), showed that the context around the transcription start sites is a crucial determinant for transcription of plant tRNA(Lys)(UUU) both in vitro and in vivo. The above transcription regulation by context around TSS differed between tRNA genes and other Pol III-dependent genes. PMID- 23103833 TI - Involvement of nitrergic system of CA1in harmane induced learning and memory deficits. AB - Harmane (HA) is a beta-carboline alkaloid derived from the Peganum harmala plant which induces memory impairment. On the other hand some of the investigations showed that beta-carboline alkaloids inhibit NO production. Thus, the aim of the present study was to investigate the role of nitrergic system of the dorsal hippocampus (CA1) in HA-induced amnesia in male adult mice. One-trial step-down passive avoidance and hole-board apparatuses were used for the assessment of memory retrieval and exploratory behaviors respectively. The data indicated that pre-training intraperitoneal (i.p.) administration of HA (12 and 16 mg/kg) decreased memory acquisition. Sole pre-training or pre-testing administration of L-NAME, a nitric oxide synthesis inhibitor (5, 10 and 15 MUg/mice, intra-CA1) did not alter memory retrieval. On the other hand, pre-training (10 and 15 MUg/mice, intra-CA1) and pre-testing (5, 10 MUg/mice, intra-CA1) injections of L-NAME restored HA-induced amnesia (16 mg/kg, i.p.). Furthermore, neither sole pre training nor pre-testing administration of l-arginine, a NO precursor (3, 6 and 9 MUg/mice, intra-CA1), altered memory retrieval. In addition, pre-testing (6 and 9 MUg/mice, intra-CA1), but not pre-training, injection of l-arginine increased HA induced amnesia (16 mg/kg, i.p.). These results suggest that the nitrergic system of CA1 is involved in HA-induced amnesia. PMID- 23103834 TI - Chronic perfusion of angiotensin II causes cognitive dysfunctions and anxiety in mice. AB - High blood pressure is a major risk factor in the onset of cerebrovascular diseases and cognitive impairment. However, mechanisms by which these occur remain unclear and treatments are, therefore, ineffective to prevent cognitive decline related to cardiovascular diseases. Angiotensin II is a peptide involved in the onset and maintenance of hypertension and its effect on cognition was studied acutely but never chronically. Hence, the aim of this study is to evaluate whether chronic hypertensive levels of angiotensin II infusion alter cognitive functions in C57BL6 mice. In this study we used subcutaneous mini-pumps containing a concentration of angiotensin II (1900 ng/kg/min) that induces malignant hypertension or a saline solution for 14 and 21 days. Blood pressure was carefully monitored by a non-invasive tail-cuff method every week throughout the experiment. Spatial memory was assessed using the Morris water maze test and anxiety was measured by the elevated plus maze and the open field tests. The results indicate learning and spatial memory deficit as well as an anxious behavior induced by angiotensin II, in comparison to the vehicle group, starting at the 3rd week of perfusion. The motricity and visual acuity were equivalent in angiotensin II perfused mice compared to their respective control. These results suggest a strong relationship between angiotensin II and the development of cognitive dysfunctions and anxiety along with sustained high blood pressure. PMID- 23103835 TI - Reducing suicidal ideation: cost-effectiveness analysis of a randomized controlled trial of unguided web-based self-help. AB - BACKGROUND: Suicidal ideation is highly prevalent, but often remains untreated. The Internet can be used to provide accessible interventions. OBJECTIVE: To evaluate the cost-effectiveness of an online, unguided, self-help intervention for reducing suicidal ideation. METHODS: A total of 236 adults with mild to moderate suicidal thoughts, defined as scores between 1-26 on the Beck Scale for Suicide Ideation (BSS), were recruited in the general population and randomized to the intervention (n = 116) or to a waitlist, information-only, control group (n = 120). The intervention aimed to decrease the frequency and intensity of suicidal ideation and consisted of 6 modules based on cognitive behavioral techniques. Participants in both groups had unrestricted access to care as usual. Assessments took place at baseline and 6 weeks later (post-test). All questionnaires were self-report and administered via the Internet. Treatment response was defined as a clinically significant decrease in suicidal ideation on the BSS. Total per-participant costs encompassed costs of health service uptake, participants' out-of-pocket expenses, costs stemming from production losses, and intervention costs. These were expressed in Euros (?) for the reference year 2009. RESULTS: At post-test, treatment response was 35.3% and 20.8% in the experimental and control conditions, respectively. The incremental effectiveness was 0.35 - 0.21 = 0.15 (SE 0.06, P = .01). The annualized incremental costs were ?5039 per participant. Therefore, the mean incremental cost-effectiveness ratio (ICER) was estimated to be -?5039/0.15 = -?34,727 after rounding (US -$41,325) for an additional treatment response, indicating annual cost savings per treatment responder. CONCLUSIONS: This is the first trial to indicate that online self-help to reduce suicidal ideation is feasible, effective, and cost saving. Limitations included reliance on self-report and a short timeframe (6 weeks). Therefore, replication with a longer follow-up period is recommended. PMID- 23103836 TI - Glycogenes mediate the invasive properties and chemosensitivity of human hepatocarcinoma cells. AB - Aberrant cell-surface glycosylation patterns are present on tumors and have been linked to tumor progression. This study aimed to identify the alterations of glycogene and N-glycan involved in tumor invasion, tumorigenicity and drug resistance in MHCC97-H and MHCC97-L human hepatocarcinoma cell lines, which have high, low metastatic potential, respectively. Using real-time PCR for quantification of glycogene and FITC-lectin binding for glycan profiling, we found that the expression of glycogenes and glycan profiling were different in MHCC97-H cells, as compared to those in MHCC97-L cells. We silenced the expression levels of glycogenes MGAT3 and MGAT5, which were over-expressed in MHCC97-L and MHCC97-H cells. Knockdown of MGAT3 expression promoted MHCC97-L cells invasion and increased resistance to 5-fluorouracil in vitro. The silencing of MGAT5 in MHCC97-H cells inhibited invasion and increased sensitivity to 5 fluorouracil in vitro. Further analysis of the N-glycan regulation by tunicamycin application or PNGase F treatment in MHCC97-H and MHCC97-L cells showed partial inhibition of N-glycan glycosylation, decreased invasion, tumorigenicity and increased sensitivity to 5-fluorouracil both in vitro and in vivo. These findings suggest that alterations of glycogene and N-glycan in human hepatocarcinoma cells correlate with tumor invasion, tumorigenicity and sensitivity to chemotherapeutic drug, and have significant implications for the development of treatment strategies. PMID- 23103837 TI - Cellular steatosis in ethanol oxidizing-HepG2 cells is partially controlled by the transcription factor, early growth response-1. AB - Recent studies have shown that the transcription factor early growth response-1 (Egr-1) regulates ethanol-induced fatty liver. However, the mechanism(s) through which ethanol oxidation controls Egr-1 is unknown. Here, using recombinant hepatoma (HepG2; VL-17A) cells that metabolize ethanol, we show that alcohol dehydrogenase catalysis of ethanol oxidation and subsequent acetaldehyde production controls Egr-1 expression. Further, the induction of Egr-1 enhances expression of other steatosis-related genes, resulting in triglyceride accumulation. Ethanol exposure increased Egr-1 promoter activity, messenger RNA and Egr-1 protein levels in VL-17A cells. Elevated Egr-1 protein was sustained by an ethanol-induced decrease in proteasome activity, thereby stabilizing the Egr-1 protein. Egr-1 induction depended on ethanol oxidation, as it was prevented when ethanol oxidation was blocked. Ethanol exposure induced Egr-1 and triglyceride accumulation only in alcohol dehydrogenase-expressing cells that produced acetaldehyde. Such induction did not occur in parental, non-metabolizing HepG2 cells or in cells that express only cytochrome P450 2E1. However, direct exposure of HepG2 cells to acetaldehyde induced both Egr-1 protein and triglycerides. Egr 1 over-expression elevated triglyceride levels, which were augmented by ethanol exposure. However, these triglyceride levels did not exceed those in ethanol exposed cells that had normal Egr-1 expression. Conversely, Egr-1 knockdown by siRNA only partially blocked ethanol-induced triglyceride accumulation and was associated not only with lower Egr-1 expression but also attenuation of SREBP1c and TNF-alpha mRNAs. Double knockdown of both Egr-1 and SREBP-1c abolished ethanol-elicited steatosis. Collectively, our findings provide important new insights into the temporal regulation by ethanol oxidation of Egr-1 and cellular steatosis. PMID- 23103838 TI - Associative recognition in mild cognitive impairment: relationship to hippocampal volume and apolipoprotein E. AB - Associative memory involves remembering relations between items of information and is critically dependent on the hippocampus, a brain structure that shows early changes in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease. We examined associative and item memory in aMCI with a focus on the role of medial-temporal lobe regions and genetic risk for Alzheimer's disease. Twenty four individuals with aMCI and 21 demographically matched healthy older adults underwent associative recognition testing, structural brain imaging, and apolipoprotein E (ApoE) genotyping. A significant interaction between group and recognition type indicated poorer associative recognition than item recognition across tasks in the aMCI group relative to controls. Within the aMCI group, associative but not item recognition showed sizable and significant correlations with hippocampal volume (but not with other medial temporal-lobe structures) and with number of ApoE epsilon4 alleles. Correlations were smaller and generally not significant in the control group. Our findings replicate and extend previous studies by showing an associative recognition impairment in aMCI that is not accounted for by an item recognition deficit, is related to structural integrity of the hippocampus, and increases with genetic risk for Alzheimer's disease. PMID- 23103839 TI - They played with the trade: MEG investigation of the processing of past tense verbs and their phonological twins. AB - How regular and irregular verbs are processed remains a matter of debate. Some English-speaking patients with nonfluent aphasia are especially impaired on regular past-tense forms like played, whether the task requires production, comprehension or even the judgement that "play" and "played" sound different. Within a dual-mechanism account of inflectional morphology, these deficits reflect disruption to the rule-based process that adds (or strips) the suffix -ed to regular verb stems; but the fact that the patients are also impaired at detecting the difference between word pairs like "tray" and "trade" (the latter being a phonological but not a morphological twin to "played") suggests an important role for phonological characteristics of the regular past tense. The present study examined MEG brain responses in healthy participants evoked by spoken regular past-tense forms and phonological twin words (plus twin pseudowords and a non-speech control) presented in a passive oddball paradigm. Deviant forms (played, trade, kwade/kwayed) relative to their standards (play, tray, kway) elicited a pronounced neuromagnetic response at approximately 130 ms after the onset of the affix; this response was maximal at sensors over temporal areas of both hemispheres but stronger on the left, especially for played and kwayed. Relative to the same standards, a different set of deviants ending in /t/ -plate, trait and kwate--produced stronger difference responses especially over the right hemisphere. Results are discussed with regard to dual- and single mechanism theories of past tense processing and the need to consider neurobiological evidence in attempts to understand inflectional morphology. PMID- 23103840 TI - Antibacterial activity of ZnO nanoparticles with a modified surface under ambient illumination. AB - In various practical applications, nanomaterials typically have functionalized surfaces. Yet, the studies of toxicity and antibacterial activity of functionalized nanoparticles are scarce. We investigated the effect of surface modifications on antibacterial activity of ZnO under ambient illumination, and we found that nanoparticles coated with different surface modifying reagents could exhibit higher or lower toxicity compared to bare ZnO, depending on the surface modifying reagent used. Different surface modifying reagent molecules resulted in differences in the release of Zn(2+) ions and the production of reactive oxygen species (ROS). However, the antibacterial activity did not correlate with the ROS levels or the Zn(2+) ion release. One of the surface-modified ZnO samples exhibited significantly lower Zn(2+) ion release while at the same time exhibiting improved antibacterial activity. In all cases, damage of the cell wall membranes and/or changes in the membrane permeability have been observed, together with the changes in ATR-FTIR spectra indicating differences in protein conformation. Mechanisms of antibacterial activity are discussed. PMID- 23103842 TI - Robotic anesthesia: not the realm of science fiction any more. AB - PURPOSE OF REVIEW: Robots are present in surgery, to a much lesser extent in the field of anesthesia. The purpose of this review is to show the latest and most important findings in robotic anesthesia. Moreover, this review argues the importance and utility of robots in anesthesia. RECENT FINDINGS: Over the years, many closed-loop systems have been developed; they were able to control only one or two of the three components of anesthesia: hypnosis, analgesia, or muscle relaxation. McSleepy controls all three components of anesthesia, from induction to emergence of anesthesia. Telemedical applications have not only led to remote monitoring but even to remotely controlled anesthesia, such as transcontinental anesthesia. A new closed-loop system for sedation, called Sedasys, could revolutionize the field of nonoperating room sedation. 'Manual robots' are used to help and replace anesthesiologists performing anesthesia procedures. Specific robots for intubation and nerve blocks have been developed and tested in humans. SUMMARY: Robots can improve performance in anesthesia and healthcare. Closed-loop systems are the basis for pharmacological robots. Safe anesthetic care might be delivered through teleanesthesia whenever qualified personnel are not available or need support. Mechanical robots are being developed for anesthesia care. PMID- 23103843 TI - Introduction of evidence-based medicine in undergraduate medical curriculum for development of professional competencies in medical students. AB - PURPOSE OF REVIEW: Current undergraduate medical curricula in most institutions around the globe do not nurture the skills, needed for self-directed lifelong learning in medical graduates, and it needs to be reformed in such a way that the medical graduate who is trained through this reformed curriculum, possesses all the competencies of a self-directed learner. Evidence-based medicine (EBM), a new vision of physician learning which is based on continuous development and assessment of competencies needed for creating self-directed learners is to be strongly advocated for inclusion in the undergraduate medical curriculum. RECENT FINDINGS: Clinical teaching opportunities which are available while treating patients, in outpatient clinic, operating room, and by the bedside need to be utilized to teach EBM. Medical curricula, both undergraduate and postgraduate, should incorporate both EBM and quality improvement training, and these should be taught in a holistic fashion. Evidence-based practice competency was shown to increase, regardless of whether evidence-based practice is delivered to medical students at an undergraduate or postgraduate level.Early introduction of EBM in the undergraduate medical curriculum, in the form of a short course, using various modes of instruction, enhances the competence of critical thinking and also influences change in attitude towards EBM positively in medical students. SUMMARY: Introduction of EBM in undergraduate medical curriculum helps in the development of professional competencies of self-directed learners in medical students. PMID- 23103844 TI - Mobile computing in medical education: opportunities and challenges. AB - PURPOSE OF REVIEW: There is an increasing importance of incorporating mobile computing into the academic medical environment. A growing majority of physicians, residents and medical students currently use mobile devices for education, access to clinical information and to facilitate bedside care. Therefore, it is important to assess the current opportunities and challenges in the use of mobile computing devices in the academic medical environment. RECENT FINDINGS: Current research has found that a majority of physicians, residents and medical students either own or use mobile devices. In addition, studies have shown that these devices are effective as educational tools, resource guides and aids in patient care. Although there are opportunities for medical education, issues of deployment must still be addressed, such as privacy, connectivity, standardization and professionalism. SUMMARY: Understanding the opportunities and challenges of using mobile computing devices in the academic medical environment can help determine the feasibility and benefits of their use for individuals and institutions. PMID- 23103841 TI - The protein tyrosine phosphatase, Shp2, positively contributes to FLT3-ITD induced hematopoietic progenitor hyperproliferation and malignant disease in vivo. AB - Internal tandem duplications (ITDs) in the fms-like tyrosine kinase receptor (FLT3-ITDs) confer a poor prognosis in acute myeloid leukemia (AML). We hypothesized that increased recruitment of the protein tyrosine phosphatase, Shp2, to FLT3-ITDs contributes to FLT3 ligand (FL)-independent hyperproliferation and STAT5 activation. Co-immunoprecipitation demonstrated constitutive association of Shp2 with the FLT3-ITD, N51-FLT3, as well as with STAT5. Knockdown of Shp2 in Baf3/N51-FLT3 cells significantly reduced proliferation while having little effect on WT-FLT3-expressing cells. Consistently, mutation of N51-FLT3 tyrosine 599 to phenylalanine or genetic disruption of Shp2 in N51-FLT3 expressing bone marrow low-density mononuclear cells reduced proliferation and STAT5 activation. In transplants, genetic disruption of Shp2 in vivo yielded increased latency to and reduced severity of FLT3-ITD-induced malignancy. Mechanistically, Shp2 co-localizes with nuclear phospho-STAT5, is present at functional interferon-gamma activation sites (GAS) within the BCL2L1 promoter, and positively activates the human BCL2L1 promoter, suggesting that Shp2 works with STAT5 to promote pro-leukemogenic gene expression. Further, using a small molecule Shp2 inhibitor, the proliferation of N51-FLT3-expressing bone marrow progenitors and primary AML samples was reduced in a dose-dependent manner. These findings demonstrate that Shp2 positively contributes to FLT3-ITD-induced leukemia and suggest that Shp2 inhibition may provide a novel therapeutic approach to AML. PMID- 23103845 TI - Basic concepts in the use of thoracic and lung ultrasound. AB - PURPOSE OF REVIEW: Recent advances were made in the field of point-of-care ultrasound (POCUS). Thoracic and lung ultrasound have become a rapid and accurate method of diagnosis of hypoxic diseases. The purpose of this article is to review the recent literature on POCUS, emphasizing on its use in the operating room. RECENT FINDINGS: Many international critical care societies published guidelines on the use of ultrasound in the installation of central venous access. More recently, evidenced-based guidelines on the use of POC lung ultrasound were published. Lung ultrasound has shown its superiority over conventional chest radiography in the diagnosis of many disorders of significant importance in anesthesiology, particularly the pneumothorax. SUMMARY: POC thoracic and lung ultrasound is used in many critical medicine fields. The aim of this review is to describe the basic lung ultrasound technique and the knowledge required in order to diagnose and treat the hypoxic patient. Emphasis is on disorder such as pleural effusion, alveolar interstitial disease, as well as pneumothorax, which is of particular importance in the field of anesthesiology. PMID- 23103846 TI - Introduction to the special ISSUE on the IV International Giardia and Cryptosporidium Conference. PMID- 23103848 TI - Remaining vigilant. PMID- 23103847 TI - Effect of one-step polishing system on the color stability of nanocomposites. AB - OBJECTIVES: This study was to compare the effect of three different one-step polishing systems on the color stability of three different types of nanocomposites after immersion in coffee for one day and seven days and determine which nanocomposite material has the best color stability following polishing with each of the one-step polishing system. METHODS: The nanocomposites tested were Tetric EvoCeram, Grandio and Herculite Precis. A total of 120 discs (40/nanocomposite, 8mm*2mm) were fabricated. Ten specimens for each nanocomposite cured under Mylar strips served as the control. The other specimens were polished with OptraPol, OneGloss and Occlubrush immersed in coffee (Nescafe) up to seven days. Color measurements were made with a spectrophotometer at baseline and after one and seven days. Two way repeated measure ANOVA, two way ANOVA and Bonferroni tests were used for statistical analyses (P<0.05). RESULTS: The immersion time was a significant factor in the discoloration of the nanocomposites. The effect of three one-step polishing systems on the color stability was also significant. The color change values of the materials cured against Mylar strips were the greatest. The lowest mean color change values were from the Occlubrush polished groups. The effect of the three different types of nanocomposite on the color change was significant. The highest color change values were with Tetric EvoCeram groups. The lowest color change values were with Herculite Precis groups. CONCLUSION: The color change of nanocomposite resins is affected by the type of composite, polishing procedure and the period of immersion in the staining agent. PMID- 23103849 TI - Master clinician: Bjorn U. Zachrisson, DDS, MSD, PHD. Interviewed by Dr Peter M. Sinclair. PMID- 23103850 TI - Anterior torque correction with bracketless fixed orthodontics. PMID- 23103851 TI - Sterilization and instrument compatibility in a digital world. PMID- 23103852 TI - Management of a relapsed midline diastema in one visit. PMID- 23103853 TI - Sturdy hooks for elastics attachment. PMID- 23103854 TI - Scissor-bite correction using miniscrew anchorage. PMID- 23103855 TI - Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. AB - Inhibition of PARP is a promising therapeutic strategy for homologous recombination-deficient tumors, such as BRCA1-associated cancers. We previously reported that BRCA1-deficient mouse mammary tumors may acquire resistance to the clinical PARP inhibitor (PARPi) olaparib through activation of the P-glycoprotein drug efflux transporter. Here, we show that tumor-specific genetic inactivation of P-glycoprotein increases the long-term response of BRCA1-deficient mouse mammary tumors to olaparib, but these tumors eventually developed PARPi resistance. In a fraction of cases, this resistance is caused by partial restoration of homologous recombination due to somatic loss of 53BP1. Importantly, PARPi resistance was minimized by long-term treatment with the novel PARP inhibitor AZD2461, which is a poor P-glycoprotein substrate. Together, our data suggest that restoration of homologous recombination is an important mechanism for PARPi resistance in BRCA1-deficient mammary tumors and that the risk of relapse of BRCA1-deficient tumors can be effectively minimized by using optimized PARP inhibitors. SIGNIFICANCE: In this study, we show that loss of 53BP1 causes resistance to PARP inhibition in mouse mammary tumors that are deficient in BRCA1. We hypothesize that low expression or absence of 53BP1 also reduces the response of patients with BRCA1-deficient tumors to PARP inhibitors. PMID- 23103856 TI - Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen activated protein kinase signaling. AB - H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and nonredundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, whereas wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTK). We show that both are necessary for exponential growth of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to the hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death. SIGNIFICANCE: The results of this study highlight a novel role for wild-type Ras signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these findings reveal that therapeutically targeting oncogenic Ras signaling alone may be ineffective owing to feedback activation of RTKs, and suggest that blocking upstream RTKs in combination with downstream effector pathways may be beneficial in the treatment of Ras-mutant tumors. PMID- 23103857 TI - Low pH enhances 2-aminoethoxydiphenyl borate-induced cell death of PC12 cells. AB - 2-Aminoethoxydiphenyl borate (2-APB) is widely used as a pharmacological tool for analysis of cellular Ca(2+) regulation. In this study, we found that external acid potentiated neural cell death induced by 2-APB in rat pheochromocytoma 12 (PC12) cells. 2-APB induced cell death in half of the PC12 cells within 30min at pH 6.6 but not at pH 7.4. The extent of the 2-APB-induced cell death increased in a dose-, time- and pH-dependent manner. Ca(2+)-imaging revealed that 2-APB increased [Ca(2+)](i) in PC12 cells at pH 6.6. Removal of extracellular Ca(2+) and chelation of intracellular Ca(2+) inhibited the 2-APB-induced cell death. Antagonists of the store-operated Ca(2+) (SOC) channel (SKF96365 and ruthenium red) blocked both 2-APB-induced cell death and Ca(2+) influx, but those for transient receptor potential channels (BCTC, TRIM and BTP2), acid-sensing ion channels (amiloride) and proton-sensing G-protein-coupled receptors (U73122) did not. These results suggest that 2-APB induces neural cell death via Ca(2+) overload through SOC channel activation under acidic pH. PMID- 23103858 TI - Infants' responsiveness to rivalrous gratings. AB - The study investigated the early development of responsiveness to rivalrous gratings. Infants were tested weekly between 6 and 16 weeks of age for their ability to discriminate between interocularly identical (fusible) lines and interocularly orthogonal (unfusible, rivalrous) lines. The stimuli were presented on an autostereoscopic monitor equipped with a face-tracking device. Two psychophysical techniques, the forced-choice preferential looking (FPL) method and measurement of looking times, were employed. Contrary to earlier findings, infants at all ages avoided looking at the rivalrous gratings instead of showing a developmental shift from a relative preference for unfusible, rivalrous gratings to a relative preference for fusible gratings. Avoidance of the rivalrous gratings became significant at 8-9weeks of age, suggesting that infants clearly exhibit binocular rivalry from that age onwards. Control experiments secured that the infants' preference for the fusible gratings was not governed by a natural preference for less over more complex line patterns. PMID- 23103859 TI - Aryl hydrocarbon receptor activation leads to impairment of estrogen-driven chicken vitellogenin promoter activity in LMH cells. AB - The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most of the toxic effects of environmental contaminants. Among the multiple pleiotropic responses elicited by AHR agonists, the antiestrogenic and endocrine-disrupting action of the receptor activation is one of the most studied. It has been demonstrated that some AHR agonists disrupt estradiol induced vitellogenin synthesis in the fish liver via a mechanism that involves crosstalk between the AHR and the estrogen receptor (ER). Chicken hepatocytes have become a model for the study of AHR action in birds and the induction of the signal and its effect in these cells are well established. However, the impact of AHR activation on estradiol-regulated responses in the chicken liver remains to be demonstrated. The aim of the present study was, therefore, to determine the effect of AHR action on ER-driven transcription in a convenient model of chicken liver cells. For this purpose, we designed a reporter construct bearing the 5' regulatory region of the chicken vitellogenin II gene and used it to transfect chicken hepatoma LMH cells. We found that beta-naphthoflavone represses ER-driven vitellogenin promoter activity and that this action is mediated by the AHR. This inhibitory crosstalk between both pathways appears to be unidirectional, since estradiol did not alter the transcript levels of an AHR target gene. Besides, and highly relevant, we show that LMH cell line transfected with a reporter construct bearing the chicken vitellogenin promoter sequence is a useful and convenient model for the study of AHR-ER interaction in chicken liver-derived cells. PMID- 23103860 TI - The relationship between semantic knowledge and conceptual apraxia in Alzheimer disease. AB - BACKGROUND: Conceptual apraxia (CA), a feature of Alzheimer disease (AD), can be detected by asking participants to identify the correct tool to act on an object. Assessment can be based on either learned associations (a tool selection test) or the mechanical properties that the tool needs to alter the target object (an alternative tool selection test). OBJECTIVES: We wanted to determine whether knowledge of semantic taxonomic relations (intrinsic properties shared by items) correlated with performance on tests for CA in people with AD or amnestic mild cognitive impairment (aMCI). METHODS: We tested 10 participants with AD, 12 with aMCI, and 18 healthy older adults for CA using an alternative tool selection test, a tool selection test, and a test of taxonomic relations. RESULTS: The aMCI group did not differ from the control group on the CA tests. The patients with AD were impaired on all tests except tool selection; their performance on the alternative tool selection test correlated significantly with their performance on the taxonomic relations test. CONCLUSIONS: The correlation between performances on the alternative tool selection test and the taxonomic relations test in AD suggests a common pathophysiologic substrate, either impairment in accessing conceptual-semantic representations or a degradation of these representations. PMID- 23103861 TI - Delusions of death in a patient with right hemisphere infarction. AB - Although a role for right hemisphere dysfunction has been hypothesized in Cotard delusion, it remains unclear which functions are disturbed. We report here the first known patient with unilateral right hemisphere lesions and delusions of death (1 of the 2 types of Cotard delusion). This man began to believe that he was dead after suffering a right hemisphere infarction involving the frontal, temporal, and parietal lobes, as well as the thalamus. He had delusions of death in the context of both depersonalization/derealization and delusional misidentifications of people and places. Neuropsychological testing revealed left hemispatial neglect and deficits in general attention. The patient's sense of body ownership and face recognition abilities were preserved. This case suggests that abnormal feelings of familiarity, which have been implicated in several delusional misidentification syndromes, contribute significantly to the development of delusions of death. If this is true, affective processes involved in the identification of people and places and in the feeling of being alive may partially overlap, and these affective processes may be supported by the right hemisphere. PMID- 23103862 TI - Resurrection of endogenous retroviruses in antibody-deficient mice. AB - The mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These include the microbiota on environmental surfaces, such as the respiratory and gastrointestinal tracts, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammalian genome. The long-term consequences for the host of interactions with these microbial species can range from mutualism to parasitism and are not always completely understood. The potential effect of one microbial symbiont on another is even less clear. Here we study the control of ERVs in the commonly used C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic MLV in B6 mice with a range of distinct immune deficiencies affecting antibody production. These recombinant retroviruses establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV activation in immunodeficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer. PMID- 23103863 TI - A map of visual space in the primate entorhinal cortex. AB - Place-modulated activity among neurons in the hippocampal formation presents a means to organize contextual information in the service of memory formation and recall. One particular spatial representation, that of grid cells, has been observed in the entorhinal cortex (EC) of rats and bats, but has yet to be described in single units in primates. Here we examined spatial representations in the EC of head-fixed monkeys performing a free-viewing visual memory task. Individual neurons were identified in the primate EC that emitted action potentials when the monkey fixated multiple discrete locations in the visual field in each of many sequentially presented complex images. These firing fields possessed spatial periodicity similar to a triangular tiling with a corresponding well-defined hexagonal structure in the spatial autocorrelation. Further, these neurons showed theta-band oscillatory activity and changing spatial scale as a function of distance from the rhinal sulcus, which is consistent with previous findings in rodents. These spatial representations may provide a framework to anchor the encoding of stimulus content in a complex visual scene. Together, our results provide a direct demonstration of grid cells in the primate and suggest that EC neurons encode space during visual exploration, even without locomotion. PMID- 23103864 TI - Direct imaging of RecA nucleation and growth on single molecules of SSB-coated ssDNA. AB - Escherichia coli RecA is the defining member of a ubiquitous class of DNA strand exchange proteins that are essential for homologous recombination, a pathway that maintains genomic integrity by repairing broken DNA. To function, filaments of RecA must nucleate and grow on single-stranded DNA (ssDNA) in direct competition with ssDNA-binding protein (SSB), which rapidly binds and continuously sequesters ssDNA, kinetically blocking RecA assembly. This dynamic self-assembly on a DNA lattice, in competition with another protein, is unique for the RecA family compared to other filament-forming proteins such as actin and tubulin. The complexity of this process has hindered our understanding of RecA filament assembly because ensemble measurements cannot reliably distinguish between the nucleation and growth phases, despite extensive and diverse attempts. Previous single-molecule assays have measured the nucleation and growth of RecA--and its eukaryotic homologue RAD51--on naked double-stranded DNA and ssDNA; however, the template for RecA self-assembly in vivo is SSB-coated ssDNA. Using single molecule microscopy, here we directly visualize RecA filament assembly on single molecules of SSB-coated ssDNA, simultaneously measuring nucleation and growth. We establish that a dimer of RecA is required for nucleation, followed by growth of the filament through monomer addition, consistent with the finding that nucleation, but not growth, is modulated by nucleotide and magnesium ion cofactors. Filament growth is bidirectional, albeit faster in the 5'->3' direction. Both nucleation and growth are repressed at physiological conditions, highlighting the essential role of recombination mediators in potentiating assembly in vivo. We define a two-step kinetic mechanism in which RecA nucleates on transiently exposed ssDNA during SSB sliding and/or partial dissociation (DNA unwrapping) and then the RecA filament grows. We further demonstrate that the recombination mediator protein pair, RecOR (RecO and RecR), accelerates both RecA nucleation and filament growth, and that the introduction of RecF further stimulates RecA nucleation. PMID- 23103865 TI - The TEL patch of telomere protein TPP1 mediates telomerase recruitment and processivity. AB - Human chromosome ends are capped by shelterin, a protein complex that protects the natural ends from being recognized as sites of DNA damage and also regulates the telomere-replicating enzyme, telomerase. Shelterin includes the heterodimeric POT1-TPP1 protein, which binds the telomeric single-stranded DNA tail. TPP1 has been implicated both in recruiting telomerase to telomeres and in stimulating telomerase processivity (the addition of multiple DNA repeats after a single primer-binding event). Determining the mechanisms of these activities has been difficult, especially because genetic perturbations also tend to affect the essential chromosome end-protection function of TPP1 (refs 15-17). Here we identify separation-of-function mutants of human TPP1 that retain full telomere capping function in vitro and in vivo, yet are defective in binding human telomerase. The seven separation-of-function mutations map to a patch of amino acids on the surface of TPP1, the TEL patch, that both recruits telomerase to telomeres and promotes high-processivity DNA synthesis, indicating that these two activities are manifestations of the same molecular interaction. Given that the interaction between telomerase and TPP1 is required for telomerase function in vivo, the TEL patch of TPP1 provides a new target for anticancer drug development. PMID- 23103866 TI - Microbiology: Bacterial power cords. PMID- 23103867 TI - Towards germline gene therapy of inherited mitochondrial diseases. AB - Mutations in mitochondrial DNA (mtDNA) are associated with severe human diseases and are maternally inherited through the egg's cytoplasm. Here we investigated the feasibility of mtDNA replacement in human oocytes by spindle transfer (ST; also called spindle-chromosomal complex transfer). Of 106 human oocytes donated for research, 65 were subjected to reciprocal ST and 33 served as controls. Fertilization rate in ST oocytes (73%) was similar to controls (75%); however, a significant portion of ST zygotes (52%) showed abnormal fertilization as determined by an irregular number of pronuclei. Among normally fertilized ST zygotes, blastocyst development (62%) and embryonic stem cell isolation (38%) rates were comparable to controls. All embryonic stem cell lines derived from ST zygotes had normal euploid karyotypes and contained exclusively donor mtDNA. The mtDNA can be efficiently replaced in human oocytes. Although some ST oocytes displayed abnormal fertilization, remaining embryos were capable of developing to blastocysts and producing embryonic stem cells similar to controls. PMID- 23103868 TI - Synaptic amplification by dendritic spines enhances input cooperativity. AB - Dendritic spines are the nearly ubiquitous site of excitatory synaptic input onto neurons and as such are critically positioned to influence diverse aspects of neuronal signalling. Decades of theoretical studies have proposed that spines may function as highly effective and modifiable chemical and electrical compartments that regulate synaptic efficacy, integration and plasticity. Experimental studies have confirmed activity-dependent structural dynamics and biochemical compartmentalization by spines. However, there is a longstanding debate over the influence of spines on the electrical aspects of synaptic transmission and dendritic operation. Here we measure the amplitude ratio of spine head to parent dendrite voltage across a range of dendritic compartments and calculate the associated spine neck resistance (R(neck)) for spines at apical trunk dendrites in rat hippocampal CA1 pyramidal neurons. We find that R(neck) is large enough (~500 MOmega) to amplify substantially the spine head depolarization associated with a unitary synaptic input by ~1.5- to ~45-fold, depending on parent dendritic impedance. A morphologically realistic compartmental model capable of reproducing the observed spatial profile of the amplitude ratio indicates that spines provide a consistently high-impedance input structure throughout the dendritic arborization. Finally, we demonstrate that the amplification produced by spines encourages electrical interaction among coactive inputs through an R(neck) dependent increase in spine head voltage-gated conductance activation. We conclude that the electrical properties of spines promote nonlinear dendritic processing and associated forms of plasticity and storage, thus fundamentally enhancing the computational capabilities of neurons. PMID- 23103870 TI - Biochemistry: A glimpse of molecular competition. PMID- 23103871 TI - Accelerated disassembly of IgE-receptor complexes by a disruptive macromolecular inhibitor. AB - IgE antibodies bind the high-affinity IgE Fc receptor (FcepsilonRI), found primarily on mast cells and basophils, and trigger inflammatory cascades of the allergic response. Inhibitors of IgE-FcepsilonRI binding have been identified and an anti-IgE therapeutic antibody (omalizumab) is used to treat severe allergic asthma. However, preformed IgE-FcepsilonRI complexes that prime cells before allergen exposure dissociate extremely slowly and cannot be disrupted by strictly competitive inhibitors. IgE-Fc conformational flexibility indicated that inhibition could be mediated by allosteric or other non-classical mechanisms. Here we demonstrate that an engineered protein inhibitor, DARPin E2_79 (refs 9, 10, 11), acts through a non-classical inhibition mechanism, not only blocking IgE FcepsilonRI interactions, but actively stimulating the dissociation of preformed ligand-receptor complexes. The structure of the E2_79-IgE-Fc(3-4) complex predicts the presence of two non-equivalent E2_79 sites in the asymmetric IgE FcepsilonRI complex, with site 1 distant from the receptor and site 2 exhibiting partial steric overlap. Although the structure is indicative of an allosteric inhibition mechanism, mutational studies and quantitative kinetic modelling indicate that E2_79 acts through a facilitated dissociation mechanism at site 2 alone. These results demonstrate that high-affinity IgE-FcepsilonRI complexes can be actively dissociated to block the allergic response and suggest that protein protein complexes may be more generally amenable to active disruption by macromolecular inhibitors. PMID- 23103872 TI - Filamentous bacteria transport electrons over centimetre distances. AB - Oxygen consumption in marine sediments is often coupled to the oxidation of sulphide generated by degradation of organic matter in deeper, oxygen-free layers. Geochemical observations have shown that this coupling can be mediated by electric currents carried by unidentified electron transporters across centimetre wide zones. Here we present evidence that the native conductors are long, filamentous bacteria. They abounded in sediment zones with electric currents and along their length they contained strings with distinct properties in accordance with a function as electron transporters. Living, electrical cables add a new dimension to the understanding of interactions in nature and may find use in technology development. PMID- 23103869 TI - Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. AB - Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis. PMID- 23103873 TI - Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells. AB - In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of toll-like receptor 3 (TLR3) immunity are prone to HSV-1 encephalitis (HSE). We tested the hypothesis that the pathogenesis of HSE involves non-haematopoietic CNS-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of interferon-beta (IFN-beta) and/or IFN-lambda1 in response to stimulation by the dsRNA analogue polyinosinic:polycytidylic acid (poly(I:C)) was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-beta and IFN-lambda1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele showed that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was rescued further by treatment with exogenous IFN-alpha or IFN-beta ( IFN alpha/beta) but not IFN-lambda1. Thus, impaired TLR3- and UNC-93B-dependent IFN alpha/beta intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3-pathway deficiencies. PMID- 23103874 TI - HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. AB - Human antibodies to human immunodeficiency virus-1 (HIV-1) can neutralize a broad range of viral isolates in vitro and protect non-human primates against infection. Previous work showed that antibodies exert selective pressure on the virus but escape variants emerge within a short period of time. However, these experiments were performed before the recent discovery of more potent anti-HIV-1 antibodies and their improvement by structure-based design. Here we re-examine passive antibody transfer as a therapeutic modality in HIV-1-infected humanized mice. Although HIV-1 can escape from antibody monotherapy, combinations of broadly neutralizing antibodies can effectively control HIV-1 infection and suppress viral load to levels below detection. Moreover, in contrast to antiretroviral therapy, the longer half-life of antibodies led to control of viraemia for an average of 60 days after cessation of therapy. Thus, combinations of potent monoclonal antibodies can effectively control HIV-1 replication in humanized mice, and should be re-examined as a therapeutic modality in HIV-1 infected individuals. PMID- 23103876 TI - The genomic landscape of species divergence in Ficedula flycatchers. AB - Unravelling the genomic landscape of divergence between lineages is key to understanding speciation. The naturally hybridizing collared flycatcher and pied flycatcher are important avian speciation models that show pre- as well as postzygotic isolation. We sequenced and assembled the 1.1-Gb flycatcher genome, physically mapped the assembly to chromosomes using a low-density linkage map and re-sequenced population samples of each species. Here we show that the genomic landscape of species differentiation is highly heterogeneous with approximately 50 'divergence islands' showing up to 50-fold higher sequence divergence than the genomic background. These non-randomly distributed islands, with between one and three regions of elevated divergence per chromosome irrespective of chromosome size, are characterized by reduced levels of nucleotide diversity, skewed allele frequency spectra, elevated levels of linkage disequilibrium and reduced proportions of shared polymorphisms in both species, indicative of parallel episodes of selection. Proximity of divergence peaks to genomic regions resistant to sequence assembly, potentially including centromeres and telomeres, indicate that complex repeat structures may drive species divergence. A much higher background level of species divergence of the Z chromosome, and a lower proportion of shared polymorphisms, indicate that sex chromosomes and autosomes are at different stages of speciation. This study provides a roadmap to the emerging field of speciation genomics. PMID- 23103877 TI - Linking the population growth rate and the age-at-death distribution. AB - The population growth rate is linked to the distribution of age at death. We demonstrate that this link arises because both the birth and death rates depend on the variance of age-at-death. This bears the prospect to separate the influences of the age patterns of fertility and mortality on population growth rate. Here, we show how the age pattern of death affects population growth. Using this insight we derive a new approximation of the population growth rate that uses the first and second moments of the age-at-death distribution. We apply our new approximation to 46 mammalian life tables (including humans) and show that it is on par with the most prominent other approximations. PMID- 23103875 TI - Layered reward signalling through octopamine and dopamine in Drosophila. AB - Dopamine is synonymous with reward and motivation in mammals. However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies. Instead, octopamine has historically been considered to be the signal for reward in insects. Here we show, using temporal control of neural function in Drosophila, that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the alpha-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the beta-adrenergic-like OCTbeta2R receptor reveals that octopamine dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought. PMID- 23103878 TI - Water-soluble graphene grafted by poly(sodium 4-styrenesulfonate) for enhancement of electric capacitance. AB - Water-soluble poly(sodium 4-styrenesulfonate) modified graphene (PSSS-GR) was successfully synthesized via covalently grafting poly(sodium 4-styrenesulfonate) (PSSS) on the surfaces of graphene (GR) nanosheets. The structure of PSSS-GR was investigated with Fourier transform infrared, x-ray photoelectron and Raman spectroscopy, thermogravimetric analysis, transmission and scanning electron microscopy and atomic force microscopy. The PSSS chains made the GR nanosheets fully exfoliate into a single-layer structure, and the PSSS layer on GR reached 90 wt%. PSSS chains displayed mutually repulsive effects on promoting GR sheets that were more stable in water. The performances of supercapacitors made of PSSS GR and unmodified GR electrodes were compared using cyclic voltammetry and galvanostatic charge/discharge techniques. The results showed that PSSS is an effective binder for graphene sheets and can increase the specific capacitance of PSSS-GR based supercapacitors and improve their rate capability. The maximum specific capacitance of the PSSS-GR based supercapacitor was 210 F g(-1) at 5 A g(-1), which was 166% higher than for one made of unmodified graphene electrodes. Electrochemical impedance spectroscopy demonstrated fast ion diffusion in the PSSS-GR electrode structure. PSSS-GR based supercapacitors can fulfil one of the essential requirements for potential electric energy storage applications. PMID- 23103879 TI - Phase-gradient microscopy in thick tissue with oblique back-illumination. AB - Phase-contrast techniques, such as differential interference contrast microscopy, are widely used to obtain morphological images of unstained biological samples. The transillumination geometry required for these techniques restricts their application to thin samples. We introduce oblique back-illumination microscopy, a method of collecting en face phase-gradient images of thick scattering samples, enabling near-video-rate in vivo phase imaging with a miniaturized probe suitable for endoscopy. PMID- 23103880 TI - The GEM mapper: fast, accurate and versatile alignment by filtration. AB - Because of ever-increasing throughput requirements of sequencing data, most existing short-read aligners have been designed to focus on speed at the expense of accuracy. The Genome Multitool (GEM) mapper can leverage string matching by filtration to search the alignment space more efficiently, simultaneously delivering precision (performing fully tunable exhaustive searches that return all existing matches, including gapped ones) and speed (being several times faster than comparable state-of-the-art tools). PMID- 23103881 TI - Ultrabright photoactivatable fluorophores created by reductive caging. AB - Sub-diffraction-limit imaging can be achieved by sequential localization of photoactivatable fluorophores, for which the image resolution depends on the number of photons detected per localization. We report a strategy for fluorophore caging that creates photoactivatable probes with high photon yields. Upon photoactivation, these probes can provide 10(4)-10(6) photons per localization and allow imaging of fixed samples with resolutions of several nanometers. This strategy can be applied to many fluorophores across the visible spectrum. PMID- 23103882 TI - Use of acupuncture in hospices and palliative care services in the UK. AB - PURPOSE: The aim of the present work was to evaluate the availability of acupuncture in UK hospices and specialist palliative care services and to identify any barriers to the use of acupuncture in these settings, to determine the characteristics of available acupuncture services and of practitioners providing acupuncture, and to determine awareness of the evidence base for the use of acupuncture in palliative care. METHODS: An online questionnaire with an invitation to participate was circulated by email to 263 hospices and specialist palliative care services in the UK. RESULTS: A response rate of 54% was obtained. Acupuncture was provided by 59% of services that responded. In general, small numbers of patients receive acupuncture as part of their palliative care treatment as inpatients, day patients or outpatients. Most practitioners were regulated health professionals who had received a Western-style training in acupuncture and used a Western-style medical acupuncture approach. Where acupuncture was not available the commonest reason given was the lack of a suitable practitioner. Most agreed that if funding and a suitable practitioner were available, acupuncture would be a useful addition to their service. The level of awareness of specific types of evidence supporting the use of acupuncture in palliative care was low, but most respondents were aware that some evidence existed. CONCLUSIONS: There is a need to increase training in acupuncture for healthcare professionals working in palliative care. There is also a need to raise awareness of the potential benefits to patients and the evidence base supporting the use of acupuncture in palliative care. PMID- 23103883 TI - Concurrent deletion of BMP4 and OTX2 genes, two master genes in ophthalmogenesis. AB - BMP4 and OTX2 are master genes in ophthalmogenesis. Mutations of BMP4 and OTX2 often lead to eye defects, including anophthalmia-microphthalmia. A significant degree of variable expressivity has been reported in heterozygous individuals with BMP4 or OTX2 mutation. Interestingly, both BMP4 and OTX2 reside on 14q22, being only 2.8 Mb apart. Previous studies reported that among three patients with 14q22 deletion involving BMP4 and OTX2, all had severe eye defects. The minimal degree of variable expressivity among these individuals who were doubly deleted for BMP4 and OTX2 could be attributed to the combinatorial relationship of the two genes observed in animal models. We herein report a patient with a concurrent deletion of BMP4 and OTX2 who exhibited bilateral microphthalmia, more specifically, anterior segment dysgenesis with microcornea. Evolutionarily conserved physical linkage of Bmp4 and Otx2 loci may suggest an advantage of the proximal alignment of the two genes. Another striking feature in the propositus was the progressive white matter loss observed by serial neuroimaging. A review of twelve previously reported patients with 14q22 microdeletion revealed decreased white matter volume in half of the patients. It remains to be elucidated whether the white matter lesion is age-dependent and progressive. In conclusion, anterior segment defects of the eyes, especially when accompanied by decreased white matter volume on neuroimaging, should raise the clinical suspicion of 14q22 microdeletion. PMID- 23103884 TI - Age-related macular degeneration and coronary heart disease: evaluation of genetic and environmental associations. AB - An association between coronary heart disease (CHD) and age-related macular degeneration (AMD) has long been postulated but results from epidemiological case control studies, and genetic analyses have been ambiguous. In this study we illuminate the association between AMD and CHD with respect to genetic and environmental risk factors, age of disease onset and AMD subgroups. AMD patients (n = 1036) and age-matched control subjects (n = 412) between 68 and 95 years of age were included in the case-control study. A medical history of CHD, cerebral stroke and arterial hypertension was determined for each individual. The assessment of interacting factors included the current use of systemic medications and smoking habits. Analysis of AMD associated genetic variants included frequent polymorphisms at the complement factor H (CFH, MIM 134370) gene (rs1061170 [p.Y402H], rs800292 [p.I62V]), the complement factor H-related 3 (CFHR3, MIM 605336)/complement factor H-related 1 (CFHR1, MIM 134371) locus (rs6677604; proxy for DeltaCFHR3/CFHR1; r(2) = 0.97) as well as the age-related maculopathy susceptibility 2 (ARMS2, MIM 611313) gene (rs10490924 [p.A69S]). Logistic regression identified a significant positive association of AMD with AMD risk variants in CFH, ARMS2, and smoking >= 20 packs/year. A history of CHD and the current use of antihyperuricemic agents were inversely associated with the disease. Significantly fewer patients with rs6677604 nonrisk genotype A/A regularly used statins. ARMS2:p.A69S risk variant was significantly associated with exsudative AMD. AMD patients with risk variants at rs1061170 (CFH:p.Y402H) and ARMS2 and smokers (>=20 packs/year) were significantly earlier affected by AMD than those carrying the non-risk variants at each locus. Our data support three major conclusions. First, the age of AMD onset is significantly influenced by genetic and environmental risk factors. Second, in support of previous reports we also show that the ARMS2 rs10490924:T allele is significantly linked to exsudative AMD. And finally, a self-reported history of CHD was inversely associated with AMD in this study. Novel therapeutic strategies aiming at preventing the development of AMD may considerably differ from those that have been developed to treat cardiovascular disorders as both common disorders likely underlie different pathomechanisms. PMID- 23103885 TI - Effects of intracerebroventricular application of insulin-like growth factor 1 and its N-terminal tripeptide on cerebral recovery following cardiac arrest in rats. AB - BACKGROUND: Following global cerebral ischaemia due to cardiac arrest (CA), selective neuronal vulnerability and delayed neuronal death with distinct signs of apoptosis could be observed in certain areas of the brain. Growth hormones like the insulin-like growth factor 1 (IGF-1) and the bioactive N-terminal tripeptide of IGF-1, glycine-proline-glutamate (GPE), exhibit strong protective properties in focal ischaemia in vivo and in vitro. To examine these promising effects on neuronal survival and cerebral recovery after experimental cardiopulmonary resuscitation, the most vulnerable hippocampal CA-1 sector was investigated. METHODS: After 6 min of CA, 54 male Wistar rats were resuscitated and were randomly assigned to 3 groups (IGF-1, GPE vs. placebo; n=6 per group) and 3 different reperfusion periods. Intracerebroventricular application of IGF-1 (1.25 MUgh(-1)), GPE (50 ngh(-1)) and placebo was performed using osmotic minipumps up to day 7 following reperfusion. After 3, 7 and 14 days, coronal brain sections were analysed by counting Nissl-positive (i.e. viable) neurons and TUNEL-positive (i.e., apoptotic) cells. All experiments were performed in a randomised and blinded setting. RESULTS: In all groups in the hippocampal CA-1 sector typical delayed neurodegeneration from day 3 to day 14 after CA could be found. No significant increase of the number of Nissl-positive neurons after IGF 1-treatment (p=0.18) as well as after GPE-treatment (p=0.14) could be observed. The number of TUNEL-positive cells could not be reduced significantly in the IGF 1 group (p=0.13), whereas GPE treatment revealed significant less TUNEL-positive cells (p=0.02). This was primarily an effect in the early phase (day 3: p=0.02) of reperfusion and was no more detectable 7 days (p=0.69) and 14 days after ROSC (p=0.30). CONCLUSION: Despite the well known neuroprotective properties of IGF-1 and GPE in ischaemic induced neuronal degeneration, this model could only reveal a short-term beneficial effect of GPE after experimental cardiac arrest in rats. (Institutional protocol number: 35-9185.81/43/00.). PMID- 23103886 TI - Initial bispectral index may identify patients who will awaken during therapeutic hypothermia after cardiac arrest: a retrospective pilot study. AB - AIM: Patients sustain a range of neurologic injuries after cardiac arrest, and determining which patients should be treated with therapeutic hypothermia (TH) is complex, often confounded by sedation and neuromuscular blockade (NMB). We evaluated bispectral index (BIS) monitoring as a tool to identify adult patients that awakened during therapeutic hypothermia. METHODS: Review of prospectively collected registry data, with retrospective chart review of patient descriptions during hypothermia. Data are presented as median (interquartile range). RESULTS: 7 of 309 patients (2.2%) treated with TH over 6 years awoke (followed commands) prior to completing hypothermia. Median age was 58 (54-66) years; 71% were male, cardiac arrest was witnessed in 6 (86%) and out-of-hospital in 6 (86%), and 4 patients (57%) were transferred from another hospital. 5 patients (71%) had an initial rhythm of ventricular tachycardia or fibrillation, time to return of spontaneous circulation was 17 (12-23)min. The BIS value after first NMB dose during TH was 63, 45, 43, 52, 62, 54, and 42 (median 52, IQR 44-58, 95% confidence interval 46-58). The median BIS value in the remaining data set (n=302) was 18 (6-36), p<0.001, and only 6% of BIS1 values were >46. CONCLUSION: Patients who awakened early had higher BIS values after the first dose of NMB. Processed EEG values after cardiac arrest may provide additional information that could assist with determining best treatment. PMID- 23103887 TI - Emergency department factors associated with survival after sudden cardiac arrest. AB - BACKGROUND: Sudden cardiac arrest (SCA) is a leading cause of death in the US. Recent innovations in post-arrest care have been demonstrated to increase survival. However, little is known about the impact of emergency department (ED) and hospital characteristics on survival to hospital admission and ultimate outcome. OBJECTIVE: We sought to describe the incidence of SCA presenting to the ED and to identify ED and hospital characteristics associated with survival to hospital admission. METHODS: We identified patients with diagnoses of atraumatic cardiac arrest or ventricular fibrillation (ICD-9 427.5 or 427.41) in the 2007 Nationwide Emergency Department Sample (NEDS), a nationally representative estimate of all ED admissions in the United States. We defined SCA as cardiac arrest in the out-of-hospital or ED settings. We used the NEDS sample design to generate nationally representative estimates of the incidence of SCA that presents to EDs. We performed unadjusted and adjusted analyses to examine the relation between patient, ED, and hospital characteristics and outcome using logistic regression. Our primary outcome was survival to hospital admission. Survival to hospital discharge was a secondary outcome. Data are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Of the 966 hospitals in the NEDS, 933 (96.6%) reported at least one SCA and were included in the analysis. We identified 38,593 cases of cardiac arrest representing an estimated 174,982 cases nationally. Overall ED SCA survival to hospital admission was 26.2% and survival to discharge was 15.7%. Greater survival to admission was seen in teaching hospitals (OR 1.3 95% CI 1.1-1.5, p=0.001), hospitals with >=20,000 annual ED visits (OR 1.3 95% CI 1.1-1.6, p=0.003), and hospitals with percutaneous coronary intervention capability (OR 1.6 95% CI 1.4-1.8, p<0.001). Higher SCA volume (>40 annually) was associated with lower survival overall (OR 0.7 95% 0.6-0.9, p=0.010), but not when transferred patients were excluded from the analysis (OR 0.8 95% CI 0.6-1.1, p=0.116). CONCLUSIONS: An estimated 175,000 cases of SCA present to or occur in US EDs each year. Percutaneous coronary intervention capability, ED volume, and teaching status were associated with higher survival to hospital admission. Emergency departments with higher annual SCA volume had lower survival rates, possibly because they transfer fewer patients. An improved understanding of the contribution of ED care to survival following SCA may be useful in advancing our understanding of how best to organize a system of care to ensure optimal outcomes for patients with SCA. PMID- 23103888 TI - Effective compression ratio--a new measurement of the quality of thorax compression during CPR. AB - PURPOSE: Computer-based feedback systems for assessing the quality of cardiopulmonary resuscitation (CPR) are widely used these days. Recordings usually involve compression and ventilation dependent variables. Thorax compression depth, sufficient decompression and correct hand position are displayed but interpreted independently of one another. We aimed to generate a parameter, which represents all the combined relevant parameters of compression to provide a rapid assessment of the quality of chest compression-the effective compression ratio (ECR). METHODS: The following parameters were used to determine the ECR: compression depth, correct hand position, correct decompression and the proportion of time used for chest compressions compared to the total time spent on CPR. Based on the ERC guidelines, we calculated that guideline compliant CPR (30:2) has a minimum ECR of 0.79. To calculate the ECR, we expanded the previously described software solution. In order to demonstrate the usefulness of the new ECR-parameter, we first performed a PubMed search for studies that included correct compression and no-flow time, after which we calculated the new parameter, the ECR. RESULTS: The PubMed search revealed 9 trials. Calculated ECR values ranged between 0.03 (for basic life support [BLS] study, two helpers, no feedback) and 0.67 (BLS with feedback from the 6th minute). CONCLUSION: ECR enables rapid, meaningful assessment of CPR and simplifies the comparability of studies as well as the individual performance of trainees. The structure of the software solution allows it to be easily adapted to any manikin, CPR feedback devices and different resuscitation guidelines (e.g. ILCOR, ERC). PMID- 23103889 TI - Coronavirus respiratory illness in Saudi Arabia. AB - Although viruses that belong to the coronavirus family are known since the 1930s, they only gained public health attention when they were discovered to be the causative agent of the severe acute respiratory syndrome (SARS) outbreak in China in 2002-2003. On 22 September 2012, the Ministry of Health (MOH) in Saudi Arabia announced the detection of what was described as a "rare pattern" of coronavirus respiratory infection in three individuals, two Saudi citizens and one person from the Gulf Region. Neither Saudi citizen survived the infection. Molecular analysis of the isolates showed that the virus belongs to the genus beta coronavirus. It is not known if the new isolates are circulating in the population or has recently diverged. The emergence of these novel isolates that resulted in fatal human infection ascertains that health authorities all over the world must be vigilant for the possibility of new global pandemics due to novel viral infection. PMID- 23103890 TI - Outbreak of cutaneous anthrax in Musalimadugu village, Chittoor district, Andhra Pradesh, India, July-August 2011. AB - INTRODUCTION: In August 2011, Chittoor district authorities reported a cluster of suspected human anthrax cases to the Andhra Pradesh state surveillance unit. We investigated this cluster to confirm its etiology, describe its magnitude, identify potential risk factors, and make recommendations for preventing similar outbreaks in the future. METHODOLOGY: Suspected cutaneous anthrax was defined as a painless skin lesion (papule, vesicle, or eschar) that appeared in a resident of Musalimadugu between July and August 2011. Clinical details and smears from skin lesions from suspected cases were collected to describe the outbreak by time, place and person. A retrospective cohort study among villagers aged >= 15 years was conducted to identify risk factors for acquiring the infection. RESULTS: Sixteen livestock in the village died between 24 June and 7 August 2011. Smears from five animals showed Gram-positive, spore bearing characteristics of Bacillus anthracis. Villagers butchered and skinned the dead animals, sold the skin, and consumed the meat after boiling it for two hours. The outbreak in humans started on 30 July, and nine suspected cases of cutaneous anthrax (attack rate: 2%, no deaths) occurred until 7 August. The attack rate was higher among those aged >=15 years. All the smears were negative on Gram staining. Individuals, who had handled, skinned, and slaughtered dead livestock were at higher risk of infection. CONCLUSIONS: We recommend ciprofloxacin prophylaxis to close family contacts. Vaccination of the livestock in the area and community education on the dangers of handling and slaughtering dead/ill livestock are necessary. PMID- 23103891 TI - Is nalidixic acid screening still valid for the detection of reduced susceptibility of fluoroquinolone with Salmonella Typhi? AB - INTRODUCTION: Considering the limitations of screening with nalidixic acid to detect reduced susceptibility to fluoroquinolones of Salmonella enterica serovar Typhi (S.Typhi) strains, we evaluated the use of a 30 ug nalidixic acid disc screening method in Pakistan. METHODOLOGY: Non duplicate nalidixic acid susceptible S. Typhi isolates (246) from 2003-2008 were retrieved from the Salmonella strain bank. Minimum inhibitory concentrations of ciprofloxacin for all strains were determined by agar dilution and further rechecked by ciprofloxacin E-tests.E. coli ATCC 25922 was used as the control strain. The MIC data for ciprofloxacin were compared with nalidixic acid disk (30 ug) zone diameters. RESULTS: Repeat testing of all S. Typhi isolates with a nalidixic acid (30 ug) disk showed 100% susceptibility with an average zone diameter of 26 mm. Agar dilution testing revealed reduced susceptibility to ciprofloxacin, with MICs of 0.125 ug/ml for three (1.2%) isolates only. Zone sizes of strains with higher MICs were significantly lower than the strains with lower MICs (20 versus 26 mm) (p value < 0.001). CONCLUSION: Estimation of fluoroquinolone MICs on every nalidixic acid susceptible S. Typhi strain is not cost effective in our setting; the proportion of strains with high fluoroquinolone MICs was found to be very low. We recommend periodic fluoroquinolone MIC determination to include all isolates with a nalidixic acid borderline zone (size 20-22 mm). PMID- 23103892 TI - Epidemiology, clinical presentation, and patterns of drug resistance of Salmonella Typhi in Karachi, Pakistan. AB - INTRODUCTION: Enteric fever remains a major public health problem in Asia. Planning appropriate preventive measures such as immunization requires a clear understanding of disease burden. We conducted a community-based surveillance for Salmonella Typhi infection in children in Karachi, Pakistan. METHODOLOGY: A de jure household census was conducted at baseline in the study setting to enumerate all individuals. A health-care facility-based passive surveillance system was used to capture episodes of fever lasting three or more 3 days in children 2 to 16 years old. RESULTS: A total of 7,401 blood samples were collected for microbiological confirmation, out of which 189 S. Typhi and 32 S. Paratyphi A isolates were identified with estimated annual incidences of 451/100,000 (95% CI: 446 - 457) and 76/100,000 (95% CI: 74 - 78) respectively. At the time of presentation, after adjusting for age, there was an association between the duration of fever and temperature at presentation, and being infected with multidrug-resistant S. Typhi. Of 189 isolates 83 were found to be resistant to first-line antimicrobial therapy. There was no statistically significant difference in clinical presentation of blood culture sensitive and resistant S. Typhi isolates. CONCLUSION: Incidence of S. Typhi in children is high in urban squatter settlements of Karachi, Pakistan. Findings from this study identified duration of fever and temperature at the time of presentation as important symptoms associated with blood culture-confirmed typhoid fever. Preventive strategies such as immunization and improvements in water and sanitation conditions should be the focus of typhoid control in urban settlements of Pakistan. PMID- 23103893 TI - Preoperative antibiotic prophylaxis practice and guideline adherence in Jordan: a multi-centre study in Jordanian hospitals. AB - INTRODUCTION: The use of antimicrobial prophylaxis for surgical procedures is one of the measures employed to prevent the development of surgical site infections (SSI). The appropriate choice of antimicrobial agents, dosage regimen, timing, duration and use of intravenous route must be evidence based. This study aimed to assess the practice of surgical antibiotic prophylaxis and adherence of practitioners to the American Society of Health-System Pharmacists (ASHP) guidelines for antimicrobial prophylaxis in surgery and to explore reasons for non-compliance. METHODOLOGY: A cross-sectional study was conducted in 20 Jordanian hospitals from October 2006 to June 2007. A questionnaire was designed to collect information from physicians regarding the practice of surgical antibiotic prophylaxis (SAP), references used for guiding SAP practice, prevalence of surgical site infection (SSI), and causative microorganisms. RESULTS: SAP was employed in almost all surgical departments of hospitals. The improper timing of antimicrobial administration for SAP was attributed to lack of knowledge of the guidelines (46.1%), while the improper antimicrobial choice was ascribed to drug unavailability (61.8%). CONCLUSION: This study shows that physicians are aware of the importance of antimicrobial prophylaxis before surgical procedures. However, further efforts are needed to ensure the implementation of the standard SAP guidelines in Jordanian hospitals. PMID- 23103894 TI - Immunological evaluation of OMP-F of native Iranian Pseudomonas aeruginosa as a protective vaccine. AB - INTRODUCTION: This study involved 300 Pseudomonas aeruginosa strains isolated from patients admitted in four Tehran hospitals. Using standard O-specific typing sera, they were all grouped into 16 strains out of 17 known P. aeruginosa. The strains were lyophilized and each was given a code according to the Collection of Standard Bacteria, Pasteur Institute of Iran (CSBPI) for further investigations. METHODOLOGY: Among all clinical samples, CSBPI: 16-190 was the most prevalent P. aeruginosa serotype which showed a high agglutination titer (4+, 320) against homologous O-specific typing sera. This serotype was selected for extraction of P. aeruginosa major outer membrane vesicles (OMP-F). OMP-F vesicles were extracted and purified according to the Deoxycholate Ultracentrifuge Differentiation Technique. Purity and molecular weight of OMP-F were determined by SDS-PAGE and the ability of OMP-F vesicles to induce high titers of antibody in rabbit, which was shown as a sharp antibody-antigen precipitation line in the agarose gel immune-diffusion technique. RESULTS: Passive immunization of mice with anti-rabbit OMP-F antisera induced a high level of protection when the mice were post-challenged with 2*LD50 of live P. aeruginosa CSBPI: 16-190. Furthermore, active immunization of mice with 50 ug of OMP-F could protect mice against 2xLD50 of live homologous (100% protection) and 15 heterologous native Iranian P. aeruginosa serotypes with 50-100% level of protection. CONCLUSIONS: These investigations indicate that purified OMP-F of CSBPI: 16-190 can be regarded as a safe protective immunogen in vaccinothrapy against all P. aeruginosa immunotype isolated in Iran. PMID- 23103895 TI - Distribution of erythrocyte binding antigen 175 (EBA-175) alleles and ABO blood groups in a hypoendemic area in Senegal. AB - INTRODUCTION: The study was conducted to determine for the first time the association between the erythrocyte binding antigen 175 (EBA-175) alleles and ABO blood groups in malaria patients living in Thies, a hypoendemic area in Senegal. METHODOLOGY: In 2007, the EBA-175 alleles and blood group types were determined by nested PCR and the Simonin test respectively in blood samples obtained from uncomplicated Plasmodium falciparum malaria positive patients. RESULTS AND CONCLUSION: In total, 129 patients were enrolled in the study. The EBA-175 genotyping showed a prevalence of 67.45% for the F-allele, 27.90% for the C allele and 4.65% of mixed C+F infection. The distribution of the ABO blood group type showed 59.8% for the O group, 19.7% for the A group, 17.2% for the B group, and 3.3% for the AB group. No correlation was noted between the EBA-175 alleles and either the blood group type or parasitemia. PMID- 23103896 TI - Trichocomaceae: biodiversity of Aspergillus spp and Penicillium spp residing in libraries. AB - INTRODUCTION: Atmospheric air is the most common vehicle for the dispersion of fungi. Fungi belonging to the genera Aspergillus and Penicillium are cosmopolitan and are classified in the family Trichocomaceae. Species of the genera are commonly found in soil, decaying organic materials, animal feed, stored grains, and other materials. This study aimed to determine the taxonomic diversity of airborne fungi of the genera Aspergillus and Penicillium residing in the dust of library environments to contribute to current knowledge of these characteristic genera. METHODOLOGY: Three libraries in the city of Cuiaba, State of Mato Grosso, Brazil, were selected as the study areas. A total of 168 samples were collected at randomized sites within each library in areas containing journals, archives, in study rooms, and in collection storage areas in two different periods, the dry season (n = 42) and the rainy season (n = 42). Samples were collected by exposing Petri dishes containing Sabouraud agar with chloramphenicol to the environmental air. Additional samples were collected with sterile swabs which were rubbed over the surface of randomly chosen books on the shelves; the swabs were subsequently incubated in the laboratory. RESULTS AND CONCLUSION: The genus Aspergillus was highlighted as one of the principal airborne fungi present in indoor environments. Aspergillus spp was identified in 1,277 (89.6%) samples and Penicillium spp in 148 (10.4%). The dry period exhibited a greater number of isolates of the two taxons. PMID- 23103898 TI - Haemophilus parainfluenzae: report of an unusual cause of neonatal sepsis and a literature review. AB - Haemphilus parainfluenzae, an unusual cause of early-onset neonatal sepsis, is rarely reported. Risk factors for this serious infection include prolonged rupture of membranes, choriamnionitis, and prematurity. A high index of suspicion, proper culture techniques, and rapid species identification are needed to diagnose H. parainfluenzae sepsis. We present the first documented case from India with a review of the literature. PMID- 23103897 TI - Rethinking therapeutic decisions for hepatitis B infection in Syria: insights into molecular monitoring. AB - INTRODUCTION: Hepatitis B virus patients are usually treated in Syria with alpha interferon and nucleos(t)ide analogues. Genotypic viral factors causing inadequate response or relapse following initial response are not routinely investigated. This study aimed to explore and discuss local therapeutic decisions from a molecular perspective. METHODOLOGY: Fifty patients with hepatitis B from Syria were tested for HBV genotyping and drug-resistance mutations by DNA sequencing. RESULTS: All patients had genotype D, which is characterized by relatively low response to interferon-based therapy. Drug-resistant viral mutant variants were detected in one fifth of the enrolled patients, and distributed similarly in both nucleos(t)ide analogues-naive and -treated patients. However, nucleos(t)ide analogues-based therapy was associated with the existence of more mutations and hence increased resistance. CONCLUSIONS: Investigating HBV genotypes and drug-resistance mutations to support treatment decisions is critically needed for efficient therapy and patients' survival. PMID- 23103899 TI - Fatal Chromobacterium violaceum septicemia in a South Indian adult. AB - Chromobacterium violaceum is a rare human pathogen that causes potentially fatal infections especially in the tropical regions. Limited awareness about this pathogen and inappropriate antibiotic therapy are some of the factors contributing to the high mortality rate. To date there have been only eight cases reported from India of which only one is an adult. To the best of our knowledge, we report here the first case of a 40-year-old man from South India with septicemic C. Violaceum infection and septic arthritis. PMID- 23103900 TI - Centripetal external quality assessment for laboratories located in remote and rural areas. PMID- 23103901 TI - Label-free in situ detection of individual macromolecular assemblies by surface enhanced Raman scattering. AB - We demonstrate label-free detection of lipid vesicles and polystyrene beads freely diffusing in aqueous solution using surface enhanced Raman scattering (SERS). The signals observed enable real-time identification and monitoring of individual particles interacting with the SERS substrate. SERS is demonstrated as a label-free method capable of monitoring transient species in solution on the millisecond time scale. PMID- 23103902 TI - Effect of chronic exposure to rimonabant and phytocannabinoids on anxiety-like behavior and saccharin palatability. AB - The acute effects of cannabinoid compounds have been investigated in animal models of anxiety-like behavior and palatability processing. However, the chronic effects of cannabinoids in such models are poorly understood. Experiment 1 compared the effects of both acute and chronic (14 days) exposure to the CB(1) receptor inverse agonist/antagonist, rimonabant, and the cannabis-derived CB(1) receptor neutral antagonist, tetrahydrocannabivarin (THCV), on: 1) time spent in the open, lit box in the Light-Dark (LD) immersion model of anxiety-like behavior and 2) saccharin hedonic reactions in the taste reactivity (TR) test of palatability processing. Experiment 2 compared the effects of chronic administration of cannabis-derived Delta(9)-tetrahydrocannabinol (Delta(9)-THC), cannabidiol (CBD) and cannabigerol (CBG) in these models. Tests were administered on Days 1, 7 and 14 of drug administration. In Experiment 1, rimonabant, but not THCV, produced an anxiogenic-like reaction in the LD immersion test and reduced saccharin palatability in the TR test; both of these effects occurred acutely and were not enhanced by chronic exposure. In Experiment 2, Delta(9)-THC also produced an acute anxiogenic-like reaction in the LD immersion test, without enhancement by chronic exposure. However, Delta(9)-THC enhanced saccharin palatability in the TR test on Day 1 of drug exposure only. CBD and CBG did not modify anxiety-like responding, but CBG produced a weak enhancement of saccharin palatability on Day 1 only. The results suggest that the anxiogenic-like reactions and the suppression of hedonic responding produced by rimonabant, are mediated by inverse agonism of the CB(1) receptor and these effects are not enhanced with chronic exposure. PMID- 23103903 TI - Potentiation of oxycodone antinociception in mice by agmatine and BMS182874 via an imidazoline I2 receptor-mediated mechanism. AB - The potentiation of oxycodone antinociception by BMS182874 (endothelin-A (ET(A)) receptor antagonist) and agmatine (imidazoline receptor/alpha(2)-adrenoceptor agonist) is well-documented. It is also known that imidazoline receptors but not alpha(2)-adrenoceptors are involved in potentiation of oxycodone antinociception by agmatine and BMS182874 in mice. However, the involvement of specific imidazoline receptor subtypes (I(1), I(2), or both) in this interaction is not clearly understood. The present study was conducted to determine the involvement of imidazoline I(1) and I(2) receptors in agmatine- and BMS182874-induced potentiation of oxycodone antinociception in mice. Antinociceptive (tail flick and hot-plate) latencies were determined in male Swiss Webster mice treated with oxycodone, agmatine, BMS182874, and combined administration of oxycodone with agmatine or BMS182874. Efaroxan (imidazoline I(1) receptor antagonist) and BU224 (imidazoline I(2) receptor antagonist) were used to determine the involvement of I(1) and I(2) imidazoline receptors, respectively. Oxycodone produced significant antinociceptive response in mice which was not affected by efaroxan but was blocked by BU224. Agmatine-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. Similarly, BMS182874-induced potentiation of oxycodone antinociception was blocked by BU224 but not by efaroxan. This is the first report demonstrating that BMS182874- or agmatine-induced enhancement of oxycodone antinociception is blocked by BU224 but not by efaroxan. We conclude that imidazoline I(2) receptors but not imidazoline I(1) receptors are involved in BMS182874- and agmatine-induced potentiation of oxycodone antinociception in mice. PMID- 23103904 TI - Effect of Mucuna pruriens (Linn.) on mitochondrial dysfunction and DNA damage in epididymal sperm of streptozotocin induced diabetic rat. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mucuna pruriens Linn. (M. pruriens) is a leguminous plant that has been recognized as an herbal medicine for improving fertility and related disorders in the Indian traditional system of medicine, however without proper scientific validations. AIM OF THE STUDY: To study the effect of ethanolic seed extract of M. pruriens on mitochondrial dysfunction and the DNA damage in hyperglycemic rat epididymal spermatozoa. MATERIALS AND METHODS: Male Wistar albino rats were divided as control (Sham), diabetes induced [streptozotocin 60 mg/kg of body weight (b.w.) in 0.1M citrate buffer] (STZ), diabetic rats administered with 200mg/kg b.w. of extract (STZ+MP) and normal rats administered with 200mg/kg b.w. of extract (Sham+MP). M. pruriens was administered (gavage) once daily for a period of 60 days. On 60th day animals were sacrificed by cervical dislocation sperm were collected from epididymis and subjected various analysis like antioxidants, ROS, lipid peroxidation (LPO), DNA damage, chromosomal integrity and mitochondrial membrane potential (MMP). RESULTS: Significant reduction in the sperm count, motility, viability and significant increase in the number of abnormal sperm in STZ compared to sham was noticed. STZ rat sperm showed significant increase in LPO and DNA damage. Both the enzymic and non-enzymic were decreased; MMP and the mitochondrial functions were severely affected in STZ group. The diabetic rats supplemented with M. pruriens showed a remarkable recovery in antioxidant levels and reduced LPO with well preserved sperm DNA. MMP and mitochondrial function test were also preserved in STZ+MP rat sperm. CONCLUSION: The present study has clearly demonstrated the potency of M. pruriens to reduce the diabetic induced sperm damage induced by oxidative stress (OS). These observations are encouraging to perform similar studies in human. PMID- 23103906 TI - Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. AB - BACKGROUND & AIMS: Dabigatran is an oral and direct inhibitor of thrombin. In a study of patients with atrial fibrillation (the RE-LY trial), twice as many subjects given dabigatran reported dyspepsia-like symptoms compared with those given warfarin (controls). We analyzed data from this trial to quantify upper gastrointestinal nonbleeding adverse events (NB-UGI AEs). METHODS: We analyzed the AE database from the RE-LY trial (18,113 subjects) and assigned NB-UGI AEs to 4 groups: those associated with gastroesophageal reflux (GERD), upper abdominal pain and dyspepsia, dysmotility, or gastroduodenal injury. We analyzed frequency, timing, and severity, and clinical variables associated with NB-UGI AEs. RESULTS: NB-UGI AEs occurred in 16.9% of subjects given dabigatran and in 9.4% of controls (relative risk [RR], 1.81; 95% confidence interval [CI], 1.66%-1.97%; P < .001). Rates of AEs were not associated with the dose of dabigatran. Among subjects with any UGI symptom who were given dabigatran (n = 2045), symptoms were rated as mild in 46.3%, moderate in 44.8%, and severe in 8.9%; these values were similar to those of controls. GERD-associated NB-UGI AEs were most frequent among the 4 groups (compared with controls, RR, 3.71; 95% CI, 2.98%-4.62%; P < .001). Four percent of subjects stopped taking dabigatran because of NB-UGI AEs (most within 3 months of starting therapy), compared with 1.7% of controls (RR, 2.34; 95% CI, 1.90%-2.88%; P < .001). NB-UGI AEs slightly increased risk of major GI bleeding among subjects given dabigatran and controls (6.8% vs 2.3%, P < .001). CONCLUSIONS: Among patients given dabigatran for atrial fibrillation, NB-UGI AEs are generally mild or moderate; 4% stopped taking the drug over a median of 21.7 months. The greatest increase was in GERD-type NB-UGI AEs. These observations should guide management and prevention strategies. PMID- 23103905 TI - Addition of an immunomodulator to infliximab therapy eliminates antidrug antibodies in serum and restores clinical response of patients with inflammatory bowel disease. AB - There are few therapeutic options for patients with inflammatory bowel disease who lose response to infliximab because they produced antibodies against the drug. We performed a retrospective analysis to investigate whether administration of immune modulators to 5 patients who developed antibodies to infliximab (ATI) restored response to this drug; 3 patients were given azathioprine/6 mercaptopurine and 2 patients were given methotrexate. Concentrations of infliximab and ATIs, and antitumor necrosis factor (TNF) activity, were analyzed using enzyme-linked immunosorbent assay-based competition assays of serum samples collected before and after patients were given the immunomodulator. In all patients, levels of ATIs gradually decreased and trough levels of infliximab increased; clinical responses were restored to all patients. In competition assays, immunomodulator-induced elimination of ATIs was associated with increased anti-TNF activity in serum. The addition of immunomodulators to therapy might be helpful to patients who have lost response to anti-TNF agents owing to formation of antidrug antibodies. PMID- 23103908 TI - An uncommon cause of biliary obstruction. PMID- 23103907 TI - Psychological treatments in functional gastrointestinal disorders: a primer for the gastroenterologist. AB - The functional gastrointestinal disorders (FGIDs) often show inadequate response to usual medical care. Psychological treatments can help improve functional gastrointestinal disorder patient outcomes, and such treatment should be considered for patients who have moderate or severe symptoms after 3-6 months of medical care and those whose symptoms are clearly exacerbated by stress or emotional symptoms. Effective psychological treatments, which are based on multiple randomized controlled trials, include cognitive behavioral therapy and hypnosis for irritable bowel syndrome and pediatric functional abdominal pain, cognitive behavioral therapy for functional chest pain, and biofeedback for dyssynergic constipation in adults. Successful referral by the gastroenterologist for psychological treatment is facilitated by educating the patient about the rationale for such treatment, reassurance about the diagnosis and continuation of medical care, firm doctor-patient therapeutic alliance, and identification of and communication with an appropriate psychological services provider. PMID- 23103909 TI - Delayed dysphagia from a foreign body granuloma mimicking a subepithelial neoplasm. PMID- 23103910 TI - Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. AB - A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach that includes high-throughput single-cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability. PMID- 23103913 TI - A facile method to observe graphene growth on copper foil. AB - A novel scanning electron microscope (SEM) method is presented for high contrast identification of each layer of pyramidal graphene domains grown on copper. We obtained SEM images by combining the advantages of the high resolution property of the secondary electron signal and the elemental sensitivity of the backscattering electron signal. Through this method, we investigated the difference in the growth mechanisms of mono-layer and few-layer graphene. Due to different lattice mismatches, both the surface adsorption process and the epitaxial growth process existed under the atmospheric growth conditions. Moreover, the copper oxidation process can be easily discovered. It is obvious from the SEM images that the graphene greatly delayed the oxidation process of the copper surface. Finally, the nucleation and growth speed of graphene domains was found to depend on the linear array distribution of surface ledges and terraces of annealed rolled copper foil. This result explains the linear rows of graphene during the growth process and accords with theoretical results. PMID- 23103912 TI - PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1alpha-mediated unfolded protein response. AB - Poly(ADP-ribose) polymerases (PARPs; also known as ADP-ribosyl transferase D proteins) modify acceptor proteins with ADP-ribose modifications of varying length (reviewed in refs , , ). PARPs regulate key stress response pathways, including DNA damage repair and the cytoplasmic stress response. Here, we show that PARPs also regulate the unfolded protein response (UPR) of the endoplasmic reticulum (ER). Human PARP16 (also known as ARTD15) is a tail-anchored ER transmembrane protein required for activation of the functionally related ER stress sensors PERK and IRE1alpha during the UPR. The third identified ER stress sensor, ATF6, is not regulated by PARP16. As is the case for other PARPs that function during stress, the enzymatic activity of PARP16 is upregulated during ER stress when it ADP-ribosylates itself, PERK and IRE1alpha. ADP-ribosylation by PARP16 is sufficient for activating PERK and IRE1alpha in the absence of ER stress, and is required for PERK and IRE1alpha activation during the UPR. Modification of PERK and IRE1alpha by PARP16 increases their kinase activities and the endonuclease activity of IRE1alpha. Interestingly, the carboxy-terminal luminal tail of PARP16 is required for PARP16 function during ER stress, suggesting that it transduces stress signals to the cytoplasmic PARP catalytic domain. PMID- 23103911 TI - beta2-syntrophin and Par-3 promote an apicobasal Rac activity gradient at cell cell junctions by differentially regulating Tiam1 activity. AB - Although Rac and its activator Tiam1 are known to stimulate cell-cell adhesion, the mechanisms regulating their activity in cell-cell junction formation are poorly understood. Here, we identify beta2-syntrophin as a Tiam1 interactor required for optimal cell-cell adhesion. We show that during tight-junction (TJ) assembly beta2-syntrophin promotes Tiam1-Rac activity, in contrast to the function of the apical determinant Par-3 whose inhibition of Tiam1-Rac activity is necessary for TJ assembly. We further demonstrate that beta2-syntrophin localizes more basally than Par-3 at cell-cell junctions, thus generating an apicobasal Rac activity gradient at developing cell-cell junctions. Targeting active Rac to TJs shows that this gradient is required for optimal TJ assembly and apical lumen formation. Consistently, beta2-syntrophin depletion perturbs Tiam1 and Rac localization at cell-cell junctions and causes defects in apical lumen formation. We conclude that beta2-syntrophin and Par-3 fine-tune Rac activity along cell-cell junctions controlling TJ assembly and the establishment of apicobasal polarity. PMID- 23103915 TI - Reliable predictions of unusual molecules. AB - Quantum chemistry can today be employed to invent new molecules and investigate their properties and chemical bonding. However, the predicted species must be viable in order to be synthesized by experimentalists. In this perspective article we describe the technology of reliable theoretical predictions and show how understanding of chemical bonding in studied chemical systems could help to design new molecular structures. We also provide a short overview of successfully predicted and already produced (in some cases) planar hypercoordinate species to demonstrate that the consistent theoretical prediction of viable molecules with unusual structures and properties is now a reliable tool for exploring new, yet unknown molecules, clusters, nanomaterials and solids. PMID- 23103914 TI - Cephalic sensory influence on forelimb movement in newborn opossums, Monodelphis domestica. AB - Like other marsupials, the opossum Monodelphis domestica is born very immature and crawls, unaided by the mother, from the urogenital opening to a nipple where it attaches and pursues its development. If the alternate, rhythmic movements of the forelimbs which allow this locomotion are generated by the developing spinal motor networks, sensory information is nonetheless needed to guide the newborn to a nipple. Behavioral, anatomical and physiological studies suggest that the auditory and the visual systems are insufficiently developed in newborn opossums to influence spinal motor centers, while the vestibular, trigeminal, and olfactory systems are likelier candidates. The trigeminal, vestibular and olfactory regions of the brain were electrically stimulated to test their relative effectiveness at eliciting forelimb movement in newborn opossums, using in vitro preparations of brain-spinal cord with the limbs attached. The minimal stimulation of the cervical spinal cord needed to induce forelimb movement was considered as threshold (T). Stimulations of the trigeminal ganglion (5G) at ~2T and of the vestibular complex at ~20T could induce the same movement, and were not statistically different, in contrast to the ~600T necessary for the olfactory bulb (OB). Neurofilament-200 immunohistochemistry and retrograde tracing with Texas-Red conjugated Dextran Amines were used to study trigeminal innervation of the facial skin and pathways by which trigeminal inputs may be relayed to the spinal cord. Numerous nerve fibers were observed in the snout dermis, especially in the maxillary region, but also elsewhere in the head skin. Some 5G cells project to the upper spinal cord, but more project to the caudal medulla where they could contact secondary trigeminal neurons or reticular cells projecting to the spinal cord. These results support a significant influence of the trigeminal and the vestibular systems, but not of olfaction, on forelimb movement of neonatal opossums. PMID- 23103916 TI - Do older people with visual impairment and living alone in a rural developing country report greater difficulty in managing stairs? AB - OBJECTIVES: Managing stairs is a challenging activity of daily living (ADL) for older people. This study aims to examine the association between visual impairment and difficulty in managing stairs among older people living alone and those living with others. METHODS: A population-based cross sectional study was conducted in rural Malaysia from 2007 till 2008. Seven hundred and sixty five older people aged 60 years and over underwent eye examination for visual impairment. Visual acuity criteria were used to define visual impairment. Presenting visual acuity was assessed using a standard metric Snellen Chart of E type. Difficulty in managing stairs was measured according to a question drawn from the Barthel Index which asks "do you need help in climbing stairs". RESULTS: Overall, the prevalence of difficulty in managing stairs among older people in our population was 135 (18.3%, 95% CI 15.7-21.2). After adjusting for important confounders the odds ratio (OR) for visual impairment and difficulty in managing stairs among older people living alone was 5.04 (95% CI 2.27, 10.62). Among older people living with others, the adjusted OR for visual impairment and difficulty in managing stairs was 3.10 (95% CI 1.52, 6.80). CONCLUSION: In a sample of older people aged 60 years and over, those living alone with visual impairment had greater difficulty in managing stairs than those living with others. Identification of these groups of older people is useful for targeting interventions. PMID- 23103917 TI - Dyslipidemia in Nigeria: prevalence and pattern. AB - BACKGROUND: Dyslipidemia is a major risk factor for cardiovascular disease. Data are scanty on the prevalence and pattern of dyslipidemia in Nigeria. However, some studies on the subject are now becoming available. This article reviews these studies on the prevalence and pattern of this important risk factor for cardiovascular disease in Nigeria. MATERIALS AND METHODS: Intensive internet search on studies done in different parts of Nigeria showing the prevalence and pattern of dyslipidemia in various focal groups that include apparently healthy individuals, the elderly, diabetics, hypertensives, and diabetic hypertensives was carried out. RESULTS: Dyslipidemia was highly prevalent in all the geopolitical zones of Nigeria with the consistent pattern being low HDL Cholesterol and high LDL-C. Overall, the prevalence of dyslipidemia ranged from 60% among apparently healthy Nigerians to 89% among diabetic Nigerians. CONCLUSION: Dyslipidemia is highly prevalent in Nigeria and health education to increase awareness of the need for and to actually screen for dyslipidemia will facilitate early detection and treatment. PMID- 23103918 TI - A comparison of two screening instruments in detecting psychiatric morbidity in a Nigerian pediatric primary care service: assessing clinical suitability and applicability. AB - BACKGROUND: To improve poor attendance and underutilization of the child and adolescent psychiatric service in the University of Ilorin Teaching Hospital, Ilorin, Nigeria, we compared a child behavior questionnaire (CBQ) with reporting questionnaire for children (RQC) for use in our primary care unit where the bulk of referrals come from to determine which is more applicable. METHODS: This was a cross-sectional two-stage study on the prevalence and pattern of psychiatric disorders in children attending the primary care unit of University of Ilorin Teaching Hospital, over a 6-month period. CBQ and RQC were completed by the mothers of 350 children aged 7-14 years in the first stage; in the second, a stratified subsample of 157 children based on scores on CBQ were interviewed using the children's version of the schedule for affective disorders and schizophrenia (Kiddie-SADS-PL). The receiver operating characteristics (ROC) analysis was carried out to determine the screening properties of CBQ and RQC. RESULTS: The optimal cutoff score for CBQ and RQC were 7 and 1, respectively. Sensitivity, specificity, and misclassification rates at the cutoff for CBQ was 0.8 (80%); 0 96 (96%); 0.083 (8.3%), and RQC was 0.90 (90%); 0.78 (78%); 0.19 (19%). The discriminating ability of CBQ indicated by the area under the curve (AUC) in the ROC was 0.93 while RQC was 0.88. CONCLUSION: Even with the evident marginal superior discriminating ability of CBQ in our study in primary care, RQC has the advantage of brevity and ease of application for workers at this level. In the child and adolescent clinic CBQ may still be preferred. PMID- 23103919 TI - The "obesity paradox" in Nigerians with heart failure. AB - BACKGROUND: Previous studies have suggested that a high body mass index (BMI) was associated with improved outcome in congestive heart failure (CHF). The aim of this study was to examine the relationship between BMI and echocardiographic variables of cardiac function in stable outpatients with heart failure. METHODS AND MATERIALS: This is a cross-sectional study in which the cardiology clinic out patients of Obafemi Awolowo University Teaching Hospital with heart failure were recruited. Patients were categorized using baseline BMI as normal weight BMI = 18.5-24.9 kg/m(2) and overweight/obese (BMI > 25.0 kg/m(2)). Risks associated with BMI groups were evaluated and the data were analyzed with the aid of SPSS 15.0 software. RESULTS: Patients with higher BMI have higher left ventricular ejection fraction and fractional shortening and lesser tendency to have an abnormal left ventricular geometry and better functional (New York Heart Association) class of heart failure at presentation. CONCLUSION: Overweight and obese patients had less severe degree of heart failure than normal weight patients and efforts should be made to prevent excessive weight loss in patients with heart failure. PMID- 23103920 TI - Prevalence of diarrhea disease and risk factors in Jos University Teaching Hospital, Nigeria. AB - BACKGROUND: Diarrhea is widely recognized as a major cause of childhood morbidity and mortality in many developing countries, particularly in sub-Saharan Africa. According to World Health Organization (WHO) report in the African region, diarrheal diseases are still leading causes of mortality and morbidity in children under five years of age. This same report indicates that each child in the said region has five episodes of diarrhea per year and that 800,000 die each year from diarrhea and dehydration. MATERIALS AND METHODS: This study examined diarrheal morbidity and associated risk factors in children under five years in Jos. A total of 340 children were seen in the Diarrhea Training Unit (DTU) of the Jos University Teaching Hospital (JUTH), Jos, over a period of 24 months (Jan 2008-Dec 2009). A semi-structured interviewer administered questionnaire was used to generate the data. All women whose children presented with diarrhea were interviewed and data generated analyzed using Epi info version 3.5.1 statistical software. RESULTS: During the study period, 13,076 children were seen in our facility, of which 340 were suffering from diarrhea, thus giving a diarrhea prevalence of 2.7%. There were 183 (54%) male and 157 (40%) female children seen with diarrhea. The mean age was 11 +/- 8.5 months. The mean duration of diarrhea was found to be 4 +/- 3.6 days. A majority of children were aged less than 6 months, consisting of 235 infants, 95 toddlers, and 10 pre-schoolers. Of the number of women seen, 242 (61%) had at least primary education, while 98 (29%) had no formal education. Diarrheal episodes were found to have a bivariate association with mothers' educational status, family type, family size, breastfeeding, and sex of child. However, only mother's educational status, diarrhea in other sibling, and breast feeding were significantly associated with the occurrence of diarrhea. Although there were more male children with diarrhea, the odds of having diarrhea was not significantly related to sex. CONCLUSION: Our study demonstrated an important relationship between diarrheal morbidity and low maternal education, nonexclusively breastfed infant, and previous diarrheal episode in a sibling. It thus meant that diarrhea morbidity is still an important problem for infants in our environment. Moreover, maternal education and exclusive breastfeeding are still relevant viable measures in curbing diarrhea in infants. PMID- 23103921 TI - Cognitive functions in patients with liver cirrhosis: assessment using community screening interview for dementia. AB - INTRODUCTION: Neurocognitive dysfunction is common in patients with liver cirrhosis who have no evidence of overt hepatic encephalopathy and is usually associated with impairment of activities of daily living in the patients. MATERIALS AND METHODS: Forty patients with liver cirrhosis without overt hepatic encephalopathy were studied along with forty-one healthy controls. Blood samples were taken from the patients for liver function tests and Hepatitis B and C screening. Liver disease severity was graded using the Child-Pugh scoring system. Community Screening Interview for the Dementia (CSID) questionnaire was administered to all subjects. The CSID questionnaire assesses the cognitive functions of the subjects in the domains of language, memory, orientation, attention/calculation, and praxis. The data were collated and analyzed with the aid of SPSS 15.0 software for frequency, means, and comparison of means using Student's t-test and one-way ANOVA. Significant level was put at P< 0.05. RESULTS: The mean age +/- SD of the patients was 46.15 +/- 15.31 years and the controls was 45.66 +/- 11.54 years. There were 30 males and 10 females in the patients group while the control had has 26 males and 15 females. Majority of the patients had secondary level of education. Nine out of 40 patients (23%) had abnormally low total CSID score. The patients with liver cirrhosis performed poorly in the domains of language, memory, attention/calculation, and praxis. There was no difference in the orientation scores between the patients and the normal controls. The type of Hepatitis virus infection, serum liver enzyme, serum albumin, serum bilirubin, prothrombin time and Child Pugh class of the patients did not influence cognitive performance in the patients. CONCLUSION: Patients with liver cirrhosis have significant cognitive impairment compared with controls and liver function tests/ clinical parameters in the patients did not correlate with their cognitive functions. PMID- 23103922 TI - Renal metastasis from prostate adenocarcinoma: a potential diagnostic pitfall. AB - Renal metastasis from prostatic origin is an uncommon event. Advanced prostate cancer locally invades the seminal vesicles, bladder and regional lymph nodes. Other metastatic sites are the lung, bone and other visceral organs. We present a 55-year old, Hausa man from Northern Nigeria who was managed as a case of infected renal cyst which later turned out to be a metastatic prostatic adenocarcinoma with a rare pattern of widespread bony metastases.Renal metastasis from prostate adenocarcinoma is a rare occurrence, however, high level of suspicion is needed in order to avoid potential diagnostic pitfall. PMID- 23103923 TI - Idiopathic bilateral strio-pallido-dentate calcinosis (Fahr's disease): a case report and review of the literature. AB - Bilateral calcification involving the basal ganglia (Fahr's disease) is a rare disease. A high index of suspicion is required to make clinical diagnosis; more so that the calcinosis may remain asymptomatic in a vast majority of cases. Movement disorder is by far the most common manifestation in symptomatic individuals. Fahr's disease is by no means absent in our environment, and increasing availability of a computed tomography-scan machine in Nigeria may enhance the case identification of Fahr's disease. This review presents a case of bilateral strio-pallido-dentate calcification; it also affirms the fact that Fahr's disease could present with hyperkinetic movement disorder (chorea) in our setting. PMID- 23103924 TI - Cervical cancer awareness and cervical screening uptake at the Mater Misericordiae Hospital, Afikpo, Southeast Nigeria. AB - BACKGROUND: Cervical cancer is the most common genital tract malignancy among women in developing countries. OBJECTIVE: To assess the awareness of cervical cancer among Igbo women in a rural population of Southeastern Nigerian and determine their uptake of cervical screening services. MATERIALS AND METHODS: A questionnaire-based descriptive cross-sectional study. Structured questionnaires were administered to female attendees to the antenatal and gynecological clinics of a secondary hospital in the outskirts of Afikpo, Southeast Nigeria over a six month period (1 st July to 31 st December 2007). Data analysis was by SPSS. RESULTS: Five hundred questionnaires were given out. Three hundred and sixty were correctly filled (72%) and analyzed. The mean age of respondents was 36.2 years, 25.0% had tertiary education and 40.3% were self employed. All the respondents were sexually active. There were high incidences of premarital sex, multiple sexual partners and abnormal vaginal discharge and low condom use. Awareness of cervical cancer (37.5%), its preventable nature (31.9%), cervical screening (25%) and screening centers (20.8%) were generally low and screening uptake (0.6%) was abysmally low. Lack of awareness, non-availability of screening centers locally, cost and time were the main reasons adduced by respondents for not being screened. Overall, 62.5% of all the respondents indicated willingness to be screened. CONCLUSION: The exposure to conditions that predispose women to cervical cancer was high, and the levels of awareness of cervical cancer and cervical screening uptake were low. Continued awareness creation, local provision of cheap and affordable services and poverty alleviation are needed to improve cervical screening uptake with the hope of reducing the incidence of cervical cancer in the long term. PMID- 23103925 TI - Profile of problems associated with psychoactive substance use among commercial motorcyclists in Abeokuta, Nigeria. PMID- 23103926 TI - Clinical presentation and outcome of severe malaria in adults in Zaria, Northern Nigeria. PMID- 23103927 TI - Consequences of increasing obesity burden on infertility treatment in the developing countries. PMID- 23103928 TI - Vertebral fracture risk factors in postmenopausal women over 50 in Valencia, Spain. A population-based cross-sectional study. AB - PURPOSE: This study aims to estimate the prevalence of risk factors for osteoporotic vertebral fracture and analyze the possible associations between these factors and the presence of densitometric osteoporosis and prevalent morphometric vertebral fracture. METHODS: Data from a population-based cross sectional sample of 804 postmenopausal women over the age of 50 years old living in the city of Valencia (Spain) were used. The women were interviewed to identify the prevalence of osteoporotic fracture risk factors and underwent a densitometry and a dorsolumbar spine X-ray. RESULTS: The most prevalent risk factors were densitometric osteoporosis (31.7%), history of parental hip fracture (19.4%), hypoestrogenism (19%), and body mass index (BMI) >= 30 kg/m(2) (35.2%). After adjusting for all covariables, densitometric osteoporosis was associated with increased age [odds ratio (OR)(65-69 years): 2.84, 95% confidence interval (CI): 1.75-4.61; OR(70-74 years): 4.01, 95% CI: 2.47-6.52; OR(75+years): 5.96, 95% CI: 3.27-10.87] and inversely associated with high BMI (OR(25.0-29.9): 0.51, 95% CI: 0.34-0.76; OR(>= 30): 0.30, 95% CI: 0.19-0.46). Morphometric vertebral fracture was associated with age (OR(65-69 years): 2.04, 95% CI: 1.03-4.05; OR(70-74 years): 4.05, 95% CI: 2.11-7.77; OR(75+years): 8.43, 95% CI: 3.97-17.93), poor educational level (OR: 1.70, 95% CI: 1.06-2.72) and with densitometric osteoporosis and BMI >= 30 kg/m(2) (OR: 3.35, 95% CI: 1.85-6.07). CONCLUSIONS: The most prevalent osteoporotic fracture risk factors were having a high BMI and the presence of densitometric osteoporosis. A higher risk of morphometric vertebral fracture in women with both low bone mineral density and high BMI was found. This association, if confirmed, has important implications for clinical practice and fracture risk tools. We also found a higher risk in women with a poor educational level. More attention should be addressed to these populations in order to control modifiable risk factors. PMID- 23103929 TI - The impact of race on outcomes of patients with early stage uterine endometrioid carcinoma. AB - OBJECTIVES: The purpose of the present study was to determine whether racial disparity exists between African American (AA) and non-African American (NAA) patients with uterine endometrioid carcinoma who received similar multidisciplinary management. METHODS: We identified 766 patients with endometrioid adenocarcinoma 2009 FIGO stages I-II who underwent hysterectomy. Patients were divided into two groups; AA and NAA. Recurrence-free survival (RFS), disease specific survival (DSS) and overall survival (OS) for two groups were calculated. RESULTS: Median follow-up was 5.1 years. 27% were AA and 73% were NAA. All patients underwent hysterectomy and oophorectomy. 80% had peritoneal cytology examination and 69% underwent lymphadenectomy. AA patients were more likely to have higher grade tumors, and higher incidence of lymphovascular space involvement (LVSI). Although the two groups were balanced with regards to surgical staging and adjuvant treatment received, the 5-year RFS and DSS were significantly lower in AA compared to NAA patients (91% vs 84%, p=0.030; 95% vs 88%, p=0.011, respectively). Overall survival was not significantly different between the two groups. On multivariate analysis, after adjusting for other prognostic factors, race (AA vs NAA) was not a significant predictor of outcome. Grade 3 tumors and the presence of LVSI were the only two independent predictors of RFS and DSS with p <= 0.001 and p <= 0.001, respectively. CONCLUSION: In this large hospital-based study, AA race was associated with a higher incidence of adverse pathological features and worse recurrence-free and disease-specific survival. However, on multivariate analysis race was not an independent prognostic factor. Further studies are needed to elucidate possible underlying molecular mechanisms for these poorer outcomes. PMID- 23103930 TI - Patient groups that fimbriectomy could reduce high grade serous ovarian cancer incidence. PMID- 23103931 TI - DNA nanotherapy for pre-neoplastic cervical lesions. AB - OBJECTIVE: This study aims to test the hypothesis that targeted nanoparticle delivery of DNA encoding HPV16-regulated diphtheria toxin (DT-A) will result in the death of HPV16-infected cells. MATERIALS AND METHODS: Plasmid constructs containing a HPV16 Long Control Region (LCR) DNA sequence upstream of DT-A or luciferase reporter (Luc) DNA sequences were used to formulate poly(beta-amino ester) nanoparticles. The effect on tumor growth of HPV/DT-A-nanoparticle injection directly into HPV16(+) CaSki human cervical cancer cell-derived xenografts in mice was determined. To evaluate the ability of the HPV16 LCR regulatory sequence to activate gene expression specifically in HPV16-infected cells, mice underwent bioluminescent optical imaging following intraperitoneal injection of HPV/Luc-nanoparticles. The use of Lutrol F127, a thermal-sensitive gel, to target delivery of nanoparticles and subsequent gene expression to cervical epithelial cells was evaluated in ex vivo cultures of mouse cervix and following intravaginal delivery of nanoparticle/gel in mice, as well as in ex vivo cultures of surgical LEEP samples. RESULTS: The selected HPV16 LCR regulatory sequence activates gene expression in both HPV16-infected cells and non-infected cells. However, in the cervix, it is specifically active in epithelial cells. Following exposure of cervical cells to HPV/DT-A-nanoparticles mixed with Lutrol F127 gel, DT-A is expressed and cells die. CONCLUSIONS: An HPV16 DNA sequence that targets gene expression specifically to HPV16-infected cells remains to be discovered. Topical application of a Lutrol F127 thermal gel/nanoparticle mix is illustrative of how to restrict exposure of cells to therapeutic nanoparticles, thereby allowing for targeted DNA delivery to cervical pre-cancerous lesions. PMID- 23103932 TI - Spatially resolved Hall effect measurement in a single semiconductor nanowire. AB - Efficient light-emitting diodes and photovoltaic energy-harvesting devices are expected to play an important role in the continued efforts towards sustainable global power consumption. Semiconductor nanowires are promising candidates as the active components of both light-emitting diodes and photovoltaic cells, primarily due to the added freedom in device design offered by the nanowire geometry. However, for nanowire-based components to move past the proof-of-concept stage and be implemented in production-grade devices, it is necessary to precisely quantify and control fundamental material properties such as doping and carrier mobility. Unfortunately, the nanoscale geometry that makes nanowires interesting for applications also makes them inherently difficult to characterize. Here, we report a method to carry out Hall measurements on single core-shell nanowires. Our technique allows spatially resolved and quantitative determination of the carrier concentration and mobility of the nanowire shell. As Hall measurements have previously been completely unavailable for nanowires, the experimental platform presented here should facilitate the implementation of nanowires in advanced practical devices. PMID- 23103933 TI - High-density integration of carbon nanotubes via chemical self-assembly. AB - Carbon nanotubes have potential in the development of high-speed and power efficient logic applications. However, for such technologies to be viable, a high density of semiconducting nanotubes must be placed at precise locations on a substrate. Here, we show that ion-exchange chemistry can be used to fabricate arrays of individually positioned carbon nanotubes with a density as high as 1 * 10(9) cm(-2)-two orders of magnitude higher than previous reports. With this approach, we assembled a high density of carbon-nanotube transistors in a conventional semiconductor fabrication line and then electrically tested more than 10,000 devices in a single chip. The ability to characterize such large distributions of nanotube devices is crucial for analysing transistor performance, yield and semiconducting nanotube purity. PMID- 23103934 TI - Nanowires: Hall effect breaks new ground. PMID- 23103935 TI - Plasmonic ELISA for the ultrasensitive detection of disease biomarkers with the naked eye. AB - In resource-constrained countries, affordable methodologies for the detection of disease biomarkers at ultralow concentrations can potentially improve the standard of living. However, current strategies for ultrasensitive detection often require sophisticated instruments that may not be available in laboratories with fewer resources. Here, we circumvent this problem by introducing a signal generation mechanism for biosensing that enables the detection of a few molecules of analyte with the naked eye. The enzyme label of an enzyme-linked immunosorbent assay (ELISA) controls the growth of gold nanoparticles and generates coloured solutions with distinct tonality when the analyte is present. Prostate specific antigen (PSA) and HIV-1 capsid antigen p24 were detected in whole serum at the ultralow concentration of 1 * 10(-18) g ml(-1). p24 was also detected with the naked eye in the sera of HIV-infected patients showing viral loads undetectable by a gold standard nucleic acid-based test. PMID- 23103936 TI - Progressive resistance versus relaxation training for breast cancer patients during adjuvant chemotherapy: design and rationale of a randomized controlled trial (BEATE study). AB - BACKGROUND AND RATIONALE: Cancer-related fatigue is a common severe symptom in breast cancer patients, especially during chemotherapy. Exercise appears to be promising in prevention or treatment of fatigue. Resistance training as an accompanying treatment to chemotherapy has been minimally investigated, yet might counteract muscle degradation and inflammation caused by many chemotherapeutics, and thus forestall or reduce fatigue. Previous exercise trials mostly compared the intervention with 'usual care'. Therefore, it is unclear to what extent the observed effects on fatigue are based on physical adaptations by exercise itself, or rather on psycho-social factors linked to the group support or attention by the trainer. METHODS AND DESIGN: The BEATE study is a randomized, controlled intervention trial comparing a 12-week supervised progressive resistance training program with a supervised group-based progressive muscle relaxation training in 100 patients with breast cancer under adjuvant chemotherapy. The primary endpoint is cancer-related fatigue; secondary endpoints include quality of life, depression, and cognitive capacity. In addition, isokinetic and isometric muscle strength, cardiorespiratory fitness, and body composition are measured, and biomarkers, such as inflammatory parameters, cortisol, and oxidative stress are analyzed in blood, saliva and urine. Safety of the resistance training during chemotherapy is monitored. DISCUSSION: Strengths of the BEATE study include the investigation of progressive resistance training parallel with chemotherapy, the choice of a control group that enables an evaluation of the physiological effects of exercise beyond potential psycho-social effects, and the comprehensive and high-quality assessment of physiological factors and biomarkers potentially related to fatigue. PMID- 23103937 TI - Vanadium-catalyzed enantioselective Friedel-Crafts-type reactions. AB - Vanadium-mediated enantioselective Friedel-Crafts (FC)-type reactions were established using the dinuclear vanadium complex (R(a),S,S)-1a. The vanadium complex promoted the FC-type reaction of imines with 2-naphthols or indoles to give corresponding adducts with high enantioselectivities. PMID- 23103938 TI - Optical detection of single nano-objects by transient absorption microscopy. AB - In recent years there has been considerable effort in developing ultra-sensitive imaging techniques based on absorption. This mini-review describes recent results from our laboratory on detecting single nano-objects using transient absorption microscopy. This technique is extremely flexible, allowing the detection of single semiconductor and metal nanostructures with high sensitivity. The goal of this review is to illustrate key points in implementing transient absorption microscopy for ultra-sensitive detection, as well as to discuss the advantages and disadvantages of this technique compared to other optical absorption based methods. PMID- 23103939 TI - Structural snapshots of the reaction coordinate for O-GlcNAc transferase. AB - Visualization of the reaction coordinate undertaken by glycosyltransferases has remained elusive but is critical for understanding this important class of enzyme. Using substrates and substrate mimics, we describe structural snapshots of all species along the kinetic pathway for human O-linked beta-N acetylglucosamine transferase (O-GlcNAc transferase), an intracellular enzyme that catalyzes installation of a dynamic post-translational modification. The structures reveal key features of the mechanism and show that substrate participation is important during catalysis. PMID- 23103941 TI - Glycobiology: The case of the missing base. PMID- 23103940 TI - DAGLbeta inhibition perturbs a lipid network involved in macrophage inflammatory responses. AB - The endocannabinoid 2-arachidonoylglycerol (2-AG) is biosynthesized by diacylglycerol lipases DAGLalpha and DAGLbeta. Chemical probes to perturb DAGLs are needed to characterize endocannabinoid function in biological processes. Here we report a series of 1,2,3-triazole urea inhibitors, along with paired negative control and activity-based probes, for the functional analysis of DAGLbeta in living systems. Optimized inhibitors showed high selectivity for DAGLbeta over other serine hydrolases, including DAGLalpha (~60-fold selectivity), and the limited off-targets, such as ABHD6, were also inhibited by the negative-control probe. Using these agents and Daglb(-/-) mice, we show that DAGLbeta inactivation lowers 2-AG, as well as arachidonic acid and eicosanoids, in mouse peritoneal macrophages in a manner that is distinct and complementary to disruption of cytosolic phospholipase-A2. We observed a corresponding reduction in lipopolysaccharide-induced tumor necrosis factor-alpha release. These findings indicate that DAGLbeta is a key metabolic hub within a lipid network that regulates proinflammatory responses in macrophages. PMID- 23103942 TI - O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis. AB - Protein O-GlcNAcylation is an essential post-translational modification on hundreds of intracellular proteins in metazoa, catalyzed by O-linked beta-N acetylglucosamine (O-GlcNAc) transferase (OGT) using unknown mechanisms of transfer and substrate recognition. Through crystallographic snapshots and mechanism-inspired chemical probes, we define how human OGT recognizes the sugar donor and acceptor peptide and uses a new catalytic mechanism of glycosyl transfer, involving the sugar donor alpha-phosphate as the catalytic base as well as an essential lysine. This mechanism seems to be a unique evolutionary solution to the spatial constraints imposed by a bulky protein acceptor substrate and explains the unexpected specificity of a recently reported metabolic OGT inhibitor. PMID- 23103946 TI - A peroxidase-active aptazyme as an isothermally amplifiable label in an aptazyme linked oligonucleotide assay for low-picomolar IgE detection. AB - A peroxidase-active hemin-aptamer was clicked onto an immunoglobulin E (IgE) binding aptamer. The resulting bifunctional aptamer was successfully used in a highly sensitive aptazyme-linked oligonucleotide assay (ALONA) for the detection of IgE. The sensitivity of the assay is enhanced by isothermal amplification of the aptazyme followed by colorimetric detection of the aptazyme's peroxidase activity, which can easily be evaluated even without advanced lab instruments. PMID- 23103947 TI - Coronary graft angioplasty guided by MSCT: an unexpected ostial stent deformation. PMID- 23103944 TI - Oxygenase-catalyzed ribosome hydroxylation occurs in prokaryotes and humans. AB - The finding that oxygenase-catalyzed protein hydroxylation regulates animal transcription raises questions as to whether the translation machinery and prokaryotic proteins are analogously modified. Escherichia coli ycfD is a growth regulating 2-oxoglutarate oxygenase catalyzing arginyl hydroxylation of the ribosomal protein Rpl16. Human ycfD homologs, Myc-induced nuclear antigen (MINA53) and NO66, are also linked to growth and catalyze histidyl hydroxylation of Rpl27a and Rpl8, respectively. This work reveals new therapeutic possibilities via oxygenase inhibition and by targeting modified over unmodified ribosomes. PMID- 23103948 TI - Site-dependency of the E/e' ratio in predicting invasive left ventricular filling pressure in patients with suspected or ascertained coronary artery disease. AB - PURPOSE: To test the accuracy of different mitral annular sites of the E/e' ratio in predicting invasive left ventricular filling pressure (LVFP) in patients hospitalized for coronary artery disease (CAD). METHODS: Forty-one patients with suspected or ascertained chronic CAD underwent non-invasive estimation of LVFP the same day as coronary angiography combined with right catheterization for pulmonary capillary wedge pressure (PCWP) assessment. The ratio between E velocity and early diastolic velocity of the mitral annulus (e') was calculated as a surrogate of PWCP by (i) averaging septal and lateral e' (E/e'A2); (ii) averaging septal, lateral, inferior, anterior (E/e'A4); (iii) using the sole septal (E/e'S); or (iv) lateral annulus (E/e'L). Patients were divided in two groups according to the PCWP: 25 with the PCWP <18 mmHg and 16 with the PCWP >= 18 mmHg. RESULTS: The two groups were comparable for gender, body mass index, blood pressure, heart rate (HR), E/A ratio, and deceleration time. The ejection fraction (EF) was lower and left atrial volume index (LAVi) greater (both P < 0.02) in patients with the PCWP >= 18 mmHg. They also exhibited higher E/e'S (P < 0.05), E/e'L (P < 0.0001), E/e'A2, and E/e'A4 (both P < 0.005) than patients with the PCWP <18 mmHg. In pooled groups, after adjusting for HR EF and LAVi, E/e'L (beta = 0.42, P < 0.01), E/e'A2 (beta = 0.32, P < 0.05), and E/e'A4 (beta = 0.31, P < 0.05) were all independently associated with PWCP. E/e'L >= 16.2 predicted PCWP >=18 mmHg with the highest diagnostic accuracy (AUC = 0.826), sensitivity (81.3%), and specificity (80%). CONCLUSIONS: In patients with CAD, E/e'L is the most accurate parameter in predicting abnormally increased LVFP. PMID- 23103943 TI - Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. AB - Cytokines dimerize their receptors, with the binding of the 'second chain' triggering signaling. In the interleukin (IL)-4 and IL-13 system, different cell types express varying numbers of alternative second receptor chains (gammac or IL 13Ralpha1), forming functionally distinct type I or type II complexes. We manipulated the affinity and specificity of second chain recruitment by human IL 4. A type I receptor-selective IL-4 'superkine' with 3,700-fold higher affinity for gammac was three- to ten-fold more potent than wild-type IL-4. Conversely, a variant with high affinity for IL-13Ralpha1 more potently activated cells expressing the type II receptor and induced differentiation of dendritic cells from monocytes, implicating the type II receptor in this process. Superkines showed signaling advantages on cells with lower second chain numbers. Comparative transcriptional analysis reveals that the superkines induce largely redundant gene expression profiles. Variable second chain numbers can be exploited to redirect cytokines toward distinct cell subsets and elicit new actions, potentially improving the selectivity of cytokine therapy. PMID- 23103949 TI - Supramolecular architectures of novel chromium(III) oxalate complexes: steric effects of the ligand size and building-blocks approach. AB - Five new oxalate complexes of chromium(III), [Hphen][Cr(phen)(C(2)O(4))(2)].2H(2)O (1), [Cr(phen)(2)(C(2)O(4))][Cr(phen)(C(2)O(4))(2)].3H(2)O (2), [Cr(phen)(2)(C(2)O(4))]NO(3).H(2)C(2)O(4).H(2)O (3), [Cr(bpy)(2)(C(2)O(4))][Cr(bpy)(C(2)O(4))(2)].3H(2)O (4) and [Cr(bpy)(2)(C(2)O(4))]NO(3).1/2H(2)C(2)O(4).4H(2)O (5) (phen = 1,10 phenanthroline, bpy = 2,2'-bipyridine), were prepared by using an (oxalato)tantalate(V) solution as a source of oxalate ligands. The compounds contain either the discrete mononuclear [Cr(L)(2)(C(2)O(4))](+) cation [L = phen (3); L = bpy (5)] or the discrete mononuclear [Cr(L)(C(2)O(4))(2)](-) anion [L = phen (1)], or both types of mononuclear ions [L = phen (2); L = bpy (4)]. The crystal structures are dominated by the hydrogen-bonding and pi...pi-stacking interactions that give rise to the overall two- (compounds 1, 2, 4, 5) or three dimensional (compound 3) architectures. Compounds 2 and 4 represent a borderline case between isostructurality and non-isostructurality; they exhibit an analogous packing of the cation and the anion units, but the crystallization water molecules occupy different positions - due to a difference in size between the phen and bpy ligands. The influence of steric factors is evident also in the case of 3 and 5, which, despite very similar chemical formulae, exert a completely different packing of the constituents. By the self-assembling of 1 and 4, used as building blocks in the reaction with calcium(II) cations, the heterobimetallic polymeric compounds {[CaCr(2)(phen)(2)(C(2)O(4))(4)].5H(2)O}(n) (6) and {[CaCr(2)(bpy)(2)(C(2)O(4))(4)].0.83H(2)O}(n) (7) were obtained. The crystal structure of 7 is reported: the [Cr(bpy)(C(2)O(4))(2)](-) unit, through the two oxalate groups, acts as a chelating ligand towards Ca cations, resulting in heterometallic one-dimensional double zigzag chains, formed of diamond-shaped units. The characterization of the compounds obtained was accomplished by the spectroscopy and thermal analysis methods. PMID- 23103950 TI - Water-mediated height artifacts in dynamic atomic force microscopy. AB - Amplitude modulation atomic force microscopy is one of the most broadly used techniques for the nanoscale characterization of a large variety of surfaces because it can routinely provide topography images with nanometer and subnanometer resolution in air, i.e. under ambient conditions, using available commercial instruments. The topographic map results from the convolution of the different interactions (van der Waals, capillary, adhesion, etc.) sensed by the probe and the presence of nanometer-thick water films on both the surface and the tip of the probe, as is usually the case under ambient conditions, can lead to apparent heights markedly different from the real heights due to formation and rupture of water menisci, particularly when the surfaces exhibit regions with different affinity to water (hydrophilic and hydrophobic). In order to systematically explore such a well-known but usually ignored phenomenon, we have performed a combined experimental and theoretical study using (hydrophobic) self assembled monolayers of stearic acid grown on (hydrophilic) freshly cleaved mica surfaces and a simplified point mass on a spring model to simulate the tip dynamics. We show that, depending on the operation parameters (free oscillation amplitude and setpoint), the apparent heights can vary in magnitude and sign (contrast inversion) and, most important, that the true height cannot be measured in the presence of water layers when surface affinity to water is not homogeneous even if menisci are not formed. We suggest to revise, within the perspective of the present investigation, those published works where the determination of heights is critical. PMID- 23103951 TI - Monte Carlo estimation of scatter effects on quantitative myocardial blood flow and perfusable tissue fraction using 3D-PET and (15)O-water. AB - In clinical cardiac positron emission tomography using (15)O-water, significant tracer accumulation is observed not only in the heart but also in the liver and lung, which are partially outside the field-of-view. In this work, we investigated the effects of scatter on quantitative myocardium blood flow (MBF) and perfusable tissue fraction (PTF) by a precise Monte Carlo simulation (Geant4) and a numerical human model. We assigned activities to the heart, liver, and lung of the human model with varying ratios of organ activities according to an experimental time activity curve and created dynamic sinograms. The sinogram data were reconstructed by filtered backprojection. By comparing a scatter-corrected image (SC) with a true image (TRUE), we evaluated the accuracy of the scatter correction. TRUE was reconstructed using a scatter-eliminated sinogram, which can be obtained only in simulations. A scatter-uncorrected image (W/O SC) and an attenuation-uncorrected image (W/O AC) were also constructed. Finally, we calculated MBF and PTF with a single tissue-compartment model for four types of images. As a result, scatter was corrected accurately, and MBFs derived from all types of images were consistent with the MBF obtained from TRUE. Meanwhile, the PTF of only the SC was in agreement with the PTF of TRUE. From the simulation results, we concluded that quantitative MBF is less affected by scatter and absorption in 3D-PET using (15)O-water. However, scatter correction is essential for accurate PTF. PMID- 23103952 TI - Dibenzo[a,c]carbazoles from 2-(2-bromoaryl)-3-arylindoles via a palladium catalyzed intramolecular C-H functionalization/C-C bond formation process. AB - The palladium-catalyzed cyclization of 2-(2-bromoaryl)-3-arylindoles provides a new versatile approach to dibenzo[a,c]carbazoles. The reaction tolerates a variety of useful substituents including chloro, nitro, ether, cyano, keto, and ester groups. PMID- 23103953 TI - Sinoscrewtine, an alkaloid with novel skeleton from the roots of Sinomenium acutum. AB - An alkaloid with novel skeleton, sinoscrewtine (1), has been isolated from the roots of Sinomenium acutum. Its structure was established by spectral analysis and X-ray crystallographic study, and its possible biosynthetic pathway was delivered. In vitro experiments, 1 showed weak injurious effects against H(2)O(2)/Abeta(25-35) induced oxidative injury in PC-12 cells and DPPH radical scavenging activity with IC(50) of 32.6MUM. PMID- 23103954 TI - Bioassay-guided isolation of urease and alpha-chymotrypsin inhibitory constituents from the stems of Lawsonia alba Lam. (Henna). AB - Seven constituents were isolated from the stems of Lawsonia alba Lam., following an activity-guided isolation, which include two new constituents, namely lawsorosemarinol (1) and lawsofructose (2), one known compound 2-(beta-d glucopyranosyloxy)-1, 4-naphthoquinone (3) and four compounds, 4-hydroxy coumarine (4), 3-(4-hyroxyphenyl)-triacontyl-(Z)-propenoate (5), 3-(4-hydroxy-3 methoxyphenyl)-triacontyl-(Z)-propenoate (6) and 7-hydroxy-4-methyl coumarin (7) first time isolated from Lawsonia alba. Their structure elucidation was based on spectroscopic data analyses. Compounds 3 and 7 showed a moderate inhibition of urease activity, while rest of them showed less than 50% inhibition. These compounds did not show any significant inhibition against alpha-chymotrypsin. PMID- 23103955 TI - Early change in blood glucose concentration is an indicator of mortality in critically ill children. AB - OBJECTIVE: Hyperglycaemia is associated with increased mortality in critically ill patients. A number of studies have highlighted an association between increased variability of blood glucose (BG) concentration and mortality, supporting a survival disadvantage if BG homeostasis is lost. By exploring the longitudinal BG profile of individual children over time, this study investigates the importance of intact homeostasis early after admission to the paediatric intensive care unit (PICU). DESIGN, SETTING, AND PATIENTS: Retrospective single centre observational study in a large multi-specialty PICU in the UK. Children admitted between August 2003 and February 2006 were included unless they met exclusion criteria. Data were merged from the PICU clinical database and blood gas analyser database by means of a unique PICU identifier. BG was measured frequently on a blood gas analyser (Bayer Rapidlink). Primary outcome was 100-day mortality. BG parameters were investigated for possible associations with mortality. MEASUREMENTS AND MAIN RESULTS: A total of 1,763 patients were included (median age 1.1 years; IQR 0.1-5.8). Although admission BG was not associated with mortality, a survival advantage was found in children who showed a reduction in BG on day 1 relative to the admission BG value (p < 0.001). This remained statistically significant (p = 0.007) after adjusting for severity of illness. CONCLUSIONS: This study supports an association between early BG profile and mortality in children admitted to PICU, with increased survival in those who demonstrate a fall in BG on day 1 relative to PICU admission. These findings are consistent with a survival advantage of intact BG homeostasis. PMID- 23103956 TI - Development and evaluation of a method for the quantification of airborne Thermoactinomyces vulgaris by real-time PCR. AB - Actinomycetes are ubiquitous and some can be potentially pathogenic for humans when present in the air of some working areas. It's notably the case for Thermoactinomyces vulgaris in composting facilities where aerial concentrations can reach high values of more than 10(7) CFU.m(-3). Workers exposure to these inhalable bioaerosols can be the source of various diseases. The literature reveals a lack of knowledge about risk assessment: there is neither dose-effects relationship for most agents, or threshold limit value. The objectives of this study were to develop and standardize a method to quantify workers exposure to bioaerosols. We have developed and evaluated a method to quantify airborne T. vulgaris based on DNA extraction of aerial microbial communities and qPCR. Four DNA extraction protocols were compared, and primers and a hydrolysis probe were designed for specific amplification of the target species (gyrB gene). This method was compared to traditional methods based on viable or cultivable counting by epifluorescence microscopy or plating on selective media. The method was applied on environmental bioaerosols sampled under real exposure conditions in composting plants. We demonstrate that the method to quantify T. vulgaris in bioaerosols is specific, sensitive and repeatable. We demonstrate the occurrence and quantified T. vulgaris in the atmosphere of composting facilities with concentrations ranging from 3*10(2) to 3*10(6)*m(-3). PMID- 23103957 TI - Anti-inflammatory effect of electroacupuncture in the C3H/HeJ mouse model of alopecia areata. PMID- 23103958 TI - Does optic nerve sheath diameter on MRI decrease with clinically improved pediatric hydrocephalus? AB - INTRODUCTION: Serial change in ventricular size is recognized as an imperfect indicator of ongoing hydrocephalus in children. Potentially, other radiographic features may be useful in determining the success of hydrocephalus interventions. In this study, optic nerve sheath diameter (ONSD), optic nerve tortuosity, and optic disk bulging were assessed as indicators of hydrocephalus control in children who underwent endoscopic third ventriculostomy (ETV) or posterior fossa tumor resection. METHODS: Sixteen children underwent ETV or tumor resection for treatment of hydrocephalus. T2-weighted axial magnetic resonance images of the orbit were obtained, and the ONSD was measured posterior to the optic globe, pre- and post-intervention. Evidence of optic disk bulging and optic nerve tortuosity was also assessed. Ventricular size was estimated using the frontal and occipital horn ratio (FOR). RESULTS: There was a significant reduction in the ONSD post-ETV (n = 9) and after tumor resection (n = 7). Average preoperative ONSD was 6.21 versus 5.71 mm postoperatively (p = 0.0017).There was also an 88% (p = 0.011) and 60% (p = 0.23) reduction in optic disk bulging and tortuosity, respectively. The FOR normalized in the tumor resection group but not the ETV group. After intervention, all patients showed improvement in signs and symptoms of hydrocephalus. CONCLUSION: In our study population, ONSD decreased in response to measures to reduce hydrocephalus. Optic disk bulging also appears to resolve. Serial reduction in ONSD, and optic disk bulging may be indicators of improved hydrocephalus following pediatric neurosurgical interventions. PMID- 23103959 TI - Are implants more reliable than severely compromised endodontically treated teeth as abutments for zirconia-based FPDs? : In vitro results of long-term preclinical load simulation. AB - OBJECTIVES: The aim was to study the impact of the defect size of endodontically treated incisors compared to dental implants as abutments on the survival of zirconia two-unit anterior cantilever-fixed partial dentures (2U-FPDs) during 10 year simulation. MATERIALS AND METHODS: Human maxillary central incisors were endodontically treated and divided into three groups (n = 24): I, access cavities rebuilt with composite core; II, teeth decoronated and restored with composite; and III as II supported by fiber posts. In group IV, implants with individual zirconia abutments were used. Specimens were restored with zirconia 2U-FPDs and exposed to two sequences of thermal cycling and mechanical loading. STATISTICS: Kaplan-Meier; log-rank tests. RESULTS: During TCML in group I two tooth fractures and two debondings with chipping were found. Solely chippings occurred in groups II (2*), IV (2*), and III (1*). No significant different survival was found for the different abutments (p = 0.085) or FPDs (p = 0.526). Load capability differed significantly between groups I (176 N) and III (670 N), and III and IV (324 N) (p < 0.024). CONCLUSION: Within the limitations of an in vitro study, it can be concluded that zirconia-framework 2U-FPDs on decoronated teeth with/without post showed comparable in vitro reliability as restorations on implants. The results indicated that restorations on teeth with only access cavity perform worse in survival and linear loading. CLINICAL RELEVANCE: Even severe defects do not justify per se a replacement of this particular tooth by a dental implant from load capability point of view. PMID- 23103960 TI - Proteomic and scanning electron microscopic analysis of submandibular sialoliths. AB - OBJECTIVES: Several theories have been proposed regarding the genesis of sialoliths, including the organic core theory, which suggests epithelial or bacterial etiology originating in the central core. Our aim was to use novel methodologies to analyze central areas (the core) of calculi from sialolithiasis patients. MATERIALS AND METHODS: The structures of the halves of six submandibular salivary stones were analyzed by scanning electron microscopy (SEM). After structural analysis, from the other six halves, samples from the central parts of the core and peripheral parts of the core were digested with trypsin and analyzed by matrix-assisted laser desorption ionization-time of flight mass spectrometry. The peptide mass fingerprints were compared with the results of in silico digestion. RESULTS: SEM analysis of the sialoliths showed that organic structures (collagen/fibrous-like structures, bacterial fragments) were visible only outside of the core in the concentric layers of external areas, but not in the core area. The mass spectrometry (MS)/MS post-source decay experiments were completed from the four, most intense signals observed in the MS spectrum and human defensin was proven to be present in three of the examined samples, originated from the peripheral region of three cores. CONCLUSIONS: Although proteomic analysis demonstrated defensin protein in the peripheral region of the core in three sialoliths, SEM failed to prove organic structures in the core. CLINICAL RELEVANCE: New investigation modalities still cannot prove organic structures in the core, henceforward challenging the organic core theory. PMID- 23103961 TI - Evaluation of the long-term storage stability of saliva as a source of human DNA. AB - OBJECTIVES: The objectives of this paper are to determine the storage stability of saliva at 37 degrees C over an 18-month period, and its influence on the DNA yield, purity, PCR protocols and genotyping efficacy. MATERIALS AND METHODS: Of the 60 participants, blood samples were obtained from 10 and saliva from 50. Samples were subjected to different storage conditions: DNA extracted immediately; DNA extracted following storage at 37 degrees C for 1, 6, 12 and 18 months. Subsequently, DNA yield, OD(260/280) and OD(260/230) ratios were measured. The isolated DNA was used to amplify exons 0-7 of the RUNX2 gene and subsequently sequenced. Furthermore, 25 SNPs were genotyped. RESULTS: The mean DNA yield, OD(260/280) and OD(260/230) ratios obtained from blood were 67.4 ng/MUl, 1.8 +/- 0.05 and 1.8 +/- 0.4 respectively. DNA yield obtained from saliva was significantly higher than blood (p < 0.0001), ranging from 97.4 to 125.8 ng/MUl while the OD(260/280) ratio ranged from 1.8 +/- 0.13 to 1.9 +/- 0.1. The success rates for the 25 SNPs ranged from 98 to 100 % for blood and 96-99 % for saliva samples with the genotype frequencies in Hardy-Weinberg equilibrium (>0.01). CONCLUSIONS: Saliva can be stored at 37 degrees C for 18 months without compromising its quality and ability to endure genetic analyses. CLINICAL RELEVANCE: Saliva is a viable source of human DNA to facilitate the feasibility of large-scale genetic studies. PMID- 23103962 TI - The outcome of surgically treated traumatic unstable pelvic fractures by open reduction and internal fixation. AB - BACKGROUND: This study was performed to evaluate functional and radiological results of pelvic ring fractures treatment by open reduction and internal fixation. METHODS: Thirty eight patients with unstable pelvic fractures, treated from 2002 to 2008 were retrospectively reviewed. The mean patients' age was 37 years (range 20 to 67). Twenty six patients were men (4 patients with type B and 22 patients with type C fracture) and 12 women (7 patients with type B and 5 patients with type C fracture). The commonest cause was a road traffic accident (N=37, about 97%). Internal fixation was done by plaque with ilioinguinal and Kocher-Langenbeek approaches for anterior, posterior pelvic wall and acetabulum fracture respectively. Quality of reduction was graded according to Majeed score system. RESULTS: There were 11 type-C and 27 type-B pelvic fractures according to Tile's classification. Thirty six patients sustained additional injuries. The commonest additional injury was lower extremity fracture. The mean follow-up was 45.6 months (range 16 to 84 months).The functional outcome was excellent in 66%, good in 15%, fair in 11% and poor in 7% of the patients with type B pelvic fractures and functional outcome was excellent in 46%, good in 27%, fair in 27% and poor in 0% of the patients with type C pelvic fractures. There were four postoperative infections. No sexual functional problem was reported. Neurologic problem like Lateral cutaneous nerve of thigh injury recovered completely in 2 patients and partially in 2 patients. There was no significant relation between functional outcome and the site of fracture (P greater than 0.005). CONCLUSIONS: Unstable pelvic ring fracture injuries should be managed surgically by rigid stabilization. It must be carried out as soon as the general condition of the patient permits, and even up to two weeks. PMID- 23103963 TI - A supramodal accumulation-to-bound signal that determines perceptual decisions in humans. AB - In theoretical accounts of perceptual decision-making, a decision variable integrates noisy sensory evidence and determines action through a boundary crossing criterion. Signals bearing these very properties have been characterized in single neurons in monkeys, but have yet to be directly identified in humans. Using a gradual target detection task, we isolated a freely evolving decision variable signal in human subjects that exhibited every aspect of the dynamics observed in its single-neuron counterparts. This signal could be continuously tracked in parallel with fully dissociable sensory encoding and motor preparation signals, and could be systematically perturbed mid-flight during decision formation. Furthermore, we found that the signal was completely domain general: it exhibited the same decision-predictive dynamics regardless of sensory modality and stimulus features and tracked cumulative evidence even in the absence of overt action. These findings provide a uniquely clear view on the neural determinants of simple perceptual decisions in humans. PMID- 23103964 TI - Fluorescent and photo-oxidizing TimeSTAMP tags track protein fates in light and electron microscopy. AB - Protein synthesis is highly regulated throughout nervous system development, plasticity and regeneration. However, tracking the distributions of specific new protein species has not been possible in living neurons or at the ultrastructural level. Previously we created TimeSTAMP epitope tags, drug-controlled tags for immunohistochemical detection of specific new proteins synthesized at defined times. Here we extend TimeSTAMP to label new protein copies by fluorescence or photo-oxidation. Live microscopy of a fluorescent TimeSTAMP tag reveals that copies of the synaptic protein PSD95 are synthesized in response to local activation of growth factor and neurotransmitter receptors, and preferentially localize to stimulated synapses in rat neurons. Electron microscopy of a photo oxidizing TimeSTAMP tag reveals new PSD95 at developing dendritic structures of immature neurons and at synapses in differentiated neurons. These results demonstrate the versatility of the TimeSTAMP approach for visualizing newly synthesized proteins in neurons. PMID- 23103965 TI - Sustained Hox5 gene activity is required for respiratory motor neuron development. AB - Respiration in mammals relies on the rhythmic firing of neurons in the phrenic motor column (PMC), a motor neuron group that provides the sole source of diaphragm innervation. Despite their essential role in breathing, the specific determinants of PMC identity and patterns of connectivity are largely unknown. We show that two Hox genes, Hoxa5 and Hoxc5, control diverse aspects of PMC development including their clustering, intramuscular branching, and survival. In mice lacking Hox5 genes in motor neurons, axons extend to the diaphragm, but fail to arborize, leading to respiratory failure. Genetic rescue of cell death fails to restore columnar organization and branching patterns, indicating these defects are independent of neuronal loss. Unexpectedly, late Hox5 removal preserves columnar organization but depletes PMC number and branches, demonstrating a continuous requirement for Hox function in motor neurons. These findings indicate that Hox5 genes orchestrate PMC development through deployment of temporally distinct wiring programs. PMID- 23103967 TI - Multiplexed detection of aquaculture fungicides using a pump-free optofluidic SERS microsystem. AB - In this work, an optofluidic SERS device optimized for on-site analytics in the field is utilized for the multiplexed detection of three fungicides that are highly regulated in aquaculture. The optofluidic SERS microsystem does not require a bulky pump for sample loading, which significantly improves its portability; the sample is simply loaded into the device by applying negative pressure using a pipette. Moreover, integrated fiber optic cables automate sample excitation and signal collection without the need for alignment on a traditional Raman microscope. The detection zone of the device consists of a porous matrix of packed silica microspheres that accumulates silver nanoparticles and adsorbed analyte molecules. This passive concentration matrix has been shown to boost the SERS signal by up to four orders of magnitude as compared to SERS in an open microfluidic channel. We were able to detect as low as 5 ppm methyl parathion, 0.1 ppb malachite green, and 5 ppb thiram simultaneously. PMID- 23103966 TI - Upregulation of cornichon transcripts in the dorsolateral prefrontal cortex in schizophrenia. AB - Schizophrenia has been proposed to be associated with abnormal glutamatergic neurotransmission. The AMPA subtype of glutamate receptors (AMPARs) mediates fast excitatory synaptic transmission in the brain, and their trafficking and function is regulated in part by AMPAR auxiliary proteins including the cornichons (CNIH) and transmembrane AMPAR-regulatory proteins. Abnormal regulation of AMPARs through altered expression of these auxiliary proteins could induce changes in glutamatergic neurotransmission and thus the pathophysiology of schizophrenia. In this study, transcript expression of cornichon homologs 1-4 was measured in the dorsolateral prefrontal cortex from schizophrenia (N=25) and comparison (N=25) patient groups by comparative quantitative real-time PCR. Significant upregulation of CNIH-1, CNIH-2, and CNIH-3 mRNA expression was found in schizophrenia, with no change in CNIH-4 expression. To determine the effect of antipsychotic treatment on the expression of these genes, cornichon mRNA expression was assayed in the frontal cortex of rats treated chronically with haloperidol decanoate and no changes in any of the cornichon transcripts were found. Abnormal expression of the CNIH family of genes is consistent with cornichon-mediated AMPAR trafficking abnormalities in schizophrenia, and suggests a new mechanism contributing toward the pathophysiology of this illness. PMID- 23103968 TI - Coupling geostatistical approaches with PCA and fuzzy optimal model (FOM) for the integrated assessment of sampling locations of water quality monitoring networks (WQMNs). AB - The assessment of the adequacy of sampling locations is an important aspect in the validation of an effective and efficient water quality monitoring network. Two geostatistical approaches (e.g., kriging and Moran's I) are presented to assess multiple sampling locations. A flexible and comprehensive framework was developed for the selection of multiple sampling locations of multiple variables which was accomplished by coupling geostatistical approaches with principal component analysis (PCA) and fuzzy optimal model (FOM). The FOM was used in the integrated assessment of both multiple principal components and multiple geostatistical approaches. These integrated methods were successfully applied to the assessment of two independent water quality monitoring networks (WQMNs) of Lake Winnipeg, Canada, which respectively included 14 and 30 stations from 2006 to 2010. PMID- 23103969 TI - Misalignments calibration in small-animal PET scanners based on rotating planar detectors and parallel-beam geometry. AB - Technological advances have improved the assembly process of PET detectors, resulting in quite small mechanical tolerances. However, in high-spatial resolution systems, even submillimetric misalignments of the detectors may lead to a notable degradation of image resolution and artifacts. Therefore, the exact characterization of misalignments is critical for optimum reconstruction quality in such systems. This subject has been widely studied for CT and SPECT scanners based on cone beam geometry, but this is not the case for PET tomographs based on rotating planar detectors. The purpose of this work is to analyze misalignment effects in these systems and to propose a robust and easy-to-implement protocol for geometric characterization. The result of the proposed calibration method, which requires no more than a simple calibration phantom, can then be used to generate a correct 3D-sinogram from the acquired list mode data. PMID- 23103970 TI - Regioselective photodimerization of pyridyl-butadienes within cucurbit[8]uril cavities. AB - The cucurbit[8]uril (CB8) templation strategy that is known to yield stereoselective photodimers of organic olefins has been extended to substituted butadienes. By virtue of its strong binding interactions with guests the rigid cavity of CB8 is capable of preorienting the diene guests to result in greater yields of stereoselective photodimers upon irradiation. The symmetry of the butadiene monomers influences the relative arrangement of the monomers in complexes leading to the observed product selectivity. PMID- 23103971 TI - Scaling up minimum enclosing ball with total soft margin for training on large datasets. AB - Recent research indicates that the standard Minimum Enclosing Ball (MEB) or the center-constrained MEB can be used for effective training on large datasets by employing the core vector machine (CVM) or generalized CVM (GCVM). However, for another extensively-used MEB, i.e., MEB with total soft margin (T-MEB for brevity), we cannot directly employ the CVM or GCVM to realize its fast training for large datasets due to the fact that the involved inequality constraint is violated. In this paper, a fast learning algorithm called FL-TMEB for scaling up T-MEB is presented. First, FL-TMEB slightly relaxes the constraints in TMEB such that it can be equivalent to the corresponding center-constrained MEB, which can be solved with the corresponding Core Set (CS) by CVM. Then, with the help of the sub-optimal solution theorem about T-MEB, FL-TMEB attempts to obtain the extended core set (ECS) by including the neighbors of some samples in the CS into the ECS. Finally, FL-TMEB takes the optimal weights of ECS as the approximation solution of T-MEB. Experimental results on UCI and USPS datasets demonstrate that the proposed method is effective. PMID- 23103972 TI - An analog implementation of biologically plausible neurons using CCII building blocks. AB - This study presents an analog implementation of the spiking neurons based on a piecewise-linear model. This model is a variation of the Izhikevich model, which is capable of reproducing different dynamic behaviors. The proposed circuit utilizes second generation current conveyors (CCII) building blocks. With the same topology and circuit values, this circuit can produce a wide variety of neuron behaviors just by tuning the reference current and voltage sources. In addition, since CCII can be considered as a building block for programmable analog arrays, based on the proposed circuit different neuron types can be implemented on programmable analog platforms. Simulation results are presented for different neuron behaviors with CMOS 350 nm +/-1.5 V technology using HSPICE. PMID- 23103973 TI - Identification of the genes involved in the secretion and self-immunity of lacticin Q, an unmodified leaderless bacteriocin from Lactococcus lactis QU 5. AB - Lacticin Q (LnqQ) produced by Lactococcus lactis QU 5 is an unmodified linear bacteriocin, which is synthesized without an N-terminal leader peptide. In vitro synthesis and in vivo expression of LnqQ have revealed the intracellular toxicity of this leaderless peptide, as well as the necessity of a dedicated secretion and self-immunity system of producer cells. Further DNA sequencing and analysis have discovered 11 putative orf genes at the LnqQ locus. None of the orf genes showed similarities to any of the bacteriocin biosynthetic genes characterized to date; however, six orf genes (orf2q-7q), not including the structural gene (lnqQ), were highly conserved at the lacticin Z locus (orf2z-7z), which is a LnqQ homologue produced by L. lactis QU 14. ORF2q (ORF2z), the gene of which is located upstream of the structural gene, is a putative transcriptional regulator, whereas ORF6q and ORF7q (ORF6z and ORF7z) form a putative ATP-binding cassette transporter. The ORF3q-5q (ORF3z-5z) are all predicted to be membrane proteins with no clear functions. Co-expression of LnqQ and ORF3q-7q in a heterologous host allowed the extracellular production of LnqQ; additionally, the expression of ORF3q-7q rendered the host cells immune to LnqQ. This self-immunity was facilitated possibly by two means; firstly, by secreting the active LnqQ peptides, thus reducing the intracellular toxicity, and secondly, by protecting the host cells from extracellularly released LnqQ. This is the first report, to our knowledge, that describes intracellular toxicity of a leaderless bacteriocin and provides a rare example of biosynthetic genes that are required for bacteriocin secretion and immunity. PMID- 23103974 TI - Direct surfactin-gramicidin S antagonism supports detoxification in mixed producer cultures of Bacillus subtilis and Aneurinibacillus migulanus. AB - Antibiotic production as a defence mechanism is a characteristic of a wide variety of organisms. In natural evolutionary adaptation, cellular events such as sporulation, biofilm formation and resistance to antibiotics enable some micro organisms to survive environmental and antibiotic stress conditions. The two antimicrobial cyclic peptides in this study, gramicidin S (GS) from Aneurinibacillus migulanus and the lipopeptide surfactin (Srf) from Bacillus subtilis, have been shown to affect both membrane and intercellular components of target organisms. Many functions, other than that of antimicrobial activity, have been assigned to Srf. We present evidence that an additional function may exist for Srf, namely that of a detoxifying agent that protects its producer from the lytic activity of GS. We observed that Srf producers were more resistant to GS and could be co-cultured with the GS producer. Furthermore, exogenous Srf antagonized the activity of GS against both Srf-producing and non-producing bacterial strains. A molecular interaction between the anionic Srf and the cationic GS was observed with circular dichroism and electrospray MS. Our results indicate that the formation of an inactive complex between GS and Srf supports resistance towards GS, with the anionic Srf forming a chemical barrier to protect its producer. This direct detoxification combined with the induction of protective stress responses in B. subtilis by Srf confers resistance toward GS from A. migulanus and allows survival in mixed cultures. PMID- 23103975 TI - A soluble diacylglycerol acyltransferase is involved in triacylglycerol biosynthesis in the oleaginous yeast Rhodotorula glutinis. AB - The biosynthesis of triacylglycerol (TAG) occurs in the microsomal membranes of eukaryotes. Here, we report the identification and functional characterization of diacylglycerol acyltransferase (DGAT), a member of the 10 S cytosolic TAG biosynthetic complex (TBC) in Rhodotorula glutinis. Both a full-length and an N terminally truncated cDNA clone of a single gene were isolated from R. glutinis. The DGAT activity of the protein encoded by RgDGAT was confirmed in vivo by the heterologous expression of cDNA in a Saccharomyces cerevisiae quadruple mutant (H1246) that is defective in TAG synthesis. RgDGAT overexpression in yeast was found to be capable of acylating diacylglycerol (DAG) in an acyl-CoA-dependent manner. Quadruple mutant yeast cells exhibit growth defects in the presence of oleic acid, but wild-type yeast cells do not. In an in vivo fatty acid supplementation experiment, RgDGAT expression rescued quadruple mutant growth in an oleate-containing medium. We describe a soluble acyl-CoA-dependent DAG acyltransferase from R. glutinis that belongs to the DGAT3 class of enzymes. The study highlights the importance of an alternative TAG biosynthetic pathway in oleaginous yeasts. PMID- 23103976 TI - A novel strategy to isolate cell-envelope mutants resistant to phage infection: bacteriophage mEp213 requires lipopolysaccharides in addition to FhuA to enter Escherichia coli K-12. AB - We have developed a direct and efficient strategy, based on a three-step method, to select bacterial cell-envelope mutants resistant to bacteriophage infection. Escherichia coli K-12 strain W3110 underwent classical transposon mutagenesis followed by replica plating and selection for mutants resistant to infection by coliphage mEp213. To verify that phage resistance was due to mutations in the cell envelope, we transformed host cells with the viral genome using electroporation and selected those in which virions were subsequently detected in the supernatant. Among the nine mutants resistant to coliphage infection that we selected, six were in the fhuA gene, two were mutated in the waaC gene, and one was mutated in the gmhD gene. The latter two gene products are involved in the synthesis of lipopolysaccharide (LPS). The efficiency of plating and adsorption of phage mEp213 was affected in these mutants. We verified that LPS is required for the efficient infection of phage lambda as well. We propose that this mutation-and-selection strategy can be used to find host factors involved in the initial steps of phage infection for any cognate pair of phage and bacteria. PMID- 23103977 TI - Induction of extracytoplasmic function sigma factors in Bacillus subtilis cells with defects in lipoteichoic acid synthesis. AB - Lipoteichoic acid (LTA) is an important cell envelope component of Gram-positive bacteria. Bacillus subtilis has four homologous genes for LTA synthesis: ltaS (yflE), yfnI, yqgS and yvgJ. The products LtaS (YflE), YfnI and YqgS are bona fide LTA synthetases, whereas YvgJ functions only as an LTA primase. To clarify whether defects in LTA on the cell envelope trigger extracytoplasmic function (ECF) sigma factors, mRNA levels of the autoregulated ECF sigma factors in cells with singly and multiply deleted alleles of the ltaS homologues were examined by real-time RT-PCR. This revealed that sigM and sigX were induced in cells with a null allele of DeltaltaS and DeltayfnI, respectively, and that no ECF sigma factor was induced in cells with a single null allele of DeltayqgS or DeltayvgJ. In cells with double null alleles (DeltaltaS and DeltayfnI), sigW and ylaC were induced in addition to sigM and sigX. Cells with triple null alleles (DeltaltaS DeltayfnI and DeltayqgS) showed a pattern of induction similar to that of the double null. In cells with quadruple null alleles, sigV and sigY were newly induced. Cells with DeltaltaS had approximately 1/4 the diglucosyldiacylglycerol and over 10 times the CDP-diacylglycerol of wild-type cells. Compensatory elevation of the mRNA level of other homologues was observed (in DeltaltaS cells the level of yfnI was elevated; in DeltayfnI cells that of yqgS and yvgJ was elevated; both were even higher in DeltaltaS DeltayfnI cells). In DeltaltaS cells, the mRNA level of yfnI was corroborated to be regulated by sigma(M), which is activated in the null mutant cells. In DeltayfnI cells, the mRNA levels of yqgS and yvgJ reverted to less than those of wild-type when a defective sigX allele was introduced. Since sigX was activated in cells with DeltayfnI, this suggests that the induction of yqgS and yvgJ is dependent on sigma(X). The LTAs produced by the four ltaS homologues seem to play distinct physiological roles to maintain the full function of LTA on the B. subtilis cell envelope. PMID- 23103978 TI - Boto, a class II transposon in Moniliophthora perniciosa, is the first representative of the PIF/Harbinger superfamily in a phytopathogenic fungus. AB - Boto, a class II transposable element, was characterized in the Moniliophthora perniciosa genome. The Boto transposase is highly similar to plant PIF-like transposases that belong to the newest class II superfamily known as PIF/Harbinger. Although Boto shares characteristics with PIF-like elements, other characteristics, such as the transposase intron position, the position and direction of the second ORF, and the footprint, indicate that Boto belongs to a novel family of the PIF/Harbinger superfamily. Southern blot analyses detected 6 12 copies of Boto in C-biotype isolates and a ubiquitous presence among the C- and S-biotypes, as well as a separation in the C-biotype isolates from Bahia State in Brazil in at least two genotypic groups, and a new insertion in the genome of a C-biotype isolate maintained in the laboratory for 6 years. In addition to PCR amplification from a specific insertion site, changes in the Boto hybridization profile after the M. perniciosa sexual cycle and detection of Boto transcripts gave further evidence of Boto activity. As an active family in the genome of M. perniciosa, Boto elements may contribute to genetic variability in this homothallic fungus. This is the first report of a PIF/Harbinger transposon in the genome of a phytopathogenic fungus. PMID- 23103979 TI - High-resolution detection of DNA binding sites of the global transcriptional regulator GlxR in Corynebacterium glutamicum. AB - The transcriptional regulator GlxR has been characterized as a global hub within the gene-regulatory network of Corynebacterium glutamicum. Chromatin immunoprecipitation with a specific anti-GlxR antibody and subsequent high throughput sequencing (ChIP-seq) was applied to C. glutamicum to get new in vivo insights into the gene composition of the GlxR regulon. In a comparative approach, C. glutamicum cells were grown with either glucose or acetate as the sole carbon source prior to immunoprecipitation. High-throughput sequencing resulted in 69 million reads and 2.6 Gb of genomic information. After mapping of these data on the genome sequence of C. glutamicum, 107 enriched DNA fragments were detected from cells grown with glucose as carbon source. GlxR binding sites were identified in the sequence of 79 enriched DNA fragments, of which 21 sites were not previously reported. Electrophoretic mobility shift assays with 40-mer oligomers covering the GlxR binding sites were performed for validation of the in vivo results. The detection of new binding sites confirmed the role of GlxR as a regulator of carbon source metabolism and energy conversion, but additionally revealed binding of GlxR in front of the 6C non-coding RNA gene and to non canonical DNA binding sites within protein-coding regions. The present study underlines the dynamics within the GlxR regulon by identifying in vivo targets during growth on glucose and contributes to the expansion of knowledge of this important transcriptional regulator. PMID- 23103980 TI - Variability of venom components in immune suppressive parasitoid wasps: from a phylogenetic to a population approach. AB - Endoparasitoid wasps develop at the expense of other insects, leading to their death. Eggs deposited inside the host body induce an immune response, which results in the formation of a melanized cellular capsule around the egg. To evade or counteract this response, endoparasitoids have evolved different strategies, the most often reported being injection into the host of immunosuppressive factors, notably venom proteins, along with the egg. The analysis of venom components has been performed independently in species of different taxa, but the present picture is far from complete. Intriguingly, the question of the level of venom variability inside species has been neglected, although it may partly determine the potential for parasitoid adaptation. Here, we present a short review of our present knowledge of venom components in endoparasitoids, as well as of the only well-known example of intraspecific variability in a venom immune suppressive protein being responsible for variation in parasitoid virulence. We then present data evidencing inter-individual variation of venom protein profiles, using a gel electrophoresis approach, both in laboratory strains and field populations of a figitid and a braconid species. Whether occurrence of such variability may permit a selection of parasitoid venom components driven by the host remains to be tested, notably in the context of the production and use of biological control auxiliaries. PMID- 23103981 TI - Size-induced reproductive constraints in an egg parasitoid. AB - The size of adult parasitoids is influenced by the quantity and quality of resources available during immature development. Gregarious development of endoparasitoids results in scramble competition where the resources are shared among individuals developing into the same host. Individuals that developed gregariously are therefore smaller and that reduced size generally translates into lower fitness due to reductions in several life history traits including longevity, mobility and traits linked to reproduction. We measured the reproductive constraints induced by size in Anaphes listronoti (Hymenoptera: Mymaridae), a facultative gregarious egg parasitoid of Curculionidae. Size decreased with number of immatures developing in a host egg for both male and female A. listronoti. This reduction in size induced a reproductive cost as both males and females produced fewer gametes when developing gregariously. Contrarily to other egg parasitoids, A. listronoti males are not prospermatogenic and produced some sperm during their adult life. Their spermatogeny index is estimated at 0.6-0.7 that places this species as moderately synspermatogenic. Female A. listronoti have an ovigeny index of 0.70 and are therefore moderately synovigenic. Large females that developed singly received a full sperm complement only when mated by a large male that also developed singly. When mating with a small triplet male, a large female received less than half her sperm complement. Large males were able to mate three females before the number of sperm transferred started to decrease. PMID- 23103982 TI - Circadian rhythms and endocrine functions in adult insects. AB - Many behavioral and physiological processes in adult insects are influenced by both the endocrine and circadian systems, suggesting that these two key physiological systems interact. We reviewed the literature and found that experiments explicitly testing these interactions in adult insects have only been conducted for a few species. There is a shortage of measurements of hormone titers throughout the day under constant conditions even for the juvenile hormones (JHs) and ecdysteroids, the best studied insect hormones. Nevertheless, the available measurements of hormone titers coupled with indirect evidence for circadian modulation of hormone biosynthesis rate, and the expression of genes encoding proteins involved in hormone biosynthesis, binding or degradation are consistent with the hypothesis that the circulating levels of many insect hormones are influenced by the circadian system. Whole genome microarray studies suggest that the modulation of farnesol oxidase levels is important for the circadian regulation of JH biosynthesis in honey bees, mosquitoes, and fruit flies. Several studies have begun to address the functional significance of circadian oscillations in endocrine signaling. The best understood system is the circadian regulation of Pheromone Biosynthesis Activating Neuropeptide (PBAN) titers which is important for the temporal organization of sexual behavior in female moths. The evidence that the circadian and endocrine systems interact has important implications for studies of insect physiology and behavior. Additional studies on diverse species and physiological processes are needed for identifying basic principles underlying the interactions between the circadian and endocrine systems in insects. PMID- 23103983 TI - Active self-healing encapsulation of vaccine antigens in PLGA microspheres. AB - Herein, we describe the detailed development of a simple and effective method to microencapsulate vaccine antigens in poly(lactic-co-glycolic acid) (PLGA) by simple mixing of preformed active self-microencapsulating (SM) PLGA microspheres in a low concentration aqueous antigen solution at modest temperature (10-38 degrees C). Co-encapsulating protein-sorbing vaccine adjuvants and polymer plasticizers were used to "actively" load the protein in the polymer pores and facilitate polymer self-healing at a temperature>the hydrated polymer glass transition temperature, respectively. The microsphere formulation parameters and loading conditions to provide optimal active self-healing microencapsulation of vaccine antigens in PLGA was investigated. Active self-healing encapsulation of two antigens, ovalbumin and tetanus toxoid (TT), in PLGA microspheres was adjusted by preparing blank microspheres containing different vaccine adjuvants (aluminum hydroxide (Al(OH)3) or calcium phosphate). Active loading of vaccine antigen in Al(OH)3-PLGA microspheres was found to: a) increase with an increasing loading of Al(OH)3 (0.88-3 wt.%) and addition of porosigen, b) decrease when the inner Al(OH)3/trehalose phase to 1 mL outer oil phase and size of microspheres was respectively >0.2 mL and 63 MUm, and c) change negligibly by PLGA concentration and initial incubation (loading) temperature. Encapsulation of protein sorbing Al(OH)3 in PLGA microspheres resulted in suppression of self healing of PLGA pores, which was then overcome by improving polymer chain mobility, which in turn was accomplished by coincorporating hydrophobic plasticizers in PLGA. Active self-healing microencapsulation of manufacturing process-labile TT in PLGA was found to: a) obviate micronization- and organic solvent-induced TT degradation, b) improve antigen loading (1.4-1.8 wt.% TT) and encapsulation efficiency (~97%), c) provide nearly homogeneous distribution and stabilization of antigen in polymer, and d) provide improved in vitro controlled release of antigenic TT. PMID- 23103984 TI - The multilayer nanoparticles formed by layer by layer approach for cancer targeting therapy. AB - The multilayer nanoparticles (NPs) were prepared for cancer-targeting therapy using the layer by layer approach. When drug-loaded Pluronic NPs were mixed with vesicles (liposomes) in the aqueous medium, Pluronic NPs were incorporated into the vesicles to form the vesicle NPs. Then, the multilayer NPs were formed by freeze-drying the vesicle NPs in a Pluronic aqueous solution. The morphology and size distribution of the multilayer NPs were observed using a TEM and a particle size analyzer. In order to apply the multilayer NPs as a delivery system for docetaxel (DTX), which is a model anticancer drug, the release pattern of the DTX was observed and the tumor growth was monitored by injecting the multilayer NPs into the tail veins of tumor (squamous cell carcinoma)-bearing mice. The cytotoxicity of free DTX (commercial DTX formulation (Taxotere(r))) and the multilayer NPs was evaluated using MTT assay. We also evaluated the tumor targeting ability of the multilayer NPs using magnetic resonance imaging. The multilayer NPs showed excellent tumor targetability and antitumor efficacy in tumor-bearing mice, caused by the enhanced permeation and retention (EPR) effect. These results suggest that the multilayer NPs could be a potential drug delivery system for cancer-targeting therapy. PMID- 23103986 TI - T cells: TCR affinity goes asymmetric. PMID- 23103987 TI - Composition of the outermost layer and concentration depth profiles of ammonium nitrate ionic liquid surfaces. AB - Differences in the surface structure of protic ionic liquids (ILs) with three different cations and a common anion; ethyl-, propyl- and 2-hydroxyethyl- (or ethanol-) ammonium nitrate (EAN, PAN and EtAN, respectively) have been observed by neutral impact collision ion scattering spectroscopy (NICISS) and metastable induced electron spectroscopy/ultraviolet photoelectron spectroscopy (MIES/UPS). NICISS is used to determine the concentration depth profiles of the elements in each IL and it reveals an enrichment of cation alkyl chains of PAN and EtAN in the outermost layer compared to EAN, and a corresponding depletion of nitrate from the outermost layer of the EtAN surface. MIES probes the molecular orbitals of only the species in the outermost layer of a sample and confirms that, while both the anion and the cation are present to some degree at the surface of all three ILs, the cation is enriched to a greater extent at the surface of PAN and EtAN compared to EAN. PMID- 23103985 TI - New concepts in the generation and functions of IgA. AB - The intestinal mucosa contains the largest population of antibody-secreting plasma cells in the body, and in humans several grams of secretory immunoglobulin A (SIgA) are released into the intestine each day. In the gut lumen, SIgA serves as a first-line barrier that protects the epithelium from pathogens and toxins. Recently, next-generation sequencing has revolutionized our understanding of the nature of the intestinal microbiota and has also shed new light on the important roles of SIgA in the regulation of host-commensal homeostasis. Here, I discuss pathways of IgA induction in the context of SIgA specificity and function. PMID- 23103988 TI - Reproducibility and robustness of metabolome analysis in rat plasma of 28-day repeated dose toxicity studies. AB - BASF has developed a rat plasma metabolomics database (MetaMap(r)Tox) containing the metabolome of more than 500 chemicals, agrochemicals and drugs, for which the toxicity is well known, derived from 28-day repeated dose toxicity studies in rats. The quality/reproducibility of data was assessed by comparing the metabolome of 16 reference compounds tested at least twice under identical experimental conditions at three time points (day 7, day 14 and day 28). Statistical correlation analysis showed that the repeated treatment induced very similar changes to the metabolome. For all repetitions the modes of action of the compounds were always correctly identified. Moreover, when compared against the metabolome of all compounds available in the MetaMap(r)Tox database, the repetitions showed in most cases the highest degree of overall similarity with the metabolome of the original study. In addition, we also evaluated the robustness of our metabolomics technique, displayed by constancy of variability in control groups over time. Based on these results, it can be concluded, that metabolomics can reproducibly be applied during toxicological in vivo testing in rats under the conditions applied here. PMID- 23103989 TI - TDP-43 and FUS/TLS yield a target-rich haul in ALS. PMID- 23103990 TI - New twist on orphan receptor GPR88 function. PMID- 23103991 TI - The medial entorhinal cortex keeps Up. PMID- 23103992 TI - Two layers of neural variability. PMID- 23103993 TI - Cdk5 keeps memory on Trk. PMID- 23103994 TI - Functions of rice NAC transcriptional factors, ONAC122 and ONAC131, in defense responses against Magnaporthe grisea. AB - NAC (NAM/ATAF/CUC) transcription factors have important functions in regulating plant growth, development, and abiotic and biotic stress responses. Here, we characterized two rice pathogen-responsive NAC transcription factors, ONAC122 and ONAC131. We determined that these proteins localized to the nucleus when expressed ectopically and had transcriptional activation activities. ONAC122 and ONAC131 expression was induced after infection by Magnaporthe grisea, the causal agent of rice blast disease, and the M. grisea-induced expression of both genes was faster and higher in the incompatible interaction compared with the compatible interaction during early stages of infection. ONAC122 and ONAC131 were also induced by treatment with salicylic acid, methyl jasmonate or 1 aminocyclopropane-1-carboxylic acid (a precursor of ethylene). Silencing ONAC122 or ONAC131 expression using a newly modified Brome mosaic virus (BMV)-based silencing vector resulted in an enhanced susceptibility to M. grisea. Furthermore, expression levels of several other defense- and signaling-related genes (i.e. OsLOX, OsPR1a, OsWRKY45 and OsNH1) were down-regulated in plants silenced for ONAC122 or ONAC131 expression via the BMV-based silencing system. Our results suggest that both ONAC122 and ONAC131 have important roles in rice disease resistance responses through the regulated expression of other defense- and signaling-related genes. PMID- 23103995 TI - Cystic fibrosis therapy: a community ecology perspective. AB - Current therapy for cystic fibrosis (CF) focuses on minimizing the microbial community and the host's immune response through the aggressive use of airway clearance techniques, broad-spectrum antibiotics, and treatments that break down the pervasive endobronchial biofilm. Antibiotic selection is typically based on the susceptibility of individual microbial strains to specific antibiotics in vitro. Often this approach cannot accurately predict medical outcomes because of factors both technical and biological. Recent culture-independent assessments of the airway microbial and viral communities demonstrated that the CF airway infection is considerably more complex and dynamic than previously appreciated. Understanding the ecological and evolutionary pressures that shape these communities is critically important for the optimal use of current therapies (in both the choice of therapy and timing of administration) and the development of newer strategies. The climax-attack model (CAM) presented here, grounded in basic ecological principles, postulates the existence of two major functional communities. The attack community consists of transient viral and microbial populations that induce strong innate immune responses. The resultant intense immune response creates microenvironments that facilitate the establishment of a climax community that is slower-growing and inherently resistant to antibiotic therapy. Newer methodologies, including sequence-based metagenomic analysis, can track not only the taxonomic composition but also the metabolic capabilities of these changing viral and microbial communities over time. Collecting this information for CF airways will enable the mathematical modeling of microbial community dynamics during disease progression. The resultant understanding of airway communities and their effects on lung physiology will facilitate the optimization of CF therapies. PMID- 23103996 TI - Endothelial progenitor cells in regeneration after acute lung injury: do they play a role? AB - Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common disorders in patients requiring critical care. The clinical management of these disorders is difficult and unrewarding, and thus they are among the most common causes of death in intensive care units. The activation and damage of pulmonary endothelium comprise the hallmark of ALI/ARDS. Therefore, the recruitment of circulating endothelial progenitor cells (EPCs) to these lesions may exert a beneficial effect on the clinical course of ALI/ARDS. Consequently, cell-based therapies using stem cells to regenerate lung tissue have emerged as potential novel treatment strategies. Although initial studies suggested implantations of exogenously administered bone marrow-derived progenitor cells into damaged vessel walls, recent evidence indicates that this is rather a rare occurrence with uncertain physiologic significance. In the past few years, different populations of progenitor cells were identified, with different functional capacities. This review (1) highlights the different populations of EPCs identified or administered in different models of ALI/ARDS, (2) reports on whether beneficial effects of EPCs could be demonstrated, and (3) puts the conflicting results of different studies into perspective. PMID- 23103997 TI - Quantifying nerve architecture in murine and human airways using three dimensional computational mapping. AB - The quantitative histological analysis of airway innervation using tissue sections is challenging because of the sparse and patchy distribution of nerves. Here we demonstrate a method using a computational approach to measure airway nerve architecture that will allow for more complete nerve quantification and the measurement of structural peripheral neuroplasticity in lung development and disease. We demonstrate how our computer analysis outperforms manual scoring in quantifying three-dimensional nerve branchpoints and lengths. In murine lungs, we detected airway epithelial nerves that have not been previously identified because of their patchy distribution, and we quantified their three-dimensional morphology using our computer mapping approach. Furthermore, we show the utility of this approach in bronchoscopic forceps biopsies of human airways, as well as the esophagus, colon, and skin. PMID- 23103998 TI - Integration of rapid DNA hybridization and capillary zone electrophoresis using bidirectional isotachophoresis. AB - We present a method for rapid, sequence-specific detection of multiple DNA fragments by integrating isotachophoresis (ITP) based DNA hybridization and capillary zone electrophoresis (CZE) using bidirectional ITP. Our method leverages the high preconcentration ability of ITP to accelerate slow, second order DNA hybridization kinetics, and the high resolving power of CZE to separate and identify reaction products. We demonstrate the speed and sensitivity of our assay by detecting 5 pM, 39 nt ssDNA target within 3 min, using a molecular beacon probe. We also demonstrate the feasibility of our assay for multiplexed detection of multiple-length ssDNA targets by simultaneously detecting 39 and 90 nt ssDNA targets. PMID- 23103999 TI - Phantom study of a new hand-held gamma-imaging probe for radio-guided surgery. AB - In recent years, hand-held mini gamma-cameras have been increasingly used to perform scintigraphic imaging during surgery. The aim of the present work was to evaluate the physical characteristics of a new high-sensitivity hand-held mini gamma-camera through specific phantom measurements. To characterize the performances of the imaging probe Guardian2 hand-held gamma-camera, we measured its sensitivity and depth transmission curve, the extrinsic spatial resolution and spatial linearity, the spatial uniformity, and the count-rate linearity. We also estimated its whole image quality through the contrast-to-noise ratio of four hot spheres (internal diameters ranging from 4.9 to 9.8 mm). The sensitivity of the imaging probe Guardian2 gamma-camera was 204 counts/s/MBq; it had a high spatial resolution (2.5 mm FWHM at contact) and optimal linearity of counts (Pearson's coefficient, R=0.999). The integral uniformity was 12.0% in the useful field of view (FOV) and 8.8% in the central FOV, whereas the differential uniformity was 5.7% in the useful FOV and 4.0% in the central FOV. The system was able to detect and distinguish all four small spheres used for the whole quality test. The contrast-to-noise ratio was evaluated both at contact with the collimator and with a 5-cm-thick interposed Plexiglas slab. The gamma-imaging probe that we evaluated demonstrated good performance, confidently allowing its use for specific clinical applications in radio-guided surgery. PMID- 23104000 TI - Preparation of radioactive praseodymium oxide as a multifunctional agent in nuclear medicine: expanding the horizons of cancer therapy using nanosized neodymium oxide. AB - OBJECTIVE: Many studies have attempted to assess the significance of the use of the beta(-)particle emitter praseodymium-142 ((142)Pr) in cancer treatment. As praseodymium oxide (Pr(2)O(3)) powder is not water soluble, it was dissolved in HCl solution and the resultant solution had to be pH adjusted to be in an injectable radiopharmaceutical form. Moreover, it was shown that the nanosized neodymium oxide (Nd(2)O(3)) induced massive vacuolization and cell death in non small-cell lung cancer. In this work, the production of (142)Pr was studied and water-dispersible nanosized Pr(2)O(3) was proposed to improve the application of (142)Pr in nuclear medicine. MATERIALS AND METHODS: Data from different databases pertaining to the production of (142)Pr were compared to evaluate the accuracy of the theoretical calculations. Water-dispersible nanosized Pr(2)O(3) was prepared using a poly(ethylene glycol) (PEG) coating or PEGylation method as a successful mode of drug delivery. Radioactive (142)Pr(2)O(3) was produced via a (142)Pr(n,gamma)(142)Pr reaction by thermal neutron bombardment of the prepared sample. RESULTS: There was good agreement between the reported experimental data and the data based on nuclear model calculations. In addition, a small part of nano-Pr(2)O(3) particles remained in suspension and most of them settled out of the water. Interestingly, the PEGylated Pr(2)O(3) nanoparticles were water dispersible. After neutron bombardment of the sample, a stable colloidal (142)Pr(2)O(3) was formed. CONCLUSION: The radioactive (142)Pr(2)O(3) decays to the stable (142)Nd(2)O(3). The suggested colloidal (142)Pr(2)O(3) as a multifunctional therapeutic agent could have dual roles in cancer treatment as a radiotherapeutic agent using nanosized (142)Pr(2)O(3) and as an autophagy inducing agent using nanosized (142)Nd(2)O(3). PMID- 23104001 TI - Is cerebral glucose metabolism affected by chemotherapy in patients with Hodgkin's lymphoma? AB - OBJECTIVE: The aim of the study was to investigate the effect of chemotherapy treatment with ABVD on brain glucose metabolism in patients with Hodgkin's disease (HD). METHODS: A total of 49 patients (23 men, 26 women; mean age 32+/-9 years) diagnosed with HD were included in the study. All of them underwent a baseline (PET0) and an interim (PET2) 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F FDG) PET/computed tomography (CT) brain scan. All patients were treated after PET0 with two cycles of ABVD consisting of doxorubicin (adriamycin), bleomycin, vinblastine, and dacarbazine for 2 months. Thirty-five patients were evaluated further 15+/-6 days after four additional cycles (PET6). Differences in brain (18)F-FDG uptake were analyzed by statistical parametric mapping (SPM2). RESULTS: Compared with PET0, PET2 showed a significantly higher metabolic activity in the right angular gyrus (Brodmann area 39) and a significant metabolic reduction in Brodmann areas 10, 11, and 32 bilaterally. All these changes disappeared at PET6. CONCLUSION: Our results support the conclusion of a very limited impact of ABVD chemotherapy on brain metabolism in patients with HD. PMID- 23104002 TI - Dynamic groundwater monitoring networks: a manageable method for reviewing sampling frequency. AB - Optimization of a water quality network through a change in sampling frequency is the only way to increase cost-efficiency without any reduction in the robustness of the data. Existing techniques define optimal sampling frequency based on analysis of historical data from the monitoring network under investigation. Their application to a large network comprised of many sites and many monitored parameters is both technical and challenging. This paper presents a simple non parametric method for reviewing sampling frequency that is consistent with highly censored environmental data and oriented towards reduction of sampling frequency as a cost-saving measure. Based on simple descriptive statistics, the method is applicable to large networks with long time series and many monitored parameters. The method also provides metrics for interpretation of newly collected data, which enables identification of sites for which a future change in sampling frequency may be necessary, ensuring that the monitoring network is both current and adaptive. Application of this method to the New Zealand National Groundwater Monitoring Programme indicates that reduction of sampling frequency at any site would result in a significant loss of information. This paper also discusses the potential for reducing analysis frequency as an alternative to reduction of sampling frequency. PMID- 23104003 TI - Iterative image reconstruction for cerebral perfusion CT using a pre-contrast scan induced edge-preserving prior. AB - Cerebral perfusion x-ray computed tomography (PCT) imaging, which detects and characterizes the ischemic penumbra, and assesses blood-brain barrier permeability with acute stroke or chronic cerebrovascular diseases, has been developed extensively over the past decades. However, due to its sequential scan protocol, the associated radiation dose has raised significant concerns to patients. Therefore, in this study we developed an iterative image reconstruction algorithm based on the maximum a posterior (MAP) principle to yield a clinically acceptable cerebral PCT image with lower milliampere-seconds (mA s). To preserve the edges of the reconstructed image, an edge-preserving prior was designed using a normal-dose pre-contrast unenhanced scan. For simplicity, the present algorithm was termed as 'MAP-ndiNLM'. Evaluations with the digital phantom and the simulated low-dose clinical brain PCT datasets clearly demonstrate that the MAP ndiNLM method can achieve more significant gains than the existing FBP and MAP Huber algorithms with better image noise reduction, low-contrast object detection and resolution preservation. More importantly, the MAP-ndiNLM method can yield more accurate kinetic enhanced details and diagnostic hemodynamic parameter maps than the MAP-Huber method. PMID- 23104004 TI - Calcium alternans in cardiac myocytes: order from disorder. AB - Calcium alternans is associated with T-wave alternans and pulsus alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this '3R theory' can reconcile many seemingly contradictory experimental observations. PMID- 23104005 TI - A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. AB - In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; P(combined) = 6.2 * 10(-34)), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r(2) <= 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe. PMID- 23104006 TI - Genome-wide association meta-analysis identifies new endometriosis risk loci. AB - We conducted a genome-wide association meta-analysis of 4,604 endometriosis cases and 9,393 controls of Japanese and European ancestry. We show that rs12700667 on chromosome 7p15.2, previously found to associate with disease in Europeans, replicates in Japanese (P = 3.6 * 10(-3)), and we confirm association of rs7521902 at 1p36.12 near WNT4. In addition, we establish an association of rs13394619 in GREB1 at 2p25.1 with endometriosis and identify a newly associated locus at 12q22 near VEZT (rs10859871). Excluding cases of European ancestry of minimal or unknown severity, we identified additional previously unknown loci at 2p14 (rs4141819), 6p22.3 (rs7739264) and 9p21.3 (rs1537377). All seven SNP effects were replicated in an independent cohort and associated at P <5 * 10(-8) in a combined analysis. Finally, we found a significant overlap in polygenic risk for endometriosis between the genome-wide association cohorts of European and Japanese descent (P = 8.8 * 10(-11)), indicating that many weakly associated SNPs represent true endometriosis risk loci and that risk prediction and future targeted disease therapy may be transferred across these populations. PMID- 23104007 TI - Inhibition of RNA lariat debranching enzyme suppresses TDP-43 toxicity in ALS disease models. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease primarily affecting motor neurons. Mutations in the gene encoding TDP-43 cause some forms of the disease, and cytoplasmic TDP-43 aggregates accumulate in degenerating neurons of most individuals with ALS. Thus, strategies aimed at targeting the toxicity of cytoplasmic TDP-43 aggregates may be effective. Here, we report results from two genome-wide loss-of-function TDP-43 toxicity suppressor screens in yeast. The strongest suppressor of TDP-43 toxicity was deletion of DBR1, which encodes an RNA lariat debranching enzyme. We show that, in the absence of Dbr1 enzymatic activity, intronic lariats accumulate in the cytoplasm and likely act as decoys to sequester TDP-43, preventing it from interfering with essential cellular RNAs and RNA-binding proteins. Knockdown of Dbr1 in a human neuronal cell line or in primary rat neurons is also sufficient to rescue TDP-43 toxicity. Our findings provide insight into TDP-43-mediated cytotoxicity and suggest that decreasing Dbr1 activity could be a potential therapeutic approach for ALS. PMID- 23104010 TI - Testing for significance of phase synchronisation dynamics in the EEG. AB - A number of tests exist to check for statistical significance of phase synchronisation within the Electroencephalogram (EEG); however, the majority suffer from a lack of generality and applicability. They may also fail to account for temporal dynamics in the phase synchronisation, regarding synchronisation as a constant state instead of a dynamical process. Therefore, a novel test is developed for identifying the statistical significance of phase synchronisation based upon a combination of work characterising temporal dynamics of multivariate time-series and Markov modelling. We show how this method is better able to assess the significance of phase synchronisation than a range of commonly used significance tests. We also show how the method may be applied to identify and classify significantly different phase synchronisation dynamics in both univariate and multivariate datasets. PMID- 23104011 TI - Dominance of a 675 nm chlorophyll(ide) form upon selective 632.8 or 654 nm laser illumination after partial protochlorophyllide phototransformation. AB - The phototransformation pathways of protochlorophyllide forms were studied in 8 14-day-old leaves of dark-germinated wheat (Triticum aestivum L.) using white, 632.8 nm He-Ne laser and 654 nm laser diode light. The photon flux density (PFD) values (0.75-360 MUmol photons m(-2) s(-1)), the illumination periods (20 ms-10 s) and the temperature of the leaves (between -60 degrees C and room temperature) were varied. The 77 K fluorescence spectra of partially phototransformed leaves showed gradual accumulation or even the dominance of the 675 nm emitting chlorophyllide or chlorophyll form at room temperature with 632.8 nm of PFD less than 200 MUmol photons m(-2) s(-1) or with 654 nm of low PFD (7.5 MUmol photons m(-2) s(-1)) up to 1 s. Longer wavelength (685 or 690 nm) emitting chlorophyllide forms appeared at illuminations under -25 degrees C with both laser lights or at room temperature when the PFD values were higher or the illumination period was longer than above. We concluded that the formation of the 675 nm emitting chlorophyllide form does not indicate the direct photoactivity of the 633 nm emitting protochlorophyllide form; it can derive from 644 and 657 nm forms via instantaneous disaggregation of the newly-produced chlorophyllide complexes. The disaggregation is strongly influenced by the molecular environment and the localization of the complex. PMID- 23104009 TI - Exome sequencing of serous endometrial tumors identifies recurrent somatic mutations in chromatin-remodeling and ubiquitin ligase complex genes. AB - Endometrial cancer is the sixth most commonly diagnosed cancer in women worldwide, causing ~74,000 deaths annually. Serous endometrial cancers are a clinically aggressive subtype with a poorly defined genetic etiology. We used whole-exome sequencing to comprehensively search for somatic mutations within ~22,000 protein-encoding genes in 13 primary serous endometrial tumors. We subsequently resequenced 18 genes, which were mutated in more than 1 tumor and/or were components of an enriched functional grouping, from 40 additional serous tumors. We identified high frequencies of somatic mutations in CHD4 (17%), EP300 (8%), ARID1A (6%), TSPYL2 (6%), FBXW7 (29%), SPOP (8%), MAP3K4 (6%) and ABCC9 (6%). Overall, 36.5% of serous tumors had a mutated chromatin-remodeling gene, and 35% had a mutated ubiquitin ligase complex gene, implicating frequent mutational disruption of these processes in the molecular pathogenesis of one of the deadliest forms of endometrial cancer. PMID- 23104012 TI - Abnormal speech processing in frequency regions where absolute thresholds are normal for listeners with high-frequency hearing loss. AB - The ability to understand speech in quiet and in a steady noise was measured for 26 listeners with audiometric thresholds below 30 dB HL for frequencies up to 3 kHz and covering a wide range (0-80 dB HL) between 3 and 8 kHz. The stimulus components were restricted to the low (<=1.5 kHz) and middle (1-3 kHz) frequency regions, where audiometric thresholds were classified clinically as normal or near-normal. Sensitivity to inter-aural phase was measured at 0.5 and 0.75 kHz and otoacoustic emission and brainstem responses were measured. For each frequency region, about half of the listeners with high-frequency hearing loss showed extremely poor intelligibility for speech in quiet and in noise. These deficits could not be accounted for by reduced audibility. Scores for speech in quiet were correlated with age, audiometric thresholds at low and at high frequencies, the amplitude of transient otoacoustic emissions in the mid frequency region, but not with inter-aural phase discrimination. The results suggest that large speech deficits may be observed in regions of normal or near normal hearing for hearing-impaired listeners. They also suggest that speech deficits may result from suprathreshold auditory deficits caused by outer hair cell damage and by factors associated with aging. PMID- 23104013 TI - EYA1-SIX1 complex in neurosensory cell fate induction in the mammalian inner ear. AB - The phosphatase-transactivator EYA1 interacts with the homeodomain protein SIX1 to form transcriptional activation complexes, which play essential roles in regulating cell proliferation, survival and induction of sensory and neuronal differentiation programs during inner ear development. Mutations of the Eya1 and Six1 genes cause profound developmental auditory defects in mice and humans. The molecular mechanisms and developmental processes controlled by the EYA1 and SIX1 complex in inner ear development and neurosensory fate induction are the focus of this review. PMID- 23104008 TI - Bayesian refinement of association signals for 14 loci in 3 common diseases. AB - To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies. PMID- 23104014 TI - Does enriched acoustic environment in humans abolish chronic tinnitus clinically and electrophysiologically? A double blind placebo controlled study. AB - Animal research has shown that loss of normal acoustic stimulation can increase spontaneous firing in the central auditory system and induce cortical map plasticity. Enriched acoustic environment after noise trauma prevents map plasticity and abolishes neural signs of tinnitus. In humans, the tinnitus spectrum overlaps with the area of hearing loss. Based on these findings it can be hypothesized that stimulating the auditory system by presenting music compensating specifically for the hearing loss might also suppress chronic tinnitus. To verify this hypothesis, a study was conducted in three groups of tinnitus patients. One group listened just to unmodified music (i.e. active control group), one group listened to music spectrally tailored to compensate for their hearing loss, and a third group received music tailored to overcompensate for their hearing loss, associated with one (in presbycusis) or two notches (in audiometric dip) at the edge of hearing loss. Our data indicate that applying overcompensation to the hearing loss worsens the patients' tinnitus loudness, the tinnitus annoyance and their depressive feelings. No significant effects were obtained for the control group or for the compensation group. These clinical findings were associated with an increase in current density within the left dorsal anterior cingulate cortex in the alpha2 frequency band and within the left pregenual anterior cingulate cortex in beta1 and beta2 frequency band. In addition, a region of interest analysis also demonstrated an associated increase in gamma band activity in the auditory cortex after overcompensation in comparison to baseline measurements. This was, however, not the case for the control or the compensation groups. In conclusion, music therapy compensating for hearing loss is not beneficial in suppressing tinnitus, and overcompensating hearing loss actually worsens tinnitus, both clinically and electrophysiologically. PMID- 23104015 TI - Cannulated screw unraveling: a case series and literature-based review of an under-recognized complication. AB - Partially threaded cannulated screws have enhanced the orthopedic surgeon's ability to fix periarticular fractures. There are many reports of complications and hardware failure during screw removal, but those during fracture fixation are under-reported and under-recognized in the literature. We describe a 21-year-old healthy man with a grade 1 open displaced medial epicondylar humerus fracture. Upon fracture fixation in the OR using a partially threaded cannulated screw over a Kirschner wire, the threads of the screw unraveled. The operating surgeon felt increased resistance and the unraveling was demonstrated on intra-operative fluoroscopy. The screw was removed by hand without hardware retention and a new K wire and cannulated screw were used for definitive fixation. We found seven previous cases reporting a similar complication with mixed presentations and results. All occurred in young healthy patients, six of which were males. Six of the seven cases made no mention of a tactile change in resistance during fixation and only one of the seven pre-drilled the cortex prior to placement of the cannulated screw. We believe that screw unraveling is an under-reported complication of fracture fixation with cannulated screws that should be recognized by the orthopedic community. We found intra-operative fluoroscopy integral to the recognition of the problem in our case and recommend its use in fracture fixation with cannulated screws. We also suggest pre-drilling of cortices, especially when operating on young patients with strong bone. PMID- 23104016 TI - Tailoring an alien ferredoxin to support native-like P450 monooxygenase activity. AB - A ferredoxin associated with biological Fe-S cluster assembly has been remodelled to transfer electrons to a P450 enzyme and support substrate oxidation at 80% of the physiological ferredoxin activity, opening up the possibility of tailoring ferredoxins to reconstitute the activity of P450 enzymes for which the electron transfer partner proteins are not known. PMID- 23104018 TI - Surface-assisted transfer hydrogenation catalysis on a gamma-Al2O3-supported Ir dimer. AB - A novel oxide-supported Ir dimer, which was found to be active for transfer hydrogenation of aromatic ketones, was prepared on a gamma-Al(2)O(3) surface from an Ir dimer complex [Ir(2){eta(5)-C(5)(CH(3))(5)}(2)(MU-CH(2))(2)] (Ir(2)) with an Ir=Ir bond. Detailed characterization of the gamma-Al(2)O(3)-supported Ir dimer (Ir(2)/gamma-Al(2)O(3)) revealed that the structure of Ir(2) consisted of an Ir dimer with an Ir-Ir bond attached to the gamma-Al(2)O(3) surface by two bridged Ir-(OAl)(2)-Ir bonds. The supported Ir(2)/gamma-Al(2)O(3) dimer with bridged Ir-(OAl)(2)-Ir bonds acted as an efficient catalyst for transfer hydrogenation (turnover number of acetophenone = 699 (24 h)), while homogeneous Ir(2), SiO(2)- and MgO-supported Ir(2) were much less active. A structural transformation at the interface of the Ir dimer and the gamma-Al(2)O(3) surface was suggested to assist the transfer hydrogenation catalysis via the formation of an Ir(2)-H(2) species on the gamma-Al(2)O(3) surface (Ir(2)-H(2)/gamma-Al(2)O(3)) as a key intermediate in the transfer hydrogenation. The present study deepened the understanding of the role and dynamic behaviour of the oxide surface in the hydrogen transfer catalysis on the supported Ir dimer. PMID- 23104017 TI - Jails, HIV testing, and linkage to care services: an overview of the EnhanceLink initiative. AB - Over 9 million persons in the United States (US) are admitted each year to jails. HIV prevalence among detainees is higher than the general population, which creates a public health need for linking HIV-infected detainees to services during jail and after release. The EnhanceLink initiative was funded as demonstration projects in 10 communities at 20 separate jails across the US. Grantees implemented and evaluated innovative models of HIV testing in jails and linkage of HIV-infected individuals to community services post release. In this paper, we describe services delivered with the EnhanceLink initiative. During 877,119 admission events, 210,267 inmates agreed to HIV testing and 822 new diagnoses of HIV were made. The majority of persons served with transitional services were previously diagnosed before the current incarceration. Cumulatively, 9,837 HIV+ persons were offered linkage and transitional services and 8,056 (82 %) accepted the offer. EnhanceLink demonstrated the feasibility of HIV testing in jail settings and provision of linkage services to enhance continuity of HIV care post-release. PMID- 23104020 TI - On designing stable magnetic vectors as carriers for malaria DNA vaccine. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) can be used as therapeutic and diagnostic agents due to their unique magnetic characteristics, provided that they are stable in physiological conditions. Here, the assembly of different magnetic vector configurations comprising SPIONs, polyethylenimine (PEI), and hyaluronic acid (HA), acting as carriers for malaria DNA vaccine encoding Plasmodium yoelii merozoite surface protein MSP1-19 (VR1020-PyMSP1-19), and their stability in different cell media were investigated. The order of assembly affected vector size, surface charge, stability, and ability to bind and release DNA. Generally, all vectors showed relatively small size of less than 200 nm in water, whereas higher degree of aggregation was observed immediately after transferring to high-ionic strength media such as 150 mM NaCl buffer and RPMI 1640 culture media (Roswell Park Memorial Institute medium). However, the pre addition of HA to DNA effectively reduced the extent of aggregation in serum-free RPMI 1640 with sizes of almost all complexes remaining below 90 nm, particularly at HA:PEI charge ratio of 100%. The presence of fetal bovine serum (FBS) in RPMI 1640 culture media further converted the surface charge of vectors from positive to negative, decreasing the size to smaller than 50 nm. Partial disassembly of some vectors was observed in water, in RPMI, and in RPMI supplemented with 10% FBS after incubation for 1h, but not in NaCl buffer, indicating that incubation of complexes in NaCl buffer prior to transfection may limit the intracellular release of plasmid DNA. DNase sensitivity assay showed that plasmid DNA vaccine encoding the PyMSP1-19 in all configurations preserved their structural integrity without damage, even after DNase I treatment for 30 min. This study demonstrated that structurally well-defined magnetic gene carriers could be designed to improve malaria DNA vaccine delivery systems, particularly for in vivo applications. PMID- 23104021 TI - Physicochemical characterization of fish protein adlayers with bacteria repelling properties. AB - Materials coated with aqueous fish protein extracts can reduce bacterial adhesion, but the mechanism behind the observed effect is not fully understood. In this study we explore the physicochemical properties of fish muscle protein adlayers on four substrates: gold, stainless steel, polystyrene and silicon dioxide. The aims were (i) to determine if the anti-adhesive effect is independent of the underlying substrate chemistry, (ii) to link the physicochemical properties of the adlayer to its ability to repel bacteria, and (iii) to elucidate the mechanism behind this effect. The main proteins on all surfaces were the muscle proteins troponin, tropomyosin, and myosin, and the lipid binding protein apolipoprotein. The quantity, viscoelasticity, and hydration of the protein adlayers varied greatly on the different substrates, but this variation did not affect the bacterial repelling properties. Our results imply that these proteins adsorb to all substrates and provide a steric barrier towards bacterial adhesion, potentially providing a universal antifouling solution. PMID- 23104022 TI - Preparation of novel magnetic fluorescent nanoparticles using amino acids. AB - Nanotechnology has opened new gates to pharmaceutical sciences and medicine from the aspect of drug delivery and imaging systems. Currently, bimodal fluorescent magnetic nanoparticles are of great interest to biomedical scientists. In order to constructing these kinds of nanoparticles, fluorescent molecules should be linked to a magnetic core, while luminescence quenching is prevented. In order to alleviate this effect, usually fluorescent molecules are attached to a magnetic core after a multistep hydrocarbon, polymer or silica coating, which significantly increases the particle's size and reduces its magnetic saturation value. In this study, for the first time, amino acids (L-lysine and L-arginine) have been used as a linker and spacer between a fluorescent molecule (FITC) and a magnetic nanoparticle (Fe(3)O(4)) in a simple, two-step synthesis. Also, 3 aminopropyltriethoxysilane (APTES) was used without any previous silica coating for fluorescent magnetic nanoparticles construction. Routinely APTES is used after silica coating by tetraethoxysilane (TEOS). Either of L-lysine, L-arginine and APTES coating provides surface functional groups which interact with the isothiocyanate group of FITC. According to the obtained results, amino acids could be used for successful construction of fluorescent magnetic nanoparticles in a simple synthesis pathway, without any significant impact on the excitation and emission properties of fluorescent molecule. PMID- 23104023 TI - A study of pH effects on the bacterial surface physicochemical properties of Acinetobacter baumannii. AB - The first step in the biofilm formation is the bacterial attachment to solid surfaces, which is dependent on the bacteria cell surface physico-chemical properties. The purpose of this work was to analyze the effect of pH on the physicochemical cell surface properties of Acinetobacter baumannii by two different methods. The cell surface properties were evaluated using the microbial adhesion to solvents method (MATS) and contact angle measurements (CAM). MATS technique allowed us to enlighten that A. baumannii was hydrophilic at the different values of pH. It was found that at a desired pH of 6.5, the strain presents a maximum and stable value of electron-donor characteristic, while the electron acceptor character increased as the pH increased. Regardless of the methods employed, the obtained results using MATS and CAM confirmed the influence of the pH on the surface physicochemical properties of A. baumannii. The cell surface electron-donor and electron-acceptor character at pH 6.5 was found to be quite similar using both methods. PMID- 23104024 TI - Effect of calcium ions on in vitro pellicle formation from parotid and whole saliva. AB - The salivary pellicle is a protein-rich, bacteria-free, self-assembling film that adsorbs to all surfaces within the oral cavity. The pellicle has numerous functions that are vital for maintaining oral health. Currently however, there are no commercially available artificial salivas that accurately mimic the complex film forming properties (i.e. film thickness and viscoelasticity) of human saliva. To understand these properties further we have examined the in vitro formation of the salivary pellicle, by adsorbing stimulated parotid saliva (PS) and whole mouth saliva (WMS) from 14 healthy volunteers, onto oxidised silicon surfaces, using a quartz crystal microbalance with dissipation monitoring (QCMD) and a dual polarisation interferometer (DPI). A dramatic impact on the hydrated mass, polymer mass, thickness and polymer concentration of the pellicle for both WMS and PS was observed when the natural calcium concentration of the respective salivas was increased from 0 mM to 10mM. In addition, QCMD data showed that on addition of 10mM calcium the salivary pellicle formed by both PS and WMS became more predominantly elastic. The results presented here also suggest that calcium can easily diffuse in and out of the pellicle, permitting free calcium exchange between the saliva and the adsorbed pellicle under physiological conditions, which may potentially facilitate the mineralisation of enamel. PMID- 23104025 TI - Enhancement of the electrochemical behavior of CuO nanoleaves on MWCNTs/GC composite film modified electrode for determination of norfloxacin. AB - A novel and facile (single-step) method was developed for the synthesis of CuO nanoleaves in the presence of a cationic polyelectrolyte, poly(diallyldimethylammonium chloride) (PDDA) at pH 10.5. The mechanism and self assembly for the formation of CuO nanoleaves are discussed. The structure and morphology of CuO nanoleaves are characterized by means of Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy (XPS), field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopic (TEM) studies. The CuO/MWCNTs modified glassy carbon (GC) electrode was fabricated via the drop-casting of CuO nanoleaves suspension on MWCNTs/GC surface. In order to investigate the electrochemical behavior of norfloxacin, cyclic voltammetry (CV) and differential pulse voltammetric analysis (DPV) were carried out and compare the oxidation behavior on CuO/MWCNTs/GC, MWCNTs/GC and bare GC. The electrocatalytic oxidation of norfloxacin was studied (pH 7.2) on CuO/MWCNTs/GC electrode and found an irreversible behavior in the range from 0 to +1.1 V with an oxidation peak at 0.91 V in physiological conditions. The quantitative detection of norfloxacin was obtained with a limit of detection of 3.21*10(-7) M within a linear range from 1 MUM to 47.7 MUM. PMID- 23104026 TI - Preparation and characterization of Paliperidone loaded solid lipid nanoparticles. AB - Solid lipid nanoparticles were prepared and studied for the possibility of entrapment of Paliperidone (PPN) an antipsychotic drug that can be used for the treatment of schizophrenia. Here we report the preparation of Paliperidone loaded solid lipid particles (SLNs) with Capmul GMS 50 K as lipid vehicle. SLNs were stabilized by a surfactant namely sodium deoxycholate which can also act as permeability enhancer. Final size of SLNs produced were approximately 200 nm which was confirmed by dynamic light scattering (DLS), atomic force microscopy (AFM) and transmission electron microscopy (TEM). SLNs appeared spherical in TEM images while dough nut like shape was observed by AFM. The entrapment efficiency of this system was found to be 55% with 4.15% of drug loading in lipid matrix. Structural characterization of SLNs by Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction (XRD) and differential scanning calorimetric (DSC) analysis revealed that, there was no interaction of PPN with lipid and PPN was well dispersed in the lipid matrix without any crystallization. PMID- 23104027 TI - Joint-action of antifouling substances in copper-free paints. AB - Due to the environmentally harmful impact of tributyltin self-polishing paints, there is a critical need of more ecological alternatives. The aim of the present work is to study the joint-action of three molecules chosen in order to combine the two modes of prevention: chemical and physical repelling of biofouling. This "hybrid" system is principally dedicated to disturb durable settlement of microfouling. Each component was chosen according to its specific properties: chlorhexidine is a bisdiguanide antiseptic with antibacterial activity, zinc peroxide is an inorganic precursor of high instable entities which react with seawater to create hydrogen peroxide, Tween 85 is a non ionic surfactant disturbing interactions between colonizing organisms and surface. Obtained results highlighted the interest on mixing such molecules to get additive action on antifouling efficiency. PMID- 23104028 TI - Starch-directed green synthesis, characterization and morphology of silver nanoparticles. AB - Silver nanoparticles were prepared by a simple chemical reduction method using ascorbic acid and starch as reducing and stabilizing agents, respectively. The effect of starch, silver ions and ascorbic acid was studied on the morphology of the silver nano-particles using UV-visible spectrophotometry. The initial reaction time min and amount of starch were important parameters for the growth of Ag-nanoparticles. The morphology was evaluated from transmission electron microscopy (TEM). The truncated triangle nano-plates (from 17 to 30 nm), polyhedron, spherical with some irregular shaped Ag-nanoparticles were formed in presence of starch. Particles are aggregated in an irregular manner, leads to the formation of butterfly-like structures of silver. Starch acts as a stabilizing, shape-directing and capping agent during the growth processes. Silver nanoparticles adsorbed electrostatically on the outer OH groups of amylose left handed helical conformation in solution. PMID- 23104029 TI - Facile surface PEGylation via tyrosinase-catalyzed oxidative reaction for the preparation of non-fouling surfaces. AB - The control of biological interactions that occur at material-cell/blood interfaces is of great importance to help maximize in vitro and in vivo performance of biomedical devices. PEGylation has been extensively used as an effective surface modification tool that can alter biological responses on device surfaces. Herein, we report a new surface PEGylation method using a tyrosinase catalyzed oxidative reaction. Tyramine (TA), an enzymatically active phenolic compound, was chemically conjugated to methoxy poly(ethylene glycol) (mPEG). Surface immobilization of mPEG-TA onto various substrates was accomplished simply and rapidly by adding tyrosinase under mild conditions. It was shown that the water contact angles on all surfaces modified with mPEG-TA were decreased, indicating successful introduction of hydrophilic PEG. In addition, the X-ray photoelectron spectroscopy (XPS) spectra demonstrated the differences in the atomic composition on the TiO(2) surface after treatment with mPEG-TA. Non fouling surfaces prevent non-specific interactions with proteins and cells; consistently, the PEGylated TiO(2) surface clearly showed a decrease in both levels of bovine serum albumin (BSA) adsorption and NIH3T3 cell attachment. Therefore, the facile surface PEGylation using a tyrosinase-catalyzed oxidative reaction should be useful for designing non-fouling surfaces of biomedical devices. PMID- 23104030 TI - Features of heat-induced amorphous complex between indomethacin and lidocaine. AB - We studied temperature-dependent phase changes in the mixture of indomethacin (IM) and lidocaine (LC) in various molar ratios by differential scanning calorimetry (DSC). DSC studies were carried out between -40 degrees C and 180 degrees C heating/cooling/heating cycle at a rate of 10 degrees C/min under a nitrogen gas flow. Although LC in the liquid state was crystallized, fused IM showed a glass transition signal upon cooling. Hence, cooling of fused IM caused it to assume the amorphous state below its glass transition temperature. Heating of the mixture of IM and LC resulted in formation of a eutectic mixture between them, and cooling of the fused mixture caused formation of the amorphous state at any molar ratio examined. It is noteworthy that the amorphous solid of the fused complex of IM and LC was in the rubber state and glass state in the mixtures containing IM between 20% and 40%, whereas there was only the glass state in the samples containing 50% IM and higher. In addition, crystallization of LC took place by cooling the fused sample containing 10% IM. PMID- 23104031 TI - Nano-formulation of paclitaxel by vitamin E succinate functionalized pluronic micelles for enhanced encapsulation, stability and cytotoxicity. AB - Vitamin E succinate (TOS) modified pluronic micelles (PF-TOS micelles) were prepared to be used as a vehicle for paclitaxel (PTX). The average size of resultant PTX-loaded PF-TOS micelles (PF-TOS-PTX-micelles) was about 58 nm. PF TOS-PTX-micelles showed enhanced encapsulation efficiency and better stability as compared to the non-modified controls. Fluorescence microscopy and high performance liquid chromatography studies showed that PTX-loaded PF-TOS micelles had excellent cellular uptake ability by human glioma U87 cells. Cytotoxicity assay revealed that PTX-loaded PF-TOS micelles demonstrated higher anti-cancer activity to U87 cells than that of the non-modified PF micelles. Pharmacokinetic studies indicated the longer systemic circulation time and slower plasma elimination rate in PTX-loaded PF-TOS micelles than that of the non-modified controls. In vivo tissue distribution studies showed that PTX-loaded PF-TOS micelles were preferably accumulated in spleen and liver. Taken together, the results evidently indicated that PF-TOS micelles improve the hydrophobic chemotherapeutic drugs delivery by means of efficient encapsulation and stabilization for anti-tumor therapy. PMID- 23104032 TI - Diffusion of dissolved ions from wet silica sol-gel monoliths: implications for biological encapsulation. AB - Divalent nickel (Ni(2+)), Cu(II)EDTA, methyl orange, and dichromate were used to investigate diffusion from hydrated silica sol-gel monoliths. The objective was to examine diffusion of compounds on a size regime relevant to supporting biological components encapsulated within silica gel prepared in a biologically compatible process space with no post-gelation treatments. With an initial sample set, gels prepared from tetraethoxysilane were explored in a factorial design with Ni(2+) as the tracer, varying water content during hydrolysis, acid catalyst present during hydrolysis, and the final concentration of silica. A second sample set explored diffusion of all four tracers in gels prepared with aqueous silica precursors and a variety of organically modified siloxanes. Excluding six outliers which displayed significant syneresis, the mean diffusion constant (D(gel)) across the entire process space of sample set 1 was 2.42*10(-10) m(2) s( 1); approximately 24% of the diffusion coefficient of Ni(2+) in unconfined aqueous solution. In sample set 2, the tracer size and not gel hydrophobicity was the primary determinant of changes in diffusion rates. A strong linear inverse correlation was found between tracer size and the magnitude of D(gel). Based on correlation with the tracers used in this investigation, the characteristic 1-h diffusion distance for carbonate species relevant to supporting active phototrophic organisms was approximately 1.5mm. These results support the notion that silica sol-gel formulations may be optimized for a given biological entity of interest with manageable impact to the diffusion of small ions and molecules. PMID- 23104033 TI - Surfactant aided biodegradation of NAPLs by Burkholderia multivorans: comparison between Triton X-100 and rhamnolipid JBR-515. AB - Both chemical surfactants and biosurfactants have been effectively used for the degradation of petroleum hydrocarbons. Chemical surfactants are known to enhance biodegradation effectively while activity of biosurfactants is also comparable and they have the additional advantage of being biodegradable. However, the mode of action of chemical surfactants and biosurfactants may vary. This work was conducted to determine the mode of action of Triton X-100 and rhamnolipid JBR-515 by exploring the factors affecting the process of surfactant aided biodegradation of model non aqueous phase liquids (NAPLs) by a naphthalene degrader, Burkholderia multivorans (NG1). Emulsification studies, growth rate and degradation rate studies were conducted and correlated with alteration in cell surface properties including surface hydrophobicity, cell surface charge and cell surface functional groups. Triton X-100 and JBR-515 demonstrated distinct mode of uptake of NAPLs. Triton X-100 enhanced bioavailability by emulsification and supported direct interfacial uptake of model NAPLs by B. multivorans (NG1). Conversely, the biosurfactant rhamnolipid JBR-515 did not demonstrate emulsification of NAPLs and enhanced bioavailability through micellar solubilization. NAPL composition influenced the alteration in the cell surface properties. For both the surfactants, increase in surfactant concentration increased the rate of utilization of aliphatic hydrocarbons from the NAPLs. PMID- 23104034 TI - In vitro cytotoxicity of a thermoresponsive gel system combining ethyl(hydroxyethyl) cellulose and lysine-based surfactants. AB - The cytotoxicity of three lysine-derived surfactants with a gemini-like structure was evaluated on HeLa cells. The half maximal effective concentration (EC(50)) was estimated from the dose-response curves and the values indicated an increase in toxicity with the increase in alkyl chain length. The shorter chain length surfactant (C(6)) was shown to be less cytotoxic than sodium dodecyl sulfate (SDS), and all the lysine-derived surfactants were less toxic than the cationic cetyl trimethylammonium bromide (CTAB). The presence of ethyl (hydroxyethyl) cellulose (EHEC), shown previously to form thermoresponsive gels in combination with these surfactants, was found to contribute to a lower toxicity on HeLa cells. The conjecture is that the polymer-surfactant interactions in forming mixed micelles are the key contributors to the enhanced biocompatibility of the hydrogels. The most promising results were obtained in the presence of either the most hydrophilic surfactant or in the presence of the longest chain-length surfactant. For the latter, very low concentrations are needed to induce a sol gel transition of EHEC semi-dilute solutions. PMID- 23104035 TI - A facile completely 'green' size tunable synthesis of maltose-reduced silver nanoparticles without the use of any accelerator. AB - A simple, straightforward, cost effective and environmentally benign method for the synthesis of highly stable and small sized silver nanoparticles (Ag-NPs) with narrow size distribution without the use of an accelerator is reported. Silver nitrate, gelatin and maltose, a non-toxic disaccharide sugar were used as silver precursor, stabiliser and reducing agent. By varying the precursor concentration and reaction time, we monitored the temporal evolution of the optical and structural properties of the as-synthesised Ag-NPs. The as-synthesised Ag-NPs were characterised using UV-vis absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM), high resolution transmission electron microscopy (HRTEM) and X-ray diffraction (XRD). The absorption maxima of the surface plasmon resonance (SPR) were blue-shifted as the reaction time increased indicating decrease in particle size. The TEM images showed that, the particles are small, well dispersed and spherical in shape. The smallest particles with an average particle diameter of 3.76+/-1.00 nm and 4.09+/ 1.83 nm were obtained at 24h for the 1.0M and 0.5M silver ion precursor solution concentration respectively. The smaller particles produced were attributed to the higher concentration of the reducing saccharides in the reaction system, which in turn increases the formation of stable silver ions in the reaction system. The HRTEM images confirmed the crystalline nature of the material while the FTIR confirmed the stabilisation of the Ag-NPs by the gelatin. PMID- 23104036 TI - Influence of nutrient conditions on the transport of bacteria in saturated porous media. AB - The influence of nutrient conditions on the transport of bacteria in packed porous media was examined in both NaCl and CaCl(2)-NaCl mixed solutions at pH 6.0. Two representative cell types, Bacillus subtilis (Gram-positive) and Escherichia coli DH5alpha (Gram-negative), were used to determine the influence of nutrient conditions on cell transport behavior. Under all examined solution conditions, the breakthrough plateaus in the presence of background nutrients in solutions for both examined bacteria types were higher than those without nutrients, indicating that the presence of nutrients in solution enhanced the bacteria transport regardless of the examined cell type (Gram-positive or Gram negative) and solution chemistry (ionic strength and ion valence). The increased bacteria transport induced by the presence of nutrient in solutions was probably not driven by the changes in the sizes of bacteria, cell surface properties (i.e., zeta potentials), or the contents of extracellular polymeric substances (EPS) since these properties were not obviously changed by the presence of nutrients in solutions. Nutrient pre-equilibration experiments demonstrated that the deposition site competition by nutrients contributed to the increased bacteria transport observed with the presence of nutrients in bacterial suspension. Additional nutrient effects on cell transport were examined from the column experiments conducted in the absence of nutrients for the cells under 2 day starvation. Starvation of bacteria also increased the bacteria transport in porous media. The sizes of bacteria, zeta potentials of bacteria, and the EPS composition were changed by the starvation process, which might be responsible for the increased transport of starved bacteria observed for both cell types examined under all solution conditions. PMID- 23104037 TI - A multi-headed surfactant as an efficient tool in solubilization of dimyristoylphosphatidycholine (DMPC) vesicles. AB - In this study, the solubilization of DMPC (dimyristoylphosphatidycholine) vesicles by a novel multi-headed surfactant, C18N3, is reported. The headgroup of the surfactant contains two types of amine groups, which are protonated at different pH values. The protonation of the headgroup has significant effect on the solubilization process. The penetration of the surfactant into a DMPC monolayer was measured at different initial surface pressures and at different pH values. A linear relationship was found between the initial surfactant pressure (pi) and the increase of the surfactant pressure (Deltapi). Furthermore, turbidity titration shows that at low pH, the phase behavior with increasing surfactant concentration in the DMPC solution is similar to conventional ionic surfactants. This can be explained by the three-stage model. TEM images at different C18N3 concentrations confirmed the process of solubilization of DMPC vesicles, and small aggregates were observed at 1 mmol/L C18N3. However, at higher pH, where the headgroup is deprotonated, the surfactant was not able to solubilize the DMPC vesicles. TEM images shows a coexistence of vesicles and a lamellar phase. The surfactant/lipid ratio of the multi-headed surfactant at pH 4 and 7 was compared to conventional nonionic surfactants with the same cross sectional area of the headgroup, and a much lower ratio was observed for the new surfactant. PMID- 23104038 TI - Facile preparation of heparin/CaCO3/CaP hybrid nano-carriers with controllable size for anticancer drug delivery. AB - A facile method to prepare inorganic/organic hybrid heparin/CaCO(3)/CaP nanoparticles for drug delivery was developed. The heparin/CaCO(3)/CaP nanoparticles were prepared by the co-precipitation of Ca(2+) ions with carbonate and phosphate ions in the presence of heparin. The effects of ion concentrations on the particle size and properties of the nanoparticles were investigated. The dynamic light scattering (DLS) particle size analysis and scanning electron microscopy (SEM) observation showed that the mean size of the hybrid nanoparticles could be controlled at less than 50 nm in the dried state through adjusting the concentrations of the inorganic ions. Fourier transform infrared (FTIR) spectroscopy indicated that the crystallization of CaCO(3) could be suppressed with the presence of phosphate ions in the co-precipitation system. X ray photoelectron spectroscopy (XPS) showed that the heparin content in the surface layer of heparin/CaCO(3)/CaP hybrid nanoparticles decreased with the increasing ion concentrations during the nanoparticle preparation. The drug loading and release properties of the hybrid nanoparticles with different sizes and different compositions were studied. The in vitro cellular cytotoxicity indicated that blank hybrid nanoparticles had good biocompatibility, whereas doxorubicin hydrochloride (DOX) loaded nanoparticles exhibited a strong cell inhibition effect, indicating that the heparin/CaCO(3)/CaP hybrid nanoparticles could be promising carriers for drug delivery. PMID- 23104039 TI - Nanocarrier based formulation of Thymoquinone improves oral delivery: stability assessment, in vitro and in vivo studies. AB - This research aims to formulate and characterize solid lipid nanoparticles (SLNs) of Thymoquinone (THQ-SLNs) for the effective treatment of liver cirrhosis. Formulations were prepared using solvent injection method and optimized by the Box-Behnken experimental design to get the desired particle size having maximized entrapment efficiency as well as percentage release. Optimized THQ-SLNs (ST-1) with appropriate characteristics (particle size=166.1+/-10.96 nm; zeta potential= 11.34+/-3.54 mV; entrapment efficiency=71.60+/-3.85%; maximum % release=70.95+/ 2.47%) were fabricated. DSC and XRD studies were carried out which collectively proved the reduced crystallinity and stability enhancing effect of the SLNs. Improved drug stability was further established by the subjection of the THQ-SLNs to accelerated stability studies (as per ICH guidelines) in contrast to the THQ suspension. In vivo studies revealed a nearly 5 fold increase in the bioavailability of ST-1 (AUC(0->infinity)=2998.91+/-260.503 MUg/mL/h) as compared to THQ suspension (AUC(0->infinity)=484.23+/-21.755 MUg/mL/h). Pharmacodynamic data exhibited a significant decrease in the serum biomarker enzymes (SGOT, SGPT and ALP) after oral administration of THQ-SLNs as compared to control and marketed (SILYBON((r))) formulations against paracetamol (PCM)-induced liver cirrhosis. The effect of the treatment was confirmed by the histopathology of the liver microtome sections. PMID- 23104040 TI - Preparation of active antibacterial LDPE surface through multistep physicochemical approach II: graft type effect on antibacterial properties. AB - Three monomers (allylamine, N-allylmethylamine and N,N-dimethylallylamine) were used for grafting onto air plasma activated LDPE surface. Antibacterial agent triclosan was anchored on such substrates. Influence of graft type on the antibacterial properties was determined. Increase of antibacterial activity and amount of deposited antibacterial agent for N-allylmethylamine and N,N dimethylallylamine monomers were examined. Surface characteristics were measured by means of static contact angle measurement with surface energy evaluation, ATR FTIR spectroscopy, XPS and SEM characterization analysis. Antibacterial properties were tested in vitro by inhibition zone method on agar plates for Staphylococcus aureus and Escherichia coli strains. PMID- 23104041 TI - Water defects induced by expansion and electrical fields in DMPC and DMPE monolayers: contribution of hydration and confined water. AB - The values of capacitance of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) monolayers on Hg, derived from cyclic voltammetry studies indicate that when the lipids are near the phase transition temperature fractures are formed at a critical area beyond that corresponding to the hydration shell of the lipids in the liquid expanded state. Similar fractures are inferred to be formed when an electric field is applied at constant area, at a breaking potential which is a function of the lipid species. These voltage values denote that energy involved in the transition induced by the electrical field is much higher for DMPE than for DMPC at low areas. This can be explained by the higher intermolecular lateral interactions by H-bonds between the ethanolamine and phosphate groups. However, at larger areas, the energy values for DMPC are as high as for DMPE which is understood to be due to the higher hydration of phosphocholine head groups. This finding gives a new insight in relation to the dynamics of the lipid head groups at the membrane interphase region in terms of the states of water between the lipids. This is congruent with previous results evaluated with the well known DeltaPi vs. surface pressure plots in monolayers of the same lipids at air-water interfaces. PMID- 23104042 TI - High-frequency phosphorus monitoring of the River Kennet, UK: are ecological problems due to intermittent sewage treatment works failures? AB - The River Kennet in southern England has exhibited excessive benthic algal growth and associated ecological problems, such as loss of macrophytes and invertebrates, since the 1980s. These ecological problems were attributed to regular peaks in phosphorus concentration, which were widely attributed to intermittent failures of the Marlborough sewage treatment works (STW). This study deployed high-frequency phosphorus auto-analysers to monitor the total reactive phosphorus (TRP) concentrations of Marlborough STW final effluent and the downstream River Kennet at hourly and 30 minute resolution respectively, between 2008 and 2009. This monitoring confirmed that the Marlborough STW was operating well within its 1000 MUg l-1 annual mean total phosphorus consent limit, with mean total P and soluble reactive P concentrations of 675 and 345 MUg l-1 respectively. There were two occasions where effluent TRP concentration exceeded 1000 MUg l-1, and only one of these resulted in a peak in TRP concentration of over 100 MUg l-1 in the River Kennet at Mildenhall. The other nine peaks of over 100 MUg l-1 in the River Kennet during the monitoring period were associated with storm events, indicating that diffuse-source inputs and remobilisation of stored within-channel phosphorus were the cause of the peaks in river concentration, rather than Marlborough STW. The value of high-frequency environmental monitoring and the problems associated with using nutrient auto-analysers in the field are discussed. Seasonal phosphorus consents for STWs could provide a useful and cost effective means to improve both water quality and river ecology in the upper River Kennet. PMID- 23104043 TI - Prophylactic stabilization for bone metastases, myeloma, or lymphoma: do we need to protect the entire bone? AB - BACKGROUND: The current operative standard of care for disseminated malignant bone disease suggests stabilizing the entire bone to avoid the need for subsequent operative intervention but risks of doing so include complications related to embolic phenomena. QUESTIONS/PURPOSES: We questioned whether progression and reoperation occur with enough frequency to justify additional risks of longer intramedullary devices. METHODS: A retrospective chart review was done for 96 patients with metastases, myeloma, or lymphoma who had undergone stabilization or arthroplasty of impending or actual femoral or humeral pathologic fractures using an approach favoring intramedullary fixation devices and long-stem arthroplasty. Incidence of progressive bone disease, reoperation, and complications associated with fixation and arthroplasty devices in instrumented femurs or humeri was determined. RESULTS: At minimum 0 months followup (mean, 11 months; range, 0-72 months), 80% of patients had died. Eleven of 96 patients (12%) experienced local bony disease progression; eight had local progression at the original site, two had progression at originally recognized discretely separate lesions, and one had a new lesion develop in the bone that originally was surgically treated. Six subjects (6.3%) required repeat operative intervention for symptomatic failure. Twelve (12.5%) patients experienced physiologic nonfatal complications potentially attributable to embolic phenomena from long intramedullary implants. CONCLUSIONS: Because most patients in this series were treated with the intent to protect the bone with long intramedullary implants when possible, the reoperation rate may be lower than if the entire bone had not been protected. However, the low incidence of disease progression apart from originally identified lesions (one of 96) was considerably lower than the physiologic complication rate (12 of 96) potentially attributable to long intramedullary implants. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 23104044 TI - High-flexion prosthesis improves function of TKA in Asian patients without decreasing early survivorship. AB - BACKGROUND: Two previous studies recently raised the possibility of a high risk of early femoral components loosening with high-flexion (HF) prostheses in Asian populations and suggested that the high failure rate of HF TKAs was associated with HF ability. However, these findings are controversial given other studies reporting a low incidence of aseptic failures in HF prostheses. QUESTIONS/PURPOSES: We therefore determined (1) the rate of achieving postoperative HF after HF TKA; (2) whether the aseptic loosening rate of HF prostheses is high; and (3) whether the survivorship was worsened in patients who achieved postoperative deep knee flexion in our cohort of Korean patients. METHODS: We retrospectively reviewed 488 patients who had 698 primary TKAs using the NexGen((r)) Legacy Posterior-Stabilized Flex system implanted from 2003 to 2010. There were 40 men and 448 women with a mean age of 68 years. We obtained Hospital for Special Surgery scores, maximal flexion, and radiographs. The minimum followup for functional and radiographic evaluations was 2 years (median, 4.8 years; range, 2-8.7 years). We performed a survival analysis on all patients for aseptic loosening. RESULTS: Three hundred sixty knees (52%) could achieve >= 135 degrees maximum flexion. Six of the 698 knees (0.9%) developed aseptic loosening (three femoral and three tibial). The survival at 5 years for aseptic loosening was 99.1%. The overall survival for aseptic failure did not differ between knees that achieved HF and those that did not. CONCLUSIONS: We observed a low incidence of early aseptic loosening of HF designs in this series. Our findings suggest HF TKAs have high survival in Asian patients at 5 years although half of the patients attained maximum flexion more than 135 degrees postoperatively. PMID- 23104046 TI - Letter to the editor: the withdrawn ASRTM THA and hip resurfacing systems: how have our patients fared over 1 to 6 years? PMID- 23104045 TI - Locking buttons increase fatigue life of locking plates in a segmental bone defect model. AB - BACKGROUND: Durability of plate fixation is important in delayed union. Although locking plates result in stronger constructs, it is not known if locking affects the fatigue life of a plate. Two locking screws on either side of the nonunion could decrease working length and increase strain in the plate. However, the reinforcing effect of the locking head on the plate may compensate, so that it is unclear whether locking reduces fatigue life. QUESTIONS/PURPOSES: We determined whether locking screws, compression screws, and locking buttons reduce or increase the fatigue life of a plate. METHODS: We tested fatigue life of four constructs using an eight-hole locking plate in a segmental defect model: (1) all locking screws (Locked; n = 5); (2) all compression screws (Unlocked; n = 5); (3) six compression screws with two locking buttons in the central holes (Button; n = 6); and (4) six compression screws with two open central holes (Open; n = 6). RESULTS: The Button group had the longest fatigue life (1.3 million cycles). There was no difference between the Locked and Unlocked groups. All of the constructs failed by fracture of the plates through a screw hole adjacent to the defect. CONCLUSIONS: Locking screws did not improve fatigue life, however a locking button increased the fatigue life of a locking plate in a segmental bone defect model. CLINICAL RELEVANCE: Locking buttons in holes adjacent to a defect may improve durability, which is important when delayed union is a possibility. PMID- 23104047 TI - Reply to letter to the editor: efficacy and degree of bias in knee injury prevention studies: a systematic review of RCTs. PMID- 23104048 TI - Sorrell v. IMS Health: issues and opportunities for informaticians. AB - In 2011, the US Supreme Court decided Sorrell v. IMS Health, Inc., a case that addressed the mining of large aggregated databases and the sale of prescriber data for marketing prescription drugs. The court struck down a Vermont law that required data mining companies to obtain permission from individual providers before selling prescription records that included identifiable physician prescription information to pharmaceutical companies for drug marketing. The decision was based on constitutional free speech protections rather than data sharing considerations. Sorrell illustrates challenges at the intersection of biomedical informatics, public health, constitutional liberties, and ethics. As states, courts, regulatory agencies, and federal bodies respond to Sorrell, informaticians' expertise can contribute to more informed, ethical, and appropriate policies. PMID- 23104049 TI - Geographical distribution of patients visiting a health information exchange in New York City. AB - OBJECTIVE: For a health information exchange (HIE) organization to succeed in any given region, it is important to understand the optimal catchment area for the patient population it is serving. The objective of this analysis was to understand the geographical distribution of the patients being served by one HIE organization in New York City (NYC). MATERIALS AND METHODS: Patient demographic data were obtained from the New York Clinical Information Exchange (NYCLIX), a regional health information organization (RHIO) representing most of the major medical centers in the borough of Manhattan in NYC. Patients' home address zip codes were used to create a research dataset with aggregate counts of patients by US county and international standards organization country. Times Square was designated as the geographical center point of the RHIO for distance calculations. RESULTS: Most patients (87.7%) live within a 30 mile radius from Times Square and there was a precipitous drop off of patients visiting RHIO affiliated facilities at distances greater than 100 miles. 43.6% of patients visiting NYCLIX facilities were from the other NYC boroughs rather than from Manhattan itself (31.9%). DISCUSSION: Most patients who seek care at members of NYCLIX live within a well-defined area and a clear decrease in patients visiting NYCLIX sites with distance was identified. Understanding the geographical distribution of patients visiting the large medical centers in the RHIO can inform the RHIO's planning as it looks to add new participant organizations in the surrounding geographical area. PMID- 23104050 TI - Identifying non-inducible ventricular tachycardia origin utilizing defibrillator electrograms. AB - INTRODUCTION: Developing an ablation strategy when the clinical arrhythmia cannot be induced is a challenge. METHODS AND RESULTS: A 72-year-old man is transferred to our facility for ventricular tachycardia (VT) storm. Endocardial and epicardial voltage mapping was normal and program stimulation failed to induce any arrhythmias. Implantable cardioverter-defibrillators (ICD) electrograms (EGMs) were recorded while pacing and compared to the stored clinical events. Ablation lesions were delivered across a narrow area of matching ICD EGM pace maps. The patient has remained arrhythmia free for 11 months. CONCLUSION: ICD EGMs may be useful in facilitating successful VT ablation when the clinical arrhythmia cannot be induced in the EP lab. PMID- 23104051 TI - Dose prescription in carbon ion radiotherapy: a planning study to compare NIRS and LEM approaches with a clinically-oriented strategy. AB - In carbon ion radiotherapy there is an urgent clinical need to develop objective tools for the conversion of relative biological effectiveness (RBE)-weighted doses based on different models. In this work we introduce a clinically oriented method to compare NIRS-based and LEM-based GyE systems, minimizing differences in physical dose distributions between treatment plans. Carbon ion plans were optimized on target volumes of cubic and spherical shapes, for RBE-weighted dose prescription levels ranging from 3.6 to 4.4 GyE. Plans were calculated for target sizes from 4 to 12 cm defining three beam geometries: single beam, opposed beam and orthogonal beam configurations. The two treatment planning systems currently employed in clinical practice were used, providing the NIRS-based and LEM-based GyE calculations. Physical dose distributions of NIRS-based and LEM-based treatment plans were compared. LEM-based prescription doses that minimize differences in physical dose distributions between the two systems were found. These doses were compared with the mean RBE-weighted dose obtained with a Monte Carlo code (FLUKA) interfaced with LEM I. In the investigated dose range, LEM based RBE-weighted prescription doses, that minimize differences with NIRS plans, should be higher than NIRS reported prescription doses. The optimal dose depends on target size, shape and position, number of beams and dose level. The opposed beam configuration resulted in the smallest average prescription dose difference (0.45 +/- 0.09 GyE). The second approach of recalculating NIRS RBE-weighted dose with a Monte Carlo code interfaced with LEM resulted in no significant difference with the results obtained from the planning study. The delivery of a voxel by voxel iso-effective plan, if different RBE models are employed, is not feasible; it is however possible to minimize differences in a treatment plan with the simple approach presented here. Dose prescription ultimately represents a clinical task under the responsibility of the radiation oncologist, the presented analysis intends to be a quantitative and objective way to assist the clinical decision. PMID- 23104052 TI - Thyroid (dys-)function in normal and disturbed pregnancy. AB - INTRODUCTION: During pregnancy, physiologic changes in maternal thyroid function take place especially due to hormonal as well as metabolic processes. Human chorionic gonadotropin activates the maternal thyroid gland leading to increased thyroid hormone production. A sufficient availability of maternal thyroid hormones is essential for fetal development, especially during the first trimester of pregnancy, when the fetal thyroid gland is not yet functional. MATERIALS AND METHODS: Current knowledge of thyroid dysfunction including thyroid autoimmunity, hypothyroidism or hyperthyroidism is summarized with special focus on miscarriage and pregnancy disorders. Therefore, a Medline research as well as an analysis of current guidelines on thyroid function and pregnancy was performed. RESULTS: A study focusing on TSH levels in normal and disturbed pregnancies, the risk of miscarriage in association with thyroid autoantibodies, and (subclinical) hypothyroidism in infertile and fertile women were included. CONCLUSION: Maternal thyroid dysfunction negatively affects pregnancy outcome. Besides a routine iodine supplementation in pregnant women and treatment of hypo as well as hyperthyroidism, TSH levels should routinely be measured in women during childbearing years and adjusted to concentrations <2.5 mIU/l in order to optimize maternal health and fetal development. PMID- 23104053 TI - The role of the serum inflammatory markers for predicting the tubo-ovarian abscess in acute pelvic inflammatory disease: a single-center 5-year experience. AB - OBJECTIVE: To compare patients with tubo ovarian abscess (TOA) and non-TOA acute pelvic inflammatory disease (PID) and to determinate admitted day laboratory cut off values for the TOA. MATERIALS AND METHODS: Files of inpatients admitted to our clinic with the diagnoses of PID and/or TOA between the years of 2006 and 2011. Laboratory and culture results were obtained from the database of hospital. A total of 73 patients diagnosed with PID and/or TOA were evaluated. Patients who were diagnosed with TOA and PID by physical and sonographic examination were assigned to group 1 and group 2, respectively. Both groups were compared in terms of laboratory, clinical, and epidemiological parameters. RESULTS: Of 73 patients admitted with the diagnosis of PID, 44 (60.3 %) were found to have TOA, and 29 (39.7 %) were not found. Mean age of patients was determined as 41.4 +/- 7.7 in group 1 and as 35.1 +/- 6.8 in group 2. Abscess was detected more frequently in patients with low socio-cultural level, and this was found to be statistically significant. The diameter of abscess was found to be >=5 cm in 39 (88.6 %) patients and <5 cm in 5 (11.4 %) patients. The average length of hospital stay was statistically significantly increased in patients with an abscess of >=5 cm in size compared to patients with an abscess of <5 cm. When C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), leukocyte counts were statistically evaluated by ROC curves, diagnostic ability of CRP, ESR and leukocyte count was found to be 73, 87, and 58 %. CRP has a specificity of 63 % and a sensitivity of 72 % if cut-off value is considered as 11.5 mg/L whereas ESR has a specificity of 83 % and a sensitivity of 79 % if cut-off value is considered as 19.5 mm/1/2 h. CONCLUSION: ESR >19.5 mm/1/2 h and CRP >11.5 mg/L were the best predictors of TOA. The high level of CRP and ESR was associated with longer duration of hospitalization and disease severity, and these levels were statistically significantly associated with TOA size of >=5 cm. PMID- 23104054 TI - Phf19 links methylated Lys36 of histone H3 to regulation of Polycomb activity. AB - Polycomb-group proteins are transcriptional repressors with essential roles in embryonic development. Polycomb repressive complex 2 (PRC2) contains the methyltransferase activity for Lys27. However, the role of other histone modifications in regulating PRC2 activity is just beginning to be understood. Here we show that direct recognition of methylated histone H3 Lys36 (H3K36me), a mark associated with activation, by the PRC2 subunit Phf19 is required for the full enzymatic activity of the PRC2 complex. Using NMR spectroscopy, we provide structural evidence for this interaction. Furthermore, we show that Phf19 binds to a subset of PRC2 targets in mouse embryonic stem cells and that this is required for their repression and for H3K27me3 deposition. These findings show that the interaction of Phf19 with H3K36me2 and H3K36me3 is essential for PRC2 complex activity and for proper regulation of gene repression in embryonic stem cells. PMID- 23104055 TI - Mechanism of repair of 5'-topoisomerase II-DNA adducts by mammalian tyrosyl-DNA phosphodiesterase 2. AB - The topoisomerase II (topo II) DNA incision-and-ligation cycle can be poisoned (for example following treatment with cancer chemotherapeutics) to generate cytotoxic DNA double-strand breaks (DSBs) with topo II covalently conjugated to DNA. Tyrosyl-DNA phosphodiesterase 2 (Tdp2) protects genomic integrity by reversing 5'-phosphotyrosyl-linked topo II-DNA adducts. Here, X-ray structures of mouse Tdp2-DNA complexes reveal that Tdp2 beta-2-helix-beta DNA damage-binding 'grasp', helical 'cap' and DNA lesion-binding elements fuse to form an elongated protein-DNA conjugate substrate-interaction groove. The Tdp2 DNA-binding surface is highly tailored for engagement of 5'-adducted single-stranded DNA ends and restricts nonspecific endonucleolytic or exonucleolytic processing. Structural, mutational and functional analyses support a single-metal ion catalytic mechanism for the exonuclease-endonuclease-phosphatase (EEP) nuclease superfamily and establish a molecular framework for targeted small-molecule blockade of Tdp2 mediated resistance to anticancer topoisomerase drugs. PMID- 23104056 TI - ATPase-dependent role of the atypical kinase Rio2 on the evolving pre-40S ribosomal subunit. AB - Ribosome synthesis involves dynamic association of ribosome-biogenesis factors with evolving preribosomal particles. Rio2 is an atypical protein kinase required for pre-40S subunit maturation. We report the crystal structure of eukaryotic Rio2-ATP-Mg(2+) complex. The active site contains ADP-Mg(2+) and a phosphoaspartate intermediate typically found in Na(+), K(+) and Ca(2+) ATPases but not protein kinases. Consistent with this finding, ctRio2 exhibits a robust ATPase activity in vitro. In vivo, Rio2 docks on the ribosome, with its active site occluded and its flexible loop positioned to interact with the pre-40S subunit. Moreover, Rio2 catalytic activity is required for its dissociation from the ribosome, a necessary step in pre-40S maturation. We propose that phosphoryl transfer from ATP to Asp257 in Rio2's active site and subsequent hydrolysis of the aspartylphosphate could be a trigger to power late cytoplasmic 40S subunit biogenesis. PMID- 23104057 TI - Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. AB - Co-receptors add complexity to cell-cell signaling systems. The secreted semaphorin 3s (Sema3s) require a co-receptor, neuropilin (Nrp), to signal through plexin As (PlxnAs) in functions ranging from axon guidance to bone homeostasis, but the role of the co-receptor is obscure. Here we present the low-resolution crystal structure of a mouse semaphorin-plexin-Nrp complex alongside unliganded component structures. Dimeric semaphorin, two copies of plexin and two copies of Nrp are arranged as a dimer of heterotrimers. In each heterotrimer subcomplex, semaphorin contacts plexin, similar to in co-receptor-independent signaling complexes. The Nrp1s cross brace the assembly, bridging between sema domains of the Sema3A and PlxnA2 subunits from the two heterotrimers. Biophysical and cellular analyses confirm that this Nrp binding mode stabilizes a canonical, but weakened, Sema3-PlxnA interaction, adding co-receptor control over the mechanism by which receptor dimerization and/or oligomerization triggers signaling. PMID- 23104058 TI - Structural basis for recognition of 5'-phosphotyrosine adducts by Tdp2. AB - The DNA-repair enzyme Tdp2 resolves 5'-phosphotyrosyl DNA adducts and mediates resistance to anticancer drugs that target covalent topoisomerase-DNA complexes. Tdp2 also participates in key signaling pathways during development and tumorigenesis and cleaves a protein-RNA linkage during picornavirus replication. The crystal structure of zebrafish Tdp2 bound to DNA reveals a deep, narrow basic groove that selectively accommodates the 5' end of single-stranded DNA in a stretched conformation. The crystal structure of the full-length Caenorhabditis elegans Tdp2 shows that this groove can also accommodate an acidic peptide stretch in vitro, with glutamate and aspartate side chains occupying the DNA backbone phosphate-binding sites. This extensive molecular mimicry suggests a potential mechanism for autoregulation and interaction of Tdp2 with phosphorylated proteins in signaling. Our study provides a framework to interrogate functions of Tdp2 and develop inhibitors for chemotherapeutic and antiviral applications. PMID- 23104060 TI - Credit for clinical trial data. PMID- 23104059 TI - The binding of Varp to VAMP7 traps VAMP7 in a closed, fusogenically inactive conformation. AB - SNAREs provide energy and specificity to membrane fusion events. Fusogenic trans SNARE complexes are assembled from glutamine-contributing SNAREs (Q-SNAREs) embedded in one membrane and an arginine-contributing SNARE (R-SNARE) embedded in the other. Regulation of membrane fusion events is crucial for intracellular trafficking. We identify the endosomal protein Varp as an R-SNARE-binding regulator of SNARE complex formation. Varp colocalizes with and binds to VAMP7, an R-SNARE that is involved in both endocytic and secretory pathways. We present the structure of the second ankyrin repeat domain of mammalian Varp in complex with the cytosolic portion of VAMP7. The VAMP7-SNARE motif is trapped between Varp and the VAMP7 longin domain, and hence Varp kinetically inhibits the ability of VAMP7 to form SNARE complexes. This inhibition will be increased when Varp can also bind to other proteins present on the same membrane as VAMP7, such as Rab32 GTP. PMID- 23104061 TI - Tracking the evolution of cancer methylomes. AB - Cellular transformation in cancer has long been associated with aberrant DNA methylation, most notably, hypermethylation of promoter sequences. A new study uses a clever approach of selective high-resolution profiling to follow DNA methylation over a time course of cellular transformation and challenges the notion that hypermethylation in cancer arises in an orchestrated fashion. PMID- 23104062 TI - Older males beget more mutations. AB - Three papers characterizing human germline mutation rates bolster evidence for a relatively low rate of base substitution in modern humans and highlight a central role for paternal age in determining rates of mutation. These studies represent the advent of a transformation in our understanding of mutation rates and processes, which may ultimately have public health implications. PMID- 23104063 TI - FOXA1 and breast cancer risk. AB - Many SNPs associated with human disease are located in non-coding regions of the genome. A new study shows that SNPs associated with breast cancer risk are located in enhancer regions and alter binding affinity for the pioneer factor FOXA1. PMID- 23104069 TI - Management strategies for acute spinal cord injury: current options and future perspectives. AB - PURPOSE OF REVIEW: Spinal cord injury is a devastating acute neurological condition with loss of function and poor long-term prognosis. This review summarizes current management strategies and innovative concepts on the horizon. RECENT FINDINGS: The routine use of steroids in patients with spinal cord injuries has been largely abandoned and considered a 'harmful standard of care'. Prospective trials have shown that early spine stabilization within 24 h results in decreased secondary complication rates. Neuronal plasticity and axonal regeneration in the adult spinal cord are limited due to myelin-associated inhibitory molecules, such as Nogo-A. The experimental inhibition of Nogo-A ameliorates axonal sprouting and functional recovery in animal models. SUMMARY: General management strategies for acute spinal cord injury consist of protection of airway, breathing, oxygenation and control of blood loss with maintenance of blood pressure. Unstable spine fractures should be stabilized early to allow unrestricted mobilization of patients with spinal cord injuries and to decrease preventable complications. Steroids are largely considered obsolete and have been abandoned in clinical guidelines. Nogo-A represents a promising new pharmacological target to promote sprouting of injured axons and restore function. Prospective clinical trials of Nogo-A inhibition in patients with spinal cord injuries are currently under way. PMID- 23104070 TI - Accessing N-heteroarylated indoles and benzimidazoles from 2-alkynyl cyclohexadienimines and cyclohexadienones through metal-catalyzed tandem reactions. AB - N-Indolyl or N-benzofuranyl indoles and benzimidazoles were prepared through metal-catalyzed tandem reactions between 2-alkynyl cyclohexadienimines or cyclohexadienones and 2-alkynylanilines or N(1)-benzylbenzene-1,2-diamine. PMID- 23104071 TI - Anti-inflammatory and antinociceptive activities of the ethanolic extract of Bougainvillea xbuttiana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bougainvillea xbuttiana is widely distributed in Mexico and it is used as an analgesic in folk medicine. AIM OF THE STUDY: In the present study the in vivo antinociceptive and anti-inflammatory effects of the Bougainvillea xbuttiana ethanolic extract have been studied in mice. MATERIALS AND METHODS: The phytochemical analysis was performed. Antinociceptive activity was evaluated through writhing and formalin test in mice. The anti-inflammatory activity was determined with the carrageenan-induced mice paw oedema model. IL-6, IL-10 and IFN-gamma levels were determined by enzyme-like immunosorbent assay, whereas TNF and nitrite levels were detected by standard assay with L929 cells and colorimetric Griess reactive, respectively. RESULTS: The results showed that the ethanolic extract of the Bougainvillea xbuttiana has significant anti inflammatory and antinociceptive activities, by inhibition of nociception induced by acetic acid and paw oedema. This extract also induced a decrease in TNF levels and an increase of IL-6, IFN-gamma and NO levels that we observed up to 2h. The highest levels of IL-10 were observed up to 4h. The ratios of pro-/anti inflammatory cytokines in sera from mice injected with the ethanolic extract, may be manifesting an anti-inflammatory status. CONCLUSIONS: The present study provides convincing evidences that Bougainvillea xbuttiana extract possesses significant anti-nociceptive and anti-inflammatory effects. PMID- 23104072 TI - Thermus tengchongensis sp. nov., isolated from a geothermally heated soil sample in Tengchong, Yunnan, south-west China. AB - A Gram-stain negative aerobic bacterium, designated YIM 77924(T), was isolated from a geothermally heated soil sample collected at Rehai National Park, Tengchong, Yunnan province, south-west China. Growth was found to occur from 55 to 75 degrees C (optimum 65 degrees C), pH 6.0-8.0 (optimum pH 7.0) and 0-1 % NaCl (w/v). Cells were observed to be rod-shaped and the colonies convex, circular, smooth, yellow and non-transparent. Phylogenetic analysis based on the 16S rRNA gene sequence indicated that strain YIM 77924(T) belongs to the genus Thermus. The 16S rRNA gene sequence similarity values between strain YIM 77924(T) and other species of the genus Thermus were all below 97 %. The polar lipids of strain YIM 77924(T) were determined to be aminophospholipid, phospholipid and glycolipid. The predominant respiratory quinone was determined to be MK-8 and the G+C content was 66.64 mol%. The major fatty acids identified were iso-C(16:0), iso-C(15:0), iso-C(17:0) and C(16:0). On the basis of the morphological and chemotaxonomic characteristics as well as genotypic data, strain YIM 77924(T) is proposed to represent a novel species, Thermus tengchongensis sp. nov., in the genus Thermus. The type strain is YIM 77924(T) (=KCTC 32025(T) = CCTCC AB2012063(T)). PMID- 23104073 TI - Selection of associated heterotrophs by methane-oxidizing bacteria at different copper concentrations. AB - Due to the increasing atmospheric concentration of the greenhouse gas methane, more knowledge is needed on the management of methanotrophic communities. While most studies have focused on the characteristics of the methane-oxidizing bacteria (MOB), less is known about their interactions with the associated heterotrophs. Interpretative tools based on denaturing gradient gel electrophoresis allowed to evaluate the influence of copper-an important enzymatic regulator for MOB-on the activity and composition of the bacterial community. Over 30 days, enrichments with 0.1, 1.0 and 10 MUM Cu(2+) respectively, showed comparable methane oxidation activities. The different copper concentrations did not create major shifts in the methanotrophic communities, as a Methylomonas sp. was able to establish dominance at all different copper concentrations by switching between both known methane monooxygenases. The associated heterotrophic communities showed continuous shifts, but over time all cultures evolved to a comparable composition, independent of the copper concentration. This indicates that the MOB selected for certain heterotrophs, possibly fulfilling vital processes such as removal of toxic compounds. The presence of a large heterotrophic food web indirectly depending on methane as sole carbon and energy source was confirmed by a clone library wherein MOB only formed a minority of the identified species. PMID- 23104074 TI - Ogataea kanchanaburiensis sp. nov. and Ogataea wangdongensis sp. nov., two novel methylotrophic yeast species from phylloplane in Thailand. AB - Three strains (KM03(T), KM13 (T) and KM15) representing two novel methylotrophic yeast species were isolated from the external surface of plant leaves, which were collected from Kanchanaburi province, Thailand, by three-consecutive enrichments in methanol broth. Strain KM03(T) was isolated from phylloplane of a mango tree (Mangifera indica) and two strains, KM13(T) and KM15, were obtained from phylloplane of different wine grapes (Vitis vinifera). The sequences of the D1/D2 region of the large subunit (LSU) rRNA gene of the two strains (KM13(T) and KM15) were identical and differed markedly from that of strain KM03(T). In terms of pairwise sequence similarity of the D1/D2 region the closest species to the strains KM13(T) and KM15 were Candida suzukii (CBS 9253(T)) and Candida nitratophila (CBS 2027(T)) but with 2.1 % nucleotide substitutions. Strain KM03(T) differed from Ogataea wickerhamii (CBS 4307(T)), its closest relative, by 2.3 % nucleotide substitutions. Phylogenetic analysis based on the D1/D2 sequences placed the three strains in the Ogataea clade. On the basis of morphological, biochemical, physiological and chemotaxonomic characteristics, the sequence analyses of the D1/D2 and the internal transcribed spacer (ITS) regions of the nuclear ribosomal RNA gene (nrRNA) operon, the three strains represent two novel Ogataea species although formation of ascospores was not observed. Ogataea kanchanaburiensis sp. nov. is proposed for strain KM03(T) (=BCC 47626(T) = NBRC 108603(T) = CBS 12673(T)). Two strains, KM13(T) and KM15, were assigned to Ogataea wangdongensis sp. nov. (type strain KM13(T) = BCC 42664(T) = NBRC 107778(T) = CBS 12674(T)). GenBank/EMBL/DDBJ accession numbers for the sequences of the D1/D2 and the ITS regions of O. kanchanaburiensis KM03(T) are AB734090 and AB734093, respectively, of O. wangdongensis KM13(T) are AB734091 and AB734094, respectively, and of O. wangdongensis KM15 are AB734092 and AB734095, respectively. PMID- 23104076 TI - Tunneling in H loss from energy selected ethanol ions. AB - The H/D loss and CH(3)/CD(3) loss reactions from energy selected ethanol isotopologue ions C(2)H(5)OH(+), C(2)D(5)OD(+), CD(3)CH(2)OH(+), and CH(3)CD(2)OH(+) have been studied by imaging threshold photoelectron photoion coincidence (iPEPICO) spectroscopy. In the lowest energy dissociation channel, the alpha-carbon loses a hydrogen or a deuterium atom. Asymmetry in the daughter ion time-of-flight (TOF) peaks, an ab initio study of the reaction rates, and shifts in the phenomenological onsets between isotopologues revealed that H/D loss is slow at its onset. Tunneling through a reverse barrier along the reaction coordinate was found to play a significant role. Modeling the data with an Eckart barrier suggests that H loss from light ethanol ions proceeds via a reverse barrier of 151 meV, which agrees very well with the ab initio result of 155 meV. The higher energy methyl loss channel appears at its thermochemical threshold, but the branching ratios for methyl and H loss as a function of the ion internal energy are not entirely consistent with statistical theory. The methyl-loss signal cannot completely outcompete the hydrogen atom loss process. The shape of the photoelectron spectrum as well as our calculations indicate that the lowest energy ethanol ion structure lies considerably below the reported IE of 10.48 eV. Franck-Condon factors are favorable for ionization to a metastable ion state, which can rearrange to a more stable equilibrium structure. Combining theoretical results with previous experimental ones yields a revised ethanol adiabatic ionization energy of 10.37 eV. This applies to all isotopologues, as the isotope effect on the ionization energy is not more than a few meV. PMID- 23104075 TI - Maternal relationship security as a moderator of home visiting impacts on maternal psychosocial functioning. AB - There is variability in home visiting program impacts on the outcomes achieved by high risk families. An understanding of how effects vary among families is important for refining service targeting and content. The current study assessed whether and how maternal attributes, including relationship security, moderate short- and long-term home visiting impacts on maternal psychosocial functioning. In this multisite RCT of home visiting in a population-based, ethnically-diverse sample of families at risk for maltreatment of their newborns (n = 643), families were randomly assigned to home visited (HV) and control groups. HV families were to receive intensive services by trained paraprofessionals from birth-3 years. Outcome data were collected when children were 1, 2, and 3 years old and 7, 8, and 9 years old. Overall, short- and long-term outcomes for HV and control mothers did not differ significantly. Demographic attributes, a general measure of overall maternal risk, and partner violence did not moderate program impact on psychosocial functioning outcomes. Maternal relationship security did moderate program impact. Mothers who scored high on relationship anxiety but not on relationship avoidance showed the greatest benefits, particularly at the long term follow-up. Mothers scoring high for both relationship anxiety and avoidance experienced some adverse consequences of home visiting. Further research is needed to determine mediating pathways and to inform and test ways to improve the targeting of home visiting and the tailoring of home visit service models to extend positive home visiting impacts to targeted families not benefiting from current models. PMID- 23104077 TI - Hydroxylation of (-)-epigallocatechin-3-O-gallate at 3'', but not 4'', is essential for the PI3-kinase/Akt-dependent phosphorylation of endothelial NO synthase in endothelial cells and relaxation of coronary artery rings. AB - (-)-Epigallocatechin-3-O-gallate (EGCg) has been shown to induce endothelium dependent nitric oxide (NO)-mediated relaxation via the redox-sensitive Src/PI3 kinase/Akt-dependent phosphorylation of endothelial NO synthase (eNOS). Although the presence of 8 hydroxyl functions, mainly on B and D rings, is essential for the EGCg-induced activation of eNOS, the relative role of each individual hydroxyl function still remains unclear. This study examined the effect of selective replacement of hydroxyl functions by methoxy moieties on either the B or D ring on the EGCg-induced phosphorylation of Akt and eNOS, formation of reactive oxygen species (ROS) and NO in cultured coronary artery endothelial cells, and endothelium-dependent relaxation of coronary artery rings. Replacement of a single hydroxyl by the methoxy group on position 3', 4' or 4'' affected little the EGCg-induced phosphorylation of Akt and eNOS, formation of ROS and NO in endothelial cells, and induction of endothelium-dependent relaxations. In contrast, the single methylation at position 3'' and the double methylation at both positions 3' and 4' reduced markedly the phosphorylation of Akt and eNOS, the formation of ROS and NO in endothelial cells and the relaxation of artery rings. These findings suggest that the hydroxyl group at the 3'' position of the gallate ring is essential and, also, to some extent, the two hydroxyl groups at positions 3' and 4', for the EGCg-induced redox-sensitive activation of eNOS leading to the subsequent NO-mediated vascular relaxation. PMID- 23104078 TI - Antihypercholesterolemic and antioxidative effects of an extract of the oyster mushroom, Pleurotus ostreatus, and its major constituent, chrysin, in Triton WR 1339-induced hypercholesterolemic rats. AB - Hypercholesterolemia and oxidative stress are known to accelerate coronary artery disease and progression of atherosclerotic lesions. In the present study, an attempt was made to evaluate the putative antihypercholesterolemic and antioxidative effects of an ethanolic extract of the oyster mushroom (Pleurotus ostreatus) and chrysin, one of its major components, in hypercholesterolemic rats. Hypercholesterolemia was induced in rats by a single intraperitoneal injection of Triton WR-1339 (300 mg/kg body weight (b.wt.)), which resulted in persistently elevated blood/serum levels of glucose, lipid profile parameters (total cholesterol, triglycerides, low-density lipoprotein-, and very low-density lipoprotein-cholesterol), and of hepatic marker enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase). In addition, lowered mean activities of hepatic antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase) and lowered mean levels of nonenzymatic antioxidants (reduced glutathione, vitamin C, and vitamin E) were observed. Oral administration of the mushroom extract (500 mg/kg b.wt.) and chrysin (200 mg/kg b.wt.) to hypercholesterolemic rats for 7 days resulted in a significant decrease in mean blood/serum levels of glucose, lipid profile parameters, and hepatic marker enzymes and a concomitant increase in enzymatic and nonenzymatic antioxidant parameters. The hypercholesterolemia ameliorating effect was more pronounced in chrysin-treated rats than in extract treated rats, being almost as effective as that of the standard lipid-lowering drug, lovastatin (10 mg/kg b.wt.). These results suggest that chrysin, a major component of the oyster mushroom extract, may protect against the hypercholesterolemia and elevated serum hepatic marker enzyme levels induced in rats injected with Triton WR-1339. PMID- 23104080 TI - Microsatellites as targets of natural selection. AB - The ability to survey polymorphism on a genomic scale has enabled genome-wide scans for the targets of natural selection. Theory that connects patterns of genetic variation to evidence of natural selection most often assumes a diallelic locus and no recurrent mutation. Although these assumptions are suitable to selection that targets single nucleotide variants, fundamentally different types of mutation generate abundant polymorphism in genomes. Moreover, recent empirical results suggest that mutationally complex, multiallelic loci including microsatellites and copy number variants are sometimes targeted by natural selection. Given their abundance, the lack of inference methods tailored to the mutational peculiarities of these types of loci represents a notable gap in our ability to interrogate genomes for signatures of natural selection. Previous theoretical investigations of mutation-selection balance at multiallelic loci include assumptions that limit their application to inference from empirical data. Focusing on microsatellites, we assess the dynamics and population-level consequences of selection targeting mutationally complex variants. We develop general models of a multiallelic fitness surface, a realistic model of microsatellite mutation, and an efficient simulation algorithm. Using these tools, we explore mutation-selection-drift equilibrium at microsatellites and investigate the mutational history and selective regime of the microsatellite that causes Friedreich's ataxia. We characterize microsatellite selective events by their duration and cost, note similarities to sweeps from standing point variation, and conclude that it is premature to label microsatellites as ubiquitous agents of efficient adaptive change. Together, our models and simulation algorithm provide a powerful framework for statistical inference, which can be used to test the neutrality of microsatellites and other multiallelic variants. PMID- 23104079 TI - Recent and ancient signature of balancing selection around the S-locus in Arabidopsis halleri and A. lyrata. AB - Balancing selection can maintain different alleles over long evolutionary times. Beyond this direct effect on the molecular targets of selection, balancing selection is also expected to increase neutral polymorphism in linked genome regions, in inverse proportion to their genetic map distances from the selected sites. The genes controlling plant self-incompatibility are subject to one of the strongest forms of balancing selection, and they show clear signatures of balancing selection. The genome region containing those genes (the S-locus) is generally described as nonrecombining, and the physical size of the region with low recombination has recently been established in a few species. However, the size of the region showing the indirect footprints of selection due to linkage to the S-locus is only roughly known. Here, we improved estimates of this region by surveying synonymous polymorphism and estimating recombination rates at 12 flanking region loci at known physical distances from the S-locus region boundary, in two closely related self-incompatible plants Arabidopsis halleri and A. lyrata. In addition to studying more loci than previous studies and using known physical distances, we simulated an explicit demographic scenario for the divergence between the two species, to evaluate the extent of the genomic region whose diversity departs significantly from neutral expectations. At the closest flanking loci, we detected signatures of both recent and ancient indirect effects of selection on the S-locus flanking genes, finding ancestral polymorphisms shared by both species, as well as an excess of derived mutations private to either species. However, these effects are detected only in a physically small region, suggesting that recombination in the flanking regions is sufficient to quickly break up linkage disequilibrium with the S-locus. Our approach may be useful for distinguishing cases of ancient versus recently evolved balancing selection in other systems. PMID- 23104082 TI - Zinc transporter 7 induced by high glucose attenuates epithelial-to-mesenchymal transition of peritoneal mesothelial cells. AB - Zinc (Zn) is an essential micronutrient and cytoprotectant involved in preventing many types of epithelial-to-mesenchymal transition (EMT)-driven fibrosis in vivo. The zinc-transporter family SLC30A (ZnT) is a pivotal factor in the regulation of Zn homeostasis. However, its function in EMT in peritoneal mesothelial cells (PMCs) remains unknown. This study explored the regulation of zinc transporters and the role they play in cell EMT, particularly in rat peritoneal mesothelial cells (RPMCs), surrounding glucose concentrations and the molecular mechanism involved. The effects of high glucose (HG) on zinc transporter gene expression were measured in RPMCs by real-time PCR. We explored ZnT7 (Slc30A7): the effect of ZnT7 over-expression and siRNA-mediated knock-down on HG-induced EMT was investigated as well as the underlying molecular mechanisms. Over-expression of ZnT7 resulted in significantly inhibited HG-induced EMT in RPMCs, while inhibition of ZnT7 expression using a considerable siRNA-mediated knock-down of RPMCs increased the levels of EMT. Furthermore, over-expression of ZnT7 is accompanied by down-regulation of TGF-beta/Smad pathway, phospho-Smad3,4 expression levels. The finding suggests that the zinc-transporting system in RPMCs is influenced by the exposure to HG. The ZnT7 may account for the inhibition of HG-induced EMT in RPMCs, likely through targeting TGF-beta/Smad signaling. PMID- 23104081 TI - Nonlinear fitness consequences of variation in expression level of a eukaryotic gene. AB - Levels of gene expression show considerable variation in eukaryotes, but no fine scale maps have been made of the fitness consequences of such variation in controlled genetic backgrounds and environments. To address this, we assayed fitness at many levels of up- and down-regulated expression of a single essential gene, LCB2, involved in sphingolipid synthesis in budding yeast Saccharomyces cerevisiae. Reduced LCB2 expression rapidly decreases cellular fitness, yet increased expression has little effect. The wild-type expression level is therefore perched on the edge of a nonlinear fitness cliff. LCB2 is upregulated when cells are exposed to osmotic stress; consistent with this, the entire fitness curve is shifted upward to higher expression under osmotic stress, illustrating the selective force behind gene regulation. Expression levels of LCB2 are lower in wild yeast strains than in the experimental lab strain, suggesting that higher levels in the lab strain may be idiosyncratic. Reports indicate that the effect sizes of alleles contributing to variation in complex phenotypes differ among environments and genetic backgrounds; our results suggest that such differences may be explained as simple shifts in the position of nonlinear fitness curves. PMID- 23104083 TI - Selective and localized radiofrequency heating of skin and fat by controlling surface distributions of the applied voltage: analytical study. AB - At low frequencies (hundreds of kHz to a few MHz), local energy absorption is proportional to the conductivity of tissue and the intensity of the internal electric field. At 1 MHz, the electric conductivity ratio between skin and fat is approximately 10; hence, skin would heat more provided the intensity of the electric field is similar in both tissues. It follows that selective and localized heat deposition is only feasible by varying electric fields locally. In this study, we vary local intensities of the internal electric field in skin, fat and muscle by altering its direction through modifying surface distributions of the applied voltage. In addition, we assess the long-term effects of these variations on tissue thermal transport. To this end, analytical solutions of the electric and bioheat equations were obtained using a regular perturbation method. For voltage distributions given by second- and eight-degree functions, the power absorption in fat is much greater than in skin by the electrode center while the opposite is true by the electrode edge. For a sinusoidal function, the absorption in fat varies laterally from greater to lower than in skin, and then this trend repeats from the center to the edge of the electrode. Consequently, zones of thermal confinement selectively develop in the fat layer. Generalizing these functions by parametrization, it is shown that radiofrequency (RF) heating of layered tissues can be selective and precisely localized by controlling the spatial decay, extent and repetition of the surface distribution of the applied voltage. The clinical relevance of our study is to provide a simple, non-invasive method to spatially control the heat deposition in layered tissues. By knowing and controlling the internal electric field, different therapeutic strategies can be developed and implemented. PMID- 23104084 TI - To DNA, all information is equal. AB - Information storage capabilities are key in most aspects of society and the requirement for storage capacity is rapidly expanding. In principle, DNA could be a high-density medium for information storage. Church and coworkers recently demonstrated how binary data can be encoded, stored in, and retrieved from a library of oligonucleotides, increasing by several orders of magnitude the amount and density of manmade information stored in DNA to date. The technology remains in its infancy and important hurdles have yet to be overcome in order to realize its potential. However, DNA may be particularly useful as a storage-medium over long time-scales (centuries), because data-access is compatible with any large scale DNA-sequencing and -synthesis technology. PMID- 23104085 TI - Electrochemical deposition and evaluation of electrically conductive polymer coating on biodegradable magnesium implants for neural applications. AB - In an attempt to develop biodegradable, mechanically strong, biocompatible, and conductive nerve guidance conduits, pure magnesium (Mg) was used as the biodegradable substrate material to provide strength while the conductive polymer, poly(3,4-ethylenedioxythiophene) (PEDOT) was used as a conductive coating material to control Mg degradation and improve cytocompatibility of Mg substrates. This study explored a series of electrochemical deposition conditions to produce a uniform, consistent PEDOT coating on large three-dimensional Mg samples. A concentration of 1 M 3,4-ethylenedioxythiophene in ionic liquid was sufficient for coating Mg samples with a size of 5 * 5 * 0.25 mm. Both cyclic voltammetry (CV) and chronoamperometry coating methods produced adequate coverage and uniform PEDOT coating. Low-cost stainless steel and copper electrodes can be used to deposit PEDOT coatings as effectively as platinum and silver/silver chloride electrodes. Five cycles of CV with the potential ranging from -0.5 to 2.0 V for 200 s per cycle were used to produce consistent coatings for further evaluation. Scanning electron micrographs showed the micro-porous structure of PEDOT coatings. Energy dispersive X-ray spectroscopy showed the peaks of sulfur, carbon, and oxygen, indicating sufficient PEDOT coating. Adhesion strength of the coating was measured using the tape test following the ASTM-D 3359 standard. The adhesion strength of PEDOT coating was within the classifications of 3B to 4B. Tafel tests of the PEDOT coated Mg showed a corrosion current (I(CORR)) of 6.14 * 10(-5) A as compared with I(CORR) of 9.08 * 10(-4) A for non-coated Mg. The calculated corrosion rate for the PEDOT coated Mg was 2.64 mm/year, much slower than 38.98 mm/year for the non-coated Mg. PMID- 23104086 TI - Development of pH-sensitive pectinate/alginate microspheres for colon drug delivery. AB - The purposes of this study were to develop and evaluate calcium pectinate/alginate microspheres (PAMs) and to exploit their pH-sensitive properties for colon-targeted delivery of encapsulated cisplatin. PAMs were prepared using an electrospraying method. The PAMs, as cores, were then coated with Eudragit S100 using a polyelectrolyte multilayer coating technique in aqueous solution. The morphology of the microspheres was observed under scanning electron microscopy. In vitro drug release studies were performed in simulated gastrointestinal fluid, and the results indicated that approximately 5 % of the cisplatin was released from the Eudragit S100-coated PAMs, and 51 % of the cisplatin was released from the uncoated PAMs at 1 h. The release of cisplatin from the Eudragit S100-coated PAMs was more sustained in simulated gastric fluid than in simulated intestinal fluid due to the increased solubility of the coating polymer in media with pH >7.0. Drug release from the Eudragit S100-coated PAMs was best described by the Higuchi's square root model. From these results, it was concluded that Eudragit S100-coated PAMs are a potential carrier for delivery of cisplatin to the colon. PMID- 23104087 TI - Injectable collagen/alpha-tricalcium phosphate cement: collagen-mineral phase interactions and cell response. AB - A bone inspired material was obtained by incorporating collagen in the liquid phase of an alpha-tricalcium phosphate cement, either in solubilized or in fibrilized form. This material was able to set in situ, giving rise to a calcium deficient hydroxyapatite (CDHA)/collagen composite. The morphology and distribution of collagen in the composite was shown to be strongly affected by the collagen pre-treatment. The interactions between collagen and the inorganic phase were assessed by FTIR. A red shift of the amide I band was indicative of calcium chelation by the collagen carbonyl groups. The rate of CDHA formation was not affected when diluted collagen solutions (1 mg/ml) were used, whereas injectability improved. The presence of solubilized collagen, even in low amount (1 %), increased cell adhesion and proliferation on the composites. Still in the absence of osteogenic medium, significant ALP activity was detected both in the inorganic and the collagen-containing cements. The maximum ALP activity was advanced in the collagen-containing cement as compared to the inorganic cement. PMID- 23104088 TI - Development and validation of a mental health subscale from the Quality of Well Being Self-Administered. AB - PURPOSE: The purpose of this study was to create and validate a mental health subscale for the Quality of Well-Being Self-Administered (QWB-SA). METHODS: The QWB-SA and other measures such as the Profile of Mood States (POMS), Medical Outcomes Study 36 Item Short Form (SF-36), EuroQOL 5D (EQ-5D), and Health Utilities Index Mark 2 (HUI) were administered to three samples: a general population (N = 3,844), a non-psychiatric medical population (N = 535), and a psychiatric population (N = 915). Independent expert ratings of which items represented the construct of mental health were used along with psychometric methods to develop and validate a 10-item QWB-SA mental health scale. RESULTS: The mental health scale demonstrated high internal consistency (Cronbach's alpha = 0.827-0.842) and strong correlations with other measures of mental health, such as the POMS (r = -0.77), mental health scale from the SF-36 (r = 0.72), EQ-5D mood item (r = 0.61), and HUI Emotion Scale (r = 0.59). It was not highly correlated with measures of physical health. Among the psychiatric population, the new mental health scale was moderately correlated with indicators of psychiatric problem severity. CONCLUSIONS: It is now possible to report outcomes and relationships with mental health in studies that use the QWB-SA. This new mental health subscale can also be used with the large volume of previously collected data using the QWB-SA to examine the impact of illnesses and interventions on mental health-related quality of life. PMID- 23104089 TI - Philosophical perspectives on response shift. AB - PURPOSE: This paper brings a philosophical perspective to response shift research with the aim of raising new critical questions, clarifying some of the concepts employed, and providing a philosophical context within which to critically examine the assumptions that shape the field. METHODS: This critical analysis aims to reveal assumptions and clarify concepts and/or definitions that undergird methodological practice and theory. RESULTS: We bring attention to the distinction of weak and strong evaluations, and the implications and consequences for construct validity and for designing patient-reported outcome measures (PROMs). We then consider the epistemology of PROMs, suggesting that they are better suited to a social constructivist approach than a scientific realist one. Finally, we examine the relationship between disability and response shift, arguing that in at least some cases, response shifts should not be understood as 'measurement bias'. CONCLUSION: Our analysis reveals various concerns and further questions related to the role that substantive values play in the assessment of QoL. It also draws response shift into a wider arena, with broader issues of interpretation, self-evaluation, the meaning of the 'good life', and the status and legitimacy we accord to various scientific methods. PMID- 23104093 TI - The insulin receptor and the kidney. AB - PURPOSE OF REVIEW: In recent years, it has become clear that the insulin receptor is important in a variety of renal cell types. It is through this transmembrane receptor that insulin, and to a lesser extent insulin-like growth factor, hormones bind and can control important cellular functions. This review will summarize the advances in our understanding of the role of the insulin receptor and insulin signalling in the glomeruli and tubules of the kidney. RECENT FINDINGS: The insulin receptor is important for podocyte function and when lost results in a number of features resembling diabetic nephropathy. Exciting recent data also highlight the importance of mammalian target of rapamycin in nutrient sensing and protein biosynthesis in the podocyte, which may also be regulated by the insulin receptor. The insulin receptor has also been shown to perform an important role in the distal regions of the renal tubules, regulating sodium excretion and blood pressure control here. SUMMARY: The insulin receptor is crucial for renal function in glomeruli and tubules. When signalling is diminished here, as may occur in insulin-resistant states, it may be responsible for a number of important renal complications including albuminuric glomerular disease and hypertension. PMID- 23104094 TI - Building a nuclear envelope at the end of mitosis: coordinating membrane reorganization, nuclear pore complex assembly, and chromatin de-condensation. AB - The metazoan nucleus is disassembled and re-built at every mitotic cell division. The nuclear envelope, including nuclear pore complexes, breaks down at the beginning of mitosis to accommodate the capture of massively condensed chromosomes by the spindle apparatus. At the end of mitosis, a nuclear envelope is newly formed around each set of segregating and de-condensing chromatin. We review the current understanding of the membrane restructuring events involved in the formation of the nuclear membrane sheets of the envelope, the mechanisms governing nuclear pore complex assembly and integration in the nascent nuclear membranes, and the regulated coordination of these events with chromatin de condensation. PMID- 23104095 TI - Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. AB - We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 (RBCK1), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-kappaB activation in response to interleukin 1beta (IL-1beta) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1beta. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1beta responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-kappaB-dependent IL 1beta responses differently in different cell types. PMID- 23104096 TI - Localized epigenetic changes induced by DH recombination restricts recombinase to DJH junctions. AB - Genes encoding immunoglobulin heavy chains (Igh) are assembled by rearrangement of variable (V(H)), diversity (D(H)) and joining (J(H)) gene segments. Three critical constraints govern V(H) recombination. These include timing (V(H) recombination follows D(H) recombination), precision (V(H) gene segments recombine only to DJ(H) junctions) and allele specificity (V(H) recombination is restricted to DJ(H)-recombined alleles). Here we provide a model for these universal features of V(H) recombination. Analyses of DJ(H)-recombined alleles showed that DJ(H) junctions were selectively epigenetically marked, became nuclease sensitive and bound RAG recombinase proteins, which thereby permitted D(H)-associated recombination signal sequences to initiate the second step of Igh gene assembly. We propose that V(H) recombination is precise, because these changes did not extend to germline D(H) segments located 5' of the DJ(H) junction. PMID- 23104098 TI - Microalgae as human food: chemical and nutritional characteristics of the thermo acidophilic microalga Galdieria sulphuraria. AB - The use of microalgae as a food source is still poorly developed because of the technical difficulties related to their cultivation and the limited knowledge about their chemical composition and nutritional value. The unicellular red microalga Galdieria sulphuraria has a very high daily productivity and its cultivation under acidic conditions avoided any bacterial contamination. G. sulphuraria can be cultured under autotrophic and heterotrophic conditions: in this study a screening of 43 strains showed that in the latter case a duplication of biomass production was obtained. The proximate composition (protein, carbohydrates, fiber and lipids), the micronutrient content (carotenoids, phycobiliproteins, chlorophylls and vitamins) together with the antioxidant activity of the biomass produced by a selected strain of G. sulphuraria under both cultivation conditions were determined. Results showed that the material is rich in proteins (26-32%) and polysaccharides (63-69%) and poor in lipids. Under heterotrophic cultivation conditions, the lipid moiety mainly contained monounsaturated fatty acids. Among micronutrients, some B group vitamins are present, beta-carotene is the main carotenoid and phycobiliproteins are present under both cultivating conditions. G. sulphuraria proteins are strictly associated with polysaccharide components and therefore not digestible. In the second part of the work, an extraction protocol using Viscozyme L, a commercial enzymatic preparation containing a mixture of polysaccharidases, was developed which made G. sulphuraria proteins a good substrate for human gastrointestinal enzymes. All in all, the data suggested that G. sulphuraria biomass has a potential use as food ingredients both for protein-rich or insoluble dietary fibre-rich applications. The low concentration of lipids and the absence of green color make this microalgae source particularly useful for the addition to many food preparations. PMID- 23104097 TI - Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. AB - Interleukin 15 (IL-15) and IL-2 have distinct immunological functions even though both signal through the receptor subunit IL-2Rbeta and the common gamma-chain (gamma(c)). Here we found that in the structure of the IL-15-IL-15Ralpha-IL 2Rbeta-gamma(c) quaternary complex, IL-15 binds to IL-2Rbeta and gamma(c) in a heterodimer nearly indistinguishable from that of the IL-2-IL-2Ralpha-IL-2Rbeta gamma(c) complex, despite their different receptor-binding chemistries. IL 15Ralpha substantially increased the affinity of IL-15 for IL-2Rbeta, and this allostery was required for IL-15 trans signaling. Consistent with their identical IL-2Rbeta-gamma(c) dimer geometries, IL-2 and IL-15 showed similar signaling properties in lymphocytes, with any differences resulting from disparate receptor affinities. Thus, IL-15 and IL-2 induced similar signals, and the cytokine specificity of IL-2Ralpha versus IL-15Ralpha determined cellular responsiveness. Our results provide new insights for the development of specific immunotherapeutics based on IL-15 or IL-2. PMID- 23104100 TI - Poly(ethylene glycol) as reaction medium for mild Mizoroki-Heck reaction in a ball-mill. AB - Phosphine-free palladium-catalyzed Mizoroki-Heck reaction was performed using ball-milling in polyethylene glycol under mild conditions. Good to excellent yields of coupling products were obtained. This activation technique also allowed the concomitant formation of round shaped Pd-PEG nanoparticles that were characterized by TEM analysis. PMID- 23104099 TI - Multiple genetic variants predict steady-state nevirapine clearance in HIV infected Cambodians. AB - OBJECTIVE: In a previous analysis involving protocol ANRS 12154, interindividual variability in steady-state nevirapine clearance among HIV-infected Cambodians was partially explained by CYP2B6 516G->T (CYP2B6*6). Here, we examine whether additional genetic variants predict nevirapine clearance in this cohort. METHODS: Analyses included Phnom Penh ESTHER (Ensemble pour une Solidarite Therapeutique Hospitaliere en Reseau) cohort participants who had consented for genetic testing. All participants were receiving nevirapine plus two nucleoside analogs. The mean individual nevirapine clearance estimates were derived from a population model developed on nevirapine concentrations at 18 and 36 months of therapy. Polymorphisms were assayed in ABCB1, CYP2A6, CYP2B6, CYP2C19, CYP3A4, CYP3A5, and NR1I2. RESULTS: Of 198 assayed loci, 130 were polymorphic. Among 129 individuals with evaluable genetic data, nevirapine clearance ranged from 1.06 to 5.00 l/h in 128 individuals and was 7.81 l/h in one individual. In bivariate linear regression, CYP2B6 516G->T (CYP2B6*6) was associated with lower nevirapine clearances (P=3.5*10). In a multivariate linear regression model conditioned on CYP2B6 516G->T, independent associations were identified with CYP2B6 rs7251950, CYP2B6 rs2279343, and CYP3A4 rs2687116. The CYP3A4 association disappeared after censoring the outlier clearance value. A model that included CYP2B6 516G->T (P=1.0*10), rs7251950 (P=4.8*10), and rs2279343 (P=7.1*10) explained 11% of interindividual variability in nevirapine clearance. CONCLUSION: Among HIV infected Cambodians, several CYP2B6 polymorphisms were associated independently with steady-state nevirapine clearance. The prediction of nevirapine clearance was improved by considering several polymorphisms in combination. PMID- 23104101 TI - Seven sirtuins for seven deadly diseases of aging. AB - Sirtuins are a class of NAD(+)-dependent deacetylases having beneficial health effects. This extensive review describes the numerous intracellular actions of the seven mammalian sirtuins, their protein targets, intracellular localization, the pathways they modulate, and their role in common diseases of aging. Selective pharmacological targeting of sirtuins is of current interest in helping to alleviate global disease burden. Since all sirtuins are activated by NAD(+), strategies that boost NAD(+) in cells are of interest. While most is known about SIRT1, the functions of the six other sirtuins are now emerging. Best known is the involvement of sirtuins in helping cells adapt energy output to match energy requirements. SIRT1 and some of the other sirtuins enhance fat metabolism and modulate mitochondrial respiration to optimize energy harvesting. The AMP kinase/SIRT1-PGC-1alpha-PPAR axis and mitochondrial sirtuins appear pivotal to maintaining mitochondrial function. Downregulation with aging explains much of the pathophysiology that accumulates with aging. Posttranslational modifications of sirtuins and their substrates affect specificity. Although SIRT1 activation seems not to affect life span, activation of some of the other sirtuins might. Since sirtuins are crucial to pathways that counter the decline in health that accompanies aging, pharmacological agents that boost sirtuin activity have clinical potential in treatment of diabetes, cardiovascular disease, dementia, osteoporosis, arthritis, and other conditions. In cancer, however, SIRT1 inhibitors could have therapeutic value. Nutraceuticals such as resveratrol have a multiplicity of actions besides sirtuin activation. Their net health benefit and relative safety may have originated from the ability of animals to survive environmental changes by utilizing these stress resistance chemicals in the diet during evolution. Each sirtuin forms a key hub to the intracellular pathways affected. PMID- 23104102 TI - Blood pressure has only minor influence on aldosterone-induced oxidative stress and DNA damage in vivo. AB - Epidemiological studies found an increased kidney cancer risk in hypertensive patients. These patients frequently present an increase in the mineralocorticoid aldosterone (Ald) due to a stimulated renin angiotensin aldosterone system (RAAS). Recently, we showed pro-oxidative and genotoxic effects of Ald in vitro. Here, we investigated the influence of blood pressure on aldosterone-induced oxidative damage. To distinguish whether effects in Sprague-Dawley rats treated with Ald were caused by Ald or by increased blood pressure, the mineralocorticoid receptor (MR) antagonist spironolactone was administered in a subtherapeutical dose, not lowering the blood pressure, and hydralazine, a RAAS-independent vasodilator, was given to normalize the pressure. With the antioxidant tempol, oxidative stress-dependent effects were demonstrated. Ald treatment caused kidney damage and oxidative and nitrative stress. Structural DNA damage and the mutagenic oxidative base modification 7,8-dihydro-8-oxoguanine were increased, as well as DNA repair activity and nuclear NF-kappaB translocation. Spironolactone and tempol decreased all markers significantly, whereas hydralazine had just slight effects. These data comprise the first report of essentially blood pressure-independent tissue- and DNA-damaging effects of Ald. A fully activated MR and the production of reactive oxygen and nitrogen species were crucial for these effects. PMID- 23104103 TI - No, Chagas disease is not the new AIDS of the Americas!. AB - Chagas disease and AIDS: the same terminology cannot be used to associate, let alone confuse, these two diseases with one another without distorting reality, as was done in a recent medical article entitled: Chagas disease: "The New HIV/AIDS of the Americas". Even though Chagas disease, like many other "neglected diseases", bears some superficial resemblance to AIDS in certain ways, it nevertheless differs from the latter in many other significant ones. PMID- 23104104 TI - Chemical input and I-V output: stepwise chemical information processing in dye sensitized solar cells. AB - As a complex system, a dye-sensitized solar cell (DSC) exhibits emergent photovoltaics not obvious from the properties of the individual components. The chemical input of 4-tert-butylpyridine (TBP) into DSC improves the open circuit voltage (V(oc)) and reduces the short circuit current (I(sc)) in I-V output through multiple interactions with the components, yet it has been difficult to distinguish the multiple interactions and correlate the interactions with the influences on I-V output due to the complexity of the system. To deal with the multiple interactions, we have adapted a conceptual framework and methodology from coordination chemistry. First, we titrated the photovoltaic interface and electrolyte with TBP to identify the stepwise chemical interaction processes. An isopotential point observed in I-V output indicates that most of the inputted chemicals interact with the electrolyte. Cyclic voltammetric titration of the electrolyte demonstrates asymmetric redox peaks and two different isopotential points, indicating that the two-step coordination-decoordination process inhibits the reduction current of the electrolyte. Second, we set an interaction model bridging the hierarchical gaps between the multiple interactions and the I-V output to address the influences on outputs from the amount of the inputs. From the viewpoint of the interaction model and interactions observed, we are able to comprehend the processes of the complex system and suggest a direction to improve V(oc) without sacrificing I(sc) in DSCs. We conclude that the conceptual framework and methodology adapted from coordination chemistry is beneficial to enhance the emergent outputs of complex systems. PMID- 23104105 TI - Pore formation in lipid bilayer membranes made of phosphatidylcholine and cholesterol followed by means of constant current. AB - This paper describes the application of chronopotentiometry to lipid bilayer research. The experiments were performed on bilayer lipid membranes composed of phosphatidylcholine and cholesterol and formed using the painting technique. Chronopotentiometric (U = f(t)) measurements were used to determine the membrane capacitance, resistance, and breakdown voltage as well as pore conductance and diameter. PMID- 23104106 TI - Phenotypic plasticity in anti-intraguild predator strategies: mite larvae adjust their behaviours according to vulnerability and predation risk. AB - Interspecific threat-sensitivity allows prey to maximize the net benefit of antipredator strategies by adjusting the type and intensity of their response to the level of predation risk. This is well documented for classical prey-predator interactions but less so for intraguild predation (IGP). We examined threat sensitivity in antipredator behaviour of larvae in a predatory mite guild sharing spider mites as prey. The guild consisted of the highly vulnerable intraguild (IG) prey and weak IG predator Phytoseiulus persimilis, the moderately vulnerable IG prey and moderate IG predator Neoseiulus californicus and the little vulnerable IG prey and strong IG predator Amblyseius andersoni. We videotaped the behaviour of the IG prey larvae of the three species in presence of either a low- or a high-risk IG predator female or predator absence and analysed time, distance, path shape and interaction parameters of predators and prey. The least vulnerable IG prey A. andersoni was insensitive to differing IGP risks but the moderately vulnerable IG prey N. californicus and the highly vulnerable IG prey P. persimilis responded in a threat-sensitive manner. Predator presence triggered threat-sensitive behavioural changes in one out of ten measured traits in N. californicus larvae but in four traits in P. persimilis larvae. Low-risk IG predator presence induced a typical escape response in P. persimilis larvae, whereas they reduced their activity in the high-risk IG predator presence. We argue that interspecific threat-sensitivity may promote co-existence of IG predators and IG prey and should be common in predator guilds with long co evolutionary history. PMID- 23104107 TI - Interactions between the predatory mite Typhlodromalus aripo and the entomopathogenic fungus Neozygites tanajoae and consequences for the suppression of their shared prey/host Mononychellus tanajoa. AB - The predatory mite Typhlodromalus aripo and the entomopathogenic fungus Neozygites tanajoae, both introduced from Brazil for control of the cassava green mite (CGM) Mononychellus tanajoa, now co-occur in cassava fields in Benin. However, studies on interactions between these two natural enemies and how they might affect CGM biological control are lacking. We determined in screenhouse experiments the effects of single and combined releases of N. tanajoae and T. aripo on CGM suppression. In the single natural enemy treatment, both T. aripo and N. tanajoae significantly reduced CGM densities, but the results of the predator (T. aripo) are more quickly measurable than those of the pathogen (N. tanajoae) in our short-term experiment. The level of CGM suppression in the combined natural enemy treatment was reduced considerably compared with T. aripo alone, but only slightly when compared with N. tanajoae alone, with a simultaneous reduction in T. aripo and N. tanajoae abundance or prevalence. In a laboratory experiment, T. aripo fed more on N. tanajoae-infected CGM than on healthy CGM and its oviposition and survival were reduced when fed on the former compared with the latter, which can help in explaining the reduction in numbers of T. aripo and consequently the considerable loss in suppression of CGM in the combined natural enemy treatment in the screenhouse experiment. Together, the screenhouse and the laboratory experiments predicted negative interactions between the two natural enemies with negative consequences for CGM biological control. Long-term field observations and rigorous field experiments that simultaneously manipulate T. aripo and N. tanajoae abundance and prevalence are needed to validate the prediction of this study. PMID- 23104108 TI - Putative role of proteins involved in detoxification of reactive oxygen species in the early response to gravitropic stimulation of poplar stems. AB - Gravity perception and gravitropic response are essential for plant development. In herbaceous species it is widely accepted that one of the primary events in gravity perception involves the displacement of amyloplasts within specialized cells. However the signaling cascade leading to stem reorientation is not fully known especially in woody species in which primary and secondary growth occur. Several different second messengers and proteins have been suggested to be involved in signal transduction of gravitropism. Reactive oxygen species (ROS) have been implicated as second messengers in several plant hormone responses. It has been shown that ROS are asymmetrically generated in roots by gravistimulation to regions of reduced growth. Proteins involved in detoxification of ROS and defense were identified by mass spectrometry: i.e., Thioredoxin h (Trx h), CuZn superoxide dismutase (CuZn SOD), ascorbate peroxidase (APX2), oxygen evolving enhancer 1 (OEE1), oxygen evolving enhancer 2 (OEE2), and ATP synthase. These differentially accumulated proteins that correspond to detoxification of ROS were analyzed at the mRNA level. The mRNA levels showed different expression patterns than those of the corresponding proteins, and revealed that transcription levels were not completely concomitant with translation. Our data showed that these proteins may play a role in the early response to gravitropic stimulation. PMID- 23104109 TI - DICER-LIKE1 processed trans-acting siRNAs mediate DNA methylation: case study of complex small RNA biogenesis and action pathways in plants. AB - Small non-coding RNAs (sRNAs) emerge as exquisite molecules that are guided for transcriptional and posttranscriptional gene regulation in eukaryotes. As one class of most important sRNAs in plants, trans-acting small interfering RNAs (ta siRNAs) initiate from microRNA (miRNA) - mediated cleavage of TAS gene transcripts and subsequently are stabilized by SUPPRESSOR OF GENE SILENCING3 (SGS3) and converted to double-stranded RNA (dsRNA) by the actions of RNA DEPENDENT RNA POLYMERASE6 (RDR6). Generally, these dsRNAs are processed by DICER LIKE4 (DCL4) and recruited into ARGONAUTE 1 (AGO1) complexes to posttranscriptionally regulate target genes by mRNA cleavage in trans. In a recent study, we discovered a non-canonical ta-siRNAs pathway: Starting from the miRNA-guided cleavage site, the dsRNAs are processed by DCL1 into 21-nt siRNAs, which associate with AGO4/6 complexes to direct DNA methylation in cis. Together with previous results that miRNAs can be produced by DCL3, loaded into AGO4 and trigger epigenetically regulation of target genes, these findings indicate much complex biogenesis, effector and action pathways exist in plant sRNAs kingdom. PMID- 23104110 TI - NAD: not just a pawn on the board of plant-pathogen interactions. AB - Many metabolic processes that occur in living cells involve oxido-reduction (redox) chemistry underpinned by redox compounds such as glutathione, ascorbate and/or pyridine nucleotides. Among these redox carriers, nicotinamide adenine dinucleotide (NAD) is the cornerstone of cellular oxidations along catabolism and is therefore essential for plant growth and development. In addition to its redox role, there is now compelling evidence that NAD is a signal molecule controlling crucial functions like primary and secondary carbon metabolism. Recent studies using integrative -omics approaches combined with molecular pathology have shown that manipulating NAD biosynthesis and recycling lead to an alteration of metabolites pools and developmental processes, and changes in the resistance to various pathogens. NAD levels should now be viewed as a potential target to improve tolerance to biotic stress and crop improvement. In this paper, we review the current knowledge on the key role of NAD (and its metabolism) in plant responses to pathogen infections. PMID- 23104112 TI - Multifaceted roles of Arabidopsis PP6 phosphatase in regulating cellular signaling and plant development. AB - Reversible protein phosphorylation catalyzed by kinases and phosphatases is a major form of posttranslational regulation that plays a central role in regulating many signaling pathways. While large families of both protein kinases and protein phosphatases have been identified in plants, kinases outnumber phosphatases. This raises the question of how a relatively limited number of protein phosphatases can maintain protein phosphorylation homeostasis in a cell. Recent studies have shown that Arabidopsis FyPP1 (Phytochrome-associated serine/threonine protein phosphatase 1) and FyPP3 encode the catalytic subunits of protein phosphatase 6 (PP6), and that they directly binds to the A subunits of protein phosphatase 2A (PP2AA proteins), and SAL (SAPS domain-like) proteins to form the heterotrimeric PP6 holoenzyme complex. Emerging evidence is suggesting that PP6, acts in opposition with multiple classes of kinases, to regulate the phosphorylation status of diverse substrates and subsequently numerous developmental processes and responses to environmental stimuli. PMID- 23104111 TI - Cross-talk between sulfur assimilation and ethylene signaling in plants. AB - Sulfur (S) deficiency is prevailing all over the world and becoming an important issue for crop improvement through maximising its utilization efficiency by plants for sustainable agriculture. Its interaction with other regulatory molecules in plants is necessary to improve our understanding on its role under changing environment. Our knowledge on the influence of S on ethylene signaling is meagre although it is a constituent of cysteine (Cys) required for the synthesis of reduced glutathione (GSH) and S-adenosyl methionine (SAM), a precursor of ethylene biosynthesis. Thus, there may be an interaction between S assimilation, ethylene signaling and plant responses under optimal and stressful environmental conditions. The present review emphasizes that responses of plants to S involve ethylene action. This evaluation will provide an insight into the details of interactive role of S and ethylene signaling in regulating plant processes and prove profitable for developing sustainability under changing environmental conditions. PMID- 23104113 TI - Metabolic alterations triggered by silicon nutrition: is there a signaling role for silicon? AB - Although the beneficial role of silicon (Si) in stimulating the growth and development of many plants is generally accepted, our knowledge concerning the physiological and molecular mechanisms underlying this response remains far from comprehensive. Considerable effort has been invested in understanding the role of Si on plant disease, which has led to several new and compelling hypotheses; in unstressed plants, however, Si is believed to have no molecular or metabolic effects. Recently, we have demonstrated that Si nutrition can modulate the carbon/nitrogen balance in unstressed rice plants. Our findings point to an important role of Si as a signaling metabolite able to promote amino acid remobilization. In this article we additionally discuss the agronomic significance of these novel observations and suggest Si nutrition as an important target in future attempts to improve yields of agronomic crops. PMID- 23104114 TI - Identification of an EMS-induced causal mutation in a gene required for boron mediated root development by low-coverage genome re-sequencing in Arabidopsis. AB - Next-generation sequencing (NGS) technologies enable the rapid production of an enormous quantity of sequence data. These powerful new technologies allow the identification of mutations by whole-genome sequencing. However, most reported NGS-based mapping methods, which are based on bulked segregant analysis, are costly and laborious. To address these limitations, we designed a versatile NGS based mapping method that consists of a combination of low- to medium-coverage multiplex SOLiD (Sequencing by Oligonucleotide Ligation and Detection) and classical genetic rough mapping. Using only low to medium coverage reduces the SOLiD sequencing costs and, since just 10 to 20 mutant F 2 plants are required for rough mapping, the operation is simple enough to handle in a laboratory with limited space and funding. As a proof of principle, we successfully applied this method to identify the CTR1, which is involved in boron-mediated root development, from among a population of high boron requiring Arabidopsis thaliana mutants. Our work demonstrates that this NGS-based mapping method is a moderately priced and versatile method that can readily be applied to other model organisms. PMID- 23104115 TI - Differential roles of auxin efflux carrier PIN proteins in hypocotyl phototropism of etiolated Arabidopsis seedlings depend on the direction of light stimulus. AB - In a recent study, we demonstrated that although the auxin efflux carrier PIN FORMED (PIN) proteins, such as PIN3 and PIN7, are required for the pulse-induced first positive phototropism in etiolated Arabidopsis hypocotyls, they are not necessary for the continuous-light-induced second positive phototropism when the seedlings are grown on the surface of agar medium, which causes the hypocotyls to separate from the agar surface. Previous reports have shown that hypocotyl phototropism is slightly impaired in pin3 single mutants when they are grown along the surface of agar medium, where the hypocotyls always contact the agar, producing some friction. To clarify the possible involvement of PIN3 and PIN7 in continuous-light-induced phototropism, we investigated hypocotyl phototropism in the pin3 pin7 double mutant grown along the surface of agar medium. Intriguingly, the phototropic curvature was slightly impaired in the double mutant when the phototropic stimulus was presented on the adaxial side of the hook, but was not impaired when the phototropic stimulus was presented on the abaxial side of the hook. These results indicate that PIN proteins are required for continuous-light induced second positive phototropism, depending on the direction of the light stimulus, when the seedlings are in contact with agar medium. PMID- 23104116 TI - 1alpha,25OH2D3 down-regulates HBp17/FGFBP-1 expression via NF-kappaB pathway. AB - The heparin binding protein 17/fibroblast growth factor-binding protein-1 (HBp17/FGFBP-1, GenBank accession no. NP-005121) has been reported to enhance angiogenesis as well as promotes tumor growth in vivo. Furthermore, this molecule was found to be highly expressed in the tissue and cell lines of oral squamous cell carcinoma (OSCC). 1alpha,25(OH)2D3 is used to study its potential to curb the expression of HBp17/FGFBP-1 in cancer cells. Consequently, we found that HBp17/FGFBP-1 mRNA and protein levels were significantly down-regulated. In this present study, we show that this event takes place via the NF-kappaB pathway since mRNA and protein levels of this pathway regulator, IkappaBalpha, were found to be significantly up-regulated. Furthermore, the promoter activity of HBp17/FGFBP-1 (region between -217 and +61) measured by a luciferase reporter assay was down-regulated following treatment. Silencing of VDR with siRNA showed the effect of 1alpha,25(OH)2D3 on HBp17/FGFBP-1. Based on these findings, we concluded that 1alpha,25(OH)2D3 down-regulated HBp17/FGFBP-1 expression via NF kappaB. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23104117 TI - Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner. AB - Alcohol is a known teratogen that is estimated to affect 2-5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23104118 TI - Survey of current vitamin D food fortification practices in the United States and Canada. AB - Widespread poor vitamin D status in all age and gender groups in the United States (USA) and Canada increases the need for new food sources. Currently ~60% of the intake of vitamin D from foods is from fortified foods in these countries. Those groups in greatest need are consuming significantly lower amounts of commonly fortified foods such as milk. Both countries allow voluntary vitamin D fortification of some other foods, although in Canada this practice is only done on a case-by-case basis. Novel approaches to vitamin D fortification of food in both countries now include "bio-addition" in which food staples are fortified through the addition of another vitamin D-rich food to animal feed during production, or manipulation of food post-harvest or pre-processing. These bio addition approaches provide a wider range of foods containing vitamin D, and thus appeal to differing preferences, cultures and possibly economic status. An example is the post-harvest exposure of edible mushrooms to ultraviolet light. However, further research into safety and efficacy of bio-addition needs to be established in different target populations. This article is part of a Special Issue entitled 'Vitamin D Workshop'. PMID- 23104119 TI - Electron transfer from Cyt b(559) and tyrosine-D to the S2 and S3 states of the water oxidizing complex in photosystem II at cryogenic temperatures. AB - The Mn(4)CaO(5) cluster of photosystem II (PSII) catalyzes the oxidation of water to molecular oxygen through the light-driven redox S-cycle. The water oxidizing complex (WOC) forms a triad with Tyrosine(Z) and P(680), which mediates electrons from water towards the acceptor side of PSII. Under certain conditions two other redox-active components, Tyrosine(D) (Y(D)) and Cytochrome b(559) (Cyt b(559)) can also interact with the S-states. In the present work we investigate the electron transfer from Cyt b(559) and Y(D) to the S(2) and S(3) states at 195 K. First, Y(D)(*) and Cyt b(559) were chemically reduced. The S(2) and S(3) states were then achieved by application of one or two laser flashes, respectively, on samples stabilized in the S(1) state. EPR signals of the WOC (the S(2)-state multiline signal, ML-S(2)), Y(D)(*) and oxidized Cyt b(559) were simultaneously detected during a prolonged dark incubation at 195 K. During 163 days of incubation a large fraction of the S(2) population decayed to S(1) in the S(2) samples by following a single exponential decay. Differently, S(3) samples showed an initial increase in the ML-S(2) intensity (due to S(3) to S(2) conversion) and a subsequent slow decay due to S(2) to S(1) conversion. In both cases, only a minor oxidation of Y(D) was observed. In contrast, the signal intensity of the oxidized Cyt b(559) showed a two-fold increase in both the S(2) and S(3) samples. The electron donation from Cyt b(559) was much more efficient to the S(2) state than to the S(3) state. PMID- 23104121 TI - Solution structure of subunit gamma (gamma(1-204)) of the Mycobacterium tuberculosis F-ATP synthase and the unique loop of gamma(165-178), representing a novel TB drug target. AB - Tuberculosis, caused by the strain Mycobacterium tuberculosis, is in focus of interest due to the emergence of multi- and extensive drug-resistant TB strains. The F(1)F(O) ATP synthase is one of the essential enzymes in energy requirement of both proliferating aerobic and hypoxic dormant stage of mycobacterium life cycle, and therefore a potential TB drug target. Subunit gamma of F-ATP synthases plays an important role in coupling and catalysis via conformational transitions of its N- and C-termini as well as the bottom segment of the globular domain of gamma, which is in close proximity to the rotating and ion-pumping c-ring. Here we describe the first production, purification and low resolution solution structure of subunit gamma (gamma(1-204), Mtgamma(1-204)) of the M. tuberculosis F-ATP synthase. Mtgamma(1-204) is a pear-like shaped protein with a molecular weight of 23 +/- 2 kDa. Protein sequence analysis of Mtgamma revealed differences in the amino acid composition to gamma subunits from other sources, in particular the presence of a unique stretch of 13 amino acid residues (Mtgamma(165-178)). NMR studies showed that Mtgamma(165-178) forms a loop of polar residues. Mtgamma(165-178) has been aligned at the bottom of the globular domain of the Escherichia coli subunit gamma, being in close vicinity to the polar residues R41, Q42, E44 and Q46 (M. tuberculosis nomenclature) of the c-ring. The putative role(s) of Mtgamma(165-178) in coupling and as a potential drug target are discussed. PMID- 23104122 TI - Mortality, health, social and economic consequences of amyotrophic lateral sclerosis: a controlled national study. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that imposes a great burden on the patient, the patient's family and society. However, we lack information about the total disease burden at a national level, especially regarding costs before and after diagnosis and the consequences for spouses. We aimed to estimate the factual direct and indirect costs of ALS in a national sample. Using records from the Danish National Patient Registry (1998 2009), 2,394 patients with ALS were identified and subsequently compared with 9,575 randomly chosen control subjects matched for age, gender and geographic area/civil status. Direct costs, including frequencies of primary and sector contacts and procedures, and medication from primary and secondary sectors, were obtained from the Danish Ministry of Health, the Danish Medicines Agency, and the National Health Security. Indirect costs included labour supply and social transfer payments, and were based on income data derived from Coherent Social Statistics. Patients with a diagnosis of ALS had poor survival. The average (95 % CI) 5-year survival rate was 0.278 (0.358-0.298) compared with 0.865 (0.858 0.872) among controls. Patients with ALS had significantly higher rates of health related contact and medication use and higher socioeconomic costs. They also had very low employment rates, while those in employment had a lower income level than control subjects. The annual mean excess health-related cost was 18,918 for each ALS patient. However, spouses showed no excess health usage; in fact, their employment and income rates were higher, and the net cost was reduced by -3,420. We conclude that ALS has serious mortality, health and socioeconomic consequences for patients. However, the consequences for spouses are complex; they tend to compensate for the social consequences to patients by increasing their net income after ALS diagnosis. PMID- 23104123 TI - Decision making in juvenile myoclonic epilepsy. AB - Recent neuroimaging studies have reported structural and functional brain abnormalities in patients with juvenile myoclonic epilepsy (JME), which may also involve cortical and subcortical networks that are important for decision making. This study is the first attempt to examine decision making in JME. Twenty-two patients with JME (median age 26.00, range 18-50) and 33 healthy controls (median age 26.00, range 18-57) participated in the study. For the JME group, the median age at seizure onset was 14.00 years (range 1-20); the median epilepsy duration was 11.50 years (range 3-45). Eleven patients (50 %) had pharmacoresistant seizures. All participants completed the Iowa Gambling Task (IGT), a widely used standard task of decision making. In this task, contingencies are not explained and feedback on previous decisions has to be used in order to learn to choose the advantageous alternatives. In the IGT, patients with JME showed difficulty in learning to choose advantageously compared to healthy controls. Difficulty was enhanced for the patients with pharmacoresistant seizures. A correlation analysis revealed an association between decision-making performance of patients with JME and executive functions. Results indicate that patients with JME have difficulty in making advantageous decisions and that persistence of seizures might be a critical factor for cognitive functioning. Findings of this study add a new aspect to the neuropsychological profile of JME. Difficulty in decision making may impair functioning of patients with JME in everyday life and affect their adherence to treatment plans. PMID- 23104124 TI - A comprehensive analysis of vascular complications in 3,889 glioma patients from the German Glioma Network. AB - Ischemic strokes, intracranial hemorrhages (ICH) and deep venous thromboembolism (DVT) are clinically important events in patients with gliomas. In this multicentre, noninterventional observational study, current data pertaining to frequency, contributing factors and outcomes of vascular events during times of anti-angiogenic therapy with the antibody against vascular endothelial growth factor, bevacizumab (BEV) was collected from the German Glioma Network. Among 3,889 glioma patients, 70 ischemic strokes (1.8 %) and 123 ICH (3.2 %) were recorded. 143 DVT (5.0 %) were recorded in 2,855 patients. Rates of DVT and ICH, but not of ischemic strokes, increased with the World Health Organization (WHO) grade of glioma. In 81 BEV-treated patients, five ischemic strokes (6.2 %), one ICH (1.2 %) and six DVT (7.4 %) were documented. Compared to patients that were not treated with BEV, ischemic stroke rate was significantly higher during treatment with BEV (p < 0.001). The rates of DVT (p = 0.123) or ICH (p = 0.571) in BEV-treated patients did not differ. On cerebral magnetic resonance imaging (MRI), BEV-related ischemic strokes appeared as diffusion-restricted sites next to contrast-enhancing tumor. 67 % of ICH, 61 % of ischemic strokes and 18 % of DVT occurred postoperatively (within 30 days after tumor resection). Outcome after postoperative ICH was significantly worse than after spontaneous ICH (p = 0.008). Ischemic stroke outcomes did not differ between postoperative and spontaneous occurrence (p = 0.401). Rate of pulmonary embolism did not differ significantly between postoperative and spontaneous DVT (p = 0.133). Relatively low rates of ICH and DVT might be partially due to a high proportion of low-grade gliomas in this patient cohort. The finding of a relevant number of symptomatic, therapy-associated intracerebral diffusion restrictions should be controlled in ongoing phase III studies. PMID- 23104125 TI - Neurological symptoms in a post-transplant patient: a cautionary tale. PMID- 23104126 TI - Semicircular canal, saccular and utricular function in patients with bilateral vestibulopathy: analysis based on etiology. AB - The diagnosis of bilateral vestibulopathy (BV) is typically established based on bilateral semicircular canal dysfunction. The degree to which both otolith organs the saccule and utricle-are also impaired in BV is not well-established, particularly with respect to the etiology and severity of BV. The aim of this study was to evaluate semicircular canal, saccular and utricular function in patients with BV due to aminoglycoside ototoxicity and bilateral Meniere's disease, and with different severities of BV. Caloric and head impulse testing were used as measures of canal function. Cervical vestibular-evoked myogenic potentials (cVEMP) and ocular VEMPs (oVEMP) were used as measures of saccular and utricular function, respectively. We enrolled 34 patients with BV and 55 controls in a prospective case-control study. Patients with BV were less likely to have saccular (61 %) or utricular (64 %) dysfunction relative to canal dysfunction (100 %). Utricular function differed significantly between patients by etiologic group: the poorest function was found in patients with BV due to aminoglycoside toxicity, and the best function in Meniere's disease patients. Canal and saccular function did not vary according to etiology. Further, utricular but not saccular function was significantly correlated with canal function. Saccular and utricular function had the strongest association with Dizziness Handicap Inventory scores relative to canal function. These data suggest that when a patient with BV is identified in a clinical context, oVEMP testing is the most sensitive test in distinguishing between aminoglycoside toxicity and bilateral Meniere's disease. Both cVEMP and oVEMP testing may be considered to evaluate the functional impact on the patient. PMID- 23104127 TI - Death by caffeine: presumptive malicious poisoning of a dog by incorporation in ground meat. AB - BACKGROUND: A 4-year-old, 37 kg, male German shepherd developed hyperthermia, tachycardia, and agitation following consumption of ground meat found in the backyard of its owner. When presented to a veterinary clinic, plasma ethylene glycol (EG) testing was positive, and the dog was given ethanol and lactated Ringer's solution intravenously. Approximately 11 h postexposure the dog died. DISCUSSION: Among tissues submitted for toxicological analysis, urine was negative for EG, ground meat was negative for certain drugs of abuse, and gastric contents were negative for zinc/aluminum phosphide and metaldehyde. Analysis of gastric contents by gas chromatography-mass spectrometry confirmed the presence of caffeine. Caffeine concentration in the ground meat was estimated at 1 %. Caffeine is a methylxanthine alkaloid with a reported canine oral median lethal dose (MLD(50)) of 140 mg/kg (range 120-200 mg/kg). A commercially available 200 mg tablet formulation of caffeine was considered to be a possible source but this was not confirmed. By conservative estimates, the dog would need to ingest approximately 500-550 g of the meat to reach the MLD(50). Acute intoxication affects the cardiovascular, pulmonary, neurologic, gastrointestinal, and metabolic systems. Although no tablet remnants were observed in the bait, tablets could have been crushed and/or dissolved. Other potential caffeine sources include guarana, brewed and concentrated coffee, and caffeine-containing beverages. Based on the history, clinical signs, and the detection of caffeine in the gastric contents and meat, a presumptive diagnosis of malicious caffeine poisoning was made. A suggested treatment regimen for caffeine intoxication in dogs is described. While few cases of accidental ingestion of caffeine by dogs have been described, the intentional use of a concentrated caffeine source to cause mortality in a dog has not been previously reported. PMID- 23104128 TI - Incorporating information on predicted solvent accessibility to the co-evolution based study of protein interactions. AB - A widespread family of methods for studying and predicting protein interactions using sequence information is based on co-evolution, quantified as similarity of phylogenetic trees. Part of the co-evolution observed between interacting proteins could be due to co-adaptation caused by inter-protein contacts. In this case, the co-evolution is expected to be more evident when evaluated on the surface of the proteins or the internal layers close to it. In this work we study the effect of incorporating information on predicted solvent accessibility to three methods for predicting protein interactions based on similarity of phylogenetic trees. We evaluate the performance of these methods in predicting different types of protein associations when trees based on positions with different characteristics of predicted accessibility are used as input. We found that predicted accessibility improves the results of two recent versions of the mirrortree methodology in predicting direct binary physical interactions, while it neither improves these methods, nor the original mirrortree method, in predicting other types of interactions. That improvement comes at no cost in terms of applicability since accessibility can be predicted for any sequence. We also found that predictions of protein-protein interactions are improved when multiple sequence alignments with a richer representation of sequences (including paralogs) are incorporated in the accessibility prediction. PMID- 23104129 TI - Antibody responses to routine pediatric vaccines administered with 13-valent pneumococcal conjugate vaccine. AB - BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) has been licensed in >100 countries to broaden coverage against pneumococcal disease. We assessed whether PCV13 interferes with immune responses to concomitantly administered routine pediatric vaccines. METHODS: Healthy US infants were randomly assigned in 2 studies to receive PCV13 or 7-valent PCV (PCV7) at age 2, 4 and 6 months concomitantly with diphtheria, tetanus, acellular pertussis, inactivated polio virus, hepatitis B and Haemophilus influenzae type b, and at age 12-15 months with measles, mumps, rubella, varicella and hepatitus A. Antibodies to pertussis antigens, diphtheria, tetanus toxoid, poliovirus types 1-3, Haemophilus influenzae type b polyribosylribitol phosphate capsular polysaccharide and polyribosylribitol phosphate capsular polysaccharide were measured 1 month after the infant series; measles, mumps, rubella, varicella and polyribosylribitol phosphate capsular polysaccharide were determined 1 month after the toddler dose. Both the percentages of responders (subjects reaching a prespecified antibody concentration) and immunoglobulin G antibody geometric mean concentrations/titers were calculated for each concomitant vaccine antigen. RESULTS: Not all assays were performed on all subjects. Data were available from 153 to 239 infants and 163-230 toddlers in the PCV13 group and 173-240 infants and 167-214 toddlers in the PCV7 group. One month after both infant series and the toddler dose, noninferiority criteria were met for all antigens with respect to percentage of responders in both PCV7 and PCV13 groups. Immunoglobulin G antibody geometric mean concentration/titer ratios (PCV13/PCV7) were 0.91-1.33 and 0.83-1.03 at 1 month after the infant series and toddler dose, respectively, and met predetermined noninferiority criteria. CONCLUSIONS: Immune responses to routine pediatric vaccines concomitantly administered with PCV13 were noninferior to responses achieved when administered with PCV7. PMID- 23104130 TI - Partial sequence of a new Partitivirus-infecting Podosphaera tridactyla, the Prunus powdery mildew agent. PMID- 23104132 TI - Identification of the molecular basis of doxorubicin-induced cardiotoxicity. AB - Doxorubicin is believed to cause dose-dependent cardiotoxicity through redox cycling and the generation of reactive oxygen species (ROS). Here we show that cardiomyocyte-specific deletion of Top2b (encoding topoisomerase-IIbeta) protects cardiomyocytes from doxorubicin-induced DNA double-strand breaks and transcriptome changes that are responsible for defective mitochondrial biogenesis and ROS formation. Furthermore, cardiomyocyte-specific deletion of Top2b protects mice from the development of doxorubicin-induced progressive heart failure, suggesting that doxorubicin-induced cardiotoxicity is mediated by topoisomerase IIbeta in cardiomyocytes. PMID- 23104131 TI - Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways. AB - Parasitic worms express host-like glycans to attenuate the immune response of human hosts. The therapeutic potential of this immunomodulatory mechanism in controlling the metabolic dysfunction that is associated with chronic inflammation remains unexplored. We demonstrate here that administration of lacto N-fucopentaose III (LNFPIII), a Lewis(X)-containing immunomodulatory glycan found in human milk and on parasitic helminths, improves glucose tolerance and insulin sensitivity in diet-induced obese mice. This effect is mediated partly through increased interleukin-10 (Il-10) production by LNFPIII-activated macrophages and dendritic cells, which reduces white adipose tissue inflammation and sensitizes the insulin response of adipocytes. Concurrently, LNFPIII treatment upregulates nuclear receptor subfamily 1, group H, member 4 (Fxr-alpha, also known as Nr1h4) to suppress lipogenesis in the liver, conferring protection against hepatosteatosis. At the signaling level, the extracellular signal-regulated kinase (Erk)-activator protein 1 (Ap1) pathway seems to mediate the effects of LNFPIII on both inflammatory and metabolic pathways. Our results suggest that LNFPIII may provide new therapeutic approaches to treat metabolic diseases. PMID- 23104133 TI - Generation of mouse and human induced pluripotent stem cells (iPSC) from primary somatic cells. AB - Cellular reprogramming consists of the conversion of differentiated cells into pluripotent cells; the so-called induced Pluripotent Stem Cells. iPSC are amenable to in vitro manipulation and, in theory, direct production of any differentiated cell type. Furthermore, iPSC can be obtained from sick individuals and subsequently used for disease modeling, drug discovery and regenerative treatments. iPSC production was first achieved by transducing, with the use of retroviral vectors, four specific transcription factors: Oct4, Klf4, Sox2 and c Myc (OKSM), into primary cells in culture Takahashi and Yamanaka, (Cell 126(4):663-676, 2006). Many alternative protocols have since been proposed: repeated transfections of expression plasmids containing the four pluripotency associated genes Okita et al. (Science 322(5903):949-953, 2008), lentiviral delivery of the four factors Sommer et al. (Stem Cells 27(3):543-549, 2009), Sendai virus delivery Fusaki et al. (Proceedings of the Japan Academy. Series B, Physical and Biological Sciences 85(8):348-362, 2009), removal of the reprogramming vectors by 'piggyBac' transposition Woltjen et al. (Nature 458(7239):766-770, 2009); Kaji et al. (Nature 458(7239):771-775, 2009), Cre recombinase excisable viruses Soldner et al. (Cell 136(5):964-977, 2009), episomal vectors Yu et al. (Science 324(5928):797-801, 2009), cell-penetrating reprogramming proteins Zhou et al. (Stem Cells 4(5):381-384, 2009), mammalian artificial chromosomes Hiratsuka et al. (PLoS One 6(10):e25961, 2011) synthetically modified mRNAs Warren et al. (Scientific Reports 2:657, 2012), miRNA Anokye-Danso et al. (Cell Stem Cell 8(4):376-388, 2009); however, although some of these methods are commercially available, in general they still need to attain the reproducibility and reprogramming efficiency required for routine applications Mochiduki and Okita (Biotechnol Journal 7(6):789-797, 2012). Herein we explain, in four detailed protocols, the isolation of mouse and human somatic cells and their reprogramming into iPSC. All-encompassing instructions, not previously published in a single document, are provided for mouse and human iPSC colony isolation and derivation. Although mouse and human iPSC share similarities in the cellular reprogramming process and culture, both cell types need to be handled differently. PMID- 23104134 TI - Highly efficient derivation of skeletal myotubes from human embryonic stem cells. AB - Human embryonic stem cells (hESCs) are a promising model for the research of embryonic development and regenerative medicine. Since the first hESC line was established, many researchers have shown that pluripotent hESCs can be directed into many types of functional adult cells in culture. However, most of the reported methods have induced differentiation through the alteration of growth factors in the culture medium. These methods are time consuming; moreover, it is difficult to obtain a pure population of the desired cells because of the low efficiency of induction. In this study, we used a lentiviral-based inducible gene expression system in hESCs to control the ectopic expression of MyoD, which is an essential transcription factor in skeletal muscle development. The induction of MyoD can efficiently direct the pluripotent hESCs into mesoderm in 24 h. The cells then become proliferated myoblasts and finally form multinucleated myotubes in vitro. The whole procedure took about 10 days, with an induction efficiency of over 90%. To our knowledge, this is the first time that hESCs have been induced into terminally differentiated cells with only one factor. In the future, these results could be a potential resource for cell therapy for diseases of muscle dysfunction. PMID- 23104135 TI - Surface lattice-engineered bimetallic nanoparticles and their catalytic properties. AB - When nanoparticles become small (ca. <5 nm), surface stress becomes significant and generates strain that results in a change of surface structures. In this regard, the surface lattice of nanoparticles can be engineered to create strains or other structural changes with atomic positions away from the normal lattice points. Such changes impact the electronic and catalytic properties of nanoparticles. Recently, several groups have reported the change of catalytic and electrocatalytic properties of bimetallic nanoparticles. In this tutorial review, we discuss the principles related to lattice strain and other distorted structures, and the catalytic properties of bimetallic nanostructures. PMID- 23104137 TI - Effect of atmosphere on solid-state amine-aldehyde condensations: gas-phase catalysts for solid-state transformations. AB - The presence of water or organic solvent vapour accelerates the solid-state condensation of solid aromatic amines and aromatic aldehydes into Schiff bases; we show the important role of catalytic triethylamine in the vapour phase in such vapour digestion synthesis, as well as in the liquid phase in synthesis via liquid-assisted grinding. PMID- 23104136 TI - N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. AB - Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the Galpha(i/o) protein-coupled receptor 18 (GPR18). However, a high-throughput beta-arrestin-based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18:12328). To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors. GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Ca(v)2.2) calcium channels was examined. Proper expression and trafficking of receptor were confirmed by the "rim-like" fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18 expressing cells. Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100:1147). Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents. Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins. Other downstream effectors of Galpha(i/o) coupled receptors, G protein-coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling. Furthermore, GPR18 did not couple to other G proteins tested: Galpha(s), Galpha(z), and Galpha(15). These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies. PMID- 23104138 TI - Plasma and urinary sulfate determination in a cohort with autism. AB - Sulfate is important for mammalian development but is not routinely measured in clinical settings. The renal NaS1 sulfate transporter maintains circulating sulfate levels and is linked to renal sulfate wasting in mice. Some autistic individuals exhibit renal sulfate wasting, but the etiology is yet unknown. We measured plasma and urinary sulfate levels, calculated the fractional excretion index (FEI) of sulfate, and screened for two loss-of-function NaS1 sequence variants (R12X and N174S) in 23 autistic individuals. The FEI sulfate values ranged from 0.13 to 0.50. NaS1 variants were detected in 18 of the 23 individuals (11 heterozygous N174S, four homozygous N174S, two heterozygous R12X, and one individual carried both R12X and N174S). Those individuals with neither sequence variant had FEI sulfate <= 0.34, whereas FEI sulfate >= 0.35 was found in about 60 % (11 of 18) of individuals that had R12X and/or N174S. This study links renal sulfate wasting with loss-of-function NaS1 sequence variants in humans. PMID- 23104140 TI - MARCH7 E3 ubiquitin ligase is highly expressed in developing spermatids of rats and its possible involvement in head and tail formation. AB - Spermatogenesis is a highly complicated metamorphosis process of male germ cells. Recent studies have provided evidence that the ubiquitin-proteasome system plays an important role in sperm head shaping, but the underlying mechanism is less understood. In this study, we localized membrane-associated RING-CH (MARCH)7, an E3 ubiquitin ligase, in rat testis. Northern blot analysis showed that March7 mRNA is expressed ubiquitously but highly in the testis and ovary. In situ hybridization of rat testis demonstrated that March7 mRNA is expressed weakly in spermatogonia and its level is gradually increased as they develop. Immunohistochemical analysis detected MARCH7 protein expression in spermiogenic cells from late round spermatids to elongated spermatids and in epididymal spermatozoa. Moreover, MARCH7 was found to be localized to the caudal end of the developing acrosome of late round and elongating spermatids, colocalizing with beta-actin, a component of the acroplaxome. In addition, MARCH7 was also detected in the developing flagella and its expression levels were prominent in elongated spermatids. We also showed that MARCH7 catalyzes lysine 48 (K48)-linked ubiquitination. Immunolocalization studies revealed that K48-linked ubiquitin chains were detected in the heads of elongating spermatids and in the acrosome/acroplaxome, neck, midpiece and cytoplasmic lobes of elongated spermatids. These results suggest that MARCH7 is involved in spermiogenesis by regulating the structural and functional integrity of the head and tail of developing spermatids. PMID- 23104141 TI - The association between cytokine gene polymorphisms and graft rejection in liver transplantation: a systematic review and meta-analysis. AB - We investigated the contribution of polymorphisms in cytokine genes (TNFa-308, IL10-1082 and -592, TGFb1-c10 and c25, and IFNg+874) on the risk of graft rejection in liver transplantation. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. In total, 12 studies were eligible and included in the study. Data extraction and assessments for risk of bias were independently performed by two reviewers. Data for allele frequencies, allelic, and genotypic effects were pooled. Heterogeneity and publication bias were assessed. Pooled minor allele frequencies for TNFa-308, IL10-1082, TGFb1-c10, TGFb1-c25, IFNg+874, and IL10-592 were 0.140 (95% CI: 0.083, 0.198), 0.432 (95% CI: 0.392, 0.472), 0.387 (95% CI: 0.307, 0.467), 0.090 (95% CI: 0.056, 0.123), 0.460 (95% CI: 0.392, 0.528), and 0.224 (95% CI: 0.178, 0.269), respectively. OnlyTNFa-308 and IL10-1082 polymorphisms were significantly associated with graft rejection. Patients who carried minor homozygous genotypes for these two polymorphisms were at 3.5 and 1.69 times higher risk of graft rejections than patients who carried major homozygous genotypes. The estimated lambdas were 0.41 and 0.47, suggesting an additive mode of effect was most likely. However, we could not detect the associations of TGFb1at c10 and c25, INFg+874, and IL10-592 polymorphisms and graft rejection. In summary, our systematic review has demonstrated that TNFa-308 and IL10-1082 are potential risk factors of poor outcomes in liver transplantation. Future updated meta-analysis studies to confirm the power of these genotypes in association with allograft rejection are needed. PMID- 23104139 TI - Comparative immunolocalisation of fibrillin-1 and perlecan in the human foetal, and HS-deficient hspg2 exon 3 null mutant mouse intervertebral disc. AB - The aim of this study was to examine the comparative localisations of fibrillin-1 and perlecan in the foetal human, wild-type C57BL/6 and HS-deficient hspg2Delta3 /Delta3- exon 3 null mouse intervertebral disc (IVD) using fluorescent laser scanning confocal microscopy. Fibrillin-1 fibrils were prominent components of the outer posterior and anterior annulus fibrosus (AF) of the foetal human IVD. Finer fibrillin-1 fibrils were evident in the inner AF where they displayed an arcade-type arrangement in the developing lamellae. Relatively short but distinct fibrillin-1 fibrils were evident in the central region of the IVD and presumptive cartilaginous endplate and defined the margins of the nuclear sheath in the developing nucleus pulposus (NP). Fibrillin-1 was also demonstrated in the AF of C57BL/6 wild-type mice but to a far lesser extent in the HS-deficient hspg2Delta3 /Delta3- exon 3 null mouse. This suggested that the HS chains of perlecan may have contributed to fibrillin-1 assembly or its deposition in the IVD. The cell matrix interconnections provided by the fibrillin fibrils visualised in this study may facilitate communication between disc cells and their local biomechanical microenvironment in mechanosensory processes which regulate tissue homeostasis. The ability of fibrillin-1 to sequester TGF-beta a well-known anabolic growth factor in the IVD also suggests potential roles in disc development and/or remodelling. PMID- 23104142 TI - Moving the agenda forward for cancer patient navigation: understanding volunteer and peer navigation approaches. AB - Across Canada, individuals diagnosed with cancer have identified concerns about access to services before, during, and following treatment, highlighting a very real uncertainty that exists about where to turn for information and assistance. Cancer patient navigation programs are emerging as effective interventions, well equipped to meet these patients' diverse needs. While many provinces have initiated professionally led navigation services, little is known about the potential for volunteer-led navigation. This article highlights pilot programs in British Columbia, Ontario, and Newfoundland, where volunteers are engaged as lay or peer providers of cancer patient navigation services. By describing the recruitment, training, and role of the navigators within each program, the paper underscores the capacity for unique programs to work within current care frameworks across distinct communities. These programs provide an innovative approach to overcoming barriers and augmenting access to supportive care for cancer patients and their family members. PMID- 23104143 TI - Development of a chronic care ostomy self-management program. AB - Each year a percentage of the 1.2 million men and women in the United States with a new diagnosis of colorectal cancer join the 700,000 people who have an ostomy. Education targeting the long-term, chronic care of this population is lacking. This report describes the development of a Chronic Care Ostomy Self-Management Program, which was informed by (1) evidence on published quality-of-life changes for cancer patients with ostomies, (2) educational suggestions from patients with ostomies, and (3) examination of the usual care of new ostomates to illustrate areas for continued educational emphases and areas for needed education and support. Using these materials, the Chronic Care Ostomy Self-Management Program was developed by a team of multi-disciplinary researchers accompanied by experienced ostomy nurses. Testing of the program is in process. Pilot study participants reported high satisfaction with the program syllabus, ostomy nurse leaders, and ostomate peer buddies. PMID- 23104144 TI - Maximizing audibility and speech recognition with nonlinear frequency compression by estimating audible bandwidth. AB - OBJECTIVE: Nonlinear frequency compression attempts to restore high-frequency audibility by lowering high-frequency input signals. Methods of determining the optimal parameters that maximize speech understanding have not been evaluated. The effect of maximizing the audible bandwidth on speech recognition for a group of listeners with normal hearing is described. DESIGN: Nonword recognition was measured with 20 normal-hearing adults. Three audiograms with different high frequency thresholds were used to create conditions with varying high-frequency audibility. Bandwidth was manipulated using three conditions for each audiogram: conventional processing, the manufacturer's default compression parameters, and compression parameters that optimized bandwidth. RESULTS: Nonlinear frequency compression optimized to provide the widest audible bandwidth improved nonword recognition compared with both conventional processing and the default parameters. CONCLUSIONS: These results showed that using the widest audible bandwidth maximized speech identification when using nonlinear frequency compression. Future studies should apply these methods to listeners with hearing loss to demonstrate efficacy in clinical populations. PMID- 23104145 TI - Understanding protein aggregation from the view of monomer dynamics. AB - Much work in recent years has been devoted to understanding the complex process of protein aggregation. This review looks at the earliest stages of aggregation, long before the formation of fibrils that are the hallmark of many aggregation based diseases, and proposes that the first steps are controlled by the reconfiguration dynamics of the monomer. When reconfiguration is much faster or much slower than bimolecular diffusion, then aggregation is slow, but when they are similar, aggregation is fast. The experimental evidence for this model is reviewed and the prospects for small molecule aggregation inhibitors to prevent disease are discussed. PMID- 23104146 TI - Prophylactic ondansetron does not prevent shivering or decrease shivering severity during cesarean delivery under combined spinal epidural anesthesia: a randomized trial. AB - OBJECTIVES: Cesarean delivery is commonly performed under regional anesthesia, which is often associated with maternal shivering. This can cause distress and interfere with monitoring. The study objective was to evaluate the antishivering efficacy of ondansetron, which reduces the incidence and severity of shivering in nonobstetric patients. We hypothesized that there would be a significant decrease in the incidence and/or severity of shivering in women who are given intravenous ondansetron 8 mg before combined spinal epidural (CSE) anesthesia, when compared with placebo. METHODS: This was a randomized, double-blinded, parallel-group, placebo-controlled trial of 118 women scheduled for elective cesarean surgery. Women received either intravenous ondansetron 8 mg (n = 58) or saline (n = 60) before CSE anesthesia (intrathecal hyperbaric bupivacaine 0.5% 2.2-2.5 mL plus fentanyl 15 MUg). The incidence and severity of shivering, measured on a validated 5-point scale, and other outcomes, such as nausea, pruritus, headache, or satisfaction, were assessed at 3 time points during the surgery and postoperative period. RESULTS: The incidence of shivering at any time point did not differ significantly between groups: ondansetron 41% versus placebo 47% (P = 0.54). The incidence of severe shivering at any time was not significantly different: ondansetron 32% versus placebo 33% (P = 0.79). There were no significant differences between the groups for any secondary outcomes. CONCLUSIONS: Intravenous ondansetron 8 mg before performing CSE anesthesia in women undergoing elective cesarean delivery does not decrease the incidence or severity of shivering. PMID- 23104147 TI - Long-term pain and functional disability after total knee arthroplasty with and without single-injection or continuous sciatic nerve block in addition to continuous femoral nerve block: a prospective, 1-year follow-up of a randomized controlled trial. AB - BACKGROUND AND OBJECTIVES: This is a follow-up to determine long-term outcomes after total knee arthroplasty (TKA) in patients enrolled in a previous randomized trial that found reduced postoperative pain after addition of sciatic nerve block to continuous femoral nerve block for TKA. METHODS: Physical function after TKA was evaluated at 3 and 12 months in patients (n = 89) receiving continuous femoral nerve block alone (group F), combined with a single-injection (group Fs) or continuous sciatic nerve block (group FCS) after TKA, until the second postoperative day. Physical function, stiffness, and pain were measured by using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oxford Knee Score 12-item knee questionnaires, and visual analog scale at rest and during mobilization before TKA and 3 and 12 months afterward. Post hoc, a median split on poor functioning (WOMAC) was analyzed. RESULTS: Western Ontario and McMaster Universities Osteoarthritis Index, Oxford Knee Score 12-item knee, and visual analog scale scores improved significantly in all patients, without any differences among groups. Median (range) WOMAC at 3 months were in group F, 83 (20-97); group Fs, 72 (25-99); and group, FCS 76 (28-100) and at 12 months 87 (35 98), 77 (43-100), and 89 (35-100), respectively. CONCLUSIONS: No differences were detected in the secondary outcomes we examined. Thus, improved postoperative outcome did not translate into improved functional outcome or long-term pain. PMID- 23104148 TI - Insulin therapy for type 2 diabetes. AB - Insulin therapy provides effective glycemic control in patients with diabetes who have deficient beta-cell function and insulin secretion. Subjects with type 2 diabetes not adequately controlled on oral agents or incretin therapies can initiate basal insulin replacement to correct fasting hyperglycemia. While all basal insulin preparations have similar efficacy in lowering fasting plasma glucose and improving A1C, the newer basal insulin analogs are associated with a lower risk of hypoglycemia than NPH insulin. Patients whose A1C levels remain above goal despite adequate basal insulin replacement need to evaluate and correct post-prandial hyperglycemia. With progressive beta-cell deficiency, rapid acting insulin preparations can be introduced before one or more meals and titrated to achieve post-prandial glycemic control. For many patients requiring full basal/bolus insulin replacement, a strategy of fixed prandial insulin doses can yield acceptable glycemic control when compared to a more sophisticated approach utilizing carbohydrate counting and matching to insulin. Concentrated insulin preparations such as U-500 have also been of value in patients with resistant type 2 diabetes. Regardless of the type of insulin replacement used, the blood glucose lowering effects of insulin need to be carefully balanced with the increasing risk of hypoglycemia, and the weight gain associated with insulin intensification. PMID- 23104150 TI - Morphometric characteristics, cell proliferation parameters and apoptosis indices do not correlate with tendency to relapse in non-functioning pituitary macroadenomas. PMID- 23104149 TI - Portal and systemic levels of visfatin in morbidly obese subjects undergoing bariatric surgery. AB - The aim of the present study was to compare the levels of visfatin in portal and systemic circulations and to assess the possible relationship of visfatin with systemic inflammation and insulin resistance in morbidly obese patients undergoing bariatric surgery. A total of 46 morbidly obese patients (BMI = 45.3 +/- 5.3 kg/m(2)) undergoing bariatric surgery were included in this study. Blood samplings were performed simultaneously from portal and systemic veins during surgery. Visfatin was measured in both portal and systemic venous samples. Besides, fasting serum levels of insulin, glucose, lipid profile, visfatin, and hs-CRP were determined in systemic venous blood samples. Insulin sensitivity was estimated using the homeostasis model assessment of insulin resistance (HOMA-IR). Visfatin concentrations were significantly higher in portal vein than systemic veins (11.9 +/- 12.1 vs. 5.1 +/- 3.3 ng/ml, p < 0.0001). While systemic levels of visfatin were significantly correlated with circulating levels of hs-CRP (r = 0.527, p < 0.0001), there were no significant correlations between portal levels of visfatin with systemic levels of hs-CRP concentrations. Substantially higher levels of visfatin in portal vein than systemic veins provide evidence that visceral adipose tissue is the major secretory source of visfatin in humans. Our findings underscore that visceral adipose tissue is an active endocrine organ that is involved in the complex interrelationship between obesity and pathologic conditions. PMID- 23104152 TI - Giant and reversible extrinsic magnetocaloric effects in La0.7Ca0.3MnO3 films due to strain. AB - Large thermal changes driven by a magnetic field have been proposed for environmentally friendly energy-efficient refrigeration, but only a few materials that suffer hysteresis show these giant magnetocaloric effects. Here we create giant and reversible extrinsic magnetocaloric effects in epitaxial films of the ferromagnetic manganite La(0.7)Ca(0.3)MnO(3) using strain-mediated feedback from BaTiO(3) substrates near a first-order structural phase transition. Our findings should inspire the discovery of giant magnetocaloric effects in a wide range of magnetic materials, and the parallel development of nanostructured bulk samples for practical applications. PMID- 23104151 TI - Mutation analysis of WNT10B in obese children, adolescents and adults. AB - Wingless-type MMTV integration site family, member 10B (WNT10B) is an activator of the Wnt pathway. The Wnt pathway is known to play an important role in maintenance and differentiation of stem cells and has been implicated in the origination of obesity. To evaluate the role of genetic variation in WNT10B in obesity further, we performed a mutation analysis on Belgian obese patients and control subjects. A mutation analysis of WNT10B by means of high-resolution melting curve analysis and direct sequencing was performed on 546 obese children and adolescents (mean Z-score of 2.6 +/- 0.6 and 2.5 +/- 0.4 respectively), 86 morbidly obese adults (mean BMI of 48.0 +/- 0.4 kg/m(2)) and 447 lean, healthy controls (mean BMI of 22.1 +/- 1.7 kg/m(2)). A total of five novel non-synonymous variants were identified. R228Q was the only coding, non-synonymous variant that was exclusively found in patients, but the variant did not co-segregate with obesity in the three investigated siblings. The remaining four variants were either found both in cases and in control samples (G181D) or only in control samples (A108P, S187R and P315S). The frequency of non-synonymous variants in lean individuals (0.9 %) was higher than in obese individuals (0.3 %) and familial co-segregation of the most promising variant in patients could not be demonstrated. Therefore, we conclude that variations in WNT10B do not contribute to human monogenic obesity in our population. PMID- 23104153 TI - Enhancement of the superconducting transition temperature of FeSe by intercalation of a molecular spacer layer. AB - The discovery of high-temperature superconductivity in a layered iron arsenide has led to an intensive search to optimize the superconducting properties of iron based superconductors by changing the chemical composition of the spacer layer between adjacent anionic iron arsenide layers. Superconductivity has been found in iron arsenides with cationic spacer layers consisting of metal ions (for example, Li(+), Na(+), K(+), Ba(2+)) or PbO- or perovskite-type oxide layers, and also in Fe(1.01)Se (ref. 8) with neutral layers similar in structure to those found in the iron arsenides and no spacer layer. Here we demonstrate the synthesis of Li(x)(NH(2))(y)(NH(3))(1-y)Fe(2)Se(2) (x~0.6; y~0.2), with lithium ions, lithium amide and ammonia acting as the spacer layer between FeSe layers, which exhibits superconductivity at 43(1) K, higher than in any FeSe-derived compound reported so far. We have determined the crystal structure using neutron powder diffraction and used magnetometry and muon-spin rotation data to determine the superconducting properties. This new synthetic route opens up the possibility of further exploitation of related molecular intercalations in this and other systems to greatly optimize the superconducting properties in this family. PMID- 23104154 TI - Structurally ordered intermetallic platinum-cobalt core-shell nanoparticles with enhanced activity and stability as oxygen reduction electrocatalysts. AB - To enhance and optimize nanocatalyst performance and durability for the oxygen reduction reaction in fuel-cell applications, we look beyond Pt-metal disordered alloys and describe a new class of Pt-Co nanocatalysts composed of ordered Pt(3)Co intermetallic cores with a 2-3 atomic-layer-thick platinum shell. These nanocatalysts exhibited over 200% increase in mass activity and over 300% increase in specific activity when compared with the disordered Pt(3)Co alloy nanoparticles as well as Pt/C. So far, this mass activity for the oxygen reduction reaction is the highest among the Pt-Co systems reported in the literature under similar testing conditions. Stability tests showed a minimal loss of activity after 5,000 potential cycles and the ordered core-shell structure was maintained virtually intact, as established by atomic-scale elemental mapping. The high activity and stability are attributed to the Pt-rich shell and the stable intermetallic Pt(3)Co core arrangement. These ordered nanoparticles provide a new direction for catalyst performance optimization for next-generation fuel cells. PMID- 23104155 TI - Autonomous motors of a metal-organic framework powered by reorganization of self assembled peptides at interfaces. AB - A variety of microsystems have been developed that harness energy and convert it to mechanical motion. Here we have developed new autonomous biochemical motors by integrating a metal-organic framework (MOF) and self-assembling peptides. The MOF is applied as an energy-storing cell that assembles peptides inside nanoscale pores of the coordination framework. The nature of peptides enables their assemblies to be reconfigured at the water/MOF interface, and thus converted to fuel energy. Reorganization of hydrophobic peptides can create a large surface tension gradient around the MOF that can efficiently power its translational motion. As a comparison, the velocity normalized by volume for the diphenylalanine-MOF particle is faster and the kinetic energy per unit mass of fuel is more than twice as great as that for previous gel motor systems. This demonstration opens the route towards new applications of MOFs and reconfigurable molecular self-assembly, possibly evolving into a smart autonomous motor capable of mimicking swimming bacteria and, with integrated recognition units, harvesting target chemicals. PMID- 23104157 TI - Cavity-containing, backbone-rigidified foldamers and macrocycles. AB - This Feature Article gives an account for a host of readily available foldamers and macrocycles with well-defined shapes and non-deformable cavities that appeared over the last decade. Efforts to create porous molecular structures have led to the establishment of an effective strategy for enforcing the folding of unnatural aromatic oligoamide strands based on an especially robust three-center (bifurcated) hydrogen-bonding interaction. Based on such a strategy, aromatic oligoamides adopting crescent and helical conformations that contain non collapsible cavities of tunable diameters have been created. Extending the same folding principle to the preparation of aromatic polyamides that would adopt pore containing helical conformation instead led to the discovery of a highly efficient, one-pot macrocyclization process. Such a one-pot macrocyclization process has been successfully applied to the preparation of macrocycles with aromatic amide, hydrazide, urea and other backbones. Mechanistic study indicates that the high efficiencies observed for the formation of these macrocycles are due to the folding of the corresponding uncyclized oligomeric precursors of the corresponding macrocycles. Oligoamide macrocycles, along with their uncyclized, cavity-containing counterparts, i.e., crescent oligoamides, bind guests such as guanidinium (G) and octylguanidinium (OG) ions with tunable selectivity. Recent studies revealed that these rigid macrocycles tend to engage in extraordinarily strong, directional aggregation, leading to nanotubular assemblies containing pores of fixed sizes. Consistent with the presence of self-assembling nanopores, oligoamide macrocycles were found to assemble into transmembrane channels with high conductance. PMID- 23104156 TI - Proliferation and migration of tumor cells in tapered channels. AB - Tumor cells depict two deviant tendencies; over-proliferation and vigorous migration. A tapered channel device is designed and fabricated for in vitro studies. We report inhibited proliferation and migration of human glioblastoma (hGBM) cells when exposed to an aptamer that is known to bind epidermal growth factor receptors (EGFR). The device is integrated with controlled ambient and microscope for providing real-time and quantitative characterization of the tumor cell behavior. The results show that hGBM cells loose proliferation and motility when exposed to the anti-EGFR aptamer. The aptamer directly inhibits and blocks EGF-induced EGFR phosphorylation. This also reduces the ability of cells to remodel their internal structure for invasion through narrow constrictions. This provides a framework for possible studies on efficacy of other inhibiting molecules. PMID- 23104158 TI - Concreteness and word production. AB - Two experiments are reported that investigated the effect of concreteness on the ability to generate words to fit sentence contexts. When participants attempted to retrieve words from dictionary definitions in experiment 1, abstract words were associated with more omissions and more alternates than were concrete words. These findings are consistent with the view that the semantic-lexical weights in the word production system are weaker for abstract than for concrete words. We found no evidence that greater competition from semantic neighbors was an additional reason why abstract words were harder to produce. Participants also reported more positive tip-of-the-tongue states (TOTs) when attempting to produce abstract words from their definitions, consistent with more phonological retrieval problems for abstract than for concrete words. In experiment 2, participants attempted to generate words to fit into a sentence that described a specific event. The difference between the numbers of abstract and concrete words recalled was significantly smaller in the event condition than in the definition condition, and evidence no longer emerged of greater phonological retrieval failure for abstract words. Overall, the results are consistent with the view that the semantic-lexical weights, but not the lexical-phonological weights, are weaker for abstract than for concrete words in the word production system. PMID- 23104160 TI - The emergency department short-stay ward in dengue fever. PMID- 23104159 TI - Image analysis and empirical modeling of gene and protein expression. AB - Protein gradients and gene expression patterns are major determinants in the differentiation and fate map of the developing embryo. Here we discuss computational methods to quantitatively measure the positions of gene expression domains and the gradients of protein expression along the dorsal-ventral axis in the Drosophila embryo. Our methodology involves three layers of data. The first layer, or the primary data, consists of z-stack confocal images of embryos processed by in situ hybridization and/or antibody stainings. The secondary data are relationships between location, usually an x-axis coordinate, and fluorescent intensity of gene or protein detection. Tertiary data comprise the optimal parameters that arise from fits of the secondary data to empirical models. The tertiary data are useful to distill large datasets of imaged embryos down to a tractable number of conceptually useful parameters. This analysis allows us to detect subtle phenotypes and is adaptable to any set of genes or proteins with a canonical pattern. For example, we show how insights into the Dorsal transcription factor protein gradient and its target gene ventral-neuroblasts defective (vnd) were obtained using such quantitative approaches. PMID- 23104161 TI - Au(III)-catalyzed intermolecular amidation of benzylic C-H bonds. AB - Au(III)-catalyzed intermolecular amidations of benzylic C-H bonds with sulfonamides and carboxamides are described. The protocol with the Au-bipy complex/N-bromosuccinimide system provides practical applications for synthesis of various amides via C-H activations. The reaction proceeds with high efficiency to give the corresponding amines, which are extremely useful synthetic intermediates. PMID- 23104162 TI - Perspectives and challenges of interferon-free therapy for chronic hepatitis C. AB - Recent data have clearly shown that a sustained virologic response can be achieved in different HCV infected patient populations with various interferon free treatment regimens. Despite the successful implementation of telaprevir- and boceprevir-based triple therapies, all-oral regimens will certainly become a first choice for a number of HCV-infected patients in the very near future, as triple therapy approaches are burdened with significant side-effects and limited success in patients with advanced liver fibrosis and prior null-response to pegylated interferon-alpha (pegIFN-alpha)/ribavirin therapy. However, available data from phase I and II clinical trials evaluating interferon-free regimens have not yet revealed a clearly outstanding all-oral combination, and numerous challenges remain to be addressed by intensive ongoing and future research. In particular, thus far evaluated all-oral regimens did not cure a satisfactory percentage of patients with unfavorable baseline characteristics, namely patients infected with HCV genotype 1a, previous null-response to pegIFN-alpha/ribavirin, or liver cirrhosis. In this review, we summarize available data of interferon free regimens for the treatment of chronic hepatitis C and assess implications for perspectives and challenges in the further development of all-oral therapies. PMID- 23104163 TI - A case of hepatopulmonary syndrome solved by mycophenolate mofetil (an inhibitor of angiogenesis and nitric oxide production). PMID- 23104164 TI - Donor-recipient matching: myths and realities. AB - Liver transplant outcomes keep improving, with refinements of surgical technique, immunosuppression and post-transplant care. However, these excellent results and the limited number of organs available have led to an increasing number of potential recipients with end-stage liver disease worldwide. Deaths on waiting lists have led liver transplant teams maximize every organ offered and used in terms of pre and post-transplant benefit. Donor-recipient (D-R) matching could be defined as the technique to check D-R pairs adequately associated by the presence of the constituents of some patterns from donor and patient variables. D-R matching has been strongly analysed and policies in donor allocation have tried to maximize organ utilization whilst still protecting individual interests. However, D-R matching has been written through trial and error and the development of each new score has been followed by strong discrepancies and controversies. Current allocation systems are based on isolated or combined donor or recipient characteristics. This review intends to analyze current knowledge about D-R matching methods, focusing on three main categories: patient-based policies, donor-based policies and combined donor-recipient systems. All of them lay on three mainstays that support three different concepts of D-R matching: prioritarianism (favouring the worst-off), utilitarianism (maximising total benefit) and social benefit (cost-effectiveness). All of them, with their pros and cons, offer an exciting controversial topic to be discussed. All of them together define D-R matching today, turning into myth what we considered a reality in the past. PMID- 23104165 TI - A hydrolytic gamma-glutamyl transpeptidase from thermo-acidophilic archaeon Picrophilus torridus: binding pocket mutagenesis and transpeptidation. AB - gamma-Glutamyl transpeptidase of a thermo-acidophilic archaeon Picrophilus torridus was cloned and expressed using E. coli Rosetta-pET 51b(+) expression system. The enzyme was expressed at 37 degrees C/200 rpm with gamma-GT production of 1.99 U/mg protein after 3 h of IPTG induction. It was improved nearby 10-fold corresponding to 18.92 U/mg protein in the presence of 2 % hexadecane. The enzyme was purified by Ni(2+)-NTA with a purification fold of 3.6 and recovery of 61 %. It was synthesized as a precursor heterodimeric protein of 47 kDa with two subunits of 30 kDa and 17 kDa, respectively, as revealed by SDS PAGE and western blot. The enzyme possesses hydrolase activity with optima at pH 7.0 and 55 degrees C. It was thermostable with a t (1/2) of 1 h at 50 degrees C and 30 min at 60 degrees C, and retained 100 % activity at 45 degrees C even after 24 h. It was inhibited by azaserine and DON and PMSF. Ptgamma-GT shared 37 % sequence identity and 53 % homology with an extremophile gamma-GT from Thermoplasma acidophilum. Functional residues identified by in silico approaches were further validated by site-directed mutagenesis where Tyr327 mutated by Asn327 introduced significant transpeptidase activity. PMID- 23104166 TI - Prospects for robust biocatalysis: engineering of novel specificity in a halophilic amino acid dehydrogenase. AB - Heat- and solvent-tolerant enzymes from halophiles, potentially important industrially, offer a robust framework for protein engineering, but few solved halophilic structures exist to guide this. Homology modelling has guided mutations in glutamate dehydrogenase (GDH) from Halobacterium salinarum to emulate conversion of a mesophilic GDH to a methionine dehydrogenase. Replacement of K89, A163 and S367 by leucine, glycine and alanine converted halophilic GDH into a dehydrogenase accepting L-methionine, L-norleucine and L-norvaline as substrates. Over-expression in the halophilic expression host Haloferax volcanii and three-step purification gave ~98 % pure protein exhibiting maximum activity at pH 10. This enzyme also showed enhanced thermostability and organic solvent tolerance even at 70 degrees C, offering a biocatalyst resistant to harsh industrial environments. To our knowledge, this is the first reported amino acid specificity change engineered in a halophilic enzyme, encouraging use of mesophilic models to guide engineering of novel halophilic biocatalysts for industrial application. Calibrated gel filtration experiments show that both the mutant and the wild-type enzyme are stable hexamers. PMID- 23104167 TI - The role of the iliotibial band during the pivot shift test. AB - PURPOSE: Several studies have suggested that the iliotibial (IT) band plays a role in knee laxity and that it may affect the magnitude of the pivot shift observed. However, the extent of the role played by the IT band, as well as its mechanism of action, is not currently known. This cadaveric study aimed to quantify the effect of the IT band and the hip abduction angle on the magnitude of anterior tibial translation (ATT) during the pivot shift. METHODS: Six fresh frozen hip-to-toes specimens were used. Serial sectioning of the anterior cruciate ligament (ACL) and the IT band was performed. Lachman and mechanized pivot shift manoeuvres were employed at each stage, and ATT of the lateral and medial compartments was measured using navigation. Three hip abduction angles were tested for each condition: 0 degrees , 15 degrees and 30 degrees . RESULTS: Sequential sectioning of the ACL and the IT band resulted in a significant increase in ATT in both the lateral (Intact = 0 +/- 0.5 mm; ACL deficient = 8.1 +/- 0.2 mm; ACL + IT deficient = 10.8 +/- 0.3 mm) and medial (Intact = 6.7 +/- 0.4 mm; ACL deficient = 8.4 +/- 0.3 mm; ACL + IT deficient = 9.9 +/- 0.3 mm) compartments. No significant increase in ATT was observed after changing the hip abduction angle at each stage. CONCLUSIONS: An increase in the magnitude of the pivot shift and the Lachman was observed as the constraint of the IT band was removed. Additionally, it was shown that the hip abduction angle at which the pivot shift test was performed did not significantly affect the magnitude of ATT in this cadaveric model. PMID- 23104168 TI - Knee joint infection after ACL reconstruction: prevalence, management and functional outcomes. AB - PURPOSE: Septic arthritis after an ACL reconstruction is a rare but serious complication. Functional outcomes of these patients have not been studied in depth in large series. The aim of this study was to determine the prevalence and management of knee joint infection following ACL reconstruction and to assess the functional outcomes. METHODS: A retrospective assessment of knee joint infections occurring after arthroscopically assisted ACL reconstructions done from 2006 to 2009 in two hospitals by the same surgical team is presented. Patients with signs and symptoms of joint infection along with blood and synovial effusion laboratory parameters suggestive of infection were considered as septic arthritis. All the patients were treated with antibiotic therapy according to antibiotic sensitivity and had at least one arthroscopic lavage. Final outcomes were assessed and compared with a control group using the KT-1000 arthrometer, functional testing and radiological examination. RESULTS: Fifteen (1.8 %) out of 810 patients included in the study were considered as a joint infection. Microbiology showed that coagulase-negative Staphylococcus was present in 10 patients, Staphylococcus Aureus in three patients (2 MSSA and 1 MRSA) and Propinebacterium sp. in one patient. In one patient, the micro-organism was unknown. At a mean follow-up of 39.3 +/- 13 months, the Lysholm score was 77.7 +/- 15.3, the IKDC score was 70.4 +/- 19.5, and the KT-1000 compared to the non-injured contralateral knee showed a mean difference of 1.3 +/- 2 mm. Functional outcomes in the control group were slightly better than those obtained in the infected group (Lysholm score; 90.7 +/ 9.4, p = 0.007. IKDC score; 86.6 +/- 6.8, p = 0.004). All but one patient retained their reconstructed ACL. CONCLUSIONS: The prevalence of septic arthritis after an ACL reconstruction in this series was 1.8 %. Arthroscopic lavages along with antibiotic treatment led us to preserve all but one graft. Functional outcomes in the infected patients were not as good as those obtained in patients without infection. PMID- 23104169 TI - Influence of glucose on the human serum albumin-flavone interaction and their antioxidant activity. AB - High levels of glucose in diabetics can react with plasma proteins through a non enzymatic process. Herein, the influence of glucose on the interaction between flavones and human serum albumin (HSA) was investigated, as well as the effect of glucose on the antioxidant potential of a flavone-HSA system. It looks like the interactions of HSA and flavones with more hydroxyl groups on ring A are more easily affected by glucose. Flavones act as hydrogen bond donors with HSA by means of interacting with glucose. With increased incubation time in air (from 1 to 23 days), the affinities of HSA for multi-hydroxyl flavones on ring A were obviously higher than for non- or mono-hydroxyl flavones on ring A. HSA significantly masked the DPPH radical scavenging potential of 7,8 dihydroxyflavone and baicalein. However, glucose obviously enhances the DPPH scavenging potential of a baicalein-HSA system. Moreover, glucose slightly weakens the DPPH scavenging potential of a 7,8-dihydroxyflavone-HSA system. PMID- 23104170 TI - Kinetic, equilibrium isotherm and thermodynamic studies of Cr(VI) adsorption onto low-cost adsorbent developed from peanut shell activated with phosphoric acid. AB - A particular agricultural waste, peanut shell, has been used as precursor for activated carbon production by chemical activation with H3PO4. Unoxidized activated carbon was prepared in nitrogen atmosphere which was then heated in air at a desired temperature to get oxidized activated carbon. The prepared carbons were characterized for surface area, surface morphology, and pore volume and utilized for the removal of Cr(VI) from aqueous solution. Batch mode experiments were conducted to study the effects of pH, contact time, particle size, adsorbent dose, initial concentration of adsorbate, and temperature on the adsorption of Cr(VI). Cr(VI) adsorption was significantly dependent on solution pH, and the optimum adsorption was observed at pH 2. Pseudo-first-order, pseudo-second-order, and intraparticle diffusion models were used to analyze the kinetic data obtained at different initial Cr(VI) concentrations. The adsorption kinetic data were described very well by the pseudo-second-order model. Equilibrium isotherm data were analyzed by the Langmuir, Freundlich, and Temkin models. The results showed that the Langmuir adsorption isotherm model fitted the data better in the temperature range studied. The adsorption capacity which was found to increase with temperature showed the endothermic nature of Cr(VI) adsorption. The thermodynamic parameters, such as Gibb's Free energy change (DeltaG degrees ), standard enthalpy change (DeltaH degrees ), and standard entropy change (DeltaS degrees ) were evaluated. PMID- 23104171 TI - Falsely elevated sodium levels during thiopental treatment in the ICU: technical interference on a laboratory device with important clinical relevance. AB - INTRODUCTION: Thiopental is a cornerstone in the treatment of refractory status epilepticus and intractable intracranial hypertension. In our center we observed that thiopental might cause falsely elevated serum sodium levels. METHODS: Triggered by a recent case experience of extremely elevated serum sodium levels during thiopental treatment, we retrospectively identified 53 patients treated with thiopental in our intensive care unit between 2007 and 2011 and evaluated electrolyte changes. We differentiated the analysis before and after introduction of a new device for sodium assays (Dimension Vista, Siemens) in the central laboratory in April 2010. Standardized in vitro laboratory tests were performed to study the effect of thiopental on sodium analysis. RESULTS: Before April 2010, serum sodium levels determined in the central laboratory showed a good agreement with the bedside point-of-care (POC) device during thiopental therapy with [sodium](laboratory) - [sodium](POC) of only 1.08 mmol/L (P = .0517). After April 2010, a strong discrepancy between laboratory values and POC values was observed with [sodium](laboratory) - [sodium](POC) = 11.57 mmol/L (P < .0001). Standardized in vitro testing confirmed that thiopental induced a dose-dependent false hypernatremia (P = .002). CONCLUSIONS: Thiopental treatment can result in falsely elevated serum sodium. This is a critical finding since high sodium levels preclude administrating mannitol or hypertonic saline for the treatment of elevated intracranial pressure. Moreover, a false high sodium level might lead to the inappropriate administration of hypotonic fluids potentially resulting in increased brain edema and even higher intracranial pressure. To our knowledge, this is the first paper describing this clinically relevant phenomenon. PMID- 23104172 TI - Emphasising the European Union's Commitment to Cancer Research: a helicopter view of the Seventh Framework Programme for Research and Technological Development. PMID- 23104173 TI - Trastuzumab and chemotherapy may be appropriate for small, node-negative, HER2 positive breast cancer. PMID- 23104175 TI - Acetylated Sp1 inhibits PTEN expression through binding to PTEN core promoter and recruitment of HDAC1 and promotes cancer cell migration and invasion. AB - Specificity protein 1 (Sp1) is often overexpressed in cancer cells. Its binding sites are known to exist in the phosphatase and tension homolog deleted on chromosome 10 (PTEN) promoter. In this study, we hypothesized that Sp1 negatively regulates PTEN expression. We used several cell lines to determine the effects of Sp1. The results showed that Sp1 overexpression inhibited the expression and promoter activity of PTEN and correspondingly upregulated AKT phosphorylation, whereas Sp1 knockdown upregulated the expression and promoter ability of PTEN and downregulated AKT phosphorylation. Moreover, a series of deletion and site directed mutations of the PTEN promoter indicated that Sp1 can inhibit PTEN promoter activity through a specific Sp1-binding site at the PTEN core promoter in vivo. Meanwhile, non-acetylated Sp1, with its loss of DNA binding activity, failed to inhibit the expression and promoter activity of PTEN. Histone deacetylase 1 was necessary for Sp1 to inhibit PTEN expression. The inverse expression of Sp1 and PTEN was found in tongue cancer cells and salivary adenoid cystic cancer (SACC)-LM cells (possessing higher potential for lung metastasis than SACC-83) as compared with that in adjacent normal tissue and SACC-83 cells, respectively. Sp1 knockdown decreased the migration and invasion of SACC-LM cells, whereas Sp1 overexpression increased the migration and invasion of SACC-83 cells. Overall, these results suggest that Sp1 is involved in the development and invasiveness of cancer through inhibition of PTEN. PMID- 23104176 TI - Chemoprevention by N-acetylcysteine of low-dose CT-induced murine lung tumorigenesis. AB - Data from the National Lung Screening Trial suggested that annual computed tomography (CT) screening of at-risk patients decreases lung cancer mortality by 20%. We assessed the effects of low-dose CT radiation in mice exposed to 4 (methylnitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) to mimic the effects of annual CT screening in heavy smokers and ex-smokers. A/J mice were treated at 8 weeks with NNK followed 1 week later by 4 weekly doses of 0, 10, 30 or 50 mGy of whole-body CT and euthanized 8 months later. Irradiated mice exhibited significant 1.8- to 2-fold increases in tumor multiplicity in males (16.1 +/- 0.8 versus 9.1 +/- 1.5 tumors per mouse; P < 0.0001) and females (21.6 +/- 0.8 versus 10.5 +/- 1.4 tumors per mouse; P < 0.0001), respectively, compared with unirradiated mice with no dose effect observed; female mice exhibited higher sensitivity to radiation exposure than did males (P < 0.0001). Similar results were obtained when tumor area was determined. To assess if the deleterious effects of radiation could be prevented by antioxidants, female mice were fed a diet containing 0.7% N-acetylcysteine (NAC) starting 3 days prior to the first CT exposure and continuing for a total of 5 weeks. NAC prevented CT induced increases in tumor multiplicity (10.5 +/- 1.2 versus 20.7 +/- 1.5 tumors per mouse; P < 0.0001) back to levels seen in NNK/unirradiated mice (10.5 +/- 1.2). Our data suggest that exposure of sensitive populations to CT radiation increases the risk of tumorigenesis, and that antioxidants may prevent the long-term carcinogenic effects of low-dose radiation exposure. This would allow annual screening with CT while preventing the potential long-term toxicity of radiation exposure. PMID- 23104177 TI - Fine-mapping of the 6q25 locus identifies a novel SNP associated with breast cancer risk in African-American women. AB - The rs2046210 single nucleotide polymorphism (SNP) in the 6q25.1 region was identified in a breast cancer genome-wide association study of Chinese women. The SNP has been replicated in European ancestry populations, but replication efforts have failed in African ancestry populations. We evaluated a total of 13 tagging SNPs in the linkage disequilibrium block around rs2046210 in a case-control study of breast cancer nested within the Black Women's Health Study, which included 1191 cases and 1941 controls. Replication of initial significant findings was carried out in 665 cases and 821 controls of African ancestry from the Women's Circle of Health Study (WCHS). No significant association was found for rs2046210 in univariate analysis. A new SNP, rs2046211, was significantly associated with reduced risk of breast cancer and was replicated in data from WCHS. In joint analyses that included both SNPs, the rs2046210-A allele was associated with increased risk of breast cancer [odds ratio (OR) = 1.14; 95% confidence interval (CI) = 1.02-1.28], and the rs2046211-G allele was associated with reduced risk (OR = 0.80; 95% CI = 0.67-0.95). Haplotype analysis confirmed these results and showed that the rs2046210-A allele is present in high-risk (rs2046211-C/rs2046210 A) and low-risk (rs2046211-G/rs2046210-A) haplotypes. Our results confirm the importance of 6q25.1 as a breast cancer susceptibility region. We replicated the rs2046210 association, after accounting for the haplotype background that included rs2046211 in African-American women, and we report the presence of a novel signal that is tagged by rs2046211. PMID- 23104179 TI - Novel pyrimidine-2,4-diamine derivative suppresses the cell viability and spindle assembly checkpoint activity by targeting Aurora kinases. AB - Mitosis represents a clinically important determination point in the life cycle of proliferating cells. One potential drug target within the mitotic machinery is the spindle assembly checkpoint (SAC), an evolutionarily conserved signaling pathway that monitors the connections between microtubules (MTs) and chromosomes. Mistakes in SAC signaling may lead to cell division errors that can trigger elimination of cancer cells at M phase or soon after exit from mitosis. In this study, we describe the cellular effects of a novel pyrimidine-2,4-diamine derivative that we discovered to inhibit the activity of SAC. The compound caused rapid escape from the mitotic arrest induced by lack of interkinetochore tension but not by lack of MT-kinetochore attachments. In cycling cells, the compound disrupted the architecture of mitotic spindle that triggered a transient M-phase arrest that was rapidly followed by a forced mitotic exit. The premature termination of M phase was found to be a consequence of precocious inactivation of SAC caused by a direct inhibitory effect of the compound on Aurora B kinase in vitro and in cells. The compound also targets Aurora A kinase and tubulin in vitro and in cells, which can explain the observed spindle anomalies. The reduced activity of Aurora B kinase resulted in polyploidy and suppression of cancer cell viability. Our data suggest that this new pharmacophore possesses interesting anticancer properties that could be exploited in development of mitosis-targeting therapies. PMID- 23104178 TI - Increased PrLZ-mediated androgen receptor transactivation promotes prostate cancer growth at castration-resistant stage. AB - Most advanced prostate cancers (PCa) will develop into the castration-resistant stage following androgen deprivation therapy, yet the molecular mechanisms remain unclear. In this study, we found PrLZ, a newly identified Prostate Leucine Zipper gene that is highly expressed in PCa could interact with the androgen receptor (AR) directly leading to enhance AR transactivation in the castration-resistant condition. PrLZ might enhance AR transactivation via a change of AR conformation that leads to promotion of AR nuclear translocation and suppression of AR degradation via modulating the proteasome pathway, which resulted in increased prostate-specific antigen expression and promoted PCa growth at the castration resistant stage. Clinical PCa sample survey from same-patient paired specimens found increased PrLZ expression in castration-resistant PCa following the classical androgen deprivation therapy. Targeting the AR-PrLZ complex via ASC J9(r) or PrLZ-siRNA resulted in suppression of PCa growth in various human PCa cells and in vivo mouse PCa models. Together, these data not only strengthen PrLZ roles in the transition from androgen dependence to androgen independence during the castration-resistant stage, but they may also provide a new potential therapy to battle PCa at the castration-resistant stage. PMID- 23104181 TI - A convenient synthesis of anthranilic acids by Pd-catalyzed direct intermolecular ortho-C-H amidation of benzoic acids. AB - An efficient method for synthesis of anthranilic acids by Pd-catalyzed ortho-C-H amidation of benzoic acids is disclosed. The amidation is proposed to proceed by carboxylate-assisted ortho-C-H palladation to form an arylpalladium(II) complex, followed by nitrene insertion to the Pd-C bond. PMID- 23104180 TI - miR-15a and miR-16 affect the angiogenesis of multiple myeloma by targeting VEGF. AB - Deregulated microRNAs (miRNAs) and their roles in cancer development have attracted much attention. Two miRNAs, miR-15a and miR-16, which act as putative tumor suppressor by targeting the oncogene BCL2, have been implicated in cell cycle, apoptosis and proliferation. In this study, we investigated the possible role of miR-15a/16 in the angiogenesis of multiple myeloma (MM). Using a stem loop quantitative reverse transcription-PCR, we analyzed miR-15a/16 expressions in bone marrow samples from newly diagnosed MM patients and a panel of MM cell lines. miRNA transfection, western blotting analysis and assay of luciferase activity were used to examine whether vascular endothelial growth factor (VEGF) is the target of miR-15a/16. The functional roles of miR-15a/16 on tumorigenesis and angiogenesis were examined by in vitro angiogenesis models and in vivo tumor xenograft model. We showed that miR-15a and miR-16 were significantly underexpressed in primary MM cells as well as in MM cell lines. The aberrant expression of miR-15a/16 was detected especially in advanced stage MM. In human MM cell lines and normal plasma cells, expression of miR-15a/16 inversely correlated with the expression of VEGF-A. Western blotting combined with the luciferase reporter assay demonstrated that VEGF-A was a direct target of miR 15a/16. Ectopic overexpression of miR-15a/16 led to decreased pro-angiogenic activity of MM cells. Finally, infection of lentivirus-miR-15a or lentivirus-miR 16 resulted in significant inhibition of tumor growth and angiogenesis in nude mice. This study suggest that miR-15a/16 could play a role in the tumorigenesis of MM at least in part by modulation of angiogenesis through targeting VEGF-A. PMID- 23104182 TI - Colloidal superparticles from nanoparticle assembly. AB - Colloidal superparticles are size- and shape-controlled nanoparticle assemblies in the form of colloidal particles. Because these superparticles can exhibit physical and chemical properties different from both individual nanoparticles and their bulk assemblies, the development of superparticle synthesis has attracted significant research attention and is emerging as a new frontier in the field of nanotechnology. In this review, we discuss theoretical considerations on the nucleation and growth of colloidal superparticles. We then present recent progress in the synthesis and characterization of monodispersed colloidal superparticles, which are important for applications such as biomedical diagnosis, biological separation, and light emitting devices. PMID- 23104183 TI - Facilitatory priming of scene layout depends on experience with the scene. AB - Facilitatory scene priming is the positive effect of a scene prime on the immediately subsequent spatial processing of a related target, relative to control primes. In the present experiments, a large set of scenes were presented, each several times. The accuracy of a relational spatial-layout judgment was the main measure (which of two probes in a scene was closer?). The effect of scene primes on sensitivity was near zero for the first presentation of a scene; advantages for scene primes occurred only after two or three presentations. In addition, a bias effect emerged in reaction times for novel scenes. These results imply that facilitatory scene priming requires learning and is top-down in nature. Scene priming may require the consolidation of interscene relations in a memory representation. PMID- 23104184 TI - Development of a short version of the Dutch version of the Spielberger STAI trait anxiety scale in women suspected of breast cancer and breast cancer survivors. AB - The objective of the current study was to develop a short form of the Dutch version of the State-Trait Anxiety Inventory (STAI) Trait scale and to provide initial validation data in a sample of breast cancer patients and survivors. This short trait anxiety (A-Trait) scale was designed to reduce time and effort required of severely ill or handicapped patients involved in extensive assessment procedures. Another goal was to assess A-Trait with minimal overlap with content that reflects Quality of Life (QoL) and fatigue. Three groups of women either completed the original Trait scale (Groups 1 and 2) or the 10-item trait version (Group 3). In Group 1, exploratory factor analysis with the Scree test, Velicer's MAP criteria and parallel analysis as tests for factor retention, indicated a 10 item Trait version reflecting two factors: Anxiety Present and Anxiety Absent. In the other groups, confirmatory factor analysis showed that the two-factor short form provided the best fit. In all three groups Trait Anxiety was highly related to Neuroticism. The correlation between Overall QoL and General Health and the Anxiety Present short scale was lower than the correlation between Overall QoL and General Health and the full form (Z = 2.20, p = .03). With this short A-Trait scale it becomes possible to study the relationship between dispositional anxiety and clinically important outcome variables without inflating estimates of these relations through psychometric contamination. PMID- 23104185 TI - Effects of a cognitive-behavioral self-help program on depressed mood for people with peripheral arterial disease. AB - The aim of the present study was to examine whether a new low-cost psychological self-help intervention program with minimal coaching could be effective in improving depressed mood in people with peripheral arterial disease (PAD). Thirteen persons with PAD and depressive symptoms participated in the self-help program, grounded in cognitive-behavioral therapy. They completed pre-test, post test and follow-up questionnaires, including the PHQ-9, to measure symptoms of depression. To evaluate changes in depression scores from pre- to post-test to follow-up measurement, non-parametric repeated measures Wilcoxon signed rank tests were performed. The results showed that participants' depression scores significantly improved from pre-test to post-test and that there was no relapse from post-test to follow-up. The cognitive-behavioral self-help intervention could be an effective tool in people with PAD, to reduce symptoms of depression. PMID- 23104186 TI - Auditory magnetic response to clicks in children and adults: its components, hemispheric lateralization and repetition suppression effect. AB - The auditory magnetic event-related fields (ERF) qualitatively change through the child development, reflecting maturation of auditory cortical areas. Clicks presented with long inter-stimulus interval produce distinct ERF components, and may appear useful to characterize immature EFR morphology in children. The present study is aimed to investigate morphology of the auditory ERFs in school age children, as well as lateralization and repetition suppression of ERF components evoked by the clicks. School-age children and adults passively listened to pairs of click presented to the right ear, left ear or binaurally, with 8-11 s intervals between the pairs and a 1 s interval within a pair. Adults demonstrated a typical P50m/N100m response. Unlike adults, children had two distinct components preceding the N100m-P50m (at ~65 ms) and P100m (at ~100 ms). The P100m dominated the child ERF, and was most prominent in response to binaural stimulation. The N100m in children was less developed than in adults and partly overlapped in time with the P100m, especially in response to monaural clicks. Strong repetition suppression was observed for P50m both in children and adults, P100m in children and N100m in adults. Both children and adults demonstrated ERF amplitude and/or latency right hemispheric advantage effects that may reflect right hemisphere dominance for preattentive arousal processes. Our results contribute to the knowledge concerning development of auditory processing and its lateralization in children and have implications for investigation of the auditory evoked fields in developmental disorders. PMID- 23104187 TI - N-heterocyclic carbene catalyzed synthesis of oxime esters. AB - A triazolium salt derived N-heterocyclic carbene catalyzes the redox esterification reaction between alpha-beta-unsaturated aldehydes and oximes. The resulting saturated oxime esters were obtained in very good yields for a broad range of aliphatic, aromatic and heteroaromatic substrates. PMID- 23104188 TI - HCT for nonmalignant disorders. PMID- 23104191 TI - Tensile failure properties of the perinatal, neonatal, and pediatric cadaveric cervical spine. AB - STUDY DESIGN: Biomechanical tensile testing of perinatal, neonatal, and pediatric cadaveric cervical spines to failure. OBJECTIVE: To assess the tensile failure properties of the cervical spine from birth to adulthood. SUMMARY OF BACKGROUND DATA: Pediatric cervical spine biomechanical studies have been few due to the limited availability of pediatric cadavers. Therefore, scaled data based on human adult and juvenile animal studies have been used to augment the limited pediatric cadaver data. Despite these efforts, substantial uncertainty remains in our understanding of pediatric cervical spine biomechanics. METHODS: A total of 24 cadaveric osteoligamentous head-neck complexes, 20 weeks gestation to 18 years, were sectioned into segments (occiput-C2 [O-C2], C4-C5, and C6-C7) and tested in tension to determine axial stiffness, displacement at failure, and load-to failure. RESULTS: Tensile stiffness-to-failure (N/mm) increased by age (O-C2: 23 fold, neonate: 22 +/- 7, 18 yr: 504; C4-C5: 7-fold, neonate: 71 +/- 14, 18 yr: 509; C6-C7: 7-fold, neonate: 64 +/- 17, 18 yr: 456). Load-to-failure (N) increased by age (O-C2: 13-fold, neonate: 228 +/- 40, 18 yr: 2888; C4-C5: 9-fold, neonate: 207 +/- 63, 18 yr: 1831; C6-C7: 10-fold, neonate: 174 +/- 41, 18 yr: 1720). Normalized displacement at failure (mm/mm) decreased by age (O-C2: 6-fold, neonate: 0.34 +/- 0.076, 18 yr: 0.059; C4-C5: 3-fold, neonate: 0.092 +/- 0.015, 18 yr: 0.035; C6-C7: 2-fold, neonate: 0.088 +/- 0.019, 18 yr: 0.037). CONCLUSION: Cervical spine tensile stiffness-to-failure and load-to-failure increased nonlinearly, whereas normalized displacement at failure decreased nonlinearly, from birth to adulthood. Pronounced ligamentous laxity observed at younger ages in the O-C2 segment quantitatively supports the prevalence of spinal cord injury without radiographic abnormality in the pediatric population. This study provides important and previously unavailable data for validating pediatric cervical spine models, for evaluating current scaling techniques and animal surrogate models, and for the development of more biofidelic pediatric crash test dummies. PMID- 23104192 TI - The cutoff amplitude of transcranial motor-evoked potentials for predicting postoperative motor deficits in thoracic spine surgery. AB - STUDY DESIGN: Prospective clinical study of intraoperative transcranial motor evoked potentials (TcMEP) amplitudes and postoperative motor deficits. OBJECTIVE: To determine the cutoff amplitude during intraoperative TcMEP monitoring for predicting postoperative motor deficits after thoracic spine surgery. SUMMARY OF BACKGROUND DATA: Several alarm points when monitoring with TcMEP have been advocated, but there have been no reports on an actual cutoff amplitude of TcMEP for predicting the occurrence of postoperative motor deficits. METHODS: Among 80 consecutive surgical cases, 28 had a deterioration in TcMEP amplitude in at least 1 monitored muscle during surgery. We examined intraoperative electrophysiological changes and postoperative motor deficits in 270 monitorable muscles in those 28 patients. Through receiver operating characteristic curve analysis, we identified the cutoff amplitudes at the intraoperative point of deterioration and at the end of surgery for predicting postoperative motor deficits in both relative and absolute values. RESULTS: The relative and the absolute cutoff amplitudes of TcMEP at the intraoperative point of deterioration and at the end of thoracic spine surgery were 12% of control amplitude and 1.9 MUV and 25% of control amplitude and 3.6 MUV, respectively. Sensitivity/specificity for those cutoff points are 88%/64%, 69%/83%, 90%/64%, and 70%/82%, respectively. CONCLUSION: We determined the cutoff amplitude for predicting postoperative motor deficits in thoracic spine surgery. The results may help establish the alarm criteria for thoracic spine surgery. PMID- 23104193 TI - Re: Nieuwenhuijse MJ, Bollen L, van Erkel AR, Dijkstra PD. Optimal intravertebral cement volume in percutaneous vertebroplasty for painful osteoporotic vertebral compression fractures. Spine 2012;37:1747-55. PMID- 23104194 TI - Postoperative magnetic resonance imaging assessment for potential compressive effects of retained posterior longitudinal ligament after anterior cervical fusions: a cross-sectional study. AB - STUDY DESIGN: A cross-sectional study. OBJECTIVE: To assess using postoperative magnetic resonance imaging whether the posterior longitudinal ligament (PLL) caused residual cord compression after anterior cervical decompression and fusion (ACDF) in a series of patients in whom the PLL was retained. SUMMARY OF BACKGROUND DATA: There is a lack of data evaluating the postoperative compressive effects of the PLL in patients undergoing ACDF providing guidance as to whether to remove or retain the PLL during discectomy to facilitate adequate decompression. METHODS: Postoperative gadolinium enhanced magnetic resonance images were reviewed in a series of 33 patients who underwent ACDF for cervical radiculomyelopathy and who had persistent or recurrent postoperative symptoms. Patients with ossification of the posterior longitudinal ligament or with a herniated disc behind the PLL were excluded from this study. RESULTS: There were no cases of discernible compression by the retained PLL identified on the magnetic resonance image (P < 0.001) as assessed by 2 independent reviewers. Four patients underwent subsequent revision surgery unrelated to the PLL. CONCLUSION: We were unable to demonstrate magnetic resonance imaging evidence to suggest that the retained PLL caused compression after ACDF in this patient cohort. Therefore we suggest that removing the PLL should be considered for reasons other than concern about residual compression. PMID- 23104195 TI - Is curve direction correlated with the dominant side of tonsillar ectopia and side of syrinx deviation in patients with single thoracic scoliosis secondary to Chiari malformation and syringomyelia? AB - STUDY DESIGN: A retrospective imaging study. OBJECTIVE: To conduct an assessment of the correlation of the coronal asymmetries between tonsillar ectopia, syrinx, and scoliosis. SUMMARY OF BACKGROUND DATA: A few reports have shown that the convex side of scoliosis was on the same side as the dominant tonsillar ectopia or syrinx deviation in a majority of patients. However, this issue remains controversial. METHODS: A retrospective study was conducted on young patients with a single thoracic scoliosis secondary to Chiari malformation type I and syringomyelia. The curve direction, side of the dominant tonsillar ectopia and side of the syrinx deviation were recorded and assessed quantitatively. The correlations between the asymmetrically displaced tonsils, eccentrically located syrinx, and curve convexity were investigated. RESULTS: A total of 39 patients were included. The concordance between the deviated side of the eccentrically located syrinx and dominant side of the asymmetrically displaced tonsils was 87.0%. In 88.5% of the patients with an asymmetrically displaced tonsil, the convex side of the scoliosis was concordant with the dominant side of the tonsillar ectopia, and in 86.2% of patients with an eccentrically located syrinx, the convex side of the scoliosis was on the same side as the deviated side of the syrinx. In addition, the dominant tonsillar ectopia, syrinx deviation, and curve direction were all on the same side in 82.6% patients with asymmetrically displaced tonsils and eccentrically located syrinx. CONCLUSION: Asymmetrically displaced tonsils and eccentrically located syrinxes were common imaging features in these patients. The thoracic spine tended to be convex to not only the dominant side of the asymmetrically displaced tonsil, but also the deviated side of the eccentrically located syrinx. The effect of syrinx deviation on curve convexity is similar to that of dominant tonsillar ectopia in the majority of patients. PMID- 23104196 TI - Cervical spinal cord contusion in professional athletes: a case series with implications for return to play. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: This report provides long term follow-up on athletes who have sustained a cervical spinal cord contusion. Their magnetic resonance (MR) image is correlated with clinical signs and symptoms. Mechanism of injury and a hypothesis of etiology are reported. SUMMARY OF BACKGROUND DATA: Current return-to-play criteria for athletes who sustain a cervical cord contusion are based on expert opinion only. Decision making for this clinical situation in athletes carries significant clinical, legal, and economic ramifications. The natural history, clinical correlation, and effect of surgery for athletic cervical cord contusions have not been established. The mechanism of injury for this entity has historically emphasized axial loading. METHODS: The case histories, physical examination, and MR images were reviewed for 4 professional athletes. All athletes had documented cervical cord contusions. None of the athletes had an acute disc herniation, fracture, instability, or focal cord compression. All athletes were contacted by telephone to assess symptoms at a minimum follow-up of 2 years after injury. RESULTS: All 4 athletes had congenital stenosis, defined as lack of CSF signal around the cord on an MR image. All underwent anterior fusions at the level of their contusion. In follow-up, 2 athletes developed new contusions: one more than 5 years later, adjacent to a fusion; and 1, 2 years later, not adjacent to his previous fusion. No athlete developed permanent neurological sequelae. The presence of a contusion did not correlate with athletes' signs and symptoms. The mechanism of injury was hyperextension. CONCLUSION: It is hypothesized that the horizontal facet orientation of the C3-C4 level, congenital stenosis, and relative hypermobility in extension are the contributing factors in the cause of this clinical entity. An anterior fusion at the C3-C4 level seems to be the most reliable method of preventing or delaying the return of symptoms. Return-to-play guidelines should emphasize the athletes' history of symptoms in context with their MR image because there is poor correlation between the finding of a contusion and the clinical presentation. Recurrence of symptoms is common and the long-term consequences of repeated episodes remain unknown. PMID- 23104197 TI - Biomechanics of lumbar cortical screw-rod fixation versus pedicle screw-rod fixation with and without interbody support. AB - STUDY DESIGN: Seven different combinations of posterior screw fixation, with or without interbody support, were compared in vitro using nondestructive flexibility tests. OBJECTIVE: To study the biomechanical behavior of a new cortical screw (CS) fixation construct relative to the traditional pedicle screw (PS) construct. SUMMARY OF BACKGROUND DATA: The CS is an alternative to the PS for posterior fixation of the lumbar spine. The CS trajectory is more sagittally and cranially oriented than the PS, being anchored in the pars interarticularis. Like PS fixation, CS fixation uses interconnecting rods fastened with top-locking connectors. Stability after bilateral CS fixation was compared with stability after bilateral PS fixation in the setting of intact disc and with direct lateral interbody fixation (DLIF) or transforaminal lateral interbody fixation (TLIF) support. METHODS: Standard nondestructive flexibility tests were performed in cadaveric lumbar specimens, allowing non-paired comparisons of specific conditions from 28 specimens (4 groups of 7) within a larger experiment of multiple hardware configurations. Condition tested and group from which results originated were as follows: (1) intact (all groups); (2) with L3-L4 bilateral PS rods (group 1); (3) with bilateral CS-rods (group 2); (4) with DLIF (group 3); (5) with DLIF + CS-rods (group 4); (6) with DLIF + PS-rods (group 3); (7) with TLIF + CS-rods (group 2), and (8) with TLIF + PS-rods (group 2). To assess spinal stability, the mean range of motion, lax zone, and stiff zone at L3-L4 were compared during flexion-extension, lateral bending, and axial rotation. RESULTS: With intact disc, stability was equivalent after PS-rod and CS-rod fixation, except that PS-rod fixation was stiffer during axial rotation. With DLIF support, there was no significant difference in stability between PS-rod and CS-rod fixation. With TLIF support, PS-rod fixation was stiffer than CS-rod fixation during lateral bending. CONCLUSION: Bilateral CS-rod fixation provided about the same stability in cadaveric specimens as PS-rod fixation regardless of the presence of interbody, TLIF, or DLIF support. PMID- 23104198 TI - Postoperative distal adding-on and related factors in Lenke type 1A curve. AB - STUDY DESIGN: A retrospective, multicenter study. OBJECTIVE: To investigate the occurrence of and factors related to postoperative adding-on in Lenke type 1A curve. SUMMARY OF BACKGROUND DATA: Although several studies have investigated factors associated with adding-on in Lenke type 1A curve, these factors have not been elucidated in a large study population. METHODS: This study included 112 patients who were followed more than 2 years after undergoing selective posterior thoracic fusion surgery for Lenke Type 1A curve (8 males, 104 females; mean age at surgery, 16.1 yr; mean follow-up, 3.6 yr). The lower instrumented vertebra (LIV) was T12 in 22 patients, L1 in 55, L2 in 32, and L3 in 3. Distal to the main thoracic curve, the end vertebra, neutral vertebra, stable vertebra (SV), and the last vertebra touching the central sacral vertical line (last touching vertebra, LTV) were determined. The occurrence and factors associated with distal adding-on were investigated. RESULTS: The mean Cobb angle and apical translation of the main thoracic curve were 54.6 degrees +/- 9.6 degrees and 53.1 +/- 20.4 mm before surgery, and 14.2 +/- 7.4 and 16.2 +/- 12.7 at follow-up, respectively. Distal adding-on was observed in 21 patients (18.8%) at follow-up. Univariate analyses identified several factors significantly associated with adding-on, including the preoperative proximal thoracic curve, the apical translation of the main thoracic curve, Miyanji's subclassification, the postsurgical proximal and main thoracic curves, the postsurgical apical translation of the main thoracic curve, the correction rate of the main thoracic curve and the clavicle angle immediately after surgery and at follow-up, and the difference in levels between the LIV and the end vertebra, neutral vertebra, LTV, and stable vertebra. Logistic regression analysis showed that the apical translation of the main thoracic curve immediately after surgery (apical translation >25 mm, odds ratio: 10.7, 95% confidence interval: 3.1-37.0, P = 0.001) and the difference in levels between LIV and LTV (LIV-LTV) (LIV-LTV <0, odds ratio: 6.7, 95% confidence interval: 1.9-23.9, P = 0.003) were significantly associated with adding-on. CONCLUSION: Since the residual apical translation of the main thoracic curve and the lowest instrumented vertebra more cranial to the last touching vertebra were significantly associated with adding-on, surgeons may need to obtain the maximum reduction of the apical translation of the main thoracic curve and to extend the LIV at least to the LTV to avoid postoperative adding-on. PMID- 23104199 TI - The omega-6 arachidonic fatty acid, but not the omega-3 fatty acids, inhibits osteoblastogenesis and induces adipogenesis of human mesenchymal stem cells: potential implication in osteoporosis. AB - Arachidonic fatty acid (AA) induces adipogenesis in human mesenchymal stem cells cultures, and high concentrations inhibit osteoblastogenesis; whereas eicosapentaenoic and docosahexaenoic fatty acids do not induce adipogenesis and do not inhibit osteoblastogenesis. In mesenchymal stem cells, omega-6 arachidonic polyunsaturated fatty acid promotes the differentiation of adipocytes and inhibits the osteoblast differentiation. While omega-3 fatty acids do not affect the adipogenic differentiation their effects on osteoblastogenesis are less relevant. An increased ratio of omega-3/omega-6 fatty acid consumption can prevent bone mass loss. INTRODUCTION: Consumption of omega-3 may protect against osteoporosis since they may inhibit osteoclastogenesis. However, with aging, MSC in bone marrow are increasingly differentiated into adipocytes, reducing the number of osteoblasts. Products derived from omega-6 and omega-3 metabolism may affect MSC differentiation into osteoblasts and adipocytes. METHODS: Human MSC have been differentiated into osteoblasts or adipocytes in the presence of omega 6 (AA), or omega-3 (DHA and EPA), and osteoblastic and adipocytic markers have been analyzed. RESULTS: AA decreases the expression of osteogenic markers and the osteoprotegerin/receptor activator of nuclear factor kappa beta ligand gene expression ratio (opg/rankl). High concentrations of AA inhibit the mineralization and cause the appearance of adipocytes in MSC differentiating into osteoblasts to a higher extent than DHA or EPA. In MSC differentiated into adipocytes, AA increases adipogenesis, while DHA and EPA do not affect it. AA caused the appearance of adipocytes in undifferentiated MSC. The lipoxygenase gene (alox15b) is induced by omega-3 in MSC induced to osteoblasts, and by omega 6 in MSC induced to adipocytes. CONCLUSIONS: An increase in the intake of omega-3 respect to omega-6 may provide protection against the loss of bone mass, since omega-6 favors the osteoclastic activity by diminishing the opg/rankl gene expression in osteoblasts and promotes MSC differentiation into adipocytes, thus diminishing the production of osteoblasts. PMID- 23104201 TI - The shuttling scaffold model for prevention of yeast pheromone pathway misactivation. AB - The molecular scaffold in the yeast pheromone pathway, Ste5, shuttles continuously between the nucleus and the cytoplasm. Ste5 undergoes oligomerization reaction in the nucleus. Upon pheromone stimulation, the Ste5 dimer is rapidly exported out of the nucleus and recruited to the plasma membrane for pathway activation. This clever device on part of the yeast cell is thought to prevent pathway misactivation at high enough levels of Ste5 in the absence of pheromone. We have built a spatiotemporal model of signaling in this pathway to describe its regulation. Our present work underscores the importance of spatial modeling of cell signaling networks to understand their control and functioning. PMID- 23104200 TI - Alterations of bone geometry, density, microarchitecture, and biomechanical properties in systemic lupus erythematosus on long-term glucocorticoid: a case control study using HR-pQCT. AB - Compared to controls, HR-pQCT at distal radius of SLE patients on chronic glucocorticoid (SLE/GC) revealed reduced bone area, vBMD, deteriorated microarchitecture, and unevenly distributed stresses limited to cortical bone. Despite similar trabecular quality, whole bone strength decreased in patients. These alterations may partly explain high fracture rates in SLE/GC. INTRODUCTION: To assess bone geometric, densitometric, microarchitectural, and biomechanical properties in patients with systemic lupus erythematosus (SLE) on long-term glucocorticoid (GC) (SLE/GC) as compared with healthy controls. METHODS: A total of 180 female SLE patients and 180 healthy controls were in this cross-sectional study to assess areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR pQCT) and microfinite element analysis (MUFEA) was performed at distal radius. RESULTS: In addition to significantly lower aBMD at femoral neck, total hip and lumbar spine, cortical area, average volumetric BMD (vBMD) and cortical vBMD also significantly reduced by 5.3, 5.7, to 1.9 % in SLE patients, respectively. Deteriorations of cortical microarchitecture were pronounced in patients, with 6.3 % reduction in cortical thickness and 13.6 % higher in cortical porosity. Local stresses were more unevenly distributed through cortical bone in patients. SLE/GC patients had decreased whole bone stiffness, estimated failure load, and apparent modulus. Parameters related to trabecular bone density and microarchitecture were comparable between patients and controls. CONCLUSION: In SLE/GC patients, despite a reduction in bone area, vBMD and deteriorated microarchitecture and unevenly distributed stresses limited to the cortical compartment, whole bone strength decreased. HR-pQCT and MUFEA were promising in elucidating the potential underlying pathophysiology of bone loss and propensity to fracture in SLE/GC and provide us additional information about alterations of bone quality which might better predict fracture risk beyond aBMD in SLE/GC. PMID- 23104202 TI - Spontaneously formed semipermeable organic-inorganic hybrid vesicles permitting molecular weight selective transmembrane passage. AB - Semipermeable organic-inorganic hybrid vesicles coated with a siloxane surface were spontaneously formed by simple dispersion of an organoalkoxysilane lipid in water. The hybrid vesicles allow the permeation of hydrophilic small molecules across the membrane without an introduction of a pore-forming protein. PMID- 23104203 TI - Clinical factors predictive of Crohn's disease complications and surgery. AB - Crohn's disease (CD) is a progressive disease that is subdivided into three phenotypes: inflammatory, stricturing and penetrating. At diagnosis, most CD patients have inflammatory disease. However, the natural history of CD is one of progression over time to structural complications of the gastrointestinal tract (strictures and fistulae) requiring hospitalizations and surgeries. There is now evidence that early treatment with immunosuppressants and biologics can halt the development of inflammatory damage/fibrosis because of their potential to induce complete mucosal healing. This change in the natural course of CD, mediated by mucosal healing, is associated with a reduction in the incidence of serious complications (those requiring hospitalization and surgeries). Nevertheless, the clinical course of CD varies considerably from one patient to another, and the exact point at which immunosuppressants and/or biologics should be used has not yet been established. Given the difficulty in predicting which individuals will progress to complications and the fact that these therapeutic agents are associated with certain risks (lymphomas and opportunistic infections), efforts are underway to identify the risk factors that will facilitate the classification of patients into high-risk and low-risk groups at the time of diagnosis and to tailor therapy accordingly. This paper is a review of the currently available evidence on the clinical risk factors predictive of CD complications and surgery. PMID- 23104204 TI - Estrogen derivatives: novel therapeutic agents for liver cirrhosis and portal hypertension. AB - Sex differences in the incidence of liver cirrhosis and portal hypertension have been reported by epidemiological studies. Previous studies have indicated that estrogen therapy improved hepatic fibrosis, inhibited the activation of hepatic stellate cells, and reduced portal pressure, whereas the administration of exogenous estrogens resulted in some potential risks, limiting their clinical use. However, the biological actions of estrogens are mediated by three subtypes of estrogen receptors (ERs): ERalpha, ERbeta, and G-protein-coupled ER. These ER subtypes act in distinct ways and exert different biological effects that mediate genomic and nongenomic events, resulting in tissue-specific responses. In addition, active estrogen metabolites, with little or no affinity for ERs, could mediate the fibrosuppressive effect of estrogens through an ER-independent pathway. Taken together, such specific estrogen derivatives as ER selective agonists, or active estrogen metabolites, would provide novel therapeutic opportunities, stratifying this hormonal treatment, thereby reducing undesired side-effects in the treatment of liver cirrhosis and portal hypertension. PMID- 23104205 TI - Probabilistic forecasting using stochastic diffusion models, with applications to cohort processes of marriage and fertility. AB - In this article, we show how stochastic diffusion models can be used to forecast demographic cohort processes using the Hernes, Gompertz, and logistic models. Such models have been used deterministically in the past, but both behavioral theory and forecast utility are improved by introducing randomness and uncertainty into the standard differential equations governing population processes. Our approach is to add time-series stochasticity to linearized versions of each process. We derive both Monte Carlo and analytic methods for estimating forecast uncertainty. We apply our methods to several examples of marriage and fertility, extending them to simultaneous forecasting of multiple cohorts and to processes restricted by factors such as declining fecundity. PMID- 23104206 TI - Modeling and forecasting health expectancy: theoretical framework and application. AB - Life expectancy continues to grow in most Western countries; however, a major remaining question is whether longer life expectancy will be associated with more or fewer life years spent with poor health. Therefore, complementing forecasts of life expectancy with forecasts of health expectancies is useful. To forecast health expectancy, an extension of the stochastic extrapolative models developed for forecasting total life expectancy could be applied, but instead of projecting total mortality and using regular life tables, one could project transition probabilities between health states simultaneously and use multistate life table methods. In this article, we present a theoretical framework for a multistate life table model in which the transition probabilities depend on age and calendar time. The goal of our study is to describe a model that projects transition probabilities by the Lee-Carter method, and to illustrate how it can be used to forecast future health expectancy with prediction intervals around the estimates. We applied the method to data on the Dutch population aged 55 and older, and projected transition probabilities until 2030 to obtain forecasts of life expectancy, disability-free life expectancy, and probability of compression of disability. PMID- 23104207 TI - Trends in late-life activity limitations in the United States: an update from five national surveys. AB - This article updates trends from five national U.S. surveys to determine whether the prevalence of activity limitations among the older population continued to decline in the first decade of the twenty-first century. Findings across studies suggest that personal care and domestic activity limitations may have continued to decline for those ages 85 and older from 2000 to 2008, but generally were flat since 2000 for those ages 65-84. Modest increases were observed for the 55- to 64 year-old group approaching late life, although prevalence remained low for this age group. Inclusion of the institutional population is important for assessing trends among those ages 85 and older in particular. PMID- 23104209 TI - The role of adjuvant radiation therapy for stage I endometrial cancer: does meta analysis reveal the answer? PMID- 23104208 TI - Docetaxel-based preoperative chemoradiation in localized gastric cancer: impact of pathological complete response on patient outcome. AB - PURPOSE: This study was conducted to evaluate the feasibility, efficacy, and toxicities of docetaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma. METHODS: Patients with localized, operable gastric or gastroesophageal adenocarcinoma received two cycles of induction chemotherapy of fluorouracil, docetaxel, and cisplatin (TPF) followed by 45 Gy of radiation and concurrent fluorouracil plus docetaxel then surgery for nonmetastatic patients. RESULTS: Forty-one patients were included. Pretreatment T3 was encountered in 56 % of patients while 61 % had N1 disease. A pathologic complete response (CR) was noted in 24 % of patients. Pathologic response was significantly associated with baseline T stage (P < 0.001) and N stage (P = 0.002). The 3-year overall survival (OS) and disease-free survival were 47.3 and 42.1 %, respectively. OS was significantly correlated with R0 resection (P = 0.027), pathological response (P = 0.01), dissected pathologically positive lymph node (P = 0.037), and postsurgery (T) stage (P = 0.02). Toxicities were manageable and there were no treatment-related deaths. CONCLUSION: Docetaxel-based chemoradiotherapy in localized gastric adenocarcinoma patients resulted in 24 % path CR and was not associated with a higher percentage of postoperative complications. A well-designed randomized controlled trial is mandatory to further endorse this evolving approach. PMID- 23104210 TI - Predictors of adverse smoking outcomes in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. AB - BACKGROUND: The impact of lung cancer screening on smoking behavior is unclear. The aims of this ancillary study of the Prostate Lung Colorectal and Ovarian Cancer Screening Trial were to produce risk prediction models to identify individuals at risk of relapse or continued smoking and to evaluate whether cancer-screening variables affect long-term smoking outcomes. METHODS: Participants completed a baseline questionnaire at trial enrollment and a supplemental questionnaire 4-14 years after enrollment, which assessed several cancer-related variables, including family history of cancer, comorbidities, and tobacco use. Multivariable logistic regression models were used to predict smoking status at completion of the supplemental questionnaire. The models' predictive performances were evaluated by assessing discrimination via the receiver operator characteristic area under the curve (ROC AUC) and calibration. Models were internally validated using bootstrap methods. RESULTS: Of the 31 694 former smokers on the baseline questionnaire, 1042 (3.3%) had relapsed (ie, reported being a current smoker on the supplemental questionnaire). Of the 6807 current smokers on the baseline questionnaire, 4439 (65.2%) reported continued smoking on the supplemental questionnaire. Relapse was associated with multiple demographic, medical, and tobacco-related characteristics. This model had a bootstrap median ROC AUC of 0.862 (95% confidence interval [CI] = 0.858 to 0.866) and a calibration slope of 1.004 (95% CI = 0.978 to 1.029), indicating excellent discrimination and calibration. Predictors of continued smoking also included multiple demographic, medical, and tobacco-related characteristics. This model had an ROC AUC of 0.611 (95% CI = 0.605 to 0.614) and a slope of 1.006 (95% CI = 0.962 to 1.041), indicating modest discrimination. Neither the trial arm nor the lung-screening result was statistically significantly associated with smoking outcomes. CONCLUSION: These models, if validated externally, may have public health utility in identifying individuals at risk for adverse smoking outcomes, who may benefit from relapse prevention and smoking cessation interventions. PMID- 23104211 TI - Acceleration of gastric tumorigenesis through MKRN1-mediated posttranslational regulation of p14ARF. AB - BACKGROUND: We investigated whether Makorin ring finger protein 1 (MKRN1), an E3 ligase, affects p14ARF-associated cellular senescence and tumorigenesis by posttranslational modification in gastric tumorigenesis. METHODS: A link between MKRN1 and ARF was examined in MKRN1 null mouse embryonic fibroblasts (MEFs) and in human fibroblasts and gastric cancer cells by silencing MKRN1 using small interfering RNA (siRNA) and short hairpin RNA (shRNA). Ubiquitination and proteasomal degradation assays were used to assess p14ARF degradation associated with MKRN1. MKRN1 and p14ARF expression levels were analyzed with immunohistochemistry in malignant and normal tissues from gastric cancer patients and with chi(2) tests. The tumor growth of gastric cancer cells stably expressing MKRN1 shRNA, p14ARF shRNA, or both was examined in mouse xenograft models (n = 4 6) and analyzed with unpaired t tests. All statistical tests were two-sided. RESULTS: MKRN1 knockout MEFs exhibited premature senescence and growth retardation with increased p19ARF protein expression. Similar results were obtained for human fibroblasts or gastric cancer cell lines by MKRN1 knockdown. Biochemical analyses confirmed that MKRN1 targets p14ARF for ubiquitination and subsequent proteasome-dependent degradation. A statistically significant association was shown between MKRN1 overexpression and p14ARF underexpression (P = .016). Xenograft analyses using p53-functional AGS or -dysfunctional SNU601 cells displayed statistically significant tumor growth retardation by silencing MKRN1, which was reversed under depletion of p14ARF (AGS cells, MKRN1 knockdown tumors vs MKRN1 and p14ARF knockdown tumors: 164.6 vs 464.8mm(3), difference = 300.2mm(3), 95% CI = 189.1 to 411.3mm(3), P < .001). CONCLUSIONS: We demonstrated that MKRN1 functions as a novel E3 ligase of p14ARF and that it potentially regulates cellular senescence and tumorigenesis in gastric cancer. PMID- 23104213 TI - Combining molecular markers with the TNM staging system to improve prognostication in stage II and III colon cancer: are we ready yet? PMID- 23104212 TI - Integrated analysis of molecular and clinical prognostic factors in stage II/III colon cancer. AB - BACKGROUND: The prognostic potential of individual clinical and molecular parameters in stage II/III colon cancer has been investigated, but a thorough multivariable assessment of their relative impact is missing. METHODS: Tumors from patients (N = 1404) in the PETACC3 adjuvant chemotherapy trial were examined for BRAF and KRAS mutations, microsatellite instability (MSI), chromosome 18q loss of heterozygosity (18qLOH), and SMAD4 expression. Their importance in predicting relapse-free survival (RFS) and overall survival (OS) was assessed by Kaplan-Meier analyses, Cox regression models, and recursive partitioning trees. All statistical tests were two-sided. RESULTS: MSI-high status and SMAD4 focal loss of expression were identified as independent prognostic factors with better RFS (hazard ratio [HR] of recurrence = 0.54, 95% CI = 0.37 to 0.81, P = .003) and OS (HR of death = 0.43, 95% CI = 0.27 to 0.70, P = .001) for MSI-high status and worse RFS (HR = 1.47, 95% CI = 1.19 to 1.81, P < .001) and OS (HR = 1.58, 95% CI = 1.23 to 2.01, P < .001) for SMAD4 loss. 18qLOH did not have any prognostic value in RFS or OS. Recursive partitioning identified refinements of TNM into new clinically interesting prognostic subgroups. Notably, T3N1 tumors with MSI-high status and retained SMAD4 expression had outcomes similar to stage II disease. CONCLUSIONS: Concomitant assessment of molecular and clinical markers in multivariable analysis is essential to confirm or refute their independent prognostic value. Including molecular markers with independent prognostic value might allow more accurate prediction of prognosis than TNM staging alone. PMID- 23104214 TI - High-throughput sequencing set to enter patient care. PMID- 23104215 TI - A tale of two countries: lung cancer care in Brazil and China. PMID- 23104218 TI - Opening doors of perception: psychedelic drugs and end-of-life care. PMID- 23104219 TI - Prediction and characterization of novel polynuclear superalkali cations. AB - A series of polynuclear superalkali cations YLi(3)(+) (Y = O(2), CO(4), C(2)O(4), and C(2)O(6)) have been studied using ab initio method. The structural characters and stabilities of these systems are found to be related to the nature of the central cores. In the lowest-energy structure of the C(2)O(4)Li(3)(+) cations, the central group features a slight distortion. While in the global minima of O(2)Li(3)(+), CO(4)Li(3)(+) and C(2)O(6)Li(3)(+) cations, the central cores are divided into various units including one peroxo group (O(2)). These YLi(3)(+) (Y = O(2), CO(4), C(2)O(4), and C(2)O(6)) species exhibit very low vertical electron affinities of 3.01-3.85 eV (except one outlier in one of the O(2)Li(3)(+) species which lie much higher in energy than the most stable structure) and hence should be classified as superalkali cations, and the corresponding neutral species can be regarded as superalkalies. Such polynuclear superalkalies are candidates to the superatoms and offered potential building blocks for the assembly of new materials in which strong electron donors are involved. PMID- 23104222 TI - Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer. AB - We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0 %, respectively, odds ratio 0.70; 95 % CI: 0.5-1.0) and significantly shorter progression-free survival (PFS: median 112.0 days [3.7 months] vs. 150.0 days [4.9 months]; p < 0.0001) and overall survival (OS: median 396.0 days [13.0 months] vs. 666.0 days [21.9 months]; p < 0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p = 0.0036), PFS (p < 0.0001) and OS (p < 0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63 % of patients. Overall, 7 % of patients discontinued and two patients (<1 %) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p < 0.0001 PFS/OS) or diarrhea (p = 0.004 OS; p = 0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in line with previous phase III trials in MBC. PMID- 23104221 TI - Collaborative modeling of the impact of obesity on race-specific breast cancer incidence and mortality. AB - Obesity affects multiple points along the breast cancer control continuum from prevention to screening and treatment, often in opposing directions. Obesity is also more prevalent in Blacks than Whites at most ages so it might contribute to observed racial disparities in mortality. We use two established simulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate the impact of obesity on race-specific breast cancer outcomes. The models use common national data to inform parameters for the multiple US birth cohorts of Black and White women, including age- and race-specific incidence, competing mortality, mammography characteristics, and treatment effectiveness. Parameters are modified by obesity (BMI of >= 30 kg/m(2)) in conjunction with its age-, race-, cohort- and time-period-specific prevalence. We measure age standardized breast cancer incidence and mortality and cases and deaths attributable to obesity. Obesity is more prevalent among Blacks than Whites until age 74; after age 74 it is more prevalent in Whites. The models estimate that the fraction of the US breast cancer cases attributable to obesity is 3.9-4.5 % (range across models) for Whites and 2.5-3.6 % for Blacks. Given the protective effects of obesity on risk among women <50 years, elimination of obesity in this age group could increase cases for both the races, but decrease cases for women >= 50 years. Overall, obesity accounts for 4.4-9.2 % and 3.1-8.4 % of the total number of breast cancer deaths in Whites and Blacks, respectively, across models. However, variations in obesity prevalence have no net effect on race disparities in breast cancer mortality because of the opposing effects of age on risk and patterns of age- and race-specific prevalence. Despite its modest impact on breast cancer control and race disparities, obesity remains one of the few known modifiable risks for cancer and other diseases, underlining its relevance as a public health target. PMID- 23104223 TI - Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells? AB - Field cancerization effects as well as isolated tumor cell foci extending well beyond the invasive tumor margin have been described previously to account for local recurrence rates following breast conserving surgery despite adequate surgical margins and breast radiotherapy. To look for evidence of possible tumor cell contamination or field cancerization by genetic effects, a pilot study (Study 1: 12 sample pairs) followed by a verification study (Study 2: 20 sample pairs) were performed on DNA extracted from HER2-positive breast tumors and matching normal adjacent mammary tissue samples excised 1-3 cm beyond the invasive tumor margin. High-resolution molecular inversion probe (MIP) arrays were used to compare genomic copy number variations, including increased HER2 gene copies, between the paired samples; as well, a detailed histologic and immunohistochemical (IHC) re-evaluation of all Study 2 samples was performed blinded to the genomic results to characterize the adjacent normal tissue composition bracketing the DNA-extracted samples. Overall, 14/32 (44 %) sample pairs from both studies produced genome-wide evidence of genetic aberrations including HER2 copy number gains within the adjacent normal tissue samples. The observed single-parental origin of monoallelic HER2 amplicon haplotypes shared by informative tumor-normal pairs, as well as commonly gained loci elsewhere on 17q, suggested the presence of contaminating tumor cells in the genomically aberrant normal samples. Histologic and IHC analyses identified occult 25-200 MUm tumor cell clusters overexpressing HER2 scattered in more than half, but not all, of the genomically aberrant normal samples re-evaluated, but in none of the genomically normal samples. These genomic and microscopic findings support the conclusion that tumor cell contamination rather than genetic field cancerization represents the likeliest cause of local clinical recurrence rates following breast conserving surgery, and mandate caution in assuming the genomic normalcy of histologically benign appearing peritumor breast tissue. PMID- 23104224 TI - Epigenetic progression of columnar cell lesions of the breast to invasive breast cancer. AB - Promoter hypermethylation of several tumour suppressor genes often occurs during breast carcinogenesis, but little is known about epigenetic silencing in the possible precursor columnar cell lesion (CCL). Promoter hypermethylation of 50 different tumour suppressor genes was assessed in normal breast tissue (N = 10), CCL (N = 15), ductal carcinoma in situ (DCIS) grade I originating in CCL (N = 5) and paired CCL (N = 15) with DCIS (N = 7) and/or invasive carcinoma (N = 14) by Methylation-specific multiplex ligation-dependent probe amplification. Increasing mean cumulative methylation levels were found from normal breast tissue to CCL to DCIS and invasive carcinoma (P < 0.001) with similar methylation levels in DCIS and invasive carcinoma. Methylation levels and frequencies (in the overall analysis and analysis of only the synchronous lesions) were the highest for RASSF1, CCND2, ID4, SCGB3A1 and CDH13. The methylation levels of ID4, CCND2, and CDH13 increased significantly from normal breast tissue to CCL and to DCIS/invasive carcinoma. RASSF1, SCGB3A1 and SFRP5 had significant higher methylation levels in CCL compared to normal breast tissue, but showed no significant differences between CCL, DCIS and invasive carcinoma. Also, no difference was found between CCLs with and without atypia, or CCLs with or without synchronous cancer. In conclusion, promoter hypermethylation for several established tumour suppressor genes is already present in CCLs, underlining that promoter hypermethylation is an early event in breast carcinogenesis. Atypia in CCL or the presence of synchronous more advanced lesions does not seem to be accompanied by higher methylation levels. PMID- 23104225 TI - Racism, other discriminations and effects on health. AB - We study the probability of perceived racism/other forms of discrimination on immigrant and Spanish populations within different public spheres and show their effect on the health of immigrants using a cross-sectional design (ENS-06). VARIABLES: perceived racism/other forms of discrimination (exposure), socio demographic (explicative), health indicators (dependent). Frequencies, prevalences, and bivariate/multivariate analysis were conducted separately for men (M) and women (W). We estimated the health problems attributable to racism through the population attributable proportion (PAP). Immigrants perceived more racism than Spaniards in workplace (ORM = 48.1; 95% CI 28.2-82.2), and receiving health care (ORW = 48.3; 95% CI 24.7-94.4). Racism and other forms of discrimination were associated with poor mental health (ORM = 5.6; 95% CI 3.9 8.2; ORW = 7.3; 95% CI 4.1-13.0) and injury (ORW = 30.6; 95% CI 13.6-68.7). It is attributed to perceived racism the 80.1% of consumption of psychotropics (M), and to racism with other forms of discrimination the 52.3% of cases of injury (W). Racism plays a role as a health determinant. PMID- 23104226 TI - Objectification and quantification of the cognitive impairment from an existing HIV infection or HIV encephalopathy using magnetic resonance spectroscopy. AB - Some patients with HIV develop dementia. Using in vivo proton nuclear magnetic resonance ((1)H-NMR) spectroscopy, it is possible to measure the metabolic changes noninvasively. In this study, it is of interest to answer the clinically relevant question of whether magnetic resonance spectroscopy is suitable for the diagnosis of HIV encephalopathy. In total, 14 HIV-positive patients were investigated by means of localized (1)H-NMR spectroscopy in the following locations: (1) the mid-parietal gray matter, (2) the parietal white matter (PWM), and (3) the frontal white matter. All patients had no other brain diseases, apart from the HIV encephalopathy. The clinical extent of HIV encephalopathy of each patient was investigated using the following tests: (1) an electroencephalogram, (2) a neurological examination and psychiatric assessment, and (3) a psychometrical test. The spectroscopic changes in the PWM were more pronounced than those in the cortex, and the myo-inositol/creatine (mI/Cr) signal showed a clear increase in the cortex. Overall, the mI/Cr ratio emerged as the most reliable and earliest parameter to indicate an HIV encephalopathy. PMID- 23104227 TI - Water consumption, not expectancies about water consumption, affects cognitive performance in adults. AB - Research has shown that water supplementation positively affects cognitive performance in children and adults. The present study considered whether this could be a result of expectancies that individuals have about the effects of water on cognition. Forty-seven participants were recruited and told the study was examining the effects of repeated testing on cognitive performance. They were assigned either to a condition in which positive expectancies about the effects of drinking water were induced, or a control condition in which no expectancies were induced. Within these groups, approximately half were given a drink of water, while the remainder were not. Performance on a thirst scale, letter cancellation, digit span forwards and backwards and a simple reaction time task was assessed at baseline (before the drink) and 20 min and 40 min after water consumption. Effects of water, but not expectancy, were found on subjective thirst ratings and letter cancellation task performance, but not on digit span or reaction time. This suggests that water consumption effects on letter cancellation are due to the physiological effects of water, rather than expectancies about the effects of drinking water. PMID- 23104228 TI - Polymerization of miniature fullerenes in the cavity of nanotubes. AB - The polymerization of four fullerenes C(28) in the cavity of closed single-walled carbon nanotube C(740) was investigated. It was shown that the formation of the oligomer of four C(28) fullerenes is observed at the pressure of 37.73 GPa, which is created by means of the charged fullerene C(60). Fullerene C(60) moves under the influence of an external electric field. PMID- 23104229 TI - Drug permeability prediction using PMF method. AB - Drug permeability determines the oral availability of drugs via cellular membranes. Poor permeability makes a drug unsuitable for further development. The permeability may be estimated as the free energy change that the drug should overcome through crossing membrane. In this paper the drug permeability was simulated using molecular dynamics method and the potential energy profile was calculated with potential of mean force (PMF) method. The membrane was simulated using DPPC bilayer and three drugs with different permeability were tested. PMF studies on these three drugs show that doxorubicin (low permeability) should pass higher free energy barrier from water to DPPC bilayer center while ibuprofen (high permeability) has a lower energy barrier. Our calculation indicates that the simulation model we built is suitable to predict drug permeability. PMID- 23104230 TI - The effects of a mid-winter 8-week course of sub-sunburn sunbed exposures on tanning, vitamin D status and colds. AB - Like UV irradiation, which generates vitamin D(3) in the skin, the hormonally active metabolite, 1,25-dihydroxyvitamin D(3), boosts innate immunity against viruses and bacteria. Epidemiologic studies have found high vitamin D levels to be associated with lower risk of infections of the upper respiratory tract (colds). We have therefore performed an intervention study in 105 young adults (ages 18-30 years; 91% female) over a mid-winter 8-week period (January-March 2010). The participants were randomised to 3 groups: (A) subjected to 3 times a week sub-sunburn sunbed exposure (n = 35), (B) daily vitamin D supplementation, @ 1000 IU (n = 37), and (C) a control group without any intervention (n = 33). The mean serum level of 25-hydroxyvitamin D (25(OH)D) dropped from 62 to 55 nmol l( 1) in group C, while these levels rose from 62 to 109 and from 58 to 93 nmol l( 1) in groups A and B, respectively (p < 0.001). The skin on the chest darkened significantly in group A (mean difference in lightness, L*, equalled -5.7, p < 0.001), correlating significantly, but weakly, with increases in 25(OH)D (3.3 nmol l(-1) per unit drop in L*, R(2) = 0.17, p = 0.014). The percentage of self reported colds with proper signs and symptoms was only slightly and not significantly reduced in groups A and B in comparison to group C: 57 and 51 versus 67%, respectively. Hence, the sub-sunburn sunbed treatment was effective in tanning and increasing the 25(OH)D serum level, more so than 1000 IU per day, but had no appreciable effect on colds. PMID- 23104231 TI - Tandem catalysis with a bifunctional site-isolated Lewis acid-Bronsted base metal organic framework, NH2-MIL-101(Al). AB - A metal-organic framework (MOF), NH(2)-MIL-101(Al), which acts as a bifunctional, site-isolated Lewis acid-Bronsted base heterogeneous catalyst, catalyzes a tandem Meinwald rearrangement-Knoevenagel condensation reaction with remarkable substrate selectivity. PMID- 23104233 TI - Engineering molecular chains in carbon nanotubes. AB - A range of mono- and bis-functionalised fullerenes have been synthesised and inserted into single-walled carbon nanotubes. The effect of the size and shape of the functional groups of the fullerenes on the resultant 1D arrays formed within the nanotubes was investigated by high resolution transmission electron microscopy and X-ray diffraction. The addition of non-planar, sterically bulky chains to the fullerene cage results in highly ordered 1D structures in which the fullerenes are evenly spaced along the internal nanotube cavity. Theoretical calculations reveal that the functional groups interact with neighbouring fullerene cages to space the fullerenes evenly within the confines of the nanotube. The addition of two functional groups to opposite sides of the fullerene cages results in a further increase in the separation of the fullerene cages within the nanotubes at the cost of lower nanotube filling rates. PMID- 23104232 TI - Fluorescence molecular painting of enveloped viruses. AB - In this study, we describe a versatile, flexible, and quick method to label different families of enveloped viruses with glycosylphosphatidylinositol modified green fluorescent protein, termed fluorescence molecular painting (FMP). As an example for a potential application, we investigated virus attachment by means of flow cytometry to determine if viral binding behavior may be analyzed after FMP of enveloped viruses. Virus attachment was inhibited by using either dextran sulfate or by blocking attachment sites with virus pre-treatment. Results from the FMP-flow cytometry approach were verified by immunoblotting and enzyme linked immunosorbent assay. Since the modification strategy is applicable to a broad range of proteins and viruses, variations of this method may be useful in a range of research and applied applications from bio-distribution studies to vaccine development and targeted infection for gene delivery. PMID- 23104234 TI - Electrochemical behavior and dioxygen reactivity of tripodal dinuclear copper complexes linked by unsaturated rigid spacers. AB - New dinucleating ligands based on two tripodal tris(2-pyridylmethyl)amine (TMPA) units linked by a series of delocalized pi-electrons spacers have been synthesized. Their di-Cu(II) complexes have been prepared and structurally characterized. As compared to the corresponding monotopic complexes, these dinuclear Cu(II) complexes reveal spectroscopic and voltammetric features ascribable to weakly perturbed electronic interactions. In the case of the anthracenyl spacer, observation both in the solid and in solution suggests that the existence of intramolecular pi-pi stacking interactions influences the geometry of the complex and hence its electronic properties. The bis-Cu(I) complexes were prepared electrochemically. In the specific case of the complex bearing a mono-alkyne spacer, addition of dioxygen in acetonitrile leads to the slow formation of a trans-MU-1,2 peroxo Cu(2) complex which shows good stability at 268 K (t(1/2) = 240 s). Analysis of the kinetics of the peroxo formation by UV vis spectroscopy suggests that the increased activation barrier for intramolecular binding of dioxygen is due to the rigidity of the spacer. PMID- 23104235 TI - Rationale in support of the use of selective dopamine D3 receptor antagonists for the pharmacotherapeutic management of substance use disorders. AB - Growing evidence indicates that dopamine (DA) D(3) receptors are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders. First, DA D(3) receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse has been shown to produce neuroadaptations in the DA D(3) system. Third, the synthesis and characterization of highly potent and selective DA D(3) receptor antagonists has permitted to further define the role of the DA D(3) receptor in drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D(3) receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in the reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior, or stress. PMID- 23104236 TI - Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin-proteasome pathway. AB - We previously generated a cytochrome P450 4F2 (CYP4F2) transgenic mouse model and demonstrated that overexpressed CYP4F2 and overproduced 20-HETE in the kidneys contribute to the increase of blood pressure in the CYP4F2 transgenic mice with normal salt intake. We currently expect to elucidate a potential mechanism of salt-related hypertension whereby diverse levels of 20-HETE interact with dietary salt on Na(+)-K(+)-2Cl(-) cotransporter, isoform 2 (NKCC2) in the kidneys of the transgenic and wild-type mice with high salt intake. High salt intake reduced about 85 % abundance of renal NKCC2 protein in the transgenic mice and about 24 % in the wild-type mice by Western blot. Furthermore, we first found that NKCC2 was ubiquitinated and interacted with Nedd4-2 by immunoprecipitation in the transgenic mice with high salt intake. In addition, inhibition of 20-HETE synthesis or proteasome activity reversed the reduction of NKCC2 expression induced by 20-HETE and high salt intake. These results suggest that 20-HETE and high salt intake synergistically decrease the expression of NKCC2 protein via Nedd4-2-mediated ubiquitin-proteasome pathway, and thereby modulate natriuresis and blood pressure. We propose that diverse levels of 20-HETE have diverse effects on blood pressure in different salt concentrations. PMID- 23104237 TI - Surface sensing and settlement strategies of marine biofouling organisms. AB - This review article summarizes some recent insights into the strategies used by marine organisms to select surfaces for colonization. While larger organisms rely on their sensory machinery to select surfaces, smaller microorganisms developed less complex but still effective ways to probe interfaces. Two examples, zoospores of algae and barnacle larvae, are discussed and both appear to have build-in test mechanisms to distinguish surfaces with different physicochemical properties. Some systematic studies on the influence of surface cues on exploration, settlement and adhesion are summarized. The intriguing notion that surface colonization resembles a parallelized surface sensing event is discussed towards its complementarity with conventional surface analytical tools. The strategy to populate only selected surfaces seems advantageous as waves, currents and storms constantly challenge adherent soft and hard fouling organism. PMID- 23104238 TI - A new locally weighted K-means for cancer-aided microarray data analysis. AB - Cancer has been identified as the leading cause of death. It is predicted that around 20-26 million people will be diagnosed with cancer by 2020. With this alarming rate, there is an urgent need for a more effective methodology to understand, prevent and cure cancer. Microarray technology provides a useful basis of achieving this goal, with cluster analysis of gene expression data leading to the discrimination of patients, identification of possible tumor subtypes and individualized treatment. Amongst clustering techniques, k-means is normally chosen for its simplicity and efficiency. However, it does not account for the different importance of data attributes. This paper presents a new locally weighted extension of k-means, which has proven more accurate across many published datasets than the original and other extensions found in the literature. PMID- 23104239 TI - Preface to the supplement issue on New Trends on Biomedical Knowledge Acquisition and Information Processing Systems. PMID- 23104240 TI - An assessment of patient behavior over time-periods: a case study of managing type 2 diabetes through blood glucose readings and insulin doses. AB - This paper focuses on assessing the behavior of a patient over time periods for managing type 2 Diabetes. In some cases, patients with type 2 diabetes not only behave differently from other patients, but the severity of a given health problem varies even for an individual patient. We focus on understanding how and when patients differ from other patients. In addition, we also look at the diversity that exists within an individual patient especially over time-periods throughout the day. Our aim is to identify such time intervals when a patient may need more targeted care. Thus, for type 2 Diabetes we identify which time-periods exhibit a mismatch in terms of the blood glucose readings and the insulin doses. For instance, if the blood glucose readings fluctuate and the insulin doses are fixed it may indicate a poor management of the insulin doses and therefore a poor management of Diabetes. Based on such findings a number of factors can be taken into consideration when drawing out a care plan for example diet, lifestyle, and type of treatment, among others. Our study uses a data mining approach, particularly clustering to study the measurements in blood glucose and doses of regular insulin for a selected number of patients. We look at their behavior on an overall days' basis, which we refer to as large-scale binning. Additionally, we study their behavior at specified time intervals throughout the day, which we refer to as small-scale binning. Our findings indicate that we are clearly able to see the trends in blood glucose readings as compared to the insulin doses for different patients indicating a well managed or a poorly managed plan. PMID- 23104241 TI - Clinical predictors of serum clozapine levels in patients with treatment resistant schizophrenia. AB - Fixed oral doses of clozapine produce up to 45-fold interindividual variability among its serum levels in patients with treatment-resistant schizophrenia. Although the relationship between serum clozapine level and its therapeutic response is uncertain, the presence of a therapeutic window and level-dependent adverse effects require the estimation of serum clozapine levels. As routine therapeutic drug monitoring of clozapine is not feasible in many clinical settings, identification of clinical predictors of serum clozapine levels is desirable. Hence, we aimed to evaluate the clinical variables associated with serum clozapine levels. We assessed the sociodemographic and clinical profiles, cognition, disability and psychopathology of 101 consecutive patients with treatment-resistant schizophrenia on a stable dose of clozapine, using standard assessment schedules. We determined their serum clozapine levels using high performance liquid chromatography with ultraviolet detection. While employing multivariate robust regression models, oral clozapine dose (P<0.001), caffeine intake (P=0.04) and Valproate comedication (P=0.005) were associated with serum clozapine levels. Serum clozapine levels above 750 ng/ml increased the risk of seizures (odds ratio 5.15; P=0.03). Clinical variables are useful to model a dosing nomogram for serum clozapine levels. The importance of caffeine consumption and Valproate comedication should be considered during clozapine dose adjustments to enhance its therapeutic response and safety profile. PMID- 23104243 TI - Response to comment: "A note on the relevance of [6]-gingerol for the prevention and/or treatment of Alzheimer's disease". PMID- 23104242 TI - An immortalized human blood-nerve barrier endothelial cell line for in vitro permeability studies. AB - Solute and macromolecular transport studies may elucidate nutritional requirements and drug effects in healthy and diseased peripheral nerves. Endoneurial endothelial cells are specialized microvascular cells that form the restrictive blood-nerve barrier (BNB). Primary human endoneurial endothelial cells (pHEndECs) are difficult to isolate, limiting their widespread availability for biomedical research. We developed a simian virus-40 large T-antigen (SV40 LTA) immortalized human BNB cell line via stable transfection of low passage pHEndECs and observed continuous growth in culture for >45 population doublings. As observed with pHEndECs, the immortalized BNB endothelial cells were Ulex Europaeus agglutinin-1-positive and endocytosed low density lipoprotein, but lost von Willebrand factor expression. Glucose transporter-1, P-glycoprotein (P-gp), gamma-glutamyl transpeptidase (gamma-GT), large neutral amino acid transporter-1 (LAT-1), creatine transporter (CRT), and monocarboxylate transporter-1 (MCT-1) mRNA expression were retained at all passages with loss of alkaline phosphatase (AP) expression after passages 16-20. Compared with an SV40-LTA immortalized human blood-brain barrier endothelial cell line, there was increased gamma-GT protein expression, equivalent expression of organic anion transporting polypeptide-C (OATP-C), organic anion transporter 3 (OAT-3), MCT-1, and LAT-1, and reduced expression of AP, CRT, and P-gp by the BNB cell line at passage 20. Further studies demonstrated lower transendothelial electrical resistance (~181 vs. 191 Omega cm(2)), equivalent permeability to fluoresceinated sodium (4.84 vs. 4.39 %), and lower permeability to fluoresceinated high molecular weight (70 kDa) dextran (0.39 vs. 0.52 %) by the BNB cell line. This cell line retained essential molecular and biophysical properties suitable for in vitro peripheral nerve permeability studies. PMID- 23104244 TI - Cytochrome P450-mediated herb-drug interaction potential of Galgeun-tang. AB - We evaluated the herb-drug interaction potential of Galgeun-tang (GGT) extracts, mediated by cytochrome P450 (CYP) inhibition/induction. Further, the effects of fermentation on the CYP-mediated herb-drug interaction potential of GGT extracts were determined. As measured by LC-ESI/MS/MS, GGT extracts (0-300MUg/mL) showed no inhibitory activity toward eight CYP isoforms (1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, and 3A4) in pooled human liver microsomes, suggesting that GGT may have low potential for herb-drug interactions mediated by CYP inhibition. Hepatic CYP expression and activity in rats treated with GGT extracts twice per day for 1week was examined. Among the tested CYP isoforms (1A1, 1A2, 1B1, 2B1, 2C11, 2E1, 3A1, 3A2, and 4A1), CYP1B1 and 4A1 were increased by GGT extracts. Hepatic activities of 7-ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase, but not midazolam hydroxylase were also elevated. These results raise the possibility that GGT extracts may increase the toxicity of environmental toxicants through the elevating CYP-dependent metabolic activation. Interestingly, the increases in CYP1B1 and CYP4A1 levels, and 7 ethoxyresorufin-O-deethylase, 7-pentoxyresorufin-O-depentylase, and chlorzoxazone 6-hydroxylase activities were attenuated by fermentation of GGT extract using Lactobacillus plantarum KFRI 402, but not 144. Further studies are needed to identify the CYP regulatory component(s) from GGT and determination its metabolism. PMID- 23104245 TI - Comparative study of equimolar doses of gamma-hydroxybutyrate (GHB), 1,4 butanediol (1,4-BD) and gamma-butyrolactone (GBL) on catalepsy after acute and chronic administration. AB - Gamma-hydroxybutyrate (GHB), and its precursors 1,4-butanediol (1,4-BD) and gamma butyrolactone (GBL) are known drugs of abuse. The ability of acute and chronic administration of equimolar doses of GHB (200mg/kg), 1,4-BD (174mg/kg) and GBL (166mg/kg) to produce catalepsy in male Swiss Webster mice was examined. GHB, 1,4 BD, GBL produced catalepsy when injected acutely. Drug treatment was then continued for 14days. Tolerance development was determined on days 6, 14, and challenged with a higher dose on day 15 in those chronically pretreated mice, and compared with naive mice. Chronic GHB produced tolerance to catalepsy, as evidenced from area under the curve (AUC) of catalepsy versus time (min-sec) on days 6 (678+/-254), 14 (272+/-247), which were less than those on day 1 (1923+/ 269). However, less tolerance was seen from GBL or 1,4-BD, as AUCs on days 6 and 14 were not significantly lower than that of day 1. In conclusion, although equimolar doses were used, expecting similar levels of GHB in the body, 1,4-BD and GBL shared only some of the in vivo effects of GHB. The rate of metabolic conversion of 1,4-BD and GBL into GHB might be responsible for the differences in the tolerance development to these drugs. PMID- 23104246 TI - Dietary exposure to inorganic arsenic of the Hong Kong population: results of the first Hong Kong total diet study. AB - Inorganic arsenic, a human carcinogen, can be found in the environment and food. In the first Hong Kong Total Diet Study, the dietary exposure of the Hong Kong people, including various age-gender subgroups, to inorganic arsenic was estimated for assessing the associated health risk. Food samples, which represented the Hong Kong people's diet, were collected and prepared "as consumed" for analysis. Concentrations of inorganic arsenic, as sum of arsenite (As(III)) and arsenate (As(V)) were determined in 600 composite samples by using inductively coupled plasma mass spectrometry. The dietary exposures were estimated by combining the analytical results with the local food consumption data of the adult population. The mean and 95th percentile of inorganic arsenic exposures of the Hong Kong people were 0.22 and 0.38MUg/kg body weight (bw)/day, respectively. Among the 12 age-gender subgroups, the respective exposures ranged from 0.19 to 0.26MUg/kg bw/day and from 0.33 to 0.46MUg/kg bw/day. The main food category that contributed inorganic arsenic was "cereals and their products" (53.5% of the total exposure), particularly rice. Having considered the carcinogenic risk of inorganic arsenic to humans, it is suggested that efforts should be made to reduce the inorganic arsenic exposure of the Hong Kong population. PMID- 23104247 TI - Effects of Korean red ginseng extracts on neural tube defects and impairment of social interaction induced by prenatal exposure to valproic acid. AB - Ginseng is one of the most widely used medicinal plants, which belongs to the genus Panax. Compared to uncured white ginseng, red ginseng has been generally regarded to produce superior pharmacological effects with lesser side/adverse effects, which made it popular in a variety of formulation from tea to oriental medicine. Using the prenatal valproic acid (VPA)-injection model of autism spectrum disorder (ASD) in rats, which produces social impairrment and altered seizure susceptibility as in human ASD patients as well as mild neural tube defects like crooked tail phenotype, we examined whether chronic administration of red ginseng extract may rescue the social impairment and crooked tail phenotype in prenatally VPA-exposed rat offspring. VPA-induced impairment in social interactions tested using sociability and social preference paradigms as well as crooked tail phenotypes were significantly improved by administration of Korean red ginseng (KRG) in a dose dependent manner. Rat offspring prenatally exposed to VPA showed higher sensitivity to electric shock seizure and increased locomotor activity in open-field test. KRG treatment reversed abnormal locomotor activity and sensitivity to electric shock to control level. These results suggest that KRG may modulate neurobehavioral and structural organization of nervous system adversely affected by prenatal exposure to VPA. PMID- 23104249 TI - Harmful effects of viral replication in seropositive hepatitis C virus renal transplant recipients. AB - BACKGROUND: Seropositivity for hepatitis C virus (HCV) predicts lower patient and graft survival after renal transplantation (RT). However, the influence of viral replication at transplantation on long-term outcome remains to be determined. METHODS: This was a retrospective study conducted in four Spanish hospitals, from 1997 to 2006. Data of all patients with RT, who displayed HCV+ (enzyme-linked immunosorbent assay), and with negative viremia at RT (NEG group) were collected (n=41). For each NEG patient enrolled, data of two patients with RT nearest in time, HCV+, and positive viremia (POS group) were also collected (n=78). RESULTS: The POS group showed a higher incidence of long-term liver disease (56.4% vs. 24.4%, P=0.0009) and episodes of transaminase elevation (38.5% vs. 7.3%, P=0.0003) and worse renal function (serum creatinine [sCr], 3.0 [2.7] vs. 1.9 [1.6] mg/dl, P=0.032; glomerular filtration rate, 43.7 [22.4] vs. 56.9 [27.9] ml/min, P=0.075). Noteworthy, 24.4% of NEG patients reactivated after RT, showing a worse patient survival (P=0.039). Active viral replication at RT and dialysis requirement in the first week remained as independent predictors of lower graft survival (death censored): hazards ratio, 3.11 (95% confidence interval, 1.34 7.19; P=0.009) and hazards ratio 3.13 (95% confidence interval, 1.53-6.37; P=0.002). CONCLUSIONS: This study shows that active viral replication at transplantation is an independent risk factor for graft failure in patients with positive serology for HCV. PMID- 23104248 TI - Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. AB - The lipoprotein receptor ligand Reelin is important for the processes of normal synaptic plasticity, dendritic morphogenesis, and learning and memory. Heterozygous reeler mice (HRM) show many neuroanatomical, biochemical, and behavioral features that are associated with schizophrenia. HRM show subtle morphological defects including reductions in dendritic spine density, altered synaptic plasticity and behavioral deficits in associative learning and memory and pre-pulse inhibition. The present studies test the hypothesis that in vivo elevation of Reelin levels can rescue synaptic and behavioral phenotypes associated with HRM. We demonstrate that a single in vivo injection of Reelin increases GAD67 expression and alters dendritic spine morphology. In parallel we observed enhancement of hippocampal synaptic function and associative learning and memory. Reelin supplementation also increases pre-pulse inhibition. These results suggest that characteristics of HRM, similar to those observed in schizophrenia, are sensitive to Reelin levels and can be modified with Reelin supplementation in male and female adults. PMID- 23104250 TI - Heart rate after cardiac transplantation-lessons from the tortoise and the shrew. AB - There is a striking consistency in the total number of heart beats accrued over a lifetime across a range of animal species despite vast differences in size. Moreover, an inverse relationship is observed between heart rate and lifespan, leading to speculation that elevated heart rate could significantly affect longevity. It is the aim of this review to analyze heart rate as a contributing factor in defining the functional lifespan of the transplanted human heart, which may unavoidably determine the longevity of the recipient. Sinus tachycardia occurs as a result of sympathetic/parasympathetic denervation, an unavoidable consequence of transplantation. The effect of elevated heart rate in this cohort has been scarcely reported. We highlight herein multitudinous mechanisms whereby elevated heart rate accelerates the deterioration in cardiac function and arterial elasticity due to injury and stress accumulation. Additionally, we propose a significant role for heart rate in confounding the alloimmune response. Tachycardia exacerbates injurious episodes of myocardial ischemia and significantly increases the production of reactive oxygen species via increased metabolism. These factors promote immune infiltration and activation, contributing to acute and chronic rejection. Further research is required to assess the potential therapeutic benefits of heart rate reduction. PMID- 23104251 TI - Treatment of cytomegalovirus disease in solid organ transplant recipients: markers of inflammation as predictors of outcome. AB - BACKGROUND: Treatment failure or relapse is common in solid organ transplant recipients treated for cytomegalovirus (CMV) disease. Because CMV infections induce a vigorous inflammatory response, we investigated whether pretreatment levels of inflammatory markers were associated with virologic and clinical outcomes. METHODS: Solid organ transplant recipients enrolled in an international multicenter trial of CMV disease treatment (the VICTOR study) were studied (n=248). Plasma levels of markers of inflammation and endothelial cell activation were assessed at baseline and during follow-up by enzyme immunoassays. RESULTS: Baseline values for the chemokine CXCL16 was an independent predictor of clinical outcome (P=0.003) and was a weak independent predictor of suppression of viral load below level of detection (LOD) (P=0.013) at day 21 after initiation of treatment. Baseline levels of the long pentraxin 3 (PTX3) was an independent predictor of suppression of viral load below LOD at day 21 (P=0.002), whereas baseline levels of von Willebrand factor (vWF) was an independent predictor of clinical outcome at day 21 (P=0.008), and vWF levels at day 21 was a weak independent inflammatory predictor of viral recurrence (P=0.018). CONCLUSIONS: The present study shows that the plasma levels of CXCL16, PTX3 and vWF at the start of treatment are independently associated with virologic and clinical treatment failure during anti-CMV therapy in solid organ transplant recipients. These findings suggest a link between CMV infection and inflammation that also may influence the outcome of anti-CMV therapy. PMID- 23104252 TI - Reactions of 3-acylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3 diphenylacetone: one-pot synthesis of functionalized 2-hydroxybenzophenones, 6H benzo[c]chromenes and benzo[c]coumarins. AB - Reactions of 3-methoxalyl-, 3-polyfluoroacyl- and 3-aroylchromones with dimethyl 1,3-acetonedicarboxylate and 1,3-diphenylacetone in the presence of DBU proceed at the C-2 atom of the chromone system with pyrone ring-opening and subsequent formal [3 + 3] cyclocondensation to functionalized 2-hydroxybenzophenones, 6H benzo[c]chromenes and benzo[c]coumarins, depending on the substituent at the 3 position. An NMR study and X-ray crystallographic analysis are reported. The compounds synthesized can be considered as promising scaffolds for the design of the novel UV-A/B and UV-B filters. PMID- 23104253 TI - Mesenchymal stem cells promote a primitive phenotype CD34+c-kit+ in human cord blood-derived hematopoietic stem cells during ex vivo expansion. AB - The purpose of this study was to evaluate the influence of bone marrow mesenchymal stem cells (BM-MSC) and exogenously added cytokines on the proliferation, primitive cell subpopulation maintenance (including the c-kit+ marker) and clonogenic capacity of hematopoietic stem cells (HSC). BM-MSC were collected from volunteer donors, isolated and characterized. Umbilical cord blood (UCB) samples were collected from healthy full-term deliveries. UCB-CD34+ cells were cultured in the presence or absence of BM-MSC and/or cytokines for 3 and 7 days. CD34+ cell proliferation was evaluated using the CSFE method and cell phenotype was determined by CD34, c-kit, CD33, CD38, HLA-DR, cyCD22 and cyCD3 detection. Cell clonogenic ability was also assessed. Exogenously added SCF, TPO and FLT3L increased CD34+ cell proliferation in the presence or absence of BM MSC, but with concomitant cell differentiation. Without any added cytokines, BM MSC are able to increase the percentage of primitive progenitors as evaluated by c-kit expression and CFU-GEMM increase. Interestingly, this latter effect was dependent on both cell-cell interactions and secreted factors. A 7-day co-culture period will be optimal for obtaining an increased primitive HSC level. Including c-kit as a marker for primitive phenotype evaluation has shown the relevance of BM-MSC and their secreted factors on UCB-HSC stemness function. This effect could be dissociated from that of the addition of exogenous cytokines, which induced cellular differentiation instead. PMID- 23104254 TI - Teeth in the line of mandibular fractures. AB - PURPOSE: This study aims to review the literature regarding the evolution of current thoughts on the management of teeth in the line of mandibular fractures (MFs). METHODS: An electronic search in PubMed was undertaken in June 2012. The titles and abstracts from these results were read to identify studies within the selection criteria-studies reporting clinical series of MFs in which the management of teeth in the fracture line was analyzed. RESULTS: The search strategy initially yielded 731 references. Twenty-seven studies were identified without repetition within the selection criteria. Additional hand searching yielded 12 additional papers. CONCLUSIONS: It is suggested that rigid fixation systems and the use of antimicrobial agents have reduced the incidence of infection in cases of teeth in the line of MFs. Tooth buds in the line of MFs should not be removed or replaced in the (alleged) proper position despite the degree of displacement, since studies showed that even tooth buds in the early stage of calcification and those involved in widely displaced fracture sites continued development and erupted. Its removal should be considered in cases of infection, which is a predictive factor of abnormality and/or impaction. Intact teeth in the fracture line should be left in situ if they show no evidence of severe loosening or inflammatory change. Permanent teeth maintained in the line of fracture should be followed up clinically and radiographically for at least 1 year to ensure that any unnecessary endodontic treatment is avoided. Teeth in the line of fracture that prevents reduction of fractures, teeth with fractured roots, a partially impacted wisdom tooth with pericoronitis, and a tooth with extensive periapical lesion should be removed. Teeth in the line of MFs should also be removed when located in sites where there is extensive periodontal damage, with broken alveolar walls, resulting in the formation of a deep pocket (making optimal healing doubtful). PMID- 23104255 TI - Multidisciplinary intensive care in extensive necrotizing fasciitis. AB - This is a case report of extensive necrotizing fasciitis (NF). A 65-year-old man presented with high fever, pain, swelling, and redness of the perineum, scrotum, and right lower limb. Based on the clinical symptoms and an imaging examination, a diagnosis of NF was made. The patient underwent an extensive exploration followed by daily bedside debridement. A diversion colostomy and six additional debridement procedures on the right thigh and perineum were subsequently performed. Although the patient had an eventful course, he recovered well under a multidisciplinary treatment regimen. The treatment and hospital course of the patient are described. PMID- 23104256 TI - Tularemia in central Anatolia. AB - BACKGROUND: Tularemia is a bacterial zoonosis with diverse clinical manifestations depending on bacterial subspecies and the route of the infection. METHODS: We collected data prospectively of cases diagnosed and treated for tularemia in our institution during the epidemics from December 2009 to August 2011. Specific antibodies were screened by a microagglutination test. Throat swab and lymph node aspirate cultures were obtained and polymerase chain reaction (PCR) was performed on these specimens. Lymph nodes were characterized on the basis of ultrasound reports. RESULTS: A total of 139 patients were confirmed with tularemia. The age range of the patients was 6-83 years (mean: 43) and 84 (60.4 %) of them were females. Patients had clinical presentations compatible with oropharyngeal (74 %), glandular (15.8 %), and oculoglandular (5.0 %) tularemia. Ultrasonography (US) was performed in 108 patients. Antibiotics (aminoglycosides, quinolones, and doxycycline) were used in 138 patients. Fine-needle aspiration (FNA) or surgical drainage of fluctuant lymph nodes were performed in 51 (39 %) patients. Therapeutic failure was observed in 43 (30.9 %) patients. Elevation of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were observed to be significantly higher in patients with therapeutic failures (p = 0.003 and 0.004, respectively). The success rate was significantly higher in patients with early treatment (p = 0.004). No difference was found between the effectiveness of aminoglycoside or quinolone treatments. The increase in the short and long axes, and the characteristics of lymph nodes detected on US were significantly associated with treatment failures (p < 0.001). Intranodal necrosis was found in 45 patients. The treatment success rate was 40 % in patients with intranodal necrosis. CONCLUSION: To the best of our knowledge, this is the first study defining the US findings of patients with tularemia and its association with treatment success. Ciprofloxacin is an effective and convenient choice in epidemics of tularemia and early treatment is still the cornerstone of successful therapies. PMID- 23104257 TI - Conversion rates of an interferon-gamma release assay and the tuberculin skin test in the serial monitoring of healthcare workers. AB - PURPOSE: Regular monitoring of latent tuberculosis (TB) infection in healthcare workers (HCWs) is recommended, but the view about the effective method and performance of serial monitoring is controversial. The aim of this study was to determine differences in conversion rates according to TB exposure risk using the tuberculin skin test (TST) and the QuantiFERON-TB Gold In-Tube (QFT-GIT), and to evaluate the reproducibility and within-subject variability of the QFT-GIT in South Korea. METHODS: Fifty-three HCWs were grouped according to their risk for TB exposure: group 1, high risk (n = 21); group 2, low risk (n = 32). Baseline and follow-up TSTs and QFT-GITs were performed from June 2009 to July 2011. Enzyme-linked immunosorbent assays (ELISAs) were repeated for the second QFT-GIT and a third QFT-GIT was performed after 8 weeks when discordant results of the second TST and QFT-GIT or a conversion or reversion were observed. RESULTS: No difference in the QFT-GIT conversion rate was evident between the two groups (15.4 vs. 6.5 %, p = 0.57), and no TST conversion was observed. The rate of QFT GIT positivity was higher in the high-risk group (first QFT-GIT: 38.1 vs. 3.1 %, p = 0.002; second QFT-GIT: 33.3 vs. 9.4 %, p = 0.039). The re-test reproducibility of QFT-GIT results was high (100 %), and the within-subject results of repetitive QFT-GITs were variable. CONCLUSIONS: Stricter prevention strategies remain necessary in HCWs at high risk of TB exposure, and serial interferon-gamma release assays (IGRAs) should be interpreted with caution in HCWs. PMID- 23104258 TI - Selectivity of bis-triazinyl bipyridine ligands for americium(III) in Am/Eu separation by solvent extraction. Part 1. Quantum mechanical study on the structures of BTBP complexes and on the energy of the separation. AB - Theoretical studies were carried out on two pairs of americium and europium complexes formed by tetra-N-dentate lipophilic BTBP ligands, neutral [ML(NO(3))(3)] and cationic [ML(2)](3+) where M = Am(III) or Eu(III), and L = 6,6'-bis-(5,6-diethyl-1,2,4-triazin-3-yl)-2,2'-bipyridine (C2-BTBP). Molecular structures of the complexes have been optimized at the B3LYP/6-31G(d) level and total energies of the complexes in various media were estimated using single point calculations performed at the B3LYP/6-311G(d,p) and MP2/6-311G(d,p) levels of theory. In the calculations americium and europium ions were treated using pseudo-relativistic Stuttgart-Dresden effective core potentials and the accompanying basis sets. Selectivity in solvent extraction separation of two metal ions is a co-operative function of contributions from all extractable metal complexes, which depend on physico-chemical properties of each individual complex and on its relative amount in the system. Semi-quantitative analysis of BTBP selectivity in the Am/Eu separation process, based on the contributions from the two pairs of Am(III) and Eu(III) complexes, has been carried out. To calculate the energy of Am/Eu separation, a model of the extraction process was used, consisting of complex formation in water and transfer of the formed complex to the organic phase. Under the assumptions discussed in the paper, this simple two step model results in reliable values of the calculated differences in the energy changes for each pair of the Am/Eu complexes in both steps of the process. The greater thermodynamic stability (in water) of the Am-BTBP complexes, as compared with the analogous Eu species, caused by greater covalency of the Am-N than Eu-N bonds, is most likely the main reason for BTBP selectivity in the separation of the two metal ions. The other potential reason, i.e. differences in lipophilic properties of the analogous complexes of Am and Eu, is less important with regard to this selectivity. PMID- 23104261 TI - Fungal meningitis from injection of contaminated steroids: a compounding problem. PMID- 23104259 TI - Influence of warfarin dose-associated genotypes on the risk of hemorrhagic complications in Chinese patients on warfarin. AB - This study was designed to evaluate the effect of the warfarin dose-associated genotypes, CYP2C9*3 (rs1057910), VKORC1 -1639 G/A (rs9923231), and CYP4F2 1347 C/T (rs2108622), on hemorrhagic complications in Han Chinese patients. Consecutively recruited patients requiring more than 1 year of warfarin treatment were followed from the initiation of warfarin anticoagulation for at least 3 months. CYP2C9*3, VKORC1 -1639 G/A, and CYP4F2 1347 C/T were genotyped by sequencing. The association between genotypes and warfarin hemorrhagic complications was evaluated using Cox proportional hazard regression, adjusted for demographic and clinical factors. Of 312 eligible patients obtaining stable warfarin anticoagulation in 3 months, 11 major and 69 minor hemorrhages occurred over 147 person-years. The CYP2C9*3 genotype conferred an increased risk of all [hazard ratio (HR) 3.07, 95 % confidence interval (CI) 1.57-6.01] and minor hemorrhage (HR 3.28, 95 % CI 1.62-6.65), but not major hemorrhage (HR 0.44, 95 % CI 0.04-4.72). CYP2C9*3 also conferred an increased risk of over-anticoagulation with international normalization ratio (INR) >=4 (HR 2.92, 95 % CI 1.08-7.85). VKORC1 -1639 G/A, and CYP4F2 rs2108622 did not confer significant increase in risk for hemorrhage or over-anticoagulation. Kaplan-Meier curves showed that time to all hemorrhagic events was significantly shorter for patients with CYP2C9*3 genotype than non-carriers (P = 0.001), but not for patients with VKORC1 -1639 G/A or CYP4F2 rs2108622 genotype (P = 0.3 and 0.2). CYP2C9*3 may be the main genetic factor in hemorrhagic complications in Chinese patients under warfarin anticoagulation. PMID- 23104260 TI - Spontaneous improvement of chronic immune thrombocytopenia in children: experience of 56 patients at a single institute. AB - Spontaneous improvement (SI) occurs more frequently in children with chronic immune thrombocytopenia (cITP) than in adults. It is generally accepted that, with the exception of splenectomy, conventional medical approaches for cITP do not change the natural course of the disease. Previous studies on pediatric cITP have reported prognostic factors associated with SI; however, it is important to know when such improvement occurs to enable optimal treatment strategies for cITP. Here, we report results of retrospective analysis of 56 consecutive pediatric patients with cITP at our institution. The median follow-up period after ITP diagnosis was 67 months (11-185 months). Of the 44 patients without splenectomy, 17 achieved SI at a median age of 8.5 years (2.3-16.5 years). The estimated incidence of SI was 24.6 +/- 6.0 % at 36 months. In 16 of the 17 patients with SI, the recovery was achieved within 18 months from diagnosis, or at an age of less than 10 years, whereas among the 24 who did not achieve spontaneous improvement both at "an age of 10 years or more" and at "18 months or more from ITP diagnosis", only one recovered spontaneously. A treatment decision tree, including the indication for splenectomy, should be considered based on this watershed point. PMID- 23104262 TI - The first lanthanide organophosphonate nanosheet by exfoliation of layered compounds. AB - Lanthanum 1,3,5-benzenetriphosphonate (LBP-II) with layered structure was obtained by a hydrothermal synthesis. LBP-II was successfully exfoliated to give nanosheets as confirmed by AFM observation. Europium or terbium-doped LBP-II as well as their dispersion solutions show photoluminescence. PMID- 23104265 TI - Jung, individuation, and moral relativity in Qohelet 7:16--17. AB - Qohelet's warning in chapter 7:16 'not to be too righteous' has commonly been interpreted by biblical scholars in ways that acquit the author of teaching immorality. This article approaches the text from a psychological critical perspective, bringing it into dialogue with the psychological maturation process of individuation in Jungian psychology. The confrontation with the shadow, made up of reprehensible qualities residing in the unconscious that a person wishes to deny, forms the prologue to this process. Projection or repression of these primitive instincts can lead to various problems, such as stagnation and neurosis. Raising the shadowy, primitive, and archaic content of the unconscious to consciousness and integrating it with the ego, however, leads to a mysterious union of opposites and a new personality, a 'self' that transcends consciousness. PMID- 23104263 TI - Cocaine-related behaviors in mice with deficient gliotransmission. AB - RATIONALE: Astrocytes play an integral role in modulating synaptic transmission and plasticity, both key mechanisms underlying addiction. However, while astrocytes are capable of releasing chemical transmitters that can modulate neuronal function, the role of these gliotransmitters in mediating behaviors associated with drugs of abuse has been largely unexplored. OBJECTIVES: The objective of the present study was to utilize mice with astrocytes that lack the ability to release chemical transmitters to evaluate the behavioral consequence of impaired gliotransmission on cocaine-related behaviors. These mice have previously been used to examine the role of gliotransmission in sleep homeostasis; however, no studies to date have utilized them in the study of addictive behaviors. METHODS: Mice expressing a dominant-negative SNARE protein selectively in astrocytes (dnSNARE mice) were tested in a variety of behavioral paradigms examining cocaine-induced behavioral plasticity. These paradigms include locomotor sensitization, conditioned place preference followed by cocaine induced reinstatement of CPP, and cocaine self-administration followed by cue induced reinstatement of cocaine-seeking behavior. RESULTS: Wild-type and dnSNARE mice demonstrated no significant differences in the development or maintenance of locomotor sensitization. While there were non-significant trends for reduced CPP following a low dose of cocaine, drug-induced reinstatement of CPP is completely blocked in dnSNARE mice. Similarly, while dnSNARE mice demonstrated a non significant trend toward reduced cocaine self-administration compared with wild type mice, dnSNARE mice do not demonstrate cue-induced reinstatement in this paradigm. CONCLUSIONS: Gliotransmission is necessary for reinstatement of drug seeking behaviors by cocaine or associated cues. PMID- 23104264 TI - The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats. AB - RATIONALE: Impulsive behavior is categorically differentiated between impulsive action, the inability to withhold from acting out a response, and impulsive choice, the greater preference for an immediate and smaller reward over a delayed but more advantageous reward. While the effects of N-methyl-D-aspartic acid (NMDA) receptor antagonists on impulsive action have been extensively characterized, there are very few and conflicting reports on the effects of this class of drugs on impulsive choice. OBJECTIVES: Using a modified adjusting delay task, we investigated the effects of uncompetitive and competitive blockade of NMDA receptors on impulsive choice. METHODS: Male Wistar rats were trained in a modified adjusting delay task, which involved repeated choice between a low reinforcing solution delivered immediately and a highly reinforcing solution delivered after a variable delay. Rats were then administered either the NMDA receptor uncompetitive antagonists ketamine or memantine, or the competitive antagonists D-AP-5 or CGS 19755. RESULTS: Ketamine treatment dose-dependently increased impulsive choice, and this effect was selective for low-impulsive but not high-impulsive rats. Similarly, memantine treatment dose-dependently increased impulsive choice with a preferential effect for low-impulsive rats. While D-AP-5 treatment did not affect impulsive choice, CGS 19755 increased impulsivity, however, at the same doses at which it caused a marked response inhibition. CONCLUSIONS: NMDA receptor uncompetitive, but not competitive, antagonists significantly increased impulsive choice, preferentially in low impulsive rats. These findings demonstrate that the effects of NMDA receptor blockade on impulsive choice are not generalizable and depend on the specific mechanism of action of the antagonist used. PMID- 23104266 TI - Spiritual well-being among HIV-infected adolescents and their families. AB - Congruence in spirituality between HIV+ adolescent (n = 40)/family (n = 40) dyads and psychological adjustment and quality of life were assessed, using the Spiritual Well-Being Scale of the Functional Assessment of Chronic Illness Therapy, Beck Depression Inventory-II, Beck Anxiety Inventory and Pediatric Quality of Life Inventory at baseline and 3-month post-intervention. Adolescents were 60 % female and 92 % African American. Congruence in spirituality between adolescent/surrogate dyads remained unchanged at 3 months. High congruence existed for "having a reason for living"; rejection of "life lacks meaning/purpose" and "HIV is a punishment from God." Adolescents were less likely to forgive the harm others caused them than their families. PMID- 23104267 TI - Purification and characterization of AHPM, a novel non-hemorrhagic P-IIIc metalloproteinase with alpha-fibrinogenolytic and platelet aggregation-inhibition activities, from Agkistrodon halys pallas venom. AB - A novel non-hemorrhagic metalloproteinase, AHPM, was purified from the venom of Agkistrodon halys pallas by a combination of ion-exchange and gel filtration chromatography. AHPM is a dimeric glycoprotein with multiple pIs around pH 7.9 and has a molecular mass of 110 kDa with two blocked N-terminuses. Partial sequence of AHPM obtained by LC-MS/MS analysis together with its dimeric nature reveals that it is a P-IIIc snake venom metalloproteinase composed of metalloproteinase, disintegrin-like and cysteine-rich domains. AHPM has a conserved DECD sequence in the disintegrin-like domain. AHPM hydrolyzes casein and fibrinogen and also dissolves fibrin clots and the proteolytic activity is abolished by EDTA, but not by PMSF, suggesting that it is a metalloproteinase. The protease hydrolyzes rapidly the Aalpha-chain of fibrinogen followed by the Bbeta-chain and does not cleave the gamma-chain. AHPM contains endogenous Zn(2+) and Ca(2+) ions at a molar ratio of 1:1.9 and 1:4.2, respectively, and Zn(2+) ions are essential for its proteolytic activity. AHPM inhibits collagen-and ADP induced platelet aggregation with half maximal inhibitory concentrations of 200 +/- 8 nM and 280 +/- 10 nM, respectively. EDTA markedly attenuates the inhibition of ADP-induced platelet aggregation by AHPM, indicating that the fibrinogenolytic activity of AHPM is involved in its inhibition of ADP-induced platelet aggregation. AHPM is devoid of hemorrhagic activity when injected (up to 30 MUg) subcutaneously into mice. AHPM is so far identified as first non-hemorrhagic P IIIc SVMP which has both fibrinolytic and platelet aggregation-inhibition activities. The bifunctional enzyme may have a potential clinical application as a thrombolytic agent. PMID- 23104268 TI - Dimerization of TCTP and its clinical implications for allergy. AB - Following the detection of histamine-releasing activity (HRA) in the supernatants of peripheral blood mononuclear cell cultures, research efforts were directed at characterizing the source of this activity, mostly focusing, on IgE-dependent histamine-releasing factors (HRFs). HRF is now variously called translationally controlled tumor protein (TCTP), p21, p23, and fortilin. TCTP exhibits cytokine like functions including release of histamine, induction of TH2 cytokines and chemoattractants, augmentation of B cell proliferation, and immunoglobulin production during late phase allergic inflammation. Because of its association with the allergic status of patients, TCTP emerged as a potential key agent in the modulation of allergic diseases. Several lines of evidence suggest that TCTP exhibits its cytokine-like functions only after it is modified by the proteases, altered oxidant-antioxidant balance and immunoglobulin E, present in the inflamed sites. This review will try to show that dimerization is the critical modification of TCTP if not the only modification, responsible for its cytokine like activity causing allergic diseases. PMID- 23104269 TI - Alteration in genes expression patterns during in vitro differentiation of mouse spermatogonial cells into neuroepithelial-like cells. AB - Pluripotent stem cells derived from testis is a new, natural, and unlimited source for cell therapy in regenerative medicine and represent a possible alternative to replacing of all cells in the body. Here, we designed a simple co culture system of spermatogonia cells with Sertoli cells for the generation of embryonic stem-like cells from mouse testis. The importance of our simple method will be clear when we compared it with other complex and time-consuming methods. Embryonic stem-like colonies with sharp border confirmed by real-time PCR, immunocytochemistry and flow cytometry assessments. Embryonic stem-like colonies were immunopositive for pluripotency markers. Transition of spermatogonia cells to embryonic stem-like cells was accompanied by extensive changes in gene expression. These changes included significant increase in pluripotency genes expression and significant decrease in germ cell-specific genes expression. Also, we proved the differentiation capacity of embryonic stem-like cells to neuroepithelial-like cells which were immunoreactive to Nestin and Neurofilament 68. Evaluation of genes expression during in vitro differentiation into neuroepithelial-like cells showed high-level expression of Nestin whether this gene approximately has no expression in undifferentiated embryonic stem-like cells. Also, expression of pluripotency genes has significantly decreased in neuroepithelial-like cells compared with embryonic stem-like cells. This study shows that embryonic stem-like cells derived from testis are capable to differentiate into neuroepithelial-like cells that may provide a cellular reservoir usable for neurodegenerative disorders. PMID- 23104271 TI - Spatially variable effects of a marine pest on ecosystem function. AB - The broad spectrum of anthropogenic pressures on many of the world's coastal bays and estuaries rarely act in isolation, yet few studies have directly addressed the interactive effects of multiple pressures. Port Phillip Bay in southeastern Australia is a semi-enclosed bay in which nutrient management is a major concern. In recent years it has been heavily invaded by marine pests. We manipulated the density of one such invader, the European fanworm Sabella spallanzanii, and showed that it causes changes in the composition of macrofauna in the surrounding sediments, provides habitat for epibiota (both fauna and flora) on Sabella tubes, and reduces the biomass of microphytobenthos on the surrounding sediments. Of greatest concern, however, was the indirect impact on nutrient cycling. We suggest that the impacts on nutrient cycling are largely due to the feeding of Sabella and the epifauna on its tubes, capturing organic N before it reaches the sediment, excreting it back up into the water column as NH4, thereby bypassing sedimentary processes such as denitrification. Most notably, the efficiency of denitrification, the key ecosystem process that permanently removes N from the system, fell by 37-53 % in the presence of Sabella. Importantly though, this study also demonstrated significant spatial variability in fauna, geochemistry and the magnitude of Sabella effects. Given that the effect of Sabella is also likely to vary in time and with changes in density, all of these sources of variability need to be considered when incorporating the effects of Sabella in nutrient management strategies. PMID- 23104270 TI - Doxorubicin and 5-fluorouracil resistant hepatic cancer cells demonstrate stem like properties. AB - The efficacy of hepatocellular carcinoma (HCC) treatment is very low because of the high percentage of recurrence and resistance to anticancer agents. Hepatic cancer stem cells (HCSCs) are considered the origin of such recurrence and resistance. Our aim was to evaluate the stemness of doxorubicin and 5 fluorouracil resistant hepatic cancer cells and establish the new method to isolate the HCSCs from primary cultured HCC tumors. HCC biopsies were used to establish primary cultures. Then, primary cells were selected for HCSCs by culture in medium supplemented with doxorubicin (0, 0.1, 0.25, 0.5 or 1 MUg/mL), 5-fluorouracil (0, 0.1, 0.25, 0.5 or 1 MUg/mL) or their combination. Selection was confirmed by detection of HCSC markers such as CD133, CD13, CD90, and the side population was identified by rhodamine 123 efflux. The cell population with the strongest expression of these markers was used to evaluate the cell cycle, gene expression profile, tumor sphere formation, marker protein expression, and in vivo tumorigenesis. Selective culture of primary cells in medium supplemented with 0.5 MUg/mL doxorubicin and 1 MUg/mL 5-fluorouracil selected cancer cells with the highest stemness properties. Selected cells strongly expressed CD13, CD133, CD90, and CD326, efflux rhodamine 123 and formed tumor spheres in suspension. Moreover, selected cells were induced to differentiate into cells with high expression of CD19 and AFP (alpha-fetoprotein), and importantly, could form tumors in NOD/SCID mice upon injection of 1 * 10(5) cells/mouse. Selective culture with doxorubicin and 5-fluorouracil will enrich HCSCs, is an easy method to obtain HCSCs that can be used to develop better therapeutic strategies for patients with HCC, and particularly HCSC-targeting therapy. PMID- 23104272 TI - Habitat heterogeneity promotes the coexistence of exotic seaweeds. AB - Despite the progressive accumulation of exotic species in natural communities, little effort has been devoted to elucidating the mechanisms underpinning the coexistence of invaders in environmentally and biologically heterogeneous systems. The exotic seaweeds, Asparagopsis taxiformis and Caulerpa racemosa, exhibit a segregated distribution on Mediterranean rocky reefs. A. taxiformis dominates assemblages in topographically complex habitats, but is virtually absent on homogenous platforms. In contrast, C. racemosa achieves extensive cover in both types of habitat. We assessed whether differences in their distribution were generated by biotic interactions (between invaders and/or between invaders and natives) or by environmental constraints. Three models were proposed to explain seaweed distribution patterns: (1) invaders inhibit one another; (2) native assemblages, differing between complex and simple habitats, prevent the establishment/spread of one invader, but not that of the other; and (3) environmental conditions regulate the establishment/persistence of the seaweeds in different habitats. We removed the dominant invader and resident assemblages in each type of habitat. Moreover, A. taxiformis thalli were transplanted into the habitat dominated by C. racemosa to establish whether its failure to colonize the simple habitat was due to the lack of propagules or post-recruitment mortality. C. racemosa spread in the complex habitat was not influenced by the removal of resident assemblages, but it was slightly enhanced by A. taxiformis removal. Neither C. racemosa removal nor that of resident assemblages promoted A. taxiformis colonization and survival in simple habitats. Our results suggest that heterogeneity in environmental conditions can promote invader coexistence by mitigating the effects of negative biotic interactions. Therefore, the accumulation of introduced species in native communities does not necessarily imply established invaders fostering further invasion. PMID- 23104274 TI - Bay-substituted perylene bisimide dye with an undistorted planar scaffold and outstanding solid state fluorescence properties. AB - Single crystal X-ray analysis reveals a flat perylene pi-scaffold for a perylene bisimide bearing bulky 2,6-diphenylphenoxy substituents at the 1,7 bay positions. The flat structure provides sharp vibronic progressions in the absorption and fluorescence spectra, the sterical shielding outstanding fluorescence quantum yields in the solid state. PMID- 23104276 TI - Hypoxia-induced decreases in SOCS3 increase STAT3 activation and upregulate VEGF gene expression. AB - Signal transducer and activator of transcription (STAT) 3 has been described as a master regulator of the signaling pathways that are involved in the mesenchymal transition of glioblastomas, which are the most aggressive type of tumors and which result in poor prognoses. Hypoxia, which is a strong inducer of vascular endothelial growth factor (VEGF), results in angiogenesis and the bulky growth of tumors. Here, we show that hypoxia induces VEGF gene expression through a STAT3 signaling cascade. Hypoxia increases the levels of aberrantly activated STAT3 by decreasing the levels of the suppressor of cytokine signaling (SOCS) 3, which is a negative regulator of the STAT3 signaling cascade. Activated STAT3 binds to the hypoxia-responsible element that is located -914 to -905 bp upstream of the transcription initiation site in the VEGF promoter and that transcriptionally regulates VEGF gene expression. This sequence closely resembled the previously defined sis-inducible element in the STAT3-binding sequences. The enforced overexpression of SOCS3 abolished the hypoxia-induced STAT3 activation and the STAT3-mediated transcriptional upregulation of the VEGF gene. In addition, activated STAT3 was found around necrotic foci in surgical specimens. These observations suggest that STAT3 is a molecular target of antiangiogenesis. PMID- 23104273 TI - Contribution of oxidative stress to pathology in diaphragm and limb muscles with Duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is a degenerative skeletal muscle disease that makes walking and breathing difficult. DMD is caused by an X-linked (Xp21) mutation in the dystrophin gene. Dystrophin is a scaffolding protein located in the sarcolemmal cytoskeleton, important in maintaining structural integrity and regulating muscle cell (muscle fiber) growth and repair. Dystrophin deficiency in mouse models (e.g., mdx mouse) destabilizes the interface between muscle fibers and the extracellular matrix, resulting in profound damage, inflammation, and weakness in diaphragm and limb muscles. While the link between dystrophin deficiency with inflammation and pathology is multi-factorial, elevated oxidative stress has been proposed as a central mediator. Unfortunately, the use of non specific antioxidant scavengers in mouse and human studies has led to inconsistent results, obscuring our understanding of the importance of redox signaling in pathology of muscular dystrophy. However, recent studies with more mechanistic approaches in mdx mice suggest that NAD(P)H oxidase and nuclear factor-kappaB are important in amplifying dystrophin-deficient muscle pathology. Therefore, more targeted antioxidant therapeutics may ameliorate damage and weakness in human population, thus promoting better muscle function and quality of life. This review will focus upon the pathobiology of dystrophin deficiency in diaphragm and limb muscle primarily in mouse models, with a rationale for development of targeted therapeutic antioxidants in DMD patients. PMID- 23104275 TI - Urinary trypsin inhibitor reduced neointimal hyperplasia induced by systemic inflammation after balloon injury in rabbits. AB - OBJECTIVES: The aims of this study were to evaluate the effect of urinary trypsin inhibitor (UTI) on the regulation of inflammatory cytokines induced by lipopolysaccharide (LPS) and the reduction of neointimal formation in rabbits. METHODS AND RESULTS: Rabbits subjected to iliac artery balloon injury were randomly divided into three groups: control group (balloon injury), LPS group (LPS + balloon injury) and UTI group (UTI + LPS + balloon injury). Systemic markers of inflammation (serum IL-1beta and TNF-alpha levels measured by ELISA) were increased after LPS administration. Arterial nuclear factor-kappaB (NF kappaB/p65) at 28 days after injury was 31.50 +/- 7.08 % of total cells in controls and 73.50 +/- 6.90 % in LPS group (P < 0.05). Morphometric analysis of the injured arteries at 28 days revealed significantly increased luminal stenosis (45.81 +/- 5.31 vs 27.93 +/- 2.85 %, P < 0.05) and neointima-to-media ratio (1.40 +/- 0.15 vs 0.68 +/- 0.12, P < 0.05) in LPS-treated animals compared with controls. This effect was reduced by UTI administration. Serum IL-1beta and TNF alpha levels and NF-kappaB/p65 expression were significantly increased in correlation with the severity of intimal hyperplasia and inhibited by UTI. CONCLUSIONS: Systemic inflammatory response concurrently with arterial vascular injury facilitated neointimal formation. UTI reduced neointimal hyperplasia by regulating inflammatory response and could be considered as a potential anti restenosis supplement. PMID- 23104277 TI - Introducing an innovation in NPWT for acute care settings. PMID- 23104279 TI - Real-time quantitative PCR, pathogen detection and MIQE. AB - Nucleic acids are the ultimate biomarker and real-time PCR (qPCR) is firmly established as the method of choice for nucleic acid detection. Together, they allow the accurate, sensitive and specific identification of pathogens, and the use of qPCR has become routine in diagnostic laboratories. The reliability of qPCR-based assays relies on a combination of optimal sample selection, assay design and validation as well as appropriate data analysis and the "Minimal Information for the Publication of real-time PCR" (MIQE) guidelines aim to improve both the reliability of assay design as well as the transparency of reporting, essential conditions if qPCR is to remain the benchmark technology for molecular diagnosis. PMID- 23104278 TI - Chiral picolylamines for Michael and aldol reactions: probing substrate boundaries. AB - Here we report on inroads concerning increased substrate breadth via the picolylamine organocatalyst template, a vicinal chiral diamine based on a pyridine-primary amine motif. The addition of cyclohexanone to beta-nitrostyrene has many catalyst solutions, but cyclopentanone and isobutyraldehyde additions continue to be challenging. PicAm-3 (10 mol%) readily allows the Michael addition of cyclopentanone or isobutyraldehyde (5.0 equiv.) to beta-nitrostyrene derivatives. By contrast, PicAm-1 (7.0 mol%) is optimal for catalyzing the aldol reaction of cyclohexanone or cycloheptanone (3.3 equiv.) with aromatic aldehydes. Eighteen products are reported and for each reaction type new products are reported (4b-d, 9c). Very good yields and stereoselectivities are generally noted. The reactions, which require an acid additive, proceed via a transient chiral enamine and a mechanistic case is put forth for a bifunctional catalysis model. PMID- 23104280 TI - Overcoming inhibition in real-time diagnostic PCR. AB - PCR is an important and powerful tool in several fields, including clinical diagnostics, food analysis, and forensic analysis. In theory, PCR enables the detection of one single cell or DNA molecule. However, the presence of PCR inhibitors in the sample affects the amplification efficiency of PCR, thus lowering the detection limit, as well as the precision of sequence-specific nucleic acid quantification in real-time PCR. In order to overcome the problems caused by PCR inhibitors, all the steps leading up to DNA amplification must be optimized for the sample type in question. Sampling and sample treatment are key steps, but most of the methods currently in use were developed for conventional diagnostic methods and not for PCR. Therefore, there is a need for fast, simple, and robust sample preparation methods that take advantage of the accuracy of PCR. In addition, the thermostable DNA polymerases and buffer systems used in PCR are affected differently by inhibitors. During recent years, real-time PCR has developed considerably and is now widely used as a diagnostic tool. This technique has greatly improved the degree of automation and reduced the analysis time, but has also introduced a new set of PCR inhibitors, namely those affecting the fluorescence signal. The purpose of this chapter is to view the complexity of PCR inhibition from different angles, presenting both molecular explanations and practical ways of dealing with the problem. Although diagnostic PCR brings together scientists from different diagnostic fields, end-users have not fully exploited the potential of learning from each other. Here, we have collected knowledge from archeological analysis, clinical diagnostics, environmental analysis, food analysis, and forensic analysis. The concept of integrating sampling, sample treatment, and the chemistry of PCR, i.e., pre-PCR processing, will be addressed as a general approach to overcoming real-time PCR inhibition and producing samples optimal for PCR analysis. PMID- 23104281 TI - Quality in the molecular microbiology laboratory. AB - In the clinical microbiology laboratory advances in nucleic acid detection, quantification, and sequence analysis have led to considerable improvements in the diagnosis, management, and monitoring of infectious diseases. Molecular diagnostic methods are routinely used to make clinical decisions based on when and how to treat a patient as well as monitor the effectiveness of a therapeutic regime and identify any potential drug resistant strains that may impact on the long term patient treatment program. Therefore, confidence in the reliability of the result provided by the laboratory service to the clinician is essential for patient treatment. Hence, suitable quality assurance and quality control measures are important to ensure that the laboratory methods and service meet the necessary regulatory requirements both at the national and international level. In essence, the modern clinical microbiology laboratory ensures the appropriateness of its services through a quality management system that monitors all aspects of the laboratory service pre- and post-analytical-from patient sample receipt to reporting of results, from checking and upholding staff competency within the laboratory to identifying areas for quality improvements within the service offered. For most European based clinical microbiology laboratories this means following the common International Standard Organization (ISO9001) framework and ISO15189 which sets out the quality management requirements for the medical laboratory (BS EN ISO 15189 (2003) Medical laboratories-particular requirements for quality and competence. British Standards Institute, Bristol, UK). In the United States clinical laboratories performing human diagnostic tests are regulated by the Centers for Medicare and Medicaid Services (CMS) following the requirements within the Clinical Laboratory Improvement Amendments document 1988 (CLIA-88). This chapter focuses on the key quality assurance and quality control requirements within the modern microbiology laboratory providing molecular diagnostics. PMID- 23104282 TI - Pre-analytical sample treatment and DNA extraction protocols for the detection of bacterial pathogens from whole blood. AB - Molecular diagnostics is an increasing popular approach for the direct detection and identification of pathogenic bacteria in clinical samples. Conventional culture techniques are time-consuming and therefore causing a delay in the diagnosis of the patient. Alternative techniques based on nucleic acid amplification offer a shorter turn-around-time and the ability to identify fastidious and non-cultivable organisms. However, molecular detection of bacteria in blood, by for example PCR, RT-PCR, or sequencing of the 16S rDNA genes is often complicated by the presence of PCR-inhibitory compounds. Here we describe several different methods for the extraction of bacterial DNA from whole blood samples. The methods differ regarding costs, hands-on time as well as regarding sensitivity. In combination with a model PCR the detection limits that can be reached using the different methods range from 1,000 to 50 cfu/ml. PMID- 23104283 TI - Detection of bacterial contamination in platelet concentrates using flow cytometry and real-time PCR methods. AB - Despite considerable advances in the safety of blood components based on the application of highly sensitive and specific screening methods to minimize the viral infection risk, the prevention of transfusion-associated bacterial infection remains a major challenge in transfusion medicine. In particular, platelet concentrates represent the greatest infectious risk of transfusion transmitted bacterial sepsis. The detection of bacterial contamination in platelet concentrates has been implemented in several blood services as a routine quality control testing. Although culture is likely to remain the gold standard method of detecting bacterial contamination, the use of rapid methods is likely to increase and play an important role in transfusion medicine in the future. In particular, flow cytometric methods and nucleic acid amplification techniques are powerful tools in bacterial screening assays. Compared to culture-based methods, the combination of high sensitivity and specificity, low contamination risk, ease of performance, and speed has made those technologies appealing alternatives to conventional culture-based testing methods. PMID- 23104285 TI - PCR detection of Haemophilus influenzae from respiratory specimens. AB - The detection of Haemophilus influenzae by conventional methods like culture is time-consuming and may give false-negative results, especially during ongoing antibiotic treatment. Therefore, non-culture based methods that are sensitive, specific, and rapid are valuable for early diagnosis and effective therapy. Here we describe a quantitative real-time PCR assay based on the outer membrane P6 gene omp6, to detect H. influenzae and its application on respiratory tract specimens. PMID- 23104284 TI - Multiplex real-time PCR assay for the detection of meticillin-resistant Staphylococcus aureus and Panton-Valentine leukocidin from clinical samples. AB - The control and prevention of meticillin-resistant Staphylococcus aureus (MRSA) is a major challenge for healthcare establishments, especially as this pathogen continues to evolve. The emergence and spread of community associated MRSA producing Panton-Valentine leukocidin (PVL) causing severe, sometimes fatal, infections in otherwise healthy people is a significant cause of concern. Patient screening to detect MRSA is now widely used as part of an effective control program to limit the spread of this pathogen. Real-time PCR targeting specific MRSA markers offers a rapid alternative to conventional methods enabling earlier intervention, such as patient isolation and decolonization treatment. Herein we describe a multiplex real-time assay that combines primers and probes to detect MRSA and the genes for PVL to provide a rapid and informative assay. PMID- 23104286 TI - Rapid detection of atypical respiratory bacterial pathogens by real-time PCR. AB - The accurate diagnosis of lower respiratory tract infection remains a challenge, with conventional diagnostic methods often failing to identify a causative agent. Here we describe a multiplex real-time PCR assay that has been validated for the detection of the rarely identified atypical bacterial pathogens: Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. Due to the complexity and poor performance of the existing cultural and serological methods for the detection of these pathogens, investigation for them is rarely initiated. This is likely to result in underdetection and empirical treatment regardless of a microbiological diagnosis. The assay described here is designed to address this need. PMID- 23104287 TI - Utilization of multiple real-time PCR assays for the diagnosis of Bordetella spp. in clinical specimens. AB - Bordetella pertussis causes an upper respiratory infection in infants, adolescents, and adults. Diagnosis of pertussis, a vaccine-preventable disease, can be difficult, but recent implementation of real-time PCR assays in laboratories has hastened the ability of clinicians to make an accurate diagnosis. In this paper we describe the method of nasopharyngeal specimen collection, extraction of DNA, and real-time PCR assays that will allow the detection and identification of Bordetella spp. in clinical specimens. PMID- 23104288 TI - Detection of Mycoplasma pneumoniae by real-time PCR. AB - Mycoplasma pneumoniae is a significant cause of respiratory disease, accounting for approximately 20% of cases of community-acquired pneumonia. Although several diagnostic methods exist to detect M. pneumoniae in respiratory specimens, real time PCR has emerged as a significant improvement for the rapid diagnosis of this pathogen. The method described herein details the procedure for the detection of M. pneumoniae by real-time PCR (qPCR). The qPCR assay described can be performed with three targets specific for M. pneumoniae (Mp181, Mp3, and Mp7) and one marker for the detection of the RNaseP gene found in human nucleic acid as an internal control reaction. Recent studies have demonstrated the ability of this procedure to reliably identify this agent and facilitate the timely recognition of an outbreak. PMID- 23104289 TI - Real-time PCR assay for the diagnosis of Pneumocystis jirovecii pneumonia. AB - Pneumocystis jirovecii is a common cause of life-threatening pneumonia among immunocompromised patients. Since P. jirovecii cannot be cultured, specific identification of it depends on examining respiratory specimens. In the last decade, PCR has been developed which allows the detection of very low levels of P. jirovecii not detectable by routine histochemical staining. We have shown that the direct immunofluorescence assay can be replaced by a real-time PCR assay given its feasibility, sensitivity, and specificity, for the detection of P. jirovecii. A negative PCR, performed on a LightCycler System((r)), enables a diagnosis of Pneumocystis jirovecii pneumonia (PjP) to be excluded, and the semiquantitative result with the application of some cutoff values can have a role in distinguishing between colonized or subclinically infected patients and PjP patients. PMID- 23104290 TI - Rapid identification of mycobacteria and rapid detection of drug resistance in Mycobacterium tuberculosis in cultured isolates and in respiratory specimens. AB - Recent advances in molecular biology and better understanding of the genetic basis of drug resistance have allowed rapid identification of mycobacteria and rapid detection of drug resistance of Mycobacterium tuberculosis present in cultured isolates or in respiratory specimens. In this chapter, several simple nucleic acid amplification-based techniques are introduced as molecular approach for clinical diagnosis of tuberculosis. A one-tube nested IS6110-based polymerase chain reaction (PCR) is used for M. tuberculosis complex identification; the use of a multiplex allele-specific PCR is demonstrated to detect the isoniazid resistance; PCR-sequencing assays are applied for rifampicin and ofloxacin resistance detection and 16S rDNA sequencing is utilized for identification of mycobacterial species from cultures of acid fast bacilli (AFB). Despite the high specificity and sensitivity of the molecular techniques, mycobacterial culture remains the "Gold Standard" for tuberculosis diagnosis. Negative results of molecular tests never preclude the infection or the presence of drug resistance. These technological advancements are, therefore, not intended to replace the conventional tests, but rather have major complementary roles in tuberculosis diagnosis. PMID- 23104291 TI - Direct detection of Mycobacterium ulcerans in clinical specimens and environmental samples. AB - Mycobacterium ulcerans is a slow-growing environmental bacterium that causes a severe skin disease known as Buruli ulcer. Rapid detection of M. ulcerans in clinical specimens is essential to ensure early diagnosis and prevention of disability. This chapter describes a real-time PCR method for the direct detection of M. ulcerans from swabs, fresh tissue biopsies, and fixed tissue sections, which are the most common types of specimens used in the diagnosis of Buruli ulcer. The chapter also briefly describes methods for PCR detection of M. ulcerans in environmental samples, as reliable detection of M. ulcerans in the environment is becoming increasingly important for understanding the ecology and transmission of this important pathogen. PMID- 23104292 TI - Detection of Bartonella spp. DNA in clinical specimens using an internally controlled real-time PCR assay. AB - Bartonella henselae is the causative agent of cat-scratch disease (CSD), usually presenting itself as a -self-limiting lymphadenopathy. In this chapter an internally controlled Taqman probe-based real-time PCR targeting the groEL gene of Bartonella spp. is described. This assay allows for the rapid, sensitive, and simple detection of Bartonella spp. in samples from CSD or endocarditis suspects, and it is suitable for implementation in the diagnostic microbiology laboratory. PMID- 23104293 TI - Simultaneous direct identification of genital microorganisms in voided urine using multiplex PCR-based reverse line blot assays. AB - Our aim was to develop and evaluate sensitive methods that would allow simultaneous direct identification of multiple potential pathogens in clinical specimens for diagnosis and epidemiological studies, using a multiplex PCR-based reverse line blot assay. We have previously developed assays suitable for detection of bacterial respiratory and systemic pathogens. In this chapter we describe, in detail, a method developed to identify 14 genital microorganisms, for use in epidemiological studies of genital infection or colonization, using first voided urine specimens. The 14 urogenital pathogens or putative pathogens studied were Trichomonas vaginalis, Streptococcus pneumoniae, Neisseria gonorrhoeae, N. meningitidis, Chlamydia trachomatis, Ureaplasma parvum, U. urealyticum, Mycoplasma hominis, M. genitalium, Gardnerella vaginalis, Haemophilus influenzae, herpes simplex virus 1 and 2, and adenovirus. Two species specific primer pairs and probes were designed for each target. The method was validated using a reference strain or a well-characterized clinical isolate of each target organism. In a clinical study among men attending sexual health clinics in Sydney, we used the assay to compare rates of detection of the 14 organisms in men with urethritis with those in asymptomatic controls and found the method to be sensitive, specific, convenient, and relatively inexpensive. PMID- 23104294 TI - Diagnosis of Clostridium difficile infection using real-time PCR. AB - Clostridium difficile is known to cause antibiotic-associated diarrhea and pseudomembranous colitis. Toxinogenic strains of the bacterium produce toxins A (TcdA) and B (TcdB), which are associated with the pathogenicity. The standard methods for diagnosis of C. difficile infection include the cell cytotoxicity assay and the culture of a toxinogenic strain. Due to the long turnaround time of these methods, more rapid methods are preferred. Enzyme immunoassays are fast, but lack sensitivity. Therefore, real-time PCR methods have been developed. The real-time PCR described in this chapter detects tcdB, the gene coding for toxin B. Since toxin A-negative, toxin B-positive strains have been reported to cause disease as well, these strains can also be detected by this method which uses an automated STAR-MagnaPure method for the optimum isolation of DNA from feces. An internal control is included as well to control for inhibition of the PCR method. PMID- 23104295 TI - Detection of pathogenic Leptospira spp. through real-time PCR (qPCR) targeting the LipL32 gene. AB - Rapid diagnosis of leptospirosis, through culture and/or serology, can be difficult without proper expertise and is often delayed due to the length of time required to obtain results. Polymerase chain reaction (PCR), more specifically the real-time detection of the amplified PCR product, is a methodology that can provide a diagnosis in a timelier manner compared to culture and serology. There are a limited number of real-time PCR (qPCR) assays for detecting Leptospira and not all of these assays are able to distinguish pathogenic from nonpathogenic species. In addition, there are a variety of probe technologies and qPCR instruments that are utilized with these assays. This chapter presents a qPCR assay that targets lipL32, a gene which is present only in pathogenic Leptospira spp. This assay utilizes a TaqMan probe and instructions for use on either the Lightcycler 1.2 (Roche Diagnostics, Indianapolis, IN) or the ABI 7500 (Applied Biosystems, Foster City, CA) are provided. PMID- 23104296 TI - Sensitive and rapid detection of Campylobacter jejuni and Campylobacter coli using loop-mediated isothermal amplification. AB - Loop-mediated isothermal amplification (LAMP) is an established nucleic acid amplification method offering rapid, accurate, and cost-effective diagnosis of infectious diseases. From the beginning of DNA extraction to final detection of Campylobacter jejuni and Campylobacter coli, the assay requires less than 50 and 90 min from a colony on selective media, and human feces, respectively. For chicken meat samples, the assay requires approximately 24-48 h from the beginning of the enrichment culture to final detection. The sensitivity of the LAMP assay is tenfold higher than that of the equivalent PCR assay. LAMP amplification can be judged by both turbidimeter analysis and visual assessment with the unaided eye. The LAMP assay is a powerful tool for rapid, simple, and sensitive detection of C. jejuni and C. coli, which may facilitate the investigation of C. jejuni and C. coli contamination in chicken, as well as the early diagnosis of C. jejuni and C. coli infection in humans. PMID- 23104297 TI - PCR detection of Helicobacter pylori in clinical samples. AB - Helicobacter pylori is an important pathogen whose primary niche is the human stomach. H. pylori is etiologically associated with gastric inflammation (gastritis), peptic ulcer disease, and gastric cancer. Both noninvasive (e.g., urea breath and stool antigen tests) and invasive (gastric biopsy for histology, culture, or PCR) tests are used for diagnosis. PCR detection of H. pylori has been reported using a variety of clinical samples including gastric biopsy, gastric juice, saliva, dental plaque, and stools as well as environmental samples. Whenever possibly, noninvasive tests are preferred over invasive tests. H. pylori are excreted in the stool. Culture from stool is variable whereas stool antigen testing is widely used. Stool consists of a complicated mixture of commensal bacteria and chemicals and often includes inhibitors of PCR. Nevertheless, simple extraction methods are available to efficiently extract DNA from human stools and nested-PCR targeting the 23S rRNA gene have proven to be highly sensitive for the detection of H. pylori. Detection of clarithromycin susceptibility/resistance is important clinically and the mutation of the 23S rRNA gene responsible for resistance can also be detected using stool. This described method can be modified for other clinical samples such as gastric juice or biopsy material. PMID- 23104298 TI - Rapid detection of the Escherichia coli genospecies in water by conventional and real-time PCR. AB - The presence of Escherichia coli has long been established as the most reliable microbiological indication of fecal contamination in water. Current recommended culture-based methods for assessing water quality by the detection of E. coli are lengthy and lack ubiquity (ability to detect most if not all strains of a target microorganism). We describe rapid and sensitive conventional and real-time PCR assays specific to E. coli and Shigella, based on the nucleotide sequence of the highly conserved elongation factor Tu (tuf) gene enabling the detection of all members of the genospecies. PMID- 23104299 TI - Multiplex real-time PCR (MRT-PCR) for diarrheagenic. AB - Diarrheagenic Escherichia coli strains are important causes of diarrhea in children from the developing world and are now being recognized as emerging enteropathogens in the developed world. Current methods of detection are too expensive and labor-intensive for routine detection of these organisms to be practical. We developed a real-time fluorescence-based multiplex PCR for the detection of all six of the currently recognized classes of diarrheagenic E. coli. The primers were designed to specifically amplify eight different virulence genes in the same reaction: aggR for enteroaggregative E. coli (EAEC), stIa/stIb and lt for enterotoxigenic E. coli (ETEC), eaeA for enteropathogenic E. coli (EPEC), stx1 and stx2 for Shiga toxin-producing E. coli (STEC), ipaH for enteroinvasive E. coli (EIEC), and daaD for diffusely adherent E. coli (DAEC). PMID- 23104300 TI - fac-Re(CO)3 complexes of 2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine "click" ligands: synthesis, characterisation and photophysical properties. AB - The syntheses of the 4-n-propyl and 4-phenyl substituted fac-Re(CO)(3) complexes of the tridentate "click" ligand (2,6-bis(4-substituted-1,2,3-triazol-1 ylmethyl)pyridine) are described. The complexes were obtained by refluxing methanol solutions of [Re(CO)(5)Cl], AgPF(6) and either the 4-propyl or 4-phenyl substituted ligand for 16 h. The ligands and the two rhenium(I) complexes were characterised by elemental analysis, HR-ESMS, ATR-IR, (1)H and (13)C NMR spectroscopy and the molecular structures of both complexes were confirmed by X ray crystallography. The electronic structure of the fac-Re(CO)(3) "click" complexes was probed using UV-Vis, Raman and emission spectroscopy, cyclic voltammetry and DFT calculations. Altering the electronic nature of the ligand's substituent, from aromatic to alkyl, had little effect on the absorption/emission maxima and electrochemical properties of the complexes indicating that the 1,2,3 triazole unit may insulate the metal centre from the electronic modification at the ligands' periphery. Both Re(I) complexes were found to be weakly emitting with short excited state lifetimes. The electrochemistry of the complexes is defined by quasi-reversible Re oxidation and irreversible triazole-based ligand reduction processes. PMID- 23104302 TI - [Cu30I16(mtpmt)12(MU(10-S4))]: an unusual 30-membered copper(I) cluster derived from the C-S bond cleavage and its use in heterogeneous catalysis. AB - The Cu(I)-mediated C-S bond cleavage of 5-methyl-4-(p-tolyl)pyrimidine-2-thiol (mtpmtH) gave one 30-nuclear cluster [Cu30I16(mtpmt)12(MU10-S4)], one polymeric complex [(bmtpms)Cu-(MU-I)]n and one tetranuclear complex [(bmptmds){Cu(MU I)}2]2; the 30-nuclear cluster displayed excellent catalytic performances in the coupling reactions of N-heterocycles and arylboronic acids and could be recycled and reused. PMID- 23104303 TI - Soft sensor control of metabolic fluxes in a recombinant Escherichia coli fed batch cultivation producing green fluorescence protein. AB - A soft sensor approach is described for controlling metabolic overflow from mixed acid fermentation and glucose overflow metabolism in a fed-batch cultivation for production of recombinant green fluorescence protein (GFP) in Escherichia coli. The hardware part of the sensor consisted of a near-infrared in situ probe that monitored the E. coli biomass and an HPLC analyzer equipped with a filtration unit that measured the overflow metabolites. The computational part of the soft sensor used basic kinetic equations and summations for estimation of specific rates and total metabolite concentrations. Two control strategies for media feeding of the fed-batch cultivation were evaluated: (1) controlling the specific rates of overflow metabolism and mixed-acid fermentation metabolites at a fixed pre-set target values, and (2) controlling the concentration of the sum of these metabolites at a set level. The results indicate that the latter strategy was more efficient for maintaining a high titer and low variability of the produced recombinant GFP protein. PMID- 23104301 TI - Phenotypic and tumor molecular characterization of colorectal cancer in relation to a susceptibility SMAD7 variant associated with survival. AB - The minor allele (G) of rs4939827, a SMAD7 (18q21) intronic variant, is associated with a lower risk of developing colorectal cancer (CRC) and poorer survival after diagnosis. Our objective was to evaluate the associations of this variant with different tumor phenotype and intratumoral molecular characteristics. We evaluated 1509 CRC cases and 2307 age-matched controls nested within the Nurses' Health Study and the Health Professionals Follow-up Study. We used the TaqMan assay to genotype rs4939827 and logistic regression to assess the association of rs4939827 with risk of CRC according to different phenotypic and molecular characteristics. We found that the minor allele (G) in rs4939827 (SMAD7, 18q21) was associated with a lower risk of developing tumor stage pT1 or pT2 CRC [multivariate odds ratio (OR), 0.73; 95% confidence interval (CI) 0.62 0.87] but not tumor stage pT3 or pT4 (multivariate OR, 1.07; 95% CI 0.93-1.23, P for heterogeneity = 1.2 * 10(-4)). The association between rs4939827 and CRC also significantly differed by methylation of RUNX3 (P for heterogeneity = 0.005). Among those with CRC, the minor allele (G) in rs4939827 was significantly associated with poorer overall survival (hazards ratio, 1.20; 95% CI, 1.02-1.42). We can conclude that the minor allele (G) of the germline intronic SMAD7 variant rs4939827 is associated with a lower risk of CRC with earlier tumor stage and CRC without methylation of the tumor suppressor RUNX3. These findings suggest that individuals with this SMAD7 variant that develop CRC are more probably to have tumors with greater invasiveness and methylation of RUNX3, which potentially contributes to their poorer observed survival. PMID- 23104304 TI - Evaluation of enalapril affecting the renin-angiotensin system in normal and stress-induced rats based on urinary metabolites of amines and cortisol. AB - INTRODUCTION: The renin-angiotensin system is distributed centrally as well as peripherally, which works in association with SNS and HPA in stress. Angiotensin is considered one of the principal hormones for bringing out stress-related changes. To find the influence of enalapril on the neuromediator of CNS and periphery, the present work was carried out. The assessment of the transmitter levels was done by estimating major urinary stress metabolites like vanillylmandelic acid, 5-hydroxyindoleacetic acid, 6-beta-hydroxycortisol and homovanillic acid in normal and stress-induced conditions and also in the absence and presence of enalapril treatment in rats. MATERIALS AND METHODS: Groups of rats were subjected to a forced swim stress one hour after daily treatment of enalapril. The 24 h urinary excretion of vanillylmandelic acid, 5 hydroxyindoleacetic acid, 6-beta-hydroxycortisol and homovanillic acid was determined in all groups under normal and stressed-induced conditions. RESULTS: Daily administration of enalapril at doses of 3, 10 and 30 mg/kg/body weight inhibited the stress-induced urinary biochemical changes. However, treatment with enalapril in normal conditions increased the excretion of all selected metabolites. CONCLUSION: It can be speculated that enalapril prevented stress induced increases of adrenergic, serotonergic and cortical mechanisms. PMID- 23104305 TI - Osmotically regulated floating asymmetric membrane capsule for controlled site specific delivery of ranitidine hydrochloride: optimization by central composite design. AB - A nondisintegrating, floating asymmetric membrane capsule (FAMC) was developed to achieve site-specific osmotic flow of a highly water-soluble drug, ranitidine hydrochloride (RHCl), in a controlled manner. Solubility suppression of RHCl was achieved by the common ion effect, using optimized coated sodium chloride as a formulation component. The capsular wall of FAMC was prepared by the phase inversion process wherein the polymeric membrane was precipitated on glass pins by dipping them in a solution of cellulose acetate followed by quenching. Central composite design was utilized to investigate the influence of independent variables, namely, level(s) of membrane former, pore former, and osmogen, on percent cumulative drug release (response). The release mechanism of RHCl through FAMC was confirmed as osmotic pumping. The asymmetry of the membrane was characterized by scanning electron microscopy that revealed a dense nonporous outer region of membrane supported by an inner porous region. Differential scanning calorimetry indicated no incompatibility between the drug and excipients. In vitro drug release in three biorelevant media, pH 2.5 (low fed), pH 4.5 (intermediate fed), and pH 6.5 (high fed), demonstrated pH-independent release of RHCl (P > 0.05). Floating ability for 12 h of the optimized FAMC9 was visually examined during the in vitro release studies that showed maximal drug release with zero-order kinetics (r (2) = 0.9991). Thus, a novel osmotically regulated floating capsular system was developed for site-specific delivery of RHCl. PMID- 23104306 TI - Formulation of niosomal gel for enhanced transdermal lopinavir delivery and its comparative evaluation with ethosomal gel. AB - The aim was to develop niosomal gel as a transdermal nanocarrier for improved systemic availability of lopinavir. Niosomes were prepared using thin-film hydration method and optimized for molar quantities of Span 40 and cholesterol to impart desirable characteristics. Comparative evaluation with ethosomes was performed using ex vivo skin permeation, fluorescence microscopy, and histopathology studies. Clinical utility via transdermal route was acknowledged using in vivo bioavailability study in male Wistar rats. The niosomal formulation containing lopinavir, Span 40, and cholesterol in a molar ratio of 1:0.9:0.6 possessed optimally high percentage of drug entrapment with minimum mean vesicular diameter. Ex vivo skin permeation studies of lopinavir as well as fluorescent probe coumarin revealed a better deposition of ethosomal carriers but a better release with niosomal carriers. Histopathological studies indicated the better safety profile of niosomes over ethosomes. In vivo bioavailability study in male Wistar rats showed a significantly higher extent of absorption (AUC(0 >infinity), 72.87 h * MUg/ml) of lopinavir via transdermally applied niosomal gel as compared with its oral suspension. Taken together, these findings suggested that niosomal gel holds a great potential of being utilized as novel, nanosized drug delivery vehicle for transdermal lopinavir delivery. PMID- 23104311 TI - Project-based learning: improving student engagement and performance in the laboratory. PMID- 23104310 TI - Quantifying dithiothreitol displacement of functional ligands from gold nanoparticles. AB - Dithiothreitol (DTT)-based displacement is widely utilized for separating ligands from their gold nanoparticle (AuNP) conjugates, a critical step for differentiating and quantifying surface-bound functional ligands and therefore the effective surface density of these species on nanoparticle-based therapeutics and other functional constructs. The underlying assumption is that DTT is smaller and much more reactive toward gold compared with most ligands of interest, and as a result will reactively displace the ligands from surface sites thereby enabling their quantification. In this study, we use complementary dimensional and spectroscopic methods to characterize the efficiency of DTT displacement. Thiolated methoxypolyethylene glycol (SH-PEG) and bovine serum albumin (BSA) were chosen as representative ligands. Results clearly show that (1) DTT does not completely displace bound SH-PEG or BSA from AuNPs, and (2) the displacement efficiency is dependent on the binding affinity between the ligands and the AuNP surface. Additionally, the displacement efficiency for conjugated SH-PEG is moderately dependent on the molecular mass (yielding efficiencies ranging from 60 to 80% measured by ATR-FTIR and ~90% by ES-DMA), indicating that the displacement efficiency for SH-PEG is predominantly determined by the S-Au bond. BSA is particularly difficult to displace with DTT (i.e., the displacement efficiency is nearly zero) when it is in the so-called normal form. The displacement efficiency for BSA improves to 80% when it undergoes a conformational change to the expanded form through a process of pH change or treatment with a surfactant. An analysis of the three-component system (SH-PEG + BSA + AuNP) indicates that the presence of SH-PEG decreases the displacement efficiency for BSA, whereas the displacement efficiency for SH-PEG is less impacted by the presence of BSA. PMID- 23104312 TI - Amperometric homogeneous competitive immunoassay in a perfluorocarbon emulsion oxygen therapeutic (PEOT). AB - The effect of a perfluorocarbon emulsion oxygen therapeutic (PEOT) on the detection of the drugs theophylline and phenytoin was explored using a commercial enzyme multiplied immunoassay technique (EMIT(r)). The EMIT technique is based on the enzymatic production of NADH, which is typically detected in serum samples spectrophotometrically. Here, amperometry using the rotating disk electrode on a single drop of solution is demonstrated to detect theophylline and phenytoin in the presence of PEOT. In the study, 2,6-dichloroindophenol (DCIP) added to the immunoassay mixture is reduced by the NADH to DCIPH2. Oxidation of DCIPH2 is monitored electrochemically at +200 mV using a glassy carbon rotating disk electrode. Slopes of amperograms are proportional to the concentration of drug in the immunoassay sample. This technique yields excellent quantitative data in the therapeutic range for both drugs in 2-20% PEOT. PMID- 23104313 TI - Potentiometric propranolol-selective sensor based on molecularly imprinted polymer. AB - A novel potentiometric sensor based on molecularly imprinted polymer (MIP) for propranolol, an adrenergic-blocking drug, was designed. The influence of molecularly imprinted polymer particle content and sodium tetraphenylborate additives in polyvinylchloride membrane was shown. The electrodes show near Nernstian responses down to 10(-4)-10(-5) M propranolol concentration. The potentiometric response of MIP-based sensor for propranolol in mixed nonaqueous medium was shown at first. Sensor selectivity relative to various inorganic cations, atenolol and metoprolol, was reported. Direct potentiometry was used to determine propranolol in aqueous modeling solutions and pharmaceutical preparations with good results. PMID- 23104314 TI - Enhancement of biological mass spectrometry by using separations based on changes in ion mobility (FAIMS and DMS). AB - Analysis of complex biological samples for low-level analytes by liquid chromatography-tandem mass spectrometry (LC-MS/MS) often requires additional selectivity. Differential mobility techniques (FAIMS and DMS) have been shown to enhance LC-MS/MS analyses by separating ions in the gas-phase on a millisecond timescale by use of a mechanism that is complementary to both liquid chromatography and mass spectrometry. In this overview, a simplified description of the operation of these devices is given and an example presented that illustrates the utility of FAIMS (DMS) for solving a challenging analytical assay. Important recent advances in the field, including work with gas modifiers, are presented, along with an outlook for the technology. PMID- 23104315 TI - An innovative bovine odorant binding protein-based filtering cartridge for the removal of triazine herbicides from water. AB - Odorant binding protein (OBP) is a multi-functional scavenger for small hydrophobic molecules dissolved in the mucus lining the nasal epithelia of mammals, characterized by broad ligand binding specificity towards a large number of structurally unrelated natural and synthetic molecules of different chemical classes. Here, we demonstrate for the first time the application of OBP as the active element of an innovative filtering matrix for the removal of environmental pollutants such as triazine herbicides from water samples. The filtering device, obtained by coupling histidine-tagged bovine OBP to a nickel nitrilotriacetic acid (Ni-NTA) agarose resin, was characterized in terms of retention capacity for the herbicides atrazine, simazine, and propazine. Analysis of these herbicides at trace levels with solid-phase microextraction followed by gas chromatography-mass spectrometry using the selected ion monitoring mode proved the capabilities of the proposed device for the decontamination of surface and groundwater samples in the 0.2-2,300 MUg/L concentration range, obtaining a reduction in the triazine content greater than 97 %, thus suggesting its possible use for the potabilization of water. PMID- 23104316 TI - Simultaneous and sensitive LC-MS/MS determination of tetrahydrocannabinol and metabolites in human plasma. AB - Cannabis is not only a widely used illicit drug but also a substance which can be used in pharmacological therapy because of its analgesic, antiemetic, and antispasmodic properties. A very rapid and sensitive method for determination of ?(9)-tetrahydrocannabinol (THC), the principal active component of cannabis, and two of its phase I metabolites in plasma has been developed and validated. After solid-phase extraction of plasma (0.2 mL), the clean extracts were analyzed by tandem mass spectrometry after a 5-min liquid chromatographic separation. The linear calibration ranges were from 0.05 to 30 ng mL(-1) for THC and 11-nor-?(9) carboxy-tetrahydrocannabinol (THC-COOH) and from 0.2 to 30 ng mL(-1) for ?(9)-(11 OH)-tetrahydrocannabinol (11-OH-THC). Imprecision and inaccuracy were always below 7 and 12 % (expressed as relative standard deviation and relative error), respectively. The method has been successfully applied to determination of the three analytes in plasma obtained from healthy volunteers after oral administration of 20 mg dronabinol. PMID- 23104317 TI - Estimation of odds of concordance based on the Aalen additive model. AB - The Cox regression model is often used when analyzing survival data as it provides a convenient way of summarizing covariate effects in terms of relative risks. The proportional hazards assumption may not hold, however. A typical violation of the assumption is time-changing covariate effects. Under such scenarios one may use more flexible models but the results from such models may be complicated to communicate and it is desirable to have simple measures of a treatment effect, say. In this paper we focus on the odds-of-concordance measure that was recently studied by Schemper et al. (Stat Med 28:2473-2489, 2009). They suggested to estimate this measure using weighted Cox regression (WCR). Although WCR may work in many scenarios no formal proof can be established. We suggest an alternative estimator of the odds-of-concordance measure based on the Aalen additive hazards model. In contrast to the WCR, one may derive the large sample properties for this estimator making formal inference possible. The estimator also allows for additional covariate effects. PMID- 23104318 TI - The role of steatosis in HBsAg seroclearance for patients with chronic hepatitis B infection: fact or fiction? PMID- 23104319 TI - Selecting patients during the "learning curve" of endoscopic Totally Extraperitoneal (TEP) hernia repair. AB - BACKGROUND: Totally Extraperitoneal (TEP) hernia surgery is associated with little postoperative pain and a fast recovery, but is a technically demanding operative procedure. Apart from the surgeon's expertise, patient characteristics and hernia-related variations may also affect the operative time and outcome. METHODS: Patient-related factors predictive of perioperative complications, conversion to open anterior repair, and operative time were studied in a cohort of consecutive patients undergoing TEP hernia repair from 2005 to 2009. RESULTS: A total of 3,432 patients underwent TEP. The mean operative time was 26 min (SD +/- 10.9), TEP was converted into an open anterior approach in 26 patients (0.8 %), and perioperative complications were observed in 55 (1.6 %) patients. Multivariable regression analysis showed that a history of abdominal surgery (OR 1.76, 95 per cent confidence interval 1.01-3.06; p = 0.05), and the presence of a scrotal (OR 5.31, 1.20-23.43; p = 0.03) or bilateral hernia (OR 2.25, 1.25-4.06; p = 0.01) were independent predictive factors of perioperative complications. Female gender (OR 5.30. 1.52-18.45; p = 0.01), a history of abdominal surgery (OR 3.96, 1.72- 9.12; p = 0.001), and the presence of a scrotal hernia (OR 34.84, 10.42-116.51, p < 0.001) were predictive factors for conversion. A BMI >= 25 (effect size (ES) 1.78, 95 % confidence interval 1.09-2.47; p < 0.001) and the presence of a scrotal (ES 5.81, 1.93-9.68; p = 0.003), indirect (ES 2.78, 2.05- 3.50, p < 0.001) or bilateral hernia (ES 10.19, 9.20-11.08; p < 0.001) were associated with a longer operative time. CONCLUSION: Certain patient characteristics are, even in experienced TEP surgeons, associated with an increased risk of conversion and complications and a longer operative time. For the surgeon gaining experience with TEP, it seems advisable to select relatively young and slender male patients with a unilateral (non-scrotal) hernia and no previous abdominal surgery to enhance patient safety and 'surgeon comfort'. PMID- 23104320 TI - The effect of preemptive analgesia with bupivacaine on postoperative pain of inguinal hernia repair under spinal anesthesia: a randomized clinical trial. AB - PURPOSE: In the absence of any study on the use of bupivacaine as a long acting local anesthetic for the purpose of inducing preemptive analgesia in patients undergoing inguinal hernia repair under spinal anesthesia, this study was conducted to provide some evidence for possible benefits of such practice. METHODS: In this randomized clinical trial, local infiltration of bupivacaine in patients undergoing inguinal hernia repair under spinal anesthesia was compared with placebo. The patients were randomly divided to two groups of 30 including the case group who received 10 cc of 0.5 % bupivacaine and the control group who received 10 cc of normal saline in the operation site before surgical incision. At the end of spinal block effect, patients were followed for symptoms of pain intensity according to numerical rating scale method, nausea, vomiting and opioid use for 24 h past the operation. RESULTS: The pain scores, nausea, vomiting and postoperative opioid use were 69.6, 76.5, 83.2 and 80 % respectively lower in first 24 h among the case group (P < 0.001, P = 0.005, P = 0.001 and P < 0.001). The number of patients with at least one analgesic request in first 24 h after operation was 64.2 % lower in case group, while time of first analgesic request was 67 % longer in treatment group (P < 0.001 and P < 0.001). CONCLUSION: The pre operative local infiltration of bupivacaine reduces pain, nausea, vomiting and opioid use in the first 24 h after inguinal hernia surgery under spinal anesthesia. Therefore, further evaluation of the efficacy of this technique as a modality of preemptive analgesia is suggested. PMID- 23104321 TI - Replacement treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating PI3K/Akt and MAPK signaling pathways. AB - We recently reported that both microRNA (miR)-143 and -145 are downregulated in human bladder cancer T24 cells and that miR-143 targets ERK5. In this study, we assessed the anti-tumor effects of combination treatment with miR-143 and -145 on bladder cancer cell lines T24, SNK57, and NKB1, in which the expression levels of miR-143 and -145 are downregulated. The ectopic expression of both miR-143 and 145 led to a significantly synergistic growth inhibition of T24 and NKB1 cells, but not that of SNK57 cells with the levels of miR-143 and -145 higher than those in T24 and NKB1 cells. The MAPK signaling pathway in NKB1 cells and both PI3K/Akt and MAPK signaling pathways in T24 cells were synergistically repressed by the co treatment with miR-143 and -145. We newly elucidated that miR-143 targeted akt and that miR-145 targeted integrin-linked kinase (ilk) in T24 cells based on the results of a luciferase activity assay. Silencing of ilk significantly inhibited the growth of all the bladder cancer cells tested. Also, the level of phosphorylated ERK1/2 in T24 cells and that of phosphorylated Akt in SNK57 and NKB1 cells were decreased by ilk silencing. This study has provided novel important evidence with regard to the functions of anti-oncogenic miR-143 and 145 and also suggests the possible use of miR-143 and -145 for combination replacement therapy in cancers in which both miRNAs are downregulated. PMID- 23104322 TI - Copper-catalyzed aerobic oxidative synthesis of alpha-ketoamides from methyl ketones, amines and NIS at room temperature. AB - A simple, efficient and practical copper-catalyzed aerobic oxidative synthesis of alpha-ketoamides from aryl methyl ketones, aliphatic amines and N-iodosuccinimide (NIS) has been developed. The one-pot reaction may proceed smoothly at room temperature in the open air. The possible mechanism for the formation of alpha ketoamides was proposed. Molecular oxygen in air functions as both an oxidant and an oxygen source. PMID- 23104323 TI - Population-level impact of the bivalent, quadrivalent, and nonavalent human papillomavirus vaccines: a model-based analysis. AB - BACKGROUND: Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines. METHODS: We developed an individual-based, transmission dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada. RESULTS: Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers. CONCLUSIONS: The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer. PMID- 23104326 TI - Rh-catalyzed linear hydroformylation of styrene. AB - Usually the Rh-catalyzed hydroformylation of styrene predominantly yields the branched, chiral aldehyde. An inversion of regioselectivity can be achieved using strong pi-acceptor ligands. Binaphthol-based diphosphite and bis(dipyrrolyl phosphorodiamidite) ligands were applied in the Rh-catalyzed hydroformylation of styrene. High selectivities up to 83% of 3-phenylpropanal were obtained with 1,1 bi-2-naphthol-based bis(dipyrrolyl-phosphorodiamidite) with virtually no hydrogenation to ethyl benzene. The coordination chemistry of those ligands towards Rh(I) was investigated spectroscopically and structurally. PMID- 23104325 TI - Human papillomavirus vaccines for cervical cancer prevention: translating possibility into reality. PMID- 23104324 TI - N-methylpurine DNA glycosylase and OGG1 DNA repair activities: opposite associations with lung cancer risk. AB - Only a minority of smokers develop lung cancer, possibly due to genetic predisposition, including DNA repair deficiencies. To examine whether inter individual variations in DNA repair activity of N-methylpurine DNA glycosylase (MPG) are associated with lung cancer, we conducted a blinded, population-based, case-control study with 100 lung cancer case patients and 100 matched control subjects and analyzed the data with conditional logistic regression. All statistical tests were two-sided. MPG enzyme activity in peripheral blood mononuclear cells from case patients was higher than in control subjects, results opposite that of 8-oxoguanine DNA glycosylase (OGG1) DNA repair enzyme activity. For lung cancer associated with one standard deviation increase in MPG activity, the adjusted odds ratio was 1.8 (95% confidence interval [CI] = 1.2 to 2.6; P = .006). A combined MPG and OGG1 activities score was more strongly associated with lung cancer risk than either activity alone, with an odds ratio of 2.3 (95% CI = 1.4 to 3.6; P < .001). These results form a basis for a future panel of risk biomarkers for lung cancer risk assessment and prevention. PMID- 23104328 TI - Visible light-induced 3-sulfenylation of N-methylindoles with arylsulfonyl chlorides. AB - The synthesis of 1-methyl-3-(arylthio)-1H-indoles has been achieved by the photoredox reaction of N-methylindoles with readily available arylsulfonyl chlorides in moderate yields. PMID- 23104327 TI - Simultaneous detection of major enteric viruses using a combimatrix microarray. AB - Various enteric viruses including norovirus, rotavirus, adenovirus, and astrovirus are the major etiological agents of food-borne and water-borne disease outbreaks and frequently cause non-bacterial gastroenteritis worldwide. Sensitive and high-throughput detection methods for these viral pathogens are compulsory for diagnosing viral pathogens and subsequently improving public health. Hence, we developed a sensitive, specific, and high-throughput analytical assay to detect most major enteric viral pathogens using "Combimatrix" platform oligonucleotide probes. In order to detect four different enteric viral pathogens in a sensitive and simultaneous manner, we first developed a multiplex RT-PCR assay targeting partial gene sequences of these viruses with fluorescent labeling for the subsequent microarray. Then, five olignonucleotides specific to each of the four major enteric viruses were selected for the microarray from the oligonulceotide pools targeting the specific genes obtained by multiplex PCR of these viruses. The oligonucleotide microarray was evaluated against stool specimens containing single or mixed viral species. As a result, we demonstrated that the multiplex RT-PCR assay specifically amplified partial sequences of four enteric viruses and the subsequent microarray assay was capable of sensitive and simultaneous detection of those viruses. The developed method could be useful for diagnosing enteric viruses in both clinical and environmental specimens. PMID- 23104329 TI - Comparison between Agrobacterium-mediated and direct gene transfer using the gene gun. AB - Agrobacterium-mediated transformation and direct gene transfer using the gene gun (microparticle -bombardment) are the two most widely used methods for plant genetic modification. The Agrobacterium method has been successfully practiced in dicots for many years, but only recently have efficient protocols been developed for grasses. Microparticle bombardment has evolved as a method delivering exogenous nucleic acids into plant genome and is a commonly employed technique in plant science. Here these two systems are compared for transformation efficiency, transgene integration, and transgene expression when used to transform tall fescue (Festuca arundinacea Schreb.). The tall fescue transformation protocols lead to the production of large numbers of fertile, independent transgenic lines. PMID- 23104330 TI - Transient gene expression in epidermal cells of plant leaves by biolistic DNA delivery. AB - Transient gene expression is a useful approach for studying the functions of gene products. In the case of plants, Agrobacterium infiltration is a method of choice for transient introduction of genes for many species. However, this technique does not work efficiently in some species, such as Arabidopsis thaliana. Moreover, the infection of Agrobacterium is known to induce dynamic changes in gene expression patterns in the host plants, possibly affecting the function and localization of the proteins to be tested. These problems can be circumvented by biolistic delivery of the genes of interest. Here, we present an optimized protocol for biolistic delivery of plasmid DNA into epidermal cells of plant leaves, which can be easily performed using the Bio-Rad Helios gene gun system. This protocol allows efficient and reproducible transient expression of diverse genes in Arabidopsis, Nicotiana benthamiana and N. tabacum, and is suitable for studies of the biological function and subcellular localization of the gene products directly in planta. The protocol also can be easily adapted to other species by optimizing the delivery gas pressure. PMID- 23104331 TI - Transformation of nuclear DNA in meristematic and embryogenic tissues. AB - Particle bombardment/biolistic delivery is a very popular method of genetic transformation of diverse targets including cells and intact tissues. Delivery of DNA through particle bombardment is genotype and species independent, nevertheless, an efficient protocol for large-scale generation of transgenic plants through embryogenic tissues with a high (>=80%) shoot regeneration efficiency is a prerequisite. Young embryogenic tissues or multiple shoot buds in early stages of induction are the most suited target tissues for recovery of transgenic plants. We describe the protocol for delivery of foreign genes using particle delivery system (Biorad gene gun, PDS-1000/He) in to the meristematic tissues of embryonic axes derived from mature seeds of castor. With the optimized physical and biological parameters, putative transformants were obtained at a frequency of 1.4% through particle gun bombardment of castor embryo axes. Also, transformation of embryogenic calli of sorghum using particle inflow gun (PIG) is described. PMID- 23104332 TI - Biolistic DNA delivery to leaf tissue of plants with the non-vacuum gene gun (HandyGun). AB - Non-vacuum gene guns such as HandyGun are flexible tools for bombardment of targets of varying size. Construction of HandyGun is simpler and cheaper than vacuum gene guns and will be described here. The conditions for maximal transient transformation efficiency of plant cells with plasmid DNA using HandyGun will be provided. PMID- 23104333 TI - HandGun-mediated inoculation of plants with viral pathogens for mechanistic studies. AB - Particle bombardment is an efficient method for virus inoculation of intact plants. This technique enables inoculation with full-length infectious clone cDNA, PCR products, virus from sap or virus preparation, and in vitro viral transcripts. The inoculation of some phloem-limited RNA and circular DNA viruses is also possible. The technique of bombardment without the use of vacuum permits the inoculation of soft-leaved plants that do not usually survive bombardment inoculation, the investigation of viral recombination in planta, promoter analysis, monitoring virus movement using an infectious clone bearing a reporter gene and the inoculation of large numbers of plants. The inoculation of whitefly borne circular DNA begomoviruses is now possible due to direct genome amplification by Rolling Circle Amplification (RCA), followed by bombardment using a device that does not require a vacuum for operation. Here we describe the inoculation of intact plants with (a) RNA virus infective clones and (b) begomoviruses after direct genome amplification by RCA, using a handheld bombardment device. PMID- 23104334 TI - Biolistics-based gene silencing in plants using a modified particle inflow gun. AB - RNA interference (RNAi) is one of the most commonly used techniques for examining the function of genes of interest. In this chapter we present two examples of RNAi that use the particle inflow gun for delivery of the DNA constructs. In one example transient RNAi is used to show the function of an anthocyanin regulatory gene in flower petals. In the second example stably transformed cell cultures are produced with an RNAi construct that results in a change in the anthocyanin hydroxylation pattern. PMID- 23104335 TI - Biolistic transformation of Caenorhabditis elegans. AB - The ability to generate transgenic animals to study gene expression and function is a powerful and important part of the Caenorhabditis elegans genetic toolbox. Transgenic animals can be created by introducing exogenous DNA into the worm germline either by microinjection or by microparticle bombardment (biolistic transformation). In this chapter we describe a simple and robust protocol to generate transgenic C. elegans animals by biolistic transformation with gold particles using the Bio-Rad PDS-1000/He system with Hepta adapter and unc-119 selection marker. We also point out the steps that need special attention to achieve successful transformations. PMID- 23104336 TI - Improved vectors for selection of transgenic Caenorhabditis elegans. AB - The generation of transgenic animals is an essential part of research in Caenorhabditis elegans. One technique for the generation of these animals is biolistic bombardment involving the use of DNA-coated microparticles. To facilitate the identification of transgenic animals within a background of non transformed animals, the unc-119 gene is often used as a visible marker as the unc-119 mutants are small and move poorly and the larger size and smoother movement of rescued animals make them clearly visible. While transgenic animals can be identified from co-bombardment with a transgene of interest and a separate unc-119 rescue plasmid, placing the unc-119 in cis on the transgene increases confidence that the resulting transgenic animals contain and express both the marker and the transgene. However, placing the unc-119 marker on the backbone of a plasmid or larger DNA construct, such as a fosmid or BAC, can be technically difficult using standard molecular biology techniques. Here we describe methods to circumvent these limitations and use either homologous recombination or Cre LoxP mediated recombination in Escherichia coli to insert the unc-119 marker on to a variety of vector backbones. PMID- 23104337 TI - Biolistic transformation of Brugia malayi. AB - Biolistics has become a versatile tool for direct gene transfer to various cell and tissue types. Following its successful use on the parasitic nematode Ascaris suum, we developed and evaluated biolistics in the transfection of the model filarial parasite Brugia malayi. Biolistics was proven to be an efficient strategy for transfection of all life stages of the parasite and paved the way for studies on elements essential for promoter function and gene regulation of filarial parasites. Here we present a biolistics protocol for the transfection of B. malayi based on the Biolistics PDS 1000/He system and gold microcarriers. PMID- 23104338 TI - Biolistic transfection of human embryonic kidney (HEK) 293 cells. AB - Due to its excellent transfectability, the human embryonic kidney (HEK) 293 cell line is widely used as an in vitro model system for transfection experiments. Particle bombardment, or biolistics technology, provides a physical transfection approach that can deliver transgene materials efficiently into many different cell lines. Transfection of 293 cells by gene gun, allows examination of transgene expression in epithelial cells, as well as studies concerning a variety of questions in neurobiology. The present study of transfection of HEK 293 cells by biolistics technology uses the plasmids gWIZ-luc encoding luciferase and gWIZ GFP encoding green fluorescence protein (GFP) as model transgenes. This system can be routinely used at varying bombarding conditions that can be adjusted according to experimental requirements and purpose, such as gene gun helium pressure, the sizes and the amount of the gold particles and the length of the spacer. The results obtained show that the Bio-Rad spacer for the gene gun should be optimized for travel distance and spreading of gold particles over a relatively small area, when used for biolistic transfection of cells dispersed in multi-well plate. PMID- 23104339 TI - Biolistic transfection of tumor tissue samples. AB - A nonviral method for gene transfer into mammalian cells has been developed using physical force which accelerates plasmid DNA-coated gold particles to high -speed and penetrate the mammalian cells. This technology of gene transfer via a biolistic transfection method has been shown to have multiple applications to mammalian gene transfer systems. This method has also been adapted for delivery of other macromolecules like RNA, microRNA, and proteins. A broad range of somatic cell types, including primary cell cultures and established cell lines, have been successfully transfected ex vivo or in vitro by using the gene gun technology, either as suspension or adherent cells in cultures. This chapter describes the general procedures for in vitro DNA transfection by particle mediated delivery to nonadherent and adherent cells. These procedures can be readily employed by using the Helios gene gun system (Bio-Rad, Hercules, CA) based on the Accell design. PMID- 23104340 TI - Biolistic transfection of freshly isolated adult ventricular myocytes. AB - Transfection of mammalian cells has long been an extremely powerful approach for the study of the effects of specific gene expression on cell function. Until recently, however, this approach has been unavailable for the study of gene function in adult cardiac myocytes. Here, an adaptation of the biolistic method to the transfection of adult cardiac myocytes is described. DNA is precipitated onto gold particles in the absence of PVP and the particles are biolistically delivered to freshly isolated adult rat cardiomyocytes via a Bio-Rad Helios System gene gun. The myocytes are cultured in the absence of bovine serum albumin and expression of the introduced genes, in phenotypically intact myocytes, is robust within 12-24 h. PMID- 23104342 TI - Biolistic DNA delivery to mice with the low pressure gene gun. AB - Biolistic DNA delivery is an approach to deliver plasmid to culture cells, plants, or animals. Plasmid DNA is usually transferred through bombardment of DNA coated particles by highly pressurized gas in various kinds of delivery vehicles. The low pressure gene gun can deliver plasmid at lower pressure. Here, we describe methods of biolistic DNA delivery to mice using the low pressure gene gun. PMID- 23104341 TI - Biolistic transfection of neurons in organotypic brain slices. AB - Transfection of postmitotic neurons is one of the most challenging goals in the field of gene delivery. Currently most procedures use dissociated cell cultures but organotypic slice preparations have significant advantages as an experimental system; they preserve the three-dimensional architecture and local environment of neurons, yet still allow access for experimental manipulations and observations. However exploring the effects of novel genes in these preparations requires a technique that can efficiently transfect cells deep into tissues. Here we show that biolistic transfection is an effective and straightforward technique with which to transfect such cells. PMID- 23104343 TI - Chemokine overexpression in the skin by biolistic DNA delivery. AB - Chemokines are a family of small, secreted proteins that function in leukocyte and tumor cell trafficking and recruiting. CC chemokine ligand 21 (CCL21)/secondary lymphoid chemokine (SLC) belongs to the inflammatory subgroup of chemokines and is expressed by stromal cells in the T-cell-rich zones of peripheral lymph nodes, afferent lymphatic endothelial cells and high endothelial venules. CCR7 (both in human and mouse) and CXCR3 (in mouse) are expressed by the most potent antigen-presenting cells (dendritic cells), naive/central memory, and effector T cells, respectively. Inflammation in the skin can induce expression of CCL21 which is subsequently drained into loco-regional lymph nodes responsible for co-localization of antigen-presenting cells and T lymphocytes, a prerequisite for induction of adaptive immune responses. Here, skin functions as a remote control for induction of targeted cell migration in vivo. This chapter describes Gene Gun administration of plasmid DNA expressing functionally active CCL21 (as an example of a chemokine) into the skin in mice and subsequent functional evaluation of the transgene expression in vivo. PMID- 23104344 TI - Enhancement of gene gun-induced vaccine-specific cytotoxic T-cell response by administration of chemotherapeutic drugs. AB - Because they specifically kill dividing cells, untargeted chemotherapeutic drugs such as platin derivatives, antimetabolites or topoisomerase inhibitors for example impact the immune system resulting in more or less profound transient lympho- and/or myelo-ablations in treated patients. Although this side effect of chemotherapeutic regimens could be assumed as immunosuppressive, it surprisingly appeared to eventually potentiate vaccination. By demonstrating that regulatory T cells that mediate inhibition of immune responses proliferate more than other CD4 positive T-cells, we identified a possible mechanism underlying the vaccine enhancing feature of certain chemotherapeutic anticancer regimen. The combination of cytostatic drugs and Gene Gun vaccination is of great interest in particular for the enhancement of antitumor, including "anti-self," vaccination strategies to treat cancer. Here we describe the effect of Gemcitabine, a standard chemotherapeutic drug, on human and mouse regulatory T-cells in vivo and present the methods allowing to trigger and detect an enhanced cytotoxic T-cell immune response using Gene Gun vaccination after Gemcitabine administration. PMID- 23104345 TI - Dendritic cell-specific biolistic transfection using the fascin gene promoter. AB - The transcriptional targeting of gene expression to selected cells by cell type specific promoters displays a fundamental tool in gene therapy. In immunotherapy, dendritic cells (DCs) are pivotal for the elicitation of antigen-specific immune responses following gene gun-mediated biolistic transfection. Here we report on transcriptional targeting of murine skin DCs using plasmids which include the promoter of the gene of the cytoskeletal protein fascin to control antigen production. Fascin, which is mandatory for the formation of dendrites, is synthesized among the hematopoietic cells exclusively by activated DCs. The activity of the promoter of the fascin gene reflects the endogenous production of the protein, being high in mature DCs but almost absent in immature DCs or other cutaneous cells. Here we describe the analysis of transgene-specific immune responses after DC-focused biolistic transfection. In conclusion, the murine fascin promoter can be readily used to target DCs in DNA immunization approaches and thus offers new opportunities for gene therapy. PMID- 23104346 TI - Particle-mediated administration of plasmid DNA on corneas of BALB/c mice. AB - Gene gun administration of DNA is an invaluable technique for transfecting tissues with only 1 MUg DNA/shot. Here, we describe a transfection technique of healthy corneas of BALB/c mice with a standard gene gun, using a technique that can avoid tissue destruction even when high pressure is used (e.g., 700 psi). The focal transfection of the cornea to improve corneal disease may be an advantage over other transfection methods in order to avoid unwanted bystander transfection in other compartments of the eye or body. PMID- 23104347 TI - Optimizing particle-mediated epidermal delivery of an influenza DNA vaccine in ferrets. AB - Particle-mediated DNA delivery technologies ("gene guns") have been shown in both animal and clinical studies to be an effective means of increasing the immunogenicity and protective efficacy of DNA vaccines. The primary goal in optimizing particle-mediated epidermal delivery (PMED) vaccination in different animal models is to achieve delivery of DNA-coated gold beads into the viable epidermis. Two key para-meters that influence this outcome include the delivery pressure, which controls the penetrative force of the beads into the skin, and the anatomical site of DNA delivery. Although the ferret has been extensively used as an experimental model for influenza infection in humans, very few studies have investigated the capacity for PMED DNA vaccination to induce protective immune responses in ferrets. Here we describe methods to optimize DNA vaccine delivery using the PowderJect XR1 gene delivery in ferrets. We first assess the effects of firing pressure on both the delivery of DNA-coated gold beads into the desired epidermal layer and the degree of DNA vaccine reporter gene expression at the target site. Second, we evaluate the impact of vaccination site (skin or tongue) on DNA vaccine immunogenicity by measuring serum antibody responses to the model antigens influenza virus hemagglutinin and hepatitis B core antigen. Results from these studies support the use of the PowderJect XR1 device in ferrets for the study of prophylactic and therapeutic DNA vaccines against clinically important diseases such as influenza virus infection. PMID- 23104348 TI - Methods for monitoring gene gun-induced HBV- and HCV-specific immune responses in mouse models. AB - The hepatitis B and C viruses (HBV/HCV) are major causes for chronic liver disease globally. For HBV new antiviral compounds can suppress the viral replication for years, but off-therapy responses are rare. Current therapies based on interferon and ribavirin can cure 45-85% of the treated HCV-infected patients largely depending on the viral genotype. New regimens including protease inhibitors will be introduced during 2011 and these will increase the cure rates for the hardest to treat HCV genotype 1 from 45 to 65%. Here a major need is to replace the immunomodulatory effects of interferon and/or ribavirin. Thus, therapeutic vaccines have a place in both chronic HBV and HCV infection. Unfortunately, none of these viruses can infect mice whereby substitute models are needed. We have used several types of murine models to predict the clinical efficacy of therapeutic vaccines for chronic HBV and HCV infections. In this chapter we describe transdermal delivery of genetic vaccines using the Helios Gene Gun device. A central role is that the model should have generally functional immune response, but with selective defects towards HBV and/or HCV. Thus, mice with stable integrated transgenes are useful. However, as a simple model to study the hepatic entry and functionality of a HBV- and/or HCV-specific immune responses other models are needed, where a killed transgenic hepatocyte is replaced by a healthy non-transgenic hepatocyte. Here we can effectively apply a technique termed hydrodynamic injection, which makes 10-30% of hepatocytes transiently transgenic for any plasmid. Within this chapter the methods used to characterize transiently transgenic mice are described. The main methods are the hydrodynamic injection technique, detection of transgene expression by immuno precipitation, western blot, and immunohistochemistry. Finally, the in vivo functionality of T cells can be determined by using stably transfected syngeneic tumor cell lines expressing HBV and/or HCV proteins. The tumor challenge model enables studies of in vivo T cell function, whereas the cytotoxicity assay is used to determine T cell function in vitro. Overall, these models effectively reveal the efficiency by which various vaccine technologies, including biolistic DNA vaccination can kill the "infected" hepatocyte. PMID- 23104349 TI - Gene gun immunization to combat malaria. AB - DNA immunization by gene gun against a variety of infectious diseases has yielded promising results in animal models. Skin-based DNA vaccination against these diseases is not only an attractive option for the clinic but can aid in the discovery and optimization of vaccine candidates. Vaccination against the protozoan parasite Plasmodium presents unique challenges: (a) most parasite associated antigens are stage-specific; (b) antibodies capable of neutralizing the parasite during the probing of the mosquitoes have to be available at high titers in order to prevent infection of the liver; (c) immunity to liver-stage infection needs to be absolute in order to prevent subsequent blood-stage parasitemia. Gene gun vaccination has successfully been used to prevent the infection of mice with the rodent malaria strain P. berghei and has been employed in a macaque model of human P. falciparum. DNA plasmid delivery by gene gun offers the opportunity to economically and efficiently test novel malaria vaccine candidates and vaccination strategies, which include the evaluation of novel molecular adjuvant strategies. Here we describe the procedures involved in making and delivering a pre-clinical malaria DNA vaccine by gene gun as well as the correct approach for the in vivo evaluation of the vaccine. Furthermore, we discuss various approaches that either have already been tested or could be employed to improve DNA vaccines against malaria. PMID- 23104350 TI - Identification of T cell epitopes of Mycobacterium tuberculosis with biolistic DNA vaccination. AB - Tuberculosis (TB) has been listed as one of the most prevalent and serious infectious diseases worldwide. The etiological pathogen of TB is Mycobacterium tuberculosis (Mtb), a facultative intracellular bacterium. Mycobacterium bovis bacillus Calmette-Guerin (BCG) is the only approved vaccine against TB to date. BCG has been widely used, but the efficacy is questionable, especially in adult pulmonary TB. Therefore, more effective, safe and reliable TB vaccines have been urgently needed. T cell-mediated cellular immune response is a key immune response for effective protective immunity against TB. DNA vaccines using Mtb antigens have been studied as promising future TB vaccines. Most TB DNA vaccine studies so far reported used intramuscular or intradermal injection with needles, as these methods tend to induce a type 1 helper T lymphocyte (Th1)-type immune response that is critical for the protective immunity. We have been using DNA vaccines with gene gun bombardment for T cell epitope identification of various Mtb antigens. We show here our strategy to identify precise Mtb T cell epitopes using DNA vaccines with gene gun bombardment. PMID- 23104351 TI - Biolistic DNA vaccination against Trypanosoma infection. AB - Immunization to protect against Trypanosoma cruzi infection has the potential to greatly decrease the burden of Chagas' disease in the Americas. Several target antigens have been explored by multiple investigators and show promise, but given that this parasite has multiple stages within the mammalian host, with both intracellular and extracellular forms, a multivalent vaccine will probably be necessary to provide complete immunity and prevent disease. Therefore, DNA immunization is an attractive method for efficient and effective delivery of multiple target antigens. In addition, the target population for a T. cruzi vaccine lives predominately in poorer rural areas in South America, making the stable DNA-gold precipitate, which does not require a cold-chain, used in biolistic immunization an attractive method for vaccination. Here we describe a biolistic immunization protocol that is capable of generating high titer antibody responses to recombinant T. cruzi vaccine targets and the in vitro preparation of T. cruzi for use in experimental vaccine challenge studies. PMID- 23104352 TI - Biolistic DNA vaccination against melanoma. AB - We describe here the use of particle-mediated gene transfer for the induction of immune responses against melanoma antigens in murine tumor models using the melanocyte differentiation antigen tyrosinase-related protein 2 (TRP2) as an antigen in a murine B16 melanoma model. We have utilized marker genes such as beta-galactosidase (betagal) and EGFP, which can be readily detected, as control antigens to establish the gene delivery and to detect antigen-specific humoral and cellular immune responses. After biolistic DNA vaccination with plasmids encoding the TRP2 gene we observed the induction of TRP2-specific T-cells and antibodies associated with vitiligo-like fur depigmentation and tumor immunity against B16 melanoma cells. Here we describe the preparation of cartridges with DNA-coated gold beads and the in vivo gene transfer into skin using the Helios Gene Gun system. We also describe protocols for the measurement of humoral and cellular immune responses against the melanocyte differentiation antigen TRP2. These protocols can subsequently be adapted to other antigens. PMID- 23104353 TI - Biolistic DNA vaccination against cervical cancer. AB - The development of cervical cancer is associated with infection by oncogenic human papillomaviruses (HPVs), of which type 16 (HPV16) is the most prevalent in HPV-induced malignant diseases. The viral oncoproteins E6 and E7 are convenient targets for anti-tumor immunization. To adapt the corresponding genes for DNA vaccination, their oncogenicity needs to be reduced and immunogenicity enhanced. The main modifications for achieving these aims include mutagenesis, rearrangement of gene parts, and fusion with supportive cellular or viral/bacterial genes or their functional parts. As HPVs are strictly human specific, an animal model of HPV infection does not exist. Therefore, immunization against HPV-induced tumors is most frequently tested in mouse models utilizing transplantable syngeneic tumor cells producing the HPV16 E6/E7 oncoproteins. In this chapter, one such cell line designated TC-1 is characterized and the effect of immunization with the modified E7 fusion gene against TC-1-induced subcutaneous tumors is described. As down-regulation of MHC class I molecules is one of the most important escape mechanisms of cervical carcinoma cells, the TC-1/A9 clone with reversibly reduced MHC class I expression has been developed and, herein, its response to DNA vaccination is also shown and compared with that of the TC-1 cells. PMID- 23104354 TI - Efficiency of biolistic DNA vaccination in experimental type I allergy. AB - Gene gun-mediated delivery of allergen-encoding plasmid DNA has been in focus for many years now as being a needle-free alternative to the protein-based desensitization regimen used in specific immunotherapy. Biolistic immunization with the Helios gene gun has proven to be potent in the induction of antigen specific CD4(+) and CD8(+) T cells. Here we describe biolistic vaccination in experimental mouse models of IgE-mediated type I allergy as well as allergen induced airway inflammation. PMID- 23104355 TI - Safety assessment of biolistic DNA vaccination. AB - DNA-based vector systems have been widely studied as new modalities for the prevention and treatment of human diseases. As for all other medicinal products, safety is an important aspect in the evaluation of such products. In this chapter we reflect on the basic safety issues which have been raised with respect to preventive and therapeutic DNA vaccines, including insertional mutagenesis in case of chromosomal integration, possible formation of anti-DNA antibodies, induction of autoimmune responses and/or immunological tolerance. In addition, local reactions at the site of administration and adverse effects resulting from plasmid DNA spread to nontarget tissues are discussed. Most importantly, however, the benefit-risk profile of a medicinal product is crucial for a decision on providing marketing authorization or not. A product has an acceptable benefit risk profile if the benefits of the product outweigh its risks for the treated patient. PMID- 23104356 TI - DiOlistics: delivery of fluorescent dyes into cells. AB - DiOlistic labeling utilizes a particle-mediated delivery system to incorporate dye into cells. Because of its random nature, this technique generates sparse fluorescent labeling which is well suited for the study of neuronal dendritic branching and dendritic spine morphology. DiOlistics is a quick, reliable and nontoxic method that can be used in combination with other techniques such as immunostaining, biolistic DNA transfection, and retrograde tracing. In this article, we describe the methods for diOlistic labeling of neurons from rodent brain slices using DiI and the imaging of neuronal and synaptic morphology using confocal microscopy. PMID- 23104357 TI - Protein antigen delivery by gene gun-mediated epidermal antigen incorporation (EAI). AB - The gene gun technology can not only be employed for efficient transfer of gene vaccines into upper layers of the skin, but also for application of protein antigens. As a tissue rich in professional antigen presenting cells, the skin represents an attractive target for immunizations. In this chapter we present a method for delivery of the model antigen ovalbumin into the skin of mice termed epidermal antigen incorporation and describe in detail how antigen-specific proliferation in draining lymph nodes can be followed by flow cytometry. PMID- 23104358 TI - Falsirhodobacter halotolerans gen. nov., sp. nov., isolated from dry soils of a solar saltern. AB - Two bacterial strains (JA744(T) and JA745) were isolated from dry soil samples collected from solar salterns at Humma, Odisha, India. Both strains were Gram stain-negative, catalase- and oxidase-positive, motile rods. Major fatty acids in both strains included C18:1omega7c, C18:0 and C16:0, while minor amounts of C10:0 3-OH, C12:0, C12:0 3-OH, C14:0 and C16:0 were also present. Diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, phosphatidylglycerol, an unidentified glycolipid, five unidentified lipids, an unidentified aminolipid and an unidentified phospholipid made up the polar lipids of both strains. Both strains had bacteriohopane derivatives (BHD1,2) and diploptene as major hopanoids. Mean genomic DNA G+C content was 75 +/- 1 mol% and the two strains were closely related (mean DNA-DNA hybridization >90%). Phylogenetic analysis based on the 16S rRNA gene sequence showed that the two strains clustered with species of the genus Rhodobacter belonging to the family Rhodobacteraceae of the class Alphaproteobacteria. The highest sequence similarity was observed with Rhodobacter sphaeroides ATH2.4.1(T) (96%) and other members of the genera Rhodobacter and Pseudorhodobacter (<96%). However, the two strains were positioned distinctly outside the group formed by the other genera of the family Rhodobacteraceae. Distinct morphological, physiological and genotypic differences from previously described taxa support the classification of these isolates as representatives of a novel species in a new genus, for which the name Falsirhodobacter halotolerans gen. nov., sp. nov. is proposed. The type strain of Falsirhodobacter halotolerans is JA744(T) (=KCTC 32158(T) =NBRC 108897(T)). PMID- 23104359 TI - Starmerella jinningensis sp. nov., a yeast species isolated from flowers of Erianthus rufipilus. AB - Five yeast strains (Ym24403, Ym24404, Ym24408, Ym24409 and Ym24410(T)) were isolated from different flowers of Erianthus rufipilus (Gramineae), a wild plant growing in the phosphorus-rich region in Yunnan Province, south-western China, and were found to be phenotypically and genetically divergent from currently recognized yeast species. Sequence analysis of the D1/D2 domain of the large subunit rRNA gene revealed that the five strains represented a novel species described as Starmerella jinningensis sp. nov. The type strain is Ym24410(T) (= CBS 11864(T) =CCTCC AY 2011002(T)). Phylogenetic analysis based on the D1/D2 region of the large subunit rRNA gene suggested that S. jinningensis sp. nov. is placed within the Starmerella clade. PMID- 23104360 TI - Candida ecuadorensis sp. nov., an ascomycetous yeast species found in two separate regions of Ecuador. AB - In the course of an on-going study aimed at cataloguing the natural yeast biodiversity found in Ecuador, two strains (CLQCA 13-025 and CLQCA 20-004(T)) were isolated from samples of cow manure and rotten wood collected in two separate provinces of the country (Orellana and Bolivar). These strains were found to represent a novel yeast species based on the sequences of their D1/D2 domain of the large-subunit (LSU) rRNA gene and their physiological characteristics. Phylogenetic analysis based on LSU D1/D2 sequences revealed this novel species to belong to the Metschnikowia clade and to be most closely related to Candida suratensis, a species recently discovered in a mangrove forest in Thailand. The species name of Candida ecuadorensis sp. nov. is proposed to accommodate these strains, with strain CLQCA 20-004(T) (=CBS 12653(T) = NCYC 3782(T)) designated as the type strain. PMID- 23104361 TI - Pontimonas salivibrio gen. nov., sp. nov., a new member of the family Microbacteriaceae isolated from a seawater reservoir of a solar saltern. AB - A Gram-staining-positive, non-motile, strictly aerobic, non-spore-forming, vibrio shaped bacterial strain, CL-TW6(T), was isolated from a reservoir seawater sample from a solar saltern in Korea. Analysis of the 16S rRNA gene sequence of strain CL-TW6(T) revealed a clear affiliation with the family Microbacteriaceae. Strain CL-TW6(T) showed the closest phylogenetic relationships with the genera Yonghaparkia and Microcella, with 16S rRNA gene sequence similarity of 94.8 95.3%. The strain grew in the presence of 1-9% sea salts, at 15-35 degrees C and at pH 7.0-9.0. The major cellular fatty acids of strain CL-TW6(T) were anteiso C15:0 (32.6%), iso-C16:0 (20.4%), iso-C15:0 (13.2%) and iso-C14:0 (11.8%) and the major menaquinones were MK-9 and MK-10. Cell-wall analysis showed that the peptidoglycan of strain CL-TW6(T) contained 2,4-diaminobutyric acid, alanine, glycine and glutamic acid. The major polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The genomic DNA G+C content of strain CL-TW6(T) was 60.0 mol%. The combined phenotypic, chemotaxonomic and phylogenetic data showed clearly that strain CL-TW6(T) could be distinguished from members of the family Microbacteriaceae with validly published names. Thus, strain CL-TW6(T) should be classified as representing a novel genus and species in the family Microbacteriaceae, for which the name Pontimonas salivibrio gen. nov., sp. nov. is proposed. The type strain of Pontimonas salivibrio is CL-TW6(T) (=KCCM 90105(T) =JCM 18206(T)). PMID- 23104362 TI - Xiangella phaseoli gen. nov., sp. nov., a member of the family Micromonosporaceae. AB - A novel endophytic actinomycete, designated strain NEAU-J5(T) was isolated from roots of snap bean (Phaseolus vulgaris L.). Comparative analysis of the 16S rRNA gene sequence indicated that NEAU-J5(T) is phylogenetically related to members of the family Micromonosporaceae. The whole-cell sugars were galactose, mannose and glucose. The predominant menaquinones were MK-9(H4) and MK-9(H6). The major fatty acids were C16:0, C18:0, C17:1omega7c, iso-C15:0 and C17:0. The phospholipids were phosphatidylmethylethanolamine, phosphatidylethanolamine, phosphatidylcholine, phosphatidylinositol and phosphatidylinositol mannoside. The DNA G+C content was 72.2 mol%. On the basis of the morphological and chemotaxonomic characteristics, phylogenetic analysis and characteristic patterns of 16S rRNA gene signature nucleotides, strain NEAU-J5(T) represents a novel species of a new genus within the family Micromonosporaceae, for which the name Xiangella phaseoli gen. nov., sp. nov. is proposed. The type strain of Xiangella phaseoli is strain NEAU-J5(T) (=CGMCC 4.7038(T)=DSM 45730(T)). PMID- 23104363 TI - Emendation of the description of the species Corynebacterium propinquum to include strains which produce urease. AB - Corynebacterium propinquum is a Gram-positive rod occasionally recovered from clinical infections which, according to 16S rRNA gene sequencing, is most closely related (>99% sequence similarity) to Corynebacterium pseudodiphtheriticum. The two species are very similar biochemically, commonly differentiated by a single test, the detection of urease, where strains of C. propinquum are described as being urease-non-producing and strains of C. pseudodiphtheriticum are described as urease-producing. In this study, historical and contemporary strains of C. propinquum and C. pseudodiphtheriticum from this laboratory were definitively characterized, which included use of rpoB sequencing. Urease-producing strains of C. propinquum as well as typical urease-non-producing isolates were identified after rpoB sequencing, with six of these being originally identified as C. pseudodiphtheriticum. Based on these observations, we propose emendation of the description of C. propinquum to include strains which produce urease. MALDI-TOF analysis may be a useful tool to differentiate these taxa. Existing commercial databases should be updated to include urease-positive strains of C. propinquum. PMID- 23104364 TI - Palaeococcus pacificus sp. nov., an archaeon from deep-sea hydrothermal sediment. AB - A hyperthermophilic, anaerobic, piezophilic archaeon (strain DY20341(T)) was isolated from a sediment sample collected from an East Pacific Ocean hydrothermal field (1 degrees 37' S 102 degrees 45' W) at a depth of 2737 m. The cells were irregular cocci, 0.8-1.5 um in diameter. Growth was observed between 50 and 90 degrees C (optimum 80 degrees C), pH 5.0 and 8.0 (optimum pH 7.0), 1% and 7% (w/v) sea salts (Sigma, optimum 3%), 1% and 4% (w/v) NaCl (optimum 3%) and 0.1 and 80 MPa (optimum 30 MPa). The minimum doubling time was 66 min at 30 MPa and 80 degrees C. The isolate was an obligate chemoorganoheterotroph, capable of utilizing complex organic compounds and organic acids including yeast extract, peptone, tryptone, casein, starch, Casamino acids, citrate, lactate, acetate, fumarate, propanoate and pyruvate for growth. It was strictly anaerobic and facultatively dependent on elemental sulfur or sulfate as electron acceptors, but did not reduce sulfite, thiosulfate, Fe(III) or nitrate. The presence of elemental sulfur enhanced growth. The G+C content of the genomic DNA was 43.6 +/- 1 mol%. 16S rRNA gene sequence analysis revealed that the closest relative of the isolated organism was Palaeococcus ferrophilus DMJ(T) (95.7% 16S rRNA gene similarity). On the basis of its physiological properties and phylogenetic analyses, the isolate is considered to represent a novel species, for which the name Palaeococcus pacificus sp. nov. is proposed. The type strain is strain DY20341(T) (=JCM 17873(T)=DSM 24777(T)). PMID- 23104365 TI - Novosphingobium lindaniclasticum sp. nov., a hexachlorocyclohexane (HCH) degrading bacterium isolated from an HCH dumpsite. AB - A yellow-pigmented, Gram-negative, aerobic, non-motile, non-spore-forming, rod shaped-bacterium, LE124(T), was isolated from a hexachlorocyclohexane (HCH) dumpsite located in Lucknow, India. The type strain LE124(T) grew well with hexachlorocyclohexane as a sole carbon source, degrading it within 24 h of incubation. Phylogenetic analysis of strain LE124(T) showed highest 16S rRNA gene sequence similarity to Novosphingobium barchaimii LL02(T) (98.5%), Novosphingobium panipatense SM16(T) (98.1%), Novosphingobium soli CC-TPE-1(T) (97.9%), Novosphingobium naphthalenivorans TUT562(T) (97.6%), Novosphingobium mathurense SM117(T) (97.5%) and Novosphingobium resinovorum NCIMB 8767(T) (97.5%) and lower sequence similarity (<97%) to all other members of the genus Novosphingobium. The DNA-DNA relatedness between strain LE124(T) and N. barchaimii LL02(T) and other related type strains was found to vary from 15% to 45% confirming that it represents a novel species. The genomic DNA G+C content of strain LE124(T) was 60.7 mol%. The predominant fatty acids were summed feature 8 (C18:1omega7c, 49.1%), summed feature 3 (C16:1omega7c/C16:1omega6c, 19.9%), C16:0 (6.7%), C17:1omega6c (4.9%) and a few hydroxyl fatty acids, C14:0 2-OH (9.4%) and C16:0 2-OH (2.1%). Polar lipids consisted mainly of phosphatidyldimethylethanolamine, phosphatidylcholine, diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, sphingoglycolipid and some unidentified lipids. The major respiratory quinone was ubiquinone Q-10. Spermidine was the major polyamine observed. Phylogenetic analysis, DNA-DNA hybridization, chemotaxonomic and phenotypic analysis support the conclusion that strain LE124(T) represents a novel species within the genus Novosphingobium for which we propose the name Novosphingbium lindaniclasticum sp. nov. The type strain is LE124(T) (=CCM 7976(T)=DSM 25409(T)). PMID- 23104366 TI - Practical aspects of arteriovenous fistula formation in the pediatric population. AB - The principle of "Fistula First" for hemodialysis has been widely adopted among adults with end-stage renal failure (ESRF). UK national targets aim to have 85 % of prevalent patients using permanent access (arteriovenous fistula or graft). Currently, hemodialysis in children relies heavily on central venous catheters (CVC). However, there is significant evidence that arteriovenous fistulae (AVF) are preferable for long-term dialysis in the pediatric population. We describe the principles of fistula formation including pre-operative work-up, surgical techniques for AVF creation, and post-operative monitoring. PMID- 23104368 TI - Genome update of Botrytis cinerea strains B05.10 and T4. AB - We report here an update of the Botrytis cinerea strains B05.10 and T4 genomes, as well as an automated preliminary gene structure annotation. High-coverage de novo assemblies and reference-based alignments led to a correction of wrong base calls, elimination of sequence gaps, and improved joining of contigs. The new assemblies have substantially lower numbers of scaffolds and a concomitant increase in the N(50).The list of protein-coding genes was generated using the evidence-driven gene predictor Augustus, with expressed sequence tag evidence and RNA-Seq data as input. PMID- 23104369 TI - Draft genome sequence of CBS 2479, the standard type strain of Trichosporon asahii. AB - Trichosporon asahii is one of the important opportunistic pathogenic fungi. Here, we first report the draft nuclear chromosome genome sequence and mitochondrial genome sequence of T. asahii CBS 2479, which is a standard strain of T. asahii that was isolated from a progressive psoriatic lesion. COG analysis predicted that 3,131 genes were assigned to 23 functional categories and that 628 genes were predicted to have a general function. PMID- 23104370 TI - Complete mitochondrial and plastid genomes of the green microalga Trebouxiophyceae sp. strain MX-AZ01 isolated from a highly acidic geothermal lake. AB - We report the complete organelle genome sequences of Trebouxiophyceae sp. strain MX-AZ01, an acidophilic green microalga isolated from a geothermal field in Mexico. This eukaryote has the remarkable ability to thrive in a particular shallow lake with emerging hot springs at the bottom, extremely low pH, and toxic heavy metal concentrations. Trebouxiophyceae sp. MX-AZ01 represents one of few described photosynthetic eukaryotes living in such a hostile environment. The organelle genomes of Trebouxiophyceae sp. MX-AZ01 are remarkable. The plastid genome sequence currently presents the highest G+C content for a trebouxiophyte. The mitochondrial genome sequence is the largest reported to date for the Trebouxiophyceae class of green algae. The analysis of the genome sequences presented here provides insight into the evolution of organelle genomes of trebouxiophytes and green algae. PMID- 23104371 TI - Genome sequence of Aureobasidium pullulans AY4, an emerging opportunistic fungal pathogen with diverse biotechnological potential. AB - Aureobasidium pullulans AY4 is an opportunistic pathogen that was isolated from the skin of an immunocompromised patient. We present here the draft genome of strain AY4, which reveals an abundance of genes relevant to bioindustrial applications, including biocontrol and biodegradation. Putative genes responsible for the pathogenicity of strain AY4 were also identified. PMID- 23104372 TI - Current trends in cardiac CT in children. AB - Cardiac CT is increasingly utilized in children thanks to advanced scan techniques reducing cardiac and respiratory motion artifacts. Consequently, clinical indications of cardiac CT are not confined to the extracardiac evaluation and extended further to the assessment of intracardiac structures, coronary arteries, ventricular volumetry, and ventricular function. In addition, dual-energy CT allows the assessment of regional lung perfusion and ventilation. Four-dimensional airway evaluation is also useful and may be added to cardiac CT protocols. At the same time, a favorable risk-benefit ratio of cardiac CT can be achieved by means of various dose-saving techniques. Therefore, flexible scan techniques with minimal motion artifacts, low dose techniques without compromising excellent image quality, and extended clinical applications towards truly cardiac assessments constitute current trends in cardiac CT in children. PMID- 23104373 TI - Diagnostics of septic arthritis in the sternoclavicular region: 10 consecutive patients and literature review. AB - BACKGROUND: Septic arthritis in the sternoclavicular (SC) region is rare and may be difficult to diagnose clinically and radiologically. It mainly affects immunocompromised persons, and can clinically be misinterpreted as tumor and rheumatic disorders. Lacking radiological reference standard, a multimodality approach may contribute to a prolonged diagnostic process. PURPOSE: To describe the diagnostics of septic arthritis in the SC region. MATERIAL AND METHODS: Between 2001 and 2011 10 patients with Staphylococcus infection in the SC region were investigated in our institution. Clinical, biochemical, radiological, and microbiological findings were studied retrospectively; all CT and MR examinations were re-evaluated. RESULTS: Initial radiography in nine patients and ultrasonography in six patients were inconclusive resulting in supplementary MRI and/or CT. Five patients examined by MRI were immediately diagnosed with septic arthritis whereas CT in five patients led to the diagnosis in only one. Three were subsequently diagnosed by MRI, but delayed more than 2.5 weeks, and one was diagnosed by surgery. The median time to diagnosis was 1.5 weeks. The delay caused by imaging was 0 days to 11.5 weeks (median 0 days). By re-evaluation overlooked complications included mediastinitis in seven patients (three diffuse, four localized), and abscesses and pleuritis each in four patients. CONCLUSION: Awareness of infection in the SC region is important to avoid diagnostic delay. MRI is proposed as the initial imaging procedure. PMID- 23104374 TI - Does the MRI or MRI contrast medium gadopentetate dimeglumine change the oxidant and antioxidant status in humans? AB - BACKGROUND: It has become evident that gadolinium-based contrast agents (GBCA) may have nephrotoxic potential. Oxidative stress is one of the most important pathways in the pathogenesis of iodinated contrast-induced nephropathy. PURPOSE: To investigate the effects of static magnetic fields and gadopentetate dimeglumine (Magnevist((r))) on oxidant/antioxidant status via measurement of total antioxidant capacity (TAC), total oxidant status (TOS), and serum malondialdehide (MDA). MATERIAL AND METHODS: Two age- and sex-matched groups of patients not under oxidative stress conditions that underwent magnetic resonance imaging (MRI) were recruited to this study. While contrast-enhanced (Magnevist((r)), 0.2 mmol/kg) MRI was performed in group 1, MRI without GBCA was performed in group 2. Fasting blood glucose, C-reactive protein, serum creatinine, liver enzymes, uric acid, and lipid parameters were examined in all patients. Peripheral venous blood samples in order to determine TAC, TOS, and MDA were collected before and 6, 24, and 72 h after the MRI procedures. The TOS:TAC ratio was used as the oxidative stress index (OSI). Patients were followed up to 72 h. RESULTS: There were no significant changes in serum TAC, TOS, and MDA levels (Delta(serum TAC), Delta(serum TOS), and Delta(MDA)) in either group 6, 24, or 72 h after the procedures (P > 0.05). Furthermore, OSI did not change after the procedures in either group (P > 0.05). CONCLUSION: Magnetic field and gadopentetate dimeglumine (Magnevist((r))) do not change the oxidant or antioxidant status at a dose of 0.2 mmol/kg. PMID- 23104375 TI - Caged circular antisense oligonucleotides for photomodulation of RNA digestion and gene expression in cells. AB - We synthesized three 20 mer caged circular antisense oligodeoxynucleotides (R20, R20B2 and R20B4) with a photocleavable linker and an amide bond linker between two 10 mer oligodeoxynucleotides. With these caged circular antisense oligodeoxynucleotides, RNA-binding affinity and its digestion by ribonuclease H were readily photomodulated. RNA cleavage rates were upregulated ~43-, 25- and 15 fold for R20, R20B2 and R20B4, respectively, upon light activation in vitro. R20B2 and R20B4 with 2- or 4-nt gaps in the target RNA lost their ability to bind the target RNA even though a small amount of RNA digestion was still observed. The loss of binding ability indicated promising gene photoregulation through a non-enzymatic strategy. To test this strategy, three caged circular antisense oligonucleotides (PS1, PS2 and PS3) with 2'-OMe RNA and phosphorothioate modifications were synthesized to target GFP expression. Upon light activation, photomodulation of target hybridization and GFP expression in cells was successfully achieved with PS1, PS2 and PS3. These caged circular antisense oligonucleotides show promising applications of photomodulating gene expression through both ribonuclease H and non-enzyme involved antisense strategies. PMID- 23104376 TI - SwissSidechain: a molecular and structural database of non-natural sidechains. AB - Amino acids form the building blocks of all proteins. Naturally occurring amino acids are restricted to a few tens of sidechains, even when considering post translational modifications and rare amino acids such as selenocysteine and pyrrolysine. However, the potential chemical diversity of amino acid sidechains is nearly infinite. Exploiting this diversity by using non-natural sidechains to expand the building blocks of proteins and peptides has recently found widespread applications in biochemistry, protein engineering and drug design. Despite these applications, there is currently no unified online bioinformatics resource for non-natural sidechains. With the SwissSidechain database (http://www.swisssidechain.ch), we offer a central and curated platform about non natural sidechains for researchers in biochemistry, medicinal chemistry, protein engineering and molecular modeling. SwissSidechain provides biophysical, structural and molecular data for hundreds of commercially available non-natural amino acid sidechains, both in l- and d-configurations. The database can be easily browsed by sidechain names, families or physico-chemical properties. We also provide plugins to seamlessly insert non-natural sidechains into peptides and proteins using molecular visualization software, as well as topologies and parameters compatible with molecular mechanics software. PMID- 23104377 TI - ClusterMine360: a database of microbial PKS/NRPS biosynthesis. AB - ClusterMine360 (http://www.clustermine360.ca/) is a database of microbial polyketide and non-ribosomal peptide gene clusters. It takes advantage of crowd sourcing by allowing members of the community to make contributions while automation is used to help achieve high data consistency and quality. The database currently has >200 gene clusters from >185 compound families. It also features a unique sequence repository containing >10 000 polyketide synthase/non ribosomal peptide synthetase domains. The sequences are filterable and downloadable as individual or multiple sequence FASTA files. We are confident that this database will be a useful resource for members of the polyketide synthases/non-ribosomal peptide synthetases research community, enabling them to keep up with the growing number of sequenced gene clusters and rapidly mine these clusters for functional information. PMID- 23104378 TI - The crystal structure of human telomeric DNA complexed with berberine: an interesting case of stacked ligand to G-tetrad ratio higher than 1:1. AB - The first crystal structure of human telomeric DNA in complex with the natural alkaloid berberine, produced by different plant families and used in folk medicine for millennia, was solved by X-ray diffraction method. The G-quadruplex unit features all-parallel strands. The overall folding assumed by DNA is the same found in previously reported crystal structures. Similarly to previously reported structures the ligand molecules were found to be stacked onto the external 5' and 3'-end G-tetrads. However, the present crystal structure highlighted for the first time, the presence of two berberine molecules in the two binding sites, directly interacting with each tetrad. As a consequence, our structural data point out a 2:1 ligand to G-tetrad molar ratio, which has never been reported before in a telomeric intramolecular quadruplex structure. PMID- 23104379 TI - Glycan fragment database: a database of PDB-based glycan 3D structures. AB - The glycan fragment database (GFDB), freely available at http://www.glycanstructure.org, is a database of the glycosidic torsion angles derived from the glycan structures in the Protein Data Bank (PDB). Analogous to protein structure, the structure of an oligosaccharide chain in a glycoprotein, referred to as a glycan, can be characterized by the torsion angles of glycosidic linkages between relatively rigid carbohydrate monomeric units. Knowledge of accessible conformations of biologically relevant glycans is essential in understanding their biological roles. The GFDB provides an intuitive glycan sequence search tool that allows the user to search complex glycan structures. After a glycan search is complete, each glycosidic torsion angle distribution is displayed in terms of the exact match and the fragment match. The exact match results are from the PDB entries that contain the glycan sequence identical to the query sequence. The fragment match results are from the entries with the glycan sequence whose substructure (fragment) or entire sequence is matched to the query sequence, such that the fragment results implicitly include the influences from the nearby carbohydrate residues. In addition, clustering analysis based on the torsion angle distribution can be performed to obtain the representative structures among the searched glycan structures. PMID- 23104380 TI - Reaction path ensemble of the B-Z-DNA transition: a comprehensive atomistic study. AB - Since its discovery in 1979, left-handed Z-DNA has evolved from an in vitro curiosity to a challenging DNA structure with crucial roles in gene expression, regulation and recombination. A fundamental question that has puzzled researchers for decades is how the transition from B-DNA, the prevalent right-handed form of DNA, to Z-DNA is accomplished. Due to the complexity of the B-Z-DNA transition, experimental and computational studies have resulted in several different, apparently contradictory models. Here, we use molecular dynamics simulations coupled with state-of-the-art enhanced sampling techniques operating through non conventional reaction coordinates, to investigate the B-Z-DNA transition at the atomic level. Our results show a complex free energy landscape, where several phenomena such as over-stretching, unpeeling, base pair extrusion and base pair flipping are observed resulting in interconversions between different DNA conformations such as B-DNA, Z-DNA and S-DNA. In particular, different minimum free energy paths allow for the coexistence of different mechanisms (such as zipper and stretch-collapse mechanisms) that previously had been proposed as independent, disconnected models. We find that the B-Z-DNA transition--in absence of other molecular partners--can encompass more than one mechanism of comparable free energy, and is therefore better described in terms of a reaction path ensemble. PMID- 23104382 TI - Value of bilateral breast cancer for identification of rare recessive at-risk alleles: evidence for the role of homozygous GEN1 c.2515_2519delAAGTT mutation. AB - Virtually all known tumor predisposing genes have been identified via the analysis of familial cancer cases. Here we argue that this approach is likely to miss recessively acting cancer genes and suggest the analysis of family history negative patients with multiple primary malignancies for identifying homozygous at-risk genotypes. We performed calculations showing that the homozygous carriers of rare recessive cancer predisposing alleles are unlikely to report a family history of the disease. We further revealed that the c.2515_2519delAAGTT homozygous mutation in a Holliday junction resolvase, GEN1, was overrepresented in women with bilateral breast cancer (BC) as compared to healthy controls [11/360 (3.1 %) vs. 18/1305 (1.4 %); odds ratio (OR) = 2.25 (1.02-4.75); p = 0.031], although this trend was not maintained in unilateral BC patients [23/1851 (1.2 %)]. Noticeably, presence of biallelic c.2515_2519delAAGTT mutation was associated with the absence of BC in mother both in bilateral and unilateral BC cases [7/239 (3.0 %) vs. 0/41 (0 %) and 21/1,558 (1.3 %) vs. 0/215 (0 %), respectively; Mantel-Haenszel p = 0.041]. Thus, this study suggests that identification of dominant and recessive cancer predisposing genes may require distinct study groups. PMID- 23104381 TI - Study of E. coli Hfq's RNA annealing acceleration and duplex destabilization activities using substrates with different GC-contents. AB - Folding of RNA molecules into their functional three-dimensional structures is often supported by RNA chaperones, some of which can catalyse the two elementary reactions helix disruption and helix formation. Hfq is one such RNA chaperone, but its strand displacement activity is controversial. Whereas some groups found Hfq to destabilize secondary structures, others did not observe such an activity with their RNA substrates. We studied Hfq's activities using a set of short RNAs of different thermodynamic stabilities (GC-contents from 4.8% to 61.9%), but constant length. We show that Hfq's strand displacement as well as its annealing activity are strongly dependent on the substrate's GC-content. However, this is due to Hfq's preferred binding of AU-rich sequences and not to the substrate's thermodynamic stability. Importantly, Hfq catalyses both annealing and strand displacement with comparable rates for different substrates, hinting at RNA strand diffusion and annealing nucleation being rate-limiting for both reactions. Hfq's strand displacement activity is a result of the thermodynamic destabilization of the RNA through preferred single-strand binding whereas annealing acceleration is independent from Hfq's thermodynamic influence. Therefore, the two apparently disparate activities annealing acceleration and duplex destabilization are not in energetic conflict with each other. PMID- 23104384 TI - Insulin sensitization via partial agonism of PPARgamma and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. AB - BACKGROUND: The present study was aimed at isolating an antidiabetic molecule from a herbal source and assessing its mechanism of action. METHODS: Embelin, isolated from Embelia ribes Burm. (Myrsinaceae) fruit, was evaluated for its potential to regulate insulin resistance, alter beta-cell dysfunction and modulate key markers involved in insulin sensitivity and glucose transport using high-fat diet (HFD) fed-streptozotocin (STZ) (40mg/kg)-induced type 2 diabetic rats. Molecular-dockings were performed to investigate the binding modes of embelin into PPARgamma, PI3K, p-Akt and GLUT4 active sites. RESULTS: Embelin (50mg/kg b wt.) reduced body weight gain, blood glucose and plasma insulin in treated diabetic rats. It further modulated the altered lipid profiles and antioxidant enzymes with cytoprotective action on beta-cell. Embelin significantly increased the PPARgamma expression in epididymal adipose tissue compared to diabetic control group; it also inhibited adipogenic activity; it mildly activated PPARgamma levels in the liver and skeletal muscle. It also regulated insulin mediated glucose uptake in epididymal adipose tissue through translocation and activation of GLUT4 in PI3K/p-Akt signaling cascade. Embelin bound to PPARgamma; it disclosed stable binding affinities to the active sites of PI3K, p-Akt and GLUT4. CONCLUSIONS: These findings show that embelin could improve adipose tissue insulin sensitivity without increasing weight gain, enhance glycemic control, protect beta-cell from damage and maintain glucose homeostasis in adipose tissue. GENERAL SIGNIFICANCE: Embelin can be used in the prevention and treatment of type 2 diabetes mellitus caused due to obesity. PMID- 23104385 TI - Organic bioelectrodes in clinical neurosurgery. AB - BACKGROUND: Clinical neurosurgery deals with surgical procedures and intensive care of illnesses in the human central and peripheral nervous system. Neurosurgery should be looked upon as a high-tech specialty and very much dependent on new technological innovations aiming at improvements of patient's treatment and outcome. During the last decades neurosurgery has improved substantially thanks to the introduction of applied imaging technologies such as computerized tomography and magnetic resonance tomography, and new surgical modalities such as the microscope, brain navigation and neuroanesthesiology. Neurosurgical disorders, which should have the potential to benefit from conductive organic bioelectrodes, include traumatic brain and spinal cord injury and peripheral nerve injuries due to external violence in the restoration of healthy communication. This holds true also for cerebral nerves altered in their functions due to benign and malignant brain and spinal cord tumors. Further, new innovative devices in the field of functional nervous tissue disorders make the use of organic conductive electrodes attractive by considering the electrical neurochemical properties of neural interfaces. CONCLUSIONS: Although in its infancy, conducting organic polymers as bioelectrodes have several potential applications in clinical neurosurgery. The time it takes for new innovations and basic research to be transferred into clinical neurosurgery should not take too long. However, a prerequisite for successful implementation is the close interdisciplinary collaboration between engineers and clinicians. This article is part of a Special Issue entitled Organic Bioelectronics-Novel Applications in Biomedicine. PMID- 23104386 TI - Protein supramolecular complex formation by site-specific avidin-biotin interactions. AB - The precise accumulation of protein functions on a nanoscale to fabricate advanced biomaterials has become possible by a bottom-up approach based on molecular self-assembly. The avidin-biotin interaction is widely employed in the design of functional protein self-assemblies. Herein we assessed how the spatial arrangement of the avidin-biotin interaction between protein building blocks affects the formation of a protein supramolecular complex (PSC). The enzymatic site-specific internal labeling of a symmetric protein scaffold, bacterial alkaline phosphatase (AP), with specifically designed biotinylation substrates revealed that the precise positioning of the biotinylation sites on AP and the linker flexibility of the substrate are critical factors for the growth of PSCs in the presence of streptavidin (SA). A potential diagnostic application of the PSCs comprised of AP and SA was demonstrated in an enzyme-linked immunosorbent assay. PMID- 23104383 TI - Pivots of pluripotency: the roles of non-coding RNA in regulating embryonic and induced pluripotent stem cells. AB - BACKGROUND: Induced pluripotent stem cells (iPSC) derived from reprogrammed patient somatic cells possess enormous therapeutic potential. However, unlocking the full capabilities of iPSC will require an improved understanding of the molecular mechanisms which govern the induction and maintenance of pluripotency, as well as directed differentiation to clinically relevant lineages. Induced pluripotency of a differentiated cell is mediated by sequential cascades of genetic and epigenetic reprogramming of somatic histone and DNA CpG methylation marks. These genome-wide changes are mediated by a coordinated activity of transcription factors and epigenetic modifying enzymes. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are now recognized as an important third class of regulators of the pluripotent state. SCOPE OF REVIEW: This review surveys the currently known roles and mechanisms of ncRNAs in regulating the embryonic and induced pluripotent states. MAJOR CONCLUSIONS: Through a variety of mechanisms, ncRNAs regulate constellations of key pluripotency genes and epigenetic regulators, and thus critically determine induction and maintenance of the pluripotent state. GENERAL SIGNIFICANCE: A further understanding of the roles of ncRNAs in regulating pluripotency may help assess the quality of human iPSC reprogramming. Additionally, ncRNA biology may help decipher potential transcriptional and epigenetic commonalities between the self renewal processes that govern both ESC and tumor initiating cancer stem cells (CSC). This article is part of a Special Issue entitled Biochemistry of Stem Cells. PMID- 23104387 TI - Examining the Binge Eating Scale in screening for binge eating disorder in bariatric surgery candidates. AB - BACKGROUND: This study assessed the utility of the Binge Eating Scale (BES) as a measure of binge eating disorder (BED) in a bariatric surgery-seeking population by (a) determining the optimal BES cut score for predicting BED, (b) calculating concordance statistics, and (c) determining the predictive value of each BES item. METHODS: Four hundred seventy-three patients presented for a psychological evaluation prior to Roux-en-Y gastric bypass surgery. The BES and the SCID semi structured interview for BED were administered. RESULTS: Receiver operating characteristic curve analyses identified an optimal BES cut score of 17, which correctly classified 78% of patients with BED. A cut score of 27 improved this statistic, but significantly increased the number of false negatives, which is undesirable for a screening assessment. Discriminant function analyses revealed that nearly all BES items significantly predicted BED. CONCLUSIONS: The BES is a valid screener of BED for patients seeking bariatric surgery; however, false positives can be expected. Administering the BES as part of a comprehensive psychological evaluation can help improve the assessment and treatment of patients presenting for bariatric surgery. PMID- 23104388 TI - Behavioral outcomes following laparoscopic sleeve gastrectomy performed after failed laparoscopic adjustable gastric banding. AB - A healthy diet and good eating behaviors are essential components of long-term success in weight maintenance after bariatric surgery. Although rates of revised bariatric surgery have increased, data on subsequent behavioral outcomes are sparse. The aim of our study was to investigate behavioral outcomes following revised laparoscopic sleeve gastrectomy (R-LSG) that was indicated for failed laparoscopic adjustable gastric banding and compare with outcomes following primary laparoscopic sleeve gastrectomy (P-LSG). Twelve patients who underwent R LSG and 25 patients who underwent P-LSG between 2007 and 2009 in our medical center completed a questionnaire that assessed weight loss, eating behaviors, physical activity, food tolerance, and satisfaction. The average time elapsed since the operation was 18 months for both groups. In the R-LSG group, more patients reported non-normative eating patterns and less healthy food selection than in the P-LSG group. Food tolerance and satisfaction were also lower after R LSG. Engagement in regular physical activity increased from 0 to 16.7 % in the R LSG group and from 8 to 33 % in the P-LSG group. After R-LSG, 58 % reported eating at scheduled times, compared with 85 % after P-LSG. Levels of healthy food selection, food tolerance, normative eating patterns, and physical activity were lower in the R-LSG group than in the P-LSG group. This study highlights the need to develop pre- and post-surgery treatment that would promote better behavioral outcomes in the growing number of individuals undergoing repeat bariatric surgery. PMID- 23104389 TI - Transumbilical laparoscopic Roux-en-Y gastric bypass with hand-sewn gastrojejunal anastomosis. AB - Single-port laparoscopic surgery has undergone significant development over the past 5 years. Single port is used in various procedures, including bariatric surgery. The aim of this paper is to describe a surgical technique for gastric bypass with a transumbilical approach (transumbilical gastric bypass-TUGB) with hand-sewn gastrojejunostomy, in selected patients who may be benefited by a better cosmetic result. The procedure begins with a transumbilical vertical incision. We use the GelPOINT single-port device and a 5-mm assistant trocar in the left flank (in the first two cases, a 2-mm subxiphoid liver retractor was used). A gastric pouch is made and calibrated with a 36-Fr bougie. The gastrojejunal anastomosis is performed by hand-sewing in two layers. A Roux-en-Y with a biliary limb of 50 cm and an alimentary limb of 120 cm is performed with a stapler. Three women were subjected to TUGB. The women were aged 28, 31, and 42 years; they had body mass indexes of 40.3, 33, and 38.2; and the operating times were 150, 200, and 150 min, respectively. The first two women underwent a Roux-en Y gastric bypass (RYGB), and the last woman underwent a RYGB with a resection of the stomach remnant. There were no conversions to open or multitrocar techniques. No complications or deaths occurred. The three patients were satisfied with the cosmetic result. The technique described for TUGB is a feasible procedure for surgeons who have previous experience with the transumbilical approach. PMID- 23104390 TI - Sleep apnea: is routine preoperative screening necessary? AB - BACKGROUND: Because perioperative complications of unrecognized obstructive sleep apnea (OSA) can be severe, many bariatric surgery programs routinely screen all patients. However, many obese non-bariatric surgery patients do not get screened. We wanted to evaluate the need for routine preoperative OSA screening. METHODS: Morbidly obese patients with a body mass index (BMI) > 40 kg/m(2) undergoing bariatric surgery--all screened for OSA--were compared to morbidly obese orthopedic lower extremity total joint replacements (TJR) patients--not screened for OSA. Cardio-pulmonary complications were recorded. RESULTS: Eight hundred eighty-two morbidly obese patients undergoing either bariatric (n = 467) or orthopedic TJR surgery (n = 415) were compared. As a result of screening, 119 bariatric surgery patients (25.5 %) were newly diagnosed with OSA, bringing the incidence to 42.8 % (200/467). Orthopedic surgery group had 72 of 415 (17.3 %) patients with pre-existing OSA. The unscreened orthopedic patients had a 6.7 % (23/343) cardiopulmonary complications rate compared to 2.6 % (7/267) for screened bariatric surgery patients. This difference was not statistically significant when adjusted for age and comorbidity (p = 0.3383). CONCLUSION: Sleep apnea screening prior to bariatric surgery identifies an additional 25 % of patients as having OSA. In this study, unscreened morbidly obese patients did not have an increased incidence of cardiopulmonary complications after surgery compared to screened patients. Prospective randomized studies should be conducted to definitively assess utility and cost effectiveness of routine OSA screening of all morbidly obese patients undergoing surgery. Preoperative OSA screening may be safely omitted when randomizing patients for such a trial. PMID- 23104391 TI - Intestinal pseudo-obstruction associated with biliary tract dilatation in a patient with systemic lupus erythematosus. AB - Intestinal pseudo-obstruction (IpsO) is an uncommon and severe complication of systemic lupus erythematosus (SLE). We report a patient with SLE who presented with IpsO and biliary dilatation (megacholedochus). The co-manifestation of these two conditions in SLE is unusual and has been reported only twice previously. The patient responded well to immunosuppressive treatment. IpsO is a rare but recognized manifestation of SLE that may be the presenting manifestation of the systemic disease or occur more commonly during disease course. Early recognition of IpsO is necessary to institute appropriate medical treatment and to avoid inappropriate surgical intervention. PMID- 23104392 TI - Intracranial hypertension associated with systemic lupus erythematosus in a young male patient. AB - Systemic lupus erythematosus (SLE) is a chronic disease that affects multiple organ systems including the central nervous system. We present a case of a young male with a new diagnosis of SLE presenting as intracranial hypertension (IH). Review of the literature suggests an association between SLE and IH and prompts a reconsideration of the exclusion of IH from the American College of Rheumatology's accepted neuropsychiatric manifestations. In addition, our case is one of the few cases of IH and SLE in males. While the data are limited, SLE associated IH in males may be different from that in females with respect to presentation and severity. PMID- 23104393 TI - Cost-effectiveness analysis for breast cancer screening: double reading versus single + CAD reading. AB - BACKGROUND: Computer-aided detection (CAD) increases breast cancer detection, but its cost-effectiveness is unknown for breast cancer screening in Japan. We aimed to determine whether screening mammography diagnosed by one physician using CAD is cost-effective when compared with the standard double reading by two physicians. METHODS: We established our model with a decision tree and Markov model concept based on feasible screening and clinical pathways, combined with prognosis of the health state transition of breast cancer. Cost-effectiveness analysis between double reading by two readers and single reading with CAD by one reader was performed from a social perspective in terms of the expected cost, life expectancy and incremental cost-effectiveness ratio (ICER). The hypothetical population comprised 50-year-old female breast cancer screening examinees. Only direct medical costs related to breast cancer screening and treatment were considered. One simulation cycle was 2 years, and the annual discount rate was 3 %. Sensitivity analysis was performed to evaluate the robustness of the model and input data. RESULTS: Single reading with CAD increased expected costs by 2,704 yen and extended life expectancy by 0.0087 years compared with double reading. The ICER was 310,805 yen per life year gained, which is below the threshold. Sensitivity analysis showed that the sensitivity and specificity of CAD and the number of breast cancer screening examinees greatly affected the results. CONCLUSIONS: Single reading using CAD in mammography screening is more cost effective than double reading, although the results are highly sensitive to the sensitivity and specificity of CAD and the numbers of examinees. PMID- 23104394 TI - Can T2-weighted 3-T breast MRI predict clinically occult inflammatory breast cancer before pathological examination? A single-center experience. AB - Occult inflammatory breast cancer (IBC) is defined as an invasive cancer without any clinical inflammatory signs but with pathologically proven dermal lymphovascular invasion. The purpose of this study is to evaluate the ability of 3-T breast MRI to predict occult IBC before pathological examination and compare its effectiveness with that of mammography (MMG) and ultrasound (US). A retrospective review of clinical, radiological, and pathological records of 460 consecutive breast cancers revealed five proved occult IBCs. We analyzed the findings of 3-T MRI, MMG, and US for these five occult IBCs. Primary breast lesions were detected by 3-T MRI, MMG, and US in all five breasts with occult IBCs. 3-T MRI revealed 40% mass type lesions and 60% non-mass-like type lesions. Kinetic curve analysis of the primary breast lesions showed a rapid initial kinetic phase in 80% of lesions and a delayed washout pattern in 60% of lesions. 3-T MRI showed slight skin thickness in 60% of breasts, whereas MMG and US showed slight skin thickness in 40 and 20% of breasts, respectively. Subcutaneous and prepectoral edema, as evaluated on T2-weighted images, was present in all five breasts with occult IBCs. The presence of subcutaneous and prepectoral edema on T2-weighted 3-T breast MRI is an important finding that should suggest the diagnosis of occult IBC before pathological examination. PMID- 23104395 TI - Epithelial cells expressing cytokeratins-19 and bone marrow micrometastases in patients with breast cancer at the time of primary surgery: clinical outcome during long-term follow-up. AB - PURPOSE: To evaluate the detection of epithelial cells in bone marrow of breast cancer patients as an indicator of metastatic disease. PATIENTS AND METHODS: Between 2001 and 2005, bone marrow biopsies were taken from 79 breast cancer patients during primary surgery. Specimens were stained immunocytochemically for epithelial cells expressing cytokeratins or epithelial membrane antigen. The long term outcomes of these patients were analyzed. RESULTS: In 51 CK-positive results of 79 patients, epithelial cells were found in the bone marrow (BM) biopsies. These patients were designated CK(+). The rate of tumor recurrence or cancer related death was significantly higher in CK(+) patients than in CK-negative patients. Multivariate analysis using the Cox regression model revealed BM status as a prognostic parameter independent of axillary lymph node status. CONCLUSION: Disseminated epithelial cells in BM are associated with poor clinical outcome in breast cancer patients. However, the presence of these cells is not a sufficient parameter, suggesting that epithelial cells in the BM of breast cancer patients at the time of surgery have limited metastatic potential. The role of these cells needs to be further evaluated. PMID- 23104396 TI - Multipurpose use of orthodontic mini-implants to achieve different treatment goals. AB - OBJECTIVES: The goal of the study was to determine whether mini-implants inserted in the palate can be used to achieve more than one treatment goal consecutively or simultaneously in the same patient. MATERIALS AND METHODS: The treatment results of 43 patients were retrospectively assessed. Two implant-supported mechanical systems per patient were applied either consecutively in 19 patients (group A) or simultaneously in 24 patients (group B). Both groups were analyzed and compared by calculating success rates for achievement of the treatment goals, survival of the mini-implants, and quality of anchorage. Durations of treatment were also analyzed for intergroup differences. RESULTS: Except for a single case in group A, the treatment goals were achieved in all patients (success rates 94.7% in group A versus 100% in group B). Anchorage loss was confined to one patient per group (success rates 94.7% in group A and 95.3% in group B). Mini implant mobility, and hence implant failure, was observed in three implants in group A (survival rate 91.8%) and two implants in group B (survival rate 95.6%). While none of these intergroup differences were statistically significant, the treatment durations in both groups differed widely: those in group B were significantly shorter (10.0 +/- 4.2 months) than those in group A (14.4 +/- 3.5 months; p = 0.001). CONCLUSION: Mini-implants inserted in the palate for skeletal anchorage can be used to achieve more than one treatment goal in the same patient. Such multipurpose application can succeed consecutively and simultaneously. The latter option can significantly expedite treatments and should, therefore, be preferred when feasible, depending on the nature of coexisting therapeutic indications in a given patient. PMID- 23104397 TI - Longitudinal soft-tissue profile changes in adolescent Class I subjects. AB - OBJECTIVE: The purpose of this study was to assess longitudinal changes in the soft-tissue profile in untreated subjects from the prepubertal through the postpubertal stages of development as defined by the cervical vertebral maturation (CVM) method. METHODS: A total of 14 boys and 15 girls who were longitudinally followed from about 10 through about 16 years of age with Class I occlusal, normal anteroposterior, and vertical skeletal relationships were selected. Lateral cephalograms at three consecutive developmental periods (prepubertal, pubertal, and postpubertal) corresponding to the different stages in CVM had to be available for all selected subjects. Eleven angular and 18 linear measurements were made. Analysis of variance was used to search for significant changes between developmental periods. Duncan's test for multiple comparisons was then used to identify the source of any significant difference. Differences between the genders were determined by using the Student t-test. RESULTS: Nasal prominence and dimensions increased more than chin, upper and lower lip prominences and dimensions. After puberty, males had more soft tissue changes than females. In females, growth changes mostly took place between the prepuberty and puberty growth periods. CONCLUSION: These results can be used by orthodontists as representative of the soft tissue profile changes during the developmental period. PMID- 23104399 TI - Characterization and evolution of a metagenome-derived lipase towards enhanced enzyme activity and thermostability. AB - In the present investigation, we used directed evolution approach to engineer a lipase from metagenomic origin. A variant S311C, was generated, characterized in detail and compared with wild type. Wild type and variant lipases were overexpressed and purified to homogeneity. The temperature optima of the purified lipases (Variant and wild type) were almost same, and found to be 45 and 50 degrees C, respectively. The variant protein was highly thermostable (54 times) as compared with the wild type at 60 degrees C. The variant displayed very high kinetic efficiency over the wild type protein. Analysis of the homology models of wild type and variant lipase showed that the substitution is on the surface of the protein. This substitution, along with hydrophobic residues in near vicinity may be involved in formation of strong hydrophobic channel leading to active site. This study identifies the role of hydrophobic interactions in protein stability along with enhancement of enzyme activity. PMID- 23104401 TI - The neglected role of reward in rehabilitation. PMID- 23104402 TI - A new family of Fe2Ln complexes built from mononuclear anionic Schiff base subunits. AB - A series of the trinuclear [{Fe(3MeO-L)(2)}(2){MU(6)-Ln(eta(2) NO(3))(H(2)O)}].nH(2)O, (Ln = Gd (2a), Tb (2b), Dy (2c), Ho (2d), Er (2e), Y (2f), H(2)-3MeO-L = 2-hydroxy-3-methoxy-phenylsalicylaldimine) complexes were prepared and thoroughly characterized. The crystal structure of 2bwas determined and it revealed that the heterotrinuclear complex consists of two anionic [Fe(3MeO-L)(2)](-) subunits coordinated to the [Tb(H(2)O)(eta(2)-NO(3))](2+) bridging moiety through the phenolato and methoxy oxygen atoms. The angular distortion within the coordination polyhedron of the [Fe(3MeO-L)(2)](-) subunits grows significantly upon coordination to the Ln atom of the bridging moiety, which consequently induces an increase in the parameter of the axial magnetic anisotropy. This conclusion is obvious from the comparison and analysis of the structural (XRD) and magnetic data of the yttrium trimer 2fand the precursor complex (Pr(3)NH)[Fe(3MeO-L)(2)] (1, Pr(3)NH = the tripropylammonium cation), where D(Fe)(1) = +0.80 cm(-1) and D(Fe)(2f) = +1.64 cm(-1). Furthermore, a weak antiferromagnetic interaction between the Fe(III) centres was found in 2f(J(FeFe) = -0.26 cm(-1)). The magnetic parameters of 2f were used in the fitting of the magnetic properties of 2a as constraints. The ferromagnetic nature of the Fe-Gd interaction in 2a was confirmed, with J(GdFe) = +1.40 cm(-1), D(Gd) = -0.26 cm( 1). Moreover, in the case of the Tb (2b) and Dy (2c) compounds, a slow relaxation of the magnetization at low temperature (below 1.9 K) was observed upon the dehydration of the parent compounds. PMID- 23104398 TI - Pacing device therapy in infants and children: a review. AB - The number of pediatric pacemakers implanted is still relatively small. Children requiring pacing therapy have characteristics that are distinct from those of adults, including physical size, somatic growth, and cardiac anomalies. Considering these features, long-term follow-up of pediatric pacemaker implantation is necessary. Selection of appropriate generators, pacing modes, pacing sites, and leads is important. Generally, epicardial leads are commonly used in small infants. On the other hand, the use of endocardial leads in children is increasing worldwide because of their benefits over epicardial leads, such as minimal invasiveness, lower pacing threshold, and longer generator longevity. Endocardial leads are not suitable for patients with intracardiac shunts because of the high risk of systemic thrombosis. Venous occlusion is another significant problem with endocardial leads. With the increase in the number of pacing device implantations, the incidence of infection from such devices is also increasing. Complete device removal is sometimes recommended to treat device infection, but experience in the removal of endocardial leads in children is still scarce. This article gives an overview of pacing therapy in the pediatric population, including discussions on new pacing systems, such as remote monitoring systems, magnetic imaging compliant pacemaker systems, and leadless pacing devices. PMID- 23104400 TI - The role of the basal ganglia in action imitation: neuropsychological evidence from Parkinson's disease patients. AB - Though previous studies have suggested that the basal ganglia are necessarily involved in action imitation, their precise role is unclear. An important source of evidence concerns patients with Parkinson's disease (PD) who suffer basal ganglia impairments. Some studies report poor execution of observed meaningful (MF) transitive (tool-related) actions but normal performance with intransitive (non-tool-related) MF and meaningless (ML) actions (Leiguarda et al. in Brain 120:75-90, 1997; Leiguarda 2001 in Neuroimage 14:137-141). In other cases, though, patients with lesions involving the basal ganglia appear impaired in imitating ML as compared to meaningful MF transitive pantomimes. Here, we tested a group of PD patients in a full 2 * 2 design with MF transitive and intransitive pantomimes and matched ML movements. PD patients generated higher scores when imitating MF transitive actions than ML-matched actions. On the other hand, ML than MF intransitive actions did not differ significantly. The performance of the patients on imitating ML transitive actions also correlated with their performance on the Corsi block test of visuospatial memory and their scores at the test of verbal fluency for phonemic categories (FAS) while MF intransitive actions correlated with FAS and the neurological evaluation (UPDRS) The results are discussed in terms of the factors that load on visual memory for action reproduction, as well as the possible role of the basal ganglia in communicative actions (for MF intransitive actions). PMID- 23104403 TI - n-Alkane chain length alters Dietzia sp. strain DQ12-45-1b biosurfactant production and cell surface activity. AB - Upon growth on n-hexadecane (C(16)), n-tetracosane (C(24)), and n-hexatriacontane (C(36)), Dietzia sp. strain DQ12-45-1b could produce different glycolipids, phospholipids, and lipopeptides. Interestingly, cultivation with C(36) increased cell surface hydrophobic activity, which attenuated the negative effect of the decline of the emulsification activity. These results suggest that the mechanisms of biosurfactant production and cell surface hydrophobicity are dependent upon the chain lengths of the n-alkanes used as carbon sources. PMID- 23104404 TI - Carboxyethylarginine synthase genes show complex cross-regulation in Streptomyces clavuligerus. AB - Carboxyethylarginine synthase is the first dedicated enzyme of clavam biosynthesis in Streptomyces clavuligerus and is present in two isoforms encoded by two separate genes. When grown on a liquid soy medium, strains with ceaS1 deleted showed only a mild reduction of clavam biosynthesis, while disruption of ceaS2 abolished all clavam biosynthesis. Creation of an in-frame ceaS2 deletion mutant to avoid polarity did not restore clavam production, nor did creation of a site-directed mutant altered only in a single amino acid residue important for activity. Reverse transcriptase PCR analyses of these mutants indicated that the failure to produce clavam metabolites could be traced to reduced or abolished transcription of ceaS1 in the ceaS2 mutants, despite the location of ceaS1 on a replicon completely separate from that of ceaS2. Western analyses further showed that the CeaS1 protein (as well as the CeaS2 protein) was absent from the ceaS2 mutants. Complementation experiments were able to restore clavam production partially, but only by virtue of restoring CeaS2 production. CeaS1 was still absent from the complemented strains. While this dependence of CeaS1 production on the expression of ceaS2 from its native chromosomal location was seen in all of the ceaS2 mutants, the effect was limited to growth in liquid medium. When the same mutants were grown on solid soy medium, clavam production was restored and CeaS1 was produced, albeit at low levels compared to the wild type. PMID- 23104405 TI - Identification of Methanoculleus spp. as active methanogens during anoxic incubations of swine manure storage tank samples. AB - Methane emissions represent a major environmental concern associated with manure management in the livestock industry. A more thorough understanding of how microbial communities function in manure storage tanks is a prerequisite for mitigating methane emissions. Identifying the microorganisms that are metabolically active is an important first step. Methanogenic archaea are major contributors to methanogenesis in stored swine manure, and we investigated active methanogenic populations by DNA stable isotope probing (DNA-SIP). Following a preincubation of manure samples under anoxic conditions to induce substrate starvation, [U-(13)C]acetate was added as a labeled substrate. Fingerprint analysis of density-fractionated DNA, using length-heterogeneity analysis of PCR amplified mcrA genes (encoding the alpha subunit of methyl coenzyme M reductase), showed that the incorporation of (13)C into DNA was detectable at in situ acetate concentrations (~7 g/liter). Fingerprints of DNA retrieved from heavy fractions of the (13)C treatment were primarily enriched in a 483-bp amplicon and, to a lesser extent, in a 481-bp amplicon. Analyses based on clone libraries of the mcrA and 16S rRNA genes revealed that both of these heavy DNA amplicons corresponded to Methanoculleus spp. Our results demonstrate that uncultivated methanogenic archaea related to Methanoculleus spp. were major contributors to acetate-C assimilation during the anoxic incubation of swine manure storage tank samples. Carbon assimilation and dissimilation rate estimations suggested that Methanoculleus spp. were also major contributors to methane emissions and that the hydrogenotrophic pathway predominated during methanogenesis. PMID- 23104407 TI - Bacterial chitinolytic communities respond to chitin and pH alteration in soil. AB - Chitin amendment is a promising soil management strategy that may enhance the suppressiveness of soil toward plant pathogens. However, we understand very little of the effects of added chitin, including the putative successions that take place in the degradative process. We performed an experiment in moderately acid soil in which the level of chitin, next to the pH, was altered. Examination of chitinase activities revealed fast responses to the added crude chitin, with peaks of enzymatic activity occurring on day 7. PCR-denaturing gradient gel electrophoresis (DGGE)-based analyses of 16S rRNA and chiA genes showed structural changes of the phylogenetically and functionally based bacterial communities following chitin addition and pH alteration. Pyrosequencing analysis indicated (i) that the diversity of chiA gene types in soil is enormous and (i) that different chiA gene types are selected by the addition of chitin at different prevailing soil pH values. Interestingly, a major role of Gram-negative bacteria versus a minor one of Actinobacteria in the immediate response to the added chitin (based on 16S rRNA gene abundance and chiA gene types) was indicated. The results of this study enhance our understanding of the response of the soil bacterial communities to chitin and are of use for both the understanding of soil suppressiveness and the possible mining of soil for novel enzymes. PMID- 23104406 TI - Gut and root microbiota commonalities. AB - Animal guts and plant roots have absorption roles for nutrient uptake and converge in harboring large, complex, and dynamic groups of microbes that participate in degradation or modification of nutrients and other substances. Gut and root bacteria regulate host gene expression, provide metabolic capabilities, essential nutrients, and protection against pathogens, and seem to share evolutionary trends. PMID- 23104408 TI - The salmonella transcriptome in lettuce and cilantro soft rot reveals a niche overlap with the animal host intestine. AB - Fresh vegetables have been recurrently associated with salmonellosis outbreaks, and Salmonella contamination of retail produce has been correlated positively with the presence of soft rot disease. We observed that population sizes of Salmonella enterica serovar Typhimurium SL1344 increased 56-fold when inoculated alone onto cilantro leaves, versus 2,884-fold when coinoculated with Dickeya dadantii, a prevalent pathogen that macerates plant tissue. A similar trend in S. enterica populations was observed for soft-rotted lettuce leaves. Transcriptome analysis of S. enterica cells that colonized D. dadantii-infected lettuce and cilantro leaves revealed a clear shift toward anaerobic metabolism and catabolism of substrates that are available due to the degradation of plant cells by the pectinolytic pathogen. Twenty-nine percent of the genes that were upregulated in cilantro macerates were also previously observed to have increased expression levels in the chicken intestine. Furthermore, multiple genes induced in soft rot lesions are also involved in the colonization of mouse, pig, and bovine models of host infection. Among those genes, the operons for ethanolamine and propanediol utilization as well as for the synthesis of cobalamin, a cofactor in these pathways, were the most highly upregulated genes in lettuce and cilantro lesions. In S. Typhimurium strain LT2, population sizes of mutants deficient in propanediol utilization or cobalamin synthesis were 10- and 3-fold lower, respectively, than those of the wild-type strain in macerated cilantro (P < 0.0002); in strain SL1344, such mutants behaved similarly to the parental strain. Anaerobic conditions and the utilization of nutrients in macerated plant tissue that are also present in the animal intestine indicate a niche overlap that may explain the high level of adaptation of S. enterica to soft rot lesions, a common postharvest plant disease. PMID- 23104409 TI - Fluorometric quantification of polyphosphate in environmental plankton samples: extraction protocols, matrix effects, and nucleic acid interference. AB - Polyphosphate (polyP) is a ubiquitous biochemical with many cellular functions and comprises an important environmental phosphorus pool. However, methodological challenges have hampered routine quantification of polyP in environmental samples. We tested 15 protocols to extract inorganic polyphosphate from natural marine samples and cultured cyanobacteria for fluorometric quantification with 4',6-diamidino-2-phenylindole (DAPI) without prior purification. A combination of brief boiling and digestion with proteinase K was superior to all other protocols, including other enzymatic digestions and neutral or alkaline leaches. However, three successive extractions were required to extract all polyP. Standard addition revealed matrix effects that differed between sample types, causing polyP to be over- or underestimated by up to 50% in the samples tested here. Although previous studies judged that the presence of DNA would not complicate fluorometric quantification of polyP with DAPI, we show that RNA can cause significant interference at the wavelengths used to measure polyP. Importantly, treating samples with DNase and RNase before proteinase K digestion reduced fluorescence by up to 57%. We measured particulate polyP along a North Pacific coastal-to-open ocean transect and show that particulate polyP concentrations increased toward the open ocean. While our final method is optimized for marine particulate matter, different environmental sample types may need to be assessed for matrix effects, extraction efficiency, and nucleic acid interference. PMID- 23104410 TI - Invertase SUC2 Is the key hydrolase for inulin degradation in Saccharomyces cerevisiae. AB - Specific Saccharomyces cerevisiae strains were recently found to be capable of efficiently utilizing inulin, but genetic mechanisms of inulin hydrolysis in yeast remain unknown. Here we report functional characteristics of invertase SUC2 from strain JZ1C and demonstrate that SUC2 is the key enzyme responsible for inulin metabolism in S. cerevisiae. PMID- 23104411 TI - Use of proteomic analysis to elucidate the role of calcium in acetone-butanol ethanol fermentation by Clostridium beijerinckii NCIMB 8052. AB - Calcium carbonate increases growth, substrate utilization, and acetone-butanol ethanol (ABE) fermentation by Clostridium beijerinckii NCIMB 8052. Toward an understanding of the basis for these pleiotropic effects, we profiled changes in the C. beijerinckii NCIMB 8052 proteome that occur in response to the addition of CaCO(3). We observed increases in the levels of different heat shock proteins (GrpE and DnaK), sugar transporters, and proteins involved in DNA synthesis, repair, recombination, and replication. We also noted significant decreases in the levels of proteins involved in metabolism, nucleic acid stabilization, sporulation, oxidative and antibiotic stress responses, and signal transduction. We determined that CaCO(3) enhances ABE fermentation due to both its buffering effects and its ability to influence key cellular processes, such as sugar transport, butanol tolerance, and solventogenesis. Moreover, activity assays in vitro for select solventogenic enzymes revealed that part of the underpinning for the CaCO(3)-mediated increase in the level of ABE fermentation stems from the enhanced activity of these catalysts in the presence of Ca(2+). Collectively, these proteomic and biochemical studies provide new insights into the multifactorial basis for the stimulation of ABE fermentation and butanol tolerance in the presence of CaCO(3). PMID- 23104412 TI - Quantitative microbial risk assessment of pathogenic vibrios in marine recreational waters of southern california. AB - This study investigated the occurrence of three types of vibrios in Southern California recreational beach waters during the peak marine bathing season in 2007. Over 160 water samples were concentrated and enriched for the detection of vibrios. Four sets of PCR primers, specific for Vibrio cholerae, V. parahaemolyticus, and V. vulnificus species and the V. parahaemolyticus toxin gene, respectively, were used for the amplification of bacterial genomic DNA. Of 66 samples from Doheny State Beach, CA, 40.1% were positive for V. cholerae and 27.3% were positive for V. parahaemolyticus, and 1 sample (1.5%) was positive for the V. parahaemolyticus toxin gene. Of the 96 samples from Avalon Harbor, CA, 18.7% were positive for V. cholerae, 69.8% were positive for V. parahaemolyticus, and 5.2% were positive for the V. parahaemolyticus toxin gene. The detection of the V. cholerae genetic marker was significantly more frequent at Doheny State Beach, while the detection of the V. parahaemolyticus genetic marker was significantly more frequent at Avalon Harbor. A probability-of-illness model for V. parahaemolyticus was applied to the data. The risk for bathers exposed to recreational waters at two beaches was evaluated through Monte Carlo simulation techniques. The results suggest that the microbial risk from vibrios during beach recreation was below the illness benchmark set by the U.S. EPA. However, the risk varied with location and the type of water recreation activities. Surfers and children were exposed to a higher risk of vibrio diseases. Microbial risk assessment can serve as a useful tool for the management of risk related to opportunistic marine pathogens. PMID- 23104413 TI - Phylogenetic, metabolic, and taxonomic diversities shape mediterranean fruit fly microbiotas during ontogeny. AB - The Mediterranean fruit fly (medfly) (Ceratitis capitata) lays eggs in fruits, where larvae subsequently develop, causing large-scale agricultural damage. Within its digestive tract, the fly supports an extended bacterial community that is composed of multiple strains of a variety of enterobacterial species. Most of these bacteria appear to be functionally redundant, with most strains sustaining diazotrophy and/or pectinolysis. At least some of these bacteria were shown to be vertically inherited, but colonization, structural, and metabolic aspects of the community's dynamics have not been investigated. We used fluorescent in situ hybridization, metabolic profiling, plate cultures, and pyrosequencing to show that an initial, egg-borne, diverse community expands throughout the fly's life cycle. While keeping "core" diazotrophic and pectinolytic functions, it also harbors diverse and fluctuating populations that express varied metabolic capabilities. We suggest that the metabolic and compositional plasticity of the fly's microbiota provides potential adaptive advantages to the medfly host and that its acquisition and dynamics are affected by mixed processes that include stochastic effects, host behavior, and molecular barriers. PMID- 23104414 TI - Autotransporter protein-encoding genes of diarrheagenic Escherichia coli are found in both typical and atypical enteropathogenic E. coli strains. AB - Autotransporter (AT) protein-encoding genes of diarrheagenic Escherichia coli (DEC) pathotypes (cah, eatA, ehaABCDJ, espC, espI, espP, pet, pic, sat, and tibA) were detected in typical and atypical enteropathogenic E. coli (EPEC) in frequencies between 0.8% and 39.3%. Although these ATs have been described in particular DEC pathotypes, their presence in EPEC indicates that they should not be considered specific virulence markers. PMID- 23104415 TI - Seasonal methane oxidation potential in manure crusts. AB - Organic crusts on liquid manure storage tanks harbor ammonia- and nitrite resistant methane oxidizers and may significantly reduce methane emissions. Methane oxidation potential (0.6 mol CH(4) m(-2) day(-1)) peaked during fall and winter, after 4 months of crust development. Consequences for methane mitigation potential of crusts are discussed. PMID- 23104416 TI - Bartonella infections in deer keds (Lipoptena cervi) and moose (Alces alces) in Norway. AB - Infections with Bartonella spp. have been recognized as emerging zoonotic diseases in humans. Large knowledge gaps exist, however, relating to reservoirs, vectors, and transmission of these bacteria. We describe identification by culture, PCR, and housekeeping gene sequencing of Bartonella spp. in fed, wingless deer keds (Lipoptena cervi), deer ked pupae, and blood samples collected from moose, Alces alces, sampled within the deer ked distribution range in Norway. Direct sequencing from moose blood sampled in a deer ked-free area also indicated Bartonella infection but at a much lower prevalence. The sequencing data suggested the presence of mixed infections involving two species of Bartonella within the deer ked range, while moose outside the range appeared to be infected with a single species. Bartonella were not detected or cultured from unfed winged deer keds. The results may indicate that long-term bacteremia in the moose represents a reservoir of infection and that L. cervi acts as a vector for the spread of infection of Bartonella spp. Further research is needed to evaluate the role of L. cervi in the transmission of Bartonella to animals and humans and the possible pathogenicity of these bacteria for humans and animals. PMID- 23104417 TI - Identification of the enzyme responsible for N-acetylation of norfloxacin by Microbacterium sp. Strain 4N2-2. AB - Microbacterium sp. 4N2-2, isolated from a wastewater treatment plant, converts the antibacterial fluoroquinolone norfloxacin to N-acetylnorfloxacin and three other metabolites. Because N-acetylation results in loss of antibacterial activity, identification of the enzyme responsible is important for understanding fluoroquinolone resistance. The enzyme was identified as glutamine synthetase (GS); N-acetylnorfloxacin was produced only under conditions associated with GS expression. The GS gene (glnA) was cloned, and the protein (53 kDa) was heterologously expressed and isolated. Optimal conditions and biochemical properties (K(m) and V(max)) of purified GS were characterized; the purified enzyme was inhibited by Mn(2+), Mg(2+), ATP, and ADP. The contribution of GS to norfloxacin resistance was shown by using a norfloxacin-sensitive Escherichia coli strain carrying glnA derived from Microbacterium sp. 4N2-2. The GS of Microbacterium sp. 4N2-2 was shown to act as an N-acetyltransferase for norfloxacin, which produced low-level norfloxacin resistance. Structural and docking analysis identified potential binding sites for norfloxacin at the ADP binding site and for acetyl coenzyme A (acetyl-CoA) at a cleft in GS. The results suggest that environmental bacteria whose enzymes modify fluoroquinolones may be able to survive in the presence of low fluoroquinolone concentrations. PMID- 23104419 TI - Transient gestational and neonatal hypothyroidism-induced specific changes in androgen receptor expression in skeletal and cardiac muscles of adult rat. AB - The present study aims to identify the association between androgen status and metabolic activity in skeletal and cardiac muscles of adult rats with transient gestational/neonatal-onset hypothyroidism. Pregnant and lactating rats were made hypothyroid by exposing to 0.05% methimazole in drinking water; gestational exposure was from embryonic day 9-14 (group II) or 21 (group III), lactational exposure was from postnatal day 1-14 (group IV) or 29 (group V). Serum was collected for hormone assay. Androgen receptor status, Glu-4 expression, and enzyme activities were assessed in the skeletal and cardiac muscles. Serum testosterone and estradiol levels decreased in adult rats of groups II and III, whereas testosterone remained normal but estradiol increased in group IV and V, when compared to coeval control. Androgen receptor ligand binding activity increased in both muscle phenotypes with a consistent increase in the expression level of its mRNA and protein expressions except in the forelimb of adult rats with transient hypothyroidism (group II-V). Glut-4 expression remained normal in skeletal and cardiac muscle of experimental rats. Specific activity of hexokinase and lactate dehydrogenase increased in both muscle phenotypes whereas, creatine kinase activity increased in skeletal muscles alone. It is concluded that transient gestational/lactational exposure to methimazole results in hypothyroidism during prepuberal life whereas it increases AR status and glycolytic activity in skeletal and cardiac muscles even at adulthood. Thus, the present study suggests that euthyroid status during prenatal and early postnatal life is essential to have optimal AR status and metabolic activity at adulthood. PMID- 23104420 TI - Angiotensin II impairs glucose utilization in obese Zucker rats by increasing HPA activity via an adrenal-dependent mechanism. AB - Angiotensin II (AngII) increases the activity of the hypothalamus-pituitary adrenal (HPA) axis. We have previously demonstrated in obese Zucker rats (OZR) that AngII-induced HPA hyperreactivity was associated with impaired glucose utilization. The aim of this study was to specify the potential role of the adrenals in regulating AngII-dependent glucose homeostasis in obesity. Adrenal specific AngII effects were determined regarding 1) the HPA axis by ACTH tests after treating OZR with AngII (9 MUg/h, s.c.) for 3 months and 2) glucose utilization by oral glucose tolerance tests (OGTT) in OZR that were adrenalectomized (adx) or sham operated and treated for 1 month with AngII (9 MUg/h, s.c.). AngII increased the corticosterone response after ACTH infusions, clearly indicating the key role of the adrenals for mediating stress reactions. Baseline levels of glucose and corticosterone were not altered by AngII treatment or by adrenalectomy. In contrast, AngII similarly reduced baseline insulin in sham and adxOZR. During OGTT, AngII increased glucose and corticosterone responses in shamOZR, whereas insulin was slightly diminished. This reaction pattern was lost when obese Zucker rats were adrenalectomized. In summary, we verified our hypothesis that the adrenal glands play a key role in worsening glucose homeostasis in obesity in response to AngII, which further supports recent findings that improvement in glucose utilization after AT1 blockade is related to reduced activity of the HPA axis. PMID- 23104422 TI - Small interfering-RNA to protein kinase C-delta reduces the proinflammatory effects of human C-reactive protein in biobreeding diabetic rats. AB - Type 1 diabetes (T1DM) is a proinflammatory state characterized by increased C reactive protein (CRP) levels. Previously we reported that human CRP accentuated macrophage activity in spontaneously diabetic biobreeding (BB) rats and also increased protein kinase C (PKC) delta. Hence we tested the effect of molecular inhibition of PKC delta on plasma and macrophage proinflammatory biomarkers using small interfering (si)RNA to PKC delta. Prior to administration of human CRP, daily for 3 days to diabetic rats, scrambled siRNA or siRNA to PKC delta was also delivered for the 3 days, and the animals were sacrificed on day 4. Peritoneal macrophages and plasma were obtained. Compared to scrambled siRNA, siRNA to PKC delta resulted in a significant decrease in biomediators of inflammation in plasma and from macrophages (IL-1, TNF-alpha, IL-6, MCP-1, KC/IL-8, and PAI -1). However, siRNA to PKC delta has no effect on superoxide release from macrophages. In conclusion, our novel data suggests that siRNA to PKC delta attenuates the proinflammatory effect of human CRP in spontaneously diabetic BB rats and could have implications with regard to attenuating inflammation and vascular complications in T1DM. PMID- 23104423 TI - A method for the synthesis of pyridines from aldehydes, alkynes and NH4OAc involving Rh-catalyzed hydroacylation and N-annulation. AB - A new method for regiocontrolled pyridine synthesis has been developed involving sequential Rh(I)-catalyzed chelation-assisted hydroacylation of alkynes with aldehydes followed by Rh(III)-promoted N-annulation of the resulting alpha,beta enones with another alkyne and NH(3). PMID- 23104421 TI - Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3. AB - We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID- 23104418 TI - Environmental transcription of mmoX by methane-oxidizing Proteobacteria in a subarctic Palsa Peatland. AB - Methane-oxidizing bacteria (MOB) that possess the soluble form of methane monooxygenase (sMMO) are present in various environments, but unlike the prevalent particulate methane monooxygenase (pMMO), the in situ activity of sMMO has not been documented. Here we report on the environmental transcription of a gene (mmoX) for this enzyme, which was attributed mainly to MOB lacking a pMMO. Our study indicates that the sMMO is an active enzyme in acidic peat ecosystems, but its importance for the mitigation of methane releases remains unknown. PMID- 23104424 TI - Weekend bias in Citizen Science data reporting: implications for phenology studies. AB - Studies of bird phenology can help elucidate the effects of climate change on wildlife species but observations over broad spatial scales are difficult without a network of observers. Recently, networks of citizen volunteers have begun to report first arrival dates for many migratory species. Potential benefits are substantial (e.g., understanding ecological processes at broad spatial and temporal scales) if known biases of citizen data reporting are identified and addressed. One potential source of bias in bird phenology studies is the tendency for more "first" migratory arrivals to be reported on weekends than on weekdays. We investigated weekend bias in data reporting for five common bird species in North America (Baltimore Oriole, Icterus galbula; Barn Swallow, Hirundo rustica; Chimney Swift, Chaetura pelagica; Purple Martin, Progne subis; and Ruby-throated Hummingbird, Archilochus colubris), and assessed whether this bias affected mean arrival dates reported using data from historical (1880-1969; N = 25,555) and recent (1997-2010; N = 63,149) Citizen Science databases. We found a greater percentage of first arrivals reported on weekends and small but significant differences in mean arrival dates (approximately 0.5 days) for four of five species. Comparing time periods, this weekend bias decreased from 33.7 % and five species in the historical time period to 32 % and three species in the recent, perhaps related to changes in human activity patterns. Our results indicate that weekend bias in citizen data reporting is decreasing over time in North America and including a 'day of week' term in models examining changes in phenology could help make conclusions more robust. PMID- 23104425 TI - Predicting malaria occurrence in southwest and north central Nigeria using meteorological parameters. AB - Malaria is a major public health problem especially in the tropics with the potential to significantly increase in response to changing weather and climate. This study explored the impact of weather and climate and its variability on the occurrence and transmission of malaria in Akure, the tropical rain forest area of southwest and Kaduna, in the savanna area of Nigeria. We investigate this supposition by looking at the relationship between rainfall, relative humidity, minimum and maximum temperature, and malaria at the two stations. This study uses monthly data of 7 years (2001-2007) for both meteorological data and record of reported cases of malaria infection. Autoregressive integrated moving average (ARIMA) models were used to evaluate the relationship between weather factors and malaria incidence. Of all the models tested, the ARIMA (1, 0, 1) model fits the malaria incidence data best for Akure and Kaduna according to normalized Bayesian information criterion (BIC) and goodness-of-fit criteria. Humidity and rainfall have almost the same trend of association in all the stations while maximum temperature share the same negative association at southwestern stations and positive in the northern station. Rainfall and humidity have a positive association with malaria incidence at lag of 1 month. In all, we found that minimum temperature is not a limiting factor for malaria transmission in Akure but otherwise in the other stations. PMID- 23104427 TI - Enantio- and periselective nitroalkene Diels-Alder reaction. AB - The periselective Diels-Alder reaction of 5-substituted pentamethylcyclopentadienes and nitroethylene has been realized by helical-chiral hydrogen bond donor catalysts. To our knowledge, this represents the first asymmetric catalytic nitroalkene Diels-Alder reaction via activation of nitroalkene, and thus establishes its proof-of-principle. PMID- 23104426 TI - Cross-talk between prion protein and quadruplex-forming nucleic acids: a dynamic complex formation. AB - Prion protein (PrP) is involved in lethal neurodegenerative diseases, and many issues remain unclear about its physio-pathological role. Quadruplex-forming nucleic acids (NAs) have been found to specifically bind to both PrP cellular and pathological isoforms. To clarify the relevance of these interactions, thermodynamic, kinetic and structural studies have been performed, using isothermal titration calorimetry, surface plasmon resonance and circular dichroism methodologies. Three quadruplex-forming sequences, d(TGGGGT), r(GGAGGAGGAGGA), d(GGAGGAGGAGGA), and various forms of PrP were selected for this study. Our results showed that these quadruplexes exhibit a high affinity and specificity toward PrP, with K(D) values within the range 62/630 nM, and a weaker affinity toward a PrP-beta oligomer, which mimics the pathological isoform. We demonstrated that the NA quadruplex architecture is the structural determinant for the recognition by both PrP isoforms. Furthermore, we spotted both PrP N terminal and C-terminal domains as the binding regions involved in the interaction with DNA/RNAs, using several PrP truncated forms. Interestingly, a reciprocally induced structure loss was observed upon PrP-NA interaction. Our results allowed to surmise a quadruplex unwinding-activity of PrP, that may have a feedback in vivo. PMID- 23104428 TI - Uptake of alpha-linolenic acid and its conversion to long chain omega-3 fatty acids in rats fed microemulsions of linseed oil. AB - The present work was designed to prepare linseed oil (LSO) microemulsion and explore the possibility of enhancing the uptake and utilization of alpha linolenic acid (ALA) present in LSO. The bioavailability of encapsulated LSO as against native oil was monitored in rats by measuring the uptake in vitro using the intestinal everted sac model and in-vivo administration of microemulsions of LSO to rats for a period of 30 days. Microemulsions were prepared by using different binding materials such as gum acacia, whey protein and lipoid. When LSO was encapsulated with gum acacia, whey protein and lipoid, the levels of ALA uptake into intestinal sacs was increased by 6, 17 and 28% as compared to oil given without encapsulation. EPA and DHA were not observed in the oil absorbed by intestinal everted sacs when given as emulsions with gum acacia or whey protein. When LSO was given as microemulsions with lipoid, EPA + DHA was observed in oil absorbed by intestinal sacs. Similarly when LSO was given as a lipoid emulsion by intubation to rats, the EPA and DHA in serum lipids were found to be 41 and 34 MUg/ml, respectively while rats given LSO without encapsulation contained EPA and DHA at 9.1 and 8.8 MUg/ml, respectively. Similar changes in omega-3 fatty acid content in liver lipids were observed when LSO was given as a microemulsion with lipoid. This study indicated that ALA was taken up and metabolized to long chain omega-3 PUFA when given as microemulsion with lipoid. PMID- 23104429 TI - Arsenic increases Pi-mediated vascular calcification and induces premature senescence in vascular smooth muscle cells. AB - Several mechanisms have been proposed to explain the vascular toxicity of arsenic. Some of them are described in this work, such as stress-induced premature senescence (SIPS), dedifferentiation, and medial vascular calcification, and they all affect vascular smooth muscle cells (VSMC). Rat aortic VSMC were treated with 1-100 uM of either sodium arsenate (As(V)), sodium arsenite (As(III)), monomethylarsonic acid, or dimethylarsinic acid. None of the treatments induced VSMC calcification in the presence of 1mM inorganic phosphate (Pi), but 1 uM As(III) did increase calcification when induced with 2.5mM Pi. A lactate dehydrogenase assay revealed that this increase was explained by a rise in cytotoxicity due to simultaneous incubation with 1 uM As(III) and 2.5mM Pi. This calcification increase was also observed in the aortas of a vascular calcification model: 5/6 nephrectomized rats fed with a high Pi diet and treated with vitamin D(3). Several known mechanisms that might explain arsenic toxicity in our experimental model were discarded: apoptosis, oxidative stress, and inflammasome activation. Nevertheless, both senescence-associated beta galactosidase activity and p21 expression were increased by As(III), which reveals the induction of SIPS. As(III) also caused dedifferentiation of VSMC, as shown by the reduced expression of the VSMC markers SM22alpha and calponin. Senescence and gene expression were also observed in the aortas of healthy rats treated with 50 ppm As(V) in drinking water for 1 month. In conclusion, both premature senescence in aortic VSMC with phenotypic dedifferentiation and the increase of Pi-induced calcification are novel mechanisms of arsenic vasculotoxicity. PMID- 23104430 TI - Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity. AB - Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical. PMID- 23104431 TI - Interaction of digitalis-like compounds with p-glycoprotein. AB - Digitalis-like compounds (DLCs), or cardiac glycosides, are produced and sequestered by certain plants and animals as a protective mechanism against herbivores or predators. Currently, the DLCs digoxin and digitoxin are used in the treatment of cardiac congestion and some types of cardiac arrhythmia, despite a very narrow therapeutic index. P-glycoprotein (P-gp; ABCB1) is the only known ATP-dependent efflux transporter that handles digoxin as a substrate. Ten alanine mutants of human P-gp drug-binding amino acids-Leu(65), Ile(306), Phe(336), Ile(340), Phe(343), Phe(728), Phe(942), Thr(945), Leu(975), and Val(982)-were generated and expressed in HEK293 cells with a mammalian baculovirus system. The uptake of [(3)H]-N-methyl-quinidine (NMQ), the P-gp substrate in vesicular transport assays, was determined. The mutations I306A, F343A, F728A, T945A, and L975A abolished NMQ transport activity of P-gp. For the other mutants, the apparent affinities for six DLCs (cymarin, digitoxin, digoxin, peruvoside, proscillaridin A, and strophanthidol) were determined. The affinities of digoxin, proscillaridin A, peruvoside, and cymarin for mutants F336A and I340A were decreased two- to fourfold compared with wild type, whereas that of digitoxin and strophanthidol did not change. In addition, the presence of a hydroxyl group at position 12beta seems to reduce the apparent affinity when the side chain of Phe(336) and Phe(942) is absent. Our results showed that a delta-lactone ring and a sugar moiety at 3beta of the steroid body are favorable for DLC binding to P gp. Moreover, DLC inhibition is increased by hydroxyl groups at positions 5beta and 19, whereas inhibition is decreased by those at positions 1beta, 11alpha, 12beta, and 16beta. The understanding of the P-gp-DLC interaction improves our insight into DLCs toxicity and might enhance the replacement of digoxin with other DLCs that have less adverse drug effects. PMID- 23104432 TI - Lung inflammatory effects, tumorigenesis, and emphysema development in a long term inhalation study with cigarette mainstream smoke in mice. AB - Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation-induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300 mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development. PMID- 23104433 TI - [Artificial heart and heart transplantation]. AB - The advances in the treatment of many different heart diseases have on the one side led to a significant prolongation of life expectancy but have also contributed to an increase of patients with heart failure. This tendency is supported even more so by the demographic development of our population. The replacement of insufficient organs has always been in the focus of medical research. In the 1960's Shumway and Lower developed the technique of cardiac transplantation and also worked intensively on the treatment and diagnosis of rejection. However, it was Barnard who, in 1967 performed the first human cardiac transplantation. Other centers followed worldwide but the mortality was high and the new therapy was controversially discussed in many journals. By the introduction of cyclosporin as a new immunosuppressive agent in 1978, results improved rapidly and cardiac transplantation became an accepted therapeutic option for patients with end stage heart failure and also for children and newborns with congenital heart defects. Today, with newer immunosuppressive regimens and improved techniques, cardiac transplantation offers excellent results with a long-term survival of nearly 50% of patients after 15 years and among the pediatric population even after 20 years. However, the donor organ shortage as well as the increasing number of elderly patients with end stage heart failure has necessitated work on other alternatives. Neither stem cell transplantation nor xenotransplantation of animal organs are yet an option and there are still some obstacles to be overcome. In contrast, the development of so called artificial hearts has made significant progress. While the first implants of totally artificial hearts were associated with many comorbidities and patients were seriously debilitated, new devices today offer a reasonable quality of life and long-term survival. Most of these systems are no longer replacing but mainly assisting the heart, which remains in place. These ventricular assist devices have been used as a bridge to transplantation for a long time and are now also offered as a destination therapy for patients who for a variety of reasons are no longer amenable to heart transplantation. Further miniaturization and a decrease of the costs will make these devices a realistic alternative to a sole medical therapy and studies have already proven the superiority in terms of survival as well as rehospitalization rates. However, at present they are still not an alternative to heart transplantation. PMID- 23104435 TI - Evidence synthesis for decision making 2: a generalized linear modeling framework for pairwise and network meta-analysis of randomized controlled trials. AB - We set out a generalized linear model framework for the synthesis of data from randomized controlled trials. A common model is described, taking the form of a linear regression for both fixed and random effects synthesis, which can be implemented with normal, binomial, Poisson, and multinomial data. The familiar logistic model for meta-analysis with binomial data is a generalized linear model with a logit link function, which is appropriate for probability outcomes. The same linear regression framework can be applied to continuous outcomes, rate models, competing risks, or ordered category outcomes by using other link functions, such as identity, log, complementary log-log, and probit link functions. The common core model for the linear predictor can be applied to pairwise meta-analysis, indirect comparisons, synthesis of multiarm trials, and mixed treatment comparisons, also known as network meta-analysis, without distinction. We take a Bayesian approach to estimation and provide WinBUGS program code for a Bayesian analysis using Markov chain Monte Carlo simulation. An advantage of this approach is that it is straightforward to extend to shared parameter models where different randomized controlled trials report outcomes in different formats but from a common underlying model. Use of the generalized linear model framework allows us to present a unified account of how models can be compared using the deviance information criterion and how goodness of fit can be assessed using the residual deviance. The approach is illustrated through a range of worked examples for commonly encountered evidence formats. PMID- 23104434 TI - Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. AB - In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3(+) regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4(+) cells. The prognostic/predictive significance of tumor infiltration by Tregs remains a matter of debate. Indeed, high levels of intratumoral Tregs have been associated with poor disease outcome in cohorts of patients affected by multiple, but not all, tumor types. This apparent discrepancy may relate to the existence of functionally distinct Treg subsets, to the fact that Tregs near-to-invariably infiltrate neoplastic lesions together with other cells from the immune system, notably CD4(+) and CD8(+) T lymphocytes and/or to peculiar features of some oncogenic programs that involve a prominent pro-inflammatory component. In this review, we will discuss the phenotype, function and clinical significance of various Treg subsets. PMID- 23104436 TI - Functional and structural effects of amyloid-beta aggregate on Xenopus laevis oocytes. AB - Xenopus laevis oocytes exposed to amyloid-beta aggregate generated oscillatory electric activity (blips) that was recorded by two-microelectrode voltage-clamp. The cells exhibited a series of "spontaneous" blips ranging in amplitude from 3.8 +/- 0.9 nA at the beginning of the recordings to 6.8 +/- 1.7 nA after 15 min of exposure to 1 MUM aggregate. These blips were similar in amplitude to those induced by the channel-forming antimicrobial agents amphotericin B (7.8 +/- 1.2 nA) and gramicidin (6.3 +/- 1.1 nA). The amyloid aggregate-induced currents were abolished when extracellular Ca(2+) was removed from the bathing solution, suggesting a central role for this cation in generating the spontaneous electric activity. The amyloid aggregate also affected the Ca(2+)-dependent Cl(-) currents of oocytes, as shown by increased amplitude of the transient-outward chloride current (T(out)) and the serum-activated, oscillatory Cl(-) currents. Electron microcopy revealed that amyloid aggregate induced the dissociation of the follicular cells that surround the oocyte, thus leading to a failure in the electro-chemical communication between these cells. This was also evidenced by the suppression of the oscillatory Ca(2+)-dependent ATP-currents, which require proper coupling between oocytes and the follicular cell layer. These observations, made using the X. laevis oocytes as a versatile experimental model, may help to understand the effects of amyloid aggregate on cellular communication. PMID- 23104437 TI - An analogue of resveratrol HS-1793 exhibits anticancer activity against MCF-7 cells via inhibition of mitochondrial biogenesis gene expression. AB - Resveratrol is a phytoalexin and polyphenol derived from grapes, berries, and peanuts. It has been shown to mediate death of a wide variety of cancer cells. Although resveratrol is considered an important potential chemotherapeutic agent, it is required at high doses to achieve a biologically or physiologically significant effect, which may be impractical for treating cancer. Thus, a more stable and potent derivative of resveratrol, with more effective tumoricidal activity, must be developed. A novel resveratrol analog, HS-1793, has recently been synthesized and was determined to exhibit a greater decrease in cancer cell viability than resveratrol. However, the underlying mechanism of HS-1793-induced cancer cell death remains unknown. We thus investigated the mechanism by which HS 1793 induces cell death and assessed whether this occurs through a mitochondrial mediated mechanism. Using the MCF-7 breast cancer cell line, we determined that HS-1793 treatment significantly increased cell death at a relatively low dose compared with resveratrol. HS-1793 treatment more significantly decreased mitochondrial membrane potential, cellular ATP concentration, and cellular oxygen consumption rate than resveratrol treatment. At the molecular level, HS-1793 treatment down-regulated the expression of major mitochondrial biogenesis regulating proteins, including mitochondrial transcriptional factor A (TFAM), Tu translation elongation factor (TUFM), and single-stranded DNA-binding protein. We conclude that HS- 1793 acts by regulating the expression of TFAM and TUFM, leading to a block in normal mitochondrial function, which sensitizes cancer cells to cell death. We therefore propose that HS-1793 can be a useful chemosensitization agent, which together with other such agents can efficiently target cancer cells. PMID- 23104439 TI - Crystal structure of pyridoxal biosynthesis lyase PdxS from Pyrococcus horikoshii. AB - Pyridoxal 5'-phosphate (PLP) is the biologically active form of vitamin B(6) and is de novo synthesized from three substrates, dihydroxyacetone phosphate (DHAP), riburose 5-phosphate (RBP), and ammonia hydrolysed from glutamine. Glutamine amidotransferase (PdxT) catalyzes the production of ammonia from glutamine, while PdxS catalyzes the following condensation of ribulose 5-phosphate (Ru5P), glyceraldehyde-3-phosphate (G3P), and ammonia. PdxS exists as a hexamer or dodecamer depending on species and makes a 1:1 complex with PdxT. Pyrococcus horikoshii PdxS has a 37 amino acids insertion region, which is found in some archaeal PdxS proteins, but its structure and function are unknown. To provide further structural information on the role of the insertion region, the oligomeric state, and ligand binding mode of P. horikoshii PdxS, the crystal structure of PdxS from P. horikoshii was solved in two forms: (i) apo form, (ii) r ibose 5-phosphate (R5P) complex and the quaternary structure of PdxS in solution was determined by analytical gel filtration. P. horikoshii PdxS forms hexamer in solution based on analytical gel filtration data. When we superimpose the structure of P. horikoshii PdxS with other dodecamer structures of PdxS, the additional insertion is located apart from the active site and induces a steric clash on the hexamer-hexamer interface of PdxS proteins. Our results suggest that the additional insertion perturbs dodecamer formation of P. horikoshii PdxS. PMID- 23104441 TI - Simplifying the conductance profiles of molecular junctions: the use of the trimethylsilylethynyl moiety as a molecule-gold contact. AB - Conductance across a metal|molecule|metal junction is strongly influenced by the molecule-substrate contacts, and for a given molecular structure, multiple conductance values are frequently observed and ascribed to distinct binding modes of the contact at each of the molecular termini. Conjugated molecules containing a trimethylsilylethynyl terminus, -C=CSiMe(3) give exclusively a single conductance value in I(s) measurements on gold substrates, the value of which is similar to that observed for the same molecular backbone with thiol and amine based contacting groups when bound to under-coordinated surface sites. PMID- 23104440 TI - Promising outcomes in glutaric aciduria type I patients detected by newborn screening. AB - Glutaric aciduria type I (GA-I) is an inborn error of lysine and tryptophan metabolism. Clinical manifestations of GA-I include dystonic or dyskinetic cerebral palsy, but when the symptoms occur, treatment is not effective. In Taiwan, newborn screening for GA-I started in 2001; we wish to evaluate the outcomes of patients detected through newborn screening. Newborns diagnosed with GA-I by abnormal dried blood spot glutarylcarnitine (C5DC) levels followed in our hospital were included in this study. They were treated with special diets, carnitine supplements, and immediate stress avoidance. Six patients were included in this study. All patients were treated prior to reaching 1 month of age. They were followed up with for 4 to 9 years. One patient had encephalopathic crisis episodes prior to turning 1 year old that caused pallidal lesions. Another patient had a chronic progressive disease during infancy that caused bilateral putamen lesions. These two patients had delayed development, but their brain lesions were resolved. The other four patients ran uneventful courses. They had normal intelligenece, ranged between average to low average level and their brain magnetic resonance imaging showed only high intensity over deep white matter. Patients with GA-I diagnosed by newborn screening have promising outcomes, though the risks of disease progression prior to 1 year of age remain significant. PMID- 23104438 TI - The nuclear localization of glycogen synthase kinase 3beta is required its putative PY-nuclear localization sequences. AB - Glycogen synthase kinase-3beta(GSK-3beta), which is a member of the serine/threonine kinase family, has been shown to be crucial for cellular survival, differentiation, and metabolism. Here, we present evidence that GSK 3beta is associated with the karyopherin beta2 (Kap beta2) (102-kDa), which functions as a substrate for transportation into the nucleus. A potential PY-NLS motif ((109)IVRLRYFFY(117)) was observed, which is similar with the consensus PY NLS motif (R/K/H)X(2-5)PY in the GSK-3beta catalytic domain. Using a pull down approach, we observed that GSK-3beta physically interacts with Kap beta2 both in vivo and in vitro. Secondly, GSK-3beta and Kap beta2 were shown to be co localized by confocal microscopy. The localization of GSK-3beta to the nuclear region was disrupted by putative Kap beta2 binding site mutation. Furthermore, in transient transfection assays, the Kap beta2 binding site mutant induced a substantial reduction in the in vivo serine/threonine phosphorylation of GSK 3beta, where- as the GSK-3beta wild type did not. Thus, our observations indicated that Kap beta2 imports GSK-3beta through its putative PY NLS motif from the cytoplasm to the nucleus and increases its kinase activity. PMID- 23104442 TI - The troubled identity of the bioethicist. AB - This paper raises questions about bioethical knowledge and the bioethical 'expert' in the context of contestation over methods. Illustrating that from the perspective of the development of bioethics, the lack of unity over methods is highly desirable for the field in bringing together a wealth of perspectives to bear on bioethical problems, that same lack of unity also raises questions as to the expert capacity of the 'bioethicist' to speak to contemporary bioethics and represent the field. Focusing in particular on public bioethics, the author argues that we need to rethink the concept of bioethicist, if not reject it. The concept of the bioethicist connotes a disciplinary or theoretical unity that is simply not present and from the perspective of public policy, it is incredibly misleading. Instead, bioethical expertise would be a capacity of a broader community, and not an individual. Such a conception of bioethics as an expert community rather than as an individual capacity, focuses our attention on the more functional question of what knowledge and skill set any individual possesses. PMID- 23104443 TI - A developmental perspective on underage alcohol use. AB - Underage alcohol use can be viewed as a developmental phenomenon because many kinds of developmental changes and expectations appear to influence this behavior and also because it has consequences for development. Data on alcohol use, abuse, and dependence show clear age-related patterns. Moreover, many of the effects that alcohol use has on the drinker, in both the short and long term, depend on the developmental timing of alcohol use or exposure. Finally, many developmental connections have been observed in the risk and protective factors that predict the likelihood of problem alcohol use in young people. Therefore, efforts to understand and address underage drinking would benefit from a developmental perspective, and the general principles of developmental psychopathology offer a useful conceptual framework for research and prevention concerned with underage drinking. PMID- 23104444 TI - Developmental processes and mechanisms: ages 0-10. AB - Little information is available on alcohol use in children up to age 10, although rates appear to be low. This age-group is not without risk, however. In fact, numerous nonspecific and specific risk factors for subsequent alcohol use are prevalent in childhood. Alcohol-nonspecific risk factors include externalizing and internalizing behaviors, as well as environmental and social factors (e.g., stress, physical abuse, or other aspects of social interaction). Nonspecific childhood factors (i.e., predictors) are being identified to target specific population subgroups for preventive interventions. These efforts have identified a variety of predictors of drinking onset during childhood or early adolescence that predict adolescent and young-adult problem drinking, as well as adult alcohol use and alcohol use disorders. Alcohol-specific risk factors also are being identified, including children's beliefs and expectancies about alcohol, as well as childhood social contexts (e.g., modeling of alcohol use by parents, portrayal of alcohol use in the mass media, and growing up in a family with an alcoholic family member). Together, these specific and nonspecific influences play a heavy role in determining a child's risk of or resilience to later alcohol use and related problems. PMID- 23104445 TI - Transitions into underage and problem drinking: summary of developmental processes and mechanisms: ages 10-15. AB - Adolescents ages 10-15 experience dramatic changes in their biological, cognitive, emotional, and social development as well as in their physical and social environments. These include the physiological and psychological changes associated with puberty; further development of the brain; changes in family, peer, and romantic relationships; and exposure to new societal and cultural influences. During this period, many adolescents also begin to use alcohol. Alcohol use during adolescence has adverse effects on the body and increases the risk of alcohol dependence later in life. To better understand why some children drink whereas others do not, researchers are examining nonspecific and alcohol specific factors that put adolescents at risk for, or which protect them from, early alcohol use and its associated problems. Nonspecific risk factors include certain temperamental and personality traits, family factors, and nonnormative development. Examples of nonspecific protective factors include certain temperamental characteristics, religiosity, and parenting factors (e.g., parental nurturance and monitoring). Among the most influential alcohol-specific risk and protective factors are a family history of alcoholism and the influences of siblings and peers, all of which shape an adolescent's expectancies about the effects of alcohol, which in turn help determine alcohol use behaviors. PMID- 23104446 TI - Underage alcohol use: summary of developmental processes and mechanisms: ages 16 20. AB - Late adolescence (i.e., the age-group between 16 and 20 years) is characterized by significant changes in neurological and cognitive processes, behavioral and social functioning, and relational and physical contexts as the individual moves toward adulthood. In this age-group, major role transitions affect almost every aspect of life. Moreover, brain development continues-and with it the development of cognitive functions, working memory, emotional and behavioral self-regulation, and decisionmaking. The adolescent's social and emotional development also continues to evolve, affecting interactions with parents, siblings, peers, and first romantic relationships. All of these changes impact drinking behavior during late adolescence, and, in fact, alcohol use, binge drinking, and heavy drinking are particularly prevalent in youth ages 16-20. Determining the common trajectories of drinking behavior in this age-group is important for understanding how adolescent alcohol use helps shape adult outcomes and for identifying risk and protective factors. It also is important to study the short- and long-term consequences of adolescent alcohol use and abuse, including alcohol's effects on the developing adolescent brain and accomplishment of important developmental tasks of this age. PMID- 23104447 TI - Overview of preventive interventions addressing underage drinking: state of the evidence and steps toward public health impact. AB - Because underage drinking is a serious public health concern and associated with numerous detrimental consequences, many interventions to prevent underage drinking have been developed. However, the effectiveness of all these interventions has not been proven. A recent review of the relevant literature that used stringent criteria for the types of studies and interventions included, as well as for the evaluation and classification of the studies, found that out of more than 400 studies screened, only 127 could be evaluated for efficacy and only 41 showed some evidence of effects. In addition, several areas were identified in which intervention research could be strengthened. For example, increased coverage is needed for understudied areas of intervention (e.g., specific types of interventions or interventions in specific populations). Other aspects of the knowledge base in this area that can benefit from further improvement include, among others, the availability of longitudinal studies, availability of information on alcohol-specific outcomes, or availability of replication studies. The standards for determining and reporting evidence of effectiveness in different studies also need to be clarified. Finally, prevention research needs to adopt public health impact-oriented models to accurately determine the potential of existing interventions to prevent underage drinking and its consequences. PMID- 23104448 TI - Improving treatment through research: directing attention to the role of development in adolescent treatment success. AB - Treatment of adolescents with alcohol use problems can be as successful as in adults, but the success often is short-lived, with most treated adolescents relapsing within a few months. Developmental differences among adolescents may contribute to this high rate of relapse, and treatment approaches that pay direct attention to the patients' developmental status may improve outcomes. To date, studies assessing adolescent alcohol treatment rarely have investigated the association between developmental stage and outcome. In addition, even experts do not fully agree on the developmentally appropriate outcomes that should be evaluated in adolescent treatment studies. Research methods and variables used to assess the outcome of adolescent alcohol treatment often rely on those used in treatment studies of adults. Developmental factors that may directly influence adolescents' amenability to treatment, such as pubertal status, psychological development (e.g., executive mental functions), social relationships, and developmental transitions, have not been adequately investigated. Studies using concepts from developmental science are needed to determine how individual characteristics, various contextual influences (e.g., from peers, family, or the social environment), and the interactions of these factors influence alcohol use behavior, amenability to treatment, and treatment outcomes. Knowledge gained in studies directly examining developmental factors should help in the design of more effective treatment programs with lower relapse rates. PMID- 23104449 TI - Current state of treatment for alcohol and other drug use disorders in adolescents. AB - Over the past decade, treatment programs have been developed specifically for adolescents with alcohol and other drug (AOD) use disorders. The vast majority of these programs use psychosocial approaches, which can be further classified into family-based interventions and multisystemic therapy, motivational enhancement therapy, behavioral therapy, and cognitive-behavioral therapy. Outcome studies have evaluated the effectiveness of the different approaches. The results indicate that all of these strategies can improve an adolescent's outcome on a variety of measures. Pharmacotherapy rarely is used in the treatment of adolescents with AOD use disorders, and existing studies only have assessed the effectiveness of agents aimed at treating coexisting psychiatric conditions. Future studies should use more consistent, state-of-the-art assessment instruments developed specifically for adolescents and also pay greater attention to an adolescent's developmental status and its impact on treatment outcome. PMID- 23104450 TI - Increased bone mineral density and decreased prevalence of osteoporosis in cervical ossification of the posterior longitudinal ligament: a case-control study. AB - Bone and mineral metabolism has been reported to affect the development of the ossification of the posterior longitudinal ligament (OPLL). The aim of this study was to compare bone mineral densities (BMD) and rate of osteoporosis between cervical OPLL and a matched control group. We also investigated the correlation of BMD with the number of cervical spine levels involved with OPLL. From 1999 to August 2011, 178 patients with cervical OPLL underwent dual-energy X-ray absorptiometry (DXA) at our institute. The control group was age-, sex-, and body mass index (BMI)-matched with the OPLL group on a 1:1 basis. BMD was measured at the lumbar spine (L1-L4), femoral neck, and total femur using DXA. Age, sex, and BMI were the same in the OPLL and control groups. BMDs of the OPLL and control groups were significantly different in the lumbar spine, femoral neck, and total femur (p = 0.0001, 0.0001, 0.009, respectively). Rates of osteopenia and osteoporosis were lower in the OPLL than in the control group according to lumbar spine and femoral neck DXA (p = 0.01, 0.03, respectively). A positive correlation was observed between lumbar spine BMD and the number of cervical spine levels involved with OPLL (p = 0.004). PMID- 23104451 TI - [Comment on the contribution by Thoralf Stange: "Possibilities for reconstruction of nasal septum defects"]. PMID- 23104453 TI - Living with a brain tumor : reaction profiles in patients and their caregivers. AB - PURPOSE: The psychological burden induced by brain tumor is profound both for the sick person and for their own family. This particular tumor not only impacts patients' quality of life, but also reduces seriously the caregivers' quality of life. We aim to describe brain tumor patients and their caregivers' quality of life during the illness and assess the existing relation between clinical and psychological features of patients and their caregivers. METHODS: The study involved 72 patients/caregivers couples. We used the following tools: Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy- Brain (FACT-Br) for patients and HADS, Caregiver Reaction Assessment Scale (CRA), 36-Item Short-Form Health Survey (SF-36) for caregivers. RESULTS: Quality of life was more compromised in caregivers than in their loved ones. The impairment of caregivers' quality of life appeared mainly in a significant reduction in their mental health. Most caregivers experienced more depressive and anxiety symptoms, as compared with patients. Clinical and psychological features of patients did not correlate with psychological patterns of their own caregivers. CONCLUSIONS: It is important to give caregivers appropriate help, care and support. Therefore, it is necessary to monitor and treat, if necessary, caregivers' anxious or depressive symptomatology that impacts their quality of life, making them more helpless, frustrated and less able to handle the situation of disease and caregiving situation. It would be desirable to give caregivers the possibility of a psychological support and equally important would be a continuous teamwork aimed to promote a better caregivers' adaptation to the patient's illness. PMID- 23104454 TI - MELD-sodium score and its prognostic value in malignancy-related ascites of pancreatic and gastric cancer. AB - BACKGROUND: Malignant ascites is a manifestation of end-stage events in a variety of cancers. There is significant lack of possible survival predictors in patients with malignancy-related ascites. Since the Model for End-Stage Liver Disease (MELD)-Na score has been shown to be a feasible and independent prognostic predictor for both short- and long-term outcome in HCC patients, we decided to test its prognostic role in other cancer types with ascites. MATERIAL AND METHODS: This is a retrospective study. The outpatient oncology clinic's records were screened for the period between 2004 and 2011. Eighty-two pancreatic and gastric cancer patients were enrolled into the study. RESULTS: The median age of patients was 59 (+/-12). Fifty-nine patients had gastric cancer and 23 had pancreatic cancer. Overall survival (OS) was 16.8 (IR, 1-98) months in gastric cancer and 16.3 (IR, 0.5-81) months in pancreatic cancer. There was no statistically significant difference between OS of gastric and pancreatic cancer. Progression-free survival (PFS) was statistically significantly longer in gastric cancer than pancreatic cancer with 16.5 (IR, 0.5-90) vs 6.5 (IR, 0.4-34) months (P = 0.04). Further analysis of data included stepwise multiple regression analysis with the dependent variable "overall survival." The model had two independent predictors and an R(2) of 82 % and a predicted R(2) of 81 %. Predictors for time to remission were PFS and MELD-Na. The regression equation for the model was: Overall survival =17.4- 0.522 MELD-Na + 0.902 PFS CONCLUSION: In this study we showed that progression-free survival and MELD-Na score are significantly related with overall survival. MELD-Na score can be one of the predictors of the survival and PFS in pancreatic and gastric cancer patients with ascites. PMID- 23104456 TI - An imidazole-based organocatalyst designed for bulk polymerization of lactide isomers: inspiration from Nature. AB - The design of an imidazole-based salt by enzyme-mimicking allowed controlling the ring-opening polymerization of L- and D-LA monomers in bulk. Kinetic study supports a bifunctional activation process only slightly different from the one occurring in Nature. PMID- 23104455 TI - 9-Aryl-9-xanthenols: a convenient platform for the design of fluorimetric and colorimetric pH indicators. AB - In aqueous and alcohol solutions, colorless and non-fluorescent derivatives of 9 aryl-9H-xanthen-9-ol equilibrate with brightly colored and fluorescent 9 arylxanthylium cations, thus offering a convenient platform for the design of dual-mode indicators for emission and absorption-based pH measurements. The position of the prototropic equilibrium depends only on the hydronium ion concentration and is not affected by general acids or other ions. Furthermore, the equilibrium equivalence point can be readily adjusted by introducing substituents in the xanthenol core. As dehydroxylation of 3,6-dialkoxy-9-(o tolyl)-9-xanthenol occurs at pH = 6.5, indicators of this type are well suited for biological applications as illustrated by in vitro cell culture studies with NIH 3T3 cells. PMID- 23104457 TI - Resection of a giant cardiac hemangioma. AB - We present a case of a 61-year-old female who underwent excision of the mass within left atrial appendage. She underwent cardiac surgery due to cardiac tumor. The tumor was measured 6 cm, and it was completely resected. After surgery, pathological examination diagnosed endocardiac-based cardiac hemangioma. The post operative course was uneventful and the patient discharged on the 18th postoperative day. PMID- 23104458 TI - Mature teratoma of the posterior mediastinum: report of a case. AB - Mediastinal teratoma generally arises in the anterior mediastinum. Posterior mediastinal teratomas have been rarely reported to date, especially in adults. We report a case of posterior mediastinal teratoma in a 57-year-old woman. The pre operative diagnostic work-up revealed a posterior mediastinal tumor with calcification and fluid components. The tumor, adhering to the descending aorta, was radically removed through video-assisted thoracic surgery. Histological examination was concluded for a mature teratoma with cystic change. The imaging features of posterior mediastinal teratomas are identical to those in the anterior mediastinum, except for their location. To be different from anterior mediastinal teratomas, benign teratomas in the posterior mediastinum are often involved with a major surrounding structure, including aorta, chest wall, and esophagus. When a posterior mediastinal tumor has the typical features of a mature teratoma in the pre-operative findings, the adhesion to the surrounding structure should be considered. PMID- 23104459 TI - Minute pulmonary meningothelial-like nodules coexisting with pulmonary cryptococcosis mimicking lung cancer. AB - A 68-year-old woman was found to have an abnormal shadow on chest X-ray. Computed tomography showed some small ground-glass opacities in the bilateral lung field and also a 22-mm tumor in the left lower lobe, which showed high accumulation on (18)F fluorodeoxyglucose positron emission tomography. Each of them was difficult to distinguish from lung cancer clinically. Preoperative localization of a small ground-glass opacity nodule with computed tomography-guided lipiodol marking and resection of each using a fluoroscopic unit was performed. Pathological findings from the small nodule showed minute pulmonary meningothelial-like nodule, and those from the tumor and fungal culture showed pulmonary cryptococcosis. To the best of our knowledge, this is the first reported case of coexisting minute pulmonary meningothelial-like nodules and pulmonary cryptococcosis mimicking lung cancer. Thoracoscopy assisted by computed tomography-guided lipiodol marking enabled us to diagnose them. PMID- 23104460 TI - Aortic arch reconstruction for interrupted aortic arch using an aberrant right subclavian artery. AB - An aberrant right subclavian artery can be used in a variety of ways in complex aortic arch reconstructions, including reconstruction of an interrupted aortic arch. Here, we described the case of a 4-month-old female infant with a type B interrupted aortic arch, who underwent arch reconstruction using an aberrant right subclavian artery. PMID- 23104461 TI - [Intensive ventilation--an update]. PMID- 23104462 TI - [Difficult to wean patients]. AB - Approximately 10% of patients with mechanical ventilation experience prolonged weaning and also have an increased morbidity and mortality. Once spontaneous breathing trials have failed the organ systems responsible should be identified. This can be accomplished during the spontaneous breathing trial using clinical examination, measurement of blood gases, echocardiography and imaging techniques. Specific patterns allow the diagnosis of pathological respiratory mechanisms, weak ventilatory muscles, heart failure, myocardial ischemia and psychiatric problems. Respiratory and cardiac limitations of weaning can be overcome by reducing the ventilatory load, training of the ventilatory muscles and reducing cardiac workload. A cooperative sedation strategy as well as an early start of weaning and rehabilitation can prevent prolonged weaning in critically ill patients. PMID- 23104463 TI - [Critical illness polyneuropathy and critical illness myopathy]. AB - Critical illness polyneuropathy (CIP) and critical illness myopathy (CIM) are frequent complications in critically ill patients and both are associated with sepsis, systemic inflammatory response syndrome (SIRS) and multiorgan failure. Major signs are muscle weakness and problems of weaning from the ventilator. Both CIP and CIM lead to elongated times of ventilation, elongated hospital stay, elongated times of rehabilitation and increased mortality. Electrophysiological measurements help to detect CIP and CIM early in the course of the disease. State of the art sepsis therapy is the major target to prevent the development of CIP and CIM. Although no specific therapy of CIP and CIM has been established in the past, the diagnosis generally improves the therapeutic management (weaning from the ventilator, early physiotherapy, etc.). This review provides an overview of clinical and diagnostic features of CIP and CIM and summarizes current pathophysiological and therapeutic concepts. PMID- 23104464 TI - Evaluation and treatment of gout as a chronic disease. AB - Gout is a disease caused by deposition of monosodium urate crystals in tissues. One of the limitations for successful treatment of gout is to consider it as an intermittent disease rather than a chronic inflammatory disease which, if improperly treated, leads to chronic clinical manifestations. In addition, gout is linked to increased cardiovascular morbidity and mortality.Urate-lowering therapy comprises both nonpharmacologic and pharmacologic interventions, but most patients will need urate-lowering drugs to achieve target therapeutic serum urate levels. Reaching target serum urate levels is associated with improvement in clinical outcomes, including a reduction of acute inflammation episodes, resolution of tophi, and improvement in health-related quality of life perception.A number of urate-lowering drugs are available but a number of patients fail to achieve or maintain therapeutic serum urate levels and go on to develop refractory chronic gout. For such patients, efforts have been made to develop new treatments (e.g., febuxostat or pegloticase).This review intends to increase the awareness of gout as a chronic deposition disease, and show that efforts should be made to properly control serum urate levels in order to achieve complete disappearance of urate crystal deposition. PMID- 23104465 TI - Cabozantinib for the treatment of advanced medullary thyroid cancer. AB - INTRODUCTION: Patients with advanced medullary thyroid cancer (MTC) have poor prognoses and limited treatment options. Improved knowledge about molecular aberrations associated with MTC and the availability of novel targeted tyrosine kinase inhibitors (TKIs) have led to new potential treatment modalities. Cabozantinib is an oral multitargeted TKI with activity against multiple receptors including RET, vascular endothelial growth factor receptor type 2 (VEGFR2), and MET that has been evaluated in MTC in the preclinical and clinical arenas. METHODS: This article reviews unmet clinical needs in advanced MTC. The authors consider novel agents that have been studied in MTC, with a focus on the investigational agent cabozantinib. Up-to-date clinical data of cabozantinib in MTC are discussed. RESULTS: Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression-free survival in patients with progressive MTC. These findings indicate that cabozantinib may be an effective therapy in advanced MTC. No improvement in overall survival has been demonstrated but data are not mature. CONCLUSION: Cabozantinib may be an effective treatment option for patients with advanced MTC and is worthy of further evaluation. PMID- 23104466 TI - CO2/ethylene oxide copolymerization and ligand variation for a highly active salen-cobalt(III) complex tethering 4 quaternary ammonium salts. AB - A cobalt(III) complex (1) of a salcy-type ligand tethering 4 quaternary ammonium salts, which is thought to act as a highly active catalyst for CO2/propylene oxide (PO) copolymerization, also shows high activity (TOF, 25,900 h(-1); TON, 518,000; 2.72 kg polymer per g cat) and selectivity (>98%) for CO2/ethylene oxide (EO) copolymerization that results in high-molecular-weight polymers (M(n), 200,000-300,000) that have strictly alternating repeating units. The related cobalt(III) complexes 11-14 were prepared through variations of the ligand framework of 1 by replacing the trans-1,2-diaminocyclohexane unit with 2,2 dimethyl-1,3-propanediamine, trans-1,2-diaminocyclopentane, or 1,1'-binaphthyl 2,2'-diamine or by replacing the aldimine bond with ketimine. These ligand frameworks are thought to favour the formation of the cis-beta configuration in complexation, and the formation of the cis-beta configuration in 11-14 was confirmed through NMR studies or X-ray crystallographic studies of model complexes not bearing the quaternary ammonium salts. Complexes 11, 13, and 14, which adopt the cis-beta configuration even in DMSO did not show any activity for CO2/PO copolymerization. Complex 12, which was constructed with trans-1,2 diaminocyclopentane and fluctuated in DMSO between the coordination and de coordination of the acetate ligand as observed for 1, showed fairly high activity (TOF, 12,400 h(-1)). This fluctuating behaviour may play a role in polymerization. However, complex 12 did not compete with 1 in terms of activity, selectivity, and the catalyst cost. PMID- 23104467 TI - Factors influencing the diagnostic process of carpal tunnel syndrome. AB - There are no studies regarding the course leading to carpal tunnel syndrome (CTS) diagnosis and factors influencing the diagnostic process. The study aim is to analyse CTS diagnostic path assessing whether the type of physician (general practitioners or specialist) may influence the manner and timing of diagnosis, and whether CTS severity at diagnosis may be predicted by factors related to Public Health Service and/or to patient. A medical history form was filled in by 375 consecutive patients with idiopathic CTS enrolled at an electromyography service. The patient answered a self-administered questionnaire on symptom severity and the neurophysiologist quantified clinical and electrophysiological CTS severity. The patients going directly to general practitioner were older and more blue collars, had minor education level, more symptom duration, more clinical and electrophysiological severity, more medical examination numbers, more time elapsing between first visit to a doctor and referral for EMG than those going to a specialist. But all variables are interrelated and when multivariate logistic regression analyses were performed, only patient age and some other few independent variables related to patient or health care but not to referring doctor could predict CTS severity at the diagnosis. Typology of the first doctor did not influence diagnostic path. The patients should reduce the time elapsing between CTS symptom onset and consulting doctor thus, permitting early treatments. Some corrective actions on diagnostic path may concern the public health service by reducing waiting lists to perform electrodiagnostic testing and giving greater information to population at risk. PMID- 23104470 TI - Stereoselective synthesis and biological evaluation of D-fagomine, D-3-epi fagomine and D-3,4-epi-fagomine analogs from D-glyceraldehyde acetonide as a common building block. AB - The stereoselective synthesis of D-fagomine, D-3-epi-fagomine, and D-3-epi fagomine analogs starting from readily available D-glyceraldehyde acetonide has been achieved. The synthesis involves diastereoselective anti-vinylation of its homoallylimine, ring-closing metathesis, and stereoselective epoxidation followed by regioselective ring-opening or stereoselective dihydroxylation. The lack of a strong activity as glycosidase inhibitors of these compounds could be advantageous for their therapeutic use as chaperones. PMID- 23104468 TI - Host factors determining the efficacy of hepatitis C treatment. AB - Combination therapy with pegylated interferon and ribavirin is the standard of care (SOC) for the treatment of chronic hepatitis C (CHC). Treating CHC with SOC may show a sustained virological response (SVR) in approximately 50-70 % of genotype 1 CHC patients and an SVR in 70-90 % of genotype 2 CHC patients. The genotype, baseline viral load, and viral kinetics (i.e., rapid virologic response and early virologic response) can be used as predictors of response-guided therapy. Nonetheless, host factors, e.g. age, ethnicity, insulin resistance, and genetic variations, may also play important roles in the SVR in CHC patients treated with SOC. Recent genome-wide association studies have demonstrated that single-nucleotide polymorphisms near the interleukin 28B gene (IL28B) were associated with SVR to treatment with SOC in CHC patients. The IL28B polymorphisms may contribute to the viral kinetics during treatment. Asian people have favorable IL28B polymorphisms. This factor may at least partly explain the high eradication rate of hepatitis C by SOC in Asia. Combination therapy with direct-acting antivirals (DAAs) and SOC can increase the SVR rates both in treatment-naive and treatment-experienced patients. Although the IL28B polymorphisms also affect the SVR of triple therapy with SOC and first-generation protease inhibitors, pilot studies have demonstrated that potent DAAs might overcome the influence of IL28B polymorphisms. Thus, the treatment of hepatitis C virus infection could be simplified in the near future. PMID- 23104469 TI - Culture systems for hepatitis E virus. AB - The lack of an efficient cell culture system for hepatitis E virus (HEV) has greatly hampered detailed analyses of this virus. The first efficient cell culture systems for HEV that were developed were capable of secreting infectious HEV progenies in high titers into culture media, using PLC/PRF/5 cells derived from human hepatocellular carcinoma and A549 cells derived from human lung cancer as host cells. The success achieved with the original genotype 3 JE03-1760F strain has now been extended to various HEV strains in fecal and serum samples obtained from hepatitis E patients and to HEV strains in fecal and serum samples and liver tissues obtained from pigs and wild boar across species barriers. In addition, infectious HEV cDNA clones of the wild-type JE03-1760F strain and its variants have been engineered. Cell culture-generated HEV particles and those in circulating blood were found to be associated with lipids and open reading frame 3 (ORF3) protein, thereby likely contributing to the assembly and release of HEV from infected cells both in vivo and in vitro. The ORF3 protein interacts with the tumor susceptibility gene 101, a critical cellular protein required for the budding of enveloped viruses, through the Pro, Ser, Ala, and Pro (PSAP) motif in infected cells; ORF3 is co-localized with multivesicular bodies (MVBs) in the cytoplasm of infected cells, thus suggesting that HEV requires the MVB pathway for the egress of virus particles. This article reviews the development of efficient cell culture systems for a wide variety of infectious HEV strains obtained from humans, pigs, and wild boar, and also provides details of a new model for virion egress. PMID- 23104471 TI - Transforming growth factor-beta genetic polymorphisms on development of liver cirrhosis in a meta-analysis. AB - Transforming growth factor-beta (TGF-beta) protein has been supposed to be a risk factor for liver cirrhosis; however, the associations between its genes (TGF-beta -509C>T and +869T>C) and liver cirrhosis remained unclear. This study was to quantitatively analyze the correlations by using a meta-analysis. Pubmed, Embase, Wanfang databases were retrieved up to November 1st, 2011. Odds ratio (OR) and 95 % confidence interval (95 %CI) were used to demonstrate the strength of association, and P < 0.05 of Z test indicated statistical significance. Combined analyses were performed by using fixed or random-effect model, depending on between-study heterogeneity. Seven studies were for TGF-beta -509C>T polymorphism, and eight studies were for +869T>C polymorphism. Combined results indicated that neither TGF-beta -509C>T nor +869T>C polymorphisms were associated with risk of liver cirrhosis [OR (95 % CI): 0.79 (0.60-1.04) for CT vs. TT of 509C>T and 0.87 (0.68-1.12) for CT vs. CC of +869T>C], with no between-study heterogeneity. In addition, subgroups analyses still inferred that two polymorphisms were not associated with risk of liver cirrhosis for HBV-infected patients, Asians and for Population-based studies. This meta-analysis indicated that neither TGF-beta -509C>T nor +869T>C polymorphisms were associated with risk of liver cirrhosis, regardless of HBV infection or not. PMID- 23104472 TI - Molecular cloning and characterization of a tropinone reductase from Dendrobium nobile Lindl. AB - A cDNA sequence that encodes a peptide with similarity to known tropinone reductases (TR) was cloned from Dendrobium nobile Lindl. The full coding region of the gene (DnTR1) is 804 bp in length which encodes a putative peptide consisting of 268 amino acids. Phylogenetic analysis showed that DnTR1 was a novel member of the TR family and evolutionarily distant from those well characterized subgroups of TRs, suggesting that DnTR1 may have distinct characteristics. Structural modeling found that DnTR1 had a similar electrostatic environment at the inner molecular surface of the substrate binding pocket with TRI encoded by Datura stramonium (DsTRI). Catalytic activity assay with recombinant protein demonstrated that DnTR1 was able to reduce tropinone, 3 quinuclidinone hydrochloride, and 4-methylcyclohexanone using NADPH as coenzyme. Gene expression profiling by qRT-PCR revealed that the DnTR1 transcript was expressed in all three vegetative organs (leaves, stems and roots) of D. nobile with the highest expression level in roots. The expression of DnTR1 mRNA was enhanced 9.5 times (P < 0.01) by treatment of methyl jasmonate at 24 h, but not affected by salicylic acid and sodium nitroprusside treatments, indicating that DnTR1 regulation may be involved in a jasmonate-dependent pathway. PMID- 23104473 TI - Modified method for combined DNA and RNA isolation from peanut and other oil seeds. AB - Isolation of good quality RNA and DNA from seeds is difficult due to high levels of polysaccharides, polyphenols, and lipids that can degrade or co-precipitate with nucleic acids. Standard RNA extraction methods utilizing guanidinium-phenol chloroform extraction has not shown to be successful. RNA isolation from plant seeds is a prerequisite for many seed specific gene expression studies and DNA is necessary in marker-assisted selection and other genetic studies. We describe a modified method to isolate both RNA and DNA from the same seed tissue and have been successful with several oil seeds including peanut, soybean, sunflower, canola, and oil radish. An additional LiCl precipitation step was added to isolate both RNA and DNA from the same seed tissues. High quality nucleic acids were observed based on A(260)/A(280) and A(260)/A(230) ratios above 2.0 and distinct bands on gel-electrophoresis. RNA was shown to be suitable for reverse transcriptase polymerase chain reaction based on actin or 60S ribosomal primer amplification and DNA was shown to have a single band on gel-electrophoresis analysis. This result shows that RNA and DNA isolated using this method can be appropriate for molecular studies in peanut and other oil containing seeds. PMID- 23104475 TI - A dual molecular beacon approach for fast detection of Mycobacterium tuberculosis. AB - The main objectives of this study were to assess a dual molecular beacon approach for fast detection of Mycobacterium tuberculosis (MT). MT beacon (Tb-B) was designed to target the unique IS6110 (114 bp) and rpoB (215 bp) fragment of the MT (H37Ra) genome, and the two fragments were inserted into the PMD-19T vector after purification, by PCR and sequencing, to construct plasmids. Different dilutions of positive plasmid standards were used for dual molecular beacon RT PCR of rpoB and IS6110, and standard curves were established.The results show that the dual molecular beacon of rpoB and IS6110 detecting MT was stable (CV is 1.91-2.68 %) with a high amplification efficiency (95.6 %). In addition, the strains of non MT did not generate fluorescence signals, while strains of MT did, indicating that the primers and molecular beacons were specific, and only MT complex was amplified. The linear range was wide (10(3)-10(11) copies/mL), and clinical specimens presenting different bacterial counts can be detected. PMID- 23104477 TI - [Apophysitis calcanei]. PMID- 23104474 TI - Transcription factor OsAP21 gene increases salt/drought tolerance in transgenic Arabidopsis thaliana. AB - Transcription factors play vital roles in stress signal transduction and gene expression modulation during plant growth and development. Sequence analysis showed that OsAP21 contained an AP2/ERF domain of 57 amino acids. By comparison of deduced amino acid sequences of AP2/ERF-related proteins, we deduced that OsAP21 is a transcription factor gene, which belonging to rice AP2/ERF family CBF/DREB subfamily. Further, we report that transgenic Arabidopsis thaliana plants expressing the OsAP21 gene exhibited stronger growth than wild type plants under salt/drought stress. Analysis of RT-PCR for RD29B gene implied that OsAP21 over-expressed plants had a higher expression level of RD29B gene than wild type plants, and drought and salt treatments could enlarge these differences. Collectively, our results indicate that OsAP21 may play an important role in the response of transgenic Arabidopsis plants to salt/drought stresses. PMID- 23104478 TI - [Bronchial carcinoma - does an updated diagnostic path make sense?]. PMID- 23104476 TI - Cyclopamine cooperates with EGFR inhibition to deplete stem-like cancer cells in glioblastoma-derived spheroid cultures. AB - Putative cancer stem cells have been identified in glioblastoma (GBM), associated with resistance to conventional therapies. Overcoming this resistance is a major challenge to manage this deadly brain tumor. Epidermal growth factor receptor (EGFR) is commonly amplified, over-expressed, and/or mutated in GBM, making it a compelling target for therapy. This study investigates the behavior of 3 primary neurosphere (NS) cell lines and their adherent counterparts originated from human GBM resections, when treated with EGFR-tyrosine kinase inhibitor erlotinib, associated or not with cyclopamine, a hedgehog pathway inhibitor. Adherent cells cultured in the presence of serum expressed the glial fibrillary acidic protein, whereas NS-forming cells cultured in serum-free medium expressed CD133, nestin, and Oct-4, markers of neural stem and progenitor cells. For the 3 adherent cell lines, erlotinib has a moderate effect (50% inhibitory concentration [IC50], >10 uM). Conversely, erlotinib induced a strong cell growth inhibition (IC50, <1 uM) on NS-forming cells, related to the EGFR gene amplification and EGFR protein expression. A short exposure to erlotinib reduced nestin-positive cell proliferation, but NS-initiating activity and self-renewal were not altered. EGFR pathway seems essential for GBM progenitor cell proliferation but dispensable for cancer stem-like cell self-renewal. Inhibition of hedgehog pathway with cyclopamine was evaluated in association with erlotinib on NS growth. Although each drug separately had no effect on sphere initiation, their combination significantly decreased the sphere number (P < .001). Our findings show synergic efficiency for erlotinib-cyclopamine association and provide a suitable in vitro model to explore drug combinations on GBM cells. PMID- 23104479 TI - [Diagnostic imaging - increased radiation burden due to a larger proportion of modern imaging]. PMID- 23104481 TI - [Venous diagnosis in suspected peripheral arterial occlusive disease - simultaneous MRA of arteries and veins detects unsuspected deep venous thrombosis]. PMID- 23104480 TI - [Non small cell lung carcinoma - evaluation of tumor heterogeneity using CT texture analysis]. PMID- 23104482 TI - [Arteriovenous malformations - endovascular therapy also feasible in concomitant aneurysms]. PMID- 23104483 TI - [Arterial stenoses - diagnostic comparison of Gd-DOTA enhanced MRA and TOF-MRA]. PMID- 23104484 TI - [Chronic obstructive lung diseases - "bronchial wall attenuation value" versus standard CT parameter]. PMID- 23104485 TI - [Intervertebral disk displacement - course of pain after CT guided percutaneous discectomy]. PMID- 23104486 TI - [Endometriosis or colorectal carcinoma - better differentiation with diffusion weighted MRT?]. PMID- 23104487 TI - [Diagnosis of posttransplantation pneumonia - the most frequent ones are bacterial pneumonias and mixed infections]. PMID- 23104491 TI - [Inclusion of the nuclear medicine and radiotherapy physician groups in needs planning and the provision of a decision barrier by G-BA with a resolution on 09 June 2012]. PMID- 23104494 TI - Strategies for identification of carbapenemase-producing Enterobacteriaceae. AB - The spread of carbapenem-hydrolysing beta-lactamases in Enterobacteriaceae is becoming a major public health issue. These beta-lactamases hydrolyse almost all beta-lactams, are plasmid-encoded and are easily transferable among enterobacterial species. They are found in multidrug-resistant isolates. Detection of these isolates from infected specimens first relies on careful recognition of any decreased susceptibility to carbapenems. After this, rapid biochemical identification of carbapenemase producers using the novel Carba NP test should be performed. Subsequently, molecular techniques can be used to identify carbapenemase genes if necessary (epidemiology). Detection of carriers relies on a preliminary screening step, with stools or rectal swabs being screened on selective culture media such as SUPERCARBA medium, which posseses the broadest spectrum for detecting any type of carbapenemase producer. PMID- 23104495 TI - Analysis of metronidazole susceptibility in different Clostridium difficile PCR ribotypes. AB - OBJECTIVES: Susceptibility to metronidazole was investigated in 81 Clostridium difficile strains, belonging to nine different PCR ribotypes, by three different laboratory methods. METHODS: MICs for 81 C. difficile clinical isolates were determined by Etest, the agar dilution method (ADM) and the agar incorporation method (AIM). Twenty selected strains were also subjected to subinhibitory concentrations of metronidazole and the MIC heterogeneity was analysed in colonies from each strain that showed increased values before and after exposure to the antibiotic, using ADM and AIM. RESULTS: Overall, the MICs obtained by Etest were lower compared with those obtained by ADM and AIM, causing discrepancies in the categorization (as susceptible or having reduced susceptibility) of some strains. Reduced susceptibility to metronidazole was observed using both ADM and AIM, with higher MIC values by AIM in isolates belonging to PCR ribotypes 001 and 010. An increase in MICs after exposure to metronidazole was observed for strains belonging to these PCR ribotypes (by Etest and ADM, but not by AIM). In particular, MICs for colonies from strains belonging to either PCR ribotype 001 or 010 were less heterogeneous by AIM compared with by ADM, suggesting a better ability of AIM to detect strains with reduced susceptibility. CONCLUSIONS: These results suggest that the presence of C. difficile subpopulations with reduced susceptibility to metronidazole in the human intestine may be one of the factors responsible for reduced antibiotic efficacy in vivo. The possibility that higher MICs may have often gone unnoticed underlines the importance of choosing the best method for MIC determination and the necessity to monitor C. difficile susceptibility to metronidazole. PMID- 23104496 TI - Distal tibial hypertrophic nonunion with deformity: treatment by fixator-assisted acute deformity correction and LCP fixation. AB - Distal tibial hypertrophic nonunion with angular deformity has been successfully treated by circular external fixator. The inconvenience of the bulky external fixator and frequent pin tract infection would not be accepted in certain cases. This study included thirteen patients (mean age 39 years) with angular deformity of the distal dia-/metaphyseal tibial shaft. Five patients were originally treated by interlocking nail, three were treated by plate and screws fixation, four treated conservatively and one had deformity secondary to fracture of a lengthening regenerate. All patients were treated by osteotomy and acute correction of the deformity using temporary unilateral fixator and internal fixation by a locking compression plate (LCP). The external fixator was removed at the end of surgery. The results were evaluated both clinically and radiologically. All osteotomies healed within 3 (2-4) months. All patients were able to work within an average of 2.3 months. The function of the upper ankle joint was unrestricted in twelve cases, and in 1 case there was a mild functional deficit. The mean follow-up was 60 months (24-120). The frontal plane alignment parameters (the mechanical axis deviation, the lateral distal tibial angle and the medial proximal tibial angle) and the sagittal alignment parameters (the posterior proximal tibial angle and the anterior distal tibial angle) were within normal values postoperatively. No cases of deep infection or failure of fixation were encountered. Acute correction of distal tibial shaft hypertrophic nonunion with deformity and LCP fixation is a reliable option in well-selected cases. PMID- 23104493 TI - Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study. AB - OBJECTIVES: Even though the use of combined drugs has been proved to be effective in other chronic infections, assessment of combined treatment of antiparasitic drugs in human Chagas' disease has not been performed. Herein, a pilot study was conducted to evaluate the tolerance and side effects of a sequential combined treatment of two antiparasitic drugs, allopurinol and benznidazole, in the chronic phase of Trypanosoma cruzi infection. PATIENTS AND METHODS: Changes in total and T. cruzi-specific T and B cells were monitored during a median follow up of 36 months. Allopurinol was administered for 3 months (600 mg/day) followed by 30 days of benznidazole (5 mg/kg/day) in 11 T. cruzi-infected subjects. RESULTS: The combined sequential treatment of allopurinol and benznidazole was well tolerated. The levels of T. cruzi-specific antibodies significantly decreased after sequential combined treatment, as determined by conventional serology and by a multiplex assay using recombinant proteins. The frequency of T. cruzi-specific interferon-gamma-producing T cells significantly increased after allopurinol treatment and decreased to background levels following benznidazole administration in a substantial proportion of subjects evaluated. The levels of total naive (CD45RA + CCR7 + CD62L+) CD4 + and CD8 + T cells were restored after allopurinol administration and maintained after completion of the combined drug protocol, along with a decrease in T cell activation in total peripheral CD4 + and CD8 + T cells. CONCLUSIONS: This pilot study shows that the combination of allopurinol and benznidazole induces significant modifications in T and B cell responses indicative of a reduction in parasite burden, and sustains the feasibility of administration of two antiparasitic drugs in the chronic phase of Chagas' disease. PMID- 23104497 TI - Hospital organization and performance: a directional distance function approach. AB - The present study considers the Italian healthcare system, investigating the aspects that might affect the efficiency of Italian hospitals. The authors analyze what influences a specific definition of efficiency, which is calculated maximizing healthcare production but minimizing potential financial losses. In other words, this work considers efficient each hospital which is able to maximize the production of medical treatments while complying, at the same time, with budget constraints. Hence, the results of this paper are twofold: from the organizational point of view, they underline the need for rebalancing the various administrative levels of hospitals; from the technical point of view, a more coherent model is proposed in order to account for all the aspects of the healthcare industry. PMID- 23104498 TI - [Latissimus dorsi transfer for the treatment of irreparable rotator tears: indication, surgical technique, and modifications]. AB - OBJECTIVE: Improvement of glenohumeral dynamic centering and active external rotation by a transfer of the latissimus dorsi tendon to the greater tuberosity or the lateral proximal humerus. INDICATIONS: Irreparable posterosuperior rotator cuff tears. CONTRAINDICATIONS: Cuff tear arthropathy, subscapularis tendon tear, deltoid insufficiency, palsy of the axillary nerve. SURGICAL TECHNIQUE: Diagnostic arthroscopy in lateral decubitus position. Placement of suture through the biceps tendon and supragleonidal tenotomy. Posterior approach. Preparation and mobilization of a pedicled latissimus dorsi flap. Second anterior incision with delta split. Debridement of the torn rotator cuff. Insertion of suture anchors in the greater tuberosity. Passing of the muscle flap inferior to the posterior deltoid and fixation with suture anchors to the greater tuberosity (where applicable suturing with remaining rotator cuff tissue). POSTOPERATIVE MANAGEMENT: Immobilization in a thorax abduction cast for 6 weeks. Passive exercises out of the cast (IR/ER 0-0-free and ABD/ADD free-45-0 degrees ). Active assistive exercises from week 4 postoperatively. Stepwise increase of passive range of motion from week 7. Unlimited active range of motion from week 10. RESULTS: After an average follow-up of 57.6 (SD 27.5) months 17 patients were examined clinically. The average age at time of surgery was 55.6 (SD 7.7) years. At follow-up the patients showed an average Constant score of 64.4 points (SD 17.4). The active external rotation in 0 degrees abduction was 16 degrees (SD 17). The 4 patients (23%) with a sonographically-detected retear of the latissimus flap presented worse clinical results. PMID- 23104499 TI - [The isolated subscapularis tendon tear: arthroscopic and open repair]. AB - OBJECTIVE: Arthroscopic or open reconstruction of isolated subscapularis tendon tears with the use of suture anchors to restore the glenohumeral function and joint biomechanics. INDICATIONS: Traumatic full-thickness tears, chronic tears with a functional deficit or decentration of the humerus head, anterosuperior rotator cuff insufficiency, symptomatic reruptures after prior arthroscopic or open surgical procedures. CONTRAINDICATIONS: Frozen shoulder, atrophy > grade II (Thomazeau) or fatty infiltration > grade III (Goutallier/Fox) of the muscle, high-grade omarthrosis. SURGICAL TECHNIQUE: Diagnostic arthroscopy and careful tendon release. If the inferior edge of the rupture is reliable visible and the tendon-mobilisation works proper, the repair is performed arthroscopically. The footprint is decorticated lightly and 1-4 suture anchors (depending on the lesion size) are placed from inferior to superior. Knots are tied starting from caudal in a modified Mason-Allen technique (alternative: single or double mattress stitches) with a slipknot and three half hitches in opposite directions. In case of larger tears, a double-row technique for better reconstruction of the trapezoidal footprint is performed. For open reconstruction, a deltopectoral approach is used to reattache the tendon in an analogous fashion. RESULTS: Arthroscopic or open repair of isolated subscapularis tendon tears (Fox type II IV) was performed in 35 patients. The Constant score increased significantly after 36 m, with no difference between these two groups. The majority of subscapularis tests were postoperatively negative, 6% in both groups showed a rerupture. A symptomatic period of > 6 m prior to the operation and a high grade atrophy and fatty infiltration of the muscle was correlated with poorer results. PMID- 23104500 TI - [Footprint and augmented anchorage]. AB - OBJECTIVE: One-stage procedure for gaining adequate bone stock and rotator cuff repair. INDICATIONS: Tears of the rotator cuff in combination with bony cysts or reduced bone quality at the footprint. CONTRAINDICATIONS: Allergies to contents of the bone void filler, fatty infiltration of infraspinatus and subscapularis of stage 3 and 4, narrowing of the subacromial space (< 7 mm). SURGICAL TECHNIQUE: We report a one-stage technique for footprint reconstruction in a rotator cuff tear-associated greater tuberosity cyst by augmenting the cystic lesion with an injectable, absorbable, biocompatible, fiber reinforced bone void filler in combination with a double row rotator cuff reconstruction technique. POSTOPERATIVE MANAGEMENT: The arm is placed in a shoulder-immobilizing abduction pillow to achieve 30 degrees abduction for a period of 4-6 weeks. The physical therapy program includes passive mobilization of the affected shoulder to 60-90 degrees flexion/abduction within the first 3 weeks. During the next 3 weeks, the passive mobilization is changed to active mobilization, starting with assisted exercises. Active exercises without limitation in range of motion are not allowed until the 7th week after surgery and moderate sports not until the third month post-surgery. RESULTS: Six patients have been treated using the presented technique. However, long term results are still missing. PMID- 23104501 TI - Comparison of the predictive performance of the Bell-Evans, Taylor-expansion and statistical-mechanics models of mechanochemistry. AB - We analyse the capacity of several models to extrapolate the activation free energies of isomerization of cyclobutene and dibromocyclopropane in a stretched polymer from strain-free parameters of the reactive site and short polymer segments. Comparison with results obtained from quantum-chemical calculations of complete conformational ensembles coupled to a stretching force reveal that the simplest model yields qualitatively accurate results at minimal computational expense. PMID- 23104503 TI - The periprosthetic capsule and connective tissue diseases: a piece in the puzzle of autoimmune/autoinflammatory syndrome induced by adjuvants. AB - Breast prostheses have been criticized for being responsible for triggering systemic autoimmune disease. The presence of breast implants causes a natural foreign body reaction characterized by the infiltration of macrophages and T cells. Using PubMed, Medline and eMedicine, we performed a systematic literature review on the stages of periprosthetic capsule formation and cells involved in order to understand which immunological pathways could be responsible for giving rise to, and the development of, connective tissue disease such as systemic sclerosis. We focused on the relationship between tissue growth factor-beta, interleukin (IL)-1, IL-6 and T helper 17 or T regulatory cells, as well as on their effects on the different steps of capsular tissue formation. A disturbance in the modulation of these key cytokines may be responsible, in susceptible individuals, for a perpetuation of the inflammatory reaction which can locally lead to capsular contracture and at the systemic level may contribute to triggering autoimmune diseases. PMID- 23104502 TI - The value of perfusion computed tomography in predicting clinically relevant vasospasm in patients with aneurysmal subarachnoid hemorrhage. AB - Delayed cerebral ischemia remains a severe potential complication of aneurysmal subarachnoid hemorrhage (SAH) possibly leading to death and disability. We evaluated a semiquantitative and visual analysis of perfusion computed tomography (PCT) as a predictor of clinically relevant vasospasm (CRV) in patients with aneurysmal SAH. Thirty-eight patients with aneurysmal SAH were analyzed yielding 145 PCT scans. PCT, clinical examination, and transcranial Doppler ultrasound (TCD) were performed on days 3, 7, 10, and 14 after hemorrhage. Cerebral blood flow, cerebral blood volume, and time to peak (TTP) were analyzed semiquantitatively using six regions of interest, and visually for signs of cerebral hypoperfusion. CRV was defined as secondary cerebral infarction (CI) seen on cranial computed tomography scans and/or delayed neurological deterioration (DND). CI occurred in 13 (34.2 %) and DND in 11 patients (28.9 %). With TCD as pretest, TTP had a sensitivity of 90 % and a specificity of 72 % (cutoff value, 0.963) as predictor for CI. TTP's sensitivity as predictor for DND was 90 % with a specificity of 61.1 % (cutoff value, 0.983). Visual analysis of TTP showed a negative predictive value of 100 % with a positive predictive value of 52 %. TTP is a sensitive and specific perfusion parameter in predicting CI in patients with SAH. Its use in the clinical setting may optimize the early treatment of patients at risk for vasospasm before the onset of clinical deterioration, especially when applying TCD as pretest. Further investigation in a larger patient population is required. PMID- 23104504 TI - Piwil2 modulates the proliferation and metastasis of colon cancer via regulation of matrix metallopeptidase 9 transcriptional activity. AB - Piwi-like protein 2 (Piwil2) has recently emerged as a putative oncogene which is amplified in several human malignancies. However, the role of Piwil2 in colon cancer remains poorly understood. The aim of this study was to investigate the clinical and pathological significance of Piwil2, and the possible role in the proliferation and metastasis of colon cancer. Primary colon cancer paired with adjacent normal colon tissue and lymph node metastasis (LNM) lesions in 66 patients' tissue microarrays (TMA) were used to determine the expression of Piwil2. Knocked down Piwil2 expression in SW620 and SW480 colon cancer cell lines was performed to evaluate the role of Piwil2 in cell proliferation, invasion, metastasis in vitro and tumorigenicity in vivo. The possible roles of Piwil2 in the regulation of a 2 kb matrix metallopeptidase 9 (MMP9) promoter fragment and on the regulation of apoptotic pathways were evaluated by using a luciferase reporter construct and Western blots, respectively. Significantly higher expression levels of Piwil2 were observed in primary colon cancer tissue and in LNM in comparison with normal colon mucosa. Piwil2 expression significantly correlated with more aggressive clinical and pathological parameters with poorer five-year metastasis-free survival and overall survival. Piwil2 silencing significantly reduced cancer cell proliferation, colony formation ability and increased apoptosis in vitro and inhibited tumor growth in vivo. Piwil2 knockdown also attenuated migration and invasion of colon cancer cells via modulation of MMP9 transcriptional activities. Our results indicate that Piwil2 moderates the proliferation and metastasis potential of colon cancer. PMID- 23104505 TI - Serum alpha1beta-glycoprotein and afamin ratio as potential diagnostic and prognostic markers in cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) affects the intra- and extrahepatic bile ducts and is commonly burdened by a late presentation and resulting high mortality rate. Accordingly, finding non-invasive biomarkers with adequate diagnostic/prognostic values is a priority in high-risk populations. In this study, we analyzed proteomes of serum samples from six CCA cases and ten healthy subjects using two dimensional polyacrylamide gel electrophoresis to identify CCA-associated spots. Thirty-six CCA-associated proteins found in sera were identified by mass spectrometry. alpha1beta-Glycoprotein (A1BG) and afamin (AFM) were detected consistently at different degrees in CCA sera compared with controls and were validated for their diagnostic and prognostic potential in a larger cohort of 64 patients with CCA, 4 with benign biliary diseases and 20 healthy subjects and compared between pre- and postsurgery serum samples from 26 CCA patients to ascertain a prognostic correlation. A single blot test developed to assess the serum A1BG/AFM ratio could detect CCA cases with 87.5% specificity, 84.4% sensitivity and the levels were significantly higher in CCA compared with controls. A high level of postoperative serum A1BG/AFM ratio was associated with worse outcomes and the infiltration of resection margins. The A1BG/AFM ratio may constitute a novel non-invasive candidate marker to diagnose CCA and its outcomes with high specificity and sensitivity. Prospective studies are awaited to demonstrate the clinical value of this observation. PMID- 23104506 TI - Effects of a cocoa diet on an intestinal inflammation model in rats. AB - Cocoa is a rich source of fiber and flavonoids with recognized antioxidant and anti-inflammatory potential. The aim of this study was to evaluate the effects of a cocoa-enriched diet on rats with dextran sulfate sodium (DSS)-induced colitis. Wistar rats were fed with either a 5% cocoa diet or standard diet. Colon inflammation was induced by DSS in the drinking water: 5% for six days and 2% over the following nine days. Colitis was assessed by body weight loss, stool consistency and blood presence in stools. A group of animals fed standard diet was treated with quercitrin (1 mg/kg) after colitis establishment. After two weeks of DSS treatment, the colon oxidative and inflammatory status and lymphocyte composition from blood and mesenteric lymph nodes (MLNs) were assessed. The cocoa-fed group did not exhibit amelioration of clinical colitis but displayed higher antioxidant activity than the colitic reference group by the restoration of colon glutathione content and prevention of lipid peroxidation. The cocoa diet showed anti-inflammatory potential because it down-regulated serum tumor necrosis factor-alpha, colon inducible nitric oxide synthase activity and decreased colon cell infiltration. The lymphocyte composition in MLNs was not modified by drinking DSS, but there was an increase in the proportion of natural killer and regulatory T-cells in the blood. These changes were not modified by cocoa. In conclusion, cocoa intake may help to inhibit the negative oxidative effects consequent to colitis, although this action is not enough to abrogate the intestinal inflammation significantly. PMID- 23104509 TI - A chemoselective Ugi-type reaction in water using TMSCN as a functional isonitrile equivalent: generation of heteroaromatic molecular diversity. AB - KF-mediated nucleophilic activation of TMSCN as a functional isonitrile equivalent establishes an efficient and chemoselective Ugi-type multicomponent reaction of a heterocyclic amidine and aldehyde with TMSCN in water. In this approach, the use of isocyanide is circumvented, known competing reactions are virtually eliminated, pure products are obtained by a non-chromatographic method, and therapeutically relevant and diverse N-fused 3-aminoimidazoles can be prepared from a wide variety of aldehydes and heterocyclic amidines. This reaction coupling with cascade cyclization provides various privileged tetracyclic heteroaromatic scaffolds. PMID- 23104510 TI - Screening substituent and backbone effects on the properties of bidentate P,P donor ligands (LKB-PP(screen)). AB - We present a computational exploration of the effect of systematic variation of backbones and substituents on the properties of bidentate, cis-chelating P,P donor ligands as captured by calculated parameters. The parameters used are the same as reported for our ligand knowledge base for bidentate P,P donor ligands, LKB-PP (Organometallics 2008, 27, 1372-1383; Organometallics 2012 31, 5302-5306), but calculation protocols have been streamlined, suitable for an extensive evaluation of ligand structures. Analysis of the resulting LKB-PP(screen) database with principal component analysis (PCA) captures the effects of changing backbones and substituents on ligand properties and illustrates how these are complementary variables for these ligands. While backbone variation is routinely employed in ligand synthesis to modify catalyst properties, only a limited subset of substituents is commonly accessed and here we highlight substituents which are likely to generate new ligand properties, of interest for the design and improved sampling of bidentate ligands in homogeneous organometallic catalysis. PMID- 23104507 TI - Oxidative stress contributes to liver damage in a murine model of alpha-1 antitrypsin deficiency. AB - Alpha-1-antitrypsin deficiency is a genetic disorder resulting in the expression of misfolded mutant protein that can polymerize and accumulate in hepatocytes, leading to liver disease in some individuals. Transgenic PiZ mice are a well characterized model, which express human alpha-1-antitrypsin mutant Z protein (ATZ protein) and faithfully recapitulate the human liver disease. Liver tissue expressing alpha-1-antitrypsin mutant Z protein exhibits inflammation, injury and replacement of damaged cells. Fibrosis and hepatocellular carcinoma (HCC) develop in aging PiZ mice. In this study, microarray analysis was performed comparing young PiZ (ZY) mice to wild-type (WY), and indicated that there were alterations in gene expression levels that could influence a number of pathways leading to liver disease. Redox-regulating genes were up-regulated in ZY tissue, including carbonyl reductase 3 (CBR3), glutathione S-transferase alpha 1 + 2 (GSTA(1 + 2)) and glutathione S-transferase mu 3 (GSTM3). We hypothesized that oxidative stress could develop in Z mouse liver, contributing to tissue damage and disease progression with age. The results of biochemical analysis of PiZ mouse liver revealed that higher levels of reactive oxygen species (ROS) and a more oxidized, cellular redox state occurred in liver tissue from ZY mice than WY. ZY mice showed little evidence of oxidative cellular damage as assessed by protein carbonylation levels, malondialdehyde levels and 8-oxo-7,8-dihydro-2' deoxyguanosine (8oxodG) staining. Aging liver tissue from PiZ older mice (ZO) had elevated ROS, generally lower levels of antioxidant enzymes than younger mice and evidence of cellular damage. These data indicate that oxidative stress is a contributing factor in the development of liver disease in this model of alpha-1 antitrypsin deficiency. PMID- 23104511 TI - Perspectives of decision-making in requests for euthanasia: a qualitative research among patients, relatives and treating physicians in the Netherlands. AB - BACKGROUND: Euthanasia has been legally performed in the Netherlands since 2002. Respect for patient's autonomy is the underpinning ethical principal. However, patients have no right to euthanasia, and physicians have no obligation to provide it. Although over 3000 cases are conducted per year in the Netherlands, there is little known about how decision-making occurs and no guidance to support this difficult aspect of clinical practice. AIM: To explore the decision-making process in cases where patients request euthanasia and understand the different themes relevant to optimise this decision-making process. DESIGN: A qualitative thematic analysis of interviews with patients making explicit requests for euthanasia, most-involved relative(s) and treating physician. PARTICIPANTS/SETTING: Thirty-two cases, 31 relatives and 28 treating physicians. Settings were patients' and relatives' homes and physicians' offices. RESULTS: Five main themes emerged: (1) initiation of sharing views and values about euthanasia, (2) building relationships as part of the negotiation, (3) fulfilling legal requirements, (4) detailed work of preparing and performing euthanasia and (5) aftercare and closing. CONCLUSIONS: A patient's request for euthanasia entails a complex process that demands emotional work by all participants. It is characterised by an intensive period of sharing information, relationship building and negotiation in order to reach agreement. We hypothesise that making decisions about euthanasia demands a proactive approach towards participants' preferences and values regarding end of life, towards the needs of relatives, towards the burden placed on physicians and a careful attention to shared decision-making. Future research should address the communicational skills professionals require for such complex decision-making. PMID- 23104512 TI - Multivariate analysis of countries' government and health-care system influences on opioid availability for cancer pain relief and palliative care: more than a function of human development. AB - BACKGROUND: Many international governmental and nongovernmental organizations regard unrelieved cancer pain as a significant global public health problem. Although opioids such as morphine are considered essential medicines in the provision of palliative care and for treating cancer pain, especially when the pain is severe, low- and middle-income countries often lack such medications. AIM: The primary aim of this study was to examine countries' government and health-care system influences on opioid availability for cancer pain and palliative care, as a means to identify implications for improving appropriate access to prescription opioids. DESIGN: A multivariate regression of 177 countries' consumption of opioids (in milligrams/death from cancer and AIDS) contained country-level predictor variables related to public health, including Human Development Index, palliative care infrastructure, and health system resources and expenditures. RESULTS: Results were highly explanatory (adjusted R(2) = 82%) and Human Development Index was the most predictive variable when controlling for all other factors in the statistical model (B = 11.875, confidence interval = 10.216, 13.534, p < 0.0001). CONCLUSIONS: Study findings demonstrate that a limited number of predictor variables characterizing a country's government and health-care system infrastructure can explain its opioid consumption level, with the greatest influence being very high Human Development Index. However, Human Development Index is not the most policy-relevant factor, and this finding should be reconciled against the reality that many countries with low or medium Human Development Index have succeeded in creating and sustaining a health-care system to strengthen cancer pain care and palliative care, including through the appropriate use of essential prescription opioids. PMID- 23104513 TI - Similarities and differences between continuous sedation until death and euthanasia - professional caregivers' attitudes and experiences: a focus group study. AB - BACKGROUND: According to various guidelines about continuous sedation until death, this practice can and should be clearly distinguished from euthanasia, which is legalized in Belgium. AIM: To explore professional caregivers' perceptions of the similarities and differences between continuous sedation until death and euthanasia. DESIGN: Qualitative data were gathered through focus groups. Questions pertained to participants' perceptions of continuous sedation. The focus groups were recorded and transcribed verbatim. Analyses were conducted by a multidisciplinary research team using constant comparison analyses. SETTING/PARTICIPANTS: We did four focus groups at Ghent University Hospital: two with physicians (n = 4 and n = 4) and two with nurses (n = 4 and n = 9). The participants could participate if they were ever involved in the use of continuous sedation until death. RESULTS: Although the differences and similarities between continuous sedation until death and euthanasia were not specifically addressed in the questions addressed in the focus groups, it emerged as an important theme in the participants' accounts. Many caregivers elaborated on the differences between both practices, particularly with regard to patients' preferences and requests, decision-making and physicians' intentions. However, some stated that the distinction between the two sometimes becomes blurred, especially when the sedating medication is increased disproportionally or when sedation is used for patients with a longer life expectancy. CONCLUSIONS: The differences and similarities between continuous sedation until death and euthanasia is an issue for several Flemish professional caregivers in their care for unbearably suffering patients at the end of life. Although guidelines strictly distinguish both practices, this may not always be the case in Flemish clinical practice. PMID- 23104514 TI - Surgery versus conservative care for neck pain: a systematic review. AB - OBJECTIVE: General practitioners refer patients with continued neck pain that do not respond well to conservative care frequently to secondary care for further assessment. Are surgical interventions to the cervical spine effective when compared to conservative care for patients with neck pain? DESIGN: Systematic review. METHOD: The search strategy outlined by the Cochrane Back Review Group (CBRG) was followed. The primary search was conducted in MEDLINE, EMBASE, CINAHL, CENTRAL, and PEDro up to June 2011. Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) of adults with neck pain, which evaluated at least one clinically relevant primary outcome measure (e.g. pain, functional status, recovery), were included. In addition, treatments had to include surgery and conservative care. Two authors independently assessed risk of bias using the criteria recommended by the CBRG and extracted the data. The quality of the evidence was rated using the GRADE method. RESULTS: Patients included had neck pain with or without radiculopathy or myelopathy. In total, three RCTs and six CCTs were identified comparing different surgical interventions with conservative care, of which one had a low risk of bias. Overall there is very low quality of evidence available on the effectiveness of surgery compared to conservative care in neck pain patients showing overall no differences. CONCLUSION: Most studies on surgical techniques comparing these to conservative care showed a high risk of bias. The benefit of surgery over conservative care is not clearly demonstrated. PMID- 23104516 TI - Factors affecting peritumoral brain edema in meningioma: special histological subtypes with prominently extensive edema. AB - Various degrees of peritumoral brain edema (PTBE) are observed in patients with intracranial meningiomas. Factors affecting the occurrence of PTBE in intracranial meningioma were investigated. PTBE was investigated retrospectively for 110 patients with primary intracranial meningiomas. Predictive factors related to PTBE were analyzed, for example patient age, sex, magnetic resonance imaging features (contrast enhancement, tumor shape, tumor location, tumor volume), angiographical features (tumor stain, pial-cortical arterial supply, venous obstruction), and histopathological features (histological subtypes, mindbomb homolog 1 labeling index (MIB1-LI)). Histological subtypes were classified into World Health Organization (WHO) grade I common type (meningothelial, transitional, fibrous), grade I uncommon type, and grade II and III types. The extent of PTBE was assessed by calculation of the edema index (EI). PTBE was present in 53 cases (48 %). Male sex, heterogeneous enhancement, superficial location, tumor volume (>=10 cm(3)), remarkable tumor stain, pial supply, venous obstruction, malignant pathology, and MIB1-LI >=4 % were correlated with PTBE in univariate analysis. Pial supply and remarkable tumor stain were correlated with PTBE in multivariate analysis. WHO grade I uncommon type had obviously higher EI than WHO grade I common type, and WHO grade II and III types (P < 0.001). Seven cases with prominently high EI (EI >=10) were all WHO grade I uncommon type, including angiomatous, microcystic, secretory, and lymphoplasmacyte-rich meningioma. Prominently extensive PTBE might indicate the presence of WHO grade I uncommon type meningioma. PMID- 23104518 TI - Mechanisms of thrombosis in paraproteinemias: the effects of immunomodulatory drugs. AB - The introduction of immunomodulatory drugs (IMiDs) has improved clinical outcome in patients with multiple myeloma (MM). However, their use has been associated with a higher risk of cardiovascular complications. The use of IMiDs with dexamethasone, chemotherapy, or in combination with erythropoietic agents enhances the risk of venous thromboembolism (VTE) up to 25%. The pathogenesis of this increased risk of VTE seen with IMiD-based combination therapy is not yet fully understood, but several mechanisms have been proposed to explain the development of this hypercoagulable state. In cancer patients, prothrombotic factors include age, chemotherapy, immobility, enhanced expression of tissue factor of malignant cells, circulating microparticles, and increased vascular endothelial growth factor (VEGF). In patients with paraproteinemias, immunoglobulin-specific mechanisms may also be involved and include hypofibrinolysis, hyperviscosity, procoagulant autoantibody production, effects of inflammatory cytokines, and acquired activated protein C resistance (APCR). In this review we will focus on IMiD-associated effects on specific thrombotic mechanisms. PMID- 23104517 TI - MiR-21 expression in the tumor cell compartment holds unfavorable prognostic value in gliomas. AB - High-grade gliomas are some of the most lethal forms of human cancer, and new clinical biomarkers and therapeutic targets are highly needed. MicroRNAs (miRNAs), a group of short noncoding RNAs, hold great potential as new biomarkers and targets as they are commonly deregulated in a variety of diseases including gliomas. MicroRNA-21 (miR-21) is the most consistently overexpressed miRNA in several cancers including gliomas and is therefore very promising as a useful clinical biomarker and therapeutic target. To better understand the role of miR 21 in gliomas, paraffin-embedded glioma tissue samples from 193 patients with grade I, II, III, and IV tumors were analyzed by in situ hybridization (ISH) using LNA-DNA chimeric probes. We found miR-21 expression in tumor cells and tumor-associated blood vessels, whereas no expression was seen in adjacent normal brain parenchyma. Using advanced image analysis we obtained quantitative estimates reflecting the miR-21 expression levels in each of these compartments. The miR-21 levels correlated significantly with grade [p = 0.027, r (s) = 0.161, 95 % confidence interval (CI), 0.015-0.301] with the highest levels measured in glioblastomas. Only tumor cell miR-21 was associated with poor prognosis when adjusting for known clinical parameters (age, grade, and sex) in a multivariate analysis [p = 0.049, hazard ratio (HR) = 1.545, 95 % CI, 1.002-2.381]. In conclusion, we have shown that miR-21 is located in both tumor cells and tumor blood vessels and that its level in the tumor cell compartment holds unfavorable prognostic value in gliomas. PMID- 23104520 TI - HDR brachytherapy: an option for preventing nonmalignant obstruction in patients after lung transplantation. AB - PURPOSE: Interventional bronchoscopy is the main treatment modality in managing benign airway obstructions following lung transplantation. We analyzed the effect of intraluminal brachytherapy on preventing recurrence of hyperplastic tissue. PATIENTS AND METHODS: From September 2002 to September 2004, a total of 24 intraluminal brachytherapy applications were carried out on 12 lung transplant patients in 15 different locations. A single dose of 3 Gy was calculated at a 5 mm distance from the catheter surface; the target volume included a stenosis plus safety interval of 0.5-1.0 cm. RESULTS: All patients had a mean 10.6 local interventions (Argon plasma coagulation, balloon dilatations, stenting) over 4.4 months before the first application of endobronchial brachytherapy, with a mean amount of 2.4 applications per month. The mean forced expiratory volume in 1 s (FEV1) was 2,219 ml in the 3 months before application of brachytherapy. After endobronchial brachytherapy, all patients experienced improvement in clinical status and respiratory function. The mean level of FEV1 in the 3 months after application was 2,435 ml (p = 0.02), and the number of invasive interventions dropped to a mean rate of 5.2 interventions in the 5.1 months after the first intervention, with an amount of 1 application per month. No treatment-related complications were seen. Four patients were treated twice, 1 patient three times, and 1 patient four times at the same localization. CONCLUSIONS: Recurrent symptomatic benign airway obstruction from hyperplastic tissue in the bronchus after lung transplantation can be successfully treated with intraluminal high dose-rate brachytherapy with a dose of 3 Gy at a 5-mm distance from the catheter surface and a longitudinal safety margin of 1 cm. PMID- 23104522 TI - Biodegradability, cytotoxicity, and physicochemical treatability of two novel perfluorooctane sulfonate-free photoacid generators. AB - There is a need for effective, environmentally compatible photoacid generators (PAGs) for application in photolithography for microelectronic device fabrication. Perfluoroalkyl sulfonates (PFAS) used in conventional PAG formulations, such as perfluorooctane sulfonate (PFOS), are under increasing scrutiny due to their widespread environmental distribution and toxicity. Recently, two new PFAS-free, PAG anions with semifluorinated sulfonate anions containing biomolecules (gamma-butyrolactone or D-glucose groups) were successfully applied as PAGs. In this study, the biodegradation potential, cytotoxicity, and physicochemical treatability of the new PAG anions was evaluated. PFOS and perfluorobutane sulfonate (PFBS) were used as reference materials in all of the assays. The new PAGs were susceptible to partial degradation by microorganisms in aerobic activated sludge, and these were also readily removed by chemical oxidative treatment with Fenton's reagent [H(2)O(2)/Fe(II)]. In contrast, the compounds were resistant to microbial and chemical attack under reductive conditions as indicated by the low removal efficiencies observed with anaerobic biodegradation assays and chemical assays with zero-valent iron, respectively. The enhanced biodegradation potential and treatability make of the new PAGs attractive materials to resolve current issues related to the lithographic performance and environmental concerns. PMID- 23104519 TI - Radiation therapy for primary carcinoma of the eyelid: tumor control and visual function. AB - BACKGROUND AND PURPOSE: Surgical excision remains the standard and most reliable curative treatment for eyelid carcinoma, but frequently causes functional and cosmetic impairment of the eyelid. We therefore investigated the efficacy and safety of radiation therapy in eyelid carcinoma. PATIENTS AND METHODS: Twenty three patients with primary carcinoma of the eyelid underwent radiation therapy. Sebaceous carcinoma was histologically confirmed in 16 patients, squamous cell carcinoma in 6, and basal cell carcinoma in 1. A total dose of 50-66.6 Gy (median, 60 Gy) was delivered to tumor sites in 18-37 fractions (median, 30 fractions). RESULTS: All but 3 of the 23 patients had survived at a median follow up period of 49 months. The overall survival and local progression-free rates were 87% and 93% at 2 years, and 80% and 93% at 5 years, respectively. Although radiation-induced cataracts developed in 3 patients, visual acuity in the other patients was relatively well preserved. There were no other therapy-related toxicities of grade 3 or greater. CONCLUSION: Radiation therapy is safe and effective for patients with primary carcinoma of the eyelid. It appears to contribute to prolonged survival as a result of good tumor control, and it also facilitates functional and cosmetic preservation of the eyelid. PMID- 23104521 TI - When are breast cancer patients old enough for the quitclaim of local control? AB - BACKGROUND: Although postoperative radiotherapy (RT) after breast-conserving surgery (BCS) halves the 10-year recurrence rate in breast cancer patients through all age groups, the question of whether RT may be omitted and replaced by endocrine therapy for women aged 70 years and older with low-risk factors has recently become an issue of debate. METHODS: Survey of the relevant recent literature (Medline) and international guidelines. RESULTS: Three randomized studies investigating the effect of RT in older women revealed significantly increased local recurrence rates when RT was omitted, and a negative impact on disease-free survival was observed in two of these trials. Despite these findings, in one of the studies omission of RT in women over 70 is recommended, leading to a respective amendment in the guidelines of the American National Comprehensive Cancer Network. Several large retrospective cohort studies analyzing the outcome of patients over 65 years with and without RT have since been published and showed a significantly improved local control in all subgroups of advanced age and stage, which predominantly translated into improved disease free and overall survival. CONCLUSION: No subgroup of elderly patients has yet been identified that did not profit from RT in terms of local control. Therefore, chronological age alone is not an appropriate criterion for deciding against or in favor of adjuvant RT. The DEGRO breast cancer expert panel explicitly discourages determination of a certain age for the omission of postoperative RT in healthy elderly women with low-risk breast cancer. For frail elderly women, treatment decisions should be individually decided on the basis of standardized geriatric assessment. PMID- 23104523 TI - Prevalence of comorbid substance use disorder during long-term central stimulant treatment in adult ADHD. AB - Central stimulant (CS) therapy is a cornerstone in treatment of adult attention deficit/hyperactivity disorder (ADHD). Substance use disorder (SUD) is a common comorbid disorder of ADHD and might complicate the treatment. Our main objectives were to investigate the prevalence of SUD during CS treatment, and identify variables associated with SUD during the treatment. The collection of data was based on a naturalistic, retrospective approach using the medical records of a cohort of all adult ADHD patients (N = 117) starting treatment with CS in a specific catchment area in the period 1997 to May 2005. A logistic regression model was applied to identify possible predictors of SUD during CS treatment. The study showed no onset of SUD during the CS treatment in the group of patients without comorbid SUD at baseline (mean CS treatment length 41.1 months). In the group of patients with comorbid SUD at baseline, 58.5 % had one or more relapses of SUD during treatment (mean CS treatment length 27.9 months). Younger age and comorbid antisocial personality disorder were associated with relapse. In a logistic regression analysis, cannabis abstinence for more than 12 months was a negative predictor for relapse of SUD. CS treatment does not precipitate onset of SUD in adults without previous SUD. PMID- 23104548 TI - Professional identity formation in medical education: the convergence of multiple domains. AB - There has been increasing emphasis on professionalism in medical education over the past several decades, initially focusing on bioethical principles, communication skills, and behaviors of medical students and practitioners. Authors have begun to discuss professional identity formation (PIF), distinguishing it as the foundational process one experiences during the transformation from lay person to physician. This integrative developmental process involves the establishment of core values, moral principles, and self awareness. The literature has approached PIF from various paradigms professionalism, psychological ego development, social interactions, and various learning theories. Similarities have been identified between the formation process of clergy and that of physicians. PIF reflects a very complex process, or series of processes, best understood by applying aspects of overlapping domains: professionalism, psychosocial identity development, and formation. In this study, the authors review essential elements of these three domains, identify features relevant to medical PIF, and describe strategies reported in the medical education literature that may influence PIF. PMID- 23104549 TI - Medical professionalism, revenue enhancement, and self-interest: an ethically ambiguous association. AB - This article explores the association between medical professionalism, revenue enhancement, and self-interest. Utilizing the sociological literature, I begin by characterizing professionalism generally and medical professionalism particularly. I then consider "pay for performance" mechanisms as an example of one way physicians might be incentivized to improve their professionalism and, at the same time, enhance their revenue. I suggest that the concern discussed in much of the medical professionalism literature that physicians might act on the basis of self-interest is over-generalized, and that instead we ought to argue about ways to distinguish permissible and impermissible self-interested actions. Also, I argue that financial incentives for medical professionals ought to be permissible but considered as "by-products" of doing what physicians are expected to do as professionals in any case. Nevertheless, I conclude that, even if a positive association between increasing professionalism and revenue enhancement can be established, in the long term it may not be an unambiguous good for physicians as professionals in that this association may tend to reduce their professional discretion. PMID- 23104550 TI - Intraoperative anastomotic dye test significantly decreases incidence of anastomotic leaks in patients undergoing resection for rectal cancer. AB - BACKGROUND: Anastomotic leakage is still a major complication in colorectal surgery. Prompt recognition and immediate treatment of anastomotic leak during surgery may reduce postoperative morbidity and mortality. Various types of intraoperative anastomotic test have been proposed to reduce the incidence of this complication. The aim of this study was to assess our experience with intraoperative dye test in rectal cancer surgery. METHODS: Between 2006 and 2009, a retrospective review of a single general surgeon's practice identified 76 patients who underwent the intraoperative dye test in rectal cancer surgery. Seventy-three of these 76 patients underwent elective surgery without creation of a diverting stoma. Diluted dye was routinely introduced into the rectal lumen to test anastomotic integrity. Intraoperative leak was repaired prior to the completion of the procedure. No routine radiological survey assessed anastomotic integrity postoperatively. RESULTS: In 11 (14.5 %) out of 76 patients, anastomotic leaks were found and treated intraoperatively. None of the 65 patients without intraoperative leaks developed clinical leaks during the follow up period. Postoperative leakage only occurred in one patient (1.3 %). He developed pelvic abscess evidenced by abdominal computed tomography scan and was treated non-operatively. CONCLUSIONS: The favorable results allow the authors to recommend the routine use of the intraoperative dye test for colorectal anastomoses. PMID- 23104551 TI - Laparoscopic low ventral rectocolpopexy (LLVR) for rectal and rectogenital prolapse: surgical technique and functional results. AB - BACKGROUND: Laparoscopic ventral rectopexy limits the risk of autonomic nerve damage, and the colpopexy allows correction of a concomitant prolapse of the middle compartment. The aim of this study is to describe a modified laparoscopic ventral rectocolpopexy procedure with a low approach to the sacral hollow (laparoscopic low ventral rectocolpopexy: LLVR). We propose this technique to manage combined rectogenital prolapse. METHODS: Between November 2006 and June 2009, all patients with symptomatic rectal prolapse associated with genital prolapse and/or enterocele underwent LLVR. Demographics, results of imaging studies, mortality, morbidity, and functional outcome were retrospectively analyzed. RESULTS: Thirty patients underwent LLVR: two patients suffered from a full-thickness rectal prolapse while 28 had symptomatic recto-anal intussusception. The mean operating time was 94 +/- 39 minutes. Conversion to laparotomy was never needed. Hospital stay ranged between 2 and 14 days (mean of 5 +/- 2.5 days). No mortality was recorded and only two complications occurred (6.6%): one trocar site incisional hernia and one vaginal suture erosion in a patient who had concomitant hysterectomy. After a mean follow-up of 13.9 months, constipation was completely resolved or improved in 92.8% patients. Significant reduction in the mean Altomare obstructed defecation score (14.7-5.6; p < 0.05) was recorded. Preoperative incontinence improved after the procedure in all patients affected. No new cases of postoperative constipation or fecal incontinence were registered. Only one case of recurrence in a patient with recto anal intussusception was recorded (3.4%), after 19 months. CONCLUSIONS: Laparoscopic low ventral rectocolpopexy is safe and associated with very low morbidity. In the medium term, it provides good result for prolapse and associated symptoms. PMID- 23104552 TI - Pancreaticoduodenectomy can be safely performed in the elderly. AB - BACKGROUND: Although pancreaticoduodenectomy has been recognized in the past for its severe complications, improvements in operative methods and perioperative management have made it a safe procedure. Therefore, pancreaticoduodenectomy can be performed in elderly patients, and our experience and outcomes are described in this report. METHODS: We retrospectively investigated 142 patients in whom pancreaticoduodenectomy was performed without stenting tubes during pancreaticojejunostomy. The patients were classified into two groups: (A) those older and (B) younger than 75 years. The outcomes, including preoperative characteristics, intraoperative characteristics, postoperative complications and mortality, are herein reported. Continuous variables were compared using Student's t test and the Chi-square test. RESULTS: There were no differences between groups A and B in terms of sex, operative time, amount of blood loss, performance status, soft pancreas rate, disease distribution and operative procedure. Comorbidities in groups A and B were statistically different. Regarding the preoperative status, the elderly patients exhibited lower serum albumin and hemoglobin levels than the younger patients. There were no differences in mortality (0 vs. 0 %), morbidity (24.3 vs. 29.5 %, p = 0.362), postoperative hospital days or major complications such as pancreatic fistula development, delayed gastric emptying, intra-abdominal abscess development, biliary fistula formation and postpancreatectomy hemorrhage. CONCLUSIONS: Pancreaticoduodenectomy can be safely performed in elderly as well as younger patients. PMID- 23104553 TI - Survival outcome of laparoscopic gastrectomy for clinical early (cT1) gastric cancer. AB - PURPOSES: Laparoscopy-assisted gastrectomy (LAG) for clinical early (cT1) gastric cancer (EGC) is superior to open gastrectomy in terms of the short-term outcome; however, long-term survival outcome remains elusive. METHODS: Four hundred and ninety-one cT1 EGC patients who underwent LAG between 1998 and 2010 were registered to evaluate the survival outcome, including 237 patients who were observed for at least 5 years (long-term, L group), while 221 patients who were observed for at least 2-5 years (intermediate term, I group). RESULTS: There were 17 deaths, including 7 patients who developed recurrence (5 in pT1 and 2 in pT4a). Two fatal cases with pStage IIB were uniquely T1N3b. Six out of the 7 recurrences occurred within 2 years after surgery. The 237 patients in the L group included 6 of the recurrent deaths (2.5 %), while the 221 patients in the I group included 1 recurrent death (0.9 %). Recurrent sites of pathological T1 cases were the liver (n = 2), lung (n = 1), ovary (n = 1), and bone (n = 1), and no peritoneal or local recurrence was found. CONCLUSIONS: Collectively, the survival outcome of EGC by LAG was excellent and LAG was acceptable as a therapeutic procedure for EGC. PMID- 23104554 TI - Laparoscopic surgery minimizes the surgical manipulation of isolated tumor cells leading to decreased metastasis compared to open surgery for colorectal cancer. AB - PURPOSES: We focused on the possible benefits of laparoscopic surgery to protect against isolated tumor cells (ITC) generated by surgical manipulation in comparison to open surgery. METHODS: We performed conventional open surgery and laparoscopic surgery for 25 and 8 cases of colorectal cancer (CRC), respectively. We compared the presence of ITC in the peripheral blood (PB) immediately after surgery via quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) for a representative epithelial marker, carcinoembryonic antigen (CEA). RESULTS: In the 25 patients who underwent open surgery, 8 of the 10 cases with metastasis were positive for ITC in PB, while 13 of the 15 cases without metastasis were negative for ITC. Therefore, we validated that there was a significant clinical usefulness for the detection of ITC in the prediction of metastasis (p = 0.0024). We limited our subsequent analysis to the CRC cases with a Dukes stage of B or C to avoid differences due to the background, and we found that the positive ITC rate for metastasis was higher in the 19 patients who underwent open surgery (42.1 %) than in the 8 who underwent laparoscopic surgery (37.5 %). CONCLUSIONS: The short observation period, especially in the laparoscopic surgery group, and the inadequate number of cases limit the ability to draw any definitive conclusions; however, laparoscopic surgery appears to minimize the surgical manipulation, thus leading to reduced ITC from primary CRC compared with open surgery. PMID- 23104555 TI - A readily accessible PNP pincer ligand with a pyrrole backbone and its Ni(I/II) chemistry. AB - The novel chelating PNP pincer ligand 2,5-bis((diphenylphosphino)methyl)-1H pyrrole (1) was prepared and its nickel coordination chemistry explored. The reaction with Ni(COD)(2) led to a diamagnetic dinuclear nickel(I) complex (4) which was also obtained by the reaction of the square planar Ni(II) complexes [(PNP-Ph(2))NiX] (X = Cl (2), X = I (3)) with Li(Et(3)BH). PMID- 23104558 TI - Complement depletion protects lupus-prone mice from ischemia-reperfusion initiated organ injury. AB - Ischemia-reperfusion (IR) injury causes a vigorous immune response that is amplified by complement activation, leading to local and remote tissue damage. Using MRL/lpr mice, which are known to experience accelerated tissue damage after mesenteric IR injury, we sought to evaluate whether complement inhibition mitigates organ damage. We found that complement depletion with cobra venom factor protected mice from local and remote lung tissue damage. Protection from injury was associated with less complement (C3) and membrane attack complex deposition, less neutrophil infiltration, and lower levels of local proinflammatory cytokine production. In addition, complement depletion was able to decrease the level of oxidative stress as measured by glutathione peroxidase 1 mRNA levels and superoxide dismutase activity. Furthermore, blockage of C5a receptor protected MRL/lpr mice from local tissue damage, but not from remote lung tissue damage. In conclusion, although treatments with cobra venom factor and C5a receptor antagonist were able to protect mice from local tissue damage, treatment with C5a receptor antagonist was not able to protect mice from remote lung tissue damage, implying that more factors contribute to the development of remote tissue damage after IR injury. These data also suggest that complement inhibition at earlier, rather than late, stages can have clinical benefit in conditions that are complicated with IR injury. PMID- 23104556 TI - Is there in vivo evidence for amino acid shuttles carrying ammonia from neurons to astrocytes? AB - The high in vivo flux of the glutamate/glutamine cycle puts a strong demand on the return of ammonia released by phosphate activated glutaminase from the neurons to the astrocytes in order to maintain nitrogen balance. In this paper we review several amino acid shuttles that have been proposed for balancing the nitrogen flows between neurons and astrocytes in the glutamate/glutamine cycle. All of these cycles depend on the directionality of glutamate dehydrogenase, catalyzing reductive glutamate synthesis (forward reaction) in the neuron in order to capture the ammonia released by phosphate activated glutaminase, while catalyzing oxidative deamination of glutamate (reverse reaction) in the astrocytes to release ammonia for glutamine synthesis. Reanalysis of results from in vivo experiments using (13)N and (15)N labeled ammonia and (15)N leucine in rats suggests that the maximum flux of the alanine/lactate or branched chain amino acid/branched chain amino acid transaminase shuttles between neurons and astrocytes are approximately 3-5 times lower than would be required to account for the ammonia transfer from neurons to astrocytes needed for glutamine synthesis (amide nitrogen) to sustain the glutamate/glutamine cycle. However, in the rat brain both the total ammonia fixation rate by glutamate dehydrogenase and the total branched chain amino acid transaminase activity are sufficient to support a branched chain amino acid/branched chain keto acid shuttle, as proposed by Hutson and coworkers, which would support the de novo synthesis of glutamine in the astrocyte to replace the ~20 % of neurotransmitter glutamate that is oxidized. A higher fraction of the nitrogen needs of total glutamate neurotransmitter cycling could be supported by hybrid cycles in which glutamate and tricarboxylic acid cycle intermediates act as a nitrogen shuttle. A limitation of all in vivo studies in animals conducted to date is that none have shown transfer of nitrogen for glutamine amide synthesis, either as free ammonia or via an amino acid from the neurons to the astrocytes. Future work will be needed, perhaps using methods for selectively labeling nitrogen in neurons, to conclusively establish the rate of amino acid nitrogen shuttles in vivo and their coupling to the glutamate/glutamine cycle. PMID- 23104557 TI - Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPARalpha-dependent and -independent pathways. AB - Creosote bush-derived nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, possesses antioxidant properties and functions as a potent antihyperlipidemic agent in rodent models. Here, we examined the effect of chronic NDGA treatment of ob/ob mice on plasma dyslipidemia, hepatic steatosis, and changes in hepatic gene expression. Feeding ob/ob mice a chow diet supplemented with either low (0.83 g/kg diet) or high-dose (2.5 g/kg diet) NDGA for 16 wk significantly improved plasma triglyceride (TG), inflammatory chemokine levels, hyperinsulinemia, insulin sensitivity, and glucose intolerance. NDGA treatment caused a marked reduction in liver weight and TG content, while enhancing rates of fatty acid oxidation. Microarray analysis of hepatic gene expression demonstrated that NDGA treatment altered genes for lipid metabolism, with genes involved in fatty acid catabolism most significantly increased. NDGA upregulated the mRNA and nuclear protein levels of peroxisome proliferator-activated receptor alpha (PPARalpha), and the activated (phosphorylated) form of AMP-activated kinase. NDGA increased PPARalpha promoter activity in AML12 hepatocytes and also prevented the fatty acid suppression of PPARalpha expression. In contrast, PPARalpha siRNA abrogated the stimulatory effect of NDGA on fatty acid catabolism. Likewise, no stimulatory effect of NDGA on hepatic fatty acid oxidation was observed in the livers of PPARalpha-deficient mice, but the ability of NDGA to reverse fatty liver conditions was unaffected. In conclusion, the beneficial actions of NDGA on dyslipidemia and hepatic steatosis in ob/ob mice are exerted primarily through enhanced fatty acid oxidation via PPARalpha-dependent pathways. However, PPARalpha-independent pathways also contribute to NDGA's action to ameliorate hepatic steatosis. PMID- 23104559 TI - Hepatocyte-specific deletion of hepatocyte nuclear factor-4alpha in adult mice results in increased hepatocyte proliferation. AB - Hepatocyte nuclear factor-4alpha (HNF4alpha) is known as the master regulator of hepatocyte differentiation. Recent studies indicate that HNF4alpha may inhibit hepatocyte proliferation via mechanisms that have yet to be identified. Using a HNF4alpha knockdown mouse model based on delivery of inducible Cre recombinase via an adeno-associated virus 8 viral vector, we investigated the role of HNF4alpha in the regulation of hepatocyte proliferation. Hepatocyte-specific deletion of HNF4alpha resulted in increased hepatocyte proliferation. Global gene expression analysis showed that a majority of the downregulated genes were previously known HNF4alpha target genes involved in hepatic differentiation. Interestingly, >=500 upregulated genes were associated with cell proliferation and cancer. Furthermore, we identified potential negative target genes of HNF4alpha, many of which are involved in the stimulation of proliferation. Using chromatin immunoprecipitation analysis, we confirmed binding of HNF4alpha at three of these genes. Furthermore, overexpression of HNF4alpha in mouse hepatocellular carcinoma cells resulted in a decrease in promitogenic gene expression and cell cycle arrest. Taken together, these data indicate that, apart from its role in hepatocyte differentiation, HNF4alpha actively inhibits hepatocyte proliferation by repression of specific promitogenic genes. PMID- 23104560 TI - Mechanosensitive Cl- secretion in biliary epithelium mediated through TMEM16A. AB - Bile formation by the liver is initiated by canalicular transport at the hepatocyte membrane, leading to an increase in ductular bile flow. Thus, bile duct epithelial cells (cholangiocytes), which contribute to the volume and dilution of bile through regulated Cl(-) transport, are exposed to changes in flow and shear force at the apical membrane. The aim of the present study was to determine if fluid flow, or shear stress, is a signal regulating cholangiocyte transport. The results demonstrate that, in human and mouse biliary cells, fluid flow, or shear, increases Cl(-) currents and identify TMEM16A, a Ca(2+)-activated Cl(-) channel, as the operative channel. Furthermore, activation of TMEM16A by flow is dependent on PKCalpha through a process involving extracellular ATP, binding purinergic P2 receptors, and increases in intracellular Ca(2+) concentration. These studies represent the initial characterization of mechanosensitive Cl(-) currents mediated by TMEM16A. Identification of this novel mechanosensitive secretory pathway provides new insight into bile formation and suggests new therapeutic targets to enhance bile formation in the treatment of cholestatic liver disorders. PMID- 23104562 TI - Prevalence of metabolic syndrome in urban Colombian adolescents aged 10-16 years using three different pediatric definitions. AB - The aim of this study was to evaluate the metabolic syndrome (MetS) prevalence in adolescents using three different definitions for this age group. The evaluated sample consisted of 718 male and 743 female adolescents. Definitions by Cook et al., de Ferranti et al. and International Diabetes Federation (IDF) for adolescents were used to estimate the prevalence of MetS. The prevalence of MetS was 8.5, 2.5 and 1.2% by de Ferranti et al., Cook et al. and IDF definitions, respectively. High fasting glucose component had the lower prevalence whereas high triglycerides levels component was the most prevalent. In obese adolescents, the prevalence of MetS was higher. MetS classification in adolescents strongly depends on the definition chosen. Further research is required for the evaluation of the current definitions (multicentric studies), and for addition or design of new and useful criteria. PMID- 23104561 TI - Conditional knockout of the Slc5a6 gene in mouse intestine impairs biotin absorption. AB - The Slc5a6 gene expresses a plasma membrane protein involved in the transport of the water-soluble vitamin biotin; the transporter is commonly referred to as the sodium-dependent multivitamin transporter (SMVT) because it also transports pantothenic acid and lipoic acid. The relative contribution of the SMVT system toward carrier-mediated biotin uptake in the native intestine in vivo has not been established. We used a Cre/lox technology to generate an intestine-specific (conditional) SMVT knockout (KO) mouse model to address this issue. The KO mice exhibited absence of expression of SMVT in the intestine compared with sex matched littermates as well as the expected normal SMVT expression in other tissues. About two-thirds of the KO mice died prematurely between the age of 6 and 10 wk. Growth retardation, decreased bone density, decreased bone length, and decreased biotin status were observed in the KO mice. Microscopic analysis showed histological abnormalities in the small bowel (shortened villi, dysplasia) and cecum (chronic active inflammation, dysplasia) of the KO mice. In vivo (and in vitro) transport studies showed complete inhibition in carrier-mediated biotin uptake in the intestine of the KO mice compared with their control littermates. These studies provide the first in vivo confirmation in native intestine that SMVT is solely responsible for intestinal biotin uptake. These studies also provide evidence for a casual association between SMVT function and normal intestinal health. PMID- 23104563 TI - Establishment of the first newborn screening program in the People's Democratic Republic of Laos. AB - OBJECTIVES: The People's Democratic Republic of Laos belongs to the minority of countries worldwide without an established newborn bloodspot screening (NBS) system. METHODS: In 2008, we initiated a pilot project of a neonatal screening system in the delivery suites of the Laotian capital, Vientiane. Samples were analysed for thyrotropin-stimulating hormone and 17-hydroxyprogesterone. RESULTS: Altogether 11 362 samples were taken; an initially high recall rate dropped eventually to just above 4%. Two cases of hypothyroidism and one case of congenital adrenal hyperplasia were identified and received timely treatment. CONCLUSIONS: In summary, we have demonstrated the feasibility of establishing an NBS system in a low-resource setting as prevalent in Laos. Obstacles for the establishment of a general NBS covering the whole country include the question of financial cover, treatment costs, and adequate teaching and supervision of technicians and doctors. PMID- 23104564 TI - Management of nutritional rickets in Indian children: a randomized controlled trial. AB - INTRODUCTION: Rickets is usually attributed to vitamin D deficiency. However, recent studies have implicated dietary calcium deficiency in its etiology. Information on relative efficacy of calcium, vitamin D or both together in healing of rickets is limited. OBJECTIVE: To study effect of treatment with calcium, vitamin D or a combination of these two on healing of nutritional rickets in young children. DESIGN: Randomized controlled trial. METHODS: Sixty seven cases of nutritional rickets in the age group of 6 months to 5 years were randomly allocated to receive vitamin D (600 000 IU single intramuscular dose), calcium (75 mg/kg/day elemental calcium orally) or a combination of the above two for a period of 12 weeks. The demographic parameters, nutritional status, dietary calcium and phytate intake were assessed for all. Radiographs (wrist and knee) and biochemical parameters (serum calcium, inorganic phosphate, alkaline phosphatase, 25-hydroxycholecalciferol and parathyroid hormone) were evaluated at baseline, 6 and 12 weeks for evidence of healing. RESULTS: Mean dietary intake of calcium in all cases was low (204 +/- 129 mg/day). Mean serum 25 hydroxycholecalciferol D level was 15.9 +/- 12.4 ng/ml, and 82.1% of patients had serum vitamin D levels <20 ng/ml, indicative of vitamin D deficiency. After 6 and 12 weeks of treatment, radiological and biochemical evidence of healing rickets was observed in all treatment groups, albeit to a variable extent. The combined end point of normal serum alkaline phosphatase and complete radiological healing at 12 weeks was observed in 50% subjects on combination therapy as compared with 15.7% subjects on vitamin D alone and 11.7% on calcium alone. CONCLUSIONS: Children with rickets had a low serum vitamin D level and a low dietary calcium intake. The best therapeutic response was seen with a combination of vitamin D and calcium than either of them given alone. TRIAL REGISTRATION NUMBER: CTRI/2010/091/000448. PMID- 23104565 TI - Zinc, copper and C-reactive protein in children with severe Plasmodium falciparum malaria in an area of unstable malaria transmission in eastern Sudan. AB - BACKGROUND: Few data exist on the role of trace element in the pathogenesis of severe malaria. OBJECTIVES: The study was conducted at Kassala Hospital, eastern Sudan, to investigate the role of zinc, copper and C-reactive protein levels in children with severe Plasmodium falciparum malaria. METHODS: Zinc, copper and C reactive protein levels were measured in sera of three groups of children (35 in each arm): those with severe malaria, those with uncomplicated P. falciparum malaria and healthy controls. RESULTS: Although the zinc levels were significantly lower, the levels of copper and C-reactive protein were significantly higher in patients with severe P. falciparum. There was a significant inverse correlation between zinc and C-reactive protein and significant positive correlation between copper and C-reactive protein. CONCLUSION: The change in zinc and copper may play a role in pathogenesis of P. falciparum malaria. PMID- 23104566 TI - Physiologic expression of the Candida albicans pescadillo homolog is required for virulence in a murine model of hematogenously disseminated candidiasis. AB - Morphogenetic conversions contribute to the pathogenesis of Candida albicans invasive infections. Many studies to date have convincingly demonstrated a link between filamentation and virulence; however, relatively little is known regarding the role of the filament-to-yeast transition during the pathogenesis of invasive candidiasis. We previously identified the C. albicans pescadillo homolog (PES1) as essential during yeast growth and growth of lateral yeast on hyphae but not during hyphal growth. Furthermore, we demonstrated that PES1 is required for virulence in vivo in a Galleria mellonella larva model of candidiasis. Here, we have used a regulatable tetO-PES1/pes1 strain to assess the contribution of C. albicans PES1 to pathogenesis in the commonly used and clinically relevant murine model of hematogenously disseminated candidiasis. Our results indicate that a physiologically controlled level of PES1 expression is required for full virulence in this animal model, with virulence defects observed both when PES1 is overexpressed and and when it is depleted. The pathogenetic defect of cells depleted of PES1 is not due to a general growth defect, as demonstrated by the fact that PES1-depleted cells still kill Caenorhabditis elegans as efficiently as the wild type due to hyphal outgrowth through worm tissues. Our results suggest a critical role of lateral yeast growth in the ability of C. albicans to normally proliferate within tissues, as well as a pivotal role for Pes1 in the normal developmental cycle of C. albicans within the mammalian host during infection. PMID- 23104567 TI - Characterization of a novel class I transcription factor A (CITFA) subunit that is indispensable for transcription by the multifunctional RNA polymerase I of Trypanosoma brucei. AB - Trypanosoma brucei is the only organism known to have evolved a multifunctional RNA polymerase I (pol I) system that is used to express the parasite's ribosomal RNAs, as well as its major cell surface antigens, namely, the variant surface glycoprotein (VSG) and procyclin, which are vital for establishing successful infections in the mammalian host and the tsetse vector, respectively. Thus far, biochemical analyses of the T. brucei RNA pol I transcription machinery have elucidated the subunit structure of the enzyme and identified the class I transcription factor A (CITFA). CITFA binds to RNA pol I promoters, and its CITFA 2 subunit was shown to be absolutely essential for RNA pol I transcription in the parasite. Tandem affinity purification (TAP) of CITFA revealed the subunits CITFA 1 to -6, which are conserved only among kinetoplastid organisms, plus the dynein light chain DYNLL1. Here, by tagging CITFA-6 instead of CITFA-2, a complex was purified that contained all known CITFA subunits, as well as a novel proline-rich protein. Functional studies carried out in vivo and in vitro, as well as a colocalization study, unequivocally demonstrated that this protein is a bona fide CITFA subunit, essential for parasite viability and indispensable for RNA pol I transcription of ribosomal gene units and the active VSG expression site in the mammalian-infective life cycle stage of the parasite. Interestingly, CITFA-7 function appears to be species specific, because expression of an RNA interference (RNAi)-resistant CITFA-7 transgene from Trypanosoma cruzi could not rescue the lethal phenotype of silencing endogenous CITFA-7. PMID- 23104568 TI - Trypanosoma brucei FKBP12 differentially controls motility and cytokinesis in procyclic and bloodstream forms. AB - FKBP12 proteins are able to inhibit TOR kinases or calcineurin phosphatases upon binding of rapamycin or FK506 drugs, respectively. The Trypanosoma brucei FKBP12 homologue (TbFKBP12) was found to be a cytoskeleton-associated protein with specific localization in the flagellar pocket area of the bloodstream form. In the insect procyclic form, RNA interference-mediated knockdown of TbFKBP12 affected motility. In bloodstream cells, depletion of TbFKBP12 affected cytokinesis and cytoskeleton architecture. These last effects were associated with the presence of internal translucent cavities limited by an inside-out configuration of the normal cell surface, with a luminal variant surface glycoprotein coat lined up by microtubules. These cavities, which recreated the streamlined shape of the normal trypanosome cytoskeleton, might represent unsuccessful attempts for cell abscission. We propose that TbFKBP12 differentially affects stage-specific processes through association with the cytoskeleton. PMID- 23104569 TI - Dsc orthologs are required for hypoxia adaptation, triazole drug responses, and fungal virulence in Aspergillus fumigatus. AB - Hypoxia is an environmental stress encountered by Aspergillus fumigatus during invasive pulmonary aspergillosis (IPA). The ability of this mold to adapt to hypoxia is important for fungal virulence and genetically regulated in part by the sterol regulatory element binding protein (SREBP) SrbA. SrbA is required for fungal growth in the murine lung and to ultimately cause lethal disease in murine models of IPA. Here we identified and partially characterized four genes (dscA, dscB, dscC, and dscD, here referred to as dscA-D) with previously unknown functions in A. fumigatus that are orthologs of the Schizosaccharomyces pombe genes dsc1, dsc2, dsc3, and dsc4 (dsc1-4), which encode a Golgi E3 ligase complex critical for SREBP activation by proteolytic cleavage. A. fumigatus null dscA-D mutants displayed remarkable defects in hypoxic growth and increased susceptibility to triazole antifungal drugs. Consistent with the confirmed role of these genes in S. pombe, both DeltadscA and DeltadscC resulted in reduced cleavage of the SrbA precursor protein in A. fumigatus. Inoculation of corticosteroid immunosuppressed mice with DeltadscA and DeltadscC strains revealed that these genes are critical for A. fumigatus virulence. Reintroduction of SrbA amino acids 1 to 425, encompassing the N terminus DNA binding domain, into the DeltadscA strain was able to partially restore virulence, further supporting a mechanistic link between DscA and SrbA function. Thus, we have shown for the first time the importance of a previously uncharacterized group of genes in A. fumigatus that mediate hypoxia adaptation, fungal virulence, and triazole drug susceptibility and that are likely linked to regulation of SrbA function. PMID- 23104570 TI - Mitochondrial porin Por1 and its homolog Por2 contribute to the positive control of Snf1 protein kinase in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae Snf1 is a member of the conserved Snf1/AMP-activated protein kinase (Snf1/AMPK) family involved in regulating responses to energy limitation, which is detected by mechanisms that include sensing adenine nucleotides. Mitochondrial voltage-dependent anion channel (VDAC) proteins, also known as mitochondrial porins, are conserved in eukaryotes from yeast to humans and play key roles in mediating mitochondrial outer membrane permeability to small metabolites, including ATP, ADP, and AMP. We previously recovered the yeast mitochondrial porin Por1 (yVDAC1) from a two-hybrid screen for Snf1-interacting proteins. Here, we present evidence that Snf1 interacts with Por1 and its homolog Por2 (yVDAC2). Cells lacking Por1 and Por2, but not respiratory-deficient rho(0) cells lacking the mitochondrial genome, exhibit reduced Snf1 activation loop phosphorylation in response to glucose limitation. Thus, Por1 and Por2 contribute to the positive control of Snf1 protein kinase. Physical proximity to the VDAC proteins and mitochondrial surface could facilitate Snf1's ability to sense energy limitation. PMID- 23104571 TI - Evidence that two Pcl-like cyclins control Cdk9 activity during cell differentiation in Aspergillus nidulans asexual development. AB - Cyclin-dependent protein kinases (CDKs) are usually involved in cell cycle regulation. However, Cdk9 is an exception and promotes RNA synthesis through phosphorylation of the carboxy-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII). The CTD is comprised of repeating heptapeptides, in which serine residues at positions 2, 5, and 7 are of crucial importance. Ser5 phosphorylation causes transcription initiation and promoter escape. However, RNAPII pauses 20 to 50 bp downstream from the transcription start site, until Cdk9 phosphorylates Ser2. This event relieves the checkpoint and promotes the processivity of elongation. Here we present evidence that in the filamentous fungus Aspergillus nidulans, a Cdk9 homologue, PtkA, serves specific functions in conidiophore development. It was previously shown that PtkA interacts with two cyclins, PclA and the T cyclin PchA. Using yeast two-hybrid screens, we identified a third cyclin, PclB, and a kinase, PipA(Bud32). Both proteins were expressed in hyphae and in conidiophores, but interaction between each protein and PtkA was restricted to the conidiophores. Deletion of pchA caused a severe growth defect, and deletion of pipA was lethal, suggesting basic functions in PtkA-dependent gene transcription. In contrast, deletion of pclB in combination with deletion of pclA essentially caused a block in spore formation. We present evidence that the phosphorylation status of the CTD of RNA polymerase II in the conidiophore changes upon deletion of pclA or pclB. Our results suggest that tissue-specific modulation of Cdk9 activity by PclA and PclB is required for proper differentiation. PMID- 23104573 TI - [A 31-year-old pregnant woman with refractory hypercalcemia]. AB - A 31-year-old pregnant woman presented with refractory severe hypercalcemia due to an advanced neuroendocrine tumor masquerading as hyperemesis gravidarum. Octreotide therapy and extensive tumor debulking surgery resulted in symptom control. After a prolonged stay in the intensive care unit due to parapneumonic acute respiratory distress syndrome, the patient delivered a healthy child. Neuroendocrine tumors are a rare complication of pregnancy and a seldom cause of refractory hypercalcemia. PMID- 23104572 TI - [Treatment resistant hypertension. Value of a new treatment concept]. AB - Sympathetic overexpression can be found in a majority of hypertensive patients. Resistant arterial hypertension requires a targeted diagnostic procedure in order to exclude secondary causes of hypertension which can be treated specifically with established therapies. If secondary reasons are not identified, the antihypertensive medication is already optimal and lifestyle changes have been realized, but still the goal of antihypertensive therapy cannot be achieved, alternative invasive therapy strategies such as renal sympathetic denervation and baroreflex activation have been developed to achieve blood pressure control. These therapies are restricted to specialized centers which treat well-defined patients with therapy-resistant hypertension. Little long-term data concerning safety and efficacy are available for the two strategies. However, they should preferably be used as an ultima-ratio and add-on pathway to conservative procedures when established medication fails to achieve blood pressure control. To date, the effectiveness of the interventional antihypertensive therapies has only been shown on patients with systolic blood pressure over 160 mmHg and a mean oral medication of five drugs. PMID- 23104574 TI - [Fever, coughing and dyspnea in a 38-year-old female kidney transplant recipient]. AB - This article reports on a 38-year-old kidney transplant patient who presented with fever, coughing and dypnea. The patient was immunosuppressed with mycophenolate and prednisone. Due to the suspicion of community acquired pneumonia antibiotic treatment was initiated and the patient was admitted to the intensive care unit. Despite antibiotic treatment the condition did not improve and in the subsequently performed bronchioalveolar lavage parainfluenza virus was diagnosed.Infections with respiratory viruses can be fatal in immunosuppressed patients. Human parainfluenza virus is the third most common pathogen of viral pneumonia. Molecular genetic detection methods allow fast and sensitive diagnosis of respiratory materials. As the treatment options are limited for these infections prophylactic measurements are important. PMID- 23104575 TI - [Results of surgically treated paediatric supracondylar humeral fractures]. AB - BACKGROUND: About 80 % of all paediatric distal humerus fractures are supracondylar fractures. PATIENTS AND METHODS: Surgically treated children with supracondylar humeral fractures between 2000-2008 were analysed retrospectively and re-evaluated for function, satisfaction, pain level and with the MAYO elbow performance score (MEPS). RESULTS: 46 patients were included. Open fractures (2 %) and vessel (0 %) or nerve (4 %) lacerations were rare, additional forearm fractures frequent (15 %). Surgery was done by closed/open reduction and crossed K-wire pinning. Main complications were movement restriction and K-wire migration. All fractures healed. 72 % of patients could be re-evaluated O 51 months after surgery. The mean differences between non-affected and affected elbows showed 8 degrees for flexion, 1 degrees for extension, 1 degrees for pronation and 0 degrees for supination. In 88 % excellent or good results could be measured with the MEPS. CONCLUSION: Regarding bony healing in all patients, well manageable complications, mostly excellent or good results in the MEPS and good function, crossed K-wire pinning after closed/open reduction is a safe standard surgical procedure for this type of fracture. PMID- 23104576 TI - Effectiveness of preoperative screening for sickle cell disease in a population with a newborn screening program: a cohort study. AB - PURPOSE: Published clinical practice guidelines recommend that all patients from ethnic groups with a high prevalence of sickle cell disease (SCD) undergo preoperative screening for this hemoglobinopathy. Newborn Screening Ontario initiated a universal sickle hemoglobinopathy screening program in 2006 as part of its regional newborn screening program. The primary objective of this study was to determine the effectiveness of selective preoperative screening for SCD based on at-risk ethnicity in Ontario, a region that has a universal newborn sickle hemoglobinopathy screening program. METHODS: The hematology laboratory database at our hospital was searched to identify all children who underwent preoperative sickle cell screening in the 42-month period starting in November 2006 (when the newborn sickle hemoglobinopathy screening program was introduced) and ending in April 2010. Medical records of all children testing positive on hemoglobin analysis were reviewed to determine perioperative outcomes. RESULTS: Our search strategy identified 710 children who were born after the introduction of newborn screening and who underwent preoperative screening. Thirty-five of these children had abnormal sickle solubility tests - one (0.14%) was a new diagnosis (not identified by newborn screening), one had been diagnosed previously, and 33 (4.65%) were identified as having sickle cell trait. Sixty children had more than one preoperative screening test performed (range, 2-4). Six of the 35 children with abnormal sickle solubility results underwent repeated testing. CONCLUSIONS: Preoperative screening based on at-risk ethnicity alone is an ineffective method of identifying additional children with SCD in Ontario, a population with universal newborn sickle hemoglobinopathy screening. In an effort to avoid unnecessary repeat testing, we propose an algorithm to help physicians decide whether to initiate preoperative sickle cell screening for children. PMID- 23104577 TI - Rosiglitazone enhances neovascularization in diabetic rat ischemic hindlimb model. AB - BACKGROUND: There is increasing evidence that peroxisome proliferator-activated receptors (PPARs) may be involved in the regulation of angiogenesis. In this study, we examined whether rosiglitazone, a PPARgamma agonist, can restore angiogenesis in a rat hindlimb ischemia model of diabetes. METHODS: Male wistar rats were divided into four groups (n=6 each): control, diabetic and control and diabetic rats who received rosiglitazone (8 mg/kg/day). Diabetes was induced by streptozotocin (55 mg/kg; ip). After 21 days, serum concentrations of nitric oxide (NO), vascular endothelial growth factor (VEGF) and soluble VEGF receptor-2 (VEGFR-2) were measured and neovascularization in ischemic legs was evaluated by immunohistochemistry. RESULTS: Capillary density and capillary/fiber ratio in hindlimb ischemia of diabetic animals were significantly lower than the control group (P<0.05). Rosiglitazone significantly restored neovascularization in diabetic animals (P<0.05). CONCLUSIONS: rosiglitazone enhances neovascularization in diabetic ischemic skeletal muscle and could be considered for treatment of peripheral artery disease in diabetic subjects. PMID- 23104578 TI - HuC-eGFP mosaic labelling of neurons in zebrafish enables in vivo live cell imaging of growth cones. AB - The field of axon guidance is taking advantage of the powerful genetic and imaging tools that are now available to visualise growth behaviour in living cells, both in vivo and in real time. We have developed a method to visualise individual neurons within the living zebrafish embryo which provides exceptional cellular resolution of growth cones and their filopodia. We generated a DNA construct in which the HuC promoter drives expression of eGFP. Injection of the plasmid into single cell fertilised zebrafish egg resulted in mosaic expression of eGFP in neurons throughout the developing embryo. By manipulating the concentration of injected plasmid, it was possible to optimise the numbers of neurons that expressed the construct so that individual growth cones could be easily visualised. We then used time-lapse high magnification widefield epifluorescence microscopy to visualise the growth cones as they were exploring their environment. Growth cones both near the surface of the embryo as well as deep within the developing brain of embryos at 20 h post fertilisation were clearly imaged. With time-lapse sequence imaging with intervals between frames as frequent as 1 s there was minimal loss of fluorescence intensity and the dynamic nature of the growth cones became evident. This method therefore provides high magnification, high resolution time-lapse imaging of living neurons in vivo and by use of widefield epifluorescence rather than confocal it is a relatively inexpensive microscopy method. PMID- 23104579 TI - Evaluation of crystallization behavior on the surface of nifedipine solid dispersion powder using inverse gas chromatography. AB - PURPOSE: To investigate crystallization behavior on the surface of amorphous solid dispersion powder using inverse gas chromatography (IGC) and to predict the physical stability at temperatures below the glass transition temperature (T (g)). METHODS: Amorphous solid dispersion powder was prepared by melt-quenching of a mixture of crystalline nifedipine and polyvinylpyrrolidon (PVP) K-30. IGC was conducted by injecting undecane (probe gas) and methane (reference gas) repeatedly to the solid dispersion at temperatures below T (g). Surface crystallization was evaluated by the retention volume change of undecane based on the observation that the surface of the solid dispersion with crystallized nifedipine gives an increased retention volume. RESULTS: On applying the retention volume change to the Hancock-Sharp equation, surface crystallization was found to follow a two-dimensional growth of nuclei mechanism. Estimation of the crystallization rates at temperatures far below T (g) using the Avrami Erofeev equation and Arrhenius equation showed that, to maintain its quality for at least three years, the solid dispersion should be stored at -20 degrees C (T (g) - 65 degrees C). CONCLUSIONS: IGC can be used to evaluate crystallization behavior on the surface of a solid dispersion powder, and, unlike traditional techniques, can also predict the stability of the solid dispersion based on the surface crystallization behavior. PMID- 23104580 TI - Molecular mobility as a predictor of the water sorption by annealed amorphous trehalose. AB - PURPOSE: The work aims at investigating the correlation of water sorption potential with different measures of molecular mobility in an annealed amorphous model compound (trehalose). METHODS: Amorphous trehalose, prepared by freeze drying, was annealed at 100 degrees C (17 degrees C < T (g)) for up to 120 h. Global molecular mobility was studied using a broadband dielectric spectrometer in the frequency range of 10(6)-10(-2) Hz. Enthalpic recovery was measured by differential scanning calorimetry and water sorption profiles were obtained using an automated vapor sorption balance. RESULTS: As a function of annealing time, there was an increase, both in average alpha-relaxation time and enthalpic recovery and a decrease in the amount of sorbed water. A strong linear correlation was observed between the water sorption potential and the dielectric relaxation time, indicating a common underlying mechanism of the effect of annealing time on these properties. Enthalpic recovery, which is widely used as a measure of structural relaxation, did not correlate well with the extent of water sorption. CONCLUSIONS: The alpha-relaxation time can be used as a predictor of the water sorption potential of amorphous trehalose. It will be of interest and value to develop such predictive models for other amorphous compounds of pharmaceutical interest. PMID- 23104581 TI - Use of a single-circuit CentriMag(r) for biventricular support in postpartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is defined by acute heart failure in the late stages of pregnancy to a few months postpartum. Cardiogenic shock in PPCM, though rare, can be life-threatening, often requiring support with mechanical circulatory support devices. We present a case of 37-year-old Caucasian female who developed cardiogenic shock within 24 hours of the delivery of her twins. The echocardiogram demonstrated severe biventricular failure which necessitated biventricular device placement and support with a CentriMag(r) centrifugal pump. This biventricular support was employed, using a single-circuit CentriMag(r) pump, using a 'Y' connection which made weaning from right-sided support and conversion to univentricular support easier and feasible. The patient recovered four weeks later and was explanted off the CentriMag(r) support and did well. This technology allows for the CentriMag(r) to be considered as an early option for biventricular support in the treatment and management of these patients as a bridge to recovery. PMID- 23104582 TI - Successful management of bleeding complications in patients supported with extracorporeal membrane oxygenation with primary respiratory failure. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a lifesaving procedure in patients with severe respiratory insufficiency failing conventional support. Bleeding complications are common due to the necessity for anticoagulation and circuit-related factors. METHODS: A retrospective review was conducted in patients requiring ECMO for respiratory failure from 7/2010 to 6/2011 to identify episodes of major bleeding, bleeding management and outcomes. RESULTS: Twenty-one patients were supported with ECMO during the study although five experienced massive bleeding related to chest tube insertion, jejunal arterio-venous malformations, distal perfusion cannula dislodgement and ventricular rupture. Patients required aggressive resuscitation or endoscopic or operative intervention, totaling 28 procedures. There were no instances of dehiscence, infection or sepsis related to interventions. Anticoagulation was stopped six hours before and restarted 24 hours after major interventions, with no thrombotic or neurologic complications. All patients weaned off ECMO were discharged. CONCLUSIONS: ECMO bleeding complications can be managed successfully via surgical and endoscopic approaches in this high-risk population. PMID- 23104583 TI - Letter to the editor: decompressive craniectomy for acute subdural hematoma. PMID- 23104584 TI - In vitro antifungal drug susceptibilities of Penicillium marneffei from China. AB - Penicillium marneffei infections in immunocompromised patients are often fatal, but early treatment with appropriate antifungal agents may have a good prognosis. To select drugs for treating P. marneffei infection in Southern China, the susceptibilities of antifungal agents against P. marneffei isolates were evaluated. Twenty-five strains of P. marneffei were isolated from patients from 2008 to 2010 in Guangxi Province of China, and 14 strains were isolated from bamboo rats. The activity of voriconazole, fluconazole, itraconazole, terbinafine, and amphotericin B on the isolates was assessed by MIC analysis. Voriconazole MIC against strains of P. marneffei ranged from 0.004 to 0.25 mg/l, and it had the lowest MIC (geometric mean values, 0.04 mg/l) in comparison to the other antifungal agents. The MICs of other antifungal agents, in order of lowest to highest, were as follows: itraconazole, terbinafine, amphotericin B, and fluconazole. The results show voriconazole and itraconazole are active against P. marneffei isolates in vitro, and terbinafine may have unrealized usefulness in the treatment of infections caused by this yeast form. PMID- 23104585 TI - Blood and body fluid exposures in health-care settings: risk reduction practices and postexposure prophylaxis for health-care workers. AB - This review of last year's literature on blood-borne pathogens (= pathogenic microorganisms that are found in human blood) focuses on hepatitis B (HBV), hepatitis C (HCV), and human immunodeficiency virus (HIV) as the most common pathogens, despite the fact that other microorganisms may cause blood-borne diseases as well. Since the prevention of blood-borne diseases is something that, in the past, has gotten a lot of attention and by now is fully integrated in all safety structures in the U.S., the recent literatures mainly have been come from resource-limited/developing countries and Europe (which, in the definition of the financial word at the present time, in some parts overlap). PMID- 23104589 TI - Presence of Torque teno sus virus in porcine circovirus type 2-associated disease in Croatia. AB - Torque teno virus (TTV) is ubiquitous and species-specific, and two different TTV species, Torque teno sus virus 1 (TTSuV1) and Torque teno sus virus 2 (TTSuV2), have been described in domestic pigs and wild boars. Whether these two species are involved in clinical cases of porcine circovirus type 2-associated disease (PCVDs) remains unknown. This study investigates the presence of TTSuV in 85 fetuses, pigs and wild boars infected by PCV2 and affected by PCVDs other than postweaning multisystemic wasting syndrome (PMWS) and porcine dermatitis and nephropathy syndrome. It also explores the genetic diversity of identified strains using phylogenetic analysis. The presence or absence of TTSuV was determined in 85 samples of PCV2-containing organs from 85 infected animals using a specific, one-step PCR method. A nucleotide distance matrix between sequences was computed to infer phylogeny based on a median-joining (MJ) network. TTSuV2 showed high prevalence in animals affected by nephropathy and proliferative and necrotising pneumonia (PNP), and both TTSuV1 and TTSuV2 showed high prevalence in wild boars affected by PMWS. TTSuV1 showed low prevalence in animals affected by nephropathy and PNP, and both TTSuV1 and TTSuV2 showed low prevalence in animals with reproductive disorders. MJ network analysis revealed significant genetic diversity among Croatian isolates. PMID- 23104590 TI - Giant dumbbell-shaped intra- and extracranial nerve schwannoma in a child presenting with glossopharyngeal neuralgia syncope syndrome: a case report and review of the literature. AB - Lower cranial nerve schwannomas are benign tumors of the neurolemmocytes of the cranial nerves. Among children, cranial nerve schwannomas are extremely rare and are predominantly associated with neurofibromatosis (NF) type 2. The purpose of the current case report is to describe a unique giant extra- and intracranial foramen jugular schwannoma in a young boy with lower cranial nerve deficits and glossopharyngeal neuralgia syncope syndrome and to review the pertinent literature. In the current case report, we illustrate the course of disease in a 14-year-old boy with a 4-month history of recurrent syncope and a big bulge on the left side of his neck. Audiometry showed deafness of the left ear. Magnetic resonance imaging (MRI) demonstrated a giant unilateral dumbbell-shaped intra- and extracranial foramen jugular schwannoma with a volume of 156 cm3 causing severe brain stem compression and obstructive hydrocephalus. The tumor was removed completely in a two-step surgery. The tumor was confirmed during surgery to originate from the glossopharyngeal nerve. The histological examination revealed the characteristic features of a schwannoma. The MRI 3 months after the second surgery confirmed complete tumor removal. The genetic examination for NF was negative. Review of literature showed that dumbbell-shaped lower cranial nerve schwannomas in the childhood population are rare. PMID- 23104591 TI - Endoscopic endonasal resection of anterior skull base meningiomas and mucosa: implications for resection, reconstruction, and recurrence. AB - BACKGROUND: Meningiomas of the anterior skull base are attractive tumors for resection via an endoscopic endonasal route. The use of the vascularized Hadad Bassagasteguy nasoseptal flap has dramatically reduced the cerebrospinal fluid (CSF) leak rate-the veritable Achilles heel of this surgical approach. Benign meningiomas, however, can erode through the nasal mucosa-the very same mucosa that is used to reconstruct the anterior cranial fossa floor. The goal of this study was to describe the presence of meningioma invasion into the mucosa in patients who underwent endoscopic endonasal resection of ventral skull base meningiomas. The implications of this finding are discussed with respect to resection, reconstruction, and recurrence. PATIENTS, MATERIALS, AND METHODS: This is a retrospective review of three patients who underwent endoscopic endonasal complete resection of ventral skull base meningiomas. Surgically excised tissues were processed for routine histopathological analysis. RESULTS: A complete resection of the bone, dura, and tumor was performed in all three cases. Both patients with visual deficits improved. The first patient to undergo endoscopic surgical resection developed a CSF leak, but the later two patients with larger tumors did not. Histopathological analysis demonstrated mucosal invasion by World Health Organization (WHO) grade I meningioma in two of the three cases. CONCLUSION: Ventral anterior skull base meningiomas can invade through bone into the mucosa. Because the endoscopic endonasal resection of these meningiomas often requires the use of a vascularized nasoseptal flap to minimize CSF leak complications, it is possible that the nasoseptal flap itself may be compromised by tumor tissue. The creation of the nasoseptal flap should take the findings of this study into consideration to minimize late recurrence. PMID- 23104592 TI - Psychosurgery: review of latest concepts and applications. AB - Although the utilization of psychosurgery has commenced in early 19th century, when compared with other neurosurgical fields, it faced many obstacles resulting in the delay of advancement of this type of surgical methodology. This was due to the insufficient knowledge of both neural networks of the brain and the pathophysiology of psychiatric diseases. The aggressive surgical treatment modalities with high mortality and morbidity rates, the controversial ethical concerns, and the introduction of antipsychotic drugs were also among those obstacles. With the recent advancements in the field of neuroscience more accurate knowledge was gained in this field offering new ideas for the management of these diseases. Also, the recent technological developments aided the surgeons to define more sophisticated and minimally invasive techniques during the surgical procedures. Maybe the most important factor in the rerising of psychosurgery is the assemblage of the experts, clinicians, and researchers in various fields of neurosciences implementing a multidisciplinary approach. In this article, the authors aim to review the latest concepts of the pathophysiology and the recent advancements of the surgical treatment of psychiatric diseases from a neurosurgical point of view. PMID- 23104593 TI - Three-dimensional computed tomographic analysis of a rare left coronary artery to left ventricle fistula. PMID- 23104594 TI - Habitual exercise correlates with exercise performance in patients with conotruncal abnormalities. AB - Cardiopulmonary exercise testing (CPET), particularly maximal oxygen consumption (VO2max), has been used to assess the outcome for patients with palliated congenital heart disease (CHD). Small studies correlating VO2max with noninvasive imaging measures of ventricular function have led to the hypothesis that VO2max reflects cardiac performance. In other settings, physical training is associated with increased VO2max. The authors hypothesized that habitual exercise correlates with VO2max to a greater degree than ventricular function in a relatively healthy cohort of patients with palliated CHD. The habitual exercise behavior of 208 subjects with conotruncal abnormalities (tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch) at the time of previously performed, study-based CPET and cardiac magnetic resonance imaging (CMR) were retrospectively assessed via questionnaire. The association of VO2max with habitual exercise duration and CMR measures of ventricular function was tested. Of 208 subjects, 89 (43 %) completed questionnaires, and 78 % of the 89 patients had a concurrent CMR. The mean VO2max was 76 +/- 21 % of that predicted. The CMR-assessed left ventricular ejection fraction was 67.6 +/- 7.4 %. The hours of habitual exercise per week correlated with VO2max (p < 0.001; r (2) = 0.14). No association was found between right and left ventricular ejection fraction, cardiac index, or right ventricular end-diastolic volume and VO2max. In this study, VO2max correlated with habitual exercise to a greater degree than CMR measurements of ventricular function. These findings highlight the importance of considering the contribution of noncardiac factors when exercise data in both clinical and research settings are interpreted. The contribution of these factors to clinical outcomes deserves further study. PMID- 23104596 TI - Unusual case of new-onset heart failure due to cor triatriatum sinister. AB - We report the case of a 30-year old man who came to the emergency department of our hospital with acute left heart failure, and was diagnosed with a rare congenital anomaly (cor triatriatrum sinister), which can mimic a severe mitral stenosis. Cor triatriatum sinister is a rare anomaly (0.1% of all cases of congenital heart disease) that is seldom diagnosed in adult patients. The hallmark of this congenital defect is the presence of a fibromuscular membrane that divides the left atrium (LA) into two chambers: a postero-superior chamber into which the pulmonary veins drain and an infero-anterior chamber (true LA) containing the mitral valve and atrial appendage. Both chambers communicate through a membrane in which one or more drain holes can be found. When the hole is significantly obstructive, it results in increased venous and arterial pressures. Even though the definitive treatment of cor triatriatum is the surgical excision of the membrane, we present a balloon dilatation case with a good response to percutaneous therapy, both initially and in the ensuing months. PMID- 23104595 TI - Tetralogy of Fallot with atrioventricular septal defect: surgical strategies for repair and midterm outcome of pulmonary valve-sparing approach. AB - Repair for tetralogy of Fallot (TOF) with complete atrioventricular septal defect (CAVSD) has been reported with good early and intermediate outcomes. Morbidity, however, remains significantly high. To date, repair of CAVSD/TOF using a pulmonary valve-sparing technique (PVS) and freedom from valve reoperation are not well defined. A study was undertaken to investigate outcomes. This study was conducted in as a retrospective investigation. Between January 1988 and December 2008, 13 consecutive patients with CAVSD/TOF were identified, and their records were reviewed retrospectively. Of these 13 patients, 9 had Rastelli type C CAVSD. Trisomy 21 was present in 9 cases (69 %; 7 with type C). Five patients had received a systemic-to-pulmonary shunt (SPS) before complete repair at a mean age 1.7 +/- 0.6 months. All the patients survived until complete repair. At complete CAVSD/TOF repair, AVSD was corrected with a two-patch technique in all patients. For eight patients (61.5 %), PVS was used. The remaining five patients had transannular patch (TAP) repair. The mean age at complete repair was 6.3 +/- 2.4 months. At complete repair, the mean cardiopulmonary bypass time was 173.5 +/- 30.6 min, and the cross-clamp time was 134.7 +/- 28.8 min. There was one hospitalization and no late deaths. The median follow-up period was 9.2 years [interquartile range (IQR), 4.7-13.3 years]. The actuarial survival was 90.0 +/- 9.5 % at 1 year, 90 +/- 9.5 % at 5 years, and 90 +/- 9.5 % at 8 years. Of the 12 survivors, 6 had some reintervention during the follow-up period. Within the first 11 years after complete repair, two patients underwent left atrioventricular (AV) valve repair, and one patient had right AV valve repair. Two patients had residual VSD closure. Four patients underwent the first right ventricular outflow tract (RVOT) reintervention for critical insufficiency or stenosis at a mean interval of 6 +/- 21) months. One patient had a second RVOT reoperation. Findings showed that CAVSD/TOF with PVS was related to significantly higher freedom from RVOT reintervention (100 % at 1, 5, and 8 years compared with 80 +/- 17.9 % at 1 year, 60 +/- 21.9 % at 5 years, and 40 +/- 21.9 % at 8 years for CAVSD/TOF using TAP; P < 0.05). No patient who underwent PVS had left ventricular outflow tract obstruction requiring reoperation. Overall freedom from any reintervention was 90.9 +/- 8.6 % at 1 year, 71.6 +/- 14.0 % at 5 years, and 53.7 +/- 8.7 % at 8 years in this group of patients. Correction of TOF with CAVSD can be performed at low risk with favorable intermediate-term survival and satisfactory freedom from reoperation. Use of TAP can be avoided in almost two thirds of patients and may influence freedom from early RVOT reintervention. PMID- 23104597 TI - Contrasting approaches to a biological problem: paul boyer, peter mitchell and the mechanism of the ATP synthase, 1961-1985. AB - Attempts to solve the puzzling problem of oxidative phosphorylation led to four very different hypotheses each of which suggested a different view of the ATP synthase, the phosphorylating enzyme. During the 1960s and 1970s evidence began to accumulate which rendered Peter Mitchell's chemiosmotic hypothesis, the novel part of which was the proton translocating ATP synthase (ATPase), a plausible explanation. The conformational hypothesis of Paul Boyer implied an enzyme where ATP synthesis was driven by the energy of conformational changes in the respiratory proteins. This was finally abandoned as an explanation of the overall process. Nevertheless the conformational understanding of the enzyme became an acceptable proposal during the early 1970s and eventually led Boyer to a view of the enzyme that incorporated both hypotheses. The correspondence between Mitchell and Boyer, both Nobel laureates, exposes their different approaches to both this enzyme and to the hypotheses of oxidative phosphorylation and illuminates a key step in the development of bioenergetics. In particular Boyer was suspicious of proton gradients, because he could not envisage a chemical mechanism for the synthesis of ATP, while Mitchell distrusted conformational arguments because he believed the proton must act vectorially at the active site of the enzyme. This resulted in two different views of the mechanisms operating in this enzyme. Ultimately while Boyer was able to marry the two approaches, Mitchell retained his insistence on the role of the proton at the active site and was thus unable to give significance to Boyer's conformational ideas. The underlying issues in this debate are discussed particularly with reference to the differing styles of Boyer and Mitchell and the influence of molecular biology, especially the development of protein technology. PMID- 23104598 TI - [Work, mental disorders and burnout: concepts and developments in diagnostics, prevention and therapy]. AB - The term burnout is associated with an intensive debate on psychological stress in the modern working environment and the potential risks for mental health imposed by working conditions. However, this important discourse on how to design working conditions is hindered by a lack of differentiation of several distinct entities: prevention of mental work strain on the one hand and treatment care for persons affected by burnout syndrome accompanied by a manifest psychiatric disorder on the other. In view of these rather different work fields several shortcomings need to be pointed out: in Germany psychosocial risk assessment and prevention of mental work strain are insufficiently carried out on a company level. Means of interventions for people with pure burnout syndrome are numerous but the evaluation in terms of efficiency and long-term effects cannot be considered satisfactory in view of the existing studies. Therapy for patients with an existing psychiatric disorder and burnout should incorporate and focus on the working context as well, for example with a corresponding facultative module. For these groups an all-encompassing stepped-care model should be developed by involving all relevant players on the company level, the political level and the healthcare system. PMID- 23104599 TI - [The processing of pain in psychiatric diseases]. AB - The perception and processing of pain is disturbed in many psychiatric diseases. Some diseases are known to show decreased perception of pain (e.g. borderline personality disorder), while others are associated with augmented pain perception (e.g. alcohol and drug dependence). The close relationship between psychiatric diseases and pain is most probably caused by aberrant processing of pain in brain structures, known to be involved in psychiatric disorders as well. Aberrant perception and processing of pain in patients with anorexia nervosa (AN) will be used to demonstrate this close relationship. Dysfunction within the insula has been suggested to account for many features of AN and might contribute to reduced pain perception. Moreover, it might lead to increased adrenergic descending inhibition associated with increased sympathetic modulation. Thus, pain research might be able to alter our view on autonomic regulation, which is putatively associated with increased cardiac mortality of the disease. PMID- 23104601 TI - [Field of tension between psychomatics and psychiatry]. AB - As a medical topic psychosomatic medicine is able to look back on an almost 100 year-old tradition. Nevertheless, questions about its definition, area of application and by whom it should be practiced remains unsolved. This causes considerable tension with the field of psychiatry which has always seen psychosomatic medicine as a subspecialty of its own discipline. In the article, the development and current position of psychosomatic medicine in German speaking countries other than Germany (Austria, Switzerland and South Tyrol) is presented. While psychosomatic care is currently planned and also partially already executed in Austria, psychosomatic medicine in Switzerland is located with general practitioners on the one hand and consultation-liaison psychiatry on the other. After the radical psychiatric reform of the late 1970s in South Tyrol psychosomatic medicine proved to be a means to remove taboos regarding psychiatric institutions and the mentally ill. PMID- 23104600 TI - [Depression: risk factor for cardiovascular disease]. AB - Major depression is an independent risk factor for the development of cardiovascular disease. In patients with existing cardiovascular disease, major depression has a large impact on the quality of life and is associated with a poor course and prognosis. Potential mechanisms responsible for this association can be categorized as biological and behavioural variables that do not exclude each other but interact. Biological factors include alterations of the autonomous nervous system, the hypothalamic-pituitary-adrenal axis, the immune system and the vascular system. Major depression also raises the risk for further diseases, such as diabetes mellitus or obesity, which themselves are associated with higher cardiovascular risks. On a behavioural level, depression is often associated with an unhealthy life style such as smoking and physical inactivity. Additionally, depressed patients have more difficulties to implement recommended behavioural changes and to adhere to medication. Furthermore, some classes of antidepressants may also increase cardiovascular risk. All these factors play an important role in the association between depression and cardiovascular disease. PMID- 23104602 TI - [Depression in old age: challenge for aging societies]. AB - Depression in old age is common and has severe consequences. The paper reviews the most recent results of population-based and primary care-based studies reporting the prevalence, course and risk factors for depression in old age. Consequences of late life depression for the individual and for the society in terms of costs of illness are outlined. Studies of health service utilization and costs showed homogeneously that healthcare costs for depressive elderly individuals are one third higher compared to non-depressive individuals even though most do not receive depression-specific treatment. Late life depression is underrecognized and undertreated and data from Germany are rare. Improvement strategies, such as collaborative care models are discussed; however, adaptation and implementation to the German context are still pending. Future demographic changes will facilitate mental health service research into late life depression. PMID- 23104603 TI - [Peripartum depression and grief after pregnancy loss: special problem areas in obstetrics]. AB - There is evidence that postpartum depression increases the risk of premature birth and developmental disabilities of the child. Risk factors include a history of depression, prenatal anxiety, lack of social support, intimate partner violence, low socioeconomic status and lack of a relationship. For women in high risk groups antenatal interventions could reveal positive effects to prevent postpartum depression. In the peripartum period routine screening is recommended to detect women at risk of developing depression. Furthermore, prenatal losses during pregnancy, specifically occurring during the first weeks of pregnancy may result in complicated grief disorders. Only very few controlled and randomized intervention studies for the treatment after prenatal loss have been conducted; however, aimed at specific high-risk groups these bereavement interventions demonstrated a high treatment efficacy. PMID- 23104605 TI - [Psychosomatic]. PMID- 23104604 TI - [Eating disorders: state of the art research and future challenges]. AB - Eating disorders are a common mental disorder during adolescence and young adulthood. While prevalence rates of eating disorders dramatically increased during the second half of the last century, these rates have remained relatively stable over the last 20 years. According to ICD-10 eating disorders are diagnostically categorized as anorexia nervosa, bulimia nervosa and atypical eating disorders or eating disorders not otherwise specified. Concerning the etiology, genetic factors are involved, especially in anorexia nervosa, as well as psychological and sociocultural factors. Evidence-based recommendations are available for the treatment of bulimia nervosa and binge eating disorder and in this context cognitive behavioral therapy is seen as the first choice. In contrast, the state of knowledge concerning the treatment of anorexia nervosa is still limited, especially concerning effective treatments for adults. Recent data only provide evidence for the effectiveness of family therapy for adolescents. Due to the lack of high quality studies, research on therapy for anorexia nervosa is a future challenge. PMID- 23104607 TI - Analysis of baseball-to-helmet impacts in major league baseball. AB - BACKGROUND: In Major League Baseball (MLB), helmet hit-by-pitch (H-HBP) incidents are a leading cause of concussion. However, not all H-HBPs result in diagnosed concussion. PURPOSE: This study was designed to (1) quantify batter concussion risk as a function of H-HBP pitch velocity, time duration batter spent on the ground post-H-HBP, first responder assessment time duration, and number of days missed post-H-HBP and (2) estimate H-HBP impact locations on the helmet with respect to current National Operating Committee on Standards for Athletic Equipment (NOCSAE) helmet test standards and correlate impact locations with concussion diagnosis. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: A retrospective case-control study of 18 MLB players with H-HBP incidents in the 2009 and 2010 seasons was undertaken. A database was compiled via quantitative and qualitative analysis using video coverage obtained from MLB. Quantitative factors included batter concussion diagnosis, pitch velocity, number of days missed post-H-HBP, time duration batter spent on the ground post-H-HBP, and first responder assessment time duration. The H-HBP impact location was among several qualitative factors developed via video analysis of each H-HBP from 4 raters. RESULTS: In our study, 9 players (50%) were diagnosed with concussion. Concussion diagnoses were more frequent for posterior versus anterior impacts. The majority of H-HBP impact locations were different from those in the current NOCSAE standard tests. First responders took an average of approximately 65 seconds (time to reach batter plus assessment time) to decide on batter removal/return to play. The 25% logistic regression concussion risk threshold for pitch velocity and days missed was 86.2 mph and 1.3 days, respectively. The number of days missed after H-HBP showed a significant correlation (P = .02) among concussed and nonconcussed batters. CONCLUSION: In professional baseball H HBP incidents, first responders should (1) be aware of pitch velocity in excess of 86 mph and (2) be provided ample time when assessing batters' removal/return to play. CLINICAL RELEVANCE: First responders should not rely solely on visual indicators such as batter reaction, holding head, or amount of time spent on the ground after H-HBP when assessing batters for concussion. Batting helmets in the MLB should maximize protection and mitigate impact dosage for H-HBP impact locations and velocity in addition to NOCSAE standard test locations and velocities. PMID- 23104608 TI - Arthroscopic single-row modified mason-allen repair versus double-row suture bridge reconstruction for supraspinatus tendon tears: a matched-pair analysis. AB - BACKGROUND: Arthroscopic double-row fixation of supraspinatus tendon tears compared with single-row techniques is still a matter of debate. HYPOTHESIS: Arthroscopic double-row rotator cuff repair using the suture bridge technique provides better clinical results and lower retear rates than does single-row repair using a modified Mason-Allen stitch technique. STUDY DESIGN: Cohort study; Level of evidence 3. METHODS: Forty patients underwent either an arthroscopic single-row modified Mason-Allen stitch (SR) (n = 20; mean age +/- SD, 61.5 +/- 7.4 y) or a modified suture bridge double-row repair (DR) (n = 20; age, 61.2 +/- 7.5 y). The anteroposterior extension was classified as Bateman I in 10% and Bateman II in 90% of patients in the SR group and as Bateman II in 80% and Bateman III in 20% of patients in the DR group. Patients were matched for sex and age. The subjective shoulder value (SSV), Constant-Murley score (CS), and Western Ontario Rotator Cuff Index (WORC) were used for clinical follow-up. Furthermore, MRI scans were conducted for analysis of tendon integrity, muscle atrophy, and fatty infiltration via semiquantitative signal intensity analysis. In addition, re-defect patterns were evaluated. RESULTS: The mean follow-up time in the SR group was 16.8 +/- 4.6 months. The mean SSV was 91.0% +/- 8.8%, mean CS was 82.2 +/- 8.1 (contralateral side, 88.8 +/- 5.3), and mean WORC score was 96.5% +/- 3.2%. The mean follow-up time in the DR group was 23.4 +/- 2.9 months, with patients achieving scores of 92.9% +/- 9.6% for the SSV, 77.0 +/- 8.6 for the CS (contralateral side, 76.7 +/- 17.1), and 90.7% +/- 12.6% for the WORC (P > .05). No significant differences were detected in the clinical outcome between groups. Tendon integrity was as follows. Type 1, none in either group; type 2, 4 SR and 5 DR; type 3, 9 SR and 10 DR; type 4, 3 SR and 3 DR; and type 5, 3 SR and 2 DR. The failure rate was 31.6% (n = 6) in the SR group and 25% (n = 5) in the DR group (P > .05). No significant differences were obtained for muscular atrophy or fatty degeneration (SR group, 0.94 +/- 0.16; DR group, 1.15 +/- 0.5) (P > .05). Re defects revealed lateral cuff failure in 83.3% of SR patients in contrast to patients treated with DR techniques. The re-defect pattern was medial cuff failure in 80% of the patients. CONCLUSION: The clinical results after modified Mason-Allen single-row versus double-mattress suture bridge technique did not demonstrate significant differences in a matched patient cohort. Concerning the failure mode, single- and double-row techniques seem to demonstrate different re defect patterns. PMID- 23104606 TI - Do cartilage repair procedures prevent degenerative meniscus changes?: longitudinal t1rho and morphological evaluation with 3.0-T MRI. AB - BACKGROUND: Cartilage repair (CR) procedures are widely accepted for treatment of isolated cartilage defects in the knee joint. However, it is not well known whether these procedures prevent degenerative joint disease. HYPOTHESIS: Cartilage repair procedures prevent accelerated qualitative and quantitative progression of meniscus degeneration in individuals with focal cartilage defects. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Ninety-four subjects were studied. Cartilage repair procedures were performed on 34 patients (osteochondral transplantation, n = 16; microfracture, n = 18); 34 controls were matched. An additional 13 patients received CR and anterior cruciate ligament (ACL) reconstruction (CR&ACL), and 13 patients received only ACL reconstruction. Magnetic resonance imaging at 3.0-tesla with T(1rho) mapping and sagittal fat saturated intermediate-weighted fast spin echo (FSE) sequences was performed to quantitatively and qualitatively analyze menisci (Whole-Organ Magnetic Resonance Imaging Score [WORMS] assessment). Patients in the CR and CR&ACL groups were examined 4 months (n = 34; n = 13), 1 year (n = 21; n = 8), and 2 years (n = 9; n = 5) after CR. Control subjects were scanned at baseline and after 1 and 2 years, ACL patients after 1 and 2 years. RESULTS: At baseline, global meniscus T(1rho) values (mean +/- SEM) were higher in individuals with CR (14.2 +/- 0.5 ms; P = .004) and in individuals with CR&ACL (17.1 +/- 0.9 ms; P < .001) when compared with controls (12.8 +/- 0.6 ms). After 2 years, there was a statistical difference between T(1rho) at the overlying meniscus above cartilage defects (16.4 +/- 1.0 ms) and T(1rho) of the subgroup of control knees without cartilage defects (12.1 +/- 0.8 ms; P < .001) and a statistical trend to the CR group (13.3 +/- 1.0 ms; P = .09). At baseline, 35% of subjects with CR showed morphological meniscus tears at the overlying meniscus; 10% of CR subjects showed an increase in the WORMS meniscus score within the first year, and none progressed in the second year. Control subjects with (without) cartilage defects showed meniscus tears in 30% (5%) at baseline; 38% (19%) increased within the first year, and 15% (10%) within the second year. CONCLUSION: This study demonstrated more severe meniscus degeneration after CR surgery compared with controls. However, progression of T(1rho) values was not observed from 1 to 2 years after surgery. These results suggest that CR may prevent degenerative meniscus changes. PMID- 23104609 TI - Intraoperative determinants of rotator cuff repair integrity: an analysis of 500 consecutive repairs. AB - BACKGROUND: Rotator cuff repair has a relatively high (20%-90%) chance of retears. Patients with an intact rotator cuff 6 months after surgery have better subjective and objective outcomes at 6 months and 2 years after rotator cuff repair than those who do not have an intact repair. PURPOSE: The aim of this study was to determine if, and if so which, intraoperative factors predict an intact repair 6 months after rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The study consisted of a cohort of 500 consecutive patients who had an arthroscopic rotator cuff repair performed by a single surgeon and an ultrasound evaluation using standard protocols of the repair 6 months after surgery. Exclusion criteria included previous fracture or shoulder surgery, incomplete or partial rotator cuff repair, and concomitant arthroplasty. Rotator cuff tear size was measured intraoperatively and mapped. The quality of the tendon, tendon mobility, and repair quality were assessed and ranked based on predetermined scales (1-4) and recorded on a specifically designed form. Logistic regression analysis was performed, with cuff integrity at 6-month follow-up as the dependent variable and tear/repair factors as the independent variables. RESULTS: The overall postoperative retear rate was 19% at 6 months. The best predictor of rotator cuff integrity was preoperative tear size (correlation coefficient, r = 0.33; P < .001). Patients with small (<=2 cm(2)) rotator cuff tears were least likely to have retears (retear rate, 10%). As the tear size increased, the retear rate increased in a linear fashion: <=2 cm(2) (10%), 2 to 4 cm(2) (16%), 4 to 6 cm(2) (31%), 6 to 8 cm(2) (50%), and >8 cm(2) (57%). Other surgeon-ranked intraoperative assessments did correlate with retears, but the correlations were relatively weak: repair quality (r = -0.17; P < .001), tendon mobility (r = -0.15; P < .001), and tendon quality (r = -0.14; P < .01). Regression analysis showed that the retear rate at 6-month follow-up was best predicted from the preoperative tear size and the surgeon-ranked repair quality: chance of retear = 0.38 + (0.02 * tear size in cm(2)) - (0.08 * repair quality). Tendon quality and tendon mobility did not contribute significantly to this prediction. CONCLUSION: Tear size was the best intraoperative predictor of repair integrity after rotator cuff repair, with tears less than 2 cm(2) twice as likely to heal than tears greater than 6 cm(2). PMID- 23104610 TI - Prevalence of abnormal hip findings in asymptomatic participants: a prospective, blinded study. AB - BACKGROUND: The prevalence of abnormal magnetic resonance imaging (MRI) findings in an asymptomatic population has yet to be determined. PURPOSE: The purpose of this study was to assess a cohort of asymptomatic people to determine the prevalence of hip lesions. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Forty-five volunteers with no history of hip pain, symptoms, injury, or surgery were recruited for enrollment in this institutional review board-approved study. The subjects underwent a unilateral MRI scan with a Siemens 3.0-tesla scanner. The extremity side evaluated by MRI was alternated. All MRI scans were reviewed by 3 fellowship-trained musculoskeletal radiologists. The scans were mixed randomly with 19 scans from symptomatic patients to blind the radiologists to the possibility of patient symptoms. An abnormal finding was considered positive when 2 of 3 radiologists agreed on its presence. RESULTS: The average age of volunteers was 37.8 years (range, 15-66 y); 60% were men. Labral tears were identified in 69% of hips, chondral defects in 24%, ligamentum teres tears in 2.2%, labral/paralabral cysts in 13%, acetabular bone edema in 11%, fibrocystic changes of the head/neck junction in 22%, rim fractures in 11%, subchondral cysts in 16%, and osseous bumps in 20%. Participants older than 35 years were 13.7 times (95% CI, 2.4-80 times) more likely to have a chondral defect and 16.7 times (95% CI, 1.8-158 times) more likely to have a subchondral cyst compared with participants 35 or younger. No other joint lesions were associated with age. Male subjects were 8.5 times (95% CI, 1.2-56 times) more likely to have an osseous bump than female subjects. No other joint lesions were associated with sex. CONCLUSION: Magnetic resonance images of asymptomatic participants revealed abnormalities in 73% of hips, with labral tears being identified in 69% of the joints. A strong correlation was seen between participant age and early markers of cartilage degeneration such as cartilage defects and subchondral cysts. PMID- 23104611 TI - Comparison between hyaluronic acid and platelet-rich plasma, intra-articular infiltration in the treatment of gonarthrosis. AB - BACKGROUND: Arthrosis is particularly prevalent in the knee. Infiltration treatment for gonarthrosis is among the most widely used techniques in orthopaedic practice. PURPOSE: To compare the clinical response of hyaluronic acid (HA) and platelet-rich plasma (PRP) treatment in 2 groups of patients affected by gonarthrosis. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 120 patients affected by clinically and radiographically documented gonarthrosis were included in this study. The gonarthrosis was graded using the Kellgren-Lawrence radiographic classification scale. The 120 patients were randomized into 2 study groups in a 1:1 ratio: 60 patients received 4 intra-articular injections of PRP (specifically, autologous conditioned plasma [ACP], 5.5 mL), and 60 patients received 4 intra-articular injections of HA (20 mg/2 mL). An unblinded physician performed infiltration once a week for 4 weeks into the knee affected by clinically relevant gonarthrosis (in both groups). All patients were evaluated with the Western Ontario and McMaster (WOMAC) score before the infiltration and at 4, 12, and 24 weeks after the first injection. RESULTS: Treatment with a local injection of ACP had a significant effect shortly after the final infiltration and a continuously improving sustained effect up to 24 weeks (WOMAC score, 65.1 and 36.5 in the HA and ACP groups, respectively; P < .001), where the clinical outcomes were better compared with the results with HA. In the HA group, the worst results were obtained for grade III gonarthrosis, whereas the clinical results obtained in the ACP group did not show any statistically significant difference in terms of the grade of gonarthrosis. The mean WOMAC scores for grade III gonarthrosis were 74.85 in the HA group and 41.20 in the ACP group (P < .001). CONCLUSION: Treatment with ACP showed a significantly better clinical outcome than did treatment with HA, with sustained lower WOMAC scores. Treatment with HA did not seem to be effective in the patients with grade III gonarthrosis. PMID- 23104612 TI - Matrix-assisted autologous chondrocyte transplantation for cartilage regeneration in osteoarthritic knees: results and failures at midterm follow-up. AB - BACKGROUND: Young patients with osteoarthritic knees are a challenging population because of a combination of high functional demands and limited indication for joint replacement. PURPOSE: To analyze the potential of the cartilage regenerative approach by documenting the results and failures of matrix-assisted autologous chondrocyte transplantation (MACT) at midterm follow-up. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Forty-four patients affected by cartilage lesions in osteoarthritic knees underwent MACT as a salvage procedure. The mean age at surgery was 42 years (range, 20-58 years), and the average defect size was 4 cm(2) (range, 1.5-9 cm(2)). Patients were prospectively evaluated with the subjective International Knee Documentation Committee (IKDC), EuroQol visual analog scale (EQ-VAS), and Tegner scores preoperatively; at 1, 2, and 5 years; and at a final assessment at 9 years' mean follow-up. Adverse events and failures were also reported. RESULTS: A statistically significant improvement was observed in all scores from the initial evaluation to the final follow-up. The mean +/- standard deviation IKDC subjective score improved from 38.0 +/- 15.8 to 67.0 +/- 18.3 at 2 years (P < .0005), with a subsequent decrease to 57.8 +/- 20.6 at the final follow-up (P = .012). The same trend was confirmed by the EQ-VAS score. The activity level revealed by the Tegner score improved at all follow-ups but without achieving the preinjury level. The analysis of the influencing factors showed the importance of the meniscus condition, revealing a significantly inferior outcome in knees with previous or combined partial meniscectomy procedures. During the study period, 12 patients had failed results, producing a cumulative failure rate of 27.3%. At the last evaluation, half of the patients considered their condition not better than before the treatment, and 39% would not repeat the treatment considering the results obtained. CONCLUSION: Despite a statistically significant improvement, the clinical outcome was poor. A higher improvement could be obtained in patients who had not undergone previous or combined meniscectomies, but this was limited over time. The failure rate was also high, regardless of the degree of osteoarthritis. Tissue-engineered cartilage implantation is questionable for this indication, and the limits of this scaffold-based procedure have to be considered if it is used as a salvage procedure for young patients affected by knee osteoarthritis. PMID- 23104613 TI - Alcohol dependence in same-sex and opposite-sex twins. AB - Males with a female co-twin are more likely to become alcohol-dependent than males with a male co-twin. According to the twin testosterone transfer model, this finding can be interpreted as indirect evidence for a role of prenatal testosterone in alcohol dependence. PMID- 23104615 TI - Neural mechanisms of improvements in social motivation after pivotal response treatment: two case studies. AB - Pivotal response treatment (PRT) is an empirically validated behavioral treatment that has widespread positive effects on communication, behavior, and social skills in young children with autism spectrum disorder (ASD). For the first time, functional magnetic resonance imaging was used to identify the neural correlates of successful response to PRT in two young children with ASD. Baseline measures of social communication, adaptive behavior, eye tracking and neural response to social stimuli were taken prior to treatment and after 4 months of PRT. Both children showed striking gains on behavioral measures and also showed increased activation to social stimuli in brain regions utilized by typically developing children. These results suggest that neural systems supporting social perception are malleable through implementation of PRT. PMID- 23104616 TI - Executive function in MCDD and PDD-NOS: a study of inhibitory control, attention regulation and behavioral adaptivity. AB - A proportion of children within the autism spectrum is at risk for severe deregulation of thought, emotion and behaviour resulting in (symptoms of) psychotic disorders over the course of development. In an attempt to identify this subgroup, children with PDD-NOS, subtype MCDD (n = 24) were compared to children with PDD-NOS (n = 23) on executive function (EF) skills. Significant differences emerged, always to the disadvantage of the children with PDD-NOS, subtype MCDD on various EF measures. The findings suggest compromised attention regulation and impaired inhibitory control in children with MCDD, which may help explain high levels of thought problems which are frequently observed in these children. Our findings provide evidence for recognizing a PDD subcategory of MCDD that is of specific interest with regard to long-term developmental risks involved. PMID- 23104617 TI - Brief Report: social disability in autism spectrum disorder: results from Research Units on Pediatric Psychopharmacology (RUPP) Autism Network trials. AB - There is growing interest in measuring social disability as a core element of autism spectrum disorders in medication trials. We conducted a secondary analysis on the Aberrant Behavior Checklist Social Withdrawal subscale using data from two federally-funded, multi-site, randomized trials with risperidone. Study 1 included 52 subjects assigned to placebo and 49 subjects to risperidone under double-blind conditions. Study 2 included 49 subjects assigned to risperidone only and 75 subjects assigned to risperidone plus parent training. After 8 weeks of treatment, all active treatments were superior to placebo (effect sizes ranging from 0.42 to 0.65). The findings suggest that the Social Withdrawal subscale may be a useful measure of social disability in acute treatment trials. PMID- 23104614 TI - Bond orientational order in liquids: Towards a unified description of water-like anomalies, liquid-liquid transition, glass transition, and crystallization: Bond orientational order in liquids. AB - There are at least three fundamental states of matter, depending upon temperature and pressure: gas, liquid, and solid (crystal). These states are separated by first-order phase transitions between them. In both gas and liquid phases a complete translational and rotational symmetry exist, whereas in a solid phase both symmetries are broken. In intermediate phases between liquid and solid, which include liquid crystal and plastic crystal phases, only one of the two symmetries is preserved. Among the fundamental states of matter, the liquid state is the most poorly understood. We argue that it is crucial for a better understanding of liquids to recognize that a liquid generally has the tendency to have a local structural order and its presence is intrinsic and universal to any liquid. Such structural ordering is a consequence of many-body correlations, more specifically, bond angle correlations, which we believe are crucial for the description of the liquid state. We show that this physical picture may naturally explain difficult unsolved problems associated with the liquid state, such as anomalies of water-type liquids (water, Si, Ge, ...), liquid-liquid transition, liquid-glass transition, crystallization and quasicrystal formation, in a unified manner. In other words, we need a new order parameter representing a low local free-energy configuration, which is a bond orientational order parameter in many cases, in addition to a density order parameter for the physical description of these phenomena. Here we review our two-order-parameter model of liquid and consider how transient local structural ordering is linked to all of the above mentioned phenomena. The relationship between these phenomena is also discussed. PMID- 23104618 TI - Neurocognitive functioning in adolescents with autism spectrum disorder. AB - There is a paucity of research studying comprehensive neurocognitive profiles of adolescents with higher functioning autism spectrum disorders (ASD). This study compared the neurocognitive profiles of higher functioning adolescents with ASD (n = 30, mean age 13.5) with that of typically developing adolescents (n = 30; mean age 13.7). Adolescents with ASD demonstrated a significantly higher mean Verbal Intelligence Quotient compared to the standardized mean. However, the ASD group had significantly lower scores than the control group on the subtests Auditory Attention and Response Set, Memory for Faces, Visuomotor Precision, and Design Copying. Thus, particular strengths were seen in verbal reasoning, while weaknesses were observed in auditory attention, facial recognition memory, and visuomotor functions in adolescents with ASD. PMID- 23104620 TI - Treatment related problems for outpatients with chronic diseases in Jordan: the value of home medication reviews. AB - BACKGROUND: Research conducted in Jordan has shown that suboptimal use of medications by outpatients along with the suboptimal role played by community pharmacists is currently a big dilemma highlighting the need for the Home Medication Review (HMR) service in the country. OBJECTIVES: To evaluate the prevalence and types of treatment related problems (TRPs) for outpatients with chronic diseases. SETTING: Patient interview was conducted at the patients' community pharmacy initially, then at their home to collect required data. METHODS: 167 patients with chronic conditions (mean age 58.9 +/- 13.54, 53 % males) were recruited. Data collected by the graduate pharmacists to conduct a HMR included patient's demographics, income, laboratory data, medical history, medication record, and adherence. A HMR was conducted for each patient by the researchers (experienced clinical pharmacists) to identify the patients' TRPs based on published literature. A focus group interview was conducted to elicit information regarding the feasibility of the HMR process and acceptability of the patient to the service. MAIN OUTCOME MEASURE: Prevalence and nature of identified TRPs, associated diseases and drugs, and patients' acceptability to the HMR service. RESULTS: The mean number of disease conditions per patient was 4.1 +/- 1.7, and the mean number of medications taken by each patient was 8.1 +/- 2.7. HMR results showed a mean number of TRPs per patient of 7.4 +/- 2.8. TRPs prevalence: 34.7 % of patients were found to have unnecessary drug therapy; 68.3 % had untreated conditions, and 74.9 % had ineffective/incomplete drug therapy; 50.3 % had inappropriate dosage regimen; 10.2 % were found to have actual adverse drug effects. A significant correlation between the number of TRPs and the number of disease states the patient had (r = 0.311, p = 0.003; Pearson correlation) and the number of drugs the patient was taking (r = 0.443, p < 0.001) was found. Patients accepted the HMR service well including the home visiting part. CONCLUSION: TRPs in Jordanian outpatients with chronic diseases visiting community pharmacies are of concern and this signifies the integral role of pharmacists to identify these TRPs and hence provide the HMR service in the country. PMID- 23104619 TI - Multiple object tracking in autism spectrum disorders. AB - Difficulties in visual attention are often implicated in autism spectrum disorders (ASD) but it remains unclear which aspects of attention are affected. Here, we used a multiple object tracking (MOT) task to quantitatively characterize dynamic attentional function in children with ASD aged 5-12. While the ASD group performed significantly worse overall, the group difference did not increase with increased object speed. This finding suggests that decreased MOT performance is not due to deficits in dynamic attention but instead to a diminished capacity to select and maintain attention on multiple targets. Further, MOT performance improved from 5 to 10 years in both typical and ASD groups with similar developmental trajectories. These results argue against a specific deficit in dynamic attention in ASD. PMID- 23104621 TI - Characteristics of elderly patients who consider over-the-counter medications as safe. AB - BACKGROUND: There is a lack of studies evaluating the factors which influence the perception of safety of over-the-counter (OTC) medications by elderly patients. OBJECTIVE: The aim of our questionnaire survey was to evaluate the perception of the risk of OTC medications by elderly patients and to identify patient associated characteristics which determine elderly persons who consider OTC medications as safe. SETTING: 25 community pharmacies in different regions of the Slovak Republic. METHODS: A 54-items questionnaire was provided to patients aged >=65 years who were purchasing at least one OTC medication during the period from May 2010 to November 2010. The questions elicited information on (a) self assessment of health status; (b) basic characteristics of OTC medications use (e.g. frequency, duration); (c) patients' knowledge on OTC medications; (d) participants' perception of the risk of OTC medications; (e) the list of OTC and prescription-only medications taken; and (f) sociodemographic characteristics of respondents. RESULTS: Of the 793 questionnaires distributed, 519 were finally included in the statistical analysis (response rate of 65.4 %). Women were prevailing in the analysed group (n = 361; 69.6 %). The average age of participants was 72.2 +/- 5.6 years. Majority (n = 392, 75.5 %) of the respondents considered OTC medications as safe. Multivariate analysis (binary logistic regression) revealed that elderly patients who considered OTC medications as safe were characterised by use of OTC medications every day (OR = 2.09), preferring a wide range of such drugs in pharmacies (OR = 2.86), considering such medications as effective (OR = 10.33), obtaining information on OTC drugs from pharmacists (OR = 1.91) and willingness to possibly purchase OTC medications outside pharmacies (OR = 3.35). On the other hand, allergic conditions as a reason for purchasing OTC medications (OR = 0.23), recommendation of a physician regarding the choice of OTC medications (OR = 0.51) and considering concurrent use of several medications as a factor increasing the risk of adverse drug reactions (OR = 0.62) emerged as important factors that decreased the probability of elderly patients considering OTC medications as safe. CONCLUSIONS: The survey identified various factors that influenced the perceptions of the safety of OTC medications by the elderly and indicated that pharmacists represent the most trusted source of information about OTC medications. PMID- 23104622 TI - Intestinal lipomatosis detected on CT. PMID- 23104623 TI - Dynamics of heme complexed with human serum albumin: a theoretical approach. AB - Human serum albumin (HSA) is the most abundant protein in the blood serum. It binds several ligands and has an especially strong affinity for heme, hence becoming a natural candidate for oxygen transport. In order to analyze the interaction of HSA-heme, molecular dynamics simulations of HSA with bound heme were performed. Based on the results of X-ray diffraction, the binding site of the heme, localized in subdomain IB, was considered. We analyzed the fluctuations and their correlations along trajectories to detect collective motions. The role of H bonds and salt bridges in the stabilization of heme in its pocket was also investigated. Complementarily, the localization of water molecules in the hydrophobic pocket and the interaction with heme were discussed. PMID- 23104626 TI - [Knee diagnostics]. PMID- 23104625 TI - Properties of the electrogenic activity of bacteriorhodopsin. AB - In this study, we analyzed the photoelectric current generated by bacteriorhodopsin adsorbed on a polymer film, "Lumirror" (Muneyuki et al. in FEBS Lett 427:109-114, 1998). We could examine the photoelectric current over a wide range of light intensity and pH values using the same membrane owing to the mechanical and chemical stability of the thin polymer film. We analyzed the photoelectric current by comparison with a simple equivalent electric circuit. Analysis of experimental results obtained at different light intensities suggested that the electromotive force of the bacteriorhodopsin was independent of light intensity. The pH dependence of the photoelectric current suggested that the bacteriorhodopsin could generate a maximum electromotive force at approximately pH 6. PMID- 23104624 TI - Comparative studies of water permeability of red blood cells from humans and over 30 animal species: an overview of 20 years of collaboration with Philip Kuchel. AB - NMR measurements of the diffusional permeability of the human adult red blood cell (RBC) membrane to water (P(d)) and of the activation energy (E(a,d)) of the process furnished values of P(d) ~ 4 * 10(-3) cm/s at 25 degrees C and ~6.1 * 10(-3) cm/s at 37 degrees C, and E(a,d) ~ 26 kJ/mol. Comparative NMR measurements for other species showed: (1) monotremes (echidna and platypus), chicken, little penguin, and saltwater crocodile have the lowest P(d) values; (2) sheep, cow, and elephant have P(d) values lower than human P(d) values; (3) cat, horse, alpaca, and camel have P(d) values close to those of humans; (4) guinea pig, dog, dingo, agile wallaby, red-necked wallaby, Eastern grey kangaroo, and red kangaroo have P(d) values higher than those of humans; (5) mouse, rat, rabbit, and "small and medium size" marsupials have the highest values of P(d) (>8.0 * 10(-3) cm/s at 25 degrees C and >10.0 * 10(-3) cm/s at 37 degrees C). There are peculiarities of E(a,d) values for the RBCs from different species. The maximum inhibition of diffusional permeability of RBCs induced by incubation with p-chloromercuribenzene sulfonate varied between 0% (for the chicken and little penguin) to ~50% (for human, mouse, cat, sheep, horse, camel, and Indian elephant), and ~60-75% (for rat, guinea pig, rabbit, dog, alpaca, and all marsupials). These results indicate that no water channel proteins (WCPs) or aquaporins are present in the membrane of RBCs from monotremes (echidna, platypus), chicken, little penguin and saltwater crocodile whereas WCPs from the membranes of RBCs from marsupials have peculiarities. PMID- 23104627 TI - Solid pseudopapillary neoplasm of the pancreas. AB - Solid pseudopapillary neoplasms (SPNs) are rare entities accounting for between 0.13 and 2.7 per cent of pancreatic tumours. This neoplasm has a predilection for females under the age of 35. The authors report this case of a SPN incidentally discovered when a 59-year-old female underwent a chest x-ray to investigate a wheeze. A subsequent CT abdomen revealed a 10 cm well-circumscribed mass adjacent to the tail of the pancreas. This mass was successfully resected. Immunohistochemical markers established the diagnosis of a SPN. The wheeze associated with the presentation of this case was unrelated to the tumour which was an incidental finding. These neoplasms are largely asymptomatic and indolent reaching a large size before detection. Diagnosis is confirmed on histology and in this case surgical resection was curative and there was no metastasis at presentation. PMID- 23104628 TI - Lower thoracic spinal cord injury without radiographic abnormality in an amateur rugby player. AB - A 37-year-old man, amateur rugby player sustained a hyperextension injury to his lower thoracic spine during a scrum collapse. The patient developed extreme hyperpathia in the T10-12 dermatome, and parasthesia from T12 to S1 in the left lower limb. Medical Research Council grade 5 power was regained rapidly within minutes of the accident, and the hyperpathia resolved within a week. MRI showed contusion of the spinal cord at T10 level but no associated osseoligamentous injury. Six months later, parasthesia and subjective weakness remained in the left lower limb. To our knowledge, this is the first description of a lower thoracic spinal cord injury without radiographic abnormality following an isolated low-energy injury in a skeletally mature patient. PMID- 23104629 TI - Recurrent non-aneurysmal, metastatic intraparenchymal haemorrhages following resection of atrial myxoma - case report and literature review. AB - Atrial myxomas are the commonest cardiac neoplasms. The most common extra-cardiac manifestations are embolic infarcts from tumour embolisation. Infrequently, aneurysm formation and intracranial haemorrhages also occur. Incredibly rare are space-occupying lesions and malignant transformation. The authors report a case of a previously healthy middle-aged lady who developed recurrent and expanding intraparenchymal haemorrhages following resection of a left atrial myxoma without any primary disease recurrence. The case described is completely different from the described literature in that her intracranial vasculature was free of aneurysms on angiography despite central nervous system haemorrhage and no myxomatous or malignant features were seen on histology of the resected symptomatic occipital lesion. The authors compare this case to the available literature and also provide a literature review. PMID- 23104630 TI - Disseminated cryptococcosis in an HIV-positive boy. AB - Cryptococcosis is rare among children, only occurring in about 1% of children with HIV. We report the case of a 12-year-old boy with disseminated cryptococcosis. He had a history of recurrent pneumonia. He then developed meningeal symptoms and was found to have disseminated Cryptococcus neoformans by cerebrospinal fluid and bone marrow aspirate culture. He was treated with amphotericin B for 2 weeks (1 mg/kg/day), and then with fluconazole orally for 8 weeks (12 mg/kg/day). He also received a new diagnosis of HIV and was started on antiretroviral therapy 2 weeks after starting antifungal treatment. At follow-up 8 weeks later, he was doing well. PMID- 23104631 TI - Lipomeningomyelocele with tethered cord syndrome: an unusual cause of paraparesis in adults. PMID- 23104632 TI - No pain, no pathology? AB - A 22-year-old girl who had a background of reflux nephropathy and urinary tact infection presented during the night with renal angle pain and vomiting. She was treated on the emergency department (ED) pyelonephritis protocol and admitted to the short stay ward. When reviewed the next morning she was aymptomatic and feeling better. It seemed likely that she would be discharged but an ED ultrasound showed right-sided hydronephrosis and some fluid between the liver and the right kidney. CT examination confirmed the suspicion of renal tract obstruction and ruptured calyx. An 8 mm calculus was found to be the cause of the pathology. Urgent urological review was organised and the system formally decompressed with a J-J stent inserted cystoscopically later that day. PMID- 23104634 TI - Recurrent urinary tract infections in a patient with Crohn's disease. PMID- 23104633 TI - Solitary metachronous splenic metastasis from cutaneous melanoma. AB - Melanoma has been found to metastasise to the spleen, usually in cases of disseminated disease. Solitary splenic metastasis from cutaneous melanoma is very rare. Herein we report the case of a 43-year-old man who developed solitary splenic metastasis from cutaneous melanoma. The patient was operated for T(4b) N(1a) Mo superficial spreading melanoma of the anterior thoracic wall. He subsequently underwent left axillary lymph node dissection due to a positive sentinel lymph node. The 33 retrieved lymph nodes were negative for metastasis. The patient received adjuvant therapy with high-dose interferon alpha-2b. After 27 months and during the follow-up visit an increasing lactate dehydrogenase serum level was observed. Furthermore, CT of the whole body revealed a solitary hypodense tumour of the spleen 9 cm*6 cm. Curative splenectomy was performed and the histopathological report confirmed metastatic melanoma to the spleen. PMID- 23104635 TI - Massively enlarged styloid process presenting as a submandibular mass. AB - A 47-year-old man is investigated in the ear, nose and throat department for a 6 month history of left submandibular swelling and pain. He underwent several investigations, before a large styloid process was found on CT imaging of the neck. The patient underwent surgical excision of the enlarged styloid process and stylohyoid ligament. He recovered well with no long-term complications and his symptoms were fully resolved. PMID- 23104636 TI - Prevention of stent thrombosis with reduced dose of prasugrel in two patients undergoing treatment of cerebral aneurysms with pipeline embolisation devices. AB - Prevention of intracranial stent thrombosis with dual-antiplatelet therapy is widely used in neuroendovascular procedures. However, the rising incidence of inadequate platelet inhibition with clopidogrel may increase complications following stent placement, especially with newer devices that possess a larger total metal surface area. While there are recent reports of prasugrel as an alternative to clopidogrel, there is no clinical evidence in neurointerventional patients regarding the use of a lower maintenance dose as an alternative strategy to gain adequate platelet inhibition while possibly reducing the risk of bleeding. We present 6-month efficacy and safety outcomes of two patients undergoing elective pipeline embolisation that were found to have inadequate platelet response to clopidogrel and subsequently transitioned to prasugrel 5 mg daily for the prevention of stent thrombosis. PMID- 23104637 TI - Bis(thiosemicarbazone) copper complexes: mechanism of intracellular accumulation. AB - The molecular basis of Alzheimer's disease has not been clearly established, but disruption of brain metal ion homeostasis, particularly copper and zinc, might be closely involved in the pathogenesis of this disease and its characteristic beta amyloid neuropathological features. The use of complexes of copper with bis(thiosemicarbazones) ([Cu(btsc)]) has been proposed for the treatment of Alzheimer's disease. Their mode of action could involve modulation of the concentration of copper or zinc, and it has been suggested that the compounds can modulate the production of beta-amyloid peptide at the neuron level. Furthermore, it has been reported that [Cu(btsc)] complexes can be reduced inside the cells. However, to our knowledge the intracellular reduction of these compounds has never been demonstrated. Thus, the goal of our study was to increase understanding of the mechanism of intracellular accumulation of [Cu(btsc)] complexes. Our results reveal that the intracellular concentration of copper inside the cells is very high and that these compounds are not P-glycoprotein substrates. This protein is a key element of the low permeability properties of the blood-brain barrier. Furthermore, no intracellular reduction of cupric ions was detected. Finally, once inside the cells, the complexes undergo aggregation, strongly suggesting that aggregation of complexes is the driving force responsible for their intracellular accumulation. PMID- 23104638 TI - Heart rate in coronary artery disease: should we lower it? AB - OPINION STATEMENT: Elevated resting heart rate is an independent risk factor for cardiovascular morbidity and mortality in patients with and without coronary artery disease. In patients with known coronary artery disease, elevated heart rate reduces diastolic filling time and increases cardiac workload, resulting in supply demand mismatch with consequent ischemia and angina. While lower heart rate is associated with better prognosis, it is not known if pharmacological reduction in heart rate is beneficial and if heart rate is merely a marker for increased risk and worse outcomes. Certainly, physiologically lower resting heart rate as attained by exercise improves morbidity and mortality. While physiological reduction in heart rate is mainly a manifestation of increased parasympathetic drive, pharmacological reduction of heart rate with beta-blockers is mediated via the sympathetic pathway and associated with mixed outcomes. In addition, beta-blockers have other cardiovascular effects (lowering blood pressure), are metabolically active, and it is unknown if the beneficial effects (if any) are mediated via reduction in heart rate versus other cardiovascular effects. Ivabradine is a new medication that lowers heart rate selectively by inhibiting the I(f) current without other cardiovascular effects, offering for the first time a therapeutic agent that selectively targets heart rate. The medication has shown promise in early trials in patients with heart failure, but it is unclear if this agent will be beneficial in patients with stable coronary artery disease without heart failure. PMID- 23104639 TI - The vascular endothelial growth factor (VEGF) +405 G/C polymorphism and its relationship with recurrent implantation failure in women in an IVF programme with ICSI. AB - PURPOSE: Successful embryo implantation depends on trophoblast proliferation, migration and, lastly, invasion of the endometrium (to anchor the trophoblast to the uterus). This invasion is mediated by locally produced soluble factors. Of these, vascular endothelial growth factor (VEGF) is the best characterized regulator of angiogenesis. Here, we investigate the association between the VEGF + 405 C/G genotype and the recurrence of embryo implantation failure in women undergoing in vitro fertilization (IVF) program with intracytoplasmic sperm injection (ICSI). METHODS: Forty women with recurrent implantation failure defined by absence of pregnancy after transfer of more than 10 embryos and 131 women control, with at least one live birth after the transfer of fewer than 10 embryos were included. Genomic DNA was analysed with an allele-specific polymerase chain reaction and a Chi-2 test was used to compare the respective VEGF + 405 C/G genotype frequencies in cases and controls. RESULTS: The frequency of the VEGF +405C/C genotype was higher in women with recurrent implantation failure after ICSI-embryo transfer than in controls (17.5 % and 5.3 %, respectively, p = 0.01). CONCLUSION: The VEGF +405 G/C polymorphism may influence embryo implantation and VEGF + 405 C/C genotype may predispose to recurrent implantation failure after ICSI-ET. PMID- 23104640 TI - Endoglin (CD105) is not a specific selection marker for endothelial cells in human islets of Langerhans. PMID- 23104642 TI - Protective and survival efficacies of Rv0160c protein in murine model of Mycobacterium tuberculosis. AB - The proline-glutamic acid (PE) and proline-proline-glutamic acid (PPE) multi-gene families code for approximately 10% of the Mycobacterium tuberculosis (Mtb) genome. These proteins are thought to be virulence factors that participate in impounding the host immune responses. While some members have been studied, the functions of most PE/PPE proteins are yet to be explored. The studies presented here have specifically characterized the roles of one of the PE proteins of Mtb, Rv0160c (PE4), in mycobacterial persistence and in prophylactic efficacy. We have expressed Rv0160c in a non-pathogenic fast-growing Mycobacterium smegmatis strain and demonstrated that the protein improves the survival of mycobacteria in macrophages and in mice. The protein has also shown its effect under physiological stress of bacteria, as evidenced by elevated expression in acidic and in hypoxic conditions. In mice, the level of Rv0160c was noticeably high during the chronic stage of tuberculosis. The seroreactivity of the protein against different categories of tuberculosis patients revealed a strong B-cell humoral response in freshly infected pulmonary tuberculosis patients. In mice, it exhibited increased IL-2, TNF, and IL-6 production. The antigenic properties of the protein directed towards the protective efficacy against the Mtb challenge. All together, our findings have identified Rv0160c as an in vivo expressed immunodominant antigen which plays a crucial role in the pathogenesis of mycobacterial disease and could prove to be a good preventive antigen for tuberculosis. PMID- 23104641 TI - A nuclear phylogenetic analysis: SNPs, indels and SSRs deliver new insights into the relationships in the 'true citrus fruit trees' group (Citrinae, Rutaceae) and the origin of cultivated species. AB - BACKGROUND AND AIMS: Despite differences in morphology, the genera representing 'true citrus fruit trees' are sexually compatible, and their phylogenetic relationships remain unclear. Most of the important commercial 'species' of Citrus are believed to be of interspecific origin. By studying polymorphisms of 27 nuclear genes, the average molecular differentiation between species was estimated and some phylogenetic relationships between 'true citrus fruit trees' were clarified. METHODS: Sanger sequencing of PCR-amplified fragments from 18 genes involved in metabolite biosynthesis pathways and nine putative genes for salt tolerance was performed for 45 genotypes of Citrus and relatives of Citrus to mine single nucleotide polymorphisms (SNPs) and indel polymorphisms. Fifty nuclear simple sequence repeats (SSRs) were also analysed. KEY RESULTS: A total of 16 238 kb of DNA was sequenced for each genotype, and 1097 single nucleotide polymorphisms (SNPs) and 50 indels were identified. These polymorphisms were more valuable than SSRs for inter-taxon differentiation. Nuclear phylogenetic analysis revealed that Citrus reticulata and Fortunella form a cluster that is differentiated from the clade that includes three other basic taxa of cultivated citrus (C. maxima, C. medica and C. micrantha). These results confirm the taxonomic subdivision between the subgenera Metacitrus and Archicitrus. A few genes displayed positive selection patterns within or between species, but most of them displayed neutral patterns. The phylogenetic inheritance patterns of the analysed genes were inferred for commercial Citrus spp. CONCLUSIONS: Numerous molecular polymorphisms (SNPs and indels), which are potentially useful for the analysis of interspecific genetic structures, have been identified. The nuclear phylogenetic network for Citrus and its sexually compatible relatives was consistent with the geographical origins of these genera. The positive selection observed for a few genes will help further works to analyse the molecular basis of the variability of the associated traits. This study presents new insights into the origin of C. sinensis. PMID- 23104643 TI - Monascus pigments. AB - Monascus pigments (MPs) as natural food colorants have been widely utilized in food industries in the world, especially in China and Japan. Moreover, MPs possess a range of biological activities, such as anti-mutagenic and anticancer properties, antimicrobial activities, potential anti-obesity activities, and so on. So, in the past two decades, more and more attention has been paid to MPs. Up to now, more than 50 MPs have been identified and studied. However, there have been some reviews about red fermented rice and the secondary metabolites produced by Monascus, but no monograph or review of MPs has been published. This review covers the categories and structures, biosynthetic pathway, production, properties, detection methods, functions, and molecular biology of MPs. PMID- 23104644 TI - Antrodia camphorata ATCC 200183 sporulates asexually in submerged culture. AB - Antrodia camphorata is a well-known Chinese medicinal mushroom that protects against diverse health-related conditions. Submerged fermentation of A. camphorata is an alternative choice for the effective production of bioactive metabolites, but the effects of nutrition and environment on mycelial morphology are largely unknown. In this study, we show that A. camphorata American Type Culture Collection 200183 can form arthrospores in the end of liquid fermentation. Different morphologies of A. camphorata in submerged culture were analyzed using scanning electron microscopy. The optimal carbon and nitrogen sources for sporulation were soluble starch and yeast extract. We found that a carbon-to-nitrogen ratio (C/N) of 40:1, MgSO4 (0.5 g/l), KH2PO4 (3.0 g/l), an initial pH 5.0, and an inoculum size of 1.5*10(5) spores/ml led to maximum production of arthroconidia. Our results will be useful in the regulation and optimization of A. camphorata cultures for efficient production of arthroconidia in submerged culture, which can be used as inocula in subsequent fermentation processes. PMID- 23104645 TI - Culture medium optimization of a new bacterial extracellular polysaccharide with excellent moisture retention activity. AB - A new kind of extracellular polysaccharide (EPS) from Pseudomonas fluorescens PGM37 was obtained and culture media was optimized using the statistical methods single factor experiments and response surface methodology (RSM) design. As a result, the optimum cultivation conditions initial pH value, medium volume, inoculum size, temperature, and rotation speed were 7.5, 100 mL/250 mL, 5%, 28 degrees C, and 180 rpm, respectively. The optimized media: sucrose 36.23 g L(-1), yeast extract 3.32 g L(-1), sodium chloride 1.13 g L(-1), and calcium chloride 0.20 g L(-1). The maximum predicted yield of EPS was 10.1163 g L(-1) under these conditions. The validation data was 10.012 g L(-1), which could strongly confirm the correlation between the experimental and theoretical values. Gas Chromatography analysis revealed that the polymer was made up of mannose and glucose in the ratio of 1:1. Infrared spectroscopy showed that the polysaccharide had beta-D-pyranoid configuration and contained no other substituent. Graded by different multiples of alcohol after specific degradation by enzyme and then detected by LC-ESI-MS, the EPS structure was beta-D-Glcp-(1, 4)-beta-D-Manp-(1, 4)-beta-D-Glcp-(1, 4)-beta-D-Manp. The moisture retention ability of the EPS was found to be superior to glycerol and only a little inferior to hyaluronic acid (HA), which presented potential application value in cosmetics and clinical medicine fields. PMID- 23104646 TI - Effects of encapsulation of microorganisms on product formation during microbial fermentations. AB - This paper reviews the latest developments in microbial products by encapsulated microorganisms in a liquid core surrounded by natural or synthetic membranes. Cells can be encapsulated in one or several steps using liquid droplet formation, pregel dissolving, coacervation, and interfacial polymerization. The use of encapsulated yeast and bacteria for fermentative production of ethanol, lactic acid, biogas, L-phenylacetylcarbinol, 1,3-propanediol, and riboflavin has been investigated. Encapsulated cells have furthermore been used for the biocatalytic conversion of chemicals. Fermentation, using encapsulated cells, offers various advantages compared to traditional cultivations, e.g., higher cell density, faster fermentation, improved tolerance of the cells to toxic media and high temperatures, and selective exclusion of toxic hydrophobic substances. However, mass transfer through the capsule membrane as well as the robustness of the capsules still challenge the utilization of encapsulated cells. The history and the current state of applying microbial encapsulation for production processes, along with the benefits and drawbacks concerning productivity and general physiology of the encapsulated cells, are discussed. PMID- 23104647 TI - Patient-reported outcomes (PROs): the significance of using humanistic measures in clinical trial and clinical practice. AB - Patient-reported outcome (PRO) is an "umbrella term" that covers a whole range of potential types of measurement but it is used specifically to refer to all measures quantifying the state of health through the evaluation of outcomes reported by the patient himself/herself. PROs are increasingly seen as complementary to biomedical measures and they are being incorporated more frequently into clinical trials and clinical practice. After considering the cultural background of PROs - that is the well known patient-centered model of medicine -, their historical profile (since 1914, the year of the first outcome measure) and typologies, the paper aims at debating their methodological complexity and implementation into practice. Some clinical trials and therapeutic managements utilizing patient-centered measures will be also analyzed. PMID- 23104648 TI - Secondary hemophagocytic lymphohistiocytosis in zoonoses. A systematic review. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome that is often fatal despite treatment. It is caused by a dysregulation in natural killer T-cell function, resulting in activation and proliferation of histiocytes with uncontrolled hemophagocytosis and cytokines overproduction. The syndrome is characterized by fever, hepatosplenomegaly, cytopenias, liver dysfunction, and hyperferritinemia. HLH can be either primary, with a genetic aetiology, or secondary, associated with malignancies, autoimmune diseases, or infections. AIM: To focus on secondary HLH complicating zoonotic diseases. MATERIALS AND METHODS: PubMed search of human cases of HLH occurring during zoonotic diseases was performed combining the terms (haemophagocytic or haemophagocytosis or hemophagocytosis or hemophagocytic or erythrophagocytosis or macrophage activation syndrome) with each one of the etiological agents of zoonoses. RESULTS: Among bacterial diseases, most papers reported cases occurring during brucellosis, rickettsial diseases and Q fever. Regarding viral diseases, most of the cases were reported in patients with avian influenza A subtype H5N1. Among the protozoan zoonoses, most of the cases were reported in patients with visceral leishmaniasis. Regarding zoonotic fungi, most of the cases were reported in AIDS patient with histoplasmosis. No cases of secondary HLH were reported in patient with zoonotic helminthes. CONCLUSIONS: Zoonotic diseases are an important cause of HLH. Secondary HLH can delay the correct diagnosis of the zoonotic disease, and can contribute to an adverse outcome. PMID- 23104649 TI - Leishmania mexicana: expression; characterization and activity assessment of E. coli-expressed recombinant CRK3. AB - OBJECTIVES AND METHODS: Previous studies have shown that CRK3 protein kinase of Leishmania mexicana is a potential drug target. Therefore, the aim of this study was to provide an active protein kinase for chemical inhibitors testing. A system was developed to express and affinity-purify recombinant L. mexicana CRK3 protein from Escherichia coli. RESULTS: Biochemical analysis has confirmed the expression of the pure kinase. The bacterial-expressed kinase was found to be inactive as a monomer. The mutated CRK3-E178 protein kinase was also found to be inactive. CONCLUSION: This study suggests that cyclin binding and phosphorylation status are both important for reconstituting protein kinase activity. Work presented by this paper has confirmed the usefulness of the prokaryotic system for production of pure homogenous recombinant protein kinase of Leishmania parasite, though this system is unable to produce active CRK3 protein kinase PMID- 23104650 TI - Aripiprazole, alcohol and substance abuse: a review. AB - Aripiprazole is an atypical antipsychotic used for schizophrenia, manic and mixed episodes associated with bipolar I disorder and as adjunctive therapy for major depressive disorder. It functions as a partial agonist at dopamine D2 and 5-HT1A receptors, and as an antagonist at the 5-HT2A receptor. The most recent results obtained from scientific research showed that dopaminergic mechanisms are involved in motivation, reward, and reinforcement of substance abuse. The use of aripiprazole and partial dopamine agonists could represent a novel strategy for normalizing dopamine neurotransmission. Many studies in the last few years have highlighted aripiprazole as a potential candidate for the treatment of different types of substance dependence. This review aims to describe recent scientific research using aripiprazole in different substance abuse disorders (i.e., alcoholism, cocaine, amphetamine and nicotine use). Furthermore, the efficacy of aripiprazole compared to other pharmacological therapies will be described. Given the low number of studies, the frequent absence of placebo or active comparators, and the low statistical power of the studies, a clear conclusion about the use of aripiprazole in alcohol/substance dependence cannot be drawn. Therefore, we suggest the need for further studies, preferably randomized and placebo-controlled. PMID- 23104651 TI - Identifying crosstalk of mTOR signaling pathway of lobular breast carcinomas. AB - BACKGROUND: Invasive lobular carcinoma (ILC) and its variants represent 5% to 15% of all invasive breast cancers diagnoses annually. AS a serine/threonine kinase, mammalian target of rapamycin (mTOR) is often a downstream effector of PI3K/Akt (phosphatidyl inositol 3-kinase/protein kinase B) signaling pathway in breasts and many types of cancer cells. Therefore, agents that target mTOR in direct or indirect manner are being developed in anti-cancer therapy. AIM: In this study, our objective here was to explore more crosstalk pathway with mTOR signaling pathway. MATERIALS AND METHODS: We collected pathways data from published database, then based on bioinformatics methods we analyzed the significant pathways in the database, additionally, the crosstalk pathways were also analyzed which were defined as those pathways which have the overlapping genes with each other. RESULTS: As we expected, the results showed that Notch signaling pathway (hsa04330), Regulation of autophagy (hsa04140), and Adipocytokine signaling pathway (hsa04920) were linked to mTOR signaling pathway. All of them have been demonstrated participate in breast cancer progression. CONCLUSIONS: We obtained some key pathways that crosstalked with mTOR signaling pathway, we hope our study could provide novel therapeutic approaches for breast cancer. PMID- 23104652 TI - Bioinformatics analysis reveals potential candidate drugs for psychological stress in ovarian cancer. AB - BACKGROUND: Women with ovarian cancer may be at increased risk for psychological distress around the time of diagnosis relative to patients diagnosed with other cancers, because of the seriousness of the disease. However, the molecular mechanism of this effect is far from clear. AIM: We sought to investigate the influence of psychological status in regulating gene expression among women with primary ovarian cancer and to identify the small molecules which exhibit similar effects with different psychological status. MATERIALS AND METHODS: DNA microarray analyses of 10 ovarian carcinomas (GSE9116, downloaded from GEO) identified 916 human transcripts that were differentially expressed in tumors from patients with high depression relative to grade-and stage-matched tumors from low depression patients, and pathways related to immune system were dysfunctional. RESULTS: Our results suggest that psychosocial stress is related to impaired immunity in ovarian cancer patients. Besides, we identified a group of small molecules which can be exploited as adjuvant drug to improve therapeutic effect for ovarian cancer, such as MS-275 and adiphenine. CONCLUSIONS: Our findings may be useful for the development of management strategies for psychological distress, and we suggest that there is a need for improvement in the quality of life of cancer outpatients being treated with chemotherapy. PMID- 23104653 TI - Prognostic significance of tyrosinase expression in sentinel lymph node biopsy for ultra-thin, thin, and thick melanomas. AB - BACKGROUND: Investigate if the tyrosinase mRNA expression may be predictive of the outcome on ultra-thin, thin, and thick melanoma patients. AIM: In our study, we sought to correlate tyrosinase mRNA expression to the outcome in a group of 71 patients with thick, thin and ultra-thin melanomas. MATERIALS AND METHODS: 71 patients with melanomas underwent a SLNB (sentinel lymph node biopsy) at the "Sapienza" University of Rome. Among these, 38 patients had thin melanomas, while the other 33 patients had thick melanomas. In every patient's sample histology, immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) was completed. We then correlated tyrosinase mRNA expression to the statistical analysis of the outcome of patients. RESULTS: Positivity of histology was found in one patient (1.4%), immunohistochemistry in five patients (7%), and tyrosinase in 52/71 (73.2%). Thickness and tyrosinase positivity were predictive for disease progression (p < 0.05). The median follow-up was 58.24 months. There were recurrences and/or deaths in both groups of patients. CONCLUSIONS: Nodal metastasis in melanoma is uncommon, especially in patients with thin melanomas. In this study, histology and immunohistochemistry were found to be non predictive for the risk of nodal metastases, while instead, tyrosinase m-RNA expression appeared to play a role in highlighting those patients with a risk of disease progression. Moreover, no differences among the thin melanoma groups of patients (0.30-0.75 mm and 0.76-1.00 mm) were observed. PMID- 23104654 TI - Non-AIDS-defining cancers among HIV-infected people. AB - The natural history of HIV infection has been greatly changed by the introduction of highly active antiretroviral therapy (HAART). As a consequence of improved immune function, the incidence of AIDS-defining cancers (ADCs), such as Kaposi's sarcoma, non-Hodgkin's lymphoma (NHL) and invasive cervical cancer, has significantly declined. On the contrary, non-AIDS-defining cancers (NADCs), such as hepatocellular carcinoma, anal cancer, lung cancer, colorectal cancer and Hodgkin's lymphoma, have gradually emerged as a major fraction of the overall cancer burden. The reasons are still partially unknown. Some of the increased risk may be explained by a high prevalence of cancer risk factors, such as smoking, alcohol consumption, human papilloma virus (HPV) infection and HCV infection among HIV-infected people. The role of immunosuppression in the development of NADCs is controversial, as several studies have not found a clear cut evidence of an association between the degree of immunosuppression and the development of NADCs. Analogously, the impact of HAART is still not well defined. Future research should focus on the etiology of NADCs, in order to shed light on the pathogenesis of cancer and ultimately to work for prevention; moreover, additional studies should evaluate the best therapeutic approaches to NADCs and the impact of cancer screening interventions among HIV-infected people, in an effort to diagnose cancer at an earlier stage. PMID- 23104655 TI - Gene variants with suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. AB - BACKGROUND: Risk factors for suicide are at least partially heritable and functional polymorphisms of targeted genes have been suggested to be implicated in the pathogenesis of this phenomenon. However, other studies examining the association between specific gene variants and suicide revealed inconsistent findings. We aims to evaluate the possible association between MAO-A3, CYP1A2*1F and GNB3 gene variants, hopelessness and suicidal risk in a sample of subjects with chronic migraine and affective temperamental dysregulation. METHODS: 56 women were genotyped for MAO-A3, CYP1A2*1F and GNB3 gene variants. Participants were also assessed using Beck Hopelessness Scale (BHS), the Temperament Evaluation of the Memphis, Pisa, Paris and San Diego-Autoquestionnaire (TEMPS-A), and the Suicidal History Self-Rating Screening Scale (SHSS). RESULTS: Patients with higher total scores on affective dysregulated temperaments are more likely to have higher BHS (11.27+/=5.54 vs. 5.73+/=3.81; t19.20 = -3.57; p < 0.01) and higher SHSS total scores (4.79+/=3.31 vs. 1.05+/-2.31; t17.74 = -3.90; p < 0.001) than those with lower total scores. 67% of patients in the dysregulated group has BHS total scores >= 9 indicating high levels of hopelessness. No association was found between MAO-A3, CYP1A2*1F and GNB3 gene variants and suicidal risk as assessed by BHS and SHSS. CONCLUSIONS: This study did not sustain the association between MAO-A3, CYP1A2*1F and GNB3 gene variants and increased suicidal risk in patients with chronic migraine and affective temperamental dysregulation. Further studies investigating the gene-environment interaction or focusing on other genetic risk factors involved in suicidal behaviour are needed. PMID- 23104657 TI - The effectiveness of extracorporeal shock wave lithotripsy in the treatment of ureteral stones in children. AB - PURPOSE: In our study, we evaluated retrospectively the efficacy of extracorporeal shock wave lithotripsy (ESWL) in the treatment of ureteral stones in children. MATERIALS AND METHODS: Between the dates of 2005-2010, 62 children who were applied ESWL due to the ureteral stone in our Clinic and consisted of 42 males and 20 girls whose mean age was 6.6+/=3.1 were evaluated. 31 (50%) of the patients were upper ureteral stone, 10 (16.1%) of them were middle ureteral stone and 21 (33.9%) of them were lower ureteral stone. The sizes of the stones were 4 to 17 mm, the average was 7.1 mm. ESWL was performed in the supine position for upper ureteral stones, in the supine/prone position for middle and lower ureteral stones. RESULTS: Stone-free rate was determined as 93.5% in three-month follow-up of the patients. Re-treatment was done at 14.5% of the patients. The implementation of ESWL was ended unsuccessfully at 4 children (6.5%). A significant difference was not detected between three-month stone-free rates in terms of the size of the stones and location. There was not any serious complication at any of the patients. CONCLUSIONS: According to these findings ESWL with its high stone-free rates and negligible complications is the first method to be refered in the treatment of ureteral stones in children. PMID- 23104656 TI - Risk factors for maternal mortality in eclampsia: analysis of 167 eclamptic cases. AB - BACKGROUND: The aim of this study was to evaluate risk factors associated with maternal mortality in patients with eclampsia. METHODS: The probable risk factors of maternal mortality including maternal age, length of hospital stay, gestational age, systolic and diastolic blood pressures; hematocrit, hemoglobin, platelet count, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase were determined from patients' charts and Odds ratios (OR) of these factors were detected using by logistic regression analysis. RESULTS: According to logistic regression model, AST [OR, (95% Confidence Interval, CI): 7.39 (2.71-20.13)]; ALT [6.45 (2.42-17.16)]; postpartum diastolic blood pressure [4.58 (1.80-11.62)]; hematocrit [3.52 (1.86 6.65)]; hemoglobin [2.67 (2.01-3.55)] were found to be significant risk factors for maternal mortality. CONCLUSIONS: In eclamptic patients, close monitoring of particular laboratory values and blood pressure, and early intervention to alterations of certain variables will provide possibility for prevention against potential complications and subsequently decreasing mortality. PMID- 23104658 TI - Effectiveness and safety assessment of lamotrigine monotherapy for treatment of epilepsy. AB - BACKGROUND: Epilepsy is a recurrent chronic nervous system disease. A correct choice of antiepileptic drug is the key to control seizures and improve patient's life quality. AIM: To study the effectiveness and safety of lamotrigine monotherapy for treatment of epilepsy, systemic evaluation was carried out on published comparative trials between lamotrigine and carbamazepine. METHODS: The retrieval method referred to the search strategy developed by Cochrane Epilepsy Group and software Rev.Man 5 was used for META analysis and forest plots. The Odds ratio (OR) was selected as the effect size and funnel plot was used to analyze the publication bias. RESULTS: A total of 9 studies and 2269 cases of patients were included in the analysis. There was no significant difference between lamotrigine and carbamazepine for treatment of epilepsy as the OR was 1.17, 95% confidence interval (CI) [0.88, 1.54]. However, lamotrigine had advantages in the overall withdrawal rate and withdrawal rate due to side effects as the ORs were 0.57, 95% CI [0.47, 0.69] and 0.41, 95% CI [0.32, 0.52]. CONCLUSIONS: Lamotrigine has certain advantages over carbamazepine for treatment of epilepsy as it has less side effects and higher tolerability. In addition, the quality of such clinical trials should be further improved to have a more comprehensive understanding. PMID- 23104659 TI - Haemophagocytic syndrome in rheumatic patients. A systematic review. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH), is a potentially fatal hyperinflammatory syndrome characterized fever, hepatosplenomegaly, and cytopenias. HLH can be either primary, with a genetic aetiology, or secondary, associated with malignancies, autoimmune diseases, or infections. Among rheumatic disorders, HLH occurs most frequently in systemic juvenile idiopathic arthritis. AIM: To draw attention on this severe syndrome that may often go undiagnosed in patient with rheumatic diseases. MATERIALS AND METHODS: PubMed search was performed by combining the terms (haemophagocytic, haemophagocytosis, hemophagocytosis, hemophagocytic, erythrophagocytosis, macrophage activation syndrome) and (rheumatic, rheumatologic, arthritis, lupus, Sjogren's syndrome, scleroderma, polymyositis, dermatomyositis, polymyalgia rheumatic, mixed connective tissue disease, polychondritis, sarcoidosis, polyarteritis nodosa, Henoch-Schonlein, serum sickness, wegener's granulomatosis, giant cell arteritis, temporal arteritis, Takayasu's arteritis, Behcet's syndrome, Kawasaki, Buerger's). RESULTS: 117 papers describing 421 patients were considered. HLH was described in systemic lupus erythematosus in 94 patients, in Still's disease in 37 patients, in rheumatoid arthritis in 13 patients, in systemic juvenile arthritis in 219 patients, in dermatomyositis in 7 patients, in Kawasaki disease in 25 patients, in systemic sclerosis in 5 patients, in Behcet disease in one patient, in polyarteritis nodosa in 6 patients, in ankylosing spondylitis in 2 patients, in mixed connective tissue disease in one patient, in sarcoidosis in 5 patients, in Sjogren's syndrome in 3 patients, in Wegener's granulomatosis in one patient, and in unclassifiable disorders in two patients. CONCLUSIONS: HLH occurring in the course of rheumatic diseases is an important and often underdiagnosed clinical entity, which can affect prognosis. PMID- 23104660 TI - The accuracy of CBCT in measuring jaws bone density. AB - BACKGROUND: The cone-beam computerized tomography (CBCT) has become widely used for oral and maxillofacial imaging, providing a good spatial resolution, gray density range, and contrast, as well as a good pixel/noise ratio. In the CBCT the dimensional accuracy is also comparable with Computer Tomography (CT), but in contrast to the CT, the gray density values of the CBCT images (voxel value [VV]) are not absolute. AIM: The aim of the study was to evaluate if there is a statistically significant difference in bone density values, defined as gray density values (VV), using two different CBCT exposure radiation (8 mAs or 15 mAs). MATERIALS AND METHODS: 10 dry mandibles were CBCT scanned using two different exposure radiation (8 mAs or 15 mAs). Using software and a radiographic template, the CBCT-scan images were overlapped and two datasets were created, each one giving the respective gray values (VV), of the same area with the same spatial coordinates. The quantified gray density values of the planned volume were measured and expressed as VV in two different exposure radiation scans Groups (Group A: 8 mAs; Group B: 15 mAs). For the statistical analysis, t-test was used. RESULTS: The differences between the CBCT gray density values (VV) of the Groups (Group A: 8 mAs; Group B: 15 mAs) were statistically significant (p <= .05). CONCLUSIONS: This study demonstrated that the use of a CBCT to evaluate the bone density of jaws is not useful when the values are taken as absolute values. In spite of the lower radiation dose and costs of CBCT, this new technique does not allow an accurate assessment of bone density. PMID- 23104661 TI - New parameter for the evaluation of disgnathic patient's surgical planning: a preliminary report. AB - BACKGROUND: Indications for treatment of patients with maxillo-mandibular malformations have to be researched both in the severity of anatomical alteration affecting the face and psychological outcomes. Indeed, it has been underlined that patients decide to undergo orthodontic and orthognathic procedure mainly for aesthetical issues. Moreover the early combined functional and surgical treatment improves relationship skills in young adults. Dealing with these "aesthetic" features pre surgical planning presents some additional challenges. Even if orthognatic surgery aims to the correct repositioning of skeletal bases but we must achieve complete patient satisfaction. AIM: The Authors present a new parameter to be considered in the planning of patients who undergo orthognatic procedure being the restitution of the face the patient would have had without any pathologic mechanism with respect of the aesthetic features of the family. MATERIALS AND METHODS: Authors identified a series of parameters discussed by Arnett et al and performed a clinical and photographic evaluation of these parameters, in latero-lateral view, directly on the relatives of the patients. A cephalometric analysis, was performed and a series of parameters has been taken into account. CONCLUSIONS: It is very difficult to standardize universal parameters acceptable and applicable for every single case, considering that patient's awareness of the anatomical defect and post-surgical satisfaction don't relate to the correct cephalometric evaluation and the real aesthetic outcomes. PMID- 23104662 TI - Low values of left ventricular ejection time in the post-anhepatic phase may be associated with occurrence of primary graft dysfunction after orthotopic liver transplantation: results of a single-centre case-control study. AB - BACKGROUND: Previous investigations on risk factors for orthotopic liver transplantation (OLT) surgery have not analyzed hemodynamic aberrations in great detail. Moreover, the usefulness of esophageal Doppler monitoring has not been extensively studied in this clinical setting. The aim of this study was to evaluate if the occurrence of primary graft dysfunction (PGD) may be anticipated by hemodynamic indexes measured by esophageal Doppler (ED) monitoring system as well as by pulmonary artery catheter (PAC) in patients undergoing OLT. MATERIALS AND METHODS: 38 OLT recipients were studied. Patients with acute liver failure or having non treated esophageal varices and those transplanted with marginal donors were excluded from the study. The haemodynamic data - measured by ED monitoring system (HemosonicTM 100, Arrow, OK, USA) and PAC - collected at the following 3 time points were considered for statistical analysis: 30 minutes after the induction of anesthesia but before skin incision, T0; 20 minutes after liver dissection, T1; at the beginning of biliary reconstruction, T2. On the basis of early outcome (72 hours after OLT), patients were distinguished into two groups: those with PGD (grade III-IV of Toronto classification) and those without PGD (grade I-II). RESULTS: LVETc (left ventricular ejection time) values, registered at the beginning of biliary reconstruction (T2), were lower in patients with PGD compared to those without PGD (p < 0.000), while there were no differences in hemodynamic parameters derived from PAC between the two groups. CONCLUSIONS: Since LVETc is related to preload, the results of this study would suggest that normovolemia could be the end point of a fluid replacement strategy in OLT setting. PMID- 23104663 TI - Evaluation of diagnostic efficacy of serum sTfR assay in iron-deficiency anemia and Beta-thalassemia trait in Shafa hospital, Ahvaz, Iran 2010. AB - BACKGROUND AND OBJECTIVES: Soluble form of transferrin receptor (TFR) called soluble TFR (sTfR) is shed mainly from the erythroid precursors and with a slower rate from other tissues into the plasma. This process of release is intensified in situations characterized with a some degree of erythroid hyperplasia or body iron stores depletion, such as seen in beta-thalassemia trait (betaTT) and iron deficiency anemia (IDA), respectively. Therefore, the employement of sTfR assay as a diagnostic tool for differentiating IDA from betaTT in case of co-existence of these two clinical entities seems to be questionable. In this work we decided to study the above-mentioned dilemma in our geographical area, south of Iran. MATERIALS AND METHODS: Whole blood (5 ml) and serum samples (2 ml) were collected from 30 patients with IDA, 30 individuals with betaTT and 30 apparently healthy cases as control group. Complete blood count (CBC) was done by blood analyzer and serum iron, serum ferritin and serum sTfR were assayed by biochemical, immunological (chemiluminescence) and Elisa Kit, respectively. RESULTS: Serum ferritin concentration in IDA group was significantly lower than the concentration seen in betaTT: 6.93 +/- 4.16 vs 47.40+/=32.33 microg/ml. The findings for sTfR serum concentration in IDA group (3.25+/=1.60 microg/ml) and betaTT group (1.86+/=0.36 microg/ml) showed a significant difference between IDA and the control group (p < 0.001), with some overlap between IDA and betaTT groups. Serum ferritin concentration and serum sTfR concentration in the control group were (65.60 +/- 58.53 microg/dl) and (1.51+/=0.22 microg/ml), respectively. The sTfR/ferritin ratio clearly showed a diagnostic superiority to ferritin assay in IDA diagnosis. CONCLUSIONS: The observed overlap in serum stfR concentrations between IDA and betaTT groups makes the sTfR assay unefficient tool for a differential diagnosis between IDA and betaTT in the early stages of IDA. An higher diagnostic potential was observed in the advanced stage of iron deficiency anemia. Calculated ratio of serum sTfR/ferritin showed the diagnostic superiority to ferritin assay alone in IDA diagnosis. PMID- 23104664 TI - Potential role of leptin against glucocorticoid-induced secondary osteoporosis in adult female rats. AB - OBJECTIVES: The present study assessed the potential role of leptin administration in the protection and intervention against glucocorticoid-induced secondary osteoporosis in female rats. MATERIALS AND METHODS: For this purpose five groups of female Sprague Dawley rats were classified into: (1) negative control group in which the healthy rats received saline as vehicle, (2) a group orally administered with prednisolone (5 mg kg b.wt.-1) daily for six months (osteoporotic group), (3) a group subcutaneously administered with leptin (400 microg kg b.wt.-1) three times weekly for six months (positive control), (4) a group orally administered with prednisolone daily with simultaneous subcutaneous administration of leptin three times weekly for six months (protective group), and (5) a group orally administered with prednisolone daily for six months then subcutaneously administered with leptin three times weekly for other six months (therapeutic group). RESULTS: The obtained data revealed that prednisolone administration resulted in significant decrease in serum osteoprotegerin (OPG) level accompanied with significant increase in serum receptor activator of nuclear factor-kappaB ligand (RANKL) and beta2-microglobulin levels in comparison with the negative control group. Moreover, prednisolone significantly decreased bone mineral density and content of different areas of the right femur bones as compared to the negative control group. Furthermore, administration of leptin with/after stopping prednisolone administration resulted in a marked modulation in the majority of bone biomarkers as well as improvement in bone mineral density and content. CONCLUSIONS: Leptin provided promising effect on bone through its direct action on bone and matrix mineralization. PMID- 23104665 TI - Oxidative stress in the closed-eyelid test: management of glaucoma. AB - BACKGROUND AND OBJECTIVES: To evaluate the role of antioxidant drugs in the tonometric increase that follows the closed eyelid test (CET), a predicitive test for glaucoma, after administration of antioxidant substances was observed. MATERIALS AND METHODS: 30 subjects of 54.57+/=5.62 years, 13 males and 17 females, were examined by measuring the ocular pressure after 1 hour from the CET, both in normal conditions and after the administration of antioxidants such as: vitamin A (50,000 IU/die), vitamin E (600 mg/die), and vitamin C (1000 mg/die). The increases in temperature of the iridocorneal angle and of the iris were also measured in the same conditions with an infrared Thermo-Precision tonometer (Sola Electro-Optics, China) both before and after CET. RESULTS: The results showed increased pressure after CET and decreased pressure after the administration of each antioxidant substance, although vitamin A was found to be more effective and with statistically significant values compared to vitamins E and C. CONCLUSIONS: Considering the responses obtained after administration of antioxidant drugs, the ocular hypertension induced after CET could be a response to mixed stress, oxidative and thermic, with degenerative effects on the trabecular meshwork (TM). Besides, in light of these considerations the research results underline that the open angle glaucoma (OAG) should be considered a multifactorial degenerative disease. PMID- 23104666 TI - Modified technique of Joseph balloon mitral valvuloplasty. AB - Joseph balloon mitral valvuloplasty is a single balloon procedure for severe symptomatic mitral stenosis. We present a case where difficulty was encountered in advancing the balloon catheter across the mitral valve by standard technique. As the left atrium was grossly dilated, every time the balloon was tracked over the 0.035" extra support wire placed in left ventricle, the wire prolapsed into left atrium. A modified method wherein the balloon was maneuvered into left ventricle with the support of 14F long introducer sheath is presented. This step is useful to complete balloon mitral valvuloplasty successfully in subset of patients with giant left atrium. PMID- 23104667 TI - Identification of tissue-specific targeting peptide. AB - Using phage display technique, we identified tissue-targeting peptide sets that recognize specific tissues (bone-marrow dendritic cell, kidney, liver, lung, spleen and visceral adipose tissue). In order to rapidly evaluate tissue-specific targeting peptides, we performed machine learning studies for predicting the tissue-specific targeting activity of peptides on the basis of peptide sequence information using four machine learning models and isolated the groups of peptides capable of mediating selective targeting to specific tissues. As a representative liver-specific targeting sequence, the peptide "DKNLQLH" was selected by the sequence similarity analysis. This peptide has a high degree of homology with protein ligands which can interact with corresponding membrane counterparts. We anticipate that our models will be applicable to the prediction of tissue-specific targeting peptides which can recognize the endothelial markers of target tissues. PMID- 23104668 TI - Urinary concentrations of estrogens and estrogen metabolites and smoking in caucasian women. AB - BACKGROUND: Smoking has been hypothesized to decrease biosynthesis of parent estrogens (estradiol and estrone) and increase their metabolism by 2 hydroxylation. However, comprehensive studies of smoking and estrogen metabolism by 2-, 4-, or 16-hydroxylation are sparse. METHODS: Fifteen urinary estrogens and estrogen metabolites (jointly called EM) were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in luteal phase urine samples collected during 1996 to 1999 from 603 premenopausal women in the Nurses' Health Study II (NHSII; 35 current, 140 former, and 428 never smokers). We calculated geometric means and percentage differences of individual EM (pmol/mg creatinine), metabolic pathway groups, and pathway ratios, by smoking status and cigarettes per day (CPD). RESULTS: Total EM and parent estrogens were nonsignificantly lower in current compared with never smokers, with estradiol significant (P(multivariate) = 0.02). We observed nonsignificantly lower 16-pathway EM (P = 0.08) and higher 4-pathway EM (P = 0.25) and similar 2-pathway EM in current versus never smokers. EM measures among former smokers were similar to never smokers. Increasing CPD was significantly associated with lower 16-pathway EM (P trend = 0.04) and higher 4-pathway EM (P-trend = 0.05). Increasing CPD was significantly positively associated with the ratios of 2- and 4-pathway to parent estrogens (P-trend = 0.01 and 0.002), 2- and 4-pathway to 16-pathway (P-trend = 0.02 and 0.003), and catechols to methylated catechols (P-trend = 0.02). CONCLUSIONS: As hypothesized, we observed lower urinary levels of total EM and parent estrogens in active smokers. Our results also suggest smoking is associated with altered estrogen metabolism, specifically increased 2- and 4 hydroxylation, decreased 16-hydroxylation, and decreased catechol methylation. IMPACT: Our study suggests how smoking might influence estrogen-related cancers and conditions. PMID- 23104670 TI - Quantifying short run cost-effectiveness during a gradual implementation process. AB - This paper examines the short run inefficiencies that arise during gradual implementation of a new cost-effective technology in healthcare. These inefficiencies arise when health gains associated with the new technology cannot be obtained immediately because the new technology does not yet supply all patients, and when there is overcapacity for the old technology in the short run because the supply of care is divided among two mutually exclusive technologies. Such efficiency losses are not taken into account in standard textbook cost effectiveness analysis in which a steady state is presented where costs and effects are assumed to be unchanging over time. A model is constructed to quantify such short run inefficiencies as well as to inform the decision maker about the optimal implementation pattern for the new technology. The model operates by integrating the incremental net benefit equations for both the period of co-existence of mutually exclusive technologies and the period after complete substitution of the old technology. It takes into account the rate of implementation of the new technology, depreciation of capital of the old technology as well as the demand curves for both technologies. The model is applied to the real world case of converting from screen film to digital mammography in the Netherlands. PMID- 23104669 TI - Cancer mortality in patients with psychiatric diagnoses: a higher hazard of cancer death does not lead to a higher cumulative risk of dying from cancer. AB - PURPOSE: Both increased as well as decreased cancer mortality among psychiatric patients has been reported, but competing death causes were not included in the analyses. This study aims to investigate whether observed cancer mortality in patients with psychiatric disorders might be biased by competing death causes. METHOD: In this retrospective cohort study on data from the Psychiatric Case Register Middle Netherlands linked to the death register of Statistics Netherlands, the risk of cancer death among patients with schizophrenia (N = 4,590), bipolar disorder (N = 2,077), depression (N = 15,130) and their matched controls (N = 87,405) was analyzed using a competing risk model. RESULTS: Compared to controls, higher hazards of cancer death were found in patients with schizophrenia (HR = 1.61, 95 % CI 1.26-2.06), bipolar disorder (HR = 1.20, 95 % CI 0.81-1.79) and depression (HR = 1.26, 95 % CI 1.10-1.44). However, the HRs of death due to suicide and other death causes were more elevated. Consequently, among those who died, the 12-year cumulative risk of cancer death was significantly lower. CONCLUSIONS: Our analysis shows that, compared to the general population, psychiatric patients are at higher risk of dying from cancer, provided that they survive the much more elevated risks of suicide and other death causes. PMID- 23104671 TI - Influence of scan duration on the accuracy of beta-amyloid PET with florbetaben in patients with Alzheimer's disease and healthy volunteers. AB - PURPOSE: Florbetaben is a beta-amyloid-targeted PET tracer with significant potential for augmenting the toolbox in the clinical diagnosis of Alzheimer's disease (AD). In dementia imaging, shortening of scan duration may simplify future clinical use. The aim of this retrospective study was to investigate the effect of scan duration on diagnostic accuracy. METHODS: PET scans obtained from 25 AD patients and 25 healthy volunteers (HVs) were analysed. In each subject, scans of three different durations (5, 10 and 20 min; all starting 90 min after injection) were obtained, randomized, and visually assessed by three experts blinded to the subject's identity and group affiliation. Presence/absence of beta amyloid and diagnostic confidence (0-100 %) were scored, and 10 % of the scans were re-read. Further, randomly selected datasets of ten AD patients and ten HVs were quantified using an established VOI-based approach and using a voxel-based approach. RESULTS: The sensitivity and specificity of the blinded read were 80 % and 96 %, respectively, for all scan durations. Diagnostic confidence was high (97 +/- 6 %, 97 +/- 6 % and 95 +/- 8 % for the 20-min, 10-min and 5-min scans, respectively; n.s.), as was interreader agreement (kappa(20 min) = 0.94, kappa(10 min) = 0.94, kappa(5 min) = 0.89; n.s.). Intrareader agreement was highest for the 20-min scan (kappa = 1.00) and lower for the 10-min scan (kappa = 0.71) and 5 min scan (kappa = 0.80; p = 0.002 and 0.003 vs. the 20-min scan). For all scan durations, composite SUVRs (Cohen's d effect size 4.5, 3.9 and 4.8 for the 5-min, 10-min and 20-min scans; p < 0.0001 each) and individual brain volumes affected by beta-amyloid (Cohen's d effect size 1.6, 1.8 and 2.0 for the 5-min, 10-min and 20-min scans; p < 0.005 each) were significantly higher in AD patients than in HVs. CONCLUSION: Reduction in scan duration did not relevantly affect the accuracy of florbetaben PET scans in discriminating between AD patients and HVs. Thus, a reduction in scan duration seems conceivable for the future clinical use of florbetaben. PMID- 23104672 TI - Diversity and evolution of a trait mediating ant-plant interactions: insights from extrafloral nectaries in Senna (Leguminosae). AB - BACKGROUND AND AIMS: Plants display a wide range of traits that allow them to use animals for vital tasks. To attract and reward aggressive ants that protect developing leaves and flowers from consumers, many plants bear extrafloral nectaries (EFNs). EFNs are exceptionally diverse in morphology and locations on a plant. In this study the evolution of EFN diversity is explored by focusing on the legume genus Senna, in which EFNs underwent remarkable morphological diversification and occur in over 80 % of the approx. 350 species. METHODS: EFN diversity in location, morphology and plant ontogeny was characterized in wild and cultivated plants, using scanning electron microscopy and microtome sectioning. From these data EFN evolution was reconstructed in a phylogenetic framework comprising 83 Senna species. KEY RESULTS: Two distinct kinds of EFNs exist in two unrelated clades within Senna. 'Individualized' EFNs (iEFNs), located on the compound leaves and sometimes at the base of pedicels, display a conspicuous, gland-like nectary structure, are highly diverse in shape and characterize the species-rich EFN clade. Previously overlooked 'non individualized' EFNs (non-iEFNs) embedded within stipules, bracts, and sepals are cryptic and may represent a new synapomorphy for clade II. Leaves bear EFNs consistently throughout plant ontogeny. In one species, however, early seedlings develop iEFNs between the first pair of leaflets, but later leaves produce them at the leaf base. This ontogenetic shift reflects our inferred diversification history of iEFN location: ancestral leaves bore EFNs between the first pair of leaflets, while leaves derived from them bore EFNs either between multiple pairs of leaflets or at the leaf base. CONCLUSIONS: EFNs are more diverse than previously thought. EFN-bearing plant parts provide different opportunities for EFN presentation (i.e. location) and individualization (i.e. morphology), with implications for EFN morphological evolution, EFN-ant protective mutualisms and the evolutionary role of EFNs in plant diversification. PMID- 23104673 TI - Submicrometer aerosol in rural and urban backgrounds in southern Poland: primary and secondary components of PM1. AB - Diurnal samples of PM(1) (submicrometer particles, having aerodynamic diameters not greater than 1 MUm) were collected at an urban background site in Zabrze (from 01.08. to 31.12.2009) and a rural background site in Raciborz (from 01.08. to 31.12.2010). The samples were analyzed for carbon (organic and elemental), water soluble ions (Na(+), NH(4) (+), K(+), Mg(2+), Ca(2+), Cl(-), NO(3)(-), SO(4)(2-)) and concentrations of 21 elements by using, respectively, a Sunset Laboratory carbon analyzer, a Herisau Metrohm AG ion chromatograph, a PANalitycal Epsilon 5 spectrometer. To perform the monthly mass closure calculations for PM(1), the chemical components were categorized into organic matter (OM), elemental carbon (EC), secondary inorganic aerosol (SIA), crustal matter (CM), marine components (MC), other elements (OE) and unidentified matter (UM). The mass contributions of secondary (SOM) and primary (POM) organic matter to PM(1) were also estimated. In average, 50 % of PM(1) in Zabrze and 40 % in Raciborz were secondary aerosol coming from the transformations of its gaseous precursors. High concentrations and mass contributions of EC and OM to PM, and probable PM acidic nature in Zabrze, indicate particularly high hazard from the ambient submicrometer particles to the inhabitants of southern Poland. PMID- 23104674 TI - Intertrochanteric fractures: comparison between two different locking nails. AB - PURPOSE: The aim of this study was to compare two intramedullary devices used in the treatment of intertrochanteric fractures. METHOD: During the period 2006-2007 46 TGN and 51 PFNA were used for the treatment of intertrochanteric fractures in our hospital. Clinical and radiological follow-up were available. Surgical time, blood loss and complications have been considered. RESULTS: The mean operative time for the TGN group was significantly higher than in the PFNA group (62 min and 45 min, respectively) with a p = 0.04. The mean blood loss was significantly higher in the TGN group (285 ml; SD 145) in relation to the PFNA group (226 ml; SD 136) with p = 0.03. Also, rate of complications was higher in the TGN group (p = 0.01). Clinical outcomes were good for both groups. Intra-operative and post operative complications in the TGN group were associated with a longer operative time and a higher blood loss, probably due to the reaming needed in TGN that can increase blood loss and risk of comminution or fracture propagation. Moreover, all but one of the procedure-related complications were observed in very elderly patients. CONCLUSIONS: Based on our results in the intertrochanteric fracture, use of PFNA should be recommended in cases of elderly and osteoporotic patients, while TGN should be used in more severely displaced fractures in patients with a slightly better bone mineral density. PMID- 23104675 TI - Acetabular fracture types vary with different acetabular version. AB - PURPOSE: Acetabular fractures typically occur in high energy trauma. Understanding of the various contributing biomechanical factors and trauma mechanisms is still limited. While several investigations figured out what role femoral position during impact plays in distinct fracture patterns, no data exists on the influence of acetabular version on the fracture type. Our study was carried out to clarify this issue. METHODS: Radiological data sets of 192 patients (145 male, 47 female, age 14-90 years) sustaining acetabular fractures were assessed retrospectively. The crossover ratio of the crossover sign and presence or absence of the posterior wall sign and ischial spine sign were used to determine acetabular retroversion on conventional radiographs. Acetabular version in the axial plane was measured on a computed tomography (CT) scan. Statistics were then performed to analyse the relationship between the acetabular fracture type according to the Letournel classification and acetabular version. RESULTS: A significant difference (p = 0.029) in acetabular version was found between fractures of the anterior [mean equatorial edge (EE) angle 19.93 degrees ] and posterior (mean EE angle 17.53 degrees ) acetabulum in the CT scan. No difference was shown on the measurements on conventional radiographs. CONCLUSIONS: Acetabular version in the axial plane has an influence on the acetabular fracture pattern. While more anteverted acetabula were frequently associated with anterior fracture types according to the Letournel classification, retroversion of the acetabulum was associated with posterior fracture types. PMID- 23104676 TI - Cutting and implanting errors in minimally invasive total knee arthroplasty using a navigation system. AB - PURPOSE: The purpose of this study was to evaluate the accuracy of bone cutting and implantation in minimally invasive total knee arthroplasty with image-free navigation. METHODS: The alignment of the tibial and femoral bone resection was measured in 40 knees during surgery. The alignment measurement was repeated after cementing the tibial and femoral components. We evaluated the cutting error and the implanting error. RESULTS: The mean tibial cutting errors were 0.5 and 0.7 degrees in the frontal and sagittal planes, respectively. The mean femoral cutting errors were 0.5 and 0.9 degrees in the frontal and sagittal planes, respectively. The mean tibial implanting errors were 1.0 and 0.9 degrees in the frontal and sagittal planes, respectively. The mean femoral implanting error was 0.7 degrees in the frontal plane. CONCLUSIONS: Computer-assisted navigation was useful in checking the alignment of both bone cut and cementation. PMID- 23104677 TI - High-intensity intermittent exercise and cardiovascular and autonomic function. AB - OBJECTIVE: The effect of 12 weeks of high-intensity intermittent exercise (HIIE) on cardiac, vascular, and autonomic function of young males was examined. METHODS: Thirty-eight young men with a BMI of 28.7 +/- 3.1 kg m(-2) and age 24.9 +/- 4.3 years were randomly assigned to either an HIIE or control group. The exercise group underwent HIIE three times per week, 20 min per session, for 12 weeks. Aerobic power and a range of cardiac, vascular, and autonomic measures were recorded before and after the exercise intervention. RESULTS: The exercise, compared to the control group, recorded a significant reduction in heart rate accompanied by an increase in stroke volume. For the exercise group forearm vasodilatory capacity was significantly enhanced, P < 0.05. Arterial stiffness, determined by pulse wave velocity and augmentation index, was also significantly improved, after the 12-week intervention. For the exercise group, heart period variability (low- and high-frequency power) and baroreceptor sensitivity were significantly increased. CONCLUSION: High-intensity intermittent exercise induced significant cardiac, vascular, and autonomic improvements after 12 weeks of training. PMID- 23104678 TI - What is extraversion for? Integrating trait and motivational perspectives and identifying the purpose of extraversion. AB - The purpose of this study was to determine whether the manifestation of extraversion (i.e., acting and being extraverted) in everyday behavior can be explained by intentional (functional) constructs, namely, goals. By using a model in which personality states serve as an outcome of specific, momentary goal pursuit, we were able to identify the function of extraversion states in everyday behavior. Using experience-sampling methodology, we asked participants to describe their state extraversion, goal pursuit, and state affect over 10 days. Results show that 18 selected goals predicted 74% of the variance in state extraversion; both within-person and between-person fluctuations in state extraversion were strongly associated with changes in momentary goal pursuit. We extended findings relating state extraversion and state positive affect, showing that the relationship between goals and positive affect was partially mediated by state extraversion. PMID- 23104679 TI - Understanding the past, predicting the future: causation, not intentional action, is the root of temporal binding. AB - Temporal binding refers to a subjective shortening of elapsed time between actions and their resultant consequences. Originally, it was thought that temporal binding is specific to motor learning and arises as a consequence of either sensory adaptation or the associative principles of the forward model of motor command. Both of these interpretations assume that the binding effect is rooted in the motor system and, critically, that it is driven by intentional action planning. The research reported here demonstrates that both intentional actions and mechanical causes result in temporal binding, which suggests that intentional action is not necessary for temporal binding and that binding results from the causal relation linking actions with their consequences. Intentional binding is thus a special case of more general causal binding, which can be explained by a theory of Bayesian ambiguity reduction. PMID- 23104680 TI - Social sampling explains apparent biases in judgments of social environments. AB - How people assess their social environments plays a central role in how they evaluate their life circumstances. Using a large probabilistic national sample, we investigated how accurately people estimate characteristics of the general population. For most characteristics, people seemed to underestimate the quality of others' lives and showed apparent self-enhancement, but for some characteristics, they seemed to overestimate the quality of others' lives and showed apparent self-depreciation. In addition, people who were worse off appeared to enhance their social position more than those who were better off. We demonstrated that these effects can be explained by a simple social-sampling model. According to the model, people infer how others are doing by sampling from their own immediate social environments. Interplay of these sampling processes and the specific structure of social environments leads to the apparent biases. The model predicts the empirical results better than alternative accounts and highlights the importance of considering environmental structure when studying human cognition. PMID- 23104681 TI - The effect of inequality frames on support for redistributive tax policies. PMID- 23104683 TI - Penetration of diesel exhaust particles through commercially available dust half masks. AB - Half masks are certified by the competent, national institutions--National Institute for Occupational Safety and Health (NIOSH) in the USA and the respective European national institutions applying common European regulations. However, certification testing is conducted with particles of NaCl, paraffin oil, or dioctyl phthalate (DOP) and at the constant flow rate, whereas particles commonly found in workplaces may differ in size, shape, and morphology from these particles. Therefore, the aim of this study was to investigate filtration efficiency of commercially available filtering facepiece half masks under the condition of exposure to diesel fumes. In this study, we focused on the particulate phase [diesel exhaust particles (DEP)] of three (petroleum diesel, ecodiesel, and biodiesel) diesel fuel combustion types. Two types of European standard-certified half masks, FFP2 and FFP - Filtering Facepiece, and three types of popular diesel fuels were tested. The study showed that the filtration efficiencies for each examined half mask and for each of diesel exhaust fumes were lower than the minimum filtration efficiency required for the standard test aerosols by the European standards. For FFP2 and FFP3 particulate half masks, standard minimum filtration efficiency is 94 and 99%, respectively, whereas 84 89% of mass of DEP from various fuels were filtered by the tested FFP2 and only 75-86% by the FFP3. The study indicated that DEP is more penetrating for these filters than the standard salt or paraffin oil test aerosols. The study also showed that the most penetrating DEP are probably in the 30- to 300-nm size range, regardless of the fuel type and the half-mask model. Finally, the pressure drops across both half masks during the 80-min tests remained below an acceptable maximum of breathing resistance-regardless of the fuel types. The respiratory system, during 40-min test exposures, may be exposed to 12-16mg of DEP if a FFP2 or FFP3 particulate half mask is used. To conclude, commercially available half masks may not ensure a sufficient level of protection of the respiratory tract against diesel exhaust fumes. PMID- 23104682 TI - Dissociable neural correlates of intention and action preparation in voluntary task switching. AB - This electroencephalographic (EEG) study investigated the impact of between-task competition on intentional control in voluntary task switching. Anticipatory preparation for an upcoming task switch is a hallmark of top-down intentional control. Meanwhile, asymmetries in performance and voluntary choice when switching between tasks differing in relative strength reveal the effects of between-task competition, reflected in a surprising bias against switching to an easier task. Here, we assessed the impact of this bias on EEG markers of intentional control during preparation for an upcoming task switch. The results revealed strong and varied effects of between-task competition on EEG markers of global task preparation-a frontal contingent negative variation (CNV), a posterior slow positive wave, and oscillatory activity in the alpha band (8-12 Hz) over posterior scalp sites. In contrast, we observed no between-task differences in motor-specific task preparation, as indexed by the lateralized readiness potential and by motor-related amplitude asymmetries in the mu (9-13 Hz) and beta (18-26 Hz) frequency bands. Collectively, these findings demonstrate that between-task competition directly influences the formation of top-down intentions, not only their expression in overt behavior. Specifically, this influence occurs at the level of global task intention rather than the preparation of specific actions. PMID- 23104684 TI - Rare peritoneal bands and recesses: incidental findings in a cadaveric dissection. AB - Variable arrangement of the visceral peritoneum would result in the formation of unexpected peritoneal bands and associated recesses. These could confound the unsuspecting clinician in both the diagnostic and therapeutic approach to the abdomen. It is thus imperative to be alert to the surprises the peritoneum may throw up and, however rare, abdominal conditions resulting from such aberrations must be kept in mind. Cadaveric dissection of an elderly female revealed a number of peritoneal anomalies. Apart from a cysto-duodenal extension of the lesser omentum, there was a bilaminar, avascular band passing from the inferior surface of the right lobe of liver to both the duodenum and the transverse colon. This anomalous band lay posterior to and distinct from the lesser omentum. The epiploic foramen was thus delimited by two unconventional folds. Further, the distal half of the transverse mesocolon failed to reach the posterior abdominal wall and instead formed an arched continuity with an aberrant mesentery of descending colon. An unusual type of peri-caecal recess was also present. PMID- 23104685 TI - Glaucoma diagnosis optic disc analysis comparing Cirrus spectral domain optical coherence tomography and Heidelberg retina tomograph II. AB - PURPOSE: To evaluate the diagnostic ability of optic nerve head parameters, measured by Cirrus spectral domain optical coherence tomography (SD OCT) and Heidelberg retina tomograph II (HRT II) to detect concomitant glaucoma. METHODS: Cirrus OCT and HRT examinations of 62 eyes of 62 patients (32 with no perimetric glaucoma and 30 with concomitant perimetric glaucoma) evaluated between August 2010 and December 2010 were retrospectively analyzed and compared with regard to the optic disc morphometric parameter, disc area, rim area, cup-to-disc ratio (CDR), and cup volume. Receiver operating characteristic curves were constructed for the parameters and areas under the curves (AUCs) were compared. RESULTS: All parameters except disc area were significantly different between Cirrus OCT and HRT. Average cup-to-disc ratio (CDR), vertical CDR, and cup volume were greater when measured by OCT compared with HRT II (P = 0.002, P < 0.001, and P < 0.001, respectively). Rim area was smaller by OCT than by HRT II (P < 0.001). Of the parameters evaluated, rim area (0.938), average CDR (0.865), and vertical CDR (0.897) had higher AUCs with OCT than with HRT II. Glaucoma diagnostic capability using the AUC was greater for OCT than for the HRT. CONCLUSIONS: Optic nerve head parameters measured by Cirrus OCT seem to be useful in differentiating glaucomatous optic nerve heads. The two types of instrument compared here should not be used interchangeably to obtain measurements of the optic disc for diagnosis of glaucoma. PMID- 23104687 TI - Voices of the poor from the margins of Bengal: structural inequities and health. AB - In opposition to the traditional approaches to health communication that treat the subaltern sectors as passive recipients of messages of enlightenment configured in top-down interventions, the culture-centered approach foregrounds the importance of listening to subaltern communities at the margins through dialogue. We build on earlier culture-centered projects in rural communities of West Bengal, India, to develop participatory research strategies for understanding the local processes through which the structural marginalization of the poor plays out in rural Bengal. Study results point toward the marginalization of the poor both communicatively and economically, attending to the ways in which communicative marginalization lies at the heart of economic oppressions. Through locally articulated concepts of "health as shortage" and "communication as shortage," community members put forth alternative rationalities of health that highlight structural resources at the heart of health. These local articulations of shortage offer an alternative rationality for organizing health promotion efforts in the rural margins of Bengal through the foregrounding of discourses of shortage. PMID- 23104686 TI - Long-term intraocular pressure changes after combined phacoemulsification, intraocular lens implantation, and vitrectomy. AB - PURPOSE: To observe long-term changes in intraocular pressure (IOP) after a combined phacoemulsification, intraocular lens implantation, and vitrectomy procedure. METHODS: This was a retrospective case series at a single hospital. Of 105 consecutive cases that received combined phacoemulsification, intraocular lens implantation, and vitrectomy for macular hole or epiretinal membrane, 85 eyes (patients) were followed up for 1 year or longer. The IOP of both eyes in the subjects who had surgery in one eye was measured at baseline and at 1, 3, 6, 12, 24, 36, 48, and 60 months postoperatively. The IOP of the treated eye was compared with the fellow eye and with the baseline value at each follow-up visit. RESULTS: Intraocular pressure in the operated eyes at 3 months after surgery was significantly lower than that at baseline and than that in the respectively fellow eyes (P < 0.001, paired-t test with Bonferroni correction). The IOP subsequently returned to the baseline value or was the same as that of the fellow eye within 3 months of the observation time point. Only two treated eyes had elevated IOP exceeding 21 mmHg after 6 months postoperatively. CONCLUSIONS: The change in the IOP after phacovitrectomy may be limited, and care when using this procedure because some eyes show increased IOP compared to the fellow eye after a long period. PMID- 23104688 TI - Comparison of DNA and RNA, and cultivation approaches for the recovery of terrestrial and aquatic fungi from environmental samples. AB - Estimates of fungal biodiversity from environmental samples are all subject to bias. Major issues are that the commonly adopted cultivation-based approaches are suitable for taxa which grow readily under laboratory conditions, while the DNA based approaches provide more reliable estimates, but do not indicate whether taxa are metabolically active. In this study, we have evaluated these approaches to estimate the fungal diversity in soil and freshwater samples from a subtropical forest, and compared these to RNA-based culture-independent approach intended to indicate the metabolically active fungal assemblage. In both soil and freshwater samples, the dominant taxon recovered by all three approaches was the same (Anguillospora furtiva). This taxon was cultivable from all samples and comprised 85-86 % DNA libraries and 90-91 % RNA libraries. The remaining taxa were phylogenetically diverse and spanned the Ascomycota, Basidiomycota, and Fungi incertae sedis. Their recovery was not consistent among the three approaches used and suggests that less abundant members of the assemblage may be subjected to greater bias when diversity estimates employ a single approach. PMID- 23104689 TI - Hay fever in a changing climate: linking an Internet-based diary with environmental data. AB - Investigating the impact of climate change on human health requires the development of efficient tools that link patient symptoms with changing environmental variables. We developed an internet-based hay fever diary linked to simultaneously recorded pollen load and weather variables in Canberra, Australia over spring 2010. We recruited 42 hay fever sufferers to complete a simple online pollen diary daily over a period of 60 days. In conjunction, daily airborne pollen load was counted and meteorological data collected simultaneously. We focused on the relationships between temperature, rainfall, pollen count and rhinoconjunctivitis symptoms. Pollen load increased after a peak rainfall event until the end of the study. Compliance was high, averaging 79% of days per person. Nasal rhinoconjunctivitis symptoms increased in concert with increasing pollen load, and then remained high. Mucosal itching increased more gradually and strongly coincided with increased daily maximum temperature. Our study successfully demonstrated the feasibility of linking pollen load and climate variables to symptoms of rhinoconjunctivitis in the Australian community. However, a larger study would better explore the nature of associations between these variables. Similar online methods could be used to monitor a range of health responses to our changing environment. PMID- 23104690 TI - Extensive inflammatory cell infiltration in human skeletal muscle in response to an ultraendurance exercise bout in experienced athletes. AB - The impact of a 24-h ultraendurance exercise bout on systemic and local muscle inflammatory reactions was investigated in nine experienced athletes. Blood and muscle biopsies were collected before (Pre), immediately after the exercise bout (Post), and after 28 h of recovery (Post28). Circulating blood levels of leukocytes, creatine kinase (CK), C-reactive protein (CRP), and selected inflammatory cytokines were assessed together with the evaluation of the occurrence of inflammatory cells (CD3(+), CD8(+), CD68(+)) and the expression of major histocompatibility complex class I (MHC class I) in skeletal muscle. An extensive inflammatory cell infiltration occurred in all athletes, and the number of CD3(+), CD8(+), and CD68(+) cells were two- to threefold higher at Post28 compared with Pre (P < 0.05). The inflammatory cell infiltration was associated with a significant increase in the expression of MHC class I in muscle fibers. There was a significant increase in blood leukocyte count, IL-6, IL-8, CRP, and CK at Post. At Post28, total leukocytes, IL-6, and CK had declined, whereas IL-8 and CRP continued to increase. Increases in IL-1beta and TNF-alpha were not significant. There were no significant associations between the magnitude of the systemic and local muscle inflammatory reactions. Signs of muscle degenerative and regenerative events were observed in all athletes with various degrees of severity and were not affected by the 24-h ultraendurance exercise bout. In conclusion, a low-intensity but very prolonged single-endurance exercise bout can generate a strong inflammatory cell infiltration in skeletal muscle of well trained experienced ultraendurance athletes, and the amplitude of the local reaction is not proportional to the systemic inflammatory response. PMID- 23104692 TI - Pretreatment with brain natriuretic peptide reduces skeletal muscle mitochondrial dysfunction and oxidative stress after ischemia-reperfusion. AB - Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 +/- 0.3 vs. 5.8 +/- 0.2 MUmol O(2).min(-1).g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 +/- 0.8 vs. 13.7 +/- 0.9 MUmol O(2).min(-1).g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 +/- 0.1 vs. 0.7 +/- 0.1, P < 0.05) and oxidative stress (+45%, 9,067 +/- 935 vs. 6,249 +/- 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5 hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels. PMID- 23104691 TI - Spatial-temporal dynamics of pulmonary blood flow in the healthy human lung in response to altered FI(O2). AB - The temporal dynamics of blood flow in the human lung have been largely unexplored due to the lack of appropriate technology. Using the magnetic resonance imaging method of arterial spin labeling (ASL) with subject-gated breathing, we produced a dynamic series of flow-weighted images in a single sagittal slice of the right lung with a spatial resolution of ~1 cm(3) and a temporal resolution of ~10 s. The mean flow pattern determined from a set of reference images was removed to produce a time series of blood flow fluctuations. The fluctuation dispersion (FD), defined as the spatial standard deviation of each flow fluctuation map, was used to quantify the changes in distribution of flow in six healthy subjects in response to 100 breaths of hypoxia (FI(O(2)) = 0.125) or hyperoxia (FI(O(2)) = 1.0). Two reference frames were used in calculation, one determined from the initial set of images (FD(global)), and one determined from the mean of each corresponding baseline or challenge period (FD(local)). FD(local) thus represented changes in temporal variability as a result of intervention, whereas FD(global) encompasses both FD(local) and any generalized redistribution of flow associated with switching between two steady state patterns. Hypoxic challenge resulted in a significant increase (96%, P < 0.001) in FD(global) from the normoxic control period and in FD(local) (46%, P = 0.0048), but there was no corresponding increase in spatial relative dispersion (spatial standard deviation of the images divided by the mean; 8%, not significant). There was a smaller increase in FD(global) in response to hyperoxia (47%, P = 0.0015) for the single slice, suggestive of a more general response of the pulmonary circulation to a change from normoxia to hyperoxia. These results clearly demonstrate a temporal change in the sampled distribution of pulmonary blood flow in response to hypoxia, which is not observed when considering only the relative dispersion of the spatial distribution. PMID- 23104693 TI - Inactivity, age, and exercise: single-muscle fiber power generation. AB - We examined the effects of mild therapeutic exercise during a period of inactivity on size and contractile functions of myosin heavy chain (MHC) type I (n = 204) and type II (n = 419) single fibers from the medial gastrocnemius in three age groups. Young adult (5-12 mo), middle-aged (24-31 mo), and old (32-37 mo) F344BNF1 rats were assigned to one of three groups: weight-bearing control, non-weight bearing (NWB), and NWB plus exercise (NWBX). Fourteen days of hindlimb suspension were applied in NWB rats. The NWBX rats exercised on the treadmill for 15 min, four times a day, during the period of NWB. The NWBX did not improve peak power, but increased normalized power of MHC type I fibers in young adult rats. In MHC type II fibers, NWBX did not change peak power, isometric maximal force, V(max), and fiber size from young adult and middle-aged rats. NWBX did not improve peak power and isometric maximal force and showed a dramatic decline in V(max) and normalized power in the old rats. Collectively, mild treadmill exercise during a period of inactivity does not improve peak power of MHC type I or type II fiber from the gastrocnemius in young, middle-aged, and old rats. However, NWBX is beneficial in enhancing normalized power of MHC type I fibers in young adult rats, most likely due to the stimulus intensity and the ability of the individual fibers to adapt to the stimulus. In contrast, several factors, such as impaired adaptation potential, inappropriate exercise intensity, or increased susceptibility to muscle damage, may contribute to the lack of improvement in the older rats. PMID- 23104694 TI - Mitochondrial morphology, topology, and membrane interactions in skeletal muscle: a quantitative three-dimensional electron microscopy study. AB - Dynamic remodeling of mitochondrial morphology through membrane dynamics are linked to changes in mitochondrial and cellular function. Although mitochondrial membrane fusion/fission events are frequent in cell culture models, whether mitochondrial membranes dynamically interact in postmitotic muscle fibers in vivo remains unclear. Furthermore, a quantitative assessment of mitochondrial morphology in intact muscle is lacking. Here, using electron microscopy (EM), we provide evidence of interacting membranes from adjacent mitochondria in intact mouse skeletal muscle. Electron-dense mitochondrial contact sites consistent with events of outer mitochondrial membrane tethering are also described. These data suggest that mitochondrial membranes interact in vivo among mitochondria, possibly to induce morphology transitions, for kiss-and-run behavior, or other processes involving contact between mitochondrial membranes. Furthermore, a combination of freeze-fracture scanning EM and transmission EM in orthogonal planes was used to characterize and quantify mitochondrial morphology. Two subpopulations of mitochondria were studied: subsarcolemmal (SS) and intermyofibrillar (IMF), which exhibited significant differences in morphological descriptors, including form factor (means +/- SD for SS: 1.41 +/- 0.45 vs. IMF: 2.89 +/- 1.76, P < 0.01) and aspect ratio (1.97 +/- 0.83 vs. 3.63 +/- 2.13, P < 0.01) and circularity (0.75 +/- 0.16 vs. 0.45 +/- 0.22, P < 0.01) but not size (0.28 +/- 0.31 vs. 0.27 +/- 0.20 MUm(2)). Frequency distributions for mitochondrial size and morphological parameters were highly skewed, suggesting the presence of mechanisms to influence mitochondrial size and shape. In addition, physical continuities between SS and IMF mitochondria indicated mixing of both subpopulations. These data provide evidence that mitochondrial membranes interact in vivo in mouse skeletal muscle and that factors may be involved in regulating skeletal muscle mitochondrial morphology. PMID- 23104695 TI - Separating in vivo mechanical stimuli for postpneumonectomy compensation: physiological assessment. AB - Following right pneumonectomy (PNX), the remaining lung expands and its perfusion doubles. Tissue and microvascular mechanical stresses are putative stimuli for initiating compensatory lung growth and remodeling, but their relative contributions to overall compensation remain uncertain. To temporally isolate the stimuli related to post-PNX lung expansion (parenchyma deformation) from those related to the sustained increase in perfusion (microvascular distention and shear), we replaced the right lung of adult dogs with a custom-shaped inflated prosthesis. Following stabilization of perfusion and wound healing 4 mo later, the prosthesis was either acutely deflated (DEF group) or kept inflated (INF group). Physiological studies were performed pre-PNX, 4 mo post-PNX (inflated prosthesis, INF1), and again 4 mo postdeflation (DEF) compared with controls with simultaneous INF prosthesis (INF2). Perfusion to the remaining lung increased ~76 113% post-PNX (INF1 and INF2) and did not change postdeflation. Post-PNX (INF prosthesis) end-expiratory lung volume (EELV) and lung and membrane diffusing capacities (DL(CO) and DM(CO)) at a given perfusion were 25-40% below pre-PNX baseline. In the INF group EELV, DL(CO) and DM(CO) remained stable or declined slightly with time. In contrast, all of these parameters increased significantly after deflation and were 157%, 26%, and 47%, respectively, above the corresponding control values (INF2). Following delayed deflation, lung expansion accounted for 44%-48% of total post-PNX compensatory increase in exercise DL(CO) and peak O(2) uptake; the remainder fraction is likely attributable to the increase in perfusion. Results suggest that expansion-related parenchyma mechanical stress and perfusion-related microvascular stress contribute in equal proportions to post-PNX alveolar growth and remodeling. PMID- 23104697 TI - Oxygen, pH, and mitochondrial oxidative phosphorylation. AB - The oxygen dependence of mitochondrial oxidative phosphorylation was measured in suspensions of isolated rat liver mitochondria using recently developed methods for measuring oxygen and cytochrome c reduction. Cytochrome-c oxidase (energy conservation site 3) activity of the mitochondrial respiratory chain was measured using an artificial electron donor (N,N,N',N'-tetramethyl-p-phenylenediamine) and ascorbate to directly reduce the cytochrome c, bypassing sites 1 and 2. For mitochondrial suspensions with added ATP, metabolic conditions approximating those in intact cells and decreasing oxygen pressure both increased reduction of cytochrome c and decreased respiratory rate. The kinetic parameters [K(M) and maximal rate (V(M))] for oxygen were determined from the respiratory rates calculated for 100% reduction of cytochrome c. At 22 degrees C, the K(M) for oxygen is near 3 Torr (5 MUM), 12 Torr (22 MUM), and 18 Torr (32 MUM) at pH 6.9, 7.4, and 7.9, respectively, and V(M) corresponds to a turnover number for cytochrome c at 100% reduction of near 80/s and is independent of pH. Uncoupling oxidative phosphorylation increased the respiratory rate at saturating oxygen pressures by twofold and decreased the K(M) for oxygen to <2 Torr at all tested pH values. Mitochondrial oxidative phosphorylation is an important oxygen sensor for regulation of metabolism, nutrient delivery to tissues, and cardiopulmonary function. The decrease in K(M) for oxygen with acidification of the cellular environment impacts many tissue functions and may give transformed cells a significant survival advantage over normal cells at low-pH, oxygen-limited environment in growing tumors. PMID- 23104698 TI - MicroRNA 138, let-7b, and 125a inhibitors differentially alter sleep and EEG delta-wave activity in rats. AB - Sleep deprivation was previously reported to alter microRNA (miRNA) levels in the brain; however, the direct effects of any miRNA on sleep have only been described recently. We determined miRNA 138 (miR-138), miRNA let-7b (let-7b), and miRNA 125a-5p (miR-125a) levels in different brain areas at the transitions between light and dark. In addition, we examined the extent to which inhibiting these miRNAs affects sleep and EEG measures. We report that the levels of multiple miRNAs differ at the end of the sleep-dominant light period vs. the end of the wake-dominant dark period in cortical areas, hippocampus, and hypothalamus. For instance, in multiple regions of the cortex, miR-138, let-7b, and miR-125a expression was higher at the end of the dark period compared with the end of the light period. Intracerebroventricular injection of a specific inhibitor (antiMIR) to miR-138 suppressed sleep and nonrapid eye movement sleep (NREMS) EEG delta power. The antiMIR to let-7b did not affect time in state but decreased NREMS EEG delta power, whereas the antiMIR to miR-125a failed to affect sleep until after 3 days and did not affect EEG delta power on any day. We conclude that miRNAs are uniquely expressed at different times and in different structures in the brain and have discrete effects and varied timings on several sleep phenotypes and therefore, likely play a role in the regulation of sleep. PMID- 23104699 TI - Short-term complexity indexes of heart period and systolic arterial pressure variabilities provide complementary information. AB - It is unclear whether the complexity of the variability of the systolic arterial pressure (SAP) provides complementary information to that of the heart period (HP). The complexity of HP and SAP variabilities was assessed from short beat-to beat recordings (i.e., 256 cardiac beats). The evaluation was made during a pharmacological protocol that induced vagal blockade with atropine or a sympathetic blockade (beta-adrenergic blockade with propranolol or central sympathetic blockade with clonidine) alone or in combination, during a graded head-up tilt, and in patients with Parkinson's disease (PD) without orthostatic hypotension undergoing orthostatic challenge. Complexity was quantified according to the mean square prediction error (MSPE) derived from univariate autoregressive (AR) and multivariate AR (MAR) models. We found that: 1) MSPE(MAR) did not provide additional information to that of MSPE(AR); 2) SAP variability was less complex than that of HP; 3) because HP complexity was reduced by either vagal blockade or vagal withdrawal induced by head-up tilt and was unaffected by beta adrenergic blockade, HP was under vagal control; 4) because SAP complexity was increased by central sympathetic blockade and was unmodified by either vagal blockade or vagal withdrawal induced by head-up tilt, SAP was under sympathetic control; 5) SAP complexity was increased in patients with PD; and 6) during orthostatic challenge, the complexity of both HP and SAP variabilities in patients with PD remained high, thus indicating both vagal and sympathetic impairments. Complexity indexes derived from short HP and SAP beat-to-beat series provide complementary information and are helpful in detecting early autonomic dysfunction in patients with PD well before circulatory symptoms become noticeable. PMID- 23104696 TI - Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function. AB - We have previously reported chronic low-intensity interval exercise training attenuates fibrosis, impaired cardiac mitochondrial function, and coronary vascular dysfunction in miniature swine with left ventricular (LV) hypertrophy (Emter CA, Baines CP. Am J Physiol Heart Circ Physiol 299: H1348-H1356, 2010; Emter CA, et al. Am J Physiol Heart Circ Physiol 301: H1687-H1694, 2011). The purpose of this study was to test two hypotheses: 1) chronic low-intensity interval training preserves normal myocardial oxygen supply/demand balance; and 2) training-dependent attenuation of LV fibrotic remodeling improves diastolic function in aortic-banded sedentary, exercise-trained (HF-TR), and control sedentary male Yucatan miniature swine displaying symptoms of heart failure with preserved ejection fraction. Pressure-volume loops, coronary blood flow, and two dimensional speckle tracking ultrasound were utilized in vivo under conditions of increasing peripheral mean arterial pressure and beta-adrenergic stimulation 6 mo postsurgery to evaluate cardiac function. Normal diastolic function in HF-TR animals was characterized by prevention of increased time constant of isovolumic relaxation, normal LV untwisting rate, and enhanced apical circumferential and radial strain rate. Reduced fibrosis, normal matrix metalloproteinase-2 and tissue inhibitors of metalloproteinase-4 mRNA expression, and increased collagen III isoform mRNA levels (P < 0.05) accompanied improved diastolic function following chronic training. Exercise-dependent improvements in coronary blood flow for a given myocardial oxygen consumption (P < 0.05) and cardiac efficiency (stroke work to myocardial oxygen consumption, P < 0.05) were associated with preserved contractile reserve. LV hypertrophy in HF-TR animals was associated with increased activation of Akt and preservation of activated JNK/SAPK. In conclusion, chronic low-intensity interval exercise training attenuates diastolic impairment by promoting compliant extracellular matrix fibrotic components and preserving extracellular matrix regulatory mechanisms, preserves myocardial oxygen balance, and promotes a physiological molecular hypertrophic signaling phenotype in a large animal model resembling heart failure with preserved ejection fraction. PMID- 23104700 TI - Aerobic exercise does not compromise muscle hypertrophy response to short-term resistance training. AB - This study tested the hypothesis that chronic aerobic and resistance exercise (AE+RE) would elicit greater muscle hypertrophy than resistance exercise only (RE). Ten men (25 +/- 4 yr) performed 5 wk unilateral knee extensor AE+RE. The opposing limb was subjected to RE. AE completed 6 hr prior to RE consisted of ~45 min one-legged cycle ergometry. RE comprised 4 * 7 maximal concentric-eccentric knee extensions. Various indexes of in vivo knee extensor function were measured before and after training. Magnetic resonance imaging (MRI) assessed m. quadricep femoris (QF) cross-sectional area (CSA), volume, and signal intensity (SI). Biopsies obtained from m. vastus lateralis determined fiber CSA, enzyme levels, and gene expression of myostatin, atrogin-1, MuRF-1, PGC-1alpha, and VEGF. Increases (P < 0.05) in isometric strength and peak power, respectively, were comparable in AE+RE (9 and 29%) and RE (11 and 24%). AE+RE showed greater increase (14%; P < 0.05) in QF volume than RE (8%). Muscle fiber CSA increased 17% after AE+RE (P < 0.05) and 9% after RE (P > 0.05). QF SI increased (12%; P < 0.05) after AE+RE, but not RE. Neither AE+RE nor RE showed altered mRNA levels. Citrate synthase activity increased (P < 0.05) after AE+RE. The results suggest that the increased aerobic capacity shown with AE+RE was accompanied by a more robust increase in muscle size compared with RE. Although this response was not carried over to greater improvement in muscle function, it remains that intense AE can be executed prior to RE without compromising performance outcome. PMID- 23104702 TI - Synthesis: a new project for the Journal of Applied Physiology. PMID- 23104701 TI - Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus. AB - The perifornical (PF) region of the posterior hypothalamus promotes wakefulness and facilitates motor activity. In anesthetized rats, local disinhibition of PF neurons by GABA(A) receptor antagonists activates orexin (OX) neurons and elicits a systemic response, including increases of hypoglossal nerve activity (XIIa), respiratory rate, heart rate, and blood pressure. The increase of XIIa is mediated to hypoglossal (XII) motoneurons by pathways that do not require noradrenergic or serotonergic projections. We hypothesized that the pathway might include OX-dependent activation locally within the PF region or direct projections of OX neurons to the XII nucleus. Adult, male Sprague-Dawley rats were urethane anesthetized, vagotomized, paralyzed, and ventilated. Gabazine (GABA(A) receptor antagonist, 0.18 mM, 20 nl) was injected into the PF region, and ~2 h later, a second gabazine injection was performed preceded by injection of a dual OX1/2 receptor antagonist (almorexant; 90 mM) either into the XII nucleus (40-60 nl at 2-3 rostrocaudal levels; n = 6 rats), or into the PF region (40-60 nl; n = 6 rats). XIIa, respiratory rate, heart rate, and arterial blood pressure were analyzed for 70 min after each gabazine injection. The excitatory effects of PF gabazine on XIIa, respiratory, and heart rates were significantly reduced by up to 44-82% when gabazine injections were preceded by PF almorexant injections, but not when almorexant was injected into the XII nucleus. These data suggest that a significant portion of XII motoneuronal and cardiorespiratory activation evoked by disinhibition of PF neurons is mediated by local OX dependent mechanisms within the posterior hypothalamus. PMID- 23104703 TI - Descending brain neurons in the cricket Gryllus bimaculatus (de Geer): auditory responses and impact on walking. AB - The activity of four types of sound-sensitive descending brain neurons in the cricket Gryllus bimaculatus was recorded intracellularly while animals were standing or walking on an open-loop trackball system. In a neuron with a contralaterally descending axon, the male calling song elicited responses that copied the pulse pattern of the song during standing and walking. The accuracy of pulse copying increased during walking. Neurons with ipsilaterally descending axons responded weakly to sound only during standing. The responses were mainly to the first pulse of each chirp, whereas the complete pulse pattern of a chirp was not copied. During walking the auditory responses were suppressed in these neurons. The spiking activity of all four neuron types was significantly correlated to forward walking velocity, indicating their relevance for walking. Additionally, injection of depolarizing current elicited walking and/or steering in three of four neuron types described. In none of the neurons was the spiking activity both sufficient and necessary to elicit and maintain walking behaviour. Some neurons showed arborisations in the lateral accessory lobes, pointing to the relevance of this brain region for cricket audition and descending motor control. PMID- 23104704 TI - Just a personal thing? A qualitative account of health behaviours and values associated with body piercing. AB - OBJECTIVES: This study investigates the perceptions of individuals with body piercings in relation to health behaviours and values specifically taking into account piercing location. METHODS: A qualitative study that employed a series of in-depth, semi-structured individual interviews using thematic analysis to analyse data. Nine individuals with a range of piercings were recruited and semi structured interviews were carried out in a West Midlands piercing studio. RESULTS: The analysis identified themes relating to the presence of body piercings that included a range of health-related outcomes such as physical appearance, health behaviours, addiction and impressions. A possible relationship between oral piercings and 'crash dieting' was also identified. CONCLUSIONS: The results suggest that from the comments made the presence of body piercings is not related to any particular health concern, which is instead comparable to the general population. These results contradict previous studies citing a relationship with high-risk health behaviours. Further large-scale studies examining these findings are warranted. PMID- 23104705 TI - Comparison of Billroth I and Roux-en-Y reconstruction after distal gastrectomy for gastric cancer: one-year postoperative effects assessed by a multi institutional RCT. AB - PURPOSE: This randomized, controlled trial evaluated the clinical efficacy of Billroth I (BI) and Roux-en-Y (RY) reconstruction at 1 year after distal gastrectomy for gastric cancer. METHODS: The primary end point was the amount of body weight lost at 1 postoperative year, and secondary end points included other items related to nutritional status such as serum albumin and lymphocyte count, as well as endoscopic examination findings of the remnant stomach and esophagus. Of the 332 patients enrolled, 163 were assigned to the BI group and 169 were randomized to the RY group. RESULTS: The loss in body weight 1 year after surgery did not differ significantly between the BI and RY groups (9.1 % and 9.7 %, respectively, p = 0.39). There were no significant differences in other aspects of nutritional status between the 2 groups. Endoscopic examination 1 year after gastrectomy showed reflux esophagitis in 26 patients (17 %) in the BI group versus 10 patients (6 %) in the RY group (p = 0.0037), while remnant gastritis was observed in 71 patients (46 %) in the BI group versus 44 patients (28 %) in the RY group (p = 0.0013); differences were significant for both conditions. Multivariable analysis showed that the only reconstruction was the independently associated factor with the incidence of reflux esophagitis. CONCLUSIONS: RY reconstruction was not superior to BI in terms of body weight change or other aspects of nutritional status at 1 year after surgery, although RY more effectively prevented reflux esophagitis and remnant gastritis after distal gastrectomy. PMID- 23104707 TI - A modified triple test for palpable breast masses: the value of ultrasound and core needle biopsy. AB - BACKGROUND: The original triple test score (TTS)--clinical examination, mammogram, and fine-needle aspiration (FNA) biopsy--has long been used to evaluate palpable breast masses. We modified the original TTS to include ultrasound (US) and core biopsy to determine their role in evaluating palpable breast masses. METHODS: A retrospective chart review of 320 female patients was performed. We developed a modified triple test score (mTTS) that included physical examination, mammogram and/or US, and FNA and/or core biopsy. For the examination and imaging score, 1-3 points were given for low, moderate, or high suspicion. Biopsy scores were characterized as benign, atypical, or malignant. Final outcome was determined by open biopsy or follow-up greater than 1 year. RESULTS: Physical examination was 92% accurate (95% confidence interval [CI] 0.89 0.96, p < 0.0001) at predicting whether a mass was benign or malignant. Imaging was 88% accurate (95% CI 0.84-0.92, p < 0.0001) and needle biopsy was 95% accurate (95% CI 0.92-0.98, p < 0.0001). The modified triple test was 99% accurate (95% CI 0.98-1.00, p < 0.0001). Each 1-point increment in the mTTS was associated with an increased risk of cancer, with an odds ratio of 9.73 (CI 5.16 18.4, p < 0.0001). For 150 patients, we compared the original TTS with the mTTS. US and core biopsy changed the scores of 24 patients; only three changed clinical management. CONCLUSIONS: For patients with a palpable breast mass and a mTTS score of 3-4, no further assessment is necessary. Those with a mTTS of 8-9 can proceed to definitive therapy. Patients with a mTTS of 5-7 require further assessment. US and/or core biopsy added little to the accuracy or predictive value of the original TTS. PMID- 23104706 TI - Effects of genomic changes in hepatitis B virus on postoperative recurrence and survival in patients with hepatocellular carcinoma. AB - PURPOSE: To determine whether the genomic changes in hepatitis B virus (HBV) affect the clinical outcomes of hepatocellular carcinoma (HCC) in patients with HBV-associated HCC treated with curative surgical resection. METHODS: A total of 247 patients with HBV-associated HCC were treated with curative surgical resection. They were followed regularly for a median of 30 months. The whole X, S, basal core promoter (BCP), and precore regions of HBV were sequenced. RESULTS: The genomic changes such as the G1896A at precore, the A1762T/G1764A at BCP, the C1653T and the T1753V at X gene, and pre-S2 deletion were not significantly associated with postoperative recurrence of HCC or survival of patients after curative resection. However, in univariate analysis, younger age, elevated serum alpha-fetoprotein level, elevated serum alanine aminotransferase level, larger tumor size, microvascular invasion, and advanced Cancer of the Liver Italian Program stage were closely associated with shorter survival after surgical resection. In multivariate analysis, only microvascular invasion revealed to be an independent risk factor of postoperative recurrence (relative risk [RR] 5.406; P < 0.001); the independent risk factors of shorter survival appeared to be infiltrative type (RR 5.110; P = 0.032), larger tumor size (RR 1.976; P = 0.047), and microvascular invasion (RR 6.118; P < 0.001). CONCLUSIONS: The postoperative recurrence or survival period may not be affected by the genomic changes at the precore, BCP, X, and pre-S2 regions in HBV of genotype C2 in patients with HBV associated HCC treated with curative surgical resection. Rather, it may be closely associated with tumor characteristics, such as the size and type of HCC or presence of microvascular invasion. PMID- 23104709 TI - Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. METHODS: We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. RESULTS: Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27 1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72-2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35-2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57-2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91-1.64) did not achieve statistical significance. CONCLUSIONS: Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion. PMID- 23104708 TI - Evaluating the prognostic factors associated with cancer-specific survival of differentiated thyroid carcinoma presenting with distant metastasis. AB - BACKGROUND: Because patients with differentiated thyroid carcinoma (DTC) presenting with distant metastasis (DM) have a particularly poor prognosis, examining the prognostic factors in this group is essential. We aimed to evaluate the prognostic factors affecting cancer-specific survival (CSS) in DTC patients presenting with DM. METHODS: Of the 1227 DTC patients, 51 (4.2 %) presented with DM at diagnosis. All patients underwent a total thyroidectomy, followed by radioiodine (RAI) ablation and postablation whole body scan (WBS). Patients were considered to have an osseous metastasis if one of the metastatic sites involved a bone, while RAI avidity was determined by any visual uptake in a known metastatic site on the first WBS. Factors predictive of CSS were determined by univariate and multivariate analyses by the Cox proportional hazard model. RESULTS: In univariate analysis, older age (relative risk [RR] 1.050, 95 % confidence interval [CI] 1.010-1.091, P = 0.014), DM discovered before WBS (RR 3.401, 95 % CI 1.127-10.309, P = 0.030), follicular thyroid carcinoma (RR 3.095, 95 % CI 1.168-8.205, P = 0.025), osseous metastasis (RR 4.695, 95 % CI 1.379 15.873, P = 0.013), non-RAI avidity (RR 3.355, 95 % CI 1.280-8.772, P = 0.014), and external beam radiotherapy to DM (RR 3.241, 95 % CI 1.093-9.614, P = 0.034) were significant poor prognostic factors for CSS. In the multivariate analysis, after adjusting for other factors, osseous metastasis (RR 6.849, 95 % CI 1.495 31.250, P = 0.013) and non-RAI avidity (RR 7.752, 95 % CI 2.198-27.027, P = 0.001) were the two independent poor prognostic factors for CSS. Older age almost reached statistically significance (RR 1.055, 95 % CI 0.996-1.117, P = 0.068). CONCLUSIONS: DTC patients presenting with DM accounted for 4.2 % of all patients. Because osseous metastasis and RAI avidity were independent prognostic factors, future therapy should be directed at improving the treatment efficacy of osseous and/or non-RAI-avid metastases. PMID- 23104710 TI - Effectiveness of OK-432 (Sapylin) to reduce seroma formation after axillary lymphadenectomy for breast cancer. AB - BACKGROUND: The occurrence of seroma formation after axillary lymphadenectomy for breast cancer cannot be ignored. Various approaches have been used in an effort to reduce it, but these results are still controversial. We aimed to describe a new method of application of OK-432 (Sapylin, heat-treated Su strain of Streptococcus) to reduce seroma formation after axillary lymphadenectomy for breast cancer and to verify the safety and efficacy of it as a beneficial supplement for conventional surgery. METHODS: A prospective, randomized analysis of consecutive quadrantectomy or mastectomy plus axillary lymphadenectomy using or not using OK-432 was designed. From July 2010 to November 2011, a total of 111 patients were enrolled in this prospective, randomized study and completed the follow-up. OK-432 applied to the axillary fossa plus placement of closed suction drainage was used in 54 patients (the experimental group); placement of closed suction drainage was used in 57 patients (the control group). RESULTS: There were no statistical significance between the two groups in terms of age, body mass index, treatment received, tumor size, number of removed lymph nodes, and lymph node status. Postoperative drainage magnitude and duration were significantly reduced in the experimental group (P = 0.008 and 0.003, respectively). One week after hospital discharge, fewer patients developed a palpable seroma in the experimental group: 10 in the experimental group versus 28 in the control group (P = 0.001). Fewer seromas needed aspiration (mean 1 [range 0-3] in the experimental group vs. mean 4 [range 1-5] in the control group; P < 0.001). There were no significant differences in terms of the incidence of complications associated with axillary lymphadenectomy (P = 0.941). CONCLUSIONS: OK-432 is a feasible and safe option for axillary lymphadenectomy for breast cancer. The use of it does not always prevent seroma formation, but it can reduce drainage magnitude and duration, as well as decrease the incidence of seroma after the removal of drainage. It may be increasingly conducted in day surgery clinics. PMID- 23104711 TI - Effects of fluid load on human urine characteristics related to workplace drug testing. AB - During workplace drug testing, urine is tested for dilution, substitution and adulteration. Donors argue that these findings are due to medical, health or working conditions or diet and genetic differences. There is a paucity of data correlating changes in urine characteristics after a fluid load to various body parameters. Therefore, five urine specimens (one in the morning, one prior to drinking 800 mL of a beverage, and three time intervals thereafter) from 12 males and 12 females were tested for four different beverages on separate occasions. Of the 480 samples, 376 were in sufficient amounts. Of these 376, 36 (10%) had creatinine <20 mg/dL but >=2 mg/dL; 27 (75%) of 36 had specific gravity <1.0030 but >1.0010. Thus, these 27 samples can be considered to be dilute; 20 (74%) of 27 were from females. For males with at least one dilute sample, body fat was 11% less and resting metabolic rate (RMR) was 29% more than males with no dilute samples (p > 0.05); for females with at least one dilute sample, height was 8% less and weight 20% less than females with no dilute samples (p > 0.05). Individuals with a higher RMR appear to have a greater potential for producing dilute urine specimens than those with a lower RMR. Thus, a dilute sample does not necessarily indicate that it was intentionally diluted. Such samples must be carefully evaluated in consideration with recent consumption of liquid by donors to avoid false accusations. PMID- 23104716 TI - The experiences of HIV-positive women living in an African village: perceptions of voluntary counseling and testing programs. AB - Kenya has approximately 1.4 million adults infected with HIV/AIDS, with a national prevalence rate of approximately 7.4%. The majority of the Kenyan people have not participated in a Voluntary Counseling and Testing (VCT) program and do not know their HIV status. This increases the likelihood of infecting others and spreading the disease. The PURPOSE: Living in fear, making the decision to be tested, the journey toward acceptance, changing behavior, planning for the future, and encouraging others to be tested. VCT programs are crucial in attaining goals related to the prevention and management of AIDS. By exploring these women's experiences and perceptions, issues concerning AIDS and the acceptance and use of VCT may be better understood. PMID- 23104717 TI - Teaching nurses sight unseen: comparing the cultural competency of online and on campus BSN faculty. AB - PURPOSE: This study supports best practices in nursing education and the need for cultural competency among faculty members. The purpose of this study was to examine the levels of cultural competency among on-campus Bachelor of Science in Nursing (BSN) faculty compared with those of online BSN faculty. DESIGN: The research used a quantitative, nonexperimental, descriptive, correlational design. The Cultural Diversity Questionnaire for Nurse Educators (CDQ-NE) was e-mailed to 500 BSN faculty at five research sites (N = 222). The instrument included Likert type scale items organized into the components of cultural competence according to Campinha-Bacote. RESULTS: The lowest levels of cultural competency were among the on-campus group (3.95). Faculty teaching both online and on-campus had the highest levels (4.0). DISCUSSION/CONCLUSIONS: A significant finding indicated that training within the past 5 years in cultural competency reflected higher scores. IMPLICATIONS: These findings suggest that some cultural competency training should be mandatory for all BSN faculty, whether it occurs during their orientations or as part of nurse-educator curricula at the graduate levels. PMID- 23104718 TI - ARIX: a randomised trial of acupuncture v oral care sessions in patients with chronic xerostomia following treatment of head and neck cancer. AB - BACKGROUND: Radiation treatment of head and neck cancer can cause chronic xerostomia which impairs patients' quality of life. The study reported here examined the efficacy of acupuncture in alleviating xerostomia symptoms especially dry mouth. PATIENTS AND METHODS: A total of 145 patients with chronic radiation-induced xerostomia >18 months after treatments were recruited from seven UK cancer centres. The study employed a randomised crossover design with participants receiving two group sessions of oral care education and eight of acupuncture using standardised methods. Patient-reported outcome (PROs) measures were completed at baseline and weeks 5, 9, 13, 17, and 21. The primary outcome was improvement in dry mouth. OBJECTIVE: saliva measurements were also carried out. RESULTS: Acupuncture compared with oral care, produced significant reductions in patient reports of severe dry mouth (OR = 2.01, P = 0.031) sticky saliva (OR = 1.67, P = 0.048), needing to sip fluids to swallow food (OR = 2.08, P = 0.011) and in waking up at night to drink (OR = 1.71, P = 0.013). There were no significant changes in either stimulated or unstimulated saliva measurements over time. CONCLUSION: Eight sessions of weekly group acupuncture compared with group oral care education provide significantly better relief of symptoms in patients suffering from chronic radiation-induced xerostomia. PMID- 23104719 TI - Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients. AB - BACKGROUND: Measurement of residual disease following neoadjuvant chemotherapy that accurately predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for clinical trials development. Several methods to assess tumor response have been described. However, the agreement between methods and correlation with survival in independent cohorts has not been reported. PATIENTS AND METHODS: We report survival and tumor response according to the measurement of residual breast cancer burden (RCB), the Miller and Payne classification and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, in 151 LABC patients. Kappa Cohen's coefficient (K) was used to test the agreement between methods. We assessed the correlation between the treatment outcome and overall survival (OS) and relapse-free survival (RFS) by calculating Harrell's C-statistic (c). RESULTS: The agreement between Miller and Payne classification and RCB classes was very high (K = 0.82). In contrast, we found a moderate-to-fair agreement between the Miller and Payne classification and RECIST criteria (K = 0.52) and RCB classes and RECIST criteria (K = 0.38). The adjusted C-statistic to predict OS for RCB index (0.77) and RCB classes (0.75) was superior to that of RECIST criteria (0.69) (P = 0.007 and P = 0.035, respectively). Also, RCB index (c = 0.71), RCB classes (c = 0.71) and Miller and Payne classification (c = 0.67) predicted better RFS than RECIST criteria (c = 0.61) (P = 0.005, P = 0.006 and P = 0.028, respectively). CONCLUSIONS: The pathological assessment of tumor response might provide stronger prognostic information in LABC patients. PMID- 23104720 TI - Benefit of adjuvant trastuzumab-based chemotherapy in T1ab node-negative HER2 overexpressing breast carcinomas: a multicenter retrospective series. AB - BACKGROUND: Randomized clinical trials showed the benefit of adjuvant trastuzumab based chemotherapy (ATBC) for node-positive and/or >1 cm HER2+ breast carcinomas. No efficacy data have been published on ATBC in large series of pT1abN0 HER2+ tumors. PATIENTS AND METHODS: This retrospective study evaluated 276 cases of pT1abN0 HER2+ breast tumors in eight French cancer centers. Factors associated with prognosis and ATBC prescription were analyzed. RESULTS: A total of 129 cases (47%) were treated with ATBC (ATBC+), 19 with chemotherapy alone, 5 with trastuzumab alone, and 123 (45%) with neither trastuzumab nor chemotherapy (ATBC ). ATBC use was associated with the date of diagnosis (before or after June 2005) and with poor prognostic features. At a median follow-up of 44 months, there were 13 recurrences in the ATBC- group and 2 in the ATBC+ group. ATBC was associated with a significant survival benefit (99% 40-month disease-free survival for ATBC+ versus 93% for ATBC- cases; P = 0.018). Lack of hormone receptors (HRs) and the presence of lymphovascular invasion (LVI) were significantly associated with a poor prognosis and a greater benefit of ATBC. CONCLUSIONS: ATBC was associated with a significantly reduced risk of recurrence in pT1abN0 HER2+ tumors, and was more beneficial in HR- and/or LVI+ tumors. PMID- 23104721 TI - A phase I dose escalation study of Ad GV.EGR.TNF.11D (TNFeradeTM Biologic) with concurrent chemoradiotherapy in patients with recurrent head and neck cancer undergoing reirradiation. AB - BACKGROUND: AdGV.EGR.TNF.11D (TNFeradeTM Biologic) is a replication-deficient adenoviral vector expressing human tumor necrosis factor alpha (TNF-alpha) under the control of the chemoradiation-inducible EGR-1 promoter. TNF-alpha has been shown to function as a radiation sensitizer. We conducted a phase I dose escalation study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of TNFeradeTM Biologic, when added to chemoradiotherapy in poor prognosis patients with recurrent, previously irradiated head and neck cancer (HNC). METHODS: TNFeradeTM Biologic was injected intratumorally on day 1 of each 14-day cycle and dose-escalated in log increments from 4 * 10(9) to 4 * 10(11) PU. Daily radiation, infusional 5-fluorouracil (5-FU), and hydroxyurea were given on days 1-5 for seven cycles (FHX). Tumor biopsies were obtained before, during, and after treatment. RESULTS: Fourteen patients were treated. DLT was reached at a dose level of 3 (4 * 10(11) PU) with three thrombotic events. The response rate was 83.3%. The median survival was 9.6 months. One patient (7.1%) remained alive 3 years after treatment. Biopsies were obtained in 90% of patients. Nearly all tumors expressed adenovirus receptors, TNF-alpha, and TNF-alpha receptors. Adenoviral DNA was detected in three biopsies from one patient. CONCLUSIONS: TNFeradeTM Biologic can be safely integrated with FHX chemoradiotherapy at an MTD of 4 * 10(10) PU. Monitoring for thrombotic events is indicated. PMID- 23104722 TI - A prognostic nomogram to predict overall survival in patients with platinum sensitive recurrent ovarian cancer. AB - BACKGROUND: Patients with platinum-sensitive recurrent ovarian cancer have variable prognosis and survival. We extend previous work on prediction of progression-free survival by developing a nomogram to predict overall survival (OS) in these patients treated with platinum-based chemotherapy. PATIENTS AND METHODS: The nomogram was developed using data from the CAELYX in Platinum Sensitive Ovarian Patients (CALYPSO) trial. Multivariate proportional hazards models were generated based on pre-treatment characteristics to develop a nomogram that classifies patient prognosis based on OS outcome. We also developed two simpler models with fewer variables and conducted model validations in independent datasets from AGO-OVAR Study 2.5 and ICON 4. We compare the performance of the nomogram with the simpler models by examining the differences in the C-statistics and net reclassification index (NRI). RESULTS: The nomogram included six significant predictors: interval from last platinum chemotherapy, performance status, size of the largest tumour, CA-125, haemoglobin and the number of organ sites of metastasis (C-statistic 0.67; 95% confidence interval 0.65-0.69). Among the CALPYSO patients, the median OS for good, intermediate and poor prognosis groups was 56.2, 31.0 and 20.8 months, respectively. When CA-125 was not included in the model, the C-statistics were 0.65 (CALYPSO) and 0.64 (AGO OVAR 2.5). A simpler model (interval from last platinum chemotherapy, performance status and CA-125) produced a significant decrease of the C-statistic (0.63) and NRI (26.4%, P < 0.0001). CONCLUSIONS: This nomogram with six pre-treatment characteristics improves OS prediction in patients with platinum-sensitive ovarian cancer and is superior to models with fewer prognostic factors or platinum chemotherapy free interval alone. With independent validation, this nomogram could potentially be useful for improved stratification of patients in clinical trials and also for counselling patients. PMID- 23104723 TI - Phase I study of humanized monoclonal antibody AVE1642 directed against the type 1 insulin-like growth factor receptor (IGF-1R), administered in combination with anticancer therapies to patients with advanced solid tumors. AB - BACKGROUND: Type 1 insulin-like growth factor receptor (IGF-1R) mediates resistance to chemotherapy and targeted agents. This study assessed the safety, pharmacokinetics (PK), and tolerability of humanized IGF-1R antibody AVE1642 with other cancer treatments. PATIENTS: Patients with advanced solid tumors received three weekly AVE1642 dosed at 6 mg/kg, chosen following previous study, with 75 (cohort A) or 100 mg/m(2) (B) docetaxel, 1250 mg/m(2) gemcitabine/100 mg erlotinib (C1), or 60 mg/m(2) doxorubicin (D1). Blood samples were assayed for PK, IGFs, and IGF-BP3. RESULTS: Fifty-eight patients received 317 AVE1642 infusions. The commonest adverse events were diarrhea (37/58 patients), asthenia (34/58), nausea (30/58), and stomatitis (21/58). Dose-limiting toxic effects in cohorts C1 (diarrhea) and D1 (neutropenia) prompted addition of cohorts C2 (1000 mg/m(2) gemcitabine/75 mg erlotinib) and D2 (50 mg/m(2) doxorubicin). Grade 3-4 hyperglycemia (three cases) accompanied steroid premedication for docetaxel administration. No PK interactions were detected. There were three partial responses in cohorts B (melanoma) and C (leiomyosarcoma, two cases) and 22 stabilizations >=12 weeks, giving a control rate of 25/57 (44%). On treatment IGF II rose by 68 +/- 25 ng/ml in patients discontinuing treatment <12 weeks, and fell by 55.5 +/- 21 ng/ml with disease control (P < 0.001). CONCLUSION: AVE1642 was tolerable with 75-100 mg/m(2) docetaxel and 1000 mg/m(2) gemcitabine/75 mg erlotinib, achieving durable disease control in 44%, with an association between IGF-II and response. PMID- 23104724 TI - A randomized, double-blind, multicenter, phase 2 study of a human monoclonal antibody to human alphanu integrins (intetumumab) in combination with docetaxel and prednisone for the first-line treatment of patients with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Intetumumab is a fully human mAb with antiangiogenic, antitumor properties which has shown potential therapeutic effect in castration-resistant prostate cancer (CRPC) patients. PATIENTS AND METHODS: In a phase 2, randomized, double-blind, multicenter study, men with metastatic CRPC without prior systemic nonhormonal therapy were randomly assigned to 75-mg/m(2) docetaxel (Taxotere) and 5-mg prednisone plus placebo (N = 65) or 10-mg/kg intetumumab (N = 66) q3w. Placebo patients with progressive disease (PD) could cross over to 10-mg/kg intetumumab alone or with docetaxel. The primary end-point was progression-free survival (PFS). The secondary end-points included tumor response (complete response + partial response, CR + PR), prostate-specific antigen (PSA) response, and overall survival (OS). RESULTS: All efficacy end-points favored placebo over intetumumab, including PFS (median 11.0 versus 7.6 months, P = 0.014), tumor response (20% versus 16%, P = 0.795), PSA response (68% versus 47%, P = 0.018), OS (median 20.6 versus 17.2 months, P = 0.163). Common all-grade adverse events (AEs) with placebo and intetumumab were alopecia (43% versus 26%); diarrhea, leukopenia (both 34% versus 27%); neutropenia (35% versus 23%). Grade >= 3 leukopenia (28% versus 17%) and neutropenia (26% versus 18%) occurred more often with placebo than with intetumumab. Intetumumab serum concentrations increased with repeated dosing and did not reach steady-state. Greater decreases in N telopeptide of type I collagen (NTx), C-telopeptide (CTx) and CTCs occurred with intetumumab than with placebo. CONCLUSION: The addition of intetumumab to docetaxel resulted in shorter PFS without additional toxicity among CRPC patients. PMID- 23104725 TI - Alcohol drinking and all cancer mortality: a meta-analysis. AB - BACKGROUND: Epidemiological studies have suggested an inconsistent relationship between alcohol drinking and risk of all cancer mortality. As far as we know, no meta-analysis has been conducted to explore this issue. PATIENTS AND METHODS: We carried out a PubMed search to find relevant articles published before April 2012 in English. Categorical and dose-response meta-analyses were conducted to identify the impact of alcohol drinking on all cancer mortality. Potential sources of heterogeneity were detected by meta-regression and stratification analyses. Sensitivity and cumulative meta-analyses were also carried out. RESULTS: Eighteen independent cohort studies met the inclusion criteria. Compared with non/occasional drinkers, the pooled relative risks (RRs) were 0.91 [95% confidence interval (CI) 0.89-0.94] for light, 1.02 (95% CI 0.99-1.06) for moderate, and 1.31 (95% CI 1.23-1.39) for heavy drinkers. Former drinkers presented a higher risk (RR = 1.32, 95% CI 1.15-1.50) than current drinkers (RR = 1.06, 95% CI 0.98-1.16). There was a J-shaped relationship between all cancer mortality and alcohol consumption in males but not in females. CONCLUSIONS: This meta-analysis confirms the health hazards of heavy drinking (>=50 g/day) and benefits of light drinking (<=12.5 g/day). Large-sample, well-designed, prospective epidemiological studies, especially on heavy drinking among women, should be developed in future. PMID- 23104726 TI - Tumor marker kinetics predict outcome in patients with relapsed disseminated non seminomatous germ-cell tumors. AB - BACKGROUND: An early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting. PATIENTS AND METHODS: Data regarding 400 patients with progressive or relapsed disseminated NSGCTs after first-line chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis. RESULTS: An unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48-3.11); P < 0.001; 2-year PFS rate: 50% versus 26%] as was the Lorch prognostic score (LPS). In the multivariate analysis, an unfavorable TMD, stratified based on the LPS, was an independent adverse prognostic factor for PFS and OS. CONCLUSION: An unfavorable TMD during the first 6 weeks after chemotherapy is associated with a poorer outcome in patients with relapsed disseminated NSGCTs. PMID- 23104727 TI - Occupational exposure profile of Pb, Mn, and Cd in nonferrous Brazilian sanitary alloy foundries. AB - In addition to the primary components of alloys, approximately 5% of the formulation may contain other metals, including lead (Pb), cadmium (Cd), arsenic, manganese (Mn), iron, phosphorus, and nickel. Workers in the foundries are exposed to several compounds; therefore, it is important to assess the levels of injury that may reflect an additive, synergistic, or antagonistic effect caused by these compounds. The mean values of the environmental evaluation of the facilities range from 16.65 to 40.31 ug m(-3) for Pb, 0.99 to 1.73 ug m(-3) for Cd, and 0.91 to 1.70 ug m(-3) for Mn. The mean values of the metal concentrations for furnace, mold, melting, and automatic melting activities range from 15.37 to 19.26 ug m(-3) for Pb, 7.07 to 9.14 ug m(-3) for Cd, and 8.83 to 16.00 ug m(-3) for Mn. Biological samples were divided into two groups: control (n = 38) and exposed (n = 45). The obtained data are3.41 +/- 3.40 and 14.89 +/- 7.82 ug dL(-1) for Pb, 0.90 +/- 0.80 and 1.91 +/- 1.90 ug g(-1) creatinine for Cd, and 0.51 +/- 0.40 and 3.17 +/- 1.93 ug g(-1) creatinine for Mn. Statistical analysis showed significant differences (p < 0.05). Positive linear correlations were established between metal concentrations in the air and the biological matrixes: Pb (r = 0.68; p < 0.001), Cd (r = 0.81; p = 0.17), and Mn (r = 0.12; p < 0.03). Regression analysis showed that professional activities can interfere with element exposure profiles in occupational settings. The analysis in the event of exposure to metals in these companies allowed investigating whether the simultaneous exposure leads to biological damage even if the levels of the compounds are within the exposure limits that are considered to be safe. PMID- 23104728 TI - Nutraceuticals of anti-inflammatory activity as complementary therapy for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by elevated oxidative stress and inflammatory biomarkers. The severe side effects of drug used during such disease necessitate the search for new and safe approaches. Food is a rich source of antioxidants and anti-inflammatory bioactive constituents including phenolic compounds, polyunsaturated fatty acids, phytosterols, toccopherols, and carotenoids. We have a series of publications dealing with the anti-inflammatory activity of different food extracts (as nutraceuticals) in experimental animals (acute and chronic inflammation model) and in clinical study (RA patients). Fish oil, primrose oil, extracts of black cumin, fenugreek, liquorice, coriander, tomato, carrot, sweet potato, broccoli, green tea, rosemary, hazelnut, walnut, wheat germ, and date in addition to the probiotic Bifidobacterium bifidum were the nutraceuticals studied. During these studies, changes in inflammatory biomarkers (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), seromucoids, fibrinogen, tumor necrosis factor alpha (TNF-alpha), prostaglandin E2), oxidative stress (malondialdehyde), antioxidant status (total antioxidant capacity, vitamin C, vitamin E, retinol, beta-carotene), the level of copper (Cu) and zinc (Zn) and colonic microflora in response to the administration of nutraceuticals have been assessed. Results of these studies showed that the majority of nutraceuticals studied possess beneficial effect toward chronic inflammatory diseases, which might be due to the presence of one or more of the above-mentioned phytochemicals. CONCLUSION: Anti inflammatory and antioxidant nutraceuticals may serve as complementary medicine for the management of RA. PMID- 23104729 TI - Expression of cytokine-induced neutrophil chemoattractant in rat lungs following an intratracheal instillation of micron-sized nickel oxide nanoparticle agglomerates. AB - OBJECTIVE: In our previous study, we reported that the micron-sized nickel oxide nanoparticle agglomerates induced neutrophil infiltration and the gene expression of the cytokine-induced neutrophil chemoattractant (CINC)-2alphabeta in a rat lung. In this study, we examined the expression of the CINCs family in the lung using the same rat model exposed to micron-sized nickel oxide nanoparticle agglomerates. METHODS: The count median diameter of nickel oxide nanoparticle agglomerates suspended in saline was 1.34 MUm (primary diameter: 8.41 nm). Male Wistar rats received an intratracheal instillation of 1 mg (3.3 mg/kg) of nickel oxide nanoparticles and were dissected at 3 days, 1 week, 1 month, 3 months, and 6 months after the instillation. The negative control group received an instillation of saline. The concentration of CINC-1 in the lung and the bronchoalveolar lavage fluid (BALF), CINC-2alphabeta in the BALF, and CINC-3 in the lung and the BALF was examined. RESULTS: The concentration of CINC-1 was elevated at 3 days, 3 months, and 6 months in the lung tissue and from 3 days to 6 months in the BALF. The concentration of CINC-2alphabeta was elevated from 3 days to 3 months in the BALF. The concentration of CINC-3 was also elevated at 3 days, 1 week, 3 months, and 6 months in the lung tissue. Infiltration of neutrophil and alveolar macrophage was observed mainly in the alveoli during the observed time period. CONCLUSION: These results suggest that CINC-1 to -3 were totally involved in the lung injury caused by micron-sized nickel oxide nanoparticle agglomerates. PMID- 23104730 TI - Association between long-term exposure to air pollution and specific causes of mortality in Scotland. AB - OBJECTIVE: This study investigated the association between long-term exposure to black smoke (BS) air pollution and mortality in two related Scottish cohorts with 25 years of follow-up. METHODS: Risk factors were collected during 1970-1976 for 15331 and 6680 participants in the Renfrew/Paisley and Collaborative cohorts respectively. Exposure to BS during 1970-1979 was estimated by inverse-distance weighted averages of observed concentrations at monitoring sites and by two alternative spatial modelling approaches which included local air quality predictors (LAQP). RESULTS: Consistent BS-mortality associations (per 10 MUg m( 3) increment in 10-year average BS) were observed in the Renfrew/Paisley cohort using LAQP-based exposure models (all-cause mortality HR 1.10 (95% CI 1.04 to 1.17); cardiovascular HR 1.11 (1.01 to 1.22); ischaemic heart disease HR 1.13 (1.02 to 1.25); respiratory HR 1.26 (1.02 to 1.28)). The associations were largely unaffected by additional adjustment for area-level deprivation category. A less consistent and generally implausible pattern of cause-specific BS mortality associations was found for inverse-distance averaging of BS concentrations at nearby monitoring sites. BS-mortality associations in the Collaborative cohort were weaker and not statistically significant. CONCLUSIONS: The association between mortality and long-term exposure to BS observed in the Renfrew/Paisley cohort is consistent with hypotheses of how air pollution may affect human health. The dissimilarity in pollution-mortality associations for different exposure models highlights the critical importance of reliable estimation of exposures on intraurban spatial scales to avoid potential misclassification bias. PMID- 23104731 TI - Association between environmental tobacco smoke exposure and dementia syndromes. AB - OBJECTIVES: Environmental tobacco smoke (ETS) has a range of adverse health effects, but its association with dementia remains unclear and with dementia syndromes unknown. We examined the dose-response relationship between ETS exposure and dementia syndromes. METHODS: Using a standard method of GMS, we interviewed 5921 people aged >=60 years in five provinces in China in 2007-2009 and characterised their ETS exposure. Five levels of dementia syndrome were diagnosed using the Automated Geriatric Examination for Computer Assisted Taxonomy instrument. The relative risk (RR) of moderate (levels 1-2) and severe (levels 3-5) dementia syndromes among participants exposed to ETS was calculated in multivariate adjusted regression models. RESULTS: 626 participants (10.6%) had severe dementia syndromes and 869 (14.7%) moderate syndromes. Participants exposed to ETS had a significantly increased risk of severe syndromes (adjusted RR 1.29, 95% CI 1.05 to 1.59). This was dose-dependently related to exposure level and duration. The cumulative exposure dose data showed an adjusted RR of 0.99 (95% CI 0.76 to 1.28) for >0-24 level years of exposure, 1.15 (95% CI 0.93 to 1.42) for 25-49 level years, 1.18 (95% CI 0.87 to 1.59) for 59-74 level years, 1.39 (95% CI 1.03 to 1.84) for 75-99 level years and 1.95 (95% CI 1.34 to 2.83) for >=100 level years. Significant associations with severe syndromes were found in never smokers and in former/current smokers. There were no positive associations between ETS and moderate dementia syndromes. CONCLUSIONS: ETS should be considered an important risk factor for severe dementia syndromes. Avoidance of ETS may reduce the rates of severe dementia syndromes worldwide. PMID- 23104732 TI - Mortality in a cohort of Staffordshire pottery workers: follow-up to December 2008. AB - OBJECTIVES: To examine mortality from lung cancer, chronic obstructive pulmonary disease (COPD) and chronic non-malignant renal disease (cNMRD) in pottery workers exposed to silica. METHODS: A cohort of Stoke-on-Trent pottery workers (N=5115), previously followed to 1992, was traced for vital status and cause of death to December 2008. Standardised mortality ratio (SMR) analyses, comparing deaths to England and Wales and Stoke-on-Trent, examined underlying cause in 1985-1992 and 1993-2008 and mentioned cause for 1993-2008. Survival analysis considered exposure duration and concentration of respirable silica for lung cancer, COPD and cNMRD, using Cox regression. RESULTS: Excess risks of lung cancer, COPD and cNMRD were seen against both England and Wales and Stoke-on-Trent for 1985-2008. SMRs for lung cancer and COPD were lower in 1993-2008 and non-significant for lung cancer against Stoke-on-Trent in that period (SMR 1.07 95% CI 0.92 to 1.25). Exposure concentration, estimated for 1943 subjects, was related to lung cancer in smokers for early but not later deaths with mean silica concentration >200 ug/m(3) among deaths to June 1992 (HR 2.80 95% CI 1.21 to 6.50). For COPD an increasing trend with duration and (non-significantly) with mean concentration was seen for early but not later deaths in smokers. No relation was observed between estimated exposures and cNMRD. CONCLUSIONS: Excess rates of death from COPD and lung cancer were more marked in the period of the first follow-up (1985 1992) than in the second, with any relation to estimated exposure being limited to the earlier period. Conclusions about COPD and exposure were limited by an early selective destruction of files. PMID- 23104733 TI - Risk of lung cancer associated with six types of chlorinated solvents: results from two case-control studies in Montreal, Canada. AB - OBJECTIVES: To determine whether exposure to various chlorinated solvents is associated with lung cancer. METHODS: Two case-control studies of occupation and lung cancer were conducted in Montreal, and included 2016 cases and 2001 population controls. Occupational exposure to a large number of agents was evaluated using a combination of subject-reported job history and expert assessment. We examined associations between lung cancer among men and six specific chlorinated solvents and two chemical families (chlorinated alkanes and alkenes). ORs were calculated using unconditional multivariate logistic regression. RESULTS: When the two studies were pooled, there were indications of an increased risk of lung cancer associated with occupational exposure to perchloroethylene (OR(any exposure) 2.5, 95% CI 1.2 to 5.6; OR(substantial exposure) 2.4, 95% CI 0.8 to 7.7) and to carbon tetrachloride (OR(any exposure) 1.2, 95% CI 0.8 to 2.1; OR(substantial exposure) 2.5, 95% CI 1.1 to 5.7). No other chlorinated solvents showed both statistically significant associations and dose-response relationships. ORs appeared to be higher among non-smokers. When the lung cancer cases were separated by histological type, there was a suggestion of differential effects by tumour type, but statistical imprecision and multiple testing preclude strong inferences in this regard. CONCLUSIONS: There were suggestive, albeit inconsistent, indications that exposure to perchloroethylene and carbon tetrachloride may increase the risk of lung cancer. Results for other solvents were compatible with absence of risk. PMID- 23104735 TI - Adverse effects of low occupational cadmium exposure on renal and oxidative stress biomarkers in solderers. AB - OBJECTIVES: Recent studies suggest adverse health effects after low exposure to cadmium (Cd). Brazing with Cd-containing solder exposes workers to Cd. The purpose of this study was to assess: (1) indicators of Cd exposure in blood (Cd B)/ urine (Cd-U); (2) the association between Cd-B, Cd-U and renal and oxidative stress biomarkers. METHODS: In this cross-sectional study Cd-B, Cd-U, renal (ie, N-acetyl-beta-D-glucosaminidase/urinary intestinal alkaline phosphatase (IAP)/microalbumin/beta-2-microglobulin/retinol binding protein and oxidative stress markers (ie, derivatives of reactive oxygen metabolites/glutathione peroxidase/superoxide dismutase (SOD)/ advanced oxidation protein products/8 hydroxy-2'-deoxyguanosin/8-isoprostanes) were determined in 36 solderers. RESULTS: Multiple linear regression analysis adjusting for age and pack-years of smoking show that IAP is statistically significantly associated with Cd-B (B=0.24; SE=0.11) and Cd-U (B=0.15; SE=0.07). Also SOD is statistically significantly associated with Cd-B (B=62.96; SE=29.62). The association between SOD and Cd-U is of borderline statistical significance (B=37.69; SE=19.59). CONCLUSIONS: While there is still some debate as whether the Cd-induced tubular effects are reversible or not, IAP and SOD appear as sensitive and potentially useful early biomarkers for the health surveillance of workers exposed to low levels of Cd. PMID- 23104736 TI - The cellular origins of disease - from bench to bedside. PMID- 23104734 TI - The Upper Midwest Health Study: gliomas and occupational exposure to chlorinated solvents. AB - OBJECTIVES: Occupational exposure to chlorinated aliphatic solvents has been associated with an increased cancer risk, including brain cancer. However, many of these solvents remain in active, large-volume use. We evaluated glioma risk from non-farm occupational exposure (ever/never and estimated cumulative exposure) to any of the six chlorinated solvents--carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, tetrachloroethylene or 1,1,1- trichloroethane-among 798 cases and 1175 population-based controls, aged 18-80 years and non-metropolitan residents of Iowa, Michigan, Minnesota and Wisconsin. Methods Solvent use was estimated based on occupation, industry and era, using a bibliographic database of published exposure levels and exposure determinants. Unconditional logistic regression was used to calculate ORs adjusted for frequency matching variables age group and sex, and age and education. Additional analyses were limited to 904 participants who donated blood specimens (excluding controls reporting a previous diagnosis of cancer) genotyped for glutathione-S transferases GSTP1, GSTM3 and GSTT1. Individuals with functional GST genes might convert chlorinated solvents crossing the blood-brain barrier into cytotoxic metabolites. RESULTS: Both estimated cumulative exposure (ppm-years) and ever exposure to chlorinated solvents were associated with decreased glioma risk and were statistically significant overall and for women. In analyses comparing participants with a high probability of exposure with the unexposed, no associations were statistically significant. Solvent-exposed participants with functional GST genes were not at increased risk of glioma. CONCLUSIONS: We observed no associations of glioma risk and chlorinated solvent exposure. Large pooled studies are needed to explore the interaction of genetic pathways and environmental and occupational exposures in glioma aetiology. PMID- 23104737 TI - Keratins and disease at a glance. PMID- 23104738 TI - The emerging role of Polycomb repressors in the response to DNA damage. AB - Polycomb group (PcG) genes encode chromatin modifiers that are involved in the maintenance of cell identity and in proliferation, processes that are often deregulated in cancer. Interestingly, besides a role in epigenetic gene silencing, recent studies have begun to uncover a function for PcG proteins in the cellular response to DNA damage. In particular, PcG proteins have been shown to accumulate at sites of DNA double-strand breaks (DSBs). Several signaling pathways contribute to the recruitment of PcG proteins to DSBs, where they catalyze the ubiquitylation of histone H2A. The relevance of these findings is supported by the fact that loss of PcG genes decreases the efficiency of cells to repair DSBs and renders them sensitive to ionizing radiation. The recruitment of PcG proteins to DNA breaks suggests that they have a function in coordinating gene silencing and DNA repair at the chromatin flanking DNA lesions. In this Commentary, we discuss the current knowledge of the mechanisms that allow PcG proteins to exert their positive functions in genome maintenance. PMID- 23104740 TI - Speaking the truth: an analysis of gender differences in serostatus disclosure practices among HIV-infected patients in St Petersburg, Russia. AB - The Russian HIV epidemic is primarily fuelled by injection drug use, but heterosexual spread may be playing an increasing role in transmission. Government funded AIDS clinics provide most HIV treatment in Russia, and represent an important contact point between the medical community and infected population. Little is known about the population actively seeking HIV treatment. To describe demographics, perceived mode of acquisition and serostatus disclosure practices of HIV-infected individuals seeking treatment in St Petersburg, Russia, we conducted a cross-sectional study of 204 HIV-infected patients presenting to the St Petersburg City AIDS Center between May and June 2007. Mean age of respondents was 28 years old, 51% were women and two-thirds (67%) reported a history of injection drug use. Men were more likely to report injection (62% versus 45%) while women were more likely to identify sexual transmission (45% versus 32%) as their perceived infection route. Predictors of serostatus disclosure were female gender, married status and higher education. Women represent half of all patients seeking HIV treatment in St Petersburg, and are more likely than men to have disclosed their HIV-positive serostatus to sexual partners. While this population may not represent the burden of HIV disease in Russia, it is an important target group for secondary prevention. PMID- 23104739 TI - Leukocyte migration from a fish eye's view. AB - In the last five years, the zebrafish (Danio rerio) has rapidly gained popularity as a model system for studying leukocyte migration and trafficking in vivo. The optical clarity of zebrafish embryos, as well as the potential for genetic manipulation and the development of tools for live imaging, have provided new insight into how leukocytes migrate in response to directional cues in live animals. This Commentary discusses recent progress in our understanding of how leukocytes migrate in vivo, including the role of intracellular signaling through phosphatidylinositol 3-kinase (PI3K) in both random and directed migration. The importance of leukocyte reverse migration in the resolution of inflammation will also be discussed. Finally, we will highlight how zebrafish models have helped to provide new insight into leukocyte migration and the way in which migration is altered in disease. PMID- 23104741 TI - Gender differences in enrolment in an HIV-treatment programme in rural Lesotho, 2006-2008: a brief report. AB - The southern African nation of Lesotho has an HIV seroprevalence of approximately 25%. To address the need for HIV care in rural Lesotho, a project called the Rural Health Initative (RHI) was launched in seven clinics in 2006. Data on enrolment were collected retrospectively and analysed for trends in gender enrolment over time. Of 6001 enrolled, 3904 were women (65.1%) and 2097 (34.9%) were men. When analysed by month of enrolment, there was a higher percentage of men enrolled in December compared with the other months of the year (chi(2) = 15.98, P < 0.001). This may be due to the migratory work of the men in the mines of South Africa and suggests a need for targeted interventions to increase male enrolments over the entire calendar year. PMID- 23104742 TI - Predictors of the short- and long-term survival of HIV-infected patients admitted to a Brazilian intensive care unit. AB - The outcomes of HIV-infected patients requiring critical care have improved. However, in developing countries, information about HIV-infected patients admitted to intensive care units (ICUs) is scarce. We describe the prognosis of HIV-infected patients admitted to a Brazilian ICU and the factors predictive of short- and long-term survival. A historical cohort study, including HIV-infected patients admitted to a Brazilian ICU at an HIV/AIDS reference hospital, was conducted. Survivors were followed up for 24 months after ICU discharge. Demographic, clinical and laboratory data, disease severity scores and mortality were evaluated. Data were analysed using survival and regression models. One hundred and twenty-five patients were studied. In-ICU and in-hospital mortality rates were 46.4% and 68.0%, respectively. Multivariate analysis showed that the in-ICU mortality was significantly associated with APACHE (Acute Physiology and Chronic Health Evaluation) II scores (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.03-1.11), mechanical ventilation (OR, 6.39; 95% CI, 1.29-31.76), tuberculosis treatment (OR, 2.62; 95% CI, 1.03-6.71), use of antiretroviral therapy (OR, 0.19; 95% CI, 0.05-0.77) and septic shock (OR, 4.38; 95% CI, 1.78 10.76). Septic shock was also associated with long-term survival (hazard ratio, 3.0; 95% CI, 1.31-6.90). In-hospital and in-ICU mortality were higher than those reported for developed countries. ICU admission mostly due to AIDS-related diseases may explain these differences. PMID- 23104743 TI - Associations between drug use and risk behaviours for HIV and sexually transmitted infections among female sex workers in Yunnan, China. AB - This is a cross-sectional study of 399 subjects conducted to explore the association between drug use and risk behaviour for HIV and sexually transmitted infections (STIs) among female sex workers (FSWs), and also to study the prevalence of HIV/STIs among drug-using FSWs (DUFSWs) and non-DUFSWs in Yunnan province of China. Demographic information, mobility, sexual and drug-using behaviours were collected and subjects were tested for HIV/STIs. Mean age was 27 years (SD = +/-7.8) and 94 (23.6%) tested positive for recent opiate use. Compared with non-DUFSWs, DUFSWs had a significantly higher prevalence of HIV (38% versus 4%, P <= 0.001), herpes simplex virus type 2 (HSV-2; 92% versus 60%, P <= 0.001) and STIs (95.7% versus 69.2%, P <= 0.001). DUFSWs had a significantly longer duration of commercial sex work compared with non-DUFSWs (median 5 versus 1 years, P <= 0.001), and had at least two clients in the last working day. DUFSWs were also more likely to work in low-end commercial sex venues and frequented a greater number of work locations than non-DUFSWs. Compared with non DUFSWs, DUFSWs were more likely to exhibit riskier sexual behaviours and greater workplace mobility. Interventions targeting drug-related behavioural changes are needed urgently in this population in order to reduce rates of HIV and STIs. PMID- 23104744 TI - Recurrent vulvovaginal candidosis among young women in south eastern Nigeria: the role of lifestyle and health-care practices. AB - This work was carried out to study the association between lifestyle, health-care practices and incidence of recurrent vulvovaginal candidosis (RVVC) among young women in south eastern Nigeria. It was a multicentre case-control study of 176 women aged between 20 and 35 years recruited from the designated health facilities. Lifestyle and health-care practice structured questionnaires were used to survey the participants. Clinical examination was performed and vaginal swabs were taken from participants for microscopy, culture and sensitivity. The germ tube test was performed for identification of Candida albicans. The results of this study showed that frequent douching with water or other fluids (odds ratio [OR](adjusted) = 2.41, 95% confidence interval [CI] = 1.25-4.66, P = 0.000), wearing tight nylon/synthetic underwear (OR(adjusted) = 4.76, 95% CI = 2.28-9.95, P = 0.000), alternative medical treatment for repeated or recalcitrant cases (OR(adjusted) = 4.84, 95% CI = 2.94-15.91, P = 0.000), were significantly associated with higher odds for RVVC and self-diagnosis and use of over-the counter antifungal medications (OR(adjusted) = 4.61, 95% CI = 2.29-9.32, P = 0.000) were associated with RVVC. Results of the fungal cultures showed that C. albicans and non-C. albicans were isolated from 83.7% and 16.3% of participants, respectively. Our results supported the association between some of the hypothesized risk factors and the occurrence of RVVC. PMID- 23104745 TI - Trends of HIV-1, HIV-2 and dual infection in women attending outpatient clinics in Senegal, 1990-2009. AB - We assessed trends in the relative prevalences of HIV-1, HIV-2 and dual HIV-1/HIV 2 infection in 10,321 women attending outpatient clinics in Senegal between 1990 and 2009. The relative prevalence of HIV-1 (defined as the proportion of seropositive subjects having HIV-1) rose sharply from 38% in 1990 until 1993 (P < 0.001), whereupon it continued to rise, but at a slower rate, reaching 72% of HIV infections in 2009. As compared with HIV-1, the relative prevalence of HIV-2 decreased sharply from 54% in 1990 until 1993 (P < 0.001) and continued to decrease at a slower rate through 2009. The relative prevalence of dual infection, as compared with HIV-1, was stable from 1990 to 1993, but decreased slightly thereafter (P < 0.001). These study findings indicate that during the early 1990s, the relative prevalence of HIV-1 increased markedly, while the relative prevalence of HIV-2 decreased and the relative prevalence of dual infection remained stable in Senegal. From 1993 to 2009, the relative prevalence of HIV-1 increased at a slower rate, while the relative prevalences of HIV-2 and dual infection decreased. These results confirm trends in HIV prevalence observed in other West African populations and provide a critical update on HIV transmission risk among women in Senegal. PMID- 23104747 TI - Can HIV-1 incidence be estimated from plasma viral load and sexual behaviour? AB - To estimate the impact of sexual practices and HIV-1 viral load status on HIV-1 incidence, we surveyed 38 men who have sex with men (MSM) on their sexual practices in the past three months. HIV-1 RNA load was measured in semen and blood contemporaneously. A Bernoulli model was developed incorporating seminal plasma viral load (SPVL), number and serostatus of partners, and number of protected and unprotected episodes of anal intercourse. Probability of transmission according to SPVL was determined by sensitivity analysis based on the correlation between blood plasma viral load (BPVL) and SPVL. There was a BPVL threshold below which SPVL was low or undetectable and above which SPVL increased geometrically. Seven subjects infected 0.93 HIV-1-negative partners and 13 subjects infected 4.28 unknown serostatus partners. Probability estimates were heavily skewed by a small number of subjects with high rates of unprotected sex and multiple sexual partners. We conclude that more HIV-1 infections may occur from increased episodes of unprotected sex with multiple partners of unknown HIV 1 serostatus. The model can be used to counsel individuals or predict epidemics, and to assess behaviour change or the impact of public health interventions. PMID- 23104746 TI - Performance of absolute CD4+ count in predicting co-infection with human T lymphotropic virus type 1 in antiretroviral-naive HIV-infected patients. AB - Early identification of patients co-infected with HIV and human T-lymphotropic virus type 1 (HTLV-1) is essential to improve care, as CD4+ T-cell counts have been revealed to be an unreliable laboratory parameter to monitor HIV infection in co-infection. Unfortunately, HTLV-1 testing is not currently available in sub Saharan Africa. We conducted this study to determine the performance of absolute CD4+ T-cell count estimation in guiding the clinical suspicion of co-infection. A cross-sectional survey was conducted in antiretroviral-naive HIV (AN-HIV) patients attending an HIV outpatient clinic in Maputo city, Mozambique. Seven hundred and one AN-HIV patients were enrolled in the study. The prevalence of HTLV-1 co-infection was 4.5% (95% confidence interval [CI] 3.0-6.0%). Logistic regression analysis showed that CD4+ T-cell count was an independent predictor of co-infection (P value: 0.000). The performance of absolute CD4+ T-cell counts in predicting co-infection was higher in symptomatic HIV patients when compared with asymptomatic HIV patients. The best performance was achieved with the cut-off of CD4+ count of 500 cells/mm(3), which gave sensitivity, specificity, positive and negative predictive values of 54.2%, 87.2%, 24.0% and 96.2%, respectively. In conclusion, our data provide evidence that the absolute CD4+ T-cell count is of moderate accuracy in guiding the clinical suspicion of co-infection in AN-HIV and its implementation could improve the care provided to a significant number of HIV patients in Mozambique. PMID- 23104748 TI - Risk factors for HIV-1 infection in India: evidence from the National Family Health Survey. AB - To study demographic, social, behavioural and biological variables as risk factors for HIV infection among men and women in India, we used data from the cross-sectional, population-based National Family Health Survery (NFHS)-3 2005 06. During the survey, 52,853 women aged 15-49 years and 50,093 men aged 15-54 years gave consent to anonymous HIV testing. HIV serostatus data for men and women were analysed for their relationships to key characteristics using bivariate and multivariate techniques. In the analysis of the study sample, in both men and women the ages of highest risk for HIV were between 25 and 34 years. Married, widowed, divorced women and men had higher odds of being HIV-positive; employed individuals also had a higher risk of being HIV-positive (odds ratio [OR] = 1.89 and 2.89, respectively). Muslim women had a lower risk (OR 0.23). Wealth was not found to be associated with HIV serostatus among men in our study sample. In women, a history of genital ulcer or sore significantly increased their risk. Circumcised men were found to be at a lower risk for HIV infection. HIV is a multi-dimensional epidemic, with demographic, residential, social, biological and behavioural factors exerting influence on individual probability of becoming infected with HIV. PMID- 23104749 TI - Anticipated changes in sexual risk behaviour following vaccination with a low efficacy HIV vaccine: survey results from a South African township. AB - We assessed the potential for anticipated changes in sexual risk-taking behaviour following hypothetical administration of a low-efficacy preventive HIV vaccine. We developed a survey and collected self-reported data from 158 HIV-negative volunteers in a cohort undergoing prescreening for Phase I/II HIV vaccine trials in Soweto. Overall, 22% reported they might use condoms less frequently; 9% reported that they might increase their frequency of sex with casual/anonymous partners; and 55% reported their sexual partners might want to use condoms less frequently knowing they were vaccinated. Multivariate analyses revealed that anticipated decrease in condom use was predicted by poor comprehension and by young age. Individuals may increase their risk-taking behaviour knowing that a vaccine would provide only incomplete protection against HIV transmission. In HIV vaccine trials and future vaccination programmes, education and risk-reduction counselling will be needed for vaccinated individuals and their partners, and mass media education campaigns may be necessary. PMID- 23104751 TI - Chlamydial partner notification in the British Association for Sexual Health and HIV (BASHH) 2011 UK national audit against the BASHH Medical Foundation for AIDS and Sexual Health Sexually Transmitted Infections Management Standards. AB - This paper reports on chlamydial partner notification (PN) performance in the 2011 BASHH national audit against the British Association for Sexual Health and HIV (BASHH) Medical Foundation for AIDS Sexual Health (MedFASH) Sexually Transmitted Infection Management Standards (STIMS). There was wide regional variation in level 3 clinic PN performance against the current standard of index case-reported chlamydial PN, with 43% (regional range 0-80%) of clinics outside London meeting the >=0.6 contacts seen per index standard, and 85% of clinics (regional range 82-88%) in London meeting the >=0.4 standard. For level 2 clinics, 39% (regional range 0-100%) of clinics outside London met the >=0.6 standard, and 43% (regional range 40-50%) of clinics in London met the >=0.4 standard. Performance for health-care worker (HCW)-verified contact attendance is also reported. New standards for each of these performance measures are proposed for all level 3 clinics: >=0.6 contacts seen per index case based on index case report, and >=0.4 contacts seen per index case based on HCW verification, both within four weeks of the first partner notification interview. The results are discussed with regard to the importance of adoption of standards by commissioners of services, relevance to national quality agendas, and the need for development of a national system of PN quality assurance measurement and reporting. PMID- 23104750 TI - UK national audit against the key performance indicators in the British Association for Sexual Health and HIV Medical Foundation for AIDS and Sexual Health Sexually Transmitted Infections Management Standards. AB - A national audit of practice performance against the key performance indicators in the British Association for Sexual Health and HIV (BASHH) and HIV Medical Foundation for AIDS Sexual Health Standards for the Management of Sexually Transmitted Infections (STIs) was conducted in 2011. Approximately 60% and 8% of level 3 and level 2 services, respectively, participated. Excluding partner notification performance, the five lowest areas of performance for level 3 clinics were the STI/HIV risk assessment, care pathways linking care in level 2 clinics to local level 3 services, HIV test offer to patients with concern about STIs, information governance and receipt of chlamydial test results by clinicians within seven working days (the worst area of performance). The five lowest areas of performance for level 2 clinics were participating in audit, having an audit plan for the management of STIs for 2009-2010, the STI/HIV risk assessment, HIV test offer to patients with concern about STIs and information governance. The results are discussed with regard to the importance of adoption of the standards by commissioners of services because of their relevance to other national quality assurance drivers, and the need for development of a national system of STI management quality assurance measurement and reporting. PMID- 23104752 TI - Lung cancer in HIV-infected patients: the experience in Brescia from 1999 to 2009. AB - Lung cancer (LC) is the most common cancer among the non AIDS-defining malignancies in the highly active antiretroviral therapy (HAART) era. We described 23 HIV infected patients with a LC diagnosis followed in the Clinic of Tropical and Infectious Diseases of Brescia during the period of 1999-2009. All of these patients except two (n = 21, 91.3%) were cigarette smokers and all had at least one risk factor for developing cancer of the lung, or predisposing comorbidities, such as a COPD (chronic obstructive pulmonary disease) or a previous pneumonia. The median age at LC diagnosis was 53.6 years (range 21.2 71.4 years). Adenocarcinoma and squamous cell carcinoma were diagnosed in 10 cases (43.5%) respectively. In 21 subjects (91.3%) cancer was detected at stage IV with metastases. The median survival was 5.95 months. Greater intervention focused on the cessation of smoking is necessary, as well as the implementation of closer screening policies, especially in HIV-positive subjects with LC risk factors. PMID- 23104753 TI - Optimal treatment for asymptomatic neurosyphilis. AB - In the pre-penicillin era, patients with asymptomatic neurosyphilis (ANS) were more likely to develop long-term neurological sequelae than those patients with normal cerebrospinal fluid (CSF). Although benzathine penicillin G cannot achieve treponemicidal levels in the CSF, decreased rates of neurological complications of syphilis and non-treponemal titre serological responses are usually observed after treatment with this antibiotic. We here a homosexual man with ANS successfully treated with benzathine penicillin G. This case suggests that reconsideration on the necessity of a lumbar puncture in HIV-infected patients with ANS is warranted. PMID- 23104754 TI - Treponemicidal levels of amoxicillin can be achieved in cerebrospinal fluid following oral treatment with only 4 g amoxicillin and 2 g probenecid daily in late stage syphilis. PMID- 23104755 TI - Atazanavir-related hyperbilirubinaemia is not highlighted in the British National Formulary. PMID- 23104756 TI - Timing of antiretrovirals in opportunistic infections. PMID- 23104757 TI - Screening for HIV among substance users undergoing detoxification. AB - The primary aim of this study was to investigate HIV infection among drug users. A total of 3538 drug users were, registered at the Outpatient Department of Central Drug Addiction Treatment Centre (CTC), Tejgoan, Dhaka, from July 2007 to June 2008. Of them, 43.2% were residents of Dhaka City and the others (56.8%) were from the different districts of Bangladesh. Among them, 1196 were recruited consecutively following defined selection criteria. Interviewer-administered questionnaires were completed and blood specimens taken. Results showed that only 0.67% were HIV-seropositive. Their socioeconomic profile included 75.0% educated, 62.5% unemployed, age ranged from 30 to 50 years, and all were married. They used heroin primarily with other illicit substances used occasionally. They reported that needle sharing when using injection drugs was infrequent. Drug users had sex with multiple commercial sexual partners and did not use condoms during sex. While Bangladesh is in the midst of international drug-trafficking and drug producing zones, and lies near high HIV prevalence countries, the country is in the embryonic stage of an HIV epidemic. Nationwide preventive measures are warranted in Bangladesh. PMID- 23104759 TI - Prevalence of hepatitis C infection in HIV-seropositive individuals in and around Belgaum, south India. AB - India has high prevalence of HIV infection. As HIV and HCV share common routes of transmission, there is every chance of an HIV-infected patient also having HCV infection. We investigated the prevalence of HCV infection in HIV seropositive individuals attending a tertiary care hospital at Belgaum, south India. A total of 16,124 serum samples from suspected patients were screened for the presence of HIV antibodies and those who tested positive for HIV were screened for HCV antibodies by using enzyme-linked immunosorbent assay (ELISA). A total of 24 (3.52%) patients were found to be co-infected with HIV and HCV. Among them, 16 (66.66%) were male and 8 (33.33%) were female. This study has revealed a relatively high prevalence of HIV/ HCV co-infection in and around Belgaum which suggests preventive and control measures should be taken against the spread of such infection in this part of India. PMID- 23104758 TI - Prevalence and associations with hepatitis B and hepatitis C infection among HIV infected adults in South Africa. AB - We assessed prevalence and factors associated with hepatitis B in a cross section of HIV-infected primary care and antinatal clinic patients in South Africa and evaluated a rapid hepatitis B surface antigen (HBsAg) assay. We enrolled 998 patients; 88% were women, median age was 29 years and median CD4 count was 354 cells/mm(3). HBsAg enzyme-linked immunosorbent assay (ELISA), anti-hepatitis B core (HBc) antibodies and hepatitis C virus antibody were positive among 4.2%, 37% and 0.1% of subjects, respectively. Univariate and multivariate associations were assessed using logistic regression. Anti-HBc antibodies were associated with alcohol use, traditional medicines and higher CD4 counts; HBsAg positivity was associated with lower CD4. Compared with the HBsAg ELISA, a rapid HBsAg test had a sensitivity of 75.0% and specificity of 99.6%. In conclusion, we identified a moderate prevalence of both HBsAg and anti-HBc. Importantly, we found that subjects with HBsAg positivity had lower CD4 counts. PMID- 23104760 TI - Characterizing viral subtypes to assess patterns of HIV transmission. AB - We characterized HIV-1 subtypes among 204 persons newly diagnosed with HIV in Ontario from 2003 to 2005 using samples from the Canadian HIV Strain and Drug Resistance Surveillance Program. We examined HIV-1 subtype by demographic characteristics and exposure category, and determined independent predictors of infection with a non-B HIV subtype using multivariate logistic regression. The distribution of HIV subtypes was: B 77.0%, C 10.3%, AG 4.9%, A 2.5%, AE 2.5% and others 3.0%. Overall, 23.0% were non-B, greater in women than in men (62.8% versus 12.4%, P < 0.0001) and persons under 35 years (31.1% versus 18.5% in those >=35, P = 0.04). Non-B subtype was predominant (78.9%) among persons from HIV endemic regions and considerable (28.6%) among other persons infected heterosexually. In multivariate modelling adjusted for gender, non-B subtype was significantly associated with birth in an HIV-endemic region (adjusted odds ratio [aOR] 59.2, P < 0.0001) and heterosexual exposure (aOR 6.3, P = 0.02). Additionally, compared with men who had sex with men, non-B subtype was greater among heterosexual women (aOR 17.8, P < 0.001) and women who injected drugs (injection drug use, aOR 13.4, P = 0.01). We found a non-negligible proportion of non-B subtypes among women infected heterosexually not from HIV-endemic countries, providing interesting insights into HIV transmission patterns. PMID- 23104761 TI - Smoking and overweight determine the likelihood of developing rheumatoid arthritis. AB - OBJECTIVES: Rheumatoid arthritis (RA) is a prototypic chronic inflammatory disease with a debilitating course if untreated. A genetic predisposition for RA is known, and its occurrence is associated with the presence of autoantibodies in the serum and with environmental factors. It is unknown if smoking and overweight are contributory factors for developing RA in individuals with RA-specific autoantibodies in the serum. METHODS: Fifty-five individuals at risk for developing RA, based on the presence of RA-specific autoantibodies in the serum, who never had any evidence of arthritis upon physical examination, were followed over time. Smoking was assessed as being never or ever smoker and body mass index as <25 (normal) or >=25 kg/m2 (overweight). Clinical endpoint was the occurrence of arthritis. Proportional hazard regression analysis was performed to investigate the potential of (combinations of) variables in predicting the onset of arthritis over time. RESULTS: After a median follow up time of 13 (IQR 6-27) months, 15 individuals (27%) developed arthritis. Smoking was associated with the development of arthritis (HR (95% CI): 9.6 (1.3 to 73.0); p=0.029). Overweight was, independently of smoking, associated with arthritis (HR (95% CI): 5.6 (1.3 to 25.0); p=0.023). The overall arthritis risk of 28% after a median of 27 months follow up increased to 60% in individuals with a smoking history combined with overweight. CONCLUSIONS: This is the first prospective study showing that smoking and overweight increase the risk of development of arthritis in a cohort of autoantibody-positive individuals at risk for developing RA. These results show the importance of life style factors in development of RA and should be critically evaluated in future clinical research aimed at disease prevention. PMID- 23104762 TI - Metabolic health in families enriched for longevity is associated with low prevalence of hand osteoarthritis and influences OA biomarker profiles. AB - OBJECTIVES: Individual metabolic characteristics and age-related changes may affect osteoarthritis (OA) risk as well as levels of potential OA biomarkers such as serum cartilage oligomeric protein (sCOMP) and urinary cross-linked C telopeptide of type 2 collagen (uCTX2). We investigated hand OA and these putative OA biomarker characteristics at different ages in individuals with a propensity for healthy ageing, in controls, and in patients with OA. METHODS: We investigated hand radiological OA (ROA) and levels of sCOMP and uCTX2 in the Leiden Longevity Study, which consisted of the middle-aged offspring of long lived sibling pairs as metabolically healthy agers and their partners as controls, and for ROA we compared patients with OA at multiple joint sites from the Genetics, osteoARthritis and Progression Study with the healthy agers and controls. RESULTS: Hand ROA mean scores were lower in the healthy agers than in controls. Lower hand ROA scores at higher ages were observed in healthy agers with low glucose levels. Furthermore, in healthy agers, a higher mean sCOMP level was observed than in controls. All study groups had higher sCOMP levels at higher chronological age. Likewise, uCTX2 levels were higher at higher chronological age in the controls and patients with OA, which was not observed in the healthy agers. CONCLUSIONS: Metabolic health in middle age is associated with less ROA and influences putative OA marker profiles, independently of chronological age. When used as OA biomarkers, it is relevant that independently of hand ROA status, uCTX2 is influenced by healthy metabolism and sCOMP is higher at higher chronological age. PMID- 23104763 TI - Simultaneous measurement of the silicon content and physiological parameters by FTIR spectroscopy in diatoms with siliceous cell walls. AB - Diatoms are the most successful biomass producers worldwide. Therefore, physiological and chemical methods to measure the cell response to a variety of abiotic factors are the focus of recent research. We used the two model diatoms Cyclotella meneghiniana and Skeletonema costatum for the development of Fourier transform infrared (FTIR) spectroscopy-based methods to measure simultaneously the elemental composition of the cells and their cell-specific physiological properties. The cells were grown in chemostat cultures to study the response of Si limitation. The model organisms showed different reactions in terms of their cell properties. Si limitation was accompanied by a drop in the growth rate, a reduced content in Si per cell and a decreased Si : C ratio. Furthermore, the C allocation pattern was changed in both diatoms under Si limitation, as shown by FTIR spectroscopy. Moreover, we used FTIR spectra to develop PLS (partial least square) regression methods to predict the Si content and the Si : C ratio for single as well as multiple species. All PLS regression models were validated by standard chemical methods and showed good prediction accuracy, with the coefficient of determination R(2) being >=0.93. We could show that it is possible to monitor phytoplankton properties such as C allocation, the Si content and the Si : C ratio at the same time via FTIR spectroscopy. PMID- 23104764 TI - Involvement of OsJAZ8 in jasmonate-induced resistance to bacterial blight in rice. AB - The plant hormone jasmonic acid (JA) has a crucial role in both host immunity and development in plants. Here, we report the importance of JA signaling in the defense system of rice. Exogenous application of JA conferred resistance to bacterial blight caused by Xanthomonas oryzae pv. oryzae (Xoo) in rice. Expression of OsJAZ8, a rice jasmonate ZIM-domain protein, was highly up regulated by JA. OsJAZ8 interacted with a putative OsCOI1, which is a component of the SCF(COI1) E3 ubiquitin ligase complex, in a coronatine-dependent manner. OsJAZ8 also formed heterodimers with other OsJAZ proteins but did not form homodimer. JA treatment caused OsJAZ8 degradation and this degradation was dependent on the 26S proteasome pathway. Furthermore, the JA-dependent OsJAZ8 degradation was mediated by the Jas domain. Transgenic rice plants overexpressing OsJAZ8DeltaC, which lacks the Jas domain, exhibited a JA-insensitive phenotype. A large-scale analysis using a rice DNA microarray revealed that overexpression of OsJAZ8DeltaC altered the expression of JA-responsive genes, including defense related genes, in rice. Furthermore, OsJAZ8DeltaC negatively regulated the JA induced resistance to Xoo in rice. On the basis of these data, we conclude that JA plays an important role in resistance to Xoo, and OsJAZ8 acts as a repressor of JA signaling in rice. PMID- 23104766 TI - Safety of florfenicol administered in feed to tilapia (Oreochromis sp.). AB - The safety of Aquaflor((r)) (50% w/w florfenicol [FFC]) incorporated in feed then administered to tilapia for 20 days (2* the recommended duration) at 0, 15, 45, or 75 mg/kg body weight/day (0, 1, 3, or 5* the recommended dose of 15 mg FFC/kg BW/d) was investigated. Mortality, behavioral change, feed consumption, body size, and gross and microscopic lesions were determined. Estimated delivered doses were >96.9% of target. Three unscheduled mortalities occurred but were considered incidental since FFC-related findings were not identified. Feed consumption was only affected during the last 10 dosing days when the 45 and 75 mg/kg groups consumed only 62.5% and 55.3% of the feed offered, respectively. There were significant, dose-dependent reductions in body size in the FFC-dose groups relative to the controls. Treatment-related histopathological findings included increased severity of lamellar epithelial hyperplasia, increased incidence of lamellar adhesions, decreased incidence of lamellar telangiectasis in the gills, increased glycogen-type and lipid-type hepatocellular vacuolation in the liver, decreased lymphocytes, increased blast cells, and increased individual cell necrosis in the anterior kidney, and tubular epithelial degeneration and mineralization in the posterior kidney. These changes are likely to be of minimal clinical relevance, given the lack of mortality or morbidity observed. This study has shown that FFC, when administered in feed to tilapia at the recommended dose (15 mg FFC/kg BW/day) for 10 days would be well tolerated. PMID- 23104765 TI - Epidemiological and experimental links between air pollution and type 2 diabetes. AB - There is increasing evidence suggesting links between exposure to environmental toxins and susceptibility to type 2 diabetes mellitus (DM). In this review, we summarize the experimental evidence to support this association that has been noted in many epidemiologic studies. Inflammation in response to particulate matter (PM(2.5)) exposure in air pollution represents a common mechanism that may interact with other pro-inflammatory influences in diet and life style to modulate susceptibility to cardiometabolic diseases. The role of innate immune cytokines released from macrophages in the lung is well known. In addition, chemokine triggers in response to air-pollution exposure may mediate a cellular response from the bone marrow/spleen through toll-like receptors (TLRs) and Nucleotide Oligomerization Domain receptors (NLRs) pathways to mediate inflammatory response in organs. Emerging data also seem to support a role for PM(2.5) exposure in endoplasmic reticulum stress-induced apoptosis and in brown adipose tissue dysfunction. Decreased expression of UCP1 in brown adipose tissue may account for reduced thermogenesis providing another link between PM(2.5) and insulin resistance. The implications of an experimental link between air pollution exposure and type 2 DM are profound as air pollution is a pervasive risk factor throughout the world and even modest alleviation in exposure may provide substantial public health benefits. PMID- 23104768 TI - Spontaneous nonmetastatic choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and teratoma in the testes of a swiss albino mouse. AB - A 12-week-old Swiss Albino mouse was presented with unilateral (left) testicular enlargement of approximately 1.5 cm in diameter and the right testicle mildly reduced in size and weight. Histopathology evaluation revealed three distinct neoplasms in the left testicle: choriocarcinoma, yolk sac carcinoma, and embryonal carcinoma. Teratoma was diagnosed in the right testicle. The histomorphological and immunohistochemical characteristics of the tumor are presented here. To the best of the authors' knowledge, this is the first report of spontaneous nonmetastasizing choriocarcinoma, yolk sac carcinoma, embryonal carcinoma, and teratoma in testes of a Swiss albino mouse. PMID- 23104767 TI - Decrease in respiratory function and electron transport chain induced by airborne particulate matter (PM10) exposure in lung mitochondria. AB - Particulate matter, with a mean aerodynamic diameter of <=10 um (PM10), exposure is considered as a risk factor for cardiovascular and respiratory diseases. The mechanism of cell damage induced by PM10 exposure is related to mitochondrial alterations. The aim of this work was to investigate the detailed alterations induced by PM10 on mitochondrial function. Since lung tissue is one of the most important targets of PM10 inhalation, isolated mitochondria from lung rat tissue were exposed to PM10 and structural alterations were analyzed by transmission electron microscopy. Mitochondrial function was evaluated by respiratory control index (RCI), membrane potential, adenosine triphosphate (ATP) synthesis, and activity of respiratory chain. Results showed that exposure to PM10 in isolated mitochondria from lung tissue caused enlarged intermembrane spaces and shape alterations, disruption of cristae, and the decrease in dense granules. Oxygraphic traces showed a concentration-dependent decrease in oxygen consumption and RCI. In addition, mitochondrial membrane potential, ATP synthesis, and activity of complexes II and IV showed an increase and decrease, respectively, after PM10 exposure. PM10 exposure induced disruption in structure and function in isolated mitochondria from lung rat tissue. PMID- 23104769 TI - What counts as cultural competency in telehealth interventions? A call for new directions. PMID- 23104770 TI - Awareness and practice of telemedicine among staff of the Federal Medical Centre at Birnin Kebbi, Nigeria. PMID- 23104771 TI - Attitudes of women in midlife to web-based interventions for promoting physical activity. AB - We explored the attitudes of women at midlife to web-based interventions for promoting physical activity. 145 women volunteered to participate in one of four online forums. The forums were for four major racial/ethnic groups. 90 volunteers were recruited for the online forums (29 Whites, 23 Hispanics, 21 African Americans, and 17 Asians). Two sets of topics on attitudes to physical activity and racial/ethnic contexts were used. Each topic had some introductory questions and related prompts, and these were posted on the online forum sites in a serial fashion during the six-month period. We used a thematic analysis. Four major themes emerged: (1) 'a matter of the source of the information'; (2) 'I can pace myself'; (3) 'lack of interpersonal interactions'; and (4) 'culture-specificity and low cost.' The women in all ethnic groups thought that the source of the information was much more important than the medium of the information (e.g. web based, booklet or face-to-face). They liked the self-controllability in web-based interventions. They preferred web-based interventions to other types of interventions because of easy accessibility, but they were concerned about lack of interpersonal interaction. None of the White or African American women indicated the need for culture-specificity in web-based interventions, but Hispanic and Asian women indicated that culture-specific interventions should be provided. Web-based interventions appear to have several advantages over conventional approaches to promoting physical activity. PMID- 23104772 TI - Perthes' disease of the hip: socioeconomic inequalities and the urban environment. AB - INTRODUCTION: Perthes' disease is a puzzling childhood hip disorder for which the aetiology is unknown. It is known to be associated with socioeconomic deprivation. Urban environments have also been implicated as a risk factor, however socioeconomic deprivation often occurs within urban environments and it is unclear if this association is the result of confounding. The objective of the current work was to gain a greater understanding of the influence of the urban/rural environment in Perthes' disease. METHODS: This was a descriptive observational study using the Scottish Morbidity Record, based in Scotland, UK using data from 2000-2010. A total of 443 patients with a discharge diagnosis of Perthes' disease were included. Socioeconomic deprivation was determined using the Scottish Index of Multiple Deprivation, and exposure to the 'urban environment' was recorded based on the Scottish Urban-Rural Classification. RESULTS: There was a strong association with socioeconomic deprivation, with rates among the most deprived quintile more than twice those of the most affluent (RR 2.1 (95% CI 1.5 to 2.9)). Urban areas had a greater rate of Perthes' disease discharges (RR 1.8 (95% CI 1.1 to 3.2)), though this was a reflection of greater deprivation in urban areas. Stratification for socioeconomic deprivation revealed similar discharge rates in urban and rural environments, suggesting that the aetiological determinants were not independently associated with urban environments. CONCLUSIONS: The occurrence of Perthes' disease within urban environments is high, yet this appears to be a reflection of higher socioeconomic deprivation exposure. Disease rates appear equivalent in similarly deprived urban and non-urban areas, suggesting that the determinant is not a consequence of the urban environment. PMID- 23104773 TI - Drug therapy for children with tuberculosis. AB - The scientific basis of drug treatment for both active tuberculosis (TB) disease and TB infection, has been established, with treatment in children being largely extrapolated from adult active disease trials. It is essential that active TB disease is excluded before asymptomatic TB infection is diagnosed and treated. Nearly half of all children with active TB disease are found as asymptomatic tuberculin, or interferon gamma release assay (IGRA), positive contacts on screening by local TB services, usually of sputum TB microscopy positive adult relatives or other index cases, but with evidence of lung infiltrate or mediastinal lymphadenopathy on the child's chest x-ray. New drug regimens for both active disease and latent infection are in development, and also some novel drugs. However, none of these have yet been tested in children, and so again data will need to be extrapolated from adult results. In addition, there are issues regarding pharmacokinetics and dosing for current drugs, particularly isoniazid. PMID- 23104774 TI - Surrey to open a new vet school. PMID- 23104775 TI - TB testing and surveillance to be strengthened in England. PMID- 23104776 TI - Badger cull postponed. PMID- 23104777 TI - Veterinary Nurses Council celebrates its first decade. PMID- 23104778 TI - AHVLA confirms spread of SBV in 2012. PMID- 23104780 TI - A(SP)A to be extended to cover all live cephalopods. PMID- 23104783 TI - Campaign aims to 'make neutering the norm'. PMID- 23104785 TI - Using antimicrobials responsibly in large and small animals. PMID- 23104786 TI - Horses for sport: how far should vets go to keep them running? PMID- 23104788 TI - Evaluating surveillance programmes: ensuring value for money. PMID- 23104789 TI - Dog owners' perceptions of breed-specific dangerous dog legislation in the UK. AB - The aim of this study was to identify both the level and source of knowledge that dog owners in the UK have of the Dangerous Dogs Act 1991. In order to acquire such information a questionnaire was designed and distributed using two main methods over a period of five months. Questionnaires were distributed via three pet-related online forums and by hand at two locations within five predefined areas in England. In total, 459 responses were received. Of these, 21.4 per cent were unable to name a single type of banned dog and 81.9 per cent of respondents agreed that information on dog legislation was not publicised enough. The knowledge of banned breeds among the dog owners surveyed was low and respondents expressed a desire to see the law relating to dangerous dogs in the UK either changed or improved. PMID- 23104790 TI - Waste milk feeding, antibiotic resistance and animal by-products regulations. PMID- 23104791 TI - Equine practitioner participation required for colic survey. PMID- 23104792 TI - Controlling TB and reducing food waste. PMID- 23104793 TI - Advanced nursing practice in menopause nursing. AB - Advanced nursing practice is a complex term that has been explored over the last 10 years within nursing as nurses have changed the boundaries of their clinical care to try and meet the needs of their patients in a rapidly changing health care setting. These roles are attractive to nurses as they can remain primarily clinically based as they progress within their careers. However there is currently no standardization in relation to job titles, educational provisions or regulations. The Department of Health issued guidance in 2010, but there is nothing mandatory to date. This short article will look at the issues involved in advanced practice in menopause nursing. PMID- 23104794 TI - First-trimester reference ranges for decidual thickness and its relation to progesterone levels. AB - AIMS: The present study aimed to provide normal reference ranges for decidual thickness measured ultrasonographically in healthy first-trimester pregnancies and to evaluate whether there was a relationship between decidual thickness and serum progesterone levels. METHODS: Decidual thickness of 173 women with a healthy gestation between 6+0 and 9+6 weeks was measured ultrasonographically and serum progesterone concentration was determined. Distribution of decidual thickness at each gestational week and its relation with serum progesterone levels was evaluated. RESULTS: Mean decidual thickness was 6.8, 5.7, 5.5, and 6.1 mm at 6th, 7th, 8th, and 9th gestational weeks, respectively. Decidual thickness showed a mild negative correlation with gestational week (rho=-0.207, P=0.006) and a mild positive correlation with serum progesterone concentrations (rho=0.191, P=0.021). CONCLUSION: The present study provided normal reference ranges for decidual thickness in healthy pregnancies in the first trimester. The association found between decidual thickness and progesterone levels might shed light on further studies investigating the predictive factors of pregnancy loss and might lead to changes in the management of threatened miscarriage. PMID- 23104795 TI - Levels of cytokines in umbilical cord blood in relation to spontaneous term labor. AB - OBJECTIVE: Inflammatory mechanisms are thought to play an important role in the process of labor, both in preterm and spontaneous term delivery. We aimed to determine whether normal spontaneous vaginal delivery (SVD) at term was associated with an inflammatory activation compared with elective cesarean section (ECS) without previous onset of labor. METHODS: Cytokine concentrations were measured in venous cord blood obtained from 60 term newborns (ECS, n=35; SVD, n=25) born to mothers with clinically uneventful pregnancy and without signs of infection. RESULTS: Both study groups showed no differences in birth weight, umbilical artery pH, Apgar at 5 min, and gender distribution. Infants delivered by ECS had lower gestational age: mean, 38.5 weeks (range, 37.0-39.6 weeks) vs. mean, 39.8 weeks (range, 37.9-42.4 weeks) (P<0.001). Concentrations of interleukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p40, IL-12p70, IL-17, IL-1 receptor antagonist, soluble IL-2 receptor alpha, granulocyte-macrophage colony-stimulating factor, interferon (IFN)-alpha2, IFN gamma, tumor necrosis factor (TNF)-alpha, TNF-beta, and interferon inducible protein 10 were not different between ECS and SVD. Newborns after SVD displayed increased levels of transforming growth factor beta1 (TGF-beta1): mean, 8580 pg/mL (95% CI, 5554-11,606) vs. mean, 4864 pg/mL (95% CI, 2471-7257) (P<0.0012). CONCLUSIONS: Our findings suggest that, in healthy, term neonates, the exposition to normal spontaneous delivery and labor is not associated with systemic activation of different inflammatory mediators compared with ECS except for TGF beta1. Further studies are needed to evaluate the immunomodulatory role of labor associated TGF-beta1 increase in fetal cord blood. PMID- 23104796 TI - Survival and neonatal outcome after fetoscopic guided laser occlusion (FLOC) of twin-to-twin transfusion syndrome (TTTS) in Sweden. AB - AIM: To determine infant survival and neonatal outcome after fetoscopic laser treatment of twin-to-twin transfusion syndrome (TTTS). RESULTS: In 53/71(75%) laser-treated TTTS cases, at least one twin was liveborn and in 42/71(59%) cases at least one twin survived infancy. Fetal survival did not differ between donors [41/71(58%)] and recipients [46/71(65%), P=0.36]. Among liveborns, infant survival was 29/41(71%) in donors and 36/46(78%) in recipients (P=0.12). Infant survival did not correlate to maternal characteristics (age, BMI, smoking or parity), gestational age at treatment or severity of TTTS (Quintero stage). No TTTS infant born before 25 weeks of gestation survived the first week. Among the 87 infant survivors, 26 (30%) had an Apgar score <7 at 5 min, 47 (54%) developed respiratory distress syndrome, 10 (11%) showed signs of severe brain damage, nine (10%) renal failure, eight (9%) bronchopulmonary dysplasia, and five (6%) infants developed retinopathy of prematurity >=stage 3. There was no significant difference in neonatal morbidity between recipients and donors. CONCLUSIONS: Fetal survival after laser treatment was comparable to that reported by other international centers. There was no significant difference in survival or neonatal morbidity between donors and recipients. Major neonatal morbidity was common, and combined with extremely preterm delivery the prognosis of TTTS is poor. PMID- 23104797 TI - Is it necessary to induce labor in cases of intrauterine growth restriction at term? AB - OBJECTIVES: Infants with intrauterine growth restriction (IUGR) have increased morbidity and mortality. The decision whether to induce labor at term or to expectantly manage these pregnancies is controversial. The aim of this study was to assess the outcomes of these two management strategies in term pregnancies. STUDY DESIGN: This retrospective cohort study compared neonatal and maternal morbidity and mortality of IUGR fetuses (estimated fetal weight below the 10th percentile) between induced and spontaneous labors. RESULTS: Records of 669 IUGR newborns were reviewed; 499 were delivered through spontaneous labor and 170 were delivered through induced labor. Epidemiology and early perinatal outcomes between the two groups were similar. The cesarean section rate was significantly higher (P<0.005) in the induced group. CONCLUSIONS: Expectant management for term IUGR pregnancies seems to be safe, with lower rates of cesarean deliveries. A large, prospective, randomized controlled trial with long-term neonatal follow-up is indicated. PMID- 23104798 TI - Delayed interval delivery in twin and triplet pregnancies: 6 years of experience in one perinatal center. AB - OBJECTIVE: This study aimed to know the outcome of delayed-interval delivery for twin and triplet pregnancies at 22+0 to 25+0 weeks of gestation. STUDY DESIGN: A retrospective cohort of twin and triplet deliveries at the 23rd to 26th weeks of gestation were managed with delayed interval delivery from 2005 to 2011. RESULTS: From 2005 until 2011, delayed delivery in five twin pregnancies and two triplet pregnancies were performed. The interval between delivery of the first fetus and the remaining twin/triplets was 1-18 days (mean, 9.7 days). In all cases, the first fetus was born vaginally. Survival of the first twin/triplet was 14.3%, whereas 57.1% of the second born twin/triplets survived. Birth weight gained due to delayed delivery was 131 g on average. No severe maternal complications were observed. When compared with a gestation age-matched group, where the delay was not possible, the delayed twin/triplet had a higher survival rate (57.1% vs. 0%, P=0.05). CONCLUSION: In multiple pregnancies with preterm delivery between completed 22 and completed 25 weeks of gestational age, delayed delivery seems to be a useful therapeutic option to achieve a better outcome of the remaining fetus or fetuses. PMID- 23104799 TI - Rapid neonatal weight gain increases risk of childhood overweight in offspring of diabetic mothers. AB - AIM: Increased neonatal weight gain has been suggested as risk factor for later overweight. Offspring of diabetic mothers (ODM) have a long-term increased overweight risk. However, the role of early postnatal weight gain for later overweight has not been addressed so far in ODM. We investigated whether increased weight gain during the first 4 months is related to later overweight in ODM. METHODS: Determinants of childhood overweight and neonatal weight gain were analyzed in 152 ODM from the Kaulsdorf Cohort Study by MANOVA and regression analyses. RESULTS: Independent of birth weight, weight gain during the first 4 months was positively related to childhood relative body weight (P=0.001). Each 100 g-increase in weight during this period increased overweight risk by 65% (95%CI: 10-247%). ODM with rapid early weight gain had a more than six-fold increased risk of later overweight (OR: 6.77; 95%CI: 1.36-33.6). Early neonatal intake of breast milk from metabolically healthy mothers protected from rapid early weight gain (P=0.03). CONCLUSIONS: Increased weight gain during the first 4 months of life is a strong, independent risk factor for childhood overweight in ODM. Preventing nutritionally-induced rapid early weight gain in ODM might be a promising strategy to lower their long-term overweight risk. PMID- 23104800 TI - Transcriptional regulation of Aggregatibacter actinomycetemcomitans lsrACDBFG and lsrRK operons and their role in biofilm formation. AB - Autoinducer-2 (AI-2) is required for biofilm formation and virulence of the oral pathogen Aggregatibacter actinomycetemcomitans, and we previously showed that lsrB codes for a receptor for AI-2. The lsrB gene is expressed as part of the lsrACDBFG operon, which is divergently transcribed from an adjacent lsrRK operon. In Escherichia coli, lsrRK encodes a repressor and AI-2 kinase that function to regulate lsrACDBFG. To determine if lsrRK controls lsrACDBFG expression and influences biofilm growth of A. actinomycetemcomitans, we first defined the promoters for each operon. Transcriptional reporter plasmids containing the 255 bp lsrACDBFG-lsrRK intergenic region (IGR) fused to lacZ showed that essential elements of lsrR promoter reside 89 to 255 bp upstream from the lsrR start codon. Two inverted repeat sequences that represent potential binding sites for LsrR and two sequences resembling the consensus cyclic AMP receptor protein (CRP) binding site were identified in this region. Using electrophoretic mobility shift assay (EMSA), purified LsrR and CRP proteins were shown to bind probes containing these sequences. Surprisingly, the 255-bp IGR did not contain the lsrA promoter. Instead, a fragment encompassing nucleotides +1 to +159 of lsrA together with the 255-bp IGR was required to promote lsrA transcription. This suggests that a region within the lsrA coding sequence influences transcription, or alternatively that the start codon of A. actinomycetemcomitans lsrA has been incorrectly annotated. Transformation of DeltalsrR, DeltalsrK, DeltalsrRK, and Deltacrp deletion mutants with lacZ reporters containing the lsrA or lsrR promoter showed that LsrR negatively regulates and CRP positively regulates both lsrACDBFG and lsrRK. However, in contrast to what occurs in E. coli, deletion of lsrK had no effect on the transcriptional activity of the lsrA or lsrR promoters, suggesting that another kinase may be capable of phosphorylating AI-2 in A. actinomycetemcomitans. Finally, biofilm formation of the DeltalsrR, DeltalsrRK, and Deltacrp mutants was significantly reduced relative to that of the wild type, indicating that proper regulation of the lsr locus is required for optimal biofilm growth by A. actinomycetemcomitans. PMID- 23104801 TI - Solution structure of Escherichia coli FeoA and its potential role in bacterial ferrous iron transport. AB - Iron is an indispensable nutrient for most organisms. Ferric iron (Fe(3+)) predominates under aerobic conditions, while during oxygen limitation ferrous (Fe(2+)) iron is usually present. The Feo system is a bacterial ferrous iron transport system first discovered in Escherichia coli K-12. It consists of three genes, feoA, feoB, and feoC (yhgG). FeoB is thought to be the main transmembrane transporter while FeoC is considered to be a transcriptional regulator. Using multidimensional nuclear magnetic resonance (NMR) spectroscopy, we have determined the solution structure of E. coli FeoA. The structure of FeoA reveals a Src-homology 3 (SH3)-like fold. The structure is composed of a beta-barrel with two alpha-helices where one helix is positioned over the barrel. In comparison to the standard eukaryotic SH3 fold, FeoA has two additional alpha-helices. FeoA was further characterized by heteronuclear NMR dynamics measurements, which suggest that it is a monomeric, stable globular protein. Model-free analysis of the NMR relaxation results indicates that a slow conformational dynamic process is occurring in beta-strand 4 that may be important for function. (31)P NMR-based GTPase activity measurements with the N-terminal domain of FeoB (NFeoB) indicate a higher GTP hydrolysis rate in the presence of potassium than with sodium. Further enzymatic assays with NFeoB suggest that FeoA may not act as a GTPase activating protein as previously proposed. These findings, together with bioinformatics and structural analyses, suggest that FeoA may have a different role, possibly interacting with the cytoplasmic domain of the highly conserved core portion of the FeoB transmembrane region. PMID- 23104802 TI - The sigmaE pathway is involved in biofilm formation by Crohn's disease-associated adherent-invasive Escherichia coli. AB - Ileal lesions of patients with Crohn's disease are colonized by adherent-invasive Escherichia coli (AIEC) bacteria that are able to adhere to and invade intestinal epithelial cells (IEC), to replicate within macrophages, and to form biofilm. Clinical observations showed that bacterial biofilms were associated with the mucosa of inflammatory bowel disease patients. In the present study, we analyzed the relationship between AIEC colonization of the gut and the formation of biofilm, focusing on the involvement of the sigma(E) pathway in the AIEC-IEC interaction. We observed that sigma(E) pathway inhibition in AIEC reference strain LF82 led to an impaired ability to adhere to and invade IEC but also induced a large decrease in the abilities to colonize the intestinal mucosa and form biofilm. This indicates that targeting of the sigma(E) pathway could be a very potent therapeutic strategy by which to interfere with the ability of AIEC to form biofilm on the gut mucosa of Crohn's disease patients. PMID- 23104803 TI - MprAB regulates the espA operon in Mycobacterium tuberculosis and modulates ESX-1 function and host cytokine response. AB - The ESX-1 secretion system exports the immunomodulatory protein ESAT-6 and other proteins important in the pathogenesis of Mycobacterium tuberculosis. Components and substrates of ESX-1 are encoded at several loci, but the regulation of the encoding genes is only partially understood. In this study, we investigated the role of the MprAB two-component system in the regulation of ESX-1 activity. We determined that MprAB directly regulates the espA gene cluster, a locus necessary for ESX-1 function. Transcript mapping determined that the five genes in the cluster form an operon with two transcriptional start points, and several MprA binding sites were detected in the espA promoter. Expression analyses and promoter constructs indicated that MprAB represses the espA operon. However, the MprAB mutant Rv-D981 secreted lower levels of EspA, ESAT-6, and the ESX-1 substrate EspB than control strains. Secretion of CFP10, which is normally cosecreted with ESAT-6, was similar in Rv-D981 and control strains, further demonstrating aberrant ESX-1 activity in the mutant. ESAT-6 induces proinflammatory cytokines, and macrophages infected with Rv-D981 elicited lower levels of interleukin 1beta (IL-1beta) and tumor necrosis factor alpha (TNF alpha), consistent with the reduced levels of ESAT-6. These findings indicate that MprAB modulates ESX-1 function and reveal a new role for MprAB in host pathogen interactions. PMID- 23104804 TI - Antibacterial activity of alkyl gallates against Xanthomonas citri subsp. citri. AB - The plant-pathogenic bacterium Xanthomonas citri subsp. citri is the causal agent of Asiatic citrus canker, a serious disease that affects all the cultivars of citrus in subtropical citrus-producing areas worldwide. There is no curative treatment for citrus canker; thus, the eradication of infected plants constitutes the only effective control of the spread of X. citri subsp. citri. Since the eradication program in the state of Sao Paulo, Brazil, is under threat, there is a clear risk of X. citri subsp. citri becoming endemic in the main orange producing area in the world. Here we evaluated the potential use of alkyl gallates to prevent X. citri subsp. citri growth. These esters displayed a potent anti-X. citri subsp. citri activity similar to that of kanamycin (positive control), as evaluated by the resazurin microtiter assay (REMA). The treatment of X. citri subsp. citri cells with these compounds induced altered cell morphology, and investigations of the possible intracellular targets using X. citri subsp. citri strains labeled for the septum and centromere pointed to a common target involved in chromosome segregation and cell division. Finally, the artificial inoculation of citrus with X. citri subsp. citri cells pretreated with alkyl gallates showed that the bacterium loses the ability to colonize its host, which indicates the potential of these esters to protect citrus plants against X. citri subsp. citri infection. PMID- 23104805 TI - A single missense mutation in a coiled-coil domain of Escherichia coli ribosomal protein S2 confers a thermosensitive phenotype that can be suppressed by ribosomal protein S1. AB - Ribosomal protein S2 is an essential component of translation machinery, and its viable mutated variants conferring distinct phenotypes serve as a valuable tool in studying the role of S2 in translation regulation. One of a few available rpsB mutants, rpsB1, shows thermosensitivity and ensures enhanced expression of leaderless mRNAs. In this study, we identified the nature of the rpsB1 mutation. Sequencing of the rpsB1 allele revealed a G-to-A transition in the part of the rpsB gene which encodes a coiled-coil domain of S2. The resulting E132K substitution resides in a highly conserved site, TKKE, a so-called N-terminal capping box, at the beginning of the second alpha helix. The protruding coiled coil domain of S2 is known to provide binding with 16S rRNA in the head of the 30S subunit and, in addition, to interact with a key mRNA binding protein, S1. Molecular dynamics simulations revealed a detrimental impact of the E132K mutation on the coiled-coil structure and thereby on the interactions between S2 and 16S rRNA, providing a clue for the thermosensitivity of the rpsB1 mutant. Using a strain producing a leaderless lacZ transcript from the chromosomal lac promoter, we demonstrated that not only the rpsB1 mutation generating S2/S1 deficient ribosomes but also the rpsA::IS10 mutation leading to partial deficiency in S1 alone increased translation efficiency of the leaderless mRNA by about 10-fold. Moderate overexpression of S1 relieved all these effects and, moreover, suppressed the thermosensitive phenotype of rpsB1, indicating the role of S1 as an extragenic suppressor of the E132K mutation. PMID- 23104806 TI - Cell death of Streptococcus mutans induced by a quorum-sensing peptide occurs via a conserved streptococcal autolysin. AB - Streptococcus mutans, a member of the human indigenous oral microbiome, produces a quorum-sensing peptide called the competence-stimulating peptide (CSP) pheromone. We previously demonstrated that S. mutans expresses its CSP pheromone under specific stresses and responds to high levels of CSP by inducing cell death in a fraction of the bacterial population. Streptococci lack the classical SOS response, and the induction of the SigX regulon has been proposed to act as a general stress response in Gram-positive bacteria. We show here that inactivation of SigX abolished the CSP-induced cell death phenotype. Among SigX-regulated genes, SMU.836 (now named lytF(Sm)), encoding a conserved streptococcal protein, is a functional peptidoglycan hydrolase involved in CSP-induced cell lysis. We also demonstrated that LytF(Sm) is most likely a self-acting autolysin, since LytF(Sm) produced by attacker cells cannot trigger CSP-induced lysis of LytF(Sm) deficient target cells present in the same environment. Electron microscopy revealed important morphological changes accompanying autolysis of CSP-induced wild-type cultures that were absent in the LytF(Sm)-deficient mutant. The LytF(Sm) promoter was activated in the physiological context of elevated concentrations of the CSP pheromone under stress conditions, such as exposure to heat, hydrogen peroxide, and acid. In a long-term survival assay, the viability of a mutant deficient in LytF(Sm) autolysin was significantly lower than that observed for the wild-type strain. The results of this study suggest that cell death of S. mutans induced by its quorum-sensing CSP pheromone may represent a kind of altruistic act that provides a way for the species to survive environmental stresses at the expense of some of its cells. PMID- 23104807 TI - Characterization of a mazEF toxin-antitoxin homologue from Staphylococcus equorum. AB - Toxin-antitoxin (TA) systems encoded in prokaryotic genomes fall into five types, typically composed of two distinct small molecules, an endotoxic protein and a cis-encoded antitoxin of ribonucleic or proteinaceous nature. In silico analysis revealed seven putative type I and three putative type II TA systems in the genome of the nonpathogenic species strain Staphylococcus equorum SE3. Among these, a MazEF system orthologue termed MazEF(seq) was further characterized. 5' rapid amplification of cDNA ends (RACE) revealed the expression and the transcriptional start site of mazE(seq), indicating an immediately upstream promoter. Heterologous expression of the putative toxin-encoding mazF(seq) gene imposed growth cessation but not cell death on Escherichia coli. In vivo and in vitro, MazF(seq) was shown to cleave at UACAU motifs, which are remarkably abundant in a number of putative metabolic and regulatory S. equorum gene transcripts. Specific interaction between MazF(seq) and the putative cognate antitoxin MazE(seq) was demonstrated by bacterial two-hybrid analyses. These data strongly suggest that MazEF(seq) represents the first characterized TA system in a nonpathogenic Staphylococcus species and indicate that MazEF modules in staphylococci may also control processes beyond pathogenicity. PMID- 23104808 TI - The extracytoplasmic function sigma factor EcfO protects Bacteroides fragilis against oxidative stress. AB - The anaerobe Bacteroides fragilis is a highly aerotolerant, opportunistic pathogen that is an important component of the human intestinal microbiota. Aerotolerance has been linked to a robust oxidative stress response, which in turn is necessary for maximal virulence in a mouse intra-abdominal abscess model. During oxidative stress, there is a dynamic change in gene expression that encompasses a third of the genome, but there is a paucity of information on factors that control this response. A large number of transcription regulators, including about 14 extracytoplasmic function (ECF) sigma factors, are affected by oxidative stress, and one of these, EcfO, was used as a model of ECF sigma factor activity during stress. Genetic and biochemical experiments showed that EcfO was located in an operon with a structurally unique anti-sigma factor, Reo. Cells deleted for EcfO were impaired during exposure to oxygen or other forms of oxidative stress, whereas reo mutants were more resistant to stress. Protein protein interaction experiments demonstrated that Reo directly interacts with and regulates the activity of EcfO. Expression microarray and chromatin affinity precipitation assays were used to identify target genes regulated by EcfO, and an EcfO recognition sequence was identified. The results revealed that EcfO controls a regulon of novel lipoproteins whose distribution in nature is restricted to members of the Bacteroidetes phylum. PMID- 23104809 TI - Helicobacter pylori 5'ureB-sRNA, a cis-encoded antisense small RNA, negatively regulates ureAB expression by transcription termination. AB - Urease is an essential component of gastric acid acclimation by Helicobacter pylori. The increased level of urease in gastric acidity is due, in part, to acid activation of the two-component system consisting of the membrane sensor HP0165 (ArsS) and its response regulator HP0166 (ArsR), which regulates transcription of the seven genes in two separate operons (ureAB and ureIEFGH) of the urease gene cluster. Recently, we identified a novel cis-encoded antisense small RNA, 5'ureB sRNA, targeted at the 5' end of ureB, which downregulates ureAB expression by truncation of the ureAB transcript at neutral pH. It is not known whether the truncated transcript is due to transcription termination or processing of the full-length mRNA by codegradation of a ureAB mRNA-sRNA hybrid complex. S1 nuclease mapping assays show that the truncated transcript is due to transcription termination. Further studies using an in vitro transcription assay found that 5'ureB-sRNA promotes premature termination of transcription of ureAB mRNA. These results suggest that the antisense small RNA 5'ureB-sRNA downregulates ureAB expression by enhancing transcription termination 5' of ureB. With this mechanism, a limited amount of 5'ureB-sRNA is sufficient to regulate the relatively high level of ureAB transcript. PMID- 23104810 TI - Identification of transport proteins involved in free fatty acid efflux in Escherichia coli. AB - Escherichia coli has been used as a platform host for studying the production of free fatty acids (FFA) and other energy-dense compounds useful in biofuel applications. Most of the FFA produced by E. coli are found extracellularly. This finding suggests that a mechanism for transport across the cell envelope exists, yet knowledge of proteins that may be responsible for export remains incomplete. Production of FFA has been shown to cause cell lysis, induce stress responses, and impair basic physiological processes. These phenotypes could potentially be diminished if efflux rates were increased. Here, a total of 15 genes and operons were deleted and screened for their impact on cell viability and titer in FFA producing E. coli. Deletions of acrAB and rob and, to a lower degree of statistical confidence, emrAB, mdtEF, and mdtABCD reduced multiple measures of viability, while deletion of tolC nearly abolished FFA production. An acrAB emrAB deletion strain exhibited greatly reduced FFA titers approaching the tolC deletion phenotype. Expression of efflux pumps on multicopy plasmids did not improve endogenous FFA production in an acrAB(+) strain, but plasmid-based expression of acrAB, mdtEF, and an mdtEF-tolC artificial operon improved the MIC of exogenously added decanoate for an acrAB mutant strain. The findings suggest that AcrAB-TolC is responsible for most of the FFA efflux in E. coli, with residual activity provided by other resistance-nodulation-cell division superfamily-type efflux pumps, including EmrAB-TolC and MdtEF-TolC. While the expression of these proteins on multicopy plasmids did not improve production over the basal level, their identification enables future engineering efforts. PMID- 23104811 TI - Characterization of the functional domains of the SloR metalloregulatory protein in Streptococcus mutans. AB - Streptococcus mutans is a commensal member of the healthy plaque biofilm and the primary causative agent of dental caries. The present study is an investigation of SloR, a 25-kDa metalloregulatory protein that modulates genes responsible for S. mutans-induced cariogenesis. Previous studies of SloR homologues in other bacterial pathogens have identified three domains critical to repressor functionality: an N-terminal DNA-binding domain, a central dimerization domain, and a C-terminal FeoA (previously SH3-like) domain. We used site-directed mutagenesis to identify critical amino acid residues within each of these domains of the SloR protein. Select residues were targeted for mutagenesis, and nonconservative amino acid substitutions were introduced by overlap extension PCR. Furthermore, three C-terminally truncated SloR variants were generated using conventional PCR. The repressor functionality and DNA-binding ability of each variant was assessed using CAT reporter gene assays, real-time semiquantitative reverse transcriptase (qRT)-PCR, and electrophoretic mobility shift assays. We identified 12 residues within SloR that cause significant derepression of sloABC promoter activity (P < 0.05) compared to the results for wild-type SloR. Derepression was particularly noteworthy in metal ion-binding site 1 mutants, consistent with the site's importance in gene repression by SloR. In addition, a hyperactive SloR(E169A/Q170A) mutant was identified as having significantly heightened repression of sloABC promoter activity, and experiments with C terminal deletion mutants support involvement of the FeoA domain in SloR-mediated gene repression. Given these results, we describe the functional domains of the S. mutans SloR protein and propose that the hyperactive mutant could serve as a target for rational drug design aimed at repressing SloR-mediated virulence gene expression. PMID- 23104812 TI - Characterization of the effects of an rpoC mutation that confers resistance to the Fst peptide toxin-antitoxin system toxin. AB - Overexpression of the Fst toxin in Enterococcus faecalis strain OG1X leads to defects in chromosome segregation, cell division and, eventually, membrane integrity. The M7 mutant derivative of OG1X is resistant to most of these effects but shows a slight growth defect in the absence of Fst. Full-genome sequencing revealed two differences between M7 and its OG1X parent. First, OG1X contains a frameshift mutation that inactivates the etaR response regulator gene, while M7 is a wild-type revertant for etaR. Second, the M7 mutant contains a missense mutation in the rpoC gene, which encodes the beta' subunit of RNA polymerase. Mutagenesis experiments revealed that the rpoC mutation was primarily responsible for the resistance phenotype. Microarray analysis revealed that a number of transporters were induced in OG1X when Fst was overexpressed. These transporters were not induced in M7 in response to Fst, and further experiments indicated that this had a direct protective effect on the mutant cells. Therefore, exposure of cells to Fst appears to have a cascading effect, first causing membrane stress and then potentiation of these effects by overexpression of certain transporters. PMID- 23104813 TI - Glycopeptide sulfation evades resistance. AB - The incidence of antibiotic resistance among pathogenic microorganisms is increasing at an alarming rate. Resistance against front-line therapeutics such as the glycopeptide antibiotic vancomycin has emerged and has spread to highly virulent pathogens, including Staphylococcus aureus. Glycopeptide antibiotics are natural products from the Actinomycetes that have a characteristic heptapeptide core. The chemical diversity of the class is achieved through glycosylation, halogenation, methylation, and acylation of the core, modifications that are implicated in improved solubility, stability, or activity of the molecule. Sulfation is yet another modification observed infrequently in glycopeptides, but its role is not known. Although glycopeptide sulfotransferases are found in the environmental metagenome and must therefore serve an evolutionary purpose, all previous studies have reported decreased antibiotic activity with sulfation. We report that sulfation of glycopeptides has little effect on the compound's ability to bind its target, the d-Ala-d-Ala peptidoglycan precursors of the bacterial cell wall. However, sulfation does impact glycopeptide dimerization, and importantly, sulfated glycopeptides are significantly less potent inducers of the resistance gene cluster vanHAX in actinomycetes. Our results begin to unravel the mystery of the biological role of glycopeptide sulfation and offer a potential new strategy for the development of new antibiotics that avoid resistance. PMID- 23104814 TI - Analysis of human vergence dynamics. AB - Disparity vergence is commonly viewed as being controlled by at least two mechanisms, an open-loop vergence-specific burst mechanism analogous to the ballistic drive of saccades, and a closed-loop feedback mechanism controlled by the disparity error. We show that human vergence dynamics for disparity jumps of a large textured field have a typical time course consistent with predominant control by the open-loop vergence-specific burst mechanism, although various subgroups of the population show radically different vergence behaviors. Some individuals show markedly slow divergence responses, others slow convergence responses, others slow responses in both vergence directions, implying that the two vergence directions have separate control mechanisms. The faster time courses usually had time-symmetric velocity waveforms implying open-loop burst control, while the slow response waveforms were usually time-asymmetric implying closed loop feedback control. A further type of behavior seen in a distinct subpopulation was a compound anomalous divergence response consisting of an initial convergence movement followed by a large corrective divergence movement with time courses implying closed-loop feedback control. This analysis of the variety of human vergence responses thus contributes substantially to the understanding of the oculomotor control mechanisms underlying the generation of vergence movements [corrected]. PMID- 23104815 TI - The Open Perimetry Interface: an enabling tool for clinical visual psychophysics. AB - Perimeters are commercially available instruments for measuring various attributes of the visual field in a clinical setting. They have several advantages over traditional lab-based systems for conducting vision experiments, including built-in gaze tracking and calibration, polished appearance, and attributes to increase participant comfort. Prior to this work, there was no standard to control such instruments, making it difficult and time consuming to use them for novel psychophysical experiments. This paper introduces the Open Perimetry Interface (OPI), a standard set of functions that can be used to control perimeters. Currently the standard is partially implemented in the open source programming language R on two commercially available instruments: the Octopus 900 (a projection-based bowl perimeter produced by Haag-Streit, Switzerland) and the Heidelberg Edge Perimeter (a CRT-based system produced by Heidelberg Engineering, Germany), allowing these instruments to be used as a platform for psychophysical experimentation. PMID- 23104816 TI - The attenuation surface for contrast sensitivity has the form of a witch's hat within the central visual field. AB - Over the full visual field, contrast sensitivity is fairly well described by a linear decline in log sensitivity as a function of eccentricity (expressed in grating cycles). However, many psychophysical studies of spatial visual function concentrate on the central +/-4.5 deg (or so) of the visual field. As the details of the variation in sensitivity have not been well documented in this region we did so for small patches of target contrast at several spatial frequencies (0.7-4 c/deg), meridians (horizontal, vertical, and oblique), orientations (horizontal, vertical, and oblique), and eccentricities (0-18 cycles). To reduce the potential effects of stimulus uncertainty, circular markers surrounded the targets. Our analysis shows that the decline in binocular log sensitivity within the central visual field is bilinear: The initial decline is steep, whereas the later decline is shallow and much closer to the classical results. The bilinear decline was approximately symmetrical in the horizontal meridian and declined most steeply in the superior visual field. Further analyses showed our results to be scale invariant and that this property could not be predicted from cone densities. We used the results from the cardinal meridians to radially interpolate an attenuation surface with the shape of a witch's hat that provided good predictions for the results from the oblique meridians. The witch's hat provides a convenient starting point from which to build models of contrast sensitivity, including those designed to investigate signal summation and neuronal convergence of the image contrast signal. Finally, we provide Matlab code for constructing the witch's hat. PMID- 23104818 TI - Awareness in contextual cueing of visual search as measured with concurrent access- and phenomenal-consciousness tasks. AB - In visual search, context information can serve as a cue to guide attention to the target location. When observers repeatedly encounter displays with identical target-distractor arrangements, reaction times (RTs) are faster for repeated relative to nonrepeated displays, the latter containing novel configurations. This effect has been termed "contextual cueing." The present study asked whether information about the target location in repeated displays is "explicit" (or "conscious") in nature. To examine this issue, observers performed a test session (after an initial training phase in which RTs to repeated and nonrepeated displays were measured) in which the search stimuli were presented briefly and terminated by visual masks; following this, observers had to make a target localization response (with accuracy as the dependent measure) and indicate their visual experience and confidence associated with the localization response. The data were examined at the level of individual displays, i.e., in terms of whether or not a repeated display actually produced contextual cueing. The results were that (a) contextual cueing was driven by only a very small number of about four actually learned configurations; (b) localization accuracy was increased for learned relative to nonrepeated displays; and (c) both consciousness measures were enhanced for learned compared to nonrepeated displays. It is concluded that contextual cueing is driven by only a few repeated displays and the ability to locate the target in these displays is associated with increased visual experience. PMID- 23104817 TI - Automatic frame-centered object representation and integration revealed by iconic memory, visual priming, and backward masking. AB - Object identities ("what") and their spatial locations ("where") are processed in distinct pathways in the visual system, raising the question of how the what and where information is integrated. Because of object motions and eye movements, the retina-based representations are unstable, necessitating nonretinotopic representation and integration. A potential mechanism is to code and update objects according to their reference frames (i.e., frame-centered representation and integration). To isolate frame-centered processes, in a frame-to-frame apparent motion configuration, we (a) presented two preceding or trailing objects on the same frame, equidistant from the target on the other frame, to control for object-based (frame-based) effect and space-based effect, and (b) manipulated the target's relative location within its frame to probe frame-centered effect. We show that iconic memory, visual priming, and backward masking depend on objects' relative frame locations, orthogonal of the retinotopic coordinate. These findings not only reveal that iconic memory, visual priming, and backward masking can be nonretinotopic but also demonstrate that these processes are automatically constrained by contextual frames through a frame-centered mechanism. Thus, object representation is robustly and automatically coupled to its reference frame and continuously being updated through a frame-centered, location-specific mechanism. These findings lead to an object cabinet framework, in which objects ("files") within the reference frame ("cabinet") are orderly coded relative to the frame. PMID- 23104819 TI - Modeling psychophysical data at the population-level: the generalized linear mixed model. AB - In psychophysics, researchers usually apply a two-level model for the analysis of the behavior of the single subject and the population. This classical model has two main disadvantages. First, the second level of the analysis discards information on trial repetitions and subject-specific variability. Second, the model does not easily allow assessing the goodness of fit. As an alternative to this classical approach, here we propose the Generalized Linear Mixed Model (GLMM). The GLMM separately estimates the variability of fixed and random effects, it has a higher statistical power, and it allows an easier assessment of the goodness of fit compared with the classical two-level model. GLMMs have been frequently used in many disciplines since the 1990s; however, they have been rarely applied in psychophysics. Furthermore, to our knowledge, the issue of estimating the point-of-subjective-equivalence (PSE) within the GLMM framework has never been addressed. Therefore the article has two purposes: It provides a brief introduction to the usage of the GLMM in psychophysics, and it evaluates two different methods to estimate the PSE and its variability within the GLMM framework. We compare the performance of the GLMM and the classical two-level model on published experimental data and simulated data. We report that the estimated values of the parameters were similar between the two models and Type I errors were below the confidence level in both models. However, the GLMM has a higher statistical power than the two-level model. Moreover, one can easily compare the fit of different GLMMs according to different criteria. In conclusion, we argue that the GLMM can be a useful method in psychophysics. PMID- 23104820 TI - Public Health Genomics and personalized healthcare: a pipeline from cell to society. PMID- 23104821 TI - CYP2E1 potentiates toxicity in obesity and after chronic ethanol treatment. AB - CYP2E1 activates several hepatotoxins and contributes to alcoholic liver damage. In this report, we review our studies on whether induction of CYP2E1 can potentiate liver injury in obesity. Acetone- or pyrazole-induced severe liver injury in obese mice as compared to obese controls and lean mice. Severe liver injury was associated with elevated oxidative and nitrosative stress and could be blunted by inhibitors of CYP2E1 and inducible nitric oxide synthase (iNOS). S Adenosyl-L-methionine (SAM) lowered the elevated oxidative and nitrosative stress, steatosis, liver injury and mitochondrial dysfunction in the pyrazole treated obese mice. The protection by SAM may have therapeutic applications against metabolic complications caused by obesity. The role of CYP2E1 in chronic ethanol-induced liver injury was studied using wild-type (WT) mice, CYP2E1 knockout (KO) mice and humanized CYP2E1 knockin (KI) mice. Ethanol produced fatty liver and oxidant stress in WT mice; these effects were blunted in the CYP2E1 KO mice but restored in the CYP2E1 KI mice. Significant liver injury was produced in the ethanol-fed KI mice in association with elevated oxidant stress and levels of human CYP2E1. Collectively, these studies show that CYP2E1 contributes to ethanol induced and obesity-induced oxidant stress and liver injury. PMID- 23104822 TI - Birth month of patients with malignant neoplasms: links to longevity? AB - BACKGROUND: In 2001, the Proceedings of National Academy of Sciences (USA) published a study on the relationship between month of birth and longevity. Subsequent studies revealed differences in month of birth among patients with acute myocardial infarction, a major killer in industrialized countries. The aim of the present study was to analyze month of birth in patients with malignant neoplasms, another major fatal disease. METHODS: The study sample consisted of 44,487 patients (22,584 male) diagnosed with a malignant neoplasm at Rabin Medical Center in 1994-2011. The number of patients born in each month of the year was calculated for the whole group and by gender. Student's t-test was used to compare mean (standard deviation) monthly, quarterly and trimester values. RESULTS: There was a strong trend (p=0.06) for a higher mean number of births in the first trimester of the year than in the second and third trimesters. The difference was significant for male patients (p=0.03) but not female patients (p=0.13-0.15). CONCLUSIONS: Patients born in the first trimester of the year are more affected by malignancies, particularly males. The overall monthly birth distribution of oncology patients is in line with the paradigm linking birth month with longevity. PMID- 23104823 TI - Hepatoprotective effects of hydroalcoholic extract of Allium hirtifolium (Persian shallot) in diabetic rats. AB - BACKGROUND: The prevalence of diabetes mellitus (DM) is dramatically increasing worldwide. Prospective studies have reported that high levels of hepatic enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), Alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) are associated with later development of diabetes. The aim of the present study was to examine the effect of hydroalcoholic extract of Allium hirtifolium (Persian shallot) on the level of liver enzymes in streptozotocin (STZ)-induced diabetic rats. METHODS: Thirty-two male rats were divided into four groups of eight. The diabetic groups received 100 and 300 mg/kg Persian shallot extract, the diabetic control and non diabetic control groups received 0.9% saline for 30 days. At the end of the experimental period, fasting blood samples were collected, and enzymes levels were measured. RESULTS: Our findings showed that hydroalcoholic extract of Persian shallot can significantly decrease serum levels of liver enzymes (AST, ALT, ALP and LDH) in treated groups in a dose-dependent fashion (p<0.05). CONCLUSIONS: Antioxidant micronutrients in the extract of Persian shallot may rehabilitate liver damages caused by free radicals in diabetic rats. PMID- 23104824 TI - Triplex PCR amplicons genotyping by high resolution melting using Rotor Gene 6000 platform. PMID- 23104825 TI - Hemodynamic study of arteriovenous fistulas for hemodialysis access. AB - Dialysis access failure and associated complications represent a major cause of morbidity in patients with renal failure. This is due to an incomplete understanding of the hemodynamics associated with both arteriovenous fistula (AVF) successes and complications. Several decades of research have been performed studying these complex hemodynamic changes. This review provides an overview of work undertaken in three key areas of AVF hemodynamic research: mathematical modeling, in vivo fluid dynamic measurements and in vitro fluid dynamic modeling. Current and future work is then summarized involving the application of a comprehensive, systematic study of dialysis access hemodynamics. The ultimate goal is the ability to predict clinical outcomes of dialysis access procedures through personalized, patient-specific surgical planning. If successful, this type of tool would allow surgeons to predict multiple-dialysis access intervention outcomes and choose a personalized approach to maximize success. PMID- 23104826 TI - Cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia. AB - Outcomes from vein graft bypass are limited by graft failure, leading causes of which include intimal hyperplasia and vasospasm. Intimal hyperplasia remains the most common cause of graft failure, but no therapeutic modalities have been shown to prevent intimal hyperplasia in humans. The small heat shock proteins are a class of naturally occurring proteins in vascular smooth muscle. These proteins have an integral role in maintenance of vascular tone and in cellular defense against various stressors. Transduction domains have enabled intracellular therapeutic delivery of peptide analogs of heat shock proteins, as well as peptide inhibitors of the kinases that phosphorylate these proteins. These cell permeant peptides have been shown to prevent vasospasm and intimal hyperplasia in vitro. Since vascular bypass using vein grafts is analogous to autologous organ transplantation, ex vivo treatment of the vein graft with cell-permeant peptide inhibitors of vasospasm and intimal hyperplasia prior to implantation provides a unique opportunity for targeted treatment of the graft to improve patency. PMID- 23104827 TI - What does it take? Comparing intensive rehabilitation to outpatient treatment for children with significant pain-related disability. AB - OBJECTIVES: This study compared outcomes between day hospital pain rehabilitation patients and patients engaged in outpatient multidisciplinary pain treatment. METHODS: This study included 100 children who presented for an initial tertiary care pain clinic evaluation. 50 patients enrolled in intensive day hospital pain rehabilitation and 50 patients pursued outpatient multidisciplinary treatment. Across 2 time points, children completed measures of functional disability, pain related fear, and readiness to change and parents completed measures of pain related fear and readiness to change. RESULTS: Across both treatment modalities, patients and parents reported improvements. Patients enrolled in intensive pain rehabilitation had significantly larger improvements in functional disability, pain-related fear, and readiness to change. Parents of day hospital patients reported larger declines in child pain-related fear and increased readiness to change compared with their outpatient counterparts. Discussion For patients with high levels of pain-related disability and distress, intensive pain rehabilitation provides rapid, dramatic improvements in functioning. PMID- 23104828 TI - Retinoblastoma related1 regulates asymmetric cell divisions in Arabidopsis. AB - Formative, also called asymmetric, cell divisions produce daughter cells with different identities. Like other divisions, formative divisions rely first of all on the cell cycle machinery with centrally acting cyclin-dependent kinases (CDKs) and their cyclin partners to control progression through the cell cycle. However, it is still largely obscure how developmental cues are translated at the cellular level to promote asymmetric divisions. Here, we show that formative divisions in the shoot and root of the flowering plant Arabidopsis thaliana are controlled by a common mechanism that relies on the activity level of the Cdk1 homolog CDKA;1, with medium levels being sufficient for symmetric divisions but high levels being required for formative divisions. We reveal that the function of CDKA;1 in asymmetric cell divisions operates through a transcriptional regulation system that is mediated by the Arabidopsis Retinoblastoma homolog RBR1. RBR1 regulates not only cell cycle genes, but also, independent of the cell cycle transcription factor E2F, genes required for formative divisions and cell fate acquisition, thus directly linking cell proliferation with differentiation. This mechanism allows the implementation of spatial information, in the form of high kinase activity, with intracellular gating of developmental decisions. PMID- 23104830 TI - Bidirectional secretions from glandular trichomes of pyrethrum enable immunization of seedlings. AB - Glandular trichomes are currently known only to store mono- and sesquiterpene compounds in the subcuticular cavity just above the apical cells of trichomes or emit them into the headspace. We demonstrate that basipetal secretions can also occur, by addressing the organization of the biosynthesis and storage of pyrethrins in pyrethrum (Tanacetum cinerariifolium) flowers. Pyrethrum produces a diverse array of pyrethrins and sesquiterpene lactones for plant defense. The highest concentrations accumulate in the flower achenes, which are densely covered by glandular trichomes. The trichomes of mature achenes contain sesquiterpene lactones and other secondary metabolites, but no pyrethrins. However, during achene maturation, the key pyrethrin biosynthetic pathway enzyme chrysanthemyl diphosphate synthase is expressed only in glandular trichomes. We show evidence that chrysanthemic acid is translocated from trichomes to pericarp, where it is esterified into pyrethrins that accumulate in intercellular spaces. During seed maturation, pyrethrins are then absorbed by the embryo, and during seed germination, the embryo-stored pyrethrins are recruited by seedling tissues, which, for lack of trichomes, cannot produce pyrethrins themselves. The findings demonstrate that plant glandular trichomes can selectively secrete in a basipetal direction monoterpenoids, which can reach distant tissues, participate in chemical conversions, and immunize seedlings against insects and fungi. PMID- 23104829 TI - Arabidopsis bZIP16 transcription factor integrates light and hormone signaling pathways to regulate early seedling development. AB - Transcriptomic adjustment plays an important role in Arabidopsis thaliana seed germination and deetiolation in response to environmental light signals. The G box cis-element is commonly present in promoters of genes that respond positively or negatively to the light signal. In pursuing additional transcriptional regulators that modulate light-mediated transcriptome changes, we identified bZIP16, a basic region/Leu zipper motif transcription factor, by G-box DNA affinity chromatography. We confirmed that bZIP16 has G-box-specific binding activity. Analysis of bzip16 mutants revealed that bZIP16 is a negative regulator in light-mediated inhibition of cell elongation but a positive regulator in light regulated seed germination. Transcriptome analysis supported that bZIP16 is primarily a transcriptional repressor regulating light-, gibberellic acid (GA)-, and abscisic acid (ABA)-responsive genes. Chromatin immunoprecipitation analysis revealed that bZIP16 could directly target ABA-responsive genes and RGA-like2, a DELLA gene in the GA signaling pathway. bZIP16 could also indirectly repress the expression of phytochrome interacting factoR3-like5, which encodes a basic helix loop-helix protein coordinating hormone responses during seed germination. By repressing the expression of these genes, bZIP16 functions to promote seed germination and hypocotyl elongation during the early stages of Arabidopsis seedling development. PMID- 23104831 TI - Spatiotemporal asymmetry of the meiotic program underlies the predominantly distal distribution of meiotic crossovers in barley. AB - Meiosis involves reciprocal exchange of genetic information between homologous chromosomes to generate new allelic combinations. In cereals, the distribution of genetic crossovers, cytologically visible as chiasmata, is skewed toward the distal regions of the chromosomes. However, many genes are known to lie within interstitial/proximal regions of low recombination, creating a limitation for breeders. We investigated the factors underlying the pattern of chiasma formation in barley (Hordeum vulgare) and show that chiasma distribution reflects polarization in the spatiotemporal initiation of recombination, chromosome pairing, and synapsis. Consequently, meiotic progression in distal chromosomal regions occurs in coordination with the chromatin cycles that are a conserved feature of the meiotic program. Recombination initiation in interstitial and proximal regions occurs later than distal events, is not coordinated with the cycles, and rarely progresses to form chiasmata. Early recombination initiation is spatially associated with early replicating, euchromatic DNA, which is predominately found in distal regions. We demonstrate that a modest temperature shift is sufficient to alter meiotic progression in relation to the chromosome cycles. The polarization of the meiotic processes is reduced and is accompanied by a shift in chiasma distribution with an increase in interstitial and proximal chiasmata, suggesting a potential route to modify recombination in cereals. PMID- 23104834 TI - Modular design of a miniaturized surgical robot system. AB - Currently, there are only a small number of robotic systems used in various surgical fields. As modified industrial robot systems have shown significant limitations in the past, specialized kinematic solutions have been proposed for specific surgical applications. The majority of these systems are designed for specific applications in only a limited number of cases. The acquisition and operating costs are high, hindering the dissemination and broad clinical application of such systems. To address this problem, a modular mini-robot system is proposed, which can be easily adapted to different application-specific requirements. Therefore, the requirements of different applications have been categorized and clustered to a standardized requirement profile. Next, a modular robot based on a hybrid kinematic module structure has been developed. This concept has been implemented and tested in in vitro studies for different applications, such as revision total hip replacement and unicondylar knee arthroplasty. User-orientated tests of the intraoperative handling, as well as accuracy tests, proved the feasibility of the concept. PMID- 23104832 TI - The DUF59 family gene AE7 acts in the cytosolic iron-sulfur cluster assembly pathway to maintain nuclear genome integrity in Arabidopsis. AB - Eukaryotic organisms have evolved a set of strategies to safeguard genome integrity, but the underlying mechanisms remain poorly understood. Here, we report that asymmetric leaves1/2 enhancer7 (AE7), an Arabidopsis thaliana gene encoding a protein in the evolutionarily conserved Domain of Unknown Function 59 family, participates in the cytosolic iron-sulfur (Fe-S) cluster assembly (CIA) pathway to maintain genome integrity. The severe ae7-2 allele is embryo lethal, whereas plants with the weak ae7 (ae7-1) allele are viable but exhibit highly accumulated DNA damage that activates the DNA damage response to arrest the cell cycle. AE7 is part of a protein complex with CIA1, NAR1, and MET18, which are highly conserved in eukaryotes and are involved in the biogenesis of cytosolic and nuclear Fe-S proteins. ae7-1 plants have lower activities of the cytosolic [4Fe-4S] enzyme aconitase and the nuclear [4Fe-4S] enzyme DNA glycosylase ROS1. Additionally, mutations in the gene encoding the mitochondrial ATP binding cassette transporter ATM3/ABCB25, which is required for the activity of cytosolic Fe-S enzymes in Arabidopsis, also result in defective genome integrity similar to that of ae7-1. These results indicate that AE7 is a central member of the CIA pathway, linking plant mitochondria to nuclear genome integrity through assembly of Fe-S proteins. PMID- 23104833 TI - Nondisjunction in favor of a chromosome: the mechanism of rye B chromosome drive during pollen mitosis. AB - B chromosomes (Bs) are supernumerary components of the genome and do not confer any advantages on the organisms that harbor them. The maintenance of Bs in natural populations is possible by their transmission at higher than Mendelian frequencies. Although drive is the key for understanding B chromosomes, the mechanism is largely unknown. We provide direct insights into the cellular mechanism of B chromosome drive in the male gametophyte of rye (Secale cereale). We found that nondisjunction of Bs is accompanied by centromere activity and is likely caused by extended cohesion of the B sister chromatids. The B centromere originated from an A centromere, which accumulated B-specific repeats and rearrangements. Because of unequal spindle formation at the first pollen mitosis, nondisjoined B chromatids preferentially become located toward the generative pole. The failure to resolve pericentromeric cohesion is under the control of the B-specific nondisjunction control region. Hence, a combination of nondisjunction and unequal spindle formation at first pollen mitosis results in the accumulation of Bs in the generative nucleus and therefore ensures their transmission at a higher than expected rate to the next generation. PMID- 23104835 TI - Neurophil gelatinase-associated lipocalin as a new biomarker in laboratory medicine. AB - Neutrophil gelatinase-associated lipocalin (NGAL) is a 25 kDa protein of the lipocalin superfamily. This protein is expressed and secreted by immune cells, hepatocytes, and renal tubular cells in various pathologic states. NGAL has recently generated great interest as an early biomarker of renal injury. However, like many other endogenous biomarkers it is not produced by just one cell type and it exists in more than one molecular form. As recent research has shown different pathological conditions may involved in the production of this molecule. This review summarizes the current knowledge about the biology of NGAL and examines the role of this molecule of acute renal injury as well as in other pathologic conditions like neoplasia, anemia, pregnancy, cardiovascular disease chronic kidney disease and in cardiorenal syndrome. Commercial and research immunoassays are used to measure NGAL in both plasma and urine but these assays are not standardized. The existence of different molecular forms of NGAL and their expression at various disease states further complicates the interpretation of the results. Pre analytical issues and biological variation are also not fully elucidated. PMID- 23104836 TI - Mobile Laboratory Unit: a disruptor solution for hemostasis management during major surgery. Usage in the context of face transplantation. AB - BACKGROUND: The management of surgical bleeding during a face transplant in a patient diagnosed with bilateral neurofibromatosis is quite complex. With the actual methods and technology for hemostasis management, it may not always be possible to give the clinician the support needed to manage operative associated bleeding. Bedside hemostasis monitors are needed urgently to assist clinicians in making the correct diagnosis in a timely manner. METHODS: Our Mobile Laboratory Unit is a disruptive solution for hemostasis management during major surgery as it allows real-time monitoring, the predominant mechanism of bleeding and goal direct coagulation therapy. The unit is an autonomous mobile platform that can be moved immediately to anywhere its service is needed and offers a complete flexible laboratory test which includes biochemistry, hematology and coagulation studies as standard equipment. RESULTS: In our case the test performed by the unit allowed us to identify the reason for our patient's bleeding at the bedside. Severely decreased clot firmness of the fibrin-based clot and a less impaired firmness of the whole blood clot, suggested an acceptable contribution of platelets to the clot quality, but decreased polymerization of fibrinogen into fibrin. CONCLUSIONS: In our opinion new insights into the pathophysiology of coagulopathy, the availability of technology such as our Mobile Laboratory Unit, and awareness of side effects of intravenous fluids should encourage the idea that perhaps it is time to change hemostasis management in operation-related bleeding. PMID- 23104837 TI - Statistical learning confirms the diagnostic significance of the anemia panel in breast cancer. AB - BACKGROUND: Diagnostic value of available tumor markers, such as cancer antigen CA 15-3 and carcinoembryonic antigen (CEA) in breast cancer is limited. There is an ongoing search for additional, potentially better diagnostic blood markers with improved clinical utility. The aim of this study is to evaluate performance of the approach based on routine blood tests accompanied by a statistical learning tool to the diagnosis of breast cancer. METHODS: Blood was collected from total of 104 subjects which were divided into two groups: breast cancer patients and a control group that consisted of asymptomatic volunteers and patients who had benign breast lesions at the time of blood collection. Random forest statistical learning method and the external method validation have been applied to evaluate diagnostic performance of 31 routine blood tests. RESULTS: The applied statistical learning approach assigned the highest diagnostic importance to the anemia panel among all analyzed blood tests that also included CA 15-3. External validation has shown utility of selected statistical approach - we were able to select tests that provide a diagnostic accuracy comparable to some diagnostic tools described in literature and based on more demanding laboratory techniques, such as gene expression microarrays. CONCLUSIONS: Inclusion of tests for anemia significantly improves diagnostic accuracy for the breast cancer in comparison to the diagnostic accuracy of the CA 15-3 alone. Application of the random forests also enables the reduction of number of laboratory tests needed for the establishment of diagnosis. Differences in relevant test values between the cancer and control group are small but application of multiparametric statistical learning ensured diagnostic accuracy of 72.0% associated by a sensitivity of 64.7% and specificity of 84.9%. PMID- 23104838 TI - The biosynthesis of caprazamycins and related liponucleoside antibiotics: new insights. AB - The first step in the membrane cycle of reactions during peptidoglycan biosynthesis is the transfer of phospho-MurNAc-pentapeptide from UDP-MurNAc pentapeptide to undecaprenyl phosphate, catalyzed by the integral membrane protein MraY translocase. Different MraY inhibitors are known and can be subdivided into classes depending on their structural composition. Caprazamycins belong to the liponucleoside class of antibiotics isolated from Streptomyces sp. MK730-62F2. They possess activity in vitro against Gram-positive bacteria, in particular against the genus Mycobacterium including Mycobacterium intracellulare, Mycobacterium avium and Mycobacterium tuberculosis. Caprazamycins and the structurally related liposidomycins and A-90289 share a unique composition of moieties. Their complex structure is derived from 5'-(beta-O aminoribosyl)-glycyluridine and comprises a unique N,N'-dimethyldiazepanone ring. Recently, the corresponding biosynthetic gene clusters of caprazamycins, liposidomycins and A-90289 have been discovered and will be compared in this review. New information is also emerging regarding the biosynthesis of liponucleoside antibiotics obtained by gene disruption experiments and biochemical investigations. PMID- 23104839 TI - Dynamics of bioenergetic microcompartments. AB - The vast majority of life on earth is dependent on harvesting electrochemical potentials over membranes for the synthesis of ATP. Generation of membrane potential often relies on electron transport through membrane protein complexes, which vary among the bioenergetic membranes found in living organisms. In order to maximize the efficient harvesting of the electrochemical potential, energy loss must be minimized, and this is achieved partly by restricting certain events to specific microcompartments, on bioenergetic membranes. In this review we will describe the characteristics of the energy-converting supramolecular structures involved in oxidative phosphorylation in mitochondria and bacteria, and photophosphorylation. Efficient function of electron transfer pathways requires regulation of electron flow, and we will also discuss how this is partly achieved through dynamic re-compartmentation of the membrane complexes into different supercomplexes. In addition to supercomplexes, the supramolecular structure of the membrane, and in particular the role of water layers on the surface of the membrane in the prevention of wasteful proton escape (and therefore energy loss), is discussed in detail. In summary, the restriction of energetic processes to specific microcompartments on bioenergetic membranes minimizes energy loss, and dynamic rearrangement of these structures allows for regulation. PMID- 23104841 TI - Empirical bayesian selection of hypothesis testing procedures for analysis of sequence count expression data. AB - Differential expression analysis of sequence-count expression data involves performing a large number of hypothesis tests that compare the expression count data of each gene or transcript across two or more biological conditions. The assumptions of any specific hypothesis-testing method will probably not be valid for each of a very large number of genes. Thus, computational evaluation of assumptions should be incorporated into the analysis to select an appropriate hypothesis-testing method for each gene. Here, we generalize earlier work to introduce two novel procedures that use estimates of the empirical Bayesian probability (EBP) of overdispersion to select or combine results of a standard Poisson likelihood ratio test and a quasi-likelihood test for each gene. These EBP-based procedures simultaneously evaluate the Poisson-distribution assumption and account for multiple testing. With adequate power to detect overdispersion, the new procedures select the standard likelihood test for each gene with Poisson distributed counts and the quasi-likelihood test for each gene with overdispersed counts. The new procedures outperformed previously published methods in many simulation studies. We also present a real-data analysis example and discuss how the framework used to develop the new procedures may be generalized to further enhance performance. An R code library that implements the methods is freely available at www.stjuderesearch.org/depts/biostats/software. PMID- 23104842 TI - Detecting differential expression in RNA-sequence data using quasi-likelihood with shrunken dispersion estimates. AB - Next generation sequencing technology provides a powerful tool for measuring gene expression (mRNA) levels in the form of RNA-sequence data. Method development for identifying differentially expressed (DE) genes from RNA-seq data, which frequently includes many low-count integers and can exhibit severe overdispersion relative to Poisson or binomial distributions, is a popular area of ongoing research. Here we present quasi-likelihood methods with shrunken dispersion estimates based on an adaptation of Smyth's (2004) approach to estimating gene specific error variances for microarray data. Our suggested methods are computationally simple, analogous to ANOVA and compare favorably versus competing methods in detecting DE genes and estimating false discovery rates across a variety of simulations based on real data. PMID- 23104844 TI - *Abstracts - 7th IN-CAM Research Symposium, Evaluating CAM Practices: Effectiveness, Integration, Economics & Safety - November 2012. AB - Abstract The following are abstracts of oral and poster presentations given at the 7th IN-CAM Research Symposium - Evaluating CAM Practices: Effectiveness, Integration, Economics & Safety, and the 4th HomeoNet Research Forum, a pre Symposium event. The IN-CAM Research Symposium was held November 2 to 4, 2012 at the Leslie Dan Faculty of Pharmacy, University of Toronto, in Toronto, Ontario, Canada. For more information, please visit: www.incamresearch.ca. PMID- 23104843 TI - Analyzing genetic association studies with an extended propensity score approach. AB - Propensity scores are commonly used to address confounding in observational studies. However, they have not been previously adapted to deal with bias in genetic association studies. We propose an extension of our previous method (Zhao et al., 2009) that uses a multilevel propensity score approach and allows one to estimate the effect of a genotype under an additive model and also simultaneously adjusts for confounders such as genetic ancestry and patient and disease characteristics. Using simulation studies, we demonstrate that this extended genetic propensity score (eGPS) can adequately adjust and consistently correct for bias due to confounding in a variety of circumstances. Under all simulation scenarios, the eGPS method yields estimates with bias close to 0 (mean=0.018, standard error=0.01). Our method also preserves statistical properties such as coverage probability, Type I error, and power. We illustrate this approach in a population-based genetic association study of testicular germ cell tumors and KITLG and SPRY4 susceptibility genes. We conclude that our method provides a novel and broadly applicable analytic strategy for obtaining less biased and more valid estimates of genetic associations. PMID- 23104845 TI - Survival curve estimation with dependent left truncated data using Cox's model. AB - The Kaplan-Meier and closely related Lynden-Bell estimators are used to provide nonparametric estimation of the distribution of a left-truncated random variable. These estimators assume that the left-truncation variable is independent of the time-to-event. This paper proposes a semiparametric method for estimating the marginal distribution of the time-to-event that does not require independence. It models the conditional distribution of the time-to-event given the truncation variable using Cox's model for left truncated data, and uses inverse probability weighting. We report the results of simulations and illustrate the method using a survival study. PMID- 23104846 TI - Endothelial lipase activity predicts high-density lipoprotein catabolism in hemodialysis: novel phospholipase assay in postheparin human plasma. AB - OBJECTIVE: A novel phospholipase assay was used to measure for the first time the behavior of endothelial and hepatic phospholipase activities in postheparin human plasma of hemodialyzed patients and its relationship with atherogenic and antiatherogenic lipoprotein levels. METHODS AND RESULTS: Endothelial and hepatic phospholipase activity was assessed in a total SN1-specific phospholipase assay, using (1-decanoylthio-1-deoxy-2-decanoyl-sn-glycero-3-phosphoryl) ethylene glycol as the substrate. Hemodialyzed patients presented lower values of total and hepatic phospholipase activity than controls: 4.4 (1.9-9.0) versus 7.5 (3.6-18.0) and 2.6 (0.7-6.2) versus 6.6 (1.3-15.2) MUmol of fatty acid released per milliliter of postheparin plasma per hour, respectively (P<0.001); however, endothelial lipase (EL) phospholipase activity was increased in patients: 1.7 (0.8-3.0) versus 1.1 (0.1-2.7) MUmol of fatty acid released per milliliter of postheparin plasma per hour (P=0.008). EL was negatively associated with high density lipoprotein (HDL)-cholesterol (r=-0.427; P=0.001), and apolipoprotein A-I levels, total phospholipase, and hepatic lipase activity were directly associated with low-density lipoprotein-cholesterol and apolipoprotein B. The association of EL and HDL-cholesterol remained significant when adjusting for waist circumference (beta=-0.26; P=0.05), and the effect of hepatic lipase on low density lipoprotein-cholesterol continued after adjusting for age (beta=0.46; P= 0.001). CONCLUSIONS: Our results support the hypothesis that EL is the predominant enzyme responsible for lipolytic catabolism of HDLs in hemodialyzed patients and resolve the apparent paradox observed between low hepatic lipase activity and decreased HDL-cholesterol levels observed in these patients. In addition, the ability to assess total hepatic lipase and EL phospholipase activity in plasma will increase our knowledge of the mechanisms involved in controlling HDL levels and cardiovascular risk in hemodialyzed patients, as well as other populations with low levels of HDL-cholesterol. PMID- 23104847 TI - Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow. AB - OBJECTIVE: In severe stenosis, von Willebrand factor (vWF) experiences millisecond exposures to pathological wall shear rates (gamma(w)). We sought to evaluate the deposition of vWF onto collagen surfaces under flow in these environments. METHODS AND RESULTS: Distinct from viscometry experiments that last many seconds, we deployed microfluidic devices for single-pass perfusion of whole blood or platelet-free plasma over fibrillar type 1 collagen (<50 ms transit time) at pathological gamma(w) or spatial wall shear rate gradients (grad gamma(w)). Using fluorescent anti-vWF, long thick vWF fibers (>20 MUm) bound to collagen were visualized at constant gamma(w)>30000 s(-1) during perfusion of platelet-free plasma, a process enhanced by EDTA. Rapid acceleration or deceleration of EDTA platelet-free plasma at grad gamma(w)=+/-1.1*10(5) to +/ 4.3*10(7) s(-1)/cm did not promote vWF deposition. At 19400 s(-1), EDTA blood perfusion resulted in rolling vWF-platelet nets, although blood perfusion (normal Ca(2+)) generated large vWF/platelet deposits that repeatedly embolized and were blocked by anti-glycoprotein Ib or the alpha(IIb)beta(3) inhibitor GR144053 and did not require grad gamma(w). Blood perfusion at venous shear rate (200 s(-1)) produced a stable platelet deposit that was a substrate for massive but unstable vWF-platelet aggregates when flow was increased to 7800 s(-1). CONCLUSIONS: Triggered by collagen and enhanced by platelet glycoprotein Ib and alpha(IIb)beta(3), vWF fiber formation occurred during acute exposures to pathological gamma(w) and did not require gradients in wall shear rate. PMID- 23104849 TI - Circulating nucleosomes and neutrophil activation as risk factors for deep vein thrombosis. AB - OBJECTIVE: The formation of neutrophil extracellular traps and the exposure of nucleosomes on these neutrophil extracellular traps contribute to coagulation activation and the propagation of deep vein thrombosis (DVT) in animal models. However, no data are available on the role of neutrophil extracellular traps or nucleosomes in patients with thrombosis. METHODS AND RESULTS: We conducted a case control study, in which levels of circulating nucleosomes and neutrophil elastase alpha1-antitrypsin complexes were assessed in plasma from 150 patients with objectified symptomatic DVT (cases) and compared with 195 patients with a clinical suspicion of DVT but in whom DVT was excluded (controls). We explored the association between both nucleosomes and elastase-alpha1-antitrypsin complexes, and the presence of DVT by calculating the odds ratio with corresponding 95% CIs. Elevated levels of both circulating nucleosomes and elastase-alpha1-antitrypsin complexes were associated with a 3-fold risk of DVT, and the associations remained similar after adjustment for potential confounders (malignancy, smoking, recent immobilization, recent hospitalization). The risk increased with higher nucleosome and elastase-alpha1-antitrypsin complex levels, suggesting a dose-dependent relationship among circulating nucleosomes, activated neutrophils, and DVT. CONCLUSIONS: Our study suggests an association among circulating nucleosomes, activated neutrophils, and presence of DVT in humans, which might have implications for treatment and prevention. PMID- 23104848 TI - Inflammatory cytokines promote mesenchymal transformation in embryonic and adult valve endothelial cells. AB - OBJECTIVE: Inflammatory activation of valve endothelium is an early phase of aortic valve disease pathogenesis, but subsequent mechanisms are poorly understood. Adult valve endothelial cells retain the developmental ability to undergo endothelial-to-mesenchymal transformation (EndMT), but a biological role has not been established. Here, we test whether and how inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) regulate EndMT in embryonic and adult valve endothelium. METHODS AND RESULTS: Using in vitro 3-dimensional collagen gel culture assays with primary cells, we determined that interleukin-6 and tumor necrosis factor-alpha induce EndMT and cell invasion in dose-dependent manners. Inflammatory-EndMT occurred through an Akt/nuclear factor-kappaB dependent pathway in both adult and embryonic stages. In embryonic valves, inflammatory-EndMT required canonical transforming growth factor-beta signaling through activin receptor-like kinases 2 and 5 to drive EndMT. In adult valve endothelium, however, inflammatory-induced EndMT still occurred when activin receptor-like kinases 2 and 5 signaling was blocked. Inflammatory receptor gene expression was significantly upregulated in vivo during embryonic valve maturation. Endothelial-derived mesenchymal cells expressing activated nuclear factor-kappaB were found distal to calcific lesions in diseased human aortic valves. CONCLUSIONS: Inflammatory cytokine-induced EndMT in valve endothelium is present in both embryonic and adult stages, acting through Akt/nuclear factor kappaB, but differently using transforming growth factor-beta signaling. Molecular signatures of valve EndMT may be important diagnostic and therapeutic targets in early valve disease. PMID- 23104850 TI - Mitochondrial motility and vascular smooth muscle proliferation. AB - OBJECTIVE: Mitochondria are widely described as being highly dynamic and adaptable organelles, and their movement is thought to be vital for cell function. Yet, in various native cells, including those of heart and smooth muscle, mitochondria are stationary and rigidly structured. The significance of the differences in mitochondrial behavior to the physiological function of cells is unclear and was studied in single myocytes and intact resistance-sized cerebral arteries. We hypothesized that mitochondrial dynamics is controlled by the proliferative status of the cells. METHODS AND RESULTS: High-speed fluorescence imaging of mitochondria in live vascular smooth muscle cells shows that the organelle undergoes significant reorganization as cells become proliferative. In nonproliferative cells, mitochondria are individual (~ 2 MUm by 0.5 MUm), stationary, randomly dispersed, fixed structures. However, on entering the proliferative state, mitochondria take on a more diverse architecture and become small spheres, short rod-shaped structures, long filamentous entities, and networks. When cells proliferate, mitochondria also continuously move and change shape. In the intact pressurized resistance artery, mitochondria are largely immobile structures, except in a small number of cells in which motility occurred. When proliferation of smooth muscle was encouraged in the intact resistance artery, in organ culture, the majority of mitochondria became motile and the majority of smooth muscle cells contained moving mitochondria. Significantly, restriction of mitochondrial motility using the fission blocker mitochondrial division inhibitor prevented vascular smooth muscle proliferation in both single cells and the intact resistance artery. CONCLUSIONS: These results show that mitochondria are adaptable and exist in intact tissue as both stationary and highly dynamic entities. This mitochondrial plasticity is an essential mechanism for the development of smooth muscle proliferation and therefore presents a novel therapeutic target against vascular disease. PMID- 23104852 TI - Determinants of successful breastfeeding initiation in healthy term singletons: a Swiss university hospital observational study. AB - AIMS: Breastfeeding significantly benefits mothers and infants. We aimed to identify the determinants of its successful initiation. METHODS: A retrospective study of 1893 mothers delivering healthy term singletons at a Swiss university hospital from 1/2008 to 3/2009 determined the associations between multiple breastfeeding and early postpartum parameters by univariate and multiple regression analysis. RESULTS: Multiparity was associated with nursing exclusively at the breast at discharge (P<0.001), less use of maltodextrin supplement (P<0.05), bottle/cup (both P<0.001), but more pacifier use (P<0.05). Among obese mothers, nursing exclusively at the breast at discharge was less frequent, and use of all feeding aids more frequent, than among normal-weight women (both P<0.001). Neuraxial anesthesia was associated with use of maltodextrin and bottle (both P<0.05) compared to no anesthesia. Delayed first skin-to-skin contact and rooming-in for <24 h/day were each associated with maltodextrin and cup (P<0.05). Nursing exclusively at the breast at discharge was less frequent (P<0.001), and bottle use more frequent (P<0.05), in women with sore nipples than in those without. CONCLUSIONS: Obesity is a potent inhibitor of breastfeeding initiation. Delivery without anesthesia by a multiparous normal-weight mother, followed by immediate skin-to-skin contact, rooming-in for 24 h/day, and dedicated nipple care, provides the best conditions for successful early postpartum breastfeeding without the need for feeding aids or nutritional supplements PMID- 23104851 TI - Lipid phosphate phosphatase 3 negatively regulates smooth muscle cell phenotypic modulation to limit intimal hyperplasia. AB - OBJECTIVE: The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. METHODS AND RESULTS: We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3 catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. CONCLUSIONS: Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk. PMID- 23104853 TI - Spatial memory, plasticity and nucleus accumbens. AB - Research on the function of the nucleus accumbens, the most ventral component of the striatal complex, has traditionally focused on locomotor activity, reward, motivation and addiction. However, based on the existence of projections to the nucleus accumbens from the allocortical regions involved in spatial navigation, it has been suggested that this structure plays a role in spatial learning and memory. Lesion and neuropharmacological studies confirm this view, also revealing the complex dynamics of the receptors involved in these processes. Moreover, the effects of post-training intra-nucleus accumbens drug administrations demonstrate the necessity of off-line neural activity within this structure in order to consolidate spatial memory. Blockade of molecular processes implicated in synaptic plasticity, such as cAMP response element-binding protein (CREB)-induced transcription or extracellular matrix remodeling, provides further experimental support to this hypothesis. These observations imply that experience-dependent synaptic plasticity responsible for long-term stabilization of spatial information might occur within the nucleus accumbens, similarly to what has been observed in the hippocampus. This suggests that a comprehensive understanding of spatial memory processing should be viewed in the context of a wider neural circuit. PMID- 23104854 TI - Cannabinoid modulation of mother-infant interaction: is it just about milk? AB - Mother-infant interactions are essential for proper neurobehavioral development of the offspring, and disruptions in those relationships may result in neuroendocrine, neurochemical and behavioral alterations at adulthood. The neural circuitries involved in mother-infant interactions have not been completely elucidated yet. The brain endocannabinoid system plays an essential role in prenatal and postnatal neurobehavioral development. Here, we will summarize and discuss the available findings about the role of endocannabinoids in three key aspects of mother-infant interactions in rodents: suckling, maternal behavior and separation-induced ultrasonic vocalizations (USVs). The studies reviewed here show that endocannabinoids are not only involved in suckling initiation and, therefore, in the feeding and growth of the offspring, but also regulate the emotional reactivity of rodent pups, as measured by the rate of isolation-induced USVs. Conversely, less information is available about endocannabinoid modulation of maternal behavior, and therefore more research in this direction is warranted. Indeed, since Cannabis sativa preparations are widely used by young people, including pregnant and lactating women, it is important to understand whether developmental exposure to cannabinoids interferes with mother-infant bond formation, potentially leading to neurodevelopmental alterations and increased vulnerability to psychopathology later in life. PMID- 23104855 TI - Serotonin and emotion, learning and memory. AB - Serotonin (5-hydroxytryptamien, 5-HT) has been linked to emotional and motivational aspects of human behavior, including anxiety, depression, impulsivity, etc. Several clinically effective drugs exert effects via 5-HT systems. Growing evidence suggests that those effects play an important role in learning and memory. Whether the role of serotonin is related to memory and/or behavioral or emotional aspects remains an important question. A key question that remains is whether 5-HT markers (e.g., receptors) directly or indirectly participate and/or contribute to the physiological and pharmacological basis of memory and its pathogenesis. The major aim of this paper is to re-examine some recent advances regarding mammalian 5-HT receptors and transporter in light of their physiological, pathophysiological and therapeutic implications for memory. We particularly address evidence involving 5-HT systems in behavioral, pharmacological, molecular, genetic and imaging results and memory. Finally, this paper aims to summarize a portion of the evidence about serotonin, memory and emotion from animal and human studies and provide an overview of potential tools, markers and cellular and molecular candidate mechanisms. It should be noted that there are several subjects that this paper only briefly touches upon, presenting only what may be the most salient findings in the context of memory, emotion and serotonin. PMID- 23104856 TI - The effects of supplemental fish oil on blood pressure and morning cortisol in normotensive adults: a pilot study. AB - PURPOSE: To determine the effects of 6wk of supplementation with fish oil (FO) on blood pressure and the morning salivary cortisol concentration in normotensive adults. METHODS: Testing was performed following an overnight fast. Subjects (n=40; 35+/-13y, mean+/-SD) rested supine for 40min, at which time blood pressure and heart rate were measured. Saliva was collected and analyzed for cortisol. Subjects were then randomly assigned to either: 4g/d of Safflower Oil (SO); or 4g/d of FO supplying 1,600mg/d eicosapentaenoic acid and 800mg/d docosahexaenoic acid. Testing was repeated following 6wk of treatment. RESULTS: Compared to SO, there was a significant decrease in systolic blood pressure with FO (SO=1.3+/-5.8 mmHg; FO=-6.8+/-10.2 mmHg; p=0.004), a significant reduction in pulse pressure (SO=0.2+/-7.8 mmHg; FO=-6.4+/-8.8 mmHg; p=0.02), and a tendency for a decrease in mean arterial pressure (SO=1.2+/-5.3 mmHg; FO=-2.5+/-7.3 mmHg; p=0.08). There was a tendency for salivary cortisol to decrease with FO (SO=0.005+/-0.129 ug/dL; FO= 0.068+/-0.148 ug/dL; p=0.072), however, this change was not significantly correlated with the change in systolic blood pressure (r=0.021, p=0.929). CONCLUSION: 6wk of supplementation with FO significantly decreases systolic blood pressure in normotensive adults and this change was not significantly correlated with a reduction in salivary cortisol. PMID- 23104857 TI - Effect of cardiac resynchronization therapy and implantable cardioverter defibrillator on quality of life in patients with heart failure: a meta-analysis. AB - AIMS: To compare the improvement of quality of life (QoL) in cardiac resynchronization therapy plus implantable cardioverter defibrillator (CRT-D) therapy with that in implantable cardioverter defibrillator (ICD) therapy alone for patients with heart failure. METHODS AND RESULTS: Medline, Embase, The Cochrane Library, and US Food and Drug Administration website were searched for published studies up to 31 December 2011. Studies were considered for inclusion if they were randomized controlled trials (RCTs) that compared the efficacy of CRT-D therapy with ICD therapy in patients with heart failure. The primary outcome of this study was improvement in QoL. Four RCTs with 1655 patients were included in this meta-analysis. Overall, the QoL score of patients in CRT-D group significantly improved [weighted mean difference (WMD): -6.02; 95% confidence interval (CI): -10.56 to -1.48] compared with that in the ICD only group. However, the benefit with respect to QoL in CRT-D group was not maintained when subset meta-analysis was performed in patients with New York Heart Association (NYHA) class I-II (WMD: 0.19; 95% CI: -3.89 to 4.72), whereas the patients with NYHA class III-IV in CRT-D group still experienced a significant improvement of QoL score compared with ICD group (WMD: -8.49; 95% CI: -13.39 to -3.59). CONCLUSIONS: CRT-D therapy improves the QoL compared with ICD therapy alone, especially in patients with moderate to severe heart failure. PMID- 23104858 TI - How European centres diagnose, treat, and prevent CIED infections: results of an European Heart Rhythm Association survey. AB - The purpose of our survey is to analyse the clinical approach used to prevent and treat cardiovascular implantable electronic device (CIED) infections in Europe. The survey involves high-volume implanting centres. According to the survey the incidence of CIED infections shows a slight decrease in most centres and is substantially under 2% in the majority of centres interviewed. However, there are still differences in terms of prophylactic antibiotic therapy: 8.9% of the centres administer oxacillin as preoperative treatment, 4.4% of them do not give any antibiotic therapy, all centres use some kind of skin antisepsis, but only 42.2% use chlorhexidine. In case of local infection, 43.5% of centres perform lead extraction as first approach. In the case of systemic infection or evidence of lead or valvular endocarditis, 95% of centres treat these conditions by extracting the leads, which indicates that the adherence to the lead extraction guidelines is quite good. PMID- 23104859 TI - Structural mapping: how to study the genetic architecture of a phenotypic trait through its formation mechanism. AB - Traditional approaches for genetic mapping are to simply associate the genotypes of a quantitative trait locus (QTL) with the phenotypic variation of a complex trait. A more mechanistic strategy has emerged to dissect the trait phenotype into its structural components and map specific QTLs that control the mechanistic and structural formation of a complex trait. We describe and assess such a strategy, called structural mapping, by integrating the internal structural basis of trait formation into a QTL mapping framework. Electrical impedance spectroscopy (EIS) has been instrumental for describing the structural components of a phenotypic trait and their interactions. By building robust mathematical models on circuit EIS data and embedding these models within a mixture model based likelihood for QTL mapping, structural mapping implements the EM algorithm to obtain maximum likelihood estimates of QTL genotype-specific EIS parameters. The uniqueness of structural mapping is to make it possible to test a number of hypotheses about the pattern of the genetic control of structural components. We validated structural mapping by analyzing an EIS data collected for QTL mapping of frost hardiness in a controlled cross of jujube trees. The statistical properties of parameter estimates were examined by simulation studies. Structural mapping can be a powerful alternative for genetic mapping of complex traits by taking account into the biological and physical mechanisms underlying their formation. PMID- 23104860 TI - Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging. AB - Oxidative DNA damage accumulates with age and is repaired primarily via the base excision repair (BER) pathway. This process is initiated by DNA glycosylases, which remove damaged bases in a substrate-specific manner. The DNA glycosylases human 8-oxoguanine-DNA glycosylase (OGG1) and NEIL1, a mammalian homolog ofEscherichia coli endonuclease VIII, have overlapping yet distinct substrate specificity. Recently, we reported that OGG1 binds to the Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein that poly(ADP-ribosyl)ates nuclear proteins in response to DNA damage and other cellular signals. Here, we show that NEIL1 and PARP-1 bind both in vitro and in vivo. PARP-1 binds to the C terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP-1. NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP-1. Furthermore, NEIL deficient fibroblasts have impaired poly(ADP-ribosyl)ation of cellular proteins after DNA damage, which can be rescued by NEIL1 expression. Additionally, PARP-1 inhibits NEIL1 incision activity in a concentration-dependent manner. Consistent with the idea of impaired DNA repair during aging, we observed differential binding of PARP-1 to recombinant NEIL1 in older mice compared to younger mice. These data further support the idea that dynamic interplay between different base excision repair proteins is important for efficient BER. PMID- 23104861 TI - Group III-A XTH genes of Arabidopsis encode predominant xyloglucan endohydrolases that are dispensable for normal growth. AB - The molecular basis of primary wall extension endures as one of the central enigmas in plant cell morphogenesis. Classical cell wall models suggest that xyloglucan endo-transglycosylase activity is the primary catalyst (together with expansins) of controlled cell wall loosening through the transient cleavage and religation of xyloglucan-cellulose cross links. The genome of Arabidopsis (Arabidopsis thaliana) contains 33 phylogenetically diverse XYLOGLUCAN ENDO TRANSGLYCOSYLASE/HYDROLASE (XTH) gene products, two of which were predicted to be predominant xyloglucan endohydrolases due to clustering into group III-A. Enzyme kinetic analysis of recombinant AtXTH31 confirmed this prediction and indicated that this enzyme had similar catalytic properties to the nasturtium (Tropaeolum majus) xyloglucanase1 responsible for storage xyloglucan hydrolysis during germination. Global analysis of Genevestigator data indicated that AtXTH31 and the paralogous AtXTH32 were abundantly expressed in expanding tissues. Microscopy analysis, utilizing the resorufin beta-glycoside of the xyloglucan oligosaccharide XXXG as an in situ probe, indicated significant xyloglucan endohydrolase activity in specific regions of both roots and hypocotyls, in good correlation with transcriptomic data. Moreover, this hydrolytic activity was essentially completely eliminated in AtXTH31/AtXTH32 double knockout lines. However, single and double knockout lines, as well as individual overexpressing lines, of AtXTH31 and AtXTH32 did not demonstrate significant growth or developmental phenotypes. These results suggest that although xyloglucan polysaccharide hydrolysis occurs in parallel with primary wall expansion, morphological effects are subtle or may be compensated by other mechanisms. We hypothesize that there is likely to be an interplay between these xyloglucan endohydrolases and recently discovered apoplastic exo-glycosidases in the hydrolytic modification of matrix xyloglucans. PMID- 23104862 TI - Genome-wide analysis of Stowaway-like MITEs in wheat reveals high sequence conservation, gene association, and genomic diversification. AB - The diversity and evolution of wheat (Triticum-Aegilops group) genomes is determined, in part, by the activity of transposable elements that constitute a large fraction of the genome (up to 90%). In this study, we retrieved sequences from publicly available wheat databases, including a 454-pyrosequencing database, and analyzed 18,217 insertions of 18 Stowaway-like miniature inverted-repeat transposable element (MITE) families previously characterized in wheat that together account for approximately 1.3 Mb of sequence. All 18 families showed high conservation in length, sequence, and target site preference. Furthermore, approximately 55% of the elements were inserted in transcribed regions, into or near known wheat genes. Notably, we observed significant correlation between the mean length of the MITEs and their copy number. In addition, the genomic composition of nine MITE families was studied by real-time quantitative polymerase chain reaction analysis in 40 accessions of Triticum spp. and Aegilops spp., including diploids, tetraploids, and hexaploids. The quantitative polymerase chain reaction data showed massive and significant intraspecific and interspecific variation as well as genome-specific proliferation and nonadditive quantities in the polyploids. We also observed significant differences in the methylation status of the insertion sites among MITE families. Our data thus suggest a possible role for MITEs in generating genome diversification and in the establishment of nascent polyploid species in wheat. PMID- 23104864 TI - Stable cognitive deficits in schizophrenia patients with comorbid obsessive compulsive symptoms: a 12-month longitudinal study. AB - BACKGROUND: Amongst schizophrenia patients, a large subgroup of up to 25% also suffers from comorbid obsessive-compulsive symptoms (OCSs). The association between comorbid OCSs in these patients and neuropsychological impairment remains unclear and somewhat contradictory. Longitudinal approaches investigating the stability of OCS-associated cognitive deficits are missing. METHODS: Thirty-seven patients with schizophrenia and comorbid OCSs and 43 schizophrenia patients without OCS were assessed with a comprehensive cognitive test battery and compared at baseline and, again, 12 months later. RESULTS: Schizophrenia patients with comorbid OCSs showed significant pronounced deficits, with increasing effect sizes over the 12-month assessment period in specific cognitive areas such as visuospatial perception and visual memory (WAIS-R block design, Rey-Osterrieth Complex Figure Test), executive functioning (perseveration in the Wisconsin Card Sorting test), and cognitive flexibility (Trail Making test B). These cognitive domains are correlated with OCS severity and are known to be candidate cognitive domains in obsessive-compulsive disorder (OCD). CONCLUSIONS: OCSs in schizophrenia is associated with specific and longitudinally stable cognitive deficits, strongly arguing for at least partially overlapping neurobiological mechanisms with OCD. Prospective studies involving patients with at-risk mental states for psychosis are necessary to decipher the interaction of cognitive impairment and the clinical manifestations of schizophrenia and OCSs. This might facilitate the definition of patients at high risk for OCSs, an early detection of subclinical levels, therapeutic interventions, and clinical monitoring. PMID- 23104863 TI - The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. AB - Although antioxidants have been repeatedly tested in animal models and clinical studies, there is no evidence that antioxidants reduce already developed age related decline. Recently we demonstrated that mitochondria targeted antioxidant 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) delayed some manifestations of aging.Here we compared effects of SkQ1 and N-acetyl-L-cysteine (NAC) on age-dependent decline in blood levels of leukocytes,growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA) in Wistar and senescence-accelerated OXYS rats. When started late in life, supplementation with SkQ1 not only prevented age-related decline but also significantly reversed it. With NAC, all the observed effects were of the lower magnitude compared with SkQ1 (in spite of that dose of NAC was 16000 times higher). We suggest that supplementation with low doses of SkQ1 is a promising intervention to achieve a healthy ageing. PMID- 23104865 TI - Insight in schizophrenia: involvement of self-reflection networks? AB - BACKGROUND: Impaired insight is a common feature in psychosis and an important predictor of variables such as functional outcome, prognosis, and treatment adherence. A cognitive process that may underlie insight in psychosis is self reflection, or the conscious evaluation of one's traits and characteristics. The current study aims to investigate the neural correlates of self-reflective processing and its relationship with insight in schizophrenia. METHODS: Forty seven schizophrenia patients and 21 healthy controls performed a self-reflection task in a functional magnetic resonance imaging (fMRI) scanner. The tasks comprised a self-reflection, close other-reflection, and a semantic (baseline) condition. Insight scores were obtained with the Schedule of Assessment of Insight Expanded. In addition, cognitive insight scores were obtained (Beck Cognitive Insight Scale [BCIS]). RESULTS: Schizophrenia patients demonstrated less activation in the posterior cingulate cortex in the self- and other reflection conditions and less activation in the precuneus in the other reflection condition compared with healthy controls. Better insight was associated with greater response in the inferior frontal gyrus, anterior insula, and inferior parietal lobule during self-reflection. In addition, better cognitive insight was associated with higher activation in ventromedial prefrontal cortex during self-reflection. CONCLUSION: In the current study, evidence for a relationship between self-reflection and insight in patients with schizophrenia was found in brain areas related to self-reflection, self/other distinction and source attribution. The findings support the rationale for a treatment that is currently under evaluation, which attempts to increase insight by enhancing self-reflection. PMID- 23104866 TI - Evaluating genetic counseling for family members of individuals with schizophrenia in the molecular age. AB - BACKGROUND: Myths and concerns about the extent and meaning of genetic risk in schizophrenia may contribute to significant stigma and burden for families. Genetic counseling has long been proposed to be a potentially informative and therapeutic intervention for schizophrenia. Surprisingly, however, available data are limited. We evaluated a contemporary genetic counseling protocol for use in a community mental health-care setting by non-genetics professionals. METHODS: We used a pre-post study design with longitudinal follow-up to assess the impact of genetic counseling on family members of individuals with schizophrenia, where molecular testing had revealed no known clinically relevant genetic risk variant. We assessed the outcome using multiple measures, including standard items and scales used to evaluate genetic counseling for other complex diseases. RESULTS: Of the 122 family members approached, 78 (63.9%) actively expressed an interest in the study. Participants (n = 52) on average overestimated the risk of familial recurrence at baseline, and demonstrated a significant improvement in this estimate postintervention (P < .0001). This change was associated with an enduring decrease in concern about recurrence (P = .0003). Significant and lasting benefits were observed in other key areas, including increased knowledge (P < .0001) and a decreased sense of stigma (P = .0047). Endorsement of the need for genetic counseling was high (96.1%). CONCLUSIONS: These results provide initial evidence of the efficacy of schizophrenia genetic counseling for families, even in the absence of individually relevant genetic test results or professional genetics services. The findings support the integration of contemporary genetic counseling for families into the general management of schizophrenia in the community. PMID- 23104867 TI - Models of longevity (calorie restriction and AC5 KO): result of three bad hypotheses. PMID- 23104870 TI - The development of a validated checklist for adult lumbar puncture: preliminary results. AB - Lumbar puncture (LP) is known to result in complications. Procedure skills should be taught and evaluated more effectively to improve health care quality. Validated checklists are central to teaching and assessing procedural skills. The results of the first step of the validation of an adult LP checklist are described. A comprehensive literature review of articles published on LP did not yield a checklist validated by the Delphi method. A modified Delphi technique, involving a panel of 9 experts, was used to develop a 20-item LP checklist for teaching and assessing LP, the first step in the validation process. The internal consistency coefficient using Cronbach's alpha was 0.79. The authors used a modified Delphi method to develop a checklist for teaching and assessing LP. For this checklist to become further validated, it should be implemented and studied in the simulation and clinical environments. PMID- 23104868 TI - Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. AB - The molecular foundations of lower-grade gliomas (LGGs)-astrocytoma, oligodendroglioma, and oligoastrocytoma-remain less well characterized than those of their fully malignant counterpart, glioblastoma. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) likely represent initiating pathogenic events. However, while IDH mutations appear to dramatically alter cellular epigenomic landscapes, definitive downstream transformative mechanisms have not been characterized. It remains likely, therefore, that additional genomic abnormalities collaborate with IDH mutation to drive oncogenesis in LGG. We performed whole exome sequencing in 4 LGGs, followed by focused resequencing in an additional 28, and found a high incidence of mutations in the ATRX gene (alpha thalassemia/mental retardation syndrome X-linked). ATRX forms a core component of a chromatin remodeling complex active in telomere biology. Mutations in ATRX have been identified in multiple tumor types and appear to cause alternative lengthening of telomeres (ALT), a presumed precursor to genomic instability. In our samples, ATRX mutation was entirely restricted to IDH-mutant tumors, closely correlated with TP53 mutation and astrocytic differentiation, and mutually exclusive with 1p/19q codeletion, the molecular hallmark of oligodendroglioma. Moreover, ATRX mutation was highly enriched in tumors of so-called early progenitor-like transcriptional subclass (~85%), which our prior work has linked to specific cells of origin in the forebrain subventricular zone. Finally, ATRX mutation correlated with ALT, providing a mechanistic link to genomic instability. In summary, our findings both identify ATRX mutation as a defining molecular determinant for a large subset of IDH-mutant gliomas and have direct implications on pathogenic mechanisms across the wide spectrum of LGGs. PMID- 23104872 TI - Mass loading induced dephasing in nanomechanical resonators. AB - This paper presents a study of dephasing of an underdamped nanomechanical resonator subject to random mass loading of small particles. A frequency noise model is presented which describes dephasing due to the attachment and detachment of particles at random points and particle diffusion along the resonator. This situation is commonly encountered in current mass measurement experiments using nanoelectromechanical (NEM) resonators. The conditions which can lead to inhomogeneous broadening and fine structure in the modes' absorption spectra are discussed. It is also shown that the spectra of the higher-order cumulants of the (complex) vibrational mode amplitude are sensitive to the parameters characterizing the frequency noise process. Hence, measurement of these cumulants can provide information not only about the mass but also about other parameters of the particles (diffusion coefficient and attachment-detachment rates). PMID- 23104873 TI - Returns of the living dead: therapeutic action of irradiated and mitotically inactivated embryonic stem cells. PMID- 23104874 TI - A twist on quantification: measuring the site occupancy of S-nitrosylation. PMID- 23104875 TI - Cytokine profile and ST-elevation myocardial infarction. PMID- 23104876 TI - Is p53 the long-sought molecular trigger for cyclophilin D-regulated mitochondrial permeability transition pore formation and necrosis? PMID- 23104877 TI - Long noncoding RNAs in cardiac development and pathophysiology. AB - Heart function requires sophisticated regulatory networks to orchestrate organ development, physiological responses, and environmental adaptation. Until recently, it was thought that these regulatory networks are composed solely of protein-mediated transcriptional control and signaling systems; consequently, it was thought that cardiac disease involves perturbation of these systems. However, it is becoming evident that RNA, long considered to function primarily as the platform for protein production, may in fact play a major role in most, if not all, aspects of gene regulation, especially the epigenetic processes that underpin organogenesis. These include not only well-validated classes of regulatory RNAs, such as microRNAs, but also tens of thousands of long noncoding RNAs that are differentially expressed across the entire genome of humans and other animals. Here, we review this emerging landscape, summarizing what is known about their functions and their role in cardiac biology, and provide a toolkit to assist in exploring this previously hidden layer of gene regulation that may underpin heart adaptation and complex heart diseases. PMID- 23104880 TI - Circulation research thematic synopsis: vascular biology and disease. PMID- 23104878 TI - Endothelial cells derived from nuclear reprogramming. AB - The endothelium plays a pivotal role in vascular homeostasis, regulating the tone of the vascular wall, and its interaction with circulating blood elements. Alterations in endothelial functions facilitate the infiltration of inflammatory cells and permit vascular smooth muscle proliferation and platelet aggregation. Therefore, endothelial dysfunction is an early event in disease processes including atherosclerosis, and because of its critical role in vascular health, the endothelium is worthy of the intense focus it has received. However, there are limitations to studying human endothelial function in vivo, or human vascular segments ex vivo. Thus, methods for endothelial cell (EC) culture have been developed and refined. Recently, methods to derive ECs from pluripotent cells have extended the scientific range of human EC studies. Pluripotent stem cells may be generated, expanded, and then differentiated into ECs for in vitro studies. Constructs for molecular imaging can also be employed to facilitate tracking these cells in vivo. Furthermore, one can generate patient-specific ECs to study the effects of genetic or epigenetic alterations on endothelial behavior. Finally, there is the opportunity to apply these cells for vascular therapy. This review focuses on the generation of ECs from stem cells; their characterization by genetic, histological, and functional studies; and their translational applications. PMID- 23104879 TI - Neuregulin in cardiovascular development and disease. AB - Studies in genetically modified mice have demonstrated that neuregulin-1 (NRG-1), along with the erythroblastic leukemia viral oncogene homolog (ErbB) 2, 3, and 4 receptor tyrosine kinases, is necessary for multiple aspects of cardiovascular development. These observations stimulated in vitro and in vivo animal studies, implicating NRG-1/ErbB signaling in the regulation of cardiac cell biology throughout life. Cardiovascular effects of ErbB2-targeted cancer therapies provide evidence in humans that ErbB signaling plays a role in the maintenance of cardiac function. These and other studies suggest a conceptual model in which a key function of NRG-1/ErbB signaling is to mediate adaptations of the heart to physiological and pathological stimuli through activation of intracellular kinase cascades that regulate tissue plasticity. Recent work implicates NRG-1/ErbB signaling in the regulation of multiple aspects of cardiovascular biology, including angiogenesis, blood pressure, and skeletal muscle responses to exercise. The therapeutic potential of recombinant NRG-1 as a potential treatment for heart failure has been demonstrated in animal models and is now being explored in clinical studies. NRG-1 is found in human serum and plasma, and it correlates with some clinical parameters, suggesting that it may have value as an indicator of prognosis. In this review, we bring together this growing literature on NRG-1 and its significance in cardiovascular development and disease. PMID- 23104881 TI - Cytosolic Ca2+-induced apoptosis in rat cardiomyocytes via mitochondrial NO-cGMP protein kinase G pathway. AB - Previously, we showed that in adult rat cardiomyocytes, nitric oxide (NO) donors stimulate mitochondrial cGMP production, followed by cytochrome c release, independently of the mitochondrial permeable transition pore. We investigated whether mitochondrial cGMP-induced cytochrome c release from cardiac mitochondria is Ca(2+)-sensitive. Mitochondria and primary cultured cardiomyocytes were prepared from left ventricles of male Wistar rats. The cytosolic Ca(2+) concentration was adjusted with Ca(2+)-EGTA buffers. Cytochrome c released from mitochondria was measured by Western blotting. Cardiomyocyte apoptosis was assessed by Annexin V staining. Cytochrome c release from cardiac mitochondria was evoked by buffered Ca(2+) (1 MUM); this was inhibited by NO-cGMP pathway inhibitors such as N(G)-monomethyl-l-arginine monoacetate (inhibitor of NO synthase), 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (NO scavenger), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, NO-sensitive guanylyl cyclase inhibitor) and voltage-dependent anion channel (VDAC) inhibitor, 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene, but not by cyclosporin A (mitochondrial permeable transition pore inhibitor). Furthermore, this release was significantly and dose dependently inhibited by 0.3-3 MUM KT5823 (protein kinase G inhibitor). At the cellular level, intracellular perfusion of cardiomyocytes with buffered Ca(2+) (1 MUM) also induced apoptosis, which was inhibited in the presence of ODQ. A membrane-permeable cGMP analog, 8-Br-cGMP, but not cGMP itself, mimicked buffered Ca(2+) actions in both cardiac mitochondria and cardiomyocytes. We further confirmed an increase in protein kinase G activity by adding cGMP in mitochondrial protein fraction. Our results suggest that mitochondrial NO-cGMP pathway-induced cytochrome c release from cardiac mitochondria, triggered by increased cytosolic Ca(2+), occurs through VDAC via the stimulation of an undiscovered mitochondrial protein kinase G. PMID- 23104883 TI - Distinction immune genes of hepatitis-induced heptatocellular carcinoma. AB - MOTIVATION: Hepatitis B virus and hepatitis C virus are the two leading causes resulting in hepatocellular carcinoma (HCC). It is observed that hepatitis C virus (HCV) is relatively difficult to induce HCC compared with hepatitis B virus (HBV). This motivates us to reveal the reasons behind this from the viewpoint of immune genes. RESULTS: To distinguish the immune genes with low-level expression in HBV-induced HCC, but high-level expression in HCV-induced HCC, the concept of distinction immune gene is proposed. A filter is then designed to screen these genes. By using gene positive network with strong correlations between genes, the genes are further filtered to form the set of key distinction immune genes. The 23 key distinction immune genes are screened, which are divided into four clusters, T cells, B cells, immune signalling and major histocompatibility complex. It is evident that the screened genes are important immune genes, which are activated in HCV-induced HCC, but inactivated in HBV-induced HCC. In HCV induced HCC, the structures of HCV adaptively update, so that they are difficult to be identified by antigens. Therefore, the clinic advice is either to increase the update speed of antigens or reduce the update speed of the viruses during the treatment of HCV-induced HCC. Moreover, it is also advised to add T cells or add the expression levels of T cells to strengthen the ability to kill cancer cells. In contrast, HBV updates slowly, but the immunity system in HBV-induced HCC has been damaged seriously. As a result, the clinic advice is to improve the immune ability of patients subjected to HBV-induced HCC, such as increasing immunoglobulin, T cells and B cells and so forth. PMID- 23104884 TI - PriVar: a toolkit for prioritizing SNVs and indels from next-generation sequencing data. AB - Next-generation sequencing has become a valuable tool for detecting mutations involved in Mendelian diseases. However, it is a challenge to identify the small subset of functionally important mutations from tens of thousands of rare variants in a whole exome/genome. Therefore, we developed a toolkit called PriVar, a systematic prioritization pipeline that takes into consideration calling quality of the variants, their predicted functional impact, known connection of the gene to the disease and the number of mutations in a gene, and inference from linkage analysis. AVAILABILITY: Executable jar package is available at http://paed.hku.hk/uploadarea/yangwl/html/software.html. PMID- 23104882 TI - Cardiotoxic and cardioprotective features of chronic beta-adrenergic signaling. AB - RATIONALE: In the failing heart, persistent beta-adrenergic receptor activation is thought to induce myocyte death by protein kinase A (PKA)-dependent and PKA independent activation of calcium/calmodulin-dependent kinase II. beta-adrenergic signaling pathways also are capable of activating cardioprotective mechanisms. OBJECTIVE: This study used a novel PKA inhibitor peptide to inhibit PKA activity to test the hypothesis that beta-adrenergic receptor signaling causes cell death through PKA-dependent pathways and cardioprotection through PKA-independent pathways. METHODS AND RESULTS: In PKA inhibitor peptide transgenic mice, chronic isoproterenol failed to induce cardiac hypertrophy, fibrosis, and myocyte apoptosis, and decreased cardiac function. In cultured adult feline ventricular myocytes, PKA inhibition protected myocytes from death induced by beta1 adrenergic receptor agonists by preventing cytosolic and sarcoplasmic reticulum Ca(2+) overload and calcium/calmodulin-dependent kinase II activation. PKA inhibition revealed a cardioprotective role of beta-adrenergic signaling via cAMP/exchange protein directly activated by cAMP/Rap1/Rac/extracellular signal regulated kinase pathway. Selective PKA inhibition causes protection in the heart after myocardial infarction that was superior to beta-blocker therapy. CONCLUSIONS: These results suggest that selective block of PKA could be a novel heart failure therapy. PMID- 23104885 TI - XiP: a computational environment to create, extend and share workflows. AB - XiP (eXtensible integrative Pipeline) is a flexible, editable and modular environment with a user-friendly interface that does not require previous advanced programming skills to run, construct and edit workflows. XiP allows the construction of workflows by linking components written in both R and Java, the analysis of high-throughput data in grid engine systems and also the development of customized pipelines that can be encapsulated in a package and distributed. XiP already comes with several ready-to-use pipeline flows for the most common genomic and transcriptomic analysis and ~300 computational components. AVAILABILITY: XiP is open source, freely available under the Lesser General Public License (LGPL) and can be downloaded from http://xip.hgc.jp. PMID- 23104886 TI - STAR: ultrafast universal RNA-seq aligner. AB - MOTIVATION: Accurate alignment of high-throughput RNA-seq data is a challenging and yet unsolved problem because of the non-contiguous transcript structure, relatively short read lengths and constantly increasing throughput of the sequencing technologies. Currently available RNA-seq aligners suffer from high mapping error rates, low mapping speed, read length limitation and mapping biases. RESULTS: To align our large (>80 billon reads) ENCODE Transcriptome RNA seq dataset, we developed the Spliced Transcripts Alignment to a Reference (STAR) software based on a previously undescribed RNA-seq alignment algorithm that uses sequential maximum mappable seed search in uncompressed suffix arrays followed by seed clustering and stitching procedure. STAR outperforms other aligners by a factor of >50 in mapping speed, aligning to the human genome 550 million 2 * 76 bp paired-end reads per hour on a modest 12-core server, while at the same time improving alignment sensitivity and precision. In addition to unbiased de novo detection of canonical junctions, STAR can discover non-canonical splices and chimeric (fusion) transcripts, and is also capable of mapping full-length RNA sequences. Using Roche 454 sequencing of reverse transcription polymerase chain reaction amplicons, we experimentally validated 1960 novel intergenic splice junctions with an 80-90% success rate, corroborating the high precision of the STAR mapping strategy. AVAILABILITY AND IMPLEMENTATION: STAR is implemented as a standalone C++ code. STAR is free open source software distributed under GPLv3 license and can be downloaded from http://code.google.com/p/rna-star/. PMID- 23104887 TI - Introducing Drugster: a comprehensive and fully integrated drug design, lead and structure optimization toolkit. AB - SUMMARY: Drugster is a fully interactive pipeline designed to break the command line barrier and introduce a new user-friendly environment to perform drug design, lead and structure optimization experiments through an efficient combination of the PDB2PQR, Ligbuilder, Gromacs and Dock suites. Our platform features a novel workflow that guides the user through each logical step of the iterative 3D structural optimization setup and drug design process, by providing a seamless interface to all incorporated packages. AVAILABILITY: Drugster can be freely downloaded via our dedicated server system at http://www.bioacademy.gr/bioinformatics/drugster/. PMID- 23104888 TI - MycPermCheck: the Mycobacterium tuberculosis permeability prediction tool for small molecules. AB - MOTIVATION: With >8 million new cases in 2010, particularly documented in developing countries, tuberculosis (TB) is still a highly present pandemic and often terminal. This is also due to the emergence of antibiotic-resistant strains (MDR-TB and XDR-TB) of the primary causative TB agent Mycobacterium tuberculosis (MTB). Efforts to develop new effective drugs against MTB are restrained by the unique and largely impermeable composition of the mycobacterial cell wall. RESULTS: Based on a database of antimycobacterial substances (CDD TB), 3815 compounds were classified as active and thus permeable. A data mining approach was conducted to gather the physico-chemical similarities of these substances and delimit them from a generic dataset of drug-like molecules. On the basis of the differences in these datasets, a regression model was generated and implemented into the online tool MycPermCheck to predict the permeability probability of small organic compounds. DISCUSSION: Given the current lack of precise molecular criteria determining mycobacterial permeability, MycPermCheck represents an unprecedented prediction tool intended to support antimycobacterial drug discovery. It follows a novel knowledge-driven approach to estimate the permeability probability of small organic compounds. As such, MycPermCheck can be used intuitively as an additional selection criterion for potential new inhibitors against MTB. Based on the validation results, its performance is expected to be of high practical value for virtual screening purposes. AVAILABILITY: The online tool is freely accessible under the URL http://www.mycpermcheck.aksotriffer.pharmazie.uni-wuerzburg.de PMID- 23104889 TI - SPSens: a software package for stochastic parameter sensitivity analysis of biochemical reaction networks. AB - SUMMARY: SPSens is a software package for the efficient computation of stochastic parameter sensitivities of biochemical reaction networks. Parameter sensitivity analysis is a valuable tool that can be used to study robustness properties, for drug targeting, and many other purposes. However its application to stochastic models has been limited when Monte Carlo methods are required due to extremely high computational costs. SPSens provides efficient, state of the art sensitivity analysis algorithms in a single software package so that sensitivity analysis can be easily performed on stochastic models of biochemical reaction networks. SPSens implements the algorithms in C and estimates sensitivities with respect to both infinitesimal and finite perturbations to system parameters, in many cases reducing variance by orders of magnitude compared to basic methods. Included among the features of SPSens are serial and parallel command line versions, an interface with Matlab, and several example problems. AVAILABILITY: SPSens is distributed freely under GPL version 3 and can be downloaded from http://sourceforge.net/projects/spsens/. The software can be run on Linux, Mac OS X and Windows platforms. PMID- 23104890 TI - A hidden Markov model to identify combinatorial epigenetic regulation patterns for estrogen receptor alpha target genes. AB - MOTIVATION: Many studies have shown that epigenetic changes, such as altered DNA methylation and histone modifications, are linked to estrogen receptor alpha (ERalpha)-positive tumors and disease prognoses. Several recent studies have applied high-throughput technologies such as ChIP-seq and MBD-seq to interrogate the altered architectures of ERalpha regulation in tamoxifen (Tam)-resistant breast cancer cells. However, the details of combinatorial epigenetic regulation of ERalpha target genes in breast cancers with acquired Tam resistance have not yet been fully examined. RESULTS: We developed a computational approach to identify and analyze epigenetic patterns associated with Tam resistance in the MCF7-T cell line as opposed to the Tam-sensitive MCF7 cell line, with the goal of understanding the underlying mechanisms of epigenetic regulatory influence on resistance to Tam treatment in breast cancer. In this study, we used ChIP-seq of ERalpha, RNA polymerase II, three histone modifications and MBD-seq data of DNA methylation in MCF7 and MCF7-T cells to train hidden Markov models (HMMs). We applied the Bayesian information criterion to determine that a 20-state HMM was best, which was reduced to a 14-state HMM with a Bayesian information criterion score of 1.21291 * 10(7). We further identified four classes of biologically meaningful states in this breast cancer cell model system, and a set of ERalpha combinatorial epigenetic regulated target genes. The correlated gene expression level and gene ontology analyses showed that different gene ontology terms were enriched with Tam-resistant versus sensitive breast cancer cells. Our study illustrates the applicability of HMM-based analysis of genome-wide high throughput genomic data to study epigenetic influences on E2/ERalpha regulation in breast cancer. PMID- 23104891 TI - RIP-chip enrichment analysis. AB - MOTIVATION: RIP-chip is a high-throughput method to identify mRNAs that are targeted by RNA-binding proteins. The protein of interest is immunoprecipitated, and the identity and relative amount of mRNA associated with it is measured on microarrays. Even if a variety of methods is available to analyse microarray data, e.g. to detect differentially regulated genes, the additional experimental steps in RIP-chip require specialized methods. Here, we focus on two aspects of RIP-chip data: First, the efficiency of the immunoprecipitation step performed in the RIP-chip protocol varies in between different experiments introducing bias not existing in standard microarray experiments. This requires an additional normalization step to compare different samples and even technical replicates. Second, in contrast to standard differential gene expression experiments, the distribution of measurements is not normal. We exploit this fact to define a set of biologically relevant genes in a statistically meaningful way. RESULTS: Here, we propose two methods to analyse RIP-chip data: We model the measurement distribution as a gaussian mixture distribution, which allows us to compute false discovery rates (FDRs) for any cut-off. Thus, cut-offs can be chosen for any desired FDR. Furthermore, we use principal component analysis to determine the normalization factors necessary to remove immunoprecipitation bias. Both methods are evaluated on a large RIP-chip dataset measuring targets of Ago2, the major component of the microRNA guided RNA-induced silencing complex (RISC). Using published HITS-CLIP experiments performed with the same cell line as used for RIP chip, we show that the mixture modelling approach is a necessary step to remove background, which computed FDRs are valid, and that the additional normalization is a necessary step to make experiments comparable. AVAILABILITY: An R implementation of REA is available on the project website (http://www.bio.ifi.lmu.de/REA) and as supplementary data file. PMID- 23104892 TI - Cross-sectional review of the response and treatment uptake from the NHS Health Checks programme in Stoke on Trent. AB - BACKGROUND: As part of national policy to manage the increasing burden of chronic diseases, the Department of Health in England has launched the NHS Health Checks programme, which aims to reduce the burden of the major vascular diseases on the health service. METHODS: A cross-sectional review of response, attendance and treatment uptake over the first year of the programme in Stoke on Trent was carried out. Patients aged between 32 and 74 years and estimated to be at >=20% risk of developing cardiovascular disease were identified from electronic medical records. Multi-level regression modelling was used to evaluate the influence of individual- and practice-level factors on health check outcomes. RESULTS: Overall 63.3% of patients responded, 43.7% attended and 29.8% took up a treatment following their health check invitation. The response was higher for older age and more affluent areas; attendance and treatment uptake were higher for males and older age. Variance between practices was significant (P < 0.001) for response (13.4%), attendance (12.7%) and uptake (23%). CONCLUSIONS: The attendance rate of 43.7% following invitation to a health check was considerably lower than the benchmark of 75%. The lack of public interest and the prevalence of significant comorbidity are challenges to this national policy innovation. PMID- 23104893 TI - Does the integration of TB medical services in the general hospital improve the quality of TB care? Evidence from a case study in China. AB - BACKGROUND: Moving the clinical services from tuberculosis (TB) dispensary to the integrated county hospital (called integrated approach) has been practiced in China; however, it is unknown the quality of TB care in the integrated approach and in the dispensary approach. METHODS: A total of 202 new TB patients were investigated using structured questionnaires in three counties implementing the integrated approach and one county implementing the dispensary approach. The quality of TB care is measured based on success rate of treatment, medical expenditure, health system delay and second-line drug use. RESULTS: The integrated approach showed a high success treatment rate. The medical expenditure in the integrated approach was USD 432, significantly lower than that in the dispensary approach (Z = -5.771, P < 0.001). The integrated approach had a shorter health system delay (5 days) than the dispensary approach (32 days). Twenty-six percent of patients in integrated hospitals were prescribed with second-line TB drugs, significantly lower than that in the TB dispensary (47%, chi(2) = 7.452, P = 0.006). However, the medical expenditure, use of second-line anti-TB drug and liver-protection drugs indeed varied greatly across the three integrated hospitals. CONCLUSIONS: The integrated approach showed better quality of TB care, but the performance of the integrated hospitals varied greatly. A method to standardize TB treatment and management of this approach is urgent. PMID- 23104895 TI - Physical rehabilitation of patients in the intensive care unit requiring extracorporeal membrane oxygenation: a small case series. AB - BACKGROUND AND PURPOSE: Neuromuscular weakness and impaired physical function are common and long-lasting complications experienced by intensive care unit (ICU) survivors. There is growing evidence that implementing rehabilitation therapy shortly after ICU admission improves physical function and reduces health care utilization. Recently, there is increasing interest and utilization of extracorporeal membrane oxygenation (ECMO) to support patients with severe respiratory failure. Patients receiving ECMO are at great risk for significant physical impairments and pose unique challenges for delivering rehabilitation therapy. Consequently, there is a need for innovative examples of safely and feasibly delivering active rehabilitation to these patients. CASE DESCRIPTION: This case report describes 3 patients with respiratory failure requiring ECMO who received physical rehabilitation to illustrate and discuss relevant feasibility and safety issues. OUTCOMES: In case 1, sedation and femoral cannulation limited rehabilitation therapy while on ECMO. In the 2 subsequent cases, minimizing sedation and utilizing a single bicaval dual lumen ECMO cannula placed in the internal jugular vein allowed patients to be alert and participate in active physical therapy while on ECMO, illustrating feasible rehabilitation techniques for these patients. DISCUSSION: Although greater experience is needed to more fully evaluate the safety of rehabilitation on ECMO, these initial cases are encouraging. We recommend systematically and prospectively tracking safety events and patient outcomes during rehabilitation on ECMO to provide greater evidence in this area. PMID- 23104894 TI - Association between VEGF splice isoforms and progression-free survival in metastatic colorectal cancer patients treated with bevacizumab. AB - PURPOSE: Bevacizumab improves survival for patients with metastatic colorectal cancer with chemotherapy, but no proven predictive markers exist. The VEGF-A splice form, VEGF(165)b, anti-angiogenic in animal models, binds bevacizumab. We tested the hypothesis that prolonged progression-free survival (PFS) would occur only in patients with low relative VEGF(165)b levels treated with bevacizumab. EXPERIMENTAL DESIGN: Blinded tumor samples from the phase III trial of FOLFOX4 +/ bevacizumab were assessed for VEGF(165)b and VEGF(total) by immunohistochemistry and scored relative to normal tissue. A predictive index (PI) was derived from the ratio of VEGF(165)b:VEGF(total) for 44 samples from patients treated with FOLFOX + bevacizumab (arm A) and 53 samples from patients treated with FOLFOX4 (arm B), and PFS, and overall survival (OS) analyzed on the basis of PI relative to median ratio. RESULTS: Unadjusted analysis of PFS showed significantly better outcome for individuals with VEGF(165)b:VEGF(total) ratio scores below median treated with FOLFOX4 + bevacizumab compared with FOLFOX4 alone (median, 8.0 vs. 5.2 months; P < 0.02), but no effect of bevacizumab on PFS in patients with VEGF(165)b:VEGF(total) ratio >median (5.9 vs. 6.3 months). These findings held after adjustment for other clinical and demographic features. OS was increased in arm A (median, 13.6 months) compared with arm B (10.6 months) in the low VEGF(165)b group, but this did not reach statistical significance. There was no difference in the high VEGF(165)b:VEGF(total) group between FOLFOX + bevacizumab (10.8 months) and FOLFOX alone (11.3 months). CONCLUSION: Low VEGF(165)b:VEGF(total) ratio may be a predictive marker for bevacizumab in metastatic colorectal cancer, and individuals with high relative levels may not benefit. PMID- 23104896 TI - Rare variant discovery and calling by sequencing pooled samples with overlaps. AB - MOTIVATION: For many complex traits/diseases, it is believed that rare variants account for some of the missing heritability that cannot be explained by common variants. Sequencing a large number of samples through DNA pooling is a cost effective strategy to discover rare variants and to investigate their associations with phenotypes. Overlapping pool designs provide further benefit because such approaches can potentially identify variant carriers, which is important for downstream applications of association analysis of rare variants. However, existing algorithms for analysing sequence data from overlapping pools are limited. RESULTS: We propose a complete data analysis framework for overlapping pool designs, with novelties in all three major steps: variant pool and variant locus identification, variant allele frequency estimation and variant sample decoding. The framework can be used in combination with any design matrix. We have investigated its performance based on two different overlapping designs and have compared it with three state-of-the-art methods, by simulating targeted sequencing and by pooling real sequence data. Results on both datasets show that our algorithm has made significant improvements over existing ones. In conclusion, successful discovery of rare variants and identification of variant carriers using overlapping pool strategies critically depend on many steps, from generation of design matrixes to decoding algorithms. The proposed framework in combination with the design matrixes generated based on the Chinese remainder theorem achieves best overall results. AVAILABILITY: Source code of the program, termed VIP for Variant Identification by Pooling, is available at http://cbc.case.edu/VIP. PMID- 23104897 TI - Why traditional statistical process control charts for attribute data should be viewed alongside an xmr-chart. AB - The use of statistical process control (SPC) charts in healthcare is increasing. The general advice when plotting SPC charts is to begin by selecting the right chart. This advice, in the case of attribute data, may be limiting our insights into the underlying process and consequently be potentially misleading. Given the general lack of awareness that additional insights may be obtained by using more than one SPC chart, there is a need to review this issue and make some recommendations. Under purely common cause variation the control limits on the xmr-chart and traditional attribute charts (eg, p-chart, c-chart, u-chart) will be in close agreement, indicating that the observed variation (xmr-chart) is consistent with the underlying Binomial model (p-chart) or Poisson model (c chart, u-chart). However, when there is a material difference between the limits from the xmr-chart and the attribute chart then this also constitutes a signal of an underlying systematic special cause of variation. We use one simulation and two case studies to demonstrate these ideas and show the utility of plotting the SPC chart for attribute data alongside an xmr-chart. We conclude that the combined use of attribute charts and xmr-charts, which requires little additional effort, is a useful strategy because it is less likely to mislead us and more likely to give us the insight to do the right thing. PMID- 23104899 TI - Different effects of bladder distention on point A-based and 3D-conformal intracavitary brachytherapy planning for cervical cancer. AB - This study sought to evaluate the differential effects of bladder distention on point A-based (AICBT) and three-dimensional conformal intracavitary brachytherapy (3D-ICBT) planning for cervical cancer. Two sets of CT scans were obtained for ten patients to evaluate the effect of bladder distention. After the first CT scan, with an empty bladder, a second set of CT scans was obtained with the bladder filled. The clinical target volume (CTV), bladder, rectum, and small bowel were delineated on each image set. The AICBT and 3D-ICBT plans were generated, and we compared the different planning techniques with respect to the dose characteristics of CTV and organs at risk. As a result of bladder distention, the mean dose (D50) was decreased significantly and geometrical variations were observed in the bladder and small bowel, with acceptable minor changes in the CTV and rectum. The average D2 cm(3)and D1 cm(3)showed a significant change in the bladder and small bowel with AICBT; however, no change was detected with the 3D-ICBT planning. No significant dose change in the CTV or rectum was observed with either the AICBT or the 3D-ICBT plan. The effect of bladder distention on dosimetrical change in 3D-ICBT planning appears to be minimal, in comparison with AICBT planning. PMID- 23104898 TI - An investigation of the depth dose in the build-up region, and surface dose for a 6-MV therapeutic photon beam: Monte Carlo simulation and measurements. AB - The percentage depth dose in the build-up region and the surface dose for the 6 MV photon beam from a Varian Clinac 23EX medical linear accelerator was investigated for square field sizes of 5 * 5, 10 * 10, 15 * 15 and 20 * 20 cm(2)using the EGS4nrc Monte Carlo (MC) simulation package. The depth dose was found to change rapidly in the build-up region, and the percentage surface dose increased proportionally with the field size from approximately 10% to 30%. The measurements were also taken using four common detectors: TLD chips, PFD dosimeter, parallel-plate and cylindrical ionization chamber, and compared with MC simulated data, which served as the gold standard in our study. The surface doses obtained from each detector were derived from the extrapolation of the measured depth doses near the surface and were all found to be higher than that of the MC simulation. The lowest and highest over-responses in the surface dose measurement were found with the TLD chip and the CC13 cylindrical ionization chamber, respectively. Increasing the field size increased the percentage surface dose almost linearly in the various dosimeters and also in the MC simulation. Interestingly, the use of the CC13 ionization chamber eliminates the high gradient feature of the depth dose near the surface. The correction factors for the measured surface dose from each dosimeter for square field sizes of between 5 * 5 and 20 * 20 cm(2)are introduced. PMID- 23104900 TI - Anti-radiation damage effect of polyethylenimine as a toll-like receptor 5 targeted agonist. AB - A number of agents are now available for use in protecting against ionizing radiation. These radiation-protective agents, however, have many adverse effects. Efforts have been made to develop new radiation-protective agents for medical application. Here, we investigated whether a compound, polyethylenimine (PEI), which activates Toll-like receptor 5 (TLR5)-mediated NF-kB signaling pathways, could have an anti-radiation effect on a mouse model. First, a cell-based screening model for an agonist of TLR5-mediated NF-kB pathway was established and then validated by activation of TLR5-mediated NF-kB luciferase reporter activity with a known TLR5 agonist, flagellin. We found that PEI induced dose-dependent activation of the TLR5-mediated NF-kB pathway, indicating that PEI is indeed a TLR5 agonist. Furthermore, the anti-radiation effect of polyethylenimine was assessed using a gamma-ray total body irradiation (TBI) mouse model. Compared with the irradiation control, both survival time and survival rate were significantly improved in mice that received either a low dose of polyethylenimine (P= 0.019) or a high dose of polyethylenimine (P< 0.001). We also observed a positive correlation between animal body weight and survival time in mice that received a low dose of polyethylenimine, a high dose of polyethylenimine and amifostine, over a period of 30 days, r= 0.42 (P< 0.02), 0.72 (P< 0.0001) and 0.95 (P< 0.0001), respectively, while a negative correlation between animal body weight and survival time was observed in the irradiation control (r= -0.89; P< 0.0001). These results indicate that polyethylenimine is a new TLR5 agonist with potential application in offering protection for patients receiving radiotherapy or in radiation-related accidents. PMID- 23104901 TI - Air versus gas tamponade in retinal detachment surgery. AB - OBJECTIVE: To compare the outcome of air tamponade with gas tamponade in primary vitrectomy for the treatment of rhegmatogenous retinal detachment (RRD). METHODS: We examined the records of 524 cases of 523 patients that underwent primary vitrectomy for RRD with air or sulphur hexafluoride 20% gas tamponade and a follow-up of at least 3 months, excluding cases with inferior retinal breaks. RESULTS: 318 cases were treated with gas and 128 cases with air. Overall, vitrectomy led to an attached retina after a single operation in 85.1% of cases. Eyes treated with air had an 81.0% chance of primary success and those treated with gas had an 86.9% success rate (p=0.083, NS, chi(2) test). Involvement of lower retinal quadrants in the retinal detachment was revealed as a significant confounding factor. After correction for this confounder using a multivariate logistic regression model, air versus gas tamponade became a statistically significant determinant for success rate (OR 1.97; p=0.012). In a sub-analysis, eyes with a retinal detachment that involved the inferior quadrants had significantly lower primary success rates when using air tamponade (69.6%), compared to gas tamponade (84.7%; p=0.009, chi(2) test). CONCLUSIONS: Gas tamponade is superior to air tamponade in retinal detachment cases with involvement of the lower quadrants. These results suggest that air tamponade should only be used in retinal detachments that are restricted to the superior quadrants. Further prospective study is needed to confirm these findings, and to address functional outcome. PMID- 23104902 TI - Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. AB - PURPOSE: Hand-held spectral domain optical coherence tomography (HHSD OCT) has greatly expanded the imaging/diagnostic capacity for clinicians managing children with intraocular retinoblastoma. We present our early experience with HHSD OCT and conventional spectral domain OCT imaging in these patients. METHODS: In this retrospective cross-sectional observational study, infants were imaged during examination under anaesthesia with HHSD OCT in the supine position. Older cooperative retinoblastoma patients were additionally imaged with upright conventional OCT. Clinical data were derived from patient charts and from a prospectively maintained interinstitutional retinoblastoma database. Complementary imaging techniques, including RetCamTM, fluorescein angiography and B-scan ultrasound, were assessed. RESULTS: Twenty-two intraocular lesions in 16 patients were imaged. HHSD OCT was used exclusively in 19 lesions, while conventional OCT was also performed in three cases. Small lesions were imaged in five cases, all of which were localised to the middle retinal layers. Clinical uses for HHSD OCT imaging identified included: diagnosis of new lesions, monitoring response to laser therapy and the identification of edge recurrences. CONCLUSIONS: Although indirect ophthalmoscopy remains the gold standard for diagnosis and treatment of retinoblastoma, HHSD OCT is a valuable tool in better understanding and managing retinoblastoma. PMID- 23104903 TI - Ankle taping and bracing for proprioception. PMID- 23104904 TI - TRM Forum on Computer Simulation and Experimental Assessment of Cardiac Function. PMID- 23104905 TI - A computer model of endo-epicardial electrical dissociation and transmural conduction during atrial fibrillation. AB - AIMS: Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. The aim of the study was to investigate the role of transmural conduction in the stability of AF episodes using a dual-layer computer model. METHODS AND RESULTS: A proof-of-principle dual layer model was developed in which connections between the layers can be introduced or removed at any time during the simulation. Using an S1-S2 protocol, a spiral wave was initiated in one of the layers, which degenerated into a complex AF pattern after connection with the other layer at six randomly chosen sites. After 6 s, connections were either retained (dual-layer simulations) or removed (single-layer simulations). Dual-layer simulations were more complex, as indicated by the higher number of waves and phase singularities. Tracking waves through both layers revealed that the number of waves in dual-layer simulations was significantly higher than in the single-layer simulations, reflecting more opportunities for reentry and a concomitant increase in AF stability. In the dual layer model, only 12% of the AF episodes died out within 6 s, while 59% died out in the single-layer model. CONCLUSION: Atrial fibrillation patterns are more complex and AF episodes are more stable in a dual-layer model. This study indicates an important role for endo-epicardial conduction for the stabilization of AF. PMID- 23104906 TI - Ablation of multi-wavelet re-entry: general principles and in silico analyses. AB - AIMS: Catheter ablation strategies for treatment of cardiac arrhythmias are quite successful when targeting spatially constrained substrates. Complex, dynamic, and spatially varying substrates, however, pose a significant challenge for ablation, which delivers spatially fixed lesions. We describe tissue excitation using concepts of surface topology which provides a framework for addressing this challenge. The aim of this study was to test the efficacy of mechanism-based ablation strategies in the setting of complex dynamic substrates. METHODS AND RESULTS: We used a computational model of propagation through electrically excitable tissue to test the effects of ablation on excitation patterns of progressively greater complexity, from fixed rotors to multi-wavelet re-entry. Our results indicate that (i) focal ablation at a spiral-wave core does not result in termination; (ii) termination requires linear lesions from the tissue edge to the spiral-wave core; (iii) meandering spiral-waves terminate upon collision with a boundary (linear lesion or tissue edge); (iv) the probability of terminating multi-wavelet re-entry is proportional to the ratio of total boundary length to tissue area; (v) the efficacy of linear lesions varies directly with the regional density of spiral-waves. CONCLUSION: We establish a theoretical framework for re-entrant arrhythmias that explains the requirements for their successful treatment. We demonstrate the inadequacy of focal ablation for spatially fixed spiral-waves. Mechanistically guided principles for ablating multi-wavelet re-entry are provided. The potential to capitalize upon regional heterogeneity of spiral-wave density for improved ablation efficacy is described. PMID- 23104907 TI - Atrial septal pacing for the termination of atrial fibrillation: study in a biophysical model of human atria. AB - AIMS: While successful termination by pacing of organized atrial tachycardias has been observed in patients, single site rapid pacing has not yet led to conclusive results for the termination of atrial fibrillation (AF). The purpose of this study was to evaluate a novel atrial septal pacing algorithm for the termination of AF in a biophysical model of the human atria. METHODS AND RESULTS: Sustained AF was generated in a model based on human magnetic resonance images and membrane kinetics. Rapid pacing was applied from the septal area following a dual-stage scheme: (i) rapid pacing for 10-30 s at pacing intervals 62-70% of AF cycle length (AFCL), (ii) slow pacing for 1.5 s at 180% AFCL, initiated by a single stimulus at 130% AFCL. Atrial fibrillation termination success rates were computed. A mean success rate for AF termination of 10.2% was obtained for rapid septal pacing only. The addition of the slow pacing phase increased this rate to 20.2%. At an optimal pacing cycle length (64% AFCL) up to 29% of AF termination was observed. CONCLUSION: The proposed septal pacing algorithm could suppress AF reentries in a more robust way than classical single site rapid pacing. Experimental studies are now needed to determine whether similar termination mechanisms and rates can be observed in animals or humans, and in which types of AF this pacing strategy might be most effective. PMID- 23104908 TI - Individualized therapy in patients with atrial fibrillation: new look at atrial fibrillation. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality, the so-called AF burden. Despite significant progress in the understanding, the mechanisms and pathophysiology of AF treatments are often unsatisfactory. This in part may be related to the complexity of this arrhythmia, as well as its evolution overtime. Atrial fibrillation has many aetiologies and underlying causes. The anti arrhythmic drugs (AADs) and interventions aimed at controlling AF should therefore be based on aetiology and associated conditions, rather than electrophysiological mechanisms. The current guideline in the management of AF in most part is based on safety and outcome. This review will discuss the approach to management, based on primary prevention of AF with the aim to target at risk factors, triggers, specific substrates related to aetiology rather than mechanisms. The development of new pharmacological agents and therapeutic strategies should consider not only evidence based, but also include patient specific personalized context system biology and pharmacology; otherwise, we will continue to see moderate drug efficacy at best and negative results and outcomes. PMID- 23104909 TI - Management of ventricular and atrial arrhythmias in humans: towards a patient specific approach. AB - The strategy of sudden cardiac death prevention by implantable cardioverter defibrillator, in primary prevention, is mainly based on the value of ejection fraction. That means that the approach is not really patient specific. A lot of implanted patients will not receive any shock. The implantation of large categories of patients is interesting on a global therapeutical point of view but, when considering the economical aspects, it would be more useful to have better selection criteria in order to obtain a more patient-specific approach, avoiding implanting patients who will never receive shocks. The parameters commonly used to select patients for implantations have a good negative predictive value but a low positive predictive value. Concerning atrial fibrillation the approach is quite different. Antiarrhythmic drug treatment has shown many limitations. Antiarrhythmic drugs are useful and safe in atrial fibrillation patients only if the contra-indications are strictly respected. The main difficulty concerns patients with both heart failure and atrial fibrillation. The story of Dronedarone development is illustrative of the necessity of a patient-specific approach in the treatment strategy of atrial fibrillation. The ATHENA trial made with Dronedarone showed a benefit in patients with underlying heart disease but no patient with advanced cardiopathy was included in the study. On the contrary, the PALLAS trial has clearly shown that the drug is contra-indicated in patients with any type of heart failure. In atrial fibrillation, a patient-specific approach is mandatory. This review illustrates the dichotomy of the two different approaches. PMID- 23104910 TI - Fully automated initiation of simulated episodes of atrial arrhythmias. AB - AIMS: To develop computational tools for automatically initiating a large number of independent episodes of atrial arrhythmias in electro-anatomical computer models of the atria and therefore facilitating the design of in silico experiments. METHODS AND RESULTS: A biophysical model of the atria was constructed from segmented medical images of the human atria of a patient with atrial fibrillation (AF). A set of 40 initial conditions were generated based on a priori knowledge about wavefront propagation and the number and location of reentries (1-6 randomly distributed over the atrial epicardium). Simulations were run from each of these initial conditions in three substrates representing different forms of AF dynamics (stable rotors; multiple unstable meandering wavelets; and wavelets broken by repolarization heterogeneities). To demonstrate the applicability of the initiation method for testing clinical of therapeutic interventions, the channel I(Kr) was blocked after 2 s of simulation and its effect on the number of functional reentries was documented. The use of pre computed initial conditions enabled to successfully generate episodes of simulated AF in each substrate. Blockade of I(Kr) channel prolonged action potential duration, resulting in a reduction of the number of functional reentries. In the substrate with unstable spiral waves, the effect was sufficiently large to terminate AF in about two-thirds of the cases. In the two other substrates, the effect was minor. CONCLUSION: These new simulation tools may help investigate in computer models therapeutic interventions in different substrates in order to identify substrate-specific optimal therapy. PMID- 23104911 TI - Dominant frequency and organization index maps in a realistic three-dimensional computational model of atrial fibrillation. AB - AIMS: To study, using simulation, the spectral characteristics of different patterns of atrial fibrillation (AF) at high spatial resolution. Dominant frequency (DF) and organization index (OI) maps have been used to approximate the location of the focal source of high frequency during AF events. METHODS AND RESULTS: A realistic three-dimensional model of the human atria that includes fibre orientation, electrophysiological heterogeneity, and anisotropy was implemented. The cellular model was modified to simulate electrical remodelling. More than 43 000 electrograms were calculated on the surface, and were processed to reconstitute the DF and OI maps. Atrial fibrillation episodes were triggered by a source of transitory and of continuous activity (both with a cycle length of 130 ms) in five different locations. The maps obtained during the AF events triggered by transitory foci did not show areas with high DF or OI values. When continuous foci were applied, the DF maps show ample zones with high values in the atrium where the focus was applied; while OI maps display smaller areas with high values, always within the areas of high DF and, in three of five locations, this high-value area was located at the site of focus application and at the nearby area. In the other two locations, the area presenting the highest OI values is small and located at the site of focus application, which allowed its precise localization. CONCLUSION: Organization index maps provide a better approximation than DF maps for the localization of ectopic sources of high frequency and continuous activity during episodes of simulated AF in remodelled tissue. PMID- 23104912 TI - Microscopic variations in interstitial and intracellular structure modulate the distribution of conduction delays and block in cardiac tissue with source-load mismatch. AB - AIMS: Reentrant activity in the heart is often correlated with heterogeneity in both the intracellular structure and the interstitial structure surrounding cells; however, the combined effect of cardiac microstructure and interstitial resistivity in regions of source-load mismatch is largely unknown. The aim of this study was to investigate how microstructural variations in cell arrangement and increased interstitial resistivity influence the spatial distribution of conduction delays and block in poorly coupled regions of tissue. METHODS AND RESULTS: Two-dimensional 0.6 cm * 0.6 cm computer models with idealized and realistic cellular structure were used to represent a monolayer of ventricular myocytes. Gap junction connections were distributed around the periphery of each cell at 10 MUm intervals. Regions of source-load mismatch were added to the models by increasing the gap junction and interstitial resistivity in one-half of the tissue. Heterogeneity in cell shape and cell arrangement along the boundary between well-coupled and poorly coupled tissue increased variability in longitudinal conduction delays to as much as 10 ms before the onset of conduction block, resulting in wavefront breakthroughs with pronounced curvature at distinct points along the boundary. Increasing the effective interstitial resistivity reduced source-load mismatch at the transition boundary, which caused a decrease in longitudinal conduction delay and an increase in the number of wavefront breakthroughs. CONCLUSION: Microstructural variations in cardiac tissue facilitate the formation of isolated sites of wavefront breakthrough that may enable abnormal electrical activity in small regions of diseased tissue to develop into more widespread reentrant activity. PMID- 23104913 TI - Similarities and differences between electrocardiogram signs of left bundle branch block and left-ventricular uncoupling. AB - AIMS: A left bundle-branch block (LBBB) electrocardiogram (ECG) type may be caused by either a block in the left branch of the ventricular conduction system or by uncoupling in the working myocardium. We used a realistic large-scale computer model to evaluate the effects of uncoupling with and without left-sided block and in combination with biventricular pacing. METHODS AND RESULTS: Action potential propagation was simulated using a reaction-diffusion model of the human ventricles. Electrocardiograms and cardiac electrograms were computed from the simulated action potentials by solving the bidomain equations. In all situations, diffuse uncoupling reduced QRS amplitude, prolonged QRS duration, and rotated the QRS axis leftward. Uncoupling by 50% increased QRS duration from 90 to 120 ms with a normal conduction system and from 140 to 190 ms when the left bundle branch was blocked. Biventricular pacing did not change QRS duration but reduced total ventricular activation time. CONCLUSION: Uncoupling in the working myocardium can mimic left-sided block in the ventricular conduction system and can explain an LBBB ECG pattern with relatively low amplitude. Biventricular pacing improves ventricular activation in true LBBB with or without uncoupling but not in case of 50% uncoupling alone. PMID- 23104914 TI - Genetic engineering of somatic cells to study and improve cardiac function. AB - AIMS: To demonstrate the utility of genetically engineered excitable cells for studies of basic electrophysiology and cardiac cell therapy. METHODS AND RESULTS: 'Zig-zag' networks of neonatal rat ventricular myocytes (NRVMs) were micropatterned onto thin elastomeric films to mimic the slow action potential (AP) conduction found in fibrotic myocardium. Addition of genetically engineered excitable human embryonic kidney cells (HEK-293 cells) ('Ex-293' cells stably expressing Kir2.1, Na(v)1.5, and Cx43 channels) increased both cardiac conduction velocity by 370% and twitch force amplitude by 64%. Furthermore, we stably expressed mutant Na(v)1.5 [A1924T (fast sodium channel mutant (substitution of alanine by threonine at amino acid 1924)] channels with hyperpolarized steady state activation and showed that, despite a 71.6% reduction in peak I(Na), these cells propagated APs at the same velocity as the wild-type Na(v)1.5-expressing Ex 293 cells. Stable expression of Ca(v)3.3 (T-type voltage-gated calcium) channels in Ex-293 cells (to generate an 'ExCa-293' line) significantly increased their AP duration and reduced repolarization gradients in cocultures of these cells and NRVMs. Additional expression of an optogenetic construct [ChIEF (light-gated Channelrhodopsin mutant)]enabled light-based control of AP firing in ExCa-293 cells. CONCLUSION: We show that, despite being non-contractile, genetically engineered excitable cells can significantly improve both electrical and mechanical function of engineered cardiac tissues in vitro. We further demonstrate the utility of engineered cells for tissue-level studies of basic electrophysiology and cardiac channelopathies. In the future, this novel platform could be utilized in the high-throughput design of new genetically encoded indicators of cell electrical function, validation, and improvement of computer models of AP conduction, and development of novel engineered somatic cell therapies for the treatment of cardiac infarction and arrhythmias. PMID- 23104915 TI - Arrhythmogenic remodelling of activation and repolarization in the failing human heart. AB - Heart failure is a major cause of disability and death worldwide, and approximately half of heart failure-related deaths are sudden and presumably due to ventricular arrhythmias. Patients with heart failure have been shown to be at 6- to 9-fold increased risk of sudden cardiac death compared to the general population. (AHA. Heart Disease and Stroke Statistics-2003 Update. Heart and Stroke Facts. Dallas, TX: American Heart Association; 2002) Thus, electrophysiological remodelling associated with heart failure is a leading cause of disease mortality and has been a major investigational focus examined using many animal models of heart failure. While these studies have provided an important foundation for understanding the arrhythmogenic pathophysiology of heart failure, the need for corroborating studies conducted on human heart tissue has been increasingly recognized. Many human heart studies of conduction and repolarization remodelling have now been published and shed some light on important, potentially arrhythmogenic, changes in human heart failure. These studies are being conducted at multiple experimental scales from isolated cells to whole-tissue preparations and have provided insight into regulatory mechanisms such as decreased protein expression, alternative mRNA splicing of ion channel genes, and defective cellular trafficking. Further investigations of heart failure in the human myocardium will be essential for determining possible therapeutic targets to prevent arrhythmia in heart failure and for facilitating the translation of basic research findings to the clinical realm. PMID- 23104916 TI - The role of action potential alternans in the initiation of atrial fibrillation in humans: a review and future directions. AB - This review highlights the role of atrial monophasic action potential duration (APD) in understanding atrial electrical properties in paroxysmal, persistent, and permanent atrial fibrillation (AF) states. Alternans of APD and rate maladaptation in a spatially divergent way appear mechanistically involved in AF initiation, development, and persistence. The underlying pathophysiology warrants further investigation. PMID- 23104917 TI - Mechanical discoordination increases continuously after the onset of left bundle branch block despite constant electrical dyssynchrony in a computational model of cardiac electromechanics and growth. AB - AIMS: To test whether a functional growth law leads to asymmetric hypertrophy and associated changes in global and regional cardiac function when integrated with a computational model of left bundle branch block (LBBB). METHODS AND RESULTS: In recent studies, we proposed that cardiac myocytes grow longer when a threshold of maximum fibre strain is exceeded and grow thicker when the smallest maximum principal strain in the cellular cross-sectional plane exceeds a threshold. A non linear cardiovascular model of the beating canine ventricles was combined with the cellular growth law. After inducing LBBB, the ventricles were allowed to adapt in shape over time in response to mechanical stimuli. When subjected to electrical dyssynchrony, the combined model of ventricular electromechanics, haemodynamics, and growth led to asymmetric hypertrophy with a faster increase of wall mass in the left ventricular (LV) free wall (FW) than the septum, increased LV end-diastolic and end-systolic volumes, and decreased LV ejection fraction. Systolic LV pressure decreased during the acute phase of LBBB and increased at later stages. The relative changes of these parameters were similar to those obtained experimentally. Most of the dilation was due to radial and axial fibre growth, and hence altered shape of the LVFW. CONCLUSION: Our previously proposed growth law reproduced measured dyssynchronously induced asymmetric hypertrophy and the associated functional changes, when combined with a computational model of the LBBB heart. The onset of LBBB leads to a step increase in LV mechanical discoordination that continues to increase as the heart remodels despite the constant electrical dyssynchrony. PMID- 23104918 TI - Microscopic magnetic resonance imaging reveals high prevalence of third coronary artery in human and rabbit heart. AB - AIM: The human coronary tree is commonly assumed to have two roots: the left and right coronary arteries (LCA and RCA, respectively). However, a third coronary artery (TCA) has been observed in humans and animals, usually arising from the right anterior aortic sinus near the RCA. Using high-resolution magnetic resonance imaging, we identified TCA prevalence and characteristics in rabbit and human hearts. METHODS AND RESULTS: Third coronary artery presence was analysed in hearts from 11 New Zealand white rabbits and 7 human cadavers, using excised tissue that was fixed, gadolinium-treated, and agar-embedded for imaging-based reconstruction. A TCA was identified in all rabbit hearts and six of seven human hearts, originating either from an independent ostium (7 of 11 rabbits, 2 of 7 humans) or an ostium shared with the RCA (4 of 11 rabbits, 4 of 7 humans). Proximal TCA cross-sectional area in rabbits was 15.3 +/- 6.0% of RCA area (mean +/- SD, based on n = 9 rabbit hearts in which reliable measurements could be taken for both vessels), and 26.7 +/- 10.1% in humans (n = 4). In all-but-one case where a TCA was observed, it originated ventral to the RCA, progressing towards the right ventricular outflow tract. In one rabbit, the TCA originated dorsal to the RCA and progressed towards the Crista terminalis in the right atrium. A fourth vessel, forming a separate aortic Vas vasorum was occasionally seen, originating from the right anterior aortic sinus either from an ostium common with (1 of 11 rabbits, 0 of 7 humans) or independent of (1 of 11 rabbits, 1 of 7 humans) the TCA. Pilot optical mapping experiments showed that TCA occlusion had variable acute effects on rabbit cardiac electrophysiology. CONCLUSION: Third coronary artery presence is common in rabbit and human hearts. Functional effects of disrupted TCA blood supply are ill-investigated, and the rabbit may be a suitable species for such research. PMID- 23104920 TI - Impact of amiodarone and cisapride on simulated human ventricular electrophysiology and electrocardiograms. AB - AIMS: Amiodarone and cisapride are both known to prolong the QT interval, yet the two drugs have different effects on arrhythmia. Cisapride can cause torsades de pointes while amiodarone is found to be anti-arrhythmic. A computational model was used to investigate the action of these two drugs. METHODS AND RESULTS: In a biophysically detailed model, the ion current conductivities affected by both drugs were reduced in order to simulate the pharmacological effects in healthy and ischaemic cells. Furthermore, restitution curves of the action potential duration (APD), effective refractory period, conduction velocity, wavelength, and the vulnerable window were determined in a one-dimensional (1D) tissue strand. Moreover, cardiac excitation propagation was computed in a 3D model of healthy ventricles. The corresponding body surface potentials were calculated and standard 12-lead electrocardiograms were derived. Both cisapride and amiodarone caused a prolongation of the QT interval and the refractory period. However, cisapride did not significantly alter the conduction-related properties, such as e.g. the wavelength or vulnerable window, whereas amiodarone had a larger impact on them. It slightly flattened the APD restitution slope and furthermore reduced the conduction velocity and wavelength. CONCLUSION: Both drugs show similar prolongation of the QT interval, although they present different electrophysiological properties in the single-cell as well as in tissue simulations of cardiac excitation propagation. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias caused by amiodarone and cisapride. PMID- 23104921 TI - Cellular and molecular correlates of ectopic activity in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with increased morbidity and mortality. Current drugs for AF treatment have limited efficacy and a substantial risk of proarrhythmic side effects, making novel drug development critical. Emerging evidence suggests that abnormal intracellular calcium (Ca(2+)) signalling is a key contributor to ectopic (triggered) electrical activity in human AF. Accordingly, atrial Ca(2+)-handling abnormalities underlying ectopic activity may constitute novel mechanism-based therapeutic approaches to treat AF. This article reviews the recent evidence for a role of cellular ectopic activity in human AF pathophysiology, discusses the molecular mechanisms underlying triggered activity in human atrial myocytes, and considers their relevance to the design of novel therapeutic options. PMID- 23104919 TI - Computational cardiology: how computer simulations could be used to develop new therapies and advance existing ones. AB - This article reviews the latest developments in computational cardiology. It focuses on the contribution of cardiac modelling to the development of new therapies as well as the advancement of existing ones for cardiac arrhythmias and pump dysfunction. Reviewed are cardiac modelling efforts aimed at advancing and optimizing existent therapies for cardiac disease (defibrillation, ablation of ventricular tachycardia, and cardiac resynchronization therapy) and at suggesting novel treatments, including novel molecular targets, as well as efforts to use cardiac models in stratification of patients likely to benefit from a given therapy, and the use of models in diagnostic procedures. PMID- 23104923 TI - Improving health care services in Northern Cyprus: a call for research and action. PMID- 23104925 TI - Why is soft bipolar disorder so hard to define? PMID- 23104922 TI - PA28gamma is a novel corepressor of HTLV-1 replication and controls viral latency. AB - The establishment of a latent reservoir by human tumor viruses is a vital step in initiating cellular transformation and represents a major shortcoming to current therapeutic strategies and the ability to eradicate virus-infected cells. Human T cell leukemia virus type 1 (HTLV-1) establishes a lifelong infection and is linked to adult T-cell leukemia lymphoma (ATLL). Here, we demonstrate that HTLV-1 p30 recruits the cellular proteasome activator PA28gamma onto the viral tax/rex mRNA to prevent its nuclear export and suppress virus replication. Interaction of p30 with a PA28gamma retaining fully functional proteasome activity is required for p30's ability to repress HTLV-1. Consistently, HTLV-1 molecular clones replicate better and produce more virus particles in PA28gamma-deficient cells. These results define a unique and novel role for the cellular factor PA28gamma in the control of nuclear RNA trafficking and HTLV-1-induced latency. Importantly, knockdown of PA28gamma expression in ATLL cells latently infected with HTLV-1 reactivates expression of viral tax/rex RNA and the Tax protein. Because Tax is the most immunogenic viral antigen and triggers strong CTL responses, our results suggest that PA28gamma-targeted therapy may reactivate virus expression from latently infected cells and allow their eradication from the host. KEY POINTS: PA28gamma acts as a co-repressor of HTLV-1 p30 to suppress virus replication and is required for the maintenance of viral latency. HTLV-1 has evolved a unique function mediated by its posttranscriptional repressor p30, which is not found in HTLV-2. PMID- 23104926 TI - A thorn in the side of evidence-based treatment for adolescent anorexia nervosa. PMID- 23104927 TI - The impact of depression heterogeneity on cognitive control in major depressive disorder. AB - OBJECTIVE: Depressed patients display a variety of deficits in neuropsychological function, and contradictory findings in the literature may be due to disorder heterogeneity. The aim of this study was to examine the impact of severity, subtype and symptoms on cognitive control. METHODS: Neuropsychological function across a range of cognitive control tasks was examined in melancholic (n = 65) and non-melancholic depressed patients (n = 59) relative to controls (n = 124). The relationship between subtype (melancholia vs non-melancholia) and anxiety was also examined. RESULTS: Melancholia was characterised by attention and working memory deficits typically associated with the dorsolateral prefrontal cortex, while non-melancholia was characterised by verbal memory recall deficits indicative of left frontal lobe and medial temporal lobe function. The severity of anxious arousal and psychomotor disturbance contributed to cognitive impairment more than the severity of depression symptoms and anxious apprehension. CONCLUSIONS: Findings highlight a differential impact of depression subtype and severity, and suggest that anxious arousal and psychomotor disturbance may contribute to poorer performance on neuropsychological tasks associated with dorsolateral prefrontal cortex function. PMID- 23104928 TI - Sanism, stigma and the belief in dangerousness. PMID- 23104929 TI - Early intervention in psychosis: evidence, evidence gaps, criticism and confusion. PMID- 23104930 TI - Avoid being 'tyrannised' by the evidence: reflections on family-based treatment in adolescent anorexia nervosa. PMID- 23104931 TI - Managing clozapine discontinuation - acute and chronic maintenance strategies. PMID- 23104932 TI - The erotic transference: dream or delusion? AB - The erotic transference can be seen as the Janus face of clinical work in psychoanalysis: it may either arise out of the positive emotions necessary for the building of new shared realities, or be fueled by falsified and distorted constructions. In the former case, the erotic transference expresses the capacity to anticipate, or "dream," the emotional relationship with the object-which is why Freud valued its transformative aspect as one of the "forces impelling [the patient] to . . . make changes"-whereas in the latter it is equivalent to a flight from psychic reality and may be imperceptibly transformed into an actual delusion. PMID- 23104933 TI - Training-induced mitochondrial adaptation: role of peroxisome proliferator activated receptor gamma coactivator-1alpha, nuclear factor-kappaB and beta blockade. AB - Interaction of peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) with other cellular signalling pathways plays an important role in training-induced mitochondrial adaptations. The purpose of this study was to examine whether pyrolidine dithiocarbamate (PDTC), a nuclear factor-kappaB inhibitor and antioxidant, and the beta-adrenergic blocker propranolol would affect the PGC-1alpha-induced mitochondrial transcription factors, enzymes and proteins involved in energy metabolism and antioxidant defense in response to endurance training. Female Sprague-Dawley rats (aged 8 weeks) were randomly divided into two groups (n = 24), one subjected to 8 weeks of treadmill training and one remaining sedentary. Each group of rats was subdivided in to three groups that were injected (i.p.) daily with PDTC (50 mg (kg body weight)(-1)), propranolol (30 mg kg(-1)) or saline as a control 1 h before the daily exercise session. Sedentary PDTC-treated rats showed 75% higher PGC-1alpha content (P < 0.01) but lower mitochondrial transcription factor A and phosphorylated cAMP responsive element binding protein (p-CREB) than control rats. Training increased PGC-1alpha by 57% (P < 0.01), cytochrome c oxidase 4 by 30% (P < 0.05) and p-CREB by 13% (P < 0.05), whereas the mitochondrial mitofusin-2 level was decreased by 24% (P < 0.01). Treatment with PDTC decreased PGC-1alpha and p-CREB content by 34 and 53% (P < 0.05), respectively, in trained rats and abolished training effects on cytochrome c oxidase 4 and mitochondrial mitofusin-2. None of the training effects was abolished by propranolol treatment. Mitochondrial superoxide dismutase activity was decreased with PDTC, whereas training-induced glutathione peroxidase activity was unaltered by either drug. The data indicates that nuclear factor-kappaB-inhibitory and antioxidant properties of PDTC can attenuate PGC 1alpha-mediated mitochondrial adaptation to endurance training, whereas the beta adrenergic pathway has little adverse effect. PMID- 23104935 TI - Dopamine infusion for postresuscitation blood pressure support after profound asphyxia in near-term fetal sheep. AB - Dopamine is commonly used for blood pressure support in the neonate, but has limited empirical evidence to support its use. We tested the hypothesis that after near-terminal asphyxia in utero, dopamine infusions would prevent secondary hypotension. Fetal sheep (122-129 days of gestation; term is 147 days) received umbilical cord occlusion for 15 min or sham occlusion (n = 5). If the mean arterial blood pressure fell below 90% of baseline within 6 h after occlusion, fetuses were randomized to either dopamine infusion starting at 4 MUg kg(-1) min( 1) and titrated according to mean arterial blood pressure up to a maximum of 40 MUg kg(-1) min(-1) (n = 5) or to the same volume of normal saline (n = 5). Dopamine infusion, initiated at a median of 180 min after occlusion (range 96-280 min), was associated with a marked but transient increase in mean arterial blood pressure and fall in femoral blood flow compared with saline. Terminal hypotension developed later in four of the five fetuses that received maximal dopamine infusions than in five of five receiving saline infusion [517 (range 240 715) versus 106 min (range 23-497) after the start of infusions, P < 0.05]. In conclusion, dopamine infusion delayed but did not prevent terminal hypotension after severe asphyxia. PMID- 23104934 TI - Bradycardic effects mediated by activation of G protein-coupled estrogen receptor in rat nucleus ambiguus. AB - The G protein-coupled estrogen receptor (GPER) has been identified in several brain regions, including cholinergic neurons of the nucleus ambiguus, which are critical for parasympathetic cardiac regulation. Using calcium imaging and electrophysiological techniques, microinjection into the nucleus ambiguus and blood pressure measurement, we examined the in vitro and in vivo effects of GPER activation in nucleus ambiguus neurons. A GPER selective agonist, G-1, produced a sustained increase in cytosolic Ca(2+) concentration in a concentration-dependent manner in retrogradely labelled cardiac vagal neurons of nucleus ambiguus. The increase in cytosolic Ca(2+) produced by G-1 was abolished by pretreatment with G36, a GPER antagonist. G-1 depolarized cultured cardiac vagal neurons of the nucleus ambiguus. The excitatory effect of G-1 was also identified by whole-cell visual patch-clamp recordings in nucleus ambiguus neurons, in medullary slices. To validate the physiological relevance of our in vitro studies, we carried out in vivo experiments. Microinjection of G-1 into the nucleus ambiguus elicited a decrease in heart rate; the effect was blocked by prior microinjection of G36. Systemic injection of G-1, in addition to a previously reported decrease in blood pressure, also reduced the heart rate. The G-1-induced bradycardia was prevented by systemic injection of atropine, a muscarinic antagonist, or by bilateral microinjection of G36 into the nucleus ambiguus. Our results indicate that GPER mediated bradycardia occurs via activation of cardiac parasympathetic neurons of the nucleus ambiguus and support the involvement of the GPER in the modulation of cardiac vagal tone. PMID- 23104936 TI - Thyroid hormone is required for growth adaptation to pressure load in the ovine fetal heart. AB - Thyroid hormone exerts broad effects on the adult heart, but little is known regarding the role of thyroid hormone in the regulation of cardiac growth early in development and in response to pathophysiological conditions. To address this issue, we determined the effects of fetal thyroidectomy on cardiac growth and growth-related gene expression in control and pulmonary-artery-banded fetal sheep. Fetal thyroidectomy (THX) and/or placement of a restrictive pulmonary artery band (PAB) were performed at 126 +/- 1 days of gestation (term, 145 days). Four groups of animals [n = 5-6 in each group; (i) control; (ii) fetal THX; (iii) fetal PAB; and (iv) fetal PAB + THX] were monitored for 1 week prior to being killed. Fetal heart rate was significantly lower in the two THX groups compared with the non-THX groups, while mean arterial blood pressure was similar among groups. Combined left and right ventricle free wall + septum weight, expressed per kilogram of fetal weight, was significantly increased in PAB (6.27 +/- 0.85 g kg(-1)) compared with control animals (4.72 +/- 0.12 g kg(-1)). Thyroidectomy significantly attenuated the increase in cardiac mass associated with PAB (4.94 +/- 0.13 g kg(-1)), while THX alone had no detectable effect on heart mass (4.95 +/- 0.27 g kg(-1)). The percentage of binucleated cardiomyocytes was significantly decreased in THX and PAB +THX groups (~16%) compared with the non THX groups (~27%). No differences in levels of activated Akt, extracellular signal-regulated kinase or c-Jun N-terminal kinase were detected among the groups. Markers of cellular proliferation but not apoptosis or expression of growth-related genes were lower in the THX and THX+ PAB groups relative to thyroid-intact animals. These findings suggest that in the late-gestation fetal heart, thyroid hormone has important cellular growth functions in both physiological and pathophysiological states. Specifically, thyroid hormone is required for adaptive fetal cardiac growth in response to pressure overload. PMID- 23104937 TI - Endothelial dysfunction in gestational hypertension induced by catechol-O methyltransferase inhibition. AB - The present study evaluated whether catechol-O-methyltransferase inhibition in pregnant rats results in increased blood pressure and vascular endothelial dysfunction as a consequence of decreased nitric oxide bioavailability. Pregnant Sprague-Dawley rats were given entacapone (a catechol-O-methyltransferase inhibitor) by gavage from the 10th to the 20th day of pregnancy. Blood pressure was measured by plethysmography in the tail artery. Vascular endothelial function and NO release were assessed both in the absence and in the presence of tempol. Systolic blood pressure increased significantly in pregnant rats treated with entacapone compared with untreated pregnant rats on days 14 (143 +/- 4 versus 122 +/- 3 mmHg) and 19 of gestation (129 +/- 4 versus 115 +/- 5 mmHg). Both conductance (aortic rings) and resistance vessels (mesenteric small arterial vessels) from entacapone-treated pregnant rats showed diminished relaxation in response to acetylcholine compared with vessels from vehicle-treated pregnant and virgin rats. In mesenteric arterioles, this endothelial dysfunction was abolished in the presence of l-NAME, indicating that it was caused by reduced NO availability, and it also improved in the presence of tempol, suggesting increased oxidative stress in hypertensive pregnant rats. Endothelial release of nitric oxide induced by calcium ionophore (A23187) was significantly greater in aortas from vehicle-treated pregnant rats than in aortas from pregnant rats given entacapone. This endothelial dysfunction seen in hypertensive rats was prevented by addition of tempol. The present study provides evidence that catechol-O methyltransferase inhibition in pregnant rats produces arterial hypertension and endothelial dysfunction due to reduced nitric oxide bioavailability. PMID- 23104938 TI - Why patient consent is best practice. PMID- 23104939 TI - Industrializing skin cancer care: better and cheaper? PMID- 23104940 TI - Dead in the water. PMID- 23104941 TI - Confusion over DNAR orders. PMID- 23104943 TI - Why the National Institutes of Health should create an institute of positive biology. PMID- 23104944 TI - Shared decision-making: enhancing the clinical relevance. PMID- 23104945 TI - Defining primary care sensitive conditions: a necessity for effective primary care delivery? AB - Primary care is a major component of England's National Health Service (NHS), responsible for approximately 300 million consultations per year with GPs in England, which represents 70-90% of all patient contacts with the NHS. In addition to providing healthcare to the registered population, GPs are charged with coordination and gatekeeping of access to services provided by secondary care, tertiary care and other allied healthcare providers. As GPs will be assuming a key role in commissioning health services in England, there is a clear opportunity to re-model care delivery to maximize outcomes, cost efficiency and patient access by focusing on diseases that are most amenable to management in primary care. It is essential that there is evidence to inform what conditions are most sensitive to management in primary care - commonly referred to as primary care sensitive conditions or ambulatory care sensitive conditions. Such definitions would aid resource planning, drafting of local management protocols and simplification of the interface between primary and secondary care for a number of chronic conditions. Indeed, inappropriate utilization of secondary care resources is likely to represent a significant opportunity cost to healthcare providers and may be less desirable for patients. PMID- 23104946 TI - Laparoscopic surgery for rectal cancer. AB - Laparoscopic surgery for colonic cancer is a safe and established alternative to traditional open colectomy. The potential advantages of shorter length of stay, faster recovery and fewer operative complications are well documented. The last 5 years has seen an increase in the number of laparoscopic colorectal operations as more surgeons learn this technique. Short and medium term results have been encouraging with respect to oncological outcomes. However, laparoscopic surgery for rectal cancer remains a contentious issue. The increased complexity of operating within the confines of the pelvis and the greater risk of oncological compromise, have led to some surgeons urging caution. We present the challenges associated with laparoscopic rectal cancer surgery and explain that appropriate patient selection, surgical planning and laparoscopic experience are the key to successful outcomes. PMID- 23104948 TI - The first British textbook of medical statistics. PMID- 23104947 TI - A systematic review and meta-analysis of the cardioprotective effects of remote ischaemic preconditioning in open cardiac surgery. AB - OBJECTIVE: To investigate the cardioprotective efficacy of remote ischaemic preconditioning (RIPC) in cardiac surgery. DESIGN: We have performed a systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials to identify randomized controlled trials involving RIPC. SETTING: Randomized controlled trials of RIPC in open cardiac surgery patients. MAIN OUTCOME MEASURES: Meta-analysis was performed with the primary outcome the standardized mean difference between intervention and control groups in 12 hour postoperative troponin concentration. Heterogeneity was examined by fixed effects meta regression. RESULTS: Ten studies with a total of 693 participants were included in the meta-analysis. RIPC reduced troponin levels 12 hours after surgery compared with control. The fixed and random effects differences were 0.35 (95% CI 0.19 to 0.51) and 0.53 (95% CI 0.18-0.88) respectively. However, important heterogeneity was present. Fixed effects meta-regression partially accounted for heterogeneity based on whether studies had full blinding, comprising blinding of patients, surgeons, anaesthetists and investigators. Studies with incomplete or no blinding demonstrated a larger estimate of effect, 0.74 (95% CI 0.47 to 1.00) compared to those with full blinding, 0.13 (95% CI - 0.07 to 0.33). CONCLUSIONS: Although our analysis suggests RIPC may result in cardiac protection during cardiac surgery, the effect was most marked in studies without full blinding, with a smaller and statistically non-significant effect in fully blinded studies. We propose that further double blind randomized controlled trials investigating the cardioprotective effects of RIPC in cardiac surgery are required to resolve the current clinical uncertainty. PMID- 23104952 TI - Fingerprinting of poultry isolates of Enterococcus cecorum using three molecular typing methods. AB - Enterococcus cecorum is an emerging challenge to the broiler industry. The organism has been implicated in septicemia, spondylitis, arthritis, and osteomyelitis in commercial broilers and broiler breeders, which lead to economic losses attributed to increased mortality and culling rates, decreased average processing weights, and increased feed conversion ratios. The current study evaluated the genetic variability of 30 clinical isolates of E. cecorum from outbreaks in Pennsylvania, using 3 molecular typing methods, namely, pulsed-field gel electrophoresis (PFGE), randomly amplified polymorphic DNA analysis, and enterobacterial repetitive intergenic consensus-PCR (polymerase chain reaction), in order to understand their genetic relatedness and to identify possible pathogenic clones. The study revealed the existence of genotypic polymorphism among E. cecorum associated with clinical disease. Of the 3 typing methods used, PFGE analysis demonstrated higher genetic variability of E. cecorum isolates compared to PCR-based methods. Also, each molecular typing method was evaluated in terms of typeability, discriminatory power, and reproducibility for application of these typing methods in fingerprinting of E. cecorum in future reference. Pulsed-field gel electrophoresis provided the most reliable results with greater discriminatory power and higher reproducibility compared to the 2 PCR-based methods. PMID- 23104953 TI - Reactive amyloidosis associated with ischial callosititis: a report with histology of ischial callosities in rhesus macaques (Macaca mulatta). AB - Ischial callosities have received little attention in veterinary medicine even though they are distinguishing anatomic organs. The organs are characterized by a pair of hairless pads of thickened epidermis, located bilaterally in the gluteal region, which overlay the tuberosities of the ischia of all Old World monkeys, gibbons, and siamangs. The current report describes a case of reactive amyloidosis associated with ischial callosititis in a rhesus macaque (Macaca mulatta). Amyloid A (AA) protein was found in the liver, spleen, small intestine, mesenteric lymph nodes, and ischial callosities by histology, Congo red stain, and immunohistochemistry. Confocal microscopy showed that many cluster of differentiation (CD)68-positive macrophages within the ischial callosities contained intracellular AA protein, which suggests that CD68-positive macrophages have an important role in the pathogenesis of reactive amyloidosis in nonhuman primates. The normal histology of ischial callosities of rhesus macaques is also documented in this report. PMID- 23104954 TI - Cerebral artery velocity determined by transcranial doppler ultrasonography in patients with beta-thalassemia intermedia compared to beta-thalassemia major. AB - We aimed to compare cerebral artery velocity and relevant clinical factors in patients with beta-thalassemia intermedia (beta-TI), beta-thalassemia major (beta TM), and healthy individuals. For this study, 60 patients with beta-TM and 64 with beta-TI were randomly selected. Sixty healthy adults comprised the control group. Time average maximum mean velocity (TAMMV) was measured in large cerebral arteries with transcranial Doppler (TCD) ultrasonography. In all arteries, TAMMV was significantly higher in the beta-TI group than that of beta-TM or controls (P < .001). Patients with beta-TM had significantly higher TAMMV than controls in most arteries evaluated (P < .001). Overall, the lack of regular blood transfusions, splenectomy, and lower age (to a lesser extent) was found to be independent influencing factors contributing to high cerebral artery velocities. Further detailed longitudinal studies are needed to confirm these results and to determine the risk of silent infarction and stroke in patients with thalassemia and abnormal TCD, with particular focus on patients with beta-TI. PMID- 23104955 TI - Monitoring residual platelet activity among patients with acute coronary syndrome. AB - Several medicines are currently used to inhibit the platelet activity. We aim to monitor the residual platelet activity (RPA) despite antiplatelet therapy and assess its relationship with major adverse events. The impedance platelet aggregation was employed to determine RPA. Totally, 202 patients with acute coronary syndrome (ACS) were followed up for 10 months for major clinical events of myocardial infarction, cerebrovascular accident (CVA), and all cause mortality, and RPA after clopidogrel loading was assessed in 30 patients. The RPA at 2 hours after 300 mg clopidogrel loading was 1 Omega (+/- 2.3 Omega) induced by adenosine diphosphate. Residual platelet activity of patients who experienced death, MI, or CVA was significantly higher than those who did not experience (P < .05). Cutoff values of RPA showed optimal negative predictive values (96%-97%) and poor positive predictive values (16%-29%). Therefore, RPA monitored by whole blood impedance platelet aggregation may have high exclusionary predictive value for the occurrence of major clinical events in patients with ACS. PMID- 23104956 TI - Effect of unfractionated and low-molecular-weight heparin on OPG, sRANKL, and von Willebrand factor concentrations during hemodialysis. AB - BACKGROUND: Endothelial dysfunction marker, von Willebrand factor (vWF), is physically connected with osteoprotegerin (OPG) in the Weibel-Palade bodies. We aimed to compare the effect of unfractionated (UFH) and low-molecular-weight (LMWH enoxaparin) heparin used as anticoagulants during hemodialysis (HD) on plasma levels and relationships of OPG, soluble receptor activator of nuclear factor kappaB Ligand (sRANKL), and vWF. METHODS: Totally 21 clinically stable chronic HD patients were randomly assigned to either enoxaparin (n = 10) or UFH (n = 11) anticoagulation and followed prospectively for 12 weeks before crossing over to the alternate therapy for further 12 weeks. The OPG, RANKL, and vWF levels were measured at T0, T10, and T180 of HD session after each period of evaluation. RESULTS: The baseline sRANKL level was higher under UFH treatment. Its over-HD level does not behave significantly different under enoxaparin and UFH treatment. Plasma OPG levels expressly changed during both enoxaparin (chi(2) analysis of variance [ANOVA] = 31.13, P < .016) and UFH (chi(2) ANOVA = 8.26, P = .016) anticoagulation, and its increment at T10 and T180 was significantly different between both the heparins. The main negative predictor of OPG concentration was the total cholesterol level (beta = -.51, P = .025). von Willebrand factor concentration remained stable during UFH anticoagulation, whereas constant, no significant increments were noticed, under enoxaparin treatment. After 10 minutes of HD, especially under enoxaparin use, a positive correlation between OPG and vWF increase was noticed (P = .03, R = .45). CONCLUSIONS: Impact of heparin on endothelial cells and simultaneously on OPG/RANK/RANKL axis reinforces the presumption of the pathophysiological linkage between bone mineralization and endothelial dysfunction in end-stage renal disease. PMID- 23104957 TI - Fatal electrolyte abnormalities following enema administration. PMID- 23104958 TI - Commentary. PMID- 23104959 TI - Commentary. PMID- 23104960 TI - A case of floating gel. PMID- 23104961 TI - Automated doctors: cell phones as diagnostic tools. PMID- 23104964 TI - The basics and the sophistication: a country doctor and the art of Grandma Moses. PMID- 23104965 TI - A controlled clinical evaluation of the Parents Plus Children's Programme for parents of children aged 6-12 with mild intellectual disability in a school setting. AB - The aim of this study was to evaluate the effectiveness of the parent training, Parents Plus Children's Programme (PPCP) as an intervention for parents of children with mild intellectual disabilities. Participants were parents of children, aged six to 12, attending a special school for children with mild general learning disability (n = 29). Minor programme adaptations were made. Pre and post-assessment included the Strengths and Difficulties Questionnaire, the Parenting Stress Index, the Kansas Parent Satisfaction Scale and parent identified personal and child-related goals. A significant reduction in clinical range scores for treatment group participants (n = 16) was observed. Conversely, clinical range scores for control group participants (n = 13) increased, or remained elevated. These preliminary results suggest that PPCP may be successfully delivered as a routine community-based intervention and aid to prevent and reduce behavioural problems, reduce parent stress and increase parent confidence and satisfaction. Further investigation of programme effectiveness for parents of children with developmental disability is warranted. PMID- 23104966 TI - It is time for a more integrated bio-psycho-social approach to ADHD. AB - The role of psychosocial factors in perpetuating and predisposing towards the development of attention deficit hyperactivity disorder (ADHD) symptoms has been neglected within the field of child mental health. Clinicians, when told that a child had a diagnosis of ADHD, have been found to underestimate the presence of psychosocial factors, and are less likely to ask about the possibility of neglect or abuse. This article details the considerable research showing links between ADHD symptoms and parental mental illness, child maltreatment, post-traumatic stress disorder (PTSD), attachment disorders and other environmental factors. Recent neuro-biological findings showing the impact on brain development of early abuse and attachment concerns are cited. The implications of these findings both for clinicians, and at policy level, are discussed, and the reasons underlying the need for a more integrated Bio-Psycho-Social approach to ADHD are outlined. PMID- 23104967 TI - Mental health problems of young refugees: duration of settlement, risk factors and community-based interventions. AB - Little is known about the characteristics of young psychologically-distressed refugees in mental health services, and how they vary according to the duration of settlement. This study of 102 young refugees referred to a community-based mental health service describes past adversities and current circumstances, referral problems, service utilization and treatment outcomes using the Strengths and Difficulties Questionnaire (SDQ). The more recently-arrived refugees had significantly higher levels of close exposure to war and violence, were more likely to have suffered separation from immediate family and to have insecure legal status. Those refugees settled longer were significantly more likely to be referred because of conduct problems while there was a trend in recent arrivals to present with internalizing pathology. A comparison of the teachers' and parents' mean SDQ scores of the study's young refugees sample and a national study representative of Great Britain as a whole showed that young refugees have higher scores in total problem and all subscales scores than the British scores. Community-based mental health services for young refugees appeared effective - significant improvement was found in SDQ scores for the sub-group (n = 24) who took up the treatments offered. The implications are discussed for service development and practitioners. PMID- 23104970 TI - Aerobic exercise intensity assessment and prescription in cardiac rehabilitation: a joint position statement of the European Association for Cardiovascular Prevention and Rehabilitation, the American Association of Cardiovascular and Pulmonary Rehabilitation and the Canadian Association of Cardiac Rehabilitation. AB - Aerobic exercise intensity prescription is a key issue in cardiac rehabilitation, being directly linked to both the amount of improvement in exercise capacity and the risk of adverse events during exercise. This joint position statement aims to provide professionals with up-to-date information regarding the identification of different exercise intensity domains, the methods of direct and indirect determination of exercise intensity for both continuous and interval aerobic training, the effects of the use of different exercise protocols on exercise intensity prescription and the indications for recommended exercise training prescription in specific cardiac patients' groups. The importance of functional evaluation through exercise testing prior to starting an aerobic training program is strongly emphasized, and ramp incremental cardiopulmonary exercise test, when available, is proposed as the gold standard for a physiologically comprehensive exercise intensity assessment and prescription. This may allow a shift from a 'range-based' to a 'threshold-based' aerobic exercise intensity prescription, which, combined with thorough clinical evaluation and exercise-related risk assessment, could maximize the benefits obtainable by the use of aerobic exercise training in cardiac rehabilitation. PMID- 23104969 TI - Differential influences of ethanol on early exposure to racemic methylphenidate compared with dexmethylphenidate in humans. AB - Enantioselective hydrolysis of oral racemic methylphenidate (dl-MPH) by carboxylesterase 1 (CES1) limits the absolute bioavailability of the pharmacologically active d-MPH isomer to approximately 30% and that of the inactive l-MPH to only 1-2%. Coadministration of dl-MPH with ethanol results in elevated d-MPH plasma concentrations accompanied by CES1-mediated enantioselective transesterification of l-MPH to l-ethylphenidate (EPH). The present study tested the hypothesis that administration of the pure isomer dexmethylphenidate (d-MPH) will overcome the influence of ethanol on d-MPH absorption by eliminating competitive CES1-mediated presystemic metabolism of l MPH to l-EPH. Twenty-four healthy volunteers received dl-MPH (0.3 mg/kg) or d-MPH (0.15 mg/kg), with or without ethanol (0.6 g/kg). During the absorption phase of dl-MPH, concomitant ethanol significantly elevated d-MPH plasma concentrations (44-99%; P < 0.005). Furthermore, immediately following the ethanol drink the subjective effects of "high," "good," "like," "stimulated," and overall "effect" were significantly potentiated (P <= 0.01). Plasma l-EPH concentrations exceeded those of l-MPH. Ethanol combined with pure d-MPH did not elevate plasma d-MPH concentrations during the absorption phase, and the ethanol-induced potentiation of subjective effects was delayed relative to dl-MPH-ethanol. These findings are consistent with l-MPH competitively inhibiting presystemic CES1 metabolism of d MPH. Ethanol increased the d-MPH area under the curve (AUC)(0-inf) by 21% following dl-MPH (P < 0.001) and 14% for d-MPH (P = 0.001). In men receiving d MPH-ethanol, the d-MPH absorption partial AUC(0.5-2 hours) was 2.1 times greater and the time to maximum concentration (T(max)) occurred 1.1 hours earlier than in women, consistent with an increased rate of d-MPH absorption reducing hepatic extraction. More rapid absorption of d-MPH carries implications for increased abuse liability. PMID- 23104972 TI - Contraception for women with systemic lupus erythematosus. PMID- 23104973 TI - HDAC inhibition decreases XIST expression on female IVP bovine blastocysts. AB - During initial development, both X chromosomes are active in females, and one of them must be silenced at the appropriate time in order to dosage compensate their gene expression levels to male counterparts. Silencing involves epigenetic mechanisms, including histone deacetylation. Major X chromosome inactivation (XCI) in bovine occurs between hatching and implantation, although in vitro culture conditions might disrupt the silencing process, increasing or decreasing X-linked gene expression. In this study, we aimed to address the roles of histone deacetylase inhibition by trichostatin A (TSA) on female preimplantation development. We tested the hypothesis that by enhancing histone acetylation, TSA would increase the percentage of embryos achieving 16-cell stage, reducing percentage of embryos blocked at 8-cell stage, and interfere with XCI in IVF embryos. We noticed that after TSA treatment, acetylation levels in individual blastomeres of 8-16 cell embryos were increased twofold on treated embryos, and the same was detected for blastocysts. Changes among blastomere levels within the same embryo were diminished on TSA group, as low-acetylated blastomeres were no longer detected. The percentage of embryos that reached the 5th cleavage cycle 118 h after IVF, analyzed by Hoechst staining, remained unaltered after TSA treatment. Then, we assessed XIST and G6PD expression in individual female bovine blastocysts by quantitative real-time PCR. Even though G6PD expression remained unaltered after TSA exposure, XIST expression was eightfold decreased, and we also detected a major decrease in the percentage of blastocysts expressing detectable XIST levels after TSA treatment. Based on these results, we conclude that HDAC is involved on XCI process in bovine embryos, and its inhibition might delay X chromosome silencing and attenuate aberrant XIST expression described for IVF embryos. PMID- 23104971 TI - Informatics in radiology: what can you see in a single glance and how might this guide visual search in medical images? AB - Diagnostic accuracy for radiologists is above that expected by chance when they are exposed to a chest radiograph for only one-fifth of a second, a period too brief for more than a single voluntary eye movement. How do radiologists glean information from a first glance at an image? It is thought that this expert impression of the gestalt of an image is related to the everyday, immediate visual understanding of the gist of a scene. Several high-speed mechanisms guide our search of complex images. Guidance by basic features (such as color) requires no learning, whereas guidance by complex scene properties is learned. It is probable that both hardwired guidance by basic features and learned guidance by scene structure become part of radiologists' expertise. Search in scenes may be best explained by a two-pathway model: Object recognition is performed via a selective pathway in which candidate targets must be individually selected for recognition. A second, nonselective pathway extracts information from global or statistical information without selecting specific objects. An appreciation of the role of nonselective processing may be particularly useful for understanding what separates novice from expert radiologists and could help establish new methods of physician training based on medical image perception. PMID- 23104974 TI - Conducting the ACTIVE randomized trial in hospice care: keys to success. AB - BACKGROUND: Untreated pain is common for patients at the end of life. Informal caregivers, often family or friends of patients, are responsible for working with hospice staff to provide pain management. Interdisciplinary team meetings conducted in hospices every 2 weeks provide an opportunity for hospice staff to communicate about pain management with informal caregivers of hospice patients. PURPOSE: We present challenges, solutions, and keys strategies for carrying out a randomized trial in the hospice setting. METHODS: We are conducting the Assessing Caregivers for Team Intervention through Video Encounters (ACTIVE) study to determine whether regular videoconferencing between hospice patients' informal caregivers and the hospice care team alters caregivers' perceptions of pain management and patients' pain. Participants must be primary caregivers for a hospice patient, at least 18 years of age, capable of providing informed consent, and have access to a computer with a high-speed Internet connection or a telephone. We randomized caregivers to participate in biweekly team meetings through video or phone conferencing (intervention) or to receive usual care from the hospice. All patients receive standard hospice care regardless of the group assignment of their informal caregiver. RESULTS: As of 1 July 2012, there have been 1038 new admissions to the participating hospices. Of 391 cases in which no contact was made, 233 patients had died or had life expectancy less than 14 days. Home visits were made to 271 interested and eligible caregivers; 249 caregivers of 233 patients were randomly assigned to the usual care or intervention arm. Enrollment is on pace to meet recruitment goals. Lessons Learned Thorough pilot testing of instruments and procedures helped us overcome barriers to conducting research in this vulnerable population. Keys to success included obtaining support from hospice medical directors, including hospice staff in study preparation, minimizing the burden on hospice staff, housing research staff in each participating hospice, using newsletters to enhance communication, developing and maintaining a detailed procedural manual, producing regular data quality reports, developing a secure site to facilitate coding videos for qualitative studies, and holding regular teleconferences with key staff. LIMITATIONS: Late enrollment of many patients in hospice left little to no time for their caregivers to take part in the intervention. Assisting caregivers of patients with very short life expectancy may require different methods. CONCLUSIONS: The challenges of conducting randomized trials with hospice patients and caregivers can be addressed with appropriate study design, well-tested research methods, and proactive monitoring of any issues or problems. PMID- 23104975 TI - Academic investigator-initiated trials and the challenge of sponsor responsibility: the Cologne Sponsor Model. AB - BACKGROUND: With the amendment to the German Drug Law in 2004, the conduct of clinical trials changed by at least two main aspects: (1) The principles of Good Clinical Practice (GCP) were implemented in the national legislation, and (2) for the first time, the function of the sponsor of a clinical trial and the clinical trial itself have become legally binding definitions. By that, legal differences between industrial and academic clinical trials no longer exist. Clinical trials initiated by investigators have to fulfil the same requirements while the entire sponsor responsibility has to be carried out by the Coordinating Investigator or his institution including implementation of a quality management system according to the GCP. PURPOSE: The Cologne Sponsor Model is an effective approach with settings, structures, basic features, action, and reporting lines, as well as funding for clinical trials initiated in an academic environment. RESULTS: The University of Cologne assumes the sponsor responsibility for clinical trials organised by the university researchers according to law. Sponsor's duties are delegated to a central operational unit of the sponsor - the Clinical Trials Center Cologne - which further delegates duties to the Coordinating Investigator. Clinical Trials Center Cologne was established in 2002 to support the performance of clinical trials at the university by offering comprehensive advisory and practical services covering all aspects of study planning and conduct. Furthermore, a specialised division of its quality management department acts as an independent sponsor's Quality Assurance Unit. The Clinical Trials Center Cologne has established a quality management system consisting of different components (1) to enable a reasoned decision to subsequent delegation, (2) for risk-based surveillance of trial conduct (audits, monitoring-checks, and reports), and (3) support and training of the Coordinating Investigator. LIMITATIONS: Double functions of persons and departments in the university environment sometimes make it difficult to define roles in such a model. Therefore, it is necessary to establish clear reporting lines and moreover to monitor regularly and carefully the roles and responsibilities. CONCLUSIONS: With the combination of central management and support, control and independence of the researchers, our model represents a 'risk-based' system that offers a sensible option that fulfils the requirements of legal regulations and GCP for trials organised within the university environment. PMID- 23104976 TI - Relative importance of doctor-reported outcomes vs patient-reported outcomes in DMARD intensification for rheumatoid arthritis: the DUO study. AB - OBJECTIVE: For optimal RA management, the current recommendation is to adapt DMARD therapy to the level of inflammation and not only of patient complaints. We designed the DUO (epidemiological study of treatment decison in RA: DROs and PROs) study to assess the relative weight of patient-reported outcomes (PROs) and doctor-reported outcomes (DROs) in DMARD intensification in RA patients. METHODS: This French, observational, multicentre, cross-sectional study was conducted in 2009 on RA patients included by rheumatologists. The percentage of patients with DMARD intensification was evaluated with regard to the concomitant DAS28-ESR and Patient Acceptable Symptom State (PASS) questionnaire assessments. Logistic regression was used to find significant criteria of DMARD intensification. The relative weight of subjective/objective criteria was assessed using attributable risk fractions. RESULTS: A total of 1107 patients were analysed (76% women; median disease duration 6 years); DMARD intensification was proposed to 15% of patients (24% of patients with DAS >3.2 and 33% of patients with non-acceptable PASS). DMARD intensification determinants comprised both DROs (high tender and swollen joint counts) and PROs (high patient global assessment of disease activity), but also short disease duration and rheumatologist characteristics (young, hospital based). Respectively, 61% and 42% of DMARD intensification were attributable to PROs and DROs. CONCLUSION: The DUO study showed DMARD intensification was predominantly based on PROs compared with DROs and influenced by disease duration and type of rheumatology practice. Most RA patients with DAS28 >3.2 had no DMARD intensification. PMID- 23104977 TI - Is cervical spine involvement in juvenile polyarthritis under-recognized? PMID- 23104978 TI - The role of attitudes about vaccine safety, efficacy, and value in explaining parents' reported vaccination behavior. AB - OBJECTIVES: To explain vaccine confidence as it related to parents' decisions to vaccinate their children with recommended vaccines, and to develop a confidence measure to efficiently and effectively predict parents' self-reported vaccine behaviors. METHOD: A sample of parents with at least one child younger than 6 years (n = 376) was analyzed using data from the HealthStyles 2010 survey. Questions were grouped into block variables to create three confidence constructs: value, safety, and efficacy. Regression equations controlling for demographic characteristics were used to identify the confidence construct(s) that best predicted parents' self-reported vaccination decisions (accept all, some, or none of the recommended childhood vaccines). RESULTS: Among the three constructs evaluated, confidence in the value of vaccines, that is the belief that vaccines are important and vaccinating one's children is the right thing to do, was the best predictor of parents' vaccine decisions, F(2, 351) = 119.199, p < .001. When combined into a block variable for analysis, two survey items measuring confidence in the value of vaccines accounted for 40% of the variance in parents' self-reported vaccine decisions. Confidence in the safety or efficacy of vaccines failed to account for additional significant variance in parent reported vaccination behavior. CONCLUSIONS: Confidence in the value of vaccines is a helpful predictor of parent-reported vaccination behavior. Attitudinal constructs of confidence in the safety and efficacy of vaccines failed to account for additional significant variance in parents' vaccination behaviors. Future research should assess the role of vaccine knowledge and tangible barriers, such as access and cost, to further explain parents' vaccination behaviors. PMID- 23104980 TI - The National Health Educator Job Analysis 2010: process and outcomes. AB - The National Health Educator Job Analysis 2010 was conducted to update the competencies model for entry- and advanced-level health educators. Qualitative and quantitative methods were used. Structured interviews, focus groups, and a modified Delphi technique were implemented to engage 59 health educators from diverse work settings and experience levels in a seven-step instrument development process. An online survey was then completed by 1,022 practicing health educators. Survey participants used 4-point ordinal scales to rank subcompetencies by frequency of use and importance and related knowledge items by cognitive levels based on the Revised Bloom's Taxonomy. Composite scores were calculated and subgroup comparisons conducted to validate 223 subcompetencies at entry (162), advanced-1 (42), and advanced-2 (19) levels of practice, along with 113 knowledge items. Advanced-level versus entry-level competencies and a comparison with the Competency Update Project model of 2006 are discussed. Implications and recommendations for the profession are provided. PMID- 23104979 TI - Financial hardship and self-rated health among low-income housing residents. AB - BACKGROUND: Self-rated health (SRH) has been shown to be predictive of morbidity and mortality. Evidence also shows that SRH is socioeconomically patterned, although this association differs depending on the indicator of socioeconomic status used. The purpose of this study was to determine the association between SRH and financial hardship among residents of low-income housing. METHODS: We analyzed cross-sectional data from the Health in Common Study (N = 828), an observational study to investigate social and physical determinants of cancer risk-related behaviors among residents of low-income housing in three cities in the Boston metropolitan area. Modified Poisson regression models were used to obtain the relative risk of low SRH (fair or poor), adjusting for demographic and socioeconomic characteristics. RESULTS: Unadjusted models revealed that the respondents reporting financial hardship were 53% more likely to report low SRH compared with those not reporting financial hardship. After controlling for demographic characteristics, socioeconomic characteristics, and psychological distress, the results showed that those reporting financial hardship were 44% more likely to report low SRH. CONCLUSION: Our results suggest that financial hardship is a robust predictor of SRH; and over and above the influence of demographic and traditional socioeconomic indicators, and even psychological distress, financial hardship remains strongly associated with low SRH. Additional research needs to be conducted to further elucidate this pathway and to better understand the determinants of variability in financial hardship among low-income housing residents to ensure the most appropriate policy levers (e.g., housing related policy, food-related policy) are chosen to improve health outcomes in this population. PMID- 23104981 TI - Acute natural killer cell pneumonia in a patient transplanted with autologous haematopoietic stem cells for systemic sclerosis. PMID- 23104982 TI - Identification of inhibitory scFv antibodies targeting fibroblast activation protein utilizing phage display functional screens. AB - Fibroblast activation protein (FAP) is a serine protease selectively expressed on tumor stromal fibroblasts in epithelial carcinomas and is important in cancer growth, adhesion, and metastases. As FAP enzymatic activity is a potent therapeutic target, we aimed to identify inhibitory antibodies. Using a competitive inhibition strategy, we used phage display techniques to identify 53 single-chain variable fragments (scFvs) after three rounds of panning against FAP. These scFvs were expressed and characterized for binding to FAP by surface plasmon resonance and flow cytometry. Functional assessment of these antibodies yielded an inhibitory scFv antibody, named E3, which could attenuate 35% of FAP cleavage of the fluorescent substrate Ala-Pro-7-amido-4-trifluoromethylcoumarin compared with nonfunctional scFv control. Furthermore, a mutant E3 scFv was identified by yeast affinity maturation. It had higher affinity (4-fold) and enhanced inhibitory effect on FAP enzyme activity (3-fold) than E3. The application of both inhibitory anti-FAP scFvs significantly affected the formation of 3-dimensional FAP-positive cell matrix, as demonstrated by reducing the fibronectin fiber orientation from 41.18% (negative antibody control) to 34.06% (E3) and 36.15% (mutant E3), respectively. Thus, we have identified and affinity-maturated the first scFv antibody capable of inhibiting FAP function. This scFv antibody has the potential to disrupt the role of FAP in tumor invasion and metastasis. PMID- 23104983 TI - Correctors of DeltaF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. AB - Most cystic fibrosis is caused by the deletion of a single amino acid (F508) from CFTR and the resulting misfolding and destabilization of the protein. Compounds identified by high-throughput screening to improve DeltaF508 CFTR maturation have already entered clinical trials, and it is important to understand their mechanisms of action to further improve their efficacy. Here, we showed that several of these compounds, including the investigational drug VX-809, caused a much greater increase (5- to 10-fold) in maturation at 27 than at 37 degrees C (<2-fold), and the mature product remained short-lived (T(1/2)~4.5 h) and thermally unstable, even though its overall conformational state was similar to wild type, as judged by resistance to proteolysis and interdomain cross-linking. Consistent with its inability to restore thermodynamic stability, VX-809 stimulated maturation 2-5-fold beyond that caused by several different stabilizing modifications of NBD1 and the NBD1/CL4 interface. The compound also promoted maturation of several disease-associated processing mutants on the CL4 side of this interface. Although these effects may reflect an interaction of VX 809 with this interface, an interpretation supported by computational docking, it also rescued maturation of mutants in other cytoplasmic loops, either by allosteric effects or via additional sites of action. In addition to revealing the capabilities and some of the limitations of this important investigational drug, these findings clearly demonstrate that DeltaF508 CFTR can be completely assembled and evade cellular quality control systems, while remaining thermodynamically unstable. He, L., Kota, P., Aleksandrov, A. A., Cui, L., Jensen, T., Dokholyan, N. V., Riordan, J. R. Correctors of DeltaF508 CFTR restore global conformational maturation without thermally stabilizing the mutant protein. PMID- 23104984 TI - Intramitochondrial hydrogen sulfide production by 3-mercaptopyruvate sulfurtransferase maintains mitochondrial electron flow and supports cellular bioenergetics. AB - It is well established that exposure of mammalian cells to hydrogen sulfide (H(2)S) suppresses mitochondrial function by inhibiting cytochrome-c oxidase (CcOX; complex IV). However, recent experimental data show that administration of H(2)S to mammalian cells can serve as an electron donor and inorganic source of energy. The aim of our study was to investigate the role of endogenously produced H(2)S in the regulation of mitochondrial electron transport and oxidative phosphorylation in isolated liver mitochondria and in the cultured murine hepatoma cell line Hepa1c1c7. Low concentrations of H(2)S (0.1-1 MUM) elicited a significant increase in mitochondrial function, while higher concentrations of H(2)S (3-30 MUM) were inhibitory. The positive bioenergetic effect of H(2)S required a basal activity of the Krebs cycle and was most pronounced at intermediate concentrations of succinate. 3-mercaptopyruvate (3-MP), the substrate of the mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3 MST) stimulated mitochondrial H(2)S production and enhanced mitochondrial electron transport and cellular bioenergetics at low concentrations (10-100 nM), while at higher concentrations, it inhibited cellular bioenergetics. SiRNA silencing of 3-MST reduced basal bioenergetic parameters and prevented the stimulating effect of 3-MP on mitochondrial bioenergetics. Silencing of sulfide quinone oxidoreductase (SQR) also reduced basal and 3-MP-stimulated bioenergetic parameters. We conclude that an endogenous intramitochondrial H(2)S-producing pathway, governed by 3-MST, complements and balances the bioenergetic role of Krebs cycle-derived electron donors. This pathway may serve a physiological role in the maintenance of mitochondrial electron transport and cellular bioenergetics. PMID- 23104986 TI - Neonatal seizure identification on reduced channel EEG. AB - Using a standard digital EEG system, we conducted simulations to determine the optimal locations and numbers of electrodes for seizure detection in neonates with reduced-channel EEG monitoring. The results showed that C3-C4 should be selected for a one-channel recording, but two-channel seizure monitoring is recommended for increased accuracy. PMID- 23104985 TI - The prostamide-related glaucoma therapy, bimatoprost, offers a novel approach for treating scalp alopecias. AB - Balding causes widespread psychological distress but is poorly controlled. The commonest treatment, minoxidil, was originally an antihypertensive drug that promoted unwanted hair. We hypothesized that another serendipitous discovery, increased eyelash growth side-effects of prostamide F(2alpha)-related eyedrops for glaucoma, may be relevant for scalp alopecias. Eyelash hairs and follicles are highly specialized and remain unaffected by androgens that inhibit scalp follicles and stimulate many others. Therefore, we investigated whether non eyelash follicles could respond to bimatoprost, a prostamide F(2alpha) analog recently licensed for eyelash hypotrichosis. Bimatoprost, at pharmacologically selective concentrations, increased hair synthesis in scalp follicle organ culture and advanced mouse pelage hair regrowth in vivo compared to vehicle alone. A prostamide receptor antagonist blocked isolated follicle growth, confirming a direct, receptor-mediated mechanism within follicles; RT-PCR analysis identified 3 relevant receptor genes in scalp follicles in vivo. Receptors were located in the key follicle regulator, the dermal papilla, by analyzing individual follicular structures and immunohistochemistry. Thus, bimatoprost stimulates human scalp follicles in culture and rodent pelage follicles in vivo, mirroring eyelash behavior, and scalp follicles contain bimatoprost-sensitive prostamide receptors in vivo. This highlights a new follicular signaling system and confirms that bimatoprost offers a novel, low risk therapeutic approach for scalp alopecias. PMID- 23104987 TI - Antibiotics for early onset neonatal infection. PMID- 23104988 TI - Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. AB - Neuroblastoma is a childhood extracranial solid tumour that is associated with a number of genetic changes. Included in these genetic alterations are mutations in the kinase domain of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK), which have been found in both somatic and familial neuroblastoma. In order to treat patients accordingly requires characterisation of these mutations in terms of their response to ALK tyrosine kinase inhibitors (TKIs). Here, we report the identification and characterisation of two novel neuroblastoma ALK mutations (A1099T and R1464STOP), which we have investigated together with several previously reported but uncharacterised ALK mutations (T1087I, D1091N, T1151M, M1166R, F1174I and A1234T). In order to understand the potential role of these ALK mutations in neuroblastoma progression, we have employed cell culture-based systems together with the model organism Drosophila as a readout for ligand-independent activity. Mutation of ALK at position 1174 (F1174I) generates a gain-of-function receptor capable of activating intracellular targets such as ERK (extracellular signal regulated kinase) and STAT3 (signal transducer and activator of transcription 3) in a ligand independent manner. Analysis of these previously uncharacterised ALK mutants and comparison with ALK(F1174) mutants suggests that ALK mutations observed in neuroblastoma fall into three classes. These classes are: (i) gain-of-function ligand-independent mutations such as ALK(F1174l), (ii) kinase-dead ALK mutants, e.g. ALK(I1250T) (Schonherr et al., 2011a) and (iii) ALK mutations that are ligand-dependent in nature. Irrespective of the nature of the observed ALK mutants, in every case the activity of the mutant ALK receptors could be abrogated by the ALK inhibitor crizotinib (Xalkori/PF-02341066), albeit with differing levels of sensitivity. PMID- 23104989 TI - Toxoplasma gondii infection induces dendritic retraction in basolateral amygdala accompanied by reduced corticosterone secretion. AB - Pathological anxiety is thought to reflect a maladaptive state characterized by exaggerated fear. Naturally occurring perturbations that reduce fear can be crucial in the search for new treatments. The protozoan parasite Toxoplasma gondii invades rat brain and removes the fear that rats have of cat odors, a change believed to be parasitic manipulation of host behavior aimed at increasing parasite transmission. It is likely that mechanisms employed by T. gondii can be used as a heuristic tool to understand possible means of fear reduction in clinical settings. Male Long-Evans rats were infected with T. gondii and compared with sham-infected animals 8 weeks after infection. The amount of circulating plasma corticosterone and dendritic arborization of basolateral amygdala principal neurons were quantified. Previous studies have shown that corticosterone, acting within the basolateral amygdala, enhances the fear response to environmental stimuli. Here we show that T. gondii infection causes a dendritic retraction in basolateral amygdala neurons. Such dendritic retraction is accompanied by lower amounts of circulating corticosterone, both at baseline and when induced by an aversive cat odor. The concerted effects of parasitism on two pivotal physiological nodes of the fear response provide an animal model relevant to interactions between stress hormones and amygdalar plasticity. PMID- 23104990 TI - Inflammation drives wound hyperpigmentation in zebrafish by recruiting pigment cells to sites of tissue damage. AB - In humans, skin is the largest organ and serves as a barrier between our body and the outside world. Skin protects our internal organs from external pathogens and other contaminants, and melanocytes within the skin protect the body from damage by ultraviolet light. These same pigment cells also determine our skin colour and complexion. Skin wounding triggers a repair response that includes a robust recruitment of inflammatory cells, which function to kill invading microbes and clear away cell and matrix debris. Once at the wound site, these innate immune cells release a barrage of cytokines that direct the activities of other cells during the repair process. Tissue damage and repair also frequently lead to alterations in skin pigmentation, in particular to wound hyperpigmentation. In this study, we describe a model of wound hyperpigmentation in the translucent zebrafish larva, where we can live-image the recruitment of melanocytes and their precursors, melanoblasts, to the wound site. We show that these pigment cells are drawn in after the initial recruitment of innate immune cells and that the inflammatory response is essential for wound hyperpigmentation. This new model will allow us to uncover the molecular link between immune and pigment cells during tissue repair and to screen for potential therapeutics to dampen wound hyperpigmentation. PMID- 23104993 TI - Trigger factors in migraine patients. AB - The objective of this study was to examine potential trigger factors in migraine patients. A total of 126 migraine patients were interviewed about possible trigger factors for migraine. The most common trigger factors were emotional stress (79%), sleep disturbance (64%) and dietary factors (44%). Sleep and stress were significant trigger factors in patients with migraine with aura, whereas environmental factors were important trigger factors in patients with migraine without aura. Stress, sleep and environmental factors were important trigger factors in women and differed significantly from men. Trigger factors are frequent in migraine patients, and avoidance of such factors may result in a better control of the disorder. PMID- 23104991 TI - Phenotypic overlap in the contribution of individual genes to CNV pathogenicity revealed by cross-species computational analysis of single-gene mutations in humans, mice and zebrafish. AB - Numerous disease syndromes are associated with regions of copy number variation (CNV) in the human genome and, in most cases, the pathogenicity of the CNV is thought to be related to altered dosage of the genes contained within the affected segment. However, establishing the contribution of individual genes to the overall pathogenicity of CNV syndromes is difficult and often relies on the identification of potential candidates through manual searches of the literature and online resources. We describe here the development of a computational framework to comprehensively search phenotypic information from model organisms and single-gene human hereditary disorders, and thus speed the interpretation of the complex phenotypes of CNV disorders. There are currently more than 5000 human genes about which nothing is known phenotypically but for which detailed phenotypic information for the mouse and/or zebrafish orthologs is available. Here, we present an ontology-based approach to identify similarities between human disease manifestations and the mutational phenotypes in characterized model organism genes; this approach can therefore be used even in cases where there is little or no information about the function of the human genes. We applied this algorithm to detect candidate genes for 27 recurrent CNV disorders and identified 802 gene-phenotype associations, approximately half of which involved genes that were previously reported to be associated with individual phenotypic features and half of which were novel candidates. A total of 431 associations were made solely on the basis of model organism phenotype data. Additionally, we observed a striking, statistically significant tendency for individual disease phenotypes to be associated with multiple genes located within a single CNV region, a phenomenon that we denote as pheno-clustering. Many of the clusters also display statistically significant similarities in protein function or vicinity within the protein-protein interaction network. Our results provide a basis for understanding previously un-interpretable genotype-phenotype correlations in pathogenic CNVs and for mobilizing the large amount of model organism phenotype data to provide insights into human genetic disorders. PMID- 23104992 TI - Toward an understanding of the evolution of Staphylococcus aureus strain USA300 during colonization in community households. AB - Staphylococcus aureus is a frequent cause of serious infections and also a human commensal. The emergence of community-associated methicillin-resistant S. aureus led to a dramatic increase in skin and soft tissue infections worldwide. This epidemic has been driven by a limited number of clones, such as USA300 in the United States. To better understand the extent of USA300 evolution and diversification within communities, we performed comparative whole-genome sequencing of three clinical and five colonizing USA300 isolates collected longitudinally from three unrelated households over a 15-month period. Phylogenetic analysis that incorporated additional geographically diverse USA300 isolates indicated that all but one likely arose from a common recent ancestor. Although limited genetic adaptation occurred over the study period, the greatest genetic heterogeneity occurred between isolates from different households and within one heavily colonized household. This diversity allowed for a more accurate tracking of interpersonal USA300 transmission. Sequencing of persisting USA300 isolates revealed mutations in genes involved in major aspects of S. aureus function: adhesion, cell wall biosynthesis, virulence, and carbohydrate metabolism. Genetic variations also included accumulation of multiple polymorphisms within select genes of two multigene operons, suggestive of small genome rearrangements rather than de novo single point mutations. Such rearrangements have been underappreciated in S. aureus and may represent novel means of strain variation. Subtle genetic changes may contribute to USA300 fitness and persistence. Elucidation of small genome rearrangements reveals a potentially new and intriguing mechanism of directed S. aureus genome diversification in environmental niches and during pathogen-host interactions. PMID- 23104994 TI - Parents' emotional intelligence and children's type I diabetes management. AB - We hypothesized that parents' emotional intelligence associates with their children's type I diabetes outcomes. Eighty-one parents, the main caregivers of their diabetic children, filled out two measures of emotional intelligence and a demographic questionnaire. Three indicators of diabetes management were collected from the patients' files: hemoglobin A1c, mean blood tests per day, and mean blood glucose levels. Emotional intelligence associated with all glycemic management indices, though differences were found between the two measures. Of the demographic factors, income level showed some association with the outcome measures. The results are discussed in light of existing theories and models. PMID- 23104995 TI - Assessing perceptions about hazardous substances (PATHS): the PATHS questionnaire. AB - How people perceive the nature of a hazardous substance may determine how they respond when potentially exposed to it. We tested a new Perceptions AbouT Hazardous Substances (PATHS) questionnaire. In Study 1 (N = 21), we assessed the face validity of items concerning perceptions about eight properties of a hazardous substance. In Study 2 (N = 2030), we tested the factor structure, reliability and validity of the PATHS questionnaire across four qualitatively different substances. In Study 3 (N = 760), we tested the impact of information provision on Perceptions AbouT Hazardous Substances scores. Our results showed that our eight measures demonstrated good reliability and validity when used for non-contagious hazards. PMID- 23104996 TI - Shame and self-acceptance in continued flux: qualitative study of the embodied experience of significant weight loss and removal of resultant excess skin by plastic surgery. AB - This study explored the embodied experience of body change using a qualitative design. Eight previous plastic surgery patients of a London hospital took part in in-depth, semi-structured interviews 1 year post a plastic surgery procedure to remove excess skin around their abdomen, resulting from weight loss. Participant interviews were analysed using Interpretative Phenomenological Analysis. Two sub themes titled 'Shame of the hidden body' and 'Lack of acceptance; the future focused body' are presented in this article. Findings are considered in relation to theories of 'Body Shame' and in the current cultural context. PMID- 23104997 TI - 'Permission to participate?' A qualitative study of participation in patients from differing socio-economic backgrounds. AB - Participation in health care is an important element of self-management in chronic illness, and policy emphasises patient's choice. Evidence suggests that this may be inequitable and inadequate, since active participation is strongly associated with socio-demographic variables. This qualitative study explores the perceptions of participation in people with differing socio-economic status with themes related to health literacy and relationship with health-care professionals. Patients perceive participation in different ways, related to their prior expectations of a health-care consultation, cultural expectations and social position. Policies aimed at simply improving 'health literacy' and choice will not be successful if these broader disparities are not addressed. PMID- 23104998 TI - Regulation of release factor expression using a translational negative feedback loop: a systems analysis. AB - The essential eukaryote release factor eRF1, encoded by the yeast SUP45 gene, recognizes stop codons during ribosomal translation. SUP45 nonsense alleles are, however, viable due to the establishment of feedback-regulated readthrough of the premature termination codon; reductions in full-length eRF1 promote tRNA-mediated stop codon readthrough, which, in turn, drives partial production of full-length eRF1. A deterministic mathematical model of this eRF1 feedback loop was developed using a staged increase in model complexity. Model predictions matched the experimental observation that strains carrying the mutant SUQ5 tRNA (a weak UAA suppressor) in combination with any of the tested sup45(UAA) nonsense alleles exhibit threefold more stop codon readthrough than that of an SUQ5 yeast strain. The model also successfully predicted that eRF1 feedback control in an SUQ5 sup45(UAA) mutant would resist, but not completely prevent, imposed changes in eRF1 expression. In these experiments, the introduction of a plasmid-borne SUQ5 copy into a sup45(UAA) SUQ5 mutant directed additional readthrough and full length eRF1 expression, despite feedback. Secondly, induction of additional sup45(UAA) mRNA expression in a sup45(UAA) SUQ5 strain also directed increased full-length eRF1 expression. The autogenous sup45 control mechanism therefore acts not to precisely control eRF1 expression, but rather as a damping mechanism that only partially resists changes in release factor expression level. The validated model predicts that the degree of feedback damping (i.e., control precision) is proportional to eRF1 affinity for the premature stop codon. The validated model represents an important tool to analyze this and other translational negative feedback loops. PMID- 23104999 TI - Abstract folding space analysis based on helices. AB - RNA has many pivotal functions especially in the regulation of gene expression by ncRNAs. Identification of their structure is an important requirement for understanding their function. Structure prediction alone is often insufficient for this task, due to algorithmic problems, parameter inaccuracies, and biological peculiarities. Among the latter, there are base modifications, cotranscriptional folding leading to folding traps, and conformational switching as in the case of riboswitches. All these require more in-depth analysis of the folding space. The major drawback, which all methods have to cope with, is the exponential growth of the folding space. Therefore, methods are often limited in the sequence length they can analyze, or they make use of heuristics, sampling, or abstraction. Our approach adopts the abstraction strategy and remedies some problems of existing methods. We introduce a position-specific abstraction based on helices that we term helix index shapes, or hishapes for short. Utilizing a dynamic programming framework, we have implemented this abstraction in the program RNAHeliCes. Furthermore, we developed two hishape-based methods, one for energy barrier estimation, called HiPath, and one for abstract structure comparison, termed HiTed. We demonstrate the superior performance of HiPath compared to other existing methods and the competitive accuracy of HiTed. RNAHeliCes, together with HiPath and HiTed, are available for download at http://www.cyanolab.de/software/RNAHeliCes.htm. PMID- 23105000 TI - Activation of PKR by RNA misfolding: HDV ribozyme dimers activate PKR. AB - Protein Kinase R (PKR), the double-stranded RNA (dsRNA)-activated protein kinase, plays important roles in innate immunity. Previous studies have shown that PKR is activated by long stretches of dsRNA, RNA pseudoknots, and certain single stranded RNAs; however, regulation of PKR by RNAs with globular tertiary structure has not been reported. In this study, the HDV ribozyme is used as a model of a mostly globular RNA. In addition to a catalytic core, the ribozyme contains a peripheral 13-bp pairing region (P4), which, upon shortening, affects neither the catalytic activity of the ribozyme nor its ability to crystallize. We report that the HDV ribozyme sequence alone can activate PKR. To elucidate the RNA structural basis for this, we prepared a number of HDV variants, including those with shortened or lengthened P4 pairing regions, with the anticipation that lengthening the P4 extension would yield a more potent activator since it would offer more base pairs of dsRNA. Surprisingly, the variant with a shortened P4 was the most potent activator. Through native gel mobility and enzymatic structure mapping experiments we implicate misfolded HDV ribozyme dimers as the PKR activating species, and show that the shortened P4 leads to enhanced occupancy of the RNA dimer. These observations have implications for how RNA misfolding relates to innate immune response and human disease. PMID- 23105001 TI - Alternative transcription start site selection leads to large differences in translation activity in yeast. AB - mRNA levels do not accurately predict protein levels in eukaryotic cells. To investigate contributions of 5' untranslated regions (5' UTRs) to mRNA-specific differences in translation, we determined the 5' UTR boundaries of 96 yeast genes for which in vivo translational efficiency varied by 80-fold. A total of 25% of genes showed substantial 5' UTR heterogeneity. We compared the capacity of these genes' alternative 5' UTR isoforms for cap-dependent and cap-independent translation using quantitative in vitro and in vivo translation assays. Six out of nine genes showed mRNA isoform-specific translation activity differences of greater than threefold in at least one condition. For three genes, in vivo translation activities of alternative 5' UTR isoforms differed by more than 100 fold. These results show that changing genes' 5' UTR boundaries can produce large changes in protein output without changing the overall amount of mRNA. Because transcription start site (TSS) heterogeneity is common, we suggest that TSS choice is greatly under-appreciated as a quantitatively significant mechanism for regulating protein production. PMID- 23105002 TI - Novel insights into the architecture and protein interaction network of yeast eIF3. AB - Translation initiation in eukaryotes is a multistep process requiring the orchestrated interaction of several eukaryotic initiation factors (eIFs). The largest of these factors, eIF3, forms the scaffold for other initiation factors, promoting their binding to the 40S ribosomal subunit. Biochemical and structural studies on eIF3 need highly pure eIF3. However, natively purified eIF3 comprise complexes containing other proteins such as eIF5. Therefore we have established in vitro reconstitution protocols for Saccharomyces cerevisiae eIF3 using its five recombinantly expressed and purified subunits. This reconstituted eIF3 complex (eIF3(rec)) exhibits the same size and activity as the natively purified eIF3 (eIF3(nat)). The homogeneity and stoichiometry of eIF3(rec) and eIF3(nat) were confirmed by analytical size exclusion chromatography, mass spectrometry, and multi-angle light scattering, demonstrating the presence of one copy of each subunit in the eIF3 complex. The reconstituted and native eIF3 complexes were compared by single-particle electron microscopy showing a high degree of structural conservation. The interaction network between eIF3 proteins was studied by means of limited proteolysis, analytical size exclusion chromatography, in vitro binding assays, and isothermal titration calorimetry, unveiling distinct protein domains and subcomplexes that are critical for the integrity of the protein network in yeast eIF3. Taken together, the data presented here provide a novel procedure to obtain highly pure yeast eIF3, suitable for biochemical and structural analysis, in addition to a detailed picture of the network of protein interactions within this complex. PMID- 23105003 TI - As fathers and felons: explaining the effects of current and recent incarceration on major depression. AB - Dramatic increases in the American imprisonment rate since the mid-1970s have important implications for the life chances of minority men with low educational attainment, including for their health. Although a large literature has considered the collateral consequences of incarceration for a variety of outcomes, studies concerned with health have several limitations: Most focus exclusively on physical health; those concerned with mental health only consider current incarceration or previous incarceration, but never both; some are cross sectional; many fail to consider mechanisms; and virtually all neglect the role of family processes, thereby overlooking the social roles current and former prisoners inhabit. In this article, we use stress process theory to extend this research by first considering the association between incarceration and major depression and then considering potential mechanisms that explain this association. Results from the Fragile Families and Child Wellbeing Study (N = 3,107) show current and recent incarceration are substantially associated with the risk of major depression, suggesting both immediate and short-term implications. In addition, consistent with stress proliferation theory, the results show the well-known consequences of incarceration for socioeconomic status and family functioning partly explain these associations, suggesting the link between incarceration and depression depends heavily on the consequences of incarceration for economic and social reintegration, not only the direct psychological consequences of confinement. PMID- 23105004 TI - Epigenetic regulation of olfactory receptor gene expression by the Myb-MuvB/dREAM complex. AB - In both mammals and insects, an olfactory neuron will usually select a single olfactory receptor and repress remaining members of large receptor families. Here we show that a conserved multiprotein complex, Myb-MuvB (MMB)/dREAM, plays an important role in mediating neuron-specific expression of the carbon dioxide (CO(2)) receptor genes (Gr63a/Gr21a) in Drosophila. Activity of Myb in the complex is required for expression of Gr63a/Gr21a and acts in opposition to the histone methyltransferase Su(var)3-9. Consistent with this, we observed repressive dimethylated H3K9 modifications at the receptor gene loci, suggesting a mechanism for silencing receptor gene expression. Conversely, other complex members, Mip120 (Myb-interacting protein 120) and E2F2, are required for repression of Gr63a in inappropriate neurons. Misexpression in mutants is accompanied by an increase in the H3K4me3 mark of active chromatin at the receptor gene locus. Nuclei of CO(2) receptor-expressing neurons contain reduced levels of the repressive subunit Mip120 compared with surrounding neurons and increased levels of Myb, suggesting that activity of the complex can be regulated in a cell-specific manner. Our evidence suggests a model in which olfactory receptors are regulated epigenetically and the MMB/dREAM complex plays a critical role in specifying, maintaining, and modulating the receptor-to-neuron map. PMID- 23105005 TI - G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. AB - G9a and GLP are conserved protein methyltransferases that play key roles during mammalian development through mono- and dimethylation of histone H3 Lys 9 (H3K9me1/2), modifications associated with transcriptional repression. During embryogenesis, large H3K9me2 chromatin territories arise that have been proposed to reinforce lineage choice by affecting high-order chromatin structure. Here we report that in adult human hematopoietic stem and progenitor cells (HSPCs), H3K9me2 chromatin territories are absent in primitive cells and are formed de novo during lineage commitment. In committed HSPCs, G9a/GLP activity nucleates H3K9me2 marks at CpG islands and other genomic sites within genic regions, which then spread across most genic regions during differentiation. Immunofluorescence assays revealed the emergence of H3K9me2 nuclear speckles in committed HSPCs, consistent with progressive marking. Moreover, gene expression analysis indicated that G9a/GLP activity suppresses promiscuous transcription of lineage-affiliated genes and certain gene clusters, suggestive of regulation of HSPC chromatin structure. Remarkably, HSPCs continuously treated with UNC0638, a G9a/GLP small molecular inhibitor, better retain stem cell-like phenotypes and function during in vitro expansion. These results suggest that G9a/GLP activity promotes progressive H3K9me2 patterning during HSPC lineage specification and that its inhibition delays HSPC lineage commitment. They also inform clinical manipulation of donor-derived HSPCs. PMID- 23105007 TI - Quantitative proteomics with siRNA screening identifies novel mechanisms of trastuzumab resistance in HER2 amplified breast cancers. AB - HER2 is a receptor tyrosine kinase that is overexpressed in 20% to 30% of human breast cancers and which affects patient prognosis and survival. Treatment of HER2-positive breast cancer with the monoclonal antibody trastuzumab (Herceptin) has improved patient survival, but the development of trastuzumab resistance is a major medical problem. Many of the known mechanisms of trastuzumab resistance cause changes in protein phosphorylation patterns, and therefore quantitative proteomics was used to examine phosphotyrosine signaling networks in trastuzumab resistant cells. The model system used in this study was two pairs of trastuzumab sensitive and -resistant breast cancer cell lines. Using stable isotope labeling, phosphotyrosine immunoprecipitations, and online TiO(2) chromatography utilizing a dual trap configuration, ~1700 proteins were quantified. Comparing quantified proteins between the two cell line pairs showed only a small number of common protein ratio changes, demonstrating heterogeneity in phosphotyrosine signaling networks across different trastuzumab-resistant cancers. Proteins showing significant increases in resistant versus sensitive cells were subjected to a focused siRNA screen to evaluate their functional relevance to trastuzumab resistance. The screen revealed proteins related to the Src kinase pathway, such as CDCP1/Trask, embryonal Fyn substrate, and Paxillin. We also identify several novel proteins that increased trastuzumab sensitivity in resistant cells when targeted by siRNAs, including FAM83A and MAPK1. These proteins may present targets for the development of clinical diagnostics or therapeutic strategies to guide the treatment of HER2+ breast cancer patients who develop trastuzumab resistance. PMID- 23105008 TI - Recognition and cleavage of related to ubiquitin 1 (Rub1) and Rub1-ubiquitin chains by components of the ubiquitin-proteasome system. AB - Of all ubiquitin-like proteins, Rub1 (Nedd8 in mammals) is the closest kin of ubiquitin. We show via NMR that structurally, Rub1 and ubiquitin are fundamentally similar as well. Despite these profound similarities, the prevalence of Rub1/Nedd8 and of ubiquitin as modifiers of the proteome is starkly different, and their attachments to specific substrates perform different functions. Recently, some proteins, including p53, p73, EGFR, caspase-7, and Parkin, have been shown to be modified by both Rub1/Nedd8 and ubiquitin within cells. To understand whether and how it might be possible to distinguish among the same target protein modified by Rub1 or ubiquitin or both, we examined whether ubiquitin receptors can differentiate between Rub1 and ubiquitin. Surprisingly, Rub1 interacts with proteasome ubiquitin-shuttle proteins comparably to ubiquitin but binds more weakly to a proteasomal ubiquitin receptor Rpn10. We identified Rub1-ubiquitin heteromers in yeast and Nedd8-Ub heteromers in human cells. We validate that in human cells and in vitro, human Rub1 (Nedd8) forms chains with ubiquitin where it acts as a chain terminator. Interestingly, enzymatically assembled K48-linked Rub1-ubiquitin heterodimers are recognized by various proteasomal ubiquitin shuttles and receptors comparably to K48-linked ubiquitin homodimers. Furthermore, these heterologous chains are cleaved by COP9 signalosome or 26S proteasome. A derubylation function of the proteasome expands the repertoire of its enzymatic activities. In contrast, Rub1 conjugates may be somewhat resilient to the actions of other canonical deubiquitinating enzymes. Taken together, these findings suggest that once Rub1/Nedd8 is channeled into ubiquitin pathways, it is recognized essentially like ubiquitin. PMID- 23105009 TI - Comparative genomic and proteomic analysis of cytoskeletal changes in dexamethasone-treated trabecular meshwork cells. AB - Changes in the actin cytoskeleton, especially the formation of cross-linked actin networks (CLANs) are thought to contribute to the increased intraocular pressure observed in primary open-angle and steroid-induced glaucoma. To better understand the effects of glucocorticoids, we employed a shotgun method to analyze global changes in the cytoskeleton and integrin signaling pathways following dexamethasone (DEX) treatment of human trabecular meshwork (HTM) cells. RNA and cell lysates were obtained from HTM cells incubated with or without DEX. Changes in protein expression were determined by mass spectrometry (MS) following differential centrifugation of cell lysates to enrich for low-abundance cytoskeletal and signaling proteins, proteolytic digestion, and a titanium dioxide column to enrich for phosphopeptides. Results were validated by Western blots. Changes in RNA levels were determined with gene arrays and RT-PCR. Overall, MS identified 318 cytoskeleton associated proteins. Five of these proteins (PDLIM1, FGFR1OP, leiomodin-1, ZO-2 and LRP16A) were only detected in DEX-treated cells by MS. However, only PDLIM1 showed a statistically significant increase at the RNA level. Other proteins with differences at both the RNA and protein levels included beta3 integrin, caveolin-1, Borg2, raftlin1, PI-3 kinase regulatory subunit alpha, transgelin, and filamin B. By immunofluorescence microscopy filamin B and PDLIM1 showed enhanced expression in human trabecular meshwork cells, but only PDLIM1 demonstrated significant localization within CLANs. Finally, MS showed that some of the cytoskeleton proteins (Borg2, leiomodin-1, LRP16A, raftlin1 and CKAP4) contained phosphorylated residues. This study suggests that DEX affects the expression of cytoskeleton proteins at the transcriptional and translational level and shows that a combined genomic and proteomic approach can be used for rapid analysis of proteins in the TM. It also shows that DEX altered the expression of components (PDLIM1 and beta3 integrins) involved in CLAN formation and provides new findings into the effects of glucocorticoids on the cytoskeleton. PMID- 23105010 TI - Evolutionary branching in a finite population: deterministic branching vs. stochastic branching. AB - Adaptive dynamics formalism demonstrates that, in a constant environment, a continuous trait may first converge to a singular point followed by spontaneous transition from a unimodal trait distribution into a bimodal one, which is called "evolutionary branching." Most previous analyses of evolutionary branching have been conducted in an infinitely large population. Here, we study the effect of stochasticity caused by the finiteness of the population size on evolutionary branching. By analyzing the dynamics of trait variance, we obtain the condition for evolutionary branching as the one under which trait variance explodes. Genetic drift reduces the trait variance and causes stochastic fluctuation. In a very small population, evolutionary branching does not occur. In larger populations, evolutionary branching may occur, but it occurs in two different manners: in deterministic branching, branching occurs quickly when the population reaches the singular point, while in stochastic branching, the population stays at singularity for a period before branching out. The conditions for these cases and the mean branching-out times are calculated in terms of population size, mutational effects, and selection intensity and are confirmed by direct computer simulations of the individual-based model. PMID- 23105011 TI - Engineering silkworms for resistance to baculovirus through multigene RNA interference. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) that infects the silkworm, B. mori, accounts for >50% of silk cocoon crop losses globally. We speculated that simultaneous targeting of several BmNPV essential genes in transgenic silkworm would elicit a stable defense against the virus. We introduced into the silkworm germline the vectors carrying short sequences of four essential BmNPV genes in tandem, either in sense or antisense or in inverted-repeat arrangement. The transgenic silkworms carrying the inverted repeat-containing transgene showed stable protection against high doses of baculovirus infection. Further, the antiviral trait was incorporated to a commercially productive silkworm strain highly susceptible to BmNPV. This led to combining the high-yielding cocoon and silk traits of the parental commercial strain and a very high level of refractoriness (>75% survival rate as compared to <15% in nontransgenic lines) to baculovirus infection conferred by the transgene. We also observed impaired infectivity of the occlusion bodies derived from the transgenic lines as compared to the wild-type ones. Currently, large-scale exploitation of these transgenic lines is underway to bring about economic transformation of sericulture. PMID- 23105012 TI - Depleting gene activities in early Drosophila embryos with the "maternal-Gal4 shRNA" system. AB - In a developing Drosophila melanogaster embryo, mRNAs have a maternal origin, a zygotic origin, or both. During the maternal-zygotic transition, maternal products are degraded and gene expression comes under the control of the zygotic genome. To interrogate the function of mRNAs that are both maternally and zygotically expressed, it is common to examine the embryonic phenotypes derived from female germline mosaics. Recently, the development of RNAi vectors based on short hairpin RNAs (shRNAs) effective during oogenesis has provided an alternative to producing germline clones. Here, we evaluate the efficacies of: (1) maternally loaded shRNAs to knockdown zygotic transcripts and (2) maternally loaded Gal4 protein to drive zygotic shRNA expression. We show that, while Gal4 driven shRNAs in the female germline very effectively generate phenotypes for genes expressed maternally, maternally loaded shRNAs are not very effective at generating phenotypes for early zygotic genes. However, maternally loaded Gal4 protein is very efficient at generating phenotypes for zygotic genes expressed during mid-embryogenesis. We apply this powerful and simple method to unravel the embryonic functions of a number of pleiotropic genes. PMID- 23105013 TI - Inferences of demography and selection in an African population of Drosophila melanogaster. AB - It remains a central problem in population genetics to infer the past action of natural selection, and these inferences pose a challenge because demographic events will also substantially affect patterns of polymorphism and divergence. Thus it is imperative to explicitly model the underlying demographic history of the population whenever making inferences about natural selection. In light of the considerable interest in adaptation in African populations of Drosophila melanogaster, which are considered ancestral to the species, we generated a large polymorphism data set representing 2.1 Mb from each of 20 individuals from a Ugandan population of D. melanogaster. In contrast to previous inferences of a simple population expansion in eastern Africa, our demographic modeling of this ancestral population reveals a strong signature of a population bottleneck followed by population expansion, which has significant implications for future demographic modeling of derived populations of this species. Taking this more complex underlying demographic history into account, we also estimate a mean X linked region-wide rate of adaptation of 6 * 10(-11)/site/generation and a mean selection coefficient of beneficial mutations of 0.0009. These inferences regarding the rate and strength of selection are largely consistent with most other estimates from D. melanogaster and indicate a relatively high rate of adaptation driven by weakly beneficial mutations. PMID- 23105014 TI - Large neurological component to genetic differences underlying biased sperm use in Drosophila. AB - Sperm competition arises as a result of complex interactions among male and female factors. While the roles of some male factors are known, little is known of the molecules or mechanisms that underlie the female contribution to sperm competition. The genetic tools available for Drosophila allow us to identify, in an unbiased manner, candidate female genes that are critical for mediating sperm competition outcomes. We first screened for differences in female sperm storage and use patterns by characterizing the natural variation in sperm competition in a set of 39 lines from the sequenced Drosophila Genetic Reference Panel (DGRP) of wild-derived inbred lines. We found extensive female variation in sperm competition outcomes. To generate a list of candidate female genes for functional studies, we performed a genome-wide association mapping, utilizing the common single-nucleotide polymorphisms (SNPs) segregating in the DGRP lines. Surprisingly, SNPs within ion channel genes and other genes with roles in the nervous system were among the top associated SNPs. Knockdown studies of three candidate genes (para, Rab2, and Rim) in sensory neurons innervating the female reproductive tract indicate that some of these candidate female genes may affect sperm competition by modulating the neural input of these sensory neurons to the female reproductive tract. More extensive functional studies are needed to elucidate the exact role of all these candidate female genes in sperm competition. Nevertheless, the female nervous system appears to have a previously unappreciated role in sperm competition. Our results indicate that the study of female control of sperm competition should not be limited to female reproductive tract-specific genes, but should focus also on diverse biological pathways. PMID- 23105018 TI - Mental health care utilization and compulsive buying. PMID- 23105015 TI - Processing body and stress granule assembly occur by independent and differentially regulated pathways in Saccharomyces cerevisiae. AB - A variety of ribonucleoprotein (RNP) granules form in eukaryotic cells to regulate the translation, decay, and localization of the encapsulated messenger RNA (mRNAs). The work here examined the assembly and function of two highly conserved RNP structures, the processing body (P body) and the stress granule, in the yeast Saccharomyces cerevisiae. These granules are induced by similar stress conditions and contain translationally repressed mRNAs and a partially overlapping set of protein constituents. However, despite these similarities, the data indicate that these RNP complexes are independently assembled and that this assembly is controlled by different signaling pathways. In particular, the cAMP dependent protein kinase (PKA) was found to control P body formation under all conditions examined. In contrast, the assembly of stress granules was not affected by changes in either PKA or TORC1 signalling activity. Both of these RNP granules were also detected in stationary-phase cells, but each appears at a distinct time. P bodies were formed prior to stationary-phase arrest, and the data suggest that these foci are important for the long-term survival of these quiescent cells. Stress granules, on the other hand, were not assembled until after the cells had entered into the stationary phase of growth and their appearance could therefore serve as a specific marker for the entry into this quiescent state. In all, the results here provide a framework for understanding the assembly of these RNP complexes and suggest that these structures have distinct but important activities in quiescent cells. PMID- 23105016 TI - Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. AB - Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time. PMID- 23105019 TI - Intraclonal genetic diversity amongst cystic fibrosis and keratitis isolates of Pseudomonas aeruginosa. AB - Given the emergence of transmissible strains of Pseudomonas aeruginosa, such as the Liverpool epidemic strain (LES), in cystic fibrosis (CF) centres, it is important to carry out regular surveillance of isolates. In a survey of 22 P. aeruginosa isolates, each from a different CF patient identified as negative for LES in a paediatric centre in Liverpool, six (23 %) were identified as being the same clone type (clone D) using array-tube genotyping. Using a series of alternative genotyping approaches [PFGE, random amplification of polymorphic DNA (RAPD), variable number of tandem repeats (VNTR) and multilocus sequence typing (MLST)], the six CF clone D isolates and eight previously identified clone D isolates associated with infections leading to keratitis were compared. All but two of the clone D isolates (both keratitis-associated) were assigned by MLST to sequence type 235 and were highly similar using VNTR analysis. However, there was considerable variation found among the isolates when using PFGE or RAPD, highlighting the limitations of these methods. The discordance with respect to two of the isolates identified by array-tube genotyping as clone D, when using all the other typing methods, emphasizes the need to use more than one method for reliable identification of strains. PMID- 23105020 TI - Burkholderia multivorans survival and trafficking within macrophages. AB - Cystic fibrosis (CF) patients are at great risk of opportunistic lung infection, particularly by members of the Burkholderia cepacia complex (Bcc). This group of bacteria can cause damage to the lung tissue of infected patients and are difficult to eradicate due to their high levels of antibiotic resistance. Although the highly virulent Burkholderia cenocepacia has been the focus of virulence research for the past decade, Burkholderia multivorans is emerging as the most prevalent Bcc species infecting CF patients in North America. Despite several studies detailing the intramacrophage trafficking and survival of B. cenocepacia, no such data exist for B. multivorans. The results of this study demonstrated that the clinical CF isolates C5568 and C0514 and an environmental B. multivorans isolate, ATCC 17616, were able to replicate and survive within murine macrophages in a manner similar to that of B. cenocepacia strain K56-2. These strains were also able to survive but were unable to replicate within human THP-1 macrophages. Differences in macrophage uptake were observed among all three B. multivorans strains; these variances were attributed to major differences in O antigen production. Unlike B. cenocepacia-containing vacuoles, which delay phagosomal maturation in murine macrophages by 6 h, all B. multivorans-containing vacuoles co-localized with lysosome-associated membrane protein-1, a late endosome/lysosomal marker, and the lysosomal marker dextran within 2 h of uptake. Together, these results indicated that, whilst both Bcc species were able to survive and replicate within macrophages, they utilized different intramacrophage survival strategies. To observe differences in virulence, the strains were compared using the Galleria mellonella (wax worm) model. When compared with the B. multivorans strains tested, B. cenocepacia K56-2 was highly virulent in this model and killed all worms within 24 h when injected at 10(7) c.f.u. B. multivorans clinical isolates C5568 and C0514 were significantly more virulent than the soil isolate ATCC 17616, which was avirulent even when worms were injected with 10(7) c.f.u. These results suggest strain differences in the virulence of B. multivorans isolates. PMID- 23105022 TI - A mutant in the Listeria monocytogenes Fur-regulated virulence locus (frvA) induces cellular immunity and confers protection against listeriosis in mice. AB - Listeria monocytogenes is a Gram-positive intracellular pathogen that is responsible for listeriosis, a potentially fatal, food-borne illness. Due to its cytoplasmic location during infection, this pathogen can mediate a long-lasting cellular immune response, which makes attenuated strains strong candidates for vaccine development. Recently, our group identified and characterized frvA (Fur regulated virulence factor A), and deletion of this gene resulted in disruption of iron homeostasis and a strong attenuation in virulence. Despite significant attenuation in the mouse infection model, the frvA mutant was capable of intracellular growth in antigen-presenting cells. Indeed, mice immunized with L. monocytogenes DeltafrvA were able to effectively stimulate specific CD8(+) T cells to the listerial epitopes LLO(91-99) and P60(217-225) at levels comparable with L. monocytogenes strain EGDe. Most notably, mice immunized with DeltafrvA then subsequently challenged with the wild-type strain were completely protected from listerial infection. On the basis of these results, we advocate the use of DeltafrvA as a live attenuated listerial vaccine, and propose that this mutant may serve as a platform for the development of a future vaccine delivery vehicle. PMID- 23105023 TI - National surveillance reveals findings of Panton-Valentine leukocidin positive meticillin-resistant Staphylococcus aureus in Serbia. PMID- 23105021 TI - Invasive candidiasis in Pakistan: clinical characteristics, species distribution and antifungal susceptibility. AB - This study reports for the first time, to our knowledge, descriptive epidemiological data for 188 invasive Candida isolates from Pakistan, including species identification and antifungal susceptibility against fluconazole, itraconazole, voriconazole, caspofungin, micafungin, anidulafungin and amphotericin. Risk factors for invasive candidiasis (IC) were determined for 96 patients from Karachi, Pakistan. In adults and neonates, Candida tropicalis (38 and 36 %, respectively) was the most common species, followed in adults by Candida parapsilosis (17.8 %), Candida glabrata (15.9 %) and Candida albicans (12.3 %). C. albicans (21 %) was the second most common in neonates. In children, C. albicans (31.9 %), C. tropicalis (26.4 %) and C. parapsilosis (19.4 %) were the most common. C. albicans IC was significantly associated with paediatric age [crude odds ratio (COR) 3.46, 95 % confidence interval (CI) 1.63-7.32]. Rare species made up 17.5 % of the total isolates studied. Resistance to fluconazole was seen in C. glabrata (15 .0%) and Candida krusei (100 .0%). Only one isolate (C. glabrata) was resistant to all three echinocandins. Low MICs of fluconazole for 98 % (184/188) of isolates tested support its continued use as an empiric therapy for IC. Non-C. albicans IC was associated with the use of beta-lactam inhibitor combinations (COR 3.16, 95 % CI 1.05-9.57). Use of healthcare devices was documented in 85.4 % of IC patients, whilst 75 .0% had been admitted to special care units. Surprisingly, 66.7 % of patients with IC were not obviously immunosuppressed. The high frequency of modifiable risk factors in this population indicates that candidaemia can be reduced with stringent antibiotic and infection control measures. These data will be useful for empiric selection of antifungals in Karachi, and contribute to global assessments of antifungal resistance. PMID- 23105024 TI - Streptococcus equi subsp. zooepidemicus meningitis in Peru. AB - A 59-year-old man with a history of fever, unsteadiness, hemiparesis, motor aphasia and consciousness disturbance was hospitalized for Streptococcus equi subsp. zooepidemicus meningitis. He denied contact with farm animals, but had a practice of consuming unpasteurized goats' cheese from an uncertain source. PMID- 23105025 TI - Prevalence of Anaplasma phagocytophilum in ruminants, rodents and ticks in Gansu, north-western China. AB - The zoonotic rickettsial pathogen Anaplasma phagocytophilum has a broad geographical distribution and a high degree of biological and clinical diversity. To determine the prevalence of Anaplasma phagocytophilum in the Gannan Tibetan Autonomous Prefecture of Gansu Province, north-western China, four ruminant species, one rodent and one tick species were examined for Anaplasma phagocytophilum infection. DNA from Anaplasma phagocytophilum was detected by nested PCR in blood samples from 21/49 sheep (42.9 %), 35/91 goats (38.5 %), 51/158 yaks (32.3 %) and 7/20 cattle-yaks (35.0 %), and in spleen samples from 2/12 rodents (16.7 %). For samples from tick larvae and nymphs, 105 pools were tested; one of 46 larval tick pools was positive and seven of 59 nymphal tick pools were positive. For adult ticks, 40/598 female ticks (6.7 %) and 26/528 male ticks (4.9 %) were positive. The prevalence of Anaplasma phagocytophilum in female ticks was higher than that in males, although the difference was not statistically significant (P>0.05). Sequences analysis based on the 16S rRNA gene indicated that the strains in the study area were distinct from previously reported Anaplasma phagocytophilum in other continents. These results add new information on the epidemiology of Anaplasma phagocytophilum and indicate the tick-animal cycle of anaplasmosis in the area. To the best of our knowledge, this is the first report of Anaplasma phagocytophilum infection in Gansu Province in north-western China. PMID- 23105026 TI - Immunological evaluation of Vi capsular polysaccharide of Salmonella enterica subsp. Typhi vaccine by serum bactericidal assay. AB - Salmonella enterica subsp. Typhi (S. Typhi) Vi antigen capsular polysaccharide (Vi-CPS) is a licensed vaccine against typhoid fever. As there is no animal model for S. Typhi fever to evaluate the protective efficacy of the Vi-CPS vaccine, a serum bactericidal assay (SBA) is the recommended 'gold standard' to evaluate its potency. Vi-CPS was extracted from S. Typhi Ty6S (CSBPI-B191) using a modified Gotschlich method. Purified Vi-CPS (50 ug) was injected intramuscularly into three groups of five rabbits; group 2 received an additional booster dose of 50 ug Vi-CPS on day 15 and group 3 received two additional boosters on days 15 and 30. The sera obtained from each group were tested by SBA on days 0, 15, 30 and 45. The anti-Vi-CPS titres for groups 1, 2 and 3 on days 15, 30 and 45 were 4, 16 and 16; 4, 32 and 32; and 16, 64 and 64, respectively. Thus, Vi-CPS was shown to be a potent immunogen, as even one dose could induce an efficient bactericidal effect against S. Typhi. Although Vi-CPS is a reliable vaccine, sometimes depolymerization during purification can affect its potency, which can be resolved through a potency test. As the passive haemagglutination test recommended by the World Health Organization does not indicate vaccine potency, we recommend using an SBA to evaluate the bactericidal ability of Vi-CPS. PMID- 23105027 TI - Tetracycline-resistant Chlamydia suis in cases of reproductive failure on Belgian, Cypriote and Israeli pig production farms. AB - Similar cases of severe reproductive failure associated with the presence of Chlamydia suis in two Belgian, one Cypriote and one Israeli pig farrowing to slaughter farms are presented. Vaginal and rectal swabs from 39 sows were examined by culture and DNA microarray. Nineteen of 23 (83 %) C. suis-positive sows were infected with tetracycline-resistant C. suis strains, as determined by MIC tests. Furthermore, boar semen from a German artificial insemination centre, intended for export, was positive for C. suis. Emergence of tetracycline resistant C. suis strains was confirmed. PMID- 23105028 TI - The 5th anniversary of Hurricane Katrina: legacy of challenges. PMID- 23105029 TI - Hurricane Katrina and the health system: lessons learned. PMID- 23105030 TI - What New Orleans' vulnerability taught us about public health preparedness: vulnerability has a face and a name. PMID- 23105031 TI - Children as bellwethers of recovery: dysfunctional systems and the effects of parents, households, and neighborhoods on serious emotional disturbance in children after Hurricane Katrina. AB - BACKGROUND: Over 160,000 children were displaced from their homes after Hurricane Katrina. Tens of thousands of these children experienced the ongoing chaos and uncertainty of displacement and transiency, as well as significant social disruptions in their lives. The objectives of this study were to estimate the long-term mental health effects of such exposure among children, and to elucidate the systemic pathways through which the disaster effect operates. METHODS: The prevalence of serious emotional disturbance was assessed among 283 school-aged children in Louisiana and Mississippi. These children are part of the Gulf Coast Child & Family Health Study, involving a longitudinal cohort of 1079 randomly sampled households in the two states, encompassing a total of 427 children, who have been interviewed in 4 annual waves of data collection since January 2006. The majority of data for this analysis was drawn from the fourth round of data. RESULTS: Although access to medical care for children has expanded considerably since 2005 in the region affected by Hurricane Katrina, more than 37% of children have received a clinical mental health diagnosis of depression, anxiety, or behavior disorder, according to parent reports. Children exposed to Hurricane Katrina were nearly 5 times as likely as a pre-Katrina cohort to exhibit serious emotional disturbance. Path analyses confirm the roles played by neighborhood social disorder, household stressors, and parental limitations on children's emotional and behavioral functioning. CONCLUSIONS: Children and youth are particularly vulnerable to the effects of disasters. They have limited capacity to independently mobilize resources to help them adapt to stressful postdisaster circumstances, and are instead dependent upon others to make choices that will influence their household, neighborhood, school, and larger social environment. Children's mental health recovery in a postdisaster setting can serve as a bellwether indicator of successful recovery or as a lagging indicator of system dysfunction and failed recovery. PMID- 23105032 TI - Effects of Hurricane Katrina on nursing facility resident mortality, hospitalization, and functional decline. AB - BACKGROUND: The study was designed to examine the 30- and 90-day mortality and hospitalization rates among nursing facility (NF) residents in the affected areas of Louisiana and Mississippi following Hurricane Katrina and to assess the rate of significant posthurricane functional decline. METHODS: A secondary data analysis was conducted using Medicare claims merged with NF resident data from the Minimum Data Set. Thirty- and 90-day mortality and hospitalization rates for long-stay (>90 days) residents residing in 141 at-risk NFs during Hurricane Katrina were compared to rates for residents residing at the same facilities during the same time period in prior nonhurricane years (2003 and 2004). Functional decline was assessed as a 4+ drop in function using a 28-point Minimum Data Set Activities of Daily Living Scale. RESULTS: There were statistically significant differences (all P < .0001) in mortality, hospitalization, and functional decline among residents exposed to Hurricane Katrina. At 30 days, the mortality rate was 3.88% among the exposed cohort compared with 2.10% and 2.28% for residents in 2003 and 2004, respectively. The 90-day mortality rate was 9.27% compared with 6.71% and 6.31%, respectively. These mortality differences translated into an additional 148 deaths at 30 days and 230 deaths at 90 days. The 30-day hospitalization rate was 9.87% compared with 7.21% and 7.53%, respectively. The 90-day hospitalization rate was 20.39% compared with 18.61% and 17.82%, respectively. Finally, the rate of significant functional decline among survivors was 6.77% compared with 5.81% in 2003 and 5.10% in 2004. CONCLUSIONS: NF residents experienced a significant increase in mortality, hospitalization, and functional decline during Hurricane Katrina. PMID- 23105033 TI - Time to recovery in diabetes and comorbidities following Hurricane Katrina. AB - BACKGROUND: The impact of a natural disaster on self-care and health care delivery has been well documented. The objective of the study was to document the recovery pattern from the impact of a natural disaster such as Hurricane Katrina on clinical and biochemical measures of diabetes and its comorbidities. METHODS: Patients were selected from Tulane University Hospital and Clinic, Southeast Louisiana Veterans Health Care System, and the Medical Center of Louisiana at New Orleans. Adults with diabetes and A(1c) measurement 6 months before (pre-K) Hurricane Katrina (February 28, 2005-August 27, 2005) and 6 to 16 months after (post-K) Katrina (March 1, 2006-December 31, 2006) were identified within the 3 facilities. Follow-up data (January 1, 2007-December 31, 2007) were 1 year after the first post-K visit. The outcome measures were hemoglobin A(1c) (HbA(1c)), systolic and diastolic blood pressure (BP), and lipids (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL], triglycerides). RESULTS: Averaged across the 3 facilities, the parameters significantly different in the follow-up period compared with pre- and post-K were HbA(1c) (P = .04), HDL, and systolic and diastolic BP (P < .0001). Parameters with significantly different patterns of change in the 3 facilities over time were HbA(1c), HDL, systolic and diastolic BP (P < .0001), and low-density lipoprotein (P < .01). CONCLUSIONS: Our results suggest that a variety of clinical and biochemical parameters related to diabetes and its comorbidities affected by natural disaster have varied the rate of recovery to predisaster levels. PMID- 23105034 TI - Population changes, racial/ethnic disparities, and birth outcomes in Louisiana after Hurricane Katrina. AB - OBJECTIVE: To examine how the demographic and other population changes affected birth and obstetric outcomes in Louisiana, and the effect of the hurricane on racial disparities in these outcomes. METHODS: Vital statistics data were used to compare the incidence of low birth weight (LBW) (<2500 g), preterm birth (PTB) (37 weeks' gestation), cesarean section, and inadequate prenatal care (as measured by the Kotelchuck index), in the 2 years after Katrina compared to the 2 years before, for the state as a whole, region 1 (the area around New Orleans), and Orleans Parish (New Orleans). Logistic models were used to adjust for covariates. RESULTS: After adjustment, rates of LBW rose for the state, but preterm birth did not. In region 1 and Orleans Parish, rates of LBW and PTB remained constant or fell. These patterns were all strongest in African American women. Rates of cesarean section and inadequate prenatal care rose. Racial disparities in birth outcomes remained constant or were reduced. CONCLUSIONS: Although risk of LBW/PTB remained higher in African Americans, the storm does not appear to have exacerbated health disparities, nor did population shifts explain the changes in birth and obstetric outcomes. PMID- 23105035 TI - Measuring individual disaster recovery: a socioecological framework. AB - BACKGROUND: Disaster recovery is a complex phenomenon. Too often, recovery is measured in singular fashion, such as quantifying rebuilt infrastructure or lifelines, without taking in to account the affected population's individual and community recovery. A comprehensive framework is needed that encompasses a much broader and far-reaching construct with multiple underlying dimensions and numerous causal pathways; without the consideration of a comprehensive framework that investigates relationships between these factors, an accurate measurement of recovery may not be valid. This study proposes a model that encapsulates these ideas into a single framework, the Socio-Ecological Model of Recovery. METHODS: Using confirmatory factor analysis, an operational measure of recovery was developed and validated using the five measures of housing stability, economic stability, physical health, mental health, and social role adaptation. The data were drawn from a sample of displaced households following Hurricane Katrina. Measures of psychological strength, risk, disaster exposure, neighborhood contextual effects, and formal and informal help were modeled to examine their direct and indirect effects on recovery using a structural equation model. FINDINGS: All five elements of the recovery measure were positively correlated with a latent measure of recovery, although mental health and social role adaptation displayed the strongest associations. An individual's psychological strength had the greatest association with positive recovery, followed by having a household income greater than $20,000 and having informal social support. Those factors most strongly associated with an absence of recovery included the time displaced since the hurricane, being disabled, and living in a community with substantial social disorder. DISCUSSION: The socio-ecological framework provides a robust means for measuring recovery, and for testing those factors associated with the presence or absence of recovery. PMID- 23105036 TI - Sleep and arousal as risk factors for adverse health and work performance in public health workers involved in the 2004 Florida hurricane season. AB - BACKGROUND: We examined the relation of sleep disturbance and arousal to work performance, mental and physical health, and day-to-day functioning in Florida Department of Health (FDOH) employees 9 months after the 2004 Florida hurricane season. METHODS: FDOH employees were contacted via e-mail 9 months after the 2004 hurricanes. Participants (N = 2249) completed electronic questionnaires including measures of sleep disturbance, arousal, work performance, physical health, mental health, day-to-day function, hurricane injury, and work demand. RESULTS: More than 18% of FDOH employees reported >= 25% reduced work performance and 11% to 15.3% reported >= 7 "bad" mental or physical health days in the past month. Sleep disturbance and elevated arousal were strongly associated with impaired work performance (odds ratios [ORs] 3.33 and 3.34, respectively), "bad" mental health (ORs 3.01 and 3.64), "bad" physical health (ORs 3.21 and 2.01), and limited day to-day function (ORs 4.71 and 2.32), even after adjusting for sex, race, age, education, and marital status. CONCLUSIONS: Among public health workers exposed to the 2004 hurricanes, sleep disturbance and arousal were associated with personal and work impairment. Future research should continue to examine the effect of repeated exposure to disasters in first responders. PMID- 23105037 TI - In their own words: displaced children's educational recovery needs after Hurricane Katrina. AB - OBJECTIVES: Children may experience psychological, physical, and educational vulnerability as the result of a disaster. Of these 3 vulnerability types, educational vulnerability has received the most limited scholarly attention. The 2 primary objectives of this research are to describe what forms of educational support displaced children said that they needed after Hurricane Katrina and to identify who or what facilitated children's educational recovery. METHODS: This article draws on data gathered through participant observation and interviews with 40 African American children between the ages of 7 and 18 years who relocated to Colorado with their families after Hurricane Katrina. RESULTS: In the first year following Hurricane Katrina, more than 75% of the children in the sample experienced a decline in grades. In subsequent years, the children reported greater satisfaction with their schools in Colorado and their overall educational experience. The children identified their teachers, peers, and educational institutions as playing the most significant role in their recovery. CONCLUSION: Through offering a child-centric perspective, this study expands prior research on postdisaster educational recovery. PMID- 23105038 TI - Ride to recovery. PMID- 23105039 TI - Emergency preparedness for residency/fellowship programs: lessons learned during Hurricane Katrina and applied during Hurricane Ike. AB - When it struck the US Gulf Coast in 2005, Hurricane Katrina severely disrupted many graduate medical education residency/fellowship programs in the region and the training of hundreds of residents/fellows. Despite the work of the Accreditation Council for Graduate Medical Education in responding to this natural disaster and facilitating communication and transfer of residents/fellows to other unaffected training programs, the storm exposed the gaps in the existing system. Subsequently, the Accreditation Council for Graduate Medical Education, with the aid of its member organizations, including the American Medical Association, developed a new disaster recovery plan to allow for a more rapid, effective response to future catastrophic events. These policies were instrumental in the rapid relocation of 597 residents/fellows from the University of Texas Medical Branch at Galveston after the landfall of Hurricane Ike in September 2008. As a further accommodation to affected trainees, medical certification boards should be as flexible as possible in waiving continuity requirements in the event of a disaster that affects residency/fellowship programs. PMID- 23105040 TI - Recovery research, Katrina's fifth anniversary, and lessons relearned. PMID- 23105041 TI - Calorie restriction does not increase short-term or long-term protein synthesis. AB - Increased protein synthesis is proposed as a mechanism of life-span extension during caloric restriction (CR). We hypothesized that CR does not increase protein synthesis in all tissues and protein fractions and that any increased protein synthesis with CR would be due to an increased anabolic effect of feeding. We used short- (4 hours) and long-term (6 weeks) methods to measure in vivo protein synthesis in lifelong ad libitum (AL) and CR mice. We did not detect an acute effect of feeding on protein synthesis while liver mitochondrial protein synthesis was lower in CR mice versus AL mice. Mammalian target of rapamycin (mTOR) signaling was repressed in liver and heart from CR mice indicative of energetic stress and suppression of growth. Our main findings were that CR did not increase rates of mixed protein synthesis over the long term or in response to acute feeding, and protein synthesis was maintained despite decreased mTOR signaling. PMID- 23105042 TI - Disability in basic and instrumental activities of daily living is associated with faster rate of decline in cognitive function of older adults. AB - BACKGROUND: The purpose of this study is to examine whether physical disability is associated with faster rate of decline in cognitive function. METHODS: A longitudinal population-based cohort of 6,678 initially nondisabled older adults from a biracial urban community was interviewed at 3-year intervals from 1993 to 2012. Cognitive function was assessed using a standardized global cognitive score, and physical disabilities using activities of daily living (ADL) and instrumental activities of daily living (IADL). RESULTS: During the follow-up period, 2,450 of 6,678 participants (37%) developed ADL and 2,069 of 4,287 participants (48%) developed IADL disability. After adjusting for demographic and physiologic confounders, cognitive function declined a mean of 0.048 unit per year before ADL disability and 0.047 unit per year before IADL disability. In comparison, the rate of cognitive decline accelerated further by 0.076 unit per year (156% increase) after ADL disability and 0.054 unit per year (115% increase) after IADL disability. Severity of ADL and IADL disabilities were also associated with faster cognitive decline following disability. CONCLUSIONS: In old age, cognitive function declines substantially faster following physical disability even after controlling for demographic and physiologic characteristics of participants. PMID- 23105043 TI - Introduction to the aging kidney. PMID- 23105044 TI - Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. AB - BACKGROUND: Age trends in estradiol and estrone levels in men and how lifestyle factors, comorbid conditions, testosterone, and sex hormone-binding globulin affect these age trends remain poorly understood, and were examined in men of the Framingham Heart Study. METHODS: Estrone and estradiol concentrations were measured in morning fasting samples using liquid chromatography tandem mass spectrometry in men of Framingham Offspring Generation. Free estradiol was calculated using a law of mass action equation. RESULTS: There were 1,461 eligible men (mean age [+/-SD] 61.1+/-9.5 years and body mass index [BMI] 28.8+/ 4.5kg/m(2)). Total estradiol and estrone were positively associated with age, but free estradiol was negatively associated with age. Age-related increase in total estrone was greater than that in total estradiol. Estrone was positively associated with smoking, BMI, and testosterone, and total and free estradiol with diabetes, BMI, testosterone, and comorbid conditions; additionally, free estradiol was associated negatively with smoking. Collectively, age, BMI, testosterone, and other health and behavioral factors explained only 18% of variance in estradiol, and 9% of variance in estrone levels. Men in the highest quintile of estrone levels had significantly higher age and BMI, and a higher prevalence of smoking, diabetes, and cardiovascular disease than others, whereas those in the highest quintile of estradiol had higher BMI than others. CONCLUSIONS: Total estrone and estradiol levels in men, measured using liquid chromatography tandem mass spectrometry, revealed significant age-related increases that were only partially accounted for by cross-sectional differences in BMI, diabetes status, and other comorbidities and health behaviors. Longitudinal studies are needed to confirm these findings. PMID- 23105046 TI - Genome sequence of Staphylococcus aureus Newbould 305, a strain associated with mild bovine mastitis. AB - Staphylococcus aureus is a major etiological agent of mastitis in ruminants. We report here the genome sequence of bovine strain Newbould 305, isolated in the 1950s in a case of bovine mastitis and now used as a model strain able to reproducibly induce chronic mastitis in cows. PMID- 23105045 TI - Frailty and sexual health in older European men. AB - BACKGROUND: There has been little research on how late-life frailty interrelates with sexual health. Our objective was to examine the association of frailty with sexual functioning and satisfaction among older men. METHODS: The study population consisted of 1,504 men aged 60 to 79 years, participating in the European Male Aging Study. Self-report questionnaires measured overall sexual functioning, sexual function-related distress, and erectile dysfunction. Frailty status was defined using a phenotype (FP) or index (FI). Associations between frailty and sexual function were explored using regression models. RESULTS: Based on the frailty phenotype, 5% of men were classified as frail, and the mean frailty index was 0.18 (SD = 0.12). Frailty was associated with decreasing overall sexual functioning and increasing sexual function-related distress in multiple linear regressions adjusted for age, smoking, alcohol consumption, living arrangements, comorbidities, and depression. Frailty was also associated with an increased odds of erectile dysfunction after adjustment for the same confounders: odds ratio = 1.99 (95% confidence interval = 1.14, 3.48) and 4.08 (95% confidence interval = 2.63, 6.36) for frailty phenotype and frailty index, respectively. CONCLUSIONS: Frailty was associated with impaired overall sexual functioning, sexual function-related distress, and erectile dysfunction. Individuals assessed for frailty-related deficits may also benefit from an appraisal of sexual health as an important aspect of well-being and quality of life. PMID- 23105047 TI - Genome sequence of the thermophile Bacillus coagulans Hammer, the type strain of the species. AB - Here we announce a 3.0-Mb assembly of the Bacillus coagulans Hammer strain, which is the type strain of the species within the genus Bacillus. Genomic analyses based on the sequence may provide insights into the phylogeny of the species and help to elucidate characteristics of the poorly studied strains of Bacillus coagulans. PMID- 23105048 TI - Genome sequence of the psychrophilic deep-sea bacterium Moritella marina MP-1 (ATCC 15381). AB - Moritella marina MP-1 is a bacterial species known for its production of docosahexaenoic acid. We present the draft genome sequence of the type strain Moritella marina MP-1 (ATCC 15381), having 4,636,778 bp with a G+C content of 40.5% and consisting of 83 contigs. PMID- 23105049 TI - Complete genome sequence of a variant of Campylobacter jejuni NCTC 11168. AB - Campylobacter jejuni NCTC 11168 is widely used in research, but at least two variants have been reported. The available genome was sequenced from a variant which later showed a different phenotype and gene expression profile. Here we present the complete genome sequence of a second variant of C. jejuni NCTC 11168. PMID- 23105050 TI - Complete genome sequences of Desulfosporosinus orientis DSM765T, Desulfosporosinus youngiae DSM17734T, Desulfosporosinus meridiei DSM13257T, and Desulfosporosinus acidiphilus DSM22704T. AB - Desulfosporosinus species are sulfate-reducing bacteria belonging to the Firmicutes. Their genomes will give insights into the genetic repertoire and evolution of sulfate reducers typically thriving in terrestrial environments and able to degrade toluene (Desulfosporosinus youngiae), to reduce Fe(III) (Desulfosporosinus meridiei, Desulfosporosinus orientis), and to grow under acidic conditions (Desulfosporosinus acidiphilus). PMID- 23105051 TI - Genome sequences of two freshwater betaproteobacterial isolates, Limnohabitans species strains Rim28 and Rim47, indicate their capabilities as both photoautotrophs and ammonia oxidizers. AB - Betaproteobacterial genus Limnohabitans represents an important part of freshwater bacterioplankton. Here, we report genome sequences of two Limnohabitans isolates, Rim28 and Rim47. They contain a complete photosynthesis gene cluster, RuBisCO, CO dehydrogenase, ammonia monooxygenase, and sulfur oxidizing genes, which indicates a great metabolic versatility of the Limnohabitans species. PMID- 23105052 TI - Genome sequence of Pseudomonas aeruginosa DQ8, an efficient degrader of n-alkanes and polycyclic aromatic hydrocarbons. AB - Pseudomonas aeruginosa DQ8, which was isolated from the crude oil polluted soil in the Daqing oilfield of China, can efficiently degrade diesel, crude oil, n alkanes, and polycyclic aromatic hydrocarbons (PAHs). Here, we present a 6.8-Mb assembly of its genome sequence. We have annotated 23 coding sequences (CDSs) responsible for catabolism of n-alkanes and PAHs. PMID- 23105053 TI - Draft genome sequence of Paenibacillus sp. strain OSY-SE, a bacterium producing the novel broad-spectrum lipopeptide antibiotic paenibacterin. AB - A strain of Paenibacillus sp., OSY-SE, was isolated from soil and found to produce a novel lipopeptide antibiotic. The antibiotic, paenibacterin, is active against Gram-negative and Gram-positive bacterial pathogens. Paenibacterin is biosynthesized by a nonribosomal peptide synthetase pathway. Here we report the draft genome sequence of Paenibacillus sp. OSY-SE. PMID- 23105054 TI - Genome sequence of Nitratireductor aquibiodomus strain RA22. AB - The genus Nitratireductor represents nitrate-reducing bacteria from the family Phyllobacteriaceae. Here we report the draft genome sequence of Nitratireductor aquibiodomus strain RA22, which contains 4,592,790 bp, with a G+C content of 61.30%, and has 4,241 protein coding genes. PMID- 23105055 TI - Complete genome sequence of Bacillus subtilis strain QB928, a strain widely used in B. subtilis genetic studies. AB - The complete genome sequence of Bacillus subtilis strain QB928 was constructed to facilitate studies in the evolution of the genetic code. With a widespread use of the strain in Bacillus subtilis genetics studies, its complete genome sequence would facilitate deeper understanding of Bacillus subtilis genetics. PMID- 23105056 TI - Genome sequence of Rhizobium sp. strain CCGE510, a symbiont isolated from nodules of the endangered wild bean Phaseolus albescens. AB - We present the genome sequence of Rhizobium sp. strain CCGE510, a nitrogen fixing bacterium taxonomically affiliated with the R. leguminosarum-R. etli group, isolated from wild Phaseolus albescens nodules grown in native pine forests in western Mexico. P. albescens is an endangered bean species phylogenetically related to P. vulgaris. In spite of the close host relatedness, Rhizobium sp. CCGE510 does not establish an efficient symbiosis with P. vulgaris. This is the first genome of a Rhizobium symbiont from a Phaseolus species other than P. vulgaris, and it will provide valuable new insights about symbiont-host specificity. PMID- 23105057 TI - Genome sequence of "Candidatus Mycoplasma haemolamae" strain purdue, a red blood cell pathogen of alpacas (Vicugna pacos) and llamas (Lama glama). AB - We report the complete genome sequence of "Candidatus Mycoplasma haemolamae," an endemic red-cell pathogen of camelids. The single, circular chromosome has 756,845 bp, a 39.3% G+C content, and 925 coding sequences (CDSs). A great proportion (49.1%) of these CDSs are organized into paralogous gene families, which can now be further explored with regard to antigenic variation. PMID- 23105058 TI - Genome sequences of three Helicobacter pylori strains isolated from atrophic gastritis and gastric ulcer patients in China. AB - Helicobacter pylori is a bacterial pathogen which can lead to several human gastric diseases. Here we describe the genome sequences of three strains isolated from atrophic gastritis and gastric ulcers patients in China. The data will permit genomic characterization of traits that may contribute to various gastric diseases. PMID- 23105059 TI - Complete genome sequence of Klebsiella pneumoniae 1084, a hypermucoviscosity negative K1 clinical strain. AB - We report the complete genome sequence of Klebsiella pneumoniae 1084, a hypermucoviscosity-negative K1 clinical strain. Sequencing and annotation revealed a 5,386,705-bp circular chromosome (57.4% G+C content), which contains 4,962 protein-coding genes, 80 tRNA genes, and 25 rRNA genes. PMID- 23105060 TI - Complete genome sequence of Burkholderia sp. Strain GG4, a betaproteobacterium that reduces 3-oxo-N-acylhomoserine lactones and produces different N acylhomoserine lactones. AB - Burkholderia sp. strain GG4, isolated from the ginger rhizosphere, possesses a unique N-acylhomoserine lactone (AHL)-modifying activity that reduces 3-oxo-AHLs to 3-hydroxy-AHLs. To the best of our knowledge, this is the first sequenced genome from a bacterium of the genus Burkholderia that shows both quorum-sensing and signaling confusion activities. PMID- 23105062 TI - Draft genome sequence of Salmonella enterica serovar Typhimurium ST1660/06, a multidrug-resistant clinical strain isolated from a diarrheic patient. AB - Salmonella enterica serovar Typhimurium is one of the most prevalent serovars of Salmonella that causes human gastroenteritis. Here, we report the draft genome sequence of the S. Typhimurium multidrug-resistant strain ST1660/06. Comparative genomic analysis unveiled three strain-specific genomic islands that potentially confer the multidrug resistance and virulence of the strain. PMID- 23105061 TI - Whole-genome sequence of N-acylhomoserine lactone-synthesizing and -degrading Acinetobacter sp. strain GG2. AB - Acinetobacter sp. strain GG2 is a quorum-sensing and quorum-quenching bacterium isolated from the ginger rhizosphere. It degrades a broad range of N acylhomoserine lactone molecules via lactonase. The genome sequence of strain GG2 may provide insights on the regulation of quorum-sensing and quorum-quenching mechanisms in this bacterium. PMID- 23105063 TI - Complete genome sequence of Brucella melitensis biovar 3 strain NI, isolated from an aborted bovine fetus. AB - From an aborted bovine fetus in China, a bacterial strain named NI was isolated and identified as Brucella melitensis by a PCR assay. Strain NI was further characterized as B. melitensis biovar 3 using biochemical assays. Here we report the complete genome sequence of strain NI. PMID- 23105064 TI - Draft genome sequence of Fusobacterium nucleatum ChDC F128, isolated from a periodontitis lesion. AB - Fusobacterium nucleatum is classified into five subspecies. F. nucleatum ChDC F128 was isolated from a periodontitis lesion and proposed as a new subspecies based on the comparison of the nucleotide sequences of the RNA polymerase beta subunit and zinc protease genes. Here, we report the draft genome sequence of the strain. PMID- 23105065 TI - Draft genome sequence of the xylan-degrading marine bacterium strain S124, representing a novel species of the genus Oceanicola. AB - We isolated a xylan-degrading bacterium from seawater of Micronesia and identified it as Oceanicola sp. strain S124. We sequenced the Oceanicola sp. S124 genome using GSFLX 454 pyrosequencing and predicted 4,433 open reading frames (ORFs) including putative saccharification and phage-related genes. PMID- 23105066 TI - Genome sequence of Pseudomonas mendocina DLHK, isolated from a biotrickling reactor. AB - Pseudomonas mendocina DLHK is an aerobic bacterium isolated from a biotrickling reactor which can remove nitric oxide, a common air pollutant from combustion exhaust gas. Here, we present the draft genome of Pseudomonas mendocina DLHK. PMID- 23105067 TI - Draft genome sequence of the Sulfobacillus thermosulfidooxidans Cutipay strain, an indigenous bacterium isolated from a naturally extreme mining environment in Northern Chile. AB - Sulfobacillus thermosulfidooxidans strain Cutipay is a mixotrophic, acidophilic, moderately thermophilic bacterium isolated from mining environments of the north of Chile, making it an interesting subject for studying the bioleaching of copper. We introduce the draft genome sequence and annotation of this strain, which provide insights into its mechanisms for heavy metal resistance. PMID- 23105068 TI - Draft genome sequence of Pontibacter sp. nov. BAB1700, a halotolerant, industrially important bacterium. AB - Pontibacter sp. nov. BAB1700 is a halotolerant, Gram-negative, rod-shaped, pink pigmented, menaquinone-7-producing bacterium isolated from sediments of a drilling well. The draft genome sequence of the strain, consisting of one chromosome of 4.5 Mb, revealed vital gene clusters involved in vitamin biosynthesis and resistance against various metals and antibiotics. PMID- 23105069 TI - Genome sequence of Dyella japonica strain A8, a quorum-quenching bacterium that degrades N-acylhomoserine lactones, isolated from Malaysian tropical soil. AB - Dyella japonica strain A8 is a Malaysian tropical soil bacterial strain which shows N-acylhomoserine lactone-degrading activity. Here, we present its draft genome sequence. A putative quorum-quenching gene was identified based on the genome sequence analysis of strain A8. To the best of our knowledge, this is the first genome announcement of a member from the genus of Dyella, and this is also the first work that reports the quorum-quenching activity of Dyella japonica. PMID- 23105070 TI - Draft genome sequence of Virgibacillus halodenitrificans 1806. AB - Virgibacillus halodenitrificans 1806 is an endospore-forming halophilic bacterium isolated from salterns in Korea. Here, we report the draft genome sequence of V. halodenitrificans 1806, which may reveal the molecular basis of osmoadaptation and insights into carbon and anaerobic metabolism in moderate halophiles. PMID- 23105071 TI - Draft genome sequence of the volatile organic compound-producing Antarctic bacterium Arthrobacter sp. strain TB23, able to inhibit cystic fibrosis pathogens belonging to the Burkholderia cepacia complex. AB - Arthrobacter sp. strain TB23 was isolated from the Antarctic sponge Lissodendoryx nobilis. This bacterium is able to produce antimicrobial compounds and volatile organic compounds (VOCs) that inhibit the growth of other Antarctic bacteria and of cystic fibrosis opportunistic pathogens, respectively. Here we report the draft genome sequence of Arthrobacter sp. TB23. PMID- 23105072 TI - Whole-genome sequence of the hypervirulent clinical strain Mycobacterium intracellulare M.i.198. AB - We report herein the draft genome sequence of Mycobacterium intracellulare clinical strain M.i.198, which consistently exhibits hypervirulence in human patients, human macrophages in vitro, and immunocompetent mice. PMID- 23105073 TI - Complete genome sequence of Mycobacterium fortuitum subsp. fortuitum type strain DSM46621. AB - Mycobacterium fortuitum is a member of the rapidly growing nontuberculous mycobacteria (NTM). It is ubiquitous in water and soil habitats, including hospital environments. M. fortuitum is increasingly recognized as an opportunistic nosocomial pathogen causing disseminated infection. Here we report the genome sequence of M. fortuitum subsp. fortuitum type strain DSM46621. PMID- 23105074 TI - Complete genome sequence of Mycobacterium vaccae type strain ATCC 25954. AB - Mycobacterium vaccae is a rapidly growing, nontuberculous Mycobacterium species that is generally not considered a human pathogen and is of major pharmaceutical interest as an immunotherapeutic agent. We report here the annotated genome sequence of the M. vaccae type strain, ATCC 25954. PMID- 23105075 TI - Draft genome sequence of a nonhemolytic fish-pathogenic Streptococcus agalactiae strain. AB - Streptococcus agalactiae is a significant Gram-positive bacterial pathogen of terrestrial and aquatic animals. A subpopulation of nonhemolytic strains which appear to be pathogenic only for poikilotherms exists. We report here the first draft genome sequence of a nonhemolytic S. agalactiae isolate recovered from a diseased fish. PMID- 23105076 TI - Genome sequence of the swine pathogen Streptococcus suis serotype 2 strain S735. AB - Streptococcus suis is a major swine pathogen responsible for significant, worldwide economic losses in the swine industry, in addition to being an emerging zoonotic agent. Strains of serotype 2 are the most commonly associated with infections causing meningitis, endocarditis, and septicemia. Here we present the genome sequence of S. suis serotype 2 strain S735. PMID- 23105077 TI - Genome sequence of Pectobacterium carotovorum subsp. carotovorum strain PCC21, a pathogen causing soft rot in Chinese cabbage. AB - Pectobacterium carotovorum is a plant-pathogenic enterobacterium responsible for soft rot in various commercially important plants. Here we report the complete genome sequence and automatic annotation of strain PCC21. PMID- 23105078 TI - Complete genome sequence of Bartonella quintana, a bacterium isolated from rhesus macaques. AB - Bartonella quintana is a re-emerging pathogen and the causative agent of a broad spectrum of disease manifestations in humans. The present study reports the complete genome of B. quintana strain RM_11, which was isolated from rhesus macaques. PMID- 23105079 TI - Draft genome sequence of Alicyclobacillus hesperidum strain URH17-3-68. AB - Alicyclobacillus hesperidum is a thermoacidophilic bacterium. We isolated strain URH17-3-68 from hot spring sludge in Tengchong, Yunnan province, China. Its extracellular products include heat- and acid-stable enzymes which are important for industrial applications. Here we report the draft genome of this strain. PMID- 23105081 TI - Draft genome sequence of an Aeromonas sp. strain 159 clinical isolate that shows quorum-sensing activity. AB - Aeromonas is a pathogenic organism that is often found to infect humans. Here we report the draft genome of a clinical isolate in Malaysia, Aeromonas sp. strain 159, which shows N-acylhomoserine lactone production. In the draft genome of strain 159, luxI and luxR homologue genes were found to be located at contig 47, and these genes are believed to be important for the quorum-sensing system present in this pathogen. PMID- 23105080 TI - Complete genome sequence of Lactobacillus helveticus R0052, a commercial probiotic strain. AB - Lactobacillus helveticus R0052 is a commercially available strain that is widely used in probiotic preparations. The genome sequence consisted of 2,129,425 bases. Comparative analysis showed that it was unique among L. helveticus strains in that it contained genes encoding mucus-binding proteins similar to those found in Lactobacillus acidophilus. PMID- 23105082 TI - Draft genome sequence of Bacillus oceanisediminis 2691. AB - Bacillus oceanisediminis 2691 is an aerobic, Gram-positive, spore-forming, and moderately halophilic bacterium that was isolated from marine sediment of the Yellow Sea coast of South Korea. Here, we report the draft genome sequence of B. oceanisediminis 2691 that may have an important role in the bioremediation of marine sediment. PMID- 23105083 TI - Genome sequence of the halotolerant Staphylococcus sp. strain OJ82, isolated from Korean traditional salt-fermented seafood. AB - Staphylococcus sp. strain OJ82 was isolated from a Korean traditional fermented squid seafood, ojingeo-jeotgal. Staphylococcus sp. OJ82 could grow and show extracellular protease and beta-galactosidase activities in the presence of extremely high saline (20%). Here, we report the genome sequence of Staphylococcus sp. OJ82. PMID- 23105084 TI - Draft genome sequence of Achromobacter piechaudii strain HLE. AB - Achromobacter piechaudii strain HLE is a betaproteobacterium (previously known as Alcaligenes faecalis) that was an early isolate with arsenite oxidase activity. This draft genome of 6.89 Mb is the second available genome for this species in the opportunistic pathogen Alcaligenaceae family. PMID- 23105085 TI - Draft genome sequence determination for cystic fibrosis and chronic granulomatous disease Burkholderia multivorans isolates. AB - Burkholderia multivorans is a Gram-negative bacterium and a member of the Burkholderia cepacia complex, which is frequently associated with respiratory infections in people with cystic fibrosis (CF) and chronic granulomatous disease (CGD). We are reporting the genome sequences of 4 B. multivorans strains, 2 from CF patients and 2 from CGD patients. PMID- 23105086 TI - Whole-genome sequence of Nocardiopsis alba strain ATCC BAA-2165, associated with honeybees. AB - The actinomycete Nocardiopsis alba was reportedly associated with honeybees in separate occurrences. We report the complete genome of Nocardiopsis alba ATCC BAA 2165 isolated from honeybee guts. It will provide insights into the metabolism and genetic regulatory networks of this genus of bacteria that enable them to live in a range of environments. PMID- 23105087 TI - Draft genome sequence of Bacillus anthracis BF-1, isolated from Bavarian cattle. AB - Bacillus anthracis BF-1 was isolated from a cow in Bavaria (Germany) that had succumbed to anthrax. Here, we report the draft genome sequence of this strain, which belongs to the European B2 subclade of B. anthracis. The closest phylogenetic neighbor of strain BF-1 is a strain isolated from cattle in France. PMID- 23105088 TI - Genome sequence of Oscillibacter ruminantium strain GH1, isolated from rumen of Korean native cattle. AB - Oscillibacter ruminantium strain GH1 was isolated from the rumen of Korean native cattle (HanWoo; Bos taurus coreanae). Here, we present the 3.07-Mb draft genome of this strain, which could reveal the presence of certain fiber-specific glycoside hydrolases and butyric acid-producing genes. PMID- 23105089 TI - Draft genome sequence of Rhodovulum sp. strain PH10, a phototrophic alphaproteobacterium isolated from a soil sample of mangrove of Namkhana, India. AB - We report the 4.8-Mb draft genome of Rhodovulum sp. strain PH10, a phototrophic bacterium belonging to class Alphaproteobacteria, isolated from a soil sample collected from the mangrove forest of Namkhana in India. This genome is the first from the genus Rhodovulum and will lead to a better understanding of the genes/pathways involved in activities like phototrophic growth and nitrogen fixation in this group of bacteria. PMID- 23105090 TI - Genome sequence of Lactococcus raffinolactis strain 4877, isolated from natural dairy starter culture. AB - The nonstarter lactic acid bacterium Lactococcus raffinolactis is prevalent in a wide range of environments, such as the dairy environment, but little is known about this species. Here, we present the draft genome of Lactococcus raffinolactis strain 4877, isolated from a natural mesophilic dairy starter culture. PMID- 23105091 TI - Genome sequence of Paenibacillus alvei DSM 29, a secondary invader during European foulbrood outbreaks. AB - Paenibacillus alvei is known as a secondary invader during European foulbrood of honeybees. Here, we announce the 6.83-Mb draft genome sequence of P. alvei type strain DSM 29. Putative genes encoding an antimicrobial peptide, a binary toxin, a mosquitocidal toxin, alveolysin, and different polyketides and nonribosomal peptides were identified. PMID- 23105092 TI - Heavy-metal resistance of a France vineyard soil bacterium, Pseudomonas mendocina strain S5.2, revealed by whole-genome sequencing. AB - Here we present the draft genome of Pseudomonas mendocina strain S5.2, possessing tolerance to a high concentration of copper. In addition to being copper resistant, the genome of P. mendocina strain S5.2 contains a number of heavy metal-resistant genes known to confer resistance to multiple heavy-metal ions. PMID- 23105093 TI - Peroxisome proliferator-activated receptor-gamma activation enhances insulin stimulated glucose disposal by reducing ped/pea-15 gene expression in skeletal muscle cells: evidence for involvement of activator protein-1. AB - The gene network responsible for inflammation-induced insulin resistance remains enigmatic. In this study, we show that, in L6 cells, rosiglitazone- as well as pioglitazone-dependent activation of peroxisome proliferator-activated receptor gamma (PPARgamma) represses transcription of the ped/pea-15 gene, whose increased activity impairs glucose tolerance in mice and humans. Rosiglitazone enhanced insulin-induced glucose uptake in L6 cells expressing the endogenous ped/pea-15 gene but not in cells expressing ped/pea-15 under the control of an exogenous promoter. The ability of PPARgamma to affect ped/pea-15 expression was also lost in cells and in C57BL/6J transgenic mice expressing ped/pea-15 under the control of an exogenous promoter, suggesting that ped/pea-15 repression may contribute to rosiglitazone action on glucose disposal. Indeed, high fat diet mice showed insulin resistance and increased ped/pea-15 levels, although these effects were reduced by rosiglitazone treatment. Both supershift and ChIP assays revealed the presence of the AP-1 component c-JUN at the PED/PEA-15 promoter upon 12-O tetradecanoylphorbol-13-acetate stimulation of the cells. In these experiments, rosiglitazone treatment reduced c-JUN presence at the PED/PEA-15 promoter. This effect was not associated with a decrease in c-JUN expression. In addition, c-jun silencing in L6 cells lowered ped/pea-15 expression and caused nonresponsiveness to rosiglitazone, although c-jun overexpression enhanced the binding to the ped/pea-15 promoter and blocked the rosiglitazone effect. These results indicate that PPARgamma regulates ped/pea-15 transcription by inhibiting c-JUN binding at the ped/pea-15 promoter. Thus, ped/pea-15 is downstream of a major PPARgamma regulated inflammatory network. Repression of ped/pea-15 transcription might contribute to the PPARgamma regulation of muscle sensitivity to insulin. PMID- 23105094 TI - Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits. AB - Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca(2+) rise by these peptides in PC12 cells was: CST-WT > CST Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of alpha-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in ~15% subjects) was strongly associated with profound reduction (up to ~2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders. PMID- 23105095 TI - Liver retinol transporter and receptor for serum retinol-binding protein (RBP4). AB - Vitamin A (retinol) is absorbed in the small intestine, stored in liver, and secreted into circulation bound to serum retinol-binding protein (RBP4). Circulating retinol may be taken up by extrahepatic tissues or recycled back to liver multiple times before it is finally metabolized or degraded. Liver exhibits high affinity binding sites for RBP4, but specific receptors have not been identified. The only known high affinity receptor for RBP4, Stra6, is not expressed in the liver. Here we report discovery of RBP4 receptor-2 (RBPR2), a novel retinol transporter expressed primarily in liver and intestine and induced in adipose tissue of obese mice. RBPR2 is structurally related to Stra6 and highly conserved in vertebrates, including humans. Expression of RBPR2 in cultured cells confers high affinity RBP4 binding and retinol transport, and RBPR2 knockdown reduces RBP4 binding/retinol transport. RBPR2 expression is suppressed by retinol and retinoic acid and correlates inversely with liver retinol stores in vivo. We conclude that RBPR2 is a novel retinol transporter that potentially regulates retinol homeostasis in liver and other tissues. In addition, expression of RBPR2 in liver and fat suggests a possible role in mediating established metabolic actions of RBP4 in those tissues. PMID- 23105096 TI - Rab26 modulates the cell surface transport of alpha2-adrenergic receptors from the Golgi. AB - The molecular mechanisms underlying the transport from the Golgi to the cell surface of G protein-coupled receptors remain poorly elucidated. Here we determined the role of Rab26, a Ras-like small GTPase involved in vesicle mediated secretion, in the cell surface export of alpha(2)-adrenergic receptors. We found that transient expression of Rab26 mutants and siRNA-mediated depletion of Rab26 significantly attenuated the cell surface numbers of alpha(2A)-AR and alpha(2B)-AR, as well as ERK1/2 activation by alpha(2B)-AR. Furthermore, the receptors were extensively arrested in the Golgi by Rab26 mutants and siRNA. Moreover, Rab26 directly and activation-dependently interacted with alpha(2B)-AR, specifically the third intracellular loop. These data demonstrate that the small GTPase Rab26 regulates the Golgi to cell surface traffic of alpha(2)-adrenergic receptors, likely through a physical interaction. These data also provide the first evidence implicating an important function of Rab26 in coordinating plasma membrane protein transport. PMID- 23105097 TI - Interleukin 1beta regulation of FoxO1 protein content and localization: evidence for a novel ceramide-dependent mechanism. AB - FoxO1 transcription factor controls the glucose and lipid metabolism, as well as cell proliferation and stress response. Akt, activated by insulin and other growth factors, phosphorylates FoxO1 causing its nuclear export and activity suppression. In this manuscript, we show that IL-1beta, a pro-inflammatory cytokine, has the opposite effects on FoxO1. IL-1beta stimulation of primary rat hepatocytes and HEK293 cells overexpressing the IL-1beta receptor (293-IL-1RI) results in increased nuclear and cytosolic FoxO1 protein but not mRNA levels. IL 1beta stimulation also elevates the levels of a mutant FoxO1 that is resistant to Akt phosphorylation. This suggests that an Akt-independent mechanism is involved. Co-stimulation with insulin does not affect the IL-1beta induction of FoxO1. The IL-1beta effects on FoxO1 are counteracted, however, by the silencing or inhibition of neutral sphingomyelinase 2 (nSMase-2) using shRNAi, scyphostatin, or GW4869, as well as by the pharmacological inhibition of JNK and ERK. Reversely, the overexpression of nSMase-2 through adenovirus-mediated gene transfer potentiates, in a JNK- and ERK-dependent manner, the IL-1beta effects. We also show that transcription of insulin-like growth factor-binding protein-1 mRNA, which requires active FoxO1, is stimulated by IL-1beta and is suppressed by the inhibition of nSMase-2 and JNK. In conclusion, we propose that IL-1beta regulates FoxO1 activity through a novel nSMase-2-dependent pathway. PMID- 23105098 TI - Resveratrol inhibits the proliferation of neural progenitor cells and hippocampal neurogenesis. AB - Resveratrol is a phytoalexin and natural phenol that is present at relatively high concentrations in peanuts and red grapes and wine. Based upon studies of yeast and invertebrate models, it has been proposed that ingestion of resveratrol may also have anti-aging actions in mammals including humans. It has been suggested that resveratrol exerts its beneficial effects on health by activating the same cellular signaling pathways that are activated by dietary energy restriction (DR). Some studies have reported therapeutic actions of resveratrol in animal models of metabolic and neurodegenerative disorders. However, the effects of resveratrol on cell, tissue and organ function in healthy subjects are largely unknown. In the present study, we evaluated the potential effects of resveratrol on the proliferation and survival of neural progenitor cells (NPCs) in culture, and in the hippocampus of healthy young adult mice. Resveratrol reduced the proliferation of cultured mouse multi-potent NPCs, and activated AMP activated protein kinase (AMPK), in a concentration-dependent manner. Administration of resveratrol to mice (1-10 mg/kg) resulted in activation of AMPK, and reduced the proliferation and survival of NPCs in the dentate gyrus of the hippocampus. Resveratrol down-regulated the levels of the phosphorylated form of cyclic AMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus. Finally, resveratrol-treated mice exhibited deficits in hippocampus-dependent spatial learning and memory. Our findings suggest that resveratrol, unlike DR, adversely affects hippocampal neurogenesis and cognitive function by a mechanism involving activation of AMPK and suppression of CREB and BDNF signaling. PMID- 23105099 TI - A novel role of Kruppel-like factor 8 in DNA repair in breast cancer cells. AB - Kruppel-like factor 8 (KLF8) regulates critical gene transcription and cellular events associated with cancer. However, the role of KLF8 in cancer remains largely unknown. Here, we report a surprisingly novel role for KLF8 in DNA repair in breast cancer cells. Comet, clonogenic, and WST-1 assays showed that KLF8 expression is required for protecting human breast cancer cells from doxorubicin induced DNA damage and cell death. Western blotting indicated that overexpression of ectopic KLF8 attenuated the levels of the DNA damage marker gammaH2A.X in doxorubicin-treated PARP-1(+/+) but not PARP-1(-/-) mouse embryonic fibroblasts, whereas the PARP-1-binding-defective KLF8 mutant failed to do so. Interestingly, in response to the DNA damage, KLF8 was phosphorylated by the DNA-dependent protein kinase catalytic subunit and, subsequently, SUMOylated by SUMO E3 ligases protein inhibitors of activated STAT (PIASs), which depends upon the interaction of KLF8 with DNA-dependent protein kinase catalytic subunit, PIASs, and PARP-1 as well as their enzymatic activities. Lastly, we show evidence that KLF8 was recruited to the DNA damage site. These results suggest a novel role and mechanism for KLF8 in the regulation of DNA repair and therapeutic resistance in breast cancer cells. PMID- 23105100 TI - Multiple evolutionarily conserved Di-leucine like motifs in the carboxyl terminus control the anterograde trafficking of NKCC2. AB - Mutations in the apical Na-K-2Cl co-transporter, NKCC2, cause type I Bartter syndrome, a life-threatening kidney disease. Yet the mechanisms underlying the regulation of NKCC2 trafficking in renal cells are scarcely known. We previously showed that naturally occurring mutations depriving NKCC2 of its distal COOH terminal tail and interfering with the (1081)LLV(1083) motif result in defects in the ER exit of the co-transporter. Here we show that this motif is necessary but not sufficient for anterograde trafficking of NKCC2. Indeed, we have identified two additional hydrophobic motifs, (1038)LL(1039) and (1048)LI(1049), that are required for ER exit and surface expression of the co-transporter. Double mutations of (1038)LL(1039) or (1048)LI(1049) to di-alanines disrupted glycosylation and cell surface expression of NKCC2, independently of the expression system. Pulse-chase analysis demonstrated that the absence of the terminally glycosylated form of NKCC2 was not due to reduced synthesis or increased rates of degradation of mutant co-transporters, but was instead caused by defects in maturation. Co-immunolocalization experiments revealed that (1038)AA(1039) and (1048)AA(1049) were trapped mainly in the ER as indicated by extensive co-localization with the ER marker calnexin. Remarkably, among several analyzed motifs present in the NKCC2 COOH terminus, only those required for ER exit and surface expression of NKCC2 are evolutionarily conserved in all members of the SLC12A family, a group of cation-chloride co-transporters that are targets of therapeutic drugs and mutated in several human diseases. Based upon these data, we propose abnormal anterograde trafficking as a common mechanism associated with mutations depriving NKCC2, and also all other members of the SLC12A family, of their COOH terminus. PMID- 23105101 TI - The phosphatase PTP-PEST/PTPN12 regulates endothelial cell migration and adhesion, but not permeability, and controls vascular development and embryonic viability. AB - Protein-tyrosine phosphatase (PTP)-PEST (PTPN12) is ubiquitously expressed. It is essential for normal embryonic development and embryonic viability in mice. Herein we addressed the involvement of PTP-PEST in endothelial cell functions using a combination of genetic and biochemical approaches. By generating primary endothelial cells from an inducible PTP-PEST-deficient mouse, we found that PTP PEST is not needed for endothelial cell differentiation and proliferation or for the control of endothelial cell permeability. Nevertheless, it is required for integrin-mediated adhesion and migration of endothelial cells. PTP-PEST-deficient endothelial cells displayed increased tyrosine phosphorylation of Cas, paxillin, and Pyk2, which were previously also implicated in integrin functions. By eliminating PTP-PEST in endothelial cells in vivo, we obtained evidence that expression of PTP-PEST in endothelial cells is required for normal vascular development and embryonic viability. Therefore, PTP-PEST is a key regulator of integrin-mediated functions in endothelial cells seemingly through its capacity to control Cas, paxillin, and Pyk2. This function explains at least in part the essential role of PTP-PEST in embryonic development and viability. PMID- 23105102 TI - Dynamic phosphorylation of tyrosine 665 in pseudopodium-enriched atypical kinase 1 (PEAK1) is essential for the regulation of cell migration and focal adhesion turnover. AB - Pseudopodium-enriched atypical kinase 1 (PEAK1) is a recently described tyrosine kinase that associates with the actin cytoskeleton and focal adhesion (FA) in migrating cells. PEAK1 is known to promote cell migration, but the responsible mechanisms remain unclear. Here, we show that PEAK1 controls FA assembly and disassembly in a dynamic pathway controlled by PEAK1 phosphorylation at Tyr-665. Knockdown of endogenous PEAK1 inhibits random cell migration. In PEAK1-deficient cells, FA lifetimes are decreased, FA assembly times are shortened, and FA disassembly times are extended. Phosphorylation of Tyr-665 in PEAK1 is essential for normal PEAK1 localization and its function in the regulation of FAs; however, constitutive phosphorylation of PEAK1 Tyr-665 is also disruptive of its function, indicating a requirement for precise spatiotemporal regulation of PEAK1. Src family kinases are required for normal PEAK1 localization and function. Finally, we provide evidence that PEAK1 promotes cancer cell invasion through Matrigel by a mechanism that requires dynamic regulation of Tyr-665 phosphorylation. PMID- 23105103 TI - Involvement of GDH3-encoded NADP+-dependent glutamate dehydrogenase in yeast cell resistance to stress-induced apoptosis in stationary phase cells. AB - Glutamate metabolism is linked to a number of fundamental metabolic pathways such as amino acid metabolism, the TCA cycle, and glutathione (GSH) synthesis. In the yeast Saccharomyces cerevisiae, glutamate is synthesized from alpha-ketoglutarate by two NADP(+)-dependent glutamate dehydrogenases (NADP-GDH) encoded by GDH1 and GDH3. Here, we report the relationship between the function of the NADP-GDH and stress-induced apoptosis. Gdh3-null cells showed accelerated chronological aging and hypersusceptibility to thermal and oxidative stress during stationary phase. Upon exposure to oxidative stress, Gdh3-null strains displayed a rapid loss in viability associated with typical apoptotic hallmarks, i.e. reactive oxygen species accumulation, nuclear fragmentation, DNA breakage, and phosphatidylserine translocation. In addition, Gdh3-null cells, but not Gdh1-null cells, had a higher tendency toward GSH depletion and subsequent reactive oxygen species accumulation than did WT cells. GSH depletion was rescued by exogenous GSH or glutamate. The hypersusceptibility of stationary phase Gdh3-null cells to stress induced apoptosis was suppressed by deletion of GDH2. Promoter swapping and site directed mutagenesis of GDH1 and GDH3 indicated that the necessity of GDH3 for the resistance to stress-induced apoptosis and chronological aging is due to the stationary phase-specific expression of GDH3 and concurrent degradation of Gdh1 in which the Lys-426 residue plays an essential role. PMID- 23105104 TI - Role of p70S6K1-mediated phosphorylation of eIF4B and PDCD4 proteins in the regulation of protein synthesis. AB - Modulation of mRNA binding to the 40 S ribosomal subunit during translation initiation controls not only global rates of protein synthesis but also regulates the pattern of protein expression by allowing for selective inclusion, or exclusion, of mRNAs encoding particular proteins from polysomes. The mRNA binding step is modulated by signaling through a protein kinase known as the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 directly phosphorylates the translational repressors eIF4E binding proteins (4E-BP) 1 and 2, releasing them from the mRNA cap binding protein eIF4E, thereby promoting assembly of the eIF4E.eIF4G complex. mTORC1 also phosphorylates the 70-kDa ribosomal protein S6 kinase 1 (p70S6K1), which subsequently phosphorylates eIF4B, and programmed cell death 4 (PDCD4), which sequesters eIF4A from the eIF4E.eIF4G complex, resulting in repressed translation of mRNAs with highly structured 5'-untranslated regions. In the present study, we compared the role of the 4E-BPs in the regulation of global rates of protein synthesis to that of eIF4B and PDCD4. We found that maintenance of eIF4E interaction with eIF4G was not by itself sufficient to sustain global rates of protein synthesis in the absence of mTORC1 signaling to p70S6K1; phosphorylation of both eIF4B and PDCD4 was additionally required. We also found that the interaction of eIF4E with eIF4G was maintained in the liver of fasted rats as well as in serum-deprived mouse embryo fibroblasts lacking both 4E-BP1 and 4E-BP2, suggesting that the interaction of eIF4G with eIF4E is controlled primarily through the 4E-BPs. PMID- 23105105 TI - Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. AB - Tauopathies are a class of neurodegenerative diseases marked by intracellular aggregates of hyperphosphorylated Tau. These diseases may occur by sporadic mechanisms in which genetic variants represent risk factors for disease, as is the case in Alzheimer disease (AD). In AD, cerebrospinal fluid (CSF) levels of soluble Tau/pTau-181 are higher in cases compared with controls. A subset of frontotemporal dementia (FTD) cases occur by a familial mechanism in which MAPT, the gene that encodes Tau, mutations are dominantly inherited. In symptomatic FTD patients expressing a MAPT mutation, CSF Tau levels are slightly elevated but are significantly lower than in AD patients. We sought to model CSF Tau changes by measuring extracellular Tau in cultured cells. Full-length, monomeric extracellular total Tau and pTau-181 were detectable in human neuroblastoma cells expressing endogenous Tau, in human non-neuronal cells overexpressing wild-type Tau, and in mouse cortical neurons. Tau isoforms influence the rate of Tau release, whereby the N terminus (exons 2/3) and microtubule binding repeat length contribute to Tau release from the cell. Compared with cells overexpressing wild type Tau, cells overexpressing FTD-associated MAPT mutations produce significantly less extracellular total Tau without altering intracellular total Tau levels. This study demonstrates that cells actively release Tau in the absence of disease or toxicity, and Tau release is modified by changes in the Tau protein that are associated with tauopathies. PMID- 23105106 TI - Interactions of the human LIP5 regulatory protein with endosomal sorting complexes required for transport. AB - The endosomal sorting complex required for transport (ESCRT) pathway remodels membranes during multivesicular body biogenesis, the abscission stage of cytokinesis, and enveloped virus budding. The ESCRT-III and VPS4 ATPase complexes catalyze the membrane fission events associated with these processes, and the LIP5 protein helps regulate their interactions by binding directly to a subset of ESCRT-III proteins and to VPS4. We have investigated the biochemical and structural basis for different LIP5-ligand interactions and show that the first microtubule-interacting and trafficking (MIT) module of the tandem LIP5 MIT domain binds CHMP1B (and other ESCRT-III proteins) through canonical type 1 MIT interacting motif (MIM1) interactions. In contrast, the second LIP5 MIT module binds with unusually high affinity to a novel MIM element within the ESCRT-III protein CHMP5. A solution structure of the relevant LIP5-CHMP5 complex reveals that CHMP5 helices 5 and 6 and adjacent linkers form an amphipathic "leucine collar" that wraps almost completely around the second LIP5 MIT module but makes only limited contacts with the first MIT module. LIP5 binds MIM1-containing ESCRT III proteins and CHMP5 and VPS4 ligands independently in vitro, but these interactions are coupled within cells because formation of stable VPS4 complexes with both LIP5 and CHMP5 requires LIP5 to bind both a MIM1-containing ESCRT-III protein and CHMP5. Our studies thus reveal how the tandem MIT domain of LIP5 binds different types of ESCRT-III proteins, promoting assembly of active VPS4 enzymes on the polymeric ESCRT-III substrate. PMID- 23105107 TI - Structural basis of molecular recognition between ESCRT-III-like protein Vps60 and AAA-ATPase regulator Vta1 in the multivesicular body pathway. AB - The AAA-ATPase Vps4 is critical for function of the multivesicular body sorting pathway, which impacts cellular phenomena ranging from receptor down-regulation to viral budding to cytokinesis. Vps4 activity is stimulated by the interaction between Vta1 and Vps60, but the structural basis for this interaction is unclear. The fragment Vps60(128-186) was reported to display the full activity of Vps60. Vta1 interacts with Vps60 using its N-terminal domain (Vta1NTD). In this work, the structure of Vps60(128-186) in complex with Vta1NTD was determined using NMR techniques, demonstrating a novel recognition mode of the microtubule-interacting and transport (MIT) domain in which Vps60(128-186) interacts with Vta1NTD through helices alpha4' and alpha5', extending over Vta1NTD MIT2 domain helices 1-3. The Vps60 binding does not result in Vta1 conformational changes, further revealing the fact that Vps4 ATPase is enhanced by the interaction between Vta1 and Vps60 in an unanticipated manner. PMID- 23105108 TI - Crystal structures of tubulin acetyltransferase reveal a conserved catalytic core and the plasticity of the essential N terminus. AB - Tubulin acetyltransferase (TAT) acetylates Lys-40 of alpha-tubulin in the microtubule lumen. TAT is inefficient, and its activity is enhanced when tubulin is incorporated in microtubules. Acetylation is associated with stable microtubules and regulates the binding of microtubule motors and associated proteins. TAT is important in neuronal polarity and mechanosensation, and decreased tubulin acetylation levels are associated with axonal transport defects and neurodegeneration. We present the first structure of TAT in complex with acetyl-CoA (Ac-CoA) at 2.7 A resolution. The structure reveals a conserved stable catalytic core shared with other GCN5 superfamily acetyltransferases consisting of a central beta-sheet flanked by alpha-helices and a C-terminal beta-hairpin unique to TAT. Structure-guided mutagenesis establishes the molecular determinants for Ac-CoA and tubulin substrate recognition. The wild-type TAT construct is a monomer in solution. We identify a metastable interface between the conserved core and N-terminal domain that modulates the oligomerization of TAT in solution and is essential for activity. The 2.45 A resolution structure of an inactive TAT construct with an active site point mutation near this interface reveals a domain-swapped dimer in which the functionally essential N terminus shows evidence of marked structural plasticity. The sequence segment corresponding to this structurally plastic region in TAT has been implicated in substrate recognition in other GCN5 superfamily acetyltransferases. Our structures provide a rational platform for the mechanistic dissection of TAT activity and the design of TAT inhibitors with therapeutic potential in neuronal regeneration. PMID- 23105109 TI - Direct and indirect control of mitogen-activated protein kinase pathway associated components, BRAP/IMP E3 ubiquitin ligase and CRAF/RAF1 kinase, by the deubiquitylating enzyme USP15. AB - The opposing regulators of ubiquitylation status, E3 ligases and deubiquitylases, are often found to be associated in complexes. Here we report on a novel interaction between the E3 ligase BRAP (also referred to as IMP), a negative regulator of the MAPK scaffold protein KSR, and two closely related deubiquitylases, USP15 and USP4. We map the interaction to the N-terminal DUSP UBL domain of USP15 and the coiled coil region of BRAP. USP15 as well as USP4 oppose the autoubiquitylation of BRAP, whereas BRAP promotes the ubiquitylation of USP15. Importantly, USP15 but not USP4 depletion destabilizes BRAP by promoting its proteasomal degradation, and BRAP-protein levels can be rescued by reintroducing catalytically active but not inactive mutant USP15. Unexpectedly, USP15 depletion results in a decrease in amplitude of MAPK signaling in response to EGF and PDGF. We provide evidence for a model in which the dominant effect of prolonged USP15 depletion upon signal amplitude is due to a decrease in CRAF levels while allowing for the possibility that USP15 may also function to dampen MAPK signaling through direct stabilization of a negative regulator, the E3 ligase BRAP. PMID- 23105110 TI - MicroRNAs in the imprinted DLK1-DIO3 region repress the epithelial-to-mesenchymal transition by targeting the TWIST1 protein signaling network. AB - Development of metastatic disease accounts for the vast majority of cancer related deaths. Nevertheless, few treatments exist that are designed to specifically inhibit processes that drive tumor metastasis. The imprinted DLK1 DIO3 region contains tumor-suppressing miRNAs, but their identity and function remain indeterminate. In this study we identify seven miRNAs in the imprinted DLK1-DIO3 region that function cooperatively to repress the epithelial-to mesenchymal transition, a critical step that drives tumor metastasis, as well as proliferation of carcinoma cells. These seven miRNAs (miRs 300, 382, 494, 495, 539, 543, and 544) repress a signaling network comprising TWIST1, BMI1, ZEB1/2, and miR-200 family miRNAs and silencing of the cluster, which occurs via hypermethylation of upstream CpG islands in human ductal carcinomas, confers morphological, molecular, and function changes consistent with an epithelial-to mesenchymal transition. Moreover, ectopic expression of miR-544 independently inhibited proliferation of numerous tumor cell lines by inducing the ATM cell cycle checkpoint pathway. These results establish the DLKI-DIO3 miRNA cluster as a critical checkpoint regulating tumor growth and metastasis and implicate epigenetic modification of the cluster in driving tumor progression. These results also suggest that promoter methylation status and miRNA expression levels represent new diagnostic tools and therapeutic targets to predict and inhibit, respectively, tumor metastasis in carcinoma patients. PMID- 23105111 TI - The lifetime of UDP-galactose:ceramide galactosyltransferase is controlled by a distinct endoplasmic reticulum-associated degradation (ERAD) regulated by sigma-1 receptor chaperones. AB - The glycosphingolipid biosynthesis is initiated by monoglycosylation of ceramides, the action of which is catalyzed either by UDP-glucose:ceramide glucosyltransferase or by UDP-galactose:ceramide galactosyltransferase (CGalT). CGalT is expressed predominantly at the endoplasmic reticulum (ER) of oligodendrocytes and is responsible for synthesizing galactosylceramides (GalCer) that play an important role in regulation of axon conductance. However, despite the importance of ceramide monoglycosylation enzymes in a spectrum of cellular functions, the mechanism that fine tunes activities of those enzymes is largely unknown. In the present study, we demonstrated that the sigma-1 receptor (Sig-1R) chaperone, the mammalian homologue of a yeast C8-C7 sterol isomerase, controls the protein level and activity of the CGalT enzyme via a distinct ER-associated degradation system involving Insig. The Sig-1R forms a complex with Insig via its transmembrane domain partly in a sterol-dependent manner and associates with CGalT at the ER. The knockdown of Sig-1Rs dramatically prolonged the lifetime of CGalT without affecting the trimming of N-linked oligosaccharides at CGalT. The increased lifetime leads to the up-regulation of CGalT protein as well as elevated enzymatic activity in CHO cells stably expressing CGalT. Knockdown of Sig-1Rs also decreased CGalT degradation endogenously expressed in D6P2T schwannoma cells. Our data suggest that Sig-1Rs negatively regulate the activity of GalCer synthesis under physiological conditions by enhancing the degradation of CGalT through regulation of the dynamics of Insig in the lipid-activated ER associated degradation system. The GalCer synthesis may thus be influenced by sterols at the ER. PMID- 23105112 TI - The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by gamma-secretase. AB - Cleavage of transmembrane receptors by gamma-secretase is the final step in the process of regulated intramembrane proteolysis (RIP) and has a significant impact on receptor function. Although relatively little is known about the molecular mechanism of gamma-secretase enzymatic activity, it is becoming clear that substrate dimerization and/or the alpha-helical structure of the substrate can regulate the site and rate of gamma-secretase activity. Here we show that the transmembrane domain of the pan-neurotrophin receptor p75(NTR), best known for regulating neuronal death, is sufficient for its homodimerization. Although the p75(NTR) ligands NGF and pro-NGF do not induce homerdimerization or RIP, homodimers of p75(NTR) are gamma-secretase substrates. However, dimerization is not a requirement for p75(NTR) cleavage, suggesting that gamma-secretase has the ability to recognize and cleave each receptor molecule independently. The transmembrane cysteine 257, which mediates covalent p75(NTR) interactions, is not crucial for homodimerization, but this residue is required for normal rates of gamma-secretase cleavage. Similarly, mutation of the residues alanine 262 and glycine 266 of an AXXXG dimerization motif flanking the gamma-secretase cleavage site within the p75(NTR) transmembrane domain alters the orientation of the domain and inhibits gamma-secretase cleavage of p75(NTR). Nonetheless, heteromer interactions of p75(NTR) with TrkA increase full-length p75(NTR) homodimerization, which in turn potentiates the rate of gamma-cleavage following TrkA activation independently of rates of alpha-cleavage. These results provide support for the idea that the helical structure of the p75(NTR) transmembrane domain, which may be affected by co-receptor interactions, is a key element in gamma-secretase-catalyzed cleavage. PMID- 23105113 TI - Mapping of the interaction site between sortilin and the p75 neurotrophin receptor reveals a regulatory role for the sortilin intracellular domain in p75 neurotrophin receptor shedding and apoptosis. AB - Neurotrophins comprise a group of neuronal growth factors that are essential for the development and maintenance of the nervous system. However, the immature pro neurotrophins promote apoptosis by engaging in a complex with sortilin and the p75 neurotrophin receptor (p75(NTR)). To identify the interaction site between sortilin and p75(NTR), we analyzed binding between chimeric receptor constructs and truncated p75(NTR) variants by co-immunoprecipitation experiments, surface plasmon resonance analysis, and FRET. We found that complex formation between sortilin and p75(NTR) relies on contact points in the extracellular domains of the receptors. We also determined that the interaction critically depends on an extracellular juxtamembrane 23-amino acid sequence of p75(NTR). Functional studies further revealed an important regulatory function of the sortilin intracellular domain in p75(NTR)-regulated intramembrane proteolysis and apoptosis. Thus, although the intracellular domain of sortilin does not contribute to p75(NTR) binding, it does regulate the rates of p75(NTR) cleavage, which is required to mediate pro-neurotrophin-stimulated cell death. PMID- 23105114 TI - Retinoic acid induces neurogenesis by activating both retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta). AB - Retinoic acid (RA) regulates gene transcription by activating the nuclear receptors retinoic acid receptor (RAR) and peroxisome proliferator-activated receptor (PPAR) beta/delta and their respective cognate lipid-binding proteins CRABP-II and FABP5. RA induces neuronal differentiation, but the contributions of the two transcriptional pathways of the hormone to the process are unknown. Here, we show that the RA-induced commitment of P19 stem cells to neuronal progenitors is mediated by the CRABP-II/RAR path and that the FABP5/PPARbeta/delta path can inhibit the process through induction of the RAR repressors SIRT1 and Ajuba. In contrast with its inhibitory activity in the early steps of neurogenesis, the FABP5/PPARbeta/delta path promotes differentiation of neuronal progenitors to mature neurons, an activity mediated in part by the PPARbeta/delta target gene PDK1. Hence, RA-induced neuronal differentiation is mediated through RAR in the early stages and through PPARbeta/delta in the late stages of the process. The switch in RA signaling is accomplished by a transient up-regulation of RARbeta concomitantly with a transient increase in the CRABP-II/FABP5 ratio at early stages of differentiation. In accordance with these conclusions, hippocampi of FABP5-null mice display excess accumulation of neuronal progenitor cells and a deficit in mature neurons versus wild-type animals. PMID- 23105115 TI - Naturally occurring carboxypeptidase A6 mutations: effect on enzyme function and association with epilepsy. AB - Carboxypeptidase A6 (CPA6) is a member of the A/B subfamily of M14 metallocarboxypeptidases that is expressed in brain and many other tissues during development. Recently, two mutations in human CPA6 were associated with febrile seizures and/or temporal lobe epilepsy. In this study we screened for additional CPA6 mutations in patients with febrile seizures and focal epilepsy, which encompasses the temporal lobe epilepsy subtype. Mutations found from this analysis as well as CPA6 mutations reported in databases of single nucleotide polymorphisms were further screened by analysis of the modeled proCPA6 protein structure and the functional role of the mutated amino acid. The point mutations predicted to affect activity and/or protein folding were tested by expression of the mutant in HEK293 cells and analysis of the resulting CPA6 protein. Common polymorphisms in CPA6 were also included in this analysis. Several mutations resulted in reduced enzyme activity or CPA6 protein levels in the extracellular matrix. The mutants with reduced extracellular CPA6 protein levels showed normal levels of 50-kDa proCPA6 in the cell, and this could be converted into 37-kDa CPA6 by trypsin, suggesting that protein folding was not greatly affected by the mutations. Interestingly, three of the mutations that reduced extracellular CPA6 protein levels were found in patients with epilepsy. Taken together, these results provide further evidence for the involvement of CPA6 mutations in human epilepsy and reveal additional rare mutations that inactivate CPA6 and could, therefore, also be associated with epileptic phenotypes. PMID- 23105116 TI - Identification of novel interaction between ADAM17 (a disintegrin and metalloprotease 17) and thioredoxin-1. AB - ADAM17, which is also known as TNFalpha-converting enzyme, is the major sheddase for the EGF receptor ligands and is considered to be one of the main proteases responsible for the ectodomain shedding of surface proteins. How a membrane anchored proteinase with an extracellular catalytic domain can be activated by inside-out regulation is not completely understood. We characterized thioredoxin 1 (Trx-1) as a partner of the ADAM17 cytoplasmic domain that could be involved in the regulation of ADAM17 activity. We induced the overexpression of the ADAM17 cytoplasmic domain in HEK293 cells, and ligands able to bind this domain were identified by MS after protein immunoprecipitation. Trx-1 was also validated as a ligand of the ADAM17 cytoplasmic domain and full-length ADAM17 recombinant proteins by immunoblotting, immunolocalization, and solid phase binding assay. In addition, using nuclear magnetic resonance, it was shown in vitro that the titration of the ADAM17 cytoplasmic domain promotes changes in the conformation of Trx-1. The MS analysis of the cross-linked complexes showed cross-linking between the two proteins by lysine residues. To further evaluate the functional role of Trx-1, we used a heparin-binding EGF shedding cell model and observed that the overexpression of Trx-1 in HEK293 cells could decrease the activity of ADAM17, activated by either phorbol 12-myristate 13-acetate or EGF. This study identifies Trx-1 as a novel interaction partner of the ADAM17 cytoplasmic domain and suggests that Trx-1 is a potential candidate that could be involved in ADAM17 activity regulation. PMID- 23105118 TI - The M2 module of the Cys-His-rich domain (CHRD) of PCSK9 protein is needed for the extracellular low-density lipoprotein receptor (LDLR) degradation pathway. AB - PCSK9 enhances the cellular degradation of the LDL receptor (LDLR), leading to increased plasma LDL cholesterol. This multidomain protein contains a prosegment, a catalytic domain, a hinge region, and a cysteine-histidine rich domain (CHRD) composed of three tightly packed modules named M1, M2, and M3. The CHRD is required for the activity of PCSK9, but the mechanism behind this remains obscure. To define the contribution of each module to the function of PCSK9, we dissected the CHRD structure. Six PCSK9 deletants were generated by mutagenesis, corresponding to the deletion of only one (DeltaM1, DeltaM2, DeltaM3) or two (DeltaM12, DeltaM13, DeltaM23) modules. Transfection of HEK293 cells showed that all deletants were well processed and expressed compared with the parent PCSK9 but that only those lacking the M2 module were secreted. HepG2 cells lacking endogenous PCSK9 (HepG2/shPCSK9) were used for the functional analysis of the extracellular or intracellular activity of PCSK9 and its deletants. To analyze the ability of the deletants to enhance the LDLR degradation by the intracellular pathway, cellular expressions revealed that only the DeltaM2 deletant retains a comparable total LDLR-degrading activity to full-length PCSK9. To probe the extracellular pathway, HepG2/shPCSK9 cells were incubated with conditioned media from transfected HEK293 or HepG2/shPCSK9 cells, and cell surface LDLR levels were analyzed by FACS. The results showed no activity of any secreted deletant compared with PCSK9. Thus, although M2 is dispensable for secretion, its presence is required for the extracellular activity of PCSK9 on cell surface LDLR. PMID- 23105117 TI - Human VRK2 (vaccinia-related kinase 2) modulates tumor cell invasion by hyperactivation of NFAT1 and expression of cyclooxygenase-2. AB - Human VRK2 (vaccinia-related kinase 2), a kinase that emerged late in evolution, affects different signaling pathways, and some carcinomas express high levels of VRK2. Invasion by cancer cells has been associated with NFAT1 (nuclear factor of activated T cells) activation and expression of the COX-2 (cyclooxygenase 2) gene. We hypothesized that VRK proteins might play a regulatory role in NFAT1 activation in tumor cells. We demonstrate that VRK2 directly interacts and phosphorylates NFAT1 in Ser-32 within its N-terminal transactivation domain. VRK2 increases NFAT1-dependent transcription by phosphorylation, and this effect is only detected following cell phorbol 12-myristate 13-acetate and ionomycin stimulation and calcineurin activation. This NFAT1 hyperactivation by VRK2 increases COX-2 gene expression through the proximal NFAT1 binding site in the COX-2 gene promoter. Furthermore, VRK2A down-regulation by RNA interference reduces COX-2 expression at transcriptional and protein levels. Therefore, VRK2 down-regulation reduces cell invasion by tumor cells, such as MDA-MB-231 and MDA MB-435, upon stimulation with phorbol 12-myristate 13-acetate plus ionomycin. These findings identify the first reported target and function of human VRK2 as an active kinase playing a role in regulation of cancer cell invasion through the NFAT pathway and COX-2 expression. PMID- 23105121 TI - Infantile adrenocortical tumor with an activating GNAS1 mutation. AB - CONTEXT: Pediatric adrenocortical tumors (ACTs) are rare and are frequently associated with tumor predisposition syndromes. Somatic GNAS1 mutations are associated with adrenocortical hyperplasia, but have not typically been reported in ACTs. OBJECTIVE: We report on genetic and histopathological findings in a 3 month-old infant presenting with a unilateral cortisol-producing ACT with malignant features. METHODS: We performed a detailed clinical evaluation of the patient along with molecular genetic testing of genes associated with ACTs in both tumor tissue and peripheral lymphocytes. We also performed a histopathological analysis of the tumor tissue. RESULTS: The patient was found to have a p.R201C-activating mutation in exon 8 of the GNAS1 gene in adrenocortical tumor tissue but not peripheral lymphocytes. This mutation is the characteristic genetic change in McCune-Albright syndrome. In contrast to previously reported GNAS1-positive tumors characterized by bimodal diffuse and nodular adrenocortical hypertrophy, our patient had a single adrenocortical mass that showed features of malignancy, including areas of necrosis, microcystic degeneration, and venous and capsular microinvasion-changes that have been seen previously in Beckwith Wiedemann syndrome. However, our patient did not have clinical features of Beckwith-Wiedemann syndrome. Further analysis revealed abnormal allele-specific hypomethylation of the KCNQ1OT1 gene in the tumor sample but not peripheral lymphocytes. CONCLUSION: This is a novel case of an activating GNAS1 mutation associated with an epigenetic alteration that may be related to adrenocortical tumorigenesis. Our findings may have implications in the molecular pathogenesis of pediatric ACTs. PMID- 23105119 TI - Roles of subunit NuoK (ND4L) in the energy-transducing mechanism of Escherichia coli NDH-1 (NADH:quinone oxidoreductase). AB - The bacterial H(+)-translocating NADH:quinone oxidoreductase (NDH-1) catalyzes electron transfer from NADH to quinone coupled with proton pumping across the cytoplasmic membrane. The NuoK subunit (counterpart of the mitochondrial ND4L subunit) is one of the seven hydrophobic subunits in the membrane domain and bears three transmembrane segments (TM1-3). Two glutamic residues located in the adjacent transmembrane helices of NuoK are important for the energy coupled activity of NDH-1. In particular, mutation of the highly conserved carboxyl residue ((K)Glu-36 in TM2) to Ala led to a complete loss of the NDH-1 activities. Mutation of the second conserved carboxyl residue ((K)Glu-72 in TM3) moderately reduced the activities. To clarify the contribution of NuoK to the mechanism of proton translocation, we relocated these two conserved residues. When we shifted (K)Glu-36 along TM2 to positions 32, 38, 39, and 40, the mutants largely retained energy transducing NDH-1 activities. According to the recent structural information, these positions are located in the vicinity of (K)Glu-36, present in the same helix phase, in an immediately before and after helix turn. In an earlier study, a double mutation of two arginine residues located in a short cytoplasmic loop between TM1 and TM2 (loop-1) showed a drastic effect on energy transducing activities. Therefore, the importance of this cytosolic loop of NuoK ((K)Arg-25, (K)Arg-26, and (K)Asn-27) for the energy transducing activities was extensively studied. The probable roles of subunit NuoK in the energy transducing mechanism of NDH-1 are discussed. PMID- 23105120 TI - High mitotic activity of Polo-like kinase 1 is required for chromosome segregation and genomic integrity in human epithelial cells. AB - Protein kinases play key roles in regulating human cell biology, but manifold substrates and functions make it difficult to understand mechanism. We tested whether we could dissect functions of a pleiotropic mitotic kinase, Polo-like kinase 1 (Plk1), via distinct thresholds of kinase activity. We accomplished this by titrating Plk1 activity in RPE1 human epithelial cells using chemical genetics and verifying results in additional lines. We found that distinct activity thresholds are required for known functions of Plk1 including (from low to high activity) bipolar spindle formation, timely mitotic entry, and formation of a cytokinesis cleavage furrow. Subtle losses in Plk1 activity impaired chromosome congression and produced severe anaphase dysfunction characterized by poor separation of chromosome masses. These two phenotypes were separable, suggesting that they stem from distinct phosphorylation events. Impaired chromosome segregation in anaphase was the most sensitive to modest loss in Plk1 activity. Mechanistically, it was associated with unpaired sister chromatids with stretched kinetochores, suggestive of merotelic attachments. The C-terminal Polo box domain of Plk1 was required for its anaphase function, although it was dispensable for forming a bipolar spindle. The ultimate effect of partial inhibition of Plk1 was the formation of micronuclei, an increase in tetraploid progeny, and senescence. These results demonstrate that different thresholds of Plk1 activity can elicit distinct phenotypes, illustrating a general method for separating pleiotropic functions of a protein kinase even when these are executed close in time. PMID- 23105122 TI - Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis? AB - AIMS: Penile, vulvar and anal squamous cell carcinomas (SCCs) share histomorphological overlap and are prone to lymphatic dissemination into inguinal nodes. Anal SCCs might derive from the anorectal zone (ARZ), anal transitional zone, squamous zone or from perianal skin. These anatomically distinct zones differ in terms of their embryological development. We sought to investigate the role of caudal-related homeobox 2 (CDX2), a homeobox gene implicated in the development and anterior/posterior pattern specification from duodenum to rectum including the ARZ, in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with histologically confirmed inguinal lymph node metastasis. METHODS: By immunohistochemistry (IHC) employing a panel of antibodies directed against CK5/6, CK7, CK20, p63, p16, CEA and CDX2, we compared 89 penile, 11 vulvar and eight anal SCCs with respect to their staining profiles. Moreover, anal SCCs were subjected to in situ hybridisation (ISH) for high-risk human papillomavirus (HPV) subtypes. RESULTS: By IHC, CDX2 expression was observed in 2/8 anal SCCs (25%) while being absent from all penile and vulvar SCCs examined. High-risk HPV subtypes were detected by ISH in all anal SCCs examined, which were uniformly p16 positive by IHC. CONCLUSIONS: CDX2 might be valuable in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with inguinal lymph node metastasis. However, despite its favourable specificity, the diagnostic benefit achieved by this observation is limited by the low sensitivity. PMID- 23105123 TI - Capillary zone electrophoresis for haemoglobinopathy diagnosis. AB - AIMS: Capillary zone electrophoresis (CE) at alkaline pH is increasingly used in haemoglobinopathy diagnosis. We report our evaluation of automated CE, using the Capillarys 2 Flex Piercing instrument, as a routine diagnostic method for the detection of variant haemoglobins and the diagnosis of beta thalassaemia. METHODS: A Capillarys 2 Flex Piercing instrument with Phoresis software was evaluated in our laboratory over a 6-week period, comparisons being made with high performance liquid chromatography (HPLC) and, for haemoglobin A(2) quantification, with microcolumn chromatography. RESULTS: The instrument was easy to use and was suitable for the quantification of haemoglobin A(2). Quantification of A(2) was precise and the percentage was stable with ageing of the blood specimen. Results differ among HPLC, CE and microcolumn chromatography and use of an instrument-specific, method-specific reference range is therefore recommended until such time as there is standardisation between methods and manufacturers. Common variant haemoglobins were provisionally identified without difficulty. There are some uncommon variant haemoglobins that are detected by HPLC but not by capillary electrophoresis, but the reverse also occurs. CONCLUSIONS: Capillary electrophoresis using a Capillarys 2 Flex Piercing instrument is suitable for haemoglobinopathy diagnosis. PMID- 23105124 TI - Comparison of a powered bone marrow biopsy device with a manual system: results of a prospective randomised controlled trial. AB - The diagnostic and clinical usefulness of a powered bone marrow biopsy device (OnControl()) versus a standard manual device (TRAP Hospital System) was studied. Primary endpoints were biopsy quality and patient pain during the procedure. Fifty patients underwent a total of 60 procedures by three expert operators in a randomised stratified fashion. Baseline demographic and clinical parameters were similar in both groups. The usage of conscious sedation, dosage of lidocaine/pethidin was similar between groups. Biopsy quality was rated 'sufficient for diagnosis' in 24/30 in the control group and 25/30 in the powered group (p=0.74). Biopsy cylinder length, procedure time (from skin contact of the biopsy needle to placement of the biopsy cylinder in the formalin container) and patient reported pain during the procedure (T1), 15 min after the procedure (T2) and 3-5 days after the procedure (T3) there were comparable between groups. In the small subgroup of patients that did not receive conscious sedation (n=15; manual 6, powered 9) significantly lower median pain scores were observed with the powered system (median pain score 3 vs 7; p=0.015). Patients were satisfied with either device whether sedation was used (sedation: median 9 for both groups, range 3-10 (manual) and 0-10 (powered)) no sedation (median 8 (manual) vs 9 (powered)). In summary bone marrow biopsies taken with the manual or powered device produce similar technical and clinical results. If no conscious sedation is used, pain during the procedure appears to be lower with the powered system. The use of a powered system seems to be justified in selected patients. PMID- 23105125 TI - Comments on "CYP3AP1*3 allele is associated with lipid-lowering efficacy of simvastatin and atorvastatin in Chinese women". PMID- 23105127 TI - Validating phenotyping cocktails: more work needs to be done. PMID- 23105129 TI - Tearing down barriers: understanding the molecular mechanisms of interploidy hybridizations. AB - Polyploidization, the process leading to more than two sets of chromosomes, is widely recognized as a major speciation mechanism that might hold the key to Darwin's 'abominable mystery', as he referred to the sudden rise of angiosperms to ecological dominance. On their way to become polyploid most plants take the route through the production of unreduced gametes that might eventually lead to viable triploid intermediates able to backcross or self-fertilize to give rise to stable polyploid plants. Polyploids are almost instantly reproductively isolated from their non-polyploid ancestors; as hybridizations of species that differ in ploidy mostly lead to non-viable progeny. This immediate reproductive barrier referred to as 'triploid block' is established in the endosperm, pointing towards an important but greatly underestimated role of the endosperm in preventing interploidy hybridizations. Parent-of-origin specific gene expression occurs predominantly in the endosperm and might cause the dosage-sensitivity of the endosperm. This article illustrates, based on the recent molecular and genetic findings mainly gained in the model species Arabidopsis thaliana, the 'journey' of unreduced gametes to triploid intermediates to polyploid plants and will also discuss the implications for interploidy and interspecies hybridizations. PMID- 23105130 TI - Modulation of plant TPC channels by polyunsaturated fatty acids. AB - Polyunsaturated fatty acids (PUFAs) are powerful modulators of several animal ion channels. It is shown here that PUFAs strongly affect the activity of the Slow Vacuolar (SV) channel encoded by the plant TPC1 gene. The patch-clamp technique was applied to isolated vacuoles from carrot taproots and Arabidopsis thaliana mesophyll cells and arachidonic acid (AA) was chosen as a model molecule for PUFAs. Our study was extended to different PUFAs including the endogenous alpha linolenic acid (ALA). The addition of micromolar concentrations of AA reversibly inhibited the SV channel decreasing the maximum open probability and shifting the half activation voltage to positive values. Comparing the effects of different PUFAs, it was found that the length of the lipophilic acyl chain, the number of double bonds and the polar head were critical for channel modulation.The experimental data can be reproduced by a simple three-state model, in which PUFAs do not interact directly with the voltage sensors but affect the voltage independent transition that leads the channel from the open state to the closed configuration. The results indicate that lipids play an important role in co ordinating ion channel activities similar to what is known from animal cells. PMID- 23105131 TI - The Brassica napus calcineurin B-Like 1/CBL-interacting protein kinase 6 (CBL1/CIPK6) component is involved in the plant response to abiotic stress and ABA signalling. AB - A CBL-interacting protein kinase (CIPK) gene, BnCIPK6, was isolated in Brassica napus. Through yeast two-hybrid screening, 27 interaction partners (including BnCBL1) of BnCIPK6 were identified in Brassica napus. Interaction of BnCIPK6 and BnCBL1 was further confirmed by BiFC (bimolecular fluorescence complementation) in plant cells. Expressions of BnCIPK6 and BnCBL1 were significantly up-regulated by salt and osmotic stresses, phosphorous starvation, and abscisic acid (ABA). Furthermore, BnCIPK6 promoter activity was intensively induced in cotyledons and roots under NaCl, mannitol, and ABA treatments. Transgenic Arabidopsis plants with over-expressing BnCIPK6, its activated form BnCIPK6M, and BnCBL1 enhanced high salinity and low phosphate tolerance, suggesting that the functional interaction of BnCBL1 and BnCIPK6 may be important for the high salinity and phosphorous deficiency signalling pathways. In addition, activation of BnCIPK6 confers Arabidopsis plants hypersensitive to ABA. On the other hand, over expression of BnCIPK6 in Arabidopsis cipk6 mutant completely rescued the low phosphate-sensitive and ABA-insensitive phenotypes of this mutant, further suggesting that BnCIPK6 is involved in the plant response to high-salinity, phosphorous deficiency, and ABA signalling. PMID- 23105132 TI - Proteomic analysis of grapevine resistance induced by Trichoderma harzianum T39 reveals specific defence pathways activated against downy mildew. AB - Downy mildew is caused by the oomycete Plasmopara viticola and is one of the most serious diseases of grapevine. The beneficial microorganism Trichoderma harzianum T39 (T39) has previously been shown to induce plant-mediated resistance and to reduce the severity of downy mildew in susceptible grapevines. In order to better understand the cellular processes associated with T39-induced resistance, the proteomic and histochemical changes activated by T39 in grapevine were investigated before and 1 day after P. viticola inoculation. A comprehensive proteomic analysis of T39-induced resistance in grapevine was performed using an eight-plex iTRAQ protocol, resulting in the identification and quantification of a total of 800 proteins. Most of the proteins directly affected by T39 were found to be involved in signal transduction, indicating activation of a complete microbial recognition machinery. Moreover, T39-induced resistance was associated with rapid accumulation of reactive oxygen species and callose at infection sites, as well as changes in abundance of proteins involved in response to stress and redox balance, indicating an active defence response to downy mildew. On the other hand, proteins affected by P. viticola in control plants mainly decreased in abundance, possibly reflecting the establishment of a compatible interaction. Finally, the high-throughput iTRAQ protocol allowed de novo peptide sequencing, which will be used to improve annotation of the Vitis vinifera cv. Pinot Noir proteome. PMID- 23105133 TI - GbTCP, a cotton TCP transcription factor, confers fibre elongation and root hair development by a complex regulating system. AB - As the most important natural raw material for textile industry, cotton fibres are an excellent model for studying single-cell development. Although expression profiling and functional genomics have provided some data, the mechanism of fibre development is still not well known. A class I TCP transcription factor (designated GbTCP), encoding 344 amino acids, was isolated from the normalized cDNA library of sea-island cotton fibre (from -2 to 25 days post anthesis). GbTCP was preferentially expressed in the elongating cotton fibre from 5 to 15 days post anthesis. Some expression was also observed in stems, apical buds, and petals. RNAi silencing of GbTCP produced shorter fibre, a reduced lint percentage, and a lower fibre quality than the wild-type plants. Overexpression of GbTCP enhanced root hair initiation and elongation in Arabidopsis and regulated branching. Solexa sequencing and Affymetrix GeneChip analysis indicated that GbTCP positively regulates the level of jasmonic acid (JA) and, as a result, activates downstream genes (reactive oxygen species, calcium signalling, ethylene biosynthesis and response, and several NAC and WRKY transcription factors) necessary for elongation of fibres and root hairs. JA content analysis in cotton also confirmed that GbTCP has a profound effect on JA biosynthesis. In vitro ovule culture showed that an appropriate concentration of JA promoted fibre elongation. The results suggest that GbTCP is an important transcription factor for fibre and root hair development by regulating JA biosynthesis and response and other pathways, including reactive oxygen species, calcium channel and ethylene signalling. PMID- 23105134 TI - IgA response in preterm neonates shows little evidence of antigen-driven selection. AB - After birth, contact to environmental Ags induces the production of IgA, which represents a first line of defense for the neonate. We sought to characterize the maturation of the repertoire of IgA H chain transcripts in circulating blood B cells during human ontogeny. We found that IgA H chain transcripts were present in cord blood as early as 27 wk of gestation and that the restrictions of the primary Ab repertoire (IgM) persisted in the IgA repertoire. Thus, B cells harboring more "mature" V(H) regions were not preferred for class switch to IgA. Preterm and term neonates expressed a unique IgA repertoire, which was characterized by short CDR-H3 regions, preference of the J(H) proximal D(H)7-27 gene segment, and very few somatic mutations. During the first postnatal months, these restrictions were slowly released. Preterm birth did not measurably accelerate the maturation of the IgA repertoire. At a postconceptional age of 60 wk, somatic mutation frequency of IgA H chain transcripts reached 25% of the adult values but still showed little evidence of Ag-driven selection. These results indicate that similar to IgG, the IgA repertoire expands in a controlled manner after birth. Thus, the IgA repertoire of the newborn has distinctive characteristics that differ from the adult IgA repertoire. These observations might explain the lower affinity and specificity of neonatal IgA Abs, which could contribute to a higher susceptibility to infections and altered responses to vaccinations, but might also prevent the development of autoimmune and allergic diseases. PMID- 23105135 TI - Differential trafficking of TLR1 I602S underlies host protection against pathogenic mycobacteria. AB - We recently identified I602S as a frequent single-nucleotide polymorphism of human TLR1 that greatly inhibits cell surface trafficking, confers hyporesponsiveness to TLR1 agonists, and protects against the mycobacterial diseases leprosy and tuberculosis. Because mycobacteria are known to manipulate the TLR system to their advantage, we hypothesize that the hyporesponsive 602S variant may confer protection by enabling the host to overcome this immune subversion. We report that primary human monocytes and macrophages from homozygous TLR1 602S individuals are resistant to mycobacterial-induced downregulation of macrophage MHC class II, CD64, and IFN-gamma responses compared with individuals who harbor the TLR1 602I variant. Additionally, when challenged with mycobacterial agonists, macrophages from TLR1 602S/S individuals resist induction of host arginase-1, an enzyme that depletes cellular arginine stores required for the production of antimicrobial reactive nitrogen intermediates. The differences in cell activation mediated by TLR1 602S and TLR1 602I are observed upon stimulation with soluble mycobacterial-derived agonists but not with whole mycobacterial cells. Taken together, these results suggest that the TLR1 602S variant protects against mycobacterial disease by preventing soluble mycobacterial products, perhaps released from granulomas, from disarming myeloid cells prior to their encounter with whole mycobacteria. PMID- 23105136 TI - Arsenic trioxide exerts antitumor activity through regulatory T cell depletion mediated by oxidative stress in a murine model of colon cancer. AB - Immunotherapy is a promising antitumor strategy that can successfully be combined with current anticancer treatment. In this study, arsenic trioxide (As(2)O(3)) was shown to increase the antitumor immune response in CT26 colon tumor-bearing mice through the modulation of regulatory T cell (T(reg)) numbers. As(2)O(3) induced T(reg)-selective depletion in vitro. In vivo, tumor-bearing mice injected with 1 mg/kg As(2)O(3) showed a significant decrease in the T(reg)/CD4 cell ratio and in absolute T(reg) count versus controls. As(2)O(3) exerted antitumor effects only in immunocompetent mice and enhanced adoptive immunotherapy effects. Inhibition of As(2)O(3)-induced T(reg) depletion by the NO synthase inhibitor N(G)-nitro-l-arginine methyl ester and the superoxide dismutase mimic manganese [III] tetrakis-(5, 10, 15, 20)-benzoic acid porphyrin suggested that it was mediated by oxidative and nitrosative stress. The differential effect of As(2)O(3) on T(reg) versus other CD4 cells may be related to differences in the cells' redox status, as indicated by significant differences in 2'7'dichlorodihydrofluorescein diacetate and 4,5-diaminofluorescein diacetate fluorescence levels. In conclusion, these results show for the first time, to our knowledge, that low doses As(2)O(3) can delay solid tumor growth by depleting T(regs) through oxidative and nitrosative bursts, and suggest that As(2)O(3) could be used to enhance the antitumor activity of adoptive immunotherapy strategies in human cancer. PMID- 23105138 TI - Primary MHC-class II(+) cells are necessary to promote resting Vdelta2 cell expansion in response to (E)-4-hydroxy-3-methyl-but-2-enyl-pyrophosphate and isopentenyl pyrophosphate. AB - Human Vgamma9delta2 (Vdelta2) T cells represent a unique effector T cell population in humans and primates detecting nonpeptid phosphoantigens, playing an important role in antimicrobial and antitumor immunity. Currently, it is believed that various leukocyte subsets can promote phosphoantigen-driven Vdelta2 cell expansion, but the essential cell type required remains elusive. We have used high purity cell sorting to analyze the cellular requirements for (E)-4-hydroxy-3 methyl-but-2-enyl-pyrophosphate (HMBPP)-driven Vdelta2 cell expansion. To our knowledge, we show for the first time that primary human MHC-class II(+) cells are indispensable for HMBPP- and isopentenylpyrophosphate-driven Vdelta2 cell expansion. In contrast, MHC-class II(-) cells are unable to promote Vdelta2 cell expansion. Moreover, purified primary human TCRalphabeta(+) T cells, CD4(+), or CD8(+) T cells also failed to promote HMBPP-mediated Vdelta2 expansion. Depletion of CD4(+)CD25(+) T cells demonstrated that inability of TCRalphabeta(+) cells to expand Vdelta2 cells was not related to the presence of regulatory T cells. Separation of MHC-class II(+) cells into dendritic cells, monocytes, and B cells revealed that dendritic cells were the most potent Vdelta2 expanders. Pulsing experiments demonstrated that HMBPP transforms MHC-class II(+) but not negative cells into Vdelta2 expanders. MHC-class II-blocking experiments with mAbs and secondary MHC-class II induction on CD4(+) T cells after CD3/CD28 costimulation indicated that MHC-class II is necessary, but not sufficient to promote Vdelta2 expansion. Our results provide novel insight into the primary cell-specific requirements for human Vdelta2 expansion. PMID- 23105137 TI - Pneumococcal surface protein A inhibits complement deposition on the pneumococcal surface by competing with the binding of C-reactive protein to cell-surface phosphocholine. AB - In the presence of normal serum, complement component C3 is deposited on pneumococci primarily via the classical pathway. Pneumococcal surface protein A (PspA), a major virulence factor of pneumococci, effectively inhibits C3 deposition. PspA's C terminus has a choline-binding domain that anchors PspA to the phosphocholine (PC) moieties on the pneumococcal surface. C-reactive protein (CRP), another important host defense molecule, also binds to PC, and CRP binding to pneumococci enhances complement C3 deposition through the classical pathway. Using flow cytometry of PspA(+) and PspA(-) strains, we observed that the absence of PspA led to exposure of PC, enhanced the surface binding of CRP, and increased the deposition of C3. Moreover, when the PspA(-) mutant was incubated with a pneumococcal eluate containing native PspA, there was decreased deposition of CRP and C3 on the pneumococcal surface compared with incubation with an eluate from a PspA(-) strain. This inhibition was not observed when a recombinant PspA fragment, which lacks the choline-binding region of PspA, was added to the PspA( ) mutant. Also, there was much greater C3 deposition onto the PspA(-) pneumococcus when exposed to normal mouse serum from wild-type mice as compared with that from CRP knockout mice. Furthermore, when CRP knockout mouse serum was replenished with CRP, there was a dose-dependent increase in C3 deposition. The combined data reveal a novel mechanism of complement inhibition by a bacterial protein: inhibition of CRP surface binding and, thus, diminution of CRP-mediated complement deposition. PMID- 23105139 TI - Atypical activation of the unfolded protein response in cystic fibrosis airway cells contributes to p38 MAPK-mediated innate immune responses. AB - Inflammatory lung disease is the major cause of morbidity and mortality in cystic fibrosis (CF); understanding what produces dysregulated innate immune responses in CF cells will be pivotal in guiding the development of novel anti-inflammatory therapies. To elucidate the molecular mechanisms that mediate exaggerated inflammation in CF following TLR signaling, we profiled global gene expression in immortalized human CF and non-CF airway cells at baseline and after microbial stimulation. Using complementary analysis methods, we observed a signature of increased stress levels in CF cells, specifically characterized by endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and MAPK signaling. Analysis of ER stress responses revealed an atypical induction of the UPR, characterized by the lack of induction of the PERK-eIF2alpha pathway in three complementary model systems: immortalized CF airway cells, fresh CF blood cells, and CF lung tissue. This atypical pattern of UPR activation was associated with the hyperinflammatory phenotype in CF cells, as deliberate induction of the PERK eIF2alpha pathway with salubrinal attenuated the inflammatory response to both flagellin and Pseudomonas aeruginosa. IL-6 production triggered by ER stress and microbial stimulation were both dependent on p38 MAPK activity, suggesting a molecular link between both signaling events. These data indicate that atypical UPR activation fails to resolve the ER stress in CF and sensitizes the innate immune system to respond more vigorously to microbial challenge. Strategies to restore ER homeostasis and normalize the UPR activation profile may represent a novel therapeutic approach to minimize lung-damaging inflammation in CF. PMID- 23105140 TI - ZBTB7B (Th-POK) regulates the development of IL-17-producing CD1d-restricted mouse NKT cells. AB - CD1d-dependent NKT cells represent a heterogeneous family of effector T cells including CD4(+)CD8(-) and CD4(-)CD8(-) subsets that respond to glycolipid Ags with rapid and potent cytokine production. NKT cell development is regulated by a unique combination of factors, however very little is known about factors that control the development of NKT subsets. In this study, we analyze a novel mouse strain (helpless) with a mis-sense mutation in the BTB-POZ domain of ZBTB7B and demonstrate that this mutation has dramatic, intrinsic effects on development of NKT cell subsets. Although NKT cell numbers are similar in Zbtb7b mutant mice, these cells are hyperproliferative and most lack CD4 and instead express CD8. Moreover, the majority of ZBTB7B mutant NKT cells in the thymus are retinoic acid related orphan receptor gammat positive, and a high frequency produce IL-17 while very few produce IFN-gamma or other cytokines, sharply contrasting the profile of normal NKT cells. Mice heterozygous for the helpless mutation also have reduced numbers of CD4(+) NKT cells and increased production of IL-17 without an increase in CD8(+) cells, suggesting that ZBTB7B acts at multiple stages of NKT cell development. These results reveal ZBTB7B as a critical factor genetically predetermining the balance of effector subsets within the NKT cell population. PMID- 23105141 TI - Broad cross-presentation of the hematopoietically derived PR1 antigen on solid tumors leads to susceptibility to PR1-targeted immunotherapy. AB - PR1 is a HLA-A2-restricted peptide that has been targeted successfully in myeloid leukemia with immunotherapy. PR1 is derived from the neutrophil granule proteases proteinase 3 (P3) and neutrophil elastase (NE), which are both found in the tumor microenvironment. We recently showed that P3 and NE are taken up and cross presented by normal and leukemia-derived APCs, and that NE is taken up by breast cancer cells. We now extend our findings to show that P3 and NE are taken up and cross-presented by human solid tumors. We further show that PR1 cross presentation renders human breast cancer and melanoma cells susceptible to killing by PR1-specific CTLs (PR1-CTL) and the anti-PR1/HLA-A2 Ab 8F4. We also show PR1-CTL in peripheral blood from patients with breast cancer and melanoma. Together, our data identify cross-presentation as a novel mechanism through which cells that lack endogenous expression of an Ag become susceptible to therapies that target cross-presented Ags and suggest PR1 as a broadly expressed tumor Ag. PMID- 23105142 TI - Endothelial cell peroxisome proliferator-activated receptor gamma reduces endotoxemic pulmonary inflammation and injury. AB - Bacterial endotoxin (LPS)-mediated sepsis involves severe, dysregulated inflammation that injures the lungs and other organs, often fatally. Vascular endothelial cells are both key mediators and targets of LPS-induced inflammatory responses. The nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARgamma) exerts anti-inflammatory actions in various cells, but it is unknown whether it modulates inflammation through actions within endothelial cells. To determine whether PPARgamma acts within endothelial cells to diminish endotoxemic lung inflammation and injury, we measured inflammatory responses and mediators in mice with endothelial-targeted deletion of PPARgamma. Endothelial cell PPARgamma (ePPARgamma) knockout exacerbated LPS-induced pulmonary inflammation and injury as shown by several measures, including infiltration of inflammatory cells, edema, and production of reactive oxygen species and proinflammatory cytokines, along with upregulation of the LPS receptor TLR4 in lung tissue and increased activation of its downstream signaling pathways. In isolated LPS-stimulated endothelial cells in vitro, absence of PPARgamma enhanced the production of numerous inflammatory markers. We hypothesized that the observed in vivo activity of the ligand-activated ePPARgamma may arise, in part, from nitrated fatty acids (NFAs), a novel class of endogenous PPARgamma ligands. Supporting this idea, we found that treating isolated endothelial cells with physiologically relevant concentrations of the endogenous NFA 10-nitro-oleate reduced LPS-induced expression of a wide range of inflammatory markers in the presence of PPARgamma, but not in its absence, and also inhibited neutrophil mobility in a PPARgamma-dependent manner. Our results demonstrate a key protective role of ePPARgamma against endotoxemic injury and a potential ePPARgamma-mediated anti-inflammatory role for NFAs. PMID- 23105143 TI - Tumor-associated macrophages promote invasion while retaining Fc-dependent anti tumor function. AB - Tumor-associated macrophages (TAMs) have been shown to promote tumor progression, and increased TAM infiltration often correlates with poor prognosis. However, questions remain regarding the phenotype of macrophages within the tumor and their role in mAb-dependent cytotoxicity. This study demonstrates that whereas TAMs have protumor properties, they maintain Fc-dependent anti-tumor function. CD11b(+)CD14(+) TAMs isolated from primary human breast tumors expressed activating FcgammaRs. To model breast cancer TAMs in vitro, conditioned medium from breast cancer cells was used to drive human peripheral monocyte differentiation into macrophages. Tumor-conditioned macrophages were compared with in vitro derived M1 and M2a macrophages and were found to promote tumor cell invasion and express M2a markers, confirming their protumor potential. However, unlike M2a macrophages, tumor-conditioned macrophages expressed FcgammaRs and phagocytosed tumor cells in the presence of a tumor Ag-targeting mAb, unmasking an underappreciated tumoricidal capacity of TAMs. In vivo macrophage depletion reduced the efficacy of anti-CD142 against MDA-MB-231 xenograft growth and metastasis in SCID/beige mice, implicating a critical role for macrophages in Fc dependent cell killing. M-CSF was identified in tumor-conditioned media and shown to be capable of differentiating macrophages with both pro- and anti-tumor properties. These results highlight the plasticity of TAMs, which are capable of promoting tumor progression and invasion while still retaining tumoricidal function in the presence of tumor-targeting mAbs. PMID- 23105145 TI - Interferon alfa therapy: toward an improved treatment for HIV infection. PMID- 23105144 TI - Pegylated Interferon alfa-2a monotherapy results in suppression of HIV type 1 replication and decreased cell-associated HIV DNA integration. AB - BACKGROUND: Antiretroviral therapy (ART)-mediated immune reconstitution fails to restore the capacity of the immune system to spontaneously control human immunodeficiency virus (HIV) replication. METHODS: A total of 23 HIV type 1 (HIV 1)-infected, virologically suppressed subjects receiving ART (CD4(+) T-cell count, >450 cells/MUL) were randomly assigned to have 180 MUg/week (for arm A) or 90 MUg/week (for arm B) of pegylated (Peg) interferon alfa-2a added to their current ART regimen. After 5 weeks, ART was interrupted, and Peg-interferon alfa 2a was continued for up to 12 weeks (the primary end point), with an option to continue to 24 weeks. End points included virologic failure (viral load, >= 400 copies/mL) and adverse events. Residual viral load and HIV-1 DNA integration were also assessed. RESULTS: At week 12 of Peg-interferon alfa-2a monotherapy, viral suppression was observed in 9 of 20 subjects (45%), a significantly greater proportion than expected (arm A, P = .0088; arm B, P = .0010; combined arms, P < .0001). Over 24 weeks, both arms had lower proportions of subjects who had viral load, compared with the proportion of subjects in a historical control group (arm A, P = .0046; arm B, P = .0011). Subjects who had a sustained viral load of <400 copies/mL had decreased levels of integrated HIV DNA (P = .0313) but increased residual viral loads (P = .0078), compared with subjects who experienced end point failure. CONCLUSIONS: Peg-interferon alfa-2a immunotherapy resulted in control of HIV replication and decreased HIV-1 integration, supporting a role for immunomediated approaches in HIV suppression and/or eradication. CLINICAL TRIALS REGISTRATION: NCT00594880. PMID- 23105147 TI - Age at Immigration and the Adult Attainments of Child Migrants to the United States. AB - Immigrants' age at arrival matters for schooling outcomes in a way that is predicted by child development theory: the chances of being a high school dropout increase significantly each year for children who arrive in a host country after the age of eight. The authors document this process for immigrants in the United States from a number of regions relative to appropriate comparison regions. Using instrumental variables, the authors find that the variation in education outcomes associated with variation in age at arrival influences adult outcomes that are important in the American mainstream, notably English-language proficiency and intermarriage. The authors conclude that children experience migration differently from adults depending on the timing of migration and show that migration during the early years of child development influences educational outcomes. The authors also find that variation in education outcomes induced by the interaction of migration and age at arrival changes the capacity of children to become fully integrated into the American mainstream as adults. PMID- 23105146 TI - Thermoresponsive Platforms for Tissue Engineering and Regenerative Medicine. PMID- 23105148 TI - Abandoning a label doesn't make it disappear: The perseverance of labeling effects. AB - Labels exert strong influence on perception and judgment. The present experiment examines the possibility that such effects may persist even when labels are abandoned. Participants judged the similarity of pairs of silhouette drawings of female body types, ordered on a continuum from very thin to very heavy, under conditions where category labels were, and were not, superimposed on the ordered stimuli. Consistent with earlier research, labels had strong effects on perceived similarity, with silhouettes sharing the same label judged as more similar than those having different labels. Moreover, when the labels were removed and no longer present, the effect of the labels, although diminished, persisted. It did not make any difference whether the labels were simply abandoned or, in addition, had their validity challenged. The results are important for our understanding of categorization and labeling processes. The potential theoretical and practical implications of these results for social processes are discussed. PMID- 23105149 TI - Fungal trunk pathogens associated with wood decay of almond trees on Mallorca (Spain). AB - Severe decline of almond trees has recently been observed in several orchards on the island of Mallorca (Balearic Islands, western Mediterranean Sea). However, the identity of the causal agents has not yet been investigated. Between August 2008 and June 2010, wood samples from branches of almond trees showing internal necroses and brown to black vascular streaking were collected in the Llevant region on the island of Mallorca. Several fungal species were subsequently isolated from the margin between healthy and symptomatic tissue. Five species of Botryosphaeriaceae (namely Botryosphaeria dothidea, Diplodia olivarum, D. seriata, Neofusicoccum australe and N. parvum), Eutypa lata, Phaeoacremonium iranianum and Phomopsis amygdali were identified based on morphology, culture characteristics and DNA sequence comparisons. Neofusicoccum parvum was the dominant species, followed by E. lata, D. olivarum and N. australe. First reports from almond include D. olivarum and Pm. iranianum. Two species are newly described, namely Collophora hispanica sp. nov. and Phaeoacremonium amygdalinum sp. nov. PMID- 23105150 TI - Three new additions to the genus Talaromyces isolated from Atlantis sandveld fynbos soils. AB - During a survey of Penicillium spp. in soils from the diverse fynbos region in the Western Cape, South Africa, a number of previously undescribed species were isolated. Three of these belong to subg. Biverticillium sensu Pitt, recently incorporated into its previously associated teleomorph genus, Talaromyces s.str. These species displayed symmetrical biverticillate penicilli, acerose phialides and poor growth at reduced water activity, typical of this group. Morphological characters of the new species were compared to known Talaromyces species. The ITS and beta-tubulin gene regions were used for phylogenetic comparisons, which confirmed the distinct nature of the three fynbos soil species described here as Talaromyces chloroloma sp. nov., T. ptychoconidium sp. nov. and T. solicola sp. nov., respectively. Talaromyces chloroloma is typically recognised by its strongly funiculose colony texture and after prolonged incubation, synnemata can be observed on CYA. Talaromyces ptychoconidium is characterised by closely appressed conidiophores that produce spirally rough-walled conidia, while T. solicola typically struggle to grow on CYA and is distinguished from similar species by its prominently rough-walled, spheroid conidia. PMID- 23105151 TI - Phylogeny and taxonomy of the genus Gliocladiopsis. AB - Using a global set of isolates and a phylogenetic approach employing DNA sequence data from five genes (beta-tubulin, histone H3, internal transcribed spacer region, 28S large subunit region and translation elongation factor 1-alpha), the taxonomic status of the genus Gliocladiopsis (Glionectria) (Hypocreales, Nectriaceae) was re-evaluated. Gliocladiopsis sagariensis is reinstated as type species for the genus, which proved to be distinct from its former synonym, G. tenuis. The purported teleomorph state of G. tenuis, Glionectria tenuis, is shown to be distinct based on morphological comparisons supported by phylogenetic inference, and is provided with a new name, Gliocladiopsis pseudotenuis. A further four species, mostly isolated from soil, are newly described, namely G. curvata (New Zealand, Ecuador and Indonesia), G. elghollii (USA), G. indonesiensis (Indonesia) and G. mexicana (Mexico). Although species of Gliocladiopsis are frequently isolated from roots of diseased plants or plant litter in soil, little is presently known of their ecology, or potential role as plant pathogens. PMID- 23105152 TI - Plectosphaerella species associated with root and collar rots of horticultural crops in southern Italy. AB - Plectosphaerella cucumerina, most frequently encountered in its Plectosporium state, is well known as a pathogen of several plant species causing fruit, root and collar rot, and collapse. It is considered to pose a serious threat to melon (Cucumis melo) production in Italy. In the present study, an intensive sampling of diseased cucurbits as well as tomato and bell pepper was done and the fungal pathogens present on them were isolated. Phylogenetic relationships of the isolates were determined through a study of ribosomal RNA gene sequences (ITS cluster and D1/D2 domain of the 28S rRNA gene). Combining morphological, culture and molecular data, six species were distinguished. One of these (Pa. cucumerina) is already known. Four new species are described as Plectosphaerella citrullae, Pa. pauciseptata, Pa. plurivora and Pa. ramiseptata. Acremonium cucurbitacearum is shown to be a synonym of Nodulisporium melonis and is transferred to Plectosphaerella as Plectosphaerella melonis comb. nov. A further three known species of Plectosporium are recombined in Plectosphaerella. PMID- 23105153 TI - A re-appraisal of Harknessia (Diaporthales), and the introduction of Harknessiaceae fam. nov. AB - Harknessiaceae is introduced as a new family in the ascomycete order Diaporthales to accommodate species of Harknessia with their Wuestneia-like teleomorphs. The family is distinguished by having pycnidial conidiomata with brown, furfuraceous margins, brown conidia with hyaline, tube-like basal appendages, longitudinal striations, and rhexolytic secession. Six species occurring on Eucalyptus are newly introduced, namely H. australiensis, H. ellipsoidea, H. pseudohawaiiensis, and H. ravenstreetina from Australia, H. kleinzeeina from South Africa, and H. viterboensis from Italy. Epitypes are designated for H. spermatoidea and H. weresubiae, both also occurring on Eucalyptus. Members of Harknessia are commonly associated with leaf spots, but also occur as saprobes and endophytes in leaves and twigs of various angiosperm hosts. PMID- 23105154 TI - Genera of diaporthalean coelomycetes associated with leaf spots of tree hosts. AB - Four different genera of diaporthalean coelomycetous fungi associated with leaf spots of tree hosts are morphologically treated and phylogenetically compared based on the DNA sequence data of the large subunit nuclear ribosomal DNA gene (LSU) and the internal transcribed spacers and 5.8S rRNA gene of the nrDNA operon. These include two new Australian genera, namely Auratiopycnidiella, proposed for a leaf spotting fungus occurring on Tristaniopsis laurina in New South Wales, and Disculoides, proposed for two species occurring on leaf spots of Eucalyptus leaves in Victoria. Two new species are described in Aurantiosacculus, a hitherto monotypic genus associated with leaf spots of Eucalyptus in Australia, namely A. acutatus on E. viminalis, and A. eucalyptorum on E. globulus, both occurring in Tasmania. Lastly, an epitype specimen is designated for Erythrogloeum hymenaeae, the type species of the genus Erythrogloeum, and causal agent of a prominent leaf spot disease on Hymenaea courbaril in South America. All four genera are shown to be allied to Diaporthales, although only Aurantiosacculus (Cryphonectriaceae) could be resolved to family level, the rest being incertae sedis. PMID- 23105155 TI - Polyphasic characterisation of three new Phyllosticta spp. AB - Three new species of Phyllosticta, P. hostae on Hosta plantaginea (China), P. schimae on Schima superba (China), and P. ilicis-aquifolii on Ilex aquifolium (UK), are described and illustrated in this study. They are compared with morphologically similar and phylogenetically closely related species. A polyphasic approach using phylogeny, host association, disease symptoms, colony and morphological characteristics, is employed to justify the introduction of the new taxa. Phylogenetic relationships of the new species with other Phyllosticta species are revealed by DNA sequence analyses based on the nrDNA-internal transcribed spacer (ITS) regions and a combined multilocus alignment of the ITS, partial translation elongation factor 1-alpha (TEF1), actin (ACT), and glyceraldehyde 3-phosphate dehydrogenase (GPDH) gene regions. PMID- 23105156 TI - Diversity and systematics of the sequestrate genus Octaviania in Japan: two new subgenera and eleven new species. AB - The sequestrate fungi of Japan, including truffle and truffle-like fungi, have not been well characterized but are potentially diverse. We investigated the diversity and phylogeny of Japanese Octaviania specimens using a multifaceted approach including scanning and transmission electron microscopy as well as analysis of nuclear ribosomal DNA (ITS and LSU) and EF-1alpha (tef1) sequences. Phylogenetic analyses indicate that the genus Octaviania is divided into three major clades, and that there are at least 12 species-level lineages in Japan. Accordingly, we describe two new subgenera, Parcaea and Fulvoglobus, and eleven new species. Subgenus Parcaea accommodates four highly divergent, but macromorphologically almost indiscernible cryptic species. We discuss not only the diversity and species delimitation within the genus Octaviania but also the phylogeography of the Japanese taxa and their relatives. PMID- 23105157 TI - Dissoconiaceae associated with sooty blotch and flyspeck on fruits in China and the United States. AB - Zasmidium angulare, a novel species of Mycosphaerellaceae, and several novel taxa that reside in Dissoconiaceae, were identified from a collection of apples and Cucurbita maxima (cv. Blue Hubbard) from China and the USA that exhibited sooty blotch and flyspeck (SBFS) signs on their host substrata. Morphology on fruit surfaces and in culture, and phylogenetic analyses of the nuclear ribosomal DNAs 28S and internal transcribed spacer regions, as well as partial translation elongation factor 1-alpha gene sequences in some cases, were used to delineate seven previously unidentified species and three known species. Pseudoveronaea was established as a new genus of Dissoconiaceae, represented by two species, P. ellipsoidea and P. obclavata. Although Pseudoveronaea was morphologically similar to Veronaea, these fungi clustered with Dissoconiaceae (Capnodiales) rather than Chaetothyriales (Herpotrichiellaceae). Ramichloridium mali comb. nov., and three novel species, R. cucurbitae, R. luteum and R. punctatum were closely related with R. apiculatum, which together formed a distinct subclade in Dissoconiaceae. Species of Dissoconium s.lat. clustered in two well-supported clades supported by distinct morphological and cultural features. Subsequently Uwebraunia, a former synonym of Dissoconium, was resurrected for the one clade, with new combinations proposed for U. australiensis, U. commune, U. dekkeri and U. musae. Furthermore, we also reported that D. aciculare, Dissoconium sp., U. commune and U. dekkeri were associated with SBFS on apples. PMID- 23105158 TI - How important are conidial appendages? AB - The genus The genus Dinemasporium is used as a case study to evaluate the importance of conidial appendages for generic level classification of coelomycetous fungi. Based on morphology and sequence data of the large subunit nuclear ribosomal RNA gene (LSU, 28S) and the internal transcribed spacers and 5.8S rRNA gene of the nrDNA operon, the genus Dinemasporium is circumscribed, and an epitype designated for D. strigosum, the type of the genus. A further five species are introduced in Dinemasporium, namely D. pseudostrigosum (isolated from Triticum aestivum, Germany and Stigmaphyllon sagraeanum, Cuba), D. americana (soil, USA), D. polygonum (Polygonum sachalinense, Netherlands), D. pseudoindicum (soil, USA), and D. morbidum (human sputum, Netherlands and hare dung, New Zealand). Brunneodinemasporium, based on B. brasiliense, is introduced to accommodate Dinemasporium-like species with tightly aggregated brown conidiogenous cells, and pale brown conidia. Dendrophoma (= Amphitiarospora) is reinstated as distinct from Dinemasporium, and an epitype designated for D. cytisporoides, characterised by its superficial, stipitate to cupulate conidiomata, and small conidia with two polar, tubular, exogenous appendages. The genus Stauronema is reduced to synonymy under Dinemasporium. Pseudolachnea (1 septate conidia) is supported as distinct from Dinemasporium (aseptate conidia), and P. fraxini introduced as a novel species. Taxa in this generic complex differ by combination of morphological characters of conidiomata, setae, conidia and appendages. Appendage morphology alone is rejected as informative at the generic level. PMID- 23105160 TI - Voice onset time is necessary but not always sufficient to describe acquisition of voiced stops: The cases of Greek and Japanese. AB - The age at which children master adult-like voiced stops can generally be predicted by voice onset time (VOT): stops with optional short lag are early, those with obligatory lead are late. However, Japanese voiced stops are late despite having a short lag variant, whereas Greek voiced stops are early despite having consistent voicing lead. This cross-sectional study examines the acoustics of word-initial stops produced by English-, Japanese-, and Greek-speaking children aged 2 to 5, to investigate how these seemingly exceptional mastery patterns relate to use of other phonetic correlates. Productions were analyzed for VOT, f0 and spectral tilt (H1-H2) in Japanese and English, and for amplitude trajectory in Greek and Japanese. Japanese voiceless stops have intermediate lag VOT values, so other "secondary" cues are needed to differentiate them from the voiced short lag VOT variant. Greek voiced stops are optionally prenasalized, and the amplitude trajectory for the voice bar during closure suggests that younger children use a greater degree of nasal venting to create the aerodynamic conditions necessary for voicing lead. Taken together, the findings suggest that VOT must be supplemented by measurements of other language-specific acoustic properties to explain the mastery pattern of voiced stops in some languages. PMID- 23105159 TI - Fungal Planet description sheets: 107-127. AB - Novel species of microfungi described in the present study include the following from Australia: Phytophthora amnicola from still water, Gnomoniopsis smithogilvyi from Castanea sp., Pseudoplagiostoma corymbiae from Corymbia sp., Diaporthe eucalyptorum from Eucalyptus sp., Sporisorium andrewmitchellii from Enneapogon aff. lindleyanus, Myrmecridium banksiae from Banksia, and Pilidiella wangiensis from Eucalyptus sp. Several species are also described from South Africa, namely: Gondwanamyces wingfieldii from Protea caffra, Montagnula aloes from Aloe sp., Diaporthe canthii from Canthium inerne, Phyllosticta ericarum from Erica gracilis, Coleophoma proteae from Protea caffra, Toxicocladosporium strelitziae from Strelitzia reginae, and Devriesia agapanthi from Agapanthus africanus. Other species include Phytophthora asparagi from Asparagus officinalis (USA), and Diaporthe passiflorae from Passiflora edulis (South America). Furthermore, novel genera of coelomycetes include Chrysocrypta corymbiae from Corymbia sp. (Australia), Trinosporium guianense, isolated as a contaminant (French Guiana), and Xenosonderhenia syzygii, from Syzygium cordatum (South Africa). Pseudopenidiella piceae from Picea abies (Czech Republic), and Phaeocercospora colophospermi from Colophospermum mopane (South Africa) represent novel genera of hyphomycetes. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa. PMID- 23105161 TI - Executive functioning moderates the relationship between motivation and adolescent depressive symptoms. AB - We investigated the association between adolescent depressive symptoms and components of executive functioning (EF), including planning (Tower of London), set-shifting (Wisconsin Card Sorting Task), and inhibition (Stop Signal Task) in a community sample of 12-14 year olds. Further, EF was tested as a moderator of motivation (as operationalized by revised Reinforcement Sensitivity Theory) effects on depressive symptoms. Results suggested that planning ability was associated with depressive symptoms. Furthermore, planning ability moderated the relationship between motivation (fight-flight- freeze system; FFFS) and depressive symptoms, such that among adolescents with poor planning ability the FFFS positively predicted depressive symptoms, but among adolescents with strong planning ability the FFFS negatively predicts depressive symptoms. Neither set shifting nor inhibition was associated with depressive symptoms. Findings highlight the need to consider multiple components of EF and to integrate motivational and executive dysfunction models to the study of depression. PMID- 23105162 TI - Sources of Parental Knowledge in Mexican American Families. AB - We examined correlates of sources of parental knowledge of youths' experiences in Mexican American families, including child self-disclosure, parental solicitation, spouse, siblings, and individuals outside the family. Home and phone interviews were conducted with mothers, fathers, and their seventh-grade male and female offspring in 246 Mexican American families. Results indicated that mothers and fathers relied on different sources of knowledge; parent-child relationship quality and cultural orientations predicted parents' sources of knowledge; and different sources had different implications for youth adjustment. Specifically, child disclosure to mothers and fathers' reliance on their spouse were consistently linked to better youth outcomes. Moderation analyses revealed that correlates of parents' knowledge sources were not always uniform across mothers and fathers or daughters and sons. PMID- 23105163 TI - MULTIFUNCTIONAL NANO-BIO MATERIALS WITHIN CELLULAR MACHINERY. AB - Functional nanoscale materials that possess specific physical or chemical properties can leverage energy transduction in vivo. Once these materials integrate with biomolecules they combine physical properties of inorganic material and the biorecognition capabilities of bio-organic moieties. Such nano bio hybrids can be interfaced with living cells, the elementary functional units of life. These nano-bio systems are capable of bio-manipulation or actuation via altering intracellular biochemical pathways. Thus, nano-bio conjugates are appealing for a wide range of applications from the life sciences and nanomedicine to catalysis and clean energy production. Here we highlight recent progress in our efforts to develop smart nano-bio hybrid materials, and to study their performance within cellular machinery under application of external stimuli, such as light or magnetic fields. PMID- 23105164 TI - Trajectories of Delinquency from Age 14 to 23 in the National Longitudinal Survey of Youth Sample. AB - This study utilized data from the National Longitudinal Survey of Youth to investigate risk trajectories for delinquency and factors associated with different trajectories, particularly substance use. The sample (N = 8,984) was 49% female. A group-based trajectory model was applied, which identified four distinct trajectories for both males and females: (1) a High group with delinquency rates consistently higher than other groups, with some decrease across the age range; (2) a Decreased group, beginning at high levels with substantial decrease to near zero; (3) a Moderate group experiencing some decline but remaining at moderate rates of delinquency through most of the age range; and (4) a consistently Low group, having low rates of delinquency declining to near zero by mid- to late-teens. The Low group was distinguished by several protective factors, including higher rates of maternal authoritative parenting style, possible lower acculturation (higher rates of non-English spoken at home), higher rates of religious activity, later substance use initiation, lower rates of early delinquent activity, less early experience with neighborhood or personal violence, and higher rates of perceiving penalty for wrongdoing. Conversely, the High group was characterized by several vulnerability factors-essentially the converse of the protective factors above. PMID- 23105165 TI - Evidence for the Recognition of Non-Nucleotide Antagonists Within the Transmembrane Domains of the Human P2Y(1) Receptor. AB - Site-directed mutagenesis was used to search for amino acid residues of the human P2Y(1) receptor involved in the binding of the P2 receptor antagonists pyridoxal 5'-phosphate-6-azophenyl-2,4-disulfonate (PPADS), its analogue 6-(2'-chloro phenylazo)-pyridoxal-alpha(5)-phosphate (MRS 2210), the suramin analogue 8-8' [carbonylbis(imino-3,1-phenylene)]bis(1,3,5-naphthalene-trisulfonate) (NF023), and Reactive blue 2. Receptors containing single amino acid replacements at positions in transmembrane helical domains (TMs) 3, 5, 6, and 7 critical for the activation of the receptor by nucleotide agonists were expressed in COS-7 (African green monkey kidney) cells. Inositol phosphate accumulation was induced by 2-methylthioadenosine 5'-diphosphate (2-MeSADP). In wild type human P2Y(1) receptors, PPADS (10 to 60 uM), MRS 2210 (10 uM), NF023 (100 uM), and Reactive blue 2 (10 uM) shifted the concentration-response curve of 2-MeSADP in a parallel manner to the right. For PPADS, a pA(2) value of 5.2 was estimated. The shifts caused by MRS 2210, NF023, and Reactive blue 2 corresponded to apparent pK(B) values of 5.6, 5.0, and 5.8, respectively. In K280A mutant receptors, the affinities of PPADS, MRS 2210, NF023, and Reactive blue 2 were about 6- to 60 fold lower than those observed at wild type receptors. The K280A mutation also caused an approximately 1,000-fold increase in the EC(50) value of the agonist 2 MeSADP, similar to previous observations. In contrast, no major change in antagonistic potency was observed at receptors with other mutations in TMs 3, 5, 6, and 7. Thus, the residue Lys(280) (6.55), which is located within the upper third of TM 6 of the human P2Y(1) receptor, is not only critical for the activation of the receptor but also plays an important role in the binding of pyridoxal derivatives and a number of other chemically unrelated P2 receptor antagonists. Lys(280) seems to belong to an overlapping region of the respective binding sites. PMID- 23105166 TI - Peer Victimization and Effortful Control: Relations to School Engagement and Academic Achievement. AB - The relations among peer victimization, effortful control, school engagement, and academic achievement were examined in a group of 390 (212 boys and 178 girls) racially diverse (38.20% Latino and 46.70% White) 6- to 10-year-old children. Specifically, a multimethod, multi-informant approach was used in which data were gathered using self-report, peer-report, and teacher-report questionnaires at three points in time: twice during the initial year of the study when children were in first and third grades and once in the fall of their second-grade and fourth-grade years, respectively. Findings showed that peer victimization was negatively correlated with effortful control; however, longitudinal analyses conducted to examine causal priority were inconclusive. Results from structural equation modeling were consistent with the hypotheses that school engagement mediated the relations between peer victimization and academic achievement, as well as between effortful control and academic achievement. PMID- 23105167 TI - Label-acquired magnetorotation for biosensing: An asynchronous rotation assay. AB - This paper presents a novel application of magnetic particles for biosensing, called label-acquired magnetorotation (LAM). This method is based on a combination of the traditional sandwich assay format with the asynchronous magnetic bead rotation (AMBR) method. In label-acquired magnetorotation, an analyte facilitates the binding of a magnetic label bead to a nonmagnetic solid phase sphere, forming a sandwich complex. The sandwich complex is then placed in a rotating magnetic field, where the rotational frequency of the sandwich complex is a function of the amount of analyte attached to the surface of the sphere. Here, we use streptavidin-coated beads and biotin-coated particles as analyte mimics, to be replaced by proteins and other biological targets in future work. We show this sensing method to have a dynamic range of two orders of magnitude. PMID- 23105168 TI - Charting the time-course of VP-ellipsis sentence comprehension: Evidence for an initial and independent structural analysis. AB - We exploited the properties of VP-ellipsis constructions containing inherently reflexive and inalienable possession verbs that severely constrained final interpretation (e.g., "The policeman perjured himself, and the fireman did too..."). Using the cross-modal lexical priming task, we found that listeners reactivated the subject NP from the first clause at the elided position in the second clause (i.e., the "strict" reading), even though verb properties disallowed such an interpretation. We also found that listeners reactivated the subject NP from the second clause, demonstrating the "sloppy" interpretation. In a final experiment we examined VP-ellipsis constructions that did not contain anaphors (e.g., "The mailman bought a tie for Easter, and his brother did too..."). We found that only the object NP of the first clause was reconstructed in the second clause. We interpret these findings as support for a parser that computes multiple interpretations on-line, yet is initially insensitive to lexical and probabilistic information. PMID- 23105169 TI - How does context play a part in splitting words apart? Production and perception of word boundaries in casual speech. AB - Four experiments examined listeners' segmentation of ambiguous schwa-initial sequences (e.g., a long vs. along) in casual speech, where acoustic cues can be unclear, possibly increasing reliance on contextual information to resolve the ambiguity. In Experiment 1, acoustic analyses of talkers' productions showed that the one-word and two-word versions were produced almost identically, regardless of the preceding sentential context (biased or neutral). These tokens were then used in three listening experiments, whose results confirmed the lack of local acoustic cues for disambiguating the interpretation, and the dominance of sentential context in parsing. Findings speak to the H&H theory of speech production (Lindblom, 1990), demonstrate that context alone guides parsing when acoustic cues to word boundaries are absent, and demonstrate how knowledge of how talkers speak can contribute to an understanding of how words are segmented. PMID- 23105170 TI - Relations between Loss of Services and Psychiatric Symptoms in Urban and Non Urban Settings following a Natural Disaster. AB - Disasters have been associated with both acute and prolonged distress and significant post-disaster psychiatric symptoms. These outcomes may be further complicated by extended periods without vital services and supplies, such as electricity and drinking water. The present study investigated the relations between post-disaster loss of services and psychiatric symptoms in urban/non urban disaster victims. Random-digit-dial methodology was used to interview 1,249 victims of Hurricane Ike, a strong storm that hit Galveston, TX in 2008. Findings demonstrated significant relations between loss of services and post-disaster symptoms of posttraumatic stress disorder (PTSD), depression, and worry. These relations varied by urban/non-urban settings; there were significant positive relations between loss of services and symptoms of depression in non-urban settings, but not in urban settings. Similarly, a stronger relation between loss of services and symptoms of PTSD also was demonstrated in non-urban compared to urban settings. Findings highlight the potential importance of pre-disaster preparation, post-disaster restoration of services, and post-disaster community support in post-disaster psychiatric outcomes, with a particular emphasis in non urban settings. PMID- 23105172 TI - Fabrication of X-ray compatible microfluidic platforms for protein crystallization. AB - This paper reports a method for fabricating multilayer microfluidic protein crystallization platforms using different materials to achieve X-ray transparency and compatibility with crystallization reagents. To validate this approach, three soluble proteins, lysozyme, thaumatin, and ribonuclease A were crystallized on chip, followed by on-chip diffraction data collection. We also report a chip with an array of wells for screening different conditions that consume a minimal amount of protein solution as compared to traditional screening methods. A large number of high quality isomorphous protein crystals can be grown in the wells, after which slices of X-ray data can be collected from many crystals still residing within the wells. Complete protein structures can be obtained by merging these slices of data followed by further processing with crystallography software. This approach of using an x-ray transparent chip for screening, crystal growth, and X-ray data collection enables room temperature data collection from many crystals mounted in parallel, which thus eliminates crystal handling and minimizes radiation damage to the crystals. PMID- 23105173 TI - On a modified electrodynamics. AB - A modification of electrodynamics is proposed, motivated by previously unremarked paradoxes that can occur in the standard formulation. It is shown by specific examples that gauge transformations exist that radically alter the nature of a problem, even while maintaining the values of many measurable quantities. In one example, a system with energy conservation is transformed to a system where energy is not conserved. The second example possesses a ponderomotive potential in one gauge, but this important measurable quantity does not appear in the gauge transformed system. A resolution of the paradoxes comes from noting that the change in total action arising from the interaction term in the Lagrangian density cannot always be neglected, contrary to the usual assumption. The problem arises from the information lost by employing an adiabatic cutoff of the field. This is not necessary. Its replacement by a requirement that the total action should not change with a gauge transformation amounts to a supplementary condition for gauge invariance that can be employed to preserve the physical character of the problem. It is shown that the adiabatic cutoff procedure can also be eliminated in the construction of quantum transition amplitudes, thus retaining consistency between the way in which asymptotic conditions are applied in electrodynamics and in quantum mechanics. The 'gauge-invariant electrodynamics' of Schwinger is shown to depend on an ansatz equivalent to the condition found here for maintenance of the ponderomotive potential in a gauge transformation. Among the altered viewpoints required by the modified electrodynamics, in addition to the rejection of the adiabatic cutoff, is the recognition that the electric and magnetic fields do not completely determine a physical problem, and that the electromagnetic potentials supply additional information that is required for completeness of electrodynamics. PMID- 23105171 TI - Memory for Patient Information as a Function of Experience in Mental Health. AB - Mental health clinicians are tasked to diagnose and treat the millions of people worldwide seeking help for mental health issues. This paper investigates the memory clinicians have for patient information. We hypothesize that clinicians encapsulate mental health knowledge through experience into more abstract concepts, as in other domains changing what clinicians remember about patients compared with non-professionals. We tested memory for realistic patient-therapist interactions in experienced clinicians, intermediately trained graduate students, and laypeople. Clinicians recalled fewer facts than intermediate trainees and as many as laypeople. Furthermore, clinicians reported more abstracted information than all other participants, providing the first empirical demonstration of knowledge encapsulation in the memory of mental health clinicians. We discuss how our results fit into the existing literature on clinical expertise in mental health and the implications of our findings for future research relevant to mental health care. PMID- 23105174 TI - Mapping and mining interictal pathological gamma (30-100 Hz) oscillations with clinical intracranial EEG in patients with epilepsy. AB - Localizing an epileptic network is essential for guiding neurosurgery and antiepileptic medical devices as well as elucidating mechanisms that may explain seizure-generation and epilepsy. There is increasing evidence that pathological oscillations may be specific to diseased networks in patients with epilepsy and that these oscillations may be a key biomarker for generating and indentifying epileptic networks. We present a semi-automated method that detects, maps, and mines pathological gamma (30-100 Hz) oscillations (PGOs) in human epileptic brain to possibly localize epileptic networks. We apply the method to standard clinical iEEG (<100 Hz) with interictal PGOs and seizures from six patients with medically refractory epilepsy. We demonstrate that electrodes with consistent PGO discharges do not always coincide with clinically determined seizure onset zone (SOZ) electrodes but at times PGO-dense electrodes include secondary seizure areas (SS) or even areas without seizures (NS). In 4/5 patients with epilepsy surgery, we observe poor (Engel Class 4) post-surgical outcomes and identify more PGO-activity in SS or NS than in SOZ. Additional studies are needed to further clarify the role of PGOs in epileptic brain. PMID- 23105175 TI - A study of serum lipid profile part-1: Establishment of normal reference values of serum lipid levels in healthy vegetarian population of Gujarat. AB - Fasting samples of 1329 apparently healthy vegetarian Gujarati population were tested for total cholesterol, triglycerides and three major fractions of lipoproteins, i.e. high density lipoproteins, low density lipoproteins and very low density lipoproteins. All the values showed marked increase with the age. Except for serum triglycerides, values differ in males and females in the age group of above 45 years. Compared to Northern Indian population low density lipoprotein and high density lipoprotein values were higher, but values of triglycerides and very low density lipoproteins were lower. There is no significant difference in total cholesterol values. Compared to Southern Indian population low density lipoprotein and very low density lipoprotein values were higher but values of triglycerides, total cholesterol and high density lipoprotein were lower. All serum lipid values were significantly lower than the Westem population. The range of values for both the sexes is presented for different age groups. PMID- 23105176 TI - A rabbit model for studying hypocholesterolemic effect of drugs and hypocholesterolemic effect of extracts of garlic (Allium sativum). AB - An experimental model of hypercholesterolemic rabbits suitable for studying the hypocholesterolemic effect of compounds was developed. Rabbits were made hypercholesterolemic by oral administration of cholesterol (100mg/kg body weight/day) suspended in groud nut oil by gastric intubation (Ryle's tube). Cholesterol can be given to rabbits from 10 days to 6 months depending on the degree of hypercholesterolemia required and duration of study of hypocholesterolemic effect. In one month cholesterol feeding experiment, the serum cholesterol level in normal controls (not given cholesterol) was 67+/-11.3 mg/dl and in cholesterol fed animals 191.3+/-70.6 mg/dl. In 2 months experiment, besides hypercholesterolemia, abnormal serum lipid profile and increase in lipid content in liver, heart and aorta were also seen. To such animals when water and methanol extracts of garlic were given along with cholesterol, there was significant decrease in serum cholesterol level. The advantage of this method over the method in which cholesterol is mixed with diet to induce hypercholesterolemia is that exactly same and calculated amount of cholesterol can be given for each animal. This minimises the variations in serum cholesterol levels in different animals. PMID- 23105177 TI - LP(a) phenotypes and levels in angiographically proven coronary heart disease patients and controls. AB - Lipoprotein Lp(a) excess has been identified as a powerful predictor of premature atherosclerotic vascular diseases. To evaluate this in a North-Indian population, 130 CAD patients and 130 controls were analyzed. The size of the apo(a) phenotypic isoforms was inversely proportional to Lp(a) concentrations. The mean concentration of Lp(a) in the CAD patients was 42+/-34 mg/dl whereas in the normal subjects it was much lower, 27+/-27 mg/dl. 157 subjects out of the total 260 subjects showed plasma levels of >20mg/dl. The frequency of high Lp(a) levels was much higher in patients(73%) than controls (43%). These data suggest (1) that there is heterogeneity of the Lp(a) polymorphism, (2) Higher Lp(a) levels were found in patients than in the controls, (3) Patients showed 1.5 fold increase in Lp(a) levels as compared to the controls. We conclude that low molecular weight apo(a) isoforms are significantly associated with increased risk of CAD in the North-Indian population. PMID- 23105178 TI - Changes in antioxidant enzyme levels and DNA damage during aging. AB - Multiple mechanisms underlie the human aging process, but interest continues in the role that free radicals and antioxidants may play. The concentrations of lymphocyte free radical generation (O(2) (-)& H(2)O(2)), DNA damage and antioxidant enzyme levels (glutathione Stransferase, superoxide dismutase and catalase) were evaluated in 110 healthy individuals with an age range of 20-80 years. The antioxidant enzyme levels were significantly less in very old age when compared to young. Moreover, the levels of free radical concentration and DNA damage were increased in the same age group with respect to younger group. Cigarette smoking had a positive relation with free radicals and DNA damage, and inverse relation with antioxidants. On the other hand, body mass was found to have positive relation with free radical generation only. The data indicate that depletion of antioxidant enzyme levels would render the older people more susceptible to free radical stress and DNA damage. PMID- 23105179 TI - Free radical generation and lipid peroxidation among the dry cell industry workers exposed to carbon. AB - A total of 75 healthy male dry cell industry workers exposed to carbon for 5, 8 and 10 years were compared with 48 controls matched for age and economic status with respect to free radical generation, lipid peroxidation and antioxidant levels. Lymphocytes were seperated from the whole blood and used for estimation of free radicals and antioxidants. Plasma lipid peroxidation products were estimated in the form of thiobarbituric acid reactive substances. Significant increase in free radical generation and lipid peroxidation products were observed in carbon exposed population than controls, and the increase was found to be significant with increase in the period of exposure. The levels of antioxidants i.e., superoxide dismutase (SOD) and catalase were found to decrease with the increase in exposure to carbon in industrial workers. These results suggest that exposure to carbon augments free radical generation, lipid peroxidation and promotes decline in antioxidant enzymes. PMID- 23105180 TI - Antigens of diagnostic and prophylactic importance inEntamoeba histolytica. AB - Amoebiasis, caused by an enteric protozoanEntamoeba histolytica, is one of the major parasitic diseases of mankind. Current estimate suggests that the parasite infects about 10% of the world population at any given time. There is an urgent need to characterize the antigenic molecules ofE. histolytica, and find out antigens which have both immunodiagnostic and prophylactic potential against amoebiasis. The results of somatic antigen analysis, using sera from immune or infected individuals, indicated that the wholeE. histolytica trophozoites, are highly complex and heterogeneous in nature and both immunodiagnostic and immuno prophylaxis activity remain mainly in a surface associated 29 kDa glycoprotein ofE. histolytica. Future studies at molecular level particularly, genes responsible for expression of this protein, their homology with other proteins and structure analysis will give better understanding about this polypeptide. Studies on excretory secretory antigens, clearly demonstrated thatE. histolytica like many organisms, also liberates certain antigenic moieties into the culture medium during in vitro cultivation and this antigen has similar diagnostic values like the conventional somatic antigens. It is important that the ESA should be prepared from the supernatant after collecting the cell and use for immunodiagnosis of amoebiasis. This is an additional source of antigen which will help in carrying out more tests using the same reagents. Further studies are needed to clarify the location of these molecules on the parasite, along with detailed biochemical and immunological characterization and their relation with the pathogenesis. PMID- 23105181 TI - Changes in serum copper levels in patients with malignant diseases undergoing radiotherapy. AB - Present study repots changes in serum copper levels (SCL) in various neoplastic diseases undergoing radiotherapy. We estimated SCLs in 140 individuals comprising of 90 previously untreated patients with various malignancies and 50 healthy controls. Patients received radiation in doses of 40-70 Gy in 4-7 weeks. SCLs were again estimated in patients following irradiation. The mean SCL was significantly higher (P<0.001) in cancer patients as compared to healthy controls. It declined significantly (P<0.001) following irradiation. However, it remained significantly higher as compared to healthy controls (P<0.01). Highest fall in SCL was seen in complete clinical responders and least in non-responders to radiation treatment. Serial estimation of SCLs may be useful in the treatment monitoring of the neoplasms undergoing radiation treatment. PMID- 23105182 TI - Role of prostaglandin in the regulation of gastric H(+)-Transporting system. AB - Prostaglandins and (PG) have been reported to be an important gastric acid suppressive factor. However, the mechanism underlying is yet to be clearly established. In vitro study with gastric microsomes in presence of both PGE(2) and PGI(2) shows a stimulation of gastric H(+) K(+)-ATPase activity below 1X10( 6)M and 2.5X10(-7)M concentrations respectively. However, with further increase in concentrations of both PGE(2) and PGI(2), H(+), K(+)-ATPase activity shows an inhibition but PGI(2) completely obliterates the K(+) stimulated part of H(+), K(+)-ATPase activity at higher concentration. The H(+)-ion transport study using chambered frog gastric mucosa shows that both PGE(2) and PGI(2) inhibit H(+)-ion transport at 5X10(-6) M and 10X10(-6)M concentrations respectively but the effect of PGI(2) is reversible. These differential effects of PGE(2) and PGI(2) on microsomal H(+), K(+)-ATPase and on H(+) transport my be caused by the differential effects of these phospholipid mediators with the gastric mucosal cell membrane. This in vitro investigation shows the role of prostaglandin (s) as a physiological switch/regulator of gastric H(+) ion transport leading to the cessation of gastric acid secretion. PMID- 23105183 TI - Salivary proteolytic activities in periodontitis, gingivitis and diabetes mellitus. AB - Elastase activity was found to be significantly increased in periodontitis (0.872+/-0.4270 absorbance units/mg protein, mean+/-S. D., 1.05+/-0.61 units/ml saliva), gingivitis (0.772+/-0.416 units/mg protein, 1.515+/-0.952 units/ml) and diabetes (0.549+/-0.286 units/mg protein, 1.20+/-0.769 units/ml) compared to normals (0.255+/-0.089) units/mg protein, 0.264+/-0.079 units/ml). Chymotryptic activity was not found to be increased in these disease conditions over the normal level (0.284+/-0.096 units/mg protein). Aminopeptidase activity was elevated only in periodontitis (0.670+0.140 units/mg protein) compared to normals (0.349+/-0.100 units/mg protein). Trypsin-like activity was also found to be significantly raised in periodontitis compared to normals when Pro-Phe-Arg-p nitroanilide (0.666+/-0.204 units/mg protein), Ile-Pro-Arg-p-nitroanilide (1.59+/ 0.260 units/mg protein) and Pyroglu-Pro-Arg-p-nitroanilide (1.82+/-0.380 units/mg protein) were used as substrates. The normal values with these three substrates were respectively, 0.454+/-0.110, 1.04+/-0.231 and 1.15+/-0.312 units/mg protein. Total protein level in saliva was found to be significantly elevated in gingivitis (209+/-66.8 mg/dl) and diabetes (204+/-68.0) compared to normal values (107+/-20.7). Increase in periodontitis was marginal (127+/-28.3 mg/dl). Expression of proteolytic activities normalized to protein level was useful in differential diagnosis. Increase in elastase level in saliva is not a specific marker for periodontal diseases. PMID- 23105184 TI - Interferences in clinical chemistry analysis. AB - Analyses of body fluids in clinical chemistry laboratory are subject to a number of interferences that affect the analytical accuracy. The interferents arise from exogenous sources like drugs and additives as well as such endogenous sources like lipemia, hemolysis and icteria. Our studies demonstrate matrix interference in the form of analytical blas between serum and aqueous matrix calibrators. The clinical chemist should constantly be aware of this factor. Correction of interferences is recommended as an integral part of the quality assurance program. PMID- 23105185 TI - Regulation of metabolic pathways in liver and kidney during experimental diabetes: Effects of antidiabetic compounds. AB - Diabetes has been classified as a disease of glucose overproduction by tissues, mainly liver and glucose underutilization by insulin requiring tissues like liver, adipose and muscle due to lack of insulin. There is, however, glucose over utilization in tissues not dependent on insulin for glucose transport like kidney, nerve and brain. There are serious complications due to this excess glucose in these tissues and their reversal is important for a good metabolic control and normalisation of other parameters. Insulin, trace metals and some plant extracts have been used to see the reversal effects of the complications of diabetes in liver and kidney in experimental diabetes. Almost complete reversal of the metabolic changes has been achieved in the activities of key enzymes of metabolic pathways in liver and kidney and an effective glucose control has been achieved suggesting a combination of therapies in the treatment of metabolic disturbance of the diabetic state. PMID- 23105186 TI - Interference of anti-T4 autoantibodies in the single step free T4 radioimmunoassays. AB - The thyroid hormone profile of a hypothyroid patient, with moderate sized diffuse goiter and history of exogenous thyroid hormone therapy, was found to be highly ambiguous. The total as well as free T4 levels were consistently high (out of range) with suppressed T3 (total and free) and elevated thyrotropin levels. We incubated the serum with the radio-iodine labelled T4 and observed that the patient's serum bound about 50.5% of the total radioactivity resulting in 85.3% interference in the radioimmunoassay. On resolving the serum proteins by cellulose acetate electrophoresis, the radioactivity was detected in the gamma globulin band. The protein profile showed mildly raised levels of IgG. Therefore it was established that the patient's serum carried T4 reactive antibodies (IgG) which were interfering in the immunoassays. Elevated anti-thyroid microsomal antibodies were also present in the patient's serum. The anti-T4 antibodies were highly specific for T4 and did not show any cross reactivity with the T3 or its analogues used in the estimation of free T3. We stripped the serum by precipitating the immunoglobulins and were successful in estimating the levels of free T4 in the stripped serum by single step radioimmunoassy. PMID- 23105187 TI - Altered maternal thyroid function: Effect of L-carnitine supplementation on fetal and neonatal myocardial free fatty acid oxidation,in vitro. AB - Effect of L-carnitine supplementation on myocardial free fatty acid oxidation,in vitro, in offsprings born of hypothyroid and hyperthyroid mothers was studied in rats. L-carnitine supplementation stimulated myocardial fatty acid oxidation during gestational period in offspring born of control and hyperthyroid mothers. In contrast L-carnitine supplementation induced stimulation in myocardial fatty acid oxidation was very less in fetuses born of hypothyroid mothers. However, in neonates born of hypothyroid mothers L-carnitine stimulated myocardial fatty acid oxidation to a great extent. The results suggested that during maternal hypothyroidism low availability of thyroid hormones to fetuses through maternal circulation and availability of less carnitine to neonates due to hypolactation might be responsible for decreased myocardial free fatty acid utilization. In neonates born of hypothyroid mothers and with cardiac energy insufficiency parenteral carnitine supplementation might be of great help to prevent mortality and morbidity of such offsprings. PMID- 23105188 TI - Studies on a new antitubercular drug, trifluoperazine: Its effect in combination with conventional antitubercular drugs in tubercular lymphadenitis. AB - After demonstrating that trifluoperazine (TFP) possesses invitro antitubercular activity against drug (single and multidrug) resistantMycobacterium tuberculosis, we initiated preliminary clinical studies in a few patients of tubercular lymphadenitis. Effect of TFP was assessed by testing the antitubercular activity of the serum of patients receiving TFP in addition to regular therapy. Patients were divided into two groups of 30 each. For ethical considerations, patients of both groups were treated initially for one month with antitubercular therapy (ATT) consisting of isoniazid, rifampicin, ethambutol and pyrazinamide and TFP was tried for 15 days only. Patients of group1 were given a single dose of TFP (5mg/day) daily from days 31 to 45 in addition to ATT, while those in group 2 received ATT only. Assessment of the antitubercular activity of the serum (testedin vitro in Youmans and Karlson's liquid medium) revealed that the serum of patients (collected on 45th day) of group1 (ATT+TFP treated) possessed much higher antitubercular activity than that of group 2 (ATT only treated) patients. Clinical examination indicated that overall improvement was seen much earlier in group1 (ATT+TFP) patients than in group 2 (ATT alone) patients. At the end of the follow up period of 6 months with ATT from 46th day onwards to both groups, there were no side effects due to TFP. Hematology and liver function tests were normal in both the groups. We suggest that TFP has good potential and therefore deserves further studies either in combination with other drugs of ATT or as one of the drugs of ATT, for the treatment of tuberculosis due to MDR strains to find a suitable effective dose without side effects. PMID- 23105189 TI - Mycobacterium tuberculosis H(37)Ra ESAS-7-An excretory-secretory antigen fraction of immunodiagnostic potential in pulmonary tuberculosis. AB - A mycobacterial excretory-secretory protein fraction ESAS-7 purified by 50% ammonium sulphate precipitation followed by SDS-PAGE fractionation was evaluated by penicillinase enzyme linked immuno-sorbent assay (ELISA) for its sensitivity and specificity in the diagnosis of pulmonary tuberculosis. At a "cut off" serum dilution of 600, 38 (90%) of 42 sera from bacteriologically confirmed tuberculosis cases, 15 (100%) of 15 sera from bacteriogically negative but anti tubercular therapy (ATT) responded cases, 3 (7%) of 43 sera from normal healthy subjects and 4 (8%) of 48 sera from non tuberculous disease control cases gave positive reaction for tubercular antibody to ESAS-7 antigen fraction containing predominantly 33-kDa protein with a sensitivity of 90% in bacteriologically confirmed cases and specificity of 92%. Further, this diagnostic assay using the ESAS-7 antigen is more sensitive requiring as little as one nanogram antigen per test compared to use of 100 nanogram EST-6 antigen reported earlier. Thus use of ESAS-7 antigen for antibody detection has good diagnostic potential with improved specificity in pulmonary tuberculosis. PMID- 23105190 TI - An immunological based study of monoclonal gammopathies among suspected individuals in Kashmir region. AB - Serum and urine samples from 513 patients clinically suspected of monoclonal gammopathies over a period of five years (1992-97) were subjected to various immunological procedures viz, electrophoresis, immunoelectrophoresis and immunoglobulin estimations. Laboratory investigations confirmed gammopathies in 10.33%. It was observed that overall age of incidence for monoclonal gammopathies in both sexes was between 42-72 years with a male to female ratio of 1.4?1. Predominant paraprotein detected was IgG type (75.47%) followed by IgA (16.98%) and Bence Jones proteins (7.55%). Amongst positive patients, 64.16% were having kappa (k) type light chains and 35.84% lambda (delta) type light chains. 69.39% patients with serum M component (IgG and IgA) had Bence Jones proteinuria. Densitometric scanning revealed that majority of IgG type paraprotein was found in the slow gamma globulin region and majority of IgA type paraprotein was found equally distributed between beta and fast gamma globulin regions. Both types had decreased albumin and alpha-2-globulin concentrations as compared to normal controls. Immunoglobulin levels in patients with paraprotein had very high levels of serum IgG (6467.0 mg%) and IgA (2714.0 mg%) in respective types of monoclonal gammopathies; the rest of immunoglobulin classes were either at normal or decreased levels. PMID- 23105191 TI - Construction of chimeric immunogens: Bioactive fragment of human IL-1beta or polytuftsin (PT) capable of eliciting immune responses to HIV peptides. AB - In this study, we have examined the effect of linking of bloactive fragment of human IL-1beta (163-171) or polytuftsin (PT, a synthetic polymer of natural immunomodulator "tuftsin") with synthetic peptides of HIV on the induction of immune response to the synthetic peptides. A panel of synthetic peptides representing defined region of gp41, gp120 and gag were used as antigens. Immunomodulators linked peptides (i.e. peptide-IL-1beta or peptide-PT) or peptide dimers were employed for immunization in Balb/c mice. Mice immunized with the peptide-immunomodulator develop effective T-cell proliferation,in vitro cytokine release and higher antibody production, but not with peptide dimers. We also found that peptide-immunomodulators induced high level of IgG2a antibody production. Furthermore, there was a positive correlation between the levels of cytokine (IL-2 & IFN-gamma) and IgG isotype production. Thus it would appear that incorporation of IL-1beta fragment or PT selectively enhances the Th1 type response to these peptides and may therefore be important for virus neutralization and clearance. However, the effect of IL-1beta fragment was found to be more pronounced than polytuftsin. Such an approach may provide effective vaccination against other infectious diseases. PMID- 23105192 TI - Effect of short term vitamin E supplementation on lipid peroxidation in acute myocardial infarction. AB - In view of sufficient body of evidence to substantiate the role of free radical mediated oxidative injury in myocardial infarction (M.I.), the utility of exogenous supplementation with antioxidant substance, vitamin E was studied. Forty patients of acute myocardial infarction were divided into two equal groups, one who received vitamin E and the other who did not. Plasma MDA levels showed a reduction in patients of M.I. who received vitamin E as well as in those who did not, however, the decrease was significantly more in the vitamin E treated subgroup. PMID- 23105193 TI - Serum magnesium levels in preterm labour in relation to socioeconomic status. AB - The present study revealed significantly lower levels of serum magnesium in patients with preterm labour without any apparent cause as compared to normal term pregnant women in labour. The values were also lower in women with low socioeconomic status, older age and consuming vegetarian diet. Hence, estimation of serum magnesium levels in pregnancy may be a useful parameter in preterm labour. PMID- 23105194 TI - Enhancement of myeloperoxidase activity in WBCS in oral cancer patients treated with Granulocyte Macrophage Colony Stimulating Factor (GM-CSF)-A pilot study. AB - In a pilot study with five oral cancer patients undergoing radiotherapy (RT) three were given Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) as a protective agent to reduce the mucosal inflammation during radiotherapy. The myeloperoxidase (MPO) enzyme activity in WBC was quantitated. The three patients showed a significant increase in the MPO activity when compared with two untreated controls indicating the efficacy of GM-CSF as a protective agent. It is suggested that further detailed studies with larger number of patients would be useful. PMID- 23105195 TI - Electrochemiluminescence-Improving the performance of immunossays. AB - The novel combination of an electrochemiluminescent label used in a magnetic microparticle-based immunoassay format defines a significantly improved level of immunodiagnostic performance. The main advantages of electrochemiluminescent immunoassays are high sensitivity, extended linearity of signal response together with speed of signal generation and measurement. These attributes in conjunction with fully automated random access analyser lead to superior level of user convenience and clinical application. Electrochmemiluminescence has been applied today to a wide range of analytes of biological interest including thyroid and fertility hormones, infectious desease, as well as various markers of cardiac, malignant and auto immune disease.However, the spectrum of applications is far from being exhausted. The capacity of this technology goes beyond current requirements for diagnostic laboratory tests. PMID- 23105197 TI - Antitubercular activity of garlic (allium sativum) extract on combination with conventional antitubercular drugs in tubercular lymphadenitis. AB - Based on our demonstration earlier that ethanol extract, water extract and a compound purified from garlic possessedin vitro antitubercular activity against drug resistant and susceptibleMycobacterium tuberculosis, we tried the effect of garlic extract in 30 patients of tubercular lymphadenitis. For ethical considerations, two groups of patients, 30 each, were given antitubercular therapy (ATT) consisting of isoniazid, rifampicin, ethambutol and pyrazinamide for 30 days. For the next 15 days (31 to 45 days) group 1 patients received 3-6 garlic pearls per day in addition to ATT while group 2 patients received ATT only. From 46th day onwards both the groups received ATT only for 6-8 months. Antitubercular activity of the serum samples collected on 45th day was assessed by its effect on the growth ofM. tuberculois. The serum of group 1 patients showed significantly much higher antitubercular activity than that of group 2 patients. Further, there was relief of dyspeptic symptoms caused by ATT therapy in patients of group 1 with garlic plus ATT therapy but no change in group 2 patients with ATT only. Liver function and hematological tests were normal in both the groups after 6 months of therapy. Garlic extracts or compounds have a good potential as antitubercular(s) drug if given as a supplement to ATT. PMID- 23105196 TI - Antioxidant vitamins and chemoprevention. AB - Free radicals play an important role in human carcinogenesis and the mechanism of their counteraction by antioxidant vitamins has been reviewed. It seems more likely that these vitamins work in concert rather than acting singly. Currently available data are compatible with the notion that these vitamins act as chemopreventives against some important cancers, e.g. carotenoids for lung cancer, ascorbic acid for salivary gland cancer, tocopherols for head and neck cancers etc. Thus, a greater consumption of fruits and vegetables should be encouraged as they are the natural sources of these chemopreventive, antioxidants along with other protective factors packaged by nature. However, much work still remains to be done to establish the role of antioxidant vitamins in carcinogenesis. PMID- 23105198 TI - Development of a highly sensitive direct microtiter plate ELISA for human serum testosterone. AB - A simple, highly sensitive, direct, competitive ELISA for human serum testosterone has been indigenously developed. Specific antisera against testosterone were raised in rabbits using testosterone-3carboxymethyl oxime (CMO) bovine serum albumin (BSA) as the antigen. For the enzyme conjugate, testoterone 3CMO was coupled with horse raddish peroxidase by the active ester method. The standard curve covered a wide range from 3.9 pg/ml to 500 pg/ml. The inter and intra-assay variation were found to be low and within the acceptable limits. Specificity and accuracy for the assay was established by having negligible crossreactivity with the related steroids and an excellent parallelism between the sample and standard dilution curve. Samples measured by RIA and ELISA showed very high degree of correlation (r=0.991). PMID- 23105199 TI - Predictive value of serum thyroglobulin in treated patients with differentiated thyroid carcinoma. AB - An in-house radioimmuno assay for serum thyroglobulin was developed in our laboratory and compared its relative sensitivity with that of whole body scan in the detection of residual tumour or metastases and evaluated the predictive value of serum thyroglobulin in the clinical course of the disease. Ninety six patients after thyroidectomy were followed up for a maximum period of five years in this study.The sensitivity and specificity of serum thyroglobulin were found to be close to that of whole body scan (85% and 94% respectively). According to this study, a serum thyroglobulin >40 ng/ml can differentiate between patients with metastases and those in remission. Serum thyroglobulin can replace whole body scan during the subsequent follow-up if the patient had concordant whole body scan and serum thyroglobulin during initial assessment. PMID- 23105200 TI - Biochemical advances in detection of the acute coronary syndromes: Implications for therapeutic decisions. AB - In this paper, I have attempted to place the evolving insights of the pathophysiology of coronary atherosclerosis in the context of the conventional perspective of clinical medicine. We strive to prevent death and to relieve suffering. Our clinical tools are critical but limited. Troponin, a biomarker of unprecedented organ specificity, in the context of the appropriate setting of new chest pain (or its equivalent syndrome), is an extraordinary aid to clinical diagnosis. Highly effective therapy is evolving which reduces loss of myocardium, undoubtedly reducing not only acute death but progression to congestive heart failure. Even if the newer therapies of the GpIIb/IIIa platelet antagonists and antithrombins are not yet widely employed, or may not be available to some physicians, the convincing demonstration of myocardial injury by troponin presents objective evidence to both the patient and the attending physician that serious compliance with a program of risk reduction must be urgently considered. Hoeg has described the mosaic of risk factors beyond the conventional and often ignored basic ones (JAMA, 1997, 277, 1387-1390). He provides thoughtful hope and encouragement for both patient and physician to do more in prevention of the subsequent predictable progression. We should look on a troponin positive vague unstable angina event as similar to a tremor which preceeds a subsequent earthquake. Although the mass of myocardium lost in such an episode may be small, it is a warning of the major acute myocardial infarction which can be predicted to follow at a later time if the course of the individual patient is not altered. Troponin is the objective evidence. PMID- 23105201 TI - The relevance of apolipoprotein E polymorphism to Alzheimer's disease. AB - The apo E gene located on chromosome 19 in humans is polymorphic. The three apo E isoforms E2, E3, and E4 are coded by three common alleles of the gene. The amyloid plaques in brains of Alzheimer disease (AD) patients are known to contain apo E. There is an increased prevalence of E4 allele in AD patients. apo E exhibits increased binding to a peptide Abeta deriving from amylold precursor protein. apo E, the risk factor for late AD disease is unable to prevent formation of paired helical filaments which in turn destabilizes neuronal microtubules.A variety of molecular techniques are available for apo E genotyping using DNA amplified by the polymerase chain reaction (PCR). The high guanine to cytosine content of apo E is problematic to the extent that the yield of PCR product and hybridization stringency can be compromised. The specificity of diagnosis of late-onset AD can be improved when results of apo E genotyping are evaluated together with clinical criteria. PMID- 23105202 TI - The role of band 3 protein in oxygen delivery by red blood cells. AB - The synergistic effects of hemoglobin, carbonic anhydrase and the band 3 protein make red blood cells the ideal vehicle for oxygen delivering to the tissues. As long as oxygen is supplied by these ideal vehicles, oxygen intoxication of the tissues is precluded. Band 3 protein mediates the "Chloride-Shift", i.e., the anion exchange of Cl(-)/HCO(3) (-). Because of the Chloride-Shift, red blood cells are able to recognize metabolically active tissues and to supply the minimum amount of oxygen to the tissues. Investigation into the molecular mechanisms of the anion exchange mediated by the band 3 protein was introduced. PMID- 23105204 TI - Therapeutic drug monitoring-A review. PMID- 23105203 TI - Biochemical diagnosis of liver disease. AB - It is important that clinicians and laboratorians, including clinical chemists and pathologists, recognize and understand the clinical significance of abnormal liver function tests. The liver regulates many important metabolic functions. Hepatic injury is associated with distortion of these metabolic functions. Hepatic disease can be evaluated and diagnosed by determining serum concentrations of a number of serum analytes. Many serum analytes exist to assist in the biochemical diagnosis of liver disease. The focus of this paper is on the analytes which are associated with hepatic necrosis, cholestasis, defects in excretion and end stage hepatic disease which results in decreased synthetic function. The abnormalities of these serum analytes will be correlated with the important types of liver disease. PMID- 23105205 TI - Clinical chemistry of anti-arrhythmic drugs. PMID- 23105206 TI - From editor's desk. PMID- 23105207 TI - Immunomonitoring followed by optimal dec therapy for successful management of clinical filariasis in an endemic area. AB - Lymphatic filariasis continues to be the major cause of clinical morbidity in India and other developing tropical countries. One of the major lacunae in the effective management of clinical filarial cases is the non-availability of a suitable diagnostic test for confirming filaria aetiology in acute, chronic and occult clinical cases where microfilariae (mf) are not usually seen in peripheral circulation. Studies in our laboratory have shown the usefulness of filarial antibody and antigen assays using microfilarial excretory-secretory (mf ES) antigen in detecting microfilaraemic, acute and chronic filarial cases and in confirming filarial aetiology in occult infections. Diethylcarbamazine citrate (DEC) is the drug of choice for lymphatic filariasis. Different regimens of DEC have been explored in the treatment of microfilaraemic cases. Immunomonitoring has shown that the seroconversion of antigen and antibody positivity was found to be very helpful in determining appropriate period of DEC treatment for clinical relief and cure in clinical filarial patients and further they did not have recurrence in most of the cases. Optimal DEC (6mg/kg body wt/day for 21 days each month for 3-12 months) therapy was found to be very effective in acute and atypical clinical manifestations such as asthmatic bronchitis, pulmonary eosinophilia, monoarthritis, recurrent upper respiratory tract infections (URI), pneumonia (super imposed infections) in children and minimal hydrocele, epididymoorchitis, lymphangitis, lymphadenitis, acute abdomen, central serous retinopathy, tenosynovitis, pain and swelling in limbs and joints in adults living in filaria endemic areas. PMID- 23105208 TI - TPS(TM) a circulating tumor marker in breast cancer. AB - Tissue polypeptide specific antigen (TPS) measures an antigenic determinant associated with human cytokeratin 18. TPS is a marker of tumor cell activity in contrast to markers related to tumor burden. The value of detecting circulating TPS lies in the early detection of recurrence by serial determinations and in the rapid assessment of the efficacy of the treatment. Pretreatment levels of TPS in patients with metastatic breast cancer are related with prognosis. Decreasing TPS levels during therapy monitoring indicate response and a fast response is correlated to favourable prognosis. Increasing TPS levels, in the presence of clinically stable disease or partial remission, predict disease progression with a considerable lead-time. Improved effectiveness in breast cancer management can be seen when TPS is used in combination with CA 15-3. When tumor marker determinations are applied in a proper way in the appropriate situation, the results can assist the oncologist. Thus monitoring of therapy in patients with metastatic breast cancer should be based upon serial TPS and CA 15-3 determinations in serum. The use of tumor marker determinations in the early follow-up interval following surgery to detect early tumor recurrence may be simpler, more sensitive and less expensive than imaging methods. PMID- 23105209 TI - Current perspectives on laboratory markers for the assessment of cardiovascular disease and myocardial damage. AB - The disruption of the endothelim is a prelude to the evolution of arteriosclerosis. Nitric oxide is critical to endothelial function. The oxidation of low density lipoprotein (LDL) mediated by small dense LDL particles contributes to the development of cardiovascular disease. The multiple effects of homocysteine including its potentiating the binding of lipoprotein(a) (LP(a)) to fibrin and its role in the formation of small dense LDL particles highlights its importance in the evolution of cardiovascular disease and justifies its measurement. Problems in measurement of homocysteine should be kept in perspective. The measurement of release of proteins from the cardiac contractile apparatus such as Troponin I has advantages over conventional measurement of cardiac enzymes and isozymes. PMID- 23105210 TI - Detection ofAspergillus Fumigatus based on Asp fl gene in clinical specimens. AB - Oligonucleotide primers were synthesised based on the gene sequence of an 18 kDa allergen/antigen ofA. fumigatus isolated from a pathogenic strain. Polymerase chain reaction (PCR) was carried out using the forward and reverse primers and genomic DNA ofA. fumigatus, A. flavus andA. niger as template. This resulted in a PCR product of 480 bp with onlyA. fumigatus. The absence of PCR product inA. flavus andA. niger with the primers of Asp fl facilitated use of these primers for detection ofA. fumigatus in clinical specimens of patients. The results were compared with microscopy, culture and serology. Application of PCR test to clinical samples of aspergillosis patients is discussed. PMID- 23105211 TI - Detection ofNeisseria Gonorrhoeae by polymerase chain reaction (PCR). AB - Three different sets of primers were designed using FASTA homology search and PRIMERSELECT for the specific detection ofNeisseria gonorrhoeae using polymerase chain reaction (PCR). These primers amplified the highly conserved regions of genes for Open Reading Frame (ORF), Outer Membrane Protein (OMP) and 23S rRNA sequences ofN. gonorrhoeae. Each of the PCR primer set was evaluated using the DNA samples isolated from eight different positive isolates ofN. gonorrhoeae cultured from urethral swabs of patients visiting Maulana Azad Medical College and Safdarjung Hospital. Amplification products were analyzed on agarose gel electrophoresis. Two sets of PCR primers, designated as Ngu1/Ngu2 and Ngu5/Ngu6, specific for ORF and OMP gene respectively, amplified four regions of the gene which may help to differentiate the various strains ofN. gonorrhoeae infecting indigenous population. In contrast, a single, specific PCR product of 650 bp was visualized on agarose gel with primers Ngu3/Ngu4, amplifying the 23S rRNA gene. Under optimum conditions, as low as 25ng of DNA isolated from eight different clinical strains ofN. gonorrhoeae could be detected by PCR using Ngu3/Ngu4 set of primers. Our results suggested that Ngu3/Ngu4 could serve as good primers for the specific, reproducible and sensitive diagnosis ofNeisseria gonorrhoeae from clinical samples. PMID- 23105212 TI - Effect of nutritional supplements and protease inhibitor on the yield of es antigens ofBrugia malayi microfilariaein vitro. AB - Brugia malayi microfilarial excretory-secretory (mf ES) antigens obtained byin vitro maintenance of mf are important tools in the immunodiagnosis of bancroftian filariasis. To increase the yield of mf ES products, the effect of nutritional supplements on the culture medium (RPMI 1640) and the maintenance temperature were studied. Supplementation of RPMI 1640 medium with organic acids and sugars of Grace's insect culture medium forin vitro maintenance of 10 lakhs of mf in 40 ml medium increased the yield of mf ES antigen from 152 MUg to 364 MUg of mean protein, content and the mean antigen titre from 200 to 400. Supplementation with phenyl methyl sulphonyl fluoride (PMSF) and shift in the culture temperature resulted in a further increase in the yield of mf ES antigen to 502 MUg of mean total protein with an antigen titre of 800. The modification resulted in a net increase of 3 fold in the protein content and 4 fold in the antigen titre of ES products. The above modifications in thein vitro maintenance of mf did not affect the diagnostic quality of mf ES antigen, which gave a sensitivity and specificity of 80% and 90% respectively in detection of filarial IgG antibodies inWuchereria bancrofti infected cases. PMID- 23105213 TI - Biochemical characterization of an immunodominant allergen/antigen ofAspergillus fumigatus. AB - An 18kDa protein was identified as a major immunodominant allergen/antigen secreted by a wild type isolate and various clinical isolates ofA. fumigatus. The protein was purified to homogeneity and the N-terminal amino acid was found to be alanine. The N-terminal 20 amino acid sequence of 18kDa was found to be similar to restrictocin, a cytotoxin secreted byAspergillus restrictus. Mass spectroscopic analysis of the purified allergen revealed a molecular size of 17.01 kDa. Immunoreactivity of the purified allergen with monoclonal antibodies and specific IgG and IgE antibodies of the patients of aspergillosis confirmed that this protein is Asp fl. PMID- 23105214 TI - T-antigen (Gal beta3 GaINAc alpha-) containing glycoproteins of human reace. AB - Desialation of cell surface glycoconjugates due to bacterial or viral infection can expose epitopes like T-antigenic structure which can also occur during oncological transformations. Human platelet plasma membrane glycoproteins were isolated by jacalin affinity chromatography. Potential T-antigen containing glycoproteins which were not reported before could be identified on the Western blot using peanut agglutinin-horse radish peroxidase (PNA-HRP) after neuraminidase treatment. Alpha-galactosyl epitopes recognized by anti-gal were found to be absent in human platelet plasma membrane glycoproteins. Under the experimental conditions employed, the Gp IIbalpha was identified most rich in T antigenic structures. Probable role of exposed T-antigenic structures and alpha galactosyl epitopes in pathological conditions is discussed. The identity of major glycoprotein bands was confirmed by differential lectin-binding studies with Concanavalin A on the Western blot. The higher binding affinity of jacalin for T-antigenic structures when compared to PNA enabled the isolation and detection of the antigen containing platelet surface glycoproteins which were not reported before. PMID- 23105215 TI - Hyperlipidemia, increased lipid peroxidation and changes in antioxidant enzymes, Na(+)-K(+)-ATPase in erythrocytes of type 2 diabetic patients in andhra pradesh. AB - Plasma levels of lipids, lipoproteins and lipid peroxides and erythrocyte Na(+) K(+) ATPase, Mg(2+)ATPase and antioxidant enzymes were measured in type-2 diabetic patients. A significant decrease in Na(+)-K(+)-ATPase activity was observed in diabetic patients which was negatively correlated with blood glucose and lipid peroxides, while the Mg(2+)-ATPase activity was increased. In the diabetic subjects the plasma concentrations of Na(+) and K(+) were increased where as erythrocyte levels of Na(+) were increased and K(+) were decreased. Hyperlipidaemia and increased levels of lipid peroxides were observed in the diabetic subjects. There was a significant increase in erythrocyte catalase activity in diabetics which positively correlated with their lipid peroxides. There was no change in GPx activities between controls and diabetics. PMID- 23105216 TI - Early oxidative change in low density lipoproteins during progressive chronic renal failure. AB - Modified low density lipoproteins (LDL), including their oxidized forms, have been widely implicated in the etiology of atherosclerosis and concomitant cardiovascular disease (CVD) in chronic renal failure (CRF). The nature of events that lead to oxidative changes in LDL proteins are not clearly understood. Thus, patients suffering from CRF were grouped into mild, moderate and severe categories based on their blood urea and serum creatinine levels. Progression of CRF was accompanied not only with gradual increase in serum malondialdehyde (MDA) but also parallel increase in conjugated diene and MDA levels in LDL fractions separated from serum. Serum superoxide dismutase (SOD) activity was concurrently found to decrease, along with a decrease in high-density lipoprotein (HDL) cholesterol, during the progression of CRF. Gradual increase in the appearance of LDL oxidation products seems to accompany progressive manifestation of CRF. The results presented suggest that determination of serum MDA and SOD levels may enhance the diagnostic significance of the study of lipid profile in determining the risk for cardio vascular disease in CRF. PMID- 23105217 TI - Thyroid hormone profile in peritransplant period in live donor kidney transplantation. AB - Chronic renal failure, characterised by two factors acting in opposite directions with respect to the serum thyroid homone levels was chosen for the study. Healthy controls, donors undergoing nephrectomy and renal transplant recipients were studied. In transplant recipients, presurgical levels of total thyroxine(TT4), free triiodothyronine(FT3) and free thyroxine(FT4) were lower than controls, and immediately after the release of arterial clamps, there was an upsurge of total triiodothyronine (TT3), TT4, FT3 and FT4 due to administered and/or endogeneously secreted catecholamines. The levels of the 7th day were comparable to the presurgical levels. The changes observed in donors and recipients were similar indicating that the hormonal changes observed are mostly due to surgical stress. Recovery in the hormonal status did not start in the first week of posttransplant period. PMID- 23105218 TI - Levels of enzymes in leukaemic mice treated withAeromonas L-asparaginase. AB - L-asparaginase isolated in our laboratory fromAeromonas has been found to be antileukaemic. In the present study changes in the levels of serum enzymes in leukaemic mice and under treatment withAeromonas L-asparaginase has been compared. A significant increase in the levels of serum lactate dehydrogenase with tumour growth and a decrease during therapy was observed. A significant decrease in alanine transaminase activity during tumour growth and an increase during treatment was noticed. Increased levels of aspartate transaminase and alkaline phosphatase was observed during enzyme therapy. Total acid phosphatase was found to be increased during tumour growth and decreased considerably during treatment. PMID- 23105219 TI - Maple syrup urine disease: An uncommon cause for neonatal metabolic distress. AB - Maple Syrup Urine Disease is an autosomal recessive disorder caused by a deficiency in the activity of the branched-chain alpha-ketoacid dehydrogenase complex. This rare disorder represents one of the causes of acute neonatal illness which results in devastating disturbances of neurological development. On investigation of 1750 infants with neurological impairment for inborn errors of amino acid metabolism, 4 neonates with classical maple syrup urine disease were detected. These otherwise normal neonates presented in the first week after birth with seizures, lethargy and refusal of feeds, hypoglycemia and metabolic acidosis. The plasma and urine concentrations of the branched-chain amino acids were increased and there was ketoaciduria. Two of these neonates expired before specific treatment could be instituted. Routine biochemical screening of neonates with acute illness could unearth many cases of this rare inherited metabolic disease. PMID- 23105220 TI - A study of spectrin and lipid peroxidation of red blood cell membrane in thalassaemia carrier. AB - The aim of the present work is to understand the lipid peroxidation of RBC membrane and the spectrin protein content of RBC membrane cytoskeleton of thalassaemic carrier state (trait) of beta and hemoglobin E variant (HbE). We have measured the hemoglobin (Hb), malondialdehyde (MDA) and spectrin content of RBC membrane of thalassaemic carrier. The spectrin content (alpha and beta band) of both beta and HbE carrier was not changed than normal individuals. However, lipid peroxidation of RBC membrane was significantly increased in both beta and HbE trait, and Hb level was also decreased in thalassaemic carrier. It may be assumed that oxidative damage by excess lipid peroxidation may have no role on irreversible membrane damage in beta thalassaemia and HbE thalassaemia carrier. PMID- 23105221 TI - Identification of a LDL-receptor in the lymphatic filarial parasiteWuchereria bancrofti. AB - Little is known about host-parasite inter-relationship in the lymphatic filarial parasites. There is no information available about the ability of these parasites to acquire cholesterol, though it is known that in general, nematodes lack the ability to synthesise cholesterolde novo. In this study, we have shown that the filarial parasites also lack the ability to incorporate labelled acetate into cholesterol, indicating the absence of the machinery for cholesterol biosynthesis. We have further shown that they elaborate a 43 kDa surface receptor for acquiring LDL-bound cholesterol. We have shown by polymerase chain reaction the presence of a 860 bp fragment indicating the presence of the gene for LDL related protein (LRP) in the human filarial parasiteWuchereria bancrofti in the genomic DNA. We have also shown that it is expressed as seen in the cDNA clones identified from an expression library. PMID- 23105222 TI - Comparative evaluation of ultramicro-and macro-chemo enzyme based assays of glucose, cholesterol and triglycerides. AB - A comparison of the absorbance, enzyme/substrate concentration, reaction efficiency and sensitivity has been made for enzyme-based clinical chemistry assays, using a conventional colorimeter versus a strip-microwell reader, in order to establish the value of ultra-microchemical procedure, with reaction volume 87 MUl (light path length=0.25 cm). By utilizing commercial kits available for the quantitation of serum glucose, cholesterol and triglycerides, it has been established that the micro method is highly cost effective (9-30 fold), reproducible and sensitive. Comparison of blood drawn by a finger prick (capillary) and venipuncture for normal and pathological specimens show reproducibility between different laboratory technologists and in reference with the values reported by an accredited reference laboratory. Since the micro method uses very little serum, it is most suitable for analyses of small smaples, from large population-based field trials. However, the assay range has to be titrated for each commercial kit to establish the enzyme/substrate equivalence. PMID- 23105223 TI - Lactoferrin in cervical mucus as a biochemical marker for inflammation. AB - Lactoferrin, an iron-binding protein, has been proposed to act as an anti infective agent and has been used as a diagnostic marker in several inflammatory disorders. A sensitive enzyme-linked immunosorbent assay developed earlier was used for lactoferrin estimation in cervical mucus. A brief study was undertaken to observe if lactoferrin is detectable in cervical mucus and to correlate its level with reproductive tract infection, if present. One hundred and twelve cervical mucus samples were collected from healthy as well as infected females. Some of these females were using CuT-200 intrauterine copper devices for contraception. Women were at different phases of their menstrual cycle. The presence of detectable amount of lactoferrin in cervical mucus was confirmed. The average level of lactoferrin in cases either with clinical symptoms of cervicitis or with proven infection by PAP smear was significantly (t=7.6, P<0.01) higher than the normal controls. CuT users have higher (P<0.01) mean level of lactoferrin than corresponding non-users. PMID- 23105224 TI - Levels of plasma soluble complement receptor 1 (sCR1) in normal Indian adult population. AB - A decrease in the membrane anchored erythrocyte complement receptor 1 (CR1) is reported as an acquired phenomenon in a number of inflammatory and autoimmune diseases with concomitant rise in soluble CR1 (sCR1) levels in plasma. There is a need to establish the normal range of sCR1 in Indian adults to assess the function and disease association of this protein. The plasma sCR1 levels of 50 healthy individuals have been estimated by an indigenously developed sandwich ELISA. sCR1 levels from 26 patients suffering from nephropathies had also been assayed which was much higher than the normal controls. This observation suggests sCR1 as a potential market for the assessment of disease activity in nephropathies. PMID- 23105225 TI - Increased erythrocyte resistance to osmotic lysis in the acute hepatitis caused by true hepatotropic viruses non-A, non-B (nanb). AB - An unexpected increase in erythrocyte osmotic resistance during viral hepatitis in two patients prompted study of effects of hepatitis (in Karad) on osmotic resistance. The test was performed by placing erythrocytes in saline solutions of decreasing osmolarity and osmotic fragility defined in terms of the saline concentration at which hemolysis begins. Study included 44 infected subjects (acute viral hepatitis non-A non-B). All forty four infected subjects showed abnormal results when compared to normal subjects. increased erythrocyte osmotic resistance i.e. hemolysis begins between 0.45% to 0.40% of NaCl and is completed between 0.25% to 0.20% NaCl, whereas in normal subjects. hemolysis begins between 0.50% to 0.45% NaCl and is completed between 0.35% to 0.30% NaCl. Osmotic resistance was observed with increase in total bilirubin (mean+/-SD) (4.6 +/ 3.6), direct bilirubin (3.0+/-2.5), SGOT (58.8+/-55.5) SGPT (114.2+/-150.3) activity. Physiologic shifts in erythrocyte osmotic resistance may be due to changes in membrane lipid ratio. PMID- 23105226 TI - Preliminary studies on serum lipids, apolipoprotein-B and oxidative stress in xanthelasma. AB - Serum lipid profile, apolipoprotein-B (apo-B), malondialdehyde levels(MDA) and superoxide dismutase (SOD) activity were assessed in 12 cases of xanthelasma with and without coronary artery disease (CAD)/hypertension (HTN) and results are compared with healthy controls. Dyslipidemia was found in 65% cases of xanthelasma as compared to 20% healthy controls. Xanthelasma patients had significantly high malondialdehyde (MDA) levels (p<0.01) and significantly decreased (p<0.05) SOD activity as compared to controls. Among xanthelasma patients, xanthelasma with CAD/HTN showed higher total cholesterol (236+/-32.7 vs 188+/-24.7 mg/dl), low density lipoprotein cholesterol (157+/-35.5 vs 113+/-16 mg/dl) and Apo-B (120.5+/-9.4 vs 114+/-19.2 mg/dl) levels as compared to xanthelasma without CAD/HTN. Results of our study indicate that xanthelasma patients with increased apo-B, MDA and decreased SOD need cardiovascular monitoring. PMID- 23105227 TI - Biochemical studies to confirm a missed case of multiple myeloma in a seventy year old male. AB - Routine investigations of a 70 year old male led to provisional diagnosis of anemia. However further investigations suggested the possibilities of carcinoma of stomach associated with pernicious anemia, multiple myeloma and megaloblastic anemia. Finally serum protein electrophoresis supported by the clinical suspicion confirmed multiple myeloma. PMID- 23105228 TI - From editor's desk. PMID- 23105229 TI - Lipid peroxidation in culinary oils subjected to thermal stress. AB - The levels of cytotoxic aldehydic products in different culinary oils, with or without thermal stress, (routine domestic or commercial frying) were determined by thiobarbituric acid method. The results showed that (i) thiobarbituric acid reactivity was much higher in edible oils rich in polyunsaturated fatty acids than those rich in saturated fatty acids or monounsaturated fatty acids, even without thermal stress, (ii) the lipid peroxide levels were in proportion to the duration of thermal stress, (iii) nature of the container used (steel, iron or teflon-coated) had no significant effect on the extent of lipid peroxidation under identical conditions of thermal stress and (iv) thermally stressed oils collected from hotels and roadside caterers contained higher levels of cytotoxic aldehydic products, when compared to oils thermally stressed under domestic frying conditions. These results suggest that dietary ingestion of thermally or autoxidatively stressed polyunsaturated fatty acid rich culinary oils is more harmful compared with those similarly treated oils rich in saturated fatty acids and monounsaturated fatty acids. PMID- 23105230 TI - Antibodies against free radical modified DNA in cancer patients. AB - In this study we have modified DNA by exposing it to ultraviolet light in the presence of hydrogen peroxide. The modified DNA was probed for binding to the antibodies present in the sera of patients suffering from various types of cancer. Higher recognition of modified DNA, as compared to native DNA, by antibodies from cancer patients has got far reaching significance. PMID- 23105231 TI - Platelet protein damage by free radicals and glycationin vitro: The pathological consequences. AB - Modification of platelet proteins by free radicals and glycation has been studied in the present work, as anin vitro model. The results of the two parameters, SDS PAGE and carbonylation study are quite corroborative. We observed that the inducers like ferrous sulphate, ascorbate (mainly in supraphysiological concentration) and glucose attack the protein in a dose dependent manner, of which ferrous sulphate is most potent. Proteins from aged and degenerative conditions like malignancy and diabetes mellitus have suffered greater damage than normal adult and foetal proteins. The individual life expectancy in terms of biological versus chronological age may also be worked out from the individual stress level. PMID- 23105232 TI - Studies on the antiperoxide and antihaemolytic action of polyamines using human erythrocytes. AB - Blood RBC's were used to study the role of polyamines, putrescine, spermidine and spermine individually as antioxidants against the peroxidative action of H(2)O(2) which leads to haemolysis of erythrocytes. Results indicated that putrescine did not act as antioxidant at all concentrations used in our studies. However, spermidine and spermine suppressed peroxidative changes in RBC's due to the action of H(2)O(2) and this suppression was greater with higher concentration of these individual polyamines used, separately. Further, all the three polyamines decreased haemolysis of erythrocytes at all concentrations studied. The action of putrescine to suppress haemolysis of RBC's without showing antioxidant property hypothetically suggests that these properties of respective polyamines may have independent mechanism of action. PMID- 23105233 TI - Detection of tubercular antibody and antigen in sera of bone and joint tuberculosis. AB - Trichloroacetic acid (TCA) solubilized and DEAE fractionatedMycobacterium tuberculosis H(37)Ra excretory-secretory (ES) antigen viz., Mtb EST DE1 and affinity purified goat antibodies to the TCA solubilized ES antigen (Mtb EST) were explored in detecting tubercular antibody and antigen respectively in sera of bone and joint tuberculosis by indirect and sandwich ELISA. Out of total 36 bone & joint tuberculosis cases, tubercular antibody was detected by indirect ELISA in 30 patients (sensitivity 83%), while circulating tubercular antigen was detected by sandwich ELISA in 27 patients (sensitivity 75%). Out of 34 non tubercular disease control cases, 10 patients showed positive reaction for antibody while only 4 patients showed positive reaction for antigen. In another group of 34 healthy subjects who were screened, 4 individuals showed positive reaction for tubercular antibody and 2 cases for antigen. This study shows that antigen detection assay using affinity purified anti Mtb EST antigen antibody is superior with overall specificity of 91% as compared to antibody detection assay with 75% specificity in bone & joint tuberculosis. PMID- 23105234 TI - A rapid method for plasma ammonia estimation using an indigenously purified enzyme. AB - Determination of ammonia level in blood is important, especially in the diagnosis of hepatic disorders. An indigenously purified enzyme was used in the standardisation of the assay. The assay is a two reagent system, requires five minutes for completion and can be performed at temperature between 25-27 degrees C. Performance of the assay was assessed by linearity, imprecision, functional sensitivity and interference studies. Lyophilised reagent I and reagent II were found stable for at least one year. The plasma level of ammonia for the controls was 13.7+/-7.3 MUMol/L, whereas for subjects of hepatic disorders, it was 69.1+/ 32.4 MUMol/L (P<0.001). The functional sensitivity was between 2-1000 MUMol/L. Within-run coefficient of variation was between 1.1-2.0% and between-run coefficient of variation was between 1.9-3.7%. The mean recovery after dilution was 99.6%. The present method can estimate ammonia up to 1000 MUMol/L without dilution of sample. Assay time of five minute may be shortened to one minute. This method is suited for routine clinical use in treatment of hepatic disorders. PMID- 23105235 TI - Serum ionised calcium in birth asphyxia. AB - Serum total and ionised calcium levels were measured at birth and at 48 hours in 25 term neonates with birth asphyxia (one minute APGAR score of 6 or less) and in 25 normal term neonates (one minute APGAR score of 7 or more). Infants were categorised into two groups TAGA (term appropriate for gestational age) and TSGA (term small for gestational age). Asphyxiated infants had significantly lower serum total and ionised calcium values at birth as well as at 48 hours. Abnormal clinical features were observed in 48% of asphyxiated infants. Low ionised calcium was detected in symptomatic babies, who had otherwise normal total calcium values. Due to hyocalcemia especially ionised calcium in asphyxiated infants and high frequency of functional derangement associated with this hypocalcemioa, serial monitoring of serum isonised calcium levels is necessary. PMID- 23105236 TI - Preliminary study on circulating serum levels of tumor necrosis factor-Alpha in patients of tuberculosis. AB - Tumor necrosis factor-alpha (TNF-alpha) has been implicated in the pathogenesis of several non-infectious and infectious diseases including tuberculosis. In a prospective longitudinal study, TNF-alpha level in blood was estimated by sandwich ELISA using anti human TNF-alpha antibody, in 22 patients with active pleuro-pulmonary and lymphnode tuberculosis before and after chemotherapy and 8 healthy controls. Six patients and six controls had detectable levels (> 5 pg/ml) of TNF-alpha in blood. The mean TNF-alpha levels in controls and cases before and after treatment were 182.4pg/ml, 896.7 pg/ml and 678.7pg/ml pg/ml respectively. Though not statistically significant, there was a trend towards younger age, shorter duration of symptoms, presence of fever and anorexia, and high ESR, in patient with high serum TNF-alpha levels. PMID- 23105237 TI - Effect of corticosteroids on elevated intracellular sodium, plasma lipid peroxide levels and reduced Na(+), K(+)-ATPase activity in patients of bronchial asthma. AB - In view of several reports that there is a lack of balance in free radicals in case of bronchial asthma (1) the effect of free radicals on cell membrane was studied by estimating the membrane bound protein Na(+), K(+)-ATPase activity and the intracellular sodium level in patients of bronchial asthma before and after a short course (one week) of oral corticosteroid (prednisolone 0.75-1mg/kg body weight) therapy. Results showed that there is a definite statistically significant rise in free radical level and intracellular sodium level and a significant lowering of Na(+), K(+)-ATPase activity in case of untreated bronchial asthma. After short course of therapy with oral corticosteroids, the free radical level and intracellular sodium level decreased significantly, together with a significant rise of the Na(+), K(+)-ATPase activity. Also, a significant negative correlation (r=-0.74) between the lipid peroxide level and the Na(+),-K(+)-ATPase activity was found in these cases. PMID- 23105238 TI - Studies on some serum enzyme levels in various liver diseases. AB - Serum alkaline phosphatase (ALP) (EC 3.1.3.1), 5'nucleotidase (5'NT) (EC 3.1.3.5), aldolase (ALD) (EC 4.1.2.13) and sorbitol dehydrogenase (SDH) (EC 1.1.1.14) were estimated in infective hepatitis, alcoholic hepatitis, chronic active hepatitis, obstructive jaundice, cirrhosis of liver and amoebic liver abscess. It was observed that serum ALP and 5'NT were significantly increased in all cases of chronic active hepatitis and obstructive hepatic disease. However, the elevation observed in the latter was much higher than the former. Serum SDH and ALD levels were elevated in all cases of infective hepatitis, studied though increase in the former was much higher than the latter, suggesting its significance in the diagnostic confirmation of this disease. Results presented suggest 5'NT and SDH as more reliable diagnostic test compared to ALP and ALD for obstructive jaundice and infective hepatitis respectively. PMID- 23105239 TI - Assessment of oxidative stress and effect of antioxidant supplementation during radiotherapy in carcinoma of upper digestive tract. AB - Oxidative stress was studied by estimating plasma levels of malondialdehyde (MDA), beta carotene, vitamin E and erythrocytic superoxide dismutase(E-SOD) activity in 50 cases of carcinoma of upper digestive tract which included carcinoma of oral cavity, pharynx and oesophagus. While plasma MDA level was found to be increased (3.5+/-1.0 nmole/ml), a significant decrease in beta carotene (81.2+/-14.5mg%), vitamin E (8.5+/-1.1 mg/L) level and E-SOD activity (657.0+/-80.6 U/G Hb) were observed in carcinoma of upper digestive tract. Patients were treated with radiotherapy which itself was toxic enough and produced its deleterious effects by generation of reactive oxygen species (ROS). As antioxdiants can detoxify ROS, beneficial effect if any, of antioxidant administration during radiotherapy was studied in two groups of patients, group A (n=5, supplemented with antioxidants) and group B (n=5, without antioxidant supplementation). Plasma MDA level was found to be elevated in both the groups but the increase in group B was significant, compared to pretreatment level. Further, body weight was found to be significantly decreased in group B patients, which was maintained in group A patients. Moreover, group A patients showed significant elevation in beta carotene concentration, thus showing beneficial effect of administration of antioxidants during radiotherapy without disturbing the desirable therapeutic effect of radiotherapy. PMID- 23105240 TI - Lipid peroxidation and spectrin of RBC membrane in hydroxyurea treated Ebeta thalassaemia. AB - The aim of the present work is to understand the effect of low dose of hydroxyurea (HU) therapy on oxidative damage of RBC membrane in non-transfused Ebeta thalassaemia. HU was administered at a dose of 30 mg/kg/day for 90 consecutive days. The percentage of spectrin and the level of malondialdehyde (MDA), fetal hemoglobin (HbF), hemoglobin (Hb) and packed cell volume (PCV) were measured. The HbF level was significantly increased after 90 days of HU therapy. MDA level of RBC membrane was decreased. There was no change in PCV, Hb and spectrin content of RBC membrane after HU therapy for 90 days in Ebeta thalassaemia. Increment of HbF in HU treated Ebeta patient may have some role on the correction of oxidative damage of RBC membrane by inhibiting further degradation of spectrin and by decreasing lipid peroxidation of red cell membrane. PMID- 23105241 TI - A rare case of two malignancies: Carcinoma of the breast and uterine cervix. AB - A female patient who had two primary cancers was investigated. Biochemical analysis of patient's serum for different parameters indicated an alteration in the metabolic process. Prognostically, the patient has shown favourable clinical features. PMID- 23105242 TI - From editor's desk. PMID- 23105243 TI - Effect of felodipine on the serum lipid profile of patients with hypertension. AB - Forty patients suffering from mild to moderate degree of hypertension were put on felodipine. Their lipid profile was analysed before the start of their therapy and consecutively at two and four months after starting felodipine. There was a statistically significant fall in the levels of serum cholesterol, serum triglycerides and serum total lipids; though no appreciable variation was observed in HDL and LDL cholesterol levels. At baseline there were a few patients who had higher than the normal range of the serum lipid profile. Analysis of these patients showed a highly significant fall in the levels of serum cholesterol, serum triglycerides, serum LDL-cholesterol and serum total lipids i.e. felodipine modified the lipid profiles of hypertensive patients in a positive way. PMID- 23105244 TI - Hypoglycemic and hypolipidemic effects of diacetodibutyl disulphide. AB - The hyperlipidemia, fatty liver and the high levels of liver and kidney thiobarbituric acid reactive substances (TBARS) observed in rats which were fed ethanol for 45 days, could be significantly reduced by feeding diacetodibutyl disulphide (DADBDS). Ethanol-induced hypoproteinemia and the rise in serum enzymes like AST (EC 2.6.1.10), ALT (EC 2.6.1.2) and ALP (EC 3.1.3.1) could also be ameliorated by DADBDS. Feeding of this compound to normal rats did not produce any change in serum or tissue lipid levels or serum enzymes or tissue TBARS except a moderate reduction in serum triacyl glycerols. DADBDS feeding to rats maintained on a high lipid diet could also reduce the serum and tissue lipid levels and also reduce the serum transaminases.DADBDS which is an aliphatic disulphide could produce hypolipidemic effects in rats fed a single large dose of ethanol, whereas dimenthol disulphide which is an aromatic disulphide was not useful as a hypolipidemic agent. Perhaps hypolipidemic effects are shown only by aliphatic disulphides and not by aromatic disulphides. Feeding of 100 mg DADBDS per kg body weight to normal fasted rats produced a mild hypoglycemia, but higher doses produced a hyperglycemic effect. This dose of DADBDS increased the serum insulin levels and reduced blood glucose levels in fasted diabetic rats, but DADBDS feeding did not alter the serum insulin levels in fasted normal rats. DADBDS is odourless and tasteless in 1% solution and it could be a better substitute for garlic for hypoglycemic and hypolipidemic studies. PMID- 23105245 TI - Direct diagnosis ofMycobacterium tuberculosis in blood samples of HIV infected patients by polymerase chain reaction. AB - We have developed a simple, economical and reproducible method for processing blood samples from HIV infected patients for diagnosis of tuberculosis. The procedure was validated on 55 samples selected for tuberculosis based on clinical criteria. 52 patients had radiological changes indicative of pulmonary tuberculosis of which only 28 were positive for AFB in sputum (sensitivity 54%) and 27 for tuberculin (sensitivity 52%). 26 HIV positive patients who showed positive X-ray did not react to tuberculin. The genus PCR probe missed 3 samples (sensitivity 94%) compared to X-ray.M.tuberculosis was detected in the blood of all X-ray positive cases by PCR using TB400 probe (sensitivity 100%) and another probe forM. tuberculosis, IS6110, missed 6 of them (sensitivity 88% compared to X ray and 89% compared to TB400). It is proposed that this simple sample processing method could be used to screen all blood samples quickly for mycobacteremia using the genus PCR and only those positive for mycobacteria need to be tested forM.tuberculosis. This would save the scarce resources and time by reducing significantly the number of samples to be screened for species confirmation. PMID- 23105246 TI - Preliminary studies on the detection ofMycobacterium avium-intracellulare complex using DNA probe from a clinical isolate. AB - Genomic DNA from a clinical isolate ofMycobacterium avium-intracellulare complex was purified and cloned in PBR 322 at the tetracycline resistance site using Bam HI restriction enzyme. A 16 kb cloned fragment was purified, radiolabeled and used as a probe. Genomic DNA isolated from nineteen MAC strains, threeM. tuberculosis strains and oneM. kansasii strain were digested with Eco RI restriction enzyme, Southern blotted and hybridized with the 16 kb cloned and labeled fragment. Twelve MAC strains showed positive hybridization although five strains gave faint signals. Positive hybridization was noted in two out of the threeM. tuberculosis strains, possibly due to shared DNA homology. No signal was received from the singleM. kansasii strain used in this study. PMID- 23105247 TI - Identification of drug-resistantMycobacterium tuberculosis by single strand conformation polymorphism and cleavase fragment length polymorphism. AB - Twenty isolates ofMycobacterium tuberculosis resistant to rifampicin(RIF), isoniazid(INH) and streptomycin(STR) were analysed by Polymerase Chain Reaction (PCR) amplification of rpoB, katG and rrs genes to evaluate comparative diagnostic significance of genetic assays. Mutations were identified by single strand conformation polymorphism (SSCP) and cleavase fragment length polymorphism (CFLP) and were confirmed by DNA sequencing. SSCP of 4 RIF resistant and 14 INH resistant isolates showed an extra peak at the level of 75-bp and 85-bp respectively, while 2 STR resistant isolates showed 2 peaks with 9 bases difference. CFLP showed a different pattern among RIF, INH and STR sensitive and resistant isolates Thus SSCP and CFLP can be used as alternative diagnostic methods for identification of mutations in RIF, INH and STR resistant strains of M.tuberculosis. PMID- 23105248 TI - Isolation, PCR based identification, and sensitivity pattern of environmental mycobacteria from leprosy and tuberculosis patients. AB - We have isolated and identified the biotype of environmental mycobacteria from the expectorate of leprosy patients, their contacts, their drinking water supply and also from the sputa samples of tuberculosis patients. 78% of the isolates from lepromatous leprosy patients and their contacts wereMycobacterium fortuitum- chelonae complex (MFC), 9%Mycobacterium avium complex (MAC), 9%Mycobacterium scrofulaceum and 4% wereMycobacterium smegmatis. Among the isolates from tuberculosis patients 63% belonged toM. fortuitum- chelonae complex, 19% toM. avium complex, 12% toMycobacterium Kansasii and 6% toM. smegmatis. All the isolates were multi-drug resistant when tested for sensitivity total of 21 drugs. TheMycobacterium fortuitum-chelonae complex organisms from leprosy contacts were more sensitive to rifampicin than those isolated from lepromatous leprosy and tuberculosis patients. Among 23 isolates from leprosy patients one isolate was resistant to 20 drugs, one isolate to 17 drugs and another isolate was resistant to 13 drugs. Among the 18 isolates from drinking water supply six showed resistance to more than 12 drugs. Polymerase Chain Reaction (PCR) and subsequent hybridisation with specific probes confirmed all the isolated strains as nontuberculous mycobacteria (Using genus primers and probe sensitivity 100%) and none asM. tuberculosis, suggesting that PCR could be used to rapidly identify mycobacteria at the genus level and to rule out tuberculosis in leprosy patients at an early stage to decide on appropriate course of therapy. PMID- 23105249 TI - Prevalence of multiple antibiotic resistance and R-plasmid inEscherichia coli isolates of hospital sewage of Aligarh city in India. AB - R-plasmids that transfer antibiotic resistance are common in the non pathogenicEscherichia coli of the gastro-intestinal tract of human beings and domestic animals, which inturn may enter into sewage. Therefore we have isolated 30Escherichia coli isolates from hospital sewage of Aligarh city. These isolates were tested for their resistance and sensitivity against 10 antibiotics. 90% isolates showed resistance against ampicillin and sulphamethizole. Of the total 30E. coli isolates 86.6% were resistant to erythromycin and rifampicin but none of them was resistant to kanamycin and streptomycin. Plasmids (mol. wt. 16.5 mega daltons) were isolated from five differentE. coli strains which harboured only a single plasmid and were characterized on the basis of antibiogram. Moreover, the transformation experiments were also performed to confirm the resistant character on the plasmid. We conclude that multiple drug resistance among most of theE. coli isolates is plasmid borne. PMID- 23105250 TI - Serum levels of bone alkaline phosphatase in breast and prostate cancers with bone metastasis. AB - BALP activity in the sera of metastatic patients of breast and prostate malignancy has increased significantly. Our studies with patients in India conform the earlier reports that BALP may have a useful complementary role in the early diagnosis of bone metastases. PMID- 23105251 TI - The changing scenario in diagnosing prostate cancer. AB - Fifty patients were evaluated for serum total PSA (Prostate Specific Antigen), free PSA (f-PSA), free/total PSA ratio (f/t PSA ratio) and TPS(TM) (Tissue Polypeptide Specific Antigen). Fifty patients were clinically evaluated and categorized into BPH (benign prostatic hypertrophy) and CaP (carcinoma prostate) with twenty-five in each category before the serological examination. Serum total PSA concentration is elevated in 80% of BPH cases while it was elevated in all cases of CaP. With total PSA>10ng/mL, f/t PSA ratio was not applicable. For TPS(TM), a cell proliferation marker these values were 32% and 92% respectively. The advanced cases of CaP were reflected by the pronounced elevations of PSA and TPS(tM) while f/t PSA ratio was much below the cut-off limit (cut-off limit=0.14). The data suggest that whentotal PSA concentration <10ng/mL, f/t PSA ratio plays a very important role in discriminating BPH and CaP. However, TPS(TM) can be used as a valuable adjunct in diagnosis and follow-up of prostate cancer patients, especially in differentiating benign from malignant cases. PMID- 23105252 TI - Separation and identification of thyroid autoantibodies in patients with thyroid disorders by hydrophobic column. AB - A method has been developed to separate and identify thyroglobulin autoantibody (TgAb) and thyroid peroxidase autoantibody (TPOAb) in serum obtained from normal and autoimmune thyroid diseases using phenyl Sepharose CL-4B hydrophobic column. The protein peaks obtained from hydrophobic column were identified as TgAb and TPOAb by comparing the elution profile of commercially purified standard thyroid autoantibodies. The similarity of the inhibitory effects of eluted proteins and of standard thyroid autoantibodies on lectin concanavalin A-RBC interaction confirmed the separation of TPO-Ab and TgAb by the hydrophobic, column. The eluted fractions from the hydrophobic column were estimated by the radio immunoassay (RIA) to confirm the presence of both auto-antibodies. This hydrophobic column method offers an advantage of visual inspection of this autoantibodies by graphic representation of peak height along with their estimation in autoimmune thyroid disorders. PMID- 23105253 TI - A test strip for the estimation of urea in serum. AB - We have developed a biostrip for determination of urea in serum. The test strip is based on enzymatic assay where urease has been immobilized on the chromatographic paper along with chromogen, phenol red. The chromogen is easily soluble in water and does not require other components for the color change. Serum urea reacts with urease and water to liberate ammonia and carbon dioxide. The liberated ammonia changes the pH of the reaction medium, which is monitored by the chromogen phenol red. A single step working reagent strip has been developed and the reaction is completed within 50 seconds at room temperature. With this test strip urea concentration is measured in serum as low as 0.15 g/L. The speed and convenience of determining urea in serum by this strip instantly makes it well suited for individuals, physicians and emergency centres. PMID- 23105254 TI - Glucometers-need for external quality control. AB - We performed a pilot accuracy study on glucometers from three sources: "Advantage" from Boehringer Mannheim (A), "Glucometer(*) 4" from Bayer (B) and "One Touch Basic" from Life Scan (C) and compared these results with the results on autoanalyzers-Dimension RxL (1) and Hitachi 704 (2). Each glucometer was tested with venous blood in duplicate, from three different groups of 20 patients each, at random, on three different days, in our outpatient phlebotomy section. The rest of the sample was collected into heparinized tubes & the plasma separated within 15 minutes of sample collection & analyzed on both the analyzers in duplicates. The data were analyzed for accuracy by tabulating the number and percentage of test values that vary from the analyzer (reference) method by 10% or less, by 10% to 20%, or greater than 20% and the results tabulated on the Accuracy Study Table. This being a pilot study and the numbers being small, it may be suggested from the Accuracy Study Table alone, that the results of glucose in whole blood done with glucometer (A) were comparable with that of plasma values without applying any factor; whereas the results with glucometers (B) & (C) need to be divided by 1.11 to be comparable with plasma results; statistically though, results with glucometer (C) were comparable with or without factor. Patients using glucometers need to be alerted about the variance in their glucose results when compared to laboratory results, more clearly by the respective companies in their product inserts. An external quality control material that is glucometer method specific is needed, so that the Clinical Biochemistry laboratory in any hospital setup can more effectively monitor the performance of the glucometers in the wards periodically. PMID- 23105255 TI - Effect of calcium channel blockers on stress-induced visceral, endocrinological and immune responses. AB - In the present study effects of five commonly used calcium channel blockers (CCBs) belonging to different chemical classes have been investigated on stress induced modulation of some visceral, endocrinological and immunological parameters in rats and mice. Restraint stress (RS) produced gastric mucosal lesions, increased plasma corticosterone levels and reduced antiSRBC antibody titre, a measure of humoral immune response and % leucocyte migration inhibition (% LMI) and foot pad thickness, measures of cell-mediated immunity. Nimodipine (10, 20 40 mg/kg, i.p.) and flunarizine (10, 20, 40 mg/kg, i.p.) antagonised the effect of RS on gastric ulcerogenesis and plasma corticosterone levels but failed to modulate the stress-induced suppression of both humoral and cell-mediated immune responses. Thus, CCBs appear to modulate stress-induced visceral, endocrinological and immune responses, albeit in a differential manner. PMID- 23105256 TI - Antagonistic effect of FePP on the ethanol mediated induction of hepatic, renal and splenic delta-amino levulinic acid synthase activityin vivo in rats. AB - In the current study, we report perturbations in hepatic, renal and splenic heme synthesis at the level of the rate limiting enzyme, delta-amino levulinic acid synthase (ALA-S) on ethanol administration independently and in conjunction with iron-protoporphyrin (FePP) in male Wistar rats. Excessive ethanol administration (5 ml/kg bw) resulted in a significant induction of hepatic, splenic and renal ALA-S activity. Simultaneous administration of FePP (50 MUmol/kg bw) reverted the observed induction response to a sharp decline. The features of the action of ethanol and FePP togetherin vivo, i.e. a substantial inhibition of ALA-S is suggestive of the beneficial effects of this formulation in acute attacks of porphyria. PMID- 23105257 TI - Inhibitory effect of metalloporphyrins in conjunction with cholesterol on hepatic phospholipase A(2) activityin vivo in rats. AB - We investigated the effect of cholesterol and the metalloporphyrins cobalt mesoporphyrin (CoMP) and chromium protoporphyrin (CrPP) on phospholipase A(2) (PLA(2)) activity and the consequent hepatic mitochondrial stability as well as on lipid concentrations. Our studies revealed that on administration of cholesterol, CrPP, CoMP as well as simultaneous adminstration of cholesterol and CrPP, there was an inhibition of PLA(2) activity. These moieties may therefore, be agents for preventing destabilisation of the mitochondrial membrane and the consequent pathological conditions which may arise due to membrane lysis. Our results revealed that cholesterol administration increased phospholipid concentration, albeit by modest amounts. Although the independent administration of metalloporphyrins led only to minor elevations in phospholipid concentration, the simultaneous administration of cholesterol and CrPP generated a steep elevation in the concentration of total phospholipid. Since cholesterol inhibits PLA(2) activity it has the potential of being therapeutic agent for preventing the pathological conditions which may arise due to membrane lysis. PMID- 23105258 TI - An opium alkaloid-papaverine ameliorates ethanol-induced hepatotoxicity: Diminution of oxidative stress. AB - In this communication, we show the modulatory potential of papaverine, an opium alkaloid and a well known vasodilator agent on the ethanol-induced hepatic oxidative stress in male Wistar rats. Ethanol treatment (50% v/v) enhanced lipid peroxidation significantly accompanied by a decline in the activities of glutathione peroxidase (G-Px), glutathione reductase (GR) and depletion in levels of hepatic glutathione (GSH). Ethanol administration increased hepatic glutathione-s-transferases (GST). Enhanced lipid peroxidation induced by ethanol was significantly reduced when papverine was coadministered (P<0.05). In addition, the depleted levels of glutathione and inhibited activities of G-Px and GR recovered significantly (P<0.05) levelling off to control values on co exposure. Papaverine (200 mg/kg bw) effectively antagonised the ethanol-induced lipid peroxidation and impaired glutathione levels and glutathione dependent enzyme systems. Our results suggest that papaverine is an effective chemopreventive agent in the liver and may suppress the ethanol-induced hepatotoxicity. PMID- 23105259 TI - Effect of dietary fish on the lipid profile of cholesterolstressed rats during copper overload. AB - The effect of dietary supplementation with Oil sardine (Sardinella longiceps) fish at 2/3 fat replacement, on serum lipids in the cholesterol-stressed copper loaded rats was studied. Hypercholesterolemic state observed during copper toxicity was not alleviated by sardines. Copper loading significantly decreased the triglyceride levels and the activity of beta-hydroxy beta-methyl glutaryl (HMG) CoA reductase. Fish supplementation was further effective in reducing the triglyceride levels in copper loaded rats. Significant increase in the serum phospholipid was observed in the fish supplemented rats during copper overload. The finding suggests that hypolipidemic potential of fish is certainly altered to some extent in copper toxicity since, it is well known that copper enhances the formation of free radicals. Thus it may be concluded that sardine fish is not effective in reducing the cholesterol levels during copper toxicity. PMID- 23105260 TI - Preliminary study on the effect of a herbal formulation "Deepaniyavati" in hyperlipidemia. AB - To examine the effect of "DeepaniyaVati", a herbal formulation in the management of hyperlipidemia, a randomized group pre-test post-test study trial was carried out on fifty male (30 to 70 yrs) hyperlipidemic volunteers who were asked to follow their normal routine diet and activity pattern throughout the investigation period. The formulation, prepared by mixing nine plant products in equal proportion, when given in a daily dose of 2g, twice a day for a period of one month, brought about an observable improvement in all the lipid parameters by significantly reducing total cholesterol (10%), low density lipoprotein cholesterol (12.76%), very low density lipoprotein cholesterol (27.4%), triglycerides (34.7%) and bringing these values much nearer to the normal levels. In control group, no such effect was noticed. A concomitant significant increase in the HDL-C levels suggests the possible utility of "Deepaniya Vati" in the management of hyperlipidemia and the need for further detailed study. PMID- 23105262 TI - From editor's desk. PMID- 23105261 TI - Diagnosis of alpha-1-antitrypsin deficiency by serum protein electrophoresis. AB - Alpha-1-antitrypsin deficiency is a hereditary disease leading to hepatitis and cirrhosis. It is the most common genetic cause of liver disease in children which must inherit the tendency from both parents to develop. It acquires the highest priority in the differential diagnosis in a child with chronic liver disease. In this case report we substantiate the role of serum protein electrophoresis, in diagnosing alpha-1-antitrypsin deficiency. PMID- 23105263 TI - Genes of renin angiotensin system and coronary heart disease. AB - Coronary constriction, proliferation of smooth muscle cells and arrhythmia are involved in the pathophysiology of coronary heart disease and its complications such as myocardial infarction and sudden death. All these effects are favoured by high angiotensin II levels. Angiotensin II is the main effector molecule of the renin angiotensin system and it acts through angiotensin II type receptors. Genetically determined differences in the expression of the components of this system could adversely affect angiotensin II concentration and subsequently heart. Consequently each component of this system represents a potential candidate in the etiology of cardiovascular disease. In this article we review the variation of the angiotensin I converting enzyme, angiotensin II type I receptor and angiotensinogen genes and their association with cardiovascular disease. PMID- 23105264 TI - Molecular basis of familial hypercholesterolemia: An Indian experience. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by a multitude of low-density lipoprotein (LDL) receptor gene mutations. The LDL receptor is a cell surface trans-membrane protein that mediates the uptake & lysosomal degradation of plasma LDI., thereby providing cholesterol to cells. Affected individuals have elevated plasma levels of LDL, which causes premature coronary atherosclerosis. FH has an estimated worldwide prevalence of 0.2%. In some subpopulations there is an increased frequency of FH and specific LDL receptor mutations are found to be common due to 'founder gene effect'. Overall, more than 300 naturally occurring LDL receptor mutations have been described. To data upto ten LDL receptor gene mutations have been identified in Indians in South Africa, suggesting increased incidence of FH among Indians. Most mutations have occurred at CpG dinucleotide, a mutational hotspot in human genetic disease. In our study in 25 hypercholesterolemic subjects we have identified two novel insertion mutations in two patients. But the mutations underlying FH are still undefined in the majority of cases. Mutational heterogeneity on the other-hand has complicated disease diagnosis at DNA level. These findings warrant application of a generalized mutation screening method in search for new LDL receptor gene defects. PMID- 23105265 TI - Hyperhomocysteinemia and cardiovascular disease: The nutritional perspectives. AB - Several members of the vitamin B-complex family are known to participate in the normal metabolism of homocysteine (Hcy). Leaving aside the genetic determinants of hyperhomocysteinemia (HHC), the deficiencies of these vitamins can also result in HHC. The situation of sustained and long standing HHC is likely to be prevalent in population groups with low/average socio-economic status, geriatric population and alcohol abusers. If not corrected by supplementation, these population groups certainly are more vulnerable to develop atherosclerosis (AS) and subsequently, cardiovascular disease (CVD). Hyperhomocysteinemia per se and/or HHC-induced oxidative stress result(s) in chronic chemical endothelial injury/dysfunction, smooth muscle proliferation, prothrombotic state and oxidation of low density lipoproteins (LDL) leading to diverse cardiovascular complications. In the first decade of the new millennium, major research efforts would be directed towards understanding the basic mechanism of HHC-induced oxidative stress and the pathophysiology of HHC-induced CVD, culminating in the evolution of hitherto unknown therapeutic strategies such as nutriceuticals and oxidant-antidotes. PMID- 23105266 TI - Molecular biology and immunology of fungal allergens. AB - Fungi are non-chlorophyllus microorganisms, which constitutes the main source of outdoor and indoor allergens. The antigens present in the spores and fragments of hyphae induce allergic responses in sensitized patients. The frequently recognized fungi associated with asthma include Alternaria, Cladosporium, Aspergillus, and Penicillium. With the advent of molecular biology techniques a number of fungal genes encoding relevant allergens have been cloned and the expressed allergens purified and characterized. In this review, we have presented the recent developments, where recombinant allergens have been used in the precise diagnosis of fungal allergy. We have also discussed the role played by these allergens and the T- and B-cell epitopes in the immune mechanism in fungal allergy. PMID- 23105267 TI - Challenges in prevention, diagnosis and therapy of emerging fungal diseases. Aspergillosis: A case study. AB - Diseases caused by pathogenic filamentous fungi, are an emerging threat to public health in the wake of increasing incidence of HIV and tuberculosis. At this point, discovery and development of fungal therapeutics and diagnostics are serious challenges for biomedical researchers. Recent technological advances in genomics and proteomics offer great scope for development of preventive and therapeutic measures for fungal diseases.Aspergillus, one of the medically important filamentous pathogenic fungi causes a wide spectrum of clinical disorders ranging from allergic aspergillosis to systemic invasive aspergillosis. Increase in incidence of drug resistance and the cytotoxic effects are two serious limitations of the antifungal drugs presently in use. This is primarily due to lack of understanding of biological mechanisms operative in these fungi. Today, it is possible to understand the biological mechanisms of the fungus for its colonisation, survival and invasion of the host. Future developments based on such leads can result in development of precise and specific diagnostic, therapeutic and preventive measures for a wide clinical spectrum of fungal diseases. PMID- 23105268 TI - Dermatophyte lipids-Composition and regulation of phospholipids. AB - This review presents the extensive work carried out on lipid components of dermatophytes, their biosynthesis, turnover and regulation. It emerges from the work done so far that the pathways of lipid biosynthesis/ degradation and the lipid composition in dermatophytes are similar to those in yeasts and other fungi. Second messengers (Ca(2+), cAMP) were demonstrated to have a regulatory role in phospholipid metabolism and they mainly act by stimulating Ca(2+)/CaM or cAMP dependent protein kinase(s). Both these kinases were purified and characterized inMicrosporum gypseum. Further work is being carried out to elucidate the molecular mechanism of regulation of phospholipid metabolism by these second messengers. PMID- 23105269 TI - Immunobiology of trophoblast cells. AB - Trophoblast cells contribute in all the stages of pregnancy starting from implantation of the embryo to parturition through their unique inherent properties of invasion, proliferation, differentiation and endocrine secretions. Hence, successful outcome of pregnancy depends greatly on the coordinated functioning of the trophoblast cells which is brouth about largely by the timely expression of integrins, adhesion molecules, cytokines, hormones and generation of nitric oxide. Loss of this coordination leads to adverse consequences like early pregnancy failures, preeclampsia, molar pregnancy and choriocarcinoma. In order to have better understanding of normal physiology of pregnancy and to assess the nature and causes of these pathological situations, in depth study of trophoblast function has been carried out by us and several other investigators. PMID- 23105270 TI - The HLA genes and their diverse polymorphism. AB - Advanced DNA level studies based on HLA class II sequence analysis have revealed considerable diversity in HLA among Asian Indians. High resolution typing of specific alleles such as DR2 and DR4 in the HLA class II region by PCR-SSP or SSOP hybridization and their associated DR-DQ haplotypes have helped to detect unique haplotypes and novel alleles which have subsequently been confirmed by sequencing. Incidentally, remarkable stability has been maintained in several other DRB1 alleles viz. DR1, DR7, DR9 and DR10. The ARMS-PCR technology has been found to be particularly useful for typing HLA-A, HLA-B and HLA-Cw alleles. These technologies are far superior over serological methods. Our studies have shown remarkable heterogeneity of common HLA-A and B alleles in Asian Indians. Molecular subtyping of HLA-A2 revealed that subtype A(*)0211 is found only in Indian population and may be the result of selection pressure in this population. Investigations into polymorphism in the HLA-B27 gene revealed that subtypes common both to the western caucasians and orientals occur in the Indian population. It is apparent that the population of the Indian subcontinent, placed as it is between the Caucasoids and Negroids on one hand and Australoids and Mongoloids on the other, provides a rich source of many HLA haplotypes. While the most frequent Caucasian haplotypes occur with a reasonable frequency in Asian Indians, those found predominantly in other ethnic groups (e.g., australian Aborigines and populations of Oceania, China and Japan) are also detected. Knowledge on this is most important for donor selection during organ and bone marrow transplantation and for designing MHC targeted vaccines in specific diseases. PMID- 23105271 TI - Molecular mimicry: Basis for autoimmunity. AB - Structural similarity between a viral protein and a self-component can trigger an autoimmune response, which is the basis of molecular mimicry. Alternatively an invading virus can induce an inflammatory response which in turn can initiate an attack by hitherto dormant T cells on a specific self-antigen, a phenomenon which is referred to as Bystander Activation. Several viruses share amino acid sequences with target self-proteins. A widely studied viral interaction is the structural mimicry of a small portion of coxsackie virus to a specific region of the enzyme glutamic acid decarboxylase (GAD) which is expressed by the beta cells of the islet of Langerhans in the pancreas leading to the destruction of insulin producing cells and the onset of Type I insulin dependent diabetes mellitus (IDDM). Knowledge of specific epitopes in GAD susceptible to autoimmune attack can permit devising therapeutic strategies for the prevention and suppression of IDDM. PMID- 23105273 TI - Clinical and oncological significance of aberrant Fas (APO-1/CD95) isoform expression in adult T-cell leukemia. AB - Fas (APO-1/CD95), a transmembrane death receptor mediating apoptosis, can induce cell deathin vivo andin vitro of not only normal T-cells but also leukemic T cells. This indicates that dysfunction in T-cell apoptosis may influence the natural history of the T-cell neoplasms, such as adult T-cell leukemia (ATL) caused by the retrovirus HTLV-1. Fas is ubiquitous, and down-regulated or mutated Fas has been widely detected in tumor cells that escape from elimination via Fas mediated apoptosis. De novo fresh ATL cells and cell lines derived from the de novo cells, however, express Fas abundantly on the cell surface and are susceptible to Fas ligand and agonistic agents. On the other hand, there are two types of Fas gene transcripts, full-length and alternatively splicing truncated forms corresponding to membrane and soluble Fas isoforms, respectively. Focusing on membrane and soluble Fas isoforms and ATL pathology mediated by apoptosis, this paper reviews and discusses our ATL cases and ATL cell lines, which provide useful "experiments of nature" for understanding the role of Fas-mediated apoptosis in tumor biology. PMID- 23105272 TI - New age adjuvants and delivery systems for subunit vaccines. AB - The dramatic advancements in the field of vaccinology has led to the formulation of chemically well defined vaccines composed of synthetic peptides and recombinant proteins derived from the immunologically dominant regions of the pathogens. Though these subunit vaccines are safer compared to the traditional vaccines they are known to be poorly immunogenic. This necessitates the use of adjuvants to enhance the immunogenicity of these vaccine formulations. The most common adjuvant for human use is alum. Research in the past has focused on the development of systemic immunity using conventional immunization protocols. In the present are, the emphasis is on the development and formulation of alternative adjuvants and delivery systems in generating systemic as well as mucosal immunity. This review mainly focuses on a variety of adjuvants (particulate as well as non-particulate) used with protective antigens of HIV, malaria, plague, leprosy using modified delivery vehicles. The experience of our laboratory and other researchers in this field clearly proves that these new age adjuvants and delivery systems undoubtedly generate enhanced immune response-both humoral and cell mediated. The choice of antigens, the nature of adjuvant used and the mode of delivery employed have a profound effect on the type of immune response generated. Besides the quantity, the quality of the antibodies generated also play a vital role in protection against these diseases. Some of the adjuvants and delivery systems used promoted high titre and affinity antibodies, which were shown to be cytophilic in nature, an important criteria in providing protection to the host. Thus the studies on these adjuvants/delivery systems with respect to various infectious diseases indicate their active role in efficient modulation of immune response along with safety and permissibility. PMID- 23105274 TI - Breast and prostate cancer. AB - There are interesting similarities between carcinomas of the breast and prostate. Both genetic and exogenous factors are probably important in the development of breast and prostate cancers. Since there is an alarming increasing trend in the incidence of both cancers worldwide including India, high level of apprehension/awareness has been created among the general educated population. Furthermore, both cancers are strongly linked with the expression of the c-erbB-2 oncogene which has been the focus of basic research in the recent past. This gene belongs to the family of growth factor receptors and it has important implication in diagnosis and future treatment modalities. PMID- 23105275 TI - Filaria associated clinical manifestations in children in an endemic area and morbidity control by immunomonitoring and optimal DEC therapy: Sevagram experience. AB - Lymphatic filariasis is a major public health problem in India with 412 million people living in bancroftian endemic areas and is a major cause of clinical morbidity. Twenty million people are reported to suffer from chronic disease manifestations such as lymphoedema, hydrocele or elephantiasis. At least twice the number have been shown to suffer from acute and occult filarial infections in an endemic area without diagnosis. Due to non-availability of suitable diagnostic test for confirming filaria aetiology other than parasitological examination, no significant study on filariasis in children has been reported earlier. Studies in our laboratory for more than a decade showed usefulness of microfilarial excretory-secretory antigen in confirming filarial aetiology in acute and occult infections in adults as well as in children. This study reports acute and atypical manifestations such as lymphadenopathy, asthmatic bronchitis, pulmonary eosinophilia, mono-arthritis, recurrent URI, pneumonia, nutritional anemia, pain in abdomen etc. in children living in filaria endemic area having no microfilaraemia but showing filaria aetiology by immunomonitoring for the presence of antibody or antigen and responding to optimal DEC therapy. PMID- 23105276 TI - Host protective immunity and vaccine development studies in lymphatic filariasis. AB - Lymphatic filariasis caused mainly by infection fromWuchereria bancrofti andBrugia malayi remains as the major cause of clinical morbidity in tropical and subtropical countries. Development of vaccine against filarial infection can act as additional measure to the existing therapeutic and vector control methods in the control of this disease. The main hurdles in the development of anti-filarial vaccine are the strict primate specificity ofWuchereria bancrofti, the paucity of parasite material, the diversity of clinical manifestations and their associated complex immune responses, lack of clear understanding on host-parasite interactions and the mechanisms involved in protective immunity. However in the past few years, the information generated in immuno-epidemiological studies, correlated with observations in experimental animals suggests that a filarial vaccine is feasible. Initially live irradiated infective larvae have been successfully used to induce high level of protective immunity in several animal models. Applying diverse strategies, variety of purified or recombinant filarial antigens have been explored for their ability to induce protection in different host-parasite systems. Some of these targeted filarial antigens induced high level of resistance in experimental animals against challenge infections. More focussed studies on thorough characterization of parasitological and immunological changes associated with resistance induced by such candidate protective antigens and on delivery mechanisms and safety aspects will be crucial in their selection for possible use in humans. PMID- 23105277 TI - Trinucleotide repeats and neuropsychiatric disorders. AB - Expansions of trinucleotide repeats at the level of genomic DNA are increasingly recognized as a cause of a number of neuropsychiatric disorders. Triplet repeat disorders are commonly classified into two groups, those with moderate CAG expansions that result in a polyglutamine stretch in the gene products and those with very long expansions, usually non-CAG, that are not translated. The triplet repeat intergeneration and intra-generational instability, and genetic anticipation characterize disorders. Most of the diseases caused by expanded CAG repeat share common features, which include neurodegeneration, a dominant pattern of inheritance and widespread expression of the gene products with neuronal loss restricted to distinct subset of neurons. Neurodegenerative changes associated of CAG expansion disorders is explained in terms of intra and extra cellular aggregation of mutant gene products, the insoluble nature of the protein(s) being attributed to the presence of polyglutamine stretches, hence their neurotoxic effects. methods based on poymerase chain reaction have become handy in the diagnosis of these genetic disorders. Progress in transgenic animal models for these disorders will be critical for understanding the progress of these disorders and for testing new therapeutic strategies. PMID- 23105278 TI - Chromosomal fragility and human genetic disorders. AB - The first report of X-linked mental retardation correlated with the presence of marker chromosome came in 1940. It was in 1990 that the molecular basis of fragile X syndrome was deciphered. This elucidation marked the discovery of a novel process of mutation designated as dynamic mutations, resulting in the expansion of a triplet repeat sequence within the human genome. Subsequently several human genetic disorders involving triplet repeat expansion have been discovered. Almost all the disorders are known to affect the nervous system and/or the brain. This review presents an overview of fragile sites in the genome and the molecular genetics of fragile X syndrome. PMID- 23105280 TI - Medicinal plants for treatment of diabetes mellitus. AB - Many plants have been used for the treatment of diabetes mellitus in Indian system of medicine and in other ancient systems of the world. Out of these only a few have been evaluated as per modern system of medicine. From many such plants only extracts have been prepared and their usefulness evaluated in experimental diabetes in animals. In some plants likeAllium cepa, Allium sativum, Ficus bengalensis, Gymnema sylvestre, Pterocarpus marsupium etc. active hypoglycemic principles have been isolated and their mechanism of action studied. Most of them seem to act directly on pancreas (pancreatic effect) and stimulate insulin level in blood. Some have extra pancreatic effect also by acting directly on tissues like liver, muscle etc. and alter favourably the activities of the regulatory enzymes of glycolysis, gluconeogenesis and other pathways. Since the plant products have less side effects, they have the potential as good hypoglycemic drugs. They may also provide clues for the development of new and better oral drugs for diabetes. PMID- 23105279 TI - Vitamin D: Actions for the new millennium. AB - The past two decades have witnessed new facets in vitamin D metabolism. Free vitamin D(3) till now considered to be limited to animal sources, has been shown to occur in plants. Further, the extrarenal synthesis of active vitamin D(3) or calcitriol has been documented in physiological as well as in certain pathological conditions. At the cellular level, calcitriol acts through a dual mechanism. The genomic pathway involves the vitamin D receptor (VDR) which is of ubiquitous distribution and linked with various diseases. Besides, a nongenomic VDR-independent pathway also exists. The biological effects of calcitriol can no longer be dismissed by merely referring to calcium/bone homeostasis. It enhances the perinatal growth and suppresses the abnormal growth, as well. The effects on the endocrine, immune, cardiovascular, reproductive and nervous systems have also been characterized. It is compelling to believe that calcitriol and/or its analogues will find extensive applications at least in the treatment of osteoporosis, perinatal growth retardation, neoplasia, psoriasis, insulin resistance and transplantation. PMID- 23105281 TI - Stress and women. AB - Stress-tension-pain occur more often in health disorders of women than anywhere in the entire spectrum of human illness. No where is the effect of rapid change more apparent than in the changing role of today's women who are subjected to pressures from all sides. Now a days women virtually take part occupy positions, in day to day activities similar to their male counterparts. An outline of conceptual consideration, biochemical overview of stress and intricacies of coping mechanisms are delineated from the point of view of stress situations in female (during reproductive life span) peculiar to them only viz menarche, menstrual cycle, pregnancy-eventualities of pregnancy-labour-delivery, purperium, postpartum psychosis, abortions-induced, spontaneous, menopause. Lipid profile and oxidative stress status as biochemical responses in these stresses were investigated. As expected observed maximal/minimal biochemical responses well correlated with peak time and at termination of stress. Present day emphasis is on menstrual regulation by intake of oral contraceptive to improve health if women prefer not to bleed every month and hormone replacement therapy for elderly women to improve post menopausal quality of life and avoiding menstrual problems at the same time. PMID- 23105282 TI - Metalloporphyrins-Applications and clinical significance. AB - The fascinating structures of naturally occurring porphyrins and metalloporphyrins have been perfected by nature to give functional dyes par excellence. The important roles these tetrapyrrolic macrocycles play in vital biological processes, in particular photosynthesis (chlorophyll), oxygen transport (hemoglobin), oxygen activation (cytochrome), have led to their characterization as 'pigments of life'. Because porphyrins possess extended pi electron systems and exhibit stability, they are finding use, to an increasing extent, in advanced materials, as components in organic metals, molecular wires, and other devices. In medicine, porphyrins are experiencing a renaissance due to the advent of photodynamic therapy of great promise in the treatment of cancer and dermatological diseases. The interdisciplinary interest porphyrins thus generate has provided the impetus to develop Novel-porphyrin like molecules anticipated to exhibit special properties, by structural variation of the tetrapyrrolic macrocycle, while maintaining a (4n+2)pi main conjugation pathway.In addition to their esoteric application in science, porphyrins have been shown to have profound implications for therapeutic purposes. Their photosensitizing properties have led to their utilization in photodynamic therapy. Certain metalloporphyrins such as SnPP are being tested as drugs for the treatment of neonatal jaundice. Metalloporphyrins are serving as SOD mimetics to combat oxidative stress and a range of metalloporphyrin complexes have been proposed as contrast agents for magnetic resonance imaging. PMID- 23105284 TI - From editor's desk. PMID- 23105283 TI - Polymerase chain reaction in the diagnosis of tuberculosis. AB - A rapid, sensitive, specific and yet economical method for the diagnosis ofM. tuberculosis and other mycobacteria in clinical specimen is a desperate and urgent requirement of the day in the laboratory diagnosis and hence management of tuberculosis. This need is further accentuated by emerging diseases like multi drug resistant tuberculosis, tuberculosis in AIDS patients and opportunistic mycobacterial infections, which do not respond to conventional anti TB therapy. Molecular methods, particularly PCR based detection ofM. tuberculosis, has come a long way since it was first described about fifteen years ago. Several probes have been developed and some of them, particularly the IS6110 and TB400 have been validated on several clinical samples. The latter has been validated on a variety of clinical specimens along with a simple sample processing method. Polymerase chain reaction based diagnosis ofM. tuberculosis has been introduced as one of the routine/confirmatory tests in clinical microbiology laboratory in some countries like Canada, the United States and the United Kingdom several years ago. The possibility of introducing PCR based direct diagnosis of drug resistance is being explored in some laboratories, particularly for drugs like rifampicin. The evolution and application of PCR for diagnosis ofM. tuberculosis is being analysed and discussed in this review. PMID- 23105285 TI - An overview of monoclonal gammapathies. AB - The neoplastic proliferation of single clones of plasma cells causes synthesis of very large amount of monoclonal immunoglobulins consisting of only one type of heavy either the gamma, alpha, mu, delta or epsilon chain or only kappa or lambda light chains. Each monoclonal immunolobulin differs idiotypically from each other. These monoclonal immunoglobulins are also called paraproteins and are frequently associated with a broad heterogeneous group of plasma cell dyscrasias. Occasionally their presence is observed in a few benign conditions and in old age. In the present review a detailed account of different types of monoclonal gammapathies are described. PMID- 23105286 TI - Antioxidants: Basis concepts in relation to the eye. AB - Antioxidants are a small group of substances that protect living cells from the destructive consequences of powerful oxidizing intermediates that can be formed from oxygen. Situations in which pro-oxidant mechanisms within the body are more active than the antioxidant mechanisms (oxidative stress) predispose and contribute to the pathogenesis of several ailments in various organs of the body. In the eye, pro-oxidant factors have been blamed for the causation of diseases such as age related macular degeneration and senile cataract. The role of pro oxidants in the genesis of certain diseases is well established however, the effectivity of antioxidants provided to the body by dietary supplementation is inconclusive. In this article we provide a review on the basic concepts of antioxidant-pro-oxidant interaction in relation to its effects on the eye. PMID- 23105287 TI - Impact of Ultra-Sensitive technology and contemporary therapy on laboratory results. AB - The introduction of ultra-sensitive labels for immunoassays has exposed some of the limitations inherent in them. Thus, for instance a major problem with acridinium esters used, as chemiluminescence label is the formation of the so called "pseudobases" at an alkaline pH, which if not suppressed can affect the rate of the chemiluminescence reaction. Chemiluminescence labels such as luminol can also be problematic when attached to antibodies and small molecules to the extent that the sensitivity of the assay can be reduced by the decrease in the intensity of chemiluminescence. The increased use of molecular methods such as polymerase chain reaction (PCR) and post PCR methods to study mutations have various pittalls, which if unrecognized and uncontrolled can lead to incorrect results and misinterpretation. Patients who are exposed to mouse immunoglobulins through imaging or therapeutic techniques can develop antibodies to mouse immunoglobulins (human anti-mouse antibodies or HAMA) which can be a major problem for non optimized immunoassays using murine monoclonal antibodies. The types of therapy such as anticoagulant used in anticoagulant therapy, blood substitute and drug therapy can impact on the measurements of some of the biochemical and other analytes. One must separate the transient, physiological effects introduced by therapy from long-term biochemical alterations due to disease. PMID- 23105288 TI - Interference in autoanalyzer analysis. AB - This paper presents certain simple procedures for assessing the most common types of interference, due to haemolysis, icterus or lipaemic serum in 19 routine Clinical Chemistry tests and suggests steps to overcome the problem in some tests. A change in the measured concentration, to be analytically significant, had to exceed 2.8 X % coefficient of variation (cv) of the intra-assay analytical variation of each assay. Haemolysis caused interference in 10 of the 19 assays investigated. A haemolysate haemoglobin concentration of 0.29 g/dl, visible to the eye, caused an analytically significant increase in creatinine kinase MB subunit (CKMB), lactate dehydrogenase (LDH), total protein, triglyceride, uric acid and urea, and a significant decrease in alkaline phosphatase (ALP), and total bilirubin. A higher concentration of haemoglobin (0.68 g/ dl) caused an additional significant increase in CK, and a decrease in direct bilirubin. Addition of bilirubin caused interference in all the peroxidase linked reactions as well as in the creatinine assay. At a serum concentration of 5.2 mg/dl it caused a decrease in creatinine, glucose, triglyceride and uric acid. At a higher concentration (15.9 mg/dl) it also decreased cholesterol. Lipaemia interference affected the least number of assays. An added triglyceride of 537-561 mg/dl caused an increase in glucose, uric acid, and amylase. At a level of 1122 mg/dl it also increased CKMB, and at a value of 2244 mg/dl it increased total and direct bilirubin. At the highest levels of haemolysis and lipaemia, the serum glutamate oxaloacetate transaminase (GOT) and giutamate pyruvate transaminase (GPT) gave erratic results. Overall uric acid and CKMB were the analytes most susceptible to interference, while serum caicium and phosphate did not suffer from any. The interference depends on the exact assay conditions used and the susceptibility of each individual laboratory's tests should be determined by them. The reasons for the interferences described are discussed. PMID- 23105290 TI - Estimation of glycated hemoglobin by 2,6-dimethylphenol: Sulphuric acid conventional method. AB - Glycated hemoglobin levels in hemolysate of normal and diabetic patients were determined by the 2,6-dimethylphenol:57.5% sulphuric acid conventional method and the values were 0.39+/-025 and 0.69+/-0.21 moles of hydroxymethylfurfural(HMF)/mole of globin, respectively. The mean increase in glycated hemoglobin values in diabetics (1.8fold) was highly significant (p<0.001). A good correlation (r=0.95) was found between the glycated hemoglobin values obtained by this method and the phenol:sulphuric acid method. The values obtained by former method were about 1.2-1.4 times the values by the phenol:sulphuric acid method. This study indicates that conventional 2,6 dimethylphenol: 57.5% sulphuric acid method is more sensitive for the estimation of glycated hemoglobin than any other method based on the same principle. It is less time consuming, reliable and hence can be employed for the routine laboratory estimation of glycated hemoglobin for the assessment of glycemic control. PMID- 23105289 TI - Enhanced bilirubin binding to different mammalian erythrocytes in the presence of magnesium ions. AB - Effect of magnesium ions on the binding of bilirubin to erythrocytes of different mammalian species, namely, human, buffalo, goat and sheep was studied. Increase in the concentration of magnesium ions led to a gradual increase in the erythrocyte-bound bilirubin in both human and buffalo erythrocytes whereas in sheep and goat erythrocytes, the pronounced increase was found beyond 2.0 and 2.7 mM MgCl(2) concentrations respectively. Percentage increase in erythrocyte-bound bilirubin was found highest in human erythrocytes followed by buffalo and sheep erythrocytes and minimum in goat erythrocytes. These differences in the binding of bilirubin to different mammalian erythrocytes can be attributed to the differential shielding effect of metal ions which involves the masking of negatively charged phosphate of phospholipids found on the erythrocyte surface. PMID- 23105291 TI - Status of epidermal growth factor receptors family in hormone-dependent carcinomas of the breast and prostate with reference to serum lipids and lipoproteins. AB - There are numerous growing evidences of resemblance between carcinomas of the breast and prostate. A total of 45 cases of these two hormone-dependent cancers along with appropriate controls were subjected for status of epidermal growth factor receptors as well as serum lipid profile. Paraffin embedded tissue sections from aforesald tumours were analysed by immunohistochemical staining for epidermal growth factor receptor (EGF-R), c-erbB-2 oncoprotein, estrogen receptor (ER) and progesterone receptor (PgR). Sera from same individuals were studied for serum lipid profile analysis. The study revealed that immunoexpression of all receptor proteins (EGF-R). c-erbB-2 was significantly higher in breast carcinoma. In addition, mean levels of triglycerides, total cholesterol, LDL-cholesterol were found to be significantly elevated while the level of HDL-cholesterol was observed to be lower among patients with breast cancer as compared to matched controls. Further, ER-positive breast cancer cases have significantly higher mean level of HDL-cholesterol when compared with ER-negative breast cancer patients. Contrary to this, no alteration in different serum lipid fractions was noticed among the patients with prostate cancer. However, a positive relationship was noticed between immunoexpressions of EGF-R and c-erbB-2 in prostate cancer. PMID- 23105292 TI - Spectrum of monoclonal gammapathies in Andhra Pradesh. AB - In the present study, monoclonal gammapathy was identified in a total of 245 patients of plasma cell dyscrasias during period of 1987 to 2000. The monoclonal band was identified in serum by agar gel electrophoresis in all the cases and in urine in a few cases. Characterization of paraprotein (monoclonal immunoglobulin class and light chain type) was carried out by employing immunoelectrophoresis and/or immunofixation electrophoresis using heavy chain specific gamma, alpha, mu, delta and epsilon and light chain specific kappa (K), lambda (lambda) antisera. Serum immunoglobulins Ig G, Ig A, and Ig M were estimated by immunoturbidometry. Serum urea, creatinine, uric acid, alkaline phosphatase, total proteins, albumin, calcium and phosphorus were estimated by using routine biochemical methods. Among the 245 cases, 73.1% monoclonal gammapathies were of secretory type and 7.3% were non-secretory. Monoclonal gammapathies were associated with 80.4% of multiple myeloma, 8.9% of solitary plasmacytoma, 4.1% of extra-medullary plasmacytoma, 3.3% of lymphoma and 2.9% of plasma cell leukemia. Classification of secretory monoclonal immunoglobulin revealed monoclonal immunoglobulin Ig G in 74%, Ig A 15% and Ig M in 2.9% cases. PMID- 23105293 TI - Leucine amino peptidase a better indicator of carcinoma of liver, biliary tract and pancreas. AB - Serum levels of leucine amino peptidase (LAP) was studied along with bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), gamma glutamyl transpeptidase (GGT), alkaline phosphatase (ALP) and the ratio of AST/ALT and GGT/AST in 25 healthy subjects and 52 patients with hepatobiliary malignancies of which 12 were with hepatocellular carcinoma, 12 with liver metastasis, 6 with obstructive jaundice, 9 with carcinoma of gall bladder, 6 with carcinoma of pancreas and 7 with periampullary carcinoma. 24 Of the 52 patients studied had jaundice and 28 were without jaundice.LAP as compared to the other enzymes AST, ALT, GGT, ALP and AST/ALT ratio and GGT/AST ratio showed 100% elevation in obstructive jaundice, carcinoma of gall bladder and pancreas and periampullary carcinoma, 91.7% elevation in hepatocellular carcinoma and 83.3% elevation in liver metastasis. On comparing the levels of these enzymes in non jaundiced and jaundiced groups, LAP was elevated in both jaundiced and non jaundiced groups in 95.8% and 92.9% cases respectively whereas the other enzymes AST showed increase from 67.9% to 100%, ALT from 21.4% to 83.3%, GGT from 71.4% to 95.4% and ALP from 82.1% to 100% in non jaundiced and jaundiced groups respectively indicating that LAP rises in hepatic dysfunction due to hepatobiliary malignancy whereas the other liver function enzymes showed increased hepatic dysfunction due to hepatobiliary malignancy with the onset of jaundice thereby indicating that LAP is a better indicator of hepatobiliary malignancy as compared to other enzymes.The quantitative methods used for determination are reliable, accurate, simple, rapid and cost effective and therefore have better application in a clinical setting. PMID- 23105294 TI - Breast cancer in developing population: A nutrition caveat. AB - From January 1992-January 1998, 1404 patients attended the "Breast Clinic" of R.N.T. Medical College M.B. Hospital, Udaipur. Out of these, 11% and 81% patients had breast cancer (B.C.) and benign breast cancer (B.B.D.) respectively. The oxidative load in B.C. was 2.32 times higher than controls, but comparable to B.B.D. beta-Carotene deficiency was uncommon in patients, whereas vitamin A deficiency was almost equally common in both B.C. and controls. Most of the patients had almost depleted levels of alpha-tocopherol and ascorbic acid but their TBAR levels were in normal range. The data in the present study when compared with B.B.D. and other local normal subjects point out: a) oxidative burden in B.C. is a consequence and not the cause of the disease, (b) oxidative stress could be one of the etiological factors in tumor expression, which need not to be malignant and c) alpha-tocopherol and ascorbic acid are not importantly responsible for higher oxidative burden in B.C. PMID- 23105295 TI - Enhanced expression of HMG-Y proteins in proliferating tissues. AB - The high mobility group (HMG) proteins I and Y are well characterised non-histone chromosomal proteins which bind to A-T rich regions of DNA and regulate gene expression and/or DNA replication. A correlation has been demonstrated between the increased expression of HMG-Y proteins and malignancy. However, it is not known whether the expression of HMGs particularly, the Y group, is a function of proliferation rate. In the present study, we have used normal tissues of calf testes, thymus and liver. The results show distinctly high expression of HMG-Y proteins in testes than in thymus and the expression was practically undetectable in liver. The results suggest that even in normal tissues there is a direct correlation between the proliferation rate and the expression of the HMG-Y proteins, which can partly explain its increased expression in cancer. PMID- 23105296 TI - Preliminary studies on the hypoglycaemic effect ofAbroma augusta in alloxan diabetic rats. AB - The hypoglycemic effect of the aqueous extract ofAbroma augusta (Family: Steculiceae) was studied in normal as well as alloxan diabetic rats. Treatement of diabetic rats with 4 ml (4gm dry weight) of agueous extract ofA. augusta for 16 weeks resulted in gradual but significant fall in fasting blood glucose and improvement in glucose tolerance. Serum total and LDL cholesterol and triacylglycerol which increased in diabetic rats showed improvement. These results show that the water extract ofA. augusta has both hypoglycemic and hypocholesterolemic effects. PMID- 23105297 TI - Insulin or sulfonylurea treatments of the diabetics differentially affect erythrocyte membrane and serum enzymes and extent of protein glycosylation. AB - Erythrocyte membrane protein glycosylation increase by 3.4 fold in diabetes. Insulin or sulfonylurea treatment did not reduce the extent of glycosylation. The serum protein glycosylation was comparable in all the groups including control. Erythrocyte membrane Na(+),K(+)-ATPase activity decreased in the diabetics; only insulin treatment partly restored the activity. Erythrocyte membrane acetylcholinesterase activity decreased only in the sulfonylurea treated group. Serum butyrylcholinesterase activity was relatively low in the diabetic and insulin treated diabetic groups. The Km and Vmax of the two components of Na(+),K(+)-ATPase from erythrocyte membranes were differently affected in the diabetic and the two treatment groups. The Vmax of acetylcholinesterase decreased only in the sulfonylurea treated group. Diabetic states resulted in decreased Vmax of components I and II of serum butyrylcholinesterase. In insulin-treated diabetics, component II was absent. Sulfonylurea group resembled diabetics.In vitro incubation with insulin differentially affected the Na(+),K(+)-ATPase and serum butyrylcholinesterase activities. PMID- 23105298 TI - Immunomodulation of ovalbumin-specific IgG and other classes of antibody response by honey in mice. AB - It was reported earlier that intraperitoneal administration of honey had immunosuppressive activity on elicitation of allergen-specific murine antibody response as evaluated by passive cutaneous anaphylaxis and double immunodiffusion methods. In this study, the immunomudulatory effect of honey is evaluated by enzyme linked immunosorbent assay (ELISA) using ovalbumin as model allergen. It was found that ovalbumin (OVA)-specific IgG antibody responses elicited with various doses of OVA were significantly suppressed by rock bee honey (p<0.01). Honey was also found to have inhibited the production of OVA-specific IgM, IgA, IgG(1), and IgG(2b) whereas that of IgG(2a) and IgG(3) were not affected. Furthermore, honey also suppressed the OVA-specific total IgG antibody response in various inbred mice with different genetic background. In addition, the suppressive activity of honey was examined in different groups of mice by injecting honey at different time intervals, before and after immunization with OVA. The anti-OVA IgG antibody response was suppressed significantly when honey was injected 12 hours prior/latter to OVA injection. These results confirm the suppressive activity of honey on antibody response and suggest possible clinical application. PMID- 23105299 TI - An audit of total and free thyroxine measurements in screening for hypo and hyperthyroidism in patients using chemiluminescence immunoassay. AB - An audit of 2509 patient specimens analyzed for both total thyroxine (TT4) and free thyroxine (FT4) by the ACS-180 automated chemiluminescence immunoassay analyzer revealed that there were 219 discrepancies (8.7% of the total). A discrepancy was defined as one analyte within its reference range and the other outside. The discrepant results were divided into 4 groups: group A: normal TT4, but decreased FT4, 101 patients (4.0%); group B: increased TT4, normal FT4, 78 patients (3.1%); group C: decreased TT4, normal FT4, 34 patients (1.4%); and group D: normal TT4, increased FT4, 6 patients (0.2%). TSH measurements were available, by a 3(rd) generation chemiluminescent assay, in 142 of these patients, and were consistent with the FT4 result in 72 patients, with TT4 in 61 cases and with neither in 9 patients. The clinical diagnosis was investigated in a subgroup of 43 endocrine patients. Thirteen of the 20 endocrine patients in group A were diagnosed as hypothyroid, with a measured serum TSH, in 11 of them, of median 14.6, range 1.2 to 46.2 MUlU/ml. Eleven of the 19 endocrine patients in group B were on thyroid replacement, with a measured serum TSH, in 7 of them of <0.01 MUlU/ml. The audit of current laboratory practice led to a suggestion to replace the current thyroid function screening strategy of measuring both TT4 and FT4 by the combination of FT4 and TSH. The reasons for the discrepancies and the alternative strategies for screening of thyroid function are discussed. PMID- 23105300 TI - Serum lipids, lipoproteins and sex-hormone binding globulin in breast cancer. AB - Serum levels of various lipid parameters, i.e., triglycerides, total cholesterol, alpha lipoprotein or high density lipoprotein (HDL)-cholesterol and beta lipoprotein or low density lipoprotein (LDL)-cholesterol were measured in a total of 138 histologically proven cases of breast cancer along with 146 control women. The mean levels of serum triglycerides, total cholesterol and LDL-cholesterol were found to be significantly higher in breast cancer cases as compared to controls. However, lower mean levels of serum HDL-cholesterol and sex-hormone binding glubulin (SHBG) were observed in breast cancer patients than the control subjects. The results indicate a probable relation between serum lipids and the activity of sex-hormones. Moreover, the study reflects an overall disturbance of lipid metabolism in the pathological process of breast cancer. PMID- 23105301 TI - Value of ascitic fluid cholesterol and serum-ascites albumin gradient in differentiating cirrhotic and malignancy related ascites. AB - In a perspective study, the ascitic fluid and serum concentration of total cholesterol, total proteins and albumin in a group of 45 patients was studied. Patients with nonmalignant or cirrhotic ascites were compared with patients having malignancy related ascites and it was proved that the ascitic fluid cholesterol and the serum ascites albumin gradient helped to differentiate cirrhotic from malignant ascites. These two parameters showed a remarkable relationship to the presence/absence of malignancy. Non malignant ascites patients had ascitic fluid cholesterol values of 19.41+/-8.33 mg/dl, as against the malignancy related ascites patients, who showed levels of 95.87+/-1.24 mg/dl. Similarly, the serum-ascites albumin gradient levels were 2.89+/-0.65 in non malignant ascites patients, while the malignancy related ascites cases had 0.86+/ 0.50. The discrimination values for cholesterol were taken as 45 mg/dl while that for serum ascites gradient was taken as 1.1. Levels of serum cholesterol, total protein and albumin were not significantly altered. PMID- 23105302 TI - Differential erythrocyte agglutination pattern in normal and cancer patients with Synadenium grantii root (Hook f) lectin. AB - In the present study the property of lectin agglutination in blood on normal and different cancer patients has been observed. The purifiedSynadenium grantii root lectin was non blood group specific and its utility as a diagnostic tool in malignancy was studied. Hemagglutination (units/ml) of red blood cells of different types of cancer was compared with the normal control's red blood cells. Out of 113 total cancer patients, only a group of 29 breast cancer patients showed significant increase in titre value (P<0.05) compared to normal control. PMID- 23105303 TI - Evaluation of serum glycoproteins in oral carcinoma. AB - The present study was conducted on thirty untreated oral cancer patients proved by clinical and histopathological evidence and thirty healthy control subjects. The levels of glycoprotein-associated carbohydrates such as hexose, hexosamine, fucose and sialic acid were found to be elevated significantly as compared to control subjects. There was a progressive rise in these markers as the stages of oral cancer advanced. PMID- 23105304 TI - Comparative analysis of RBC membrane lipids in thalassemia, and iron deficiency anemia in relation to hypochromia and oxidant injury. AB - The effect of an intrinsic defect in the red cell and pronounced hypochromia on oxidative damage to RBC membrane lipids was compared in beta-thalassemia and iron deficiency anemia (IDA), which have a varied etiology but equivalent low hemogiobin content. The study was planned to correlate the etiology of the disorders to the severity of lipid imbalance and RBC hemolysis in membranes of both the conditions. Results indicated a fall of lysophosphatidylcholine(LPC), phosphatidylethanolamine(PE) and the unsaturated to saturated fatty acid ratio in both conditions, while phosphatidylcholine(PC) increased only in thalassemia. However, irrespective of the disease, sphingomyelin(SM), total cholesterol and phospholipid levels elevated and the hydrogen peroxide stress test indicated increased susceptibility of both pathologic RBCs to peroxidation. Present findings indicate that IDA and thalassemla, allow for considerable amounts of oxidative damage to membrane lipids, irrespective of their etiologles, and thus point hypochromia as an important contributor for inducing lipid imbalance and RBC hemolysis. PMID- 23105305 TI - Serum apolipoproteins in the patients of myocardial infarction in different age groups. AB - The level of serum cholesterol (Ch), serum-high density lipoprotein cholesterol (HDLc), serum-low density lipoprotein cholesterol (LDLc), serum very low density lipoprotein cholesterol (VLDLc), Triglyceride (Tg), Apolipoprotein A-1, B and ratio of Apolipoprotein A1/B were observed in 151 survivors of myocardial infarction in different age groups. A significant increase was found in the level of triglyceride, LDLc, apolipoprotein-B and a significant decrease in apolipoprotein-A1 and the ratio of apolipoprotein A1/B. No significant alteration was found in serum cholesterol, HDLc except in the age group of 31-40 years and 41-50 years and VLDLc. Thus, serum Apo A-1 and Apo-B may be considerably better markers for coronary artery disease than traditional lipid parameters. PMID- 23105306 TI - Feasibility of determination of fertile period in Indian women based on urinary hormone estimations. AB - Baseline data available on the excretory profiles of estrone giucuronide (E(1)G), pregnanediol glucuronide (PdG) and luteinising hormone (LH) on human menstrual cycles (n=104) was retrospectively analysed for identifying the limits of fertile period (FP) to be used as natural method of family planning. The limits of fertile period are suggested based on centile distribution of E(1)G and PdG levels during defined phase of menstrual cycle. Two approaches, which do not involve any mathematical calculation are suggested. In approach A, fertile period is said to have started when E(1)G value of 35 ng/ml is reached and is said to have ended when the PdG value of 2 MUg/ml on two consecutive days is obtained. The criteria were applied to 30 test cycles in whom authentic fertile period was identified based on excretory profiles of E(1)G, PdG and LH throughout the menstrual cycles. When approach A was followed the authentic fertile period was covered in 27 cycles giving an accuracy of 90% with a mean fertile period length of 9.11+1.9 days. In approach B, the cut off limit of E(1)G value was increased to 55 ng/ml in order to reduce the days of abstinence. Though the length of the fertile period was reduced to 7.2+1.5 days the accuracy of the approach was 66.6%. Thus the approach A which has accuracy of 90% may appeal to determined couples who wish to practice family planning by periodic abstinence or restrict the use of barrier methods. PMID- 23105307 TI - Isolation ofMycobacterium Tuberculosis 31 kDa antigen protein of diagnostic interest from culture filtrate using anti-ES-31 antibody by affinity chromatography. AB - Proteins secreted into the culture medium byMycobacterium tuberculosis (M. tb) are shown to be source of antigens of immunodiagnostic interest. Anin vitro released 31 kDa antigen ESAS-7F isolated fromM.tb H(37)Ra culture filtrate by salt precipitation, SDS-PAGE and cation exchange fast protein liquid chromatography (FPLC) was shown earlier to be a diagnostically important antigen fraction. In this report, we describe the isolation of ESAS-7F antigen using monospecific antibody coupled to sepharose CL-4B column. The percentage recovery of ESAS-7F antigen using affinity chromatography was approximately 8% of the total ES antigen proteins compared to 0.05% obtained by conventional purification steps using salt precipitation, SDS-PAGE and FPLC. Similar seroreactivity was observed by the antigen isolated by both the methods in indirect ELISA. Affinity chromatography helped in an increased recovery of ESAS-7F antigen and obviates the need for time consuming conventional purification steps. PMID- 23105308 TI - Host pathogen interactions in allergic and invasive fungal diseases: Diagnostic and therapeutic implications. PMID- 23105309 TI - Adenosine and its role in asthma. AB - Endogenous adenosine formed from ADP and AMP by the action of ATPase and 5' nucleotidase is known to cause bronchoconstriction and asthma in humans. It has been suggested that this action of adenosine is due to its binding to specific purino receptors in the mast cells in the lungs and consequent release of mediators which elicit bronchoconstriction and asthma. The release of these mediators leading to asthma was also believed to be due to vagal stimulation by adenosine. Though the role of adenosine in causing bronchoconstriction leading to asthma is well confirmed the actual mode of action and details of the mechanisms involved in the clinical manifestation of asthma remain unclear. PMID- 23105310 TI - Cadmium, carcinogen, co-carcinogen and anti carcinogen. AB - As a stress agent, inducing apoptosis and blocking it, Cd can have both helpful and harmful effects. The atmosphere is a thin envelope which makes the worid a global village. Cd is the most toxic metal in air. As both the first and second messenger of the stress response, it is synergistically toxic with all other stressors, including many other carcinogens. Elimination of Pb and its replacement with added benzene in gasoline appears to have increased the toxicity of atmospheric Cd. With scientific understanding of the molecular basis of Cd's role in carcinogenesis and anti-carcinogenesis, primary cancer prevention can be practiced by reducing Cd and chemical air pollution and educating the public on smoke cessation, healthy eating habits and stress reduction. Using the existing information on Cd and its effects, determinations could be made on established cancers so that individualized treatment protocols can be developed to improve patient care. PMID- 23105311 TI - Therapeutic uses ofCurcuma longa (turmeric). AB - Curcuma longa commonly known as tumeric is traditionally used as a spice in Indian food. A wide range of biological activities e.g. anticancer, antimicrobial, antiinflammatory and free radical scavenging activity of the plant suggests a logical basis for its traditional use in foodstuff. Various phytothreapeutic uses ofCurcuma longa have been reviewed. PMID- 23105312 TI - Separation of serum LD isoenzymes by capillary electrophoresis. AB - Separation and quantitative estimation of the isoenzymes of lactate dehydrogenase(LD) in serum were accomplished with capillary electrophoresis system. An uncoated fused silica capillary column 50 cm long, 75MUm I.D. and substrate containing running buffer including L-lactic acid and NAD(+) were used for the separation of serum LD isoenzymes. The resulting product of "NADH" was detected at 340 nm. Injection of 10 nL of five fold diluted serum sample were performed by pressure injection within 2 seconds. The isoenzymes were separated at 10 kV of voltage for 5 min, by turning off the voltage applied for 30 min incubation at 24 degrees C for reaction between substrate and isoenzymes, and applying voltage of 30 min. Under these conditions, the isoenzymes of LD were detected by a NADH generated as isoenzyme of LD-5 emerged at 20 min, LD-1 peak at 23.5 min with close to baseline separation of the other isoenzymes which emerge between LD-5 to LD-1, after the emergence to LD-1 peak, followed another peak, termed "sample shock": The results obtained by the proposed method correlated well with those by gel electrophoresis systemes (r=0.92~0.98) for each five LD isoenzymes, respectively. Within-run precision CVs for 5 replicate analysis were 3.01 (LD-3, mean 14.6%)%~7.82% (LD-4, mean 4.22%.), respectively. PMID- 23105313 TI - Serum proteins analysis by capillary electrophoresis. AB - The purpose of this study was to evaluate the efficacy of multi-capillary electrophoresis instrument in clinical laboratory. An automated clinical capillary electrophoresis system was evaluated for performing serum proteins electrophoresis and immuno-fixation electrophoresis by subtraction. In this study the performance of capillary electrophoresis was compared with the cellulose acetate membrane electrophoresis and agarose gel immunofixation electrophoresis for serum proteins. The results of capillary electrophoresis and cellulose acetate membrane electrophoresis were good (r=0.89~0.97) for protein fractions and A/G ratio except for beta-gobulin fraction (r=0.60). Both within-run and day to day precisions (CVs) of assay results for 5 main fractions and A/G ratio (n=10) were between 0.3~6.3%. The reference ranges of serum protein fractions obtained from 200 healthy individuals by cellulose acetate membrane electrophoresis were almost equal to that of capillary electrophoresis except for alpha-1 globulin fraction. No significant difference of electropherograms between cellulose acetate electrophoresis and capillary electrophoresis was observed in the abnormal serum such as presence of bilirubin (<20mg/dl), hemoglobin (<300 mg/dl), lipid (Intralipos <1%) and samples from patients with acute phase response, liver injury, polyclonal hyper gammaglobulinemia or M-proteinemia. The method of capillary immuno-fixation electrophoresis by subtraction showed good agreement with agarose gel immunofixation electrophoresis by subtraction identifying 30 monoclonal gammmopathy patient samples. PMID- 23105314 TI - Interaction ofLabeo rohita lectin (LRP) with mycobacterial surface oligosaccharide. AB - A C-type mannose specific lectin (LRP) isolated from plasma of fresh water fishLabeo rohita showed 500 times higher specificity towards cell surface oligosaccharide (LAM) ofMycobacterium tuberculosis (H37Rv). Using biotinylated LRP, binding between lectin and LAM was demonstrated by ELISA and it was observed that even 3ng of oligosaccharides might be detected using only 1MUg of biotinylated lectin. PMID- 23105315 TI - Vitamin E supplementation on biochemical changes observed in agricultural field workers exposed to different classes of pesticides. AB - A total of 41 healthy male pesticide sprayers exposed to different clases of pesticides for 3-5 years were compared with 21 controls matched for age and economic status with respect to free radical generation, lipid peroxidation, antioxidant status, cholesterol, lipoprotein status and haematological profile. Plasma lipid peroxidation was estimated in the form of thiobarbituric acid reactive substances (TBARS) produced. Significant increase in TBARS was observed in sprayers population when compared with control subjects and the level of TBARS increased with increase in the duration of exposure. The levels of antioxidants such as glutathione (GSH) were significantly depleted, whereas those of superoxide dismutase (SOD) were remarkably increased than control population. Significant reduction in total cholesetrol, alteration in lipoprotein fractions and nonsignificant changes in hematological parameters were observed. These results suggested that exposure to pesticidal residual drift augments the free radical generation, and lipid peroxidation. Decline in non-enzymatic antioxidant and elevation of enzymatic antioxidant were observed. Supplementation of alpha tocopherol for 45 days resulted in the partial restoration of these biochemical changes produced by pesticides. PMID- 23105316 TI - Hypoglycaemic, hypolipidemic and antioxidant properties of tulsi (Ocimum sanctum linn) on streptozotocin induced diabetes in rats. AB - Effect of oral administration of 200 mg/Kg body weight of the aqueous extract ofOcimum sanctum (Tulsi) mixed with diet for eight weeks to diabetic (streptozotocin induced) rats was studied. There was significant reduction in fasting blood glucose, serum lipid profile, lipid peroxidation products, (LPO) and improvement in glucose tolerance. The aqueous extract also decreased LPO formation (thiobarbituric acid reactive substances TBARS) and increased antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), glutathione transferase (GT) and one antioxidant reduced glutathione (GSH) in plasma and rat liver, lung, kidney and brain. The decrease in TBARS and increase in GSH, SOD, CAT, GPX, and GT clearly shows the antioxidant property ofOcimum sanctum. PMID- 23105317 TI - A biologically active constituent of withania somnifera (ashwagandha) with antistress activity. AB - In Ayurvedic medicine,Withania somnifera (Ashwagandha) is well known for its anti stress activity. A passive rat experimental model, where the animals are subjected to multiple stress of cold, hypoxia, restraint (C-H-R) has been developed to evaluate adaptogenic properties of various fractions of W. somnifera root extracts. We have carried out extraction of roots of W. somnifera with water and further isolated one of the active constituents called compound X and also tested its anti-stress activity in C-H-R model. The effect of administration of W. somnifera water suspension (360 mg/Kg bw) and compound X (20mg/Kg bw) on the fall and recovery of colonic temperature was noted. There was an increase of ~38% and ~54% in the time taken to attain T(rec) 23 degrees C by rats given a single dose of fresh aqueous suspension and biologically active constituent (Compound X) respectively, where as decrease in the recovery time to attain T(rec) 37 degrees C is ~13% and ~33% respectively, as compared to control group. It is clear that rats treated with the fresh aqueous suspension and compound X ofWithania somnifera, could withstand the multiple stress of C-H-R better than control group. PMID- 23105318 TI - Serum oestradiol in women with carcinomas of the breast and uterine cervix. AB - Endogenous oestrogens are thought to be involved in breast cancer, but few studies could show the direct relationship between hormones and pathological process of the disease. In the present study, oestradiol was estimated in the serum of pre-and postmenopausal breast cancer patients along with normal healthy controls and patients with carcinoma of the uterine cervix which is not dependent on oestrogens. Premenopausal patients with breast cancer showed higher levels of oestradiol as compared to premenopausal control women as well as cervical cancer patients. Whereas, no statistically significant differences were observed in serum oestradiol levels amongst postmenopausal groups of breast cancer, cervical cancer and normal women. The result of the study reflects the association of oestradiol as well as its difference in the pathological events of pre and postmenopausal breast cancer. PMID- 23105319 TI - Assay of tubercular antibody, circulating free and immune complexed antigen in the diagnosis of pulmonary tuberculosis. AB - Analysis of tubercular antibody, circulating free and immune complexed antigen (CIC-Ag) was done in confimed pulmonary tuberculosis sera by ELISA, using ES-31 antigen and affinity purified anti ES-31 antibody. Twenty three of 25 (92%) tuberculosis sera were positive for IgG antibody to ES-31 antigen. Using anti ES 31 antibody, free tubercular antigen could be detected in 20 of 25 (80%) cases whereas circulating immune complexed antigen (CIC-Ag) in 18 of 25 (72%) cases by sandwich ELISA. Of the two sera showing absence of antibody, one showed presence of free and CIC-Ag whereas the other showed the presence of free antigen. Thus antigen assay may be used as an adjunct tool for confirmation of pulmonary tuberculosis. PMID- 23105320 TI - Evaluation of sevafilachek immunoassays and rapid ICT-filariasis test for detection of bancroftian filariasis. AB - A comparative analysis was made on the utility of SEVAFILACHEK-stick based immunoassays and commercially available ICT-filariasis test to detect active infection in different groups of bancroftian filariasis. The SEVAFILACHEK immunoassays were found to be useful to detect filarial infection in microfilaraemia and in a significant number of clinical filarial cases with acute, chronic and occult clinical manifestations. In the clinical cases, microfilariae are not usually detected in peripheral circulation. Employing SEVAFILACHEK assays 6 and 5 of the 7 samples of patients with chronic filarial disease, and 6 and 5 of 6 microfilaraemic cases gave positivity for filarial IgG antibodies and antigen respectively. Four of the 6 occult filarial samples were positive for antibodies and antigen. Filarial antigen was detected by ICT filariasis test in blood samples of all the 6 microfilariaemic cases, 1 chronic filarial and 2 occult filarial samples. The main advantage of ICT assay is its rapid format and convenience for field use. PMID- 23105321 TI - Haemoglobin electrophoresis in diagnosing a case of sickle cell anaemia associated with beta-thalassemia. AB - Alkaline haemoglobin electrophoresis is a useful tool in diagnosing beta thalassemia and sickle-cell anaemia. In this report, using this simple technique, beta-thalassemia associated with sickle-cell anaemia is diagnosed. This is the first case we have diagnosed in our laboratory using agarose gel electrophoresis. PMID- 23105322 TI - Lipid peroxidation and glutathione peroxidase in ischemic heart disease. AB - With the growing interest in the concept of free radicals in the pathogenesis of myocardial ischemia, it was thought worthwhile to study the changes in lipid peroxides and antioxidant enzyme glutathione peroxidase (GPx) in ischemic heart disease (IHD). The study was carried out on 76 patients of IHD-38 of acute myocardial infarction (AMI) and 38 of stable ischemic heart disease (SIDH). They were age and sex matched with 38 normal healthy controls. A significant increase (p<0.001) in lipid peroxides as malondialdehyde (MDA) (5.9+/-0.7 mmol/L) and a decrease in GPx (24.6+/-2.2 U/gmHb) was found in patients of AMI when compared with controls. There was no significant difference in these values in SIHD. Thus this study confirms the earlier findings that MDA and GPx are useful parameters in IHD and their magnitude is dependent on severity and/or duration of ischemia. We suggest that these tests would be of use in smaller institutions with limited facilities. PMID- 23105323 TI - A preliminary report on the role of yoga asanas on oxidative stress in non insulin dependent diabetes mellitus. AB - Nineteen subjects of non-insulin dependent diabetes mellitus (NIDDM) between the age group of 30-60 yrs were studied to see the effect of specific yoga asanas on fasting and postprandial blood glucose (FBG, PPG), serum malondialdehyde (MDA) and glycosylated hemoglobin (HbA(1)) in addition to drug treatment and diet control. The duration of diabetes ranged from 1-10 years. Patients with renal, cardiac and proliferative retinal diseases were excluded from the study. The same patients served as their own control. Subjects were called in the morning to the cardio-respiratory laboratory and were given training by a yoga expert. Yoga asanas included Suryanamskar, Tadasan, TriKonasan, Padmasan, Pranayam, Paschimottanasan, Ardhmatsyendrasan, Pavanmukthasan, Sarpasan and Shavasan. The asanas were done every day for 40 days for 30-40 min. FBG, PPG, serum MDA and HbA(1) were estimated before and after 40 days of yoga asanas regimen. Significant reduction was seen in FBG from 220 mg/dl to 162 mg/dl, PPG from 311 mg/dl to 255 mg/dl, MDA from 6 nmol/l to 3 nmol/l and HbA(1), from 8.8% to 6.4%. Subjects felt better and were relieved of their stresses and had an improvement in their day to day performance. The decrease was statistically significant (p<0.0001 for FBG and PPG, p<0.001 for MDA and for HbA(1)). PMID- 23105324 TI - Thyroid hormone status in protein energy malnutrition in Indian children. AB - Thyroid hormonal status was measured in 80 malnourished children of different grades (I-IV) of protein energy malnutrition (PEM). Serum levels of tri-iodo thyronine (T(3)), thyroxine (T(4)) and thyroid stimulating hormone (TSH) were measured by radioimmunoassay. The results were compared with 20 healthy, age and sex matched controls. Levels of T(3) and T(4) were significantly low in PEM cases whereas TSH levels were similar in PEM cases when compared to controls. PMID- 23105325 TI - Application of tumor markers in ovarian malignancies. AB - Ovarian cancer is the fifth leading cause of death in women. The incidence of this malignancy increases in women over the age of 40. The overall five years survival is less than 30%, as most women present with advanced stage disease. Until recently, detection of early stage ovarian cancer has been difficult since it is usually nonpalpable and asymptomatic. The definitive diagnosis of an ovarian mass is a common problem in gynecologic patients with adnexal mass. The routine standard evaluation for adnexal masses includes patient's history, physical examination, ultrasound and histopathological examination. These parameters individually or in combination have little predictive value. The accuracy of diagnostic tools are of immense value and great concern to practicsing Gynecologists and Oncologists. The clinical application of serum concentration of CA 125, AFP and hCG is of great help not only as diagnostic aid but also in monitoring efficacy of any treatment modality like chemotherapy, radiotherapy or surgical resection. Additionally, evaluation of tumor marker concentration helps in predicting early biochemical recurrence and in prognostication in different types of ovarian malignancies. The ability to differentiate a malignant mass from a benign pelvic mass pretherapeutically could be enhanced optimally by additional use of tumor markers such as cancer antigen CA-125, alphafetoprotein and human chorionic gonadotrophin in pre-and postmenopausal women. PMID- 23105326 TI - From editor's desk. PMID- 23105327 TI - Screening for lead poisoning in urban school children of southern India using capillary and venous blood samples. AB - Our study aimed at comparing lead and zinc protoporphyrin (ZPP) levels in capillary and venous blood samples in a small population and to employ an easier method of sample collection for a major screening program in school children in major Indian cities. An awareness program on lead and its effects was conducted in two different schools. A total of thirty urban school children from South India, with an age group between 4-12 years consented for dual blood sampling and reported for the study. Venous and capillary blood samples were obtained simultaneously. Blood lead and zinc protoporphyrin (ZPP) levels were estimated using ESA Lead Analyzer and Haematofluorometer respectively. A significant correlation between capillary and venous ZPP (r=0.98) and lead (r=0.99) was observed. Rank sum test showed that there is no statistically significant difference between capillary and venous ZPP (P=0.891) and lead (P=0.672) values. This pilot study recommends that screening for lead may be done using capillary blood samples since significant correlation is observed between capillary and venous blood measurements. Obtaining samples using this mode is a non-invasive, less expensive, quick and easy method in children. Appropriately performed capillary sampling may be considered as an acceptable alternative to venipuncture for screening of blood for lead poisoning both in children and adults. PMID- 23105328 TI - Analysis of SEVA TB ES-31 antigen specific immunoglobulins IgM, IgA and IgG in sera of sputum and culture positive pulmonary tuberculosis. AB - Tuberculosis remains major health problem in India and developing countries Immunodiagnosis has important role in screening, diagnosis and management of tuberculosis. SEVA TB ES-31 antigen has shown potential in detecting tuberculous IgG antibody in earlier studies from our laboratory. In the present study we have analysedSEVA TB ES-31 antigen specific immunoglobulinsIgM, IgA and IgG in clinically and bacteriologically confirmed pulmonary tuberculosis cases to determine the usefulness of specific immunoglobulin class in the diagnosis of patients attending the hospital.Of the 30 cases of pulmonary tuberculosis 25 (83.3%) were positive for IgG, 19 (63.3%) for IgM and 16 (53.3%) for IgA. On combining IgG and IgM positivity, sensitivity was increased to 93.3%. While combining IgG and IgA positivity, sensitivity increased to 90%. However specificity was decreased to 66.6% and 70% for both of these combinations respectively. It could be envisaged from this study that IgG antibody detection against ES-31 antigen showed acceptable sensitivity (83.3%) and specificity (86.6%) compared to IgM or IgA alone or in combination. When immune responses were analysed according to degree of sputum positivity, IgG response was observed to be predominant in all grades, compared to IgM or IgA antibody. The addition of IgM or IgA as an adjunct test increases the sensitivity but at the cost of specificity. Hence the detection of IgG alone is more useful compared to IgM or IgA assay, in detecting tuberculosis disease cases coming to the hospital. PMID- 23105329 TI - Fetal lead exposure: Encephalopathy in a child. AB - It is well known that lead exposure in the early period of pre pregnancy and antenatal life leads to serious health complications. In this case report, a five month old child who was suffering from encephalopathy was finally confirmed a victim of lead exposure, the source being the environment and the family. We report this case with complete clinical investigation including blood lead analysis. This case report highlights the various ways in which lead may accumulate in the body. It is also aimed at increasing awareness regarding the pathogenesis and clinical manifestations of lead toxicity. The literature survey done reveals that this is the youngest age at which lead toxicity has been documented in India. PMID- 23105330 TI - Changes in erythrocyte membrane glycoproteins during leukaemia. AB - Changes in erythrocyte membrane glycoproteins during, leukaemia were investigated in one hundred patients. Control group contained normal ones. The total protein and protein bound total carbohydrates (neutral sugars) in the glycoproteins extracted from the erythrocyte membrane showed significant reduction in total protein and protein bound total carbohydrates before radiotherapy. However, after the radiotherapy there was further reduction in total protein by 10.41% whereas there was increase in total carbohydrates by 9.98%. Qualitative analysis reveals that with the help of lectins one can pin point the sugars which appear or disappear due to leukaemia. The test could be of a diagnostic value. PMID- 23105331 TI - Serum glycoconjugates and ceruloplasmin in cancer of uterine cervix. AB - The present study was done to assess the levels of glycoconjugates and ceruloplasmin in sera of patients with cervical cancer. Serum hexoses, hexosamines, sialic acid and fucose are elevated in a variety of inflammatory and neoplastic conditions. All the glycoconjugates, except fucose were increased in serum of patients compared to controls. Also, hexoses and sialic acid levels were high in patients with later stages of cancer compared to patients with early stage disease (P=<0.0001, P=0.03). Serum ceruloplasmin was increased in patients with early stage cancer (51.5mg/dl) and with late stage cancer (61mg/dl) compared to controls (38mg/dl). The elevated glycoconjugates may be the result of inflammatory reaction associated with neoplasia, as serum ceruloplasmin (an acute phase reactant) is also increased in these patients. PMID- 23105332 TI - Serum markers for early diagnosis of non-'Q' wave and 'Q' wave myocardial infarction. AB - The present study conducted on twenty-five uncomplicated cases of acute myocardial infarction diagnosed by clinical and electrocardiographic findings indicated significantly increased level of cardiac Troponin-T and increased activities of the enzymes total creatine kinase, creatine kinase-MB, aspartate transaminase and lactate dehydrogenase as compared to the twenty-five healthy control subjects. The level of cardiac Troponin-T and the activities of the enzymes total creatine kinase, creatine kinase-MB, aspartate transaminase and lactate dehydrogenase was found to be higher in "Q" wave myocardial infarction patients as compared to the non-"Q" wave and the controls. Since cardiac Troponin T has been shown to increase in unstable angina and renal failure without cardiac disease and creatine kinase-MB activity has been found to be normal in patients with unstable angina and increase very slightly in patients with renal failure, it was concluded that a combination of cardiac Troponin-T and creatine kinase-MB activity was sufficient for the early diagnosis of acute myocardial infarction. PMID- 23105333 TI - Studies on the effect of monosodium glutamate (MSG) administration on the activity of xanthine oxidase, superoxide dismutase and catalase in hepatic tissue of adult male mice. AB - Subcutaneous administration of monosodium glutamate (MSG), to normal adult male mice, for six consecutive days at dose levels of 4 and 8 mg/g body weight, significantly increased the level of free radical initiating enzyme, xanthine oxidase, whereas the activity of free radical scavenging enzymes, like catalase and superoxide dismutase was significantly decreased in hepatic tissue. These observations suggested that ingestion of MSG at dose level of 4 mg/g body weight and above, induced oxidative stress in the hepatic tissue of adult male mice. PMID- 23105334 TI - Oxidative stress and antioxidants in tubercular meningitis. AB - Oxidative stress is implicated in the etiopathogenesis of a variety of human diseases. Therefore, in the present study, erythrocyte lipid peroxidation, percentage hemolysis, antioxidant enzymes viz., glutathione reductase, glutathione peroxidase, superoxide dismutase and plasma antioxidants viz., ceruloplasmin, vitamins A,E and C have been determined in 19 patients with tubercular meningitis (TBM) and 50 normals. Six patients who were treated with antibiotics were considered for the follow up. The statistical analysis was carried out by Mann Whitney U test and Wilcoxon rank sum test. Lipid peroxidation (P<0.02), percentage hemolysis (P<0.001) and plasma ceruloplasmin (P<0.0001) of TBM patients were significantly higher, whereas erythrocyte glutathione reductase (P<0.05) and plasma antioxidant vitamins A, E and C (P<0.01, P<0.05 respectively) were significantly lower than those of the controls. In the follow up patients the glutathione reductase and catalase levels were significantly high (P<0.05) compared to their pre-treated condition. Vitamin C and E levels have attained normal range. This study indicated that the blood antioxidant status of TBM patients which was low compared to controls improved after treatment, suggesting the role of free radicals in TBM. PMID- 23105335 TI - Role of pump prime in the etiology of cardio-pulmonary bypass associated acidosis. AB - The development of metabolic acidosis during cardio-pulmonary bypass (CPB) is a well recognized but poorly explained phenomenon. It has been hypothesized that it is purely a development after the delivery of pump prime. A retrospective study was conducted at our hospital on 68 patients who underwent elective coronary artery bypass grafting (CABG). Sampling of arterial blood was performed at three time intervals: (T(1)) Baseline, prior to induction; (T(2)) 5 minutes after initiation of CPB and prior to administration of cardioplegia solution; (T3) during rewarming prior to weaning the patient off CPB. Measurements of Na(+), K(+), Cl(-), pH, pCO(2), HCO(3) (-), Base excess, Anion gap, Strong ion difference at each collection point were performed. Results were analyzed in a quantitative manner. On delivery of pump prime, all patients' developed metabolic acidosis. However, it is very important to distinguish the metabolic acidosis as their management varies. Anion gap has been found to be useful in managing peri operative metabolic acidosis. PMID- 23105336 TI - Serum Lp(a) in diabetics with and without evidence of clinical nephropathy-A preliminary study. AB - Type 2 diabetes is associated with a marked increase in the risk of coronary artery disease. Dyslipidaemia is believed to be a major cause of this increased risk. Recently, elevated levels of lipoprotein (a), Lp(a), have been reported to be associated with an increased risk. However there is very little data regarding Lp(a) concentrations and type 2 diabetes from India. The objective of the study was to assess serum Lp(a) levels in type 2 diabetics with and with out evidence of clinical nephropathy. We estimated serum Lp(a) levels in 30 control subjects, 30 diabetics without evidence of clinical nephropathy and 30 diabetics with evidence of clinical nephropathy. Statistical analysis showed that Lp(a) levels were increased in diabetic patients with nephropathy (mean 46.3+/-17.6 mg/dl). The Lp(a) levels however did not differ significantly between control (mean 20.2+/-15.9 mg/dl) and diabetics without nephropathy (mean 22.6+/-13.1mg/dl). Thus diabetes per se seems to have little or no influence on serum Lp(a) levels, however elevated levels were seen in patients with nephropathy. PMID- 23105337 TI - Potent antiulcerogenic activity of ethanol extract of leaf ofPiper betle Linn by antioxidative mechanism. AB - Pretreatment of an ethanolic extract of leaf ofPiper betle linn at a dose of 200mg/kg body weight, orally administered to rats for ten consecutive days, was found to possess a significant protective action against gastric lesions induced by indomethacin. The extract pretreatment resulted in significant increase in superoxide dismutase (SOD) and catalase (CAT) activity, increase in mucus, hexosamine and total thiol group content, but marked reduction in oxidatively damaged protein and peroxidised lipid levels as compared to untreated ulcerated control. The extract was also found to possess both superoxide and hydroxyl free radical scavenging action. The present observations establish the efficacy of the extract in prevention of experimentally induced peptic ulcer by indomethacin and antioxidant property appears to be predominantly responsible for such cytoprotective activity in the experimental model. PMID- 23105338 TI - Acute and chronic toxicity studies on partially purified hypoglycemic preparation from water extract of bark ofFicus bengalensis. AB - Acute and chronic toxicity studies were conducted to assess toxicity of a partially purified preparation from the water extract of the bark ofFicus bengalensis, which was demonstrated in our earlier studies to have significant hypoglycemic and hypocholesteroiemic effect on alloxan induced, mild and severe diabetes in rabbits. LD(50) of this preparation was found to be ~1 gm/kg in rats when given orally. For chronic toxicity studies 3 doses of aqueous preparation were given to 3 groups of rats. First group received 5 times ED(50) (50 mg/kg), second group 10 times ED(50) (100 mg/kg) and the third group 15 times ED(50) (150 mg/kg) for 3 months. Fourth group which served as control was given water. After three months, blood was collected for studying biochemical and hematological parameters. Blood glucose, serum cholesterol, liver and kidney function tests, haemoglobin, total and differential leukocyte count were determined. Animals were sacrificed and histopathological examination of liver, heart and kidneys was carried out. Results of the study showed that partially purified preparation fromFicus bengalensis is not toxic by all the above mentioned parameters. PMID- 23105339 TI - Vitamin a status in children with diarrhoea. AB - Vitamin A status was measured in 50 pre-school children with acute and persistent diarrhoea. It was measured by (a) Fluorometric micromethod and (b) Conjunctival impression cytology (CIC). The results were compared with 25 normal children. Vitamin A status was lower in children with persistent diarrhoea whereas the results were comparable between the children with acute diarrhoea and control subjects. PMID- 23105340 TI - Modifications in flow cytometric estimation of t cell subsets and b cells in peripheral blood to reduce the cost of investigation. AB - The development of monoclonal antibodies combined with flow cytometry has revolutionized the analysis of lymphocyte subsets. These newer methods using the Q-prep leucocyte preparation system require only 1-2 ml of blood as compared to 10 ml required traditionally. One of the main impediments in the use of this superior technology in Indian laboratories has been the high cost of reagents. This study evaluated methods to reduce the cost of assays. In the first experiment from 26 healthy subjects, 2ml venous blood samples in EDTA (ethylenediamine tetra-acetate) were obtained. Each sample was divided into two equal portions, one portion was stained using diluted monoclonal antibody, whereas the other portion was stained using standard concentrations of antibodies. In the second experiment, blood samples from 12 subjects were again divided into 2 portions; one portion of each pair was processed using commercial Q-prep reagents while the other portion was processed using our own reagents. In the first experiment, which evaluated use of a diluted antibody against the standard recommended concentrations, a 5-tube panel that estimated CD3, CD4, CD8, CD20 was used. In the second experiment CD3, CD4 and CD8 were estimated. The total cost per sample for a 5-panel estimation was however reduced from $39.11 to $1.10.Given the proven advantages of using a whole blood stain-lyse method for T cell subset estimations, its use should be encouraged in developing country settings. With the suggested methods the whole blood Q-prep could be performed at appreciably reduced costs, without loss in precision. PMID- 23105341 TI - Sensitivity and specificity of isolated antigen fromPlasmodium falciparum culture supernatant. AB - Immunological sensitivity and specificity properties of isolated Plasmodium falciparum (GPL) antigen from culture supernatant have been measured and compared with malarial antigens and non malarial filtered paper blood sera for potency and efficacy. Latex bead coded GPL, Pf and RESA antigens immunoreaction properties of human filter paper blood samples (FPB) were studied by laser light scattering immunoassay (LIA) and Enzyme linked immunoabsorbent assay (ELISA) techniques. Results of GP. antigen sensitivity study by LIA method showed a very high malaria antibody binding response (MABR) i.e. 6% compared with 78% with RESA and 88% Pf antigens. Malaria detection by ELISA method also found similar results. Specificity study of GPL antigen for different non malarial filter paper blood sera (NMFS) showed no immunoreaction however Pf and RESA antigen showed few positive immunological responses. These results suggest that sensitivity and specificity properties of isolated GPL antigen is better than other antigens. PMID- 23105342 TI - Apolipoprotein E4 polymorphism as risk factor for coronary heart disease among Indian subjects. AB - Apolipoprotein E genotypes and lipid and lipoprotein levels were determined in hypercholesterolemic and angiographically vertified CHD subjects and compared against 90 normolipidemic controls. The epsilon4 allele was significantly prevalent in the hypercholesterolemic and CHD subjects. Significant increase in total cholesterol levels in apo epsilon4 containing subjects were observed in the hypercholesterolemic and CHD group. The study suggests that the epsilon4 allele by influencing the lipid levels could act as a risk factor for CHD. PMID- 23105343 TI - Analysis of Bcl I and Xba I polymorphism in factor VIII gene to detect carriers of haemophilia a in Andhra Pradesh. AB - The efficacy of two intragenic polymorphic markers of factor VIII gene has been examined in Andhra Pradesh population with a view to confirm/revise the strategy for carrier detection that would be precise and economical. The haemophilia A carrier was detected using Bcl I and Xba I polymorphic sites in intron 18 and 22 respectively. The cumulative efficiency of these two sites for detection of carriers is 100% since all 15 families tested were informative for one of these polymorphisms, thus confirming their usefulness for factor VIII gene mutations found in Andhra Pradesh. PMID- 23105344 TI - Polymorphism (C677T) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene: A preliminary study on north Indian men. AB - An elevated level of plasma homocysteine, sulfur containing amino acid generated through demethylation of methionine has been widely accepted as a risk factor for cardiovascular disease (CVD). The increase can result from genetic and/or nutrient related disturbances in the remethylation or transsulfuration pathways for homocysteine metabolism. A common mutation (C677T) in the gene encoding for the enzyme 5, 10-methylenetetrahydrofolate reductase (MTHFR) or deficiency of the B vitamins namely folic acid, B(12), B(6) can lead to hyperhomocysteinemia.In the present study, we have investigated the incidence of the (C677T) MTHFR polymorphism in the North Indian males. 141 angiographically proven coronary artery disease (CAD) patients and 55 age and sex matched healthy volunteers were examined for the association between MTHFR gene polymorphism and CAD. The MTHFR genotyping was performed using polymerase chain reaction (PCR) followed by restriction-isotyping with Hinf 1 endonuclease. A trend for higher 'T' allele frequency (0.19) was observed in patients than in controls (0.16). However no significant association was found between C677T mutation and CAD severity. The lack of statistical significance could be due to the small sample size studied. Hence a larger study including various ethnic groups is warranted. PMID- 23105345 TI - Effect of latent iron deficiency on gaba and glutamate neuroreceptors in rat brain. AB - Eight weeks of latent iron deficiency in weaned female rats of Sprague Dawley strain maintained on experimental low-iron diet (18-20 mg/Kg) did not significantly change the gross body weight and tissue weights of brain and liver. Packed cell volume (PCV) and hemoglobin concentration remained unaltered. However, non-heme iron content in liver and brain decreased significantly (P<0.001). The activities of glutamate dehydrogenase, glutamic acid decarboxylase, and GABA-transaminase (GABA-T) in brain decreased by 15%, 11.4% and 25.7% respectively. However, this decrease was not statistically significant. Binding of(3)H Muscimol at pH 7.5 and 1 mg protein/assay increased by 143% (P<0.001) in synaptic vesicular membranes from iron-deficient rats as compared to the controls.(3)H glutamate binding to the synaptic vesicles was also carried out under similar condition. However, the L-glutamate binding was reduced by 63% in the vesicular membranes of iron deficient animals. These studies in dicate that iron plays an important functional role in both excitatory and inhibitory neurotransmitter receptors. PMID- 23105346 TI - HPLC method for amino acids profile in biological fluids and inborn metabolic disorders of aminoacidopathies. AB - Quantification of total and individual amino acids in biological fluids such as plasma, urine and cerebrospinal fluid has an important diagnostic implication in laboratory medicine. The present paper describes protocols for the assay of total amino acids by modified method based on dinitrophenyl and HPLC profile involving pre-column derivatization with o-pthalaldehyde (OPA) derivatization, respectively. The method, based on the alkylation of-SH groups prior to OPA derivatization of amino acids followed by reverse phase high performance liquid chromatography, provide a comprehensive profile of more than twenty amino acids (including-SH group containing) in a single run lasting about 45 minutes. The present study, apart from establishing the normal profile of amino acids in plasma of Indian sub population, also presents HPLC profile for some of the rare amino acidopathies. PMID- 23105347 TI - Effect of (-)epicatechin in modulating calicum-atpase activity in normal and diabetic human erythrocytes. AB - Aqueous extract of the wood ofPterocarpus marsupium, commonly known as 'bijasar', is used in Indian Ayurveda system of medicine for treatment of diabetes. The active anti-diabetic principle in its aqueous extract has been found to be ( )epicatechin, a flavonoid. The present work was undertaken to study the effect of (-)epicatechin on erythrocyte membrane Ca(++)-ATPase from type 2 diabetic patients. The activity of erythrocyte Ca(++)-ATPase was significantly lower in type 2 diabetics.In vitro insulin treatment of erythrocyte ghosts, resulted in the increase of Ca(++)-ATPase activity in diabetic patients. Treatment with ( )epicatechin (1mM) resulted in an increase in the activity of erythrocyte Ca(++) ATPase in both normal individuals and type 2 diabetic patients. The insulin like effect of (-)epicatechin on erythrocyte membrane Ca(++)-ATPase in type 2 diabetics is an interesting finding. Further work is needed to elucidate the mechanism of action of (-)epicatechin on modulation of erythrocyte membrane bound enzymes. PMID- 23105348 TI - Hypoglycemic, hypolipidemic and antioxidant properties of combination ofCurcumin fromCurcuma longa, Linn, and partially purified product fromAbroma augusta, Linn. in streptozotocin induced diabetes. AB - Dietary spice components ofCurcuma longa andAbroma augusta have been screened for their protective effect against reactive oxygen species induced lipid peroxidation. They have been found to be efficient antioxidant when administered in combination. The purpose of the study was to investigate the effect of oral administration (300mg/Kg) of the aqueous extract of turmeric whose active ingredient isCurcumin andAbromine powder as a hypoglycemic agent mixed with diet. The effect of this aqueous extract on blood glucose, lipid peroxidation (LPO) and the antioxidant defense system in rat tissues like liver, lung, kidney and brain was studied for 8 weeks in streptozotocin induced diabetic rats. The administration of an aqueous extract of turmeric and abromine powder resulted in a significant reduction in blood glucose and an increase in total haemoglobin. The aqueous extract also resulted in decreased free radical formation in the tissues studied.The decrease in thiobarbituric acid reactive substances (TBARS) and increase in reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) clearly showed the antioxidant property of the mixture. It is suggested that these changes initially counteract the oxidative stress in diabetes however, a gradual decrease in the antioxidative process may be one of the factors which results in chronic diabetes. These results indicate that the mixture of the two plants have shown antidiabetic activity and also reduced oxidative stress in diabetes. A combination ofAbroma augusta and Curcuma longa also restored the other general parameters in diabetic animals. The results were statistically analyzed and indicated that combination of herbal extracts showed better efficacy as compared to individual herbal plant extracts used. PMID- 23105349 TI - Antioxidant activity of ethanol extract of rhizome ofPicrorhiza kurroa on indomethacin induced gastric ulcer during healing. AB - Oral administration of ethanol extract of the rhizome ofPirorhiza kurroa at a dose of 20mg/kg body weight, for 10 consecutive days, was found to enhance the rate of healing on Indomethacin-induced gastric ulcer in rats, compared to the ulcerated group without treatment. The level of peroxidised lipid, in terms of thiobarbituric acid reactive species (TBARS), in gastric tissue, was increased in ulcerated rats which was restored to near normalcy on treatment with ethanol extract. The specific activity ofin vivo antioxidant enzymes, viz SOD and catalase and total tissue sulfhydryl (thiol) group, which were markedly decreased in ulcerated group, were found to be significantly elevated (p<0.05), on treatment with the above extract, at the specified dose, compared to the indomethacin-induced ulcerated group without any supporting treatment. The present study thus suggests that the ethanol extract of rhizome ofPicrorhiza kurroa, at the dose of 20mg/kg body weight, accelerated the healing of stomach wall of indomethacin induced gastric ulcerated rats by anin vivo free radical scavenging action. PMID- 23105350 TI - An integrated problem-based curriculum for biochemistry teaching in medical sciences. PMID- 23105351 TI - Effect of antihypertensive drugs on cardiac enzymes in hypertension with myocardial infarction in NIDDM. AB - Enzymology is a diagnostic indicator for myocardial infarction and diabetes in hypertension patients. Therefore the selection of methods for measurement of cardiac enzyme, Aspartate transaminase (AST), Creatine kinase(CK), and isoenzyme of creatine kinase (MB form), determine the effectiveness of antihypertension drug would provide the physician with diagnostic and prognostic clinical evidence. PMID- 23105352 TI - delta-ALA levels in serum and urine-A diagnostic tool for possible lead poisoning. AB - We present 2 cases of lead poisoning, the first of a child playing with painted toys and the second of an adult on local medicine. The former presented with acute abdomen and the latter with peripheral muscle weakness. We propose that raised serum delta-amino leavulinic acid (delta-ALA) levels strongly point towards the possibility of lead poisoning. PMID- 23105353 TI - Unusual changes in colostrum composition in lactating Indian women having medical complications during pregnancy-A pilot study. AB - Colostrum, the mammary secretion during first 2-4 days of lactation, provides all the essential components of nutrition and passive immunity required by the newborn. Pregnancy induced hypertension (PIH), glucose intolerance and anaemia are common medical complications observed during pregnancy in Indian women and their effects were studied on the composition of colostrum collected within 24 hours of delivery from lactating women included in the study. PIH during pregnancy significantly decreased colostrum IgA and total proteins, but showed a significant increase in K(+) levels, where as women with glucose intolerance showed a significant decrease in total lipids and lactose and an increase in Na(+) levels in colostrum compared to normal controls. The group with anaemia also showed a significant decrease in colostrum IgA and total protein levels when compared with the control group. Awareness about the changes that occur in the composition of colostrum during complicated pregnancies can be an important and useful tool for preventive and protective paediatrics. PMID- 23105354 TI - Poly A RNA status and expression of milli (m) and micro (MU) calpains in skeletal muscle of duchenne muscular dystrophy patients. AB - Poly A RNA status and itsin vitro translation in a rabbit reticulolysate cell free system, were assessed in the skeletal muscle of young boys with Duchenne muscular dystrophy. Compared to normals there is a significant 48% increase in poly A RNA content of dystrophic muscle and its translatability was increased by 56% based on(35)S methionine incorporation into total protein systhesised. Immunoprecipitation of the translated products with monospecific antibodies showed that there is a 2.6 fold and a 2 fold increase in m and MU calpains respectively. This underlines the importance of both synthetic and degenerative activities in the early pathology in DMD muscle. PMID- 23105355 TI - Antioxidant activity ofcurculigo orchioides in carbon tetrachloride-induced hepatopathy in rats. AB - In this study antioxidant activity of methanol extract of rhizomes ofCurculigo orchioides (MEC) was investigated using carbon tetrachloride (CCl(4))-intoxicated rat liver as the experimental model. The hepatotoxic rats were administered MEC for 90 days (daily, orally at the dose of 70 mg per kg body weight). Lipid peroxidation (LPO) in CCl(4)-intoxicated rats was evidenced by a marked increment in the levels of thiobarbituric acid reactive substances (TBARS) and diene conjugates (CD), and also a distinct diminution in glutathione (GSH) content in the liver. In CCl(4)+MEC-treated rats these biochemical parameters attained an almost normal level. The decreased activity of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GRD) in CCl(4)-intoxicated rats, and its retrieval towards near normalcy in CCl(4)+MEC-administered rats revealed the efficacy of MEC in combating oxidative stress due to hepatic damage. Elevated level of glutathione transferase(GTS) observed in hepatotoxic rats too showed signs of retuming towards normalcy in MEC co-administered animals, thus corroborating the antioxidant efficacy of MEC. The findings provide a rationale for further studies on isolation of active principles and its pharmacological evaluation. PMID- 23105356 TI - Estimation of CKMB from riqas control serum at 37 degree celsius. AB - The quality control sera commonly available in market does not provide the value of CKMB. The CKMB kit of Randox laboratories contains two lyophilized control sera. But the stability of the control serum after reconstitution with 2ml of distilled water is 5 days at 2-8 degree Celsius, 8hrs at 25 degree Celsius and 4 weeks at-20 degree Celsius when frozen once. Hence stability after reconstitution is not sufficient to fulfill the daily need of a laboratory. In quest of a good internal quality assessment (IQA) sample trial run has been performed at 37 degree Celsius using external quality assessment (EQA) samples obtained from Randox international quality assessment sample (RIQAS). The trial run was found to be successful. PMID- 23105357 TI - Genetic factors for aids progression: Analyses of HIV-1 resistant genes in India and therapeutic potentials of novel catalytic RNA and DNA molecules. PMID- 23105358 TI - Clinical aspects of tuberculosis. PMID- 23105359 TI - Rare case of iatrogenic pan hypopituitarism. AB - Excess glucocorticoids exert feedback suppression on hypothalamus and pituitary, Thereby the release of CRH and ACTH are suppressed which results in bilateral adrenal cortical atrophy, at the same time patients is having features of latrogenic Cushing syndrome.The interesting part of this case is excess glucocorticoids have exerted cross feedback suppression on hypothalamus and pituitary resulting in suppression of release of GHRH, GH and LHRH, LH and FSH also from hypothalamus and pituitary thereby resulting in growth retardation as well as hypogonadotrophic hypogonadism. Combination of feedback and cross feedback effect of excess glucocorticoids are seen in one patient which is an interesting part of the case. PMID- 23105360 TI - Alteration of serum beta 2-microglobulin in oral carcinoma. AB - Serum beta(2)-microglubin (beta(2)-m) levels were measured in oral carcinoma patients and compared with normal healthy controls. It was observed that there was a significant rise in serum beta(2)-microglobulin in oral carcinoma patients. Progressively higher values were obtained as the cancer advanced clinically. Therefore the estimation of serum beta(2)-microglobulin may be useful as one of a battery of tests in the assessment of oral carcinoma patients. PMID- 23105361 TI - Effect of iron deficiency on developing rat brain. AB - Iron deficiency evolves, slowly through several stages. Early iron deficiency caused a depletion in iron stores as shown by a reduction in the levels of hepatic non heme iron (44%) in the 7 days old pups born to iron deficient mothers. The hemoglobin levels and PCV (packed cell volume) were significantly reduced only after the age of three weeks. The activities of GABA (gamma-amino butyric acid) shunt enzymes viz. GDH, GAD and GABA-T (glutamate dehydrogenase, glutamate decarboxylase and GABA-transaminase, respectively) and GABA content were found to decrease during gestation and/or lactation iron deficiency at 1 week (wk), 2wk, 3wk and 4wk of age in the developing rat brains. However GABA binding showed a significant increase at different age groups. The iron deficiency during lactational exposure showed significant alteration in most of the parameters only at the age of 3 weeks onwards. On rehabilitation with iron supplemented diet for 2 weeks, these altered parameters could not attain corresponding control values. A prolonged iron deficiency causing alterations in GABA may lead to neurological and behavioral alterations. PMID- 23105362 TI - Reversal of diabetic retinopathy in streptozotocin induced diabetic rats using traditional Indian anti-diabetic plant,Azadirachta indica (L.). AB - This study was carried out to investigate the effect of oral feeding of water extract of fresh leaves ofAzadirachta indica (Fam:Meliaceae) in streptozotocin induced diabetes and its associated retinopathy in rats. Treatment of the diabetic rats with aqueous extract of leaves ofA. indica at a dose of 250 mg/kg body weight for 16 weeks resulted in gradual but significant fall in blood glucose and improvement in serum total, LDL and HDL cholesterol and triacylglycerol which increased in diabetic rats. It also showed improvement in body weight and reversed retinopathy. PMID- 23105363 TI - Calcineurin activity as an indicator of oxidative stress in normal islet cells and insulinoma cells. AB - A comparative study was conducted to evaluate calcineurin activity in normal pancreatic beta cells and insulinoma cells in relation to their oxidative state. In comparison to normal islets, insulinoma cells had enhanced oxidative stress as evidenced by increased content of thiobarbituric acid reactive substances. In addition, diminished activity of calcineurin in insulinoma cells was concomitant with decreased content of reduced glutathione and glutathione peroxidase activity signifying diminished antioxidant status in these cells. Culturing insulinoma cells in presence of the calcineurin inhibitor cyclosporin A resulted in further decrease of calcineurin activity with restoration of glutathione peroxidase but without restoration of reduced glutathione levels. These results indicate that an estimate of oxidative stress in pancreatic islets and insulinoma cells can be obtained by assaying calcineurin activity. PMID- 23105364 TI - Gingival crevicular fluid a marker of the periodontal disease activity. AB - Gingival crevicular fluid (GCF) is an inflammatory exudate that can be collected at the gingival margin or within the gingival crevice. The biochemical analysis of the fluid offers a non invasive means of assessing the host response in periodontal disease. Active phase of periodontal disease process can be measured or assessed by the constituents of gingival fluid. Bacterial enzymes, bacterial degradation products, connective tissue degradation products, host mediated enzymes, inflammatory mediators, extracellular matrix proteins either together or individually can be detected in higher levels in gingival crevicular fluid during active phase of periodontitis. PMID- 23105365 TI - Hyperhomocysteinemia: An emerging risk factor for cardiovascular disease. AB - There is considerable epidemiological evidence, which confirms the importance of plasma homocysteine as a powerful predictor of future risk of coronary heart disease and other complications of atherosclerosis. Treatment of hyperhomocysteinemia varies with the underlying cause. However, an inexpensive vitamin supplementation with folic acid, vitamin B12 and vitamin B 6 is generally effective in reducing homocysteine concentrations. Several randomised, controlled trials evaluating the effects of folic acid based supplements on homocysteine concentrations have been conducted over the last decade. In most patients, folic acid alone, and in combination of vitamin B12 and B6, has been shown to reduce homocysteine concentrations within four to six weeks after the initiation of therapy (34).However, no study has yet demonstrated that lowering of homocysteine by vitamin supplementation decreases the cardiovascular morbidity or mortality. Avoidance of excessive meat intake and increased consumption of fresh vegetables and fruits is a dietary measure, which has many health benefits, including a potential to reduce elevated homocysteine levels. The other reasonable approach is to determine levels of fasting homocysteine in high risk patients and it may be advisable to increase their intake of vitamin fortified foods and/or to suggest the daily use of supplemental vitamins. Several large scale randomised trials like Heart Outcomes Prevention Evaluation (HOPE-2) Study, Mcmaster University, Canada, Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SERCH), Clinical Trial Service Unit, Oxford, U.K, Cambridge Heart Antioxidant Study (CHAOS-2) University of Cambridge, U.K, Bergen Vitamin Study, University of Bergen Norway, Women's Antioxidant and Cardiovascular Disease Study (WACS) Harvard Medical School, U.S.A, Prevention with a combined inhibitor and folate in Coronary Heart Disease (PACIFIC) study, University of Sydney, Australia, and many others are ongoing to assess the effect of homocysteine-lowering by vitamin supplementation on risk of vascular disease. PMID- 23105366 TI - Antioxidant effect ofPhyllanthus emblica fruits on healing of indomethacin induced gastric ulcer in rats. AB - Post-treatment of the indomethacin induced ulcerated rats at the optimal dose of 100 mg/kg body-wt. orally for 7 consecutive days with the lyophilized aqueous extract of the fruits ofPhyllanthus emblica L. syn.Emblica officinalis Gaertn. (Euphorbiaceae) exhibited highly significant (p<0.001) enhancement of secretion of catalase, reduced glutathione and decrease in malonyldialdehyde (MDA). Furthermore, the gross morphological observation and highly significant (p<0.001) decrease of ulcer index (81.43%) indicated healing effect of the extract on gastric ulcer. PMID- 23105367 TI - Quantification of urinary urate with alkylamine glass-bound uricase and arylamine glass-bound peroxidase. AB - Uric acid in urine was analyzed using porcine liver uricase and horseradish peroxidase immobilized on alkylamine and arylamine glass beads (pore diameter 55nm) respectively. The minimum detection limit was 5.0mg/0.1 ml urine. The recovery of added uric acid was 92%. Within and between assay CVS were <1.3% and <5.3% respectively. A good correlation (r=0.93) was found between urinary urate values obtained by a commercial kit method and the present method. The uric acid in 24hr urine of apparently healthy adults and person sufering from various diseases was found to be 450 to 900mg/24hr, 659mg/24hr (range, mean) and 910 1400mg/24hr, 1145 mg/24hr (range, mean) respectively with the present method. PMID- 23105368 TI - Induction of IgE antibody response by the green seed extract ofVigna sinensis in mice. AB - Sensitization to ingested foods is a known fact and several food allergens have been characterized. It has been observed in our survey that the people complained of allergic symptoms after consumption of the vegetableVigna sinensis. In this study, the experiments were carried to investigate the IgE antibody response against the green seed extract of vigna sinensis in mice and found that the primary, secondary and tertiary immunization with or without adjuvant by different doses induced a significant production of IgE antibodies. The presence of IgE antibodies in the mice sera were determined by passive cutaneous anaphylaxis and enzyme linked immunosorbent assay. It was also confirmed that these allergens were found to be heat resistant and shared a common epitope(s) with the other legume foods, as evidenced by the cross-reactive studies. PMID- 23105369 TI - Kinetic analysis of LDL oxidation in IHD and IHD risk subjects in Indian population. AB - High plasma concentration of low-density lipoprotein (LDL) is associated with increased risk of atherosclerosis. Modified forms of LDL, especially oxidized LDL play a major role in its pathogenesis. This article gives detailed insight into the kinetics ofin vitro LDL oxidation by copper at different concentrations in normal and high-risk group subjects. Basal level of oxidatively modified LDL was significantly higher in ischaemic heart disease (IHD) and IHD hyperlipidemic subjects compared to normolipidemic and, hyperlipidemic control subjects, respectively. Derivatization of amino groups of apo-lipoprotein as monitored by estimating free amino groups concentration, was significantly higher in high-risk group and established IHD cases. Kinetics of oxidation was studied with two different concentrations of CuSO(4) (2.5 mM and 7.5 mM). thiobarbituric acid reactive substances (TBARS) level increases with time, and up to 95% oxidation was observed in 8 hr. About 60-65% less free amino groups were observed in native LDL isolated from IHD patients compared to normal subjects. Study also showed an increase in two oxidative products studied, 20alpha-OH-cholesterol and 4 cholesten-3-one with oxidation time accompanied by corresponding decrease in LDL cholesterol. Increase in oxidative species was more evident in high-risk group and IHD patient. Basal level of oxidatively modified LDL measured in terms of TBARS was significantly higher in present study, strongly support that the extent of LDL oxidation monitored as TBARS and FAG level in circulating-LDL could be used as risk marker for high risk group. PMID- 23105370 TI - Tissue polypeptide specific antigen in the post therapeutic evaluation of patients with ovarian and colorectal cancer. AB - The study was designed to evaluate the significance of tissue polypeptide specific antigen (TPS) in patients with histologically proven ovarian and colorectal cancer following treatment along with CA125 (in ovarian cancer) and CEA (in colorectal cancer). Patients were grouped as follows:: Patients with stable disease: Patients with metastasis and relapseIn patients with ovarian and colorectal cancer, the mean TPS levels were significantly higher in patients of group II compared to group I. The percentage of patients above cut-off levels for TPS were 17.4% in group I and 95.5% in group II. Similar results were observed with the mean levels of CA125. In colorectal cancer patients, the percentage of patients above cut-off levels for CEA and TPS were 70% and 30% in group I and 100% in group II for both the markers. Our observations indicate that TPS may be used as a common marker to indicate metastases in patients with ovarian and colorectal cancer. PMID- 23105371 TI - Clinico-Biochemical indexing of calcium urolithiasis on the basis of urinary citrate to calcium ratio and inhibition of mineralisation of urinary stone forming minerals by human urine. AB - Urinary citric acid and calcium levels have been estimated in the urine of 20 normal healthy persons as well as 12 urinary stone patients. Inhibition efficiency of these urine samples towards the mineralisation of urinary stone forming minerals, viz., calcium phosphate, oxalate or carbonate, has been studied in an experimental model. Statistical correlation of the above data has been made by computing the coefficient of determination and unexplained variance. Clinico biochemical indexing of calcium urolithiasis risk factor has been attempted in the light of the data. PMID- 23105372 TI - Microscopic haematuria as an occult filarial infection in bhubaneshwar an endemic area for bancroftian filariasis. AB - Sera samples of 7 microscopic haematuria cases collected before and after treatment with Diethylcarbamazine citrate, (DEC), 9 microfilaraemic cases and 19 endemic normal individuals were analysed for filarial antigen and IgG antibody levels. Filarial antigen was detected in 5 of the 7 microscopic haematuria cases, of which 3 turned negative for antigen after treatment with DEC. While none of the 7 haematuria cases were positive for filarial IgG antibodies, before the DEC treatment, all of them turned positive after DEC treatment. The sensitivity and specificity values(to detect mf +ve cases) were 89% and 90% respectively for the detection of filarial antigen and 78% and 95% respectively for the detection of filarial IgG antibodies. PMID- 23105373 TI - Investigations on protein adsorption onin-vivo sensor membrane surfaces. AB - In order to understand the mechanism of fauling of electrode surfaces ofin vivo electrochemical sensors used for monitoring whole blood, the investigations on protein adsorption on the membrane surfaces were undertaken. Using an oxygen sensor, the protein adsorption studies were carried out on two different polymeric surfaces-teflon (PTFE) and polyurethane (PU)-using Scanning Electron Microscopy and Fourier Transform Infrared Spectrophotometry. Investigations reveal that even a single protein like albumin or fibrinogen tend to adhere to the sensor membrane surface and influences the electrochemical characteristics of the sensor. The influence is more significant, in the case of PTFE membrane. PMID- 23105374 TI - Lipid peroxidation in erythrocytes of patients with type 2 diabetes mellitus. AB - Lipid peroxidation by measurement of Thiobarbituric Acid Reactive Substances (TBARS) and antioxidant status by determining the activities of the enzymes, Catalase (Cat), Glutathione Peroxidase (GPx) and Superoxide Dismutase (SOD) and the level of Reduced Glutathione (GSH) in the erythrocytes of patients with type 2 Diabetes Mellitus were investigated. It was observed that the level of TBARS in the erythrocytes was increased by 50% showing a significant generation of free radicals in the erythrocytes of these patients. The activities of both Cat and SOD were enhanced while that of GPx was not altered. The level of GSH was also not changed. PMID- 23105375 TI - Altered antioxidant enzyme profile in wound healing. AB - The effects of the alcoholic extract of the flowers ofIxora coccinea were studied on some of the antioxidant enzymes in dead space wounds created in rats. Increases in the tensile strength of the wound and in the level of lysyl oxidase, the crucial enzyme for collagen maturation, were observed indicating a definite prohealing action. In addition, a highly significant increase in the levels of catalase, glutathione peroxidase and glutathione reductase was observed in the drug-treated group. Thus, the gain in tensile strength may be attributed not only to the better cross-linking but also to the antioxidant properties of the drug. PMID- 23105376 TI - Separation of antihemophilic factor VII from human plasma by column chromatography. AB - TMAE-Fractogel 650 (M) (Trimethylaminoethyl) is an ion exchange medium can be used to capture factor VIII (F VIII) directly from plasma. Previous reports have focused on the use of DEAE-Fractogel 650 (M) (Dimethylaminoethyl) ion exchange medium to capture F VIII from cryoprecipitate and plasma. Our main objectives were (I) to standardise the purification of FVIII from human plasma by column chromatographic technique. (II) to study the recovery of FVIII activity in purified fraction at 18-20 degrees C process condition. (III) to study the effect of virucidal step on recovery of FVIII activity and (IV) to study the effect of lyophilisation on FVIII activity. In this report, Citrate Phosphate Dextrose (CPD) plasma was batch stirred with dry DEAE-Sephadex A50, filtered, diluted, loaded on to a column packed with TMAE-Fractogel and chromatographed. Most of the unwanted proteins flowed through the gel unadsorbed. Bound F VIII was eluted by increasing the ionic strength of the buffer. This purification step gave an overall 80% recovery from the plasma with a specific activity of 0.97 IU FVIII/mg protein. The purified F VIII fraction was made virus safe by employing the virucidal technique developed by New York Blood Centre (NYBC). There was 48.43% loss of FVIII activity in Virus inactivation treatment and the loss of FVIII activity in lyophilisation was 8.45% which is acceptable. This method of purification gave a higher yield of FVIII than cryoprecipitation, and is a promising alternative method to cryoprecipitation of F VIII. PMID- 23105377 TI - Oxidative injury and antioxidant vitamins E and C in Schizophrenia. AB - Susceptibility of Schizophrenic patients to lipid peroxidation relative to healthy control subjects was investigated by measuring the malondialdehyde (MDA) levels in plasma. The main finding was that Schizophrenic patients were more susceptible than control subjects to oxidative damage as evident from increased MDA levels in plasma. Antioxidant levels are also depleted in Schizophrenic patients when compared to normal subjects as evident from decreased levels of vitamins E and C in the plasma. Impaired antioxidant defense and increased lipid peroxidation suggests that treatment with antioxidants (Vitamin E, Vitamin C, beta carotene) at the initial stages of illness may prevent further oxidative injury and deterioration of associated neurological deficits in Schizophrenia. PMID- 23105378 TI - Effect of ketoacids on H(2)O(2) induced cataract. AB - Cataract is one of the leading causes of visual disability often leading to blindness in the elderly population. One of the causes is oxidation of proteins present in lens, by hydrogen peroxide (H(2)O(2)). In the present study 100 goat lenses were analyzed to determine the protective efficacy of ketoacids, against the oxidative insult by H(2)O(2). The ketoacids used were (pyruvate, alpha ketoglutarate and oxaloacetate), that are constantly produced endogenously. The lenses were incubated as control and experimental groups in TC-199 media for 72 hrs. H(2)O(2) concentration of 10mM was used to induce cataract. The biochemical parameters measured were levels of malondialdehyde (MDA), a lipid peroxidation product and activity of glutathione peroxidase (G-Px), an enzymatic antioxidant. The results showed a significant increase in the levels of MDA and significant decrease in the activity of G-Px in the cataractous lenses as compared to control. After addition of ketoacids (pyruvate (10mM), alpha ketoglutarate (20mM) and oxaloacetate (20mM)) separately, the levels of MDA decreased significantly and the activity of G-Px increased significantly. The results suggest that the ketoacids can be very promising antioxidants for the treatment of cataract. They may also be useful in treating other disabilities related to acute and chronic oxidative stress. PMID- 23105379 TI - Blood glutathione peroxidase and selenium in abortion. AB - This study was carried out to estimate the levels of glutathione peroxidase and selenium in blood of abortion cases. Glutathione peroxidase and selenium were determined in 52 abortion cases (22 in 1(st) trimester, 30 in second trimester), 45 normal pregnant cases and 25 nonpregnant control cases. The selenium concentration in whole blood and plasma in abortion cases was almost the same as in normal pregnant women but significantly low when compared with the control non pregnant group. The glutathione levels was higher in abortion cases when compared with normal pregnant and non-pregnant control groups. Red cell and plasma glutathione peroxidase activities of women who had abortion were significantly lower compared with both non-pregnant control group and normal pregnancies. PMID- 23105380 TI - Effect of nicorandil and amlodipine on bio-chemical parameters during isoproterenol induced myocardial necrosis in rats. AB - OBJECTIVE: To investigate the protective effect of nicorandil and amlodipine in isoproterenol induced myocardial necrosis in rats. METHODS: The effect of nicorandil and amlodipine on bio-chemical parameters during isoproterenol induced myocardial necrosis in rats was examined by determining the activity of creatine phosphokinase (CK), lactate dehydrogenase (LDH), and transaminases (AST, ALT) in the serum of the animals. RESULTS: Isoproterenol (150mg/kg/day) administered rats showed statistically significant rise in activities of LDH(1.02+/-0.19 to 1.85+/ 0.05), CK(4.3+/-0.19 to 7.37+/-.27), AST(0.38+/-.03 to 0.78+/-.05) and ALT(0.19+/ .017 to 0.346+/-.027) in the serum. Pre-co-treatment of rats with nicorandil and amlodipine significantly lowered the raised levels of these enzymes and thereby restoring the enzyme activity to near normal as was clear from the chart i.e. LDH was 1.10+/-0.04, CK was 4.37+/-0.19, AST and ALT were 0.39+/-0.028 and 0.199+/ 0.04 respectively. CONCLUSION: It is demonstrated that pre-co-treatment with nicorandil and amlodipine either alone or in combination help in providing protective effect on isoproterenol induced myocardial necrosis. PMID- 23105381 TI - Serum lipoprotein (a) and lipid profile in young South Indian patients with myocardial infarction. AB - Coronary artery disease is now a major health problem in India. In past few decades the battle to reduce the incidence of coronary artery disease has led the researchers to look for various clinical markers, which would help early diagnosis of the diseases. The present study was undertaken to assess the level of lipoprotein (a) [Lp(a)] and few other lipids in selected myocardial infarction (MI) patients below 45 years without having any traditional risk factors but with positive family history. Fasting blood samples were taken from 65 patients and their total cholesterol, LDL cholesterol, VLDL cholesterol, HDL cholesterol, triglycerides and serum Lp(a) were determined. The control group consisted of 50 age matched healthy individuals. The mean Lp(a) level was 58.6+/-3.20 mg/dl in patients and 19.70+/-0.18 mg/dl in controls. Thus Lp(a) levels were found significantly higher in patients with MI (p<0.05 for patients versus control) as compared to the controls. There was no significant difference in the levels of total cholesterol (TC), LDL, VLDL HDL, TGL as compared to controls but there was an increase in TC/HDL cholesterol ratio. The results of this study suggest that high level of Lp(a) and TC/HDL ratio has a distinctive association with MI, independent of other common coronary risk factors. Hence, Lp(a) level in serum emerges to be a promising marker for diagnosis of coronary artery diseases. PMID- 23105382 TI - Serum creatine phosphokinase in thyroid disorders. AB - The decreased serum levels of triiodothyroinine (T3) and thyroxine (T4) in hypothyroid patients is well established but whether there is any correlation of creatinephosphokinase (CPK) with hypothyroidism is not well established. There is a paucity of reference on this study. Therefore a study of serum CPK and thyroid profile was carried out in thyroid diseases. In hypothyroid patients T3, T4 levels in serum were found to be lowered with an increase level of thyroid stimulating hormone (TSH) associated with marked rise in serum CPK level. In hyperthyroid patients serum levels of T3, T4 were found to be increased with decrease in TSh with significant decrease in creatine phosphokinase level. Serum creatine phosphokinase levels thus show an inverse relation with serum T3, T4 levels. PMID- 23105383 TI - Effect of latent iron deficiency on GABA and glutamate neuroreceptors in rat brain. AB - Eight weeks of latent iron deficiency in weaned female rats of Sprague Dawley strain maintained on experimental low-iron diet (18-20 mg/kg) did not significantly change the gross body, weight and tissue weights of brain and liver. Packed cell volume (PCV) and hemoglobin concentration remained unaltered. However, non-heme iron content in liver and brain decreased significantly (p<0.001). The activities of glutamate dehydrogenase, glutamic acid decarboxylase, and GABA-transaminase (GABA-T) in brain decreased by 15%, 11.4% and 25.7% respectively. However, this decrease was not statistically significant. Binding of(3)H Muscimol at pH 7.5 and 1 mg protein/assay increased by 143% (p<0.001) in synaptic vesicular membranes from iron-deficient rats as compared to the controls.(3)H glutamate binding to the synaptic vesicles was also carried out under similar condition. However, the L-glutamate binding was reduced by 63% in the vesicular membranes of iron deficient animals. These studies indicate that iron plays important functional role in both excitatory and inhibitory neurotransmitter receptors. PMID- 23105384 TI - Immunodiagnosis of tuberculosis: An update. AB - Tuberculosis is still a major health problem in most developing countries and its incidence is rising in many developed countries. This resurgence has been attributed to the HIV epidemic and TB has been declared as a global health emergency by WHO in 1993. The diagnosis of tuberculosis mainly depends upon initial clinical suspicion and radiographic findings with subsequent bacteriological confirmation by sputum smear examination and culture. Lack of sensitivity in smear examination, non specificity of radiological findings, extended tum around time ofMycobacterium tuberculosis culture and difficulties in diagnosing paucibacillary, childhood and extrapulmonary tuberculosis has necessitated to explore the utility of immunodiagnosis of tuberculosis as a convenient and cost effective test to supplement clinical information for definite diagnosis. Many commercial tests are available in the market for diagnosis of TB. Most of these tests are based on the detection of IgG, IgA and IgM antibodies to specific mycobacterial antigen or mixture of antigens. Indigenous immunoassay systems have explored excretory-secretory ES-31 mycobacterial antigen for immunodiagnosis of TB. Many a time there is lack of consistent elevation in all the three Ig classes in active infection thus making it more important to determine the ideal antibody isotype assay for reliable diagnosis of tuberculosis and to save the costs of the patient for unnecessary investigations. PMID- 23105385 TI - Raised Serum Lactate Dehydrogenase associated with gangrenous small bowel volvulus: A case report. AB - Usually CPK, CK-MB and lactate dehydrogenase (LDH) enzymes are measured in blood during the period of myocardial infarction. The changes in LDH assay indicates duration of the infarction.The level of lactate dehydrogenase is 500 times greater in tissue than those found in serum. A small mass of damaged tissue causes leakage of enzyme and increases its level in serum.Any cause of tissue break down/hemolysis which is sufficiently severe can produce LDH pattern similar to that in myocardial infarction.We report this case of small bowel volvulus showing significant increase in LDH.It may be due to tissue necrosis which increases the level of LDH in serum. PMID- 23105386 TI - Effect of herbal hypoglycemic agents on oxidative stress and antioxidant status in diabetic rats. AB - In the present study the antioxidative potential ofMomordica charantia, Azadirachta indica, Allium sativum andOcimum sanctum was assessed in streptozotocin induced diabetic rats. Lipid peroxide levels were also measured in normal, diabetic and treated animals. Malondialdehyde (MDA) levels were significantly higher and antioxidant activity was found low in diabetic groups as compared to the control groups, and significant alteration in both the MDA levels and antioxidant activity was also observed when the above herbal hypoglycemic agents were given to diabetic rats. On the basis of our results we conclude thatM. charantia, A. indica, A. sativum andO. sanctum are not only useful in controlling the lipid peroxide levels but are also helpful in further strengthening the antioxidant potential. PMID- 23105387 TI - Biochemical effects of various pesticides on sprayers of grape gardens. AB - A total of 85 healthy male pesticide sprayers in grape garden exposed to different class of pesticides for 3 to 10 years were compared with 75 controls matched for age with respect to serum cholinesterase, serum total protein, albumin, AST, ALT, hematological parameters such as Hb, Hct, RBC and serum lipid peroxidation. Serum lipid peroxidation was estimated in the form of thiobarbituric acid reactive substances (TBARS) produced. Significant decrease was observed in serum cholinesterase, serum total proteins, albumin and hematological parameters viz. Hb, Hct and RBC. Significant increase in lipid peroxidation, AST, ALT, was observed in exposed group when compared with control. These results suggest that the long term exposure of various pesticides on sprayers of grape garden affect liver, heme biosynthesis and decrease serum cholinesterase. PMID- 23105388 TI - Biotinidase deficiency-Diagnosis by enzyme assay and a follow-up study. AB - A 3 month old male child was brought to the hospital with complaints of skin rashes, developmental delay, seizures, seborrheic dermatitis, alopecia and mild, acidosis. The child was subjected to a simple metabolic screening protocol. The result of the screening and the clinical symptoms provided an index pointing towards biotinidase deficiency., a rare autosomal recessive, inherited metabolic disorder. The enzyme was then assayed by using n-biotinylp-aminobenzoate as substrate and the diagnosis confirmed. A follow-up of the case indicated the efficacy, of biotin supplementation in biotinidase deficiency. PMID- 23105389 TI - Determination of cancer antigen 125 in ovarian carcinoma. AB - Appropriate therapeutic measures can improve the life expectancy of patients with ovarian malignancy. There has been a pressing need for serodiagnostic assays to enable, the close patient monitoring. Cancer Antigen 125 (CA125) has been described as a useful marker in patient monitoring for ovarian malignancy. Keeping this in view, the present study was planned. 40 consecutive female patients of ovarian carcinoma (mean age 52.4+/-10.7 years) were selected for serum CA125 analysis during the period of year 1995-2001. The tumour marker concentration was compared with histologic types of ovarian tumour and the FIGO staging of the disease. 25 healthy females (mean age 35.2-10.4 years) served as control. Mean serum CA125 concentrations in patients with papillary serous adenocarcinoma(Mean+/-%CV 1571+/-121.5 U/ml) was much higher than patients with mucinous adenocarcinoma(775+/-78U/ml). Mean serum CA125 concentration in endometrioid carcinoma was very high(2853+/-136 U/ml). The patient with clear cell carcinoma however had shown moderate increase(60 U/ml). No correlation was found between serum CA125 concentration and the FIGO staging of disease.Quantitation of CA125 was most helpful in monitoring the response of treatment and followup of the patients after completion of their treatment. Posttherapeutically its concentration showed more than 50% reduction in almost all (91.4%) patients (P<0.001). Importantly these patients had also shown significant regression of the disease clinically and radiologically. 8.6% of patients had shown static or increase in serum CA125 concentration which was associated with either clinically static or progressive disease. Recurrence of the disease was noted in patients who had shown increase in serum CA125 concentration (biochemical recurrence) in the followupHowever, in our test population biochemical recurrence(increase in serum marker concentration) preceded the clinical or radiological recurrence by an average of 6.5 months.Kaplan meier survival analysis for evaluation of overall survival in our test subjects showed an overall survival of 32% at one year and median survival of 9 months with confidence interval of 6.34 to 11.66. We conclude that serum CA125 is a useful marker for monitoring the treatment and predicting an early recurrence of the disease in ovarian carcinoma patients. A study in larger number of patients is needed to define its exact role in the management of the carcinoma ovary. PMID- 23105390 TI - Study of apolipoproteinc3 Sstl polymorphism in healthy volunteers from Northern India. AB - Several studies including a small case-control (hypertriglyceridemic/normotriglyceridemic individuals) study by us revealed close association between rare S2 allele ofAPOC3 Sstl polymorphism and hypertriglyceridemia. With the understanding that Asian Indians are highly vulnerable to the adverse effects of hypertriglyceridemia, we extended the investigation and studied the frequency distribution of this polymorphism in 216 healthy volunteers from Northern plains of India. We found that more than 50% of the study population had one or two S2 allele. This may suggest that a larger fraction of this population is genetically predisposed to hypertriglyceridemia. PMID- 23105391 TI - Effects of some antituberculous and anti-leprotic drugs on cathepsins B, H and L. AB - The cysteine proteinases like cathepsins B, L and H are main hydrolytic enzymes present in lysosomes and play an important role in intracellular protein degradation. Tuberculosis and leprosy, both are tissue- destructive diseases. Main drugs used in chemotherapy of these diseases may inhibit the main lysosomal cysteine proteinases i.e. cathepsins B, L and H released during tissue destruction and thus prevent the further destruction of tissue by these enzymes. So the aim of this study is to see the effect of antituberculous and antileprotic drugs on these proteolytic enzymes. The effect of commonly used antituberculous and antileprotic drugs was screened on the activities of purified brain lysosomal cysteine proteinases namely cathepsins B [EC 3.4.22.1], L [EC 3.4.22.15] and H [EC 3.4.22.16]. Among the antileprotic drugs, only clofazimine inhibited the enzymic activities whereas dapsone had no effect whatsoever. In antituberculous drugs, rifampicin was the most inhibitory while isoniazid had little inhibitory potency. Streptomycin and pyrazinamide did not effect the activities at all. As regards the mechanism of inhibition, clofazimine and isoniazid inhibited the enzymes in a non-competitive manner with K values of 0.25 mM and 5.0 mM for cathepsin B, 0.071 mM and 0.833 mM for cathepsin L and 1.513 mM and 0.885 mM for cathepsin H, While rifampicin could effect in a competitive manner with K(i) values of 0.03 mM, 0.125 mM and 0.027 mM for cathepsin B, L and H respectively. PMID- 23105392 TI - Serodiagnosis of tuberculosis using two ELISA systems. AB - Serodiagnosis by ELISA has been widely explored over the years, in the diagnosis of tuberculosis. Two ELISA systems were evaluated for detection of mycobacterial antibodies in pulmonary and extra pulmonary tuberculosis. The two test assays explored were ERBA LISA (TB IgG) test (Anda Biologicals) which uses A60 antigen complex found in the cytosol of typical and atypical mycobacteria, and SEVA TB (IgG) ELISA, which uses a 31 kDa, glycoprotein antigen purified fromM. tb H(37)Ra culture filtrate. Sera from 98 proven tuberculosis [pulmonary TB (48), tuberculous lymphadenopathy (30), tuberculous meningitis (15) & genitourinary TB (5)] were studied along with 32 healthy controls. The overall positivity obtained using ERBA LISA (TB IgG) test and SEVA TB (IgG) ELISA test was 72.9% and 91.6% in pulmonary tuberculosis, 43.3% and 76.6% in tuberculous lymphadenopathy respectively. The sensitivity of ERBA LISA test in tuberculous meningitis and genito-urinary TB was significantly low (26.6% & 40% respectively) compared to sensitivity obtained using SEVA TB ELISA (86.6% & 60% respectively) with overall specificity of 60% and 87.5%. Thus SEVA TB IgG ELISA test was found to be more sensitive than ERBA LISA in detecting IgG antibodies in tuberculous sera, in particular in extra pulmonary tuberculosis cases. PMID- 23105393 TI - Effect ofCoccinia indica (L.) andAbroma augusta (L.) on glycemia, lipid profile and on indicators of end-organ damage in streptozotocin induced diabetic rats. AB - InAyurvedic system of medicine in India, not only extracts of one plant or the other but also a combination of plant extracts are used for the treatment of diabetes mellitus. The present paper reports the combined effect ofAbroma augusta andCoccinia indica known to be useful for the treatment of diabetes in Ayurveda on the fasting blood sugar, glucose tolerance and lipid profile of Streptozotocin (STZ) induced albino rats. 300mg of water extract of the mixture of dried powdered roots ofA. augusta and leaves ofC. indica in equal proportions was given once daily for 8 weeks. After 8 weeks of treatment of Streptozotocin (STZ) diabetic rats, the fasting blood sugar came down to almost normal value and improvement in glucose tolerance and serum lipid profile were also observed. PMID- 23105394 TI - Redistribution of glucose-6-phosphate dehydrogenase in response to cerebral ischemia in rat brain. AB - Glucose-6-phosphate dehydrogenase (G6PD), a cytoplasmic enzyme, plays a protective role during oxidative stress in eucaryotic cells, since they provide coenzymes and substrates to the primary antioxidant enzymes. The redistribution of G6PD in the hippocampus was studied post-ischemia (PI). There was a characteristic localisation of G6PD in pyramidal cell layers of the rat hippocampus. In hippocampus CA1 cells were stained weakly whereas CA3 cells showed strong histochemical staining. Ischemia induced up-regulation of G6PD in the hippocampus was in a specific manner. First, the activity increased in the whole hippocampus (at 4 hours PI) which persisted 6 hrs PI in CA1 area. However G6PD activity decreased in the CA3 area & dentate gyrus. At 10 & 24 hrs PI, activity decreased in CA1 area but normalised in CA3 area & dentate gyrus compared to controls. This suggests that the sensitive CA1 neurons are transiently capable of generating an anti-oxidative arsenal to cope with the oxidative stress in the first few hours PI. We can conclude that the brain contains inducible endogenous mechanisms that are capable of enhancing the ability of neurons to withstand lethal ischemic challenge. PMID- 23105395 TI - Cardioprotective activity of synthetic guggulsterone (E and Z-isomers) in isoproterenol induced myocardial ischemia in rats: A comparative study. AB - Guggulsterone, a mixture of cis (E) and trans (Z) isomers (7?3 w/w) was synthesized from 16-DPA. The isomers were separated by column chromatography and evaluated for cardioprotective and antioxidant activities. Myocardial necrosis induced by isoproterenol in rats caused marked increase in serum creatine phosphokinase and glutamate pyruvate transaminase. Simultaneously in ischemic heart, phospholipase, xanthine oxidase and lipid peroxides were enhanced following depletion of glycogen, phospholipids and cholesterol. Treatment with guggulsterone and its both isomers at the dose of 50 mg/kg po., significantly protected cardiac damage as assessed by the reversal of blood and heart biochemical parameters in ischemic rats. The cardioprotective activity of guggulsterone and of both the isomers were compared with that of gemfibrozil at the same doses. Guggulsterone and both the isomers at tested concentrations (5 20mM) inhibited oxidative degradation of lipids in human low-density lipoprotein and rat liver microsomes induced by metal ionsin vitro. The drug counteracted against the generation of superoxide anions (O(2)) and hydroxyl radicals (OH(-)) in non-enzymic test systems. It is suggested that cardioprotective and antioxidant activities of synthetic guggulsterone and guggulsterone obtained from gum resinCommiphora mukul that contains isomers E & Z in the ratio of 46?54w/w are the same. PMID- 23105396 TI - Maternal and fetal indicators of oxidative stress in various obstetric complications. AB - The present study demonstrates the incidence of increased lipid peroxidation and protein oxidation in both maternal and fetal erythrocytes as markers of oxygen radical activity in different complications of pregnancy. In fetuses born after premature rupture of membranes, lipid peroxidation was significantly elevated as indicated by increased malondialdehyde levels (p<0.05) as compared to controls. Proteolytic activity in the erythrocytes of mothers in this group was also significantly high (p<0.01). In patients delivered by lower segment cesarian section, lipid peroxidation and proteolytic activity in maternal erythrocytes were significantly high (p<0.05 and p<0.001 respectively). In patients with prolonged second stage of labour, lipid peroxidation and proteolytic activity in maternal erythrocytes was significantly higher than in controls (p<0.001 and p<0.05 respectively). In this group, endogenous protein damage due to oxidative stress was significantly high both in the mother and the fetus (p<0.001 and p<0.05 respectively). PMID- 23105397 TI - Two cases of hereditary fructose intolerance. AB - Hereditary fructose intolerance is a rare cause of hepatic cirrhosis in the young. The disorder has a reported frequency of 1 in 20000 live births and no case has been reported from India so far. We report two cases of hereditary fructose intolerance, both with bilateral cataracts and one with cirrhosis of the liver. PMID- 23105398 TI - Evaluation of clinical utility of serum enzymes and troponin-T in the early stages of acute myocardial infarction. AB - Laboratory infarction diagnostics are based on the detection of elevated serum activities of total Creatine Kinase (CK), Creatine Kinase isoensyme MB, (CKMB), Lactate dehydrogenase (LDH), isoenzyme forms of LDH and transaminases. Determination of these cardiac marker enzymes permits a highly sensitive diagnosis of transmural myocardial infarction. In such patients the diagnosis of acute myocardial infarction can be confirmed by the clinical, symptoms, and changes in the ECG in addition to the enzyme assays. The 50 AMI patients selected in the present study were those admitted to the ICCU of Shri Krishna Hospital, Karamsad. The blood samples were taken at the time of admission (ie. within four hours of the start of chest pain). The samples were analyzed for CK, CKMB, SGOT, (Serum glutamate oxaloactate transaminase) alphaHBDH alpha-hydroxybutyrate dehydrogenase and troponin T. The serum CKMB activity in AMI showed an increase only 5-6 hours after the commencement of chest pain. The elevation in SGOT and alphaHBDH was still delayed. At the same time we could observe that the cardiac Troponin T (cTnT) was elevated at the time of admission of the patient itself. This increase of cTnT in AMI patients was 20 times higher than the normal blood donors. The controls included 25 normal blood donors and 25 patients with polytraumatic injuries with no chest contusion. The study shows that cTnT estimation could serve in the early diagnosis of AMI. The increase of cardiac troponin T in AMI patients was 20 times higher than the normal blood donors in AMI patients at the time of admission. Cardiac troponin T in serum appears to be a more sensitive indicator of myocardial cell injury than CKMB activity and its detection in the circulation may be a useful prognostic indicator in patients with unstable angina as well. When the blood of normal blood donors or that of patients with polytraumatic injury was analysed the troponin T values were well within the normal range in both the above categories showing that cardiac troponin T is highly specific for heart tissue. Although CKMB and cardiac troponin T are released soon after the myocardial injury, the release of cardiac troponin T is much earlier than CKMB thereby invalidating the important role of cardiac troponin T in diagnosing AMI. Cardiac troponin T has been shown to be highly sensitive for cardiac injury and not elevated in any other trauma, heavy exercise or skeletal muscle injury. Cardiac troponin T is ordinarily undetectable in healthy individuals, and so its measurement can serve as a powerful tool in the diagnosis of AMI. PMID- 23105399 TI - Hyper prolinuria and hyper-hydroxy prolinuria in children with mental retardation. AB - Three thousand cases with mental retardation referred from different hospitals were screened for aminoacid disorders. Among them one case of hyperprolinuria and another case of hyperprolinuria with hyper hydroxyprolinuria were detected. These are the first cases to be reported from the state of Andhra Pradesh. PMID- 23105400 TI - Standardization of homocysteine on HPLC using DTT as reductant. AB - Determination of plasma total homocysteine by high-pressure liquid chromatography (HPLC) usually requires reduction of protein bound or free homocysteine disulphides into thiols by a reducing agent and the liberated thiols are then derivatized by a fluorescent marker. In this study we have standardized the HPLC method for homocysteine measurement using dithiothreitol (DTT) as reductant.The results of plasma total homocysteine values obtained by HPLC were compared with IMx method. The difference between the two means was statistically insignificant [P=0.616847 (two tail)] Linear regression analysis showed strong correlation between the two methods (r=0.983). Using this method we have analyzed 132 controls and 130 Coronary Heart Disease (CHD) patients for plasma total homocysteine, wherein, the mean plasma total homocysteine levels were 10.51+/ 8.36 and 11.51+/-10.06 MUmol/L respectively. Our research study suggests that DTT method is a simple and inexpensive assay for homocysteine determination in human plasma for research application. PMID- 23105402 TI - Attempting to maintain normoglycemia during cardiopulmonary bypass with insulin may initiate post-operative hypoglycemia. AB - Cardiopulmonary bypass is known to cause alterations in insulin secretion and resistance, resulting in profound hyperglycemia. Aggressive treatment of the resulting hyperglycemia intra-operatively could result in a severe degree of post operative hypoglycemia. We undertook this prospective non-randomized clinical study to compare the alterations in glucose homeostasis in diabetic (group A, n=50) and non-diabetic (Group B, n=50) patients undergoing moderate hypothermic (30 degrees C) cardiopulmonary bypass for coronary artery bypass grafting (CABG). All patients had a fasting blood sugar level done on the morning of surgery. Blood sugars were monitored intra-operatively and post-operatively at fixed time intervals. Intra-operative hyperglycemia was treated aggressively by a continuous, infusion of injecting plain insulin. Both the groups experienced similar significant increase in blood glucose levels during bypass ('p'=0.00003). However, the mean blood glucose level upon arrival in the intensive care unit was significantly decreased in group B compared to group A (p=0.0002). 60% of group B and 10% of group A patients required treatment for post-operative hypoglycemia (blood glucose level <60mg/dl). This clinical study reveals that attempting to maintain normoglycemia in this setting with Insulin may initiate post-operative hypoglycemia. PMID- 23105401 TI - Biochemical markers for alcohol consumption. AB - A variety of laboratory tests are available to assist in the diagnosis of alcohol consumption and related disorders. The levels of intake at which laboratory results become abnormal vary from person to person. Laboratory tests are particularly useful in settings where cooperativeness is suspected or when a history is not available. Several biochemical and hematological tests, such as gamma-glutamyltransferase (GGT) activity, aspartate aminotransferase (AST) activity, high-density lipoprotein cholesterol (HDL-C) content of serum, and erythrocyte mean corpuscular volume (MCV) are established markers of alcohol intake. Their validity as markers is based largely on correlations with recent intake at a single time point and on decreases in elevated values when heavy drinkers abstain from alcohol. These readily available laboratory tests provide important prognostic information and should be integral part of the assessment of persons with hazardous alcohol consumption. There are several other markers with considerable potential for more accurate reflection of recent alcohol intake. These include carbohydrate deficient transferrin, beta-hexosaminidase, acetaldehyde adducts and the urinary ratio of serotonin metabolites, 5 hydroxytryptophol and 5-hydroxyindoleacetic acid. These markers provide hope for more sensitive and specific aids to diagnosis and improved monitoring for intake. PMID- 23105403 TI - Lipid profile in middle class Bengali population of Kolkata. AB - Fasting samples of 1396 apparently healthy, middle class Bengali population of Kolkata, West Bengal were tested for total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol and very low density lipoprotein cholesterol, over a period of three years. The values obtained were (in mg/dl) 190+/-33, 132+/-42, 53+/-10, 116+/-30 and 21+/-7 respectively. When these subjects were grouped according to the age and sex, no appreciable difference were observed between most of the groups. Triglyceride was found to be low and HDL cholesterol was high in women below 30 years when compared with men of similar age. Beyond 60 years, cholesterol level as well as low density lipoprotein cholesterol was found to be gradually increased in case of women. Besides these changes, other minor differences were not statistically significant. It is suggested that the lipid values of the present study should be taken as a base parameters and the clinical evaluation be made on the basis of these finding. PMID- 23105404 TI - Evaluation of serum mucoproteins in patients suffering from liver cancers. AB - Mucoproteins are normal and essential constituents of different types of cells, tissues, and organs in our body. Interestingly, an increase in the serum mucoprotein has been described in several malignant disorders in various studies. To study this in the cases of hepatocellular carcinoma thirty five patients suffering from histologically or cytologically confirmed hepatocellular carcinoma were tested for serum mucoprotein in the Department of Biochemistry and the Department of Pathology of North Bengal Medical College for a period of one and a half years against matched healthy controls. The serum mucoprotein was found to be increased significantly in the cases suffering from hepatocellular carcinoma (p<0.001). So, the present study suggests a strong correlation between the mucoprotein level and carcinomatous changes in the hepatocellular tissues. PMID- 23105405 TI - Studies on biochemical changes with special reference to oxidant and antioxidants in malaria patients. AB - Oxidative stress plays an important role in the development of malarial anemia. The present study was undertaken to study the role of oxidant and antioxidants in the patients ofPlasmodium falciparum malaria (n=25),Plasmodium vivax malaria (n=25) as against the normal control subjects (n=25). The parameters included are the hematological [hemoglobin, erythrocyte adenosine deaminase (ADA) activity, ADP-induced platelet aggregation] and serum total lipid peroxide as an index of oxidative stress and antioxidants [erythrocytic superoxide dismutase (SOD) activity, serum vitamin E] & serum iron.Significant alterations in all above parameters were noted in both groups of malaria patients as compared to control subjects. Maximum significant alterations in hematological parameters were noticed inP. falciparum infection as compared toP. vivax malaria (p<0.001). Substantial rise in serum total lipid peroxides and a significant reduction in antioxidants such as serum vitamin E and serum iron were noted inP. falciparum malaria as compared toP. vivax malaria (p<0.001), whereas maximum decline in erythrocytic SOD activity was observed inP. vivax infection as compared toP. falciparum malaria (p<0.05). Follow-up examination revealed the restoration of the levels of all biochemical parameters to the normal level after 20 days of antimalarial therapy.The study specified severity ofP. falciparum malaria and also functional duality of oxidant. PMID- 23105406 TI - Reversible suppression of nitric oxide system in essential hypertension. AB - Despite enormous research in the field of hypertension, its pathophysiology still remains largely unresolved and appears to be multifactorial. In the present communication, we have analyzed the status of nitric oxide (NO) in the patients with essential hypertension and age matched controls. We have found that the levels of NO are lowered in essential hypertension. The normalization of blood pressure by administration of antihypertensive therapy causes rise in the NO level indicating that perturbed NO status in essential hypertension is reversible. Addition of antioxidant to the antihypertensive drugs causes a further, though non significant, rise in the levels of NO, suggesting that antioxidants may be combined with antihypertensive drugs as adjunct in the management of essential hypertension. PMID- 23105407 TI - Role of essential trace minerals on the absorption of heavy metals with special reference to lead. AB - Heavy metals are important toxicants known to exert adverse effects in humans and animals, given sufficient exposure and accumulation in the body. This has a great concern both at personal and public health risk. Heavy metals are also known to interact with the essential trace minerals at the level of absorption and also during the metabolism. The adverse effects of the absorbed and accumulated heavy metals include neurological, reproductive, renal and hematological systems. Children are more sensitive than adults to the effects of lead. Efforts are made to understand the mechanism of the interactions of heavy metals with essential trace minerals at the level of absorption. With available sensitive and specific methodologies like Anodic Stripping Voltammetry for the evaluation of the levels of toxic heavy metals such as lead, cadmium, mercury etc., better understanding of heavy metal absorption is made possible.Due to the poor nutritional standards, risk of heavy metal exposure is still a major concern in developing countries. Studies carried out by the author have provided evidence towards the understanding of the prevailing mechanisms of metal-metal interaction at the intestinal level. During growth and development the demand for the essential minerals being at higher level, differentiation of various essential metals and heavy metals pose an inherent problem due to certain common properties shared by them. With this approach to the problem of heavy metal toxicity, it is preventable not only with environmental intervention but also by the nutritional management. PMID- 23105408 TI - Secondary immunization inhibits drug induced apoptosisin vivo. AB - Immunization with a proper dose of an antigenic stimulus leads to cell proliferation and antibody response of circulating lymphocytes. We have previously observed that Secondary immunized spleenocytes resist ceramide mediated apoptosisin vitro. Our present study is aimed at investigating thein vivo effect of immunization on apoptosis. Mice were subjected to either Primary or Secondary dose with Tetanus Toxoid. Unimmunized spleenocytes served as controls. Unimmunized, Primary and Secondary immunized mice were later exposed to chemotherapeutic drugs such as Etoposide/Methotrexate/Vincristine to induce apoptosis. Apoptosis was studied by using the Feulgen reaction on 5MU thin parafin sections of spleen. It was observed that Secondary immunized mice showed a lower percentage of apoptosis as compared to Primary or Unimmunized mice that was subjected to either of the chemotherapeutic drugs. It was thus concluded that Secondary immunization inhibits the process of chemotherapeutic drug induced apoptosis in vivo. PMID- 23105410 TI - Toxicology and free radicals scavenging property of Tamra bhasma. AB - Free radicals are implicated in various chronic diseases. There has always been a search for new antioxidants. In this paper we have investigated Tamra bhasma, a metallic ayurvedic preparation. It is a time-tested medicine in Ayurveda and is in clinical use for various ailments specifically the free radical mediated diseases. Our results show that Tamra bhasma inhibits lipid peroxidation (LPO), prevents the rate of aerial oxidation of reduced glutathione (GSH) content and induces the activity of superoxide dismutase (SOD) in rat liver homogenate in the bi-phasic manner. The drug was orally given for 7, 15 and 30 days in different doses. Best protective response was found at the dose of 0.5mg/100g body weight in albino rats, although it showed some histopathological changes at the dose of 20mg/100g body weight. The results suggest that this Ayurvedic preparation is not merely a source of copper metal, but it is a strong anti-oxidant with no detectable adverse effect in lower doses of therapeutic range. PMID- 23105409 TI - Characterization of lectins and their specificity in carcinomas-An appraisal. AB - Lectins, a group of specific glycoproteins present in animal as well as plant cells, are used as differentiating markers to study cancers and metastatic cell lines. This property of lectins depends on the process of cellular glycosylation. Glycosylation of some of the extracellular membrane proteins and lipids maintains the cell/cell and cell/matrix interactions. Chemical alterations in glycosylation play an important role in the metastatic behavior of tumor cells. Carbohydrate residues of the membrane glycoproteins can be detected using lectins due to their binding specificity to carbohydrates. Lectins, therefore have gained an importance in the field of cancer research. Galectins, a specialized group of lectin like proteins that are Ca+ independent and galactoside binding, are also considered as differentiation markers in some specific cancers like the carcinomas of thyroid.Thus the use of lectins and galectins to identify specific carbohydrates present on cell surface help in invasion and metastasis processes. PMID- 23105411 TI - Effect of garlic (Allium sativum L.) extract on degree of hydration, fructose, sulphur and phosphorus contents of rat eyelens and intestinal absorption of nutrients. AB - Influence of aqueous garlic extract on degree of hydration, fructose, sulphur and phosphorus contents of rat eyelens and intestinal absorption of nutrients were assessed. Inclusion of garlic extract in culture medium containing glucose and xylose inhibited the hydration of rat eyelens, whereas galactose evinced the reverse trend. Aqueous garlic extract in general decreased the concentration of fructose and phosphorus, whereassulphur concentration increased when rat eyelenses, were incubated with galactose and xylose. Garlic extract inhibited intestinal absorption of glutamic acid, sucrose and glucose to different extents. The rate of absorption of glutamic acid was found to be considerably higher than that of glucose and sucrose. PMID- 23105412 TI - Oxidant and antioxidant status in vegetarians and fish eaters. AB - An adequate antioxidant reserve which is usually present in a vegetarian diet is associated with higher life expectancy. On the other hand habitual consumption of fish is associated with lower risk of cardiovascular diseases which is attributed to the polyunsaturated fatty acids (PUFA) present in it. However the PUFA are readily susceptible to oxidation leading to the formation of free radicals which is known to be involved in the causation of several diseases.The oxidant antioxidant status of 23 vegetarians and 22 fish eaters was studied by determining the plasma lipid peroxides measured as malondialdehyde (MDA) and the antioxidants, viz. glutathione (GSH), ascorbic acid, ceruloplasmin and uric acid.Results show that the ascorbic acid values were significantly higher in vegetarians. In addition, MDA correlated negatively with ascorbic acid only in vegetarians. However, correlation of MDA with glutathione showed a significant negative correlation only in fish eaters. There was no statistically significant difference in the MDA, GSH, ceruloplasmin and uric acid levels. The mechanism behind these findings are not clear and needs to be explored. PMID- 23105413 TI - Effect of thiazide drug compound on the testicular protein and cholesterol contents of albino rat. AB - In this study the effect of thiazide diuretic compound on the protein and cholesterol contents in the testes of albino rats as the experimental model. The drug thiazide was administered orally daily for 10,20 and 30 days at the dose of 100mg/kg body weight. Total protein decrease in the testes of rats were evidenced may be due to the side effects of thiazide drug compound which is linked with the hyponatremia and protein metabolism. An elevated level of cholesterol contents observed in thiazide treated rats also revealed that the side effect of drug compound thiazide and also may be due to the stimulation of catecholamine which is stimulated therefore, the biochemical estimation such as protein and cholesterol in the testes after the thiazide treatment determined the effectiveness of diuretic drug compound would provide clinical evidences of their side effects. PMID- 23105414 TI - Evaluation of urinary abnormalities in urolithiasis patients: A study from North India. AB - Metabolic abnormalities were investigated in 44 stone patients with first time (group 1) and 56 with 2 times stone formation (group 2), and in 25 normal individuals. 24hr urine was analysed spectrophotometrically for oxalate, calcium, magnesium, citrate, uric acid, phosphate and creatinine. Hypocitraturia and hyperoxaluria were the common abnormalities in the stone formers. Stone patients had significantly higher urinary oxalate, calcium and uric acid and lower phosphate than normal individuals. Citrate/calcium and magnesium/calcium ratio were significantly high in normal individuals than stone formers. Patients in group 2 excreted significantly higher urinary calcium and lower citrate that patients in group 1. Citrate/calcium ratio was higher in group 1 than group 2. Hypocitraturia, hyperoxaluria, hypercalciuria and increased citrate/calcium and magnesium/calcium ratio seem to be an essential risk factor for stone formation. Patients with recurrent stone formation could be distinguished from patients with first time stone formation on the basis of urinary calcium and citrate. PMID- 23105415 TI - Effect of type II collagen treatment on the antioxidant status in immune tissues of adjuvant induced arthritic rats. AB - Adjuvant induced arthritis (AIA) is a model widely used to study Rheumatoid arthritis (RA). In the present study, lipid peroxides level in spleen and thymus of AIA rats was observed to be significantly high compared to normal rats. A significant decrease in ascorbic acid (ASA), reduced glutathione (GSH), superoxide dismutase activity (SOD) was also observed in spleen and thymus of AIA rats compared to normal rats. There was also a steady increase in the circulating immune complex level (CIC) throughout the experimental period in serum of AIA rats. In the present investigation, it was decided to study the effect of pre and post treatment with TYPE II collagen on the antioxidant status and the circulating immune complex level in AIA rats. The results from the present work indicates that the pretreatment with TYPE II collagen was effective in bringing significant changes on all the parameters studied in AIA rats. The post treatment with TYPE II collagen was effective in bringing significant changes on the CIC immune complex level and GSH content in the thymus tissue of AIA rats. The present work suggests that the pre treatment with TYPE II collagen was more effective in suppressing the disease than the post treatment. PMID- 23105417 TI - Cancer in south Karnataka and its paradoxical relation to diabetes mellitus. AB - The present work identifies a high incidence of oral cancer in south Karnataka. The primary reason for this could be due to extensive addiction to tobacco alone or tobacco and alcohol in most of these patients. The next in intensity was cancer of the breast and cervix among the cancer patients surveyed in south Karnataka. Majority of these patients had no specific addiction and the exact reason for this high incidence remains unclear. Only a small percentage of patients exhibited other types of organ related cancer. It has been reported that the incidence percentage of diabetes mellitus and cancer in India, parallel each other. However, we observed a low incidence of diabetes mellitus patients also having cancer in south Karnataka. Though the exact reason for this remains unclear an attempt has been made here to explain this phenomenon, hypothetically using information in literature, which suggests a suppression of cellular regenerative activity by sugar and sugar phosphates. Cellular regenerative activity is well known to be a prerequisite for cancer. PMID- 23105416 TI - Dietary restriction (DR) and its advantages. AB - Dietary restriction (DR) also called dietary control or calorie restriction is reported to have many advantages with regard to human health. It leads to suppression of obesity, mitigates free radicals and increases available antioxidants which are accounted for extending the life span of individuals. DR is also reported to induce synthesis of heat shock proteins in animals as a control mechanism against stress. Further, it is known to play a significant role in decreasing toxicity and lethality due to a variety of toxic chemicals and drugs by stimulating tissue repair damaged by the toxicants leading to restoration of intact organ and its functions. Moreover, extensive work done on animals indicate DR has an important role in suppressing certain types of cancer. In this review an effort is made to highlight the various advantages of DR from the point of human health perspective. PMID- 23105418 TI - Comparative account of serum lipids, lipoproteins and apolipoprotein-B in patients of coronary artery disease. AB - Serum total lipids (cholesterol and triglyceride), lipoproteins (VLDL, LDL and HDL) and Apolipoprotein-B levels of normal healthy individuals (n=25) and coronary artery disease patients (n=25) were estimated. The objective of the present study was to ascertain the role of apo-B in causation and inheritance of coronary artery disease. It was observed that on an average serum total cholesterol and triglyceride more than 200 mg/dl bring the individuals to a risk of coronary artery disease (CAD) irrespective of the age. CAD patients achieved this value at an early age (35-45 years). Similarly VLDL and LDL levels were found to be significantly raised in CAD patients when compared to that of age matched normal individuals, with patients achieving risk values at an early age. HDL levels were found to be significantly lower in CAD patients as compared to normal individuals. Serum apo-B levels were significantly raised in CAD patients as compared to age matched normal individuals. Patients with positive family history of CAD had raised serum apo-B levels than those having negative family history. A positive coefficient of correlation was observed between serum apo-B and LDL levels suggesting that more the number of Apo-B particles, more will be the synthesis of atherogenic particle (LDL). Patients with negative family history had serum apo-B levels closer to those of normal individuals and in these individuals HDL levels were found to be significantly lowered, suggesting that loss of scavenger role of HDL could be the risk factor responsible for the causation of CAD in these patients, with negative family history of coronary artery disease. PMID- 23105419 TI - Circadian periodicity of plasma lipid peroxides and anti-oxidant enzymes in pulmonary tuberculosis. AB - The circadian periodicity of plasma lipid peroxide levels and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were studied in 50 clinically, bacteriologically and radiologically proven fresh cases of pulmonary tuberculosis (age: 21-45 years) and 60 age-matched healthy volunteers with diurnal activity from 06?00 to about 22?00 and nocturnal rest. A marked circadian variation in plasma lipid peroxide level was recorded in healthy subjects and pulmonary tuberculosis patients with significant amplitude and acrophase around 16?21 and 17?12 respectively. The acrophase tended to be delayed in tuberculosis patients. Furthermore, a statistically significant circadian rhythm was found in SOD, CAT and GPx activities in normal volunteers and pulmonary tuberculopsis patients. SOD and CAT enzyme activity was noted to be maximum at 06?00 and minimum at 00?00 in tuberculosis patients. The circadian acrophase for GPx activity was recorded at 16?15 in normals and around 22?45 in patients. Moreover, the activity was found to be decreased at all sampling hours during 24-hours sleep-awake period in patients in comparison to healthy counterparts. The MESOR and circadian amplitude also decreased markedly. The decreased activity of measured antioxidant enzymes in pulmonary tuberculosis patients could probably be associated with oxidative stress and/or decreased anti oxidant defensive mechanism in such patients. PMID- 23105420 TI - Serum calcium levels in patients with essential hypertension and their first degree relatives. AB - Calcium plays an important role in the pathophysiology of essential hypertension. Serum calcium levels were measured in 117 subjects with essential hypertension and 77 first-degree relatives. The results showed that serum calcium levels were significantly (p<0.01) decreased in both males and females with essential hypertension and their first-degree relatives when compared with the normotensive controls. This is the first study in Indian population. PMID- 23105421 TI - Report of a trial with lyophilised QC sera in the CMCH/ACBI EQAS programmes in India. AB - 2000 vials of lyophilized QC of two different levels (low and high) were donated by Roche Diagnostics GmbH, through the IFCC and received by CMCH in June 2001. A total of 240 la boratories were enrolled for this 6 month pilot study. In addition to the 12 analytes in the liquid QC programme, six additional analytes, LDH, triglyceride, urate, total bilirubin, phosphate and amylase were included. It was also possible to measure sodium and potassium by ion selective electrode (ISE) methods in the QC for the first time.The performance of the laboratories for the existing 12 analytes using liquid stabilized QC was compared to the performance using lyophilized QC. Using a statistical comparison of the methodwise mean variance index score (MVIS) values, five assays viz glucose, albumin, cholesterol, and SGOT and SGPT performance was the same in liquid QC and lyophilized QC. Three assays viz urea, calcium and creatinine were significantly better, and 4 assays total protein, sodium, potassium and ALP were significantly worse. However the overall VIS (OMVIS) for the laboratories was the same and the ranking pattern of this 6 month OMVIS was also unaltered.The lyophilized QC scheme highlighted a negative bias between flame and ISE methods for sodium and potassium, and a definite standardization problem in reporting LDH and amylase results, but triglyceride, urate and total bilirubin assays were performing well.It was concluded that the introduction of lyophilized QCs will not cause any deterioration of performance to participating laboratories. Stability of the material seems to be good and the laboratories are generally using a good reconstitution technique. PMID- 23105422 TI - Modified assay procedure for the estimation of serum glucose using microwell reader. AB - Determination of blood glucose levels is very important to know the physiological condition of the human beings as the hormonal imbalance may cause abnormalities in glucose metabolism. The traditional methods of glucose estimation by colorimetric and titrimetric methods were involved with huge expenditure and time. The modified colorimetric microwell reader method proposed in the present study was performed with small quantities of sample and reagents with the same linearity that was observed in the normal colorimetric analysis. The modified method not only reduces the cost of the test to almost one third of the normal colorimetric method but also provide an opportunity to screen the large number of samples in a short duration of time. PMID- 23105423 TI - Correlation of serum retinol and its relation with lipid prolile in Indian cancer patients. AB - The present study was undertaken to investigate the relation of retinol with lipid profile of patients with cancers of breast, stomach, oesophagus, colon, gallbladder, pancreas, lung and cervix. Serum retinol was assayed in 120 patients and 40 healthy normal control by reverse phase HPLC using CLC-ODS C-18 columns and retinyl acetate as an internal standard.Significant decease in serum cholesterol and LDL was observed in patients with cancers of esophagus, colon, stomach, pancreas and gallbladder respectively.Retinol was reduced in all forms of cancers but pronounced decrease was observed in oesophagus, gallbladder, pancreas, stomach and colon. Serum Retinol in all patients was directly correlated with total cholesterol and LDL. These findings suggest that therapeutic modalities of this vitamin could be planned for these patients, as vitamin A is known to act as an antioxidant for prevention of certain cancers. PMID- 23105424 TI - pre-operative serum potassium levels and peri-operative outcomes in patients undergoing cardiac surgery. AB - Although potassium is critical for normal electro physiology, the associations between pre-operative serum potassium level and peri-operative adverse events such as arrhythmias in cardiac surgery have not been examined in detail.The objective of this study was to determine the prevalence of abnormal pre-operative serum potassium levels and whether such levels were associated with adverse peri operative events in 50 patients undergoing coronary artery bypass grafting. Intra operative and post-operative arrhythmias, the need for cardio-pulmonary resuscitation, cardiac death and death due to any cause prior to discharge from the post-operative intensive care unit were studied. The incidence for adverse outcome was 0.5% for death, 0.5% for cardiac death and 2% for cardio pulmonary resuscitation in patients with hypokalemia (serum potassium level <3.5 meq. L( 1)). Hypokalemia was found to be a predictor of serious peri-operative (OR:2.2; 95% Cl: 1.2-4.1) and post-operative arrhythmias (OR: 1.7;95%Cl: 1.0-2.7).Pre operative potassium repletion is low cost and low risk treatment measure and the data from this study suggests that screening and repletion be considered in patients scheduled for cardiac surgery. PMID- 23105425 TI - Evaluation of FSH, LH and testosterone levels in different subgroups of infertile males. AB - Gonadotropins (FSH, LH) and testosterone are the prime regulators of germ cell development. Abnormal spermatogenesis is often associated with altered serum gonadotropins and testosterone. FSH, LH and testosterone levels were estimated in 96 infertile men of whom 35 were azoospermic, 35 were oligozoospermic, 11 were with varicocele and 15 were with histopathological abnormalities like hypospermatogenesis, spermatid arrest and sertoli-cell only syndrome. Results showed statistically significant (p<0.05), increase in the mean FSH and LH levels in all the infertile males studied when compared with the fertile controls (n=35). However, there is no significant difference in the mean levels of testosterone between the infertile and fertile men. PMID- 23105426 TI - Nutriceuticals in health and disease prevention. AB - Available evidence suggests that we can not dismiss the potential value of nutriceuticals in disease and inhibition of atherosclerosis. Epidemiologic data suggest that antioxidant supplementation may be associated with a reduced risk of clinical events from atherosclerosis; howere, interventional trials only support a role for vitamin E in this regard. Many studies suggest that a link between fruit and vegetables in diet or the amounts of plasma antioxidant vitamins (ascorbic acid, tocopherols and carotenoids) and risk of death from cancer or coronary heart disease. The usefulness of antioxidant for prevention of cardiovascular disease is yet to be proven. However, studies offer important insights that together with the development of methods to identify individuals most likely to benefit, provide hope to clinicians seeking to use antioxidant vitamins with safety and efficacy for the treatment and prevention of cardiovascular disease. Only continued investigation into the mechanism (s) of action of candidate agents will determine whether they hold promise as a therapeutic intervention and only then, they can be recommended routinely to the patients. Thus, nutriceuticals are becoming more widely accepted as an adjunct to conventional therapies. PMID- 23105427 TI - Ascorbic acid status in third trimester of pregnancy, at delivery and in cord blood. AB - Ascorbic acid levels in 30 subjects in their third trimester of pregnancy were estimated. Their haematological parameters (packed cell volume, haemoglobin and mean cell haemoglobin concentration) were also determined. The values were compared with that of 30 non-pregnant women (control group). The ascorbic acid status of newly born babies using cord blood were determined along with that of their mothers at delivery. The ascorbic acid level of 0.92+/-0.37 mg/dl was reported in third trimester. This value was not significantly (P>0.05) lower than in the control group (1.04+/-0.4 mg/dl). The result showed that the ascorbic acid level at delivery was significantly (P<0.05) higher than that of the control group. The ascorbic acid levels in the cord blood of the newly born babies were significantly (P<0.01) higher than the maternal level. There was insignificant difference in the haematological parameters between the pregnant and non-pregnant women. PMID- 23105428 TI - Antioxidant effect of methanolic extract ofSolanum nigrum berries on aspirin induced gastric mucosal injury. AB - The antiulcerogenic effects of the methanolic extract ofSolanum nigrum berries (SBE) on aspirin induced ulceration in rats with respect to antioxidant status in the gastric mucosa have been investigated. Oxygen free radicals are considered to be important factors in the pathogenesis of gastric ulcer. The level of lipid peroxides, which were elevated highly in rats with acute gastric mucosal injury was taken as an index of oxidative stress. The activities of antioxidant defense enzymes were also decreased considerably by oral gastric administration of aspirin. The decreased levels of antioxidant enzymes and increased mucosal injury were altered to near normal status upon pretreatment with (SBE) when compared to the ulcer induced rats. The results indicate that (SBE) may exert its gastroprotective effect by a free radical scavenging action. Our observations suggest that (SBE) may have considerable therapeutic potential in the treatment of gastric diseases. PMID- 23105429 TI - Early detection of prostate cancer: evaluating the diagnostic performance of prostate specific antigen by comparing with histological technique among africans. AB - This study was conducted to investigate the diagnostic performance characteristics of prostate specific antigen (PSA) by comparing serum PSA value with histological findings in patients suspevted of having prostate cancer in Aminu Kano Teaching Hospital. Nigeria. Clinical and Laboratory records were examined and collated for serum PSA values, together with histological findings of biopsy specimen, clinical diagnosis, age of patients, and mode of presentation. The serum PSA values were determined by ELECSYS 1010 autoanalysers Roche, Germany based on electrochemiluminescence immunoassay technique. The results show that serum PSA values increase with age in the assymptomatic non cancer patients who came for medical check up but were within normal limit. In prostatic disease conditions PSA values were raised in benign prostatic hyperplasia 35.957+/- 4.0315ng/ml, in undifferentiated carcinoma 56.22+/ 4.295ng/ml and adenocarcinoma >100ng/ml as compared to the normal range (0 4ng/ml). These cases were confirmed by histological diagnosis. It is concluded that PSA evaluations is a sensitive marker for prostate cancer but because of various other conditions that affect serum PSA concentration, other methods of investigations such as Digital Rectal examination, Trans Urethral Ultra Sonography and histological examination should be combined to confirm diagnosis. Prognosis of patients will be better if early diagnosis is made. PMID- 23105430 TI - Serum lipid profile in patients with acute myocardial infarction. AB - Serum lipids and lipoproteins were estimated in 29 patients with acute myocardial infarction during acute phase (day 1,2,3), predischarge and after three months. Serum total lipids, total cholesterol (TC) and LDL-cholesterol (LDLc) showed no significant change during the hospital stay and three months followup. HDL cholesterol (HDLc), however, started falling from day 2 onwards with statistically significant reduction at pre-discharge and remained so at 3 months. The ratios of TC/HDLc and LDLc/HDLc showed significant increase on predischarge day as compared to day 1. Serum triglycerides also showed an increasing trend after myocardial infarction with a significant increase on day 3 and predischarge as compared to day 1. it is concluded that the optimum time for assessment of serum lipid profile in patients with myocardial infarction seems to be within 24 hours of the acute episode. PMID- 23105431 TI - Studies of biochemical parameters in breast cancer with and without metastasis. AB - The study includes 102 confirmed cases of carcinoma breast with and without metastasis and 25 healthy non-pregnant females. They were evaluated for blood levels of Ferritin, GSH, LDH, ALP, GGT and Hb before and 21 days after mastectomy. A significant increase (p<0.001) was observed in ferritin, LDH and GSH levels in cancer patients without metastasis in comparison to normal control subjects. Patients with metastasis had further elevated (p<0.001) levels of Ferritin, ALP and GGT as compared to non-metastatic patients. Mastectomy in both the cases i.e. with and without metastasis resulted in non-significant decrease in all the biochemical parameters suggesting that longer follow up could confirm post surgery decrease in the biochemical parameters. The results of the study suggest cost effective, usefulness of Ferritin, ALP, GGT and GSH/Hb ratio in differentiating breast cancer patients with and without metastasis which can be assayed in smaller laboratories. PMID- 23105432 TI - Studies on homocysteine demonstrating its significance as a possible tool for differential diagnosis in occlusive vascular disease. AB - Homocysteine (Hcy) is a non-protein forming amino-acid, whose metabolism is at the intersection of two metabolic pathways: remethylation and transsulfuration which are dependent on the vitamins folic acid, B(12) and B(6), and the enzymes methylenetetrahydrofolate reductase and cystathionine-beta-synthetase. A deficiency of any of these vitamins or enzymes results in hyperhomocysteinemia. This causes oxidative and other damage to blood vessels, thus affecting various organ systems of the body. As part of our ongoing research on cardiovascular risk factors, we have studied the Hcy levels in the plasma of normal controls and those suffering from vascular diseases. It was observed that Hcy is significantly higher in patients of vascular diseases (21.59+/-1.28 MUmol/L, mean+/-SEM), as compared to normal controls (11.33+/-0.18 MUmol/L). This significance, was more pronounced in cases of venous thrombosis (26.77+/-2.43 MUmol/L) as opposed to cases of arterial block (17.27+/-0.84 MUmol/L). This signifies that Hcy estimation would be beneficial in obtaining a differential diagnosis in addition to being a modifiable vascular risk factor. PMID- 23105433 TI - Serum dehydroepiandrosterone and lipid peroxides in human volunteers of different age groups. AB - The objective of the present study was to evaluate the changes in serum dehydroepiandrosterone (DHEA) and lipid peroxide levels during ageing in human subjects. Random blood samples were collected from a total of 128 apparently normal human volunteers of both sexes, whose age ranged between 21-70 years. The subjects were divided into groups of a decade years of age difference. Serum levels of dehydroepiandrosterone (DHEA), lipid peroxides as malondialdehyde (MDA), and insulin were analysed in all the subjects recruited in the study. In the present study there was decrease in serum DHEA levels with age (11.30 to 7.99 ng/ml). However the differences were significant only after 50 years up to 70 years. Serum MDA levels of these subjects were higher (3.91 to 4.74 ng/ml) as compared to the values reported earlier (2.64 to 3.94 ng/ml). The serum MDA levels also showed an increasing trend with age but the increase was significant only in the 40-50 years age group and values plateaud off at later ages. The MDA and DHEA levels in women in general were lower than in men and this could be due to female hormones, which are known to protect lipid against peroxidation. There was a significant negative correlation between age and DHEA (r=-0.311 P<0.05) and positive correction between MDA and age (r=+0.405 P<0.01). No significant differences were seen in serum insulin, albumin and total protein levels. These preliminary findings support the possible utility of DHEA and MDA as markers for chronological ageing. PMID- 23105434 TI - Assessment of oxidative stress and antioxidant status in age related cataract in a rural population. AB - Oxidative stress was assesed by estimating lipid peroxidation product (LPO) in the form of thiobarbituric acid reactive substances (TBARS), enzymatic antioxidants in the form of superoxide dismutase (SOD), catalase and nonenzymatic antioxidant vitamins e.g. vitamin C, beta carotene and vitamin E in either serum or plasma or erythrocytes in 190 cases of age related cataract in the age group of 50-80 years. 190 cases were grouped into three morphological types namely, 73 cases of cortical, 77 cases of posterior subcapsular and 40 cases of nuclear cataract and values of LPO and antioxidants were compared with 78 cases of age matched healthy control groups. Plasma TBARS levels were cataract cases when compared with control groups. There were no significant differences in the erythrocyte levels of catalase and plasma levels of Vit E between cataract cases and control groups. No significant changes of parameters were seen among three different morphological types of age related cataract. The present study shows that the oxidative stress may play an important role in the age related cataract. PMID- 23105435 TI - Determination of immunoreactivity ofPlasmodium falciparum antigens, serum dilutions and biomaterials. AB - Immunoreactivity properties of serum dilutions andPlasmodium falciparum malaria antigens were measured and compared by ELISA technique using different ELISA plates to evaluate the role of antigens and serum dilutions for optimum binding. Also effort has been made to see the effect of reaction surface and material i.e. ELISA plates for binding capacity. Serological properties were estimated by ELISA methods for detection of malaria and determination of immunological characteristics. Three Pf antigens (PfAg) i.e. ring infected erythrocyte surface antigen: AR-1 (RESA), histidine-rich protein 2 antigen (HRP-2) and glycophospholipid antigen (grown and developed Pf antigen from PSJ-M strain): GPL1 have been used for serological testing of human blood samples by Enzyme Link Immunosorbant Assay (ELISA). 1?100, 1?1000 and 1?10000 dilutions of Pf positive and negative serum (50 samples in each group) and 1?1000 dilution of Pf antigens were used to measure immunoreactive properties by ELISA method. Result of PfAg serum immunoreactivity study showed that GPL1 has the highest degree of immuno binding reactivity compared to other Pf antigens. HRP-2 and RESA antigens showed no significant difference to each other. Study also found that Costar and Fastec ELISA plates have a better Ag-Ab binding capability compared to immulon and Falcon plates at all dilutions of serum. Serum dilution of 1?100 showed best binding and reactivity with Pf antigens followed by 1?1000 and 1?10000 showed lowest reactivity. PMID- 23105436 TI - Evaluating role of oxidative stress in determining the pathogenesis of falciparum malaria induced acute renal failure. AB - Serum malondialdehyde was measured in sixty-one falciparum malaria cases, which include thirty uncomplicated, and thirty-one complicated with acute renal failure. Twenty-six healthy individuals were also studied as controls. Serum malondialdehyde level was found to be significantly elevated in falciparum malaria induced acute renal failure cases when compared with uncomplicated falciparum malaria (p<0.001) and healthy controls (p<0.001). A positive correlation with the raised urea, creatinine and bilirubin levels were significant (r=0.62, p<0.025; r=0.65, p<0.05 and r=0.72, p<0.001 respectively) indicating the severity of complication with rise of lipid peroxides in falciparum malaria induced acute renal failure cases. PMID- 23105437 TI - Salivary glycoproteins as indicators of oral diseases. AB - The present study deals with the estimation of total carbohydrate, protein bound carbohydrate, bound fucose and sialic acid along with total protein in disease conditions like gingivitis, periodontitis and their comparison with the normals.The neutral hexose values in gingivitis (8.08+/-2.20mg/100mg protein) and periodontitis (12.5+/-2.16mg/ 100mg protein) decreased significantly when expressed per 100 mg protein compared to normals (19.8+/-1.89mg/100mg protein). This might be because of higher protein concentration in these two clinical conditions. The ethanol insoluble hexose values were significantly reduced in both these conditions compared to controls (3.71+/-1.64,5.91+/-1.63,7.65+/ 0.86mg/100mg protein respectively). The ethanol soluble hexose values were also found to be drastically reduced. This decrease in saliva appears to be characteristic feature of oral diseases. In gingivitis and periodontitis fucose level was found to be increased compared to normals when expressed as a function of salivary volume. However in terms of protein concentration the values in gingivitis (2.95+/-1.59), periodontitis (3.26+/-0.98) and normals (3.20+/ 0.50mg/100mg) were not different. Sialic acid in ethanol insoluble fraction of salivary samples mg/100mg protein was found to be significantly reduced in both gingivitis (0.78+/-0.33) and periodontitis (0.95+/-0.31) compared to controls (1.92+/-0.33). PMID- 23105438 TI - Changes in serum ceruloplasmin levels with commonly used methods of contraception. AB - It is a well established fact that long term use of oral contraceptives is hazardous to health. The most common methods of contraception used by women in reproductive age group include use of oral contraceptives and copper "T". One of the causative factors for the side effects of the "pill" is presumed to be increase in serum cereloplasmin levels which has pro-oxidant activity. The present study involves the study of serum ceruloplasmin levels in two groups of subjects i.e. 30 women using oral contraceptive and 30 women using copper "T". 30 healthy females in reproductive age group were chosen as controls. It was observed that oral contraceptives increase the serum ceruloplasmin levels (p < 0.001) and the difference is highly significant as compared to no change (p < 0.1) in the groups using copper "T" as contraceptives. PMID- 23105439 TI - Enteromorpha compressa (L.) Greville an edible green alga as a source of antiallergic principle (S). AB - Enteromorpha compressa a marine green algal species grows extensively in North coastal Andhra Pradesh. Besides its nutritional importance it has also been identified as source of anti-anaphylactic compound(s).E. compressa extracts alleviated the IgE levels raised against ovalbumin and other allergens in mice. Further,Enteromorpha extract also significantly down regulated the serum IgE levels in different murine models irrespective of their genetic background. The results obtained in this study suggest thatE. compressa extract has compound(s), which inhibit IgE immune response and may have potential in curing various types of allergies. PMID- 23105440 TI - A comparative study of lens protein glycation in various forms of cataract. AB - The aim of this study was to estimate and compare the levels of glycated protein in the lens extracted from patients with cataract of various etiologies. A total of 72 cataract lens were collected. The levels of total proteins, glucose and glycated protein in the lens were studied. Plasma protein and fasting glucose levels were also estimated. The amount of glycation of lens was significantly higher in case of hypermature senile cataract (p<0.01) when compared with other types of cataracts. The levels of lens glucose between the various types of cataracts did not differ significantly. These results indicate that the level of lens glucose alone is not the only determining factor of lens protein glycation. PMID- 23105441 TI - The significance of troponin T and CK-MB release in coronary artery bypass surgery. AB - Measurement of cardiac markers is an index of care standard in the assessment and diagnosis of cardiovascualr disease. Two of the major cardiac markers are Creatine Kinase isoenzyme CK-MB and Troponin T, which are extensively used in the diagnosis of heart disease. The release of Troponin T and creatine kinase isoenzyme (CK-MB) was investigated in 50 coronary artery bypass surgery patients. Measurement of plasma samples was carried out at five different time points, namely before surgery, 1,6,12,24 hours after surgery. The results indicated that CK-MB level were increased by a factor more than four times compared with the upper limit of baseline (befor surgery). Troponin T concentration showed more than six fold over the upper limit of baseline (before surgert) at 1,6,12,24 hours after surgery. In order to assess the significance of the length of the surgical procedure on the release of Troponin T and CK-MB, the surgery patient were divided into two groups according to the length of the surgical procedure: group I was selected on the basis that the surgical procedure they underwent lasted above 90 minutes and group II with a surgical procedure below 90 minutes. Both Troponin T and CK-MB showed a significant increase in-group I compared to group II. To investigate the likelihood that this effect is party due to myocardial infarction during surgery, the patients were divided into two groups: Group A with some sings of myocardial infarction on Q wave of ECG and group B without any change. The results showed approximately a two-fold increase of these markers in-group A compared to group B. Since these markers reach into blood following damage to myocardial their increase in patients with time course surgery of more than 90 minutes and those with a probability of MI during operation, indicating that these patient fall into a high risk group of repeat (MI) after surgery. PMID- 23105442 TI - UV-B Induced stimulation of phosphatidylinositol 3-kinase in human fetal hepatocytes. AB - We investigated the effect of UV-B irradiation on PI 3-kinase activity in human fetal hepatocytes. When cells were exposed to monochromatic (304nm) UV-B light, a significant increase in intracellular PI 3-kinase activity was observed in a dose dependent manner with maximal activity upon 1500 Jm(-2) irradiation. At 1500 Jm( 2) dose PI 3-kinse activity increased by 80% in membrane fraction of fetal hepatocytes of 25 weeks gestation. PI 3-kinse inhibitors wortmannin and LY294002 specifically inhibited the UV-B induced lipid kinase activity and blocked significantly the UV-B induced cell viability. The data suggests a correlation between cell survival and elevated levels of PI 3-kinase and suggest that UV-B irradiation at a dose of 1500 Jm(-2) is ideal for fetal hepatocyte transplantation. Also, PI 3-kinase levels could be a representative marker for viable UV-B irradiated fetal hepatocytes for transplantation. PMID- 23105444 TI - Study of adenosine deaminase activity in pulmonary tuberculosis and other common respiratory diseases. AB - Tuberculosis has, in a short span of time, become a major health problem in the third world or developing countries like India. In view of this, a retrospective study was conducted to study Adenosine deaminase activity in serum and pleural fluid in patients affected with Pulmonary Tuberculosis and other common non tubercular chronic respiratory diseases. The study was carried out on 100 patients suffering from various pulmonary disorders, between January 2002 and August 2002. Thirty-five normal healthy individuals were included as control subjects. ADA estimation was done by sensitive colorimetric method. The study revealed that the serum ADA activity was higher in patients of tuberculous pulmonary and pleural diseases and non-tuberculous pulmonary diseases than in control subjects. The mean serum ADA activity in the patients' group was 35.5+/ 6.93 u/l as compared to 16.20+/-2.85 u/l in control group, showing a highly significant (P?0.001) difference. ADA activity was highest in tuberculous pleuropulmonary diseases. The pleural fluid ADA activity was higher in pyogenic pleural effusion than in tuberculous pleural effusion. PMID- 23105443 TI - Recent insights on biochemical and molecular basis for developing antihaemostatic agents: A review. AB - The normal coagulation process is initiated by disruption and exposure of the subendothelial components of blood vessels. Platelets adhere to subendothelium bound von Willebrand factor via glycoprotein (GP) Ib complex. This initial interaction per se and the release of platelet agonists transduce signals that leads to the rise in intracellular Ca2+ which induces shape change, prostaglandin synthesis, release of granular contents and conformational changes in platelet Gp IIb-IIIa. Gp IIb-IIIa in activated platelets binds fibrinogen and other adhesive proteins and mediates platelet cohesion the primary haemostatic plug. Furthermore, the activated platelets due to aggregation, result in the formation of fibrin (secondary hemostasis). Normally the haemostatic process plays a delicate balance between keeping the blood in the fluid state to maintain flow and rapidly forming an occluding plug following vessel injury. Thrombosis occurs because of alteration in this delicate balance. Arterial thrombosis occurs in the setting of previous vessel wall injury mostly because of atherosclerosis, while venous thrombosis occurs in areas of stasis. The recent advances in understanding of the haemostatic process have led to a better understanding of the mechanism of action of many antithrombotic drugs and identification of new targets for drug development. The molecular target of the ticlopidine has been identified. Large numbers of IIb-IIIa inhibitors have been developed. The mechanism of action of heparin has been defined at the molecular level. As a result, a synthetic pentasaccharide, based on antithrombin-binding domain of heparin, has been developed and tested successfully in clinical trials. New generation direct thrombin inhibitors are being developed. Factor Xa has a critical position at the convergence of intrinsic and extrinsic pathway. The clinical tolerability and the efficacy of low molecular weight heparins has established that inhibition of further thrombin generation, by blocking factor Xa alone can be an effective way of preventing thrombus growth without inactivating thrombin. A large number of specific factor Xa inhibitors are under development. Some of these are in preliminary clinical trials and appear to be promising. Future clinical trials will determine whether these new drugs will provide better risk-benefit ratio in treatment of thrombotic disorders. Similarly role of thrombolytics has been clearly established in many diseases including coronary artery disease. PMID- 23105445 TI - Racial and ethnic variation of PSA in global population: Age specific reference intervals for serum prostate specific antigen in healthy South Indian males. AB - The serum PSA is universally accepted as the useful and clinically relevant tumor marker for monitoring therapy and identifying early recurrence in patients of carcinoma prostate throughout the world. However, application of serum PSA is limited to screening for early adenocarcinoma prostate among males above fifty years of age.Serum PSA concentration varies from one population to another in different parts of the world. Many groups of workers have selected 4 ng/ml of serum PSA as upper limit of normal range without giving due consideration for age specific increase in serum PSA. There is no single report available on normal decade wise age specific reference intervals for serum PSA in Indian males.The present study is undertaken to establish age specific reference intervals in healthy Indian males from 20-89 years belonging to subpopulation of Andhra Pradesh from South India. Our results revealed lowest concentration of 95 percentile serum PSA in Indian males compared to other populations globally. Contrary to this, healthy Afro Americans were found to have highest concentration of serum PSA compared to all other populations. PMID- 23105446 TI - Role of oxidative stress and antioxidants in aetiopathogenesis and management of oral submucous fibrosis. AB - Lipid peroxidation product, malonaldehyde (MDA) and antioxidants were estimated in plasma and erythrocytes of 34 cases of oral submucous fibrosis (OSMF) of different grades with equal number of healthy controls to evaluate the association of reactive oxygen species (ROS) and OSMF. While plasma MDA was found to be significantly higher in patients (3.3+/-0.4 nmole/ml, P<0.001) as compared to controls (2.4+/-0.5 nmole/ml), plasma beta carotene and vitamin E levels were found to be decreased significantly in patients (81.7+/-14.3 MUg/100 ml, P<0.001; 9.3+/-0.9 mg/L, P<0.01 respectively) with respect to healthy controls (110+/-20.8 MUg/100 ml and 10.1+/-1.2 mg/L). The decrease in beta-carotene and vitamin E was found to be more significant in OSMF grade II and III than in grade I. After 6 weeks of oral administration of beta-carotene and vitamin E, patients showed increase in plasma level of these two antioxidants along with decrease in MDA level associated with clinical improvement. PMID- 23105447 TI - Effect of immobilisation stress on lipid peroxidation and lipid profile in rabbits. AB - Stress is one of the basic factors in the aetiology of a number of diseases such as atherosclerosis, coronary heart disease, aging, liver disease etc. Hence this work was designed to study the effect of stress in the form of forced immobilisation stress on lipid peroxidation and lipid profile in rabbits. The study was conducted in 25 healthy rabbits of either sex. Rabbits were subjected to forced immobilisation for two hours everyday for consecutive seven days. Blood samples were collected on day 1, 3 and 7 after immobilisation period. Malondialdehyde (MDA), a marker of lipid peroxidation was estimated by TBA assay method. Lipid profile was analysed by multichannel autoanalyser. There was statistically significant increase in MDA, total cholesterol, LDL, VLDL and triglycerides with immobilisation. These findings indicate that stress in the form of forced immobilisation increases lipid peroxidation and alter lipid profile, which may be responsible for pathophysiology of various diseases. PMID- 23105448 TI - Adenosine deaminase levels in cerebrospinal fluid as a diagnostic test for tuberculous meningitis in children. AB - Adenosine deaminase activity (ADA) was estimated in cerebrospinal fluid (CSF) of 30 patients of tuberculous meningitis (TBM) and 10 patients each of partially treated pyomeningitis (PTM), aseptic meningitis (AM) and pyogenic meningitis (PM). Mean ADA levels in CSF of TBM patients were higher (18.22 U/L) as compared to 6.28 U/L, 3.43 U/L and 7.98 U/L in PTM, AM and PM respectively. This difference of ADA values in CSF between TBM and other types of meningitis was statistically significant (p<0.01) different. Sensitivity and specificity of ADA levels in CSF of children to diagnose tuberculous meningitis was 66.6% and 90% respectively at 10 U/L cut off of ADA levels in CSF. ADA levels in CSF could also differentiate PTM, AM and PM from TBM with a specificity of 90%, 100% and 80% respectively. PMID- 23105449 TI - Stability of total and free prostate specific antigen in serum samples at different storage conditions. AB - The present preliminary study was performed to find out stability of total prostate specific antigen (PSA) and free prostate specific antigen (FPSA) in serum of healthy males as well as in patients of benign and malignant disorders of prostate at various freezing and nonfreezing temperatures and at different duration of time.The results of our study indicated long-term stability of both the analytes in frozen serum. Serum total and free PSA were stable only for three to four days in regular refrigerators in unfrozen states. Clotted blood kept at room temperature (25 degrees C-30 degrees C) did not cause change in concentrations of both the analytes for twenty four hours. PMID- 23105450 TI - Enzymuria pattern in early post renal transplant period: Diagnostic usefulness in graft dysfunction. AB - Serum creatinine does not distinguish between various causes of graft dysfunction. Serial assay of proximal tubular enzymes N-Acetyl-D-glucosaminidase (NAG), Alanine aminopeptidase (AAP) and Gamma glutamyl transferase (GGT) in urine was done to assess their usefulness in distinguishing various causes of graft dysfunction. Daily serum creatinine and enzymuria were measured in 32 consecutive renal allograft recipients for first 15 postoperative days. Graft dysfunction was defined as >20% increase in serum creatinine and >100% increase in enzymuria over the baseline. The diagnosis of graft dysfunction was based upon clinical criteria, ultrasonography, cyclosporin trough level, allograft biopsy, response to anti-rejection therapy and alteration of cyclosporin dosage. Fifteen episodes of graft dysfunction were identified in 15 patients. The sensitivity and specificity of the enzymes (NAG, AAP and GGT) for predicting graft dysfunction were 87.5%, 86.9%, 88.5% and 98.2%, 98.2%, 97.9% respectively. There was a significant increase in enzymuria during acute tubular necrosis (ATN) and acute rejection episode compared to cyclosporin nephrotoxicity (p<0.01). Enzymuria assay provides a simple, reliable and noninvasive method to distinguish cyclosporin nephrotoxicity from acute tubular necrosis and acute rejection in renal allograft recipients. PMID- 23105451 TI - Faecal fat content in healthy adults by the 'acid steatocrit method'. AB - Malabsorption syndromes causing steatorrhoea are quite common in India. Estimation of faecal fat is an important non-invasive investigation, which provides vital information regarding the occurrence of malabsorption. The aim of this study was to estimate the fat excretion per day in stools of apparently healthy adults on an unrestricted diet in random spot stool samples using the Acid Steatocrit Method, which provides an alternate, simpler and yet reliable method of stool fat estimation. Several studies have proved the correlation of the acid steatocrit method with the conventional methods. In India, however, there has been no published data regarding the normal levels of fat in the stools, by the acid steatocrit method. We follow the normal range values, as set by the United States and the European countries, not having a range for the Indian population. Hence, we took up a preliminary study, to estimate stool fat in a section of normal and healthy Indian population. The result obtained after screening 600 healthy and normal adults, showed the mean of stool fat to be 8.72 gms/24 hours, which is much higher than that, defined by Western literature (7 gms/24 hours). This can be accounted for, by the cultural and ethnic variations in dietary and food habits. Further studies are required in the same direction, involving larger population groups, and in different malabsorptive conditions. PMID- 23105452 TI - Effect of streptozotocin-induced diabetes on oxidative energy metabolism in rat liver mitochondria-A comparative study of early and late effects. AB - The reports in the literature on effects of diabetes on mitochondrial energy linked functions are conflicting. Hence we carried out systematic studies to evaluate the effects at the early and the late stages of the disease using STZ diabetic rat as a model. At the end of one week, after induction of diabetes, respiration rates with glutamate and succinate as the substrates increased; respiration rates with other substrates e.g. beta-hydroxybutyrate, pyruvate + malate and ascorbate + TMPD were not affected despite substantial decrease in the beta-hydroxybutyrate dehydrogenase activity and cytochrome b and c+c(1) contents. Insulin treatment brought about increase in the cytochrome contents beyond control values. The ATPase activity was generally low in the diabetic animals and was not restored by insulin treatment.At the end of one month, the respiratory activities with all the substrates were generally low. Insulin treatment either restored or stimulated the respiration rates beyond control values. The content of cytochromes was differentially affected in the diabetic animals, but insulin treatment caused significant increase beyond control levels. The pattern for ATPase activity was similar to the early effects.At both the stages i.e. early and late stages of diabetes the mitochondria were tightly coupled. The ADP/O ratios were in normal expected ranges and the respiratory control ratios were comparable with the control groups. Insulin treatment resulted in apparent restoration of respiratory activity. However, the effects on the cytochromes and dehydrogenases activities were differential. Taken together the two observations would suggest that the mitochondria were not re-instated to normality despite apparent restoration of respiratory function. PMID- 23105453 TI - Oxidants and antioxidants in hypoxic ischaemic encephalopathy. AB - In the present study, the role of serum lipid peroxide and serum nitric oxide as oxidants and erythrocytic superoxide dismutase & serum vitamin E as antioxidants were determined in the 50 neonates with hypoxic ischaemic encephalopathy. (HIE) as against 25 healthy neonates as controls 50 patients of HIE were further divided into two groups i. e. mild and moderate HIE patients. All subjects were in the age group of 37-41 weeks of gestation. The levels of serum lipid peroxide, serum nitric oxide and erythrocytic superoxide dismutase were significantly elevated in both groups of neonates with HIE than those of controls (P<0.001), whereas serum vitamin E levels were significantly decreased in both groups of HIE patients than those of controls (P<0.001). A positive correlation was obtained between serum lipid peroxide and erythrocytic superoxide dismutase (r=+0.86). Alterations in the status of oxidants and antioxidants indicate role of free radicals in the development of HIE. PMID- 23105455 TI - Quantitation of proteinuria by spot urine sampling. AB - Few studies have shown that calculation of protein/creatinine ratio in a spot urine sample correlates well with the 24-hour urine collection. A study was conducted to compare the accuracy of a spot urinary protein/creatinine ratio (P/C ratio) and urinary dipstick (albustix) with the 24-hour urine protein (24-HUP). Fifty samples from 26 patients were collected. This included a 24-hour urine sample followed by the next voided spot sample. The protein/creatinine ratio was calculated and dipstick (albustix) was performed on the spot sample. This was compared with the 24-hour urine protein excretion. The correlation between the three samples was statistically highly significant (p=<0.001) for all levels of proteinuria. The normal value of protein/creatinine ratio in Indian children was also estimated on 100 normal children attending the OPD and was calculated to be 0.053 (S.E of mean+/-0.003). PMID- 23105454 TI - Should we use carbohydrate deficient transferrin as a marker for alcohol abusers? AB - Carbohydrate deficient transferrin (CDT) is one of the conventional markers for chronic alcohol consumption, is used by researchers and clinicians. A number of enzymes are affected by ethanol intake. The induction or inhibition of sialyl transferase and plasma sialidase may be involved in the CDT level elevation. An alteration of protein transport during post-translational modification could be a primary mechanism in the impairment of protein metabolism associated with chronic alcohol abuse. Transferrin being a steroid responsive protein, sex-based hormonal variations might contribute to the lower sensitivity of CDT. Varying hormonal statuses such as pregnancy, use of contraceptives, menopause/ menstrual cycle can alter iron homeostasis in women. CDT levels are markedly affected by iron homeostasis. Several CDT assay methods appeared promising, but it is not readily apparent which technique is the most accurate. Moreover, false-positive results of CDT have been reported in non-alcohol related hepatic failure and in rare conditions. Therefore clinical interpretation of CDT needs careful assessment in patients with alcohol-related or non-alcohol-related health disorders. PMID- 23105456 TI - Serum iron, copper and zinc status in maternal and cord blood. AB - Pregnancy is associated with increased demand of all the nutrients like Iron, Copper, Zinc etc. and deficiency of any of these could affect pregnancy, delivery and out come of pregnancy. With this consideration, the study was conducted on 80 mothers and newborns and 20 age matched control women. Out of 80 mothers, 34 had Iron deficiency anemia and their Hb levels were below 9.0 gm/d(1). Pregnant women had significantly lower Iron and Zinc levels while Copper and Total Iron Binding Capacity (TIBC) were significantly higher (P<0.001). Newborns had significantly elevated Iron and Zinc levels and low levels of Copper and TIBC as compared to their mothers irrespective of Iron deficiency anemia. Micronutrient status of newborn was found to be dependent on their mother's micronutrient status. Besides, results also suggest micronutrient interactions, which are reflected in Iron/Zinc, Iron/Copper and Zinc/Copper ratios. In view of this, there is need for proper, adequate and balanced micronutrient supplementation during pregnancy to affect a healthy outcome. PMID- 23105457 TI - Lipoprotein (A): Better assessor of coronary heart disease risk in south Indian population. AB - In an attempt to search for risk factors which can explain the increasing prevalence of coronary heart disease (CHD) in Indian population, we conducted a case-control study to assess the association of Lipoprotein (a)(Lp(a)) with CHD. One hundred and fifty one consecutive patients with clinical and angiographic evidence of CHD and forty-nine healthy controls were drawn for the study. Triglycerides, very low density cholesterol (VLDL-C), total cholesterol (total C)/high density cholesterol (HDL-C) ratio, low density cholesterol (LDL-C)/HDL cholesterol ratio and Lp(a) were found to be higher in patients than controls. In female sex and in those with family history of CHD, higher total and LDL cholesterol levels were observed to be associated with higher Lp(a) levels. Lp(a) levels were also found to be higher in triple vessel disease than other vessel disease patients. Significant difference in Lp(a) levels were observed between normal coronaries vs. single and triple vessel disease(P<0.05) and also between single vs. double and triple vessel disease (P<0.01).Lp(a) levels correlated positively with vessel severity(P<0.005). Lp(a) levels >25 mg/dl were associated with coronary heart disease (Odds ratio 1.98 P<0.05 95% CI 0.007-1.18). Our findings suggest a cut-off level of 25mg/dl for determination of risk of CHD. Studies from different areas involving larger sample size are needed to confirm the findings of the present study. PMID- 23105458 TI - Clinical usefulness of alterations in sialic acid, sialyl transferase and sialoproteins in breast cancer. AB - Sialic acid, the end moieties of the carbohydrate chains are biologically important and essential for functions of glycoconjugates and are reported to be altered in cancer patients. Two hundred and twenty five breast cancer (BC) patients, 100 patients with benign breast disease (BBD) and 100 healthy females (controls) were enrolled for the study. Eight hundred and twenty four follow-up samples of 225 breast carcinoma patients were also evaluated. The association of sialic acid forms, sialyltransferase and alpha-2-6 sialoproteins levels with presence and extent as well as prognosis of breast carcinoma was studied. Serum sialic acid forms and sialyltransferase revealed significantly elevated levels among untreated breast cancer patients as compared to the controls, patients with BBD as well as cancer patients in remission. Non-responders showed comparable levels of the markers with those found in breast cancer patients at the time of diagnosis. Higher levels of sialic acid forms at diagnosis were associated with poor prognosis. A positive correlation between serum levels of different forms of sialic acids and extent of malignant disease was observed. The changes in serum proteins with terminal alpha-2-6 sialic acid correlated well with alterations in the levels of sialic acid forms and sialyltransferase. Malignant tissues showed elevated levels of sialic acid and sialyltransferase as compared to surrounding normal tissues.The results suggested potential utility of these markers in evaluation of clinical outcome. PMID- 23105459 TI - Estimation of reference values in liver function test in health plan individuals of an urban south Indian population. AB - Reference intervals in clinical chemistry are commonly based on results of measurements in reference western population or are taken from the western literature. Reference Values are thought to aid physicians to interpret results of measurements and, should be representative of a defined group of individuals. This group should be as similar as possible to the patients under investigation. The reference population in this, study has been recruited from the individuals attending the Health Plan Clinic who fulfill the defined inclusion and exclusion criteria as well as defined partition criteria. The samples were sorted based on the decision by the physician. The emerging group of individuals was considered as a reference population for the hospital patients and the results of measurements in this study was evaluated statistically, to stress on the urgent need to establish the in-house reference values. The reference limits are defined as the central 95 percentile of the population after eliminating the outliers. The lower, reference limit is the 2.5 percentile while the upper reference limit constituted the 97.5 percentile for the population. PMID- 23105460 TI - Oxidant-antioxidant status in colorectal cancer patients-Before and after treatment. AB - Erythrocyte antioxidant glutathione and malondialdehyde levels in erythrocytes and plasma glutathione S-transferase levels were estimated in patients with colorectal cancer and compared to controls. Further, the patients underwent four weeks of radiotherapy with adjuvant chemotherapy. The same parameters were estimated after four weeks of radiotherapy and compared with pretreatment levels. It was observed that there was a decrease in erythrocyte glutathione and malondialdehyde levels in patients with colorectal cancer compared to controls, but not in case of GST. However, after chemoradiotherapy, there were no statistically significant differences in all the parameters studied. PMID- 23105461 TI - Identification and purification of an aspartic proteinase from human semen. AB - To purify and evaluate the molecular changes associated with an aspartic protease (Cathepsin D) in human semen from infertile subjects. Cathepsin D was purified from normo-, oligo- and azoospermic semen, by a procedure involving detergent solubilisation, affinity chromatography and gel filtration chromatography. The enzyme from normo-, oligo- and azoospermic samples was purified 86, 60 and 44 fold respectively. The purified enzyme appeared as a single band on SDS as well as on native PAGE irrespective of the pathological conditions. The molecular weight of Cathepsin D from oligospermic and normospermic samples was 40 kDa while that of azoospermic sample was found to be 43 kDa. The enzyme was inhibited by pepstatin while other proteinase inhibitors and metal ions did not have any effect. Purified Cathepsin D from azoospermic sample differs from normospermia and oligospermia. PMID- 23105462 TI - Cardiac troponin-T and CK-MB (mass) levels in cardiac and non cardiac disease. AB - Serum cardiac troponin T (cTnT) and CKMB (mass) were analysed in three groups of patients. The first group (n=32) were patients with acute coronary syndromes including myocardial infarction. The second group (n=35)were patients with hypertension. The third group (n=24) were patients who had succumbed to non cardiac diseases. In all 3 groups, cardiac troponin T was elevated when compared with controls (p<0.001). However, CKMB elevation was not significant in all groups. CKMB levels correlated well with troponin T levels only when CKMB was greater than 50 ng/ml (r=1.00). Small elevations of troponin T identifies minimal cardiac necrosis and patients can benefit from early invasive therapy. PMID- 23105463 TI - Enumeration of lymphocyte subsets using flow cytometry: Effect of storage before and after staining in a developing country setting. AB - Lymphocyte subset estimations by flow cytometry in population-based studies require transportation of samples from the field site to the laboratory. As samples arrive late in the day they have to wait overnight before being processed. The effect of two possible approaches, sample storage for 24 h before staining and immediate staining with analysis after 24 h and 48 h were evaluated. Two sets of experiments were performed with EDTA (ethylenediamine tetra-acetate) anticoagulated peripheral blood. In the first experiment, after collection, each sample was divided into two portions. One portion was stained at the time of blood collection and the other 24 h later after keeping it at room temperature (38-45 degrees C). In the second experiment, blood samples were stained within 1 2 h. Each sample was analyzed immediately upon completion of staining process and subsequently after 24 h and 48 h of storage at 4 degrees C. Results suggest that blood collected in EDTA can be processed using whole blood lysis method, after storage at room temperature (38-45 degrees C) for 24 h with some but not significant alteration in T-cell subsets. Storage at 4 degrees C after staining for 24 h results in a lesser and insignificant loss of cells or alteration of T cell subsets and may be the method of choice. PMID- 23105464 TI - Correlative study of fluoride content in urine, serum and urinary calculi. AB - Fluoride content was measured in 100 urinary stones retrieved by open surgery of stone formers admitted at PGIMS Rohtak and their respective urine and serum and compared with those of healthy individuals. The concentration of fluoride was also measured in the sources of drinking water of these stone formers. The concentration of fluoride was definitely significantly higher in serum (p>0.01) and highly significantly higher in urine (p>-0.001) of stone formers compared to those of healthy individuals. The content of oxalate in serum and 24 h urine of the stone formers was also measured, which was increased significantly (p<0.005 and p<0.001) compared to healthy individuals. The concentration of fluoride was probably significantly higher in drinking water of these stone formers than the normal ones. There was a positive correlation between the content of fluoride of urinary stones and urine of stone patients (r=.88); stone and serum (r=.62); drinking water and stone (r=.85) and their urine and serum (r=.54); urine and drinking water (r=.83) and serum and water (r=.51). These results indicate a definite role of fluoride in urinary stone formation. PMID- 23105465 TI - Evaluation of antioxidant properties of berries. AB - The present paper focuses on assessing the levels of various enzymatic and non enzymatic antioxidants in selected berries of Indian sub-continent viz., gooseberry, grapes, orange and tomato. This study has revealed that orange, tomato and grapes possess predominant quantities of enzymatic antioxidants namely SOD, catalase and glutathione peroxidase respectively. The levels of antioxidants analyzed namely reduced glutathione, vitamin C and vitamin A were maximal in grapes, orange and tomato respectively. All the extracts of berries included in the present study inhibited iron inducedin vitro lipid peroxidation in erythrocytes, the extend of inhibition being highest for gooseberry and orange compared to tomato and grapes which could be attributed to their in-built antioxidant system. PMID- 23105466 TI - 1, 25-Dihydroxycholecalciferol (1,25-(OH)(2) D(3)) levels in osteoporosis. AB - In the present study primary involution osteoporosis and vitamin D levels were studied in 60 subjects including thirty controls. The biochemical analysis of serum calcium, phosphorus, ALP, albumin and vitamin D(3) (1,25-(OH)(2) D(3)) levels were significantly decreased in osteoporotic patients when compared to non osteoporotic control group. There was a significant correlation of magnitude of sun exposure with 1,25-(OH)(2) D(3) levels. Similarly, vitamin D intake in the diet has a significant correlation with 1,25-(OH)(2) D(3) concentration. However, no correlation could be obtained between vitamin D(3) levels with increasing age. Among the biochemical markers serum calcium, phosphorus, ALP and albumin could not be correlated with 1,25-(OH)(2) D(3) levels. PMID- 23105467 TI - Superoxide dismutase and catalase activities and their correlation with malondialdehyde in schizophrenic patients. AB - Free radical mediated pathological processes may have a role in schizophrenia. Free radicals (oxy radicals, such as superoxide, hydroxyl ions and nitric oxide) cause cell injury, when they are generated in excess or when the antioxidant defense is impaired. Both these processes seem to be affected in schizophrenia. In this study we investigated erythrocyte superoxide dismutase (SOD) and catalase (CAT) activities as antioxidant enzymes, malondialdehyde (MDA) as a sign of lipid peroxidation in schizophrenic patients. Activities of superoxide dismutase, catalase and malondialdehyde were greater in patients compared with the control group which may reflect increased oxidative stress in the brain tissue of schizophrenics. In the patient group erythrocyte SOD and CAT activities were weakly negative correlated with MDA concentration. These data reveal that antioxidant defense mechanisms might be impaired in schizophrenic patients. These findings also provide a theoretical basis for the development of novel therapeutic strategies, such as antioxidant supplementation. PMID- 23105468 TI - Study of interleukin-1 receptor antagonist (IL-1Ra) gene polymorphism in healthy individuals from Northern India. AB - Cytokines play a key role in immune responses and inflammation. IL-1Ra is a naturally occurring structural variant of IL-1 that competitively inhibits receptor binding of IL-1. We have investigated the polymorphism in intron-2 of the interleukin-1 receptor antagonist gene in North Indian population. This genetic variation has been of great interest due to its possible association with a variety of human diseases primarily of epithelial and endothelial cell origin such as urolithiasis etc. Allele frequencies of the IL-1Ra polymorphism vary among different populations but there is no data till date reported from India. The present study was carried out to determine the IL-1Ra gene Polymorphism in 165 normal unrelated individuals from North India. We obtained an allelic frequency of 63.94, 30.61, 4.55, 0.90 for A, B, C and D allele and percentage of genotypes AA, BB, CC, DD, A/B, A/C, A/D and B/C were 49.7, 18.2, 2.42, 0.60, 24.2, 3.63, 0.60, 0.60 respectively. Our results suggested that the frequency and distribution of this polymorphism in India is substantially different from other populations and ethnic groups. PMID- 23105469 TI - Study of magnesium, glycosylated hemoglobin and lipid profile in diabetic retinopathy. AB - The present study was undertaken in 100 subjects, 30 diabetics without complication (group I), 40 diabetics with retinopathy (group II) and 30 non diabetic as normal control group (group III). Blood sugar levels, magnesium, cholesterol and triglyceride were analyzed from plasma and serum. The results were correlated with degree of diabetic control from the levels of glycosylated hemoglobin. Serum magnesium levels in group II were found to be significantly lowered than in group I. There was also significant difference in magnesium levels of group I and group III. We found a significant correlation between the glycosylated hemoglobin and magnesium levels in our study.The results also indicate that the patients with diabetic retinopathy showed significant rise in serum cholesterol and triglyceride. Probably hypomagnesemia and increased serum cholesterol and triglyceride levels are responsible for microvascular changes in diabetes leading to retinopathy. The purpose of this study was thus to gather information about the degree of control of diabetes and magnesium status. PMID- 23105470 TI - Serum adenosine deaminase, 5' nucleotidase and malondialdehyde in acute infective hepatitis. AB - Serum adenosine deaminase (ADA), 5' nucleotidase (5'NT) and malondialdehyde (MDA) were estimated in patients with acute infective hepatitis (AIH) along with the routine parameters of liver disease. Present study is done to evaluate these special parameters in patients with clinical history of AIH and to assess the utility of these parameters as diagnostic/ prognostic indices of liver function and to correlate special parameters with routine live function tests (LFT). ADA, 5'NT and MDA along with routine LFT was estimated in 25 patients with AIH and 25 samples from healthy voluntary blood donars served as the control group. Routine LFT was estimated by standard clinical chemistry procedures on dade behring analyser and ADA, 5'NT and MDA were estimated by berthlot reaction, fiske and subbarao method and thiobarbituric acid method respectively.Statistical analysis showed that serum ADA, 5'NT and MDA were significantly higher in patients as compared with the controls. There was a significant positive correlation between ADA and total bilirubin and MDA and total bilirubin. Hence we can conclude that these tests would be more sensitive to diagnose the patients with AIH and that the raised bilirubin levels could be looked upon, as a protective mechanism which the liver has evolved in order to combat oxidative stress. PMID- 23105471 TI - Enhanced anti-proteases inLabeo rohita fed with diet containing herbal ingredients. AB - Aqueous root extract ofAchyranthes aspera was incorporated in the experimental diet ofLabeo rohita (rohu). Control diet was prepared without root extract. Feeding of fishes with experimental diet has significantly (p<0.05) enhanced the serum anti-proteases level than fishes fed with control diet. PMID- 23105472 TI - Study on arsenic level in ground water of Delhi using hydride generator accessory coupled with atomic absorption spectrophotometer. AB - Surveillance of drinking water is essentially a health measure intended to protect the public from water borne diseases. Hydride generator accessory coupled with atomic absorption spectrophotometer was used to analyze arsenic level in 49 ground water samples collected from different areas of Delhi. Arsenic level in ground water samples was in the range of 0.0170 to 0.100 ppm (Mean-0.0431, Standard Deviation-0.0136, Std. error of Mean-0.00194) with minimum concentration at Raney Well No. 7 (0.0170 ppm) and maximum at Kotla Mubarak Pur (0.100 ppm). Arsenic containing sediments and percolation of chemicals into soil as the result of dumping of garbage rich in chemicals into open landfills could be the possible source of arsenic in ground water of Delhi. Extensive survey and continuous monitoring is required to be made to assess the magnitude of problem and earlier intervention. PMID- 23105473 TI - Antidyslipidemic and antioxidant activities of different fractions ofTerminalia arjuna stem bark. AB - Terminalia arjuna (T. arjuna) stem bark was successively extracted with petroleum ether (A), solvent ether (B), ethanol (C) and water (D). The lipid lowering activity of these four fractions A, B, C, and D was evaluatedin vivo in two models viz., triton WR-1339 induced hyperlipemia in rats as well as fructose rich high fat diet (HFD) fed diabetic- dyslipidemic hamsters. Hyperlipidemia induced by triton caused marked increase in the plasma levels of total cholesterol (Tc), triglyceride (Tg) and phospholipids (PL) in rats. After treament withT. arjuna fractions A, B, C, and D at the doses of 250 mg/kg per oral (p.o.),only the ethanolic fraction (C) exerted significant lipid lowering effect as assessed by reversal of plasma levels of Tc, Tg and PL in hyperlipidemic rats. In another experiment, feeding with HFD produced marked dyslipidemia as observed by increased levels of plasma Tc, Tg, glucose (Glu), glycerol (Gly) and free fatty acids (FFA) in hamsters. After treatment withT. arjuna fractions at the doses of 250 mg/kg p.o. only two fraction (B and C) could exert significant lowering in the plasma levels of lipids and Glu. in dyslipidemic hamsters.In vitro experimentT. arjuna fractions at tested concentrations (50-500 MUg/ml) inhibited the oxidative degradation of lipids in human low density lipoprotein and rat liver microsomes induced by metal ions. These fractions when tested against generation of oxygen free radicals at the concentrations (50-500 MUg/ml), counteracted the formation of superoxide anions (O(-2)) and hydrodyl radicals (OH) in non enzymic test systems. The efficacy ofT. arjuna fractions as antidyslipidemic and antioxidant agents was found, fraction C> fraction B> fraction A. PMID- 23105474 TI - Leucine amino peptidase a better indicator of disseminated malignant disease. AB - Leucine amino peptidase (LAP) activity was studied in serum and urine samples of 25 healthy ambulant subjects, 20 patients with localised and 41 patients with malignant disseminated disease. Serum levels of the enzyme were elevated but not significantly in both localised and disseminated disease whereas the urinary activity of the enzyme was markedly elevated in disseminated disease (p<0.001) as compared to localised disease. This quantitative method used for determination is reliable, accurate, simple, rapid and cost effective and therefore has better application as an indicator of disseminated disease in a clincal setting. PMID- 23105475 TI - Evaluation of hypoglycemic and antioxidant effect ofOcimum sanctum. AB - Ocimum sanctum leaves have been traditionally used in treatment of diabetes mellitus. Dietary supplementation of fresh tulsi leaves in a dose of 2 gm/kg BW for 30 days led to significant lowering of blood glucose levels in test group. Intake ofOcimum sanctum also led to significant increase in levels of superoxide dismutase, reduced glutathione and total thiols, but marked reduction in peroxiodised lipid levels as compared to untreated control group. The leaves were found to possess both superoxide and hydroxyl free radical scavenging action. The present observations establish the efficacy ofOcimum sanctum leaves in lowering blood glucose levels and antioxidant property appears to be predominantly responsible for hypoglycemic effect. PMID- 23105476 TI - Evaluation of microsatellite instability in tumors of central nervous system: A pilot study. AB - Microsatellite instability (MSI) characterized by alterations at simple repetitive genomic sequences is a distinct mechanism in tumorogenesis. Central nervous system (CNS) tumors have been reported to exhibit MSI, indicator of defective mismatch repair system with controversies. The present study was undertaken to examine sixteen primary brain and two spinal tumors for MSI at six mono: BAT-26, BAT-40, BAX, TGFbetaRII, IGFIIR and hMSH3 and four dinucleotide loci: D2S123, D9S1851, D9S283 and D18S58. Polymerase chain reaction (PCR) was done to amplify tumour and blood DNA, analyzed on 8% denaturing Polyacrylamide gel followed by autoradiography. Out of 18 CNS tumors examined, 39% exhibited MSI at BAT-26, BAT-40, D9S1851, D9S283 and D18S58 in tumoral DNA. However, no alteration was observed at BAX, TGFbetaRII, IGFIIR, hMSH3 and D2S123 loci. Low incidence of MS1-high hypothesizes role of MSI in evolution of CNS tumors but not in cancer initiation or progression. PMID- 23105477 TI - Detection of L1 CAM mutation in a male child with mental retardation. AB - Recent studies have presented evidence for the involvement of L1CAM gene mutations in various X-linked mental retardation syndromes. The neural cell adhesion molecule, L1CAM is a transmembrane protein belonging to the super family of the immunoglobulins that play a key role in embryonic development of the nervous system and is involved in memory and learning. No studies were carried out from India on L1 CAM gene in X-linked mental retardation syndromes. Hence, an investigation was taken up to delineate the role of L1CAM gene in mental retardation.Two families (Family I and Family II) having only two members affected with mental retardation in each family were studied for mutations in L1CAM gene. In family II, the younger sibling showed deletion involving region between the nucleotide 13,773 (intron 25) and 14,158 (intron 27) region. The mutation what we observed in younger sibling of the family II is a novel mutation which was not hitherto reported in the world literature. PMID- 23105478 TI - Pro-oxidant and anti-oxidant status in patients of sickle cell anaemia. AB - The role of oxidant damage to red cells in sickle cell anaemia has been of interest in recent years. Although, available reports suggest that sickle cell erythrocytes are susceptible to endogenous free radical mediated oxidant damage there remains discrepancy in the status of antioxidant enzymes and antioxidant vitamins in these patients. In view of this, 107 cases of sickle cell anaemia (36 'SS' and 71 'AS' pattern-as confirmed by haemoglobin electrophoresis) were subjected to analysis of malondialdehyde, ascorbic acid, superoxide dismutase and albumin. The results were compared with 54 age and sex matched healthy controls. The results indicate a marked increase in lipid peroxidation and superoxide dismutase levels in both 'SS' and 'AS' types of sickle cell anaemia as compared to controls. Although no difference was observed in the levels of albumin in these groups the levels of ascorbic acid were significantly depleted in sickle cell anaemia patients. The results are indicative of enhanced lipid peroxidation along with imbalance in the pro-oxidant and antioxidant status in patients of sickle cell anaemia. PMID- 23105479 TI - Efficacy of topical honey therapy against silver sulphadiazine treatment in burns: A biochemical study. AB - Thermal injury is associated with biochemical changes. The present study was undertaken to investigate relation of oxidative free radical generation and related biochemical parameters in burn trauma. The specific aim was to compare the levels of serum lipid peroxide, Ceruloplasmin and Uric Acid in burn patients during treatment with Silver Sulfadiazine Cream and honey therapy. It is a single blind prospective controlled study involving comparison of biochemical changes after treatment with silver sulfadiazine and honey treatment in burn injury. In burn trauma, there is excessive activity of free radicals at the site of injury. This is reflected in elevated blood levels of Lipid peroxide, Ceruloplasmin & Uric Acid. Honey therapy was was shown to decline the levels of serum Lipid peroxide, while there was mild increments in serum Ceruloplasmin levels whereas there was no significant effect on serum Uric Acid levels as compared to silver sulfadiazine treatment. Honey therapy seems to accelerate the process of healing. It has positive effect in reducing oxidative stressful state in burn trauma than the silver sulfadiazine treatment that results in rapid wound healing. PMID- 23105480 TI - Study on construction of cDNA libraries from rat normal liver and regeneration liver with smart technique. AB - The aim of the study is to construct cDNA libraries from the normal liver and regeneration liver of rat by SMART (switching mechanism at 5' end of RNA transcript) technique and analyze their quality. The total RNA was separated from the normal liver and regeneration liver of rat and the frist-strand cDNA was synthesized through reverse transcription by a modified oligo (dT) primer (contained sfi IB site) while the SMART oligonucleotide (contained sfi IA site) was utilized as a template so that the first-strand cDNA could be extended over the 5' end of mRNA. The double-strand cDNA was amplified by LD-PCR (long-distance PCR) with the above two primers and then digested by sfi I (IA & IB) restriction, enzyme. After cDNA size fractionation through Chroma Spin 400 column, the double strand cDNA was ligated into the sfi I-digested lambda TripIEx2 vector and then the recombinant DNA was packagedin vitro. The unamplified rat normal liver cDNA library consists of 1.3*10(7) pfu/ml, and regeneration liver cDNA library consists of 1.6*10(7) pfu/ml in which the percentage of recombinant clones both are about 100%. Through testing, the high quality cDNA libraries containing full length cDNA of rat normal liver and regeneration liver have been constructed. The titer of the amplified cDNA library is 4.5*10(10) pfu/ml and 3.6*10(10) pfu/ml. the average exogenous inserts of the recombinants both are about 1.5 kb. These results show that the normal liver and regeneration liver of rat cDNA libraries both have an excellent quality and lay solid foundation to study liver functions and the mechanism of liver regeneration. PMID- 23105481 TI - Study on construction of cDNA library of the treated changliver cell and quality analysis. AB - The study aims to construct cDNA library of Changliver cell by SMART (switching mechanism at 5' end of RNA transcript) technique and analyze its quality. cDNA of Changliver cell was made with RT-PCR and LD-PCR (long-distance PCR), the cDNA library was constructed with SMART cDNA library construction kit. Through testing, the high quality cDNA library containing whole long cDNA of Changliver cell had been constructed. The titer of the amplified cDNA library was 4.5 * 10(10) pfu/ml and the average exogenous inserts of the recombinants is 1.5 kb. These results showed that the Changliver cell cDNA library had an excellent quality and lay foundation for screening whole long cDNA of related genes. PMID- 23105482 TI - Effect of arogh-A polyherbal formulation on the marker enzymes in isoproterenol induced myocardial injury. AB - To study the protective role of Arogh on isoproterenol induced myocardial damage in rats. The effect of Arogh pretreatment on isoproterenol induced myocardial damage was assessed by studying the levels of lipid peroxides and changes in the activity of marker enzymes such as creatine kinase, lactate dehydrogenase and transaminases in serum and heart tissue. In isoproterenol administered rats, a significant decrease was observed in the activity of marker enzymes in the heart with a corresponding increase in their levels in serum. Lipid peroxide levels increased significantly in the serum and heart. In rats pretreated with arogh, the level of lipid peroxides and the activity of marker enzymes were maintained at near normal values. Pretreatment with Arogh offered a protective effect against isoproterenol induced myocardial damage in rats as evidenced by LDH isoenzyme patterm and histopathological studies of heart tissue. PMID- 23105484 TI - Antihyperglycemic effect of water extract of dry fruits ofTerminalia chebula in experimental diabetes mellitus. AB - Water extract of dry fruits ofTerminalia chebula (Hindi-Harda, Telugu-Karakkaya) at a dose of 200 mg/kg body weight improved the glucose tolerance as indicated by 44% of reduction in the peak blood glucose at 2(nd) hour in glucose tolerance test in diabetic (streptozotocin induced) rats. Treatment of diabetic rats with an initial fasting blood glucose of 253+/-9.4 mg/dl daily once with the water extract (200 mg/kg) for two weeks brought down the fasting blood glucose to 123+/ 8.4 mg/dl which is only slightly above the normal value. These results indicate that water extract of Terminalia chebula improves glucose tolerance and brings down fasting blood glucose in diabetic rats. PMID- 23105483 TI - Aerial pollen diversity in India and their clinical significance in allergic diseases. PMID- 23105485 TI - Effect of antimalarials treatment on rat liver lysosomal function-Anin vivo study. AB - Effects of treatmentin vivo with the antimalarials:chloroquine (CQ), primaquine (PQ) and quinine(Q) on lysosomal enzymes and lysosomal membrane integrity were examined. Treatment with the three antimalarials showed an apparent increase in the membrane stability. CQ treatment resulted in increase in both the 'free' and 'total' activities of all the enzymes i.e. acid phosphatase, RNase II, DNase II and cathepsin D. PQ treatment lowered the 'free' and 'total' activities of acid phosphatase and cathepsin D, but the DNase II activities increased. Treatment with Q resulted in increased 'free' and 'total' activities of RNase II and DNase II. While 'free' activities of acid phosphatase and cathepsin D were low; the 'total' activities increased significantly. Our results suggest that a generalized increase in free nucleases activities following prolonged treatment with antimalarials may lead to cell damage and/or necrosis. PMID- 23105486 TI - Autoimmune thyroid disorders-An update. AB - BACKGROUND: Autoimmune thyroid disease (AITD), a common organ specific autoimmune disorder is seen mostly in women between 30-50 yrs of age. Thyroid autoimmunity can cause several forms of thyroiditis ranging from hypothyroidism (Hashimoto's thyroiditis) to hyperthyroidism (Graves'Disease). Prevalence rate of autoimmune mediated hypothyroidism is about 0.8 per 100 and 95% among them are women. Graves' disease is about one tenth as common as hypothyroidism and tends to occur more in younger individuals. Both these disorders share many immunologic features and the disease may progress from one state to other as the autoimmune process changes. Genetic, environmental and endogenous factors are responsible for initiation of thyroid autoimmunity. At present the only confirmed genetic factor lies in HLA complex (HLA DR-3) and the T cell regulatory gene (CTLA 4). A number of environmental factors like viral infection, smoking, stress & iodine intake are associated with the disease progression. The development of antibodies to thyroid peroxidase (TPO) thyroglobulin (TG) and Thyroid stimulating hormone receptor (TSH R) is the main hallmark of AITD. Circulating T Lymphocytes are increased in AITD and thyroid gland is infiltrated with CD4+ and CD8+ T Cells. Wide varieties of cytokines are produced by infiltrated immune cells, which mediate cytotoxicity leading to thyroid cell destruction. Circulating antibodies to TPO and TG are measured by immunofluorescense, hemagglutination, ELISA & RIA. TSHR antibodies of Graves' disease can be measured in bioassays or indirectly in assays that detect antibody binding to the receptor. PMID- 23105487 TI - Homocysteine status and acute myocardial infarction among Tamilians. AB - Myocardial infarction is a major consequence of coronary artery disease. Apart from the traditional risk factors of myocardial infarction, recently many reports have suggested that hyperhomocysteinemia plays important role in myocardial infarction. Plasma homocysteine level was determined in 60 myocardial infarction patients and in 35 age matched healthy individuals. Statistically significant differences (p<0.01) were observed in the mean of plasma homocysteine concentrations between the acute myocardial infarction patients (24.59+/-6.14 mM/L) and in normal healthy individuals (13.73 +/-3.54 mM/L). The level of homocysteine in myocardial infarction patients is significantly high (p <0.01) among myocardial infarction patients when compared to that of the controls. The the present study indicates a strong association between plasma homocysteine and acute myocardial infarction among Tamilians, thus implying plasma homocysteine as a possible risk factor for myocardial infarction. PMID- 23105488 TI - Effect of vitamin E on platelet enzymatic anti-oxidants in the patients of myocardial infarction. AB - Effect of administration of 600 mg. vitamin E each day, for six days, was observed on activity of some of the anti-oxidant enzymes and levels of malondialdehyde (as an index of free radical mediated damage) in the platelets of patients reperfused after myocardial infarction. It has been found that vitamin E administration significantly lowers the level of malondialdehyde in the patients. Vitamin E administration increases the activities of anti oxidant enzymes (viz. superoxide dismutase, glutathione reductase and catalase) tested both in the patients and healthy controls. Vitamin E administration causes general stimulation of anti-oxidant enzyme activities both in healthy persons and the patients, however, lowering of lipid per-oxidation upon administration of vitamin E is specific for patients. These findings exhibit beneficial role of vitamin E administration in the management of the patients reperfused after myocardial infarction. PMID- 23105489 TI - Effect of vitamin E on the platelet xanthine oxidase and lipid peroxidation in the patients of myocardial infarction. AB - Platelets play important role in precipitating ischaemic myocardial syndromes in many ways. One of the consequences of ischaemic diseases is excessive generation of oxygen derived free radicals that have numerous pathophysiological consequences. Platelet pro-oxidant enzyme, xanthine oxidase is one of the sources of generation of free radicals. In the present paper, we report the effect of administration of vitamin E along with aspirin on the levels of platelet xanthine oxidase and extent of free radical mediated damage in the patients reperfused after myocardial infarction.Our findings show that administration of 400 mg. vitamin E for six days along with 80 mg. aspirin has an excellent anti-oxidant effect as evidenced by reduced platelet xanthine oxidase activity and lowering of malondialdehdye (MDA) levels which is an index of the extent of free radical mediated damage. PMID- 23105490 TI - Antioxidant status and peroxidative stress in mother and newborn -A pilot study. AB - Serum antioxidant status and peroxidative stress was estimated in 30 pregnant women, their newborn infants and 25 non-pregnant women. Serum Ascorbic acid, alpha-tocopherol, retinol & beta-carotene levels were found to be significantly reduced and peroxidative stress was significantly higher in mothers as compared to matched non-pregnant women. Newborn had significantly higher levels of ascorbic acid as compared to their mother but had significantly lower levels of lipid soluble vitamins. The peroxidative stress in newborn was found to be significantly less as compared to their mothers. A positive correlation of ascorbic acid and alpha-tocopherol levels between mother and newborn reflects that their status in mother does influence the newborn status. PMID- 23105491 TI - Biochemical diagnosis of alcoholism. AB - Medically diagnosed alcoholics can be differentiated reliably from non-alcoholics using clinically laboratory tests. In the present study, patients with liver diseases either due to alcohol or without alcohol compared with a group of normal healthy persons. Heavy drinkers showed significantly lower body weight and percent body fat, and low BMI compared with other groups. The percentage of hemoglobin and total number of RBC were found to be significantly decreased, whereas mean corpuscular volume (MCV) significantly increased in alcoholic liver disease (ALD). Hyperbilirubinemia, hyperuricemia and hypoalbuminemia correlate with alcohol intake. Albumin/globulin ratio significantly decreased in ALD. In acute liver injury AST/ALT ratio is <=1.0, whereas in alcoholic hepatitis it is always >1.0. Moderately elevated level of ALP and high GGT values are good discriminator of alcoholic patients. Alcohol-induced liver injury is linked to oxidative stress as observed by decreased level of reduced glutathione and ascorbic acid, and increased level of thiobarbituric acid reactive substances. PMID- 23105492 TI - Alteration in some antioxidant enzymes in cardiac tissue upon monosodium glutamate [MSG] administration to adult male mice. AB - 4mg and 8mg monosodium glutamate per gram body weight was administered subcutaneously for 6 consecutive days to normal adult male mice and its effect was seen on 31(st) day after the last injection on some antioxidant enzymes in heart. A significant dose dependent increase in lipid peroxidation and xanthine oxidase level was observed, whereas the activity of free radical scavenging enzymes such as superoxide dismutase and catalase was decreased in both monosodium glutamate treated groups (Group-2 and Group-3). So, the present work suggested that monosodium glutamate at dose level of 4mg/g body weight and above induced oxidative stress in the cardiac tissue by changing the activity of free radical initiating enzyme such as xanthine oxidase and scavenging enzymes like superoxide dismutase and catalase. PMID- 23105493 TI - Influence of aerobic treadmill exercise on blood glucose homeostasis in noninsulin dependent diabetes mellitus patients. AB - The role of treadmill exercise on blood glucose homeostasis in noninsulin dependent diabetes mellitus (NIDDM) were studied using males between age of 45 and 60 years (X-52), who were clinically and biochemically-confirmed cases of NIDDM were taken into study group. Control group comprised of 10 males between age group of 45 to 60 (X-53) years. All the subjects were assessed by physician and were investigated to confirm diabetic status. The whole study period was extended for 6 weeks. The significant decrease in postprandial blood sugar (44.4 mg% for the study group and 32.2mg% for the control group) with a significant inter group difference (P<0.05) was observed. The mean decrease in fasting blood sugar (39.4mg% for the study group and 27.4mg% for the control group), with a marginal inter group difference (P<0.05) was observed. The treadmill exercise was found to be a definite tool in addition to drug and diet in glycemic control. PMID- 23105494 TI - Altered pattern of lipids in plasma and erythrocyte membranes of rheumatoid arthritis patients. AB - The present study has investigated the levels of lipids, lipoprotein cholesterol (HDL and LDL cholesterol), thiobarbituric acid reactive substances (TBARS) and vitamin E in plasma and erythrocyte membranes of twenty two clinically diagnosed adult rheumatoid arthritis patients and an equal number of age matched healthy subjects. The levels of lipids and lipoprotein cholesterol were markedly reduced in patients with rheumatoid arthritis as compared to healthy subjects. The altered lipid pattern may be related to decreased lipoprotein cholesterol, fatty acids and impairment in antioxidant defence mechanism. PMID- 23105495 TI - Picrotoxin-induced convulsions and lysosomal function in the rat brain. AB - The effect of picrotoxin-induced convulsions on lysosomal function in rat brain were evaluated by measuring the free as well as total acid phosphatase, cathepsin D, acid ribonuclease (RNAse II) and acid deoxyribonuclease (DNAse II) activities. Following picrotoxin treatment the free RNAse II activity increased whereas the total activities of practically all the other enzymes decreased. Paradoxically, the cathepsin D activity, free as well the total was completely abolished. In case of all the enzymes the ratio of Total activity/Free activity decreased indicating increased lysosomal membrane fragility which could lead to process of neurodegeneration in the epileptic animals. PMID- 23105496 TI - Alterations of serum cholesterol and serum lipoprotein in breast cancer of women. AB - Fasting blood sample of 50 normal subjects (control) and 100 patients of breast cancer were investigated for serum total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, very low density lipoprotein, high density lipoprotein cholesterol:low density lipoprotein cholesterol ratio and total cholesterol:high density lipoprotein cholesterol ratio during breast cancer of women. Five cancer stages, types, age groups, parity and menopausal status were undertaken for the study. It was observed that there was a significant rise in serum total cholesterol and low density lipoprotein cholesterol whereas high density lipoprotein cholesterol and very low density lipoprotein cholesterol were not significant. The ratio of high density lipoprotein cholesterol:low density lipoprotein cholesterol and total cholesterol:high density lipoprotein cholesterol values increased significantly in breast cancer patients. PMID- 23105497 TI - Lipid peroxide levels and antioxidant status in alcoholic liver disease. AB - The present study was conducted to evaluate some of the components of antioxidant defense system and oxidative damage in 20 male patients of alcoholic liver disease (ALD). The results were compared with 20 healthy male smokers and 20 healthy male non-smokers volunteers. Patients were subjected to detailed clinical examination and laboratory investigations. Blood samples were collected for estimating reduced glutathione (GSH), total thiols (T-SH) malondialdehyde (MDA), transaminases (AST, ALT), glutathione-S-transferease (GST) and gammaglutamyl transferase (GGT). Serum aspartate amino transferase (AST)/alanine amino transferase (ALT) ratio was significantly (p<0.01) reduced in ALD patients as compared to the controls. However, the core of utility of MDA and GST was found to be significantly (p<0.01) increased in ALD patients compared to controls. There was a significant negative correlation of MDA with both GSH and TSH. Plasma GGT levels were significantly (p<0.01) increased in alcoholics and the enzyme showed a significant positive correlation with MDA. These results give enough evidence of increased oxidative stress and compromised antioxidant defense system in patients with ALD. PMID- 23105498 TI - Isolation and characterization of mitochondria from goat hearts. AB - Cardiac mitochondria provide energy for the contraction/relaxation cycle. The aim of our study was to isolate and characterize mitochondria from Caprine hearts under control and in-vitro induced ischemia. A decrease in activities of all the enzymes was observed in the ischemic models. Further characterization of proteins was done by SDS-PAGE and BN-PAGE. Lipids have been characterized by analyzing the phospholipids by HPTLC and fatty acids by GLC in both groups. Our results indicated that injury occurs early in the course of ischemia and progresses during ischemia. TBARS and carbonyl content have also been measured. The in-vitro effects of fatty acids have been studied on the enzymes and complexes of mitochondria. PMID- 23105499 TI - Effect of ethanol on liver antioxidant defense systems: Adose dependent study. AB - Alcohol induced oxidative stress is linked to the metabolism of ethanol. In this study it has been observed that administration of ethanol in lower concentration caused gain in body and liver weight. while higher concentration of ethanol caused lesser gain in body and liver weight. Ethanol treatment enhanced lipid peroxidation significantly, depletion in levels of hepatic glutathione and ascorbate, accompanied by a decline in the activities of glutathione peroxidase and glutathione reductase, and increased in hepatic glutathione s-transferase activity. Interestingly catalase activity increases in lower concentration of ethanol exposure, and decreased in higher concentration. Superoxide dismutase activity was also increased on ethanol exposure. But, ethanol feeding did not show any effect on glucose-6-phosphate dehydrogenase activity. Ethanol ingestion perturbs the antioxidant system in a dose and time dependent manner. PMID- 23105500 TI - Effect of vitamin A supplementation on hematopoiesis in children with anemia. AB - Fifty children (1-4 years age) presenting with microcytic hypochromic anemia (hemoglobin less than 10g/dl) were studied in two groups of 25 each. Group I was supplemented with iron (ferrous sulphate 6 mg/kg/d) while group II in addition to iron was also supplemented with vitamin A (5000 IU/d). Hemoglobin concentration was found to be significantly increased after 4 weeks of iron supplementation. Rise in hemoglobin was comparatively more in-group II, as compared to group I, after 8 and 12 weeks. Serum iron was significantly higher after 4 weeks in both the groups. Packed cell volume (PCV) and retinol levels increased significantly in-group II only. The data suggests that supplementation of vitamin A improves hematopoiesis. PMID- 23105501 TI - Interaction of LDL and platelets in ischaemic and ischaemic risk subjects. AB - Platelets play a vital role in the progression of atherosclerosis and thrombosis, a major cause of death worldwide. Platelets are activated by many triggers like elevated LDL in blood resulting in aggregation and formation of plaque. The purpose of this study was to investigate the effect of LDL and signal transduction inhibitor on the activation of platelets in Ischaemic risk subjects. Platelets from IHD and hyperlipidemic subjects were hypersensitive to ADP, as higher levels of platelet aggregation were observed in these groups. LDL from IHD hyperlipidemic subjects was more effective in activating platelets from any other group. Ox-LDL was more effective in activating platelets than native-LDL as monitored by level of platelet aggregation induced by PAF and thrombin. Calcium channel blocker, nifedipine and verapamil inhibited platelet aggregation at micromolar level. Protein kinase inhibitor, staurosporine was effective in inhibiting ADP induced aggregation at nanomolar level. PMID- 23105502 TI - Can serum Glutathione-S-transferase levels in carcinoma cervix be a predictor of radiation response? AB - We conducted a pilot study wherein serum Glutathione-S-transferase levels were measured before and after radiotherapy in carcinoma cervix patients and correlated with response to treatment during a two-year follow-up period. Out of 17 patients who received radiotherapy, 9 showed a significant decrease (p<0.005) while 8 showed significant increase (p<0.004) in post radiotherapy glutathione-S transferase values as compared to pre treatment values respectively. These patients were followed up for two years and we observed that 71% who had significant increase in post radiotherapy values had relapse of cancer within 2 years where as 66% of those who had significant decrease in post radiotherapy values had no evidence of relapse. This shows that alterations in serum Glutathione-S-transferase levels may help us to predict radiation response. PMID- 23105503 TI - Arterial blood gas management during cardiopulmonary bypass. AB - This study sought to investigate the effects of alpha-stat and pH stat regimens on cardiac outcome during moderate hypothermic cardiopulmonary bypass. 100 patients undergoing elective coronary artery bypass grafting (CABG) were randomly assigned with respect to the target value for PaCO(2) during cardiopulmonary bypass (CPB) into 2 groups. In 50 patients the target PaCO(2) was 40 mmHg, measured at a standard electrode temperature of 37 degrees C while in the other 50 patients the target PaCO(2) was 40 mmHg, corrected to the patients nasopharyngeal temperature (lowest value reached: 32+/-0.5 degrees C). There were no significant differences between groups with regards to cardiac outcome such as appearance of new 'Q' waves on the electrocardiogram, postoperative creatinine kinase-MB fraction, systemic vascular resistance (SVR), cardiac index (Cl), need for inotropic or intra-aortic balloon pump support and the length of postoperative ventilation or intensive care unit stay. These findings support the hypothesis that CO(2) management during CPB at moderate hypothermia has no clinically significant effect on cardiac outcome. PMID- 23105504 TI - Oxidant status and lipid profile in vegetarians and fish eaters. AB - Habitual consumption of moderate amounts of fish is associated with reduced mortality from coronary heart disease. However the beneficial effects of fish enriched diet seem contradictory, due to the susceptibility of the PUFAs in them to oxidation. It is also acclaimed that vegetarians in general, have a lower serum total cholesterol and LDL-cholesterol and a better antioxidant status. This contradiction was the basis for the study, where the validity of the above finding was tested in a general population consuming a vegetarian or predominantly fish diet as a regular dietary habit. The oxidant status and the lipid profile of 23 vegetarians and 22 fish eaters was studied by estimating the plasma lipid peroxides measured as malondialdehyde (MDA) and the lipid parameters viz. Total Cholesterol (TC), HDL-Cholesterol (HDL-C) and triglycerides (TG). Statistical analysis was carried out to compare the MDA values and the lipemic status between the two groups. MDA was also correlated with the various lipid indices among the study groups. None of the compared and correlated values was statistically significant, although certain altered trends were seen. From this study, it may be concluded that oxidant status and lipid profile does not vary significantly in the two groups, suggesting that neither a vegetarian diet nor a fish diet has a definite benefit over the other. PMID- 23105505 TI - Comparative effect of olive oil and fish oil supplementation in combating gentamicin induced nephrotoxicity in rats. AB - The present study is related to the comparative effects of fish oil and olive oil supplementation on gentamicin induced nephrotoxicity in rats. Three treatment groups (Pretrement, Co-treatment and post treatment) were chosen for the study. Nephrotoxicity in rats was induced by intraperitonial administration of gentamicin (80 mg/kg/d) for 3,5,7,10,& 12 consecutive days. The animals were sacrificed 12 hrs after last treatment in each group. The maximum nephrotoxicity was developed on 10 days treatment of gentamicin. For each group a control group was taken without any oil or gentamicin treatment. Beneficial effects of oils were evidenced by reduced serum urea and creatinine concentrations in the group receiving oils compared to the non oil treatment animals receiving gentamicin only. Further, the changed values of alkaline phosphatase and acid phosphatase activity retumed to normal in kidney and liver tissue homogenates after fish and olive oil treatment. In this study, it was found that co-treatment of fish and olive oil is more effective antagonist of gentamicin induced nephrotoxicity. However fish oil was found to be more effective. Hypercholesteromia associated with gentamicin induced nephrotoxicity is also lowered by oil supplementations. The beneficial effects of these oils are due to counteracting effect of the biochemical alterations induced by the drug. PMID- 23105506 TI - Effect of spironolactone on acid and alkaline phosphatase in the testes of albino rat. AB - The biological activity of the mineralocorticoid antagonist, spironolactone depend upon its metabolism. In this study the effect of diuretic drug compound spironolactone on the acid and alkaline phosphatase in the testes of albino rat. The drug spironolactone was administered orally daily for 7(th), 14(th) and 21(st) days at the dose of 100 mg/kg body weight. Among them, the side effects of drug are that the degradation of alkaline phosphatase in the testes; while acid phosphatase increased significantly may be due to 7a-thiospironolactone is a tissue metabolite of spironolactone and may contribute to the testicular enzymes, therapeutic actions and some other side effects. It is suggested that the decrease and increase of alkaline and acid phosphatase in the testes of albino rat are the due to the side effects of spironolactone drug compound. PMID- 23105507 TI - Lipid composition and amino acid uptake during rotavirus infection and protection with trypsin inhibitor in malnourished infant mice. AB - The aim of the study was to evaluate the influence of rotavirus (RV) and soyabean trypsin inhibitor (TI) on lipid composition and uptake of glucose and glycine in rotavirus (RV) infected malnourished (PEM) infant mice. Malnutrition was achieved in animals by doubling the litter size. Cholesterol (Ch) and phospholipd (PL) contents, uptake levels of glucose and glycine were determined in jejunum and ileum portion of small intestine. Increase in Ch/PL ratios was observed in PEM+RV group. The levels became comparable in PEM+RV+TI as compared to PEM. Uptake levels of glucose and glycine increased in PEM animals. With rotavirus (PEM+RV+TI group), the levels decreased which became comparable to PEM. Changes in uptake and lipid composition with rotavirus and trypsin inhibitor may be responsible for altering membrane fluidity and organization during rotavirus diarrhea. The results establish the importance of trypsin inhibitor during oral infection with rotavirus. PMID- 23105508 TI - Diagnostic role of the antibody response to the 38kDa, 16kDa proteins and lipoarabinomannan of mycobacterium tuberculosis. AB - The antibody response to the 38kDa, 16kDa and Lipoarabinomannan (LAM) antigens ofMycobacterium tuberculosis was evaluated using three different ELISAs based on these antigens. The study group included tuberculosis patients (n=52), patients with HIV and TB co-infection (n=10), other chest symptomatics (n=5), HIV infected individuals (n=10), leprosy cases (n=7) and healthy controls (n=75). The results indicate that the 38kDa and LAM based ELISA for IgM/IgG has a low specificity (ranging from 69-85%) and sensitivity (ranging from 55-78%). When three ELISAs are carried out on a single patient the probability of detection of tuberculosis was significantly increased to 95.2% indicating that a single ELISA test is of low sensitivity and that a combination of ELISA's may be needed to be of any value as a diagnostic test for tuberculosis. Additionally, a western blot assay of the serum antibody response to protein fraction ofM. tuberculosis was analysed in 15 tuberculosis patients and five healthy controls. A multiple antibody response to various M.tuberculosis proteins was observed which varied from patient to patient as compared to controls who showed a single 38-39 kDa protein band positivity. These finding suggest that a western blot assay which determines the antibody response to a set of antigenic components ofM. tuberculosis could be a better serological test for the diagnosis of tuberculosis in our population. PMID- 23105509 TI - Evidence for oxidative stress in osteoarthritis. AB - Evidence of increased oxidative stress in patients of osteoarthritis in comparison with healthy control subjects was investigated by measuring the thiobarbituric acid reactive substances (TBARS), vitamin C, reduced glutathione (GSH) and the activities of superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in erythrocytes. It was observed that osteoarthritis patients were more susceptible to oxidative damage than controls as evident from increased TBARS and decreased ascorbic acid, GSH, catalase and GPx in erythrocytes. Significant increase in SOD activity found in patients might be an adaptive response. With the understanding of the role of antioxidants in arthritis, it is becoming increasingly clear that these agents seem to be beneficial in osteoarthritis. PMID- 23105510 TI - Study of some common biochemical bone turnover markers in postmenopausal women. AB - Markers of bone formation in serum include total and bone specific alkaline phosphatase, osteocalcin and Type 1 collagen carboxy terminal extension peptide. Bone resorption can be assessed by measuring plasma tartarate resistant acid phosphtase and urinary excretion of collagen degradation products: hydroxyproline, hydroxylysine glycosides and more recently the pyridinium crosslinks and associated peptides. We compared the excretion of hydroxyproline in women of reproductive age group to those of menopausal age group and found a significant difference in the two age groups. Urinary hydroxyproline was found to be significantly raised in post menopausal women. Thus hydroxyproline maybe used as the earliest indicator in the prognostic assessment of postmenopausal women of their risk of developing osteoporosis and fracture. PMID- 23105511 TI - Effect of fluoxetine on weight reduction in obese patients. AB - Obesity is one of the most important health problems, which many people suffer from it. As a chronic disease, it is a precipitating factor for many medical conditions like hypertension, diabetes mellitus, hyperlipidemia, coronary artery disease, sleep apnea syndrome and some malignancies (breast, uterus, prostate and colon carcinoma). With attention to this fact that obesity is an independent risk factor associated with significant increase in morbidity and mortality, treatment of overweight individuals is very important. One of the medications for short term weight loss is fluoxetin. In this clinical trial study, fluoxetin effect on weight loss induction during 8 weeks was investigated. 201 cases with BMI between 25-42 were selected randomly (113 female and 88 male) and all received fluoxetine (40 mg daily) for 8 weeks. Measurement was carried out after the 4(th) and 8(th) week of administration and 4 weeks after end of treatment. Management of 9 cases (4 due to weight gain and 5 due to headache) were discontinued after 4 weeks of treatment. Data assessments were performed using t-test and SPSS program. Mean body weight at first visit was 89.32+/-13.30kg. At the 4(th), 8(th) week of treatment and 4 weeks after study, the mean body weight of cases reached 86.09+/ 13.27 (p=0.00), 82.69+/-11.31 (p=0.00) and 81.97+/-13.26 (p=0.00) respectively. Mean BMI at first visit was 34.90+/-5.20kg/m(2). At 4(th), 8(th) weeks of treatment it was 33.72+/-5.20kg/m(2) and 32.40+/-5.18kg/m(2) respectively. Mean weight loss at 4(th) and 8(th) weeks of treatment was 3.24kg and 6.67kg respectively without any weight gain at the end of the 4(th) week after discontinuation of the drug. Fluoxetine is an effective, well-tolerated and relatively safe drug for short-term treatment of obesity. PMID- 23105512 TI - Cystatin C-A novel marker of glomerular filtration rate: A review. AB - Glomerular filtration rate is routinely assessed by measuring the serum markers such as urea nitrogen and serum creatinine. Although these markers are widely used to assess renal function but they do not perform optimally in certain clinical settings. There is thus a practical need for an easily automated alternative to plasma creatine, which would be more specific, sensitive and reliable from the analytical and clinical view point. Compared with the above endogenous markers, and time consuming laborious tests, Cystatin C facilitates the recognition of abnormal renal function in children, as its reference range is constant beyond the 1(st) year of life. This review mainly focuses on the diagnostic performance of Cystatin C against other renal markers in the pediatric population and in specific subpopulations of patients. PMID- 23105513 TI - Oxidative stress in metabolic syndrome. AB - As antioxidants play a protective role in the pathophysiology of diabetes and cardiovascular diseases, understanding the physiological status of antioxidant concentration among people at high risk for developing these conditions, such as Metabolic Syndrome, is of interest. In present study out of 187 first degree non diabetic relatives and 192 non-diabetic spouses, 33.1% and 19.7% were found to have metabolic syndrome respectively. Subjects with metabolic syndrome (>=3 risk factors) had poor antioxidants status as reflected by significantly low levels of vitamin A, C & E and significantly increased (p<0.01) oxidative stress as compared to those without metabolic syndrome. At the same time serum insulin levels and insulin resistance were found to be significantly high (p<0.001) in metabolic syndrome. A strong positive correlation (r=0.946; p<0.001) between oxidative stress and insulin resistance was observed in metabolic syndrome. Low levels of antioxidants and increased oxidative stress with insulin resistance in metabolic syndrome suggests that besides therapeutic life style changes (TLC) as suggested in ATP III guidelines inclusion of antioxidant vitamins, fruits and vegetable could be beneficial to ward off the consequences of metabolic syndrome. PMID- 23105514 TI - Reduced glutathione: Importance of specimen collection. AB - Glutathione, the dominant intracellular thiol, plays an important protective role against oxidative stress. The accidental findings of increased reduced glutathione level postprandially as compared to post absorptive level prompted the design of present study. Reduced Glutathione levels were estimated in 50 healthy individuals in post absorptive and postprandial phase by taking whole blood in ACD bulb. Mean postprandial reduced Glutathione (9.60+/-3.39 MUmole/gm of Hb) is significantly increased than mean postabsorptive level (5.53+/-0.88 MUmole/gm of Hb; p<0.001). It also shows positive correlation (r=0.65) between these two GSH levels. So present study suggests that post absorptive specimen collection is preferable over random or postprandial as the former reflects the true basal level of reduced glutathione. PMID- 23105515 TI - Antioxidant and lipid lowering activities of Indian black tea. AB - Indian black tea; CTC leaf and dust, produced by Tata Tea Limited, Kolkata, (India) was studiedin vitro as potential scavenger of oxygen free radicals. Super oxide anions were generated in a system containing xanthine-xanthine oxidase (enzymic system) and by NADH- phenozine methosulphate (non enzymic system). Anions were assayed in terms of uric acid formation and reduction of nitroblue tetrazolium salt, which were shown to be suppressed by tea extracts. Extracts from both leaf and dust also inhibted the formation of hydroxyl radicalsin vitro in the enzymic system comprising hypoxanthine-Cu(+2)-sodium ascorbate and xanthine oxidase and in non enzymic system of deoxyribose-Cu(+2)-sodium ascorbate and H(2)O(2) as well as the Cu(+2) induced lipid peroxidation in human low density lipoprotein. Feeding with black tea in normal rats for sixty days increased their antioxidant activity and their liver microsomes were shown to be protected against peroxidation of lipids as stimulated by metal ions with enzymic or non enzymic reactants. Furthermore feeding with tea extracts in normal as well as triton WR-1339 induced hyperlipidemic rats caused decrease in their plasma levels of total cholesterol, phospholipids and triglycerides. The antioxidant and lipid lowering activities of both extracts from CTC leaf and dust tea was comparable and may be due to the presence of natural products like catechin and others. PMID- 23105516 TI - Effect of ocimum flavonoids as a radioprotector on the erythrocyte antioxidants in oral cancer. AB - Flavonoids extracted from the leaves of Indian holy basil, Ocimum sanctum showed promising results as radioprotector in rodents. Hence it was thought pertinent to analyze the antioxidants of erythrocytes in oral cancer patients who were concurrently treated with radiation and ocimum flavonoids. Oral cancer patients consisted of 2 groups. Group A (n=17) received radiation alone while Group B(n=17) received radiation and ocimum flavonoids(OF). Samples of heparinised blood were collected prior to treatment, 15 and 30 days respectively after treatment. Blood from normal healthy volunteers were taken as controls (n=25). Erythrocytes were analyzed for the antioxidants viz. glutathione, glucose 6 phosphate dehydrogenase, glutathione peroxidase and superoxide dismutase by the standard methods. Results of analysis indicated that erythrocytes from cancer patients (Group A and B) had significantly high glutathione levels before as well as after treatment compared to controls. It was observed that Group B which received OF showed a significant reduction in glutathione levels in comparison with Group A. All the other parameters showed no statistical significant changes. Results of the study suggest that erythrocytes from cancer patients responded to oxidative stress by elevating glutathione levels, while a decrease in glutathione levels observed in Group B, could be due to the free radical scavenging effect of OF, sparing the glutathione. However OF did not seem to exert its effect on other antioxidants of erythrocytes. PMID- 23105517 TI - Usefulness of serum CA 15.3 and histopathological prognostic indices in breast cancer. AB - Prognostic factors influence the modality and course of therapy in breast cancer. These include both histopathological and biochemical variables. This study was aimed to find out if any correlation exists between the biochemical tumor marker serum CA 15.3, and the lymph node staging of Nottingham's Prognostic Index (NPI). It was observed that serum CA 15.3 showed a statistically significant correlation with lymph node staging of NPI. Therefore it is concluded that CA 15.3 can be utilized as a useful prognostic marker, particularly in cases where histopathological variables such as tumor size and grade have been altered by pre operative chemotherapy. PMID- 23105518 TI - Antral and duodenal disaccharidases in patients of duodenal ulcer and non-ulcer dyspepsia. AB - Duodenal ulcer is a common disease and is considered acid-peptic disease. Duodenal ulcer patients are known to have higher incidence of antral gastritis and duodentitis than general population. Thus one can expect some alteration in the enzyme products of mucosal cells of antrum and duodenum in this condition. The present study was planned in 30 patients of duodenal ulcer and 30 of non ulcer dyspepsia. After overnight fast, upper gastrointestinal endoscopy was done using forward viewing fibreoptic endoscope. Two pairs of biopsies were taken from the antrum and two from the descending duodenum using standard biopsy forceps. One pair of biopsy from each site was taken in 10% formal saline for histopathological examination. One pair of biopsies from each site was collected in saline for the measurement of disaccharidases by Dahlquist method. Activities of lactase, sucrase and maltase were significantly higher in descending duodenum mucosa as compared to antral mucosa in both groups. Activities of these enzymes in antrum and duodenum of both groups did not differ significantly. No significant difference was found in disaccharidases in antrum and descending duodenum in patients with or without histological gastritis. This study suggests that the disaccharidases do not change in antrum and duodenum of ulcer patients as compared to the patients with non-ulcer dyspepsia. PMID- 23105519 TI - Semen characteristics: Advancement in andrological assessment. AB - Progress in diagnosis of infertility, has been dramatically increased during the past decades with changes occurring in virtually all aspects of infertility research, thus providing innovative diagnostic testing and sophisticated instrumentation for improved management and treatment of infertility. There are about 50% of infertile couples who are suffering because of male infertility. Semen examination is a basic investigation for these infertile couples. It not only reveals the quantity and quality of sperm but also the quality of the seminal plasma, which is essential for normal sperm function. In this review, the recent advancement in investigation procedures has been analyzed which are very important in clinical practice to (a) evaluate the sperm fertilizing ability (Acrosin, aniline blue, HOS), (b) characterization of male accessory sex glands secretions (Fructose, alpha-glucosidase, PSA) and (c) the management of azoospermic patients. It is believed that use of such diagnostic procedures will facilitate wide selection of patients for whom an effective therapy might be then possible. PMID- 23105520 TI - Polymorphonuclear leukocyte mediated oxidative inactivation of alpha-1-proteinase inhibitor: Modulation by nitric oxide. AB - Alpha-1-proteinase inhibitor activity was studied in presence of resting and activated polymorphonuclear leucocytes. Four different agonists; phorbol myristic acetate, N-formyl-methionyl-leucyl-phenylalanine, opsonised zymosan and arachidonic acid decreased the inhibitor activity by 23.3%, 20%, 12% and 16.6^ respectively. The inhibitor activity was protected by using various free radical scavengers. Catalase and superoxide dismutase both restored activity by about 18%, mannitol by 13% and sodium azide by 17.3%. The inhibitor activity was also protected significantly by pretreatment of polymorphs with L-Arg, a precursor of nitric oxide, before activation. L-Arg was also observed to suppress the generation of superoxide and hydroxyl radical appreciably. The nitric oxide synthase inhibitor, aminoguanidine drastically inhibited the nitrite release and reversed the protection offered by L-Arg to the inhibitor activity. Our results indicate a multifactorial nature of the inactivation process, the culprit species being superoxide, hydrogen peroxide, hydroxyl radical and hypohalides. Nitric oxide seems to scavenge the superoxide radical directly after its formation rather than inhibiting its generation by NADPH oxidase as was believed earlier. PMID- 23105521 TI - A case of IgA multiple myeloma: Nutritional perspective in diagnostic testing. AB - A 64-year-old security guard and longstanding known hypertensive presented with hypertensive heart disease (HHD), weight loss, an enlarged prostate, and a spontaneously fractured rib. Malignancy of the prostate with possible metastases to the ribs was strongly suspected. Biochemical profiling revealed a paraprotein. Other biochemical and hematological correlates that were on hand before serum protein electrophoresis were rather atypical. Paraprotein studies by immunofixation revealed IgA myelomatosis. Unlike previous reports from Caucasians there was normocalcaemia, normal protein level, microcytic hypochromia, low MCHC, cholesterol level at the lower limit of the reference range and normal urea level (in the face of markedly raised creatinine level). Nutritional modulation of the classical laboratory features of this disease may account for the fairly atypical laboratory picture.The need to appreciate the influence of nutritional status on the laboratory (especially biochemical) features of a disease and thus interpretation of diagnostic tests appears of exceptional current importance, given the widening gap in socioeconomic status and the level of poverty between the resource poor and developed countries from which the classical, clinical and laboratory features of most diseases were first described.This case report reminds of the need not only to recognize theoretically the impact of nutritional status on the laboratory characteristics of a disease but of the practical application of the nutritional perspective in the interpretation of diagnostic investigations, especially in nutritionally disadvantaged communities. PMID- 23105522 TI - Plasma antioxidant vitamins and lipid peroxidation products in pregnancy induced hypertension. AB - It has been suggested that antioxidant systems are impaired in pregnancy induced hypertension and hence patients are exposed to oxidative stress. In order to investigate the relationship between lipid peroxidation and certain antioxidant parameters in blood of pregnancy induced hypertension (PIH) cases, 25 normotensive and 23 PIH samples were studied. In the present study, thiobarbituric acid reactive substances showed a tendency to increase, however the increase remained statistically insignificant. Plasma ascorbic acid level remained unaltered and Vitamin E showed a tendency to increase in the study group. The findings implicate oxidative stress in the disease and cite the biochemical rationale for clinical trials of antioxidants to prevent and treat pregnancy induced hypertension. PMID- 23105523 TI - Healthcare biotechnology in India. AB - Biotechnology in India has made great progress in the development of infrastructure, manpower, research and development and manufacturing of biological reagents, biodiagnostics, biotherapeutics, therapeutic and, prophylactic vaccines and biodevices. Many of these indigenous biological reagents, biodiagnostics, therapeutic and prophylactic vaccines and biodevices have been commercialized. Commercially when biotechnology revenue has reached $25 billions in the U.S. alone in 2000 excluding the revenues of biotech companies that were acquired by pharmaceutical companies, India has yet to register a measurable success. The conservative nature and craze of the Indian Industry for marketing imported biotechnology products, lack of Government support, almost non existing national healthcare system and lack of trained managers for marketing biological and new products seem to be the important factors responsible for poor economic development of biotechnology in India. With the liberalization of Indian economy, more and more imported biotechnology products will enter into the Indian market. The conditions of internal development of biotechnology are not likely to improve in the near future and it is destined to grow only very slowly. Even today biotechnology in India may be called to be in its infancy. PMID- 23105524 TI - Identification and characterization of polyubiquitin gene from cDNA library of aspergillus fumigatus. AB - Aspergillus fumigatus (Afu) causes allergic and invasive forms of diseases in humans. In order to identify genes relevant for pathogenesis, a total of 235 cDNA clones were randomly selected and sequenced from cDNA library of Afu. One of the partially sequenced cDNA clones was homologous to polyubiquitin. Sequencing of the complete cDNA clone showed an open reading frame of 912 bases. Comparison with genomic sequence of Afu using BlastN program, revealed that polyubiquitin gene comprises of 992 bases and contains one intron of 80 bases. The recombinant expression of fusion protein showed an approximately molecular weight of 43-kDa on SDS-PAGE. The translation product of the cDNA sequence showed four tandem repeats of 76 amino acid residues in a single polyubiquitin protein and showed 100% identity with polyubiquitin protein sequences of S. cerevisiae, N. crassa, C. albicans, S. pombe, and M. grisae. Polyubiquitin gene is known to play important role in a variety of cellular processes and recently have been implicated in fungal pathogenesis. Identification of polyubiquitin gene of Afu has opened up scope to study its role in understanding Aspergillus biology and pathogenesis. PMID- 23105526 TI - Effect of low-dose omega-3 fatty acids substitution on blood pressure, hyperinsulinemia and dyslipidemia in Indians with essential hypertension: A pilot study. AB - The present study comprised 100 patients of essential hypertension who were screened for fasting hyperinsulinemia, which was detected in 77% cases. Twenty such hyperinsulinemic cases were subjected to 4 weeks of dietary control phase followed by 6 weeks of omega-3 fatty acids substitution [either 0.6 g/d (group 1) or 1.2 g/d (group 2)]. The mean basal fasting plasma insulin levels were significantly higher (p<0.001) in patients of hypertension when compared to normal controls (126.51+/-80.36 and 19.35+/-12.61 MUU/ml respectively). At the end of 4 weeks of diet control only, no significant change was observed in any parameter. After substitution of omega-3 fatty acid, a significant reduction of fasting plasma insulin levels in both group 1 (29%) and group 2 (22.8%) was observed (p<0.001). Significant reduction of systolic and diastolic blood pressure (16.4% and 25% respectively), serum cholesterol, triglycerides and low density lipoprotein was also noted in both groups (p<0.001), while high density lipoprotein increased by ~8 mg% in both groups. Thus omega-3 fatty acid substituion in low dose along-with curtailment of dietary omega-6 fatty acid may be used as an adjunctive measure in the management of essential hypertension. PMID- 23105525 TI - New dimensions in vaccinology: A new insight. AB - The development of vaccines to prevent infectious diseases has been one of the most important contributions of biomedical sciences. Increasing understanding in biochemistry, molecular biology, molecular genetics and related fields have provided an opportunity for the development of new generation vaccines that are based on rational design approaches. This is possible because of proper understanding of the microbial-genetics, biochemistry, host-pathogen interaction and recent developments in molecular immunology. Another important improvement made in the quality of vaccine production is the incorporation of immunomodulators or adjuvants with modified delivery vehicles viz liposomes, Iscoms and microspheres apart from alum being used as a gold standard. This article reviews the art of vaccination from Jenner period to present day context highlighting all the developments made at each stage of the vaccine development. Various criteria have been discussed regarding the selection of epitopes that expand B & T cells, its linkage with other accessory cells of the immune system, means to overcome MHC linked immune unresponsiveness, enhanced antigen processing and presentations that specially induce either helper or cytotoxic or mucosal immune responses were critically discussed. PMID- 23105527 TI - Prevalence of insulin resistance in first degree relatives of type-2 diabetes mellitus patients: A prospective study in north Indian population. AB - A total of 172 first degree relatives (FDRs) and 178 controls were included in this study. All the cases and controls were subjected to various anthropometric measurements, fasting and postprandial glucose estimation, fasting insulin measurement and fasting lipid profile. Results revealed the prevalence of Impaired Fasting Glucose (IFG) (cases 37% Vs controls 11.6%), Impaired Glucose Tolerance (IGT) (cases 34.3% Vs controls 11.2%) and diabetes (cases 11.05% controls 3.37%) was significantly higher in first degree relatives. Insulin resistance was measured using various methods, which included fasting plasma insulin (FPI), Homeostasis Model Assessment for Insulin Resistance (HOMA(IR)), insulin sensitivity index (ISI) (Mffm/l). Prevalence of insulin resistance (Insulin Resistance) as observed comparing FPI and HOMA(IR) in cases and controls was 43.6% and 11.24% (P=0.005) and 37.8% and 12.47% (P=0.000) respectively. Prevalence of IR (Insulin Resistance) observed in cases having Normal Glucose Tolerance (NGT), Impaired Fasting Glucose (IFG), Impaired Glucose Tolerance (IGT) and diabetes mellitus measuring FPI Vs HOMA(IR) was 37.5% vs 30.2%, 45% vs 40%, 38.98% vs 37.28% and 36.84% vs 31.57% as accordingly. However, ISI (Mffm/l) was not found to be a promising index for IR due to its poor specificity. Though HOMA is taken as gold standard for measurement of IR globally, our study observed fasting plasma insulin representing high sensitivity (89.7%) and specificity (93.3%) as compared to HOMA. Thus FPI had emerged in this work as a simple and reliable test for diagnosing insulin resistance across the population susceptible to develop diabetes including FDRs. PMID- 23105528 TI - Study of lipid profile from RIQAS quality control sample. AB - The laboratory of the present author is a participant of Randox International Quality Assessment Scheme (RIQAS). The author receives twenty six samples for thirty nine general chemistry analysis per year, reports of which are to be sent fortnightly. Amongst thirty nine analytes there are partial lipid profile parameters like total cholesterol and triglycerides. So, the author decided to run a pilot study of full lipid profile from these samples. At the first phase four samples from two different cycles were considered as test materials. The reports of these samples were quite satisfactory. The trial run was given for fifteen consecutive days. (Presented by the author in the Annual Conference of ACBI, 2004).The success of trial runs for fifteen days proved that EQA samples from RIQAS may be used for full lipid profile analysis. Results were compared against Randox internal quality control samples (IQA) and were found to be accurate and reproducible. PMID- 23105529 TI - Monitoring oxidative stress in patients with non-alcoholic and alcoholic liver diseases. AB - Ethanol-induced liver injury may be linked, at least partly, to an oxidative stress resulting from increased free radical production and/or decreased antioxidant defence. Distinguishing alcoholic and non-alcoholic liver disease has important implications. This study looked at the possible changes between alcoholic and non-alcoholic liver diseases by examining the presence of oxidative damage, as monitored by several parameters relating to oxidative stress. Lipid peroxides concentration, superoxide dismutase activity and glutathione S transferase activity increased, where as glutathione content, glutathione peroxidase activity and glutathione reductase activity decreased among the tested subjects in comparison to normal healthy group. Determination of these parameters may be valuable in the evaluation of liver disease. However, oxidative stress related enzymes and non-enzymes can not be utilized as a marker for alcoholic liver diseases, as these parameters responded in the same way after liver is damaged irrespective of their cause. Their level may help in determining the degree of liver damage. Degree of oxidative injury was similar in patients with non-alcoholic liver disease and in moderate drinkers; while significantly higher in heavy drinkers. The differences between the groups might be based on the type of liver pathological condition rather than its etiology (i.e. alcohol and non alcohol related causes). PMID- 23105530 TI - Rat serum electrolytes, lipid profile and cardiovascular activity onNauclea latifolia leaf extract administration. AB - Aqueous extract of the leaf and root ofNauclea latifolia Sm. (Rubiaceae) is used in Nigerian folk medicine for the treatment of hypertension. This work is carried out to investigate the effect ofNauclea latifolia leaf extract on lipid profile and cardiovascular activity of rats. Normal and 10% coconut oil fed rats were treated with the water-soluble fraction of the ethanol extract ofNauclea latifolia leaf for 2 weeks. Forty-eight mature male albino rats of the Wistar strain were divided into two experiments of four groups, each group having 6 animals. Experiment I animals were treated with the water-soluble fraction of the ethanol extract whilst experiment II animals were fed 10% coconut oil meal before treatment with the water-soluble fraction of the ethanol extract. A single oral dose ofNauclea latifolia was 170, 340 and 510 mg/kg body wt/day of the extracts respectively for 2 wks. There was no significant change in the lipid profile of the experimental animals as compared with the controls. There was about 40% relaxation on contracted thoracic aorta that was pre-contracted with 2 MUM phenylephrine. The viability of the tissue was tested against 10 MUM of acetylcholine. There was no significant (P>0.05) change in Na(+) concentration in the serum. However, the K(+) concentration in the serum of the experimental animals showed a significant increase. The study shows that ethanol extract ofNauclea latifolia has vasodilator action on the aorta and that lipid profiles of experimental rats were not affected. Furthermore, the increase in the K(+) may be contributing to the vasodilator effect ofNauclea latifolia. PMID- 23105531 TI - Impact of iodine deficiency on thyroid function in pregnant African women - A possible factor in the genesis of 'small for dates' babies. AB - The effect of iodine deficiency (ID) on thyroid function in African women during pregnancy and postnatal period was examined, for which very limited information is available. Serum T(4), T(3), TSH, TBG, thyroxine binding capacity (TBK), free thyroxine index (FT(4)I=T(4)/TBK) and T(4)/TBG were determined by ELISA technique in 32 pregnant women (resident of Plateau state, Nigeria- an ID zone) through pregnancy upto term delivery, and in 5 women up to 6 weeks post delivery. Urinary iodide level was measured at delivery to determine the degree of iodine deficiency. Results were matched with a non pregnant control comprising 44 subjects. 5555 birth weights (BW) of term babies in the region were analysed to determine the prevalence of 'small for dates' (SFD) babies in the population. Results show that the level of serum FT(4)I was elevated very significantly at late gestation (P<.001) but the women were not hyperthyroid, suggesting a marked disturbance in binding of T(4) with TBG during pregnancy. Five women with SFD babies were found in 'compensated hypothyroid state' and showed a significant depression (p<.01) in serum T(4)/TBG, T(4), FT(4)I and T(3) levels to a low normal range, with a concurrent significant rise (p.<.001) in TSH level (above normal range) throughout pregnancy. Incidence of SFD babies was higher (p.<.001) in ID zone (Bassa 15.2%) compared to control zone (Jos 9.8%). It is concluded that a state of maternal 'subclinical (compensated) hypothyroidism' during pregnancy possibly plays an important role in the aetiopathogenesis of SFD babies in Africans. A normal reference range for thyroid parameters at various stages of pregnancy in healthy African women is established for the first time. PMID- 23105532 TI - Role of heat stable fraction of alkaline phosphatase as an adjunct to ca 125 in monitoring patients of epithelial ovarian carcinoma. AB - Heat stable fraction (HSF) of alkaline phosphatase (ALP) was evaluated as an adjunct to CA 125 as a tumour marker for epithelial ovarian cancer in a follow-up study. In our study group 63.4% of patients had elevated HSF levels (>=10U/L) and 93.3% had elevated CA 125 levels (>35U/mL). The sensitivity of CA 125 and HSF was 93.3% and 63.3% respectively. The decline in the activity of HSF, over the pre-op levels was highly significant after the first (p=0.001) chemotherapy cycle and significant after the second and third cycles (p<0.029). Thereafter, HSF activity was almost undetectable. The decrease in CA 125 levels over the pre-op levels was significant after the first, second, third (p<0.001) and fourth (p<0.034) chemotherapy cycle. HSF can be used alone or as an adjunct to CA 125 in screening and monitoring patients of ovarian carcinoma especially in remote areas where sophisticated facilities are not available and in patients in which CA 125 levels are not raised preoperatively. PMID- 23105533 TI - Protein nanotechnology - A powerful futuristic diagnostic technique. AB - Healthcare can be maintained well, when diagnosis is quick, accurate, cost effective and painless. DNA and RNA based diagnosis may not reveal the right information for certain diseases. Identification and quantification of proteins and their folding mechanism are very important in diagnosis of diseases. Small quantities of proteins, which generally escape from detection and are responsible for the diseases, now can be quantified by protein nanotechniques which aids in the diagnosis. In this review, we have summarized the recent developments in nanotechnologies such as protein microarrays, biosensors etc. and their application in diagnosis of diseases at proteomics level have also been discussed. PMID- 23105534 TI - Comparison of two methods of estimation of low density lipoprotein cholesterol, the direct versus friedewald estimation. AB - Current recommendations of the Adult Treatment Panel and Adolescents Treatment Panel of National Cholesterol Education Program make the low-density lipoprotein cholesterol (LDL-C) levels in serum the basis of classification and management of hypercholesterolemia. A number of direct homogenous assays based on surfactant/solubility principles have evolved in the recent past. This has made LDL-C estimation less cumbersome than the earlier used methods. Here we compared one of the direct homogenous assays with the widely used Friedewald's method of estimation of LDL-C to see the differences and correlation. We used direct homogenous assay kit to estimate serum LDL-C and high-density lipoprotein cholesterol (HDL-C). Serum Triglyceride (TG) and Total Cholesterol (TC) was estimated and using Friedewald's formula LDL-C was calculated. The LDL-C level obtained by both methods in 893 fasting serum samples were compared. The statistical methods used were paired t-test and Pearson's correlation.There was significant difference in the mean LDL-C levels obtained by the two methods at the TG levels <200 mg/dl (p<0.02) and TC levels >150 mg% (p<0.001). The correlation coefficient (r) between Friedewald's and direct assay estimation was 0.88. Friedewald's method classified 23.5 % of patients as high cardiac risk whereas there were 17.58% by direct assay.Both had good correlation even though the serum triglyceride and total cholesterol levels affect the difference in LDL C estimated by both methods. Taking into account the cost and performance, Friedewald's method is as good or even better for classifying and managing patients. PMID- 23105535 TI - Role of oxidative stress in ethanol induced germ cell apoptosis - An experimental study in rats. AB - The study was undertaken to evaluate the possible involvement of oxidative stress in the pathogenesis of ethanol induced testicular atrophy in rats. Adult male rats were orally administered ethanol at a dose of 1.6 g/kg body weight/day for four weeks. Twenty-four hours after the last treatment the rats were sacrificed using anesthetic ether. Testes were removed and weighed. Apoptosis was studied by using the Feulgen reaction on 5 MU thin paraffin sections of testis. Testicular homogenate was prepared and centrifuged. The supernatant was used for the estimation of extent of lipid peroxidation and antioxidant defense status. There was significant reduction in body weight: and in testicular weight and diameter in ethanol treated rats. Extent of germ cell apoptosis was significantly high in ethanol treated rats. Ethanol treated rats showed significantly high tissue TBARS level and glutathione S-transferase activity; and low tissue ascorbic acid, reduced glutathione, superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities. Chronic ethanol administration resulted in high oxidative stress in the testes either due to increased extent of lipid peroxidation or due to decreased antioxidant defenses, and thereby induces germ cell apoptosis leading to testicular atrophy. PMID- 23105536 TI - Role of bilirubin, vitamin C and ceruloplasmin as antioxidants in coronary artery disease [CAD]. AB - A study has been carried out on 250 CAD patients to see how the serum levels of three antioxidants i.e., Vitamin C, Bilirubin and Ceruloplasmin are related to the CAD risk factors and characteristics in these patients. The number of severe category CAD patients declined by 7-18% with increasing serum levels of the three antioxidants and, triple vessel disease declined by 14-20%. A decline of 39% in Myocardial Infarction (MI) occurred with increasing serum Ceruloplasmin. Serum Ceruloplasmin was significantly lower in the MI group compared to the non MI group CAD patients. There was a steady and a significant decline in the mean values of serum levels of cholesterol, Triglyceride, VLDL cholesterol along with BMI with increasing serum level. The study indicates that with increasing serum levels of the three antioxidants studied, the % MI along with % Triple vessel disease and severity of CAD goes down suggesting that the modifiable risk factors have to be suitably modified in order to maintain a reasonably high level of these antioxidants, as the risk factors are inversely related to the serum antioxidant levels. PMID- 23105537 TI - Risk factors for coronary heart disease in type II diabetes mellitus. AB - Cardiovascular complications are the major cause of morbidity and mortality in diabetic patients. An attempt has been made to evaluate the risk factors for coronary heart disease in type II diabetics. In the present study the levels of fasting and postprandial plasma glucose, total cholesterol, low density lipoproteins, triglycerides were high and the levels of high density lipoproteins were low in the type II diabetics compared to controls. The markers of free radical induced injury i.e. malondialdehyde and nitrite/nitrate were high while total antioxidant status a marker for antioxidant protection against reactive oxygen species was low in diabetics compared to controls. The study therefore suggests the importance of assessing these markers of oxidative stress and antioxidant capacity along with the other routine investigations in diabetic patients for initiating antioxidant therapy in addition to primary and secondary preventive measures to mitigate the devastating consequences of diabetes leading to coronary heart disease. PMID- 23105538 TI - Correlation between chemical components of billary calculi and bile & sera and bile of gallstone patients. AB - Total cholesterol, total bilirubin, calcium, oxalate, inorganic phosphate, magnesium, iron, copper, sodium and potassium were analyzed quantitatively in gallstones, bile of gall bladder and sera of 200 patients of cholelithiasis (52 cholesterol, 76 mixed and 72 pigment stone patients) and their contents were correlated between calculi and bile and sera and bile in these three type of stone patients. A significant positive correlation was observed between total cholesterol, total bilirubin of calculi and bile, copper of bile and sera of cholesterol stone patients, copper of calculi and bile, total bilirubin, oxalate, magnesium, potassium of sera and bile of pigment stone patients and oxalate and iron of stone and bile, total bilirubin, oxalate, sodium of sera and bile of mixed stone patients. A significant negative correlation was found between magnesium of serum and bile of cholesterol stone patients, oxalate of calculi and bile of pigment stone patients and magnesium of serum and bile of mixed stone patients. PMID- 23105539 TI - Seminal plasma levels of 15-F2alpha-isoprostane, malondialdehyde and total homocysteine in normozoospermic and asthenozoospermic males. AB - It has been proposed that oxidative stress plays an important role in male infertility. The aims of this study were to compare seminal plasma levels of 15 F2t-isoprostane (8-iso-PGF2alpha), malondialdehyde (MDA), and total (sum of free and bound) homocysteine (tHcy) from normozoospermic vs. asthenozoospermic men, and to examine the relationships between tHcy and lipid peroxidation products. The study was a case-control study with a simple random sampling. The case group was consisted of 15 asthenozoospermic males. This group was compared with 15 normozoospermic men. Seminal plasma levels of 15-F2alpha-isoprostane and tHcy were measured using commercially available enzyme immunoassay (EIA) kits. MDA levels were determined by the thiobarbituric acid (TBA) assay. The Mann-Whitney U test was used to compare two groups. Coefficients of correlation were calculated using Spearman's correlation analysis. All hypothesis tests were two-tailed with statistical significance assessed at the p value <0.05 level. MDA levels were higher in asthenozoospermic subjects than in control subjects (0.72+/-0.06 MUM vs. 0.40+/-0.06 MUM; p<0.05). No differences were seen in 15-F2alpha-isoprostane levels in asthenozoospermic subjects and controls (65.00+/-3.20 pg/ml vs. 58.17+/ 4.12 pg/ml; p>0.05). Interestingly, tHcy levels were to be slightly higher in asthenozoospermic subjects than in controls (6.18+/-1.17 MUM vs. 4.8+/-0.52 MUM). Sperm motility was inversely correlated with seminal plasma 15-F2alpha isoprostane and MDA levels, respectively (p<0.05). In summary, seminal plasma levels of 15-F2alpha-isoprostane and tHcy showed no significant difference between normozoospermic and asthenozoospermic men. Sperm motility was not correlated with seminal plasma levels of tHcy. No relationship was found between tHcy and lipid peroxidation. PMID- 23105541 TI - Subtypes of ADH2 gene in alcoholics. AB - Alocholism is the multifactorial disease influenced by genetic environmental interaction and genetic variation of the genes may be associated with alcohol dependence due to its modified function in behavioral and physiological responses. In the present study, genetic variation was detected in the subtypes of gene, coding for the alcohol metabolizing enzyme Alcohol Dehydrogenase 2 (ADH2). Blood samples were collected from the alcoholic and non alcoholic subjects and genotyping was performed using PCR-RFLP (Polymerase Chain Reaction Restriction Fragment Length Polymorphism), analysis to determine genetic polymorphisms in the ADH2 gene subtypes. The three subtypes of ADH2 gene (ADH2.1, ADH2.2 and ADH2.3) were found in both alcoholics (Family History Positive and Family History Negative) as well as non alcoholics. PMID- 23105540 TI - Molecular mechanism of pathogenesis of dengue virus: Entry and fusion with target cell. AB - Dengue fever is one of the major health problems in India. Interaction with specific receptor(s) at the cell surface is one of the first events in the pathogenesis of Dengue virus. However, relatively little is known about these receptors. Cellular receptors in human monocytes and mouse neural cells are main target for the viral infection. The envelope protein of the virus (E-protein) plays important role in attachment of virus to target cells and their interaction with cellular receptors. The modulation of receptor gene(s) and/or protein(s) can be used as a method for interfering with virus entry and can thus become a new method for disease prevention. The receptors can be purified by affinity chromatography using E-protein as ligand. It has been reported that addition of highly sulfated heparan sulfate prevents E-protein binding to target cells suggesting that heparan sulfate is utilized by dengue envelope protein to bind to target cells. PMID- 23105542 TI - Establishment of reference intervals in Indian population. AB - The central role of the laboratory scientist is to aid the clinician, in interpreting observed values, by providing relevant reference values in a convenient and practical form. In India, reference values used in laboratories have been established in the western population. But these can be questioned due to differences in genetic load, lifestyle, and diet. This review highlights the approach for establishing reference values in our population using the IFCC guidelines and our observations from our data as compared to the reported values in our laboratory. PMID- 23105543 TI - Iron deficiency anaemia: Effect on congnitive development in children: A review. AB - Iron deficiency evolves slowly through several stages. Early iron deficiency caused a depletion in iron stores as shown by a reduction in the levels of hepatic non-heme iron in the new born of iron deficient mothers. Of particular importance is the effect on central nervous system, which leads to the defects in the cognition and learning processes in humans. Evidence is strong that in many under developed countries iron deficiency is the main cause of anaemia and supplementation under trial conditions may prevent some defects of iron deficiency but not all. PMID- 23105544 TI - Urinary enzymes in nephrotic syndrome. AB - Tubular damage is a complication associated with nephrotic syndrome and increased levels of urinary enzymes are of significant value in detection of the same. The aim of our study was to evaluate the use of urinary lysozyme and trehalase as markers of tubular dysfunction in nephrotic syndrome. This study assessed 35 nephrotic syndrome patients and 30 healthy controls matched for age and sex. Urine samples were examined at pretreatment and post treatment (8 weeks) stages for proteinuria, lysozyme and trehalase. At pretreatmant stage there was significant increase in urinary lysozyme and trehalase as compared to controls (p<0.001). A good correlation was observed between degree of proteinuria and urinary lysozyme (p<0.001;r=0.80) and trehalase (p<0.001; r=0.74). At the end of 8 weeks of treatment, the patients showed significant decrease in their urinary lysozyme and trehalase activity (p<0.001) but no correlation with degree of proteinuria was observed. Our results indicate that enzymes like lysozyme and trehalase can be used as markers of tubular dysfunction. PMID- 23105545 TI - Catalase: A repertoire of unusual features. AB - Catalases are antioxidant enzymes which catalyze the breakdown of hydrogen peroxide to water and oxygen, and are one of the oldest enzymes to be studied biochemically. The first crystal structure of a catalase appeared in the year 1980 and it revealed the tetrameric nature of the enzyme and presence of channels accessing the deeply buried active site heme. An interesting feature of the tetrameric structure is the characteristic interweaving or arm exchange of the subunits. The recent elucidation of the crystal structure of transport proteins (porins, aquaporins) showed that these proteins are also tetrameric in nature and posses channels. However, recent specific investigations focusing on the roles for these channels, in the mechanism of enzyme action of catalases, revealed significant similarities with that observed for the transport of water and/or glycerol, in aquaporins. PMID- 23105546 TI - Production of recombinant enveloped structural proteins from the Chinese WSSV isolate. AB - The white spot syndrome virus (WSSV) is one of the deadly pathogens of penaeid shrimps and other crustaceans. The WSSV virion consists of an enveloped rod shaped nucleocapsid enclosing a large circular double stranded DNA genome of 305 Kb with 181 open reading frames. The two major structural genes, VP19 and VP28 were amplified from the genomic DNA of Chinese isolate of WSSV and cloned in pUCm T vector and sub cloned in pET-30a (+) vector. The expressions of genes inE. coli (BL21) were confirmed by SDS-PAGE analysis. The clones were sequenced, submitted to the gene bank and the Xiang Shan strain of WSSV were compared with the previous reported sequence of WSSV of various regions which revealed that VP19 and VP28 gene sequences had certain differences from the sequences of similar genes of the isolate already reported. The recombinant proteins expressed, purified and characterized. PMID- 23105547 TI - Neurohumoral alterations and their role in amoebiasis. AB - Amoebiasis is world wide in distribution and continues to be an important Public health problem. Intestinal amoebiasis may be present as dysentery, diarrhea or may stimulate other intra abdominal conditions. Clinical symptoms may not be seen in majority of patients, while amebic cysts are passed in the stool. This single celled parasite is transmitted to humans via contaminated water and food. Amoebic dysentery can be accompanied by amebic infection of the liver and other organs. The present study was carried out to evaluate the changes in the circulating levels of neurohumors, their metabolizing enzymes and cortisol in these patients both before and after one month of chemotherapy. In the patients of amoebiasis the circulating acetylcholine (ACh), histamine, histaminase, cortisol, 5-Hydroxy tryptamine (serotonin) levels were significnatly enhanced with no change in the Dopamine-beta-hydroxylase (DBH) activity, while the activities of erythrocyte aceytylcholinesterase (AChE) and plasma Monoamine oxidase (MAO) were found decreased in comparison to normal healthy controls. After one month of treatment all the parameters reverted towards their control values, while the level of plasma histaminase remained still significantly high. The normal DBH activity reflects that there is no alteration in the circulating catecholamine levels. while the alteration in the levels of histamine, serotonin and cortisol may be due to the nonspecific response of the body to the stress of the disease and the parasitic infestation. PMID- 23105548 TI - Standardization of a dilution method for cyclosporin (C2) estimation in renal transplant patients. AB - Accurate monitoring of blood cyclosporin C2 levels is vital to prevent over immunosuppression and acute renal toxicity in patients who receive organ transplant. The matrix used to dilute patients' C2 samples prior to the assay affected the final measured values. Hence there was a need to develop a method of dilution that would accurately estimate C2 levels when cyclosporin levels were beyond the calibration range of the method employed. Whole blood, cyclosporin free hemolysate and cell and protein free supernatant obtained after pretreatment of normal blood were used to dilute patients' C2 samples. C2 was measured in 188 patients using the supernatant method of dilution. C2 was correlated with Co and dose of cyclosporin received by the patient. The use of cell and protein free supernatant obtained after pretreatment of normal blood as a C2 diluent detected higher levels of C2 in the sample. Measured C2 correlated significantly with Co and the cyclosporin dose received by the patient. The uniformly aqueous cell and protein free supernatant ensures uniform dilution of the patients' C2 sample and measures higher cyclosporin levels. PMID- 23105549 TI - Antimicrobial activity ofTerminalia bellerica. AB - The antimicrobial activity of crude and methanol extract ofTerminalia bellerica dry fruit was tested by disc diffusion method, against 9 human microbial pathogens. Crude aqueous extract of dry fruit at 4 mg concentration showed zone of inhibition ranging from 15.5-28.0 mm.S. aureus was found to be highly susceptible forming highest zone of inhibition, suggesting thatT. bellerica was strongly inhibitory towards this organism. These pathogens were highly sensitive to the methanol extract forming 14.0 to 30.0 mm zone of inhibition suggesting that the methanol extract ofT. bellerica was more effective than crude extract against most of the microbes tested exceptE. coli (enteropathogen) andP. aeruginosa. The minimal inhibitory concentrations (MICs) of crude and methanol extracts were determined by broth dilution technique which ranged from 300 to >2400 MUg/ml and 250 MUg to >2000 MUg/ml respectively, indicating thatT. bellerica was highly effective againstS. aureus with lower MIC values. There were some biochemical alterations induced byT. bellerica. These results indicate thatT. bellerica dry fruit possesses potential broad spectrum antimicrobial activity. PMID- 23105550 TI - Changes in levels of serum glycoproteins in major depressive disorders. AB - The present study deals with estimation of levels of fractions of serum glycoproteins, protein bound hexose (PBH), protein bound hexosamine (PBHex), protein bound fucose (PBF), protein bound sialic acid (PBS) and protein bound carbohydrate (PBC) in thirty patients of Major Depressive Disorders (MDD) in comparison with thirty normal subjects. In patients of MDD, the level of PBH, PBHex, PBF, PBS and PBC were significantly higher as compared to the normal subjects (p<0.05). In patients, of MDD, after one-month treatment with fluoxetine, the levels of PBH, PBHex, PBF, PBS and PBC were significantly decreased as compared to the levels of these fractions in same patients of MDD before beginning of the treatment (p<0.05). Based on findings of the present study, it can be concluded that changes in the level of serum glycoproteins level before and after treatment with fluoxetine can be correlated with clinical status of MDD. PMID- 23105551 TI - Serum calcium measurement: Total versus free (ionized) calcium. AB - Measurement of serum free (ionized) calcium (Ca(++)) reflects true calcium status of the body in health and disease. Present study evaluates efficacy of Ca(++) over total calcium (CaT) in serum for calcium status. 52 subjects were enrolled for study. Anaerobic fasting blood sample for Ca(++) measurement and autoclaved plain bulb for estimation of CaT, Total protein (TP) and Albumin was used. CaT, Corrected CaT, Ca(++), Calculated Ca(++) were measured and correlated. Corrected CaT and calculated Ca(++) were derived from the measured parameters. Study group showed significant difference between CaT and corrected CaT (p<0.006), Ca(++) and calculated Ca(++) (p<0.001). Negligible correlation was observed between Ca(++) and serum protein. Positive correlation was observed between CaT and calculated Ca(++), TP and albumin. Findings indicate that Ca(++) levels are independent of serum protein status. With scrupulous sampling, Ca(++) may be a better parameter than presently used CaT for assessing calcium status in serum. PMID- 23105552 TI - Free radical injury and antioxidant status in patients with benign prostate hyperplasia and prostate cancer. AB - Reactive oxygen species and other free radicals are known to be the mediators of phenotypic and genotypic changes that lead from mutation to neoplasia. There are some primary antioxidants such as glutathione peroxidase (GPx), glutathione S transferases (GSTs) and reduced glutathione, which protect against callular and molecular damage caused by the reactive oxygen metabolites (ROMs). The present study was conducted to determine the level of malondialdehyde (MDA), as an index of lipid peroxidation, along with the GPx, GSTs activities and level of reduced glutathione in 45 prostate cancer (PC) patients, 55 benign prostate hyperplasia (BPH) patients as compared to the controls. Significant higher levels of MDA and GSTs activities in the serum, (P<0.005) and significant lower levels of reduced GSH concentration and GPx activity in blood haemolysates (P<0.05) of PC and BPH patients were observed as compared to the controls. The relatively higher GSTs activity and low level of reduced GSH may be due to the response of increased reactive oxygen metabolites production in the blood. The higher MDA and lower GPx activities may be inadequate to detoxify high levels of H(2)O(2) into H(2)O leading to the formation of the(*)OH radical followed by MDA. This result hypothesizes that oxidant-antioxidant imbalance may be one of the major factor responsible for the development of prostate cancer and benign prostate hyperplasia. PMID- 23105553 TI - Effect of pyridoxine (Vitamin-B(6)) supplementation on calciuria and oxaluria levels of some normal healthy persons and urinary stone patients. AB - Effect of pyridoxine (Vitamin-B(6)) supplementation on calciuria and oxaluria levels of 20 normal healthy persons and 17 urinary stone patients has been studied. Mean 24 hr urinary calcium and oxalate levels of controls (healthy persons) and stone patients were estimated in presupplementation period and at every 20 days interval during supplementation. Stone patients were divided into two groups viz., mild hyperoxaluriacs and moderate hyperoxaluriacs, based on their pre-supplementation (base line) oxaluria levels. 60 days of pyridoxine supplementation, at the rate of 10 mg/day, resulted in a significant decrease (p<0.01 for mild hyperoxaluriacs and p<0.001 for moderate hyperoxaluriacs) in mean 24 hr urinary oxalate levels of urinary stone patients. The corresponding decrement in mean oxaluria level of controls was, however, only mild. The decrease of mean calciuria level of controls as well as stone patients, upon pyridoxine supplementation, were also found to be only mild and not significant. Utility of pyridoxine therapy in oxalate urolithiasis has been discussed in the light of results. PMID- 23105554 TI - Use of specific IgE to fractions of gynandropsis gynandra pollen inin vitro diagnostic test. AB - The study was aimed at presence of specific IgE antibody levelsinvitro to the identified antigen. Based on positive skin test with Gynandropsis gynandra and elevated levels of total IgE (>325 IU/ml) 104 patients were selected. Healthy, asymptomatic individuals (25) with low total IgE (<325 IU/ml) were included as controls. The mean OD values by ELISA for specific IgE were 0.67+/-0.21, 0.57+/ 0.18 and 0.56+/-0.18 with whole pollen antigen, 46-37 kD fraction and 36-32 kD fraction, respectively. The specificity and sensitivity between skin test positivity with whole pollen antigen verses fraction with mol.wt 46-37 kD was 90% and 90% and for fraction with mol.wt 36-32 kD was found to be 81.1% and 89.4%. The clusters with molecular weights 46-37 kD and 36-32 kD may be useful inin vitro diagnostic test. Fractions within these clusters need to be identified for a higher specificity. PMID- 23105555 TI - A sensitive and economical modified method for estimation of cerebrospinal fluid proteins. AB - Cerebrospinal fluid protein estimation is a routine diagnostic tool for various diseases. The proposed modified bromocresol green (BCG) method is applicable to automated as well as manual measurements. Protein concentrations and absorbance at 600 nm are linearly related throughout a wide range of concentrations from 10 mg % to 2000 mg %. Ninety C.S.F. samples were analyzed and results obtained by both the modified BCG method and routine pyrogallol red method were compared. An excellent co-relation was observed (n=90, g=0.996, P<0.001). PMID- 23105556 TI - Urinary catecholamine metabolites: Capillary gas chromatography method and experience with 12 cases of neuroblastoma. AB - We propose a rapid, simple metodology for routine analysis of human urine to detect vanillylmandelic and homovanillic acid related to neuroblastoma. The assay were specific capillary gas chromatography with flame ionization detection. In this methodology an internal standard is used and the procedure involves ethyl ester formation without isolation of the compounds of interest. The run time is 36 minutes. We also report quantitative results for urinary vanillylmandelic and homovanillic acid in neuroblastoma patients, demonstrating the diagnostic value of this method. PMID- 23105557 TI - Thyroid hormones status during pregnancy in normal Iranian women. AB - Pregnancy is associated with significant, but reversible changes in thyroid function studies, which are among the most profound seen as a result of a normal physiologic state. The present study was carried out to find out alterations in thyroid function tests in each trimester in normal pregnant women as compared to non-pregnant women in Tabriz-Iran. A case-control study designed with 229 normal pregnant women that randomly selected from the first (64 samples), the second (92 samples), and the third (73 samples) trimesters and 250 randomly selected non pregnant healthy female controls. Age range in both groups was 16-40 years. Thyroid function tests carried out by measuring serum levels of thyroid stimulating hormone (TSH), free and total thyroxin (FT(4), TT(4)), and free and total triiodothyronine (FT(3), TT(3)) by commercially available radio immunoassay kits. We found that mean TT(4) increased progressively during pregnancy. Our study showed increasing in serum levels of TT(3) in the second trimester and then declining during the third trimester compared with non-pregnant women. We showed that FT(4) strongly decreased during the third trimester. Free T(3) showed declining in the second and third trimesters. Mean TSH did not show significant difference in each trimester compared with non-pregnant women. The thyroid function tests in pregnancy should be interpreted against gestational age-related reference intervals to avoid mis-interpretation of thyroid function during pregnancy. PMID- 23105558 TI - Laboratory accreditation-procedural guidelines. PMID- 23105559 TI - Incidence of microalbuminuria in tobacco chewers. AB - It is well established that smoking increases the risk for cardiovascular disease. From the studies in diabetic subjects it has been shown that smoking induces microalbuminuria and accelerates the progression to end stage renal disease. Little is known whether smoking is also related to microalbuminuria and renal end organ damage in non diabetic subjects. The hypothesis which was put forward that tobacco chewing is related to microalbuminuria and renal functional changes in non diabetic subjects. We therefore performed a population based study in the Anand city of Gujarat in which we studied the relation between tobacco chewing and urinary albumin excretion. Tobacco chewers had a higher urinary albumin excretion (Albumin excretion 373+/-13.9 mg/day: P<0.01) than those who do not consume tobacco. In conclusion tobacco chewing is associated with albuminuria. PMID- 23105560 TI - Iron store and free radicals in thalassemia. AB - Hyper-ferrous state is the result of multiple transfusions, whereby the iron excess in such conditions may be toxic to the organism. Patients suffering from thalassemia receive multiple transfusions. In the eastern part of India, both beta(0)-thalassemia and heterozygous Ebeta-thalassemia occur. This paper expresses the hyper-ferrous state, leading to iron overload in these two conditions and also reports the increased generation of free radicals, consequent to the iron overload. PMID- 23105561 TI - Evaluation of serum adenosine deaminase and 5'-nucleotidase activities as probable markers in ovarian cancer. AB - Adenosine deaminase (ADA) and 5'-nucleotidase (5'-NT) activities were measured in sera of patients with ovarian cancer and patients with benign ovarian tumour. The results were compared with that of a control group consisting of healthy women. ADA levels were significantly increased (P<0.001) in the ovarian cancer group (n=50) but not in the benign group (n=28) when compared to the controls (n=20). The results indicate that ADA and 5'-NT levels may help to differentiate malignant conditions from benign tumours of the ovary in addition to the existing tests such as serum CA-125 levels and histopathological study. PMID- 23105562 TI - Serum gamma glutamyl transferase (gamma-GT) activity in alcoholics with liver abscess and chronic alcoholics. AB - Gamma Glutamyl Transferase (gamma-GT) is a microsomal enzyme. Its activity in serum is assayed in alcoholics with liver abscess and alcoholics without liver abscess after screening by ultrasonography. The enzyme activity in serum is increased by 334% in the patients with liver abscess compared to normal control subjects (p<0.0001), and 172% when compared to patients with chronic alcoholism without liver abscess (p<0.0001). The enzyme activity was increased by 59.3% in the serum of patients without liver abscess compared to the normal control subjects (p<0.001). Measurement of gamma-GT in serum appears to be a sensitive index in the diagnosis of alcoholics with liver abscess. PMID- 23105563 TI - Detection of enzymes dehydrogenases and proteases inBrugia malayi filarial parasites. AB - Lymphatic filariasis caused mainly by infection fromW. bancrofti andB. malayi remains a major cause of clinical morbidity in tropical and subtropical countries. Analysis ofB. malayi mf, infective larval and adult worm lysates for the activity of enzymes led to the demonstration of activities of three key enzymes of carbohydrate metabolism viz., Malate dehydrogenase (MDH), Malic enzyme (ME) and Glucose-6-phosphate dehydrogenase (G6PDH) in all the three stages of the parasite. The specific activity of all the three dehydrogenases was significantly high in mf lysate compared to their activity in lysates of the other two stages (P<0.001). Analysis by native polyacrylamide gel to their activity inlysates of the other two stages (P<0.001). Analysis by native polyacrylamide gel electrophoresis (PAGE) using 7.5% non-gradient gel showed the presence of two isoforms of each of the three enzymes (MDH, ME & G6PDH) in mf lysate, while only one form of each enzyme was present in L(3) larval and adult worm lysates. Further proteolytic enzyme activity was demonstrated both in microfilarial and infective larval lysates ofB. malayi. While both mf and L(3) larval lysates showed optimal protease activity at alkaline pH of 9.0, the mf lysate showed increased activity also at pH 3.0. The infective larval lysate was markedly inhibited by Tosylamide-L-Phenylalanine chloromethyl ketone (TPCK), a thiol protease inhibitor, while the protease activity in mf lysate was significantly inhibited by both TPCK and a serine protease inhibitor Phenyl Methyl Sulphonyl Flouride (PMSF). In sodium do-decyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), using gelatin copolymerized gel, the microfilarial lysate showed 3 protease molecules of 40 kDa, 180 kDa and 200 kDa and the L(3) larval lysate had 6 protease molecules of 18, 25, 37, 49, 70 and 200 kDa size. PMID- 23105564 TI - Estradiol regulates insulin dependent stimulation of LDL-receptor expression in HepG(2) cells. AB - The low density lipoprotein, one of the major vehicle for extraneous cholesterol, internalizes into the cells through the process of LDL-receptor mediated endocytosis. The expression of LDL-receptor on the cell surface is a function of various hormone regulated transcription of the receptor gene. The present study elucidates the differential expression pattern of LDL-receptor protein in human hepatoma HepG(2) cells by the influence of two hormones, insulin and estrogen (beta-estradiol), as compared to the basal level expression of the receptor protein. The combined effect of insulin and beta-estradiol reveals that beta estradiol is the ultimate regulator between these two hormones and supershades the message of insulin on LDL-receptor expression. The receptor protein level immunobloted by anti LDL-receptor antibody after treating cells with insulin, beta-estradiol and mixture of both also reflects the same phenomena. This comparative study makes it consistent that cell saturation with sterol (beta estradiol) is the prime regulator of LDL-receptor expression between the two hormones, insulin and estrogen. PMID- 23105565 TI - Estimation of mRNA levels of interleukin (IL)-10, tumor necrosis factor (TNF) alpha, IL-4 and interferon (IFN)-gamma in HIV infected children in Mumbai. AB - Cytokines, viral load and opportunistic infections play an important role in HIV disease progression. Hundred children vertically infected with HIV were enrolled to determine mRNA levels of TNF-alpha, IL-10, IL-4 and IFN-gamma. These levels were estimated by amplifying cytokine mRNA from peripheral blood mononuclear cells. Severity of HIV was staged by the reduction in CD(4) (+) T cells and the onset of opportunistic infections. IL-10 mRNA levels were observed to increase with the severity. Despite the rising IL-10 mRNA levels, TNF-alpha mRNA levels increased with severity of HIV and decrease in CD(4) (+) T cell counts. IL-4 mRNA levels increased with the reduction in CD(4) (+) T cell numbers. Depleting mRNA levels of IFN-gamma contributed to the worsening of HIV disease. Increase in TNF alpha and IL-4 levels appended to the disease severity by upregulation of the viral replication. Increased IL-10 levels and decreased IFN-gamma levels predisposed the children to HIV associated opportunistic infections, which in return contributed to cytokine disarray. PMID- 23105566 TI - Isolation and culture of Leydig cells from adult rats. PMID- 23105567 TI - Prostate specific antigen in patients of benign prostate hypertrophy and carcinoma prostate. AB - Prostate Specific Antigen (PSA) has emerged as the most applicable and important tumor marker for carcinoma prostate. In the present study PSA was determined in serum of healthy subjects, patients of benign prostate hypertrophy (BPH) and Carcinoma Prostate (Ca-P) to evaluate its diagnostic efficiency in day to day management of prostate cancer patients and in differentiating patients of early prostate cancer from those with BPH. Receiver operating characteristic curve (ROC) revealed 2 ng/ml and 10 ng/ml cut off serum PSA level for BPH and untreated carcinoma prostate patients (Ca-P). An extremely significant increase (P<0.0001) was observed in mean PSA concentration in BPH patients and adenocarcinoma prostate patients when compared to healthy males. Clinical relevance of PSA was highlighted by a case study of cancer patient prior to any therapy till death. PMID- 23105568 TI - Effects of short-term hormone replacement on atherogenic indices in Indian postmenopausal women. AB - Indian ethnicity by itself is a strong risk factor for development of CAD in Indian postmenopausal women due to lower HDL levels as compared to Whites and women of oriental origin. We evaluated and compared the short-term effects of menopause, estrogen replacement therapy and combined estrogen and progestin replacement therapy on various atherogenic indices. 40 postmenopausal women, both surgical and natural (20 each) were selected. 10 surgical postmenopausal women were given 0.625 mg conjugated estrogens daily for 6 months and 10 natural postmenopausal women were given 0.625 mg conjugated estrogen with 2.5 mg medroxyprogesterone acetate daily. 20 women were included in the control group and given placebo. Fasting venous blood samples were analyzed for extended lipid profile and calculated atherogenic indices before starting the therapy and after 1,3 and 6 months. LDL and Apolipoprotein B increased (p<0.05) and those of Apolipoprotein A1 and HDL decreased in the control groups. In both the study groups levels of serum cholesterol and LDL decreased (p<0.05) and those of HDL and Apolipoprotein A1 increased (p<0.01). LDL/HDL, Apo B/ApoA1, Total Cholesterol/HDL decreased significantly (p<0.05) in both the study groups compared to the control groups. The effect of estrogen alone was more significant as compared to combination therapy. Log Triglycerides (TG)/HDL ratio showed a decrease in women on estrogen alone but the difference was not significant. Our study confirms that short term HRT has a favorable effect on atherogenic indices in Indian postmenopausal women. PMID- 23105569 TI - A comparative study of reactive oxygen species (ROS) related parameters in rat tissues. AB - Reactive oxygen species (ROS) are believed to be responsible for pathogenesis of various diseases affecting tissues and systems. ROS generated by mitochondrial electron transport chain as well as extra-mitochondrially are eliminated by the respective defense mechanisms. We checked the activity of ROS generating system such as xanthine oxidase and also the parameter of ROS defense mechanism e.g. superoxide dismutase (SOD), catalase, glutathione peroxidase (GPox), reduced glutathione content (GSH) and glucose-6-phosphate dehydrogenase (G6PDH) in mitochondrial and post-mitochondrial fractions from various tissues (liver, kidney, brain and heart) of normal rats. Extent of lipid peroxidation (LPO) which is immediate consequence of ROS generation was also examined. Our results shows that significant tissue-specific differences exist in mitochondrial and cytosolic ROS generating systems and ROS defense mechanisms. PMID- 23105570 TI - Sialic acid in cardiovascular diseases. AB - Sialic acid, the acylated derivatives of 9-carbon sugar neuraminic acid, present as terminal component of oligosaccharide chains of many glycoproteins and glycolipids, has been recognized to be involved in the regulation of a great variety of biological phenomena. Studies have shown that serum sialic acid predicts both coronary heart disease and stroke mortality and reflects the existence or activity of an atherosclerotic process. Most of the studies have shown an elevation in serum sialic acid concentration in coronary heart disease and a positive correlation between the raised serum sialic acid and the severity of the coronary lesions is observed. However, a few contradictory reports are also available. Racial differences in serum sialic acid have also been reported and correlated with international differences in the prevalence of atherosclerosis. Reduced sialic acid content of platelets, erythrocytes and lipoproteins may play important role in the pathogenesis of atherosclerosis. Elucidation of the mechanism of alternation in sialic acid concentration may throw more light on its potential clinical utility. Hence more studies are needed to designates sialic acid as a cardiovascular risk factor/marker. PMID- 23105571 TI - Effect of lecithin in the treatment of ethanol mediated free radical induced hepatotoxicity. AB - Alcoholic liver disease (ALD) develops as a consequence of priming and sensitizing mechanisms rendered by cross-interactions of primary mechanistic factors and secondary risk factors. Liver damage due to consumption of alcohol may be caused by oxygen radicals such as superoxide and hydroxyl radicals, generated during the metabolism of ethanol by the microsomal oxidizing system. Lecithin, an important class of phospholipids contains choline, which is considered as lipotropic factor. The effects of this lecithin as a hepatoprotective drug on body weight and antioxidant status of ethanol-exposed rats were studied. The results were compared with the effects of tocopheryl acetate. From the present study, it can be concluded that ethanol-induced stress can be partly prevented by tocopheryl acetate, and showed best result. Abstination from alcohol also involved for little hepatic regeneration. Supplementation of lecithin showed better effect compared to abstination from alcohol on reversing the effect of ethanol induced liver damage in the present study. Moreover, preventive measures were found to be better than curative treatment. Antioxidants are likely to provide beneficial effects on hepatocyes via desensitization against oxidant stress while inhibiting primary mechanism for expression of proinflammatory and cytotoxic mediators. However, abstinence from alcohol, proper nutrition, and supplementation of antioxidants, vitamins and hepatoprotective drugs are some of the therapeutic options. PMID- 23105572 TI - Study on arsenic level in public water supply of Delhi using hydride generator accessory coupled with atomic absorption spectrophotometer. AB - Exposure to arsenic has been associated with several health hazards. Worldwide the main reason for chronic human intoxication with arsenic is intake of contaminated drinking water. Air acetylene type of atomic absorption spectrophotometer in combination with hydride generator accessory was used to analyze arsenic level in 25 water samples collected from 25 booster pumping stations and 313 water samples collected from tap water supply of 62 areas of Delhi. Results were analyzed using SPSS and Barlett's Chi Square Test. Mean arsenic level detected in water samples collected from booster pumping stations was 0.00976 ppm (Range 0.000-0.017 ppm, Standard Deviation 0.006 and Standard error of Mean 0.00118). Maximum arsenic level (0.017 ppm) was found in water samples of booster pumping stations of Mehrauli, Punjabi Bagh and Ramjas Road. Mean arsenic level detected in samples collected from tap water supply was 0.013 ppm (Range 0-0.0430 ppm, Standard Deviation 0.00911 and Standard error of Mean 0.000515). In water samples of 42 areas arsenic level detected was exceeding WHO/EPA permissible limit of 0.01 ppm (10 ppb). The mean arsenic level detected in water samples of booster pumping station was within WHO/EPA permissible limit while mean arsenic level detected in tap water samples was marginally higher. Mixing of ground water and contamination through broken or leaking channel could be the possible reason of higher arsenic level in tap water. Continuous monitoring of quality of drinking water is required particularly in view of water contamination caused by industrial waste and uncontrolled ground water extraction. PMID- 23105573 TI - Ischemia modified albumin: A novel marker for acute coronary syndrome. AB - Early identification of patients with acute myocardial infarction is of prime importance due to the associated very high mortality. Only 22% of the patients presenting at emergency cardiology care with chest pain have coronary disease. A number of biochemical tests like CKMB and Troponin-T/I have been introduced for early detection of the coronary syndrome (ACS). Ischemia modified albumin (IMA) has been recently introduced as a marker of myocardial ischemia. We estimated serum IMA in four sequential samples from 25 patients admitted to ICCU. Twenty five healthy volunteers formed the control group from which the normal range was derived. IMA was significantly raised in ischemia patients than in controls as well as compared to the patients who did not have cardiac ischemia. IMA demonstrated good discrimination between the ischemic and the non-ischemic patients with an Odds Ratio of 16.9 (6.29-46.87) than CKMB which showed an Odds Ratio of 2.07 (1.18-6.08). Sensitivity and specificity of IMA for the detection of ACS was 78.0% and 82.7% compared to 58.0% and 60.0%, respectively for the CK MB assay. The area under the ROC curve of IMA for ischemic v/s non-ischemic patients was 0.834. IMA appears to be developing into a new and very potent marker, of cardiac ischemia. PMID- 23105574 TI - Effect of obesity and insulin resistance on diabetic control. AB - Diabetes Mellitus in obese and non-obese Indian individuals. AIMS: Effect of Obesity and insulin resistance on diabetic control. SETTINGS AND DESIGN: 50 each groups Diabetic individuals obese and non-obese. METHODS AND MATERIAL: On selected 50 each group diabetic patient and normal, following blood investigations has been performed-Plasma Glucose, Glycohemoglobin and Serum Insulin. STATISTICAL ANALYSIS USED: Individuals patient's results were analyzed and compared with the normal controls. RESULTS AND CONCLUSION: The changes in glycosylated haemoglobin are mainly proportional to the post lunch glucose level (r=0.773) (p<0.01) and not correlated to circulating insulin or the body mass index. However the levels were higher in obese diabetes (Type I and II both) than in non-obese. Mechanism of resistance in insulin receptor interactions due to obesity is well known. However, obesity does not seem to affect directly glycosylated haemoglobin. Under such circumstances, the reduction of weight for a diabetic person can improve sugar control by minimizing insulin resistance and thereby can improve glycosylated haemoglobin levels. PMID- 23105575 TI - Serial composition of human milk in preterm and term mothers. AB - Human milk samples were collected from 86 mothers induced in the study on days 3, 7, 14 and 28 of lactation. The mothers were divided into three groups on the basis of gestation viz. group 1: 37-41 weeks (n=41), group II: 33-36 (n=23) and group III: <33 weeks gestation (n=22). All the samples were analysed for the estimation of fat, lactose and protein. The results obtained from the investigations were statistically analysed. The analysis of the results revealed a lower amount of fat and lactose in preterm milk as compared to term milk (p<0.01). These were found to increase in amount with increasing postnatal age (p<0.05). The protein levels were observed to be significantly higher in preterm than term milk (p<0.01). These were observed to decrease significantly with increase in postnatal age (p<0.01). PMID- 23105576 TI - Raised serum homocysteine levels in patients of coronary artery disease and the effect of vitamin B12 and folate on its concentration. AB - Homocysteine(Hcy) has been implicated as a novel risk factor of Coronary Artery Disease (CAD) among Asian Indians, but many studies done in India failed to reveal any direct correlation. It has also been reported that Folic acid and Vitamin B12 levels inversely affect serum levels of homocysteine. In this study, we looked at the levels of homocysteine among patients with CAD. The effect of Vitamin B12, Folate and other risk factors on homocysteine levels were also evaluated. Mean homocysteine levels in cases (22.81+/-13.9, n=70) were significantly higher (p=<0.001) than the controls (7.77+/-7.3, n=70). However no statistically significant correlation could be deduced between homocysteine Vitamin B12, and Folate. Cumulative analysis have indicated an increase in homocysteine levels among patients with CAD with every additional risk factor. PMID- 23105577 TI - Evaluation of oxidative stress in pregnancy induced hypertension. AB - This work was undertaken to investigate correlation between oxidative stress and initiation of pathogenesis of pregnancy induced hypertension (PIH). Fifty primigravidae in age group of 20-35 years and gestational age 28-42 weeks with PIH were taken as cases. Twenty healthy primigravidae with no medical and surgical complications of pregnancy and with blood pressure <=140/90 mm Hg served as controls. The cases were again subgrouped as severe preeclampsia (12 in number) and mild pre-eclampsia (38 in number). All of them were evaluated for serum malondialdehyde (MDA), Serum vitamin E and plasma vitamin C levels. The serum MDA levels were raised significantly in women with mild preeclampsia (P<0.01) and in women with severe preeclampsia (P<0.01) in comparison to normal primi gravida. The serum vitamin E levels were decreased in primi gravida with mild preeclampsia (p<0.1) and in primi with severe pre eclampsia (P<0.1) in comparison to normal primi gravida but the fall was not statistically significant. There was a significant fall (P<0.05) in the vitamin C levels in primi with mild preeclampsia than in the normal primi. The vitamin C levels in severe preeclamptic patients were lower than the normal primi but the fall was not statistically significant (P=0.10). The serum MDA and vitamin E showed a negative correlation in all the cases. The serum MDA and plasma vitamin C also showed a negative correlation in the control and study group. This observation suggests that in hypertensive disorders of pregnancy there is an imbalance between lipid peroxidation and antioxidant vitamin status because of oxidative stress. The decreased serum concentrations of the antioxidant vitamins supports the hypothesis that lipid peroxidation is an important causative factor in the pathogenesis of preeclampsia. The rise in antioxidants is probably to compensate the increased peroxide load in severe preeclampsia. PMID- 23105578 TI - Lipid peroxidation and antioxidant status in blood of rheumatoid arthritis patients. AB - The main objective of the study was to assess the oxidative stress in plasma and erythrocytes of rheumatoid arthritis patients by measuring the levels of thiobarbituric acid reactive substances (TBARS), non-enzymatic antioxidants (vitamin E, C and reduced glutathione) and enzymatic antioxidants [superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHPx)]. This study has been conducted on twenty-two adult female rheumatoid arthritis patients and an equal number of healthy subjects. Elevated lipid peroxidation and multidirectional changes in the antioxidant defence system were noticed in patients with rheumatoid arthritis. The enhanced lipid peroxidation accompanied by disturbance in antioxidant status indicates that rheumatoid arthritis patients are more prone to free radical mediated oxidative damage. PMID- 23105579 TI - Relationship of plasma homocysteine with lipid profile parameters in ischemic heart disease. AB - The present study was undertaken to explore the relationship of plasma homocysteine with other biochemical parameters in ischemic heart disease. Plasma levels of total homocysteine was measured by HPLC-fluorescence detection with internal standard in 60 ischemic heart disease patients and were compared with 30 age matched normal healthy controls. The significant increase of plasma homocysteine was observed in both myocardial infarction and chronic stable ischemic heart disease patients when compared with the controls. The hyperhomocysteinemia appears be to due to increased body demand of vitamins such as folic acid, vitamin B(12), B(6), B(2) either alone or in combination to regulate normal homocysteine metabolism. PMID- 23105580 TI - Maternal and fetal indicators of oxidative stress during intrauterine growth retardation (IUGR). AB - The present study demonstrates the possibility of increased lipid peroxidation and protein oxidation in both maternal and fetal erythrocytes as markers of oxygen radical activity during intrauterine growth retardation. The erythrocyte MDA levels were significantly elevated in mothers of IUGR babies when compared to controls (p<0.01). The endogenous protein damage due to oxidative stress was significantly higher in IUGR mothers when compared to controls (p<0.05). Similarly the proteolytic activity in erythrocyte lysates against oxidatively damaged hemoglobin was significantly increased in mothers of IUGR babies compared to controls (p<0.001).In fetuses born with IUGR, both lipid peroxidation and proteolytic activity were significantly increased when compared to normal newborns (p<0.01).The result of this study indicates that oxidative stress was induced both in IUGR babies and their mothers which is manifested as increased lipid peroxidation and protein oxidant damage. PMID- 23105581 TI - Studies on the age dependent changes in serum adenosine deaminase activity and its changes in hepatitis. AB - Serum Adenosine deaminase (ADA) activity in normal healthy control subjects increases upto 30 years, remains steady between 31-60 years of age and shows a steep increase in the age group of 61-70 years. This was compared with serum aspartate transaminase (AST) and alanine transaminase (ALT) activity which also showed a gradual increase upto 40 years of age and decreased thereafter. The activities of serum ADA, AST and ALT increased in patients with hepatitis of all age groups compared to their respective controls. The degree of increase in the activities of the above enzymes in hepatitis, decreased with age. The present study also shows that while studying serum ADA activity in hepatitis for diagnostic purposes, the value obtained in a particular age group should be compared with normal range of values for the respective age group only. PMID- 23105582 TI - A study of the interaction between ropranolol and NSAIDs in protein binding by gel filtration method. AB - Drug protein binding phenomena can lead to some interesting drug-drug interactions when one drug displaces another in the binding site. Studies of protein binding are conducted by several methods including equilibrium dialysis, ultra-filtration and chromatographic methods. Gel filtration is a simple chromatographic method in protein binding studies. Propranolol binds to plasma proteins by 90%-95% in circulation system and other drugs with high protein binding may displace it. In this study protein binding of propranolol has been studied using gel filtration to Bovine Serum Albumin (BSA) alone and in the presence of Acetyl salicylic acid (ASA), Indomethacin and mefenamic acid has been studied using gel filtration method. The results indicated that ASA decreased protein binding of propranolol by 20% to BSA and other drugs did not displace propranolol from the binding site. Therefore, ASA may alter pharmacological effects of propranolol. PMID- 23105583 TI - Study of lipid peroxide and lipid profile in diabetes mellitus. AB - The study was designed to find out the correlation between lipid peroxidation, lipoprotein levels to severity and complication of diabetes mellitus. Degree of lipid peroxidation was measured in terms of malondialdehyde (MDA) along with lipid profile and blood glucose in diabetes mellitus. It is categorised into insulin dependent diabetes mellitus (IDDM), non insulin dependent diabetes mellitus (NIDDM) and diabetes mellitus(DM) with complication.Total 112 known diabetic patients and 52 non-diabetic controls were studied. These patients were grouped as per the concentration of fasting blood glucose level i.e. controlled, poorly controlled, and uncontrolled group. There are significant increase in the lipid peroxide (MDA) and lipid profile except HDL cholesterol which is decreased, has been found in all groups as compared to controls In NIDDM group lipid peroxidation was markedly increased than IDDM group and it was higher in DM with complications. Other finding observed was that the level of lipid peroxide increased as per the increase in concentration of blood glucose. The increase lipid peroxidation in the hyperglycemic condition may be explained, as the superoxide dismutase enzyme which is antioxidant becomes inactive due the formation of superoxide radical within the cell. Maximum lipid peroxidation leads to the damage of the tissue and organs which results into complication in diabetic patients. High levels of total cholesterol appear due to increased cholesterol synthesis. The triglyceride levels changes according to the glycemic, control. The increase may be due to overproduction of VLDL-TG.It is concluded that good metabolic control of hyperglycemia will prevent in alteration in peroxidation and the lipid metabolism, which may help in good prognosis and preventing manifestation of vascular and secondary complication in diabetes mellitus. PMID- 23105584 TI - Effect of supplementation of vitamin E, vitamin C and reduced glutathione on copper ion induced lipoprotein oxidation in renal diseased patients-Anin vitro study. AB - The oxidative modification of lipoprotein especially low density lipoprotein (LDL) plays a key role in the initiation and progression of atherosclerosis. Serum apolipoproteinB (apoB) level is found to be an important marker for atherosclerosis. The present paper focuses on the measurement of serum apoB levels and the effect of Vitamin E, Vitamin C and reduced glutathione on the copper ion induced oxidation of LDL + VLDL (VLDL-Very Low Density Lipoprotein) lipoprotein fraction isolated from the serum of chronic renal failure (CRF) and renal transplanted patients. The level of apoB is significantly higher in the serum of transplanted patients when compared to CRF patients and normal subjects. The level of TBARS formed in oxidized LDL + VLDL lipoprotein fraction of CRF and renal transplanted patients are significantly increased than normal even in the presence of antioxidants but the level of TBARS produced, with antioxidants is comparatively lesser than that produced by oxidized lipoprotein fraction without antioxidants. It may be concluded than that produced by oxidized lipoprotein fraction without antioxidants. It may be concluded that oxidation of LDL can be prevented at an earlier stage by Vitamin E supplementation. The supplementation with Glutathione serves as the best method of preventing the lipoprotein oxidation among the renal diseased patients. PMID- 23105585 TI - Internet resources and biochemistry. AB - The Internet is a massive expanding body of information, which is likely to play a significant role for clinical Biochemists and researchers in patient health care across the world. This expansion has been matched by an increase in the number of individuals using the Internet. Since its inception in December 1969 the Internet has grown rapidly and is anticipated to expand 100% in the coming next few years. This review illustrates to the Biochemists many uses of the Internet and hopefully provides a useful resource for professional and personal use. To explain the origin, functions, use and impact of the Internet and to provide a list of important website addresses related to Biochemistry. We undertook a detail scan of the Internet and identified a large number of websites pertaining to Biochemistry. The sites were then thoroughly searched to evaluate their potential usefulness to Biochemists, clinicians and researchers. This overview of the Internet and a compilation of important web-site addresses are expected to stimulate and inculcate Biochemists in the use of the web in teaching, training and research. PMID- 23105586 TI - Effect of increasing duration of diabetes mellitus type 2 on glycated hemoglobin and insulin sensitivity. AB - Non-insulin dependent diabetes mellitus (NIDDM) is the most rapidly growing chronic metabolic disorder in the world. With advancement in the age and duration of diabetes there is a gradual tendency for the level of blood sugar to rise along with a subsequent increase in the HbA1c as well as in the fasting insulin level. Whether this is an aging process or increased frequency of diabetes is still controversial. The correlation between glucose and insulin sensitivity is consistent with the idea that the degree of chronic hyperglycemia is a cause of excessive insulin resistance in type 2 diabetes, i.e. the insulin resistance which characterizes type 2 diabetes but not nondiabetic subjects matched for age, gender, family history and duration of diabetes. The study comprised a total of 76 subjects out of which 30 were normal, non-diabetic persons and the rest 46 were diabetics with different duration of time in years, after being diagnosed diabetic. Data was analyzed after dividing the subjects into four groups-Group 1 comprised of one year old diabetics, Group 2 was made up of those, who had diabetes, for the past 2-5 years, Group 3 included patients who were diabetic since more than 5 years and Group 4 included non-diabetics as the normal control group. The results obtained indicated that the HbA1c levels showed a significant increase with the duration of diabetes as well as the insulin level showed a significant correlation after adjustment for age, sex and duration of diabetes. PMID- 23105587 TI - Multiplex PCR for rapid detection of exonal deletions in patients of duchenne muscular dystrophy. AB - Duchenne muscular dystrophy (DMD) is the most common X-linked disorder in children affecting 1 in 3500 males. Since, as of now, we have no treatment for DMD, carrier detection and prenatal diagnosis is the most important preventive strategy. Multiplex PCR helps in rapid detection of hot spot exonal deletions (positive in 65% of cases) as many exons can be identified in a single run. 10 children with characterstic clinical features of DMD and chorionic villus samples of 10 antenatal patients with positive family history were studied. We identified a deletion mutation in exon 49 of the dystrophin gene in a 4 yr old boy referred with signs and symptoms suggestive of DMD using primers for exons 45, 48, 49, 43, 44, 19, 3, 8, 13 and muscle promoter, subjected to multiplex polymerase chain reaction (PCR) and agarose/Nu-Sieve gel electrophoresis. These genetic methods aid in prenatal diagnosis of DMD as well as confirmation of diagnosis in children with signs and symptoms suggestive of the disease. PMID- 23105588 TI - Effect of antioxidants and antibiotics on levels of seminal oxidative stress in leukocytospermic infertile men. AB - Defective sperm function is the most common cause of infertility. A prospective study was carried out to correlate the concentration of nitrite (the stable metabolite of nitric oxide) in seminal plasma with leukocytospermia, and sperm membrane integrity. Total Fifty-seven normozoospermic subjects with and without leukocytospermia visiting the Infertility clinic at KH and MRC, Karad, were included in the present study. Semen samples were checked for sperm concentration, total sperm count, sperm motility, seminal leukocyte concentration and sperm membrane integrity as Hypoosmotic Swelling Test. Similarly the concentration of nitrite in seminal plasma was measured by Griess reaction and total antioxidant power measured as ferric reducing ability of plasma. The concentration of nitrite in seminal plasma was found to be raised with significantly increased leukocyte concentration in semen. Also significantly lowered levels of total antioxidant power along with defective sperm function was observed. Our results suggest that supplementary treatment of antioxidants with antibiotic for leukocytospermic infertile male patients may improve the sperm membrane integrity. PMID- 23105589 TI - Antioxidant status in neonatal jaundice before and after phototherapy. AB - Phototherapy has been related to increased oxidative stress and lipid peroxidation. In the present study, thirty full term jaundiced neonates with appropriate weight were analyzed before and after completion of phototherapy for malondialdehyde (MDA), reduced glutathione (GSH), total thiols, vitamin C and superoxide dismutase (SOD) levels in hemolysate and albumin levels in plasma. These parameters were analyzed in cord blood samples of 20 healthy neonates as control. It was observed that levels of MDA were elevated significantly (p<0.001) in patients as compared to controls and that the levels increased significantly after phototherapy (p<0.001). Levels of SOD were also found to be increased significantly as compared to controls and the levels rose after phototherapy (p<0.001). On the other hand, the levels of non-enzymatic antioxidants such as GSH, total thiols and vitamin C were significantly low (p<0.001) as compared to controls and the levels decreased significantly after phototherapy (p<0.001). The plasma albumin levels also were found to be decreased significantly after phototherapy (p<0.01). Therefore, phototherapy increases oxidative stress and should be used with care. PMID- 23105590 TI - Choronic effects of Lamotrigine on liver function in adult male rats. AB - A number of newly developed antiepileptic drugs are currently in use, among them Lamotrigine (LTG) is more common. Despite the extensive use of this drug, it has not been possible to predict the side effects especially the hepatotoxic reactions after long-term treatment. The present study was designed to find out alterations in the activities of liver enzymes after chronic exposure of rats to different dose of LTG. Adults male (Wistar) rats were treated orally with LTG [5 mg/kg body weight or 25 mg/kg body wt.] for 60 days. After the experimental period, auto analyzer carried out liver function tests. The liver histopathology was obtained after scarifying the rats. There was a significant increase in the level of ALP, AST, ALT and bilirubin at therapeutic dose of LTG. The increase level of these enzymes and bilirubin at toxic dose were much higher and significant. However, the total protein and albumin significantly decreased at toxic dose of LTG. Elevation of liver enzymes and bilirubin after chronic exposure of rats to high dose of LTG reflects hepatocellular damage that may lead to hepatitis. It is concluded that regular liver function and drug monitoring should follow the treatment with LTG. PMID- 23105591 TI - Impaired hypothalamic-pituitary-gonadal axis function in men with diabetes mellitus. AB - In view of association of diabetes mellitus and male infertility, present study was designed to investigate the functional status of hypothalamic pituitary gonadal (HPG) axis in diabetic men. Thirty-five diabetic men (BMI 22.24+/-0.21) in the age group 20-40 (30.6+/-4.7) years were selected. Twenty-five healthy men (BMI 23.85+/-0.25), in the same age group (29.5+/-4.8) served as control. Blood samples were collected for hormonal and biochemical estimations. Diabetic men had significantly low serum testosterone with low LH and FSH, hypercholesterolemia, hypertriglyceridemia, hypoalbuminemia and increased oxidative stress. Low serum testosterone in diabetic men was accompanied by low LH and FSH; the inability of the pituitary gland to respond appropriately to a decline in testosterone implying central effect of high serum glucose on the interaction between the nervous and endocrine system. Nutritional deficiency, increased oxidative stress and increased aromatase activity due to excessive body fat might have also contributed to low serum testosterone. PMID- 23105592 TI - Study of enzyme activities in the descending part of the duodenum in patients of duodenal ulcer. AB - The aim of this study was to measure the levels of lactase, sucrase, maltase, leucine amino peptidase and gamma-glutamyl transpeptidase in duodenum of Indian patients with duodenal ulcer. The effect of duodenum inflammation on these brush border enzymes has also been analysed in this study. Levels of lactase, sucrase, maltase, leucine amino peptidase and gamma-glutamyl transpeptidase were assessed in duodenal biopsies of 20 patients of duodenal ulcer and 20 non-ulcer dyspepsia. The duodenal biopsy specimens were also examined histopathologically for presence or absence of inflammation. There was no significant difference (p>0.05) in the activity of above mentioned enzyme levels in both the groups. Only levels of gamma-glutamyl transpeptidase were significantly decreased in patients of duodenal ulcer with duodenal inflammation. This study shows that only the levels of gamma-glutamyl transpeptidase were significantly decreased in patients of duodenal ulcer with inflammation but no change in duodenal enzymes due to duodenal ulcer as compared to non-ulcer dyspepsia. PMID- 23105593 TI - Significance of tumor markers in lung cancer. AB - The objective was to test the utility of the cytokeratins CYFRA 21-1, tissue polypeptide specific antigen (TPS), Neuron specific enolase (NSE) and Carcino Embryonic antigen (CEA) in patients with lung cancer and in the pleural fluid of the patients with lung cancer and also the predicting ability of these tumor markers with respect to the histological types [including non small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] and pathological stages. 40 normal subjects and 222 cases of histological proven lung cancer were studied. The findings suggest that TPS and CYFRA 21-1, are useful serum markers for the diagnosis of NSCLC and NSE seems to be useful tumor marker for monitoring course of patients especially SCLC. The combined use of these cytokeratin markers TPS and CYFRA 21-1 may provide additional information for prognosis. PMID- 23105594 TI - Evaluation of urinary abnormalities in nephrolithiasis patients from Marathwada region. AB - Urinary abnormalities were evaluated in 100 renal stone patients with first episode of renal stone having age 22 to 45 years from both sex and compared to 100 normal healthy control group having same age group from both sex. Twenty-four hours urinary oxalate, calcium, uric acid, sodium, magnesium, phosphorus and citrate were estimated. The urinary pH was also determined. In stone formers urinary oxalate, calcium, sodium and uric acid excretions were significantly higher when compared with control group. Whereas citrate, phosphate and magnesium excretion were significantly lower in stone formers when compared with control.The pH of urine in stone formers was lower than the controls. High dietary intake of purine rich diet causes elevated excretion of uric acid, which leads to calcium oxalate crystal formation and precipitation. Other risk factors such as urinary oxalate, calcium also related to formation of renal calculi.Hypocitraturia is the main cause of renal calculi along with hypomagnesiuria and hypophosphaturia in the patient of Marathwada region. On the basis of urinary abnormalities further stone formation in the patient can be prevented by dietary modifications. PMID- 23105595 TI - Oxidised LDL, HDL cholesterol, LDL cholesterol levels in patients of coronary artery disease. AB - Coronary artery disease is a major cause of morbidity and has various risk factors. Lipid profile i.e. low HDL-cholesterol, high LDL cholesterol, high total cholesterol, high triglycerides playing important role in its causation. Recently interest has been shown in the oxidized fraction of LDL as one of the risk factors. In the present study 60 age and sex matched normal healthy individuals were taken as controls and 60 patients of CAD were taken. Cholesterol was measured by enzymatic method, HDL cholesterol by phosphotungstate precipitation method. Serum levels of LDL fraction of cholesterol was measured by a new and simpler method of precipitation. Result was expressed as mol/L of diene conjugates. It was observed that LDL cholesterol, VLDL cholesterol, total cholesterol, total cholesterol: HDL cholesterol, LDL cholesterol: HDL cholesterol were significantly raised and HDL cholesterol was significantly low in patients. (p<0.001). Though HDL cholesterol was significantly raised in females as compared to males in both the groups (p<0.001). Serum level of total cholesterol, oxidized LDL:HDL cholesterol were also raised significantly (p<0.05). The level of oxidized LDL showed an increasing trend in patients. PMID- 23105596 TI - Cerebrospinal fluid free sialic acid and aspartate transaminase levels in meningitis. AB - BACKGROUND: Sialic acid (SA) is a nine carbon sugar derived from mannosamine and pyruvate. High levels of sialic acid and aspartate transaminase (AST) levels in cerebrospinal fluid have been described in pyogenic meningitis (PM) compared to tubercular meningitis (TBM). OBJECTIVES: To evaluate the levels of CSF free SA in PM and TBM and to assess the correlation between CSF free SA and CSF glucose or total protein levels. PATIENTS AND METHODS: A total of 122 subjects were studied and divided into children and adults. Further, these have been subdivided into controls, PM and TBM. CSF free SA was estimated by thiobarbituric acid assay of Warren and AST by Reitmann and Frankel method. RESULTS: CSF free SA and AST levels in children and adults were significantly high in PM (p<0.001) as compared to TBM and controls. CONCLUSION: A very high CSF free SA and AST were found to be characteristic of PM, making them useful parameters to differentiate PM from TBM. PMID- 23105597 TI - Serum lipids and malondialdehyde levels in primiparous patients with pregnancy induced hypertension. AB - BACKGROUND: Pregnancy induced hypertension (PIH) contributes to 15.6% maternal mortality in India. In Behrampur, Orissa, maternal deaths due to PIH was 32%, which is twice the national incidence. Hence in this population, some factors associated with severity of PIH were studied. Serum lipid concentrations and malondialdehyde (MDA) levels were correlated with severity of PIH and birth weight of the neonate. PATIENTS #ENTITYSTARTX00026; METHODS: 70 primiparous PIH patients and 20 healthy controls were studied. Serum lipids and MDA were estimated. Maternal blood pressures and birth weights of the neonate were recorded. RESULTS AND CONCLUSION: Serum cholesterol, triglyceride, LDL, VLDL and MDA were significantly elevated in primiparous PIH patients when compared to control subjects. Average birth weight of babies born to mothers with PIH was less than those born to control subjects. The most significant factor was that in this geographical area, 26% of the primiparous patients with PIH were below 20 years of age while only 15% of the controls were less than 20 years, indicating that younger maternal age was a contributing factor to PIH. PMID- 23105598 TI - Biological variation of plasma ferritin in healthy adult males in south Indian population-A sample study. AB - A sample study of biological variation of plasma ferritin in healthy adult males 19-25 years of age (n=6) in the Indian population was determined. Venous blood was collected on 3 non-consecutive days during a 3 week period. Plasma ferritin was measured using enzyme linked immunoassay in an automated immunoassay system. Analytical and Biological variation was calculated. We found a mean biological variation of 21.64%. Thus, our results indicate that biological variation contributed most to the intraindividual variation. PMID- 23105599 TI - Place of salivary beta glucuronidase activity in head & neck cancers. AB - Salivary beta-glucuronidase activity was studied in 20 healthy subjects without habits and 10 with habits, 38 untreated patients of advanced head and neck cancer and 21 patients after treatment either after surgery or radiation.Salivary beta glucuronidase activity was elevated in untreated cases of head and neck cancer (p<0.001), with a fall in the activity after treatment. The post operative fall in the activity of salivary beta-glucuronidase activity was highly significant (p<0.001) as compared to post radiation. This test can be utilized in the diagnosis and also for monitoring the course of the disease. PMID- 23105600 TI - Acrosin activity in spermatozoa of infertile Nigerian males. AB - The objective of this study was to evaluate acrosin activity in spermatozoa of infertile Nigerian men and to compare with those of the fertile men. The acrosin activity was evaluated using the Acroscreen reagent kit. The acrosin activity of the fertile men was 40.7+/-5.2 mIU/10(6) sperm (range 30.1-51.3) and those of the infertile men was 22.4+/-8.33 mIU/10(6) sperm (range 5.7-39.1). The difference in the mean was statistically significant (P<0.001). There was a subpopulation of the infertile men who had their acrosin activity within normal range of the fertile men, 32.9+/-1.57 mIU/10(6) sperm. But the difference in the mean was statistically significant (P<0.001). Acrosin activity decreased with increased morphological changes in the spermatozoa. It is concluded that acrosin activity in the infertile Nigerian men is significantly lower than that in the fertile men. Acrosin activity may also be affected by morphological changes in the spermatozoa. PMID- 23105601 TI - Lipid peroxidation of fish oils. AB - Fish and fish oils are the richest sources of omega-3 fatty acids. However, they are susceptible to lipid peroxidation due to their high degree of unsaturation. In the present study, the level of thiobarbituric acid reactive material in various fish oils available in the market with and without added Vitamin E was determined. The peroxide levels in fish oil heated to food frying temperature of 180 degrees C and the effect of addition of vitamin E has also been studied. The results indicate that the peroxide levels in almost all the products available in the market were abnormally high irrespective of their Vitamin E content. This might be due to the inefficient methods used for processing and storage of fish oils. Addition of vitamin E was found to have a significant effect in lowering the rate of peroxidation of fish oil during thermal stress, showing that association of antioxidants with omega-3 fatty acids lowers the rate of lipid peroxidation. PMID- 23105602 TI - Tumor necrosis factor alpha (TNF-alpha) and estrogen hormone in osteoarthritic female patients. AB - Osteoarthritis of knee joints is a disease of old age in both sex. It is very common after the age of 40 years in elderly females or in postmenopausal phase of females. It is characterized by narrowing of space in joints due to inflammation. The exact mechanism of inflammation in this disease is not yet clear. Tumor necrosis factor alpha (TNF-alpha) may involve in onset of disease. The present study is being carried out in 130 female subject of age group 40-60 years suffering from osteoarthritis of knee joints and 50 normal healthy control female subjects. A correlation is made between TNF-alpha and estrogen and found significant inverse correlation (r<0.001), between TNF-alpha and estrogen hormone in osteoarthritic female patients as compared to normal healthy control female group. PMID- 23105603 TI - A study of serum zinc, selenium and copper levels in carcinoma of esophagus patients. AB - The association of serum trace elements like selenium, zinc and copper has been found in different types of cancer. This study was conducted to see the serum level of these three trace elements in cancer esophagus patients. Biopsy confirmed cancer esophagus, 24 patients (12 males, 12 females, mean age 54.5+/ 11.65 year with 23 healthy subjects (16 males, 7 females, mean age 44 +/-13.82 years) were included in this study. Both control and study group patients were of same socio-economic status and dietary habits. Serum zinc and copper level were estimated using standard absorption spectrometer technique and serum selenium by Hydride generation method.We observed significant low serum levels of zinc and selenium while high level of serum copper in carcinoma esophagus patients, as compared with normal healthy controls. This shows an association of serum selenium zinc and copper with cancer esophagus. PMID- 23105604 TI - External quality assurance-Role of ACBI/CMC scheme. PMID- 23105605 TI - Aims of IFCC and my own goals. PMID- 23105606 TI - Genetic determinants of hyperhomocysteinemia in atherosclerosis. AB - Hyperhomocysteinemia (Hhcy) is an independent risk factor for the development of atherosclerosis. The mechanisms by which HHcy promotes cardiovascular disease may be due to activation of pro-inflammatory factors, endoplasmic reticulum (ER) stress and oxidative stress. We aimed to study (i) gene mutations that cause HHcy. (ii) Estimation of inflammatory marker like ultrasenitive C-reactive proteins (hs-CRP) and total antioxidant levels (iii) determination of Hcy- dependent gene expression in vivo. 25 HHcy patients and 25 healthy controls were taken for this study. Mutation detection in MTHFR, CBS, MS and eNOS gene was by PCR-based restriction enzyme analysis and subsequently expression study was carried out by Reverse Transcriptase PCR and cloning technique. A significant association of HHcy with MTHFR (C677T) and MS (A2756G) genotype was observed (p<0.05). There was no association of Hhcy and eNOS genotype. The Hhcy patients, showed no expression of the ER stress gene, GRP78 in lymphocytes. Our study showed no effect of Hcy on the CD18 gene (pro-inflammatory pathway) expression, but a significant association of tHcy and hs-CRP levels in HHcy grp (t=2.28, p<0.05). This shows that HHcy induces inflammatory response, which could lead to tissue injury in the pathogenesis of the atherosclerotic process. Our findings show higher mRNA expression of manganese superoxide dismutase (Mn SOD) in HHcy group as compared to the control group. The Total Antioxidant Status (TAS) estimated was found to be significantly lower in the HHcy group as compared to healthy normals (t=4.8, p<0.01). Taken together these findings strongly suggest that the adverse effects of homocysteine are at least partly mediated by oxidative stress. Our study supports the hypothesis that Hcy evokes adverse vascular effects by promoting oxidative damage to endothelial cells. PMID- 23105607 TI - Immunoproteomic analysis of secretory proteins ofAspergillus fumigatus with specific IGE immunoreactivity. AB - Allergenic/antigenic proteins are known to induce Type I and Type III hypersensitivity reactions leading to allergic bronchopulmonary aspergillosis (ABPA) in immunocompetent host. The common structural features or intrinsic properties of the allergens/antigens leading to allergenicity in a host are not well understood. In the current report, comparative analysis of proteins on two dimensional gel electrophoresis (2D-3) and specific IgE immunoblots ofA. fumigatus secretory proteins (1(st), 2(nd) and 3(rd) week culture filtrate proteins) was carried out. We observed a total of 159 proteins in 1(st), 2(nd) and 3(rd) week culture filtrates ofA. fumigatus. Specific IgE immunoreactivity was observed in 75 proteins with different intensity. Third week culture filtrate showed maximum number of proteins, 142, and specific IgE immunoreactive proteins, 65. MALDI-TOF analysis resulted in putative identification of two allergens as hypothetical protein YBL057c fromSaccharomyces cereviseae and unnamed protein product fromDebaryomyces hansenii (similar to IPF14568 ofCandida albicans). Identification of a repertoire of specific IgE immunoreactive proteins will facilitate the studies on structure-function relationship of these proteins relevant for diagnosis and pathogenesis. PMID- 23105608 TI - Immune response to n-terminal and c-terminal deletion mutants of Aspergillus fumigatus major allergen ASP F 3. AB - The ubiquitous fungus Aspergillus fumigatus causes allergic rhinitis, asthma, sinusitis and allergic bronchopulmonary aspergillosis. A number of major allergens from A. fumigatus are purified, but their structure-function role in the pathogenesis of disease is not known. Such information is essential for devising alternative therapy of fungal allergic diseases. In the present study, N terminal and C-terminal deletion mutants ofAsp f 3 were constructed and their immunopathological responses studied in a mice model of allergy. Three mutants viz,Asp f 3 (aa 33-168), (aa 1-142), and (aa 23-142) were made by deleting certain amino acids from epitopic regions of full lengthAsp f 3, a major allergen of A. furnigatus. TheAsp f 3 and three mutated proteins were expressed in pET vector. The C-terminal deletion mutantAsp f 3 (aa 1-142) induced elevated IFN gamma but low levels of IL-4 by spleen cells. This mutant also showed significant downregulation of peripheral blood eosinophils and lung inflammation in immunized mice. The N-terminal deletion mutantAsp f 3 (aa 33-168) also exhibited an immuno suppressive effect in terms of IgE production and induction of Th2 cytokine. The results indicate thatrAsp f 3 and its deletion mutants induced distinct immune inflammatory responses in mice on challenge with these proteins. The non-IgE binding deletion mutants ofAsp f 3 (aa 1-142 and aa 33-168) could deviate Th2 immune response with a concomitant reduction in airway inflammation and infiltration of inflammatory cells. PMID- 23105609 TI - Comparative analysis of RBC membrane fatty acids, proteins and glycophorin in patients with heterozygous beta thalassemia and iron deficiency anemia. AB - Membrane lipid and protein composition was compared in erythrocytes from iron deficiency anemia (IDA) and heterozygous beta thalassemia patients. The study was planned to correlate the influence of iron deficiency with the intrinsic defect of the heterozygous condition on the membrane structural integrity as well as to investigate whether there are differences in membrane changes between the two conditions. Results indicate high levels of saturated fatty acids and low unsaturated fatty acids in both disorders although arachidonic acid and the unsaturation index were lower in heterozygous thalassemia than IDA. Nevertheless, neither of the conditions provoked any alterations in membrane protein or glycophorin suggesting alterations in the lipid moiety only. Present findings indicate that irrespective to the etiology, both, iron deficiency and the heterozygous condition show a common pattern of lipid derangement, which may in turn result in increased membrane rigidity and decreased cellular deformability. PMID- 23105610 TI - Oxidative stress, alpha-tocopherol, ascorbic acid and reduced glutathione status in schizophrenics. AB - A disturbance in the antioxidant defense system including alpha-tocopherol, ascorbic acid and reduced glutahtione metabolism due to free radical induced oxidative injury has been implicated in various neuro-psychiatric disorders. The roles of these antioxidants, changes in their blood levels and correlation with oxidative stress were studied in a common psychiatric illness Schizophrenia. Fifty-eight subjects of either sex ranging in age from 18-60 years divided into two age groups (<=40 and >40 years) diagnosed for schizophrenia, and forty age and sex-matched normal subjects as controls were included in the study. Blood samples were analyzed for malondialdehyde (MDA), alpha-tocopherol, total ascorbic acid (TAA), dehydro ascorbic acid (DHAA), reduced ascorbic acid (RAA), leucocyte ascorbic acid (LAA) and reduced glutathione (GSH). A decrease in the levels of alpha-tocopherol, total ascorbic acid and reduced glutathione was found in schizophrenics compared to normal controls. Further a significant rise in oxidative stress and decreased antioxidant status was observed in the chronic stage of schizophrenia as compared to those in acute condition. A significant rise in dehydroascorbic acid with concomitant fall in reduced ascorbic acid suggests scavenging action of ascorbic acid and its utilization with increased oxidative stress as indicated by high blood malondialdehyde levels. Leucocyte ascorbic acid, a better index of ascorbic acid status was also found to be reduced in schizophrenics, suggesting depletion of body stores of ascorbic acid and the condition worsened with advancing age. PMID- 23105611 TI - Association of plasma level of thiobarbituric acid reactive substances with extent of hepatocellular injury in preterm infants with cholestatic jaundice. AB - The present study was designed to determine the association between extent of hepatocellular injury and plasma level of thiobarbituric acid reactive substances (TBARS) in pre term infants with cholestasis. Preterm infants (<35 weeks gestation) admitted to the neonatal intensive care unit were enrolled (with their parents informed consent) in either the 'cholestasis' group (if their direct bilirubin was >2 mg/dl) (n=25) or in the control group (n=16). Blood samples for measurement of TBARS, direct bilirubin and transaminases were obtained with-in 24 hours of enrollment. The cholestasis and control groups were comparable with respect to gestational age, birth weight and Apgar score. Serum direct bilirubin, SGOT (EC 2.6.1.1) and SGPT (EC 2.6.1.2) levels were significantly high in the cholestasis group. Plasma levels of TBARS in cholestasis group were correlated with SGOT (F=276.92; P<0.0001) and SGPT (F=355.17; P<0.0001) and differed significantly between cholestatic and control infants. Our findings suggest that oxidative stress in preterm infants with cholestasis is associated with hepatocellular injury. PMID- 23105612 TI - The use of lysosomal enzymuria in the early detection and monitoring of the progression of diabetic nephropathy. AB - Recent acquisitions on the early detection and monitoring of the progression of diabetic complications (nephropathy) using the techniques of enzymology (lysosomal enzymes) are reviewed. it appears that the kidney is the principal source of urinary lysosomal enzymes. Urinary samples for lysosomal enzyme determination can be either 24-hour or spot-collection. The use of synthetic substrates (4-methylumbelliferyl substrates) provides an easy, inexpensive, sensitive and highly reproducible method of lysosomal enzyme assay. It is recommended that more than one enzyme be assayed in the process. The use of fractional enzyme excretion (FEE) ratios is further recommended. The urinary lysosomal glycosidases investigated and found to be of particular diagnostic value in the early detection of diabetic nephropathy include N-acetyl-beta-D glucosaminidase (beta-hexosaminidase, NAG), beta-glucuronidase and beta galactosidase, with NAG being the most useful indicator. Urinary NAG can be used in monitoring the progression of diabetic nephropathy. The fluorimetric assay of lysosomal glycosidases is particuarly recommended in developing countries since it is simple, sensitive and inexpensive. PMID- 23105613 TI - Positive influence of Methotrexate-Hydroxychloroquine combination on the expression of GM-CSF receptor on neutrophils of synovial fluid in rheumatoid arthritis. AB - Granulocyte Macrophage Colony Stimulating Factor (GM-CSF) has been inducted as a mediator of inflammation in rheumatoid arthritis. Methotrexate combination therapy forms an important component of the treatment regimen in rheumatoid arthritis. The present study was undertaken to evaluate the influence of Methotrexate-Hydroxychloroquine (MTX-HCQ) combination and Sulfsalazine- Hydroxychloroquine (SSZ-HCQ) combination on the expression GM-CSFR in neutrophils isolated from synovial fluids. 15 cases of confirmed rheumatoid arthritis patients who presented at the hospital for surgical correction of joint deformities were selected for the study. Neutrophils isolated from the synovial fluids were used as the source of the receptor for quantitation on an enzyme immunoassay (EIA). The EIA was developed and standardized in our laboratory for quantification of the GM-CSF R. The findings are suggestive of the fact that the administration of MTX-HCQ combination has positive influence on the expression of the GM-CSF R on neutrophils as against SSZ-HCQ combination. The physiological basis of this increase needs further investigation. PMID- 23105614 TI - Role of ethanol on aluminum induced biochemical changes on rat brain. AB - Aluminum and alcohol, both are well-accepted neurotoxin. The plausible mechanisms for their neurotoxicity are also common. Therefore, the effect of ethanol on aluminum induced biochemical changes in rat brain is being studied. In the present study, ethanol exposure significantly affected the aluminum and protein content of brain. The activities of acid phosphatase and alkaline phosphatase were also changed. Aluminum exposure, on the other hand, contributed significantly in the alterations of aluminum content, acid phosphatase acivity and aspartate aminotransferase activity. Though ethanol co-exposure significantly influenced the aluminum load of brain, the interactions of these two neurotoxins were found to be significant only in case of acid phosphatase activity of brain. Therefore, it can be suggested that general neurotoxicity produced by aluminum is not modified by ethanol. However, the aluminum load caused by aluminum exposure, may be influenced by ethanol co-exposure. PMID- 23105615 TI - Effect of buspirone: An anxiolytic drug on blood glucose in humans. AB - The present study investigated the effect of an antianxiety drug, buspirone on blood glucose and plasma insulin level concerning the role of 5-HT(1A) receptors in blood glucose regulation in healthy humans. Twelve healthy male volunteers were administered single oral doses of buspirone (10 mg) or placebo, in a randomized, crossover way, followed by oral glucose load (75 gm in 200 ml) at reported T(max) i.e. the time of peak plasma concentration of the respective administered drug. The blood samples were collected as predose, postdose and post oral glucose load at 0.5, 1.0, 1.5, 2.0, 2.5 and 3.0 hr to investigate the effect of buspirone or placebo at basal blood glucose and plasma insulin level and after oral glucose load induced (postprandial) blood glucose and plasma insulin level. Blood glucose and plasma insulin concentrations were estimated by glucose hexokinase method and enzyme linked immunosorbent assay (ELISA) method respectively. The concentration of blood glucose was significantly (p<0.05) decreased after oral glucose load following administration of buspirone in comparison with placebo however no significant change was observed in the fasting blood glucose and plasma insulin (fasting and oral glucose load induced) level. In conclusions, the present study findings show that buspirone produced a significant alteration in blood glucose level in healthy humans. In addition, study results also indicate that the involvement of serotonergic (5-HT, receptors) mechanism of blood glucose regulation in humans is different from animals. PMID- 23105616 TI - Serum alpha-2-macroglobulin, antitrypsin and antichymotrypsin activities in patients receiving treatment with cyclosporine. AB - Cyclosporine has been reported to function as an inhibitor of the chymotrypsin like activity of proteasome. We hypothesized that the administration of an exogenous proteinase inhibitor may affect the activities of the naturally occurring serum anti proteinases. The aim of this study was to observe the pattern of alteration of serum alpha 2 macroglobulin (AMG), alpha 1- antitrypsin (AT) and alpha 1-antichymotrypsin (ACT) activities in renal transplant patients receiving the immunosuppressive drug, cyclosporine. Patients (97) who had received a single renal allograft were inducted into the study. Subjects were on a twice-daily dosage of cyclosporine capsules. Trough (Co) and two-hour post dose (C 2) cyclosporine levels were regularly estimated and all patients had stable creatinine levels. In 5 newly transplanted patients, antiproteinase activities were estimated weekly over a 4-week period as their cyclosporine doses were gradually tapered. Average serum activities of ACT and AMG in the transplant group were significantly less than in the control group (p<0.002 and p<0.003 respectively). AT and ACT activities fell gradually over 4 weeks. AMG activities showed a biphasic pattern, initially falling by almost 50% in the second week, increasing marginally in the third week and decreasing to less than 50% of the activities observed in the first week. Serum antiproteinase activities of serum alpha 2 macroglobulin (AMG), alpha 1-antitrypsin (AT) and alpha 1 antichymotrypsin (ACT) were found to be altered in renal transplant patients receiving cyclosporine. PMID- 23105617 TI - Post prandial plasma glucose level less than the fasting level in otherwise healthy individuals during routine screening. AB - During routine screening, some otherwise healthy individuals who showed remarkably lower post prandial (at 2 hour) plasma glucose without any symptom were subjected to extended glucose tolerance test and a few of them to extended post meal tolerance test as well. It was observed that post prandial (at 2 hour) plasma glucose after glucose administration was significantly lower than the fasting level (p<0.05-p<0.001). However, post prandial plasma glucose at 2 hour after their usual meal exhibited a significantly higher level than the fasting and post glucose level (p<0.05-p<0.001). Glucose appears to be a stronger agent than the more natural mixed meal in these individuals in causing post prandial lowering of plasma glucose. Hence, these individuals are to be evaluated with their usual meals before considering further investigations. Like upper limit, there is the need to have a consensus lower limit of reference interval of blood glucose level. PMID- 23105618 TI - Lack of precision in HbA(1c) values on variant II in cases of hemoglobin Q India. AB - This study was carried out to check the precision of HbA(1c) values on Bio-Rad Variant II in cases of a rare hemoglobin variant Q India. The study was carried out over a three month period on samples collected for HbA(1c) estimation. Seven out of eleven patients showed variable results of HbA(1c) with a very high and unacceptable intraday mean coefficient of variation (CV) of 9.93%. We conclude, that the results of HbA(1c) on Variant II can not be reported without adversely affecting HbA(1c) as a marker of long-term glycemic control in patients who have hemoglobin Q India. The HbA(1c) value of these patients needs to be assessed by a different instrument/method or the glycemic control be monitored by an alternate test like serum Fructosamine. PMID- 23105619 TI - Evaluation of polymerase chain reaction for rapid diagnosis of clinically suspected tuberculous pleurisy. AB - Pleural effusion is one of the commonest presentations of tuberculosis, the clinical manifestations being typically abrupt resembling bacterial pneumonia. Since delayed hypersensitivity is the underlying immune response, bacterial load is very low. Owing to these facts, tuberculous pleurisy as an extra-pulmonary disease poses a diagnostic dilemma. The conventional bacteriological methods rarely detect Mycobacterium tuberculosis in pleural fluid and are of limited use in diagnosis of tuberculous pleurisy. We evaluated the efficacy of polymerase chain reaction (PCR) in the diagnosis of tuberculous pleurisy by targeting the gene segment coding for MPB64 protein specific forMycobacterium tuberculosis. Based on the clinical criteria, 82 patients with lymphocytic exudative pleural effusion were included in the study. Patients were analyzed in two groups; one group consisting of 48 patients of tubercular pleural effusion confimed by various diagnostic procedures and another group of 34 patients comprising of non tubercular pleural effusion. There were no false positive results by PCR and the specificity worked out to be 100%. Twenty two patients tested positive for Mantoux with a sensitivity of 45%. ZN-staining for AFB was found in samples from 15 patients (20% sensitivity). ADA was positive for 28 patients with a sensitivity of 53%. PCR was positive for 32/48 patients (67% sensitivity). Thus, PCR was found to be more sensitive than any other conventional method in diagnosis of clinically suspected tubercular pleurisy. PMID- 23105621 TI - Comparing age-wise reference intervals for serum creatinine concentration in a "Reality check" of the recommended cut-off. AB - An increase in the communication within the healthcare services, both nationally and internationally, has strengthened the need for harmonization of measurements and reference intervals in laboratory medicine. In the present report, the calculated reference interval for serum creatinine (sCr) levels of healthy normal individuals (n=1121) in different sex and age groups are compared with the established interval. The calculated reference interval for sCr level was 0.4-1.3 mg/dL and 0.6 to 1.3 mg/dL in the age groups of 21-40 and 41-60 years respectively. The difference between the mean sCr values in total males and total females (age range 21-60 years) was statistically significant (p<0.0001); When male and female subjects were analyzed age-group wise, the data showed a significant difference in mean sCr values (p<0.0001) in three age groups (21-30, 31-40 and 41-50 years) however, in older age group (51-60 years), the difference was non-significant (p=0.07). The reference ranges were 0.7-1.3 and 0.4-1.0 mg/dL for males and females respectively where the lower limit was 0.1-0.2 units less than that of standard limits. An increase in the mean value of sCr was observed particularly in females with an increase in age. Hence it is of interest to validate an age specific reference ranges for sCr in our population. PMID- 23105620 TI - Role of reactive oxygen species and antioxidants on pathophysiology of male reproduction. AB - The excessive generation of reactive oxygen species (ROS) by abnormal spermatozoa and contaminating leukocytes has been defined as one of the few etiologies for male infertility. Administration of antioxidants in patients with 'male factor' infertility has begun to attract considerable interest. The main difficulty of such an approach is our incomplete understanding of the role of free radicals in normal and abnormal sperm function leading to male infertility. Mammalian spermatozoa membranes are very sensitive to free radical induced damage mediated by lipid peroxidation, as they are rich in polyunsaturated fatty acids. Limited endogenous mechanisms exist to reverse these damages. ROS attacks the fluidity of the sperm plasma membrane and the integrity of DNA in the sperm nucleus. ROS induced DNA damage accelerate the germ cell apoptosis. Unfortunately spermatozoa are unable to repair the damage induced by excessive ROS as they lack the cytoplasmic enzymes required to accomplish the repair. Assessment of such oxidative stress status (OSS) may help in the medical treatment. Treatment strategies must be directed toward lowering of ROS levels to keep only a small amount necessary to maintain normal cell function. PMID- 23105622 TI - The influence of tobacco smoking on humoral immune response in insulin dependent diabetic pregnancy. AB - Tobacco smoking products have a heavy impact on the public health of developed as well as non-developed countries by being a main etiologic factor for the induction of cardiovascular diseases and tobacco-related cancer. The purpose of this study was to determine the influence of tobacco smoking on the measurement of the humoral immune response in Egyptian pregnant women with type 1 diabetes. Concentrations of serum immunoglobulin A, G and M in 35 smoking, 35 non-smoking pregnant women with type 1 diabetes and 35 matched normal women were measured by ELISA. Women were matched by age and working life with controls. Measurements suggested that diabetic smokers had decreased levels of IgG and IgM in their sera. It was found that normal individuals had mean IgA, IgG and IgM levels of 2.80 mg/ml, 9.33 mg/ml and 1.66 mg/ml, respectively while non-smoker women suffering from type 1 diabetes had mean levels of 3.47 mg/ml, 10.97 mg/ml and 2.05 mg/ml (p<0.0004,p<0.0001 andp<0.0002). However, the mean level of IgA, IgG and IgM in diabetic smoker sera was determined to be 3.33 mg/ml, 8.07 mg/ml and 1.31 mg/ml, respectively (p<0.003,p<0.0001 andp<0.0001). The obtained results suggest that toxic smoke components were immuno-suppressant and may well play a part in the complex immuno-pathogenesis interaction. The increased risk of smoking in insulin dependent diabetic pregnant women during pregnancy is a further reason to encourage pregnant women to quit tobacco smoking. PMID- 23105623 TI - Lipid profile in leukemia and Hodgkin's disease. AB - A number of epidemiologic studies has been published in recent years showing an increase risk of death from cancer in subjects with low plasma cholesterol levels. Although several authors proposed that hypocholesterolemia is predisposing factor for cancer development, no causative relation has been established so far and that it may be that low plasma cholesterol is secondary to malignant disease. Hence, the present study was undertaken to examine the lipid profile in children patients with leukemia and Hodgkin's disease in comparison with age matched controls. The study included 52 normal healthy controls and 105 patients with leukemia and Hodgkin's disease. Lipid profile included serum cholesterol, HDL & LDL cholesterol and triglycerides. Serum cholesterol, HDL & LDL cholesterol were found to be inversely associated with incidence of cancer, whereas triglycerides were significantly elevated in cancer patients. The inverse association between cancer and serum cholesterol may reflect a physiological response to early undiagnosed stages of cancer. PMID- 23105624 TI - Comparative study on lipid peroxidation and antioxidant vitamins E and C inFalciparum andVivax malaria. AB - Reactive oxygen species are thought to be involved in the pathogenesis of Malaria. To assess the extent of oxidative stress, a study was conducted in patients withPlasmodium falciparum malaria andPlasmodium Vivax malaria. Plasma Thiobarbituric acid reactive substances (TBARS) were measured to assess the degree of lipid peroxidation. Antioxidant status was measured by estimating the levels of Vitamins E and C. Results were compared with age and sex matched control subjects. This study suggests that plasma TBARS levels were significantly increased in malaria patients. The patients withP. falciparum infection showed significantly increased levels of lipid peroxides when compared toP. vivax malaria. The antioxidant Vitamins E and C were decreased significantly in malaria patients in both the groups. Maximum decline in Vitamin C was observed inP. vivax malaria. Therefore it is been hypothesized that antioxidant Vitamins E and C could provide protection against the oxidative stress induced by malaria. PMID- 23105625 TI - Prevention of isoproterenol-induced cardiac hypertrophy by eugenol, an antioxidant. AB - Recent reports on the involvement of calcineurin in cardiac hypertrophy and its susceptibility to free radicals, prompted us to examine possible beneficial effects of dietary antioxidants in this regard. In continuation of initialin vitro studies revealing eugenol to be a potent calcineurin inhibitor, we investigated its ability to reverse isoproterenol-induced cardiac hypertrophy in rats. Intraperitoneal administration of isoproterenol (1 mg/kg body wt/day for 10 days) induced cardiac hypertrophy with increased heart weight and enhanced apoptosis of myocytes concomitant with accumulation of reactive oxygen species, decreased glutathione contents, increased activities of calcineurin and protein kinase C in ventricular tissue. Administering eugenol for 3 days (1 mg/kg body wt/twice a day), followed by combined administration of isoproterenol and eugenol resulted in significant reversal of cardiac hypertrophy and restoration of above changes. These results suggest that eugenol, a natural antioxidant of dietary origin, may offer potential benefits in the management of cardiac hypertrophy. PMID- 23105626 TI - Blood zinc protoporphyrin, serum total protein, and total cholesterol levels in automobile workshop workers in relation to lead toxicity: Our experience. AB - Blood zinc protoporphyrin (ZPP), serum total protein (TP), and total cholesterol (TC) levels in automobile workshop workers in relation to lead toxicity were analysed. In the present study, automobile workshop workers (healthy male workers at an age between 28 and 35 from four major automobile workshops in Kottayam, Kerala State, India) and the control (male healthy adults at an age between 28 and 35 residing at Aymanam, a distant village at Kottayam District, Kerala having reduced or no chance of lead exposure) displayed significant difference in blood lead (BPb) and blood ZZP (BZPP) level. The mean value of BPb in automobile workshop workers was 15.76+/-0.33 MUg/dl, while in the control it was 8.20+/-0.15 MUg/dl. In automobile workshop workers, the mean value of BZPP was 34.2+/-0.62 MUg/dl. The control group exhibited a mean of 11.5+/-0.22 MUg/dl. Automobile workshop workers exhibited significant increase in BZPP was corresponding to the increase in BPb level. The total protein levels estimated in automobile workshop workers showed significant decrease compared to control individuals, but was within the reference range of healthy individuals. The mean value of TP level in automobile workshop workers and control was 6.9+/-0.13 g/dl and 7.71+/-0.18 g/dl, respectively. There was no significant difference in blood haemoglobin (BHb) level among the automobile workshop workers and control. The serum TC level in automobile workshop workers showed significant decrease compared to the control individuals, but was with in the reference range of healthy individuals. The mean level of serum TC in automobile workshop workers was 162.00+/-3.44 mg/dl and the same in control was 172.86+/-4.32 mg/dl. The present study affirms occupational lead toxicity in automobile workshop workers and its effect on serum protein and cholesterol levels. PMID- 23105627 TI - Proxidant and antioxidant status in patients of type II Diabetes Mellitus with IHD. AB - Patients with type II Diabetes Mellitus (NIDDM) are more prone to Ischaemic Heart Disease (IHD). Although, oxygen free radicals are known to contribute to the development of IHD, conflicting reports are available regarding the antioxidant status in patients of NIDDM complicated with IHD. This study was undertaken to investigate the oxidative status in patients of NIDDM and to assess their correlation with plasma glucose, glycosylated haemoglobin and duration of diabetes. The levels of malondialdehyde were significantly increased where as levels of superoxide dismutase, Glutathione peroxidase and vitamin C were significantly decreased in diabetics without complications and non-diabetics with IHD when compared with the controls. The levels of malondialdehyde and Glutathione peroxidase were significantly increased where as levels of superoxide dismutase and vitamin C were significantly decreased in diabetics with IHD when compared with diabetics without complications and non-diabetics with IHD. The implications of the results are discussed. PMID- 23105628 TI - Antidiabetic effect ofT. arjuna bark extract in alloxan induced diabetic rats. AB - The present study was carried out to evaluate the antidiabetic effect of T. arjuna stembark extract and to study the activities of hexokinase, aldolase and phosphoglucoisomerase, and gluconeogenic enzymes such as glucose-6-phosphatase and fructose-1,6-diphosphatase in liver and kidney of normal and alloxan induced diabetic rats. Oral administration of ethanolic extract of bark (250 and 500mg/kg body weight) for 30 days, resulted in significant decrease of blood glucose from 302.67+/-22.35 to 82.50+/-04.72 and in a decrease in the activities of glucose-6 phosphatase, fructose-1,6-disphosphatase, aldolase and an increase in the activity of phosphoglucoisomerase and hexokinase in tissues. However, in the case of 250 mg/kg body weight of extract, less activity was observed. The study clearly shows that the bark extract ofT. arjuna possesses potent antidiabetic activity. PMID- 23105629 TI - Differential pH sensitivity of tissue superoxide dismutases. AB - Superoxide dismutase (SOD) activities in the human and rat RBCs and rat liver, kidney, brain and heart mitochondria as well as cytosolic fractions were determined by the pyrogallol assay procedure with slight modifications. Measurements were carried out in 0.1 M potassium phosphate buffer pH 8.0 and 9.2 to assess the pH stability of the SODs from various systems. Under these conditions the SODs from different systems including RBCs exhibited differential pH stability i.e. they displayed differential susceptibility at pH 9.2. Even in a given tissue, the mitochondrial and cytosolic SODs contents show a tissue specific pattern. Our results also suggest that measurements carried out at pH 8.0 may give more realistic estimates of SOD activities. PMID- 23105630 TI - Oxidative stress and calcium-phosphorus levels in Rheumatoid arthritis. AB - Generation of reactive oxygen species is an important factor in the development and maintenance of rheumatoid arthritis (RA) in humans. This study was undertaken to investigate interplay among oxidants, antioxidants and pathogenesis of Rheumatoid arthritis. Serum levels of lipid peroxides, nitric oxide, vitamin E and ratio of calcium/phosphorus in RA patients were determined and compared with normal healthy controls. Significant increases in lipid peroxides (p<0.001) and nitric oxide (p<0.001) levels were found in patients presenting with RA as compared to controls. Whereas significant decrease in vitamin E (P<0.001) and calcium/phosphorus ratio (p<0.001) were found in Rheumatoid arthritis patients as compared to controls. Positive correlation was found between lipid peroxides and nitric oxide as well as between vitamin E and calcium. While lipid peroxides and nitric oxide were correlated negatively with vitamin E. whereas negative correlation was observed between MDA and Calcium/Phosphorus ratio in patients with rheumatoid arthritis. Our findings suggest that there is a close association between bone loss and oxidative threat in patients presenting with Rheumatoid arthritis. PMID- 23105631 TI - In vitro inhibition of lipid peroxidation in fish by turmeric (Curcuma longa). AB - The beneficial effects of ?-3 fatty acids on human health have been well documented. Fish and fish oils are the richest sources of ?-3 fatty acids. However, due to their high degree of unsaturation, they are highly susceptible to lipid peroxidation. Regular consumption of peroxidised oils may represent a risk factor for the induction and development of atherosclerosis. In view of the above reports, it was considered necessary to study the effects of tumeric on fish lipid peroxidation during standard cooking practices and on time-dependent changes in the peroxidation of fish homogenate. The antioxidant effect of alpha tocopherol was also studied to confirm the relevance of the study. The results suggest that turmeric may be considered as a safe, cheap and readily usable antioxidant for food preparations. PMID- 23105632 TI - Urinary N-acetyl beta glucosaminidase and gamma glutamyl transferase as early markers of diabetic nephropathy. AB - Albumin and enzymes-N-acetyl-beta-glucosaminidase (NAG) and gamma glutamyl transferase (GGT) were estimated in the morning random urine samples of 196 albustix negative diabetic patients to evaluate the clinical utility of these urinary enzymes as early markers of diabetic nephropathy. Albumin was estimated by immunoturbidimetric method and enzymes by linetic essay within six hours of voiding of urine. The urinary albumin and urinary enzyme concentration was calculated in terms of ratio with respect to urinary creatinine. Correlation coefficient (r) bewween urinary albumin and urinary enzymes in normoalbuminuric, microalbuminuric and overall diabetic cases was 0.23, 0.32 and 0.40 respectively for NAG, and 0.08, 0.06 and 0.18 respectively for GGT. NAG excretion was found increased in 34%, 63.7% and 49.5% of normoalbuminuric, microalbuminuric and overall diabetic cases respectively while GGT in 6.4%, 24.5% and 15.8%. The correlation coefficient between urinary albumin and NAG in normoalbuminuric, microalbuminuric, and overall diabetic patients with increased NAG excretion was found only 0.31, 0.27 and 0.35 respectively. No correlation was found between duration of diabetes and enzyme excretion. The study suggests that urinary NAG or GGT or both together do not have any clinical significance as an early marker of diabetic nephropathy. PMID- 23105633 TI - Effect of methyl mercury induced free radical stress on nucleic acids and protein: Implications on cognitive and motor functions. AB - Mercury pollution and acute neurotoxicity of mercury is well known. The recent reports suggest the adverse effect of low dose mercury, though the available literature is still silent on its mechanism. This study was therefore undertaken to probe the effect of low dose methyl mercury induced heavy metal toxicity on free radical stress and its impact on behaviour of male albino rats. Male albino rats were exposed to 1 mg/kg body wt of methylmercury chloride for seven days, on day 8 they were tested for motor and memory functions. They were sacrificed later for biochemical estimations for rate of lipid peroxidation, nucleic acids, proteins in cerebrum, cerebellum and brain stem. There was an increase in the rate of lipid peroxidation showing methyl mercury induced free radical stress. The motor and memory functions demonstrated a clear decline, besides there was a lowering in the levels of nucleic acids and proteins as compared to controls. The results are important in view of recent reports that methyl mercury induced free radical stress results in early ageing and may serve as an initiating factor more specifically for neurodegenerative disorders like Alzeihemer's disease and dementias. The current findings support the notion that incorporating dietary antioxidants like curcumin, ascorbic acid and alpha-tocopherol in routine diet from early age may help combat the risk of developing such disorders in ensuing years. PMID- 23105634 TI - Serum lipids in hypothyroidism: Our experience. AB - In order to determine whether the screening of lipid profile is justified in patients with hypothyroidism we estimated serum lipids in cases having different levels of serum TSH. 60 patients of hypothyroidism in the age group of 20 to 60 yrs were studied for thyroid profile over a period of one year. On the basis of serum TSH level the cases were divided into three groups: In the first group TSH concentration was 8.8+/-2.99 MUlU/ml, 95% confidence interval (Cl) 8.8+/-1.07, whereas serum total cholesterol and LDL-chol levels were 196+/-37.22 and 126+/ 29.17 mg/dl respectively. The statistical analysis of these two groups showed a significant correlation between raised TSH levels and serum total cholesterol and LDL-chol (P<0.05 & P<0.01) respectively. We conclude that hypothyrodism is associated with changes in lipid profile. PMID- 23105635 TI - Defect in mitochondrial functions in damaged human mitral valve. AB - Mitochondrial diseases are a heterogeneous group of disorders in which a primary mitochondrial dysfunction is proven by morphological, biochemical, and genetic examinations. The mitral valve has important function in the regulation of blood flow from one chamber to another. Often, the mitral valve becomes abnormal with age, in Rheumatic fever or it is abnormal from birth (Congenital) or it can be destroyed by infection i.e. bacterial endocarditis and needs replacement. Myocardial function depends on energy produced by mitochondria and in any of these disease conditions, mitochondrial functions and enzyme activities may be impaired. With this in view, we analyzed the relationship between preoperative clinical conditions (as per New York heart Association) and extent of mitochondrial enzyme activities in damaged Human mitral valve in two types of heart disease such as Rheumatic Heart Disease (RHD) and Bacterial Endocarditis (BE). Thirty nine Patients undergoing cardiopulmonary bypass (CPB) for routine valvular heart surgery were included in the study. Controls included 11 normal porcine mitral valve samples without any evidence of heart disease. Mitochondrial enzymes like cytochrome oxidase (COX), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), citrate synthase (CS) and ATPase were determined. Mitochondrial COX, SDH, CS and Total ATPase activities were significantly decreased in disease condition like BE and RHD when compared with control (P<0.001). On the other hand as per New York Heart Association (NYHA) preoperative clinical classification, all the mitochondrial enzymes were significantly (p<0.05) impaired in class IV as compared with NYHA class I, II and III. Present study shows that impairment in the mitochondrial enzymes activities are more pronounced in bacterial endocarditis (BE). It also indicates that damage to mitochondrial enzymes are most pronounced in NYHA class IV. PMID- 23105636 TI - Plasma oxidant-antioxidant status in different respiratory disorders. AB - This study confirms the fact that in different respiratory disorders, the status of plasma oxidants and antioxidants shifts from normal. The status of oxidants in plasma as represented by malondialdehyde (MDA) levels increased significantly in the conditions of chronic obstructive pulmonary disease (COPD), emphysema, bronchiectasis and bronchial asthma. The two vitamin antioxidants vitamin C and vitamin E showed decreased levels than in controls. In patients with COPD the endogenous antioxidant viz. reduced glutathione (GSH) estimated from whole blood was comparable to that of control group, whereas in patients with emphysema, bronchiectasis and bronchial asthma, GSH concentration was increased to that of control group. The activity of enzyme superoxide dismutase (SOD) was significantly decreased in all study groups. Pulmonary function tests were found to have no correlation with MDA and antioxidants. PMID- 23105637 TI - Study of serum lipid profile in pregnancy induced hypertension. AB - Four groups of subjects: normal healthy normotensive nonpregnant women (Group A), normal normotensive pregnant women (Group B), women with preeclamptic toxaemia (Group C) and eclamptic women (Group D): with fifty subjects in each group, were investigated for serum lipid profile in the third trimester of pregnancy. There was significant increase in serum triglyceride and VLDL cholesterol leve as well as decrease in LDL cholesterol in normal pregnancy, while total cholesterol and HDL cholesterol levels did not show any statistically significant alteration. The preeclampsia (Group C) was associated with a significant rise in triglyceride and VLDL cholesterol and fall in HDL cholesterol concentration, while eclamptic women showed significant fall in HDL cholesterol and rise in LDL cholesterol as compared to normal pregnant women. However, interestingly, elevation of the ratios of total cholesterol: HDL cholesterol and triglyceride: HDL cholesterol as well as diminuition of the ratio of HDL cholesterol: VLDL cholesterol showed statistical significance in pregnancy induced hypertension in both Groups C and D, while eclamptic women showed significant elevation of LDL cholesterol: HDL cholesterol ratio in addition. PMID- 23105638 TI - Organochlorine pesticides BHC and DDE in human blood in and around Madurai, India. AB - In this study blood samples are taken from two groups of people, one that has direct exposure to pesticides (agriculturists & public health workers) the second group, which has indirect exposure to pesticides through food chain. The objective of our investigation is to analyze the blood of the patients with minimum health complaints and skin diseases for the residue of the banned organochlorine pesticides DDE and BHC using Gas Chromatography. High concentrations of both BHC&DDE were observed in the serum samples of the people who had direct exposure to the pesticides, namely agriculturalists and public health workers with few exceptions. The pesticide residue concentration in serum ranges from 0.006 to 0.130 ppm for BHC and 0.002 to 0.033 ppm for DDE. Significance of this study reveals that the presence of these banned pesticides in human serum. PMID- 23105639 TI - Paraoxonase activity and antibodies to oxidized-LDL in chronic renal failure patients on renal replacement therapy. AB - Serum paraoxonase (PON1) and antibodies to oxidized-LDL (anti ox-LDL) were measured in chronic renal failure subjects on renal replacement therapy such as hemodialysis (HD) peritoneal dialysis (PD) and transplantation (Txp). Paraoxonase activity was significantly lower in HD and PD group (P<0.001) than in control subjects. In transplant patients, paraoxonase activity was not significantly different from that of controls. Antibodies to ox-LDL was significantly higher in HD, PD and Transplant patients (P<0.0001) compared to control subjects. High titers of antibodies were observed in the HD group compared to the PD and Transplant subjects. A decrease in paraoxonase activity and high titers of Antibodies to ox-LDL in the dialysis group suggest a decreased cardio protective effect of HDL and enhanced risk of premature cardiovascular complications. Whereas in case of transplant subjects, there seems to be restoration of PON1 activity, but elevated levels of anti-oxLDL could still be a potential atherogenic factor. Hence, we propose that estimation of these two parameters can be used as a useful index to measure the cardiac risk in the above patient category. PMID- 23105640 TI - Depleted nitrite and enhanced oxidative stress in urolithiasis. AB - Crystal aggregation and retention are critical events for the formation of kidney stones. There is a close association between crystal development and free radical activity in vivo. In the present study 30 subjects presenting with urolithiasis were included. Serum levels of total lipid peroxides, nitric oxide (as nitrite), alpha-tocopherol, plasma ascorbic acid (vitamin C) and erythrocyte superoxide dismutase activity were measured. These findings were compared with 30 age matched control subjects irrespective of sex. Student's 't' test was applied for statistical analysis. There was a significant increase in lipid peroxides (p<0.001), where as significant decrease in nitrite (p<0.01) and alpha-tocopherol (p<0.001) levels were observed. Plasma ascorbate (p>0.05) and erythrocyte superoxide dismutase activity (p>0.05) was also found to be decreased but the difference was not statistically significant which suggests that oxidative stress is evident in urolithiasis with depletion in antioxidant status where as decrease in nitric oxide may be less abetting in disease condition. PMID- 23105642 TI - Ambulatory diabetic patient with remarkable hypoglycaemia. PMID- 23105641 TI - Effect ofOcimum sanctum (Tulsi) and vitamin E on biochemical parameters and retinopathy in streptozotocin induced diabetic rats. AB - This study was carried out to see the effect of the aqueous extract ofOcitum sanctum Linn (Tulsi) with Vitamin E on biochemical parameters and retinopathy in the streptozotocin-induced diabetic albino male rats. Adult albino male rats weighing 150-200 gm were made diabetic by intraperitoneal injection of streptozotocin in the dose 60 mg/kg in citrate buffer (pH 6.3). The diabetic animals were left for one month to develop retinopathy. Biochemical parameters like plasma glucose, oral glucose tolerance and glycosylated hemoglobin HbA(1c), were measured along with lipid profile, and enzymes like glutathione peroxidase (GPX), lipid peroxidase (LPO), superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) in normal, untreated diabetic rats and diabetic rats treated withOcimum sanctum L extracts and vitamin E. Fluorescein angiography test was done for assessing retinopathy. Results on biochemical parameters were analyzed statistically by using ANOVA followed by Dunnet's 't'-test. A p-value of <0.05 was considered as significant. Evaluation of biochemical profile in treated groups showed statistically significant reduction in plasma levels of glucose, HbA(1c), lipid profile and LPO, and elevation of GPX, SOD, CAT and GST. Treatment of the diabetic animals withOcimum sanctum and Vitamin E, alone and in combination for 16 weeks showed reversal of most of the parameters studied including plasma glucose levels. Angiography showed improvement in retinal changes following combined antidiabetic treatment. PMID- 23105643 TI - Metabolic syndrome: Early identification prevents type II diabetes and cardiovascular disease. PMID- 23105644 TI - Brain type natriuretic peptide (BNP)-A marker of new millennium in diagnosis of congestive heart failure. AB - The burden of disease in patients with congestive heart failure is high. The future of BNP looks promising as it may be a better diagnostic tool for the diagnosis of CHF in developing countries in new millennium. Natriuretic peptide hormones, a family of vasoactive peptides with many favourable physiological properties, have emerged as important contenders for development of diagnostic tools and therapeutic agents in cardiovascular disease. Measurement of B-type natriuretic peptide has become as an easy-to-perform bedside test. The clinical and diagnostic significance of the measurement of plasma Nt-proBNP in the diseases of the cardiovascular system with particular emphasis on the assessment of patients with heart failure and their effects on predicting survival rate. The plasma levels of Nt-proBrain Natriuretic peptide responds more vigorously after myocardial infarction than those of other natriuretic peptides. This article is an attempt to give a short overview on the utility of BNP-blood levels for the diagnosis and treatment of heart failure. PMID- 23105646 TI - Risk prediction-Homocysteine in Coronary Heart Disease. AB - Majority of patients who experience a Coronary Heart disease event have one or more of the conventional risk factors for atherosclerosis and so do many people who have not yet experienced such an event. Thus predictive models based on conventional risk factors have lower than the desired accuracy, providing a stimulus to search for new factors to predict accurately the risk of CHD. In this regard newer risk factors like homocysteine, Lp(a), insulin resistances are the important ones and are called as 'novel risk factors'. The study was undertaken to find the prediction of CHD risk by homocysteine in comparison with other conventional risk factors. The data obtained suggests a very high sensitivity, specificity and accuracy with above 90% positive prediction value for homocysteine in CHD patients when compared to commonest conventional risk factors. PMID- 23105645 TI - Biochemical markers of myocardial injury. AB - The serum markers of myocardial injury are used to help in establishing the diagnosis of myocardial infarction. The older markers like aspartate amino transferase, creatine kinase, lactate dehydrogenase etc. lost their utility due to lack of specificity and limited sensitivities. Among the currently available markers cardiac troponins are the most widely used due to their improved sensitivity specificity, efficiency and low turn around time. Studies have shown that cardiac troponins should replace CKMB as the diagnostic 'gold standard' for the diagnosis of myocardial injury. The combination of myoglobin with cardiac troponins has further improved the accuracy in the diagnosis of acute coronary syndromes and thereby reducing the hospital stay and patients' money. Among the other new markers of early detection of myocardial damage, heart fatty acid binding protein, glycogen phosphorylase BB and myoglobin/carbonic anhydrase III ratio seem to be the most promising. But the search for the most ideal marker of myocardial injury is still on. PMID- 23105647 TI - Cardioprotective response to chronic administration of vitamin E in isoproterenol induced myocardial necrosis: Hemodynamic, biochemical and ultrastructural studies. AB - The present study evaluated the cardioprotective potential of vitamin-E by studying its effect on hemodynamic parameters, lipid peroxidation, myocyte injury marker and ultrastructural changes in model of isoproterenol-induced myocardial necrosis in rats. Wistar albino male rats (150-200 g) were randomly divided into saline, ISP control, and vit E groups. Vitamin E group was administered vitamin E at a dose of 100mg/kg/day while saline and ISP control groups received saline orally for one month. On 29(th) and 30(th) day, ISP (85 mg/kg, sc) was administered at an interval of 24 h to vit E and ISP control rats. On 31(st) day, rats of all groups were anesthetized and hemodynamic parameters were recorded. At the end of experimentation, animals were sacrificed; hearts were excised and processed for biochemical and ultrastructural studies. ISP administration produced marked cardiac necrosis as evidenced by significant decrease in my ocardial creatine kinase-MB as well as increase in malonaldialdehyde levels. ISP induced myocardial necrosis resulted in myocardial dysfunction as evidenced by significant depression in heart rate and mean arterial pressure in the ISP control group as compared to saline control. Salient ultrastructural changes including extensive loss of myofibrils, muscle necrosis, loss of mitochondria, and formation of several intracytoplasmic vacuoles and lipid droplets further confirmed the ISP-induced myocardial damage. However, subsequent to ISP challenge, vit E treatment significantly preserved the myocardium by restoring myocardial CK-MB activity, inhibiting the ISP-induced lipid peroxidation and ultrastructural changes. Additionally, pre-and co-treatment of vit E prevented the deleterious ultrastructural changes caused by ISP. These beneficial effects of chronic vit E treatment also translated into significant restoration of the altered hemodynamic parameters. The present study clearly demonstrated the cardioprotective potential of vit E at dose of 100 mg/kg in ISP-induced model of myocardial necrosis in rats. The significant restoration of altered hemodynamic parameters, myocardial CK-MB activity, prevention of ISP-induced rise in lipid peroxidation and ultrastructural changes may confirm its cardioprotective effect. PMID- 23105648 TI - Effect of caffeine on the risk of coronary heart disease- A re-evaluation. AB - The effect of caffeine intake on the risk of coronary heart disease was studied. Twenty-one rats used were randomly divided into three experimental groups, the first group served as the control while the second and third groups were administered caffeine orally at doses of 10mg/kg body weight and 20mg/kg body weight respectively for fourteen days. Caffeine, at 10mg/kg body weight, significantly increased (P<0.05) serum LDL- cholesterol concentration and coronary heart disease risk ratio while it significantly reduced (P<0.05) serum triacylglycerol concentration when compared with controls. At 20mg/kg body weight, caffeine significantly increased (P<0.05) coronary heart disease risk ratio while it significantly reduced (P<0.05) serum HDL-cholesterol concentration and serum triacylgycerol concentration when compared with controls. No dose response effect was observed possibly suggestive of a threshold effect. These results suggest that caffeine predisposes consumers of caffeine containing beverages to coronary heart disease. PMID- 23105649 TI - A serial follow up study of cardiac marker enzymes during the week after acute myocardial infarction. AB - Laboratory infarction diagnostics are based on the detection of elevated serum activities of creatine kinase (CK) Creatine kinase Isoenzyme MB (CKMB) and Transaminases. Determination of these cardiac marker enzymes permits the diagnosis of transmural myocardial infarction. However in such patients the diagnosis of acute myocardial infarction can be confirmed by the clinical symptoms and changes in the ECG, in addition to the enzyme assays. The 50 AMI patients selected in the present study were those admitted to the ICCU of Shri Krishna Hospital, Karamsad. The blood samples were taken at Zero hours (i.e. at the time of admission of the patient). Within 6 hrs of the starting of chest pain, 1.5 million units of streptokinase were mixed with 100 to 150ml of normal saline and administered by infusion over a period of one hour. The blood samples were further collected at intervals of 6 hrs, 14hrs, 32hrs, 48hrs, 5(th) day and 7(th) day. The blood samples were analyzed for CK, CKMB, SGOT, alpha HBDH and Cardiac specific Troponin T. By 6hrs the CK and CKMB values had started rising, the rise continuing at 14hrs with peak values at 32hrs. The CK showed a slight decrease by 48 hrs. The cardiac Troponin T showed wide time window from 4 hrs to 7(th) day for detecting myocardial damage. The maximum cardiac Troponin T values were during the first 24hrs. Cardiac Troponin T in serum appears to be a more sensitive and early indicator of myocardial cell injury in comparison to CKMB. PMID- 23105650 TI - Caprine cardiac sarcoplasmic reticulum isolation and biochemical characterisation with emphasis on Ca(2+)-adenosine triphosphatase. AB - This study was aimed at isolating, in its pure form, and characterizing the sarcoplasmic reticulum from caprine (Capra hircus) heart. The sarcoplasmic reticulum from thirty caprine heart ventricular homogenates was isolated and purified. It was characterized on the basis of both, its protein and lipid composition. The protein content was 142+/-10 mg/g of tissue. Ca(2+)-ATPase activity equaled 3.75+/-1.06mmol Pi/mg protein/min while the uptake rate was 24+/ 1.14 nmol/mg protein/min. 205kD, 110kD, 90kD, 84kD, 66kD, 55kD and 29kD molecular weight proteins were seen on an SDS polyacrylamide gel. Triglyceride, Cholesterol and Phospholipids (phosphatidylethanolamine, phosphatidylinositol, phosphatidylcholine, sphingomyelin and phosphatidylserine) were present in increasing order of their concentration. Long chain fatty acids predominated over the unsaturated ones. The ryanodine receptor displayed two binding sites for ryanodine. Characterisation encompassing the above biochemical aspects of normal caprine cardiac sarcoplasmic reticulum was thus achieved after isolating it in the pure form. PMID- 23105651 TI - Antioxidant status in patients with acute myocardial infarction. AB - Free radicals play an important role in the pathogenesis of tissue damage in many clinical disorders, including atherosclerosis. Antioxidants protect the body from damage caused by free radicals. In this study we investigated oxidative stress, antioxidants and inflammatory molecules in patients with acute myocardial infarction. This study has been carried out on 106 patients with acute myocardial infarction, (89 men and 17 females). The control group consisted of 50 healthy, age-matched subjects (40 men and 10 females). Levels of Glucose, lipid profile, glutathione reduced, glutathione peroxidase, Superoxide dismutase, Glycosylated hemoglobin, fibrinogen, vitamin C, vitamin E, malondialdehyde, ceruloplasmin, adenosine deaminase, lysozyme and sialic acid were measured. Malondialdehyde and ceruloplasmin levels were significantly high and antioxidants such as vitamin C, vitamin E, glutathione reduced, glutathione peroxidase and superoxide dismutase were significantly decreased in diabetic and non-diabetic AMI patients as compared with control (p<0.001). Inflammatory markers showed significant rise in diabetic patients as compared with controls. Our results clearly show increased inflammation and oxidative stress in patients with acute myocardial infarction. Depression of antioxidant system in these patients confirms this conclusion. PMID- 23105652 TI - Tumor marker requests in a general teaching Turkish hospital. AB - Serum tumor markers may be requested inappropriately by clinicians. In this retrospective study, we aimed to investigate the appropriateness of TM requests in our hospital. Patients in the study were identified from the TM requests for 3 months between June-August 2004, using the laboratory database. A total of 2249 patients (1351 men, 898 women) were included in the study and there were 6570 TM requests. The number of requests were 1050 (16%) for Carbohydrate Antigen 19-9, 993 (15.1%) for Cancer Antigen 125, 941 (14.3%) for Prostate Specific Antigen, 921 (14%) for free PSA, 925 (14.1%) for Cancer Antigen 15-3, 788 (12%) for Alphafetoprotein, 730 (11.1%) for Carcinoembryonic Antigen and 222 (3.4%) for AFP/Human Chorionic Gonadotrophin. Our findings support the idea that for the evidence-based use of TM requests the education of clinical staff is required. Clear clinical guidelines including recommendations about the appropriate use of TM can be useful for this education process. Careful audit studies are also useful to determine the impact of these guidelines on the practice of evidence based laboratory medicine. PMID- 23105653 TI - Correlation study of Carcino Embryonic Antigen & Cancer Antigen 15.3 in pretreated female breast cancer patients. AB - Carcino Embryonic Antigen (CEA) and Cancer Antigen 15.3 (CA15.3) are the most common tumor markers in breast cancer patients. Measurement of circulating tumor markers is a non-invasive quantitative method. Serum levels of CEA and CA 15.3 were studied in female breast cancer patients prior to treatment. To evaluate the utility of these markers, 207 Breast carcinoma patients belonging to all the stages were considered. Healthy age matched 75 female individuals formed the control group. The serum levels of CEA and CA 15.3 were analyzed by Enzyme Linked Immunosorbent Assay (ELISA). Results were taken and compared with stages, tumor size, node and grade. The serum CA 15.3 levels were significant in all the study parameters whereas serum CEA levels showed no significant changes with any of the parameters. Measurement of serum CA 15.3 levels showed significant correlation (24.8%) with advanced stages and larger tumor sizes, whereas serum CEA levels did not show any significant correlation in breast cancer patients prior to treatment. PMID- 23105654 TI - Interleukin-1 receptor antagonist gene polymorphism and obesity: A pilot study from north India. AB - The main adverse consequences of excess bodyweight are cardiovascular disease, type II diabetes, and several cancers, IL-1Ra serum concentration has been reported earlier to increase in human obesity and it is therefore assumed that the polymorphism of IL-1Ra may influence cytokine production. We designed this study to investigate whether the IL-1Ra polymorphism was associated with obesity. A total number of 103 individuals; 19 lean (BMI<25 Kg/m(2)), 51 overweight (BMI 25-29.9 Kg/m(2)) and 33 obese (BMI>=30.0 Kg/m(2)) were enrolled in this study. Genotyping was performed using a polymerase chain reaction PCR amplification of the intron-2 fragment harboring a variable number of tandem repeat (VNTR) nucleotide sequences 86 pb of tandem repeat. The PCR products were separated on 2% agarose gel. Statistical analysis was performed using SPSS software (version 11.5). We found no significant difference in genotype and allele frequencies between the three groups; lean vs. overweight and lean vs. obese (p=0.323; 0.202; 0.123 and 0.068 resp). However, an increased risk for obesity had a propensity to be higher in those having genotype II/II. This genotype has been reported to be a 'high producer' of IL-1Ra. Although no statistically significant relationship between IL-1Ra polymorphism and BMI was observed, however, a trend towards an increase of allele(*)II in overweight and obese group was observed. This may suggest that IL-1Ra appears to be induced by inflammatory stimuli as well as obesity-associated factors. This is relatively a pilot study: but nevertheless, may assist in identifying the pathophysiological cause for obesity. PMID- 23105655 TI - Paired values of serum fructosamine and blood glucose for the screening of gestational diabetes mellitus: A retrospective study of 165 Saudi pregnant women. AB - This study reports the utilization of serum fructosamine and blood glucose for the screening of gestational diabetes mellitus (GDM). Blood samples from 165 pregnant women were analyzed for fasting blood glucose (FBG), random blood glucose (RBG) and serum fructosamine. The actual fructosamine levels were corrected for serum protein (c-Fruct) for more precise presentation. Two cut-off values of FBG (>5.3 mmol/L and >7.0 mmol/L) and RBG (>7.8 mmol/L and >11.0 mmol/L) were used to classify hyperglycemic subjects for subsequent evaluation. The average values+/-standard deviations for FBG, RBG and cFruct were 5.865+/ 1.95, 7.767+/-3.21 and 2.387+/-0.47 mmol/L, respectively. FBG levels were significantly correlated with RBG (Pearson correlation=0.597, P<0.001). Significant correlations were also observed between cFruct and FBG (Pearson correlation=0.673, P<0.001) or RBG (Pearson correlation=0.641, P<0.001). Out of 165 subjects, 24 (14.5%) cases were classified as hyperglycemic on the basis of FBG>7.0 mmol/L or RBG>11.0 mmol/L; use of lower cut-off values resulted higher frequencies of hyperglycemia. Whereas, a combined criteria of FBG>5.3 mmol/L and cFruct >2.5 mmol/L predicted 35 patients as the most probable hyperglycemic as compared to 32 patients identified using the criteria of RBG >7.8 mmol/L and cFruct >2.5 mmol/L. These criteria were associated with 4.8% and 3.6% false positivity at the expense of 3.6% and 3.0% false-negative outcomes, respectively. The levels of FBG, RBG and cFruct were significantly higher in hyperglycemic groups (irrespective of grouping criteria) as compared to the respective normal groups. In conclusion, these findings clearly indicate that the paired values of cFruct with FBG or RBG could help in filtering high-risk individuals for OGTT and therefore avoiding a unnecessary OGTT. PMID- 23105656 TI - Treatment of streptozotocin induced diabetes in male rats by immunoisolated transplantation of islet cells. AB - Insulin injection is the main way to combat against insulin-dependent diabetes mellitus effects. Today in some laboratories in the world, the investigators are trying to find some treatments for this disease with insulin-secreting pancreatic islet cells transplantation. Donor tissue in each step of work was prepared from 36 adult male wistar Rats weighted 250-300 grams (75-90 days). Transplantation was done in rats after 2-4 weeks induction of diabetes with 60mg/kg of streptozotocin injection by intravenous method. Encapsulation of pancreatic islet cells allows for transplantation in the absence of immunosuppression. This technique that is called "immunoisolation" is based on the principle that transplanted tissue is protected for the host immune system by an artificial or natural membrane. In this study, the levels of insulin, C-peptide and glucose in diabetic rats have been reached to normal range as compared to un-diabetic rats in 20 days after transplantation of islet cells, so that testis is immunoisolated place for islet cells transplantation. Inside the testis subcutaneously and intrapretoneally implantation of pure islet cells graft, that is a natural immunoisolation method, rapidly and permanently normalized the diabetic state of streptozocin-administered animals. PMID- 23105657 TI - Antihyperglycemic and antilipidperoxidative effects ofTephrosia purpurea seed extract in streptozotocin induced diabetic rats. AB - The aim of the present study was to evaluate the antihyperglycemic and antilipidperoxidative effects of ethanolic seed extract ofTephrosia purpurea (TpEt) in streptozotocin induced diabetic rats. Hyperglycemia associated with an altered hexokinase and glucose 6 phosphatase activities, elevated lipid peroxidation, disturbed enzymatic and non-enzymatic antioxidants status were observed in streptozotocin induced diabetic rats. Oral administration of "TpEt" at a dose of 300mg/kg bw showed significant antihyperglcemic and antilipidperoxidative effects as well as increased the activities of enzymatic antioxidants and levels of non enzymatic antioxidants. We also noticed that the antihyperglycemic effect of plant drug (TpEt) was comparable to that of the reference drug glibenclamide. Our results clearly indicate that "TpEt" has potent antihyperglycemic and antilipidperoxidative effects in streptozotocin induced diabetic rats and therefore further studies are warranted to isolate and characterize the bioactive antidiabetic principles from "TpEt". PMID- 23105658 TI - Diabetic cardiomyopathy and reactive oxygen species (ROS) related parameters in male and female rats: A comparative study. AB - Studies were carried out to examine and compare the effects of alloxan-diabetes on reactive oxygen species (ROS) related parameters in the heart from male and female rats. Effects of insulin treatment were also evaluated. The diabetic state severely compromised the ROS defense mechanism in the cardiac tissue and the effects were more pronounced in the female than in the male rats. There was several fold increase in the xanthine oxidase (XO) activity in general and the magnitude of increase was higher in the females; insulin treatment resulted in further increase in the XO activity. The glucose-6-phosphate dehydrogenase (G6PDH) and catalase activities decreased and the reduced glutathione (GSH) content in mitochondria was completely depleted in diabetic state with significant decrease in the GSH levels in the post-mitochondrial fraction; the effect was more pronounced in the females. The superoxide dismutase (SOD) and glutathione peroxidase (GPox) activities increased in the diabetic state to a greater extent in male rats. Insulin treatment had restorative action only on some parameters. In conclusion, our results suggest that diabetic state may further compromise the weak ROS defense systems in the heart thus initiating a lesion at the level of mitochondria which ultimately leads to cardiomyopathy and the effects are especially more pronounced in the females. Our results also pointed out that insulin treatment was ineffective in restoring ROS related parameters. PMID- 23105659 TI - Comparison between erythrocyte hemoglobin and spectrin glycosylation and role of oxidative stress in type-2 diabetes mellitus. AB - New findings on organization of blood cell cytoskeleton represent an exciting aspect of modem cell biology and hematology, which is an interesting investigation to study diabetes. The present study was undertaken in 150 subjects. Out of these, 30 subjects were controls (Group I) and 30 were type-2 diabetics without any complication (Group II), while remaining 90 subjects were type-2 diabetics with complication (Group III). We determined erythrocyte spectrin and hemoglobin glycosylation and also estimated plasma lipid peroxide, nitric oxide and erythrocyte glutathione peroxidase activity to assess the status of oxidative stress. There was a significant increase in spectrin (P<0.001) and hemoglobin (P<0.001) glycosylation in Group II and III as compared to Group I and spectrin glycosylation was nearly three times more as compared to hemoglobin, whereas plasma levels of lipid peroxide (P<0.001) as well as nitric oxide (P<0.001) were found to be significantly increased and GPx activity (P<0.001) was significantly decreased in Group II and III as compared to Group I. However, it was also observed that spectrin (P>0.05) and hemoglobin (P>0.05) glycosylation was not significantly different in Group II and III. In contrast, there was significant rise in lipid peroxide (P<0.001), nitric oxide (P<0.001) and fall in GPx activity (P<0.001) in Group III when compared to Group II. Increased erythrocyte protein glycosylation and oxidative stress is clearly evident from our study. However, to understand the exact interplay between these two mechanisms, further studies are required. PMID- 23105660 TI - Effect of short term supplementation of tomatoes on antioxidant enzymes and lipid peroxidation in type-II diabetes. AB - The objective of the present study is to evaluate the beneficial effect of tomatoes, which are rich source of Lycopene, relatively a new carotenoid known to play an important role in human health and disease. In this study lipid peroxidation rate was measured by estimating Malondialdehyde and the levels of serum enzymes involved in antioxidant activities like Super Oxide Dismutase, Glutathione Peroxidase, Glutathione Reductase, Reduced Glutathione, in type-II diabetic group (n=40) and age matched control group (n=50), and observed significantly lower levels of antioxidant enzymes and very high lipid peroxidation rate in type-II diabetes when compared to control group (p<0.001). Short term supplementation with tomatoes (cooked) to diabetic group for a period of 30 days, showed a significant improvement in antioxidant enzyme levels (p<0.001) and decreased lipid peroxidation rate (p<0.001) suggesting the supplementation with tomato lycopene may serve as the best method of preventing the oxidative stress in diabetic patients. PMID- 23105661 TI - Oxidative stress is the primary event: Effects of ethanol consumption in brain. AB - Damaging effects of reactive oxygen species on living systems are well documented. They include oxidative attack on vital cell constituents. Chronic ethanol administration is able to induce an oxidative stress in the central nervous system. In the present study, 16-18 week-old male albino rats of Wistar strain were exposed to different concentration of ethanol for 4 weeks. This exposure showed profound effect on body weight. Ascorbic acid level; and activities of alkaline phosphatase and aspartate transaminase in the brain are dependent on the concentration of ethanol exposure. Chronic ethanol ingestion elicits statistically significant increase in thiobarbituric acid reactive substances level and decrease in gluatathione level in the brain. It reduces superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities in a dose dependent manner. However, histological examination could not reveal any pathophysiological changes. Therefore, we conclude that biochemical alterations and oxidative stress related parameters respond early in alcoholism than the histopathological changes in brain. PMID- 23105662 TI - Biochemical activity of selenium and glutathione on country made liquor (CML) induced hepatic damage in rats. AB - The serum and hepatic enzymes of rats were studied after exposed to country made liquor (CML) along with two chelating agents (glutathione and Selenium). There was a significant increase in several serum enzyme levels (viz., aspartate transaminase, alanine transaminase, alkaline phosphatase, sorbitol dehydrogenase, glutamate dehydrogenase, bilirubin) and decrease in various hepatic enzymes (Succinic dehydrogenase, Glucose 6-phosphatase, 5'Nucleotiease, Acid phosphatase, Acid ribonuclease, Cytochrome P-450) due to repeated administration of CML (2ml/100g of body weight). Results of this study revealed that the GSH and Se could give a significant protective action in serum and hepatic enzymes of CML exposed rats. PMID- 23105663 TI - Protective role ofPhyllanthus niruri against nimesulide induced hepatic damage. AB - Present study aimed to evaluate the protective role of the aqueous extract of Phyllanthus niruri (P. niruri) against nimesulide-induced hepatic disoder in mice by determining levels of glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) in serum and also by measuring the hepatic content of the antioxidant enzymes, superoxide dismitase (SOD) and catalase (CAT); the free radical scavenger, reduced glutathione (GSH) and thiobarbituric acid reacting substances (TBARS). Aqueous extract of P. niruri was administered either orally or intraperitoneally in different doses and times as needed for the experiments. Intraperitoneal of the extract (100 mg/kg body weight for seven days) reduced nimesulide (750 mg/kg body weight for 3 days) induced increased levels of GOT (37.0+/-1.8 units/ml in control group vs. 91.8+/ 2.0 units/ml in nimesulide treated group vs. 35.0+/-1.0 units/ml in extract treated group), GPT (30.0+/-2.1 units/ml in control group vs. 88.4+/-2.9 units/ml in nimesulide treated group vs. 34.1+/-1.8 units/ml in extract treated group), and ALP (7.86+/-0.47 KA units/ml in control group vs. 23.80+/-0.60 KA units/ml in nimesulide treated group vs. 7.30+/-0.40 KA units/ml, in extract treated group) to almost nomal. In addition, P. niruri restored the nimesulide induced alterations of hepatic SOD (550+/-20 units/mg total protein in control group vs. 310+/-13 units/mg total protein in nimesulide treated group vs. 515+/-10 units/mg total protein in extract treated group), CAT (99.5+/-2 units/mg total protein in control group vs. 25.0+/-1.5 units/mg total protein in nimesulide treated group vs. 81.0+/-0.8 units/mg total protein in extract treated group), GSH (90+/-3 nmoles/mg total protein in control group vs. 17+/-4.2 nmoles/mg total protein in nimesulide treated group vs. 81+/-1 nmoles/mg total protein in extract treated group) and TBARS (measured as MDA, 36.6+/-3.0 nmoles/g liver tissue in control group vs. 96.3+/-5.2 nmoles/g liver tissue in nimesulide treated group vs. 41.2+/ 1.7 nmoles/g liver tissue in extract treated group) contents. Dose-dependent studies showed that the herb could protect liver even if the nimesulide-induced injury is severe. Intraperitoneal administration of the extract showed better protective effect than oral administration. Combining all, the data suggest that P. niruri possesses hepatoprotective activity against nimesulide-induced liver toxicity and probably acts via an antioxidant defense mechanism. To the best of our knowledge, this is the first report of the hepatoprotective action of P. niruri against nimesulide induced liver damage. PMID- 23105664 TI - Hypocholesterolemic and hepatoprotective effects of flaxseed chutney: Evidence from animal studies. AB - Rats fed with hypercholesterolemic diet showed a significant increase in serum total-cholesterol, liver homogenate total-cholesterol, HDL-cholesterol and changed LDL-cholesterol, and HDL/LDL ratio in comparison to control. Flaxseedchutney (FC) supplemented diet (15%, w/w) was found to be more effective in restoring lipid profile changes in rats fed with cholesterol, (1.0%). The activities of serum marker enzymes glutamate oxaloacetate transminase (GOT), glutamate pyruvate transaminase (GPT) and alkaline phosphatase (ALP) were elevated significantly in carbon tetrachloride induced rats. Administration of flaxseedchutney (15%, w/w) resulted in depletion of serum marker enzymes and exhibited recoupment thus showing significant hepatoprotective effect. It was observed that flaxseedchutney supplemented diet could lower the serum cholesterol and as a potential source of antioxidants it could exert protection against hepatotoxic damage induced by carbon tetrachloride (CCl(4)) in rats. PMID- 23105665 TI - Protective effect ofBacopa monniera L. on cytarabine induced biochemical changes in chick embryo. AB - Bacopa monniera, a medicinal plant distributed throughout India. Cytosine arabinoside (1-beta-arabinofuranosylcytosine; Ara-C) is the most important antimetabolite chemotherapeutic drug used for acute leukemia. In this study we examined the chemoprotective property of an ethanolic extract of Bacopa monniera on biochemical changes in chick embryo. CA caused biochemical changes in a concentration and time dependent manner in amniotic fluid, liver and heart tissues. Ethanolic extract of BM given to chick embryo at doses of 2, 4, 6 mg per egg. There is significant decrease in biochemical levels of glucose, protein, urea, uric acid, creatinine and inorganic phosphorus. Enzymatic activities of alkaline phosphatase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase and malatedehydrogenase were also decreased with dose dependent manner in amniotic fluid, liver and heart tissues. PMID- 23105666 TI - Lipid peroxidation and antioxidant vitamins in urolithasis. AB - The present, study was conducted to determine the level of malondialdehyde (MDA) as an index of free radial induced lipid peroxidation and antioxidant vitamins vitamins A, vitamin C and vitamin E in 75 confirmed cases of urolithiasis. Significantly high level of MDA (p<0.001) with significantly low levels of vitamin E (p<0.001) and vitamin A (p<0.001) with no significant decrease in vitamin C (p>0.05) were observed in the plasma of urolithiasis cases as compared to normal controls. In conclusion, it appears that a role of lipid peroxidation and oxidative function exists in the pathogenesis of urolithiasis. But, the exact mechanism how this occurs remains to be elucidated. PMID- 23105667 TI - Age related changes in lipid peroxidation and antioxidants in elderly people. AB - Advanced age is associated with an accumulation of free radical damage, which leads to physiological and clinical modifications. Age related changes resulting from free radical reactions include increasing levels of lipid peroxides, alterations in enzyme activities and greater osmotic fragility. The present study was conducted to estimate the level of lipid peroxidation product-Malondialdehyde and antioxidants Catalase and Glutathione in elderly people. An increase in lipid peroxidation and decrease in antioxidants was observed in normal elderly people. Highly significant increase in MDA and decrease in antioxidants was observed in elderly people when complicated with diabetes and hypertension. Supplementation of antioxidants may prevent further oxidative injury in elderly people. PMID- 23105668 TI - Study of oxidative stress and enzymatic antioxidants in normal pregnancy. AB - Pregnancy is a physiological state accompanied by a high-energy demand and an increased oxygen requirement. Augmented levels of oxidative stress would be expected because of the increased intake and utilization of oxygen. Evidence of increased oxidative stress in normal pregnancy in comparison with nonpregnant controls was estimated by measuring Thiobarbituric acid reactive substance (TBARS), enzymatic antioxidants like Superoxide dismutase, Glutathione peroxidase, Glutathione reductase and catalase. It was observed that pregnant women were more susceptible to oxidative damage than non-pregnants as indicated by increased TBARS and decreased antioxidants. PMID- 23105669 TI - Experimental therapeutic intervention with alpha tocopherol in ethanol induced testicular injuries in rats. AB - Infertility is well-established harmful effect in chronic alcoholism and so far, there is no effective treatment for this condition. The study was conducted to determine the effects of alpha tocopherol on ethanol induced testicular injuries in male albino rats of Wistar strain. Five groups (n=6) of animals were used. Group I served as control. Group II received daily 1.6g ethanol/kg body weight/day for 4 weeks orally. Group III received 1.6g ethanol+80mg alpha tocopherol/kg body weight/day for four weeks orally. Group IV received 1.6g ethanol/kg body weight for/day 4 weeks and followed by 80mg alpha tocopherol/kg body weight/day for four weeks orally. Group V received 1.6g ethanol/kg body weight/day orally for 4 weeks, followed by 4 weeks abstinence. Twently-four hours after the last treatment the rats were sacrificed using anesthetic ether. Testes were removed and used for the estimation of extent of lipid peroxidation and tissue levels of antioxidants and steroidogenic enzymes. Alpha tocopherol treatment increased the activities of testicularDelta(5), 3beta-HSD. Moreover, the treatment was also associated with significant decrease in testicular oxidative stress. Ethanol-induced oxidative stress and decreased steroidogenesis can be reversed by treatment with alpha tocopherol. PMID- 23105670 TI - Effect ofVitex negundo leaf extract on the free radicals scavengers in complete Freund's adjuvant induced arthritic rats. AB - The effect of the oral administration ofVitex negundo leaf extract on the levels of enzymic and non-enzymic antioxidants were studied in the adjuvant induced arthritic (AIA) rats The levels of antioxidant enzymes such as SOD, CAT, GPx, G6PD, GSH and Vit-C were estimated in various groups of the experimental rats. It was observed that the antioxidant enzyme levels in the AIA were significantly low when compared to normal rats. A significant decrease in enzymic antioxidant-SOD, CAT, GPx, G6PD and non-enzymic antioxidant-GSH, Vit-C were observed in the liver of AIA rats compared to the normal rats. These results suggest that the leaf extract ofVitex negundo possesses antioxidant activity. PMID- 23105671 TI - A study of thyroid status in hyperemesis gravidarum. AB - Study was undertaken to assess thyroid status in hyperemesis gravidarum. 150 women pregnant with <20 weeks of gestation were selected randomly and out of these 100 women presenting with hyperemesis formed study group while 50 normal pregnant women served as controls. 53% of hyperemetic pregnant women were primigravidae and 82% of pregnant women presented with vomiting at less than 12 weeks of gestation. Statistically significant, 22% of hyperemetic women had increased serum T(3) levels while T(4) levels were increased in 67% of women in study group as compared to 8% and 16% respectively in control group. TSH levels were decreased in 18% of hyperemetic women as compared to 8% in control group with decrease in mean TSH level statistically significant. 22% of hyperemetic women had electrolyte disturbances and 7% were ketonuric. In clinically euthyroid women, biochemically altered thyroid function can attribute to vomiting and its prolongation to second trimester. PMID- 23105672 TI - Modification of thyroid stimulating hormone estimation method in alpha prime LS system (SFRI). AB - The alpha prime LS (APLS) system consists of both enzyme linked immunosorbant assay (ELISA) and chemiluminescence immunoassay (CLIA) processing arrangements. All the programmes are open and accessible to modification. But, as CLIA kits are system dedicated kits, so the option for user defined programme may only be utilized for modification as and when it is absolutely necessary. The author had, some problem during routine performances with thyroid stimulating hormone (TSH) Monobind, U.S.A, kits. So, the author modified the incubation temperature, time of decontamination, use of signal reagents and finally the calibration pattern. PMID- 23105674 TI - Neurometabolic disorders. PMID- 23105673 TI - Development of a rapid and inexpensive plasma glucose estimation by two-point kinetic method based on glucose oxidase-peroxidase enzymes. AB - A rapid and inexpensive plasma glucose estimation by two-point kinetic method based on glucose oxidase and peroxidase enzymes has been developed it takes only 11/2 minutes of time and validity of the method has been discussed. PMID- 23105675 TI - Metabolomics: Impact on diagnosis and monitoring of 'inborn'/ 'acquired' metabolic disorders. PMID- 23105676 TI - Apoptosis in health and disease and modulation of apoptosis for therapy: An overview. AB - Apoptosis a physiological mechanism that eliminates excessive, damaged or unwanted cells, is a highly regulated pathway important for maintaining homeostasis in multicellular organisms. It can be initiated through various signals via the extrinsic pathway which involves death receptors, or via the intrinsic pathway which is initiated by intracellular damage and involves the mitochondria and release of cytochrome c from it to further activate caspases. The Bcl-2 family of proteins is situated upstream to the irreversible damage of cellular constituents and is an important checkpoint in the fate of a cell. The pro-apoptotic members, BH3 only members include BID, BAD and BIM. They directly or indirectly activate multidomain BAX/BAK that constitute the requisite gateway to the intrinsic pathway which operates at the mitochondrial surface and endoplasmic reticulum. In contrast, antiapoptotic members such as Bcl-2, Bcl-XL bind and sequester activation. Downstream of mitochondria, the apoptosome involvement is seen to generate caspase activity. Post mitochondria regulation involves IAPs, and their inhibitors. The pathogenesis of several diseases such as cancer, neurodegenerative disorders, autoimmune disorders, heart disease, infectious diseases including AIDS is closely related to aberrant apoptosis. Consequently interest has emerged in employing various the rapeutic approaches such as gene therapy, antisense therapy, recombinant biologicals, organic and combinatorial chemistry, to specifically target apoptosis signaling pathways such as death receptors FAS/TRAIL, Bcl-2, p53, IAPs, SMAC and caspases, etc. and are now advancing from preclinical to clinical phase. PMID- 23105678 TI - Calcineurin activity in children with Mental handicap. AB - Calcineurin, a Ca(2+)-Calmodulin dependent protein phosphatase, is important for Ca(2+) mediated signal transduction. The main objective of this study was to examine the potential role of calcineurin in idiopathic mental handicap. Calcineurin levels were estimated in 20 children in the age group of 5-16 years with idiopathic mental handicap attending the Special. Education Centre for the Mentally Handicapped in Hyderabad. The results of the present study showed decreased activity of serum calcineurin in children with idiopathic mental handicap compared to those of normal subjects in the same age group. The observations thus suggest impaired calcineurin activity in children with mental handicap. Calcineurin that is involved in biosynthesis and release of neurotransmitters at the synaptic terminal brain is affected thereby causing brain damage and leading to mental handicap. Impaired calcineurin activity was already indicated in many human diseases such as Down's syndrome, Alzheimers, Brain ischemia, cardiac hypertrophy etc. It is therefore necessary to check the calcineurin levels in children with mental handicap to understand the role of calcineurin in the causation of Mental handicap. PMID- 23105677 TI - Tumour markers: An overview. AB - Tumor Markers comprise a wide spectrum of biomacromolecules synthesized in excess concentration by a wide variety of neoplastic cells. The markers could be endogenous products of highly active metabolic malignant cells or the products of newly switched on genes, which remained unexprssed in early life or newly acquired antigens at cellular and sub-cellular levels. The appearance of tumor marker and their concentration are related to the genesis and growth of malignant tumors in patients. An ideal tumor marker should be highly sensitive, specific, reliable with high prognostic value, organ specificity and it should correlate with tumor stages. However, none of the tumor markers reported to date has all these characteristics. Inspite of these limitations, many tumor markers have shown excellent clinical relevance in monitoring efficacy of different modes of therapies during entire course of illness in cancer patients. Additionally, determination of markers also helps in early detection of cancer recurrence and in prognostication. PMID- 23105679 TI - Effect of folic acid and vitamin B(12) administration on phenytoin induced toxicity in rats. AB - Folic acid and vitamin B(12) are very important vitamins needed for normal cellular metabolic activities. The effects of folic acid and vitamin B(12) on liver integrity of growing Wistar albino rats following therapeutic dose of phenytoin administration were investigated. The activities of serum AST, ALT, ALP were investigated. Serum total protein level and lipid profile were also measured as indices of biochemical changes. The ingestion of phenytoin alone in rats significantly reduced serum protein while AST, ALT activities incresed as compared to the control (P<0.05). Supplementation of phenytoin with oral administration of 70microgram/kg body wt of folic acid resulted in a significant reversal in serum total protein and suppression in serum AST and ALT activities. Vitamin B(12) supplementation did not afford any significant protection against the effect of phenytoin ingestion but rather phenytoin toxicity was exacerbated in this study. However, the combined effects of vitamin B(12) and folic acid ameliorated the effects of phenytoin on serum enzymes of experimental rats. The effect of combination of phenytoin with folic acid or folic acid and vitamin B(12) is an interesting finding. Supplementation of phenytoin with folic acid or combination of these vitamins may be recommended for the purpose of ameliorating the adverse biochemical changes which are associated with phenytoin therapy. Further work is ongoing to help elucidate the effects of phenytoin and these vitamins on oxidative stress inducing mechanism. PMID- 23105680 TI - A clinical study on cortisol and certain metabolites in some chronic psychosomatic disorders. AB - Present clinical study involved two groups of psychosomatic disorders, bronchial asthma and rheumatoid arthritis. In the study, the levels of plasma cortisol, blood glucose, total cholesterol and triglycerides were estimated in 125 clinical subjects, (50 normal controls, and 40 having bronchial asthma and 35 suffering from rheumatoid arthritis. The results showed a significant change in the levels of plasma cortisol and blood glucose in both the stressed clinical groups' vis-a vis normal controls. The levels of atherogenic lipids (total cholesterol and triglycerides) were found quite elevated in both the diseased groups. However, in rheumatoid arthritis, the physiological changes were relatively more pronounced. The findings of this study indicate that rheumatoid arthritis is a relatively more chronic and late onset disorder as the functional performance of hypothalamopituitary-adrenocortical axis gradually declines with passage of time and the ability of the adrenocortical response to return to normalcy becomes impaired. PMID- 23105681 TI - Effect of diet oils on lipid levels of the brain of rats. AB - The effects of sunflower oil, olive oil, margarine, soybean oil and butter on cholesterol and triglyceride levels were investigated in the brain of rats. Rats were fed with a diet containing 15% of the oils for a period of 8 weeks. The rats were then decapitated, brain samples were removed, homogenized and cholesterol and TG levels were measured. Brain cholesterol and Triglycerides levels of all animals receiving different oils were significantly higher according to the contol except TG level of animals receiving margarine. Brain cholesterol levels of the vegetable oils were statistically higher than those receiving saturated oil. Thus, cholesterol level of the rats fed with olive oil group was significantly higher than that of the other groups but those receiving sunflower oil group and Triglycerides level of the animals receiving olive oil was significantly higher than that of the other groups except animal supplemented with soybean oil. Thus, it is concluded that brain lipid levels of rats are differently effected by various oils and mechanism of which needs to be investigated. PMID- 23105682 TI - Assessment of glycemic potential ofMusa paradisiaca stem juice. AB - The present study reveals the effect of Musa paradisiaca stem juice on blood glucose level (BGL) of normal & diabetic rats. The dose of 500 mg/kg bodyweight produces a significant rise of 28.3% in blood glucose level after 6h of oral administration in normal rats. Whereas, in sub diabetic rats the same dose produces a rise of 16.4% in blood glucose levels within 1h during glucose tolerance test (GTT) and a rise of 16% after 4 h in fasting blood glucose levels of severe diabetic cases. These results were unexpected and important to report as other species of Musa like Musa sapientum has been reported for its hypoglycemic effect. PMID- 23105683 TI - Glycemic control modifies the association between microalbuminuria and c-reactive protein in Type 2 Diabetes Mellitus. AB - Microalbuminuria and C-reactive protein reflect closely related components of the same disease process. The present study attempts to evaluate whether any association exists between C-reactive protein and microalbuminuria in Type 2 Diabetes Mellitus patients with poor and adequate glycemic control. It was observed that in diabetics with poor glycemic control, microalbuminuria showed a significant positive correlation with C-reactive protein and the prevalence of microalbuminuria was significantly more at elevated C-reactive protein levels. These parameters were not significant in subjects with adequately controlled disease. Further, there was a significant increase in levels of microalbuminuria in patients with poor glycemic control when compared to well-controlled diabetics at comparative levels of C-reactive protein. This study supports the hypothesis that endothelial dysfunction and inflammatory activity are involved in the pathogenesis of microalbuminuria and underscores the importance of glycemic control in the progression of inflammation in diabetes. PMID- 23105684 TI - Induction of diabetes by Streptozotocin in rats. AB - The objective of this study is to induce experimental diabetes mellitus by Streptozotocin in normal adult Wistar rats via comparison of changes in body weight, consumption of food and water, volume of urine and levels of glucose, insulin and C-peptide in serum, between normal and diabetic rats. Intra-venous injection of 60mg/kg dose of Streptozotocin in adult wistar rats, makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes mellitus in the 2-4 days. Induction of experimental diabetes mellitus is indeed the first step in the plan of purification of pancreatic Langerhans islet cells of normal rats for transplanting under the testis subcutaneous of experimentally induced diabetic rats. Streptozotocin induces one type of diabetes which is similar to diabetes mellitus with non ketosis hyperglycemia in some animal species. For induction of experimental diabetes in male adult rats weighted 250-300 grams (75-90 days), 60mg/kg of Streptozotocin was injected intravenously. Three days after degeneration of beta cells, diabetes was induced in all animals. The diabetic and normal animals were kept in the metabolic cages separately and their body weight, consumption of food and water, urine volume, the levels of serum glucose, insulin and C-peptide quantities in all animals were measured and then these quantities were compared. For a microscopic study of degeneration of Langerhans islet beta cells of diabetic rats, sampling from pancreas tissue of diabetic and normal rats, staining and comparison between them, were done. Induction of diabetes with Streptozotocin decreases Nicotinamide-adenine dinucleotide (NAD) in pancreas islet beta cells and causes histopathological effects in beta cells which probably intermediates induction of diabetes. In this study, we used Streptozotocin for our experiments in induction of experimental diabetes mellitus. After Induction of diabetes, consumption of food and water, volume of urine and glucose increased in the diabetic animals in comparison with normal animals, but the weight of body and the volume of insulin and C-peptide decreased in the diabetic animals. Sampling and staining of pancreas tissue of diabetic and normal rats showed that the Langerhans islet beta cells of diabetic rats have been clearly degenerated. In three days, Streptozotocin makes pancreas swell and at last causes degeneration in Langerhans islet beta cells and induces experimental diabetes. It also changes normal metabolism in diabetic rats in comparison with normal rats. Consumption of water and food, volume of urine, serum glucose increases in diabetic animals in comparison with normal rats but the levels of serum insulin, C-peptide and body weight decreases. PMID- 23105685 TI - A comparative study on the effects of diet and exercise, metformin and metformin+pioglitazone treatment on NIDDM patients. AB - A comparative study on two groups of newly diagnosed nonobese and obese NIDDM patients who were 15 in each group and treated by diet cum exercise and metfromin monotherapy respectively and a third group of 15 obese NIDDM patients whose hyperglycemia was not first controlled by a combination therapy of metformin and sulfonylurea and therefore changed over to a different combination therapy of metformin and ploglitazone, was carried out before and after a period of three months treatment. The mild hyperglycemia in the 1(st) group and the moderate or severe hyperglycemia with accompanied disorders of serum enzymes such as AST, ALT, GGT and the level of HBA(10) observed with 2(nd) and 3(rd) groups of obese NIDDM patients were significantly ameliorated by the respective mode of treatments. Here the efficacies of the three types of treatment are substantiated and further it specifically depicts the success with the choice of combination therapy with metformin and pioglitazone in the third group of obese diabetics. PMID- 23105686 TI - Type-2 diabetes related intermediate phenotypic traits in north Indian diabetics. AB - Asian Indians are known to be at a higher risk of developing T2DM, but the underlying genetic factor in this population is still not well understood. T2DM is a complex genetic trait and assessment of disease related intermediate phenotypic traits is an important initial step towards any systematic genomic study. Therefore, in the present study we have assessed diabetes related intermediate phenotypic traits of insulin secretion and insulin resistance in the patients belonging to this population. The study included 157 T2DM patients of either sex ranging in age from 45-80 years and 84 non-diabetic subjects with no family history of diabetes, ranging in age from 45 to 75 years served as controls. Intermediate phenotypic traits studied were BMI, W: H ratio, fasting free fatty acid level and Insulin resistance and secretion. Diabetics were found to have significantly higher W: H ratio (p<0.001), FFA (p<0.001) and HOMA-R (p<0.001) as compared to non-diabetics. However, there was no significant difference in their BMI and HOMA-beta. There was a positive correlation between FFA level and HOMA-R among diabetics, but not among controls. These findings suggest that in abdominal obesity FFA mediated insulin resistance is an important causative factor underlying T2DM in this population. Moreover, comparable HOMA beta in diabetics reflects compensatory insulin hyper secretion in these subjects. There is a need to examine relative contribution and precise nature of genetic factor in their tendency for central obesity, free fatty acidemia and insulin resistance. PMID- 23105687 TI - Evaluation of thyroid function in diabetes mellitus in Calabar, Nigeria. AB - The prevalence of abnormal thyroid hormone levels in diabetes mellitus in Nigeria is not well described. To determine the incidence of abnormal thyroid hormone levels in diabetics in Calabar, Nigeria, fasting blood samples from 161 diabetic subjects and 105 non-diabetic controls were analysed. Free thyroxine (FT), thyroid stimulating hormone (TSH), total triiodothyronine (T(3)) and total thyroxine (T(4)) kits obtained from Biomerica Inc. of USA were used for the analysis. TSH levels (1.80+/-1.62) in diabetics were significantly lower (p=0.016) than the level in non-diabetic controls (2.34+/-1.24). Male diabetics had lower (p<0.05) levels of TSH (1.192+/-0.68 miu/ml) than diabetic females (1.90+/-1.70 mlu/mt). The level of T(3) in diabetic males (125+/-97ng/ml) was higher than the level in females (98+/-75ng/dl). TSH (F=2.74, p=0.049), T(4)(F=56.87, p=0.001), T(3)(F=56.44, P=0.001) in diabetics and FT(4) (F=5.74, p=0.002) in controls showed significant variation with the ages of the subjects. Out of 161 diabetics subjects studies 26.6% had low plasma thyroid hormone levels (FT(4)>2.01 ng/dl). This study has shown a high incidence (46.5%) of abnormal thyroid hormone levels among the diabetics in Nigeria (hypothyroidism 26.6%, hyperthyroidism, 19.9%). The prevalence of hypothyroidism was higher in women (16.8%) than in men (9.9%), while hyperthyroidism was higher in males (11%) than in females (8%). This study has defined thyroid function status of diabetics in Calabar, Nigeria probably the first of such work in Africa. PMID- 23105688 TI - The triad-iodine deficiency, hyperlipidaemia, high coronary risk- in a 'maternal neonate' population of rural Africa. AB - In order to see the pattern of changes in differential serum lipid and lipoprotein fractions as a risk marker of coronary complication in paired 'maternal-neonate' blood samples in an iodine deficient zone, 26 pregnant women and their corresponding new born infants at term delivery from the iodine deficient Bassa region of Plateau state, Nigeria were assessed and the results were compared with those seen in a similar 44 group of women and their newborns assessed in non lodine deficient region of Jos. The serum thyroid function and lipid and lipoprotein profiles were determined by 'ELISA' and 'enzymatic' methods respectively. Urinary iodide excretion level was also measured in 14 pregnant women in Bassa, 23 pregnant women in Jos and 16 non pregnant control from Jos. Results indicate that the pregnant women assessed in Bassa were iodine deficient (P<0.01) and their thyroid status was strikingly reduced as reflected by a drop in serum level of T4/TBG ratio (P<0.01) and a rise in TSH (P<0.005) in comparison to that seen in Jos. There was marked hypertriglyceridaemia and total hypercholesterolaemia (P<0.005), with differential significant rise in LDL cholestotol fraction (P<0.005) in the women assessed in Bassa as compared to Jos. The HDL cholesterol however dropped less significantly in the group (P<0.05) with a concurrent marked rise (P<0.001) in the serum ratio of LDL cholesterol/HDL cholesterol, total cholesterol/HDL cholesterol and triglycerides/HDL cholesterol in the lodine deficient group. A similar pattern of changes were seen in the corresponding neonates in the Bassa group as compared to Jos group. It is concluded that the pregnant women and their newborn offsprings living in a longstanding environmental iodine deficiency run a higher risk of developing coronary complications than those living in non endemic region. It is striking that such newborns surrounded by a continued state of lodine deficient may at a later adult-period of life develop marked risk of coronary complication and other features of hyperlipidaemias associated with varying thyroid insufficiency and accompanied iodine deficiency disorders. Prophylaxis measures as intervention has been highlighted. PMID- 23105689 TI - Caprine cardiac sarcoplasmic reticulum: Effect of simulated ischemia on membrane structure and Ca(2+)-ATPase activity. AB - The sarcoplasmic reticulum was isolated and characterized in the pure form from normal caprine (Capra hircus) hearts. Under ischemic condition, fatty acids like palmitic acid, palmitoyl carnitine and oleic acid accumulatein vivo. These are known to have a detrimental effect on membrane components. The effects of simulated ischemia on the Ca(2+)-ATPase were studied using these fatty acidsin vitro at concentrations at which they occurin vivo in the ischemic heart. All three fatty acids inhibited Ca(2+)-ATPase activity. At lower concentrations, palmitoyl carnitine was the most potent, followed by oleic acid while palmitic acid displayed the least potency. Electron microscopy studies with fatty acids showed morphological disruptions in SR vesicles. The decline in Ca(2+)-ATPase activity could be attributed to the change in membrane morphology. PMID- 23105690 TI - Xanthine oxidase as a marker of myocardial infarction. AB - In the present communication, we report remarkably elevated levels of xanthine oxidase activity in the blood of the patients with myocardial infarction when compared to age and sex matched healthy persons. Highly significant increase of malondialdehyde, serving as an index of lipid peroxidation and thus free radical mediated damage, has also been found in the patients. We propose the measurement of the blood levels of xanthine oxidase, a very simple, reliable and less time consuming method as an indicator of myocardial infarction. PMID- 23105691 TI - Plasma proteins and proteinuria in gestational malaria. AB - The plasma concentrations of total protein, albumin, immunoglobulins IgG, IgA and IgM and urinary protein were assayed in 250 pregnant Nigerian women with malaria and compared with 250 healthy pregnant women which served as controls. The mean values of plasma total proteins, albumin, IgG and IgA were significantly lowered (P<0.05) while a slight increase in IgM was observed in the malaria patients. Urinary proteins value of 23.10+/-0.50 mg/dl was obtained for the pregnant women with malaria, this was significantly higher (P<0.05) than that of the controls with the corresponding value of 15.32+/-0.09 mg/dl. This study has therefore demonstrated elevations of the urinary and decrease in plasma proteins in gestational malaria. These findings suggest that the protein profile should be considered in the diagnosis and treatment of malaria. PMID- 23105692 TI - Hospital based preliminary study on osteoporosis in postmenopausal women. AB - The awareness of osteoporosis has grown world wide in recent years. This silently progressing metabolic bone disease is widely prevalent in India, and osteoporotic fractures are a common cause of morbidity and mortality in adult Indian men and women. Rapid bone loss occurs in postmenopausal women due to hormonal factors which lead to increased risk of fractures. Biochemical markers of bone metabolism are used to assess skeletal turnover. A cross-sectional study of 150 pre- and post menopausal women was carried out at S.D.M College of Medical Sciences and Hospital, Dharwad, during the period of May 2005 to September 2005. The study group consisted of 75 Premenopausal women in the age group of 25-45 years and 75 Postmenopausal women in the age group of 46-65 years. Bone formation markers (Total Calcium, lonised calcium, Phosphorus, Alkaline phosphatase), and bone resorption markers (Urinary Hydroxyproline) were analysed in pre and post menopausal women. Bone formation markers, Total and lonised calcium were significantly decreased (p<0.001) and Alkaline phosphatase was significantly increased (p<0.001) in postmenopausal women compared to premenopausal women. Bone resorption markers, Urinary hydroxyproline excretion was significantly increased (p<0.001) in postmenopausal women. The results from this study suggest that simple, easy, common biochemical markers can still be used to assess the bone turnover in postmenopausal women and hence their risk of developing osteoporosis and fractures. PMID- 23105693 TI - Effect of supplementation of vitamin C and E on oxidative stress in osteoporosis. AB - Osteoporosis encompasses a wide spectrum of conditions associated with imbalance of osteoclastic and osteoblastic activities. The increased activity of osteoclasts leads to increased free radical formation and hence lipid peroxidation. Present study probes into the role of antioxidants as a palliative treatment for osteoporosis. It involved 50 healthy controls and 75 clinically diagnosed osteoporosis patients. Both the groups underwent baseline assessment of biochemical markers viz. osteoblastic markers: serum Alkaline phosphatase. Free or ionic calcium and Inorganic phosphorus, osteoclastic markers: serum Tartarate resistant acid phosphatase and Malondialdehyde and the antioxidant status: serum Superoxide dismutase and Erythrocyte reduced glutathione. The osteoporotic group was then divided into groups A (Vitamin E-Evinal 400 mg), B (Vitamin C-Celin 500 mg), C (Vitamin E+C-Evinal+Celin) for antioxidant supplementation for a period of 90 days. The results reveal that there is significant fall in concentration of serum MDA (p<0.001), TrACP (p<0.01). Improvement in antioxidant status is reflected by significant rise in concentration of serum SOD (p<0.001) and erythrocyte GSH (p<0.001) after 90 days of antioxidant supplementation in osteoporosis. The findings indicate that on the whole bone status improved with prolonged antioxidant vitamin supplementation, which can be used as a palliative treatment for osteoporosis. The efficacy is not affected whether the vitamins are administered singly or conjointly. PMID- 23105694 TI - Serum ferroxidase albumin ratio as a marken in pulmonary tuberculosis. AB - Serum ferroxidase and albumin levels were determined in 98 patients of tubercuiosis, of whom 49 were freshly diagnosed, sputum positive (group-I) & 49 were completely treated patients (group-II). Forty nine age and sex matched healthy individuals were taken as controls. Mean+/-SD of serum ferroxidase and albumin levels in controls, group-I and group-II was found to be 864.35+/-106.35 IU/L & 3.91+/-0.234 g/dL, 1603.76+/-222.65 IU/L & 3.24+/-0.518 g/dL and 1001.78+/ 201.63 IU/L & 3.82+/-0.43 g/dL, respectively. Serum ferroxidase in group I was significantly higher as compared to controls and group-II (p<0.01). The decreased levels of serum albumin in group I, as compared to control and group-II was statistically significant (p<0.01). Serum ferroxidase: albumin ratio (Ferroxidase in International Unit per gram of albumin) in group I (50.47+/-10.36 IU/g) was significantly higher than controls (22.22+/-3.3 IU/g), (p<0.001) while in group II it was significantly lower (26.72+/-7.18 IU/g, p<0.001) than group-I and close to control values. Serum ferroxidase: albumin ratio (IU/g) can therefore be incorporated as a surrogate marker to assist in diagnosis and prognosis of pulmonary tuberculosis. PMID- 23105695 TI - Evaluation of serum zinc level and plasma SOD activity in senile cataract patients under oxidative stress. AB - An imbalance in the systemic redox status leading to oxidative stress has been an important factor in development of senile cataracts, which is reflected by an increase in serum TBARS and a decrease in plasma SOD activity. Zinc has been an important cofactor required for structural stability of SOD. In the present study the role of serum zinc level and plasma SOD activity was analyzed in senile cataract patients showing significant oxidative stress. Serum TBARS, plasma SOD and serum zinc level was measured in thirty randomly selected senile cataract patients against properly matched controls. Although, the analysis of means showed a significant increase in serum TBARS and decrease in plasma SOD and serum zinc level in cases, but plasma SOD was found to be just significantly correlated (p=0.05) with the serum zinc only in the cases. The results of partial correlation studies and multiple regression analysis, also, showed only a significant correlation and predictable dependence between serum TBARS and plasma SOD, excluding any role of serum zinc level. The present study concludes that it is chiefly the plasma SOD activity, but not the serum zinc level, that determines the proneness of the patients for development of senile cataract. PMID- 23105696 TI - Circulating Immune complexes (CIC) as marker for disease progress in oral cancer. AB - Oral Cancer is one of the five leading sites of cancer in Indian population. The circulating immune complexes were investigated in 100 serum samples of 60 oral cancer patients having different grades of the disease and 40 patients with precancerous lesions obtained from Nair Hospital Dental collage, Mumbai. The results obtained were compared with those of group of 40 healthy blood donors. Elevated levels of Circulating Immune Complexes were observed in oral cancer patients and patients with oral precancerous lesions. 92% positive samples were observed in well differentiated squamous cell carcinoma whereas 100% positive samples were observed in both moderately and poorly differentiated squamous cell carcinoma. Oral leukoplakia and oral submucous fibrosis showed 15% and 90% positivity respectively. Increased level of Circulating Immune complexes in high grade tumor suggest that Circulating Immune complexes is likely to contribute in evaluating the degree of malignancy, but follow up study is needed to draw any conclusion regarding it's prognostic role. PMID- 23105697 TI - X-linked adreno leukodistrophy: Profiles of very long chain fatty acids in plasma and fibroblasts in eigth Serbian patients. AB - X-linked adrenoleukodistrophy is a severe neurodegenerative disorder with impaired very long chain fatty acid metabolism. The disease associated ABCD1 gene encodes a peroxisomal membrane protein which belongs to the superfamily of ATP binding cassette transporters. We investigated eight male X-ALD patients diagnosed among 142 suspected patients referred for investigation. Plasma levels of very long chain fatty acids were measured at our laboratory using capillary gas chromatography. Eight cases of childhood X-ALD were diagnosed. This is the first published series of Serbian patients with X-ALD. In addition, diagnosis identifies carriers, which could be benefit for genetic counselling and prenatal diagnosis. PMID- 23105698 TI - Scientific evaluation of some Ayurvedic preparations for correction of iron deficiency and anemia. AB - A number of preparations are available in Ayurved for treatment of anemia and iron deficiency. This study was designed to evaluate efficacy of some of them. Six most commonly used Ayurvedic iron containing preparations (Navayasa Curna, Punarnavadi Mandura, Dhatri Lauha, Pradarantaka Lauha, Sarva-Juara-Hara Lauha and Vrihat Yakrdari Lauha) were given in a dose of 250 mg b.d. for 30 days to six groups of iron deficient anemic patients; each group consisting of 20 patients. A control group was given Allopathic preparation-Irex-12, (containing-ferrous fumarate, vitamin C, folic acid and vitamin B(12)); 1 capsule daily for 30 days for comparison. All hematological and iron parameters were determined before and after completion of treatment. The results showed that there was statistically significant rise (p<0.001) in all of them-Hb, PCV, TRBC, MCV, MCH, MCHC and plasma iron, percent saturation and plasma ferritin. Total iron binding capacity decreased significantly (p<0.001). The response of most of Ayurvedic preparations was better than Allopathic preparation and there was no side effect as observed with iron salts The Hb regeneration rate was 0.10 g/dl/day for Allopathic preparation; while it was above this value for all Ayurvedic preparations exceptPradarantaka Lauha which was least effective.Sarva-Juara-Hara Lauha was the drug of choice as Hb regeneration with it was highest 0.16 g/dl/day. Upon analysis of Ayurvedic drugs, these results were found to be consistent and correlated with iron content of the preparation. PMID- 23105699 TI - Effects of flaxseed(Linum usitatissimum) chutney on gamma-glutamyl transpeptidase and micronuclei profile in azoxymethane treated rats. AB - Antioxidant property of flaxseed chutney was evident by decreasing lipid peroxidation (TBARS) and predictor enzyme gamma-glutamyl transpeptidase profile and micronuclei formation in azoxymethane treated rats. After 10 weeks, rats fed with either fiber-free basal diet or Antioxidant diet exhibited over sevenfold increase in gamma-glutamyl transpeptidase activity and nearly fourfold increase in micronuclei load in comparison to controls (p<0.001). A significant reduction in both gamma-glutamyl transpeptidase level (52%) and micronuclei formation (47%) was observed in fiber-free basal diet/Antioxidant diet/flaxseed chutney diet fed rats. Relative to rats fed fiber-free basal diet, the profile of gamma-glutamyl transpeptidase and micronuclei load was not significantly altered. PMID- 23105700 TI - Hepatoprotective effect ofHygrophila spinosa andCassia occidentalis on carbon tetrachloride induced liver damage in experimental rats. AB - The present study was undertaken to analyze the levels of some known antioxidant (both enzymic and non enzymic) activities in the rootsof Hygrophila spinosa andCassia occidentalis also to find out the hepatoprotective effect of the same in carbon tetrachloride induced liver damage in albino rats. The roots were found to be rich in antioxidants. Liver damage in rats were induced by carbon tetrachloride. To find out the hepatoprotective activity, the aqueous extract of the plant root samples were administrated to rats for 15 days. The serum marker enzymes Aspartate transaminase, Alanine transaminase and Gama Glutamyl were measured in experimental animals. The increased enzyme levels after liver damage with carbon tetrachloride were nearing to normal value when treated with aqueous extract of the root samples. Histopathological observation also proved the hepatoprotectivity of the root samples. PMID- 23105701 TI - Role of Helicobacter pylori and hyperammonemia in subclinical hepatic encephalopathy in cirrhosis of liver. AB - In a prospective study of 47 patients of subclinical hepatic encephalopathy in cirrhosis of liver, aged between 23 and 60 years, 49% showed Helicobacter pylori positivity by rapid urease test. The baseline characters of patients (mean age, serum creatinine, sereum albumin, serum bilirubin, prothrombin time) were similar among patients with and without Helicobacter infection in all the patients. There was no statistically significant difference in blood ammonia levels in either group of patients. Blood ammonia values showed good correlation with the functional state of liver function but they did not show statistically significant difference between two groups of patients in any of Child Pugh classes. It is concluded that Helicobacter pylori does not contribute significantly to blood ammonia levels and the severity of hepatic encephalopathy. PMID- 23105702 TI - Oxidative stress and antioxidant status in cervical cancer patients. AB - Cervical cancer (CaCx) is a global public health problem as it is the second most common cancer leading to the death of women worldwide. Many references revealed that the low levels of antioxidants induce the generation of free radicals leading to DNA damage and further mutations. In the present study attempt have been made to evaluate the levels of serum Lipid peroxide, Nitric Oxide (NO(.)) Erythrocytic-Superoxide Dismutase (RBC-SOD), Vitamin-C, serum Copper (Cu) and serum Zinc (Zn). 120 patients were divided in 4 groups according to the increasing CaCx stages i.e. stage I, II, III & IV respectively. All the patients were around the age group of 25-65 years. 30 healthy women between the same age group were treated as controls. Highly significant increased values of MDA, NO(.) and Cu were observed (p<0.001) whereas the activity of RBC-SOD, levels of Vitamin C and Zn were significantly decreased in CaCx patients as compared with healthy controls (p<0.001). Cu/Zn ratio was found to be altered in CaCx patients. From our findings it can be concluded that the oxidative stress is induced among CaCx patients, which inturn increases the risk of CaCx. PMID- 23105703 TI - An extended chemical analysis of gallstone. AB - Chemical composition of gall stones is essential for aetiopathogensis of gallstone disease. We have reported quantitative chemical analysis of total cholesterol bilirubin, calcium, iron and inorganic phosphate in 120 gallstones from haryana. To extend this chemical analysis of gall stones by studying more cases and by analyzing more chemical constituents. A quantitative chemical analysis of total cholesterol, total bilirubin, fatty acids, triglycerides, phospholipids, bile acids, soluble proteins, sodium potassium, magnesium, copper, oxalate and chlorides of biliary calculi (52 cholesterol, 76 mixed and 72 pigment) retrieved from surgical operation of 200 patients from Haryana state was carried out. Total cholesterol as the major component and total bilirubin, phospholipids, triglycerides, bile acids, fatty acids (esterified), soluble protein, calcium, magnesium, iron, copper, sodium, potassium, inorganic phosphate, oxalate and chloride as minor components were found in all types of calculi. The cholesterol stones had higher content of total cholesterol, phospholipids, fatty acids (esterified), inorganic phosphate and copper compared to mixed and pigment stones. The mixed stones had higher content of iron and triglycerides than to cholesterol and pigment stones. The pigment stones were richer in total bilirubin, bile acids, calcium, oxalate, magnesium, sodium, potassium, chloride and soluble protein compared to cholesterol and mixed stones. Although total cholesterol was a major component of cholesterol, mixed and pigment gall stone in Haryana, the content of most of the other lipids, cations and anions was different in different gall stones indicating their different mechanism of formation. PMID- 23105704 TI - Xanthelasma Palpebrarum-clinical and biochemical profile in a tertiary care hospital of Delhi. AB - Xanthelasma Palpebrarum is the most common of the xanthomas with asymptomatic, symmetrical, bilateral, soft, yellow, velvety, polygonal papules around the eyelids. Xanthelasmas may be associated with hyperlipidemia. This prospective study included 66 clinically diagnosed patients with Xanthelasma Palpebrarum and 50 controls with non-inflammatory skin disorders. Serum triglyceride, cholesterol, HDL, LDL and VLDL estimated in all cases indicated that patients with Xanthelasma Palpebrarum have underlying lipid abnormalities. PMID- 23105705 TI - Serum enzymes in thermal injury. AB - Various metabolic and biological changes follow burn injury. Serum Thio barbituric acid reactive substances (TBARS), transaminases, alkaline phosphatase and amylase were measured in 43 patients with thermal injury over the first 10 days of post burn period. No clear correlation between elevated serum enzymes except amylase and the burn size was observed on admission. Mean serum TBARS were significantly increased in the burn patients. Transaminases values increased till 5(th) day then declined on 10(th) day, whereas alkaline phosphatase and amylase activities continued to rise till day 10. It is concluded that functional disturbances occur in liver and pancreas around a week after thermal injury. Monitoring serum ALP and amylase in postburn period has valuable prognostic importance. PMID- 23105706 TI - Alkaptonuric ochronosis: Report of a case and brief review. AB - Alkaptonuria, a metabolic disorder characterized by a triad of homogentisic aciduria, arthritis and ochronosis is one of the first conditions in the charter of group of inborn errors of metabolism proposed to have Mendelian recessive inheritance. It is due to the deficiency of the enzyme homogentisic acid oxidase which catalyzes the conversion of homogentisic acid to maleylacetoacetic acid in the catabolism of tyrosine. Homogentisic acid thus accumulates in cells and body fluids and its oxidized polymers bind to collagen, leading to progressive deposition of grey to bluish black pigment resulting in degenerative changes in cartilage, intervertebral disc and other connective tissues, leading to arthritis which is the only disabling effect in an affected older individual. However the diagnosis can be made in neonates when blackish stain is noticed in an unwashed diaper. Alkaptonuria is treated symptomatically, surgical intervention necessitates in advanced stages, treatment with ascorbic acid (Vitamin C) and dietary restrictions of food containing phenylalanine and tyrosine have proved to be successful in alleviating the symptoms. PMID- 23105707 TI - Genetic susceptibility to lead poisoning-A case report. AB - Lead poisoning is well documented in persons occupationally exposed to lead. What is less known is, that even in persons working in lead based industries, the effect of lead and the appearance of signs and symptoms of lead poisoning is genetically determined. Three genes related to lead metabolism, exhibiting polymorphism have already been demonstrated-deltaALA-dehydratase, Vitamin D receptor gene and Hemochromatosis gene. These alleles determine the susceptibility of the individuals to lead. We present here a case of a lead acid battery worker, who presented without any signs and symptoms of lead poisoning except for a very high level of blood lead (82.8MUg/dl and 47.5MUg/dl 9 months later). PMID- 23105709 TI - Progress in IJCB: Online editorial workflow and e-publishing. PMID- 23105708 TI - Hypermagnesemia in diabetic end stage renal disease (ESRD) patients. PMID- 23105710 TI - The APFCB at 25: Working for the common good. PMID- 23105711 TI - Alcohol induced effects on kidney. AB - After administration ethanol and its metabolites go through kidneys and are excreted into urine, and its content in the urine is higher than that of the blood and the liver. Chronic ethanol administration decreases the renal tubular reabsorption and reduces renal function. Multiple functional abnormalities of renal tubules may be associated with ethanol-induced changes in membrane composition and lipid peroxidation. The vulnerability of the kidney to oxidative damage has been partly attributed to its high content of long-chain polyunsaturated fatty acids. Renal ultra structural abnormalities due to ethanol exposure may be important in the genesis of functional disturbances. Increased oxidative stress and endothelial dysfunction with their complex interrelationships are relevant aspects of atherogenesis in chronic renal failure. Antioxidants, particularly polyphenols are expected to decrease the vulnerability of the kidney to oxidative challenges. PMID- 23105712 TI - Detection of inherited metabolic diseases in children with mental handicap. AB - Mental Retardation is a condition where complex interactions of intrinsic and extrinsic factors hamper mental and sometimes physical growth of the child during developmental period. This study was carried out to detect cause of Mental Retardation in 2000 cases of developmental delay by a multidisciplinary team comprising of a Pediatrician, Cytogeneticist, Biochemist, Psychologist and Speech and Occupational therapists. The causes for developmental delay are broadly divided into Genetic, Environmental and Idiopathic (no specific cause found) factors. The complete diagnosis was possible in 1192(60%) cases. Genetic factors were found in 477(23.8%) cases and environmental factors covered 692(34.6%) cases as a cause of retardation. The most common genetic cause is chromosomal abnormalities which were found in 355 (17.75%) cases. Another major group comprising of 122 (6.1%) cases was that of the disorders which follow Mendelian inheritance. Autosomal recessive conditions, which covers majority of metabolic disorders, are detected in 48(2.4%) cases. During this screening the most common inherited metabolic condition detected is Mucopolysaccharidosis, a Lysosomal Storage Disorder followed by Amino acid abnormalities like Phenylketonuria, Alkaptonuria and Tyrosinuria. PMID- 23105713 TI - Resistance towards calcium induced bilirubin dependent hemolysis in porcine erythrocytes. AB - Hemolysis of erythrocytes from human and porcine blood was studied at different calcium chloride (CaCl(2)) concentrations (0.04-1.83 mM) and at a constant bilirubin concentration (72 mM). Although, human erythrocytes showed significant hemolysis (64%) at the highest CaCl(2) concentration (1.83 mM) used in this study, remarkable resistance to this phenomenon was observed with porcine erythrocytes as only 11% hemolysis was observed. A similar pattern in the behavior of both human and porcine erythrocytes was observed when parameter such as bilirubin concentration or time of incubation with bilirubin was varied. Other divalent cations such as Mn(2+), Ba(2+) and Mg(2+) were either least effective or ineffective in inducing hemolysis in presence of bilirubin. Serum albumin played a protective role in this phenomenon in a concentration dependent manner, as no hemolysis was observed at a bilirubin/albumin molar ratio of 1:1 or less. Differences in the structural make-up of proteins and lipids in the erythrocyte membranes of the two species may account for their different behavior. PMID- 23105714 TI - Evaluation of comparative and combined antimutagenic potential of vitamin C and vitamin E using histidine mutant Salmonella typhimurium strains. AB - Chemoprevention represents a new intervention strategy to control some type of carcinogenesis especially in subjects at high risk for cancer development. Experimental and epidemiological data indicate that a variety of nutritional factors including vitamin C and E are effective to lower the risk of some types of cancer. However large prospective studies have failed to find such significant association. A comparative and combined in vitro antimutagenic potential of two antioxidant vitamins ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) were evaluated using Ame's Salmonella typhimurium test assay. Directly acting mutagens such as sodium azide (NaN(3)) and 4-Nitro-o-phenylenediamine (NPDA), and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were used to induce mutation in salmonella strains TA 98 and TA 100. Vitamin C significantly (P < 0.01) and dose dependently inhibited the mutagenicity induced by all the three mutagens. The percent inhibitions of vitamin C at 15 mg/plate were 33.8% (NaN(3)), 52.5 % (MNNG) and 55.4 % (NPDA). Vitamin E (15 mg/plate) was effective to inhibit mutagenicity induced by NaN3 and MNNG but did not inhibit mutation induced by NPDA. Combination of vitamins (vitamin C plus vitamin E) produced only an additive antimutagenic activity when compared to their activity at 5 mg/plate. The results of the study concluded that vitamin C is a better antimutagenic agent than vitamin E and combination of vitamins did not produce any synergistic activity. PMID- 23105715 TI - The response of liver lipid peroxidative and antioxidant defense systems of protein undernourished rats to liver regeneration. AB - The response of liver lipid peroxidative and antioxidant defense system of protein undernourished rats to liver regeneration induced by partial hepatectomy was examined in rats. Animals were divided into four groups; A,B,C and D of four animals each. Animals in group A were maintained on 16% casein diet while those in groups B, C and D were placed on low-protein diet (5% casein) for fourteen weeks and fed ad libitum. 72 hours before sacrifice, partial hepatectomy was carried out on animals in group D while animals in group C were sham-operated. The results show that protein undernutrition induced an increase in lipid peroxidation but reduced catalase activity, glutathione level and superoxide dismutase activity when compared with well-nourished rats. Liver regeneration however, resulted in significant increases in lipid peroxidation and catalase activity but significant reductions in glutathione level and superoxide dismutase activity in protein undernutrition rats when compared with their sham-operated counterparts. These results suggest that liver regeneration induced by partial hepatectomy exacerbates lipid peroxidation in protein undernutrition rats and that Catalase plays a major role in the mopping up of reactive oxygen species generated following liver regeneration in partially hepatectomised protein undernutrition rats. PMID- 23105716 TI - Lipid peroxidation and the levels of antioxidant enzymes in coronary artery disease. AB - Coronary Artery Disease is the major cause of mortality and morbidity worldwide. Traditional risk factors account for only half of the morbidity and mortality from coronary artery disease. There is substantial evidence that oxidative stress plays the major role in the atherosclerotic process. The present study was undertaken to evaluate the level of lipid peroxidation (by measuring malondialdehyde) and antioxidant enzymes (ceruloplasmin, glutathione, superoxide dismutase) in coronary artery disease. Serum malondialdehyde levels and serum ceruloplasmin levels were significantly raised in all the subgroups of study group as compared to control group (p<0.001). Whole blood glutathione levels and hemolysate superoxide dismutase activity was significantly decreased in all the subgroups of study group as compared to control group (p<0.001). Above results suggests that the patients of coronary artery disease show increased oxidative stress and decreased levels of antioxidant enzymes. So it is recommended that the management protocol for coronary artery disease patients should include antioxidant supplementation along with simultaneous lowering of lipid peroxidation. PMID- 23105717 TI - Some oxidative stress related parameters in patients with head and neck carcinoma. AB - Forty cases of head and neck cancer were studied for plasma superoxide dismutase, malondialdehyde and thiol levels and results were compared with a group of forty normal healthy volunteers. Mean plasma superoxide dismutase activity was not found to be altered while malondialdehyde concentration was significantly higher when compared with the control group. On the other hand, mean thiol level was significantly lowered. The data suggests increased level of oxidative stress in patients with head and neck cancer. PMID- 23105718 TI - Lipid peroxidation and antioxidant status in patients with rheumatoid arthritis. AB - The changes in the erythrocyte lipid peroxidation products (MDA), levels of glutathione (GSH), ascorbic acid and plasma vitamin E (non enzymatic antioxidant parameters) and activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GP(X)), catalase in erythrocytes and plasma glutathione - S - transferase (GST) activity were estimated in patients with rheumatoid arthritis. This work was undertaken to assess oxidative stress and anti oxidant status in patients with rheumatoid arthritis. It was observed that there was a significant increase in erythrocyte MDA levels, activities of SOD, GP(X), plasma GST and a significant decrease in erythrocyte GSH, ascorbic acid, plasma vitamin E levels and catalse activity in patients with rheumatoid arthritis when compared to controls. The results of our study suggests higher oxygen free radical production, evidenced by increased MDA and decreased GSH, ascorbic acid, vitamin E and Catalase activity, support to the oxidative stress in rheumatoid arthritis. The increased activities of antioxidant enzymes may be a compensatory regulation in response to increased oxidative stress. PMID- 23105719 TI - Correlation between lipid peroxidation and non-enzymatic antioxidants in pregnancy induced hypertension. AB - The present study was designed to evaluate the lipid peroxidation and non enzymatic antioxidants in pregnancyinduced hypertension (PIH) compared with healthy normal pregnant and non-pregnant as controls. 75 cases were studied of which 25 were normal healthy controls (Group A), 25 healthy pregnant women (Group B) of third trimester and 25 were PIH (Group C) of the same trimester. In PIH, malondialdehyde a lipid peroxidation product was significantly increased as compared to normal pregnant and non-pregnant controls. The nonenzymatic antioxidants like reduced glutathione, Vitamin-E, Vitamin-C and Vitamin-A were significantly decreased in normal pregnants as compared to controls. A further significant decrease was noticed in PIH compared to normal pregnants. A significant negative correlation was detected between lipid peroxidation and non enzymatic antioxidant levels. Our study clearly indicates a relationship between elevated lipid peroxidation, decreased non-enzymatic antioxidant in PIH. The measurement of non-enzymatic antioxidants in plasma may be useful predictor of the likely development of PIH. PMID- 23105720 TI - Seminal plasma levels of free 8-isoprostane and its relationship with sperm quality parameters. AB - There is growing evidence that damage to spermatozoa by reactive oxygen species play a key role in male infertility. The aim of this study was to assess seminal plasma free 8-Isoprostane levels in men with asthenozoospermia, asthenoteratozoospermia and oligoasthenoteratozoospermia compared to normozoospermic males and its correlation with seminal parameters. The case group consisted of men with asthenozoospermia (n=15), asthenoteratozoospermia (n=16) and oligoasthenoteratozoospermia (n=15). The control group consisted of 16 males with normozoospermia. After Purification of Free 8-Isoprostane by affinity column, its concentration was measured by enzyme immunoassay method. Free 8 Isoprostane evaluation showed significantly greater values in the total case group (n=46) versus control group (18.23+/-3.56 vs 2.6+/-0.38 ng/ml). In each case group free 8-Isoprostane also showed a significant increasing compared to normozoospermic males. Free 8-Isoprostane showed an inversely significant correlation with sperm motility and sperm morphology. Lipid peroxidation could have significant role in etiology of sperm abnormalities. Measurement of 8 Isoprostane can be used as a specific biomarker for assessing lipid peoxidation in sperm. PMID- 23105721 TI - Effect of chloride and diamide on sheep kidney, lung and serum angiotensin converting enzyme. AB - The effect of chloride and diamide on angiotensin converting enzyme (ACE) activity from sheep kidney, lung and serum was investigated by using Hip-His-Leu as substrate. Optimum chloride concentrations were 400-1000 mM for kidney, 700 mM for lung and 1000 mM for serum. Optimum chloride concentration increased ACE activity of serum and lung 1.70 folds and 2.73 folds respectively of the activity at physiological chloride concentrations, suggesting that the effect of salt on blood pressure may be due to the chloride sensitivity of ACE. The difference in effect of chloride on lung, kidney and serum ACE suggest that each tissue ACE has unique three dimentional structure. Increased pulmonary and serum ACE activity on pretreatment with diamide indicates that tissue oxidation may alter blood pressure. PMID- 23105722 TI - Isolation and purification of rat islet cells by flow cytometry. AB - Flow cytometry has been employed as a method to study homogeneity of isolated islet subpopulations. After collagenase digestion of rat pancreas and elutriation of tissue fragments, islets were isolated and dissociated, and cells were analyzed and sorted according to their low forward angle light scattering properties by using automated flow cytometry. A standardized procedure was developed for the preparation of rat islet cell grafts for purification of islet cells. In this process, after collagenase digestion of pancreas, islets were isolated, dissociated, identification by dithizone method and then with enzymatic procedure by DNase and trypsin, the islet cells changed into single cells and beta cells were identified by immunofluorescence method and then assayed by flow cytometry. Methods have been developed for the preparation of suspension of viable rat pancreatic islet cells and their analysis and sorting in the fluorescence activated cell sorter (FACC IV, Becton Dickinson, Sunnyvale, Ca). Flow cytometry of these cells indicated that there were 91% of beta cells in cell suspension. Most of the exocrine particles were lost during digestion. Purified endocrine islet cell grafts were prepared by pure beta-cells, without endocrine non-beta cells. The purified aggregates were devoid of endocrine non-beta cells and damaged cells. PMID- 23105723 TI - Protective influence of vitamin E on the antioxidant defence system in the whole blood and liver of normal and alloxan-induced diabetic rats. AB - The effect of oral administration of vitamin E for twenty-eight consecutive days on blood glucose, reduced glutathione levels, antioxidant enzymes (superoxide dismutase and catalase activities), and levels of malondialdehyde (as an index of free radical-mediated lipid peroxidation) was observed in the whole blood and liver of normal and alloxan-induced diabetic rats. It was found that oral administration of vitamin E significantly (p<0.05) lowered the blood glucose level and increased the body weight of the diabetic rats. The activities of superoxide dismutase and levels of reduced glutathione increased significantly (p<0.05) while the level of lipid peroxidation decreased. PMID- 23105724 TI - Relationship between free iron and glycated hemoglobin in uncontrolled type 2 diabetes patients associated with complications. AB - Free iron in serum has been found in several disease conditions including diabetes. In the present work, we studied the relationship between free iron, fasting blood glucose (FBG) and glycated haemoglobin (HbA(1c)). Study was carried out on 50 type 2 diabetes cases under poor glycemic control associated with complications, 53 type 2 diabetes cases under good glycemic control and 40 healthy controls. We estimated free iron, both ferrous (Fe(+2)) and ferric (Fe(+3)) form, protein thiols, lipid hydroperoxides, FBG, HbA1c and serum ferritin levels in serum. There was a significant increase in free iron in Fe(+3) state (p <0.01), HbA(1c) (p<0.01), serum ferritin (p<0.01), lipid hydroperoxides (p<0.01) and significant decrease in protein thiols (<0.01) in diabetes cases under poor glycemic control compared to diabetes cases under good glycemic control and healthy controls. Free iron correlated positively with HbA(1c) (p<0.01). Poor glycemic control and increase in glycation of haemoglobin is contributing to the increase in free iron pool which is known to increase oxidant generation. PMID- 23105725 TI - Incidence of microalbuminuria in hypertensive patients. AB - The prevalence of microalbuminuria was assessed in 174 albustix negative hypertensive patients by estimating albumin in the morning random urine samples by immunoturbidimetric method within four hours of voiding of urine. The urine samples were not stored and collected without any preservatives. The urinary albumin was calculated in terms of ratio with respect to urinary creatinine and expressed as albumin creatinine ratio (mg/g). Out of 174 albustix negative hypertensives, 58 (33.3%) patients were found to have microalbuminuria. The prevalence of microalbuminuria in males and females was found to be 34% and 30.7% respectively. No correlation was found between the Body Mass Index (BMI) and albumin excretion (r(2) = 0.0271) and between duration of hypertension and urinary albumin excretion (r(2) = 0.0042). Prevalence of microalbuminuria in nonsmokers and non-alcoholic hypertensives was 20%. The prevalence in alcoholics, smokers and both smokers and alcoholics was found to be 35%, 42% and 41% respectively. The high prevalence of microalbuminuria than the various reported studies on the subject demands establishment of a screening programme for microalbuminuria, implementation of specific intervention methods and education of hypertensive patients about the consequences of smoking and alcohol on possible involvement of renal system. PMID- 23105726 TI - Serum cortisol, immunoglobulins and some complements among depressed patients. AB - Psychiatric disorders especially depression are associated with a variety of changes in immunity parameters. In this work, an attempt was carried out to make estimation about the correlation between immunity and depression through the measuring of IgG, IgA, and IgM and complements (C3 and C4) levels in the serum of patients and comparing them with the corresponding levels of healthy control group. The results showed a significant increase in serum level of C3, C4, cortisol, IgG and no significant differences were noticed in the level of IgA and IgM in the depressed patients group as compared with control group. A slight positive correlation was observed between cortisol versus IgG in depressed patients that is not found in normal subjects. Thus in depression, human body defenses psychologically and sometimes this defense transformed into immunological resistance that is expressed as different measurable changes in immunological parameters. PMID- 23105727 TI - Pleural fluid MDA and serum-effusion albumin gradient in pleural effusion. AB - Pleural fluid malondialdehyde (PMDA) and serum effusion albumin gradient(SEAG) were estimated in 60 patients of pleural effusion of diverse etiologies. The results were compared with Light's criteria to distinguish between transudates and exudates. The mean PMDA level was 0.68+/-0.24nmol/ml and 1.17+/-0.25nmol/ml in transudates and exudates respectively showing a statistically significant (p<0.05) rise in exudates in comparison to transudates. SEAG registered a significant fall in exudates (P<0.001) when compared with transudates. PMDA revealed a positive correlation with pleural protein(r=+0.30) and a significant negative association with SEAG (r= -0.33).Sensitivity and specificity of PMDA were better than the parameters of Light's criteria. Whereas SEAG documented approximately equal sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) with Light's criteria. Therefore PMDA and SEAG can be taken together in addition to Light's criteria to strengthen the discrimination between transudates and exudates in borderline cases of pleural effusion. PMID- 23105728 TI - Effect of n-3 fatty acid supplementation on blood glucose, lipid profile and cytokines in humans: A pilot study. AB - This study was undertaken to evaluate the effects of n-3 fatty acid supplementation on blood glucose, lipid profile and cytokines in humans. Twenty adult healthy subjects were supplemented with 1g/day fish oil concentrate capsules for 2 weeks. Fasting blood samples were taken at baseline and again after 2 week intervention. Fish oil supplementation significantly lowered fasting serum concentrations of total cholesterol, triacylglycerol, very low density lipoprotein and low density lipoprotein (P < 0.01). Also high density lipoprotein increased significantly compared with baseline value (P < 0.01). Fish oil did not significantly altere the fasting blood glucose concentration but significantly reduced the serum cytokines (P < 0.001). This study demonstrated that eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) supplementation altered serum lipids, lipoprotein and cytokine concentrations in normal human subjects even at the small dose of 660 mg of EPA plus DHA per day. It appears that EPA plus DHA can be a safe and perhaps beneficial supplement to inflammatory diseases. PMID- 23105729 TI - Diagnosis of acute myocardial infarction: CK-MB versus cTn-T in Indian patients. AB - The comparative diagnostic efficacy of two cardiac markers: CK-MB and cTn-T, has scarcely been investigated in Indian patients of acute myocardial infarction. The present study was conducted for the same objective. The present study comprised of 59 patients. Males were 44 (75%) and females were 15 (25 %). The age of patients ranged from 32-84 years with mean age of 62.8 yrs. The mean age of males and females were 60 and 63 yrs respectively. All patients presented with history of chest pain with a 12 leads ECG proven MI (ST Elevation, discordant T-waves). CK-MB was estimated in peripheral blood samples at 0,24,48 and 72 hours by an autoanalyzer. Following 12 hours of admission bed side Troponin-T test was done employing cTn-T marker kit. Initially (0 hr), in 50% patients CK-MB was elevated. By end of 24 hours all the patients were CKMB positive and peak level was attained at 24 hrs. Then it tended to decline over next 48 hrs. There were no false positive or negative results. The cTn-T test was positive only in 22 % of ECG positive infarctions. However, the cTn-T positive cases were always accompanied by a higher CK-MB levels. A significantly lower cTn-T positive cases in Indian patients can only be attributed to some difference in amino acid sequence of Indian cTn-T and occidental cTn-T. A larger study from other Indian cardiac centers can either substantiate or contradict our results. PMID- 23105730 TI - Effect of vitamin E on protein bound carbhohydrate complexes in radiation treated oral squamous cell carcinoma patients. AB - Serum glycoproteins were evaluated in oral squamous cell carcinoma patients treated with radiotherapy and also the effect of vitamin E was studied. Cell surface glycoconjugates are important parameters in the detection of malignancy. Thus, the objective of the present study is to evaluate the efficacy of vitamin E on glycoproteins in oral cavity cancer patients treated with radiotherapy. The study includes 26 age and sex matched normal healthy individuals and 26 patients with squamous cell carcinoma of oral cavity. These patients were divided into two groups, one for radiotherapy alone (at a dosage of 6000 cGy in five fractions per week for a period of six weeks) and the other for radiotherapy plus vitamin E supplementation (at a dosage of 400 IU / day of vitamin E) for the entire period of radiotherapy. Levels of hexose, hexosamine, fucose and sialic acid were increased in oral squamous cell carcinoma patients and a significant decrease was observed in radiation treated patients when compared to control. The levels of glycoconjugates were significantly decreased in radiation treated patients supplemented with vitamin E. This measurement may be useful in assessing disease progression and identifying patients resistant to therapy and a possible role of vitamin E on reduction in glycoconjugate levels of radiation treated oral squamous cell carcinoma patients. PMID- 23105731 TI - Erythrocyte glutathione status in human visceral leishmaniasis. AB - A glutathione redox cycle is a major antioxidant defense system for the detoxification of reactive oxygen species within erythrocytes. Reactive oxygen species such as superoxide anions, hydrogen peroxide and hydroxyl radicals are generated as a host defense mechanism for killing of engulfed Leishmania donovani, a causative agent of visceral leishmaniasis, are capable of damaging lipids and other biomolecules when produced in excess. Erythrocytes are most vulnerable to Reactive oxygen species. In present study we aimed to evaluate erythrocyte reduced glutathione (GSH) levels as an antioxidant and erythrocyte malondialdehyde (MDA) as a marker of lipid peroxidation. The study included twenty-five Visceral leishmaniasis patients and they were followed up after their complete chemotherapy with antileishmanial drugs (sodium stibogluconate) for 30 days. Forty six age and sex matched healthy individuals were taken as controls. GSH levels in erythrocytes of visceral leishmaniasis patients were increased in spite of significant increased erythrocyte MDA as compared to controls. Whereas erythrocyte GSH and MDA levels of follow up patients were decreased as compared to patients before treatment groups. We concluded that visceral leishmaniasis patients are in oxidative stress which most likely induces the endogenous antioxidant such as GSH or its poor utilization by cells. PMID- 23105732 TI - A preliminary study of protein thiols and serum cholinesterase in assisted reproduction. AB - In this study we sought to investigate the levels of serum protein thiols and cholinesterase levels before and after intrauterine insemination (IUI).We observed 68% patients showed a decrease in protein thiols and 63% showed a decrease in serum cholinesterase levels after insemination as compared to their respective pre procedure levels. The fall in thiols was statistically significant (p=0.021) indicating there is increased oxidative stress after the procedure. However, we could not comment on any reason for the fall in cholinesterase. Whether the changes in above parameters may have some implication on the overall success rate of IUI is yet to be ascertained. PMID- 23105733 TI - Unusually high serum CA19.9 in gastric carcinoma: A case report. AB - We describe a case of poorly differentiated adenocarcinoma of stomach, which did not present typical symptoms of gastrointestinal malignancy on first visit. The patient, a 62 year old smoker presented with shortness of breathe and pain in right lumbar region with no history of fever. Bone scans revealed multiple hot spots in skull, sternum, lumbar vertebrae and both iliac crests. A series of tumor markers were ordered which include PSA, CEA, CA19.9, CA 72.4 and AFP. Serum PSA and AFP concentrations were within normal range. Serum CEA and CA 72.4 were raised significantly. Markedly elevated levels of serum CA19.9 were found (>45000 U/ml) in this patient. CT chest and bronchoscopic examination ruled out the possibility of cancer lung. Upper GI tract endoscopy was done to find out lesion in GI tract. An ulcerative lesion was found in lesser curvature of stomach. Histopathological examination of endoscopic biopsy revealed a poorly differentiated adenocarcinoma of stomach. An unusually high serum CA19.9 (>45000U/ml) in case of gastric carcinoma has not been reported earlier. PMID- 23105734 TI - Trends in clinical biochemistry: Diagnostics. PMID- 23105736 TI - Effect of pH on spectral characteristics of P5C-ninhydrin derivative: Application in the assay of ornithine amino transferase activity from tissue lysate. AB - Currently available method(s) for assaying pyrroline-5-carboxylate (P5C), an important intermediate metabolite of ornithine, proline and glutamate metabolic pathways, are cumbersome or not sensitive enough for microanalysis. The present study involving the synthesis of P5C followed by purity check, molecular mass (amu =113.1) determination by mass spectrometry and spectral characterization of P5C-ninhydrin derivative (lambda max: 510 nm) confirmed the authenticity of the preparation. Studies on the effect of pH on spectral characteristics of P5C ninhydrin derivative demonstrated a significant change with respect to lambda max (620 nm) and several ~ 12 fold increase in molar extinction coefficient (epsilon: 1.96 * 10(5)) in alkaline conditions (pH:7.0-8.0) as compared to the reported Molar epsilon of 1.65 * 10(4) at max lambda 510 nm in ethanolic solution. The modified method, with the improved sensitivity, is adopted for the assay of ornithine amino transferase activity in WBC's/platelets lysate(s) from human blood. PMID- 23105735 TI - Predisposition of genetic polymorphism with the risk of urolithiasis. AB - Urolithiasis is a relevant clinical problem with a subsequent burden for health system. The aim of this review is to provide recent progress made using genetic polymorphisms to define pathophysiology, to identify persons at risk for kidney stone disease and to predict treatment response. Population case-control studies are useful both as an alternative and an adjunct as compared to family studies. These involve either whole genome scanning or candidate gene approaches. While whole genome scanning is likely to be widely used in future, at present, candidate gene studies are more feasible. When performing candidate gene case control studies factors such as study design, methods for recruitment of case and controls, selection of candidate genes, functional significance of polymorphisms chosen for study and statistical analysis require close attention to ensure that only genuine associations are detected. Some of the significant genes that play role in stone formation include calcitonin receptor gene (CTR), vitamin D receptor (VDR), Urokinase, Interleukin, (IL-1beta, IL-Ra), E-Cadherin, Androgen & oestrogen receptor gene, vascular endothelial growth factor (VEGF) and Arginine p21. In our case-control study we studied CTR, VDR, Urokinase, IL-1beta(-511 and +3954), IL-Ra from north India and predict that VDR, IL-beta (-511) and IL-1Ra gene may be used as a possible genetic marker for earlier detection in patients who are at risk for calcium oxalate stone disease. Further, linkage disequilibrium and haplotype structure of a certain candidate gene is important for association analysis. When a certain polymorphic allele has been found to be associated with disease, it is further explained on basis of LD and haplotype structure by one or more other alleles. Once it is determined which haplotype carries the risk allele, by means of molecular biological functional analyses, the variants on that haplotype allele truly causing the effect can be determined. PMID- 23105737 TI - Higher alleles of apolipoprotein B gene 3' VNTR: Risk for gallstone disease. AB - BACKGROUND: Imbalance in cholesterol homeostasis may lead to gallstone disease. Apolipoprotein B is sole component of low-density lipoprotein and plays an important role in cholesterol metabolism. The present study was carried out to explore the association of APOB 3' VNTR, exon 26 XbaI and signal peptide insertion/ deletion polymorphisms with gallstone disease. 214 ultrasonographically proven gallstone patients and 322 healthy, age and sex matched controls were taken for the study. Genotyping was done using PCR followed by polyacrylamide gel electrophoresis for VNTR and insertion/ deletion analysis. For APOB XbaI polymorphism PCR product was digested with XbaI restriction enzyme, followed by agarose gel electrophoresis. All statistical analyses were done using SPSS v11.5. Higher repeat alleles of APOB 3' VNTR polymorphism were more frequent in gallstone patients than in controls. Alleles with more than 57 repeats were present only in patient group. Long (L) alleles with repeat higher than 49, were significantly higher (P=0.000; OR=3.705, 95% CI 2.577-5.326) and medium (M) alleles were lower (P=0.000; OR=0.406, 95% CI 0.304-0.542) in patients than in controls. To nullify the effect of gender, data was further stratified into male and female population. APOB 3' VNTR, L alleles were imposing risk and M alleles were protective in both male and female population. APOBXbaI and insertion/deletion polymorphisms were not found to be associated with the gallstone disease. Longer alleles of APOB 3' VNTR occur more frequently in gallstone patients, and may be an important risk factor for the development of gallstone disease. APOB XbaI and signal peptide insertion/deletion polymorphisms may not be contributing to the risk for gallstone disease. PMID- 23105738 TI - Hyperinsulinemia predisposes to NAFLD. AB - Metabolic syndrome contributes to pathogenesis of Type-2 diabetes and CAD. Insulin Resistance is the key factor of metabolic syndrome implicated in development of Non Alcoholic Fatty Liver Disease (NAFLD). In present study we have investigated the prevalence of NAFLD in metabolic syndrome and contribution of metabolic risk factors in causation of NAFLD in non-diabetic North Indian male population. The study was conducted on 495 non-diabetic, nonalcoholic subjects (age 30-65 years). Metabolic Syndrome was assessed by using ATP III and ADA (2005) criteria. Anthropometric factors-Waist circumference and blood pressure were measured. Fasting serum samples were analyzed for Glucose, Triglycerides, Cholesterol and its fractions, Insulin, Alanine transaminase, Aspartate transaminase, Gamma glutamyl transferase and free fatty acids. Insulin resistance was estimated by Homeostasis Model and Insulin sensitivity by QUICKI Index. Liver ultrasonographic scanning was used for assessing fatty liver. The prevalence of metabolic syndrome and NAFLD was 24% and 14.8% respectively in non-alcoholic population and 27% of metabolic syndrome had NAFLD which was associated with hyperinsulinemia, insulin resistance, insulin insensitivity along with elevated levels of waist circumference, blood pressure, triglyceride, FFA and decreased HDL-Cholesterol. The prevalence of NAFLD increased with insulin resistance and clustering of metabolic risk factors. PMID- 23105739 TI - Study of genetic, metabolic and inflammatory risk factors in patients of acute ischemic stroke. AB - Stroke is the third leading cause of death and foremost cause of disability. Based on studies in CAD patients, a focus has been shifted on genetic and inflammatory markers as risk factors for stroke besides deranged lipid profile. The present study was aimed to ascertain the role of Lipoprotein (a), C-Reactive protein (CRP) levels and lipids in patients of ischemic stroke. The study was done in 82 subjects including 40 Computerized Tomography (CT) proven patients of ischemic stroke and 42 age and sex matched controls. Complete biochemical parameters including lipid profile were carried out on autoanalyzer using standard kits and reagents. Lipoprotein (a) [Lp(a)] was determined by immunoturbidimetric assay. Atherogenic indices (Total cholesterol/ HDL, LDL/HDL and Lipid Tetrad Index) were calculated using these lipid parameters. The CRP levels were measured semi-quantitatively by latex agglutination test method. Out of 40 stroke patients, 38 had abnormalities in lipid profile (As per ATP III guidelines). A significant difference was seen in serum cholesterol, LDL cholesterol and atherogenic indices between the patients and controls. The difference in CRP levels in cases and control subjects was highly significant (4.78+/-0.72 mg/dl vs 0.76 +/-0.70, p<0.001). 96.5% of patients with raised CRP had abnormal lipid levels also. CRP levels in stroke patients showed significant correlation with total cholesterol and LDL (p<0.001), Lp (a) (p=0.002) and atherogenic indices (p<0.05). Raised CRP levels in stroke patients were significantly associated with large territory infarcts, severe disability and poor functional outcome (p<0.05).Genetic [Lp(a)], metabolic (deranged Lipid profile) and inflammatory factors (CRP) together are instrumental in causing cerebrovascular arteriosclerosis leading to ischaemic stroke and can be used as important markers to identify patients at risk of severe stroke and to institute aggressive preventive strategies. PMID- 23105740 TI - Influence of blood specimen collection method on various preanalytical sample quality indicators. AB - Preanalytical errors contribute to a large proportion of total laboratory errors. In order to achieve continuous laboratory improvement, it is important to focus on all phases of patient specimen testing i.e. preanalytical, analytical and post analytical. With large variations in the way venous blood specimens are collected using diverse devices in the country, the effect of such practices on specimen quality is not known. The purpose of this study was to monitor fourteen specimen preanalytical quality indicators in order to compare the usage of evacuated blood collection devices with needle and syringe open collection using either disposable tubes or re-washed glass vials. The study involved 26638 patient specimens assessed over a period of 6 months. The results demonstrated that evacuated closed blood collection resulted in an approximate 100-fold reduction in the incidence of hemolysis in samples. Similarly, there was a 200-fold reduction in incidence of insufficient specimen quantity while using evacuated collection system. It was also found that incidence of specimen contamination, improper volume of sample collected, and specimen spillage was also lower when the evacuated collection system was used. Further, it was also observed that the facility with a laboratory information system demonstrated much lower specimen identification and related errors. The observed results clearly demonstrate that the usage of the evacuated blood collection system resulted in improvement of preanalytical specimen quality as compared to needle and syringe usage. PMID- 23105741 TI - Association of hyperhomocysteinemia to alcohol withdrawal in chronic alcoholics. AB - This study is conducted in chronic alcoholics to assess the association of an Individual's level of serum homocysteine with the success of achieving alcohol deaddiction in the patient. The patients' nutrition status is also assessed. 50 chronic alcoholics admitted to a deaddiction center were inducted into the study. Patients underwent an 8 weeks holistic program to promote rehabilitation from alcoholism. All the patients were addicted to alcohol for 8 - 10 years. Of the 50 patients enrolled, 39 of them completed the 8 weeks program including complete abstinence from alcohol during this period. Fasting blood samples were collected on admission and again after 8 weeks of alcohol abstinence for analyses of serum homocysteine and serum prealbumin, transferrin, total proteins and albumin, gammaglutamyl transferase (GGT) and alanine transaminase (ALT). Of the 50 patients enrolled in the study, 39 completed the 8 weeks rehabilitation program. 11 patients discontinued within 2 weeks of admission. During the 8 weeks of complete alcohol abstinence, patients were given a balanced diet and multivitamin supplements. A significant improvement in their nutritional status was noted by the elevation of serum levels of prealbumin, transferrin, total proteins and albumin. Serum homocysteine levels decreased significantly (p<0.002) to normal levels from previous hyperhomocytenemia. This was accompanied by decrease in serum GGT and ALT levels indicating improved liver functions. Serum estimation of homocysteine in chronic alcoholics is important to assess whether the patient will have a successful rehabilitation. Normal homocysteine levels are achieved after dietary changes and abstinence from alcohol. Timely correction of hyperhomocysteinemia also provides successful rehabilitation. PMID- 23105742 TI - Serum homocysteine levels in cerebrovascular accidents. AB - Hyperhomocysteinemia has been considered an independent risk factor in the development of stroke. The present study was undertaken to evaluate serum homocysteine levels in patients with cerebrovascular accidents among the Manipuri population and to compare with the normal cases. Ninety-three cerebrovascular accident cases admitted in the hospital were enrolled for the study and twenty seven age and sex matched individuals free from cerebrovascular diseases were taken as control group. Serum homocysteine levels were estimated by ELISA method using Axis homocysteine EIA kit manufactured by Ranbaxy Diagnostic Ltd. India. The finding suggests that hyperhomocysteinemia is associated with cerebrovascular accident with male preponderance, which increases with advancing age. However, whether hyperhomocysteinemia is the cause or the result of cerebrovascular accidents needs further investigations. PMID- 23105743 TI - Plasma MDA and antioxidant vitamins in diabetic retinopathy. AB - Hyperglycemia and dyslipidemia in diabetes mellitus induce increased lipid peroxidation and peroxyl radical formation, an important mechanism in genesis of microangiopathy. We took up a study on oxidative stress, measured by plasma MDA and antioxidant vitamin status in type - 2 DM patients with and without retinopathy and compared them with a control non-diabetic group. Lipid peroxidation marker MDA was significantly elevated (p < 0.001) in both the diabetic groups whereas, serum vitamin E and vitamin C registered a significant fall (p<0.001) as compared to controls. Our correlation study revealed a significant positive association between plasma MDA with both fasting and 2hr post prandial plasma glucose (r=0.81, p < 0.001, r=0.92, p <0.001) suggesting the role of hyperglycemia in free radical production. Plasma MDA also depicted significant positive relation (p< 0.001) with all lipid parameters except serum HDLc pointing the role of dyslipidemia towards lipid peroxidation. Plasma MDA level was also found to be negatively correlated with both the vitamins (p<0.001, p<0.001) in the study group explaining their protective consumption in the oxidative process prevailing in diabetic retinopathy. PMID- 23105744 TI - Serum cystatin C as a marker to identify patients with moderately impaired renal function. AB - The low molecular weight protein cystatin C produced by all nucleated cells and eliminated by glomerular filtration is of special benefit as a marker of renal function. A study was therefore undertaken to investigate whether serum cystatin C could be used as a marker to identify patients with moderately impaired renal function. A cross-sectional descriptive hospital based study was carried out and serum cystatin C was measured in fifty subjects aged 12 to 74 years with a 24 hr creatinine clearance estimation done at the same time. The gold standard creatinine clearance was used to compare the predicted glomerular filtration rate measured using serum cystatin C. Predicted glomerular filtration rate gave a sensitivity of 82% and specificity of 68% with a diagnostic cut-off value of 1.25mg/L cystatin C for identification of patients with moderately impaired renal function with a single random blood sample. PMID- 23105745 TI - Study of glycemic profile of Cajanus cajan leaves in experimental rats. AB - The present study deals with the evaluation of glycemic profile of aqueous extract of Cajanus cajan leaves in streptozotocin induced type 2 diabetic rats. Single oral administration of graded doses of aqueous extract of Cajanus cajan leaves showed significant increment of 14.3 % in fasting blood glucose levels of normal rats. The sub diabetic and mild diabetic models have also shown hyperglycemic effect from the same variable doses of the extract. The dose of 1000 mg/kg showed the maximum rise of 17.1, 71.2 and 50.7 % in Blood glucose levels of normal, sub and mild diabetic rats respectively during glucose tolerance test. The study of leaves was taken into consideration on the basis of earlier reported hypoglycemic activity of Cajanus cajan seeds. However the results observed were found just opposite and therefore it may be useful in controlling hypoglycemia, occasionally caused due to excess of insulin and other hypoglycemic drugs. PMID- 23105746 TI - Radioprotective effects of ocimum flavonoids on leukocyte oxidants and antioxidants in oral cancer. AB - Oxidants (NADPH oxidase and myeloperoxidase) and antioxidants (GSH,GSH peroxidase, SOD and glucose 6 phosphate dehydrogenase, that provides NADPH for antioxidants) were assayed in the neutrophils from oral cancer patients, in three stages viz, baseline samples,15 days after radiation and 30 days following radiation. These samples were obtained from 2 groups of patients. Group A that received radiation alone and Group B that received radiation and ocimum flavonoids,a radioprotector. The results showed a significant fall in the SOD levels in the second follow up of group B.Glucose 6 phosphate dehydrogenase showed significant increase only in the first follow up of patients who received Ocimum flavonoids. Except for these findings all other parameters remained statistically nonsignificant. PMID- 23105747 TI - Changes in serum seromucoid following compensatory hyperparathyroidism: A sequel to chronic fluoride ingestion. AB - This study was conducted to find out the possible underlying mechanism of various manifestation of fluorosis, a disease caused by excess ingestion of fluoride. For this the fluoride belt of Jaipur district was selected. The parameters selected were serum Parathyroid hormone, the levels of which are directly affected by fluoride intake. The levels of serum seromucoid, serum and leucocyte ascorbic acid, serum sialic acid (SSA) reflects ground substance metabolism. The study was conducted on two hundred children, selected from four areas (50 from each area) consuming water containing 2.4, 4.6, 5.6 and 13.6 mg/l of fluoride. Drinking water fluoride and serum fluoride were measured by Ion selective electrode method. Serum parathyroid by RIA and all other parameters were measured spectrophotometrically. The results revealed an increase in levels of fluoride, parathyroid hormone and seromucoid in serum with increasing water fluoride concentrations. Serum Calcium and serum ascorbic acid were found in normal range, how ever leucocyte ascorbic acid were decreased. A high positive correlation among fluoride concentration in drinking water and serum parathyroid hormone (r=0.967), and, serum parathyroid hormone and serum seromucoid concentration (r=0.935) was also observed The results indicated that secondary hyperparathyroidism due to hypocalcemic stress caused by excess fluoride ingestion disturbs normal metabolism of ground substance in calcified tissues of the body reflected as altered levels of the components of ground substance in the serum. PMID- 23105748 TI - Adjustments of serum lactate dehydrogenase isoenzymes and their significance in monitoring the treatment in patients with tubercular pyothorax. AB - The adjustments and diagnostic significance of polyacrylamide gel electrophoretic (PAGE) profiles of lactate dehydrogenase isoenzymes (LDH: 1.1.1.27) was evaluated in the sera and pleural fluid of patients with tubercular pyothorax. Sera and pleural fluid samples were randomly collected from 72 and 18 patients respectively at two different timings; first, when patients were admitted to the Hospital and second, after an intensive phase of treatment. Sera of 20 healthy individuals served as control. Our results demonstrate significant differences in sera LDH (sLDH) and pleural fluid LDH (pfLDH) isoenzymes. In patients the order of LDH isoenzyme in sera and pleural fluid followed: LDH-5>-4>-2>-3>-1 and LDH-5> 4>-3>-2>-1 respectively. The ranking of activity levels in control was LDH-2>-1> 3>-5>-4. In the second phase of sampling from 31 patients, values of sLDH isoenzymes showed recovery and resembled profiles of controls. Therefore, the sLDH zymograms of patients can be used as the prognostic marker, since they tend to reach the normal level during recovery signifying the effect of chemotherapy in hospitalized patients. Moreover, according to the present findings on LDH-PAGE profiles, the levels of LDH-5 and-4 rise in pyothorax patients significantly (P<0.05). This elevation along with the rise in total LDH activity may, therefore, be used in the diagnosis and monitoring of tubercular pyothorax. PMID- 23105749 TI - Evaluation of oxidative stress, antioxidants and prolactin in infertile women. AB - The objective of the study was to estimate the serum concentrations of oxidative stress markers-lipid hydroperoxide (MDA-Malondialdehyde), lactate dehydrogenase (LDH), nitrite; and ferric reducing antioxidant power (FRAP) - a measure of total antioxidant capacity in serum. Serum nitrite levels were high in fertile women than in infertile women (p<0.001), whereas MDA was high in infertile women than in fertile group (p<0.018). On classifying the entire group of women with infertility based on the etiology, serum MDA and LDH levels were higher in women with infertility due to unexplained factor than in women with other causes contributing to infertility compared to controls (p<0.001, p<0.02). A positive correlation among serum prolactin and nitrite suggested that hyperprolactinemia could contribute to infertility by inducing oxidative damage. Serum FRAP levels showed no significant difference in the groups studied. Lipid peroxidation was high in women with unexplained infertility which may be due to hyperprolactinemia. PMID- 23105750 TI - Seasonal variations in markers of stress and oxidative stress in rats. AB - High ambient temperature has been reported to increase oxidative stress by increasing lipid peroxidation and decreasing antioxidant defence in transition dairy cows. It is also known to cause an increase in plasma cortisol levels in goats, European hedgehog and human volunteers. High levels of glucocorticoids have been reported to decrease blood glutathione and erythrocyte superoxide dismutase activity in rats. Although institutional animal houses in research laboratories of developed countries maintain animals in air-conditioned rooms at constant temperature, the same is not true of animal houses in the developing countries especially those belonging to smaller institutions and this could affect the results of the experiments being conducted on these animals. The present research study was done to assess the effects of seasonal variations on the status of erythrocyte oxidative damage, antioxidant defence and plasma cortisol levels in adult female Wistar rats. Rats were kept in their home cages and were left in non-air-conditioned procedure rooms in two different seasons, Hot season (March-May) and Cool season (June to September). Erythrocyte Thiobarbituric acid reactive substances and plasma cortisol levels were significantly increased in rats exposed to high ambient temperature and humidity of the hot season as compared to the rats of the cool season. Erythrocyte reduced glutathione levels, erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the hot season group of rats. The results of our experiments showed that exposure of adult female Wistar rats to high ambient temperature and humidity of the hot season increases neuroendocrine stress, oxidative stress and decreases antioxidant defence in them. PMID- 23105751 TI - Effect of irbesartan on streptozotocin induced diabetic nephropathy: An interventionary study. AB - Effect of irbesartan, an angiotensin II receptor antagonist, was studied in streptozotocin (STZ) induced diabetic nephropathy. Polyuria, proteinuria, blood urea, creatinine clearance, and urinary electrolytes were determined to assess kidney damage. There was a significant increase in urine volume, urinary protein and blood urea in STZ induced diabetic rats. On the other hand, irbesartan treatment resulted in a significant reduction in urinary protein and blood urea in these rats. Irbesartan treatment also improved creatinine clearance and exhibited a natriuretic effect in these animals. Results suggest that irbesartan treatment ameliorate STZ induced diabetic nephropathic changes, in rats. PMID- 23105752 TI - A biochemical study on variability of Superoxide dismutase, Catalase and Glutathione peroxidase in dry cleaners. AB - Several chemicals which induce cytotoxicity are broadly classified into three types and they are organophosphate, organochlorine and carbomate compounds. Perchloroethylene has been clearly identified as a carcinogen in experimental animals and it's a very common carcinogen used for dry clean purpose. Hence, in the present study, blood samples from dry cleaners were taken, Superoxide dismutase, Catalase and Glutathione peroxidase activity was estimated in blood samples of dry cleaners. There was a significant increase in the activity of Catalase, Glutathione Peroxidase, Superoxide Dismutase in dry cleaners of chronically exposed to perchloroethylene as compared to controls. The increased activities of antioxidant enzymes may be a compensatory regulation in response to increased oxidative stress induced by perchloroethylene. PMID- 23105753 TI - Lead toxicity as a result of herbal medication. AB - Awareness about the toxic effects of non-essential metals is still lacking in developing countries. Lead is one among them, which ranks second in the Agency for Toxic Substances and Disease Registry' s top 20 lists of toxic metals. Some of the herbal medicines prepared from certain roots and leaves are known to contain this toxic metal at alarming levels. We have a case of a person who suffered from the toxic effects of lead such as vomiting and colicky abdominal pain after consuming a herbal remedy for Jaundice treatment. This went unrecognized initially because of the presence of multiple problems like Malaria and Renal calculi. Lead poisoning as causative factor for anemia, vomiting and colic were confirmed only when blood lead concentration was estimated. A combination of chelation therapy and nutritional supplementation was found to be useful in reducing the body lead burden. PMID- 23105754 TI - Location of the 70bp VNTR polymorphic site is in third intron of IL-4 gene. PMID- 23105755 TI - Accreditation requirement of laboratory medicine in India. PMID- 23105757 TI - A comparative study on oxidative stress and antioxidant status in ischemic stroke patients with and without diabetes. AB - The study was conducted to find out the extent of lipid peroxidation and antioxidant status in ischemic stroke patients (ISPs) with and without diabetes. Malondialdehyde (MDA) was studied as a marker of lipid peroxidation. Glutathione (GSH), uric acid and ceruloplasmin were estimated to study the antioxidant potential of ISPs. Significantly higher levels of MDA were found in both the groups of ISPs and the increase in MDA was more in ISPs without diabetes. GSH levels were decreased significantly in both the groups of ISPs and maximum decline was found in ISPs with diabetes. Uric acid levels were significantly increased in both the groups of ISPs. Ceruloplasmin levels were increased significantly in ISPs without diabetes, whereas its levels were slightly decreased in ISPs with diabetes. A negative correlation was found between MDA and the antioxidants GSH, uric acid and ceruloplasmin in ISPs with diabetes. This study suggests that there is an association between ischemic stroke and increased oxidative stress and the antioxidant potential is impaired in both the groups of ISPs with and without diabetes. PMID- 23105756 TI - Malnutrition-inflammation-atherosclerosis syndrome in Chronic Kidney disease. AB - Chronic kidney disease is becoming a major health problem globally and in India an alarming number of about 8 million people are suffering from this disease. Patients undergoing hemodialysis have a high prevalence of protein-energy malnutrition and inflammation. As these two conditions often occur concomitantly in hemodialysis patients, they have been referred together as 'malnutrition inflammation-atherosclerosis syndrome' to emphasize the important association with atherosclerotic cardiovascular disease. The three factors related to the pathophysiology in these patients are dialysis related nutrient loss, increased protein catabolism and hypoalbuminemia. Inflammation in Chronic Kidney disease is the most important factor in the genesis of several complications in renal disease. Pro-inflammatory cytokines like IL-1 and TNF-alpha play a major role in the onset of metabolic alterations in Chronic Kidney disease patients. Atherosclerosis is a very frequent complication in uremia due to the coexistence of hypertension, hyperhomocysteinemia, inflammation, malnutrition and increased oxidative stress, generation of advanced glycation end products, advanced oxidation protein products, hyperlipidemia and altered structural and functional ability of HDL. LDL-cholesterol, apolipoprotein (A), apolipoprotein (B), and Lp(a) are also associated with atherosclerosis. Studies have now provided enormous data to enable the evaluation of the severity of malnutrition inflammation-atherosclerosis syndrome as well as effective monitoring of these patients. PMID- 23105758 TI - RBC membrane composition in insulin dependent diabetes mellitus in context of oxidative stress. AB - Glyco-oxidation is considered as a source of permanent, cumulative, oxidative damage to long lived proteins in ageing and in diabetes. Although RBC depends solely on glucose for energy purpose, hyperglycemic state glycosylates hemoglobin, creates oxidative stress and puts the cellular components at risk. In view of this, RBC membrane composition was analyzed in diabetic patients. The results were compared with healthy age and sex matched control groups. When RBC membrane components such as protein, sialic acid, phospholipids and cholesterol were determined in insulin dependent diabetes mellitus, a significant rise in phospholipids and cholesterol and significant fall in sialic acid and protein content was noted. RBC membrane composition showed pronounced alterations in insulin dependent diabetes mellitus. These changes were accompanied by higher levels of lipid peroxidation products like Malondialdehyde. PMID- 23105759 TI - Normal delivery induced stress alters glutathione peroxidase and TNF-alpha in elderly primigravidas mononuclear cells. AB - To probe the glutathione peroxidase (GPx) activity coupled to ROS and TNF-alpha levels in younger versus elderly primigravidas. Monocytes were isolated from blood of young and elderly primigravidas after 12 hrs, 24 hrs and 14 days postpartum. Age-matched healthy female donors served as controls. Thereafter, the above monocytes were subjected to evaluation of GPx activity, levels of pro inflammatory cytokine TNF-alpha and reactivity/specificity towards anti-TNF-alpha antibody. Suppression in GPx activity with simultaneous enhancement of TNF-alpha levels in monocytes was observed after 12 hrs and 24 hrs of spontaneous labor pain-induced maternal delivery through normal vaginal route. Conversely, an enhancement of GPx activity and decrease in TNF-alpha levels were observed on day 14 of postpartum, thereby indicating reversal of the impaired neutralizing mechanisms. The antioxidant network combating ROS was stronger in younger primigravidas. Capability of TNF-alpha and ROS suppression was somewhat lesser in elderly primigravidas even 14 days of postpartum via normal vaginal route. The capability of GPx activity enhancement with simultaneous suppression in ROS and TNF-alpha, decreases in elderly primigravidas. This may act as one of the important parameters leading to a variety of complications encountered by elderly primigravidas. PMID- 23105760 TI - Effect of vitamin E supplementation on oxidative stress in hemodialysis patients. AB - Hemodialysis represents a chronic stress status for its recipients. Many hypotheses state that this may be associated with oxidative stress. Thus, there may be deficiency of antioxidants like erythrocytic superoxide dismutase, catalase, vitamin E or increased generation of free radicals like superoxide anions. A study was carried out to investigate oxidant and antioxidant status in chronic renal failure patients undergoing hemodialysis and effect of vitamin E supplementation on these two status. Blood samples were collected from patients before and after hemodialysis and from controls. The samples were analyzed for quantitation of MDA as index of lipid peroxide, nitric oxide, vitamin E, vitamin C and enzymatic antioxidants namely erythrocyte SOD and catalase. As compared to controls, the levels of serum MDA were significantly increased and activities of erythrocyte SOD and catalase, levels of serum nitric oxide, serum vitamin E and plasma vitamin C were significantly decreased both before and after hemodialysis. The efficiency of vitamin E therapy in hemodialysis patients was assessed by re evaluating oxidant and antioxidant status of same patients after supplementation of vitamin E. Vitamin E supplementation caused decrease in serum MDA and increase in levels of serum nitric oxide, vitamin E, vitamin C and activities of erythrocytic SOD and catalase. Our results suggest the presence of oxidative stress and the possible preventive role of vitamin E therapy in hemodialysis patients. PMID- 23105761 TI - Antidiabetic and antioxidant effects of Picrorhiza kurrooa rhizome extracts in diabetic rats. AB - Picrorhiza kurrooa is mentioned in Ayurveda for the treatment of many disorders, but it has not been subjected to systematic scientific investigations to assess its antidiabetic effect. The oral administration of aqueous and methanol extracts of P. kurrooa rhizomes (250 and 500 mg / kg body weight / day) for 15 days significantly reduced blood glucose, glycosylated haemoglobin and increased total hemoglobin, plasma insulin in alloxan-induced diabetes in albino rats. The treatment also showed significant correction in the level of nitric oxide radicals, superoxide radicals, peroxynitrite radical, lipid peroxidation, glutathione, glutathione reductase, glutathione-S-transferase, glutathione peroxidase, superoxide dismutase and catalase in the pancreas of alloxan diabetic rats. PMID- 23105762 TI - Detection of Helicobacter pylori using nested polymerase chain reaction in gastric biopsy samples. AB - Helicobacter pylori remains a controversial organism with regards to humans, its epidemiology still unclear nearly two decades after discovery. The present study was undertaken to estimate the prevalence of the organism in the gastrointestinal tract in symptomatic and asymptomatic subjects to understand its precise natural history in India. A total of 154 specimens were a part of the study. These included gastric biopsies from peptic ulcer disease and Non ulcer dyspepsia subjects, as visualized on endoscopy, saliva and stool samples from apparently normal healthy adults. Nested polymerase chain reaction was performed using the primers Hp1, Hp2, Hp3 targeting 16S rRNA gene. A prevalence of 65.1%, 100%, 66.7%, and 73.3% respectively was observed by polymerase chain reaction. No association was observed between the H.pylori status and the disease condition of the patient. PMID- 23105763 TI - Use of glycated hemoglobin (HbA(1C)) and impaired glucose tolerance in the screening of undiagnosed diabetes in the Malaysian population. AB - Although HbA(1C) is widely accepted as a useful index of mean blood glucose in type 2 diabetic patients its usefulness as screening test for diabetes has been controversial. The present study was undertaken to determine whether the level of HbA(1C) predicted diabetes in a prediabetic group of subjects. Plasma lipids, oral glucose tolerance, HbA(1C) was determined in 90 normal control subjects, 57 offspring of one type 2 diabetes mellitus parent and 11 diagnosed type 2 diabetes mellitus individuals. The mean age of participants was 44.5 yrs (not significantly different amongst the three groups) and the mean body mass index was 26.8 (not significantly different amongst the three groups). Two hours after a 75 g glucose challenge, the offspring had a significantly higher plasma glucose level (mean = 7.1 mmol/L, p value = 0.002) than the normals. Similarly the HbA(1C) values were higher in the offspring than in the normals (mean = 5.78%, p value = 0.016). Besides the significantly higher values for oral glucose tolerance test and HbA(1C), the diabetics also were significantly higher for triglycerides (mean = 2.25mmol/L), total cholesterol (mean = 6.24mmol/L) and systolic blood pressure (mean = 138.45mm Hg) than the offspring (P value = 0.031, 0.006, 0.010) and the normals (P value = 0.026, 0.018, 0.002) respectively. The mean values of diastolic blood pressure, LDL cholesterol and HDL cholesterol were not significantly different amongst the three groups. PMID- 23105764 TI - Sex hormone binding globulin in breast cancer. AB - The present study was undertaken to determine the significance of sex hormone binding globulin, the major and specific binding protein for testosterone and estradiol, in breast cancer. Among breast cancer patients, lower serum levels of Sex hormone binding globulin and higher levels of testosterone were observed. Sex hormone binding globulin showed an inverse relationship with testosterone and total cholesterol, and a direct relation with HDL-cholesterol. By the western blot analyses, Sex hormone binding globulin was detected in all biological samples that we examined. In the breast tumor tissue sections, immuno-staining for Sex hormone binding globulin was confined in cell cytoplasm and 29% cases were positive, which showed no association with the investigated prognostic markers of breast cancer such as ER and HER-2/neu over-expression. In this study, decreased circulating levels of Sex hormone binding globulin in breast cancer patients possibly indicate higher bioavailable estrogens. PMID- 23105765 TI - Plasma Homocysteine, Folate and Vitamin B(12) levels in senile cataract. AB - Elevated plasma Homocysteine level is an independent risk factor for age related (senile) cataract. Certain nutritional deficiencies, in particular Folate, Vitamin B(12), Vitamin B(6) relate inversely with Homocysteine level. This study was undertaken to evaluate the plasma level of Vitamin B(12), Folate, and Homocysteine of cataract patients and to study the interplay between them. Serum Homocysteine level is significantly increased in cataract patients when compared with control (p< 0.001). There was a significant decrease in the level of Folate as compared with control (p<0.001). There was a negative correlation between Homocysteine vs. Vitamin B(12) (p<0.01) and Folate (p<0.01) in the Cataract patients. Our findings suggest that increased plasma Homocysteine level is associated with decreased plasma levels of Folate and VitaminB(12) in Cataract patients, which might have a possible role in the root cause of cataract pathogenesis. PMID- 23105766 TI - Effect of Vitamin B(12) and Folate on Homocysteine levels in colorectal cancer. AB - Folate and cobalamin (Vitamin B(12)) are two essential micronutrients involved in one-carbon metabolism, which affects heart disease, neural tube defects and cancer. Methylenetetrahydrofolate reductase, the key enzyme involved in one carbon metabolism produces methyl tetrahydrofolate from methylene tetrahydrofolate, which in turn donates methyl group to homocysteine to generate methionine. There exist two common low function polymorphic variants of the methylenetetrahydrofolate reductase gene involving nucleotides 677 C->T and 1298 A->C, which are associated with hyperhomocysteinemia. These polymorphisms are also linked with increased risk for certain cancers such as breast cancer and at the same time providing a protective effect on colorectal cancer. In this case control study, we have evaluated levels of folic acid, vitamin B(12) and homocysteine in patients with colorectal cancer. Folate and homocysteine levels did not differ significantly between the two groups; however an increasing trend was noticed with increase in homocysteine levels. Vitamin B(12) levels were increased in cases compared to control group. PMID- 23105767 TI - Correlation between serum lipid profile and carotid intima-media thickness in Polycystic Ovarian Syndrome. AB - Abnormal lipid profile is often found in women with Polycystic Ovary Syndrome. To assess the impact of abnormal lipid profile on atherosclerosis in young Polycystic Ovary Syndrome women, carotid intima-media thickness as judged by B mode ultrasonography were done in 30 young (18-35 yrs) Polycystic Ovary Syndrome women and in similarly age-matched 30 apparently healthy controls. Compared to controls, young Polycystic Ovary Syndrome women had significantly elevated serum total cholesterol, triglyceride and LDL-C levels and carotid intima-media thickness. HDL-C level did not differ significantly between two groups of women. In Polycystic Ovary Syndrome women carotid intima-media thickness was positively correlated with serum total cholesterol, triglyceride and LDL-C and negatively correlated with serum HDL-C. Our study suggests that even young Polycystic Ovary Syndrome women are prone to atherosclerosis from early age. PMID- 23105768 TI - Effect of anti-epileptic drugs in pregnancy and teratogenesis. AB - Epilepsy raises special concern in women during pregnancy. Antiepileptic drugs are known to induce major and minor malformations in the foetus. Aim of the study was to find an association between maternal serum alpha fetoprotein levels, foetal abnormalities and antiepileptic drugs mediated teratogenicity. Maternal serum alpha feto protein levels, kidney and liver function tests in age matched normal pregnant women and seizure free epileptic pregnant women during 12-14 weeks of gestation were estimated. Cases were subjected to ultrasonography at 11(th)-14(th) week of pregnancy and again at 20(th) week of pregnancy. maternal serum alfa feto protein was assayed by a specific Electro Chemiluminescence Immuno Assay test. There was no significant difference in kidney and liver function tests in cases as compared to controls. There were elevated levels of alpha feto protein in cases as compared to controls but this was not statistically significant. No anomalies were detected in ultrasound reports. Most women had normal full term delivery with healthy children but of low birth weight. No correlation was seen between maternal serum alfa feto protein levels and antiepileptic drug leading to teratogenesis. PMID- 23105769 TI - Thyroidal regulation of substrate kinetics properties of cytochrome oxidase in rat liver mitochondria. AB - Effects of thyroidectomy (T(x)) and subsequent treatment with 3,5,3' triiodothyronine (T(3)), and combined treatment (T(R)) with T(3) + thyroxine (T(4)) on substrate kinetics properties of cytochrome oxidase of rat liver mitochondria were examined. T(x) resulted in lowering of cytochromes content with decrease in the enzyme activity, and K(m) and V(max). T(3) and T(R) regimens restored the cytochromes contents and the V(max) values to normal. In control, T(3) and T(R) groups the enzyme activity resolved in two kinetic components; in T(x) group three kinetic components were evident. The K(m) values for all components decreased significantly in the experimental groups with concomitant increase in catalytic efficiency, K(cat)/K(m). Significant alterations in the contents of total phospholipid and of cholesterol were noted while the changes in the phospholipids composition were only of restricted nature. Regression analysis revealed that total phospholipid, cholesterol and phosphatidylcholine, phosphatidylethanolamine play significant role in fine tuning the enzyme activity. PMID- 23105770 TI - Diagnostic strategies for subclinical hypothyroidism. AB - The aim of this study is to delineate laboratory diagnostic strategies for subclinical hypothyroidism in patients who are clinically symptomatic but may have a normal thyroid profile. Tri - iodothyronine (T(3)), thyroxine (T(4)), thyroid stimulating hormone (TSH) and anti thyroid peroxidase antibodies (anti TPO) were estimated on fasting blood samples from 99 patients using electrochemiluminescence methods on ELECSYS 1010 (Roche). 74% of study subjects had elevated anti-TPO levels.61% patients had subclinical hypothyroidism. 45 of the 61 subclinical hypothyroid patients had elevated anti-TPO levels (73%). This is an important finding suggesting an autoimmune etiology for subclinical thyroid dysfunction with a higher risk of developing overt hypothyroidism. PMID- 23105771 TI - Relationship between hs-CRP and cardiac efficiency in chronic alcoholics. AB - High sensitive C-reactive protein (hs-CRP), a non-specific marker of inflammatory status has considerable interest focused due to its ability to predict myocardial infarction, stroke, peripheral arterial disease and sudden cardiac death. Alcoholics are known to be associated with inflammation of heart. This study was taken up to look for an association between consumption of alcoholic beverages over 10 years and serum concentration of hs-CRP. 3 groups were studied, 30 age matched control, 30 non-drinkers with cardio vascular complications and 30 alcoholics with history of cardio-vascular disease. Blood was analyzed for hs CRP. Results indicated that the level of hs-CRP was 0.17 +/- 0.16 mg/lit in group 1; 0.79 +/- 0.41 mg/lit in group 2 and 1.67 +/- 0.16 mg/lit in group 3. A correlation was also obtained between the hs-CRP levels and cardiac efficiency in chronic alcoholics. The elevated hs-CRP levels in chronic alcoholic with heart disease could probably be due to enhanced damaging effect of alcohol on the heart and other organs. PMID- 23105772 TI - A study of prolonged jaundice screen in healthy term babies. AB - Prolonged jaundice in most of the term babies is associated with breast milk but in some cases it can be a marker for a range of hepatobiliary, hematological, metabolic, endocrine, infectious and genetic disorders that are associated with significant mortality and morbidity if not diagnosed in time. A diagnosis of conjugated hyperbilirubinaemia warrants urgent investigation. Protocols for investigating prolonged jaundice screen vary in complexity and the yield from screen has not been assessed. In order to address these issues, we carried out a study on healthy term babies referred to our day unit with prolonged jaundice. Infants were examined by pediatrician and investigations done as per unit protocol. Prolonged jaundice screen was found to be helpful in excluding biliary atresia and to support the diagnosis of breast milk jaundice. Present study concluded that negative prolonged jaundice screen is reassuring in healthy term babies and further investigations are unwarranted unless otherwise specified. PMID- 23105773 TI - Blood glutathione levels in head and neck malignancies. AB - Blood glutathione was estimated in fifty patients of head and neck cancer in the age group of 18-76 years and the results were compared with a group of normal healthy controls. Mean blood glutathione level was found to be significantly lowered in patients than the controls. Irrespective of the site, TNM classification, histopathology, and character of lesion, fall in blood glutathione was nearly same in all the patients. The mean level was significantly increased after radiotherapy when compared with the levels before radiotherapy. The decreased levels of GSH in-patients with head and neck cancer, observed in the present study, may be due to its increased utilization by the cells. The results suggest that patients with head and neck cancer have increased oxidative stress. PMID- 23105774 TI - Biochemical parameters in neuroblastoma. AB - Apart from the biochemical parameters routinely used like Vanillyl Mandellic Acid for the patients with neuroblastoma the parameters like neuron specific enolase, ferritin, lactate dehydrogenase, gamma glutamyl transferase were also studied to assess the utility in diagnosing the patients with neuroblastoma. The study involved 40 healthy ambulatory subjects and 30 untreated cases of histologically proved neuroblastoma referred to the Tata Memorial Hospital for further management and treatment. The urinary Vanillyl Mandellic Acid levels and the serum levels of neuron specific enolase, ferritin, lactate dehydrogenase had increased significantly, p<0.001 whereas the gamma glutamyl transferase had decreased significantly p<0.001, as compared to the normal. Serum neuron specific enolase, ferritin, lactate dehydrogenase alongwith urinary Vanillyl Mandellic Acid could be of help in diagnosing the patients with neuroblastoma. PMID- 23105775 TI - Oxidative stress and antioxidant status in normolipidemic AMI patients. AB - The objective of the study was to observe the correlation between oxidative stress and antioxidants in myocardial infarct patients with normal lipid profile. In the present study investigation of lipid peroxidation and antioxidants were done in patients. This study was carried out on 165 AMI patients, (123 males and 42 females). The control group consisted on 165 normal healthy age-sex matched subjects (123 males and 42 females). Levels of Superoxide dismutase, Glutathione Peroxidase, Catalase, Malondialdehyde and Conjugated dienes were measured. The study found Superoxide dismutase, Glutathione Peroxidase, Catalase were significantly lower in activities (p<0.001) in AMI patients compared to controls. The markers of lipid peroxidation namely Malondialdehyde and Conjugated dienes were higher in AMI patients as compared to controls (p<0.001). The present study is clearly suggestive of increased oxidative stress in AMI patients. Oxidative stress appears as an etiological factor for myocardial infraction as a consequence the free radical scavengers levels are lowered in AMI patient. PMID- 23105776 TI - Adenosine deaminase and C-reactive protein in cerebrospinal fluid for differential diagnosis of tubercular meningitis in children. AB - Adenosine deaminase and C-reactive protein in CSF were assessed in 72 cases of Tubercular meningitis, 24 cases of partially treated pyogenic meningitis, 20 cases of Aseptic meningitis and 8 cases of febrile seizures. Mean Adenosine deaminase value was 12.12+/-3.13 IU/L for Tubercular meningitis group. It was significantly higher (p<0.001) as compared to partially treated pyogenic meningitis (5.39+/-2.70 IU/L) and aseptic meningitis (1.92+/-0.56 IU/L) groups. A combination of clinical criteria along with biochemical test of Adenosine deaminase and C-reactive protein in CSF increased the sensitivity of diagnosing Tubercular meningitis and differentiating it from other forms of meningitis at an early stage. PMID- 23105777 TI - An unusual case of familial hyperlipidaemia. AB - A 40 days old male baby born to a consanguineous couple was found to have highly viscous and milky serum with caking of chylomicrons on refrigeration of serum. Cholesterol was 889.5 mg/dl (23.04mmol/L) and Triglycerides 12881 mg/dl (141.69mmol/L). He was active and did not have any hepatospleenomegaly, xanthomas or dysmorphic features. Thyroid functions were normal. Lipid electrophoresis showed thick chylomicron band. There was positive family history of hypertriglyceridemia in a first cousin. Both siblings and both parents of the index case had normal lipid profiles. This child was referred to higher centre where he was put on Lipid lowering drugs (Gemfibrozil), Iron drops and special formula for feeding containing medium chain fatty acids. PMID- 23105778 TI - Fringe thoughts on Indian scientific research with focus to biochemical and biomedical studies. PMID- 23105780 TI - Oxidative stress and antioxidant status in patients with chronic myeloid leukemia. AB - Chronic myeloid leukemia is a myeloproliferative disorder with a unique rearrangement, the Philadelphia chromosome. Oxidative stress, a pervasive condition of an increased number of reactive oxygen species, is now recognized to be prominent feature of various diseases and their progression. Thus antioxidants, which control the oxidative stress state, represent a major line of defense regulating overall true state of health. The relationship between antioxidants status and levels of well-known markers of oxidative stress that are measured as lipid peroxides and oxidized proteins reflect better health indices and postures. The aim of this study was to evaluate the role of oxidative stress in pathophysiology of Chronic myeloid leukemia by measuring the circulating plasma lipid peroxide levels in terms of malonyldialdehyde, total lipid hydroperoxide and oxidized proteins as protein carbonyl whereas antioxidant status were estimated in terms of reduced glutathione and total thiol in plasma of Chronic myeloid leukemia patients. The present study included 47 Chronic myeloid leukemia patients and 20 age-and sex-matched healthy subjects. Out of 47 Chronic myeloid leukemia patients, 31 were in chronic phase (CML-CP) and 16 in accelerated phase (CML-AP). The median age of Chronic myeloid leukemia patients was 33 years and that of controls was 32 years. Oxidative stress and antioxidant status in plasma were evaluated by spectrophotometric procedures. There was a significant increase (p<0.05) in plasma malonyldialdehyde, total lipid hydroperoxide and protein carbonyl levels in Chronic myeloid leukemia patients as compared to healthy subjects. Our results also showed that plasma malonyldialdehyde and protein carbonyl levels were markedly elevated (p<0.05) in both chronic phase (CML-CP) and accelerated phase (CML-AP) as compared to healthy volunteers. Antioxidant status was found to be significantly decreased (p<0.05) in Chronic myeloid leukemia patients and its phases as compared to healthy participants. It could be concluded that oxidative stress may be associated with the pathophysiology of Chronic myeloid leukemia. PMID- 23105781 TI - hs-CRP and oxidative stress in young CAD patients: A pilot study. AB - Premature coronary artery disease (CAD) is common in India. We, therefore, studied oxidative stress, dyslipidemia, and high sensitivity-C reactive protein (hs-CRP) levels in young CAD patients. Present study consisted of male CAD patients below 40 years and age and sex matched healthy controls (n=30 each). Fasting blood samples were analyzed for serum lipid profile, malondialdehyde, antioxidant enzymes and hs-CRP levels. Dyslipidemia was observed in 90% of the young CAD patients, of which 72.2% showed increased serum triglycerides and decreased HDL-cholesterol. LDL-cholesterol levels were high in 77.8%. Serum malondialdehyde and hs-CRP levels were increased significantly (p<0.0001) as compared to controls. hs-CRP levels were in high risk range in all the young patients. However, glutathione peroxidase activity was reduced significantly (p<0.05). Our data suggests that elevated hs-CRP levels along with dyslipidemia and oxidative stress adds to the predictive value of premature CAD in young Indians. PMID- 23105782 TI - Oxidative stress and disturbance in antioxidant balance in beta thalassemia major. AB - Repeated blood transfusion in beta thalassemia major patients may lead to peroxidative tissue injury by secondary iron overload. In the present study, 72 children with beta thalassemia major were included. Serum levels of total lipid peroxides, Iron, Total Iron Binding Capacity, Copper, Zinc, Vitamin E, plasma Total Antioxidant Capacity, activity of Erythrocyte Superoxide Dismutase, were measured. The findings were compared with 72 age matched healthy controls irrespective of sex. A significant increase in the levels of lipid peroxide and Iron (p<0.001), whereas, significant decrease in the levels of vitamin-E, Total Antioxidant Capacity and Total Iron Binding Capacity (p<0.001) was observed. Serum Zinc was significantly increased (p<0.001) with significant decrease in the levels of copper (p<0.001). Non Significant increase in the activity of Erythrocyte Superoxide Dismutase (p>0.05) was found in the patients when compared with controls. This suggest that oxidative stress and reduced antioxidant defense mechanism play an important role in pathogenesis of beta thalassemia major. PMID- 23105783 TI - Effects of chronic ethanol exposure on renal function tests and oxidative stress in kidney. AB - After administration, ethanol and its metabolites go through the kidneys and are excreted into urine. The kidney seems to be the only vital organ generally spared in chronic alcoholics. Therefore, we investigated the multiple effects of chronic ethanol exposure on renal function tests and on oxidative stress related parameters in the kidney. Chronic ethanol (1.6 g ethanol/ kg body weight/ day) exposure did not show any significant change in relative weight (g/ 100g body weight) of kidneys, serum calcium level or glutathione s-transferase activity. However, urea and creatinine concentration in serum, and TBARS level in kidney elevated significantly, while reduced glutathione content and activities of glutathione peroxidase, glutathione reductase and superoxide dismutase diminished significantly after 12 weeks of ethanol exposure. Catalase activity showed increased activity after 4 weeks of ethanol exposure and decreased activity after 12 weeks of ethanol exposure. Genesis of renal ultrastructural abnormalities after 12 weeks of ethanol exposure may be important for the development of functional disturbances. This study revealed that chronic ethanol exposure for longer duration is associated with deleterious effects in the kidney. PMID- 23105784 TI - Evaluation of immunohistochemistry and enzyme linked immunosorbent assay for HER 2/neu expression in breast carcinoma. AB - HER-2 is overexpressed in approximately 20-30% of invasive Breast Cancer. ECD of the HER-2 protein is frequently cleaved and released into the circulation, where it can be detected by ELISA in up to 45% of patients with metastatic breast cancer. The objective of our study was to compare the current methods for the detection of HER-2 protein. Tissue HER-2 levels were studied in 100 breast cancer patients by IHC and compared with serum HER-2 levels by ELISA. IHC frequency was 29%. Serum HER-2 ECD was positive in 42% of patients. A statistically significant correlation was observed. HER-2 detected by IHC correlates significantly with serum HER-2 levels detected by ELISA. Thus, ELISA is a reliable and economical tool to assess the HER-2 status in tumors, when breast tissue sample is not available. PMID- 23105785 TI - Plasma proteinase inhibitory activity in ectopic and molar pregnancy. AB - Antitryptic, antichymotryptic and alpha 2- macroglobulin activities were measured in sera of normal nonpregnant and normal pregnant women and women with tubal ectopic pregnancy and molar pregnancies in the first 5 to 7 weeks of pregnancy calculated from the last menstrual period. While alpha 2-macroglobulin decreased in early normal pregnancy compared to nonpregnant state (p<0.001), in ectopic and molar pregnancies there was an increase in alpha 2- macroglobulin activity (p < 0.001), as compared to nonpregnant and normal pregnant women. Antitryptic activity did not increase in normal and ectopic pregnancy, however was increased in molar pregnancy (p < 0.01). Antichymotryptic activities did not show a change either in normal pregnancy or in cases of ectopic and molar pregnancy. Drop in alpha 2- macroglobulin activity to near normal levels in ectopic, 6 weeks post surgery, correlated well with the decrease in beta-hCG. However, in molar pregnancy, alpha 2- macroglobulin remained elevated even when the beta-hCG levels in serum returned to zero 10 weeks after surgery. The studies suggest a major role for circulating proteinase inhibitors especially alpha 2-macroglobulin in regulating proteinase activity in normal, ectopic and molar pregnancy. PMID- 23105779 TI - The biochemical womb of schizophrenia: A review. AB - The conclusive identification of specific etiological factors or pathogenic processes in the illness of schizophrenia has remained elusive despite great technological progress. The convergence of state-of-art scientific studies in molecular genetics, molecular neuropathophysiology, in vivo brain imaging and psychopharmacology, however, indicates that we may be coming much closer to understanding the genesis of schizophrenia. In near future, the diagnosis and assessment of schizophrenia using biochemical markers may become a "dream come true" for the medical community as well as for the general population. An understanding of the biochemistry/ visa vis pathophysiology of schizophrenia is essential to the discovery of preventive measures and therapeutic intervention. PMID- 23105786 TI - Calcium antagonist prevents calcium flux induced necrosis and apoptosis in ischemic reperfusion of rat liver. AB - Ca(2+) accumulation in mitochondria is responsible for the cell abnormality associated with ischemia and reperfusion injury. The present study was aimed to evaluate the efficacy of Ca(2+) channel blocker- amlodipine on the mitochondrial Ca(2+) accumulation in ischemic and reperfusion (I/R) induced liver injury. Eighteen wistar rats were divided in sham-operated control group-I (n = 6), ischemia and reperfusion group-II (n = 6) and amlodipine treated group-III (1 mg/kg body weight /daily by oral route for 7 days before induced ischemia reperfusion manouver) (n = 6). Rats were subjected to 1h of hepatic ischemia followed by 3 h reperfusion. Mitochondrial Ca(2+) content was measured and damage of mitochondria was confirmed by transmission electron microscopic examination. Bcl-2 gene expression was measured by reverse transcriptase polymerase chain reaction method. Pretreatment with Amlodipine effectively counteracted the alternation in mitochondrial Ca(2+) content. TEM and expression of Bcl-2 protein confirms the restoration of cellular normalcy and accredits the cytoprotective role of Amlodipine against I/R induced hepatic injury. These findings showed that the mechanism of regulation of Bcl-2 gene expression by amlodipine may be the inhibitory action of Ca(2+) entry into mitochondria and prevent apoptosis and necrosis. PMID- 23105787 TI - Correlation between Apgar score and urinary uric acid to creatinine ratio in perinatal asphyxia. AB - A randomized case control hospital based study was conducted over 12 months time on 31 asphyxiated and 31 normal newborn to see whether urinary uric acid can be used as a marker of perinatal asphyxia and can be correlated with the clinical diagnosis by Apgar score. Uric acid and creatinine were estimated in spot urine within 24 hours after birth in both cases and controls. A ratio between concentrations of uric acid to creatinine was estimated and compared between cases and controls. It was found that the ratios were significantly higher in cases than controls (3.1+/- 1.3 vs 0.96+/- 0.54; P < 0.001) and among asphyxia patients, a significant negative linear correlation was found between the uric acid to creatinine ratio and the Apgar score (r = -0.857, P < 0.001). So urinary uric acid to creatinine ratio can be used as an additional non-invasive dispace, easy and at the same time early biochemical marker of birth asphyxia which biochemically supports the clinical diagnosis and severity grading of asphyxia by Apgar score. PMID- 23105788 TI - Influence of pranayamas and yoga-asanas on serum insulin, blood glucose and lipid profile in type 2 diabetes. AB - A distinguishable feature of type 2 diabetes besides hyperglycemia and deranged lipid profile is an impaired insulin secretion, peripheral insulin resistance and obesity which has become a major health concern worldwide. India with an estimated 31million diabetics in 2000 and 79mllions by the yr 2030 has the highest number of type 2 diabetics in the world. In this study, we aimed to see if yoga-asanas and pranayamas have any influence in modifying certain biochemical parameters. Sixty patients of uncomplicated type 2 diabetes (age 35-60 yrs of 1 10 yrs duration) were divided into two groups: Group 1 (n=30): performed yoga along with the conventional hypoglycemic medicines and group 2 (n=30): patients who only received conventional medicines. Duration of the study was 45 days. Basal recordings of blood glucose (fasting and post-prandial), lipid profile and serum insulin were taken at the time of recruitment and the second reading after forty five days. Results showed a significant improvement in all the biochemical parameters in group 1 while group 2 showed significant improvement in only few parameters, thus suggesting a beneficial effect of yoga regimen on these parameters in diabetic patients. PMID- 23105789 TI - Serum copper in Alzheimer's disease and vascular dementia. AB - Alzheimer's disease is the most common form of dementia in the elderly and it's prevalence is rapidly rising. Oxidative stress plays important role in the pathophysiology of Alzheimer's disease. Metals like copper, iron derived through diet can act as pro-oxidant under oxidative stress. In the present study, serum copper levels were evaluated in 50 patients with Alzheimer's disease, 24 patients with Vascular Dementia and 30 controls. All the groups were also investigated for serum ceruloplsmin levels. The mean copper levels in Alzheimer's disease and Vascular Dementia were significantly raised compared to controls. An attempt has been made to study the relationship of serum copper with ceruloplasmin. Our study found weak correlation between copper and ceruloplasmin levels in Alzheimer's disease and Vascular Dementia. PMID- 23105790 TI - Oxidative stress and serum alpha(1) - Antitrypsin in smokers. AB - The present study was undertaken to evaluate the levels of serum lipid peroxide, nitric oxide end poducts, erythrocytic superoxide dismutase activity and serum alpha(1)-antitrypsin in smokers. Total 90 active cigarette smokers were subdivided into Group I (subjects with smoking habit of less than 10 cigarettes per day) and Group II (with smoking habit of more than 10 cigarettes per day). In both groups lipid peroxide and nitric oxide end products were significantly increased with significantly decrease in erythrocytic superoxide dismutase activity and serum alpha(1)-antitrypsin as compared to controls. Our findings show enhanced oxidative stress and reduced alpha(1)-antitrypsin in cigarette smokers. Further increase in number of cigarettes per day exacerbates the oxidative stress with decrease in alpha(1)-antitrypsin. PMID- 23105791 TI - A Pilot clinical study to evaluate the effect of Emblica officinalis extract (AmlamaxTM) on markers of systemic inflammation and dyslipidemia. AB - Emblica officinalis Gaertn., commonly known as the Indian gooseberry or "Amla", has been used as health food for centuries in India and other Asian countries. The biological effects of amla have been attributed to the antioxidant properties of the low-molecular weight hydrolysable tannins present in the fruit. AmlamaxTM is a purified, standardized, dried extract of amla containing about 35% galloellagi tannins along with other hydrolysable tannins. Our earlier studies on rabbits showed significant reduction in total cholesterol and triglycerides as well as increase in HDL. The present study extends these results to human volunteers. Two doses of the extract were evaluated - 500 mg and 1000 mg per day for 6 months. Blood samples were collected at the 3rd and 6th months showed reduction in total and LDL cholesterols and enhancement of beneficial HDL cholesterol. In addition, blood CRP levels, a marker for inflammation, were also significantly reduced. Since dyslipidemia and inflammation are the two major components of cardiovascular diseases, the present results must be considered encouraging and indicate the potential of AmlamaxTM in the management of heart diseases. PMID- 23105793 TI - Effect of water extract of Trichosanthes dioica fruits in streptozotocin induced diabetic rats. AB - In rats with streptozotocin induced severe diabetes mellitus, aqueous extract of Trichosanthes dioica fruits at a dose of 1000mg/kg body weight daily once for 28 days reduced the levels of fasting blood glucose, postprandial glucose, asparate amino transferase, alanine amino transferase, alkaline phosphatase, creatinine, urine sugar and urine protein where as total protein and body weight was increased. No toxic effect was observed during LD50. Our study suggests that further detailed toxicity studies and mechanism of action of T. dioica would be useful for undertaking human trials. PMID- 23105792 TI - Evaluation of the radioprotective effect of turmeric extract and vitamin E in mice exposed to therapeutic dose of radioiodine. AB - The aim of this study was to evaluate the radioprotective effect of turmeric extract (40 mg/kg body weight) and vitamin E (alpha- tocopherol acetate, 400 IU/kg body weight) supplementation on lipid peroxidation, reduced glutathione and antioxidant defense enzymes in various organs like liver, kidney and salivary glands at 24 h in adult Swiss mice. (131)Iodine exposure significantly increased lipid peroxidation in kidney and salivary glands in comparison to control animals. Pre supplementation with turmeric extract for 15 days showed significant lowering of lipid peroxidation in kidney. On the other hand vitamin E pre supplementation showed marked reduction in lipid peroxidation in salivary glands. Reduced glutathione levels decreased significantly in liver after radiation exposure. However, pre supplementation with turmeric extract and vitamin E did not improve glutathione levels in liver. In conclusion, we have observed differential radioprotective effect of turmeric extract and vitamin E in kidney and salivary glands. However, Vitamin E seems to offer better radioprotection for salivary glands which is known to be the major site of cellular destruction after radioiodine therapy in patients. PMID- 23105794 TI - Preliminary studies on the hypoglycemic effect of Peganum harmala L. Seeds ethanol extract on normal and streptozotocin induced diabetic rats. AB - Peganum harmala L. (Zygophyllaceae) is a traditional medicine used for the treatment of variety of human ailments, including antidepression, hallucination, antileishmaniasis etc. We report for first time the hypoglycemic activity of the ethanolic extract of this plant at two dose levels of 150 and 250mg/kg bw in sucrose challenged normal as well as in rats with streptozotocin induced diabetes. The oral administration of ethanolic extract causes maximum fall of blood glucose level to 22.9% (p<0.05) and 29.4% (p<0.01) respectively with the two doses in normal and 30.3% (p<0.01) and 48.4% (p<0.001) in diabetic rats. The standard drug metformin treated group showed 28.0% (p<0.01) and 45.5% (p<0.001) respectively in normal and diabetic rats. The above results show that the ethanolic extract of P. harmala is as effective as metformin in reducing the blood glucose levels of normoglycemic and streptozotocin-induced diabetic rats. PMID- 23105795 TI - Antidiabetic and ameliorative potential of Ficus bengalensis bark extract in streptozotocin induced diabetic rats. AB - The aim of the present study was to evaluate the antidiabetic and ameliorative potential of aqueous extract of Ficus bengalensis bark in streptozotocin induced diabetic rats. The effect of oral administration of aqueous extract of F. bengalensis bark on blood glucose, serum electrolytes, serum glycolytic enzymes, liver microsomal protein, hepatic cytochrome P-450 dependent monooxygenase enzymes and lipid peroxidation in liver and kidney of streptozotocin -induced diabetic rats was studied. Oral administration of Ficus bengalensis to fed, fasted and glucose loaded diabetic rats significantly [F > 0.05 (ANOVA) and P< 0.05 (DMRT)] decreased the blood glucose level at 5 hrs and restored the levels of serum electrolytes, glycolytic enzymes and hepatic cytochrome P-450 dependent enzyme systems and decreased the formation of liver and kidney lipid peroxides at the end of 12 weeks. Further, the aqueous extract of Ficus bengalensis at a dose of 500mg/kg/day exhibits significant antidiabetic and ameliorative activity as evidenced by histological studies in normal and Ficus bengalensis treated streptozotocin induced diabetic rats. On the basis of our findings, it could be used as an antidiabetic and ameliorative agent for better management of diabetes mellitus. PMID- 23105796 TI - Modified uremic rat model - A tool for uremic studies in rats. AB - Experimental model of chronic renal failure in rats have been described by many authors and has also been widely used in various studies. Many of these methods used highly sophisticated instruments which was difficult in our settings. The resection model was ideal in our experimental set-up, but this model had the risk of excessive bleeding and hypovolemia. In our study we used a combination of partial resection and ligation of the renal artery to create two models of stable uremia A and Moderate uremia B. Severe uremia. Both these models were compared with a sham operated group which served as controls. Following surgical procedure, the development of uremia was monitored by serial estimation of blood urea and serum creatinine levels that were measured at regular intervals (bi weekly). From two weeks onwards the animals in the experimental group showed a significant elevation in the serum urea levels and a consistent elevation in the serum creatinine levels upto eight weeks when compared to the animals in the sham operated group. We established a modified method of producing renal failure which can be maintained for a period of six weeks. This model is simple, reproducible and less complicated that can be used for several studies relating to renal failure in the field of research. PMID- 23105797 TI - Urinary protein thiols in different grades of proteinuria. AB - Total thiol status of plasma, especially thiol groups over protein contributes maximum to the plasma antioxidant status of the body. Serum protein thiols were found to be decreased in various disease conditions including chronic renal failure patients. Only few studies determined the levels of urinary protein thiols in disease conditions. The current study was designed to know the levels of urinary protein thiols in patients with different grades of proteinuria. The study was conducted on urine of 40 healthy controls and 61 cases with proteinuria. Based on proteinuria cases were further divided into two groups; group I - microproteinuria (150-300 mg protein/d), 32 cases, group II - frank proteinuria (>300 mg protein/d), 29 cases. Urinary thiol levels were determined by spectrophotometric method using dithionitrobenzoic acid. A significant decrease (p<0.01) in urinary thiol in group I and group II cases was observed in present study and this decrease was associated with proteinuria. PMID- 23105798 TI - Biotin metabolism defect - A case report. AB - Defects in biotin metabolism are mainly associated with either the enzyme Biotinidase or Holocarboxylase synthetase. Defects in either enzymes depletes biotin utilization by the cells. Holocarboxylase synthetase deficiency is an inherited disorder in which the body is unable to use the vitamin biotin effectively. This condition is inherited in an autosomal recessive pattern. We present a case of a 9 year old girl with atypical symptomology as a case holocarboxylase synthetase deficiency, who demonstrated an increased excretion of propionic and methyl malonic acids, with her biotinidase activity being normal. She demonstrated remarkable improvement on biotin supplementation. PMID- 23105799 TI - To enhance the performance and efficiency. PMID- 23105801 TI - Usefulness of ferroxidase activity of ceruloplasmin in the diagnosis of Wilson's disease. AB - Serum ceruloplasmin is one of the most commonly used screening tests for Wilson's disease. However immunological assays for ceruloplasmin are not recommended for diagnosis and management of Wilson's disease through calculation of free copper index. Enzymatic methods using non-physiological substrates have toxicity and stability problems, making them difficult to automate. Ferroxidase assays may be a satisfactory alternative for measuring serum ceruloplasmin. The o-dianisidine hydrochloride manual method for estimation of serum ceruloplasmin enzyme activity was compared with an automated method using the ferroxidase activity of ceruloplasmin in measurement in a double blind study in 91 consecutive patients screened for Wilson's disease. The o-dianisidine and ferroxidase methods both successfully identified 7 patients with Wilson's disease. Values for these 7 patients in the o-dianisidine and ferroxidase methods were median 5.0 (range 0 16.0 U/L) and median 45.0 (range 4-166 U/L) respectively. There were 7 other positive values (<62 U/L) with the o-diansidine method and 2 (<200 U/L) with the ferroxidase method, where WD was not confirmed. ROC curves for both methods showed area under the curve of 0.998 for o-dianisidine and 0.997 for ferroxidase. Using literature cut off values of 62 U/L and 200 U/L respectively both methods had 100% sensitivity and specificity was 91.7% (o-dianisidine) and 97.6% (ferroxidase). For the o-dianisidine assay, specificity was improved to 98.8% using a cut off of 22.5 U/L. In the 84 persons (46 adults and 38 children) in whom the diagnosis of Wilson's disease was not established, the mean value for ceruloplasmin activity by the o-dianisidine and ferroxidase methods was 124.7 +/- 48.7 U/L and 571.4 +/- 168.1 U/L respectively. There were no significant differences between sex or age of patients (p > 0.29). In a subsequent evaluation with 372 specimens, the Pearson correlation coefficient between the assays was 0.908, p < 0.01, slope 4.06, intercept 265.8, with the manual assay as the x axis. The ferroxidase assay is a suitable replacement for the o-dianisidine assay in detecting patients with Wilson's disease. PMID- 23105800 TI - Role of oxidative stress while controlling iron deficiency anemia during pregnancy - Indian scenario. AB - Iron Deficiency anemia ranks 9(th) among 26 diseases with highest burden. Asia bears 71% of this global burden. Adverse maternal and birth outcome associated with hemoglobin status renders the issue worth attention. Indian scenario has worsened over the period despite continuous international and national efforts. This indicates some lacunae in the approach and strategies applied. Various reports state that even with maximum effort to increase outreach and monitoring for adherence to Iron schedule, consumer's compliance remains abysmally low. Recent studies has pointed out biological basis of side effects (gastrointestinal complains and systemic events) as raised oxidative stress for which iron is the key catalyst. Up till now the only target of research has been to raise hemoglobin of pregnant women above 11gm/dl. With the reports of pregnancy specific morbidities i.e. hemorrhage and septicemia with low hemoglobin, eclampsia, small for gestation age, gestational diabetes with higher ranges of hemoglobin, alarm is raised to define optimum range. Use of oxidative stress as biochemical marker with different doses and schedules has been defined because India lack information for its own population upon oxidative stress status when iron is supplemented as per current guidelines. Studies done in India and abroad have defined that too much and too less, both may raise oxidative stress and studies of this sort may provide biochemical scale for optimization. This review therefore has evaluated currently available Indian research and reports to understand the need of future research area. Important findings from other countries have been incorporated for comparison. PMID- 23105802 TI - Analysis of protein posttranslational modifications by mass spectrometry: With special reference to haemoglobin. AB - Mass spectrometry provides a convenient platform for the study of different protein post translational modifications from clinical specimen. Analysis of different post translational modifications of hemoglobin like glycation and glutathionylation can provide useful information on the disease progression and the possible outcome of therapies. In the present study, we have addressed post translational modifications of hemoglobin like glutathionylation and glycation in relation to diabetes and chronic renal failure. We found that both alpha and beta chains of human hemoglobin are glycated irrespective of the extent of glycemia as evidenced by a mass increment of 162 Da. The phenomenon of glutathionylation was observed with only the beta globin chain of hemoglobin probably due to the presence of an accessible cysteine residue indicated by a mass increment of 305 Da. Also, the extent of gltuathionylation observed in the CRF patients could correlate with the severity of the oxidative stress owing to renal replacement therapies like dialysis and transplantation. PMID- 23105803 TI - Evaluation of reference intervals of serum lipid profile from healthy population in Western Maharashtra. AB - Fasting samples of 914 subjects from healthy population were analyzed for total cholesterol, triglyceride and three major fractions of lipoproteins i.e. high density lipoprotein cholesterol, low lipoprotein cholesterol and very low-density lipoprotein cholesterol. The values obtained were (in mg/dl) 165.7+/-30.2,88.36+/ 31.2, 44.86+/-10.68, 101.66+/-29.8 and 18.11+/-7.35 respectively. When these subjects were grouped according to the age and sex, no appropriate differences were observed between most of the groups. Triglycerides were found to be low and HDL cholesterol was high in female when compared with male of similar age. Beyond age 40 years cholesterol level and low density lipoprotein cholesterol was found to be gradually increased in case of women. Minor difference was observed with dietary pattern. Present study suggests that clinical evaluation of patient should be made on the basis of these reference values for Western Maharashtra population. PMID- 23105804 TI - Estimation of plasma haemoglobin by a modified kinetic method using o-tolidine. AB - Measurement of plasma hemoglobin is useful in variety of clinical conditions. In the present study we have developed a kinetic method to estimate plasma haemoglobin by using o-tolidine. This method is sensitive, rapid, economical, simple and less influenced by interfering substances. It measures plasma haemoglobin in the range of 6 to 400 mg/L (normal range < 50 mg/L) in less than two minutes and can be easily automated. PMID- 23105805 TI - Multiple matrix metalloproteinases in type II collagen induced arthritis. AB - To study the relative contribution of various matrix degrading enzymes in the pathogenesis of arthritis, changes in the levels of various matrix metalloprtoteinases (MMPs) during the progression of collagen induced arthritis was studied in experimental animals. Arthritis was induced in male wistar rats by injecting an emulsion containing collagen type II and Freund's complete adjuvant. The duration of the experiment was 35 days. Synovial effusate was collected at regular intervals after induction. At the end of the experiment serum and cartilage were collected and analysed. Synovial fluid of osteoarthritic patients was also analyzed. Levels of MMP-2, MMP-3, MMP-9 and MT1-MMP were found to be high in synovial effusate and cartilage of experimental animals. In synovial effusate of arthritic animals the expression of MMP-3 was found to be high during the early stages while increase in MMP-2 and MMP-9 occurred at later stages. Synovial fluid of osteoarthritic patients also showed elevated levels of MMP-2, MMP-3 and MMP-9. Our results indicated that sequential action of MMPs such as MMP 3, MMP-2 and MMP-9 can cause degradation of articular cartilage extracellular matrix. PMID- 23105806 TI - Erythrocytic adenosine deaminase in post myocardial infarction angina patients. AB - A comparative study on the levels of erythrocyte adenosine deaminase and lipid peroxidation has been undertaken in post myocardial infarction angina patients along with age and sex matched healthy individuals serving as control. Present findings show that levels of adenosine deaminase is highly elevated in post myocardial infarction angina patients compared to healthy persons. Malondialdehyde levels are also significantly increased in post myocardial infarction angina patients. The study shows that adenosine deaminase has an important implication in ischemic myocardial syndrome. PMID- 23105807 TI - Thyroid disorders in women of Puducherry. AB - Thyroid stimulating hormone (TSH), Free Thyroxine (FT(4)) and Free Triiodothyronine (FT(3)) were assayed in 505 women of this region. 60 women had previous history of thyroid disease. The remaining 445 women formed the "Disease free group". A "Reference group" was obtained by excluding women with previous and present history of thyroid dysfunction. Of the total 505 women examined 15.8% had thyroid dysfunction and 84.2% were euthyroid. 11.5% were hypothyroid (9.5% sub-clinical) and 1.8% hyperthyroid (1.2% clinical). The geometric mean TSH for the total population was 2.65 MUIU/ml. It was significantly (p=0.025) lower in the reference population 2.17 MUIU/ml. There was no significant difference in the FT(3) and FT(4) values between groups. 19% of women over 60 years had elevated TSH above 4.5 MUIU/ml. The 2.5 and 97.5 percentiles of the reference population was 1.1-5.2 MUIU/ml. 6.1% of women in the reference group had TSH levels above the reference intervals. Hypothyroidism particularly sub-clinical hypothyroidism is predominantly present amongst women in this iodine sufficient region. Evaluation of thyroid status could help in early detection and treatment. PMID- 23105808 TI - Diagnostic efficiency of amylase and type IV collagen in predicting chronic pancreatitis. AB - Chronic pancreatitis, an irreversible inflammatory disease of the pancreas, is associated with the replacement of the destroyed parenchyma by extended development of fibrosis. Despite marked progress in diagnostic tools, no consensus has been reached in diagnosis of chronic pancreatitis. In this study we examined the hematological and biochemical parameters among 40 chronic pancreatitis patients within 18 to 67 yrs. ESR level and ALP activity was elevated in 40% cases. Serum amylase activity increased in 32 patients and it showed significant correlation with ALP (r=0.458, p=0.003), CA-19.9 (r=0.556, p<0.001), and calcium level (r=-0.472, p=0.002). Type IV collagen level in chronic pancreatitis also elevated (164.4 +/- 55.5 ng/ml) and showed negative significant correlation with calcium level (r= -0.505, p=0.001). However, no significant correlation was observed between amylase activity and type IV collagen (r=0.289, p= 0.07). PMID- 23105809 TI - Hypoglycemic, lipid lowering and antioxidant activities in root extract of Anthocephalus indicus in alloxan induced diabetic rats. AB - The present study was carried out to evaluate the hypoglycemic, lipid lowering and antioxidant activities in root extract of Anthocephalus indicus (A indicus) in alloxan inducd diabetic rats. Oral administration of ethanol extract of root (500mg/ kg body weight) for 21 days resulted in significant decrease in the levels of blood glucose, triglycerides, total cholesterol, phospholipid and free fatty acids. Furthermore, the root extract (100-400MUg) inhibited the generation of superoxide anions and hydroxyl radicals, in both enzymic and non-enzymic systems, in vitro. The result of the present study demonstrated hypoglycemic, lipid lowering and antioxidant activities in root extract of A indicus, which could help in prevention of diabetic dyslipidemia and related diseases. PMID- 23105810 TI - Evaluation of antioxidant profile and activity of amalaki (Emblica officinalis), spirulina and wheat grass. AB - Aqueous and alcoholic extracts of amalki (Emblica officinalis), spirulina and wheatgrass were prepared and analyzed for antioxidant vitamin content (vitamin C and E), total phenolic compounds. Antioxidant status, reducing power and effect on glutathione S-transferase (GST) activity were evaluated in vitro. Vitamin C content of crude amalaki powder was found to be 5.38 mg/g, while very less amount 0.22 mg/g was detected in wheat grass. Amalki was rich in vitamin E like activity, total phenolic content, reducing power and antioxidant activity. Total antioxidant activity of aqueous extract of amalki, spirulina and wheat grass at 1mg/ml concentration were 7.78, 1.33 and 0.278 mmol/l respectively. At similar concentrations the total antioxidant activity of alcoholic extract of amalaki, spirulina and wheat grass was 6.67, 1.73 and 0.380 mmol/l respectively. Amalki was also found to be rich source of phenolic compounds (241mg/g gallic acid equivalent). Alcoholic extract of wheat grass showed 50 % inhibition in FeCl(2)- ascorbic acid induced lipid peroxidation of rat liver homogenates in vitro. Both aqueous and alcoholic extracts of amalaki inhibited activity of rat liver glutathione S-transferase (GST) in vitro in dose dependant manner. Since GST acts as powerful drug metabolizing enzyme its inhibition by amalaki offers possibility of its use for lowering therapeutic dose of herbal preparations. The aqueous extracts of both amalki and spirulina also showed protection against t-BOOH induced cytotoxicity and production of ROS in cultured C(6) glial cells. PMID- 23105811 TI - Comparison of lipid profile and antioxidant enzymes among south Indian men consuming coconut oil and sunflower oil. AB - In this study, we compared the lipid profile and antioxidant enzymes of normal and diabetic subjects consuming two different types of oil as cooking medium. 70 normal, healthy subjects were taken as controls and 70 subjects with Type 2 diabetes were recruited in patient group. Each group was further subdivided into two subgroups of 35 subjects each, consuming coconut oil and sunflower oil respectively as cooking medium. Samples of blood were collected and analyzed for serum total cholesterol, triacylglycerols, and cholesterol in lipoprotein fractions. Total glutathione and glutathione peroxidase were measured in erythrocytes and superoxide dismutase in serum. Triacylglycerols, LDL and VLDL cholesterol levels were high in the diabetic subjects compared to the controls. Total glutathione and glutathione peroxidase values showed significant decrease in diabetic subjects as compared to the controls, while superoxide dismutase values showed significant difference between coconut oil consuming groups. Though lipid profile parameters and oxidative stress were high in Type 2 diabetic subjects compared to controls, no pronounced changes for these parameters were observed between the subgroups (coconut oil vs. sunflower oil). PMID- 23105812 TI - A study on the hypoglycemic and hypolipidemic effects of an ayurvedic drug Rajanyamalakadi in diabetic patients. AB - A study was undertaken for evaluating the hypoglycemic and hypolipidemic effects of an ayurvedic medicine "Rajanyamalakadi" containing Curcuma longa, Emblica officinalis and Salacia oblonga in type II diabetic patients over a period of 3 months. Ethical committee consent for the study was given by the Director, Indian Systems of Medicine, Kerala. A total of 43 patients with established diabetes mellitus as adjudged from clinical features and FBS values, appeared for the camp (Age group 35-75 yrs). An informed consent for the study was obtained from each patient. The clinical proforma was given to each patient to collect data such as height, weight, diet pattern, previous history of illness etc. The ongoing antidiabetic medications were stopped under medical supervision and the patients were provided with 'Rajanyamalakadi' tablets (dose 1-2 tablets each weighing 500mg). The dosage of the drug was decided by the supervising medical officer on a case to case basis, taking note of the clinical conditions and responsiveness of the patients. The patients were monitored for three months, who were divided into 6 groups based on their age and again into two groups, 5 & 6, based on their mean FBS values. ie; Normal Persons, Diabetics of age groups 35-45yrs, 46-55yrs, >55yrs and those with FBS < 145.9 mg% and > 145.9 mg%. The Ayurvedic medicine "Rajanyamalakadi" has showed significant antidiabetic, hypolipidemic and antioxidant effects. In addition to that significant ameliorating effects on the elevated serum AST and ALT activities were also demonstrated by the treatment. The nutraceuticals present in the drug like Terpenoids, Polyphenols, Curcumin etc are responsible for the medicinal effects. PMID- 23105813 TI - Antidiabetic effect of Withania coagulans in experimental rats. AB - The present study defines the systematic evaluation and the role of minerals in glycemic potential of aqueous extract of Withania coagulans fruits in order to develop an effective and safe alternative treatment for diabetes mellitus. Laser Induced Breakdown Spectroscopy was used for glycemic element detection. The study is based on the results of lowering in blood glucose levels of normal, sub, mild and severely diabetic rats assessed during fasting blood glucose, glucose tolerance test and post prandial glucose studies. The dose of 1000mg/ kg was identified as the most effective dose, which reduces the Fasting Blood Glucose level maximum by 33.2% at 4h in normal rats during fasting blood glucose studies. Glucose tolerance test studies of normal, sub and mild diabetic rats showed the maximum reduction of 15.7, 28.9 and 37.8% at 3h respectively. Long-term study in case of severely diabetic rats showed reduction of 52.9 and 54.1% in Fasting Blood Glucose and Post Prandial Glucose levels respectively after 30 days of treatment. The present study, besides confirming hypoglycemic and antidiabetic activities of aqueous extract of W. coagulans, helps in identifying the role of trace minerals like Mg & Ca responsible for antidiabetic potential of this potent indigenous shrub. PMID- 23105814 TI - Effect of exogenous L-ornithine L-aspartate on ethanol induced testicular injury in Wistar rats. AB - To investigate reversibility of ethanol induced testicular injuries on treatment with L-ornithine-L-aspartate, male Wistar rats were treated with ethanol (1.6g/kg b.wt/day) and L-ornithine- L-aspartate (200mg/kg b.wt/ day) for 4 weeks. L ornithine-L-aspartate effectively prevented the ethanol induced body and testes weight reduction; changes in testicular weight well correlated with body weight. Drug exhibited an ability to counteract ethanol induced oxidative challenge as it effectively reduced testicular TBARS and increased tissue ascorbic acid, GSH and activities of superoxide dismutase, catalase, GSH-Red and Se-GSH-Px. However the drug didn't show promising effect on inhibitory effect of ethanol on testicular D5, 3-beta and 17-beta HSD (hydroxy steroid dehydrogenase). PMID- 23105815 TI - Oxidative stress in Parkinson's disease. AB - Oxidative stress contributes to the cascade, leading to dopamine cell degeneration in Parkinson's disease. However, oxidative stress is intimately linked to other components of the degenerative process, such as mitochondrial dysfunction, excitotoxicity, nitric oxide toxicity and inflammation. It is therefore difficult to determine whether oxidative stress leads to or is a consequence of, these events. Oxidative stress was assessed by estimating lipid peroxidation product in the form of thiobarbituric acid reactive substances, nitric oxide in the form of nitrite & nitrate. Enzymatic antioxidants in the form of superoxide dismutase, glutathione peroxidase, catalase, ceruloplasmin and non enzymatic antioxidant vitamins e.g. vitamin E and C in either serum or plasma or erythrocyte in 40 patients of Parkinson's disease in the age group 40-80 years. Trace elements e.g. copper, zinc and selenium were also estimated. Plasma thiobarbituric acid reactive substances and nitric oxide levels were Significantly high but superoxide dismutase, glutathione peroxidase, catalase, ceruloplasmin, vitamin-E, vitamin-C, copper, zinc and selenium levels were significantly low in Parkinson's disease when compared with control subjects. Present study showed that elevated oxidative stress may be playing a role in dopaminergic neuronal loss in substentia nigra pars compacta and involved in pathogenesis of the Parkinson's disease. PMID- 23105816 TI - Total antioxidant capacity and lipid peroxidation in liver transplantation. AB - Liver transplantation is an accepted therapy for chronic liver disease patients. These patients generally have low levels of fat soluble vitamins, which have important antioxidant roles. Therefore, this study was undertaken to investigate whether such patients had evidence of antioxidant depletion and increased lipid peroxidation before transplant and whether the subsequent ischemia and reperfusion encountered during liver transplantation have any effect on antioxidant levels and lipid peroxidation. We assessed plasma total antioxidant capacity and serum lipid peroxide in 12 patients undergoing liver transplantation and equal numbers of healthy subjects. We found that before reperfusion, antioxidant levels were significantly decreased along with significantly elevated lipid peroxidation levels as compared with healthy controls (P<0.001). On reperfusion of the liver graft, further declined values of total antioxidant accompanied with highly elevated lipid peroxidation were seen than those of pre reperfusion samples (P<0.001). This data shows that patients undergoing liver transplant have lowered antioxidant defenses and evidence of free radical damage, which compound the additional insult of reperfusion injury. Therefore antioxidant therapy in these patients before transplantation may ameliorate the effects of reperfusion. PMID- 23105817 TI - Nitric oxide: A useful indicator in acute allograft rejection after liver transplantation. AB - The aim of this study was to monitor serum nitric oxide levels at various times, intraoperatively and following liver transplantation in humans. Nitric oxide production was assessed by cadmium reduction method in 15 patients undergoing liver transplantation. We observed strong correlation between nitric oxide production and allograft rejection. Sustained rise in nitric oxide level after transplantation might provide an indication of acute allograft rejection. Therefore measurement of nitric oxide, a stable end product appears to be an excellent marker that can help in the development of strategies intended to improve graft viability and patient's survival. PMID- 23105818 TI - Preanalytical variables and laboratory performance. PMID- 23105819 TI - Whether western normative laboratory values used for clinical diagnosis are applicable to Indian population? An overview on reference interval. AB - Reference Intervals denote normative values related to laboratory parameters/analytes used by diagnostic centers for clinical diagnosis. International guidelines recommend that every country must establish reference intervals for healthy individuals belonging to a group of homogeneous population. Considering enormous racial and ethnic diversity of Indian population, it is mandatory to establish reference intervals specific to Indian population. The overview on reference interval describes why the national organizations in India need to initiate nationwide efforts to establish its own laboratory standards for apparently healthy reference individuals belonging to our polygenetic, polyethnic, polyracial, multilinguistic and multicultural predominantly rural and appreciable urban Indian population with varied dietary habits. PMID- 23105820 TI - Oxygen free radical modified DNA: Implications in the etiopathogenesis of Systemic lupus erythematosus. AB - The present study was designed to probe the possible role of singlet oxygen and superoxide anion radical modified DNA in the etiopathogenesis of Systemic lupus erythematosus. These species were generated by the exposure of riboflavin to 365 nm UV light. Modified DNA showed single strand breaks, hyperchromicity at 260nm and decrease in Tm. The modified DNA induced high titer antibodies in experimental animals. The antibodies showed reactivity with various nucleic acid polymers, a property commonly associated with Systemic lupus erythematosus anti DNA autoantibodies. Systemic lupus erythematosus sera showed preferential binding of modified DNA over native DNA in direct binding and competitive binding solid phase immunoassays and band shift assays. The results suggest for the possible involvement of the singlet- superoxide modified DNA as a potential trigger for anti- DNA autoantibody production in SLE and thus in the etiopathogenesis of the disease. PMID- 23105821 TI - Expressed sequence tags of Aspergillus fumigatus: Extension of catalogue and their evaluation as putative drug targets and/or diagnostic markers. AB - Aspergillus fumigatus a fungal pathogen is implicated in a spectrum of allergic and invasive disorders in humans. Validation of transcriptome of pathogen is essential for understanding its virulence mechanism and to identify new therapeutic targets/diagnostic markers. In order to rapidly identify genes of Aspergillus fumigatus we adopted sequencing of cDNA clones. Our earlier effort has lead to identification of 68 expressed sequence tags of Aspergillus fumigatus. Present study describes 52 more expressed sequence tags generated by sequencing 200 phage clones of a non-normalized cDNA library. One of the cDNA clones comprised of the complete coding region for tetratricopeptide repeat domain protein gene. Various homology search algorithms were employed to assign functions to expressed sequence tags coding for hypothetical proteins, and relevance of these expressed sequence tags or their protein products as drug targets/diagnostic markers was examined by searching for homologues in fungi and human. PMID- 23105822 TI - MTHFR (Ala 222 Val) polymorphism and AMI in patients with type II diabetes mellitus. AB - The prevalent Ala222Val single nucleotide polymorphism of the MTHFR gene has been shown to be associated with type II diabetes. The objective of the present study was to find out whether there is genetic predisposition for development of acute myocardial infarction in type II diabetes mellitus among South Indian Tamil population. PCR-based restriction enzyme analysis was performed in DNA isolated from 120 acute myocardial infarction patients with diabetes mellitus and 100 non diabetic healthy individuals with no documented cardiovascular diseases. The results indicate that the MTHFR 677TT genotype is absent in both case and controls. The MTHFR 677CT genotype was observed among 32 (26.7 %) cases and 20 (20%) controls and the MTHFR 677CC genotype among 88 (73.3%) cases and 80 (80%) controls. The allelic frequencies were in accordance to Hardy Weinberg equilibrium. There was no statistical difference in genotype distribution between cases and controls. In conclusion, we suggest that the analysis of MTHFR genotyping for C677T polymorphism alone need not be considered to find out whether there is genetic predisposition for development of acute myocardial infarction in type II diabetes mellitus among South Indian Tamil population. PMID- 23105823 TI - The nucleotide sequence of Shigella flexneri 1A: A common Indian isolate. AB - We report complete sequences of 2 genes of S.flexneri 1a an Indian isolate for the first time. Shigella is causative agent of shigellosis or bacillary dysentery. Genomic library was constructed by shotgun approach. Sequencing was carried out using Big Dye terminator chemistry using ABI 3730 48 capillary DNA analyzer. 170 recombinants were subjected to nucleotide sequencing. Sequence data was analyzed, of these 2 clones showed presence of complete genes out of the total clones sequenced. Annotations were done using various bioinformatics tools. Gene Sfo676 on contig SF21B11, 513 bp long codes for a protein 170 aa long with molecular weight of 18836.5 daltons. The protein is 99 % identical to S. flexneri 2a 301 and not with any other strain of Shigella. It has 7 different sites for phosphorylation, myristoylation and glycosylation. Predicted cellular localization is cytoplasmic membrane. SF0368 is another full-length gene SF0368 on contig SF69C1 is a 312 nucleotide long. It is 103 aa long with molecular weight 11394.0 daltons. Protein is 100% identical to S. flexneri 2a 301 and 99% with S. sonnei strain 046. The gene shows difference when compared with S.sonnei in mono and dinucleotide frequency as well as amino acid composition. PMID- 23105824 TI - Dyslipidemia in pregnancy may contribute to increased risk of neural tube defects -a pilot study in north Indian population. AB - Neural tube defects are congenital structural abnormalities of the brain and vertebral column resulting from improper or non-timely closure of the neural tube. Prevalence of neural tube defects is reported to be higher among women with diabetes mellitus and obesity. This study was designed to investigate the relation between the presence of dyslipidemia in antenatal patients and the risk of fetal neural tube defects. The present study was an observational, cross sectional study involving 129 pregnant women in 16 to 18 weeks gestation period. Of these, 80 women had normal pregnancies and 49 were clinically high-risk cases for neural tube defects. Fasting blood samples were analyzed for blood sugar and lipid profile by enzymatic assay and alpha-fetoprotein levels using Enzyme Immunoassay. Alpha-fetoprotein (AFP) values were converted to Multiples of Median (MoM) appropriate for the gestational age. Based on AFP values, women were labeled as screen negative (AFP <2 MoM, n= 102) and screen positive (AFP > 2 MoM, n =27). Screen positive women were further evaluated by ultrasound and 21 women were found to carry a neural tube defects positive pregnancy. Statistical analysis was done on SPSS software. Body weight of the women showed a significant positive correlation with serum triglycerides, plasma sugar and AFP MoM values. A significant difference was observed in serum cholesterol levels (p= 0.038), triglycerides (p=0.001) and plasma sugar levels (p=0.002) between normal women and those with neural tube defects positive pregnancy. The Odds ratio for neural tube defects risk in dyslipidemic cases was 24.23 (CI 4.73 - 148.60) with a relative risk of 12.12. Dyslipidemia especially hypertriglyceridemia was found to be significantly associated with fetal neural tube defects. PMID- 23105825 TI - Clinicopathological spectrum of non-alcoholic fatty liver disease among patients in Kerala. AB - Non-alcoholic fatty liver disease and its more aggressive form, non-alcoholic steatohepatitis are entities that are becoming more and more interesting to the medical community in general. A total of 93 Non-alcoholic fatty liver disease patients (64 male and 29 female) within the age range between 28 to 63 years were studied. All of them showed elevated alanine aminotransferase level (104.07 +/- 56.04). Aspartate aminotransferase level (58.13 +/- 31.96) was elevated more than its normal level in 82% cases and AST to ALT ratio was found 0.59 +/- 0.26. Predisposing factors were diabetes mellitus (37%), obesity (13%) and hyperlipidemia (41%). In addition, 32% of the subjects were overweight.18% of the patients had elevated serum bilirubin. Our findings recommend a lower cutoff value than suggested by the World Health Organization for overweight and obesity among this racial-ethnic group. PMID- 23105826 TI - Non enzymatic glycosylation of IgG and their urinary excretion in patients with diabetic nephropathy. AB - Diabetic nephropathy is a major cause of end stage renal disease. Increased excretion of albumin has widely been recognized as an early manifestation of diabetic nephropathy particularly in subjects with diabetes mellitus. However, certain other proteins besides albumin may be excreted in high amount during early phase of diabetic nephropathy. The serum and urinary IgG, Glycosylated hemoglobin, fructosamine and glycosylated IgG were evaluated in the present study. Thirty-two patients of Type 2 Diabetes without any complications, thirty one patients of Type 2 Diabetes with nephropathy, twenty-six patients of non diabetic nephropathy and forty normal healthy individuals were enrolled in this study. Subjects were grouped based on their serum creatinine level. Serum IgG, glycosylation of IgG and urinary IgG excretion were increased significantly in diabetic patients compared to healthy controls, which were further increased significantly in chronic renal failure patients with respect to the clinical stage of nephropathy. A positive correlation was observed between glycosylation of IgG and IgG excretion (R(2)=0.5995, 0.7114 respectively) in diabetic patients without any complications and diabetic nephropathy patients only, suggesting a significant role of IgG glycosylation in the vascular clearances of IgG during diabetic nephropathy. PMID- 23105827 TI - Stability of total and free prostate specific antigen in serum submitted to intermittent cold storage conditions. AB - The goal of this study was to determine the stability of Total Prostrate Specific antigen (PSA-T) and Free Prostrate Specific Antigen (PSA-F) in archival serum stored at 4 degrees C and -20 degrees C and subjected to temperature shift due to interruption in power supply. Our study showed that PSA-T was stable up to 285 days and PSA-F was stable for 158 days under these conditions. Since power supply interruption is an unavoidable problem in developing nations, our study has implication on the validity of measurement of PSA-T and PSA-F in serum that was not properly stored due to emergency situations and for certain types of retrospective studies. PMID- 23105828 TI - Effects of insulin, glimepiride and combination therapy of insulin and metformin on blood sugar and lipid profile of NIDDM patients. AB - In the present study the efficacies of therapy with insulin, sulphonylurea or insulin + metformin on NIDDM patients are compared. One group which was on a definite dose of insulin therapy, but with uncontrolled diabetes was treated by doubling the insulin dose, a second group whose diabetes was not controlled by glibenclamide was switched over to another sulphonylurea viz; glimepiride and a third group whose diabetes was not controlled by insulin therapy was switched over to a combination therapy with insulin +metformin. After recording their initial blood parameters all the groups were treated as above for 3 months, and the parameters were again determined. The fasting blood sugar and serum lipids of the first group were controlled significantly, but the values were far above normal range. However HDL Cholesterol and atherogenic index were near normal range. In glimepiride treated group, none of the parameters showed any amelioration. In the combined therapy group, control of blood sugar and atherogenic index was more or less the same as for group 1, but hyperlipidemia remained slightly above that of the same. From the findings we can infer that in long term diabetes treatment higher doses of insulin and combined therapy with insulin and metformin may be more beneficial than with low doses of insulin or sulfonyl urea alone. PMID- 23105829 TI - Escherichia coli lipopolysaccharide administration alters antioxidant profile during hypercholesterolemia. AB - Pathogens, especially Gram-negative bacteria or bacterial endotoxin, along with other classical factors, may be involved in inflammatory response within the aortic endothelium during the progression of cardiovascular disease. Studies have shown that bacterial endotoxin activates various inflammatory processes in the body. Our study aims to establish a correlation between endotoxemia and vascular expression of antioxidant enzymes. Swiss albino mice (4 weeks old) were fed a high fat diet for 24 weeks and then were administered Escherichia coli endotoxin intraperitonealy, for 4 weeks. Tissue antioxidant enzymes, serum levels of IL-6 and TNF alpha were measured from the mice. We report that i.p. administration of endotoxin to hyperlipidemic mice resulted in elevation of superoxide dismutase and catalase enzymes, which was paralleled by a systemic reduction of serum cholesterol and LDL expression. Myeloperoxidase levels were also found to be elevated in aortic tissue, while an increase was also observed in the serum cytokine levels. PMID- 23105830 TI - Hypomagnesaemia in type-2 diabetes mellitus patients: A study on the status of oxidative and nitrosative stress. AB - This study was undertaken to evaluate the levels of plasma magnesium, lipid peroxides, nitric oxide end products, erythrocyte membrane lipid peroxides, erythrocyte reduced glutathione and erythrocyte superoxide dismutase activity in type-2 diabetes mellitus patients. 60 patients with type-2 diabetes mellitus and 30 healthy control subjects were included in this study. Among 60 type-2 diabetic patients, 30 patients were without complication and 30 patients were with various complications. Decreased levels of plasma magnesium, erythrocyte reduced glutathione and erythrocyte superoxide dismutase activity while increased levels of plasma lipid peroxides, nitric oxide end products and erythrocyte membrane lipid peroxides were observed in patients with type-2 diabetes mellitus. We propose that, under the shadow of hypomagnesaemia, there is excessive production of reactive oxygen species and reactive nitrogen species as reflected by elevated lipid peroxides and nitric oxide end products concomitant with dwindled antioxidants and suggest their association with late complications in type-2 diabetes mellitus. PMID- 23105831 TI - Stimation of reference interval of lipid profile in Assamese population. AB - 12hrs fasting samples of 1485 apparently healthy, Assamese population in the age group of 20-80 yrs., mostly from the urban area of Assam were tested for serum lipid profile that includes total cholesterol, triacylglycerol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) over a period of three years. The values (median and range in mg/dl) obtained were 170 (93-263); 110 (40-256); 40 (23-73); 103 (40-173) and 22 (8-51) respectively. After grouping these subjects according to the age and sex no significant difference were observed between most of the groups. Median and upper range of total cholesterol, HDL-C and LDL-C were found to be higher in women than in men in all the age groups. But triacylglycerol and VLDL-C concentrations were observed to be higher in the men than women except in age group of 61-70 yrs. It can be suggested that lipid values obtained in this study can be used as the reference value, based on which clinical correlation can be made. PMID- 23105832 TI - Study of oxidative stress in obsessive compulsive disorder in response to treatment with Fluoxetine. AB - Oxidative stress has been found to play important role in several neuropsychiatric diseases including Obsessive Compulsive Disorder. A longitudinal case control study was conducted to evaluate the oxidative stress in 30 newly diagnosed obsessive compulsive disorder patients and same number of control patients. Serum thiobarbituric acid reacting substances, plasma ascorbate were assessed to evaluate oxidative stress and Yale Brown obsessive compulsive scale for disease severity before and after treatment with Fluoxetine at the average dosage of 40 mg/day. Improvement in Yale Brown obsessive compulsive scale score by about 43% after 12 weeks treatment was associated with significantly decreased thiobarbituric acid reacting substances and increased plasma ascorbate values (p < 0.05). The newly diagnosed obsessive compulsive disorder patients had higher serum thiobarbituric acid reacting substances as well as a lower plasma ascorbate levels than the control population. Thus, the present study suggested a significant role of oxidative stress in obsessive compulsive disorder and showed that a successful treatment with Fluoxetine not only improves the clinical scenario but also reduces the oxidative stress that may further improve the prognosis of the disease. PMID- 23105833 TI - Cartap and carbofuran induced alterations in serum lipid profile of Wistar rats. AB - Wistar rats of 6-8 weeks in age weighing between 120-150 g were exposed to the fixed doses of each of the carbamate pesticides such as cartap (50% LD(50)) and carbofuran (50% LD(50)) as well as a combination of these two with 25% LD(50) of each for one week. The effect of treatments was studied in terms of serum lipid parameters such as high-density lipoprotein, total cholesterol, triglyceride, low density lipoprotein and very low-density lipoprotein. Treatment with individual doses of carbofuran (50% LD(50)) and cartap (50 % LD(50)) caused significant alterations in the levels of serum lipid parameters. The pesticides treatment resulted in marked decrease in the level of serum high-density lipoprotein where as that of other lipids got significantly elevated. Further, the rats exhibited relatively higher impact of pesticides when treated with the compounds in combination (25 % LD(50) of each). The results indicated that these compounds when used together may exert enhanced effect on the levels of serum lipids in rat. PMID- 23105834 TI - Effect of oral ingestion of different forms of silver on tissue content of some essential elements in chicks. AB - Silver is ingested in India in the form of varak, Ayurvedic bhasm and water contained in silver utensils, but nobody knows their effects. We have examined the effect of interaction of silver ingested in the form of varak (leaf), bhasm (ash) and water (colloidal solution) on some essential elements (Na, K, Ca, Mg, Cu, Fe and Zn) in blood, liver, spleen and kidneys of chicks. The results showed significant rise of silver in all the tissues and significant fall in copper in the blood. The greatest rise was obtained in blood silver by silver sol while it had the lowest amount of silver. Iron significantly increased in tissues but somewhat decreased in blood. Zinc content increased in all the tissues by leaf and ash but decreased by sol. No consistent pattern was seen in case of other elements. PMID- 23105835 TI - Uric acid a better scavenger of free radicals than vitamin C in rheumatoid arthritis. AB - Uric acid an endogenous aqueous antioxidant in normal humans is present in much higher concentrations than vitamin C and has been known to cover 2/3(rd) of the free radical scavenging capacity in plasma. In the present study average uric acid levels of patients of rheumatoid arthritis were found to be close to the normal individuals. A unique feature was observed after classifying the patients on the basis of the duration of suffering, the patients having longer duration of disease had least uric acid levels as compared to those suffering from relatively lesser period, similar trend was observed in the ascorbic acid estimations. The decline in uric acid values with progression of the disease was much more than what was observed in case of ascorbic acid suggesting the significant role of uric acid in scavenging of free radicals. Too much lowering of Uric Acid should be checked and vitamin C should be supplemented in diet for maintaining the balance between pro oxidant and antioxidant forces to check pro oxidant insult in rheumatoid arthritis. PMID- 23105836 TI - Improvement in electrolyte imbalance in critically ill patient after magnesium supplementation - A case report. AB - Hypomagnesaemia is common finding in current medical practice mainly in critically ill, post-operative patients and patients admitted to ICU in tertiary cancer cases. Magnesium has been directly implicated in hypokalemia, hypocalcaemia and dysrrthymias. We report a case of 60 year old patient, suffering from rectal carcinoma for a period of one year with confirmed hypokalemia, hypocalcaemia and hyponatremia. Magnesium supplementation corrected the underlying multiple electrolyte disturbances in the patient thus, establishing a positive correlation of magnesium with sodium, potassium and calcium. PMID- 23105837 TI - Antioxidant basket: Do not mix apples and oranges. PMID- 23105838 TI - Inborn errors of metabolism: Review and data from a tertiary care center. AB - Inherited metabolic disorders are a heterogeneous group of genetic conditions mostly occurring in childhood. They are individually rare but collectively numerous, causing substantial morbidity and mortality. We have retrospectively reviewed a total of eight hundred and sixty nine cases with different age groups that had been referred from several diagnostic centers and hospitals of India to the Department of Metabolism in Narayana Hrudayalaya, as cases suspected with inborn errors of metabolism. Advanced techniques applied were to diagnose the disorders of inborn errors of metabolism. Data analyzed indicates occurrence of several metabolic disorders in our population. The need to screen for an inborn error of metabolism arises out of the fact that most cases take to irreversible effects as time progress. Emphasis has to be laid on early detection and prompt management, which could help in alleviating symptoms and preventing complications and consequent incapacitation. PMID- 23105839 TI - Study of mutations in p53 tumour suppressor gene in human sporadic breast cancers. AB - Using Polymerase Chain Reaction followed by Single Strand Conformation Polymorphism analysis, we studied thirty seven cases of primary human breast cancer for the presence of mutations in exons 5 and 7 of p53 tumour suppressor gene. Only one of the thirty seven tumours tested (2.7%) showed the electrophoretic mobility shift indicative of a mutation in exon 5 of the p53gene, while no such mobility shift was noted in exon 7. Our finding is in contrast to the findings in previous studies, wherein the mutation frequency has been reported to be 13-30% by direct DNA analysis. This may be related to the ethnicity and local population prevalence rather than technique. PMID- 23105840 TI - Increased serum concentrations of Soluble CD40 Ligand as a prognostic marker in patients with Acute Coronary Syndrome. AB - CD40-CD40L interaction plays a significant role in the pathogenesis of atherosclerosis and coronary artery disease. The clinical predictive value of Soluble CD40 Ligand (sCD40L) was evaluated in patients with Acute Coronary Syndrome (ACS) and Non-Cardiac Chest Pain (NCCP). The levels of serum soluble CD 40 ligand were measured by ELISA in 485 patients admitted to emergency care unit, of which 89 patients were diagnosed as NCCP. The levels of sCD40L were significantly increased in patients with ACS when compared to controls and NCCP. Receiver Operator Characteristic (ROC) Curve analysis showed sCD40L to be a good discriminator between patients with ischemic heart disease and patients without ischemic heart disease. The area under the curve was found to be 0.940 with 95% CI (0.915 to 0.960) (P<0.0001). The cut off value from the ROC curve was 2.99 ng/ml, above which sCD40L was considered to be positive. Combined assessment of sCD40L, Troponin I and CK-MB enhanced the risk prediction and early classification of patients. sCD40L seems to be a promising biomarker for identification and risk stratification for patients with acute coronary syndrome. PMID- 23105841 TI - Cellular immune response to infection by different genotypes of hepatitis C virus. AB - The present study aimed to estimate the cellular immune response to infection by different HCV genotypes in some Egyptian patients with chronic liver disease. HCV RNA and HCV genotypes were conducted using type-specific primers to amplify the core region of HCV genome. The levels of IFN-gamma and TNF-alpha, PIIINP, SOD enzyme were also determined. The results showed that genotype 4 was the prevalent one (88.57%).Genotype 3 was found mixed with genotype 2 and 4 (11.42% and 34.28% respectively). Genotype 1 was absent from patients under study. No significant differences were observed in the level of IFN-gamma interferon, SOD enzyme and ALT enzyme between those genotypes. On the other hand the level of TNF-alpha was greatly increased in patients infected with mixed HCV genotypes 3, 4 compared with patients with genotype 4 and those infected with mixed genotypes 2, 3. Otherwise PIIINP was decreased significantly of the same group compared with other groups. PMID- 23105842 TI - Effects of interaction of vitamin A and Rauwolfia vomitoria root bark extract on marker enzymes of cardiac diseases. AB - Serum creatine kinase (CK), creatine kinase isoenzyme (CK-MB) and aspartate aminotransferase (AST) are key players in the diagnostic study of cardiac complications. These enzymes are specific diagnostic markers of myocardial infarction and hypertension is a disease condition characterized with a wide range of complications, including myocardial infarction. In this study, we determined the effects of interaction of vitamin A and Rauwolfia vomitoria (RV) root bark extract on marker enzymes of cardiac diseases. CK and CK-MB activities had significant decrease in the group of animals with concomitant administration of vitamin A (40 IU/kg body wt.) and 150 mg/kg body wt. of RV root bark extract. At the interaction of vitamin A with 300 mg/kg body wt. RV root bark extract, CK MB only showed significant (p >= 0.05) decrease while CK decreased insignificantly. Also at the interaction of vitamin A with 300 mg/kg body wt. RV root bark extract, AST increased significantly but decreased significantly at the interaction of vitamin A (40 IU/kg body wt.) and 150 mg/kg body wt. of RV root bark extract. Our findings showed that vitamin A dose did not lower the activities of cardiac marker enzymes. However, concomitant administration of RV root bark extract at 150 mg/kg body wt. with vitamin A shows significant reduction in the activities of CK, CK-MB and AST. These findings suggest that interaction of vitamin A with RV root bark extract would be a meaningful ethno pharmaceutical approach in the management of myocardial infarction and treatment of hypertension. PMID- 23105843 TI - Effect of ingestion of copper bhasm on red cell indices, iron parameters and essential elements in chicks. AB - In order to scientifically evaluate the effect of copper bhasm, it was orally administered in a dose of 2 mg/day for seven days to one month old male chicks. There was significant fall in total red cells, and rise in plasma iron, PCV and MCV indicating hemolysis, compensated by increased heme synthesis. A significant increase in plasma iron binding capacity points to beneficial effect of copper bhasm on liver as transferrin is synthesized in liver. Ferritin (storage iron) was unaltered in seven days treatment. The effect of copper bhasm on tissue distribution of essential elements was variable. Calcium, sodium and potassium were significantly increased in all the tissues. The last two may have been contributed by the bhasm itself. Magnesium behaviour was similar to calcium. Iron and zinc showed variable effects. Copper level in whole blood, plasma and erythrocytes increased significantly showing that copper bhasm was well absorbed and the effect observed can be ascribed to it. The bhasm was well tolerated and no growth retardation was seen. PMID- 23105844 TI - Ethanolic leaves extract of Trianthema portulacastrum L. ameliorates aflatoxin B(1) induced hepatic damage in rats. AB - Aflatoxins are potent hepatotoxic and hepatocarcinogenic agents. Reactive oxygen species and consequent peroxidative damage caused by aflatoxin are considered to be the main mechanisms leading to hepatotoxicity. The present investigation aims at assessing the hepatoprotective effect of ethanolic leaves extract of Trianthema portulacastrum on aflatoxin B(1) (AFB(1))-induced hepatotoxicity in a rat model. The hepatoprotection of T. portulacastrum is compared with silymarin, a well known standard hepatoprotectant. Lactate dehydrogenase, alkaline phosphatase, alanine and aspartate aminotransferases were found to be significantly increased in the serum and decreased in the liver of AFB(1) administered (1 mg/kg bw, orally) rats, suggesting hepatic damage. Marked increase in the lipid peroxide levels and a concomitant decrease in the enzymic (superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and glutathione-S-transferase) and nonenzymic (reduced glutathione, vitamin C and vitamin E) antioxidants in the hepatic tissue were observed in AFB1 administered rats. Pretreatment with T. portulacastrum (100 mg/kg/p.o) and silymarin (100 mg/kg /p.o) for 7 days reverted the condition to near normal. The results of this study indicate that the ethanolic leaves extract of T. portulacastrum is a potent hepatoprotectant as silymarin. PMID- 23105845 TI - Association between plasma homocysteine and riboflavin status in Acute Lymphoblastic Leukemia in children. AB - Remethylation of homocysteine to methionine is dependent on an adequate supply of one or more of the B vitamins like folate, vitamin B(12) and vitamin B(6). Plasma total homocysteine (tHcy) is also influenced by genetic factors such as polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene. MTHFR is a flavo enzyme and a key player in folate metabolism and changes in its activity could modify the susceptibility to Acute Lymphoblastic Leukemia (ALL). In this case - control study we have examined the effect of riboflavin status as measured by erythrocyte glutathione reductase activation coefficient (EGRAC) on homocysteine levels along with vitamin B(12) and folate in pediatric ALL. Folate and B(12) levels were significantly lower among cases as compared to controls while EGRAC and tHcy did not differ significantly among the groups. The multivariate regression analysis revealed that in the ALL group EGRAC significantly influences tHcy levels suggesting that riboflavin availability may be a predictor of tHcy levels in patients with ALL. This finding may have implications for tHcy lowering therapy. PMID- 23105846 TI - Correlation of bone mineral density with biochemical markers in post menopausal women. AB - To evaluate the magnitude of bone loss in postmenopausal women and to study the effect of a selective estrogen Receptor Modulator, raloxifene, on bone loss by quantitative ultrasound of calcaneus and serum bone specific alkaline phosphatase (BAP). Postmenopausal women with ostesopenia/osteoporosis were assigned randomly to receive placebo (n=30) or raloxifene (60mg/d, n=30) with calcium (500mg/day) and vitamin D (250 IU/day). The bone mineral density (BMD) and BAP levels were measured at the beginning of therapy and six months later. They were subjected to statistical analysis (t test, p value) using SPSS statistical package. 70% of postmenopausal women suffered from osteopenia/osteoporosis. After raloxifene therapy, there was improvement in the BMD but this was not statistically significant (p>0.05). There was a fall in the value of serum BAP by 26.6% (p<0.05). Raloxifene has a favourable effect on bone turnover as evident from changes in BMD and a significant fall in serum BAP. PMID- 23105847 TI - Serum anti - TPO levels in benign and malignant breast tumors. AB - Breast cancer is a hormone dependent neoplasm. Conflicting results regarding the clinical correlation between breast cancer and thyroid diseases have been reported. The objective of this study was to determine the association of anti - TPO levels in patients having complaints of a lump in breast. Serum samples and Fine needle aspiration cytology (FNAC) samples were collected from 31 female patients with a lump in breast between the age group of 20-75 years. 31 age matched normal healthy controls were also examined for the same parameters. Serum samples were analyzed for its anti - TPO levels. FNAC reports confirmed patients as having duct cell carcinoma. They had raised serum anti - TPO levels compared to controls. FNAC results of others (n=26) were reported as fibroadenoma whose anti - TPO levels were less than the controls. PMID- 23105848 TI - Biochemical profile and outcome in normal and high risk subjects. AB - The present study was carried out to assess the biochemical profile and outcome of pregnancy and study the adverse consequences if any, among normal and high risk pregnant women. The study group included 182 normal and 168 high risk cases attending to private and Government Hospitals in Bangalore. The high risk groups were: Pregnancy induced hypertension (PIH), gestational diabetes mellitus (GDM), Adolescents and anemic cases. Lipid peroxidation was enhanced in PIH and GDM groups (5.56 nmol/ml and 3.98 nmol/ml) MDA values as compared to other groups. Vitamin E levels were significantly (p< 0.05) lower in PIH group (0.38 mg/dl) as compared to other groups. Caesarean as a mode of delivery indicating more number of complications were higher among GDM (61.9%) followed by PIH group. Incidences of low birth weight were observed more in PIH group. The study revealed occurrence of oxidative stress and adverse outcome among high risk pregnancy groups. PMID- 23105849 TI - A sensitive assay for ornithine amino transferase in rat brain mitochondria by ninhydrin method. AB - To establish/develop an assay method for measuring Ornithine Aminotransferase (EC.2.6.1.13) activity using rat brain mitochondria as a source of enzyme in presence and absence of Pyridoxal Phosphate (PLP). The modified method, with the improved sensitivity, is adopted for the assay of ornithine amino transferase activity in rat brain mitochondria. The enzyme activity was measured at 620 nm, the study showed that reaction was optimum at 37 degrees C for 30 minutes. The assay is sensitive enough to detect activity at the order of nanomoles pyrroline 5-carboxylate/mg protein/minute and can be compared as an alternative to the radio isotopic method which is more cumbersome and aminobenzaldehyde method which is less sensitive. The K(m) & V(max) shows maximum activity in the presence of Pyridoxal Phosphate (Coenzyme) concentration at 0.05mM when compared with absence of Pyridoxal Phosphate as higher the concentration of Pyridoxal Phosphate affects the affinity of the enzyme to substrate. The OAT activity in different tissues of the rat was also studied and highest activity was found in liver and kidney. PMID- 23105850 TI - Effect of green tea extract and vitamin C on oxidant or antioxidant status of rheumatoid arthritis rat model. AB - Elevated free radical generation in inflamed joints and impaired antioxidant system has been implicated in rheumatoid arthritis (RA). Green tea extracts (GTE) have been shown to reduce inflammation in inflammatory arthritis murine model. This study investigates possible mechanisms by which vitamin C and GTE protect joints in RA rat model. This study included forty adult male rats that were divided into four groups (10 rats each); control group, collagen II induced RA group (CII), CII treated with vitamin C (CII + Vit C) and CII treated with GTE (CII + GTE) in physiology laboratory, Assiut University, Egypt. After 45 days of treatment, plasma levels of lipid peroxides (LPO), nitric oxide (NO), ceruloplasmin (CP), superoxide dismutase (SOD), uric acid (UA) and glutathione (GSH) were detected using colorimetric methods, PGE(2) using ELISA and copper (Cu) and zinc (Zn) using spectrometer. In CII group, levels of LPO, NO, PGE(2), UA, CP, Cu were higher while SOD, GSH, Zn were lower than controls. In groups treated with vitamin C and GTE, levels of SOD, GSH were increased while levels of LPO, NO, PGE(2), Cu, CP were decreased compared with CII group. Levels of UA were decreased and Zn increased in GTE treated group compared with CII group. GTE treated group showed higher Zn and low Cu levels compared with vitamin C treated group. This study suggests proper GTE and vitamin C intake may effectively normalize the impaired oxidant/antioxidant system and delaying complication of RA. PMID- 23105851 TI - Evaluation of oxidative stress and antioxidant status of pregnant women suffering from malaria in Cameroon. AB - Oxidative stress is thought to be involved in the pathophysiology of malaria, especially in pregnancy where natural resistance is markedly reduced. In the present study we investigated oxidative stress in 315 pregnant women out of which 159 had Plasmodium falciparum malaria and 154 controls. We evaluated the level of lipid peroxidation products (MDA level) in the plasma, the activity of erythrocyte antioxidant defense enzymes, superoxide dismutase (SOD, EC: 1.15.1.1) and catalase (Cat, EC: 1.11.1.6) as well as the ability to resist oxidative stress by the FRAP (Ferric Reducing Ability of Plasma) assay. Total erythrocyte protein levels were also examined. For the two groups of patients, several differences between the biochemical parameters tested were found. Median parasitaemia in women with malaria was 25,392 parasites/MUl of blood (Range1200 82000), while in controls we had no parasites found in thin and thick smears. Levels of lipid peroxidation products (MDA) were significantly higher in patients with parasitemia than in healthy asymptomatic volunteers (mean: 0.844 +/- 0.290 and 0.384 +/- 0.129 respectively, p<0.001). This MDA level was higher in primigravidea and also correlates well with parasite density (p<0.001). Catalase activity in erythrocytes of women with malaria did not differ statistically from that of controls. In contrast, SOD activity of patients with malaria was found to be significantly higher than that of controls (mean: 0.7899 +/- 0.2777 and 0.4263 +/- 0.2629 respectively, p<0.05). FRAP values declined, from parasitemic patients (1.4619 +/- 0.6565) compare to controls (2.4396 +/- 0.8883, p<0.05), particularly in the first and third trimester of gestation (p<0.05 and p<0.01 respectively). Finally, total erythrocyte protein concentrations of women with malaria did not differ from that of the controls. Our results suggest an imbalance between oxidants and antioxidants in pregnant women suffering from malaria, a situation which could lead to severe damage for either the mother or the fetus. Therefore, further research should be done to assess the potential benefits of antioxidant supplementation for the pregnant women suffering from malaria. PMID- 23105852 TI - Protective effect of ascorbic acid against oxidative damage induced by hydrogen peroxide in cultured human peripheral blood lymphocytes. AB - Hydrogen peroxide is one of the reactive oxygen species for cellular injury. It is overproduced during oxidative stress and is known to damage proteins, nucleic acids and cell membranes. The present study was aimed to study the protective effect of ascorbic acid against the toxic doses of hydrogen peroxide using lipid peroxidation and cytokinesis blocked micronucleus assay. Hydrogen peroxide was studied at 50, 100 and 200MUM and was found to increase a dose dependent increase in lipid peroxidation and micronuclei frequency. The treatment of 100 and 200MUM of hydrogen peroxide separately along with 20, 40 and 80MUM of ascorbic acid showed a dose dependent decrease in the lipid peroxidation and micronuclei frequency. The results suggest a protective effect of ascorbic acid against the hydrogen peroxide induced oxidative damage in cultured human peripheral blood lymphocytes. PMID- 23105853 TI - Effects of chronic ethanol consumption in blood: A time dependent study on rat. AB - Alcohol consumption and health outcomes are complex and multidimensional. Ethanol (1.6g / kg body weight/ day) exposure initially affects liver function followed by renal function of 16-18 week-old male albino rats of Wistar strain weighing 200-220 g. Chronic ethanol ingestion increased in thiobarbituric acid reactive substances level and glutathione s-transferase activity; while decreased reduced gluatathione content and activities of catalase, glutathione peroxidase and glutathione reductase in a time dependent manner in the hemolysate. Though superoxide dismutase activity increased initially might be due to adaptive response, but decreased later. Elevation of serum nitrite level and transforming growth factor-b(1) activity indicated that long-term ethanol consumption may cause hepatic fibrosis and can elicit pro-angiogenic factors. However, no alteration in vascular endothelial growth factor-C activity indicated that ethanol consumption is not associated with lymphangiogenesis. Therefore, we conclude that long-term ethanol-induced toxicity is linked to an oxidative stress, which may aggravate to fibrosis and elevate pro-angiogenic factors, but not associated with lymphangiogenesis. PMID- 23105854 TI - Effect of oral antioxidant supplementation on lipid peroxidation during radiotherapy in head and neck malignancies. AB - The objectives of the present study were to ascertain the variations in the serum levels of malondialdehyde and total antioxidant status, in head and neck malignancies with different stages, with and without oral antioxidant supplementation, before and after radiotherapy, and to validate the protective effects of an antioxidant supplementation during radiotherapy. The pretreatment values of serum malondialdehyde were significantly raised, while that of serum total antioxidant status were significantly declined in all the stages of head and neck malignancies, when compared with the healthy controls values (P<0.001). A significant correlation was observed related to the studied parameters and different stages of the disease. The study suggests that an oral antioxidant supplementation during radiotherapy is an effective mode in reducing oxidative stress. Antioxidant supplementation during radiotherapy may serve as an adjuvant therapy in malignancies offering a protection to normal cells that may further reduce the risk of developing secondary cancers. PMID- 23105855 TI - Role of ascorbic acid in human seminal plasma against the oxidative damage to the sperms. AB - This study evaluated the extent of oxidative stress by measuring malondialdehyde and ascorbic acid in the seminal plasma of human subjects with different fertility potential. Semen samples from 148 subjects were evaluated (48 normozoospermics, 34 oligoasthenoteratozoospermics, 34 asthenoteratozoospermics and 32 azoospermics). malondialdehyde level was found to be significantly higher in the abnormal groups (oligoasthenoterato and asthenoterato-zoospermics) than normozoospermics (P < 0.01). Negative correlation was also found between malondialdehyde level, sperm concentration, sperm motility and sperm morphology. Level of ascorbic acid was found to be significantly higher in normozoospermics than other abnormal groups (P < 0.01). It was found to be correlated positively with all seminogram parameters and negatively with malondialdehyde level. The study revealed that, excess lipid peroxidation reflected by high malondialdehyde level with reduced ascorbic acid in human seminal plasma is associated with poor semen quality where as ascorbic acid content has positive correlation with fertility potential. PMID- 23105857 TI - Chronomics and chronobiology in health and disease. PMID- 23105856 TI - Acalculous gallbladder distension in a young child due to HAV infection: Diagnostic dilemma. AB - Gall bladder distension with acute viral acalculous cholecystitis is a rare event in pediatric cases with a high incidence of perforation, gallbladder necrosis and mortality. We report a two and a half year old female child presenting with fever, vomiting, pain abdomen, mild hepatosplenomegaly and tenderness in right hypochondrium. Laboratory investigations revealed hyperbilirubinemia and elevated alkaline phosphatase, but there was no evidence of bacterial or parasitic infection. Serology for viral hepatitis suggested acute Hepatitis A infection. Ultrasonographically, distended inflamed gallbladder without calculous was observed. Finally acute acalculous cholecystitis due to Hepatitis A virus was diagnosed and the child responded to the conservative management. PMID- 23105860 TI - Influence of method of specimen collection on various preanalytical sample quality indicators in EDTA blood collected for cell counting. AB - Improving specimen quality as well as healthcare worker (HCW) safety poses significant concerns for today's laboratories. With an increasing number of diagnostic tests requested, laboratory professionals are faced with challenges to reduce laboratory errors, improve the quality of laboratory results to assure accurate diagnosis and implement initiatives to ensure healthcare worker safety and minimize risk of exposure to bloodborne pathogens. A prior study conducted in 2008 reported that variations in blood collection methods for clinical chemistry assays may affect overall specimen quality. As a follow up, the current study assessed the quality of 22563 patient specimens for cell counting in EDTA blood collection tubes that were obtained with needle and syringe collection (open) using either disposable tubes or re-washed glass vials or with an evacuated blood collection system (closed). Based on the observations, the use of the evacuated blood collection system resulted in better preanalytical specimen quality as compared with needle and syringe collection. The findings also showed an approximately 70-fold reduction in the incidence of clotting as well as fewer instrument-generated flags using the evacuated collection system. In addition, the use of an evacuated collection system for venous blood collection demonstrated lesser chance of blood exposure to healthcare workers. PMID- 23105859 TI - Reference intervals for serum total cholesterol, HDL-cholesterol, LDL cholesterol, triglycerides, Lp (a), apolipoprotein A-I, A-II, B, C-II, C-III, and E in healthy South Indians from Andhra Pradesh. AB - The incidence of cardiovascular and cerebrovascular disease is steadily increasing in South East Asian countries including Indian sub continent. Many lipids, apolipoproteins and Lp (a) except HDL-C and apo A-I, A-II are implicated as risk factors for coronary artery disease and cerebrovascular disease. There is great need to have national guidelines for each country like the ATP III guidelines recommended for U.S. population. For recommending appropriate medical decision limits, it is mandatory that each country establishes reference intervals pertaining to their population due to dietary, genetic and environmental diversity. In the present study, reference intervals for serum lipids, apolipoproteins and Lp (a) were established in a total of 1923 healthy Indian reference individuals comprising 1161 healthy men and 762 healthy women from Andhra Pradesh. For each analyte viz., serum total cholesterol, HDL-C, LDL C, triglycerides, Lp (a), Apo A-I, Apo A-II, B, C-II, C-III and E, mean, two SD, median, confidence limits of mean, different percentile values are presented. The study also includes decade wise changes in each analyte and comparison of lipids, lipoproteins and Lp (a) among few populations covering U.S., India, Japan, Sweden, Finland and China. Reference Intervals for all lipid and lipoprotein parameters will immensely help in assessing associated risk for cardiovascular and cerebrovascular diseases in India. Additionally, the results will be beneficial in formulating our own guidelines pertaining to Indian population. PMID- 23105858 TI - Reactive oxygen species, reactive nitrogen species and antioxidants in etiopathogenesis of diabetes mellitus type-2. AB - Diabetes mellitus type-2 (DMT-2) is a hyperglycemic syndrome with several characteristic features. It continues to rise unabatedly in all pockets of the world, parallels with affluence and can be controlled but not cured. It has a definite involvement of genetic component but environmental factors play overwhelmingly dominant role in etiopathogenesis. Insulin resistance (IR) and obesity are singular instigators of DMT-2. The various events cause critical defects in insulin signaling cascade followed by beta-cell dysfunction. Over a period of time, numerous other metabolic aberrations develop, resulting in diabetic complications which could be both vascular (cardiovascular complications, nephropathy, neuropathy, retinopathy and embryopathy) or a vascular (cataract and glaucoma etc). It has been proposed that all these abnormal events are initiated or activated by a common mechanism of superoxide anion, which is accompanied with generation of a variety of reactive oxygen species (ROS), reactive nitrogen specie (RNS) and resultant heightened oxidative stress (OS). Provoked OS causes IR and altered gene expressions. Hyperglycemia induces OS through multiple routes: a)stimulated polyol pathway where in <= 30% glucose can be diverted to sorbitol and fructose, b)increased transcription of genes for proinflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1) c) activation of protein kinase-C (PKC) leading to several molecular changes d)increased synthesis of Advanced Glycation End Products (AGEs) e)changes in a receptor far AGEs and f) autooxidation of glucose with formation of ketoimines and AGEs. All these processes are accompanied with alteration in redox status, ROS, RNS and OS which trigger DMT-2 and its complications. Initial hurriedly planned and executed experimental and clinical studies showed promising results of antioxidant therapies, but recent studies indicate that excess intake/supplement may have adverse outcomes including increased mortality. It is advocated that antioxidants should be given only if preexisting deficiency is present. Selection of antioxidant is another important aspect. Lastly but most importantly the impact of OS is not obligatory but facultative. As such only those diabetic patients will be benefited by antioxidant therapies that have impelling punch of prooxidants. PMID- 23105861 TI - Usefulness of lipase / amylase ratio in acute pancreatitis in South Indian population. AB - This retrospective study was conducted to assess the serum lipase / amylase ratio in acute pancreatitis for South Indian population attending the clinics of Gastroenterology and Emergency medicine in the last five years. One thousand one hundred and thirty two patients (768 males and 364 females) with acute pancreatitis (AP) were selected for the study. The diagnosis of AP was based on clinical evaluation, Computed Tomography (CT) findings and biochemical parameters such as serum lipase and amylase. Based on the etiology, the groups were divided into alcoholic, biliary and miscellaneous AP. Based on CT findings, groups were divided into mild, moderate and severe AP. Serum lipase, amylase and lipase / amylase ratio were calculated and statistically analyzed. Serum lipase levels in alcoholic group (3226.3 +/- 1384.7) were significantly lower in comparison to biliary (6064.5 +/- 1640.8) group though the levels were not significantly different from miscellaneous group (2132.3 +/- 1210). Serum amylase values were significantly lower in alcoholic group (923.4 +/- 557.5) in comparison to biliary (1736.2 +/- 390.7) and there was significant difference between alcoholic and miscellaneous group (535.8 +/- 477.6). The serum lipase / amylase ratio > 4 occurred in alcoholic group than with biliary and miscellaneous group. The sensitivity and specificity to predict alcoholic AP with lipase / amylase ratio at >4.0 was 84 % and 59 % respectively. In conclusion the serum lipase to amylase ratio greater than 3.0 could be used to differentiate but keeping the cut off at 4.0 would be of higher sensitivity without much change in specificity. The serum lipase to amylase ratio with a cut off of 3.0 or greater is not useful to differentiate the severe AP from milder AP. Hence, serum amylase and lipase are important for evaluation of pancreatitis though it is not a gold standard for the diagnosis or assessment of severity of acute pancreatitis. PMID- 23105862 TI - Hyperammonemia and hepatic status during valproate therapy. AB - The present study was conducted to assess correlation of ammonia levels with valproate levels in epileptic patients presenting with valproate toxicity and also whether liver enzymes and ammonia levels could serve as biochemical marker of valproate toxicity. 100 patients with epilepsy who had received valproate therapy for more than 12 months and had presented with valproate toxicity and 100 controls were included in the study. The serum valproate, ammonia and liver enzymes were measured in these subjects. In patients with valproate toxicity, the mean level of serum valproate was 110.91 +/- 28.68 mg/dL (therapeutic range 50 100 mg/dL). Serum ammonia was higher (86.37 +/- 39.90 ug/dL) in patients with valproate toxicity compared to controls (68.73 +/- 30.07 ug/dL). Out of 100 patients, only 37 patients had serum valproate level > 120 mg/dL and 22 patients had raised levels of valproate as well as ammonia. Age < 30 years and serum ammonia > 69 MUg/dL is risk factors for valproate toxicity. Serum ammonia, liver enzymes should be regularly investigated in patients on valproate therapy for early diagnosis of valproate toxicity. PMID- 23105863 TI - Biochemical markers of liver and kidney function are influenced by thyroid function-a case-controlled follow up study in Indian hypothyroid subjects. AB - Thyroid hormones regulate the renal hemodynamics and basal metabolic rate of most cells. This hospital-based case-control study was done to evaluate the changes in biochemical markers of liver and kidney function in hypothyroid subjects before and after treatment. The study included 176 subjects randomly selected from Thyroid clinics. Serum T(3), T(4), TSH, Liver and Kidney Function tests were analysed using standard kits. Forty-six hypothyroid patients were re-evaluated 6 weeks after thyroxine substitution therapy. Hypothyroid subjects (n=80) showed significantly raised serum creatinine and uric acid levels as compared to euthyroid subjects (n=96). After 6 weeks of thyroxine replacement, serum creatinine and uric acid decreased significantly and were comparable to euthyroid group. A positive correlation of ALT, AST, uric acid, protein and albumin with TSH levels (p<0.05) and negative correlation of serum T(4) levels with ALT, AST, proteins (p<0.05) was observed in the hypothyroid group. Hypothyroidism results in reversible impairment of hepatorenal function. PMID- 23105864 TI - Effect of vitamin C and E activity on surgically removed cataractous human lens epithelium cells. AB - Oxidative stress has been proposed as a common underlying mechanism of cataractogenesis. Experimental and observational data suggest that micronutrients like vitamin C and vitamin E with antioxidant capabilities may retard the development of age-related cataract. Effect of these factors on lens epithelium cells, center of lens metabolic activities, is not completely elucidated. The aim of present study was to examine the effect of vitamin C and E on surgically removed lens epithelium cells of patients with cataract. Capsulorhexis samples were collected from 170 patients, admitted for cataract surgery. Catalase specific activity was estimated in lens epithelium cells with and without vitamin (C or E) treatment at different concentration for different time duration. Student's t-test was employed for data analysis. We observed that in ex-vivo condition, a) both vitamin C and E bring about a decrease in catalase activity in lens epithelial cells. b) vitamin C showed toxic effect at high concentration. c) 100MUM was the optimum concentration at which both vitamins showed maximum antioxidant activity. It was concluded that both vitamin C and E has direct effect on lens epithelium cells. At optimum concentration, they can reduce oxidative stress in these cells thus can support to prevent or delay cataract development. PMID- 23105865 TI - Relationship between PON1L55M and Q192R gene polymorphisms and high APO B/APO A-I ratios. AB - Elevated Apolipoprotein B Apolipoprotein A-I ratio is a risk factor for predicting coronary artery disease (CAD). Paraoxonase 1 (PON1) is a high density lipoprotein (HDL) associated serum enzyme. PON1 protects lowdensity lipoproteins (LDLs) from oxidative modifications and thus has a protective effect against CAD progression. There are two common polymorphisms, Q192R and L55M, in PON1 gene. There may be a relationship between these polymorphisms and elevated ApoB/ApoA-I ratios. Therefore, we decided to evaluate effect of these polymorphisms on individuals with high and normal ApoB/ApoA-I ratios. To evaluate Q192R and L55M polymorphisms in Iranian case group (n=75) with high ApoB/ApoA-I ratio, and control group (n=75) with normal ApoB/ApoA-I ratio, we carried out PCR using specific primers. Then, we digested PCR products by RFLP. ApoB and ApoA-I levels were determined by immunoturbidimetry method. Genotype frequencies for Q192R were determined: 49.3%QQ, 44%QR, 6.7%RR in case group, and 53.3%QQ, 33.3%QR, 13.4%RR in controls (P= 0.236). Genotype frequencies for L55M were determined: 21.3%LL, 68%LM, 10.7%MM in case group and 42.7%LL, 52%LM, 5.3%MM in controls (P= 0.016). A significant relationship between L55M polymorphism and familial history of cardiovascular disease was found (P= 0.011). In our study PON1L55M polymorphism was associated with high ApoB/ApoA-I ratios in case group. Thus, L55M polymorphism may be an independent risk factor for cardiovascular disease. Since L55M polymorphism was associated with familial history of cardiovascular disease, it is better to evaluate L55M polymorphism in younger ages even in the absence of high ApoB/ApoA-I ratios. PMID- 23105866 TI - Circulating levels of cell adhesion molecules in hypertension. AB - Hypertension causes complications such as coronary atherosclerosis and thrombosis wherein inflammatory factors play significant role. In the present study inflammatory molecules such as cell adhesion molecules (CAMs); endothelial (E) selectin, platelet (P)-selectin, intercellular CAM-1 (ICAM-1), vascular CAM-1 (VCAM-1) and platelet endothelial CAM-1 (PECAM-1) were analysed in subjects newly diagnosed with hypertension with no secondary cause against normotensive healthy individuals. In each group 57 subjects were recruited and soluble (s) levels of CAMs were analysed by ELISA. As compared to controls median of sE-selectin (49.2%, P=0.001), sP-selectin (54.3%, P=0.001), and sICAM-1 (18.9%, P=0.012) were significantly elevated in hypertensive subjects. Significant negative correlation was observed of sP-selectin (spearman rank correlation coefficient (rs) =-0.345, p=0.027) and sPECAM-1 (rs =-0.446, p=0.003) with age in hypertension group. Hypertension may increase expression of certain CAMs while younger hypertensives in addition are also at increased risk of atherothrombosis. PMID- 23105867 TI - Circulating vascular endothelial growth factor and nitric oxide in patients with liver cirrhosis: A possible association with liver function impairment. AB - Hemodynamic disorders of liver cirrhosis complicated with portal hypertension are associated with an increased angiogenesis in animal model of portal hypertension and cirrhosis which were linked to increased expression of vascular endothelial growth factor (VEGF) and nitric oxide (NO). The aim of study was to evaluate the serum concentration of VEGF and total nitric oxide (NO) in liver cirrhosis and the possible association with the degree of liver insufficiency. VEGF and NO were measured in serum of 64 patients with liver cirrhosis by ELISA and spectrophotometry respectively. The significant increase of serum VEGF was observed in liver cirrhosis compared to healthy individuals as well as serum NO (106.1 +/- 66.7 vs. 41.5 +/- 6 pg/mL, P < 0.05; 113.5 +/- 65.8 vs. 20.8 +/- 3.8 MUmol/l, P< 0.001, respectively). Serum VEGF and NO showed significant associations with biochemical indices of liver function and with Child-pugh score where they were increased respectively to the degree of liver insufficiency. A significant association of raised serum NO in early stage of portal hypertension reflect its benefit in early expect of portal hypertension but, high serum VEGF in late stage may reflect its prognostic value in liver cirrhosis. PMID- 23105868 TI - Antidyslipidaemic activity of Glycyrrhiza glabra in high fructose diet induced dsyslipidaemic Syrian golden hamsters. AB - The root of Glycyrrhiza glabra is a traditional medicine used mainly for the treatment of peptic ulcer, hepatitis C, pulmonary and skin diseases, although clinical and experimental studies suggest that it has several other useful pharmacological properties such as antiinflammatory, antiviral, antimicrobial, antioxidative, anticancer activities, immunomodulatory, hepatoprotective and cardioprotective effects. Glycyrrhizinic acid, a major component of licorice, has antiulcer effect by raising the local concentration of prostaglandins that promote mucous secretion and cell proliferation in the stomach. Glycyrrhizin shows hepatoprotective effect by preventing changes in cell membrane permeability, inhibiting phospholipase A(2) (PLA(2)) and increasing survival rate of hepatocytes. Glabridin has effect in melanogenesis and inflammation by inhibiting the tyrosinase activity of melanocytes. alpha-glycyhrritinic acid exhibits anti-inflammatory activity by inhibiting glucocorticoid metabolism. In present study ethanolic (95%) extract of root of Glycyrrhiza glabra and its fractions were investigated for its antidyslipidaemic activity on HFD induced dyslipidaemic hamsters. Ethanolic extract and its ethyl acetate soluble, water soluble and hexane soluble fractions decreased serum level of total cholesterol by 25.9, 38.0, 39.0 and 26.3%, respectively. On the other hand ethanolic extract, ethyl acetate soluble, water soluble and hexane soluble fraction increased the serum HDL-cholesterol level by 14.8, 34.3, 27.3 and 17.2%, respectively. Ethanolic extract, ethyl acetate fraction, aqueous fraction and hexane fraction decreased triglyceride level by 31.3, 37.2, 41.2 and 28.9%, respectively. The reduction in LDL-cholesterol level by ethanolic extract, ethyl acetate soluble fraction and water soluble fraction were 43.9, 31.0, 33.4 and 24.6%, respectively. PMID- 23105869 TI - Curative effect of Cynodon dactylon against STZ induced hepatic injury in diabetic rats. AB - The aim of the study was to ascertain the role of ethanolic extract of Cynodon dactylon against hepatic complications in streptozotocin (STZ) induced type 2 diabetic models. Effect of the pre identified most effective dose of 500 mg/kg body weight was studied on hepatic injury caused by chemically induced diabetes by 55 mg/kg body weight i.p. injection of STZ in male Wistar rats. The dose of 500mg/kg body weight given once daily for 14 days reduced the levels of serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, alkaline phosphatase, creatinine and urine sugar significantly (P<0.05) with increase in total protein, haemoglobin and body weight was increased. High LD(50) validates its high margin of safety. PMID- 23105870 TI - Effect of ethanolic leaf extract of Trianthema portulacastrum L. On aflatoxin induced hepatic damage in rats. AB - The aim of this study was to investigate the ethanolic leaf extract of Trianthema portulacastrum L. (Family: Aizoaceae) on aflatoxin induced hepatic damage in rats. Aflatoxin intoxication in rats significantly (p < 0.001) elevated the levels of serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), and total bilirubin, which indicated acute hepatocellular damage and biliary obstruction. Ethanolic leaf extract of T. portulacastrum showed dose dependent decrease in the levels of SGPT, SGOT, ALP and total bilirubin. Minimum effective dose of extract was found to be 100 mg/kg body weight. Results obtained from histopathological studies also supported hepatoprotective activity against aflatoxin-induced hepatotoxicity. Thus the study demonstrates that T. portulacastrum possess antihepatotoxic effect against aflatoxin. PMID- 23105871 TI - Attenuation of oxidative stress in streptozotocin-induced diabetic rats by Eucalyptus globulus. AB - In traditional medicine, Eucalyptus globulus (eucalyptus) was used for the treatment of diabetes mellitus. Hyperglycemia in diabetes has been associated with increased formation of reactive oxygen species (ROS) and oxidative damage to tissue compounds. The aim of this study was to evaluate the effects of eucalyptus in the diet (20 g/Kg) and drinking water (2.5 g/L) on lipid peroxidation, protein oxidation and antioxidant power in plasma and liver homogenate, as well as glycated-Hb (HbA(1C)) of blood in streptozotocin-induced diabetic rats for a period of 4 weeks. Diabetes induced in rats by a single intraperitoneal injection of streptozotocin (STZ, 65 mg/Kg). At the end of the treatment period, the level of plasma glucose, plasma and liver malondialdehyde (MDA, the main product of lipid peroxidation), protein carbonyl (PC, one of the protein oxidation products) and HbA(1C) increased and ferric reducing antioxidant power (FRAP) decreased in diabetic rats compared to normal rats. Eucalyptus administration for 4 weeks caused a significant decrease in the plasma glucose levels, plasma and liver MDA, PC and HbA(1C), also a concomitant increase in the levels of FRAP in diabetic treated rats. In conclusion, the present study showed that eucalyptus posses antioxidant activities. Eucalyptus probably restores antioxidant power, due to the improved hyperglycemia in streptozotocin-induced diabetic rats. PMID- 23105872 TI - Oxidative stress in cases of chronic fluoride intoxication. AB - This study was conducted to find out the level of oxidative stress and effect of supplementation of vitamin C, D and Calcium on levels of SOD, serum and urinary fluoride in children residing in endemic fluorosis area. For this the fluoride belt of Jaipur district was selected. The parameters selected were Super oxide dismutase, serum fluoride and urinary fluoride. The study was conducted on one hundred children, selected from four areas (25 from each area) consuming water containing 1.2, 2.4, 5.6 and 13.6 mg/l of fluoride. Drinking water fluoride, serum and urinary fluoride were measured by Ion selective electrode method. Serum SOD by Xanthine oxidase method using kit of Ransod (kit cat. No. SD125). The post treatment values showed a significant reduction in serum fluoride and SOD. Urinary fluoride levels increased significantly in post treatment stage. The results revealed a normal SOD levels in all groups but an increasing trend was observed with increasing fluoride concentration. Treatment with Calcium, Vitamin D and Vitamin C showed a significant reduction in serum fluoride and SOD and increase in urinary fluoride. A high positive correlation between pretreatment and post treatment group was observed in serum fluoride, SOD and urinary fluoride (P < 0.05). The study indicated an increasing oxidative stress in cases of fluorosis with increasing drinking water fluoride concentration. Treatment with Calcium, Vitamin D and Vitamin C resulted a significant reduction in serum fluoride and SOD and increase in urinary fluoride. PMID- 23105873 TI - Effect of varying durations of pyramid exposure - an indication towards a possibility of overexposure. AB - Miniature replicas modeled after the Great Pyramid of Giza are believed to concentrate geoelectromagnetic energy within their cavities and hence act as antistressors in humans and animals. Although there are not many reports of adverse effects of 'overexposure' in the pyramid, subjects have claimed to feel uneasy after certain duration of staying in the pyramid. The present study was aimed to analyze the effects of prolonged pyramid exposure on plasma cortisol level, markers of oxidative damage and antioxidant defense in erythrocytes of adult female Wistar rats. Rats were divided into three groups, normal controls (NC, n=6) that were maintained under standard laboratory conditions in their home cages, pyramid exposed group-2 (PE-2, n=6) & pyramid exposed group-4 (PE-4, n=6) where the rats were housed under the pyramid for 6 hours/day for 2 weeks and 4 weeks respectively. Plasma cortisol and erythrocyte TBARS levels were significantly lower in both PE-2 and PE-4 rats and erythrocyte GSH levels and GSH Px activity were significantly higher in them as compared to the NC rats. There was no significant difference in the results for these parameters between the PE 2 and PE-4 rats except for erythrocyte GSH-Px activity which was significantly more in the PE-2 rats than in the PE-4 rats. Although these results don't confirm any adverse effects of prolonged exposure in pyramids, they indicate a possibility of such adverse effects. PMID- 23105874 TI - Plasma lactate as prognostic marker of septic shock with acute respiratory distress syndrome. AB - The present study was conducted to study the significance of lactate as a prognostic marker in patients of septic shock with acute respiratory distress syndrome. This study was conducted on 50 critically ill patients of septic shock with acute respiratory distress syndrome between the age group of 20-60 years and 50 controls. Plasma lactate and serum electrolytes were determined among controls and patients. Arterial blood gas analysis for pO(2), pCO(2) and pH was carried out among patients. Arterial base excess and anion gap were calculated and lactate was correlated with base excess, anion gap and pCO(2) at 5% level of significance. Higher lactate, negative arterial base excess, high anion gap, low pO(2) and high pCO(2) were observed among patients. Lactate was positively correlated pCO(2) and anion gap and negatively with pO(2) and base excess among patients. Hyperlactatemia increasing with progression of septic shock with acute respiratory distress syndrome may suggest that lactate may be used as noninvasive prognostic marker or guide to resuscitation. PMID- 23105875 TI - Wolfram syndrome - clinical and diagnostic details. AB - Wolfram syndrome, a rare genetic disorder is characterized by juvenile onset diabetes mellitus and optic atrophy. We describe two cases of wolfram syndrome belonging to same family; 25 year old female and her only 15 year old brother. In female, diabetes mellitus and optic atrophy were manifested in 1(st) decade, diabetes insipidus in 2(nd) decade and hypoacusis at the age of 25 years. Her ophthalmic evaluation revealed bilateral optic atrophy, decreased vision and peripheral constriction of visual field. However she didn't have any renal dysfunction which is also considered to be one of the features of the syndrome. Though associated psychiatric features are later manifestations of the syndrome she was admitted with alleged suicidal consumption at the age of 25 years. The brother was asymptomatic except for the diabetes mellitus and insipidus. PMID- 23105876 TI - Effective laboratory quality management towards preventing medical liability cases. PMID- 23105878 TI - Potential of mycobacterial excretory secretory protein antigens (sevatb ES-31, ES 43, EST-6 and ES-20) as biomarkers to detect Mycobacterium tuberculosis bacilli. AB - There is a need for a simple and reliable method to identify Mycobacterium tuberculosis from nontuberculous mycobacteria (NTM). The utility of mycobacterial ES-31, ES-43, EST-6 or ES-20 antigen as a biomarker for differentiation of Mycobacterium tuberculosis bacilli from nontuberculous mycobacteria was explored using Fluorescein isothiocyanate conjugated antibodies against these antigens. Detection of these antigens was done from M.tb H(37)Ra and H(37)Rv DSS antigen. The presence of antigen in bacilli using FITC labelled antibody was indicated by green fluorescence on the cell surface while, its absence by no fluorescence under microscope. In M.tb H(37)Ra and H(37)Rv bacilli, fluorescence was observed on addition of FITC labelled anti ES-31 and anti ES-43 antibody; whereas no fluorescence was observed in case of EST-6 and ES-20 antibody conjugates. However all the antigens were detected in detergent soluble sonicate antigen of tubercle bacilli on addition of FITC conjugates. Fluorescence was not observed for ES-31, ES-43, EST-6 and ES-20 antigen in any of the tested NTM as well as in Escherichia coli. SEVA TB ES-31 and ES-43 may be used as biomarkers to distinguish M.tuberculosis bacilli from NTM. PMID- 23105877 TI - MicroRNAs: Potential biomarkers in cancer. AB - microRNAs (miRNAs) are evolutionarily conserved small noncoding RNAs, also known as micromanagers of gene expression. Polymorphisms in the miRNA pathway (miR polymorphisms) are emerging as powerful tools to study the biology of a disease and have the potential to be used in disease prognosis and diagnosis. Advancements in the miRNA field also indicate a clear involvement of deregulated miRNA gene signatures in cancers, and several polymorphisms in pre-miRNA, miRNA binding sites or targets have been found to be associated with various cancers. The miRNA polymorphisms have also been reported to influence tumor aggressiveness as well as survival of cancer patients. miRNAs have a revolutionary impact on cancer research over recent years. They emerge as important players in tumorigenesis, leading to a paradigm shift in oncology. The extensive and comprehensive use of miRNA microarrays has enabled the identification of a number of miRNAs as potential biomarkers for cancer. Many miRNAs have been identified to act as oncogenes, tumor suppressors, or even modulators of cancer stem cells and metastasis. Some studies not only reported the identified miRNA biomarkers, but also deciphered their target genes and the underlying mechanisms. The rapid discovery of many miRNA targets and their relevant pathways has contributed to the development of miRNA-based therapeutics. PMID- 23105879 TI - Circulating thrombotic and haemostatic components in patients with coronary artery disease. AB - The study aimed to analyze the circulating levels of thrombotic and haemostatic components; tissue factor, tissue factor pathway inhibitor, tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with acute myocardial infarction at presentation (Group 1, n=49), unstable angina and Non-ST elevated MI after treatment (Group 2, n=22), stable angina (Group 3, n=18) and healthy individuals (Group 4, n=31). Significant finding was increase in tissue factor not only in Group 1 (2.0 fold, P=0.001), Group 2 (2.2 fold, P=0.015) but also in Group 3 (1.8 fold, P=0.018) as compared to controls. In Group 1 Plasminogen activator inhibitor-1 increased significantly (35.8%, P=0.02). Tissue factor pathway inhibitor and tissue plasminogen activator demonstrated increase in Group 1 of age<40 years while insignificant changes in elder patients. Increased thrombotic and decreased fibrinolytic conditions in acute myocardial infarction patients were observed. Increase TF in stable angina demonstrates procoagulant status in these patients as well. PMID- 23105880 TI - Kinetic study of low density lipoprotein oxidation by copper. AB - Oxidation of Low Density Lipoprotein (LDL) is regarded as a key event in the development of atherosclerosis. The aim of this study was to investigate effect of various copper concentrations on LDL oxidation kinetic profile as a mechanism in atherosclerosis process. LDL was isolated from plasma and its oxidation with copper was investigated by monitoring the formation of conjugated dienes. Based on time course of the formation of conjugated diene was observed at concentrations of 0.5 to 10 uM copper, represented the conventional kinetics of LDL oxidation with an inhibition period followed by a propagation phase. In contrast, at concentrations of 20 to 50 uM copper, LDL oxidation proceeded after a negligibly short lag-time followed by a distinct propagation phase. At lower copper concentrations of about 0.5 uM, LDL oxidation can be combined in 4 consecutive oxidation phase. The increasing copper concentration (to 10 uM) lowered the first propagation and shortened the seconded inhibition period until they melted into one apparent kinetic phase. But in copper concentrations of about 20 to 50 uM, increasing copper concentration increased the first propagation and the second inhibition but lowered the second propagation phase. The results of this investigation on the copper dependence of the oxidation kinetics suggest that LDL contains two different copper binding sites. Copper bound to the low affinity binding sites with molar ratio of 200 to 500 of copper / LDL. These ions bound to the high affinity binding sites with molar ratio of copper / LDL of 5 to 100. PMID- 23105881 TI - Role of plasma amino acids and gaba in alcoholic and non-alcoholic fatty liver disease-a pilot study. AB - Alcohol appears to affect brain function, primarily by interfering with the action of gamma-aminobutyric acid (GABA) and other neurotransmitters. As alcohol is mainly metabolized in the liver, therefore we undertook this pilot study to monitor the patterns of changes in plasma amino-acid concentrations due to alcoholic and nonalcohol fatty liver disease and their relation with plasma GABA level. Plasma amino-acid concentrations were measured in 25 alcoholic liver disease (ALD) patients, 18 non-alcoholic fatty liver disease (NAFLD) patients, and 24 age and sex matched control subjects by HPLC. GABA concentration was elevated, while isoleucine and leucine levels reduced significantly in ALD patients compared to the control subjects. Methionine and phenylalanine levels elevated and valine content reduced significantly in ALD patients compared to other two groups, and GABA level was significantly correlated with methionine and phenylalanine. Plasma concentration of lysine was significantly reduced in both groups of liver disease patients compared to the control group, but was not correlated with GABA level. Glycine and tyrosine levels reduced significantly in NAFLD patients compared to other two groups and were significantly correlated with GABA. Interestingly, though amino acids such as alanine, histidine, proline and serine were not affected by liver diseases, but were significantly correlated with GABA level. This pilot study indicated that alcoholic liver disease presented a more deranged plasma amino acid pattern than nonalcoholic, and the amino acid imbalances. More studies are necessary to identify the role of any particular amino acid on brain function and on neurotransmitter(s). PMID- 23105882 TI - Effect of hemodialysis on circulating cystatin c levels in patients with end stage renal disease. AB - Plasma cystatin C is an emerging parameter to assess kidney function. Its utility in assessing the adequacy of hemodialysis in patients with end-stage-renal disease has however not been established with certainty. This study was therefore carried out to assess the usefulness of serum cystatin C estimation in patients undergoing low flux membrane hemodialysis. Serum creatinine and cystatin C were estimated in 20 patients before and after undergoing hemodialysis. The mean serum creatinine decreased from a pre-dialysis value of 7.72 mg/dL to a post-dialysis value of 2.90 mg/dL. On the contrary, the mean serum cystatin C levels were found to increase from a pre-dialysis value of 5.97 mg/L to a post-dialysis value of 8.25 mg/L. Therefore, serum cystatin C cannot be used to monitor dialysis adequacy. It however, serves as a surrogate marker of the inadequacy of low flux membrane bicarbonate hemodialysis in clearing low molecular weight proteins from the circulation. PMID- 23105883 TI - Lipid abnormalities, lipoprotein (a) and apoprotein pattern in non-dialyzed patients with chronic kidney disease. AB - The present study was carried out to explore the altered lipid, lipoprotein and apoprotein abnormalities along with lipoprotein (a) in chronic kidney disease patients with stage I to V which were further divided into group 1 (stage I and II), group 2 (stage III and IV) and group 3 (stage V). 50 chronic kidney disease patients with stage I to V and 20 healthy normal subjects as controls were recruited for this study. Among the various parameters tested triglyceride levels were high in group 1 and 2, whereas VLDL cholesterol, Lp (a) and apo B levels were significantly high in all the groups when compared to controls (P<0.05). However, LDL cholesterol level was significantly low in group 3 only as compared to control group (P<0.05). Apoprotein AI values also showed significant decrease in all groups as compared to controls (P<0.05). Though total cholesterol levels in group 1 and LDL levels in group 1 and 2 were higher than controls, but the values attained not statistically significant (P>0.05). In conclusion high levels of VLDL cholesterol, Lp (a), apo B and low levels of apoprotein AI as reported in this study are the major lipid disorders in the development of cardiovascular complications at all the stages in these patients. PMID- 23105884 TI - Moderately high altitude habitation modulates lipid profile and alkaline phosphatase activity in aged Khasis of Meghalaya. AB - The indigenous Khasis inhabit different geographical and climatic locations of Meghalaya. In this study, we intended to find out whether habitation in moderately high altitude place has any effect on the lipid and liver profile amongst the aged Khasis. The level of various serum parameters under lipid and liver profile were analyzed and compared from aged (65-70 years) male Khasi residents of moderately high (Shillong city) and low (Byrnihat) altitude places. Results obtained from the lipid profile data show decreased total serum cholesterol (29%), triglyceride (27%) and LDL-cholesterol (42%) level in the old Khasis of Shillong compared to Byrnihat. Furthermore, the alkaline phosphatase activity was significantly raised (47%) in the old Khasis from Shillong as against Byrnihat. The decreased level of total cholesterol, triglyceride and LDL cholesterol in old Khasis from Shillong may be due to living and acclimatization in high altitude with low annual temperature. Moderately high elevation could have acted as a stressor, thereby reducing the level of serum cholesterol, triglyceride and LDL-cholesterol, which may put them at a lower risk of cardiovascular diseases. In comparison, old residents of Byrnihat with high cholesterol, triglyceride and LDL-cholesterol levels may elevate their risk of coronary complications. The raised alkaline phosphatase activity amongst the old Khasis of Shillong could be due to increased bone and/or intestinal turnover as a result of living in high altitude, which, however, may elevate the risk of osteoporosis. Taken together, we conclude that low cholesterol, triglyceride and LDL-cholesterol levels, accompanied with high alkaline phosphatase activity amongst the old Khasis of Shillong, could be due to the influence of high altitude and mild climatic conditions that prevails. PMID- 23105885 TI - Utility of serum LDH isoforms in the assessment of mycobacterium tuberculosis induced pathology in TB patients of Sahariya tribe. AB - The present study was carried out in the Sahariya tribe of Central India, which reportedly have high prevalence of pulmonary tuberculosis. Total serum LDH and its tissue specific isoforms were estimated in TB patients and matched healthy controls to test the utility of LDH as diagnostic marker for tuberculosis. About 210 sputum positive cases and 328 age and sex matched sputum negative controls were recruited. The spectrophotometeric and densitometric analysis of each LDH isoform was carried out in both cases and controls. The mean values of serum LDH were estimated and compared for each class by t-test. The statistical comparisons were made between sputum negative controls and sputum positive cases by Mann Whitney's U test. The spectrophotometric estimation of serum LDH revealed significant (P=0.0016) increase in its level in cases (290 IU/L) as compared to controls (248 IU/L). The densitometric analysis of individual LDH isoforms in cases and controls demonstrated significant elevation in LDH1 (P>0.05), LDH2 (P>0.05) and LDH3 (P<0.005) in sputum positive cases in comparison to sputum negative controls. Our study revealed a positive correlation between serum LDH level and the presence of mycobacteria and their load, suggesting utility of LDH as an important diagnostic marker of tuberculosis induced stress, at least in tribal areas lacking access to modern clinical tests. PMID- 23105886 TI - Modification of Jaffe's kinetic method decreases bilirubin interference: A preliminary report. AB - The negative interference of bilirubin on serum creatinine determined by the kinetic alkaline picrate (Jaffe) reaction is the unresolved problem. Though high performance liquid chromatography and gas chromatography with mass spectroscopy have been proposed to be gold standards for creatinine estimation but they are not readily available in most of the clinical chemistry laboratories due to economic and technical constraints. Most of the present day analyzers use Jaffe's kinetic method without deproteinization. Though enzymatic methods are now routinely used as most accurate method but they are not acceptable due to cost constraints. Hence this study was planned to find out a possible solution to the problem of bilirubin interference by a minor modification in the commonly used Jaffe method so that it is amenable for use on the currently used analyzers. PMID- 23105887 TI - Ameliorating reactive oxygen species-induced in vitro lipid peroxidation in brain, liver, mitochondria and DNA damage by Zingiber officinale Roscoe. AB - Iron is an essential nutrient for a number of cellular activities. However, excess cellular iron can be toxic by producing reactive oxygen species (ROS) such as superoxide anion (O(2) (-)) and hydroxyl radical (HO(.)) that damage proteins, lipids and DNA. Mutagenic and genotoxic end products of lipid peroxidation can induce the decline of mitochondrial respiration and are associated with various human ailments including aging, neurodegenerative disorders, cancer etc. Zingiber officinale Roscoe (ginger) is a widely used spice around the world. The protective effect of aqueous ethanol extract of Z. officinale against ROS-induced in vitro lipid peroxidation and DNA damage was evaluated in this study. The lipid peroxidation was induced by hydroxyl radical generated from Fenton's reaction in rat liver and brain homogenates and mitochondrial fraction (isolated from rat liver). The DNA protection was evaluated using H(2)O(2)-induced changes in pBR 322 plasmid and Fenton reaction-induced DNA fragmentation in rat liver. The results indicated that Z. officinale significantly (P<0.001) protected the lipid peroxidation in all the tissue homogenate/mitochondria. The extract at 2 and 0.5 mg/ml could protect 92 % of the lipid peroxidation in brain homogenate and liver mitochondria respectively. The percent inhibition of lipid peroxidation at 1mg/ml of Z. officinale in the liver homogenate was 94 %. However, the extract could partially alleviate the DNA damage. The protective mechanism can be correlated to the radical scavenging property of Z. officinale. The results of the study suggest the possible nutraceutical role of Z. officinale against the oxidative stress induced human ailments. PMID- 23105888 TI - Copper and ceruloplasmin levels in relation to total thiols and GST in type 2 diabetes mellitus patients. AB - Presence of oxidative stress in type 2 diabetes mellitus (DM) is well proved. Current study was undertaken to know the relation between fasting plasma glucose (FPG) and copper along with antioxidants like total thiols and ceruloplasmin, and antioxidant enzyme glutathione S transferase (GST). The study group consisted of a total of 201 subjects which included nondiabetic healthy control subjects (n = 78) and diabetic patients (n = 123). Plasma total thiols, GST, copper and ceruloplasmin levels were measured all the subjects using spectrophotometric methods and FPG levels were determined in clinical chemistry analyzer Hitachi 912. There was significant increase in FPG (P<0.001) and copper (P<0.001) and decrease in ceruloplasmin (P<0.001) and protein thiols (P<0.001) in type 2 DM cases compared to healthy controls. There was no significant change in GST between type 2 DM cases and controls. There was significant negative correlation of FPG with antioxidants like ceruloplasmin (r = -0.420, P<0.001) and total thiols (r = -0.565, P<0.001). Protein thiols correlated positively with ceruloplasmin (r = 0.364, P<0.001). Our study indicates possible increase in copper mediated generation of ROS leading to increased consumption of available antioxidants in the body. PMID- 23105889 TI - Clinical correlation of alteration of endogenous antioxidant-uric acid level in major depressive disorder. AB - Derangement of antioxidant levels in major depressive disorder had been correlated with oxidative damage. The effect of Selective Serotonin Re-Uptake Inhibitors on endogenous antioxidant uric acid levels in major depressive disorder has never been examined. This was a prospective; open labeled, parallel, 12 weeks study, in which serum uric acid levels and Hamilton Rating Scale for Depression score were estimated in age and sex matched thirty-six healthy and forty major depressive disorder subjects before and after fluoxetine and citalopram treatment. Significant decrease in serum uric acid (P<0.0001) was observed in newly diagnosed major depressive disorder subjects when compared to healthy subjects. The trend was reversed after 6 weeks more significantly after 12 weeks of treatment with improvement in Hamilton Rating Scale for Depression score. Also, Significant and negative correlation was found between Hamilton Rating Scale for Depression score and serum uric acid level (r= -0.864, P<0.001) after 12 weeks of treatment. Treatment with fluoxetine or citalopram reverses endogenous antioxidants like uric acid and improves Hamilton Rating Scale for Depression score in major depressive disorder. PMID- 23105890 TI - Role of reactive oxygen species in pathogenesis of nephrotic syndrome. AB - Nephrotic syndrome is the common chronic disorder characterized by alteration of permeability of the glomerular capillary wall, resulting in its inability to restrict the urinary loss of proteins. Nephrotic syndrome is characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia associated with peripheral edema. The molecular basis of glomerular permselectivity remains largely unknown. In recent years it has been proposed that Nephrotic syndrome is a consequence of an imbalance between oxidant and antioxidant activity. The present study was aimed to test that the reactive oxygen species are the mediators of excessive protein permeability and other complications of Nephrotic syndrome. For this 30 adults with Nephrotic syndrome were studied. The control group comprised 30 healthy adults matched for age. Serum levels of lipid peroxides, nitric oxide (NO?), alpha- tocopherol, ascorbic acid, erythrocyte superoxide dismutase activity, serum albumin, uric acid, cholesterol and plasma total antioxidant capacity were measured. Student's 't' test was applied for statistical analysis. There was a significant increase in lipid peroxide (1.58 +/- 0.42 in controls, 3.64 +/-1.3 in patients) (P<0.001) levels in study group as compared with controls. alpha-tocopherol (12.95 +/- 1.04 in controls, 9.93 +/- 1.43 in patients) (P<0.001), erythrocyte SOD activity(1.88 +/- 0.9 in controls 1.07 +/- 0.5 in patients) (P=0.01), serum albumin(4.06 +/- 0.50 in controls, 3.04 +/- 0.11 in patients) (P<0.001), and plasma total antioxidant capacity (847.33 +/- 126.83 in controls, 684.00+/-102.94 in patients) (P<0.001) were significantly decreased. There was non-significant increase in uric acid (P>0.05), a non-significant decrease in NO? (38.48 +/- 15.47 in controls 37.47 +/- 14.27 in patients) (P>0.05) and ascorbic acid levels ascorbic acid,( 0.95 +/- 0.31in controls 0.79 +/- 0.30 in patients) (P>0.05) in study group as compared with controls. Imbalance between oxidants and antioxidants may contribute to pathogenesis of proteinuria and related complications in nephrotic syndrome. PMID- 23105891 TI - Antioxidant effect of carnosine pretreatment on cisplatin-induced renal oxidative stress in rats. AB - Cisplatin mediated nephrotoxicity is remarkably documented by reactive oxygen species. Carnosine is a naturally occurring dipeptide and has a scavenging property. The aim of present study was to assess the lipid peroxidation and antioxidant enzymes in association with oxidative stress in cisplatin -treated and 10 subsequent doses of carnosine-pretreated rats. 24 male Albino Wistar rats, were randomly divided into four groups (n=6). Group I remains untreated; Group II received Cisplatin (3 mg / kg) for 5 alternate days; Group III received Carnosine (10 mg / kg) for consecutive 10 days; Group IV received Carnosine (10 mg / kg) before administration of Cisplatin (3 mg / kg). The effects of carnosine on cisplatin-induced nephrotoxicity were evaluated by plasma creatinine, urea, malondialdehyde, nitrate; kidney tissue malondialdehyde, 4-HNE, superoxide dismutase and catalase activities. Cisplatin-induced oxidative stress was indicated by increased level of tissue MDA, 4-HNE and decreased level of tissue GSH, SOD and Catalase. Marked elevation of kidney weight and reduced body weight and pathological changes in kidney tissues were also observed in Cisplatin treated rats. Carnosine reduced these pathological changes and counteracted the deleterious effects of cisplatin. The results divulge the beneficial effect of Carnosine pretreatment with cisplatin in experimental rat model. PMID- 23105892 TI - An audit questionnaire that examines specifically the management of technical activities clauses in ISO 15189. AB - The aim of this study was to design an audit questionnaire that focuses on the management of the technical activities in a Diagnostic Pathology Laboratory. The ISO 15189 Standard is written in such a way that it continually moves back and forth from topics where the auditor needs to question bench level staff, to topics where the auditor needs to question Technical Management Staff. This makes for a disjointed audit process - both Bench Staff and Technical Managers are repeatedly interrupted. The solution was to do a clause by clause analysis of the Standard and assign the major responsibility for the compliance to each clause to either Technical Managers or Bench Staff. The Clauses were then grouped under four topic headings regardless of whether they were a Section 4 or Section 5 Clause. Two questionnaires have emerged - the one described in this work and one directed primarily towards the activities of bench staff. There are 95 questions and it takes approximately two hours to complete. PMID- 23105893 TI - Characterization of a hemoglobin variant: HbQ-India / IVS 1-1 [G>T]-beta thalassemia. AB - Hemoglobin Q- India (alpha) 64 Asp -> His is an alpha chain variant which is generally found in heterozygous state and presents normal hematological blood picture. Here we report a rare case of HbQ-India with a thalassemic phenotype that has been analyzed using a combination of mass spectrometry, gene sequencing and PCR analysis. This combined analyses revealed the HbQ variant to be associated with a beta chain mutation, IVS 1-1 [G>T]. Though HbQ has earlier been reported with thalassemic trait using different techniques, this is the first report of a compound alpha and beta chain Hb heterozygous mutant involving HbQ and IVS1-1 being validated using Mass Spectrometry and Reverse dot blot hybridization. PMID- 23105894 TI - Can ionic imbalance in HIV disease be attributed to certain underlying opportunistic infections? PMID- 23105895 TI - Immunomodulators of helminthes: Promising therapeutics for autoimmune disorders and allergic diseases x. PMID- 23105896 TI - Endoplasmic reticulum stress in diabetes: New insights of clinical relevance. AB - The endoplasmic reticulum (ER) is a cellular compartment responsible for multiple important cellular functions including the biosynthesis and folding of newly synthesized proteins destined for secretion, such as insulin. A myriad of pathological and physiological factors perturb ER function and cause dysregulation of ER homeostasis, leading to ER stress. Accumulating evidence suggests that ER stress plays a role in the pathogenesis of diabetes, contributing to pancreatic beta-cell loss and insulin resistance. ER stress may also link obesity, inflammation and insulin resistance in type 2 diabetes. In this review, we address the transition from physiology to pathology, namely how and why the physiological UPR evolves to a proapoptotic ER stress response in diabetes and its complications. Special attention was given to elucidate how ER stress could explain some of the 'clinical paradoxes' such as secondary sulfonylurea failure, initial worsening of retinopathy during tight glycemic control, insulin resistance induced by protease inhibitors and other clinically relevant observations. PMID- 23105897 TI - Polymorphisms in the vitamin D receptor and the androgen receptor gene associated with the risk of urolithiasis. AB - Transcriptional activity of the vitamin D receptor (VDR) gene is regulated by androgen receptor (AR) gene and both are associated with renal stone formation. We examined gene polymorphisms of VDR (PCR-RFLP) and AR (GeneScan analysis) in 125 stone formers and 150 controls from north India. Genotype Ff of Fok-I and Tt of Taq-I demonstrated significantly higher risk (P<0.001, OR=3.559 and P=0.019, 1.830 respectively). Variant f allele exhibited 1.7-folds higher risk. Ff of Fok I and Aa of Apa-I gene polymorphism showed higher risk in males only. Mean CAG repeat was significantly higher in hypercalciuric patients as compared to normocalciuric (mean=21.62 +/- 3.384 vs. 20.11 +/- 3.182; P=0.034). Combined effects 1.8-folds higher risk in patients with Tt genotype of Taq-I and short CAG repeat. Thus, association of FokI and TaqI VDR gene polymorphisms suggest VDR as an important genetic marker for urolithiasis. Further, patients with combination of Tt of Taq-I and short CAG repeat were at higher risk for stone formation. PMID- 23105898 TI - Urinary 8-OHdG: A marker of oxidative stress to DNA and total antioxidant status in essential hypertension with South Indian population. AB - Establishment of non-invasive urinary biomarker for the early prediction of essential hypertension (EH) is important. We evaluated whether estimation of urinary DNA, serves as a marker to predict the extent of cellular oxidative stress in essential hypertension. A total of 180 South Indian subjects aged 30-65 were recruited for the study. Of these hypertensive subjects investigated, 30 were newly diagnosed and were not on any antihypertensive drugs, but had systolic blood pressure 140-160 mmHg and diastolic blood pressure 95-100 mmHg and 75 hypertensive patients who already on drug therapy for one year and 75 were South Indian normotensive healthy controls with blood pressure <= 120/80 mmHg. The 8 OHdG level in urine was significantly increased in hypertensive patients (both newly diagnosed and who already on drug therapy) compared with control group. The significant increase in 8-OHdG was observed in newly diagnosed hypertensive patients compared with hypertensive patients who already on drug therapy. There was a significant decrease in serum TAS value in essential hypertensive group when compared to control group. The urinary 8-OHdG was independently correlated with serum TAS. Decreased TAS levels, which reflect to increased oxidative stress, may be the reason of increased urinary 8-OHdG in South Indian hypertensive patients. Our preliminary data suggest that the competitive ELISA for 8-OHdG appears to be a simple method for quantifying the extent of oxidative stress. PMID- 23105899 TI - Matrix metalloproteinase-3 (MMP-3) -1612 5A/6A promoter polymorphism in coronary artery disease in Indian population. AB - Matrix metalloproteinases (MMPs) play important role in the pathogenesis of coronary artery disease (CAD). 5A allele of -1612 5A/6A polymorphism of MMP-3 is associated with two fold higher activity than 6A allele. Present study was designed to analyse the association of this polymorphism with CAD in Indian population. Subjects included in the study were patients with stable angina (n=35), unstable angina (n=53), patients with recent event of myocardial infarction (MI) (MI Group-1, n=56) and patients at presentation of the acute MI (MI Group-2, n=49). Controls were healthy individuals (n=99). Genotyping of MMP-3 5A/6A polymorphism was carried out by PCR-based restriction digestion method. The genotype distribution of patient groups did not deviate from controls. Serum MMP 3 levels were significantly elevated at presentation of the acute MI by 36.8% (P=0.031) as compared to controls and more associated with 6A genotype suggesting discrepancy between in vitro transfection experiment and peripheral MMP-3 levels. PMID- 23105900 TI - Association between insulin resistance and hypothyroidism in females attending a tertiary care hospital. AB - The effect of thyroid status on insulin sensitivity is of great interest but despite various studies there is conflicting data on this subject. The study group comprised of 25 female subjects each with subclinical hypothyroidism, overt hypothyroidism and euthyroid controls. Serum samples of all the patients were assayed for thyroid profile, Insulin and lipid profile. Homeostasis model of assessment (HOMA-IR) was employed to assess the level of insulin resistance. Patients with hypothyroidism demonstrated insulin resistance and dyslipidemia as observed by the higher HOMA-IR and cholesterol and triglyceride levels respectively as compared to the controls. A significantly positive correlation between TSH and HOMA-IR level was also observed in the hypothyroidism group. Thyroid dysfunction leads to alterations in glucose and lipid metabolism which is an important risk factor for cardiovascular diseases. The dyslipidemia and insulin resistance should be managed aggressively to reduce the impending risk. PMID- 23105901 TI - Microalbuminuria: An inexpensive, non invasive bedside tool to predict outcome in critically ill patients. AB - This study was conducted to evaluate whether microalbuminuria on admission and after 24 hrs of admission to intensive care unit (ICU) predicts outcome as well as the Acute Physiology and Chronic Health Evaluation (APACHE) II severity illness score, the current accepted method of doing so. The study was carried out in a 20 bed mixed medical-surgical ICU of a tertiary care hospital. Of 525 consecutive adult patients with ICU stay of more than 24 hrs, 238 were included for the study. Patients with pregnancy, menstruation, anuria, macroscopic hematuria, urinary tract infection, marked proteinuria due to renal and post renal structural diseases, were excluded. Spot urine samples were collected on admission to ICU and 24 hrs thereafter. Urine albumincreatinine ratio (ACR) was measured on ICU admission (ACR1) and after 24 hrs (ACR2) and expressed in mg/g. Patient demographics were noted on admission. For disease severity scoring, APACHE II scores were calculated. Each patient was followed up throughout their ICU stay for a maximum of 28 days and the following outcome data were obtained: ICU length of stay and ICU mortality. Of the 238 patients, 196 survived while 42 patients died in the ICU. Non-survivors had a significantly higher median ACR2 [162.7 mg/g (IQR 69.5-344.3)] in comparison to the survivors who had a median ACR2 = 54.4 mg/g (IQR 19.0-129.1) (P< 0.0001). The median ACR1 [161.0 mg/g (IQR 29.0-369.3)] of non-survivors was higher than the median ACR1 [80.4 mg/g (IQR 35.1-167.6)] of survivors but failed to reach statistical significance (P= 0.0948). In a receiver operating characteristic curve (ROC) analysis, ACR2 emerged as the best indicator of mortality [(area under curve (AUC) of ACR2 = 0.71 > AUC (ACR1) =0.58 > AUC (DeltaACR) =0.55] similar to the currently used APACHE II scores (AUC = 0.78) (P=0.3). At a cutoff of 101 mg/g, ACR2 had a sensitivity of 69%, specificity of 67%, positive predictive value of 31% and a negative predictive value of 91% for predicting mortality in the critically ill patients. Absence of significant microalbuminuria at 24 hrs of ICU admission may help to predict survival in the ICU. PMID- 23105902 TI - Evaluation of plasma hormone concentrations using Enzyme-Immunoassay/Enzyme linked Immunosorbent assay in healthy Indian men: Effect of ethnicity. AB - The study involved three ethnic groups of India; Rajputs, Gorkhas and South Indians. Each group consisted of ~40 healthy, male soldiers between 20-50 years. The reference ranges for cortisol, testosterone, prolactin, arginine vasopressin and proAtrial natriuretic peptide(1-98) were determined using Enzyme-Immunoassay (EIA) while plasma levels of thyroid-stimulating hormone, triiodothyronine, free triiodothyronine, thyroxine and freethyroxine were measured using Enzyme-linked immunosorbent assay (ELISA). The results indicated that plasma hormone concentrations were within physiological range and inter-ethnic differences were most prominent between north- (Rajputs and Gorkhas) and south- Indians. In comparison to Radioimmunoassay, the EIA method for prolactin, thyroid-stimulating hormone, free-thyroxine gave higher values while the ELISA method for triiodothyronine, free-triiodothyronine, and thyroxine gave lower values. These differences are due to differences in assay standards and design. PMID- 23105903 TI - Diagnosis of gastrointestinal tuberculosis: Using cytomorphological, microbiological, immunological and molecular techniques - A study from Central India. AB - The present study included three groups: (A) age and gender matched control (n=24) with no previous signs of M. tuberculosis complex (MTBC) infection, (B) patients (n=28) diagnosed with gastro-intestinal TB (GITB), (C) patients (n=50) with clinical and histo-pathological signs of GITB, but were culture and AFB negative. Real time assay performed using fluorescence resonance energy transfer hybridization probes showed a positivity index of 36 % in group C, i.e. 18 were found reactive from the total 50 cases studied. In addition, immune characterization of these 18 cases showed depleted CD(4) (+) count and increased levels of IFN-gamma and TNF-alpha cytokines. No positive case was found in group A, while in group B, out of total 28 cases studied 27 were found positive. A combinatorial diagnostic approach for rapid detection and characterization of GITB might provide specific therapeutic strategies for prevention and treatment of the infection in future. PMID- 23105904 TI - Biochemical and genetic studies on cardiometabolic syndrome. AB - Cardiometabolic syndrome is one of the major public health issues of this century which describes a cluster of clinical characteristics. Seventy two patients with coronary artery disease (CAD) and cardiometabolic syndrome and forty healthy age and sex matched normal controls were selected for this study. Detailed clinical epidemiological and anthropometric characteristics were noted. Lipid profile and Cytokinesis-block micronuclei (CBMN) assay using cytochalasin B were carried out in all the subjects. Serum total cholesterol, triglyceride and LDL-cholesterol was significantly higher and HDL cholesterol was significantly lower in patients compared to their normal counter-parts (P<0.05). CBMN frequency of the patients was significantly higher at all ages compared to their normal counter parts (P<0.05). Various risk factors like diabetes, hypertension, dyslipidemia, abdominal obesity, smoking and alcoholism were found influenced the CBMN frequency; but the changes were not significant. From this study it can be concluded that DNA damage was found to be higher in patients with cardiometabolic syndrome which may be attributed to the generation of free radicals associated with alcohol consumption, tobacco use, dyslipidemia and glucose intolerance and the accumulation of free radicals with increase in age. PMID- 23105905 TI - Effect of Lecithin and silymarin on D-galactosamine induced toxicity in isolated hepatocytes and rats. AB - To investigate Lecithin for its hepatoprotective activity against D-galactosamine (D-GalN) induced toxicity in freshly isolated rat hepatocytes and animal models. Freshly isolated rat hepatocytes were exposed to Dgalactosamine (30 mM) along with/without lecithin (100 MUg/ml) and the levels of selected liver enzymes were measured. Thirty six Wistar strain albino rats were used for the in vivo investigations. Lecithin 50 and 100 mg/kg.b.wt were administered for one week by oral route. Liver damage was induced by intra peritoneal administration of 400 mg/kg b.wt D-galactosamine. The antihepatotoxic effect of lecithin was observed in freshly isolated rat hepatocytes at concentration 100 MUg/ml and was found to be similar to that of the standard silymarin used. Its in vivo hepatoprotective effect at 100 mg/kg b.wt was comparable with that of the standard silymarin at 100 mg/kg body weight. Lecithin was able to normalise the biochemical levels which were altered due to D-galactosamine intoxication in freshly isolated rat hepatocytes and also in animal models. PMID- 23105906 TI - Effect of Curcuma longa freeze dried rhizome powder with milk in STZ induced diabetic rats. AB - This study deals with the effects of freeze dried rhizome powder of Curcuma longa (C. longa) dissolved in milk on normal as well as diabetic models. Diabetes of type II and type I was within 3 days of a single administration of doses of 45 and 65 mg kg(-1) of streptozotocin respectively. Various parameters such as blood glucose levels, triglycerides, total cholesterol, high density lipoprotein, very low density lipoprotein, low density lipoprotein, serum glutamic oxaloacetic transaminase, serum glutamic pyruvate transaminase, alkaline phosphatase, creatinine, hemoglobin, urine protein and urine sugar in addition to body weight were taken in to consideration and were analyzed after administration of variable doses of rhizome powder. The dose of 200 mg kg(-1) was identified as the most effective dose as it increased HDL, Hb and bw (P<0.05) with significant decrease in the levels of blood glucose, lipid profile and hepatoprotective enzymes (P<0.001). PMID- 23105907 TI - Effects of garlic extract treatment in normal and streptozotocin diabetic rats infected with Candida albicans. AB - The anti-candidial effect of garlic extract (Allium sativum L.) was investigated in normal and streptozotocin-induced diabetic rats. Diabetes was induced after a single intraperitoneal injection of streptozotocin (60 mg/kg). Rats were divided into six groups with fifteen rats in each group: (1) Normal control rats (2) Control rats + C. albicans (3) Control rats + garlic extract + C. albicans (4) Diabetic control rats (5) Diabetic rats + C. albicans (6) Diabetic rats + garlic extract + C. albicans. The concerned groups were inoculated with C.albicans on the 15 th day. At the end of one month experiment, fasted rats were killed by cervical decapitation. Blood was collected for estimation of glucose and C. albicans concentrations were estimated in liver and kidneys homogenates. A significant increase was observed in serum glucose levels in diabetic rats. A loss of bodyweight, polydipsia and polyphagia were observed in diabetic rats. Administration of alcoholic extract of garlic (0.25 g/kg body weight) reduced the hyperglycemia, polydipsia, polyphagia and associated weight loss of streptozotocin-treated rats. Administration of garlic extract significantly reduced C. albicans concentrations in liver and kidneys homogenates in infected control and diabetic rats. It is concluded that garlic extract improves candidia infection in diabetic rats. PMID- 23105908 TI - Confirmatory studies on the antioxidant and antidiabetic effect of quercetin in rats. AB - Quercetin (QE), one of natural flavanoid group, was widely distributed as a secondary metabolite in plant kingdom. It has been believed that oxidative stress plays a role in the pathogenesis of diabetes mellitus (DM). The aim of the present study was the evaluation of possible effects of QE on blood glucose and antioxidant enzymes in experimental streptozotocin (STZ)-induced diabetes in rats. STZ was injected intraperitoneally with single dose of 50 mg/kg for diabetes induction. QE (15 mg/kg bw day, intraperitoneal (i.p.) injection) was injected for 3 days prior to STZ administration; these injections were continued to the end of the study (for 25 days). Glucose tolerance test and random plasma glucose were done for all animals. Cellular antioxidant enzymes such as glutathione peroxidase (GSHPx), superoxide dismutase (SOD) and catalase (CAT) activities were measured in pancreatic homogenates. Quercetin had no effect on plasma glucose level of normal animals but its pre- treatment was able to prevent diabetes induced by single intraperitoneal injection of streptozocintreated rats. Antioxidant enzyme activity significantly decreased in STZ induced diabetic group. QE treatment significantly increased the antioxidant enzyme activities. It could be concluded that quercetin, a flavonoid with antioxidant properties, exerting its beneficial antidiabetic effects. PMID- 23105909 TI - Antihyperglycemic, antihyperlipidemic and antioxidative potential of Prosopis cineraria bark. AB - Alloxan administration in male Swiss albino mice, induced diabetes by increasing blood glucose concentration and reducing hepatic glycogen content as compared to normal control group. Besides, serum lipid profile parameters such as total cholesterol, triglyceride, low-density lipoprotein and very low-density lipoprotein-cholesterol were also elevated, whereas, the level of high-density lipoprotein-cholesterol was reduced significantly (P<0.05) in diabetic mice. Treatment of diabetic animals with crude ethanolic extract of bark of Prosopis cineraria (P. cineraria) for 45 days, significantly lowered blood glucose level, elevated hepatic glycogen content and maintained body weight and lipid-profile parameters towards near normal range. Declined activity of antioxidant enzymes and concentration of non-enzymatic antioxidants were also normalized by drug treatment, thereby reducing the oxidative damage in the tissues of diabetic animals and hence indicating the anti-diabetic and antioxidant efficacy of the extract. PMID- 23105910 TI - Effect of soy proteins Vs soy isoflavones on lipid profile in postmenopausal women. AB - Soy isoflavones and soy proteins are being considered as possible alternatives to postmenopausal hormone replacement therapy. This study was undertaken to evaluate effects of these two preparations on symptoms and lipid profile in postmenopausal women. The study was done in 75 postmenopausal women with FSH levels = 30 mIU/ml. These women were randomly divided into 3 groups (n=25). Study group I was given soy proteins 30gm/day containing 60 mg soy isoflavones. Study group II was given soy isoflavones (60 mg/day). The control group was given casein protein 30 gm/day. The menopausal symptoms were assessed by Kupperman Index. Fasting blood samples were analyzed for serum lipid profile, apolipoprotein A1 and B, Leutenizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) at the beginning of therapy, 4 and 12 weeks after initiation of therapy. A highly significant improvement in postmenopausal symptoms was observed in both the study groups. A highly significant improvement was seen in serum lipid profile and Apolipoprotein A1 and B in women taking soy proteins whereas women taking soy isoflavones demonstrated significant improvement in serum triglycerides only. Both soy proteins and soy isoflavones are helpful in alleviating postmenopausal symptoms but soy proteins offer a greater health advantage due to their beneficial effect on serum lipid profile. PMID- 23105911 TI - hs-CRP: A potential marker for hypertension in Kashmiri population. AB - Hypertension is the most important public health problem in developing countries and one of the major risk factors for cardiovascular diseases, and it has been reported that hypertension is in part an inflammatory disorder and several workers have reported elevated levels of CRP in hypertensive individuals. The main aim of the present study was to evaluate the association between blood pressure and serum CRP levels across the range of blood pressure categories including prehypertension. A total of 104 patients and 63 control subjects were included in the present study. The level of CRP in the serum samples was estimated by a high sensitivity immunoturbidometric assay. Standard unpaired student's 't' test was used for comparison of hs-CRP levels between hypertensive patients and normotensive control subjects and between patient groups with different grades of hypertension and different durations of hypertensive histories. The mean serum hs-CRP level in hypertensive patients was 3.26 mg/L compared with 1.36 mg/L among normotensive control subjects (P<0.001). On comparison with normotensive control subjects, the hs-CRP levels vary significantly both with grades and duration of hypertension, with most significant difference found in patients with prehypertension (P<0.001), followed by Stage-I (P=0.01) and Stage-II(P=0.02) hypertensives. Significant difference in hs-CRP levels was also found in patients with shorter duration of hypertensive history (<= 1year) when compared with those with >=5 years of hypertensive history (P<0.01). Our study reveals a graded association between blood pressure and CRP elevation in people with hypertension. Individuals with prehypertension or with shorter duration of hypertension (<=1 Year) had significantly a greater likelihood of CRP elevation in comparison to chronic stage-I or stage-II hypertensives. PMID- 23105912 TI - Cerebro-spinal and renal ochronosis: A rare case report. AB - Alkaptonuria, a rare inborn error of tyrosine metabolism, characterized by the absence of homogentisic acid oxidase results in the accumulation of homogentisic acid in the body. Associated renal failure and cerebral infarction is rare and usually occurs in the later stages of the disease. We report a 55-year-old male who presented, initially with features of stroke and degenerative arthritis. He had pigmentation of sclerae, darkening of urine on long standing, abnormal renal profile, degenerative arthritis and cerebral infarction. Alkaptonuria was suspected and biochemical tests confirmed mild renal impairment, homogentisic acid in urine and homogentisic acid crystal was detected cytologically in urine sediment. Such a case of Alkaptonuric ochronosis with cerebrovascular and renal complications have been rarely reported in the previous literature. PMID- 23105913 TI - MOMENT-BASED METHOD FOR RANDOM EFFECTS SELECTION IN LINEAR MIXED MODELS. AB - The selection of random effects in linear mixed models is an important yet challenging problem in practice. We propose a robust and unified framework for automatically selecting random effects and estimating covariance components in linear mixed models. A moment-based loss function is first constructed for estimating the covariance matrix of random effects. Two types of shrinkage penalties, a hard thresholding operator and a new sandwich-type soft-thresholding penalty, are then imposed for sparse estimation and random effects selection. Compared with existing approaches, the new procedure does not require any distributional assumption on the random effects and error terms. We establish the asymptotic properties of the resulting estimator in terms of its consistency in both random effects selection and variance component estimation. Optimization strategies are suggested to tackle the computational challenges involved in estimating the sparse variance-covariance matrix. Furthermore, we extend the procedure to incorporate the selection of fixed effects as well. Numerical results show promising performance of the new approach in selecting both random and fixed effects and, consequently, improving the efficiency of estimating model parameters. Finally, we apply the approach to a data set from the Amsterdam Growth and Health study. PMID- 23105914 TI - Generating Phenotypical Erroneous Human Behavior to Evaluate Human-automation Interaction Using Model Checking. AB - Breakdowns in complex systems often occur as a result of system elements interacting in unanticipated ways. In systems with human operators, human automation interaction associated with both normative and erroneous human behavior can contribute to such failures. Model-driven design and analysis techniques provide engineers with formal methods tools and techniques capable of evaluating how human behavior can contribute to system failures. This paper presents a novel method for automatically generating task analytic models encompassing both normative and erroneous human behavior from normative task models. The generated erroneous behavior is capable of replicating Hollnagel's zero-order phenotypes of erroneous action for omissions, jumps, repetitions, and intrusions. Multiple phenotypical acts can occur in sequence, thus allowing for the generation of higher order phenotypes. The task behavior model pattern capable of generating erroneous behavior can be integrated into a formal system model so that system safety properties can be formally verified with a model checker. This allows analysts to prove that a human-automation interactive system (as represented by the model) will or will not satisfy safety properties with both normative and generated erroneous human behavior. We present benchmarks related to the size of the statespace and verification time of models to show how the erroneous human behavior generation process scales. We demonstrate the method with a case study: the operation of a radiation therapy machine. A potential problem resulting from a generated erroneous human action is discovered. A design intervention is presented which prevents this problem from occurring. We discuss how our method could be used to evaluate larger applications and recommend future paths of development. PMID- 23105915 TI - Racial Disparities in Depression and Life Satisfaction After Spinal Cord Injury: A Mediational Model. AB - PURPOSE: To identify the relationship of race and gender with 3 aspects of life satisfaction and depressive symptoms after spinal cord injury (SCI), evaluating the extent to which socioeconomic factors mediate any observed relationships. METHODS: Adults with traumatic SCI of at least 1-year duration (N = 1,549) were identified through a Southeastern United States SCI Model System of care, and cross-sectional survey data were collected at a Southeastern United States medical university. Three aspects of life satisfaction (home life satisfaction, vocational satisfaction, global satisfaction) were measured using 20 satisfaction items from the Life Situation Questionnaire-Revised. The Older Adult Health and Mood Questionnaire measured depressive symptoms. MANCOVA assessed mediation of socioeconomic status between race and life satisfaction and depression. RESULTS: Home life satisfaction and vocational satisfaction were significantly related to race, with White participants scoring higher than Black participants during the first stage of the regression. However, socioeconomic factors mediated the relationships such that race was no longer significant after considering economic factors. Race was significantly associated with global satisfaction after adjusting for socioeconomic factors. Depression was not significantly related to race. Gender was unrelated to all study outcomes. Of the socioeconomic mediators, family income was a significant predictor of each outcome, whereas education was only predictive of vocational satisfaction. CONCLUSION: Socioeconomic factors are important mediators of the relationship between race and certain aspects of life satisfaction among persons with SCI. Family income and, to a lesser extent, education should be considered when evaluating race differences in life satisfaction after SCI. PMID- 23105916 TI - Air quality interventions and spatial dynamics of air pollution in Delhi and its surroundings. AB - The paper examines the spatial distribution of air pollution in response to recent air quality regulations in Delhi, India. Air pollution was monitored at 113 sites spread across Delhi and its surrounding areas from July-December 2003. From the analysis of these data three important findings emerge. First, air pollution levels in Delhi and its surroundings were significantly higher than that recommended by the World Health Organization (WHO). Second, air quality regulations in the city adversely affected the air quality of the areas surrounding Delhi. Third, industries and trucks were identified as the major contributors of both fine and coarse particles. PMID- 23105917 TI - Improving Preschoolers' Language and Literacy Skills through Web-Mediated Professional Development. AB - MyTeachingPartner (MTP) is a web-mediated approach that provides ongoing support for teachers to improve the quality of their interactions with children. This study examined the effects of MTP on the preschool language and literacy development of children who are at risk for later academic difficulties. Results of this randomized controlled trial indicated that for English-only classrooms, teachers receiving a high level of support had students who made greater gains in language and literacy skills than teachers who only received access to a curricular supplement. Three implications are drawn from these findings: (1) on going, video-based consultation holds promise not only for altering teacher-child interactions, but also improving children's learning, (2) technology allows teachers to receive intensive, effective support from a distance, and (3) there is still much to be learned about how professional development can support effective teaching of language and literacy skills to children whose home language is not English. PMID- 23105918 TI - "Native" Objects and Collaborators: Infants' Object Choices and Acts of Giving Reflect Favor for Native Over Foreign Speakers. AB - Infants learn from adults readily and cooperate with them spontaneously, but how do they select culturally appropriate teachers and collaborators? Building on evidence that children demonstrate social preferences for speakers of their native language, Experiment 1 presented 10-month-old infants with videotaped events in which a native and a foreign speaker introduced two different toys. When given a chance to choose between real exemplars of the objects, infants preferentially chose the toy modeled by the native speaker. In Experiment 2, 2.5 year-old children were presented with the same videotaped native and foreign speakers, and played a game in which they could offer an object to one of two individuals. Children reliably gave to the native speaker. Together, the results suggest that infants and young children are selective social learners and cooperators, and that language provides one basis for this selectivity. PMID- 23105919 TI - What's Faith Got to Do with It? Religiosity Among Women Who Use Methamphetamine. AB - Religiosity is not found to be consistently protective in mental health and substance use outcomes among illicit drug users. This study examines the association between religiosity, mental health and drug use among a community recruited sample of women who use methamphetamine. The majority of the sample (74%) had high scores of religious faith. In multivariate analysis, those with high scores had higher odds of self-reporting a mental health diagnosis and of being psychologically dependent upon methamphetamine, and were less likely to report injection risk. Further examination of the role of religiosity in the lives of women who use methamphetamine is advised. PMID- 23105920 TI - Open Quantum Dynamics Calculations with the Hierarchy Equations of Motion on Parallel Computers. AB - Calculating the evolution of an open quantum system, i.e., a system in contact with a thermal environment, has presented a theoretical and computational challenge for many years. With the advent of supercomputers containing large amounts of memory and many processors, the computational challenge posed by the previously intractable theoretical models can now be addressed. The hierarchy equations of motion present one such model and offer a powerful method that remained under-utilized so far due to its considerable computational expense. By exploiting concurrent processing on parallel computers the hierarchy equations of motion can be applied to biological-scale systems. Herein we introduce the quantum dynamics software PHI, that solves the hierarchical equations of motion. We describe the integrator employed by PHI and demonstrate PHI's scaling and efficiency running on large parallel computers by applying the software to the calculation of inter-complex excitation transfer between the light harvesting complexes 1 and 2 of purple photosynthetic bacteria, a 50 pigment system. PMID- 23105921 TI - Anticancer activity of proapoptotic peptides is highly improved by thermal targeting using elastin-like polypeptides. AB - Inducing apoptosis in cancer cells is an effective strategy for cancer therapy. The cationic alpha-helix forming KLAKLAKKLAKLAK peptide (KLAK) has been known to induce apoptosis by disrupting the mitochondria. In the present study, we have designed a thermally targeted KLAK peptide by genetically engineering the KLAK sequence to the carboxy terminus of the heat responsive biopolymer elastin-like polypeptide (ELP). The cellular internalization of ELP-KLAK was made possible by engineering a cell penetrating peptide sequence (SynB1) to the amino terminus of ELP. The SynB1-ELP1-KLAK fusion polypeptide was cytotoxic against both estrogen receptor positive and negative human breast cancer cell lines. The potency of SynB1-ELP1-KLAK was further enhanced when mild hyperthermia was added to the treatment. In response to hyperthermia, SynB1-ELP1-KLAK selectively triggered apoptosis, which was associated with disruption of the mitochondria. The thermally responsive SynB1-ELP-KLAK polypeptide can have improved tumor targeting by the application of mild hyperthermia. Furthermore, the pharmacokinetic properties of ELP can prevent degradation of KLAK in vivo, and the use of SynB1 can mediate tumor cell uptake, thereby augmenting the effect of KLAK. PMID- 23105922 TI - Survey of the Applications of NGS to Whole-Genome Sequencing and Expression Profiling. AB - Recently, the technologies of DNA sequence variation and gene expression profiling have been used widely as approaches in the expertise of genome biology and genetics. The application to genome study has been particularly developed with the introduction of the next-generation DNA sequencer (NGS) Roche/454 and Illumina/Solexa systems, along with bioinformation analysis technologies of whole genome de novo assembly, expression profiling, DNA variation discovery, and genotyping. Both massive whole-genome shotgun paired-end sequencing and mate paired-end sequencing data are important steps for constructing de novo assembly of novel genome sequencing data. It is necessary to have DNA sequence information from a multiplatform NGS with at least 2* and 30* depth sequence of genome coverage using Roche/454 and Illumina/Solexa, respectively, for effective an way of de novo assembly. Massive short-length reading data from the Illumina/Solexa system is enough to discover DNA variation, resulting in reducing the cost of DNA sequencing. Whole-genome expression profile data are useful to approach genome system biology with quantification of expressed RNAs from a whole-genome transcriptome, depending on the tissue samples. The hybrid mRNA sequences from Rohce/454 and Illumina/Solexa are more powerful to find novel genes through de novo assembly in any whole-genome sequenced species. The 20* and 50* coverage of the estimated transcriptome sequences using Roche/454 and Illumina/Solexa, respectively, is effective to create novel expressed reference sequences. However, only an average 30* coverage of a transcriptome with short read sequences of Illumina/Solexa is enough to check expression quantification, compared to the reference expressed sequence tag sequence. PMID- 23105923 TI - CysQ of Cryptosporidium parvum, a Protozoa, May Have Been Acquired from Bacteria by Horizontal Gene Transfer. AB - Horizontal gene transfer (HGT) is the movement of genetic material between kingdoms and is considered to play a positive role in adaptation. Cryptosporidium parvum is a parasitic protozoan that causes an infectious disease. Its genome sequencing reported 14 bacteria-like proteins in the nuclear genome. Among them, cgd2_1810, which has been annotated as CysQ, a sulfite synthesis pathway protein, is listed as one of the candidates of genes horizontally transferred from bacterial origin. In this report, we examined this issue using phylogenetic analysis. Our BLAST search showed that C. parvum CysQ protein had the highest similarity with that of proteobacteria. Analysis with NCBI's Conserved Domain Tree showed phylogenetic incongruence, in that C. parvum CysQ protein was located within a branch of proteobacteria in the cd01638 domain, a bacterial member of the inositol monophosphatase family. According to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, the sulfate assimilation pathway, where CysQ plays an important role, is well conserved in most eukaryotes as well as prokaryotes. However, the Apicomplexa, including C. parvum, largely lack orthologous genes of the pathway, suggesting its loss in those protozoan lineages. Therefore, we conclude that C. parvum regained cysQ from proteobacteria by HGT, although its functional role is elusive. PMID- 23105924 TI - Differential Expression of PKD2-Associated Genes in Autosomal Dominant Polycystic Kidney Disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by formation of multiple fluid-filled cysts that expand over time and destroy renal architecture. The proteins encoded by the PKD1 and PKD2 genes, mutations in which account for nearly all cases of ADPKD, may help guard against cystogenesis. Previously developed mouse models of PKD1 and PKD2 demonstrated an embryonic lethal phenotype and massive cyst formation in the kidney, indicating that PKD1 and PKD2 probably play important roles during normal renal tubular development. However, their precise role in development and the cellular mechanisms of cyst formation induced by PKD1 and PKD2 mutations are not fully understood. To address this question, we presently created Pkd2 knockout and PKD2 transgenic mouse embryo fibroblasts. We used a mouse oligonucleotide microarray to identify messenger RNAs whose expression was altered by the overexpression of the PKD2 or knockout of the Pkd2. The majority of identified mutations was involved in critical biological processes, such as metabolism, transcription, cell adhesion, cell cycle, and signal transduction. Herein, we confirmed differential expressions of several genes including aquaporin-1, according to different PKD2 expression levels in ADPKD mouse models, through microarray analysis. These data may be helpful in PKD2-related mechanisms of ADPKD pathogenesis. PMID- 23105925 TI - Possibility of the use of public microarray database for identifying significant genes associated with oral squamous cell carcinoma. AB - There are lots of studies attempting to identify the expression changes in oral squamous cell carcinoma. Most studies include insufficient samples to apply statistical methods for detecting significant gene sets. This study combined two small microarray datasets from a public database and identified significant genes associated with the progress of oral squamous cell carcinoma. There were different expression scales between the two datasets, even though these datasets were generated under the same platforms - Affymetrix U133A gene chips. We discretized gene expressions of the two datasets by adjusting the differences between the datasets for detecting the more reliable information. From the combination of the two datasets, we detected 51 significant genes that were upregulated in oral squamous cell carcinoma. Most of them were published in previous studies as cancer-related genes. From these selected genes, significant genetic pathways associated with expression changes were identified. By combining several datasets from the public database, sufficient samples can be obtained for detecting reliable information. Most of the selected genes were known as cancer related genes, including oral squamous cell carcinoma. Several unknown genes can be biologically evaluated in further studies. PMID- 23105926 TI - CaGe: A Web-Based Cancer Gene Annotation System for Cancer Genomics. AB - High-throughput genomic technologies (HGTs), including next-generation DNA sequencing (NGS), microarray, and serial analysis of gene expression (SAGE), have become effective experimental tools for cancer genomics to identify cancer associated somatic genomic alterations and genes. The main hurdle in cancer genomics is to identify the real causative mutations or genes out of many candidates from an HGT-based cancer genomic analysis. One useful approach is to refer to known cancer genes and associated information. The list of known cancer genes can be used to determine candidates of cancer driver mutations, while cancer gene-related information, including gene expression, protein-protein interaction, and pathways, can be useful for scoring novel candidates. Some cancer gene or mutation databases exist for this purpose, but few specialized tools exist for an automated analysis of a long gene list from an HGT-based cancer genomic analysis. This report presents a new web-accessible bioinformatic tool, called CaGe, a cancer genome annotation system for the assessment of candidates of cancer genes from HGT-based cancer genomics. The tool provides users with information on cancer-related genes, mutations, pathways, and associated annotations through annotation and browsing functions. With this tool, researchers can classify their candidate genes from cancer genome studies into either previously reported or novel categories of cancer genes and gain insight into underlying carcinogenic mechanisms through a pathway analysis. We show the usefulness of CaGe by assessing its performance in annotating somatic mutations from a published small cell lung cancer study. PMID- 23105927 TI - Decreases in Casz1 mRNA by an siRNA Complex Do not Alter Blood Pressure in Mice. AB - Recent genomewide association studies of large samples have identified genes that are associated with blood pressure. The Global Blood Pressure Genetics (Global BPgen) and Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) consortiums identified 14 loci that govern blood pressure on a genomewide significance level, one of which is CASZ1 confirmed in both Europeans and Asians. CASZ1 is a zinc finger transcription factor that controls apoptosis and cell fate and suppresses neuroblastoma tumor growth by reprogramming gene expression, like a tumor suppressor. To validate the function of CASZ1 in blood pressure, we decreased Casz1 mRNA levels in mice by siRNA. Casz1 siRNA reduced mRNA levels by 59% in a mouse cell line. A polyethylenimine-mixed siRNA complex was injected into mouse tail veins, reducing Casz1 mRNA expression to 45% in the kidney. However, blood pressure in the treated mice was unaffected, despite a 55% reduction in Casz1 mRNA levels in the kidney on multiple siRNA injections daily. Even though Casz1 siRNA-treated mice did not experience any significant change in blood pressure, our study demonstrates the value of in vivo siRNA injection in analyzing the function of candidate genes identified by genomewide association studies. PMID- 23105928 TI - Efficient mining of interesting patterns in large biological sequences. AB - Pattern discovery in biological sequences (e.g., DNA sequences) is one of the most challenging tasks in computational biology and bioinformatics. So far, in most approaches, the number of occurrences is a major measure of determining whether a pattern is interesting or not. In computational biology, however, a pattern that is not frequent may still be considered very informative if its actual support frequency exceeds the prior expectation by a large margin. In this paper, we propose a new interesting measure that can provide meaningful biological information. We also propose an efficient index-based method for mining such interesting patterns. Experimental results show that our approach can find interesting patterns within an acceptable computation time. PMID- 23105929 TI - An efficient approach to mining maximal contiguous frequent patterns from large DNA sequence databases. AB - Mining interesting patterns from DNA sequences is one of the most challenging tasks in bioinformatics and computational biology. Maximal contiguous frequent patterns are preferable for expressing the function and structure of DNA sequences and hence can capture the common data characteristics among related sequences. Biologists are interested in finding frequent orderly arrangements of motifs that are responsible for similar expression of a group of genes. In order to reduce mining time and complexity, however, most existing sequence mining algorithms either focus on finding short DNA sequences or require explicit specification of sequence lengths in advance. The challenge is to find longer sequences without specifying sequence lengths in advance. In this paper, we propose an efficient approach to mining maximal contiguous frequent patterns from large DNA sequence datasets. The experimental results show that our proposed approach is memory-efficient and mines maximal contiguous frequent patterns within a reasonable time. PMID- 23105930 TI - Comparative evaluation of intron prediction methods and detection of plant genome annotation using intron length distributions. AB - Intron prediction is an important problem of the constantly updated genome annotation. Using two model plant (rice and Arabidopsis) genomes, we compared two well-known intron prediction tools: the Blast-Like Alignment Tool (BLAT) and Sim4cc. The results showed that each of the tools had its own advantages and disadvantages. BLAT predicted more than 99% introns of whole genomic introns with a small number of false-positive introns. Sim4cc was successful at finding the correct introns with a false-negative rate of 1.02% to 4.85%, and it needed a longer run time than BLAT. Further, we evaluated the intron information of 10 complete plant genomes. As non-coding sequences, intron lengths are not limited by a triplet codon frame; so, intron lengths have three phases: a multiple of three bases (3n), a multiple of three bases plus one (3n + 1), and a multiple of three bases plus two (3n + 2). It was widely accepted that the percentages of the 3n, 3n + 1, and 3n + 2 introns were quite similar in genomes. Our studies showed that 80% (8/10) of species were similar in terms of the number of three phases. The percentages of 3n introns in Ostreococcus lucimarinus was excessive (47.7%), while in Ostreococcus tauri, it was deficient (29.1%). This discrepancy could have been the result of errors in intron prediction. It is suggested that a three phase evaluation is a fast and effective method of detecting intron annotation problems. PMID- 23105931 TI - Web-based database and viewer of East asian copy number variations. AB - We have discovered copy number variations (CNVs) in 3,578 Korean individuals with the Affymetrix Genome-Wide SNP array 5.0, and 4,003 copy number variation regions (CNVRs) were defined in a previous study. To explore the details of the variants easily in related studies, we built a database, cataloging the CNVs and related information. This system helps researchers browsing these variants with gene and structure variant annotations. Users can easily find specific regions with search options and verify them from system-integrated genome browsers with annotations. PMID- 23105932 TI - Perspectives of integrative cancer genomics in next generation sequencing era. AB - The explosive development of genomics technologies including microarrays and next generation sequencing (NGS) has provided comprehensive maps of cancer genomes, including the expression of mRNAs and microRNAs, DNA copy numbers, sequence variations, and epigenetic changes. These genome-wide profiles of the genetic aberrations could reveal the candidates for diagnostic and/or prognostic biomarkers as well as mechanistic insights into tumor development and progression. Recent efforts to establish the huge cancer genome compendium and integrative omics analyses, so-called "integromics", have extended our understanding on the cancer genome, showing its daunting complexity and heterogeneity. However, the challenges of the structured integration, sharing, and interpretation of the big omics data still remain to be resolved. Here, we review several issues raised in cancer omics data analysis, including NGS, focusing particularly on the study design and analysis strategies. This might be helpful to understand the current trends and strategies of the rapidly evolving cancer genomics research. PMID- 23105934 TI - Identifying Copy Number Variants under Selection in Geographically Structured Populations Based on F-statistics. AB - Large-scale copy number variants (CNVs) in the human provide the raw material for delineating population differences, as natural selection may have affected at least some of the CNVs thus far discovered. Although the examination of relatively large numbers of specific ethnic groups has recently started in regard to inter-ethnic group differences in CNVs, identifying and understanding particular instances of natural selection have not been performed. The traditional F(ST) measure, obtained from differences in allele frequencies between populations, has been used to identify CNVs loci subject to geographically varying selection. Here, we review advances and the application of multinomial-Dirichlet likelihood methods of inference for identifying genome regions that have been subject to natural selection with the F(ST) estimates. The contents of presentation are not new; however, this review clarifies how the application of the methods to CNV data, which remains largely unexplored, is possible. A hierarchical Bayesian method, which is implemented via Markov Chain Monte Carlo, estimates locus-specific F(ST) and can identify outlying CNVs loci with large values of F(ST). By applying this Bayesian method to the publicly available CNV data, we identified the CNV loci that show signals of natural selection, which may elucidate the genetic basis of human disease and diversity. PMID- 23105933 TI - Alternative splicing and its impact as a cancer diagnostic marker. AB - Most genes are processed by alternative splicing for gene expression, resulting in the complexity of the transcriptome in eukaryotes. It allows a limited number of genes to encode various proteins with intricate functions. Alternative splicing is regulated by genetic mutations in cis-regulatory factors and epigenetic events. Furthermore, splicing events occur differently according to cell type, developmental stage, and various diseases, including cancer. Genome instability and flexible proteomes by alternative splicing could affect cancer cells to grow and survive, leading to metastasis. Cancer cells that are transformed by aberrant and uncontrolled mechanisms could produce alternative splicing to maintain and spread them continuously. Splicing variants in various cancers represent crucial roles for tumorigenesis. Taken together, the identification of alternative spliced variants as biomarkers to distinguish between normal and cancer cells could cast light on tumorigenesis. PMID- 23105935 TI - Interaction Effects of Lipoprotein Lipase Polymorphisms with Lifestyle on Lipid Levels in a Korean Population: A Cross-sectional Study. AB - Lipoprotein lipase (LPL) plays an essential role in the regulation of high density lipoprotein cholesterol (HDLC) and triglyceride levels, which have been closely associated with cardiovascular diseases. Genetic studies in European have shown that LPL single-nucleotide polymorphisms (SNPs) are strongly associated with lipid levels. However, studies about the influence of interactions between LPL SNPs and lifestyle factors have not been sufficiently performed. Here, we examine if LPL polymorphisms, as well as their interaction with lifestyle factors, influence lipid concentrations in a Korean population. A two-stage association study was performed using genotype data for SNPs on the LPL gene, including the 3' flanking region from 7,536 (stage 1) and 3,703 (stage 2) individuals. The association study showed that 15 SNPs and 4 haplotypes were strongly associated with HDLC (lowest p = 2.86 * 10(-22)) and triglyceride levels (lowest p = 3.0 * 10(-15)). Interactions between LPL polymorphisms and lifestyle factors (lowest p = 9.6 * 10(-4)) were also observed on lipid concentrations. These findings suggest that there are interaction effects of LPL polymorphisms with lifestyle variables, including energy intake, fat intake, smoking, and alcohol consumption, as well as effects of LPL polymorphisms themselves, on lipid concentrations in a Korean population. PMID- 23105936 TI - Effect of genetic predisposition on blood lipid traits using cumulative risk assessment in the korean population. AB - Dyslipidemia, mainly characterized by high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels, is an important etiological factor in the development of cardiovascular disease (CVD). Considering the relationship between childhood obesity and CVD risk, it would be worthwhile to evaluate whether previously identified lipid-related variants in adult subjects are associated with lipid variations in a childhood obesity study (n = 482). In an association analysis for 16 genome-wide association study (GWAS)-based candidate loci, we confirmed significant associations of a genetic predisposition to lipoprotein concentrations in a childhood obesity study. Having two loci (rs10503669 at LPL and rs16940212 at LIPC) that showed the strongest association with blood levels of TG and HDL-C, we calculated a genetic risk score (GRS), representing the sum of the risk alleles. It has been observed that increasing GRS is significantly associated with decreased HDL-C (effect size, -1.13 +/- 0.07) compared to single nucleotide polymorphism combinations without two risk variants. In addition, a positive correlation was observed between allelic dosage score and risk allele (rs10503669 at LPL) on high TG levels (effect size, 10.89 +/- 0.84). These two loci yielded consistent associations in our previous meta-analysis. Taken together, our findings demonstrate that the genetic architecture of circulating lipid levels (TG and HDL-C) overlap to a large extent in childhood as well as in adulthood. Post-GWAS functional characterization of these variants is further required to elucidate their pathophysiological roles and biological mechanisms. PMID- 23105937 TI - Replication of the Association of the 6q22.31c Locus near GJA1 with Pulse Rate in the Korean Population. AB - Pulse rate is known to be related to diverse phenotypes, such as cardiovascular diseases, lifespan, arrhythmia, hypertension, lipids, diabetes, and menopause. We have reported two genomewide significant genetic loci responsible for the variation in pulse rate as a part of the Korea Association Resource (KARE) project, the genomewide association study (GWAS) that was conducted with 352,228 single nucleoride polymorphisms typed in 8,842 subjects in the Korean population. GJA1 was implied as a functionally causal gene for pulse rate from the KARE study, but lacked evidence of replication. To re-evaluate the association of a locus near GJA1 with pulse rate, we looked up this signal in another GWAS conducted in a Health Examinee-shared cohort of 3,703 samples. Not only we were able to confirm two pulse rate loci (1q32.2a near CD46 and 6q22.13c near LOCL644502) identified in the KARE GWAS, we also replicated a locus (6q22.31c) near GJA1 by the lookup in the Health Examinee GWAS. Considering that the GJA1 encoded protein is a major component of cardiac gap junctions, a functional study might be necessary to validate its genuine molecular biological role in the synchronized contraction of the heart. PMID- 23105938 TI - Genetic Analysis of SCN5A in Korean Patients Associated with Atrioventricular Conduction Block. AB - Recent several studies have shown that the genetic variation of SCN5A is related with atrioventricular conduction block (AVB); no study has yet been published in Koreans. Therefore, to determine the AVB-associated genetic variation in Korean patients, we investigated the genetic variation of SCN5A in Korean patients with AVB and compared with normal control subjects. We enrolled 113 patients with AVB and 80 normal controls with no cardiac symptoms. DNA was isolated from the peripheral blood, and all exons (exon 2-exon 28) except the untranslated region and exon-intron boundaries of the SCN5A gene were amplified by multiplex PCR and directly sequenced using an ABI PRISM 3100 Genetic Analyzer. When a variation was discovered in genomic DNA from AVB patients, we confirmed whether the same variation existed in the control genomic DNA. In the present study, a total of 7 genetic variations were detected in 113 AVB patients. Of the 7 variations, 5 (G87A-A29A, intervening sequence 9-3C>A, A1673G-H558R, G3578A-R1193Q, and T5457C D1819D) have been reported in previous studies, and 2 (C48G-F16L and G3048A T1016T) were novel variations that have not been reported. The 2 newly discovered variations were not found in the 80 normal controls. In addition, G298S, G514C, P1008S, G1406R, and D1595N, identified in other ethnic populations, were not detected in this study. We found 2 novel genetic variations in the SCN5A gene in Korean patients with AVB. However, further functional study might be needed. PMID- 23105939 TI - Sample size and statistical power calculation in genetic association studies. AB - A sample size with sufficient statistical power is critical to the success of genetic association studies to detect causal genes of human complex diseases. Genome-wide association studies require much larger sample sizes to achieve an adequate statistical power. We estimated the statistical power with increasing numbers of markers analyzed and compared the sample sizes that were required in case-control studies and case-parent studies. We computed the effective sample size and statistical power using Genetic Power Calculator. An analysis using a larger number of markers requires a larger sample size. Testing a single nucleotide polymorphism (SNP) marker requires 248 cases, while testing 500,000 SNPs and 1 million markers requires 1,206 cases and 1,255 cases, respectively, under the assumption of an odds ratio of 2, 5% disease prevalence, 5% minor allele frequency, complete linkage disequilibrium (LD), 1:1 case/control ratio, and a 5% error rate in an allelic test. Under a dominant model, a smaller sample size is required to achieve 80% power than other genetic models. We found that a much lower sample size was required with a strong effect size, common SNP, and increased LD. In addition, studying a common disease in a case-control study of a 1:4 case-control ratio is one way to achieve higher statistical power. We also found that case-parent studies require more samples than case-control studies. Although we have not covered all plausible cases in study design, the estimates of sample size and statistical power computed under various assumptions in this study may be useful to determine the sample size in designing a population-based genetic association study. PMID- 23105940 TI - Performance Comparison of Two Gene Set Analysis Methods for Genome-wide Association Study Results: GSA-SNP vs i-GSEA4GWAS. AB - Gene set analysis (GSA) is useful in interpreting a genome-wide association study (GWAS) result in terms of biological mechanism. We compared the performance of two different GSA implementations that accept GWAS p-values of single nucleotide polymorphisms (SNPs) or gene-by-gene summaries thereof, GSA-SNP and i-GSEA4GWAS, under the same settings of inputs and parameters. GSA runs were made with two sets of p-values from a Korean type 2 diabetes mellitus GWAS study: 259,188 and 1,152,947 SNPs of the original and imputed genotype datasets, respectively. When Gene Ontology terms were used as gene sets, i-GSEA4GWAS produced 283 and 1,070 hits for the unimputed and imputed datasets, respectively. On the other hand, GSA SNP reported 94 and 38 hits, respectively, for both datasets. Similar, but to a lesser degree, trends were observed with Kyoto Encyclopedia of Genes and Genomes (KEGG) gene sets as well. The huge number of hits by i-GSEA4GWAS for the imputed dataset was probably an artifact due to the scaling step in the algorithm. The decrease in hits by GSA-SNP for the imputed dataset may be due to the fact that it relies on Z-statistics, which is sensitive to variations in the background level of associations. Judicious evaluation of the GSA outcomes, perhaps based on multiple programs, is recommended. PMID- 23105941 TI - Characteristics in Molecular Vibrational Frequency Patterns between Agonists and Antagonists of Histamine Receptors. AB - To learn the differences between the structure-activity relationship and molecular vibration-activity relationship in the ligand-receptor interaction of the histamine receptor, 47 ligands of the histamine receptor were analyzed by structural similarity and molecular vibrational frequency patterns. The radial tree that was produced by clustering analysis of molecular vibrational frequency patterns shows its potential for the functional classification of histamine receptor ligands. PMID- 23105942 TI - Mechanisms Underlying Isovolumic Contraction and Ejection Peaks in Seismocardiogram Morphology. AB - A three-dimensional (3D) finite element electromechanical model of the heart is employed in simulations of seismocardiograms (SCGs). To simulate SCGs, a previously developed 3D model of ventricular contraction is extended by adding the mechanical interaction of the heart with the chest and internal organs. The proposed model reproduces the major peaks of seismocardiographic signals during the phases of the cardiac cycle. Results indicate that SCGs record the pressure of the heart acting on the ribs. In addition, the model reveals that the rotation of the rib with respect to the heart has a minor effect on seismocardiographic signal morphology during the respiratory cycle. SCGs are obtained from 24 human volunteers and their morphology is analyzed. Experimental results demonstrate that the peak of the maximum acceleration of blood in the aorta occurs at the same time as the global minimum of the SCG. It is confirmed that the first SCG peak after the electrocardiogram R-wave corresponds to aortic valve opening, as determined from the impedance cardiogram (p = 0.92). The simulation results reveal that the SCG peaks corresponding to aortic valve opening and the maximum acceleration of blood in the aorta result from ventricular contraction in the longitudinal direction of the ventricles and a decrease in the dimensions of the ventricles due to the ejection of blood, respectively. PMID- 23105943 TI - Closed-Form Approximations of First-Passage Distributions for a Stochastic Decision-Making Model. AB - In free response choice tasks, decision making is often modeled as a first passage problem for a stochastic differential equation. In particular, drift diffusion processes with constant or time-varying drift rates and noise can reproduce behavioral data (accuracy and response-time distributions) and neuronal firing rates. However, no exact solutions are known for the first-passage problem with time-varying data. Recognizing the importance of simple closed-form expressions for modeling and inference, we show that an interrogation or cued response protocol, appropriately interpreted, can yield approximate first-passage (response time) distributions for a specific class of time-varying processes used to model evidence accumulation. We test these against exact expressions for the constant drift case and compare them with data from a class of sigmoidal functions. We find that both the direct interrogation approximation and an error minimizing interrogation approximation can capture a variety of distribution shapes and mode numbers but that the direct approximation, in particular, is systematically biased away from the correct free response distribution. PMID- 23105944 TI - Is combination therapy for chronic hepatitis C toxic for cardiac function? AB - BACKGROUND: Many types of cardiovascular complications such as; cardiac arrhythmias, impaired cardiac function, myocardial ischemia and decreased left ventricular function, have been attributed to interferon therapy. OBJECTIVES: The aim of this study was to evaluate the effects of combination therapy pegylated interferon and ribavirin on left ventricular systolic and diastolic functions in patients with a chronic hepatitis C infection. PATIENTS AND METHODS: A total of 120 patients, eligible for hepatitis C virus (HCV) treatment with pegylated interferon and ribavirin, were included in this study. All patients underwent a full cardiovascular baseline examination including; detailed medical history, thorough clinical examination, 12 lead electrocardiogram (ECG), and echocardiography. A cardiac evaluation was performed at the beginning and six months after starting combination therapy. RESULTS: No significant changes regarding cardiac symptoms including; shortness of breath, cough, palpitations, chest pain and hypertension, were found during or six months after starting the combined therapy. ECG findings showed statistically non-significant decreases in the QT interval, while corrected QT showed statistically non-significant increases six months after beginning combined therapy, when compared to their values before treatment. Also with regard to the echocardiography findings, there was no statistically significant difference found between any of the echocardiography parameters six months after starting combined therapy compared to their values before treatment. CONCLUSIONS: The results of our study suggest that, combination therapy does not cause a significant deterioration in cardiac function in patients with a chronic hepatitis C infection, and it may be used safely in patients without cardiac disease. PMID- 23105945 TI - A molecular assay of tumor radiosensitivity: a roadmap towards biology-based personalized radiation therapy. AB - The last two decades have seen technological developments that have led to more accurate delivery of radiation therapy (RT), which has resulted in clinical gains in many solid tumors. However, a fundamental question and perhaps the next major hurdle is whether biological strategies can be developed to further enhance the effectiveness and efficiency of RT. This article addresses the development of a novel genomics-based molecular assay to predict tumor radiosensitivity, and proposes that this assay may prove pivotal in the development of biologically guided RT. PMID- 23105946 TI - Adhesion mechanism in a DOPA-deficient foot protein from green mussels(). AB - The holdfast or byssus of Asian green mussels, Perna viridis, contains a foot protein, pvfp-1, that differs in two respects from all other known adhesive mussel foot proteins (mfp): (1) instead of the hallmark L-3,4 dihydroxyphenylalanine (DOPA) residues in mfp-1, for example, pvfp-1 contains C(2)-mannosyl-7-hydroxytryptophan (Man7OHTrp). (2) In addition, pvfp-1 chains are not monomeric like mfp-1 but trimerized by collagen and coiled-coil domains near the carboxy terminus after a typical domain of tandemly repeated decapeptides. Here, the contribution of these peculiarities to adhesion was examined using a surface forces apparatus (SFA). Unlike previously studied mfp-1s, pvfp-1 showed significant adhesion to mica and, in symmetric pvfp-1 films, substantial cohesive interactions were present at pH 5.5. The role of Man7OHTrp in adhesion is not clear, and a DOPA-like role for Man7OHTrp in metal complexation (e.g., Cu(2+), Fe(3+)) was not observed. Instead, cation-pi interactions with low desolvation penalty between Man7OHTrp and lysyl side chains and conformational changes (raveling and unraveling of collagen helix and coiled-coil domains) are the best explanations for the strong adhesion between pvfp-1 monomolecular films. The strong adhesion mechanism induced by cation-pi interactions and conformational changes in pvfp-1 provides new insights for the development of biomimetic underwater adhesives. PMID- 23105947 TI - Opportunities in proteomics to understand hepatitis C and HIV coinfection. AB - Antiretroviral therapy has significantly reduced morbidity and mortality associated with HIV infection. However, coinfection with HCV results in a more complicated disease course for both infections. HIV infection dramatically impacts the natural history of chronic liver disease due to HCV. Coinfected patients not on antiretroviral therapy for HIV develop liver fibrosis and cirrhosis at a faster rate, clear acute infection less commonly and respond to IFN-alpha-based therapy for chronic infection less often than HCV-monoinfected patients. The interaction between these two viruses, the immune system and the fibrotic machinery of the liver remains incompletely understood. In this review, we discuss recent advances in proteomics as applied to HCV and HIV and highlight issues in coinfection that are amenable to further discovery through proteomic approaches. We focus on clinical predictors of liver fibrosis and treatment outcome as these have the greatest potential clinical applicability. PMID- 23105948 TI - What's special about human language? The contents of the "narrow language faculty" revisited. AB - In this review we re-evaluate the recursion-only hypothesis, advocated by Fitch, Hauser and Chomsky (Hauser, Chomsky & Fitch, 2002; Fitch, Hauser & Chomsky, 2005). According to the recursion-only hypothesis, the property that distinguishes human language from animal communication systems is recursion, which refers to the potentially infinite embedding of one linguistic representation within another of the same type. This hypothesis predicts (1) that non-human primates and other animals lack the ability to learn recursive grammar, and (2) that recursive grammar is the sole cognitive mechanism that is unique to human language. We first review animal studies of recursive grammar, before turning to the claim that recursion is a property of all human languages. Finally, we discuss other views on what abilities may be unique to human language. PMID- 23105949 TI - Substance-use disorders in adolescents and adults with ADHD: focus on treatment. AB - A high prevalence of comorbidity of ADHD and substance-use disorders (SUDs) has been shown in the literature. In this article, the literature for the treatment of adolescents and adults with co-occurring ADHD and SUD is examined. Findings from pharmacotherapy suggest mild improvement in ADHD without demonstrable changes in SUD unless the addiction was stabilized prior to treating the ADHD. No unique adverse effects, worsening of SUD, misuse or diversion of stimulants are reported in the included studies. Treating ADHD pharmacologically in individuals with ADHD plus SUD only has a modest impact on ADHD and SUD that is not observed in controlled trials. Limited data in adults with ADHD and brief abstinence of their SUD showed improvements in both ADHD and SUD with treatment. Further studies of cognitive behavioral therapy, sequencing of therapies and longer term treatment outcomes for groups with ADHD and active SUD are necessary. PMID- 23105951 TI - Reversible high blood CEA and CA19-9 concentrations in a diabetic patient. PMID- 23105950 TI - Essential tremor is not a neurodegenerative disease. AB - The pathophysiology of essential tremor (ET) remains unknown. Standard neuropathological studies have reported no consistent changes but a detailed study found neurodegeneration in all ET cases - 24% demonstrated lower brainstem Lewy body (LB) inclusions and 76% experienced a loss of cerebellar Purkinje cells (PCs) and its sequelae. We review the evidence on neurodegeneration in ET. The prevalence of LB inclusions in ET brains is similar to that in the asymptomatic general population. These incidental LB disease cases have evidence for reduced striatal tyrosine hydroxylase levels, as found in Parkinson's disease, but there is no evidence for reduced tyrosine hydroxylase levels in ET patients. Reduced mean PC counts in ET cases compared with the controls reported by some studies could not be replicated by others. Most ET cases have the same number of PCs as controls of a comparable age. Neither the lower brainstem LB inclusions nor the cerebellar PC loss represent the neurodegenerative basis of ET. Further studies are needed to determine the pathophysiology of ET. PMID- 23105952 TI - Breaking the Deadlock: Simultaneously Discovering Attribute Matching and Cluster Matching with Multi-Objective Metaheuristics. AB - In this paper, we present a data mining approach to address challenges in the matching of heterogeneous datasets. In particular, we propose solutions to two problems that arise in integrating information from different results of scientific research. The first problem, attribute matching, involves discovery of correspondences among distinct numeric features (attributes) that are used to characterize datasets that have been collected and analyzed in different research labs. The second problem, cluster matching, involves discovery of matchings between patterns (clusters) across datasets. We treat both of these problems together as a multi-objective optimization problem. A multi-objective metaheuristics algorithm is described to find the optimal solution and compared with the genetic algorithm. The utility of this approach is demonstrated in a series of experiments using synthetic and realistic datasets that are designed to simulate heterogeneous data from different sources. PMID- 23105953 TI - Minocycline prevents IL-6 increase after acute ischemic stroke. AB - Higher levels of the inflammatory biomarker interleukin-6 (IL-6) correlate with poor clinical outcome in acute ischemic stroke (AIS). Minocycline (MC) is a known anti-inflammatory agent; thus, the effect of MC on IL-6 in the first 24 h of AIS was investigated to determine potential anti-inflammatory activity. The Minocycline to Improve Neurologic Outcome in Stroke (MINOS) study was a non randomized dose-escalation (3.0-10.0 mg/kg) trial of IV MC for AIS within 6 h of onset. Plasma IL-6 samples were collected prior to MC treatment at 1, 24, and 72 h and compared to those collected in a separate observational study of blood biomarkers in AIS. IL-6 levels were measured by commercially available ELISA kits. The lower limit of detection for IL-6 was 1 pg/ml. Sixty MINOS subjects and 29 non-MINOS subjects were enrolled, and there was no difference in baseline stroke severity. There was no significant difference in IL-6 level pre-MC treatment at 1, 24, or 72 h. However, the odds of a non-detectable IL-6 at 24 h in MINOS were 8.94 (95% CI 2.62-30.46) compared with non-MINOS subjects. It is likely that even low doses of MC have a potent systemic anti-inflammatory effect in AIS. Whether this results in improved outcome will be tested in a randomized clinical trial. PMID- 23105954 TI - Expanding occupational sun safety to an outdoor recreation industry: a translational study of the Go Sun Smart program. AB - A successful occupational sun-protection program was translated to 67 ski areas where the effectiveness of two dissemination strategies was assessed. An industry professional association distributed materials to the resorts. Half of the resorts received the basic dissemination strategy (BDS) in which the materials were simply distributed to the resorts. In a randomized trial, the BDS was compared with an enhanced dissemination strategy (EDS) that added interpersonal contact with managers. Employees (n=2,228) at worksites that received the EDS had elevated program exposure (74.0% at EDS vs. 57.5% at BDS recalled a message). Exposure increased at two levels of program use: from less than four (55% exposed) to four to eight (68%) and to nine or more (82%) program items in use. More employees exposed to messages engaged in sun-safety behaviors than those unexposed. At worksites using nine or more items (versus 4-8 or <4), employees engaged in additional sun-safety behaviors. Program effects were strongly mediated by increased self-efficacy. Partnerships with industry associations facilitate dissemination of evidence-based programs. Dissemination methods are needed to maximize implementation and exposure to reduce health risk behaviors. PMID- 23105955 TI - Recent Developments in Shape-Controlled Synthesis of Silver Nanocrystals. AB - This feature article introduces our recent work on understanding the roles played by citrate and poly(vinyl pyrrolidone) (PVP) as capping agents in seed-mediated syntheses of Ag nanocrystals with controlled shapes. We have demonstrated that citrate and PVP selectively bind to Ag(111) and Ag(100) surfaces, respectively, and thus favor the formation of Ag nanocrystals enclosed preferentially by {111} or {100} facets. In addition, we have quantified the coverage density of PVP adsorbed on the surface of Ag nanocubes. Based on the mechanistic understanding, a series of Ag nanocrystals with controlled shapes and sizes have been successfully synthesized by using different combinations of seeds and capping agents: single-crystal spherical/cubic seeds with citrate for cuboctahedrons and octahedrons or with PVP for cubes and bars; and plate-like seeds with citrate for enlarged thin plates or with PVP for thickened plates. PMID- 23105956 TI - Predicting Breast Cancer Endocrine Responsiveness Using Molecular Imaging. AB - The estrogen receptor (ER) is expressed on the vast majority of newly diagnosed breast cancers, yet not all ER-positive tumors will respond to endocrine therapy. Selecting patients for endocrine therapy can be considered as a series of predictive tests: does the tumor express the ER and if so, will the endocrine therapy interact with the target to produce a response? These are both challenges to which molecular imaging is functionally suited. Imaging of the ER has been most successful using 16-alpha[18F]-flouro-17beta-estradiol (FES) positron emission tomography (PET). Functional imaging of the ER using FES-PET has been shown to be a predictive tool in determining response to endocrine therapy, and PET imaging of the ER can be used to measure the pharmacodynamic effect of ER directed endocrine therapy. This article reviews the literature on FES-PET as a functional tool in predicting response to endocrine therapy in breast cancer and discusses future directions. PMID- 23105957 TI - MANIFOLD LEARNING FOR ANALYSIS OF LOW-ORDER NONLINEAR DYNAMICS IN HIGH DIMENSIONAL ELECTROCARDIOGRAPHIC SIGNALS. AB - The dynamical structure of electrical recordings from the heart or torso surface is a valuable source of information about cardiac physiological behavior. In this paper, we use an existing data-driven technique for manifold identification to reveal electrophysiologically significant changes in the underlying dynamical structure of these signals. Our results suggest that this analysis tool characterizes and differentiates important parameters of cardiac bioelectric activity through their dynamic behavior, suggesting the potential to serve as an effective dynamic constraint in the context of inverse solutions. PMID- 23105958 TI - Evaluating the prognostic significance of FBXW7 expression level in human breast cancer by a meta-analysis of transcriptional profiles. AB - The tumor suppressor gene FBXW7 is mutated in numerous types of human cancers leading to loss of its function and/or expression. However the clinic significance of FBXW7 alterations remains largely unknown. Here, we carried out a meta-analysis of 10 gene expression microarray studies for a total 1900 patients of breast cancer with clinic information to evaluate the prognostic impact of FBXW7 mRNA expression. The FBXW7 mRNA levels significantly reduced in breast cancer compared to normal tissues. In addition, significant difference in the FBXW7 mRNA levels was found among molecular subtypes (normal-like, luminal A, luminal B, ERBB2 and basal). ERBB2 and basal tumors had significantly lower average FBXW7 mRNA level than normal-like tumors, whereas luminal A and B tumors have the lowest average FBXW7 mRNA level. The patients with higher FBXW7 mRNA level significantly increased disease-free survival, particularly in the group of patients with ER negative and basal subtype tumors. Moreover, higher FBXW7 mRNA level also significantly increased overall survival in the patients with ER negative tumors. But we strikingly found opposite effect of FBXW7 expression on overall survival in different subtypes. The patients with higher FBXW7 mRNA level significantly decreased overall survival in normal-like subtype while the patients with higher FBXW7 mRNA level significantly increased overall survival in ERBB2 and Basal subtype. Taken together, our results suggest that FBXW7 mRNA levels were a prognostic factor for disease-free and overall survival according to ER status and molecular subtypes. PMID- 23105960 TI - Refugees' views of the effectiveness of support provided by their host countries. AB - BACKGROUND: The war in former Yugoslavia, which commenced in 1990, caused the biggest refugee crisis in Europe since World War II. There are numerous research investigations into the trauma and associated problems. However, there is no available publication concerning refugees' own perception of the provided support in host countries. AIMS: To investigate how refugees evaluated support received (helpful or detrimental) and what kinds of support they wish to receive in the future. METHOD: The study participants were 854 refugees from former Yugoslavia settled in the United Kingdom, Germany, and Italy. Alongside demographic data, they were assessed using International Neuropsychiatric Interview (MINI), Life Stressor Checklist-Revised (LSC-R), Manchester Short Assessment of Quality of Life (MANSA), Matrix for Recording Health Care, Social Interventions (MACSI), and an open questions interview. RESULTS: Data revealed that 99.3% of refugees received some kind of support. The most frequent support (98.7%) was primary health care and the least frequent (34.7%) was support in employment and further training. The most helpful (27.5%) was primary health care, and the most detrimental (11.6%) was legal support. The most desired types of support were help in employment (31.8%) and further education/training (20.5%). The educational level of refugees affected their perceptions of support as detrimental or desired. CONCLUSIONS: There are different levels of received and desired support among host countries. There are also differences in the perception of received and desired support with regard to the refugees' educational levels. PMID- 23105959 TI - Practical dynamic contrast enhanced MRI in small animal models of cancer: data acquisition, data analysis, and interpretation. AB - Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) consists of the continuous acquisition of images before, during, and after the injection of a contrast agent. DCE-MRI allows for noninvasive evaluation of tumor parameters related to vascular perfusion and permeability and tissue volume fractions, and is frequently employed in both preclinical and clinical investigations. However, the experimental and analytical subtleties of the technique are not frequently discussed in the literature, nor are its relationships to other commonly used quantitative imaging techniques. This review aims to provide practical information on the development, implementation, and validation of a DCE-MRI study in the context of a preclinical study (though we do frequently refer to clinical studies that are related to these topics). PMID- 23105962 TI - A Copper-Catalyzed Arylation of Tryptamines for the Direct Synthesis of Aryl Pyrroloindolines. AB - An operationally simple, copper-catalyzed arylation of N-tosyltryptamines provides direct access to C3-aryl pyrroloindolines. A range of electron-donating and electron-withdrawing substituents is tolerated on both the indole backbone and the aryl electrophile. These reactions occur under ambient temperatures and with equimolar quantities of the coupling partners. PMID- 23105963 TI - Effects of Aerobic Fitness and Adiposity on Coagulation Biomarkers in Men vs. Women with Elevated Blood Pressure. AB - A hypercoagulable state is a potential mechanism linking elevated blood pressure (BP), adiposity and a sedentary lifestyle to development of coronary heart disease (CHD). We examined relationships among aerobic fitness and adiposity in 76 sedentary subjects with elevated BP. Blood levels of plasminogen activator inhibitor-1 (PAI-1), D-dimer, von Willebrand factor (vWF) and thrombomodulin were assessed as biomarkers of coagulation. In individuals with elevated BP, percent body fat and fitness were associated with biomarkers indicative of a hypercoagulable state, even after demographic and metabolic factors were considered. D-dimer was positively associated with percent body fat (beta=0.37, p=0.003). PAI-1 was higher in men than in women (beta=-0.31, p=0.015) and associated with lower VO2peak (beta=-0.35, p=0.024). Thrombomodulin was positively associated with VO2peak (beta=0.56, p< 0.01). vWF was not significantly associated with fitness or adiposity. Our results emphasise that both percent body fat and physical fitness are important in the maintenance of haemostatic balance. PMID- 23105964 TI - Role of practice-based research networks in comparative effectiveness research. AB - Comparative effectiveness research fundamentally reorients how clinical evidence is generated and used with the goal of providing actionable information to decision-makers. To achieve this, it is vital that decision-makers and the research enterprise are engaged from research inception, to evidence generation and translation. Practice-based research networks are affiliated clinicians in diverse communities with the goal of conducting research to improve care. Practice-based research networks have the potential to advance all phases of the comparative effectiveness research cycle. The aim of this paper is to explore current and potential roles of practice-based research networks in conducting comparative effectiveness research. PMID- 23105961 TI - Pulmonary circulation at exercise. AB - The pulmonary circulation is a high-flow and low-pressure circuit, with an average resistance of 1 mmHg/min/L in young adults, increasing to 2.5 mmHg/min/L over four to six decades of life. Pulmonary vascular mechanics at exercise are best described by distensible models. Exercise does not appear to affect the time constant of the pulmonary circulation or the longitudinal distribution of resistances. Very high flows are associated with high capillary pressures, up to a 20 to 25 mmHg threshold associated with interstitial lung edema and altered ventilation/perfusion relationships. Pulmonary artery pressures of 40 to 50 mmHg, which can be achieved at maximal exercise, may correspond to the extreme of tolerable right ventricular afterload. Distension of capillaries that decrease resistance may be of adaptative value during exercise, but this is limited by hypoxemia from altered diffusion/perfusion relationships. Exercise in hypoxia is associated with higher pulmonary vascular pressures and lower maximal cardiac output, with increased likelihood of right ventricular function limitation and altered gas exchange by interstitial lung edema. Pharmacological interventions aimed at the reduction of pulmonary vascular tone have little effect on pulmonary vascular pressure-flow relationships in normoxia, but may decrease resistance in hypoxia, unloading the right ventricle and thereby improving exercise capacity. Exercise in patients with pulmonary hypertension is associated with sharp increases in pulmonary artery pressure and a right ventricular limitation of aerobic capacity. Exercise stress testing to determine multipoint pulmonary vascular pressures-flow relationships may uncover early stage pulmonary vascular disease. PMID- 23105965 TI - Comparative effectiveness research in chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease affects millions worldwide. It is America's third leading cause of death, and results in significant morbidity and cost. Although many therapies exist and are being developed to alleviate symptoms and decrease morbidity and mortality in chronic obstructive pulmonary disease, most have only been studied in placebo-controlled efficacy studies in highly selected populations. Comparative effectiveness and translational research in chronic obstructive pulmonary disease will require the development of infrastructures to support collaboration between researchers and the stakeholders who generate, disseminate and use new knowledge. Methodologies need to evolve to both prioritize research questions and to conduct collaborative comparative effectiveness research studies. Given the impracticality of testing every clinical intervention in comparative pragmatic trials for comparative effectiveness research in chronic obstructive pulmonary disease, we advocate expanding methodology that includes the use of observational databases with serially performed effectiveness analyses and quasi-experimental designs that include following healthcare changes longitudinally over time to assess benefit, harm, subgroups and cost. PMID- 23105966 TI - Prioritizing comparative effectiveness research for cancer diagnostics using a regional stakeholder approach. AB - AIMS: This paper describes our process to engage regional stakeholders for prioritizing comparative effectiveness research (CER) in cancer diagnostics. We also describe a novel methodology for incorporating stakeholder data and input to inform the objectives of selected CER studies. MATERIALS & METHODS: As an integrated component to establishing the infrastructure for community-based CER on diagnostic technologies, we have assembled a regional stakeholder group composed of local payers, clinicians and state healthcare representatives to not only identify and prioritize CER topics most important to the western Washington State region, but also to inform the study design of selected research areas. A landscape analysis process combining literature searches, expert consultations and stakeholder discussions was used to identify possible CER topics in cancer diagnostics. Stakeholders prioritized the top topics using a modified Delphi/group-nominal method and a standardized evaluation criteria framework to determine a final selected CER study area. Implementation of the selected study was immediate due to a unique American Recovery and Reinvestment Act funding structure involving the same researchers and stakeholders in both the prioritization and execution phases of the project. Stakeholder engagement was enhanced after study selection via a rapid analysis of a subset of payers' internal claims, coordinated by the research team, to obtain summary data of imaging patterns of use. Results of this preliminary analysis, which we termed an 'internal analysis,' were used to determine with the stakeholders the most important and feasible study objectives. RESULTS: Stakeholders identified PET and MRI in cancers including breast, lung, lymphoma and colorectal as top priorities. In an internal analysis of breast cancer imaging, summary data from three payers demonstrated utilization rates of advanced imaging increased between 2002 and 2009 in the study population, with a great deal of variability in use between different health plans. Assessing whether breast MRI affects treatment decisions was the top breast cancer study objective selected by the stakeholders. There were other high-priority research areas including whether MRI use improved survival that were not deemed feasible with the length of follow-up time following MRI adoption. CONCLUSION: Continuous stakeholder engagement greatly enhanced their enthusiasm for the project. We believe CER implementation will be more successful when undertaken by regional stakeholders. PMID- 23105967 TI - When not to copy: female fruit flies use sophisticated public information to avoid mated males. AB - Semen limitation (lack of semen to fertilize all of a female's eggs) imposes high fitness costs to female partners. Females should therefore avoid mating with semen-limited males. This can be achieved by using public information extracted from watching individual males' previous copulating activities. This adaptive preference should be flexible given that semen limitation is temporary. We first demonstrate that the number of offspring produced by males Drosophila melanogaster gradually decreases over successive copulations. We then show that females avoid mating with males they just watched copulating and that visual public cues are sufficient to elicit this response. Finally, after males were given the time to replenish their sperm reserves, females did not avoid the males they previously saw copulating anymore. These results suggest that female fruit flies may have evolved sophisticated behavioural processes of resistance to semen limited males, and demonstrate unsuspected adaptive context-dependent mate choice in an invertebrate. PMID- 23105968 TI - Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs. AB - Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS. PMID- 23105969 TI - Spontaneous knotting of self-trapped waves. AB - We describe theory and simulations of a spinning optical soliton whose propagation spontaneously excites knotted and linked optical vortices. The nonlinear phase of the self-trapped light beam breaks the wave front into a sequence of optical vortex loops around the soliton, which, through the soliton's orbital angular momentum and spatial twist, tangle on propagation to form links and knots. We anticipate similar spontaneous knot topology to be a universal feature of waves whose phase front is twisted and nonlinearly modulated, including superfluids and trapped matter waves. PMID- 23105970 TI - Transparent, flexible supercapacitors from nano-engineered carbon films. AB - Here we construct mechanically flexible and optically transparent thin film solid state supercapacitors by assembling nano-engineered carbon electrodes, prepared in porous templates, with morphology of interconnected arrays of complex shapes and porosity. The highly textured graphitic films act as electrode and current collector and integrated with solid polymer electrolyte, function as thin film supercapacitors. The nanostructured electrode morphology and the conformal electrolyte packaging provide enough energy and power density for the devices in addition to excellent mechanical flexibility and optical transparency, making it a unique design in various power delivery applications. PMID- 23105971 TI - Counterflow dielectrophoresis for trypanosome enrichment and detection in blood. AB - Human African trypanosomiasis or sleeping sickness is a deadly disease endemic in sub-Saharan Africa, caused by single-celled protozoan parasites. Although it has been targeted for elimination by 2020, this will only be realized if diagnosis can be improved to enable identification and treatment of afflicted patients. Existing techniques of detection are restricted by their limited field applicability, sensitivity and capacity for automation. Microfluidic-based technologies offer the potential for highly sensitive automated devices that could achieve detection at the lowest levels of parasitemia and consequently help in the elimination programme. In this work we implement an electrokinetic technique for the separation of trypanosomes from both mouse and human blood. This technique utilises differences in polarisability between the blood cells and trypanosomes to achieve separation through opposed bi-directional movement (cell counterflow). We combine this enrichment technique with an automated image analysis detection algorithm, negating the need for a human operator. PMID- 23105972 TI - Simultaneous detection of ricin and abrin DNA by real-time PCR (qPCR). AB - Ricin and abrin are two of the most potent plant toxins known and may be easily obtained in high yield from the seeds using rather simple technology. As a result, both toxins are potent and available toxins for criminal or terrorist acts. However, as the production of highly purified ricin or abrin requires sophisticated equipment and knowledge, it may be more likely that crude extracts would be used by non-governmental perpetrators. Remaining plant-specific nucleic acids in these extracts allow the application of a real-time PCR (qPCR) assay for the detection and identification of abrin or ricin genomic material. Therefore, we have developed a duplex real-time PCR assays for simultaneous detection of ricin and abrin DNA based on the OmniMix HS bead PCR reagent mixture. Novel primers and hybridization probes were designed for detection on a SmartCycler instrument by using 5'-nuclease technology. The assay was thoroughly optimized and validated in terms of analytical sensitivity. Evaluation of the assay sensitivity by probit analysis demonstrated a 95% probability of detection at 3 genomes per reaction for ricin DNA and 1.2 genomes per reaction for abrin DNA. The suitability of the assays was exemplified by detection of ricin and abrin contaminations in a food matrix. PMID- 23105974 TI - A three-year survey on the worldwide occurrence of mycotoxins in feedstuffs and feed. AB - Between January 2009 and December 2011, a total of 7049 corn, soybean/soybean meal, wheat, dried distillers grains with solubles (DDGS) and finished feed samples were analyzed for the occurrence of aflatoxins (Afla), zearalenone (ZEN), deoxynivalenol (DON), fumonisins (FUM) and ochratoxin A (OTA). Samples were sourced in the Americas, Europe and Asia. Afla, ZEN, DON, FUM and OTA were present respectively in 33%, 45%, 59% 64% and 28% of analyzed samples between 2009 and 2011. From the 23,781 mycotoxin analyzes performed, 81% were positive for at least one mycotoxin. Results of this survey are provided by calendar year, in order to potentially show different trends on mycotoxin occurrence in distinct years: by commodity type and within the same commodity, and by region, to potentially reveal differences in mycotoxin contamination in commodities sourced in diverse regions. PMID- 23105973 TI - Comparative immunohistochemical analysis of ochratoxin A tumourigenesis in rats and urinary tract carcinoma in humans; mechanistic significance of p-S6 ribosomal protein expression. AB - Ochratoxin A (OTA) is considered to be a possible human urinary tract carcinogen, based largely on a rat model, but no molecular genetic changes in the rat carcinomas have yet been defined. The phosphorylated-S6 ribosomal protein is a marker indicating activity of the mammalian target of rapamycin, which is a serine/threonine kinase with a key role in protein biosynthesis, cell proliferation, transcription, cellular metabolism and apoptosis, while being functionally deregulated in cancer. To assess p-S6 expression we performed immunohistochemistry on formalin-fixed and paraffin-embedded tumours and normal tissues. Marked intensity of p-S6 expression was observed in highly proliferative regions of rat renal carcinomas and a rare angiosarcoma, all of which were attributed to prolonged exposure to dietary OTA. Only very small OTA-generated renal adenomas were negative for p-S6. Examples of rat subcutaneous fibrosarcoma and testicular seminoma, as well as of normal renal tissue, showed no or very weak positive staining. In contrast to the animal model, human renal cell carcinoma, upper urinary tract transitional cell carcinoma from cases of Balkan endemic nephropathy, and a human angiosarcoma were negative for p-S6. The combined findings are reminiscent of constitutive changes in the rat tuberous sclerosis gene complex in the Eker strain correlated with renal neoplasms, Therefore rat renal carcinogenesis caused by OTA does not obviously mimic human urinary tract tumourigenesis. PMID- 23105975 TI - Macrophage-targeted therapy: CD64-based immunotoxins for treatment of chronic inflammatory diseases. AB - Diseases caused by chronic inflammation (e.g., arthritis, multiple sclerosis and diabetic ulcers) are multicausal, thus making treatment difficult and inefficient. Due to the age-associated nature of most of these disorders and the demographic transition towards an overall older population, efficient therapeutic intervention strategies will need to be developed in the near future. Over the past decades, elimination of activated macrophages using CD64-targeting immunotoxins has proven to be a promising way of resolving inflammation in animal models. More recent data have shown that the M1-polarized population of activated macrophages in particular is critically involved in the chronic phase. We recapitulate the latest progress in the development of IT. These have advanced from full-length antibodies, chemically coupled to bacterial toxins, into single chain variants of antibodies, genetically fused with fully human enzymes. These improvements have increased the range of possible target diseases, which now include chronic inflammatory diseases. At present there are no therapeutic strategies focusing on macrophages to treat chronic disorders. In this review, we focus on the role of different polarized macrophages and the potential of CD64 based IT to intervene in the process of chronic inflammation. PMID- 23105976 TI - Aspergillus oxylipin signaling and quorum sensing pathways depend on g protein coupled receptors. AB - Oxylipins regulate Aspergillus development and mycotoxin production and are also involved in Aspergillus quorum sensing mechanisms. Despite extensive knowledge of how these oxylipins are synthesized and what processes they regulate, nothing is known about how these signals are detected and transmitted by the fungus. G protein-coupled receptors (GPCR) have been speculated to be involved as they are known oxylipin receptors in mammals, and many putative GPCRs have been identified in the Aspergilli. Here, we present evidence that oxylipins stimulate a burst in cAMP in A. nidulans, and that loss of an A. nidulans GPCR, gprD, prevents this cAMP accumulation. A. flavus undergoes an oxylipin-mediated developmental shift when grown at different densities, and this regulates spore, sclerotial and aflatoxin production. A. flavus encodes two putative GprD homologs, GprC and GprD, and we demonstrate here that they are required to transition to a high density development state, as well as to respond to spent medium of a high density culture. The finding of GPCRs that regulate production of survival structures (sclerotia), inoculum (spores) and aflatoxin holds promise for future development of anti-fungal therapeutics. PMID- 23105977 TI - Intranasal rapamycin rescues mice from staphylococcal enterotoxin B-induced shock. AB - Staphylococcal enterotoxin B (SEB) and related exotoxins produced by Staphylococcus aureus are potent activators of the immune system and cause toxic shock in humans. Currently there is no effective treatment except for the use of intravenous immunoglobulins administered shortly after SEB exposure. Intranasal SEB induces long-lasting lung injury which requires prolonged drug treatment. We investigated the effects of rapamycin, an immunosuppressive drug used to prevent graft rejection, by intranasal administration in a lethal mouse model of SEB induced shock. The results show that intranasal rapamycin alone delivered as late as 17 h after SEB protected 100% of mice from lethal shock. Additionally, rapamycin diminished the weight loss and temperature fluctuations elicited by SEB. Intranasal rapamycin attenuated lung MCP-1, IL-2, IL-6, and IFNgamma by 70%, 30%, 64%, and 68% respectively. Furthermore, short courses (three doses) of rapamycin were sufficient to block SEB-induced shock. Intranasal rapamycin represents a novel use of an immunosuppressant targeting directly to site of toxin exposure, reducing dosages needed and allowing a wider therapeutic window. PMID- 23105978 TI - Interaction between Shiga toxin and monoclonal antibodies: binding characteristics and in vitro neutralizing abilities. AB - Monoclonal antibodies (MAbs) have been employed either for diagnosis or treatment of infections caused by different pathogens. Specifically for Shiga toxin producing Escherichia coli (STEC), numerous immunoassays have been developed for STEC diagnosis, showing variability in sensitivity and specificity when evaluated by reference laboratories, and no therapy or vaccines are currently approved. Thus, the aim of this work was the characterization of the interaction between MAbs against Stx1 and Stx2 toxins and their neutralizing abilities to enable their use as tools for diagnosis and therapy. The selected clones designated 3E2 (anti-Stx1) and 2E11 (anti-Stx2) were classified as IgG1. 3E2 recognized the B subunit of Stx1 with an affinity constant of 2.5 * 10(-10) M, detected as little as 6.2 ng of Stx1 and was stable up to 50 oC. In contrast, 2E11 recognized the A subunit of Stx2, was stable up to 70 oC, had a high dissociation constant of 6.1 * 10(-10) M, and detected as little as 12.5 ng of Stx2. Neutralization tests showed that 160 ng of 3E2 MAb inhibited 80% of Stx1 activity and 500 ug 2E11 MAb were required for 60% inhibition of Stx2 activity. These MAb amounts reversed 25 to 80% of the cytotoxicity triggered by different STEC isolates. In conclusion, these MAbs show suitable characteristics for their use in STEC diagnosis and encourage future studies to investigate their protective efficacy. PMID- 23105980 TI - The Effect of Gender, Age, and Nationality on the Personal Space Preferences in Children's Hospitals among Iranian and German Children and Adolescents. AB - BACKGROUND: Patients in the therapeutic environment worry about their health and therapy; they are away from their usual social activities, and these entire put a great deal of stress on them, and delay their therapy by affecting their immune system and reducing their spiritual power. OBJECTIVES: The present study seeks to investigate the effect of gender, age, and nationality of children on their personal space preferences during hospital stay in children's hospitals the dependent variable, i.e., personal space preference, was measured in hospital rooms with or without a barrier to separate children's beds. (Barriers could be curtains or walls). PATIENTS AND METHODS: The research method was descriptive survey research, and the participants included 120 Iranian children staying at Tehran children's hospitals and 104 German children staying at Stuttgart's children hospitals, who were chosen through stratified random sampling.(in all wards except infectious wards) The data was gathered through self report questionnaires and analyzed conducting categorical methods of Logic Log Linear Analysis and Logistic Regression methods using the SPSS software. RESULTS: The results show that Iranian children, contrary to German children, prefer a space without any barrier, and that girls prefer closed spaces more than boys. Regarding the age, it was revealed that children and adolescents have nearly similar preferences. Finally, remarkable differences were found among groups with regard to their desired kind of barrier. CONCLUSIONS: Preferring a space without a barrier, which provides more chances for social interaction among individuals, shows that the majority of children prefer to have social interactions and contacts in the hospital that is in line with the results of similar studies. Last preference (separating the beds with curtains) was not generally favored by the respondents, which is in line with the results of similar studies in 2006. PMID- 23105981 TI - High Rate of Virological Response to Peginterferon alpha-2a-Ribavirin Among Non Cirrhotic Iranian Hemophilia Patients With Chronic Hepatitis C. AB - BACKGROUND: Hepatitis C is a major reason of morbidity and mortality among hemophilia patients. Although combination therapy with peginterferon (peg-INF) and ribavirin is considered as standard treatment for chronic hepatitis C (CHC), but more evidence of the efficacy and safety is needed. OBJECTIVES: In this study, efficacy and tolerability of combination therapy with peginterferon alpha 2a-ribavirin was investigated among hemophilia HCV infected patients. PATIENTS AND MATERIALS: In a quasi-experimental, 45 naive hemophilia patients with chronic HCV received 180 mg of pegylated interferon (Pegasys) by subcutaneous injection weekly plus an oral dose of 800-1200 ug ribavirin daily according to body weight. The treatment continued 48 weeks in patients with genotype one and 24 weeks in those with genotype 3. Sustained virological response (SVR) was considered as efficacy of treatment. RESULT: Forty three patients (95.6%) reached to end of treatment response (ETR); only two (4.4%) patients did not respond and were discontinued from treatment. None of 43 patients relapsed. SVR obtained in 43 of 45 patients (95.6%), in multivariate logistic regression model, third month's treatment WBC (WBC > 2000) remained the only significant predictor of SVR. Regimen dose reduced in three patients; two of those because of ALT increasing and other one for his retinal bleeding. In repeated measurement analysis, alanine aminotransferase (ALT) and hemoglobin (Hb) decreased significantly during treatment, but reduction of platelet (PLT) was not significant. CONCLUSIONS: Results show high efficacy and safety of combination therapy of Peg-IFN-alpha 2a plus ribavirin among hemophiliacs with chronic hepatitis C. PMID- 23105979 TI - The biological control of the malaria vector. AB - The call for malaria control, over the last century, marked a new epoch in the history of this disease. Many control strategies targeting either the Plasmodium parasite or the Anopheles vector were shown to be effective. Yet, the emergence of drug resistant parasites and insecticide resistant mosquito strains, along with numerous health, environmental, and ecological side effects of many chemical agents, highlighted the need to develop alternative tools that either complement or substitute conventional malaria control approaches. The use of biological means is considered a fundamental part of the recently launched malaria eradication program and has so far shown promising results, although this approach is still in its infancy. This review presents an overview of the most promising biological control tools for malaria eradication, namely fungi, bacteria, larvivorous fish, parasites, viruses and nematodes. PMID- 23105982 TI - Prevalence of hepatitis B and C infections and HCV genotypes among haemophilia patients in ahvaz, southwest iran. AB - BACKGROUND: Transfusion-transmitted hepatitis is the most important cause of transmitted infections by the parenteral route in patients with haemophilia. OBJECTIVES: This study was performed to determine the prevalence of HBV, HCV, and different genotypes of HCV among haemophilia patients in Ahvaz city, southwest Iran. PATIENTS AND METHODS: A cross-sectional study was conducted on 87 haemophilia patients referred to the Hemoglobinopathy and Thalassemia research centre during February 2008 to March 2009. Patients, sera were tested for HBsAg and anti-HCV using ELISA and confirmed by PCR (HBV) and RT-PCR (HCV). HCV genotypes were determined with HCV genotype specific primers using HCV genotyping kit. RESULTS: The overall prevalence rate of HBsAg and anti-HCV were 1.1% (95% CI: 0-3.39) and 54% (95% CI: 43.5-64.4), respectively. Forty two of the anti-HCV patients (89.3%) were also HCV RNA positive. The prevalence of anti-HCV seropositivity was significantly higher (P = 0.0008) among patients who had started to receive transfusions before implementation of blood donor screening. Moreover, the number of transfusion were significantly associated with anti-HCV and HCV RNA positivity (P = 0.0041 and P = 0.023, respectively). The predominant HCV genotype among haemophilia patients in our region was 1a (26/42, 61.9%), although genotypes 1b and 3a were found in 26.1% (11/42) and 11.9% (5/42) of the patients, respectively. CONCLUSIONS: It appears stringent donor selection procedures reduced HCV infection in multi-transfused patients, but it is still serious risk for these subjects. PMID- 23105983 TI - Quick Diagnosis in Obstructive Sleep Apnea Syndrome: WatchPAT-200. AB - BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is a highly prevelant disorder and found in approximately 2-4% of middle-aged adults. OBJECTIVES: To assess the efficacy of Watch-PAT-200 in the diagnosis of obstructive sleep apnea syndrome (OSAS). PATIENTS AND METHODS: Patients suspected of having OSAS underwent overnight Level I polisomnography and simultaneously wore Watch-PAT-200 in the sleep laboratory. RESULTS: 51 adult patients included in the study. The average age was 45.3+/-10.5 years and the average body mass index (BMI) was 29.4+/-4.0 kg/m2. There was a high agreement between PSG and Watch PAT regarding apnea-hypopnea index, respiratory disturbance index and oxygen desaturation index. Significant but a low agreement was found in stage 1 and 2 of non-REM sleep when two methods compared. No agreement was found between PSG and Watch-PAT regarding stage 3 and 4 of non-REM sleep. Very low agreement was found between PSG and Watch-PAT regarding the REM sleep. CONCLUSIONS: Watch-PAT-200 is an effective method in the diagnosis of OSAS. PMID- 23105984 TI - Investigate the Role of Glutathione S Transferase (GST) Polymorphism in Development of Hypertension in UAE Population. AB - BACKGROUND: GST is a family of enzymes that are important in protection of the body against oxidative stress. OBJECTIVES: Investigate the association between GSTT1 and GSTM1 polymorphism and hypertension. MATERIALS AND METHODS: GSTT1 and GSTM1 genotypes were detected by PCR. The fragments were then analyzed by agarose gel electrophoresis. RESULTS: There is no significant association between GSTT1 & GSTM1 polymorphism and hypertension (OR = 2.4, P > 0.05 and OR = 1.6, P > 0.05) CONCLUSIONS: GSTT1 & GSTM1 polymorphism can be considered a risk factor for hypertension. PMID- 23105985 TI - Effect of Pentoxifylline Administration on Mast Cell Numbers and Degranulation in a Diabetic and Normoglycemic rat Model Wound Healing. AB - BACKGROUND: Wound healing is a complicated and integrated process. Researches in the molecular level on human and animal models have indicated several molecular changes related to the effect of diabetes on wound healing process. OBJECTIVES: Increasing number of researches implicates the influence of mast cells on skin wound repairing. In this study the effect of systemic pentoxifylline (PTX) administration (daily dose of 25mg/kg twice a day, for 7 consecutive days) on normoglycemic (NG) and diabetic (DB) wistar rat's wound healing by secondary intention was studied. MATERIALS AND METHODS: In this study forty eight wistar rats (weighting 250-350g) were divided randomly in two groups: Normoglycemic and diabetic, each group was divided into experimental and control groups, experimental received intraperitoneal (PTX) and controls received distilled water (DW). The number and maturing process of mast cells was evaluated by counting the number of types of mast cells [1][2][3] microscopically and by stereological methods on day 3 and 7 after surgery. RESULTS: In this study it was cleared that in wound healing process PTX caused increasing the number of type 2 mast cells in all experimental groups(P = 0.00). In normoglycemic experimental group, receiving PTX there was decrease in the number of type3 mast cells, comparing experimental NG groups (P = 0.00). CONCLUSIONS: In all PTX treated groups delay in converting type 2 into type 3 mast cell was seen. Pentoxifylline causes decreasing mast cell degranulation in wound healing process. PMID- 23105986 TI - A Comparison of Blood-lead Level (BLL) in Opium-dependant Addicts With Healthy Control Group Using the Graphite Furnace/atomic Absorption Spectroscopy (GF-AAS) Followed by Chemometric Analysis. AB - BACKGROUND: A comparison of oral/inhaled opium addicts with a healthy control group was investigated. Using the graphite furnace atomic absorption spectroscopy (GF-AAS) followed by chemometric analysis, sub-to-low ug L-1 concentrations of blood lead level (BLL) was detected in both the addict and the control groups. MATERIALS AND METHODS: In this study, BLL of 78 subjects (Iranian volunteers) in two opium-addicted (patient group) and healthy control groups was evaluated. All the volunteers were men. The patient group was comprised of 39 patients who used opium orally or by inhalation with a mean age of 48.6 +/- 7.3 years. The patient group was selected through systematic incidental sampling from 150 orally or by inhalation opium-addicted patients referred to Shariati Hospital located in Tehran .The control group (39 subjects) was matched with the patient group with regard to age and sex and with a mean age of 44.8 +/- 5.6 years. RESULTS: The mean concentration of lead was found to be significantly lower (P = 0.0001) in control group (16.70 +/- 12.51 MUg/dL) compared to addicts (57.04 +/- 46.03 MUg/dL). When the addicts were divided into various age groups, there appeared to be a significant difference (p= 0.0451) in blood lead concentration as a function of age, however when the control group was considered, no difference was observed (P = 0.51). Also, a tendency (P = 0.048) towards increasing BLL with respect to BMI was observed due to drug consumption, but there was no significant variation between BLL concentration and BMI when the control group was considered (P = 0.35). CONCLUSIONS: It was observed that the BLL in opium-addicts was significantly higher than that of the healthy control group. The mean difference of both groups was statistically significant. PMID- 23105987 TI - Nasopharyngeal carcinoma with skull base erosion cytologic findings. AB - Nasopharyngeal carcinoma (NPC) occurs more frequently in patients with south-east Asian racial backgrounds. This disease may spreads superiorly to the skull base and intracranium followed by skull base destruction. We report a 56 year-old man presented with headache and diplopia. Magnetic resonance imaging (MRI) revealed extension of destructive mass from ethmoid sinus to the parenchyma. Intraoperative touch cytology showed loose syncytial sheets of pleomorphic abnormal epithelial cells, dyskeratotic cells with abnormal chromatin clumping and irregular nuclear outlines, in a necrotic background. These findings were infavor of keratizing squamous cell carcinoma which was confirmed by histopathology. During interpretation of intraoperative imprint cytology of central nervous system tumors, the possibility of local invasive tumors like NPC should be considered. PMID- 23105988 TI - Bilateral Cochlear Implantation in Meningitis, Is it Mandatory? A Case Report. AB - These days cochlear implantation is the accepted modality to rehabilitate deafened people. Meningitis is still a life threatening disease which may lead to deafness due to sole disease or secondary to ototoxic drugs used to stop the disaster [1]. Sepsis and/or meningitis may harm neonates whom are taking care in nurseries. TEOAE neonatal hearing screening programs are unable to find all of these deafened children and ABR would be necessary to explore most of them [2].Cochlear implantation should be performed as soon as possible and before complete ossification of cochlea. PMID- 23105989 TI - Guillain-Barre-like Syndrome, as a Rare Presentation of Adult T-cell Leukemia Lymphoma (ATLL): A Case Report. AB - We report a 21-year-old woman who was admitted because of unilateral facial paresis and then developed progressive ascending flaccid tetraparesis with generalized areflexia. Electrodiagnostic studies revealed acute motor axonal polyradiculoneuropathy (AMAN type of Guillain-Barre Syndrome). Further evaluations revealed severe leukocytosis, increased erythrocyte sedimentation rate (ESR), increased protein content and presence of a few lymphocytes in cerebrospinal fluid (CSF), and then presence of human T-cell lymphotropic virus type 1 (HTLV-I) in serum and CSF. Finally, biopsy of the enlarged lymph nodes resulted in the diagnosis of Adult T-cell Leukemia-Lymphoma. The HTLV-1 has been endemic to certain parts of Iran like Khorasan province in the northeast since 1985 with 2.3% prevalence rate of infection. Thus, some rare neurologic complications occasionally occur in this area as a result of being infected with HTLV-1. PMID- 23105990 TI - Lichen planopilaris: histopathological study of vertical sections of scalp biopsies in 44 patients. PMID- 23105991 TI - Abdominal tuberculosis with a cocoon. PMID- 23105992 TI - Seasonal Effects on Bell's Palsy: Four-Year Study and Review of the Literature. PMID- 23105993 TI - Interaction among hormones or peptides may be involved in gastric motor physiology. PMID- 23105994 TI - Hot water swallows may improve symptoms in patients with achalasia. PMID- 23105995 TI - Biomechanics of esophageal function in eosinophilic esophagitis. AB - Eosinophilic Esophagitis (EoE) is a chronic inflammatory disease of the esophagus triggered by an immune response that leads to symptoms of dysphagia, chest pain, and food impaction. EoE is a clinicopathologic syndrome that requires clinical symptoms and pathologic findings for a diagnosis. The inflammatory process and eosinophilic infiltration of the esophagus in EoE lead to fibrosis and structural changes within the esophagus that cause esophageal dysfunction. The biomechanics of the esophageal function in EoE have been explored using manometry, impedance planimetry, barium esophagograms, and endoscopic ultrasound. These studies have identified several biomechanical changes to the esophagus in EoE including pan esophageal pressurization on manometry, changes in esophageal compliance with decreased distentisbility by impedance planimetry, decreased esophageal luminal diameter by esophagograms, and dysfunction in the esophageal longitudinal muscles by endoscopic ultrasound. Treatments for the disease involve dietary changes, immunosuppressive drugs, and dilation techniques. However, the data regarding the effect of these therapies on altering mechanical properties of the esophagus is limited. As the pathogenesis of esophageal dysfunction in EoE appears multifactorial, further study of the biomechanics of EoE is critical to better diagnose, monitor and treat the disease. PMID- 23105996 TI - High-resolution Manometry: Esophageal Disorders Not Addressed by the "Chicago Classification". AB - The development of the high-resolution esophageal manometry (HRM) and the Chicago classification have improved the diagnosis and management of esophageal motility disorders. However, some conditions have yet to be addressed by this classification. This review describes findings in HRM which are not included in the current Chicago classification based on the experience in our center. This includes the analysis of the upper esophageal sphincter, proximal esophagus, longitudinal muscle contraction, disorders related to gastroesophageal reflux disease and respiratory symptoms. The utility of provocative tests and the use of HRM in the evaluation of rumination syndrome and post-surgical patients will also be discussed. We believe that characterization of the manometric findings in these areas will eventually lead to incorporation of new criteria into the existing classification. PMID- 23105998 TI - The role of cholecystokinin 1 receptor in prolactin inhibited gastric emptying of male rat. AB - BACKGROUND/AIMS: Prolactin (PRL) is essential for the lactating mammals, while cholecystokinin (CCK) does inhibit gastric emptying (GE). Present study attempted to determine whether both peptides interacted on the male rat GE, particularly the role of putative CCK1 receptor. METHODS: Acute hyperprolactinemia of male rats was induced by the intraperitoneal injection of ovine PRL (oPRL) in several divided doses 15 minutes before motility study. Rat chronic hyperprolactinemia was induced by the graft of 2 pituitary glands into the capsule of left kidney, while control rats received cerebral cortex graft only. Motility study was conducted 6 weeks later after graft surgery. Fifteen minutes after the intragastric feeding of radiochromium, rat was sacrificed to measure GE via the distribution of radioactivities within stomach and intestine. Among the CCK1 receptor blocking study using lorglumide, rats were divided to receive the regimens in terms of oPRL-vehicle plus lorglumide-vehicle, oPRL plus lorglumide vehicle, oPRL-vehicle plus lorglumide and oPRL plus lorglumide. Plasma CCK level was measured using a homemade radioimmunoassay kit. RESULTS: Compared to vehicle treatment, acute hyperprolactinemic rats under highest dose (2.0 mg/kg) of oPRL treatment showed delayed GE (70.6% +/- 3.0% vs 42.1% +/- 6.6%, P < 0.05). Chronic hyperprolactinemic rats under graft surgery also showed inhibited GE (70.5% +/- 1.7% vs 54.5% +/- 4.7%, P < 0.05). Both models finally obtained elevated plasma CCK levels (P < 0.05). Lorglumide itself did not influence GE, however, delayed GE under oPRL treatment was restored following the concomitant lorglumide treatment. CONCLUSIONS: Our study suggests that PRL may delay male rat GE via a mechanism of endogenous CCK activation involving the peripheral CCK1 receptor. PMID- 23105997 TI - Rectal hyposensitivity. AB - Impaired or blunted rectal sensation, termed rectal hyposensitivity (RH), which is defined clinically as elevated sensory thresholds to rectal balloon distension, is associated with disorders of hindgut function, characterised primarily by symptoms of constipation and fecal incontinence. However, its role in symptom generation and the pathogenetic mechanisms underlying the sensory dysfunction remain incompletely understood, although there is evidence that RH may be due to 'primary' disruption of the afferent pathway, 'secondary' to abnormal rectal biomechanics, or to both. Nevertheless, correction of RH by various interventions (behavioural, neuromodulation, surgical) is associated with, and may be responsible for, symptomatic improvement. This review provides a contemporary overview of RH, focusing on diagnosis, clinical associations, pathophysiology, and treatment paradigms. PMID- 23105999 TI - Response of esophagus to high and low temperatures in patients with achalasia. AB - BACKGROUND/AIMS: Achalasia patients would feel exacerbated dysphagia, chest pain and regurgitation when they drink cold beverages or eat cold food. But these symptoms would relieve when they drink hot water. Reasons are unknown. METHODS: Twelve achalasia patients (mean age, 34 +/- 10 years; F:M, 3:9) who never had any invasive therapies were chosen from Peking Union Medical College Hospital. They were asked to fill in the questionnaire on eating habits including food temperature and related symptoms and to receive high-resolution manometry examination. The exam was done in 2 separated days, at swallowing room temperature (25C) then hot (50C) water, and at room temperature (25C) then cold (2C) water, respectively. Parameters associated with esophageal motility were analyzed. RESULTS: Most patients (9/12) reported discomfort when they ate cold food. All patients reported no additional discomfort when they ate hot food. Drinking hot water was effective in 5/8 patients who ever tried to relieve chest pain attacks. On manometry, cold water increased lower esophageal sphincter (LES) resting pressure (P = 0.003), and prolonged the duration of esophageal body contraction (P = 0.002). Hot water decreased LES resting pressure and residue pressure during swallow (P = 0.008 and P = 0.002), increased LES relaxation rate (P = 0.029) and shortened the duration of esophageal body contraction (P = 0.003). CONCLUSIONS: Cold water could increase LES resting pressure, prolong the contraction duration of esophageal body, and exacerbate achalasia symptoms. Hot water could reduce LES resting pressure, assist LES relaxation, shorten the contraction duration of esophageal body and relieve symptoms. Thus achalasia patients are recommended to eat hot and warm food and avoid cold food. PMID- 23106000 TI - Examination of the effects of vardenafil on esophageal function using multichannel intraluminal impedance and manometry. AB - BACKGROUND/AIMS: To evaluate the effects of the phosphodiesterase type 5 (PDE5) inhibitor vardenafil on esophageal function, including bolus transit, using multichannel intraluminal impedance and esophageal manometry (MII-EM). METHODS: Sixteen healthy volunteers (15 men) underwent an MII-EM study including 10 liquid swallows and 10 viscous swallows in a seated position after fasting. Then, each subject was asked to ingest 50 mL distilled water or 10 mg vardenafil dissolved in 50 mL water, in a double-blind manner. After 25 minutes, the MII-EM study was repeated. RESULTS: Eight men received vardenafil and eight subjects received water. Resting and residual lower esophageal sphincter pressures differed significantly only in the vardenafil group (from 18 +/- 6.7 to 6.6 +/- 5.3 mmHg, P < 0.001 and from 4.9 +/- 2.6 to 2.1 +/- 3.6 mmHg, P = 0.006, respectively). Mean distal esophageal amplitude decreased significantly only in the vardenafil group (from 86.7 +/- 41.6 to 34.0 +/- 38.0 mmHg, P < 0.05). Complete bolus transits of liquid and viscous meals decreased significantly only after vardenafil ingestion (from 80.2% +/- 13.8% to 49.4% +/- 27.9%, P < 0.05 and from 72.8% +/- 33.6% to 21.5% +/- 29.0%, P = 0.01, respectively). CONCLUSIONS: Vardenafil decreased esophageal bolus transit in the seated position, despite decreased lower esophageal sphincter pressure. PMID- 23106001 TI - Functional gastrointestinal disorders induced by esophageal atresia surgery: is it valid in humans? AB - BACKGROUND/AIMS: Functional gastrointestinal disorders (FGID) affect 15%-20% of the general pediatric and adult population. Animal models suggest that a neonatal stress such as invasive procedures and maternal separation could be responsible for visceral hypersensitivity and FGID. We tested the hypothesis that congenital esophageal atresia (EA), a condition corrected during the neonatal period and associated with multiple stresses, is a clinically significant risk factor for the development of FGID later in life. We postulated that, to be clinically significant, the effect of neonatal stress on the incidence of FGID should be as strong as that of enteric infections in the development of irritable bowel syndrome in children. METHODS: Subjects with EA and healthy controls were enrolled in this multicenter cohort study. Gastrointestinal symptoms were assessed by a questionnaire and FGID was diagnosed using the Rome III criteria. RESULTS: Fifty-three children (25 girls; median age, 12 years) with EA were compared to 72 age- and sex-matched controls. Although 11 children with EA (21%) had a FGID diagnosis versus 8 controls (11%), this difference was not significant (chi(2) = 2.20, P > 0.05). In subjects with EA, the presence of associated malformations, the occurrence of complications during the first month, and the length of hospital stay > 30 days did not influence the incidence of FGID. Chronic abdominal pain was present in 38% of subjects with EA versus 25% of controls (P > 0.05). CONCLUSIONS: Neonatal stress secondary to surgical correction of EA is not a clinically significant risk factor for the development of FGID in childhood. PMID- 23106002 TI - Gastric emptying in migraine: a comparison with functional dyspepsia. AB - BACKGROUND/AIMS: Gastric stasis in migraineurs remains controversial. The aim of this study is to investigate gastric emptying (GE) time, and any associations between GE parameters and dyspeptic symptoms among patients with functional dyspepsia (FD) and migraine without any gastrointestinal symptoms during the interictal period. METHODS: We enrolled 27 migraine patients, 32 FD patients and 12 healthy people as controls, and performed GE scintigraphy as gastric function test. Gastrointestinal symptoms were evaluated in the FD and migraine. RESULTS: The age-adjusted mean gastric half-emptying time in FD (125.51 +/- 52.55 minutes) patients was longer than in migraineurs (100.82 +/- 23.94 minutes, P = 0.035) and controls (95.25 +/- 23.29 minutes, P = 0.021). The percentage of gastric retention was higher in FD than in migraine. However, migraineurs did not show an obvious delayed gastric emptying or an increase of gastric retention when compared to the normal controls. The association between each dyspeptic symptom and GE parameters was not significant, but postprandial fullness and early satiety showed a tendency of delayed GE. In migraineurs, GE time did not show significant association with nausea and vomiting during interictal periods. CONCLUSIONS: Delayed GE does not appear to be a mechanism that patients with FD and migraine have in common. Migraineurs without dyspepsia during interictal period had normal GE, and further study for association with FD should be investigated. PMID- 23106003 TI - Computed tomography assessment of intestinal gas volumes in functional gastrointestinal disorders. AB - BACKGROUND/AIMS: Many patients with functional gastrointestinal disorders (FGIDs) rank sensations of bloating and distension among their most debilitating symptoms. Previous studies that have examined intestinal gas volume (IGV) in patients with FGIDs have employed a variety of invasive and imaging techniques. These studies are limited by small numbers and have shown conflicting results. The aim of our study was to estimate, using CT of the abdomen and pelvis (CTAP), IGV in patients attending FGID clinic and to compare IGV in patients with and without FGID. METHODS: All CTAP (n = 312) performed on patients (n = 207) attending a specialized FGID clinic over 10-year period were included in this study. Patients were classified into one of 3 groups according to the established clinical grading system, as organic gastrointestinal disorder (OGID, ie, patients with an organic non-functional disorder, n = 84), FGID (n = 36) or organic and functional gastrointestinal disorder (OFGID, ie, patients with an organic and a functional disorder, n = 87). Two independent readers blinded to the diagnostic group calculated IGV using threshold based 3D region growing with OsiriX. RESULTS: Median IGVs for the FGID, OGID, and OFGID groups were 197.6, 220.6 and 155.0 mL, respectively. Stepwise linear regression revealed age at study, gender, and calculated body mass index to predict the log IGV with an r(2) of 0.116, and P < 0.001. There was a significant positive correlation between age and IGV in OGID (Spearman's = 0.253, P = 0.02) but this correlation was non-significant in the other groups. CONCLUSIONS: Although bloating is a classic symptom in FGID patients, IGV may not be increased compared with OGID and OFGID patients. PMID- 23106004 TI - Association between irritable bowel syndrome and restless legs syndrome: a comparative study with control group. AB - BACKGROUND/AIMS: As a common gastrointestinal (GI) disorder, irritable bowel syndrome (IBS) has been reported to be associated with some psychological and neurological factors. This study aimed to evaluate the prevalence rate of restless legs syndrome (RLS) in a sample of IBS patients and to compare this prevalence with that of matched healthy controls. METHODS: This prospective comparative study was conducted in Tehran, Iran during 2010-2011. Based on the Rome III criteria, a total number of 225 definite IBS patients and 262 age- and sex-matched healthy controls were recruited in the final assessment to compare the prevalence rate of RLS between the 2 groups. RESULTS: RLS was significantly more frequent in IBS group (25.3% vs 6.5%, P < 0.001) which led to an odds ratio (OR) of 4.89 (95% CI, 2.75-8.70). IBS patients with co-morbid RLS significantly suffered more from stomach pain (96.5% vs 86.3%, OR = 4.36 [95% CI, 1.00-19.12]), nausea (40.4% vs 21.4%, OR = 2.48 [95% CI, 1.30-4.73]) and vomiting (10.5% vs 2.4%, OR = 4.82 [95% CI, 1.31-17.76]). CONCLUSIONS: By enrolling a considerable number of IBS patients and healthy controls, our study showed a significantly higher prevalence of RLS in IBS patients. Surprisingly, a higher prevalence rate of RLS was also accompanied with a more severe discomfort and stomach pain in IBS patients. It seems that screening patients with IBS for RLS may lead to greater identification of RLS and improved treatment for both conditions. PMID- 23106005 TI - Role of Cytolethal Distending Toxin in Altered Stool Form and Bowel Phenotypes in a Rat Model of Post-infectious Irritable Bowel Syndrome. AB - BACKGROUND/AIMS: Campylobacter jejuni infection is a leading cause of acute gastroenteritis, which is a trigger for post-infectious irritable bowel syndrome (PI-IBS). Cytolethal distending toxin (CDT) is expressed by enteric pathogens that cause PI-IBS. We used a rat model of PI-IBS to investigate the role of CDT in long-term altered stool form and bowel phenotypes. METHODS: Adult Sprague Dawley rats were gavaged with wildtype C. jejuni (C+), a C. jejunicdtB knockout (CDT-) or saline vehicle (controls). Four months after gavage, stool from 3 consecutive days was assessed for stool form and percent wet weight. Rectal tissue was analyzed for intraepithelial lymphocytes, and small intestinal tissue was stained with anti-c-kit for deep muscular plexus interstitial cells of Cajal (DMP-ICC). RESULTS: All 3 groups showed similar colonization and clearance parameters. Average 3-day stool dry weights were similar in all 3 groups, but day to-day variability in stool form and stool dry weight were significantly different in the C+ group vs both controls (P < 0.01) and the CDT- roup (P < 0.01), but were not different in the CDT- vs controls. Similarly, rectal lymphocytes were significantly higher after C. jejuni (C+) infection vs both controls (P < 0.01) and CDT-exposed rats (P < 0.05). The counts in the latter 2 groups were not significantly different. Finally, c-kit staining revealed that DMP-ICC were reduced only in rats exposed to wildtype C. jejuni. CONCLUSIONS: In this rat model of PI-IBS, CDT appears to play a role in the development of chronic altered bowel patterns, mild chronic rectal inflammation and reduction in DMP-ICC. PMID- 23106006 TI - Techniques of functional and motility test: how to perform and interpret intestinal permeability. AB - Transport of molecules across the intestinal epithelium takes place through 2 major routes, ie, trans-cellular and paracellular. Assessment of intestinal permeability is performed to assess the overall function of transport through the intestinal epithelial paracellular route. Urinary excretion of disaccharides and monosaccharides and ratio of their excretion is a basis for measurement of intestinal permeability. Lactulose and mannitol ratio is the most commonly used test for assessment of small intestinal permeability and the most reliable method for measurement of concentration of lactulose and mannitol in the urine is high performance liquid chromatography. After the measurement of concentration of probes in the urine; the results are expressed as the ratio of percentage excretion of the ingested dose of lactulose and mannitol in the urine. Testing of intestinal permeability is not required for routine patient care, however it is an important tool to understand the function of the paracellular transport in the research setting. Increase in intestinal permeability has been implicated in the pathogenesis of many autoimmune diseases including celiac disease, Crohn's disease, type I diabetes and food allergy. PMID- 23106007 TI - Complete radiological findings in gallstone ileus. PMID- 23106008 TI - High-resolution Anorectal Manometry and Anal Endosonographic Findings in the Evaluation of Fecal Incontinence. PMID- 23106009 TI - How can we predict the successful outcome after treatment in achalasia patients? (Gastroenterology 2012;143:328-335). PMID- 23106010 TI - New Consensus on the Management of Barrett's Dysplasia and Early Stage Esophageal Adenocarcinoma: Limited Evidence, but Best Available Guidance (Gastroenterology 2012;143:336-346). PMID- 23106011 TI - Are solifenacin and ramosetron really ideal to treat irritable bowel syndrome? PMID- 23106012 TI - Are Solifenacin and Ramosetron Really Ideal to Treat Irritable Bowel Syndrome?: Author's Reply. PMID- 23106013 TI - Psychological factors influence the symptoms of gastroesophageal reflux disease. PMID- 23106014 TI - Psychological Factors Influence the Symptoms of Gastroesophageal Reflux Disease: Author's Reply. PMID- 23106015 TI - "Holes in my head": a case of primary delusional parasitosis in a patient with end-stage renal disease. PMID- 23106016 TI - A case of sleep masturbation related to dopamine agonist therapy. PMID- 23106017 TI - A case of chloroquine-induced recurrent mania. PMID- 23106018 TI - Two patients with delayed neuropsychiatric sequelae caused by exposure to carbon monoxide under the same conditions. PMID- 23106019 TI - A case of drug overdose-induced, severe electrocardiogram abnormalities: investigation through plasma drug concentrations. PMID- 23106020 TI - The resolution of eczema during treatment with lamotrigine: a case report. PMID- 23106021 TI - Successful electroconvulsive therapy in a young woman with chronic catatonia. PMID- 23106022 TI - Circadian synchronization linked to a successful treatment in a severely depressed adolescent. PMID- 23106023 TI - Efficacy of adjunctive aripiprazole in major depressive disorder: a pooled response quartile analysis and the predictive value of week 2 early response. AB - OBJECTIVE: To assess varying levels of response to aripiprazole adjunctive to standard antidepressant therapy (ADT) and the predictive value of an early response for a sustained response. METHOD: This post hoc analysis of 3 similarly designed randomized, double-blind, placebo-controlled phase 3 studies investigated the efficacy and safety of adjunctive aripiprazole to standard ADT in patients with major depressive disorder (DSM-IV-TR criteria) who had a prior inadequate response to 1-3 ADTs (CN138-139 [September 2004-December 2006], CN138 163 [June 2004-April 2006], and CN138-165 [March 2005-April 2008]). Response levels were defined as percent decreases from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score after 6 weeks of treatment, with a <= 25% decrease for minimal, > 25 to < 50% decrease for partial, >= 50% to < 75% decrease for moderate, and >= 75% decrease for a robust response to treatment. RESULTS: More patients receiving adjunctive aripiprazole exhibited a partial (23.9% vs 17.9%, P = .017), moderate (23.1% vs 15.0%, P < .001), and robust response (14.3% vs 7.4%, P < .001) compared with adjunctive placebo. Adjunctive aripiprazole treatment compared with adjunctive placebo treatment was associated with a significantly greater proportion of patients achieving an early response (week 2, >= 50% reduction in MADRS total score, n = 110/539 vs n = 47/525, P < .001, number needed to treat = 9) and an endpoint response (relative risk = 1.7, 95% CI = 1.4-2.0, P < .001, number needed to treat = 7). A univariate logistic regression analysis revealed that an early response was a significant predictor of endpoint remission (P < .001). CONCLUSIONS: Aripiprazole augmentation was associated with a significantly greater proportion of patients achieving a partial, moderate, or robust response to treatment compared with ADT alone. Patients showing an early response (week 2) to augmentation maintained their response through endpoint, suggesting that clinicians may make clinically meaningful decisions early during treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00095823, NCT00095758, and NCT00105196. PMID- 23106024 TI - Increased use of antidepressants in women decreases suicides in men: an ecological study. AB - OBJECTIVE: The suicide rate has decreased in many countries, while the use of antidepressants has increased. In our previous study, the decrease in suicide rate between 1994 and 2001 was greater in men than in women, but the increase in use of antidepressants was greater in women than in men. We hypothesized that the increase in the use of antidepressants in women associates with the decrease in suicide rate in men. METHOD: Population-based suicide rate and reimbursed antidepressant prescriptions, an indicator of antidepressant use, between 1994 and 2001 in Finland were analyzed in the whole population. Variance in the suicide rates in men and women was explained by antidepressant prescriptions for men and women, age, time period, and geographical region in Poisson regression analyses. RESULTS: The decrease in suicide rate in men associated significantly with the increase in antidepressant prescriptions in women even though the model took into account the effect of increased antidepressant prescriptions in men, as well as the effects of age, time, and region (risk ratio [RR] = 0.70, P = .004, in the model without age; RR = 0.89, P = .048 in the complete model). However, the decrease in suicide rate in women did not associate with the increase in antidepressant prescriptions in men. CONCLUSIONS: Increased prescription of antidepressants in women associates with a decreased suicide rate in men. Increased use of antidepressive medication in women may decrease depressiveness in their microsocieties and thereby reduce the risk of suicides also in men. PMID- 23106025 TI - Effect of comorbid depression on outcomes in diabetes and its relationship to quality of care and patient adherence: a statewide primary care ambulatory research and resources consortium study. AB - OBJECTIVE: To determine whether current depression was associated with poorer quality of care and poorer patient adherence to treatment regimens and whether current depression was associated with patient diabetes outcomes independent of its relationships to quality of care and patient adherence among patients with diabetes. METHOD: This study was conducted in the offices of family physicians who belong to the Statewide Primary Care Ambulatory Research and Resources Consortium from March 2006 to March 2011. Seven primary care physicians enrolled 10 to 20 English- or Spanish-speaking patients with diabetes presenting for routine follow-up visits. Subjects included 106 patients who completed a questionnaire documenting their depressive symptoms, compliance with diabetes therapy, diabetes-related quality of life, and patient satisfaction. The physicians completed a 4-item questionnaire concerning whether the patient had depression and any depression treatments that they ordered. All questions were answered either "yes" or "no." A practice research coordinator evaluated the quality of diabetes care provided and ordered hemoglobin A(1c) (HbA(1c)) testing for the patient. RESULTS: Depression was associated with poorer compliance, quality of care, diabetes-related quality of life, and patient satisfaction; only HbA(1c) levels did not correlate with depression. When adjusting for compliance and quality of care, depression was still associated with poorer quality of life and satisfaction (P <= .001). While physician recognition and treatment of depression were less than optimal, depression severity was a significant predictor of receiving some form of mental health intervention (P <= .05) except for the provision of mental health counseling. Poor diabetes control was associated with the provision of counseling (P <= .10), while poor quality of life was associated with recognition of depression (P <= .10). CONCLUSION: Depression was independently associated with satisfaction and quality of life but not diabetes control. Although depression severity was an important predictor of depression recognition and treatment, poor quality of life was a predictor of recognition, and poor diabetes control was a predictor of receiving mental health counseling. PMID- 23106026 TI - Primary care-mental health integration programs in the veterans affairs health system serve a different patient population than specialty mental health clinics. AB - OBJECTIVE: To assess whether Primary Care-Mental Health Integration (PC-MHI) programs within the Veterans Affairs (VA) health system provide services to patient subgroups that may be underrepresented in specialty mental health care, including older patients and women, and to explore whether PC-MHI served individuals with less severe mental health disorders compared to specialty mental health clinics. METHOD: Data were obtained from the VA National Patient Care Database for a random sample of VA patients, and primary care patients with an ICD-9-CM mental health diagnosis (N = 243,806) in 2009 were identified. Demographic and clinical characteristics between patients who received mental health treatment exclusively in a specialty mental health clinic (n = 128,248) or exclusively in a PC-MHI setting (n = 8,485) were then compared. Characteristics of patients who used both types of services were also explored. RESULTS: Compared to patients treated in specialty mental health clinics, PC-MHI service users were more likely to be aged 65 years or older (26.4% vs 17.9%, P < .001) and female (8.6% vs 7.7%, P = .003). PC-MHI patients were more likely than specialty mental health clinic patients to be diagnosed with a depressive disorder other than major depression, an unspecified anxiety disorder, or an adjustment disorder (P < .001) and less likely to be diagnosed with more severe disorders, including bipolar disorder, posttraumatic stress disorder, psychotic disorders, and alcohol or substance dependence (P < .001). CONCLUSIONS: Primary Care-Mental Health Integration within the VA health system reaches demographic subgroups that are traditionally less likely to use specialty mental health care. By treating patients with less severe mental health disorders, PC-MHI appears to expand upon, rather than duplicate, specialty care services. PMID- 23106027 TI - Sulfotransferase 4A1 Haplotype 1 (SULT4A1-1) Is Associated With Decreased Hospitalization Events in Antipsychotic-Treated Patients With Schizophrenia. AB - OBJECTIVE: To evaluate a common genetic variant, sulfotransferase 4A1 haplotype 1 (SULT4A1-1), as a predictor of hospitalization events due to the exacerbation of schizophrenia for patients treated with antipsychotic medications. Haplotypes were determined using single nucleotide polymorphism data. METHOD: The study included 417 white subjects from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study with a DSM-IV diagnosis of schizophrenia. Patients were assigned to 1 of 4 atypical antipsychotics (olanzapine, quetiapine, risperidone, or ziprasidone) or to the first-generation antipsychotic perphenazine. Kaplan-Meier survival analysis and Cox proportional hazards regression models were used to measure if haplotype status impacted hospitalization events for these 5 treatments. Haplotype status was evaluated for its relationship to hospitalization events regardless of treatment and for the individual treatments, with or without previous exacerbation. Data for the CATIE study were collected from January 2001 to December 2004. The current post hoc analysis was performed between May 2011 and August 2011. RESULTS: In phase 1 of the trial, considering only the first hospitalization events, the haplotype had a significant impact on hospitalization events, with a hazard ratio for SULT4A1-1( ) versus SULT4A1-1(+) of 2.54 (P = .048). When prior exacerbation was included in the model for phase 1, the hazard ratio was 2.34 (P = .072) considering only the first hospitalization event and 2.71 (P = .039) considering all hospitalization events in the phase. When data for all phases were evaluated, SULT4A1-1(-) status was associated with increased hospitalization risk for subjects treated with olanzapine, with a hazard ratio of 8.26 (P = .041), and possibly for subjects treated with quetiapine, with a hazard ratio of 6.80 (P = .070). CONCLUSIONS: The SULT4A1-1 haplotype may be an important predictor of risk of hospitalization. SULT4A1-1(+) status was significantly associated with decreased risk of hospitalization when the subjects were treated with olanzapine. PMID- 23106028 TI - Antipsychotic adherence and its correlation to health outcomes for chronic comorbid conditions. AB - OBJECTIVE: To examine the relationship between adherence to antipsychotics and adherence to medications for cardiometabolic conditions (diabetes, hypertension, and hyperlipidemia) and subsequent health care utilization and expenditures in patients with schizophrenia and preexisting cardiometabolic conditions. METHOD: Medstat MarketScan Medicaid databases from 2004 to 2008 were used to identify a retrospective cohort of schizophrenia patients (ICD-9-CM codes 295.1-295.3, 295.6, or 295.9) with preexisting cardiometabolic medication use who had initiated antipsychotic treatments. Patients who initiated a second-generation antipsychotic between July 1, 2004, and December 31, 2006, were identified as the new user cohort. Comorbid conditions were identified if patients had at least 1 inpatient or 2 outpatient claims for hypertension, hyperlipidemia, and/or diabetes (ICD-9-CM codes 401.xx to 405.xx inclusive, 272.xx inclusive, and 250.xx inclusive, respectively) and were using medication to manage these conditions prior to antipsychotic initiation. Adherence to cardiometabolic medications was compared between adherent and nonadherent patients taking antipsychotics using the proportion of days covered over 8 quarters categorized as phases of treatment to reflect initiation (1, days 1-90), continuation (2-4, days 91-360), and maintenance (5-8, days 361-520). Proportion of days covered values >= 0.80 were deemed adherent. Prior period antipsychotic adherence was used to predict cardiometabolic medication adherence, health care utilization, and expenditures using generalized estimating equations and negative binomial regressions. RESULTS: The final population represented 1,006 patients. Antipsychotic adherence during continuation was a significant predictor of medication adherence for hypertension (odds ratio [OR] = 2.40, 95% CI = 1.67-3.44), diabetes (OR = 2.28, 95% CI = 1.43-3.67), and hyperlipidemia (OR = 2.16, 95% CI = 1.11-4.20) during maintenance. Antipsychotic adherence during continuation resulted in significantly lower emergency room use (OR = 0.67, 95% CI = 0.52-0.87), lower inpatient use (OR = 0.77, 95% CI = 0.56-1.06, not significant), and significantly higher outpatient ($996, 95% CI = $663-$1,330), medication ($652, 95% CI = $542 $762), and total health ($1,371, 95% CI = $490-$2,252) expenditures during maintenance. CONCLUSION: Antipsychotic adherence was associated with better adherence to cardiometabolic medications and a potential reduction in emergency room and inpatient service utilization. Clinicians should consider adherence to both antipsychotic and cardiometabolic medications when caring for patients with schizophrenia and comorbid conditions. PMID- 23106030 TI - Review of the safety of second-generation antipsychotics: are they really "atypically" safe for youth and adults? AB - OBJECTIVE: There is general consensus that second-generation antipsychotics are at least as effective as and more tolerable than first-generation antipsychotics. We address questions of safety and tolerability in both the short-term and long term use of these medications by reviewing the existing literature in youth and adults. DATA SOURCES: A MEDLINE search was conducted via PubMed using the following keywords (in various combinations): typical antipsychotics, atypical antipsychotics, children, adolescents, side effects, weight gain, diabetes, metformin, metabolic syndrome, and CATIE. Only English-language articles published from 2000-2010 were included. The bibliographies of papers identified through MEDLINE searches were also reviewed. RESULTS: Six adult studies were analyzed in detail. A summary of the data suggests that there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol, while olanzapine, clozapine, quetiapine, and risperidone appear to be more highly associated. There may be less difference than originally thought concerning frequency of extrapyramidal side effects among these medications. All of these antipsychotics, including perphenazine, are similarly efficacious in treating psychosis, with the exception of clozapine, which demonstrates significantly more effectiveness. Although the studies on youth tend to be small (few subjects with large age ranges of 4 to 19 years) and short term in comparison to the adult studies, the data reviewed from 5 studies suggest that, in youth, olanzapine may be associated with the greatest weight gain, extrapyramidal side effects and metabolic changes are quite prevalent, and the antipsychotics studied seem to be similarly effective. CONCLUSIONS: Considering effectiveness, safety, and tolerability, this literature review suggests that in adults there may be a lower association of weight gain and diabetes with ziprasidone, aripiprazole, and haloperidol as compared with olanzapine, clozapine, quetiapine, and risperidone. Youth may be particularly sensitive to weight gain, especially with olanzapine, as well as extrapyramidal side effects and metabolic changes. The literature suggests similar effectiveness among the antipsychotics, perhaps with the exception of clozapine having greater effectiveness, at least in adults. PMID- 23106029 TI - A Review of Potential Adverse Effects of Long-Term Opioid Therapy: A Practitioner's Guide. AB - OBJECTIVE: Review, synthesize, and summarize recent evidence on adverse effects of long-term opioid treatment for noncancer pain and present an organ system based guide for primary care physicians in initiating and monitoring patients receiving chronic opioid therapy. DATA SOURCES: A search for studies published in peer-reviewed journals from 2005 to 2011 was conducted using MEDLINE, Agency for Healthcare Research and Quality Clinical Guidelines and Evidence Reports, and the Cochrane Database of Systematic Reviews. Related citations and expert recommendations were included. DATA EXTRACTION: Studies were selected if the search terms opioid and the organ system of interest were in the article's title, abstract, or text. Systems considered were gastrointestinal, respiratory, cardiovascular, central nervous, musculoskeletal, endocrine, and immune. Of 1,974 initially reviewed articles, 74 were selected for evidence regarding effects of chronic opioid use on that organ system. Of these articles, 43 were included on the basis of direct relevance to opioid prescriptions in the primary care setting. DATA SYNTHESIS: A qualitative review was performed because the number of articles pertaining to specific adverse effects of opioids was typically small, and the diversity of adverse effects across systems precluded a quantitative analysis. RESULTS: Through a variety of mechanisms, opioids cause adverse events in several organ systems. Evidence shows that chronic opioid therapy is associated with constipation, sleep-disordered breathing, fractures, hypothalamic pituitary-adrenal dysregulation, and overdose. However, significant gaps remain regarding the spectrum of potentially opioid-related adverse effects. Opioid related adverse effects can cause significant declines in health-related quality of life and increased health care costs. CONCLUSIONS: The diverse adverse effects potentially caused by chronic opioid therapy support recommendations for judicious and selective opioid prescribing for chronic noncancer pain by primary care physicians. Additional research clarifying the risks and management of potential adverse effects of chronic opioid therapy is needed to guide clinical practice. PMID- 23106031 TI - The shadow people: a glimpse into dementia with lewy bodies. PMID- 23106033 TI - Psychotherapy at the end of life. PMID- 23106032 TI - Found in feces: differential diagnosis, workup, and treatment. PMID- 23106035 TI - Research on MI in Equipoise: The Case of Living Organ Donation. AB - Residual ambivalence prior to live organ donation has been shown to predict worse physical and psychological outcomes for the donor following surgery. We are studying whether MI can help individuals who have agreed to become living organ donors to resolve residual ambivalence about their decision. In this situation, ethical practice demands that the counselor take up a stance of equipoise, equally welcoming of strengthened resolve to donate or a decision not to do so. This paper describes our adaptations of MI for this unique application. PMID- 23106034 TI - Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia. AB - A reduction in low density lipoprotein (LDL) cholesterol or an increase in high density lipoprotein (HDL) cholesterol can reduce the risk of development of atherosclerosis through overlapping or independent mechanisms. However, the clinical outcome of combined therapy remains in debate. In this study, we first characterized effects of various constructs of helper-dependent adenoviral vector (HDAd) expressing apolipoprotein E3 or LDL receptor (LDLR) in vivo on plasma cholesterol levels. Using this information, we designed experiments and compared the effects of long-term (28 weeks) LDL cholesterol lowering or raising HDL cholesterol, or a combination of both on advanced atherosclerosis in Ldlr(-/-) mice, a mouse model of familial hypercholesterolemia. Our major findings are: (i) various factors influence in vivo functional activity, which appear to be context dependent; (ii) apolipoprotein AI (APOAI) gene transfer, which raises HDL cholesterol, retards progression of atherosclerosis but does not induce regression; (iii) LDLR or LDLR and APOAI combination gene therapy induces lesion regression; however, LDLR gene transfer accounts for the majority of the effects of combined gene therapy; (iv) LDLR gene therapy reduces interleukin-7, which is a master regulator of T-cell homeostasis, but APOAI gene therapy does not. These results indicate that LDL cholesterol lowering is effective and sufficient in protection against atherosclerosis and induction of regression of pre-existing atherosclerosis. PMID- 23106036 TI - Gut Microbiota and Obesity. AB - The current obesity epidemic clearly has many causes, including the impact of our modern world on both our diet and our lifestyle/physical activity. Although many interventions have been recommended, the prevalence of obesity continues to rise and has forced a re-evaluation of the potential interventions that could have an impact. In recent years it has been definitively shown that microbiota in the gastrointestinal tract are altered in obese individuals. Recent data provide a potential mechanistic understanding of the interactions between microbiota and obesity and allow potential new interventions to the control of obesity to be proposed. PMID- 23106037 TI - Effect of Agglomeration on the Toxicity of Nano-sized Carbon Black in Sprague Dawley Rats. AB - OBJECTIVES: Recent studies have shown that nano-sized carbon black is more toxic than large respirable carbon black because of its higher surface area. However, it is not clear if carbon black made larger by agglomeration demonstrates decreased toxicity. The purpose of this study was to verify if agglomeration affects the toxicity of carbon black using three differently prepared nano-sized carbon black aerosols in nose-only inhalation chambers for 13 weeks. METHODS: Printex 90 was selected as a representative nano-sized carbon black. To generate aerosols of three different types of agglomerates, Printex 90 was dispersed in distilled water by three different methods: vortex, vortex+sonication, and vortex+sonication with dispersion in a stabilizer. Then, the three differently prepared solutions were aerosolized through venturi nozzles. Male Sprague-Dawley rats were exposed to Printex 90 aerosols in a nose-only exposure chamber for 6 h/d, 5 d/wk for 13 weeks at a concentration of approximately 9 mg/m(3). RESULTS: Numbers of total cells in the bronchoalveolar lavage (BAL) fluid, macrophages, and polymorphonuclear leukocytes were increased and carbon black masses were clearly seen in BAL cells and lung tissues of rats exposed to Printex 90. However, few differences were found between the three differently agglomerated aerosols. In addition, there were no significant differences in other parameters, such as body weight, lung function or cytokine levels in BAL fluid following carbon black exposure. CONCLUSIONS: Only mild to moderate respiratory effects were found in rats exposed to nano-sized carbon black at 9 mg/m(3) for 13 weeks. Agglomeration did not affect the toxicity of nano-sized carbon particles. PMID- 23106038 TI - The Margin of Exposure of 5-Hydroxymethylfurfural (HMF) in Alcoholic Beverages. AB - OBJECTIVES: 5-Hydroxymethylfurfural (HMF) regularly occurs in foods and in alcoholic beverages. However, the risk of HMF associated with alcohol consumption has not been systematically studied, so that this study will provide the first quantitative risk assessment of HMF for consumers of alcoholic beverages. METHODS: Human dietary intake of HMF via alcoholic beverages in the European Union was estimated based on WHO alcohol consumption data combined with our own survey data (n=944) and literature data (n=147) about the HMF contents of different beverage groups (beer, wine, spirits and unrecorded alcohol). The risk assessment was conducted using the margin of exposure (MOE) approach. RESULTS: For olfactory epithelium metaplasia in female mice, a benchmark dose (BMD) of 127 mg/kg bodyweight (bw)/d and a BMD lower confidence limit (BMDL) of 79 mg/kg bw/d were calculated from National Toxicology Program oral long-term animal experiments. The average human exposure to HMF from alcoholic beverages was estimated at 6.0E-3 mg/kg bw/d, which is approximately 8.5% of the total dietary exposure. In comparison of the human exposure with BMDL, the MOE was 13,167 for average alcohol consumption scenarios, which is a value that would be generally assumed as safe for threshold based compounds. CONCLUSIONS: The results show that the risk from HMF to the alcohol-consuming population is rather low and the priority for risk management (e.g. to reduce the contamination) is also low. Further toxicological research about HMF is required to further elucidate its mechanism. PMID- 23106039 TI - The Role of p53 in Marijuana Smoke Condensates-induced Genotoxicity and Apoptosis. AB - OBJECTIVES: Marijuana is one of the most frequently abused drug in Korea and its adverse health effects are controversial. p53 is known to be crucial in regulating the DNA damage responses, and adverse effects can occur when it is regulated by marijuana smoke. We evaluated a role of p53 on genotoxic effect and apoptosis in lung cancer cells exposed to marijuana smoke condensates (MSCs). METHODS: The p53-related genotoxicity and apoptosis of MSCs were evaluated using in vitro bioassay, viz., comet assay, cytokinesis-block micronucleus assay and apoptosis assay. We used two cell lines with differential p53 expression (p53 wildtype (WT) H460 and p53-null H1299). RESULTS: MSCs significantly increased DNA breakages and chromosomal changes in p53-WT H460 and p53-null H1299 cells. The genotoxicity induced by MSCs in p53-null H1299 cells showed greater sensitivity than p53-WT H460 cells. Moreover, MSCs showed a significant increase in reactive oxygen species production and apoptosis. The apoptotic responses induced by MSCs were higher in p53-WT H460 cells than in p53-null H1299 cells. Significantly increased mRNA expression or apoptosis related genes, including p53, caspase-3, and Bax/Bcl-2 ratio were observed in the p53-WT H460 cells exposed to MSCs. CONCLUSIONS: These results suggest that MSCs induce DNA/chromosomal damages and apoptosis in human lung cancer cells and p53 plays an important role in the cellular response to MSCs. The present study may have border implications for our understanding of pulmonary diseases. PMID- 23106041 TI - In vitro growth of mouse preantral follicles: effect of animal age and stem cell factor/insulin-like growth factor supplementation. AB - OBJECTIVE: To determine whether animal age impacts in vitro preantral follicle growth. Effects of hCG, stem cell factor (SCF), and/or insulin-like growth factor (IGF) supplementation in growth medium were also investigated. METHODS: Intact preantral follicles were mechanically isolated from fresh ovaries of BDF1 mice and cultured in growth medium for 9 to 11 days. Surviving follicles with antrum formation were transferred to maturation medium for 14 to 18 hours. Follicle survival, antrum formation, and retrieval of metaphase II (MII) oocytes were compared among three age categories (4-5, 7-8, and 10-11 week-old). By using 7- to 8-week-old mice, preantral follicles were cultured in growth medium supplemented with hCG (0, 5, or 10 mIU/mL), SCF (50 ng/mL), IGF-1 (50 ng/mL), and SCF+IGF-1. RESULTS: Seven- to eight-week-old mice showed a higher follicle survival and antrum formation and produced more MII oocytes compared to other groups. In the 7- to 8-week-old mice, supplementation of 5 mIU/mL hCG significantly enhanced the antrum formation but the percentage of MII oocytes was similar to that of the control. Supplementation of SCF+IGF-1 did not enhance follicle survival or antrum formation but the percentage of MII oocytes increased modestly (39.1%) than in the control (28.6%, statistically not significant). CONCLUSION: Seven- to eight-week-old mice showed better outcomes in growth of preantral follicles in vitro than 4- to 5- or 10- to 11-week-old mice. Supplementation of hCG enhanced antrum formation and supplementation of SCF+IGF-1 yielded more mature oocytes; hence, these should be considered in the growth of preantral follicles in vitro. PMID- 23106040 TI - Regulation and 3 dimensional culture of tertiary follicle growth. AB - It has been revealed that multiple cohorts of tertiary follicles develop during some animal estrous cycle and the human menstrual cycle. To reach developmental competence, oocytes need the support of somatic cells. During embryogenesis, the primordial germ cells appear, travel to the gonadal rudiments, and form follicles. The female germ cells develop within the somatic cells of the ovary, granulosa cells, and theca cells. How the oocyte and follicle cells support each other has been seriously studied. The latest technologies in genes and proteins and genetic engineering have allowed us to collect a great deal of information about folliculogenesis. For example, a few web pages (http://www.ncbi.nlm.nih.gov; http://mrg.genetics.washington.edu) provide access to databases of genomes, sequences of transcriptomes, and various tools for analyzing and discovering genes important in ovarian development. Formation of the antrum (tertiary follicle) is the final phase of folliculogenesis and the transition from intraovarian to extraovian regulation. This final step coordinates with the hypothalamic-pituitary-ovarian axis. On the other hand, currently, follicle physiology is under intense investigation, as little is known about how to overcome women's ovarian problems or how to develop competent oocytes from in vitro follicle culture or transplantation. In this review, some of the known roles of hormones and some of the genes involved in tertiary follicle growth and the general characteristics of tertiary follicles are summarized. In addition, in vitro culture of tertiary follicles is also discussed as a study model and an assisted reproductive technology model. PMID- 23106042 TI - Blastocyst transfer in frozen-thawed cycles. AB - OBJECTIVE: It is well known that fresh blastocyst transfer results in better pregnancy outcomes with a smaller number of transferred embryos compared with cleavage stage embryo transfer. However, in terms of frozen-thawed blastocyst transfer, only a few studies are available. We aimed to evaluate clinical outcomes of frozen-thawed embryo transfer (FET) with blastocysts. METHODS: Retrospective analysis of FET cycles with blastocysts (B-FET) between Jan 2007 and June 2009 was performed. Age-matched FET cycles with cleavage stage embryos (C-FET) during the same period were collected as controls. A total of 58 B-FET cycles were compared with 172 C-FET cycles and also compared with those of post thaw extended culture blastocysts from frozen pronuclear stage embryos (22 cycles). RESULTS: There was no difference in the patient characteristics of each group. The embryos' survival rates after thawing were comparable (>90%) and there was no difference in the implantation rate or clinical and ongoing pregnancy rate among the three groups. CONCLUSION: In FET, blastocyst transfers may not present better pregnancy outcomes than cleavage stage embryo transfers. A further large scale prospective study is needed. PMID- 23106044 TI - Letter to the Editor: A cohort study and not a case control study. PMID- 23106043 TI - Outcomes of preimplantation genetic diagnosis using either zona drilling with acidified Tyrode's solution or partial zona dissection. AB - OBJECTIVE: To review the outcomes of preimplantation genetic diagnosis (PGD) using zona drilling with acid Tyrode's solution (chemical zona pellucida drilling, chemical ZD) and those of partial zona dissection (PZD). METHODS: Clinical outcomes of seventy-one couples undergoing 85 PGD cycles from January 2005 to December 2010 were included. Blastocyst formation and the hatching rate, clinical pregnancy rate, ongoing pregnancy rate, implantation rate, and fetal gender ratio of the PZD and chemical ZD groups were compared. RESULTS: Application of PZD resulted in a significantly higher rate of clinical pregnancy (40.7% vs. 15.4%, p=0.022), ongoing pregnancy (35.6% vs. 11.5%, p=0.023), and implantation (18.1% vs. 5.7%, p=0.007) compared with chemical ZD. Among non transferred embryos, the rate of blastocyst formation on day 5 (49.1% vs. 39.5%, p=0.016) and hatching on day 6 (47.2% vs. 26.5%, p<0.001) were also significantly higher in the PZD group. CONCLUSION: The mechanical zona dissection method showed better outcomes than chemical ZD in terms of the blastocyst development and pregnancy rate. In this study, the fact that chemical ZD was conducted in different period from mechanical method should be considered in interpreting the result. PMID- 23106045 TI - The Author Response: A cohort study and not a case control study. PMID- 23106046 TI - Bridging the Gap: Understanding Embryonic Intervertebral Disc Development. AB - The intervertebral disc (IVD) is a multi-component structure consisting of a heterogeneous population of cells that form the central nucleus pulposus, encased by the fibrous annulus fibrosus and the cartilage end-plate. The essential function of the IVD is to withstand biomechanical forces, confer tensile strength and flexibility in motion to the spine. Disc degenerative disease (DD) is a prevalent ailment that affects the general population, often manifesting either in the form of lower back pain or as deformities of the spine such as degenerative lumbar scoliosis or in severe cases as disc herniation. With the aid of mutant mouse models generated through traditional knock-out strategies and spontaneous mutants, scientists have been able to elucidate some of the fundamental mechanisms of embryonic IVD development. Mutual interaction between the notochord and vertebral bodies are instrumental in the proper formation of the IVD. In this review, the known and proposed molecular mechanisms underlying these processes and the areas that require further investigation are discussed. Sufficient knowledge on the molecular mechanisms of IVD formation and the etiology of IVD degeneration is currently lacking and this has greatly hampered efforts to design appropriate and effective therapies for DD. With the dawn of the next-generation sequencing and better tools to engineer the genome, elucidation of the mechanism of IVD formation and the molecular basis of the pathology of DD ought to be an appealing avenue for researchers to pursue. PMID- 23106047 TI - To what extent can artificial neural network support nuclear medicine? AB - Artificial Neural Networks (ANN) are computer programs that emulate the operation of a large number of processing units that mimic the fundamental mechanisms of the biological activity of nervous cells as well as their connections and interactions. As a human brain, an ANN has the ability to learn from the experience of general relations between variables and thus ANN are particularly suitable to capture the natural complexity of medical data. Today ANN are widely used as a tool for computer aided diagnosis. This editorial discusses to what extent ANN can support Nuclear Medicine. PMID- 23106048 TI - Postoperative granulomas versus tumor recurrence: PET and SPET scans as strategic adjuvant tools to conventional neuroradiology. AB - A mandatory differential diagnosis between postoperative granulomas and tumor recurrence is required whenever space-occupying lesions are detected at the surgical site, few months after removal of the intracranial neoplasm, because these two pathologies can often mimic each other clinically, by imaging techniques and even macroscopically. Since history or signs of inflammation may be lacking, and neurological complaints are generally nonspecific, a thorough imaging investigation is usually the only way to diagnosis. Herein we discuss the pathological basis and timing of granuloma formation along with the imaging characteristics and nuclear medicine findings necessary to confirm or exclude the diagnosis of tumor recurrence. In conclusion, the high sensitivity of positron emission tomography and the wide availability of single photon emission tomography can identify certain parameters (isometabolism, uptake in macrophages, etc.) to support differential diagnosis between postoperative granulomas and tumor recurrence. PMID- 23106049 TI - Feasibility of estimation of brain volume and 2-deoxy-2-(18)F-fluoro-D-glucose metabolism using a novel automated image analysis method: application in Alzheimer's disease. AB - The development of clinically-applicable quantitative methods for the analysis of brain fluorine-18 fluoro desoxyglucose-positron emission tomography ((18)F-FDG PET) images is a major area of research in many neurologic diseases, particularly Alzheimer's disease (AD). Region of interest visualization, evaluation, and image registration (ROVER) is a novel commercially-available software package which provides automated partial volume corrected measures of volume and glucose uptake from (18)F-FDG PET data. We performed a pilot study of ROVER analysis of brain (18)F-FDG PET images for the first time in a small cohort of patients with AD and controls. Brain (18)F-FDG-PET and volumetric magnetic resonance imaging (MRI) were performed on 14 AD patients and 18 age matched controls. Images were subjected to ROVER analysis, and voxel-based analysis using SPM5. Volumes by ROVER were 35% lower than MRI volumes in AD patients (as hypometabolic regions were excluded in ROVER-derived volume measurement ) while average ROVER- and MRI-derived cortical volumes were nearly identical in control population. Whole brain volumes when ROVER-derived and whole brain metabolic volumetric products (MVP) were significantly lower in AD and accurately distinguished AD patients from controls (Area Under the Curve (AUC) of Receiver Operator Characteristic (ROC) curves 0.89 and 0.86, respectively). This diagnostic accuracy was similar to voxel-based analyses. Analysis by ROVER of (18)F-FDG-PET images provides a unique index of metabolically-active brain volume, and can accurately distinguish between AD patients and controls as a proof of concept. In conclusion, our findings suggest that ROVER may serve as a useful quantitative adjunct to visual or regional assessment and aid analysis of whole-brain metabolism in AD and other neurologic and psychiatric diseases. PMID- 23106050 TI - Age-related inflammatory changes in the spine as demonstrated by (18)F-FDG PET:observation and insight into degenerative spinal changes. AB - Our aim was to determine whether the inflammatory component associated with age related degenerative changes in the spine can be assessed by (18)F-fluoro-2 deoxy-D-glucose positron emission tomography ((18)F-FDG-PET). Mean and maximum standardize uptake values (SUV(mean) and SUV(max)) of intervertebral discs and spinous processes were measured in 45 patients who had undergone (18)F-FDG-PET for any clinical indication. Correlations between age and FDG-PET indices (SUV(mean) and SUV(max) of intervertebral discs and spinous processes) were determined. Pearson's correlation coefficients between age and intervertebral disc SUV(mean), between age and intervertebral disc SUV(max), and between age and spinous process SUV(mean) were 0.4821, 0.3946, and 0.5017 (P<0.05), indicating moderate positive correlations between these parameters. However, Pearson's correlation coefficient between age and spinous process SUV(max)was 0.7998 (P>0.05), indicating no correlation between these two parameters. In conclusion, intensity of (18)F-FDG uptake in the intervertebral discs and spinous processes generally increases with aging, which is likely to reflect associated inflammatory processes. PMID- 23106051 TI - Is there an added clinical value of "true"whole body(18)F-FDG PET/CT imaging in patients with malignant melanoma? AB - Accurate and reliable staging of disease extent in patients with malignant MM is essential to ensure appropriate treatment planning. The detection of recurrent or residual malignancy after primary treatment is important to allow for early intervention and to optimise patient survival. 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) PET or PET computed tomography (PET/CT) is indicated for surveillance of malignant MM due to its high sensitivity and specificity for soft-tissue or nodal recurrences and metastases. It has been claimed that including lower extremities and skull in addition to 'eyes to thigh' images in PET/CT evaluation of metastatic MM routinely is warranted. We have studied retrospectively the reports of whole-body PET/CT scans in all patients with MM scanned in our Department from April 2005 to December 2010. All PET abnormalities in the brain/scalp and lower extremities were tabulated by location and whether they were 'expected' or 'unexpected'. Findings were correlated with pathology, other imaging studies, and clinical follow-up. In this study, 398 PET/CT examinations in 361 patients with MM were included. Results showed that twelve of the 398 (3%) scans had brain/scalp abnormalities, with only 4 (1.0%) showing unexpected abnormalities. Twenty nine of the 398 (7.2%) scans showed lower extremity abnormalities, with only 5 (1.2%) showing unexpected abnormalities. In no case was an isolated unexpected malignant lesion identified in the brain/scalp or lower extremities. In conclusion, whole body PET/CT scan showed about 1% unexpected primary or metastatic MM lesions involving the head or lower extremities, which seldom offered significant additional clinical benefit and were unlikely to change clinical management. No clinically significant change in staging would have occurred. Routine 'eyes to thighs' images were adequate for this subset of patients. PMID- 23106052 TI - Imaging proliferation in human leukemia-tumor bearing mice with (18)F-FLT: Comparison with (18)F-FDG PET. AB - Leukemia threatens human life due to its uncontrolled proliferative malignancy. 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) has been suggested as a new positron emission tomography (PET) tracer for imaging tumor proliferation. The aim of the study was to investigate the usefulness of (18)F-FLT PET for imaging human leukemia-tumor bearing mice, compared with fluorine-18-fluorodesoxyglucose ((18)F-FDG PET). In vitro the experiments of (18)F-FLT and (18)F-FDG uptake were performed in K562 cell lines at various time points and radioactive tracer uptake was measured in a gamma counter. (18)F-FLT and (18)F-FDG PET imaging were performed both in the same mouse when eight tumor-bearing mice models of human chronic myeloid leukemia were established successfully by injecting K562 cells. Regions of interest were drawn over the tumor, the crossed normal tissue was regarded as background and the ratio of tumor to non-tumor counts (T/NT) in tissues was calculated. A higher uptake of (18)F-FLT (15min, 5.73+/-0.05%; 30min, 5.90+/-0.06%; 60min, 6.16+/-0.19%; 120min, 6.32+/-0.08%) than that of (18)F-FDG (15min, 1.05+/-0.10%; 30min, 1.11+/-0.14%; 60min, 1.14+/-0.37%; 120 min, 1.36+/-0.25%) was observed in K562 cells in the tracer uptake experiment. Ratios of T/NT of (18)F-FLT PET (0.5h, 5.39+/-0.42; 1h, 4.88+/-0.43; 2h, 3.81+/ 0.38) were higher than those of (18)F-FDG PET/CT (0.5h, 0.34+/-0.12; 1h, 0.21+/ 0.06; 2h, 0.13+/-0.05) after injection. Both uptake and T/NT differences of (18)F-FLT versus (18)F-FDG were significant (P>0.05). In conclusion, (18)F-FLT and (18)F-FDG quantitative and semi-quantitative uptake measurements resulting from cell lines and PET imaging respectively suggested a promising potential of (18)F-FLT for metabolic imaging of human chronic myeloid leukemia. PMID- 23106053 TI - New normal values not related to age and sex, of glomerular filtration rate by (99m)Tc-DTPA renal dynamic imaging, for the evaluation of living kidney graft donors. AB - The aim of this study was to investigate the normal values of glomerular filtration rate (GFR) by technetium-99m diaethylene-triamine-pentaacetic acid ((99m)Tc-DTPA) renal dynamic imaging for living kidney graft donors. In a total of 212 candidate donors, GFR was examined using (99m)Tc-DTPA renal dynamic imaging. Donors with GFR>=80mL/(min*1.73m(2)) and as low as with GFR>=70mL/(min*1.73m(2)) but a normal endogenous creatinine clearance rate (CCr) were quantified for living kidney donation. Differences in GFR levels based on sex and age were analyzed using rank correlation coefficient. Out of the 212 candidates, 161 were finally selected as kidney graft donors. The double kidney total GFR between the male and female donor groups, the GFR levels among differently-aged donor groups, and the GFR levels between the elderly (>55 years) and young- and middle-aged (<=55 years) donor groups did not show any significant difference (P>0.05). After kidney donation, renal function measured by blood urea nitrogen (BUN) and serum creatinine of all donors returned to normal within one week, and no serious complications were noticed. In conclusion, renal dynamic imaging by (99m)Tc-DTPA had a good accuracy and repeatability in GFR evaluation for living kidney donors. Candidate donors with GFR between 70mL/(min*1.73m(2)) and 80mL/(min*1.73m(2)) can be selected as kidney donors after strict screening. In living kidney donors GFR is not significantly correlated with age or sex. PMID- 23106054 TI - Lower limb deep vein thrombosis in patients with suspected pulmonary embolism detected with (99m)Tc-MAA simultaneously with lung perfusion scan. AB - The aim of this study was to evaluate the incidence of deep vein thrombosis (DVT) in patients with suspected pulmonary embolism (PE) and the relation between PE and the site of DVT by using technetium-99m-macroaggregated human serum albumin ((99m)Tc-MAA) radionuclide venography (RNV). Technetium-99m-MAA RNV was performed simultaneously with lung perfusion scintigraphy in 123 patients with suspected PE. The incidence of DVT in patients with suspected PE was 58.54%. The incidence of DVT in patients with PE was 77.46%, while in patients without PE was 32.69%. The rate of proximal DVT in patients with PE was 74.55%, while in patients without PE was 47.06%. The average embolic lung segments in patients with proximal DVT and patients with distal DVT were 6.2+/-2.3 and 3.1+/-1.2, respectively. In conclusion, lower limb (99m)Tc-MAA RNV demonstrated a high incidence (58.54%) of DVT in patients with suspected PE. The prevalence of DVT was higher in patients with PE than in patients without PE. Pulmonary embolism was more likely to occur in patients with proximal DVT, and more embolic lung segments were detected in patients with proximal DVT. PMID- 23106055 TI - Imaging beyond the striatonigral dopaminergic system in Parkinson's disease. AB - Parkinson 's disease (PD) is characterized by progressive loss of dopaminergic neurons in the nigrostriatal pathway, but this seems to constitute only part of the whole pathological process of the disease. Accumulating data have documented the concomitant degeneration of other dopaminergic pathways and of the serotonergic, cholinergic and noradrenergic neurotransmitter systems. In addition, pathologic process is not only restricted in the brain, since the spinal cord and the peripheral autonomic nervous system are also affected. The pathogenesis of PD remains unclear. The use of positron emission tomography and single photon emission tomography may contribute to the understanding of these aspects of the disease. This review will discuss the role of PET and SPET in imaging the extrastriatal dopaminergic system and other neurotransmitter systems as well as the imaging of microglial activation and cardiac sympathetic denervation in PD. In conclusion, several PET and SPET ligands can detect changes in extrastriatal dopaminergic system as well as in the serotonergic, cholinergic and noradrenergic systems in PD and also explore its possible correlation with motor and non motor symptoms. The use of PET scintigraphy allows the detection of microglial activation in PD, while (123)I-MIBG scintigraphy depicts cardiac sympathetic denervation in PD and is a useful imaging tool for differentiating PD from other types of parkinsonism. PMID- 23106056 TI - Uncommon metastases from differentiated thyroid carcinoma. AB - Differentiated thyroid carcinoma (DTC) usually behaves in an indolent manner with low metastatic potential. The major sites of distant metastases are the lung and bone. Metastases to the brain, eye, breast, liver, kidney, muscle and skin are rare or relatively rare. These metastases have almost always appeared in patients with advanced disease and are often associated with poor prognosis but overlooked in clinical practice. Recognizing them has a significant impact on clinical decision-making and prognosis of the patients. Treatment in these patients should be individualized and an alternative therapeutic approach should be considered. Care should be taken to determine whether a (131)I uptake focus found at an unexpected site of (131)I- whole body scan (WBS) is a DTC metastasis or a false positive (131)I uptake. Imaging with (131)I-SPET/CT is of incremental value in the finding of rare metastases from DTC. In conclusion, DTC can have unusual metastatic presentations and patterns. Post-therapy (131)I-WBS and (131)I-SPET/CT play an important role in the management of patients with DTC. PMID- 23106057 TI - Incidental detection of rare mesenteric inflammatory pseudotumor by (18)F-FDG PET. AB - A 60 years old asymptomatic male underwent fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) for his medical check-up, and abnormal (18)F-FDG uptake was observed in the retroperitoneum. The maximum standardized uptake value (SUV (max)) was 5.2. Based on CT, MRI and (18)F-FDG PET findings, the differential diagnosis included specific or non-specific inflammatory change, malignant lymphoma, trauma, gastrointestinal stromal tumor and soft-tissue sarcoma. Tumor resection was performed, and the histopathological finding was an inflammatory pseudotumor (IPT) originating at the mesentery in the retropetonium. After two years and eight months from his initial operation, recurrent IPT was detected by (18)F-FDG PET for follow-up, although he was asymptomatic. The IPT could be of traumatic origin since the patient suffered a severe abdominal trauma 6 months before. A mesenteric IPT is very rare, and to our knowledge, this is the first case report of (18)F-FDG PET detecting a mesenteric IPT. In conclusion, when abnormal high (18)F-FDG uptake is observed in the mesentery incidentally in clinical routine examination, IPT should be included as one of the differential diagnoses. (18)F-FDG may be useful in detecting local recurrence and follow-up after operation. PMID- 23106059 TI - Rhabdomyolysis after spin class? AB - Two case reports involving the increasingly popular activity of "spinning" underscore the need for proper conditioning and adequate hydration before exercising strenuously. PMID- 23106060 TI - Diagnosing and treating opioid dependence. AB - The surge in opioid abuse highlights the importance of questioning patients about their use of prescription analgesics--and knowing when and how to intervene. PMID- 23106061 TI - Postmenopausal bleeding-first steps in the workup. AB - Is it endometrial cancer? When a postmenopausal woman presents with unexpected vaginal bleeding, this algorithm and review can help you answer that question without delay. PMID- 23106062 TI - Battling influenza: changes for the 2012-2013 season. AB - A revised vaccine algorithm aids in decision making for children ages 6 months to 8 years; a newly approved quadrivalent LAIV should be available for the 2013-2014 season. PMID- 23106063 TI - PURLs: Rethinking antibiotics for sinusitis: again. AB - Previous evidence rejected the need for antibiotics to treat acute rhinosinusitis, unless the symptoms were severe. A new study finds little reason to prescribe them even then. PMID- 23106064 TI - Hyperpigmentation and atrophy. AB - We suspected a malignancy, but a conversation with the patient provided a telling clue. PMID- 23106065 TI - Clinical Inquiry: Can calcium supplements cause serious adverse effects in healthy people? AB - Yes, according to studies with some limitations. Calcium supplements with or without vitamin D increase the risk of myocardial infarction, with numbers needed to harm (NNH) over 5 years of 69 to 240 (strength of recommendation: B, meta analyses of randomized controlled trials that evaluated a predominantly older female population and were limited by study designs). PMID- 23106066 TI - Clinical Inquiry: What treatments relieve painful heel cracks? AB - Emollient cream may alleviate pain and dryness and improve the appearance of heel cracks. PMID- 23106067 TI - Hypothyroidism management: is an annual check of TSH level always necessary? AB - Perhaps not. Less frequent measurements may be appropriate for some patients. Our study reveals when you may be able to safely extend the monitoring cycle. PMID- 23106068 TI - Managing hypoglycemia in primary care. AB - LEARNING OBJECTIVES: Compare the risk of hypoglycemia among glucose-lowering agents. Identify patient risk factors and behaviors that increase the risk of hypoglycemia. Describe techniques physicians may use to identify patients at risk for hypoglycemia. Describe patient education strategies regarding hypoglycemia. PMID- 23106069 TI - Introducing the National Institute for Health and Clinical Excellence. AB - England and Wales' National Institute for Health and Clinical Excellence ensures quality and cost effectiveness for drugs and treatments in the NHS. Helen Jaques looks at what it does and why. PMID- 23106070 TI - Scandinavia's journal for cardiologists and cardiothoracic surgeons. AB - Scandinavian Cardiovascular Journal began as a journal for cardiothoracic surgery, but joining forces with cardiology has increased the impact factor and number of subscribers. PMID- 23106072 TI - Retraction notice to "Effect of cadmium on resumption of respiration in cotyledons of germinating pea seeds" [Ecotoxicol. Environ. Saf. 73(6) (2010) 1246 1254]. PMID- 23106071 TI - Guidelines and guesswork. AB - With ever more guidelines being published, Lois Rogers looks at their development and shortcomings PMID- 23106073 TI - Vital signs are unreliable. PMID- 23106074 TI - Functional axillary anatomy: time for a new look at the clavipectoral fascia? PMID- 23106075 TI - An optical switch for a motor protein. AB - Light-triggered motor: Incorporation of a photocleavable group onto a phosphoserine residue of the regulator of a motor protein allows light-induced activation with spatial and temporal precision inside a living cell. PMID- 23106076 TI - Genome mining reveals two novel bacterial sesquiterpene cyclases: (-) germacradien-4-ol and (-)-epi-alpha-bisabolol synthases from Streptomyces citricolor. AB - Now found in bacteria: An increasing number of genome sequences indicate that bacteria possess a variety of terpenoid cyclase genes. The characterization of two sesquiterpene cyclase (SC) genes found in the draft genome sequence of Streptomyces citricolor is described here. Our study strongly supports the idea that genome mining is a useful approach in revealing the terpenoid diversity in bacteria. PMID- 23106077 TI - Prenylation of flavonoids by using a dimethylallyltryptophan synthase, 7-DMATS, from Aspergillus fumigatus. AB - Production of typical plant metabolites by a fungal enzyme: Fungal prenyltransferases of the DMATS superfamily are mainly involved in the biosynthesis of prenylated indole alkaloids, but also catalyze the prenylation of tyrosine and naphthalene derivatives. In this study, nine prenylated flavonoids were produced by using the recombinant dimethylallyltryptophan synthase 7-DMATS from Aspergillus fumigatus. PMID- 23106078 TI - Assessing oxazole bioisosteres as mutasynthons on the rhizoxin assembly line. AB - Chain armor against tumor cells: The oxazole side chain in the antimitotic agent rhizoxin S2 (1) was successfully replaced through mutasynthesis by using an engineered mutant impaired in heterocyclization. Incorporation of 12 non-natural surrogates into fully processed rhizoxin analogues revealed a remarkable substrate flexibility of the PKS-NRPS hybrid. PMID- 23106079 TI - Mutant malonyl-CoA synthetases with altered specificity for polyketide synthase extender unit generation. AB - Tailoring guide: We have used structure-guided saturation mutagenesis followed by colorimetric screening to identify mutant malonyl-CoA synthetases with altered substrate specificity. One particular mutant displayed a 240-fold shift in specificity (see graphic). These mutant enzymes will be useful tools for providing extender units to probe the activity of polyketide synthases. PMID- 23106080 TI - A modular and noncovalent transduction system for leucine-zipper-tagged proteins. AB - Modes of transport: A leucine-zipper-tagged GFP was transported into cells by "zipping" it (red) to it's complementary leucine zipper (blue) functionalized with a cell-penetrating peptide (CPP). This transport system has an inherent modularity as the CPP is "clicked" to the leucine zipper, and then noncovalently bound to the protein, thus making it system particularly useful for targeting studies. PMID- 23106082 TI - High-resolution characterization of intrinsic disorder in proteins: expanding the suite of (13)C-detected NMR spectroscopy experiments to determine key observables. AB - Order in disorder: The characterization of intrinsically disordered proteins by NMR spectroscopy is a necessity on the one hand and a continuous challenge on the other. We propose two experiments that provide diagnostic parameters to monitor the degree of unfolding of a polypeptide. The test was performed on the yeast Cox17 protein, known to gain its function through maturation from an intrinsically disordered state (see figure). PMID- 23106081 TI - N-methyl-substituted fluorescent DAG-indololactone isomers exhibit dramatic differences in membrane interactions and biological activity. AB - N-methyl-substituted diacylglycerol-indololactones (DAG-indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCalpha. We present a comprehensive analysis of membrane interactions and biological activities of several DAG-indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG-indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands. PMID- 23106083 TI - Triplex-forming twisted intercalating nucleic acids (TINAs): design rules, stabilization of antiparallel DNA triplexes and inhibition of G-quartet-dependent self-association. AB - The majority of studies on DNA triple helices have been focused on pH-sensitive parallel triplexes with Hoogsteen CT-containing third strands that require protonation of cytosines. Reverse Hoogsteen GT/GA-containing antiparallel triplex forming oligonucleotides (TFOs) do not require an acidic pH but their applicability in triplex technology is limited because of their tendency to form undesired highly stable aggregates such as G-quadruplexes. In this study, G-rich oligonucleotides containing 2-4 insertions of twisted intercalating nucleic acid(TINA) monomers are demonstrated to disrupt the formation of G-quadruplexes and form stable antiparallel triplexes with target DNA duplexes. The structure of TINA-incorporated oligonucleotides was optimized, the rules of their design were established and the optimal triplex-forming oligonucleotides were selected. These oligonucleotides show high affinity towards a 16 bp homopurine model sequence from the HIV-1 genome; dissociation constants as low as 160 nM are observed whereas the unmodified TFO does not show any triplex formation and instead forms an intermolecular G-quadruplex with T(m) exceeding 90 degrees C in the presence of 50 mM NaCl. Here we present a set of rules that help to reach the full potential of TINATFOs and demonstrate the effect of TINA on the formation and stability of triple helical DNA. PMID- 23106084 TI - Work experience: Stepping stones. PMID- 23106085 TI - A conversation with Jean Wilson. Interview by Ushma S. Neill. PMID- 23106088 TI - Surgical management of intraductal papillary mucinous neoplasms. PMID- 23106086 TI - Complement, oxidants, and endothelial injury: how a bedside observation opened a door to vascular biology. AB - A single encounter with a dialysis patient led to the study of complement and neutrophil aggregation, which in turn spawned our work and the remarkable development of the field of vascular biology. As our understanding of these cellular interactions and the signaling pathways involved in these processes has expanded, so has our appreciation for the broad impact of this work on an array of human diseases. PMID- 23106089 TI - Gastric cancer - state of the art in Japan. PMID- 23106090 TI - Synthesis of pinacol arylboronates from aromatic amines: a metal-free transformation. AB - A metal-free borylation process based on Sandmeyer-type transformation using arylamines derivatives as the substrates has been developed. Through optimization of the reaction conditions, this novel conversion can be successfully applied to a wide range of aromatic amines, affording borylation products in moderate to good yields. Various functionalized arylboronates, which are difficult to access by other methods, can be easily obtained with this metal-free transformation. Moreover, this transformation can be followed by Suzuki-Miyaura cross-coupling without purification of the borylation products, which enhances the practical usefulness of this method. A possible reaction mechanism involving radical species has been proposed. PMID- 23106091 TI - Tensile lattice distortion does not affect oxygen transport in yttria-stabilized zirconia-CeO2 heterointerfaces. AB - Biaxially textured epitaxial thin-film heterostructures of ceria and 8 mol % yttria-stabilized zirconia (8YSZ) were grown using pulsed laser deposition (PLD) with the aim to unravel the effect of the interfacial conductivity on the charge transport properties. Five different samples were fabricated, keeping the total thickness constant (300 nm), but with a different number of heterointerfaces (between 4 and 60). To remove any potential contribution of the deposition substrate to the total conductivity, the heterostructures were grown on (001) oriented MgO single-crystalline wafers. Layers free of high-angle grain boundaries and with low density of misfit dislocations were obtained, as revealed by X-ray diffraction (XRD) and high-resolution transmission electron microscopy (HR-TEM) analysis. The crystallographic quality of these samples allowed the investigation of their conduction properties, suppressing any transport effects along grain boundaries and/or interfacial dislocation pathways. Electrochemical impedance spectroscopy (EIS) and secondary ion mass spectroscopy (SIMS) measurements showed that for these samples the interfacial conductivity has a negligible effect on the transport properties. PMID- 23106092 TI - Influence of endogenous ferulic acid in whole wheat flour on bread crust aroma. AB - The influence of wheat flour type (refined (RWF)/whole (WWF)) on bread crust aroma was investigated. Differences were characterized by aroma extract dilution analysis and quantified utilizing stable isotope surrogate standards. For RWF breads, five aroma compounds were higher in concentration, 2-acetyl-1-pyrroline, 4-hydroxy-2,5-dimethyl-3(2H)-furanone, 2-phenylethanol, 2-acetyl-2-thiazoline, and 2,4-dihyroxy-2,5-dimethyl-3(2H)-furanone, by 4.0-, 3.0-, 2.1-, 1.7-, and 1.5 fold, respectively, whereas three compounds were lower, 2-ethyl-3,5 dimethylpyrazine, (E,E)-2,4-decadienal, and (E)-2-nonenal by 6.1-, 2.1-, and 1.8 fold, respectively. A trained sensory panel reported the perceived aroma intensity of characteristic fresh refined bread crust aroma was significantly higher in RWF compared to WWF crust samples. Addition of 2-acetyl-1-pyrroline, 4 hydroxy-2,5-dimethyl-3(2H)-furanone, 2-phenylethanol, 2-acetyl-2-thiazoline, and 2,4-dihyroxy-2,5-dimethyl-3(2H)-furanone to the WWF crust (at concentrations equivalent to those in the RWF crust) increased the intensity of the fresh refined bread crust aroma attribute; no significant difference was reported when compared to RWF crust. The liberation of ferulic acid from WWF during baking was related to the observed reduction in these five aroma compounds and provides novel insight into the mechanisms of flavor development in WWF bread. PMID- 23106093 TI - Exercise therapy improves mental and physical health in schizophrenia: a randomised controlled trial. AB - OBJECTIVE: The objective of this multicenter randomised clinical trial was to examine the effect of exercise versus occupational therapy on mental and physical health in schizophrenia patients. METHOD: Sixty-three patients with schizophrenia were randomly assigned to 2 h of structured exercise (n = 31) or occupational therapy (n = 32) weekly for 6 months. Symptoms (Positive and Negative Syndrome Scale) and cardiovascular fitness levels (Wpeak and VO2peak ), as assessed with a cardiopulmonary exercise test, were the primary outcome measures. Secondary outcome measures were the Montgomery and Asberg Depression Rating Scale, Camberwell Assessment of Needs, body mass index, body fat percentage, and metabolic syndrome (MetS). RESULTS: Intention-to-treat analyses showed exercise therapy had a trend-level effect on depressive symptoms (P = 0.07) and a significant effect on cardiovascular fitness, measured by Wpeak (P < 0.01), compared with occupational therapy. Per protocol analyses showed that exercise therapy reduced symptoms of schizophrenia (P = 0.001), depression (P = 0.012), need of care (P = 0.050), and increased cardiovascular fitness (P < 0.001) compared with occupational therapy. No effect for MetS (factors) was found except a trend reduction in triglycerides (P = 0.08). CONCLUSION: Exercise therapy, when performed once to twice a week, improved mental health and cardiovascular fitness and reduced need of care in patients with schizophrenia. PMID- 23106095 TI - Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. AB - Juvenile myoclonic epilepsy is the most common idiopathic epilepsy syndrome and is considered a benign seizure disorder that responds well to antiepileptic drug treatment, in particular sodium valproate. By definition, routine brain imaging shows no abnormalities, but advanced imaging studies have identified functional and structural abnormalities in the frontal cortex and thalamus. Neuropsychological studies revealed subtle cognitive deficits in patients with JME, mainly implicating the frontal lobes. These findings are in keeping with anecdotal reports of behavioral problems in JME. Cognitive dysfunction in otherwise healthy siblings of patients with JME and a high heritability support the concept of a genetically determined thalamo-frontocortical network dysfunction, accounting for the cognitive impairment and cognitively triggered "motor seizures." PMID- 23106094 TI - Characterization of long-acting beta2-adrenergic agonists utilization in asthma patients. AB - OBJECTIVE: Because of the serious safety risks, Food and Drug Administration (FDA) has recommended that long-acting beta2-adrenergic agonists (LABAs) be reserved for patients whose asthma cannot be adequately managed with asthma control medication. The objective of the study is to assess prescribing patterns for LABAs prior to the FDA's drug safety communication issued on 2 June 2010. METHODS: Data were extracted from IMS Health Plan Claims database for asthma patients who had a new LABA therapy during 2005-2009. The proportion of LABA incident episodes preceded by inhaled corticosteroid (ICS) or leukotriene receptor antagonists (LTRAs) was examined. The medication-concurrent ratio (MCR), defined as the ratio of overlapping therapy days of single-ingredient (SI) LABAs and non-LABA products to the total days of SI LABAs, was calculated. Four criteria were used to estimate poorly controlled asthma prior to LABA initiation. RESULTS: Of the 228 047 asthma patients, fixed-dose combination (FDC) LABAs were used by the majority of patients (96%). Prior use of ICS or LTRAs was observed in 64% and 31% of SI and FDC LABA incident episodes, respectively. The median MCR for SI LABAs was 62%. Approximately half of the patients met at least one criterion for poorly controlled asthma prior to LABA use. CONCLUSIONS: Substantial proportion of patients was prescribed LABAs without prior use of ICS or LTRAs, or other indicators of poor asthma control. These findings suggest that asthma guidelines were not entirely followed in clinical practice during the study period. PMID- 23106096 TI - Influence of zirconia abutment preparation on the fracture strength of single implant lithium disilicate crowns after chewing simulation. AB - OBJECTIVE: The use of all-ceramic crowns over zirconia abutments is a well established esthetic treatment option in implant dentistry; however, the effect of the mechanical processing due to abutment preparation has not been investigated under functional loading. The purpose of the study was to evaluate the influence of the zirconia abutment preparation depth and preparation mode on the fracture strength and fracture mode of lithium disilicate crowns after chewing simulation. MATERIAL AND METHODS: Seventy single implant-supported lithium disilicate glass-ceramic crowns (IPS e.max Press, Ivoclar Vivadent) were adhesively cemented (Multilink Automix, Ivoclar Vivadent) onto zirconia abutments (ZirDesign, Astra Tech) using implants with a diameter of 4.5 mm and a length of 15.0 mm (Osseospeed, Astra Tech). Study design concerned the replacement of a maxillary central incisor (11.0 mm in height and 8.0 mm in width). Subgroups (n = 7) were subjected to dynamic loading (C) up to 1.2 * 10(6) loading cycles at 135 degrees with 98N in a thermomechanical chewing simulator (Kausimulator, Willytech); followed by quasi-static loading at a cross-head speed of 0.5 mm/min until fracture in a universal testing machine (Z010/TN2S, Zwick). Additional subgroups were also subjected to quasi-static loading (S) at 135 degrees . Lithium disilicate implant crowns were divided into five study groups (n = 14) according to the abutment preparation depth [A (control): 0.5 mm, B: 0.7 mm, C: 0.9 mm, and preparation mode [(No label): milling by the manufacturer, (P): copy milling by the Celay System (Mikrona)]. RESULTS: All specimens survived dynamic loading and mean fracture strengths (N) after quasi-static loading were as follows: Group SA: 384 +/- 84; Group CA: 403 +/- 67; Group SB: 294 +/- 95; Group CB: 374 +/- 75; Group SC: 332 +/- 52; Group CC: 373 +/- 105; Group SPB: 332 +/- 80; Group CPB: 499 +/- 91; Group SPC: 380 +/- 101; and Group CPC: 358 +/- 54. CONCLUSIONS: Statistical analysis using multiple linear regression showed that both the preparation depth and mode had no influence on the fracture strength of the implant crowns (P > 0.05); however, fracture strength increased statistically significantly after 5 years chewing simulation (P = 0.01). PMID- 23106097 TI - Performance goals in conflictual social interactions: towards the distinction between two modes of relational conflict regulation. AB - Socio-cognitive conflict has been defined as a situation of confrontation with a disagreeing other. Previous research suggests that individuals can regulate conflict in a relational way, namely by focusing on social comparison between relative levels of competences. Relational conflict regulation has been described as yielding particularly negative effects on social interactions and learning, but has been understudied. The present research addresses the question of the origin of relational conflict regulation by introducing a fundamental distinction between two types of regulation, one based on the affirmation of one's own point of view and the invalidation of the other's (i.e., 'competitive' regulation), the other corresponding to the protection of self-competence via compliance (i.e., 'protective' regulation). Three studies show that these modes of relational conflict regulation result from the endorsement of distinct performance goals, respectively, performance-approach goals (trying to outperform others) and performance-avoidance goals (avoiding performing more poorly than others). Theoretical implications for the literature on both conflict regulation and achievement goals are discussed. PMID- 23106098 TI - Association of connexin43 with E3 ubiquitin ligase TRIM21 reveals a mechanism for gap junction phosphodegron control. AB - Gap junctions (GJs) are sites of direct cell-to-cell communication formed by the connexin (Cx) family of ion channel proteins. The aberrant intercellular communication mediated by GJs is associated with a variety of hereditary and acquired human diseases. GJs utilize a highly interconnected network that is indispensible for synthesis, trafficking and degradation of their constituent proteins. By unbiased proteomic examination and network enrichment, we identified interacting components of the ubiquitin proteasome system associated with Cx43. LC-MS/MS identification and quantification of tryptic peptides from IP materials revealed a variety of interacting candidates, including the E3 ligase TRIM21 and ubiquitin. The interaction of Cx43 with TRIM21 was confirmed by confocal microscopy and coimmunoprecipitation of these proteins from C6 rat glioma and mouse primary astrocyte cultures. To gain a better understanding of this interaction, complexes isolated by high-resolution size-exclusion chromatography revealed signal integration by phosphorylation, ubiquitylation and proteolytic turnover within complexes of Cx43/TRIM21. Cx43/TRIM21 is also responsive to E1 UBE1 and E2 UbcH5a, with the interruption of this activity being an effective inhibitor of in vitro ubiquitin-conjugation. Mathematical models of these complexes demonstrated a mechanism for the switch-like degradation of GJs that were validated in EGF-stimulated cell cultures. Our finding of the interaction of Cx43 with TRIM21 provides mechanisms for the down-regulation of GJ intercellular communication that are known to impact a variety of physiological processes. PMID- 23106099 TI - Unravelling the role of the central metal ion in the electronic structure of tris(8-hydroxyquinoline) metal chelates: photoemission spectroscopy and hybrid functional calculations. AB - The electronic structures of tris(8-hydroxyquinolinato)-erbium(III) (ErQ(3)) and tris(8-hydroxyquinolinato)-aluminum(III) (AlQ(3)) have been studied by means of core level and valence band photoemission spectroscopy with the theoretical support of hybrid Heyd-Scuseria-Ernzerhof density functional theory, to investigate the role played by the central metal atom. A lower binding energy (0.2 eV and 0.3 eV, respectively) of the O 1s and N 1s core levels has been observed for ErQ(3) with respect to AlQ(3). Differences in the valence band spectra, mainly related to the first two peaks next to the highest occupied molecular orbital (HOMO), have been ascribed to an energetic shift (to 0.4 eV lower energies for ErQ(3)) of the sigma molecular orbital between the oxygen atoms and the central metal atom. A lower (by 0.5 eV) ionization energy has been measured for the ErQ(3). The interpretation of these results is based on a reduced interaction between the central metal atom and the ligands in ErQ(3), with increased electronic charge around the ligands, due to the higher ionic radius and the lower electronegativity of Er with respect to Al. PMID- 23106101 TI - Family boundary structures and child adjustment: the indirect role of emotional reactivity. AB - Structural and system theories propose that disruptions in family subsystem functioning increase risk for youth maladjustment. While there is growing evidence to support this proposition, studies that specifically focus on the larger family system remain relatively rare. Furthermore, the pathways that connect problems in family subsystem alliances to externalizing or internalizing problems in youth are as yet largely unexplored. This study examined youth emotional reactivity (anger and sadness) to family conflict as an indirect pathway of the association between family boundary disturbances and youth adjustment in a sample of two-parent families (N = 270). Observational coding was used to group families into Balanced, Dyadic, or Disengaged family alliance structures and to assess youth emotional reactivity, and parent-report was used to assess youth psychopathology. Structural equation modeling indicated both anger and sadness served as indirect pathways through which family boundary disturbances are linked with youth adjustment. In addition, gender was tested as a moderator and important gender differences were found. Specifically, boys were directly impacted by dyadic disturbances while girls were directly impacted by family disengagement. The findings help target goals for intervention and indicate that worthwhile objectives may include realigning family subsystem boundaries, changing family communication patterns, and improving affective coping skills for youth. PMID- 23106100 TI - Suppression of pain-related behavior in two distinct rodent models of peripheral neuropathy by a homopolyarginine-conjugated CRMP2 peptide. AB - The N-type voltage-gated calcium channel (CaV2.2) is a clinically endorsed target in chronic pain treatments. As directly targeting the channel can lead to multiple adverse side effects, targeting modulators of CaV2.2 may prove better. We previously identified ST1-104, a short peptide from the collapsin response mediator protein 2 (CRMP2), which disrupted the CaV2.2-CRMP2 interaction and suppressed a model of HIV-related neuropathy induced by anti-retroviral therapy but not traumatic neuropathy. Here, we report ST2-104 -a peptide wherein the cell penetrating TAT motif has been supplanted with a homopolyarginine motif, which dose-dependently inhibits the CaV2.2-CRMP2 interaction and inhibits depolarization-evoked Ca(2+) influx in sensory neurons. Ca(2+) influx via activation of vanilloid receptors is not affected by either peptide. Systemic administration of ST2-104 does not affect thermal or tactile nociceptive behavioral changes. Importantly, ST2-104 transiently reduces persistent mechanical hypersensitivity induced by systemic administration of the anti retroviral drug 2',3'-dideoxycytidine (ddC) and following tibial nerve injury (TNI). Possible mechanistic explanations for the broader efficacy of ST2-104 are discussed. PMID- 23106102 TI - Tough love or hostile domination? Psychological control and relational induction in cultural context. AB - The authors examined 2 forms of parental psychological control and how they related to child behavior problems in 2 cultural groups. A sample of 165 Hong Kong (HK) Chinese and 96 European American (EA) parents completed measures of parental control strategies, parental rejection, and child behavior problems. The use of hostile psychological control (criticism, interference, invalidation) was more strongly associated with the use of relational induction (guilt induction, shaming, reciprocity, social comparison) among EAs compared with HK parents. Psychological control was related to parental rejection across both groups, but it was only independently associated with child behavior problems for EA families. Relational induction, on the other hand, was not associated with child behavior problems in either group but was more strongly associated with parental rejection among EAs compared with HK parents. The findings suggest that there are distinguishable forms of psychological control that may have distinctive implications for parent-child relations and child behavioral adjustment depending on the cultural context. PMID- 23106103 TI - Dynamic properties of functional connectivity in the rodent. AB - Functional connectivity mapping with resting-state magnetic resonance imaging (MRI) has become an immensely powerful technique that provides insight into both normal cognitive function and disruptions linked to neurological disorders. Traditionally, connectivity is mapped using data from an entire scan (minutes), but it is well known that cognitive processes occur on much shorter time scales (seconds). Recent studies have demonstrated that the correlation between the blood oxygenation level-dependent (BOLD) MRI signal from different areas varies over time, motivating a further exploration of these fluctuations in apparent connectivity. However, it has also been shown that similar changes in correlation can arise when the timing relationships between voxels are randomized (Handwerker et al., 2012 ). In this work, we show that functional connectivity in the anesthetized rat exhibits dynamic properties that are similar to those previously observed in awake humans (Chang and Glover, 2010 ) and anesthetized monkeys (Hutchison et al., 2012 ). Sliding window correlation between BOLD time courses obtained from bilateral cortical and subcortical regions of interest results in periods of variable positive and negative correlation for most pairs of areas except homologous areas in opposite hemispheres, which exhibit a primarily positive correlation. A comparison with sliding window correlation of randomly matched time courses suggests that with the exception of homologous areas and sensorimotor connections, the dynamics cannot be distinguished from random fluctuations in correlation over time, supporting the idea that some of these dynamic patterns may be due to inherent properties of the signal rather than variations in neural coherence. Within the pairs of areas where the dynamics are most different from those of randomly matched time courses, ten common patterns of connectivity are identified, and their occurrence as a function of time is plotted for all animals. The observation of time-varying correlation in the rodent model will facilitate the future multimodal experiments needed to determine whether the changes in apparent connectivity are linked to underlying neural variability. PMID- 23106104 TI - Viability and activity of bifidobacteria during refrigerated storage of yoghurt containing Mangifera pajang fibrous polysaccharides. AB - The viability and activity of Bifidobacterium pseudocatenulatum G4, B. longum BB 536 and yoghurt cultures (Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus) were studied in yoghurt containing 0.75% Mangefira pajang fibrous polysaccharides (MPFP) and inulin. Growth of probiotic organisms, their proteolytic activities, the production of short chain fatty acids (lactic, acetic and propionic) and the pH of the yoghurt samples were determined during refrigerated storage at 4 degrees C for 28 d. B. pseudocatenulatum G4 and B. longum BB 536 showed better growth and activity in the presence of MPFP and inulin, which significantly increased the production of short chain fatty acids as well as the proteolytic activity of these organisms. PRACTICAL APPLICATION: This is the first study reported on produce synbiotic yoghurt as a functional food for specified health uses contains bifidobacteria and M. pajang fibrous polysaccharides. M. pajang fibrous polysaccharides can be used as a prebiotic particularly in dairy products to increase the viability and activity of bifidobacteria which can be used as probiotic to exert health benefit to the human by yoghurt that is considered common use in society; thus, the benefits of synbiotic yoghurt are readily accessible to the member of society. PMID- 23106105 TI - Review article: faecal incontinence in children: epidemiology, pathophysiology, clinical evaluation and management. AB - BACKGROUND: Faecal incontinence (FI) in children is a significant gastrointestinal problem, with great personal and social impacts. It is characterised by recurrent loss of faecal matter into the underwear. Both functional and organic causes contribute to its aetiology with the former predominating. AIM: To review the epidemiology, pathophysiology, clinical evaluation and management of functional faecal incontinence in children. METHODS: A PubMed search was conducted using search terms f(a)ecal incontinence, and encopresis. Articles on epidemiology, pathophysiology, clinical evaluation, investigation and management of functional FI in children were retrieved and assessed. RESULTS: Community prevalence of this distressing problem ranges from 0.8% to 7.8% globally. Male: female ratio varies from 3:1 to 6:1. The diagnosis of FI is often based on established clinical criteria. The majority (82%) have constipation associated functional FI. Biopsychosocial factors play a crucial role in the pathogenesis. Limited physiological testing of anorectal function is recommended in the diagnostic procedures, particularly in children with atypical symptoms and possible organic disorders. Management of FI needs a multidisciplinary approach which includes establishment of an effective doctor patient partnership, understanding the underlying mechanisms, pharmacotherapy and behavioural treatment. Approximately 15% of children with functional nonretentive faecal incontinence (FNRFI) had the same symptoms at the age of 18 years. CONCLUSION: Significant therapeutic advances have been made for retentive faecal incontinence, but treatment options for functional nonretentive faecal incontinence are limited. Limited long-term outcome data show that the majority outgrow faecal incontinence. A substantial proportion of children progress to adulthood with faecal incontinence. PMID- 23106106 TI - [Nle3,d-Phe6 ]-gamma2 -melanocyte-stimulating hormone possesses the renal excretory but not the cardiovascular actions of the native gamma2 -melanocyte stimulating hormone in anaesthetized rats. AB - The present study compared the cardiovascular and renal actions of gamma(2) melanocyte-stimulating hormone (gamma(2) MSH) with those of the synthetic analogue [Nle(3) ,d-Phe(6) ]-gamma(2) MSH (NDP-gamma(2) MSH) and explored the effects of high dietary salt intake on the renal actions of NDP-gamma(2) MSH. Both peptides were infused systemically (3-1000 nmol/kg) and intrarenally (500 fmol/min) into innervated and renally denervated rats fed either a normal (0.4% NaCl) or high-salt (4% NaCl; HS) diet. Mean arterial pressure (MAP), glomerular filtration rate (GFR), urinary sodium excretion (U(N) (a) V), urinary output (UV) and fractional sodium excretion were determined, as was expression of the melanocortin MC(3) receptor in inner medullary collecting duct (IMCD) epithelial cells. Both renal and systemic infusion of gamma(2) MSH increased MAP by 23 +/- 2% and 54 +/- 4%, respectively, but equivalent doses of NDP-gamma(2) MSH had no significant pressor effects. Both peptides had similar natriuretic and diuretic effects in rats fed a normal salt diet. However, NDP-gamma(2) MSH increased U(N) (a) V and UV by two- to threefold in rats fed the normal salt diet and by six- to sevenfold in rats fed the HS diet. Furthermore, NDP-gamma(2) MSH induced a 3.5 fold increase in GFR only in rats fed the HS diet. These renal effects of NDP gamma(2) MSH were not abolished by prior renal denervation. Rats fed the HS diet also exhibited a 4.5-fold increase in MC(3) receptor expression in IMCD epithelial cells. Intrarenal infusion of NDP-gamma(2) MSH induced the natriuretic but not the cardiovascular effects exhibited by gamma(2) MSH. The renal activities may be attributed to a direct binding of NDP-gamma(2) MSH to MC(3) receptors expressed in IMCD cells, leading to a potent natriuretic effect that is independent of renal innervation. PMID- 23106107 TI - Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study. AB - BACKGROUND: Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long-term safety. Interleukin (IL) 17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity. OBJECTIVES: To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1kappa monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 * 25 mg (n = 29), 3 * 25 mg (n = 26), 3 * 75 mg (n = 21) or 3 * 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12-week treatment period, patients entered a follow-up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator's Global Assessment (IGA) and PASI 90 and 50 response rates. RESULTS: After 12 weeks of treatment, secukinumab 3 * 150 mg and 3 * 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0.001 and P = 0.002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 * 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0.005) and were consistently higher for the 3 * 150 mg and 3 * 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 * 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow-up period. Secukinumab was well tolerated. Two cases of neutropenia (<= grade 2) were reported in the 3 * 150 mg cohort. CONCLUSIONS: Treatment with subcutaneous secukinumab 3 * 75 mg and 3 * 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate-to-severe psoriasis. PMID- 23106108 TI - Treatment of chronic hepatitis C with pegylated interferon-alpha in a patient with recurrent autoimmune thrombotic thrombocytopenic purpura. PMID- 23106109 TI - Focal preauricular dermal dysplasia in a newborn. AB - We report a case of focal preauricular dermal dysplasia in an 18-day-old healthy girl. We discuss the classification of focal preauricular dermal dysplasia within the spectrum of focal facial dermal dysplasia and aplasia cutis congenita. PMID- 23106110 TI - Perceived control relates to better functional health and lower cardio-metabolic risk: the mediating role of physical activity. AB - OBJECTIVE: The objective of the current study was to examine empirically associations between perceived control and indicators of functional health (grip strength) and cardio-metabolic risk (hemoglobin A1C, High Density Lipoprotein Cholesterol [HDL-C], Systolic Blood Pressure [SBP], Pulse Rate [PR], and Waist Circumference [WC]) and to explore the mediating role of physical activity. METHOD: Using cross-sectional data from the nation-wide Health and Retirement Study (N = 4,292; Mean age = 68, range 50-97; 59% women), we examined whether perceived control was predictive of the various health indicators over and above sociodemographic characteristics. We also used mediation models to test whether those direct associations were mediated by physical activity. RESULTS: Findings indicated that perceiving more control related to better grip strength and lower cardio-metabolic risk. To illustrate, a 1 SD increase in control is associated with 2.5 fewer years of aging on grip strength, 10 fewer years of aging for hemoglobin A1C, 14.5 fewer years of aging for HDL-C, 3.7 fewer years of aging for pulse rate, and 5.75 fewer years of aging for waist circumference. We also found that physical activity mediated five of the six control-health associations. CONCLUSIONS: Our findings demonstrate the importance of perceived control as predictor of functional and physiological health and the role of physical exercise as a behavioral mediator of these associations. Our results suggest that control may serve as a facilitator of positive health outcomes, including functional health, cardio-metabolic risk, and physical activity. Findings provide impetus for future research to elucidate mechanisms underlying the health implications of perceived control. PMID- 23106111 TI - How dynamic are exercise group dynamics? Examining changes in cohesion within class-based exercise programs. AB - OBJECTIVE: Within exercise class settings, group cohesion has consistently been found to predict adherence behaviors, and has been identified as a salient target for intervention-based initiatives. Drawing upon theorizing from the field of group dynamics, exercise class cohesion is often conceptualized as a dynamic construct that requires several classes to form and once it is formed, continues to change over time. Despite the salience of this "dynamic" contention for informing physical activity interventions, this theorizing has yet to be empirically tested. METHOD: In this study a multilevel modeling framework was used to examine changes in exercise class cohesion over time. Exercisers (N = 395) completed measures of cohesion following the second, fifth, and eighth classes of their respective programs (N = 46). RESULTS: Mean levels of social cohesion changed significantly over time whereas mean levels of task cohesion did not. These patterns were largely consistent across persons and groups. CONCLUSIONS: These findings suggest that within group-based exercise programs social and task cohesion possesses different levels of dynamism, and that this dynamism (or lack thereof) might have important implications for future research and interventions involving physical activity groups. PMID- 23106112 TI - Understanding persons with mental illness who are and are not criminal justice involved: a comparison of criminal thinking and psychiatric symptoms. AB - Research has begun to elucidate that persons with mental illness become involved in the criminal justice system as a result of criminality and not merely because of their mental illness. This study aims to clarify the similarities and differences in criminal thinking and psychiatric symptomatology between persons with mental illness who are and are not criminal justice involved. Male and female (n = 94) participants admitted to an acute psychiatric facility completed measures to assess criminal thinking (i.e., Psychological Inventory of Criminal Thinking Styles and Criminal Sentiments Scale-Modified) and psychiatric symptomatology (Millon Clinical Multiaxial Inventory-Third Edition). In addition to the inpatient sample, 94 incarcerated persons with mental illness from a previously conducted study were selected based on their match with the current sample on several key demographic and psychiatric variables. The results of this study indicated that hospitalized persons with mental illness with a history of criminal justice involvement evidenced similar thinking styles to persons with mental illness who were incarcerated. Persons with mental illness without criminal justice involvement evidenced fewer thinking styles supportive of a criminal lifestyle than the incarcerated sample. Furthermore, the persons with mental illness sample with no history of criminal justice involvement showed significantly lower levels of psychopathology shown to be risk factors for criminal justice involvement (e.g., antisocial personality, drug dependence, alcohol dependence). These findings have implications for offender-type classification, development of targeted treatment interventions, and program placement. PMID- 23106113 TI - Editorial: Novel drug therapies in the treatment of SAH. PMID- 23106114 TI - Four-year outcome of mild cognitive impairment: the contribution of executive dysfunction. AB - OBJECTIVE: The contribution of executive cognition (EC) to the prediction of incident dementia remains unclear. This prospective study examined the predictive value of EC for subsequent cognitive decline in persons with mild cognitive impairment (MCI) over a 4-year period. METHOD: One hundred forty-one persons with MCI (amnestic and nonamnestic, single- and multiple-domain) received a baseline and two biennial follow-up assessments. Eighteen tests, assessing six different aspects of EC, were administered at baseline and at 2-year follow-up, together with screening cognitive and daily functioning measures. Longitudinal logistic regression models and generalized estimating equations (GEE) were used to examine whether EC could predict progression to a Clinical Dementia Rating Scale (CDR; C. P. Hughes, L. Berg, W. L. Danziger, L. A. Coben, & R. L. Martin, 1982, A new clinical scale for the staging of dementia, British Journal of Psychiatry, Vol. 140, pp. 566-572) score of 1 or more over the 4-year period, first at the univariate level and then in the context of demographic and clinical characteristics, daily functioning measures, and other neurocognitive factors. RESULTS: Over the 4-year period, 56% of MCI patients remained stable, 35% progressed to CDR >= 1, and 8% reverted to normal (CDR = 0). Amnestic MCI subtypes were not associated with higher rates of progression to dementia, whereas subtypes with multiple impairments were so associated. Eight out of the 18 EC measures, including all three measures assessing inhibition of prepotent responses, predicted MCI outcome at the univariate level. However, the multivariate GEE model indicated that age, daily functioning, and overall cognitive functioning best predicted progression to dementia. CONCLUSION: Measures of EC (i.e., inhibitory control) are associated with MCI outcome. However, age and global measures of cognitive and functional impairment are better predictors of incident dementia. PMID- 23106116 TI - Constraints on information processing capacity in adults with ADHD. AB - OBJECTIVE: Researchers in the cognitive sciences have demonstrated the existence of processing capacity bottlenecks in the human brain. These capacity bottlenecks restrict our ability to process and act on environmental information. The purpose of the current study was to examine whether adults with attention-deficit hyperactivity disorder (ADHD) show reduced capacity of working memory and response selection mechanisms. METHOD: Thirty-eight young adults with ADHD and 33 comparison adults were assessed using two measures of processing capacity. A dual choice-response task (psychological refractory period [PRP] task) measured response selection capacity, and an n-back task measured working memory capacity. These tasks measured capacity by assessing the degree to which increasing processing load disrupted performance. RESULTS: Results confirmed that performance declined as cognitive load was increased, and this was true for both groups on each task. On the PRP task, the performance decline resulting from increased cognitive load was more pronounced in the ADHD group than in the control group, indicative of reduced response selection capacity in the ADHD group. On the n-back task, however, there was no group difference in the degree to which increasing processing load disrupted performance. CONCLUSIONS: Results indicate that adults with ADHD show a specific capacity reduction of response selection. This evidence suggests a dissociation between working memory and response selection capacities, and it may have implications for understanding cognitive dysfunction in adults with ADHD. PMID- 23106117 TI - Neural correlates of race-related social evaluations for African Americans and white Americans. AB - OBJECTIVE: To examine differences in patterns of brain activation associated with a race-related social evaluative task for a sample of African American and White American adults. METHOD: Participants were exposed to images of White American and African American targets embedded in various contexts across three emotional valences: angry/hostile, happy/joyful, and neutral/ambiguous. Functional magnetic resonance imaging was used to measure brain activity. RESULTS: Between-group comparisons revealed that African Americans, as compared to White Americans, exhibited activation in the inferior frontal gyrus and parahippocampal gyrus to images of happy (vs. neutral) same-race targets. White Americans, compared, to African Americans displayed activation in the inferior frontal gyrus and anterior cingulate cortex to images of happy (vs. neutral) same-race targets. Activation in limbic areas was observed for African Americans to neutral (vs. happy) images of White American targets, while no significant pattern of activation was found for White Americans to images of neutral/ambiguous African American targets. A significant correlation was found between scores for previous exposure to race related incidents and amygdala activation for African Americans to White American targets. CONCLUSION: White Americans generally exhibited more activation in regions associated with conflict resolution and cognitive control, while African Americans exhibited activation mostly in areas associated with emotion and memory. Our findings further imply that previous exposure to race-related incidents for African Americans may alter neural responses to White American targets in imaging studies. Implications of the findings are discussed. PMID- 23106115 TI - Decomposing attention-deficit/hyperactivity disorder (ADHD)-related effects in response speed and variability. AB - OBJECTIVE: Slow and variable reaction times (RTs) on fast tasks are such a prominent feature of attention-deficit/hyperactivity disorder (ADHD) that any theory must account for them. However, this has proven difficult because the cognitive mechanisms responsible for this effect remain unexplained. Although speed and variability are typically correlated, it is unclear whether single or multiple mechanisms are responsible for group differences in each. RTs are a result of several semi-independent processes, including stimulus encoding, rate of information processing, speed-accuracy trade-offs, and motor response, which have not been previously well characterized. METHOD: A diffusion model was applied to RTs from a forced-choice RT paradigm in two large, independent case control samples (NCohort 1 = 214 and NCohort 2 = 172). The decomposition measured three validated parameters that account for the full RT distribution and assessed reproducibility of ADHD effects. RESULTS: In both samples, group differences in traditional RT variables were explained by slow information processing speed, and unrelated to speed-accuracy trade-offs or nondecisional processes (e.g., encoding, motor response). CONCLUSIONS: RT speed and variability in ADHD may be explained by a single information processing parameter, potentially simplifying explanations that assume different mechanisms are required to account for group differences in the mean and variability of RTs. PMID- 23106118 TI - Attentional requirements during acquisition and consolidation of a skill in normal readers and developmental dyslexics. AB - OBJECTIVE: Previous research demonstrated that individuals with developmental dyslexia (DD) may suffer from a deficit in the acquisition stage of a new skill, whereas consolidation processes seem to be preserved. The present study was designed to examine whether this impaired acquisition was attributable to a lack of automatization, and whether the reported preserved consolidation was attributable to the use of DDs' conscious compensation strategies. These aims were implemented by testing a skill-learning task in dyslexics and normal readers using a dual task paradigm. The impact of dual task costs on participants' performance was used as an indication for automaticity. METHOD: DD and control groups completed a sequence-learning task over a first session (acquisition) and a second session 24 hours later (consolidation). The task was performed by half of the participants under a full attention condition and by the other half under a divided attention condition. RESULTS: Consistent with previous reports in the literature, divided attention impaired sequence learning in both groups. Nevertheless, divided attention resulted in delayed acquisition of the motor skill in the DD group compared with normal readers. Finally, divided attention enhanced motor procedural consolidation only in the control group. CONCLUSIONS: The differential effect of divided attention on acquisition and consolidation of procedural skill in DD and normal readers supports the cerebellum deficit hypothesis in DD. In addition, the enhanced skill consolidation in normal readers under divided attention suggests that attentional requirements are not necessary for all types of human learning. PMID- 23106119 TI - Bimanual control processes and the role of handedness. AB - OBJECTIVE: Bimanual movements are a fundamental motor skill. Whereas substantial research is available from right-handers, much less is known from left-handers. Accordingly, in the present electroencephalography (EEG) study we evaluated bimanual behavior in left- versus right-handers. METHOD: Thirteen left-handers and 13 right-handers took part in the experiment. Cortical dynamics were evaluated by means of EEG coherence in the beta frequency band (14-28 Hz), and behavioral performance was measured using motor error. RESULTS: The EEG data revealed that right-handers showed a left-sided lateralization pattern whereas left-handers demonstrated a bilateral organization pattern during symmetrical actions. Asymmetry of the bimanual task demands modified the hemispheric profile for both groups and resulted in an additional involvement of the motor nondominant hemisphere. Brain-behavioral correlations underlined that response planning strongly relied on the left hemisphere irrespective of handedness whereas the motor-dominant hemisphere drove response execution. CONCLUSION: The findings suggest that skilled motor planning may develop preferentially in the left hemisphere. PMID- 23106121 TI - Supercritical or compressed CO2 as a stimulus for tuning surfactant aggregations. AB - Surfactant assemblies have a wide range of applications in areas such as the chemical industry, material science, biology, and enhanced oil recovery. From both theoretical and practical perspectives, researchers have focused on tuning the aggregation behaviors of surfactants. Researchers commonly use solid and liquid compounds such as cosurfactants, acids, salts, and alcohols as stimuli for tuning the aggregation behaviors. However, these additives can present economic and environmental costs and can contaminate or modify the product. Therefore researchers would like to develop effective methods for tuning surfactant aggregation with easily removable, economical, and environmentally benign stimuli. Supercritical or compressed CO(2) is abundant, nontoxic, and nonflammable and can be recycled easily after use. Compressed CO(2) is quite soluble in many liquids, and the solubility depends on pressure and temperature. Therefore researchers can continuously influence the properties of liquid solvents by controlling the pressure or temperature of CO(2). In this Account, we briefly review our recent studies on tuning the aggregation behaviors of surfactants in different media using supercritical or compressed CO(2). Supercritical or compressed CO(2) serves as a versatile regulator of a variety of properties of surfactant assemblies. Using CO(2), we can switch the micellization of surfactants in water, adjust the properties of reverse micelles, enhance the stability of vesicles, and modify the switching transition between different surfactant assemblies. We can also tune the properties of emulsions, induce the formation of nanoemulsions, and construct novel microemulsions. With these CO(2) responsive surfactant assemblies, we have synthesized functional materials, optimized chemical reaction conditions, and enhanced extraction and separation efficiencies. Compared with the conventional solid or liquid additives, CO(2) shows some obvious advantages as an agent for modifying surfactant aggregation. We can adjust the aggregation behaviors continuously by pressure and can easily remove CO(2) without contaminating the product, and the method is environmentally benign. We can explain the mechanisms for these effects on surfactant aggregation in terms of molecular interactions. These studies expand the areas of colloid and interface science, supercritical fluid science and technology, and chemical thermodynamics. We hope that the work will influence other fundamental and applied research in these areas. PMID- 23106120 TI - Positive exercise test and obstructive spirometry in young male conscripts associated with persistent asthma 20 years later. AB - BACKGROUND: Asthma often begins in childhood or early adulthood and is a common disease among conscripts. The identification of long-term predictive factors for persistent asthma may lead to improved treatment opportunities and better disease control. OBJECTIVE: Our aim was to study the prognostic factors of the severity of asthma among 40-year-old male conscripts whose asthma began in youth. METHODS: We studied 119 conscripts who were referred to the Central Military Hospital during 1987-1990 due to asthma and who attended a follow-up visit approximately 20 years later. Asthma severity was evaluated during military service according to the medical records, and 20 years later during a follow-up visit using Global Initiative for Asthma guidelines. We used the results of lung function and allergy tests at baseline as predictors of current persistent asthma. RESULTS: Compared with baseline, asthma was less severe at follow-up: 11.8% of subjects were in remission, 42.0% had intermittent asthma, 10.9% had mild persistent asthma, and 35.3% had moderate/severe persistent asthma (p < .001). In multivariate models, a positive exercise test at baseline yielded an odds ratio (OR) of 3.2 (95% CI 1.0-9.8, p = .046), a decreased FEV1/FVC % predicted an OR of 4.0 (95% CI 1.7-9.3, p = .002), and a decreased FEF50% % predicted an OR of 2.8 (95% CI 1.3-6.4, p = .012) for current persistent asthma. CONCLUSIONS: About half of the men had persistent asthma at the 20-year follow-up. Positive exercise tests and obstructive spirometry results were related to the persistence of asthma and may be useful long-term prognostic factors for asthma severity. PMID- 23106122 TI - Study of a two-stage photobase generator for photolithography in microelectronics. AB - The investigation of the photochemistry of a two-stage photobase generator (PBG) is described. Absorption of a photon by a latent PBG (1) (first step) produces a PBG (2). Irradiation of 2 in the presence of water produces a base (second step). This two-photon sequence (1 + hnu -> 2 + hnu -> base) is an important component in the design of photoresists for pitch division technology, a method that doubles the resolution of projection photolithography for the production of microelectronic chips. In the present system, the excitation of 1 results in a Norrish type II intramolecular hydrogen abstraction to generate a 1,4-biradiacal that undergoes cleavage to form 2 and acetophenone (Phi ~ 0.04). In the second step, excitation of 2 causes cleavage of the oxime ester (Phi = 0.56) followed by base generation after reaction with water. PMID- 23106123 TI - Chemical composition and antioxidative activity of Echinophora platyloba DC. essential oil, and its interaction with natural antimicrobials against food-borne pathogens and spoilage organisms. AB - This study was undertaken to determine the chemical composition and antioxidative capacity of Echinophora platyloba DC. essential oil, and its antimicrobial potency against Listeria monocytogenes, Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, Salmonella typhimurium, Escherichia coli O157:H7, Pseudomonas aeruginosa, Candida albicans, Candida tropicalis, Rhodotorula rubra, and Rhodotorula mucilaginosa. The essential oil was analyzed by GC and GC-MS; and evaluated for its antioxidative and antimicrobial (singly or in combination with chitosan, nisin, monolaurin, or amphotericin B) activity. Thirty-three components were characterized representing 95.69% of the total oil composition in which thymol, trans-ocimene, carvacrol, and (E)-sesqui-lavandulol were the major constituents. The oil exhibited high scavenging (IC(50): 49.7 +/- 2.3 MUg/mL) and relative antioxidative activity (RAA%: 85.21 +/- 0.4) in 1,1-diphenyl-2 picrylhydrazyl radicals and beta-carotene/linoleic acid bleaching assays, respectively. The oil showed antimicrobial activity against L. monocytogenes, B. cereus, B. subtilis, S. aureus, S. typhimurium, E. coli O157:H7, P. aeruginosa, C. albicans, C. tropicalis, R. Rubra, and R. mucilaginosa. Moreover, R. mucilaginosa and P. aeruginosa were the most susceptible and most resistant organisms, respectively. Regarding the checkerboard data, 47 fractional inhibitory concentration index (FICIs) (<= 0.5) indicated synergistic, whereas 7 FICIs (>0.5 to 1) indicated additive effect. Consequently, E. platyloba DC. essential oil could be used as a recommended natural antioxidant and antimicrobial substance for food preservation. PMID- 23106125 TI - The "Reading the Mind in the Eyes" test: systematic review of psychometric properties and a validation study in Italy. AB - INTRODUCTION: The "Reading the Mind in the Eyes" test (henceforth, Eyes test) is a simple but advanced Theory of Mind test, and it is widely used across different cultures. This study assessed the reliability and construct (convergent and discriminant) validity of the Eyes test in Italy. METHODS: A sample of 18- to 32 year-old undergraduate students of both sexes (N=200, males=46%) were invited to fill in the Italian version of the Eyes test, the Empathy Quotient (EQ), the Toronto Alexithymia Scale (TAS), and the Marlowe-Crowne Social Desirability Scale (SDS). RESULTS: Internal consistency (Cronbach's alpha) was .605. Confirmatory factor analysis provided evidence for a unidimensional model, with maximal weighted internal consistency reliability=.719. Test-retest reliability for the Eyes test, as measured by intraclass correlation coefficient, was .833 (95% confidence interval=.745 to .902). Females scored significantly higher than males on both the Eyes test and the EQ, replicating earlier work. Those participants who scored lower than 30 on the EQ (n=10) also scored lower on the Eyes test than those who did not (p<.05). Eyes test scores were not related to social desirability. CONCLUSIONS: This study confirms the validity of the Eyes test. Both internal consistency and test-retest stability were good for the Italian version of the Eyes test. PMID- 23106124 TI - The fungal alpha-aminoadipate pathway for lysine biosynthesis requires two enzymes of the aconitase family for the isomerization of homocitrate to homoisocitrate. AB - Fungi produce alpha-aminoadipate, a precursor for penicillin and lysine via the alpha-aminoadipate pathway. Despite the biotechnological importance of this pathway, the essential isomerization of homocitrate via homoaconitate to homoisocitrate has hardly been studied. Therefore, we analysed the role of homoaconitases and aconitases in this isomerization. Although we confirmed an essential contribution of homoaconitases from Saccharomyces cerevisiae and Aspergillus fumigatus, these enzymes only catalysed the interconversion between homoaconitate and homoisocitrate. In contrast, aconitases from fungi and the thermophilic bacterium Thermus thermophilus converted homocitrate to homoaconitate. Additionally, a single aconitase appears essential for energy metabolism, glutamate and lysine biosynthesis in respirating filamentous fungi, but not in the fermenting yeast S. cerevisiae that possesses two contributing aconitases. While yeast Aco1p is essential for the citric acid cycle and, thus, for glutamate synthesis, Aco2p specifically and exclusively contributes to lysine biosynthesis. In contrast, Aco2p homologues present in filamentous fungi were transcribed, but enzymatically inactive, revealed no altered phenotype when deleted and did not complement yeast aconitase mutants. From these results we conclude that the essential requirement of filamentous fungi for respiration versus the preference of yeasts for fermentation may have directed the evolution of aconitases contributing to energy metabolism and lysine biosynthesis. PMID- 23106126 TI - Identification of phosphorylation sites in the COOH-terminal tail of the MU opioid receptor. AB - Phosphorylation is considered a key event in the signalling and regulation of the MU opioid receptor (MOPr). Here, we used mass spectroscopy to determine the phosphorylation status of the C-terminal tail of the rat MOPr expressed in human embryonic kidney 293 (HEK-293) cells. Under basal conditions, MOPr is phosphorylated on Ser(363) and Thr(370), while in the presence of morphine or [D Ala2, NMe-Phe4, Gly-ol5]-enkephalin (DAMGO), the COOH terminus is phosphorylated at three additional residues, Ser(356) , Thr(357) and Ser(375). Using N-terminal glutathione S transferase (GST) fusion proteins of the cytoplasmic, C-terminal tail of MOPr and point mutations of the same, we show that, in vitro, purified G protein-coupled receptor kinase 2 (GRK2) phosphorylates Ser(375), protein kinase C (PKC) phosphorylates Ser(363), while CaMKII phosphorylates Thr(370). Phosphorylation of the GST fusion protein of the C-terminal tail of MOPr enhanced its ability to bind arrestin-2 and -3. Hence, our study identifies both the basal and agonist-stimulated phospho-acceptor sites in the C-terminal tail of MOPr, and suggests that the receptor is subject to phosphorylation and hence regulation by multiple protein kinases. PMID- 23106129 TI - The rising tide of cholecystectomy for biliary dyskinesia. AB - BACKGROUND: Expert consensus defines biliary dyskinesia as a rare disorder of the gall-bladder characterised by pain and impaired gall-bladder function. AIM: To determine trends in cholecystectomy rates for biliary dyskinesia in the United States. METHODS: As biliary dyskinesia does not have a distinct diagnosis code, the narrative diagnoses for patients were reviewed and abstracted for 200 patients treated for the most commonly used diagnosis codes for biliary dyskinesia (validation sample). Time trends in cholecystectomies and hospitalisations for biliary diseases were assessed using the Nationwide Inpatient Sample (Agency for Healthcare Research and Quality) based on codes for cholecystectomy and diagnosis codes for different biliary disorders. RESULTS: In the validation sample, biliary dyskinesia accounted for 81% of the patients with ICD-9 code 575.8 (gall-bladder disease not elsewhere specified). Between 1997 and 2010, admissions for acute cholecystitis and complications of gallstone disease decreased slightly, whereas admissions with the primary diagnosis code ICD-9 575.8 tripled. This rise was most pronounced in the paediatric population (700% increase), with biliary dyskinesia accounting for more than 10% of cholecystectomies. Compared with acute biliary diseases, significantly more of the elective hospitalisations were covered by private insurances. CONCLUSIONS: Practice patterns differ from expert opinion, with biliary dyskinesia accounting for an increasing fraction of cholecystectomies. The rise in these elective interventions is associated with a shift to a younger, low risk and predominantly privately insured population. Considering the benign nature of biliary dyskinesia, it is time to reassess the need for operative interventions, which have never been compared with active conservative therapy. PMID- 23106128 TI - Magnetic source imaging and ictal SPECT in MRI-negative neocortical epilepsies: additional value and comparison with intracranial EEG. AB - PURPOSE: To investigate the utility of magnetic source imaging (MSI) and ictal single photon emission computed tomography (SPECT), each compared with intracranial electroencephalography (EEG) (ICEEG), to localize the epileptogenic zone (EZ) and predict epilepsy surgery outcome in patients with nonlesional neocortical focal epilepsy. METHODS: Studied were 14 consecutive patients with nonlesional neocortical epilepsy who underwent presurgical evaluation including ICEEG, positive MSI, and localizing subtraction Ictal SPECT coregistered to MRI (SISCOM) analysis. Follow-up after epilepsy surgery was >= 24 months. ICEEG, MSI, and SPECT results were classified using a sublobar classification. KEY FINDINGS: Of 14 patients, 6 (42.9%) became seizure-free after surgery. Sublobar ICEEG focus was completely resected in 11 patients; 5 (45.5%) of them became seizure- free. Concordance of ICEEG and MSI and complete focus resection was found in 5 (35.7%) patients; 80% of them became seizure-free. Sublobar ICEEG-MSI concordance and complete focus resection significantly increased the chance of seizure freedom after epilepsy surgery (p = 0.038). In contrast, of the 6 patients (42.9%) with concordant ICEEG and SISCOM and complete focus resection, only 66.7% became seizure-free (p = 0.138). Assuming concordant results, the additive value to ICEEG alone for localizing the EZ is higher with ICEEG-MSI (odds ratio 14) compared to ICEEG-SISCOM (odds ratio 6). SIGNIFICANCE: This study shows that combination of MSI and/or SISCOM with ICEEG is useful in the presurgical evaluation of patients with nonlesional neocortical epilepsy. Concordant test results of either MSI or SISCOM with ICEEG provide useful additive information for that provided by ICEEG alone to localize the EZ in this most challenging group of patients. When sublobar concordance with ICEEG is observed, MSI is more advantageous compared to SISCOM in predicting seizure-free epilepsy surgery outcome. PMID- 23106130 TI - Antiangiogenic effects and mechanisms of trans-ethyl p-methoxycinnamate from Kaempferia galanga L. AB - Kaempferia galanga L. (Zingiberaceae) is an aromatic herb and a popular spice used as a condiment in Asian cuisine. The ethanol extract of the dried plant and its successive four subfractions were investigated on zebrafish model by quantitative endogenous alkaline phosphatase assay. Both n-hexane and ethyl acetate fractions had antiangiogenic activity, and two major active components (trans-ethyl p-methoxycinnamate and kaempferol) showed potent antiangiogenic effects on wild-type zebrafish. Because of its much stronger effect and no antiangiogenic activity reported, trans-ethyl p-methoxycinnamate was further investigated for its action mechanism. It dose dependently inhibited vessel formation on both wild- and Tg(fli1a:EGFP)y1-type zebrafish embryos. The semiquantitative reverse transcription polymerase chain reaction assay suggested that trans-ethyl p-methoxycinnamate affects multiple molecular targets related to angiogenesis. In vitro, it specifically inhibited the migration and tube formation of human umbilical vein endothelial cells. In vivo, it could block bFGF induced vessel formation on Matrigel plug assay. PMID- 23106131 TI - Onychomycosis in immunosuppressed children receiving chemotherapy. AB - Onychomycosis in children has a low incidence worldwide; certain conditions such as immunosuppression have been described as risk factors for it. We studied 72 children receiving chemotherapy for different neoplasms to determine the frequency of onychomycosis. Only one patient had white superficial onychomycosis from Trichophyton rubrum, a frequency of 1.3%, not different from that reported in healthy patients. PMID- 23106133 TI - Roger Cotton Histopathology Prize 2011. PMID- 23106134 TI - Microscopic features associated with mycophenolate mofetil in gastric and colonic biopsies. PMID- 23106135 TI - Multiplex polymerase chain reaction with DNA pooling: a cost-effective strategy of genotyping rare blood types. AB - OBJECTIVES/AIMS: This work aims to develop a multiplex polymerase chain reaction combined with DNA pooling for mass screening for rare blood types. BACKGROUND: The differences in most blood group antigens are associated with single nucleotide polymorphisms (SNPs), which are used in detecting blood antigen expression at the molecular level. However, all existing sequence-specific primers polymerase chain reaction (PCR-SSP) assays for blood typing genotype one or several SNPs individually. DNA pooling is a way that reduces the amount of genotyping required. METHODS: A sensitive multiplex PCR-SSP assay testing pooled DNA was established to detect the rare Fy(b) and S alleles. It was applied to screen a total of 4490 donor samples via testing 898 DNA pools. The samples in the positive pools were further tested individually. Then the positive samples, including Fy(a-b+)/Fy(a+b+) and S+s-/S+s+ genotypes, were tested via two PCR-SSP assays for alleles Fy(a) and s. The rare genotypes Fy(a-b+) and S+s- were verified using serologic tests and sequencing analysis. RESULTS: Two hundred and fifty-four donors were tested positive for the Fy(b) allele, whereas 101 donors were positive for the S allele. Among the 254 Fy(b+) donors, 5 were Fy(a-b+) and 249 were Fy(a+b+). Among the 101 S+ donors, 3 were S+s- and 98 were S+s+. The rare Fy(b) and S alleles comprised 2.28 and 1.16%, respectively. The PCR-SSP assays were confirmed by sequencing analysis and serological test. CONCLUSION: A multiplex PCR assay was combined with DNA pooling to reduce the number of tests required, making large-scale screening feasible. PMID- 23106132 TI - Diabetes in older adults: a consensus report. PMID- 23106136 TI - The effect of antibrowning agents on inhibition of potato browning, volatile organic compound profile, and microbial inhibition. AB - Burbank and Norkotah potato slices were dipped into 3% sodium acid sulfate (SAS), citric acid (CA), sodium erythorbate (SE), malic acid (MA), sodium acid pyrophosphate (SAPP), or a combination of SAS-CA-SE. Browning by polyphenol oxidase (PPO) obtained from potato extract with 0.04 to 0.016 g/mL of antibrowning solutions at pH 2.0 to 6.9 were measured by UV-Vis spectroscopy. The color of slices dipped in antibrowning solutions at pHs 2 to 7 and stored at 4 degrees C for 15 d was measured every 5 d by colorimeter. Headspace analysis of volatiles in raw and cooked potato samples was performed by selected ion flow tube mass spectrometer (SIFT-MS) and soft independent modelling by class analogy (SIMCA) analysis of the calculated odor activity values (OAV) determined interclass distances. Microbial growth was measured at 15 d. At unadjusted pHs (1.1 to 7.1), the PPO browning of the control and samples with SAPP was not significantly different, SAS, CA, and MA produced some inhibition and SE and SAS CA-SE prevented browning. At pH 5 to 7, only SE and SAS-CA-SE were effective browning inhibitors. Based on the color of potato slices, SE was the most effective at pH 2 to 7, but SAS was most effective at unadjusted pH. Cooking increased volatile levels in the treated potatoes and decreased differences between volatile profiles. Differences between cooked samples may not be noticeable by the consumer because volatiles with high discriminating powers have low OAVs. SAS, CA, and SAS-CA-SE treatments inhibited microbial growth but SAPP, control, and SE did not, most likely due to pH. PRACTICAL APPLICATION: Antibrowning agents inhibit polyphenol oxidase, increasing shelf life and consumer acceptability of processed raw potato products by preserving the color. Their effectiveness was shown to be mainly due to a pH effect, except SE, which was not pH dependent. MA, CA, and SAS-CA-SE are better acidulants for inhibition of color change as well as growth of spoilage bacteria, yeast, and mold than SAPP, the industry standard. PMID- 23106137 TI - Effectiveness of a process-oriented patient-tailored outpatient neuropsychological rehabilitation programme for patients in the chronic phase after ABI. AB - The objective of this prospective cohort study was to examine the effectiveness of an outpatient neuropsychological rehabilitation programme for patients with acquired brain injury (ABI) and their relatives. The participants were 26 ABI patients with a mean age of 44.7 (SD 11.7) years and 24 caregivers. Mean time since injury was 3.0 (SD 3.6) years. The intervention consisted of a patient tailored process-oriented neuropsychological rehabilitation programme focusing on facilitation of the adaptation process. Repeated measurements were taken prior to treatment (T0), directly after treatment (T1) and 6 months later (T2). Primary outcome measures were cognitive failures (CFQ), quality of life (SA-SIP30), and individualised goals (GAS). Patients improved significantly on individualised goals between T0 and T1 (p < .01). This effect retained at T2. There were no significant differences on CFQ and SA-SIP30. The programme had a positive effect on attainment of the patient's individual goals. This was not associated with a higher level of participation or a better quality of life. PMID- 23106138 TI - Text messaging to measure asthma medication use and symptoms in urban African American emerging adults: a feasibility study. AB - OBJECTIVE: Urban African American adolescents and young adults face disproportionate risk of asthma morbidity and mortality. This study was the first to assess the feasibility of Ecological Momentary Assessment via text messaging to measure asthma medication use and symptoms in African Americans aged 18-25 years. METHODS: This study used automated text messaging with N = 6 participants for 14 consecutive days. Participants sent event-based messages whenever they experienced asthma symptoms or took asthma rescue or controller medications. They also received time-based messages daily that prompted for a response about asthma medications or symptoms. RESULTS: Feasibility was assessed using response rates and participant feedback. Rates of event-based messages were relatively low (M = 0.85 messages sent per participant/day), but participants were very responsive to time-based messages (78.5%). All participants expressed positive feedback about the program, though 40.0% reported confusion with event-based messages and most preferred time-based messages. The assessment found low medication adherence rates and reasons for missing medication consistent with previous research with youth with asthma. CONCLUSION: Text messaging may be a useful method to measure medication use and symptoms in "real time," particularly using time-based prompts. Results could be used to provide personalized feedback on adherence as part of a tailored intervention. PMID- 23106140 TI - Interleukin-26, a highly cationic T-cell cytokine targeting epithelial cells. AB - Interleukin-26 (IL-26) is a member of the IL-10 cytokine family due to sequence homology. IL-26 was discovered, since the gene is strongly overexpressed in T cells which are growth transformed by herpesvirus saimiri. The IL-26 gene maps to human chromosome 12q15 between the genes for two other T-cellular class-II cytokines, namely interferon-gamma (lFN-gamma) and lL-22. IL-26, IL-22, and IFN gamma are co expressed by activated T cells and, especially, by Th17 cells. IL-26 forms homodimers and adheres to glycosaminoglycans on cell surfaces, presumably due to its positive charge. IL-26 specifically targets the lL-26-specific heterodimeric receptor complex consisting of IL-20R1 and IL-10R2 which is typically expressed on epithelial cells such as colon carcinoma cells or keratinocytes. IL-26 stimulation induces STAT1 and STAT3 phosphorylation, CD54 surface expression, and cytokine secretion as shown for IL-8 and IL-10. IL-26 seems to act as a cell surface-associated and rather proinflammatory T-cell cytokine at the epithelial barrier, possibly linking T-cell response with epithelial functions. PMID- 23106141 TI - Elucidating the role of aromatic interactions in rotational barriers involving aromatic systems. AB - The measurement of aryl-naphthyl rotational barriers, DeltaG(?), in various solvents for two substituted 1,8-diarylnaphthalenes by dynamic (1)H NMR showed that DeltaG(?) trends in aromatic systems can be fully rationalized only when considering the different types of aromatic interactions that can be established in the ground and transition states, namely, intramolecular interactions involving the aromatic rings and specific solvation interactions. PMID- 23106139 TI - The metal transporter SMF-3/DMT-1 mediates aluminum-induced dopamine neuron degeneration. AB - Aluminum (Al(3+)) is the most prevalent metal in the earth's crust and is a known human neurotoxicant. Al(3+) has been shown to accumulate in the substantia nigra of patients with Parkinson's disease (PD), and epidemiological studies suggest correlations between Al(3+) exposure and the propensity to develop both PD and the amyloid plaque-associated disorder Alzheimer's disease (AD). Although Al(3+) exposures have been associated with the development of the most common neurodegenerative disorders, the molecular mechanism involved in Al(3+) transport in neurons and subsequent cellular death has remained elusive. In this study, we show that a brief exposure to Al(3+) decreases mitochondrial membrane potential and cellular ATP levels, and confers dopamine (DA) neuron degeneration in the genetically tractable nematode Caenorhabditis elegans (C. elegans). Al(3+) exposure also exacerbates DA neuronal death conferred by the human PD-associated protein alpha-synuclein. DA neurodegeneration is dependent on SMF-3, a homologue to the human divalent metal transporter (DMT-1), as a functional null mutation partially inhibits the cell death. We also show that SMF-3 is expressed in DA neurons, Al(3+) exposure results in a significant decrease in protein levels, and the neurodegeneration is partially dependent on the PD-associated transcription factor Nrf2/SKN-1 and caspase Apaf1/CED-4. Furthermore, we provide evidence that the deletion of SMF-3 confers Al(3+) resistance due to sequestration of Al(3+) into an intracellular compartment. This study describes a novel model for Al(3+) induced DA neurodegeneration and provides the first molecular evidence of an animal Al(3+) transporter. PMID- 23106143 TI - Hyphal heterogeneity in Aspergillus oryzae is the result of dynamic closure of septa by Woronin bodies. AB - Hyphae of higher fungi are compartmentalized by septa. These septa contain a central pore that allows for inter-compartmental and inter-hyphal cytoplasmic streaming. The cytoplasm within the mycelium is therefore considered to be a continuous system. In this study, however, we demonstrate by laser dissection that 40% of the apical septa of exploring hyphae of Aspergillus oryzae are closed. Closure of septa correlated with the presence of a peroxisome-derived organelle, known as Woronin body, near the septal pore. The location of Woronin bodies in the hyphae was dynamic and, as a result, plugging of the septal pore was reversible. Septal plugging was abolished in a DeltaAohex1 strain that cannot form Woronin bodies. Notably, hyphal heterogeneity was also affected in the DeltaAohex1 strain. Wild-type strains of A. oryzae showed heterogeneous distribution of GFP between neighbouring hyphae at the outer part of the colony when the reporter was expressed from the promoter of the glucoamylase gene glaA or the alpha-glucuronidase gene aguA. In contrast, GFP fluorescence showed a normal distribution in the case of the DeltaAohex1 strain. Taken together, it is concluded that Woronin bodies maintain hyphal heterogeneity in a fungal mycelium by impeding cytoplasmic continuity. PMID- 23106144 TI - Assessment of the risk of a bluetongue outbreak in Europe caused by Culicoides midges introduced through intracontinental transport and trade networks. AB - The importation of infected hosts and the arrival of windborne infected Culicoides (Diptera: Ceratopogonidae) were considered unlikely mechanisms for bluetongue virus (BTV) incursion into a BTV-free area during the recent BTV serotype 8 (BTV-8) epidemic in northern Europe. Therefore, alternative mechanisms need to be considered. Air, sea and land transport networks continue to expand, and an important consequence of this is vector-borne pathogen importation. One important aspect of bluetongue (BT) epidemiology not yet addressed is the potential movement of infected Culicoides via transport and trade networks. Therefore, a risk assessment model was constructed to assess the probability of a BTV outbreak as a consequence of the introduction of Culicoides via these networks. The model was applied to calculate the risk for a BTV-8 epidemic in Spain in 2007 caused by the introduction of Culicoides from affected northern European countries. The mean weighted annual risk for an outbreak caused by transportation of a single vector from an affected northern European country varied from 1.8 * 10(-7) to 3.0 * 10(-13), with the highest risks associated with Culicoides imported from Belgium, the Netherlands, Germany and France. For this mechanism to pose a significant risk to BTV-free countries, a large number of vectors would have to be transported. PMID- 23106145 TI - Association between epilepsy and cysticercosis and toxocariasis: a population based case-control study in a slum in India. AB - PURPOSE: To assess the association between epilepsy and exposure to the parasites, Toxocara canis and Taenia solium in a slum-community in India. METHODS: A door-to-door survey to determine the prevalence of epilepsy was carried out by trained field workers. For every case, one age- and gender-matched control was selected from the same community. Serologic evaluation was carried out to detect antibodies against T. canis and T. solium. KEY FINDINGS: The crude prevalence of active epilepsy was 7.2 per 1,000. We enrolled 114 people with active epilepsy and 114 controls. The prevalence of antibodies to T. canis was similar in people with active epilepsy (4.7%; 5 of 106 people) and in controls (5.7%; 6 of 106 people). The prevalence of antibodies to T. solium was 25.5% (27 of 106) in people with active epilepsy, significantly higher than in controls (12.3%; 13 of 106 cases; p = 0.02). Adjusted conditional (fixed-effects) logistic regression estimated an odds ratio of 2.8 (95% confidence interval 1.2-6.8) for detection of T. solium antibodies. Nineteen people with active epilepsy demonstrated evidence of neurocysticercosis (NCC) on magnetic resonance imaging (MRI), including 7 (36.5%) with solitary cysticercus granuloma. SIGNIFICANCE: Our findings do not support an association between epilepsy and exposure to T. canis in the community studied. A significant association between T. solium exposure and epilepsy was observed. Of those with active epilepsy and evidence of NCC on MRI, a large proportion demonstrated solitary cysticercus granuloma. PMID- 23106146 TI - Hot phonon dynamics in graphene. AB - The dynamics of hot phonons in supported, suspended, and gated monolayer graphene was studied by using time-resolved anti-Stokes Raman spectroscopy. We found that the hot phonon relaxation is dominated by phonon-phonon interaction in graphene, and strongly affected by the interaction between graphene and the substrate. Relaxation via carrier-phonon coupling, known as Landau damping, is ineffective for hot phonons which are in thermal equilibrium with excited carriers. Our findings provide a basis for better management of energy dissipation in graphene devices. PMID- 23106147 TI - Ultrafast proton dynamics in aqueous amino acid solutions studied by resonant inelastic soft X-ray scattering. AB - Resonant inelastic soft X-ray scattering (RIXS) has been used to study the electronic structure of glycine and lysine in aqueous solution. Upon variation of the pH value of the solution from acidic to basic, major changes of the nitrogen K edge RIXS data are observed for both amino acids, which are associated with the protonation and deprotonation of the amino groups. The experimental results are compared with simulations based on density functional theory, yielding a detailed understanding of the spectral changes, as well as insights into the ultrafast proton dynamics in the intermediate core-excited/ionized state of the RIXS process. PMID- 23106148 TI - Treatment of children with acute myeloid leukaemia who relapsed after allogeneic haematopoietic stem cell transplantation. AB - Despite improvements in diagnosis and treatment, 30-40% of children with acute myeloid leukaemia (AML) experience relapse. For those who relapse after allogeneic haematopoietic stem cell transplantation (allo-HSCT), the prognosis is particularly poor, with limited reported literature on these patients. We reviewed the clinical course of 49 children with AML (28 males, 21 females) who received allo-HSCT between 1993 and 2011, and who had subsequently relapsed. Study endpoints included (i) complete remission (CR) rate after intensive chemotherapy, and prognostic factors for CR, (ii) disease-free survival (DFS) and overall survival (OS) for patients who achieved CR and (iii) OS for recipients of intensive chemotherapy and prognostic factors for OS. Of the 36 patients who received intensive chemotherapy after post-HSCT relapse, 26 (72%) achieved CR. For patients who achieved CR, 5-year DFS and OS were 32.6 +/- 10.2% and 44.4 +/- 11.1%, respectively. For all recipients of intensive chemotherapy, 5-year OS was 31.6 +/- 8.7%. Cumulative incidence of treatment-related death was 14.4%. All three recipients of second HSCT died. Amongst prognostic factors predicting improved survival, only disease status at HSCT (early first CR vs. others) proved significant in multivariate study (Hazard Ratio 2.42, 95% Confidence Interval 1.02-5.74, P = 0.045). Treatment with curative intent was able to salvage a minor but important subset of children with AML who relapsed post-allogeneic transplant. PMID- 23106150 TI - Fermented tea improves glucose intolerance in mice by enhancing translocation of glucose transporter 4 in skeletal muscle. AB - The antihyperglycemic effects of tea are well documented. However, the effects of fermented tea on the translocation of glucose transporter 4 (GLUT4), the major glucose transporter for glucose uptake in the postprandial period, in skeletal muscle and the underlying molecular mechanisms are not fully understood. This study investigated the translocation of GLUT4 and its related signaling pathways in skeletal muscle of male ICR mice given fermented tea. Intake of oolong, black, or pu-erh tea for 7 days enhanced GLUT4 translocation to the plasma membrane of skeletal muscle. Each type of fermented tea stimulated the phosphorylation of phosphoinositide 3-kinase (PI3K), Akt/protein kinase B, and AMP-activated protein kinase (AMPK). Fermented tea also increased the protein expression of insulin receptor. These results strongly suggest that fermented tea activates both PI3K/Akt- and AMPK-dependent signaling pathways to induce GLUT4 translocation and increases the expression of insulin receptor to improve glucose intolerance. PMID- 23106151 TI - Implantable cardioverter-defibrillators: is there life after death? PMID- 23106152 TI - Time-to-death-related change in positive and negative affect among older adults approaching the end of life. AB - Late-life development may imply terminal processes related with time-to-death rather than with chronological age. In this study, we applied the time-to-death perspective to affective well-being. Using a 15-year observational interval including five measurement occasions with a large sample of deceased participants (N = 1,671; mean age = 75.60; mean time-to-death = 6.83 years, at first occasion) from the Longitudinal Aging Study Amsterdam (LASA), we examined (1) whether intraindividual trajectories in positive (PA) and negative affect (NA) can be better described in terms of time-to-death as compared to chronological age; (2) whether time-to-death-related change in PA and NA follows a terminal decline (linear change) versus terminal drop (accelerating change) pattern, and (3) whether transition points in PA and NA, marking the beginning of the terminal change period, can be identified. For both PA and NA, multilevel mixed models of linear and quadratic time-to-death and age-related trajectories confirmed that time-to-death accounts for more intraindividual variance and reveals a better fit to the data than chronological age. Quadratic time-to-death-related trends fitted better than linear trajectories, thus indicating terminal drop of affective well being, in terms of decreases of PA and increases of NA accelerating as death comes close. Also, change of NA was linked to time-to-death more strongly than PA change. Transition points to the terminal phase were found at 5.6 and 3.7 years for PA and NA, respectively. In conclusion, affective development toward the end of the human life span may be better understood as a death-related-rather than age-graded-process. PMID- 23106153 TI - Striving to feel good: ideal affect, actual affect, and their correspondence across adulthood. AB - The experience of positive affect is essential for healthy functioning and quality of life. Although there is a great deal of research on ways in which people regulate negative states, little is known about the regulation of positive states. In the present study we examined age differences in the types of positive states people strive to experience and the correspondence between their desired and actual experiences. Adults aged 18-93 years of age described their ideal positive affect states. Then, using experience-sampling over a 7-day period, they reported their actual positive affect experiences. Two types of positive affect were assessed: low-arousal (calm, peaceful, relaxed) and high-arousal (excited, proud). Young participants valued both types of positive affect equally. Older participants, however, showed increasingly clear preferences for low-arousal over high-arousal positive affect. Older adults reached both types of positive affective goals more often than younger adults (indicated by a smaller discrepancy between actual and ideal affect). Moreover, meeting ideal levels of positive low-arousal affect (though not positive high-arousal affect) was associated with individuals' physical health, over and above levels of actual affect. Findings underscore the importance of considering age differences in emotion-regulatory goals related to positive experience. PMID- 23106155 TI - Health services research and anaesthesia. PMID- 23106154 TI - Automated quantification of locomotion, social interaction, and mate preference in Drosophila mutants. AB - Automated tracking methods facilitate screening for and characterization of abnormal locomotion or more complex behaviors in Drosophila. We developed the Iowa Fly Locomotion and Interaction Tracker (IowaFLI Tracker), a MATLAB-based video analysis system, to identify and track multiple flies in a small arena. We report altered motor activity in the K(+) and Na(+) channel mutants, Hk(1) and para(ts1), which had previously been shown to display abnormal larval locomotion. Environmental factors influencing individual behavior, such as available "social space," were studied by using IowaFLI Tracker to simultaneously track multiple flies in the same arena. We found that crowding levels affect individual fly activity, with the total movement of individual flies attenuated around a particular density. This observation may have important implications in the design of activity chambers for studying particular kinds of social interactions. IowaFLI Tracker also directly quantifies social interactions by tracking the amount of time individuals are in proximity to one another-visualized as an "interactogram." This feature enables the development of a "target-preference" assay to study male courtship behavior where males are presented with a choice between two immobilized, decapitated females, and their locomotion and interactions quantified. We used this assay to study the chemosensory mutants olf D (para(olfD), sbl(2)) and Gr32a and their preferences towards virgin or mated females. Male olf D flies showed reduced courtship levels, with no clear preference towards either, whereas Gr32a males preferentially courted with virgin females over mated females in this assay. These initial results demonstrate that IowaFLI Tracker can be employed to explore motor coordination and social interaction phenomena in behavioral mutants of Drosophila. PMID- 23106156 TI - Factors associated with infantile eczema in Hangzhou, China. AB - The removal of aggravating factors is important to reduce the severity of infantile eczema, but there are few studies on the assessment and identification of the aggravating factors in infantile eczema. Parents of children with infantile eczema ages 1 to 10 months (N = 250) were recruited. Parents were required to complete a questionnaire. Two hundred forty-two (96.8%) children had skin dryness, 80% bathed with soap or shower gel, 82% often perspired, 84.8% wore tight-fitting clothes, 80.8% dressed in five layers of thick clothing, 85.6% were in contact with wool or feathers, and 59.2% were exposed to sunlight (>20 minutes/day). Eczema severity was greater after vaccination in 20%. Two hundred thirty-five mothers avoided eating potential food allergens (e.g., milk, egg whites, and fish), but this failed to improve the severity of symptoms in 93.6% of the children. Thirty patients had Neocate as a substitute for cow's milk, which resulted in symptom severity improvement in 10%. Thirty children were given food allergens, which exacerbated symptoms in 13.3%. One hundred twenty-eight (51.2%) of the children were treated with corticosteroid ointment; 62.5% had the ointment applied for only 2 to 3 days, and 6.2% had the corticosteroid ointment applied to weeping lesions. The vast majority of parents did not know about the aggravating factors for infantile eczema. The results demonstrated a strong need for educational programs to help parents understand and control infantile eczema. PMID- 23106157 TI - Comparison of intradermal injection with iontophoresis of abobotulinum toxin A for the treatment of primary axillary hyperhidrosis: a randomized, controlled trial. AB - BACKGROUND: Botulinum neurotoxin type A (BTX-A) injection is the treatment of choice for idiopathic axillary hyperhidrosis (IAH) refractory to conventional treatments. OBJECTIVE: This study compared the efficacy of BTX-A injection and iontophoresis for treatment of IAH in a randomized controlled trial. METHODS: In eleven patients with the diagnosis of IAH, one axilla was randomly treated with injections of 1.5 mL (250 MU) of BTX-A, and the other side was treated with BTX-A administered by iontophoresis. The amount of sweating, skin hydration, transepidermal water loss, pain, and patient satisfaction on both axilla were compared with baseline levels, and also between both sides 1 week, 1 month, and 6 months after treatment. RESULTS: The injection side had significantly less sweat production than the iontophoresis side 1 week, 1 month, and 6 months after treatment (84%, 76%, and 50% vs. 73%, 22%, and 32%, respectively). The response to iontophoresis was more stable than that to injection. Participants' pain perception during the procedure score was significantly less on the iontophoresis side compared with the injection side (15.0 vs. 20.0, p < 0.05). CONCLUSION: This study has shown that injection is a more effective method for the administration of BTX-A, though iontophoresis can also be considered a non-invasive and painless method in some patients. PMID- 23106159 TI - Synthesis of oxazoles from enamides via phenyliodine diacetate-mediated intramolecular oxidative cyclization. AB - A group of functionalized oxazoles were synthesized in moderate to good yields from enamides via phenyliodine diacetate (PIDA)-mediated intramolecular cyclization. The main advantageous features of the present method include its broad substrate scope and the heavy-metal-free characteristic of the oxidative carbon-oxygen bond formation process. PMID- 23106158 TI - A multiplex PCR assay for the rapid and sensitive detection of methicillin resistant Staphylococcus aureus and simultaneous discrimination of Staphylococcus aureus from coagulase-negative staphylococci. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a global health concern, which had been detected in food and food production animals. Conventional testing for detection of MRSA takes 3 to 5 d to yield complete information of the organism and its antibiotic sensitivity pattern. So, a rapid method is needed to diagnose and treat the MRSA infections. The present study focused on the development of a multiplex PCR assay for the rapid and sensitive detection of MRSA. The assay simultaneously detected 4 genes, namely, 16S rRNA of the Staphylococcus genus, femA of S. aureus, mecA that encodes methicillin resistance, and one internal control. It was rapid and yielded results within 4 h. The analytical sensitivity and specificity of the multiplex PCR assay was evaluated by comparing it with the conventional method. The analytical sensitivity of the multiplex PCR assay at the DNA level was 10 ng DNA. The analytical specificity was evaluated with 10 reference staphylococci strains and was 100%. The diagnostic evaluation of MRSA was carried out using 360 foodborne staphylococci isolates, and showed 99.1% of specificity, 96.4% of sensitivity, 97.5% of positive predictive value, and 97.3% of negative predictive value compared to the conventional method. The inclusion of an internal control in the multiplex PCR assay is important to exclude false-negative cases. This test can be used as an effective diagnostic and surveillance tool to investigate the spread and emergence of MRSA. PMID- 23106160 TI - Declines in peer conflict from preschool through first grade: influences from early attachment and social information processing. AB - The transition from preschool to early school years is critical for the growth of social skills. Using data from the NICHD Study of Early Child Care and Youth Development (for this study N = 942), the purpose of this study was to evaluate the longitudinal influence of attachment security and social information processing skills (social problem-solving and hostile attribution biases) on normative changes in peer conflict over the transition from preschool to first grade. Using latent growth curve modeling (LGM), this study found that children exhibited progressive declines in peer conflict over this period. Security of attachment (assessed via the Attachment Q-Set at 24 months) was related to lower rates of peer conflict in first grade, and steeper declines in peer conflict from 54 to 84 months. Differences in children's social information processing (assessed at 54 months) were marginally related to steeper declines in peer conflict. These findings suggest that the social skills and social expectations associated with early attachment security, together with subsequent advances in social information processing, are related to changes in peer conflict during the transition to school. PMID- 23106161 TI - Serum gamma-glutamyltransferase and alanine aminotransferase levels are correlated with hematocrit in a general population of outpatients. PMID- 23106162 TI - X-ray fluorescence analysis of iron and manganese distribution in primary dopaminergic neurons. AB - Transition metals have been suggested to play a pivotal role in the pathogenesis of Parkinson's disease. X-ray microscopy combined with a cryogenic setup is a powerful method for elemental imaging in low concentrations and high resolution in intact cells, eliminating the need for fixation and sectioning of the specimen. Here, we performed an elemental distribution analysis in cultured primary midbrain neurons with a step size in the order of 300 nm and ~ 0.1 ppm sensitivity under cryo conditions by using X-ray fluorescence microscopy. We report the elemental mappings on the subcellular level in primary mouse dopaminergic (DAergic) and non-DAergic neurons after treatment with transition metals. Application of Fe(2+) resulted in largely extracellular accumulation of iron without preference for the neuronal transmitter subtype. A quantification of different Fe oxidation states was performed using X-ray absorption near edge structure analysis. After treatment with Mn(2+) , a cytoplasmic/paranuclear localization of Mn was observed preferentially in DAergic neurons, while no prominent signal was detectable after Mn(3+) treatment. Immunocytochemical analysis correlated the preferential Mn uptake to increased expression of voltage gated calcium channels in DAergic neurons. We discuss the implications of this differential elemental distribution for the selective vulnerability of DAergic neurons and Parkinson's disease pathogenesis. PMID- 23106164 TI - ABC transporters of antimicrobial peptides in Firmicutes bacteria - phylogeny, function and regulation. AB - Antimicrobial peptides (AMPs) are a group of antibiotics that mainly target the cell wall of Gram-positive bacteria. Resistance is achieved by a variety of mechanisms including target alterations, changes in the cell's surface charge, expression of immunity peptides or by dedicated ABC transporters. The latter often provide the greatest level of protection. Apart from resistance, ABC transporters are also required for the export of peptides during biosynthesis. In this review the different AMP transporters identified to date in Firmicutes bacteria were classified into five distinct groups based on their domain architecture, two groups with a role in biosynthesis, and three involved in resistance. Comparison of the available information for each group regarding function, transport mechanism and gene regulation revealed distinguishing characteristics as well as common traits. For example, a strong correlation between transporter group and mode of gene regulation was observed, with three different types of two-component systems as well as XRE family transcriptional regulators commonly associated with individual transporter groups. Furthermore, the presented summary of the state-of-the-art on AMP transport in Firmicutes bacteria, discussed in the context of transporter phylogeny, provides insights into the mechanisms of substrate translocation and how this may result in resistance against compounds that bind extracellular targets. PMID- 23106163 TI - Current status of robot-assisted laparoscopic radical prostatectomy: how does it compare with other surgical approaches? AB - The aim was to review the current status and evaluate the outcomes of robot assisted laparoscopic radical prostatectomy in comparison with open radical prostatectomy and laparoscopic radical prostatectomy. Between January 2008 and June 2012, published English language comparative studies comparing robot assisted laparoscopic radical prostatectomy with either open radical prostatectomy and/or laparoscopic radical prostatectomy were reviewed. End-points for this review include oncological, functional and perioperative outcomes, and complications. Compared with laparoscopic radical prostatectomy and/or open radical prostatectomy, robot-assisted laparoscopic radical prostatectomy offered at least equivalent oncological control. Current evidence seems to suggest a superiority of robot-assisted laparoscopic radical prostatectomy over open radical prostatectomy and laparoscopic radical prostatectomy in terms of functional outcomes, such as urinary continence and potency. Risks of perioperative complications were also low after robot-assisted laparoscopic radical prostatectomy. Robot-assisted laparoscopic radical prostatectomy offers at least equivalent oncological and functional outcomes with low risks of complications when compared with open radical prostatectomy and laparoscopic radical prostatectomy. However, there is a paucity of high-level evidence available in current literature. PMID- 23106165 TI - Ultrastructure of rabbit embryos exposed to hyperthermia and anti-Hsp 70. AB - The aim of the study was to determine the effect of short-term hyperthermia and Hsp70 blockage on ultrastructural changes in cell organelles and nucleoli of rabbit preimplantation embryos. The embryos were cultured either at 37.5 degrees C (control, C) or 41.5 degrees C (hyperthermia, HT) during 6 h. The antibody against Hsp70 was added into the culture medium (4 MUg/ml) of morula stage embryos from C and HT groups. After termination of the culture, the embryos were processed for transmission electron microscopy. The embryos exposed to hyperthermia showed increased volume of lipid droplets, considerable occurrence of cellular debris in the perivitelline space and slight changes in the occurrence of microvilli on the surface of trophoblastic cells. In the embryos exposed to anti-Hsp 70 at 37.5 degrees C, there were considerable changes in mitochondria morphology, decreased volume of dense bodies in the cytoplasm and considerable changes in the occurrence of microvilli on the surface of trophoblastic cells. In the group of embryos exposed simultaneously to hyperthermia and anti-Hsp 70, mitochondria were also expanded and swollen; the volume of flocculent vesicles and lipid droplets was increased and the volume of dense bodies in the cytoplasm was diminished. General organization of the cytoplasm in groups with anti-Hsp70 was characterized by cell organelle segregation. Averaged size of the nucleolar area was significantly increased in the embryos exposed to hyperthermia, whereas in the group exposed to the anti Hsp70 without hyperthermia it was significantly diminished. Hyperthermia also caused disintegration of compact status of the nucleoli. In presence of anti-Hsp 70, the structural changes, described within the nucleoli during hyperthermia, were not observed. In conclusion, these results document ultrastructural changes in cell organelles of rabbit preimplantation embryo caused by hyperthermia, and also changes in the nucleolar structures, at which presence of Hsp-70 inhibit these changes. PMID- 23106167 TI - High-capacity lithium-ion battery conversion cathodes based on iron fluoride nanowires and insights into the conversion mechanism. AB - The increasing demands from large-scale energy applications call for the development of lithium-ion battery (LIB) electrode materials with high energy density. Earth abundant conversion cathode material iron trifluoride (FeF(3)) has a high theoretical capacity (712 mAh g(-1)) and the potential to double the energy density of the current cathode material based on lithium cobalt oxide. Such promise has not been fulfilled due to the nonoptimal material properties and poor kinetics of the electrochemical conversion reactions. Here, we report for the first time a high-capacity LIB cathode that is based on networks of FeF(3) nanowires (NWs) made via an inexpensive and scalable synthesis. The FeF(3) NW cathode yielded a discharge capacity as high as 543 mAh g(-1) at the first cycle and retained a capacity of 223 mAh g(-1) after 50 cycles at room temperature under the current of 50 mA g(-1). Moreover, high-resolution transmission electron microscopy revealed the existence of continuous networks of Fe in the lithiated FeF(3) NWs after discharging, which is likely an important factor for the observed improved electrochemical performance. The loss of active material (FeF(3)) caused by the increasingly ineffective reconversion process during charging was found to be a major factor responsible for the capacity loss upon cycling. With the advantages of low cost, large quantity, and ease of processing, these FeF(3) NWs are not only promising battery cathode materials but also provide a convenient platform for fundamental studies and further improving conversion cathodes in general. PMID- 23106168 TI - Photophysics of a cis axially disubstituted macrocycle: rapid intersystem crossing in a tin(IV) phthalocyanine with a half-domed geometry. AB - We have studied the photophysical properties of a tin(IV) phthalocyanine which coordinates two myristate groups through their carboxylate functionalities in a cis disposition at the tin center. Such a coordination mode, anisobidentate through the same side of the macrocycle, makes this phthalocyanine acquire a capped or half-domed shape. This bis myristate tin(IV) molecule shows an intersystem crossing channel which populates the triplet manifold with high efficiency and with a time constant of 300 ps, about an order of magnitude faster than planar phthalocyanines, including some previously reported tin(IV) phthalocyanines. For comparison purposes, we also include the description of a planar silicon(IV) phthalocyanine that keeps the more common stereochemistry, of trans type, with the same axial myristate groups. The characterization of these systems included steady state and time-resolved spectroscopy through femtosecond fluorescence up-conversion and transient absorption. We also studied the initial S(n) -> S(1) internal conversion dynamics when these compounds are excited to upper states with 387.5 nm light. In addition, we include measurements of the rate for singlet oxygen production through the formation of an ESR-active adduct in aerated solutions. Such measurements indicate that, associated to its photophysics, the tin(IV) phthalocyanine produces (1)O(2) with an efficiency significantly larger than the silicon(IV) counterpart, making it an interesting option for sensitization applications. Finally, we performed excited state calculations at the TD-DFT level which describe the effects of the reduced symmetry together with the state ordering and indicate the presence of near dark intermediate states between the Q and B transitions for both of these macrocycles. PMID- 23106166 TI - Barcoding of biting midges in the genus Culicoides: a tool for species determination. AB - Biting midges of the genus Culicoides (Diptera: Ceratopogonidae) are insect vectors of economically important veterinary diseases such as African horse sickness virus and bluetongue virus. However, the identification of Culicoides based on morphological features is difficult. The sequencing of mitochondrial cytochrome oxidase subunit I (COI), referred to as DNA barcoding, has been proposed as a tool for rapid identification to species. Hence, a study was undertaken to establish DNA barcodes for all morphologically determined Culicoides species in Swedish collections. In total, 237 specimens of Culicoides representing 37 morphologically distinct species were used. The barcoding generated 37 supported clusters, 31 of which were in agreement with the morphological determination. However, two pairs of closely related species could not be separated using the DNA barcode approach. Moreover, Culicoides obsoletus Meigen and Culicoides newsteadi Austen showed relatively deep intraspecific divergence (more than 10 times the average), which led to the creation of two cryptic species within each of C. obsoletus and C. newsteadi. The use of COI barcodes as a tool for the species identification of biting midges can differentiate 95% of species studied. Identification of some closely related species should employ a less conserved region, such as a ribosomal internal transcribed spacer. PMID- 23106170 TI - Does subgroup membership information lead to better estimation of true subscores? AB - Haberman (2008) suggested a method to determine if subtest scores have added value over the total score. The method is based on classical test theory and considers the estimation of the true subscores. Performance of subgroups, for example, those based on gender or ethnicity, on subtests is often of interest. Researchers such as Stricker (1993) and Livingston and Rupp (2004) found that the difference in performance between the subgroups often varies over the different subtests. We suggest a method to examine whether the knowledge of the subgroup membership of the examinees leads to a better estimation of the true subscores. We apply our suggested method to data from two operational testing programmes. The knowledge of the subgroup membership of the examinees does not lead to a better estimation of the true subscore for the data sets. PMID- 23106171 TI - Aplasia cutis congenita of the arm with associated radial dysplasia: case report, review of the literature, and proposed classification. AB - Aplasia cutis congenita (ACC), congenital absence of skin, is most common on the scalp but may rarely occur on the trunk and limbs. It is a physical finding that can occur in isolation or as part of a heterogeneous group of syndromes. It can affect localized to widespread areas of absent or atrophic, scarred skin at birth. We report a case of ACC of the distal right forearm associated with radial dysplasia in a newborn boy. According to the Frieden classification of ACC, this case, along with other similar reported cases, highlights the need to adjust the classification scheme commonly used for ACC so that it reflects the associated limb abnormalities with ACC of the extremities. Only five cases describing the association of radial dysplasia with ACC of the arm were found in the literature. Greater awareness of this association may allow for early intervention and better outcomes in children with ACC of the extremities. PMID- 23106172 TI - Double Schiff base adducts of 2,3-butanedione with glycine: formation of pyrazine rings with the participation of amino acid carbon atoms. AB - The 1,2-dicarbonyl compounds are well-known for their ability to undergo a one-to one interaction with amino acids and generate aroma-active pyrazines through the Strecker reaction. An earlier publication reported the generation of tetrahydropyrazine moiety from the double addition of amino acids to 1,2 dicarbonyl compounds. To evaluate the potential of this intermediate to undergo oxidation and form pyrazines, a model system composed of glycine and 2,3 butanedione was evaluated under pyrolytic conditions at 250 degrees C, as well as under pressurized high-temperature conditions at 120 degrees C. These studies have indicated the unexpected formation of 2,3-dimethylpyrazine and 2,3,5 trimethylpyrazine in addition to the expected tetramethylpyrazine. Isotope labeling studies using [13C-1]glycine (98%), [13C-2]glycine (99%), and [15N]glycine (98%) have shown that, as expected, tetramethylpyrazine was completely unlabeled, whereas 51% of 2,3-dimethylpyrazine incorporated two 13C-2 atoms from glycine, 20% incorporated one atom, and 29% was unlabeled. Furthermore, the label incorporation pattern in the major mass spectral fragment at m/z 67 indicated that the C-2 atoms originating from glycine reside in the ring system of 2,3-dimethylpyrazine. The formation of doubly labeled 2,3 dimethylpyrazine was rationalized through proposition of the double addition of glycine to 2,3-butanedione, and the formation of singly labeled isotopomer was justified by sequential Schiff base formation of 2-amino-butan-3-one first with the Strecker aldehyde and then followed by glycine. This pathway can also generate the double-labeled pyrazine. Finally, the unlabeled pyrazine was proposed to form through the Strecker reaction of 2,3-butanedione and its degradation product glyoxal with glycine. The proposed pathways were also consistent with the observed label distribution patterns of 2,3,5 trimethylpyrazine. PMID- 23106173 TI - Variance in coronary venous anatomy: a critical determinant in optimal candidate selection for cardiac resynchronization therapy. AB - BACKGROUND: Knowledge of coronary sinus (CS) anatomy and its variations is one of the important factors determining the final position of left ventricle pacing lead during cardiac resynchronization therapy. METHODS: Coronary venous system anatomy, including number, diameter, and opening angles of tributaries, was studied in 50 normal formalin-fixed adult cadaveric hearts. RESULTS: Thebesian valve (TV) and Vieussens valve were present in 64% and 60% cases, respectively. CS ostium coverage of >=75% by TV was seen in 25% (8/32) cases. Number of prominent tributaries lying between anterior interventricular vein and middle cardiac vein varied from 1-4. In 28% of hearts, only one prominent tributary was present. Midlateral vein (average diameter 1.75 +/- 0.66 mm) with an average distance of 43.5 +/- 12.2 mm from coronary ostium was present in 58% (29/50) hearts, of which it formed an acute angle with CS axis in four (13.39%) cases. Posterolateral vein (average diameter 1.62 +/- 0.45 mm) with an average distance of 33.4 +/- 11.7 mm from coronary ostium was found in 72% (36/50) cases and formed an acute angle with CS in three (8.33%) cases. CONCLUSIONS: Restrictive TV covering >=75% CS ostium (25% cases), presence of single prominent tributary (28% cases), and formation of acute angle of tributary with CS axis (1/4 cases with anterolateral vein, 4/29 cases with midlateral vein, 3/36 cases with posterolateral vein, and 3/28 cases with posterior veins of the left ventricle) can impede successful cannulation of CS. PMID- 23106174 TI - Distinguishing radiation fibrosis from tumour recurrence after stereotactic ablative radiotherapy (SABR) for lung cancer: a quantitative analysis of CT density changes. AB - BACKGROUND: For patients treated with stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer, benign computed tomography (CT) changes due to radiation-induced lung injury (RILI) can be difficult to differentiate from recurrence. We measured the utility of CT image feature analysis in differentiating RILI from recurrence, compared to Response Evaluation Criteria In Solid Tumours (RECIST). MATERIALS AND METHODS: Twenty-two patients with 24 lesions treated with SABR were selected (11 with recurrence, 13 with substantial RILI). On each follow-up CT, consolidative changes and ground glass opacities (GGO) were contoured. For each lesion, contoured regions were analysed for mean and variation in Hounsfield units (HU), 3D volume, and RECIST size during follow-up. RESULTS: One hundred and thirty-six CT scans were reviewed, with a median imaging follow-up of 26 months. The 3D volume and RECIST measures of consolidative changes could significantly distinguish recurrence from RILI, but not until 15 months post-SABR; mean volume at 15 months [all values +/- 95% confidence interval (CI)] of 30.1 +/- 19.3 cm(3) vs. 5.1 +/- 3.6 cm(3) (p = 0.030) and mean RECIST size at 15 months of 4.34 +/- 1.13 cm vs. 2.63 +/- 0.84 cm (p = 0.028) respectively for recurrence vs. RILI. At nine months post-SABR, patients with recurrence had significantly higher-density consolidative changes (mean at nine months of -96.4 +/- 32.7 HU vs. -143.2 +/- 28.4 HU for RILI; p = 0.046). They also had increased variability of HU, an image texture metric, measured as the standard deviation (SD) of HU, in the GGO areas (SD at nine months of 210.6 +/- 14.5 HU vs. 175.1 +/- 18.7 HU for RILI; p = 0.0078). CONCLUSIONS: Quantitative changes in mean HU and GGO textural analysis have the potential to distinguish RILI from recurrence as early as nine months post-SABR, compared to 15 months with RECIST and 3D volume. If validated, this approach could allow for earlier detection and salvage of recurrence, and result in fewer unnecessary investigations of benign RILI. PMID- 23106175 TI - A randomized controlled trial of support group intervention after breast cancer treatment: results on sick leave, health care utilization and health economy. AB - BACKGROUND: More than 50% of breast cancer patients are diagnosed before the age of 65. Returning to work after treatment is, therefore, of interest for both the individual and society. The aim was to study the effect of support group intervention on sick leave and health care utilization in economic terms. MATERIAL AND METHODS: Of 382 patients with newly diagnosed breast cancer, 191 + 191 patients were randomized to an intervention group or to a routine control group, respectively. The intervention group received support intervention on a residential basis for one week, followed by four days of follow-up two months later. The support intervention included informative-educational sections, relaxation training, mental visualization and non-verbal communication. Patients answered a questionnaire at baseline, two, six and 12 months about sick leave and health care utilization. RESULTS: There was a trend towards longer sick leave and more health care utilization in the intervention group. The difference in total costs was statistically significantly higher in the intervention group after 12 months (p = 0.0036). CONCLUSION: Costs to society were not reduced with intervention in its present form. PMID- 23106176 TI - Weight loss in patients with head and neck cancer during and after conventional and accelerated radiotherapy. AB - BACKGROUND: Weight loss is common among patients with squamous cell carcinoma of the head and neck (SCCHN) and is mainly due to tumor and treatment related factors. The aim of the present study was to evaluate weight loss in patients with SCCHN undergoing two different radiotherapy (RT) schedules. MATERIAL AND METHODS: Nutritional data were analyzed from the ARTSCAN study, a controlled randomized prospective Swedish multicenter study conducted with the aim of comparing conventional fractionation (2.0 Gy per day, total 68 Gy during 7 weeks) and accelerated fractionation (1.1 + 2.0 Gy per day, total 68 Gy during 4.5 weeks). Seven hundred and fifty patients were randomized and 712 patients were followed from the start of RT in the present nutritional study. RESULTS: The patients had a weight loss of 11.3% (+/- 8.6%) during the acute phase (start of RT up to five months after the termination of RT). No difference in weight loss was seen between the two RT fractionation schedules (p = 0.839). Three factors were significantly predictive for weight loss during the acute phase, i.e. tumor site, overweight/obesity or lack of tube feeding at the start of RT. Moreover, the nadir point of weight loss occurred at five months after the termination of RT. CONCLUSION: The results of the present study showed no difference in weight loss between the two RT fractionation schedules and also highlight that weight loss in SCCHN is a multifactorial problem. Moreover, the nadir of weight loss occurred at five months after the termination of treatment which calls for more intense nutritional interventions during the period after treatment. PMID- 23106177 TI - Attachment in the brain: adult attachment representations predict amygdala and behavioral responses to infant crying. AB - Current research found that adult attachment representations influence neural, emotional, and behavioral responses to infant crying, thus validating the Berkeley Adult Attachment Interview with functional Magnetic Resonance Imaging. This study examined amygdala activation, feelings of irritation, and the use of excessive force as indicated by grip strength using a handgrip dynamometer during exposure to infant crying and scrambled control sounds in 21 women without children. Individuals with insecure attachment representations showed heightened amygdala activation when exposed to infant crying compared to individuals with secure attachment representations. In addition, insecure individuals experienced more irritation during infant crying and used more excessive force than individuals with a secure representation. Amygdala hyperactivity might be one of the mechanisms underlying the experience of negative emotions during exposure to infant crying in insecure individuals and might explain why insecure parents respond inconsistently to infant signals or reject their infants' attachment behavior. PMID- 23106178 TI - Intergenerational relations of attachment: a research synthesis of urban/rural Mexican samples. AB - Intergenerational relations of attachment, including adult state of mind, adult care giving quality, and infant behavior, were examined in urban and rural samples. The sample included 66 dyads of contrasting populations, 35 middle-high urban Spanish speaking families and 31 rural Indian peasant families. Measures included the Adult Attachment Interview (George, Kaplan, & Main, 1985 /1996), home observations of mother-infant, and the Strange Situation attachment assessment (Ainsworth, Blehar, Waters, & Wall, 1978 ). Reliability among independent coders of Spanish AAI transcripts was established for the first time. Moreover, significant relations among the instruments were found, supporting the validity of the AAI to predict infant's attachment classifications and mothers sensitive care of their infants across cultures. Results further supported the cross-cultural robustness of core features of attachment theory and, to some extent, the pathway from adult state of mind through responsive care to attachment security. PMID- 23106179 TI - Maternal sensitivity mediates the link between maternal insightfulness/resolution and child-mother attachment: the case of children with Autism Spectrum Disorder. AB - This study examined the hypothesis that maternal sensitivity mediates the association between maternal Insightfulness/Resolution and child attachment in a sample of preschool age boys with Autism Spectrum Disorders. This study used the Insightfulness Assessment to assess insightfulness and the Reaction to Diagnosis Interview to assess mothers' resolution. Maternal sensitivity was assessed from mother-child play observations, and the security of children's attachment was assessed using the Strange Situation Procedure. The results supported the mediation model, and their implications for attachment research, research on intervention in autism, and clinical work are discussed. PMID- 23106180 TI - Attachment representations in internationally adopted children. AB - Using the Story Stem Assessment Profile, attachment representations were analyzed in a group of 40 internationally adopted children studied after an average of 40 months since their adoption. These children were compared to 58 children living with their birth families and with no experience of maltreatment, and to 50 children who were living in Spanish institutions. All of the children were between four and eight years of age at the time of study. Findings indicated that the adoptees' representations were more negative than those of the control group, but similar to those of the institutionalized children. The associations between different indicators of attachment representations, as well as the role of adopted children's characteristics (pre-adoption experiences, adoption age, time with the adoptive family) were also analyzed. The results showed a long-term impact of early adversity, a certain degree of heterogeneity in the attachment representations' of both the adopted and the institutionalized children, and the role played by certain background and individual variables. PMID- 23106181 TI - Sensitive parenting as a cross-cultural ideal: sensitivity beliefs of Dutch, Moroccan, and Turkish mothers in the Netherlands. AB - The primary goal of this study is to test the hypothesis that beliefs about the ideal sensitive mother are similar across Dutch, Moroccan, and Turkish mothers living in the Netherlands. A total of 75 mothers with at least one child between the ages of six months and six years described their views about the ideal sensitive mother using the Maternal Behavior Q-Sort (Pederson, Moran, & Bento, 1999 ). These views were highly similar within and across cultural and socio economic groups. Nevertheless, family income fully mediated the relationship between ethnic background and sensitivity beliefs; income of minority mothers was lower which was in turn predictive of a lower sensitivity belief score. Our findings suggest that the main behavioral markers of sensitivity are valued by mothers from different cultural backgrounds. The role of socio-economic status in sensitivity beliefs is consistent with the Family Stress Model. PMID- 23106182 TI - Attachment states of mind in late adolescence and the quality and course of romantic relationships in adulthood. AB - The purpose of this study was to examine the longitudinal relations between attachment state of mind in late adolescence and romantic relationships in adulthood. Participants were drawn from two independent studies that were conducted respectively in 1992 and 1996 and that involved the administration of the Adult Attachment Interview (AAI) to 167 college students. They were followed up in 2007 (N = 99) to investigate different aspects of their romantic relationships since college. Those who had shown greater preoccupation with attachment in the AAI were more likely to be single in adulthood and to report romantic relationships of shorter length. In addition, they reported lower levels of intimacy, commitment, and passion in their current or recent romantic relationships. Dismissing tendencies were associated with higher levels of perceived passion in romantic relationships. Most of these associations remained significant after controlling for intervening life events, different dimensions of individual adjustment, socio-economic status, as well as probable life events derived from the AAI. PMID- 23106184 TI - Overlooked issues and unique perspectives on the DSM-5: Introduction to the special series. AB - The publication of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) will transform the way in which personality disorders are conceptualized and diagnosed. Much consideration has been given to the proposed changes and their implications for clinicians and researchers. In this special series, Personality Disorders: Theory, Research, and Treatment adds to this conversation by presenting unique perspectives and issues that have received less attention, but that warrant consideration, as the publication of DSM-5 approaches. Our introduction provides an overview of the key issues in four articles in this special series, considering them within the context of the proposed DSM-5 revisions. PMID- 23106185 TI - Antisocial personality disorder in DSM-5: missteps and missed opportunities. AB - This paper evaluates the proposal for antisocial personality disorder (ASPD) in the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5). Some aspects of the proposal are appealing: personality disorders will be assessed using trait criteria, and these criteria are similar to trait descriptions of DSM-IV ASPD. Other aspects of the proposal are less appealing. First, the DSM-5 will depend on a newly constructed personality trait system rather than relying on a well validated, widely studied one. Second, the trait profile of ASPD is incomplete; although this profile reflects the traits included in DSM-IV, it maps poorly onto the full personality profile of ASPD. Third, the DSM Workgroup missed an opportunity to finally unify ASPD and psychopathy; history and research suggest that these disorders have diverged mistakenly. Fourth, the newly proposed criteria of impairments in self- and interpersonal functioning are of questionable derivation and utility. PMID- 23106186 TI - A randomised controlled trial of dexmedetomidine for suspension laryngoscopy. AB - We randomly allocated 80 patients to intravenous dexmedetomidine (0.25, 0.5, or 1 MUg.kg(-1) ) or placebo 15 min before anaesthetic induction. Dexmedetomidine 0.5 and 1.0 MUg.kg(-1) significantly reduced the mean (95% CI) propofol effect-site concentrations by 0.83 (0.63-1.03) MUg.ml(-1) , p = 0.001 and 1.29 (1.12-1.46) MUg.ml(-1) , p = 0.0003 at intubation, by 1.05 (0.85-1.25 MUg.ml(-1) , p = 0.0006 and 1.33 (1.15-1.51) MUg.ml(-1) , p = 0.0002 when surgery started, and by 0.59 (0.39-0.79) MUg.ml(-1) , p = 0.030 and 0.72 (0.57-0.87) MUg.ml(-1) , p = 0.004 on completion of surgery, respectively. Patients' tracheas were extubated sooner after 0.5 and 1.0 MUg.kg(-1) dexmedetomidine, by 5.36 (2.39-8.32) min, p = 0.009 and 7.37 (3.24-11.51) min p = 0.003, respectively. Tachycardic responses to intubation were present in five placebo patients and no dexmedetomidine patients. Bradycardia was treated after dexmedetomidine in six patients: five after 1.0 MUg.kg(-1) ; and one after 0.25 MUg.kg(-1) . Single-dose dexmedetomidine can reduce anaesthetic requirements, with both desirable and undesirable haemodynamic effects. PMID- 23106187 TI - Expression of angiotensin II and its receptors in cyclosporine-induced gingival overgrowth. AB - BACKGROUND AND OBJECTIVES: The renin-angiotensin system (RAS) is considered as a hormonal circulatory system involved in maintaining blood pressure, electrolyte and fluid homeostasis. RAS components can be synthesized in local tissues and are found to play a role in gingival overgrowth. The drug-induced gingival overgrowth (DIGO) is a fibrotic condition, which is associated with multiple factors, including inflammation and adverse drug effects such as cyclosporine A. This study was directed forward to the identification of the angiotensinogen, angiotensin II (Ang II) and its receptors AT1 /AT2 expression in DIGO tissues and cyclosporine-treated human gingival fibroblast cells. MATERIAL AND METHODS: Gingival samples were obtained from patients with cyclosporine-induced gingival overgrowth, chronic periodontitis and normal healthy subjects. The total RNA was isolated and reverse transcription-polymerase chain reaction was performed for angiotensinogen, Ang II and AT1 /AT2 receptor. Ang II protein was estimated from tissue by enzyme immunoassay. The expression of Ang II and its receptors were also examined in gingival fibroblast cells treated with cyclosporine. RESULTS: Ang II mRNA and protein expression was significantly higher in patients with DIGO than in patients with periodontitis and healthy subjects. The AT1 mRNA was expressed more than AT2 in all examined tissues. In gingival fibroblasts, Ang II and AT1 expressions were increased with cyclosporine incorporation compared to controls. CONCLUSION: These results suggest that cyclosporine can modulate local expression of RAS components such as angiotensinogen, Ang II and its receptors in gingival tissues and gingival fibroblast cells. PMID- 23106188 TI - Factors associated with the enactment of safety belt and motorcycle helmet laws. AB - It has been shown that road safety laws, such as motorcycle helmet and safety belt laws, have a significant effect in reducing road fatalities. Although an expanding body of literature has documented the effects of these laws on road safety, it remains unclear which factors influence the likelihood that these laws are enacted. This study attempts to identify the factors that influence the decision to enact safety belt and motorcycle helmet laws. Using panel data from 31 countries between 1963 and 2002, our results reveal that increased democracy, education level, per capita income, political stability, and more equitable income distribution within a country are associated with the enactment of road safety laws. PMID- 23106189 TI - Azobisisobutyronitrile initiated aerobic oxidative transformation of amines: coupling of primary amines and cyanation of tertiary amines. AB - In the presence of a catalytic amount of radical initiator AIBN, primary amines are oxidatively coupled to imines and tertiary amines are cyanated to alpha aminonitriles. These "metal-free" aerobic oxidative coupling reactions may find applications in a wide range of "green" oxidation chemistry. PMID- 23106190 TI - A widely conserved molecular switch controls quorum sensing and symbiosis island transfer in Mesorhizobium loti through expression of a novel antiactivator. AB - ICEMlSym(R7A) of Mesorhizobium loti is an integrative and conjugative element (ICE) that confers the ability to form a nitrogen-fixing symbiosis with Lotus species. Horizontal transfer is activated by TraR and N-acyl-homoserine lactone (AHL), which can stimulate ICE excision in 100% of cells. However, in wild-type cultures, the ICE is excised at low frequency. Here we show that QseM, a widely conserved ICE-encoded protein, is an antiactivator of TraR. Mutation of qseM resulted in TraR-dependent activation of AHL production and excision, but did not affect transcription of traR. QseM and TraR directly interacted in a bacterial two-hybrid assay in the presence of AHL. qseM expression was repressed by a DNA binding protein QseC, which also activated qseC expression from a leaderless transcript. QseC differentially bound two adjacent operator sites, the lower affinity of which overlapped the -35 regions of the divergent qseC-qseM promoters. QseC homologues were identified on ICEs, TraR/TraM-regulated plasmids and restriction-modification cassettes, suggesting a conserved mode of regulation. Six QseC variants with distinct operators were identified that showed evidence of reassortment between mobile elements. We propose that QseC and QseM comprise a bimodal switch that restricts quorum sensing and ICEMlSym(R7A) transfer to a small proportion of cells in the population. PMID- 23106191 TI - Structural characteristics of pumpkin pectin extracted by microwave heating. AB - To improve extraction yield of pumpkin pectin, microwave heating was adopted in this study. Using hot acid extraction, pumpkin pectin yield decreased from 5.7% to 1.0% as pH increased from pH 1.0 to 2.0. At pH 2.5, no pectin was recovered from pumpkin flesh powder. After a pretreatment at pH 1.0 and 25 degrees C for 1 h, pumpkin powder was microwave-extracted at 120 degrees C for 3 min resulting in 10.5% of pectin yield. However, premicrowave treatment at 60 degrees C for 20 min did not improve extraction yield. When microwave heating at 80 degrees C for 10 min was applied after premicrowave treatment, final pectin yield increased to 11.3%. When pH was adjusted to 2.0, the yield dropped to 7.7% under the same extraction conditions. Molecular shape and properties as well as chemical composition of pumpkin pectin were significantly affected depending on extraction methods. Galacturonic acid content (51% to 58%) of pumpkin pectin was lower than that detected in commercial acid-extracted citrus pectin, while higher content of neutral sugars and acetyl esters existed in pumpkin pectin structure. Molecular weight (M(w) ) and intrinsic viscosity (eta(w) ) determined for microwave extracted pumpkin pectins were substantially lower than acid-extracted pectin, whereas polydispersity was greater. However, microwave-extracted pectin at pH 2.0 had more than 5 times greater M(w) than did the pectin extracted at pH 1.0. The eta(w) of microwave-extracted pectin produced at pH 2.0 was almost twice that of other microwave-extracted pectins, which were comparable to that of acid extracted pectin. These results indicate that extraction yield of pumpkin pectin would be improved by microwave extraction and different pectin structure and properties can be obtained compared to acid extraction. PRACTICAL APPLICATION: Pumpkin is a promising alternative source for pectin material. Pumpkin pectin has a unique chemical structure and physical properties, presumably providing different functional properties compared to conventional commercial pectin sources. Depending on the conditions to produce pumpkin pectin, diverse molecular structures can be obtained and utilized in various food applications. PMID- 23106193 TI - Preoperative prediction of malignant involvement of resected ureters in patients undergoing radical cystectomy for bladder cancer. AB - OBJECTIVE: To investigate preoperative predictors of ureteral involvement of bladder malignancy and to develop a novel preoperative model for the prediction of ureteral involvement in bladder cancer patients undergoing radical cystectomy. METHODS: This study included 197 consecutive bladder cancer patients treated with radical cystectomy. The correlations of preoperative factors with ureteral involvement were analyzed by univariate analysis with Pearson's chi(2-) test and multivariate logistic regression analysis with a stepwise selection procedure. RESULTS: Positive ureteral involvement was observed in 38 (19.3%) patients. Tumor location (involvement of the vesical trigone), clinical T stage (>= cT3) and the number of tumors (>= 3), but not sex, tumor grade and histological features determined by transurethral resection of bladder tumor, tumor size, shape of tumor, concomitant presence of carcinoma in situ, preoperative intravesical therapy, number of transurethral resection of bladder tumor procedures or the presence of hydronephrosis were significantly associated with ureteral involvement in the univariate analysis. Multivariate logistic regression analysis confirmed that the aforementioned three significant factors identified in the univariate analysis were significant independent predictors of ureteral involvement. The probability of ureteral involvement estimated by a combination of these three parameters was well correlated with the real incidence (R = 0.904, P = 0.0021). CONCLUSIONS: Tumor location (involvement of vesical trigone), clinical T stage (>= cT3) and the number of tumors (>= 3) are significant independent preoperative predictors of ureteral involvement of malignancy in bladder cancer patients undergoing radical cystectomy. Our predictive model might be useful for preoperative prediction of ureteral tumor involvement. PMID- 23106194 TI - Endothelial cell damage following sulfur mustard exposure in rabbits and its association with the delayed-onset ocular lesions. AB - OBJECTIVE: Ocular injuries following exposure to the toxic agent sulfur mustard (SM) are characterized by acute corneal erosions and inflammation of the anterior segment that may be followed by delayed corneal injuries, expressed clinically by neovascularization and epithelial defects. The present study aimed to investigate the effects of SM on corneal endothelium (CE) during the acute and delayed phase in relation to the development of the long-term pathology. METHODS: Rabbit eyes were exposed to SM vapor. A clinical follow-up including pachymetry for measurement of corneal thickness were conducted up to 3 months following exposure. In vivo analysis of corneal endothelium in the central and peripheral cornea was carried out, using a contact specular microscopy. Morphometric analysis of cell area and number of cells was performed, to include the acute and delayed phases. Eyes were taken for histology at different time points following exposure (1 h to 3 months). TUNEL staining (Terminal deoxynucleotidyl transferase dUTP nick end labeling) was conducted for detection of apoptosis during the acute phase. RESULTS: SM induced acute corneal erosions and prolonged anterior segment inflammation. Corneal thickness increased within hours, declined after few days but remained higher compared to baseline value for months after the exposure, indicating a chronic edema. Apoptotic alterations were first observed at 6 h resulting in a significant decline in the number of endothelial cells at 24-48 h following exposure. Healing of the endothelium was relatively fast and at one week the Descemet's membrane was resurfaced, yet, the density and morphology of the cells was often abnormal. Moreover, histological evaluation revealed deformation and enlargement of many cells (polymegathism and pleomorphism), thickening and double layered Descemet's membrane. These changes were more pronounced in corneas displaying delayed pathology. DISCUSSION AND CONCLUSIONS: SM induced apoptotic cell death of endothelial cells that was accompanied by corneal edema. The impaired healing of the endothelium, including the decrease in endothelial cell density was associated with the delayed-onset injuries. Since human corneal endothelium is almost amitotic, endothelium toxicity should be taken into consideration when testing potential treatments against ocular injuries following SM exposure. PMID- 23106195 TI - In-situ SAXS study of aqueous clay suspensions submitted to alternating current electric fields. AB - Aqueous colloidal suspensions of clay platelets display a sol/gel transition that is not yet understood. Depending on the nature of the clay, liquid-crystalline behavior may also be observed. For example, the suspensions of beidellite display a nematic phase whereas those of montmorillonite do not. Both beidellite and montmorillonite have a "TOT" structure but the structural electric charge is located in the tetrahedral layer for the former and in the octahedral layer for the latter. We built a setup to perform SAXS experiments on complex fluids submitted to an electric field in situ. We found that the fluid nematic phase of beidellite suspensions readily aligns in the field. However, the field had no influence on the gels, showing that the orientational degrees of freedom of the platelets are effectively frozen. Moreover, strong platelet alignment was induced by the field in the isotropic phase of both clays, in a similar way, regardless of their ability to form a nematic phase. This surprising result would suggest that the orientational degrees of freedom are not directly involved in the sol/gel transition. The ability to induce orientational order in the isotropic phase of clay suspensions can be exploited to prepare materials of controlled anisotropy. PMID- 23106196 TI - A ferrocene-functionalized [2]rotaxane with two fluorophores as stoppers. AB - In the past few decades, bistable [2]rotaxanes have been extensively studied because of their applications in the fields of functional molecules and molecular machines. In this paper, a di-ferrocene-functionalized [2]rotaxane with two fluorophores as stoppers was designed, prepared, and studied. In this bistable [2]rotaxane, a dibenzo-24-crown-8 macrocycle functionalized with two ferrocene moieties as electron donors can reversibly shuttle between two distinct stations, namely, a dialkylammonium recognition site and a N-methyltriazolium recognition site, by external acid-base stimuli, which has been demonstrated using (1)H NMR spectroscopy. It has been shown that, by introducing two ferrocene units into the macrocycle component, the fluorescence of two fluorescent stoppers, namely, the anthracene fluorophore and the 4-morpholin-naphthalimide fluorophore, can be changed in an alternate mode by an adjustable, distance-dependent photoinduced electron transfer process that occurs between the ferrocene electron donors and each of the two fluorophores. PMID- 23106198 TI - Investigating the chemical changes of chlorogenic acids during coffee brewing: conjugate addition of water to the olefinic moiety of chlorogenic acids and their quinides. AB - Coffee is one of the most popular and consumed beverages in the world and is associated with a series of benefits for human health. In this study we focus on the reactivity of chlorogenic acids, the most abundant secondary metabolites in coffee, during the coffee brewing process. We report on the hydroxylation of the chlorogenic acid cinnamoyl substituent by conjugate addition of water to form 3 hydroxydihydrocaffeic acid derivatives using a series of model compounds including monocaffeoyl and dicaffeoylquinic acids and quinic acid lactones. The regiochemistry of conjugate addition was established based on targeted tandem MS experiments. Following conjugate addition of water a reversible water elimination yielding cis-cinnamoyl derivatives accompanied by acyl migration products was observed in model systems. We also report the formation of all of these derivatives during the coffee brewing process. PMID- 23106197 TI - Motor origins of tool use. AB - The current study examines the developmental trajectory of banging movements and its implications for tool use development. Twenty (6- to 15-month-old) infants wore reflective markers while banging a handled cube; movements were recorded at 240 Hz. Results indicated that through the second half-year, banging movements undergo developmental changes making them ideally suited for instrumental hammering and pounding. Younger infants were inefficient and variable when banging the object: Their hands followed circuitous paths of great lengths at high velocities. By 1 year, infants showed consistent and efficient straight up down hand trajectories of smaller magnitude and velocity, allowing for precise aiming and delivering dependable levels of force. The findings suggest that tool use develops gradually from infants' existing manual behaviors. PMID- 23106200 TI - Atrio-hisian fibers anatomy and electrophysiology. AB - INTRODUCTION: In this case, electrophysiology and histology could be studied in the same heart. Clinical investigation, clinical electrophysiology, and postmortem serial histological sections of the septum were analyzed. METHODS: A patient with repeated seizures and a short PR interval with narrow QRS complex underwent electrophysiologic studies. RESULTS: The patient died while experiencing a very rapid supraventricular tachycardia and histologic examination showed a atrio-hisian bypass tract. CONCLUSION: In our study, the lack of lengthening of the PR interval in spite of progressively premature atrial stimulation connected with the presence of atrio-hisian bypass tract. PMID- 23106201 TI - Ease of intrauterine contraceptive device insertion in family planning settings. AB - BACKGROUND: Intrauterine devices (IUDs) provide highly effective contraception for women worldwide. Reluctance to insert IUDs in the primary care setting may relate to concern about potential difficulty and complications, particularly in nulliparous women. AIMS: To determine the practitioner, patient and procedural factors associated with abandoned IUD insertion, practitioner-reported difficulty of insertion and adverse events during IUD insertions in the family planning setting. METHODS: This was a prospective study over a 12-month period of consecutive IUD insertions in four family planning clinics across New South Wales and Queensland. Patient, practitioner and device-related factors associated with abandoned IUD insertion, practitioner-reported ease of insertion and immediate insertion-related adverse events were analysed using logistic regression. RESULTS: Of 996 insertion procedures, successful insertion occurred in 95%, and 90% were reported as easy by the inserting doctor, including 80% of those in nulliparous women. Patient characteristics associated with an abandoned insertion were nulliparity (AOR 5.19; 2.49-10.82) or caesarean section-only deliveries (AOR 5.38; 2.58-11.22) and with practitioner-reported difficult insertion, nulliparity alone (AOR 1.98; 1.11-3.54). Practitioners inserting fewer than 100 IUDs over the 12-month study period more frequently rated insertions as difficult (AOR 1.76; 1.08-2.88). Complications occurred in 34 women and were more likely in nulliparous women (AOR 4.51; 2.16-9.39). CONCLUSIONS: Most IUDs can be successfully inserted, even in nulliparous women, in a primary care setting. Referral to a specialist may be appropriate for some women who are nulliparous or had caesarean section-only deliveries, depending on the experience of the practitioner. PMID- 23106203 TI - Identification of two-component system AfsQ1/Q2 regulon and its cross-regulation with GlnR in Streptomyces coelicolor. AB - The two-component system AfsQ1/Q2 of Streptomyces coelicolor was identified in our previous work as a pleiotropic regulator for antibiotic biosynthesis and morphological differentiation under the condition of a minimal medium supplemented with 75 mM glutamate. In this work, we report the dissection of the mechanism underlying the function of AfsQ1/Q2 on antibiotic production and also the identification of the AfsQ1/Q2 regulon. The results showed that AfsQ1/Q2 stimulated antibiotic ACT, RED and CDA production directly through the pathway specific activator genes actII-ORF4, redZ and cdaR respectively. In addition, expression of sigQ that encodes a sigma factor and is divergently transcribed from afsQ1 was also subject to direct regulation by AfsQ1/Q2. The precise AfsQ1 binding sites in the upstream regions of these target genes were determined by DNase I footprinting assays coupled with site-directed DNA mutagenesis. By computational prediction and functional analysis, at least 17 new AfsQ1 targets were identified, including pstS gene encoding a high-affinity phosphate-binding protein and two developmental genes whiD, bldM. For the AfsQ1/Q2 regulon, an AfsQ1 binding motif comprising the sequence GTnAC-n(6) -GTnAC has been defined. Interestingly, we found from electrophoretic mobility shift assays and transcriptional analysis that AfsQ1/Q2 can also function as a repressor for nitrogen assimilation, and AfsQ1 can compete with GlnR for the promoter regions of glnA and nirB, suggesting the cross-regulation between AfsQ1/Q2 and GlnR in nitrogen metabolism. These findings suggested that AfsQ1/Q2 is important not only for antibiotic biosynthesis but also in maintaining the metabolic homeostasis of nutrient utilization under the stress of high concentration of glutamate in S. coelicolor. PMID- 23106204 TI - Incidence and risk of treatment for benign prostatic hyperplasia in Japanese men: a 15-year longitudinal community-based study. AB - OBJECTIVES: To determine the incidence of and the risk factors for treatment in Japanese men with benign prostatic hyperplasia/lower urinary tract symptoms enrolled into a longitudinal community-based study. METHODS: A total of 267 of 319 men aged 40-79 years were eligible for this study, with nearly 15 years of follow up. Their medical records were checked to look for any medical treatment for benign prostatic hyperplasia/lower urinary tract symptoms. The risk of treatment for benign prostatic hyperplasia/lower urinary tract symptoms was determined by calculating the hazard ratio using the Cox proportional hazards model. Five baseline parameters were considered: the International Prostate Symptom Score, the peak urinary flow rate, the prostate volume, the serum prostate-specific antigen and the internal prostatic architecture on transrectal ultrasonography. RESULTS: Data were successfully collected for 171 men (64%; 121 survivors and 50 deceased). During approximately 1900 person-years of follow up, the overall incidence of treatment for benign prostatic hyperplasia/lower urinary tract symptoms was 15.4/1000 person-years. All five parameters were statistically significant predictors of future treatment for benign prostatic hyperplasia/lower urinary tract symptoms: International Prostate Symptom Score greater than 7 (hazard ratio 6.2, P < 0.001), prostate volume greater than 30 mL (hazard ratio 4.3, P = 0.002), peak urinary flow rate less than 12 mL/s (hazard ratio 4.4, P < 0.001), prostate-specific antigen greater than 1.4 ng/mL (hazard ratio 4.0, P < 0.001) and internal prostatic architecture group 3 (hazard ratio 3.2, P = 0.002). CONCLUSIONS: Severity of lower urinary tract symptoms, decreased peak urinary flow rate, enlarged prostate volume, high prostate-specific antigen value and internal prostatic architecture at baseline are independent risk factors for treatment in Japanese men presenting with benign prostatic hyperplasia/lower urinary tract symptoms. PMID- 23106205 TI - Unraveling unidirectional threading of alpha-cyclodextrin in a [2]rotaxane through spin labeling approach. AB - We present here the results of a CW-ESR investigation of a double spin labeled alpha-cyclodextrin-based [2]rotaxane that is characterized by the presence of nitroxide labels both at the wheel and at the dumbbell. This was accomplished by synthesizing a spin labeled alpha-CD (the wheel) that was mechanically blocked on a thread containing a nitroxide unit by a Cu(I) catalyzed azide-alkyne cycloaddition (CuAAC). Both ESI-MS analysis and NMR spectroscopy were used to provide evidence of the threading processes. Because of the unsymmetrical structure of both the wheel and the axle, two different geometrical isomers could be predicted on the basis of the orientation of the CD along the thread. By combining molecular dynamic calculations and information extracted from the CW ESR spectra, we were able to determine the geometrical nature of the isomer that was isolated as the only species. The ESR spectra showed J-coupling between the two mechanically connected nitroxide units and were analyzed by a model assuming three main molecular states. The intramolecular noncovalent nature of spin exchange was confirmed by reversibly switching the magnetic interaction on-off by changing the pH of the solution in the presence of a competing macrocyclic host. PMID- 23106206 TI - Effects of cranberry components on human aggressive periodontitis gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Aggressive periodontitis (AgP) causes rapid periodontal breakdown involving AgP gingival fibroblast production of cytokines [i.e. interleukin (IL)-6, a bone metabolism regulator], and matrix metalloproteinase (MMP)-3. Lipopolysaccharide upregulates fibroblast IL-6 and MMP-3, via transcription factors (i.e. NF-kappaB). Cranberry (Vaccinium macrocarpon) inhibits lipopolysaccharide-stimulated macrophage and normal gingival fibroblast activities, but little is known of its effects on AgP fibroblasts. Objectives of this study are to use AgP fibroblasts, to determine cytotoxicity of cranberry components or periodontopathogen (Fusobacterium nucleatum, Porphyromonas gingivalis) lipopolysaccharide +/- cranberry components, and effects of cranberry components on lipopolysaccharide-stimulated NF-kappaB activation and IL-6 and MMP 3 production. MATERIAL AND METHODS: AgP fibroblasts were incubated <= 6 d with high molecular weight non-dialyzable material (NDM) (derived from cranberry juice (1-500 MUg/mL) or lipopolysaccharide (1 MUg/mL) +/- NDM. Membrane damage and viability were assessed by enzyme activity released into cell supernatants and activity of a mitochondrial enzyme, respectively. Secreted IL-6 and MMP-3 were measured by ELISA. NF-kappaB p65 was measured via binding to an oligonucleotide containing the NF-kappaB consensus site. Data were analyzed using analysis of variance and Scheffe's F procedure for post hoc comparisons. RESULTS: Short-term exposure to NDM, or lipopolysaccharide +/- NDM caused no membrane damage. NDM (<= 100 MUg/mL) or lipopolysaccharide +/- NDM had no effect on viability <= 7 d exposure. NDM (50 MUg/mL) inhibited lipopolysaccharide-stimulated p65 (P <= 0.003) and constitutive or lipopolysaccharide-stimulated MMP-3 (P <= 0.02). NDM increased AgP fibroblast constitutive or lipopolysaccharide-stimulated IL-6 (P <= 0.0001), but inhibited normal human gingival fibroblast IL-6 (P <= 0.01). CONCLUSION: Lack of toxicity of low NDM concentrations, and its inhibition of NF kappaB and MMP-3, suggest that cranberry components may regulate AgP fibroblast inflammatory responses. Distinct effects of NDM on AgP and gingival fibroblast production of IL-6 (which can have both positive and negative effects on bone metabolism) may reflect phenotypic differences in IL-6 regulation in the two cell types. PMID- 23106207 TI - RD Lawrence lecture 2012: assessing aetiology in diabetes: how C-peptide, CRP and fucosylation came to the party! AB - Assigning the correct aetiology in diabetes is important for treatment, understanding prognosis and for follow-up of family members. Despite these benefits, many are missing out on the opportunity to have testing for monogenic forms of diabetes. This review gives the clinical features of the commoner forms of monogenic diabetes and examines which clinical and biological markers can be used to identify those at highest risk of having Maturity onset diabetes of the young (MODY). MODY is characterised by young-onset, familial diabetes which is C peptide positive, beta-cell antibody negative and not associated with metabolic syndrome. Differentiating from type 1 and type 2 diabetes can be challenging due to the overlap of clinical features. In type 1 diabetes, insulin production ceases after the honeymoon period. Thus C-peptide can be used to detect those with persisting insulin secretion who might have a different cause for their diabetes. In type 2 diabetes, most have insulin resistance, so absence of metabolic syndrome could be used to identify those most likely to have MODY. Another approach is to look for non-pancreatic features associated with mutations in MODY genes. Following results from Genome-wide association studies, we have shown that those with HNF1A mutations (the commonest form of MODY) have decreased serum levels of highly-sensitive C-reactive protein (hsCRP) and altered patterns of plasma protein fucosylation. These features can differentiate HNF1A-MODY from common forms of diabetes with a high degree of discriminative accuracy. Using combinations of clinical features and new biomarkers in diagnostic pathways will help increase diagnosis rates of MODY. PMID- 23106208 TI - Social amplification of wildfire risk: the role of social interactions and information sources. AB - Wildfire is a persistent and growing threat across much of the western United States. Understanding how people living in fire-prone areas perceive this threat is essential to the design of effective risk management policies. Drawing on the social amplification of risk framework, we develop a conceptual model of wildfire risk perceptions that incorporates the social processes that likely shape how individuals in fire-prone areas come to understand this risk, highlighting the role of information sources and social interactions. We classify information sources as expert or nonexpert, and group social interactions according to two dimensions: formal versus informal, and generic versus fire-specific. Using survey data from two Colorado counties, we empirically examine how information sources and social interactions relate to the perceived probability and perceived consequences of a wildfire. Our results suggest that social amplification processes play a role in shaping how individuals in this area perceive wildfire risk. A key finding is that both "vertical" (i.e., expert information sources and formal social interactions) and "horizontal" (i.e., nonexpert information and informal interactions) interactions are associated with perceived risk of experiencing a wildfire. We also find evidence of perceived "risk interdependency"--that is, homeowners' perceptions of risk are higher when vegetation on neighboring properties is perceived to be dense. Incorporating social amplification processes into community-based wildfire education programs and evaluating these programs' effectiveness constitutes an area for future inquiry. PMID- 23106209 TI - Effects of GSM 900 MHz on middle cerebral artery blood flow assessed by transcranial Doppler sonography. AB - Mobile phone use has increased worldwide but its possible effects on the brain remain unclear. The aim of the present study was to investigate the effect of acute exposure to a radio frequency electromagnetic field (RF EMF) generated by a mobile phone operating in the Global System for Mobile Communication (GSM) 900 MHz on cerebral blood flow. Twenty-nine volunteers attended two experimental sessions: a sham exposure session and a real exposure session in a cross-over double-blind study in which a mobile phone was positioned on the left side of the head. In one session, the mobile phone was operated without RF radiation (sham phone) and in the other study it was operated with RF radiation (real phone) for 20 min. Thus, each subject served as its own control. Middle cerebral artery blood flow was monitored noninvasively by transcranial Doppler sonography to measure middle cerebral artery blood flow velocity. Pulsatility index and resistance index were also evaluated. A voluntary breath holding physiological test was carried out as a positive control for testing cerebral vasoreactivity. Hemodynamic variables were recorded and analyzed before, during and after mobile phone exposure. No significant changes were detected in studied variables in middle cerebral arteries during sham or real exposure. In the exposed side the cerebral blood flow velocity, the pulsatility index and the resistance index during sham and real exposure were respectively: [61.9 +/- 1.3, 61.7 +/- 1.3 cm/s (P = 0.89)]; [0.93 +/- 0.03, 0.90 +/- 0.02 (P = 0.84)] and [0.58 +/- 0.01, 0.58 +/- 0.01 (P = 0.96)] at baseline; and [60.6 +/- 1.3, 62 +/- 1.6 cm/s (P = 0.40)]; [0.91 +/- 0.03, 0.87 +/- 0.03 (P = 0.97)]; [0.57 +/- 0.01, 0.56 +/- 0.01 (P = 0.82)] after 20 min of exposure. Twenty minutes of RF exposure to a mobile phone does not seem to affect the cerebral circulation. PMID- 23106211 TI - Kr-86 ion-beam irradiation of hydrated DNA: free radical and unaltered base yields. AB - This work reports an ESR and product analysis investigation of Kr-86 ion-beam irradiation of hydrated DNA at 77 K. The irradiation results in the formation and trapping of both base radicals and sugar phosphate radicals (DNA backbone radicals). The absolute yields (G, MUmol/J) of the base radicals are smaller than the yields found in similarly prepared gamma-irradiated DNA samples, and the relative yields of backbone radicals relative to base radicals are much higher than that found in gamma-irradiated samples. From these results, we have elaborated our radiation chemical model of the track structure for ion-beam irradiated DNA as it applies to krypton ion-beams. The base radicals, which are trapped as ion radicals or reversibly protonated or deprotonated ion radicals, are formed almost entirely in the track penumbra, a region in which radiation chemical effects are similar to those found in gamma-irradiated samples. By comparing the yields of base radicals in ion-beam samples to the yields of the same radicals in gamma-irradiated samples, the partition of energy between the low-LET region (penumbra) and the core is experimentally determined. The neutral sugar and other backbone radicals, which are not as susceptible to recombination as are ion radicals, are formed largely in the track core. The backbone radicals show a linear dose response up to very high doses. Unaltered base release yields in Kr-86 irradiated hydrated DNA are equal to sugar radical yields within experimental error limits, consistent with radiation-chemical processes in which all base release originates with sugar radicals. Two phosphorus-centered radicals from fragmentation of the DNA backbone are found in low yields. PMID- 23106212 TI - Covalently linked tandem lesions in DNA. AB - Reactive oxygen species (ROS) generate a type of DNA damage called tandem lesions, two adjacent nucleotides both modified. A subcategory of tandem lesions consists of adjacent nucleotides linked by a covalent bond. Covalently linked tandem lesions generate highly characteristic liquid chromotography-tandem mass spectrometry (LC-MS/MS) elution profiles. We have used this property to comprehensively survey X-irradiated DNA for covalently linked tandem lesions. A total of 15 tandem lesions were detected in DNA irradiated in deoxygenated aqueous solution, five tandem lesions were detected in DNA that was irradiated in oxygenated solution. PMID- 23106210 TI - Cytokines in radiobiological responses: a review. AB - Cytokines function in many roles that are highly relevant to radiation research. This review focuses on how cytokines are structurally organized, how they are induced by radiation, and how they orchestrate mesenchymal, epithelial and immune cell interactions in irradiated tissues. Pro-inflammatory cytokines are the major components of immediate early gene programs and as such can be rapidly activated after tissue irradiation. They converge with the effects of ionizing radiation in that both generate free radicals including reactive oxygen and nitrogen species (ROS/RNS). "Self" molecules secreted or released from cells after irradiation feed the same paradigm by signaling for ROS and cytokine production. As a result, multilayered feedback control circuits can be generated that perpetuate the radiation tissue damage response. The pro-inflammatory phase persists until such times as perceived challenges to host integrity are eliminated. Antioxidant, anti-inflammatory cytokines then act to restore homeostasis. The balance between pro-inflammatory and anti-inflammatory forces may shift to and fro for a long time after radiation exposure, creating waves as the host tries to deal with persisting pathogenesis. Individual cytokines function within socially interconnected groups to direct these integrated cellular responses. They hunt in packs and form complex cytokine networks that are nested within each other so as to form mutually reinforcing or antagonistic forces. This yin-yang balance appears to have redox as a fulcrum. Because of their social organization, cytokines appear to have a considerable degree of redundancy and it follows that an elevated level of a specific cytokine in a disease situation or after irradiation does not necessarily implicate it causally in pathogenesis. In spite of this, "driver" cytokines are emerging in pathogenic situations that can clearly be targeted for therapeutic benefit, including in radiation settings. Cytokines can greatly affect intrinsic cellular radiosensitivity, the incidence and type of radiation tissue complications, bystander effects, genomic instability and cancer. Minor and not so minor, polymorphisms in cytokine genes give considerable diversity within populations and are relevant to causation of disease. Therapeutic intervention is made difficult by such complexity; but the potential prize is great. PMID- 23106215 TI - Development of polyclonal antibody-based indirect enzyme-linked immunosorbent assay for the detection of Alicyclobacillus strains in apple juice. AB - A sort of specific polyclonal anti-Alicyclobacillus antibody was generated by immunizing New Zealand white rabbits, and a sensitive indirect enzyme-linked immunosorbent assay (ELISA) was developed for Alicyclobacillus detection in apple juice. A set of experimental parameters such as concentration of antigen, dilutions of the antibody and goat anti-rabbit IgG-horseradish peroxidase conjugate, selection of the blocking reagent, incubation time, and temperature was optimized. The cross-reactivity of the antibody was evaluated by ELISA and the result was consistent with Western blot analysis. The detection limit of the ELISA was about 10(5) colony forming units (CFU)/mL in apple juice samples. Samples were detected by ELISA and conventional culture method, and the ELISA results gave a good agreement with the results obtained by plating on Alicyclobacillus acidoterrestris medium agar. ELISA takes a total detection time of 6 to 7 h, which is less than the time of conventional techniques requiring more than 24 to 48 h. These results indicated that the established ELISA was a potential useful analytical method for detection of Alicyclobacillus in apple juice. PMID- 23106213 TI - Radioprotective role in lung of the flaxseed lignan complex enriched in the phenolic secoisolariciresinol diglucoside (SDG). AB - While dietary wholegrain Flaxseed (FS) has potent anti-inflammatory, anti fibrotic and antioxidant properties in murine models of acute and chronic lung injury, the main bioactive ingredient that contributes to these protective effects remains unknown. This study evaluated the lignan complex of FS (FLC) enriched in secoisolariciresinol diglucoside with respect to lung radioprotective and tumor radiosensitizing efficacy using a mouse model of thoracic radiation induced pneumonopathy. C57/Bl6 mice were fed 0% FS, 10% FS, 10% FLC or 20% FLC for 3 weeks, then irradiated with a single fraction (13.5 Gy) of X-ray radiation treatment (XRT). Mouse survival was monitored for 4 months after irradiation and inflammatory lung parameters were evaluated in bronchoalveolar lavage (BAL) fluid. Gene and protein levels of protective antioxidant and phase II enzymes were evaluated in lung tissue using qPCR and protein levels were verified by immunoblotting. Prolonged administration of the FLC diet was well tolerated and was not associated with any toxicity. Importantly, comparable to the whole grain 10% FS diet, irradiated mice fed 10% and 20% FLC diets displayed improved survival. Improved hemodynamic measurements were also recorded in irradiated mice fed 10% FS or 10% FLC diet compared to irradiated 0% FS fed mice. Flaxseed lignan complex diet also attenuated polymorphonuclear infiltration and overall lung inflammation to levels comparable to those in nonirradiated mice. Flaxseed lignan complex, similarly to FS, up-regulated gene expression as well as protein levels of protective antioxidant enzymes such as heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1). Dietary FLC induced radiosensitizing effects in our murine model of metastatic lung cancer. Importantly, protection of normal tissue does not thwart tumor cell death by radiation treatment. The dietary lignan complex of FS, mainly consisting of the phenolic secoisolariciresinol, is protective against radiation pneumonopathy in vivo while not hindering the tumoricidal effects of radiotherapy. PMID- 23106216 TI - Development of a mouse model for sulfur mustard-induced ocular injury and long term clinical analysis of injury progression. AB - CONTEXT: Sulfur mustard (SM) is a highly reactive vesicating agent that can induce severe ocular injury. The clinical features of this injury have been well documented, but the molecular basis for this pathology is not well understood. Identification and validation of specific targets is necessary in the effort to develop effective therapeutics for this injury. Currently used rabbit models are not well suited for many molecular studies because the necessary reagents are not widely available. However, these reagents are widely available for the mouse model. OBJECTIVE: Our objective is to develop a mouse model of SM-induced ocular injury suitable for the study of the molecular mechanisms of injury and the evaluation of therapeutics. MATERIALS AND METHODS: Ocular exposure to sulfur mustard vapor was accomplished by using a vapor cup method. Dose response studies were conducted in female BALB/c mice. An exposure dose which produced moderate injury was selected for further study as moderate injury was determined to be amenable to studying the beneficial effects of potential therapeutics. Histopathology and inflammatory markers were evaluated for up to 28 days after exposure, while clinical injury progression was evaluated for 1 year post exposure. RESULTS: A biphasic ocular injury was observed in mice exposed to SM. Acute phase SM ocular injury in mice was characterized by significant corneal epithelium loss, corneal edema, limbal engorgement, and ocular inflammation. This was followed by a brief recovery phase. A delayed injury phase then ensued in the following weeks to months and was characterized by keratitis, stromal edema, infiltrates, neovascularization, and eventual corneal scarring. DISCUSSION AND CONCLUSIONS: SM-induced ocular injury in mice is consistent with observations of SM-induced ocular injury in humans and rabbit models. However, in the mouse model, the SM ocular injury, a more rapid onset of the delayed injury phase was observed. We have developed an animal model of SM injury that is suitable for studies to elucidate molecular mechanisms of injury and identify potential therapeutic targets. PMID- 23106217 TI - alpha(V)beta(3) integrin crystal structures and their functional implications. AB - Many questions about the significance of structural features of integrin alpha(V)beta(3) with respect to its mechanism of activation remain. We have determined and re-refined crystal structures of the alpha(V)beta(3) ectodomain linked to C-terminal coiled coils (alpha(V)beta(3)-AB) and four transmembrane (TM) residues in each subunit (alpha(V)beta(3)-1TM), respectively. The alpha(V) and beta(3) subunits with four and eight extracellular domains, respectively, are bent at knees between the integrin headpiece and lower legs, and the headpiece has the closed, low-affinity conformation. The structures differ in the occupancy of three metal-binding sites in the betaI domain. Occupancy appears to be related to the pH of crystallization, rather than to the physiologic regulation of ligand binding at the central, metal ion-dependent adhesion site. No electron density was observed for TM residues and much of the alpha(V) linker. alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM demonstrate flexibility in the linker between their extracellular and TM domains, rather than the previously proposed rigid linkage. A previously postulated interface between the alpha(V) and beta(3) subunits at their knees was also not supported, because it lacks high-quality density, required rebuilding in alpha(V)beta(3)-1TM, and differed markedly between alpha(V)beta(3)-1TM and alpha(V)beta(3)-AB. Together with the variation in domain domain orientation within their bent ectodomains between alpha(V)beta(3)-AB and alpha(V)beta(3)-1TM, these findings are compatible with the requirement for large structural changes, such as extension at the knees and headpiece opening, in conveying activation signals between the extracellular ligand-binding site and the cytoplasm. PMID- 23106218 TI - Synthesis of cyclic Py-Im polyamide libraries. AB - Cyclic Py-Im polyamides containing two GABA turn units exhibit enhanced DNA binding affinity, but extensive studies of their biological properties have been hindered due to synthetic inaccessibility. A facile modular approach toward cyclic polyamides has been developed via microwave-assisted solid-phase synthesis of hairpin amino acid oligomer intermediates followed by macrocyclization. A focused library of cyclic polyamides 1-7 targeted to the androgen response element (ARE) and the estrogen response element (ERE) were synthesized in 12-17% overall yield. The Fmoc protection strategy also allows for selective modifications on the GABA turn units that have been shown to improve cellular uptake properties. The DNA binding affinities of a library of cyclic polyamides were measured by DNA thermal denaturation assays and compared to the corresponding hairpin polyamides. Fluorescein-labeled cyclic polyamides have been synthesized and imaged via confocal microscopy in A549 and T47D cell lines. The IC(50) values of compounds 1-7 and 9-11 were determined, revealing remarkably varying levels of cytotoxicity. PMID- 23106219 TI - Use of computed tomography to identify atrial fibrillation associated differences in left atrial wall thickness and density. AB - INTRODUCTION: Left atrial (LA) tissue characteristics may play an important role in atrial fibrillation (AF) induction and perpetuation. Although frequently used in clinical practice, computed tomography (CT) has not been employed to describe differences in LA wall properties between AF patients and controls. We sought to noninvasively characterize AF-associated differences in LA tissue using CT. METHODS: CT images of the LA were obtained in 98 consecutive patients undergoing AF ablation and in 89 controls. A custom software algorithm was used to measure wall thickness and density in four prespecified regions of the LA. RESULTS: On average, LA walls were thinner (-15.5%, 95% confidence interval [CI] -23.2 to 7.8%, P < 0.001) and demonstrated significantly lower density (-19.7 Hounsfield Units [HU], 95% CI -27.0 to -12.5 HU, P < 0.001) in AF patients compared to controls. In linear mixed models adjusting for demographics, clinical variables, and other CT measurements, the average LA, interatrial septum, LA appendage, and anterior walls remained significantly thinner in AF patients. After adjusting for the same potential confounders, history of AF was associated with reduced density in the LA anterior wall and increased density below the right inferior pulmonary vein and in the LA appendage. CONCLUSION: Application of an automated measurement algorithm to CT imaging of the atrium identified significant thinning of the LA wall and regional alterations in tissue density in patients with a history of AF. These findings suggest differences in LA tissue composition can be noninvasively identified and quantified using CT. PMID- 23106220 TI - Synchronous dynamics of observed and predicted values of anti-influenza drugs in environmental waters during a seasonal influenza outbreak. AB - Time-dependent dynamics in the concentrations of four anti-influenza drugs (oseltamivir, oseltamivir carboxylate, zanamivir, and amantadine) in environmental waters collected from the Yodo River basin, Japan, were monitored for the first time over a 1 year period (July 2010 to June 2011). The clear, convex dynamic profiles of oseltamivir, oseltamivir carboxylate, and zanamivir during a 3 month seasonal influenza outbreak (January to March 2011) were synchronized well with that of the numbers of influenza patients treated with the drugs. The highest levels in sewage treatment plants (STPs) and river waters were, respectively, 177 and 60 ng/L (oseltamivir), 827 and 288 ng/L (oseltamivir carboxylate), and 30 and 15 ng/L (zanamivir). Fixed levels of amantadine were detectable year-round (100-200 ng/L in the STPs and 10-30 ng/L in river waters). The predicted convex profiles of oseltamivir, oseltamivir carboxylate, and zanamivir in both STPs and river waters were significantly correlated (0.714 < R < 0.932) with the observed values. The profiles were predicted successfully by simple mathematical principles, taking the number of influenza patients, quantities of Tamiflu and Relenza used, dilution by drainwaters passing through STPs, removal rates at STPs, dilution rates in river effluents, and attenuation rates in rivers into consideration. PMID- 23106222 TI - An event-related potential study of adolescents' and young adults' judgments of moral and social conventional violations. AB - The neurocognitive development of moral and conventional judgments was examined. Event-related potentials were recorded while 24 adolescents (13 years) and 30 young adults (20 years) read scenarios with 1 of 3 endings: moral violations, conventional violations, or neutral acts. Participants judged whether the act was acceptable or unacceptable when a rule was assumed or removed. Across age, reaction times were faster for moral than conventional violations when a rule was assumed. Adolescents had larger N2 amplitudes than adults for moral and neutral, but not conventional, acts. N2 amplitudes were larger when a rule was removed than assumed for moral, but not conventional, violations. These findings suggest that the neurocognitive mechanisms underlying moral and conventional judgments continue to develop beyond early adolescence. PMID- 23106223 TI - Structure of molten CaSiO3: neutron diffraction isotope substitution with aerodynamic levitation and molecular dynamics study. AB - We have performed neutron diffraction isotopic substitution experiments on aerodynamically levitated droplets of CaSiO(3), to directly extract intermediate and local structural information on the Ca environment. The results show a substantial broadening of the first Ca-O peak in the pair distribution function of the melt compared to the glass, which comprises primarily of 6- and 7-fold coordinated Ca-polyhedra. The broadening can be explained by a redistribution of Ca-O bond lengths, especially toward longer distances in the liquid. The first order neutron difference function provides a test of recent molecular dynamics simulations and supports the MD model which contains short chains or channels of edge shared Ca-octahedra in the liquid state. It is suggested that the polymerization of Ca-polyhedra is responsible for the fragile viscosity behavior of the melt and the glass forming ability in CaSiO(3). PMID- 23106224 TI - Carbon-bridged oligo(phenylenevinylene)s: stable pi-systems with high responsiveness to doping and excitation. AB - The high responsiveness of pi-conjugated materials to external stimuli, such as electrons and photons, accounts for both their utility in optoelectronic applications and their chemical instability. Extensive studies on heteroatom stabilized pi-conjugated systems notwithstanding, it is still difficult to combine high performance and stability. We report here that carbon-bridged oligo(p-phenylenevinylene)s (COPV-n) are not only more responsive to doping and photoexcitation but also more stable than the conventional p-phenylenevinylenes and poly(3-hexylthiophene), surviving photolysis very well in air, suggesting that they could serve as building blocks for optoelectronic applications. Activation of the ground state by installation of bond angle strain toward the doped or photoexcited state and the flat, rigid, and hindered structure endows COPVs with stimuli-responsiveness and stability without recourse to heteroatoms. For example, COPV-6 can be doped with an extremely small reorganization energy and form a bipolaron delocalized over the entire pi-conjugated system. Applications to bulk and molecular optoelectronic devices are foreseen. PMID- 23106225 TI - Melanoma epidemiology, prognosis and trends in Latvia. AB - BACKGROUND: Melanoma incidence and mortality rates are increasing worldwide within the white population. Clinical and histological factors have been usually used for the prognosis and assessment of the risk for melanoma. OBJECTIVES: The aim of the study was to describe the clinical and histopathological features of the cutaneous melanoma (CM) in the Latvian population, to test the association between melanoma features and patient survival, and to assess the time trends for melanoma incidence. METHODS: We undertook a descriptive, retrospective analysis of archive data of 984 melanoma patients treated at the largest oncological hospital of Latvia, Riga East University Hospital Latvian Oncology Centre (LOC), between 1998 and 2008. Cox proportional hazards model was used to analyse patient survival and autoregressive models were applied to detect trends in melanoma incidence over time for various categories of melanoma. RESULTS: The study showed a significant ascending trend in melanoma incidence in Latvia during the time period from 1998 to 2008 (beta = 1.83, 95% CI = 1.15-2.91, P = 0.011). Nodular melanoma was the most common tumour subtype with a frequency of 39.2%. Ulceration was present in 45.2% of melanomas. The mean Breslow thickness was 6.0 mm (6.8 mm) and no significant decline in median Breslow thickness was observed during the study period (P = 0.609). A better overall prognosis was detected for females in comparison with males (HR = 1.49; 95% CI = 1.22-1.81; P < 0.001). CONCLUSIONS: There is a steady increase in melanoma incidence in Latvia with the majority of melanomas diagnosed at late stages with poor prognosis for survival. PMID- 23106226 TI - Implementation of a clinical practice guideline for antenatal magnesium sulphate for neuroprotection in Australia and New Zealand. AB - Health professionals at 25 Australian and New Zealand tertiary maternity hospitals were surveyed about local implementation of a clinical practice guideline for antenatal magnesium sulphate for fetal neuroprotection. Seventy-six percent of respondents reported that their hospital is currently following a guideline; 36% confirmed that their hospital is auditing uptake. Estimates of uptake ranged from 53 to 90%. Ongoing education and support are needed to ensure that the guidelines are optimally implemented, and uptake and important health outcomes are monitored. PMID- 23106227 TI - Biomimetic synthesis and biological evaluation of Aplidiopsamine A. AB - The first total synthesis of Aplidiopsamine A, a rare 3H-pyrrolo[2,3-c]quinoline alkaloid from the Aplidiopsis confluata, has been achieved following the proposed biosynthesis. This biomimetic synthesis requires only five steps and proceeds in 20.8% overall yield. Biological evaluation across large panels of discrete molecular targets identified that Aplidiopsamine A is a highly selective PDE4 inhibitor, a target for numerous CNS disorders. PMID- 23106228 TI - PFT1, a transcriptional Mediator complex subunit, controls root hair differentiation through reactive oxygen species (ROS) distribution in Arabidopsis. AB - Root hair morphogenesis is driven by an amalgam of interacting processes controlled by complex signaling events. Redox processes and transcriptional control are critical for root hair development. However, the molecular mechanisms that integrate redox state and transcription are largely unknown. To elucidate a possible role of transcriptional Mediators in root hair formation, we analyzed the Arabidopsis root hair phenotype of T-DNA insertion lines that harbor homozygous mutations in genes encoding Mediator subunits. Genetic evidence indicates that the Mediator subunits PFT1/MED25 and MED8 are critical for root hair differentiation, but act via separate mechanisms. Transcriptional profiling of pft1 roots revealed that PFT1 activates a subset of hydrogen peroxide (H(2)O(2))-producing class III peroxidases. pft1 mutants showed perturbed H(2)O(2) and superoxide (O(2)(.-)) distribution, suggesting that PFT1 is essential to maintain redox homeostasis in the root. Chemical treatments rescued the pft1 mutant phenotype, indicating that correct reactive oxygen species (ROS) distribution is an essential prerequisite for root hair differentiation. In addition, PFT1 positively regulates cell wall remodeling genes that are essential for root hair formation. Our results demonstrate that PFT1 maintains ROS distribution which, in turn, controls root hair differentiation. Thus, our findings reveal a novel mechanism in which the Mediator controls ROS homeostasis by regulating the transcriptional machinery. PMID- 23106229 TI - The velvet complex governs mycotoxin production and virulence of Fusarium oxysporum on plant and mammalian hosts. AB - Fungal pathogens provoke devastating losses in agricultural production, contaminate food with mycotoxins and give rise to life-threatening infections in humans. The soil-borne ascomycete Fusarium oxysporum attacks over 100 different crops and can cause systemic fusariosis in immunocompromised individuals. Here we functionally characterized VeA, VelB, VelC and LaeA, four components of the velvet protein complex which regulates fungal development and secondary metabolism. Deletion of veA, velB and to a minor extent velC caused a derepression of conidiation as well as alterations in the shape and size of microconidia. VeA and LaeA were required for full virulence of F. oxysporum on tomato plants and on immunodepressed mice. A critical contribution of velvet consists in promoting chromatin accessibility and expression of the biosynthetic gene cluster for beauvericin, a depsipeptide mycotoxin that functions as a virulence determinant. These results reveal a conserved role of the velvet complex during fungal infection on plants and mammals. PMID- 23106230 TI - The cost-effectiveness and budget impact of Vietnam's methadone maintenance treatment programme in HIV prevention and treatment among injection drug users. AB - We analysed the cost-effectiveness and budget impact of the methadone maintenance treatment (MMT) programme in HIV prevention and treatment among injection drug users (DUs) in Vietnam. The costs and health outcomes of providing MMT for opioid dependent DUs versus non-MMT were estimated using a decision analytical model. Probabilistic sensitivity analysis using Monte Carlo simulation was conducted to justify uncertainties of model parameters simultaneously. The incremental cost effectiveness ratio (ICER) of MMT in HIV prevention was US$3324 per one averted HIV case. The decision model showed that the cost-effectiveness ratio of MMT and non-MMT strategies was US$480 and US$204 per 1 quality-adjusted life year (QALY), equivalent to 0.43 and 0.18 times the gross domestic product per capita (GDPpc). The ICER for MMT versus non-MMT strategy was US$1964, approximately 1.76 times the GDPpc/QALY, classifying MMT as a cost-effective intervention. At the willingness to pay threshold of three times the GDPpc, the probability of MMT and non-MMT strategies being cost-effective was 80.3 and 19.7%, respectively. The budget impact of scaling up MMT from 2011 to 2015 will be US$97 million for 65% coverage or US$49 million for treating 80,000 DUs. The results indicated that MMT was cost-effective in HIV prevention and treatment among DUs who were opioid dependent. PMID- 23106231 TI - Application of Bayesian networks in quantitative risk assessment of subsea blowout preventer operations. AB - This article proposes a methodology for the application of Bayesian networks in conducting quantitative risk assessment of operations in offshore oil and gas industry. The method involves translating a flow chart of operations into the Bayesian network directly. The proposed methodology consists of five steps. First, the flow chart is translated into a Bayesian network. Second, the influencing factors of the network nodes are classified. Third, the Bayesian network for each factor is established. Fourth, the entire Bayesian network model is established. Lastly, the Bayesian network model is analyzed. Subsequently, five categories of influencing factors, namely, human, hardware, software, mechanical, and hydraulic, are modeled and then added to the main Bayesian network. The methodology is demonstrated through the evaluation of a case study that shows the probability of failure on demand in closing subsea ram blowout preventer operations. The results show that mechanical and hydraulic factors have the most important effects on operation safety. Software and hardware factors have almost no influence, whereas human factors are in between. The results of the sensitivity analysis agree with the findings of the quantitative analysis. The three-axiom-based analysis partially validates the correctness and rationality of the proposed Bayesian network model. PMID- 23106232 TI - Structure and immuno-stimulating activities of a new heteropolysaccharide from Lentinula edodes. AB - In this study, a new heteropolysaccharide, here called L2, was separated from the fruit body of Lentinula edodes. Chemical and physical analyses indicated that L2 has a molecular weight of 26 KDa and consists of glucose (87.5%), galactose (9.6%), and arabinose (2.8%), but it does not possess a triple-helical conformation. Stimulation of the production of nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) in RAW 264.7 cells showed that L2 has significant immune activities involving toll-like receptor 2 (TLR2). Further studies demonstrated that the activities of L2 exhibited high stability in wide range of pH from 4.0 to 10.0, when the thermal processing temperature was below 121 degrees C. Our findings revealed that a new heteropolysaccharide without triple-helical conformation from Lentinula edodes shows immuno stimulating activities involving TLR2 at modest pH and thermal processing conditions, which enable it to act as an active component in foods. PMID- 23106234 TI - Long-term exogenous application of melatonin delays drought-induced leaf senescence in apple. AB - To examine the potential roles of melatonin in drought tolerance, we tested the effects of its long-term exogenous application on 'Hanfu' apple (Malus domestica Borkh.). When 100 MUm melatonin was added to soils under drought conditions, the resultant oxidative stress was eased and leaf senescence was delayed. This molecule significantly reduced chlorophyll degradation and suppressed the up regulation of senescence-associated gene 12 (SAG12) and pheophorbide a oxygenase (PAO). Such treatment also alleviated the inhibition of photosynthesis brought on by drought stress. We also investigated quenching and the efficiency of Photosystem II (PSII) photochemistry under dark and light conditions and found that melatonin helped to maintain better function of PSII under drought. The addition of melatonin also controlled the burst of hydrogen peroxide, possibly through direct scavenging and by enhancing the activities of antioxidative enzymes and the capacity of the ascorbate-glutathione cycle. Thus, understanding this effect of melatonin on drought tolerance introduces new possibilities to use this compound for agricultural purposes. PMID- 23106235 TI - Mechanistic study of glycosylation using a prop-1-enyl donor. AB - Studies have been conducted to elucidate the mechanism of glycosylation reactions using a prop-1-enyl donor isomerized directly from an allyl glycoside. The reactions promoted by NIS/TfOH can take place in high yields in acetonitrile at room temperature. Activation of the anomeric prop-1-enyl group often leads to both the desired glycoside (e.g., 9) and the addition-reaction product (e.g., the anomeric mixed acetal 10). TfOH perhaps has a dual role in the reaction: i.e., (a) producing IOTf in situ to activate the prop-1-enyl group and (b) catalyzing the transformation from the addition-reaction product to the desired glycoside (e.g., from 10 to 9). The latter process involves multiple competing pathways. PMID- 23106237 TI - Influence of genotypic variations on antioxidant properties in different fractions of tomato. AB - The purpose of this study was to determine the antioxidant potential of phytochemicals present in 15 commercially important tomato genotypes specifically developed for growing in different geographical regions (high altitude and plain). Antioxidant components of tomatoes, namely lycopene, anthocyanin, ascorbic acid, total phenolics, quenching capacity of free radicals, and titratable acidity were analyzed in skin, pulp and seed fractions of the tomato fruits. Results of our study revealed that the antioxidant potency of tomato fruit fractions were in the order of Skin>Pulp>Seeds. Lycopene, anthocyanin content and free radical quenching ability was higher in the high altitude cultivars, whereas total phenolics, ascorbic acid and titratable acidity were seen higher in the plain region cultivars. In general, the outcome of this study showed that, the high altitude cultivars (Sindhu and Shalimar) were superior in antioxidant capacities. In conclusion, with this study it could be established that genetic factors play an important role in determining the antioxidants level and activity of the tomato genotypes and hence it is very important to select the right genotype to get the maximum health benefit. PRACTICAL APPLICATION: Phytochemicals present in the tomatoes are the major determinants of antioxidant potency of the fruits. To study the effect of genotype, it is necessary to grow the cultivars in ideal condition to assess the antioxidants level and activity, to select the right genotype for human consumption that gives better physiological benefit to the consumer. PMID- 23106236 TI - Chitosan-sodium alginate blended polyelectrolyte complexes as potential multiparticulate carrier system: colon-targeted delivery and gamma scintigraphic imaging. AB - OBJECTIVES: The objective of this study is to develop stable, biodegradable chitosan-sodium alginate-based dual, ionic cross-linked multiparticulate system (microbeads) of tinidazole for targeted colon delivery and sustained drug release for the treatment of amoebiasis and thereby evaluating its targeting approach through in vivo gamma scintigraphic imaging technique. METHODS: The chitosan sodium alginate-based multiparticulate system developed was producing sustained effect by virtue of its mechanical strength using double ionotropic gelation method utilizing calcium chloride and sodium sulfate as first and second cross linkers respectively. Prepared formulations were evaluated for percent yield, drug entrapment efficiency, particle size, degree of swelling, in vitro kinetics, and in vivo targeting potentials using gamma scintigraphic imaging technique. RESULTS: The obtained particulates were spherical, free flowing, and had a mean particle size ranging from 1.422 mm to 1.881 mm, whereas percent yield and percent drug entrapment efficiency was found to be in between 72.61 to 82.43% and 63.25 to 79.32% respectively. CONCLUSION: The prepared multiparticulate system showed better sustained release property and in vivo ability to target colon for drug delivery. Hence, the developed multiparticulate system could be a promising device to achieve greater site-specificity to colon. PMID- 23106238 TI - Domain differences in early social interactions. AB - Different social experiences help children develop distinctions between domains of norms. This study investigated whether mothers respond differently to moral, prudential, and pragmatic norms during the 2nd year, a period that precedes the time when children are able to make explicit distinctions between these norms. Sixty mothers of infants between 11 and 23 months were interviewed. Mothers' reports of their initial interventions, changes in intervention following noncompliance, and emotional reactions depended on normative domain. Initial interventions were less differentiated by domain for mothers of older than for mothers of younger children. These findings suggest that children have social experiences in the 2nd year that are associated with distinctions among normative domains. PMID- 23106239 TI - Nitroso-dienophile additions to dendralenes: a short synthesis of branched aminosugars. AB - The first heteroatom-based dienophile cycloadditions to cross-conjugated alkenes ([n]dendralenes) are reported. Nitroso-dienophiles undergo smooth single and double Diels-Alder additions to the parent dendralenes with orientational regio- and stereoselectivity and, notably, with reactivity that depends upon the parity of the [n]dendralene. The first crystal structure of a cross-conjugated hexaene is reported. Vasella's nitroso-sugar reagent gives a highly enantiomerically enriched double cycloadduct with [3]dendralene. This bicyclic oxazine is successively dihydroxylated and then ring-opened to form a branched chain diamino tetrol. PMID- 23106241 TI - Nitrate-induced early transcriptional changes during imbibition in non-after ripened Sisymbrium officinale seeds. AB - We have here demonstrated for the first time that nitrate not only accelerates testa rupture of non- AR seeds but also modifies expression pattern of the cell wall remodeling proteins (mannanases; SoMAN6 and SoMAN7) and key genes belonging to metabolism and signaling of ABA (SoNCED6, SoNCED9, SoCYP707A2 and SoABI5) and GAs (SoGA3ox, SoGA20ox, SoGA2ox and SoRGL2). These results were obtained during Sisymbrium officinale seed imbibition in the absence of endosperm rupture. Exogenous ABA induced a notable inhibition of testa rupture in both absence and presence of nitrate being this effect sharply reversed by GA(4+7). However, nitrate was capable to provoke testa rupture in absence of ABA synthesis. The expression of SoMAN6 and SoMAN7 were positively altered by nitrate. Although ABA synthesis seems apparent at the start of non-AR seed imbibition, taken together the results of SoNCED6, SoNCED9 and SoCYP707A2 expression seem to suggest that nitrate leads to a strong net ABA decrease. Likewise, nitrate positively affected the SoABI5 expression when the SoNCED9 expression was also stimulated. By contrast, at the early and final of imbibition, nitrate clearly inhibited the SoABI5 expression. The expression of SoGA2ox6 and SoGA3ox2 are strongly inhibited by nitrate whereas of SoGA20ox6 was stimulated. On the other hand, SoRGL2 transcript level decreased in the presence of nitrate. Taken together, the results presented here suggest that the nitrate signaling is already operative during the non-AR S. officinale seeds imbibition. The nitrate, in cross-talk with the AR network likely increases the favorable molecular conditions that trigger germination. PMID- 23106242 TI - Reduced immunohistochemical expression of Discoidin Domain Receptor 1 (DDR1) in vitiligo skin. PMID- 23106240 TI - Gas-phase studies of substrates for the DNA mismatch repair enzyme MutY. AB - The gas-phase thermochemical properties (tautomeric energies, acidity, and proton affinity) have been measured and calculated for adenine and six adenine analogues that were designed to test features of the catalytic mechanism used by the adenine glycosylase MutY. The gas-phase intrinsic properties are correlated to possible excision mechanisms and MutY excision rates to gain insight into the MutY mechanism. The data support a mechanism involving protonation at N7 and hydrogen bonding to N3 of adenine. We also explored the acid-catalyzed (non enzymatic) depurination of these substrates, which appears to follow a different mechanism than that employed by MutY, which we elucidate using calculations. PMID- 23106243 TI - Can we use a lower intravaginal dose of misoprostol in the medical management of miscarriage? A randomised controlled study. AB - BACKGROUND: The optimal dose of misoprostol to be used in the medical management of miscarriage before 13 weeks has not been resolved. AIM: To evaluate the effectiveness and side effect profile of two different dosages of misoprostol. METHODS: A randomised controlled, equivalence study comparing 400 vs 800 MUg misoprostol per vaginum (PV) on an outpatient basis. The allocated dose was repeated the next day if clinically the products of conception had not been passed. Complete miscarriage was evaluated using two methods: ultrasound criteria on Day 7 and the need for surgical management (clinical criteria). Equivalence was demonstrated if the 95% confidence interval [CI] of the observed risk difference between the two doses for complete miscarriage lay between -15.0 and 15.0%. Differences in side effects and patient satisfaction were evaluated using patient-completed questionnaires. RESULTS: One hundred and fifty-eight women were allocated to receive 400 MUg and 152 women to 800 MUg misoprostol for the management of missed (91.3%) or incomplete (8.7%) miscarriage. The rate of induced complete miscarriage was equivalent using both ultrasound criteria (observed risk difference (ORD) -4.6%, 95% CI -12.8 to 3.7%; P = 0.313) and clinical criteria (ORD -5.6%, 95% CI -14.8 to 3.6%; P = 0.273). Following the 400 MUg dose, the reported rate of fever/rigors was lower (ORD -15.6%, 95% CI -28.1 to -3.0%; P = 0.015), and more women reported their decision to undergo medical management as a good decision (ORD 15.2%, 95% CI 2.8 to 27.7%; P = 0.018). CONCLUSION: Four hundred-microgram misoprostol PV can be recommended for the medical management of miscarriage on an outpatient basis. PMID- 23106244 TI - Comment on "Feather meal: a previously unrecognized route for reentry into the food supply of multiple pharmaceuticals and personal care products (PPCPs)". PMID- 23106245 TI - Imitating others' actions: transcranial magnetic stimulation of the parietal opercula reveals the processes underlying automatic imitation. AB - The human tendency to imitate gestures performed by conspecifics is automatic in nature. However, whether this automatic imitation can be considered as a true imitative phenomenon or only as a special instance of spatial compatibility is still being debated. New evidence suggests that automatic imitation, otherwise known as 'imitative compatibility', shall be considered as a phenomenon that operates independently from spatial compatibility. So far there are only a few investigations directly aimed at identifying the neural structures dedicated to this process. In the present study, we applied double-pulse transcranial magnetic stimulation (TMS) over the parietal opercula to further investigate the role of these regions in coding imitative compatibility. We found that a temporary disruption of parietal opercula caused the reduction of the imitative compatibility relative to the sham condition. In particular, the TMS interference with the parietal opercula's activity modulated the imitative compatibility but not the spatial compatibility, suggesting that these two processes are likely to be independent. PMID- 23106246 TI - Red cell- and platelet-derived microparticles in G6PD: any other confounding? PMID- 23106247 TI - Abscisic acid accumulation modulates auxin transport in the root tip to enhance proton secretion for maintaining root growth under moderate water stress. AB - Maintenance of root growth is essential for plant adaptation to soil drying. Here, we tested the hypothesis that auxin transport is involved in mediating ABA's modulation by activating proton secretion in the root tip to maintain root growth under moderate water stress. Rice and Arabidopsis plants were raised under a hydroponic system and subjected to moderate water stress (-0.47 MPa) with polyethylene glycol (PEG). ABA accumulation, auxin transport and plasma membrane H(+)-ATPase activity at the root tip were monitored in addition to the primary root elongation and root hair density. We found that moderate water stress increases ABA accumulation and auxin transport in the root apex. Additionally, ABA modulation is involved in the regulation of auxin transport in the root tip. The transported auxin activates the plasma membrane H(+)-ATPase to release more protons along the root tip in its adaption to moderate water stress. The proton secretion in the root tip is essential in maintaining or promoting primary root elongation and root hair development under moderate water stress. These results suggest that ABA accumulation modulates auxin transport in the root tip, which enhances proton secretion for maintaining root growth under moderate water stress. PMID- 23106248 TI - Editorial: Genetics And Athletics. PMID- 23106249 TI - Rising income and the subjective well-being of nations. AB - We explored whether rising income in nations is associated with increasing subjective well-being (SWB), with several advances over earlier work. Our methods are improved in that across time, the same well-being questions were asked in the same order, and we employed broad and equivalent representative samples over time from a large number of nations. We also assessed psychosocial factors that might mediate the relation of income and SWB. We found that changes in household income were associated with concomitant changes in life evaluations, positive feelings, and negative feelings. The effects of gross domestic product (GDP) change were weaker and significant only for life evaluations, perhaps because GDP was a less certain index of the standard of living of the average household. The association of income and SWB is more likely to occur when the average person's material welfare accompanies rising income, when people become more satisfied with their finances, and when people become more optimistic about their futures. People did not adapt to the income rises during the period of years we studied, in that income rises produced SWB increases that did not return to earlier levels. It appears that previous researchers failed to come to agreement because of the small sample sizes of the nations, the inconsistent methods across years and surveys, and the lack of measures of potential mediating variables. Analyses of income relative to people in one's nation and between-nation slopes together suggest that income standards are now largely global, with little effect of national social comparison. PMID- 23106250 TI - Self-determination, self-regulation, and the brain: autonomy improves performance by enhancing neuroaffective responsiveness to self-regulation failure. AB - The importance of autonomous motivation in improving self-regulation has been a focal topic of motivation research for almost 3 decades. Despite this extensive research, however, there has not yet been a mechanistic account of how autonomous motivation works to boost self-regulatory functioning. To address this issue, we examined the role of autonomy in 2 basic self-regulation tasks while recording a neural signal of self-regulation failure (i.e., the error-related negativity; ERN). Based on the notion that autonomy improves self-regulation, we anticipated that autonomous motivation would enhance neuroaffective responsiveness to self regulatory failure and thus improve performance relative to controlled motivation. In Study 1 (N = 43), we found that trait autonomy was positively associated with self-regulatory performance and that this effect was mediated by increased brain-based sensitivity to self-regulation failure, as demonstrated by a larger ERN. Study 2 (N = 55) replicated and extended this pattern using an experimental manipulation of autonomy; when autonomous motivation was contextually supported, task performance increased relative to those for whom autonomy was undermined and those in a neutral condition. In addition, this effect was mediated by both increased perceptions of autonomy and larger ERN amplitudes. These findings offer deeper insight into the links among motivational orientation, brain-based performance monitoring, and self-regulation. PMID- 23106251 TI - Self-affirmation can enable goal disengagement. AB - Much research has shown that after being self-affirmed, people respond to challenges in healthy, productive ways, including better task performance. The current research demonstrates that self-affirmation can also deflate motivation and performance, a pattern consistent with goal disengagement. We posited that being self-affirmed and then attempting but failing at a task would lead people to retreat from the goal. In support of this hypothesis, 4 experiments found that the combination of self-affirmation and the experience of failure led to demotivation and effort reduction. Experiment 1 found that self-affirmed participants, more so than nonaffirmed participants, reported being open to goal disengagement. Experiment 2 found that affirming core values before trying a task beset with failure reduced task motivation and performance. Experiment 3 demonstrated the robustness of the effect and found that failure on one task reduced motivation and performance on a new but related task. Experiment 4 revealed that being self-affirmed and experiencing failure caused participants to feel less capable of pursuing their goals, which produced poorer performance. These findings suggest that affirming the self can lead people to internalize the implications of failure, which in turn leads to goal disengagement. PMID- 23106252 TI - The dynamics of relationship promotion: controlling the automatic inclination to trust. AB - A dynamic model of how trust regulates relationship promotion is proposed. The model assumes that trust has both impulsive (i.e., automatic attitude toward the partner) and reflective (i.e., beliefs about the partner's caring) forms. Because overriding evaluative impulses requires self-regulatory resources, the model further posits that self-regulatory capacity controls whether people strengthen relationship connections in the face of threats to reflective trust. Two experiments and 1 longitudinal daily diary study utilizing convergent manipulations and measures of self-regulatory capacity supported the model. Results revealed that acute uncertainty about a partner's caring increased relationship-promotive sentiment and behavior when (a) people lacked self regulatory resources to question impulsively trusting sentiments and (b) when people had self-regulatory resources available to override impulsively distrusting sentiments. In contrast, acute uncertainty about a partner's caring decreased relationship-promotive sentiment and behavior when (a) people lacked the self-regulatory capacity to question impulsively distrusting sentiments and (b) when people had the self-regulatory capacity available to override impulsively trusting sentiments. PMID- 23106253 TI - Tpeak - Tend and Tpeak - Tend /QT ratio as markers of ventricular arrhythmia risk in cardiac resynchronization therapy patients. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) increases transmural dispersion of repolarization (TDR) and can be pro-arrhythmic. However, overall arrhythmia risk was not increased in large-scale CRT clinical trials. Increased TDR as measured by T(peak ) -T(end) (TpTe) was associated with arrhythmia risk in CRT in a single-center study. This study investigates whether QT interval, TpTe, and TpTe/QT ratio are associated with ventricular arrhythmias in patients with CRT-defibrillator (CRT-D). METHODS: Post-CRT-D implant electrocardiograms of 128 patients (age 71.3 years +/- 10.3) with at least 2 months of follow-up at our institution's device clinic (mean follow-up of 28.5 months +/- 17) were analyzed for QT interval, TpTe, and TpTe/QT ratio. Incidence of ventricular arrhythmias was determined based on routine and directed device interrogations. RESULTS: Appropriate implantable cardioverter-defibrillator therapy for sustained ventricular tachycardia or ventricular fibrillation was delivered in 18 patients (14%), and nonsustained ventricular tachycardia (NSVT) was detected but did not require therapy in 58 patients (45%). Patients who received appropriate defibrillator therapy had increased TpTe/QT ratio (0.24 +/- 0.03 ms vs 0.20 +/- 0.04, P = 0.0002) and increased TpTe (105.56 +/- 20.36 vs 87.82 +/- 22.32 ms, P = 0.002), and patients with NSVT had increased TpTe/QT ratio (0.22 +/- 0.04 vs 0.20 +/- 0.04, P = 0.016). Increased QT interval was not associated with risk of ventricular arrhythmia. The relative risk for appropriate defibrillator therapy of T(p) T(e) /QT ratio >= 0.25 was 3.24 (P = 0.016). CONCLUSION: Increased TpTe and increased TpTe/QT ratio are associated with increased incidence of ventricular arrhythmias in CRT-D. The utility of TpTe interval and TpTe/QT ratio as potentially modifiable risk factors for ventricular arrhythmias in CRT requires further study. PMID- 23106254 TI - Socioeconomic differences in sport and physical activity among Italian adults. AB - We aimed to assess the extent of socioeconomic differences in sport and physical activity among Italian adults. A secondary data analysis of a multipurpose survey carried out by the National Institute of Statistics in 2006 in Italy was performed. We found marked differences in the practice of physical activity and sport by socioeconomic position. Subjects with a higher educational level were more likely to be physically active, practising more frequently both sport and physical activity. The Odds Ratio (OR) of regular physical activity for the highest educated compared to the lowest educated males was 1.70 (95% Confidence Interval [CI]: 1.38, 2.08), and the OR of sport participation was 2.03 (95% CI: 1.51, 2.72). Among females, the corresponding ORs were 1.32 (95% CI: 1.08, 1.63) and 2.26 (95% CI: 1.51, 3.38). Similar differences in physical activity and sport were found in relation to occupation and material conditions. Almost all sports were more frequently practised by subjects of higher socioeconomic status. Socioeconomic differences in sport and physical activity may derive from economic or cultural barriers. Policies to reduce inequalities and ensure access to sport independently of socioeconomic position are strongly needed. PMID- 23106255 TI - Similar reference intervals for total testosterone in healthy young and elderly men: results from the Odense Androgen Study. AB - CONTEXT: Ageing in men is associated with changes in levels of sex hormones. OBJECTIVE: To evaluate differences in sex hormones in young and elderly men and the significance of comorbidity and fat mass on sex hormones in elderly men. DESIGN: Cross-sectional. PATIENTS: Seven hundred and eighty-three men aged 20-29 years and 600 men aged 60-74 years randomly recruited from the background population. MEASUREMENTS: Sex hormones and sex hormone-binding globulin (SHBG) were measured, and reference intervals were determined in healthy individuals in both groups and in elderly men stratified according to whether they were obese or lean (waist circumference >=102 cm). RESULTS: Sex hormones were lower and SHBG higher in elderly men compared with the young cohort. Lower cut-offs for total testosterone (TT) in healthy, young and elderly men were similar [Lower cut-off (95% CI): Young: 11.7 (11.2-12.1) vs elderly: 11.2 (10.3-12.1) nmol/l], but lower and higher cut-offs of bioavailable testosterone (BT) and free testosterone (FT) were higher in young men. Higher levels of androgens were found in healthy elderly men compared with those with a chronic disease or obesity. Androgens were inversely associated with central fat mass (CFM), whereas SHBG was inversely and directly associated with CFM and lower extremity fat mass, respectively, in both young and elderly men. CONCLUSION: Reference intervals for TT were comparable in healthy young and elderly men, but reference intervals for FT and BT were lower in elderly men due to higher levels of SHBG. Androgens and SHBG were lower in elderly men with chronic disease and inversely associated with CFM. PMID- 23106257 TI - Calculating quantities of ice for cooling and maintenance of freshly harvested fish at sea. AB - A new generalized model for predicting quantities of ice to cool and maintain freshly harvested fish at sea in insulated boxes is presented. The model addresses the universal need for fisherman to know in advance of going to sea just how much ice will be needed to cool down the expected day's catch to a desired temperature, maintain the catch, and to allow for losses. Illustrative predictions are presented for southern bluefin tuna (SBT) (Thunnus maccoyii) for a range of day's catch from 2000 to 8000 kg in ambient temperature ranging from 15 to 35 degrees C. The amount of ice needed to cool down SBT from an initial uniform harvest temperature of 28 degrees C to a maintenance temperature of 5 degrees C is shown to be the controlling contribution to total ice needed. Predictions highlight that a useful, safe rule-of-thumb is 1 kg of ice will be needed for each 3.5 kg of SBT. Importantly, the model is based on fundamental principles and predictive accuracy is demonstrated to be largely insensitive to a range of assumptions including volume of the void in the insulated boxes and overall coefficient of heat influx from ambient. The model can be used to predict the number of insulated boxes of defined dimension that will be needed to cool and hold the fish, ice and water for a wide range of fish species. It will be of interest to fisherman and boat owners and agents who invest in ice to preserve fish at sea. PRACTICAL APPLICATION: This research addresses the universal need for fisherman to know in advance of going to sea how much ice will be needed on board boats to cool down an expected day's catch to a desired temperature, maintain the catch and to allow for losses. The model is generalized and can be applied to a wide range of fish species. PMID- 23106258 TI - Small-angle neutron scattering study of organic-phase aggregation in the TALSPEAK process. AB - The Trivalent Actinide-Lanthanide Separation by Phosphorus reagent Extraction from Aqueous Komplexes (TALSPEAK) process is a solvent extraction based method for separating trivalent lanthanides (Ln(3+)) from trivalent actinide cations in used nuclear fuel reprocessing. In conventional TALSPEAK, the extractant solution is di(2-ethylhexyl)phosphoric acid (HDEHP) in 1,4-diisopropylbenzene (DIPB). The aqueous medium is diethylenetriamine-N,N,N',N",N"-pentaacetic acid (DTPA) in a concentrated lactic acid (HL) buffer. Lanthanides are extracted by HDEHP/DIPB, while the actinides remain in the aqueous phase as DTPA complexes. Lactic acid is extracted both independently of the lanthanides and as Ln/HL/HDEHP mixed complex(es). Previous results indicate that lanthanides are extracted both as the mixed complex and as a binary Ln(DEHP.HDEHP)(3) species. Small-angle neutron scattering (SANS) has been applied to study the self-organization properties of solute molecules in xylene solutions containing HDEHP, HL, selected lanthanide ions, and water. The scattering results demonstrate that the dominant HDEHP species is the hydrogen bonded dimer, (HDEHP)(2). Absent lanthanides, lactic acid is extracted as the 1:3 complex (HL.(HDEHP)(3)). Scattering in samples containing up to 0.005 M lanthanides (prepared by extracting lanthanides from aqueous media containing 1.0 M buffered lactic acid) indicates that the dominant metal complex is Ln(DEHP.HDEHP)(3). At 0.013 M extracted lanthanide, the scattering results indicate lower Ln:DEHP stoichiometry and larger scattering particles. At higher metal concentrations, the SANS results indicate large aggregates, the largest aggregates achieving a size equivalent to 20 HDEHP monomers as the primary scattering entity. Analysis of particle shapes indicates best fits with a uniform oblate spheroid particle. These results are discussed in connection with the results of a number of complementary observations that have been made on this system. PMID- 23106259 TI - Lipaemic plasma induces haemolysis in resuspended red cell concentrate. AB - INTRODUCTION: We investigated whether haemolysis in red cells suspended in plasma was affected by the lipid content and/or methylene blue (MB) treatment of fresh frozen plasma (FFP). We also investigated whether haemolysis was affected by the conditions under which lipaemic plasma was stored. METHODS: Study 1: Visibly lipaemic (n = 22) or nonlipaemic FFP (n = 24) units were thawed, pooled and split into identical pairs, one of which was MB treated. These units were used to resuspend red cell concentrates (RCC) and tested for haemolysis immediately and after 24 and 48 h of storage at 2-6 degrees C. Study 2: Fresh plasma was aliquoted into 15-ml tubes and stored in one of four ways as follows: room temperature; 2-6 degrees C; frozen and thawed; or twice frozen and thawed. A sample of RCC was resuspended in each of these plasmas and haemolysis measured after 2 h. Study 3: Plasma was divided into 15-ml tubes and stored as in study 2 followed by storage left standing upright in a refrigerator (2-6 degrees C) for 24 h (with the exception of the room temperature sample). Plasma was separated into top, middle and bottom fractions and used to resuspend RCC that were assessed for haemolysis after 2 h. RESULTS: The levels of haemolysis in RCC were immediately greater when suspended in lipaemic plasma (0.70 +/- 0.53% v 0.05 +/- 0.06% for nonlipaemic plasma), which increased further on subsequent storage for 48 h (1.22 +/- 0.40% v 0.15 +/- 0.14% for nonlipaemic plasma). This was irrespective of whether plasma was MB treated. Lipaemic plasma stored frozen and then thawed resulted in the greatest haemolysis. In lipaemic plasma stored at 2-6 degrees C, the chylomicron-rich top fraction caused the highest level of haemolysis. CONCLUSION: Haemolysis in red cells is increased in those suspended in lipaemic plasma and is dependent upon the storage conditions of that plasma prior to suspension. These data are relevant to the choice of plasma used to suspend red cells for neonatal exchange transfusion. PMID- 23106260 TI - Utilisation of preconception care in women with pregestational diabetes in Western Australia. AB - This study investigated the level of awareness of the availability of preconception care in a tertiary obstetric hospital for women with type 1 and 2 diabetes, the willingness of these women to attend for preconception counselling and the barriers that may impact upon access to preconception care in Western Australia. The results show greater effort is needed to improve the awareness of women about the importance of preconception care and their willingness to attend the clinic. Access to consistent preconception care should be available for all women with diabetes. The counselling process should be individualised to accommodate different needs. PMID- 23106261 TI - Stereoregulations of pyrimidinone based chiral auxiliary in aldol and alkylation reactions: a convenient route to oxyneolignans. AB - (S)-4-Isopropyl-1-phenyltetrahydropyrimidin-2(1H)-one was synthesized and evaluated as a chiral auxiliary for asymmetric acetate and propionate aldol reactions, by generation of titanium and lithium enolates, affording excellent yields and stereoselectivities for syn and anti aldol diastereomers, respectively. High stereoselectivities were also obtained in lithium mediated alkylation reactions. The application of the auxiliary was exemplified in the asymmetric synthesis of a natural oxyneolignan, (+)-(7S,8S)-4-hydroxy-3,3',5' trimethoxy-8',9'-dinor-8,4'-oxyneoligna-7,9-diol-7'-oic acid. PMID- 23106262 TI - An implicit theories of personality intervention reduces adolescent aggression in response to victimization and exclusion. AB - Adolescents are often resistant to interventions that reduce aggression in children. At the same time, they are developing stronger beliefs in the fixed nature of personal characteristics, particularly aggression. The present intervention addressed these beliefs. A randomized field experiment with a diverse sample of Grades 9 and 10 students (ages 14-16, n = 230) tested the impact of a 6-session intervention that taught an incremental theory (a belief in the potential for personal change). Compared to no-treatment and coping skills control groups, the incremental theory group behaved significantly less aggressively and more prosocially 1 month postintervention and exhibited fewer conduct problems 3 months postintervention. The incremental theory and the coping skills interventions also eliminated the association between peer victimization and depressive symptoms. PMID- 23106264 TI - Divalent-anion salt effects in polyelectrolyte multilayer depositions. AB - We systematically investigate the effects of divalent anions on the assembly of polyelectrolyte multilayers by fabricating polystyrene sulfonate (PSS)/polyallylamine hydrochloride (PAH) multilayer films from aqueous solutions containing SO(4)(2-), HPO(4)(2-), or organic dicarboxylate dianions. The chosen concentrations of these anions (i.e., <=0.05 M) allow us to isolate their effects on the assembly process from those of the polyelectrolyte solubility or solution ionic strength (maintained constant at MU = 1.00 M by added NaCl). Compared to a control film prepared from solutions containing only Cl(-) anions, stratified multilayers deposited in the presence of dianions exhibit increased UV absorbance, thickness, and roughness. From the dependence of film properties on the solution concentration of SO(4)(2-) and number of polyelectrolyte layers deposited, we derive a generic model for the PSS/PAH multilayer formation that involves adsorption of PAH aggregates formed in solution via electrostatic interactions of PAH with bridging dianions. Experiments using HPO(4)(2-) and organic dicarboxylate species of varying structure indicate that the separation, rigidity, and angle between the discrete negatively charged sites in the dianion govern the formation of the PAH aggregates, and therefore also the properties of the multilayer film. A universal linear relationship between film UV absorbance and thickness is observed among all dianion types or concentrations, consistent with the model. PMID- 23106263 TI - Bypass of a psoralen DNA interstrand cross-link by DNA polymerases beta, iota, and kappa in vitro. AB - Repair of DNA interstrand cross-links in mammalian cells involves several biochemically distinctive processes, including the release of one of the cross linked strands and translesion DNA synthesis (TLS). In this report, we investigated the in vitro TLS activity of a psoralen DNA interstrand cross-link by three DNA repair polymerases, DNA polymerases beta, kappa, and iota. DNA polymerase beta is capable of bypassing a psoralen cross-link with a low efficiency. Cell extracts prepared from DNA polymerase beta knockout mouse embryonic fibroblasts showed a reduced bypass activity of the psoralen cross link, and purified DNA polymerase beta restored the bypass activity. In addition, DNA polymerase iota misincorporated thymine across the psoralen cross-link and DNA polymerase kappa extended these mispaired primer ends, suggesting that DNA polymerase iota may serve as an inserter and DNA polymerase kappa may play a role as an extender in the repair of psoralen DNA interstrand cross-links. The results demonstrated here indicate that multiple DNA polymerases could participate in TLS steps in mammalian DNA interstrand cross-link repair. PMID- 23106266 TI - Catalytic enantioselective O-nitrosocarbonyl aldol reaction of beta-dicarbonyl compounds. AB - The first example of a Cu-catalyzed asymmetric O-nitrosocarbonyl aldol reaction is described. This novel protocol allows convenient access to highly enantioenriched alpha-hydroxy-beta-ketoesters including the antibacterial natural product kjellmanianone (up to 99% ee). MnO(2) was introduced as a mild efficient oxidant for the in situ generation of nitrosocarbonyl species from hydroxamic acid derivatives. PMID- 23106267 TI - Tentative identification of phenolic compounds in olive pomace extracts using liquid chromatography-tandem mass spectrometry with a quadrupole-quadrupole-time of-flight mass detector. AB - The reuse of agronomical residues is a pending goal for sustainable agriculture. Particular residues in olive-oil-producing countries are leaves, wastewater, and olive pomace. Olive leaves and wastewaters have been previously characterized by isolation of the phenolic fraction. However, olive pomace has not yet been qualitatively characterized as a source of phenols. Olive pomace extracts were obtained using superheated solvent extraction using 50:50 (v/v) water/ethanol as a leaching mixture at 160 degrees C. The extracts were analyzed by liquid chromatography coupled to tandem mass spectrometry using a quadrupole-quadrupole time-of-flight (QqTOF) hybrid mass analyzer (R = 25,000-45,000). Qualitative analysis was supported upon measurement of accurate masses for precursor and product ions as well as their isotopic distribution. Identification was focused on the main families of phenolic compounds present in extra virgin olive oil. The potential of this residue as a rich source of phenols with antioxidant properties has been proven. PMID- 23106268 TI - Lmx1a is an activator of Rgs4 and Grb10 and is responsible for the correct specification of rostral and medial mdDA neurons. AB - The LIM homeodomain transcription factor Lmx1a is a very potent inducer of stem cells towards dopaminergic neurons. Despite several studies on the function of this gene, the exact in vivo role of Lmx1a in mesodiencephalic dopamine (mdDA) neuronal specification is still not understood. To analyse the genes functioning downstream of Lmx1a, we performed expression microarray analysis of LMX1A overexpressing MN9D dopaminergic cells. Several interesting regulated genes were identified, based on their regulation in other previously generated expression arrays and on their expression pattern in the developing mdDA neuronal field. Post analysis through in vivo expression analysis in Lmx1a mouse mutant (dr/dr) embryos demonstrated a clear decrease in expression of the genes Grb10 and Rgs4, in and adjacent to the rostral and dorsal mdDA neuronal field and within the Lmx1a expression domain. Interestingly, the DA marker Vmat2 was significantly up regulated as a consequence of increased LMX1A dose, and subsequent analysis on Lmx1a-mutant E14.5 and adult tissue revealed a significant decrease in Vmat2 expression in mdDA neurons. Taken together, microarray analysis of an LMX1A overexpression cell system resulted in the identification of novel direct or indirect downstream targets of Lmx1a in mdDA neurons: Grb10, Rgs4 and Vmat2. PMID- 23106269 TI - The pollen tube: a soft shell with a hard core. AB - Plant cell expansion is controlled by a fine-tuned balance between intracellular turgor pressure, cell wall loosening and cell wall biosynthesis. To understand these processes, it is important to gain in-depth knowledge of cell wall mechanics. Pollen tubes are tip-growing cells that provide an ideal system to study mechanical properties at the single cell level. With the available approaches it was not easy to measure important mechanical parameters of pollen tubes, such as the elasticity of the cell wall. We used a cellular force microscope (CFM) to measure the apparent stiffness of lily pollen tubes. In combination with a mechanical model based on the finite element method (FEM), this allowed us to calculate turgor pressure and cell wall elasticity, which we found to be around 0.3 MPa and 20-90 MPa, respectively. Furthermore, and in contrast to previous reports, we showed that the difference in stiffness between the pollen tube tip and the shank can be explained solely by the geometry of the pollen tube. CFM, in combination with an FEM-based model, provides a powerful method to evaluate important mechanical parameters of single, growing cells. Our findings indicate that the cell wall of growing pollen tubes has mechanical properties similar to rubber. This suggests that a fully turgid pollen tube is a relatively stiff, yet flexible cell that can react very quickly to obstacles or attractants by adjusting the direction of growth on its way through the female transmitting tissue. PMID- 23106270 TI - Counterattacking drug-resistant tuberculosis: molecular strategies and future directions. PMID- 23106271 TI - Targeting antibiotic resistance mechanisms in Mycobacterium tuberculosis: recharging the old magic bullets. PMID- 23106274 TI - Inhibitors of mycobacterial efflux pumps as potential boosters for anti tubercular drugs. AB - Tuberculosis is one of the major causes of infection across the world. The emergence of multi-, extensively- and totally drug-resistant strains of Mycobacterium tuberculosis contributes to the lack of therapeutic options available. The mechanisms associated with this resistance could involve mutations in genes coding for target proteins, decreased permeability, increased efflux and so on. Resistance mediated by efflux systems has become more relevant, since these systems help the bacteria to extrude antibiotics until relevant mutations emerge and become established in the population. Therefore, compounds that inhibit these transport systems are of major importance and have been studied in the last few years. Not only do these compounds act on the bacterial efflux systems but they have also been explored for their dual role as boosters of the macrophage-infected cells. The search for novel compounds or combinations of adjuvant compounds and antibiotics to treat mycobacterial multidrug-resistant infections has become a major goal in the treatment of these diseases. PMID- 23106273 TI - Strategies for potentiation of ethionamide and folate antagonists against Mycobacterium tuberculosis. AB - Antifolates inhibit de novo folate biosynthesis, whereas ethionamide targets the mycolate synthetic pathway in Mycobacterium tuberculosis. These antibiotics are effective against M. tuberculosis but their use has been hampered by concerns over toxicity and low therapeutic indexes. With the increasing spread of drug resistant forms, interest in using old drugs for tuberculosis treatment has been renewed. Specific inhibitors targeting resistance mechanisms could sensitize M. tuberculosis to these available, clinically approved drugs. This review discusses recently developed strategies to boost the antituberculous activity of ethionamide and antifolates. These approaches might help broaden the currently limited chemotherapeutic options of not only drug-resistant but also drug susceptible tuberculosis, which still remains one of the most common infectious diseases in the developing world. PMID- 23106275 TI - Reappraising the use of beta-lactams to treat tuberculosis. AB - The emergence of multidrug-resistant and extensively drug-resistant tuberculosis calls for novel approaches to treatment. Recent studies have shown that BlaC, the beta-lactamase of Mycobacterium tuberculosis, is the major determinant of beta lactam resistance. This review invites the reader to explore evidence in order to answer the questions: can beta-lactam and beta-lactamase inhibitors adequately treat M. tuberculosis infection and are they a viable option in the management of resistant tuberculosis today? PMID- 23106276 TI - Elimination of intracellularly residing Mycobacterium tuberculosis through targeting of host and bacterial signaling mechanisms. AB - With more than 2 billion latently infected people, TB continues to represent a serious threat to human health. According to the WHO, 1.1 million people died from TB in 2010, which is equal to approximately 3000 deaths per day. The causative agent of the disease, Mycobacterium tuberculosis, is a highly successful pathogen having evolved remarkable strategies to persist within the host. Although normally, upon phagocytosis by macrophages, bacteria are readily eliminated by lysosomes, pathogenic mycobacteria actively prevent destruction within macrophages. The strategies that pathogenic mycobacteria apply range from releasing virulence factors to manipulating host molecules resulting in the modulation of host signal transduction pathways in order to sustain their viability within the infected host. Here, we analyze the current status of how a better understanding of both the bacterial and host factors involved in virulence can be used to develop drugs that may be helpful to curb the TB epidemic. PMID- 23106278 TI - WhiB7, a transcriptional activator that coordinates physiology with intrinsic drug resistance in Mycobacterium tuberculosis. AB - Current tuberculosis treatment regimens are notoriously limited, lengthy and becoming increasingly ineffective due to the emergence of drug-resistant mutant strains of Mycobacterium tuberculosis. The intrinsic resistance of M. tuberculosis to the majority of available drugs relies both on the impermeability of its cell envelope, and its ability to activate specific genes and physiological states. WhiB7 is a transcriptional regulatory protein underlying this adaptive process. Transcription of the whiB7 gene is upregulated in response to a variety of antibiotics having different structures and targets, as well as in response to metabolic signals. The whiB7 regulon activates various systems of intrinsic drug resistance involving antibiotic export, antibiotic inactivation (by chemical modifications of the drug or its target) and significant changes to thiol redox balance. Drugs have been identified that inactivate resistance determinants in the whiB7 regulon, thereby potentiating the activities of diverse antibiotics against M. tuberculosis. PMID- 23106277 TI - Targeting the mycobacterial envelope for tuberculosis drug development. AB - The bacterium that causes tuberculosis, Mycobacterium tuberculosis, possesses a rather unique outer membrane composed largely of lipids that possess long-chain and branched fatty acids, called mycolic acids. These lipids form a permeability barrier that prevents entry of many environmental solutes, thereby making these bacteria acid-fast and able to survive extremely hostile surroundings. Antitubercular drugs must penetrate this layer to reach their target. This review highlights drug development efforts that have added to the slowly growing tuberculosis drug pipeline, identified new enzyme activities to target with drugs and increased the understanding of important biosynthetic pathways for mycobacterial outer membrane and cell wall core assembly. In addition, a portion of this review looks at discovery efforts aimed at weakening this barrier to decrease mycobacterial virulence, decrease fitness in the host or enhance the efficacy of the current drug repertoire by disrupting the permeability barrier. PMID- 23106279 TI - Targeting the global regulator Lsr2 as a novel approach for anti-tuberculosis drug development. AB - Leprosy serum reactive clone 2 (Lsr2; Rv3597c) is a recently identified nucleoid associated protein that acts as a global transcriptional regulator of Mycobacterium tuberculosis. Strikingly, Lsr2 appears to play a critical role in controlling the expression of virulence-associated genes. Here the authors outline the current knowledge concerning this novel global regulator and its potential as a target for chemotherapeutic intervention. Compounds that induce high level expression of lsr2 may lead to abolishment of virulence traits and render the bacterium incapable of causing infection and/or disease. Alternatively, compounds that either silence lsr2 expression or block the protein's function could be lethal since it has been postulated that lsr2 is essential in M. tuberculosis. PMID- 23106282 TI - Periplasmic arabinogalactan glycoproteins act as a calcium capacitor that regulates plant growth and development. AB - Arabinogalactan glycoproteins (AGPs) are implicated in virtually all aspects of plant growth and development, yet their precise role remains unknown. Classical AGPs cover the plasma membrane and are highly glycosylated by numerous acidic arabinogalactan polysaccharides O-linked to hydroxyproline. Their heterogeneity and complexity hindered a structural approach until the recent determination of a highly conserved repetitive consensus structure for a 15-sugar residue arabinogalactan subunit with paired glucuronic carboxyls. Based on NMR data and molecular dynamics simulations, we identify these carboxyls as potential intramolecular Ca(2+)-binding sites. Using rapid ultrafiltration assays and mass spectrometry, we verified that AGPs bind Ca(2+) tightly (K(d) ~ 6.5 MUM) and stoichiometrically at pH 5. Ca(2+) binding is reversible in a pH-dependent manner. As typical AGPs contain c. 30 Ca(2+)-binding subunits and are bulk components of the periplasm, they represent a Ca(2+) capacitor discharged at low pH by stretch-activated plasma membrane H(+)-ATPases, hence a substantial source of cytosolic Ca(2+). We propose that these Ca(2+) waves prime the 'calcium oscillator', a signal generator essential to the global Ca(2+) signalling pathway of green plants. PMID- 23106283 TI - Dynamic function of the alkyl spacer of acetogenins as potent inhibitors of mitochondrial complex I. A molecular dynamics simulation approach. AB - Acetogenins are among the most potent of the known inhibitors of complex I (NADH ubiquinone oxidoreductase) in mitochondrial electron transfer system. Elucidation of the dynamic function of the alkyl spacer linking the two toxophores (i.e., the hydroxylated tetrahydrofuran and the gamma-lactone rings) is critical for fully understanding their inhibition mechanism. To this end, using molecular dynamics simulations a structure-activity relationship study of a series of acetogenins was performed for the first time using this approach. Our results clearly indicated that both, the length and the molecular flexibility of the spacer, were crucial for taking an active conformation. A partially folded conformation with an optimal length (bis-tetrahydrofuran rings and 13 carbon atoms) of about 16 A with a high molecular flexibility might depict an active form of the spacer. In addition, we demonstrated that the bis-tetrahydrofuran derivatives are able to overcome the shortage of the length of the spacer more efficiently than the mono tetrahydrofuran derivatives with the help of the additional tetrahydrofuran, which acts as a pseudospacer. Our results obtained from molecular dynamics calculations supported the use of a combined decane/water system as a good solvent model to simulate the biological environment of acetogenins acting as inhibitor of complex I. PMID- 23106280 TI - Targeting drug tolerance in mycobacteria: a perspective from mycobacterial biofilms. AB - Multidrug chemotherapy for 6-9-months is one of the primary treatments in effective control of tuberculosis, although the mechanisms underlying the persistence of its etiological agent, Mycobacterium tuberculosis, against antibiotics remain unclear. Ever-mounting evidence indicates that the survival of many environmental and pathogenic microbial species against antibiotics is influenced by their ability to grow as surface-associated multicellular communities called biofilms. In recent years, several mycobacterial species, including M. tuberculosis, have been found to form drug-tolerant biofilms in vitro through genetically controlled mechanisms. In this review, the authors discuss the relevance of the in vitro mycobacterial biofilms in understanding the antibiotic recalcitrance of tuberculosis infections. PMID- 23106284 TI - Synthesis and in vitro cytotoxicity studies of certain novel heterocycles derived from bis 1, 2, 4-triazoles and their DNA damage studies. AB - Synthesis and evaluation of cytotoxicity of a series of heterocyclic compounds derived from 1, 4-bis-(5- [hydrazinocarbonylmethylthio]-4-phenyl-1,2,4-triazol-3 yl) butane (1a-b) are described. The triazolo-triazoles (9-15) and thiadiazoles (16-18) were prepared from respective thiosemicarbazide intermediates (2-8). The Schiff bases (19-24) were prepared from (1a, b) by reacting with different carboxaldehydes in acetic acid medium. All the synthesized compounds were characterized by IR, NMR and Mass spectral studies. The compounds were evaluated for in vitro cytotoxicity potential using the standard MTT assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29 and Breast Cancer MDA MB-231. The DNA damage activity of the compound 24 was evaluated by alkaline comet assay. PMID- 23106285 TI - Variable selection based QSAR modeling on Bisphenylbenzimidazole as Inhibitor of HIV-1 reverse transcriptase. AB - The emergence of mutant virus in drug therapy for HIV-1 infection has steadily risen in the last decade. Inhibition of reverse transcriptase enzyme has emerged as a novel target for the treatment of HIV infection. The aim to decipher the structural features that interact with receptor, we report a quantitative structure activity relationship (QSAR) study on a dataset of thirty seven compounds belonging to bisphenylbenzimidazoles (BPBIs) as reverse transcriptase inhibitors using enhanced replacement method (ERM), stepwise multiple linear regression (Stepwise-MLR) and genetic function approximation (GFA) method for selecting a subset of relevant descriptors, developing the best multiple linear regression model and defining the QSAR model applicability domain boundaries. The enhanced replacement method was found to give better results r2=0.8542, Q2(loo) = 0.7917, r2pred = 0.7812) at five variables as compared to stepwise MLR and GFA method, evidenced by internal and external validation parameters. The modified r2 (r2m) of the training set, test set and whole data set were calculated and are in agreement with the enhanced replacement method. The results of QSAR study rationalize the structural requirement for optimum binding of ligands. The developed QSAR model shows that hydrophobicity, flexibility, three dimensional surface area, volume and shape of molecule are important parameters to be considered for designing new compounds and to decipher reverse transcriptase enzyme inhibition activity of these compounds at molecular level. The applicability domain was defined to find the similar analogs with better prediction power. PMID- 23106286 TI - Dynamic thermal field-induced gradient soft-shear for highly oriented block copolymer thin films. AB - As demand for smaller, more powerful, and energy-efficient devices continues, conventional patterning technologies are pushing up against fundamental limits. Block copolymers (BCPs) are considered prime candidates for a potential solution via directed self-assembly of nanostructures. We introduce here a facile directed self-assembly method to rapidly fabricate unidirectionally aligned BCP nanopatterns at large scale, on rigid or flexible template-free substrates via a thermally induced dynamic gradient soft-shear field. A localized differential thermal expansion at the interface between a BCP film and a confining polydimethylsiloxane (PDMS) layer due to a dynamic thermal field imposes the gradient soft-shear field. PDMS undergoes directional expansion (along the annealing direction) in the heating zone and contracts back in the cooling zone, thus setting up a single cycle of oscillatory shear (maximum lateral shear stress ~12 * 10(4) Pa) in the system. We successfully apply this process to create unidirectional alignment of BCP thin films over a wide range of thicknesses (nm to MUm) and processing speeds (MUm/s to mm/s) using both a flat and patterned PDMS layer. Grazing incidence small-angle X-ray scattering measurements show absolutely no sign of isotropic population and reveal >=99% aligned orientational order with an angular spread Deltatheta(fwhm) <= 5 degrees (full width at half maximum). This method may pave the way to practical industrial use of hierarchically patterned BCP nanostructures. PMID- 23106287 TI - Increment of antimycobaterial activity on lichexanthone derivatives. AB - A new dihydropyranexanthone derived from the natural xanthone lichexanthone (1) was synthesised and, together with other 18 derivatives including omega-bromo and omega-aminoalkoxylxanthones (containing methyl, ethyl, propyl, tertbutylamino and piperidinyl moieties), were tested against Mycobacterium tuberculosis. Nine omega aminoalkoxylxanthones showed good antimycobacterial activity, and their in vitro cytotoxicity was determined using VERO cells in order to calculate the selectivity index (SI). One of these nitrogenated xanthone derivatives showed very promising results, with MIC of 2.6 MUM and SI of 48. This MIC is comparable to values found in "first and second line" drugs commonly used to treat TB. In order to understand better about this compound, it was evaluated together with two other ones that showed good SI, against resistant clinical strains of M. tuberculosis to verify the existence of cross-resistance. A chemometrical approach was useful to establish a pattern of antitubercular activity among the group of omega-aminoalkoxylxanthones, according to some structural and chemical features. PMID- 23106288 TI - Standardized care pathway versus conventional approach in the management of patients presenting with faint at the University of Utah. AB - BACKGROUND: Despite the availability of guidelines, the evaluation of patients with faint continues to be inconsistent. The purpose of this study was to test the hypothesis that utilization of a new standardized-care pathway (Faint Algorithm) reduces hospital admissions and improves diagnostic yield when compared to the conventional approach in the evaluation of patients with faint. METHODS: We reviewed the data of 154 consecutive patients presenting with faint to the Faint and Fall Clinic at the University of Utah (standardized group) and 100 patients previously evaluated for faint using the conventional approach (conventional group). RESULTS: Using a standardized approach, only 4% of patients were admitted when compared to 20% in the conventional group (P < 0.001). The rate of diagnosis at initial evaluation was similar between the groups; however, at 45 days, it was greater in the standardized group when compared to the conventional group (57% vs 45% in the total population, P = 0.09; 57% vs 39% in the outpatient subgroups, P = 0.02). The number of tests or consultations associated with additional charges was significantly lower in the standardized group when compared to the conventional group (1.9 +/- 1.0 vs 2.6 +/- 1.2, P = 0.001). CONCLUSIONS: The use of a standardized approach in the evaluation of patients with faint decreased the number of hospital admissions and increased the rate of diagnosis at 45 days. This was achieved with less utilization of costly tests and consultations. PMID- 23106289 TI - The potential of toe flexor muscles to enhance performance. AB - The metatarsal phalangeal joint (MPJ) and its crossing toe flexor muscles (TFM) represent the link between the large energy generating leg extensor muscles and the ground. The purpose of this study was to examine the functional adaptability of TFM to increased mechanical stimuli and the effects on walking, running and jumping performance. Fifteen men performed a heavy resistance TFM strength training with 90% of the maximal voluntary isometric contraction (MVIC) for 7 weeks (560 contractions) for the left and right foot. Maximal MPJ and ankle plantar flexion moments during MVICs were measured in dynamometers before and after the intervention. Motion analyses (inverse dynamics) were performed during barefoot walking, running, and vertical and horizontal jumping. Athletic performance was determined by measuring jump height and distance. Left (0.21 to 0.38 Nm . kg(-1); P < 0.001) and right (0.24 to 0.40 Nm . kg(-1); P < 0.001) MPJ plantar flexion moments in the dynamometer, external MPJ dorsiflexion moments (0.69 to 0.75 Nm . kg(-1); P = 0.012) and jump distance (2.25 to 2.31 m; P = 0.006) in horizontal jumping increased significantly. TFM responded highly to increased loading within a few weeks. The increased force potential made a contribution to an athlete's performance enhancement. PMID- 23106290 TI - Marked eosinophilia with abnormal basophilic granules in acute graft-versus-host disease post-allogeneic haemopoietic stem cell transplant for acute myeloid leukaemia without CBFB-MYH11 mutation. PMID- 23106291 TI - Curing neonatal jaundice with 'language of friendship and rays of hope' in the 18th century. PMID- 23106292 TI - Pre and post-operative treatments for prevention of atrial fibrillation after cardiac surgery. AB - Post-operative atrial fibrillation (AF) occurs in up to 40% of cardiac surgery patients and represents the most common post-operative arrhythmic complication. Post-operative AF is associated with impaired cardiac hemodynamics, increased incidence of serious complications (e.g. heart failure, stroke), prolonged hospitalization and increased healthcare costs. Therefore, treatment of post operative AF would decrease health-care costs during hospitalization and improve the prognosis of patients following cardiovascular surgery. Current consensus guidelines recommend beta-blockers, amiodarone and sotalol for post-operative AF prophylaxis. However, new pharmacological agents have been associated with a reduction in post-operative AF frequency, including inhibition of the renin angiotensin aldosterone system (RAAS) using angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), statins, antioxidant agents, magnesium supplementation and antiarrhythmic drugs. The aim of this review is to analyse and determine the efficiency of existing therapies in the reduction of post-operative AF development. PMID- 23106293 TI - Enhanced architecture of lipid-carbon nanotubes as langmuir-blodgett films to investigate the enzyme activity of phospholipases from snake venom. AB - The immobilization of biomolecules in films with a controlled architecture permits the access of information on the molecular interactions, not only between film components, but also between the film and substances in the external environment. In this study, we investigated the immobilization of the phospholipase A(2) from snake venoms (4-nitro-3-(octanoyloxy)benzoic acid, OBZ) in solid supports as a Langmuir-Blodgett (LB) film, followed by incorporation of carbon nanotubes (CNTs). The hybrid film was characterized by infrared spectroscopy and the interactions with its catalytic substrate were investigated. The presence of CNTs leads to a structure with an adequate environment to preserve the enzyme properties, leading to an optimum catalytic activity. This enhanced architecture was exploited in terms of vibrational spectroscopy, which indicated changes in the secondary structure of the enzyme upon contact with the catalytic substrate. PMID- 23106294 TI - Trout-skin gelatin-based edible films containing phenolic antioxidants: effect on physical properties and oxidative stability of cod-liver oil model food. AB - Trout-skin (Oncorhynchus mykiss) gelatin-based films containing antioxidants (epigallocatechin gallate (EGCG), 50 and 250 ppm w/w) and green tea powder (1% and 20% w/w of gelatin) were tested for tensile strength, elastic modulus, and elongation, and oxygen and water vapor transmission rates, in vitro antioxidant activity using the DPPH (2,2-diphenyl-1-picrylhydrazyl) assay and effect on stabilizing cod-liver oil held under mild thermal abuse conditions. Cod-liver oil overlaid with films was stored at 40 degrees C for 20 d and analyzed for peroxide value (PV) and thiobarbituric acid reactive substances (TBARS). Antioxidant activity was retained in films containing green tea powder, but was reduced (P < 0.05) in EGCG films (20 d, 23 degrees C). Water vapor transmission rate of the films incorporated with antioxidants did not change significantly (P > 0.05), but the oxygen transmission rate for films with 50 ppm EGCG and 20% green tea powder was significant (P < 0.05). Other physical properties varied with antioxidant incorporation. The TBARS and PV of control oil increased from 0.05 +/- 0.01 to 4.71 +/- 0.30 g MDA/kg oil and from 3.6 +/- 0.2 to 178.3 +/- 24.5 millieq peroxides/kg oil, respectively, after 20 d. For cod-liver oil covered with control or antioxidant-containing films, TBARS remained below 0.37 g MDA/kg oil and PV below 7 millieq peroxides/kg oil. Incorporation of antioxidants to the films did not reduce oil oxidation (P > 0.05) at the levels tested and this was confirmed by activation energy calculations. The rate of oil oxidation was more dependent upon the inherent oxygen barrier property of the films than the presence of antioxidants. PRACTICAL APPLICATION: This research has the potential to enhance the utilization of fish skins, a valuable food processing by product, as edible films with natural antioxidants to extend the shelf life of foods. The film physical properties and barrier to oxygen and water are investigated. PMID- 23106295 TI - An evaluation of early cardiometabolic risk factors in children and adolescents with Turner syndrome. AB - BACKGROUND AND OBJECTIVES: Turner syndrome (TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra-myocellular lipid between young TS girls and an age- and BMI standard deviation scores (SDS)-matched healthy female cohort. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. Nineteen TS and 17 control girls (13.7 +/- 2.5 vs 12.7 +/- 3.4 years of age, respectively, P = 0.30). Multiple-sample oral glucose tolerance test with measurement of fasting insulin, LDL, HDL, triglycerides, adiponectin and highly sensitive C-reactive protein (hsCRP) was performed. Subcutaneous adipose tissue, visceral adipose tissue intramyocellular lipid levels evaluated by magnetic resonance techniques. Insulin secretion (IS), sensitivity (Si) and the insulin secretion-sensitivity index (ISSI-2) were calculated from oral glucose tolerance test data. RESULTS: Five TS and no controls had impaired fasting glucose or impaired glucose tolerance; none had type 2 diabetes mellitus. Insulin sensitivity and insulin secretion were similar between groups; ISSI-2 was lower in TS (923.5 +/- 307.3 vs 659.1 +/- 387.3; P = 0.03). TS girls had higher blood pressure (82.5 +/- 13.6 vs 73.5 +/- 5.5 mmHg; P = 0.0146), waist circumference (76.0 +/- 11.8 vs 65.9 +/- 9.7; P = 0.0087) and subcutaneous adipose tissue (135.6 +/- 88.6 vs 69.3 +/- 59.9; P = 0.01) than controls. Visceral adipose tissue, intramyocellular lipid levels and adiponectin were not different between groups. TS girls also had higher triglycerides (1.1 +/- 0.6 vs 0.7 +/- 0.3; P = 0.003), total cholesterol (4.4 +/- 0.7 vs 3.9 +/- 0.4; P = 0.02) and hsCRP (2.0 +/- 1.9 vs 0.8 +/- 0.3; P = 0.01). CONCLUSIONS: TS girls exhibit more cardiometabolic risk factors and reduced beta cell function compared with age- and BMI-SDS-matched girls. Increased awareness of early risk of type 2 diabetes mellitus and hypertension in TS girls is needed. PMID- 23106296 TI - Preparation and characterization of conducting mixed-valence 9,9'-dimethyl-3,3' bicarbazyl rectangular nanowires. AB - The facile synthesis of an organic electric conducting nanowire is described. The simple oxidation of 9-methylcarbazole by iron(III) perchlorate in a methanol/acetonitrile mixture under atmospheric pressure and temperature produces abundant nanowires without using a template. The nanowire consists of 9,9' dimethyl-3,3'-dicarbazyl and has a rectangular nanowire shape with an average diameter of 397 +/- 50 nm and length of 17 +/- 5 MUm. The results of the elemental analysis, (1)H NMR, FT-IR, XPS, and ESR measurements revealed that the chemical composition of the nanowire is (dicarbazyl)(0.12)(dicarbazylium.ClO(4)( ))(0.88).H(2)O. This result, combined with the UV-vis-NIR measurement, demonstrates that 9,9'-dimethyl-3,3'-dicarbazyl stacks in a mixed valence state. The nanowire is electroactive and has an electric conductivity of 3.0 * 10(-5) S cm(-1). PMID- 23106297 TI - Oridonin: targeting programmed cell death pathways as an anti-tumour agent. AB - Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has drawn rising attention for its remarkable apoptosis- and autophagy inducing activity and relevant molecular mechanisms in cancer therapy. Apoptosis is a well known type of cell death, whereas autophagy can play either pro survival or pro-death roles in cancer cells. Accumulating evidence has recently revealed relationships between apoptosis and autophagy induced by oridonin; however, molecular mechanisms behind them remain to be discovered. In this review, we focus on highlighting updated research on oridonin-induced cell death signalling pathways implicated in apoptosis and autophagy, in many types of cancer. In addition, we further discuss cross-talk between apoptosis and autophagy induced by oridonin, in cancer. Taken together, these findings open new perspectives for further exploring oridonin as a potential anti-tumour agent targeting apoptosis and autophagy, in future anti-cancer therapeutics. PMID- 23106298 TI - Comparison between 8-prenylnarigenin and narigenin concerning their activities on promotion of rat bone marrow stromal cells' osteogenic differentiation in vitro. AB - A number of recent studies have suggested that flavonols (a class of phytochemical with many biological activities), might exert protective effects against post-menopausal bone loss. In the present study, we compared naringenin (NG) and 8-prenylnaringenin (PNG), two major naturally occurring flavonols, on in vitro differentiation of osteoblasts and bone resorbing activity, of rat bone marrow stromal cells (BMSCs). Our results indicated that both compounds, at 10( 6) m, enhanced BMSCs' differentiation. Then effects of the two compounds at 10( 6) m on ALP activity, osteocalcin secretion and calcium deposition, were compared over a time course. Numbers and areas of colonies stained for ALP (CFU F(ALP) ) expression, and mineralized bone nodules, were histochemically analysed after 12 days and 16 days osteogenic induction, respectively. Expression of BMP 2, OPG, OSX, RUNX-2 genes and p38MAPK protein were examined using real-time PCR and western blotting, respectively. The data presented indicate that PNG, significantly enhanced the rat BMSCs' differentiation and mineralization through the BMP-2/p38MAPK/Runx2/Osterix signal pathway, greater than did NG. In conclusion, PNG has a more pronounced ability to enhance osteoblast differentiation and mineralization, than NG. PMID- 23106299 TI - Unravelling the retention of proliferation and differentiation potency in extensive culture of human subcutaneous fat-derived mesenchymal stem cells in different media. AB - OBJECTIVES: This study has intended to investigate longevity of subcutaneous fat derived mesenchymal stem cells (SF-MSCs) under extensive culturing. It has also focused on optimization of culture media for them over prolonged periods in vitro. MATERIALS AND METHODS: We evaluated SF-MSCs with reference to phenotypic characterization, proliferative ability, karyotype stability and differentiation potency with early (P3) and late passage (P20) conditions, using four different media, DMEM-LG, ALPHA-MEM, DMEM-F12 and DMEM-KO. RESULTS: This study unravels retention of SF-MSC characteristics in facets of phenotypic expression profile (CD 90, CD 105, CD 73, CD 34, CD 29, CD 54, CD 49d, CD 117, HLA-DR, CD 166, CD 31, CD 44), proliferative characteristics, karyotyping and differentiation potency prolonged culturing to P25 in all media. Population doubling time (PDT) in Alpha MEM, DMEM LG, DMEM F 12, DMEM KO were identified to be (1.81, 1.84, 1.9, 2.08 days) at early passage and (2.93, 2.94, 3.12, 3.06 days) at late passage. As a corollary, Alpha MEM and DMEM LG serve as appropriate basal media for SF-MSC when proliferative potency is considered. CONCLUSIONS: In research, it is imperative that SF-MSC uphold their expansion potency in the aforesaid attributes in all media over extensive culturing, thereby transforming their colossal in vitro potency, with the aim of curing a wide horizon of diseases. PMID- 23106300 TI - CD133: holy of grail of neuro-oncology or promiscuous red-herring? AB - The CD133 glycoprotein is a controversial cancer stem cell marker in the field of neuro-oncology, based largely on the now considerable experimental evidence for the existence of both CD133+ve and CD133-ve populations as tumour-initiating cells. It is thought that decreasing oxygen tension enhances the complex regulation and phenotype of CD133 in glioma. In light of these ideologies, establishing the precise functional role of CD133 is becoming increasingly critical. In this article, we review the complex regulation of CD133 and its extracellular epitope AC133, and associated alterations, to tumour cell behaviour by hypoxia. Furthermore, its role in functional modulation of tumours, rather than determination of a specific stem cell type is therefore alluded to, while evidence for and against its ability as a cancer stem cell marker in primary brain tumours, is critically evaluated. Thus, the suggestion that CD133 may be a central 'holy grail' in identifying core cells for propagation of malignant glial neoplasms seems increasingly less convincing. It remains to be seen, however, whether CD133 is randomly expressed on such brain tumour cell populations or whether it is of major significance to brain biological behaviour. PMID- 23106301 TI - The mechanisms of nadroparin-mediated inhibition of proliferation of two human lung cancer cell lines. AB - OBJECTIVES: Clinical data suggest that heparin treatment improves survival of lung cancer patients, but the mechanisms involved are not fully understood. We investigated whether low molecular weight heparin nadroparin, directly affects lung cancer cell population growth in conventionally cultured cell lines. MATERIALS AND METHODS: A549 and CALU1 cells' viability was assessed by MTT and trypan blue exclusion assays. Cell proliferation was assessed using 5-bromo-2 deoxyuridine incorporation. Apoptosis and cell-cycle distribution were analysed by flow cytometry; cyclin B1, Cdk1, p-Cdk1 Cdc25C, p-Cdc25C and p21 expressions were analysed by western blotting. mRNA levels were analysed by real time RT-PCR. RESULTS: Nadroparin inhibited cell proliferation by 30% in both cell lines; it affected the cell cycle in A549, but not in CALU-1 cells, inducing arrest in the G(2) /M phase. Nadroparin in A549 culture inhibited cyclin B1, Cdk1, Cdc25C and p Cdc25C, while levels of p-Cdk1 were elevated; p21 expression was not altered. Dalteparin caused a similar reduction in A549 cell population growth; however, it did not alter cyclin B1 expression as expected, based on previous reports. Fondaparinux caused minimal inhibition of A549 cell population growth and no effect on either cell cycle or cyclin B1 expression. CONCLUSIONS: Nadroparin inhibited proliferation of A549 cells by inducing G(2) /M phase cell-cycle arrest that was dependent on the Cdc25C pathway, whereas CALU-1 cell proliferation was halted by as yet not elucidated modes. PMID- 23106302 TI - Inhibition of human in vitro osteoclastogenesis by Equisetum arvense. AB - OBJECTIVES: Equisetum arvense has long been used in traditional medicines to treat different disorders, including bone pathologies. In this study a hydromethanolic extract of E. arvense was assessed for its effects on human osteoclastogenesis. MATERIALS AND METHODS: Osteoclast precursors were maintained in non-stimulated and stimulated (presence of M-CSF and RANKL) conditions, or in co-cultures with osteoblasts. Cell cultures were treated with 0.00016-0.5 mg/ml of a hydromethanolic E. arvense extract. RESULTS: The extract did not affect spontaneous osteoclastogenesis. In osteoclast precursors committed to osteoclastogenesis (stimulated or co-cultured with osteoblasts), E. arvense caused dose-dependent inhibitory effect that became statistically significant at concentrations >=0.004 mg/ml. This was observed using different osteoclast differentiation and activation markers. Cell response was associated with changes in relative contribution of MEK and NFkB signalling pathways, as well as PGE2 production. As there were differences in the response of osteoclast precursors maintained in the presence of inductive factors, or co-cultured with osteoblastic cells, it seems that E. arvense extract had the ability to modulate osteoclastogenesis, either by acting directly on osteoclast precursor cells, and/or via osteoblasts. CONCLUSIONS: Equisetum appeared to have a negative effect on human osteoclastogenesis, which is in line with its putative beneficial role in pathophysiological conditions associated with increased osteoclastic activity, and might suggest potential utility for treatment with bone regeneration strategies. PMID- 23106303 TI - Attentional gating models of object substitution masking. AB - Di Lollo, Enns, and Rensink (2000) proposed the computational model of object substitution (CMOS) to explain their experimental results with sparse visual maskers. This model supposedly is based on reentrant hypotheses testing in the visual system, and the modeled experiments are believed to demonstrate these reentrant processes in human vision. In this study, I analyze the main assumptions of this model. I argue that CMOS is a version of the attentional gating model and that its relationship with reentrant processing is rather illusory. The fit of this model to the data indicates that reentrant hypotheses testing is not necessary for the explanation of object substitution masking (OSM). Further, the original CMOS cannot predict some important aspects of the experimental data. I test 2 new models incorporating an unselective processing (divided attention) stage; these models are more consistent with data from OSM experiments. My modeling shows that the apparent complexity of OSM can be reduced to a few simple and well-known mechanisms of perception and memory. PMID- 23106304 TI - Psychological distance can improve decision making under information overload via gist memory. AB - Making a decision can be especially difficult when it is based upon a large amount of information. A number of demonstrations in the literature suggest that decision making under information overload leads to suboptimal outcomes. In this article, we draw on construal level theory (Trope & Liberman, 2003) and fuzzy trace theory (Brainerd & Reyna, 1993) to suggest that psychologically distancing oneself from the information can be beneficial to decision making under information overload. Specifically, we propose that distancing prompts organization of information in terms of its gist. Across 4 studies, we demonstrated that increasing spatial distance, temporal distance, and abstraction lead to better decision outcomes when decision makers were overloaded with many pieces of information per decision. Furthermore, we showed that the relationship between psychological distance and decision outcome is mediated by gist memory. PMID- 23106305 TI - The cost and benefit of implicit spatial cues for visual attention. AB - Processing concepts with implicit spatial meaning or metaphorical spatial association has been shown to engage visuospatial mechanisms, causing either facilitation or interference with concurrent visual processing at locations compatible with the concepts. It is, however, unclear when interference or facilitation should be expected. It is possible that both effects result from the same processes that interact differently with different visual tasks (e.g., facilitating detection and interfering with discrimination). Alternatively, the 2 effects might represent different temporal stages of the same kind of processes, which can interfere with a congruent visual task at early stages but can cause facilitation at later stages. Finally, the 2 effects might be due to the differences in the underlying representations of concepts, particularly the differences between abstract and concrete concepts. Results of the present study are consistent with the view that interference and facilitation represent 2 temporal stages of the same kind of processes. In addition, the results reveal the unexpected importance of using multiple conceptual categories (as opposed to a single category) in observing the time course of the effects. PMID- 23106306 TI - Mortality by clinical characteristics in a tertiary care cohort of adult patients with chronic epilepsy. AB - The authors evaluated the contribution of various clinical characteristics to mortality risk and underlying causes of death among all adult patients with epilepsy seen at the Department of Neurology, Oulu University Hospital in Finland during 1996 and 1997. Hazard ratios (HRs) for mortality in 1998-2006 relative to a population-based reference cohort were estimated using Cox modeling, with adjustment for age and gender. The HR for total mortality was 2.66 (95% confidence interval [CI] 2.09-3.39). Infectious etiology of epilepsy (HR 5.77, 95% CI 2.52-13.2) and a seizure frequency of >=1 per month (HR 4.42, 95% CI 3.00 6.52) related to high risks of death. Cancer (21%), ischemic heart disease (15%), and accidents (12%) caused most of the potential years of life lost. Despite recent advances in treatment of epilepsy and improved seizure control, chronic epilepsy still carries a substantially increased risk of death. PMID- 23106307 TI - Interactions of soluble guanylate cyclase with a P-site inhibitor: effects of gaseous heme ligands, azide, and allosteric activators on the binding of 2'-deoxy 3'-GMP. AB - Nitric oxide (NO) elicits a wide variety of physiological responses by binding to the heme in soluble guanylate cyclase (sGC) to stimulate cGMP production. Although nucleotides, such as ATP or GTP analogues, have been reported to regulate the signaling of NO binding from the heme site to the catalytic site, the other regulatory functions of nucleotides remain unexamined. Among the nucleotides tested, we found that 2'-d-3'-GMP acted as a potent noncompetitive inhibitor with respect to Mn-GTP, when the ferrous enzyme combined with NO, CO, or allosteric activator BAY 41-2272. 2'-d-3'-GMP also displayed nearly identical patterns of inhibition for the ferric enzyme, in which the binding of N(3)(-) or BAY 41-2272 significantly increased the inhibitory effects of the nucleotide. Equilibrium dialysis measurements using the CO-ligated enzyme in the presence of allosteric activators demonstrated that 2'-d-3'-GMP exclusively binds to the catalytic site of sGC. Furthermore, the affinity of 2'-d-3'-GMP for the enzyme was found to increase upon addition of foscarnet, an analogue of PP(i). These findings together with other kinetic results imply that 2'-d-3'-GMP acts as a P site inhibitor probably by forming a dead-end complex, sGC-2'-d-3'-GMP-PP(i), in the catalytic reaction. The formation of the complex of the enzyme with 2'-d-3' GMP does not seem to be associated with changes in the Fe-proximal His bond strength, because the CO coordination state or the redox potentials of the enzyme heme complex are virtually unaffected. PMID- 23106308 TI - Human insulin versus porcine insulin in rhesus monkeys with diabetes mellitus. AB - BACKGROUND: Monkeys with insulin-dependent diabetes are important preclinical animal models for islet transplantation. Exogenous insulin should be administered to achieve good glycemic control and minimize the long-term vascular complications associated with diabetes until the graft function recovered completely. However, the effect of multiple daily injections of porcine or human insulin and the long-term effects of porcine insulin have not been studied in diabetic rhesus monkeys. METHODS: Diabetic rhesus monkeys, using a 6-month self control insulin comparison experiment, were used to detect the incidence of adverse events and long-term diabetes complication events after long-term administration of porcine insulin. RESULTS: In this study, we found that a 20% higher dose of porcine insulin results in similar glycemic control as the human insulin regimen, and adverse events were seldom reported when porcine insulin was administered. Moreover, long-term injection with porcine insulin could delay the rate and severity of diabetes-related complications. CONCLUSIONS: Porcine insulin as a competent candidate for regular insulin therapy to maintain blood glucose levels in insulin-dependent diabetic monkeys during preclinical studies of islet transplantation. PMID- 23106310 TI - Liquid structure of 1-ethyl-3-methylimidazolium alkyl sulfates by X-ray scattering and molecular dynamics. AB - We report a joined X-ray diffraction and molecular dynamics study on the series of 1-ethyl-3-methylimidazolium alkyl sulfates (alkyl = ethyl, butyl, hexyl, octyl) ionic liquids. A general good agreement between experimental and theoretical structure functions has been found for each term of the series in all ranges of q values. Once the quality of the employed force field in reproducing structural data was tested, we used dynamics simulations to access information on morphology and properties of these systems. The series of ionic liquids presents nanoscale structural heterogeneity, whose size depends on the anion alkyl chain size. Analyzing our simulation data on the basis of alkyl chain length, we propose a structural model consistent with the presence of low q peaks. PMID- 23106311 TI - Effect of deglycosylation of cellobiose dehydrogenases on the enhancement of direct electron transfer with electrodes. AB - Cellobiose dehydrogenase (CDH) is a monomeric extracellular flavocytochrome composed of a catalytic dehydrogenase domain (DH(CDH)) containing flavin adenine dinucleotide (FAD), a cytochrome domain (CYT(CDH)) containing heme b, and a linker region connecting the two domains. In this work, the effect of deglycosylation on the electrochemical properties of CDH from Phanerochaete chrysosporium (PcCDH) and Ceriporiopsis subvermispora (CsCDH) is presented. All the glycosylated and deglycosylated enzymes show direct electron transfer (DET) between the CYT(CDH) and the electrode. Graphite electrodes modified with deglycosylated PcCDH (dPcCDH) and CsCDH (dCsCDH) have a 40-65% higher I(max) value in the presence of substrate than electrodes modified with their glycosylated counterparts. CsCDH trapped under a permselective membrane showed similar changes on gold electrodes protected by a thiol-based self-assembled monolayer (SAM), in contrast to PcCDH for which deglycosylation did not exhibit any different electrocatalytical response on SAM-modified gold electrodes. Glycosylated PcCDH was found to have a 30% bigger hydrodynamic radius than dPcCDH using dynamic light scattering. The basic bioelectrochemistry as well as the bioelectrocatalytic properties are presented. PMID- 23106312 TI - Young children's response tendencies toward yes-no questions concerning actions. AB - Two experiments investigated response tendencies of preschoolers toward yes-no questions about actions. Two hundred 2- to 5-year-old children were asked questions concerning actions commonly associated with particular objects (e.g., drinking from a cup) and actions not commonly associated with particular objects (e.g., kicking a toothbrush). The impact of delay and comprehension of questions were also investigated. Results revealed a consistent developmental transition: Younger children tended to display a yes bias whereas older children did not display a bias unless they faced incomprehensible questions, in which case they displayed a nay-saying bias. Delay shifted children's responses in such a way that "no" answers were given more often. These findings hold important implications regarding the use of yes-no questions with children. PMID- 23106313 TI - Familial benign chronic pemphigus and doxycycline: a review of 6 cases. AB - BACKGROUND: Hailey-Hailey disease (HHD) or familial benign chronic pemphigus is a rare autosomal dominant inherited skin disorder, characterized by flaccid vesicles and erosions on the intertriginous areas. Current treatments are not particularly effective. We report 6 cases dramatically improving with doxycycline. CASE REPORTS: 6 patients, aged from 33 to 77 years old, presented with a variable 4 to 40 year history of severe treatment-resistant HHD. All 6 patients were then treated successfully with doxycycline 100 mg per day for at least 3 months. DISCUSSION: An improvement was observed in all 6 patients from 1 week to 3 months after the beginning of treatment. Relapses were observed after various periods. Maintenance half-dose therapy seemed to be beneficial in patients experiencing recurrence. Only one patient developed gastro-intestinal intolerance. No other side effects were reported. Currently, 2 patients have improved and present a decreased number of exacerbations, 2 others are in complete remission after more than 5 years of follow-up. Treatment efficiency is difficult to evaluate in HHD as it is a rare condition. No controlled studies have been published. Local treatments may improve inflammation but do not treat the underlying cause, targeted systemic therapies exist but there is little evidence supporting their use, physical treatments are cumbersome. Besides their antibiotic potential, tetracycline antibiotics also have anti-inflammatory properties and anticollagenase activity via inhibition of matrix metalloproteinases. CONCLUSIONS: Doxycycline appears to be an interesting therapeutic option in Hailey-Hailey disease. PMID- 23106314 TI - Non-cell autonomous regulation of life cycle transitions in the model brown alga Ectocarpus. AB - The model brown alga Ectocarpus has a haploid-diploid life cycle, involving alternation between two independent multicellular generations, the gametophyte and the sporophyte. Recent work has shown that alternation of generations is not determined by ploidy but is rather under genetic control, involving at least one master regulatory locus, OUROBOROS (ORO). Using cell biology approaches combined with measurements of generation-specific transcript abundance we provide evidence that alternation of generations can also be regulated by non-cell autonomous mechanisms. The Ectocarpus sporophyte produces a diffusible factor that causes major developmental reprogramming in gametophyte cells. Cells become resistant to reprogramming when the cell wall is synthetized, suggesting that the cell wall may play a role in locking an individual into the developmental program that has been engaged. A functional ORO gene is necessary for the induction of the developmental switch. Our results highlight the role of the cell wall in maintaining the differentiated generation stage once the appropriate developmental program has been engaged and also indicate that ORO is a key member of the developmental pathway triggered by the sporophyte factor. Alternation between gametophyte and sporophyte generations in Ectocarpus is surprisingly labile, perhaps reflecting an adaptation to the variable seashore environment inhabited by this alga. PMID- 23106315 TI - Increased urinary aldosterone excretion is associated with subcutaneous not visceral, adipose tissue area in obese individuals: a possible manifestation of dysfunctional subcutaneous adipose tissue. AB - BACKGROUND: Aldosterone is reported to be associated with obesity and is a risk factor for metabolic syndrome. Metabolic abnormalities are more strongly associated with visceral adipose tissue (VAT) than with subcutaneous adipose tissue (SAT). OBJECTIVE: We examined whether aldosterone is more closely associated with VAT area than with SAT area in obese individuals. METHODS: We enrolled 81 Japanese patients (46 men, mean age 43 +/- 13 years and 35 women, mean age 53 +/- 10 years) suspected of metabolic disorders and measured plasma and 24-h urinary aldosterone, as well as SAT and VAT areas. SAT and VAT areas were measured at the umbilical level by computed tomography. RESULTS: Spearman's rank correlation analysis showed that urinary aldosterone was significantly and positively correlated with body mass index, waist circumference, SAT area, alanine aminotransferase, C-reactive protein, plasma immune-reactive insulin, plasma renin activity and estimated glomerular filtration rate, and negatively correlated with age and blood glucose. Urinary aldosterone was not correlated with VAT area (r = 0.013, P = 0.906). Multivariate regression analyses revealed that log SAT area, age and diastolic blood pressure were significant (P = 0.001, 0.001 and 0.032, respectively) predictors of log urinary aldosterone excretion rate. CONCLUSION: Our results indicate that urinary aldosterone excretion is positively associated with SAT but not with VAT area in the middle-aged obese individuals.Urinary aldosterone is also negatively correlated with age. PMID- 23106316 TI - 2-(3-Oxo-1,3-diphenylpropyl)malonic acids as potent allosteric ligands of the PIF pocket of phosphoinositide-dependent kinase-1: development and prodrug concept. AB - The protein kinase C-related kinase 2 (PRK2)-interacting fragment (PIF) pocket of phosphoinositide-dependent kinase-1 (PDK1) was proposed as a novel target site for allosteric modulators. In the present work, we describe the design, synthesis, and structure-activity relationship of a series of 2-(3-oxo-1,3 diphenylpropyl)malonic acids as potent allosteric activators binding to the PIF pocket. Some congeners displayed AC(50) values for PDK1 activation in the submicromolar range. The potency of the best compounds to stabilize PDK1 in a thermal stability shift assay was in the same order of magnitude as that of the PIF pocket binding peptide PIFtide, suggesting comparable binding affinities to the PIF pocket. The crystal structure of PDK1 in complex with compound 4h revealed that additional ionic interactions are mainly responsible for the increased potency compared to the monocarboxylate analogues. Notably, several compounds displayed high selectivity for PDK1. Employing a prodrug strategy, we were able to corroborate the novel mechanism of action in cells. PMID- 23106317 TI - Oxetane ring enlargement through nucleophilic trapping of radical cations by acetonitrile. AB - Oxidative electron transfer cycloreversion of trans,trans-2-cyclopropyl-4-methyl 3-phenyloxetane, using triphenylthiapyrylium perchlorate as a photosensitizer, leads to distonic 1,4-radical cations; subsequent cleavage gives rise to fragmentation products (pathway a), whereas nucleophilic trapping by acetonitrile affords a ring expanded oxazine (pathway b). PMID- 23106318 TI - Zoonosis and veterinary control. PMID- 23106319 TI - The veterinary profession and blowfly control. PMID- 23106320 TI - Multisite randomised controlled trial to evaluate polypropylene clips applied to the breech of lambs as an alternative to mulesing. I: effects on body weight, breech bare area measurements and scores, wrinkle scores and faecal and urine staining. AB - OBJECTIVE: To assess the effects of application of occlusive polypropylene clips to lambs on body weight, breech bare area measurements and scores, wrinkle scores, and faecal and urine stain scores. PROCEDURES: A randomised controlled trial using 32,028 lambs was conducted on 208 properties across Australia. Polypropylene clips were applied at lamb marking. At each site, 160 lambs were weighed, measured for breech bare area and scored for bare area, wrinkle, dag and urine staining, and skin type and thickness. Lambs were allocated to a control (no clips) or treatment (breech and tail clips) group. Lambs were assessed on days 14 (range 10-19) and 55 (range 34-129) after clip application for body weight, breech bare area measurements and scores. On day 55 the operators also scored wrinkling and urine staining. RESULTS: At an average of 55 days after treatment, treated ewe and wether lambs had 16% and 21% greater horizontal bare area measurements, and 31.7% and 32.7% higher bare area scores than control lambs, respectively. The ewes and wether lambs also had lower wrinkle (6.8% and 5.8%, respectively) and dag scores (12% and 12.3%, respectively) than controls. Treated ewes had lower urine stain scores (18.8%) than controls. However, body weight was slightly lower in clip-treated lambs compared with controls by 0.320 kg (1.2%) and 0.430 kg (1.6%) for ewes and wethers, respectively. CONCLUSION: Polypropylene clips applied to the breech and tail of lambs increased breech bare area and reduced dag, urine and wrinkle scores. Improvements in these measures of factors that predispose to blowfly strike suggest that the application of clips may reduce the risk of breech flystrike. PMID- 23106321 TI - Multisite randomised controlled trial to evaluate polypropylene clips applied to the breech of lambs as an alternative to mulesing. II: multivariate analysis of relationships between clip treatment and operator, sheep, farm and environmental factors. AB - OBJECTIVE: A multivariate analysis approach was used to evaluate both the effects of application of occlusive polypropylene clips to the breech on bare area measurements and scores of lambs, and the influence of operator, region, sheep, farm and environmental factors on outcomes. PROCEDURES: A randomised controlled trial using 32,028 lambs was conducted on 208 commercial wool-growing properties across Australia. Differences in bare area measurements and scores between groups were estimated and analysed using a mixed model to investigate the effects of operator differences, farm and environmental factors and the interactions among these factors. RESULTS: Clip-treated lambs with higher body weight at visit 1 had higher bare area measures and scores, but lower changes in dag and urine scores. Lambs with tight skin showed improved response in bare area scores and measurements after clip treatment, but lambs with a high wrinkle score at visit 1 showed less response to the treatment in their urine, dag and wrinkle and bare area scores. These effects of the clip treatment were not significantly influenced by estimated fleece fibre diameter, operator or region, but were significantly influenced by farm. CONCLUSIONS: The effect of occlusive clips on breech measurements and scores was significantly influenced by body weight, skin type and thickness, wrinkle score and sex of the lamb, but not by region, operator or estimated fibre diameter. The clip treatment significantly improved characteristics that influence the susceptibility of lambs to flystrike under most conditions. PMID- 23106323 TI - Cyromazine resistance detected in Australian sheep blowfly. AB - OBJECTIVE: To investigate the cause of cyromazine failure to protect lambs from flystrike. METHODS: Lucilia cuprina larvae from a Nimmitabel (New South Wales) population associated with failure of a cyromazine spray-on to protect lambs from flystrike were compared with larvae from a susceptible field strain and a reference susceptible laboratory strain in laboratory bioassays. Batches of neonate blowfly larvae were transferred onto homogenised bovine liver containing varying concentrations of cyromazine or dicyclanil and the numbers of larvae pupating and completing development were recorded. RESULTS: Based on the ability of larvae to complete development on liver homogenate containing 1 mg/kg cyromazine, the phenotypic frequency of resistance in the Nimmitabel population was estimated to be approximately 4%. Compared with a susceptible field strain, the Nimmitabel population was 3-fold more resistant to cyromazine and twice as resistant to dicyclanil at the LC95 level (lethal concentration killing 95% of larvae). In the laboratory, the Nimmitabel strain responded to sequential exposure of larvae to food containing cyromazine by becoming more resistant. Resistance to cyromazine was incompletely dominant, giving resistant larvae a survival advantage over susceptible types over a relatively narrow range of cyromazine concentrations. CONCLUSION: Cyromazine resistance was detected in a field population of L. cuprina. Low-level cross-resistance to dicyclanil was also confirmed. Until more is known about the resistance, the prudent recommendation to control flystrike by this blowfly population is topical treatment with ivermectin. PMID- 23106324 TI - Veterinary infection control in Australia: is there control? AB - There is little information relating to infection control procedures in Australian veterinary practices. This review summarises the findings of international studies in the area of zoonoses and infection control, and discusses potential reasons for the apparent complacency about these issues in veterinary practice. It is the authors' opinion that legislative changes governing veterinary practice in Australia should be implemented. The curricula in veterinary schools should also emphasise infection control. These measures would significantly improve safety issues associated with the control of zoonoses in veterinary practice. PMID- 23106325 TI - Temporary regression of locally invasive polypoid rhinosinusitis in a dog after photodynamic therapy. AB - A 5-year-old male cross-breed dog with chronic rhinosinusitis was presented. Computed tomography (CT) revealed opacities consistent with soft tissue or fluid in the left nasal cavity and frontal sinus. A diagnosis of chronic rhinosinusitis with myxomatous polyps was based on the histology of biopsy samples, so prednisolone treatment was administered for 1 month. Although the clinical signs slightly improved, no changes were observed on the CT images. At 8 months after the initial presentation, the dog was treated with antivascular photodynamic therapy (PDT) using benzoporphyrin derivative monoacid ring A and, 11 days later, CT revealed remarkably decreased soft tissue opacity; the facial swelling and sneezing also resolved. Three additional sessions of PDT were performed at 114, 210, and 303 days after the first PDT because of recurrence of clinical signs. The disease was well controlled for approximately 10 months by antivascular PDT. PMID- 23106326 TI - Comparison of acetate tape impression with squeezing versus skin scraping for the diagnosis of canine demodicosis. AB - This study compared the sensitivity of acetate tape impression and skin squeezing with that of deep skin scraping for the diagnosis of demodicosis in dogs. Demodex canis was detected in 100% of acetate tape impressions obtained after skin squeezing and in 90% of deep skin scrapings. There was a significant difference (P < 0.001) between the techniques in the total number of mites detected. Acetate tape impression with skin squeezing was found to be more sensitive than deep skin scraping and is an alternative diagnostic method for canine demodicosis. PMID- 23106327 TI - Case series of equine pituitary pars intermedia dysfunction in a tropical climate. AB - The clinical manifestations of equine pituitary pars intermedia dysfunction (PPID) in temperate climates are well described. The classic presentation is that of an older animal with hirsutism, laminitis, poor muscle tone, pendulous abdomen and weight loss. This case series highlights the additional clinical signs of anhidrosis and heat stress with secondary exercise intolerance that were seen as primary presenting problems in equids with PPID in the hot, humid conditions of a tropical climate. The clinical signs resolved with medical treatment for PPID. PMID- 23106328 TI - Diagnosis, treatment and outcomes for koala chlamydiosis at a rehabilitation facility (1995-2005). AB - OBJECTIVE: To document the application of diagnostics and treatments at one rehabilitation facility over 10 years and their effects on recovery and post release survival of 88 koalas treated for chlamydiosis, and to highlight associated wildlife care issues with potential significance to animal welfare and disease ecology. DESIGN: Using a retrospective analysis of medical records, we identified risk factors for successful release using a logistic regression model and descriptive statistics. PROCEDURE: We examined the clinical presentation, signalment, diagnostics, treatments, outcomes and whether released koalas were re presented by the end of 2008 indicating post-release survival. RESULTS: Records of 88 koalas were included. Treatments and diagnostics were directed at the anatomical site displaying clinical signs. Younger age and use of ancillary treatments were associated with successful release. The type, route and duration of the treatments used were not those theorised to result in microbial cure. Despite this, approximately 50% of koalas were released and many survived in the wild for extended periods. CONCLUSIONS: Wildlife rehabilitators' records can guide research priorities and the development of care facilities and policies. This study identified the need for more accessible chlamydial diagnostic tests and veterinary support of carers, and the need for a more rigorous assessment of novel therapies. Current treatment regimens appear to be moderately successful in terms of clinical improvement, but it is unclear which aspects are responsible for the success or whether microbial cure is achieved. The long-term effect of released koalas on wild populations requires further study to assess its contribution to the conservation of koala populations. PMID- 23106330 TI - Live exports in the spotlight again. PMID- 23106331 TI - Chemical properties and oxidative stability of perilla oils obtained from roasted perilla seeds as affected by extraction methods. AB - The chemical properties and oxidative stability of perilla oils obtained from roasted perilla seeds as affected by extraction methods (supercritical carbon dioxide [SC-CO(2)], mechanical press, and solvent extraction) were studied. The SC-CO(2) extraction at 420 bar and 50 degrees C and hexane extraction showed significantly higher oil yield than mechanical press extraction (P < 0.05). The fatty acid compositions in the oils were virtually identical regardless of the extraction methods. The contents of tocopherol, sterol, policosanol, and phosphorus in the perilla oils greatly varied with the extraction methods. The SC CO(2) -extracted perilla oils contained significantly higher contents of tocopherols, sterols, and policosanols than the mechanical press-extracted and hexane-extracted oils (P < 0.05). The SC-CO(2) -extracted oil showed the greatly lower oxidative stability than press-extracted and hexane-extracted oils during the storage in the oven under dark at 60 degrees C. However, the photooxidative stabilities of the oils were not considerably different with extraction methods. PMID- 23106332 TI - Small-molecule inhibition of c-MYC:MAX leucine zipper formation is revealed by ion mobility mass spectrometry. AB - The leucine zipper interaction between MAX and c-MYC has been studied using mass spectrometry and drift time ion mobility mass spectrometry (DT IM-MS) in addition to circular dichroism spectroscopy. Peptides comprising the leucine zipper sequence with (c-MYC-Zip residues 402-434) and without a postulated small molecule binding region (c-MYC-ZipDeltaDT residues 406-434) have been synthesized, along with the corresponding MAX leucine zipper (MAX-Zip residues 74 102). c-MYC-Zip:MAX-Zip complexes are observed both in the absence and in the presence of the reported small-molecule inhibitor 10058-F4 for both forms of c MYC-Zip. DT IM-MS, in combination with molecular dynamics (MD), shows that the c MYC-Zip:MAX-Zip complex [M+5H](5+) exists in two conformations, one extended with a collision cross section (CCS) of 1164 +/- 9.3 A(2) and one compact with a CCS of 982 +/- 6.6 A(2); similar values are observed for the two forms of c-MYC ZipDeltaDT:MAX-Zip. Candidate geometries for the complexes have been evaluated with MD simulations. The helical leucine zipper structure previously determined from NMR measurements (Lavigne, P.; et al. J. Mol. Biol. 1998, 281, 165), altered to include the DT region and subjected to a gas-phase minimization, yields a CCS of 1247 A(2), which agrees with the extended conformation we observe experimentally. More extensive MD simulations provide compact complexes which are found to be highly disordered, with CCSs that correspond to the compact form from experiment. In the presence of the ligand, the leucine zipper conformation is completely inhibited and only the more disordered species is observed, providing a novel method to study the effect of interactions of disordered systems and subsequent inhibition of the formation of an ordered helical complex. PMID- 23106333 TI - rTMS over human motor cortex can modulate tremor during movement. AB - Abnormally large tremor during movement is a symptom of many movement disorders and significantly impairs activities of daily living. The aim of this study was to investigate whether repetitive magnetic brain stimulation (rTMS) can reduce tremor size during human movement. We hypothesised that inhibitory rTMS over motor cortex would reduce tremor size during subsequent movement. The study involved 26 healthy young adults (21 +/- 2 years) and began with application of single TMS stimuli to measure baseline corticospinal excitability. The response to stimulation was recorded in hand muscles with electromyography. Subjects then performed a 3-min task to measure baseline tremor during movement. This involved matching index finger position with a moving target on a computer screen. Tremor was recorded with an accelerometer on the fingernail. Finger acceleration was analysed with fast-Fourier transform to quantify tremor in the physiological range (7.8-12.2 Hz). Subjects then received 10 min of real (n = 13) or sham (n = 13) inhibitory rTMS. Tremor and corticospinal excitability were then remeasured. Real rTMS significantly decreased corticospinal excitability by ~30% (P = 0.022) and increased tremor size during movement by ~120% (P = 0.047) relative to sham rTMS. However, the direction of tremor change was opposite to that hypothesised for inhibitory rTMS. The results suggest that rTMS over human motor cortex can modulate action tremor and the level of corticospinal excitability may be important for setting the amplitude of action tremor in healthy young adults. PMID- 23106334 TI - Rapid and complete reconstitution of autologous haemopoiesis after cord blood infusion in treatment-naive patients with severe aplastic anemia receiving high dose cyclophosphamide/ATG therapy. AB - Although high-dose cyclophosphamide seems to achieve durable complete remission, there are still concerns about its too much early toxicity. So, we designed a clinical study to investigate the effects of high-dose cyclophosphamide/ATG combined with cord blood infusion as first-line therapy for patients with severe aplastic anemia. PATIENTS AND METHOD: Between January 2003 and September 2007, we treated 16 treatment-naive patients with severe aplastic anemia with cord blood infusion after high-dose cyclophosphamide (50 mg/kg/d * 2) and rabbit antithymocyte globulin (3 mg/kg/d * 5) therapy. RESULTS: Although only one patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid autologous hematopoietic recovery. The median recovery time for neutrophils and platelets was only 23 and 37 d after infusion of cord blood. Of the 15 responding patients, all patients achieved treatment-free remission: nine patients met the criteria for a complete remission; six patients achieved a partial remission. CONCLUSION: Infusion of cord blood after high-dose cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a high response rate in patients with treatment-naive patients with severe aplastic anemia. These promising results merit further investigation and confirmation on a larger number of patients. PMID- 23106335 TI - Adsorption of N-nitrosodimethylamine precursors by powdered and granular activated carbon. AB - Activated carbon (AC) has been shown to remove precursors of halogenated disinfection byproducts. Granular and powdered activated carbon (GAC, PAC) were investigated for their potential to adsorb N-nitrosodimethylamine (NDMA) precursors from blends of river water and effluent from a wastewater treatment plant (WWTP). At bench scale, waters were exposed to lignite or bituminous AC, either as PAC in bottle point experiments or as GAC in rapid small-scale column tests (RSSCTs). NDMA formation potential (FP) was used as a surrogate for precursor removal. NDMA FP was reduced by 37, 59, and 91% with 3, 8, and 75 mg/L of one PAC, respectively, with a 4-h contact time. In RSSCTs and in full-scale GAC contactors, NDMA FP removal always exceeded that of the bulk dissolved organic carbon (DOC) and UV absorbance at 254 nm. For example, whereas DOC breakthrough exceeded 90% of its influent concentration after 10,000 bed volumes of operation in an RSSCT, NDMA FP was less than 40% of influent concentration after the same bed life of the GAC. At full or pilot scale, high NDMA FP reduction ranging from >60 to >90% was achieved across GAC contactors, dependent upon the GAC bed life and/or use of a preoxidant (chlorine or ozone). In all experiments, NDMA formation was not reduced to zero, which suggests that although some precursors are strongly sorbed, others are not. This is among the first studies to show that AC is capable of adsorbing NDMA precursors, but further research is needed to better understand NDMA precursor chemical properties (e.g., hydrophobicity, molecular size) and evaluate how best to incorporate this finding into full-scale designs and practice. PMID- 23106336 TI - Gold-coated silver dendrites as SERS substrates with an improved lifetime. AB - Nanostructured silver is known to yield the highest signal-enhancement factors in surface-enhanced Raman spectroscopy, but its low chemical stability toward oxidation presents a challenge in the realization of Ag-based SERS substrates with long operating lifetimes. Here, a study of the long-term stability of silver dendrites as SERS substrates is reported. SERS spectra of 1,2-benzenedithiol monolayers on Ag dendrites, acquired over a period of time in excess of 1 year, shows appreciable degradation with time. However, no degradation is observed in the spectra of monolayers deposited on Ag dendrites that were coated with a monolayer-thin Au film deposited by an immersion plating process. X-ray photoelectron spectra confirm the oxidation of the uncoated Ag dendrites whereas no chemical changes are detected in the Au-coated ones. These results suggest that the galvanic displacement of Au on preformed Ag nanostructures provides a suitable route to producing SERS-active substrates with long operating and/or shelf lifetimes. PMID- 23106338 TI - Incidence, clinical characteristics and outcome in Norwegian children with periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; a population-based study. AB - AIM: To describe the incidence, epidemiology, clinical presentation and clinical outcome of children with the syndrome of periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) in a population-based study. METHODS: In a prospective population-based study, all children in South Rogaland, Norway, diagnosed with PFAPA during 2004-2010 were evaluated clinically, and parents were interviewed systematically. A follow-up interview was performed for all patients. RESULTS: A total of 46 children (32 boys; p = 0.011) were diagnosed with PFAPA. We calculated an incidence of 2.3 per 10 000 children up to 5 years of age. The median age of onset was 11.0 months (quartiles: 5.0, 14.8). Nearly 37 children were followed until resolution. In 17 of these, a tonsillectomy was performed with prompt resolution of PFAPA in all. The median age of spontaneous resolution was 60.2 months (range 24-120) and in children with tonsillectomy 50.9 months (range 15-128). CONCLUSION: The incidence of PFAPA was 2.3 per 10 000 children up to 5 years of age. In the majority of cases, onset of symptoms may be during the first year of life. PMID- 23106337 TI - Sphingosine 1-phosphate induces filopodia formation through S1PR2 activation of ERM proteins. AB - Previously we demonstrated that the sphingolipids ceramide and S1P (sphingosine 1 phosphate) regulate phosphorylation of the ERM (ezrin/radixin/moesin) family of cytoskeletal proteins [Canals, Jenkins, Roddy, Hernande-Corbacho, Obeid and Hannun (2010) J. Biol. Chem. 285, 32476-3285]. In the present article, we show that exogenously applied or endogenously generated S1P (in a sphingosine kinase dependent manner) results in significant increases in phosphorylation of ERM proteins as well as filopodia formation. Using phosphomimetic and non phosphorylatable ezrin mutants, we show that the S1P-induced cytoskeletal protrusions are dependent on ERM phosphorylation. Employing various pharmacological S1PR (S1P receptor) agonists and antagonists, along with siRNA (small interfering RNA) techniques and genetic knockout approaches, we identify the S1PR2 as the specific and necessary receptor to induce phosphorylation of ERM proteins and subsequent filopodia formation. Taken together, the results demonstrate a novel mechanism by which S1P regulates cellular architecture that requires S1PR2 and subsequent phosphorylation of ERM proteins. PMID- 23106339 TI - Site-specific S-nitrosylation of integrin alpha6 increases the extent of prostate cancer cell migration by enhancing integrin beta1 association and weakening adherence to laminin-1. AB - The increased mortality in prostate cancer is usually the result of metastatic progression of the disease from the organ-confined location. Among the major events in this progression cascade are enhanced cell migration and loss of adhesion. Moreover, elevated levels of nitric oxide (NO) and inducible nitric oxide synthase (iNOS) found within the tumor microenvironment are hallmarks of progression of this cancer. To understand the role of nitrosative stress in prostate cancer progression, we investigated the effects of NO and iNOS on prostate cancer cell migration and adhesion. Our results indicate that ectopic expression of iNOS in prostate cancer cells increased the extent of cell migration, which could be blocked by selective ITGalpha6 blocking antibody or iNOS inhibitors. Furthermore, iNOS was found to cause S-nitrosylation of ITGalpha6 at Cys86 in prostate cancer cells. By comparing the activities of wild type ITGalpha6 and a Cys86 mutant, we showed that treatment of prostate cancer cells with NO increased the level of ITGalpha6 heterodimerization with ITGbeta1 but not with ITGbeta4. Finally, S-nitrosylation of ITGalpha6 weakened its binding to laminin-beta1 and weakened the adhesion of prostate cancer cells to laminin-1. In conclusion, S-nitrosylation of ITGalpha6 increased the extent of prostate cancer cell migration, which could be a potential mechanism of NO- and iNOS induced enhancement of prostate cancer metastasis. PMID- 23106340 TI - Diabetes self-management, depressive symptoms, quality of life and metabolic control in youth with type 1 diabetes in China. AB - AIMS AND OBJECTIVES: To assess diabetes self-management, depressive symptoms, quality of life and metabolic control in a cohort of youth with type 1 diabetes in mainland China. Predictors of self-management and depressive symptoms were also explored. BACKGROUND: Studies have shown that adaptation to childhood chronic illness is important in determining outcomes. Few studies have been reported on the behavioural, psychosocial and physiological adaptation processes and outcomes in Chinese youth with type 1 diabetes. DESIGN: This is a cross sectional study as part of a multi-site longitudinal descriptive study. Data for this report were collected at baseline. METHODS: A convenience sample of 136 eligible youth was recruited during follow-up visits in hospitals in 14 major cities of Hunan Province (located in central southern mainland China) from July 2009-October 2010. Data were collected on socio-demographic background, clinical characteristics, diabetes self-management, depressive symptoms, quality of life and metabolic control. RESULTS: Diabetes self-management was lower in Chinese youth compared with a US cohort and was associated with insulin treatment regimen, treatment location, depressive symptoms and gender. A total of 17.6% of youth reported high depressive symptoms, and depressive symptoms were correlated with family annual revenue, school attendance, peer relationship and parent-child relationship. The mean score of global satisfaction with quality of life was 17.14 +/- 3.58. The mean HbA1c was 9.68%. CONCLUSIONS: Living with type 1 diabetes poses considerable challenges, and Chinese youth report lower self management than US youth and high depressive symptoms. Metabolic control and quality of life were sub-optimal. RELEVANCE TO CLINICAL PRACTICE: More clinic visits, treatment for high depressive symptoms and an intensive insulin regimen may improve diabetes self-management for youth with type 1 diabetes in China. Culturally appropriate interventions aimed at helping them adapt to living with the disease and improving outcomes are urgently needed. PMID- 23106343 TI - Atopic dermatitis 2.0: from the clinical phenotype to the molecular taxonomy and stratified medicine. AB - Atopic dermatitis (AD) is a paradigmatic inflammatory chronic skin disease. As for other chronic skin diseases, (i) the spectrum of the clinical phenotype and severity as well as (ii) the genetic background and (iii) the underlying mechanisms strongly suggest a high degree of pathophysiological heterogeneity yet leading to a similar clinical pattern, that is, the eczematous skin lesion, but showing distinct progression patterns. This review suggests to exploit the recent knowledge about AD for a novel approach proposing a tentative first molecular taxonomy of this disease based on the genotype and endophenotype. The consequences in terms of personalized prevention and management are delineated. PMID- 23106342 TI - Early onset absence epilepsy: 1 in 10 cases is caused by GLUT1 deficiency. AB - Glucose transporter 1 (GLUT1) deficiency caused by mutations of SLC2A1 is an increasingly recognized cause of genetic generalized epilepsy. We previously reported that >10% (4 of 34) of a cohort with early onset absence epilepsy (EOAE) had GLUT1 deficiency. This study uses a new cohort of 55 patients with EOAE to confirm that finding. Patients with typical absence seizures beginning before 4 years of age were screened for solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) mutations or deletions. All had generalized spike waves on electroencephalography (EEG). Those with tonic and/or atonic seizures were excluded. Mutations were found in 7 (13%) of 55 cases, including five missense mutations, an in-frame deletion leading to loss of a single amino acid, and a deletion spanning two exons. Over both studies, 11 (12%) of 89 probands with EOAE have GLUT1 deficiency. Given the major treatment and genetic counseling implications, this study confirms that SLC2A1 mutational analysis should be strongly considered in EOAE. PMID- 23106341 TI - Altered fate of tendon-derived stem cells isolated from a failed tendon-healing animal model of tendinopathy. AB - We hypothesized that altered fate of tendon-derived stem cells (TDSCs) might contribute to chondro-ossification and failed healing in the collagenase-induced (CI) tendon injury model. This study aimed to compare the yield, proliferative capacity, immunophenotypes, senescence, and differentiation potential of TDSCs isolated from healthy (HT) and CI tendons. TDSCs were isolated from CI and healthy Sprague-Dawley rat patellar tendons. The yield, proliferative capacity, immunophenotypes, and senescence of TDSCs (CI) and TDSCs (HT) were compared by colony-forming unit assay, BrdU assay, flow cytometry, and beta-galactosidase activity assay, respectively. Their osteogenic and chondrogenic differentiation potentials and mRNA expression of tendon-related markers were compared using standard assays. More TDSCs, which showed a lower proliferative potential and a higher cellular senescence were present in the CI patellar tendons compared to HT tendons. There was a higher alkaline phosphatase activity and mineralization in TDSCs (CI) in both basal and osteogenic media. More chondrocyte-like cells and higher proteoglycan deposition, Sox9 and collagen type II expression were observed in TDSCs (CI) pellets upon chondrogenic induction. There was a higher protein expression of Sox9, but a lower mRNA expression of Col1a1, Scx, and Tnmd in TDSCs (CI) in a basal medium. In conclusion, TDSCs (CI) showed altered fate, a higher cellular senescence, but a lower proliferative capacity compared to TDSCs (HT), which might contribute to pathological chondro-ossification and failed tendon healing in this animal model. PMID- 23106345 TI - Dynamics in N-isopropylacrylamide-acrylic acid copolymer aqueous solution from mechanical spectroscopy. AB - Gaining control over precise and predictable structures of colloidal systems and understanding the abundant dynamic behaviors remains a formidable challenge. In this study, low-frequency mechanical spectroscopy was applied to investigate the dynamics of aqueous solutions of N-isopropylacrylamide-acrylic acid (NIPAM-AA) copolymers with three different AA contents. A mechanical loss valley was found for the solution with low molar fraction of AA (f(AA)), f(AA) = 25 and 50 mol %, and a loss peak was shown for the solution with f(AA) = 75 mol %. The former is suggested to be due to the particle glass phase of repulsive micelles above the low critical solution temperature, whereas the latter is associated with the alpha relaxation behavior of NIPAM-AA/water mixture at high concentrations. The relaxation time of the alpha relaxation seems to follow a simple Arrhenius temperature dependence. The activation energy H is ~53 kJ/mol, and the larger H value is suggested to be due to multiple strong hydrogen bonds in the copolymer solution. The present work demonstrates that by controlling the proportion of ingredients in the colloidal systems the systems can exhibit distinct dynamic behaviors, which is helpful in the design and fabrication of colloids. PMID- 23106346 TI - Studying dissolution with a model integrating solid-liquid interface kinetics and diffusion kinetics. AB - A dissolution model that integrates the solid-liquid interface kinetics and the mass transport kinetics is introduced. Such a model reduces to the Noyes-Whitney equation under special conditions, but offers expanded range of applicability and flexibility fitting dissolution profiles when interfacial kinetics and interfacial concentration deviate from the assumptions implied in the Noyes Whitney equation. General solutions to the integrated dissolution model derived for noninteractive solutes as well as for solutes participating in ionization equilibrium are discussed. Parameters defining the integrated dissolution model are explained conceptually along with practical ways for their determinations. Conditions under which the model exhibits supersaturation features are elaborated. Simulated dissolution profiles using the integrated dissolution model for published experimental data exhibiting supersaturation features are illustrated. PMID- 23106347 TI - Treatment of atopic keratoconjunctivitis in patients with atopic dermatitis: is ocular application of tacrolimus an option? PMID- 23106348 TI - Postprandial cardiac autonomic function in Prader-Willi syndrome. AB - CONTEXT: Individuals with Prader-Willi syndrome (PWS) have a high cardiovascular risk, the mechanism of which is unclear. There may be dysfunction in the autonomic nervous system (ANS) in PWS. OBJECTIVE: To measure, as indicators of cardiac autonomic function, postprandial heart rate variability (HRV) and arterial stiffness in adults with PWS. METHODS: Ten adults with PWS were compared with 11 matched healthy obese subjects and 9 healthy lean subjects. Electrocardiographic traces and arterial stiffness were recorded over a period of 10 minutes at -60, 0, 30, 60, 120 and 240 minutes after consumption of a standardized 600-kCal breakfast. Frequency domain analysis was performed using fast Fourier transform to estimate power spectral density in the full spectrum and in low-frequency (LF 0.04-0.15 Hz) and high-frequency (HF 0.15-0.40 Hz) bands. RESULTS: ANCOVA revealed a reduced LF HRV meal response in adults with PWS compared with obese controls, with no differences in HF HRV, LF/HF ratio, heart rate, total power or arterial stiffness meal responses. CONCLUSIONS: This study assessed cardiac autonomic function in adults with PWS compared with matched obese and lean subjects in response to a meal. Results suggest impaired postprandial ANS responsiveness in PWS, which could contribute to both the known increased cardiovascular risk and obesity. PMID- 23106349 TI - Polyphenols extracted from black tea (Camellia sinensis) residue by hot compressed water and their inhibitory effect on pancreatic lipase in vitro. AB - Polyphenols, retained in black tea wastes following the commercial production of tea beverages, represent an underutilized resource. The purpose of this study was to investigate the potential use of hot-compressed water (HCW) for the extraction of pancreatic lipase-inhibiting polyphenols from black tea residues. Black tea residues were treated with HCW at 10 degrees C intervals, from 100 to 200 degrees C. The resulting extracts were analyzed using high-performance liquid chromatography-mass spectrometry and assayed to determine their inhibitory effect on pancreatic lipase activity in vitro. Four theaflavins (TF), 5 catechins, 2 quercetin glycosides, quinic acid, gallic acid, and caffeine were identified. The total polyphenol content of extracts increased with increasing temperature but lipase inhibitors (TF, theaflavin 3-O-gallate, theaflavin 3'-O-gallate, theaflavin 3,3'-O-gallate, epigallocatechin gallate, and epicatechin gallate) decreased over 150 degrees C. All extracts inhibited pancreatic lipase but extracts obtained at 100 to 140 degrees C showed the greatest lipase inhibition (IC(50) s of 0.9 to 1.3 MUg/mL), consistent with the optimal extraction of TFs and catechins except catechin by HCW between 130 and 150 degrees C. HCW can be used to extract pancreatic lipase-inhibiting polyphenols from black tea waste. These extracts have potential uses, as dietary supplements and medications, for the prevention and treatment of obesity. PMID- 23106350 TI - Copper-catalyzed enantioselective allylic substitution with alkylboranes. AB - The first catalytic enantioselective allylic substitution reaction with alkylboron compounds has been achieved. The reaction between alkyl-9-BBN reagents and primary allylic chlorides proceeded with excellent gamma-selectivities and high enantioselectivities under catalysis of a Cu(I)-DTBM-SEGPHOS system. The protocol produces terminal alkenes with an allylic stereogenic center branched with functionalized sp(3)-alkyl groups. The reaction with a gamma-silicon substituted allyl chloride affords an efficient strategy for the enantioselective synthesis of functionalized alpha-stereogenic chiral allylsilanes. PMID- 23106351 TI - How cutaneous eruptions help to understand the mode of action of kinase inhibitors. PMID- 23106352 TI - 'Is it safe?' Safety is a process, not a question. PMID- 23106353 TI - Direct primary closure without undermining in the repair of vermilionectomy defects of the lower lip. PMID- 23106354 TI - Site-specific immunophenotyping of keloid disease demonstrates immune upregulation and the presence of lymphoid aggregates. AB - BACKGROUND: Keloid disease (KD) is a common fibroproliferative disorder of unknown aetiology. T cells and macrophages are increased in KD and are thought to contribute to its pathogenesis. However, while a link between inflammation and fibrotic disorders is well known for other disorders, it remains undetermined in KD. OBJECTIVES: Systematically to immunophenotype the inflammatory infiltrate of KD in situ in a site-specific manner, and to compare this with normal skin and scar tissue. METHODS: Sixty-eight keloid cases were screened for the presence of all three (intralesional, perilesional and extralesional) keloid-associated specific tissue sites. Subsequently, a complete set of 25 keloid biopsies (from different patients) was compared with normal skin (n = 11) and normal scar (n = 11) samples and subjected to systematic, site-specific quantitative immunohistomorphometry and histochemistry, using a range of immunological markers of B cells, T cells, macrophages, mast cells (MCs) and Langerhans cells. RESULTS: T cells, B cells, degranulated and mature MCs (coexpressing OX40 ligand) and alternative macrophages (M2) were all significantly increased in intralesional and perilesional KD sites compared with normal skin and scar tissue (P < 0.05). Additionally, 10 of 68 KD cases (15%) showed the presence of distinctive lymphoid aggregates, which resembled mucosa-associated lymphoid tissue (MALT). CONCLUSIONS: The increased number and activity of MCs and M2 may implicate inflammation in the fibrotic process in KD. The distinct KD-associated lymphoid aggregate resembles MALT, for which we propose the term 'keloid-associated lymphoid tissue' (KALT). It may perpetuate inflammatory stimuli that promote KD growth. KALT, MCs and M2 are promising novel targets for future KD therapy. PMID- 23106355 TI - UV-initiated hydrosilylation on hydrogen-terminated silicon (111): rate coefficient increase of two orders of magnitude in the presence of aromatic electron acceptors. AB - UV-initiated (254 nm) hydrosilylation of hexadecene on Si(111)-H has been studied in the presence of various aliphatic and aromatic molecules (additives). Many of these additives cause an enhancement in the pseudo-first-order rate coefficient (k(obs)) of hydrosilylation, some up to 200* faster than observed in neat hexadecene. It is proposed that these additives capture the photoejected electron from the surface, thereby increasing the probability of reaction of the alkene with the surface hole (h(+)), leading to Si-C bond formation. While the ability of these additives to increase k(obs) is related to their reduction potential, aromatic additives are particularly efficient; we suspect this is due to the relatively strong physisorption of the aromatic molecules leading to a favorable geometry for electron transfer. The presence of these additives permits the use of a much lower intensity of UV light (~30 MUW/cm(2)), reducing the probability of photodegradation of the monolayer, and maximum coverage can be reached within minutes. PMID- 23106356 TI - Application of a Raney-cobalt-mediated tandem reductive cyclization protocol to total syntheses of the Aspidosperma alkaloids (+/-)-limaspermidine and (+/-)-1 acetylaspidoalbidine. AB - The racemic modification of the Aspidosperma alkaloid limaspermidine (1) has been prepared in ten steps including one involving a Raney-cobalt-mediated tandem reductive cyclization of nitrile 8 to give the tetracyclic system 9b. Compound (+/-)-1 has been converted over two steps into (+/-)-1-acetylaspidoalbidine [(+/ )-13]. PMID- 23106357 TI - Introgression and selection shaping the genome and adaptive loci of weedy rice in northern China. AB - As a weed of rice paddy fields, weedy rice has spread worldwide. In northern China, the expansion of weedy rice has been rapid over the past two decades. Its evolutionary history and adaptive mechanisms are poorly understood. Evolutionary relationships between northern weedy rice and rice cultivars were analyzed using presumed neutral markers sampled across the rice genome. Genes involved in rice domestication were evaluated for their potential roles in weedy rice adaptation. Seed longevity, a critical trait of weedy rice, was examined in an F(2) population derived from a cross between weedy rice and a rice cultivar to evaluate weedy rice adaptation and the potential effect of candidate genes. Weedy rice in northern China was not derived directly from closely related wild Oryza species or from the introgression of indica subspecies. Introgression with local cultivars, coupled with selection that maintained weedy identity, shaped the evolution of weedy rice in northern China. Weedy rice is a unique system with which to investigate how weedy plants adapt to an agricultural environment. Our finding that extensive introgression from local cultivars, combined with the continuing ability to maintain weedy genes, is characteristic of weedy rice in northern China provides a clue for the field control of weedy rice. PMID- 23106358 TI - alpha-1-C-butyl-1,4-dideoxy-1,4-imino-l-arabinitol as a second-generation iminosugar-based oral alpha-glucosidase inhibitor for improving postprandial hyperglycemia. AB - We report on the synthesis and the biological evaluation of a series of alpha-1-C alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis of the derivatives was achieved by asymmetric allylic alkylation, ring closing metathesis, and Negishi cross-coupling as key reactions. alpha-1-C-Butyl LAB is a potent inhibitor of intestinal maltase, isomaltase, and sucrase, with IC50 values of 0.13, 4.7, and 0.032 MUM, respectively. Matrix-assisted laser desorption ionization time-of-flight mass spectrometric analysis revealed that this compound differs from miglitol in that it does not influence oligosaccharide processing and the maturation of glycoproteins. A molecular docking study of maltase-glucoamylase suggested that the interaction modes and the orientations of alpha-1-C-butyl-LAB and miglitol are clearly different. Furthermore, alpha-1-C butyl-LAB strongly suppressed postprandial hyperglycemia at an early phase, similar to miglitol in vivo. It is noteworthy that the effective dose was about 10-fold lower than that for miglitol. alpha-1-C-Butyl-LAB therefore represents a new class of promising compounds that can improve postprandial hyperglycemia. PMID- 23106359 TI - Within-river phosphorus retention: accounting for a missing piece in the watershed phosphorus puzzle. AB - The prevailing "puzzle" in watershed phosphorus (P) management is how to account for the nonconservative behavior (retention and remobilization) of P along the land-freshwater continuum. This often hinders our attempts to directly link watershed P sources with their water quality impacts. Here, we examine aspects of within-river retention of wastewater effluent P and its remobilization under high flows. Most source apportionment methods attribute P loads mobilized under high flows (including retained and remobilized effluent P) as nonpoint agricultural sources. We present a new simple empirical method which uses chloride as a conservative tracer of wastewater effluent, to quantify within-river retention of effluent P, and its contribution to river P loads, when remobilized under high flows. We demonstrate that within-river P retention can effectively mask the presence of effluent P inputs in the water quality record. Moreover, we highlight that by not accounting for the contributions of retained and remobilized effluent P to river storm-flow P loads, existing source apportionment methods may significantly overestimate the nonpoint agricultural sources and underestimate wastewater sources in mixed land-use watersheds. This has important implications for developing effective watershed remediation strategies, where remediation needs to be equitably and accurately apportioned among point and nonpoint P contributors. PMID- 23106360 TI - Spectrum of mutations in gastrointestinal stromal tumor patients - a population based study from Slovakia. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract and are characterized by presence of mutations in tyrosine kinases cKIT (KIT) and PDGFRalpha (PDGFRA). Mutations identified are highly heterogeneous, but some mutations are associated with specific clinical features of the tumor. Samples from 278 GIST patients collected during the period 2004-2011 were screened for mutations in exons 9, 11, 13, and 17 of KIT and 12, 14 and 18 of PDGFRA. Results of mutation screening were summarized and tested for possible association with clinical parameters of tumors. Mutations were identified in 83.81% of patients. Most frequent mutations were found in KIT exon 11 reaching frequency of 62.95%. Other exons contributed to the mutation pool with frequencies 8.27%, 7.55%, 2.52%, 1.44%, 1.08%, and 0.00%, in decreasing order KIT exon 9, PDGRFA exons 18 and 12, KIT exon 13, PDGFRA exon 14, and KIT exon 17. General linear model analysis showed no effect of any individual analyzed mutation on the phenotypic variables, but we confirmed association between mutations KIT exon 9 p. 503-504_dup2, and PDGFRA exon 18 p. D842V and intestinal and gastric localization of tumors. PMID- 23106362 TI - Amino-imino adenine tautomerism induced by the cooperative effect between metal ion and H2O/NH3. AB - Tautomerization processes of amino-imino adenine isomer (A -> A1) in five different environments are studied by the density functional theory (B3LYP) method. The five environments are metal ion (M, M = K(+), Na(+), Cu(+), Zn(+), Ca(2+), Mg(2+), Cu(2+), Zn(2+)) coordinated bidentate system, either monowater (W) or monoammonia (N) attached system, both metal ion and monowater cooperative system (M-W), and both metal ion and monoammonia cooperative system (M-N). Results show that the complexes formed by noncanonical rare imino form A1 are more stable than those formed by the canonical amino one in most of these environments. The tautomerization of A -> A1 becomes quite easy in either M-W or M-N system. It is noteworthy that under divalent M-N environment the A -> A1 process meets with particularly lower and even free energy barrier, indicating the instability of the amino adenine isomer and probable existence of more stable imino adenine isomer. Expanding studies for the microhydration at the metal ion of the M-N system predict the required number (n) of water molecules to remain the amino adenine isomer A (AMNnW) stable. The number of n is 2, 3, 3, and 4 for M = Ca(2+), Zn(2+), Cu(2+), and Mg(2+), respectively. The present study provides further understanding for the amino-imino tautomerization behavior of the most stable adenine under the influence of several related closely factors, and is useful for rational design of these different environments for the purposes of prevention and control of pyrimidines mispairing, which is responsible for the mutagenic properties of the nucleic acid bases. PMID- 23106363 TI - Slow unfolding pathway of hyperthermophilic Tk-RNase H2 examined by pulse proteolysis using the stable protease Tk-subtilisin. AB - The unfolding speed of some hyperthermophilic proteins is significantly slower than those of their mesostable homologues. Ribonuclease H2 from the hyperthermophilic archaeon Thermococcus kodakarensis (Tk-RNase H2) is stabilized by its remarkably slow unfolding rate. In this work, we examined the slow unfolding pathway of Tk-RNase H2 by pulse proteolysis using a superstable subtilisin-like serine protease from T. kodakarensis (Tk-subtilisin). Tk subtilisin has enzymatic activity in highly concentrated guanidine hydrochloride (GdnHCl), in which Tk-RNase H2 unfolds slowly. The native state of Tk-RNase H2 was completely resistant to Tk-subtilisin, whereas the unfolded state (induced by 4 M GdnHCl) was degraded by Tk-subtilisin. Degradation products of Tk-RNase H2 created from pulse proteolysis during its unfolding were detected by tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis. We identified the cleavage sites in Tk-RNase H2 by N-terminal sequencing and mass spectrometry and constructed mimics of the unfolding intermediate of Tk-RNase H2 by protein engineering. The mimics were biophysically characterized. We found that the native state of Tk-RNase H2 (N-state) changed to the I(A)-state that was digested by Tk-subtilisin in the early stage of unfolding. In the slow unfolding pathway, the I(A)-state shifted to two intermediate forms, I(B)-state and I(C)-state. The I(B)-state was digested by Tk-subtilisin in the C-terminal region, but the I(C) state was a Tk-subtilisin resistant form. These states gradually unfolded through the I(D)-state, in which the N-terminal region was digested. The results indicate that pulse proteolysis, by a superstable protease, was a suitable strategy and an effective tool for analyzing intermediate structures of proteins with slow unfolding properties. We also showed that the N-terminal region contributes to the slow unfolding of Tk-RNase H2, and the C-terminal region is important for folding and stability. PMID- 23106364 TI - Novel insights into mechanisms of food allergy and allergic airway inflammation using experimental mouse models. AB - Over the last decades, considerable efforts have been undertaken in the development of animal models mimicking the pathogenesis of allergic diseases occurring in humans. The mouse has rapidly emerged as the animal model of choice, due to considerations of handling and costs and, importantly, due to the availability of a large and increasing arsenal of genetically modified mouse strains and molecular tools facilitating the analysis of complex disease models. Here, we review latest developments in allergy research that have arisen from in vivo experimentation in the mouse, with a focus on models of food allergy and allergic asthma, which constitute major health problems with increasing incidence in industrialized countries. We highlight recent novel findings and controversies in the field, most of which were obtained through the use of gene-deficient or germ-free mice, and discuss new potential therapeutic approaches that have emerged from animal studies and that aim at attenuating allergic reactions in human patients. PMID- 23106361 TI - Effects of the alpha2-adrenergic receptor agonist dexmedetomidine on neural, vascular and BOLD fMRI responses in the somatosensory cortex. AB - This article describes the effects of dexmedetomidine (DEX) - the active ingredient of medetomidine, which is the latest popular sedative for functional magnetic resonance imaging (fMRI) in rodents - on multiple unit activity, local field potential (LFP), cerebral blood flow (CBF), pial vessel diameter [indicative of cerebral blood volume (CBV)], and blood oxygenation level dependent (BOLD) fMRI. These measurements were obtained from the rat somatosensory cortex during 10 s of forepaw stimulation. We found that the continuous intravascular systemic infusion of DEX (50 MUg/kg/h, doses typically used in fMRI studies) caused epileptic activities, and that supplemental isoflurane (ISO) administration of ~0.3% helped to suppress the development of epileptic activities and maintained robust neuronal and hemodynamic responses for up to 3 h. Supplemental administration of N(2)O in addition to DEX nearly abolished hemodynamic responses even if neuronal activity remained. Under DEX + ISO anesthesia, spike firing rate and the delta power of LFP increased, whereas beta and gamma power decreased, as compared with ISO-only anesthesia. DEX administration caused pial arteries and veins to constrict nearly equally, resulting in decreases in baseline CBF and CBV. Evoked LFP and CBF responses to forepaw stimulation were largest at a frequency of 8-10 Hz, and a non-linear relationship was observed. Similarly, BOLD fMRI responses measured at 9.4 T were largest at a frequency of 10 Hz. Both pial arteries and veins dilated rapidly (artery, 32.2%; vein, 5.8%), and venous diameter returned to baseline slower than arterial diameter. These results will be useful for designing, conducting and interpreting fMRI experiments under DEX sedation. PMID- 23106365 TI - Performance evaluation of different design alternatives for microfabricated nonporous fused silica pillar columns for capillary electrochromatography. AB - An experimental study comparing the performance of different designs for microfabricated column structures for microchip capillary electrochromatography is presented. The work is a follow-up to our previously published modeling and simulation study on the same topic. Experiments were performed using fused silica microchips with and without octadecyltrimethoxysilane coating for nonretained and retained modes of operation, respectively. Showing the same trends as the modeling results, the foil shape produces a significant decrease in plate height with an increase of around 15% in mobile phase velocity in nonretained measurements of Coumarin 480 (C480). Measured plate heights at 1 kV/cm applied electric field were 0.77, 1.33, and 1.42 MUm for foil, diamond, and hexagon, respectively. Chromatographic runs of C480 yielded minimal plate height values of 1.85 and 3.28 MUm for foil and diamond, respectively. The optimization of the shape and placement of the structures appeared to have a considerable impact on the achievable performance. PMID- 23106366 TI - Hepatitis C virus infection and diabetes: not a straightforward relationship. PMID- 23106367 TI - Can fish oil dissolve gallstones? PMID- 23106368 TI - Pro-oxidants or anti-oxidant defenses? Which one to blame in non-alcoholic steatohepatitis pathogenesis? PMID- 23106369 TI - Education and Imaging: gastrointestinal: eosinophilic ascites. PMID- 23106370 TI - Education and Imaging: gastrointestinal: outbreak; proctocolitis mimicking inflammatory bowel disease. PMID- 23106371 TI - Education and Imaging: hepatobiliary and pancreatic: primary bile duct lymphoma. PMID- 23106372 TI - Coordination of word recognition and oculomotor control during reading: the role of implicit lexical decisions. AB - The coordination of word-recognition and oculomotor processes during reading was evaluated in eye-tracking experiments that examined how word skipping, where a word is not fixated during first-pass reading, is affected by the lexical status of a letter string in the parafovea and ease of recognizing that string. Ease of lexical recognition was manipulated through target-word frequency (Experiment 1) and through repetition priming between prime-target pairs embedded in a sentence (Experiment 2). Using the gaze-contingent boundary technique the target word appeared in the parafovea either with full preview or with transposed-letter (TL) preview. The TL preview strings were nonwords in Experiment 1 (e.g., bilnk created from the target blink), but were words in Experiment 2 (e.g., sacred created from the target scared). Experiment 1 showed greater skipping for high frequency than low-frequency target words in the full preview condition, but not in the TL preview (nonword) condition. Experiment 2 showed greater skipping for target words that repeated an earlier prime word than for those that did not, with this repetition priming occurring both with preview of the full target and with preview of the target's TL neighbor word. However, time to progress from the word after the target was greater following skips of the TL preview word, whose meaning was anomalous in the sentence context, than following skips of the full preview word whose meaning fit sensibly into the sentence context. Together, the results support the idea that coordination between word-recognition and oculomotor processes occurs at the level of implicit lexical decisions. PMID- 23106373 TI - Contingent involuntary motoric inhibition: the involuntary inhibition of a motor response contingent on top-down goals. AB - Effective motor control involves both the execution of appropriate responses and the inhibition of inappropriate responses that are evoked by response-associated stimuli. The inhibition of a motor response has traditionally been characterized as either a voluntary act of cognitive control or a low-level perceptual bias arising from processes such as inhibition of return and priming. Involuntary effects of top-down goals on motoric inhibition have been reported, but involve the perseveration of an inhibitory strategy. It is unknown whether the inhibition of a motor response can be selectively triggered by a goal-relevant stimulus, reflecting the automatic activation of a top-down inhibitory strategy. Here we show that irrelevant flankers that share the color of a no-go target elicit the inhibition of their associated motor response while other-colored flankers do not, even when participants have sufficient time to prepare for the upcoming target while ignoring the flankers. Our results demonstrate contingent involuntary motoric inhibition: motoric inhibition can be automatically triggered by a stimulus based on top-down goals. PMID- 23106374 TI - Exogenous attentional capture by subliminal abrupt-onset cues: evidence from contrast-polarity independent cueing effects. AB - In the present study, we tested whether subliminal abrupt-onset cues capture attention in a bottom-up or top-down controlled manner. For our tests, we varied the searched-for target-contrast polarity (i.e., dark or light targets against a gray background) over four experiments. In line with the bottom-up hypothesis, our results indicate that subliminal-onset cues capture attention independently of the searched-for target-contrast polarity (Experiment 1), and this effect is not stronger for targets that matched the searched-for target-contrast polarity (Experiment 2). In fact, even to-be-ignored cues associated with a no-go response captured attention in a salience-driven way (Experiment 3). For supraliminal cues, we found attentional capture only by cues with a matching contrast polarity, reflecting contingent capture (Experiment 4). The results point toward a specific role of subliminal abrupt onsets for attentional capture. PMID- 23106375 TI - Two mechanisms of distractor dilution: visual selection in a continuous flow. AB - Distractor dilution, which reflects little distractor interference in a context of high display load but easy target processing, has sparked debate between theoretical viewpoints. These two viewpoints can be integrated into a model in which grouping and the efficacy of attention control influence the relative activation strength between the distractor and nontarget representations. In a context in which nontargets and a distractor were presented in separate task irrelevant regions, the dilution effect was replicated when nontargets were grouped with the target, and the effect was reduced when the distractor was grouped with the target (Experiments 1 to 3). When nontargets were presented in a task-relevant region and the distractor was presented in a task-irrelevant region, the dilution effect was replicated when attention control was effective in accumulating nontarget information (Experiment 4b). The dilution effect was reduced when control was ineffective in a short stimulus duration of 50 ms (Experiment 4a), in a circular arrangement of stimuli (Experiment 5), or in a context in which the distractor location was random (Experiment 6). The dilution effect occurred either before (Experiment 1b) or after (Experiment 4b) the engagement of attention control on a continuum of visual selection through bottom up and top-down process interactions. PMID- 23106376 TI - Two new oxidation products obtained from the biotransformation of asiatic acid by the fungus Fusarium avenaceum AS 3.4594. AB - Asiatic acid (AA) is a natural triterpenoid possessing anti-inflammatory, anticancer, neuroprotective, and hepatoprotective activities. Structural modification of AA may provide valuable information for further structure activity relationship analysis. Biotransformation is an efficient, specific, and environment friendly technology for structural modification of complicated natural products. In this study, the capabilities of twenty-five strains of filamentous fungi to transform AA were screened. Two new and one known oxidation products metabolized by Fusarium avenaceum AS 3.4594 were isolated. Their chemical structures were characterized as 2-oxo-3beta,15alpha,23-trihydroxyurs-12 en-28-oic acid (1), 3-oxo-2,15alpha,23-trihydroxyurs-1,12-dien-28-oic acid (2), and 2-oxo-3beta,23-dihydroxyurs-12-en-28-oic-acid (3) by extensive analysis of spectroscopic data. PMID- 23106377 TI - Effect of the DNA end of tethering to electrodes on electron transfer in methylene blue-labeled DNA duplexes. AB - Electron transfer (ET) in redox-labeled double-stranded (ds) DNA tethered to electrodes through the alkanethiol linker at either the 3' or 5' DNA end and bearing methylene blue (MB) conjugated to the opposite end of DNA is shown to depend on the DNA end of tethering to electrodes. For 3' tethering, a nanoscale diffusion of the positively charged MB redox probe (and thus of the individual DNA molecules) to the negatively charged electrode surface provided the highest apparent diffusion and ET rates as a result of the tilting of 3'-tethered DNA (as compared to 5'-tethered DNA) versus the normal to the surface. Dynamic values of the tilting angle varied between 57 and 45 degrees for 16-mer and 22-mer 3' tethered DNA, and 5'-tethering was correlated with an upright orientation of DNA at the electrode surface. The values of the diffusion coefficient D(MB) corrected for tilting angles were similar for 5'- and 3'-tethered DNA and ranged between 5.4 * 10(-12) and 2.5 * 10(-12) cm(2) s(-1), whereas the ET rate constant k(ET)(dif) fit the 4.7 * 10(-6)-10.3 * 10(-6) cm s(-1) range for 22-mer and 16 mer dsDNA, respectively. Those values, when related to the nanometer (10(-7) cm) diffusion distances (the length of the studied DNA), allow relatively fast diffusion-limited ET at an apparent rate that may exceed the rate of the corresponding surface-confined ET process. This phenomenon is of particular importance for molecular electronics and electrochemical genosensor development. PMID- 23106380 TI - Phase tag-assisted synthesis of benzo[b]carbazole end-capped oligothiophenes. AB - The introduction and removal of a phase tag have been used to trigger cyclization events in a new synthesis of benzo[b]carbazoles. The approach has been exploited in a tag-assisted approach to new benzo[b]carbazole end-capped oligothiophenes for preliminary evaluation as semiconductors. PMID- 23106379 TI - hnRNP A1 mediates the activation of the IRES-dependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress. AB - A growing amount of evidence suggests the involvement of ER (endoplasmic reticulum) stress in lipid metabolism and in the development of some liver diseases such as steatosis. The transcription factor SREBP-1 (sterol-regulatory element-binding protein 1) modulates the expression of several enzymes involved in lipid synthesis. Previously, we showed that ER stress increased the SREBP-1a protein level in HepG2 cells, by inducing a cap-independent translation of SREBP 1a mRNA, through an IRES (internal ribosome entry site), located in its leader region. In the present paper, we report that the hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) interacts with 5'-UTR (untranslated region) of SREBP-1a mRNA, as an ITAF (IRES trans-acting factor), regulating SREBP-1a expression in HepG2 cells and in primary rat hepatocytes. Overexpression of hnRNP A1 in HepG2 cells and in rat hepatocytes increased both the SREBP-1a IRES activity and SREBP 1a protein level. Knockdown of hnRNP A1 by small interfering RNA reduced either the SREBP-1a IRES activity or SREBP-1a protein level. hnRNP A1 mediates the increase of SREBP-1a protein level and SREBP-1a IRES activity in Hep G2 cells and in rat hepatocytes upon tunicamycin- and thapsigargin-induced ER stress. The induced ER stress triggered the cytosolic relocation of hnRNP A1 and caused the increase in hnRNP A1 bound to the SREBP-1a 5'-UTR. These data indicate that hnRNP A1 participates in the IRES-dependent translation of SREBP-1a mRNA through RNA protein interaction. A different content of hnRNP A1 was found in the nuclei from high-fat-diet-fed mice liver compared with standard-diet-fed mice liver, suggesting an involvement of ER stress-mediated hnRNP A1 subcellular redistribution on the onset of metabolic disorders. PMID- 23106378 TI - Posthemispherectomy hydrocephalus: results of a comprehensive, multiinstitutional review. AB - PURPOSE: Hemispherectomy surgery for medically intractable epilepsy is known to cause hydrocephalus in a subset of patients. Existing data regarding the incidence of, and risk factors for, developing posthemispherectomy hydrocephalus have been limited by the relatively small number of cases performed by any single center. Our goal was to better understand this phenomenon and to identify risk factors that may predispose patients to developing hydrocephalus after hemispherectomy surgery. METHODS: Fifteen pediatric epilepsy centers participated in this study. A retrospective chart review was performed on all available patients who had hemispherectomy surgery. Data collected included surgical techniques, etiology of seizures, prior brain surgery, symptoms and signs of hydrocephalus, timing of shunt placement, and basic demographics. KEY FINDINGS: Data were collected from 736 patients who underwent hemispherectomy surgery between 1986 and 2011. Forty-six patients had preexisting shunted hydrocephalus and were excluded from analysis, yielding 690 patients for this study. One hundred sixty-two patients (23%) required hydrocephalus treatment. The timing of hydrocephalus ranged from the immediate postoperative period to 8.5 years after surgery, with 43 patients (27%) receiving shunts >90 days after surgery. Multivariate regression analysis revealed anatomic hemispherectomies (odds ratio [OR] 4.1, p < 0.0001) and previous brain surgery (OR 1.7, p = 0.04) as independent significant risk factors for developing hydrocephalus. There was a trend toward significance for the use of hemostatic agents (OR 2.2, p = 0.07) and the involvement of basal ganglia or thalamus in the resection (OR 2.2, p = 0.08) as risk factors. SIGNIFICANCE: Hydrocephalus is a common sequela of hemispherectomy surgery. Surgical technique and prior brain surgery influence the occurrence of posthemispherectomy hydrocephalus. A significant portion of patients develop hydrocephalus on a delayed basis, indicating the need for long term surveillance. PMID- 23106381 TI - Lectin from Erythrina cristagalli supports undifferentiated growth and differentiation of human pluripotent stem cells. AB - Lectins are carbohydrate-binding proteins, which occur ubiquitously in nature and are abundant in all living organisms from bacteria to mammals. They have several biological functions among which cell adhesion is well known and characterized. Based on the characterization of the glycome of human embryonic stem cells (hESCs), we have investigated the properties of glycan-binding lectins as a novel class of culture support matrices supporting hESC culture. We report that an Erythrina cristagalli lectin (agglutinin) (ECA) matrix supported the undifferentiated growth and significantly increased the plating efficiency of both hESC and human induced pluripotent stem cells when used in conjunction with pinacidil, an antihypertensive drug with ROCK inhibition activity. As a matrix, ECA maintained pluripotency, robust proliferation with a normal karyotype, and the ability to differentiate both in vitro and in vivo. Therefore, our findings indicate that lectins are potential candidates for design of culture and differentiation methods, and that ECA is a potent simple defined matrix for human pluripotent stem cells. PMID- 23106383 TI - Short-axis substitution approach selectively optimizes electrical properties of dibenzothiophene-based phosphine oxide hosts. AB - Two dibenzothiophene (DBT)-based phosphine oxide hosts, named 4 diphenylphosphoryl dibenzothiophene (DBTSPO) and 4,6-bis(diphenylphosphoryl) dibenzothiophene (DBTDPO), were prepared by short-axis substitution with the aim to selectively adjust electrical properties. The combined effects of short-axis substitution and the involvement of electron-donating S atom in conjugation effectively suppress the influence of electron-withdrawing diphenylphosphine oxide (DPPO) moieties on the frontier molecular orbitals and the optical properties. Therefore, DBTSPO and DBTDPO have the nearly same hole injection ability and the excited energy levels, while more electron-transporting DPPOs and the symmetrical configuration endow DBTDPO with enhanced electron injecting/transporting ability. As the result, on the basis of this short-axis substitution effect, the selective adjustment of electrical properties was successfully realized. With the high first triplet energy level (T(1)) of 2.90 eV, the suitable energy levels of the highest occupied molecular orbital and the lowest unoccupied molecular orbital of -6.05 and -2.50 eV and the improved carrier-transporting ability, DBTDPO supported its blue- and white-emitting phosphorescent organic light-emitting diodes as the best low-voltage-driving devices reported so far with the lowest driving voltages of 2.4 V for onset and <3.2 V at 1000 cd m(-2) (for indoor lighting) accompanied with the high efficiencies of >30 lm W(-1) and excellent efficiency stability. PMID- 23106382 TI - Escherichia coli glutathionylspermidine synthetase/amidase: phylogeny and effect on regulation of gene expression. AB - Glutathionylspermidine synthetase/amidase (Gss) and the encoding gene (gss) have only been studied in Escherichia coli and several members of the Kinetoplastida phyla. In the present article, we have studied the phylogenetic distribution of Gss and have found that Gss sequences are largely limited to certain bacteria and Kinetoplastids and are absent in a variety of invertebrate and vertebrate species, Archea, plants, and some Eubacteria. It is striking that almost all of the 75 Enterobacteria species that have been sequenced contain sequences with very high degree of homology to the E. coli Gss protein. To find out the physiological significance of glutathionylspermidine in E. coli, we have performed global transcriptome analyses. The microarray studies comparing gss(+) and Deltagss strains of E. coli show that a large number of genes are either up regulated (76 genes more than threefold) or down-regulated (35 genes more than threefold) by the loss of the gss gene. Most significant categories of up regulated genes include sulfur utilization, glutamine and succinate metabolism, polyamine and arginine metabolism, and purine and pyrimidine metabolism. PMID- 23106384 TI - Rivaroxaban prevents painful cutaneous infarctions in livedoid vasculopathy. PMID- 23106385 TI - Survival of Lactobacillus rhamnosus GG as influenced by storage conditions and product matrixes. AB - Mortality resulting from diarrhea especially that occurs in children younger than 5 y of age ranks 3rd among all deaths caused by infectious diseases worldwide. Probiotics such as Lactobacillus rhamnosus GG are clinically shown to effectively reduce the incidence of diarrhea in children. A food substrate is one of the major factors regulating the colonization of microorganisms in human gastrointestinal tracts. Peanut butter is a nutritious, low-moisture food that could be a carrier for probiotics. In this study, we observed the influence of storage conditions and product matrixes on the survival of L. rhamnosus GG. Cells of L. rhamnosus GG were inoculated into full fat or reduced fat peanut butter at 10(7) CFU/g. Inoculated peanut butter was stored at 4, 25, or 37 degrees C for 48 wk. Samples were drawn periodically to determine the populations of L. rhamnosus GG. Results showed that there was no significant decrease in the viable counts of L. rhamnosus GG in products stored 4 degrees C. The survivability of L. rhamnosus GG decreased with increasing storage temperature and time. Product matrixes did not significantly affect the survival of L. rhamnosus GG except at 37 degrees C. Populations of L. rhamnosus GG were preserved at >6 logs in products stored at 4 degrees C for 48 wk and at 25 degrees C for 23 to 27 wk. At 37 degrees C, the 6-log level could not be maintained for even 6 wk. The results suggest that peanut butter stored at 4 and 25 degrees C could serve as vehicles to deliver probiotics. PMID- 23106386 TI - Structural basis for the potent and selective inhibition of casein kinase 1 epsilon. AB - Casein kinase 1 epsilon (CK1epsilon) and its closest homologue CK1delta are key regulators of diverse cellular processes. We report two crystal structures of PF4800567, a potent and selective inhibitor of CK1epsilon, bound to the kinase domains of human CK1epsilon and CK1delta as well as one apo CK1epsilon crystal structure. These structures provide a molecular basis for the strong and specific inhibitor interactions with CK1epsilon and suggest clues for further development of CK1delta inhibitors. PMID- 23106387 TI - Long-term follow-up and salvage surgery in patients with T2N0M0 squamous cell carcinoma of the glottic larynx following concurrent chemoradiation therapy with cisplatin and 5-fluorouracil for laryngeal preservation. AB - CONCLUSION: Patients who received concurrent chemoradiation therapy or radiation therapy alone were followed over a long term. The complete response (CR), 10-year survival, and 10-year larynx preservation rates were 87.5%, 95.3%, and 75.1%, respectively. Statistically, concurrent chemoradiation therapy contributes to laryngeal preservation but not to the survival rate. OBJECTIVE: To determine the additive and synergistic effects of anticancer chemotherapy combined with chemoradiation therapy for squamous cell carcinoma (SCC) of the glottic larynx. METHODS: Eighty-nine patients with untreated T2N0M0 SCC of the glottic larynx were included. Thirty-two patients received treatment cycles consisting of intravenous cisplatin (CDDP) on day 1 (80 mg/m(2)) and intravenous 5-fluorouracil (5-FU) over 120 h on days 2-6 (600 mg/m(2)/day) every 4 weeks. Radiotherapy was delivered by a 4 MV linac X-ray machine at a dose of 66 Gy. Fifty-seven patients received radiotherapy alone. RESULTS: After chemoradiation therapy, the overall response, CR, 10-year survival, and 10-year larynx preservation rates were 100%, 87.5%, 95.3%, and 75.1%, respectively. Side effects included leukopenia, neutropenia, mucositis, and dermatitis. Seven patients (21.9%) required salvage surgery. Pathological findings confirmed that the treatment regimen caused marked cancer tissue degeneration. Histologic examination of surgical specimens suggested that the safety margin for partial laryngectomy was 4 mm from the gross tumor. PMID- 23106388 TI - Role of gold nanoparticles capping density on stability and surface reactivity to design drug delivery platforms. AB - Five-nanometer sized gold nanoparticles (Au NPs) stabilized with citrate ions have been reacted with various amounts of dihydrolipoic acid (DHLA) (*28, *56, *140, *222, relative to Au NPs). Ligand exchange between citrate and the dithiol resulted in DHLA-capped Au NPs, whose degree of inertia was found to be related to the density of capping. The results revealed the importance of DHLA coating density to enhance the colloidal stability and modulate the reactivity toward free radicals and proteins of biological relevance. Thus, Au NPs capped with the highest amount of DHLA were found to be the ones that were, first, the most resistant to environmental changes, then characterized by the lowest residual catalytic reactivity of their metallic core, and finally the lowest interacting with proteins through nonspecific adsorption. The physicochemical properties conferred to Au NPs prepared with the *222 excess should be valuable for further pharmaceutical development of nanoparticle platforms. PMID- 23106391 TI - Symmetrical hydrogen bonds in iridium(III) alkoxides with relevance to outer sphere hydrogen transfer. AB - A chelating ligand formed by deprotonation of 2-(2'-pyridyl)-2-propanol stabilizes a distorted trigonal bipyramidal geometry in a 16e(-) d(6) 5 coordinate iridium complex with the alkoxide acting as a pi donor. Ambiphilic species such as AcOH bearing both nucleophilic and electrophilic functionality form adducts with the unsaturated iridium complex which contain strong intramolecular O...H...O hydrogen bonds that involve the basic alkoxide oxygen. Density functional theory (DFT) calculations on the isolated cations reproduce with high accuracy the geometrical features obtained via X-ray diffraction and corroborate the presence of very short hydrogen bonds with O...O distances of about 2.4 A. Calculations further confirm the known trend that the hydrogen position in these bonds is sensitive to the O...O distance, with the shortest distances giving rise to symmetrical O...H...O interactions. Dihydrogen is shown to add across the Ir-O pi bond in a presumed proton transfer reaction, demonstrating bifunctional behavior by the iridium alkoxide. PMID- 23106389 TI - Mode of delivery, mutans streptococci colonization, and early childhood caries in three- to five-year-old Thai children. AB - OBJECTIVE: To investigate whether mode of delivery is associated with mutans streptococci (MS) colonization and early childhood caries (ECC) in preschool Thai children. METHODS: Three hundred and fifty mothers and their 3- to 5-year-old children (184 born vaginally and 166 born by Caesarean section) participated in the study. Data included a dental examination, MS colonization assessed by the Dentocult((r)) SM Strip Mutans method, and a questionnaire survey of family socio demographic information, as well as children's birth history, dietary habits, and oral health practices. RESULTS: Overall, ECC prevalence was 56% in 3-year-old and 78% in 5-year-old Thai children. Compared to children delivered by C-section, vaginally born children experienced increased ECC prevalence (73.8% versus 59.6%; P = 0.009) and were more likely to have higher MS scores (OR = 1.8, 95% CI = 1.1 2.9), adjusting for mother's gestational age, MS score, feeding practice habits; child's age and tooth brushing habits. Children's MS scores were highly correlated with their mothers' MS scores (P < 0.001). Additionally, children's age, MS colonization, and mothers' prechewing feeding habits were the most significant risk indicators for ECC in Thai children. CONCLUSION: Our findings suggest that mode of delivery is significantly correlated with MS colonization and caries outcomes in young Thai children. Future studies are needed to further understand the possible biological mechanisms linking mode of child delivery to the colonization of cariogenic microbiota and development of ECC. PMID- 23106390 TI - The dual effect of abscisic acid on stomata. AB - The classical view that the drought-related hormone ABA simply acts locally at the guard cell level to induce stomatal closure is questioned by differences between isolated epidermis and intact leaves in stomatal response to several stimuli. We tested the hypothesis that ABA mediates, in addition to a local effect, a remote effect in planta by changing hydraulic regulation in the leaf upstream of the stomata. By gravimetry, porometry to water vapour and argon, and psychrometry, we investigated the effect of exogenous ABA on transpiration, stomatal conductance and leaf hydraulic conductance of mutants described as ABA insensitive at the guard cell level. We show that foliar transpiration of several ABA-insensitive mutants decreases in response to ABA. We demonstrate that ABA decreases stomatal conductance and down-regulates leaf hydraulic conductance in both the wildtype Col-0 and the ABA-insensitive mutant ost2-2. We propose that ABA promotes stomatal closure in a dual way via its already known biochemical effect on guard cells and a novel, indirect hydraulic effect through a decrease in water permeability within leaf vascular tissues. Variability in sensitivity of leaf hydraulic conductance to ABA among species could provide a physiological basis to the isohydric or anisohydric behaviour. PMID- 23106392 TI - A dynamic model for eye-position-dependence of spontaneous nystagmus in acute unilateral vestibular deficit (Alexander's Law). AB - Spontaneous nystagmus (SN) is a symptom of acute vestibular tone asymmetry. Alexander's Law (AL) states that slow-phase velocity of SN is higher when looking in the direction of fast-phases of nystagmus and lower in the slow-phase direction. Earlier explanations for AL predict that during SN, slow-phase eye velocity is a linear function of eye position, increasing linearly as eye deviates towards the fast-phase direction. Recent observations, however, show that this is often not the case; eye velocity does not vary linearly with eye position. Such new findings necessitate a re-evaluation of our understanding of AL. As AL may be an adaptive response of the vestibular system to peripheral lesions, understanding its mechanism could shed light on early adaptation strategies of the brain. Here, we propose a physiologically plausible mechanism for AL that explains recent experimental data. We use a dynamic control system model to simulate this mechanism and make testable predictions. This mechanism is based on the known effects of unilateral vestibular deficit on the response of the ipsi- and contralesional vestibular nuclei (VN) of the brainstem. This hypothesis is based on the silencing of the majority of ipsilesional VN units, which creates an asymmetry between the responses of the ipsi- and contralesional VN. Unlike former explanations, the new hypothesis does not rely on lesion detection strategies or signals originating in higher brain structures. The proposed model demonstrates possible consequences of acute peripheral deficits for the function of the velocity-to-position neural integrator of the ocular motor system and the vestibulo-ocular reflex. PMID- 23106393 TI - Remote supervision of health professionals in areas of workforce need: time to extend the model? PMID- 23106394 TI - Ripple classification helps to localize the seizure-onset zone in neocortical epilepsy. AB - PURPOSE: Fast ripples are reported to be highly localizing to the epileptogenic or seizure-onset zone (SOZ) but may not be readily found in neocortical epilepsy, whereas ripples are insufficiently localizing. Herein we classified interictal neocortical ripples by associated characteristics to identify a subtype that may help to localize the SOZ in neocortical epilepsy. We hypothesize that ripples associated with an interictal epileptiform discharge (IED) are more pathologic, since the IED is not a normal physiologic event. METHODS: We studied 35 patients with epilepsy with neocortical epilepsy who underwent invasive electroencephalography (EEG) evaluation by stereotactic EEG (SEEG) or subdural grid electrodes. Interictal fast ripples and ripples were visually marked during slow-wave sleep lasting 10-30 min. Neocortical ripples were classified as type I when superimposed on epileptiform discharges such as paroxysmal fast, spike, or sharp wave, and as type II when independent of epileptiform discharges. KEY FINDINGS: In 21 patients with a defined SOZ, neocortical fast ripples were detected in the SOZ of only four patients. Type I ripples were detected in 14 cases almost exclusively in the SOZ or primary propagation area (PP) and marked the SOZ with higher specificity than interictal spikes. In contrast, type II ripples were not correlated with the SOZ. In 14 patients with two or more presumed SOZs or nonlocalizable onset pattern, type I but not type II ripples also occurred in the SOZs. We found the areas with only type II ripples outside of the SOZ (type II-O ripples) in SEEG that localized to the primary motor cortex and primary visual cortex. SIGNIFICANCE: Neocortical fast ripples and type I ripples are specific markers of the SOZ, whereas type II ripples are not. Type I ripples are found more readily than fast ripples in human neocortical epilepsy. Type II-O ripples may represent spontaneous physiologic ripples in the human neocortex. PMID- 23106395 TI - Use of Atlantic salmon, Salmo salar L., farm treatment data and bioassays to assess for resistance of sea lice, Lepeophtheirus salmonis, to emamectin benzoate (SLICE((r)) ) in British Columbia, Canada. PMID- 23106396 TI - Amyloid-beta oligomers are sequestered by both intracellular and extracellular chaperones. AB - The aberrant aggregation of the amyloid-beta peptide into beta-sheet rich, fibrillar structures proceeds via a heterogeneous ensemble of oligomeric intermediates that have been associated with neurotoxicity in Alzheimer's disease (AD). Of particular interest in this context are the mechanisms by which molecular chaperones, part of the primary biological defenses against protein misfolding, influence Abeta aggregation. We have used single-molecule fluorescence techniques to compare the interactions between distinct aggregation states (monomers, oligomers, and amyloid fibrils) of the AD-associated amyloid beta(1-40) peptide, and two molecular chaperones, both of which are upregulated in the brains of patients with AD and have been found colocalized with Abeta in senile plaques. One of the chaperones, alphaB-crystallin, is primarily found inside cells, while the other, clusterin, is predominantly located in the extracellular environment. We find that both chaperones bind to misfolded oligomeric species and form long-lived complexes, thereby preventing both their further growth into fibrils and their dissociation. From these studies, we conclude that these chaperones have a common mechanism of action based on sequestering Abeta oligomers. This conclusion suggests that these chaperones, both of which are ATP-independent, are able to inhibit potentially pathogenic Abeta oligomer-associated processes whether they occur in the extracellular or intracellular environment. PMID- 23106398 TI - Mechanistic insights into the stabilization of srcSH3 by PEGylation. AB - Protein PEGylation (attaching PEG chains to proteins) has been widely used in pharmaceuticals and nanotechnology. Although it is widely known that PEGylation can increase the thermodynamic stability of proteins, the underlying mechanism remains elusive. In this Article, we studied the effect of PEGylation on the thermodynamic and kinetic stability of a protein, SH3. We show that the thermodynamic stability of SH3 is enhanced upon PEGylation, mainly due to the slowing of the unfolding rate. Moreover, PEGylation can decrease the solvent accessible surface area of SH3, leading to an increase of the m-value (the change in free energy with respect to denaturant concentration, which is a measure of the transition cooperativity between corresponding states). Such an effect also causes an enhancement of the thermodynamic stability. We quantitatively measured how the physical properties of PEG, such as the molecular weight and the number of PEGylation sites, affect the stabilization effect. We found that the stabilization effect is largely dependent on the number of PEGylation sites but only has a weak correlation with the molecular weight of the attached PEG. These experimental findings inspire us to derive a physical model based on excluded volume effect, which can satisfactorily describe all experimental observations. This model allows quantitatively calculating the free energy change upon PEGylation based on the change of water excluded zone on the protein surface. Although it is still unknown whether such a mechanism can be extended to other proteins, our work represents a key step toward the understanding of the nature of protein stabilization upon PEGylation. PMID- 23106397 TI - Activation of the insulin-like growth factor-1 receptor alters p27 regulation by the epidermal growth factor receptor in oral squamous carcinoma cells. AB - BACKGROUND: Although oral squamous cell carcinomas (OSCCs) commonly overexpress the epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitors (TKIs) exhibit poor efficacy clinically. Activation of the insulin-like growth factor-1 receptor (IGF1R) induces resistance of OSCC cells to EGFR-TKIs in vitro. This study seeks to evaluate the changes in cell cycle status in OSCC cells in response to gefitinib and IGF1R activation. METHODS: SCC-25 OSCC cells were used for in vitro analyses. RESULTS: Gefitinib caused a 50% reduction in S-phase population, and IGF1R activation caused a 2.8-fold increase; combined treatment yielded a baseline S-phase population. Gefitinib treatment increased the cyclin dependent kinase inhibitor p27, and this was not abrogated by IGF1R activation. pT157-p27 was noted by immunoblot to be decreased on gefitinib treatment, but this was reversed with IGF1R activation. T157 phosphorylation contributes to cytoplasmic localization of p27 where it can promote cell proliferation and cell motility. Using both subcellular fractionation and immunofluorescence microscopy techniques, IGF1R stimulation was noted to increase the relative cytoplasmic localization of p27; this persisted when combined with gefitinib. CONCLUSIONS: IGF1R activation partially reverses the cell cycle arrest caused by gefitinib in OSCC cells. While IGF1R stimulation does not eliminate the gefitinib-induced increase in total p27, its phosphorylation state and subcellular localization are altered. This may contribute to the ability of the IGF1R to rescue OSCC cells from EGFR-TKI treatment and may have important implications for the use of p27 as a biomarker of cell cycle arrest and response to therapy. PMID- 23106400 TI - Success brings responsibility and our colleagues respond. PMID- 23106401 TI - New zest for public health optometry. PMID- 23106399 TI - Structural characterization of plasma metabolites detected via LC-electrochemical coulometric array using LC-UV fractionation, MS, and NMR. AB - Liquid chromatography (LC) separation combined with electrochemical coulometric array detection (EC) is a sensitive, reproducible, and robust technique that can detect hundreds of redox-active metabolites down to the level of femtograms on column, making it ideal for metabolomics profiling. EC detection cannot, however, structurally characterize unknown metabolites that comprise these profiles. Several aspects of LC-EC methods prevent a direct transfer to other structurally informative analytical methods, such as LC-MS and NMR. These include system limits of detection, buffer requirements, and detection mechanisms. To address these limitations, we developed a workflow based on the concentration of plasma, metabolite extraction, and offline LC-UV fractionation. Pooled human plasma was used to provide sufficient material necessary for multiple sample concentrations and platform analyses. Offline parallel LC-EC and LC-MS methods were established that correlated standard metabolites between the LC-EC profiling method and the mass spectrometer. Peak retention times (RT) from the LC-MS and LC-EC system were linearly related (r(2) = 0.99); thus, LC-MS RTs could be directly predicted from the LC-EC signals. Subsequent offline microcoil-NMR analysis of these collected fractions was used to confirm LC-MS characterizations by providing complementary, structural data. This work provides a validated workflow that is transferrable across multiple platforms and provides the unambiguous structural identifications necessary to move primary mathematically driven LC-EC biomarker discovery into biological and clinical utility. PMID- 23106402 TI - There are people in Australia who have poor vision or eye disease that is avoidable. What more can we do? PMID- 23106403 TI - Topiramate and the retina: an abridged classification. PMID- 23106405 TI - Microbiological properties and biogenic amines of whole pike-perch (Sander lucioperca, linnaeus 1758): a perspective on fish safety during postharvest handling practices and frozen storage. AB - The biogenic amines (tyramine, histamine, cadaverine, and puterscine) and microbiological properties (mesophilic, psychrotrophic, and Pseudomonas spp.) of whole pike-perch (Sander lucioperca) was investigated during 2 d prestorage icing and 90 d frozen storage (-24 degrees C). At the end of ice storage, a noticeable increase only was found for puterscine level (P < 0.05), and microbial loads of fish increased in comparison with fresh fish (P < 0.05). During the frozen storage, as time passed, a continuous increase of biogenic amines and decrease of bacterial load (except for Pseudomonas spp. at the last 30 d) was detected (P < 0.05). The total contents of biogenic amines ranged from 6.24 to 91.76 MUg/g during the investigated period. Puterscine was the major amine detected in pike perch and its concentration varied between 1.75 and 56.95 MUg/g; due to a more step-wise increase it was a good quality indicator. At the end of storage, all of the obtained values are below the tolerable maximum amounts based on available regulations. Based on biogenic amines content and microbial load, it could be concluded that pike-perch can be consumed without any health risks after 2 d icing condition and 90 d frozen storage. PMID- 23106408 TI - Above-room-temperature magnetodielectric coupling in a possible molecule-based multiferroic: triethylmethylammonium tetrabromoferrate(III). AB - A possible above-room-temperature molecular multiferroic, triethylmethylammonium tetrabromoferrate(III) (1), has been discovered. Its ferroelectric and magnetic phase transitions take place at almost the same temperature (~360 K), resulting in strong magnetodielectric (MD) coupling, with a MD ratio of 18% at 0.6 MHz. Interestingly, 1 also undergoes a low-temperature ferroelectric-ferroelectric phase transition with an Aizu notation of 6mmF6 and small magnetic and dielectric anomalies at 171 K. PMID- 23106407 TI - A/H5N1 prepandemic influenza vaccine (Vepacel(r)): a guide to its use. AB - Vepacel(r) is a prepandemic influenza vaccine (whole virion, Vero cell-derived, inactivated) containing antigen of H5N1 strain A/Vietnam/1203/2004 and is approved for use in the EU. Clinical immunogenicity studies with the vaccine have demonstrated good functional neutralizing antibody responses against the vaccine strain (A/Vietnam/1203/2004), and cross-reactivity against H5N1 strains from other clades. In general, adverse events observed in clinical immunogenicity studies with a whole virions H5N1 vaccine (A/Vietnam/1203/2004) were similar to those reported with non-adjuvanted, inactivated, split virion seasonal influenza vaccines. PMID- 23106409 TI - Comparison with published systems of a new staging system for papillary and follicular thyroid carcinoma. AB - BACKGROUND: Several staging systems exist to estimate the prognosis for patients with thyroid carcinoma. Our goal was to develop a new staging system to predict cancer-specific survival (CSS) and evaluate it against published systems. METHODS: The Cedars-Sinai Medical Center (CSMC)'s staging system was derived using data from an adjusted analysis of 1622 patients with differentiated thyroid carcinomas (DTCs) from the CSMC Thyroid Cancer Center. Mean follow-up time was 11.8 years. There were 1180 female and 442 male patients with a mean age of 46. Staging systems reviewed include University of Alabama (Birmingham) and M.D. Anderson Cancer Center (UAB-MDACC); the Tumor-Node-Metastasis (TNM) 5th and 7th editions; Memorial Sloan-Kettering (MSK); the National Thyroid Cancer Treatment Cooperative Study (NTCTCS); Ohio State; Clinical Class; Metastases, Age, Completeness of resection, Invasion, and tumor Size (MACIS); Noguchi; and the Yildirim model for predicting outcomes. The proportion of variance explained (PVE) and the C-index were computed to rank and compare each staging system's ability to predict CSS with this patient population. RESULTS: Adjusted hazard ratios revealed that age at surgery of >45 years, the presence of distant metastases, capsular invasion, and vascular invasion were the most significant predictors of CSS in this patient population. The final CSMC risk score consists of low-, moderate-, and high-risk groups. Among the well-differentiated thyroid carcinoma staging systems, the CSMC and NTCTCS ranked highest with PVE values of 5% and 4.3%, respectively, while the NTCTCS and CSMC staging systems were reversed using the C-index (0.77 and 0.76, respectively). CONCLUSION: The PVE and C-index values were relatively low across all applicable staging systems and varied in each study reviewed. This suggests that no one staging system has been shown to be superior to another across different patient populations with DTC. In the future, additional factors, such as biological markers, added to the clinical and pathological characteristics may lead to the development of superior staging systems. PMID- 23106410 TI - A new spirocyclic compound from the liquid culture of entomogenous fungus Isaria cateniannulata. AB - A new spirocyclic compound named (2S, 5S, 7S)-3alpha-hydroxyl-exogonic acid (1) was isolated from the liquid culture of entomogenous fungus Isaria cateniannulata. The structure and relative stereochemistry of 1 were elucidated by extensive spectroscopic analysis and by comparison of its NMR data with those of known compound. Compound 1 showed weak inhibitory activity against HeLa with IC(50) value of 80.5 MUg ml(- 1). PMID- 23106411 TI - The association between psoriasis and dyslipidaemia: a systematic review. AB - Psoriasis may be associated with dyslipidaemia, a known risk factor for cardiovascular disease. This systematic review aims to synthesize evidence for the association between psoriasis and dyslipidaemia. Through a systematic search using MEDLINE, Embase and the Cochrane Central Register, from 1 January 1980 to 1 January 2012, we identified 25 observational studies that met the inclusion criteria. These 25 studies included over 2.4 million participants, among whom 265,512 were patients with psoriasis. Twenty studies (80%) reported that psoriasis was significantly associated with dyslipidaemia, with odds ratios (ORs) for dyslipidaemia ranging from 1.04 to 5.55 in 238,385 patients with psoriasis, from a population of 2,340,605 participants. Specifically, four studies defining dyslipidaemia as triglyceride levels >= 150 mg dL reported significantly increased ORs of 1.20-4.98 for hypertriglyceridaemia in psoriasis. Three studies found that patients with psoriasis presented with significantly increased ORs (1.36-1.77) for high-density lipoprotein cholesterol levels < 40 mg dL , and two studies found hyperlipoproteinaemia to be significantly elevated in patients with psoriasis (ORs 1.55 and 2.09). One cohort study found a significantly higher incidence of hyperlipidaemia among patients with psoriasis (hazard ratio 1.17; 95% confidence interval 1.11-1.23). Among studies that assessed the severity of psoriasis, in 2662 patients with mild psoriasis and 810 patients with severe psoriasis, higher odds of dyslipidaemia were seen in patients with severe psoriasis. Five of the 25 studies (20%) in our review did not show any significant relationship between psoriasis and dyslipidaemia. This systematic review found that psoriasis was significantly associated with greater odds and incidence of dyslipidaemia. Greater psoriasis severity appeared to be associated with higher prevalence of dyslipidaemia. PMID- 23106412 TI - Concurrent chemoradiation therapy with docetaxel (DOC) for laryngeal preservation in T2N0M0 glottic squamous cell carcinomas. AB - CONCLUSION: Concurrent chemoradiation therapy with docetaxel (DOC) at a dose of 10 mg/m(2) twice a week contributed to laryngeal preservation. OBJECTIVE: To determine laryngeal preservation following concurrent chemoradiation therapy with DOC. METHODS: A total of 141 patients with untreated T2N0M0 squamous cell carcinoma of the glottic larynx were included in the study. The treatments were either radiation therapy alone or DOC intravenously administered at a dose of 10 mg/m(2) once or twice a week during radiotherapy with 4 MV linac X-ray (total of 66 Gy for 33 days). RESULTS: The response and CR rates were 100% and 90.5% in the once-weekly combination group, and 100% and 97.6% in the twice-weekly combination group, respectively. The 5-year survival rates were 76.8% in the once-weekly combination group and 96.8% in the twice-weekly combination group. The 5-year laryngeal preservation rates were 83.8% in the once-weekly combination group and 97.6% in the twice-weekly combination group. The most common side effects were mucositis, dermatitis, and alopecia. The patients who received DOC twice a week showed more severe cancer tissue degeneration, and pathological examination of serial sections indicated that the safety margin for partial laryngectomy was considered to be 3 mm from the gross tumor with good glottal closure. PMID- 23106413 TI - Acidobacteria dominate the active bacterial communities of Arctic tundra with widely divergent winter-time snow accumulation and soil temperatures. AB - The timing and extent of snow cover is a major controller of soil temperature and hence winter-time microbial activity and plant diversity in Arctic tundra ecosystems. To understand how snow dynamics shape the bacterial communities, we analyzed the bacterial community composition of windswept and snow-accumulating shrub-dominated tundra heaths of northern Finland using DNA- and RNA-based 16S rRNA gene community fingerprinting (terminal restriction fragment polymorphism) and clone library analysis. Members of the Acidobacteria and Proteobacteria dominated the bacterial communities of both windswept and snow-accumulating habitats with the most abundant phylotypes corresponding to subdivision (SD) 1 and 2 Acidobacteria in both the DNA- and RNA-derived community profiles. However, different phylotypes within Acidobacteria were found to dominate at different sampling dates and in the DNA- vs. RNA-based community profiles. The results suggest that different species within SD1 and SD2 Acidobacteria respond to environmental conditions differently and highlight the wide functional diversity of these organisms even within the SD level. The acidic tundra soils dominated by ericoid shrubs appear to select for diverse stress-tolerant Acidobacteria that are able to compete in the nutrient poor, phenolic-rich soils. Overall, these communities seem stable and relatively insensitive to the predicted changes in the winter-time snow cover. PMID- 23106414 TI - The ability of soil bacteria to receive the conjugative IncP1 plasmid, pKJK10, is different in a mixed community compared to single strains. AB - Horizontal gene transfer by conjugation is common among bacterial populations in soil. It is well known that the host range of plasmids depends on several factors, including the identity of the plasmid host cell. In the present study, however, we demonstrate that the composition of the recipient community is also determining for the dissemination of a conjugative plasmid. We isolated 15 different bacterial strains from soil and assessed the conjugation frequencies of the IncP1 plasmid, pKJK10, by flow cytometry, from two different donors, Escherichia coli and Pseudomonas putida, to either 15 different bacterial strains or to the mixed community composed of all the 15 strains. We detected transfer of pKJK10 from P. putida to Stenotrophomonas rhizophila in a diparental mating, but no transfer was observed to the mixed community. In contrast, for E. coli, transfer was observed only to the mixed community, where Ochrobactrum rhizosphaerae was identified as the dominating plasmid recipient. Our results indicate that the presence of a bacterial community impacts the plasmid permissiveness by affecting the ability of strains to receive the conjugative plasmid. PMID- 23106416 TI - The role of medial prefrontal cortex in extinction and reinstatement of alcohol seeking in rats. AB - The prelimbic (PL) and infralimbic (IL) medial prefrontal cortex (mPFC) are thought to play opposing roles in drug-seeking behaviour. Specifically, the PL promotes drug-seeking whereas the IL is necessary for the inhibition of drug seeking during extinction. We studied the roles of the PL, IL and dorsal peduncular PFC (DP) in the expression of context-induced reinstatement, reacquisition and extinction of alcoholic beer-seeking. In context-induced reinstatement (renewal), animals were trained to nosepoke for alcoholic beer (context A), extinguished (context B) and then tested in context A and B. In reacquisition, animals received the same instrumental training and extinction without any contextual manipulation. On test, alcoholic beer was again available and responding was compared with naive controls. Just prior to the test, rats received bilateral infusion of baclofen/muscimol into the PL, IL or DP. Reversible inactivation of the PL attenuated ABA renewal but augmented reacquisition. Reversible inactivation of IL had no effect on the reinstatement or reacquisition of alcoholic beer-seeking and had no effect on extinction expression (ABB and AAA). IL inactivation did, however, increase the latencies with which animals responded on test but only when animals were tested in the extinction context. DP inactivation had no effect on reinstatement or reacquisition. These studies are inconsistent with the view that PL and IL exert opposing effects on drug-seeking. Rather, they support the view that PL is important for retrieval of drug-seeking contingency information and that the use of contextual information is enhanced with IL manipulation. PMID- 23106415 TI - Oral hygiene and cardiometabolic disease risk in the survey of the health of Wisconsin. AB - OBJECTIVES: Poor oral health is an increasingly recognized risk factor for cardiovascular disease (CVD) and type 2 diabetes (T2D), but little is known about the association between toothbrushing or flossing and cardiometabolic disease risk. The purpose of this study was to examine the degree to which an oral hygiene index was associated with CVD and T2D risk scores among disease-free adults in the Survey of the Health of Wisconsin. METHODS: All variables were measured in 2008-2010 in this cross-sectional design. Based on toothbrushing and flossing frequency, an oral hygiene index (poor, fair, good, excellent) was created as the primary predictor variable. The outcomes, CVD and T2D risk score, were based on previous estimates from large cohort studies. There were 712 and 296 individuals with complete data available for linear regression analyses in the CVD and T2D samples, respectively. RESULTS: After covariate adjustment, the final model indicated that participants in the excellent (beta +/- SE = -0.019 +/ 0.008, P = 0.020) oral hygiene category had a significantly lower CVD risk score as compared to participants in the poor oral hygiene category. Sensitivity analyses indicated that both toothbrushing and flossing were independently associated with CVD risk score, and various modifiable risk factors. Oral hygiene was not significantly associated with T2D risk score. CONCLUSIONS: Regular toothbrushing and flossing are associated with a more favorable CVD risk profile, but more experimental research is needed in this area to precisely determine the effects of various oral self-care maintenance behaviors on the control of individual cardiometabolic risk factors. These findings may inform future joint medical-dental initiatives designed to close gaps in the primary prevention of oral and systemic diseases. PMID- 23106417 TI - Composition-controlled PtCo alloy nanocubes with tuned electrocatalytic activity for oxygen reduction. AB - Modification of the electronic structure and lattice contraction of Pt alloy nanocatalysts through control over their morphology and composition has been a crucial issue for improving their electrocatalytic oxygen reduction reaction (ORR) activity. In the present work, we synthesized PtCo alloy nanocubes with controlled compositions (Pt(x)Co NCs, x = 2, 3, 5, 7, and 9) by regulating the ratio of surfactants and the amount of Co precursor to elucidate the effect of the composition of nanocatalysts on their ORR activity. Pt(x)Co NCs had a Pt-skin structure after electrochemical treatment. The electrocatalysis experiments revealed a strong correlation between ORR activity and Co composition. Pt3Co NCs exhibited the best ORR performance among the various Pt(x)Co NCs. From density functional theory calculations, a typical volcano-type relationship was established between ORR activity and oxygen binding energy (E(OB)) on NC surfaces, which showed that Pt3Co NCs had the optimal E(OB) to achieve the maximum ORR activity. X-ray photoelectron spectroscopy and X-ray diffraction measurements demonstrated that the electronic structure and lattice contraction of the Pt(x)Co NCs could be tuned by controlling the composition of NCs, which are highly correlated with the trends of E(OB) change. PMID- 23106418 TI - Commentary on: Cox M, Malcolm M. Fairgrieve SI. A new digital method for the objective comparison of frontal sinuses for identification. J Forensic Sci 2009;54(4):761-72. PMID- 23106420 TI - Practical and efficient strategy for evaluating oral absolute bioavailability with an intravenous microdose of a stable isotopically-labeled drug using a selected reaction monitoring mass spectrometry assay. AB - A strategy of using selected reaction monitoring (SRM) mass spectrometry for evaluating oral absolute bioavailability with concurrent intravenous (i.v.) microdosing a stable isotopically labeled (SIL) drug was developed and validated. First, the isotopic contribution to SRM (ICSRM) of the proposed SIL drug and SIL internal standard (IS) was theoretically calculated to guide their chemical synthesis. Second, the lack of an isotope effect on drug exposure was evaluated in a monkey study by i.v. dosing a mixture of the SIL and the unlabeled drugs. Third, after the SIL drug (100 MUg) was concurrently i.v. dosed to humans, at T(max) of an oral therapeutic dose of the unlabeled drug, both drugs in plasma specimens were simultaneously quantified by a sensitive and accurate SRM assay. This strategy significantly improves bioanalytical data quality and saves time, costs, and resources by avoiding a traditional absolute bioavailability study or the newer approach of microdoses of a radio-microtracer measured by accelerator mass spectrometry. PMID- 23106421 TI - Validation of anamnestic diagnostic criteria for recurrent aphthous stomatitis. AB - BACKGROUND: Recurrent aphthous stomatitis (RAS) is characterized by painful recurrent oral ulcers and is typically diagnosed via history and clinical examination. Our aim was to validate a set of anamnestic diagnostic criteria (RASDX) to increase the accuracy of RAS diagnosis, particularly when a clinical examination is not feasible. METHODS: Participants were enrolled during an unmatched case-control study. RASDX consisted of an initial phone screening using standardized questionnaires and recognition of RAS photographs in the clinic. The proportion of agreement with an examination by an oral medicine expert was calculated. RESULTS: A total of 115 participants were scheduled for a clinical diagnostic visit and 11 were withdrawn. The remaining 104 participants were aged 18-50 years, 54% women, 64% White and 20% Hispanic. Of these, all 49 controls with negative RASDX had no clinical ulcers. Of the 54 cases diagnosed with RAS by RASDX, 53 were clinically confirmed to have RAS lesions (99% agreement; exact one sided 95% CI = 95-100%). CONCLUSIONS: RASDX, based on a combination of history and photograph recognition, was highly accurate compared with a diagnosis that employed an oral examination. PMID- 23106423 TI - Effect of dosage failed of first antiepileptic drug on subsequent outcome. AB - PURPOSE: The recent definition of drug-resistant epilepsy proposed by the International League Against Epilepsy (ILAE) stipulated failure of an adequate trial of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules to achieve seizure freedom. Doses failed were not specifically discussed. We explored the effect of the doses at which the first and second AED regimens failed on subsequent outcomes in a population of adults with newly diagnosed epilepsy followed for up to 20 years. METHODS: Patients in whom epilepsy was diagnosed and the first AED prescribed between July 1, 1982 and April 1, 2006, were followed until March 31, 2008. Dosage at which an AED failed was categorized according to the World Health Organization's defined daily dose (DDD) for each drug. Cumulative incidence curves for time to final seizure freedom (no seizure for at least 1 year on unchanged dosage at last follow up) were stratified by whether the first regimen was failed at doses above or below the 25%, 50%, or 75% cutoffs for the DDD of each AED. KEY FINDINGS: Among patients who had taken a second regimen (n = 327), those in whom the first AED failed at doses above the various cutoffs (particularly 50% and 75% DDD) had lower probability of becoming seizure-free at last follow-up (p = 0.06 for 25% DDD, p < 0.001 for both 50% and 75% DDD). The same difference was observed for patients who had taken a third regimen (n = 141; p = 0.23 for 25% DDD, p < 0.01 for 50% DDD; and p = 0.002 for 75% DDD). A trend to higher seizure-free rate was observed in patients who had taken the third regimen when both the first and second regimens failed at <75% DDD. The difference remained significant after adjusting for covariates when using 50% DDD as the cutoff for patients who took a second regimen (hazard ratio 1.60, 95% confidence interval 1.08-2.37). SIGNIFICANCE: Higher failure dosage of the first AED predicts poorer subsequent outcome. This methodology could be used to refine further the ILAE definition of drug-resistant epilepsy by exploring the doses need to fail to provide an adequate AED trial. PMID- 23106422 TI - H(2)azapa: a versatile acyclic multifunctional chelator for (67)Ga, (64)Cu, (111)In, and (177)Lu. AB - Preliminary experiments with the novel acyclic triazole-containing bifunctional chelator H2azapa and the radiometals (64)Cu, (67)Ga, (111)In, and (177)Lu have established its significant versatile potential as an alternative to 1,4,7,10 tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for metal-based radiopharmaceuticals. Unlike DOTA, H2azapa radiolabels quantitatively with (64)Cu, (67)Ga, (111)In, and (177)Lu in 10 min at room temperature. In vitro competition experiments with human blood serum show that (64)Cu remained predominantly chelate-bound, with only 2% transchelated to serum proteins after 20 h. Biodistribution experiments with [(64)Cu(azapa)] in mice reveal uptake in various organs, particularly in the liver, lungs, heart, intestines, and kidneys. When compared to [(64)Cu(DOTA)](2-), the lipophilic neutral [(64)Cu(azapa)] was cleared through the gastrointestinal tract and accumulated in the liver, which is common for lipophilic compounds or free (64)Cu. The chelator H2azapa is a model complex for a click-based bifunctional chelating agent, and the lipophilic benzyl "place-holders" will be replaced by hydrophilic peptides to modulate the pharmacokinetics and direct activity away from the liver and gut. The solid-state molecular structure of [In(azapa)(H2O)][ClO4] reveals a very rare eight coordinate distorted square antiprismatic geometry with one triazole arm bound, and the structure of [(64)Cu(azapa)] shows a distorted octahedral geometry. The present study demonstrates significant potential for bioconjugates of H2azapa as alternatives to DOTA in copper-based radiopharmaceuticals, with the highly modular and "clickable" molecular scaffold of H2azapa easily modified into a variety of bioconjugates. H2azapa is a versatile addition to the "pa" family, joining the previously published H2dedpa ((67/68)Ga and (64)Cu), H4octapa ((111)In, (177)Lu, and (90)Y), and H5decapa ((225)Ac) to cover a wide range of important nuclides. PMID- 23106424 TI - Clinical applicability of the Macular Degeneration Detection Device (MDD-2): a novel photostress recovery measurement device. AB - BACKGROUND: Diseases affecting the macula, such as age-related macular degeneration (AMD), diabetic retinopathy and central serous retinopathy can result in impaired photostress recovery time (PSRT) despite normal visual acuity and fundoscopic appearance. The MDD-2 Macular Degeneration Detection Device is a novel flash photostress recovery device. In this study, we examine the repeatability of the MDD-2 in a normal population and its suitability for incorporation into routine clinical practice. METHODS: One hundred (60 female) subjects (mean age 35 +/- 8 years; range 18 to 66 years) were recruited to partake in this study. The photostress recovery time was measured using the MDD-2 on three occasions in the dominant eye and one final occasion in the non-dominant eye to assess measurement repeatability. All subjects were in good ocular health. Visual acuity and iris colour were recorded for each participant. RESULTS: Repeated measures analysis of variance revealed a statistically significant learning effect on intra-measurement repeatability (p < 0.01). Although paired t test analysis revealed statistically significant differences between repeated measures both within and between eyes (p < 0.05 for all) the correlation between repeat measurements is statistically significant (p < 0.05 for all), and the coefficient of repeatability reaches clinically acceptable levels once the initial photostress recovery time, which demonstrated increased variability and latency compared to all subsequent measures, is excluded. CONCLUSION: The MDD-2 provides highly repeatable measurements of photostress recovery time among young naive subjects, following verbal explanation of the task and only one 'practise' measurement. The measurement is also highly repeatable between eyes, providing a potential immediate clinical biomarker of ocular health. PMID- 23106425 TI - Retracing the routes of introduction of invasive species: the case of the Sirex noctilio woodwasp. AB - Understanding the evolutionary histories of invasive species is critical to adopt appropriate management strategies, but this process can be exceedingly complex to unravel. As illustrated in this study of the worldwide invasion of the woodwasp Sirex noctilio, population genetic analyses using coalescent-based scenario testing together with Bayesian clustering and historical records provide opportunities to address this problem. The pest spread from its native Eurasian range to the Southern Hemisphere in the 1900s and recently to Northern America, where it poses economic and potentially ecological threats to planted and native Pinus spp. To investigate the origins and pathways of invasion, samples from five continents were analysed using microsatellite and sequence data. The results of clustering analysis and scenario testing suggest that the invasion history is much more complex than previously believed, with most of the populations being admixtures resulting from independent introductions from Europe and subsequent spread among the invaded areas. Clustering analyses revealed two major source gene pools, one of which the scenario testing suggests is an as yet unsampled source. Results also shed light on the microevolutionary processes occurring during introductions, and showed that only few specimens gave rise to some of the populations. Analyses of microsatellites using clustering and scenario testing considered against historical data drastically altered our understanding of the invasion history of S. noctilio and will have important implications for the strategies employed to fight its spread. This study illustrates the value of combining clustering and ABC methods in a comprehensive framework to dissect the complex patterns of spread of global invaders. PMID- 23106426 TI - Cylindrocyclophane biosynthesis involves functionalization of an unactivated carbon center. AB - The cylindrocyclophanes are a family of natural products that share a remarkable paracyclophane carbon scaffold. Using genome sequencing and bioinformatic analyses, we have discovered a biosynthetic gene cluster involved in the assembly of cylindrocyclophane F. Through a combination of in vitro enzyme characterization and feeding studies, we confirm the connection between this gene cluster and cylindrocyclophane production, elucidate the chemical events involved in initiating and terminating an unusual type I polyketide synthase assembly line, and discover that macrocycle assembly involves functionalization of an unactivated carbon center. PMID- 23106427 TI - Ronidazole pharmacokinetics in cats following delivery of a delayed-release guar gum formulation. AB - Ronidazole (RDZ) is the only known effective treatment for feline diarrhea caused by Tritrichomonas foetus. This study aimed to develop guar gum-coated colon targeted tablets of RDZ and to determine the pharmacokinetics of this delayed release formulation in cats. Guar gum-coated tablets were administered orally once to five healthy cats (mean dose 32.3 mg/kg). The tablets were then administered once daily for 5 days to four cats (mean dose 34.5 mg/kg), and absorption studies repeated on day 5. Plasma was collected and analyzed for RDZ concentration, and pharmacokinetic noncompartmental and deconvolution analysis were performed on the data. There was negligible RDZ release until after 6 h, and a delayed peak plasma concentration (mean Cmax 28.9 MUg/mL) at approximately 14.5 h, which coincides with colonic arrival in cats. Maximum input rate (mg/kg per hour) occurred between 6 and 16 h. This delayed release of ronidazole from guar gum-coated tablets indicates that release of RDZ may be delayed to deliver the medication to a targeted area of the intestine. Repeated dosing with guar gum tablets to steady-state did not inhibit drug bioavailability or alter the pharmacokinetics. Such targeted RDZ drug delivery may provide improved efficacy and reduce adverse effects in cats. PMID- 23106428 TI - Loss of estrogen receptor Beta expression in follicular thyroid carcinoma predicts poor outcome. AB - BACKGROUND: Well-differentiated follicular thyroid carcinomas (FTCs) usually act indolently, while aggressively acting tumors are difficult to detect early enough. Estrogen receptors (ERs) have prognostic significance in many cancers. Thyroid diseases, including neoplasms, are associated with the female sex. The prognostic significance of ERs in FTCs has not been reported previously. METHODS: We studied the role of ERalpha and ERbeta in 83 cases of follicular thyroid adenoma (FTA) and 43 FTC cases, including seven cases of poorly differentiated FTC, obtained from the Department of Surgery, Helsinki University Central Hospital between 1990 and 2009. Patient follow-up was conducted until March 2011. Expression of ERalpha, ERbeta, and MIB-1/Ki-67 was investigated by immunohistochemistry and correlated with clinicopathological characteristics, including survival. RESULTS: Two major observations were apparent. First, ERbeta expression was significantly higher in FTA than in FTC, and it was a stronger differential diagnostic marker than MIB-1/Ki-67. Second, low ERbeta expression correlated with poor survival in FTC. All cancer-specific deaths due to FTC were among low ERbeta-score patients. CONCLUSION: ERbeta is a differential marker for malignancy and could thus be used as a preoperative tool. FTC patients with a low ERbeta score need more thorough follow-up and may benefit from more aggressive treatment. PMID- 23106429 TI - Hypoxic conditions and exercise-to-rest ratio are likely paramount. PMID- 23106431 TI - (18)F-FDG-PET/CT predicts early tumor recurrence in living donor liver transplantation for hepatocellular carcinoma. AB - The prognosis including (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) for the early recurrence for hepatocellular carcinoma (HCC) after living donor liver transplantation (LDLT) was not well established. Consecutive patients who underwent (18)F-FDG-PET/CT and subsequent LDLT for HCC from March 2005 to June 2011 were enrolled. The 191 patients with a median follow-up of 26.1 months were evaluated. There were 20 patients (10.5%) with early recurrence (<=6 months), 18 patients (9.4%) with late recurrence (>6 months), and 153 patients (80.1%) with no recurrence. Fifty-five patients (28.8%) displayed increased PET/CT tumor uptake. Three-year overall and disease-free survival for PET/CT-positive patients were 65.5% and 57.1%, respectively, while PET/CT-negative patients showed respective values of 89.8% and 86.8% (P = 0.001 vs. P < 0.001). Tumor variables associated with PET/CT positive finding were preoperative AFP level, Milan, UCSF criteria, maximum tumor size, total tumor size, differentiation, vascular invasion, and serosal invasion. PET/CT-positive status was identified as an independent prognostic factor for disease-free survival influencing early recurrence in multivariable analysis (HR 3.945, 95% CI 1.196-13.016, P = 0.024). (18)F-FDG-PET/CT is an independent and significant predictor of early tumor recurrence in LDLT for HCC. PMID- 23106432 TI - Cofactor binding triggers a molecular switch to allosterically activate human UDP alpha-D-glucose 6-dehydrogenase. AB - Human UDP-alpha-D-glucose dehydrogenase (hUGDH) catalyzes the NAD(+)-dependent oxidation of UDP-alpha-D-glucose (UDG) to produce UDP-alpha-D-glucuronic acid. The oligomeric structure of hUGDH is dynamic and can form two distinct hexameric complexes in solution. The active form of hUGDH consists of dimers that undergo a concentration-dependent association to form a hexamer with 32 symmetry. In the presence of the allosteric feedback inhibitor UDP-alpha-D-xylose (UDX), hUGDH changes shape to form an inactive, horseshoe-shaped complex. Previous studies have identified the UDX-induced allosteric mechanism that changes the hexameric structure to inhibit the enzyme. Here, we investigate the role of the 32 symmetry hexamer in the catalytic cycle. We engineered a stable hUGDH dimer by introducing a charge-switch substitution (K94E) in the hexamer-building interface (hUGDH(K94E)). The k(cat) of hUGDH(K94E) is ~160-fold lower than that of the wild type enzyme, suggesting that the hexamer is the catalytically relevant state. We also show that cofactor binding triggers the formation of the 32 symmetry hexamer, but UDG is needed for the stability of the complex. The hUGDH(K94E) crystal structure at 2.08 A resolution identifies loop(88-110) as the cofactor responsive allosteric switch that drives hexamer formation; loop(88-110) directly links cofactor binding to the stability of the hexamer-building interface. In the interface, loop(88-110) packs against the Thr131-loop/alpha6 helix, the allosteric switch that responds to the feedback inhibitor UDX. We also identify a structural element (the S-loop) that explains the indirect stabilization of the hexamer by substrate and supports a sequential, ordered binding of the substrate and cofactor. These observations support a model in which (i) UDG binds to the dimer and stabilizes the S-loop to promote cofactor binding and (ii) cofactor binding orders loop(88-110) to induce formation of the catalytically active hexamer. PMID- 23106434 TI - Perineural granulomatous inflammation: a potential harbinger of perineural invasion in cutaneous squamous cell carcinoma. PMID- 23106433 TI - Two new compounds with cytotoxic activity on the human melanoma A375-S2 cells from Daphne giraldii callus cells. AB - Four compounds were isolated from Daphne giraldii callus cells, and their structures were characterized as daphnenone (1), daphnolon (2), R-( - )-1-(4' hydroxyphenyl)-3-hydroxy-5-phenyl-1,5-pentandione (3), and S-(+)-daphneolone-4'-O beta-d-glucoside (4) on the basis of MS, NMR spectrographic analysis, and chemical methods. All of the four compounds possessed C6-C5-C6 carbon skeleton, and among them, 3 and 4 were two new compounds. In activity screening test, compounds 1, 2, 3, and 4 showed different degrees of cytotoxic activity against the tumor cells of human melanoma A375-S2 by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl-2H-tetrazolium hydrobromide method, with IC(50) values of 29.8, 51.0, 41.0, and 150.0 MUM, respectively. Furthermore, we found the important target which could explain the cytotoxic mechanism of the four compounds by using autodock 4.0, a structure-guided discovery approach, and the important residues CYS532, GLY534, and SER535 of B-Raf kinase have been discovered. PMID- 23106435 TI - Alternative cardiolipin synthase Cls1 compensates for stalled Cls2 function in Staphylococcus aureus under conditions of acute acid stress. AB - Staphylococcus aureus possesses two distinct cardiolipin (CL) synthase genes, cls1 and cls2. It was previously shown that cls2 encodes a housekeeping-type CL synthase. However, the role of cls1 is elusive; a cls1 mutant was found to be equal to the wild type in terms of CL accumulation and stress tolerance. Here, we report that the physiological role of cls1 is to synthesize CL under conditions of acute low-pH stress. Below pH 2.6, the cls1 mutant (i.e. carrying Cls2 alone) could not produce CL, while the cls2 mutant (carrying Cls1) effectively accumulated CL. The cls1-dependent CL production was quick (within 5 min) and did not require de novo protein synthesis. Together with the results of phylogenetic analyses, our findings suggest that cls1 was generated through the duplication of cls2 after the divergence of the genus Staphylococcus and that the alternative CL synthase encoded by this gene confers improved survival in the face of acute acid stress. PMID- 23106436 TI - Differential responses of circadian Per2 expression rhythms in discrete brain areas to daily injection of methamphetamine and restricted feeding in rats. AB - Behavioral rhythms induced by methamphetamine (MAP) and daily restricted feeding (RF) in rats are independent of the circadian pacemaker in the suprachiasmatic nucleus (SCN), and have been regarded to share a common oscillatory mechanism. In the present study, in order to examine the responses of brain oscillatory systems to MAP and RF, circadian rhythms in clock gene, Period2, expression were measured in several brain areas in rats. Transgenic rats carrying a bioluminescence reporter of Period2-dLuciferase were subjected to either daily injection of MAP or RF of 2 h at a fixed time of day for 14 days. As a result, spontaneous movement and wheel-running activity were greatly enhanced following MAP injection and prior to daily meal under RF. Circadian Per2 rhythms were measured in the cultured brain tissues containing one of the following structures: the olfactory bulb; caudate-putamen; parietal cortex; substantia nigra; and SCN. Except for the SCN, the circadian Per2 rhythms in the brain tissues were significantly phase delayed by 1.9 h on average in MAP-injected rats as compared with the saline controls. On the other hand, the circadian rhythms outside the SCN were significantly phase-advanced by 6.3 h on average in rats under RF as compared with those under ad libitum feeding. These findings indicate that the circadian rhythms in specific brain areas of the central dopaminergic system respond differentially to MAP injection and RF, suggesting that different oscillatory mechanisms in the brain underlie the MAP-induced behavior and pre-feeding activity under RF. PMID- 23106437 TI - Single-strain inoculation may create spurious correlations between legume fitness and rhizobial fitness. PMID- 23106440 TI - Quantification of Gly m 4 protein, a major soybean allergen, by two-dimensional liquid chromatography with ultraviolet and mass spectrometry detection. AB - Soybean (Glycine max) is considered a major allergenic food. Gly m 4 is one of several soybean allergens that has been identified to cause an allergic reaction, typically the symptoms are localized effects including the skin, gastrointestinal tract, or respiratory tract. Soybean allergens are considered a complete food allergen in that they are capable of inducing specific IgE as well as eliciting a range of severity from mild rashes up to anaphylaxis. In this study, we have isolated, purified, and characterized an endogenous Gly m 4 protein. The endogenous protein has 88.0% sequence homology with the theoretically predicted Gly m 4 sequence. Following detailed characterization, an assay was developed for quantification of endogenous Gly m 4 using two-dimensional liquid chromatography with ultraviolet and mass spectrometric detection (2DLC-UV/MS). A linear relationship (R(2) > 0.99) was observed over the concentration range of 12.5 531.7 MUg/mL. Over the linear range, the assay recoveries (percent relative error, % RE) ranged from -1.5 to 10.8%. The assay precision (percent coefficient of variation, % CV) was measured at three different Gly m 4 levels on each of the 4 days and did not exceed 11.2%. The developed method was successfully applied to quantify Gly m 4 level in 10 commercial soybean lines. To the best of our knowledge, this represents the first quantitative assay for an intact endogenous Gly m 4 protein. PMID- 23106439 TI - Demographic, socioeconomic, and behavioral factors affecting patterns of tooth decay in the permanent dentition: principal components and factor analyses. AB - OBJECTIVES: Dental caries of the permanent dentition is a multifactorial disease resulting from the complex interplay of endogenous and environmental risk factors. The disease is not easily quantitated due to the innumerable possible combinations of carious lesions across individual tooth surfaces of the permanent dentition. Global measures of decay, such as the DMFS index (which was developed for surveillance applications), may not be optimal for studying the epidemiology of dental caries because they ignore the distinct patterns of decay across the dentition. We hypothesize that specific risk factors may manifest their effects on specific tooth surfaces leading to patterns of decay that can be identified and studied. In this study, we utilized two statistical methods of extracting patterns of decay from surface-level caries data to create novel phenotypes with which to study the risk factors affecting dental caries. METHODS: Intra-oral dental examinations were performed on 1068 participants aged 18-75 years to assess dental caries. The 128 tooth surfaces of the permanent dentition were scored as carious or not and used as input for principal components analysis (PCA) and factor analysis (FA), two methods of identifying underlying patterns without a priori knowledge of the patterns. Demographic (age, sex, birth year, race/ethnicity, and educational attainment), anthropometric (height, body mass index, waist circumference), endogenous (saliva flow), and environmental (tooth brushing frequency, home water source, and home water fluoride) risk factors were tested for association with the caries patterns identified by PCA and FA, as well as DMFS, for comparison. The ten strongest patterns (i.e. those that explain the most variation in the data set) extracted by PCA and FA were considered. RESULTS: The three strongest patterns identified by PCA reflected (i) global extent of decay (i.e. comparable to DMFS index), (ii) pit and fissure surface caries and (iii) smooth surface caries, respectively. The two strongest patterns identified by FA corresponded to (i) pit and fissure surface caries and (ii) maxillary incisor caries. Age and birth year were significantly associated with several patterns of decay, including global decay/DMFS index. Sex, race, educational attainment, and tooth brushing were each associated with specific patterns of decay, but not with global decay/DMFS index. CONCLUSIONS: Taken together, these results support the notion that caries experience is separable into patterns attributable to distinct risk factors. This study demonstrates the utility of such novel caries patterns as new outcomes for exploring the complex, multifactorial nature of dental caries. PMID- 23106441 TI - Cooperative dissolved organic carbon assimilation by a linuron-degrading bacterial consortium. AB - Dissolved organic matter (DOM) is the primary environmental carbon source for heterotrophic bacteria and its quality and quantity have been shown to affect microbial community structure and functioning. In that context, it was examined whether a bacterial consortium synergistically degrading the herbicide linuron extends this synergism toward natural DOM degradation. Biodegradable dissolved organic carbon (BDOC) of DOM of various origins and concomitant growth was determined for the consortium members in isolation and in combination. BDOC decreased with increasing DOM aromaticity, which is a recalcitrance indicator. BDOC in DOM of low aromaticity was 40-50% for all inocula. For DOM with high aromaticity, BDOC decreased with increasing aromaticity and was inoculum dependent, that is, BDOC was > 23% for consortium members in combination compared with BDOC < 16% for isolated strains. The observed BDOC and growth indicated that synergism existed within the consortium for degradation of DOM of both low and high aromaticity. All members benefited from this synergism as growth of all strains increased when incubated in combination, but their relative growth benefit depended on DOM composition. These data suggest that consortia benefit more than individual pesticide degraders from environmental DOM due to cooperation. This is important to understand the effects of DOM on stability and activity of pollutant-degrading consortia. PMID- 23106438 TI - Post-tonsillectomy haemorrhage more common than previously described--an institutional chart review. AB - CONCLUSIONS: Risk of post-tonsillectomy haemorrhage (PTH) was higher compared with previous studies and may be associated with the criteria used. Male gender and the use of haemostatic agents in the primary operation were associated with increased risk of PTH, whereas the use of non-steroidal anti-inflammatory drugs (NSAIDs) or dexamethasone was not. OBJECTIVES: The aim of the study was to investigate the risk of PTH in adult patients, and its association with the use of NSAIDs, dexamethasone, paracetamol, serotonin (5-HT(3)) receptor antagonists, haemostatic agents, age and gender during preceding tonsillectomy (TE). METHODS: All PTH complications that resulted in an adult TE patient re-contacting the hospital were retrospectively recorded during a 12-month period. PTH types were allocated into three categories: (I) a history of bleeding, (II) bleeding requiring direct pressure or electrocautery under local anaesthesia or (III) reoperation under general anaesthesia. RESULTS: A total of 842 adult TE patients (aged between 16 and 85.8 years) were included in the study. Of these, 122 patients experienced PTH (risk 14.5%). Risk of category III PTH was 1.5%. Risk factors for PTH were the use of haemostatic agents (p = 0.006) and male gender (p = 0.011). The use of NSAID, opioid, 5-HT(3) receptor antagonist and dexamethasone medication did not significantly alter the number of postoperative bleeding events. PMID- 23106442 TI - Designed short RGD peptides for one-pot aqueous synthesis of integrin-binding CdTe and CdZnTe quantum dots. AB - We have designed a series of short RGD peptide ligands and developed one-pot aqueous synthesis of integrin-binding CdTe and CdZnTe quantum dots (QDs). We first examined the effects of different RGD peptides, including RGDS, CRGDS, Ac CRGDS, CRGDS-CONH2, Ac-CRGDS-CONH2, RGDSC, CCRGDS, and CCCRGDS, on the synthesis of CdTe QDs. CRGDS were found to be the optimal ligand, providing the CdTe QDs with well-defined wavelength ranges (500-650 nm) and relatively high photoluminescence quantum yields (up to 15%). The key synthesis parameters (the pH value of the Cd2+-RGD precursors and the molar ratio of RGD/Cd2+) were assessed. In order to further improve the optical properties of the RGD-capped QDs, zinc was then incorporated by the simultaneous reaction of Cd2+ and Zn2+ with NaHTe. By using a mixture of CRGDS and cysteine as the stabilizer, the quantum yields of CdZnTe alloy QDs reached as high as 60% without any post treatment, and they also showed excellent stability against time, pH, and salinity. Note that these properties could not be obtained with CRGDS or cysteine alone as the stabilizer. Finally, we demonstrated that the RGD-capped QDs preferentially bind to cell surfaces because of the specific recognition of the RGD sequence to cell surface integrin receptors. Our synthesis strategy based on RGD peptides thus represents a convenient route for opening up QD technologies for cell-specific tagging and labeling applicable to a wide range of diagnostics and therapy. PMID- 23106444 TI - Combining Meyer-Schuster rearrangement with aldol and Mannich reactions: theoretical study of the intermediate interception strategy. AB - Interception of the transient allenyl enolate intermediate of the vanadium catalyzed Meyer-Schuster rearrangement with aldehydes and imines has been studied computationally using density functional theory. Mechanistic details of the catalytic cycles for each of the reaction variants are established. In particular, it is shown that the active form of the catalyst contains two triphenylsiloxy ligands, the transesterification of vanadate occurs via sigma bond metathesis, and vanadium enolate is directly involved in the key C-C bond formation. The calculations also provide support for the dissociative course of the key 1,3-shift step. The stereochemistry of the reaction is thoroughly investigated, and the obtained energy barriers reproduce and rationalize the experimentally observed (Z)-, (E)-selectivity. The calculated free energy profiles are analyzed in terms of efficiency of the intermediate enolate interception. It is shown that the investigated reactions represent borderline cases, in which the intermediate trapping is only slightly favored over the undesired isomerization pathway. PMID- 23106446 TI - Allergic airway diseases in childhood - marching from epidemiology to novel concepts of prevention. AB - In the past years, a wide range of epidemiological, clinical, and experimental studies have produced remarkable advances in the field of respiratory allergies in childhood. By the recent investigations on epidemiological trends, risk factors, and prevention of asthma and allergic rhinitis, various exiting concepts have been challenged, and novel innovative approaches have been developed. Pediatric Allergy and Immunology (PAI), with a number of highly relevant contributions between 2010 and 2012, has become an important forum in this area. The prevalence of asthma in some developed countries may have reached a plateau, while in developing countries, where the prevalence was previously low, allergic diseases are still on the increase. A wide array of risk and protective factors, including hygiene, infections, outdoor and indoor air pollution, allergen exposure, breast-feeding practices, nutrition, and obesity, play a multifaceted role in shaping the observed worldwide trends of respiratory allergies. Under the guidance of recent research, prediction and prevention strategies in the clinical practice are progressively changing, the focus moving away from avoidance of allergen exposure and toward tolerance induction. PMID- 23106443 TI - Pulmonary fat embolism--a prospective study within the forensic autopsy collective of the Republic of Iceland. AB - In the last century, studies established the origin of pulmonary fat embolism (PFE) and identified mechanical trauma as main source for PFE. This prospective study focused on determining a possible influence of cardiopulmonary resuscitation (CPR), in the context of an aging population, on the occurrence of PFE. Lung tissue samples from 256 bodies were examined using the twin-edged knife technique without preliminary fixation but after staining with Sudan III. PFE grading was determined according to Falzi and performed at a 10* magnification. For statistical analysis, bodies were grouped by age, gender, and putrefaction and categorized following whether they had experienced trauma, CPR, the combination of both, or no mechanical impact. There was a significant correlation of trauma, CPR, and the combination of both to PFE but no noticeable influence of gender or putrefaction. An age over 70 years promotes a PFE due to resuscitation. PMID- 23106447 TI - The EAACI pediatric section: looking back over 2012 and forward to 2013. PMID- 23106449 TI - Si/Ge superlattice nanowires with ultralow thermal conductivity. AB - The engineering of nanostructured materials with very low thermal conductivity is a necessary step toward the realization of efficient thermoelectric devices. We report here the main results of an investigation with nonequilibrium molecular dynamics simulations on thermal transport in Si/Ge superlattice nanowires aiming at taking advantage of the inherent one dimensionality and the combined presence of surface and interfacial phonon scattering to yield ultralow values for their thermal conductivity. Our calculations revealed that the thermal conductivity of a Si/Ge superlattice nanowire varies nonmonotonically with both the Si/Ge lattice periodic length and the nanowire cross-sectional width. The optimal periodic length corresponds to an order of magnitude (92%) decrease in thermal conductivity at room temperature, compared to pristine single-crystalline Si nanowires. We also identified two competing mechanisms governing the thermal transport in superlattice nanowires, responsible for this nonmonotonic behavior: interface modulation in the longitudinal direction significantly depressing the phonon group velocities and hindering heat conduction, and coherent phonons occurring at extremely short periodic lengths counteracting the interface effect and facilitating thermal transport. Our results show trends for superlattice nanowire design for efficient thermoelectrics. PMID- 23106448 TI - Plasma disposition and milk excretion of eprinomectin following pour-on administration in lactating donkeys. PMID- 23106450 TI - Effect of supplementation of taurine or trehalose in extender on immunolocalization of tyrosine phosphoproteins in buffalo and cattle (Karan Fries) cryopreserved spermatozoa. AB - The present study assessed the effects of incorporation of Taurine or Trehalose in extender on immunolocalization of tyrosine phosphoproteins, Cryocapacitation and other sperm quality parameters (motility, viability and membrane integrity) in post-thawed sperm from Buffalo (Murrah) and Cattle (Karan Fries). Six ejaculates from six individual bulls from both species were chosen at random and split into four aliquots: one aliquot without dilution (fresh sample), another diluted in egg yolk tris-citrate (EYTC) extender and the rest of aliquots with EYTC dilution supplemented with taurine (50 mm) or trehalose (100 mm), respectively, and cryopreserved. Following cryopreservation, semen were thawed and assessed for standard semen quality parameters. Extent of capacitation in cryopreserved spermatozoa was measured by inducing in vitro acrosome reaction followed by dual staining. Immunolocalization of tyrosine phosphoproteins was carried out by immunocytochemistry using primary antibody clone pT-154 (anti phosphotyrosine antibody) and FITC-conjugated secondary antibody. Immunofluorescent signals were analysed for level of protein tyrosine phosphorylation in spermatozoa. Post-thaw semen evaluation showed supplementation of taurine or trehalose to EYTC extender significantly (p < 0.05) increased motility, viability and membrane integrity of spermatozoa in both species. Percentage of cryocapacitated spermatozoa was significantly (p < 0.05) higher in cattle as compared to buffalo and degree of cryocapacitaion of spermatozoa decreased significantly (p < 0.05) upon supplementation of additives in both the species. It was also found that tyrosine phosphoproteins were localized differentially in fresh and cryopreserved spermatozoa. Supplementation of taurine or trehalose to freezing extender changed the localization of tyrosine phosphoproteins in cryopreserved spermatozoa similar to fresh in both the species. The results obtained clearly indicated that supplementation of taurine or trehalose to EYTC prior to cryopreservation improves Buffalo and Cattle sperm quality in terms of cryocapacitation and immunolocalization of tyrosine phosphoproteins during freezing-thawing process. PMID- 23106452 TI - Biomechanical and computational evaluation of two loading transfer concepts for pancarpal arthrodesis in dogs. AB - OBJECTIVE: To evaluate 2 plate designs for pancarpal arthrodesis and their effects on load transfer to the respective bones as well as to develop a computational model with directed input from the biomechanical testing of the 2 constructs. SAMPLE: Both forelimbs from the cadaver of an adult castrated male Golden Retriever. PROCEDURES: CT imaging was performed on the forelimb pair. Each forelimb was subsequently instrumented with a hybrid dynamic compression plate or a castless pancarpal arthrodesis plate. Biomechanical testing was performed. The forelimbs were statically loaded in the elastic range and then cyclically loaded to failure. Finite element (FE) modeling was used to compare the 2 plate designs with respect to bone and implant stress distribution and magnitude when loaded. RESULTS: Cyclic loading to failure elicited failure patterns similar to those observed clinically. The mean +/- SD error between computational and experimental strain was < 15% +/- 13% at the maximum loads applied during static elastic loading. The highest bone stresses were at the distal extent of the metacarpal bones at the level of the screw holes with both plates; however, the compression plate resulted in slightly greater stresses than did the arthrodesis plate. Both models also revealed an increase in bone stress at the proximal screw position in the radius. The highest plate stress was identified at the level of the radiocarpal bone, and an increased screw stress (junction of screw head with shaft) was identified at both the most proximal and distal ends of the plates. CONCLUSIONS AND CLINICAL RELEVANCE: The FE model successfully approximated the biomechanical characteristics of an ex vivo pancarpal plate construct for comparison of the effects of application of different plate designs. PMID- 23106453 TI - Ultrasonographic assessment of the thyroid gland and adjacent anatomic structures in Indo-Pacific bottlenose dolphins (Tursiops aduncus). AB - OBJECTIVE: To evaluate the use of ultrasonography for thyroid gland assessment in healthy Indo-Pacific bottlenose dolphins (Tursiops aduncus), describe the ultrasonographic appearance of the thyroid gland and adjacent anatomic structures, and identify potential associations between variations in thyroid gland morphology and demographic features in this species. ANIMALS: 18 captive Indo-Pacific bottlenose dolphins. PROCEDURES: 1,404 ultrasonographic examinations of the thyroid gland and adjacent anatomic structures (eg, cervical lymph nodes, musculature, and vasculature) were performed during the > 3-year study period. Shape, echogenicity, and homogeneity of thyroid glands were assessed, and glands were categorized into morphological configurations on the basis of results of 2-D and 3-D ultrasonographic evaluation. Associations between demographic factors and thyroid gland morphology were assessed. RESULTS: Thyroid lobes appeared elliptical or fusiform in the transverse scan plane and round to oval in longitudinal scan planes; morphologically, glands comprised 2 lobes joined by an isthmus or a roughly diamond-shaped structure located on the ventral surface of the trachea. Major blood vessels and cervical lymph nodes were identified. Thyroid parenchyma was typically uniform and homogeneous, with echogenic reticulations and well-defined borders. Thyroid glands were hypoechoic or isoechoic relative to the sternocephalicus muscle; echogenicity was greater in adolescents than in adults. Thyroid gland volume differed between sexes, between sexually mature and immature dolphins, and among age groups and was positively correlated with body length and weight. CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasonography provided a reliable and repeatable method for evaluation of thyroid glands and adjacent anatomic structures in live dolphins. PMID- 23106454 TI - Evaluation of anesthetic, analgesic, and cardiorespiratory effects in dogs after intramuscular administration of dexmedetomidine-butorphanol-tiletamine-zolazepam or dexmedetomidine-tramadol-ketamine drug combinations. AB - OBJECTIVE: To compare anesthetic, analgesic, and cardiorespiratory effects in dogs after IM administration of dexmedetomidine (7.5 MUg/kg)-butorphanol (0.15 mg/kg)-tiletamine-zolazepam (3.0 mg/kg; DBTZ) or dexmedetomidine (15.0 MUg/kg) tramadol (3.0 mg/kg)-ketamine (3.0 mg/kg; DTrK) combinations. ANIMALS: 6 healthy adult mixed-breed dogs. PROCEDURES: Each dog received DBTZ and DTrK in a randomized, crossover-design study with a 5-day interval between treatments. Cardiorespiratory variables and duration and quality of sedation-anesthesia (assessed via auditory stimulation and sedation-anesthesia scoring) and analgesia (assessed via algometry and electrical nerve stimulation) were evaluated at predetermined intervals. RESULTS: DBTZ or DTrK induced general anesthesia sufficient for endotracheal intubation <= 7 minutes after injection. Anesthetic quality and time from drug administration to standing recovery (131.5 vs 109.5 minutes after injection of DBTZ and DTrK, respectively) were similar between treatments. Duration of analgesia was significantly longer with DBTZ treatment, compared with DTrK treatment. Analgesic effects were significantly greater with DBTZ treatment than with DTrK treatment at several time points. Transient hypertension (mean arterial blood pressure > 135 mm Hg), bradycardia (heart rate < 60 beats/min), and hypoxemia (oxygen saturation < 90% via pulse oximetry) were detected during both treatments. Tidal volume decreased significantly from baseline with both treatments and was significantly lower after DBTZ administration, compared with DTrK, at several time points. CONCLUSIONS AND CLINICAL RELEVANCE: DBTZ or DTrK rapidly induced short-term anesthesia and analgesia in healthy dogs. Further research is needed to assess efficacy of these drug combinations for surgical anesthesia. Supplemental 100% oxygen should be provided when DBTZ or DTrK are used. PMID- 23106455 TI - Effects of anesthetic drugs on canine splenic volume determined via computed tomography. AB - OBJECTIVE: To evaluate effects of commonly used anesthetics administered as single bolus injections on splenic volume. ANIMALS: 10 adult Beagles. PROCEDURES: A randomized crossover study was conducted. Computed tomography was performed on dogs to determine baseline splenic volume and changes after IV injection of assigned drug treatments. Dogs were allowed to acclimate for 10 minutes in a plastic crate before acquisition of abdominal CT images. Treatments were administered at 7-day intervals and consisted of IV administration of saline (0.9% NaCl) solution (5 mL), acepromazine maleate (0.03 mg/kg), hydromorphone (0.1 mg/kg), and dexmedetomidine (0.005 mg/kg) to all 10 dogs; thiopental (8 mg/kg) to 5 of the dogs; and propofol (5 mg/kg) to the other 5 dogs. Splenic volume was calculated from the CT images with image processing software. A repeated-measures ANOVA was performed, followed by a Bonferroni post hoc test. RESULTS: No significant difference in splenic volume was detected between the acepromazine, propofol, and thiopental treatments, but splenic volume was greater with these drugs than with saline solution, hydromorphone, and dexmedetomidine. Splenic volume was less with hydromorphone, compared with dexmedetomidine, but splenic volume with hydromorphone and dexmedetomidine did not differ significantly from that with saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of acepromazine, thiopental, and propofol resulted in splenomegaly. Dexmedetomidine did not alter splenic volume. Hydromorphone slightly decreased splenic volume. Propofol should not be used when splenomegaly is not desirable, whereas hydromorphone and dexmedetomidine may be used when it is best to avoid splenic enlargement. PMID- 23106456 TI - Effects of meloxicam on hematologic and plasma biochemical analysis variables and results of histologic examination of tissue specimens of Japanese quail (Coturnix japonica). AB - OBJECTIVE: To determine the effects of meloxicam on values of hematologic and plasma biochemical analysis variables and results of histologic examination of tissue specimens of Japanese quail (Coturnix japonica). ANIMALS: 30 adult Japanese quail. PROCEDURES: 15 quail underwent laparoscopic examination of the left kidneys, and 15 quail underwent laparoscopic examination and biopsy of the left kidneys. Quail in each of these groups received meloxicam (2.0 mg/kg, IM, q 12 h; n = 10) or a saline (0.9% NaCl) solution (0.05 mL, IM, q 12 h; control birds; 5) for 14 days. A CBC and plasma biochemical analyses were performed at the start of the study and within 3 hours after the last treatment. Birds were euthanized and necropsies were performed. RESULTS: No adverse effects of treatments were observed, and no significant changes in values of hematologic variables were detected during the study. Plasma uric acid concentrations and creatine kinase or aspartate aminotransferase activities were significantly different before versus after treatment for some groups of birds. Gross lesions identified during necropsy included lesions at renal biopsy sites and adjacent air sacs (attributed to the biopsy procedure) and pectoral muscle hemorrhage and discoloration (at sites of injection). Substantial histopathologic lesions were limited to pectoral muscle necrosis, and severity was greater for meloxicam treated versus control birds. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam (2.0 mg/kg, IM, q 12 h for 14 days) did not cause substantial alterations in function of or histopathologic findings for the kidneys of Japanese quail but did induce muscle necrosis; repeated IM administration of meloxicam to quail may be contraindicated. PMID- 23106457 TI - Tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders. AB - OBJECTIVE: To determine the tissue distribution of enrofloxacin after intramammary or simulated systemic administration in isolated perfused sheep udders by measuring its concentration at various sample collection sites. SAMPLE: 26 udders (obtained following euthanasia) from 26 healthy lactating sheep. PROCEDURES: For each isolated udder, 1 mammary gland was perfused with warmed, gassed Tyrode solution. Enrofloxacin (1 g of enrofloxacin/5 g of ointment) was administered into the perfused gland via the intramammary route or systemically via the perfusion fluid (equivalent to a dose of 5 mg/kg). Samples of the perfusate were obtained every 30 minutes for 180 minutes; glandular tissue samples were obtained at 2, 4, 6, and 8 cm from the teat base after 180 minutes. The enrofloxacin content of the perfusate and tissue samples was analyzed via high-performance liquid chromatography with UV detection. RESULTS: After intramammary administration, maximun perfusate enrofloxacin concentration was detected at 180 minutes and, at this time, mean tissue enrofloxacin concentration was detected and mean tissue enrofloxacin concentration was 123.80, 54.48, 36.72, and 26.42 MUg/g of tissue at 2, 4, 6, and 8 cm from the teat base, respectively. Following systemic administration, perfusate enrofloxacin concentration decreased with time and, at 180 minutes, tissue enrofloxacin concentrations ranged from 40.38 to 35.58 MUg/g of tissue. CONCLUSIONS AND CLINICAL RELEVANCE: By 180 minutes after administration via the intramammary or systemic route in isolated perfused sheep mammary glands, mean tissue concentration of enrofloxacin was greater than the minimum inhibitory concentration required to inhibit growth of 90% of many common mastitis pathogens in sheep. Use of either route of administration (or in combination) appears suitable for the treatment of acute mastitis in sheep. PMID- 23106458 TI - Investigation of forelimb hoof wall strains and hoof shape in unshod horses exercised on a treadmill at various speeds and gaits. AB - OBJECTIVE: To investigate forelimb hoof wall strains and shape changes in unshod horses undergoing regular moderate exercise on a treadmill at selected speeds and gaits. ANIMALS: 6 horses of various body types. PROCEDURES: Each horse was exercised on a treadmill (walking, trotting, and cantering, with or without galloping at 12.5 m/s) 3 times a week for 4 consecutive weeks; duration of each exercise session ranged from 10 to 14 minutes. During the 4-week period, the proximal hoof circumference (PHC) and toe angle (TA) of each forelimb hoof were measured weekly with a flexible measuring tape and a hoof gauge, respectively. Forelimb hoof wall strains were measured bilaterally at the toe and each quarter (3 strain gauges) immediately before the first and after the last exercise session. RESULTS: Strain measurements revealed a consistent pattern of deformation of the hoof wall in both forelimbs at all gaits; strains increased during the stance phase of the stride. Strain values were dependent on site and gait. Compared with initial findings, mean TA increased significantly, whereas mean PHC did not, after the 4-week exercise period. A relationship between TA changes and hoof wall strains could not be established. CONCLUSIONS AND CLINICAL RELEVANCE: In unshod horses, forelimb hoof wall strains were affected by site and gait, but not by discrete changes in TA; PHC did not change in response to moderate regular exercise. The pattern of hoof loading was consistent despite significant changes in TA. PMID- 23106459 TI - Mechanical and morphological properties of trabecular bone samples obtained from third metacarpal bones of cadavers of horses with a bone fragility syndrome and horses unaffected by that syndrome. AB - OBJECTIVE: To determine morphological and mechanical properties of trabecular bone of horses with a bone fragility syndrome (BFS; including silicate-associated osteoporosis). SAMPLE: Cylindrical trabecular bone samples from the distal aspects of cadaveric third metacarpal bones of 39 horses (19 horses with a BFS [BFS bone samples] and 20 horses without a BFS [control bone samples]). PROCEDURES: Bone samples were imaged via micro-CT for determination of bone volume fraction; apparent and mean mineralized bone densities; and trabecular number, thickness, and separation. Bone samples were compressed to failure for determination of apparent elastic modulus and stresses, strains, and strain energy densities for yield, ultimate, and failure loads. Effects of BFS and age of horses on variables were determined. RESULTS: BFS bone samples had 25% lower bone volume fraction, 28% lower apparent density, 18% lower trabecular number and thickness, and 16% greater trabecular separation versus control bone samples. The BFS bone samples had 22% lower apparent modulus and 32% to 33% lower stresses, 10% to 18% lower strains, and 41 % to 52% lower strain energy densities at yield, ultimate, and failure loads, compared with control bone samples. Differences between groups of bone samples were not detected for mean mineral density and trabecular anisotropy. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that horses with a BFS had osteopenia and compromised trabecular bone function, consistent with bone deformation and pathological fractures that develop in affected horses. Effects of this BFS may be systemic, and bones other than those that are clinically affected had changes in morphological and mechanical properties. PMID- 23106460 TI - In vitro cytoprotective effects of acetylsalicylic acid, carprofen, meloxicam, or robenacoxib against apoptosis induced by sodium nitroprusside in canine cruciate ligament cells. AB - OBJECTIVE: To determine whether incubation of cruciate ligament cells with acetylsalicylic acid, carprofen, meloxicam, or robenacoxib provides protection against apoptosis induced by sodium nitroprusside (SNP). SAMPLE: Explants of cranial (CCL) and caudal (CaCL) cruciate ligaments from eight 1-day-old Beagles. PROCEDURES: Primary cultures of CCL and CaCL cells were created via enzymatic dissociation of cruciate explants. Purified cell cultures were incubated for 2 hours without (controls) or with 1 of 3 concentrations of 1 of 4 NSAIDs (10, 100, or 200 MUg of acetylsalicylic acid/mL; 0.1, 1, or 10 MUg of carprofen/mL; 0.1, 1, or 10 MUg of meloxicam/mL; or 0.1, 1, or 10 MUg of robenacoxib/mL) and subsequently incubated for 18 hours with 1 of 3 concentrations of SNP in an attempt to induce mild, moderate, or severe cytotoxic effects. Cell viability and apoptosis were analyzed via a cell proliferation assay and flow cytometry, respectively. Prostaglandin E(2) concentrations were measured via an ELISA. RESULTS: Cytoprotective effects of NSAIDs were dependent on the extent of SNP induced apoptosis and were greatest in CCL and CaCL cell cultures with moderate SNP-induced cytotoxic effects. Preincubation with an NSAID improved cell viability by 15% to 45% when CCL and CaCL cells were subsequently incubated with SNP. Carprofen (10 MUg/mL) had the greatest cytoprotective effects for CCL and CaCL cells. Incubation with NSAIDs resulted in a nonsignificant decrease in PGE(2) production from SNP-damaged cells. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that carprofen, meloxicam, and robenacoxib may reduce apoptosis in cells originating from canine cruciate ligaments. PMID- 23106461 TI - Mitochondrial dysfunction in myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy. AB - OBJECTIVE: To compare mitochondrial complex I and complex IV activity in myocardial mitochondria of clinically normal dogs, clinically normal dogs exposed to inhalation anesthesia, and dogs affected with dilated cardiomyopathy. SAMPLE: Myocardial samples obtained from 21 euthanized dogs (6 clinically normal [control] dogs, 5 clinically normal dogs subjected to inhalation anesthesia with isoflurane prior to euthanasia, 5 dogs with juvenile-onset dilated cardiomyopathy, and 5 dogs with adult-onset dilated cardiomyopathy). PROCEDURES: Activity of mitochondrial complex I and complex IV was assayed spectrophotometrically in isolated mitochondria from left ventricular tissue obtained from the 4 groups of dogs. RESULTS: Activity of complex I and complex IV was significantly decreased in anesthetized dogs, compared with activities in the control dogs and dogs with juvenile-onset or adult-onset dilated cardiomyopathy. CONCLUSIONS AND CLINICAL RELEVANCE: Inhalation anesthesia disrupted the electron transport chain in the dogs, which potentially led to an outburst of reactive oxygen species that caused mitochondrial dysfunction. Inhalation anesthesia depressed mitochondrial function in dogs, similar to results reported in other species. This effect is important to consider when anesthetizing animals with myocardial disease and suggested that antioxidant treatments may be beneficial in some animals. Additionally, this effect should be considered when designing studies in which mitochondrial enzyme activity will be measured. Additional studies that include a larger number of animals are warranted. PMID- 23106463 TI - Investigation of hydration processes of the equine hoof via nuclear magnetic resonance microscopy. AB - OBJECTIVE: To examine the distribution of water in hoof wall specimens of horses via nuclear magnetic resonance (NMR) microscopy and determine changes in water distribution during hydration. SAMPLE: 4 hoof wall specimens (2 obtained from the dorsum and 1 each obtained from the lateral quarter and lateral heel regions) of the stratum medium of healthy hooves of 1 horse. PROCEDURES: Equine hoof wall specimens were examined via NMR microscopy. Proton density-weighted 3-D images were acquired. Changes during water absorption were assessed on sequential images. RESULTS: The inner zone of the stratum medium had higher signals than did the outer zone. Areas of high signal intensity were evident in transverse images; these corresponded to the distribution of horn tubules. During water absorption, the increase in signal intensity started at the bottom of a specimen and extended to the upper region; it maintained the localization pattern observed before hydration. The relationship between the local maximal signals in areas corresponding to the horn tubules and minimal signal intensities in areas corresponding to the intertubular horn was similar and maintained approximately a linear distribution. CONCLUSIONS AND CLINICAL RELEVANCE: Based on the premise that signal intensity reflects water content, hydration in the equine hoof wall during water absorption occurred concurrently in the tubules and intertubular horn, and there was maintenance of the original water gradients. This technique can be applied for the assessment of pathophysiologic changes in the hoof wall on the basis of its hydration properties. PMID- 23106462 TI - Associations among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine ratio, and ventricular remodeling in dogs with myxomatous mitral valve disease. AB - OBJECTIVE: To assess relationships among serum N-terminal procollagen type III concentration, urinary aldosterone-to-creatinine concentration ratio (UAC), and clinical variables in dogs with myxomatous mitral valve disease (MMVD) and healthy dogs. ANIMALS: 162 dogs with MMVD and 24 healthy control dogs of comparable age and body weight. PROCEDURES: Blood and urine samples were collected from each dog. Dogs with MMVD underwent echocardiography and ECG. Ventricular diameter measurements were normalized for body weight. Serum N terminal procollagen type III and urinary aldosterone concentrations were measured via radioimmunoassay. Each dog was examined on 1 to 3 occasions. Examinations were repeated at approximately 6-month intervals. RESULTS: Serum N terminal procollagen type III concentration decreased with increasing severity of MMVD and was negatively associated with age and left ventricular end-diastolic and end-systolic diameters. The UAC increased with prior percentage change in left ventricular end-diastolic diameter per month, subsequent percentage change in left ventricular end-systolic diameter per month, and treatment with diuretics and was negatively associated with age. Both UAC and serum N-terminal procollagen type III concentration were higher in Cavalier King Charles Spaniels than in other breeds when other measured variables were controlled for. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with MMVD, echocardiographic indicators of left ventricular remodeling appeared to be associated with a decrease in serum concentration of a marker of collagen type III turnover and an increase in urinary aldosterone concentration. PMID- 23106464 TI - Plasma 25-hydroxyvitamin D(3) concentrations in Hermann's tortoises (Testudo hermanni) exposed to natural sunlight and two artificial ultraviolet radiation sources. AB - Objective-To determine the effect of various UVB radiation sources on plasma 25 hydroxyvitamin D(3) concentrations in Hermann's tortoises (Testudo hermanni). Animals-18 healthy Hermann's tortoises. Procedures-Tortoises were exposed to sunlight in an outdoor enclosure located in the natural geographic range of Hermann's tortoises (n = 6 tortoises) or a self-ballasted mercury-vapor lamp (6) or fluorescent UVB-emitting lamp (6) in an indoor enclosure for 35 days. Plasma samples were obtained from each tortoise on the first (day 0) and last (day 35) days of the study, and concentrations of 25-hydroxyvitamin D(3) were determined. Amount of UVB radiation in enclosures was measured. Results-Mean +/- SD plasma 25-hydroxyvitamin D(3) concentrations for tortoises exposed to the mercury-vapor and fluorescent lamps were significantly lower on day 35 (155.69 +/- 80.71 nmol/L and 134.42 +/- 51.42 nmol/L, respectively) than they were on day 0 (368.02 +/- 119.34 nmol/L and 313.69 +/- 109.54 nmol/L, respectively). Mean +/- SD plasma 25 hydroxyvitamin D(3) concentration for tortoises exposed to sunlight did not differ significantly between days 0 (387.74 +/- 114.56 nmol/L) and 35 (411.51 +/- 189.75 nmol/L). Mean day 35 plasma 25-hydroxyvitamin D(3) concentration was significantly higher for tortoises exposed to sunlight versus those exposed to mercury-vapor or fluorescent lamps. Sunlight provided significantly more UVB radiation than did the mercury-vapor or fluorescent lamps. Conclusions and Clinical Relevance-Plasma 25-hydroxyvitamin D(3) concentrations differed between tortoises exposed to sunlight and those exposed to artificial UVB sources. Exposure to sunlight at a latitude similar to that of the natural geographic range is recommended for healthy and calcium-deficient tortoises. PMID- 23106466 TI - Assessment of methods of evaluating sarcopenia in old dogs. AB - OBJECTIVE: To evaluate clinically applicable methods of assessing lean body mass in dogs and compare muscle mass and inflammatory markers in healthy young and old dogs. ANIMALS: 9 healthy young (1 to 5 years old) and 10 old (> 8 years old) Labrador Retrievers with a body condition score of 5 to 6 of 9. PROCEDURES: Radiography of the thoracolumbar region was performed for measurement of epaxial muscle height at the level of T13-L1. Computed tomographic images were obtained for the measurement of the epaxial and temporal muscles. Ultrasonography also was performed for regional muscle measurements at these same sites and the quadriceps muscle. Serum C-reactive protein, insulin-like growth factor-1, and tumor necrosis factor-alpha concentrations also were measured, and dogs' activity for 14 days was assessed with an activity monitor. RESULTS: Mean epaxial muscle area measured by ultrasonography was significantly lower in the old group, compared with the young group, whereas epaxial muscle area measured by CT was only significantly lower in the old group after normalization for vertebral height. Neither temporal and quadriceps muscle measurements nor serum C-reactive protein or insulin-like growth factor-1 concentrations were significantly different between age groups. Tumor necrosis factor-alpha concentrations were undetectable in all dogs. CONCLUSIONS AND CLINICAL RELEVANCE: This study documented reduced epaxial muscle area in healthy old Labrador Retrievers, consistent with the syndrome of sarcopenia. Ultrasonography and CT were feasible methods of measuring epaxial muscle area, but much additional research is required to assess this method. A better understanding of underlying mechanisms of sarcopenia as well as methods for slowing progression is needed. PMID- 23106465 TI - Assessment of the long-term effect of vaccination on transmission of infectious bovine rhinotracheitis virus in cattle herds hyperimmunized with glycoprotein E deleted marker vaccine. AB - OBJECTIVE: To assess long-term effects and risk factors for the efficacy of hyperimmunization protocols against infectious bovine rhinotracheitis (IBR) during a longitudinal field study of dairy and dairy-beef mixed farms. ANIMALS: Approximately 7,700 cows from 72 farms. PROCEDURES: Farms were assigned to 3 treatment groups (hyperimmunization groups [HIGs] 1 and 2, which were hyperimmunized with glycoprotein E [gE]-deleted marker vaccines, and a nonintervention group [NIG]). Cattle in HIG 1 were initially vaccinated with an attenuated vaccine, whereas cattle in HIG 2 were initially vaccinated with an inactivated-virus vaccine. Cattle in both HIGs received booster inoculations with inactivated-virus vaccines at 6-month intervals. The risk for gE seroconversion was compared among experimental groups via a shared frailty model with a piecewise constant baseline risk to correct for seasonal and secular effects. RESULTS: Risk for gE seroconversion significantly decreased over time for the HIGs, compared with the NIG. Seasonal changes in the risk of gE seroconversion were detected, with a higher risk during winter periods, compared with grazing periods. No significant difference was detected between HIGs 1 and 2. The only significant risk factor was the number of buildings for cattle on a farm; the higher the number of buildings, the lower the risk for gE seroconversion. Prevalence of IBR decreased over time in both HIGs but remained constant or increased in the NIG. CONCLUSIONS AND CLINICAL RELEVANCE: Hyperimmunization via repeated administration of attenuated and inactivated-virus gE-deleted marker vaccines as well as inactivated-virus vaccines may provide a method for control of IBR. PMID- 23106468 TI - Evaluation of intraocular pressure in conscious Hermann's tortoises (Testudo hermanni) by means of rebound tonometry. AB - OBJECTIVE: To determine intraocular pressure (IOP) in healthy Hermann's tortoises (Testudo hermanni). ANIMALS: 26 outdoor-housed Hermann's tortoises (13 males and 13 females); body weight ranged from 255 to 2,310 g, and age ranged from 4 to > 50 years. PROCEDURES: After a preliminary ophthalmic evaluation was performed, IOP was measured by means of a rebound tonometer in both eyes of each tortoise. Three measurements were obtained for each eye; successive measurements were obtained from alternate eyes. Each measurement was based on the mean of 6 values automatically provided by the rebound tonometer. Statistical analysis was used to evaluate correlations between variables and to identify sex- or size-related IOP variations, and changes in IOP over multiple measurements. RESULTS: Mean +/- SEM IOP of the 52 eyes was 15.74 +/- 0.20 mm Hg (range, 9 to 22 mm Hg). Results for t tests did not reveal significant differences in IOP between the right and left eyes or between males and females. A significant moderate negative correlation (r = -0.41; r(2) = 0.169) between IOP and body weight was detected. Results of repeated-measures ANOVA revealed a significant increase in IOP over multiple measurements. CONCLUSIONS AND CLINICAL RELEVANCE: Rebound tonometry was a practical and rapid means of determining IOP in small- to medium-sized tortoises that required minimal manual restraint of the animals. Establishing IOP values in healthy Hermann's tortoises will provide a reference frame for use during complete ophthalmic examinations, thus allowing clinicians to diagnose a broader spectrum of ocular pathological conditions in tortoises. PMID- 23106467 TI - Immunohistochemical characterization of feline oral squamous cell carcinoma. AB - OBJECTIVE: To evaluate the expression of Ki67 and epidermal growth factor receptor (EGFR), mitotic index (MI), and microvascular density (MVD) in feline oral squamous cell carcinoma (SCC) via immunohistochemical staining on archival tumor tissues and to seek a correlation between these markers and clinical variables. SAMPLE: 22 archived tumor samples of feline oral SCC. PROCEDURES: Immunohistochemical staining for Ki67, MVD, and EGFR was performed and scored. Patient survival information was obtained from the medical records. These molecular markers as well as MI were correlated with tumor locations and patient survival time. RESULTS: The 22 tumors had wide variation in Ki67 expression, MI, MVD, and EGFR expression. Tongue SCC had higher MVD than did mandibular and maxillary SCC. Tumor expression of EGFR was inversely proportional to survival time. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that EGFR expression might be a valuable prognostic factor for treatment outcome in feline oral SCC. It also identified higher angiogenesis in tongue SCC, compared with mandibular and maxillary SCC, which may account for a different clinical outcome. Further prospective characterization of feline oral SCC may provide a better understanding of the underlying molecular factors that drive its behavior and offer the possibility for future patient-specific treatment plans. PMID- 23106470 TI - Evaluation of a novel suture material for closure of intestinal anastomoses in canine cadavers. AB - OBJECTIVE: To compare leakage and maximum intraluminal pressures for a novel suture material with pressures for comparable suture material when used in closure of intestinal anastomoses in canine cadavers. SAMPLE: Healthy intestines from cadavers of dogs euthanized for reasons unrelated to the study. PROCEDURES: 18 anastomoses were performed on intestinal sections within 72 hours after dogs were euthanized and intestinal samples collected. Anastomoses were performed with a simple continuous suture pattern. Leakage and maximum intraluminal pressures were measured and recorded for 6 control segments and 18 anastomosed sections. A barbed glycomer 631 suture (size 4-0 United States Pharmacopeia [USP]) was compared with glycomer 631 sutures (sizes 3-0 and 4-0 USP). Results for leakage and maximum intraluminal pressures were compared via an ANOVA. RESULTS: The barbed glycomer 631 suture material leaked at a significantly higher pressure than did the comparable glycomer 631 suture materials. Maximum intraluminal pressures were not significantly different among the suture materials. CONCLUSIONS AND CLINICAL RELEVANCE: Barbed glycomer 631 4-0 USP suture material was as effective as glycomer 631 suture materials and may be a safe alternative for use in closure of enterectomies in dogs. PMID- 23106469 TI - Effects of high-intensity training on lipid metabolism in Thoroughbreds. AB - OBJECTIVE: To investigate the effects of high-intensity training (HIT) on carbohydrate and fat metabolism in Thoroughbreds. ANIMALS: 12 Thoroughbreds (3 to 4 years old; 6 males and 6 females). PROCEDURES: Horses performed HIT for 18 weeks. They ran at 90% or 110% of maximal oxygen consumption ((V)O(2max)) for 3 minutes (5 d/wk) and were subjected to incremental exercise testing (IET) before and after training. Blood samples were collected during IET, and muscle samples were obtained from the gluteus medius muscle immediately after IET. Phosphofructokinase, citrate synthase, and beta-3-hydroxyacyl CoA dehydrogenase (beta-HAD) activities were measured to determine glycolytic and oxidative capacities. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) and fatty acid translocase (FAT/CD36) protein contents were detected via western blotting. Metabolome analysis was performed via capillary electrophoresis-electrospray ionization mass spectrometry to measure substrate concentrations related to carbohydrate metabolism. RESULTS: Peak speed during IET and (V)O(2max) increased after HIT. Activities of citrate synthase and beta-HAD increased after HIT, whereas phosphofructokinase activity remained unchanged. The PGC-1alpha and FAT/CD36 protein contents increased after HIT, but plasma lactate concentration and the respiratory exchange ratio decreased after HIT. The plasma free fatty acid concentration increased after HIT, whereas the glucose concentration was not altered. Fructose 1,6-diphosphate, phosphoenolpyruvate, and pyruvate concentrations decreased after HIT. CONCLUSIONS AND CLINICAL RELEVANCE: HIT caused an increase in oxidative capacity in equine muscle, which suggested that there was a decreased reliance on carbohydrate utilization and a concomitant shift toward fatty acid utilization during intensive exercise. PMID- 23106471 TI - Evaluation of inflammatory and hemostatic surgical stress responses in male cats after castration under general anesthesia with or without local anesthesia. AB - OBJECTIVE: To characterize acute inflammatory and hemostatic surgical stress responses following castration in cats and to evaluate whether the addition of local anesthesia to the anesthetic protocol attenuates these responses. ANIMALS: 39 male cats. PROCEDURES: Cats undergoing castration were randomly assigned to 2 groups: both groups underwent surgery with general anesthesia, and 1 group additionally received a local anesthetic (lidocaine [2.0 mg/kg in total, divided intratesticularly and SC]) prior to incision. Blood samples were collected after anesthetic induction (baseline) and 1, 5, and 24 hours later. Thromboelastography and coagulation variables (activated partial thromboplastin time [aPTT] and prothrombin time [PT]) were analyzed; fibrinolysis was assessed with plasma D dimer concentrations. The acute-phase response was evaluated via measurement of plasma fibrinogen and serum amyloid A (last time point, 28 hours) concentrations. Hematologic variables were analyzed at baseline and 1, 5, and 24 hours later. RESULTS: Evidence of hemostatic and inflammatory activation after surgery was detected in both groups. Maximum amplitude and G (global clot strength) were significantly increased at 24 hours, and significant, but not clinically relevant, decreases were detected in aPTT at 5 and 24 hours and in PT at 24 hours, compared with baseline values. Serum amyloid A concentrations were significantly higher at 24 and 28 hours than at baseline, and plasma fibrinogen concentration was significantly increased at 24 hours; WBC and RBC counts and Hct were significantly increased at multiple time points. No differences between groups were detected for any variables. CONCLUSIONS AND CLINICAL RELEVANCE: Castration appeared to induce hypercoagulability and an acute-phase inflammatory response in cats. Local anesthesia with lidocaine did not attenuate this response. PMID- 23106472 TI - Evaluation of methods for cell harvesting and the biological properties at successive passages of canine bone marrow stromal cells. AB - OBJECTIVE: To compare methods for harvesting canine bone marrow stromal cells (BMSCs) and determine the biological properties of canine BMSCs at successive passages in vitro. SAMPLE: BMSCs collected from the femurs of 9 Beagles. PROCEDURES: A fibroblast assay was performed to compare 2 methods for harvesting BMSCs: the aspiration and perfusion method. Flow cytometric analysis was performed to evaluate the cell surface markers. Changes in proliferative activity were analyzed by examining radioactivity of hydrogen 3-thymidine. Cell senescence was studied via senescence-associated beta-galactosidase staining, and differentiation properties (osteogenesis and adipogenesis) were estimated in association with passage. RESULTS: The aspiration method yielded significantly more fibroblasts than the perfusion method. The cells harvested by both methods gave positive results for CD44 and CD90 and negative results for CD34 and CD45. After induction, the cells had osteogenic and adipogenic phenotypes. The biological properties of BMSCs harvested by the aspiration method were estimated in association with passage. With increasing number of passages, the proliferative activity was reduced and the proportion of cells with senescence associated beta-galactosidase staining was increased. The capacity of differentiation was reduced at passage 3. CONCLUSIONS AND CLINICAL RELEVANCE: The aspiration method was superior for collection of BMSCs. In early passages, canine BMSCs had the proliferative activity and potential of osteogenic and adipogenic differentiation, but this decreased with increased number of passages. Consideration of passage will be important to the success of any strategy that seeks to regenerate tissue though the use of BMSCs. PMID- 23106473 TI - Comparison of pharmacokinetic variables for creatinine and iohexol in dogs with various degrees of renal function. AB - OBJECTIVE: To compare pharmacokinetics and clearances of creatinine and iohexol as estimates of glomerular filtration rate (GFR) in dogs with various degrees of renal function. ANIMALS: 50 Great Anglo-Francais Tricolor Hounds with various degrees of renal function. PROCEDURES: Boluses of iohexol (40 mg/kg) and creatinine (647 mg/kg) were injected IV. Blood samples were collected before administration and 5 and 10 minutes and 1, 2, 4, 6, and 8 hours after administration. Plasma creatinine and iohexol concentrations were assayed via an enzymatic method and high-performance liquid chromatography, respectively. A noncompartmental approach was used for pharmacokinetic analysis. Pharmacokinetic variables were compared via a Bland-Altman plot and an ANOVA. RESULTS: Compared with results for creatinine, iohexol had a significantly higher mean +/- SD plasma clearance (3.4 +/- 0.8 mL/min/kg vs 3.0 +/- 0.7 mL/min/kg) and a significantly lower mean volume of distribution at steady state (250 +/- 37 mL/kg vs 539 +/- 73 mL/kg), mean residence time (80 +/- 31 minutes vs 195 +/- 73 minutes), and mean elimination half-life (74 +/- 20 minutes vs 173 +/- 53 minutes). Despite discrepancies between clearances, especially for high values, the difference was < 0.6 mL/min/kg for 34 (68%) dogs. Three dogs with a low GFR (< 2 mL/min/kg) were classified similarly by both methods. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma iohexol and creatinine clearances can be used interchangeably for screening patients suspected of having chronic kidney disease (ie, low GFR), but large differences may exist for dogs with a GFR within or above the reference range. PMID- 23106474 TI - The prognosis of idiopathic generalized epilepsy. AB - Prognosis describes the trajectory and long-term outcome of a condition. Most studies indicate a better prognosis in idiopathic generalized epilepsy (IGE) in comparison with other epilepsy syndromes. Studies looking at the long-term outcome of different IGE syndromes are relatively scant. Childhood absence epilepsy appears to have a higher rate of remission compared to juvenile absence epilepsy. In absence epilepsies, development of myoclonus and generalized tonic clonic seizures predicts lower likelihood of remission. Although most patients with juvenile myoclonic epilepsy (JME) achieve remission on antiepileptic drug therapy, <20% appear to remain in remission without treatment. Data on the prognosis of other IGE syndromes are scarce. There are contradictory findings reported on the value of electroencephalography as a predictor of prognosis. Comparisons are made difficult by study heterogeneity, particularly in methodology and diagnostic criteria. PMID- 23106475 TI - Interpretation of multisegment bronchoalveolar lavage in cats (1/2001-1/2011). AB - BACKGROUND: Cytologic results from bronchoscopic BAL in cats with naturally occurring respiratory disease have not been reported, and the clinical utility of multisegment lavage has not been evaluated. HYPOTHESIS: BAL cytology from 2 separate lung segments in cats will have similar cell counts, cytologic interpretation, or both. ANIMALS: Eighty-seven cases in 85 cats (2 examined twice) with naturally occurring lower respiratory disease. METHODS: A combined prospective/retrospective evaluation of all cats with multisegment BAL was performed. BAL fluid was evaluated for total nucleated cell counts, differential cell counts, and cytologic characteristics at each lavage site. BAL fluid was categorized as eosinophilic, neutrophilic, lymphocytic, hypercellular, or mixed. Radiographs were assessed for diffuse or focal disease. RESULTS: Clinical diagnoses included inflammatory airway disease (n = 63), pneumonia (n = 15), neoplasia (n = 6), and undetermined (n = 3). Total nucleated cell counts varied between sites regardless of radiographic evidence of focal or diffuse radiographic disease. In 28/87 cases (32%), cell counts differed between lavage sites by 2.2-40 fold. BAL yielded similar cytologic interpretation of inflammation in 45/87 (52%) cases. In 8/14 cases that had BAL performed at the site of a focal radiographic infiltrate, as well as at a site of diffuse infiltrates, the same inflammatory interpretation was made at each site. CONCLUSIONS AND CLINICAL IMPORTANCE: Total and differential cell counts in BAL fluid often differ between lung segments in cats with lower respiratory disease, and caution is warranted when using a single BAL cytology to define the inflammatory response in cats with spontaneously occurring lower respiratory tract disease. PMID- 23106476 TI - Adiposity blunts the positive relationship of thyrotropin with proprotein convertase subtilisin-kexin type 9 levels in euthyroid subjects. AB - BACKGROUND: Effects of thyroid function status on lipoprotein metabolism may extend into the euthyroid range. Low-density lipoprotein (LDL) metabolism is governed by proprotein convertase subtilisin-kexin type 9 (PCSK9), which down regulates LDL receptor expression, resulting in higher LDL cholesterol (LDL-C). Here, we tested whether plasma PCSK9 correlates with thyroid function in nonobese and obese euthyroid subjects. METHODS: We assessed the extent to which plasma PCSK9 is determined by thyrotropin (TSH) in 74 euthyroid subjects (31 women; TSH between 0.5 and 4.0 mU/L and free thyroxine [FT4] between 11.0 and 19.5 pM) with varying degrees of obesity (body mass index [BMI] ranging from 20.2 to 40.4 kg/m(2)). RESULTS: TSH, FT4, PCSK9, non-high-density lipoprotein cholesterol (non HDL-C), LDL-C, and apolipoprotein B (apoB) levels were not different between 64 nonobese subjects (BMI<30 kg/m(2)) and 10 obese subjects (BMI>=30 kg/m(2); p>0.20 for each). PCSK9 correlated positively with TSH in nonobese subjects (r=0.285, p=0.023). In contrast, PCSK9 was not associated positively with TSH in obese subjects (r=-0.249, p=0.49). The relationship of PCSK9 with TSH was different between nonobese and obese subjects when taking age, sex, FT4, and the presence of anti-thyroid antibodies into account (multiple linear regression analysis: beta=-0.320, p=0.012 for the interaction term between the presence of obesity and TSH on PCSK9), and was also modified by BMI as a continuous trait (beta=-0.241, p=0.062 for the interaction term between BMI and TSH on PCSK9). Non-HDL-C, LDL-C, and apoB levels were dependent on PCSK9 in nonobese subjects (p<=0.01 for each), but not in obese subjects (p>0.50), Accordingly, BMI interacted negatively with PCSK9 on non-HDL-C (p=0.028) and apoB (p=0.071). CONCLUSIONS: This study suggests that circulating PCSK9 levels correlate with thyroid function even in the normal range. This relationship appears to be blunted by obesity. Thyroid functional status may influence cholesterol metabolism through the PCSK9 pathway. PMID- 23106477 TI - Role of vernalization and of duplicated FLOWERING LOCUS C in the perennial Arabidopsis lyrata. AB - FLOWERING LOCUS C (FLC) is one of the main genes influencing the vernalization requirement and natural flowering time variation in the annual Arabidopsis thaliana. Here we studied the effects of vernalization on flowering and its genetic basis in the perennial Arabidopsis lyrata. Two tandemly duplicated FLC genes (FLC1 and FLC2) were compared with respect to expression and DNA sequence. The effect of vernalization on flowering and on the expression of FLC1 was studied in three European populations. The genetic basis of the FLC1 expression difference between two of the populations was further studied by expression quantitative trait locus (eQTL) mapping and sequence analysis. FLC1 was shown to have a likely role in the vernalization requirement for flowering in A. lyrata. Vernalization decreased its expression and the northern study populations showed higher FLC1 expression than the southern one. eQTL mapping between two of the populations revealed one eQTL affecting FLC1 expression in the genomic region containing the FLC genes. Most FLC1 sequence differences between the study populations were found in the promoter region and in the first intron. Variation in the FLC1 sequence may cause differences in FLC1 expression between late- and early-flowering A. lyrata populations. PMID- 23106478 TI - A common problem for neonatal intensive care units: late preterm infants, a prospective study with term controls in a large perinatal center. AB - Compared with term infants, late preterm infants are immature physiologically and metabolically, and have higher risks for medical complications such as respiratory distress, hypoglycemia, hyperbilirubinemia, sepsis, feeding difficulty and poor neurodevelopmental outcomes. The incidence of late preterm birth is increasing. We evaluated the clinical and demographic characteristics, short-term outcomes and clinical courses of late preterm infants admitted to our neonatal intensive care unit (NICU). Data from NICU admissions of 605 late preterm and 1477 term infants in the 1-year period between June 2010 and May 2011 were analyzed. There were 2004 late preterm deliveries and 18,854 total deliveries. Of late preterm infants, 30% were admitted to the NICU. The mean gestational age and birth weight were 35(1/7) weeks and 2352 g, respectively. The admission diagnoses were respiratory distress (46.5%), low birth weight (17.5%), jaundice (13.7%), feeding difficulty (13.1%), polycythemia (8.1%) and hypoglycemia (4%); these morbidity rates were higher than those in term infants (p < 0.001). The overall mean hospitalization period was 7.5 +/- 9.1 days. The respective mortality and rehospitalization rates were 2.1% and 4.4%, which were higher than those for term infants (p < 0.001). In conclusion, late preterm infants should be followed closely for the complications just after birth, and preventive strategies should be developed. PMID- 23106479 TI - Development of a 16S-23S rRNA intergenic spacer-based quantitative PCR assay for improved detection and enumeration of Lactococcus garvieae. AB - Lactococcus garvieae is an important foodborne pathogen causing lactococcosis associated with hemorrhagic septicemia in fish worldwide. A real-time quantitative polymerase chain reaction (qPCR) protocol targeting the 16S-23S rRNA intergenic spacer (ITS) region was developed for the detection and enum-eration of L. garvieae. The specificity was evaluated using genomic DNAs extracted from 66 cocci strains. Fourteen L. garvieae strains tested were positive, whereas 52 other strains including Lactococcus lactis ssp. lactis, Lactococcus lactis ssp. hordniae and Lactococcus lactis ssp. cremoris did not show a specific signal. The minimal limit of detection was 2.63 fg of purified genomic DNA, equivalent to 1 genome of L. garvieae. The optimized protocol was applied for the survey of L. garvieae in naturally contaminated fish samples. Our results suggest that the qPCR protocol using ITS is a sensitive and efficient tool for the rapid detection and enumeration of L. garvieae in fish and fish-containing foods. PMID- 23106480 TI - Cross-sectional assessment of pain and physical function in skeletal dysplasia patients. AB - Short stature skeletal dysplasia (SD) patients have orthopedic and neurologic complications causing significant pain and physical disability. We conducted a large cross-sectional online survey in 361 people with short stature SD (>10 years) to describe pain prevalence, characteristics, and the relationship between pain and function. Chronic pain prevalence per Brief Pain Inventory (BPI) was 70.3%. Women reported more pain than men (73% vs 63% p = 0.04). Pain Severity Score (average of current, worst, least and average pain) averaged 3.3 +/- 2, while the Pain Interference Score (with daily activities) averaged 3.4 +/- 2.7 on a 10-point scale. Per Bleck scale, 20.5% had little or no functional capacity. Increasing age and decreased ambulation independently predicted chronic pain. Chronic pain is prevalent in short stature SD patients and associated with poor physical function. Further study is required to clarify the temporal relationship among pain, function and treatments. PMID- 23106481 TI - The problem with peptide presumption and the downfall of target-decoy false discovery rates. AB - In proteomics, peptide-tandem mass spectrum match scores and target-decoy database derived false discovery rates (FDR) are confidence indicators describing the quality of individual and sets of tandem mass spectrum matches. A user can impose a standard by prescribing a limit to these values, equivalent to drawing a line that separates better from poorer quality matches. As a result of setting narrower parent ion mass tolerances to reflect the better resolution of modern mass spectrometers, target-decoy derived FDRs can diminish. FDRs lowered this way consequently drive down the lower-limit for peptide-spectrum match score acceptance. Hence, data quality confidence appears to improve even while fragmentation evidence for some spectra remains weak. One negative outcome can be the presumed identification of peptides that do not exist. The options researchers have to improve proteomics data confidence are not panaceas, and there may be no satisfying solution as long as peptides are identified from a circumscribed list of proteins scientists wish to find. PMID- 23106483 TI - 'Cobblestone' papillomatous linear papules of the upper lip: a new sign of Costello syndrome. PMID- 23106482 TI - Chemical constituents of Arisaema franchetianum tubers. AB - A novel pyrrolidine alkaloid, (2R*,3S*,5S*)-N,2-dimethyl-3-hydroxy-5-(10 phenyldecyl)pyrrolidine (1), and 17 known compounds were isolated from Arisaema franchetianum Engl. (Araceae) tubers. The 17 compounds were bergenin (2), emodin (3), caffeic acid (4), nobiletin (5), 3-O-beta-d-galactopyranosyl-hederagenin 28 O-beta-d-xylopyranosyl(1 -> 6)-beta-d-galactopyranosyl ester (6), coniferin (7), qingyangshengenin (8), methylconiferin (9), syringaresinol 4'-O-beta-d glucopyranoside (10), gagaminine (11), perlolyrine (12), (S)-1-(1'-hydroxyethyl) beta-carboline (13), 1-(beta-carboline-1-yl)-3,4,5-trihydroxy-1-pentanone (14), 1 methoxycarbonyl-beta-carboline (15), indolo[2,3-alpha]carbazole (16), 4 hydroxycinnamic acid methyl ester (17), and methyl 4-[2-hydroxy-2-(4-hydroxy-3 methoxyphenyl)-1-(hydroxymethyl)ethyl] ferulate (18). The inhibitory activities of compound 1 and its N-methyl derivative (1a) against porcine respiratory and reproductive syndrome virus (PRRSV), human leukemic K562 cells, and human breast cancer MCF-7 cells were evaluated. Compounds 1 [50% inhibited concentration (IC(50)) = 12.5 +/- 0.6 MUM] and 1a (IC(50) = 15.7 +/- 0.9 MUM) were cytotoxic against K562 cells. Compound 1a also had a weak effect on PRRSV with an IC(50) value of 31.9 +/- 6.0 MUM [selectivity index (SI) = 18.7]. PMID- 23106484 TI - Extracellular matrix rigidity controls podosome induction in microvascular endothelial cells. AB - BACKGROUND INFORMATION: Podosomes are actin-based structures involved in cell adhesion, migration, invasion and extracellular matrix degradation. They have been described in large vessel endothelial cells, but nothing is known concerning microvascular endothelial cells. Here, we focussed on liver sinusoidal endothelial cells (LSECs), fenestrated microvascular cells that play major roles in liver physiology. Liver fibrosis induces a dedifferentiation of LSECs leading notably to a loss of fenestrae. Because liver fibrosis is associated with increased matrix stiffness, and because substrate stiffness is known to regulate the actin cytoskeleton, we investigated the impact of matrix rigidity on podosome structures in LSECs. RESULTS: Using primary LSECs, we demonstrated that microvascular endothelial cells are able to form constitutive podosomes. Podosome presence in LSECs was independent of cytokines such as transforming growth factor beta or vascular endothelial growth factor, but could be modulated by matrix stiffness. As expected, LSECs lost their differentiated phenotype during cell culture, which was paralleled by a loss of podosomes. LSECs however retained the capacity to form active podosomes following detachment/reseeding or actin destabilising drug treatments. Finally, constitutive podosomes were also found in primary microvascular endothelial cells from other organs. CONCLUSIONS: Our results show that microvascular endothelial cells are able to form podosomes without specific stimulation. Our data suggest that the major determinant of podosome induction in these cells is substrate rigidity. PMID- 23106485 TI - Endolymphatic hydrops revealed by magnetic resonance imaging in patients with atypical Meniere's disease. AB - CONCLUSION: Our study showed that patients with atypical Meniere's disease had endolymphatic hydrops (EH) in both the cochlea and the vestibule. Using an imaging method, we provide evidence that atypical Meniere's disease is a true variant of classic Meniere's disease. OBJECTIVES: The aim of present study was to investigate images of the endolymphatic space in patients with atypical Meniere's disease (cochlear and vestibular Meniere's disease). METHODS: Sixty-four patients divided into two groups were enrolled in this study. The first group included 36 patients who had fluctuating hearing loss without vertigo, as candidates for cochlear Meniere's disease (CMD). The second group included 28 patients who had recurrent vertigo without hearing loss, as candidates for vestibular Meniere's disease (VMD). The patients underwent 3 T magnetic resonance imaging (MRI) after injection of gadolinium enhancement medium intratympanically or intravenously. We evaluated EH using MRI. RESULTS: Of 56 ears (36 patients) with CMD, 38 showed EH in the cochlea and 44 showed EH in the vestibule. Of 56 ears (28 patients) with VMD, 29 showed EH in the cochlea and 47 showed EH in the vestibule. The VMD group had a significant vestibular predominance in EH distribution whereas the CMD group showed no significant regional predominance of EH. PMID- 23106486 TI - Re: Prevalence of ejaculatory disorders in urban men-results of a random-sample survey. PMID- 23106487 TI - Detection and quantitation of trace phenolphthalein (in pharmaceutical preparations and in forensic exhibits) by liquid chromatography-tandem mass spectrometry, a sensitive and accurate method. AB - Phenolphthalein, an acid-base indicator and laxative, is important as a constituent of widely used weight-reducing multicomponent food formulations. Phenolphthalein is an useful reagent in forensic science for the identification of blood stains of suspected victims and for apprehending erring officials accepting bribes in graft or trap cases. The pink-colored alkaline hand washes originating from the phenolphthalein-smeared notes can easily be determined spectrophotometrically. But in many cases, colored solution turns colorless with time, which renders the genuineness of bribe cases doubtful to the judiciary. No method is known till now for the detection and identification of phenolphthalein in colorless forensic exhibits with positive proof. Liquid chromatography-tandem mass spectrometry had been found to be most sensitive, accurate method capable of detection and quantitation of trace phenolphthalein in commercial formulations and colorless forensic exhibits with positive proof. The detection limit of phenolphthalein was found to be 1.66 pg/L or ng/mL, and the calibration curve shows good linearity (r(2) = 0.9974). PMID- 23106489 TI - Role of inter- and intramolecular bonding on impact sensitivity. AB - A picture of impact sensitivity based on the bond bundles of the electron charge density is developed, allowing the role of both inter- and intramolecular bonding interactions to be investigated. Impact sensitive materials were found to have a convergent intramolecular bond bundle with a low electron count that serves as a trigger linkage, while insensitive materials do not. The shape and electron count of the intramolecular bond bundles was found to change between the gas phase and solid state due to the formation of intermolecular bond bundles. In the case of polynitrobenzenes, this change was subtle and did not affect the trigger linkages. However, the intermolecular bond bundles in crystalline RDX (hexahydro 1,3,5-trinitro-1,3,5-triazine) change from C-N trigger linkages in the gas phase to N-N trigger linkages in the solid state. This observation offers a theoretical justification of the experimentally observed differences in the decomposition behavior of gas phase and crystalline RDX. PMID- 23106488 TI - Genetic epidemiology of Charcot-Marie-Tooth disease. AB - BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The frequency of different CMT genotypes has been estimated in clinic populations, but prevalence data from the general population is lacking. Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth disease type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. The CMT phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P(0) ) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. X-linked Charcot-Marie Tooth disease (CMTX) is caused by mutations in the connexin32 (cx32) gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions. AIMS: Estimate prevalence of CMT. Estimate frequency of Peripheral Myelin Protein 22 (PMP22) duplication and point mutations, insertions and deletions in Cx32, Early growth response 2 (EGR2), MFN2, MPZ, PMP22 and Small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Description of novel mutations in Cx32, MFN2 and MPZ. Description of de novo mutations in MFN2. MATERIAL AND METHODS: Our population based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist, and classified clinically, neurophysiologically and genetically. Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included in the MFN2 study. We screened for point mutations in the MFN2 gene. We describe four novel mutations, two in the connexin32 gene and two in the MPZ gene. RESULTS: A total of 245 affected from 116 CMT families from the general population of eastern Akershus county were included in the genetic epidemiological survey. In the general population 1 per 1214 persons (95% CI 1062-1366) has CMT. Charcot-Marie Tooth disease type 1 (CMT1), CMT2 and intermediate CMT were found in 48.2%, 49.4% and 2.4% of the families, respectively. A mutation in the investigated genes was found in 27.2% of the CMT families and in 28.6% of the affected. The prevalence of the PMP22 duplication and mutations in the Cx32, MPZ and MFN2 genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations, insertions or deletions in the EGR2, PMP22 or SIMPLE genes. Four known and three novel mitofusin 2 (MFN2) point mutations in 8 unrelated Norwegian CMT families were identified. The novel point mutations were not found in 100 healthy controls. This corresponds to 3.4% (8/232) of CMT families having point mutations in MFN2. The phenotypes were compatible with CMT1 in two families, CMT2 in four families, intermediate CMT in one family and distal hereditary motor neuronopathy (dHMN) in one family. A point mutation in the MFN2 gene was found in 2.3% of CMT1, 5.5% of CMT2, 12.5% of intermediate CMT and 6.7% of dHMN families. Two novel missense mutations in the MPZ gene were identified. Family 1 had a c.368G>A (Gly123Asp) transition while family 2 and 3 had a c.103G>A (Asp35Asn) transition. The affected in family 1 had early onset and severe symptoms compatible with Dejerine Sottas syndrome (DSS), while affected in family 2 and 3 had late onset, milder symptoms and axonal neuropathy compatible with CMT2. Two novel connexin32 mutations that cause early onset X-linked CMT were identified. Family 1 had a deletion c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247 while family 2 had a c.536G>A (Cys179Tyr) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade and the nerve conduction velocities were in the intermediate range. DISCUSSION: Charcot-Marie-Tooth disease is the most common inherited neuropathy. At present 47 hereditary neuropathy genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is likely that at least 30-50 CMT genes are yet to be identified. The identified known and novel point mutations in the MFN2 gene expand the clinical spectrum from CMT2 and intermediate CMT to also include possibly CMT1 and the dHMN phenotypes. Thus, genetic analyses of the MFN2 gene should not be restricted to persons with CMT2. The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and DSS, while milder changes cause the phenotypes CMT1 and CMT2. The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode. CONCLUSION: Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 1214. CMT1 and CMT2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype- phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. Two novel phenotypes were ascribed to the MFN2 gene, however further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN. PMID- 23106491 TI - General one-step self-assembly of isostructural intermetallic Co(II)(3)Ln(III) cubane aggregates. AB - A new family of Co/rare-earth intermetallic cubane aggregates [Co3Ln(hmp)4(OAc)5H2O] (Ln = Dy, Ho, Er, Tm, Yb, Y) have been synthesized by self assembly. Single-crystal X-ray diffraction analysis revealed that they are remarkably isostructural in showing a common [Co3Ln] core. Magnetic studies showed that the Dy, Er, Tm, Yb, and Y complexes are ferromagnetic. The Dy complex exhibits the largest magnetocaloric effect (-DeltaSm = 12.58 J kg(-1) K(-1)), which can be attributed to the large magnetic density of Dy(III). PMID- 23106490 TI - Neural regulation of the time course for cocaine-cue extinction consolidation in rats. AB - Sites within the hippocampus, amygdala and prefrontal cortex may regulate how responses maintained by cues associated with cocaine are extinguished. To test the role of various brain sites in the consolidation of cocaine-cue extinction learning, the dorsal subiculum (dSUB), rostral basolateral amygdala (rBLA) and infralimbic prefrontal cortex (IL) were manipulated in rats. Following cocaine self-administration training (cues present, cocaine available), responding was assessed during 1-h extinction tests (cues present, no cocaine available). To study extinction consolidation specifically, the protein synthesis inhibitor anisomycin or vehicle was infused bilaterally into the dSUB, rBLA or IL either immediately following or 6 h after the first two of three extinction training sessions. With manipulations made immediately after extinction sessions, infusions of anisomycin into the dSUB or the rBLA deterred extinction. Rats maintained elevated levels of cocaine seeking relative to vehicle despite the absence of cocaine delivery. Manipulations of IL had no effect. Control studies showed that bilateral protein synthesis inhibition in dSUB and rBLA 6 h after the extinction sessions ended was unable to deter extinction. Rats reduced cocaine seeking in the usual manner in the absence of cocaine delivery. Collectively, these findings suggest that the dSUB and rBLA are neural substrates important for consolidation of cocaine-cue extinction learning and have time-dependent roles. Understanding the contribution of individual neural substrates for cocaine-cue extinction consolidation may help guide treatment strategies aimed at enhancing cue exposure therapy in cocaine-dependent people. PMID- 23106492 TI - Differential immune response in mice immunized with the A, R or C domain from TcSP protein of Trypanosoma cruzi or with the coding DNAs. AB - In a murine model of experimental Trypanosoma cruzi (H8 strain) infection, we investigated the induction of protective immunity against the domains [amino (A), repeats (R) and carboxyl (C)] of the surface protein (SP), a member of the trans sialidase (TS) superfamily. Recombinant proteins and plasmid DNA coding for the respective proteins were used to immunize BALB/c mice, and the humoral response and cytokine levels were analysed. Immunization with the recombinant proteins induced higher levels of anti-TcSP antibodies than immunization with the corresponding DNAs, and analysis of serum cytokines showed that immunization with both recombinant proteins and naked DNA resulted in a Th1-Th2 mixed T-cell response. Mice immunized with either recombinant proteins or plasmid DNA were infected with blood trypomastigotes. The recombinant protein-immunized mice showed a variable reduction in peak parasitemia, and most died by day 60. Only the pBKTcSPR-immunized mice exhibited a significant reduction in peak parasitemia and survived the lethal challenge. DNA-based immunization with DNA coding for the repeats domain of TcSP is a good candidate for the development of a vaccine against experimental T. cruzi infection. PMID- 23106493 TI - Children monosensitized to pine nuts have similar patterns of sensitization. AB - BACKGROUND: Several cases of pine nut allergies and anaphylaxis have been reported in the literature, but only few pine nut allergens have been characterized. The aim of this research is to identify through immunoelectrophoretic techniques the major pine nut allergens in a group of children monosensitized to pine nuts. METHODS: We studied five children with pine nut allergies and no other sensitization to food except to pine nuts, confirmed by in vivo (prick test, prick-to-prick) and in vitro tests (specific IgE determinations [CAP-FEIA]). The protein profile of pine nuts was analyzed by Sodium Dodecyl sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE). Immunoblotting was performed after incubation of membranes with the sera from the children included in the present study. RESULTS: Immunoblotting (SDS-PAGE) demonstrated five similar bands between 6 and 47 kDa in all the subjects studied. CONCLUSION: These bands should be considered the potential allergens for pine nut allergic children. PMID- 23106495 TI - Au/Au@polythiophene core/shell nanospheres for heterogeneous catalysis of nitroarenes. AB - Monodisperse Au/Au@polythiophene core/shell nanospheres were facilely prepared through the reduction of gold precursor, AuCl4-, by 2-thiopheneacetonitrile in an aqueous solution. Concomitantly, 2-thiopheneacetonitrile polymerized during this redox process. As a result, Au nanoparticle was encapsulated by conductive polymer shell to afford novel core/shell nanospheres. Interestingly, the shell was composed of very tiny Au nanoparticles surrounded with thiophene polymers. Thus, the new material is best described as Au/Au@polythiophene core/shell nanospheres. FT-IR spectroscopy revealed that the Au nanoparticles were coordinated by the C=N groups of the polythiophene shell. Some of the C=N groups were partially hydrolyzed into COOH groups during the redox process because of the acidic reaction condition. The shell was conductive based on the typical ohmic behavior found in electrical measurement. The Au/Au@polythiophene core/shell nanospheres were found to be very active catalysts for the hydrogenation of various nitroarene compounds into corresponding aminoarene compounds in the presence of NaBH4. Both hydrophilic and hydrophobic nitroarenes were efficiently hydrogenated under mild conditions. PMID- 23106494 TI - The C-terminal domain of tetanus toxin protects motoneurons against acute excitotoxic damage on spinal cord organotypic cultures. AB - The C-terminal domain of tetanus toxin (Hc-TeTx) has been suggested to act as a neuroprotective agent by activating signaling pathways related to neurotrophins and also to exert anti-apoptotic effects. Here, we show the beneficial properties of the recombinant protein Hc-TeTx to protect spinal motoneurons against excitotoxic damage. In vitro spinal cord organotypic cultures were used to assess acute glutamate excitotoxic damage. Our results indicate that Hc-TeTx treatment improves motoneuron survival within a short therapeutical window (the first 2 h post-injury). Within this interval, we found that p44/p42 MAP kinase (ERK1/2) and glycogen synthase kinase-3 (GSK3beta) signaling pathways play a crucial role in the neuroprotective effect. Moreover, we demonstrated that Hc-TeTx treatment initiate autophagy which is ERK1/2- and GSK3beta-dependent. These findings suggest a possible therapeutical tool to improve motoneuron survival immediately after excitotoxic insults or during the secondary injury phase that occurs after spinal cord trauma. PMID- 23106496 TI - Reconstructing the evolutionary history of an endangered subspecies across the changing landscape of the Great Central Valley of California. AB - Identifying historic patterns of population genetic diversity and connectivity is a primary challenge in efforts to re-establish the processes that have generated and maintained genetic variation across natural landscapes. The challenge of reconstructing pattern and process is even greater in highly altered landscapes where population extinctions and dramatic demographic fluctuations in remnant populations may have substantially altered, if not eliminated, historic patterns. Here, we seek to reconstruct historic patterns of diversity and connectivity in an endangered subspecies of woodrat that now occupies only 1-2 remnant locations within the highly altered landscape of the Great Central Valley of California. We examine patterns of diversity and connectivity using 14 microsatellite loci and sequence data from a mitochondrial locus and a nuclear intron. We reconstruct temporal change in habitat availability to establish several historical scenarios that could have led to contemporary patterns of diversity, and use an approximate Bayesian computation approach to test which of these scenarios is most consistent with our observed data. We find that the Central Valley populations harbour unique genetic variation coupled with a history of admixture between two well differentiated species of woodrats that are currently restricted to the woodlands flanking the Valley. Our simulations also show that certain commonly used analytical approaches may fail to recover a history of admixture when populations experience severe bottlenecks subsequent to hybridization. Overall our study shows the strength of combining empirical and simulation analyses to recover the history of populations occupying highly altered landscapes. PMID- 23106497 TI - Paratuberculosis (Johne's disease) in cattle and other susceptible species. AB - Paratuberculosis (Johne's disease) is a widespread and costly disease. This consensus statement will summarize recommendations regarding diagnosis, control, and treatment of Johne's disease in cattle and other species. Each section of recommendations is followed by a statement that subjectively characterizes the strength of the supporting evidence. The role played by Mycobacterium avium subsp. paratuberculosis (MAP) in the pathogenesis has been a matter of controversy for many years. This statement concludes with an assessment of the evidence in favor of MAP as a potential zoonotic pathogen. PMID- 23106498 TI - In antisynthetase syndrome, amyloidosis is rare and might not be related to the disease. PMID- 23106499 TI - Protein-losing enteropathy in a dog with lymphangiectasia, lymphoplasmacytic enteritis and pancreatic exocrine insufficiency. AB - This is a report of seven-year-old male Akita mixed dog, with protein-losing enteropathy (PLE). He had a history of chronic vomiting and diarrhea with anorexia/hyporexia. Previously he suffered acute abdomen about eight months prior to this visit. Our dog showed uncommon combination of diseases that could cause PLE since it was affected by inflammatory bowel disease (IBD), intestinal lymphangiectasia (IL), and exocrine pancreatic insufficiency (EPI). The dog had most of the abnormalities found in IL, as well as hypoalbuminemia, hyperglobulinemia, lymphopenia, hypocalcemia, and hypercholesterolemia. During endoscopy exam, we found changes characteristic of IL such as irregular small white spots. We took biopsies from stomach, duodenum, and cecum. These biopsies showed infiltration by lymphocytes and plasmatic cells in the lamina propria also, the duodenal biopsies showed moderate dilation of the lymphatic vessels. The patient had 2.1 ug/mL of TLI, this result was compatible with EPI. We assume that the first pathology in this animal was IBD, which caused chronic pancreatitis (CP) that in turn progressed to EPI. It is also possible that IL was secondary to IBD. We have reported for the first time the correlation of IBD and EPI in dogs. This should change our approach to treating chronic diarrhea in dogs. Therefore, we propose that dogs diagnosed with EPI should also be subjected to endoscopy and intestinal biopsy. Similarly, to rule out secondary EPI, TLI should be measured routinely in dogs with IBD. PMID- 23106500 TI - Protection of salvianolic acid A on rat brain from ischemic damage via soluble epoxide hydrolase inhibition. AB - Epoxyeicosatrienoic acids (EETs) and their regulating enzyme soluble epoxide hydrolase (sEH) have been associated with ischemic stroke. Salvianolic acid A (SAA) is proved to display potent cerebroprotection. However, little information is available about the link between them. This study aimed to investigate whether SAA exhibits its protective effects in rats subjected to middle cerebral artery occlusion (MCAO) through sEH and EETs. The results showed that SAA treatment ameliorated neurological deficits and reduced infarct volume. Notably, the beneficial effects of SAA were attenuated by co-administration of (14,15 epoxyeicosa-5(Z)-enoic acid (14,15-EEZE)), a putative selective EETs antagonist. Furthermore, SAA increased the 14,15-EET levels in the blood and brain of sham and MCAO rats. Assay for hydrolase activity showed that 1 and 3 mg/kg of SAA significantly diminished brain sEH activity of MCAO rats. A fluorescent assay in vitro indicated that SAA could inhibit recombinant human sEH activity in a concentration-dependent manner (IC(50) = 1.62 MUmol/l). Immunohistochemical analysis showed that SAA at the doses of 1 and 3 mg/kg significantly decreased sEH protein expression in hippocampus CA1 region of MCAO rats. In conclusion, cerebral protection of SAA is mediated, at least in part, via inhibiting sEH to increase EETs levels. PMID- 23106501 TI - Protein crystallization and biosensor applications of hydrogel-based molecularly imprinted polymers. AB - We have characterized the imprinting capability of a family of acrylamide polymer based molecularly imprinted polymers (MIPs) for bovine hemoglobin (BHb) and trypsin (Tryp) using spectrophotometric and quartz crystal microbalance (QCM) sensor techniques. Bulk gel characterization on acrylamide (AA), N hydroxymethylacrylamide (NHMA), and N-isopropylacrylamide (NiPAM) gave varied selectivities when compared with nonimprinted polymers. We have also harnessed the ability of the MIPs to facilitate protein crystallization as a means of evaluating their selectivity for cognate and noncognate proteins. Crystallization trials indicated improved crystal formation in the order NiPAM0.05). Results: All the implants were osseointegrated. Four control implants were excluded from the analysis due to the exposure of the coronal portion of the fixture. At T1, T2 and T3, statistically significant differences were found by comparing the mean width of the bucco-lingual bone between control and test groups. The mean values decreased during the observation period in both groups; statistically significant differences within controls were detected at T1, T2 and T3, and at T2 and T3 within tests. Conclusions: The outcomes of present study suggested that porcine bone enabled to avoid bucco lingual crestal bone changes in implants immediately placed in fresh extraction sockets. PMID- 23106507 TI - Antibiotic susceptibility of periodontal Enterococcus faecalis. AB - BACKGROUND: Enterococcus faecalis may contribute to periodontal breakdown in heavily infected subgingival sites, particularly in patients responding poorly to mechanical forms of periodontal therapy. Because only limited data are available on the antimicrobial sensitivity of enterococci of subgingival origin, this study evaluates the in vitro antibiotic susceptibility of E. faecalis isolated from periodontitis patients in the United States. METHODS: Pure cultures of 47 subgingival E. faecalis clinical isolates were each inoculated onto specially prepared broth microdilution susceptibility panels containing vancomycin, teicoplanin, and six oral antibiotics of potential use in periodontal therapy. After incubation in ambient air for 18 to 20 hours, minimal inhibitory drug concentrations were determined using applicable Clinical and Laboratory Standards Institute criteria and interpretative guidelines. The organisms were additionally evaluated for in vitro resistance to metronidazole at 4 MUg/mL. RESULTS: Periodontal E. faecalis exhibited substantial in vitro resistance to tetracycline (53.2% resistant), erythromycin (80.8% resistant or intermediate resistant), clindamycin (100% resistant to 2 MUg/mL), and metronidazole (100% resistant to 4 MUg/mL). In comparison, the clinical isolates were generally sensitive to ciprofloxacin (89.4% susceptible; 10.6% intermediate resistant) and 100% susceptible in vitro to ampicillin, amoxicillin/clavulanate, vancomycin, and teicoplanin. CONCLUSIONS: Tetracycline, erythromycin, clindamycin, and metronidazole revealed poor in vitro activity against human subgingival E. faecalis clinical isolates, and would likely be ineffective therapeutic agents against these species in periodontal pockets. Among orally administered antibiotics, ampicillin, amoxicillin/clavulanate, and ciprofloxacin exhibited marked in vitro inhibitory activity against periodontal E. faecalis, and may be clinically useful in treatment of periodontal infections involving enterococci. PMID- 23106508 TI - Periodontal disease and pregnancy hypertension: a clinical correlation. AB - BACKGROUND: Periodontal disease is thought to be associated with increased risk of systemic diseases and adverse pregnancy outcomes, including pregnancy hypertension (PH). The aim of the present study is to find the prevalence of periodontal disease in females with PH in a rural-based medical institute. METHODS: The present case control study was performed with 200 females, 100 with PH and 100 without PH. Antenatal periodontal screening was performed within 72 hours of their hospital admission for delivery. The periodontal parameters assessed were oral hygiene index-simplified, gingival index, mean probing depth, and loss of attachment. RESULTS: Prevalence of periodontal disease was 65.5% and was significantly higher (P <0.0001) in females with hypertension (relative risk = 1.5; 95% confidence interval [CI] = 1.3 to 1.9). Socioeconomic status, education, occupation, and body mass index did not appear to influence the relationship between periodontal disease and PH on bivariate multiple logistic regression analysis. Nulliparous females were at higher odds to develop periodontal disease and PH (odds ratio = 1.7; 95% CI = 0.5 to 6.1). As the severity of periodontal disease increased from moderate to severe, the severity of hypertension also increased (r(2) = 0.8 and 0.5 for moderate and severe periodontal disease, respectively). CONCLUSION: Periodontal disease is more prevalent in females with PH. PMID- 23106509 TI - Effect of essential oil and chlorhexidine mouthwashes on gingival fibroblast survival and migration. AB - BACKGROUND: Chemical plaque control is the most commonly recommended means of oral hygiene after periodontal surgery. Commercially available mouthwashes contain a variety of active ingredients that have bactericidal properties but may potentially be toxic to the host cells. The goal of this in vitro study is to investigate the effect of commercially available mouthwashes on the survival and migratory capacity of human fibroblasts. METHODS: Human gingival and periodontal ligament (PDL) fibroblasts were treated with commercially available mouthwashes that contained either chlorhexidine (CHX) or essential oils (EO) as the active ingredient. Each mouthwash was tested over a range of concentrations for its ability to affect fibroblast survival and migration, as well as long-term effects on cell viability. RESULTS: Undiluted mouthwashes induced near-complete cell death 24 hours after only a 60-second treatment. Dilutions of 15% to 20% for both CHX and EO mouthwashes resulted in 50% cell death. When diluted to 10% to 15%, EO did not reduce cell migration, whereas similar dilutions of CHX resulted in reduced cell migration. Concentrations of 10% of both EO and CHX mouthwashes retained most of their antibacterial capacity. Treatment with EO did not result in gingival fibroblast death, whereas 5% CHX resulted in near-complete gingival fibroblast death 7 days after exposure. CONCLUSIONS: The results of this in vitro study indicate that diluted EO displayed no detectable detrimental effects on human gingival and PDL fibroblasts, whereas diluted CHX reduced both cell migration and long-term survival. Both solutions retained their antimicrobial activity in lower concentrations. PMID- 23106510 TI - Association between periodontitis and gestational diabetes mellitus: a case control study. AB - BACKGROUND: Some studies have reported an association between gestational diabetes mellitus (GDM) and periodontitis. The aim of the present study is to analyze this potential association and the influence of risk variables associated with GDM. METHODS: This case-control study includes 360 women, 90 with GDM and 270 controls. Participants received a full-mouth periodontal examination with a record of bleeding on probing (BOP), probing depth (PD), and clinical attachment level (CAL). Periodontitis is defined as the presence in >=4 teeth of >=1 sites with PD >=4 mm and CAL >=3 mm associated with BOP. The influence of risk variables in the occurrence of GDM is tested through univariate analysis and multivariate logistic and multinomial regression. Odds ratio (ORs) and respective confidence intervals (CIs) are calculated and reported. RESULTS: The prevalence of periodontitis was 40% in the case group (GDM) and 46.3% in the control group. There was a lack of association between periodontitis and GDM (OR = 0.74; 95% CI = 0.40 to 1.38). The multivariate final logistic regression model retained the following as significant variables associated with GDM: maternal age (OR = 2.65; 95% CI = 1.97 to 3.56), chronic hypertension (OR = 3.16; 95% CI = 1.35 to 7.42), and body mass index (OR = 1.99; 95% CI = 1.41 to 2.81). CONCLUSIONS: A high prevalence of periodontitis was found among cases and controls, with no association between periodontitis and GDM. The present study suggests the need for implementation of health policies directed to the periodontal care of pregnant women. PMID- 23106511 TI - A randomized, double-masked clinical trial comparing four periodontitis treatment strategies: 1-year clinical results. AB - BACKGROUND: The benefit of full-mouth disinfection (FDIS) over traditional scaling and root planing (SRP) remains equivocal, and it is not known whether the use of adjunctive antibiotics may enhance the effect of FDIS. The aim of the present study is to test the hypothesis that there is no difference in the 1-year clinical outcome of therapy among groups of patients treated with conventional SRP performed over 2 to 3 weeks, or same-day FDIS, with or without adjunctive metronidazole. METHODS: A total of 184 patients with moderate-to-severe periodontitis were randomly allocated to one of four treatment groups: 1) FDIS+metronidazole; 2) FDIS+placebo; 3) SRP+metronidazole; or 4) SRP+placebo. Recordings of plaque, bleeding on probing, probing depth (PD), and clinical attachment level (CAL) were carried out in four sites per tooth at baseline and at 3 and 12 months after treatment. RESULTS: No differences were observed in the mean CAL or PD values between the four experimental groups at baseline and 3 or 12 months post-treatment. All four groups displayed significant improvements in all parameters. However, using absence of pockets >=5 mm as the criterion for treatment success, the two groups receiving adjunctive metronidazole performed significantly better than the two placebo groups. CONCLUSION: Metronidazole had a significant, adjunctive effect in patients with a metronidazole-sensitive subgingival microbiota on the clinical parameters of CAL, PD, and absence of pockets >=5 mm. PMID- 23106512 TI - Effectiveness of periodontal treatment to improve metabolic control in patients with chronic periodontitis and type 2 diabetes: a meta-analysis of randomized clinical trials. AB - BACKGROUND: It was recently suggested that scaling and root planing (SRP) may help to improve glycemic and metabolic control in patients with chronic periodontitis (CP) and type 2 diabetes mellitus (DM2); however, the effectiveness of SRP in this role remains unclear. This meta-analysis assesses the effectiveness of SRP in improving glycemic and metabolic control in patients with CP and DM2. METHODS: A literature search of electronic databases was performed for articles published through May 16, 2012, followed by a manual search of several dental journals. A meta-analysis was conducted according to the recommendations of the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Weighted mean differences (MDs) and 95% confidence intervals (CIs) were calculated for glycated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), total cholesterol (TC), triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL and LDL, respectively). All outcomes were evaluated as changes from baseline to the end of follow-up. Heterogeneity was assessed with the chi(2)-based Cochran Q test and I(2) statistic. The level of significance was set at P <0.05. RESULTS: After the study selection process, five randomized clinical trials were included. Results of the meta-analysis indicated that SRP was effective in the reduction of HbA1c (MD = 0.65; 95% CI 0.43 to 0.88; P <0.05) and FPG (MD = 9.04; 95% CI 2.17 to 15.9; P <0.05), but no significant differences were found in the reduction of TC, TG, HDL, or LDL. No evidence of heterogeneity was detected. CONCLUSION: The meta analysis results seem to support the effectiveness of SRP in the improvement of glycemic control in patients with CP and DM2; however, future studies are needed to confirm these results. PMID- 23106514 TI - Coxiella burnetii shedding during the peripartum period and subsequent fertility in dairy cattle. AB - The objective of this study was to assess the effects of Coxiella burnetii shedding or seropositivity on post-partum recovery and subsequent fertility in high-producing dairy cows. Given the difficulty in diagnosing C. burnetii infection at the farm level, an exhaustive series of tests in 43 pregnant animals that delivered at least one live calf were conducted, including blood serology and PCR of milk or colostrum, cotyledons (only at parturition), faeces, vaginal fluid against C. burnetii on gestation Day 171-177, at parturition and on Days 1 7, 8-14, 15-21, 22-28, 29-35 and 90-97 post-partum. During scheduled herd visits, ultrasonography (US) of the genital tract and examination of vaginal fluid were performed on Days 15-21 (V1), 22-28 (V2), 29-35 (V3) and 51-57 (V4) post-partum by the same veterinarian. Logistic regression analysis revealed that the likelihood of suffering endometritis (the presence of echogenic intrauterine fluid (IUF), cervical diameter of >=4 cm or endometrial thickness >=0.75 cm) was lower in C. burnetii-seropositive animals (OR = 0.10), compared with C. burnetii seronegative animals. According to Kaplan-Meier survival analysis, C. burnetii seronegative and non-shedding cows showed a delayed return to luteal activity and conception was delayed in non-shedding animals, compared with the remaining animals. Overall, the results of our study provide useful insight into the effects of C. burnetii infection on post-partum recovery and subsequent fertility. In particular, animals not infected with Coxiella seem to be susceptible to infection and not protected against the bacterium in dairy herds. The elevated costs of determining an infection at the farm level, make monitoring of cows virtually impossible from a clinical point of view. PMID- 23106513 TI - Utilizing a water-soluble cryptophane with fast xenon exchange rates for picomolar sensitivity NMR measurements. AB - Hyperpolarized (129)Xe chemical exchange saturation transfer ((129)Xe Hyper-CEST) NMR is a powerful technique for the ultrasensitive, indirect detection of Xe host molecules (e.g., cryptophane-A). Irradiation at the appropriate Xe-cryptophane resonant radio frequency results in relaxation of the bound hyperpolarized (129)Xe and rapid accumulation of depolarized (129)Xe in bulk solution. The cryptophane effectively "catalyzes" this process by providing a unique molecular environment for spin depolarization to occur, while allowing xenon exchange with the bulk solution during the hyperpolarized lifetime (T(1) ~ 1 min). Following this scheme, a triacetic acid cryptophane-A derivative (TAAC) was indirectly detected at 1.4 picomolar concentration at 320 K in aqueous solution, which is the record for a single-unit xenon host. To investigate this sensitivity enhancement, the xenon binding kinetics of TAAC in water was studied by NMR exchange lifetime measurement. At 297 K, k(on) ~ 1.5 * 10(6) M(-1) s(-1) and k(off) = 45 s(-1), which represent the fastest Xe association and dissociation rates measured for a high-affinity, water-soluble xenon host molecule near rt. NMR line width measurements provided similar exchange rates at rt, which we assign to solvent-Xe exchange in TAAC. At 320 K, k(off) was estimated to be 1.1 * 10(3) s(-1). In Hyper-CEST NMR experiments, the rate of (129)Xe depolarization achieved by 14 pM TAAC in the presence of radio frequency (RF) pulses was calculated to be 0.17 MUM.s(-1). On a per cryptophane basis, this equates to 1.2 * 10(4)(129)Xe atoms s(-1) (or 4.6 * 10(4) Xe atoms s(-1), all Xe isotopes), which is more than an order of magnitude faster than k(off), the directly measurable Xe-TAAC exchange rate. This compels us to consider multiple Xe exchange processes for cryptophane-mediated bulk (129)Xe depolarization, which provide at least 10(7)-fold sensitivity enhancements over directly detected hyperpolarized (129)Xe NMR signals. PMID- 23106515 TI - Role of a short tandem leucine/arginine repeat in strong mutator phenotype acquisition in a clinical isolate of Salmonella Typhimurium. AB - In this prospective study, a strong mutator strain of Salmonella Typhimurium was isolated from a collection of 130 human clinical strains of Salmonella. Sequence analysis of the mutS, mutL, and mutH genes, which encode three proteins that are essential for initiation of methyl-directed DNA mismatch repair, revealed insertion of a short tandem repeat (STR) of leucine/alanine in the histidine kinase-like ATPase domain of MutL. The role of this STR in the acquisition of the strong mutator phenotype was confirmed by the construction of an isogenic mutant (6bpinsmutL) from a normomutator strain of Salmonella Heidelberg. This result adds to the sparse body of knowledge about strong mutators and highlights the role of this STR as a hotspot for the acquisition of a strong mutator phenotype in Salmonella. PMID- 23106516 TI - Selectivity and mechanisms driven by reaction dynamics: the case of the gas-phase OH(-) + CH3ONO2 reaction. AB - Well-established statistical approaches such as transition-state theory based on high-level calculated potential energy profiles are unable to account for the selectivity observed in the gas-phase OH(-) + CH(3)ONO(2) reaction. This reaction can undergo bimolecular nucleophilic displacement at either the carbon center (S(N)2@C) or the nitrogen center (S(N)2@N) as well as a proton abstraction followed by dissociation (E(CO)2) pathway. Direct dynamics simulations yield an S(N)2:E(CO)2 product ratio in close agreement with experiment and show that the lack of reactivity at the nitrogen atom is due to the highly negative electrostatic potential generated by the oxygen atoms in the ONO(2) group that scatters the incoming OH(-). In addition to these dynamical effects, the nonstatistical behavior of these reactions is attributed to the absence of equilibrated reactant complexes and to the large number of recrossings, which might be present in several ion-molecule gas-phase reactions. PMID- 23106517 TI - 18O enrichment in phosphorus pools extracted from soybean leaves. AB - The objective of this study was to investigate the isotopic composition of oxygen bound to phosphate (delta(18)O-PO(4)) in different phosphorus (P) pools in plant leaves. As a model plant we used soybean (Glycine max cv Toliman) grown in the presence of ample P in hydroponic cultures. The leaf blades were extracted with 0.3 M trichloroacetic acid (TCA) and with 10 M nitric acid. These extractions allowed measurement of the TCA-soluble reactive P (TCA P) that is rapidly cycled within the cell and the total leaf P. The difference between total leaf P and TCA P yielded the structural P which includes organic P compounds not extractable by TCA. P uptake and its translocation and transformation within the soybean plants lead to an (18)O enrichment of TCA P (delta(18)O-PO(4) between 16.9 and 27.50/00) and structural P (delta(18)O-PO(4) between 42.6 and 68.0 0/00) compared with 12.40/00 in the phosphate in the nutrient solution. delta(18)O values of phosphate extracted from soybean leaves grown under optimal conditions are greater than the delta(18)O-PO(4) values of the provided P source. Furthermore, the delta(18)O-PO(4) of TCA P seems to be controlled by the delta(18)O of leaf water and the activity of inorganic pyrophosphatase or other pyrophosphatases. PMID- 23106518 TI - Asymmetry of positioning nystagmus in posterior canalolithiasis. AB - CONCLUSIONS: Ewald's third law is correct in the posterior semicircular canal and the intensity of stimulatory nystagmus is 2.7 times as strong as that of inhibitory nystagmus. OBJECTIVES: Ewald's third law states that a flow of endolymph away from the ampulla causes more stimulation than a flow toward the ampulla in the posterior canal. The aims of this study were to quantify the asymmetry of positioning nystagmus in posterior canalolithiasis and to confirm the validity of Ewald's third law. METHODS: Subjects were 20 patients who revealed typical vertical/torsional positioning nystagmus in the Dix-Hallpike test, 14 females and 6 males, with a mean age of 55.2 years. Nystagmus was recorded using an infrared camera and the findings were converted to digital data. Using ImageJ, we performed three-dimensional video-oculography and measured maximum slow-phase velocity of three components (horizontal, vertical, and torsional). RESULTS: The mean value of maximum slow-phase velocity (sum of three components) in the head-hanging position was 42.3 degrees /s and that in the sitting position was 15.6 degrees /s. The former was significantly greater than the latter (p < 0.01). PMID- 23106519 TI - Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. AB - Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS. PMID- 23106520 TI - The impact of epilepsy on patients' lives. AB - The impact of epilepsy is multifaceted and extensive on its effects. The occurrence of seizures is unpredictable and often dangerous, increasing the risk of injury, hospitalization and mortality, and adversely affecting a patient's mental health, often resulting in anxiety, depression or cognitive impairment. Seizures can also result in stigmatization and social exclusion, with detrimental effects on an individual's confidence and self-esteem. However, the burden of epilepsy extends beyond the effects of seizures themselves. In particular, individuals with epilepsy are significantly more likely to have medical or psychiatric comorbidities than those without epilepsy, and comorbidity in patients with epilepsy has been shown to be strongly correlated with negative impacts on subjective health status and quality of life (QoL). In addition, antiepileptic drug (AED) treatment is commonly associated with side effects, which further impair patients' QoL. Patient surveys provide valuable insights into what matters to patients in their daily lives and highlight important discrepancies between the perceptions of patients and their physicians. For example, survey data show that physicians underestimate the number of patients experiencing AED side effects and the impact of these on patients. Screening questionnaires can help physicians to quickly identify problems with treatment side effects; also, to recognize comorbidities such as depression that are otherwise difficult to identify in a time-limited consultation. Ultimately, successful management of epilepsy requires a holistic approach to care, with treatment tailored to the individual patient's needs; this can only be achieved through effective doctor-patient communication and the full involvement of a multidisciplinary care team. PMID- 23106521 TI - Ideal characteristics of an antiepileptic drug: how do these impact treatment decisions for individual patients? AB - Effective management of epilepsy requires a holistic approach that takes into account the needs of the individual patient. Antiepileptic drug (AED) treatment must therefore look beyond efficacy to ensure that the patient's overall health status and quality of life (QoL) are optimized. Because the primary objective of AED treatment is to control seizures over the long term, the ideal AED should, first and foremost, demonstrate sustained efficacy and favourable tolerability. In addition, it should have a broad spectrum of activity; its pharmacokinetic profile should be stable and predictable and allow the option of once-daily dosing; and it should not interact with other medications and concomitant AEDs. Because the efficacy of first-line AEDs is broadly comparable, choice of treatment should be based on the individual patient's specific clinical characteristics. In particular, the primary and secondary prevention of comorbid conditions should be taken into consideration, because this can reduce the risk of mortality and improve health outcomes and QoL. Treatment selection must also take into account the patient's particular lifestyle and priorities, to maximize the likelihood of long-term treatment adherence. Advances in genetic testing may help inform choice of treatment - not only by elucidating a patient's underlying aetiology, but also by helping to avoid unnecessary side effects. Although certain patient populations (e.g. women of childbearing potential, adolescents, the elderly) require particular consideration when choosing the most appropriate treatment, every patient's unique clinical characteristics and personal circumstances must be taken into account to ensure treatment success and optimize their QoL. PMID- 23106522 TI - Zonisamide: its pharmacology, efficacy and safety in clinical trials. AB - Zonisamide is a benzisoxazole derivative, chemically unrelated to other antiepileptic drugs, that appears to have multiple mechanisms of action, including inhibition of Na(+) channels and reduction of T-type Ca(2+) currents. It is currently licensed in Europe and the USA for adjunctive treatment of partial seizures in adults, and in Europe as monotherapy for treatment of partial seizures in adults with newly diagnosed epilepsy. Zonisamide displays predictable, dose-dependent pharmacokinetics and has a half-life of ~60 h, allowing once- or twice-daily administration. It has a low potential for interactions with other medications, including oral contraceptives. The clinical efficacy of adjunctive zonisamide therapy has been established in four pivotal, phase III, randomized, double-blind, placebo-controlled trials, which together included approximately 850 patients, aged 12-77 years, with refractory partial epilepsy. In all four trials, zonisamide 300-600 mg/day resulted in significant reductions in median total seizure rates vs placebo, and zonisamide was generally well tolerated; the most frequently reported adverse events being somnolence, dizziness and anorexia/weight loss. Subanalysis of the primary European trial indicated that zonisamide was effective when administered as first-line adjunctive treatment, and a long-term extension to the same trial demonstrated that the efficacy and safety/tolerability of adjunctive zonisamide was sustained for up to 36 months. Once-daily monotherapy with zonisamide (200-500 mg/day) has been shown to be non-inferior to, and as well tolerated as, twice-daily monotherapy with controlled-release carbamazepine (400-1200 mg/day) in adults with newly diagnosed partial epilepsy. Zonisamide has also been shown to have favourable long-term retention rates, an important indication of its overall effectiveness. PMID- 23106523 TI - Zonisamide in clinical practice. AB - Zonisamide is currently licensed in Europe and the USA for the adjunctive treatment of partial seizures (with or without secondary generalization) in adults, based on the results of four pivotal, randomized, double-blind, placebo controlled trials. It is also licensed in Europe as monotherapy for adults with newly diagnosed partial epilepsy, based on the results of a randomized, double blind, non-inferiority trial. Because clinical trials are conducted under tightly controlled conditions, using rigid dosing schedules and employing strict exclusion/exclusion criteria, there is a need for 'real-world' evidence of an antiepileptic drug's effectiveness and tolerability in clinical practice, where patients are much more diverse in terms of clinical characteristics and treatment is tailored to the individual's specific needs. Several studies have demonstrated that adjunctive treatment with zonisamide is effective when administered under everyday clinical practice conditions, with a favourable safety/tolerability profile similar to that observed in clinical trials. In the Zonisamid im Alltag Der Epilepsiepatienten (ZADE) study, almost 80% of patients showed a reduction in seizure frequency of >=50% over a median follow-up of 18 weeks, and over one third of patients became seizure free. Data from these clinical practice studies also indicate that zonisamide is effective and generally well tolerated when administered as a first-line adjunctive treatment and is associated with high retention rates and improvements in quality of life. Evidence from these clinical practice studies therefore complements data from zonisamide's clinical trial programme, providing pragmatic information on the likely benefits and risks of treatment under real-life conditions. PMID- 23106524 TI - Extracellular ATP differentially affects epileptiform activity via purinergic P2X7 and adenosine A1 receptors in naive and chronic epileptic rats. AB - PURPOSE: Adenosine is considered an endogenous anticonvulsant. However, much less is known about the putative effects of its precursor, ATP, on epilepsy. Therefore, we tested whether ATP and its receptors are able to modulate epileptiform activity in the medial entorhinal cortex of the rat. METHODS: Recurrent epileptiform discharges (REDs) were induced by elevating extracellular potassium concentration combined with application of bicuculline in brain slices from naive and pilocarpine-treated chronic epileptic rats. Field potentials were recorded from layer V/VI of the medial entorhinal cortex. KEY FINDINGS: REDs in slices from naive animals had a higher incidence and a shorter duration than in slices from chronic epileptic animals. Exogenous application of ATP reversibly reduced the incidence of REDs in naive and chronic epileptic slices via activation of adenosine A(1) receptors without discernible P2 receptor effects. This effect was stronger in slices from chronic epileptic rats. In slices from naive rats, the P2X7 receptor antagonist A 740003 slightly but significantly reduced the amplitude of slow field potentials of REDs. In slices from chronic epileptic rats, none of the P2 receptor antagonists affected the parameters of REDs. SIGNIFICANCE: Our results suggest that endogenously released ATP differentially modulates REDs by activation of A(1) and P2X7 receptors. Although it has a minor proepileptic effect by direct activation of P2X7 receptors, its metabolite adenosine reduces the epileptiform activity via activation of A(1) receptors. The exact effect of ATP on neural activity depends on the actual activity of ectonucleotidases and the expression level of the purinergic receptors, which both alter during epileptogenesis. In addition, our data suggest that P2X7 receptor antagonists have a minor antiepileptic effect. PMID- 23106525 TI - H/D isotopic and temperature effects in the polarized IR spectra of hydrogen-bond cyclic trimers in the crystal lattices of acetone oxime and 3,5-dimethylpyrazole. AB - Polarized IR spectra of hydrogen-bonded acetone oxime and 3,5-dimethylpyrazole crystals were measured at 293 and 77 K in the nu(X-H) and nu(X-D) band frequency ranges. These crystals contain molecular trimers in their lattices. The individual crystal spectral properties remain in a close relation with the electronic structure of the two different molecular systems. We show that a vibronic coupling mechanism involving the hydrogen-bond protons and the electrons on the pi-electronic systems in the molecules determines the way in which the vibrational exciton coupling between the hydrogen bonds in the trimers occurs. A strong coupling in 3,5-dimethylpyrazole trimers prefers a "tail-to-head"-type Davydov coupling widespread via the pi-electrons. A weak through-space exciton coupling in acetone oxime trimers involves three adjacent hydrogen bonds in each cycle. The relative contribution of each exciton coupling mechanism in the trimer spectra generation is temperature and the molecular electronic structure dependent. This explains the observed difference in the temperature-induced evolution of the compared spectra. The mechanism of the H/D isotopic "self organization" processes in the crystal hydrogen bonds was also analyzed. The two types of the hydrogen-bond trimers exhibit the same way, in which the H/D isotopic recognition mechanism occurs. In acetone oxime and 3,5-dimethylpyrazole trimers, identical hydrogen isotope atoms exist in these entire hydrogen-bond systems. PMID- 23106526 TI - Distinct strains of Leishmania major induce different cytokine mRNA expression in draining lymph node of BALB/c mice. AB - Four genotypically distinct strains of L. major collected from persons residing in different endemic areas of cutaneous leishmaniasis in Iran were evaluated in BALB/c mice. Parasite virulence was evaluated by measuring the parasite burden in the lymph nodes. Immunogenicity of the strains was assessed by analysis of cytokines mRNA expression levels in popliteal lymph nodes of the mice in early (3, 16, 40 h) and late (week 1, W3, W5 and W8) time periods after infection. The expression of cytokines mRNA, namely Ifng, Il2,Il4,Il10 and Il12, was quantitated by real-time PCR. The lowest and the highest parasite loads were induced by Damghan (2.15 * 107) and Shiraz (9.59 * 109) strains, respectively. Moreover, Damghan strain elicited higher expression levels of Ifng and Il2 mRNA and the highest ratio of Ifng/Il4 mRNA expression compared with the other strains at 40 h and 8 weeks post-infection. The results indicate that the inoculation of BALB/c mice with different strains induced high diversity in parasite burden and cytokines gene expression. Amongst the four strains, Damghan strain showed the lowest parasite load and the highest tendency to induce expression of Th1 cytokines gene and might be considered as a safe and immunogenic strain. PMID- 23106527 TI - Diagnosis of skull fractures according to postmortem interval: an experimental approach in a porcine model. AB - Most studies on fracture morphology of fresh or dry bones, specifically skull bones, have a limited focus, and they are often based on observations rather than experimental tests. This study characterized pig cranial fractures sustained under known impact conditions. An impact machine (mobile carriage guided by columns) was used to perform a fracture on each skull. Impacts were performed at the same energy level on fresh and dry bones, with two types of impactor: a sharp striker (n = 50) and a blunt striker (n = 50). We found distinct features under different conditions, including osseous flakes on fresh bones, 90 degrees fracture angles on dry bones, and more fractures with greater fragmentation on dry bones. These features highlighted the effects of time on perimortem fracture characteristics and the importance of bone storage conditions in the study of fracture genesis. PMID- 23106528 TI - Oral food challenge: safety, adherence to guidelines and predictive value of skin prick testing. AB - BACKGROUND: The diagnostic gold standard of food allergy is the oral food challenge (OFC). Data on severe reactions and drug use during OFC are scarce. Our aims were (i) to investigate the prevalence and spectrum of reactions' severity during OFC and to assess drug use and epinephrine use in anaphylaxis due to OFC; (ii) to investigate the predictive value of the skin prick test wheal size for the outcome of OFCs. METHODS: A retrospective charts review of children undergoing OFC at three Allergy Centres between January 2007 and December 2008 was performed. RESULTS: A total of 544 OFCs were analysed. Most frequently involved foods were egg, milk and wheat. 254/526 (48.3%) were positive. 167 (65.7%) were defined mild reactions, 81 (31.9%) multiorgan reactions and 6 (2.4%) anaphylaxis. No patients had cardiovascular symptoms. Data on treatments were available in 98.8% OFCs. In half of them antihistamines were used vs. 10% cases in which steroids were preferred. Six children (2.4%) were treated with Epinephrine inhalation, 5 (2%) with beta-2 inhalation, 8 (3.1%) with steroid inhalation. One child was treated with IM Epinephrine + IV fluids. Skin prick tests predictive cut-off were 9 mm for albumen, 7 for yolk, 13 for fresh albumen, 10 for alpha-lactalbumin, seven for casein, eight for beta-lactoglobulin, 20 for cow's milk and 10 for fresh cow's milk. CONCLUSION: OFCs performed in controlled settings by expert Allergists are safe. Consideration needs to be given as to whether the Anaphylaxis' Guideline need to be modified when applied in treating patients undergoing OFC. PMID- 23106529 TI - The effects of cyclosporine on platelet function and cyclooxygenase expression in normal dogs. AB - BACKGROUND: Cyclosporine has been shown to alter platelet plasma membranes and have a hypercoagulable effect in humans, leading to thromboembolic complications. HYPOTHESIS/OBJECTIVES: Our hypothesis was that by modulating platelet reactivity, cyclosporine increases the risk of thromboembolic complications. The objective was to determine the effects of cyclosporine on primary hemostasis in normal dogs. ANIMALS: Eight healthy, intact female dogs. METHODS: A repeated-measures design utilized flow cytometry to evaluate platelet expression of platelet reactivity markers (P-selectin and phosphatidylserine) and COX-1 and COX-2 during the administration of 2 cyclosporine dosages (19 mg/kg q12h [immunosuppressive dosage] and 5 mg/kg q24h [atopy dosage]). Urine 11-dehydro-thromboxane-B(2) (11 dTXB(2) ) concentration was normalized to urine creatinine concentration, and platelet function was analyzed by PFA-100. RESULTS: After a week of the immunosuppressive dosage, all platelet reactivity markers showed a significant decrease in mean fluorescent intensity (MFI). After the atopy dosage, only P selectin and COX-2 MFI demonstrated a change from baseline, decreasing by 29% (P = .013) and 31% (P = .003), respectively. Urinary 11-dTXB(2) -to-creatinine ratio significantly increased at all time points during the immunosuppressive dosage, but no significant change occurred during administration of the atopy dosage. PFA 100 closure times using collagen/ADP cartridges increased by 62% (P = .008) with the immunosuppressive dosage and decreased by 45% with the atopy dosage (P = .035). No significant changes in closure times occurred with collagen/epinephrine cartridges. CONCLUSIONS AND CLINICAL IMPORTANCE: Our study suggests that, similar to what is observed in humans, cyclosporine alters the platelet plasma membrane and increases thromboxane production in dogs, especially at immunosuppressive dosages. PMID- 23106530 TI - Efficacy of interventions to improve motor performance in children with developmental coordination disorder: a combined systematic review and meta analysis. AB - AIM: The aim of this study was to review systematically evidence about the efficacy of motor interventions for children with developmental coordination disorder (DCD), and to quantify treatment effects using meta-analysis. METHOD: Included were all studies published between 1995 and 2011 that described a systematic review, (randomized) clinical trial, or crossover design about the effect of motor intervention in children with DCD. Studies were compared on four components: design, methodological quality, intervention components, and efficacy. Twenty-six studies met the inclusion criteria for the review. Interventions were coded under four types: (1) task-oriented intervention, (2) traditional physical therapy and occupational therapy, (3) process-oriented therapies, and (4) chemical supplements. For the meta-analysis, effect sizes were available for 20 studies and their magnitude (weighted Cohen's d [d(w) ]) was compared across training types. RESULTS: The overall effect size across all intervention studies was d(w) =0.56. A comparison between classes of intervention showed strong effects for task-oriented intervention (d(w) =0.89) and physical and occupational therapies (d(w) =0.83), whereas that for process-oriented intervention was weak (d(w) =0.12). Of the chemical supplements, treatment with methylphenidate was researched in three studies (d(w) =0.79) and supplementation of fatty acids plus vitamin E in one study (no effect). The post hoc comparison between treatment types showed that the effect size of the task-oriented approach was significantly higher than the process-oriented intervention (p=0.01) and comparison (p=0.006). No significant difference in the magnitude of effect size between traditional physical and occupational therapy approaches and any of the other interventions emerged. INTERPRETATION: In general, intervention is shown to produce benefit for the motor performance of children with DCD, over and above no intervention. However, approaches from a task-oriented perspective yield stronger effects. Process-oriented approaches are not recommended for improving motor performance in DCD, whereas the evidence for chemical supplements for children with DCD is currently insufficient for a recommendation. PMID- 23106531 TI - Two new compounds from an endophytic fungus Alternaria solani. AB - Two new secondary metabolites, named 7-dehydroxyl-zinniol (1) and 20-hydroxyl ergosta-4,6,8(14),22-tetraen-3-one (2), were isolated from the culture of Alternaria solani, an endophytic fungal strain residing in the roots of Aconitum transsectum. Their structures were elucidated on the basis of comprehensive spectroscopic analyses including IR, ESI-MS, HR-ESI-MS, 1D and 2D NMR. Biological activity tests indicated that compound 1 showed moderate anti-HBV activity. PMID- 23106533 TI - Authors' response (to letter published in J Periodontol 2011;82:1521). PMID- 23106534 TI - Cryopreservation of precision-cut tissue slices. AB - 1.Cryopreservation of precision-cut tissue slices (PCTS) would have many advantages for drug development and would encourage more extensive use of the PCTS preparation. 2.Three methods have been studied to date: slow freezing, fast freezing, and vitrification. 3.Slow freezing can be very effective for some PCTS but is devastating to rat liver PCTS. Fast freezing can be successful for rat liver PCTS but is devastating to renal PCTS and has given inconsistent results even for rat liver PCTS. Vitrification has been effective for some slice systems but less effective for rat liver PCTS. Rat liver PCTS appear to be particularly difficult to cryopreserve well. 4.The general cryobiological principles of slow freezing, rapid freezing, and vitrification are reviewed. The empirical literature on the cryopreservation of PCTS has not taken sufficient account of these principles, and may, for example, include the effects of easily preventable osmotic injury. 5.More attention is needed to the effects of cryopreservation on specific cell types within PCTS and to the general integrity and viability of cryopreserved PCTS. Drug metabolism as a sole endpoint of study can be highly misleading. 6.Better application of cryobiological principles may enable improved results in the future. PMID- 23106535 TI - Sleep/wake dependent changes in cortical glucose concentrations. AB - Most of the energy in the brain comes from glucose and supports glutamatergic activity. The firing rate of cortical glutamatergic neurons, as well as cortical extracellular glutamate levels, increase with time spent awake and decline throughout non rapid eye movement sleep, raising the question whether glucose levels reflect behavioral state and sleep/wake history. Here chronic (2-3 days) electroencephalographic recordings in the rat cerebral cortex were coupled with fixed-potential amperometry to monitor the extracellular concentration of glucose ([gluc]) on a second-by-second basis across the spontaneous sleep-wake cycle and in response to 3 h of sleep deprivation. [Gluc] progressively increased during non rapid eye movement sleep and declined during rapid eye movement sleep, while during wake an early decline in [gluc] was followed by an increase 8-15 min after awakening. There was a significant time of day effect during the dark phase, when rats are mostly awake, with [gluc] being significantly lower during the last 3-4 h of the night relative to the first 3-4 h. Moreover, the duration of the early phase of [gluc] decline during wake was longer after prolonged wake than after consolidated sleep. Thus, the sleep/wake history may affect the levels of glucose available to the brain upon awakening. PMID- 23106537 TI - The renaissance of the collective unconscious? PMID- 23106536 TI - Constitutive knockout of the membrane cytoskeleton protein beta adducin decreases mushroom spine density in the nucleus accumbens but does not prevent spine remodeling in response to cocaine. AB - The adducin family of proteins associates with the actin cytoskeleton in a calcium-dependent manner. Beta adducin (betaAdd) is involved in synaptic plasticity in the hippocampus; however, the role of betaAdd in synaptic plasticity in other brain areas is unknown. Using diolistic labeling with the lipophilic dye DiI, we found that the density of mature mushroom-shaped spines was significantly decreased in the nucleus accumbens (NAc) in brain slices from betaAdd-knockout (KO) mice as compared to their wildtype (WT) siblings. The effect of 10 days of daily cocaine (15 mg/kg) administration on NAc spine number and locomotor behavior was also measured in betaAdd WT and KO mice. As expected, there was a significant increase in overall spine density in NAc slices from cocaine-treated WT mice at this time-point; however, there was a greater increase in the density of mushroom spines in betaAdd-KO animals following chronic cocaine administration than in WT. In addition, betaAdd-KO mice showed elevated locomotor activity in response to cocaine treatment compared to WT siblings. These results indicate that betaAdd is required for stabilising mature spines under basal conditions in the NAc, but that lack of this protein does not prevent synaptic remodeling following repeated cocaine administration. In addition, these data are consistent with previous studies suggesting that betaAdd may normally be involved in stabilising spines once drug- or experience-dependent remodeling has occurred. PMID- 23106538 TI - Covalent cargo loading to molecular shuttles via copper-free "click chemistry". AB - An important prerequisite for molecular shuttle-based functional devices is the development of adequate linker chemistries to load and transport versatile cargoes. Copper-free "click chemistry" has not been applied before to covalently load cargo onto molecular shuttles propelled by biological motors such as kinesin. Due to the high biocompatibility and bioorthogonality of the strain promoted azide-alkyne cycloaddition, this approach has pronounced advantages compared to previous methods. PMID- 23106539 TI - Toward full peptide sequence coverage by dual fragmentation combining electron transfer and higher-energy collision dissociation tandem mass spectrometry. AB - Increasing peptide sequence coverage by tandem mass spectrometry improves confidence in database search-based peptide identification and facilitates mapping of post-translational modifications and de novo sequencing. Inducing 2 fold fragmentation by combining electron-transfer and higher-energy collision dissociation (EThcD) generates dual fragment ion series and facilitates extensive peptide backbone fragmentation. After an initial electron-transfer dissociation step, all ions including the unreacted precursor ions are subjected to collision induced dissociation which yields b/y- and c/z-type fragment ions in a single spectrum. This new fragmentation scheme provides richer spectra and substantially increases the peptide sequence coverage and confidence in peptide identification. PMID- 23106540 TI - Probing of the assembly structure and dynamics within nanoparticles during interaction with blood proteins. AB - Fully understanding the influence of blood proteins on the assembly structure and dynamics within nanoparticles is difficult because of the complexity of the system and the difficulty in probing the diverse elements and milieus involved. Here we show the use of site-specific labeling with spin probes and fluorophores combined with electron paramagnetic resonance (EPR) spectroscopy and fluorescence resonance energy transfer (FRET) measurements to provide insights into the molecular architecture and dynamics within nanoparticles. These tools are especially useful for determining nanoparticle stability in the context of blood proteins and lipoproteins and have allowed us to quantitatively analyze the dynamic changes in assembly structure, local stability, and cargo diffusion of a class of novel telodendrimer-based micellar nanoparticles. When combined with human plasma and individual plasma components, we find that non-cross-linked nanoparticles immediately lose their original assembly structure and release their payload upon interaction with lipoproteins. In contrast, serum albumins and immunoglobulin gamma have moderate affects on the integrity of the nanoparticles. Disulfide cross-linked nanoparticles show minimal interaction with lipoproteins and can better retain their assembly structure and payload in vitro and in vivo. We further demonstrate how the enhanced stability and release property of disulfide cross-linked nanoparticles can be reversed in reductive conditions. These findings identify factors that are crucial to the performance of nanomedicines and provide design modes to control their interplay with blood factors. PMID- 23106541 TI - Light-induced damage to the retina: current understanding of the mechanisms and unresolved questions: a symposium-in-print. AB - Light-induced injury to the retina resembles many features of several retinal degenerative diseases, particularly age-related macular degeneration. This Symposium-in-Print on Retinal Photodamage discusses the mechanisms involved and protective strategies to increase the retinal resistance to damage and/or to counteract its deleterious effects. Recent results help explaining the wavelength dependence of susceptibility of the retina to photodamage and different sites of the initial injury for shorter- and longer-wavelength light. Still, there are many unanswered questions pointing toward next directions in research so as to increase the understanding of the responses of the retina to photodamage and help to develop effective therapeutic approaches for retinal degenerations. PMID- 23106543 TI - Transcriptome-wide polymorphisms of red abalone (Haliotis rufescens) reveal patterns of gene flow and local adaptation. AB - Global climate change is projected to accelerate during the next century, altering oceanic patterns in temperature, pH and oxygen concentrations. Documenting patterns of genetic adaptation to these variables in locations that currently experience geographic variation in them is an important tool in understanding the potential for natural selection to allow populations to adapt as climate change proceeds. We sequenced the mantle transcriptome of 39 red abalone (Haliotis rufescens) individuals from three regions (Monterey Bay, Sonoma, north of Cape Mendocino) distinct in temperature, aragonite saturation, exposure to hypoxia and disease pressure along the California coast. Among 1.17 * 10(6) Single Nucleotide Polymorphisms (SNPs) identified in this study (1.37% of the transcriptome), 21 579 could be genotyped for all individuals. A principal components analysis concluded that the vast majority of SNPs show no population structure from Monterey, California to the Oregon border, in corroboration with several previous studies. In contrast, an FST outlier analysis indicated 691 SNPs as exhibiting significantly higher than expected differentiation (experiment-wide P < 0.05). From these, it was possible to identify 163 genes through BLAST annotation, 34 of which contained more than one outlier SNP. A large number of these genes are involved in biomineralization, energy metabolism, heat-, disease- or hypoxia-tolerance. These genes are candidate loci for spatial adaptation to geographic variation that is likely to increase in the future. PMID- 23106544 TI - Impact of Toll-like receptor-4 and tumour necrosis factor gene polymorphisms in patients with hidradenitis suppurativa. AB - BACKGROUND: Recent evidence has suggested that deranged immune responses play a role in the pathogenesis of hidradenitis suppurativa (HS). OBJECTIVES: To investigate the role of single nucleotide polymorphisms (SNPs) of the tumour necrosis factor (TNF) and Toll-like receptor 4 (TLR4) genes in the physical course of HS; these genes encode for proteins implicated in the immune response of the host. METHODS: DNA was isolated from 190 patients with HS and 84 healthy controls. SNPs at the promoter regions -376G/A, -238G/A and -308G/A of the TNF gene and the Asp299Gly and Thr399Ile SNPs of the TLR4 gene were determined by polymerase chain reaction (PCR) and digestion of the PCR product by restriction enzymes; after electrophoresis on 2.0% agarose gel, products were visualized on under ultraviolet radiation. RESULTS: The presence of the -238 TNF gene polymorphism was associated with a predisposition to HS (P = 0.027). Susceptibility to the disease was strongly correlated with the presence of AGG/GGA/AGA/GAA TNF haplotypes in 32 (17%) patients compared with two (2%) controls (P < 0.001, odds ratio 8.30, 95% confidence interval 1.94-35.52). The frequency of HS exacerbations and disease severity were greater in patients carrying any of the GAG/AGG/GGA/AGA/GAA haplotypes of the TNF gene. Thirty-two patients were given TNF antagonists. Nineteen of these patients were carriers of the GGG haplotype of the TNF gene, whereas 13 were carriers of other haplotypes; favourable responses as evidenced by the Sartorius score were registered in 15 (79%) and five (38%, P = 0.025), respectively. Carriage of the TLR4 gene alleles was not associated with any disease parameter. CONCLUSIONS: A significant role of SNPs at the promoter region of the TNF gene is indicated for susceptibility to HS and for response to TNF antagonists. PMID- 23106545 TI - Superselective intra-arterial chemotherapy for laryngeal preservation in carcinoma of the anterior oropharyngeal wall. AB - CONCLUSION: Superselective intra-arterial chemotherapy, which can provide local control and laryngeal preservation, is safe and useful for preserving pharyngeal and laryngeal functions. OBJECTIVE: To evaluate superselective intra-arterial chemotherapy in terms of the contribution to survival and laryngeal preservation in squamous cell carcinoma (SCC) of the anterior oropharyngeal wall. METHODS: A total of 51 patients with SCC of the anterior oropharyngeal wall received intra arterial administration of docetaxel at 60 mg/m(2) and cisplatin at 60 mg/m(2) anterogradely, followed by intravenous continuous infusion of 5-fluorouracil at 750 mg/m(2)/day over 120 h starting on day 2. Neck lymph node metastases were treated by neck dissection. RESULTS: The 5- and 10-year survival rates of the 51 patients were 72.8% and 66.4%, respectively. The 5-year survival rates of patients with T2, T3, T4a, and T4b cancer were 100%, 88.7%, 41.9%, and 33.3%, respectively. The 5- and 10-year laryngeal preservation rates of the 51 patients were 63.4% and 30.0%, respectively. The 5-year laryngeal preservation rates of patients with T2, T3, T4a, and T4b cancer were 100%, 75.2%, 23.6%, and 33.3%, respectively. No irreversible side effects, complications, or sequelae were reported. PMID- 23106546 TI - Comparison of two implant-supported molar distalization systems. AB - OBJECTIVE: To examine skeletal, dental, and soft tissue effects of the Miniscrew Implant Supported Distalization System (MISDS) and the Bone-Anchored Pendulum Appliance (BAPA). MATERIALS AND METHODS: Among 28 patients displaying Angle Class II malocclusion, 14 patients with a mean age of 14.8 +/- 3.6 years treated with MISDS were included in the first group, and 14 patients with a mean age of 14.5 +/- 1.5 years treated with BAPA were included in the second group. The pretreatment and posttreatment lateral cephalograms were analyzed. Statistical evaluation was carried out using the paired Shapiro-Wilk test, the paired-sample t-test, and the unpaired t-test. RESULTS: Upper posterior teeth were distalized successfully in both groups. Nearly bodily distalization was seen in the MISDS group, whereas significant distal tipping of the upper first molars was observed in the BAPA group (P < .001). There were no statistically significant changes in the sagittal position of the maxilla and mandible and in the position of the upper incisors as a result of treatment in either group. CONCLUSIONS: Both methods provided absolute anchorage for distalization of posterior teeth; however, almost translatory distal movement was encountered in the MISDS group, and substantial distal tipping of the maxillary molars accompanied distalization in the BAPA group. PMID- 23106548 TI - Validity and limitations of the bridged annulene model for porphyrins. AB - According to the bridged annulene model, macrocyclic aromaticity of a porphyrinoid species can be attributed to the annulene-like main macrocyclic conjugation pathway (MMCP). Macrocyclic aromaticity, however, is given theoretically as a sum of contributions from all macrocyclic circuits. We found that the aromaticity due to each macrocyclic circuit is determined formally but broadly by Huckel's [4n + 2] rule of aromaticity. Nitrogen atoms in the pyrrolic rings effectively suppress the variation in the number of pi electrons staying along each macrocyclic circuit. As a result, all or most macrocyclic circuits in oligopyrrolic macrocycles are made aromatic (or antiaromaitc) in phase with the MMCP. Thus, the MMCP is not a determinant of macrocyclic aromaticity but can be regarded as a good indicator of this quantity. This is why the bridged annulene model appears to hold for many porphyrins. PMID- 23106547 TI - Fatal intoxications in a forensic autopsy material from Epirus, Greece, during the period 1998-2010. AB - In this retrospective study, we report the epidemiological characteristics of all poisoning deaths in Epirus, Greece, from 1998 to 2010; we present the toxicological findings and the statistical evaluation of the results. This is the first detailed scientific report on all the officially certified poisoning deaths concerning part of the Greek population. A total of 126 poisoning fatalities were recorded, 67 of them being mono-intoxications (53.2%). The cause of poisoning was as follows: drugs of abuse (60%); carbon monoxide (19.8%); pesticides (9.5%); corrosives (4.8%); pharmaceuticals (4.8%); and spider bite (0.8%). The most frequently detected poisonous substances were as follows: heroin (65 cases), ethanol (55), benzodiazepines (42), carbon monoxide (25), cocaine (17), cannabinoids (17) and pesticides (12). Increasing tendency in poisoning death rates was recorded, due to an increase in accidental poisoning deaths attributed mainly to drugs of abuse (total, accidental, and drugs-of-abuse poisoning death rates per 100,000 inhabitants per year were 1.87, 1.19, and 0.79, respectively, in the period 1998-2002 and 3.97, 3.41, and 2.55, respectively, in the period 2007-2010). PMID- 23106549 TI - Reactive depth and performance of an electrochemical carbon nanotube network as a function of mass transport. AB - Three-dimensional porous electrodes often suffer from diffusional mass-transfer limitations that may be overcome by having the target solution flow through the electrode. Here, we examine the reactive depth and performance of an electrochemical carbon nanotube (CNT) network toward phenol removal and oxidation in the batch and flow configurations where mass transport into the CNT network is predominantly via diffusion and convection, respectively. Scanning electron microscopy depth profile imaging of phenol electropolymerization is used as a direct probe of the reactive depth. In the batch case, electropolymerization is observed to be greatest at the network surface nearest the cathode and decreases linearly to near zero at a depth of 25 MUm. In stark contrast, electropolymerization is observed to be independent of the depth in the flow configuration. In agreement with the depth profile results, phenol removal is increased up to 10-fold, the current efficiency is increased by at least 2-fold, and susceptibility toward passivation is reduced in the flow versus batch configuration. Thus, the enhanced electrochemical performance in the flow configuration is partially due to the convective "activation" of the internal CNT network electron-transfer sites that are diffusion-inaccessible. PMID- 23106551 TI - Specific 12CbetaD(2)12CgammaD(2)S13CepsilonHD(2) isotopomer labeling of methionine to characterize protein dynamics by 1H and 13C NMR relaxation dispersion. AB - Protein dynamics on the micro- to millisecond time scale is increasingly found to be critical for biological function, as demonstrated by numerous NMR relaxation dispersion studies. Methyl groups are excellent probes of protein interactions and dynamics because of their favorable NMR relaxation properties, which lead to sharp signals in the (1)H and (13)C NMR spectra. Out of the six different methyl bearing amino acid residue types in proteins, methionine plays a special role because of its extensive side-chain flexibility and the high polarizability of the sulfur atom. Methionine is over-represented in many protein-protein recognition sites, making the methyl group of this residue type an important probe of the relationships among dynamics, interactions, and biological function. Here we present a straightforward method to label methionine residues with specific (13)CHD(2) methyl isotopomers against a deuterated background. The resulting protein samples yield NMR spectra with improved sensitivity due to the essentially 100% population of the desired (13)CHD(2) methyl isotopomer, which is ideal for (1)H and (13)C spin relaxation experiments to investigate protein dynamics in general and conformational exchange in particular. We demonstrate the approach by measuring (1)H and (13)C CPMG relaxation dispersion for the nine methionines in calcium-free calmodulin (apo-CaM). The results show that the C terminal domain, but not the N-terminal domain, of apo-CaM undergoes fast exchange between the ground state and a high-energy state. Since target proteins are known to bind specifically to the C-terminal domain of apo-CaM, we speculate that the high-energy state might be involved in target binding through conformational selection. PMID- 23106552 TI - Bone tissue microarchitectural characteristics at dental implant sites part 2: correlation with bone classification and primary stability. AB - OBJECTIVE: To investigate in vivo the correlation between the bone microarchitecture of implant bone sites, bone tissue classification subjectively assessed in radiographs and primary implant stability. MATERIAL AND METHODS: Periapical and panoramic radiographs were obtained from 32 partially edentulous patients. Three surgeons classified bone quality at implant sites using two different methods: assessments in periapical and panoramic radiographs (PP) and according to the classification proposed by Lekholm and Zarb (L&Z). During the implant insertion, bone biopsies were taken, and three-dimensional parameters were measured by microcomputed tomography (microCT). Insertion torque value (ITV) and initial implant stability quotient (ISQ) were recorded at the moment of the implantation. ISQ was also recorded at the uncovering stage of a traditional implant protocol. RESULTS: Bone types 2 and 3 were the most prevalent classifications according to PP (54.3%) and L&Z (58.7%). The mean and standard deviation values of primary stability variables were 38.7(16.7) for ITV, 75.3 (7.7) for initial ISQ and 79.3 (6.8) for uncovering ISQ. Several microCT original and factor variables were found to correlate with bone tissue classifications and primary stability variables. L&Z correlated with architecture (r = 0.31; P < 0.05), density (r = -0.43; P < 0.01) and bulk (r = -0.35; P < 0.05), whereas ITV correlated with architecture (r = -0.40; P < 0.01) and density (r = 0.51; P < 0.01). Multiple linear regression analysis revealed that density and bulk explained 32% of the variability of L&Z bone classification, while density and architecture explained 42% of the variability of ITV. CONCLUSIONS: This study demonstrates the first step in validating L&Z classification. MicroCT provides objective and detailed quantitative data on bone microarchitecture. Intraosseous implant stability is mainly determined by the density of the bone. ITVs could be a good indicator of primary implant stability, whereas ISQs measurements have some limitations and should not be used alone. PMID- 23106553 TI - Dermatopathology of the foreskin: an institutional experience of over 400 cases. AB - BACKGROUND: Diseases of the foreskin may manifest with an array of pathologic findings, including potentially under-recognized dermatologic conditions. Herein, we summarize an institutional experience in foreskin dermatopathology. METHODS: Diagnoses rendered on foreskin specimens between 1982 and April 2009 were obtained through a computer-based keyword search. Cases given normal, non specific or descriptive diagnoses were reviewed by a dermatopathologist. RESULTS: Keyword search yielded 414 foreskin diagnoses. Interpretations included normal foreskin (n = 131), benign lesions (n = 262) and malignant/dysplastic entities (n = 21). Of 353 cases given normal, descriptive or non-specific diagnoses, 334 were reviewed. Of reviewed cases, 209 (63%) were given more specific diagnoses [e.g. spongiotic dermatitis (n = 115), lichen sclerosus et atrophicus (LSA; n = 41), interface/lichenoid dermatitis (n = 26), psoriasiform dermatitis (n = 7)]. Discrepancy between the clinical and pathologic impression was frequently noted (n = 77). CONCLUSIONS: This study shows benign inflammatory lesions represent the most frequent foreskin pathology. When possible, specific diagnoses should be rendered, as accurate classification may be of clinical importance. There is an abundance of recent literature on the role of circumcision in disease prevention, and this topic is explored. We discuss the theoretical possibility that foreskin inflammation compromises the mucosal/epithelial barrier, thus playing a role in disease transmission. PMID- 23106554 TI - Two new taraxasterol-type triterpenes from Pergularia tomentosa growing wild in Algeria. AB - Two new triterpenes of the taraxasterol skeleton are isolated for the first time form Pergularia tomentosa L. of Algerian origin. The new compounds were named pergularine A and pergularine B. In addition, eight known compounds were isolated from the plant including oleic acid, (9Z,12Z)-octadecadienoic acid, alpha-amyrin, 3-acetyltaraxasterol, 3-taraxasterol, 16alpha-hydroxytaraxasterol-3-acetate, 3 epi-micromeric acid, and (9Z,12Z)-octadecadienoic acid glucoside. All known compounds are isolated for the first time from P. tomentosa L. PMID- 23106556 TI - Reduced proliferative and differentiative activity of mouse pink-eyed dilution melanoblasts is related to apoptosis. AB - The mouse pink-eyed dilution (p) locus is known to control the melanin content, melanosome morphology, and tyrosinase activity in melanocytes. However, it is not well known whether the p allele is involved in regulating melanocyte proliferation, differentiation, and death. The aim of this study is to investigate in detail the role of the p allele in melanocyte proliferation, differentiation, and death using a cell culture system. The epidermal cell suspensions of the neonatal dorsal skin derived from wild type mice at the p locus (black, C57BL/10JHir-P/P) and their congenic mutant (pink-eyed dilution, C57BL/10JHir-p/p) were cultured with serum-free melanoblast-proliferation medium (MDMDF) and melanocyte-proliferation medium (MDMD). The proliferation and differentiation of p/p melanoblasts in MDMDF or MDMD were greatly inhibited compared with those of P/P melanoblasts and melanocytes. It is possible that apoptosis is related to the reduced proliferative and differentiative activity of p/p melanoblasts/melanocytes. The addition of apoptosis-inhibitors, such as caspase-9 inhibitor (C9I) and Bax-inhibiting peptide (BIP) into MDMDF or MDMD stimulated the proliferation and differentiation of p/p melanoblasts. In contrast, in P/P melanoblasts and melanocytes, C9I and BIP failed to stimulate their proliferation and differentiation. The number of apoptotic keratinocytes and melanoblasts/melanocytes in p/p mice was greater than in P/P mice. Moreover, expression of C9 and Bax in keratinocytes and melanoblasts/melanocytes in p/p mice was greater than in P/P mice. These results suggest that the increased apoptosis in keratinocytes and melanoblasts/melanocytes is related to the reduced proliferative and differentiative activity of p/p melanoblasts. PMID- 23106555 TI - Catalytic enantioselective allylic amination of unactivated terminal olefins via an ene reaction/[2,3]-rearrangement. AB - The enantioselective allylic amination of unactivated terminal olefins represents a direct and attractive strategy for the synthesis of enantioenriched amines. We have developed the first use of a nitrogen-containing reagent and a chiral palladium catalyst to convert unfunctionalized olefins into enantioenriched allylic amines via an ene reaction/[2,3]-rearrangement. PMID- 23106557 TI - Spindle assembly and spatial distribution of gamma-tubulin during abortive meiosis and cleavage division in the parthenogenetic water flea Daphnia pulex. AB - In most animal species, centrosomes, the main microtubule-organizing centers, usually disintegrate in oocytes during meiosis and are reconstructed from sperm provided centrioles before the first cleavage division. In parthenogenetic oocytes, however, no sperm-derived centrosome-dependent microtubule nucleation is expected, as fertilization does not occur. The water flea Daphnia pulex undergoes parthenogenesis and sexual reproduction differentially in response to environmental cues. We used immunofluorescence microscopy with anti-alpha-tubulin and anti-gamma-tubulin antibodies to examine spindle formation and the occurrence of centrosomes during parthenogenetic oogenesis and the subsequent cleavage division in D. pulex. The spindle formed in abortive meiosis in parthenogenesis is barrel-shaped and lacks centrosomes, whereas the spindle in the subsequent cleavage division is typically spindle-shaped, with centrosomes. During abortive meiosis, gamma-tubulin is localized along the spindle, while in the first cleavage division it is localized only at the spindle poles. Thus, D. pulex should provide a useful comparative model system for elucidating mechanisms of spindle formation and improving our understanding of how evolutionary modification of these mechanisms is involved in the switch from sexual to parthenogenetic reproduction. PMID- 23106558 TI - Caste differentiation pathways in the neotropical termite Armitermes holmgreni (Isoptera: Termitidae). AB - The present study investigated the caste differentiation system of Armitermes holmgreni in natural colonies from the Atlantic Forest in northeastern Brazil. Thirteen measurements were made of the termites encountered in three colonies. The morphometric differences among the instars were analyzed using principal component analysis (PCA). The differentiation patterns of the nymphal lineages of A. holmgreni agreed with earlier descriptions of species of the Termitidae family, with one larval instar followed by five nymphal instars and alates. Nymphoid neotenics became differentiated starting at the fourth or fifth nymphal instar. Two larval instars were observed in the apterous lineage before the appearance of workers, presoldiers, and soldiers. Both workers and soldiers had only one instar each. The A. holmgreni workers consisted of male and female individuals, without sexual dimorphism, a situation that had not been previously recognized among the Syntermitinae. The A. holmgreni soldiers consisted only of female individuals, a pattern observed in most species of Termitinae and Macrotermitinae. The differentiation of nymphoid neotenics starting at the fourth or fifth nymphal instar has also been reported for Armitermes euamignathus. The general patterns of differentiation of A. holmgreni were similar to those previously observed in other species of Syntermitinae. PMID- 23106559 TI - Postmating isolation in six species of three genera (Hoplobatrachus, Euphlyctis and Fejervarya) from family Dicroglossidae (anura), with special reference to spontaneous production of allotriploids. AB - In light of reproductive isolation being a fundamental aspect of the biological species concept, we performed crossing experiments using six species from three genera (Hoplobatrachus, Euphlyctis and Fejervarya) of family Dicroglossidae to explore postmating isolation in dicroglossid frogs. Our results revealed gametic isolation among these genera, although the intergeneric hybrids between female E. cyanophlyctis and male H. chinensis were not viable at the tadpole stage, while the hybrids between female E. cyanophlyctis and male H. tigerinus were inviable at the hatching stage. These results showed complete hybrid inviability between the two genera. Almost all interspecific hybrids between female H. tigerinus and male H. chinensis died of underdevelopment at the tadpole stage, whereas several hybrids developed normally and survived to maturity. Chromosomal observations and mtDNA and allozyme analyses confirmed that these mature hybrids were allotriploid, with two maternal genomes and one paternal genome. The present results suggest that the allotriploids were produced spontaneously, and histological observations confirmed their sex as sterile males. We also investigated the molecular relationships between H. tigerinus, H. chinensis, and the interspecific allotriploids by mitochondrial Cytb, 12S and 16S rRNA gene analyses. The maternal inheritance mode of mitochondrial genomes was retained in the hybrids. Finally, the present results suggest that the degree of postmating isolation reflects phylogenetic relationship. In addition, we speculate that allotriploids may be produced via hybridization among cryptic species. PMID- 23106560 TI - Insights into Korean red fox (Vulpes vulpes) based on mitochondrial cytochrome b sequence variation in East Asia. AB - The red fox (Vulpes vulpes) is the most widely distributed terrestrial carnivore in the world, occurring throughout most of North America, Europe, Asia, and North Africa. In South Korea, however, this species has been drastically reduced due to habitat loss and poaching. Consequently, it is classified as an endangered species in Korea. As a first step of a planned red fox restoration project, preserved red fox museum specimens were used to determine the genetic status of red foxes that had previously inhabited South Korea against red foxes from neighboring countries. Total eighty three mtDNA cytochrome b sequences, including 22 newly obtained East Asian red fox sequences and worldwide red fox sequences from NCBI, were clustered into three clades (i.e., I, II, and III) based on haplotype network and neighbor-joining trees. The mean genetic distance between clades was 2.0%. Clade III contained South Korean and other East Asian samples in addition to Eurasian and North Pacific individuals. In clade III, South Korean individuals were separated into two lineages of Eurasian and North Pacific groups, showing unclear phylogeographic structuring and admixture. This suggests that South Korean red fox populations may have been composed of individuals from these two different genetic lineages. PMID- 23106561 TI - Molecular tools for species and sex identification in the mixed-species flocks of bean geese and white-fronted geese. AB - Genetic studies on protected species can be difficult, particularly when they form a mixed-species flock with other species. The bean goose (Anser fabalis), which is internationally recognized as a threatened species, was observed to form overwintering foraging flocks with white-fronted goose (Anser albifrons) at agricultural lands to feed on the grains in Korea. Non-invasive samples such as feces and feather that are readily available in their foraging ground can be useful for understanding the structure and composition of populations, but they often require specific experimental conditions due to small amount or low quality of DNA. In this study, we designed sets of primers that would allow efficient molecular identification of species and sex of individuals of bean geese and white-fronted geese. Species-specific primers (WFG-F/BG-F and G-R), developed from ND2 region of mitochondrial DNA, produced PCR products with different sizes which allow easy species identification without further sequencing. Based on published CHD 1 sequences, we designed internal primers (Gsex-F and Gsex-R) for sex determination that can be used in nested PCR after applying P2/P8 primers, and our methods clearly showed high success rate of molecular sexing from non invasive samples. These molecular tools open the possibilities for genetic studies using non-invasive samples collected from a mixed-species aggregation containing bean geese and white-fronted geese. PMID- 23106562 TI - Genetic composition of communal roosts of the Eurasian Magpie (Pica pica) inferred from non-invasive samples. AB - Many animal species form communal roosts in which they aggregate and sleep together. Several benefits of communal roost have been suggested, but due to lack of data on relatedness among group members, it is unknown whether these benefits can be amplified by the formation of kin-based communal roosts. We investigate the genetic composition of two winter roosts of Eurasian Magpies (Pica pica), using microsatellite markers on non-invasive samples. Using permutation tests by reshuffling the alleles presented in the roosts, we determined that individuals in the communal roosts of magpies were not more related than expected by chance, suggesting that kinship may not be a driving force for the formation of communal roosts in magpies. However, the pairwise relatedness and estimated relationship based on a maximum likelihood approach revealed that the roosts involve both kin and non-kin. Relatedness coefficients varied widely within a roost, indicating that family subgroups form a small proportion of the total number of birds in a roost. Our results suggest that ecological benefits of communal roost in animals are sufficient for the evolution of communal roosts without any involvement of kinship. PMID- 23106563 TI - Scales microstructure of snakes from the Egyptian area. AB - The morphology of many organisms seems to be related to the environments in which they live. Many snakes are so similar in their morphological patterns that it becomes quite difficult to distinguish any adaptive divergence that may have occurred. Many authors have suggested that the microstructure of the reptile's scales has important functional value. Herein, we investigate variations on the micromorphology of the external surface of dorsal scales on the head, the mid body region (trunk), and the tail of Rhomphotyphlops braminus (Typhlopidae), Eryx jaculus (Boidae), Psammophis sibilans (Colubridae), Naja haje (Elapidae) and Echis carinatus (Viperidae). The specimens were metallized and analyzed by scanning electron microscopy. All species displayed unique dorsal scale surface microstructures of the investigated regions. The microstructural pattern of the scales of head, trunk, and tail differs in different species of these snakes. In conclusion, we detected ecomorphologic relationships between extant dorsal scale microstructures and snake microhabitat, enabling us to hypothesize that environmental pressures have significant influences not only on these animals' macrostructure, but also on its microstructure as well. PMID- 23106564 TI - Ancient colonization and within-island vicariance revealed by mitochondrial DNA phylogeography of the mountain hare (Lepus timidus) in Hokkaido, Japan. AB - We examined the phylogenetic status and history of the mountain hare Lepus timidus in and around Hokkaido using mitochondrial cytochrome b (cyt b) sequences from 158 samples from Hokkaido and 14 from Sakhalin, as well as four samples from the Korean hare, L. coreanus. The phylogenetic analysis of the cyt b sequences generated in this study and obtained from DNA databases showed the clear genetic specificity of the Hokkaido lineage as a clade. The Hokkaido lineage was estimated to have diverged from the other conspecific and L. coreanus lineages 0.46 and 0.30 million years ago (Mya), respectively. These results suggest that the common ancestor of the mitochondrial lineage in Hokkaido and Korea inhabited Far East Asia before colonization by the present continental lineages of L. timidus, including the Sakhalin population. We estimated the time of the most recent common ancestor of the Hokkaido population to be 0.17 Mya, and found two distinct haplogroups within the island. One group had greater genetic diversity (mean number of pairwise differences: pi = 0.0188 +/- 0.0108) and appears to have expanded from the west to the entire island of Hokkaido. The other had lower genetic diversity (pi = 0.0038 +/- 0.0037) and its distribution was concentrated in the east. These contrasting west/east trends indicate that the Hokkaido population was fragmented in the past, and then subsequently expanded. Our study suggests that Hokkaido was an important refugium for boreal species in the far eastern region, and allowed the formation of various population genetic structures within the island. PMID- 23106565 TI - Testis-specific cell adhesion molecule, CEACAM6-L, forms homophilic interaction at the cell adhesion site in vitro. AB - Ceacam6-L (carcinoembryonic antigen-related cell adhesion molecule 6-long) has recently been isolated from rat testis by differential display technique followed by RT-PCR and DNA sequence analysis. CEACAM6-L is a member of the immunoglobulin (Ig) superfamily and composed of an Ig-like domain, three IgCAM domains, a transmembrane region, and a short intracellular domain. We previously reported that CEACAM6-L was localized at the interface between Sertoli cells and elongating/elongated spermatids and might be an adhesion molecule contributing to apical ectoplasmic specialization in testis. In this study, we investigate the adhesive capacities and the complex structures of CEACAM6-L, using COS-7 cells as a study model. Transfection and immunoprecipitation experiments showed that CEACAM6-L expressed in the cells was distributed to the plasma membrane and interacted homophilically between transfected COS-7 cells. A chemical cross linking experiment and a binding assay with recombinant CEACAM6-L proteins suggested that CEACAM6-L could form trans-tetra complexes, constructed by cis homodimers at the adhesion site between COS-7 cells expressing CEACAM6-L. We hypothesized that CEACAM6-L expressed in both germ cells and Sertoli cells forms homophilic trans-tetra complexes between these cells in the seminiferous epithelium. PMID- 23106567 TI - Evaluation of the intestinal toxicity and transport of xenobiotics utilizing precision-cut slices. AB - 1.The precision-cut intestinal slice (PCIS) technology is a relatively new addition to the battery of in vitro assays for evaluation of xenobiotic toxicity, metabolism, and transport. 2.The intestine is an important target for drug induced toxicity due to its high exposure after oral administration. Therefore, the prediction of drug-induced intestinal side effects remains a significant safety issue in pharmaceutical development. Although animal experiments have been proven useful, species differences and the requirement for reduction of animal use warrant the development of in vitro methods which can apply human tissue. 3.The enterocytes lining the villi express high activities of enzymes and transporters involved in drug disposition. They vary highly in activities: along the length of the intestine and along the villi, gradients of expression levels of the enzymes and proteins exist, which necessitates an in vitro model that can reflect the different regions of the intestine. 4.In this chapter, the application of PCIS in studies on transport and toxicity of xenobiotics is reviewed. PCIS can be prepared from each region of the intestine and from various species in a similar manner, and the results published so far indicate that they represent a promising model to evaluate intestinal toxicity and transport. PMID- 23106568 TI - Assessment of meiotic spindle configuration and post-warming bovine oocyte viability using polarized light microscopy. AB - The objectives of this study were to assess the efficiency of polarized light microscopy (PLM) in detecting microtubule-polymerized protein in in vitro-matured bovine oocytes; to examine its effects on oocyte developmental competence; and to assess the meiotic spindle of in vitro-matured oocytes after vitrification/warming and further assessment of oocyte developmental competence. In the first experiment, the presence of microtubule-polymerized protein (MPP) was confirmed as a positive PLM signal detected in 99.1% of analysed oocytes (n = 115), which strongly correlated (r = 1; p < 0.0001) with the presence of MPP as confirmed by immunostaining. In the second experiment, oocytes (n = 651) were exposed or not (controls) to PLM for 10 min and then fertilized and cultured in vitro. Oocytes exposed to PLM did not significantly differ from controls with regard to cleavage, total blastocyst and expanded blastocyst rates and cell numbers. In the third experiment, meiotic spindles were detected in 145 of 182 oocytes (79.6%) following vitrification and warming. Interestingly, after parthenogenetic activation and in vitro culture, oocytes that displayed a positive PLM signal PLM(+) differed significantly from PLM(-) in cleavage and Day 8 blastocyst rates. These results suggest that polarized light microscopy is an efficient system to detect microtubule-polymerized protein in in vitro-matured bovine oocytes and does not exert detrimental effects on bovine oocyte developmental competence. Moreover, PLM could be used as a tool to assess post warming viability in vitrified bovine oocytes. PMID- 23106569 TI - Is vitamin C intake too low in dialysis patients? AB - Vitamin C has several well-established roles in physiology including synthesis of collagen, carnitine and epinephrine, absorption of dietary iron, and mobilization of storage iron for erythropoeisis. Loss of several of these functions explains the pathology of scurvy, where defective collagen synthesis and anemia are major symptoms. Vitamin C deficiency is very common in dialysis patients and may arise from dialytic vitamin C clearance, restricted intake of vitamin C-rich foods, and increased vitamin C catabolism in vivo from inflammation. In the dialysis population, greater vitamin C intake may be needed for optimal health. Relationships between intake, body distribution, inflammation, and dialytic losses are complex and need further study. Concern about vitamin C metabolism leading to accumulation of tissue oxalate has led to the recommendation that vitamin C intake equals, but not exceeds, the intake recommended for the general population. Vitamin C deficiency in dialysis patients may have clinical consequences; a study in Renal Research Institute clinics found an association with periodontal disease. Data also support a role for vitamin C in prevention of dialysis-related anemia. New research questions are proposed in this editorial, with a discussion of strategies to determine the optimal provision of vitamin C for CKD patients. PMID- 23106570 TI - Major vault protein promotes locomotor recovery and regeneration after spinal cord injury in adult zebrafish. AB - In contrast to mammals, adult zebrafish recover locomotor functions after spinal cord injury (SCI), in part due to axonal regrowth and regeneration permissivity of the central nervous system. Upregulation of major vault protein (MVP) expression after spinal cord injury in the brainstem of the adult zebrafish prompted us to probe for its contribution to recovery after SCI. MVP is a multifunctional protein expressed not only in many types of tumours but also in the nervous system, where its importance for regeneration is, however, unclear. Using an established zebrafish SCI model, we found that MVP mRNA and protein expression levels were increased in ependymal cells in the spinal cord caudal to the lesion site at 6 and 11 days after SCI. Double immunolabelling showed that MVP was co-localised with Islet-1 or tyrosine hydroxylase around the central canal of the spinal cord in sham-injured control fish and injured fish 11 days after surgery. MVP co-localised with the neural stem cell marker nestin in ependymal cells after injury. By using an in vivo morpholino-based knock-down approach, we found that the distance moved by MVP morpholino-treated fish was reduced at 4, 5 and 6 weeks after SCI when compared to fish treated with standard control morpholino. Knock-down of MVP resulted in reduced regrowth of axons from brainstem neurons into the spinal cord caudal to the lesion site. These results indicate that MVP supports locomotor recovery and axonal regrowth after SCI in adult zebrafish. PMID- 23106571 TI - High-throughput multiplexed competitive immunoassay for pollutants sensing in water. AB - The present study described the development and evaluation of a new fully automated multiplex competitive immunoassay enabling the simultaneous detection of five water pollutants (okadaic acid (OA), 2-chloro-4-ethylamino-6 isopropylamino-1,3,5-triazine (atrazine), 2.4-dichlorophenoxyacetic acid (2,4-D), 2,4,6-trinitrotoluene (TNT), and 1,3,5-trinitroperhydro-1,3,5-triazine (RDX)). The technology is taking advantage of an optical-clear pressure-sensitive adhesive on which biomolecules can be immobilized and that can be integrated within a classical 96-well format. The optimization of the microarray composition and cross-reaction was performed using an original approach where probe molecules (haptens) were conjugated to different carriers such as protein (bovine serum albumin or ovalbumin), amino-functionalized latex beads, or dextran polymer and arrayed at the surface of the adhesive. A total of 17 different probes were then arrayed together with controls on the adhesive surface and screened toward their specific reactivity and cross-reactivity. Once optimized, the complete setup was used for the detection of the five target molecules (less than 3 h for 96 samples). Limits of detection of 0.02, 0.01, 0.01, 100, and 0.02 MUg L(-1) were found for OA, atrazine, 2,4-D, TNT, and RDX, respectively. The proof of concept of the multiplex competitive detection (semiquantitative or qualitative) of the five pollutants was also demonstrated on 16 spiked samples. PMID- 23106572 TI - Metabolic perturbance in autism spectrum disorders: a metabolomics study. AB - Autism spectrum disorders (ASD) are a group of biological disorders with associated metabolic derangement. This study aimed to identify a pattern of metabolic perturbance in ASD using metabolomics in urinary specimens from 48 children with ASD and 53 age matched controls. Using a combination of liquid- and gas-chromatography-based mass spectrometry, we detected the levels of 82 metabolites (53 of which were increased) that were significantly altered between the ASD and the control groups using osmolality normalized data. Pattern analysis showed that the levels of several amino acids such as glycine, serine, threonine, alanine, histidine, glutamyl amino acids and the organic acid, taurine were significantly (p<=0.05) lower in ASD children. The levels of antioxidants such as carnosine were also reduced in ASD (p=0.054). Furthermore, several gut bacterial metabolites were significantly altered in ASD children who had gastrointestinal dysfunction. Overall, this study detected abnormal amino acid metabolism, increased oxidative stress, and altered gut microbiomes in ASD. The relationship of altered gut microbial co-metabolism and the disrupted metabolisms requires further investigation. PMID- 23106573 TI - The reversibility of UV-B induced alterations in optical properties of the rabbit cornea depends on dose of UV irradiation. AB - Solar UVB radiation evokes photokeratitis, accompanied by increased corneal hydration and changes in corneal transparency, resulting in increased light absorption. Corneal optical properties are disturbed and visual acuity decreased. The aim of this study was to investigate the reversibility of these UVB-induced changes. Rabbit corneas were irradiated with UVB doses of 0.5 J cm(-2) or 1.01 J cm(-2) during 4 days. Some rabbits were sacrificed after the last irradiation and some 2 months later. Corneas were investigated spectrophotometrically for light absorption, and corneal hydration was evaluated by central corneal thickness with an ultrasonic pachymeter. Corneal impression cytologies were examined immunohistochemically for proinflammatory cytokines and malondialdehyde. The increased corneal light absorption, hydration and the staining of immunohistochemical markers found in corneas after irradiation returned to normal values during 2 months in corneas irradiated with the lower UVB dose. In contrast, in corneas irradiated with the higher UVB dose, a moderate but statistically significant increase in corneal light absorption, hydration and positive immunohistochemical stainings remained as residual changes. This was in contrast to normal corneas, where the staining of proinflammatory cytokines as well as malondialdehyde was negative. In conclusion, the reversibility of UVB induced disturbances was dependent on UVB dose. PMID- 23106574 TI - An investigation of rheumatoid arthritis loci in patients with early-onset psoriasis validates association of the REL gene. AB - BACKGROUND: Phenotypically diverse autoimmune conditions share common genetic susceptibility loci and underlying molecular pathways. OBJECTIVES: By systematically searching for single nucleotide polymorphisms (SNPs) associated with another autoimmune disease, rheumatoid arthritis (RA), we aimed to elucidate novel genetic markers of psoriasis. METHODS: We investigated 18 SNPs, previously confirmed as being associated with RA, in a U.K. cohort of 623 patients with early-onset psoriasis (presenting before age 40 years), comparing them with 2662 control subjects. RESULTS: Our findings confirm the association of early-onset psoriasis with REL (rs13031237, P=0.0027). The minor allele of REL had opposing effects upon susceptibility to disease in patients with psoriasis and RA. CONCLUSION: Similar exploration of additional autoimmune loci and fine mapping of such regions may provide further insight into the genetics and molecular pathophysiology of psoriasis. PMID- 23106575 TI - CD31 immunohistochemical staining in Kaposi Sarcoma. PMID- 23106577 TI - Model for an online, virtual medical textbook generated from HTML-coded links to virtual microscopic slides. PMID- 23106578 TI - Atrophic vaginitis: concordance and interpretation of slides in the College of American Pathologists Cervicovaginal Interlaboratory Comparison Program in Gynecologic Cytopathology. AB - CONTEXT: Atrophic vaginitis is a commonly reported subset of Papanicolaou test results that are negative for intraepithelial lesion or malignancy, but interpretive criteria overlap with atrophic changes and other entities, hindering concordance among observers. OBJECTIVES: To report on the participant concordance from 2000 to 2009 in the College of American Pathologists Interlaboratory Comparison Program in Gynecologic Cytopathology, with a reference interpretation of atrophic vaginitis, and to investigate cytologic features of good and poorly performing slides to identify criteria useful in the interpretation of atrophic vaginitis. DESIGN: We summarized 18 302 responses from the program for slides with a reference interpretation of atrophic vaginitis. We randomly selected 18 Papanicolaou test results (3 conventional, 4 SurePath, and 11 ThinPrep) from good and poor performers for prospective, blinded criteria scoring for the following features: abundance of neutrophils, more than 100 degenerating parabasal cells, more than 25% necrotic background, more than 100 pseudoparakeratotic cells, and the presence of stripped or streaked nuclei, histiocytes, and superficial or intermediate squamous cells. RESULTS: Most Papanicolaou test results (>90%) with a specific reference interpretation of atrophic vaginitis were categorized as negative. Cytotechnologists are more likely than pathologists are to label it negative for intraepithelial lesion or malignancy (NILM) and are equally likely to mistake it for a high-grade lesion. Degenerating parabasal cells, pseudoparakeratosis, and necrotic background are associated with atrophic vaginitis (P = .001) on Papanicolaou. Abundant neutrophils (>100 per *400 field) are also significantly correlated (P = .01). CONCLUSIONS: Exact concordance to atrophic vaginitis is less than 90%. Most of the discrepancies are negative results for intraepithelial lesion or malignancy. Advanced atrophic features are as significant as neutrophils are to the interpretation of atrophic vaginitis. PMID- 23106579 TI - Selective immunohistochemical markers to distinguish between metastatic high grade urothelial carcinoma and primary poorly differentiated invasive squamous cell carcinoma of the lung. AB - CONTEXT: Distinction between primary lung carcinomas and metastases from other sites, especially the urinary tract, is a common diagnostic dilemma. As urothelial carcinomas can demonstrate a broad range of morphology and frequently demonstrate squamous differentiation, discerning metastatic urothelial carcinoma to the lung from primary pulmonary squamous cell carcinoma can be challenging. OBJECTIVE: To investigate immunostains that may aid in the distinction of urothelial carcinoma metastatic to the lung. DESIGN: Staining patterns of 14 markers in primary urothelial carcinoma of the bladder and primary squamous cell carcinoma of the lung were examined to establish a diagnostic panel. These antibodies were subsequently tested on tumors taken from 30 patients with a paired urinary tract and metastatic lung lesion. RESULTS: The best markers to distinguish poorly differentiated metastatic urothelial carcinoma from primary pulmonary squamous cell carcinoma were CK7, CK20, GATA-3, CK14, desmoglein-3, and uroplakin III, with the utility of the latter dependent upon the quantity of tissue available for analysis. The observed percentage positive staining in nonmetastatic urothelial carcinoma versus primary pulmonary squamous cell carcinoma with these antibodies was as follows: CK7 (100% versus 33%), CK20 (54% versus 7%), GATA-3 (78% versus 23%), CK14 (32% versus 77%), desmoglein-3 (11% versus 87%), and uroplakin III (14% versus 0%). Similar expression patterns were observed among the paired cases. CONCLUSION: When interpreted in correlation with clinical history and histomorphology, a panel of immunostains including CK7, CK20, GATA-3, CK14, desmoglein-3, and uroplakin III may be a useful adjunct in the distinction of metastatic urothelial carcinoma to the lung. PMID- 23106580 TI - Mucinous carcinomas of the gallbladder: clinicopathologic analysis of 15 cases identified in 606 carcinomas. AB - CONTEXT: There are virtually no data in the literature regarding the incidence, patterns, and clinicopathologic characteristics of mucinous carcinomas (MCs) of the gallbladder (GB). OBJECTIVE: To determine the incidence of mucinous differentiation in invasive GB carcinomas and the clinicopathologic characteristics of those that qualify as MC. DESIGN: Primary invasive GB carcinomas (n = 606) were reviewed for mucinous differentiation. Some degree of mucin production was identified in 40 cases (6.6%); however, only 15 (2.5%) were qualified for the World Health Organization definition of MC (stromal mucin deposition constituting >50% of the tumor). RESULTS: The mean age was 65 years, and the female to male ratio was 1.1 (versus 3.9 for conventional pancreatobiliary-type GB adenocarcinomas; P = .04). A significant proportion of the cases (8 of 12, 67%) presented with the clinical picture and intraoperative findings that were interpreted as acute cholecystitis. Mean and median tumor sizes were larger than those of conventional adenocarcinomas (4.8 and 3.4 cm versus 2.9 and 2.5 cm, respectively; P = .01). Most (13 of 15, 87%) cases presented with pT3 tumors (versus 48% for ordinary GB carcinomas; P = .01). Two cases had almost an exclusive colloid pattern (>90% composed of well-defined stromal mucin nodules that contained scanty carcinoma cells, most of which were floating within the mucin). Eight cases were of mixed-mucinous type, showing a mixture of colloid and noncolloid patterns. Five others had prominent signet-ring cells, both floating within the mucin (which constituted >50% of the tumor by definition) and infiltrating into the stroma as individual signet-ring cells in some areas. Immunohistochemical analysis performed on the 7 cases that had available tissue revealed CK7 in 4 of 7 (57%), CK20 in 2 of 7 (29%), MUC1 in 4 of 7 (57%), MUC2 in 6 of 7 (86%), CDX2 in 1 of 7 (14%), MUC5AC in 6 of 7 (86%), MUC6 in 0 of 7 (0%), and loss of E-cadherin in 6 of 7 (86%). The MLH1 and MSH2 were retained in 6 of 7 cases (100%). Follow-up information was available for 13 cases: 11 (85%) died of disease (1-37 months) and 2 (15%) were alive (23 months and 1 month). Overall survival of MCs was significantly worse than that of conventional adenocarcinomas (13 versus 26 months; P = .01); however, that did not seem to be independent of stage. CONCLUSIONS: Mucinous carcinomas constitute 2.5% of GB carcinomas. They present with an acute cholecystitis-type picture. Most MCs are a mixed-mucinous, not pure colloid, type. They are typically large and advanced tumors at the time of diagnosis and thus exhibit more-aggressive behavior than do ordinary GB carcinomas. Immunophenotypically, they differ from conventional GB adenocarcinomas by MUC2 positivity, from intestinal carcinomas by an often inverse CK7/20 profile, from pancreatic mucinous carcinomas by CDX2 negativity, and from mammary colloid carcinomas by a lack of MUC6. Unlike gastrointestinal MCs, they appear to be microsatellite stable. PMID- 23106581 TI - Expression of human telomerase reverse transcriptase in vulvar intraepithelial neoplasia and squamous cell carcinoma: an immunohistochemical study with survivin and p53. AB - CONTEXT: Human telomerase reverse transcriptase (hTERT), an enzyme that enables cells to overcome replicative senescence and to divide indefinitely, is overexpressed in many cancers and their precursor lesions. OBJECTIVE: To test whether hTERT expression is related to neoplastic progression and resistance to apoptosis in vulvar epithelia. DESIGN: Immunoexpression of hTERT was evaluated in 101 formalin-fixed, paraffin-embedded archival vulvar epithelia consisting of normal squamous vulvar epithelia (n = 25), lichen sclerosus (n = 10), high grade classic vulvar intraepithelial neoplasia (n = 16), differentiated vulvar intraepithelial neoplasia (n = 18), and vulvar invasive keratinizing squamous cell carcinoma (n = 32) and related to survivin and p53 expression. Immunostaining for all factors was scored for moderate and strong intensities with regard to quantity to determine upregulation and overexpression (score 0, 0% immunoreactive cells; score 1+, <5% immunoreactive cells; score 2+, 5% to 50% immunoreactive cells; score 3+, >50% immunoreactive cells). Score 3+ was considered as overexpression. RESULTS: Nuclear hTERT immunoexpression was closely related to survivin reactivity, increased from normal vulvar squamous epithelia to lichen sclerosus and to high-grade classic vulvar intraepithelial neoplasia, differentiated vulvar intraepithelial neoplasia, and invasive keratinizing squamous cell carcinoma (P < .001), and followed the morphologic distribution of atypical squamous epithelial cells. Overexpression of hTERT was comparable to that seen for p53 in invasive keratinizing squamous cell carcinoma (P = .62); significant differences were calculated for differentiated vulvar intraepithelial neoplasia (P = .003) and high-grade classic vulvar intraepithelial neoplasia (P = .001). CONCLUSION: Human telomerase reverse transcriptase is upregulated in vulvar intraepithelial neoplasia and invasive keratinizing squamous cell carcinoma compared with nonneoplastic squamous epithelia of the vulva as an apparently early and preinvasive event in the neoplastic transformation, with development of cellular longevity and resistance to apoptosis by survivin activation as associated features, independent of the etiology of vulvar intraepithelial neoplasia. PMID- 23106582 TI - Familial idiopathic interstitial pneumonia: histopathology and survival in 30 patients. AB - CONTEXT: Familial idiopathic interstitial pneumonia (F-IIP) describes the unexplained occurrence of diffuse parenchymal lung disease in related individuals. Prevailing wisdom suggests that the histopathology of F-IIP is indistinguishable from that of idiopathic pulmonary fibrosis, namely, usual interstitial pneumonia (UIP). OBJECTIVE: To define the histopathology of F-IIP in lung tissue samples. DESIGN: Tissue sections from 30 patients with F-IIP, enrolled in a national research program, were evaluated by 3 pulmonary pathologists using 15 predefined histopathologic features. Each feature was recorded independently before a final diagnosis was chosen from a limited list dichotomized between UIP or "not UIP." These 2 groups were then compared to survival. RESULTS: The consensus diagnosis for the F-IIP cohort was an unclassifiable parenchymal fibrosis (60%), with a high incidence of histopathologic honeycombing, fibroblast foci, and smooth muscle in fibrosis. Usual interstitial pneumonia, strictly defined, was identified in less than half of the F-IIP cases (range, 23%-50%). Interobserver agreement was fair (kappa = 0.37) for 2 observers for the overall diagnosis of UIP. Findings unexpected in UIP were prevalent. The survival for the entire F-IIP cohort was poor, with an estimated mortality of 93% and a median age at death of 60.9 years. Subjects with UIP had a shorter survival and younger age at death. CONCLUSIONS: Pulmonary fibrosis was the dominant histopathology identified in our patients, but diagnostic features of UIP were seen in less than 50% of the samples. Overall survival was poor, with mortality accelerated apparently by the presence of a UIP pattern of disease. PMID- 23106583 TI - Spiral array: a new high-throughput technology covers tissue heterogeneity. AB - CONTEXT: Tissue array is a well-established technique that connects basic research with clinical applications and allows for the validation of many pathobiologic events from gene expression dysregulation to genomic aberrations. However, conventional tissue array has several limitations such as poor representation of tissue heterogeneity, destruction of donor tissue blocks due to coring, and usage of particular specimens that have limited evaluable material (tissue from thin specimens or needle biopsies). OBJECTIVE: To show the noninferiority and superiority of the new technique named Spiral Array-which allows for improved representation of the donor tissue while keeping the architectural details of the donor block intact-to that of the conventional tissue array. We compared the morphologic features of both methods. DESIGN: We created both Spiral Array and conventional tissue array for 25 lung adenocarcinomas and 50 multiple tumors of various organs. The degree of coverage of tissue heterogeneity was examined by observing the range of the staining intensity differences in immunohistochemistry, using cytokeratin 7 and epidermal growth factor receptor (EGFR); the degree of morphologic preservation was tested by level of accurate prediction among 3 pathologists of the histopathologic diagnosis and organ type. RESULTS: The Spiral Array showed better representations of the range of staining intensity for EGFR (P = .01). The level of accuracy for predicting organ type was significantly higher in Spiral Array than conventional tissue array (P = .047), whereas it was not significantly different between the 2 techniques for the histologic diagnosis. CONCLUSION: Our data indicate that Spiral Array has benefits for covering tissue heterogeneity and preserving better morphology. PMID- 23106584 TI - Biological variations of leukocyte numerical and morphologic parameters determined by UniCel DxH 800 hematology analyzer. AB - CONTEXT: The Coulter DxH 800 hematology analyzer can determine leukocyte numerical parameters (total leukocyte counts and differentials). It also measures intrinsic biophysical properties of these cells in their near-native state. These morphologic measurements are known as cell population data (CPD). OBJECTIVE: To study, for the first time, the biological variations of morphologic parameters or CPD and reinvestigate numerical parameters using the newest Coulter hematology analyzer. Design.-Forty adult volunteers (21 women, 19 men) were included. All participants maintained their normal lifestyles. Blood samples were drawn in duplicate by a single experienced phlebotomist and analyzed within 2 hours using a single analyzer. Before each batch analysis, the instrument quality controls were performed using the same lots of reagents. RESULTS: Within-subject (CV(I)) and between-subjects (CV(G)) biological variations for numerical parameters are smaller than previously reported. Cell population data have much smaller overall CV(I) and CV(G) compared to numerical parameters, suggesting that these parameters are less variable around the homeostatic set point intraindividually and interindividually. Index of individuality (ratio of CV(I)/CV(G)) for CPD was low. In addition, intraday and interday biological variations of all parameters are fairly constant. CONCLUSIONS: These observations are clinically valuable. Data on CV(I) and analytical precision may be used to generate objective delta check values for use in quality management. Comparing CV(I) and CV(G) on CPD may allow us to decide the utility of traditional population-based reference ranges. Documentation of CPD on biological variations is an essential prerequisite in the development of any new application clinically. PMID- 23106585 TI - Metastatic tumors to the colon and rectum: a multi-institutional study. AB - CONTEXT: Unlike the small bowel, the colorectal mucosa is seldom the site of metastatic disease. Objective.-To determine the incidence of truly colorectal metastases, and subsequent clinicopathologic findings, in a substantial colorectal cancer population collected from 7 European centers. DESIGN: During the last decade, 10 365 patients were identified as having colorectal malignant tumors, other than systemic diseases. Data collected included patient demographics, clinical symptoms, treatment, the presence of metastases in other sites, disease-free interval, follow-up, and overall survival. All secondary tumors resulting from direct invasion from malignant tumors of the contiguous organs were excluded, as well as those resulting from lymph node metastases or peritoneal seeding. RESULTS: Only 35 patients were included (10 men) with a median age of 59 years. They presented with obstruction, bleeding, abdominal pain, or perforation. The leading source of metastases was the breast, followed by melanoma. Metastases were synchronous in 3 cases. The mean disease-free interval for the remaining cases was 6.61 years. Surgical resection was performed in 28 cases. Follow-up was available for 26 patients; all had died, with a mean survival time of 10.67 months (range, 1-41 months). CONCLUSIONS: Colorectal metastases are exceptional (0.338%) with the breast as a leading source of metastases; they still represent a late stage of disease and reflect a poor prognosis. Therefore, the pathologist should be alert for the possibility of secondary tumors when studying large bowel biopsies. Any therapy is usually palliative, but our results suggest that prolonged survival after surgery and complementary therapy can be obtained in some patients. PMID- 23106586 TI - Immunohistochemistry for immunoglobulin G4 on paraffin sections for the diagnosis of pemphigus. AB - CONTEXT: Pemphigus is a group of autoimmune vesiculobullous diseases characterized by immunoglobulin G (IgG) antibodies directed against desmosomal adhesion proteins, with IgG4 being the predominant subclass in active diseases. Direct immunofluorescence for IgG performed on fresh-frozen tissue plays a crucial role in diagnosing pemphigus. However, the diagnosis might be hindered when frozen tissue is not available. OBJECTIVE: To evaluate the usefulness of immunohistochemistry for IgG4 performed on paraffin sections as a diagnostic test for pemphigus. DESIGN: Eighteen immunofluorescence-proven pemphigus cases (12 pemphigus vulgaris, 6 pemphigus foliaceus) were studied. Four normal skin specimens and 32 nonpemphigus vesiculobullous disease specimens served as controls. Paraffin sections of all cases were examined immunohistochemically for IgG4 expression. Positivity was defined as distinct, condensed, continuous immunoreactivity localized to the intercellular junctions of keratinocytes. RESULTS: The immunostains were independently evaluated in a masked manner by 3 pathologists, with a 100% interobserver agreement. Nine of 12 pemphigus vulgaris cases (sensitivity 75.0%), and 4 of 6 pemphigus foliaceus cases (sensitivity 66.7%), were positive for IgG4 immunostain. The overall sensitivity was 72.2%. One control specimen (bullous pemphigoid) showed IgG4 positivity (specificity 97.2%). In specimens demonstrating acantholysis, 8 of 10 pemphigus vulgaris cases (sensitivity 80.0%) and 4 of 4 pemphigus foliaceus cases (sensitivity 100.0%) were positive for IgG4. The overall sensitivity for specimens with acantholytic lesions was 85.7%. CONCLUSION: Immunohistochemistry for IgG4 provides a reasonably sensitive and highly specific test for diagnosing pemphigus, especially when frozen tissue is not available, and active acantholytic lesions are examined. PMID- 23106587 TI - Comparison study of the rates of manual peripheral blood smear review from 3 automated hematology analyzers, Unicel DxH 800, ADVIA 2120i, and XE 2100, using international consensus group guidelines. AB - CONTEXT: In the clinical laboratory, it is important both to reduce the number of peripheral blood slide reviews to save time and money and to avoid reporting false results. OBJECTIVE: To determine differences in the slide review rates of 3 widely used automated hematologic analyzers, the Unicel DxH 800 (Beckman Coulter Inc, Fullerton, California), ADVIA 2120i (Siemens Diagnostics, Tarrytown, New York), and XE 2100 (Sysmex, Kobe, Japan), using International Consensus Group for Hematology Review guidelines. DESIGN: A total of 1485 samples were tested, and 300 were manually reviewed. Slide review rates, sensitivity, specificity, and false-positive and false-negative rates were estimated using consensus group rules and compared using chi(2) tests, Fisher exact tests, or generalized estimating equations. RESULTS: Unicel DxH 800, ADVIA 2120i, and XE 2100 showed 22.8%, 20.2%, and 28.6% slide review rates; 14.3%, 14.3%, and 9.7% false-negative rates; and 13.7, 11.3%, and 17.3% false-positive rates, respectively. All analyzers showed significantly higher false-negative rates than that of the consensus group (2.9%). CONCLUSIONS: False-negative rates were higher than the recommended levels. Among 3 automated hematologic analyzers, XE 2100 showed the highest rate of slide review. Because the present study clearly shows that the slide review rates have distinct characteristics among the studied analyzers, each individual laboratory should consider selecting the most appropriate analyzer according to clinical characteristics. Analyzers with high sensitivity may be advantageous in outpatient settings for screening patients, whereas analyzers with high specificity may be beneficial in inpatient settings for efficient patient care. PMID- 23106588 TI - Teaching laboratory medicine to medical students: implementation and evaluation. AB - CONTEXT: Laboratory medicine is an integral component of patient care. Approximately 60% to 70% of medical decisions are based on laboratory results. Physicians in specialties that order the tests are teaching medical students laboratory medicine and test use with minimal input from laboratory scientists who implement and maintain the quality control for those tests. OBJECTIVE: To develop, implement, and evaluate a 1.5-day medical student clinical laboratory experience for fourth-year medical students in their last month of training. DESIGN: The experience was devised and directed by laboratory scientists and included a panel discussion, laboratory tours, case studies that focused on the goals and objectives recently published by the Academy of Clinical Laboratory Physicians and Scientists, and medical-student presentations highlighting salient points of the experience. The same knowledge quiz was administered at the beginning and end of the experience and 84 students took both quizzes. RESULTS: A score of 7 or more was obtained by 16 students (19%) on the initial quiz, whereas 34 (40%) obtained the same score on the final quiz; the improvement was found to be statistically significant (P = .002; t = 3.215), particularly in 3 out of the 10 questions administered. CONCLUSIONS: Although the assessment can only measure a small amount of knowledge recently acquired, the improvement observed by fourth-year medical students devoting a short period to learning laboratory medicine principles was encouraging. This medical student clinical laboratory experience format allowed teaching of a select group of laboratory medicine principles in 1.5 days to an entire medical school class. PMID- 23106589 TI - Successful implementation of a longitudinal, integrated pathology curriculum during the third year of medical school. AB - CONTEXT: There are few published examples of pathology instruction during the clinical years of medical student training. This lack of exposure to pathology may lead to poor understanding of laboratory testing and the role of pathologists in patient care. OBJECTIVE: To design, implement, and evaluate a pathology curriculum integrated into a longitudinal clerkship for third-year medical students. DESIGN: The curriculum includes an introductory session during the transition week course, pathologist participation in longitudinal student case conferences, and a pathology elective. The curriculum was evaluated by using surveys consisting of both multiple choice and written responses. RESULTS: A total of 55 students participated in the longitudinal curriculum during the 2009 2010 academic year and 8 students, only one of whom stated a career interest in pathology, participated in the elective. More than 80 pathology topics were discussed and, for the first time, pathologists received teaching awards from the third-year students. All elective students would recommend the elective to colleagues; feedback also suggested an improved understanding of pathology as a profession. At the end of the year, 31% of all students, compared to only 19% in the initial survey, knew that most of an anatomic pathologist's caseload consists of specimens from living patients (P = .13). In addition, elective student interaction with a pathology faculty member directly led to an improvement in test reporting. CONCLUSIONS: A novel longitudinal curriculum allowed for the creative integration of pathology into third-year students' clinical training and led to better student understanding of the role of pathologists in patient care. PMID- 23106590 TI - Albert C. Broders' paradigm shifts involving the prognostication and definition of cancer. AB - CONTEXT: In the 19th and early 20th centuries, cancer was defined by the demonstration of invasion and metastases, based upon gross findings at surgery or autopsy. Although histopathologic examination of tumors became possible with greater and greater resolution over time, the definition of cancer remained the same. Tumors with features suggesting the biological "potential" to invade and metastasize were not cancers until they had achieved their potential. Prognostication based upon histopathologic analyses of tumor biopsies and resection specimens was not possible, as the concepts of tumor grading and staging did not exist until the 1920s and 1930s, respectively. OBJECTIVE: To examine the history of tumor grading and the concept of "carcinoma in situ" and to explore the role of Albert C. Broders, MD, and others in these discoveries. DESIGN: To address these topics, standard historiographic methods were used to examine available primary and secondary historical sources. RESULTS: Early in his career, Broders described tumor grading, showing for the first time that histopathologic findings could independently predict prognosis. This discovery quickly begat tumor staging and eventually the whole predictive biomarker field. Later in his career, Broders described carcinoma in situ, thereby changing the very definition of cancer. CONCLUSION: Historians recognize that science progresses through a series of paradigm shifts. Most clinician-scientists, even those at the very top of their fields, never make a discovery so dramatic that it changes their field forever. In the 1920s and 1930s, Albert C. Broders published 2 observations that forever changed cancer diagnosis, prognostication, and treatment. PMID- 23106591 TI - Micropapillary carcinoma: new variant of prostatic acinar adenocarcinoma. AB - A micropapillary variant of prostatic acinar adenocarcinoma has not been reported in the literature. Herein, we report a case of a 50-year-old patient who presented with an elevated prostate-specific antigen concentration and was subsequently diagnosed with prostatic acinar adenocarcinoma on biopsy. Radical prostatectomy specimen revealed prostatic carcinoma with Gleason score 4 + 5 = 9/10, with micropapillary component constituting 80% of tumor volume. Immunohistochemical studies of the prostate carcinoma showed a homogeneously positive prostate-specific antigen and alpha-methylacyl-CoA racemase, high molecular-weight cytokeratin, and p63 protein cocktail pattern of staining in both micropapillary and conventional components. Pelvic lymph nodes were negative for metastatic disease. In contrast to the aggressive behavior of micropapillary carcinomas of other organs, the disease in our patient has thus far followed a more benign course, with low stage on presentation and a 2-year follow-up free of disease. However, prognostic correlation should be established on large series in order to assign this variant to a grade category within the Gleason scheme. PMID- 23106592 TI - Small cell carcinoma of the urinary bladder: a rare, aggressive neuroendocrine malignancy. AB - Small cell carcinoma of the urinary bladder is a rare, often fatal, disease. Its presenting symptoms and gross morphology are similar to those of conventional urothelial carcinoma, whereas its prognosis is much poorer with frequent metastasis. Small cell carcinoma of the urinary bladder shares similar histology with its counterparts in other organs; however, its immunoreactivity to conventional neuroendocrine markers is low. Its diagnosis is thus considered permissible on morphologic grounds alone. Multimodal treatments are often employed, although no definite treatment algorithm has been established. For this extremely aggressive malignancy with an as-yet inconclusive etiology, further studies are needed to clarify its molecular pathogenesis to serve as a basis for diagnostic markers and therapeutic targets. The clinical, morphologic, immunoreactive, molecular, and therapeutic features of bladder small cell carcinoma are reviewed, including a detailed discussion on the utility of immunohistochemical markers. PMID- 23106595 TI - Drug resistance and IS6110-RFLP patterns of Mycobacterium tuberculosis in patients with recurrent tuberculosis in northern Thailand. AB - The emergence of drug resistant Mycobacterium tuberculosis has become a global threat to tuberculosis (TB) prevention and control efforts. This study aimed to determine the drug resistance profiles and DNA fingerprints of M. tuberculosis strains isolated from patients with relapsed or retreatment pulmonary TB in Chiang Rai province in northern Thailand. Significant differences in multidrug resistance (MDR) (P = 0.025) and resistance to isoniazid (P = 0.025) and rifampin (P = 0.046) between first and second registrations of patients with retreatment TB were found. However, there were no significant differences in resistance to any drugs in patients with relapsed TB. The rate of MDR-TB strains was 12.2% among new patients at first registration, 22.5% among patients with recurrence who had previously undergone treatment at second registration and 12.5% at third registration. Two retreatment patients whose initial treatment had failed had developed MDR-TB with resistance to all TB drugs tested, including rifampin, isoniazid, streptomycin and ethambutol. IS6110-RFLP analysis revealed that 66.7% (10/15 isolates) of MDR-TB belonged to the Beijing family. In most cases, IS6110 RFLP patterns of isolates from the same patients were identical in relapse and retreatment groups. However, some pairs of isolates from retreatment patients after treatment failure had non-identical IS6110-RFLP patterns. These results suggest that, after failure and default treatment, patients with retreatment tuberculosis have a significantly greater risk of MDR-TB, isoniazid and rifampin resistance than do other patients. PMID- 23106594 TI - Cross-linking protein glutathionylation mediated by O2-arylated bis diazeniumdiolate "Double JS-K". AB - Attachment of glutathione (GSH) to cysteine residues in proteins (S glutathionylation) is a reversible post-translational modification that can profoundly alter protein structure and function. Often serving in a protective role, for example, by temporarily saving protein thiols from irreversible oxidation and inactivation, glutathionylation can be identified and semiquantitatively assessed using anti-GSH antibodies, thought to be specific for recognition of the S-glutathionylation modification. Here, we describe an alternate mechanism of protein glutathionylation in which the sulfur atoms of the GSH and the protein's thiol group are covalently bound via a cross-linking agent, rather than through a disulfide bond. This form of thiol cross-linking has been shown to occur and has been confirmed by mass spectrometry at the solution chemistry level, as well as in experiments documenting the potent antiproliferative activity of the bis-diazeniumdiolate Double JS-K in H1703 cells in vitro and in vivo. The modification is recognized by the anti-GSH antibody as if it were authentic S-glutathionylation, requiring mass spectrometry to distinguish between them. PMID- 23106596 TI - Characteristic electroencephalographic findings by photic driving in patients with migraine-associated vertigo. AB - CONCLUSIONS: Patients with migraine-associated vertigo (MAV) may have a higher incidence of photic-driven electroencephalography (EEG) response. The occurrence of photic-driven responses for stimulation at frequencies of 10, 12, and 15 Hz can be considered a positive indicator for MAV. Although photic driving is not specific to migraine, patients with MAV have a higher incidence of photic driving. The distinction between Meniere's disease and MAV by means of EEG would be another interesting topic of research. OBJECTIVE: The objective of this study was to distinguish between patients with MAV and patients with other vestibulopathies (VPs) using EEG. METHODS: EEG with intermittent photic stimulation (PS) at frequencies between 3 and 24 Hz was recorded to quantify photic driving in patients with MAV (n = 21) and VPs (n = 15). The presence or absence of photic driving was determined; a score of 1 was counted for response to a particular frequency. RESULTS: Total scores were calculated for each patient for statistical comparison. There was a significant difference in the average total score between MAV and VP patients (p < 0.05), and photic-driven responses were observed for 10, 12, and 15 Hz stimulation. PMID- 23106593 TI - Calpain inhibitor attenuated optic nerve damage in acute optic neuritis in rats. AB - Optic neuritis (ON), which is an acute inflammatory autoimmune demyelinating disease of the central nervous system (CNS), often occurs in multiple sclerosis (MS). ON is an early diagnostic sign in most MS patients caused by damage to the optic nerve leading to visual dysfunction. Various features of both MS and ON can be studied following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, in Lewis rats. Inflammation and cell death in the optic nerve, with subsequent damage to the retinal ganglion cells in the retina, are thought to correlate with visual dysfunction. Thus, characterizing the pathophysiological changes that lead to visual dysfunction in EAE animals may help develop novel targets for therapeutic intervention. We treated EAE animals with and without the calpain inhibitor calpeptin (CP). Our studies demonstrated that the Ca(2+)-activated neutral protease calpain was upregulated in the optic nerve following induction of EAE at the onset of clinical signs (OCS) of the disease, and these changes were attenuated following treatment with CP. These reductions correlated with decreases in inflammation (cytokines, iNOS, COX-2, and NF-kappaB), and microgliosis (i.e. activated microglia). We observed that calpain inhibition reduced astrogliosis (reactive astroglia) and expression of aquaporin 4 (AQP4). The balance of Th1/Th2 cytokine production and also expression of the Th1-related CCR5 and CXCR3 chemokine receptors influence many pathological processes and play both causative and protective roles in neuron damage. Our data indicated that CP suppressed cytokine imbalances. Also, Bax:Bcl-2 ratio, production of tBid, PARP-1, expression and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated after treatment with CP. Our results demonstrated that CP decreased demyelination [loss of myelin basic protein (MBP)] and axonal damage [increase in dephosphorylated neurofilament protein (de-NFP)], and also promoted intracellular neuroprotective pathways in optic nerve in EAE rats. Thus, these data suggest that calpain is involved in inflammatory as well as in neurodegenerative aspects of the disease and may be a promising target for treating ON in EAE and MS. PMID- 23106597 TI - Exploring the reactions of Fe+ and FeO+ with NO and NO2. AB - We report for the first time temperature dependences (from 300 to 600 K) of the reactions of Fe(+) and FeO(+) with NO and NO(2). Both ions react quickly with NO(2), and their rate constants have weak negative temperature dependences. The former is consistent with the calculated energy profile along the Fe(+) + NO(2) reaction coordinate. Ground state Fe(+) reacts with NO(2) to produce only FeO(+), while FeO(+) reacts with NO(2) to produce NO(+) exclusively. Certain source conditions produce excited Fe(+), as evidenced by production of primary NO(+), which is endothermic with the ground state by 0.35 eV. The room temperature rate constants are in agreement with previous values. For the reactions of Fe(+) and FeO(+) with NO, we find an upper limit of <1.0 * 10(-12) cm(3) s(-1) for both rate constants, in contrast to a previous report of a rate constant of ~1.7 * 10( 11) cm(3) s(-1) for Fe(+) + NO. Because this is an endothermic process, the prior report interpreted the reaction as a termolecular process involving two NO molecules; instead, we show that the previous results were likely due to an NO(2) impurity. Implications for other metal cation reactions which have been speculated to occur by the termolecular mechanism are discussed. PMID- 23106598 TI - Comorbidities and survival in obstructive sleep apnoea beyond the age of 50. AB - BACKGROUND: Although mortality risk associated with obstructive sleep apnoea (OSA) tends to disappear from the age of 50, it has been suggested that OSA treatment by continuous positive airway pressure (CPAP) improves survival even in older subjects. Life expectancy of subjects with several diseases is worse if OSA coexists. The objectives of this study were to evaluate the relevance of comorbidities in the relationship between OSA and mortality, and in the effect of CPAP on survival, in subjects >= 50 years old. METHODS: Data from 810 patients studied by polysomnography for suspected OSA between 1991 and 2000 were retrospectively evaluated. In 2009, state of survival and use of CPAP were enquired. Three hundred and thirteen subjects were < 50 and 497 were >= 50 years at diagnosis. RESULTS: Age and comorbidities, but not apnoea/hypopnoea index (AHI) or lowest nocturnal arterial oxygen saturation (Nadir SaO(2)), predicted mortality in the whole sample. Nadir SaO(2) was related to mortality among the younger subjects without comorbidities (P = 0.01), but not among the older subjects. In the older patients with an AHI > 30 CPAP treatment was associated with a better survival only if comorbidities coexisted. CONCLUSIONS: Unlike in younger subjects, in subjects >= 50 years old, comorbidities do not mask an effect of OSA on mortality. Among OSA subjects >= 50 years old, comorbidities could separate those who may expect an improvement in survival with CPAP treatment from those who may not. Possibly, after the age of 50, OSA per se does not affect survival, but worsens prognosis of subjects with coexisting diseases. PMID- 23106599 TI - Head circumference needs to be measured. PMID- 23106600 TI - Optimizing treatment with risperidone long-acting injections. PMID- 23106601 TI - Cholinesterase inhibitory constituents from Ficus bengalensis. AB - Bengalensinone (22beta-hydroxylup-12,20-dien-3-one; 1), a new lupane triterpene, and benganoic acid (2), a new apocarotenoid, together with lupanyl acetate, 3 acetoxy-9(11),12-ursandiene, stigmasterol, alpinumisoflavone, 4 hydroxyacetophenone, 4-hydroxybenzoic acid, 4-hydroxymellein, and p-coumeric acid were isolated from the methanolic extract of the aerial roots of Ficus bengalensis. The structures of these compounds were established by the combination of 1D NMR (1H and 13C NMR) and 2D NMR (HMQC, HMBC, and COSY) analyses, and mass spectrometry (EI-MS and HR-EI-MS), and in comparison with literature data of the related compounds. Compounds 1 and 2 displayed inhibitory potential against enzyme cholinesterase in a concentration-dependent manner with IC50 values 194.5 and 154.5 MUM for acetylcholinesterase and 224.9 and 120.0 MUM for butyrycholinesterase, respectively. PMID- 23106602 TI - Electrostatic spray deposition of porous SnO2/graphene anode films and their enhanced lithium-storage properties. AB - Porous SnO2/graphene composite thin films are prepared as anodes for lithium ion batteries by the electrostatic spray deposition technique. Reticular-structured SnO2 is formed on both the nickel foam substrate and the surface of graphene sheets according to the scanning electron microscopy (SEM) results. Such an assembly mode of graphene and SnO2 is highly beneficial to the electrochemical performance improvement by increasing the electrical conductivity and releasing the volume change of the anode. The novel engineered anode possesses 2134.3 mA h g-1 of initial discharge capacity and good capacity retention of 551.0 mA h g-1 up to the 100th cycle at a current density of 200 mA g-1. This anode also exhibits excellent rate capability, with a reversible capacity of 507.7 mA h g-1 after 100 cycles at a current density of 800 mA g-1. The results demonstrate that such a film-type hybrid anode shows great potential for application in high energy lithium-ion batteries. PMID- 23106603 TI - In vitro assessment of artifacts induced by titanium dental implants in cone beam computed tomography. AB - OBJECTIVE: The objective of this study was to evaluate the geometric pattern and the intensity of artifacts around titanium implants in cone beam computed tomography (CBCT) using an in vitro model. MATERIAL AND METHODS: Ten test models, each containing one 4.1-mm-diameter titanium implant, were cast from a human mandible using silicone impression material and dental stone. Each model contained an implant in one of the following single-tooth gaps: 37, 36, 34, 33, 31, 41, 43, 44, 46, and 47. For control purposes, three models without implants were produced. Each model was scanned five times using a CBCT scanner. Gray values (GV) were recorded at eight circumferential positions around the implants at 0.5 mm, 1 mm, and 2 mm from the implant surface (GVTest ). GV were measured in the corresponding volumes of interest (VOI) in the models without implants (GVControl ). Differences of gray values (DeltaGV) between GVTest and GVControl were calculated as percentages. To detect differences between GVTest and GVControl , the 95% confidence interval (CI) was computed for the values of DeltaGV. Repeated measures ANOVA was used for the comparison of DeltaGV at 0.5 mm, 1 mm, and 2 mm from the implant surface. RESULTS: Artifacts reflected by altered GV were always present in the proximity of titanium implants, regardless of the implant position. When comparing GVTest and GVControl , increased GV were found at the buccal and lingual aspects of the implant sites, whereas regions with reduced GV were located along the long axis of the mandibular body of the test models. A significant decrease in artifact intensity was found with increasing distance from the buccal implant surface (DeltaGV0.5 mm : 45 +/- 10% [SD], DeltaGV1 mm : 28 +/- 14% [SD], DeltaGV2 mm : 14 +/- 7% [SD]) (P < 0.001). CONCLUSION: Artifacts around titanium implants in CBCT images were distributed according to a geometrical pattern. PMID- 23106604 TI - Effect of forensic evidence on criminal justice case processing. AB - This study examined the role and impact of forensic evidence on case-processing outcomes in a sample of 4205 criminal cases drawn from five U.S. jurisdictions. Regression analyses demonstrated that forensic evidence played a consistent and robust role in case-processing decisions. Still, the influence of forensic evidence is time- and examination-dependent: the collection of crime scene evidence was predictive of arrest, and the examination of evidence was predictive of referral for charges, as well as of charges being filed, conviction at trial, and sentence length. The only decision outcome in which forensic evidence did not have a general effect was with regard to guilty plea arrangements. More studies are needed on the filtering of forensic evidence in different crime categories, from the crime scene to its use by investigators, prosecutors, and fact-finders, and to identify factors that shape decisions to collect evidence, submit it to laboratories, and request examinations. PMID- 23106605 TI - Genome-wide association reveals genetic basis for the propensity to migrate in wild populations of rainbow and steelhead trout. AB - Little is known of the genetic basis of migration despite the ecological benefits migratory species provide to their communities and their rapid global decline due to anthropogenic disturbances in recent years. Using next-generation sequencing of restriction-site-associated DNA (RAD) tags, we genotyped thousands of single nucleotide polymorphisms (SNPs) in two wild populations of migratory steelhead and resident rainbow trout (Oncorhynchus mykiss) from the Pacific Northwest of the United States. One population maintains a connection to the sea, whereas the other population has been sequestered from its access to the ocean for more than 50 years by a hydropower dam. Here we performed a genome-wide association study to identify 504 RAD SNP markers from several genetic regions that were associated with the propensity to migrate both within and between the populations. Our results corroborate those in previous quantitative trait loci studies and provide evidence for additional loci associated with this complex migratory life history. Our results suggest a complex multi-genic basis with several loci of small effect distributed throughout the genome contributing to migration in this species. We also determined that despite being sequestered for decades, the landlocked population continues to harbour genetic variation associated with a migratory life history and ATPase activity. Furthermore, we demonstrate the utility of genotyping-by-sequencing and how RAD-tag SNP data can be readily compared between studies to investigate migration within this species. PMID- 23106606 TI - A rapidly expanding immature teratoma originating from a neurohypophyseal germinoma. PMID- 23106607 TI - The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study. AB - Acute kidney injury (AKI) is characterized by deterioration in kidney function resulting in multisystem abnormalities. Much of the morbidity and mortality associated with AKI result from a systemic inflammatory response syndrome (SIRS). This study described herein is a prospective, single-arm, multicenter US study designed to evaluate the safety and efficacy of the Selective Cytopheretic Device (SCD) treatment on AKI requiring continuous renal replacement therapy (CRRT) in the ICU. The study enrolled 35 subjects. The mean age was 56.3+/-15. With regard to race, 71.4% of the subjects were Caucasian, 22.9% were Black, and 5.7% were Hispanic. Average SOFA score was 11.3+/-3.6. Death from any cause at Day 60 was 31.4%. Renal recovery, defined as dialysis independence, was observed in all of the surviving subjects at Day 60. The results of this pilot study indicate the potential for a substantial improvement in patient outcomes over standard of care therapy, which is associated with a greater than 50% 60-day mortality in the literature. The SCD warrants further study in scientifically sound, pivotal trial to demonstrate reasonable assurance of safety and effectiveness. PMID- 23106608 TI - Infrared and Raman imaging spectroscopy of ex vivo skin. AB - This primer describes and illustrates experimental protocols for both Fourier transform infrared (FTIR) spectroscopic imaging and confocal Raman mapping of ex vivo skin and thereby acquaints the reader with these measurement techniques, including the temporal and spatial limitations associated with each technique. The experimental conditions by which the unique 'molecular histology' information obtained from confocal Raman mapping and infrared spectroscopic mapping of ex vivo skin is generated will be described. Raman and FTIR spectra of tissue, when collected in spatially resolved arrays, permit the generation of 'molecular images' of tissue components and tissue organization without the use of fluorescent labels or chemical stains. To illustrate the molecular information from ex vivo skin that can be spectroscopically imaged with confocal Raman and infrared microspectroscopy, we have collected new data using both techniques and generated spectral images which illustrate the capacity of each technique to provide unique insights into skin histology, biochemistry and biophysics. Understanding the measurement possibilities and specific constraints of both approaches is a prerequisite to their meaningful use as powerful research tools in skin research. PMID- 23106610 TI - Application of CFD simulation to predicting upper-room UVGI effectiveness. AB - This study outlines the potential for Computational Fluid Dynamics (CFD) simulation to be used to predict upper-room ultraviolet germicidal irradiation (UVGI) effectiveness to aid system design and the development of future guidance. A numerical study of two wall-mounted UVGI lamps in a mechanically ventilated test chamber is used to assess the influence of modeling parameters on prediction of dose distribution and microorganism inactivation. Irradiance fields for both UVGI fixtures are obtained via radiometry and implemented in the model. A series of sensitivity studies consider the importance of UVGI field accuracy and computational grid and turbulence model selection. Results show that 2D irradiance fields are sufficient for calculating dose and in-activation, whereas a 1D field is inadequate for modeling purposes. Further parametric studies consider the effects of ventilation parameters, UVGI lamp configuration and microorganism susceptibility. These demonstrate the feasibility of modeling the interaction of the airflow and UV field in a room to quantify the dose distribution. Microorganism in-activation can also be accomplished by employing passive scalars and species transport models, however, further validation data are necessary before this can be used to make reliable quantitative predictions. PMID- 23106611 TI - Proteomic and phosphoproteomic analysis of chicken embryo fibroblasts infected with cell culture-attenuated and vaccine strains of Marek's disease virus. AB - Vaccination is an effective strategy to reduce the loss of chickens in the poultry industry caused by Marek's Disease (MD), an avian lymphoproliferative disease. The vaccines currently used are from attenuated serotype 1 Marek's disease virus (MDV) or naturally nononcogenic MDV strains. To prepare for future immunity breaks, functional genomic and proteomic studies have been used to better understand the underlying mechanisms of MDV pathogenicity and the effects induced by the vaccine viruses. In this study, a combined approach of quantitative GeLC-MSE and qualitative ERLIC/IMAC/LC-MS/MS analysis were used to identify abundance changes of proteins and the variations of phosphorylation status resulting from the perturbations due to infection with an attenuated oncogenic virus strain (Md11/75C) and several nononcogenic virus strains (CVI988, FC126 and 301B) in vitro. Using this combined approach, several signal transduction pathways mapped by the identified proteins were found to be altered at both the level of protein abundance and phosphorylation. On the basis of this study, a kinase-dependent pathway to regulate phosphorylation of 4E-BP1 to modulate assembly of the protein translation initiation complex was revealed. The differences of 4E-BP1 phosphorylation patterns as well as the measured abundance changes among several other proteins that regulate host transcriptional and translational activities across the virus strains used in this study provide new insight for future functional and biochemical characterization of specific proteins involved in MDV pathogenesis. PMID- 23106612 TI - Investigation of the hepatic glucuronidation pattern of the Fusarium mycotoxin deoxynivalenol in various species. AB - Deoxynivalenol (DON) is one of the most abundant mycotoxins contaminating food and feed worldwide. Upon absorption, the major portion of the toxin is excreted by humans and animal species as glucuronide. However, consistent in vitro data on DON glucuronidation are lacking. In the present study, the metabolism of DON was investigated using liver microsomes from humans and six different animal species. It was shown that all animal and human liver microsomes led to the formation of up to three different mono-O-glucuronides with significant interspecies differences. While the activity of human liver microsomes was low (0.8 to 2.2 pmol.min(-1).mg(-1)), bovine liver and rat liver microsomes conjugated DON with activities of 525 pmol.min(-1).mg(-1) and 80 pmol.min(-1).mg(-1), respectively. PMID- 23106613 TI - On the preparation and determination of configurational stability of chiral thio- and bromo[D1]methyllithiums. AB - Thio- and bromo[D(1)]methyllithiums (ee 99%) were generated from the respective stannanes by tin-lithium exchange at temperatures ranging from 0 to -95 degrees C. Thio[D(1)]methyllithiums 6 were found to be microscopically configurationally labile on the time scale of the thiophosphate-alpha-mercaptophosphonate rearrangement even at -95 degrees C. Thio[D(1)]methyllithiums 13a and 13b underwent a thia-[2,3]-Wittig rearrangement down to -95 degrees C and 13b only down to -50 degrees C. The former were microscopically configurationally stable below -95 degrees C, and the latter racemized completely at -50 degrees C. Chiral bromo[D(1)]methyllithiums are chemically unstable at -78 degrees C but microscopically configurationally stable at the time scale of their addition to benzaldehyde and acetophenone. PMID- 23106614 TI - Treatment options for residual insomnia in schizophrenia. PMID- 23106615 TI - Nesfatin-1, corticotropin-releasing hormone, thyrotropin-releasing hormone, and neuronal histamine interact in the hypothalamus to regulate feeding behavior. AB - Nesfatin-1, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and hypothalamic neuronal histamine act as anorexigenics in the hypothalamus. We examined interactions among nesfatin-1, CRH, TRH, and histamine in the regulation of feeding behavior in rodents. We investigated whether the anorectic effect of nesfatin-1, alpha-fluoromethyl histidine (FMH; a specific suicide inhibitor of histidine decarboxylase that depletes hypothalamic neuronal histamine), a CRH antagonist, or anti-TRH antibody affects the anorectic effect of nesfatin-1, whether nesfatin-1 increases CRH and TRH contents and histamine turnover in the hypothalamus, and whether histamine increases nesfatin-1 content in the hypothalamus. We also investigated whether nesfatin-1 decreases food intake in mice with targeted disruption of the histamine H1 receptor (H1KO mice) and if the H1 receptor (H1-R) co-localizes in nesfatin-1 neurons. Nesfatin-1 suppressed feeding was partially attenuated in rats administered with FMH, a CRH antagonist, or anti-TRH antibody, and in H1KO mice. Nesfatin-1 increased CRH and TRH levels and histamine turnover, whereas histamine increased nesfatin-1 in the hypothalamus. Immunohistochemical analysis revealed H1-R expression on nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus. These results indicate that CRH, TRH, and hypothalamic neuronal histamine mediate the suppressive effects of nesfatin-1 on feeding behavior. PMID- 23106616 TI - Dexamethasone suppresses cochlear Hes1 expression after noise exposure. AB - CONCLUSION: Dexamethasone provides protection against noise-induced hearing loss (NIHL) possibly by suppressing cochlear Hes1 expression via a glucocorticoid receptor (GR)-dependent mechanism. OBJECTIVES: The purpose of the present study was to explore whether hairy and enhancer of split 1 (Hes1) was involved in the protective effect of dexamethasone against NIHL. METHODS: Guinea pigs, which were administered intraperitoneal injections of either saline, 1.0 mg/kg dexamethasone, 20.0 mg/kg RU38,486, or a combination of both drugs (dexamethasone plus RU38,486) for 5 consecutive days, were exposed to white-band noise (115 dB sound pressure level). The expression level of Hes1 in cochleae was compared using real-time RT-PCR and Western blot analysis. RESULTS: Noise exposure for 3 h induced auditory brainstem response (ABR) threshold elevations, outer hair cell losses, and increase of Hes1 expression. Dexamethasone pretreatment prevented the NIHL with decreased Hes1 expression, which could be blocked by GR antagonist RU38,486. PMID- 23106617 TI - Infrared spectra of M-eta2-C2H2 and HM-C=CH produced in reactions of laser ablated group 6 metal atoms with acetylene. AB - The pi and C-H insertion complexes (M-eta(2)-C(2)H(2) and HM-C=CH) are identified in the matrix infrared spectra from reactions of laser-ablated Group 6 metal atoms with acetylene. In annealing, the pi complex is produced, and it converts to the insertion product during photolysis with no trace of the vinylidene product. This observation is consistent with the considerably higher activation energy to H(2)CCM than that to HM-CCH in the previously proposed reaction path, whereas the three plausible products are in fact energetically comparable. The back-donations in the Group 6 metal pi complexes are evidently weaker than those in the Groups 3-5 metal analogues but still stronger than those in the main group and Group 7-10 metal systems. The insertion complexes have bent CMH moieties in contrast with the linear Mn complex. PMID- 23106618 TI - Synthesis of steroid-oligonucleotide conjugates for a DNA site-encoded SPR immunosensor. AB - The excellent self-assembling properties of DNA and the excellent specificity of the antibodies to detect analytes of small molecular weight under competitive conditions have been combined in this study. Three oligonucleotide sequences (N(1)up, N(2)up, and N(3)up) have been covalently attached to three steroidal haptens (8, hG, and 13) of three anabolic-androgenic steroids (AAS), stanozolol (ST), tetrahydrogestrinone (THG), and boldenone (B), respectively. The synthesis of steroid-oligonucleotide conjugates has been performed by the reaction of oligonucleotides carrying amino groups with carboxyl acid derivatives of steroidal haptens. Due to the chemical nature of the steroid derivatives, two methods for coupling the haptens and the ssDNA have been studied: a solid-phase coupling strategy and a solution-phase coupling strategy. Specific antibodies against ST, THG, and B have been used in this study to asses the possibility of using the self-assembling properties of the DNA to prepare biofunctional SPR gold chips based on the immobilization of haptens, by hybridization with the complementary oligonucleotide strands possessing SH groups previously immobilized. The capture of the steroid-oligonucleotide conjugates and subsequent binding of the specific antibodies can be monitored on the sensogram due to variations produced on the refractive index on top of the gold chip. The resulting steroid-oligonucleotide conjugates retain the hybridization and specific binding properties of oligonucleotides and haptens as demonstrated by thermal denaturation experiments and surface plasmon resonance (SPR). PMID- 23106619 TI - Where does it hurt? PMID- 23106620 TI - Imaging or imagining? Is equine diagnostic imaging evidence based? PMID- 23106621 TI - Chronicle of a death foretold. PMID- 23106622 TI - Respiratory responses to exercise in the horse. AB - Horses are elite athletes when compared with other mammalian species. In the latter, performance is limited by cardiovascular or musculoskeletal performance whereas in athletic horses it is the respiratory system that appears to be rate limiting and virtually all horses exercising at high intensities become hypoxaemic and hypercapnoeic. This is due to both diffusion limitation and a level of ventilation inadequate for the metabolic level that enables horses to exercise at these intensities. In conjunction with these blood gas changes, total pulmonary resistance increases and the work of breathing rises exponentially and airflow eventually plateaus despite increases in inspiratory and expiratory intrapleural pressures. Horses breathe at comparatively high frequencies when galloping due to the tight 1:1 coupling of strides to breathing. Whether this effects gas exchange and, if so, to what extent, has not been fully elucidated. PMID- 23106623 TI - Laminitis: recent advances and future directions. PMID- 23106624 TI - Endocrinological aspects of the pathophysiology of equine laminitis. PMID- 23106625 TI - Sepsis-related laminitis. PMID- 23106626 TI - Supporting limb laminitis: the four important 'whys'. PMID- 23106627 TI - Progress towards effective prevention and therapy for laminitis. PMID- 23106628 TI - The present state and future of laminitis research. PMID- 23106629 TI - A review of recent advances and current hypotheses on the pathogenesis of acute laminitis. AB - With the increasing number of studies being published on the different experimental models used to induce and study acute laminitis, the pathophysiological events associated with these various models (i.e. starch overload, oligofructose overload, black walnut extract and hyperinsulinaemia) can be compared more realistically. Within this review, the mechanisms for metabolic vs. inflammatory laminitis are discussed, and the question of how pasture laminitis may fit into any of the proposed mechanisms is addressed. PMID- 23106630 TI - Modulation of Paecilomyces lilacinus antimicrobial metabolite production by co culturing with Salmonella typhimurium. AB - Fungi are important organisms related to the production of antibiotics, many of which are commercially available and used in the clinic to treat infections. Infectious diseases represent a leading cause of death worldwide, being a severe threat to public health, especially with the rise of multi-resistant microorganisms. Therefore, the search for new antibiotic substances is regaining importance. The aim of this study was to evaluate the modulation of the antimicrobial activity of Paecilomyces lilacinus extracts obtained after fungal cultivation in challenging growing conditions, which included the co-cultivation with Salmonella typhimurium, in different levels of inactivation. Two methodologies were used to achieve the antimicrobial response levels of the extracts: disc diffusion and broth microdilution. The extracts showed selective antibacterial activity in response to the presence of bacterial DNA in the medium. The extracts were analysed by HPLC that corroborated that parameter variation influenced the extract chemical profiles. PMID- 23106631 TI - An ultrasonography-cytology protocol for the diagnostic management of regional nodes in a subset of patients with Merkel cell carcinoma of the skin. AB - BACKGROUND: The status of regional lymph nodes (LNs) is one of the most consistent predictors of survival in Merkel cell carcinoma (MCC). In cases of clinically localized disease, current practice involves sentinel lymph node (SLN) assessment. OBJECTIVES: To propose ultrasonography (US) followed by fine needle aspiration cytology (FNAC) and immunohistochemistry as a useful diagnostic tool in the pre-surgical management of patients with MCC. METHODS: US of LNs was performed in 75 patients with MCC (22 with stage III tumours; 53 with stage I II). In patients with US suspected disease, US coupled with FNAC of the LN was performed. Smears were examined by routine cytological staining supplemented with immunohistochemical staining for cytokeratin 20. All patients underwent surgical removal of regional LNs. RESULTS: In all 22 patients with stage III tumours, US was indicative of tumour deposits and FNAC confirmed metastases to LNs. In 11 of 53 patients with localized MCC without clinical evidence of nodal disease, US revealed enlarged, equivocal nodes where FNAC was performed. Ten LNs were cytologically positive for metastases, and one was negative. Upon histological examination, the FNAC-negative case showed a metastasis 5 mm in diameter. In all the other 42 cases with no clinical or US evidence of LN involvement, only SLN biopsy was performed and in six cases small metastatic foci were detected. Ultimately, of the 53 stage I-II MCC, 17 had positive LN involvement. In 10 cases (59%) metastases were detected by FNAC, and in seven cases, were detected by SLN biopsy. CONCLUSIONS: In a selected subset (~20%) of patients with MCC with clinically localized disease, US followed by FNAC in the suspect LN is a valid alternative to the classical protocol of SLN histological examination. PMID- 23106632 TI - Detection of Salmonella spp. from large volumes of water by modified Moore swabs and tangential flow filtration. AB - This study compares the use of tangential flow filtration (TFF), normal flow filtration and modified Moore swabs (MMS) for the concentration and detection of Salmonella, spiked at 1-760 CFU l(-1), from 10 l of surface water. Two immunomagnetic separation (IMS) methods, Pathatrix and Dynabeads, for further concentration of Salmonella were compared following filtration and overnight enrichment. Detection of Salmonella by PCR, qPCR or culture-based methods was compared. TFF and MMS preformed equally well in concentrating Salmonella. MMS was able to consistently concentrate Escherichia coli O157:H7 for culture-based detection; only at the higher concentrations tested was the TFF able to consistently concentrate E. coli O157:H7 for culture-based detection. Salmonella, at population densities <10 CFU l(-1) in 10 l of spiked surface water, could be reliably (6/6) detected within 2 days by combining TFF or MMS, with IMS Pathatrix and qPCR. The theoretical limit of detection for Salmonella is considered to be sufficiently sensitive to meet all the practical screening purposes for surface waters in an agricultural setting intended for application to edible horticultural crops. PMID- 23106633 TI - Ectopic bone formation in and soft-tissue response to P(CL/DLLA)/bioactive glass composite scaffolds. AB - OBJECTIVES: To characterize biological response to subcutaneously implanted macroporous poly(epsilon-caprolactone/D,L-lactide)-based scaffolds, and to evaluate the effect of bioactive glass (BAG) filler and osteogenic cells to the tissue response and ectopic bone formation. MATERIAL AND METHODS: In the first part of this study, six different scaffold types were screened in a rat subcutaneous implantation model. The polymer scaffolds with 70/30 caprolactone/lactide ratio and corresponding composites with < 45 MUm BAG filler size were chosen for the further ectopic bone formation assay. The scaffolds were loaded with differentiating bone marrow stromal cells and implanted subcutaneously in syngeneic rats. RESULTS: With plain scaffolds, only mild foreign body reaction with no signs of gross inflammation was observed after 4 weeks of implantation. Furthermore, the scaffolds were fully invaded by well vascularized soft connective tissue. Overall, all the tested scaffold types showed an appropriate host response. With cell-seeded scaffolds, several loci of immature mineralizing tissue and small amounts of mature bone were observed after 4 weeks. The incidence of mature bone formation was two and four in polymer scaffolds and composites, respectively (n = 8). After twelve weeks, mature bone was observed in only one polymer scaffold but in seven composites (n = 8). Excluding bone formation, the host response was considered similar to that with cell-free scaffolds. CONCLUSIONS: Plain scaffolds supported the ingrowth of well vascularized fibroconnective tissue. Furthermore, cell seeded composites with BAG filler showed enhanced ectopic bone formation in comparison with corresponding neat polymer scaffolds. PMID- 23106634 TI - Combustion smoke-induced inflammation in the cerebellum and hippocampus of adult rats. AB - AIMS: The effect of combustion smoke inhalation on the respiratory system is widely reported but its effects on the central nervous system remain unclear. Here, we aimed to determine the effects of smoke inhalation on the cerebellum and hippocampus which are areas vulnerable to hypoxia injury. METHODS: Adult male Sprague-Dawley rats were subjected to combustion smoke inhalation and sacrificed at 0.5, 3, 24 and 72 h after exposure. The cerebellum and hippocampus were subjected to Western analysis for VEGF, iNOS, eNOS, nNOS and AQP4 expression; ELISA analysis for cytokine and chemokine levels; and immunohistochemistry for GFAP/AQP4, RECA-1/RITC and TUNEL. Aminoguanidine (AG) was administered to determine the effects of iNOS after smoke inhalation. RESULTS: Both the cerebellum and hippocampus showed a significant increase in VEGF, iNOS, eNOS, nNOS and AQP4 expression with corresponding increases in inflammatory cytokines and chemokines and increased AQP4 expression and RITC permeability after smoke exposure. AG was able to decrease the expression of iNOS, followed by VEGF, eNOS, nNOS, RITC and AQP4 after smoke exposure. There was also a significant increase in TUNEL+ cells in the cerebellum and hippocampus which were not significantly reduced by AG. Beam walk test revealed immediate deficits after smoke inhalation which was attenuated with AG. CONCLUSION: The findings suggest that iNOS plays a major role in the central nervous system inflammatory pathophysiology after smoke inhalation exposure with concomitant increase in proinflammatory molecules, vascular permeability and oedema, for which the cerebellum appears to be more vulnerable to smoke exposure than the hippocampus. PMID- 23106635 TI - Growing trees in child brains: graph theoretical analysis of electroencephalography-derived minimum spanning tree in 5- and 7-year-old children reflects brain maturation. AB - The child brain is a small-world network, which is hypothesized to change toward more ordered configurations with development. In graph theoretical studies, comparing network topologies under different conditions remains a critical point. Constructing a minimum spanning tree (MST) might present a solution, since it does not require setting a threshold and uses a fixed number of nodes and edges. In this study, the MST method is introduced to examine developmental changes in functional brain network topology in young children. Resting-state electroencephalography was recorded from 227 children twice at 5 and 7 years of age. Synchronization likelihood (SL) weighted matrices were calculated in three different frequency bands from which MSTs were constructed, which represent constructs of the most important routes for information flow in a network. From these trees, several parameters were calculated to characterize developmental change in network organization. The MST diameter and eccentricity significantly increased, while the leaf number and hierarchy significantly decreased in the alpha band with development. Boys showed significant higher leaf number, betweenness, degree and hierarchy and significant lower SL, diameter, and eccentricity than girls in the theta band. The developmental changes indicate a shift toward more decentralized line-like trees, which supports the previously hypothesized increase toward regularity of brain networks with development. Additionally, girls showed more line-like decentralized configurations, which is consistent with the view that girls are ahead of boys in brain development. MST provides an elegant method sensitive to capture subtle developmental changes in network organization without the bias of network comparison. PMID- 23106636 TI - A rising tide: the increasing age and psychiatric length of stay for individuals with mild intellectual disabilities. AB - BACKGROUND: It is unclear whether the substantial decline in number and duration of admissions for patients with intellectual disability (ID) have occurred uniformly over time with respect to age, gender, severity of disability, legal status and location of treatment. METHOD: A retrospective analysis of NHS (National Health Service) admissions for ID and use of NHS ID beds in England between 1998/9 and 2007/8. RESULTS: NHS admissions for ID halved from 37,736 to 18,091, and admissions with a primary diagnosis of ID to beds reduced by 71% from 21,866 to 6420. This reduction was most marked among children with the result that the average age of those admitted increased from 26 years to 36 years. Mean length of stay shortened except for mild ID where it increased from 131 days to 244 days (the median increased from 6 days to 32 days). There was an 18% reduction in the number of patients with ID who were legally detained to NHS facilities but a 170% increase in those to private facilities (from 202 to 545). CONCLUSIONS: The number of patients with ID admitted to NHS facilities, especially children, has fallen dramatically. There has been a marked shift towards legal detentions to private facilities. The most notable finding was the increased duration of admissions for those with mild ID, possibly indicating that substituting mainstream for specialist services for this group has had negative consequences. PMID- 23106637 TI - Metabolic analysis of the cutaneous fungi Malassezia globosa and M. restricta for insights on scalp condition and dandruff. AB - Dandruff is a global consumer problem, characterized by flaking and scaling of the scalp, accompanied by itch and irritancy. However, the aetiology of the condition remains poorly understood, although there is a strong consensus that the cutaneous fungi Malassezia globosa and M. restricta are a major contributory factor. Although there is a paucity of understanding on how these commensal microorganisms adopt a pathogenic phenotype, a rich source of potential insights now exists in the shape of the recently published whole-genome sequence of M. globosa, a functional annotation and metabolic reconstruction of which is freely accessible via the integrated microbial genomes (IMG) online community resource (http://www.hmpdacc-resources.org/cgi-bin/imgm_hmp/main.cgi). In these studies, we have taken a combined in-silico and in-vitro approach to investigate aspects of lipid and amino acid metabolism by M. globosa and M. restricta that have the potential to impact on scalp condition and dandruff. The IMG platform was employed to analyse the metabolism of triacylglycerols and fatty acids, as well as the aromatic amino acid tryptophan, by M. globosa, to investigate pro inflammatory pathways linked in the literature to dandruff and pityriasis versicolour, respectively. Results were equivocal, leaving question marks over the ability of M. globosa to fully degrade unsaturated fatty acids and metabolize tryptophan to indole-3-pyruvic acid. In-vitro assay systems were then developed to study the biotransformation of these metabolites by both M. globosa and M. restricta, as well as their effect on human keratinocytes, and the results here indicated that neither unsaturated fatty acids nor indole derivatives are likely to be major aetiological factors in dandruff. PMID- 23106638 TI - Alcohol problems as a risk factor for postdisaster depressed mood among U.S. veterans. AB - Alcohol problems may impede adaptive, proactive responses to disaster-related injury and loss, thus prolonging the adverse impact of disasters on mental health. Previous work suggests that veterans of the U.S. armed forces have a relatively high prevalence of alcohol misuse and other psychiatric disorders. This is the first study to estimate the impact of predisaster alcohol problems on postdisaster depressed mood among veterans, using data that were collected before and after the 1994 Northridge, CA, earthquake. The authors assessed the impact of alcohol problems on postdisaster depressed mood in an existing clinical cohort of veterans who experienced the 6.7-magnitude earthquake that struck Northridge in January 1994. One to 3 months after the disaster, interviewers contacted participants by telephone to administer a follow-up questionnaire based on a survey that had been done preearthquake. Postearthquake data were obtained on 1,144 male veterans for whom there were preearthquake data. We tested a predictive path model of the relationships between latent variables for predisaster alcohol problems, functional limitations, and depressed mood on latent variables representing postdisaster "quake impact" and depressive mood. Results showed that veterans who had more alcohol problems before the earthquake experienced more earthquake-related harms and severely depressed mood after the earthquake, compared with those who had fewer alcohol problems. Programs serving veterans with a high prevalence of alcohol problems should consider designing disaster response protocols to locate and assist these patients in the aftermath of disasters. PMID- 23106640 TI - Review of manual control methods for handheld maneuverable instruments. AB - By the introduction of new technologies, surgical procedures have been varying from free access in open surgery towards limited access in minimal access surgery. Improving access to difficult-to-reach anatomic sites, e.g. in neurosurgery or percutaneous interventions, needs advanced maneuverable instrumentation. Advances in maneuverable technology require the development of dedicated methods enabling surgeons to stay in direct, manual control of these complex instruments. This article gives an overview of the state-of-the-art in the development of manual control methods for handheld maneuverable instruments. It categorizes the manual control methods in three levels: a) number of steerable segments, b) number of Degrees Of Freedom (DOF), and c) coupling between control motion of the handle and steering motion of the tip. The literature research was completed by using Web of Science, Scopus and PubMed. The study shows that in controlling single steerable segments, direct as well as indirect control methods have been developed, whereas in controlling multiple steerable segments, a gradual shift can be noticed from parallel and serial control to integrated control. The development of multi-segmented maneuverable instruments is still at an early stage, and an intuitive and effective method to control them has to become a primary focus in the domain of minimal access surgery. PMID- 23106639 TI - Responding to tobacco craving: experimental test of acceptance versus suppression. AB - Acceptance and Commitment Therapy (ACT) provides a theoretical rationale for "acceptance" of thoughts and feelings, and proscribes suppression, a more intuitive and commonly used coping strategy. Suppression is theorized to have negative consequences not applicable to acceptance, including depletion in self control and ironic postsuppression rebound effects. However, it remains largely unknown whether these strategies differentially affect frequency of drug-related thoughts, craving intensity, drug use behavior, or other relevant outcomes. Adult smokers (N = 162) were randomly assigned to receive a brief laboratory-based coping intervention (acceptance or suppression) or were not given coping instructions (control group) and then were exposed to smoking cues. Results indicated that the suppression group was successful at suppressing thoughts of smoking, as they reported fewer thoughts of smoking than the other two groups. Also, both coping strategies were associated with benefits with respect to craving and affect. However, there were no group differences in depletion, and rebound effects did not occur when coping was discontinued. Following the laboratory session, all participants attempted to quit or at least reduce their smoking for 3 days; the acceptance and suppression groups resumed use of their strategy. At 3-day follow-up, the acceptance and suppression groups reported greater self-efficacy for avoiding smoking when experiencing craving compared to the control group. However, there were no group differences in the number of cigarettes smoked during the 3 days. This study provides support for the value of acceptance-based coping, but it also suggests that more research is needed to differentiate its benefits compared to suppression. PMID- 23106641 TI - New detachable occlusion balloon unit for transrectal natural orifice translumenal endoscopic surgery. AB - INTRODUCTION: Transrectal natural orifice translumenal endoscopic surgery (NOTES) requires a good endoluminal view and adequate intrarectal bacterial clearance in the working area. We developed a new occlusion balloon unit with an easily detachable inflation device, which allows the surgeon a clear working area distal to the balloon. MATERIAL AND METHODS: The effectiveness of the sealing balloon and the extent of macroscopic and histopathological injury to the bowel wall at the site of balloon placement were examined in 12 pigs. RESULTS: The mean time to place and inflate the balloon unit was 12.0 +/- 3.5 min, effective air-tightness lasted for 21.0 +/- 12.0 min. There was no leakage of dye (methylene blue) past the balloon when pressure was maintained >6.70 +/- 0.08 kPa (6.62-6.78 kPa). After gut irrigation, good visibility was maintained in the working area for six hours, and adequate bacterial clearance was maintained for three hours. There were no macroscopic signs of intestinal wall damage at the site of balloon placement. Histopathological examination showed only patchy mucosal damage and submucosal thrombus at the site of balloon placement. CONCLUSION: This newly developed occlusion balloon unit helps to establish good visibility and adequate bacterial clearance for endoluminal surgical procedures. PMID- 23106642 TI - Apelin regulates the electrophysiological characteristics of atrial myocytes. AB - BACKGROUND: Apelin, a potential agent for treating heart failure, has various ionic effects on ventricular myocytes. However, the effects of apelin on the atrium are not clear. The purpose of this study was to investigate the acute effects of apelin on the electrophysiological characteristics of atrial myocytes. METHOD: Whole-cell patch-clamp techniques were used to investigate the action potential (AP) and ionic currents in isolated rabbit left atrial (LA) myocytes before and after the administration of apelin. RESULT: Apelin reduced LA AP duration measured at 90%, 50% and 20% repolarization of the amplitude by 11 +/- 3%, 24 +/- 5%, 30 +/- 7% at 1 nM (n = 11), and by 14 +/- 4%, 36 +/- 6% and 45 +/- 5% at 10 nM (n = 11), but not at 0.1 nM. Apeline (0.1, 1, 10 nM) did not change the amplitude, or resting membrane potential in LA myocytes. Apelin (1 nM) increased sodium currents, ultra-rapid potassium currents and the reverse mode of sodium-calcium exchanger currents, but decreased late sodium currents and L-type calcium currents and did not change transient outward currents or inward rectifier potassium currents in LA myocytes. CONCLUSIONS: Apelin significantly changed the atrial electrophysiology with a shortening of AP duration, which may be caused by its effects on multiple ionic currents. PMID- 23106644 TI - Deracemization of alpha-aryl hydrocoumarins via catalytic asymmetric protonation of ketene dithioacetals. AB - An unprecedented catalytic asymmetric protonation of ketene dithioacetals is described. Various racemic alpha-aryl hydrocoumarin derivatives are transformed into enantioenriched dithioacetal-protected hydrocoumarins in the presence of a chiral Bronsted acid catalyst. A newly developed phosphoric acid, featuring the 3,5-bis(pentafluorothio)phenyl (3,5-(SF(5))(2)C(6)H(3)) substituent, is introduced. The obtained products can be easily converted into either hydrocoumarins or the corresponding chromans via simple hydrolysis or hydrogenation, respectively. PMID- 23106645 TI - Existence of a lower critical radius for incorporation of silica particles into zinc during electro-codeposition. AB - Recently, it was shown that the surface modification of silica particles with -SH functional groups enables their electro-codeposition with zinc. Here, however, we report that no incorporation into Zn can be observed for such modified particles with diameters of <100 nm, while incorporation is possible for particles with diameters of 225 nm and larger. Furthermore, when silica particles are functionalized with mixtures of -SH and -Cl functional groups, which affect the interface energy at the particle/metal interface differently but have similar interfacial energies for the particle/electrolyte interface, it is found that, for successful incorporation of the particles, a minimum amount of -SH functional groups is needed. An explanation for these observations has been derived based on energetic considerations regarding the interfaces involved in the process. PMID- 23106643 TI - Identifying novel protein complexes in cancer cells using epitope-tagging of endogenous human genes and affinity-purification mass spectrometry. AB - Affinity-purification mass spectrometry (AP-MS) is the preeminent technique for identification of eukaryotic protein complexes in vivo. AP-MS workflows typically express epitope-tagged bait proteins, immunopurify, and then identify associated protein complexes using mass spectrometry. However, challenges of existing strategies include the construction of expression vectors for large open reading frames and the possibility that overexpression of bait proteins may result in expression of nonphysiological levels of the bait protein with concomitant perturbation of endogenous protein complexes. To address these issues, we use human cell lines with epitope-tagged endogenous genes as AP-MS substrates to develop a platform that we call "knock-in AP-MS", thereby avoiding the challenges of expression vector construction and ensuring that expression of tagged proteins is driven by endogenous regulatory mechanisms. Using three different bait genes (MRE11A, DNMT1 and APC), we show that cell lines expressing epitope-tagged endogenous genes make good substrates for sensitive and reproducible identification of protein interactions using AP-MS. In particular, we identify novel interactors of the important oncoprotein Adenomatous Polyposis Coli (APC), including an interaction with Flightless-1 homologue (FLII) that is enriched in nuclear fractions. PMID- 23106646 TI - Psycho-oncological aspect of surgery in palliative care: our satisfactory experience using a V-Y island flap. AB - CONCLUSIONS: Our reconstruction method using a V-Y island flap was minimally invasive and yielded a satisfactory esthetic result without impairing the patient's postoperative quality of life (QOL). OBJECTIVE: Malignant skin tumors of the head and neck often affect the patient's appearance and QOL. Therefore, surgery for terminally staged patients with malignant skin tumors may be a treatment of choice for surgeons in a palliative care team to improve and sustain the patient's QOL. METHODS: We describe our experience of surgical treatment of a large primary malignant skin tumor in the head performed as part of palliative care in a 38-year-old woman in the terminal stage. We developed a V-Y island flap that did not result in postoperative alopecia. RESULTS: After surgery, the patient did not have alopecia and her hair hid the scar. The patient and her family were greatly satisfied with the result. Although the surgery did not extend her life, it alleviated her depressed condition caused by the uncomfortable primary tumor. PMID- 23106647 TI - Stochasticity in single-molecule nanoelectrochemistry: origins, consequences, and solutions. AB - Electrochemical detection of single molecules is being actively pursued as an enabler of new fundamental experiments and sensitive analytical capabilities. Most attempts to date have relied on redox cycling in a nanogap, which consists of two parallel electrodes separated by a nanoscale distance. While these initial experiments have demonstrated single-molecule detection at the proof-of-concept level, several fundamental obstacles need to be overcome to transform the technique into a realistic detection tool suitable for use in more complex settings (e.g., studying enzyme dynamics at single catalytic event level, probing neuronal exocytosis, etc.). In particular, it has become clearer that stochasticity--the hallmark of most single-molecule measurements--can become the key limiting factor on the quality of the information that can be obtained from single-molecule electrochemical assays. Here we employ random-walk simulations to show that this stochasticity is a universal feature of all single-molecule experiments in the diffusively coupled regime and emerges due to the inherent properties of brownian motion. We further investigate the intrinsic coupling between stochasticity and detection capability, paying particular attention to the role of the geometry of the detection device and the finite time resolution of measurement systems. We suggest concrete, realizable experimental modifications and approaches to mitigate these limitations. Overall, our theoretical analyses offer a roadmap for optimizing single-molecule electrochemical experiments, which is not only desirable but also indispensable for their wider employment as experimental tools for electrochemical research and as realistic sensing or detection systems. PMID- 23106649 TI - Identification of the minimal promoter for specific expression of the GABArho1 receptor in retinal bipolar cells. AB - gamma-aminobutyric acid (GABA)rho receptors regulate rapid synaptic ion currents in the axon end of retinal ON bipolar neurons, acting as a point of control along the visual pathway. In the GABArho1 subunit knock out mouse, inhibition mediated by this receptor is totally eliminated, showing its role in neural transmission in retina. GABArho1 mRNA is expressed in mouse retina after post-natal day 7, but little is known about its transcriptional regulation. To identify the GABArho1 promoter, in silico analyses were performed and indicated that a 0.290-kb fragment, flanking the 5'-end of the GABArho1 gene, includes putative transcription factor-binding sites, two Inr elements, and lacks a TATA-box. A rapid amplification of cDNA ends (RACE) assay showed three transcription start sites (TSS) clustered in the first exon. Luciferase reporter assays indicated that a 0.232-kb fragment upstream from the ATG is the minimal promoter in transfected cell lines and in vitro electroporated retinae. The second Inr and AP1 site are important to activate transcription in secretin tumor cells (STC-1) and retina. Finally, the 0.232-kb fragment drives green fluorescent protein (GFP) expression to the inner nuclear layer, where bipolar cells are present. This first work paves the way for further studies of molecular elements that control GABArho1 transcription and regulate its expression during retinal development. PMID- 23106648 TI - A focused educational program after religious services to improve organ donation in Hispanic Americans. AB - Religion is an important determinant in Hispanic Americans (HA) becoming organ donors as HA often believe religion forbids donation. We investigated the effect of an educational program targeting HA organ donation in places of worship. A prospective observational study was conducted at four Catholic churches with a high percentage of HA. A 45-min "culturally sensitive" educational program, conducted in Spanish, was implemented. Organ donation awareness, knowledge, perception, and beliefs, as well as the intent to become an organ donor, were measured before and after the intervention. Differences between before and after the intervention were analyzed. A total of 182 surveys were conducted before and 159 surveys were conducted after the educational program. A significant increase was observed in organ donation knowledge (54% vs. 70%, p<0.0001), perception (43% vs. 58%, p<0.0001), and beliefs (50% vs. 60%, p=0.0001). However, no significant difference was found in the willingness to discuss donation with family, intent to-donate, or registering to donate after the intervention. This study demonstrates that a focused educational program in places of worship can significantly improve HA knowledge, perceptions, and beliefs regarding organ donation. Further work is needed to understand why intent-to-donate does not increase despite the increase in organ donation awareness. PMID- 23106650 TI - Optical characterization of PEG-supported 7-hydroxy-4-methyl-coumarin in distilled water solution. AB - The optical properties of 7-hydroxy-4-methyl coumarin immobilized on polyethylene glycol support and dissolved in distilled water solution are compared with the optical properties of the dye dissolved in ethanol and discussed on the basis of the formation of different chemical species of the dye molecule. The presence of the polymeric support affects both the absorption and emission features of the coumarin by changing the chemical equilibrium among the different species typically observed at the ground and excited states. The optical properties of synthesized PEG-supported coumarins are able to warrant biomedical applications in water-based environment and enable us to gain insight into the photophysical activity of coumarins; in particular, the steric hindrance of the polymeric support inhibits, as expected, the formation of the tautomeric form of the compound in the excited state, a further proof of the single-step neutral to tautomer reaction in coumarins. PMID- 23106651 TI - A novel beta(0)-thalassemia frameshift mutation: [HBB:c.216delT]. AB - A 33-year-old adult male of Greek ethnicity, with hematological indices suggesting beta(0)-thalassemia (beta(0)-thal) trait, was investigated for HBB gene mutations in the course of preparation for preimplantation genetic diagnosis (PGD). Application of a routine diagnostic protocol, consisting of sequence analysis of the HBB gene, coupled to multiplex ligation-dependent probe amplification (MLPA), identified a single nucleotide deletion (-T) at codon 72 [HBB: c.216delT], leading to a novel pathogenic frameshift and protein-truncating beta(0)-thal mutation (p.Phe72LeufsX18). PMID- 23106652 TI - Evolution and diversity of Arsenophonus endosymbionts in aphids. AB - Endosymbiotic bacteria are important drivers of insect evolutionary ecology, acting both as partners that contribute to host adaptation and as subtle parasites that manipulate host reproduction. Among them, the genus Arsenophonus is emerging as one of the most widespread lineages. Its biology is, however, entirely unknown in most cases, and it is therefore unclear how infections spread through insect populations. Here we examine the incidence and evolutionary history of Arsenophonus in aphid populations from 86 species, characterizing the processes that shape their diversity. We identify aphids as harbouring an important diversity of Arsenophonus strains. Present in 7% of the sampled species, incidence was especially high in the Aphis genus with more than 31% of the infected species. Phylogenetic investigations revealed that these Arseno phonus strains do not cluster within an aphid-specific clade but rather exhibit distinct evolutionary origins showing that they undergo repeated horizontal transfers (HT) between distantly related host species. Their diversity pattern strongly suggests that ecological interactions, such as plant mediation and parasitism, are major drivers for Arsenophonus dispersal, dictating global incidence across insect communities. Notably, plants hosting aphids may be important ecological arenas for global exchange of Arsenophonus, serving as reservoirs for HT. PMID- 23106654 TI - Complex asthma endotypes, differential chemokine responses and birth cohort studies: solving equations with multiple variables. PMID- 23106655 TI - What's on the menu for prediction of natural history of cow's milk allergy beyond casein cocktails and epitope soup? PMID- 23106656 TI - Exposure of immunologically naive laboratory rodents to antigen via the airways. Where does tolerance stop and sensitization begin? AB - Conventional rodent models of respiratory allergy that employ intraperitoneal sensitization to aeroallergen plus adjuvant, have offered greatly to our current knowledge of the pathophysiology of allergic airway diseases. Notwithstanding this significant contribution, non-adjuvant aided sensitization via respiratory presentation of the allergen, is more naturally relevant and more closely mimics the human exposure. Nevertheless, in the experimental setting, primary respiratory exposure to inert antigen is likely to lead to inhalation tolerance. Inasmuch as divergent and discrepant results are often reported in experimental models employing this method of sensitization, we set out to review the relative literature and identify and discuss factors that are liable to interfere in such protocols and modify the immune response, hence leading to variable outcomes. Protocol design features (including the use of anaesthesia, the nature and dosage of the antigen and the strain/age/sex and handling of the animals) as well as environmental factors (including airborne substances, viruses and lipopolysaccharide) have been identified as key modulators of the immune response that evolves, following primary airway exposure of laboratory rodents to aeroallergen. Delineation of the effect of those factors to induction or abrogation of inhalation tolerance can have important implications in the design of both improved experimental protocols of respiratory allergy and methods to intercept sensitization to inert aeroallergens in the clinical field. PMID- 23106657 TI - Adherence in severe asthma. AB - Adherence in asthma is an important cause for concern. Although nearly 50% of asthma patients are considered poorly adherent to therapeutic advices, adherence is still difficult to assess, understand and improve despite major medical consequences. In this review, we revisited the literature of the last 10 years related to adherence in severe asthma. The concepts have changed and "compliance" is usually replaced by "adherence". Assessment of adherence is addressing ethical issues, but provides important insight into difficult-to-treat asthma. Different tools have been used but none is routinely recommended. Health-related outcomes (poor control, exacerbations, hospitalizations, lung function decline), which are clearly associated with severe asthma, are often worsened by non-adherence with consequences also on patient related outcomes (quality of life). The potential behaviour associated with non-adherence and all other related factors including easy-to-recognize psychological traits can help for patient's future management. Therapeutic educational interventions have been recognized with a scientifically proven efficiency even though evolution and improvements are needed. A multidisciplinary approach is required in severe asthma. Therapeutic adherence for a given patient is always a prerequisite to any other aspects when addressing severe asthma phenotypes. Severe asthma should be considered only in those who still experienced poor asthma outcomes despite optimal adherence. At a glance, poor adherence and severe asthma should be considered antinomic. Better understanding of the causes and customised management are potential future directions. PMID- 23106658 TI - Trichuris suis ova therapy for allergic rhinitis does not affect allergen specific cytokine responses despite a parasite-specific cytokine response. AB - BACKGROUND: Parasitic helminths have been shown to reduce inflammation in most experimental models of allergic disease, and this effect is mediated via cytokine responses. However, in humans, the effects of controlled helminth infection on cytokine responses during allergy have not been studied. OBJECTIVE: The aim was to investigate whether infection with the nematode parasite Trichuris suis alters systemic cytokine levels, cellular cytokine responses to parasite antigens and pollen allergens and/or the cytokine profile of allergic individuals. METHODS: In a randomized double-blinded placebo-controlled clinical trial (UMIN trial registry, Registration no. R000001298, Trial ID UMIN000001070, URL: http://www.umin.ac.jp/map/english), adults with grass pollen-induced allergic rhinitis received three weekly doses of 2500 Trichuris suis ova (n = 45) or placebo (n = 44) over 6 months. IFN-gamma, TNF-alpha, IL-4, IL-5, IL-10 and IL-13 were quantified via cytometric bead array in plasma. Cytokines, including active TGF-beta, were also quantified in supernatants from peripheral blood mononuclear cells cultured with parasite antigens or pollen allergens before, during and after the grass pollen season for a sub-cohort of randomized participants (T. suis ova-treated, n = 12, Placebo-treated, n = 10). RESULTS: Helminth infection induced a Th2-polarized cytokine response comprising elevated plasma IL-5 and parasite-specific IL-4, IL-5 and IL-13, and a global shift in the profile of systemic cytokine responses. Infection also elicited high levels of the regulatory cytokine IL-10 in response to T. suis antigens. Despite increased production of T. suis-specific cytokines in T. suis ova-treated participants, allergen-specific cytokine responses during the grass pollen season and the global profile of PBMC cytokine responses were not affected by T. suis ova treatment. CONCLUSIONS AND CLINICAL RELEVANCE: This study suggests that cytokines induced by Trichuris suis ova treatment do not alter allergic reactivity to pollen during the peak of allergic rhinitis symptoms. PMID- 23106659 TI - Cord blood Th2-related chemokine CCL22 levels associate with elevated total-IgE during preschool age. AB - BACKGROUND: Early-life immune deviation is suspected in the inception of atopic disease. OBJECTIVE: To investigate the association between cord blood chemokines and the subsequent development of atopic biomarkers and clinical end-points during the first 6 years of life. METHODS: The Th1-associated chemokines CXCL10 and CXCL11 and the Th2-associated chemokines CCL17 and CCL22 were assessed in cord blood of asymptomatic at-risk newborn children from the Copenhagen Prospective Study on Asthma in Childhood (COPSAC(2000) ) birth cohort and associated with the longitudinal development of biomarkers and clinical end points of asthma, eczema, and allergic rhinitis during the first 6 years of life. RESULTS: Cord blood CCL22 levels were significantly associated to total-IgE levels measured at four time-points during the first 6 years of life; overall odds ratio, 1.54 [CI, 1.25-1.89; P < 0.0001]. CXCL10 and CXCL11 were not associated with development of any atopic disorders or biomarkers. CONCLUSION AND CLINICAL RELEVANCE: High cord blood levels of the Th2 related chemokine CCL22 were significantly associated with high total- IgE levels during the first 6 years of life, but not with specific sensitization, asthma, eczema or allergic rhinitis. This suggests an inborn skewing of the immune system in healthy newborns developing elevated total- IgE later in life. PMID- 23106660 TI - Interleukin-25 promotes basic fibroblast growth factor expression by human endothelial cells through interaction with IL-17RB, but not IL-17RA. AB - BACKGROUND: Unlike other IL-17 family members, the Th2-derived cytokine IL-25 (IL 17E) induces (promotes) Th2 responses. One or both of the two receptors for IL-25 (IL-17RA, IL-17RB) is expressed on inflammatory cells and tissue structural cells, suggesting that in addition to promoting Th2-type inflammation IL-25 may also act on structural cells at sites of Th2-type inflammation such as in the asthmatic bronchial mucosa to promote remodelling changes. OBJECTIVE: Our previous studies showed elevated expression of IL-25 and IL-17RB immunoreactivity in asthmatic airways with co-localization of the latter to endothelial cells. We therefore hypothesized that IL-25 acts on endothelial cells through this receptor to induce production of the key angiogenic and remodelling cytokine basic fibroblast growth factor (bFGF). METHODS: Polymerase chain reaction (PCR) immunocytochemistry/immunohistochemistry and ELISA were employed to detect expression of IL-17RB, IL-17RA and bFGF by human vascular endothelial cells (HUVEC) and immunoreactivity for IL-25 and bFGF in asthmatic bronchial biopsies. Receptor-blocking antibodies, PCR and an in vitro angiogenesis assay were used to investigate whether IL-25 acts on IL-17RB or IL-17RA to induce bFGF expression and angiogenesis. PCR was also employed to investigate the signalling pathways involved in IL-25-mediated bFGF expression. RESULTS: HUVEC constitutively expressed IL-17RB, IL-17RA and bFGF. Production of the latter was further increased by IL-25, but attenuated after blockade of the IL-17RB, but not the IL 17RA receptor. Neutralization of endogenous VEGF and bFGF completely abrogated IL 25-induced angiogenesis which was also inhibited by blocking IL-17RB, but not IL 17RA. The PI3K-specific inhibitor LY294002 also completely attenuated IL-25 induced bFGF expression. Immunoreactivity for IL-25 and bFGF was elevated in the asthmatic bronchial mucosa and the expression of each correlated with the other. CONCLUSIONS AND CLINICAL RELEVANCE: Our data support the hypothesis that IL-25 contributes to elevated bFGF in asthmatic airways by acting on the endothelial cell IL-17RB receptor through PI3K-signalling pathways. Targeting the pathways might benefit therapy of airways remodelling. PMID- 23106661 TI - Allergic rhinitis is associated with otitis media with effusion: a birth cohort study. AB - BACKGROUND: Childhood otitis media with effusion is a common disease and a link to allergic diseases has been suggested. OBJECTIVE: To investigate the association between atopic disease and otitis media with effusion diagnosed according to strict objective case definitions by age 6 years. METHODS: We evaluated 291 children in the 6th year of life from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) 2000 birth cohort. Otitis media with effusion was diagnosed based on tympanometric and objective evaluation. Asthma, eczema, allergic- and non-allergic rhinitis was diagnosed prospectively by pre defined algorithms. Nasal mucosal swelling was assessed using acoustic rhinometry and nasal eosinophilia from scrapings. Analyses were performed using logistic regression and adjusted for dog, cat and smoking exposure, paternal atopy, household income, older siblings, gender and number of acute otitis media episodes. RESULTS: Otitis media with effusion was diagnosed in 39% of the cohort and was associated with allergic rhinitis (aOR = 3.36, CI = 1.26-8.96, P = 0.02), but not with nasal mucosal swelling, nasal oeosinophilia, non-allergic rhinitis, asthma or eczema. CONCLUSION: Otitis media with effusion is closely associated with allergic rhinitis presumably caused by allergic inflammation, but not mechanical nasal mucosal swelling. These findings warrant an increased awareness of otitis media with effusion in children with allergic rhinitis. PMID- 23106662 TI - Perinatal factors and respiratory health in children. AB - BACKGROUND: There is conflicting evidence regarding the associations between anthropometric birth measures and asthma and lung function in children, particularly for apparently healthy infants born at term. OBJECTIVE: Our objective was to elucidate these relationships paying particular attention to features of study design and analysis that may threaten the validity of previous studies in this field. METHODS: We analysed data from a cohort of children with a family history of asthma who were recruited antenatally. Anthropometric birth measures and potential confounders were recorded at birth and within the first year of life. Lung function and asthma outcomes were measured at 8 years of age. Airway hyperresponsiveness (AHR) was measured by methacholine challenge. The potential for a reversal paradox, due to inclusion of covariates on the causal pathway, was investigated. RESULTS: Four hundred and fifty (73% of the initial cohort) children were tested at age 8 years. Birth weight in the lowest tertile was associated with current asthma (OR 1.95, 95% CI 1.08, 3.54) and recent wheeze (OR 1.87, 95%CI 1.08, 3.24), but not with AHR (OR 1.37, 95% CI 0.68, 2.78). Birth weight was positively associated with lung function. Current height modified the relationship between birth length and lung function suggesting that post-natal growth has an effect on this relationship. CONCLUSIONS: Low birth weight is associated with a greater risk of current asthma and lower lung function at 8 years in children with a family history of asthma. Current height should be treated as an effect modifier when investigating the fetal origins hypothesis. PMID- 23106663 TI - Individual cow's milk allergens as prognostic markers for tolerance development? AB - BACKGROUND: Cow's milk allergy (CMA) is one of the most common causes of food allergy in the first years of life. Fortunately, the majority of children with CMA develop clinical tolerance with time. However, no good individual markers exist to predict whether this will occur. Therefore, a prognosis to identify children with persistent CMA at diagnosis would be helpful. OBJECTIVE: In this study, we sought to assess whether measurement of IgE to individual allergens of cow's milk (CM) would separate patients with persistent CMA from those who became clinically tolerant to CM over time. METHODS: A total of 52 patients ranging from 3 months to 114 months of age with proven CMA by DBPCFC were followed over time. From these 52 patients, 32 (61.5%) patients became tolerant in the analysed time period. All patients were rechallenged at least once, some were rechallenged two or three times. Serum was analysed prior to each challenge for specific IgE, IgG and IgG4 binding to crude CM protein as well as to individual allergens of CM. RESULTS: The individual likelihood of outgrowing CMA significantly correlates with a low level of CM-specific IgE as well as a low level of specific IgE to alpha-lactalbumin, beta-lactoglobulin (Bos d5.0102), kappa-casein and alpha(s1) casein. No significant correlation was found for IgE levels to total casein, lactoferrin, beta-casein and beta-lactoglobulin (Bos d5.0101) as well as IgG and IgG4 levels to alpha-lactalbumin, beta-lactoglobulin and total casein. CONCLUSIONS: CM-specific IgE is a good prognostic marker for persistence of CMA. In addition, component-resolved diagnostic showed similar results. However, in our view, the rising laboratory costs do not justify a measurement on a daily basis. Additional determination of specific IgG or IgG4 levels was not useful in predicting tolerance development in our study population. PMID- 23106664 TI - Sensitization induces hypersensitivity in trigeminal nerve. AB - BACKGROUND AND AIMS: Trigeminal neuralgia is one of the chronic neuropathic pains. The aetiology remains unclear. Chronic inflammation is proposed playing a role in the pathogenesis of trigeminal neuralgia. This study aims to assess the role of allergic inflammation in the pathological status of trigeminal neuralgia. METHODS: Allergic inflammation was induced in the infraorbital skin of rats. The expression of 5-HT receptor 3 (R3) in the trigeminal nerve and mastocytosis in the local tissue were observed by immunohistochemistry. The hyperalgesia status of the trigeminal nerve was determined by quantitatively recording the head withdrawal threshold to mechanical stimulation of the infraorbital nerve territory. RESULTS: After sensitization, the expression of 5-HT R3 in the trigeminal nerve and the frequency of mast cells were markedly increased in the epidermal tissue of the infraorbital area. Applying exogenous 5-HT to the local tissue also increased the expression of 5-HT R3 in the trigeminal nerve. The threshold of mechanical allodynia to stimuli was significantly lower in sensitized rats than control rats, which could be blocked by pre-treatment with either 5-HT R3 antagonists, or neurokinin-1 antagonists, or mast cell stabilizers. CONCLUSIONS: Allergic inflammation can induce the overexpression of 5-HT R3 in the trigeminal nerve to induce the hyperalgesia status in the trigeminal nerve. The 5-HT R3 may be a therapeutic target in the treatment of trigeminal neuralgia. PMID- 23106665 TI - Lipid transfer proteins: the most frequent sensitizer in Italian subjects with food-dependent exercise-induced anaphylaxis. AB - BACKGROUND: Specific food-dependent exercise-induced anaphylaxis (S-FDEIAn) is a distinct form of food allergy in which symptoms are elicited by exercise performed after ingesting food to which the patient has become sensitised. Non specific FDEIAn (NS-FDEIAn) is a syndrome provoked by exercise performed after ingesting any food. OBJECTIVE: We sought to identify the culprit allergenic molecules in patients with FDEIAn, combining 'classic' allergy testing with an allergenic molecule-based microarray approach for IgE detection. METHODS: All subjects were evaluated who reported at least one episode of anaphylaxis in association with physical exercise performed within 4 h after a meal. We performed skin prick tests (SPT) with commercial food extracts, prick plus prick tests (P + P) with fresh foods (P + P), and serum specific IgE assays by means of both the ImmunoCAP (CAP) and the ISAC 89 microarray system (ISAC). RESULTS: Among our 82 FDEIAn patients, the most frequent suspected foods were tomato, cereals, and peanut. SPT, P + P, and CAP displayed different degrees of sensitivity. Each test disclosed some positivities not discovered by others. Seventy-nine subjects were positive to at least one food (49 to more than 20), whereas three were negative. All suspected foods were positive to at least one of SPT, P + P, and CAP. When tested using the ISAC, 64 (78%) subjects were positive to Pru p 3 [peach lipid transfer protein (LTP)], 13 were positive to other food allergen molecules, and five displayed negative results to all food allergenic molecules. Overall, 79 patients probably had S-FDEIAn and the other 3 NS-FDEIAn. CONCLUSIONS: Multiple food hypersensitivity represents a clinical hallmark of a large percentage of FDEIAn patients. The very high prevalence of IgE to the LTP suggests a role of this allergen group in causing S-FDEIAn. PMID- 23106668 TI - Understanding performance deficits in developmental coordination disorder: a meta analysis of recent research. AB - AIM: Developmental coordination disorder (DCD) is a significant disorder of childhood, characterized by core difficulties in learning fine and/or gross motor skills, and the attendant psychosocial problems. The aim of the meta-analysis presented here (the first on DCD since 1998) was to summarize trends in the literature over the past 14 years and to identify and describe the main motor control and cognitive deficits that best discriminate children with DCD from those without. METHOD: A systematic review of the literature published between January 1997 and August 2011 was conducted. All available journal papers reporting a comparison between a group of children with DCD and a group of typically developing children on behavioural measures were included. RESULTS: One hundred and twenty-nine studies yielded 1785 effect sizes based on a total of 2797 children with DCD and 3407 typically developing children. Across all outcome measures, a moderate to large effect size was found, suggesting a generalized performance deficit in children with DCD. The pattern of deficits suggested several areas of pronounced difficulty, including internal (forward) modelling, rhythmic coordination, executive function, gait and postural control, catching and interceptive action, and aspects of sensoriperceptual function. INTERPRETATION: The results suggest that the predictive control of action may be a fundamental disruption in DCD, along with the ability to develop stable coordination patterns. Implications for theory development and intervention are discussed. PMID- 23106669 TI - Two-year course of anxiety disorders: different across disorders or dimensions? AB - OBJECTIVE: This study compares diagnostic and symptom course trajectories across different anxiety disorders, and examines the role of anxiety arousal vs. avoidance behaviour symptoms in course prediction. METHOD: Data were from 834 subjects with a current anxiety disorder from the Netherlands Study of Depression and Anxiety (NESDA) who were re-interviewed after 2 years. DSM-IV-based diagnostic interviews and Life Chart Interviews (LCI) were used to assess the diagnostic and symptom course trajectory over 2 years. Anxiety arousal and avoidance behaviour symptoms were measured with LCI, Beck Anxiety Inventory and Fear Questionnaire. RESULTS: Prognosis varied across disorders, with favourable remittance rates of 72.5% for panic disorder without agoraphobia and 69.7% for generalized anxiety disorder; gradually declining to 53.5% for social phobia and 52.7% for panic disorder with agoraphobia. Only 42.9% of those with multiple anxiety disorder remitted, and this group showed a more chronic course than pure anxiety disorders. Both baseline duration and severity were course predictors. Avoidance behaviour symptoms predicted the outcome better than anxiety arousal symptoms. CONCLUSIONS: These data suggest that the specific anxiety disorders such as recognized by DSM-IV are useful in predicting the outcome and that this may be determined largely by the relative severity of avoidance behaviour that patients have developed. PMID- 23106670 TI - Antimicrobial efficacy of cryotreatment against Enterococcus faecalis in root canals. AB - The purpose of this investigation was to evaluate intracanal bacterial reduction by cryotreatment using a dental instrument equipped with a duct and connected to a cryogenic fluid source. A total of 86 roots were infected with Enterococcus faecalis and incubated. After incubation, the contaminated roots were divided into three study groups: 35 roots irrigated with 2 ml of a 5% sodium hypochlorite (NaOCl) solution, 35 roots irrigated with 2 ml of a 5% NaOCl solution and further treated with cryo and 10 roots irrigated with 2 ml of saline solution, plus positive and negative controls. Subsequent to each irrigation treatment, the residual bacterial colonies were counted. The use of cryo-instrumentation in association with NaOCl irrigation significantly reduced the number of Ent. faecalis (P < 0.01) in the root canal compared with controls. The interesting potential of cryotreatment should be further investigated through clinical studies aimed to establish a correct irrigation protocol. Within the limits of the study, the cryotreatment seems to have a greater effect on the reduction in bacteria compared to a standard NaOCl irrigation. PMID- 23106671 TI - Toward the total synthesis of (+/-)-andrastin C. AB - An efficient approach to generate a fully functionalized cyclopenta[a]phenanthrene 34, the basic carbon framework of andrastin C (1c), is described. The present synthetic route features a stereoselective intramolecular Diels-Alder reaction of triene 12 and an intramolecular carbonyl ene reaction of 3-phenanthrenyl-2-(methoxymethoxy)propanal 31. PMID- 23106672 TI - Quality of life of parents living with a child suffering from atopic dermatitis before and after a 3-month treatment with an emollient. AB - Atopic dermatitis (AD) can be extremely disabling and may cause psychological problems for affected children and their families. Moisturizers and emollients are important in the baseline daily skin care of patients with AD. To assess the effect of a 3-month, twice-daily treatment with an emollient on the quality of life (QoL) of parents with a child with mild to moderate AD (SCORing Atopic Dermatitis [SCORAD] <= 30, a multicenter open trial was performed by eight dermatologists on 191 volunteers. Evaluation by the dermatologist of the child's clinical condition (SCORAD) and of the efficacy and overall safety of the treatment was associated with a QoL questionnaire completed by one parent of the atopic child. A self-assessment of the global QoL and of the efficacy and overall safety was also performed. During the study, mean SCORAD dropped from 28 to 12 (p < 0.001), with good improvement in skin dryness and pruritus criteria. At the same time, the self-assessment of the global parent QoL scores dropped from 4.4 to 2.1 (p < 0.001) with 60%, 48% and 79% favorable parent opinions regarding wellbeing or improvement of the health condition, quality of sleep, and efficacy of the emollient, respectively. This trial revealed the efficacy of the product in improving parent QoL (85% of parents noted improvement in QoL), and its global safety was considered to be very good or good, with 80% favorable opinions in parents' declarative judgements and dermatologists' assessments. The emollient evaluated improves the course of AD and can improve the QoL of patients and their families. PMID- 23106673 TI - Epidermolysis bullosa pruriginosa: further clarification of the phenotype. AB - A defect in type VII collagen causes dystrophic epidermolysis bullosa (DEB). The pruriginosa variant (DEB-Pr) is unique because its initial presentation may be delayed until adolescence or adulthood, and its predominant feature is scarring and pruritus without the characteristic skin fragility of DEB. We describe three families with multiple affected members in which DEB-Pr shows an autosomal dominant inheritance pattern. All affected individuals were examined, and three previously unreported COL7A1 mutations were identified. PMID- 23106675 TI - Branchiooculofacial syndrome and bilateral ectopic thymus: report of a family. AB - Branchiooculofacial syndrome (BOFS) is a rare autosomal-dominant condition characterized by branchial cleft sinus and ophthalmologic and craniofacial abnormalities that can range from mild to severe forms. Ectopic thymus, an uncommon condition with just over 100 cases reported in the literature, is seen in BOFS. We report a family with BOFS affecting the mother and two daughters, showing the dominant inheritance and variable phenotypical expression of BOFS. PMID- 23106674 TI - A significant proportion of children with morphea en coup de sabre and Parry Romberg syndrome have neuroimaging findings. AB - En coup de sabre (ECDS) and Parry-Romberg syndrome (PRS) are variants of linear morphea on the head and neck that can be associated with neurologic manifestations. Intracranial abnormalities on computed tomography (CT) and magnetic resonance imaging (MRI) are present in a significant proportion of individuals with these conditions. We describe 32 children from our institution with ECDS or PRS; neuroimaging was performed in 21 cases. We also review 51 additional cases from the literature. Nineteen percent of the children at our institution with ECDS or PRS had intracranial abnormalities on MRI, half of whom were asymptomatic. Hyperintensities on T2-weighted sequences were the most common finding, present in all children with intracranial abnormalities on MRI. Seizures (13%) and headaches (9%) were the most common neurologic symptom. Neurologic symptoms were not correlated with neuroimaging abnormalities, with two asymptomatic children having marked MRI findings and only two of nine symptomatic children having an abnormal MRI. Similarly the severity of the superficial disease did not predict neurologic involvement; a child with subtle skin involvement had striking MRI findings and seizures, whereas another with a bony defect had no brain parenchymal involvement. Neurologic symptoms and neuroimaging abnormalities are found in a surprisingly substantial percentage of children with ECDS and PRS. Early recognition of neurologic involvement is necessary because it affects treatment choices. Because clinical predictors of intracranial abnormalities are poor, strong consideration should be given to obtaining an MRI before treatment initiation to assist in management decisions and establish a baseline examination. PMID- 23106676 TI - Febrile illness with papular and vesicular exanthem and ulceronecrotic plaques. PMID- 23106677 TI - An adolescent boy with persistent penile and scrotal erythema and swelling. PMID- 23106678 TI - An erythematous ear. PMID- 23106679 TI - Retinoic acid: a familiar teratogen. PMID- 23106680 TI - Response to "Response of tufted angiomas to low-dose aspirin". PMID- 23106681 TI - Factors affecting the first service conception rate of cows in smallholder dairy farms in Bangladesh. AB - The successful outcome of an insemination is a combination of both male and female fertility-linked factors. We investigated the first service conception rate of cows at artificial insemination (AI) in the smallholder dairy farms in Bangladesh. Frozen straws were prepared from ejaculates of Bos indicus (n = 7) and Bos indicus * Bos taurus (n = 7) AI bulls. Fertility was determined from 6101 first services in cows that were performed by 18 technicians in four regions between April 2004 and March 2005. Pregnancy was diagnosed by rectal palpation between 60 and 90 days post-insemination. The Asian version of Artificial Insemination Database Application (AIDA ASIA) was used for bulls-, cows- and AI related data recording, and later retrieved for analysis. The mean +/- SD number of inseminations performed from individual bulls and their conception rates were 436.0 +/- 21.6 and 50.7 +/- 1.9%, respectively. Logistic regression demonstrated body condition scores (BCS), heat detection signs, months of AI and their interactions had greatest effects (odds ratios: 1.24-16.65, p < 0.04-0.001) on first service conception rate in cows. Fertility differed (p < 0.02-0.001) between the regions, previous calving months, months of AI, BCS, parity and heat detection signs of cows. Inseminations based on mounting activity (n = 2352), genital discharge (n = 3263) and restlessness and/or other signs (n = 486) yielded a conception rate of 53.6%, 48.8% and 50.1%, respectively (p < 0.05). Conception rate between technicians ranged between 43.4% and 58.6% (p < 0.05). The days interval from calving to first service (overall mean +/- SD = 153.4 +/- 80.6) had relationship (p < 0.001) with BCS, months of previous calving and parity of the cows. Fertility at AI in smallholder farms can be improved by training farmers on nutrition and reproductive management of the cows. PMID- 23106682 TI - A free energy approach to the prediction of olefin and epoxide mutagenicity and carcinogenicity. AB - The mutagenic and carcinogenic effects of strong alkylating agents, such as epoxides, have been attributed to their ability to covalently bind DNA in vivo. Most olefins are readily oxidized to reactive epoxides by CytP450. In an effort to develop predictive models for olefin and epoxide mutagenicity, the ring openings of 15 halogen-, alkyl-, alkenyl-, and aryl-substituted epoxides were modeled by quantum-mechanical transition state calculations using MP2/6-31+G(d,p) in the gas phase and in aqueous solution. Free energies of activation (DeltaG(?)) and free energies of reaction (DeltaG(rxn)) were computed for each epoxide in the series. This study finds that an aqueous solution DeltaG(rxn) threshold value of approximately -14.7 kcal/mol can be used to discern mutagenic/carcinogenic epoxides (DeltaG(rxn) < -14.7 kcal/mol) from nonmutagens/noncarcinogens (DeltaG(rxn) > -14.7 kcal/mol). The computed reaction thermodynamics are appropriate regardless of ring-opening mechanism in vivo and are thus proposed as an effective in silico screen and design guideline for decreasing potential mutagenicity and carcinogenicity of olefins and their respective epoxides. PMID- 23106683 TI - Increased expression of cell adhesion molecule 1 by mast cells as a cause of enhanced nerve-mast cell interaction in a hapten-induced mouse model of atopic dermatitis. AB - BACKGROUND: Neuroimmunological disorders are involved in the pathogenesis of atopic dermatitis (AD), partly through enhanced sensory nerve-skin mast cell interaction. Cell adhesion molecule 1 (CADM1) is a mast-cell adhesion molecule that mediates the adhesion to, and communication with, sympathetic nerves. OBJECTIVES: To investigate the role of mast cell CADM1 in the pathogenesis of AD, CADM1 expression levels by comparing between lesional and nonlesional skin mast cells of an AD mouse model, which was developed by repeated application of trinitrochlorobenzene, and to examine, in cocultures, how the alterations in CADM1 detected in lesional mast cells might affect the sensory nerve-mast cell interaction. METHODS: AD-like lesional and nonlesional skin mast cells were collected separately by laser capture microdissection. CADM1 expression was examined by reverse transcription-polymerase chain reaction and CADM1 immunohistochemistry. In cocultures, adhesion between dorsal root ganglion (DRG) neurites and IC2 mast cells was analysed by loading a femtosecond laser-induced impulsive force on neurite-attendant IC2 cells, while cellular communication was monitored as the IC2 cellular response ([Ca(2+)]i increase) after nerve-specific stimulant-induced DRG activation. RESULTS: AD-like lesional mast cells expressed three-fold more CADM1 transcripts than nonlesional cells. This was supported at the protein level, shown by immunohistochemistry. In coculture, CADM1 overexpression in IC2 cells strengthened DRG neurite-IC2 cell adhesion and doubled the population of IC2 cells responding to DRG activation. A function blocking anti-CADM1 antibody abolished these effects in a dose-dependent manner. CONCLUSIONS: Increased expression of CADM1 in mast cells appeared to be a cause of enhanced sensory nerve-mast cell interaction in a hapten-induced mouse model of AD. PMID- 23106684 TI - The role of partners and children for employees' psychological detachment from work and well-being. AB - This study examined the role of partners and children for employees' psychological detachment from work during off-job time. Building on boundary theory, we hypothesized that not only employees' own work-home segmentation preference but also their partners' work-home segmentation preference is associated with employees' psychological detachment. In addition, partners' psychological detachment should influence employees' psychological detachment. We hypothesized that the presence of children in the household moderates partners' influence on employees' psychological detachment. Further, we expected both employees' and their partners' psychological detachment to contribute to employees' well-being. Participants were 114 dual-earner couples who responded to Web-based questionnaires. The hypotheses were tested with multilevel analyses, using the actor-partner interdependence model. Results confirmed our hypotheses. Employees' and their partners' work-home segmentation preferences were associated with employees' psychological detachment. The presence of children moderated the relation between partners' work-home segmentation preference and employees' psychological detachment. The relation was weaker when there were children in the household. Moreover, employees' and their partners' psychological detachment were positively associated. Again, the relation was weaker when there were children in the household. Finally, both employees' and their partners' psychological detachment contributed to employees' well-being. PMID- 23106685 TI - How important are work-family support policies? A meta-analytic investigation of their effects on employee outcomes. AB - This meta-analysis examines relationships between work-family support policies, which are policies that provide support for dependent care responsibilities, and employee outcomes by developing a conceptual model detailing the psychological mechanisms through which policy availability and use relate to work attitudes. Bivariate results indicated that availability and use of work-family support policies had modest positive relationships with job satisfaction, affective commitment, and intentions to stay. Further, tests of differences in effect sizes showed that policy availability was more strongly related to job satisfaction, affective commitment, and intentions to stay than was policy use. Subsequent meta analytic structural equation modeling results indicated that policy availability and use had modest effects on work attitudes, which were partially mediated by family-supportive organization perceptions and work-to-family conflict, respectively. Additionally, number of policies and sample characteristics (percent women, percent married-cohabiting, percent with dependents) moderated the effects of policy availability and use on outcomes. Implications of these findings and directions for future research on work-family support policies are discussed. PMID- 23106686 TI - Test of slope and intercept bias in college admissions: a response to Aguinis, Culpepper, and Pierce (2010). AB - Research on the predictive bias of cognitive tests has generally shown (a) no slope effects and (b) small intercept effects, typically favoring the minority group. Aguinis, Culpepper, and Pierce (2010) simulated data and demonstrated that statistical artifacts may have led to a lack of power to detect slope differences and an overestimate of the size of the intercept effect. In response to Aguinis et al.'s (2010) call for a revival of predictive bias research, we used data on over 475,000 students entering college between 2006 and 2008 to estimate slope and intercept differences in the college admissions context. Corrections for statistical artifacts were applied. Furthermore, plotting of regression lines supplemented traditional analyses of predictive bias to offer additional evidence of the form and extent to which predictive bias exists. Congruent with previous research on bias of cognitive tests, using SAT scores in conjunction with high school grade-point average to predict first-year grade-point average revealed minimal differential prediction (DeltaR2intercept ranged from .004 to .032 and DeltaR2slope ranged from .001 to .013 depending on the corrections applied and comparison groups examined). We found, on the basis of regression plots, that college grades were consistently overpredicted for Black and Hispanic students and underpredicted for female students. PMID- 23106687 TI - Ethics in action: consent-gaining interactions and implications for research practice. AB - This article deals with the topic of social psychological research methods in practice, by examining how informed consent is gained from research participants. In most research, the consent-gaining process is hidden from analytic scrutiny and is dealt with before data collection has begun. In contrast, conversation analytic research, which records interactional encounters from beginning to end, enables examination of this methodological 'black box'. We explored how 'requests' to consent in research played out across different institutional settings. We found that participants had to 'opt-out' of a research process that was already underway. Consent-gaining sequences constrained opting out in two ways: (1) because research activity was already underway, it must be stopped affirmatively by participants; (2) consent-gaining turns were tilted in favour of continued participation, making opting out a dispreferred response. We also found a mismatch between what ethics guidelines specify about consent-gaining 'in theory' and what actually happens 'in practice'. Finally, we make suggestions about interventions in and recommendations for existing practice to best achieve informed consent. PMID- 23106688 TI - Management and quality indicators of diabetes mellitus in people with intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities (ID) are at a higher risk of developing diabetes compared with the non-intellectually disabled population, as a consequence of genetic syndromes and because this cohort are more exposed to many of the identified risk factors. However, little is known about the management of diabetes in this population. The aim of this study was to examine the demographics, health and the diabetes quality of care indicators used with people with ID in one region of the UK. METHODOLOGY: This was a quantitative study using a postal survey design. An anonymised questionnaire was posted to all community ID teams and supported living/residential facilities requesting information on the demographics, health and quality of care indicators for people with ID who have diabetes on their caseloads. RESULTS: In total 186 questionnaires were returned. Results showed that 125 people with ID had Type 2 diabetes (67%) and 61 people had Type 1 (33%). Significantly more people with Down syndrome and Autistic Spectrum Disorder had Type 1 diabetes. This study found that 6% had glycossylated glucose levels (HbA1c) greater than 9.5% and for 52% the levels were between 6.5% and 9.4%. Individuals reported to have poor glycaemic control were statistically more likely to have Type 1 diabetes and be younger, live with parents or independently and be obese. Results also illustrate that the national standards for good diabetes management were only partially met. DISCUSSION: Because of their enhanced predisposition for the development of diabetes this population merits particular attention with regards to screening for the onset of diabetes. The extent to which the quality of diabetes care indicators were achieved was variable but results suggest that for many people the indices were not met, that glycaemic control was poor, that only a quarter were of normal weight, that many were hypertensive and that almost a quarter had no record of their lipid levels. These findings provoke two important questions: first, who should be responsible for promoting diabetes management in this client group and second, how can service provision be tailored to better meet their needs? Greater collaborative working and education is required between ID services, primary healthcare and diabetes clinicians in order to promote the health and meet the quality indicators of diabetes care among this population. PMID- 23106689 TI - Cytokines expression in saliva and peri-implant crevicular fluid of patients with peri-implant disease. AB - OBJECTIVE: This study aimed to measure the levels of GM-CSF, IL-1beta, IL-2, IL 4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IFN-gamma and TNF-alpha in peri-implant crevicular fluid (PICF) and saliva from patients with peri-implant disease. METHODS: Twenty two total edentulous patients were divided into two groups: Mucositis (MU) patients with bone loss around the implants until the first thread and pocket depth <=3 mm, and Peri-implantitis (PI) patients with at least one implant with bone loss around two or more threads and pocket depth >=4 mm. The clinical parameters evaluated were probing pocket depth, bleeding on probing, and percentage of plaque. PICF samples were collected from MU sites, and from shallow (SPI) and deep (DPI) sites in PI. Unstimulated whole and parotid duct saliva was collected from all patients. The cytokines were measured by a multiplexed immunoassay. RESULTS: PI patients had a higher percentage of plaque compared with MU (P = 0.02). MU sites had lower pocket depth compared to SPI (P = 0.001) and to DPI (P <= 0.001). In PICF, the levels of IL-1beta were significantly higher in SPI sites compared to MU (P = 0.03). In the saliva from parotid, IL-8 and IL-12 were significantly higher in patients with PI (P = 0.04). CONCLUSION: Elevated levels of IL-1beta in PICF seem to be a characteristic trait of patients with peri-implantitis. The parotid duct saliva showed a significant increase in expression of IL-8, which might be related to a systemic response. PMID- 23106690 TI - Chemical characterization and flexural strength of a denture base acrylic resin with monomer 2-tert-butylaminoethyl methacrylate. AB - PURPOSE: The objectives of this study were to investigate the flexural strength (FS) and chemical interaction between 2-tert-butylaminoethyl methacrylate (TBAEMA) and a denture base acrylic resin. MATERIALS AND METHODS: Specimens were divided into five groups according to the concentration of TBAEMA incorporated in acrylic resin Onda-Cryl (0%, 1%, 2%, 3%, 4%) and were submitted to Fourier transform infrared spectroscopy (FTIR), electron spectroscopy for chemical analysis (XPS-ESCA), and differential scanning calorimetry (DSC) analyses. FS of the specimens was tested, and results were analyzed by ANOVA/Tukey's test (alpha < 0.05). RESULTS: Different nitrogen ratios were observed on specimens' surfaces: 0.36%, 0.54%, 0.35%, and 0.20% for groups 1%, 2%, 3%, and 4%, respectively. FTIR indicated copolymerization of acrylic resin and TBAEMA, and DSC results demonstrated a decrease in glass transition temperature (Tg ). Significant differences were found for FS (p < 0.05). The mean values were 91.1 +/- 5.5,(A) 77.0 +/- 13.1,(B) 67.2 +/- 12.5,(B) 64.4 +/- 13.0,(B) and 67.2 +/- 5.9(B) MPa for groups 0%, 1%, 2%, 3% and 4%, respectively (same superscript letters indicate no significant difference). CONCLUSIONS: The incorporation of TBAEMA in acrylic resin resulted in copolymerization and the presence of amine groups on specimens' surfaces, and in decreases of Tg and FS. PMID- 23106692 TI - Type I: families, planning and errors. PMID- 23106693 TI - Comparison of cardioprotective efficacy resulting from a combination of atorvastatin and ischaemic post-conditioning in diabetic and non-diabetic rats. AB - The aim of the present study was to investigate whether the combination of acute or chronic atorvastatin treatment with ischaemic post-conditioning (IPost) exerts differential effects within the hearts of diabetic and non-diabetic rats. Diabetic and non-diabetic rats were randomly assigned to one of six groups: (i) a non-conditioned group; (ii) a group subjected to IPost; (iii) acute statin treatment (50 MUmol/L atorvastatin during reperfusion) without IPost; (iv) acute statin treatment plus IPost; (v) chronic statin treatment (10 mg/kg atorvastatin per day for 2 weeks) without IPost; and (vi) chronic statin treatment plus IPost. The hearts from rats in each group were subjected to 30 min global ischaemia, followed by 120 min reperfusion. Infarct size, haemodynamics and Akt and endothelial nitric oxide synthase (eNOS) expression were examined. In hearts from diabetic rats, IPost did not limit infarct size or recover contractile dysfunction. Acute atorvastatin treatment with IPost limited infarct size and recovered contractile dysfunction in hearts from both diabetic and non-diabetic rats and further activated Akt and eNOS signalling pathways to enhance these protective effects in hearts from diabetic rats. Chronic statin treatment with IPost neither reduced infarct size nor increased recovery of myocardial dysfunction in hearts from both diabetic and non-diabetic rats; this may be associated with inhibition of Akt and eNOS phosphorylation. The combination of acute atorvastatin treatment with IPost had a greater protective effect within hearts from diabetic rats, but chronic statin treatment with IPost failed to protect against reperfusion injury in hearts from either diabetic or non-diabetic rats. These findings will be important for the design of future clinical investigations. PMID- 23106691 TI - Proteomic profile identifies dysregulated pathways in Cornelia de Lange syndrome cells with distinct mutations in SMC1A and SMC3 genes. AB - Mutations in cohesin genes have been identified in Cornelia de Lange syndrome (CdLS), but its etiopathogenetic mechanisms are still poorly understood. To define biochemical pathways that are affected in CdLS, we analyzed the proteomic profile of CdLS cell lines carrying mutations in the core cohesin genes, SMC1A and SMC3. Dysregulated protein expression was found in CdLS probands compared to controls. The proteomics analysis was able to discriminate between probands harboring mutations in the different domains of the SMC proteins. In particular, proteins involved in the response to oxidative stress were specifically down regulated in hinge mutated probands. In addition, the finding that CdLS cell lines show an increase in global oxidative stress argues that it could contribute to some CdLS phenotypic features such as premature physiological aging and genome instability. Finally, the c-MYC gene represents a convergent hub lying at the center of dysregulated pathways, and is down-regulated in CdLS. This study allowed us to highlight, for the first time, specific biochemical pathways that are affected in CdLS, providing plausible causal evidence for some of the phenotypic features seen in CdLS. PMID- 23106694 TI - Variability of cyclosporine concentrations by HPLC and TDX monoclonal assay methods, application of a correction factor, and description of a novel clinical approach to determine the practical consequences of changing assay technique. AB - Cyclosporine (CSA) is an immunosuppressant used for the prevention of graft rejection and graft-versus-host disease (GVHD) during hematopoietic stem cell transplantation. Therapeutic drug monitoring (TDM) is recommended to ensure efficacy and prevent toxicity. Several immunoassay assay are commercially available for measuring CSA drug concentrations. Differences in the cross reactive metabolites measured by specific immunoassay tests contribute to the significant lack of specificity which has been reported between immunoassays and high performance liquid chromatography (HPLC) test results. Inter-assay test results can affect interpretation of CSA drug concentrations and potentially compromise patient outcomes. The current study analyzed 72 paired HPLC-monoclonal TDX (TDXm) CSA drug concentrations and calculated a clinically reliable correction factor which could be applied to HPLC-TDXm results for TDM. A unique concordance-discordance simulation model was utilized to validate the correction factor for clinical use. PMID- 23106695 TI - Biliary sludge during hyperemesis gravidarum and later occurrence of gallstones. PMID- 23106697 TI - Central auditory processing. Are the emotional perceptions of those listening to classical music inherent in the composition or acquired by the listeners? AB - CONCLUSIONS: There is seemingly some inherent component in selected musical compositions that elicits specific emotional perceptions, feelings, and physical conduct. OBJECTIVES: The purpose of the study was to determine if the emotional perceptions of those listening to classical music are inherent in the composition or acquired by the listeners. METHODS: Fifteen kindergarten students, aged 5 years, from three different sociocultural groups, were evaluated. They were exposed to portions of five purposefully selected classical compositions and asked to describe their emotions when listening to these musical pieces. All were instrumental compositions without human voices or spoken language. In addition, they were played to an audience of an age at which they were capable of describing their perceptions and supposedly had no significant previous experience of classical music. RESULTS: Regardless of their sociocultural background, the children in the three groups consistently identified similar emotions (e.g. fear, happiness, sadness), feelings (e.g. love), and mental images (e.g. giants or dangerous animals walking) when listening to specific compositions. In addition, the musical compositions generated physical conducts that were reflected by the children's corporal expressions. Although the sensations were similar, the way of expressing them differed according to their background. PMID- 23106696 TI - Arsenic trioxide prevents nitric oxide production in lipopolysaccharide stimulated RAW 264.7 by inhibiting a TRIF-dependent pathway. AB - Arsenic trioxide (ATO) is one of the most potent drugs in cancer chemotherapy, and is highly effective in treating both newly diagnosed and relapse patients with acute promyelocytic leukemia (APL). Despite a number of reports regarding the molecular mechanisms by which ATO promotes anti-tumor or pro-apoptotic activity in hematological and other solid malignancies, the effects of ATO on immune responses remain poorly understood. To further understand and clarify the effects of ATO on immune responses, we sought to examine whether ATO affects the production of nitric oxide (NO) in a lipopolysaccharide (LPS)-stimulated mouse macrophage cell line, RAW 264.7. Arsenic trioxide was found to prevent NO production in a dose-dependent manner. Arsenic trioxide significantly inhibited the increase in inducible nitric oxide synthase (iNOS) at both the mRNA and protein levels. Furthermore, our analyses revealed that the inhibitory effect of ATO on iNOS expression was ascribed to the prevention of IRF3 phosphorylation, interferon (IFN)-beta expression, and STAT1 phosphorylation, but not the prevention of the MyD88-dependent pathway. Taken together, our results indicate that ATO prevents NO production by inhibiting the TIR-domain-containing adaptor protein inducing IFN-beta (TRIF)-dependent pathway, thus highlighting an anti inflammatory property of ATO in innate immunity. PMID- 23106698 TI - omega-3 fatty acid eicosapentaenoic acid attenuates MPP+-induced neurodegeneration in fully differentiated human SH-SY5Y and primary mesencephalic cells. AB - Eicosapentaenoic acid (EPA), a neuroactive omega-3 fatty acid, has been demonstrated to exert neuroprotective effects in experimental models of Parkinson's disease (PD), but the cellular mechanisms of protection are unknown. Here, we studied the effects of EPA in fully differentiated human SH-SY5Y cells and primary mesencephalic neurons treated with MPP(+) . In both in-vitro models of PD, EPA attenuated an MPP(+) -induced reduction in cell viability. EPA also prevented the presence of electron-dense cytoplasmic inclusions in SH-SY5Y cells. Then, possible mechanisms of the neuroprotection were studied. In primary neurons, EPA attenuated an MPP(+) -induced increase in Tyrosine-related kinase B (TrkB) receptors. In SH-SY5Y cells, EPA down-regulated reactive oxygen species and nitric oxide. This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo-oxygenase-2 (COX-2), as MPP(+) increased the expression of these enzymes. Furthermore, EPA prevented an increase in cytosolic phospholipase A2 (cPLA2), an enzyme linked with COX-2 in the potentially pro-inflammatory arachidonic acid cascade. Lastly, EPA attenuated an increase in the bax:bcl-2 ratio, and cytochrome c release. However, EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential. This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD. PMID- 23106699 TI - Quantitative genetic approaches to evolutionary constraint: how useful? AB - The study of evolutionary constraint is an active and important area, and genetic correlations and quantitative genetic techniques more generally have been the dominant approach to constraint. Here, I argue that genetic correlations are not very useful for studying constraint, review recent alternative approaches, and briefly discuss the state of our knowledge of the evolutionary importance of constraints caused by genetic variance and covariance. PMID- 23106700 TI - Dissecting the genetic architecture of F1 hybrid sterility in house mice. AB - Hybrid sterility as a postzygotic reproductive isolation mechanism has been studied for over 80 years, yet the first identifications of hybrid sterility genes in Drosophila and mouse are quite recent. To study the genetic architecture of F(1) hybrid sterility between young subspecies of house mouse Mus m. domesticus and M. m. musculus, we conducted QTL analysis of a backcross between inbred strains representing these two subspecies and probed the role of individual chromosomes in hybrid sterility using the intersubspecific chromosome substitution strains. We provide direct evidence that the asymmetry in male infertility between reciprocal crosses is conferred by the middle region of M. m. musculus Chr X, thus excluding other potential candidates such as Y, imprinted genes, and mitochondrial DNA. QTL analysis identified strong hybrid sterility loci on Chr 17 and Chr X and predicted a set of interchangeable autosomal loci, a subset of which is sufficient to activate the Dobzhansky-Muller incompatibility of the strong loci. Overall, our results indicate the oligogenic nature of F(1) hybrid sterility, which should be amenable to reconstruction by proper combination of chromosome substitution strains. Such a prefabricated model system should help to uncover the gene networks and molecular mechanisms underlying hybrid sterility. PMID- 23106701 TI - The genetic architecture of a complex ecological trait: host plant use in the specialist moth, Heliothis subflexa. AB - We used genetic mapping to examine the genetic architecture of differences in host plant use between two species of noctuid moths, Heliothis subflexa, a specialist on Physalis spp., and its close relative, the broad generalist H. virescens. We introgressed H. subflexa chromosomes into the H. virescens background and analyzed 1462 backcross insects. The effects of H. subflexa-origin chromosomes were small when measured as the percent variation explained in backcross populations (0.2-5%), but were larger when considered in relation to the interspecific difference explained (1.5-165%). Most significant chromosomes had effects on more than one trait, and their effects varied between years, sexes, and genetic backgrounds. Different chromosomes could produce similar phenotypes, suggesting that the same trait might be controlled by different chromosomes in different backcross populations. It appears that many loci of small effect contribute to the use of Physalis by H. subflexa. We hypothesize that behavioral changes may have paved the way for physiological adaptation to Physalis by the generalist ancestor of H. subflexa and H. virescens. PMID- 23106702 TI - The genetic basis of a complex functional system. AB - The relationship between form and function can have profound effects on evolutionary dynamics and such effects may differ for simple versus complex systems. In particular, functions produced by multiple structural configurations (many-to-one mapping, MTOM) may dampen constituent trade-offs and promote diversification. Unfortunately, we lack information about the genetic architecture of MTOM functional systems. The skulls of teleost fishes contain both simple (lower jaw levers) as well as more complex (jaws modeled as 4-bar linkages) functional systems within the same craniofacial unit. We examined the mapping of form to function and the genetic basis of these systems by identifying quantitative trait loci (QTL) in hybrids of two Lake Malawi cichlid species. Hybrid individuals exhibited novelty (transgressive segregation) in morphological components and function of the simple and complex jaw systems. Functional novelty was proportional to the prevalence of extreme morphologies in the simple levers; by contrast, recombination of parental morphologies produced transgression in the MTOM 4-bar linkage. We found multiple loci of moderate effect and epistasis controlling jaw phenotypes in both the simple and complex systems, with less phenotypic variance explained by QTL for the 4-bar. Genetic linkage between components of the simple and complex systems partly explains phenotypic correlations and may constrain functional evolution. PMID- 23106703 TI - Food plant derived disease tolerance and resistance in a natural butterfly-plant parasite interactions. AB - Organisms can protect themselves against parasite-induced fitness costs through resistance or tolerance. Resistance includes mechanisms that prevent infection or limit parasite growth while tolerance alleviates the fitness costs from parasitism without limiting infection. Although tolerance and resistance affect host-parasite coevolution in fundamentally different ways, tolerance has often been ignored in animal-parasite systems. Where it has been studied, tolerance has been assumed to be a genetic mechanism, unaffected by the host environment. Here we studied the effects of host ecology on tolerance and resistance to infection by rearing monarch butterflies on 12 different species of milkweed food plants and infecting them with a naturally occurring protozoan parasite. Our results show that monarch butterflies experience different levels of tolerance to parasitism depending on the species of milkweed that they feed on, with some species providing over twofold greater tolerance than other milkweed species. Resistance was also affected by milkweed species, but there was no relationship between milkweed-conferred resistance and tolerance. Chemical analysis suggests that infected monarchs obtain highest fitness when reared on milkweeds with an intermediate concentration, diversity, and polarity of toxic secondary plant chemicals known as cardenolides. Our results demonstrate that environmental factors-such as interacting species in ecological food webs-are important drivers of disease tolerance. PMID- 23106704 TI - Phylogenetic constraints in key functional traits behind species' climate niches: patterns of desiccation and cold resistance across 95 Drosophila species. AB - Species distributions are often constrained by climatic tolerances that are ultimately determined by evolutionary history and/or adaptive capacity, but these factors have rarely been partitioned. Here, we experimentally determined two key climatic niche traits (desiccation and cold resistance) for 92-95 Drosophila species and assessed their importance for geographic distributions, while controlling for acclimation, phylogeny, and spatial autocorrelation. Employing an array of phylogenetic analyses, we documented moderate-to-strong phylogenetic signal in both desiccation and cold resistance. Desiccation and cold resistance were clearly linked to species distributions because significant associations between traits and climatic variables persisted even after controlling for phylogeny. We used different methods to untangle whether phylogenetic signal reflected phylogenetically related species adapted to similar environments or alternatively phylogenetic inertia. For desiccation resistance, weak phylogenetic inertia was detected; ancestral trait reconstruction, however, revealed a deep divergence that could be traced back to the genus level. Despite drosophilids' high evolutionary potential related to short generation times and high population sizes, cold resistance was found to have a moderate-to-high level of phylogenetic inertia, suggesting that evolutionary responses are likely to be slow. Together these findings suggest species distributions are governed by evolutionarily conservative climate responses, with limited scope for rapid adaptive responses to future climate change. PMID- 23106706 TI - Connecting the dots of nonlinear reaction norms unravels the threads of genotype environment interaction in Drosophila. AB - Two contrasting views can characterize the attitude of many studies toward reaction norms (RNs). An "optimistic" view attempts to use a linear model to describe RN variation; and a "pessimistic" view emphasizes RNs complexity without using any model to describe them. Here, we have analyzed the shape of 40 RNs of five traits of Drosophila mediopunctata in response to 11 temperatures. Our results, along with several other studies, show that RNs are typically curves best explained by nonlinear models. Estimating the set of 40 RNs on the basis of three rather than 11 temperatures produces a scenario, typical of the pessimistic view, where the linear model is either nonsignificant or a poor explanatory model. Moreover, we show that RN nonlinearity can significantly affect the conclusions of studies using the linear model. We propose a middle ground view on RNs which recognizes their general nonlinearity. Such view could, on the one hand, explain part of the important phenomenon of genotype-environment interaction emphasized by the pessimistic view. Moreover, it may explain features and patterns which are being ignored by the optimistic view. We suggest the parabolic model as first step to reveal patterns which were ignored before, or not fully appreciated. PMID- 23106707 TI - Clinal variation in seed traits influencing life cycle timing in Arabidopsis thaliana. AB - Early life-history transitions are crucial determinants of lifetime survival and fecundity. Adaptive evolution in early life-history traits involves a complex interplay between the developing plant and its current and future environments. We examined the plant's earliest life-history traits, dissecting an integrated suite of pregermination processes: primary dormancy, thermal induction of secondary dormancy, and seasonal germination response. We examined genetic variation in the three processes, genetic correlations among the processes, and the scaling of germination phenology with the source populations' climates. A spring annual life history was associated with genetic propensities toward both strong primary dormancy and heat-induced secondary dormancy, alone or in combination. Lineages with similar proportions of winter and spring annual life history have both weak primary dormancy and weak thermal dormancy induction. A genetic bias to adopt a spring annual strategy, mediated by rapid loss of primary dormancy and high thermal dormancy induction, is associated with a climatic gradient characterized by increasing temperature in summer and rainfall in winter. This study highlights the importance of considering combinations of multiple genetically based traits along a climatic gradient as adaptive strategies differentiating annual plant life-history strategies. Despite the genetic-climatic cline, there is polymorphism for life-history strategies within populations, classically interpreted as bet hedging in an unpredictable world. PMID- 23106705 TI - Genomic basis of aging and life-history evolution in Drosophila melanogaster. AB - Natural diversity in aging and other life-history patterns is a hallmark of organismal variation. Related species, populations, and individuals within populations show genetically based variation in life span and other aspects of age-related performance. Population differences are especially informative because these differences can be large relative to within-population variation and because they occur in organisms with otherwise similar genomes. We used experimental evolution to produce populations divergent for life span and late age fertility and then used deep genome sequencing to detect sequence variants with nucleotide-level resolution. Several genes and genome regions showed strong signatures of selection, and the same regions were implicated in independent comparisons, suggesting that the same alleles were selected in replicate lines. Genes related to oogenesis, immunity, and protein degradation were implicated as important modifiers of late-life performance. Expression profiling and functional annotation narrowed the list of strong candidate genes to 38, most of which are novel candidates for regulating aging. Life span and early age fecundity were negatively correlated among populations; therefore, the alleles we identified also are candidate regulators of a major life-history trade-off. More generally, we argue that hitchhiking mapping can be a powerful tool for uncovering the molecular bases of quantitative genetic variation. PMID- 23106708 TI - Local adaptation and the evolution of phenotypic plasticity in Trinidadian guppies (Poecilia reticulata). AB - Divergent selection pressures across environments can result in phenotypic differentiation that is due to local adaptation, phenotypic plasticity, or both. Trinidadian guppies exhibit local adaptation to the presence or absence of predators, but the degree to which predator-induced plasticity contributes to population differentiation is less clear. We conducted common garden experiments on guppies obtained from two drainages containing populations adapted to high- and low-predation environments. We reared full-siblings from all populations in treatments simulating the presumed ancestral (predator cues present) and derived (predator cues absent) conditions and measured water column use, head morphology, and size at maturity. When reared in presence of predator cues, all populations had phenotypes that were typical of a high-predation ecotype. However, when reared in the absence of predator cues, guppies from high- and low-predation regimes differed in head morphology and size at maturity; the qualitative nature of these differences corresponded to those that characterize adaptive phenotypes in high- versus low-predation environments. Thus, divergence in plasticity is due to phenotypic differences between high- and low-predation populations when reared in the absence of predator cues. These results suggest that plasticity might initially play an important role during colonization of novel environments, and then evolve as a by-product of adaptation to the derived environment. PMID- 23106709 TI - Comparison of non-Gaussian quantitative genetic models for migration and stabilizing selection. AB - The balance between stabilizing selection and migration of maladapted individuals has formerly been modeled using a variety of quantitative genetic models of increasing complexity, including models based on a constant expressed genetic variance and models based on normality. The infinitesimal model can accommodate nonnormality and a nonconstant genetic variance as a result of linkage disequilibrium. It can be seen as a parsimonious one-parameter model that approximates the underlying genetic details well when a large number of loci are involved. Here, the performance of this model is compared to several more realistic explicit multilocus models, with either two, several or a large number of alleles per locus with unequal effect sizes. Predictions for the deviation of the population mean from the optimum are highly similar across the different models, so that the non-Gaussian infinitesimal model forms a good approximation. It does, however, generally estimate a higher genetic variance than the multilocus models, with the difference decreasing with an increasing number of loci. The difference between multilocus models depends more strongly on the effective number of loci, accounting for relative contributions of loci to the variance, than on the number of alleles per locus. PMID- 23106710 TI - Influence of viral replication mechanisms on within-host evolutionary dynamics. AB - Viruses replicate their genomes using a variety of mechanisms, leading to different distributions of mutations among their progeny. Yet, models of viral evolution often only consider the mean mutation rate. To investigate when and how replication mechanisms impact viral evolution, we analyze the early dynamics of within-host infection for two idealized cases: when all offspring virions from an infected cell carry the same genotype, mutated or not; and when mutations occur independently across offspring virions. Other replication life histories fall between these extremes. Using branching process models, we study the probability that viral infection becomes established when mutations are lethal, and in the more general case of two strains of different fitness. For a given mean mutation rate, we show that a lineage of viruses with correlated mutations is less likely to survive than with independent mutations, but when it survives, the viral population grows faster. While this holds true for all parameter regimes, replication life history has a quantitatively significant influence on viral dynamics when stochastic effects are important and when mutations are crucial for survival-conditions typical of evolutionary escape situations. PMID- 23106711 TI - Spite versus cheats: competition among social strategies shapes virulence in Pseudomonas aeruginosa. AB - Social interactions have been shown to play an important role in bacterial evolution and virulence. The majority of empirical studies conducted have only considered social traits in isolation, yet numerous social traits, such as the production of spiteful bacteriocins (anticompetitor toxins) and iron-scavenging siderophores (a public good) by the opportunistic pathogen Pseudomonas aeruginosa, are frequently expressed simultaneously. Crucially, both bacteriocin production and siderophore cheating can be favored under the same competitive conditions, and we develop theory and carry out experiments to determine how the success of a bacteriocin-producing genotype is influenced by social cheating of susceptible competitors and the resultant impact on disease severity (virulence). Consistent with our theoretical predictions, we find that the spiteful genotype is favored at higher local frequencies when competing against public good cheats. Furthermore, the relationship between spite frequency and virulence is significantly altered when the spiteful genotype is competed against cheats compared with cooperators. These results confirm the ecological and evolutionary importance of considering multiple social traits simultaneously. Moreover, our results are consistent with recent theory regarding the invasion conditions for strong reciprocity (helping cooperators and harming noncooperators). PMID- 23106712 TI - Phenotypic stochasticity protects lytic bacteriophage populations from extinction during the bacterial stationary phase. AB - It is generally thought that the adsorption rate of a bacteriophage correlates positively with fitness, but this view neglects that most phages rely only on exponentially growing bacteria for productive infections. Thus, phages must cope with the environmental stochasticity that is their hosts' physiological state. If lysogeny is one alternative, it is unclear how strictly lytic phages can survive the host stationary phase. Three scenarios may explain their maintenance: (1) pseudolysogeny, (2) diversified, or (3) conservative bet hedging. To better understand how a strictly lytic phage survives the stationary phase of its host, and how phage adsorption rate impacts this survival, we challenged two strictly lytic phage lambda, differing in their adsorption rates, with stationary phase Escherichia coli cells. Our results showed that, pseudolysogeny was not responsible for phage survival and that, contrary to our expectation, high adsorption rate was not more detrimental during stationary phase than low adsorption rate. Interestingly, this last observation was due to the presence of the "residual fraction" (phages exhibiting extremely low adsorption rates), protecting phage populations from extinction. Whether this cryptic phenotypic variation is an adaptation (diversified bet hedging) or merely reflecting unavoidable defects during protein synthesis remains an open question. PMID- 23106713 TI - The distribution of mutational fitness effects of phage phiX174 on different hosts. AB - Adaptation depends greatly on the distribution of mutation fitness effects (DMFE), but the phenotypic expression of mutations is often environment dependent. The environments faced by multihost pathogens are mostly governed by their hosts and therefore measuring the DMFE on multiple hosts can inform on the likelihood of short-term establishment and longer term adaptation of emerging pathogens. We explored this by measuring the growth rate of 36 mutants of the lytic bacteriophage phiX174 on two host backgrounds, Escherichia coli (EcC) and Salmonella typhimurium (StGal). The DMFE showed higher mean and variance on EcC than on StGal. Most mutations were either deleterious or neutral on both hosts, but a greater proportion of mutations were deleterious on StGal. We identified two mutations with beneficial fitness effects on EcC that were neutral on StGal. Host-specific differences in fitness were associated with particular functional classes of genes involved in the initial stages of infection in accordance with previous studies of host specificity. Overall, there was a positive correlation between the effects of mutations on each host, suggesting that most new mutations will have general, rather than host-specific fitness effects. We consider these results in light of simple fitness landscape models of adaptation and discuss the relevance of context-dependent DMFE for multihost pathogens. PMID- 23106714 TI - Evolutionary rescue of sexual and asexual populations in a deteriorating environment. AB - The environmental change experienced by many contemporary populations of organisms poses a serious risk to their survival. From the theory of evolutionary rescue, we predict that the combination of sex and genetic diversity should increase the probability of survival by increasing variation and thereby the probability of generating a type that can tolerate the stressful environment. We tested this prediction by comparing experimental populations of Chlamydomonas reinhardtii that differ in sexuality and in the initial amount of genetic diversity. The lines were serially propagated in an environment where the level of stress caused by salt increased over time from fresh water to the limits of marine conditions. In the long term, the combination of high diversity and obligate sexuality was most effective in supporting evolutionary rescue. Most of the adaptation to high-salt environments in the obligate sexual-high diversity lines had occurred by midway through the experiment, indicating that positive genetic correlations of adaptation to lethal stress with adaptation to sublethal stress greatly increased the probability of evolutionary rescue. The evolutionary rescue events observed in this study provide evidence that major shifts in ways of life can arise within short time frames through the action of natural selection in sexual populations. PMID- 23106716 TI - Size-dependent mortality and competition interactively shape community diversity. AB - Body size is recognized as a major factor in evolutionary processes mediating sympatric diversification and community structuring. Life-history types with distinct body sizes can result from two fundamental mechanisms, size-dependent competition and size-dependent mortality. While previous theoretical studies investigated these two processes in separation, the model analyzed here allows both selective forces to affect body-size evolution interactively. Here we show for the first time that in the presence of size-dependent competition, size dependent mortality can give rise to multiple, coexisting size morphs representing the final outcomes of evolution. Moreover, our results demonstrate that interactions between size-dependent competition and mortality can create characteristic abrupt changes in size structure and nonmonotonic patterns of biological diversity along continuous and monotonic environmental gradients. We find that the two selective forces differentially affect the body-size ratios of coexisting morphs: size-dependent competition results in small and relatively constant ratios, whereas size-dependent mortality can open niches for morphs that greatly differ in body size. We show that these differential effects result in characteristic distributions of size ratios across communities, which we suggest can help detect the concurrent action and relative influence of size-dependent competition and mortality in nature. PMID- 23106717 TI - More than bindin divergence: reproductive isolation between sympatric subspecies of a sea urchin by asynchronous spawning. AB - The evolution of reproductive barriers is crucial to the process of speciation. In the Echinoidea, studies have focused on divergence in the gamete recognition protein, bindin, as the primary isolating mechanism among species. As such, the capacity of alternate mechanisms to be effective reproductive barriers and the phylogenetic context in which they arise is unclear. Here, we examine the evolutionary histories and factors limiting gene exchange between two subspecies of Heliocidaris erythrogramma that occur sympatrically in Western Australia. We found low, but significant differentiation between the subspecies in two mitochondrial genes. Further, coalescent analyses suggest that they diverged in isolation on the east and west coasts of Australia, with a subsequent range expansion of H. e. erythrogramma into Western Australia. Differentiation in bindin was minimal, indicating gamete incompatibility is an unlikely reproductive barrier. We did, however, detect strong asynchrony in spawning seasons; H. e. erythrogramma spawned over summer whereas H. e. armigera spawned in autumn. Taken together, we provide compelling evidence for a recent divergence of these subspecies and their reproductive isolation without gamete incompatibility. Western Australian H. erythrogramma may therefore present an intriguing case of incipient speciation, which depends on long-term persistence of the factors underlying this spawning asynchrony. PMID- 23106718 TI - Complex interactions between paternal and maternal effects: parental experience and age at reproduction affect fecundity and offspring performance in a butterfly. AB - Parental effects can greatly affect offspring performance and are thus expected to impact population dynamics and evolutionary trajectories. Most studies have focused on maternal effects, whereas fathers are also likely to influence offspring phenotype, for instance when males transfer nutrients to females during mating. Moreover, although the separate effects of maternal age and the environment have been documented as a source of parental effects in many species, their combined effects have not been investigated. In the present study, we analyzed the combined effects of maternal and paternal age at reproduction and a mobility treatment in stressful conditions on offspring performance in the butterfly Pieris brassicae. Both paternal and maternal effects affected progeny traits but always via interactions between age and mobility treatment. Moreover, parental effects shifted from male effects expressed at the larval stage to maternal effects at the adult stage. Indeed, egg survival until adult emergence significantly decreased with father age at mating only for fathers having experienced the mobility treatment, whereas offspring adult life span decreased with increasing mother age at laying only for females that did not experience the mobility treatment. Overall, our results demonstrate that both parents' phenotypes influence offspring performance through nongenetic effects, their relative contribution varying over the course of progeny's life. PMID- 23106719 TI - Paternal care: direct and indirect genetic effects of fathers on offspring performance. AB - Knowledge of how genetic effects arising from parental care influence the evolution of offspring traits comes almost exclusively from studies of maternal care. However, males provide care in some taxa, and often this care differs from females in quality or quantity. If variation in paternal care is genetically based then, like maternal care and maternal effects, paternal effects may have important consequences for the evolution of offspring traits via indirect genetic effects (IGEs). IGEs and direct-indirect genetic covariances associated with parental care can contribute substantially to total heritability and influence predictions about how traits respond to selection. It is unknown, however, if the magnitude and sign of parental effects arising from fathers are the same as those arising from mothers. We used a reciprocal cross-fostering experiment to quantify environmental and genetic effects of paternal care on offspring performance in the burying beetle, Nicrophorus vespilloides. We found that IGEs were substantial and direct-indirect genetic covariances were negative. Combined, these patterns led to low total heritabilities for offspring performance traits. Thus, under paternal care, offspring performance traits are unlikely to evolve in response to selection, and variation in these traits will be maintained in the population despite potentially strong selection on these traits. These patterns are similar to those generated by maternal care, indicating that the genetic effects of care on offspring performance are independent of the caregiver's sex. PMID- 23106715 TI - Linkage to the mating-type locus across the genus Microbotryum: insights into nonrecombining chromosomes. AB - Parallels have been drawn between the evolution of nonrecombining regions in fungal mating-type chromosomes and animal and plant sex chromosomes, particularly regarding the stages of recombination cessation forming evolutionary strata of allelic divergence. Currently, evidence and explanations for recombination cessation in fungi are sparse, and the presence of evolutionary strata has been examined in a minimal number of fungal taxa. Here, the basidiomycete genus Microbotryum was used to determine the history of recombination cessation for loci on the mating-type chromosomes. Ancestry of linkage with mating type for 13 loci was assessed across 20 species by a phylogenetic method. No locus was found to exhibit trans-specific polymorphism for alternate alleles as old as the mating pheromone receptor, indicating that ages of linkage to mating type varied among the loci. The ordering of loci in the ancestry of linkage to mating type does not agree with their previously proposed assignments to evolutionary strata. This study suggests that processes capable of influencing divergence between alternate alleles may act at loci in the nonrecombining regions (e.g., gene conversion) and encourages further work to dissect the evolutionary processes acting upon genomic regions that determine mating compatibility. PMID- 23106720 TI - Partitioning the effects of spatial isolation, nest habitat, and individual diet in causing assortative mating within a population of threespine stickleback. AB - Assortative mating is measured as a phenotypic or genotypic correlation between mates. Although biologists typically view assortative mating in terms of mate preference for similar partners, correlations between mates can also arise from phenotypic spatial structure arising from spatial isolation or habitat preferences. Here, we test whether diet-assortative mating within an ecologically variable population of threespine stickleback results from small-scale geographic isolation or microhabitat preference. We find evidence for assortative mating in the form of a positive correlation between mated pairs' diets (measured using stable isotopes). Stable isotopes reveal diet differences between different nesting areas and among individuals using different nest habitat within a nesting area. This spatial segregation of diet types should generate some assortative mating, but is insufficient to explain the observed assortment strength. Significant male-female isotope correlations remain after controlling for spatial variables. We therefore conclude that sticklebacks' diet-assortative mating arises from additional behavioral preference. More generally, our results illustrate the point that spatial segregation can only drive appreciable levels of phenotypic assortative mating when environment-phenotype correlations are parallel and strong in both sexes. Consequently, intraspecific assortative mating may typically entail mating preferences rather than just spatial cosegregation of phenotypes. PMID- 23106721 TI - Male contest competition and the coevolution of weaponry and testes in pinnipeds. AB - Male reproductive success is influenced by competitive interactions during precopulatory and postcopulatory selective episodes. Consequently, males can gain reproductive advantages during precopulatory contest competition by investing in weaponry and during postcopulatory sperm competition by investing in ejaculates. However, recent theory predicts male expenditure on weaponry and ejaculates should be subject to a trade-off, and should vary under increasing risk and intensity of sperm competition. Here, we provide the first comparative analysis of the prediction that expenditure on weaponry should be negatively associated with expenditure on testes mass. Specifically, we assess how sexual selection influences the evolution of primary and secondary sexual traits among pinnipeds (seals, sea lions, and walruses). Using recently developed comparative methods, we demonstrate that sexual selection promotes rapid divergence in body mass, sexual size dimorphism (SSD), and genital morphology. We then show that genital length appears to be positively associated with the strength of postcopulatory sexual selection. However, subsequent analyses reveal that both genital length and testes mass are negatively associated with investment in precopulatory weaponry. Thus, our results are congruent with recent theoretical predictions of contest-based sperm competition models. We discuss the possible role of trade offs and allometry in influencing patterns of reproductive trait evolution in pinnipeds. PMID- 23106722 TI - Sexual selection and the evolution of complex color patterns in dragon lizards. AB - Many species have elaborate and complex coloration and patterning, which often differ between the sexes. Sexual selection may increase the size or intensity of color patches (elaboration) in one sex or drive the evolution of novel signal elements (innovation). The latter potentially increases color pattern complexity. Color pattern complexity may also be influenced by ecological factors related to predation and environment; however, very few studies have investigated the effects of both sexual and natural selection on color pattern complexity across species. We used a phylogenetic comparative approach to examine these effects in 85 species and subspecies of Australian dragon lizards (family Agamidae). We quantified color pattern complexity by adapting the Shannon-Wiener diversity index. There were clear sex differences in color pattern complexity, which were positively correlated with both sexual dichromatism and sexual size dimorphism, consistent with the idea that sexual selection plays a significant role in the evolution of color pattern complexity. By contrast, we found little evidence of a link between environmental factors and color pattern complexity on body regions exposed to predators. Our results suggest that sexual selection rather than natural selection has led to increased color pattern complexity in males. PMID- 23106723 TI - Testing the influence of family structure and outbreeding depression on heterozygosity-fitness correlations in small populations. AB - Theory predicts that positive heterozygosity-fitness correlations (HFCs) arise as a consequence of inbreeding, which is often assumed to have a strong impact in small, fragmented populations. Yet according to empirical data, HFC in such populations seem highly variable and unpredictable. We here discuss two overlooked phenomena that may contribute to this variation. First, in a small population, each generation may consist of a few families. This generates random correlations between particular alleles and fitness (AFCs, allele-fitness correlations) and results in too liberal tests for HFC. Second, in some contexts, small populations receiving immigrants may be more impacted by outbreeding depression than by inbreeding depression, resulting in negative rather than positive HFC. We investigated these processes through a case study in tadpole cohorts of Pelodytes punctatus living in small ponds. We provide evidence for a strong family structure and significant AFC in this system, as well as an example of negative HFC. By simulations, we show that this negative HFC cannot be a spurious effect of family structure, and therefore reflects outbreeding depression in the studied population. Our example suggests that a detailed examination of AFC and HFC patterns can provide valuable insights into the internal genetic structure and sources of fitness variation in small populations. PMID- 23106724 TI - Behavioral evidence for fruit odor discrimination and sympatric host races of Rhagoletis pomonella flies in the Western United States. AB - The recent shift of Rhagoletis pomonella (Diptera: Tephritidae) from its native host downy hawthorn, Crataegus mollis, to introduced domesticated apple, Malus domestica, in the eastern United States is a model for sympatric host race formation. However, the fly is also present in the western United States, where it may have been introduced via infested apples within the last 60 years. In addition to apple, R. pomonella also infests two hawthorns in the West, one the native black hawthorn, C. douglasii, and the other the introduced English ornamental hawthorn, C. monogyna. Here, we test for behavioral evidence of host races in the western United States. through flight tunnel assays of western R. pomonella flies to host fruit volatile blends. We report that western apple, black hawthorn, and ornamental hawthorn flies showed significantly increased levels of upwind-directed flight to their respective natal compared to nonnatal fruit volatile blends, consistent with host race status. We discuss the implications of the behavioral results for the origin(s) of western R. pomonella, including the possibility that western apple flies were not introduced, but may represent a recent shift from local hawthorn fly populations. PMID- 23106725 TI - TiO2 nanotip arrays: anodic fabrication and field-emission properties. AB - In contrast to the main-stream strategy of growing convex nanostructures upward from the substrates and using them as cold electron sources, it is illustrated in this article that growing concave nanostructures downward into substrates also results in configurations suitable for field emission. Well-ordered TiO2 nanotube arrays were developed on the titanium foils in two-step anodizations. Simultaneously, arrays of sharp nanotips, which resembled the Spindt emitter arrays in appearance, also manifested themselves on the outmost surface of the foils. These nanotips were actually the remainder of the titanium foil surfaces that survived dissolution during anodization. Annealing transformed the amorphous TiO2 nanotips into anatase crystals and further to rutile. Despite the lack of an overall large aspect ratio, the sharpness of these nanotips guaranteed sufficiently strong electric fields for electron extraction. As a result, field emission was readily obtained from the TiO2 nanotip arrays, either before or after annealing. Photoelectron spectroscopy of the samples demonstrated that the majority of the emitted electrons came from local states in the band gap. Annealing at an appropriate temperature increased these local states and improved the field-emission capability of the samples. PMID- 23106726 TI - News from the editors: a winner of 2011 Developmental Science Early Career Research Prize. PMID- 23106727 TI - Toddlers recognize words in an unfamiliar accent after brief exposure. AB - Both subjective impressions and previous research with monolingual listeners suggest that a foreign accent interferes with word recognition in infants, young children, and adults. However, because being exposed to multiple accents is likely to be an everyday occurrence in many societies, it is unexpected that such non-standard pronunciations would significantly impede language processing once the listener has experience with the relevant accent. Indeed, we report that 24 month-olds successfully accommodate an unfamiliar accent in rapid word learning after less than 2 minutes of accent exposure. These results underline the robustness of our speech perception mechanisms, which allow listeners to adapt even in the absence of extensive lexical knowledge and clear known-word referents. PMID- 23106728 TI - Simulating the role of visual selective attention during the development of perceptual completion. AB - We recently proposed a multi-channel, image-filtering model for simulating the development of visual selective attention in young infants (Schlesinger, Amso & Johnson, 2007). The model not only captures the performance of 3-month-olds on a visual search task, but also implicates two cortical regions that may play a role in the development of visual selective attention. In the current simulation study, we used the same model to simulate 3-month-olds' performance on a second measure, the perceptual unity task. Two parameters in the model - corresponding to areas in the occipital and parietal cortices - were systematically varied while the gaze patterns produced by the model were recorded and subsequently analyzed. Three key findings emerged from the simulation study. First, the model successfully replicated the performance of 3-month-olds on the unity perception task. Second, the model also helps to explain the improved performance of 2-month olds when the size of the occluder in the unity perception task is reduced. Third, in contrast to our previous simulation results, variation in only one of the two cortical regions simulated (i.e. recurrent activity in posterior parietal cortex) resulted in a performance pattern that matched 3-month-olds. These findings provide additional support for our hypothesis that the development of perceptual completion in early infancy is promoted by progressive improvements in visual selective attention and oculomotor skill. PMID- 23106729 TI - Class matters: 12-month-olds' word-object associations privilege content over function words. AB - A fundamental step in learning words is the development of an association between a sound pattern and an element in the environment. Here we explore the nature of this associative ability in 12-month-olds, examining whether it is constrained to privilege particular word forms over others. Forty-eight infants were presented with sets of novel English content-like word-object pairings (e.g. fep) or novel English function-like word-object (e.g. iv) pairings until they habituated. Results indicated that infants associated novel content-like words, but not the novel function-like words, with novel objects. These results demonstrate that the mechanism with which basic word-object associations are formed is remarkably sophisticated by the onset of productive language. That is, mere associative pairings are not sufficient to form mappings. Rather the system requires well formed noun-like words to co-occur with objects in order for the linkages to arise. PMID- 23106730 TI - Preschool children's interpretation of object-initial sentences: neural correlates of their behavioral performance. AB - The acquisition of the function of case-marking is a key step in the development of sentence processing for German-speaking children since case-marking reveals the relations between sentential arguments. In this study, we investigated the development of the processing of case-marking and argument structures in children at 3, 4;6 and 6 years of age, as well as its processing in adults. Using EEG, we measured event-related potentials (ERPs) in response to object-initial compared to subject-initial German sentences including transitive verbs and case-marked noun phrases referring to animate arguments. We also tested children's behavioral competence in a sentence-picture matching task. Word order and case-marking were manipulated in German main clauses. Adults' behavioral performance was close to perfect and their ERPs revealed a negativity for the processing of the topicalized accusative marked noun phrase (NP1) and no effect for the second NP (NP2) in the object-initial structure. Children's behavioral data showed a significant above-chance outcome in the subject-initial condition for all age groups, but not for the object-initial condition. In contrast to adults, the ERPs of 3-year-olds showed a positivity at NP1, indicating difficulties in processing the non-canonical object-initial structures. Children at the age of 4;6 did not differ in the processing patterns of object-initial vs. subject-initial sentences at NP1 but showed a slight positivity at NP2. This positivity at NP2, which implies syntactic integration difficulties, is more pronounced in 6-year-olds but is absent in adults. At NP1, however, 6-year-olds show the same negativity as adults. In sum, the behavioral and electrophysiological findings demonstrate that children in each age group use different strategies, which are indicative of their developmental stage. While 3-year-olds merely detect differences in the two sentence structures without being able to use this information for sentence comprehension, 4;6-year-olds proceed to use mainly a word-order strategy, processing NP1 in both conditions in the same manner, which leads to processing difficulties upon detecting case-marking cues at NP2. At the age of 6, children are able to use case-marking cues for comprehension but still show enhanced effort for correct thematic-role assignment. PMID- 23106731 TI - Biracial and monoracial infant own-race face perception: an eye tracking study. AB - We know that early experience plays a crucial role in the development of face processing, but we know little about how infants learn to distinguish faces from different races, especially for non-Caucasian populations. Moreover, it is unknown whether differential processing of different race faces observed in typically studied monoracial infants extends to biracial infants as well. Thus, we investigated 3-month-old Caucasian, Asian and biracial (Caucasian-Asian) infants' ability to distinguish Caucasian and Asian faces. Infants completed two within-subject, infant-controlled habituation sequences and test trials as an eye tracker recorded looking times and scanning patterns. Examination of individual differences revealed significant positive correlations between own-race novelty preference and scanning frequency between eye and mouth regions of own-race habituation stimuli for Caucasian and Asian infants, suggesting that facility in own-race face discrimination stems from active inspection of internal facial features in these groups. Biracial infants, however, showed the opposite effect: An 'own-race' novelty preference was associated with reduced scanning between eye and mouth regions of 'own-race' habituation stimuli, suggesting that biracial infants use a distinct approach to processing frequently encountered faces. Future directions for investigating face processing development in biracial populations are discussed. PMID- 23106732 TI - Go naked: diapers affect infant walking. AB - In light of cross-cultural and experimental research highlighting effects of childrearing practices on infant motor skill, we asked whether wearing diapers, a seemingly innocuous childrearing practice, affects infant walking. Diapers introduce bulk between the legs, potentially exacerbating infants' poor balance and wide stance. We show that walking is adversely affected by old-fashioned cloth diapers, and that even modern disposable diapers - habitually worn by most infants in the sample - incur a cost relative to walking naked. Infants displayed less mature gait patterns and more missteps and falls while wearing diapers. Thus, infants' own diapers constitute an ongoing biomechanical perturbation while learning to walk. Furthermore, shifts in diapering practices may have contributed to historical and cross-cultural differences in infant walking. PMID- 23106733 TI - Temporal discounting of monetary rewards in children and adolescents with ADHD and autism spectrum disorders. AB - It has been difficult to differentiate attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in terms of some aspects of their cognitive profile. While both show deficits in executive functions, it has been suggested that they may differ in their response to monetary reward. For instance, children with ADHD prefer small immediate over large delayed rewards more than typically developing controls. One explanation for this is that they discount the value of rewards to a higher degree as they are moved into the future. The current study investigated whether children with ADHD can be differentiated from those with ASD in terms of reward discounting. Thirty-nine children (8-16 y) with ADHD, 34 children with ASD and 46 typically developing controls performed a hypothetical monetary temporal discounting task. Participants were instructed to make repeated choices between small variable rewards (0, 5, 10, 20, 30?) delivered immediately and large rewards delivered after a variable delay. Children with ADHD but not ASD discounted future rewards at a higher rate than typically developing controls. These data confirm steeper discounting of future rewards in ADHD and add to a small but growing literature showing that the psychological profile of ADHD can be distinguished from that of ASD in terms of disrupted motivational processes. PMID- 23106735 TI - Influence of bilingualism on memory generalization during infancy. AB - Very few studies have examined the cognitive advantages of bilingualism during the first two years of development, and a majority of the studies examining bilingualism throughout the lifespan have focused on the relationship between multiple languages and cognitive control. Early experience with multiple language systems may influence domain-general processes, such as memory, that may increase a bilingual child's capacity for learning. In the current study, we found that bilingual, but not monolingual, infants were able to generalize across cues at 18 months. This is the first study to show a clear bilingual advantage in memory generalization, with more equal or balanced exposure to each language significantly predicting ability to generalize. PMID- 23106736 TI - Origins of the human pointing gesture: a training study. AB - Despite its importance in the development of children's skills of social cognition and communication, very little is known about the ontogenetic origins of the pointing gesture. We report a training study in which mothers gave children one month of extra daily experience with pointing as compared with a control group who had extra experience with musical activities. One hundred and two infants of 9, 10, or 11 months of age were seen at the beginning, middle, and end of this one-month period and tested for declarative pointing and gaze following. Infants'ability to point with the index finger at the end of the study was not affected by the training but was instead predicted by infants' prior ability to follow the gaze direction of an adult. The frequency with which infants pointed indexically was also affected by infant gaze following ability and, in addition, by maternal pointing frequency in free play, but not by training. In contrast, infants' ability to monitor their partner's gaze when pointing, and the frequency with which they did so, was affected by both training and maternal pointing frequency in free play. These results suggest that prior social cognitive advances, rather than adult socialization of pointing per se, determine the developmental onset of indexical pointing, but socialization processes such as imitation and adult shaping subsequently affect both infants' ability to monitor their interlocutor's gaze while they point and how frequently infants choose to point. PMID- 23106734 TI - The relationship between puberty and social emotion processing. AB - The social brain undergoes developmental change during adolescence, and pubertal hormones are hypothesized to contribute to this development. We used fMRI to explore how pubertal indicators (salivary concentrations of testosterone, oestradiol and DHEA; pubertal stage; menarcheal status) relate to brain activity during a social emotion task. Forty-two females aged 11.1 to 13.7 years underwent fMRI scanning while reading scenarios pertaining either to social emotions, which require the representation of another person's mental states, or to basic emotions, which do not. Pubertal stage and menarcheal status were used to assign girls to early or late puberty groups. Across the entire sample, the contrast between social versus basic emotion resulted in activity within the social brain network, including dorsomedial prefrontal cortex (DMPFC), the posterior superior temporal sulcus, and the anterior temporal cortex (ATC) in both hemispheres. Increased hormone levels (independent of age) were associated with higher left ATC activity during social emotion processing. More advanced age (independent of hormone levels) was associated with lower DMPFC activity during social emotion processing. Our results suggest functionally dissociable effects of pubertal hormones and age on the adolescent social brain. PMID- 23106737 TI - Neural correlates of perceptual narrowing in cross-species face-voice matching. AB - Integrating the multisensory features of talking faces is critical to learning and extracting coherent meaning from social signals. While we know much about the development of these capacities at the behavioral level, we know very little about the underlying neural processes. One prominent behavioral milestone of these capacities is the perceptual narrowing of face-voice matching, whereby young infants match faces and voices across species, but older infants do not. In the present study, we provide neurophysiological evidence for developmental decline in cross-species face-voice matching. We measured event-related brain potentials (ERPs) while 4- and 8-month-old infants watched and listened to congruent and incongruent audio-visual presentations of monkey vocalizations and humans mimicking monkey vocalizations. The ERP results indicated that younger infants distinguished between the congruent and the incongruent faces and voices regardless of species, whereas in older infants, the sensitivity to multisensory congruency was limited to the human face and voice. Furthermore, with development, visual and frontal brain processes and their functional connectivity became more sensitive to the congruence of human faces and voices relative to monkey faces and voices. Our data show the neural correlates of perceptual narrowing in face-voice matching and support the notion that postnatal experience with species identity is associated with neural changes in multisensory processing (Lewkowicz & Ghazanfar, 2009). PMID- 23106738 TI - Chimpanzees and bonobos exhibit divergent spatial memory development. AB - Spatial cognition and memory are critical cognitive skills underlying foraging behaviors for all primates. While the emergence of these skills has been the focus of much research on human children, little is known about ontogenetic patterns shaping spatial cognition in other species. Comparative developmental studies of nonhuman apes can illuminate which aspects of human spatial development are shared with other primates, versus which aspects are unique to our lineage. Here we present three studies examining spatial memory development in our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (P. paniscus). We first compared memory in a naturalistic foraging task where apes had to recall the location of resources hidden in a large outdoor enclosure with a variety of landmarks (Studies 1 and 2). We then compared older apes using a matched memory choice paradigm (Study 3). We found that chimpanzees exhibited more accurate spatial memory than bonobos across contexts, supporting predictions from these species' different feeding ecologies. Furthermore, chimpanzees - but not bonobos - showed developmental improvements in spatial memory, indicating that bonobos exhibit cognitive paedomorphism (delays in developmental timing) in their spatial abilities relative to chimpanzees. Together, these results indicate that the development of spatial memory may differ even between closely related species. Moreover, changes in the spatial domain can emerge during nonhuman ape ontogeny, much like some changes seen in human children. PMID- 23106739 TI - Visual size perception and haptic calibration during development. AB - It is still unclear how the visual system perceives accurately the size of objects at different distances. One suggestion, dating back to Berkeley's famous essay, is that vision is calibrated by touch. If so, we may expect different mechanisms involved for near, reachable distances and far, unreachable distances. To study how the haptic system calibrates vision we measured size constancy in children (from 6 to 16 years of age) and adults, at various distances. At all ages, accuracy of the visual size perception changes with distance, and is almost veridical inside the haptic workspace, in agreement with the idea that the haptic system acts to calibrate visual size perception. Outside this space, systematic errors occurred, which varied with age. Adults tended to overestimate visual size of distant objects (over-compensation for distance), while children younger than 14 underestimated their size (under-compensation). At 16 years of age there seemed to be a transition point, with veridical perception of distant objects. When young subjects were allowed to touch the object inside the haptic workspace, the visual biases disappeared, while older subjects showed multisensory integration. All results are consistent with the idea that the haptic system can be used to calibrate visual size perception during development, more effectively within than outside the haptic workspace, and that the calibration mechanisms are different in children than in adults. PMID- 23106740 TI - Learning without representational change: development of numerical estimation in individuals with Williams syndrome. AB - Experience engenders learning, but not all learning involves representational change. In this paper, we provide a dramatic case study of the distinction between learning and representational change. Specifically, we examined long- and short-term changes in representations of numeric magnitudes by asking individuals with Williams syndrome (WS) and typically developing (TD) children to estimate the position of numbers on a number line. As with TD children, accuracy of WS children's numerical estimates improved with age (Experiment 1) and feedback (Experiment 2). Both long- and short-term changes in estimates of WS individuals, however, followed an atypical developmental trajectory: as TD children gained in age and experience, increases in accuracy were accompanied by a logarithmic-to linear shift in estimates of numerical magnitudes, whereas in WS individuals, accuracy increased but logarithmic estimation patterns persisted well into adulthood and after extensive training. These findings suggest that development of numerical estimation in WS is both arrested and atypical. PMID- 23106742 TI - Phonotactic acquisition in healthy preterm infants. AB - Previous work has shown that preterm infants are at higher risk for cognitive/language delays than full-term infants. Recent studies, focusing on prosody (i.e. rhythm, intonation), have suggested that prosodic perception development in preterms is indexed by maturational rather than postnatal/listening age. However, because prosody is heard in-utero, and preterms thus lose significant amounts of prenatal prosodic experience, both their maturation level and their prosodic experience (listening age) are shorter than that of full-terms for the same postnatal age. This confound does not apply to the acquisition of phonetics/phonotactics (i.e. identity and order of consonants/vowels), given that consonant differences in particular are only perceived after birth, which could lead to a different developmental pattern. Accordingly, we explore the possibility that consonant-based phonotactic perception develops according to listening age. Healthy French-learning full-term and preterm infants were tested on the perception of consonant sequences in a behavioral paradigm. The pattern of development for full-term infants revealed that 7-month-olds look equally at labial-coronal (i.e. /pat/) compared to coronal labial sequences (i.e. /tap/), but that 10-month-olds prefer the labial-coronal sequences that are more frequent in the French lexicon. Preterm 10-month-olds (having 10 months of phonetic listening experience but 7 months of maturational age) behaved as full-term 10-month-olds. These results establish that preterm developmental timing for consonant-based phonotactic acquisition is based on listening age (experience with input). This questions the interpretation of previous results on prosodic acquisition in terms of maturational constraints, and raises the possibility that different constraints apply to the acquisition of different phonological subcomponents. PMID- 23106741 TI - Doing gesture promotes learning a mental transformation task better than seeing gesture. AB - Performing action has been found to have a greater impact on learning than observing action. Here we ask whether a particular type of action - the gestures that accompany talk - affect learning in a comparable way. We gave 158 6-year-old children instruction in a mental transformation task. Half the children were asked to produce a Move gesture relevant to the task; half were asked to produce a Point gesture. The children also observed the experimenter producing either a Move or Point gesture. Children who produced a Move gesture improved more than children who observed the Move gesture. Neither producing nor observing the Point gesture facilitated learning. Doing gesture promotes learning better than seeing gesture, as long as the gesture conveys information that could help solve the task. PMID- 23106743 TI - Exploring the potential energy surface for the interaction of sterically hindered trichloro(diethylenetriamine)gold(III) complexes with water. AB - The reactivity of gold(III) complexes is analyzed for a series of derivatives of 3-azapentane-1,5-diamine (dien) tridentate ligand that can contain some bulky substituents. Two distinct series of compounds are considered where the dien ligand is either deprotonated (R-dien-H) or protonated (R-dien) at the secondary amine where R = ethyl (Et) or methyl (Me). While the deprotonated species will occur in neutral and basic solutions, the protonated forms are likely to be present in acidic environment. Hydration reaction (water/Cl(-) ligand exchange) of 14 complexes is modeled with quantum chemical calculations. Our calculations predict that the reactivity decreases with the increase in the molecular volume of the substituted dien ligand, and the calculated rate constants are in satisfactory agreement with experimental results. In addition, quantitative structure/reactivity models are proposed where the angle between the entering and leaving groups in the transition state structure (the reactivity angle) is used as a molecular descriptor. These models explain the trend of the relative reactivity of these complexes and can be used to design new ligands for gold(III) complexes aiming to adjust the reactivity of the complex. PMID- 23106744 TI - Novel approaches to epilepsy treatment. AB - The aim of epilepsy treatment is to achieve complete seizure freedom. Nonetheless, numerous side effects and seizure resistance to antiepileptic drugs (AEDs) affecting about 30-40% of all patients are main unmet needs in today's epileptology. For this reason, novel approaches to treat epilepsy are highly needed. Herein, we highlight recent progress in stem-cell-based and gene transfer based therapies in epilepsy according to findings in animal models and address their potential clinical application. Multiple therapeutic targets are described, including neuropeptides, neurotrophic factors, and inhibitory neurotransmitters. We also address new molecular-genetic approaches utilizing optogenetic technology. The therapeutic strategies presented herein are predominately aimed toward treatment of partial/focal epilepsies, but could also be envisaged for targeting key seizure propagation areas in the brain. These novel strategies provide proof-of-principle for developing effective treatments for refractory epilepsy in the foreseeable future. PMID- 23106746 TI - Moral status: what a bad idea! AB - BACKGROUND: Advocates of people with disabilities sometimes have advanced their cause within a conceptual frame of human exceptionalism, shaped specifically by one or another proposal about a moral property or capacity with which human individuals alone are endowed. METHODS: This essay is a philosophical reflection about the notion of moral status. RESULTS: Arguments presented here show, however, that framing the pursuit of protection for people with disabilities in terms of humanity's exceptional moral status is more hazardous than helpful. CONCLUSIONS: Appeals to moral status do not settle debates about whether there are obligations to provide protection and support for individuals with disabilities because the idea of moral status is as contentious as the disagreements it is invoked to resolve. PMID- 23106747 TI - The voting rights of adults with intellectual disabilities: reflections on the arguments, and situation in Kenya and England and Wales. AB - Article 29 of the Convention on the Rights of Persons with Disabilities guarantees equality of political rights, including the right to vote and stand for election. The affirmation of these rights, first guaranteed by the Universal Declaration of Human Rights, raises an important question given the long-standing association between political rights and beliefs concerning the abilities of citizens to reason and act independently: how and to what degree can people identified as having intellectual disabilities participate in a defining act of the democratic process? Focused specifically on the right to vote, this paper addresses the question by (1) introducing the debates that have surrounded the voting rights of this population; and (2) reporting on recent attempts in Kenya, and in England and Wales, to promote voting by people with intellectual disabilities. It concludes by considering the effectiveness of the different approaches these countries have adopted. PMID- 23106748 TI - The ITINERIS scale on the rights of persons with intellectual disabilities: development, pilot studies and application at a country level in South America. AB - BACKGROUND: The ITINERIS scale on the rights of persons with intellectual disabilities (ISRPID) was developed to measure the extent to which people with intellectual disabilities (ID) exercise their rights. METHOD: The ISRPID was produced through a virtual Delphi group with 37 professionals and relatives of people with ID from four continents and was refined in small pilot groups with persons with ID in Argentina. It has 30 items and can be self-administered or completed by a proxy. Versions in three languages (English, Spanish and Portuguese) are available. Following its development, the ISRPID was applied in Chile to 705 persons with ID and to a control group of 524 college students without ID. RESULTS: Statistical analysis showed that family relationships, community participation, living arrangements and level of disability affect the experience of rights among people with ID. Importantly, with structured supports, people with ID appear able to exercise their rights to a level comparable to that of their peers without ID. CONCLUSIONS: With further development, the ISRPID may be an appropriate scale to monitor the exercise of rights contained in the United Nations Convention on the Rights of Persons with Disabilities at an individual or group level. PMID- 23106749 TI - Mind the gap: the human rights of children with intellectual disabilities in Egypt. AB - BACKGROUND: Children with intellectual disabilities (IDs) have the same human value as other children and are entitled to their basic human rights. And yet, in developing countries they face many barriers to accessing these rights. This study focuses on children with IDs in Egypt. METHOD: A new measure, the Human Rights of children with Intellectual Disabilities-Egypt, was developed to assess (1) awareness of the human rights of children with IDs and (2) perceptions of the extent to which children with IDs currently have access to these rights. RESULTS: The questionnaire was completed by 200 respondents across Egypt. Of great concern, there was a widespread lack of awareness of the rights of children with IDs. Moreover, respondents reported that they believed that this group of children had limited access to health care and treatment, including mental health care, social care, education and rehabilitation. CONCLUSION: While the sample size was small, the findings identify the urgency in Egypt of (1) raising public awareness of the human rights of children with IDs, and (2) implementing and sustaining changes to improve access to these rights. The new government is responsible for ensuring that its apparent commitment to human rights is now translated into effective action to make tangible improvements in the lives of children with IDs and their families. PMID- 23106750 TI - Experiencing rights within positive, person-centred support networks of people with intellectual disability in Australia. AB - BACKGROUND: This research describes issues related to human rights as they arose within the everyday lives of people in nine personal support networks that included adult Australians with an intellectual disability (ID). METHOD: The research was part of a wider 3-year ethnographic study of nine personal support networks. A major criterion for recruitment was that people in these networks were committed to actively developing the positive, meaningful future of an adult family member with an ID. Data were collected from November 2007 to March 2011 via interviews, participant observations and analysed within the framework of situational analysis. Findings were checked with network members. RESULTS: The issue of rights was challenging to network members. Subtle rights violations could have a major impact on an individual with a disability. Network members worked to protect the rights of people with ID by building and maintaining an empathic and respectful support network, developing the person's self-confidence and autonomy and ensuring that the person with an ID was an active member of the personal support network. CONCLUSION: The maintenance of rights within a supportive environment remains a difficult task. It can be facilitated by a deep knowledge and respect for the person being supported, the promotion of his or her active participation in the planning and provision of support, and an experimental and reflective approach. PMID- 23106751 TI - Protection, participation and protection through participation: young people with intellectual disabilities and decision making in the family context. AB - BACKGROUND: Research suggests that persons with intellectual disabilities (ID) are expected to be more compliant than persons without disabilities and that expectations for compliance begin in childhood. No study, however, seems yet to have included a primary focus on the participatory rights, or rights to express opinions, desires and preferences and to be heard and taken seriously in decision making among young people with ID who are not yet considered legally adult. The purpose of the two current studies was to explore how the right to participation is negotiated for young people with ID in a family context and to determine family members' recommendations for strategies to facilitate the participation of young people with ID. METHOD: In the first study, four young people with ID, their mothers and two siblings from four families took part in semi-structured interviews about decision making in the family context. In the second study, a mother and daughter from the first study discussed and developed strategies to promote participation for young people with ID. RESULTS: In the first study, all participants communicated that young people with ID follow an age-typical yet restricted pattern of participation in decisions about their lives. Young people's participation was consistently framed by familial norms and values as well as their families' desire to protect them. In the second study, both participants suggested communication about the outcomes of real or imagined decisions would help young family members rehearse decision-making strategies that would facilitate their autonomy while remaining within the bounds of familial norms, values and perceptions of safety. CONCLUSIONS: Although young people with ID may make fewer independent decisions about their lives than typically developing peers, support in decision making can enable both increased protection and independence. PMID- 23106752 TI - Health advocacy: a vital step in attaining human rights for adults with intellectual disability. AB - BACKGROUND: People with intellectual disability (ID) experience health inequity compared with the general population, a key contributing factor being disparities in social determinants of health. The enactment of the United Nations Convention on the Rights of Persons with Disabilities (CRPD) provides a platform for the progression and promotion of health and other interconnected rights to address barriers to the highest attainable standard of health for this populace. Rights can be brought to life through advocacy efforts. This paper explores the meaning, perceptions and experiences of advocacy by family members and paid support workers of adults with ID and locates the findings within a health and human rights discourse. METHODS: As part of a larger randomised controlled trial, 113 parents and 84 support workers of adults with ID completed a telephone interview that included open-ended questions about their understanding and experiences of advocacy. Thematic analysis was used to identify relevant themes. RESULTS: Five key themes were identified. The first underscored how advocacy to 'speak up' for the person with ID is integral to both parent and support worker roles. The second and third themes considered the contexts for advocacy efforts. Access to quality health care was a core concern, along with advocacy across other areas and sectors to address the person's wider psychosocial needs. The remaining themes highlighted the many dimensions to advocacy, including differences between parent and support worker views, with parental advocacy being an expression of 'caring' and support workers motivated by a 'duty of care' to protect the individual's 'rights'. CONCLUSION: Parent and support worker advocacy provides one means to address the social determinants of health and fulfilment of health rights of and for people with ID. Policy and practice in the context of governmental obligation under the CRPD should support advocacy and make health rights the reality not rhetoric for this group of men and women. PMID- 23106753 TI - Service development for intellectual disability mental health: a human rights approach. AB - BACKGROUND: People with intellectual disability (ID) experience higher rates of major mental disorders than their non-ID peers, but in many countries have difficulty accessing appropriate mental health services. The aim of this paper is to review the current state of mental health services for people with ID using Australia as a case example, and critically appraise whether such services currently meet the standards set by the Convention on the Rights of Persons with Disabilities. METHODS: The literature regarding the current state of mental health services for people with ID was reviewed, with a particular focus on Australia. RESULTS: The review highlighted a number of issues to be addressed to meet the mental health needs of people with ID to ensure that their human rights are upheld like those of all other citizens. Many of the barriers to service provision encountered in Australia are likely also to be relevant to other nations, including the culture of division between disability and mental health services, the inadequate training of both disability and mental health workers in ID mental health, and the lack of relevant epidemiological data. None of these barriers are insurmountable. CONCLUSIONS: Recommendations are made for adopting a human rights-based approach towards the development and provision of mental health services for people with ID. These include improved policy with measurable outcomes, improved service access via clear referral pathways and the sharing of resources across disability and mental health services, and improved service delivery through training and education initiatives for both the mental health and disability workforce. PMID- 23106754 TI - Health self-advocacy training for persons with intellectual disabilities. AB - BACKGROUND: People with intellectual disabilities (ID) have unequal access to health care. While systemic efforts are addressing health inequalities, there remains a need to demonstrate that persons with ID can increase their health self advocacy skills. METHOD: A randomised control design with up to 6-month follow-up was used to evaluate the 3Rs (Rights, Respect and Responsibility) health self advocacy training program for persons with ID (n = 31). Training involved teaching participants to recognise and redress health rights violations in the context of respect and responsibility. Training materials included PowerPoint slides and interactive video scenarios illustrating health rights, respect and responsibility problem and non-problems. Two-hour training sessions were conducted twice a week in a group format where participants played a game and answered questions. RESULTS: The health rights training group made significantly more correct responses on post training and follow-up tests than the control group. Training effects generalised to untrained scenarios and in situ health interviews. CONCLUSIONS: The results of this study suggest that persons with ID can learn complex skills related to health self-advocacy. More research is needed to improve in situ generalisation. PMID- 23106755 TI - The human rights context for ethical requirements for involving people with intellectual disability in medical research. AB - BACKGROUND: The history of ethical guidelines addresses protection of human rights in the face of violations. Examples of such violations in research involving people with intellectual disabilities (ID) abound. We explore this history in an effort to understand the apparently stringent criteria for the inclusion of people with ID in research, and differences between medical and other research within a single jurisdiction. METHOD: The history of the Helsinki Declaration and informed consent within medical research, and high-profile examples of ethical misconduct involving people with ID and other groups are reviewed. The UN Convention on the Rights of Persons with Disabilities is then examined for its research implications. This background is used to examine a current anomaly within an Australian context for the inclusion of people with ID without decisional capacity in medical versus other types of research. RESULTS: Ethical guidelines have often failed to protect the human rights of people with ID and other vulnerable groups. Contrasting requirements within an Australian jurisdiction for medical and other research would seem to have originated in early deference to medical authority for making decisions on behalf of patients. CONCLUSIONS: Stringent ethical requirements are likely to continue to challenge researchers in ID. A human rights perspective provides a framework for engaging both researchers and vulnerable participant groups. PMID- 23106756 TI - Preparation of albumin from human plasma by heat denaturation method in plasma bag. AB - AIM: In many countries, there is surplus plasma which is thrown out. Due to the high cost of albumin as a pharmaceutical product, it is not widely available for all patients. Therefore, we considered direct preparation of albumin in the plasma bag. BACKGROUND: Human plasma has many unique features compared with prepared pharmaceutical products because of its human origin. In countries which do not have a plasma fractionation industry, shortages for plasma products are commonplace. METHODS: Albumin stabiliser was added to the plasma in the bag to stabilised albumin molecule and make it resistant to heat. When the plasma bag was heated, other plasma proteins are irreversibly precipitated and can be separated by centrifugation. Finally, albumin is filtered and pasteurized in plasma bag. RESULTS: The purity of prepared albumin is >99% and the yield is 21 g per liter of plasma. Polymer content of pasteurized albumin measuring with High Performance Liquid Chromatography (HPLC) was less than 1%. CONCLUSIONS: Since albumin preparation in plasma bag is a simple and cheap technology, it has the potential for use in the production of a safe plasma derived product, although suitability for human use would require appropriate clinical assessment for safety. Using this method, albumin could be prepared from all types of plasma. This method is suggested as a possible method of albumin production for all countries which do not have a plasma fractionation industry and even for the countries with low plasma supplies. PMID- 23106757 TI - Transanal minimally invasive surgery: an initial experience. AB - BACKGROUND: Transanal minimally invasive surgery (TAMIS) is a novel approach used for the resection of rectal lesions. The purpose of this study was to review our initial experience with TAMIS. METHODS: Between March 2012 and May 2012, we collected clinical data on patients who underwent the TAMIS procedure. This included patient demographics, tumour characteristics, operative technique, histological results and post-operative outcomes. RESULTS: Three patients successfully underwent TAMIS resection of rectal lesions. All tumours were tubulovillous adenomas with high-grade dysplasia, with one also having a small focus of adenocarcinoma. Clear margins were achieved in all cases. One case was complicated by a post-operative bleed, requiring a return to theatre. CONCLUSIONS: TAMIS is a feasible and cost-effective alternative to transanal endoscopic microsurgery for resection of rectal lesions. It may have a shorter learning curve, especially for laparoscopic surgeons already proficient in single port procedures. PMID- 23106758 TI - Characteristics of lactic acid bacteria isolates and their inoculating effects on the silage fermentation at high temperature. AB - Thermotolerant strains of lactic acid bacteria (LAB) were screened for their suitability for silage making at high temperatures. Four selected strains were identified by 16S rRNA sequencing analyses and added to unwilted and wilted Italian ryegrass for ensiling at 45 degrees C. All four strains (HT1, HT2, HT3 and HT4) grew at 50 degrees C and pH 4.0. Strains HT1 and HT2 were identified as Lactobacillus rhamnosus; HT3 and HT4 were identified as Lact. fermentum. Strains HT1 and HT2 were the most effective at improving the fermentation quality of Italian ryegrass silage, irrespective of wilting, as indicated by lower pH values, less NH(3) -N, and more lactic acid. In contrast, strains HT3, HT4 and a commercial inoculant consisting of Lact. plantarum and Pediococcus acidilactici conferred no or reduced benefits. Wilting alone did not improve the fermentation quality of Italian ryegrass at 45 degrees C. Inoculating with thermotolerant Lact. rhamnosus HT1 and HT2 could improve the fermentation quality of silage at high temperatures. Lactobacillus rhamnosus HT1 and HT2 can be used as inoculants for silage making in the tropics and subtropics and could play an important role in developing silage production in such regions. SIGNIFICANCE AND IMPACT OF THE STUDY: Grasses are often difficult to ensile in the tropics and subtropics because of the high temperatures there. To solve this problem, we screened for thermotolerant lactic acid bacteria and obtained two valuable strains of Lactobacillus rhamnosus, HT1 and HT2, which proved to be beneficial to silage fermentation at high temperatures. Lactobacillus rhamnosus HT1 and HT2 can be used as inoculants for silage making in the tropics and subtropics, and will play an important role in developing silage production in such regions. PMID- 23106759 TI - Promoting healthy weight with "stability skills first": a randomized trial. AB - OBJECTIVE: Although behavioral weight-loss interventions produce short-term weight loss, long-term maintenance remains elusive. This randomized trial examined whether learning a novel set of "stability skills" before losing weight improved long-term weight management. Stability skills were designed to optimize individuals' current satisfaction with lifestyle and self-regulatory habits while requiring the minimum effort and attention necessary. METHOD: Overweight/obese women (N = 267) were randomly assigned to one of two 6-month interventions and assessed at baseline and at 6, 12, and 18 months. Maintenance First women participated first in an 8-week stability skills maintenance module and then in a standard 20-week behavioral weight-loss program. Weight Loss First women participated first in a standard 20-week behavioral weight-loss program and then in a standard 8-week problem-solving skills maintenance module. There was no intervention staff contact during the 12-month follow-up period (6-18 months). RESULTS: As designed, Maintenance First participants lost the same percentage of initial weight during the 6-month intervention period as Weight Loss First participants (M = -8.6%, SD = 5.7, vs. M = -9.1%, SD = 6.9; t = -0.6, p = .52). However, Maintenance First participants regained significantly less weight during the 12-month follow-up period (6-18 months) than Weight Loss First participants (M = 3.2 lb, SD = 10.4, vs. M = 7.3 lb, SD = 9.9 [M = 1.4 kg, SD = 4.7, vs. M = 3.3 kg, SD = 4.5]; t = 3.3, p = .001, d = 0.4). CONCLUSION: Learning stability skills before losing weight was successful in helping women to maintain weight loss without intervention staff contact during follow-up. These results can inform the study design of future innovative interventions. PMID- 23106760 TI - Process predictors of the outcome of group drug counseling. AB - OBJECTIVE: This study examined the relation of process variables to the outcome of group drug counseling, a commonly used community treatment, for cocaine dependence. METHOD: Videotaped group drug counseling sessions from 440 adult patients (23% female, 41% minority) were rated for member alliance, group cohesion, participation, self-disclosure, as well as positive and non-positive feedback and advice during the 6-month treatment of cocaine dependence. Average, session-level, and slopes of process scores were evaluated. Primary outcomes were monthly cocaine use (days using out of 30), next session cocaine use, and duration of sustained abstinence from cocaine. Secondary outcomes were endorsement of 12-step philosophy and beliefs about substance abuse. RESULTS: More positive alliances (with counselor) were associated with reductions in days using cocaine per month and next-session cocaine use and increases in endorsement of 12-step philosophy. Patient self-disclosure about the past and degree of participation in the group were generally not predictive of group drug counseling outcomes. More advice from counselor and other group members were consistently associated with poorer outcomes in all categories. Individual differences in changes in process variables over time (linear slopes) were generally not predictive of treatment outcomes. CONCLUSIONS: Some group behaviors widely believed to be associated with outcome, such as self-disclosure and participation, were not generally predictive of outcomes of group drug counseling, but alliance with the group counselor was positively associated, and advice giving was negatively associated, with the outcome of treatments for cocaine dependence. PMID- 23106761 TI - Manualized therapy for PTSD: flexing the structure of cognitive processing therapy. AB - OBJECTIVE: This study tested a modified cognitive processing therapy (MCPT) intervention designed as a more flexible administration of the protocol. Number of sessions was determined by client progress toward a priori defined end-state criteria, "stressor sessions" were inserted when necessary, and therapy was conducted by novice CPT clinicians. METHOD: A randomized, controlled, repeated measures, semicrossover design was utilized (a) to test the relative efficacy of the MCPT intervention compared with a symptom-monitoring delayed treatment (SMDT) condition and (b) to assess within-group variation in change with a sample of 100 male and female interpersonal trauma survivors with posttraumatic stress disorder (PTSD). RESULTS: Hierarchical linear modeling analyses revealed that MCPT evidenced greater improvement on all primary (PTSD and depression) and secondary (guilt, quality of life, general mental health, social functioning, and health perceptions) outcomes compared with SMDT. After the conclusion of SMDT, participants crossed over to MCPT, resulting in a combined MCPT sample (n = 69). Of the 50 participants who completed MCPT, 58% reached end-state criteria prior to the 12th session, 8% at Session 12, and 34% between Sessions 12 and 18. Maintenance of treatment gains was found at the 3-month follow-up, with only 2 of the treated sample meeting criteria for PTSD. Use of stressor sessions did not result in poorer treatment outcomes. CONCLUSIONS: Findings suggest that individuals respond at a variable rate to CPT, with significant benefit from additional therapy when indicated and excellent maintenance of gains. Insertion of stressor sessions did not alter the efficacy of the therapy. PMID- 23106762 TI - A case of recalcitrant epidermolysis bullosa acquisita responsive to rituximab therapy. AB - Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disorder that occurs infrequently in children. Although typically associated with a good prognosis in children, there are rare cases that are refractory to treatment with conventional immunosuppressive therapy. Rituximab, an anti-CD20 monoclonal antibody, has been reported to be effective in the adult form of EBA. We report a case of a child with severe and recalcitrant EBA exhibiting a sustained response to treatment with rituximab. PMID- 23106763 TI - Graphene transforms wide band gap ZnS to a visible light photocatalyst. The new role of graphene as a macromolecular photosensitizer. AB - We report the assembly of nanosized ZnS particles on the 2D platform of a graphene oxide (GO) sheet by a facile two-step wet chemistry process, during which the reduced graphene oxide (RGO, also called GR) and the intimate interfacial contact between ZnS nanoparticles and the GR sheet are achieved simultaneously. The ZnS-GR nanocomposites exhibit visible light photoactivity toward aerobic selective oxidation of alcohols and epoxidation of alkenes under ambient conditions. In terms of structure-photoactivity correlation analysis, we for the first time propose a new photocatalytic mechanism where the role of GR in the ZnS-GR nanocomposites acts as an organic dye-like macromolecular "photosensitizer" for ZnS instead of an electron reservoir. This novel photocatalytic mechanism is distinctly different from all previous research on GR semiconductor photocatalysts, for which GR is claimed to behave as an electron reservoir to capture/shuttle the electrons photogenerated from the semiconductor. This new concept of the reaction mechanism in graphene-semiconductor photocatalysts could provide a new train of thought on designing GR-based composite photocatalysts for targeting applications in solar energy conversion, promoting our in-depth thinking on the microscopic charge carrier transfer pathway connected to the interface between the GR and the semiconductor. PMID- 23106764 TI - Bladder neck preservation during minimally invasive radical prostatectomy: a standardised technique using a lateral approach. PMID- 23106765 TI - Comparative analysis of prostate-specific antigen free survival outcomes for patients with low, intermediate and high risk prostate cancer treatment by radical therapy. Results from the Prostate Cancer Results Study Group. PMID- 23106768 TI - Ureteroscopy assisted retrograde nephrostomy: a new technique for percutaneous nephrolithotomy (PCNL). PMID- 23106769 TI - Characterization of rat liver proteins adducted by reactive metabolites of menthofuran. AB - Pulegone is the major constituent of pennyroyal oil, a folkloric abortifacient that is associated with hepatotoxicity and, in severe cases, death. Cytochrome P450-mediated oxidation of pulegone generates menthofuran, which is further oxidized to form electrophilic reactive intermediates, menthofuran epoxide and the ring-opened gamma-ketoenal, both of which can form adducts to hepatocellular proteins. Modification of hepatocellular proteins by the electrophilic reactive intermediates of menthofuran has been implicated in hepatotoxicity caused by pennyroyal oil. Herein, we describe the identification of several proteins that are the likely targets of menthofuran-derived reactive metabolites. These proteins were isolated from the livers of rats treated with a hepatotoxic dose of menthofuran by two-dimensional gel electrophoresis (2D-gel) separation and detected by Western blot analysis using an antiserum developed to detect protein adducts resulting from menthofuran bioactivation. The antibody-reacting proteins were excised from the 2D-gel and subjected to tryptic digestion for analysis of peptide fragments by LC-MS/MS. Although 10 spots were detected by Western blot analysis, only 4 were amenable to characterization by LC-MS/MS: serum albumin, mitochondrial aldehyde dehydrogenase (ALDH2), cytoplasmic malate dehydrogenase (MDH1), and mitochondrial ATP synthase subunit d. No direct adduct was detected, and, therefore, we complemented our analysis with enzyme activity determination. ALDH2 activity decreased by 88%, and ATP synthase complex V activity decreased by 34%, with no activity changes to MDH1. Although the relationship between these reactive metabolite adducted proteins and hepatotoxicity is not clear, these targeted enzymes are known to play critical roles in maintaining cellular homeostasis. PMID- 23106771 TI - Weight of the resected specimen after transurethral resection as a new predictive variable for recurrence of non-muscle-invasive bladder tumour. AB - OBJECTIVE: To evaluate the role of the weight of the resected specimen after transurethral resection as a predictive factor for recurrence and progression of non-muscle-invasive bladder tumour (NMIBT). PATIENTS AND METHODS: The weight of the resected tumour was measured consecutively in 144 subjects who underwent transurethral resection of bladder tumours at our institution. The median (interquartile range [IQR]) follow-up was 58 (61.3) months. The probability of recurrence and progression at 1 and 5 years were calculated using the currently accepted variables. Thresholds for the specimen weight were determined according to percentiles and receiver-operating characteristic curves. RESULTS: The median (IQR) weight of the specimen was 6 (16) g. Multivariate analysis showed that the weight of the resected specimen was an independent predictive risk factor for recurrence at a threshold value of 6 g with a hazard ratio of 1.7 (95% confidence interval: 1.048-2.761) P = 0.03. Progression was not associated with the weight of the resected specimen. CONCLUSIONS: The weight of the resected specimen is a new variable for predicting the risk of recurrence of NMIBT. Tumours weighing >6 g, according to the present data, have a 1.7-fold higher likelihood of recurrence than those tumours that weigh less. PMID- 23106770 TI - Perceived burden and neuropsychiatric morbidities in adults with 22q11.2 deletion syndrome. AB - BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a common genetic subtype of intellectual disability (ID) remarkable for its constellation of congenital, developmental and later-onset features. Survival to adulthood is now the norm, and serious psychiatric illness is common in adults. However, little is known about the experiences and perceived needs of individuals with 22q11.2DS and their caregivers at time of transition from paediatric to adult models of care and beyond. METHOD: We administered a mail survey to 84 caregivers of adults with 22q11.2DS and 34 adult patients themselves, inquiring about medical and social services, perceived burden and major challenges in adulthood in 22q11.2DS. Standard quantitative and qualitative methods were used to analyse the responses. RESULTS: Fifty-three (63.1%) caregivers and 20 (58.8%) adults with 22q11.2DS completed the survey. Perceived burden was high, with psychiatric illness and/or behavioural issues considered the most challenging aspects of adulthood in 22q11.2DS by the majority of caregivers (70.0%) and many patients themselves (42.9%). Irrespective of the extent of ID and the presence or absence of other major features, caregivers expressed dissatisfaction with medical and social services for adults, including at time of transition from paediatric care. CONCLUSIONS: To our knowledge, this is the first study to examine the subjective experiences of adults with 22q11.2DS and their caregivers and to identify their perceived needs for services. Better awareness of 22q11.2DS and its later-onset manifestations, early diagnosis and treatment of psychiatric illness, additional support at time of transition and dedicated clinics for adults with 22q11.2DS may help to improve patient outcomes and reduce caregiver burden. PMID- 23106772 TI - The use of custom-milled zirconia teeth to address tooth abrasion in complete dentures: a clinical report. AB - A patient exhibited severe abrasion of resin posterior denture teeth including perforation of the denture base. New dentures were provided to explore the application of zirconia teeth for complete dentures. [Correction added to online publication 07 November 2012: "Zirconium" corrected to "Zirconia".] Traditional denture procedures were combined with fixed prosthodontic CAD/CAM procedures to fabricate custom-designed four-tooth posterior segments in hollow crown form to reduce weight and with a retentive form for interlocking to the denture base. The new dentures were successful in reducing wear of the denture teeth over the short term follow-up period. PMID- 23106773 TI - The impact of blood coagulability on atherosclerosis and cardiovascular disease: a rebuttal. PMID- 23106774 TI - Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives and the behavior of o- and p-(hydroxymethyl)benzoates under reductive alkylation conditions. AB - Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives, using lithium in ammonia-tetrahydrofuran in the presence of tert-butyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of o- and p-(hydroxymethyl)benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions. PMID- 23106775 TI - First-principles modeling of biological systems and structure-based drug-design. AB - Molecular modeling techniques play a relevant role in drug design providing detailed information at atomistic level on the structural, dynamical, mechanistic and electronic properties of biological systems involved in diseases' onset, integrating and supporting commonly used experimental approaches. These information are often not accessible to the experimental techniques taken singularly, but are of crucial importance for drug design. Due to the enormous increase of the computer power in the last decades, quantum mechanical (QM) or first-principles-based methods have become often used to address biological issues of pharmaceutical relevance, providing relevant information for drug design. Due to their complexity and their size, biological systems are often investigated by means of a mixed quantum-classical (QM/MM) approach, which treats at an accurate QM level a limited chemically relevant portion of the system and at the molecular mechanics (MM) level the remaining of the biomolecule and its environment. This method provides a good compromise between computational cost and accuracy, allowing to characterize the properties of the biological system and the (free) energy landscape of the process in study with the accuracy of a QM description. In this review, after a brief introduction of QM and QM/MM methods, we will discuss few representative examples, taken from our work, of the application of these methods in the study of metallo-enzymes of pharmaceutical interest, of metal-containing anticancer drugs targeting the DNA as well as of neurodegenerative diseases. The information obtained from these studies may provide the basis for a rationale structure-based drug design of new and more efficient inhibitors or drugs. PMID- 23106776 TI - Efficacy prediction of jamu formulations by PLS modeling. AB - Indonesian herbal medicines made from mixtures of several plants are called "Jamu." The efficacy of a particular Jamu is determined by its ingredients i.e. the composition of the plants. Thus, we modeled the ingredients of Jamu formulas using Partial Least Squares Discriminant Analysis (PLS-DA) in order to predict their efficacy. The plants used in each Jamu medicine served as the predictors, whereas the efficacy of each Jamu provided the responses. Utilizing response predictions obtained from PLS-DA, we predicted the efficacies of Jamu formulations using two methods: maximum response prediction and maximum probability. In predictions of Jamu efficacy, the maximum response prediction method produced a smaller error than that the maximum probability method. Furthermore, utilizing the PLS-DA coefficient matrix, we determined the efficacy for which a plant is most useful, based on its largest coefficients. PMID- 23106777 TI - Molecular determinants of the bacterial resistance to fluoroquinolones: a computational study. AB - Quinolones constitute a large class of antibacterial agents whose action is mediated through the formation of a ternary complex with DNA and either, DNA Gyrase or topoisomerase IV, resulting in the inhibition of DNA replication. In order to get a deeper insight into the features of the complex formation, we carried out docking studies of fifteen diverse quinolones to the cleaved topoisomerase IV-DNA complex. Docking studies were performed using the crystal structures of the cleaved complex with levofloxacin and moxifloxacin (pdb entries 3K9F and 2XKK, respectively) using the GOLD software. Ligands dock in positions similar to those of the crystal structures. Analysis of the results reveals that bound quinolones appear intercalated between the two nucleotides that are involved in the DNA cleavage and exhibit hydrogen bonds with Arg(117) and, the latter mediated though a water molecule. Arg(117) has not been described to be involved in resistance, since it is putatively involved in the enzymatic reaction and its mutation would be lethal for the organism. Mutants of Ser(79) exhibit resistance to quinolones which can be explained by the loss of an important anchoring point. Interestingly, quinolone resistance observed in Asp(83) mutants cannot be explained directly on the basis of the loss of a direct interaction, but could be explained on the basis of its involvement at the entrance of the ligands to their binding pocket since the residue is located at the mouth of the pocket. The results of the present study suggest that the 4-keto and 3-carboxyl groups of the fluoroquinolones bind a Mg(2+) before binding to the cleaved topoisomarase IV-DNA complex and use Asp(83) for entry into the binding pocket. Accordingly, mutations that do not conserve the binding capacity for the quinolone-Mg(2+) complex will prevent the binding of this class of ligands. The results we present here are also compared with the structure of PD0305970 a 2,4 dione active against the Ser(79) and Asp(83) mutants. PMID- 23106778 TI - Post-docking optimization and analysis of protein-ligand interactions of estrogen receptor alpha using AMMOS software. AB - Understanding protein-ligand interactions is a critical step in rational drug design/virtual ligand screening. In this work we applied the AMMOS_ProtLig software for post-docking optimization of estrogen receptor alpha complexes generated after virtual ligand screening protocol. Using MOE software we identified the ligand-receptor interactions in the optimized complexes at different levels of protein flexibility and compared them to the experimentally observed interactions. We analyzed in details the binding sites of three X-ray complexes of the same receptor and identified the key residues for the protein ligand interactions. The complexes were further processed with AMMOS_ProtLig and the interactions in the predicted poses were compared to those observed in the X ray structures. The effect of employing different levels of flexibility was analyzed. The results confirmed the AMMOS_ProtLig applicability as a helpful postdocking optimization tool for virtual ligand screening of estrogen receptors. PMID- 23106779 TI - Computational modeling of environmentally responsive hydrogels (ERH) for drug delivery system. AB - The present work aims at computational analysis of environmentally responsive hydrogels with enormous prospective in the formulation aspect of drug delivery systems. The drug delivery potential of hydrogels to the targets is owing to the specific stimuli responsive nature of the hydrogels. The environmental factors looked upon in the study are changes in pH, alteration of temperature and glucose concentration rise originated in the body as a result of various disease conditions. Polymers, synthetic polypeptides and dendrimers have been used in the present work to study the feasibility of drug delivery. The computational methods have been used to formulate polymer properties, pharmacokinetics and toxicity studies. Diverse interactions approximating electrostatic, hydrophobic and hydrogen bond interactions acquire place during incorporation of drugs within the polymer and dendrimers. The covalent and electrostatic interactions between a drug and the surface of polymer and dendrimer have been analyzed. The docking interaction studies have been performed and the best polymer and dendrimer complex have been selected based on the docking score, binding energy and interaction energy with the drugs. G5 generation of poly amidoamine dendrimers and poly N-Ndiethyl acrylamide (PDEAAM) have been identified as most suitable stimuli-responsive effective drug carriers for anti diabetic drugs and diuretics. Favorable results have been obtained while using poly acrylic acid (PAA) for corticosteroids and polylysine for diabetic drugs. ConA protein along with poly aspartic acid also showed good results. PMID- 23106780 TI - Experimental and computational studies on the inhibition of acetylcholinesterase by curcumin and some of its derivatives. AB - Recent studies have demonstrated several biological activities of curcumin with therapeutic potential against Alzheimer's disease, among them the inhibition of the enzyme acetylcholinesterase (AChE). Aiming at identifying the chemical features relevant for this activity, the inhibition of curcumin and a set of 7 derivatives against AChE of E. electricus was measured. These derivatives presented lower activity than curcumin, allowing for the identification of possible unfavorable enzyme-inhibitor interactions. Our computational approach was to dock the molecules to the active site of AChE, followed by an analysis of hydrogen bonds and close contacts to relevant aromatic amino acid residues. To account for inhibitory activity, we sought to define the common structural features between known acetylcholinesterase inhibitors and the tested derivatives. A pharmacophore model was generated, which consisted of two hydrophobic, one aromatic and one hydrogen bond acceptor features. We conclude that the presence of two aromatic rings and the distance between them, allows curcumin and its derivatives to favorably interact with both the quaternary and peripheral sites of AChE. Hydrogen bonds can be formed with the quaternary and acyl sites, which should further stabilize the complex. The acylation of the hydroxyl groups and the reduction of the conjugated double bonds lowered the inhibitory activity, pointing to the modification of the keto-enol moiety as the best alternative for the design of more potent curcumin derivatives as acetylcholinesterase inhibitors. PMID- 23106781 TI - Acute congestive heart failure due to ruptured mitral chordae tendineae in late pregnancy. AB - A 31-year-old woman complained of dyspnea and orthopnea at 38 weeks of gestation. A grade 3/6 pansystolic murmur was heard, and echocardiography revealed severe mitral regurgitation with a hyperechoic obstacle on the posterior mitral valve leaflet, consistent with a diagnosis of acute heart failure due to a ruptured chordae tendineae or an infectious endocarditis. An emergency cesarean section was performed under general anesthesia. A male infant was born weighing 2928 g with Apgar scores of 7 and 8 at 1 and 5 min, respectively. The patient was managed in the intensive care unit and underwent open-heart surgery for mitral valve repair on postpartum day 3. The two chordal tendineae appeared torn and frail, and a mitral annuloplasty was performed. No finding of infectious endocarditis was observed. Because it is a dramatic and life-threatening clinical situation, proper diagnosis and treatment in the intensive care unit assure a good outcome for both mother and fetus. PMID- 23106782 TI - Expression of aquaporin water channels in equine endometrium is differentially regulated during the oestrous cycle and early pregnancy. AB - The expression of 12 different aquaporin subtypes in equine endometrium was examined at the mRNA and protein level. Endometrial samples were obtained during anoestrus, oestrus, 8, and 14 days after ovulation in non-pregnant mares, and 14 days after ovulation in pregnant mares. Quantitative PCR revealed a time dependent pattern for all aquaporin subtypes examined except for AQP10 and 12. AQP3, 5 and 7 showed highest mRNA abundance 8 days after ovulation, while AQP0 and 2 were most abundant at Day 14 of the cycle in non-pregnant mares. At 14 days of pregnancy, AQP1, 4, 8, 9 and 11 displayed highest expression levels. Western blot analysis confirmed protein expression of AQP0, 2 and 5. Immunohistochemistry localized protein expression to luminal and glandular epithelial and stromal cells. AQP0 staining intensity was highest in samples obtained on Day 14 of the oestrous cycle. AQP2 immunoreactivity seemed to be stronger in samples collected 14 days after ovulation from non-pregnant animals, in particular luminal epithelial staining. Samples collected 8 days after ovulation from cyclic animals were characterized by intense AQP5 staining of glandular epithelium, predominantly in the deeper glands. Progesterone treatment of anoestrous mares did not enhance expression of AQPs, indicating that factors other than progesterone are required for the up-regulation of certain AQP subtypes during dioestrus. In conclusion, it seems that an equine-specific collaboration of aquaporin subtypes contributes to changes in endometrial fluid content occurring throughout the oestrous cycle and contributes to endometrial receptivity during early pregnancy in the mare. PMID- 23106783 TI - Behavioral and monoamine changes following severe vitamin C deficiency. AB - Severe vitamin C deficiency (ascorbic acid; AA) was induced in gulo-/- mice incapable of synthesizing their own AA. A number of behavioral measures were studied before and during the deprivation period, including a scorbutic period, during which weight loss was observed in the mice. Mice were then resuscitated with AA supplements. During the scorbutic period, gulo-/- mice showed decreased voluntary locomotor activity, diminished physical strength, and increased preference for a highly palatable sucrose reward. These behaviors all returned to control levels following resuscitation. Altered trial times in subordinate mice in the tube test for social dominance in the AA-deprived mice persisted following resuscitation and may signify a depressive-like behavior in these mice. Biochemical analyses were undertaken following a second deprivation period. AA deficiency was accompanied by decreased blood glucose levels, oxidative damage to lipids and proteins in the cortex, and decreases in dopamine and serotonin metabolites in both the cortex and striatum. Given the reasonably high proportions of the population that do not consume sufficient AA in the diet, these data have important implications for physical and psychological function in the general population. PMID- 23106784 TI - Critical determinants of the epilepsy treatment gap: a cross-national analysis in resource-limited settings. AB - PURPOSE: Epilepsy is one of the most common serious neurologic disorders worldwide. Our objective was to determine which economic, health care, neurology, and epilepsy-specific resources were associated with untreated epilepsy in resource-constrained settings. METHODS: A systematic review of the literature identified community-based studies in resource-constrained settings that calculated the epilepsy treatment gap, the proportion with untreated epilepsy, from prevalent active epilepsy cases. Economic, health care, neurology, and epilepsy-specific resources were taken from existing datasets. Poisson regression models with jackknifed standard errors were used to create bivariate and multivariate models comparing the association between treatment status and economic and health resource indicators. Relative risks were reported. KEY FINDINGS: Forty-seven studies of 8,285 individuals from 24 countries met inclusion criteria. Bivariate analysis demonstrated that individuals residing in rural locations had significantly higher risks of untreated epilepsy (relative risk [RR] 1.63; 95% confidence interval [CI] 1.26-2.11). Significantly lower risks of untreated epilepsy were observed for higher physician density (RR 0.65, 95% CI 0.55-0.78), presence of a lay (RR 0.74, 95% CI 0.60-0.91) or professional association for epilepsy (RR 0.73, 95% CI 0.59-0.91), or postgraduate neurology training program (RR 0.67, 95% CI 0.55-0.82). In multivariate models, higher physician density maintained significant effects (RR 0.67; 95% CI 0.52-0.88). SIGNIFICANCE: Even among resource-limited regions, people with epilepsy in countries with fewer economic, health care, neurology, and epilepsy-specific resources are more likely to have untreated epilepsy. Community-based epilepsy care programs have improved access to treatment, but in order to decrease the epilepsy-treatment gap, poverty and inequalities of health care, neurology, and epilepsy resources must be dealt with at the local, national, and global levels. PMID- 23106785 TI - Delayed graft function is not associated with an increased incidence of renal allograft rejection. AB - Delayed graft function (DGF) is considered as a risk factor for renal allograft rejection, but this association might be confounded by diagnostic biases (e.g., higher biopsy frequency in patients with DGF, inclusion of clinically diagnosed rejection episodes, and limited details on the rejection phenotype). This retrospective study including 329 deceased donor transplantations aimed to clarify a causal relationship between DGF and rejection. DGF occurred in 93/329 recipients (28%), whereas immediate graft function (IGF) in 236/329 recipients (72%). The percentage of patients with >=1 allograft biopsy within the first year post-transplant was similar between the DGF and IGF group (96% vs. 94%; p=0.60). The cumulative one-yr incidence of biopsy-proven clinical (35% vs. 34%; p=0.62) and combined (sub)clinical rejection (58% vs. 60%; p=0.79) was not different between the two groups. Furthermore, there were no differences regarding rejection phenotypes/severities and time frame of occurrence. By multivariable Cox regression analysis, donor-specific HLA antibodies, younger recipient age, and immunosuppressive regimens were independent predictors for clinical rejection, while DGF was not. These results in an intermediate sized, but thoroughly investigated patient population challenge the concept that DGF is a risk factor for rejection and highlights the need for additional studies in this regard. PMID- 23106786 TI - New species of Parapharyngodon (Nematoda: Pharyngodonidae) in Rhinella marina (Anura: Bufonidae) from Grenada, West Indies. AB - Parapharyngodon grenadaensis n. sp. (Nematoda: Pharyngodonidae) from the large intestine of the cane toad, Rhinella marina, is described and illustrated. Parapharyngodon grenadaensis n. sp. is the 48th species assigned to the genus and the 16th species from the Neotropical region. It differs from other species in the genus by possessing 4 pairs of caudal papillae, an echinate anterior cloacal lip, and a blunt spicule of 67-104 MUm. This is only the second report of R. marina harboring a species of Parapharyngodon. PMID- 23106788 TI - Physical health outcomes in prisoners with intellectual disability: a cross sectional study. AB - BACKGROUND: People with intellectual disability (ID) in the general population and people in prison experience unrecognised medical conditions and inadequate disease prevention. Among prisoners, those with an ID may be particularly disadvantaged. The aim of this study was to identify demographic, health and health-related characteristics of adult prisoners who screened positive for ID. METHODS: Cross-sectional data were collected via face-to-face administration of a structured questionnaire in seven prisons in Queensland, Australia, between 2008 and 2010. Participants were adult prisoners within 6 weeks of release from custody. We identified ID using a pragmatic screening tool. Prisoners who scored <85 on the Hayes Ability Screening Index and either (a) reported having attended a special school or (b) reported having been diagnosed with an ID were considered to have screened positive for ID. We compared the characteristics of participants who screened positive and negative for ID using univariable and multivariable logistic regression. RESULTS: Screening positive for ID was associated with younger age, identifying as Indigenous and lower educational achievement. Prisoners who screened positive for ID were more likely to have been diagnosed with medical conditions such as heart disease (odds ratio; 95% confidence interval = 2.1; 1.0-4.2) and hearing problems (2.2; 1.3-3.7), after adjustment for age, sex, education level and Indigenous status. Screen-positive prisoners were less likely to have received preventive care interventions such as testing for hepatitis A infection (0.4; 0.2-0.6), and immunisation for tuberculosis (0.4; 0.2-0.8). Prisoners with possible ID were more likely to be obese (1.7; 1.1-2.7). CONCLUSIONS: Adult prisoners who screen positive for ID have worse health outcomes than their non-disabled peers. An improved understanding of physical health characteristics prior to release can direct treatment and support pathways out of the criminal justice system and inform transitional planning of health services for this profoundly disadvantaged group. PMID- 23106787 TI - Intraperitoneal delivery of a small interfering RNA targeting NEDD1 prolongs the survival of scirrhous gastric cancer model mice. AB - The prognosis of patients with advanced diffuse-type gastric cancer (GC), especially scirrhous gastric cancer (SGC) remains extremely poor. Peritoneal carcinomatosis is a frequent form of metastasis of SGC. With survival rates of patients with peritoneal metastasis at 3 and 5 years being only 9.8% and 0%, respectively, development of a new treatment is urgently crucial. For such development, the establishment of a therapeutic mouse model is required. Among the 11 GC cell lines we examined, HSC-60 showed the most well-preserved expression profiles of the Hedgehog and epithelial-mesenchymal transition pathways found in primary SGCs. After six cycles of harvest of ascitic tumor cells and their orthotopic inoculation in scid mice, a highly metastatic subclone of HSC-60, 60As6 was obtained, by means of which we successfully developed peritoneal metastasis model mice. The mice treated with small interfering (si) RNA targeting NEDD1, which encodes a gamma-tubulin ring complex-binding protein, by the atelocollagen-mediated delivery system showed a significantly prolonged survival. Our mouse model could thus be useful for the development of a new therapeutic modality. Intraperitoneal administration of siRNAs of targeted genes such as NEDD1 could provide a new opportunity in the treatment of the peritoneal metastasis of SGC. PMID- 23106789 TI - Arsenic control during aquifer storage recovery cycle tests in the Floridan Aquifer. AB - Implementation of aquifer storage recovery (ASR) for water resource management in Florida is impeded by arsenic mobilization. Arsenic, released by pyrite oxidation during the recharge phase, sometimes results in groundwater concentrations that exceed the 10 ug/L criterion defined in the Safe Drinking Water Act. ASR was proposed as a major storage component for the Comprehensive Everglades Restoration Plan (CERP), in which excess surface water is stored during the wet season, and then distributed during the dry season for ecosystem restoration. To evaluate ASR system performance for CERP goals, three cycle tests were conducted, with extensive water-quality monitoring in the Upper Floridan Aquifer (UFA) at the Kissimmee River ASR (KRASR) pilot system. During each cycle test, redox evolution from sub-oxic to sulfate-reducing conditions occurs in the UFA storage zone, as indicated by decreasing Fe(2+) /H2 S mass ratios. Arsenic, released by pyrite oxidation during recharge, is sequestered during storage and recovery by co-precipitation with iron sulfide. Mineral saturation indices indicate that amorphous iron oxide (a sorption surface for arsenic) is stable only during oxic and sub-oxic conditions of the recharge phase, but iron sulfide (which co precipitates arsenic) is stable during the sulfate-reducing conditions of the storage and recovery phases. Resultant arsenic concentrations in recovered water are below the 10 ug/L regulatory criterion during cycle tests 2 and 3. The arsenic sequestration process is appropriate for other ASR systems that recharge treated surface water into a sulfate-reducing aquifer. PMID- 23106790 TI - Subacute cutaneous lupus erythematosus presenting in childhood: a case report and review of the literature. AB - A 2-year-old African American, Hispanic boy presented with well-defined, violaceous, annular dermal plaques without scale over the upper extremities, face, lower extremities, and buttocks. The clinical presentation and laboratory studies were consistent with a diagnosis of subacute cutaneous lupus erythematous (SCLE). SCLE presenting in childhood is exceedingly rare, with only eight cases previously reported. It is important to clinically differentiate SCLE from other eruptions more common to children, such as atopic dermatitis, urticarial drug eruptions, and psoriasis vulgaris, because progression to systemic lupus erythematous (SLE) may occur. SLE needs to be closely followed. We present the first case (to our knowledge) of SCLE in a child of African American or Hispanic descent and provide a table of other documented pediatric presentations of SCLE for comparison. PMID- 23106791 TI - In vitro diagnostic assays are effective during the acute phase of delayed-type drug hypersensitivity reactions. AB - BACKGROUND: Previous reports have suggested that drug-specific lymphocyte proliferation assays (LPA) can be used retrospectively to confirm the culprit drug following delayed-type drug hypersensitivity reactions (DHR). However, only limited evidence supports their use in aiding acute clinical management. The aim of this study was to compare the LPA against combination cytokine assays for potential use in the acute setting. METHODS: A total of 43 patients with DHR (19 during the acute reaction, 20 after recovery, four during acute and after recovery) and 14 control subjects without DHR were investigated using ex vivo analysis of drug-specific proliferation, and interferon (IFN)-gamma and interleukin (IL)-4 production. RESULTS: Healthy controls showed negative drug specific proliferation and cytokine release in contrast to individuals with a known sensitivity (P < 0.0001). The assays demonstrated a test specificity of 95% (LPA), 83% (IFN-gamma) and 92% (IL-4). The sensitivity of combined measurement of drug-specific IFN-gamma and IL-4 cytokines during acute DHR was better than LPA (82% vs. 50%), but all assays were less sensitive during the recovery phase. The correlation between LPA and IFN-gamma assays was strong (r = 0.7, P < 0.0001), whereas the IL-4 assay did not correlate as well with either of these assays. In contrast to LPA, drug enzyme-linked immunosorbent spot assays showed positive responses in patients concurrently taking immunosuppressive medication. CONCLUSIONS: In vitro assays of drug-specific IFN-gamma and IL-4 production offer potential for use as rapid diagnostic tests. Cytokine detection offers distinct advantages over the LPA, including a shorter assay time, a greater sensitivity and effectiveness in testing immunosuppressed patients. PMID- 23106793 TI - Talking about what we do .... PMID- 23106792 TI - Predictors of two forms of attrition in a longitudinal health study involving ageing participants: an analysis based on the Whitehall II study. AB - BACKGROUND: Longitudinal studies are crucial providers of information about the needs of an ageing population, but their external validity is affected if partipants drop out. Previous research has identified older age, impaired cognitive function, lower educational level, living alone, fewer social activities, and lower socio-economic status as predictors of attrition. METHODS: This project examined attrition in participants of the Whitehall II study aged between 51-71 years, using data from questionnaires participants have completed biennially since 1985 when the study began. We examine the possibility of two distinct forms of attrition--non-response and formally requesting to withdraw- and whether they have different predictors. Potential predictors were age, gender, marital status, occupational grade, retirement, home ownership, presence of longstanding illness, SF-36 quality of life scores, social participation and educational level comparing participants and those who had withdrawn from the study. RESULTS: The two forms of attrition share many predictors and are associated but remain distinct. Being older, male, having a lower job grade, not being a home owner, not having a long standing illness, having higher levels of education, and not having retired, were all associated with a greater probability of non-response; being married was associated with higher probability in women and lower in men. Being older, male, having a lower job grade, not being a home owner, having lower SF-36 scores, taking part in fewer social activities, and not having a long standing illness, were all associated with greater probability of withdrawal. CONCLUSIONS: The results suggest a strong gender effect on both routes not previously considered in analyses of attrition. Investigators of longitudinal studies should take measures to retain older participants and lower level socio-economic participants, who are more likely to cease participating. Recognition should be given to the tendency for people with health problems to be more diligent participants in studies with a medical screening aspect, and for those with lower socio-economic status (including home ownership), quality of life and social participation, to be more likely to request withdrawal. Without taking these features into account, bias and loss of power could affect statistical analyses. PMID- 23106794 TI - PEGylated graphene oxide-mediated protein delivery for cell function regulation. AB - Delivery of proteins into cells may alter cellular functions as various proteins are involved in cellular signaling by activating or deactivating the corresponding pathways and, therefore, can be used in cancer therapy. In this study, we have demonstrated for the first time that PEGylated graphene oxide (GO) can be exploited as a nanovector for efficient delivery of proteins into cells. In this approach, GO was functionalized with amine-terminated 6-armed polyethylene glycol (PEG) molecules, thereby providing GO with proper physiological stability and biocompatibility. Proteins were then loaded onto PEG grafted GO (GO-PEG) with high payload via noncovalent interactions. GO-PEG could deliver proteins to cytoplasm efficiently, protecting them from enzymatic hydrolysis. The protein delivered by GO-PEG reserves its biological activity that regulates the cell fate. As a result, delivery of ribonuclease A (RNase A) led to cell death and transport of protein kinase A (PKA) induced cell growth. Taken together, this work demonstrated the feasibility of PEGlyated GO as a promising protein delivery vector with high biocompatibility, high payload capacity and, more importantly, capabilities of protecting proteins from enzymatic hydrolysis and retaining their biological functions. PMID- 23106795 TI - Application of the functionally generated path technique to restore mandibular molars in bilateral group function occlusion. AB - The functionally generated path (FGP) is a static representation of the opposing cusps' dynamic eccentric movements from a centric position to achieve optimal articulation and occlusal harmony. When understood and appreciated, use of the FGP technique is a straightforward and practical method to achieve harmonious occlusal anatomy of restorations with the anterior determinant/anterior guidance, the posterior determinant/condylar guidance, existing occlusal and cuspal anatomy, and the neuromuscular system. Although the FGP technique is normally used in the fabrication of maxillary posterior indirect restorations, it is described and applied here in the fabrication of mandibular posterior restorations that maintained the patient's bilateral group function occlusion while eliminating the nonworking side and protrusive interferences. This novel procedure involved the use of a stone crib to intraorally construct a stone core that captured the FGP recording while simultaneously indexing to the contralateral and ipsilateral mandibular dentition. This technique lends additional stability to the stone core to minimize error during the mounting process. PMID- 23106796 TI - Transient swelling of the Schneiderian membrane after transversal sinus augmentation: a pilot study. AB - OBJECTIVE: The predictability and simplicity of the Summers' technique for sinus floor elevation encouraged many clinicians to consider this new approach. The impact of such intervention on the sinus mucosa has, however, not been explored extensively. This pilot study followed the response of the Schneiderian membrane, longitudinally, via cone-beam CT images. MATERIAL AND METHODS: Ten consecutive patients (five women, mean age 58.7 years) referred for implant therapy in the posterior part of the maxilla, in combination with a trans-alveolar sinus floor elevation (13 sinuses involved), were enrolled. CBCT images were taken prior to and at 1 week and 1 month after surgery. The changes in thickness of the Schneiderian membrane were scored at nine standardized points per sinus using reformatted cross-sectional images. RESULTS: One week after sinus floor elevation, the Schneiderian membrane showed a significant swelling of 9.2 mm in the middle (SD 0.3; P < 0.005), 7.2 mm medially (SD 2.5; P < 0.005) and 3.9 mm laterally (SD 0,3; P < 0.05), respectively, resulting in an overall mean of 6.7 mm (SD 2.6), which fully disappeared 3 weeks later. This swelling involved the entire floor of the sinus and not only the augmented area. CONCLUSIONS: Within the limitations of this pilot study, one can conclude that the Schneiderian membrane responds with a significant "transient" swelling (5-10* its size) during the first weeks of healing. PMID- 23106798 TI - Effect of media composition, including gelling agents, on isolation of previously uncultured rumen bacteria. AB - The aim of this study was to develop novel anaerobic media using gellan gum for the isolation of previously uncultured rumen bacteria. Four anaerobic media, a basal liquid medium (BM) with agar (A-BM), a modified BM (MBM) with agar (A-MBM), an MBM with phytagel (P-MBM) and an MBM with gelrite (G-MBM) were used for the isolation of rumen bacteria and evaluated for the growth of previously uncultured rumen bacteria. Of the 214 isolates composed of 144 OTUs, 103 isolates (83 OTUs) were previously uncultured rumen bacteria. Most of the previously uncultured strains were obtained from A-MBM, G-MBM and P-MBM, but the predominant cultural members, isolated from each medium, differed. A-MBM and G-MBM showed significantly higher numbers of different OTUs derived from isolates than A-BM (P < 0.05). The Shannon index indicated that the isolates of A-MBM showed the highest diversity (H' = 3.89) compared with those of G-MBM, P-MBM and A-BM (H' = 3.59, 3.23 and 3.39, respectively). Although previously uncultured rumen bacteria were isolated from all media used, the ratio of previously uncultured bacteria to total isolates was increased in A-MBM, P-MBM and G-MBM. PMID- 23106800 TI - Feature versus spatial strategies by orangutans (Pongo abelii) and human children (Homo sapiens) in a cross-dimensional task. AB - Despite the fact that photographic stimuli are used across experimental contexts with both human and nonhuman subjects, the nature of individuals' perceptions of these stimuli is still not well understood. In the present experiments, we tested whether three orangutans and 36 human children could use photographic information presented on a computer screen to solve a perceptually corresponding problem in the physical domain. Furthermore, we tested the cues that aided in this process by pitting featural information against spatial position in a series of probe trials. We found that many of the children and one orangutan were successfully able to use the information cross-dimensionally; however, the other two orangutans and almost a quarter of the children failed to acquire the task. Species differences emerged with respect to ease of task acquisition. More striking, however, were the differences in cues that participants used to solve the task: Whereas the orangutan used a spatial strategy, the majority of children used a feature one. Possible reasons for these differences are discussed from both evolutionary and developmental perspectives. The novel results found here underscore the need for further testing in this area to design appropriate experimental paradigms in future comparative research settings. PMID- 23106801 TI - Sharing mates and nest boxes is associated with female "friendship" in European starlings, Sturnus vulgaris. AB - Breeding decisions in birds involve both mate and nest choice, and there is increasing evidence that social influences may modulate individual choices. Female preferences may be affected by other females' preferences and mutual choice cannot always be excluded, which makes the whole pattern more complex than assumed by most sexual selection models. Social transmission may be facilitated by particular social bonds, therefore prebreeding social networks may influence later mate choices. The other case where females share mate or resources is polygyny, generally viewed to only benefit males. If mutual benefits may arise then mechanisms should evolve to reduce the reproductive cost for females such as to reduce the cost of aggression by sharing their mate with a preferred same-sex social partner. We tested the hypothesis that females' mating decisions may be influenced by the prebreeding social network and that social partner relations established prior to breeding may share decisions (mate/sites) in a facultatively polygynous species, the European starling. Two experiments were designed to test the relative importance of male or nest by following the whole dynamics of the breeding cycle from the prebreeding period until mate and nest selection. In both cases socially isolated females tended to be excluded from breeding, while prebreeding social partners tended to share mates and to nest in close proximity, mate copying leading in some case to polygyny. The final pattern resulted both from female "likes and dislikes" and male preferences for some females. Aggressive interactions between females were rare. Vocal sharing between females may have been a clue for males as to the degree of social integration of these females. PMID- 23106797 TI - NIR-activated content release from plasmon resonant liposomes for probing single cell responses. AB - Technological limitations have prevented the interrogation and manipulation of cellular activity in response to bioactive molecules within model and living systems that is required for the development of diagnostic and treatment modalities for diseases, such as cancer. In this work, we demonstrate that gold coated liposomes are capable of encapsulation and on-demand release of signaling molecules with a spatial and temporal resolution leading to activation of individual cells. As a model system, we used cells modified to overexpress a certain G-protein coupled receptor, the CCK2 receptor, and achieved its activation in a single cell via the localized release of its agonist. This content release was triggered by illumination of the liposomes at wavelengths corresponding to the plasmon resonance of the gold coating. The use of plasmon resonant liposomes may enable on-demand release of a broad range of molecules using biologically safe near-infrared light and without molecule chemical modification. In combination with the spectral tunability of plasmon resonant coating, this technology may allow for multiplexed interrogation of complex and diverse signaling pathways in model or living tissues with unprecedented spatial and temporal control. PMID- 23106799 TI - The impact of body mass index on surgical outcomes of robotic partial nephrectomy. AB - Study Type--Therapy (case series) Level of Evidence 4. "What's known on the subject?" and "What does the study add?" Obesity is associated with higher incidence of renal cell carcinoma. Laparoscopic and robotic partial nephrectomy (RPN) was shown to be technically feasible in the obese population. In the present study we evaluated the impact of obesity on outcome of RPN, in a large cohort of patients. In the present study, obese patients had a higher American Society of Anesthesiologists score and larger tumour size. We evaluated obesity as a categorical and a continuous variable, and we adjusted for confounding factors. We categorized obesity based according to the WHO classification of obesity. We described our technical modifications to overcome difficulties that can be encountered during the surgery. Obese patients had a higher estimated blood loss, but no difference in blood transfusion rate, operation duration or warm ischaemia time. OBJECTIVE: * To assess the impact of body mass index (BMI) on the surgical outcomes of robotic partial nephrectomy (RPN). PATIENTS AND METHODS: * Medical charts of 250 consecutive patients who underwent RPN at our institution between 2006 and 2010 were reviewed. * Patients were categorized based on their BMI into four groups per international classification of obesity into: normal (BMI < 25 kg/m(2)), overweight (25-29.9), obese (30-39.9) and morbidly obese (>= 40). * Preoperative characteristics as well as perioperative and postoperative outcomes were analysed and compared between the groups. RESULTS: * Of the 250 patients, 43 (17.2% of the entire cohort) were non-obese, 104 (41.6%) were overweight, 75 (30%) were obese, and 28 (11.2%) were morbidly obese. * Groups were similar in terms of age, gender, history of previous surgery and nephrometry score (P = 0.5). * Patients with higher BMI had a higher American Society of Anesthesiologists (ASA) score (median 3 for obese and morbidly obese groups vs 2 for non-obese groups; P = 0.002) and tumour size (median 3.6, 2.9, 2.5 and 2.3 cm in those who were morbidly obese, obese, overweight and with normal BMI, respectively; P = 0.005). * Patients within the morbidly obese group had a higher estimated blood loss (median 250 mL) than other groups (median: 200, 200, 150 mL, respectively) (P = 0.03). * No significant difference was detected between the groups in terms of operation duration, warm ischaemia time, transfusion rate and postoperative complications. CONCLUSION: * Robotic partial nephrectomy represents an effective treatment modality for renal tumours providing equivalent surgical outcomes even for patients with BMI up to 60 kg/m(2). PMID- 23106803 TI - One-trial memory and habit contribute independently to matching-to-sample performance in rhesus monkeys (Macaca mulatta). AB - Multiple memory systems often act together to generate behavior, preventing a simple one-to-one mapping between cognitive processes and performance in specific tests. Process dissociation procedures (PDPs) have been adopted in both humans and monkeys to quantify one-trial memory and habit, with the assumption that these two processes make independent contributions to performance. Violations of this independence assumption could produce artificial dissociations. Evidence for independence has been reported in humans, but similar tests have not been conducted with monkeys until now. In a within-subjects design using a matching-to sample task, we manipulated one-trial memory strength and habit strength simultaneously. Memory delay intervals and encoding conditions affected one-trial memory scores without affecting habit scores. In contrast, biased reinforcement selectively changed habit scores but not one-trial memory scores. This behavioral double dissociation clearly shows that one-trial memory and habit can be manipulated independently, validating PDP as a valuable tool for cross-species studies of learning and memory and reinforcing the view that one-trial memory and habits are served by distinct brain systems. PMID- 23106802 TI - Signal recognition by green treefrogs (Hyla cinerea) and Cope's gray treefrogs (Hyla chrysoscelis) in naturally fluctuating noise. AB - This study tested three hypotheses about the ability of female frogs to exploit temporal fluctuations in the level of background noise to overcome the problem of recognizing male advertisement calls in noisy breeding choruses. Phonotaxis tests with green treefrogs (Hyla cinerea) and Cope's gray treefrogs (Hyla chrysoscelis) were used to measure thresholds for recognizing calls in the presence of noise maskers with (a) no level fluctuations, (b) random fluctuations, or level fluctuations characteristic of (c) conspecific choruses and (d) heterospecific choruses. The dip-listening hypothesis predicted lower signal recognition thresholds in the presence of fluctuating maskers compared with nonfluctuating maskers. Support for the dip-listening hypothesis was weak; only Cope's gray treefrogs experienced dip listening and only in the presence of randomly fluctuating maskers. The natural soundscapes advantage hypothesis predicted lower recognition thresholds when level fluctuations resembled those of natural soundscapes compared with artificial fluctuations. This hypothesis was rejected. In noise backgrounds with natural fluctuations, the species-specific advantage hypothesis predicted lower recognition thresholds when fluctuations resembled species-specific patterns of conspecific soundscapes. No evidence was found to support this hypothesis. These results corroborate previous findings showing that Cope's gray treefrogs, but not green treefrogs, experience dip listening under some noise conditions. Together, the results suggest level fluctuations in the soundscape of natural breeding choruses may present few dip-listening opportunities. The findings of this study provide little support for the hypothesis that receivers are adapted to exploit level fluctuations of natural soundscapes in recognizing communication signals. PMID- 23106804 TI - Object permanence in domestic dogs (Canis lupus familiaris) and gray wolves (Canis lupus). AB - Recent evidence suggests that phylogenetic constraints exerted on dogs by the process of domestication have altered the ability of dogs to represent the physical world and the displacement of objects. In this study, invisible (Experiment 1) and visible (Experiment 2) displacement problems were administered to determine whether domestic dogs' and gray wolves' cognitive capacities to infer the position of a hidden object differ. The results revealed that adult dogs and wolves performed similarly in searching for disappearing objects: Both species succeeded the visible displacement tasks but failed the invisible displacement problems. We conclude that physical cognition for finding hidden objects in domestic dogs and gray wolves is alike and unrelated to the process of domestication. PMID- 23106805 TI - Heterospecific discrimination of Poecile vocalizations by zebra finches (Taeniopygia guttata). AB - Previous perceptual research with black-capped and mountain chickadees has demonstrated that the D note of the namesake chick-a-dee call controlled species based discrimination compared to other note types in this call. In the current experiment, we sought to determine whether discrimination performance of the chickadees was controlled by stimulus-specific properties or due to learning through experience. To accomplish this, we tested zebra finches, a songbird species that is distantly related to chickadees, and also unfamiliar with black capped and mountain chickadee vocalizations, on the same species-based discrimination on which black-capped and mountain chickadees were previously trained. We found that zebra finches learned the discrimination in the fewest number of trials with the D note, compared to other note types (i.e., the A, B, and C notes). In addition, we compared the current results to earlier work and found that zebra finches learned the discrimination in fewer trials compared to black-capped chickadees, and, across all species, males learned the discrimination in fewer trials than females. We discuss the roles that acoustic complexity and learning play in classification of the three species of songbirds tested. More generally, these results point to the benefits derived from testing members of each sex in species that vary in their natural history, vocal output, and phylogenetic relatedness as a means to uncover the mechanisms underlying acoustic communication. (PsycINFO Database Record (c) 2013 APA, all rights reserved). PMID- 23106806 TI - Primary health care nurses' knowledge practice and client teaching of early detection measures of breast cancer in Ibadan. AB - BACKGROUND: Early detection of breast cancer is vital to effective management and outcome of breast cancer. It has been suggested that women given information and instruction about breast self- examination and breast awareness by health care professionals demonstrated higher knowledge and confidence and tend to practice breast self-examination more than those who received information from other sources. Breast Self-Examination (BSE) and Clinical Breast Examination (CBE) have been recommended as Early Detection Measures (EDM) for developing countries. This study evaluated Primary Health Care (PHC) nurses' knowledge, practice and client teaching of EDM of breast cancer. METHODS: A descriptive study that utilized stratified random method to select PHC settings for the study. Data was collected from 120 trained nurses in selected settings. This represented 66.3% of total population of PHC nurses (181) in Ibadan. The instrument for data collection was a structured questionnaire that explored the bio data of participants, knowledge, practice and client teaching of EDMs of breast cancer. Ethical approval was obtained from the Ethical Review Committee of Oyo State Ministry of Health, Nigeria. RESULTS: The mean age of the participants was 44.4+/-7.5 years. About half (52.2%) were double qualified (Registered Nurse and Midwife). Only 23 (20.0%) of the participants considered painless lump as an early sign of breast cancer while 47 (40.9%) considered pain as an early sign. BSE was listed as EDM of breast cancer by 80.9% of the participants while 40% and 30% listed CBE and mammogram respectively. Only eight (7.9%) have had a mammogram. The logistic regression of client teaching on four variables showed that for every increase in knowledge of breast cancer the odds of client teaching significantly increased by 7.5% (95% CI = 1.27 - 1.125). There were also significant relationships between knowledge of EDM, practice of BSE and client teaching. CONCLUSIONS: It is vital that attention should be given to enhance breast cancer EDMs among the PHC nurses to be able to enhance health deviation self-care of the clients. Nurses' knowledge, practice as well as client teaching especially at PHC level, will contribute to early detection of breast cancer. PMID- 23106807 TI - Human rights and intellectual disabilities in an era of 'choice'. AB - BACKGROUND: Efforts to uphold and promote the human rights of people with intellectual disabilities (ID) are being affected by the increasing emphasis on 'choice' in the delivery of social care services. While rights presume subjects or selves to whom they apply, there is a disconnect between the subjects presumed within human rights frameworks and the variable capacities of a heterogeneous ID population. This disconnect is amplified by choice discourses which characterise current service provision based upon neoliberal ideologies. METHOD: Conceptual assumptions and theoretical positions associated with human rights in relation to people with ID are critically examined. RESULTS: The analysis results in an argument that current conceptualisations of personhood in relation to human rights exclude people with ID. The adverse effects of this exclusion are exacerbated within services which emphasise the permissive rights associated with a neoliberal agenda of 'choice' over protective rights. CONCLUSIONS: In order to ensure that the human rights of people with ID are upheld, neoliberal emphases on choice need to be tempered and a more nuanced and inclusive notion of personhood in relation to universal human rights needs to be adopted. PMID- 23106809 TI - Comparison of complication rates for unilateral and bilateral percutaneous nephrolithotomy (PCNL) using a modified Clavien grading system. AB - OBJECTIVE: To compare complication rates of unilateral vs bilateral percutaneous nephrolithotomy (PCNL) using the modified Clavien grading system. PATIENTS AND METHODS: Single-institution retrospective chart review. Identified patients who had synchronous bilateral PCNL (B-PCNL) over an 11-year period (2000-2011). B PCNL patients were matched by age, gender, and stone burden per renal unit with patients who underwent unilateral PCNL (U-PCNL) over the same period. Complications were recorded and classified using the modified Clavien classification system, and then compared with a two-sided chi-square test of proportions. RESULTS: In all, 47 B-PCNL patients [mean (range) age 54 (14-84) years] and 78 U-PCNL patients [mean (range) age 54 (17-91 years] were compared. The mean (range) stone burden per renal unit was 2.8 (0.7-7.0) cm and 2.9 (0.7 9.0) cm, respectively. The overall complication rate was higher for B-PCNL (53.2% vs 30.8%, P = 0.013). Rates of Grade I and Grade II complications trended toward being higher in the B-PCNL group. Low-grade complications (Grade I and II combined) occurred more often in the B-PCNL group (P = 0.011); the most common low-grade complication was fever. Two procedures terminated for poor visualisation due to bleeding were successfully completed in delayed fashion with no transfusion and were classified as Grade I complications. There were equivalently low rates of Grade III complications. There were no Grade IV or V complications. CONCLUSIONS: B-PCNL carries a higher overall complication rate than U-PCNL when the modified Clavien system is used for classification. Patients undergoing U-PCNL who have more than one tract dilatation have a higher complication rate than those who have only one tract dilatation. High-grade complications are uncommon for both procedures. PMID- 23106808 TI - Prevalence and incidence density rates of chronic comorbidity in type 2 diabetes patients: an exploratory cohort study. AB - BACKGROUND: Evidence-based diabetes guidelines generally neglect comorbidity, which may interfere with diabetes management. The prevalence of comorbidity described in patients with type 2 diabetes (T2D) shows a wide range depending on the population selected and the comorbid diseases studied. This exploratory study aimed to establish comorbidity rates in an unselected primary-care population of patients with T2D. METHODS: This was a cohort study of 714 adult patients with newly diagnosed T2D within the study period (1985-2007) in a practice-based research network in the Netherlands. The main outcome measures were prevalence and incidence density rates of chronic comorbid diseases and disease clusters. All chronic disease episodes registered in the practice-based research network were considered as comorbidities. We categorised comorbidity into 'concordant' (that is, shared aetiology, risk factors, and management plans with diabetes) and 'discordant' comorbidity. Prevalence and incidence density were assessed for both categories of comorbidity. RESULTS: The mean observation period was 17.3 years. At the time of diabetes diagnosis, 84.6% of the patients had one or more chronic comorbid disease of 'any type', 70.6% had one or more discordant comorbid disease, and 48.6% and 27.2% had three or more chronic comorbid diseases of 'any type' or of 'discordant only', respectively. A quarter of those without any comorbid disease at the time of their diabetes diagnosis developed at least one comorbid disease in the first year afterwards. Cardiovascular diseases (considered concordant comorbidity) were the most common, but there were also high rates of musculoskeletal and mental disease. Discordant comorbid diseases outnumbered concordant diseases. CONCLUSIONS: We found high prevalence and incidence density rates for both concordant and discordant comorbidity. The latter may interfere with diabetes management, thus future research and clinical practice should take discordant comorbidity in patients with T2D into account. PMID- 23106812 TI - Positive correlation between serum levels of adiponectin and homocysteine in pre eclampsia. AB - AIM: The aims of the present study were to assess the correlation between homocysteine and adiponectin and the homocysteine-to-adiponectin ratio in pre eclampsia compared with normal pregnant women. MATERIALS AND METHODS: The study population consisted of 30 women with pre-eclampsia and 30 normal pregnant women. Serum levels of total adiponectin and total homocysteine were assessed using commercially available enzyme-linked immunosorbent assay methods. Data are presented as median. RESULTS: Serum levels of total adiponectin correlated directly with total homocysteine in both pre-eclampsia (r = 0.48, P = 0.01) and normal pregnancy (r = 0.68, P = 0.001). The homocysteine-to-adiponectin ratio was increased significantly in pre-eclampsia compared with normal pregnancy (0.90 vs 0.70, P = 0.03). Compared with normal pregnancy, women with severe pre-eclampsia showed significant increase in total adiponectin (14.29 vs 10.24, P = 0.01), total homocysteine (13.80 vs 7.25, P = 0.000) and homocysteine-to-adiponectin ratio (0.92 vs 0.70, P = 0.02). Women with mild pre-eclampsia had higher values of total adiponectin (16.19 vs 10.24, P = 0.000) and total homocysteine (13.11 vs 7.25, P = 0.000) compared with normal pregnancy. No significant differences were observed between mild and severe pre-eclampsia. CONCLUSION: The present study showed a positive association between adiponectin and homocysteine in pre eclampsia. The homocysteine-to-adiponectin ratio may be an informative biomarker for the disease diagnosis and therapeutic monitoring. PMID- 23106811 TI - Integrative analysis of neuroblastoma and pheochromocytoma genomics data. AB - BACKGROUND: Pheochromocytoma and neuroblastoma are the most common neural crest derived tumors in adults and children, respectively. We have performed a large scale in silico analysis of altogether 1784 neuroblastoma and 531 pheochromocytoma samples to establish similarities and differences using analysis of mRNA and microRNA expression, chromosome aberrations and a novel bioinformatics analysis based on cooperative game theory. METHODS: Datasets obtained from Gene Expression Omnibus and ArrayExpress have been subjected to a complex bioinformatics analysis using GeneSpring, Gene Set Enrichment Analysis, Ingenuity Pathway Analysis and own software. RESULTS: Comparison of neuroblastoma and pheochromocytoma with other tumors revealed the overexpression of genes involved in development of noradrenergic cells. Among these, the significance of paired-like homeobox 2b in pheochromocytoma has not been reported previously. The analysis of similar expression patterns in neuroblastoma and pheochromocytoma revealed the same anti-apoptotic strategies in these tumors. Cancer regulation by stathmin turned out to be the major difference between pheochromocytoma and neuroblastoma. Underexpression of genes involved in neuronal cell-cell interactions was observed in unfavorable neuroblastoma. By the comparison of hypoxia- and Ras-associated pheochromocytoma, we have found that enhanced insulin like growth factor 1 signaling may be responsible for the activation of Src homology 2 domain containing transforming protein 1, the main co-factor of RET. Hypoxia induced factor 1alpha and vascular endothelial growth factor signaling included the most prominent gene expression changes between von Hippel-Lindau- and multiple endocrine neoplasia type 2A-associated pheochromocytoma. CONCLUSIONS: These pathways include previously undescribed pathomechanisms of neuroblastoma and pheochromocytoma and associated gene products may serve as diagnostic markers and therapeutic targets. PMID- 23106813 TI - Photoinduced intramolecular cyclopentanation vs photoprotolytic oxametathesis in polycyclic alkenes outfitted with conformationally constrained aroylmethyl chromophores. AB - Intramolecular photoinduced cyclizations are investigated in photoprecursors assembled in a modular fashion via a Diels-Alder reaction of acetylenic dienophiles with subsequent Michael additions of aromatic ketones to install a chromophore capable of initiating Paterno-Buchi cycloadditions or radical cyclization cascades. The protolytic oxametathesis in these systems allows for rapid access to novel polycyclic scaffolds decorated by formyl groups and carboxylates suitable for subsequent modifications. In conformationally constrained photoprecursors, a radical rearrangement takes place resulting in intramolecular 1,3-diradical cyclopentanation of the double bond. PMID- 23106814 TI - Regulation of mRNA expression in breast cancer - a cis-tematic trans-action. AB - Large research consortia such as the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas and International Cancer Genomics Consortium are systematically interrogating large sets of tumor samples through integrated analysis of genome-wide DNA copy number and promoter methylation, transcriptome-wide RNA expression, protein expression and exome-wide sequencing. A recent METABRIC study explored the effects of cis-acting and trans acting factors of gene expression regulation in breast cancer. By making their data sets publicly available, these large consortia are inviting new types of analysis that have the potential to drive breast cancer research into previously unexplored avenues. PMID- 23106815 TI - Intrauterine idiopathic amputation of the head of a porcine foetus. AB - An anencephalic full-term porcine foetus accompanied by a mummified head was submitted for examination. The neck almost entirely lacked skin and was covered by granulation tissue as were the exposed parts of the spine and spinal cord. The case represents a rare case of intrauterine amputation. A definitive cause could not be established because the placenta was not available. The most likely cause is strangulation of the neck. Such strangulation could be due to a defect of the allantoamnion with herniation of the foetal head or entanglement by amniotic constriction bands. PMID- 23106816 TI - Insulin solubility transitions by pH-dependent interactions with proinsulin C peptide. AB - Proinsulin processing into insulin and C-peptide in the secretory granules of the pancreatic beta-cells occurs under mildly acidic conditions and at high peptide concentrations (> 10 mm). Mature insulin has reduced solubility and a propensity to adopt an amyloid-like structure, but is physiologically released as a mixture of a zinc-containing core and a zinc-free, C-peptide-rich fluid phase. C-peptide is known to function in the insulin secretion, but its exact mode of interaction is not established. We now demonstrate that C-peptide in sub-stoichiometric amount versus insulin coprecipitates with insulin at the pH found in secretory vesicles. Precipitation is reversible and the precipitate is dissolved by elevation of the pH. This effect was found to be dependent on relatively conserved glutamate residues in the otherwise poorly conserved C-peptide. Together, the data show that C-peptide has the ability to influence insulin solubility. The physiological pH changes between insulin processing and release sites may therefore affect the quaternary structure of insulin, as well as the phase transitions during insulin sorting and secretion. STRUCTURED DIGITAL ABSTRACT: Insulin and C-peptide bind by molecular sieving (View Interaction: 1, 2) C-peptide and Insulin bind by dynamic light scattering (View Interaction: 1, 2) C-peptide and Insulin bind by fluorescence technology (View Interaction: 1, 2, 3, 4). PMID- 23106818 TI - Opportunities to Build Groundwater Resilience in the Semi-Arid Tropics. AB - Agricultural water management (AWM) is the adaptation strategy for increasing agricultural production through enhancing water resources availability while maintaining ecosystem services. This study characterizes groundwater hydrology in the Kothapally agricultural watershed, in hard rock Deccan plateau area in India and assesses the impact of AWM interventions on groundwater recharge using a calibrated and validated hydrological model, SWAT, in combination with observed water table data in 62 geo-referenced open wells. Kothapally receives, on average, 750 mm rainfall (nearly 90% of annual rainfall) during the monsoon season (June to October). Water balance showed that 72% of total rainfall was converted as evapotranspiration (ET), 16% was stored in aquifer, and 8% exported as runoff from the watershed boundary with AWM interventions. Nearly 60% of the runoff harvested by AWM interventions recharged shallow aquifers and rest of the 40% increased ET. Water harvesting structures (WHS) contributed 2.5 m additional head in open wells, whereas hydraulic head under natural condition was 3.5 m, resulting in total 6 m rise in water table during the monsoon. At the field scale, WHSs recharged open wells at a 200 to 400 m spatial scale. PMID- 23106817 TI - Varicella precipitating febrile ulceronecrotic Mucha-Habermann disease. AB - We report a 9-year-old boy with skin lesions clinically and histologically compatible with pityriasis lichenoides et varioliformis acuta that evolved to the severe variant febrile ulceronecrotic Mucha-Habermann disease and finally to pityriasis lichenoides chronica. Varicella-zoster virus (VZV) was isolated in culture medium from the skin lesions and serum serology was positive for VZV. This is the first time that a virus has been isolated in culture in this condition. PMID- 23106819 TI - Well-defined colloidal 2-D layered transition-metal chalcogenide nanocrystals via generalized synthetic protocols. AB - While interesting and unprecedented material characteristics of two dimensionality (2-D) layered nanomaterials are emerging, their reliable synthetic methodologies are not well developed. In this study we demonstrate general applicability of synthetic protocols to a wide range of colloidal 2-D layered transition-metal chalcogenide (TMC) nanocrystals. As distinctly different from other nanocrystals, we discovered that 2-D layered TMC nanocrystals are unstable in the presence of reactive radicals from elemental chalcogen during the crystal formation. We first introduce the synthesis of titanium sulfide and selenide where well-defined single crystallinity and lateral size controllability are verified, and then such synthetic protocols are extended to all of group IV and V transition-metal sulfide (TiS(2), ZrS(2), HfS(2), VS(2), NbS(2), and TaS(2)) and selenide (TiSe(2), ZrSe(3), HfSe(3), VSe(2), NbSe(2), and TaSe(2)) nanocrystals. The use of appropriate chalcogen source is found to be critical for the successful synthesis of 2-D layered TMC nanocrystals. CS(2) is an efficient chalcogen precursor for metal sulfide nanocrystals, whereas elemental Se is appropriate for metal selenide nanocrystals. We briefly discuss the effects of reactive radical characteristics of elemental S and Se on the formation of 2-D layered TMC nanocrystals. PMID- 23106820 TI - Assessing the utility of the willingness/prototype model in predicting help seeking decisions. AB - Prior research on professional psychological help-seeking behavior has operated on the assumption that the decision to seek help is based on intentional and reasoned processes. However, research on the dual-process prototype/willingness model (PWM; Gerrard, Gibbons, Houlihan, Stock, & Pomery, 2008) suggests health related decisions may also involve social reaction processes that influence one's spontaneous willingness (rather than planned intention) to seek help, given conducive circumstances. The present study used structural equation modeling to evaluate the ability of these 2 information-processing pathways (i.e., the reasoned pathway and the social reaction pathway) to predict help-seeking decisions among 182 college students currently experiencing clinical levels of psychological distress. Results indicated that when both pathways were modeled simultaneously, only the social reaction pathway independently accounted for significant variance in help-seeking decisions. These findings argue for the utility of the PWM framework in the context of professional psychological help seeking and hold implications for future counseling psychology research, prevention, and practice. PMID- 23106821 TI - Discrepancies confer vulnerability to depressive symptoms: a three-wave longitudinal study. AB - Discrepancies (i.e., a subjective sense of falling short of one's own standards) are a key part of the perfectionism construct. Theory suggests discrepancies confer vulnerability to depressive symptoms. Since most research in this area is cross-sectional, longitudinal research is needed to disentangle directionality of relationships and to permit stronger causal inferences. Determining whether discrepancies are an antecedent of depressive symptoms, a consequence of depressive symptoms, or both is critical to understanding the discrepancies depressive symptoms relationship. Knowledge about the temporal stability of discrepancies is also only starting to emerge, and it is unclear whether discrepancies predict incremental variance in depressive symptoms above and beyond neuroticism (i.e., a dispositional tendency to experience negative emotional states). The present study tested relationships among discrepancies, neuroticism, and depressive symptoms in 127 1st-year undergraduates using a 3 wave longitudinal design. Results suggest discrepancies may be understood as a trait-state where people are both highly consistent in their rank order on discrepancies and fluctuate somewhat in the level of discrepancies they experience at a particular point in time. As hypothesized, discrepancies predicted increases in depressive symptoms, even after controlling for neuroticism. Contrary to hypotheses, depressive symptoms did not predict changes in discrepancies. This study extends a long tradition of theory noting the depressing consequences of believing that one has fallen short of one's own standards. Harsh self-criticism and unobtainable self-expectations involving a strong sense of imperfection may be part of the premorbid personality of people vulnerable to depressive symptoms. PMID- 23106822 TI - Human umbilical vein endothelial cell vaccine therapy in patients with recurrent glioblastoma. AB - We aimed to assess the clinical efficacy of glutaraldehyde-fixed human umbilical vein endothelial cell (HUVEC) vaccine for the treatment of patients with recurrent glioblastoma. Patients of a HUVEC vaccine group received intradermal injections of 5 * 10(7) HUVEC weekly during the first month, and every 2 weeks from the second month, until progression of the disease was observed. Salvage treatment consisted of multimodal chemotherapy, radiation, including gamma-knife therapy, and/or repeated surgery, when feasible. Hazard ratios for death were calculated using a Cox model. A total of 17 patients with recurrent glioblastoma were enrolled in this study. All the patients received the initial treatment consisting of maximal safe surgical resection, followed by radiotherapy of 50-80 Gy or more, with concomitant and adjuvant chemotherapy consisting of temozolomide or nimustine (ACNU). A total of 352 vaccinations were performed for the patients of the HUVEC vaccine group (median number of vaccination = 11 doses; range 3-122 doses). The median progression-free survival and overall survival were 5.5 and 11.4 months, respectively. The median overall survival from the diagnosis was 24.3 months. The HUVEC vaccine therapy significantly prolonged the tumor doubling time and contributed to reducing the tumor growth rate. Hematological adverse reactions due to chemotherapy were recognized: one patient experienced grade III leukocytopenia and one showed grade II lymphocytopenia. Associated with the HUVEC vaccine therapy, a delayed-type hypersensitivity-like skin reaction developed at the injection site. The HUVEC vaccine therapy effectively controlled disease progression, without evident adverse effects, except for a delayed-type hypersensitivity-like skin reaction at the injection site. PMID- 23106823 TI - Clone libraries and single cell genome amplification reveal extended diversity of uncultivated magnetotactic bacteria from marine and freshwater environments. AB - Magnetotactic bacteria (MTB), which orient along the earth's magnetic field using magnetosomes, are ubiquitous and abundant in marine and freshwater environments. Previous phylogenetic analysis of diverse MTB has been limited to few cultured species and the most abundant and conspicuous members of natural populations, which were assigned to various lineages of the Proteobacteria, the Nitrospirae phylum as well as the candidate division OP3. However, their known phylogenetic diversity still not matches the large morphological and ultrastructural variability of uncultured MTB found in environmental communities. Here, we used analysis of 16S rRNA gene clone libraries in combination with microsorting and whole-genome amplification to systematically address the entire diversity of uncultured MTB from two different habitats. This approach revealed extensive and novel diversity of MTB within the freshwater and marine sediment samples. In total, single-cell analysis identified eight different phylotypes, which were only partly represented in the clone libraries, and which could be unambiguously assigned to their respective morphotypes. Identified MTB belonged to the Alphaproteobacteria (seven species) and the Nitrospirae phylum (two species). End sequencing of a small insert library created from WGA-derived DNA of a novel conspicuous magnetotactic vibrio identified genes with highest similarity to two cultivated MTB as well as to other phylogenetic groups. In conclusion, the combination of metagenomic cloning and single cell sorting represents a powerful approach to recover maximum bacterial diversity including low-abundant magnetotactic phylotypes from environmental samples and also provides access to genomic analysis of uncultivated MTB. PMID- 23106824 TI - An alternate impression technique for ocular prostheses. AB - This article describes an alternative two-step ocular prosthesis impression technique that employs two materials of different consistencies. The method is intended to provide better adaptation to underlying tissues, increased mobility of the prosthesis owing to improvements in facial contours, and improved esthetics, as well as offering the patient greater comfort and security. These advantages and this prosthesis' relative ease of fabrication mean it should be considered as the first step in the management of untreated anophthalmic sockets. PMID- 23106825 TI - A preliminary evaluation of the effectiveness of the Cystic Fibrosis Foundation Mentoring Program for Respiratory Care. AB - BACKGROUND: In 2008 the Cystic Fibrosis (CF) Foundation launched the Respiratory Therapy Mentoring Program, which pairs a respiratory therapist (RT) relatively new to CF (apprentice) with a highly experienced RT (mentor) from a similar CF care center. We wished to determine if we had achieved our short-term goal of increasing CF-specific knowledge among the apprentices who participated in the program. METHODS: Selected apprentices were each matched with a mentor, based on characteristics of CF population, clinical setting, center size, and geographic location of their care centers. Apprentices completed a CF-specific RT knowledge self assessment tool prior to and after a site visit to their mentor's center. Mentors also completed a post site visit knowledge self assessment tool regarding their apprentice. RESULTS: Thirty-seven apprentices completed a pre and post site visit knowledge self assessment tool. The median pre and post site visit scores were 12 and 31 (P < .001) respectively. The mentors' post site visit scores of their apprentices (median 29, P = .07) did not significantly differ from the apprentices' post site visit scores. CONCLUSIONS: The results of this preliminary evaluation suggest that the RT mentoring program has achieved its short-term goal of increasing CF-specific knowledge among RTs relatively new to CF care. PMID- 23106827 TI - Diagnostic tests in urology: percentage of free prostate-specific antigen (PSA). AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Free to total PSA ratios are commonly used as an adjunct to total PSA levels to better define an individual's risk for prostate cancer; however, its strengths and weaknesses are not well understood. This article illustrates the use of likelihood ratios that can be generated from the reported sensitivities and specificities from given free to total PSA thresholds in either increasing or decreasing an individual patient's probability of prostate cancer. Understanding the strengths and limitations of free to total PSA testing will help clinicians anticipate whether its use is indicated or not. PMID- 23106828 TI - Graphene coatings: probing the limits of the one atom thick protection layer. AB - The limitations of graphene as an effective corrosion-inhibiting coating on metal surfaces, here exemplified by the hex-reconstructed Pt(100) surface, are probed by scanning tunneling microscopy measurements and density functional theory calculations. While exposure of small molecules directly onto the Pt(100) surface will lift the reconstruction, a single graphene layer is observed to act as an effective coating, protecting the reactive surface from O(2) exposure and thus preserving the reconstruction underneath the graphene layer in O(2) pressures as high as 10(-4) mbar. A similar protective effect against CO is observed at CO pressures below 10(-6) mbar. However, at higher pressures CO is observed to intercalate under the graphene coating layer, thus lifting the reconstruction. The limitations of the coating effect are further tested by exposure to hot atomic hydrogen. While the coating can withstand these extreme conditions for a limited amount of time, after substantial exposure, the Pt(100) reconstruction is lifted. Annealing experiments and density functional theory calculations demonstrate that the basal plane of the graphene stays intact and point to a graphene-mediated mechanism for the H-induced lifting of the reconstruction. PMID- 23106829 TI - Effects of pre-weaning energy substitutions on post-weaning follicle development, steroid hormones and subsequent litter size in primiparous sows. AB - The present study investigated the effects of pre-weaning energy substitutions on follicular development, endocrine characteristics and subsequent litter size in primiparous sows. Sows were fed a standard lactation diet (14.1 DE MJ/kg) and then allocated to a Control (C, n = 24), Fat (F, n = 23), Sugar (S, n = 23) or post-weaning Regumate (positive control; R, n = 22) treatment at 9 days before weaning of the C, F and S treatments. During the treatment period (8 days), 1 kg of the lactation diet was substituted with 1 kg of a fat-rich (F, 23.85 DE MJ/kg) or sugar-rich (S, 15.75 DE MJ/kg) substitution for F and S sows, respectively. For the R treatment, sows were weaned 8 days earlier than other treatments and fed a lactation diet at 3.5 kg with two doses of altrenogest as topdressing from 1 day before weaning until the day on which the other sows were weaned. The F treatment aimed to increase energy intake, and the S treatment aimed to elevate post-prandial glucose and insulin concentrations. Weaning-to-ovulation interval tended to be reduced in the S treatment compared with C (p = 0.06) and F (p = 0.08) treatments. Body weight (BW) loss during the treatment period, post-weaning follicle development, plasma oestradiol and pre-weaning leptin did not differ among C, F and S sows, although BW loss was lower and leptin was higher in the R treatment. Post-ovulatory progesterone concentration in the S treatment was higher (p < 0.05). Sows in the S and R treatments had a greater proportion of litters with larger litter sizes (p < 0.05). The outcome suggests that increasing circulating insulin and glucose concentrations during late lactation or a week of metabolic recovery positively improves subsequent litter size in primiparous sows. PMID- 23106830 TI - Falls in older persons with intellectual disabilities: fall rate, circumstances and consequences. AB - BACKGROUND: Falling is a common cause of injuries and reduced quality of life. Persons with intellectual disabilities (ID) are at increased risk for falls and related injuries. As the number of elderly persons with ID is growing rapidly, it is imperative to gain insight into the quantity of the problem of falling, the circumstances that precipitate falls and to better understand their aetiology in persons with ID. This is the first study to prospectively investigate fall rate, circumstances and fall consequences in older adults with mild to moderate ID. METHOD: Eighty-two individuals with mild to moderate ID, 50 years and over [mean age 62.3 (SD = 7.6), 34 male], participated in this study, which was conducted at three service providers for persons with ID in the Netherlands. Falls were registered for 1 year with monthly fall registration calendars to determine the fall rate (mean number of falls per person per year). Information on fall circumstances and consequences was obtained from questionnaires completed by caregivers and study participants after each fall. RESULTS: We determined that the fall rate in this sample was 1.00 fall per person per year. Thirty-seven participants reported at least one fall (range 1-6). Sex and age were not related to falls. Most falls occurred while walking (63.3%), outside (61.7%) and in familiar environments (88.9%). Importantly, 11.5% of falls resulted in severe injuries, approximately half of which were fractures. CONCLUSION: The circumstances and consequences of falls in persons with ID are comparable to those of the general elderly population, but the rate is substantially higher. As such, appropriate fall prevention strategies must be developed for individuals with ID. PMID- 23106831 TI - Huckel and Mobius bond-shifting routes to configuration change in dehydro[4n+2]annulenes. AB - Computational investigation of the potential energy surfaces of dehydro[10]- and dehydro[14]annulenes revealed that mechanisms involving Huckel and Mobius pi-bond shifting can explain the observed or proposed configuration change reactions. Unlike the case of annulenes, in which bond-shift midpoints correspond to transition states, for transformations of dehydroannulenes with Deltatrans = 0, "hidden" Huckel bond shifts occur on the side of an energy hill, on the way to a cumulenic, purely conformational transition state. For example, interconversion between CTCCTC-dehydro[14]annulene (1a) and CCTCTC-dehydro[14]annulene (2a) has a CCSD(T)/cc-pVDZ//BHLYP/6-31G* barrier of 18.7 kcal/mol, consistent with experimental observations, and proceeds via a conformational transition state, with Huckel pi-bond shifts occurring both before and after the transition state. However, when Deltatrans = 1, a true Mobius pi-bond shift transition state was located. The isomerization of CCTC-dehydro[10]annulene (10) to CCCC dehydro[10]annulene (11) occurs by an initial "hidden" Huckel bond shift, followed by passage through a Mobius bond-shift transition state to 11, with an overall barrier of 29.8 kcal/mol at the CASPT2(12,12)/cc-pVDZ//(U)BHLYP/6-31G* level of theory. This is the lowest energy pathway between 10 and 11, in contrast to a cyclization/ring-opening route via a bicyclic allene described in previous reports. PMID- 23106832 TI - Risk of venous thrombosis in patients with major illnesses: results from the MEGA study. AB - BACKGROUND: The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high-risk groups that may provide a basis for personalized prevention. METHODS: This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case-control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self-reported history of major illnesses. RESULTS: Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI]1.0-2.9); kidney disease, OR 3.7 (95% CI 2.3-5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2 1.9); multiple sclerosis, OR 2.4 (95% CI 1.3-4.3); heart failure, OR 1.7 (95% CI 1.2-2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4-9.9); arterial thrombosis, OR 1.5 (95% CI 1.2-1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5-1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2-192.2), increased FIX (OR 35.3; 95% CI 14.2-87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9-228.3), FV Leiden (OR 84.2; 95% CI 19.5-363.6), and blood group non-O (OR 53.1; 95% CI 30.9 91.4) were associated with increased venous thrombosis risks. CONCLUSIONS: All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia. PMID- 23106833 TI - Androgen receptor association with mitotic chromatin - analysis with introduced deletions and disease-inflicting mutations. AB - Sequence and structural anomalies in the gene for androgen receptor (AR) or its protein are associated with a range of clinical manifestations. Observations from living cells have shown that AR translocates to the nucleus upon ligand binding, where it forms typical 'nuclear foci' that are considered as sites of gene transcription. Recently, we reported the ligand-mediated association of AR with mitotic chromatin and suggested its role in 'transcription memory', proposing a 'biopit model'. In the present study, we show that each of the AR domains is obligatory for its association with mitotic chromatin and also that full-length AR is necessary for efficient association. In addition, deletion or point mutations in bipartite nuclear localization signal (NLS) revealed impaired localization, 'nuclear foci' formation and abolished AR binding with mitotic chromatin. Interestingly, well-characterized AR-NLS mutants associated with the manifestation of pathological conditions (prostate cancer and androgen insensitivity syndrome) exhibited differential behaviour on mitotic chromatin and also impaired receptor localization and 'nuclear foci' formation. Finally, we report that, in addition to its functions in nuclear import, DNA binding, acetylation, N/C-termini interactions and transactivation, the AR-NLS region also functions as 'mitotic chromatin binding-determining region' and has a novel role in the regulation of the AR association with mitotic chromatin. PMID- 23106834 TI - Endometrial scratching to improve pregnancy rate in couples with unexplained subfertility: a randomized controlled trial. AB - AIM: The aim of this study was to examine the effect of endometrial scratching in women with unexplained infertility. MATERIAL AND METHODS: A randomized controlled trial was conducted in Mansoura University Teaching Hospital and a private practice setting. A total of 105 couples with unexplained infertility were randomly allocated into two groups: group A comprised 54 women who underwent endometrial scratching in the luteal phase of a spontaneous menstrual cycle; and group B included 51 women who underwent a placebo procedure. The main outcome measured was cumulative clinical pregnancy rate after 6 months and miscarriage rate. RESULTS: Clinical pregnancy rate was significantly higher in the women experiencing endometrial biopsy than in the control group (25.9% and 9.8%, respectively, P = 0.04). There was no significant difference in miscarriage rate between pregnant women in the endometrial injury group and pregnant women in the control group (12.5% and 16.5%, respectively, P = 0.79). CONCLUSIONS: Endometrial scratching may improve clinical pregnancy rates in couples with unexplained infertility. Adequately powered studies are mandated to confirm or refute the findings. PMID- 23106835 TI - Penile length and girth restoration in severe Peyronie's disease using circular and longitudinal grafting. PMID- 23106837 TI - Clinical applications of glass ionomers in endodontics: a review. AB - Glass ionomer cements (GICs) are biocompatible and have capacities to release fluoride and to bond to dentine, and thus are appropriate for use in endodontics. This paper reviews the composition and properties of different GICs, including their biocompatibility and antibacterial activity, their applications as intraorifice barriers and root canal sealers, and their use in the repair of root perforations, root-end fillings and temporary coronal restorations. PMID- 23106838 TI - Arrest of non-cavitated dentinal occlusal caries by sealing pits and fissures: a 36-month, randomised controlled clinical trial. AB - OBJECTIVE: This study aimed to evaluate the progression of sealed non-cavitated dentinal occlusal caries in a randomised controlled clinical trial. MATERIALS AND METHODS: Sixty teeth with non-cavitated dentinal occlusal caries were selected in patients with a high risk for caries. Patients were randomly divided into two groups so that each group included 30 teeth. Patients in the experiment group were given oral hygiene instructions and a fissure sealant. Patients in the control group were given oral hygiene instructions only. Caries progression and sealant loss were monitored over a period of 36 months by clinical and radiographic examinations. RESULTS: Clinical and radiographic progression of caries was significantly more frequent in the control group than in the experiment group. Three teeth lost their sealant and showed caries progression, but this was apparent only at the 12-month follow-up. At the 24- and 36-month recall appointments, neither sealant loss nor caries progression were observed. CONCLUSION: The pit and fissure sealant utilised in this study was shown to be effective in arresting carious lesions at 36 months. PMID- 23106839 TI - Estimation of the costs of smoking-related oral disease: a representative South Korean study. AB - OBJECTIVES: The objectives of this study were to estimate the socioeconomic and psychological costs associated with smoking-related oral disease (SROD) with the aim of generating objective data that could be used in smoking cessation counselling by dental care providers and could also serve as data with which to set standards and criteria for use in dental health insurance. METHODS: Patients were sourced from the 11 dental hospitals associated with dental schools in South Korea. A total of 1,288 of 10,080 patients with SROD were selected to participate in the study for a period of 2 years from January 2009 to March 2011. Data collected were analysed using spss Version 17.0. RESULTS: Among the SRODs, the most common was periodontal disease (40.7%). Periodontal disease accounted for the highest social and economic costs. Mouth cancer accounted for the highest psychological cost. CONCLUSIONS: In order to reduce associated socioeconomic and psychological costs, dental care providers and government should provide more proactive and more efficient smoking cessation programmes. PMID- 23106840 TI - Fluoridation advocacy in Queensland: a long and winding road. AB - BACKGROUND: By 1977, all Australian states and mainland territories, with the exception of Queensland, had widely implemented adjusted water fluoridation. This disparity in public health policy persisted until 2008. METHODS: This study analyses the sociopolitical and socioeconomic backgrounds that underpinned the repeal of the Fluoridation of Public Water Supplies Act (1963) and its replacement with the Water Fluoridation Act (2008). The authors used a literature review and historic method. References are in the public domain. RESULTS: The devolution, without funding, of a discretionary local authority power to fluoridate contributed to the perennial low fluoridation status in Queensland. A window of opportunity for fluoridation advocates opened between 2003 and 2008. Now that 87% of Queenslanders have access to optimally fluoridated water, Queensland premier Anna Bligh has largely delivered on a promise made in 2007 to fluoridate water supplies across the state. CONCLUSIONS: The implementation of adjusted water fluoridation requires not only political stability and resolve, but also centralised authority. The last of these factors must embrace the decision, the funding and the indemnity. State control over water-related infrastructure and water treatment enhances prospects for fluoridation. The roles of opinion polls, internal advisers and departmental figures are also confirmed. Political repercussions were minimal. PMID- 23106841 TI - The Caries Assessment Spectrum and Treatment (CAST) index: face and content validation. AB - OBJECTIVES: The aim of this study was to establish the face and content validity of the Caries Assessment Spectrum and Treatment (CAST) index. This hierarchical epidemiological index consists of 10 codes covering the spectrum of carious lesion progression and describing conditions ranging from the absence of carious lesions to the presence of sealants and restorations, the presence of lesions in enamel and dentine, and the presence of advanced stages of carious lesion in pulpal tissue and tissue surrounding the tooth. METHODS: Using the RAND modified e-Delphi consensus method, a set of 17 statements related to the content, including the codes and descriptions used, and suitability of the CAST index were scored on a scale of 1-9 by 15 senior epidemiologists from 15 countries over three rounds of assessment. Agreement of >= 75% was required to indicate consensus on a statement. RESULTS: Consensus was reached on 14 statements in the first round, none in the second and on the remaining three statements in the third round. To obtain feedback on the initial validation of the index and to test its external validity, 41 epidemiologists from 24 countries were requested to assess the validated statements. Minor changes to 10 of the 17 statements' content and descriptions were suggested; this necessitated the resubmission of the modified CAST index to the original 15 epidemiologists. Consensus of >= 80% was reached on all 10 statements regarding codes and their descriptions. CONCLUSIONS: After a total of four rounds with the panel members and one round with the feedback group, the CAST index was approved for face and content validity. External validity was obtained. The participating epidemiologists found the RAND modified e-Delphi consensus method to be a suitable instrument for reaching consensus. PMID- 23106836 TI - Minimal intervention dentistry for managing dental caries - a review: report of a FDI task group. AB - This publication describes the history of minimal intervention dentistry (MID) for managing dental caries and presents evidence for various carious lesion detection devices, for preventive measures, for restorative and non-restorative therapies as well as for repairing rather than replacing defective restorations. It is a follow-up to the FDI World Dental Federation publication on MID, of 2000. The dental profession currently is faced with an enormous task of how to manage the high burden of consequences of the caries process amongst the world population. If it is to manage carious lesion development and its progression, it should move away from the 'surgical' care approach and fully embrace the MID approach. The chance for MID to be successful is thought to be increased tremendously if dental caries is not considered an infectious but instead a behavioural disease with a bacterial component. Controlling the two main carious lesion development related behaviours, i.e. intake and frequency of fermentable sugars, to not more than five times daily and removing/disturbing dental plaque from all tooth surfaces using an effective fluoridated toothpaste twice daily, are the ingredients for reducing the burden of dental caries in many communities in the world. FDI's policy of reducing the need for restorative therapy by placing an even greater emphasis on caries prevention than is currently done, is therefore, worth pursuing. PMID- 23106842 TI - Use of barrier protection for sexual activity among women who have sex with women. AB - OBJECTIVE: To assess the frequency and associations of barrier protection use during sexual activity in a population of women who have sex with women (WSW). METHODS: WSW were invited to participate in an international internet-based survey. Information regarding ethnodemographics, sexual health, and barrier use during sexual activities was collected. RESULTS: The study cohort comprised 1557 participants. Barrier use was least prevalent during digital genital stimulation (11.3% ever used barriers) and most prevalent during stimulation with a sex toy (34.4% ever used barriers). Univariate analysis revealed that women in non monogamous relationships were more likely than monogamous women to always use barrier protection for sexual activity (14.3% vs 3.5%). On multivariate analysis, there was no association between barrier use and frequency of casual sexual activity or history of sexually transmitted infection. Small associations were noted between barrier use and certain sexual activities, age, race, and number of partners. CONCLUSION: Many WSW do not use barrier protection during sexual activity, even in the context of potentially risky sexual behaviors. Safer-sex practices among WSW merit increased attention from healthcare providers and public health researchers. PMID- 23106843 TI - "He hasn't got the real toolkit!" Young children's reasoning about real/not-real status. AB - During the preschool years, children develop an understanding of 2 types of real/not-real distinctions: ontological status and authenticity (Bunce & Harris, 2008). Two studies compared 3- to 5-year-old children's real/not-real judgments and justifications for 3 types of contrast involving a real entity and either a fictional character, a child dressing-up, or a Lego toy. As expected, all children discriminated between the real entities and toys and dressing-up, and they justified their judgments on the basis of authenticity. In contrast, only older children consistently discriminated between the real entities and fictional characters on the basis of ontological status. In Study 2, the real and not-real entities were presented as pairs rather than individually to define the intended contrast. This manipulation increased children's ability to discriminate between the real and not-real entities on the basis of authenticity. Together, these results support the hypothesis that understanding reality status on the basis of authenticity develops before ontological status. The development of reasoning about real/not-real status is discussed. PMID- 23106845 TI - The antecedents and consequences of racial/ethnic discrimination during adolescence: does the source of discrimination matter? AB - In the current study, we examined the precursors and consequences of discrimination for 876 Latino, African American, and Asian American adolescents (Mage = 16.9 years, SD = 0.43). The race/ethnic characteristics of schools and neighborhoods influenced adolescents' perceptions of the race/ethnic climates of these contexts. In turn, adolescents who viewed climates more negatively were more likely to perceive discriminatory treatment by school personnel, peers, and societal institutions. Discrimination from these 3 sources exerted differential influence on developmental outcomes: Greater discrimination from school personnel was associated with poorer academic performance, greater discrimination from peers was associated with more psychological maladjustment, and greater societal discrimination was associated with heightened racial awareness. Relations were consistent across race/ethnic groups and gender. Implications for intervening to reduce racial discrimination and other social stigmas are discussed. PMID- 23106844 TI - Theory-driven intervention for changing personality: expectancy value theory, behavioral activation, and conscientiousness. AB - Considerable evidence suggests that personality traits may be changeable, raising the possibility that personality traits most linked to health problems can be modified with intervention. A growing body of research suggests that problematic personality traits may be altered with behavioral intervention using a bottom-up approach. That is, by targeting core behaviors that underlie personality traits with the goal of engendering new, healthier patterns of behavior that, over time, become automatized and manifest in changes in personality traits. Nevertheless, a bottom-up model for changing personality traits is somewhat diffuse and requires clearer integration of theory and relevant interventions to enable real clinical application. As such, this article proposes a set of guiding principles for theory-driven modification of targeted personality traits using a bottom-up approach, focusing specifically on targeting the trait of conscientiousness using a relevant behavioral intervention, Behavioral Activation (BA), considered within the motivational framework of expectancy value theory (EVT). We conclude with a real case example of the application of BA to alter behaviors counter to conscientiousness in a substance-dependent patient, highlighting the EVT principles most relevant to the approach and the importance and viability of a theoretically driven, bottom-up approach to changing personality traits. PMID- 23106846 TI - Charting early trajectories of executive control with the shape school. AB - Despite acknowledgement of the importance of executive control for learning and behavior, there is a dearth of research charting its developmental trajectory as it unfolds against the background of children's sociofamilial milieus. Using a prospective, cohort-sequential design, this study describes growth trajectories for inhibitory control and cognitive flexibility across the preschool period in relation to child sex and sociofamilial resources. At ages 3, 3.75, 4.5, and 5.25 years, children (N = 388) from a broad range of social backgrounds were assessed using the Shape School, a graduated measure of executive control incorporating baseline, inhibitory control, and cognitive flexibility conditions. Measures of children's proximal access to learning resources and social network supports were collected at study entry. Findings revealed substantial gains in accuracy and speed for all Shape School conditions, these gains being particularly accelerated between ages 3 and 3.75 years. Improvements in inhibitory control were more rapid than those in flexible switching. Age-related differences in error and self correction patterns on the Shape School also suggest qualitative changes in the underlying processes supporting executive performance across early childhood. Children from homes with fewer learning resources showed a subtle lag in inhibition and cognitive flexibility performance that persisted at kindergarten entry age, despite exhibiting gradual catch up to their more advantaged peers for the nonexecutive, baseline task condition. The study provides a unique characterization of the early developmental pathways for inhibitory control and cognitive flexibility and highlights the critical role of stimulating early educational resources for shaping the dynamic ontogeny of executive control. PMID- 23106847 TI - Full-field optical coherence microscopy is a novel technique for imaging enteric ganglia in the gastrointestinal tract. AB - BACKGROUND: Noninvasive methods are needed to improve the diagnosis of enteric neuropathies. Full-field optical coherence microscopy (FFOCM) is a novel optical microscopy modality that can acquire 1 MUm resolution images of tissue. The objective of this research was to demonstrate FFOCM imaging for the characterization of the enteric nervous system (ENS). METHODS: Normal mice and EdnrB(-/-) mice, a model of Hirschsprung's disease (HD), were imaged in three dimensions ex vivo using FFOCM through the entire thickness and length of the gut. Quantitative analysis of myenteric ganglia was performed on FFOCM images obtained from whole-mount tissues and compared with immunohistochemistry imaged by confocal microscopy. KEY RESULTS: Full-field optical coherence microscopy enabled visualization of the full thickness gut wall from serosa to mucosa. Images of the myenteric plexus were successfully acquired from the stomach, duodenum, colon, and rectum. Quantification of ganglionic neuronal counts on FFOCM images revealed strong interobserver agreement and identical values to those obtained by immunofluorescence microscopy. In EdnrB(-/-) mice, FFOCM analysis revealed a significant decrease in ganglia density along the colorectum and a significantly lower density of ganglia in all colorectal segments compared with normal mice. CONCLUSIONS & INFERENCES: Full-field optical coherence microscopy enables optical microscopic imaging of the ENS within the bowel wall along the entire intestine. FFOCM is able to differentiate ganglionic from aganglionic colon in a mouse model of HD, and can provide quantitative assessment of ganglionic density. With further refinements that enable bowel wall imaging in vivo, this technology has the potential to revolutionize the characterization of the ENS and the diagnosis of enteric neuropathies. PMID- 23106848 TI - HIV-1 infection is associated with changes in nuclear receptor transcriptome, pro inflammatory and lipid profile of monocytes. AB - BACKGROUND: Persistent residual immune activation and lipid dysmetabolism are characteristics of HIV positive patients receiving an highly active antiretroviral therapy (HAART). Nuclear Receptors are transcription factors involved in the regulation of immune and metabolic functions through the modulation of gene transcription. The objective of the present study was to investigate for the relative abundance of members of the nuclear receptor family in monocytic cells isolated from HIV positive patients treated or not treated with HAART. METHODS: Monocytes isolated from peripheral blood mononuclear cells (PBMC) were used for analysis of the relative mRNA expressions of FXR, PXR, LXR, VDR, RARalpha, RXR, PPARalpha, PPARbeta, PPARgamma and GR by Real-Time polymerase chain reaction (PCR). The expression of a selected subset of inflammatory and metabolic genes MCP-1, ICAM-1, CD36 and ABCA1 was also measured. RESULTS: Monocytes isolated from HIV infected patients expressed an altered pattern of nuclear receptors characterized by a profound reduction in the expressions of FXR, PXR, PPARalpha, GR, RARalpha and RXR. Of interest, the deregulated expression of nuclear receptors was not restored under HAART and was linked to an altered expression of genes which supports both an immune activation and altered lipid metabolism in monocytes. CONCLUSIONS: Altered expression of genes mediating reciprocal regulation of lipid metabolism and immune function in monocytes occurs in HIV. The present findings provide a mechanistic explanation for immune activation and lipid dysmetabolism occurring in HIV infected patients and could lead to the identification of novel potential therapeutic targets. PMID- 23106850 TI - Prospects for using combined engineered bacterial enzymes and plant systems to rhizoremediate polychlorinated biphenyls. AB - The fate of polychlorinated biphenyls (PCBs) in soil is driven by a combination of interacting biological processes. Several investigations have brought evidence that the rhizosphere provides a remarkable ecological niche to enhance the PCB degradation process by rhizobacteria. The bacterial oxidative enzymes involved in PCB degradation have been investigated extensively and novel engineered enzymes exhibiting enhanced catalytic activities toward more persistent PCBs have been described. Furthermore, recent studies suggest that approaches involving processes based on plant-microbe associations are very promising to remediate PCB contaminated sites. In this review emphasis will be placed on the current state of knowledge regarding the strategies that are proposed to engineer the enzymes of the PCB-degrading bacterial oxidative pathway and to design PCB-degrading plant-microbe systems to remediate PCB-contaminated soil. PMID- 23106849 TI - Perinatal nicotine exposure induces asthma in second generation offspring. AB - BACKGROUND: By altering specific developmental signaling pathways that are necessary for fetal lung development, perinatal nicotine exposure affects lung growth and differentiation, resulting in the offsprings' predisposition to childhood asthma; peroxisome proliferator-activated receptor gamma (PPARgamma) agonists can inhibit this effect. However, whether the perinatal nicotine-induced asthma risk is restricted to nicotine-exposed offspring only; whether it can be transmitted to the next generation; and whether PPARgamma agonists would have any effect on this process are not known. METHODS: Time-mated Sprague Dawley rat dams received either placebo or nicotine (1 mg/kg, s.c.), once daily from day 6 of gestation to postnatal day (PND) 21. Following delivery, at PND21, generation 1 (F1) pups were either subjected to pulmonary function tests, or killed to obtain their lungs, tracheas, and gonads to determine the relevant protein markers (mesenchymal contractile proteins), global DNA methylation, histone 3 and 4 acetylation, and for tracheal tension studies. Some F1 animals were used as breeders to generate F2 pups, but without any exposure to nicotine in the F1 pregnancy. At PND21, F2 pups underwent studies similar to those performed on F1 pups. RESULTS: Consistent with the asthma phenotype, nicotine affected lung function in both male and female F1 and F2 offspring (maximal 250% increase in total respiratory system resistance, and 84% maximal decrease in dynamic compliance following methacholine challenge; P < 0.01, nicotine versus control; P < 0.05, males versus females; and P > 0.05, F1 versus F2), but only affected tracheal constriction in males (51% maximal increase in tracheal constriction following acetylcholine challenge, P < 0.01, nicotine versus control; P < 0.0001, males versus females; P > 0.05, F1 versus F2); nicotine also increased the contractile protein content of whole lung (180% increase in fibronectin protein levels, P < 0.01, nicotine versus control, and P < 0.05, males versus females) and isolated lung fibroblasts (for example, 45% increase in fibronectin protein levels, P < 0.05, nicotine versus control), along with decreased PPARgamma expression (30% decrease, P < 0.05, nicotine versus control), but only affected contractile proteins in the male trachea (P < 0.05, nicotine versus control, and P < 0.0001, males versus females). All of the nicotine-induced changes in the lung and gonad DNA methylation and histone 3 and 4 acetylation were normalized by the PPARgamma agonist rosiglitazone except for the histone 4 acetylation in the lung. CONCLUSIONS: Germline epigenetic marks imposed by exposure to nicotine during pregnancy can become permanently programmed and transferred through the germline to subsequent generations, a ground-breaking finding that shifts the current asthma paradigm, opening up many new avenues to explore. PMID- 23106851 TI - Does journal club membership improve research evidence uptake in different allied health disciplines: a pre-post study. AB - BACKGROUND: Although allied health is considered to be one 'unit' of healthcare providers, it comprises a range of disciplines which have different training and ways of thinking, and different tasks and methods of patient care. Very few empirical studies on evidence-based practice (EBP) have directly compared allied health professionals. The objective of this study was to examine the impact of a structured model of journal club (JC), known as iCAHE (International Centre for Allied Health Evidence) JC, on the EBP knowledge, skills and behaviour of the different allied health disciplines. METHODS: A pilot, pre-post study design using maximum variation sampling was undertaken. Recruitment was conducted in groups and practitioners such as physiotherapists, occupational therapists, speech pathologists, social workers, psychologists, nutritionists/dieticians and podiatrists were invited to participate. All participating groups received the iCAHE JC for six months. Quantitative data using the Adapted Fresno Test (McCluskey & Bishop) and Evidence-based Practice Questionnaire (Upton & Upton) were collected prior to the implementation of the JC, with follow-up measurements six months later. Mean percentage change and confidence intervals were calculated to compare baseline and post JC scores for all outcome measures. RESULTS: The results of this study demonstrate variability in EBP outcomes across disciplines after receiving the iCAHE JC. Only physiotherapists showed statistically significant improvements in all outcomes; speech pathologists and occupational therapists demonstrated a statistically significant increase in knowledge but not for attitude and evidence uptake; social workers and dieticians/nutritionists showed statistically significant positive changes in their knowledge, and evidence uptake but not for attitude. CONCLUSIONS: There is evidence to suggest that a JC such as the iCAHE model is an effective method for improving the EBP knowledge and skills of allied health practitioners. It may be used as a single intervention to facilitate evidence uptake in some allied health disciplines but may need to be integrated with other strategies to influence practice behaviour in other practitioners. An in-depth analysis of other factors (e.g. individual, contextual, organisational), or the relative contribution of these variables is required to better understand the determinants of evidence uptake in allied health. PMID- 23106853 TI - OnabotulinumtoxinA: a meta-analysis of duration of effect in the treatment of glabellar lines. AB - BACKGROUND: Duration of effect of aesthetic treatments with botulinum toxin potentially influences subject satisfaction, treatment frequency, and annual costs, but quantitative outcomes for measuring duration of effect and correlations with subject satisfaction have yet to be fully elucidated. METHODS AND MATERIALS: Phase III clinical trials with similar designs were identified and their data pooled to ascertain duration of clinical effect of onabotulinumtoxinA in glabellar muscles. Duration was calculated using the Kaplan-Meier method for investigator-rated Facial Wrinkle scale (FWS) scores and subject global assessment (SGA) of glabellar lines. Responders were determined according to FWS score at maximum contraction and at repose 30 days after injection. RESULTS: Data from four trials with 621 onabotulinumtoxinA-treated (20 U) subjects were analyzed, 523 of these (84.2%) were identified as day-30 responders on the FWS at maximum contraction. Pooled median duration of effect for day-30 responders was 120 days for FWS at maximum contraction and 131 days for FWS at repose. Higher day 30 SGA scores were correlated with a greater duration of effect on dynamic, but not static lines. CONCLUSION: Treatment of glabellar lines with 20 U of onabotulinumtoxinA resulted in sustained clinical benefit for 4 months in more than 50% of responders; subject satisfaction increased with duration of effect. PMID- 23106852 TI - Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug. AB - Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought. PMID- 23106854 TI - Probing local electromechanical effects in highly conductive electrolytes. AB - The functionality of a variety of materials and devices is strongly coupled with electromechanical effects which can be used to characterize their functionality. Of high interest is the investigation of these electromechanical effects on the nanoscale which can be achieved by using scanning probe microscopy. Here, an electrical bias is applied locally to the scanning probe tip, and the mechanical sample response is detected. In some applications with electromechanical phenomena, such as energy storage or for biological samples, a liquid environment is required to provide full functionality and sample stability. However, electromechanical sample characterization has mostly been applied in air or under vacuum due to the difficulties of applying local electric fields in a conductive environment. Here, we present a detailed study of piezoresponse force microscopy of ferroelectric samples in liquid environments as a model system for electromechanical effects in general. The ionic strength of the liquid is varied, and possibilities and limitations of the technique are explored. Numerical simulations are used to explain the observed phenomena and used to suggest strategies to work in liquid environments with high ionic strength. PMID- 23106855 TI - Diagnostic tests in urology: urine cytology. AB - What's known on the subject? and What does the study add? Urine cytology is frequently used by urologists to evaluate patients with microscopic or gross haematuria. The results of urine cytology can be used as impetus to perform or triage further diagnostic studies, e.g. cystoscopy. The impact of urine cytology results on patient care warrants clarifying. This evidence-based medicine article explores how positive or negative urine cytology will impact the probability that a patient has urothelial carcinoma of the bladder before cystoscopy. PMID- 23106857 TI - Validity of the reciprocity approach for determination of surface wave motion. AB - Expressions for the displacements and the stresses for surface wave motion generated by a time-harmonic line load applied to the surface of an isotropic linearly elastic half-space are determined in a simple manner by the use of the reciprocity theorem. It is shown that their amplitudes show perfect agreement with the corresponding amplitudes obtained in the conventional manner by applying the Fourier transform technique. As an application of the reciprocity approach, the surface wave motion generated by uniform pressure over a cylindrical cavity located on the surface of a half-space has been determined. The analytical results have been verified by comparison with boundary element method (BEM) results. For a prescribed frequency and depth of the cavity, the analytical and BEM results are graphically displayed versus the surface length of the cavity, and show excellent agreement. PMID- 23106856 TI - Patient and work flow and costs associated with staff time and facility usage at a comprehensive cancer centre in Quebec, Canada--a time and motion study. AB - BACKGROUND: Mapping patient and work flow and cost analysis studies can help determine the most efficient and cost effective way of providing health services while still maintaining the best standards of care. This study used both time and motion methodology and hospital data to assess the contribution of staff time and facility usage to the overall cost of cancer care during patient visits to a comprehensive cancer centre in Quebec, using metastatic colorectal cancer as a model. METHODS: A workflow diagram was created mapping direct and indirect steps involved during a patient's physician or treatment (FOLFOX/bevacizumab or XELOX/bevacizumab) visit. Staff were timed as they performed each task and this data together with compensation amounts were used to calculate personnel costs. Mean work times and 95% confidence intervals (CI) were calculated. Operation and maintenance (O&M) costs for the Centre were calculated using information from hospital databases. All costs were presented in constant Canadian dollars for the 2010-2011 fiscal year period. RESULTS: For physician visits, direct and indirect personnel costs were $9.25 (95%CI:$7.00-$11.51) and O&M costs were $60.21, for a total of $69.46 (95%CI:$67.21-$71.72). For treatment visits, personnel and O&M costs were $71.91 (95%CI:$45.53-$98.29) and $62.00 respectively for a total of $133.91 (95%CI:$107.53-$160.29). When calculated for treatment alone, the total cost was $136.06 (95%CI:$109.16-$162.95) for FOLFOX/bevacizumab and $119.94 (95%CI:$96.89-$142.99) for XELOX/bevacizumab. The highest cumulative personnel costs were for the pharmacists and nurses ($38.87 and $34.82 respectively). Regarding patient flow, total time in between steps was 77.6 and 49.5 minutes for a physician or treatment visit respectively. CONCLUSIONS: This study from a health care provider's perspective, demonstrated that in the context of increasingly expensive therapies, costs associated with staff time and facility usage do not contribute greatly to the overall cost of treating cancer at this cancer centre. It also illustrated the need for improvements in patient and work flow to reduce wait times in the clinic. PMID- 23106858 TI - Estimating the local viscoelastic properties from dispersive shear waves using time-frequency ridge analysis. AB - Modulated low-frequency shear waves can be non-invasively generated locally within a medium, by the oscillatory acoustic radiation force resulting from the interference of two focused quasi-CW ultrasound beams of slightly different frequencies. The propagation of such shear waves within a viscoelastic medium is known to be affected by the dispersive effects of viscosity. Specifically, a low frequency (LF) spectral component was shown to arise with increased viscosities and higher modulation frequencies and appear as a 'slow' wave at the end of the shear waveform. In this paper, the shear dispersion characteristics are studied based on the Pseudo-Wigner-Ville distribution (PWVD) in the time-frequency domain. The ridges of the PWVD are then extracted and used to calculate the frequency-dependent shear speed, by identifying the LF dispersive component both in time and frequency. Using numerical simulations, it is shown that this way of estimating the shear dispersion is more efficient and robust than the conventional phase-delay Fourier method. Thus, more accurate estimates of the local shear modulus and viscosity of the propagating medium could be achieved. The effects of noise on the proposed method are also discussed. PMID- 23106859 TI - Generation of uniform lesions in high intensity focused ultrasound ablation. AB - High intensity focused ultrasound (HIFU) is emerging as an effective oncology treatment modality according to the clinical experience in the last decade. The temperature at the focus can reach over 65 degrees C within seconds, denaturing cellular proteins and resulting in coagulative necrosis. HIFU parameters are usually kept the same for each treatment spot in tumor ablation. Because of the thermal diffusion from nearby spots, the lesion size will gradually increase as the HIFU therapy progresses, which leads to insufficient treatment of initial spots and over exposure of later ones. From the viewpoint of the physician, uniform lesions with the least energy exposure and the least energy are preferred in tumor ablation. In this study, an algorithm was developed to determine the number of HIFU pulses delivered to each spot in order to generate uniform lesions that fill the region-of-interest completely. The exposure energies required using different scanning pathways (raster scanning, spiral scanning from the center to the outside, and spiral scanning from the outside to the center), spot spacing (1mm, 2mm, 4mm, and 6mm) and motion time (from 0s to 400s) were compared with each other. It is found that spiral scanning from the outside to the center with spot spacing of 2mm and motion time less than 10s needs the least numbers of pulses or HIFU energy in uniform lesion production with the minimal temperature elevation. In addition, the effects of thermal properties of tissue (i.e., specific heat capacity, convective heat transfer coefficient, and thermal conductivity) on HIFU ablation were investigated in order to determine the HIFU treatment planning for various targets. Uniform lesion production in the transparent gel phantom and ex vivo bovine liver samples using the proposed algorithm proved effective and accord with the simulation for different scanning pathways by an extracorporeal clinical HIFU system. Therefore, dynamically adjusting ultrasound exposure energy can improve the efficacy and safety of HIFU ablation, and the treatment planning depends on the scanning protocol and thermal properties of the target. PMID- 23106861 TI - The wound healing effects of vitamin A eye drops after a corneal alkali burn in rats. AB - PURPOSE: We investigated the wound healing effect of retinyl palmitate eyedrops following a corneal alkali burn in rats. METHODS: A total of 160 Sprague-Dawley male rats were divided into two groups and central corneas were injured by contacting eyes with filter paper saturated with 0.01 m NaOH for 45 seconds. Vitamin A group was treated with retinyl palmitate and antibiotic (Cravit((r)) : 0.5% levofloxacin) eye drops four times daily for 3 days and the control group with vehicle and antibiotic eye drops. Corneal wound healing by fluorescein staining and impression cytologic analysis were conducted at 0, 24, 48 and 72 hr after injury. Vascular endothelial growth factor A (VEGF-A), thrombospondin 2, matrix metalloproteinase 9 (MMP 9) and transforming growth factor-beta (TGF-beta) were measured in corneas by ELISA, immunofluorescent staining and real-time PCR. RESULTS: Corneal wound healing was better in the vitamin A group than in the control group. Early sprouting of new vessel was observed in the control group at 72 hr, but not in the vitamin A group. Corneal thrombospondin 2 proteins in ELISA were higher in the vitamin A group, but VEGF-A, MMP 9 and TGF-beta proteins were higher in the control group (p < 0.05). Similarly, thrombospondin 2 immunofluorescent staining was stronger, whereas VEGF-A, MMP 9 and TGF-beta staining were weaker in the vitamin A group (p < 0.05). In addition, thrombospondin 2 mRNA levels were higher, whereas VEGF-A, MMP 9 and TGF-beta mRNA levels were lower in the vitamin A group (p < 0.05). CONCLUSIONS: Retinyl palmitate eye drops can inhibit VEGF-A and activate thrombospondin 2 and improve conjunctival impression cytologic findings. Furthermore, retinyl palmitate eye drops were found to promote corneal healing after an alkali burn in rats. PMID- 23106862 TI - Corneal endothelial cell density after ruthenium plaque radiation therapy for iris melanoma patients. PMID- 23106864 TI - Streptokinase variants from Streptococcus pyogenes isolates display altered plasminogen activation characteristics - implications for pathogenesis. AB - Streptococcus pyogenes (group A streptococcus, GAS) secretes streptokinase, a potent plasminogen activating protein. Among GAS isolates, streptokinase gene sequences (ska) are polymorphic and can be grouped into two distinct sequence clusters (termed cluster type-1 and cluster type-2) with cluster type-2 being further divided into sub-clusters type-2a and type-2b. In this study, far-UV circular dichroism spectroscopy indicated that purified streptokinase variants of each type displayed similar secondary structure. Type-2b streptokinase variants could not generate an active site in Glu-plasminogen through non-proteolytic mechanisms while all other variants had this capability. Furthermore, when compared with other streptokinase variants, type-2b variants displayed a 29- to 35-fold reduction in affinity for Glu-plasminogen. All SK variants could activate Glu-plasminogen when an activator complex was preformed with plasmin; however, type-2b and type-1 complexes were inhibited by alpha(2) -antiplasmin. Exchanging ska(type-2a) in the M1T1 GAS strain 5448 with ska(type-2b) caused a reduction in virulence while exchanging ska(type-2a) with ska(type-1) into 5448 produced an increase in virulence when using a mouse model of invasive disease. These findings suggest that streptokinase variants produced by GAS isolates utilize distinct plasminogen activation pathways, which directly affects the pathogenesis of this organism. PMID- 23106863 TI - Plasmin-dependent proteolysis of tissue factor pathway inhibitor in a mouse model of endotoxemia. AB - BACKGROUND: The development of a procoagulant state in sepsis, owing to aberrant expression of tissue factor (TF) and a sharp decrease in the level of its major inhibitor, TF pathway inhibitor (TFPI), could lead to microthrombotic organ failure. The mechanism for the decline in TFPI activity in the lung could involve plasmin-mediated cleavage of the inhibitor. OBJECTIVE: To investigate the effect of plasmin generation on lung-associated TFPI activity, in normal conditions and during infusion of endotoxin (lipopolysaccharide [LPS]) in mice. METHODS: Plasmin generation and TFPI activity were assayed in the lungs of mice deficient in tissue-type plasminogen (Plg) activator (t-PA) or Plg, at 2 h after LPS or saline injection. RESULTS: The sharp loss of lung-associated TFPI activity at 2 h after LPS challenge paralleled the abrupt increase in plasmin generation. TFPI activity was significantly retained in both t-PA(-/-) and Plg(-/-) mice, which are unable to generate plasmin. CONCLUSION: The increased plasmin generation during the early stages of sepsis could cleave/inactivate TFPI and thus lead to thrombotic complications. PMID- 23106865 TI - Psychological therapies for people with intellectual disabilities: comments on a matrix of evidence for interventions in challenging behaviour. AB - BACKGROUND: Psychological therapies with a proven efficacy in the general population are being adapted for use with people who have intellectual disabilities in community settings. METHODS: A systematic review of peer-reviewed literature published between 1980 and 2010 was carried out, to identify the evidence base for effective psychological interventions in challenging behaviour. Relevant databases were searched using applied key terms. Evidence was graded, according to the quality of the research. A best-evidence Matrix was produced to improve guidance for service providers and practitioners in the range, volume and quality of psychological interventions. RESULTS: There is a limited amount of efficacy research that meets the most stringent standards of empirical evidence. CONCLUSIONS: It is important to broaden the evidence base and consider the context of psychological interventions, alongside the values underpinning care and treatment. PMID- 23106866 TI - Cervical clamp with ring forceps to prevent prolapse of an intrauterine balloon in the management of postpartum hemorrhage. AB - An intrauterine balloon tamponade is a simple but highly effective method for the management of postpartum hemorrhage. However, treatment failure can occur due to prolapse of an intrauterine balloon into the vagina. We present two cases with a successful maneuver in maintaining the intrauterine placement of the balloon by clamping the cervix with two ring forceps in the management of postpartum hemorrhage. Although the balloon was initially expelled through a dilated cervix, a cervical clamp using ring forceps prevented displacement of the balloon, and the hemorrhage ceased. Clamping the cervix with two ring forceps to retain the balloon can be a simple and readily available approach to consider when an intrauterine balloon tamponade does not work due to its expulsion. PMID- 23106868 TI - The status of surgical simulation. PMID- 23106869 TI - Medical expulsion therapy for urinary calculi. PMID- 23106870 TI - Laparoscopic training of urology in China: current status. PMID- 23106867 TI - Relationship between overactive bladder and irritable bowel syndrome: a large scale internet survey in Japan using the overactive bladder symptom score and Rome III criteria. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is known to be an association between overactive bladder (OAB) and irritable bowel syndrome (IBS). The study investigates the association between OAB and IBS using an internet-based survey in Japan. It is the first to investigate the prevalence and severity of OAB in the general population using the OAB symptom score questionnaire. OBJECTIVE: To investigate the association between overactive bladder (OAB) and irritable bowel syndrome (IBS) by using an internet-based survey in Japan. SUBJECTS AND METHODS: Questionnaires were sent via the internet to Japanese adults. The overactive bladder symptom score was used for screening OAB, and the Japanese version of the Rome III criteria for the diagnosis of IBS was used for screening this syndrome. RESULTS: The overall prevalence of OAB and IBS was 9.3% and 21.2%, respectively. Among the subjects with OAB, 33.3% had concurrent IBS. The prevalence of OAB among men was 9.7% and among women it was 8.9%, while 18.6% of men and 23.9% of women had IBS. Concurrent IBS was noted in 32.0% of men and 34.8% of women with OAB. CONCLUSION: Taking into account a high rate of concurrent IBS in patients with OAB, it seems to be important for physicians to assess the defaecation habits of patients when diagnosing and treating OAB. PMID- 23106871 TI - A randomized controlled trial of postoperative tumor lysate-pulsed dendritic cells and cytokine-induced killer cells immunotherapy in patients with localized and locally advanced renal cell carcinoma. AB - BACKGROUND: It remains a challenge to inhibit the local recurrence or distant metastasis of localized or locally advanced renal cell carcinoma (RCC) after surgical resection. We investigated the feasibility, safety and efficacy of immunotherapy using autologous tumor lysate (TL)-pulsed dendritic cells (DCs) and cytokine-induced killer (CIK) cells in patients with localized or locally advanced RCC. METHODS: From January 2001 to July 2009, we collected 137 patients that met the selection criteria and randomly divided them into three groups. After surgery, immunotherapy with TL-pulsed DCs-CIK cells (DC-CIK group) and interferon (IFN)-alpha (IFN-alpha group) was performed in 46 patients, respectively. The other 45 patients received no postoperative adjuvant therapy (the control group). The changes in the numbers of T lymphocyte subsets, including CD4(+)CD25(high) regulatory T cells (Treg), were determined before the operation and after immunotherapy. The overall survival was compared among the three groups. RESULTS: An increase of the CD4(+)/CD8(+) ratio and a decrease of CD4(+)CD25(high) cells were observed after TL-pulsed DC-CIK cells or IFN-a immunotherapy. All patients tolerated the TL-pulsed DC-CIK cells immunotherapy very well, and side effects in the DC-CIK group were less than in the IFN-alpha group. The metastasis and recurrence rates were significantly decreased after TL pulsed DC-CIK cells or IFN-alpha immunotherapy compared with the control group (P < 0.01). The Log-rank test showed that the overall survival rates were significantly higher in the DC-CIK group and IFN-alpha group than that in the control group (P < 0.01), but there was no difference between the DC-CIK group and IFN-alpha group (P > 0.05). CONCLUSION: Postoperative immunotherapy with TL pulsed DC-CIK cells may prevent recurrence/metastasis and increase the overall survival rate after surgery in localized or locally advanced RCC. PMID- 23106872 TI - Multiple factors related to detrusor overactivity in Chinese patients with benign prostate hyperplasia. AB - BACKGROUND: Detrusor overactivity (DO) is a known cause of lower urinary tract symptoms and occurs in 50% - 75% of benign prostate hyperplasia (BPH) patients. We sought to investigate the clinical and urodynamic factors that are associated with the presence of DO in Chinese BPH patients. METHODS: Two hundred and eighty seven consecutive patients with clinical BPH were retrospectively evaluated in this study. Each patient underwent urodynamic evaluation and completed the International Prostate Symptom Score (IPSS) and Quality of Life (QoL) questionnaire. Patients with neurological symptoms or other diseases likely to affect detrusor functions were strictly excluded. The 184 BPH patients included in the study were divided into groups according to the presence of DO as shown in urodynamic tests. Univariate analysis of factors associated with the presence of DO were performed using Student's t-test and the Mann-Whitney test; multivariate analysis used stepwise Logistic regressions. The relationship between degree of bladder outlet obstruction (BOO) and DO was also investigated using a linear-by linear association test. RESULTS: Of 184 BPH patients, DO was present in 76 (41.3%). On univariate analysis, patients with DO were older (P = 0.000), and showed smaller maximal bladder capacity (MBC, P = 0.000) and voided volume (P = 0.000), higher maximal detrusor pressure (P = 0.000) and projected isovolumetric pressure (PIP) (P = 0.005), higher Abrams-Griffiths number (P = 0.000) and degree of bladder outlet obstruction (P = 0.000), higher IPSS (P = 0.000) and irritative IPSS subscores (P = 0.000). Stepwise Logistic regression analysis showed that PIP (OR = 1.012, 95% CI 1.002 - 1.023, P = 0.019), age (OR = 1.030, 95%CI 1.005 - 1.067, P = 0.059), and MBC (OR = 0.993, 95%CI 0.990 - 0.996, P = 0.000) were independent risk factors for DO in BPH patients. Linear-by-linear association tests indicated a positive linear association between DO and severity of BOO, with incidence of DO increasing with BOO grade (P = 0.000). CONCLUSIONS: In Chinese BPH patients, PIP, MBC, and age were independent factors affecting the presence of DO. DO incidence continuously increases with the degree of BOO. PMID- 23106873 TI - Risk factors for delayed graft function in cardiac death donor renal transplants. AB - BACKGROUND: Delayed graft function (DGF) is common in kidney transplants from organ donation after cardiac death (DCD) donors. It is associated with various factors. Determination of center-specific risk factors may help to reduce the incidence of DGF and improve the transplantation results. The aim of this study is to define risk factors of DGF after renal transplantation. METHODS: From March 2010 to June 2012, 56 cases of recipients who received DCD kidneys were selected. The subjects were divided into two groups: immediate graft function (IGF) and DGF groups. Transplantation factors of donors and recipients as well as early post transplant results of recipients were compared between the two groups. RESULTS: On univariate analysis, preoperative dialysis time of recipients (P < 0.001), type of dialysis (P = 0.039), human leucocyte antigen (HLA) mismatch sites (P < 0.001), the cause of brain death (P = 0.027), body mass index (BMI) of donors (P < 0.001), preoperative infection (P = 0.002), preoperative serum creatinine of donors (P < 0.001), norepinephrine used in donors (P < 0.001), cardiopulmonary resuscitation (CPR) of donors (P < 0.001), warm ischemia time (WIT) (P < 0.001) and cold ischemia time (CIT) (P < 0.001) showed significant differences. Recipients who experienced DGF had a longer hospital stay, and higher level of postoperative serum creatinine. CONCLUSION: Multiple risk factors are associated with DGF, which had deleterious effects on the early post-transplant period. PMID- 23106874 TI - OX40 mRNA in peripheral blood as a biomarker of acute renal allograft rejection. AB - BACKGROUND: Acute rejection remains an important cause of renal allograft dysfunction and the need for accurate diagnosis is essential to successfully treat transplant recipients. The purpose of this study was to determine the costimulatory molecules OX40 and OX40L messenger RNA (mRNA) levels in peripheral blood mononuclear cells (PBMCs) to predict acute renal transplant rejection. METHODS: The whole blood samples from 20 recipients with biopsy-confirmed acute rejection (rejection group), 20 recipients with stable graft function and normal biopsy results (stable group) after kidney transplantation, and 20 healthy volunteers (control group) were collected. The mRNA levels of OX40 and OX40L were analyzed with TaqMan real-time reverse transcriptase polymerase chain reaction (RT-PCR). The association of OX40 and OX40L mRNA levels with disease severity was investigated. RESULTS: There was no significant difference of OX40, OX40L mRNA levels in PBMCs between the stable group and control group (P > 0.05). The levels of OX40 and OX40L mRNA were significantly higher in the rejection group than in the control group (P < 0.01 and P < 0.05, respectively). Non-significantly higher OX40L mRNA and significantly higher OX40 mRNA in PBMCs were observed in subjects in the rejection group compared with the stable group (P > 0.05 and P < 0.01, respectively). Receiver operating characteristic (ROC) curve analysis demonstrated that OX40 mRNA levels could discriminate recipients who subsequently suffered acute allograft rejection (area under the curve, 0.908). OX40 and OX40L mRNA levels did not significantly correlate with serum creatinine levels in the rejection group (P > 0.05). Levels of OX40 mRNA after anti-rejection therapy were lower than those at the time of protocol biopsy in the rejection group (P < 0.05). CONCLUSION: Our data suggest that measurement of OX40 mRNA levels after transplant might offer a noninvasive means for recognizing recipients at risk of acute renal allograft rejection. PMID- 23106875 TI - A novel set of surgical instruments facilitate the procedure of laparoscopic pyeloplasty. AB - BACKGROUND: Open pyeloplasty has been historically described as the gold standard for the surgical treatment of ureteropelvic junction obstruction (UPJO), even if new techniques have recently gained a prominent role in this field. Laparoscopic pyeloplasty (LP) is not widely prevelant because of the technically challenging nature and it represents the gold standard for UPJO only in expert hands. To overcome some difficulties and technical challenges encountered during pure laparoscopic pyeloplasty, we designed a set of new instruments and assessed them using porcine model. METHODS: According to the ideas from the surgeons, our medical engineer designed three new instruments, including the right angle laparoscopy scissors, the petal-shape ureter dilator and the guide tube. Four experienced laparoscopic experts were involved in a no survival porcine study to assess the help of these new instruments. Four experiments were conducted on live pigs that weighed 22 to 25 kg at the same time. After general anesthesia was administered, transperitoneal ureteroureterostomy was performed using standard laparoscopic instruments, including placing the double J stent anterograde. Then, the opposite lateral was done by the same surgeon plus these new devices for side by-side comparative analysis. All experts were interviewed to assess these new instruments by the questionnaire based on the visual analog scale (VAS) from 1 (none) to 10 (very much). RESULTS: The procedures were all technically successful. The right angle laparoscopy scissors and the guide tube were accepted by all participants and the Help Score were 6.75 and 4.25 respectively, at the same time the New Difficulty Score 1.25 and 1.75. However, the petal-shape ureter dilator got 1.5 Help Score and 6.5 New Difficulty Score. These surgeons made a negative comment and one of surgeons recommended the stone basket was more suitable. CONCLUSION: The right angle laparoscopy scissors and the guide tube may be helpful to minimize some difficulties in pure laparoscopic pyeloplasty. PMID- 23106876 TI - Are Partin tables suitable for Chinese patients with prostate cancer? AB - BACKGROUND: Recently, the number of patients with prostate cancer who needed to be treated with radical prostatectomy increased rapidly in China. There is still a difference between clinical staging and the post-operative final pathologic staging; hence, an excellent tool for accurately predicting the pathologic stages of prostate cancer is needed urgently in clinical practice. The Partin tables are the most popular and widely used tool for predicting the pathologic stages of prostate cancer because of its high accuracy and ease of implementation. The aim of this study was to externally validate the accuracy of the three versions of the Partin tables in predicting the post-operative pathologic stages in Chinese patients with prostate cancer. METHODS: We retrospectively analyzed the data from 203 patients with prostate cancer who underwent radical prostatectomies between June 2000 and May 2012. The accuracies of the three versions of the Partin tables in predicting the post-operative pathologic stages in Chinese patients with prostate cancer were evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Using the 1997, 2001, and 2007 Partin tables for predicting the current cases, the AUC of organ confinement (OC) was 0.877, 0.788, and 0.726; the AUC of extracapsular extension (ECE) was 0.525, 0.615, and 0.608; the AUC of seminal vesicle invasion (SVI) was 0.875, 0.649, and 0.820; and the AUC of pelvic lymph node invasion (LNI) was 0.808, 0.758, and 0.735 respectively. CONCLUSIONS: The accuracies of the three versions of Partin tables in predicting OC, SVI, and LNI were good, especially the 2001 Partin table for SVI. In contrast, the accuracy of the three versions of the Partin tables in predicting ECE was fair. The 1997 Partin table was much better than the 2007 table in predicting OC, and the 2001 table in predicting SVI. The 2007 Partin table did not show any advantages. PMID- 23106877 TI - ADAM9 decreases in castration resistant prostate cancer and is a prognostic factor for overall survival. AB - BACKGROUND: A disintegrin and metalloprotease 9 (ADAM9) is a membrane-anchored enzyme which is considered to be involved in some diseases including tumor. However, the role of ADAM9 in castration resistant prostate cancer (CRPC) is not clear. This study aimed to explore the different expressions on protein and messenger RNA (mRNA) level of ADAM9 between hormonal sensitive prostate cancer (HSPC) and CRPC tissue, and find the correlation with prognosis. METHODS: Clinicopathologic characteristics of 106 HSPC and 76 CRPC cases were collected. The ADAM9 expressions were analyzed using immunohistochemistry. ADAM9 mRNA of 32 additional cases (16 HSPC and 16 CRPC patients) were analyzed via quantitative real-time polymerase chain reaction (RT-PCR). The prediction values of variables for overall survival (OS) of CRPC patients were analyzed using Cox regression. RESULTS: ADAM9 protein expression was significantly downregulated in CRPC compared with HSPC tissue (31.6% vs. 81.1%, P < 0.001). The relativity transcription level of ADAM9 mRNA was 0.45 for CRPC tissue and 1.0 for HSPC tissue (P = 0.002). In the CRPC group, patients with low ADAM9 protein expression were significantly associated with shorter OS than patients with high expression (38.6 months vs. 57.8 months, hazard rate (HR) = 2.638, P = 0.023). CONCLUSION: ADAM9 expression was low in CRPC, correlated with poor prognosis and might be involved in the succession from HSPC to CRPC by various functions. PMID- 23106878 TI - Androgen replacement therapy improves psychological distress and health-related quality of life in late onset hypogonadism patients in Chinese population. AB - BACKGROUND: Late onset hypogonadism negatively impacts on men's psychological well-being. This study was conducted to examine the interrelationship among symptoms of testosterone deficiency, psychological well-being, and quality of life. METHODS: Eligible subjects were randomized into active treatment and control groups, and were asked to complete the following questionnaires at baseline and month 6: aging male's symptoms (AMS) rating scale, hospital anxiety and depression scale (HADS), perceived stress scale (PSS) and the short form health survey-12 (SF-12). In this study, men were treated and monitored for 6 months with oral testosterone undecanoate (TU) capsules or vitamin E/C capsules in a single-blinded fashion. All in the active treatment group were administered a total of 120 - 160 mg TU orally on a daily basis. Total and free T levels between baseline and month 6 were compared. RESULTS: One hundred and sixty eligible subjects were recruited and followed up. In the active treatment group, total serum testosterone concentrations before and after intervention were (7.98 +/- 0.73) nmol/L and (13.7 +/- 1.18) nmol/L. The mean HADS anxiety subscale scores for the subjects at baseline and at month 6 were 3.47 +/- 0.4 and 1.72 +/- 0.2, respectively (t = 1.526, P < 0.05). Additionally, the mean HADS depression subscale scores were 4.91 +/- 0.6 and 2.39 +/- 0.3, respectively (t = 3.466, P < 0.05). The mean scores on PSS for the subjects at baseline and at month 6 were 12.88 +/- 2.1 and 9.83 +/- 1.7, respectively (t = 4.009, P < 0.05). Significantly improved SF-12 could be observed (t = 1.433 and 1.118, respectively; both P < 0.05). No significant changes were observed in the control group at month 6. CONCLUSION: Androgen replacement not only improves androgen deficiency associated symptoms, but also enhances comprehensive improvement in psychological issues. PMID- 23106879 TI - Efficacy and safety of bipolar plasma vaporization of the prostate with "button type" electrode compared with transurethral resection of prostate for benign prostatic hyperplasia. AB - BACKGROUND: Transurethral resection of prostate (TURP) has been considered as the standard treatment for benign prostatic hyperplasia (BPH). However, issues that have not yet been overcome for TURP include bleeding and absorption of irrigation fluid. Thus, novel improvement of the surgery is necessary. This study aimed to evaluate the efficacy and safety of bipolar plasma vaporization of the prostate (BPVP) with "button-type" electrode against standard TURP for BPH. METHODS: From January 2009 to January 2012, 30 patients who scheduled for surgical treatment of BPH surgical treatment were enrolled in the trial with provided consent for the study. Patients were prospectively randomized 1:1 to undergo either BPVP or TURP. Participants were blinded to the randomization scheme. All cases were assessed preoperatively and followed at 1, 3, and 6 months postoperatively by indwelling catheter time, blood loss, hospital stays, International Prostate Symptom Score (IPSS), quality of life (QOL), and Qmax. RESULTS: BPVP was significantly superior to TURP in terms of indwelling catheter time ((4.1 +/- 4.1) days vs. (6.8 +/- 6.8) days, P = 0.000), blood loss ((64.7 +/- 103.8) ml vs. (254.7 +/- 325.4) ml, P = 0.040), hospital stay ((8.7 +/- 1.0) days vs. (11.7 +/- 1.5) days, P = 0.000), IPSS ((4.2 +/- 8.0) vs. (9.3 +/- 3.7), P = 0.049), QOL ((1.5 +/- 0.8) vs. (2.6 +/- 1.4), P = 0.027), Qmax ((16.3 +/- 5.7) ml/s vs. (12.5 +/- 3.1) ml/s, P = 0.038), hemoglobin ((130.7 +/- 9.4) g/L vs. ((122.1 +/- 11.9) g/L, P = 0.047), Na(+) level ((138.6 +/- 2.1) mmol/L vs. ((137.2 +/- 2.0) mmol/L, P = 0.046) and operation time ((39.0 +/- 15.5) minutes vs. ((69.3 +/- 24.8) minutes, P = 0.004). And there were no statistical differences between BPVP group and TURP group in preoperatively assessment: patient's age ((70.9 +/- 7.1) years vs. (71.9 +/- 6.1) years, P = 0.736), IPSS ((24.6 +/- 4.7) vs. (27.3 +/- 5.9), P = 0.100), QOL ((5.1 +/- 0.8) vs. (5.1 +/- 1.0), P = 0.940), Qmax ((4.4 +/- 2.7) ml/s vs. (5.3 +/- 2.6) ml/s, P = 0.314), hemoglobin ((137.4 +/- 8.7) g/L vs. (139.2 +/- 10.4) g/L, P = 0.623), Na(+) level ((140.5 +/- 1.8) mmol/L vs. (141.3 +/- 1.4) mmol/L, P = 0.192) and prostate volume ((59.0 +/- 17.4) ml vs. (70.1 +/- 28.8) ml, P = 0.276). CONCLUSIONS: Compared with TURP, BPVP with "button-type" electrode shows superior efficacy and safety. Therefore, BPVP with "button-type" electrode represents a valuable endoscopic treatment alternative for BPH patients. PMID- 23106880 TI - Laparoendoscopic single-site radical prostatectomy: technique and initial outcomes. AB - BACKGROUND: Laparoendoscopic single-site surgery radical prostatectomy (LESS-RP) is a challenging urological procedure and needs to be further evaluated. This study was undertaken to illustrate the safety and initial results of pure LESS-RP with conventional available instruments. METHODS: A prospective clinical database was established in September 2010 to assess the outcome following the introduction of LESS-RP at our institution. By June 2012, six procedures had been performed. The mean patient age was 74.7 (74.0 - 76.0) years. The mean body mass index (BMI) was 23.8 (19.5 - 32.2) kg/m(2). The LESS-RP was preformed through an extra-peritoneal approach using single port access with QudaPort, 0 degrees lens 5 mm flexible tip video-laparoscope and available conventional laparoscopic instruments. Parameters assessed were operative time, estimated blood loss, intra operative complications, drainage time, postoperative pain score (visual analogue pain scale (VAPS), 0 - 10), pathological results, and postoperative prostate specific antigen (PSA) levels. RESULTS: LESS-RP was completed for all six cases without additional trocar placement or conversion to standard laparoscopic or open radical prostatectomy. The mean operative times were 252.5 (190.0 - 305.0) minutes, estimated blood loss was 300 (100 - 500 ml). There was no documentable intraoperative complication. The mean wound-drainage time was 5.2 (2.0 - 7.0) days, and the first postoperative day VAPS was 0.8 (0 - 3.0). Final pathological staging was pT2aN0M0 in four cases and pT2cN0M0 in two cases. Surgical margins were negative for all cases. The one-month post-operative PSA was less than 0.02 ng/ml in each case. All patients were continent without pad usage at 1 year postoperatively. CONCLUSION: The technique of pure LESS-RP is feasible and early outcomes are acceptable. PMID- 23106881 TI - Clipping the extremity of ureter prior to nephroureterectomy is effective in preventing subsequent bladder recurrence after upper urinary tract urothelial carcinoma. AB - BACKGROUND: Bladder recurrent disease is still a challenge in the treatment of upper tract urothelial carcinoma (UTUC). This controlled study aims to investigate the efficacy of early clipping of the distal ureter prior to nephroureterectomy (NU) to prevent bladder recurrence after UTUC. METHODS: Patients with clinical diagnosis of UTUC were subjected to open trans-peritoneal NU and were randomly divided into two groups. One group received modified NU: clipping the distal ureter prior to NU; while the other group underwent traditional standard NU. Subsequent bladder recurrence was the primary endpoint. RESULTS: From January 2007 to December 2009, 85 eligible cases were enrolled in this study. Modified NU and standard NU were performed on 42 and 43 patients, respectively. Operation time ((215.73 +/- 21.26) minutes vs. (220.19 +/- 15.35) minutes), blood loss ((105.15 +/- 11.32) ml vs. (110.12 +/- 9.07) ml), transfusion event (11.20% vs. 9.78%), and the in-patient time (10.0 days vs 9.5 days) were not significant between the two groups. After a median follow-up of 28 months (5 - 60), six (14.3%) cases who received modified NU had bladder recurrence, which was significantly lower compared with 15 (34.9%) patients from the group that underwent standard NU (P = 0.026). In univariate and multivariate analysis, tumor grade (HR 4.33, 95%CI 2.66 - 6.30, P = 0.01) and operation type (HR 2.35, 95%CI 1.53 - 3.48, P = 0.041) were independent risk factors for subsequent bladder recurrence after UTUC. CONCLUSIONS: Clipping the distal ureter at the beginning of NU significantly reduces bladder recurrence after UTUC. It is reasonable to conclude that clipping the distal portion of ureter trans peritoneal is an effective surgical procedure for the treatment of UTUC. PMID- 23106882 TI - Total endoscopic nephroureterectomy for native kidney ipsilateral to transplanted kidney. AB - BACKGROUND: From limited exposure with management of the native distal ureter ipsilateral to the transplanted kidney, we usually choose open nephroureterectomy (NU) or laparoscopic NU combined with an open approach in renal transplant (RTx) recipients. We herein describe our preliminary experience with total endoscopic NU with bladder cuff (BC) excision and evaluate its feasibility for RTx recipients. METHODS: From August 2008 to June 2011, eight RTx recipients underwent total endoscopic NU with BC excision for clinically presumed native upper urinary tract urothelial carcinoma (UUT-UC) ipsilateral to the transplanted kidney. Cystoscopic circumferential excision of the ipsilateral ureteral orifice with BC was followed by retroperitoneal laparoscopic NU using early ureteral ligation without primary BC closure. The intact specimen was removed through a 3 cm flank incision (an enlarged trocar site). Perioperative and pathological data and oncological outcomes were collected and analyzed. RESULTS: All endoscopic procedures were completed successfully without major complications and with open conversion. The mean estimated blood loss was 100 ml with no blood transfusion. The mean operating room time was 234.8 minutes, mean time to ambulation was 2.6 days, and mean hospital stay was 9.0 days. Pathological findings confirmed UUT-UC in seven recipients, two with bladder UC. During the mean 25.2-month follow-up, none of the recipients developed recurrence, while two developed contralateral UUT-UC after the first NU. CONCLUSION: Total endoscopic NU with BC excision is technically feasible and safe for RTx recipients. PMID- 23106883 TI - Gliosis after traumatic brain injury in conditional ephrinB2-knockout mice. AB - BACKGROUND: In response to the injury of the central nervous system (CNS), the astrocytes upregulate the expression of glial fibrillary acidic protein (GFAP), which largely contributes to the reactive gliosis after brain injury. The regulatory mechanism of this process is still not clear. In this study, we aimed to compare the ephrin-B2 deficient mice with the wild type ones with regard to gliosis after traumatic brain injury. METHODS: We generated ephrin-B2 knockout mice specifically in CNS astrocytes. Twelve mice from this gene-knockout strain were randomly selected along with twelve mice from the wild type littermates. In both groups, a modified controlled cortical impact injury model was applied to create a closed traumatic brain injury. Twenty-eight days after the injury, Nissl staining and GFAP immunofluorescence staining were used to compare the brain atrophy and GFAP immunoreactivity between the two groups. All the data were analyzed by t-test for between-group comparison. RESULTS: We successfully set up the conditional ephrin-B2 knockout mice strain, which was confirmed by genotyping and ephrin-B2/GFAP double staining. These mice developed normally without apparent abnormality in general appearance. Twenty-eight days following brain injury, histopathology revealed by immunohistochemistry showed different degrees of cerebral injuries in both groups. Compared with wild-type group, the ephrin-B2 knockout group exhibited less brain atrophy ratio for the injured hemispheres (P = 0.005) and hippocampus (P = 0.027). Also the wild-type group demonstrated greater GFAP immunoreactivity increment within hippocampal regions (P = 0.008). CONCLUSIONS: The establishment of conditional ephrin-B2 knockout mice provides us with a new way to explore the role of ephrin-B2 in astrocytes. Our findings revealed less atrophy and GFAP immunoreactivity in the knockout mice strain after traumatic brain injury, which implied ephrin-B2 could be one of the promoters to upregulate gliosis following brain injury. PMID- 23106884 TI - Epicardial radiofrequency ablation for left ventricular aneurysm related ventricular arrhythmias during off-pump coronary artery bypass surgery. AB - BACKGROUND: Left ventricular aneurysm (LVA) is one of the serious complications after acute myocardial infarction. We attempted to evaluate the preliminary efficacy of LVA repair combined with epicardial radiofrequency ablation for ventricular arrhythmia during off-pump coronary artery bypass grafting (OPCAB). METHODS: From June 2009 to April 2011, 31 patients with LVA had angina symptoms and ventricular arrhythmia. In all patients, circular and cross-shaped radiofrequency epicardial ablations were performed using unipolar ablation pen along the border between the aneurysm wall and normal cardiac tissue and in the central zone of the aneurysms, followed by a linear placation of ventricular aneurysms on beating heart. RESULTS: All the patients showed complete recovery. The average number of grafted vessels was 2.7 +/- 1.3. Intraoperative examinations revealed that the ventricular arrhythmia was effectively controlled by radiofrequency ablation. All cases had been followed up for one year. Holter monitoring revealed a significant reduction in ventricular arrhythmias (P < 0.05). Echocardiography showed significant increase in left ventricular ejection fraction (P < 0.05) and decrease in left ventricular end-diastolic diameter (P < 0.05). CONCLUSIONS: For patients with ventricular aneurysm and preoperative malignant arrhythmia, aneurysm repair plus epicardial radiofrequency ablation in OPCAB was found to be an effective and feasible therapeutic technique. However, medium- to long-term therapeutic efficacy of this method remains to be determined by future studies and observations. PMID- 23106885 TI - Ultrasound facilitates identification of combined spinal-epidural puncture in obese parturients. AB - BACKGROUND: The palpation method is widely used in clinical practice to identify the puncture site of combined spinal-epidural (CSE) blocks, but it is usually difficult to accurately locate the puncture site in obese parturients. Accurate identification of the puncture site is crucial for successful CSE block. The objective of this study was to evaluate the impact of ultrasound imaging on the success rate of CSE puncture in obese parturients. METHODS: Sixty obese parturients with a body mass index >= 30 kg/m(2) who were scheduled for caesarean section were randomized into two equal-sized groups for location of the puncture site: an ultrasound group and a palpation group. The success rate of puncture at the first puncture site, the number of puncture attempts, duration of CSE procedure, time taken to determine the puncture site, and the depth of the epidural space were compared between groups. The frequencies of complications such as puncture site hemorrhage, neurological damage, and inadvertent dural puncture were also studied. RESULTS: There were no differences in age, body weight, height, body mass index, or gestational age between the two groups. The success rate of puncture at the first puncture site was significantly higher in the ultrasound group than the palpation group (100.00% vs. 70.00%, P = 0.004). The number of puncture attempts was significantly lower in the ultrasound group than the palpation group (chi(2) = 6.708, P = 0.035). The time taken for determining the puncture site was (0.30 +/- 0.12) minutes in the palpation group and (2.60 +/- 0.61) minutes in the ultrasound group (P < 0.001). The duration of CSE procedure was (7.67 +/- 1.52) minutes in the palpation group and (9.37 +/- 1.35) minutes in the ultrasound group (P < 0.001). The depth of the epidural space was similar in both groups (P = 0.586). Puncture site hemorrhage was observed in 6 (20.00%) patients in the palpation group and 2 (6.67%) patients in the ultrasound group (P = 0.255). CONCLUSIONS: Ultrasound imaging improves the rate of successful puncture at the first puncture site and decreases the number of puncture attempts. It facilitates CSE puncture in obese parturients. PMID- 23106886 TI - Transcatheter closure of large patent ductus arteriosus with severe pulmonary arterial hypertension in adults: immediate and two-year follow-up results. AB - BACKGROUND: Transcatheter closure of patent ductus arteriosus (PDA) is a well established procedure and an accepted treatment modality for small to moderate sized PDA. This study aimed to evaluate the immediate and follow-up results of transcatheter closure of large PDAs with severe pulmonary arterial hypertension (PAH) in adults. METHODS: After a complete hemodynamic evaluation differentiating from the reversibility of severe PAH, transcatheter closure of PDA was performed. Patients were followed up clinically and echocardiographically at 24 hours, 1 month, 3 months, 6 months, 12 months and 24 months after occlusion. RESULTS: Twenty-nine patients had successful occlusion, pulmonary artery pressure (PAP), left ventricular ejection fraction (LVEF) and fractional shortening (FS) significantly decreased immediately after occlusion ((106 +/- 25) mmHg vs. (50 +/ 14) mmHg, P < 0.01; (63.7 +/- 7.2)% vs. (51.4 +/- 10.1)%, P < 0.01 and (36.9 +/- 8.2)% vs. (28.9 +/- 8.6)%, P < 0.05, respectively). At 1 month after PDA closure, the signs and symptoms improved markedly in all 29 patients, and PDAs were completely closed and remained closed during the follow-up. Eighteen patients having different degrees of dyspnea were treated with angiotensin converting enzyme inhibitor (ACEI) and/or digoxin after occlusion. Nine patients whose pulmonary vascular resistence (PVR) > 6 Wood units accepted targeted PAH therapy. After 1 to 3 months of peroral drug therapy, their exercise tolerance improved from New York Heart Association (NYHA) class III-IV to NYHA class I. During follow-up, no latent arrhythmias were found, the left atrial diameter (LAD), left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left ventricular mass index (LVMI) and pulmonary artery systolic pressure (PASP) decreased significantly (P < 0.05), and FS and LVEF recovered compared to the immediate postclosure state. However, FS and LVEF remained low compared to the preclosure state. CONCLUSIONS: Transcatheter closure of large PDA with severe PAH is feasible, effective, and safe in adults. Significant left ventricular systolic changes may occur after closure of large PDA, and left ventricular function usually recovers within a few months. PMID- 23106887 TI - Identification of Nedd4 as a novel regulator in Hedgehog signaling. AB - BACKGROUND: Hedgehog (Hh) signaling plays an important role in both embryonic development and postnatal tissue homeostasis. Aberrant Hh activation results in a large variety of cancers. This study was designed to discover novel modulators in Hh signaling pathway. METHODS: We performed yeast-two-hybrid screening and immunoprecipitation to identify the interaction of Nedd4 and Smo. To verify whether Nedd4 is involved in the regulation of Hh signaling, we monitored the activation of Gli-luciferase reporter by overexpressing Nedd4 together with Gli luciferase reporter. In order to examine the role of endogenous Nedd4 in regulating Hh signaling, we used a short hairpin RNA (shRNA) interference strategy to silence the Nedd4 expression, and then perform dual-luciferase reporter assay. Statistical comparisons were performed by Student's t tests. RESULTS: We showed that Nedd4 binds to Smo in the transfected HEK293 cells. Overexpression of Nedd4 alone did not significantly activate the Gli reporter compared to pcDNA3 control (Nedd4 group: dimethyl sulfoxide (DMSO), relative luciferase unit (RLU) 1.87 +/- 0.41). However, Smo agonist (SAG)-stimulated activation of Gli-luciferase reporter was markedly potentiated in Nedd4 transfected cells (Nedd4 group: SAG, RLU 13.49 +/- 1.04, P < 0.05), indicating that overexpression of Nedd4 increases Gli luciferase reporter activity and Nedd4 induced activation of Hh signaling is activity dependent. In Nedd4 knockdown NIH 3T3 cells, the luciferase reporter activity was measured basally and after SAG treatment. In scrambled cells, compared to DMSO, SAG could activate reporter activity by (4.16 +/- 0.84)-fold. In Nedd4 knockdown cells, the luciferase reporter activation by SAG was significantly inhibited (SAG, RLU 1.72 +/- 0.24, P < 0.05); knockdown of Nedd4 did not change the basal activity of luciferase activity (DMSO, RLU 0.86 +/- 0.11), suggesting that the loss of Nedd4 expression diminishes Gli-dependent activity in the Hh pathway and the regulation of Nedd4 in the Hh signaling pathway is activity-dependent. CONCLUSION: Nedd4 positively regulates the Hh pathway and provides a potential target for inhibiting Hh signaling in cancer therapy. PMID- 23106888 TI - Correlation between dynamic contrast-enhanced MRI and histopathology in the measurement of tumor and breast volume and their ratio in breast cancer patients: a prospective study. AB - BACKGROUND: Earlier studies have examined the association between the diameter of primary tumors measured by magnetic resonance imaging (MRI) and histopathology in breast cancer patients. However, the diameter does not completely describe the dimensions of the breast tumor or its volumetric proportion relative to the whole breast. The association between breast tumor volume/breast volume ratios measured by these two techniques has not been reported. METHODS: Seventy-three patients were recruited from female patients with primary breast tumors admitted to our center between January and December 2010. They were divided into two groups. Group A (n = 46) underwent modified radical mastectomy (MRM), and Group B (n = 27) underwent preoperative neoadjuvant chemotherapy before MRM. They were examined by dynamic-contrast enhanced MRI (DCE-MRI) to measure breast volumes (BVs), tumor volumes (TVs), and tumor volume/breast volume ratios (TV/BV). These measurements were compared with histopathology results after MRM, and the associations between MRI and pathology were analyzed by linear regression and Bland-Altman analysis. RESULTS: For Group A, the correlation coefficients for BVs, TVs, and TV/BV ratios measured by the two techniques were 0.938, 0.921, and 0.897 (all P < 0.001), respectively. For Group B, the correlation coefficients for BVs, TVs, and TV/BV ratios were 0.936, 0.902, and 0.869 (all P < 0.01), respectively. The results suggest statistically significant correlations between these parameters measured by the two techniques for both groups. CONCLUSION: For these patients, BVs, TVs, and TV/BV ratios measured by DCE-MRI significantly correlated with those determined by histopathology. PMID- 23106889 TI - High volume practice proved the safety of off-pump coronary artery bypass surgery in left main coronary artery lesions: a two-year single center experience. AB - BACKGROUND: Left main coronary artery (LMCA) stenosis has been recognized as a risk factor for early death among patients undergoing coronary artery bypass grafting (CABG). This study aimed to assess if LMCA lesions pose an additional risk of early or mid-term mortality and/or a major adverse cardiac and cerebrovascular event (MACCE) after off-pump coronary artery bypass grafting (OPCABG), compared with non-left main coronary artery stenosis (non-mainstem disease). METHODS: From January 1, 2009 to December 31, 2010, 4869 patients had a primary isolated OPCABG procedure at Beijing Anzhen Hospital. According to the pathology of LMCA lesions, they were retrospectively classified as a non-mainstem disease group (n = 3933) or a LMCA group (n = 936). Propensity scores were used to match the two groups, patients from the non-mainstem disease group (n = 831) were also randomly selected to match patients from the LMCA group (n = 831). Freedom from MACCE in the two groups was calculated using the Kaplan-Meier method. RESULTS: The difference in the mortality and the rate of MACCE during the first 30 days between the non-mainstem disease group and the LMCA group did not reach statistical significance (P = 0.429, P = 0.127 respectively). With a mean follow-up of (12.8 +/- 7.5) months and a cumulative follow-up of 1769.6 patient years, the difference in the freedom from MACCEs between the two groups, calculated through Kaplan-Meier method, did not reach statistical significance (P = 0.831). CONCLUSION: Analysis of a high volume of OPCABG procedures proved that LMCA lesions do not pose additional early and mid-term risk to OPCABG. Therefore, a LMCA lesion is as safe as non-mainstem disease lesion during the OPCABG procedure. PMID- 23106890 TI - A multi-center, double-blind, randomized, parallel group study to evaluate the effects of two different doses of losartan on morbidity and mortality in Chinese patients with symptomatic heart failure intolerant of angiotensin converting enzyme inhibitor treatment. AB - BACKGROUND: There have been no mortality/morbidity endpoint studies with losartan in Chinese heart failure patients. The objective was to evaluate the effects of high-dose vs. low-dose losartan on clinical outcomes in Chinese subjects with heart failure. METHODS: This study was a post hoc analysis of the Heart failure Endpoint evaluation of Angiotensin II Antagonist losartan (HEAAL) trial (n = 545). Chinese adults with symptomatic heart failure (New York Heart Association (NYHA) II-IV) intolerant of treatment with angiotensin converting enzyme (ACE) inhibitors were randomized to losartan 150 mg or 50 mg daily. The primary endpoint was the composite event rate of all-cause death or hospitalization for heart failure. Safety and tolerability were assessed. RESULTS: Median follow-up was 4.8 years. Baseline characteristics were generally similar to the overall HEAAL cohort. Overall, 120 (44.1%) subjects in the losartan 150 mg group and 137 (50.2%) subjects in the losartan 50 mg group died (any cause) or were hospitalized for heart failure (hazard ratio (OR) 0.807, 95%CI 0.631 - 1.031). There were no notable differences between treatment groups in the proportion of subjects with adverse experiences. CONCLUSION: The results of this post hoc analysis in Chinese subjects, although not powered to show significance, were generally consistent with the main study results, which demonstrated a significantly reduced risk of all cause death or hospitalization for heart failure with daily losartan 150 mg vs. losartan 50 mg in subjects with symptomatic heart failure and intolerance to ACE inhibitors, supporting the use of the higher dose for optimum clinical benefit. PMID- 23106891 TI - Enhanced expression of proneurotrophins in elevated introcular pressure-induced rat retinal ischemia. AB - BACKGROUND: Proneurotrophins such as the precursor of nerve growth factor (proNGF) and the precursor of brain-derived neurotrophic factor (proBDNF) interacted with sortilin and p75(NTR) to form a complex capable of activating an apoptotic signaling. We found that the expression of p75(NTR) and sortilin was increased in ischemic retina induced by elevated intraocular pressure (IOP), but the protein expression changes of proNGF and proBDNF in the same situation were not clear. This study aimed to ascertain the protein expression changes of proNGF and proBDNF in ischemic retina induced by elevated IOP. METHODS: Expression of proBDNF and proNGF was examined by double-labeling immunochemistry in normal rat retina, examined using Western blotting and analyzed using statistical methods in ischemic retina induced by elevated IOP. RESULTS: Immunocytochemistry showed that the proBDNF expressed in the ganglion cell layer (GCL) while the proNGF primarily existed in both the nerve fiber layers (NFL) and large ganglion cell bodies of normal rat retina. Western blotting analysis demonstrated that the molecule weights of 28 kD (proBDNF)/25 kD (proNGF) band were increased significantly (P < 0.05) at days 3, 5 and 7 after retinal elevated-IOP-induced ischemia. CONCLUSION: ProBDNF expressed in the GCL and proNGF primarily presented in NFL and large ganglion cell bodies of normal rat retina, the protein expression forms of 28 kD proBDNF and 25 kD proNGF increased in ischemic retina induced by elevated IOP. PMID- 23106892 TI - Quantitative detection of Streptococcus mutans and bacteria of dental caries and no caries groups in permanent teeth from a north China population. AB - BACKGROUND: Streptococcus mutans (S. mutans) is the prime pathogen of dental caries. There are few reports that studied the relationship between S. mutans, bacteria and dental caries in permanent teeth when compared to those in primary teeth. This study aimed to detect S. mutans and bacteria of dental caries and non caries groups in permanent teeth from a north China population by real-time polymerase chain reaction (PCR) and compare the relationship between the number of these bacteria and the prevalence of dental caries in permanent teeth. METHODS: Human saliva samples were collected from 142 subjects with permanent teeth. According to their dental tooth (DT), 142 subjects were divided into a dental caries group (DT >= 1) and a non-caries group (DT = 0). With specific primers for S. mutans and 16S rRNA, the total number of S. mutans and total bacteria of 142 saliva samples were detected by real-time PCR and statistically analyzed. RESULTS: There was no significant difference between the detection rates of S. mutans (P = 0.118) and medians of S. mutans (P = 0.115). The ratio of S. mutans to total bacteria in people with dental caries was significantly higher than in those without caries (P < 0.001), but the total number of bacteria in people with dental caries was significantly lower than in those without caries (P < 0.001). CONCLUSIONS: S. mutans had different effects on caries in the permanent teeth of several individuals from a north China population. The ratios of S. mutans to total bacteria in saliva detected by real-time PCR with Sm479F/R and 16S RNA primers were closely associated with the prevalence of dental caries in the same population. These assays may be useful for the assessment of an individual's risk of dental caries. PMID- 23106893 TI - Investigation on the indication of ipsilateral adrenalectomy in radical nephrectomy: a meta-analysis. AB - BACKGROUND: With a trend that renal tumors are being detected at an earlier stage, classical radical nephrectomy is being reconsidered. More conservative techniques are being proposed. To clarify the indication for synchronous adrenalectomy in radical nephrectomy for renal cell carcinoma which has been questioned since the 1980s, this study evaluates the role of adrenalectomy and recommends a new indication for adrenalectomy in renal cell carcinoma. METHODS: A systemic search was performed, using PubMed and Google Scholar, of all English language studies published up to March 2012 that compared adrenalectomy with adrenal-sparing surgery, in surgery for renal cell carcinoma. We assessed preoperative imaging for adrenal involvement and the relationship of tumor location with adrenal metastases. Twenty-one studies (20 retrospective and 1 prospective) involving 11 736 patients were included. RESULTS: The mean incidence of ipsilateral adrenal involvement from renal cell carcinoma was 4.5%. Synchronous adrenalectomy did not alter survival (hazard ratio (HR) = 0.89, 95% confidence interval (CI) 0.67 - 1.19, P = 0.43; odds ratio (OR) = 1.10, 95%CI 0.84 - 1.44, P = 0.49). Upper pole tumors were not associated with a higher incidence of ipsilateral adrenal metastases. Pooled preoperative imaging: sensitivity, specificity, positive predictive value and negative predictive value were 92% (95%CI 0.84 - 0.97), 95% (95%CI 0.93 - 0.96), 71.6% and 98.5% respectively. CONCLUSIONS: Adrenal involvement from renal cell carcinoma is rare, even in advanced tumours. Synchronous adrenalectomy does not offer any benefit, even for "high risk" patients. We suggest that only patients with a positive preoperative adrenal finding on preoperative imaging for a solitary adrenal metastasis should undergo adrenalectomy as part of the radical nephrectomy. PMID- 23106894 TI - Meta-analysis of pancreaticoduodenectomy prospective controlled trials: pancreaticogastrostomy versus pancreaticojejunostomy reconstruction. AB - BACKGROUND: Pancreaticogastrostomy (PG) has been proposed as an alternative to pancreaticojejunostomy (PJ), assuming that postoperative complications are less frequent. The aim of this research was to compare the safety of PG with PJ reconstruction after pancreaticoduodenectomy. METHODS: Articles of prospective controlled trials published until the end of December 2010 comparing PJ and PG after PD were searched by means of MEDLINE, EMBASE, Cochrane Controlled Trials Register databases, and Chinese Biomedical Database. After quality assessment of all included prospective controlled trials, meta-analysis was performed with Review Manager 5.0 for statistic analysis. RESULTS: Overall, six articles of prospective controlled trials were included. Of the 866 patients analyzed, 440 received PG and 426 were treated by PJ. Meta-analysis of six prospective controlled trials (including RCT and non-randomized prospective trial) revealed significant difference between PJ and PG regarding postoperative complication rates (OR, 0.53; 95%CI, 0.30 - 0.95; P = 0.03), pancreatic fistula (OR, 0.47; 95%CI, 0.22 - 0.97; P = 0.04), and intra-abdominal fluid collection (OR, 0.42; 95%CI, 0.25 - 0.72; P = 0.001). The difference in mortality was of no significance. Meta-analysis of four randomized controlled trials (RCT) revealed significant difference between PJ and PG regarding intra-abdominal fluid collection (OR, 0.46; 95% CI, 0.26 - 0.79; P = 0.005). The differences in pancreatic fistula, postoperative complications, delayed gastric emptying, and mortality were of no significance. CONCLUSIONS: Meta-analysis of six prospective controlled trials (including randomized controlled trials (RCT) and non randomized prospective trial) revealed significant difference between PJ and PG regarding overall postoperative complications, pancreatic fistula, and intra abdominal fluid collection. Meta-analysis of four RCT revealed significant difference between PJ and PG with regard to intra-abdominal fluid collection. The results suggest that PG may be as safe as PJ. PMID- 23106895 TI - Role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor-inducible 14 (Fn14) axis in rheumatic diseases. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily of structurally related cytokines and is known to induce proliferation, migration, differentiation, apoptotic cell death, inflammation, and angiogenesis. These physiological processes are induced by the binding of TWEAK to fibroblast growth factor-inducible 14 (Fn14), a highly inducible cell surface receptor that is linked to several intracellular signaling pathways, including the nuclear factor-kappaB (NF-kappaB) pathway. This review discusses the role of the TWEAK-Fn14 axis in several rheumatic diseases and the potential therapeutic benefits of modulation of the TWEAK-Fn14 pathway. PMID- 23106896 TI - Perioperative and late outcomes of laparoscopic fundoplication for neurologically impaired children with gastro-esophageal reflux disease. AB - BACKGROUND: Persistent gastro-esophageal reflux (GER) due to various pathological factors often results in overt clinical symptoms and signs, which is termed as gastro-esophageal reflux disease (GERD). Affected children usually present with failure to thrive, recurrent pneumonia or apnea. Many neurologically impaired children have symptoms related to GERD. Although laparoscopic fundoplication has been established to be an effective treatment modality for children with GERD, data on its role and long-term efficacy for neurologically impaired patients remain sparse. The aim of this study was to review the results of such patients who underwent laparoscopic fundoplication. METHODS: A retrospective review was performed from 1998 to 2009. All children with neurological impairment who had laparoscopic fundoplication were included. RESULTS: Fifty-nine GERD patients (male = 32, female = 27; mean age 6 years) were identified. All subjects showed symptoms of frequent emesis; 32 of them had history of hematemesis (54.2%); 54 had feeding difficulty; 35 (59.3%) had associated respiratory symptoms, including recurrent pneumonia. Gastrostomy was performed concurrently in 39 cases. There was no conversion to open procedure nor was there intra-operative complications and operative mortality. Emesis or hematemesis was controlled adequately in all. However, respiratory symptoms were not controlled in 10 patients (16.9%), and five of them required further respiratory assistance including nasal airway tube and tracheostomy. Clinical recurrence of GERD was not observed in any subject. Twelve patients died during follow-up (range from 3 months to 9 years) due to severe respiratory complications, cardiac arrest, and brain tumor. CONCLUSIONS: Laparoscopic fundoplication is an excellent procedure for controlling clinically significant symptoms in neurological impaired patients with GERD. Further studies are required to assess the improvement of the quality of life in such patients. PMID- 23106897 TI - Zero ischemia partial nephrectomy. PMID- 23106898 TI - The organ donation in China. PMID- 23106899 TI - Intra-arterial chemotherapy for pelvic recurrence after radical cystectomy for bladder urothelial cancer. PMID- 23106900 TI - Sjogren's syndrome with extremely elevated plasma alpha-fetoprotein that responded to immunosuppressant treatment. PMID- 23106901 TI - Intrapulmonary calcifying fibrous pseudotumour of the lung. PMID- 23106902 TI - A cystic vestibular schwannoma with a fluid-fluid level. PMID- 23106904 TI - The apostrophe in medical eponyms. PMID- 23106903 TI - Predominant microvessel proliferation in coronary stent restenotic tissue in patients with diabetes: insights from optical coherence tomography image analysis. AB - BACKGROUND: Coronary optical coherence tomography (OCT) enables virtual depiction of histological findings of in-stent restenotic tissue. The aim of this study was to investigate the microvessel proliferation within in-stent restenotic tissue and the influence of diabetes mellitus (DM). METHODS: We examined 54 in-stent restenotic coronary artery lesions (stenotic area>50%) from 50 consecutive patients including 28 with DM (56%) and 9 insulin-treated DM patients (18%); who underwent coronary time-domain OCT imaging with automatic pull back (1mm/s, 20 frames/s). Microvessels were defined as low-signal cavities with a diameter of 50 150 microns and a trajectory parallel to the lumen recognized on 3 consecutive cross-sectional OCT image frames. The microvessel index was calculated as the number of frames with microvessel/total number of frames * 100. Patients were stratified into 3 groups: 1) without microvessels, 2) with a low (< median value) microvessel index, 3) with a high microvessel index. RESULTS: Microvessels were detected in 566 frames (3.1%) from 26 lesions (48%) in 24 patients (48%). A greater incidence of DM and higher serum glucose levels were observed in the high microvessel index group (DM: 42% vs 58% vs 83%, p=0.049; serum glucose level: 118.2 +/- 44.6 vs 122.6 +/- 31.0 vs 172.8 +/- 63.1mg/dL, p=0.03 between low and high microvessel index group, p=0.005 between no microvessel and high microvessel index group). CONCLUSIONS: Microvessel formation may be a unique pathophysiological factor of in-stent restenoses in patients with DM. PMID- 23106906 TI - Adherence to ethical standards in publishing scientific articles: a statement from the International Journal of Cardiology. AB - All authors of manuscripts in the International Journal of Cardiology are required to make a binding statement that they as authors adhere to the following principles: 1. That the corresponding author has the approval of all other listed authors for the submission and publication of all versions of the manuscript. 2. That all people who have the right to be recognised as authors have been included on the list of authors and everyone listed as an author has made an independent material contribution to the manuscript. 3. That the work submitted in the manuscript is original and has not been published elsewhere and is not presently under consideration of publication by any other journal other than in oral, poster or abstract format. 4. That the material in the manuscript has been acquired according to modern ethical standards and has been approved by the legally appropriate ethical committee. 5. That the article does not contain material copied from anyone else without their written permission and that all material which derives from prior work, including from the same authors, is properly attributed to the prior publication by proper citation. 6. That all material conflicts of interest have been declared including the use of paid medical writers and their funding source. 7. That the manuscript will be maintained on the servers of the journal and held to be a valid publication by the journal only as long as all statements in these principles remain true. 8. That if any of the statements above ceases to be true the authors have a duty to notify the journal as soon as possible so that the manuscript can be withdrawn. PMID- 23106905 TI - Randomized comparison of new dual-antiplatelet therapy (aspirin, prasugrel) and triple-antiplatelet therapy (aspirin, clopidogrel, cilostazol) using P2Y12 point of-care assay in patients with STEMI undergoing primary PCI. AB - BACKGROUND: Both new dual antiplatelet therapy (DAT; aspirin and prasugrel) and triple antiplatelet therapy (TAT; aspirin, clopidogrel and cilostazol) are more potent than classic DAT (aspirin and clopidogrel). We compared the antiplatelet efficacy between new DAT and TAT in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary coronary percutaneous coronary intervention (PCI). METHODS: Forty patients who were eligible for primary PCI were prospectively randomized to DAT group (n=20) or TAT group (n=20) immediately after hospital arrival. The primary end point was P2Y12 reaction unit (PRU) determined with the VerifyNow P2Y12 point-of-care assay at the time of discharge. RESULTS: PRU value at discharge was significantly lower in patients receiving DAT compared with that of TAT (84.5 +/- 44.7 vs. 128.4 +/- 74.9, p=0.032). Percent platelet inhibition was significantly higher for DAT compared with TAT at discharge (72.1 +/- 12.2 vs. 57.5 +/- 23.5, p=0.020). Inter-patient variability of PRU values at discharge was significantly smaller in patient taking DAT compared with TAT (p=0.026). CONCLUSION: A new DAT is more potent antiplatelet therapy than TAT in patients with STEMI undergoing primary PCI. PMID- 23106907 TI - Early respiratory therapy reduces postoperative atelectasis in children undergoing lung resection. AB - BACKGROUND: Early physiotherapy reduces pulmonary complications after lung resection in adult patients. However, the effectiveness and the techniques used in postoperative physiotherapy in children undergoing lung resection have not been well described. Therefore, the standardization of a physiotherapeutic attendance after lung resection in children is necessary. METHODS: This was a retrospective and prospective, interventional, descriptive, and quantitative study. We evaluated 123 pediatric subjects undergoing lung resection. Fifty-two children were prospectively submitted to a standardized physiotherapy protocol that included a mask with a positive expiratory pressure of 10 cm H2O, expiratory rib cage compression, coughing, lifting the upper limbs, and ambulation, starting within the first 4 hours after surgery and continuing 3 times each day. A historical control group of 71 subjects received physiotherapeutic techniques without specific standardization and with variability in the start date and number of days attended. We recorded the presence of postoperative complications, prolonged air leak, postoperative bronchoscopy, the time of chest tube removal, and hospital stay following surgery. RESULTS: The group that received a standardized protocol of physiotherapy had fewer instances of atelectasis than the control group (15.4% vs 7.6%, P = .01). Subjects in the control group were more likely than those in the intervention group to require fiberoptic bronchoscopy for bronchial toilet (n = 14 [19.7%] vs n = 5 [9.6%], P <= .001). There was no difference in the time of drainage or hospital stay between the groups. CONCLUSIONS: Implementation of a standardized physiotherapeutic protocol after lung resection in children decreases atelectasis but does not reduce the time of chest tube removal or the duration of hospital stay. PMID- 23106908 TI - Experiences of involuntary admission in an approved mental health centre. AB - The aim of this qualitative study was to gain an understanding of what it means to have an involuntary hospital admission. A sample of six people who were detained at an approved Irish mental health centre consented to recount their experiences were interviewed. The interview transcripts were analysed using Interpretative Phenomenological Analysis. Three superordinate themes were identified: 'The early days', 'Experiences of treatment' and 'Moving on?'. 'The early days' represented participants' initial feelings and opinions of the experience of coming into the approved centre. 'Experiences of treatment' refers to participants' experiences of medication and relationships with staff. Finally, the theme 'Moving on?' represented participants' views on how they adjusted to involuntary admission. 'Learning the way' was central to the participants' notion of moving on. The findings suggest that the meaning of detention is a varied one that evokes an array of emotional responses for participants and highlights the need for a renewed way of thinking and doing concerning those subject to involuntary. PMID- 23106910 TI - SET overexpression decreases cell detoxification efficiency: ALDH2 and GSTP1 are downregulated, DDR is impaired and DNA damage accumulates. AB - Alcohol and tobacco consumption are risk factors for head and neck squamous cell carcinoma (HNSCC). Aldehyde dehydrogenase 2 (ALDH2) and glutathione S-transferase pi 1 (GSTP1) are important enzymes for cellular detoxification and low efficiencies are implicated in cancer. We assessed the potential role of SET protein overexpression, a histone acetylation modulator accumulated in HNSCC, in gene regulation and protein activity of ALDH2 and GSTP1. SET was knocked down in HN13, HN12 and Cal27, and overexpressed in HEK293 cells; ethanol and cisplatin were the chemical agents. Cells with SET overexpression (HEK293/SET, HN13 and HN12) showed lower ALDH2 and GSTP1 mRNA levels and trichostatin A increased them (real-time PCR). Ethanol upregulated GSTP1 and ALDH2 mRNAs, whereas cisplatin upregulated GSTP1 in HEK293 cells. SET-chromatin binding revealed SET interaction with ALDH2 and GSTP1 promoters, specifically via SET NAP domain; ethanol and cisplatin abolished SET binding. ALDH2 and GSTP1 efficiency was assessed by enzymatic and comet assay. A lower ALDH2 activity was associated with greater DNA damage (tail intensity) in HEK293/SET compared with HEK293 cells, whereas HN13/siSET showed ALDH2 activity higher than HN13 cells. HN13/siSET cells showed increased tail intensity. Cisplatin-induced DNA damage response showed negative relationship between SET overexpression and BRCA2 recruitment. SET downregulated repair genes ATM, BRCA1 and CHEK2 and upregulated TP53. Cisplatin-induced cell cycle arrest occurred in G(0) /G(1) and S in HEK293 cells, whereas HEK293/SET showed G(2) /M stalling. Overall, cisplatin was more cytotoxic for HN13 than HN13/siSET cells. Our data suggest a role for SET in cellular detoxification, DNA damage response and genome integrity. PMID- 23106909 TI - High mosquito burden and malaria transmission in a district of the city of Douala, Cameroon. AB - BACKGROUND: Rapid demographic growth in Douala city, Cameroon, has resulted in profound ecological and environmental changes. Although demographic changes can affect anopheline mosquito breeding sites, there is a lack of understanding about the epidemiological impact that such changes might have on vector ecology and malaria transmission. METHODS: A 12-month entomological study was conducted in a highly populated district of Douala called Ndogpassi. Adult mosquitoes were collected using two methods: 1) human landing catches (HLC); and 2) Centers for Disease Control and Prevention (CDC) light traps; these methods were used twice monthly from January to December 2011. Mosquito genus and species were identified with morphological and molecular diagnostic tools. The sampling efficiency of the CDC light trap and HLC were compared. Anopheles gambiae infection with Plasmodium falciparum was detected using ELISA. Susceptibility to DDT, permethrin, and deltamethrin insecticides were also determined. RESULTS: A total of 6923 mosquitoes were collected by HLC (5198) and CDC light traps (1725). There was no equivalence in the sampling efficiency between light traps and human landing catches (P > 0.01). With 51% of the total, Culex was the most common, followed by Anopheles (26.14%), Mansonia (22.7%) and Aedes (0.1%). An. gambiae ss (M form) comprised ~98% of the total anophelines collected. An. gambiae had a biting rate of 0.25 to 49.25 bites per human per night, and was the only species found to be infected with P. falciparum. A P. falciparum infection rate of 0.5% was calculated (based on enzyme-linked immunosorbent assays using the circumsporozoite surface protein). The entomological inoculation rate was estimated at 31 infective bites per annum. Insecticide susceptibility tests on An. gambiae females revealed a mortality rate of 33%, 76% and 98% for DDT, permethrin and deltamethrin, respectively. The West African kdr allele (L1014F) was detected in 38 of the 61 An. gambiae analyzed (62.3%). CONCLUSIONS: The present study revealed seasonal malaria transmission in Douala. High levels of An. gambiae were detected along with a high prevalence of insecticide resistance in this vector population. These findings highlight the need to promote use of insecticide-impregnated bed nets in Douala. PMID- 23106911 TI - Future body mass index modelling based on macronutrient profiles and physical activity. AB - BACKGROUND: An accurate system of determining the relationship of macronutrient profiles of foods and beverages to the long-term weight impacts of foods is necessary for evidence-based, unbiased front-of-the-package food labels. METHODS: Data sets on diet, physical activity, and BMI came from the Food and Agriculture Organization (FAO), the World Health Organization (WHO), the Diabetes Control and Complications Trial (DCCT), and Epidemiology Diabetes Intervention and Complications (EDIC). To predict future BMI of individuals, multiple regression derived FAO/WHO and DCCT/EDIC formulas related macronutrient profiles and physical activity (independent variables) to BMI change/year (dependent variable). Similar formulas without physical activity related macronutrient profiles of individual foods and beverages to four-year weight impacts of those items and compared those forecasts to published food group profiling estimates from three large prospective studies by Harvard nutritional epidemiologists. RESULTS: FAO/WHO food and beverage formula: four-year weight impact (pounds)=(0.07710 alcohol g+11.95 (381.7+carbohydrates g per serving)*4/(2,613+kilocalories per serving)-304.9 (30.38+dietary fiber g per serving)/(2,613+kilocalories per serving)+19.73 (84.44+total fat g)*9/(2,613+kilocalories per serving)-68.57 (20.45+PUFA g per serving)*9/(2,613+kilocalories per serving))*2.941-12.78 (n=334, R(2)=0.29, P < 0.0001). DCCT/EDIC formula for four-year weight impact (pounds)=(0.898 (102.2+protein g per serving)*4/(2,297+kilocalories per serving)+1.063 (264.2+carbohydrates g per serving)*4/(2,297+ kilocalories per serving)-13.19 (24.29+dietary fiber g per serving)/ (2,297+kilocalories per serving)+ 0.973 (74.59+(total fat g per serving-PUFA g per serving)*9/(2,297+kilocalories per serving))*85.82-68.11 (n=1,055, R(2)=0.03, P < 0.0001). (FAO/WHO+ DCCT/EDIC formula forecasts averaged correlated strongly with published food group profiling findings except for potatoes and dairy foods (n=12, r=0.85, P = 0.0004). Formula predictions did not correlate with food group profiling findings for potatoes and dairy products (n=10, r= -0.33 P=0.36). A formula based diet and exercise analysis tool is available to researchers and individuals: http://thehealtheconomy.com/healthTool/. CONCLUSIONS: Two multiple regression derived formulas from dissimilar databases produced markedly similar estimates of future BMI for 1,055 individuals with type 1 diabetes and female and male cohorts from 167 countries. These formulas predicted the long-term weight impacts of foods and beverages, closely corresponding with most food group profiling estimates from three other databases. If discrepancies with potatoes and dairy products can be resolved, these formulas present a potential basis for a front-of the-package weight impact rating system. PMID- 23106912 TI - Stress as a modifier of biodiversity effects on ecosystem processes? AB - Does stress, defined as a reduction in growth by external constraints, modify biodiversity effects on ecosystem functioning? That is, are diversity effects stronger under stressful, as opposed to favourable conditions? The study by Fugere et al. (2012) in this issue borrows the stress-gradient hypothesis from plant ecology to explore this issue in an aquatic detritus-detritivore system. Although they find weak support for their hypothesis, the study opens the door for future experimental and theoretical investigations into the role of stress in modifying the relationship between the diversity of animal communities and ecosystem processes. PMID- 23106913 TI - Uncovering the origin of the black stains in Lascaux Cave in France. AB - Lascaux Cave in France was discovered in 1940. Since being opened to visitors the cave has suffered three major microbial outbreaks. The current problem is the fast dissemination of black stains which are threatening the Palaeolithic paintings. Previous data pointed to the involvement of new fungal species in the formation of black stains on the rock walls and ceiling. However, it appears that there could be other reasons for the formation of different and extensive black stains coating the surface of the clayey sediments. Our analyses reveal that black stains on clayey sediments are mainly produced by Acremonium nepalense, a manganese oxide-depositing fungus, widely distributed in the cave. Thus, in Lascaux Cave, the black stains have a dual origin: on limestone rocks they are mainly produced by the accumulation of fungal melanins, and on clayey sediments by the biogenic deposition of black manganese oxides. PMID- 23106914 TI - Bench-to-bedside review: An approach to hemodynamic monitoring--Guyton at the bedside. AB - Hemodynamic monitoring is used to identify deviations from hemodynamic goals and to assess responses to therapy. To accomplish these goals one must understand how the circulation is regulated. In this review I begin with an historical review of the work of Arthur Guyton and his conceptual understanding of the circulation and then present an approach by which Guyton's concepts can be applied at the bedside. Guyton argued that cardiac output and central venous pressure are determined by the interaction of two functions: cardiac function, which is determined by cardiac performance; and a return function, which is determined by the return of blood to the heart. This means that changes in cardiac output are dependent upon changes of one of these two functions or of both. I start with an approach based on the approximation that blood pressure is determined by the product of cardiac output and systemic vascular resistance and that cardiac output is determined by cardiac function and venous return. A fall in blood pressure with no change in or a rise in cardiac output indicates that a decrease in vascular resistance is the dominant factor. If the fall in blood pressure is due to a fall in cardiac output then the role of a change in the return function and cardiac function can be separated by the patterns of changes in central venous pressure and cardiac output. Measurement of cardiac output is a central component to this approach but until recently it was not easy to obtain and was estimated from surrogates. However, there are now a number of non-invasive devices that can give measures of cardiac output and permit the use of physiological principles to more rapidly appreciate the primary pathophysiology behind hemodynamic abnormalities and to provide directed therapy. PMID- 23106915 TI - Rural Indonesia women's traditional beliefs about antenatal care. AB - BACKGROUND: The Indonesia Maternal Mortality Rate (MMR) of 420/100.00 live births remains among the highest in East Asia while coverage of births assisted by skilled providers is still low. Traditional beliefs have been a key factor associated with the choice between midwives or traditional birth attendants (TBA) and the low number of antenatal care visits in rural West Sumatra. METHODS: We conducted three focus groups with 16 women from rural West Java to describe their perception regarding issues related to traditional beliefs. Focus group discussions provided data for the content analysis. RESULTS: The majority of the 16 women interviewed was from Village Dago, West Java and had only an elementary school education. Their ages ranged from 19 to 40 years. Most were multiparous housewives with an income of IDR 918.750 per month, which was lower than the monthly income in West Java (IDR. 1.172.060). Emerging from the focus group discussion were four main themes regarding their pregnancy and traditional beliefs: 1) pregnancy was a normal cycle in women's life (pregnancy is a natural phenomena, not a sickness; no recognition of danger signs during pregnancy and death of baby or mother during pregnancy was brought about by God's will); 2) women followed the traditional beliefs (positive motivation to follow the traditional beliefs and fear of not following the traditional beliefs); 3) relying on TBA called paraji rather than midwife (parajis are kind, tolerant and patient and have more experience than midwives; more accessibility than midwives and encouragement of natural birth) and 4) midwives are more secure than paraji; (they use a medical standard of care). CONCLUSIONS: Women's beliefs grounded in religion and tradition permeated the village culture making it difficult to counter their long held health practices with practices based on recent advances in health care. Use of TBA in this village was still dominant and women believed that following traditional beliefs led to a healthy pregnancy therefore, they also followed all relatives' suggestions. Understanding the complexities of local culture is the first step to improving women's awareness of how to preserve their pregnancy and prevent complications. PMID- 23106917 TI - Diagnostic tests in urology: an introduction. AB - What's known on the subject? and What does the study add? In our everyday practice as urologists, we often face diagnostic uncertainty that prompts us to perform a range of diagnostic tests to determine the probability that a patient has an underlying condition. Unfortunately, some diagnostic tests do not help us 'rule in' our 'rule out' a disease. These clinically unhelpful tests are not the best allocation of our healthcare system's resources. This series will discuss the quality of evidence supporting the use of common diagnostic tests in urology. This discussion represents an important dimension of the decision-making process and appropriate interpretation of these tests. Through this series we hope to improve patient care by encouraging and informing readers to exercise selective application of these diagnostic tests to reduce the burden of rising and ultimately unsustainable healthcare costs. PMID- 23106916 TI - Study protocol: Screening and Treatment of Alcohol-Related Trauma (START) - a randomised controlled trial. AB - BACKGROUND: The incidence of mandibular fractures in the Northern Territory of Australia is very high, especially among Indigenous people. Alcohol intoxication is implicated in the majority of facial injuries, and substance use is therefore an important target for secondary prevention. The current study tests the efficacy of a brief therapy, Motivational Care Planning, in improving wellbeing and substance misuse in youth and adults hospitalised with alcohol-related facial trauma. METHODS AND DESIGN: The study is a randomised controlled trial with 6 months of follow-up, to examine the effectiveness of a brief and culturally adapted intervention in improving outcomes for trauma patients with at-risk drinking admitted to the Royal Darwin Hospital maxillofacial surgery unit. Potential participants are identified using AUDIT-C questionnaire. Eligible participants are randomised to either Motivational Care Planning (MCP) or Treatment as Usual (TAU). The outcome measures will include quantity and frequency of alcohol and other substance use by Timeline Followback. The recruitment target is 154 participants, which with 20% dropout, is hoped to provide 124 people receiving treatment and follow-up. DISCUSSION: This project introduces screening and brief interventions for high-risk drinkers admitted to the hospital with facial trauma. It introduces a practical approach to integrating brief interventions in the hospital setting, and has potential to demonstrate significant benefits for at-risk drinkers with facial trauma. TRIAL REGISTRATION: The trial has been registered in Australian New Zealand Clinical Trials Registry (ANZCTR) and Trial Registration: ACTRN12611000135910. PMID- 23106918 TI - Silicone septum leakage at the origin of a drug overdose in a patient implanted with an intrathecal pump. AB - INTRODUCTION: Intrathecal (IT) pump failures usually result in decreased drug administration and symptom reoccurrence with or without withdrawal syndrome. We report a case of a leaking silicone septum associated to a systemic drug overdose. CASE REPORT: An 84-year-old patient treated with IT clonidine for chronic back pain presented with a state of confusion, visual hallucinations, and hypertension two hours after an unremarkable pump (SynchroMed EL, Medtronic, Minneapolis, MN, USA) refill. The reservoir was emptied and 14 mL (8.4 mg of clonidine) was found to be missing (difference between retrieved and expected volumes). The pump was refilled and a check on the next day showed again a loss of 3.5 mL. A malfunction was suspected and the pump was replaced (SynchroMed II, Medtronic). The inspection of the external surface of the pump revealed severe damage to the silicone septum with multiple gouges due to needle scarring. A fluid leak also was clearly seen through the septum. DISCUSSION: The signs and symptoms presented by this patient are consistent with clonidine overdose that resulted from a combination of a possible accidental pocket fill and a definite septum leak into the subcutaneous tissue. The damage to the silicone could be due to the loss of the nontraumatic properties of the Huber needles that are rubbed against the metallic case in attempting to locate the injection port during refill procedures. CONCLUSION: This observation is the first description of a silicone septum damage contributing to a pump dysfunction and drug overdose despite the use of appropriate needles for refilling. PMID- 23106919 TI - Primary Ewing's sarcoma of vulva: a case report and a review of the literature. AB - Ewing sarcomas/peripheral primitive neuroectodermal tumors (ES/pPNET) are extremely rare in the vulva. A review of the literature reveals only 14 previously reported possible cases. Here we reported a case of primary extraskeletal Ewing's sarcoma (EES) of the vulva in a 37-year-old woman. Characteristic histologic features of ES/pPNET were present in this case, including a monomorphic population of small round blue cells with cytoplasmic glycogen confirmed by periodic acid-Schiff, membrane staining with CD99 and nuclear staining with FLI-1. After surgery, the patient was found to have pulmonary metastasis and then received six cycles of polychemotherapy. She is still alive with stable disease after 1 year of follow up. Our findings underline the crucial role of immunohistochemical techniques in the differential diagnosis of small round cell tumors in these unusual locations. We also give a summary about the clinical and pathological features of the primary ES/pPNET in the vulva reported previously in the literature. PMID- 23106920 TI - Platelet-based coagulation: different populations, different functions. AB - Platelets in a thrombus interact with (anti)coagulation factors and support blood coagulation. In the concept of cell-based control of coagulation, three different roles of platelets can be distinguished: control of thrombin generation, support of fibrin formation, and regulation of fibrin clot retraction. Here, we postulate that different populations of platelets with distinct surface properties are involved in these coagulant functions. Platelets with elevated Ca(2+) and exposed phosphatidylserine control thrombin and fibrin generation, while platelets with activated alpha(IIb) beta(3) regulate clot retraction. We review how coagulation factor binding depends on the platelet activation state. Furthermore, we discuss the ligands, platelet receptors and downstream intracellular signaling pathways implicated in these coagulant functions. These insights lead to an adapted model of platelet-based coagulation. PMID- 23106921 TI - Ang-2 upregulation correlates with increased levels of MMP-9, VEGF, EPO and TGFbeta1 in diabetic eyes undergoing vitrectomy. AB - PURPOSE: Angiogenesis in diabetic retinopathy (DR) is a multifactorial process regulated by hypoxia-induced growth factors and inflammatory cytokines. In addition to the angiogenic switch, the proteolytic processing and altered synthesis of the extracellular matrix are critical steps in this disease. This study was performed to evaluate the levels of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9), angiopoietin-1 and angiopoietin-2 (Ang-1 and Ang-2), vascular endothelial growth factor (VEGF), erythropoietin (EPO) and transforming growth factor-beta1 (totalTGFbeta1) in the vitreous of diabetic eyes undergoing vitrectomy compared with control eyes operated because of macular hole or pucker. METHODS: Prospective consecutive controlled observational study performed in the unit of vitreoretinal surgery in Finland during the years 2006-2008. Vitreous samples were collected before the start of the conventional 3-ppp vitrectomy. Vitreous MMP-2 and MMP-9, Ang-1 and Ang-2, VEGF, EPO and TGFbeta1 concentrations were measured from 69 patients with Type 1 or 2 diabetes and 40 controls. RESULTS: Comparison of eyes with DR with controls revealed that the mean vitreous concentrations of proMMP-2 (p = 0.0015), totalMMP 2 (p = 0.0011), proMMP-9 (p = 0.00001), totalMMP-9 (p < 0.00001), Ang-2 (p < 0.00001), VEGF (p < 0.00001), EPO (p < 0.00001) and totalTGFbeta1 (p = 0.000026) were significantly higher in the former group. A multivariate logistic regression analysis suggested intravitreal Ang-2 concentration being the key marker of PDR (p = 0.00025) (OR = 1507.9). CONCLUSION: The main new finding is that the intravitreal concentrations of Ang-2 correlated significantly with MMP-9, VEGF, EPO and TGFbeta1 levels in diabetic eyes undergoing vitrectomy. Thus, these factors could promote retinal angiogenesis synergistically. PMID- 23106922 TI - Maternal Opioid Treatment: Human Experimental Research (MOTHER) Study: maternal, fetal and neonatal outcomes from secondary analyses. PMID- 23106924 TI - Maternal Opioid Treatment: Human Experimental Research (MOTHER)--approach, issues and lessons learned. AB - AIMS: The Maternal Opioid Treatment: Human Experimental Research (MOTHER) project, an eight-site randomized, double-blind, double-dummy, flexible-dosing, parallel-group clinical trial is described. This study is the most current--and single most comprehensive--research effort to investigate the safety and efficacy of maternal and prenatal exposure to methadone and buprenorphine. METHODS: The MOTHER study design is outlined, and its basic features are presented. CONCLUSIONS: At least seven important lessons have been learned from the MOTHER study: (i) an interdisciplinary focus improves the design and methods of a randomized clinical trial; (ii) multiple sites in a clinical trial present continuing challenges to the investigative team due to variations in recruitment, patient populations and hospital practices that, in turn, differentially impact recruitment rates, treatment compliance and attrition; (iii) study design and protocols must be flexible in order to meet the unforeseen demands of both research and clinical management; (iv) staff turnover needs to be addressed with a proactive focus on both hiring and training; (v) the implementation of a protocol for the treatment of a particular disorder may identify important ancillary clinical issues worthy of investigation; (vi) timely tracking of data in a multi-site trial is both demanding and unforgiving; and (vii) complex multi site trials pose unanticipated challenges that complicate the choice of statistical methods, thereby placing added demands on investigators to effectively communicate their results. PMID- 23106923 TI - Buprenorphine treatment of opioid-dependent pregnant women: a comprehensive review. AB - AIMS: This paper reviews the published literature regarding outcomes following maternal treatment with buprenorphine in five areas: maternal efficacy, fetal effects, neonatal effects, effects on breast milk and longer-term developmental effects. METHODS: Within each outcome area, findings are summarized first for the three randomized clinical trials and then for the 44 non-randomized studies (i.e. prospective studies, case reports and series and retrospective chart reviews), only 28 of which involve independent samples. RESULTS: Results indicate that maternal treatment with buprenorphine has comparable efficacy to methadone, although difficulties may exist with current buprenorphine induction methods. The available fetal data suggest buprenorphine results in less physiological suppression of fetal heart rate and movements than methadone. Regarding neonatal effects, perhaps the single definitive conclusion is that prenatal buprenorphine treatment results in a clinically significant less severe neonatal abstinence syndrome (NAS) than treatment with methadone. The limited research suggests that, like methadone, buprenorphine is compatible with breastfeeding. Data available thus far suggest that there are no deleterious effects of in utero buprenorphine exposure on infant development. CONCLUSIONS: While buprenorphine produces a less severe neonatal abstinence syndrome than methadone, both methadone and buprenorphine are important parts of a complete comprehensive treatment approach for opioid-dependent pregnant women. PMID- 23106925 TI - Fetal assessment before and after dosing with buprenorphine or methadone. AB - AIM: To determine pre- and post-dosing effects of prenatal methadone compared to buprenorphine on fetal wellbeing. DESIGN: A secondary analysis of data derived from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial. SETTING: Six United States sites and one European site that provided comprehensive opioid-dependence treatment to pregnant women. PARTICIPANTS: Eighty-one of the 131 opioid-dependent pregnant women completing the MOTHER clinical trial, assessed between 31 and 33 weeks of gestation. MEASUREMENTS: Two fetal assessments were conducted, once before and once after study medication dosing. Measures included mean fetal heart rate (FHR), number of FHR accelerations, FHR reactivity in the fetal non-stress test (NST) and biophysical profile (BPP) score. FINDINGS: Significant group differences were found for number of FHR accelerations, non-reactive NST and BPP scores (all Ps < 0.05). There were no significant group differences before time of dosing. Significant decreases (all Ps < 0.05) occurred from pre- to post-dose assessment for mean FHR, FHR accelerations, reactive NST and fetal movement. The decrease in accelerations and reactive NST were significant only for fetuses in the methadone group, and this resulted in a significantly lower likelihood of a reactive NST compared to fetuses in the buprenorphine group. CONCLUSION: Buprenorphine compared with methadone appears to result in less suppression of mean fetal heart rate, fetal heart rate reactivity and the biophysical profile score after medication dosing and these findings provide support for the relative safety of buprenorphine when fetal indices are considered as part of the complete risk-benefit ratio. PMID- 23106926 TI - Predicting treatment for neonatal abstinence syndrome in infants born to women maintained on opioid agonist medication. AB - AIM: To identify factors that predict the expression of neonatal abstinence syndrome (NAS) in infants exposed to methadone or buprenorphine in utero. DESIGN AND SETTING: Multi-site randomized clinical trial in which infants were observed for a minimum of 10 days following birth, and assessed for NAS symptoms by trained raters. PARTICIPANTS: A total of 131 infants born to opioid dependent mothers, 129 of whom were available for NAS assessment. MEASUREMENTS: Generalized linear modeling was performed using maternal and infant characteristics to predict: peak NAS score prior to treatment, whether an infant required NAS treatment, length of NAS treatment and total dose of morphine required for treatment of NAS symptoms. FINDINGS: Of the sample, 53% (68 infants) required treatment for NAS. Lower maternal weight at delivery, later estimated gestational age (EGA), maternal use of selective serotonin re-uptake inhibitors (SSRIs), vaginal delivery and higher infant birthweight predicted higher peak NAS scores. Higher infant birthweight and greater maternal nicotine use at delivery predicted receipt of NAS treatment for infants. Maternal use of SSRIs, higher nicotine use and fewer days of study medication received also predicted total dose of medication required to treat NAS symptoms. No variables predicted length of treatment for NAS. CONCLUSIONS: Maternal weight at delivery, estimated gestational age, infant birthweight, delivery type, maternal nicotine use and days of maternal study medication received and the use of psychotropic medications in pregnancy may play a role in the expression of neonatal abstinence syndrome severity in infants exposed to either methadone or buprenorphine. PMID- 23106927 TI - Differences in the profile of neonatal abstinence syndrome signs in methadone- versus buprenorphine-exposed neonates. AB - AIMS: To compare the profile of signs of neonatal abstinence syndrome (NAS) in methadone- versus buprenorphine-exposed infants. DESIGN, SETTING AND PARTICIPANTS: Secondary analysis of NAS data from a multi-site, double-blind, double-dummy, flexible-dosing, randomized clinical trial. Data from a total of 129 neonates born to opioid-dependent women who had been assigned to receive methadone or buprenorphine treatment during pregnancy were examined. MEASUREMENTS: For 10 days after delivery, neonates (methadone = 72, buprenorphine = 57) were assessed regularly using a 19-item modified Finnegan scale. Data from neonates who required pharmacological treatment (methadone = 41, buprenorphine = 27) were included up to the time treatment was initiated. The incidence and mean severity of the total NAS score and each individual sign of NAS were calculated and compared between medication conditions, as was the median time until morphine treatment initiation among treated infants in each condition. FINDINGS: Two NAS signs (undisturbed tremors and hyperactive Moro reflex) were observed significantly more frequently in methadone-exposed neonates and three (nasal stuffiness, sneezing, loose stools) were observed more frequently in buprenorphine-exposed neonates. Mean severity scores on the total NAS score and five individual signs (disturbed and undisturbed tremors, hyperactive Moro reflex, excessive irritability, failure to thrive) were significantly higher among methadone-exposed neonates, while sneezing was higher among buprenorphine exposed neonates. Among treated neonates, methadone-exposed infants required treatment significantly earlier than buprenorphine-exposed infants (36 versus 59 hours postnatal, respectively). CONCLUSIONS: The profile of neonatal abstinence syndrome differs in methadone- versus buprenorphine-exposed neonates, with significant differences in incidence, severity and treatment initiation time. Overall, methadone-exposed neonates have a more severe neonatal abstinence syndrome. PMID- 23106928 TI - Neonatal neurobehavior effects following buprenorphine versus methadone exposure. AB - AIM: To determine the effects of in utero exposure to methadone or buprenorphine on infant neurobehavior. DESIGN: Three sites from the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study, a double-blind, double-dummy, randomized clinical trial participated in this substudy. SETTING: Medical Centers that provided comprehensive maternal care to opioid-dependent pregnant women in Baltimore, MD, Providence, RI and Vienna, Austria. PARTICIPANTS: Thirty-nine full term infants. MEASUREMENTS: The Neonatal Intensive Care Unit (NICU) Network Neurobehavioral Scale (NNNS) was administered to a subgroup of infants on postpartum days 3, 5, 7, 10, 14-15 and 28-30. FINDINGS: While neurobehavior improved for both medication conditions over time, infants exposed in utero to buprenorphine exhibited fewer stress-abstinence signs (P < 0.001), were less excitable (P < 0.001) and less over-aroused (P < 0.01), exhibited less hypertonia (P < 0.007), had better self-regulation (P < 0.04) and required less handling (P < 0.001) to maintain a quiet alert state relative to in utero methadone-exposed infants. Infants who were older when they began morphine treatment for withdrawal had higher self-regulation scores (P < 0.01), and demonstrated the least amount of excitability (P < 0.02) and hypertonia (P < 0.02) on average. Quality of movement was correlated negatively with peak NAS score (P < 0.01), number of days treated with morphine for NAS (P < 0.01) and total amount of morphine received (P < 0.03). Excitability scores were related positively to total morphine dose (P < 0.03). CONCLUSION: While neurobehavior improves during the first month of postnatal life for in utero agonist medication-exposed neonates, buprenorphine exposure results in superior neurobehavioral scores and less severe withdrawal than does methadone exposure. PMID- 23106929 TI - Opioid dependence during pregnancy: relationships of anxiety and depression symptoms to treatment outcomes. AB - AIMS: To examine the relationship of anxiety and depression symptoms with treatment outcomes (treatment discontinuation, rates of ongoing use of illicit drugs and likelihood of preterm delivery) in opioid-dependent pregnant women and describe their use of psychotropic medications. DESIGN AND SETTING: Secondary data analysis from a randomized clinical trial of treatment for opioid dependence during pregnancy. PARTICIPANTS: A total of 175 opioid-dependent pregnant women, of whom 131 completed treatment. MEASUREMENTS: Symptoms of anxiety and depression were captured with the 15-item Mini International Neuropsychiatric Interview (MINI) screen. Use of illicit drugs was measured by urine drug screening. Preterm delivery was defined as delivery prior to 37 weeks' gestation. Self-reported use of concomitant psychotropic medication at any point during the study was recorded. FINDINGS: Women reporting only anxiety symptoms at study entry were more likely to discontinue treatment [adjusted odds ratio (OR) = 4.56, 95% confidence interval (CI) : 1.91-13.26, P = 0.012], while those reporting only depression symptoms were less likely to discontinue treatment (adjusted OR = 0.14, 95% CI : 0.20-0.88, P = 0.036) compared to women who reported neither depression nor anxiety symptoms. No statistically significant between-group differences were observed for ongoing illicit drug use or preterm delivery. A majority (61.4%) of women reported use of concomitant psychotropic medication at some point during study participation. CONCLUSIONS: Opioid agonist-treated pregnant patients with co-occurring symptoms of anxiety require additional clinical resources to prevent premature discontinuation. PMID- 23106930 TI - Infections and obstetric outcomes in opioid-dependent pregnant women maintained on methadone or buprenorphine. AB - AIMS: To characterize infections and compare obstetric outcomes in opioid dependent pregnant women who participated in a randomized clinical trial comparing agonist medications, methadone and buprenorphine. DESIGN: Incidence of infections was identified as part of the screening medical assessment. As part of a planned secondary analysis, analysis of variance and polytomous logistic regressions were conducted on obstetric outcome variables using treatment randomization condition (maternal maintenance with either methadone or buprenorphine) as the predictor variable, controlling for differences between study sites. SETTING: Six United States sites and one European site that provided comprehensive treatment to opioid-dependent pregnant women. PARTICIPANTS: Pregnant opioid-dependent women (n = 131) who delivered while participating in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. MEASUREMENTS: Obstetric, infectious and other maternal medical complications captured by medical records, physical examination, blood tests and self-report. Neonatal medical complications captured by medical records. FINDINGS: Hepatitis C was the most common infection (32.3%), followed by hepatitis B (7.6%) and chlamydia (6.1%) among participants at study enrollment. Maternal methadone versus buprenorphine maintenance was associated with a higher incidence of preterm labor (P = 0.04) and a significantly higher percentage of signs of respiratory distress in neonates at delivery (P = 0.05). Other medical and obstetric complications were infrequent in the total sample, as well as in both methadone and buprenorphine conditions. CONCLUSIONS: Buprenorphine appears to have an acceptable safety profile for use during pregnancy. PMID- 23106932 TI - Relationship between metabolic syndrome and cognition in patients with schizophrenia. AB - BACKGROUND: The metabolic syndrome (MetS) and cognitive impairments are common in schizophrenia. Both are associated with poor outcomes, which have received increasing medical and mental health attention. Whether MetS is associated with impaired cognitive functions in schizophrenia has not been thoroughly addressed. The aim of this study was to compare the association between patients with and without MetS and its contributing components with neurocognitive performance. We hypothesized that patients with MetS would be associated with more impaired cognitive performance. METHODS: 159 patients with schizophrenia or schizoaffective disorder, with available metabolic data were included in the study. Patients were classified as either having or not having MetS as defined by the NCEP Adult Panel-III criteria. All patients completed neurocognitive and metabolic tests. RESULTS: Of the 159 patients, 43.34% had MetS. Patients without the MetS performed significantly better on tests measuring processing speed (p=0.050), attention/vigilance (p=0.040), working memory (p=0.041) and problem solving/reasoning (p=0.050) compared with those with MetS. Patients with MetS showed significantly lower cognitive domain scores. After Bonferroni correction greater waist circumference was associated with lower scores on attention/vigilance (beta=-0.551; p<=.0083), HDL was positively associated with scores on attention/vigilance (beta=0.900, p<=.0083) and higher triglycerides were associated with lower scores on attention/vigilance (beta=-1.004, p<=.0083). CONCLUSIONS: Schizophrenia patients with MetS showed significant cognitive impairments in three key cognitive domains. Aggressive medical treatment of the constituent components of MetS may provide the potential for important beneficial effects on patients' cognitive functioning. PMID- 23106931 TI - Effect of hepatitis C virus status on liver enzymes in opioid-dependent pregnant women maintained on opioid-agonist medication. AB - AIM: To examine hepatic enzyme test results throughout the course of pregnancy in women maintained on methadone or buprenorphine. DESIGN: Participants were randomized to either methadone or buprenorphine maintenance. Blood chemistry tests, including liver transaminases and hepatitis C virus (HCV) status, were determined every 4 weeks and once postpartum. As part of a planned secondary analysis, generalized mixed linear models were conducted with aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) as the dependent variables. SETTING: Six US sites and one European site that provided comprehensive treatment to pregnant opioid-dependent women. PARTICIPANTS: A total of 175 opioid-dependent pregnant women enrolled in the Maternal Opioid Treatment: Human Experimental Research (MOTHER) study. FINDINGS: ALT, AST and GGT levels decreased for all subjects across pregnancy trimesters, rising slightly postpartum. HCV-positive subjects exhibited higher transaminases at all time-points compared to HCV-negative subjects, regardless of medication (all Ps < 0.05) condition. Both HCV-positive and negative buprenorphine-maintained participants exhibited lower GGT levels than those who were methadone-maintained (P < 0.05). CONCLUSIONS: Neither methadone nor buprenorphine appear to have adverse hepatic effects in the treatment of pregnant opioid-dependent women. PMID- 23106933 TI - Global gene expression in the bovine corpus luteum is altered after stimulatory and superovulatory treatments. AB - Equine chorionic gonadotrophin (eCG) has been widely used in superovulation and artificial insemination programmes and usually promotes an increase in corpus luteum (CL) volume and stimulates progesterone production. Therefore, to identify eCG-regulated genes in the bovine CL, the transcriptome was evaluated by microarray analysis and the expression of selected genes was validated by qPCR and western blot. Eighteen Nelore crossbred cows were divided into control (n=5), stimulated (n=6) and superovulated groups (n=7). Ovulation was synchronised using a progesterone device-based protocol. Stimulated animals received 400 IU of eCG at device removal and superovulated animals received 2000 IU of eCG 4 days prior. Corpora lutea were collected 7 days after gonadotrophin-releasing hormone administration. Overall, 242 transcripts were upregulated and 111 transcripts were downregulated in stimulated cows (P <= 0.05) and 111 were upregulated and 113 downregulated in superovulated cows compared to the control animals (1.5 fold, P <= 0.05). Among the differentially expressed genes, many were involved in lipid biosynthesis and progesterone production, such as PPARG, STAR, prolactin receptors and follistatin. In conclusion, eCG modulates gene expression differently depending on the treatment, i.e. stimulatory or superovulatory. Our data contribute to the understanding of the pathways involved in increased progesterone levels observed after eCG treatment. PMID- 23106935 TI - Empirical evaluation of grouping of lower urinary tract symptoms: principal component analysis of Tampere Ageing Male Urological Study data. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: The ICS has divided LUTS into three groups: storage, voiding and post-micturition symptoms. The classification is based on anatomical, physiological and urodynamic considerations of a theoretical nature. We used principal component analysis (PCA) to determine the inter-correlations of various LUTS, which is a novel approach to research and can strengthen existing knowledge of the phenomenology of LUTS. After we had completed our analyses, another study was published that used a similar approach and results were very similar to those of the present study. We evaluated the constellation of LUTS using PCA of the data from a population-based study that included >4000 men. In our analysis, three components emerged from the 12 LUTS: voiding, storage and incontinence components. Our results indicated that incontinence may be separate from the other storage symptoms and post-micturition symptoms should perhaps be regarded as voiding symptoms. OBJECTIVE: To determine how lower urinary tract symptoms (LUTS) relate to each other and assess if the classification proposed by the International Continence Society (ICS) is consistent with empirical findings. MATERIALS AND METHODS: The information on urinary symptoms for this population-based study was collected using a self-administered postal questionnaire in 2004. The questionnaire was sent to 7470 men, aged 30-80 years, from Pirkanmaa County (Finland), of whom 4384 (58.7%) returned the questionnaire. The Danish Prostatic Symptom Score-1 questionnaire was used to evaluate urinary symptoms. Principal component analysis (PCA) was used to evaluate the inter-correlations among various urinary symptoms. RESULTS: The PCA produced a grouping of 12 LUTS into three categories consisting of voiding, storage and incontinence symptoms. Post micturition symptoms were related to voiding symptoms, but incontinence symptoms were separate from storage symptoms. In the analyses by age group, similar categorization was found at ages 40, 50, 60 and 80 years, but only two groups of symptoms emerged among men aged 70 years. The prevalence among men aged 30 was too low for meaningful analysis. CONCLUSIONS: This population-based study suggests that LUTS can be divided into three subgroups consisting of voiding, storage and incontinence symptoms based on their inter-correlations. Our empirical findings suggest an alternative grouping of LUTS. The potential utility of such an approach requires careful consideration. PMID- 23106934 TI - Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study. AB - BACKGROUND: Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe. METHODS: The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had >= 1 iPTH value recorded, and >= 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates. RESULTS: There were 6369 patients included in the analysis. Mean +/- SD person-time at risk was 13.1 +/- 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150-300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13-1.78 mmol/L and 2.10-2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses. CONCLUSIONS: These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe. PMID- 23106937 TI - Thermal stress responses in the bacterial biosphere of the Great Barrier Reef sponge, Rhopaloeides odorabile. AB - Marine sponges are diverse, abundant and provide a crucial coupling point between benthic and pelagic habitats due to their high filtration rates. They also harbour extensive microbial communities, with many microbial phylotypes found exclusively in sponge hosts and not in the seawater or surrounding environment, i.e. so-called sponge-specific clusters (SCs) or sponge- and coral-specific clusters (SCCs). We employed DNA (16S rRNA gene) and RNA (16S rRNA)-based amplicon pyrosequencing to investigate the effects of sublethal thermal stress on the bacterial biosphere of the Great Barrier Reef sponge Rhopaloeides odorabile. A total of 8381 operational taxonomic units (OTUs) (97% sequence similarity) were identified, affiliated with 32 bacterial phyla from seawater samples, 23 bacterial phyla from sponge DNA extracts and 18 bacterial phyla from sponge RNA extracts. Sublethal thermal stress (31 degrees C) had no effect on the present and/or active portions of the R. odorabile bacterial community but a shift in the bacterial assemblage was observed in necrotic sponges. Over two-thirds of DNA and RNA sequences could be assigned to previously defined SCs/SCCs in healthy sponges whereas only 12% of reads from necrotic sponges could be assigned to SCs/SCCs. A rapid decline in host health over a 1 degrees C temperature increment suggests that sponges such as R. odorabile may be highly vulnerable to the effects of global climate change. PMID- 23106936 TI - Influences of microbubble diameter and ultrasonic parameters on in vitro sonothrombolysis efficacy. AB - PURPOSE: To quantify the effects of microbubble (MB) size, elasticity, and pulsed ultrasonic parameters on in vitro sonothrombolysis (ultrasound [US]-mediated thrombolysis) efficacy. MATERIALS AND METHODS: Monodispersive MBs with diameters of 1 MUm or 3 MUm were exposed to pulsed US (1 MHz or 3 MHz) to lyse rabbit blood clots. Sonothrombolysis efficacy (clot mass loss) was measured as functions of MB size and concentration, ultrasonic frequency and intensity, pulse duration (PD), pulse repeat frequency (PRF), and duty factor. RESULTS: Sonothrombolysis at 1 MHz was more effective using 3-MUm MBs and at 3 MHz using 1-MUm MBs. Sonothrombolysis was more effective at 1 MHz when>=75% of MBs remained intact, especially for 3 MUm MBs; improving sonothrombolysis by increasing PRF from 100 Hz to 400 Hz at 3 MHz was associated with increasing 3-MUm MB survival. However, 60% of 1-MUm MBs were destroyed during maximal sonothrombolysis at 3 MHz, indicating that considerable MB collapse may be required for sonothrombolysis under these conditions. CONCLUSIONS: The ability to control MB size and elasticity permits using a wide range of US parameters (eg, frequency, intensity) to produce desired levels of sonothrombolysis. Comparable, maximal sonothrombolysis efficacy was achieved at 20-fold lower intensity with 3-MUm MBs (0.1W/cm(2)) than with 1-MUm MBs (2.0W/cm(2)), a potential safety issue for in vivo sonothrombolysis. US parameters that maximized MB survival yielded maximal sonothrombolysis efficacy except with 1-MUm MBs at 3MHz where most MBs were destroyed. PMID- 23106938 TI - Transcript mapping of Cotton leaf curl Burewala virus and its cognate betasatellite, Cotton leaf curl Multan betasatellite. AB - BACKGROUND: Whitefly-transmitted geminiviruses (family Geminiviridae, genus Begomovirus) are major limiting factors for the production of numerous dicotyledonous crops throughout the warmer regions of the world. In the Old World a small number of begomoviruses have genomes consisting of two components whereas the majority have single-component genomes. Most of the monopartite begomoviruses associate with satellite DNA molecules, the most important of which are the betasatellites. Cotton leaf curl disease (CLCuD) is one of the major problems for cotton production on the Indian sub-continent. Across Pakistan, CLCuD is currently associated with a single begomovirus (Cotton leaf curl Burewala virus [CLCuBuV]) and the cotton-specific betasatellite Cotton leaf curl Multan betasatellite (CLCuMuB), both of which have recombinant origins. Surprisingly, CLCuBuV lacks C2, one of the genes present in all previously characterized begomoviruses. Virus-specific transcripts have only been mapped for few begomoviruses, including one monopartite begomovirus that does not associate with betasatellites. Similarly, the transcripts of only two betasatellites have been mapped so far. The study described has investigated whether the recombination/mutation events involved in the evolution of CLCuBuV and its associated CLCuMuB have affected their transcription strategies. RESULTS: The major transcripts of CLCuBuV and its associated betasatellite (CLCuMuB) from infected Nicotiana benthamiana plants have been determined. Two complementary sense transcripts of ~1.7 and ~0.7 kb were identified for CLCuBuV. The ~1.7 kb transcript appears similar in position and size to that of several begomoviruses and likely directs the translation of C1 and C4 proteins. Both complementary sense transcripts can potentially direct the translation of C2 and C3 proteins. A single virion-sense transcript of ~1 kb, suitable for translation of the V1 and V2 genes was identified. A predominant complementary-sense transcript was also confirmed for the betasatellite. CONCLUSIONS: Overall, the transcription of CLCuBuV and the recombinant CLCuMuB is equivalent to earlier mapped begomoviruses/betasatellites. The recombination events that featured in the origins of these components had no detectable effects on transcription. The transcripts spanning the mutated C2 gene showed no evidence for involvement of splicing in restoring the ability to express intact C2 protein. PMID- 23106939 TI - A role for p21-activated kinase 7 in the development of gastric cancer. AB - p21-activated kinase (PAK)7 (also known as PAK5) is a member of the group B PAK family of serine/threonine protein kinases, which are effectors of the small GTPases Rac and CDC42. PAK7 can promote neurite outgrowth, induce microtubule stabilization, and activate cell survival signaling pathways. However, the role of PAK7 in cancer is still poorly understood. Here, we showed that PAK7 expression was upregulated in different gastric cancer cell lines and gastric cancer tissues, as compared with human embryonic kidney 293 cells and adjacent normal tissues, respectively. The results suggested that PAK7 expression was related to gastric cancer progression. Thus, we employed lentivirus-mediated small interfering RNA to inhibit PAK7 expression, to investigate the role of PAK7 in human gastric carcinogenesis. RNA interference efficiently downregulated expression of PAK7 in SGC-7901 and MGC-803 cells at both mRNA and protein levels. Knockdown of PAK7 inhibited human gastric cancer cell proliferation by inducing cell cycle arrest in G(0)/G(1) phase, in concordance with the downregulation of CDK2, CDC25A, and cyclin D1. Our data suggest that PAK7 is a new hallmark of gastric cancer, in which PAK7 might contribute to gain of tumor growth potential, acting by affecting the expression of cell cycle regulators. Therefore, PAK7 may be an attractive candidate as a therapeutic target in gastric cancer. PMID- 23106940 TI - Age trends in the prevalence of cervical squamous intraepithelial lesions among HIV-positive women in Cameroon: a cross-sectional study. AB - BACKGROUND: Cervical squamous intra-epithelial lesions (SIL) are more frequent in HIV-positive women overall. However the appropriate age at which to begin and end cervical cancer screening for early detection of lesions in HIV-positive women is not clear. We assessed the age-specific prevalence of any SIL and SIL requiring colposcopy in HIV-positive women in Cameroon. METHODS: We enrolled, interviewed and conducted conventional cervical cytology in 282 women, aged 19-68 years, initiating antiretroviral therapy in three clinics in Cameroon. In bivariable analyses, the crude relationship between age and the presence of lesions was assessed using locally weighted regression (LOWESS) methods. In multivariate analyses, generalized linear models with prevalence as the outcome, an identity link and a binomial distribution, were used to estimate prevalence differences. Bias analyses were conducted to assess the potential effect of inaccuracies in cytology. RESULTS: SIL were detected in 43.5% of the 276 women with satisfactory samples, 17.8% of whom had ASC-H/HSIL. On average, women aged 26 to 59 tended to have a slightly higher prevalence of any SIL than other women (Prevalence difference PD: 6.5%; 95%CI: -11.4, 24.4%). This PD was a function of CD4 count (heterogeneity test p-value =0.09): amongst patients with CD4 counts less than 200cells/uL, the prevalence was higher in patients aged 26-59, while there was essentially no difference amongst women with CD4 counts greater than 200 cells/uL. ASC-H/HSIL were present in women as young as 19 and as old as 62. Overall the prevalence of ASC-H/HSIL increased by 0.7% (95%CI: -3.8%, 5.1%) per decade increase in age. CONCLUSION: Both severe and less severe lesions were prevalent at all ages suggesting little utility of age-targeted screening among HIV-positive women. Nevertheless, the long-term evolution of these lesions needs to be assessed in prospective studies. PMID- 23106941 TI - Facial emotion expression recognition by children at familial risk for depression: high-risk boys are oversensitive to sadness. AB - BACKGROUND: Offspring of depressed parents are at greatly increased risk for mood disorders. Among potential mechanisms of risk, recent studies have focused on information processing anomalies, such as attention and memory biases, in the offspring of depressed parents. In this study we examined another information processing domain, perceptual sensitivity to emotion cues in facial expressions, as a potential mechanism of risk that characterizes the offspring of depressed parents. METHODS: The study included 64 children at familial-risk for depression and 40 low-risk peers between the ages 7 and 13(Mage = 9.51; SD = 2.27). Participants were presented with pictures of facial expressions that varied in emotional intensity from neutral to full-intensity sadness or anger (i.e., emotion recognition), or pictures of faces morphing from anger to sadness (emotion discrimination). After each picture was presented, children indicated whether the face showed a specific emotion (i.e., sadness, anger) or no emotion at all (neutral) using a forced choice paradigm. We examined group differences in the intensity of emotion that suggested greater sensitivity to specific emotions. RESULTS: In the emotion recognition task, boys (but not girls) at familial-risk for depression identified sadness at significantly lower levels of emotional intensity than did their low-risk peers. The high and low-risk groups did not differ with regard to identification of anger. In the emotion discrimination task, both groups displayed over-identification of sadness in ambiguous mixed faces but high-risk youth were less likely to show this labeling bias than their peers. CONCLUSION: Our findings are consistent with the hypothesis that enhanced perceptual sensitivity to subtle traces of sadness in facial expressions may be a potential mechanism of risk among boys at familial-risk for depression. This enhanced perceptual sensitivity does not appear to be due to biases in the labeling of ambiguous faces. PMID- 23106942 TI - Disease management programs for patients with asthma in Germany: a longitudinal population-based study. AB - BACKGROUND: The primary aim of the disease management program (DMP) for patients with asthma is to improve health outcomes and to reduce costs. Five years after its introduction in Germany, no consensus has yet been reached as to whether DMP has been effective in reaching these goals. OBJECTIVE: To evaluate the DMP for asthma in Bavaria using routinely collected subject medical records. METHODS: A longitudinal population-based study encompassing over 100,000 DMP participants between 2006 (when the program began) and 2010. RESULTS: The prescription rate of oral corticosteroids dropped from 15.7% in 2006 to 13.6% in 2007, and again from 7.5% in 2008 to 5.9% in 2010 (P < .001). The proportion of subjects with asthma self-management education increased from 4.4% to 23.4% (P < .001). Utilization of an individual asthma action plan increased from 40.3% to 69.3% (P < .001). Hospitalization decreased from 2.8% to 0.7% (P < .001). CONCLUSIONS: In the first 4 years of DMP there was an improvement in pharmacotherapy and patient self management. The proportion of subjects requiring hospitalization decreased. Our results suggest that the German DMP for asthma has been effective in enhancing the quality of care in regard to an improved symptom frequency, adherence to guidelines, pharmacotherapy, and hospitalization. PMID- 23106944 TI - Judith Graham Pool and the discovery of cryoprecipitate. PMID- 23106945 TI - Reply to von Willebrand's disease and postpartum haemorrhage by Chee et al. PMID- 23106946 TI - A Canadian survey of self-infusion practices in persons with haemophilia A. PMID- 23106943 TI - Nitrilases in nitrile biocatalysis: recent progress and forthcoming research. AB - Over the past decades, nitrilases have drawn considerable attention because of their application in nitrile degradation as prominent biocatalysts. Nitrilases are derived from bacteria, filamentous fungi, yeasts, and plants. In-depth investigations on their natural sources function mechanisms, enzyme structure, screening pathways, and biocatalytic properties have been conducted. Moreover, the immobilization, purification, gene cloning and modifications of nitrilase have been dwelt upon. Some nitrilases are used commercially as biofactories for carboxylic acids production, waste treatment, and surface modification. This critical review summarizes the current status of nitrilase research, and discusses a number of challenges and significant attempts in its further development. Nitrilase is a significant and promising biocatalyst for catalytic applications. PMID- 23106947 TI - Oxygen-induced hypercapnia in COPD: myths and facts. AB - During our medical training, we learned that oxygen administration in patients with chronic obstructive pulmonary disease (COPD) induces hypercapnia through the 'hypoxic drive' mechanism and can be dangerous. This mindset frequently results in the reluctance of clinicians to administer oxygen to hypoxemic patients with COPD. However, this fear is not based on evidence in the literature. Here, we will review the impact and pathophysiology of oxygen-induced hypercapnia in patients with acute exacerbation of COPD and recommend a titrated oxygen management. PMID- 23106949 TI - Dietary practices of Saudi women during puerperium. AB - AIM: Poor maternal health sometimes can be a consequence of practicing different myths during puerperium. This cross-sectional study describes the practice of different myths regarding diet among Saudi women. MATERIAL AND METHODS: The study comprised women attending the postnatal clinic at the Mother and Child Hospital in Buraidah from January to December 2011. RESULTS: Almost 65.9% of women were using a combination of herbs such as ginger (zingiber officinale), hilba (fenugreek) and black seeds (nigella sativa). The multinomial logistic regression of herbs on age, education, occupation, parity and mode of delivery was statistically significant (chi2 [48] = 214.645, P < 0.001). Hilba was more commonly used by women with instrumental delivery. It was common for women to avoid different fruits and vegetables (33.89%). Eggs were avoided by 16.5% of women and 11% avoided cold drinks. The multinomial logistic regression of diet on age, education, occupation, parity and mode of delivery was statistically significant (chi2 [72] = 389.861, P < 0.001). Individuals below college level education were more likely to avoid fruits, vegetables and cold drinks in their diet. CONCLUSION: Health education programs are needed to improve knowledge about dietary malpractices during puerperium. This may help eliminate myths regarding avoidance of certain dietary components. PMID- 23106948 TI - Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma. AB - Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status. OBJECTIVE: * To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: * A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. * The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. * The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. * The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment. RESULTS: * A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. * TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. * Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001). CONCLUSIONS: * TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. * We report for the first time the independent prognostic role of baseline TB in multivariate analysis. * We believe that this information could be translated into clinical practice. PMID- 23106950 TI - Novel use of narrow paddle electrodes for occipital nerve stimulation--technical note. AB - OBJECTIVES: Occipital nerve stimulation (ONS), an established treatment for medically intractable headache syndromes, has lead migration rates quoted up to 24%. In a series of patients with ideal characteristics for this treatment modality, we describe an operative technique for ONS involving the novel use of narrow paddle electrodes: "S8 Lamitrode" (St. Jude Medical [SJM], St. Paul, MN, USA). MATERIALS AND METHODS: Five patients (occipital neuralgia [ON] = 4; chronic migraine [CM] = 1) were treated with ONS between 2010 and 2011. All patients had a successful trial of peripheral neurostimulation (Algotec Ltd, Crawley, UK) therapy. Operative technique involved the use of a park-bench position, allowing simultaneous exposure of the occipital and infraclavicular regions. Through a retromastoid/occipital incision just beneath the external occipital protruberance, exposing the extrafascial plane, the S8 Lamitrode is implanted to intersect both greater occipital nerves for bilateral pain or unilateral greater and lesser occipital nerves for unilateral ON or with significant component of the pain relating to the lesser occipital nerve. RESULTS: Over the median follow up of 12 months, there were no episodes of lead migration or revision. There also was significant improvement in symptoms in all patients. CONCLUSIONS: This is the first reported use of S8 Lamitrode electrode for ONS. This narrow electrode is suited for this role leading to minimal trauma during surgical placement, facilitates resolution of problems with lead migration, and optimizes effect with stimulation focused more in direction of the occipital nerves without skin involvement. To date, the SJM Genesis neurostimulation system, with percutaneous electrodes only, is CE mark approved in Europe for peripheral nerve stimulation of the occipital nerves for the management of pain and disability for patients diagnosed with intractable CM. Further developments and studies are required for better devices to suit ONS, thereby avoiding frequently encountered problems and which may clarify the role of paddle leads in ONS. PMID- 23106951 TI - The relationship between the optical density of cataract and its influence on retinal nerve fibre layer thickness measured with spectral domain optical coherence tomography. AB - PURPOSE: The purpose of this study was to model the influence of cataract on Spectral Domain Optical Coherence Tomography (SDOCT) image quality and Retinal Nerve Fibre Layer (RNFL) thickness measurements. METHODS: SDOCT images, made with two different devices (3DOCT-1000, Topcon and Cirrus HD-OCT), before and after cataract surgery were compared and judged against measurements from normal subjects using artificial filters simulating the effects of cataract. Optical density of the images was calculated based on a mathematical model described previously. RESULTS: In total, forty-eight eyes were included for pre- and postoperative cataract extraction measurements. OCT image quality significantly (p < 0.001) improved postoperative and postoperative RNFL thickness was significantly (p < 0.001) thicker in both groups of patients. The measurements using artificial filters showed a rather precise linear relation between change in filter induced optical density and change in RNFL thickness (R = 0.941, p < 0.001 for 3DOCT-1000 and R = 0.785, p < 0.001 for Cirrus HD-OCT). For the patient groups, the relation was less marked, 3DOCT-1000 Rs = 0.697, p < 0.03 and Cirrus HD-OCT Rs = 0.444, p < 0.03. The predictive potential based on the found linear relationship between OCT-effective optical density of cataract and the cataract induced underestimation was however limited, and mean difference +/- SD between predicted and measured RNFL thickness were 1.68 +/- 7.55 (3DOCT-1000) and 3.71 +/ 2.97 (Cirrus HD-OCT) micron. CONCLUSIONS: A linear relationship exists between OCT-effective optical density of cataract and underestimation of RNFL thickness measured with OCT. This finding holds promise to correct for cataract-induced changes in RNFL measurements, but will differ for each type of OCT device. PMID- 23106952 TI - An old drug for a new application: potential benefits of sildenafil in wound healing. AB - PURPOSE: Several studies have evaluated the effects of sildenafil on the tissue repair and wound healing. In the present review, the impact of sildenafil on the wound healing in all available clinical and non-clinical (experimental) studies has been discussed. METHODS: A literature search was performed using PubMed, Scopus, Medline, Embase, Cochrane central register of controlled trials and Cochrane database systematic reviews. Related articles indexed in Google Scholar were also included. Key words used as search terms were 'phosphodiesterase inhibitor', 'sildenafil', 'skin', 'cutaneous', 'skin lesion', 'skin damage', 'wound', and 'wound healing'. No time limitation was considered in this review. RESULTS: A total of 15 animal studies, 7 case reports, and 2 small clinical studies have reported the effects of sildenafil on the wound healing. The effects included skin flaps and grafts, anastomosis, systemic sclerosis and Raynaud's disease. CONCLUSIONS: The available data support the beneficial effects of sildenafil in improvement of tissue healing in various conditions. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106953 TI - Management of delirium in adult critically ill patients: an overview. AB - Delirium is a common manifestation of acute, reversible, brain dysfunction in critically ill patients. It is associated with increased morbidity and mortality in the intensive care unit (ICU). Detection and prevention of risk factors for delirium is critical. Daily assessment for delirium should be part of the treatment strategies. Although, non-pharmacologic treatment have been successful, often, pharmacologic intervention is necessary. Currently, there are no approved medications indicated for the treatment of ICU delirium. The objective of this review article is to provide a comprehensive overview of non pharmacologic and pharmacologic options for the treatment of ICU delirium. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106954 TI - Regional differences in the components of luminal water from rat gastrointestinal tract and comparison with other species. AB - PURPOSE: The bile acids, phospholipids, inorganic ions, and pH in luminal fluid are very important factors for the dissolution and oral absorption of solid drugs. In this study, we evaluated the regional differences in these factors in the rat GI tract. The solubility of griseofulvin, a poorly water-soluble drug, in the luminal fluid in each segment was also measured. In addition, the data from rats were compared with those from other species published previously to evaluate the species differences in the composition of luminal fluid. METHODS: Rat abdomen was opened and residual water was sampled from each region of GI tract to measure the various components concentrations. RESULTS: The total bile acid and phospholipid concentrations were much higher in the lower jejunum and upper jejunum, respectively, than in the other regions. The solubilities of griseofulvin in the lower jejunal fluid (153-260 ug/mL) were about 1.5-2 times higher than those in the upper jejunal fluid (99-146 ug/mL). The regional differences in inorganic ions and pH were also observed. As for species differences, the total bile acid and phospholipid concentration in rats GI tract were much higher than those of dogs and humans. CONCLUSION: These informations about the regional differences and species differences of the components in the GI fluid should be very useful to consider dissolution and oral absorption of solid drugs. PMID- 23106955 TI - Simultaneous determination of levocetirizine and pseudoephedrine in dog plasma by liquid chromatography-mass spectrometry in the presence of dextrocetirizine. AB - PURPOSE: This study describes the development of a rapid and sensitive LC-ESI-MS assay for simultaneous enantioselective determination of levocetirizine and pseudoephedrine in dog plasma in the presence of dextrocetirizine. METHODS: Separations were achieved on an Ultron ES-OVM chiral column using the mobile phase consisting of 10 mM aqueous NH4OAc (pH 6.6) and acetonitrile (9:1 v/v). RESULTS: The retention times of pseudoephedrine, dextrocetirizine, levocetirizine and diazepam (internal standard) were 5.2, 8.3, 9.6 and 11.6 min, respectively, and the total run time was less than 15 min. The assay was validated to demonstrate the linearity, accuracy and precision, recovery and stability. The calibration curves were linear over the concentration range from 1 - 200 ng/mL for levocetirizine and from 5 - 1000 ng/mL for pseudoephedrine. CONCLUSIONS: The developed assay was successfully applied to a pharmacokinetic study after oral administration of the racemic cetirizine (0.5 mg/kg, or 0.25 mg/kg as levocetirizine) and pseudoephedrine (12 mg/kg) in the dog. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106956 TI - Effects of experimental hyperlipidemia on the pharmacokinetics of tadalafil in rats. AB - PURPOSE: Hyperlipidemia is associated with an increased risk of erectile dysfunction. In this study, we investigated the effects of hyperlipidemia on the pharmacokinetics of tadalafil, a novel therapeutic agent for erectile dysfunction, in rats with experimental hyperlipidemia. METHODS: Tadalafil (1 mg/kg) was administered to control rats and rats with poloxamer-407-induced hyperlipidemia (1 g/kg, i.p.). In addition, we performed in vitro studies to determine the hepatic metabolism in S9 fractions, intestinal absorption, and plasma protein binding. RESULTS: Hyperlipidemia dramatically increased tadalafil's the total area under the plasma concentration-time curve from time 0 to infinity after intravenous (2.09-fold) and oral (11.9-fold) administration, and decreased total body clearance (0.537-fold) and apparent volume of distribution at the steady state (0.438-fold) after intravenous administration of tadalafil. Further, we observed decreased in vitro hepatic S9 metabolism, intestinal first-pass metabolism, and unbound fraction of tadalafil. CONCLUSIONS: The alterations in the pharmacokinetics of tadalafil observed in rats with poloxamer 407-induced hyperlipidemia may be attributable to a decrease in hepatic and intestinal metabolism and unbound fraction of tadalafil in the plasma. These findings have potential therapeutic implications for predicting the pharmacokinetic responses of humans to hyperlipidemia. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106957 TI - In vitro characterization of the oxidation of a pyridinium metabolite of haloperidol by human placenta: the effect of smoking. AB - PURPOSE: The antipsychotic drug haloperidol can be metabolised to pyridinium metabolites haloperidol pyridinium (HP+) and reduced haloperidol pyridinium (RHP+). These pyridinium metabolites were proposed to contribute to the extrapyramidal side effects of haloperidol, because they are structural analogues of N-methyl-4-phenylpyridinium (MPP+), a well-known neurotoxin. RHP+ can be oxidized to HP+ by CYP1A1. In the current study, the oxidation of RHP+ to HP+ was investigated using human placenta microsomal preparations which contain relatively high levels of CYP1A1. METHODS: Cytochrome P450 isoenzymes responsible for the metabolism of RHP+ were characterized in vitro using human placenta microsomal preparations from smokers and non-smokers. RESULTS: A comparison of the metabolic activities between smokers and non-smokers suggests that smokers had higher activities for the oxidation of RHP+. A selective antibody against CYP1A1 was a partial inhibitor of RHP+ oxidase in placenta from smokers but had no effect in placenta from non-smokers. Furafylline and ketokonazole were shown to be stronger inhibitors of the oxidation of RHP+ to HP+ in liver than in placenta. This seems to indicate important contributions of CYP1A1 and CYP3A7 as compared to CYP1A2 and CYP3A4, respectively, because furafylline and ketokonazole are stronger inhibitors of CYP1A2 and CYP3A4 than CYP1A1 and CYP3A7, respectively. Interestingly, alpha-naphathoflavone enhanced the metabolic activity in liver microsomes due to its activator effect on CYP3A4. On the other hand, alpha-naphathoflavone partially inhibited the activity in placenta microsomes, indicating a role played by CYP1A1 or CYP1A2 in the oxidation of RHP+ in placenta. CONCLUSIONS: These data indicate that CYP1A1 plays an important role in the oxidation of RHP+ to HP+ in placenta from smokers. CYP3A7 and CYP3A4 could also play important roles in the metabolism of RHP+ in placenta microsomes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106958 TI - Development of lyophilized gemini surfactant-based gene delivery systems: influence of lyophilization on the structure, activity and stability of the lipoplexes. AB - PURPOSE: Cationic gemini surfactants have been studied as non-viral vectors for gene therapy. Clinical applications of cationic lipid/DNA lipoplexes are restricted by their instability in aqueous formulations. In this work, we investigated the influence of lyophilization on the essential physiochemical properties and in vitro transfection of gemini surfactant-lipoplexes. Additionally, we evaluated the feasibility of lyophilization as a technique for preparing lipoplexes with long term stability. METHODS: A gemini surfactant [12 7NH-12] and plasmid DNA encoding for interferon-gamma were used to prepare gemini surfactant/pDNA [P/G] lipoplexes. Helper lipid DOPE [L] was incorporated in all formulation producing a [P/G/L] system. Sucrose and trehalose were utilized as stabilizing agents. To evaluate the ability of lyophilization to improve the stability of gemini surfactant-based lipoplexes, four lyophilized formulations were stored at 25C for three months. The formulations were analyzed at different time-points for physiochemical properties and in vitro transfection. RESULTS: The results showed that both sucrose and trehalose provided anticipated stabilizing effect. The transfection efficiency of the lipoplexes increased 2-3 fold compared to fresh formulations upon lyophilization. This effect can be attributed to the improvement of DNA compaction and changes in the lipoplex morphology due to the lyophilization/rehydration cycles. The physiochemical properties of the lyophilized formulations were maintained throughout the stability study. All lyophilized formulations showed a significant loss of gene transfection activity after three months of storage. Nevertheless, no significant losses of transfection efficiency were observed for three formulations after two months storage at 25 C. CONCLUSION: Lyophilization significantly improved the physical stability of gemini surfactant-based lipoplexes compared to liquid formulations. As well, lyophilization improved the transfection efficiency of the lipoplexes. The loss of transfection activity upon storage is most probably due to the conformational changes in the supramolecular structure of the lipoplexes as a function of time and temperature rather than to DNA degradation. PMID- 23106959 TI - Co-delivery of doxorubicin and PSC 833 (Valspodar) by stealth nanoliposomes for efficient overcoming of multidrug resistance. AB - PURPOSE: This study was aimed at developing co-encapsulated stealth nanoliposomes containing PSC 833, an efficient MDR modulator, and doxorubicin (DOX) in order to increase the effectiveness and decrease adverse effects of the anticancer drug. METHODS: In attempt to increase the encapsulation efficiency of drugs, different methods for liposome preparation were tested and the effect of different parameters such as drug to lipid molar ratio, cholesterol mole percent and lipid compositions, were investigated. The final product with a lipid composition of EPC:DSPE-PEG2000:Chol (60:5:30 %mol) was prepared by thin layer film hydration method. After preparation of empty liposomes, DOX and PSC 833 were loaded using ammonium sulfate gradient and remote film loading methods, respectively. Physical characteristics of optimized liposomes (DOX/PSC-L) such as particle size, zeta potential, encapsulation efficiency, in-vitro drugs release and stability were evaluated. Furthermore, in vitro cytotoxicity study of various liposomal formulations as well as drugs, solutions against resistant human breast cancer cell line, T47D/TAMR-6, was evaluated using MTT assay. RESULTS: The best formulation showed a narrow size distribution with average diameter of 91.3 +/- 0.2 nm with zeta potential of -6 +/- 1.2, the encapsulation efficiency for DOX and PSC 833 were more than 95% and 65.5%, respectively. In DOX-resistant T47D/TAMR-6 cells, dual-agent stealth liposomes showed significantly greater cytotoxicity (P < 0.05) than free DOX and liposomal DOX plus free PSC 833 treatments. CONCLUSIONS: Co-encapsulation of DOX and PSC 833 presents a promising anticancer formulation, capable of effective reversal of drug resistance, and should be explored further in therapeutic studies with animal tumor xenograft models. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106960 TI - A correlative model to predict in vivo AUC for nanosystem drug delivery with release rate-limited absorption. AB - PURPOSE: Drug release from nanosystems at the sites of either absorption or effect biophase is a major determinant of its biological action. Thus, in vitro drug release is of paramount importance in gaining insight for the systems performance in vivo. METHODS: A novel in vitro in vivo correlation, IVIVC, model denoted as double reciprocal area method was presented and applied to 19 drugs from 55 nano formulations with total 336 data, gathered from literature. RESULTS: The proposed model correlated the in vitro with in vivo parameters with overall error of 12.4 +/- 3.9%. Also the trained version of the model predicted the test formulations with overall error of 15.8 +/- 3.7% indicating the suitability of the approach. A theoretical justification was provided for the model considering the unified classical release laws. CONCLUSION: The model does not necessitate bolus intravenous drug data and seems to be suitable for IVIVC of drugs with release rate-limited absorption. PMID- 23106961 TI - Pluronic(r) F-127 and Pluronic Lecithin Organogel (PLO): main features and their applications in topical and transdermal administration of drugs. AB - Topical drug treatment aims at providing high concentrations of drugs at the site of application so as to avoid adverse systemic effects associated with oral administration. Smart polymers, or stimuli-responsive polymers, are able to respond to a stimulus by showing physical or chemical changes in their behaviour as, for example, the delivery of the drug carried by them. The thermo-responsive nature of Pluronic(r) F-127 (Basf, Ludwigshafen, Germany) makes it an excellent candidate for the delivery of drugs at various application sites. In recent years, PF-127, and later, Pluronic lecithin organogels (PLO), have attracted particular interest in the design of dermal and transdermal delivery systems with a view to promoting, improving or retarding drug permeation through the skin, bearing in mind that for topical delivery systems, accumulation in the skin with minimal permeation is desired, while for systemic delivery, the opposite behaviour is preferred. In this review, we discuss the properties and characteristics of PF-127 and Pluronic lecithin organogels (PLO), and present many examples and advantages of the application of these polymeric systems in topical and transdermal administration of drugs. This article is open to POST PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 23106962 TI - Validity and reliability of criterion based clinical audit to assess obstetrical quality of care in West Africa. AB - BACKGROUND: In Mali and Senegal, over 1% of women die giving birth in hospital. At some hospitals, over a third of infants are stillborn. Many deaths are due to substandard medical practices. Criterion-based clinical audits (CBCA) are increasingly used to measure and improve obstetrical care in resource-limited settings, but their measurement properties have not been formally evaluated. In 2011, we published a systematic review of obstetrical CBCA highlighting insufficient considerations of validity and reliability. The objective of this study is to develop an obstetrical CBCA adapted to the West African context and assess its reliability and validity. This work was conducted as a sub-study within a cluster randomized trial known as QUARITE. METHODS: Criteria were selected based on extensive literature review and expert opinion. Early 2010, two auditors applied the CBCA to identical samples at 8 sites in Mali and Senegal (n = 185) to evaluate inter-rater reliability. In 2010-11, we conducted CBCA at 32 hospitals to assess construct validity (n = 633 patients). We correlated hospital characteristics (resource availability, facility perinatal and maternal mortality) with mean hospital CBCA scores. We used generalized estimating equations to assess whether patient CBCA scores were associated with perinatal mortality. RESULTS: Results demonstrate substantial (ICC = 0.67, 95% CI 0.54; 0.76) to elevated inter-rater reliability (ICC = 0.84, 95% CI 0.77; 0.89) in Senegal and Mali, respectively. Resource availability positively correlated with mean hospital CBCA scores and maternal and perinatal mortality were inversely correlated with hospital CBCA scores. Poor CBCA scores, adjusted for hospital and patient characteristics, were significantly associated with perinatal mortality (OR 1.84, 95% CI 1.01-3.34). CONCLUSION: Our CBCA has substantial inter-rater reliability and there is compelling evidence of its validity as the tool performs according to theory. TRIAL REGISTRATION: Current Controlled Trials ISRCTN46950658. PMID- 23106963 TI - Control of lipid metabolism by adipocyte FGFR1-mediated adipohepatic communication during hepatic stress. AB - BACKGROUND: Endocrine FGF19 and FGF21 exert their effects on metabolic homeostasis through fibroblast growth factor receptor (FGFR) and co-factor betaKlotho (KLB). Ileal FGF19 regulates bile acid metabolism through specifically FGFR4-KLB in hepatocytes where FGFR1 is not significant. Both FGF19 and FGF21 activate FGFR1-KLB whose function predominates in adipocytes. Recent studies using administration of FGF19 and FGF21 and genetic ablation of KLB or adipocyte FGFR1 indicate that FGFR1-KLB mediates the response of adipocytes to both FGF21 and FGF19. Here we show that adipose FGFR1 regulates lipid metabolism through direct effect on adipose tissue and indirect effects on liver under starvation conditions that cause hepatic stress. METHODS: We employed adipocyte-specific ablations of FGFR1 and FGFR2 genes in mice, and analyzed metabolic consequences in adipose tissue, liver and systemic parameters under normal, fasting and starvation conditions. RESULTS: Under normal conditions, the ablation of adipose FGFR1 had little effect on adipocytes, but caused shifts in expression of hepatic genes involved in lipid metabolism. Starvation conditions precipitated a concurrent elevation of serum triglycerides and non-esterified fatty acids, and increased hepatic steatosis and adipose lipolysis in the FGFR1-deficient mice. Little effect on glucose or ketone bodies due to the FGFR1 deficiency was observed. CONCLUSIONS: Our results suggest an adipocyte-hepatocyte communication network mediated by adipocyte FGFR1 that concurrently dampens hepatic lipogenesis and adipocyte lipolysis. We propose that this serves overall to mete out and extend lipid reserves for neural fuels (glucose and ketone bodies), while at the same time governing extent of hepatosteatosis during metabolic extremes and other conditions causing hepatic stress. PMID- 23106964 TI - Comparison of transperitoneal and retroperitoneal laparoscopic nephrectomy for renal cell carcinoma: a systematic review and meta-analysis. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Laparoscopic nephrectomy is now considered to be the reference procedure for kidney cancer. It can be performed via a transperitoneal or retroperitoneal approach. Each approach has its advantages and disadvantages. No definitive conclusions regarding objective difference between the two approaches have been reached to date. This meta-analysis indicates that in appropriately selected patients, especially patients with posteriorly located renal tumors, the retroperitoneal approach may be faster and equally safe compared with the transperitoneal approach. OBJECTIVE: To evaluate the efficiency and safety of the retroperitoneal and transperitoneal approaches in laparoscopic radical/partial nephrectomy (RN/PN) for renal cell carcinoma. METHODS: A systematic search of PUBMED, EMBASE, and the Cochrane Library was performed to identify prospective randomized controlled trials and retrospective observational studies that compared the outcomes of the two approaches. Outcomes of interest included perioperative and postoperative variables, surgical complications and oncological variables. RESULTS: Twelve studies assessing transperitoneal laparoscopic RN (TLRN) vs retroperitoneal laparoscopic RN (RLRN) and six studies assessing transperitoneal laparoscopic PN (TLPN) vs retroperitoneal laparoscopic PN (RLPN) were included. The RLRN approach had a shorter time to renal artery control (weighted mean difference [WMD] 68.65 min; 95% confidence interval [CI] 40.80-96.50; P < 0.001) and a lower overall complication rate (odds ratio 2.12; 95% CI 1.30-3.47; P = 0.003) than TLRN. RLPN had a shorter operating time (WMD 48.85 min; 95% CI 29.33-68.37; P < 0.001) and a shorter length of hospital stay (WMD 1.01 days; 95% CI 0.39-1.63; P = 0.001) than TLPN. There were no significant differences between the retroperitoneal and transperitoneal approaches in other outcomes of interest. CONCLUSIONS: This meta analysis indicates that, in appropriately selected patients, especially patients with posteriorly located renal tumours, the retroperitoneal approach may be faster and equally safe compared with the transperitoneal approach. Despite our rigorous methodology, conclusions drawn from our pooled results should be interpreted with caution because of the inherent limitations of the included studies. PMID- 23106965 TI - Hypertension in a young boy: an energy drink effect. AB - BACKGROUND: Use of energy drinks has significantly increased in recent times. Besides athletes, teenagers and students are among the most common consumers. However, popularity is also increasing among the younger and older age groups. Most of the users believe that they are a good source of instant energy and are unaware of its high Caffeine content resulting in harmful effects on health. CASE PRESENTATION: We report the case of a young boy who presented with palpitations and high blood pressure as a result of energy drinks usage. He had been consuming a "Sting" energy drink on regular basis while studying for long hours during his O' level Exams. His medical examination revealed Sinus tachycardia and high blood pressure. Rest of the examination and lab workup was within normal limits. His pulse and blood pressure returned to normal range after discontinuing Sting usage. CONCLUSION: Several studies have reported numerous health hazards including cardiac effects associated with energy drinks. Warning labeling should be done on these drinks regulating the content of Caffeine and its harmful effects on health. PMID- 23106966 TI - A favourable response to surgical intervention and hyperbaric oxygen therapy in pyoderma gangrenosum. AB - Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterised with ulcerations. Inflammatory bowel diseases (ulcerative colitis and Crohn's disease) and haematologic diseases (leukaemia, preleukaemia and monoclonal gammopathy) have been reported in about 40-50% of PG patients in whom the treatment of the underlying disease is important for the improvement of the lesions. We herein report a colorectal adenocarcinoma patient with PG, who responded partially to topical treatments and systemic immunosuppressants and healed completely with the aid of surgical wound repair and hyperbaric oxygen therapy. PMID- 23106967 TI - Editorial comment: Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma. PMID- 23106968 TI - Isolation and biological activities of decanal, linalool, valencene, and octanal from sweet orange oil. AB - Product 1 (82.25% valencene), product 2 (73.36% decanal), product 3 (78.12% octanal), and product 4 (90.61% linalool) were isolated from sweet orange oil by combined usage of molecular distillation and column chromatography. The antioxidant activity of sweet orange oil and these products was investigated using 2,2-diphenyl-1-picrylhydrazyl and reducing power assays. In this test, product 1 (82.25% valencene), product 2 (73.36% decanal), and product 4 (90.61% linalool) had antioxidant activity, but lower than sweet orange oil. The antimicrobial activity was investigated in order to evaluate their efficacy against 5 microorganisms. The results showed that sweet orange oil, product 2 (73.36% decanal), product 3 (78.12% octanal), and product 4 (90.61% linalool) had inhibitory and bactericidal effect on the test microorganisms (except Penicillium citrinum). Valencene did not show any inhibitory effect. Saccharomyces cerivisiae was more susceptible, especially to the crude sweet orange oil (minimal inhibitory concentration 6.25 MUL/mL). The cytotoxicity was evaluated on Hela cells using the 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. All test samples showed significant cytotoxicity on the cell lines with IC(50) values much less than 20 MUg/mL. PMID- 23106969 TI - Establishment and characterization of two human breast carcinoma cell lines by spontaneous immortalization: Discordance between Estrogen, Progesterone and HER2/neu receptors of breast carcinoma tissues with derived cell lines. AB - BACKGROUND: Breast cancer is one of the most common cancers among women throughout the world. Therefore, established cell lines are widely used as in vitro experimental models in cancer research. METHODS: Two continuous human breast cell lines, designated MBC1 and MBC2, were successfully established and characterized from invasive ductal breast carcinoma tissues of Malaysian patients. MBC1 and MBC2 have been characterized in terms of morphology analysis, population doubling time, clonogenic formation, wound healing assay, invasion assay, cell cycle, DNA profiling, fluorescence immunocytochemistry, Western blotting and karyotyping. RESULTS: MBC1 and MBC2 exhibited adherent monolayer epithelial morphology at a passage number of 150. Receptor status of MBC1 and MBC2 show (ER+, PR+, HER2+) and (ER+, PR-, HER2+), respectively. These results are in discordance with histopathological studies of the tumoral tissues, which were triple negative and (ER-, PR-, HER2+) for MBC1 and MBC2, respectively. Both cell lines were capable of growing in soft agar culture, which suggests their metastatic potential. The MBC1 and MBC2 metaphase spreads showed an abnormal karyotype, including hyperdiploidy and complex rearrangements with modes of 52-58 chromosomes per cell. CONCLUSIONS: Loss or gain in secondary properties, deregulation and specific genetic changes possibly conferred receptor changes during the culturing of tumoral cells. Thus, we hypothesize that, among heterogenous tumoral cells, only a small minority of ER+/PR+/HER2+ and ER+/PR /HER2+ cells with lower energy metabolism might survive and adjust easily to in vitro conditions. These cell lines will pave the way for new perspectives in genetic and biological investigations, drug resistance and chemotherapy studies, and would serve as prototype models in Malaysian breast carcinogenesis investigations. PMID- 23106970 TI - Bubble nasal CPAP, early surfactant treatment, and rapid extubation are associated with decreased incidence of bronchopulmonary dysplasia in very-low birth-weight newborns: efficacy and safety considerations. AB - BACKGROUND: Current literature has been inconsistent in demonstrating that minimizing the duration of mechanical ventilation in very-low-birth-weight (VLBW) newborns reduces lung damage. OBJECTIVE: To determine if introduction of bubble nasal CPAP (bnCPAP), early surfactant treatment, and rapid extubation (combined bnCPAP strategy) in our community-based neonatal ICU reduced bronchopulmonary dysplasia (BPD). METHODS: This was a 7-year retrospective,single-institution review of respiratory outcomes in 633 VLBW babies before and after introduction of the combined bnCPAP strategy. Coincident changes in newborn care were taken into account with a logistic regression model. RESULTS: The average percentage of VLBW newborns with BPD decreased to 25.8% from 35.4% (P = .02), reaching a minimum in the last post-bnCPAP year of22.1% (P = .02). When other coincident changes in newborn care during the study years were taken into account, VLBW babies in the post-bnCPAP years had a 43% lower chance of developing BPD(P = .003, odds ratio 0.43, 95% CI 0.25- 0.75). Decreases occurred in mechanical ventilation and the percentage of infants discharged on diuretics and on supplemental oxygen. Among the subset of extremely-low-birth-weight newborns, improved respiratory outcomes in the post-bnCPAP years,as compared to outcomes in the pre-bnCPAP years, included an increase in the percentage alive and off mechanical ventilation at 1 week postnatal age (P < .001), a more rapid extubation rate(P < .03), a decrease in the median days on mechanical ventilation (P = .002), and a decrease in the percentage with BPD plus died (P = .01). Post bnCPAP extremely-low-birth-weight babies had a statistically significant decrease in retinopathy of prematurity, an increase in low-grade intraventricular hemorrhage, and a decrease in ductal ligations. CONCLUSIONS: A combined BnCPAP strategy may contribute to a reduction of BPD, after adjusting for concurrent treatments. PMID- 23106971 TI - Iron deficiency and fatigue in adolescent females with heavy menstrual bleeding. AB - Iron deficiency and fatigue are common problems in adolescent females. Heavy menstrual bleeding (HMB) is associated with both iron deficiency and fatigue. The aim of this study was to define baseline ferritin values and fatigue symptoms in a population of young females with excessive menstrual blood loss, as compared to healthy controls. The study population included 11 to 17-year-old menstruating females presenting to an Adolescent Gynaecology Clinic, Menorrhagia Clinic or Sports Medicine clinic. To evaluate the degree and effects of menstrual blood loss, we utilized the Ruta Menorrhagia Severity Score. We investigated the symptoms of fatigue using the Fatigue Severity Scale. We evaluated possible predictors of ferritin level (age, body mass index, fatigue scores and Menorrhagia Severity Score) using generalized linear models. A total of 48 adolescents with HMB and 102 healthy adolescents completed the study. Iron deficiency and elevated fatigue scores were common findings in young women with HMB. Both fatigue severity scores and menorrhagia severity scores were significantly higher in young women with HMB as compared to healthy controls. In adolescents with HMB, 87.5% had ferritin levels <=40 ng mL(-1), and 29.2% had ferritin levels <=15 ng mL(-1). Our generalized linear models did not identify any significant univariate relationships between ferritin levels and patient age, body mass index, fatigue score or menorrhagia score. Iron deficiency and symptoms of fatigue are common findings in young women with HMB. Fatigue severity scores are significantly higher in young women with HMB as compared to healthy controls. PMID- 23106972 TI - Optimal glycemic control in neurocritical care patients. AB - Currently, the major issue in glycemic control in neurocritical care patients is that tight glycemic control (target range of 80 to 110 mg/dL) using intensive insulin therapy is associated with higher rates of hypoglycemia without an improvement in survival rate. The review by Kramer and colleagues in this issue of Critical Care confirms these data but provides solid evidence about the relationship between hyperglycemia and worsened neurological outcome after acute brain injury. In accordance with the conclusions of Kramer and colleagues, we recommend that a glucose control goal in neurocritical care patients be in the 'moderate' target range (110 to 180 mg/dL). In addition, we recommend adequate nutrition before and during insulin infusion, avoidance of insulin as a bolus, and the use of continuous insulin infusion, beginning with low doses with titration to individual sensitivity. Careful and accurate glycemic monitoring is especially important when insulin is infused. PMID- 23106973 TI - Involvement of acetylcholine-alpha7nAChR in the protective effects of arterial baroreflex against ischemic stroke. AB - AIMS: Decreased baroreflex sensitivity is associated with poor outcome in many cardiovascular diseases including stroke, but the molecular mechanism underlying this relationship is unclear. This work was designed to test the hypothesis that acetylcholine (ACh) and alpha7 nicotinic ACh receptor (alpha7nAChR) mediate the protection of arterial baroreflex against stroke. METHODS: Sinoaortic denervation (SAD) was used to impair the function of arterial baroreflex, and anticholinesterase agents were used to activate the cholinergic system and increase endogenous ACh. Middle cerebral artery occlusion (MCAO) was performed in the alpha7nAChR knockout (KO) mice and Sprague-Dawley rats. RESULTS: We found decreased expression of vesicular ACh transporter (VAChT) and alpha7nAChR in rat brain after SAD. In rats subjected to MCAO, neostigmine significantly reduced the infarct size. The protective effects of neostigmine were abolished by selective nAChR antagonist vecuronium but not by mAChR antagonist anisodamine. In addition, the effect of neostigmine disappeared in alpha7nAChR KO mice. In cultured neurons, ACh inhibited cell death induced by H(2) O(2) . In cultured microglial cells, ACh decreased the release of proinflammatory cytokines induced by lipopolysaccharide. These in vitro effects were blocked by selective alpha7nAChR antagonists. CONCLUSION: Taken together, these findings indicate that the ACh alpha7nAChR involved in the protective effects of arterial baroreflex against ischemic stroke. PMID- 23106974 TI - MPTP animal model of Parkinsonism: dopamine cell death or only tyrosine hydroxylase impairment? A study using PET imaging, autoradiography, and immunohistochemistry in the cat. AB - AIMS: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin widely used to produce experimental models of Parkinson's disease in laboratory animals. It is believed to cause a selective destruction of substantia nigra dopamine neurons, mainly based on a large reduction of tyrosine hydroxylase (TH), the catecholamine's synthesizing enzyme. Unlike Parkinson's disease in humans, however, all animal models are able to recover more or less rapidly from the MPTP induced Parkinsonian syndrome. This raises the question as whether MPTP causes a cell death with a decrease in dopamine transporter or a simple impairment of TH. METHODS: To respond to this question, we quantified in a cat model of Parkinson's disease (MPTP 5 mg/kg i.p. during 5 days) the dopamine transporter using positron emission tomography (PET) imaging and autoradiography of [(11) C]PE2I and compared the data with the TH-immunoreactivity. RESULTS: We found no changes in [(11) C]PE2I PET binding either 5 or 26 days after MPTP treatment when compared to baseline levels. Similarly, there were no significant changes in [(11) C]PE2I autoradiographic binding in the cat brain one week after MPTP treatment. In sharp contrast, MPTP treated cats exhibited severe Parkinson-like motor syndrome during the acute period with a marked decrease in TH-immunoreactivity in the striatum. CONCLUSION: These data suggest that MPTP toxicity impairs efficiently TH and that such an effect is not necessarily accompanied by significant reduction of dopamine transporter seen with in vitro or in vivo [(11) C]PE2I binding. PMID- 23106975 TI - Effects of poststroke hypertension and hyperglycemia on functional outcomes in stroke patients without history of hypertension or diabetes. PMID- 23106976 TI - Ghrelin attenuated cerebral ischemia reperfusion injury in rats. PMID- 23106977 TI - Cerebral blood flow increase during prolonged hyperbaric oxygen exposure may not be necessary for subsequent convulsion. PMID- 23106978 TI - Tacrine-6-ferulic acid, a novel multifunctional dimer against Alzheimer's disease, prevents oxidative stress-induced neuronal death through activating Nrf2/ARE/HO-1 pathway in HT22 cells. PMID- 23106979 TI - A case of late-onset riboflavin responsive multiple acyl-CoA dehydrogenase deficiency with novel mutations in ETFDH gene. PMID- 23106980 TI - Baseline nutritional status is prognostic factor after definitive radiochemotherapy for esophageal cancer. AB - Identify prognostic factors for survival and patterns of treatment failure after definitive radiochemotherapy for esophageal cancer. Between 2003 and 2006, 143 patients with squamous cell carcinoma and adenocarcinoma of the esophagus were retrospectively reviewed. Median age was 65 years (42-81). Median radiation dose was 62.5 Gy (38-72) with 1.8-2 Gy fraction. Median follow-up was 20.8 months (2.8 92.4). Three and 5-year local recurrence-free survival rates were 58.3% and 50.9%. In univariate analysis, traversable esophageal stricture was a prognostic factor. Three, 5-year locoregional recurrence-free survival rates were 42.4% and 34.9%. In multivariate analysis, traversable esophageal stricture and stage < IIB were independent prognostic factors. Three and 5-year disease-free survival rates were 30.5% and 25.9%. In multivariate analysis, Nutritional Risk Index (NRI) >= 97.5 and performance status (PS) = 0 were independent prognostic factors. Median, 3, and 5-year overall survival rates were 22.1 months, 34.4%, and 19.8%. In multivariate analysis, independent prognostic factors were NRI >= 97.5 and PS = 0. Median survival times for the NRI classes (no denutrition, moderate and severe denutrition) were 29.5, 19.7, and 12 months (P = 0.0004), respectively. A major impact of baseline NRI was found in terms of survival; it should be included in future prospective trials. PMID- 23106981 TI - Low parasitism rates in parthenogenetic bagworm moths do not support the parasitoid hypothesis for sex. AB - The parasite hypothesis for sex is one of the many theories that have been suggested to solve the mystery of the widespread occurrence of sex despite its high short-term costs. It suggests that sexual lineages have an evolutionary advantage over parthenogens because they can frequently generate new genotypes that are temporarily less prone to coevolving parasites. In this study, we looked for further supporting evidence for the parasite hypothesis of sex in an attempt to understand the coexistence of sexual and parthenogenetic bagworm moths (Naryciinae). The bagworm moths and their parasitoids form one of the few natural host-parasite systems where sexual and parthenogenetic hosts are apparently not separated by ecological or geographical barriers. Furthermore, in support of the parasite hypothesis for sex, parthenogenetic presence is negatively correlated with parasitism rate. We specifically tested, by identifying the reproductive mode of the parasitized individuals, whether parasitoids preferentially attack the parthenogens in sites with both sexual and parthenogenetic forms, as predicted by the parasite hypothesis. We collected hosts from sites with different frequencies of parthenogenetic and sexual moths. A DNA barcoding approach was used to determine the reproductive mode of the parasitized hosts. Furthermore, we investigated whether differences in host and parasitoid phenology could provide an alternative explanation for the variation in parasitism rates between parthenogens and sexuals. Our results contradict the prediction of the parasite hypothesis because parthenogenetic bagworm moths were less parasitized than sexuals in sympatric sites. Our findings can be explained by differences in phenology between the parthenogenetic and sexual moths rather than genetic incompatibility between parthenogenetic hosts and parasitoids. The stable coexistence of sexual and parthenogenetic Naryciinae despite the many apparent costs of sex in this system remains a mystery. Our work adds to the list of studies were the assumptions of the parasite hypothesis for sex are not all met. PMID- 23106982 TI - Role of the yeast multidrug transporter Qdr2 in cation homeostasis and the oxidative stress response. AB - We have identified QDR2 in a screening for genes able to confer tolerance to sodium and/or lithium stress upon overexpression. Qdr2 is a multidrug transporter of the major facilitator superfamily, originally described for its ability to transport the antimalarial drug quinidine and the herbicide barban. To identify its physiological substrate, we have screened for phenotypes dependent on QDR2 and found that Qdr2 is able to transport monovalent and divalent cations with poor selectivity, as shown by growth tests and the determination of internal cation content. Moreover, strains overexpressing or lacking QDR2 also exhibit phenotypes when reactive oxygen species- producing agents, such as hydrogen peroxide or menadione were added to the growth medium. We have also found that the presence of copper and hydrogen peroxide repress the expression of QDR2. In addition, the copper uptake of a qdr2 mutant strain is similar to a wild type, but the extrusion is clearly impaired. Based on our results, we propose that free divalent copper is the main physiological substrate of Qdr2. As copper is a substrate for several redox reactions that occur within the cytoplasm, its function in copper homeostasis explains its role in the oxidative stress response. PMID- 23106984 TI - State of the Journal, 2012. PMID- 23106983 TI - Tumor-associated macrophages correlate with progesterone receptor loss in endometrial endometrioid adenocarcinoma. AB - AIM: It has been well established that tumor-associated macrophages (TAMs) play a tumor promoting role in endometrial endometrioid adenocarcinoma (EEC). But the association with TAMs and sex hormone receptor expression, and progression of precancerous endometrial lesions in EEC has been little reported. MATERIAL AND METHODS: We used immunohistochemistry to examine the expression of CD68, CD34, vascular endothelial growth factor (VEGF), estrogen receptor (ER) and progesterone receptor (PR) in 95 cases of EEC, as well as 35 cases of endometrial hyperplasia (including 15 atypical hyperplasia, 10 complex hyperplasia and 10 simple hyperplasia). We also correlated TAMs count with various clinicopathological factors, sex hormone receptor, and prognostic value in patients with EEC. RESULTS: We identified that TAMs count increased linearly with disease progression (mean count per case at * 200 magnification: simple hyperplasia, 6.30; complex hyperplasia, 11.20; atypical hyperplasia, 29.40; EEC 55.81, respectively; P < 0.001), that microvascular density (MVD) also increased accordingly (27.50, 30.20, 50.13 and 59.94, respectively; P < 0.001). The expression of progesterone receptor, not of estrogen receptor, significantly decreased with disease progression (P < 0.05). Moreover, histopathologic grades, International Federation of Gynecology and Obstetrics (FIGO) stage (2009), depth of myometrial invasion, pelvic lymph node metastasis, lymphovascular space invasion, and expression of PR and VEGF were associated with TAMs count (P = 0.0001, P = 0.004, P = 0.0001, P = 0.04, P = 0.0001, P = 0.0001, P = 0.0001, respectively). Progesterone receptor expression was also associated with histopathologic grades, lymphovascular space invasion, VEGF and high TAMs (P = 0.035, P = 0.022, P = 0.014, P = 0.001, respectively). The estimated 5-year survival rate of patients with low TAMs was significantly higher than those with high TAMs (96.4% vs 69.8%, P = 0.002). CONCLUSION: TAMs are potentially related to PR loss and progression of precancerous endometrial lesions in EEC. PMID- 23106985 TI - Beyond high definition: attitude and evidence bringing OT in HD-3D. PMID- 23106986 TI - PromOTing occupational therapy: words, images, and actions. PMID- 23106987 TI - Functional impact of constraint therapy and bimanual training in children with cerebral palsy: a randomized controlled trial. AB - OBJECTIVE: We compared children's self-care performance and caregivers' perception of children's performance on functional goals established for children with hemiplegic cerebral palsy (CP) after unimanual constraint-induced movement therapy (CIMT) or hand-arm bimanual intensive training (HABIT). METHOD: Sixteen children with CP were randomized to the CIMT or HABIT group. Interventions lasted for 15 days, 6 hr/day, totaling 90 hr. We used the Pediatric Evaluation of Disability Inventory and the Canadian Occupational Performance Measure (COPM) to assess the children's daily functioning and mixed analyses of variance to compare group means on functional test scores before and after intervention. RESULTS: Both groups showed significant improvements on functional measures. Group * Assessment interaction in COPM performance revealed greater improvements for the HABIT group after intervention (p = .04). CONCLUSION: The results suggest that specificity of training exists only for performance of specific goals established by parents and that both CIMT and HABIT can be used to increase children's daily functioning. PMID- 23106988 TI - Effect of robotic-assisted three-dimensional repetitive motion to improve hand motor function and control in children with handwriting deficits: a nonrandomized phase 2 device trial. AB - OBJECTIVE: We explored the efficacy of robotic technology in improving handwriting in children with impaired motor skills. METHOD: Eighteen participants had impairments arising from cerebral palsy (CP), autism spectrum disorder (ASD), attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or other disorders. The intervention was robotic-guided three-dimensional repetitive motion in 15-20 daily sessions of 25-30 min each over 4-8 wk. RESULTS: Fine motor control improved for the children with learning disabilities and those ages 9 or older but not for those with CP or under age 9. All children with ASD or ADHD referred for slow writing speed were able to increase speed while maintaining legibility. CONCLUSION: Three-dimensional, robot-assisted, repetitive motion training improved handwriting fluidity in children with mild to moderate fine motor deficits associated with ASD or ADHD within 10 hr of training. This dosage may not be sufficient for children with CP. PMID- 23106989 TI - Development of the comprehensive observations of proprioception (COP): validity, reliability, and factor analysis. AB - OBJECTIVE: We developed an observational tool, the Comprehensive Observations of Proprioception (COP), for identifying proprioceptive processing issues in children with developmental disabilities. METHOD: Development of the COP underwent three phases. First, we developed items representing proprioceptive functions on the basis of an extensive literature review and consultation with occupational therapists. We then established interrater reliability and content, construct, and criterion validity. Finally, we completed a factor analysis of COP ratings of 130 children with known developmental disabilities. RESULTS: Adequate validity and reliability were established. Factor analysis revealed a four-factor model that explained the underlying structure of the measure as it was hypothesized. CONCLUSION: The COP is a valid criterion-referenced short observational tool that structures the clinician's observations by linking a child's behaviors to areas identified in the literature as relevant to proprioceptive processing. It takes 15 min to administer and can be used in a variety of contexts, such as the home, clinic, and school. PMID- 23106990 TI - Weekly Calendar Planning Activity (WCPA): a performance-based assessment of executive function piloted with at-risk adolescents. AB - OBJECTIVE: We piloted the Weekly Calendar Planning Activity (WCPA), a performance based measure of executive function (EF), to establish a baseline for at-risk adolescents. METHOD: Participants were 113 youths ages 16-21 who were enrolled at a charter school for youth returning to high school after dropping out. We administered the WCPA and collected demographic information. RESULTS: On average, participants spent 15.9 min on the WCPA, made 7.9 errors, and followed 4.0 of 5 possible rules. No ceiling effect was observed in overall accuracy. Participants used a mean of 3.1 strategies (standard deviation = 1.9) while completing the WCPA. Participants who used more strategies spent more time planning and completing the task and were more accurate. CONCLUSION: The WCPA may be useful to occupational therapists as a performance measure of EF. This assessment allows evaluation of complex task performance, strategy use, self-evaluation of performance, and error patterns, which can be used in developing intervention strategies. PMID- 23106991 TI - Assessing the sensitivity of the evaluation of social interaction: comparing social skills in children with and without disabilities. AB - OBJECTIVE: We examined the sensitivity of the Evaluation of Social Interaction (ESI) as a measure of the overall quality of social interaction in children as they engage in social exchanges in a natural context with typical social partners. METHOD: We compared the ESI measures of 23 children with disabilities with those of 23 children without disabilities, matched by age and gender. RESULTS: Paired t-test analysis revealed a statistically significant difference, t(22) = -4.065, p = .001, in the quality of social interaction for the two groups of children, indicating sensitivity of the ESI. CONCLUSION: The results support the use of the ESI to measure quality of social interaction in a natural context. PMID- 23106992 TI - Effect of pencil grasp on the speed and legibility of handwriting in children. AB - OBJECTIVE: Pencil grasps other than the dynamic tripod may be functional for handwriting. This study examined the impact of grasp on handwriting speed and legibility. METHOD: We videotaped 120 typically developing fourth-grade students while they performed a writing task. We categorized the grasps they used and evaluated their writing for speed and legibility using a handwriting assessment. Using linear regression analysis, we examined the relationship between grasp and handwriting. RESULTS: We documented six categories of pencil grasp: four mature grasp patterns, one immature grasp pattern, and one alternating grasp pattern. Multiple linear regression results revealed no significant effect for mature grasp on either legibility or speed. CONCLUSION: Pencil grasp patterns did not influence handwriting speed or legibility in this sample of typically developing children. This finding adds to the mounting body of evidence that alternative grasps may be acceptable for fast and legible handwriting. PMID- 23106993 TI - Effectiveness of the California Tri-Pull Taping method for shoulder subluxation poststroke: a single-subject ABA design. AB - OBJECTIVE: I evaluated the effectiveness of the California Tri-Pull Taping method for clients with poststroke inferior shoulder subluxation of the glenohumeral joint. METHOD: Ten participants were followed for 9 wk using an interrupted time series quasi-experimental single-subject ABA design to examine shoulder pain, activities of daily living (ADL) function, active range of motion, tape comfort, and subluxation. RESULTS: The California Tri-Pull Taping method decreased inferior subluxation significantly from baseline to intervention but not at postintervention. Active range of motion was significantly increased in shoulder flexion and abduction between the baseline and intervention and the intervention and postintervention phases. Functional ADL scores were significant. The taping was reported to be comfortable. No significant difference in pain was found. CONCLUSION: This intervention is a promising adjunct to the management of the hemiplegic subluxed shoulder that warrants further research. PMID- 23106994 TI - Development and validation of tools for evaluation of orthosis fabrication. AB - This study is the first phase of research aimed at developing new educational approaches to enhance occupational therapy students' orthosis fabrication skills. Before the effectiveness of training can be determined, a method for evaluating performance must be established. Using the Delphi method, we developed a global rating scale and checklist for evaluating technical competence when fabricating metacarpophalangeal (MCP) joint-stabilizing orthoses. To determine the reliability and validity of these tools, three evaluators used them to assess and score orthotic fabrication performance by experienced and student occupational therapists. The results suggest that these measurement tools are valid and reliable indicators of the technical skills involved in fabricating an MCP joint stabilizing orthosis. Future studies should focus on building on these tools to evaluate communication skills, technical skills for making other types of orthoses, and effectiveness of training programs. PMID- 23106995 TI - Behavioral, neurophysiological, and descriptive changes after occupation-based intervention. AB - OBJECTIVE: We evaluated the effects of occupation-based intervention on poststroke upper-extremity (UE) motor recovery, neuroplastic change, and occupational performance in 1 research participant. METHOD: A 55-yr-old man with chronic stroke and moderately impaired UE motor function participated in 15 sessions of occupation-based intervention in a hospital setting designed to simulate a home environment. We tested behavioral motor function (Fugl-Meyer Assessment, Stroke Impact Scale, Canadian Occupational Performance Measure) and neuroplasticity (transcranial magnetic stimulation [TMS]) at baseline and at completion of intervention. We collected descriptive data on occupational participation throughout the study. RESULTS: All behavioral outcomes indicated clinically relevant improvement. TMS revealed bihemispheric corticomotor reorganization. Descriptive data revealed enhanced occupational performance. CONCLUSION: Occupation-based intervention delivered in a hospital-based, homelike environment can lead to poststroke neuroplastic change, increased functional use of the affected UE, and improved occupational performance. PMID- 23106996 TI - Survey of the low vision rehabilitation curricula in occupational therapy and occupational therapy assistant programs. AB - OBJECTIVE: We examined the preclinical curricular content pertaining to low vision rehabilitation (LVR) included in occupational therapy (OT) and occupational therapy assistant (OTA) programs. METHOD: An e-mail survey containing questions about program structure and the extent of course material related to LVR in the curriculum was sent to directors of all accredited OT and OTA programs in the United States. RESULTS: One hundred nineteen programs responded. The curricula of all but 1 program included LVR content. Twenty-four programs included a required course with a primary emphasis on LVR. Forty-four programs had faculty with advanced training in LVR or experience working in a LVR clinic. CONCLUSION: Given that almost all respondent programs integrate LVR content into their required preclinical coursework, we recommend that LVR be incorporated into the Accreditation Council for Occupational Therapy Education standards so as to ensure knowledge of LVR within existing programs and enhance the quality of education in LVR. PMID- 23106997 TI - Occupational therapy in neurological disorders: looking ahead to the American Occupational Therapy Association's centennial vision. AB - The Centennial Vision articulated by the American Occupational Therapy Association includes moving the profession to being science driven and evidence based. The American Journal of Occupational Therapy contributes to this vision by publishing high-quality research. I reviewed research in the practice area of neurological rehabilitation published between May 2010 and October 2011. In particular, I reviewed effectiveness and efficacy studies, instrument development and testing, and basic research studies. Concerns emerging from the review were (1) few studies in neurological rehabilitation; (2) many disorders not represented; (3) exclusive use of impairment-level outcomes in some studies; and (4) high preponderance of case series designs in effectiveness studies. To achieve the Centennial Vision, the field needs to improve the volume and diversity of research in neurological rehabilitation. It is also important to modify academic and clinical practice to enable occupational therapists to spend more time in producing high-quality evidence to support the crucial role they play in neurological rehabilitation. PMID- 23106998 TI - Influence of task and tool characteristics on scissor skills in typical adults. AB - To clarify expectations for mature cutting skills and investigate the influences of cutting task and scissor type, we videotaped 60 typical adults cutting three shapes with two different types of scissors. The videotapes were reviewed, and 38 aspects of grasp and cutting motions were rated. Percentages of participants who used a particular grip or cutting motion for each shape with each scissor type were reported and compared. Findings included variations in grasp that depended on the scissor type used and variations in cutting motions that depended on the shape being cut. Improved understanding of mature scissor skills and the effect of variations in the cutting task and scissor type used will allow more effective assessment of and intervention for children and adults with cutting difficulties. Specific implications for practice are discussed. PMID- 23106999 TI - Development and validation of a 15-item lifestyle screening for community dwelling older adults. AB - The Health Enhancement Lifestyle Profile-Screener (HELP-Screener) is a 15-item self-report questionnaire conceptually excerpted from the original 56-item HELP. This article describes the development and validation of the HELP-Screener with a sample of 483 community-dwelling older adults. Data derived from the sample were first analyzed using the Rasch dichotomous model. Unidimensionality and data model fit of the HELP-Screener were largely supported by the analyses of principal components of residuals, fit statistics, local dependency, differential item functioning, and item hierarchy. To delineate the clinical significance of the test results, the cutoff score for the HELP-Screener was established through the mean and standard deviation generated from the study sample. The HELP Screener can serve as a time-efficient screening for identifying older adults who may require a comprehensive evaluation through HELP and, as a result, who may benefit from a lifestyle intervention. Of note, more studies are planned to further corroborate psychometric properties of this new instrument. PMID- 23107001 TI - A study of patient satisfaction after cataract surgery with implantation of different types of intraocular lenses. AB - BACKGROUND: The implementation of capitated payment has driven medical institutions through developing balance billing for medical services. By exploring the patients' decision-making factors on different self-pay items, a reference for the pricing and sales strategy for the related products can be formed. The major purposes of this study were to analyze the determinants of preoperative selection and postoperative satisfaction with implantation of different types of intraocular lenses in cataract surgery. METHODS: This cross sectional study consisted of 127 patients that were 50 years of age and older, and who had phacoemulsification with intraocular lens implantation in both eyes. Data were collected by using a structured questionnaire. The following parameters were measured: access to medical care, attitude towards receiving medical products at one's own expense, overall patient satisfaction and postoperative visual clarity. RESULTS: The results showed that the patient's gender, educational level and economic status influenced the type of intraocular lens chosen. Patients in the insurance group cared about access to medical care, and patients in the balance billing group cared about product differentiation. ANOVA results showed no statistically significant differences in the overall satisfaction of the patients among the groups with different types of intraocular lenses. Patients that received cataract surgery with implantation of multifocal intraocular lenses had better vision when trying to view smaller objects and when looking at objects under strong light. CONCLUSIONS: Manufacturers should increase the number of differences between their products, and health care providers can then recommend the appropriate intraocular lens in accordance with the needs or demands of their patients, and also by keeping in mind the financial constraints of their patients. PMID- 23107000 TI - Impact of sleep disturbance on patients in treatment for mental disorders. AB - BACKGROUND: In clinical practice, sleep disturbance is often regarded as an epiphenomenon of the primary mental disorder. The aim of this study was to test if sleep disturbance, independently of primary mental disorders, is associated with current clinical state and benefit from treatment in a sample representative of public mental health care clinics. METHOD: 2246 patients receiving treatment for mental disorders in eight public mental health care centers in Norway were evaluated in a cross-sectional study using patient and clinician reported measures. Patients reported quality of life, symptom severity, and benefit from treatment. Clinicians reported disorder severity, level of functioning, symptom severity and benefit from treatment. The hypothesis was tested using multiple hierarchical regression analyses. RESULTS: Sleep disturbance was, adjusted for age, gender, time in treatment, type of care, and the presence of any primary mental disorder, associated with lower quality of life, higher symptom severity, higher disorder severity, lower levels of functioning, and less benefit from treatment. CONCLUSION: Sleep disturbance ought to be considered a stand-alone therapeutic entity rather than an epiphenomenon of existing diagnoses for patients receiving treatment in mental health care. PMID- 23107002 TI - Gender, trauma type, and PTSD prevalence: a re-analysis of 18 nordic convenience samples. AB - BACKGROUND: The aim of the study was to examine a possible trauma type related variance in the gender difference of posttraumatic stress disorder (PTSD) prevalence. METHODS: An analysis was conducted on 18 convenience sample studies including data from a total of 5220 participants. The studies all applied the Harvard Trauma Questionnaire - part IV to assess PTSD. Cohen's d was used to measure variance in gender differences. Trauma types included disasters and accidents, violence, loss, chronic disease and non-malignant diseases. RESULTS: The results showed an overall gender difference in PTSD prevalence similar to previous findings. Thus, women had a two-fold higher prevalence of PTSD than men. Besides categorical analyses, dimensional analyses of PTSD severity were also performed; the latter were associated with twice as large effect sizes. Females were more vulnerable to PTSD after disasters and accidents, followed by loss and non-malignant diseases. In violence and chronic disease, the gender differences were smallest. CONCLUSIONS: The findings support the existence of a trauma type related variance in gender differences in PTSD prevalence. PMID- 23107003 TI - Designing simulator tools for rail research: the case study of a train driving microworld. AB - The microworld simulator paradigm is well established in the areas of ship navigation and spaceflight, but has yet to be applied to rail. This paper presents a case study aiming to address this research gap, and describes the development of a train driving microworld as a tool to overcome some common research barriers. A theoretical framework for microworld design is tested and used to explore some key methodological issues and characteristics of train driving, enhancing theory development and providing a useful guideline for the designers of other collision-avoidance systems. A detailed description is given of the ATREIDES (Adaptive Train Research Enhanced Information Display & Environment Simulator) microworld, which simulates the work environment of a train driver in a high-speed passenger train. General indications of the testable driving scenarios that may be simulated are given, and an example of an ATREIDES based study is presented to illustrate its applied research potential. The article concludes with a review of the design process, considers some strengths and limitations, and explores some future initiatives towards enhancing the systematic study of rail research in the human factors community. PMID- 23107004 TI - Rapid detection and respirometric profiling of aerobic bacteria on panels of selective media. AB - AIMS: To evaluate high-throughput optical oxygen microrespirometry for selective detection and predictive identification of aerobic bacteria. METHODS AND RESULTS: Using GreenLight probe, standard 384-well plates and time-resolved fluorescence reader, a representative panel of 16 partially selective media and 9 aerobic bacteria (Escherichia coli, Bacillus cereus, Staphylococcus aureus, Campylobacter jejuni, Yersinia enterocolitica, Pseudomonas aeruginosa, Streptococcus pyogenes, Salmonella typhimurium and Listeria innocua) were analysed. For each medium, bacterial strain and dilution, growth profiles were recorded, from which calibrations, doubling/generation times and growth patterns in different media were determined. Analytical performance, selectivity and general usability of the method were assessed, and mixed bacterial cultures were analysed. CONCLUSION: The microrespirometry platform facilitates simple, real-time detection and predictive identification of aerobic bacteria by looking at the patterns of their growth and respiration in several media and determining their growth and doubling times. SIGNIFICANCE AND IMPACT OF THE STUDY: The new screening method can be used for routine microbiological analysis and testing of aerobic bacterial cultures as well as complex food, environmental and clinical samples. PMID- 23107005 TI - Nurses' intention to leave their profession: a cross sectional observational study in 10 European countries. AB - BACKGROUND: As the European population ages, the demand for nursing care increases. Yet, a shortage of nurses at the labour market exists or is predicted for most European countries. There are no adequate solutions for this shortage yet, and recruitment of future nurses is difficult. Therefore, retaining nurses for the profession is urgent. OBJECTIVE: To determine factors associated with nurses' intention to leave the profession across European countries. DESIGN: A multi-country, multi-centre, cross-sectional analysis of survey data. SETTING: 2025 surgical and medical units from 385 hospitals in ten European countries that participated in the RN4Cast study. Hospital selection was based on a stratified randomised selection procedure. PARTICIPANTS: All nurses from the participating medical and surgical hospital wards received a survey. 23,159 nurses (64%) returned the survey. METHODS: The nurse survey included questions about intention to leave the profession, nurse characteristics, factors related to work environment, patient-to-nurse staffing ratio, burnout and perceived quality and safety of care. Multilevel regression analyses with 'intention to leave the profession' as dependent variable were conducted for all 10 countries combined as well as per country. RESULTS: Overall, 9% of the nurses intended to leave their profession. This varied from 5 to 17% between countries. Seven factors were associated with intention to leave the profession at European level: nurse physician relationship (OR 0.86; 95%CI 0.79-0.93), leadership (OR 0.78; 95% CI 0.70-0.86), participation in hospital affairs (0.68; 95%CI 0.61-0.76), older age (OR 1.13; 95%CI 1.07-1.20), female gender (OR 0.67; 95%CI 0.55-0.80), working fulltime (OR 0.76; 95%CI 0.66-0.86) and burnout (OR 2.02; 95%CI 1.91-2.14). The relevance of these factors differed for the individual countries. Nurse perceived staffing adequacy, patient-to-nurse staffing ratio, perceived quality and safety of care and hospital size were not associated with intention to leave at a European level. CONCLUSION: Burnout is consistently associated with nurses' intention to leave their profession across the 10 European countries. Elements of work environment are associated with intention to leave the nursing profession but differ between countries, indicating the importance of national contexts in explaining and preventing nurses' intention to leave their profession. PMID- 23107006 TI - Attention deficit hyperactivity disorder among children exposed to secondhand smoke: a logistic regression analysis of secondary data. AB - BACKGROUND: A growing body of literature examines the association of postnatal secondhand smoke exposure with attention deficit hyperactivity disorder (ADHD) in children, but the findings are mixed. OBJECTIVE: We compare prevalence of ADHD in children aged 4-15 years who were exposed to postnatal secondhand smoke with prevalence in those who were not exposed, and examine the association of postnatal secondhand smoke exposure with ADHD using both reported and cotinine measured secondhand smoke exposure. DESIGN AND SETTING: We analyze secondary data from the 1999-2004 U.S. National Health and Nutrition Examination Surveys. PARTICIPANTS: Analyses using reported secondhand smoke exposure and cotinine measured exposure included 6283 and 6033 children aged 4-15 respectively, including 419 and 404 children who either had a reported physician diagnosis of ADHD or were taking stimulant medications. METHODS: The association of secondhand smoke exposure with ADHD was examined by two multiple logistic regression models that differ in the secondhand smoke measurement used. RESULTS: After controlling for maternal smoking during pregnancy, gender, age, race/ethnicity, preschool attendance, health insurance coverage, and exposure to lead, children with reported secondhand smoke exposure at home were more likely to have ADHD (adjusted odds ratio=1.5, 95% confidence interval: 1.1-2.0) than those who were not exposed. After controlling for these covariates, children with detectable cotinine levels were more likely to have ADHD (adjusted odds ratio=1.8, 95% confidence interval: 1.3-2.5) than those with non-detectable levels. CONCLUSIONS: Our findings suggest that secondhand smoke exposure in children is strongly associated with ADHD independent of other risk factors and this association is robust using both measurements of secondhand smoke exposure. Further research is needed to understand the mechanism underlying this association. Nurses and other healthcare professionals can play an important role in encouraging parents to quit smoking to reduce children's exposure to secondhand smoke and their risk of ADHD. PMID- 23107007 TI - Skin ulcer caused by venous extravasation of heroin. AB - The accidental leakage of the compound, in this case heroin, from the veins where it is injected, causes the formation of tissue lesions. Similar mechanisms lead to progressive tissue necrosis, which, if not immediately treated, results in the loss of the relevant function. A 57-year-old man presented a skin lesion on the posterior region of the left forearm with extensive necrosis of skin and subcutaneous layer involving the underlying muscle planes, caused by a venous extravasation of heroin that he reports having injected himself. The wound size is 15 * 10 cm; it had a sanious, fibrinous, secreting and smelly bottom. In this period, the patient was subjected to daily focused dressing before debridement of the lesion through a collagenase plus hyaluronic acid ointment: Bionect Start(r); (FIDIA Pharmaceutical, Abano, Italy). The therapeutic choice was rewarded with a complete resolution of the wound through a non-invasive technique and over a short period. Avoiding the hospitalisation of the patient achieved a reduction of risks for him and of the costs for the National Health Service (NHS). The Bionect Start(r); (FIDIA Pharmaceutical) as well as allowing the healing of the wound also decreased significantly the pain felt by the patient, the amount of exudate and the bad smell improving in a non-negligible way his quality of life. PMID- 23107008 TI - Distribution of nuchal translucency thickness in Japanese fetuses. AB - AIM: To establish reference values for the nuchal translucency (NT) thickness in Japanese fetuses. MATERIAL AND METHODS: Ultrasonographic measurements of the crown-rump length (CRL) and NT were performed from 11 to 13 + 6 weeks of gestation in consecutive Japanese fetuses examined during prenatal visits between February 2011 and January 2012. The median, 5th and 95th percentiles of the NT thickness with 5 mm intervals of the CRL were confirmed. RESULTS: A total of 970 cases were enrolled in the study. The median NT thickness for a CRL between 45 and 80 mm ranged from 1.2 mm to 1.9 mm, and the 95th percentile of these values ranged from 2.1 mm to 3.2 mm, respectively. CONCLUSION: The reference values for the NT thickness in Japanese fetuses were determined. These values should be useful for fetal biometry, morphological assessment and first trimester screening for chromosomal abnormalities in Japan. PMID- 23107009 TI - The genome of murine cytomegalovirus is shaped by purifying selection and extensive recombination. AB - The herpesvirus lifestyle results in a long-term interaction between host and invading pathogen, resulting in exquisite adaptation of virus to host. We have sequenced the genomes of nine strains of murine cytomegalovirus (a betaherpesvirus), isolated from free-living mice trapped at locations separated geographically and temporally. Despite this separation these genomes were found to have low levels of nucleotide variation. Of the more than 160 open reading frames, almost 90% had a dN/dS ratio of amino acid substitutions of less than 0.6, indicating the level of purifying selection on the coding potential of MCMV. Examination of selection acting on individual genes at the codon level however indicates some level of positive selection, with 0.03% of codons showing strong evidence for positive selection. Conversely, 1.3% of codons show strong evidence of purifying selection. Alignments of both genome sequences and coding regions suggested that high levels of recombination have shaped the MCMV genome. PMID- 23107010 TI - Developments in quantitative mass spectrometry for the analysis of proteome dynamics. AB - Two of the primary responses in a cell when perturbed are modulation of the dynamics of its constituent gene expression and protein abundance to restore steady-state homeostasis. To obtain a detailed model of the restoration of this balance, it is necessary to examine the kinetics of transcription and translation, thus going beyond establishing mere abundance levels of transcripts and proteins. In this review we discuss proteomic approaches that utilize genomic tagging and metabolic labeling to reveal turnover kinetics for cellular proteins in a high-throughput manner. Novel metabolic and multiplexed labeling techniques coupled to mass spectrometry, in combination with next-generation sequencing approaches, provide tools for studying the principles of cellular adaptation and dynamics in unprecedented detail. PMID- 23107011 TI - Image-guided percutaneous renal cryoablation: preoperative risk factors for recurrence and complications. AB - OBJECTIVE: To investigate the value of the R.E.N.A.L nephrometry scoring system in predicting treatment success for image-guided percutaneous cryoablation (PCA). PATIENTS AND METHODS: The study included 139 patients with renal masses treated with PCA. Preoperative computed tomography or magnetic resonance images were reviewed by a urology resident. The primary endpoint variable was incomplete treatment or tumour recurrence. R.E.N.A.L. scores were categorized into low (4 6), moderate (7-9), and high (10-12). Logistic regression analysis was conducted to predict tumour recurrence. Additional variables collected included age at surgery, American Society of Anesthesiologists score, lesion size, skin-to-tumour distance, skin-to-hilum distance, and number of treatment cryoprobes. RESULTS: At a median follow-up of 24 months, there were 10 tumour recurrences (six moderate and four high R.E.N.A.L. score categories). Nephrometry score and number of probes used were not associated with recurrence (odds ratio [OR] 1.02, P = 0.9 and P = 0.53, respectively). The tumour distances for patients with recurrence and no recurrence were 10.8 cm and 8.5 cm, respectively (P <= 0.05), the skin-to tumour distance was associated with treatment failure (OR 1.24, P = 0.015); for each unit increase in the mean value, patients were 1.5 times more likely to have a tumour recurrence (95% confidence interval [CI] 1.04-1.72). The model that best predicted complications included the number of probes used (P = 0.002) and R.E.N.A.L. score (OR 1.35, P = 0.027). For each additional probe used, patients were twice as likely to have complications (OR 1.98, 95% CI 1.28-3.05). With each unit increase in R.E.N.A.L. score, patients were 1.5 times more likely to experience a complication (OR 1.49, 95% CI 1.05-2.11). CONCLUSIONS: An increased skin-to-tumour distance is associated with a higher risk of treatment failure after PCA. Furthermore, an increase in both R.E.N.A.L nephrometry score and number of probes used was associated with an increased risk of complications after PCA. The R.E.N.A.L. nephrometry score as a measure of tumour complexity was not associated with tumour recurrence. PMID- 23107012 TI - Airway management disasters in the ICU--lessons learned? AB - The C-MAC video laryngoscope substantially reduced poor glottic views and increased intubation success in ICU patients with at least one predictor for difficult intubation. However, all video-assisted and optical intubation devices have different view angles, thus producing different images with particular distortion, and even experts in 'old-fashioned' airway management need a substantial level of training with a certain device before using it safely and successfully in critical situations and patients. Video laryngoscopes, regardless of a particular brand or device, cannot be used intuitively - they require expert skills and routines to be turned into a life-saving airway management tool. PMID- 23107013 TI - Peri-operative morbidity and mortality related to radical cystectomy: a multi institutional retrospective study in Japan. AB - What's known on the subject? and What does the study add? Radical cystectomy remains associated with comparatively high perioperative morbidity and mortality, despite improvements in surgical techniques and perioperative care. At present, most studies on the complications associated with open radical cystectomy were derived from Western academic high-volume centres, and data from Japan and other Asian countries were very limited. Using the modified Clavien grading system and 11 category grouping reported from MSKCC, we observed that 68% of patients experienced at least one complication within 90 days of surgery, and 17% of patients experienced major complications (90-day mortality rate = 2%), which were compatible with reports from Western high-volume centres. As far as we know, our report is the largest one regarding perioperative morbidity and mortality in Asian patients who underwent radical cystectomy. OBJECTIVE: To determine the type, incidence and severity of 90-day morbidity after radical cystectomy in our institution and our affiliated hospitals in accordance with a standard reporting methodology. At present, most studies on complications associated with open radical cystectomy are derived from Western academic high-volume centres and data from Japan and other Asian countries remain very limited. PATIENTS AND METHODS: The study comprised a retrospective multi-institutional study. The records were reviewed of 928 patients who underwent open radical cystectomy between 1997 and 2010. All complications within 90 days of surgery were categorized into 11 specific categories and graded in accordance with the modified Clavien system. Multivariate regression models were used to determine predictors of complications. RESULTS: At least one complication was observed in 635 (68%) patients and a major (grade 3-5) complication was observed in 156 (17%) patients. The most common complication categories were infectious (30%), gastrointestinal (26%), wound-related (21%) and genitourinary (15%). The 30-day mortality rate was 0.8% and the 90-day mortality rate was 2%. A multivariate regression model showed that previous cardiovascular comorbidity and type of urinary diversion (i.e. ileal conduit or neobladder) were significant factors for any and major complications. CONCLUSIONS: Surgical complication-related radical cystectomy is significant and both previous cardiovascular comorbidity and the type of urinary diversion were found to be significant factors for any and major complications. The 90-day mortality rate was 2%, which is compatible with reports from Western high-volume centres. PMID- 23107014 TI - A bibliometric analysis of geographic publication variations in the Journal of Cardiothoracic and Vascular Anesthesia from 1990 to 2011. AB - OBJECTIVE: The bibliometrics of the anesthesiology literature has shifted substantially during the past 3 decades. The present authors analyzed the Journal of Cardiothoracic and Vascular Anesthesia (JCVA) at selected time intervals from 1990 to 2011 to quantify temporal variations in geographic publication patterns. The authors also determined whether previously described reductions in North American research productivity were accompanied by similar decreases in the number of other forms of publication in JCVA. DESIGN: An observational study. SETTING: Internet analysis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The number of research articles, case reports and conferences, review articles, and letters in each issue of the journal were quantified in each of 4 time intervals consisting of consecutive 4-year periods (1990-1993, 1996-1999, 2002 2005, and 2008-2011). Forty-three countries published a total of 2,587 articles (ie, 1,141 research articles, 735 case reports, 175 review articles, and 536 letters) during the 4 time periods examined. Progressive decreases in the percentage of research articles, case reports, and letters, but not review articles, from North America were observed over time. Significant increases in the percentage of research articles and letters contributed by European authors in 2008 to 2011 were observed compared with 1990 to 1993. The percentage of all publications from the Middle East and Australasia increased significantly, whereas South America and Africa were relatively minor contributors to JCVA throughout the study period. CONCLUSIONS: The present bibliometric analysis indicates that JCVA has changed from a journal that primarily published work from countries in North America and Europe to one in which the Middle East and Australasia now make a substantial number of contributions. These results suggest that JCVA has evolved into a truly international journal since its inception in 1987. PMID- 23107015 TI - Noise levels in modern operating rooms during surgery. AB - OBJECTIVE: To determine if differences in noise levels exist in the cardiac operating room at various critical points. DESIGN: Prospective, nonrandomized study. SETTING: Cardiac operating rooms of a university hospital. PARTICIPANTS: Cardiac surgical patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The noise level was monitored in the operating room for 23 patients undergoing cardiac surgery requiring general anesthesia during room setup, induction, skin incision, 60 minutes after surgical incision, termination of extracorporeal circulation, emergence (drapes down), and transport. RESULTS: At each data point (induction, emergence, termination of extracorporeal circulation, emergence [drapes down], and transport), noise levels were louder than the baseline reference at room setup, surgical skin incision, and 60 minutes into the surgery. CONCLUSIONS: The aim of this study was to compare the level of noise in the operating room at times determined critical for anesthesiologists compared with other surgical periods. This study consistently showed that noise in the operating room is louder during the critical anesthesia components of the case. Several studies have found that the loudest sound levels recorded in an operating room are related to the use of particular surgical tools, which are not used typically during the induction and emergence from anesthesia. This suggests that the increased sound levels during these periods may be somewhat controllable by the health care providers in the room. PMID- 23107016 TI - Another use for transesophageal echocardiography during aortic valve bypass surgery. PMID- 23107017 TI - Aortic stenosis and 3-dimensional echocardiography: the saga continues. PMID- 23107019 TI - A novel NOD1- and CagA-independent pathway of interleukin-8 induction mediated by the Helicobacter pylori type IV secretion system. AB - The type IV secretion system (T4SS) of Helicobacter pylori triggers massive inflammatory responses during gastric infection by mechanisms that are poorly understood. Here we provide evidence for a novel pathway by which the T4SS structural component, CagL, induces secretion of interleukin-8 (IL-8) independently of CagA translocation and peptidoglycan-sensing nucleotide-binding oligomerization domain 1 (NOD1) signalling. Recombinant CagL was sufficient to trigger IL-8 secretion, requiring activation of alpha5 beta1 integrin and the arginine-glycine-aspartate (RGD) motif in CagL. Mutation of the encoded RGD motif to arginine-glycine-alanine (RGA) in the cagL gene of H. pylori abrogated its ability to induce IL-8. Comparison of IL-8 induction between H. pylori DeltavirD4 strains bearing wild-type or mutant cagL indicates that CagL-dependent IL-8 induction can occur independently of CagA translocation. In line with this notion, exogenous CagL complemented H. pylori DeltacagL mutant in activating NF kappaB and inducing IL-8 without restoring CagA translocation. The CagA translocation-independent, CagL-dependent IL-8 induction involved host signalling via integrin alpha5 beta1 , Src kinase, the mitogen-activated protein kinase (MAPK) pathway and NF-kappaB but was independent of NOD1. Our findings reveal a novel pathway whereby CagL, via interaction with host integrins, can trigger pro inflammatory responses independently of CagA translocation or NOD1 signalling. PMID- 23107018 TI - Obesity is associated with a lower resting oxygen saturation in the ambulatory elderly: results from the cardiovascular health study. AB - BACKGROUND: The contribution of obesity to hypoxemia has not been reported in a community-based study. Our hypothesis was that increasing obesity would be independently associated with lower SpO2 in an ambulatory elderly population. METHODS: The Cardiovascular Health Study ascertained resting SpO2 in 2,252 subjects over age 64. We used multiple linear regression to estimate the association of body mass index (BMI) with SpO2 and to adjust for potentially confounding factors. Covariates including age, sex, race, smoking, airway obstruction (based on spirometry), self reported diagnosis of emphysema, asthma, heart failure, and left ventricular function (by echocardiography) were evaluated. RESULTS: Among 2,252 subjects the mean and median SpO2 were 97.6% and 98.0% respectively; 5% of subjects had SpO2 values below 95%. BMI was negatively correlated with SpO2 (Spearman R = -0.27, P < .001). The mean difference in SpO2 between the lowest and highest BMI categories (< 25 kg/m(2) and >= 35 kg/m(2)) was 1.33% (95% CI 0.89-1.78%). In multivariable linear regression analysis, SpO2 was significantly inversely associated with BMI (1.4% per 10 units of BMI, 95% CI 1.2-1.6, for whites/others, and 0.87% per 10 units of BMI, 95% CI 0.47-1.27, for African Americans). CONCLUSIONS: We found a narrow distribution of SpO2 values in a community-based sample of ambulatory elderly. Obesity was a strong independent contributor to a low SpO2, with effects comparable to or greater than other factors clinically associated with lower SpO2. PMID- 23107020 TI - Thoracoscopic surgery for refractory cases of secondary spontaneous pneumothorax. AB - INTRODUCTION: Secondary spontaneous pneumothorax (SSP) can be life threatening because patients often have severe lung disease with other coexisting diseases such as heart disease. In this study, we evaluate the feasibility of thoracoscopic surgery to treat SSP and discuss thoracoscopic techniques for managing complicated cases. METHODS: We retrospectively evaluated the outcome of thoracoscopic surgeries in 21 SSP patients. RESULTS: Fifteen patients had chronic emphysema, four had interstitial pneumonia, and two had inflammatory lung disease. All patients presented with persistent air leaks, and their median preoperative hospital stay was 11 days. All patients underwent thoracoscopic surgery. In 12 patients, the leaking bullae were excised by endoscopic stapling. Fibrin glue was used in 16 cases and polyglycolic acid sheets in 17. Polyglycolic acid sheets and fibrin glue without bullectomy were used in three cases. Air leaks were treated by simple stapling in four cases and by gelatin-resorcin formaldehyde glue in five. Median postoperative hospital stay was 8 days. No patients required conversion to open surgery. Postoperative complications such as persistent air leaks, pneumonia, and acute respiratory failure were observed in six patients. Four recurrences of pneumothorax were observed during the median postoperative follow-up period of 19.3 months. CONCLUSION: Our results suggest that thoracoscopic surgery is feasible and less invasive than open surgery for high-risk patients, and it improves patient quality of life. Various techniques to stop air leaks enabled us to treat patients with refractory SSP. PMID- 23107021 TI - Closing the access barrier for effective anti-malarials in the private sector in rural Uganda: consortium for ACT private sector subsidy (CAPSS) pilot study. AB - BACKGROUND: Artemisinin-based combination therapy (ACT), the treatment of choice for uncomplicated falciparum malaria, is unaffordable and generally inaccessible in the private sector, the first port of call for most malaria treatment across rural Africa. Between August 2007 and May 2010, the Uganda Ministry of Health and the Medicines for Malaria Venture conducted the Consortium for ACT Private Sector Subsidy (CAPSS) pilot study to test whether access to ACT in the private sector could be improved through the provision of a high level supply chain subsidy. METHODS: Four intervention districts were purposefully selected to receive branded subsidized medicines - "ACT with a leaf", while the fifth district acted as the control. Baseline and evaluation outlet exit surveys and retail audits were conducted at licensed and unlicensed drug outlets in the intervention and control districts. A survey-adjusted, multivariate logistic regression model was used to analyse the intervention's impact on: ACT uptake and price; purchase of ACT within 24 hours of symptom onset; ACT availability and displacement of sub optimal anti-malarial. RESULTS: At baseline, ACT accounted for less than 1% of anti-malarials purchased from licensed drug shops for children less than five years old. However, at evaluation, "ACT with a leaf" accounted for 69% of anti malarial purchased in the interventions districts. Purchase of ACT within 24 hours of symptom onset for children under five years rose from 0.8% at baseline to 26.2% (95% CI: 23.2-29.2%) at evaluation in the intervention districts. In the control district, it rose modestly from 1.8% to 5.6% (95% CI: 4.0-7.3%). The odds of purchasing ACT within 24 hours in the intervention districts compared to the control was 0.46 (95% CI: 0.08-2.68, p=0.4) at baseline and significant increased to 6.11 (95% CI: 4.32-8.62, p<0.0001) at evaluation. Children less than five years of age had "ACT with a leaf" purchased for them more often than those aged above five years. There was no evidence of price gouging. CONCLUSIONS: These data demonstrate that a supply-side subsidy and an intensive communications campaign significantly increased the uptake and use of ACT in the private sector in Uganda. PMID- 23107022 TI - Synergic effect of curcumin or lycopene with irradiation upon oral squamous cell carcinoma cells. AB - OBJECTIVE: An in vitro study was carried out to evaluate the effect of curcumin, lycopene, and irradiation upon oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Curcumin and lycopene were administrated at doses of 3, 4.25, 5.50, and 6.75 MUM in PE/CA-PJ15 OSCC cultures irradiated with different doses (1, 2.5, and 5 Gy), followed by evaluation of the effects upon cell viability, apoptosis, and migration after 24, 48, and 72 h of incubation. RESULTS: The application of curcumin or lycopene to the tumor cells during 24, 48, and 72 h without irradiation exerted an inhibitor effect upon cell viability and increased cell apoptosis. The maximum reduction in cell viability and the peak apoptotic effect was recorded with the 5.50 and 6.75 MUM doses, for both curcumin and lycopene. Likewise, curcumin and lycopene exerted a synergic effect upon both variables on applying irradiation. Lastly, the 5.50 and 6.75 MUM drug doses, together with 5 Gy of irradiation, yielded the greatest decrease in cell migration capacity with both curcumin and lycopene. CONCLUSIONS: Curcumin and lycopene increase cytotoxic activity in the PE/CA-PJ15 cell line and reduce cell migration capacity, while the combination of curcumin or lycopene with irradiation exerts a synergic effect. PMID- 23107023 TI - Gastroesophageal reflux disease and patterns of reflux in patients with idiopathic pulmonary fibrosis using hypopharyngeal multichannel intraluminal impedance. AB - Idiopathic pulmonary fibrosis (IPF) is a diffuse fibrotic lung disease of unknown etiology. The association between IPF and gastroesophageal reflux disease (GERD) has been suggested. The objective of this study was to determine the prevalence of GERD and assess the proximity of reflux events in patients with histologically proven IPF using hypopharyngeal multichannel intraluminal impedance (HMII). This is a retrospective review of prospectively collected data from patients with histologically confirmed IPF (via lung biopsy) who underwent objective esophageal physiology testing including high-resolution manometry and HMII. Defective lower esophageal sphincter (LES) was defined as either LES pressure of <5.0 mmHg, total length of LES of <2.4 cm, or intra-abdominal length of LES of <0.9 cm. Abnormal esophageal motility was considered present when failed swallows >=30% and/or mean wave amplitude <30 mmHg was present. HMII used a specialized impedance catheter to directly measure laryngopharyngeal reflux (LPR) and full column reflux (reflux 2 cm distal to the upper esophageal sphincter). Based on the previous study of healthy subjects, abnormal proximal exposure was considered present when LPR >=1/day and/or full column reflux >=5/day were present. From October 2009 to June 2011, 46 patients were identified as having pulmonary fibrosis and sufficient HMII data. Of 46, 10 patients were excluded because of concomitant connective tissue diseases, and 8 patients were excluded because they had undergone lung transplantation, which may impact the patterns of reflux. The remaining 28 patients with histologically confirmed IPF (male 16, female 12) were included in this study. Mean age and BMI were 60.4 years (range, 41-78) and 28.4 (range, 21.1 38.1), respectively. All patients except one were symptomatic; 23 (82%) patients had concomitant typical GERD symptoms such as heartburn, whereas 4 (14%) patients had isolated pulmonary symptoms such as cough. Esophageal mucosal injury such as esophagitis and Barrett's esophagus was found in 17 (71%) patients, whereas hiatal hernia was found in 19 (73%) patients. Abnormal proximal exposure, which occurred almost exclusively in the upright position, was present in 54% (15/28) of patients. There was no significant difference in clinical symptoms, objective findings of GERD, and pulmonary functions such as forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and diffusing capacity of the lung for carbon monoxide (DLCO) between patients with and without abnormal proximal exposure. Although the total number of reflux events was significantly higher in patients with abnormal proximal exposure, a large number of patients had a negative DeMeester score regardless of whether abnormal proximal exposure was present (patients with, 80%; those without, 85%). Patients with abnormal proximal exposure more likely had a defective LES compared with those without (93% vs. 75%). Fourteen patients (56%) had abnormal esophageal motility including aperistaltic esophagus (n = 9). This first study of HMII in patients with IPF demonstrated that GERD is highly prevalent (>70%), and abnormal proximal reflux events such as LPR and full column reflux are common despite a frequently negative DeMeester score. HMII may be beneficial in the work-up of GERD in patients with IPF. PMID- 23107024 TI - Population differences in response to hypoxic stress in Atlantic salmon. AB - Understanding whether populations can adapt to new environmental conditions is a major issue in conservation and evolutionary biology. Aquatic organisms are increasingly exposed to environmental changes linked with human activities in river catchments. For instance, the clogging of bottom substratum by fine sediments is observed in many rivers and usually leads to a decrease in dissolved oxygen concentrations in gravel beds. Such hypoxic stress can alter the development and even be lethal for Atlantic salmon (Salmo salar) embryos that spend their early life into gravel beds. In this study, we used a common garden experiment to compare the responses to hypoxic stress of four genetically differentiated and environmentally contrasted populations. We used factorial crossing designs to measure additive genetic variation of early life-history traits in each population. Embryos were reared under normoxic and hypoxic conditions, and we measured their survival, incubation time and length at the end of embryonic development. Under hypoxic conditions, embryos had a lower survival and hatched later than in normoxic conditions. We found different hypoxia reaction norms among populations, but almost no population effect in both treatments. We also detected significant sire * treatment interactions in most populations and a tendency for heritability values to be lower under stressful conditions. Overall, these results reveal a high degree of phenotypic plasticity in salmon populations that nevertheless differ in their adaptive potential to hypoxia given the distinct reaction norms observed between and within populations. PMID- 23107026 TI - Collaborating for better care of our veterans. PMID- 23107025 TI - In-depth study of personality disorders in first-admission patients with substance use disorders. AB - BACKGROUND: Assessment of comorbid personality disorders (PDs) in patients with substance use disorders (SUDs) is challenging due to symptom overlap, additional mental and physical disorders, and limitations of the assessment methods. Our in depth study applied methods to overcome these difficulties. METHOD: A complete catchment area sample of 61 consecutively admitted patients with SUDs, with no previous history of specialized treatment (addiction clinics, psychiatry) were studied, addressing PDs and associated clinical and demographic variables. The thorough assessments included the Psychiatric Research Interview for Substance and Mental Disorders and the Structured Clinical Interview for DSM-IV Axis II Personality Disorders. RESULTS: Forty-six percent of the SUD patients had at least one PD (16% antisocial [males only]; 13% borderline; and 8% paranoid, avoidant, and obsessive-compulsive, respectively). Cluster C disorders were as prevalent as Cluster B disorders. SUD patients with PDs were younger at the onset of their first SUD and at admission; used more illicit drugs; had more anxiety disorders, particularly social phobia; had more severe depressive symptoms; were more distressed; and less often attended work or school. CONCLUSION: The psychiatric comorbidity and symptom load of SUD patients with PDs differed from those of SUD patients without PDs, suggesting different treatment needs, and stressing the value of the assessment of PDs in SUD patients. PMID- 23107027 TI - The seven Rs of supporting opinion and avoiding plagiarism. PMID- 23107029 TI - Implementing AORN recommended practices for transfer of patient care information. AB - The Joint Commission estimates that 80% of serious medical errors are associated with miscommunication during patient transfers. Patient transfers may occur between a wide array of settings: between physicians' offices or preoperative areas and traditional ORs or ambulatory settings, between emergency departments or interventional suites and the OR, and between other areas where the exchange of patient information occurs. AORN's "Recommended practices for transfer of patient care information" serves as a guide for establishing achievable practices that promote a safe level of care during perioperative patient transfers. Strategies for the successful implementation of the recommended practices include promoting teamwork, including with the patient and the patient's family members; developing effective communication skills; documenting processes; creating and adhering to policies and procedures; and establishing quality management programs. PMID- 23107030 TI - Reducing the frequency of immediate-use sterilization: a systematic multidisciplinary approach. AB - Efforts to comply with AORN's recommended practices for sterilization led a multidisciplinary team at H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, to undertake a quality improvement project to reduce the frequency of immediate-use (previously called flash) sterilization. Team members determined that time pressures on sterile processing department personnel, staff members' inability to find items on the peel pack cart, and shortages of some instruments led to an increased reliance on immediate-use sterilization. By tracking which instruments were most likely to be sterilized for immediate use, reorganizing the peel pack cart and instrument trays, and purchasing some additional instruments, team members were able to reduce the frequency of immediate-use sterilization by as much as 70%. It is important for perioperative nurses to participate as members of multidisciplinary quality improvement teams to implement practice changes. Shared governance is critical to any improvement project to help provide positive outcomes for the organization and for patient care. PMID- 23107031 TI - Identifying potential areas of infectivity on high-touch locations in the OR. AB - Personnel at an ambulatory surgery center in Franklin, Wisconsin, used the nationwide emphasis on minimizing health care-associated infections as the impetus to set up an investigation to determine the effectiveness of cleaning procedures for the OR and stationary OR equipment. During the course of one week, we examined areas that we considered to be high touch (ie, with the greatest frequency of multiple hand contacts) for effective cleaning and decontamination in one OR by using a commercial cleaning verification system commonly used in the food service industry and standard culture methods. As a result of this project, we determined that the cleaning and disinfection at our facility was effective. In the process, we gained insight into the dynamics of the cleaning procedure under actual conditions. This project reports a simple method of maintaining or improving cleaning protocols in a cost-effective manner. PMID- 23107032 TI - Translating evidence to practice for mechanical venous thromboembolism prophylaxis. AB - Perioperative staff nurses at Aurora Health Care, Milwaukee, Wisconsin, questioned variations in the use of mechanical venous thromboembolism prophylaxis and sought to improve the consistency of prophylaxis care and ensure use of evidence-based practices. A work group consisting of perioperative clinical nurse specialists, a nurse clinician, and a staff nurse performed a systematic literature review to determine best practices for the implementation of mechanical venous thromboembolism prevention in the perioperative period. Key practices identified included optimal application times for initiating mechanical prophylaxis before the surgical procedure and the use of unilateral mechanical prophylaxis for some orthopedic procedures. We found no published consensus regarding a cumulative benefit from combining sequential compression devices and graduated compression stockings and no clinical evidence to support the use of alternative configurations for specialty procedural tables to prevent venous thromboembolism. We disseminated the best practices that we identified within our hospital and to the greater nursing community through posters and presentations. PMID- 23107033 TI - Care of the patient with cystic fibrosis. PMID- 23107034 TI - Safety in ambulatory surgery centers: occupational safety and health administration surveys. PMID- 23107036 TI - Privacy gone awry. PMID- 23107037 TI - Optimizing hemostatic practices: matching the appropriate hemostat to the clinical situation. AB - Achieving hemostasis is a critical focus of clinicians working in the surgical setting, given that uncontrolled surgical bleeding is associated with increased mortality rates and higher costs of care. As principal members of the surgical team, perioperative nurses are in an optimal position to plan and direct care during a bleeding event and throughout a patient's surgical stay. This supplement includes an assessment of the clinical and economic effects of surgical bleeding, a thorough review of available therapies, and a detailed comparison of these products to demonstrate which agents are best suited for a given clinical situation. By understanding the basic science of coagulation and hemostasis and current advances in topical hemostatic agents, including their safety, efficacy, and judicious use, perioperative nurses will be empowered to better assist the surgeon in optimizing patient outcomes. PMID- 23107038 TI - Beneficial effects of short-term combination exercise training on diverse cognitive functions in healthy older people: study protocol for a randomized controlled trial. AB - BACKGROUND: Results of previous studies have shown that exercise training can improve cognitive functions in healthy older people. Some studies have demonstrated that long-term combination exercise training can facilitate memory function improvement better than either aerobic or strength exercise training alone. Nevertheless, it remains unclear whether short-term combination exercise training can improve diverse cognitive functions in healthy older people or not. We investigate the effects of four weeks of short-term combination exercise training on various cognitive functions (executive functions, episodic memory, short-term memory, working memory, attention, reading ability, and processing speed) of healthy older people. METHODS: A single-blinded intervention with two parallel groups (combination exercise training; waiting list control) is used. Testers are blind to the study hypothesis and the participants' group membership. Through an advertisement in a local newspaper, 64 healthy older adults are recruited and then assigned randomly to a combination exercise training group or a waiting list control group. Participants in the combination exercise training group must participate in the short-term combination exercise training (aerobic and strength exercise training) three days per week during the four weeks (12 workouts in total). The waiting list group does not participate in the combination exercise training. The primary outcome measure is the Stroop test score: a measure of executive function. Secondary outcome measures are assessments including the Verbal Fluency Task, Logical Memory, First and Second Names, Digit Span Forward, Digit span backward, Japanese Reading Test, Digit Cancellation Task, Digit Symbol Coding, and Symbol Search. We assess these outcome measures before and after the intervention. DISCUSSION: This report is the first of a study that investigates the beneficial effects of short-term combination exercise training on diverse cognitive functions of older people. Our study is expected to provide sufficient evidence of short-term combination exercise's effectiveness. TRIAL REGISTRATION: This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (Number UMIN000007828). PMID- 23107039 TI - The effect of food type (fish nuggets or French fries) on oil blend degradation during repeated frying. AB - Oil that is reused multiple times for deep frying goes through changes in chemical composition and physical characteristics, affecting the quality of the fried foods. In this study, the effect of the food type (fish nuggets or French fries) on the degradation of an oil blend during the deep-fat frying of each food at 180 degrees C during 12 days was determined, and the characteristics of the fried products were evaluated. The degradation of oil during repeated use was relatively faster when fish nuggets were fried than when French fries were fried, as higher values of total polar compounds were obtained. PRACTICAL APPLICATION: The results are useful for producers of French fries and fish nuggets, such as restaurants or fast foods sellers, providing them with practical guidelines within the permitted values established by the regulatory authorities. The studied foods have high economic importance and are different in their composition. Under the studied conditions, the tested oil blend may be used during 4 d (4 h per day) with a daily replenishment, without discarding the oil when frying fish nuggets, and must be discarded after 8 d when French fries are processed. This suggestion allows preparing safe fried foods for consumers. PMID- 23107040 TI - Homoisocitrate dehydrogenase from Candida albicans: properties, inhibition, and targeting by an antifungal pro-drug. AB - The LYS12 gene from Candida albicans, coding for homoisocitrate dehydrogenase was cloned and expressed as a His-tagged protein in Escherichia coli. The purified gene product catalyzes the Mg(2+)- and K(+)-dependent oxidative decarboxylation of homoisocitrate to alpha-ketoadipate. The recombinant enzyme demonstrates strict specificity for homoisocitrate. SDS-PAGE of CaHIcDH revealed its molecular mass of 42.6 +/- 1 kDa, whereas in size-exclusion chromatography, the enzyme eluted in a single peak corresponding to a molecular mass of 158 +/- 3 kDa. Native electrophoresis showed that CaHIcDH may exist as a monomer and as a tetramer and the latter form is favored by homoisocitrate binding. CaHIcDH is an hysteretic enzyme. The K(M) values of the purified His-tagged enzyme for NAD(+) and homoisocitrate were 1.09 mM and 73.7 MUM, respectively, and k(cat) was 0.38 s(-1). Kinetic parameters determined for the wild-type CaHIcDH were very similar. The enzyme activity was inhibited by (2R,3S)-3-(p-carboxybenzyl)malate (CBMA), with IC(50) = 3.78 mM. CBMA demonstrated some moderate antifungal activity in minimal media that could be enhanced upon conversion of the enzyme inhibitor into its trimethyl ester derivative (TMCBMA). TMCBMA is the first reported antifungal for which an enzyme of the AAP was identified as a molecular target. PMID- 23107041 TI - Histopathologic profiles of coronary atherosclerosis by myocardial bridge underlying myocardial infarction. AB - OBJECTIVE: Anatomic properties of myocardial bridge (MB) are sometimes responsible for myocardial infarction (MI) through the changes in the atherosclerosis distribution in the left ascending coronary artery (LAD). The purpose of this study was to investigate histopathologic profiles of atherosclerotic lesions resulting from the MB presence in the LAD in the MI cases. METHODS: In 150 consecutive autopsied MI hearts either with MBs [MI(+)MB(+); n = 67] or without MBs [MI(+)MB(-); n = 83] and 100 normal hearts with MBs [MI(-)MB(+)], LADs were consecutively cross-sectioned at 5-mm intervals. The most advanced intimal lesion and unstable plaque-related lesion characteristics (UPLCs) in each section were histopathologically evaluated in conjunction with the anatomic properties of the MB, such as its thickness, length, location, and MB muscle volume burden (MMV: the total volume of MB thickness multiplied by MB length). RESULTS: The MB showed a significantly greater thickness (P = 0.0090), length (P = 0.0300), and MMV (P = 0.0019) in MI(+)MB(+) than in MI(-)MB(+). Mean age of acute MI cases was significantly younger (P = 0.0227) in MI(+)MB(+) than in MI(+)MB(-). Frequency of plaque fissure/rupture in the proximal LAD was significantly higher in acute MI cases of MI(+)MB(+) than in MI(+)MB(-). UPLCs tended to be located proximally in MI(+)MB(+) and frequent 2.0 cm or more proximal to the MB entrance in MI(+)MB(+). CONCLUSION: In MI(+)MB(+), UPLCs tend to be located more proximally, and a plaque in the LAD proximal to the MB is prone to rupture, resulting in MI at younger age. PMID- 23107042 TI - Lymphocyte-suppressing and systemic anti-inflammatory effects of high-dose metformin in simvastatin-treated patients with impaired fasting glucose. AB - OBJECTIVE: No previous study has investigated whether metformin produces any effect on lymphocyte secretory function in patients with glucose metabolism abnormalities. METHODS: Sixty-two subjects with impaired fasting glucose (IFG) treated for at least 3 months with simvastatin were allocated into one of two groups receiving, respectively, metformin (3 g daily) or placebo for the following 90 days. Plasma lipids, glucose homeostasis markers, plasma C-reactive protein and intercellular adhesion molecule-1 levels, as well as lymphocyte release of proinflammatory cytokines were determined before randomization and at the end of the treatment. RESULTS: Fifty-eight patients completed the study. Metformin, but not placebo, administered to simvastatin-treated IFG subjects reduced plasma levels of C-reactive protein, soluble intercellular adhesion molecule-1, as well as lymphocyte release of interleukin-2, interferon-gamma and tumor necrosis factor-alpha, which was accompanied by the improvement in insulin sensitivity and a reduction in free fatty acid levels. CONCLUSIONS: The obtained results indicate that metformin potentiates lymphocyte-suppressing and systemic anti-inflammatory effects of simvastatin in subjects with IFG. These effects of statin-metformin combination therapy may play a role in the prevention and treatment of atherosclerosis and its complications in patients with early glucose metabolism abnormalities. PMID- 23107044 TI - Low HDL-C predicts risk and PCI outcomes in the Han Chinese population. AB - BACKGROUND: High-density lipoprotein cholesterol (HDL-C) can predict the occurrence and prognosis of coronary heart disease (CHD) in the Western population; however, the role of HDL-C in Chinese populations is unclear. Thus, we investigated the predictive value of HDL-C on the risk and clinical outcomes of CHD in the Han Chinese population. METHODS: In a case-control study, plasma HDL-C levels of CHD patients and controls were evaluated to analyse the diagnostic value of HDL-C on CHD. In a prospective cohort study, the predictive value of HDL-C on the development of major adverse cardiovascular events (MACE) was determined in CHD patients who underwent a percutaneous coronary intervention (PCI). RESULTS: In the case-control study, HDL-C levels were significantly lower in patients with CHD (n = 375) compared to the controls (n = 328, P < 0.05). There were more male patients in the CHD group than in the control group. Logistic regression analysis showed that, relative to other lipid parameters, the relationship between HDL-C levels and CHD showed the strongest association. A stratified analysis showed that gender did not affect the relationship between HDL-C levels and CHD. The prospective cohort study found that in the low HDL-C subgroup of CHD patients (n = 249) who underwent PCI, 62 (24.9%) patients experienced a MACE during the 120-week follow-up period. However, only 15 (6.8%) patients experienced a MACE in the high HDL-C subgroup (n = 219; P < 0.05). Kaplan-Meier analysis revealed that the MACE rate and death rate were significantly higher in the low HDL-C subgroup than in their counterparts with high HDL-C levels (P < 0.05). The Cox regression analysis showed that HDL-C was an independent predictor of a MACE during the follow-up period (hazard ratio = 0.395, P = 0.005). CONCLUSIONS: Low HDL-C was the most powerful lipid parameter for predicting the risk and the clinical outcome of CHD in the Han Chinese population. PMID- 23107043 TI - Joint effect of insulin signaling genes on cardiovascular events and on whole body and endothelial insulin resistance. AB - OBJECTIVE: Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity. DESIGN AND SETTING: 1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction-MI, stroke and cardiovascular death) in 733 patients (2186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose <126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs). RESULTS: 1. Risk variants jointly predicted cardiovascular events (HR = 1.181; p = 0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p = 0.006). 3. A significant association was also observed with ISI (p = 0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p = 0.009). CONCLUSIONS: Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies. PMID- 23107045 TI - Bacteriocin immunity proteins play a role in quorum-sensing system regulated antimicrobial sensitivity of Streptococcus mutans UA159. AB - OBJECTIVE: Antimicrobial sensitivity of Streptococcus mutans can be modulated by putative bacteriocin immunity proteins. Bacteria use a quorum sensing (QS) system to regulate physiological activities including bacteriocin production, antimicrobial response, and biofilm formation. QS system of S. mutans is dependent on competence stimulating peptide (CSP), whose precursor is encoded by comC. However, whether bacteriocin immunity proteins play a role in QS system regulated S. mutans antimicrobial sensitivity is still unknown. We hypothesize that bacteriocin immunity proteins encoded by immA and immB play roles in QS regulated antimicrobial sensitivity in S. mutans UA159. DESIGN: In this study, sensitivity of S. mutans UA 159 comC mutant in planktonic and biofilm states to clinically used antimicrobials was investigated by the plate count method and confocal laser scanning microscopy. The effect of immA and immB inactivation on S. mutans antimicrobial sensitivity was studied. The expression of immA and immB in S. mutans comC mutant before and after chlorhexidine (CHX) treatment was also examined. RESULTS: It was found that comC, immA and immB mutation resulted in enhanced antimicrobial sensitivity to sodium fluoride (NaF), CHX and ampicillin (AMP) in planktonic states. After 2% CHX treatment, the live/dead cell ratio in comC mutant and wild strain biofilms decreased 67% and 39% (P<0.05). The expression of immA and immB was up-regulated in wild strain after CHX treatment, while the up-regulation of immB was largely inhibited in comC mutant (P<0.05). CONCLUSIONS: These findings suggest that the effect of S. mutans UA159 comC mutation on antimicrobial sensitivity can be due, in part, to attenuation of the expression of the bacteriocin immunity proteins related genes. PMID- 23107047 TI - The effect of dentinal fluid flow during loading in various directions- simulation of fluid-structure interaction. AB - OBJECTIVES: This study uses a fluid-structure interaction (FSI) simulation to evaluate the fluid flow in a dental intrapulpal chamber induced by the deformation of the tooth structure during loading in various directions. METHODS: The FSI is used for the biomechanics simulation of dental intrapulpal responses with the force loading gradually increasing from 0 to 100N at 0 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees on the tooth surface in 1s, respectively. The effect of stress or deformation on tooth and fluid flow changes in the pulp chamber are evaluated. RESULTS: A horizontal loading force on a tooth may induce tooth structure deformation, which increases fluid flow velocity in the coronal pulp. Thus, horizontal loading on a tooth may easily induce tooth pain. CONCLUSION: This study suggests that experiments to investigate the relationship between loading in various directions and dental pain should avoid measuring the bulk pulpal fluid flow from radicular pulp, but rather should measure the dentinal fluid flow in the dentinal tubules or coronal pulp. The FSI analysis used here could provide a powerful tool for investigating problems with coupled solid and fluid structures in dental biomechanics. PMID- 23107046 TI - Imaging analysis of early DMP1 mediated dentine remineralization. AB - OBJECTIVE: This study assessed the micro-morphological changes in demineralized dentine scaffold following incubation with recombinant dentine matrix protein 1 (rDMP1). DESIGN: Extracted human molar crowns were sectioned into 6 beams (dimensions: 0.50mm*1.70mm*6.00mm), demineralized and incubated overnight in 3 different media (n=4): rDMP1 in bovine serum albumin (BSA), BSA and distilled water. Samples were placed in a chamber with simulated physiological concentrations of calcium and phosphate ions at constant pH 7.4. Samples were immediately processed for transmission electron microscopy (TEM) and field emission-scanning electron microscopy (FE-SEM) after 1 and 2 weeks. RESULTS: Analysis of the scaffold showed that decalcification process retained the majority of endogenous proteoglycans and phosphoproteins. rDMP1 treated samples promoted deposition of amorphous calcium phosphate (ACP) precursors and needle shaped hydroxyapatite crystals surrounding collagen fibrils. The BSA group presented ACP bound to collagen with no needle-like apatite crystals. Samples kept in distilled water showed no evidence of ACP and crystal apatite. Results from rDMP1 immobilized on dentine matrix suggests that the acidic protein was able to bind to collagen fibrils and control formation of amorphous calcium phosphate and its subsequent transformation into hydroxyapatite crystals after 2 weeks. CONCLUSION: These findings suggest a possible bio-inspired strategy to promote remineralization of dentine for reparative and regenerative purposes. PMID- 23107048 TI - Calcitonin gingival crevicular fluid levels and pain discomfort during early orthodontic tooth movement in young patients. AB - OBJECTIVES: To investigate the previously unreported presence of calcitonin (CT) levels in gingival crevicular fluid (GCF), its variations during initial orthodontic tooth movement in both tension and compression sites, and its possible association with the experienced dental pain. DESIGN: Fifteen children (mean age: 12.6 years) requiring orthodontic closure of the upper midline diastema were included. We collected GCF from the compression and tension sites of the upper right central incisor (experimental) and first bicuspid (control), before and after (1h, 24h, 7d, 15d) beginning of treatment. Calcitonin levels were determined by Western blot. Pain intensity was assessed using a visual analogue scale. RESULTS: Calcitonin levels were higher in the compression site versus the control site at 7d (p=0.014). Intragroup comparisons showed an increment of CT between 1h and 7d (680.81+/-1672.60pg/30s, p=0.010) in the compression site. No significant changes were found in the tension and control sites. Calcitonin levels and pain intensity were negatively associated during the period from 24h to 15d (r=-0.54, p=0.05). CONCLUSIONS: CT levels in the GCF significantly increased in the compression site after the short term after application of orthodontic forces. These changes were negatively associated with the perceived patient's dental pain during the period from 24h to 15d. PMID- 23107049 TI - Dipeptidyl peptidase IV inhibitor improves the salivary gland histology of spontaneously diabetic mice. AB - OBJECTIVES: The incretin-based therapy might be effective in patients possessing certain levels of preserved pancreatic beta-cells. However, doubts still exist regarding the efficacy of this atment in the recovery of tissues damaged by type 1 diabetes. Thus, the objective of this study was to evaluate the treatment with MK0431 in salivary glands of spontaneously diabetic mice, focusing mainly on the possible therapeutic and hypoglycaemic effects of this dipeptidyl peptidase IV inhibitor in the recovery of these salivary tissues. METHODS AND RESULTS: Twenty mice were divided into two groups of 10 animals each: group I (NOD diabetic/untreated) and group II (NOD diabetic MK0431/treated). The group II was treated during 4 weeks with MK0431 mixed in the food. The group I was maintained in the same way without receiving, however, any treatment. Glucose levels were monitored during treatment and salivary glands samples were collected at the end of treatment for the histological examination under both transmitted and polarized light microscopy. High glucose levels were observed in untreated animals, while in animals with treatment, reduction of these levels was observed. Tissue restructuring was also observed in animals submitted to therapy with MK0431, mainly in relation to the attempt to extracellular matrix reorganization. CONCLUSIONS: According to results, the treatment with this dipeptidyl peptidase IV inhibitor contributed to the general homeostasis of the organism and to the reestablishment of both epithelial and stromal compartments which were damaged by the hyperglycaemic condition, demonstrating that the incretin-based therapy may be an important complementary treatment for the type 1 diabetic condition. PMID- 23107051 TI - Subsequent pregnancy after a ruptured rudimentary uterine horn pregnancy. PMID- 23107050 TI - Prediction of periodontopathic bacteria in dental plaque of periodontal healthy subjects by measurement of volatile sulfur compounds in mouth air. AB - OBJECTIVES: The aim of this study was to determine whether measurements of volatile sulfur compounds (VSCs) are useful to predict colonization of periodontopathic bacteria. For this purpose, we assessed the relationships among distributions of 4 species of periodontopathic bacteria in tongue coating and dental plaque, oral conditions including VSC concentration in mouth air, and smoking habit of periodontal healthy young subjects. METHODS: The subjects were 108 young adults (mean age, 23.5+/-2.56 years) without clinical periodontal pockets. Information regarding smoking habit was obtained by interview. After VSC concentration in mouth, air was measured with a portable sulfide monitor (Halimeter((r))), non-stimulated saliva flow and dental caries status were assessed, and tongue coating and dental plaque samples were collected from the subjects. The tongue coating samples were weighed to determine the amount. The colonization of Porphyromonas gingivalis, Tannerella forsythia, Prevotella intermedia, and Treponema denticola in both tongue coating and plaque samples was investigated using species-specific polymerase chain reaction assays. RESULTS: Significant relationships were observed between the colonization of periodontopathic bacteria in tongue coating and plaque samples, especially that of P. gingivalis. VSC concentration showed the most significant association with colonization of P. gingivalis in both tongue coating and dental plaque. Logistic regression analysis demonstrated that the adjusted partial correlation coefficient [Exp(B)] values for VSC concentration with the colonization of P. gingivalis, P. intermedia, and T. denticola in dental plaque were 135, 35.4 and 10.4, respectively. In addition, smoking habit was also shown to be a significant variable in regression models [Exp(B)=6.19, 8.92 and 2.53, respectively]. Therefore, receiver operating characteristic analysis was performed to predict the colonization of periodontal bacteria in dental plaque in the subjects divided by smoking habit. Based on our results, we found cut-off values that indicated likelihood ratios (LR) within the efficient range for positive findings in both groups. CONCLUSION: The present results demonstrated that measurement of VSC concentration in mouth air is a useful method to predict the presence of colonization of some periodontopathic bacteria in dental plaque. PMID- 23107052 TI - Cervical pregnancy treated by uterine artery embolisation combined with office hysteroscopy. AB - OBJECTIVE: To evaluate the safety and efficacy of uterine artery embolisation in conjunction with hysteroscopic resection of trophoblast in the conservative treatment of cervical ectopic pregnancies. STUDY DESIGN: Five women diagnosed with cervical pregnancies at University Hospital of Foggia, Italy, between May 2009 and February 2012 underwent uterine artery embolisation followed by office hysteroscopic resection of trophoblast. Data on operating time, blood loss, blood transfusion, conversion to other techniques, complications related to surgery, change of serum beta-hCG level, hospitalisation days and outcome of the women after discharge were collected. RESULTS: The mean hysteroscopic operative time was 9.8 min, and the blood loss was negligible in all cases. Blood transfusion was not needed for any of the women. None of the women required conversion to other techniques. In all cases the operations were uneventful. The serum beta-hCG level in all the cases declined to normal within 15 days of surgery. The total hospitalisation time was 4 days in all the cases. No vaginal bleeding or other side effects were observed throughout and after the treatment, all women recovered without complications. CONCLUSIONS: Uterine artery embolisation with office hysteroscopic resection is an effective option in treatment of cervical ectopic pregnancy. PMID- 23107053 TI - Pathogenesis of the syndrome of hemolysis, elevated liver enzymes, and low platelet count (HELLP): a review. AB - HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome is serious for the mother and the offspring. HELLP occurs in 0.2-0.8% of pregnancies and in 70-80% of cases it coexists with preeclampsia (PE). This review concerns the pathogenetic mechanisms of HELLP syndrome with an emphasis on differences between HELLP and early onset PE. The syndromes show a familial tendency. A previous HELLP pregnancy is associated with an increased risk of HELLP as well as PE in subsequent pregnancies, indicating related etiologies. No single world-wide genetic cause for excessive risk of HELLP or PE has been identified. Combinations of multiple gene variants, each with a moderate risk, with contributing effects of maternal and environmental factors, are probable etiological mechanisms. Immunological maladaptation is the most probable trigger of the insult to the invading trophoblast. This insult occurs early in the first trimester, as indicated by marker molecules in maternal blood. The levels of fetal messenger RNAs in maternal blood at gestational weeks 15-20 are significantly more abnormal in HELLP than in PE, suggesting that the insult is more extensive in HELLP. High levels of HLA-DR in maternal blood in women with HELLP may suggest a similarity to the rejection reaction. In third trimester placentas, gene derangement is more extensive in HELLP. Anti-angiogenic factors released into maternal blood induce the maternal syndromes. Maternal blood levels of anti-angiogenic sFlt1 are similar, but endoglin and Fas Ligand levels are possibly higher in HELLP than in PE. These factors trigger the vascular endothelium, resulting in an enhanced inflammatory response which is stronger in HELLP. Activated coagulation and complement, with high levels of activated leucocytes, inflammatory cytokines, TNF alpha, and active von Willebrand factor, induce thrombotic microangiopathy with platelet-fibrin thrombi in microvessels. The angiopathy results in consumption of circulating platelets, causes hemolysis in affected microvessels and reduces portal blood flow in the liver. Placental Fas Ligand damages hepatocytes, resulting in periportal necrosis. In about one half of women with HELLP, activation of coagulation factors and platelets precipitates disseminated intravascular coagulation, which in a minority becomes uncompensated and contributes to life-threatening multiorgan failure. PMID- 23107054 TI - 'The missing links': understanding how context and mechanism influence the impact of public involvement in research. AB - INTRODUCTION: It is now more widely recognized that public involvement in research increases the quality and relevance of the research. However, there are also more questions as to exactly how and when involvement brings added value. THE NATURE OF THE CURRENT EVIDENCE OF IMPACT: Based on the findings of recent literature reviews, most reports of public involvement that discuss impact are based on observational evaluations. These usefully describe the context, the type of involvement and the impact. However, the links between these factors are rarely considered. The findings are therefore limited to identifying the range of impacts and general lessons for good practice. Reflecting on the links between context, mechanism and outcome in these observational evaluations identifies which aspects of the context and mechanism could be significant to the outcome. Studies that are more in line with the principles of realistic evaluation can test these links more rigorously. Building on the evidence from observational evaluations to design research that explores the 'missing links' will help to address the question 'what works best, for whom and when'. CONCLUSIONS: We conclude that a more intentional and explicit exploration of the links between context, mechanism and outcome, applying the principles of realistic evaluation to public involvement in research, should lead to a more sophisticated understanding of the factors that increase or decrease the likelihood of positive outcomes. This will support the development of more strategic approaches to involvement maximizing the benefits for all involved. PMID- 23107055 TI - A comparative study of accumulated total mercury among white muscle, red muscle and liver tissues of common carp and silver carp from the Sanandaj Gheshlagh Reservoir in Iran. AB - The Sanandaj Gheshlagh Reservoir (SGR) is a mercury polluted lake that is located in the West of Iran. Common carp (Cyprinus carpio) and silver carp (Hypophthalmichthys molitrix) are the most abundant fishes in the SGR. A total of 48 common and silver carps (24 each) were captured randomly, using 50*6 m gill net (mesh size: 5*5 cm) during July to December 2009. Each month, the levels of accumulated total mercury (T-Hg) in white muscle, red muscle and liver tissues of these fishes were measured using an Advanced Mercury Analyzer (Model; Leco 254 AMA, USA) on the dry weight basis. There were no statistically significant differences between T-Hg concentrations in white muscle, red muscle and liver in common carp in comparison with similar tissues in silver carp (P>0.05). The content of T-Hg in liver tissue of both species was lower than of white and red muscle tissues. Higher levels of accumulated T-Hg were observed during summer. Results showed that T-Hg concentrations in common and silver carps target tissues were strongly dependent on age, length and weight (P<0.05). The results indicated that the levels of accumulated T-Hg in tissues of all samples with weights of over 850 g were greater than those limits established by WHO and FAO (500 ng g( 1)). PMID- 23107056 TI - Metal toxicity and biodiversity in serpentine soils: application of bioassay tests and microarthropod index. AB - Eco-toxicological or bioassay tests have been intensively discussed as tools for the evaluation of soil quality. Tests using soil organisms, including microarthropods and plants, allow direct estimates to be made of important soil characteristics and functions. In this study we compared the results obtained by two in vitro standard bioassays following ISO or OECD guidelines: (i) the short term-chronic phytotoxicity germination and root elongation test using three different plant species Cucumis sativus L. (Cucurbitaceae), Lepidium sativum L. (Brassicaceae), and Medicago sativa L. (Fabaceae) and (ii) the inhibition of reproduction of Folsomia candida (Collembola) by soil pollutants to investigate the toxicity of a serpentine soil present in the Italian Apennines, rich in heavy metals such as Ni, Cr, and Co. In addition, microarthropod communities were characterised to evaluate the effects of metal contents on the soil fauna in natural conditions. Abundances, Acari/Collembola ratio, biodiversity indices and the QBS-ar index were calculated. Our results demonstrate that the two in vitro tests distinguish differences correlated with metal and organic matter contents in four sub-sites within the serpentinite. Soil fauna characterisation, not previously performed on serpentine soils, revealed differences in the most vulnerable and adapted groups of microarthropods to soil among the four sub sites: the microarthropod community was found to be rich in term of biodiversity in the sub-site characterised by a lower metal content and a higher organic matter content and vegetation. PMID- 23107057 TI - Stabilization of hydrogen peroxide using phthalic acids in the Fenton and Fenton like oxidation. AB - The stabilization of hydrogen peroxide was evaluated in Fenton reaction with phthalic acid as a stabilizer. The stabilization effect was high at a low pH0.2 ng/mL), and Kaplan-Meier analysis was performed to determine BCR-free survival rates in AA, AC and CA men. RESULTS: A total of 483 men underwent RP for clinically OC disease (CM, n = 309, AA, n = 93 and AC, n = 81). The mean patient age was 59 years, with AA men being younger than CA men (58 vs 60 years, P< 0.05). The mean (range) follow-up was 49 (13-133) months with no significant difference among the groups. The men in the AC cohort had a higher mean PSA level than AA and CA men (8.8 vs 6.2 and 5.0 ng/mL, respectively, P< 0.05) and more clinical GS >=7 (44%) tumours than AA (8%) and CA men (0%; P< 0.01). On multivariate analysis, controlling for stage, grade, PSA level and margins, AA and AC race were independent predictors of BCR. AA and AC men had significantly lower 5-year BCR-free survival (76 and 74%, respectively) than CA men (98% [P < 0.001]). CONCLUSIONS: This international comparison of clinicopathological outcomes in AA, AC and CA men undergoing RP shows that AA and AC men present similarly with more aggressive disease features than CA men and have lower 5-year BCR-free survival. Both AA and AC race are significant predictors of BCR, independently of stage, grade, PSA level and margin status. Further research is needed to elucidate and correct the mechanisms behind the observed difference in outcome among these populations. PMID- 23107068 TI - How to assess tonsilloliths and styloid chain ossifications on cone beam computed tomography images. AB - OBJECTIVE: The aim of this study was to establish an anatomical guideline in cone beam computed tomography (CBCT) images to discriminate soft-tissue calcifications, specifically, tonsilloliths, and styloid chain ossification (SCO) in the multiplanar reconstruction screen of the i-CAT Vision. MATERIALS AND METHODS: We analyzed 100 pairs of CBCT images and panoramic digital radiographies regarding the presence or absence of tonsilloliths and SCO. The intraobserver agreement varied from excellent to good. The statistical analyses included Mann Whitney test, chi-square test, Spearman test, Student's t-test, and Wilcoxon test. The analyses were repeated without the guideline to verify its effectiveness. RESULTS: A total of 25 tonsilloliths were found in panoramic images while CBCT images revealed 60. Panoramic and CBCT images showed 42% and 63% of patients positive to SCO, respectively. We found a statistically significant difference when comparing the presence of tonsilloliths and SCO between panoramic and CBCT images (Wilcoxon test P < 0.05). The analyses without the guideline showed that the observer tended to diagnoses more false-positive SCO. CONCLUSION: Based on the results, we can suggest that CBCT images are more suitable to differentiate tonsilloliths and SCO than panoramic images. The guideline was more important to diagnosis SCO than tonsilloliths. SCO was misclassified in 34% without the guideline. PMID- 23107069 TI - European quality clearance of new microbiological diagnostics. AB - Laboratory-based diagnosis of infectious diseases is evolving quickly. New technologies and new tests are frequently commercialized, and although guidelines for their proper clinical validation do exist, these are often at the national or regional level. Therefore, the guidelines remain open to interpretation, and are not always applied properly. One of the main questions is how a high level of test quality can be maintained by European legislation. How can product quality be reliably and independently assessed and how can the penetration of sub standard assays in the European market be managed and hopefully prevented? We here propose that local initiatives, including external quality assessment, public health initiatives, and close multidisciplinary collaborations between manufacturers and academic research institutes, may accelerate decision-making. Vigilance in test quality assessment and legal simplification are important key concepts warranting selective use of those diagnostic tests that comply with the highest quality standards. PMID- 23107071 TI - Low long-lasting insecticide nets (LLINs) use among household members for protection against mosquito bite in Kersa, Eastern Ethiopia. AB - BACKGROUND: In Ethiopia, despite the increasing availability of long-lasting insecticide treated nets (LLINs), the LLINs use among LLINs owning households has not been satisfactory. Identifying the circumstances and the associated factors is necessary to achieve the Millennium Development Goal targets. We aimed to assess barriers related with LLIN use at the household level. METHODS: A cross sectional survey was conducted in Kersa Demographic Surveillance and Health Research Center (KDS-HRC) from October to November 2010. A total of 2867 households were selected from a surveillance database using a simple random sampling technique. The data were collected by interviewing women, direct observation of LLINs conditions and use, and in-depth interviewing of key informants. Multivariate analysis was used to determine independent predictors of LLIN non-use. RESULTS: Of the total surveyed households, 65.5% (1879) had at least one LLIN, but 33.5% (630) LLINs owned households had used at least one LLIN the night before the survey. Low educational level of women, low awareness on malaria prevention, unavailability of separate sleeping room, LLIN colour preference, and unavailability of enough LLINs to the household members were the main barriers to LLIN use. A supplementary qualitative interview with key informants also identified that poor condition of LLINs; undermining the extent of malaria; and using the LLIN for other purposes as the main reasons for non use. CONCLUSIONS: This study indicates that only about one third of LLIN owned households are actually using at least one LLIN for protection against mosquito bite. Thus, majority of the residents are at higher risk of mosquito bite and acquiring of malaria infection. Households living in fringe zone are not benefiting from the LLIN protection. Further progress in malaria prevention can be achieved by specifically targeting populations in fringe zones and conducting focused public education to increase LLIN use. PMID- 23107070 TI - Simulation of malaria epidemiology and control in the highlands of Western Kenya. AB - BACKGROUND: Models of Plasmodium falciparum malaria epidemiology that provide realistic quantitative predictions of likely epidemiological outcomes of existing vector control strategies have the potential to assist in planning for the control and elimination of malaria. This work investigates the applicability of mathematical modelling of malaria transmission dynamics in Rachuonyo South, a district with low, unstable transmission in the highlands of western Kenya. METHODS: Individual-based stochastic simulation models of malaria in humans and a deterministic model of malaria in mosquitoes as part of the OpenMalaria platform were parameterized to create a scenario for the study area based on data from ongoing field studies and available literature. The scenario was simulated for a period of two years with a population of 10,000 individuals and validated against malaria survey data from Rachuonyo South. Simulations were repeated with multiple random seeds and an ensemble of 14 model variants to address stochasticity and model uncertainty. A one-dimensional sensitivity analysis was conducted to address parameter uncertainty. RESULTS: The scenario was able to reproduce the seasonal pattern of the entomological inoculation rate (EIR) and patent infections observed in an all-age cohort of individuals sampled monthly for one year. Using an EIR estimated from serology to parameterize the scenario resulted in a closer fit to parasite prevalence than an EIR estimated using entomological methods. The scenario parameterization was most sensitive to changes in the timing and effectiveness of indoor residual spraying (IRS) and the method used to detect P. falciparum in humans. It was less sensitive than expected to changes in vector biting behaviour and climatic patterns. CONCLUSIONS: The OpenMalaria model of P. falciparum transmission can be used to simulate the impact of different combinations of current and potential control interventions to help plan malaria control in this low transmission setting. In this setting and for these scenarios, results were highly sensitive to transmission, vector exophagy, exophily and susceptibility to IRS, and the detection method used for surveillance. The level of accuracy of the results will thus depend upon the precision of estimates for each. New methods for analysing and evaluating uncertainty in simulation results will enhance the usefulness of simulations for malaria control decision-making. Improved measurement tools and increased primary data collection will enhance model parameterization and epidemiological monitoring. Further research is needed on the relationship between malaria indices to identify the best way to quantify transmission in low transmission settings. Measuring EIR through mosquito collection may not be the optimal way to estimate transmission intensity in areas with low, unstable transmission. PMID- 23107072 TI - The 6-minute walk test in chronic respiratory failure: does observed or predicted walk distance better reflect patient functional status? AB - BACKGROUND: Acquiring 6-min walk test (6MWT) data from patients undergoing noninvasive mechanical ventilation due to chronic hypercapnic respiratory failure is limited. We aimed to assess whether the actual 6-min walk distance (6MWD) or the percent predicted 6MWD is a better reflection of the respiratory function of patients using home noninvasive ventilation (NIV) due to chronic hypercapnic respiratory failure. METHODS: This was a cross-sectional observational study. The 6MWT was performed in subjects using home NIV. Diagnoses were grouped as COPD, obesity hypoventilation syndrome (OHS), kyphoscoliosis, and parenchymal lung disease. Sex, age, and body mass index (BMI) were used to calculate ideal 6MWD. Male: 1,140 m - (5.61 * BMI) - (6.94 * age), and subtract 153 m for the lower limit of normal. Female: 1,017 m - (6.24 * BMI) - (5.83 * age), and subtract 139 m for the lower limit of normal. The 6MWD and percent-of-predicted 6MWD were compared relative to arterial blood gas, spirometry values, and diagnosis. RESULTS: The 6MWT was performed in 144 subjects, median (IQR) age 62 y (55-71 y). The male/female ratio, median (IQR) 6MWD, and percent-of-predicted 6MWD values were: COPD 32/6, 316 m (226-390 m), and 59.4% (42.5-68.9%); OHS 24/28, 303 m (240 362 m), and 73.0% (63.0-82.0%); kyphoscoliosis 16/7, 420 m (318-462 m), and 70.5% (56.0-75.2%); and parenchymal lung disease 19/12, 333 m (273-372 m), and 67.1% (46.7-74.7%). The correlation of percent-of-predicted 6MWD with spirometry and arterial blood gas values were better than with the actual 6MWD. CONCLUSIONS: The percent-of-predicted 6MWD was better correlated with respiratory function than actual 6MWD for subjects using home NIV due to chronic hypercapnic respiratory failure with COPD, OHS, kyphoscoliosis, and parenchymal lung disease. PMID- 23107074 TI - A comparative study of thulium laser resection of the prostate and bipolar transurethral plasmakinetic prostatectomy for treating benign prostatic hyperplasia. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Thulium laser is a new generation of surgical laser. It is a minimally invasive technology with several advantages, including rapid vaporization and minimal tissue damage and bleeding. However, details regarding the safety and efficacy of thulium laser in treating BPH remains unknown. We performed a comparative study in 100 patients with BPH of the safety and efficacy of thulium laser resection of the prostate (TMLRP, n = 50) and bipolar transurethral plasmakinetic prostatectomy (TUPKP, n = 50). We found that the efficacy and indications were the same in TMLRP and TUPKP. In TUPKP, the morbidity of urethrostenosis was low, and was nearly bloodless in surgery and had higher safety. Nevertheless, TUPKP is more suitable for patients with larger prostate volume. OBJECTIVE: To compare the safety and short-term efficacy of thulium laser resection of the prostate (TMLRP) and bipolar transurethral plasmakinetic prostatectomy (TUPKP) for the treatment of patients with benign prostatic hyperplasia (BPH). METHODS: A total of 100 patients diagnosed with BPH were randomly divided into two groups, treated with either TMLRP (50, group 1) or TUPKP (50, group 2). There was no significant difference in preoperative variables such as age, prostate volume, prostate-specific antigen (PSA) level, International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ) and postvoid residual urine volume (PVR) between the two groups. The perioperative parameters and therapeutic effects were recorded and compared between the two groups. RESULTS: There were significant differences in the following parameters between the two groups (TMLRP vs TUPKP [mean +/- SD]): operation duration, 61.2 +/- 24.2 vs 30.14 +/- 15.9 min; catheterization time, 1.8 +/- 0.4 vs 3.2 +/- 0.6 d; postoperative hospital stay, 3.3 +/- 0.8 vs 4.1 +/- 1.3 d. The volume of blood loss and postoperative bladder irrigation were significantly lower in TMLRP group than in the TUPKP group. At 1 month after the operation, there were four cases of urethral stricture in the TUPKP group. At 3 months after the operation, IPSS, quality of life (QoL), Qmax and PVR were significantly improved, with no significant difference between the two groups. CONCLUSIONS: TMLRP is superior to TUPKP in terms of safety, blood loss, recovery time and complication rate, and is as efficacious as TUPKP for treating BPH. Operation duration was significantly longer in the TMLRP group than in the TUPKP group. PMID- 23107073 TI - Host microtubule plus-end binding protein CLASP1 influences sequential steps in the Trypanosoma cruzi infection process. AB - Mammalian cell invasion by the protozoan parasite Trypanosoma cruzi involves host cell microtubule dynamics. Microtubules support kinesin-dependent anterograde trafficking of host lysosomes to the cell periphery where targeted lysosome exocytosis elicits remodelling of the plasma membrane and parasite invasion. Here, a novel role for microtubule plus-end tracking proteins (+TIPs) in the co ordination of T. cruzi trypomastigote internalization and post-entry events is reported. Acute silencing of CLASP1, a +TIP that participates in microtubule stabilization at the cell periphery, impairs trypomastigote internalization without diminishing the capacity for calcium-regulated lysosome exocytosis. Subsequent fusion of the T. cruzi vacuole with host lysosomes and its juxtanuclear positioning are also delayed in CLASP1-depleted cells. These post entry phenotypes correlate with a generalized impairment of minus-end directed transport of lysosomes in CLASP1 knock-down cells and mimic the effects of dynactin disruption. Consistent with GSK3beta acting as a negative regulator of CLASP function, inhibition of GSK3beta activity enhances T. cruzi entry in a CLASP1-dependent manner and expression of constitutively active GSK3beta dampens infection. This study provides novel molecular insights into the T. cruzi infection process, emphasizing functional links between parasite-elicited signalling, host microtubule plus-end tracking proteins and dynein-based retrograde transport. Highlighted in this work is a previously unrecognized role for CLASPs in dynamic lysosome positioning, an important aspect of the nutrient sensing response in mammalian cells. PMID- 23107075 TI - Resolution of critical haemodynamic instability with urgent decompressive mini laparotomy for abdominal compartment syndrome--a case report. PMID- 23107076 TI - A growing role for hypertrophy in senescence. PMID- 23107077 TI - Every birth a healthy birth. PMID- 23107079 TI - Noninvasive prenatal testing for fetal trisomies in a routinely screened first trimester population. AB - OBJECTIVE: We sought to assess performance of noninvasive prenatal testing for fetal trisomy in a routinely screened first-trimester pregnancy population. STUDY DESIGN: This was a cohort study of 2049 pregnant women undergoing routine screening for aneuploidies at 11-13 weeks' gestation. Plasma cell-free DNA analysis using chromosome-selective sequencing was used. Laboratory testing on a single plasma sample of 2 mL was carried out blindly and results were provided as risk score (%) for trisomies 21 and 18. RESULTS: Trisomy risk scores were given for 95.1% (1949 of 2049) of cases including all 8 with trisomy 21 and 2 of the 3 with trisomy 18. The trisomy risk score was >99% in the 8 cases of trisomy 21 and 2 of trisomy 18 and <1% in 99.9% (1937 of 1939) of euploid cases. CONCLUSION: Noninvasive prenatal testing using chromosome-selective sequencing in a routinely screened population identified trisomies 21 and 18 with a false-positive rate of 0.1%. PMID- 23107080 TI - Feasibility and economic impact of same-day discharge for women who undergo laparoscopic hysterectomy. AB - OBJECTIVE: We examined the use, safety, and economic impact of same-day discharge for women undergoing laparoscopic hysterectomy. STUDY DESIGN: We identified women in the Perspective database who underwent laparoscopic hysterectomy from 2000 through 2010. Discharge was classified as same-day, 1 day, and >=2 days. Multivariable models were used to examine predictors of same-day discharge, reevaluation, and cost. RESULTS: Among 128,634 women, 34,070 (26.5%) were discharged on the day of surgery. Same-day discharge increased from 11.3% in 2000 to 46.0% by 2010 (P < .0001). The rate of reevaluation within 60 days was 4.0% for those discharged same day, 3.6% after a 1-day stay, and 5.1% for patients whose stay was >=2 days (P < .0001). In a multivariable model, patients discharged on postoperative day 1 were less likely to require reevaluation (risk ratio, 0.89; 95% confidence interval, 0.82-0.96), but costs were $207 (95% confidence interval, $179-234) greater. CONCLUSION: Same-day discharge after laparoscopic hysterectomy is safe and associated with decreased cost. PMID- 23107081 TI - Cervical lidocaine for IUD insertional pain: a randomized controlled trial. AB - OBJECTIVE: Anticipated pain with intrauterine device (IUD) insertion may be a barrier to widespread use. Our objective was to evaluate the efficacy of intracervical 2% lidocaine gel for pain relief with IUD insertion. STUDY DESIGN: We performed a double-blind, randomized controlled trial of women undergoing IUD insertion. Participants were randomly assigned to 2% lidocaine or placebo gel. Study gel (3 mL) was placed 3 minutes prior to IUD insertion. Pain scores were measured at various time points using a 10-point visual analog scale. RESULTS: Of the 200 participants randomized, 199 completed the study. Pain scores among lidocaine and placebo arms were similar at tenaculum placement (lidocaine and placebo: median, 4; range, 0-10; P = .15) and with insertion (lidocaine: median, 5; range, 1-10; placebo: median, 6; range, 0-10; P = .16). These results did not differ by parity. CONCLUSION: Topical or intracervical 2% lidocaine gel prior to IUD insertion does not decrease pain scores. PMID- 23107082 TI - Bilateral uterine artery chemoembolization with methotrexate for cesarean scar pregnancy. AB - OBJECTIVE: The objective of the study was to assess the efficacy of uterine arteries embolization (UAE) for the treatment of cesarean scar pregnancies (CSP). STUDY DESIGN: Forty-six women with CSP were identified between March 2008 and March 2010. All of the patients underwent UAE combined with local methotrexate. RESULTS: Forty-five patients were successfully treated. One patient had an emergency hysterectomy after 20 days because of massive vaginal hemorrhage. The mean time until normalization of serum beta-human chorionic gonadotrophin was 37.7 days, and the mean time until CSP mass disappearance was 33.3 days. The mean hospitalization time was 10.5 days. The complications were mainly fever and pain, which were alleviated with symptomatic treatment. All 45 patients had recovered their normal menstruation at follow-up. CONCLUSION: Bilateral uterine artery chemoembolization with methotrexate appears to be a safe and effective treatment for CSP and causes less morbidity than current approaches. PMID- 23107083 TI - An educational workshop and student competency in pregnancy options counseling: a randomized controlled trial. AB - OBJECTIVE: We sought to determine the effect of a pregnancy options counseling workshop focusing on communication skills and ethics on medical student competency. STUDY DESIGN: This educational trial randomized 105 third-year students to performance of an objective structured clinical examination before or after participation in the workshop assessed by a blinded reviewer. The primary outcome variable was student-level global competency in options counseling; secondary outcomes included competency components of general communication. RESULTS: Global competency was achieved by 36% of students in the preworkshop group and 50% in the postworkshop group (P = .16). Students who participated in the workshop demonstrated higher communication skills. Student ratings of objective structured clinical examination quality were 96-100% positive, with 80% reporting an increase in comfort with options counseling and 88% reporting increased comfort with communication skills. CONCLUSION: Participation in a workshop focusing on conscientious refusal positively improved communication skills, but did not significantly impact students' competency in pregnancy options counseling. PMID- 23107084 TI - Discussion: 'Topiramate in pregnancy and risk of oral clefts,' by Margulis et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Margulis AV, Mitchell AA, Gilboa SM, et al; National Birth Defects Prevention Study. Use of topiramate in pregnancy and risk of oral clefts. Am J Obstet Gynecol 2012;207:405.e1-7. PMID- 23107085 TI - The source of 17P used in NICHD trial. PMID- 23107087 TI - [Asymptomatic neonatal neurocutaneous melanosis]. AB - Giant congenital nevi in 1% of cases are associated with anomalies of the central nervous system, which are characteristic of neurocutaneous melanosis. When neurocutaneous melanosis becomes symptomatic, it is associated with a poor prognosis. With recommended neonatal screening, asymptomatic neonatal cases are being discovered more frequently. On the basis of this observation, we consider various aspects of this association. PMID- 23107088 TI - [Spontaneous intraperitoneal rupture of hydronephrosis in an infant]. AB - Spontaneous intraperitoneal rupture of hydronephrosis is a rare complication. We report a case in a 30-month old boy admitted for fever, with a temperature up to 38.5 degrees C, and abdominal distension. The diagnosis was made intraoperatively. The treatment consisted of an emergency internal urinary diversion and a deferred definitive cure of the pyelo-ureteral junction stenosis. Surgical management in two steps is more prudent and beneficial. PMID- 23107089 TI - [Neonatal diarrhea due to congenital glucose-galactose malabsorption: report of seven cases]. AB - Congenital glucose-galactose malabsorption (CGGM) is a rare autosomal recessive disorder, which presents as a protracted diarrhea in early neonatal life. We describe the clinical history, diagnostic evaluation, and management of 7 children with CGGM in western France. There were 4 girls and 3 boys from 5 families, born between 1984 and 2010. The principal complaint was a neonatal onset of watery and acidic severe diarrhea complicated by hypertonic dehydration. The diarrhea stopped with fasting. In 2 cases, the family history supported the diagnosis. In the other cases, elimination of glucose and galactose (lactose) from the diet resulted in the complete resolution of diarrhea symptoms. In 2 cases, the H2 breath tests were positive. In 2 cases, the HGPO or oral glucose tolerance test (OGTT) demonstrated an abnormal curve with glucose and a normal curve with fructose. DNA sequencing was not used. When glucose and galactose were eliminated from the diet, the infants had normal growth and development. In conclusion, CGGM is a rare etiology of neonatal diarrhea; however, the diagnosis is easy to make and the prognosis is excellent. PMID- 23107090 TI - [Use of supplementation for breast-fed neonates in the maternity ward]. AB - OBJECTIVES: The aim of this study was to evaluate our practices regarding the use of supplementation for breast-fed neonates. METHODS: A descriptive and prospective study conducted between 22/05/2010 and 23/03/2010 comprising breast fed, healthy, singleton infants at the Maternity University Hospital of Tours. Indications for supplementation were collected prospectively by paramedics. RESULTS: The study included 281 breast-fed neonates, of whom 99 (35 %) received supplementation. Supplemented neonates were more often children of primiparae (61.6 % versus 44%; P=0.005), or born to mothers without experience of breast feeding (69.7% versus 48.9%; P=0.001), born by cesarean section (21.2% versus 10.4%; P=0.01), or were small for gestational age (10.1 % versus 6.6%; P=0.003). The main indications were: to prevent additional weight loss, hunger of the newborn, hypoglycemia, and difficulty to breast-feed. Twenty-nine percent of the neonates were given supplements without medical indication. CONCLUSION: One third of breast-fed infants receive supplementation, not always medically justified. A better understanding of medical indications would avoid supplementation being given to breast-fed infants. PMID- 23107091 TI - [Antibiotic treatment of appendicular peritonitis in children: is the oral route done?]. AB - The use of intravenously administered antibiotics has several disadvantages including hospitalization costs, infectious risk, and patient discomfort. The objective of this study was to estimate the proportion of children receiving intravenous antibiotic therapy (IV), for whom there was a switch to an oral route conforming to the criteria established by the American Pediatric Surgical Association (APSA). A cohort of 100 children hospitalized for acute appendicitis with generalized peritonitis or abscess were analyzed. In this study, we compared the criteria of switching to an oral route as recommended by the APSA (disappearance of the pain, normalization of white blood cells, afebrile for 48 hours, return to bowel function) and by reports from the literature (afebrile, tolerating regular diet). In 47.5% of the children, there was a switch to an oral route conforming to the APSA recommendations. In children having a late switch, the average duration of the IV treatment was of 7.6 +/- 3.6 days associated with 62 days of avoidable IV antibiotics. The duration of hospitalization and antibiotic treatment was significantly higher in children having a late switch (P=0.04; P=0.01, respectively). Concerning the criteria reported in the literature, 14.5% of children were not switched to an oral route. Meeting the criteria from the literature would have resulted in 199 days of avoidable IV antibiotics. A significant number of days of IV antibiotics could have been avoided. However, the large number of exclusion criteria in the APSA analysis suggests that practitioners do not follow these recommendations or objective criteria. The criteria proposed in the literature could decrease the duration of IV antibiotics and the associated hospitalization costs. PMID- 23107092 TI - Species, essence and explanation. AB - Michael Devitt (2008, 2010) has argued that species have intrinsic essences. This paper rebuts Devitt's arguments, but in so doing it shores up the anti essentialist consensus in two ways that have more general interest. First, species membership can be explanatory even when species have no essences; that is, Tamsin's membership of the tiger species can explain her stripyness, without this committing us to any further claim about essential properties of tigers. Second, even the views of species that appear most congenial to essentialism namely phenetic and genotypic cluster accounts-do not entail strong forms of intrinsic essentialism. PMID- 23107093 TI - The concept of cause is of extraordinary importance for the sciences. Introduction. PMID- 23107094 TI - Genomic amplification of the human telomerase gene (hTERC) associated with human papillomavirus is related to the progression of uterine cervical dysplasia to invasive cancer. AB - BACKGROUND: Human papillomavirus (HPV) infection plays an etiological role in the development of cervical dysplasia and cancer. Amplification of human telomerase gene (hTERC) and over expression of telomerase were found to be associated with cervical tumorigenesis. This study was performed to analyze genomic amplification of hTERC gene, telomerase activity in association with HPV infection in different stages of cervical intraepithelial neoplasia (CIN) and cervical cancer. We were studying the role of hTERC in the progression of uterine cervical dysplasia to invasive cancer, and proposed an adjunct method for cervical cancer screening. METHODS: Exfoliated cervical cells were collected from 114 patients with non neoplastic lesion (NNL, n=27), cervical intraepithelial neoplasia (CIN1, n=26, CIN2, n=16, CIN3, n=24) and cervical carcinoma (CA, n=21), and analyzed for amplification of hTERC with two-color fluorescence in situ hybridization (FISH) probe and HPV-DNA with Hybrid Capture 2.From these patients, 53 were taken biopsy to analyze telomerase activity by telomeric repeat amplification protocol (TRAP) and expression of human telomerase reverse transcriptase (hTERT), with immunohistochemistry (IHC). All biopsies were clinically confirmed by phathologists. RESULTS: Amplification of hTERC was significantly associated with the histologic diagnoses (p<0.05). The positive correlation was found between the level of hTERC amplification and histologic grading of dysplasia (CIN2/3 from CIN1 or normal, P=0.03). A profounding increase in the accumulation of HPV and hTERC positive cases was observed in the CIN3 subgroup compared with the CIN2 group, 25% versus 62.96%, respectively (p=0.007). CONCLUSIONS: hTERC ampliffication can be detected with FISH technique on exfoliated cervical cells. Amplification of hTERC and HPV infection are associated with more progressive CIN3 and CA. The testing of hTERC amplification might be a supplementary to cytology screening and HPV test, especially high-risk patients. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1857134686755648. PMID- 23107096 TI - Establishment of relationship between mean and maximum velocities in narrow sewers. AB - The maximum velocity in any channel cross section might be as important as the mean velocity. It is easier to measure the maximum velocity than the mean velocity, and many flow rate sensors measure maximum velocity and convert it to mean velocity for the evaluation of the discharge. The experimental results obtained from two actual sites and the comparison with their estimated values, are presented in this study. The plots of isovel lines of the primary velocity from each site are presented. Concerning narrow channel properties, it was observed that the maximum velocity occurred below the free surface. Several series of measurements from these sites were collected to explore the relationship between the cross-sectional mean (U(mean)) and maximum velocity (U(max) under different hydraulic conditions. Additional velocity data and measurements in flumes and rivers were also collected from work of other researchers in order to compare this relationship in different cases. It was found that the ratio of the U(mean) on U(max) in narrow channels was higher than that in rivers with a large aspect ratio (width/water height). PMID- 23107095 TI - An exploration of patient and family engagement in routine primary care visits. AB - BACKGROUND: Older adults are commonly accompanied to routine medical visits. Whether and how family companion behaviours relate to visit processes is poorly understood. OBJECTIVE: To examine family companion behaviours in relation to older adults' medical visit processes. DESIGN AND PARTICIPANTS: Observational study of 78 accompanied primary care patients ages 65 and older. MAIN OUTCOME MEASURES: Medical visit communication (coded using RIAS), patient verbal activity (as a proportion of visit statements) and visit duration (in min), from audio recordings. RESULTS: Companions' facilitation of patient involvement was associated with greater patient question asking (P = 0.017) and orienting statements, less passive agreement (P = 0.004) and social talk (P = 0.013) and visits that were 3.4 min longer (P = 0.025). Facilitation of patient understanding was associated with less physician question asking (P = 0.004), visits that were 3.0 min longer (P = 0.031), and lower patient verbal activity (30.3% vs. 36.9% of visit statements; P = 0.028). Facilitation of doctor understanding was associated with greater patient biomedical information giving (P = 0.049). Autonomy detracting behaviours were not associated with visit duration but were associated with lower levels of patient verbal activity (36.3% vs. 29.1% of visit statements; P = 0.041). When companions assumed more behaviours, medical visits were incrementally longer (16.1, 19.5, 21.7 min, corresponding to 0-1, 2-4 and 5+ behaviours; P < 0.001 both contrasts), and patients were less verbally active (35.6%, 33.9%, 27.1% of visit statements; P = 0.09 and P = 0.009, respectively). DISCUSSION: Behaviours assumed by patients' companions were associated with visit communication, patient verbal activity and visit duration. CONCLUSIONS: Interventions to capitalize on family companions' presence may benefit medical visit processes. PMID- 23107097 TI - Editorial comment. PMID- 23107099 TI - NADiA ProsVue prostate-specific antigen slope is an independent prognostic marker for identifying men at reduced risk of clinical recurrence of prostate cancer after radical prostatectomy. AB - OBJECTIVE: To validate the hypothesis that men displaying serum prostate-specific antigen (PSA) slopes <= 2.0 pg/mL/mo after prostatectomy, measured using a new immuno-polymerase chain reaction diagnostic test (NADiA ProsVue), have a reduced risk of clinical recurrence as determined by positive biopsy, imaging findings, or death from prostate cancer. MATERIALS AND METHODS: From 4 clinical sites, we selected a cohort of 304 men who had been followed up for 17.6 years after prostatectomy for clinical recurrence. We assessed the prognostic value of a PSA slope cutpoint of 2.0 pg/mL/mo against established risk factors to identify men at low risk of clinical recurrence using uni- and multivariate Cox proportional hazards regression and Kaplan-Meier analyses. RESULTS: The univariate hazard ratio of a PSA slope >2.0 pg/mL/mo was 18.3 (95% confidence interval 10.6-31.8) compared with a slope <= 2.0 pg/mL/mo (P <.0001). The median disease-free survival interval was 4.8 years vs >10 years in the 2 groups (P <.0001). The multivariate hazard ratio for PSA slope with the covariates of preprostatectomy PSA, pathologic stage, and Gleason score was 9.8 (95% confidence interval 5.4 17.8), an 89.8% risk reduction for men with PSA slopes <= 2.0 pg/mL/mo (P <.0001). The Gleason score (<7 vs >= 7) was the only other significant predictor (hazard ratio 5.4, 95% confidence interval 2.1-13.8, P = .0004). CONCLUSION: Clinical recurrence after radical prostatectomy is difficult to predict using established risk factors. We have demonstrated that a NADiA ProsVue PSA slope of <= 2.0 pg/mL/mo after prostatectomy is prognostic for a reduced risk of prostate cancer recurrence and adds predictive power to the established risk factors. PMID- 23107100 TI - Optimal duration of macrolide treatment for chronic sinusitis after endoscopic sinus surgery. AB - OBJECTIVE: The objective is to determine the appropriate duration of postoperative macrolide therapy for chronic rhinosinusitis to obtain a favourable outcome with endoscopic sinus surgery (ESS). METHODS: The effectiveness of postoperative macrolide treatment was examined in patients with chronic rhinosinusitis who underwent ESS, by comparing 3-month (44 patients) and 6-month administration (66 patients) of clarithromycin (CAM) (200mg/day). Evaluation was made based on subjective symptoms and endoscopic findings at 3, 6 and 12 months after surgery. RESULTS: Seventeen (3-month CAM group) and 22 (6-month CAM group) subjects were able to be followed up to 12 months after surgery. No difference in effectiveness was observed between the groups until 6 months after surgery, but the 6-month treatment group showed significantly higher disappearance rates and significantly lower visual analogue scale (VAS) scores in the subjective symptoms of rhinorrhea and postnasal drip at 12 months after surgery. The positive finding rate of postnasal drip by endoscopic examination was also significantly lower in the 6-month treatment group at 12 months after surgery. These changes over time indicated gradual deterioration after discontinuation of CAM treatment in the 3 month treatment group, whereas a small improvement was observed after discontinuation in the 6-month treatment group. CONCLUSION: The results indicate that chronic sinusitis patients with rhinorrhea or postnasal drip should be treated with macrolides for 6 months after surgery in order to improve the long term outcome of endoscopic sinus surgery. PMID- 23107102 TI - A systematic review of stereotactic radiotherapy ablation for primary renal cell carcinoma. AB - What's known on the subject? and What does the study add? At present, little is known about the role of stereotactic ablative body radiotherapy in the treatment of primary renal cell carcinoma. The published evidence to date totals 126 patients worldwide. The majority of evidence is retrospective in nature. The present study adds context to the current literature by providing an overall summary of the evidence. OBJECTIVE: * To critically assess the use of stereotactic ablative body radiotherapy (SABR) for the treatment of primary renal cell carcinoma with particular focus on local control and toxicity outcomes. METHODS: * A systematic search on PubMed was performed in January 2012 independently by two radiation oncologists using structured search terms. * Secondary manual searches were performed on citations in relevant publications and abstracts in major radiotherapy journals. * Outcomes, techniques, biological doses and scientific rigour of the studies were analysed. RESULTS: * In total 10 publications (seven retrospective and three prospective) were identified. A wide range of techniques, doses and dose fractionation schedules were found. * A total of 126 patients were treated with between one and six fractions of SABR. Median or mean follow-up ranged from 9 to 57.5 months. A weighted local control was reported of 93.91% (range 84%-100%). * The weighted rate of severe grade 3 or higher adverse events was 3.8% (range 0%-19%). The weighted rate of grade 1-2 minor adverse events was 21.4% (range 0%-93%). The most commonly employed fractionation schedule was 40 Gy delivered over five fractions. CONCLUSIONS: * Current literature suggests that SABR for primary renal cell carcinoma can be delivered with promising rates of local control and acceptable toxicity. * However, there was insufficient evidence to recommend a consensus view for dose fractionation or technique. * This indicates the need for further prospective studies assessing the role of this technique in medically inoperable patients. PMID- 23107101 TI - Control of directional change after mechanical stimulation in Drosophila. AB - BACKGROUND: Proper adjustment of moving direction after external mechanical stimulation is essential for animals to avoid danger (e.g. predators), and thus is vital for survival. This process involves sensory inputs, central processing and motor outputs. Recent studies have made considerable progress in identifying mechanosensitive neurons and mechanosensation receptor proteins. Our understandings of molecular and cellular mechanisms that link mechanosensation with the changes in moving direction, however, remain limited. RESULTS: In this study, we investigate the control of movement adjustment in Drosophila. In response to gentle touch at the anterior segments, Drosophila larvae reorient and select a new direction for forward movement. The extent of change in moving direction is correlated with the intensity of tactile stimuli. Sensation of gentle touch requires chordotonal organs and class IV da neurons. Genetic analysis indicates an important role for the evolutionarily conserved immunoglobulin (Ig) superfamily protein Turtle (Tutl) to regulate touch-initiated directional change. Tutl is required specifically in post-mitotic neurons at larval stage after the completion of embryonic development. Circuit breaking analysis identified a small subset of Tutl-positive neurons that are involved in the adjustment of moving direction. CONCLUSION: We identify Tutl and a small subset of CNS neurons in modulating directional change in response to gentle touch. This study presents an excellent starting point for further dissection of molecular and cellular mechanisms controlling directional adjustment after mechanical stimulation. PMID- 23107103 TI - Chromogenic in situ hybridization is a reliable alternative to fluorescence in situ hybridization for diagnostic testing of 1p and 19q loss in paraffin-embedded gliomas. AB - Recent studies imply the importance of rapid and reliable diagnostic assessment of 1p/19q status in oligodendroglial tumors. To date, fluorescence in situ hybridization (FISH) is the most commonly applied technique. FISH, however, has several technical shortcomings that are suboptimal for diagnostic applications: results must be viewed in a fluorescence microscope, results are usually evaluated by a single investigator only, and signal fading excludes physical archiving. Also, in gliomas, the distinction of diffusely infiltrating tumor cells from reactively altered normal tissue may be challenging in fluorescence microscopy. Dual-color chromogenic in situ hybridization (CISH) has started to replace FISH in some diagnostic tests performed in pathology. Here, we present the first single institute experience with a side-by-side analysis of 1p/19q FISH and CISH in a series of 42 consecutive gliomas. FISH and CISH produced identical results for 1p and 19q in 93% of cases (n = 39/42). Discrepant results were reevaluated by repeated FISH and a polymerase chain reaction (PCR)-based microsatellite marker analysis for loss of heterozygosity. Reevaluation confirmed CISH data in all three cases. We conclude that CISH is a reliable alternative in 1p/19q testing in paraffin-embedded tissues likely to be more sensitive to detect 1p/19q status than FISH analysis. PMID- 23107106 TI - Drug and therapeutics committees in Danish hospitals: a survey of organization, activities and drug selection procedures. AB - To implement rational pharmacotherapy in hospitals, it is important to develop, implement and evaluate hospital drug formularies (HDFs). A report from Denmark recommended standardizing activities of the drug and therapeutics committees (DTCs) in Denmark, but little is known about their current organization. The aim of the study was to describe the organization of DTCs in Denmark, how HDFs are developed and implemented, and to what extent policies that support the use of HDFs exist. A questionnaire was developed based on previous research and guidelines and contained 20 questions, which were divided into the following subjects: structure, activities, drug selection and implementation. The questionnaire was sent to the chairmen of the nine DTCs in Denmark. The response rate was 100% (9/9). The DTCs varied in structure and activities; meetings were held between 2 and 6 times annually, and the duration of the meetings lasted between 1 and 2.5 hr. Eight (89%) DTCs developed HDFs, policies and guidelines (P&Gs) that supported the use of HDFs. Eight (89%) had established criteria for inclusion of drugs on the HDFs, and seven had developed criteria for generic substitution and therapeutic interchange. The number of trade names on the HDFs varied between 116 and 1195. The nine DTCs in Denmark varied considerably regarding structure and activity. The main activity was to develop formularies, and most of the committees developed policies that supported medication use. PMID- 23107105 TI - Attitudes toward technology-based health information among adult emergency department patients with drug or alcohol misuse. AB - Technology-based screening and interventions are emerging solutions to the challenge of addressing substance use in the emergency department (ED). A standardized questionnaire of adult patients at a large-volume, urban, academic ED assessed interest in, and potential barriers to, technology-based substance use information. Questionnaire topics included substance use, access to technology, preferences for health information, and perceived barriers to technology interventions. Among the 430 participants, mean age was 39 years and 55% were female; 37% reported alcohol misuse and 52% drug misuse. Access to technology was high. Technology was preferred by 46% of alcohol misusers (vs. 43% non-misusers, p=0.65) but only 41.9% of drug misusers (vs. 56% non-drug misusers, p=0.005). In multivariate analyses, drug misuse was associated with decreased interest in receiving technology-based information. Cited barriers included confidentiality, complexity, and time. Our findings suggest that drug misusers in particular may wish to have reassurances about the confidentiality of technology based interactions. PMID- 23107104 TI - Oral chronic graft-versus-host disease: current pathogenesis, therapy, and research. AB - Optimal management of complex autoimmune diseases requires a multidisciplinary medical team including dentists to care for lesions of the oral cavity. In this review, we discuss the presentation, prevalence, diagnosis, and treatment of oral manifestations in chronic graft-versus-host disease (cGVHD), which is a major late complication in patients treated by allogeneic hematopoietic stem cell transplantation. We assess current general knowledge of systemic and oral cGVHD and present general treatment recommendations based on literature review and our clinical experience. Additionally, we review areas where the understanding of oral cGVHD could be improved by further research and address tools with which to accomplish the long-term goal of providing better health and quality of life to patients with cGVHD. PMID- 23107107 TI - Gender differences in the association of insulin resistance with metabolic risk factors among Korean adolescents: Korea National Health and Nutrition Examination Survey 2008-2010. AB - AIMS: We investigated the association of insulin resistance with metabolic syndrome (MetS) and its components among Korean adolescents. METHODS: We analyzed the Korea National Health and Nutrition Examination Survey (2008-2010). Adolescents aged 10-18 years without diabetes (1584 boys and 1388 girls) were evaluated. Insulin resistance was assessed by homeostasis model assessment insulin resistance (HOMA-IR), and MetS was diagnosed according to the 2007 International Diabetes Federation criteria for adolescents. RESULTS: The prevalence of MetS was 1.4% among boys and 1.7% among girls. Girls in the highest quartile of HOMA-IR were significantly more likely to have MetS compared to girls in the lower quartiles independent of survey year, age, body mass index, white blood cell count, and alanine aminotransferase [odds ratio (OR), 5.33; 95% confidence interval (CI), 1.57-18.11]. Moreover, compared to girls in the lowest quartile of HOMA-IR, girls in the highest quartile significantly exhibited large waist circumference (OR, 3.22; 95% CI, 1.01-10.35), high triglycerides (OR, 6.43; 95% CI, 2.83-14.58), and low high-density lipoprotein-cholesterol (HDL-C) (OR, 2.49; 95% CI, 1.50-4.11). However, such associations were not found among boys. CONCLUSIONS: Our results suggest that insulin resistance may be independently associated with MetS, large waist circumference, high triglycerides, and low HDL C only among girls. PMID- 23107108 TI - Lack of association between genetic polymorphisms within KCNQ1 locus and type 2 diabetes in Tunisian Arabs. AB - AIMS: Polymorphisms of KCNQ1 were previously associated with type 2 diabetes (T2DM) in select Caucasian and non-Caucasian populations. We investigated the association of rs231361, rs231359, rs151290, rs2237892, rs2283228, rs2237895, and rs2237896 KCNQ1 polymorphisms with T2DM in Tunisian Arabs. SUBJECTS AND METHODS: Subjects comprised 900 T2DM patients and 600 normoglycemic controls. KCNQ1 genotyping was done by allelic discrimination (real-time PCR) and PCR-RFLP methods; the contribution of KCNQ1 polymorphisms to T2DM were analyzed by Haploview and regression analysis. RESULTS: Minor allele frequency (MAF) of the 7 tested KCNQ1 variants was comparable between T2DM cases and controls. Mild association of rs2237892 genotypes with T2DM was seen (P=0.014), highlighted by the significant association of the C/T genotype with increased T2DM risk (OR, 2.11; 95%CI, 1.25-3.53), after adjusting for BMI, gender, systolic and diastolic blood pressure, and serum lipid profile. Heterogeneity in linkage disequilibrium pattern between tested KCNQ1 variants analyzed was seen. Two-locus (rs231361 and rs231359) and 5-locus (remaining 5 SNPs) haplotype analysis did not reveal any significant association with any of the haplotypes contained in either block 1 or block 2. CONCLUSION: These results indicate that there was no evidence for an association of KCNQ1 polymorphisms with T2DM in Tunisian Arabs. PMID- 23107109 TI - Permanent neonatal diabetes caused by a novel mutation in the INS gene. AB - Neonatal diabetes mellitus (DM) is a rare condition that can be either transient or permanent. In this case report, we describe a novel mutation (p.L30Q) in the INS gene resulting in permanent DM in a four-month-old female who presented with polyphagia, polyuria, irritability, and hyperglycemia with glucosuria and ketonuria without acidosis. PMID- 23107110 TI - The reliability and validity of the Japanese version of the Diabetes Family Behavior Checklist (DFBC) for assessing the relationship between type 2 diabetes mellitus patients and their families with respect to adherence to treatment regimen. AB - AIMS: An appropriate questionnaire for assessing family support of self management behavior of Japanese Type 2 diabetes patients has yet to be developed. We produced a Japanese version of the Diabetes Family Behavior Checklist (DFBC) and tested its reliability and validity. METHODS: The study enrolled Japanese patients with Type 2 diabetes mellitus who were living with their families: 158 patients in the Insulin Group and 169 in the Oral Hypoglycemic Agents Group. The external validity of the DFBC was tested with questionnaires of self-managed dietary and exercise behaviors, the Appraisal of Diabetes Scale (ADS), and HbA1c. RESULTS: The DFBC comprised two components: "Negative" and "Positive" feedbacks. Cronbach's alpha in the subcategories was >=0.93, and the test-retest showed an intraclass correlation coefficient of 0.89. "Positive" and "Negative" scores correlated with self-managed dietary and/or exercise behaviors, the ADS scores in the both Groups. For patients having HbA1c levels of <=6.8% there was a correlation between their "Positive" and "Negative" scores and the scores of their families in both Groups. CONCLUSION: The DFBC showed evidence of validity and reliability and may be a useful tool for quick assessment of self-managed treatment behavior of Japanese Type 2 diabetes patients and support received from their family. PMID- 23107111 TI - Transcription factor-7-like 2 gene variants are strongly associated with type 2 diabetes in Lebanese subjects. AB - We tested the association of TCF7L2 variants with type 2 diabetes (T2DM) in 691 Lebanese people and 919 controls. rs7901695, rs4506565, rs7903146, rs12243326, rs7895340, and rs12255372 minor allele frequencies were higher in T2DM. Haplotype analysis (rs7901695-rs4506565-rs7903146-rs12243326-rs7895340-rs11196205 rs12255372) identified positively- (2122112, 2222222) and negatively- (1111111) T2DM-associated haplotypes. TCF7L2 is a common T2DM candidate gene in Lebanese people. PMID- 23107112 TI - Multicentre studies of insecticide-treated durable wall lining in Africa and South-East Asia: entomological efficacy and household acceptability during one year of field use. AB - BACKGROUND: Indoor residual spraying (IRS) is a primary method of malaria vector control, but its potential impact is constrained by several inherent limitations: spraying must be repeated when insecticide residues decay, householders can tire of the annual imposition and campaign costs are recurrent. Durable lining (DL) can be considered an advanced form of long-lasting IRS where insecticide is gradually released from an aesthetically attractive wall lining material to provide vector control for several years. A multicentre trial was carried out in Equatorial Guinea, Ghana, Mali, South Africa and Vietnam to assess the feasibility, durability, bioefficacy and household acceptability of DL, compared to conventional IRS or insecticide-treated curtains (LLITCs), in a variety of operational settings. METHODS: This study was conducted in 220 households in traditional rural villages over 12-15 months. In all sites, rolls of DL were cut to fit house dimensions and fixed to interior wall surfaces (usually with nails and caps) by trained teams. Acceptability was assessed using a standardized questionnaire covering such topics as installation, exposure reactions, entomology, indoor environment, aesthetics and durability. Bioefficacy of interventions was evaluated using WHO cone bioassay tests at regular intervals throughout the year. RESULTS: The deltamethrin DL demonstrated little to no decline in bioefficacy over 12-15 months, supported by minimal loss of insecticide content. By contrast, IRS displayed a significant decrease in bioactivity by 6 months and full loss after 12 months. The majority of participants in DL households perceived reductions in mosquito density (93%) and biting (82%), but no changes in indoor temperature (83%). Among those households that wanted to retain the DL, 73% cited protective reasons, 20% expressed a desire to keep theirs for decoration and 7% valued both qualities equally. In Equatorial Guinea, when offered a choice of vector control product at the end of the trial (DL, IRS or LLITCs), DL consistently emerged as the most popular intervention regardless of the earlier household allocation. CONCLUSIONS: Just as long-lasting insecticidal nets overcame several of the technical and logistical constraints associated with conventionally treated nets and then went to scale, this study demonstrates the potential of DL to sustain user compliance and overcome the operational challenges associated with IRS. PMID- 23107113 TI - Work-family conflict and burnout among Chinese female nurses: the mediating effect of psychological capital. AB - BACKGROUND: Burnout among nurses not only threatens their own health, but also that of their patients. Exploring risk factors of nurse' burnout is important to improve nurses' health and to increase the quality of health care services. This study aims to explore the relationship between work-family conflict and burnout among Chinese female nurses and the mediating role of psychological capital in this relationship. METHODS: This cross-sectional study was performed during the period of September and October 2010. A questionnaire that consisted of the Maslach Burnout Inventory-General Survey (MBI-GS), the work-family conflict scale and the psychological capital questionnaire (PCQ-24) scale, as well as demographic and working factors, was distributed to nurses in Liaoning province, China. A total of 1,332 individuals (effective response rate: 78.35%) became our subjects. Hierarchical linear regression analyses were performed to explore the mediating role of psychological capital. RESULTS: Both work interfering family conflict and family interfering work conflict were positively related with emotional exhaustion and cynicism. However, work interfering family conflict was positively related with professional efficacy whereas family interfering work conflict was negatively related with it. Psychological capital partially mediated the relationship of work interfering family conflict with emotional exhaustion and cynicism; and partially mediated the relationship of family interfering work conflict with emotional exhaustion, cynicism and professional efficacy. CONCLUSION: Work-family conflict had effects on burnout and psychological capital was a mediator in this relationship among Chinese nurses. Psychological capital was a positive resource for fighting against nurses' burnout. PMID- 23107114 TI - Partial nephrectomy online: a preliminary evaluation of the quality of health information on the Internet. AB - What's known on the subject? and What does the study add? Patients are highly likely to access the Internet for health information, and studies have reported that inaccurate or low-quality information may alter patients' expectations and negatively impact informed decision-making. In a unique collaboration with the Health On the Internet (HON) Foundation, we evaluated the top 20 search results for the urology search term 'partial nephrectomy,' and identified the highest and lowest scoring criteria to increase awareness of areas of concern and improvement. OBJECTIVE: To further evaluate the quality of information available on the Internet with regard to the management of localized renal cancer, we evaluated websites providing information on 'partial nephrectomy' in conjunction with the Health On the Internet (HON) Foundation. Many patients now utilize the Internet as a resource to provide further information on disease, treatments and outcomes, and health information on the Internet is largely unregulated. Inaccurate information may contribute to unrealistic expectations and dissatisfied patients. PATIENTS AND METHODS: A google.com search identified the top 30 websites for the search term 'partial nephrectomy'. The HON Foundation evaluated each website according to the eight principles for Health on the Internet code of conduct (HONcode) certification and reported the overall frequency of certification, as well as individual website compliance with each of the principles. RESULTS: Overall, seven (23.3%) of 30 websites met the requirements of HONcode certification and an additional two (6.7%) websites were under review to maintain their certification based on updating their resources. The remaining 21 (70%) websites did not meet the standards for certification. The lowest performing criteria included proper citation of medical information and a clear distinction of advertising from editorial content. CONCLUSIONS: The low rate of HONcode compliance for these websites illustrates the poor quality of information that patients may encounter when researching options for nephron sparing surgery, which may have a significant impact on patient decision-making and treatment choices. Physicians should be aware of the quality of Internet resources and how to best use these tools to help guide patients to websites with valid information. PMID- 23107116 TI - Chiral separations and enantioselectivity. PMID- 23107115 TI - The Hsp90-Sti1 interaction is critical for Leishmania donovani proliferation in both life cycle stages. AB - The heat shock protein 90 plays a pivotal role in the life cycle control of Leishmania donovani promoting the fast-growing insect stage of this parasite. Equally important for insect stage growth is the co-chaperone Sti1. We show that replacement of Sti1 is only feasible in the presence of additional Sti1 transgenes indicating an essential role. To better understand the impact of Sti1 and its interaction with Hsp90, we performed a mutational analysis of Hsp90. We established that a single amino acid exchange in the Leishmania Hsp90 renders that protein resistant to the inhibitor radicicol (RAD), yet does not interfere with its functionality. Based on this RAD-resistant Hsp90, we established a combined chemical knockout/gene complementation (CKC) approach. We can show that Hsp90 function is required in both insect and mammalian life stages and that the Sti1-binding motif of Hsp90 is crucial for proliferation of insect and mammalian stages of the parasite. The Sti1-binding motif in Leishmania Hsp90 is suboptimal optimizing the motif increased initial intracellular proliferation underscoring the importance of the Hsp90-Sti1 interaction for this important parasitic protozoan. The CKC strategy we developed will allow the future analysis of more Hsp90 domains and motifs in parasite viability and infectivity. PMID- 23107117 TI - The use of methyl-beta-cyclodextrin to solubilize cholesterol prior to coating onto a C18 stationary phase. AB - The use of methyl-beta-cyclodextrin (MBCD) as a mobile phase additive in reversed phase liquid chromatography is explored, with the primary goal of using MBCD to solubilize cholesterol in reversed-phase mobile phases for cholesterol-coating of C18 stationary phases. MBCD is shown to increase the solubility of cholesterol in typical reversed-phase mobile phases, especially when the stoichiometric ratio of MBCD to cholesterol exceeds 2:1. Additional equivalents of MBCD further increase solubility, or allow for weaker solvents to be used. The use of weaker solvents allows for larger coating levels of cholesterol onto a C18 stationary phase than are possible without the use of MBCD. Stationary phases coated with cholesterol using MBCD as a co-additive have different selectivity than uncoated phases, especially with regards to phenyl and shape selectivity. Further, the use of MBCD as a mobile phase additive for the elution of cholesterol is examined. It is seen via van't Hoff analysis that the reduction in retention of cholesterol when MBCD is added to the mobile phase is enthalpically driven. PMID- 23107118 TI - Plant metabolomics: resolution and quantification of elusive peaks in liquid chromatography-mass spectrometry profiles of complex plant extracts using multi way decomposition methods. AB - Previous studies on LC-MS metabolomic profiling of 127 F2 Barbarea vulgaris plants derived from a cross of parental glabrous (G) and pubescent (P) type, revealed four triterpenoid saponins (hederagenin cellobioside, oleanolic acid cellobioside, epihederagenin cellobioside, and gypsogenin cellobioside) that correlated with resistance of plants against the insect herbivore, Phyllotreta nemorum. In this study, for the first time, we demonstrate the efficiency of the multi-way decomposition method PARAllel FACtor analysis 2 (PARAFAC2) for exploring complex LC-MS data. PARAFAC2 enabled automated resolution and quantification of several elusive chromatographic peaks (e.g. overlapped, elution time shifted and low s/n ratio), which could not be detected and quantified by conventional chromatographic data analysis. Raw LC-MS data of 127 F2 B. vulgaris plants were arranged in a three-way array (elution time point*mass spectra*samples), divided into 17 different chromatographic intervals and each interval were individually modeled by PARAFAC2. Three main outputs of the PARAFAC2 models described: (1) elution time profile, (2) relative abundance, and (3) pure mass spectra of the resolved peaks modeled from each interval of the chromatographic data. PARAFAC2 scores corresponding to relative abundances of the resolved peaks were extracted and further used for correlation and partial least squares (PLS) analysis. A total of 71 PARAFAC2 components (which correspond to actual peaks, baselines and tails of neighboring peaks) were modeled from 17 different chromatographic retention time intervals of the LC-MS data. In addition to four previously known saponins, correlation- and PLS-analysis resolved five unknown saponin-like compounds that were significantly correlated with insect resistance. The method also enabled a good separation between resistant and susceptible F2 plants. PARAFAC2 spectral loadings corresponding to the pure mass spectra of chromatographic peaks matched well with experimentally recorded mass spectra (correlation based similarity >95%). This enabled to extract pure mass spectra of highly overlapped and low s/n ratio peaks. PMID- 23107119 TI - Direct and simultaneous determination of trace-level carbon tetrachloride, peroxyacetyl nitrate, and peroxypropionyl nitrate using gas chromatography electron capture detection. AB - Gas chromatography equipped with electron capture detector (GC-ECD) has been widely used for detecting atmospheric peroxyacetyl nitrate (PAN) and peroxypropionyl nitrate (PPN). However, to the best of our knowledge, only a few capillary columns have been adopted for separation to achieve the direct and simultaneous analysis of the two atmospheric pollutants. This paper demonstrates a novel method for directly and simultaneously measuring atmospheric carbon tetrachloride (CCl(4)), PAN, and PPN using GC-ECD with a DB-1 separation column. The responses of the GC-ECD to PAN, PPN, and CCl(4) were individually calibrated by using gas mixtures prepared via volatilization of synthesized solutions of PAN and PPN or high-purity CCl(4) reagent in a Teflon Bag. The concentrations of PAN and PPN in the synthesized solutions were quantified by ion chromatography (IC). Further calibration of the GC-ECD for PAN was conducted by in situ photochemical formation of gaseous PAN which was quantified by a NO(x) analyzer. The two calibration methods agreed well with each other, and the overall uncertainties for measuring atmospheric PAN were estimated to be +/- 13% and +/- 15% based on the calibrations of IC and NO(x), respectively. The detection limits (three times the signal to noise ratio) for PAN, PPN, and CCl(4) were estimated to be 22, 36, and 5 pptv (parts per trillion by volume), respectively. The atmospheric concentrations of these compounds were measured for several days in August in Beijing, and the values obtained in this study were found to be in good agreement with the data reported in the literature for Beijing using other GC-ECD methods. PMID- 23107120 TI - A novel open-tubular capillary electrochromatography using beta-cyclodextrin functionalized graphene oxide-magnetic nanocomposites as tunable stationary phase. AB - Chip-based enantioselective open-tubular capillary electrochromatography (OT-CEC) with beta-cyclodextrin (beta-CD) conjugated graphene oxide-magnetic nanocomposites (GO/Fe(3)O(4) NCs) as stationary phase was developed. GO/Fe(3)O(4) NCs with high magnetic responsivity, excellent solubility and high dispersibility in water were prepared through a facile and controllable in situ chemical deposition strategy. beta-CD was then adsorbed onto the GO/Fe(3)O(4) surface to form GO/Fe(3)O(4)/beta-CD NCs which were localized to the pre-nominated position in polydimethylsiloxane (PDMS) microchannels with the help of magnets. The resultant GO/Fe(3)O(4)/beta-CD NCs not only have the magnetism of Fe(3)O(4) NPs that make them easily manipulated by an external magnetic field, but also have the larger surface which can incorporate much more chiral selector molecules. In addition, the successful beta-CD decorations endowed GO/Fe(3)O(4)/beta-CD NCs with excellent wettability and led to enhanced stability against high ionic strength. Compared with the native PDMS microchip, the modified surfaces exhibited more stable and suppressed electroosmotic mobility, and less nonspecific adsorption toward analytes. Successful baseline separation of tryptophan enantiomers was achieved in less than 50s with a resolution factor of 1.65 utilizing a separation length of 37 mm coupled with in-column amperometric detection. Factors that influence the chiral separation resolution were examined. Under the optimized conditions, the proposed modified chip revealed adequate repeatability concerning run-to-run and day-to-day. These results show that the use of GO/Fe(3)O(4)/beta-CD NCs within microfluidic channels hold great promise for a variety of analytical schemes. PMID- 23107121 TI - Determination of six microcystins and nodularin in surface and drinking waters by on-line solid phase extraction-ultra high pressure liquid chromatography tandem mass spectrometry. AB - Microcystins and nodularin are cyclic peptides hepatotoxins produced by cyanobacterial genera (blue-green algae). Toxic cyanobacterial blooms are a worldwide problem, as reported in several countries, like China, Australia, or the United States. Therefore, it is necessary to develop sensitive and reliable analytical methodology to determine this type of toxins in water at parts per billion levels, or even lower. In this work, the potential of solid-phase extraction coupled on-line to ultra-high-pressure liquid chromatography/electrospray tandem mass spectrometry (SPE-UHPLC-MS/MS) has been investigated for the efficient quantification and confirmation of microcystins LR, RR, YR, LY, LW, LF and nodularin in surface and drinking water samples, at sub-ppb levels. The method developed involves the injection of only 1 mL of water sample into the on-line SPE-UHPLC-MS/MS system and allows the rapid determination of the compounds selected (8 min of chromatographic run), avoiding laborious sample treatment. The method was validated in surface and drinking water by means of recovery experiments at 0.25 and 1 MUg L(-1). Average recoveries (n=5) ranged from 71 to 116%, with relative standard deviations (RSDs) lower than 15%. For microcystins LR, RR, YR and nodularin, a third level was also assayed (0.1 MUg L( 1)) obtaining satisfactory data too. Limits of detection between 0.002 and 0.0405 MUg L(-1) were estimated (0.0005 MUg L(-1) for nodularin). The developed method was applied to the analysis of water samples collected in the province of Castellon (Spain). The acquisition of three MS/MS transitions for each compound allowed the unequivocal confirmation of positive samples, which was supported by the accomplishment of ion intensity ratios and retention time when compared with reference standards. PMID- 23107122 TI - Effect of the thermal environment on the efficiency of packed columns in supercritical fluid chromatography. AB - When a packed column is operated at temperatures and pressures near the critical point in supercritical fluid chromatography, the thermal environment in which it is placed has a significant impact on retention and efficiency. We measured the retention factors, plate heights, and related parameters for elution of a test mixture of alkylbenzenes with 5% methanol/95% carbon dioxide mobile phase on a 250 mm * 4.6 mm i.d. column packed with 5-micron Luna-C18 particles. Separations were performed at outlet pressures from 100 to 150 bar and a column oven temperature of 323K. For a bare column thermostated with convective air, significant efficiency losses were observed for outlet pressures equal to or less than 120 bar. These large efficiency losses are attributed to radial temperature gradients. Addition of foam insulation resulted in significant improvements in efficiency. Operating the column in still air using a commercially available column heater provided the best overall performance, with no measurable efficiency loss over the entire range of pressures studied. A reduced plate height of 1.88 was obtained at an optimum flow rate of 3.0 mL/min at 100 bar outlet pressure and with the temperature of the incoming mobile phase set approximately 2.3K above the temperature of the column oven. Retention time repeatability for all three thermal conditions was equal to or less than 0.5% RSD. These results demonstrate that it is possible to perform fast, efficient separations with excellent repeatability using SFC under near-critical conditions if the thermal environment is optimized to minimize the generation of radial temperature gradients. PMID- 23107125 TI - Trade-off between the benefits of lithium treatment and the risk of chronic kidney disease. PMID- 23107123 TI - Medical emergency teams are associated with reduced mortality across a major metropolitan health network after two years service: a retrospective study using government administrative data. AB - INTRODUCTION: Medical emergency teams (MET) are implemented to ensure prompt clinical review of patients with deteriorating physiology with the intention of averting further deterioration, cardiac arrest and death. We sought to determine if MET implementation has led to reductions in hospital mortality across a large metropolitan health network utilising routine administrative data submitted by hospitals to the Department of Health Victoria. METHODS: The Victorian admissions episodes data set (VAED) contains data on all individual hospital separations in the State of Victoria, Australia. After gaining institutional ethics approval, we extracted data on all acute admissions to metropolitan hospitals for which we had information on the presence and timing of a MET system. Using logistic regression we determined whether there was an effect of MET implementation on mortality controlling for age, gender, Charlson comorbidity diagnostic groupings, emergency admission, same day admission, ICU admission, mechanical ventilation, year, indigenous ethnicity, liaison nurse service and hospital designation. RESULTS: 5911533 individual admissions and 73,599 associated deaths from July 1999 to June 2010 were included in the analysis. 52.2% were male and median age was 57(42-72 IQR). Mortality rates for MET and non-MET periods were 3.92 (3.88-3.95 95%CI) and 4.56 (4.51-4.61 95%CI) deaths per 1000 patient days with a rate ratio after adjustment for year of 0.88 (0.86-0.89 95%CI) P < 0.001. In a multivariable logistic regression, mortality was associated with a MET team being active in the hospital for more than 2 years. The odds ratio for mortality in hospitals where a MET system had been in place for greater than 4 years duration was 0.90 (0.88 0.92). Mortality during the first 2 years of a MET system being in place was not statistically different from pre-MET periods. CONCLUSIONS: Utilising routinely collected administrative data we demonstrated that the presence of a hospital MET system for greater than 2 years was associated with an independent reduction in hospital mortality across a major metropolitan health network. Mortality benefits after the introduction of a MET system take time to become apparent. PMID- 23107126 TI - A 61 year diabetic man with methicillin-sensitive Staphylococcus aureus septic arthritis and acute renal failure: a case of IgA-dominant postinfectious glomerulonephritis. PMID- 23107127 TI - Fabry disease and immunoglobulin A nephropathy. PMID- 23107129 TI - Outcomes of percutaneous endoscopic gastrostomy tube insertion in respiratory impaired amyotrophic lateral sclerosis patients under noninvasive ventilation. AB - BACKGROUND: Percutaneous endoscopic gastrostomy (PEG) tube placement in amyotrophic lateral sclerosis (ALS) patients with impaired respiratory function is associated with an increased risk of peri-procedural and post-interventional complications. It was the aim of the study to analyze peri- and post interventional complications and survival after PEG tube placement under noninvasive ventilation (NIV) in ALS patients with various degrees of respiratory impairment. METHODS: Twenty-six subjects were included in this retrospective case study. Prior to PEG tube placement, training with ventilatory support via an oronasal mask was performed with ALS subjects on the pneumology ward. PEG placement was then performed under continuous NIV. FVC, sniff nasal inspiratory pressure, and demographic data were assessed. Complication rates and 1-month and overall survival rates were analyzed. RESULTS: There were no deaths within 24 hours after PEG placement. One subject died within the first month. The mean survival rate after PEG was 12 +/- 10 months (range 0.6-42 months). There was no difference in post-PEG survival between subjects with moderately (> 50%) and severely (< 50%) impaired FVC. CONCLUSIONS: In this case series, PEG tube insertion was associated with minimal peri- and post-procedural complications. The low complication rate might be due to the systematic use of procedural NIV in ALS subjects. PMID- 23107128 TI - The local immune response of mice after Helicobacter suis infection: strain differences and distinction with Helicobacter pylori. AB - Helicobacter (H.) suis colonizes the stomach of pigs and is the most prevalent gastric non-H. pylori Helicobacter species in humans. Limited information is available on host immune responses after infection with this agent and it is unknown if variation in virulence exists between different H. suis strains. Therefore, BALB/c and C57BL/6 mice were used to compare colonization ability and gene expression of various inflammatory cytokines, as determined by real-time PCR, after experimental infection with 9 different H. suis strains. All strains were able to persist in the stomach of mice, but the number of colonizing bacteria at 59 days post inoculation was higher in stomachs of C57BL/6 mice compared to BALB/c mice. All H. suis strains caused an upregulation of interleukin (IL)-17, which was more pronounced in BALB/c mice. This upregulation was inversely correlated with the number of colonizing bacteria. Most strains also caused an upregulation of regulatory IL-10, positively correlating with colonization in BALB/c mice. Only in C57BL/6 mice, upregulation of IL-1beta was observed. Increased levels of IFN-gamma mRNA were never detected, whereas most H. suis strains caused an upregulation of the Th2 signature cytokine IL-4, mainly in BALB/c mice. In conclusion, the genetic background of the murine strain has a clear impact on the colonization ability of different H. suis strains and the immune response they evoke. A predominant Th17 response was observed, accompanied by a mild Th2 response, which is different from the Th17/Th1 response evoked by H. pylori infection. PMID- 23107130 TI - Preparation and evaluation of mesoporous cellular foams coating of solid-phase microextraction fibers by determination of tetrabromobisphenol A, tetrabromobisphenol S and related compounds. AB - Two kinds of mesoporous cellular foams (MCFs), including mesoporous silica materials (MCF-1) and phenyl modified mesoporous materials (Ph-MCF-1), were synthesized and for the first time used as fiber-coating materials for solid phase microextraction (SPME). By using stainless steel wire as the supporting core, four types of fibers were prepared by sol-gel method and immobilized by epoxy-resin method. To evaluate the performance of the home-made fibers for SPME, seven brominated flame retardants (BFRs), including tetrabromobisphenol A (TBBPA), tetrabromobisphenol S (TBBPS) and related compounds were selected as analytes. The main parameters that affect the extraction and desorption efficiencies, such as extraction temperature, extraction time, desorption time, stirring rate and ionic strength of samples were investigated and optimized. The optimized SPME coupled with high performance liquid chromatography (HPLC) was successfully applied to the determination of the seven BFRs in water samples. The linearity range was from 5.0 to 1000 MUg L(-1) for each compound except TBBPS (from 1.0 to 1000 MUg L(-1)), with the correlation coefficients (r(2)) ranging from 0.9993 to 0.9999. The limits of detection of the method were 0.4-0.9 MUg L( 1). The relative standard deviations varied from 1.2 to 5.1% (n=5). The repeatability of fiber-to-fiber and batch-to-batch was 2.5-6.5% and 3.2-6.7%. The recoveries of the BFRs from aqueous samples were in the range between 86.5 and 103.6%. Compared with three commercial fibers (100 MUm PDMS, 85 MUm PA and 65 MUm PDMS/DVB), the MCFs-coated fiber showed about 3.5-fold higher extraction efficiency. PMID- 23107132 TI - Discriminant analysis in the presence of interferences: combined application of target factor analysis and a Bayesian soft-classifier. AB - A method is described for performing discriminant analysis in the presence of interfering background signal. The method is based on performing target factor analysis on a data set comprised of contributions from analyte(s) and interfering components. A library of data from representative analyte classes is tested for possible contributing factors by performing oblique rotations of the principal factors to obtain the best match, in a least-squares sense, between test and predicted vectors. The degree of match between the test and predicted vectors is measured by the Pearson correlation coefficient, r, and the distribution of r for each class is determined. A Bayesian soft classifier is used to calculate the posterior probability based on the distributions of r for each class, which assist the analyst in assessing the presence of one or more analytes. The method is demonstrated by analyses performed on spectra obtained by laser induced breakdown spectroscopy (LIBS). Single and multiple bullet jacketing transfers to steel and porcelain substrates were analyzed to identify the jacketing materials. Additionally, the metal surrounding bullet holes was analyzed to identify the class of bullet jacketing that passed through a stainless steel plate. Of 36 single sample transfers, the copper jacketed (CJ) and non-jacketed (NJ) class on porcelain had an average posterior probability of the metal deposited on the substrate of 1.0. Metal jacketed (MJ) bullet transfers to steel and porcelain were not detected as successfully. Multiple transfers of CJ/NJ and CJ/MJ on the two substrates resulted in posterior probabilities that reflected the presence of both jacketing materials. The MJ/NJ transfers gave posterior probabilities that reflected the presence of the NJ material, but the MJ component was mistaken for CJ on steel, while non-zero probabilities were obtained for both CJ and MJ on porcelain. Jacketing transfer from a bullet to steel as the projectile passed through the steel also proved difficult to analyze. Over 50% of the samples left insufficient transfer to be identified. Transfer from NJ and CJ jacketing was successfully identified by posterior probabilities greater than 0.8. PMID- 23107133 TI - Ultrasensitive one-step rapid detection of ochratoxin A by the folding-based electrochemical aptasensor. AB - A one-step electrochemical aptasensor using the thiol- and methylene blue- (MB-) dual-labeled aptamer modified gold electrode for determination of ochratoxin A (OTA) was presented in this research. The aptamer against OTA was covalently immobilized on the surface of the electrode by the self-assembly effect and used as recognition probes for OTA detection by the binding induced folding of the aptamer. Under the optimal conditions, the developed electrochemical aptasensor demonstrated a wide linear range from 0.1 pg mL(-1) to 1000 pg mL(-1) with the limit of detection (LOD) of 0.095 pg mL(-1), which was an extraordinary sensitivity compared with other common methods for OTA detection. Moreover, as a practical application, this proposed electrochemical aptasensor was used to monitor the OTA level in red wine samples without any special pretreatment and with satisfactory results obtained. Study results showed that this electrochemical aptasensor could be a potential useful platform for on-site OTA measurement in real complex samples. PMID- 23107131 TI - Review on recent advances in the analysis of isolated organelles. AB - The analysis of isolated organelles is one of the pillars of modern bioanalytical chemistry. This review describes recent developments on the isolation and characterization of isolated organelles both from living organisms and cell cultures. Salient reports on methods to release organelles focused on reproducibility and yield, membrane isolation, and integrated devices for organelle release. New developments on organelle fractionation after their isolation were on the topics of centrifugation, immunocapture, free flow electrophoresis, flow field-flow fractionation, fluorescence activated organelle sorting, laser capture microdissection, and dielectrophoresis. New concepts on characterization of isolated organelles included atomic force microscopy, optical tweezers combined with Raman spectroscopy, organelle sensors, flow cytometry, capillary electrophoresis, and microfluidic devices. PMID- 23107134 TI - Layer by layer assembly of catalase and amine-terminated ionic liquid onto titanium nitride nanoparticles modified glassy carbon electrode: study of direct voltammetry and bioelectrocatalytic activity. AB - A novel, simple and facile layer by layer (LBL) approach is used for modification of glassy carbon (GC) electrode with multilayer of catalase and nanocomposite containing 1-(3-Aminopropyl)-3-methylimidazolium bromide (amine terminated ionic liquid (NH(2)-IL)) and titanium nitride nanoparticles (TiNnp). First a thin layer of NH(2)-IL is covalently attached to GC/TiNnp electrode using electro-oxidation method. Then, with alternative self assemble positively charged NH(2)-IL and negatively charged catalase a sensitive H(2)O(2) biosensor is constructed, whose response is directly correlated to the number of bilayers. The surface coverage of active catalase per bilayer, heterogeneous electron transfer rate constant (k(s)) and Michaelis-Menten constant (K(M)) of immobilized catalase were 3.32*10( 12) mol cm(-2), 5.28s(-1) and 1.1 mM, respectively. The biosensor shows good stability, high reproducibility, long life-time, and fast amperometric response with the high sensitivity of 380 MUA mM(-1)cm(-2) and low detection limit of 100 nM at concentration range up to 2.1 mM. PMID- 23107135 TI - Sulfide determination in hydrothermal seawater samples using a vibrating gold micro-wire electrode in conjunction with stripping chronopotentiometry. AB - A rapid electrochemical stripping chronopotentiometric procedure to determined sulfide in unaltered hydrothermal seawater samples is presented. Sulfide is deposited at -0.25 V (vs Ag/AgCl, KCl 3M) at a vibrating gold microwire and then stripped through the application of a reductive constant current (typically -2 MUA). The hydrodynamic conditions are modulated by vibration allowing a short deposition step, which is shown here to be necessary to minimize H(2)S volatilization. The limit of detection (LOD) is 30 nM after a deposition step of 7s. This LOD is in the same range as the most sensitive cathodic voltammetric technique using a mercury drop electrode and is well below those reported previously for other electrodes capable of being implemented in situ. PMID- 23107136 TI - Halogen bonding: a new retention mechanism for the solid phase extraction of perfluorinated iodoalkanes. AB - For the first time, halogen-bonding interaction is utilised in the solid phase extraction of perfluorinated iodoalkane (PFI). Nine PFIs, as model analytes, were tested, and analyses by UV, (19)F NMR and Raman spectroscopies demonstrate that the PFIs are extracted by a strong anion exchange (SAX) sorbent from n-hexane due to the C-I...Cl(-) halogen-bonding interactions. The results also show that the adsorptivities of SAX for the diiodoperfluoro-alkanes (diiodo-PFIs) were much stronger than those for the perfluoroalkyl iodides (monoiodo-PFIs). Specifically, the recoveries for 1,6-diiodoperfluorohexane and 1,8-diiodoperfluorooctane were higher than 80% when 100mL of sample spiked with a 5 ng mL(-1) analyte mixture was extracted. Interestingly, SAX had no adsorption for hexafluorobenzene at all, which is known to be unable to form a halogen bond with Cl(-). The analytical performance of the halogen bond-based SPE-GC-MS method for the diiodo-PFIs was also examined in soil samples. The sorbent SAX enabled the selective extraction of four diiodo-PFIs successfully from soil samples. The recoveries of the diiodo PFIs extracted from 5 g soil sample at the 100 ng g(-1) spike level were in the range of 73.2-93.8% except 26.8% for 1,2-diiodoperfluoroethane. The limit of detection varied from 0.02 to 0.04 ng g(-1) in soil samples. Overall, this work reveals the great application potential of halogen bonding in the field of solid phase extraction to selectively extract compounds with strong halogen-bonding abilities. PMID- 23107137 TI - Determination of hydroxylated metabolites of polycyclic aromatic hydrocarbons in sediment samples by combining subcritical water extraction and dispersive liquid liquid microextraction with derivatization. AB - A sample preparation method for the determination of hydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) in sediment samples was developed using gas chromatography-mass spectrometry (GC-MS). Dispersive liquid-liquid microextraction (DLLME) with derivatization was performed following the subcritical water extraction (SWE) that provided which was provided by accelerated solvent extraction (ASE). Several important parameters that affected both SWE extraction and DLLME, such as the selection of organic modifier, its volume, extraction temperature, extraction pressure and extraction time were also investigated. High sensitivity of the hydroxylated PAHs derivatives by N-(tert butyldimethylsilyl)-N-methyl-trifluoroacetamide (MTBSTFA) could be achieved with the limits of detection (LODs) ranging from 0.0139 (2-OH-nap) to 0.2334 MUg kg( 1) (3-OH-fluo) and the relative standard deviations (RSDs) between 2.81% (2-OH phe) and 11.07% (1-OH-pyr). Moreover, the proposed method was compared with SWE coupled with solid phase extraction (SPE), and the results showed that ASE-DLLME was more promising with recoveries ranging from 57.63% to 91.07%. The proposed method was then applied to determine the hydroxylated metabolites of phenanthrene in contaminated sediments produced during the degradation by two PAH-degraders isolated from mangrove sediments. PMID- 23107138 TI - Highly specific revelation of rat serum glycopeptidome by boronic acid functionalized mesoporous silica. AB - Although the specific profiling of endogenous glycopeptides in serum is highly inclined towards the discovery of disease biomarkers, studies on the endogenous glycopeptides (glycopeptidome) have never been conducted because of several factors. These factors include the high dynamic range of serum proteins, the inadequacy of traditional sample preparation techniques in proteomics for low molecular-weight (LMW) proteins, and the relatively low abundances of glycopeptides. Boronic acid-functionalized mesoporous silica was synthesized in this study to overcome the limitations of the state-of-the-art methods for glycopeptidome research. The boronic acid-functionalized mesoporous silica exhibited excellent selectivity by analyzing glycopeptides in the mixture of glycopeptides/non-glycopeptides at molar ratio of 1:100, extreme sensitivity (the limit of detection was at the fmol level), good binding capacity (40 mg g(-1)), as well as the high post-enrichment recovery of glycopeptides (up to 88.10%). The as-prepared material possessing both glycopeptide-suitable pore size and glycopeptide-specific selectivity has shown special capability for enriching the endogenous glycopeptides. Fifteen unique glycosylation sites mapped to 15 different endogenous glycopeptides were identified in rat serum. The established protocol revealed for the first time the rat serum glycopeptidome. PMID- 23107139 TI - Rapid differentiation of Panax ginseng and Panax quinquefolius by matrix-assisted laser desorption/ionization mass spectrometry. AB - A matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS)-based method has been developed for rapid differentiation between Panax ginseng and Panax quinquefolius, two herbal medicines with similar chemical and physical properties but different therapeutic effects. This method required only a small quantity of samples, and the herbal medicines were analyzed by MALDI-MS either after a brief extraction step, or directly on the powder form or small pieces of raw samples. The acquired MALDI-MS spectra showed different patterns of ginsenosides and small chemical molecules between P. ginseng and P. quinquefolius, thus allowing unambiguous differentiation between the two Panax species based on the specific ions, intensity ratios of characteristic ions or principal component analysis. The approach could also be used to differentiate red ginseng or P. quinquefolius adulterated with P. ginseng from pure P. ginseng and pure Panax quinquefolium. The intensity ratios of characteristic ions in the MALDI-MS spectra showed high reproducibility and enabled quantitative determination of ginsenosides in the herbal samples and percentage of P. quinquefolius in the adulterated binary mixture. The method is simple, rapid, robust, and can be extended for analysis of other herbal medicines. PMID- 23107140 TI - Simple and label-free electrochemical assay for signal-on DNA hybridization directly at undecorated graphene oxide. AB - Exploring graphene oxide (GO), DNA hybridization detection usually relies on either GO decoration or DNA sequences labeling. The former endows GO with desired chemical, optical, and biological properties. The latter adopts labeled molecules to indicate hybridization. In the present work, we propose a simple, label-free DNA assay using undecorated GO directly as the sensing platform. GO is anchored on diazonium functionalized electrode through electrostatic attraction, hydrogen bonding or epoxy ring-opening. The pi-pi stacking interaction between hexagonal cells of GO and DNA base rings facilitates DNA immobilization. The adsorbed DNA sequence is specially designed with two parts, including immobilization sequence and probe sequence. In the absence of target, the two sequences lie nearly flat on GO platform. In the presence of target, probe hybridizes with it to form double helix DNA, which 'stands' on GO. While the immobilization sequence part remains 'lying' on GO surface. Hence, DNA hybridization induces GO interfacial property changes, including negative charge and conformational transition from 'lying' ssDNA to 'standing' dsDNA. These changes are monitored by electrochemical impedance spectroscopy and adopted as the analytical signal. This strategy eliminates the requirement for GO decoration or DNA labeling, representing a comparatively simple and effective way. Finally, the principle is applied to the detection of conserved sequence of the human immunodeficiency virus 1 pol gene fragment. The dynamic detection range is from 1.0*10(-12) to 1.0*10(-6) M with detection limit of 1.1*10(-13) M with 3sigma. And the sequences with double- or four-base mismatched are readily distinguishable. In addition, this strategy may hold great promise for potential applications from DNA biosensing to nanostructure framework construction based on the versatile DNA self-assembly. PMID- 23107141 TI - Capillary electrophoresis of heparin and other glycosaminoglycans using a polyamine running electrolyte. AB - This study involves the use of polyamines as potential resolving agents for the capillary electrophoresis (CE) of glycosaminoglycans (GAGs), specifically heparin, dermatan sulfate, chondroitin sulfate, over-sulfated chondroitin sulfate (OSCS), and hyaluronan. All of the compounds can be separated from each other with the exception of chondroitin sulfate and hyaluronan. Using optimization software, the final run conditions are found to be 200 mM ethylenediamine and 45.5 mM phosphate as the electrolyte with -14 V applied across a 50 MUm ID*24.5 cm fused silica capillary at 15 degrees C. The ion migration order, with OSCS as the last instead of the first peak, is in contrast to previous reports using either a high molarity TRIS or lithium phosphate run buffer with narrower bore capillaries. Total analysis time is 12. 5 min and the relative standard deviation of the heparin migration time is about 2.5% (n=5). The interaction mechanism between selected polyamines and heparin is explored using conductivity measurements in addition to CE experiments to show that an ion-pairing mechanism is likely. PMID- 23107142 TI - Characterization of plasmid burden and copy number in Saccharomyces cerevisiae for optimization of metabolic engineering applications. AB - Many metabolic engineering and genetic engineering applications in yeast rely on the use of plasmids. Despite their pervasive use and the diverse collections available, there is a fundamental lack of understanding of how commonly used DNA plasmids affect the cell's ability to grow and how the choice of plasmid components can influence plasmid load and burden. In this study, we characterized the major attributes of the 2 micron and centromeric plasmids typically used in yeast by examining the impact of choice of selection marker, promoter, origin of replication, and strain ploidy on conferred growth rates and plasmid copy number. We conclude that the 'plasmid burden', as demonstrated by a reduced growth rate, is primarily due to the choice of selection marker, especially when auxotrophic markers are utilized. The plasmid burden traditionally attributed to replication and maintenance of plasmid DNA plays only a minor role in haploid yeast yet is much more significant in diploid strains. The selection marker can also significantly change plasmid copy number. In fact, plasmid copy number can be influenced to some extent by all of the parameters tested. The information presented in this study will allow for more rational design and selection of plasmids for engineering applications. PMID- 23107143 TI - Prevalence of congenital hereditary sensorineural deafness in Australian Cattle Dogs and associations with coat characteristics and sex. AB - BACKGROUND: Congenital hereditary sensorineural deafness (CHSD) occurs in many dog breeds, including Australian Cattle Dogs. In some breeds, CHSD is associated with a lack of cochlear melanocytes in the stria vascularis, certain coat characteristics, and potentially, abnormalities in neuroepithelial pigment production. This study investigates phenotypic markers for CHSD in 899 Australian Cattle Dogs. RESULTS: Auditory function was tested in 899 Australian Cattle Dogs in family groups using brainstem auditory evoked response testing. Coat colour and patterns, facial and body markings, gender and parental hearing status were recorded.Deafness prevalence among all 899 dogs was 10.8% with 7.5% unilaterally deaf, and 3.3% bilaterally deaf, and amongst pups from completely tested litters (n = 696) was 11.1%, with 7.5% unilaterally deaf, and 3.6% bilaterally deaf.Univariable and multivariable analyses revealed a negative association between deafness and bilateral facial masks (odds ratio 0.2; P <= 0.001). Using multivariable logistic animal modelling, the risk of deafness was lower in dogs with pigmented body spots (odds ratio 0.4; P = 0.050).No significant associations were found between deafness and coat colour.Within unilaterally deaf dogs with unilateral facial masks, no association was observed between the side of deafness and side of mask. The side of unilateral deafness was not significantly clustered amongst unilaterally deaf dogs from the same litter. Females were at increased risk of deafness (odds ratio from a logistic animal model 1.9; P = 0.034) after adjusting for any confounding by mask type and pigmented body spots. CONCLUSIONS: Australian Cattle Dogs suffer from CHSD, and this disease is more common in dogs with mask-free faces, and in those without pigmented body patches. In unilaterally deaf dogs with unilateral masks, the lack of observed association between side of deafness and side of mask suggests that if CHSD is due to defects in molecular pigment pathways, the molecular control of embryonic melanoblast migration from ectoderm to skin differs from control of migration from ectoderm to cochlea. In Australian Cattle Dogs, CHSD may be more common in females. PMID- 23107144 TI - Regarding "Aberrant origin of the long head of the biceps: a case series". PMID- 23107145 TI - Midterm results of a total shoulder prosthesis fixed with a cementless glenoid component. AB - BACKGROUND: The aim of this study was to evaluate the midterm results and complications of a total shoulder arthroplasty implanted with a metal-backed, bone-ingrowth glenoid component. MATERIALS AND METHODS: In total, 62 patients (65 shoulders) diagnosed with primary osteoarthritis were treated with total shoulder arthroplasty with a cementless glenoid component. The mean age was 66 years (range, 54-85 years). Fifty-three patients were evaluated after a mean of 64 months (range, 26-85 months). Functional results were documented by use of the age- and sex-adjusted Constant score. Radiolucent line (RLL) assessment of the glenoid component was performed by use of true anteroposterior and axillary views. RESULTS: The Constant score improved significantly from 49% preoperatively to 89.8% postoperatively (P < .0001). Active range of motion improved significantly for flexion (from 118 degrees to 146 degrees ), abduction (from 87 degrees to 133 degrees ), and external rotation (from 21 degrees to 44 degrees ) (P < .0001). In 3 cases (5.7%), RLLs of 1 mm or less were present, and 1 case (1.8%) had an RLL of 2 mm or less in 1 zone. Glenoid component loosening occurred in 5 cases (9.4%) because of breakage of the cage screw. Four of these patients presented preoperatively with a type B1 glenoid and one patient with type A2. Two of the patients who underwent revision also had a complete tear of the rotator cuff. The revision rate was 11.3% (6 patients) after a mean of 68 months. CONCLUSION: After midterm follow-up, clinical outcomes of patients operated on with a cementless, metal-backed glenoid implant improved significantly. However, an unacceptable rate of complications and revisions was found. Glenoid loosening predominantly occurred in patients with preoperative eccentric glenoid morphology and was also related to cranial migration of the proximal humerus during the follow-up period. PMID- 23107146 TI - Regarding "Diagnostic accuracy of five orthopedic clinical tests for diagnosis of superior labrum anterior posterior (SLAP) lesions". PMID- 23107147 TI - The shoulder remplissage procedure for Hill-Sachs defects: does technique matter? AB - BACKGROUND: This biomechanical study evaluated the effects of 3 remplissage techniques on shoulder stability and motion in a Hill-Sachs (HS) instability model. MATERIALS AND METHODS: Cadaveric forequarters were tested on an active shoulder simulator. Three remplissage techniques were performed for 15% and 30% HS defects. Testing conditions included intact and 15% and 30% HS defects, and the 3 remplissage techniques: T1, anchors in the defect valley; T2, anchors in humeral head rim; and T3, anchors in valley with medial suture placement. Outcomes included stability, internal-external rotation range of motion (IE-ROM), and joint stiffness. RESULTS: All remplissage techniques improved shoulder stability. In 15% HS defects tested in adduction, T3 significantly reduced IE-ROM (P = .037), whereas T1 and T2 did also (mean IE-ROM reductions: T1, 14 degrees ; T2, 11 degrees ; T3, 21 degrees ), but not to significance (P >= .088). In abduction, no significant reductions in IE-ROM occurred (P >= .060). In 30% HS defects tested in adduction (mean reduction IE-ROM: T1, 11 degrees ; T2, 19 degrees ; T3, 28 degrees ) and abduction (mean reduction: T1, 9 degrees ; T2, 15 degrees ; T3, 21 degrees ), all techniques significantly reduced IE-ROM (P <= .046). All techniques increased joint stiffness from 100% to 320% beyond the Bankart repair alone. A significant increase in joint stiffness was observed for T3 compared with the 30% HS group (P = .004), whereas T2 trended toward an increase (P = .078). There was no significant increase in joint stiffness with T1 (P = .249). CONCLUSIONS: All remplissage techniques enhanced shoulder stability, restricted ROM, and increased joint stiffness. No significant differences were found between anchors placed in the valley (T1) vs those placed in the humeral head rim (T2). Medial suture placement (T3) resulted in the greatest joint stiffness values and mean restriction in motion. PMID- 23107148 TI - Iodine deficiency and subclinical hypothyroidism are common in cystic fibrosis patients. AB - BACKGROUND: Disorders of thyroid function have been inconsistently described in cystic fibrosis (CF) patients and in CF transmembrane regulator protein knockout animals. The literature lacks reports on iodine status of CF individuals. We hypothesize, that iodine deficiency is common in CF and account for abnormal thyroid function in CF patients. METHODS: We investigated 129 children, adolescents, and adults with CF, who were living in the northern part of Bavaria/Germany. Malnutrition and lung function were analyzed. Urinary iodine excretion, TSH (thyroid-stimulating hormone), and ft4 (free thyroxine) were measured and set in relation to population-based, age-adjusted reference ranges. RESULTS: Subclinical hypothyroidism (normal fT4, elevated TSH) was found in 11.6% of subjects, and iodine deficiency in 83.7%. No correlations were found with age, BMI, status of malnutrition, or lung function. CONCLUSION: Dramatic iodine deficiency was found in our cohort of CF patients. This condition can cause subclinical hypothyroidism; therefore, an individual iodine supplementation program is necessary and should be started immediately. PMID- 23107149 TI - Exploring autism research collaboration between Japan and United States Joint Academic Conference on Autism Spectrum Disorders, December, 2011. PMID- 23107150 TI - Activated hepatic stellate cells mediate the differentiation of macrophages. AB - AIM: Liver macrophages play integral roles in both the progression and resolution of hepatic inflammation and fibrosis, comprising opposing functions that largely coincide with the activation state of nearby hepatic stellate cells (HSC). While cross-talk between HSC and macrophages may be essential at various stages of inflammation and fibrogenesis, many facets of this interaction have yet to be thoroughly explored. Here, we examine the potential roles of HSC-derived signaling molecules as mediators of liver macrophage differentiation. METHODS: Human peripheral blood mononuclear cells (PBMC) were differentiated to macrophages in the presence or absence of cultured HSC-derived conditioned media. The phenotype of resulting macrophages was characterized by examination of cell surface marker expression, antigen-presenting capabilities and cytokine secretion. RESULTS: Conditioned media from activated human HSC promoted the differentiation of a unique set of macrophages that differed in morphology and function from both classical (M1) and alternative (M2) macrophages, expressing increased levels of CD14 and CD16, as well as a distinct interleukin (IL)-6(high) /IL-10(low) /transforming growth factor (TGF)-beta(high) expression profile. These macrophages expressed high levels of CD206, CD209, CD80 and human leukocyte antigen DR, though no significant increases in antigen presentation were apparent. HSC-derived macrophages exhibited specific activation of p38 mitogen activated protein kinase, and inhibition of this activation by p38 inhibitors during differentiation effectively reversed increases in IL-6 and TGF-beta. CONCLUSION: The present results suggest that HSC-derived signaling molecules promote differentiation of liver macrophages with both pro-inflammatory and profibrotic functions. Furthermore, these effects appear to be mediated, at least partially, in a p38-dependent manner. PMID- 23107151 TI - Anaphylaxis caused by hidden soybean allergens in pillows. PMID- 23107152 TI - Aberrant glycosylation of IgA in Wiskott-Aldrich syndrome and X-linked thrombocytopenia. PMID- 23107153 TI - Carbon nanotubes functionalized with sodium hyaluronate restore bone repair in diabetic rat sockets. AB - OBJECTIVE: We evaluated the effects of sodium hyaluronate (HY) and carbon nanotubes functionalized with HY (HY-CNT) on bone repair in the tooth sockets of diabetic rats. MATERIALS AND METHODS: Diabetes was induced by streptozotocin (50 mg kg(-1) i.v.), and the sockets were divided into normal control, diabetic control, diabetic treated with HY (1%), and diabetic treated with HY-CNT (100 MUg ml(-1)) groups. The sockets were analyzed according to the percentage of bone formation and the number of cell nuclei. RESULTS: The percentage of bone trabeculae was lower in diabetic control animals (11.16 +/- 5.10% vs 41.92 +/- 6.34% in normal animals) after 14 days. Treating diabetic animals with HY or HY CNT significantly increased the percentage of neoformed trabeculae (HY: 29.43 +/- 3.29%; HY-CNT: 36.90 +/- 3.07%). Moreover, the sockets of diabetic animals had an increased number of cell nuclei and HY or HY-CNT reduced this parameter. CONCLUSION: Our results indicate that HY and HY-CNT restore bone repair in the tooth sockets of diabetic rats, suggesting that these biomaterials are potential adjuvant therapies for the management of diabetes. PMID- 23107154 TI - Expression patterns of epithelial-mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy. AB - OBJECTIVE: To analyse the expression patterns of multiple molecular markers implicated in epithelial-mesenchymal transition (EMT) in localized prostate cancer (PC), in order to clarify the significance of these markers in patients undergoing radical prostatectomy (RP). PATIENTS AND METHODS: Expression levels of 13 EMT markers, namely E-cadherin, N-cadherin, beta-catenin, gamma-catenin, fibronectin, matrix metalloproteinase (MMP) 2, MMP-9, Slug, Snail, Twist, vimentin, ZEB1 and ZEB2, in RP specimens from 197 consecutive patients with localized PC were evaluated by immunohistochemical staining. RESULTS: Of the 13 markers, expression levels of E-cadherin, Snail, Twist and vimentin were closely associated with several conventional prognostic factors. Univariate analysis identified these four EMT markers as significant predictors for biochemical recurrence (BR), while serum prostate-specific antigen, Gleason score, seminal vesicle invasion (SVI), surgical margin status (SMS) and tumour volume were also significant. Of these significant factors, expression levels of Twist and vimentin, SVI and SMS appeared to be independently related to BR on multivariate analysis. There were significant differences in BR-free survival according to positive numbers of these four independent factors. That is, BR occurred in four of 90 patients who were negative for risk factors (4.4%), 21 of 83 positive for one or two risk factors (25.3%) and 19 of 24 positive for three or four risk factors (79.2%). CONCLUSION: Measurement of expression levels of potential EMT markers, particularly Twist and vimentin, in RP specimens, in addition to conventional prognostic parameters, would contribute to the accurate prediction of the biochemical outcome in patients with localized PC following RP. PMID- 23107155 TI - Case report: When measured free T4 and free T3 may be misleading. Interference with free thyroid hormones measurements on Roche(r) and Siemens(r) platforms. AB - : A 59-year old female patient presented with apathy and 6 kg weight gain. Investigations revealed severe primary hypothyroidism (TSH>100 MUIU/ml). L thyroxine (L-T4) was started and titrated up to 75 MUg, once daily, with clinical improvement. Other investigations revealed very high titres of anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies. After three months, there was a fall in TSH to 12.74 MUIU/ml, however, with unexpectedly high free T4 (FT4) - 6.8 ng/ml and free T3 (FT3) - 6.7 pg/ml concentrations [reference range (rr): 0.8-1.9 ng/ml and 1.5-4.1 pg/ml (Siemens(r)), respectively]. At this stage L-T4 was stopped, and this was followed by a rapid increase in TSH (to 77.76 MUIU/ml) and some decrease in FT4 and FT3, however FT4 concentration remained elevated (2.1 ng/ml). Following this, L-T4 was restarted. On admission to our Department, she was clinically euthyroid on L-T4, 88 MUg, once daily. Investigations on Roche(r) platform confirmed mildly elevated TSH - 5.14 (rr: 0.27-4.2 MUIU/ml) with high FT4 [4.59 (rr: 0.93-1.7 ng/ml)] and FT3 [4.98 (rr: 2.6-4.4 pg/ml)] concentrations. Other tests revealed hypoechogenic ultrasound pattern typical for Hashimoto thyroiditis. There was no discrepancy in calculated TSH value following TSH dilution (101% recovery). Concentrations of FT4 and FT3 were assessed on the day of discontinuation of L-T4 and after four days by the means of Abbott(r) Architect I 1000SR platform. These revealed FT4 and FT3 concentrations within the reference range [e.g., FT4 - 1.08 ng/ml (rr: 0.7-1.48)] vs 4.59 ng/ml (rr: 0.93-1.7, Roche(r)), FT3 - 3.70 pg/ml (rr: 1.71-3.71) vs 4.98 (rr: 2.6-4.4, Roche(r))], confirming assay interference. Concentrations of ferritin and SHBG were normal. CONCLUSIONS: Clinicians must be aware of possible assay interference, including the measurements of FT4 and FT3 in the differential diagnosis of abnormal results of thyroid function tests that do not fit the patient clinical presentation. PMID- 23107157 TI - Effects of chimeric decoy oligodeoxynucleotide in the regulation of transcription factors NF-kappaB and Sp1 in an animal model of atherosclerosis. AB - Atherosclerosis is a multifactorial and progressive disease in which the inflammatory reaction and inflammation-related factors play important roles at all stages. Modulation of NF-kappaB and Sp1 expression may be important targets for the prevention and treatment of atherosclerotic vascular disease. To develop a novel therapeutic approach in atherosclerosis, we examined the simultaneous suppression of the transcription factors NF-kappaB and Sp1 which regulate inflammation. We employed chimeric decoy oligodeoxynucleotide (ODN) containing the consensus of NF-kappaB and Sp1-binding sites to suppress these transcription factors simultaneously and to test chimeric decoy for anti-atherogenic effects in an atherogenic diet-induced atherosclerotic mouse model with inflammatory stimulation. C57BL/6 mice were fed with an atherogenic diet (15% fat, 1.25% cholesterol and 0.5% cholic acid) for 12 weeks to induce atherosclerosis; lipopolysaccharide (LPS, 2 mg/kg) was intraperitoneally injected in the first week of study to simulate underlying infectious burden during development of atherosclerosis. Decoy ODNs were injected into tail vein at 2, 4, 6, 8, 10 and 12 weeks after only three LPS injections in mice fed the atherogenic diet. Chimeric decoy ODN alleviated atherosclerotic changes and reduced serum cholesterol and inflammatory cytokines. In accordance with these results, the expressions of atherosclerotic markers were inhibited by chimeric decoy ODN. Chimeric decoy ODN modulates multiple pathogenic aspects of an atherogenic diet-induced atherosclerosis with inflammatory stimulation: hypercholesterolaemia and inflammation. Therefore, this study demonstrates the efficacy of chimeric decoy ODN on atherosclerosis with immunological complication. PMID- 23107158 TI - Severe form of encephalopathy associated with 2009 pandemic influenza A (H1N1) in Japan. AB - BACKGROUND: Every year, an estimated 200-500 children in Japan develop influenza associated encephalopathy (IAE), and 10-30% of these children die. OBJECTIVE: To clarify the clinical features of a severe form of acute encephalopathy seen with 2009 pandemic influenza A (H1N1). STUDY DESIGN: This retrospective survey examined 20 children with acute encephalopathy associated with the 2009 pandemic influenza A (H1N1) who died or were in a prolonged deep coma with a flat electroencephalogram tracing and loss of spontaneous respiration. We obtained demographic, clinical, laboratory, and neuroimaging data through interviews with the attending physicians and chart reviews. RESULTS: Subjects were 13 boys and seven girls. Their median age was 45 (range 11-200) months. Five patients had one or more pre-existing conditions. Acute encephalopathy developed within 2 days after influenza onset in 16 patients. As the initial neurological symptom, delirious behavior was seen in six children, and brief seizures in six. Eighteen patients were comatose within 6h of the onset of encephalopathy. Marked brain edema on computed tomography (CT) was seen in all but one patient. Brainstem lesions on CT were recognized in 12 patients. Sixteen patients died 0-45 (median 2.5) days after the onset of acute encephalopathy, and the others remained in deep comas without spontaneous respiration. CONCLUSIONS: The clinical course of the patients was characterized by an onset with mild neurological symptoms and rapid deterioration of consciousness into coma. Head CT revealed marked cerebral edema, often associated with brainstem lesions. PMID- 23107159 TI - Wave reflection quantification based on pressure waveforms alone--methods, comparison, and clinical covariates. AB - Within the last decade the quantification of pulse wave reflections mainly focused on measures of central aortic systolic pressure and its augmentation through reflections based on pulse wave analysis (PWA). A complementary approach is the wave separation analysis (WSA), which quantifies the total amount of arterial wave reflection considering both aortic pulse and flow waves. The aim of this work is the introduction and comparison of aortic blood flow models for WSA assessment. To evaluate the performance of the proposed modeling approaches (Windkessel, triangular and averaged flow), comparisons against Doppler measurements are made for 148 patients with preserved ejection fraction. Stepwise regression analysis between WSA and PWA parameters are performed to provide determinants of methodological differences. Against Doppler measurement mean difference and standard deviation of the amplitudes of the decomposed forward and backward pressure waves are comparable for Windkessel and averaged flow models. Stepwise regression analysis shows similar determinants between Doppler and Windkessel model only. The results indicate that the Windkessel method provides accurate estimates of wave reflection in subjects with preserved ejection fraction. The comparison with waveforms derived from Doppler ultrasound as well as recently proposed simple triangular and averaged flow waves showed that this approach may reduce variability and provide realistic results. PMID- 23107160 TI - Mathematical modelling of the lower urinary tract. AB - The lower urinary tract is one of the most complex biological systems of the human body as it involved hydrodynamic properties of urine and muscle. Moreover, its complexity is increased to be managed by voluntary and involuntary neural systems. In this paper, a mathematical model of the lower urinary tract it is proposed as a preliminary study to better understand its functioning. Furthermore, another goal of that mathematical model proposal is to provide a basis for developing artificial control systems. Lower urinary tract is comprised of two interacting systems: the mechanical system and the neural regulator. The latter has the function of controlling the mechanical system to perform the voiding process. The results of the tests reproduce experimental data with high degree of accuracy. Also, these results indicate that simulations not only with healthy patients but also of patients with dysfunctions with neurological etiology present urodynamic curves very similar to those obtained in clinical studies. PMID- 23107161 TI - Problems with sex among gay and bisexual men with diagnosed HIV in the United Kingdom. AB - BACKGROUND: A significant research literature exists that details the sexual health and sexual behaviour of gay and bisexual men who have diagnosed HIV. However, much of this research has focussed on HIV transmission risk behaviours among this group, rather than seeking to understand their sexual health and sexual well-being more broadly. There have been growing calls for interventions to support people with diagnosed HIV to achieve health and well-being, including sexual health and well-being. A detailed understanding of the problems people in this group face, and how they might be overcome, is required to facilitate such interventions. METHODS: One thousand two hundred and seventeen gay and bisexual men with diagnosed HIV were recruited by convenience sampling through charitable AIDS service organisations, genitourinary medicine clinics and local authority agencies to complete a survey of their health and social care needs. Respondents were asked to report any problems they had with regards to sex during the 12 months prior to survey completion. They were also asked to describe what support might help them to overcome any problems they experienced. RESULTS: Overall, 70.5% of the gay and bisexual men with diagnosed HIV completing the survey reported one or more problems with sex within the previous 12 months. Most commonly reported problems include loss of libido (44.0%, n=540), poor self-image or low self confidence (43.9%, n=534), worries about passing HIV to potential sexual partners (37.3%, n=454), and fears of rejection from sexual partners (34.7%, n=422). Responses varied according to age, time since diagnosis, and whether or not the respondent was currently taking anti-retroviral therapy. Qualitative analysis of data relating to what support might help men overcome problems with sex indicate a need for therapeutic support to increase self esteem and confidence, clarity on criminalisation of HIV transmission, the tackling of HIV related stigma and help to achieve a higher quality (as opposed to quantity) of sex. CONCLUSIONS: The findings indicate a need for the maintenance and expansion of services to meet the significant needs of people with diagnosed HIV, especially as these intersect with their ability to negotiate sex that is satisfying. PMID- 23107163 TI - Partial nephrectomy online: a preliminary evaluation of the quality of health information on the internet. PMID- 23107162 TI - Evaluation of the malaria rapid diagnostic test SDFK90: detection of both PfHRP2 and Pf-pLDH. AB - BACKGROUND: Rapid diagnosis of Plasmodium falciparum infections is important because of the potentially fatal complications. SDFK90 is a recently marketed malaria rapid diagnostic test (RDT) targeting both histidine-rich protein 2 (PfHRP2) and P. falciparum-specific Plasmodium lactate dehydrogenase (Pf-pLDH). The present study evaluated its diagnostic accuracy. METHODS: SDFK90 was tested against a panel of stored whole blood samples (n= 591) obtained from international travellers suspected of malaria, including the four human Plasmodium species and Plasmodium negative samples. Microscopy was used as a reference method, corrected by PCR for species diagnosis. In addition, SDFK90 was challenged against 59 P. falciparum samples with parasite density >=4% to assess the prozone effect (no or weak visible line on initial testing and a higher intensity upon 10-fold dilution). RESULTS: Overall sensitivity for the detection of P. falciparum was 98.5% and reached 99.3% at parasite densities >100/MUl. There were significantly more PfHRP2 lines visible compared to Pf-pLDH (97.3% vs 86.9%), which was mainly absent at parasite densities <100/MUl. Specificity of SDFK90 was 98.8%. No lot-to-lot variability was observed (p = 1.00) and test results were reproducible. A prozone effect was seen for the PfHRP2 line in 14/59 (23.7%) P. falciparum samples tested, but not for the Pf-pLDH line. Few minor shortcomings were observed in the kit's packaging and information insert. CONCLUSIONS: SDFK90 performed excellent for P. falciparum diagnosis. The combination of PfHRP2 and Pf-pLDH ensures a low detection threshold and counters potential problems of PfHRP2 detection such as gene deletions and the prozone effect. PMID- 23107164 TI - Overattachment and perceived disability in chronic migraineurs. AB - OBJECTIVES: The aim of this cross-sectional study was to assess whether stagnation dimensions and depression were associated with perceived disability in chronic migraineurs. METHODS: Participants were 69 consecutive adult outpatients admitted to the Regional Referral Headache Centre of the Sant'Andrea Hospital in Rome, Italy. Patients were administered the Center for Epidemiologic Studies Depression Scale, the Stagnation Scale, and the Italian Perceived Disability Scale. They also compiled a headache diary to compute headache frequency. RESULTS: Patients with higher perceived disability (compared to patients with lower perceived disability) reported higher depression and higher symptoms of stagnation. The effect of Overattachment, a dimension of the Stagnation Scale, on perceived disability was only in part mediated by the severity of depressive symptoms. CONCLUSION: Our results confirm that many patients with chronic migraine report symptoms of stagnation, and that investigating the presence of the stagnation syndrome may be useful for understanding the psychology of chronic migraineurs. PMID- 23107165 TI - Comparison of lumbar drainage and external ventricular drainage for clearance of subarachnoid clots after Guglielmi detachable coil embolization for aneurysmal subarachnoid hemorrhage. AB - OBJECTIVE: Subarachnoid clots play an important role in development of delayed vasospasm after subarachnoid hemorrhage (SAH). The purpose of this study was to compare clearance of subarachnoid clots using external ventricular drainage (EVD) or lumbar drainage (LD) after Guglielmi detachable coil (GDC) embolization for aneurysmal SAH. METHODS: The subjects were 51 treated with GDC coil embolization for aneurysmal Fisher group 3 SAH within 72 h of ictus. Software-based volumetric quantification of the subarachnoid clots was performed on CT scans and the hemoglobin (Hb) level was measured in CSF drained from each catheter. RESULTS: Clearance of subarachnoid clots was more rapid in patients treated with LD (n=34) compared to those treated with EVD (n=17). The Hb level in CSF was significantly higher in the LD group on Days 4-5 after onset of SAH (P<0.05), but was higher in the EVD group on Days 8-9. The incidence of symptomatic vasospasm did not differ between the two groups. The rate of occurrence of a new low density area on CT scans was higher in patients treated with EVD, but not significantly higher than the rate in the LD group. CONCLUSION: GDC embolization followed by lumbar drainage accelerates the reduction of subarachnoid clots, but EVD may contribute to stasis of hemorrhage within subarachnoid spaces. PMID- 23107166 TI - Computed tomography imaging for Mycobacterium xenopi infections, a clearer path for diagnosis? PMID- 23107168 TI - Detecting adsorption space in carbon nanotubes by benzene uptake. AB - Experimental results of benzene and nitrogen adsorption from gaseous phase and benzene adsorption and kinetics of the process from aqueous solution, measured on a series of eight commercial closed carbon nanotubes, are presented. Additionally we show the results of adsorption on compressed nanotubes. Using simple analytical approach and the analysis of adsorption and kinetics results it is concluded that in the "architecture" of nanotubes very important role has been played by isolated nanotubes. PMID- 23107169 TI - Brucella abortus induces intracellular retention of MHC-I molecules in human macrophages down-modulating cytotoxic CD8(+) T cell responses. AB - Brucella abortus elicits a vigorous Th1 immune response which activates cytotoxic T lymphocytes. However, B. abortus persists in its hosts in the presence of CD8(+) T cells, establishing a chronic infection. Here, we report that B. abortus infection of human monocytes/macrophages inhibited the IFN-gamma-induced MHC-I cell surface expression. This phenomenon was dependent on metabolically active viable bacteria. MHC-I down-modulation correlated with the development of diminished CD8(+) cytotoxic T cell response as evidenced by the reduced expression of the activation marker CD107a on CD8(+) T lymphocytes and a diminished percentage of IFN-gamma-producing CD8(+) T cells. Inhibition of MHC-I expression was not due to changes in protein synthesis. Rather, we observed that upon B. abortus infection MHC-I molecules were retained within the Golgi apparatus. Overall, these results describe a novel mechanism based on the intracellular sequestration of MHC-I molecules whereby B. abortus would avoid CD8(+) cytotoxic T cell responses, evading their immunological surveillance. PMID- 23107167 TI - Polymorphic variants in exon 8 at the 3' UTR of the HLA-G gene are associated with septic shock in critically ill patients. AB - INTRODUCTION: Critically ill patients are characterized as individuals hospitalized in the Intensive Care Unit (ICU) and can evolve to sepsis, septic shock or even death. Among others, genetic factors can influence the outcome of critically ill patients. HLA-G is a non-classical class Ib molecule that has limited protein variability, presenting seven isoforms generated by alternative splicing, and presents immunomodulatory properties. Polymorphisms at the 3'UTR are thought to influence HLA-G gene expression. It was previously observed that increased sHLA-G5 levels were predictive of survival among septic shock patients. We assessed the frequencies of 7 polymorphisms in exon 8 at the 3' UTR of HLA-G and associated these variants with different clinical outcomes in critically ill patients. METHODS: Exon 8 at the 3' UTR of the HLA-G gene from 638 critically ill subjects was amplified by PCR and sequenced. Genotypes were identified using FinchTV software v.1.4.0 and the most probable haplotype constitution of each sample was determined by PHASE software v.2.1. Haplotype frequencies, linkage disequilibrium, heterozygosity test and Hardy-Weinberg Equilibrium were estimated using ARLEQUIN software v.3.5. RESULTS: Among all critically ill patients, an association between carriers of the +2960IN_+3142 G_+3187A haplotype and septic shock (P = 0.047) was observed. Septic patients who carried the +2960IN_+3142G_+3187A haplotype presented an increased risk for septic shock (P = 0.031). CONCLUSIONS: The present study showed, for the first time, an association between polymorphisms in exon 8 at the 3 'UTR of HLA-G gene and outcomes of critically ill patients. These results may be important for understanding the mechanisms involved in evolution to septic shock in critically ill patients. PMID- 23107171 TI - Reduced contrast medium in abdominal aorta CTA using a multiphasic injection technique. AB - PURPOSE: The purpose of this study was to determine if with a multiphasic injection technique the administered amount of contrast medium for abdominal computerized tomographic angiography (CTA) can be decreased, whilst improving CT image quality. MATERIALS AND METHODS: In 30 patients a multiphasic injection method was compared to the standard uniphasic contrast medium injection protocol. Fifteen patients underwent abdominal CTA with a standard uniphasic injection protocol (protocol I) receiving 100mL of a non-ionic radiopaque contrast agent (Ioversol). The second group of 15 patients underwent CTA with a multiphasic injection protocol (protocol II) receiving a total of 89 mL Ioversol. Vascular contrast enhancement and difference in enhancement uniformity were assessed quantitatively and image quality was assessed by three independent radiologists. RESULTS: Quantitative assessment of the vascular contrast enhancement showed that there was no significant difference in enhancement uniformity for patients between the protocols. The image quality was rated as being good to excellent in 81.8% and 88.0% of the scans, for protocol I and protocol II, respectively. However these differences were not statistically significant. CONCLUSION: By using a multiphasic injection technique with CTA of the abdominal aorta a reduction of 11 percent of contrast medium can be realized. Enhancement patterns are quantitatively as well as qualitatively comparable to the standard contrast medium injection protocol. PMID- 23107170 TI - Adjuvant and immunostimulatory effects of a D-galactose-binding lectin from Synadenium carinatum latex (ScLL) in the mouse model of vaccination against neosporosis. AB - Vaccination is an important control measure for neosporosis that is caused by a coccidian parasite, Neospora caninum, leading to abortion and reproductive disorders in cattle and serious economic impacts worldwide. A D-galactose-binding lectin from Synadenium carinatum latex (ScLL) was recently described by our group with potential immunostimulatory and adjuvant effects in the leishmaniasis model. In this study, we evaluated the adjuvant effect of ScLL in immunization of mice against neosporosis. First, we investigated in vitro cytokine production by dendritic cells stimulated with Neospora lysate antigen (NLA), ScLL or both. Each treatment induced TNF-alpha, IL-6, IL-10 and IL-12 production in a dose-dependent manner, with synergistic effect of NLA plus ScLL. Next, four groups of C57BL/6 mice were immunized with NLA + ScLL, NLA, ScLL or PBS. The kinetics of antibody response showed a predominance of IgG and IgG1 for NLA + ScLL group, whereas IgG2a response was similar between NLA + ScLL and NLA groups. Ex vivo cytokine production by mouse spleen cells showed the highest IFN-gamma/IL-10 ratio in the presence of NLA stimulation for mice immunized with NLA + ScLL and the lowest for those immunized with ScLL alone. After parasite challenge, mice immunized with NLA + ScLL or ScLL alone presented higher survival rates (70-80%) and lower brain parasite burden as compared to PBS group, but with no significant changes in morbidity and inflammation scores. In conclusion, ScLL combined with NLA was able to change the cytokine profile induced by the antigen or lectin alone for a Th1 biased immune response, resulting in high protection of mice challenged with the parasite, but with low degree of inflammation. Both features may be important to prevent congenital neosporosis, since protection and low inflammatory response are necessary events to guide towards a successful pregnancy. PMID- 23107172 TI - A practical MRI grading system for osteoarthritis of the knee: association with Kellgren-Lawrence radiographic scores. AB - PURPOSE: To propose a reproducible and constant MR grading system for osteoarthritis of the knee joint that provides high interobserver and intraoberver agreement and that does not require complicated calculation procedures. MATERIALS AND METHODS: This retrospective study sample included 44 men and 65 women who underwent both MRI and plain radiography of the knee at our institution. All patients were older than 50 years of age (mean 57.7) and had clinically suspected osteoarthritis of the knee. The standard of 4 grades on the MR grade scale was based mainly on cartilage injury and additional findings. Kellgren-Lawrence grades were assessed for the same patient group. The relationship between the results was determined. Statistical analyses were performed including kappa statistics, categorical regression analysis and nonparametric correlation analysis. RESULTS: The interobserver and intraoberver agreements between the two readers in the grading of osteoarthritis were found to be almost perfect. Interobserver and intraobserver agreements were slightly lower for the MR grading system than for the Kellgren-Lawrence grading scale. The correlation between the MR grade and Kellgren-Lawrence grade was very high and did not differ with patient age. The MR grades were highly correlated with the Kellgren-Lawrence grades and showed excellent interobserver and intraobserver agreements. CONCLUSION: This new MR grading system for osteoarthritis of the knee joint is reproducible and may be helpful for the grading of osteoarthritis of the knee without requiring reference to plain radiography. PMID- 23107173 TI - Albuterol delivery by 4 different nebulizers placed in 4 different positions in a pediatric ventilator in vitro model. AB - BACKGROUND: The type of aerosol generator and the position in the ventilator circuit are crucial to determine aerosol delivery during mechanical ventilation. We compared lung deposition of albuterol aerosols generated by 4 different nebulizers placed in-line in 4 different positions in a pediatric ventilator model. METHODS: Two brands of continuously operated jet nebulizer (6 L/ min, oxygen), an ultrasonic, and a vibrating mesh were compared when placed at the ventilator, the humidifier, the Y-piece, and 30 cm before the Y-piece. The jet, ultrasonic, and vibrating mesh nebulizers were operated for 5, 15, and 15 min, respectively. The tested solutions contained 2.5 mg, 5.0 mg, and 7.5 mg of albuterol sulfate. The ventilator settings were: pressure-regulated volume control mode, tidal volume 200 mL, breathing frequency 20 breaths/min, PEEP 5 cm H2O, FIO2 0.4, inspiratory time 0.75 s, bias flow 2 L/min, and heater 37 degrees C. The circuit was connected in series to a 5.5 mm cuffed endotracheal tube, a deposition filter, and a lung model. Albuterol was measured by spectrophotometry. RESULTS: Intra-device comparison: the jet and vibrating mesh nebulizers performed best at either the ventilator or humidifier, and worst at the Y-piece. The ultrasonic nebulizer performed best at the humidifier and worst at the Y-piece. Inter-device comparison: the vibrating mesh nebulizer outperformed both jet nebulizers at all tested positions, and the ultrasonic nebulizer when placed at either the ventilator or the humidifier. Lung deposition increased for the jet and ultrasonic nebulizers, but not for vibrating mesh nebulizer, when increasing the loading volume while maintaining the nominal dose. CONCLUSIONS: The vibrating mesh nebulizer was the most efficient device. The nebulizers were more efficient when placed at either the ventilator or the humidifier, and less efficient when placed at either the Y-piece or 30 cm from the Y-piece. These conclusions are valid for the tested conditions. Data regarding optimization of operating conditions should not be extrapolated among nebulizers of different operating principles. PMID- 23107176 TI - Introduction. PMID- 23107174 TI - High diversity of genetic lineages and virulence genes in nasal Staphylococcus aureus isolates from donkeys destined to food consumption in Tunisia with predominance of the ruminant associated CC133 lineage. AB - BACKGROUND: The objective of this study was to determine the genetic lineages and the incidence of antibiotic resistance and virulence determinants of nasal Staphylococcus aureus isolates of healthy donkeys destined to food consumption in Tunisia. RESULTS: Nasal swabs of 100 donkeys obtained in a large slaughterhouse in 2010 were inoculated in specific media for S. aureus and methicillin-resistant S. aureus (MRSA) recovery. S. aureus was obtained in 50% of the samples, being all of isolates methicillin-susceptible (MSSA). Genetic lineages, toxin gene profile, and antibiotic resistance mechanisms were determined in recovered isolates. Twenty-five different spa-types were detected among the 50 MSSA with 9 novel spa-types. S. aureus isolates were ascribed to agr type I (37 isolates), III (7), II (4), and IV (2). Sixteen different sequence-types (STs) were revealed by MLST, with seven new ones. STs belonging to clonal clomplex CC133 were majority. The gene tst was detected in 6 isolates and the gene etb in one isolate. Different combinations of enterotoxin, leukocidin and haemolysin genes were identified among S. aureus isolates. The egc-cluster-like and an incomplete egc-cluster-like were detected. Isolates resistant to penicillin, erythromycin, fusidic acid, streptomycin, ciprofloxacin, clindamycin, tetracycline, or chloramphenicol were found and the genes blaZ, erm(A), erm(C), tet(M), fusC were identified. CONCLUSIONS: The nares of donkeys frequently harbor MSSA. They could be reservoirs of the ruminant-associated CC133 lineage and of toxin genes encoding TSST-1 and other virulence traits with potential implications in public health. CC133 seems to have a broader host distribution than expected. PMID- 23107177 TI - The challenge of quality cancer care for family caregivers. AB - OBJECTIVES: To provide an overview of the factors that challenge family caregivers of patients with cancer and review issues related to the role of family members as caregivers. DATA SOURCES: Research based and other articles and reports from the government and professional groups. CONCLUSION: There are many challenges for family caregivers of cancer patients. Nurses must be sensitive to the unmet needs of caregivers and provide the support they need to provide patient care. Health policy is needed to provide support to these caregivers. IMPLICATIONS FOR NURSING PRACTICE: Nurses must take a leadership role to provide standards, guidelines, and best practices for support of the caregiver. PMID- 23107178 TI - The challenge of quality care for family caregivers in pediatric cancer care. AB - OBJECTIVES: To discuss the needs and potential interventions for parental caregivers of children with cancer. DATA SOURCES: Published articles between 2002 and 2012. CONCLUSION: In general, parents do adjust and cope with their child's cancer, but a significant majority experience post-traumatic stress symptoms. Families also report that the shift to parenting a child with cancer is very disruptive to identity and family structure and can cause negative outcomes for mothers, father, and siblings. There is growing evidence of post-traumatic growth and resilience in parents of children with cancer. Recent studies have suggested that targeted interventions may relieve distress. IMPLICATIONS FOR NURSING PRACTICE: Nurses can support families in the difficult transition to having a child with cancer and may be able to intervene to reduce long-term distress in families. PMID- 23107179 TI - Caregivers of older adults with cancer. AB - OBJECTIVE: To review key aspects of family caregiving as it applies to older adults with cancer, discuss the implications of caregiving on the physical and emotional health of caregivers, and discuss future research needs to optimize the care of older adults with cancer and their caregivers. DATA SOURCES: Literature review. CONCLUSION: The number of older adults with cancer is on the rise and these older adults have significant caregiving needs. There is a physical, emotional, and financial toll associated with caregiving. IMPLICATIONS FOR NURSING PRACTICE: As the population of the United States ages, it will be even more important that we identify vulnerable older adults, understand their caregiving needs, and mobilize health care and community resources to support and assist their caregivers. PMID- 23107180 TI - Physical well-being of oncology caregivers: an important quality-of-life domain. AB - OBJECTIVES: To provide an overview of research and practice related to the physical well-being of oncology caregivers. DATA SOURCES: Literature retrieved through the PubMed and CINAHL databases. CONCLUSION: Caregivers play an important role in supporting people with cancer at every stage of the illness trajectory. Because caregiving is inherently stressful, caregivers should be routinely included in the assessment and treatment of patients with cancer. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses are uniquely positioned to play a vital role in recognizing caregiver strain and intervening to break the cycle of unremitting physical and psychosocial burden. PMID- 23107181 TI - The impact of caregiving on the psychological well-being of family caregivers and cancer patients. AB - OBJECTIVES: To provide an overview of patient and caregiver emotional distress; examine the sources of their distress, review evidence-based interventions that can reduce distress, and provide guidelines for assessment and intervention. DATA SOURCES: Peer-reviewed publications. CONCLUSION: There is a significant, reciprocal relationship between patient and caregiver emotional distress. Sources of distress vary by phase of illness. Evidence-based interventions can reduce distress and anxiety, but often are not implemented in practice. IMPLICATIONS FOR NURSING PRACTICE: Nurses need to assess patients and family caregivers for distress and intervene to reduce distress by fostering patient-caregiver teamwork, communication, and self-care; providing information; and referring to resources as needed. PMID- 23107182 TI - Enhancing the social well-being of family caregivers. AB - OBJECTIVES: To provide an overview of key issues and resources useful for oncology professionals to support the social well-being of patients and their families. A caregiver narrative highlights examples of the importance of addressing the social impact of illness. DATA SOURCES: Review of the literature and Web sites related to social well-being of oncology patients and families. CONCLUSION: Culture influences social well-being and impacts caregiving across the life span. Coping with cancer creates a myriad of social implications with potentially significant impacts on communication; sexuality, intimacy and sexual expression; education, finances, work, and leisure. IMPLICATIONS FOR NURSING PRACTICE: Nurses spend the greatest amount of time with patients and their families and therefore have an especially important role in identifying and addressing social needs. An interdisciplinary approach to care that includes the assessment of those at high risk and family meetings increases opportunities to address the complex multidimensional social concerns associated with oncology care. PMID- 23107183 TI - Deriving meaning and faith in caregiving. AB - OBJECTIVES: To review assessment of spiritual needs of family caregivers and four core interventions by nurses in addressing spirituality: presence, deep listening, bearing witness and compassion in action. DATA SOURCES: Literature review. CONCLUSION: Spirituality is increasingly recognized as a key domain of quality of life and essential to quality cancer care. In addition to the needs of patients, family caregivers also experience enormous spiritual needs throughout cancer diagnosis and treatment. Nurses can provide valuable spiritual assessment of family caregivers and support them as they seek support services to address spiritual needs. IMPLICATIONS FOR NURSING PRACTICE: Family caregiving can be a time of growth and meaning when support is provided by nurses and their colleagues. PMID- 23107184 TI - Targeting communication interventions to decrease caregiver burden. AB - OBJECTIVES: To describe family communication patterns that give shape to four types of family caregivers: Manager, Carrier, Partner, and Loner. DATA SOURCES: Case studies of oncology family caregivers and hospice patients selected from data collected as part of a larger, randomized controlled trial aimed at assessing family participation in interdisciplinary team meetings. CONCLUSION: Each caregiver type demonstrates essential communication traits with nurses and team members; an ability to recognize these caregiver types will facilitate targeted interventions to decrease family oncology caregiver burden. IMPLICATIONS FOR NURSING PRACTICE: By becoming familiar with caregiver types, oncology nurses will be better able to address family oncology caregiver burden and the conflicts arising from family communication challenges. With an understanding of family communication patterns and its impact on caregiver burden, nurses can aid the patient, family, and team to best optimize all quality-of-life domains for patient and family caregiver. PMID- 23107185 TI - Distance caregiving a parent with cancer. AB - OBJECTIVE: To discuss the new phenomenon of distance caregiving, with an emphasis on the experience of adult children providing distance caregiving to a parent with cancer. DATA SOURCES: Literature review and author research. CONCLUSION: Although the research is limited, it forms the foundation for beginning to describe the phenomenon and the associated psychosocial burdens that distance caregivers are struggling with. IMPLICATIONS FOR NURSING PRACTICE: With the growing population of distance caregivers, it is important for nurses to address these burdens. Interventions for clinical practice are recommended. PMID- 23107186 TI - Nursing role implications for family caregiving. AB - OBJECTIVE: To describe the clinical, education, and research roles of professional nurses caring for family caregivers. DATA SCORES: Review of literature and Websites on the professional nursing role and family caregivers. CONCLUSION: The growing number of family caregivers of cancer patients will need education and support. The professional oncology nurse is best suited to assess, teach, and support these family caregivers, as well as contribute to the evidence base of these areas of practice. IMPLICATIONS FOR NURSING PRACTICE: Professional nurses caring for oncology patients need to expand their role to include additional support and education of family caregivers. PMID- 23107187 TI - Clinical update: colon, rectal, and anal cancers. AB - OBJECTIVES: To present an updated review of the incidence, risk factors, staging, diagnosis, and treatment of colon, rectal, and anal cancers, as well as nursing care associated with managing patients diagnosed with these malignancies. DATA SOURCES: Published research reports, epidemiologic data, published patient management guidelines, and institution-based clinical tools. CONCLUSION: While significant advances in the management of colon, rectal, and anal cancers in the past decade have extended patient survival, there remain some unanswered questions. Further clinical and molecular research will help individualize patient care, refining current therapeutic strategies and treatment decision making aids while minimizing symptoms of disease and treatment. IMPLICATIONS FOR NURSING PRACTICE: Nurses need to be familiar with risk factors, disease course, and current and emerging therapies to assist patients with treatment decision making, and to anticipate and intervene in managing disease and treatment-induced problems. Early identification and management of distressing symptoms can help to avoid life-threatening effects and promote patient adherence to prescribed therapies; timely patient/family education may minimize anxiety and promote self management. PMID- 23107188 TI - Lower urinary tract symptoms and depression. AB - Study Type--Symptom prevalence (cohort) Level of Evidence 2b. What's known on the subject? and What does the study add? Depression plays an important role in pathogenesis of BPH. Our study shows that prostatic symptoms can be helpful in the screening for depression. OBJECTIVE: * To evaluate the relationship between lower urinary tract symptoms (LUTS) and depression in men through validated questionnaires. PATIENTS AND METHODS: * Healthy male workers (n = 673) were invited to a free health check-up. * Patients underwent a detailed medical examination. * All participants completed the International Prostate Symptom Score (IPSS) questionnaire and the Beck Depression Inventory (BDI). RESULTS: * Under multiple logistic regression analysis (adjusted for total testosterone and age), a significant effect of IPSS on BDI score was observed: mild depression (BDI score >9): odds ratio (OR) 1.092, 95% confidence interval (CI) 1.056-1.129; P < 0.001; moderate-to-severe depression (BDI score >19): OR 1.093, 95% CI 1.031 1.159; P = 0.003; and severe depression (BDI score >29): OR 1.176, 95% CI 1.048 1.320; P = 0.006. CONCLUSIONS: * In healthy men, LUTS are significantly associated with depression. * The treatment of LUTS is very important for the mental health of older men. PMID- 23107190 TI - Identification of dental root canals and their medial line from micro-CT and cone beam CT records. AB - BACKGROUND: Shape of the dental root canal is highly patient specific. Automated identification methods of the medial line of dental root canals and the reproduction of their 3D shape can be beneficial for planning endodontic interventions as severely curved root canals or multi-rooted teeth may pose treatment challenges. Accurate shape information of the root canals may also be used by manufacturers of endodontic instruments in order to make more efficient clinical tools. METHOD: Novel image processing procedures dedicated to the automated detection of the medial axis of the root canal from dental micro-CT and cone-beam CT records are developed. For micro-CT, the 3D model of the root canal is built up from several hundred parallel cross sections, using image enhancement, histogram based fuzzy c-means clustering, center point detection in the segmented slice, three dimensional inner surface reconstruction, and potential field driven curve skeleton extraction in three dimensions. Cone-beam CT records are processed with image enhancement filters and fuzzy chain based regional segmentation, followed by the reconstruction of the root canal surface and detecting its skeleton via a mesh contraction algorithm. RESULTS: The proposed medial line identification and root canal detection algorithms are validated on clinical data sets. 25 micro-CT and 36 cone-beam-CT records are used in the validation procedure. The overall success rate of the automatic dental root canal identification was about 92% in both procedures. The algorithms proved to be accurate enough for endodontic therapy planning. CONCLUSIONS: Accurate medial line identification and shape detection algorithms of dental root canal have been developed. Different procedures are defined for micro-CT and cone-beam CT records. The automated execution of the subsequent processing steps allows easy application of the algorithms in the dental care. The output data of the image processing procedures is suitable for mathematical modeling of the central line. The proposed methods can help automate the preparation and design of several kinds of endodontic interventions. PMID- 23107189 TI - Clinical and histological findings of denture stomatitis as related to intraoral colonization patterns of Candida albicans, salivary flow, and dry mouth. AB - PURPOSE: Multifactorial etiological factors contribute to denture stomatitis (DS), a type of oral candidiasis; however, unlike other oral candidiasis, DS can occur in a healthy person wearing a denture. In this study, we therefore attempt to explore the association between candida, denture, and mucosal tissue using (1) exfoliative cytology, (2) the candidal levels present in saliva, on mucosal tissues and on denture surfaces, and (3) the salivary flow rate and xerostomic symptoms. MATERIALS AND METHODS: A cross-sectional study enrolled 32 edentulous participants, 17 without DS as controls and 15 with DS (Newton's classification type II and III). Participants with systemic or other known oral conditions were excluded. Participants completed a xerostomia questionnaire, and salivary flow rates were measured. Samples of unstimulated whole saliva (UWS) and stimulated whole saliva (SWS) were collected. UWS was used for fungal culturing. Periodic acid-Schiff (PAS) stain and quantitative exfoliative cytology were performed on samples from affected and unaffected mucosa from each participant. Levels of Candida species (albicans and non-albicans) were determined in salivary samples (expressed as colony-forming units, CFU), as well as from swab samples obtained from denture fitting surfaces, in addition to affected and unaffected mucosa. RESULTS: There were no significant differences in salivary flow rates, mucosal wetness, or frequency of reported dry mouth comparing participants with and without DS. Exfoliative cytology of mucosal smears demonstrated significantly higher (p= 0.02) inflammatory cell counts in DS patients, as compared with smears of healthy denture-wearers. Candida albicans was significantly more prevalent in saliva (p= 0.03) and on denture surfaces (p= 0.002) of DS participants, whereas mucosal candidal counts and the presence of cytological hyphae did not show significant difference comparing DS to healthy participants. CONCLUSIONS: In this investigation, we presented a unique group of healthy edentulous patients. This population may reflect the general DS population without systemic or other oral diseases. The prominent etiological factor for DS in this population is the presence of candida in denture and saliva. We found that other factors such as saliva flow/xerostomia, fitting of the denture, and the presence of candida in the mucosa, are less important in this population. Therefore, DS treatments in healthy patients should first focus on sanitization of an existing denture and/or fabrication of a new denture. PMID- 23107191 TI - Bonding effectiveness of self-adhesive composites to dentin and enamel. AB - Self-adhesive composites (SACs) are claimed to bond to tooth substrate without a separate adhesive. Bonding effectiveness data are however still limited. OBJECTIVES: In SubProject 1, the hypothesis was tested that the micro-tensile bond strength (MUTBS) to dentin of two flowable SACs was alike that of a one-step self-etch adhesive (1-SEa) combined with a flowable composite (flowC). In SubProject 2, the hypothesis was tested that the nature of the smear layer did not affect the MUTBS of the SACs to dentin/enamel. METHODS: SubProject 1: The MUTBS to bur-cut dentin of two SACs (Fusio Liquid Dentin, Pentron; Vertise Flow, Kerr) was measured and compared to that of four 1-SEa/flowC combinations (AdheSe One/Tetric EvoFlow, Ivoclar Vivadent; Adper Prompt L-Pop/Filtek Supreme XT Flowable, 3M ESPE; iBond/Venus flow, Heraeus Kulzer; Xeno V/X-flow, Dentsply) and of one 3-step etch-and-rinse adhesive (3-E&Ra: OptiBond FL, Kerr) combined with Premise Flowable (Kerr). The effect of pre-etching dentin with phosphoric acid on the MUTBS of the SAC Vertise Flow (Kerr) was measured as well. SubProject 2: The MUTBS of the two SACs and one 1-SEa/flowC combination (Adper Prompt L-Pop/Filtek Supreme XT Flowable, 3M ESPE) to either bur-cut or SiC-paper ground dentin/enamel was measured. The effect of pre-etching enamel with phosphoric acid on the MUTBS of the SAC Vertise Flow (Kerr) was also measured. RESULTS: SubProject 1: The MUTBS to dentin of both SACs was significantly lower than that of the 1-SEa/flowC and the 3-E&Ra/flowC combinations, of which the latter performed best. The SAC Fusio Liquid Dentin (Pentron) bonded significantly better to dentin than Vertise Flow (Kerr), except when dentin had additionally been pre-etched with phosphoric acid. SubProject 2: Surface smear did not interfere with bonding of the SACs to dentin/enamel, while their MUTBS remained significantly lower than that of the 1 SEa/flowC combination. Prior phosphoric-acid etching of dentin/enamel significantly ameliorated the bonding effectiveness of Vertise Flow (Kerr). SIGNIFICANCE: The bonding effectiveness of flowable SACs underscores that of 1 SEa's and one 'gold-standard' 3-E&Ra when combined with their proprietary flowable composite. Consequently, routine clinical application of SACs should be carefully considered. PMID- 23107192 TI - Incorporation of antimicrobial agents can be used to enhance the antibacterial effect of endodontic sealers. AB - AIM: The antibacterial activity of five endodontic sealers against three different microorganism strains alone and following incorporation of 2% benzalkonium chloride (BC) and 2% cetylpyridinium chloride (CPC) was evaluated. METHODOLOGY: The agar diffusion method was used to determine the inhibitory effect of the following endodontic sealers: RoekoSeal, Endomethasone N, N2, Apexit Plus and AH plus, on Streptococcus mutans - ATCC 25175, Lactobacillus casei - ATCC 4646 and Actinomyces viscosus - ATCC 19246. Bacterial strains were inoculated into BHIB, and incubated in an anaerobic atmosphere (37 degrees C). From the bacteria grown in the liquid medium, the density of the inoculum was set to be equivalent to McFarland 2 standard. In Shaedler agar, 350 MUL of the bacterial suspension were equally spread. Specimens (4 mm * 6 mm) were prepared from each material without and with addition of 2% BC or 2% CPC. The inhibition zones were determined after 2 days, after 7 days and after 21 days of incubation. RESULTS: The largest inhibition zones were shown at zero time in all cases, with progressively less inhibition at 7 and 21 days. Endomethasone N and N2 showed the most intense antimicrobial activity, while RoekoSeal showed the least antimicrobial effect. The most susceptible microorganism was A. viscosus. Greater antimicrobial effects were found following incorporation of BC or CPC, and generally, BC gave greater inhibition zones than CPC. CONCLUSIONS: Adding either BC or CPC has the potential to improve clinical outcomes with endodontic sealers, as these substances enhance the short-term antimicrobial effects of the sealers. PMID- 23107193 TI - Peroxisome proliferator-activated receptor (PPAR) gamma polymorphism, vitamin D, bone mineral density and periodontitis in postmenopausal women. AB - OBJECTIVES: PPARg regulates bone metabolism and inflammation. Our previous study suggested PPARg Pro12Ala polymorphism to represent a susceptibility factor for periodontitis in pregnant Japanese women. Several recent papers have drawn attention to a possible link between low bone mineral density (BMD) and periodontitis in postmenopausal women. Since the pathogenesis for both involve bone remodeling, they might share common risk factors such as gene polymorphisms and vitamin D level. The present study investigated possible associations between the PPARgPro12Ala polymorphism, periodontitis, BMD and serum 25(OH)D in postmenopausal Japanese women. MATERIALS AND METHODS: PPARgPro12Ala genotypes of 359 women were determined by PCR-RFLP. BMD and periodontal parameters of each woman were measured. Serum 25(OH)D levels were determined by radioimmunoassay. RESULTS: PPARgPro12Ala polymorphism was not associated with periodontitis or BMD as an independent factor. Serum 25(OH)D was significantly higher in Ala allele carriers compared to non-carriers. Only in the Ala allele carriers, positive correlations were found between mean clinical attachment level and BMD, between BMD and 25(OH)D, and between percentage of sites with probing depth >= 4 mm and 25(OH)D. CONCLUSIONS: PPARgPro12Ala polymorphism was not independently associated with periodontitis or BMD. However, the polymorphism might be a modulator of the relationship between the two conditions in postmenopausal Japanese women. PMID- 23107194 TI - Palpation- and ultrasound-guided brachial plexus blockade in Hispaniolan Amazon parrots (Amazona ventralis). AB - OBJECTIVE: To compare palpation-guided with ultrasound-guided brachial plexus blockade in Hispaniolan Amazon parrots. STUDY DESIGN: Prospective randomized experimental trial. ANIMALS: Eighteen adult Hispaniolan Amazon parrots (Amazona ventralis) weighing 252-295 g. METHODS: After induction of anesthesia with isoflurane, parrots received an injection of lidocaine (2 mg kg(-1)) in a total volume of 0.3 mL at the axillary region. The birds were randomly assigned to equal groups using either palpation or ultrasound as a guide for the brachial plexus block. Nerve evoked muscle potentials (NEMP) were used to monitor effectiveness of brachial plexus block. The palpation-guided group received the local anesthetic at the space between the pectoral muscle, triceps, and supracoracoideus aticimus muscle, at the insertion of the tendons of the caudal coracobrachial muscle, and the caudal scapulohumeral muscle. For the ultrasound guided group, the brachial plexus and the adjacent vessels were located with B mode ultrasonography using a 7-15 MHz linear probe. After location, an 8-5 MHz convex transducer was used to guide injections. General anesthesia was discontinued 20 minutes after lidocaine injection and the birds recovered in a padded cage. RESULTS: Both techniques decreased the amplitude of NEMP. Statistically significant differences in NEMP amplitudes, were observed within the ultrasound-guided group at 5, 10, 15, and 20 minutes after injection and within the palpation-guided group at 10, 15, and 20 minutes after injection. There was no statistically significant difference between the two groups. No effect on motor function, muscle relaxation or wing droop was observed after brachial plexus block. CONCLUSIONS AND CLINICAL RELEVANCE: The onset of the brachial plexus block tended to be faster when ultrasonography was used. Brachial plexus injection can be performed in Hispaniolan Amazon parrots and nerve evoked muscle potentials were useful to monitor the effects on nerve conduction in this avian species. Neither technique produced an effective block at the doses of lidocaine used and further study is necessary to develop a useful block for surgical analgesia. PMID- 23107218 TI - Diagnosis and treatment of latent infection with Mycobacterium tuberculosis. AB - In clinical practice, latent infection with Mycobacterium tuberculosis is defined by the presence of an M. tuberculosis-specific immune response in the absence of active tuberculosis. Targeted testing of individuals from risk groups with the tuberculin skin test or an interferon-gamma release assay is currently the best method to identify those with the highest risk for progression to tuberculosis. Positive predictive values of the immunodiagnostic tests are substantially influenced by the type of test, the age of the person who is tested, the prevalence of tuberculosis in the society and the risk group to which the person belongs. As a general rule, testing should only be offered when preventive chemotherapy will be accepted in the case of a positive test result. Preventive chemotherapy can effectively protect individuals at risk from the development of tuberculosis, although at least 3 months of combination therapy or up to 9 months of monotherapy are required, and overall acceptance rate is low. Improvements of the current generation of immunodiagnostic tests could substantially lower the number of individuals that need to be treated to prevent a case of tuberculosis. If shorter treatment regimens were equally effective than those currently recommended, acceptance of preventive chemotherapy could be much improved. PMID- 23107219 TI - A new 'face' for bipolar disorders? PMID- 23107220 TI - A randomized, double-blind, controlled trial evaluating the effect of intranasal insulin on neurocognitive function in euthymic patients with bipolar disorder. AB - BACKGROUND: Neurocognitive deficits are prevalent, persistent, and implicated as mediators of functional impairment in adults with bipolar disorder. Notwithstanding progress in the development of pharmacological treatments for various phases of bipolar disorder, no available treatment has been proven to be reliably efficacious in treating neurocognitive deficits. Emerging evidence indicates that insulin dysregulation may be pertinent to neurocognitive function. In keeping with this view, we tested the hypothesis that intranasal insulin administration would improve measures of neurocognitive performance in euthymic adults with bipolar disorder. METHODS: Sixty-two adults with bipolar I/II disorder (based on the Mini International Neuropsychiatric Interview 5.0) were randomized to adjunctive intranasal insulin 40 IU q.i.d. (n = 34) or placebo (n = 28) for eight weeks. All subjects were prospectively verified to be euthymic on the basis of a total score of <= 3 on the seven-item Hamilton Depression Rating Scale (HAMD-7) and <= 7 on the 11-item Young Mania Rating Scale (YMRS) for a minimum of 28 consecutive days. Neurocognitive function and outcome was assessed with a neurocognitive battery. RESULTS: There were no significant between-group differences in mean age of the subjects {i.e., mean age 40 [standard deviation (SD) = 10.15] years in the insulin and 39 [SD = 10.41] in the placebo groups, respectively}. In the insulin group, n = 27 (79.4%) had bipolar I disorder, while n = 7 (21.6%) had bipolar II disorder. In the placebo group, n = 25 (89.3%) had bipolar I disorder, while n = 3 (10.7%) had bipolar II disorder. All subjects received concomitant medications; medications remained stable during study enrollment. A significant improvement versus placebo was noted with intranasal insulin therapy on executive function (i.e., Trail Making Test-Part B). Time effects were significant for most California Verbal Learning Test indices and the Process Dissociation Task-Habit Estimate, suggesting an improved performance from baseline to endpoint with no between-group differences. Intranasal insulin was well tolerated; no subject exhibited hypoglycemia or other safety concerns. CONCLUSIONS: Adjunctive intranasal insulin administration significantly improved a single measure of executive function in bipolar disorder. We were unable to detect between-group differences on other neurocognitive measures, with improvement noted in both groups. Subject phenotyping on the basis of pre existing neurocognitive deficits and/or genotype [e.g., apolipoprotein E (ApoE)] may possibly identify a more responsive subgroup. PMID- 23107221 TI - A descriptive study of older bipolar disorder residents living in New York City's adult congregate facilities. AB - OBJECTIVES: Much of the research on geriatric bipolar disorder is from outpatient populations or epidemiological surveys with small samples. In contrast, in this study a descriptive analysis was conducted of geriatric and younger adult residents with bipolar disorder or mania in non-clinical adult congregate facilities (ACFs) in the greater New York City region. METHODS: A total of 2602 ACF residents were evaluated in 19 facilities, across multiple demographic and health domains. Within this sample, 200 residents had chart diagnoses of bipolar disorder or mania. Among these, 50 geriatric residents (age >= 60) were compared to 50 younger adult residents (age < 50) on a number of demographic and health measures. RESULTS: Based on chart diagnoses, the overall prevalence of bipolar disorder was 7.8%. Compared to other studies of outpatient, epidemiological, and census samples, both older and younger residents with bipolar disorder had higher rates of cognitive impairment, impairment in executive functioning, vision impairment, and proportion of residents who had never been married. The younger group also had higher rates of obesity and the elderly group had a greater proportion of residents without high-school education. Both age groups had rates of lithium or valproate use comparable to those found in outpatient studies. Comparing the two age groups, the elderly sample had lower overall cognitive and executive functioning, and was using a larger number of medication classes than the younger group. The elderly group also had a larger proportion of residents who were separated/divorced or widowed compared to the younger group, which had higher rates of never-married residents. CONCLUSIONS: Overall, both age groups had relatively high rates of bipolar disorder, with significant cognitive impairment, medical burden, obesity, mental health service use, and lower education levels, as compared to outpatient, epidemiological, and census samples. Of note was the significant cognitive impairment across age groups. PMID- 23107222 TI - Lamotrigine as add-on treatment to lithium and divalproex: lessons learned from a double-blind, placebo-controlled trial in rapid-cycling bipolar disorder. AB - OBJECTIVES: A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex. METHODS: During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18-65 years with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained in or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis. RESULTS: During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean +/- standard error change from baseline on the MADRS total score was -8.5 +/- 1.7 points for lamotrigine and 9.1 +/- 1.5 points for placebo (p = not significant; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo. CONCLUSIONS: The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double blind treatment. PMID- 23107223 TI - In contrast to matrix metalloproteinases, serum adiponectin concentrations increase after radioiodine treatment of thyrotoxicosis. AB - BACKGROUND: Matrix metalloproteinases (MMPs), together with their tissue inhibitors (TIMPs), remodel extracellular matrix under physiological and pathological conditions and are implicated in pathogenesis of cardiovascular diseases, cancer and in chronic inflammation. We have endeavoured to assess whether concentrations of MMPs, TIMPs, and anti-inflammatory adiponectin are altered by pharmacological treatment of acute thyrotoxicosis or by radioiodine therapy (RIT). MATERIAL AND METHODS: We measured serum concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2, and adiponectin, TSH, free T4 (FT4) and free T3 (FT3) in 15 patients (4 males), age (years) 51.8+/-15.3 (mean+/-SD) with hyperthyroidism treated with thiamazole (Group 1) and in 20 subjects (2 males), treated for thyrotoxicosis with radioiodine, age 52.3+/-12.4 (Group 2), where blood samples were taken before RIT, visit 1 (V1), seven days post RIT, visit 2 (V2), and two to three months post RIT, visit 3 (V3). RESULTS: In Group 1 there was no significant change in concentrations of MMP-2, MMP-9, TIMP-1, TIMP-2 or adiponectin, despite a fall in FT4 and FT3 (8.74+/-4.79 pg/ml vs 3.54+/-2.40 pg/ml, for FT3, and 4.48 +/-2.21 ng/ml vs 1.02+/-1.07 ng/ml, for FT4, p<0.001). In Group 2 RIT did not cause any acute change in serum MMP-2, MMP-9, TIMP-1 and TIMP-2 or adiponectin (V1 vs V2). However, there was a significant increase in serum adiponectin [from 15201+/-8860 ng/ml (V1) to 19373+/-8657 ng/ml (at V3), p<0.05], and TIMP-2 at V3 [from 129+/-45 ng/ml (V1) to 149+/-38 ng/ml (V3), p<0.01]. There was no significant change MMP-2, MMP-9 and TIMP-1 between V1 and V3. There was a decrease in FT4 and FT3 from 24.4+/-15.4 pmol/l (V1) to 14.7+/ 10.6 pmol/l (V3), and from 10.0+/-5.65 (V1) to 6.1+/-4.8 pmol/l (V2), p<0.01, for FT4 and FT3, respectively. CONCLUSIONS: Radioiodine therapy of thyrotoxicosis does not alter serum MMP-2, MMP-9 or TIMP-1 concentrations either acutely or after about three months of observation. An increase in serum adiponectin might reflect favourable effects of radioiodine administration on cardiovascular risk factors, while an increase in TIMP-2 (principal MMP-2 inhibitor) might lead to a decrease in free MMP-2 concentrations. PMID- 23107224 TI - The kinase inhibitor Sorafenib impairs the antiviral effect of interferon alpha on hepatitis C virus replication. AB - Recently, it was shown that the kinase inhibitor Sorafenib efficiently blocks HCV replication by inhibition of c-Raf. However, a longer treatment with higher doses of Sorafenib might be associated with adverse effects. Therefore, it was analysed whether a decreased dose of Sorafenib can be applied in combination with interferon alpha to obtain additive antiviral, but at the same time decreased adverse effects. However, Sorafenib abolishes the inhibitory effect of interferon alpha on HCV replication and vice versa. In order to reveal the underlying mechanisms, we observed that on the one hand IFNalpha activates c-Raf and thereby counteracts the inhibitory effect of Sorafenib on HCV replication that is based on the Sorafenib-dependent inhibition of c-Raf. On the other hand we found that the IFNalpha-induced PKR-phosphorylation depends on c-Raf. So, Sorafenib as a potent inhibitor of c-Raf prevents the IFNalpha-dependent PKR phosphorylation. Moreover, Sorafenib inhibits c-Raf-independent the phosphorylation of STAT1 resulting in an impaired induction of IFNalpha-dependent genes. Taken together, these data indicate that a combined application of Sorafenib and interferon alpha in order to obtain an antiviral effect is not useful since Sorafenib exerts an inhibitory effect on targets that are crucial for the transduction of interferon alpha-dependent antiviral response. PMID- 23107226 TI - Children's and adults' memory for emotional pictures: examining age-related patterns using the Developmental Affective Photo System. AB - Two studies were conducted to examine theoretical questions about children's and adults' memory for emotional visual stimuli. In Study 1, 7- to 9-year-olds and adults (N=172) participated in the initial creation of the Developmental Affective Photo System (DAPS). Ratings of emotional valence, arousal, and complexity were obtained. In Study 2, DAPS pictures were presented to 20 8- to 12 year-olds and 30 adults, followed by a recognition memory test. Children and adults recognized aversive images better than neutral images. Moreover, children and adults recognized high and moderate arousal images more accurately than low arousal images. Adults' memory for neutral images exceeded that of children, but there were no developmental differences in memory for aversive pictures. Theoretical and methodological implications are discussed. PMID- 23107225 TI - ORCHIDS: an observational randomized controlled trial on childhood differential susceptibility. AB - BACKGROUND: A central tenet in developmental psychopathology is that childhood rearing experiences have a major impact on children's development. Recently, candidate genes have been identified that may cause children to be differentially susceptible to these experiences (i.e., susceptibility genes). However, our understanding of the differential impact of parenting is limited at best. Specifically, more experimental research is needed. The ORCHIDS study will investigate gene-(gene-)environment interactions to obtain more insight into a) moderating effects of polymorphisms on the link between parenting and child behavior, and b) behavioral mechanisms that underlie these gene-(gene )environment interactions in an experimental design. METHODS/DESIGN: The ORCHIDS study is a randomized controlled trial, in which the environment will be manipulated with an intervention (i.e., Incredible Years parent training). In a screening, families with children aged 4-8 who show mild to (sub)clinical behavior problems will be targeted through community records via two Dutch regional healthcare organizations. Assessments in both the intervention and control condition will be conducted at baseline (i.e., pretest), after 6 months (i.e., posttest), and after 10 months (i.e., follow-up). DISCUSSION: This study protocol describes the design of a randomized controlled trial that investigates gene-(gene-)environment interactions in the development of child behavior. Two hypotheses will be tested. First, we expect that children in the intervention condition who carry one or more susceptibility genes will show significantly lower levels of problem behavior and higher levels of prosocial behavior after their parent(s) received the Incredible Years training, compared to children without these genes, or children in the control group. Second, we expect that children carrying one or more susceptibility genes will show a heightened sensitivity to changes in parenting behaviors, and will manifest higher emotional synchronization in dyadic interchanges with their parents. This may lead to either more prosocial behavior or antisocial behavior depending on their parents' behavior. TRIAL REGISTRATION: Dutch Trial Register (NTR3594). PMID- 23107227 TI - The estimation of cardiac output by the Nexfin device is of poor reliability for tracking the effects of a fluid challenge. AB - INTRODUCTION: The Nexfin device estimates arterial pressure by the volume clamp method through a finger pneumatic cuff. It also allows to estimate cardiac index (CInoninv) by pulse contour analysis of the non-invasive arterial pressure curve. We evaluated the ability of the device to track changes in cardiac index induced by a fluid challenge. METHODS: We included 45 patients for whom a volume expansion (500 mL of saline infused over 30 min) was planned. The volume expansion-induced changes in cardiac index measured by transpulmonary thermodilution (CIinv, PiCCO device) and in CInoninv were recorded. RESULTS: In seven patients, the Nexfin could not record the arterial curve due to finger hypoperfusion. Considering both the values obtained before and after volume expansion (n = 76 pairs of measurements), the bias (lower and upper limits of agreement) between CIinv and CInoninv was 0.2 (-1.8 to 2.2) L/min/m2. The mean change in CInoninv was 10 +/- 11%. The percentage error of CInoninv was 57%. The correlation between the changes in CIinv and CInoninv observed during volume expansion was significant (P = 0.0002) with an r2 = 0.31. CONCLUSIONS: The estimation of CI by the Nexfin device in critically ill patients is not reliable, neither for estimating absolute values of CI nor for tracking its changes during volume expansion. PMID- 23107228 TI - Consequences of flagellin export through the type III secretion system of Pseudomonas syringae reveal a major difference in the innate immune systems of mammals and the model plant Nicotiana benthamiana. AB - Bacterial flagellin is perceived as a microbe (or pathogen)-associated molecular pattern (MAMP or PAMP) by the extracellular pattern recognition receptors, FLS2 and TLR5, of plants and mammals respectively. Flagellin accidently translocated into mammalian cells by pathogen type III secretion systems (T3SSs) is recognized by nucleotide-binding leucine-rich repeat receptor NLRC4 as a pattern of pathogenesis and induces a death-associated immune response. The non-pathogen Pseudomonas fluorescens Pf0-1, expressing a Pseudomonas syringae T3SS, and the plant pathogen P. syringae pv. tomato DC3000 were used to seek evidence of an analogous cytoplasmic recognition system for flagellin in the model plant Nicotiana benthamiana. Flagellin (FliC) was secreted in culture and translocated into plant cells by the T3SS expressed in Pf0-1 and DC3000 and in their DeltaflgGHI flagellar pathway mutants. DeltafliC and DeltaflgGHI mutants of Pf0-1 and DC3000 were strongly reduced in elicitation of reactive oxygen species production and in immunity induction as indicated by the ability of challenge bacteria inoculated 6 h later to translocate a type III effector-reporter and to elicit effector-triggered cell death. Agrobacterium-mediated transient expression in N. benthamiana of FliC with or without a eukaryotic export signal peptide, coupled with virus-induced gene silencing of FLS2, revealed no immune response that was not FLS2 dependent. Transiently expressed FliC from DC3000 and Pectobacterium carotovorum did notinduce cell death in N. benthamiana, tobacco or tomato leaves. Flagellin is the major Pseudomonas MAMP perceived by N. benthamiana, and although flagellin secretion through the plant cell wall by the T3SS may partially contribute to FLS2-dependent immunity, flagellin in the cytosol does not elicit immune-associated cell death. We postulate that a death response to translocated MAMPs would produce vulnerability to the many necrotrophic pathogens of plants, such as P. carotovorum, which differ from P. syringae and other (hemi)biotrophic pathogens in benefitting from death associated immune responses. PMID- 23107229 TI - N-3 fatty acids and membrane microdomains: from model membranes to lymphocyte function. AB - This article summarizes the author's research on fish oil derived n-3 fatty acids, plasma membrane organization and B cell function. We first cover basic model membrane studies that investigated how docosahexaenoic acid (DHA) targeted the organization of sphingolipid-cholesterol enriched lipid microdomains. A key finding here was that DHA had a relatively poor affinity for cholesterol. This work led to a model that predicted DHA acyl chains in cells would manipulate lipid-protein microdomain organization and thereby function. We then review how the predictions of the model were tested with B cells in vitro followed by experiments using mice fed fish oil. These studies reveal a highly complex picture on how n-3 fatty acids target lipid-protein organization and B cell function. Key findings are as follows: (1) n-3 fatty acids target not just the plasma membrane but also endomembrane organization; (2) DHA, but not eicosapentaenoic acid (EPA), disrupts microdomain spatial distribution (i.e. clustering), (3) DHA alters protein lateral organization and (4) changes in membrane organization are accompanied by functional effects on both innate and adaptive B cell function. Altogether, the research over the past 10 years has led to an evolution of the original model on how DHA reorganizes membrane microdomains. The work raises the intriguing possibility of testing the model at the human level to target health and disease. PMID- 23107230 TI - Ectobiotic and endobiotic bacteria associated with Eutreptiella sp. isolated from Long Island Sound. AB - Diversity and functional association of bacteria with Eutreptiella sp. was investigated. 16S rDNA analysis of ectobiotic bacteria revealed various lineages of Alphaproteobacteria and abundant Gammaproteobacteria, specifically Marinobacter. Antibiotic treatment yielded axenic cultures, and experiments based on them indicated that ectobiotic bacteria likely provide vitamin B(12) and other growth-enhancing factors for the alga. Further, DAPI staining and transmission electron microscopy revealed endobiotic bacteria in the cytoplasm of algal cells. 16S rDNA analysis showed that the bacteria belonged to one species that was most closely related to Rickettsiales endosymbionts of other organisms and phylogenetically affiliated with a new group of aquatic Rickettsiales. Observations from a diel experiment indicated that the endobiotic bacteria reproduced asynchronously with Eutreptiella sp. and had no adverse effects on lipid production (bioenergetics) or growth of the host alga. Our study reveals a diverse microbiome associated with this euglenoid alga, offering a system for studying the roles of algae-bacteria associations. PMID- 23107231 TI - Bovine viral diarrhea virus in free-ranging wild ruminants in Switzerland: low prevalence of infection despite regular interactions with domestic livestock. AB - BACKGROUND: In the frame of an eradication program for bovine viral diarrhea (BVD) in Swiss livestock, the question was raised whether free-ranging wildlife could threaten the success of this sanitary measure. Therefore, we conducted serological and virological investigations on BVD virus (BVDV) infections in the four indigenous wild ruminant species (roe deer, red deer, Alpine chamois and Alpine ibex) from 2009 to 2011, and gathered information on interactions between wild and domestic ruminants in an alpine environment by questionnaire survey. RESULTS: Thirty-two sera out of 1'877 (1.7%, 95% confidence interval [CI] 1.2 2.4) were seropositive for BVDV, and a BVDV1 sub genotype h virus was found in a seropositive chamois (0.05%, 95% CI 0.001-0.3). The seropositive animals originated from sub-alpine or alpine regions and significantly more seropositive red deer, chamois and ibex than roe deer were found. There were no statistically significant differences between sampling units, age classes, genders, and sampling years. The obtained prevalences were significantly lower than those documented in livestock, and most positive wild ruminants were found in proximity of domestic outbreaks. Additionally, BVDV seroprevalence in ibex was significantly lower than previously reported from Switzerland. The survey on interspecific interactions revealed that interactions expected to allow BVDV transmission, from physical contacts to non-simultaneous use of the same areas, regularly occur on pastures among all investigated ruminant species. Interactions involving cervids were more often observed with cattle than with small ruminants, chamois were observed with all three domestic species, and ibex interacted mostly with small ruminants. Interactions related to the use of anthropogenic food sources were frequently observed, especially between red deer and cattle in wintertime. CONCLUSIONS: To our knowledge, this is the first report of BVDV RNA isolated from an Alpine chamois. Nevertheless, our results suggest that BVDV infections are only sporadic in Swiss wild ruminants, despite regular occurrence of interactions with potentially infected livestock. Overall, serological, virological and ethological data indicate that wildlife is currently an incidental spill-over host and not a reservoir for BVDV in Switzerland. PMID- 23107232 TI - Transbronchial biopsy is useful in predicting UIP pattern. AB - BACKGROUND: Usual interstitial pneumonia (UIP), is a necessary feature pathologically or radiologically for the diagnosis of idiopathic pulmonary fibrosis (IPF). The predictive value of transbronchial biopsy (TBB) in identifying UIP is currently unknown. The objective of this study is to assess the accuracy with which histopathologic criteria of usual interstitial pneumonia (UIP) can be identified in transbronchial biopsy (TBB) and to assess the usefulness of TBBx in predicting a the diagnosis of UIP pattern. We conducted a retrospective blinded and controlled analysis of TBB specimens from 40 established cases of UIP and 24 non-UIP interstitial lung diseases. RESULTS: Adequate TBB specimens were available in 34 UIP cases (85% of all UIP cases). TBB contained histopathologic criteria to suggest a UIP pattern (ie. at least one of three pathologic features of UIP present; patchy interstitial fibrosis, fibroblast foci, honeycomb changes) in 12 cases (30% of all UIP cases). Sensitivity, specificity, positive and negative predictive values for the two pathologists were 30% (12/40), 100% (24/24), 100% (12/12), 46% (24/52) and 30% (12/40), 92% (22/24), 86% (12/14), 55% (22/40) respectively. Kappa coefficient of agreement between pathologists was good (0.61, 95% CI 0.31-0.91). The likelihood of identifying UIP on TBB increased with the number and size of the TBB specimens. CONCLUSION: Although sensitivity is low our data suggest that even modest amount of patchy interstitial fibrosis, fibroblast foci, honeycomb changes detected on TBB can be highly predictive of a UIP pattern. Conversely, the absence of UIP histopathologic criteria on TBB does not rule out UIP. PMID- 23107233 TI - Pulmonary mucormycosis: what is the best strategy for therapy? PMID- 23107234 TI - Use of forced eruption to enhance a pontic site in the anterior maxilla. AB - Extraction of teeth leads to bone resorption that can result in asymmetrical hard and soft tissue topography. This article describes a technique to enhance a pontic site in the anterior maxilla by using forced eruption as an alternative to conventional hard and soft tissue augmentation surgeries. Forced eruption is a well-known procedure and its use in developing a pontic site for a fixed dental prosthesis is described in this clinical report. PMID- 23107235 TI - Long-term follow-up of implant treatment for oligodontia in an actively growing individual: a clinical report. AB - An 11-year-old patient with a history of oligodontia and hypohidrotic ectodermal dysplasia had implants placed in the anterior and posterior mandible as part of his prosthetic rehabilitation. The maxilla was restored by using traditional prosthodontic methods. The long-term follow-up of the treatment is presented, and the clinical implications of placing implants in an actively growing child are discussed. PMID- 23107236 TI - Minimally invasive treatment of the atrophic posterior maxilla: a proof-of concept prospective study with a follow-up of between 36 and 54 months. AB - STATEMENT OF PROBLEM: In the posterior maxilla, tooth loss is usually associated with alveolar bone resorption and sinus pneumatization, limiting the placement of implants without grafting procedures. PURPOSE: The purpose of this study was to evaluate a minimally invasive treatment of the atrophic posterior maxilla, with axial and tilted implants and immediate loading. The research hypothesis was that the combination of a guided, minimally invasive approach and the biomimetic features of computer-aided design and computer-aided manufacturing (CAD/CAM) abutments would be an effective alternative to maxillary sinus floor augmentation procedures with reduced bone resorption around implants. MATERIAL AND METHODS: Twenty-seven consecutive participants (female=12, male=15) (mean age 54.18 years) with severe atrophy of the posterior maxilla were treated by using guided surgery with immediately loaded axial (39) and tilted (42) implants supporting CAD/CAM zirconia (39) and titanium (42) abutments (81 total) and partial fixed prostheses. Each participant underwent a computed tomography scan, after which 2 or 3 implants were positioned with a flapless or miniflap approach. The drilling protocol was adapted to the bone density of each implant site to obtain an insertion torque ranging between 40 and 50 Ncm. CAD/CAM customized abutments composed of zirconia or titanium were fixed to the implants with prosthetic screws tightened with a torque of 35 Ncm. An acrylic resin interim restoration reinforced with metal was placed immediately. Five to 6 months after initial loading, a zirconia framework was manufactured, and a definitive prosthesis was placed. Clinical and radiological controls were performed at baseline and after 1 and 3 years to assess implant and prosthesis survival and success rate and compare marginal bone remodeling of axial and tilted implants. Inferential statistics for radiological data were acquired by using the Mann-Whitney U-test. All statistical comparisons were conducted at the .05 significance level. RESULTS: The mean follow-up period was 43.3 months (ranging from 36 months to 54 months). The cumulative implant survival rate was 96.3% at 3 years. All prosthetic restorations were stable and in good function, resulting in a cumulative prosthetic survival rate of 100%. Three restorations had chipping of the veneer material; thereafter, the cumulative prosthetic success rate was 91.9%. CONCLUSIONS: Treatment of the posterior partially edentulous atrophic maxilla with guided surgery and immediate loading of tilted and straight implants supporting short-span partial fixed dental prostheses is effective. PMID- 23107237 TI - Clinical evaluation of the association between noncarious cervical lesions and occlusal forces. AB - STATEMENT OF PROBLEM: Noncarious cervical lesions (NCCLs) are a frequent challenge in clinical dental practice, given the variety of opinions regarding their etiology, diagnosis, and treatment. PURPOSE: The purpose of this study was to assess the potential relationship between occlusal forces and the occurrence of NCCLs. MATERIAL AND METHODS: The participant population consisted of 111 volunteers (30 male and 81 female, mean age 23.6 years). General personal information was recorded, after which participants were examined for the presence and location of NCCLs, gingival recession, fracture lines, dental and restoration fractures, presence and location of tooth wear, type of occlusal guidance scheme for lateral mandibular movements, and existence of occlusal interference or premature contacts. The participants were divided according to the presence or absence of NCCLs, and data were statistically analyzed with the Independent t test, the Chi-square test, and the Fisher exact test (alpha=.05). RESULTS: A significant association was found between the presence of NCCLs and age (P=.008), gingival recession (P<.001), occlusal trauma (P<.001), presence (P<.001) and location of tooth wear, and group function as occlusal guidance scheme in lateral excursive movements (P<.001). CONCLUSIONS: A strong relationship between the presence of NCCLs and occlusal overload was found. PMID- 23107238 TI - Applying microwave technology to sintering dental zirconia. AB - STATEMENT OF PROBLEM: When sintering zirconia, conventional processing may not provide uniform heating and consumes more energy than an alternative method using microwave energy. PURPOSE: The purpose of this study was to compare the surface quality, mechanical and physical properties, and dimensional stability obtained by sintering yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) in a conventional furnace versus a microwave furnace. MATERIAL AND METHODS: Twenty bars of Y-TZP were prepared from Zircad blocks. Ten specimens were used for sintering in a conventional furnace. The remaining 10 specimens were sintered in a microwave furnace. The sintering temperature used for both techniques was 1500 degrees C. The flexural strength of all specimens was measured with the 3-point bend test with a universal testing machine with a cross head speed of 1.0 mm/min. Density was measured by applying the Archimedes method, and specimen length, width, and thickness were measured with a digital micrometer. The phase composition and average grain size of these ceramics were examined by using X-ray diffraction, and microstructure characteristics were studied with scanning electron microscopy. Data obtained were analyzed by using independent t tests (alpha=.05). RESULTS: No significant difference between conventional and microwave sintering for either flexural strength, t18=0.49 (P=.63) or density, t18=0.07 (P=.95) was found. Specimens in both groups exhibited a uniform firing shrinkage of approximately 24.6% in all dimensions. The surface of selected specimens examined with a scanning electron microscope showed no visible difference in grain shape or porosity size between the 2 sintering methods. CONCLUSIONS: Under the conditions of this study, it appears that either microwave or conventional zirconia sintering may be used for processing zirconia for dental use. However, microwave energy provides uniformity of heating, allowing the use of higher heating rates, which can increase productivity and save energy. PMID- 23107239 TI - Predicting marginal fit of CAD/CAM crowns based on the presence or absence of common preparation errors. AB - STATEMENT OF PROBLEM: Confusion exists as to what constitutes an ideal ceramic crown preparation and whether certain deviations from the ideal can affect the marginal fit of the milled restoration. PURPOSE: This study evaluated the marginal gap of E4D crowns fabricated on preparations completed by clinicians with varying levels of expertise to identify whether common errors affect marginal fit. MATERIAL AND METHODS: The fit of 75 crowns fabricated with the E4D system on preparations of varying quality were examined for marginal fit by using the replica technique. These same preparations were then visually examined for common criteria for ceramic restorations and placed in one of 3 categories: excellent, fair, or poor. These visual examinations sought the presence of common preparation errors, particularly those involving the finish line. The average marginal gap values and standard deviations were calculated for each category, and the Kruskal-Wallis test was used to determine significance. RESULTS: The results showed a statistically significant correlation between the marginal fit of a CAD/CAM fabricated crown and the quality of the preparation. The mean marginal gap of the crowns fabricated on ideal preparations was 38.5 um, those considered fair had a mean marginal gap of 58.3 um, while those categorized as poor averaged 90.1 um. The fit differences among all 3 groups were statistically significant (P<.05). CONCLUSIONS: Within the limitations of this in vitro study, it can be concluded that preparation quality has a significant impact on marginal gap on crowns fabricated with a CAD/CAM system. PMID- 23107240 TI - Effect of different airborne-particle abrasion/bonding agent combinations on the bond strength of a resin cement to a base metal alloy. AB - STATEMENT OF PROBLEM: Investigation of surface treatments to improve the bond of resin cements to metals may contribute to the longevity of metal ceramic restorations. PURPOSE: The purpose of this study was to evaluate the efficacy of surface treatments on the shear bond strength (SBS) of a resin cement to nickel chromium (NiCr) alloy. MATERIAL AND METHODS: Eighty cast NiCr alloy disks (9 * 3 mm) were divided into 8 groups (n=10), which received 1 of the following surface treatments: 1) 50 um Al(2)O(3) particles + silane; 2) 120 um Al(2)O(3) + silane; 3) 30 um silica-modified Al(2)O(3) (Cojet Sand) + silane; 4) 120 um Al(2)O(3) followed by 110 um silica-modified Al(2)O(3) (Rocatec) + silane; 5) 50 um Al(2)O(3) + metal primer; 6) 120 um Al(2)O(3) + metal primer; 7) 30 um silica modified Al(2)O(3) (Cojet Sand) + metal primer; and 8) 120 um Al(2)O(3) followed by 110 um silica-modified Al(2)O(3) (Rocatec) + metal primer. The silane was RelyX Ceramic Primer and the metal primer Alloy Primer. RelyX ARC resin cement was bonded to NiCr alloy surfaces. Specimens were thermally cycled before shear mode testing. Data (MPa) were analyzed by 1-way ANOVA and the Tukey test (alpha=.05). Failure mode was determined with a stereomicroscope (*20). RESULTS: The results revealed that surface treatment was significant (P<.001). There was no significant difference between 50 um and 120 um Al(2)O(3) particles, regardless of the bonding agent used (silane or metal primer). Cojet Sand provided lower SBS than Rocatec, both in the groups treated with silane (P<.001) and metal primer (P<.01). No significant difference was observed between silane and metal primer in the groups abraded with 50 um and 120 um Al(2)O(3) particles. Metal primer decreased the SBS of both Cojet Sand and Rocatec groups (P<.001). Rocatec + silane had the highest SBS and Cojet Sand + metal primer the lowest. All groups presented 100% adhesive failure. CONCLUSIONS: Particle size influenced SBS only in the groups abraded with silica-modified Al(2)O(3). The bonding agent did not affect SBS in the groups abraded with Al(2)O(3). Alloy Primer was not chemically compatible with silica-modified Al(2)O(3). Both mechanical (particle size) and chemical (silica/silane interaction) factors contributed to the high SBS of Rocatec + silane. PMID- 23107241 TI - Management of patients with excessive gingival display for maxillary complete arch fixed implant-supported prostheses. AB - Maxillary complete arch fixed implant-supported prostheses are a popular treatment option for edentulous patients. Excessive gingival display or gummy smile in edentulous patients is relatively uncommon. However, many partially edentulous patients or completely dentate patients with compromised dentition and excessive gingival display may seek a fixed implant-supported prosthesis. Some of these patients may be candidates for immediate implant placement and insertion of the prosthesis, while others may carry over their preexisting excessive gingival display to the edentulous state for a variable period of time. Both types of patients require meticulous treatment planning and often require additional preprosthetic interventions before the placement of dental implants. This report provides an overview of the etiology, diagnosis, treatment planning, and options for management of patients with excessive gingival display who seek a maxillary complete arch fixed implant-supported prosthesis. PMID- 23107242 TI - Fabrication of a functional palatal saliva reservoir by using a resilient liner during processing of a complete denture. AB - One of the major problems associated with xerostomic patients is the poor tolerance and retention of removable dental prostheses because of thin dry atrophic mucosa and lack of a saliva film. The use of salivary substitutes can improve lubrication, provide irrigation for dry mucosa, provide significant relief from symptoms, and also improve the retention of removable prostheses. These substitutes can be delivered over prolonged periods by using saliva reservoirs in the prosthesis itself. This report describes a novel technique for the fabrication of a functional palatal saliva reservoir in edentulous xerostomic patients. The technique uses a resilient liner in the floor of the reservoir. The tongue presses against the liner during swallowing, resulting in flow of saliva substitute through a hole in the anterior part of the floor of the reservoir. PMID- 23107243 TI - Multidrug-resistant NDM-1 Klebsiella outbreak and infection control in endoscopic urology. AB - What's known on the subject? and What does the study add? Since the first case of multidrug-resistant New Delhi metallo-beta-lactamase (NDM-1) Klebsiella and Escherichia coli UTI in January 2008, there have been more reports of cases worldwide. Urology is a specialty uniquely vulnerable to these organisms because the NDM-1 carriers tend to be the common UTI-causing organisms. Further, the nature of the procedures involved in endoscopy in the urinary tract confers the potential for direct exposure and transmission of the organisms that commonly cause UTI. Although decontamination by sterilization of urological endoscopes and surgical instruments is well established in the operating theatre suite, there were no national standardized guidelines for infection control measures with respect to the video camera head in endoscopic urology in the UK. This paper reports the first UK outbreak of NDM-1 Klebsiella UTI, for which the common source of infection was rapidly traced to the endoscopic camera head in the urology theatre, where single-use sterile disposable plastic camera sheaths were not routinely used and the camera head was regularly cleaned with detergent wipes. We found that infection control practices vary across UK urology units. In the context of infection control, we highlight a need for standardized practice in the use of camera sheaths and in the decontamination process for endoscopic video camera heads. Either sterilization or use of single-use sterile disposable plastic camera sheaths with regular cleaning of the camera head using approved disinfectant for all endoscopy work is recommended. OBJECTIVES: * To report the first UK outbreak of NDM-1 Klebsiella, for which the common source of infection was rapidly traced to the endoscopic camera head in the urology theatre, where camera sheathing was not routinely used and the camera head was regularly cleaned with detergent wipes. * To survey the use of camera sheath and infection control practices in endoscopy in urology in the UK. PATIENTS AND METHODS: * A structured questionnaire was conducted via telephone interview with urological theatre sisters/charge nurses from all urological units across the UK. * Data on the use of camera sheath, cleaning practices, type of disinfectant used and choice of prophylactic antibiotics were obtained. RESULTS: * Out of 206 NHS urology units, 158 (77%) units across the UK were surveyed. Forty-one (25.9%) do not use camera sheaths, 16 (10.1%) were used dependent on the consultant's preference, and the remaining 101 (63.9%) routinely used camera sheath. * Twenty-one (13.3%) units clean the camera head only at the end of the operating list and the remainder clean after every case. * The choice of cleaning agent/disinfectant used varied considerably. They are broadly categorised as alcoholic wipes 90 (57%), detergent wipes 46 (29.1%) and soapy water 21 (13.3%). * The choice of prophylactic antibiotic includes gentamicin alone (96.3%), augmentin alone (1.4%), gentamicin/amoxicillin (0.7%) and cefuroxime alone (0.7%). CONCLUSIONS: * In the context of infection control, we highlight the need for a standardized practice in the use of camera sheaths and the process of decontamination of the endoscopic camera head. * Either sterilization or use of single-use sterile disposable plastic camera sheath with regular cleaning of the camera head using approved disinfectant for all endoscopy work is recommended. PMID- 23107244 TI - Shoulder arthroscopy literature remains controversial. PMID- 23107246 TI - Death after fluid extravasation in hip arthroscopy. PMID- 23107248 TI - Platelet-rich plasma versus hyaluronic Acid. PMID- 23107249 TI - Attachment of the anteroinferior glenohumeral ligament-labrum complex to the glenoid: an anatomic study. AB - PURPOSE: To determine the morphology of the attachment of the anteroinferior glenohumeral ligament-labrum complex (AIGHL-LC) to the anterior rim of the glenoid. METHODS: Sixty-six cadaveric shoulders with a mean age of 81 years were studied. The length of the AIGHL-LC attachment in the superoinferior direction and its depth in the mediolateral direction at the 2-, 3-, 4-, and 5-o'clock positions were measured. The radial histologic sections from the center of the glenoid at the 2- and 4-o'clock positions were used for histologic examinations. RESULTS: The mean length of the AIGHL-LC attachment was 11.7 mm. The mean depth was 4.7 mm (1.6 mm on the articular cartilage and 3.0 mm on the glenoid neck) at the 2-o'clock position, 6.7 mm (2.4 mm and 4.3 mm, respectively) at the 3-o'clock position, 8.4 mm (3.0 mm and 5.4 mm, respectively) at the 4-o'clock position, and 6.8 mm (2.5 mm and 4.3 mm, respectively) at the 5-o'clock position. The depth of the AIGHL-LC attachment was the greatest at the 4-o'clock position (P < .01) and the smallest at the 2-o'clock position (P < .05). Histologically, the AIGHL-LC attached to both the cartilage and bone in 52 shoulders (86.7%) at the 2-o'clock position and in 53 shoulders (88.3%) at the 4-o'clock position. CONCLUSIONS: The depth of the AIGHL-LC attachment was the greatest at the 4-o'clock position and the smallest at the 2-o'clock position. At the 4-o'clock position, the AIGHL-LC attaches to both the articular cartilage and bone in 88% of shoulders whereas it attaches only to bone in 12%. CLINICAL RELEVANCE: This study provides fundamental information on the AIGHL-LC attachment. Because healing of the AIGHL-LC to the articular cartilage cannot be expected, the same attachment area as to the bone and cartilage observed in normal shoulders needs to be created on the glenoid neck during Bankart repair to obtain the physiological strength of the AIGHL-LC. PMID- 23107250 TI - Femoral graft bending angle and femoral tunnel geometry of transportal and outside-in techniques in anterior cruciate ligament reconstruction: an in vivo 3 dimensional computed tomography analysis. AB - PURPOSE: To compare femoral graft bending angles and femoral tunnel geometries between the transportal (TP) and outside-in (OI) techniques after anatomic double bundle (DB) anterior cruciate ligament (ACL) reconstruction. METHODS: Thirty-nine patients underwent DB ACL reconstruction with the TP and OI techniques. They were randomized on the day of surgery to either the TP group (group I, 21 cases) or the OI group (group II, 18 cases). Femoral graft bending angle, femoral tunnel geometry, posterior wall breakage, and tunnel communication were assessed by computed tomography imaging with OsiriX imaging software (Pixmeo, Geneva, Switzerland). RESULTS: The mean anteromedial (AM) and posterolateral (PL) femoral graft bending angles of group II (97.3 degrees +/- 8.3 degrees and 97.4 degrees +/- 8.6 degrees , respectively) were significantly more acute than those of group I (108.2 degrees +/- 8.4 degrees and 109.9 degrees +/- 8.8 degrees , respectively) (P < .001). The mean AM femoral tunnel length of group II (34.3 +/- 3.9 mm) was significantly longer than that of group I (31.9 +/- 2.7 mm) (P = .02). However, the mean PL femoral tunnel lengths did not differ between groups. In 7 cases-4 cases (19.0%) in group I and 3 cases (16.6%) in group II-the femoral tunnel communication was found around the intra-articular aperture. Posterior wall breakage was observed in 5 cases (23.8%), which were all in AM femoral tunnels of group I. CONCLUSIONS: The OI technique resulted in more acute femoral graft bending angles (difference of 10.9 degrees and 12.5 degrees for AM and PL, respectively) and longer mean AM femoral tunnel lengths (difference of 2.4 mm) than the TP technique after anatomic DB ACL reconstruction, even though these small differences might be unlikely to be of clinical significance. Femoral tunnel communication was found in both groups, and posterior wall breakage was observed in AM femoral tunnels with the TP technique. LEVEL OF EVIDENCE: Level I, prospective randomized trial. PMID- 23107251 TI - Rapidly progressive osteoarthritis after arthroscopic labral repair in patients with hip dysplasia. AB - Recent reports of poor clinical outcomes after arthroscopic surgery in hips with marked dysplasia have emerged. Arthroscopic resection of the hypertrophic labrum in cases of dysplasia, especially in the absence of periacetabular osteotomy (PAO), has been implicated. Some patients will refuse PAO because it is a major open procedure, opting for a less invasive arthroscopic procedure. We present the cases of 2 young adults with marked dysplasia who had rapidly progressive osteoarthrosis despite arthroscopic labral repair. Though perhaps beneficial as an isolated procedure in borderline or mild dysplasia cases, arthroscopic hip surgery, even labral repair, may best be performed with PAO in cases with more severe dysplasia. Albeit attractive as a less invasive labral-preserving surgery, arthroscopic labral repair not only may fail to provide symptomatic improvement but may compromise or preclude a later PAO if rapidly progressive osteoarthrosis ensues. Hip arthroscopy may best be performed concurrently with or after PAO but not proceeding PAO in patients requiring both procedures. PMID- 23107253 TI - Full hazards of smoking and benefits of stopping for women. PMID- 23107254 TI - Body composition, inflammation and thermogenesis in pathways to obesity and the metabolic syndrome: an overview. AB - According to the World Health Organization, overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health. What constitutes 'abnormal' fat accumulation in this definition is not specified, but this most likely represents a consensus term that encapsulates the importance of adipose tissue dysfunctions, rather than solely excess fat per se, in the pathogenesis of disease entities of the metabolic syndrome, particularly type 2 diabetes and cardiovascular diseases. Over the past decades, such abnormalities in fat accumulation have been linked to a pattern of fat distribution characterized by disproportionate fat deposition in the abdomen; to limits in the capacity of adipose tissue to expand resulting in the burden of fat storage being shifted to 'lean' tissues/organs as ectopic fat; and to the secretion (by both intrinsic and infiltrated cells within the adipose tissue mass) of a plethora of cytokines and other factors which via their autocrine, paracrine and/or endocrine actions underscore a state of chronic low-grade inflammation. These links have formed the basis of a multitude of adipocentric concepts that have stimulated basic and clinical research aimed at explaining differential susceptibilities to cardiometabolic diseases according to diet and lifestyle, birth weight and post natal growth patterns, menopausal transition and the ageing process, race and ethnicity--often within the framework of hypotheses constructed around thrifty genotypes or thrifty phenotypes, and around overlapping molecular pathways implicated in metabolic inflammation, thermogenesis and body composition regulation. It is against this background of rapidly advancing research in metabolic health--fuelled as much by the search for early markers of cardiometabolic risks as by the search for 'druggable' molecular targets for treating obesity and its comorbidities--that fundamental concepts, controversies and novel research avenues relevant to the theme of 'Body composition, Inflammation and Thermogenesis in Pathways to Obesity and the Metabolic Syndrome' are addressed in this overview and the 10 review articles in this supplement reporting the proceedings of the 6th Fribourg Obesity Research Conference (FORC 2011). PMID- 23107252 TI - The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK. AB - BACKGROUND: Women born around 1940 in countries such as the UK and USA were the first generation in which many smoked substantial numbers of cigarettes throughout adult life. Hence, only in the 21st century can we observe directly the full effects of prolonged smoking, and of prolonged cessation, on mortality among women in the UK. METHODS: For this prospective study, 1.3 million UK women were recruited in 1996-2001 and resurveyed postally about 3 and 8 years later. All were followed to Jan 1, 2011, through national mortality records (mean 12 woman-years, SD 2). Participants were asked at entry whether they were current or ex-smokers, and how many cigarettes they currently smoked. Those who were ex smokers at both entry and the 3-year resurvey and had stopped before the age of 55 years were categorised by the age they had stopped smoking. We used Cox regression models to obtain adjusted relative risks that compared categories of smokers or ex-smokers with otherwise similar never-smokers. FINDINGS: After excluding 0.1 million women with previous disease, 1.2 million women remained, with median birth year 1943 (IQR 1938-46) and age 55 years (IQR 52-60). Overall, 6% (66,489/1,180,652) died, at mean age 65 years (SD 6). At baseline, 20% (232,461) were current smokers, 28% (328,417) were ex-smokers, and 52% (619,774) were never-smokers. For 12-year mortality, those smoking at baseline had a mortality rate ratio of 2.76 (95% CI 2.71-2.81) compared with never-smokers, even though 44% (37,240/85,256) of the baseline smokers who responded to the 8-year resurvey had by then stopped smoking. Mortality was tripled, largely irrespective of age, in those still smoking at the 3-year resurvey (rate ratio 2.97, 2.88 3.07). Even for women smoking fewer than ten cigarettes per day at baseline, 12 year mortality was doubled (rate ratio 1.98, 1.91-2.04). Of the 30 most common causes of death, 23 were increased significantly in smokers; for lung cancer, the rate ratio was 21.4 (19.7-23.2). The excess mortality among smokers (in comparison with never-smokers) was mainly from diseases that, like lung cancer, can be caused by smoking. Among ex-smokers who had stopped permanently at ages 25 34 years or at ages 35-44 years, the respective relative risks were 1.05 (95% CI 1.00-1.11) and 1.20 (1.14-1.26) for all-cause mortality and 1.84 (1.45-2.34) and 3.34 (2.76-4.03) for lung cancer mortality. Thus, although some excess mortality remains among these long-term ex-smokers, it is only 3% and 10% of the excess mortality among continuing smokers. If combined with 2010 UK national death rates, tripled mortality rates among smokers indicate 53% of smokers and 22% of never-smokers dying before age 80 years, and an 11-year lifespan difference. INTERPRETATION: Among UK women, two-thirds of all deaths of smokers in their 50s, 60s, and 70s are caused by smoking; smokers lose at least 10 years of lifespan. Although the hazards of smoking until age 40 years and then stopping are substantial, the hazards of continuing are ten times greater. Stopping before age 40 years (and preferably well before age 40 years) avoids more than 90% of the excess mortality caused by continuing smoking; stopping before age 30 years avoids more than 97% of it. FUNDING: Cancer Research UK, Medical Research Council. PMID- 23107255 TI - Beyond the body mass index: tracking body composition in the pathogenesis of obesity and the metabolic syndrome. AB - Body composition is related to various physiological and pathological states. Characterization of individual body components adds to understand metabolic, endocrine and genetic data on obesity and obesity-related metabolic risks, e.g. insulin resistance. The obese phenotype is multifaceted and can be characterized by measures of body fat, leg fat, liver fat and skeletal muscle mass rather than by body mass index. The contribution of either whole body fat or fat distribution or individual fat depots to insulin resistance is moderate, but liver fat has a closer association with (hepatic) insulin resistance. Although liver fat is associated with visceral fat, its effect on insulin resistance is independent of visceral adipose tissue. In contrast to abdominal fat, appendicular or leg fat is inversely related to insulin resistance. The association between 'high fat mass + low muscle mass' (i.e. 'sarcopenic adiposity') and insulin resistance deserves further investigation and also attention in daily clinical practice. In addition to cross-sectional data, longitudinal assessment of body composition during controlled under- and overfeeding of normal-weight healthy young men shows that small decreases and increases in fat mass are associated with corresponding decreases and increases in insulin secretion as well as increases and decreases in insulin sensitivity. However, even under controlled conditions, there is a high intra- and inter-individual variance in the changes of (i) body composition; (ii) the 'body composition-glucose metabolism relationship' and (iii) glucose metabolism itself. Combining individual body components with their related functional aspects (e.g. the endocrine, metabolic and inflammatory profiles) will provide a suitable basis for future definitions of a 'metabolically healthy body composition'. PMID- 23107256 TI - Ethnic variability in adiposity, thrifty phenotypes and cardiometabolic risk: addressing the full range of ethnicity, including those of mixed ethnicity. AB - Ethnic groups vary in cardiometabolic risk, but the underlying mechanisms remain unclear. Several components of body composition variability (fat/lean ratio, fat distribution, lean mass composition and metabolism, and adipose tissue biology) are increasingly linked with cardiometabolic risk and vary substantially across ethnic groups. Constituents of lean mass are proposed to contribute to 'metabolic capacity', a generic trait favouring the maintenance of homeostasis. Adiposity is proposed to contribute to 'metabolic load', which at higher levels challenges metabolic homeostasis, elevating cardiometabolic risk. Ethnic differences in body composition, representing different load-capacity ratios, may therefore contribute to ethnic variability in cardiometabolic risk. Ecological and evolutionary factors potentially contributing to ethnic variability in body composition are explored. In contemporary populations, clinicians encounter an increasing range of ethnicity, along with many individuals of mixed-ethnic ancestry. Increasing understanding of the contribution of body composition to cardiometabolic risk may reduce the need to treat ethnic groups as qualitatively different. A conceptual model is proposed, treating insulin sensitivity and stroke risk as composite functions of body composition variables. Operationalizing this model may potentially improve the ability to assess cardiovascular risk across the full ethnicity spectrum, and to predict cardiometabolic consequences of excess weight gain. PMID- 23107257 TI - Visceral fat and metabolic inflammation: the portal theory revisited. AB - Abdominal (central) obesity strongly correlates with (hepatic) insulin resistance and type 2 diabetes. Among several hypotheses that have been formulated, the 'portal theory' proposes that the liver is directly exposed to increasing amounts of free fatty acids and pro-inflammatory factors released from visceral fat into the portal vein of obese patients, promoting the development of hepatic insulin resistance and liver steatosis. Thus, visceral obesity may be particularly hazardous in the pathogenesis of insulin resistance and type 2 diabetes. Herein, we will critically review existing evidence for a potential contribution of portally drained free fatty acids and/or cytokines to the development of hepatic insulin resistance. PMID- 23107258 TI - Revisiting the diacylglycerol-induced insulin resistance hypothesis. AB - Obesity is associated with skeletal muscle insulin resistance, which is a crucial step in the development of type 2 diabetes. Among the mechanisms by which obesity may lead to insulin resistance, lipotoxicity is one of the hypotheses being explored; others include inflammation or the oxidative stress hypotheses. This review focuses on the role of diacylglycerols (DAG), a family of lipid metabolites implicated in the pathogenesis of lipotoxicity and insulin resistance. While recent studies report contradictory results in humans with regard to the importance of DAG-induced insulin resistance in skeletal muscle, other current literature highlight a potential role for DAG as signalling molecules. This review will discuss possible hypotheses explaining these contradictory results and the need to explore further the role of DAG in human metabolism. PMID- 23107259 TI - Impaired protein metabolism: interlinks between obesity, insulin resistance and inflammation. AB - Metabolic and structural changes in skeletal muscle that accompany obesity are often associated with the development of insulin resistance. The first events in the pathogenesis of this disorder are considered as an accumulation of lipids within skeletal muscle due to blunted muscle capacity to oxidize fatty acids. Fat infiltration is also associated with muscle fibre typology modification, decrease in muscle mass and impairments in muscle strength. Thus, as a result of obesity, mobility and quality of life are affected, and this is in part due to quantitative and qualitative impairments in skeletal muscle. In addition, the insulin resistance related to obesity results not only in defective insulin stimulated glucose disposal but has also detrimental consequences on protein metabolism at the skeletal muscle level and whole-body level. This review highlights the involvement of fat accumulation and insulin resistance in metabolic disorders occurring in skeletal muscle during the development of obesity, and the impairments in the regulation of protein metabolism and protein turnover in the links between obesity, metabolic inflammation and insulin resistance. PMID- 23107260 TI - mTOR signalling: the molecular interface connecting metabolic stress, aging and cardiovascular diseases. AB - The continuing increase in the prevalence of obesity and metabolic disorders such as type-II diabetes and an accelerating aging population globally will remain the major contributors to cardiovascular mortality and morbidity in the 21st century. It is well known that aging is highly associated with metabolic and cardiovascular diseases. Growing evidence also shows that obesity and metabolic diseases accelerate aging process. Studies in experimental animal models demonstrate similarity of metabolic and cardiovascular phenotypes in metabolic diseases and old age, e.g. insulin resistance, oxidative stress, chronic low grade inflammation, cardiac hypertrophy, cardiac fibrosis, and heart failure, as well as vascular dysfunctions. Despite intensive research, the molecular mechanisms linking metabolic stress, aging, and ultimately cardiovascular diseases are still elusive. Although the mammalian target of rapamycin (mTOR) signalling is a well known regulator of metabolism and lifespan in model organisms, its central role in linking metabolic stress, aging and cardiovascular diseases is recently emerging. In this article, we review the evidence supporting the role of mTOR signalling as a molecular interface connecting metabolic stress, aging and cardiovascular diseases. The therapeutic potentials of targeting mTOR signalling to protect against metabolic and age-associated cardiovascular diseases are discussed. PMID- 23107261 TI - Molecular pathways linking metabolic inflammation and thermogenesis. AB - Obesity is caused by chronic positive energy balance because of higher energy intake relative to energy expenditure. Thermogenesis, the capacity of an organism to produce heat, is an important component of energy expenditure. Thus targeting the molecular mechanisms controlling thermogenesis could be an effective strategy for the prevention or treatment of obesity. Thermogenesis is modulated by three major factors: environmental temperature, nutrient quantity and quality, and by systemic inflammation. Obesity is now recognized to be a state of chronic low grade systemic inflammation, which has been proposed to play a major role in the pathogenesis of obesity and obesity-associated diseases. This review discussed the molecular pathways that are recruited during metabolic inflammation and that are also implicated in the control of thermogenesis and energy balance. It emerges that the complex signalling network recruited during metabolic inflammation exerts a balanced action on the modulation of thermogenesis and energy balance, with some pathways promoting weight gain whereas other pathways have opposite actions. It is thus concluded that immunomodulation of metabolic inflammation, rather than an anti-inflammatory intervention aiming at its suppression, may be a more promising strategy to increase thermogenesis for the treatment or prevention of obesity and its associated diseases. PMID- 23107262 TI - The adipose organ: white-brown adipocyte plasticity and metabolic inflammation. AB - White adipocytes can store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions are contained in multiple fat depots forming the adipose organ. In this review, we outline the plasticity of this organ in physiological (cold exposure, physical exercise and lactation) and pathological conditions (obesity). We also highlight molecules and signalling pathways involved in the browning phenomena of white adipose tissue. This phenotypic change has proved to be effective in the protection against the metabolic disorders associated to obesity and diabetes, not only because brown adipocytes are more 'healthy' than white adipocytes, but also because the simple size reduction of white adipocytes that characterizes the first steps of transdifferentiation can be useful in determining how to avoid triggering death based on critical size and the consequent chronic low-grade inflammation due to macrophage infiltration. Thus, a better understanding of the molecular mechanisms at the basis of white-brown transdifferentiation can be extremely useful to exploit new therapeutic strategies to combat the increasing incidence of metabolic diseases. PMID- 23107263 TI - Core temperature: a forgotten variable in energy expenditure and obesity? AB - A substantial proportion of energy expenditure is utilized for maintenance of the 'warm-blooded' or homoeothermic state. In normally active humans, this compartment of energy output approximates 40% of total energy expenditure. Many mammalian species utilize regulated decreases in temperature, such as hibernation or shallow torpor, as a means of energy conservation. Inherited forms of rodent obesity (ob/ob mouse, fa/fa rat) have lower core temperatures and withstand cold poorly. Obese humans, however, have normal core temperatures. This review addresses the role of core temperature in the metabolic economy of the obese state and raises the possibility that (i) lower temperatures may contribute to the increase in metabolic efficiency that accompanies weight loss in the obese; and (ii) that lower core temperatures may have initiated weight gain in the pre obese state and that the normal temperatures in the obese may represent metabolic compensation to restore energy balance and limit further weight gain. PMID- 23107264 TI - Adaptive thermogenesis in human body weight regulation: more of a concept than a measurable entity? AB - According to Lavoisier, 'Life is combustion'. But to what extent humans adapt to changes in food intake through adaptive thermogenesis--by turning down the rate of heat production during energy deficit (so as to conserve energy) or turning it up during overnutrition (so as to dissipate excess calories)--has been one of the most controversial issues in nutritional sciences over the past 100 years. The debate nowadays is not whether adaptive thermogenesis exists or not, but rather about its quantitative importance in weight homoeostasis and its clinical relevance to the pathogenesis and management of obesity. Such uncertainties are likely to persist in the foreseeable future primarily because of limitations to unobtrusively measure changes in energy expenditure and body composition with high enough accuracy and precision, particularly when even small inter-individual variations in thermogenesis can, in dynamic systems and over the long term, be important in the determining weight maintenance in some and obesity and weight regain in others. This paper reviews the considerable body of evidence, albeit fragmentary, suggesting the existence of quantitatively important adaptive thermogenesis in several compartments of energy expenditure in response to altered food intake. It then discusses the various limitations that lead to over- or underestimations in its assessment, including definitional and semantics, technical and methodological, analytical and statistical. While the role of adaptive thermogenesis in human weight regulation is likely to remain more a concept than a strictly 'quantifiable' entity in the foreseeable future, the evolution of this concept continues to fuel exciting hypothesis-driven mechanistic research which contributes to advance knowledge in human metabolism and which is bound to result in improved strategies for the management of a healthy body weight. PMID- 23107266 TI - The AJT Report: news and issues that affect organ and tissue transplantation. Genetic factor may limitkidney donation. AB - Recent studies have shown that African Americans have genetic variants that appear to incrementally increase their risk for ESRD. This month, "The AJT Report" explores the dilemma now facing transplant professionals: Should African American potential live kidney donors be prospectively genotyped and warned about possible associations between genetic background and outcomes? Also this month, "The AJT Report" checks in on the status of some living donor outcomes research. PMID- 23107267 TI - Literature watch: implications for transplantation. PMID- 23107268 TI - Can we stop waiting for godot? Establishing selection criteria for simultaneous liver-kidney transplantation. PMID- 23107269 TI - Mounting evidence suggests safety and efficacy of immunizations posttransplantation. PMID- 23107270 TI - Living donor liver transplantation for hepatocellular carcinoma: through the looking glass. PMID- 23107272 TI - Acute renal failure in a kidney donor. PMID- 23107274 TI - Morphological features of the internal carotid artery: advantages of combining linear and convex probes in duplex ultrasonography. AB - RATIONALE AND OBJECTIVES: Previous research has determined that carotid abnormalities (CAs) are partly located >3 cm above the carotid bifurcation. However, identifying CAs occurring in this location using high-frequency linear probes is difficult. The aim of this study was to explore the efficacy of a combination of high-frequency and low-frequency probes in duplex ultrasonography for identifying morphologic features of the internal carotid artery (ICA). MATERIALS AND METHODS: A total of 1055 ICAs from 532 patients were analyzed. CAs were classified prospectively according to the criteria of Wain et al, Weibel and Fields, and Metz et al. The diagnostic rates of high-frequency ultrasonography alone and a combination of high-frequency and low-frequency ultrasonography were compared. The distances from the carotid bifurcation to the initial point of the CA and to the mandibular angle were also measured. RESULTS: High-frequency ultrasonography detected 23.2% of CAs, and the combination detected 32.2% of CAs (P < .001) in the 1055 ICAs. Of these CAs, 32.4% and 16.8% began >2.5 and >3 cm above the carotid bifurcation, respectively. The distance between the carotid bifurcation and the mandibular angle was <1.5 cm in 100 arteries (9.48%). The diameter of the distal ICA was larger in patients with CAs than in those without CAs (4.33 +/- 0.52 vs 4.13 +/- 0.49 mm, P < .001). CONCLUSIONS: Combining high frequency and low-frequency probes is better than high-frequency probes alone to assess morphologic features of the ICA in duplex ultrasonography. Low-frequency convex probes should be added to traditional ultrasonography for the evaluation of morphologic features of the ICA before carotid endarterectomy, carotid artery stenting, and CA angioplasty. PMID- 23107275 TI - Rapid sequential injections of hyperpolarized [1-13C]pyruvate in vivo using a sub kelvin, multi-sample DNP polarizer. AB - The development of hyperpolarized technology utilizing dynamic nuclear polarization (DNP) has enabled the rapid measurement of (13)C metabolism in vivo with very high SNR. However, with traditional DNP equipment, consecutive injections of a hyperpolarized compound in an animal have been subject to a practical minimum time between injections governed by the polarization build-up time, which is on the order of an hour for [1-(13)C]pyruvate. This has precluded the monitoring of metabolic changes occurring on a faster time scale. In this study, we demonstrated the ability to acquire in vivo dynamic magnetic resonance spectroscopy (MRS) and 3D magnetic resonance spectroscopic imaging (MRSI) data in normal rats with a 5 min interval between injections of hyperpolarized [1 (13)C]pyruvate using a prototype, sub-Kelvin dynamic nuclear polarizer with the capability to simultaneously polarize up to 4 samples and dissolve them in rapid succession. There were minimal perturbations in the hyperpolarized spectra as a result of the multiple injections, suggesting that such an approach would not confound the investigation of metabolism occurring on this time scale. As an initial demonstration of the application of this technology and approach for monitoring rapid changes in metabolism as a result of a physiological intervention, we investigated the pharmacodynamics of the anti-cancer agent dichloroacetate (DCA), collecting hyperpolarized data before administration of DCA, 1 min after administration, and 6 min after administration. Dramatic increases in (13)C-bicarbonate were detected just 1 min (as well as 6 min) after DCA administration. PMID- 23107278 TI - Real-world effectiveness of clozapine in patients with bipolar disorder: results from a 2-year mirror-image study. AB - OBJECTIVES: Clozapine remains the drug of choice for treatment-resistant schizophrenia but the evidence for its use in severe bipolar disorder (BD) remains sparse. METHODS: A pharmaco-epidemiologic database study was carried out in Denmark, investigating the effectiveness of clozapine in BD patients (without a schizophrenia-spectrum disorder), between 1996 and 2007, using a two-year mirror-image design. RESULTS: A total of 21473 patients with a lifetime diagnosis of International Classification of Diseases-10 (ICD-10) BD were identified, of which only 326 (1.5%) were treated with clozapine and were included in the mirror image analysis. The mean follow-up time was 544 +/- 280 days, the mean clozapine dose was 307.4 mg [95% confidence interval (CI): 287.9-328.2], and 39.3% were male. During clozapine treatment, the mean number of bed-days decreased from 177.8 (95% CI: 149.4-211.6) to 34.6 (95% CI: 24.8-48.2) (p < 0.001). The mean number of admissions was reduced from 3.2 (95% CI: 2.9-3.7) to 2.0 (95% CI: 1.6 2.4) (p < 0.001). Overall, 240 patients (73.6%) had reduced bed-days and 130 (39.9%) were not admitted while treated with clozapine. Moreover, the number of psychotropic co-medications was reduced from 4.5 defined daily doses (DDD) (25-75 percentiles: 2.4-8.2) to 3.9 DDD (25-75 percentiles: 2.4-6.1) (p = 0.045). Somatic hospital visits for intentional self-harm/overdose reduced significantly from 8.3% to 3.1% (p = 0.004). However, non-psychotropic co-medication use for medical conditions did not increase; 0.7 DDD (25-75 percentiles: 0.0-2.9) to 0.8 DDD (25-75 percentiles: 0.1-2.89) (p = 0.3). CONCLUSIONS: Clozapine use for BD was associated with a significant and clinically relevant reduction in the number of bed-days, psychiatric admissions, psychotropic co-medications, and hospital contact for self-harm/overdose, without increased medical treatments. Clozapine seems to be an appropriate choice for treatment-resistant BD and should be investigated in randomized controlled trials. PMID- 23107277 TI - Changes in the expression of MMP2, MMP9, and ColIV in stromal cells in oral squamous tongue cell carcinoma: relationships and prognostic implications. AB - BACKGROUND: Type IV collagen (ColIV) is the most important scaffold for the basement membrane (BM) proteins, and plays an important role in regulating and limiting tumour invasion and metastasis. METHODS: Here, we observed the changes in morphology and distribution of type IV collagen (ColIV) in the basement membrane (BM) surrounding nests of carcinoma in 48 patients with oral tongue squamous cell (OTSCC). We examined the correlation between the expressions of ColIV, MMP-2 and MMP-9 and the prognosis of OTSCC patients. The intensity and patterns of expression were assessed immunohistochemically using anti-human mouse monoclonal MMP-2, MMP-9 and Col IV antibodies. Statistical analyses were performed to determine the prognostic correlations of ColIV, MMP-2, and MMP-9 levels. RESULTS: MMP-2 and MMP-9 expressions in OTSCC were higher than those in normal oral mucosa and dysplastic oral mucosa group(MMP-2 iOD: 66.40 +/- 24.20, 134.69 +/- 37.08, and 357.79 +/- 116.78; MMP-9 iOD: 88.05 +/- 23.85, 307.13 +/- 93.22, and 791.31 +/- 260.52; in normal, dysplastic oral mucosa, and tumour tissues, respectively, P < 0.01); however, ColIV immunoreactivity was lower (ColIV iOD: 406.87 +/- 62.95, 247.83 +/- 42.30, and 151.92 +/- 38.17 in normal, dysplastic oral mucosa, and tumour tissues, respectively, P < 0.01). High tumour and stromal MMP-2 and MMP-9 expression was significantly associated with positive lymph node status. Col IV expression was associated with positive lymph node status (P < 0.05), and have negatively correlated with the expression of MMP-2 and MMP-9. Overall survival was significantly shorter in patients with high tumour and stromal MMP-2 and MMP-9 expression, and tended to be shorter in patients with low ColIV expression. CONCLUSIONS: Degradation of ColIV was closely related to increased MMP-2 and MMP-9 expression; MMP-9 have more important function than MMP-2 during the cancer development. Monitoring changes in the expression of ColIV, MMP-2, and MMP-9 may be a useful technique for assessing prognoses in OTSCC patients. PMID- 23107279 TI - Diffusion of HEMA through human carious and non-carious dentin in vitro. AB - PURPOSE: The aim of this study was to evaluate the diffusion of 2-Hydroxyethyl methacrylate (HEMA) from resin cement through dentin both affected and unaffected by caries through high-performance liquid chromatography (HPLC) at two time intervals. MATERIALS AND METHODS: Ten freshly extracted restoration-free, caries free and ten extracted carious human third molar teeth were used in this study. Standardized box-shaped Class I inlay cavities (6 mm long, 3 mm wide, 2 mm deep) were prepared in all teeth with a high-speed handpiece mounted on a standard cavity machine. In teeth affected by caries, after preparation, the remaining carious lesions were removed, with their removal guided by a proprietary caries detector dye. The remaining dentin thickness (RDT) between the pulpal wall of the cavity and the roof of the pulp chamber was measured at multiple points for each tooth so that groups of 10 teeth each were prepared with RDT 1.2 +/- 0.5 mm. Lithium disilicate-based ceramic inlays were manufactured to restore the prepared cavities. A polypropylene chamber was attached to the cementoenamel junction of each tooth to contain 1 ml distilled water. Then, ceramic inlays were cemented with chemically polymerized resin cement (Multilink Automix) according to the manufacturer's instructions. Water elutes were analyzed by HPLC at 4.32 minutes and 24 hours. HEMA diffusion amounts were analyzed using two-way ANOVA and Tukey HSD tests (p < 0.05). RESULTS: HEMA was detected in the pulp chamber elutes of all the teeth. The diffused HEMA amounts were not significantly different between the affected caries and the unaffected groups (p= 0.80) or between time periods (p= 0.44). The carious dentin did not influence the amount of HEMA diffused through the dentin to the pulp space. CONCLUSIONS: The highest amount of eluted HEMA concentration detected was not viewed as critical for pulp tissue since the diffused HEMA amounts were below the level of cytotoxicity, according to the literature. PMID- 23107276 TI - Association of MYLIP rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. AB - BACKGROUND: The association of rs3757354 single nucleotide polymorphism (SNP) in the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP, also known as IDOL) gene and serum lipid levels is not well known in the general population. The present study aimed to detect the association of rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. METHOD: A total of 627 subjects of Bai Ku Yao minority and 614 participants of Han nationality were randomly selected from our stratified randomized cluster samples. Genotyping of the rs3757354 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. RESULTS: The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P<0.05 0.001). The frequency of G allele was 49.92% in Bai Ku Yao and 56.27% in Han (P<0.05). The frequencies of AA, GA and GG genotypes were 25.52%, 49.12% and 25.36% in Bai Ku Yao, and 19.87%, 47.72% and 32.41% in Han (P<0.05); respectively. There were no significant differences in the genotypic and allelic frequencies between males and females in both ethnic groups. The levels of HDL-C in Bai Ku Yao were different among the genotypes (P<0.05), the G allele carriers had higher serum HDL-C levels than the G allele noncarriers. The levels TC, HDL-C and ApoAI in Han were different among the genotypes (P<0.05 for all), the participants with GA genotype had lower serum TC, HDL-C and ApoAI levels than the participants with AA genotype. These findings were found only in females but not in males. The levels of TG and HDL-C in Bai Ku Yao were correlated with the genotypes, whereas the levels of TC in Han, and TC, LDL-C in Han females were associated with the genotypes (P<0.05 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, and body mass index in both ethnic groups (P<0.05-0.001). CONCLUSIONS: The present study suggests that the MYLIP rs3757354 SNP is associated with serum TC, HDL-C and ApoAI levels in the Bai Ku Yao and Han populations. But the association is different between the two ethnic groups. PMID- 23107280 TI - Characterization of the novel HLA-DQB1*06:48 allele by group-specific sequencing. AB - HLA-DQB1*06:48 has single nucleotide polymorphisms within codons 70 and 62 of exon 2 (GGG>AGG and AAG>AAC) relative to HLA-DQB1*06:02:01 and HLA-DQB1*06:37. This results in amino acid differences (G>R and K>N) that will change the polarity and charge of the encoded antigen and may therefore affect its peptide repertoire. PMID- 23107281 TI - Attrition and generalizability in longitudinal studies: findings from a 15-year population-based study and a Monte Carlo simulation study. AB - BACKGROUND: Attrition is one of the major methodological problems in longitudinal studies. It can deteriorate generalizability of findings if participants who stay in a study differ from those who drop out. The aim of this study was to examine the degree to which attrition leads to biased estimates of means of variables and associations between them. METHODS: Mothers of 18-month-old children were enrolled in a population-based study in 1993 (N=913) that aimed to examine development in children and their families in the general population. Fifteen years later, 56% of the sample had dropped out. The present study examined predictors of attrition as well as baseline associations between variables among those who stayed and those who dropped out of that study. A Monte Carlo simulation study was also performed. RESULTS: Those who had dropped out of the study over 15 years had lower educational level at baseline than those who stayed, but they did not differ regarding baseline psychological and relationship variables. Baseline correlations were the same among those who stayed and those who later dropped out. The simulation study showed that estimates of means became biased even at low attrition rates and only weak dependency between attrition and follow-up variables. Estimates of associations between variables became biased only when attrition was dependent on both baseline and follow-up variables. Attrition rate did not affect estimates of associations between variables. CONCLUSIONS: Long-term longitudinal studies are valuable for studying associations between risk/protective factors and health outcomes even considering substantial attrition rates. PMID- 23107282 TI - Bioinformatics prediction of miRNAs in the Prunus persica genome with validation of their precise sequences by miR-RACE. AB - We predicted 262 potential MicroRNAs (miRNAs) belonging to 70 miRNA families from the peach (Prunus persica) genome and two specific 5' and 3' miRNA rapid amplification of cDNA ends (miR-RACE) PCR reactions and sequence-directed cloning were employed to accurately validate 61 unique P. persica miRNAs (Ppe-miRNAs) sequences belonging to 61 families comprising 97 Ppe-miRNAs. Validation of the termini nucleotides in particular can define the real sequences of the Ppe-miRNAs on peach genome. Comparison between predicted and validated Ppe-miRNAs through alignment revealed that 43 unique orthologous sequences were identical, while the remaining 18 exhibited some divergences at their termini nucleotides. Quantitative real-time polymerase chain reaction (qRT-PCR) was further employed to analyze the expression of all the 61 miRNAs and 10 putative targets of 8 randomly selected Ppe-miRNAs in peach leaves, flowers and fruits at different stages of development, where both the miRNAs and the putative target genes showed tissue-specific expression. PMID- 23107283 TI - FENO measurement and sputum analysis for diagnosing asthma in clinical practice. AB - OBJECTIVES: To determine the diagnostic accuracy of fractional exhaled nitric oxide (FENO) measurement in pneumologists routine diagnostic work-up; and to determine the impact of the inflammatory pattern on diagnostic accuracy. METHODS: Prospective diagnostic study in 393 patients attending a private practice of pneumologists with complaints suspicious of obstructive airway disease (OAD). Index test was FENO measurement. Reference standard was the Tiffeneau ratio (FEV(1)/VC) or airway resistance as assessed by whole body plethysmography, with additional bronchoprovocation or bronchodilator testing. Morning sputum was analysed with smear slides which were prepared and stained by Giemsa. RESULTS: 154 patients were diagnosed as having asthma (145 diagnoses based on bronchial provocation, 9 based on bronchodilator results), 5 had COPD. For the whole group, asthma could be ruled in at FENO > 71 ppb (PPV 80%; 95% CI 63-90%) and ruled out at FENO <= 9 ppb (NPV 82%; 95% CI 67-91%) (area under the curve (AUC) = 0.656; 95% CI 0.600-0.712; p < 0.001). 128 patients delivered sputum. FENO was 44.3 ppb (sd 48.9) in patients with predominant eosinophilic inflammation, 18.5 ppb with neutrophilic inflammation, and 23.1 ppb in others (p = 0.003). Diagnostic accuracy of FENO increased when patients with neutrophilic inflammation were omitted from analysis (AUC = 0.745; 95% CI 0.651-0.838; p < 0.001). Then asthma could be ruled in at FENO > 31 ppb (PPV 82%; 95% CI 63-92%) and ruled out at FENO <= 12 ppb (NPV 81%; 95% CI 62-91%). CONCLUSIONS: FENO measurement can be useful as an additional diagnostic tool in pneumologists' practice. The diagnostic value of FENO could be improved when inflammatory patterns are taken into account. PMID- 23107284 TI - NT-proBNP independently predicts long term mortality after acute exacerbation of COPD - a prospective cohort study. AB - BACKGROUND: Cardiovascular disease is prevalent and frequently unrecognized in patients with chronic obstructive pulmonary disease (COPD). NT-proBNP is an established risk factor in patients with heart failure. NT-proBNP may also be released from the right ventricle. Thus serum NT-proBNP may be elevated during acute exacerbations of COPD (AECOPD). The prognostic value of NT-proBNP in patients hospitalized with AECOPD is sparsely studied. Our objective was to test the hypothesis that NT-proBNP independently predicts long term mortality following AECOPD. METHODS: A prospective cohort study of 99 patients with 217 admissions with AECOPD. Clinical, electrocardiographic, radiological and biochemical data were collected at index and repeat admissions and analyzed in an extended survival analysis with time-dependent covariables. RESULTS: Median follow-up time was 1.9 years, and 57 patients died during follow-up. NT-proBNP tertile limits were 264.4 and 909 pg/mL, and NT-proBNP in tertiles 1 through 3 was associated with mortality rates of 8.6, 35 and 62 per 100 patient-years, respectively (age-adjusted log-rank p<0.0001). After adjustment for age, gender, peripheral edema, cephalization and cTnT in a multivariable survival model, the corresponding hazard ratios for dying were 2.4 (0.95-6.0) and 3.2 (1.3-8.1) (with 95% confidence intervals in parentheses, p-value for trend 0.013). CONCLUSIONS: NT-proBNP is a strong and independent determinant of mortality after AECOPD. PMID- 23107285 TI - Implementation of an efficacious intervention for high risk women in Mexico: protocol for a multi-site randomized trial with a parallel study of organizational factors. AB - BACKGROUND: Studies of implementation of efficacious human immunodeficiency virus (HIV) prevention interventions are rare, especially in resource-poor settings, but important, because they have the potential to increase the impact of interventions by improving uptake and sustainability. Few studies have focused on provider and organizational factors that may influence uptake and fidelity to core intervention components. Using a hybrid design, we will study the implementation of an efficacious intervention to reduce sexually transmitted infections (STIs) among female sex workers (FSWs) in 12 cities across Mexico. Our protocol will test a 'train-the-trainer' implementation model for transporting the Mujer Segura (Healthy Woman) intervention into community-based organizations (CBOs). METHODS: We have partnered with Mexican Foundation for Family Planning (Mexfam), a non-governmental organization that has CBOs throughout Mexico. At each CBO, trained ethnographers will survey CBO staff on characteristics of their organization and on their attitudes toward their CBO and toward the implementation of evidence-based interventions (EBIs). Then, after CBO staff recruit a sample of 80 eligible FSWs and deliver a standard-care, didactic intervention to 40 women randomly selected from that pool, a Mexfam staff person will be trained in the Mujer Segura intervention and will then train other counselors to deliver Mujer Segura to the 40 remaining participating FSWs. FSW participants will receive a baseline behavioral assessment and be tested for HIV and STIs (syphilis, gonorrhea, and chlamydia); they will be reassessed at six months post-intervention to measure for possible intervention effects. At the same time, both qualitative and quantitative data will be collected on the implementation process, including measures of counselors' fidelity to the intervention model. After data collection at each CBO is complete, the relative efficacy of the Mujer Segura intervention will be analyzed, and across CBOs, correlations will be examined between individual and organizational provider characteristics and intervention efficacy. DISCUSSION: This cooperative, bi national research study will provide critical insights into barriers and facilitating factors associated with implementing interventions in CBOs using the 'train the trainer' model. Our work builds on similar scale-up strategies that have been effective in the United States. This study has the potential to increase our knowledge of the generalizability of such strategies across health issues, national contexts, and organizational contexts. TRIAL REGISTRATION: NCT01465607. PMID- 23107286 TI - Sleep disordered breathing in heart failure patients with reduced versus preserved ejection fraction. AB - BACKGROUND: This study aimed to investigate and compare prevalence of sleep disordered breathing (SDB) in Japanese patients with heart failure with reduced ejection fraction (HFrEF) versus those with HF with preserved EF (HFpEF). METHODS: This study consecutively included 101 Japanese patients (77 males) with de novo CHF. Echocardiography was performed twice, on admission and at discharge. All patients underwent portable overnight polygraphy within one week before discharge. The patients were stratified into two groups based on LVEF on admission, HFrEF (R group; LVEF<50%, n=82) or HFpEF (P group; LVEF?50%, n=19); the prevalence of SDB and sleep study data were assessed. RESULTS: When patients with the apnea hypopnea index >=15 were defined as having SDB, 50% of the study patients had SDB (OSA, 10%; CSA, 39%; MSA, 1%). No significant differences in the prevalence of SDB or sleep data as well as RVSP, E/e' or plasma brain natriuretic peptide (BNP) were found between the two groups. CONCLUSIONS: SDB was identified in 50% of de novo Japanese HF patients. When E/e', RVSP and plasma BNP did not significantly differ between the two groups, the prevalence of SDB was similar regardless of LVEF. PMID- 23107288 TI - Modeling foam delivery mechanisms in deep vadose-zone remediation using method of characteristics. AB - This study investigates foam delivery mechanisms in vadose-zone remediation by using Method of Characteristics (MoC), a mathematical tool long been used for the analysis of miscible and immiscible flooding in porous media in petroleum industry. MoC converts the governing material-balance partial differential equations into a series of ordinary differential equations, and the resulting solutions are in a form of wave propagation (more specifically, for chemical species and phase saturations) through the system as a function of time and space. Deep vadose-zone remediation has special features compared to other conventional remediation applications. They include, not limited to, a high level of heterogeneity, a very dry initial condition with low water saturation (S(w)), pollutants such as metals and radionuclides fully dissolved in groundwater, and a serious concern about downward migration during the remediation treatments. For the vadose-zone remediation processes to be successful, the injected aqueous phase should carry chemicals to react with pollutants and precipitate them for immobilization and stabilization purposes. As a result, foams are believed to be an effective means, and understanding foam flow mechanism in situ is a key to the optimal design of field applications. Results show that foam delivery mechanism is indeed very complicated, making the optimum injection condition field specific. The five major parameters selected (i.e., initial saturation of the medium, injection foam quality, surfactant adsorption, foam strength, and foam stability) are shown to be all important, interacting with each other. Results also imply that although dry foam injection is generally recommended, too dry injection condition is found to hurt this process due to slow foam propagation. PMID- 23107287 TI - Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children. AB - INTRODUCTION: Differentiating between sterile inflammation and bacterial infection in critically ill patients with fever and other signs of the systemic inflammatory response syndrome (SIRS) remains a clinical challenge. The objective of our study was to mine an existing genome-wide expression database for the discovery of candidate diagnostic biomarkers to predict the presence of bacterial infection in critically ill children. METHODS: Genome-wide expression data were compared between patients with SIRS having negative bacterial cultures (n = 21) and patients with sepsis having positive bacterial cultures (n = 60). Differentially expressed genes were subjected to a leave-one-out cross-validation (LOOCV) procedure to predict SIRS or sepsis classes. Serum concentrations of interleukin-27 (IL-27) and procalcitonin (PCT) were compared between 101 patients with SIRS and 130 patients with sepsis. All data represent the first 24 hours of meeting criteria for either SIRS or sepsis. RESULTS: Two hundred twenty one gene probes were differentially regulated between patients with SIRS and patients with sepsis. The LOOCV procedure correctly predicted 86% of the SIRS and sepsis classes, and Epstein-Barr virus-induced gene 3 (EBI3) had the highest predictive strength. Computer-assisted image analyses of gene-expression mosaics were able to predict infection with a specificity of 90% and a positive predictive value of 94%. Because EBI3 is a subunit of the heterodimeric cytokine, IL-27, we tested the ability of serum IL-27 protein concentrations to predict infection. At a cut point value of >=5 ng/ml, serum IL-27 protein concentrations predicted infection with a specificity and a positive predictive value of >90%, and the overall performance of IL-27 was generally better than that of PCT. A decision tree combining IL-27 and PCT improved overall predictive capacity compared with that of either biomarker alone. CONCLUSIONS: Genome-wide expression analysis has provided the foundation for the identification of IL-27 as a novel candidate diagnostic biomarker for predicting bacterial infection in critically ill children. Additional studies will be required to test further the diagnostic performance of IL-27. The microarray data reported in this article have been deposited in the Gene Expression Omnibus under accession number GSE4607. PMID- 23107289 TI - Dechlorination of short chain chlorinated paraffins by nanoscale zero-valent iron. AB - In this study, nanoscale zero-valent iron (NZVI) particles were synthesized and used for the reductive dehalogenation of short chain chlorinated paraffins (SCCPs) in the laboratory. The results show that the dechlorination rate of chlorinated n-decane (CP(10)) by NZVI increased with decreased solution pH. Increasing the loading of NZVI enhanced the dechlorination rate of CP(10). With an increase in temperature, the degradation rate increased. The reduction of CP(10) by NZVI was accelerated with increasing the concentration of humic acid up to 15 mg/L but then was inhibited. The dechlorination of CP(10) within the initial 18 h followed pseudo-first order rate model. The formation of intermediate products indicates a stepwise dechlorination pathway of SCCPs by NZVI. The carbon chain length and chlorination degree of SCCPs have a polynominal impact on dechlorination reactions. PMID- 23107290 TI - Investigation into the causes for the changed biodegradation process of dissolved pyrene after addition of hydroxypropyl-beta-cyclodextrin (HPCD). AB - Bioremediation of surface waters contaminated with polycyclic aromatic hydrocarbons (PAHs) is a serious problem, often limited by the low bioavailability of contaminants as a result of their low aqueous solubility. In this study, we studied the influence of hydroxypropyl-beta-cyclodextrin (HPCD) addition on the biodegradation of dissolved pyrene in aqueous solution. Five types of unidentified bacterial strains were used with a concentration of pyrene under its solubility limit. The reduction of pyrene content was monitored during the biodegradation process using synchronous fluorimetry. The presence of HPCD changed the rate of pyrene biodegradation by microorganisms due to the formation of an inclusion complex between pyrene and HPCD. The hydrophobicity and the emulsifying activity of microorganisms relative to their biodegrading capacity were investigated. The results indicated that hydrophobicity and emulsifying activity of the microorganisms were important factors that can influence the biodegradation process. The hydrophobicity and emulsifying activity were strongly correlated with the biodegrading capacity of the microorganisms toward pyrene in the presence of solubilizing agents or organized media. PMID- 23107291 TI - Enhanced visible-light induced degradation of benzene on Mg-ferrite/hematite/PANI nanospheres: in situ FTIR investigation. AB - The dramatic enhanced visible-light photocatalytic activity of Mg ferrite/hematite nanospheres photocatalysts on benzene were obtained after hybridized by polyaniline (PANI) using the chemisorption method. The samples were characterized by scanning electron microscope, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectra and UV-Vis diffuse reflectance spectroscopy. The enhancement of photocatalytic degradation of benzene under visible-light irradiation was mainly ascribed to the high efficiency of charge separation induced by the hybrid effect of PANI and Mg ferrite/hematite. By using the in situ FTIR technique, ethyl acetate, carboxylic acid and aldehyde could be regarded as the intermediate products, and CO(2) is determined as the final product during the reaction process. PMID- 23107292 TI - Effectiveness of interventions to promote physical activity among socioeconomically disadvantaged women: a systematic review and meta-analysis. AB - Physical activity is important for preventing weight gain and obesity, but women experiencing socioeconomic disadvantage are at high risk of inactivity. This study aimed to determine the effectiveness of interventions to increase physical activity among women experiencing disadvantage, and the intervention factors (i.e. physical activity measure, delivery mode, delivery channel, setting, duration, use of theory, behavioural techniques, participant age, risk of bias) associated with effectiveness. We conducted a meta-analysis of controlled trials using random-effects models and meta-regression. Seven databases were searched for trials among healthy women (18-64 years), which included a physical activity intervention, any control group, and statistical analyses of a physical activity outcome at baseline and post-intervention. Nineteen studies were included (n = 6,339). Because of substantial statistical heterogeneity (chi(2) = 53.61, df = 18, P < 0.0001, I(2) = 66%), an overall pooled effect is not reported. In subgroup analyses, between-group differences were evident for delivery mode, which modestly reduced heterogeneity (to 54%). Studies with a group delivery component had a standardized mean difference of 0.38 greater than either individual or community-based delivery. Programs with a group delivery mode significantly increase physical activity among women experiencing disadvantage, and group delivery should be considered an essential element of physical activity promotion programs targeting this population group. PMID- 23107294 TI - Expression patterns of epithelial-mesenchymal transition markers in localized prostate cancer: significance in clinicopathological outcomes following radical prostatectomy. PMID- 23107293 TI - A novel co-infection model with Toxoplasma and Chlamydia trachomatis highlights the importance of host cell manipulation for nutrient scavenging. AB - Toxoplasma and Chlamydia trachomatis are obligate intracellular pathogens that have evolved analogous strategies to replicate within mammalian cells. Both pathogens are known to extensively remodel the cytoskeleton, and to recruit endocytic and exocytic organelles to their respective vacuoles. However, how important these activities are for infectivity by either pathogen remains elusive. Here, we have developed a novel co-infection system to gain insights into the developmental cycles of Toxoplasma and C. trachomatis by infecting human cells with both pathogens, and examining their respective ability to replicate and scavenge nutrients. We hypothesize that the common strategies used by Toxoplasma and Chlamydia to achieve development results in direct competition of the two pathogens for the same pool of nutrients. We show that a single human cell can harbour Chlamydia and Toxoplasma. In co-infected cells, Toxoplasma is able to divert the content of host organelles, such as cholesterol. Consequently, the infectious cycle of Toxoplasma progresses unimpeded. In contrast, Chlamydia's ability to scavenge selected nutrients is diminished, and the bacterium shifts to a stress-induced persistent growth. Parasite killing engenders an ordered return to normal chlamydial development. We demonstrate that C. trachomatis enters a stress-induced persistence phenotype as a direct result from being barred from its normal nutrient supplies as addition of excess nutrients, e.g. amino acids, leads to substantial recovery of Chlamydia growth and infectivity. Co-infection of C. trachomatis with slow growing strains of Toxoplasma or a mutant impaired in nutrient acquisition does not restrict chlamydial development. Conversely, Toxoplasma growth is halted in cells infected with the highly virulent Chlamydia psittaci. This study illustrates the key role that cellular remodelling plays in the exploitation of host intracellular resources by Toxoplasma and Chlamydia. It further highlights the delicate balance between success and failure of infection by intracellular pathogens in a co-infection system at the cellular level. PMID- 23107295 TI - The use of type 1 collagen scaffold containing stromal cell-derived factor-1 to create a matrix environment conducive to partial-thickness cartilage defects repair. AB - Despite the presence of cartilage-derived mesenchymal stem cells (C-MSCs) and synovial membrane-derived mesenchymal stem cells (SM-MSCs) populations, partial thickness cartilage defects, in contrast to the full-thickness defects, are devoid of spontaneous repair capacity. This study aims to create an in situ matrix environment conducive to C-MSCs and SM-MSCs to promote cartilage self repair. Spontaneous repair with MSCs migration into the defect area was observed in full-thickness defects, but not in partial-thickness defects in rabbit model. Ex vivo and in vitro studies showed that subchondral bone or type 1 collagen (col1) scaffold was more permissive for MSCs adhesion than cartilage or type 2 collagen (col2) scaffold and induced robust stromal cell-derived factors-1 (SDF 1) dependent migration of MSCs. Furthermore, creating a matrix environment with col1 scaffold containing SDF-1 enhanced in situ self-repair of partial-thickness defects in rabbit 6 weeks post-injury. Hence, the inferior self-repair capacity in partial-thickness defects is partially owing to the non-permissive matrix environment. Creating an in situ matrix environment conducive to C-MSCs and SM MSCs migration and adhesion with col1 scaffold containing SDF-1 can be exploited to improve self-repair capacity of cartilage. PMID- 23107296 TI - The role of integrin-linked kinase/beta-catenin pathway in the enhanced MG63 differentiation by micro/nano-textured topography. AB - Micro/nano-texturing is a promising approach to produce biomaterials with better tissue integration properties, but the underlying mechanisms are only partially understood. We propose that the integrin-linked kinase (ILK)/beta-catenin pathway may play a role in mediating the signals of topographical cues to cells. To confirm the hypothesis, human MG63 osteoblasts are cultured on the micro/nano textured topographies (MNTs) to assess the cell differentiation in terms of collagen secretion, extracellular matrix mineralization, and osteogenesis-related gene expression. The expression of beta-catenin, ILK and integrin beta1 and beta3 is assayed by real-time polymerase chain reaction and the protein levels of beta catenin, phosphorylated glycogen synthase kinase 3beta (p-GSK3beta) and ILK are determined by western blot. The ILK silenced MG63 induced by small interfering RNA is cultured on the samples and the cell functions and the levels of beta catenin, GSK3beta and p-GSK3beta are determined. The results show that the MNTs enhance MG63 differentiation and it is related to the higher expression of integrin beta1 and beta3 and ILK, which activate the beta-catenin signaling by initiating beta-catenin expression and inhibiting its degradation by phosphorylating GSK3beta. ILK silencing attenuates the beta-catenin signaling activation and the enhanced MG63 differentiation by the MNTs. Our results explicitly demonstrate the role of the ILK/beta-catenin pathway in mediating the signals from topographical cues to osteoblasts to tailor differentiation and provide new target points for biomaterials modification and biofunctionalization to attain better clinical performance. PMID- 23107297 TI - Anti-tumor immune responses of tumor-associated macrophages via toll-like receptor 4 triggered by cationic polymers. AB - Agonists of toll-like receptors (TLRs) are potential therapeutic reagents for cancer immunotherapy. Cationic polymers such as polyethyleneimine (PEI) with nucleic acid drug delivery capability are approved for use in clinical trials, and recent reports indicate that these cationic polymers have significant immunological activity mediated by TLRs. In the present study, we demonstrated that cationic polymers such as PEI and cationic dextran could reverse tumor associated macrophages (TAMs) polarization and promote IL-12 expression both in vitro and in vivo. The stimulatory role of cationic polymers was remarkably attenuated in TAMs pre-treated with TLR-4 blocking antibody or TAMs from TLR-4 knockout mice. Additionally, these cationic polymers exerted direct tumoricidal activity by promoting Th 1 and NK cell infiltration, suppressing tumor angiogenesis and prolonging the survival of sarcoma-bearing wild-type. These phenomena were abrogated in TLR-4 knockout mice, suggesting that the immune stimulation was primarily mediated by TLR-4. In conclusion, these results demonstrated that cationic polymers could transform the immunotolerogenic phenotype of TAMs through TLR-4 signaling, thereby promoting therapeutic anti tumor immunity. Our present study suggests a new class of drugs as a candidate for future cancer immunotherapy. PMID- 23107298 TI - Impact of cilostazol on angiographic restenosis after balloon angioplasty for infrapopliteal artery disease in patients with critical limb ischemia. AB - OBJECTIVE: To investigate whether cilostazol reduces restenosis and revascularization after infrapopliteal angioplasty. DESIGN: This study was a retrospective analysis of a multicenter prospective registry. MATERIALS AND METHODS: Between February and April 2011, 63 patients (68 limbs, 101 lesions) with critical limb ischemia (CLI) were enrolled. Of these, 32 were cilostazol treated and 31 were the non-cilostazol-treated group. Outcome measures were binary restenosis by angiogram, reocclusion, target lesion revascularization (TLR), limb salvage rate and complete wound healing at 3 months. RESULT: Procedural success was obtained in all patients. The backgrounds and lesion characteristics of patients with isolated tibial artery disease and CLI did not differ significantly between the two groups. In a lesion-based analysis, binary restenosis and reocclusion were significantly lower in the cilostazol group than in the non-cilostazol group (56.8% vs. 86.0%; p = 0.015, 20.5% vs. 43.6%; p = 0.015, respectively). The TLR was also significantly lower in the cilostazol group (27.5% vs. 52.8%, p = 0.014). After adjustment for covariables, cilostazol was found to be associated with reduced angiographic restenosis, reocclusion and TLR rates in CLI patients at 3 months after infrapopliteal angioplasty. However, it remained unclear whether cilostazol was also associated with improved clinical outcomes. CONCLUSION: Cilostazol may be associated with reduced restenosis, reocclusion and clinically driven TLR at 3 months after infrapopliteal angioplasty. PMID- 23107299 TI - Robust outcome models safeguard patients and surgeons alike. PMID- 23107300 TI - Comment on: 'Effects of statin therapy on abdominal aortic aneurysm growth: a meta-analysis and meta-regression of observational comparative studies'. PMID- 23107301 TI - AARC clinical practice guideline: transcutaneous monitoring of carbon dioxide and oxygen: 2012. AB - An electronic literature search for articles published between January 1990 and September 2011 was conducted by using the PubMed, CINAHL, SCOPUS, and Cochrane Library databases. The update of this clinical practice guideline is the result of reviewing a total of 124 articles: 3 randomized controlled trials, 103 prospective trials, 1 retrospective study, 3 case studies, 11 review articles, 2 surveys and 1 consensus paper on transcutaneous monitoring (TCM) for P(tcO(2)) and P(tcCO(2)). The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria: (1) Although P(tcCO(2)) has a good correlation with P(aCO(2)) and is a reliable method to evaluate plasma CO(2) levels, it is recommended that arterial blood gas values be compared to transcutaneous readings taken at the time of arterial sampling, in order to verify the transcutaneous values, and periodically as dictated by the patient's clinical condition. (2) It is suggested that P(tcCO(2)) may be used in clinical settings where monitoring the adequacy of ventilation is indicated. (3) It is suggested that P(tcO(2)) and P(tcCO(2)) may be used in determining the adequacy of tissue perfusion and monitoring of reperfusion. (4) It is suggested that TCM should be avoided in the presence of increased thickness or edema of the skin and/or subcutaneous tissue where the sensor is applied. (5) It is recommended that sites used for a TCM be changed as often as necessary and that they be alternated and observed to avoid thermal injury. Manufacturer recommendations should be followed. PMID- 23107302 TI - Where should the recruitment maneuver go? PMID- 23107303 TI - Inhaled anesthetic for life-threatening bronchospasm: is it ready for prime time? PMID- 23107304 TI - Carbon dioxide entrainment during high-frequency oscillatory ventilation: a model analysis. PMID- 23107305 TI - Conjugated linoleic acid or omega 3 fatty acids increase mitochondrial biosynthesis and metabolism in skeletal muscle cells. AB - BACKGROUND: Polyunsaturated fatty acids are popular dietary supplements advertised to contribute to weight loss by increasing fat metabolism in liver, but the effects on overall muscle metabolism are less established. We evaluated the effects of conjugated linoleic acid (CLA) or combination omega 3 on metabolic characteristics in muscle cells. METHODS: Human rhabdomyosarcoma cells were treated with either DMSO control, or CLA or combination omega 3 for 24 or 48 hours. RNA was determined using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Mitochondrial content was determined using flow cytometry and immunohistochemistry. Metabolism was quantified by measuring extracellular acidification and oxygen consumption rates. RESULTS: Omega 3 significantly induced metabolic genes as well as oxidative metabolism (oxygen consumption), glycolytic capacity (extracellular acidification), and metabolic rate compared with control. Both treatments significantly increased mitochondrial content. CONCLUSION: Omega 3 fatty acids appear to enhance glycolytic, oxidative, and total metabolism. Moreover, both omega 3 and CLA treatment significantly increase mitochondrial content compared with control. PMID- 23107306 TI - Myocardial scars correlate with eletrocardiographic changes in chronic Trypanosoma cruzi infection for dogs treated with Benznidazole. AB - OBJECTIVES: The cardiac form of Chagas disease is evidenced by a progressive cardiac inflammation that leads to myocarditis, fibrosis and electrocardiographic (ECG) conduction abnormalities. Considering these characteristics, the aim of this study was to prospectively evaluate the early ECG changes in dogs that were experimentally inoculated with Benznidazole (Bz)-susceptibly (Berenice-78) and Bz resistant (VL-10, and AAS) Trypanosoma cruzi strains and, later, evaluate the efficacy of Bz treatment for preventing these ECG alterations. METHODS: Electrocardiographic changes of treated and untreated animals were prospectively evaluated for up to 270 days after infection, at which point collagen (right atrium) quantification was performed. RESULTS: All infected dogs had a high intensity of heart fibrosis (4616.00 +/- 1715.82 collagen/74931 MUm(2) in dogs infected with Berenice-78 strain, 5839.2 +/- 1423.49 collagen/74931 MUm(2) in infected by AAS and 6294.40 +/- 896.04 collagen/74931 MUm(2) in animals infected with VL-10 strain), while 78.57% of all infected dogs showed ECG alterations. Bz Therapy reduced or prevented fibrosis in Bz-susceptible Berenice-78 (2813.00 +/- 607.13 collagen/74931 MUm(2) ) and Bz-resistant AAS strains (4024 +/- 1272.44 collagen/74931 MUm(2) ), coincident with only 10% de ECG alterations at 270 days. However, in those animals infected with a Bz-resistant VL-10 strain, specific treatment did not alter collagen deposition (6749.5 +/- 1596.35 collagen/74931 MUm(2) ) and there was first atrioventricular block and chamber overload at 120 and 270 days after infection, with 75% abnormal ECG exams. CONCLUSIONS: These findings indicate that an effective antiparasitic treatment in the early stage of Chagas disease can lead to a significant reduction in the frequency and severity of the parasite-induced cardiac disease, even if parasites are not completely eliminated. PMID- 23107308 TI - Non-suture technique for rabbit oviduct anastomosis with 2-octyl cyanoacrylate: a histopathologic and biomechanical analysis. AB - AIM: The aim of this study was to investigate histological and biomechanical properties of oviduct anastomosis with 2-octyl cyanoacrylate (OCA) in the rabbit. MATERIAL AND METHODS: Sixty female rabbits were randomly divided equally into three groups: A (control), B (traditional catgut suture), and C (non-suture technique using OCA). After suture or OCA anastomosis, gross examination (adhesion formation) and histopathology (hematoxylin-eosin), ultrastructure (transmission electron microscopy), and biomechanics (bursting pressure) on para anastomotic site were investigated on oviduct taken at 1 (A1, B1, C1) and 4 (A2, B2, C2) weeks, respectively. RESULTS: Adhesion score in group B was more severe than that in groups A and C at 1 and 4 weeks. Histopathology showed that acute endosalpingitis in group B was the most intense at 1 week, followed by significantly more tissue stimulation induced by catgut and foreign-body giant cells in group B than in group C at 4 weeks. Ultrastructural damage of ciliated cells was reversed partly (B2) and completely (C2) at 4 weeks. Bursting pressure in C1 was weaker than that in B1, followed by no significant difference at 4 weeks. CONCLUSION: Non-suture using OCA for oviduct anastomosis can be accepted as a new-perspective technique. PMID- 23107309 TI - A conserved HLA-A*02:28 associated HLA haplotype, A*02:28-B*15:11-DRB1*09:01, restricted to Taiwanese. AB - HLA-A*02:28, found in a Korean and a Japanese, was reported independently to the IMGT/HLA database in 2003 and 2005, respectively. We report here eight Taiwanese unrelated bone marrow hematopoietic stem cell donors carrying A*02:28 detected during our routine HLA typing exercise. The probable HLA-A, -B and -DRB1 haplotype in association with A*02:28 may be deduced from the eight marrow stem cell donor as A*02:28-B*15:11-DRB1*09:01. Our result suggests A*02:28-B*15:11 DRB1*09:01 is a conserved HLA haplotype restricted to Taiwanese. PMID- 23107307 TI - Sex differences in fear conditioning in posttraumatic stress disorder. AB - BACKGROUND: Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined. METHODS: Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer generated colored circles that were paired (CS+) or unpaired (CS-) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task. RESULTS: Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS- trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD. CONCLUSIONS: In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD. PMID- 23107310 TI - Validation of the Cutaneous Lupus Disease Area and Severity Index (CLASI) using physician- and patient-assessed health outcome measures. AB - BACKGROUND: The Cutaneous Lupus Disease Area and Severity Index (CLASI) has not been validated using rheumatologist-conducted disease activity and damage assessments, especially cutaneous assessments. Active skin disease and skin damage may have substantial effects on patient-reported outcomes and on body image. OBJECTIVE: We sought to validate the CLASI against: (1) physician-assessed disease activity and damage measures; and (2) patient-reported assessment of quality of life and body image. METHODS: Cross-sectional data were collected from 31 patients with cutaneous lupus erythematosus. Cutaneous disease activity and damage were measured by using the CLASI. Disease activity (using the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus [SLE] Disease Activity Index [SLEDAI}), damage (Systemic Lupus International Collaboration Clinics-American College of Rheumatology Damage Index [SDI]), quality of life (LupusPRO), and body image (Body Image Quality of Life Inventory) were obtained. Descriptive statistics and Spearman correlations were ascertained. RESULTS: Mean (SD) age was 42.3 (12.8) years; 97% were women. The mean (SD) CLASI activity and damage scores were 10.5 (7.4) and 9.9 (9.5). Correlations noted were: total CLASI activity and SLEDAI-rash (r = 0.42, P = .02), CLASI-mucosal and SLEDAI-mucosal (r = 0.65, P = .001), CLASI-recent hair loss and SLEDAI-alopecia (r = 0.61, P = .001), and total CLASI activity and LupusPRO symptoms domain (r = 0.38, P = .04). Total CLASI-damage correlated with SDI-scarring/alopecia (r = 0.51, P = .004), SDI-extensive scarring/panniculum (r = 0.55, P = .003), and SDI skin ulceration (r = 0.36, P = .05). CLASI scalp scarring correlated with SDI skin scarring/alopecia (r = 0.94, P = .001). CLASI activity on the face and nose was associated with significant concerns on the Body Image Quality of Life Inventory. LIMITATIONS: Limitations include small sample size. CONCLUSION: CLASI activity and damage scores correlate with physician-assessed cutaneous activity and damage in cutaneous lupus erythematosus in patients with SLE. Cutaneous activity in visible areas may generate body image concerns. PMID- 23107311 TI - Fitzpatrick skin phototype is an independent predictor of squamous cell carcinoma risk after solid organ transplantation. AB - BACKGROUND: Solid organ transplant recipients (OTR) are at an increased risk of developing squamous cell carcinoma (SCC) of the skin after transplantation. In predominantly white cohorts, Fitzpatrick skin type (FST) has been reported to be a risk factor for developing posttransplantation skin cancers. OBJECTIVE: Our goal was to determine if FST is a statistically significant risk factor for the development of SCC after solid organ transplantation in a diverse US population of OTR. METHODS: A cohort of OTR completed a questionnaire of demographic factors, transplant type, FST, and skin cancer history. Univariate and multivariate analyses were performed to determine the risk factors for development of SCC after transplantation. RESULTS: As expected, male subjects had an increased risk for SCC compared with female subjects (P = .02), and those aged 50 years and older at the time of transplantation were more likely to develop SCC compared with those younger than 50 years (P < .001). The risk of SCC increased with each incremental decrease in FST, from FST VI to FST I (linear test for trend P < .001). LIMITATIONS: Our questionnaire did not ask specifically about immunosuppressive medications; instead, organ transplant category was used as a proxy for level of immunosuppression. CONCLUSIONS: FST, a patient-reported variable, is an independent risk factor for the development of SCC in OTR, and should be elicited from patients who have gone or will undergo organ transplantation. PMID- 23107312 TI - Effects of manganese on routine semen quality parameters: results from a population-based study in China. AB - BACKGROUND: Manganese (Mn) is an essential element in humans but its effect on semen quality is unclear. This study therefore aimed to assess the effects of Mn on semen quality in healthy men with no occupational exposure to Mn. METHODS: Semen samples were obtained from healthy Chinese men 20-59 years old who were recruited from six provinces in China. Individuals with urogenital tract diseases, tuberculosis, or occupational exposure to heavy metals were excluded. A questionnaire survey was conducted, and the external genitalia, semen quality, and serum Mn levels were examined. RESULTS: A total of 1,179 volunteers were enrolled in this study. The median serum Mn concentration was 8.2 MUg/L (25th percentile (P25)=3.7 MUg/L, P75=16.2 MUg/L). After adjusted area (six provinces), abstinence interval, season, registered residence, age of subjects, education level, income, smoking, and drinking, the risk of teratospermia was increased at serum Mn concentrations >19.40 MUg/L (P80) group, with an adjusted odds ratio of 2.27 (95% confidence interval: 1.18-4.37). CONCLUSION: High serum Mn levels appeared to have harmful effects on sperm morphology and motility among healthy men with no occupational exposure to Mn. PMID- 23107313 TI - Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver. AB - Poor prenatal nutrition, acting through epigenetic processes, induces persistent changes in offspring phenotype. We investigated the effect of maternal fat intake on polyunsaturated fatty acid (PUFA) status and on the epigenetic regulation of Fads2, encoding Delta6 desaturase (rate limiting in PUFA synthesis), in the adult offspring. Rats (n=6 per dietary group) were fed either 3.5% (w/w), 7% (w/w) or 21% (w/w) butter or fish oil (FO) from 14 days preconception until weaning. Offspring (n=6 males and females per dietary group) were fed 4% (w/w) soybean oil until postnatal day 77. 20:4n-6 and 22:6n-3 levels were lower in liver phosphatidylcholine (PC) and phosphatidylethanolamine and plasma PC (all P<.0001) in offspring of dams fed 21% than 3.5% or 7% fat regardless of type. Hepatic Fads2 expression related inversely to maternal dietary fat. Fads2 messenger RNA expression correlated negatively with methylation of CpGs at -623, -394, -84 and 76 bases relative to the transcription start site (all P<.005). Methylation of these CpGs was higher in offspring of dams fed 21% than 3.5% or 7% fat; FO higher than butter. Feeding adult female rats 7% fat reduced 20:4n-6 status in liver PC and Fads2 expression and increased methylation of CpGs -623, -394, -84 and -76 that reversed in animals switched from 7% to 4% fat diets. These findings suggest that fat exposure during development induces persistent changes, while adults exhibit a transient response, in hepatic PUFA status in offspring through epigenetic regulation of Fads2. Thus, epigenetic regulation of Fads2 may contribute to short- and long-term regulation of PUFA synthesis. PMID- 23107315 TI - Comparison of a frozen human foreskin fibroblast cell assay to an enzyme immunoassay and toxigenic culture for the detection of toxigenic Clostridium difficile. AB - This study set out to validate the Hs27 ReadyCell assay (RCCNA) as an alternative CCNA method compared against a commonly used commercial enzyme immunoassay (EIA) method and toxigenic culture (TC) reference standard. A total of 860 samples were identified from those submitted to the Health Protection Agency microbiology laboratories over a 30-week period. RCCNA performed much better than EIA when using TC as a gold standard, with sensitivities of 90.8% versus 78.6% and positive predictive value of 87.3% to 81.9%, respectively. The Hs27 Human Foreskin Fibroblast ReadyCells are an easy-to-use and a sensitive CCNA method for the detection of toxigenic Clostridium difficile directly from stool. A turnaround time of up to 48 h for a negative result and possible need for repeat testing make it an unsuitable method to be used in most clinical laboratory setting. PMID- 23107314 TI - Regional differences in clinical care among patients with type 1 diabetes in Brazil: Brazilian Type 1 Diabetes Study Group. AB - BACKGROUND: To determine the characteristics of clinical care offered to type 1 diabetic patients across the four distinct regions of Brazil, with geographic and contrasting socioeconomic differences. Glycemic control, prevalence of cardiovascular risk factors, screening for chronic complications and the frequency that the recommended treatment goals were met using the American Diabetes Association guidelines were evaluated. METHODS: This was a cross sectional, multicenter study conducted from December 2008 to December 2010 in 28 secondary and tertiary care public clinics in 20 Brazilian cities in north/northeast, mid-west, southeast and south regions. The data were obtained from 3,591 patients (56.0% females and 57.1% Caucasians) aged 21.2 +/- 11.7 years with a disease duration of 9.6 +/- 8.1 years (<1 to 50 years). RESULTS: Overall, 18.4% patients had HbA1c levels <7.0%, and 47.5% patients had HbA1c levels >= 9%. HbA1c levels were associated with lower economic status, female gender, age and the daily frequency of self-blood glucose monitoring (SBGM) but not with insulin regimen and geographic region. Hypertension was more frequent in the mid-west (32%) and north/northeast (25%) than in the southeast (19%) and south (17%) regions (p<0.001). More patients from the southeast region achieved LDL cholesterol goals and were treated with statins (p<0.001). Fewer patients from the north/northeast and mid-west regions were screened for retinopathy and nephropathy, compared with patients from the south and southeast. Patients from the south/southeast regions had more intensive insulin regimens than patients from the north/northeast and mid-west regions (p<0.001). The most common insulin therapy combination was intermediate-acting with regular human insulin, mainly in the north/northeast region (p<0.001). The combination of insulin glargine with lispro and glulisine was more frequently used in the mid-west region (p<0.001). Patients from the north/northeast region were younger, non-Caucasian, from lower economic status, used less continuous subcutaneous insulin infusion, performed less SBGM and were less overweight/obese (p<0.001). CONCLUSIONS: A majority of patients, mainly in the north/northeast and mid-west regions, did not meet metabolic control goals and were not screened for diabetes-related chronic complications. These results should guide governmental health policy decisions, specific to each geographic region, to improve diabetes care and decrease the negative impact diabetes has on the public health system. PMID- 23107316 TI - Comparison of immunologic and molecular assays for the diagnosis of gastrointestinal viral infections. AB - The performance of immunochromatographic and enzyme-linked immunosorbent assays (RIDA(r)QUICK and RIDASCREEN(r), R-Biopharm) was compared with real-time reverse transcription-polymerase chain reaction techniques for the diagnosis of gastrointestinal viral infections. The sensitivity of the immunologic methods was comparable to polymerase chain reaction for the diagnosis of rotavirus and astrovirus, while it was reduced for detection of norovirus and adenovirus. PMID- 23107317 TI - Evaluation of the radiopacity of luting cements by digital radiography. AB - PURPOSE: The aim of this study was to evaluate the radiopacity of eight contemporary luting cements using direct digital radiography. MATERIALS AND METHODS: Ten specimens, (5 mm diameter, 1 mm high) were prepared for each material tested (RelyX ARC, RelyX U100, RelyX Unicem, Nexus 2, Nexus 3, Metacem, Breeze, Adhesor zinc phosphate). The specimens were stored in a moist chamber at 37 degrees C until completely set, then radiographed using a Kodak digital sensor and an aluminum step wedge with variable thicknesses (1 to 13 mm in 1-mm increments) used for reference. A Kodak 2100 intraoral X-ray unit was operated at 60 kV, 7 mA, and 0.20 seconds. According to international standards, the radiopacity of the specimens was compared with that of the aluminum step wedge using the equal-density area tool of the Kodak Dental Imaging software (ver. 6.7). Data were analyzed by ANOVA and Tukey's test. RESULTS: Adhesor zinc phosphate cement showed the highest radiopacity of all materials and dentin. Breeze showed the lowest radiopacity (p < 0.05). No significant difference in radiopacity was observed between dentin and RelyX ARC, Nexus 2, or Metacem (p > 0.05). The radiopacities of Nexus 3 and RelyX Unicem were significantly higher than those of other resin cements and dentin (p < 0.05). CONCLUSIONS: All materials showed radiopacity above the minimum recommended by the International Organization for Standardization and the American National Standards/American Dental Association. Breeze had less radiopacity than dentin. PMID- 23107318 TI - A new brace treatment similar for adolescent scoliosis and kyphosis based on restoration of thoracolumbar lordosis. Radiological and subjective clinical results after at least one year of treatment. AB - STUDY DESIGN: A prospective treatment study with a new brace was conducted Objective. To evaluate radiological and subjective clinical results after one year conservative brace treatment with pressure onto lordosis at the thoracolumbar joint in children with scoliosis and kyphosis. SUMMARY OF BACKGROUND DATA: Conservative brace treatment of adolescent scoliosis is not proven to be effective in terms of lasting correction. Conservative treatment in kyphotic deformities may lead to satisfactory correction. None of the brace or casting techniques is based on sagittal forces only applied at the thoracolumbar spine (TLI= thoracolumbar lordotic intervention). Previously we showed in patients with scoliosis after forced lordosis at the thoracolumbar spine a radiological instantaneous reduction in both coronal curves of double major scoliosis. METHODS: A consecutive series of 91 children with adolescent scoliosis and kyphosis were treated with a modified symmetric 30 degrees Boston brace to ensure only forced lordosis at the thoracolumbar spine. Scoliosis was defined with a Cobb angle of at least one of the curves [greater than or equal to] 25 degrees and kyphosis with or without a curve <25 degrees in the coronal plane. Standing radiographs were made i) at start, ii) in brace at beginning and iii) after one year treatment without brace. RESULTS: Before treatment start 'in brace' radiographs showed a strong reduction of the Cobb angles in different curves in kyphosis and scoliosis groups (sagittal n = 5 all p < 0.001, pelvic obliquity p < 0.001). After one year of brace treatment in scoliosis and kyphosis group the measurements on radiographs made without brace revealed an improvement in 3 Cobb angles each. CONCLUSION: Conservative treatment using thoracolumbar lordotic intervention in scoliotic and kyphotic deformities in adolescence demonstrates a marked improvement after one year also in clinical and postural criteria. An effect not obtained with current brace techniques. PMID- 23107319 TI - A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma. AB - What's known on the subject? and What does the study add? A few published studies investigating single or various PI3K/AKT/mTOR signalling components have produced inconsistent results. Moreover, PI3K regulatory subunit p85a and activated p70S6K expression levels have not been previously examined in urothelial carcinoma (UC). The present study addresses simultaneously all key members of PI3K/AKT/mTOR signalling cascade supporting a differential implication of PI3K/AKT/mTOR pathway components in urothelial tumorigenesis. Furthermore, we propose p-4E-BP1 as a potential prognostic marker in UC, which might assist the selection of patients more likely to benefit from chemotherapy regimens based on PI3K/AKT/mTOR pathway inhibition. Finally, the present study indicates PIK3CA/AKT1 mutational status as a potential predictive marker for time-to-recurrence. OBJECTIVE: * To perform a comprehensive simultaneous assessment of all key members of phosphoinositide 3 kinase/v-akt murine thymoma viral oncogene/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway along with AKT homolog 1 (AKT1) and PIK3 catalytic alpha polypeptide (PIK3CA) mutations in bladder urothelial carcinoma (UC). * Published information is limited to a few studies looking into single or various combinations of members of this pathway with inconsistent results. In particular the expression status of phosphorylated (p-)p70S6 kinase (p70S6K) and p85a subunit of PI3K has not been tested in UC. PATIENTS AND METHODS: * Paraffin embedded transurethral resection tissue from 113 patients with UC was investigated for the association of p85aPI3K, p-AKT, p-mTOR, p-p70S6K and p-4E BP1 (eukaryotic initiation factor 4E-binding protein 1) expression status, as well as PIK3CA and AKT1 mutations with p-extracellular signal-regulated kinase 1/2 (ERK1/2), fibroblast growth factor receptor 3 (FGFR3), pathological features, recurrence and cancer-specific survival. RESULTS: * With the exception of p p70S6K, all others components of the PI3K/AKT/mTOR pathway were upregulated in UCs as compared with normal urothelium. * p-mTOR expression strongly correlated with its upstream p-AKT and marginally with its downstream p-p70S6K. p85aPI3K and p-ERK1/2 levels were also marginally correlated. * PIK3CA and AKT1 mutations were distinctly uncommon and mutually exclusive, without any association with pathological features. However, the presence of AKT1 mutations was associated with increased FGFR3 levels and was restricted to p85aPI3K immunonegative cases, whereas PIK3CA mutant cases had marginally lower p85aPI3K levels. * The presence of PIK3CA single or combined with AKT1 mutations was associated with shorter recurrence-free survival in univariate survival analysis. An inverse relationship was established between p-4E-BP1 immunopositivity and histological grade or T category, as well as between p-p70S6K levels and T category, the latter relationship being of marginal significance. * p-4E-BP1 nuclear expression was marginally associated with the presence of lymphovascular invasion and adversely affected survival in multivariate, but not in univariate analysis. CONCLUSIONS: * PI3K/AKT/mTOR signalling components appear to be differentially implicated in urothelial tumorigenesis and, with the exception of p85aPI3K, are unrelated to the PIK3CA or AKT1 mutational status. * Our findings propose p-4E-BP1 as a potential prognostic marker in UC independent of its association with pathological features, which might assist the selection of patients more likely to benefit from PI3K/AKT/mTOR axis inhibition. * PIK3CA/AKT1 mutational status may have a place in the prediction of time-to-recurrence. PMID- 23107320 TI - Simple binary segmentation frameworks for identifying variation in DNA copy number. AB - BACKGROUND: Variation in DNA copy number, due to gains and losses of chromosome segments, is common. A first step for analyzing DNA copy number data is to identify amplified or deleted regions in individuals. To locate such regions, we propose a circular binary segmentation procedure, which is based on a sequence of nested hypothesis tests, each using the Bayesian information criterion. RESULTS: Our procedure is convenient for analyzing DNA copy number in two general situations: (1) when using data from multiple sources and (2) when using cohort analysis of multiple patients suffering from the same type of cancer. In the first case, data from multiple sources such as different platforms, labs, or preprocessing methods are used to study variation in copy number in the same individual. Combining these sources provides a higher resolution, which leads to a more detailed genome-wide survey of the individual. In this case, we provide a simple statistical framework to derive a consensus molecular signature. In the framework, the multiple sequences from various sources are integrated into a single sequence, and then the proposed segmentation procedure is applied to this sequence to detect aberrant regions. In the second case, cohort analysis of multiple patients is carried out to derive overall molecular signatures for the cohort. For this case, we provide another simple statistical framework in which data across multiple profiles is standardized before segmentation. The proposed segmentation procedure is then applied to the standardized profiles one at a time to detect aberrant regions. Any such regions that are common across two or more profiles are probably real and may play important roles in the cancer pathogenesis process. CONCLUSIONS: The main advantages of the proposed procedure are flexibility and simplicity. PMID- 23107322 TI - Systemic sclerosis - focus on dermatological aspects. Part 2: diagnostics, therapy. AB - Systemic sclerosis is a chronic inflammatory multiorgan disease which may involve the skin and internal organs to a varying extent. Pathogenetically the vasculature, connective tissue and the immune system are involved in a yet to be defined sequence and impact. Case history and results of physical as well as laboratory examinations will determine individually adapted further organ imaging or invasive procedures. Based on their results therapy is initiated which may include supportive measures such as physiotherapy as well as basic skin care and avoidance of any trauma. Many agents are available for the circulatory problems including Raynaud phenomenon and digital ulcers such as calcium channel blockers, ACE inhibitors and intravenous prostacyclin derivatives, as well as endothelin receptor blockers and phosphodiesterase inhibitors. Immunosuppressive and immunomodulatory agents are of varying efficacy depending on organ involvement. Though various therapeutic measures are available, beneficial effects are limited and associated with various unwanted effects. In any case, the therapy has to be individually adapted to the disease stage and course of the disease. PMID- 23107326 TI - Cell-based therapies for epidermolysis bullosa - from bench to bedside. AB - Significant progress has been made over the past two decades in molecular genetics of epidermolysis bullosa (EB), a group of heritable blistering disorders, with diagnostic and prognostic implications. More recently, novel molecular approaches have been developed towards potential treatment of EB, with emphasis on gene-, protein-, and cell-based strategies. This overview highlights cell-based approaches that have recently been tested in pilot clinical trials, attesting to the potential of regenerative medicine for blistering skin diseases. PMID- 23107328 TI - Post-implantation erythema. PMID- 23107332 TI - Submental transposition flap for a large defect after excision of a recurrent basal cell carcinoma on the chin. PMID- 23107337 TI - Comparison of national gestational weight gain guidelines and energy intake recommendations. AB - Although data showing adverse effects with high and low gestational weight gain (GWG) come from a large number of countries, a variety of guidelines about the GWG exist. Our objectives were to compare existing GWG and energy recommendations across various countries, as well as the rationale or evidence on which they were based. We used the United Nations' Human Developmental Index to determine the ranking of the country to ensure broad sampling and then searched for guidelines. We first searched the national government websites, and if necessary searched Medline and EMBASE, Global Health databases, and bibliographies of published articles for both guidelines and the studies on which they were based. We found guidelines for 31% of the countries, and 59% of these had a GWG recommendation, 68% had an energy intake recommendation (EIR), and 36% had both. About half of the GWG guidelines are similar to the 2009 American Institutes of Medicine (IOM) and 73% of the EIRs are similar to the 2006 IOM. Despite the documented relationship between both high GWG and adverse outcomes for women and infants and low GWG and adverse outcomes in infants, there are a wide variety of guidelines for GWG and energy recommendations by different countries around the world. PMID- 23107338 TI - C-kit expression in spermatogonia damaged by doxorubicin exposure in mice. AB - AIM: The purpose of this study was to assess the relationship between chronically impaired spermatogenesis induced by exposing mice to doxorubicin (DXR) and expression of the infertility factor c-kit. METHOD: Eight-week-old male Institute for Cancer Research (ICR) mice were intraperitoneally treated with DXR (0.15 mg/kg, DXR group) or saline (0.15 mg/kg, control group) twice weekly for five weeks and were killed 14 weeks after initial exposure. The animals were sacrificed and bilateral testes were removed and weighed. The testes were stored for the mRNA assay and were fixed for immunohistochemistry. Some testicular samples were fixed in 10% formalin for histopathological examination. RESULTS: Testicular weight (67.6 +/- 9.7 mg, P < 0.05), sperm motility (18 +/- 6.0%, P < 0.05) and the fertilization rate (2-to-16-cell embryos, 5%; P < 0.05) were significantly lower in the DXR group than in the control group. In the DXR group there was severe tissue damage from the spermatogonia onward, and the Sertoli cell ratio was lower in the DXR group than in the control group (38% vs. 9%, P < 0.05). In addition, there was a decrease in c-kit protein expression, and the amount of c-kit messenger ribonucleic acid (mRNA) expression according to a semiquantitative method was also decreased. CONCLUSION: Expression of c-kit in the mice with chronically impaired spermatogenesis induced by long-term, low-dose administration of DXR correlated with the decrease in the number of spermatogonia. PMID- 23107339 TI - Clinical efficacy of botanical extracts from Eupatorium adenophorum against the scab mite, Psoroptes cuniculi. AB - This study evaluated the in vivo clinical efficacy of Crofton weed (Eupatorium adenophorum) extracts against the scab mite, Psoroptes cuniculi. A 30-day experiment was performed using New Zealand rabbits that were naturally infested with P. cuniculi on a farm. Rabbits were randomly divided into five groups (6 animals per group); animals in groups A, B and C were treated in each ear topically with 2 ml of 1.0, 0.5 and 0.25 g/ml (w/v) E. adenophorum ethanol extract, respectively. Animals in groups D and E were treated with ivermectin (by injection; positive controls) and glycerol with water only (by embrocation; negative controls), respectively. Each rabbit was treated twice with separate treatments on days 0 and 7. Rabbits were observed daily and detailed examinations were performed on days 0, 7, 14 and 30, to inspect the presence or absence of mites and scabs/crusts. Clinical infection and the degree of recovery were evaluated, and the rate of reduction in mites and clinical efficacy rate (%) were calculated. The clinical effect of treatment with E. adenophorum extracts was similar to treatment with ivermectin. Seven days after the initial treatment, the mean clinical scores (presence of scabs/crusts) decreased from 3.32, 3.08 and 3.17 to 0.37, 0.47 and 0.48 in the left ears of animals in groups A, B and C, respectively, and from 3.53, 3.73 and 3.67 to 0.40, 0.45 and 0.48 in the right ears of animals in groups A, B and C, respectively, which were similar to the observations recorded in the positive control rabbits. However, the clinical score for negative control rabbits did not decrease significantly (P>0.05) during the experiment, and this changed from 3.32 to 2.75 in the left ears and from 3.50 to 3.25 in the right ears, and there were no significant differences in clinical efficacy between left and right ears. After two treatments (7 days space), the rabbits in groups A, B, C and D had recovered completely 30 days after the last treatment and no recurrences of infection were observed. These results indicate that E. adenophorum contains potent compounds for the effective control of animal acariasis. PMID- 23107340 TI - The reliability and validity of physiotherapist visual rating of dynamic pelvis and knee alignment in young athletes. AB - PURPOSE: To investigate visual rating of pelvis and knee position in young athletes during lower extremity functional tests. METHODS: Pelvis and knee alignment, in 23 athletes, was visually rated by 66 physiotherapists. Peak two dimensional (2D) and three-dimensional (3D) kinematics were also quantified. Ratings were compared to consensus visual ratings of an expert panel. The consensus ratings were also compared to peak kinematics. Reliability was determined using percentage agreement (PA) and the first order agreement coefficient (AC1). Sensitivity, specificity, diagnostic odds ratio (DOR) and differences in kinematics between groups based on the expert visual ratings were calculated to assess rating validity. RESULTS: Mean intra-rater agreement was substantial (PA: 79-88%, AC1: 0.60-0.78). Inter-rater agreement ranged from fair to substantial (PA: 67-80%; AC1: 0.37-0.61). Sensitivity (>=80%) and specificity (>=50%) were acceptable for all tests except the Drop Jump. Experience (DOR 1.6 2.8 times better) and slower movement (4.9 times better) improved rating accuracy. Peak 3D and 2D kinematics were different between groups rated as having good versus poor alignment by the experts. CONCLUSIONS: Visual rating by physiotherapists is a valid tool for identifying young athletes with poor frontal plane dynamic pelvis and knee alignment. PMID- 23107343 TI - Clinical experience with stem cells and other cell therapies in neurological diseases. AB - To overcome the limited capacity of the CNS for regeneration, the theoretical alternative would be to use stem cells for more effective management of chronic degenerative and inflammatory neurological conditions, and also of acute neuronal damage from injuries or cerebrovascular diseases. Although the adult brain contains small numbers of stem cells in restricted areas, this intrinsic stem cell repertoire is small and does not measurably contribute to functional recovery. Embryonic cells carrying pluripotent and self-renewal properties represent the stem cell prototype, but there are additional somatic stem cells that may be harvested and expanded from various tissues during adult life. Stem cell transplantation is based on the assumption that such cells may have the potential to regenerate or support the survival of the existing, partially damaged cells. This review summarizes the state-of-the-art and the clinical worldwide experience with the use of various types of stem cells in neurological diseases. PMID- 23107342 TI - Role of matrix metalloproteinases 2 and 9 in ex vivo Trypanosoma cruzi infection of human placental chorionic villi. AB - BACKGROUND: Chagas' disease is caused by the haemophlagelated protozoan Trypanosoma cruzi (T. cruzi). During congenital transmission the parasite breaks down the placental barrier. In the present study we analyzed the participation of matrix metalloproteases (MMPs) in the extracellular matrix (ECM) remodeling during T. cruzi ex vivo infection of human placental chorionic villi explants. METHODS: Chorionic villi from healthy woman placentas were incubated in the presence or absence of 105 or 106 T. cruzi trypomastigotes (Y strain) with or without the MMPs inhibitor doxycycline. Effective infection was tested measuring parasite DNA by real time PCR (qPCR). MMP-2 and MMP-9 expression were determined by western blotting and immunohistochemistry and their activities were measured by zymography. The effect of MMPs on ECM structure was analyzed histochemically. RESULTS: T. cruzi induces the expression and activity of MMP-2 and MMP-9 in chorionic villi. Inhibition of the MMPs prevents the tissue damage induced by T. cruzi and partially decreases the ex vivo infection of the chorionic villi. CONCLUSION: MMPs are partially responsible for the ECM changes observed in human chorionic villi during T. cruzi infection and participate in tissue invasion. On the other hand, MMPs may be part of a local placental antiparasitic mechanism. PMID- 23107341 TI - Immunomodulatory molecules are released from the first trimester and term placenta via exosomes. AB - The semiallogenic fetus is tolerated by the maternal immune system through control of innate and adaptive immune responses. Trophoblast cells secrete nanometer scale membranous particles called exosomes, which have been implicated in modulation of the local and systemic maternal immune system. Here we investigate the possibility that exosomes secreted from the first trimester and term placenta carry HLA-G and B7 family immunomodulators. Confocal microscopy of placental sections revealed intracellular co-localization of B7-H1 with CD63, suggesting that B7-H1 associates with subcellular vesicles that give rise to exosomes. First trimester and term placental explants were then cultured for 24 h. B7H-1 (CD274), B7-H3 (CD276) and HLA-G5 were abundant in pelleted supernatants of these cultures that contained microparticles and exosomes; the latter, however, was observed only in first trimester pellets and was nearly undetectable in term explant-derived pellets. Further purification of exosomes by sucrose density fractionation confirmed the association of these proteins specifically with exosomes. Finally, culture of purified trophoblast cells in the presence or absence of EGF suggested that despite the absence of HLA-G5 association with term explant-derived exosomes, it is present in exosomes secreted from mononuclear cytotrophoblast cells. Further, differentiation of cytotrophoblast cells reduced the presence of HLA-G5 in secreted exosomes. Together, the results suggest that the immunomodulatory proteins HLA-G5, B7-H1 and B7-H3, are secreted from early and term placenta, and have important implications in the mechanisms by which trophoblast immunomodulators modify the maternal immunological environment. PMID- 23107344 TI - Human papillomavirus distribution in invasive cervical carcinoma in sub-Saharan Africa: could HIV explain the differences? AB - OBJECTIVES: To describe human papillomavirus (HPV) distribution in invasive cervical carcinoma (ICC) from Mali and Senegal and to compare type-specific relative contribution among sub-Saharan African (SSA) countries. METHODS: A multicentric study was conducted to collect paraffin-embedded blocks of ICC. Polymerase chain reaction, DNA enzyme immunoassay and line probe assay were performed for HPV detection and genotyping. Data from SSA (Mozambique, Nigeria and Uganda) and 35 other countries were compared. RESULTS: One hundred and sixty four ICC cases from Mali and Senegal were tested from which 138 were positive (adjusted prevalence = 86.8%; 95% CI = 79.7-91.7%). HPV16 and HPV18 accounted for 57.2% of infections and HPV45 for 16.7%. In SSA countries, HPV16 was less frequent than in the rest of the world (49.4%vs. 62.6%; P < 0.0001) but HPV18 and HPV45 were two times more frequent (19.3%vs. 9.4%; P < 0.0001 and 10.3%vs. 5.6%; P < 0.0001, respectively). There was an ecological correlation between HIV prevalence and the increase of HPV18 and the decrease of HPV45 in ICC in SSA (P = 0.037 for both). CONCLUSION: HPV16/18/45 accounted for two-thirds of the HPV types found in invasive cervical cancer in Mali and Senegal. Our results suggest that HIV may play a role in the underlying HPV18 and HPV45 contribution to cervical cancer, but further studies are needed to confirm this correlation. PMID- 23107345 TI - Effects of corticosteroid on the expressions of neuropeptide and cytokine mRNA and on tenocyte viability in lateral epicondylitis. AB - BACKGROUND: The purpose of this study was to determine the reaction mechanism of corticosteroid by analyzing the expression patterns of neuropeptides (substance P (SP), calcitonin gene related peptide (CGRP)) and of cytokines (interleukin (IL) 1alpha, tumor growth factor (TGF)-beta) after corticosteroid treatment in lateral epicondylitis. In addition, we also investigated whether corticosteroid influenced tenocyte viability. METHODS: The corticosteroid triamcinolone acetonide (TAA) was applied to cultured tenocytes of lateral epicondylitis, and the changes in the mRNA expressions of neuropeptides and cytokines and tenocyte viabilities were analyzed at seven time points. Quantitative real-time polymerase chain reaction and an MTT assay were used. RESULTS: The expression of SP mRNA was maximally inhibited by TAA at 24 hours but recovered at 72 hours, and the expressions of CGRP mRNA and IL-1alpha mRNA were inhibited at 24 and 3 hours, respectively. The expression of TGF-beta mRNA was not significant. Tenocyte viability was significantly reduced by TAA at 24 hours. CONCLUSIONS: We postulate that the reaction mechanism predominantly responsible for symptomatic relief after a corticosteroid injection involves the inhibitions of neuropeptides and cytokines, such as, CGRP and IL-1alpha. However the tenocyte viability was compromised by a corticosteroid. PMID- 23107346 TI - Effects of L-theanine or caffeine intake on changes in blood pressure under physical and psychological stresses. AB - BACKGROUND: L-theanine, an amino acid contained in green tea leaves, is known to block the binding of L-glutamic acid to glutamate receptors in the brain, and has been considered to cause anti-stress effects by inhibiting cortical neuron excitation. Both L-theanine and caffeine, which green tea contains, have been highlighted for their beneficial effects on cognition and mood. METHODS: In this study, we investigated the effects of orally administered L-theanine or caffeine on mental task performance and physiological activities under conditions of physical or psychological stress in humans. Fourteen participants each underwent three separate trials, in which they orally took either L-theanine + placebo, caffeine + placebo, or placebo only. RESULTS: The results after the mental tasks showed that L-theanine significantly inhibited the blood-pressure increases in a high-response group, which consisted of participants whose blood pressure increased more than average by a performance of a mental task after placebo intake. Caffeine tended to have a similar but smaller inhibition of the blood pressure increases caused by the mental tasks. The result of the Profile of Mood States after the mental tasks also showed that L-theanine reduced the Tension Anxiety scores as compared with placebo intake. CONCLUSIONS: The findings above denote that L-theanine not only reduces anxiety but also attenuates the blood pressure increase in high-stress-response adults. PMID- 23107347 TI - How valid are the 'persistent and residual antimicrobial properties' described by Beausoleil et al.? PMID- 23107348 TI - Catamenial diabetic ketoacidosis--a diagnostic dilemma in ED. PMID- 23107349 TI - Improving child health promotion practices in multiple sectors - outcomes of the Swedish Salut Programme. AB - BACKGROUND: To improve health in the population, public health interventions must be successfully implemented within organisations, requiring behaviour change in health service providers as well as in the target population group. Such behavioural change is seldom easily achieved. The purpose of this study was to examine the outcomes of a child health promotion programme (The Salut Programme) on professionals' self-reported health promotion practices, and to investigate perceived facilitators and barriers for programme implementation. METHODS: A before-and-after design was used to measure programme outcomes, and qualitative data on implementation facilitators and barriers were collected on two occasions during the implementation process. The sample included professionals in antenatal care, child health care, dental services and open pre-schools (n=144 pre implementation) in 13 out of 15 municipalities in a Swedish county. Response rates ranged between 81% and 96% at the four measurement points. RESULTS: Self reported health promotion practices and collaboration were improved in all sectors at follow up. Significant changes included: 1) an increase in the extent to which midwives in antenatal care raised issues related to men's violence against women, 2) an increase in the extent to which several lifestyle topics were raised with parents/clients in child health care and dental services, 3) an increased use of motivational interviewing (MI) and separate 'fathers visits' in child health care 4) improvements in the supply of healthy snacks and beverages in open pre-schools and 5) increased collaboration between sectors. Main facilitators for programme implementation included cross-sectoral collaboration and sector-specific work manuals/questionnaires for use as support in everyday practice. Main barriers included high workload, and shortage of time and staff. CONCLUSION: This multisectoral programme for health promotion, based on sector specific intervention packages developed and tested by end users, and introduced via interactive multisectoral seminars, shows potential for improving health promotion practices and collaboration across sectors. Consideration of the key facilitators and barriers for programme implementation as highlighted in this study can inform future improvement efforts. PMID- 23107350 TI - Household disposables as breeding habitats of dengue vectors: linking wastes and public health. AB - An assessment of the household wastes as larval habitats of the dengue vectors was made considering Kolkata, India, as geographical area. Wastes of four major categories, namely, earthen, porcelain, plastic and coconut shells were monitored for positive with immature of either Aedes aegypti or Aedes albopictus. Twenty six types of wastes with varying size and shape, resembling containers, were identified that hosted mosquito immature. The number of waste containers positive for Aedes immature varied significantly (P<0.05) with respect to location, type and month. The relative density of Aedes immature in the waste containers varied significantly (P<0.05) with the types and months. The significant interaction between the month, waste container types and density of Aedes immature suggest that the household wastes are important contributors to the maintenance of the population of Aedes mosquito in the city. Based on the relative density of mosquito immature in the wastes, cluster analysis allowed segregation and classification of the wastes and their importance as mosquito larval habitats. Apparently, the containers that are most frequently disposed off contributed largely to the sustenance of Aedes mosquito population in the city. This calls for a strict legislation towards disposal as well as enhanced management of the household wastes. A link between the wastes disposed and subsequent conversion to the mosquito larval habitats cautions for continuance of Aedes population and possibility of dengue epidemics if the existing management practices are not improved. PMID- 23107351 TI - [Giant oesophagogastric haematoma]. PMID- 23107352 TI - Relationship between body fat and masticatory function. AB - PURPOSE: The aim of this cross-sectional study was to investigate the relationship between body fat and masticatory function. MATERIALS AND METHODS: One hundred dentate and partially edentulous participants (33 male; mean age, 39.7 +/- 16.6 years) were selected. Body fat was established through body mass index (BMI). Masticatory function was evaluated by quantifying occlusal pairs and determining masticatory efficiency and swallowing threshold with the sieving method. During the swallowing threshold test, chewing rate was registered. Masticatory ability was also evaluated with a 5-point Likert scale questionnaire. Data were analyzed with Spearman and chi-square tests, as well as binary logistic regression analysis for the presence of increased BMI (alpha= 0.05). RESULTS: Age (rho = 0.517), occlusal pairs (chi-square = 26.353), masticatory efficiency (chi square = 30.935), masticatory ability (chi-square = 25.132; p < 0.001), and swallowing threshold (chi-square = 8.730; p < 0.005) were related to BMI. Age (odds ratio, OR = 1.048, 95% CI = 1.008 to 1.089) and lower masticatory efficiency (OR = 4.792, 95% CI = 1.419 to 16.183) were predictive of increased body fat (p < 0.05). Gender (chi-square = 0.402, p= 0.526) and chewing rate (rho =-0.158, p= 0.117) were not related to BMI. CONCLUSIONS: These results suggest that people with lower masticatory efficiency may be at risk for increased body fat. PMID- 23107354 TI - Cough strength, secretions and extubation outcome in burn patients who have passed a spontaneous breathing trial. AB - The aim of this study was to develop a clinical prediction model to inform decisions about the timing of extubation in burn patients who have passed a spontaneous breathing trial (SBT). Rapid shallow breathing index, voluntary cough peak flow (CPF) and endotracheal secretions were measured after each patient had passed a SBT and just prior to extubation. We used multiple logistic regression analysis to identify variables that predict extubation outcome. Seventeen patients failed their first trials of extubation (14%). CPF and endotracheal secretions are strongly associated with extubation outcome (p<0.0001). Patients with CPF <=60 L/min are 9 times as likely to fail extubation as those with CPF >60 L/min (risk ratio=9.1). Patients with abundant endotracheal secretions are 8 times as likely to fail extubation compared to those with no, mild and moderate endotracheal secretions (risk ratio=8). Our clinical prediction model combining CPF and endotracheal secretions has strong predictive capacity for extubation outcome (area under receiver operating characteristic curve=0.96, 95% confidence interval 0.91-0.99) and therefore may be useful to predict which patients will succeed or fail extubation after passing a SBT. PMID- 23107355 TI - Letter to the editor. PMID- 23107353 TI - Acceleration of insulin pharmacodynamic profile by a novel insulin infusion site warming device. AB - BACKGROUND AND OBJECTIVE: Subcutaneously injected rapid-acting insulin analogs do not replicate physiologic insulin action due to delays in their onset and peak action resulting in postprandial glucose excursions. The InsuPatch (IP) is a novel insulin infusion site warming device developed to accelerate insulin action by increasing blood flow to the area of insulin absorption. Thirteen adolescents with type 1 diabetes (T1D, mean age 14 +/- 4 yr) were enrolled in this study to investigate the effect of the IP on the pharmacodynamics and pharmacokinetics of a 0.2 unit/kg bolus dose of aspart insulin using the euglycemic clamp technique. RESEARCH DESIGN AND METHODS: Each subject underwent two euglycemic clamp procedures on separate occasions: one with IP and one without IP activation in random order. RESULTS: When the insulin bolus was given with IP activation as compared to without IP activation, time to reach maximum insulin action (T(GIRmax)) and to reach 50% maximum action (T(50%GIRmax)) were 35 and 18 min earlier (125 +/- 8 min vs. 90 +/- 6 min, p = 0.002 and 58 +/- 5 min. vs. 40 +/- 3 min, p = 0.01, respectively), and the area under curve, AUC(GIR 0-90 min), reflecting early glucodynamic action, was significantly greater (p = 0.001). IP activation also accelerated the rise in plasma insulin levels after the bolus (p = 0.03) and resulted in a higher peak (p = 0.04) and greater overall increase (p = 0.02) in plasma insulin levels. CONCLUSIONS: Our results show that insulin infusion site warming with IP activation accelerates the time action profile of aspart insulin which may be of benefit to current open-loop and future closed loop insulin delivery in patients with T1D. PMID- 23107356 TI - Mortality after treating severe burns with traditional Amish home remedies: a case report, literature review and ethical discussion. PMID- 23107357 TI - Sexual dysfunctions induced by stress of timed intercourse and medical treatment. AB - OBJECTIVE: To understand the effect of stress incurred by timed intercourse (TI) on sexual dysfunction in relation to anxiety and aggression in men facing TI. PATIENTS AND METHODS: This study involved 439 men and was conducted during a 3 year period between 1 July 2008 and 30 June 2011. Various characteristics were evaluated, including newly acquired erectile dysfunction (ED), ejaculatory dysfunction (EjD), anxiety levels (using the Beck Anxiety Inventory [BAI]), self reported aggression (using the Buss Perry Aggression Questionnaire [BPAQ]), hormone levels (such as follicle-stimulating hormone, luteinizing hormone, testosterone, prolactin and oestradiol) and semen parameters. RESULTS: A total of 188 men (42.8%) and 26 men (5.92%) experienced ED and EjD, respectively. Luteinizing hormone, testosterone and oestradiol were significantly lower in men with ED (P < 0.05). The men who required high doses of tadalafil had significantly higher scores on both the BAI and the BPAQ subscales (P < 0.001). BAI and subscales of BPAQ were higher in males with delayed ejaculation (P < 0.001). CONCLUSIONS: TI imposes a great deal of stress on male partners, potentially causing ED and EjD, and elevates anxiety levels, which leads to aggression. Physicians and clinicians should acknowledge the potentially harmful effects of TI on men. Furthermore, both female and male patients should be cautioned about the increased likelihood of ED and EjD as the number of incidents of TI increases. PMID- 23107358 TI - Surgical treatment of lumbar spinal stenosis with microdecompression and interspinous distraction device insertion. A case series. AB - BACKGROUND: Interspinous distraction devices (IPDD) are indicated as stand-alone devices for the treatment of spinal stenosis. The purpose of this study is to evaluate the results of patients undergoing surgery for spinal stenosis with a combination of unilateral microdecompression and interspinous distraction device insertion. METHODS: This is a prospective clinical and radiological study of minimum 2 years follow-up. Twenty-two patients (average age 64.5 years) with low back pain and unilateral sciatica underwent decompressive surgery for lumbar spinal stenosis. Visual Analogue Scale, Oswestry Disability Index and walking capacity plus radiologic measurements of posterior disc height of the involved level and lumbar lordosis Cobb angle were documented both preoperatively and postoperatively. One-sided posterior subarticular and foraminal decompression was conducted followed by dynamic stabilization of the diseased level with an IPDD (X STOP). RESULTS: The average follow-up time was 27.4 months. Visual Analogue Scale and Oswestry Disability Index improved statistically significantly (p < 0.001) in the last follow-up exam. Also, the walking distance increased in all patients but two. Posterior intervertebral disc height of the diseased level widened average 1.8 mm in the postoperative radiograph compared to the preoperative. No major complication, including implant failure or spinous process breakage, has been observed. CONCLUSIONS: The described surgical technique using unilateral microdecompression and IPDD insertion is a clinically effective and radiologically viable treatment method for symptoms of spinal stenosis resistant to non-operative treatment. PMID- 23107359 TI - Changes of insulin resistance and beta-cell function in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnant period: a case-control study. AB - AIM: The aim of this study was to observe insulin resistance and beta-cell function changes among women diagnosed with gestational impaired glucose tolerance or gestational diabetes mellitus (GDM) in mid-pregnancy. MATERIAL AND METHODS: Sixty-four pregnant women receiving prenatal care underwent an oral glucose tolerance test at 20-24 weeks of gestation and an insulin release test. The GDM group included 34 pregnant women diagnosed with gestational impaired glucose tolerance or GDM, and the subjects with normal blood glucose were the control group. Insulin resistance and islet beta-cell function changes were observed with the oral glucose tolerance test and insulin release test. RESULTS: The homeostatic model assessment-beta levels in late pregnancy were higher than those in mid-pregnancy for both groups, and the primary time effect was statistically significant. The early insulin secretion index (DeltaI(30)/DeltaG(30)) values in mid- and late pregnancy were lower in the GDM group. The values of the area under the curve of blood glucose in mid- and late pregnancy were higher in the GDM group than those in the control group. Insulin resistance was higher in GDM patients than in normal pregnant women. CONCLUSIONS: Insulin resistance was aggravated, and beta-cell's ability to compensate for the increased insulin resistance by modulating insulin secretion was aggravated, as gestational week increased in women with gestational diabetes and normal pregnant women. Insulin resistance in women with GDM is higher than in pregnant women with normal metabolism of glucose. PMID- 23107360 TI - Bayesian semiparametric regression models to characterize molecular evolution. AB - BACKGROUND: Statistical models and methods that associate changes in the physicochemical properties of amino acids with natural selection at the molecular level typically do not take into account the correlations between such properties. We propose a Bayesian hierarchical regression model with a generalization of the Dirichlet process prior on the distribution of the regression coefficients that describes the relationship between the changes in amino acid distances and natural selection in protein-coding DNA sequence alignments. RESULTS: The Bayesian semiparametric approach is illustrated with simulated data and the abalone lysin sperm data. Our method identifies groups of properties which, for this particular dataset, have a similar effect on evolution. The model also provides nonparametric site-specific estimates for the strength of conservation of these properties. CONCLUSIONS: The model described here is distinguished by its ability to handle a large number of amino acid properties simultaneously, while taking into account that such data can be correlated. The multi-level clustering ability of the model allows for appealing interpretations of the results in terms of properties that are roughly equivalent from the standpoint of molecular evolution. PMID- 23107361 TI - Decreased expression of microRNA let-7i and its association with chemotherapeutic response in human gastric cancer. AB - BACKGROUND: MicroRNA let-7i has been proven to be down-regulated in many human malignancies and correlated with tumor progression and anticancer drug resistance. Our study aims to characterize the contribution of miRNA let-7i to the initiation and malignant progression of locally advanced gastric cancer (LAGC), and evaluate its possible value in neoadjuvant chemotherapeutic efficacy prediction. METHODS: Eighty-six previously untreated LAGC patients who underwent preoperative chemotherapy and radical resection were included in our study. Let 7i expression was examined for pairs of cancer tissues and corresponding normal adjacent tissues (NATs), using quantitative RT-PCR. The relationship of let-7i level to clinicopathological characteristics, pathologic tumor regression grades after chemotherapy, and overall survival (OS) was also investigated. RESULTS: Let 7i was significantly down-regulated in most tumor tissues (78/86: 91%) compared with paired NATs (P < 0.001), and low levels of let-7i were significantly correlated with local invasion, lymphatic metastasis, and poor pathologic tumor response. Multivariate Cox regression analysis revealed that low let-7i expression was an unfavorable prognostic factor of OS (hazard ratio (HR) = 2.316, P = 0.024) independently of other clinicopathological factors, including tumor node metastasis (TNM) stage (HR = 3.226, P = 0.013), depth of infiltration (HR = 4.167, P < 0.001), and lymph node status (HR = 2.245, P = 0.037). CONCLUSIONS: These findings indicate that let-7i may be a good candidate for use a therapeutic target and a potential tissue marker for the prediction of chemotherapeutic sensitivity and prognosis in LAGC patients. PMID- 23107362 TI - Structured shared decision-making using dialogue and visualization: a randomized controlled trial. AB - OBJECTIVE: The aim of this study is to evaluate a method, "Counseling in Dialogue" (CD), developed to increase the quality of counseling in youth mental health. Decisional conflict was used as indicator of the quality of counseling and shared decision-making. METHODS: 94 children aged 2-12 years were randomized into a CD group and a care as usual (CU) group. In a before-and-after design decisional conflict was measured using the decisional conflict scale (DCS) for parents (N=133) and the Provider Decision Process Assessment Instrument for therapists (PDPAI, N=20). 81 children had follow-up data. RESULTS: Compared with parents of the CU group, parents of the CD group reported significantly less decisional conflict after counseling (difference mothers: -0.38 (95%CI -0.56; 0.19), p<.001; fathers: -0.22 (95%CI -0.44; -0.01), p=.045). 98% of the mothers and 96% of the fathers in the CD group accepted the recommended treatment, compared to 71% (fathers) and 77% (mothers) in the CU group, p<0.05. Decisional conflict of the therapists was low in both groups after counseling (difference: 0.03 (95%CI -0.19; 0.14), p=.741). CONCLUSION: The counseling procedure significantly lowered decisional conflict of the parents and promoted the acceptance of the recommended treatment. PMID- 23107363 TI - Identification of novel anaplastic lymphoma kinase (ALK) inhibitors using a common feature pharmacophore model derived from known ligands crystallized with ALK. AB - In this investigation, a common feature pharmacophore model of anaplastic lymphoma kinase inhibitors was developed based on several known anaplastic lymphoma kinase inhibitors that were co-crystallized with anaplastic lymphoma kinase. The established pharmacophore model Hypo1 was carefully validated and then adopted to screen two in silico chemical databases, Specs (202 408 compounds) and Enamine (1 105 894 compounds), for retrieving novel anaplastic lymphoma kinase inhibitors. The hit compounds were further filtered using a fast bumping-check tool and molecular docking. Finally, 25 compounds were selected and purchased from market. The bioactivity of these compounds was firstly measured at the cellular level against a typical anaplastic lymphoma kinase mutant-driven cancer cell line, Karpas299. And six of them showed a good anti-viability activity. The kinase inhibitory potency against the recombinant human anaplastic lymphoma kinase kinase was tested to the most active compound at the cellular level, T0508-5181 (from Specs), which gave a half maximal inhibitory concentration (IC(50)) of 5.3 MUM. PMID- 23107364 TI - Differences in neuropeptide Y-induced secretion of endothelin-1 in left and right human endocardial endothelial cells. AB - The aim of the study was to test the hypothesis that neuropeptide Y (NPY) may induce endothelin-1 (ET-1) secretion in left (hLEECs) and right (hREECs) human endocardial endothelial cells. Furthermore, the type of NPY receptor implicated could be different in NPY-induced secretion in hLEECs and hREECs. Using immunofluorescence coupled to real 3D confocal microscopy and ELISA, our results showed that stimulation of secretion by NPY induced the release of ET-1 from both right and left human ventricular endocardial endothelial cells (hEECs) in a time dependent manner. Furthermore, the secretory capacity of hREECs was higher than that of hLEECs. In addition, our results showed that the effect of NPY on ET-1 secretion in hLEECs was only due to activation of Y(5) receptors. However, the effect of NPY on ET-1 secretion in hREECs was due to mainly Y(2) and partially Y(5) receptors activation. In conclusion, our results suggest that differences in excitation-secretion coupling exist between hREECS and hLEECs which may contribute to the functional differences between right and left ventricular muscle. Furthermore, high NPY level contributes to ET-1 release by hEECs and Y(2) and Y(5) receptors antagonists may be used for regulation of ET-1 secretion in the heart. PMID- 23107365 TI - Arcuate NPY neurons sense and integrate peripheral metabolic signals to control feeding. AB - NPY neuron in the hypothalamic arcuate nucleus is a key feeding center. Studies have shown that NPY neuron in the arcuate nucleus has a role to induce food intake. The arcuate nucleus is structurally unique with lacking blood brain barrier. Peripheral energy signals including hormones and nutrition can reach the arcuate nucleus. In this review, we discuss sensing and integrating peripheral signals in NPY neurons. In the arcuate nucleus, ghrelin mainly activates NPY neurons. Leptin and insulin suppress the ghrelin-induced activation in 30-40% of the ghrelin-activated NPY neurons. Lowering glucose concentration activates 40% of NPY neurons. These results indicate that NPY neuron in the arcuate nucleus is a feeding center in which major peripheral energy signals are directly sensed and integrated. Furthermore, there are subpopulations of NPY neurons in regard to their responsiveness to peripheral signals. These findings suggest that NPY neuron in the arcuate nucleus is an essential feeding center to induce food intake in response to peripheral metabolic state. PMID- 23107366 TI - Evaluation of significant sources influencing the variation of physico-chemical parameters in Port Blair Bay, South Andaman, India by using multivariate statistics. AB - Port Blair is the capital city of Andaman & Nicobar Islands, the union territory of India. More than 50% of the population of these islands lives around Port Blair Bay. Therefore the anthropogenic effects in the bay water were studied for monitoring purpose from seven stations. Physico-chemical parameters of seawater were analyzed in samples collected once in every 3 months for 2 years from seven sampling stations located in Port Blair Bay, South Andaman Island to evaluate the spatial and tidal variation. Cluster analysis and factor analysis were applied to the experimental data in an attempt to understand the sources of variation of physico-chemical parameters. In cluster analysis, the stations Junglighat Bay and Phoenix Bay having high anthropogenic influence formed a separate group. The factors obtained from factor analysis indicated that the parameters responsible for physico-chemical variations are mainly related to land run-off, sewage outfall and tidal flow. PMID- 23107367 TI - The effects of oil exposure and weathering on black-needle rush (Juncus roemerianus) marshes along the Gulf of Mexico. AB - Oil exposure has been shown to be detrimental to several salt marsh plants however little information is available for Juncus roemerianus. Thirty-two mesocosms were established with J. roemerianus sod and replicate marshes were exposed to Louisiana sweet crude oil to test oil dose (6, 12, and 24 L m-2) and weathering (oil weathered for 0 days, 3 days, and 3 weeks). Juncus were monitored following oil exposure for culm survival, photosynthetic rates, and C assimilation rates. Oil dosage had a significant effect among wetlands with low dose (6 L m-2) mesocosms having higher culm survival, photosynthetic rates, and C assimilation rates than medium or high dose wetlands (12 or 24 L m-2). Oil weathering did not elicit significant differences between treated wetlands however full strength wetlands (un-weathered oil) consistently had the lowest culm survivorship, photosynthetic rates, and C-assimilation rates. From our results, J. roemerianus marshes may be very susceptible to oil exposure. PMID- 23107368 TI - How does scapula motion change after reverse total shoulder arthroplasty? A preliminary report. AB - BACKGROUND: Arm elevation is composed of glenohumeral and scapulothoracic motion. Many reports have addressed changes of scapular position across a spectrum of shoulder disease. However, no study has examined changes in scapular position after reverse total shoulder arthroplasty (RTSA). The purpose of this study was to evaluate the changes in scapular position after RTSA compared to patients' contralateral, nonoperated shoulder. METHODS: Seven patients that underwent RTSA for cuff tear arthropathy from July 2007 to October 2008 were enrolled. The distance between the long axis of the thoracic spine and the inferior pole of the scapula (lateralization of the scapula) was measured on shoulder A-P radiographs at 0 degrees (the neutral position) and at 30, 60, 90, and 120 degrees of shoulder abduction. In addition, the angle between the long axis of the thoracic spine and medial border of the scapula was measured and compared with the patients' contralateral shoulder. RESULTS: Scapulohumeral rhythm was 2.4:1 on the operated shoulder and 4.1:1 on the nonoperated, contralateral shoulder at 120 degrees of abduction. The distance between the line of the interspinous process of upper thoracic vertebra and the inferior pole of the scapula showed a negative slope at 0 to 30 degrees abduction on the operated side, but beyond 30 degrees of abduction, this distance showed a more sudden increase than in the contralateral shoulder. The angle between the vertical vertebral line and the scapular medial border also showed greater increase beyond 30 degrees abduction on the operated limb. CONCLUSIONS: The pattern of scapular position after RTSA, was found to differ from that of the contralateral shoulder, and showed a more scapular upward rotation. PMID- 23107369 TI - The effect of emotional distress on persistent pelvic girdle pain after delivery: a longitudinal population study. AB - OBJECTIVE: To study the prognosis for pelvic girdle pain, and to explore the association between presence of emotional distress during pregnancy and pelvic girdle syndrome 6 months after delivery. DESIGN: Longitudinal population study. SETTING: Norway, for the period 1999-2008. POPULATION: A follow-up of 41 421 women in the Norwegian Mother and Child Cohort who reported pelvic girdle pain at 30 weeks of gestation. METHODS: Data were obtained by self-administered questionnaires in weeks 17 and 30 of gestation, and 6 months after delivery. MAIN OUTCOME MEASURE: Pelvic girdle syndrome 6 months after delivery, defined as pain in the anterior pelvis and on both sides in the posterior pelvis. RESULTS: Six months after delivery, 78.0% of the women had recovered, 18.5% reported persistent pain in one or two pelvic locations, 3.0% reported pelvic girdle syndrome and 0.5% reported severe pelvic girdle syndrome. The recovery rates decreased with increasing levels of pain severity in pregnancy. Being emotionally distressed at two time points during pregnancy was associated with the presence of pelvic girdle syndrome (adjusted OR 1.5, 95% CI 1.2-1.9) and severe pelvic girdle syndrome (adjusted OR 1.9, 95% CI 1.1-3.1), after adjustment for pain severity in pregnancy, other medical conditions, body mass index, age at menarche, previous low back pain, and smoking during pregnancy. CONCLUSIONS: In this follow-up of women with pelvic girdle pain in pregnancy, the recovery rates after delivery were high. Our findings suggest that the presence of emotional distress during pregnancy is independently associated with the persistence of pelvic girdle pain after delivery. PMID- 23107370 TI - Emergence of a new focus of Plasmodium malariae in forest villages of district Balaghat, Central India: implications for the diagnosis of malaria and its control. AB - OBJECTIVE: During an epidemiological study (January-July 2012) on malaria in forest villages of Central India, Plasmodium malariae-like malaria parasites were observed in blood smears of fever cases. We aimed to confirm the presence of P. malariae using molecular tools i.e. species-specific nested polymerase chain reaction (PCR) and DNA sequencing. METHODS: All fever cases or cases with history of fever in 25 villages of Balaghat district were screened for malaria parasite using bivalent rapid diagnostic test and microscopy after obtaining written informed consent. Nested PCR was employed on microscopically suspected P. malariae cases. DNA sequences in the target region for PCR diagnosis were analysed for all the suspected cases of P. malariae. RESULTS: Among the 22 microscopy suspected P. malariae cases, nested PCR confirmed the identity of P. malariae in 19 cases. Among these 14 were mono P. malariae infections, three were mixed infection of P. malariae with Plasmodium falciparum and two were mixed infection of P. malariae with Plasmodium vivax. Clinically P. malariae subjects generally presented with fever and headache. However, the typical 3-day pattern of quantum malaria was not observed. The parasite density of P. malariae was significantly lower than that of P. vivax and P. falciparum. DISCUSSIONS: Plasmodium malariae may have been in existence in forest villages of central India but escaped identification due to its close resemblance to P. vivax. The results re-affirm the importance of molecular methods of testing on routine basis for efficacious control strategies against malaria. PMID- 23107371 TI - Shortening tobacco life cycle accelerates functional gene identification in genomic research. AB - Definitive allocation of function requires the introduction of genetic mutations and analysis of their phenotypic consequences. Novel, rapid and convenient techniques or materials are very important and useful to accelerate gene identification in functional genomics research. Here, over-expression of PmFT (Prunus mume), a novel FT orthologue, and PtFT (Populus tremula) lead to shortening of the tobacco life cycle. A series of novel short life cycle stable tobacco lines (30-50 days) were developed through repeated self-crossing selection breeding. Based on the second transformation via a gusA reporter gene, the promoter from BpFULL1 in silver birch (Betula pendula) and the gene (CPC) from Arabidopsis thaliana were effectively tested using short life cycle tobacco lines. Comparative analysis among wild type, short life cycle tobacco and Arabidopsis transformation system verified that it is optional to accelerate functional gene studies by shortening host plant material life cycle, at least in these short life cycle tobacco lines. The results verified that the novel short life cycle transgenic tobacco lines not only combine the advantages of economic nursery requirements and a simple transformation system, but also provide a robust, effective and stable host system to accelerate gene analysis. Thus, shortening tobacco life cycle strategy is feasible to accelerate heterologous or homologous functional gene identification in genomic research. PMID- 23107372 TI - Influence of achieved paternity on quality of life in testicular cancer survivors. AB - OBJECTIVE: To investigate the influence of achieved/non-achieved paternity on quality of life (QoL) in testicular cancer (TC) survivors. PATIENTS AND METHODS: We invited TC survivors treated at our department between 1989 and 2006 to complete a QoL assessment, including the European Organisation for the Research and Treatment of Cancer QoL questionnaire, EORTC QLQ-C30 (version 3.0(c))/+ TC26, and follow-up questions. A total of 311 TC survivors answered the questionnaire, of whom 207 patients who did not desire paternity were excluded. The remaining 104 patients who stated a desire for paternity after TC treatment were further divided in group A (TC survivors who achieved paternity; n = 51) and group B (TC survivors who did not achieve paternity; n = 53). The data obtained were statistically analysed. RESULTS: Significant differences between groups regarding QoL were detected for social functioning (P = 0.002), emotional functioning (P = 0.001), general QoL (P = 0.018), fatigue (P = 0.025), pain (P = 0.01), sleeping problems (P = 0.024), treatment satisfaction (P = 0.039), financial aspects (P = 0.006), sexual problems (P = 0.017), body image problems (P < 0.001), dyspnoea (P = 0.005) and cognitive functioning (P = 0.019). For all scales except 'sexual enjoyment', patients in group A were found to have a better long-term QoL than those in group B. CONCLUSIONS: Whilst acknowledging the shortcomings in retrospective analyses, we believe our data clearly underline the important impact on QoL for TC survivors of achieved paternity. Counselling patients early at diagnosis as well as using cryopreservation of semen in all potential patients before treatment (only excluding patients definitely claiming they do not wish to achieve paternity) should therefore be regarded as the standard of care. PMID- 23107373 TI - E-consultation for DSD: a global platform for access to expert advice. AB - Electronic consultation (e-consultation) has been used for some years to facilitate communication between patients and their doctors, but it is also emerging as a valuable tool aiding communication between clinicians, both primary care and specialists, about a patient's care. Telehealth systems are being developed to provide video consultations to support diagnosis and management, as well as supporting clinical networks and health professional education. In some world regions, it seems increasingly likely that most rare diseases will be managed through a network of centres of expertise, and e-consultation systems may become a vital component of the service provided by these networks. Long-distance consultation across geographical and national boundaries has been used between colleagues in DSD for many years. However, the development of a robust and secure e-consultation service within the international DSD community appears to be timely. It will extend the current database and e-learning facilities, and should be achieved with the objective of providing expert opinion on a worldwide basis. It is proposed to install a steering committee to oversee the various practical, legal and cultural issues setting standards on data collection and exchange. The opportunity to broaden access to healthcare for all DSD patients and to widen discussion across the DSD community is valuable, and it is the view of the authors that this should be pursued and developed. PMID- 23107374 TI - Monitoring and controlling disease spread through live animal market networks. PMID- 23107375 TI - The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives. AB - The Brown-Vialetto-Van Laere syndrome is a rare neurological disorder which may present at all ages with sensorineural deafness, bulbar palsy and respiratory compromise. Fazio-Londe syndrome is considered to be the same disease entity. Recently it was demonstrated that in some patients the disease is caused by mutations in the SLC52A3 gene which encodes the intestinal (hRFT2) riboflavin transporter. In these patients riboflavin deficiency is the cause of the BVVL/FL syndrome and supplementation of riboflavin proved a life saving treatment. Mutations in the SLC52A2 gene and the SLC52A1 (GPR172B) gene, coding for human riboflavin transporters hRFT3 and hRFT1 have been associated with the BVVL syndrome as well. We performed a review of the literature, with emphasis on the natural history and the effects of treatment in these patients. A total of 35 publications were traced reporting on the clinical presentation of 74 patients who presented before age 18. The most prevalent symptoms were bulbar palsy, hearing loss, facial weakness and respiratory compromise. Death was reported in 28 of the 61 untreated patients, with a very low survival in patients presenting before age 4. All 13 patients who were treated with riboflavin survived, with a strong clinical improvement after days to months of treatment in eight patients. Three patients demonstrated a stable clinical course and treatment was stopped early in two patients. Abnormalities in plasma flavin levels and/or plasma acylcarnitine profiles were observed in some but not in all patients, and also patients with normal plasma flavin levels and acylcarnitine profiles demonstrated a striking clinical improvement on riboflavin supplementation. It is now clear that proper diagnosis requires mutation analysis of all three transporter genes and treatment should be started immediately without first awaiting results of molecular analysis. Clinical improvement may be rapid or gradual over a period of more than 12 months. PMID- 23107376 TI - Clinical and prognostic implications of beta1, 6-N-acetylglucosaminyltransferase V in patients with gastric cancer. AB - Aberrant beta1, 6-N-acetylglucosaminyltransferase V (MGAT5) expression in malignant tissues has been reported to be involved in the development of various cancers and their progression, through altering N-glycan branching. We aimed to investigate the clinical and prognostic values of MGAT5 and improve the risk stratification in patients with gastric cancer. MGAT5 expression was retrospectively analyzed by immunohistochemistry in three independent sets comprising 313 patients from China with gastric adenocarcinoma. Results were assessed for association with clinical features and overall survival using Kaplan Meier analysis. Prognostic values of MGAT5 expression and clinical outcomes were evaluated by Cox regression analysis. A molecular prognostic stratification scheme incorporating MGAT5 expression was determined in patients with late-stage gastric cancer by using receiver operating characteristic analysis. The results show that low intratumoral MGAT5 density, which was associated with poor differentiation, N classification, TNM stage, and Kiel stage, was an independent prognosticator for poor overall survival. The combination of intratumoral MGAT5 expression and TNM or Kiel staging systems had a better predictive power for overall survival. Applying the prognostic value of intratumoral MGAT5 density to TNM stage III+IV and Kiel stage IIIB+IV groups showed a better risk stratification for overall survival in patients with late-stage gastric cancer. In conclusion, integrating intratumoral MGAT5 density that was recognized as an independent prognostic marker into current clinical staging systems significantly improved prognostic stratification of patients with late-stage gastric cancer. This refined risk stratification scheme might aid in appropriate therapeutic options and ultimately improve the outcomes of patients with advanced-stage disease. PMID- 23107377 TI - Diagnostic and pathogenetic role of cafe-au-lait macules in nevoid basal cell carcinoma syndrome. AB - Cafe au lait spots (CALS) are common dermatologic findings that can at the same time arise in a variety of pathologic conditions such as Neurofibromatosis type 1 (NF1), together with numerous hereditary syndromes for which they represent either diagnostic criteria or associated elements (McCune Albright, Silver Russell, LEOPARD, Ataxia-Telangiectasia). A review of the literature also revealed two cases of association with NBCCS. We report here the case of a female proband with CALS associated to Nevoid Basal Cell Carcinoma Syndrome (NBCCS) with known PTCH1 germline mutation (C.1348-2A>G) who had been misdiagnosed with NF1 in her childhood because of 5 CALS and cutaneous nodules. The patient presented a giant cell tumor of the skin, palmar and calcaneal epidermoidal cystic nodules, odontogenic keratocystic tumors and deformity of the jaw profile. Her family history brought both her brother and father to our attention because of the presence of KCOTs diagnosed at early age: after genetic testing, the same PTCH1 germline mutation was identified in the three family members. Clinical criteria are used for discerning NF1 diagnosis (size, number and onset age), while there are no definite guidelines concerning CALS except for their presence. In our experience, we have noted an association of CALS with NBCCS; this seems interesting because we already know clinical criteria are a dynamic entity and can be modified by epidemiologic evidences. PMID- 23107378 TI - Lexical and gestural symbols in left-damaged patients. AB - Motor activations reported during action-word understanding have raised the question as to whether the system for motor production contains semantically relevant information. Cognitive neuropsychologists have provided compelling evidence that damage to the system for production of object-directed (transitive) actions does not necessarily lead to detrimental changes in the individuals' ability to understand the corresponding action words, and vice versa. We addressed this question focusing on intransitive symbolic gestures (emblems; e.g., waving goodbye), which are known to engage different resources, or neural representations, than object-directed actions, and are thought to enjoy a special relationship with language, due to a lexicalized relation between form (the gesture) and its meaning. We tested 12 left-damaged patients (and 17 healthy controls) on praxis (imitation and gesturing-to-verbal-command) and lexical semantic tasks (naming and word-picture matching) involving the same emblems. With the group-level analyses, we replicated correlations between praxis and language deficits typically observed in left-damaged patients. The analyses of patients' performance at the single-case level, however, revealed double dissociations between the ability to produce emblems and the ability to retrieve and recognize their lexical-semantic definition. Double dissociations, even in the event of positive group-level correlations across tasks, imply that the motor representation of a gesture and the lexical-semantic representation of the corresponding word rely on functionally independent system. This study is the first systematic neuropsychological investigation of the relationship between the lexical-semantic and the motor representation of emblems, the closest counterpart of words in the gestural domain. PMID- 23107379 TI - Recollection in adolescents with Autism Spectrum Disorder. AB - INTRODUCTION: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder primarily affecting social interaction and communication. Recently, there has been interest in whether people with ASD also show memory deficits as a result of abnormal brain development. However, at least in adolescents with ASD, the recollection component of episodic memory has rarely been explored. This paper is an evaluation of recollection in three different experiments in adolescents with ASD, using both objective (source discrimination) and subjective methods (Remember-Know judgments). METHODS: Three experiments were designed to measure different aspects of contextual information: sensory/perceptual information (Experiment 1), temporal information (Experiment 2) and spatial information (Experiment 3). To measure objective and subjective recollection, for all three experiments, all participants were presented with information to learn in a specific context. At the recognition stage, they were asked whether they remembered the information or just knew the information was there (R/K response, subjective method). To assess the quality of these subjective judgments, participants justified their Remember responses using the contextual information. After the recognition task, to assess source memory (objective measure), all items presented at encoding were represented and participants have to recall the source for all these items. RESULTS: All three experiments showed that adolescents with ASD could correctly recall source information. However, in the first experiment adolescents with ASD gave significantly fewer Remember responses than controls. CONCLUSIONS: These findings point to a specific and subtle recollection impairment in adolescents with ASD, at least when subjective methods are used. We discuss how these might relate to differences in the self and to the brain abnormalities in ASD. PMID- 23107380 TI - Mentalising music in frontotemporal dementia. AB - Despite considerable recent interest, the biological basis and clinical diagnosis of behavioural variant frontotemporal dementia (bvFTD) pose unresolved problems. Mentalising (the cognitive capacity to interpret the behaviour of oneself and others in terms of mental states) is impaired as a prominent feature of bvFTD, consistent with involvement of brain regions including ventro-medial prefrontal cortex (PFC), orbitofrontal cortex and anterior temporal lobes. Here, we investigated mentalising ability in a cohort of patients with bvFTD using a novel modality: music. We constructed a novel neuropsychological battery requiring attribution of affective mental or non-mental associations to musical stimuli. Mentalising performance of patients with bvFTD (n = 20) was assessed in relation to matched healthy control subjects (n = 20); patients also had a comprehensive assessment of behaviour and general neuropsychological functions. Neuroanatomical correlates of performance on the experimental tasks were investigated using voxel based morphometry of patients' brain magnetic resonance imaging (MRI) scans. Compared to healthy control subjects, patients showed impaired ability to attribute mental states but not non-mental characteristics to music, and this deficit correlated with performance on a standard test of social inference and with carer ratings of patients' empathic capacity, but not with other potentially relevant measures of general neuropsychological function. Mentalising performance in the bvFTD group was associated with grey matter changes in anterior temporal lobe and ventro-medial PFC. These findings suggest that music can represent surrogate mental states and the ability to construct such mental representations is impaired in bvFTD, with potential implications for our understanding of the biology of bvFTD and human social cognition more broadly. PMID- 23107382 TI - Risk factors of early and late onset pre-eclampsia. AB - AIMS: The aim of this study was to identify the differences in risk factors between early and late onset pre-eclampsia. MATERIAL AND METHODS: A case-control study was carried out involving pregnancies with pre-eclampsia (152 early onset and 297 late onset) and 449 controls at King Chulalongkorn Memorial Hospital, Bangkok, Thailand between 1 January 2005 and 31 December 2010. The data were reviewed from antenatal and delivery records. RESULTS: Factors which were significantly associated with increased risk for both early and late onset pre eclampsia were family history of diabetes mellitus, high pre-pregnancy body mass index >= 25 kg/m(2) and weight gain >= 0.5 kg per week. History of chronic hypertension (odds ratio 4.4; 95% confidence interval 2.1-9.3) was significantly associated with increased risk for only early onset pre-eclampsia, while family history of chronic hypertension (odds ratio 18; 95% confidence interval 6-54) was significantly associated with increased risk for only late onset pre-eclampsia. CONCLUSIONS: The risk factors that differ between early and late onset of pre eclampsia were history of chronic hypertension and family history of chronic hypertension. Family history of diabetes mellitus, pre-pregnancy body mass index >= 25 kg/m(2) and weight gain >= 0.5 kg per week were risk factors of both early and late onset pre-eclampsia. These risk factors are of value to obstetricians in identifying patients at risk for pre-eclampsia and in implementing primary prevention. PMID- 23107381 TI - Dg-Dys-Syn1 signaling in Drosophila regulates the microRNA profile. AB - BACKGROUND: The Dystrophin Glycoprotein Complex (DGC) is at the center of significant inheritable diseases, such as muscular dystrophies that can be fatal and impair neuronal function in addition to muscle degeneration. Recent evidence has shown that it can control cellular homeostasis and work via Dystrophin signaling to regulate microRNA gene expression which implies that disease phenotypes hide an entourage of regulatory and homeostatic anomalies. Uncovering these hidden processes could shed new light on the importance of proper DGC function for an organism's overall welfare and bring forth new ideas for treatments. RESULTS: To better understand a role for the DGC in these processes, we used the genetically advantageous Drosophila muscular dystrophy model to conduct a whole animal microarray screen. Since we have recently found that dystrophic symptoms can be caused by stress even in wild type animals and are enhanced in mutants, we screened stressed animals for microRNA misregulation as well. We were able to define microRNAs misregulated due to stress and/or dystrophy. Our results support the hypothesis that there is a Dystrophin and Dystroglycan dependent circuitry of processes linking stress response, dystrophic conditions and cellular signaling and that microRNAs play an important role in this network. Verification of a subset of our results was conducted via q-PCR and revealed that miR-956, miR-980 and miR-252 are regulated via a Dystroglycan Dystrophin-Syntrophin dependent pathway. CONCLUSIONS: The results presented in this study support the hypothesis that there is a Dystrophin and Dystroglycan dependent circuitry of processes that includes regulation of microRNAs. Dystrophin signaling has already been found to occur in mammalian musculature; however, our data reveals that this regulation is evolutionarily conserved and also present in at least neuronal tissues. Our data imply that Dystroglycan Dystrophin-Syntrophin signaling through control of multiple microRNAs is involved in highly managed regulation of gene expression required to adapt cellular homeostasis that is compromised under stress and dystrophic conditions. PMID- 23107383 TI - Progress in emerging therapies for advanced prostate cancer. AB - The landscape of prostate cancer treatment is rapidly changing as extensive research into potential therapies yields new options. In this article, the literature is reviewed to identify emerging therapies for advanced prostate cancer. Emphasis is placed on agents that have been approved in the United States of America (USA) and the European Union, or that have reached phase III clinical studies. Several new therapies have been approved in recent years across different stages of the natural history of the disease. Degarelix, a luteinizing hormone-releasing hormone antagonist, has been approved for reducing testosterone to castrate levels in hormone-sensitive disease. No new agents have been approved for use in combination with docetaxel chemotherapy, the current standard of care for metastatic castration-resistant prostate cancer. One immunotherapy, sipuleucel-T, has been approved (USA only) in the pre-docetaxel setting. Cabazitaxel, a next-generation taxane, and abiraterone acetate, an inhibitor of androgen biosynthesis, have both been approved as second-line agents following chemotherapy. Enzalutamide (MDV3100), an androgen receptor antagonist, has been shown to increase overall survival in the post-chemotherapy setting in metastatic disease. Denosumab, an antibody-based bone-targeted agent, has been approved for the prevention of skeletal-related events in patients with bone metastases. Radium-223 chloride, an alpha-emitting radiopharmaceutical, is likely to gain approval soon following promising results in a phase III trial. Clinical studies involving other promising agents are ongoing. The emergence of these therapies adds to the growing armamentarium against prostate cancer. PMID- 23107385 TI - Fabrication of a surgical splint in an emergency situation: a clinical report. AB - Fractures involving pediatric jaws most often require a splint to prevent the fragments from being displaced; however, impression making presents a challenge. This article describes the fabrication of a surgical splint over an ideal cast, which is subsequently refitted with a tissue conditioner onto the patient's jaw. The highlight of this technique is the elimination of an impression procedure, thereby reducing clinical and laboratory time and easing pain in the child. PMID- 23107386 TI - Reduced graphene oxide field-effect transistor for label-free femtomolar protein detection. AB - We report reduced graphene oxide field effect transistor (R-GO FET) biosensor for label-free ultrasensitive detection of a prostate cancer biomarker, prostate specific antigen/alpha1-antichymotrypsin (PSA-ACT) complex. The R-GO channel in the device was formed by reduction of graphene oxide nanosheets networked by a self-assembly process. Immunoreaction of PSA-ACT complexes with PSA monoclonal antibodies on the R-GO channel surface caused a linear response in the shift of the gate voltage, V(g,min), where the minimum conductivity occurs. The R-GO FET can detect protein-protein interactions down to femtomolar level with a dynamic range over 6-orders of magnitude in the V(g,min) shift as a sensitivity parameter. High association constants of 3.2 nM(-1) and 4.2 nM(-1) were obtained for the pH 6.2 and pH 7.4 analyte solutions, respectively. The R-GO FET biosensor showed a high specificity to other cancer biomarker in the phosphate buffered saline solutions as well as in the human serum. PMID- 23107387 TI - Recruiting and engaging new mothers in nutrition research studies: lessons from the Australian NOURISH randomised controlled trial. AB - BACKGROUND: Despite important implications for the budgets, statistical power and generalisability of research findings, detailed reports of recruitment and retention in randomised controlled trials (RCTs) are rare. The NOURISH RCT evaluated a community-based intervention for first-time mothers that promoted protective infant feeding practices as a primary prevention strategy for childhood obesity. The aim of this paper is to provide a detailed description and evaluation of the recruitment and retention strategies used. METHODS: A two stage recruitment process designed to provide a consecutive sampling framework was used. First- time mothers delivering healthy term infants were initially approached in postnatal wards of the major maternity services in two Australian cities for consent to later contact (Stage 1). When infants were approximately four months old mothers were re-contacted by mail for enrolment (Stage 2), baseline measurements (Time 1) and subsequent random allocation to the intervention or control condition. Outcomes were assessed at infant ages 14 months (Time 2) and 24 months (Time 3). RESULTS: At Stage 1, 86% of eligible mothers were approached and of these women, 76% consented to later contact. At Stage 2, 3% had become ineligible and 76% could be recontacted. Of the latter, 44% consented to full enrolment and were allocated. This represented 21% of mothers screened as eligible at Stage 1. Retention at Time 3 was 78%. Mothers who did not consent or discontinued the study were younger and less likely to have a university education. CONCLUSIONS: The consent and retention rates of our sample of first time mothers are comparable with or better than other similar studies. The recruitment strategy used allowed for detailed information from non consenters to be collected; thus selection bias could be estimated. Recommendations for future studies include being able to contact participants via mobile phone (particularly text messaging), offering home visits to reduce participant burden and considering the use of financial incentives to support participant retention. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry Number ACTRN12608000056392. PMID- 23107388 TI - Selective depletion of alloreactive T cells leads to long-term islet allograft survival across a major histocompatibility complex mismatch in diabetic mice. AB - Islet cell transplantation as a therapy for type 1 diabetes has been limited by progressive graft loss. Significant immunosuppression including T-cell ablation has been used in an attempt to limit islet rejection. Here, we show that CD3(+) lymphocytes depleted of alloreactive T cells selected from a mixed lymphocyte reaction (MLR), where responder BALB/c splenocytes stained with carboxyfluorescein succinimidyl ester (CFSE) were stimulated with irradiated C57BL/6 splenocytes for 5 days, infused into diabetic immunodeficient mice are capable of restoring a broad T-cell repertoire and specifically do not reject islet transplants from the strain (C57BL/6) used in the original depletion. These mice demonstrate reconstitution with CD4(+) and CD8(+) T cells, the capacity to reject third-party grafts (CBA), and restoration of interferon-gamma (IFN-gamma) responses to third-party alloantigens. Over time, both forkhead box P3-positive (Foxp3(+)) T regulatory cells (Tregs) and gammadelta T cells expand, suggesting a role for peripheral tolerance, in addition to the initial depletion of alloreactive T cells, in long-term islet graft survival. Our results suggest that immune restoration with CD3(+) lymphocytes where alloreactive T cells are removed can restore cognate immunity without islet allograft loss and recurrence of diabetes. PMID- 23107389 TI - Weight-related concerns related to drug use for women in substance abuse treatment: prevalence and relationships with eating pathology. AB - Women in substance abuse treatment increasingly report weight-related concerns as motivation for drug use. However, limited research has explored the nature of these concerns or examined whether women in substance abuse treatment with weight related concerns related to drug use differ from those who do not on variables relevant to eating pathology. Using a sample of 297 women in substance abuse treatment, this study examined two intertwined issues: (1) the prevalence and nature of weight-related concerns related to drug use and (2) whether women who endorse weight-related concerns related to drug use differ from those without weight-related concerns on body dissatisfaction, eating pathology, perceived pressure and internalization of thin-ideal media, and appearance-related drug-use expectancies. Descriptive analyses indicated that the majority of participants were concerned about gaining weight during treatment and/or that weight gain could trigger drug relapse. Analyses of variance revealed that women who reported weight-based concerns (both with regards to weight gain during treatment and relapse potential) endorsed higher levels of body dissatisfaction, dieting, bulimic symptoms, and thin-ideal internalization than women who did not endorse weight-related concerns. Results suggest that substance abuse treatment programs should be aware of and address weight-related concerns around drug use for women. PMID- 23107390 TI - Serum ferritin is associated with markers of insulin resistance in Japanese men but not in women. AB - OBJECTIVE: Several epidemiological studies have reported that high concentrations of circulating ferritin, a marker of iron stores, are related to insulin resistance (IR); however, questions remain regarding inconsistent data between Asian men and women and the inadequate consideration of potential confounding effects on the relationship between ferritin and IR. Our aim was to examine the relationship between serum ferritin concentrations and IR markers in the Japanese population. MATERIALS/METHODS: We analyzed data (n=493) from a cross-sectional survey conducted in 2009 among a Japanese working population aged 20-68years. Fasting serum ferritin and insulin levels and fasting plasma glucose levels were determined, and the homeostatic model assessment of IR (HOMA-IR) was calculated. Multiple regression analysis was performed with adjustments for demographic and lifestyle factors, body mass index and serum C-reactive protein. RESULTS: Fasting insulin and HOMA-IR significantly increased with increasing levels of serum ferritin after adjustment for covariates in men (P for trend=.005 and .001, respectively). Compared with men in the lowest tertile of serum ferritin, those in the highest tertile had a 24% higher HOMA-IR score. Additional data suggested a positive association between iron intake and HOMA-IR (P for trend=.07) in men. Neither serum ferritin nor iron intake was related to IR markers in women, even in postmenopausal women. CONCLUSIONS: Serum ferritin concentrations were positively associated with fasting insulin and HOMA-IR in men but not in women, suggesting an important role of iron storage in the pathogenesis of IR in Japanese men. PMID- 23107391 TI - Learning the lessons from 1000 robot-assisted radical prostatectomy procedures. PMID- 23107392 TI - Subtle cognitive deficits in severe alcohol addicts--do they show a specific profile? AB - Although alcohol dependency is a burden to society, data on cognitive performance in therapy-resistant patients after multiple withdrawals are poor. In this study, 22 patients without reported cognitive deficits and 20 control subjects performed extensive cognitive testing and a motor task assessing short-term memory. Patients displayed subtle deficits (mainly in executive function), while memory functions were relatively unimpaired. Our results suggest that subtle frontal executive deficits may contribute to a poor prognosis, but could be missed by routine clinical tests. PMID- 23107393 TI - Clavien classification of semirigid ureteroscopy complications: a prospective study. AB - OBJECTIVE: To prospectively report and grade the perioperative complications of ureteroscopy (URS) for stone removal using a semirigid ureteroscope with the modified Clavien classification system and to identify the determinants of the complications. METHODS: From August 2010 to November 2011, the prospective data from 120 consecutive patients (71 men and 49 women) who had undergone primary unstented URS at a resident training center were analyzed. Patients with renal failure, pyonephrosis, diabetes mellitus, hypertension, and congenital ureteral abnormalities were excluded (n = 29). The data recorded included patient demographics, stone size and location, and complications according to the modified Clavien classification system. RESULTS: Of the 120 patients, 36 (30%) experienced 79 complications. The stone size was <= 10 mm in 56 and >10 mm in 64 patients. The stone location was the lower, mid-, and upper ureter in 62, 58, and 3 patients, respectively. The latter 3 were excluded because of the small sample size. Grade 1, 2, 3a, 3b, 4a, and 4b complications were encountered in 46 (38.3%), 18 (15%), 3 (2.5%), 10 (8.3%), 1 (0.8%), and 1 (0.8%) patient, respectively. The incidence of complications was greater for stones >10 mm, a mid versus distal ureteral location, impacted stones, and surgery performed by a resident. The incidence was not affected by patient sex, stone laterality, or lithotripter type. The patients with complications had a longer operative time (75 vs 46.5 minutes), longer hospitalization (4.8 vs 1.5 days), and lower stone free rate (64% vs 97%). CONCLUSION: Most complications were grade 1-3 (98%), and grade 4 complications were rare (<2%) with URS. The present study is probably the first to prospectively study the complications of URS using the modified Clavien classification system. PMID- 23107394 TI - Editorial comment. PMID- 23107396 TI - Socioeconomic and clinical factors influence the interval between positive prostate biopsy and radical prostatectomy. AB - OBJECTIVE: To examine socioeconomic and clinical factors that may predict a longer interval between prostate biopsy and radical prostatectomy (RP). METHODS: The Columbia University Urologic Oncology Database was queried for patients who underwent RP from 1990-2010. Time to surgery (TTS) was defined as the period between the most recent positive prostate biopsy and date of surgery. Clinical factors examined included: age, D'Amico risk group, year of surgery, body mass index, and comorbidities. Socioeconomic factors included race/ethnicity, relationship status, income, and distance to treatment center. The relationship between clinical/socioeconomic factors and TTS was evaluated using univariate and multivariate regression models. RESULTS: Two-thousand five-hundred seventy-three patients were included in the analysis. Median TTS was 48 days (IQR 35-70, range 43-1103), and 71% of patients underwent RP within 60 days after the most recent positive biopsy. On multivariate analysis, living further from the medical center was associated with shorter TTS (P = .01), whereas more recent year of surgery (P = .01), comorbid cardiovascular disease (P = .007), African-American (P = .005) or Hispanic race (P = .005), divorced relationship status (P = .01), and lower income (P = .003) were all associated with longer TTS. CONCLUSION: Patients often experience widely variable intervals between the diagnosis and treatment of localized prostate cancer. Longer intervals before surgery may point to disparities in access to prostate cancer care, and not increased decision-making time by the patient. PMID- 23107397 TI - Prostate cancers of different zonal origin: clinicopathological characteristics and biochemical outcome after radical prostatectomy. AB - OBJECTIVE: To evaluate the effect of prostate cancer zonal origin on the biochemical outcome after radical prostatectomy, to analyze clinicopathological features of tumors arising in different zones and to test the ability of the nomogram to predict the probability of transition zone cancer at radical prostatectomy. METHODS: Our cohort consisted of 1441 patients who underwent radical prostatectomy who did not receive neoadjuvant treatment. Clinicopathological characteristics and biochemical outcomes were compared between the groups of men with different zonal location of prostate cancer. Performance of the nomogram in predicting cancer location was evaluated with respect to discrimination and calibration. RESULTS: The rates of positive margin were similar in men with transition zone and mixed tumors and were significantly higher than those with peripheral zone tumors. Most of the positive margins in patients with transition zone and mixed cancers were located at the apico anterior part of the gland. On multivariate analysis, transition zone cancer location was associated with better biochemical recurrence-free survival (P = .043). The Harrel c-index of the models that did and did not include zonal origin of cancer was 0.810 and 0.807, respectively. Performance of the nomogram was poor. CONCLUSION: The association between transition zone tumor origin and the risk of biochemical recurrence does not add important predictive value to the standard prognostic factors. Although information about the risk of prostate cancer involvement of the transition zone may be important for surgical planning, our ability to predict this risk preoperatively is limited. PMID- 23107398 TI - Role of immediate confirmatory prostate biopsy to ensure accurate eligibility for active surveillance. AB - OBJECTIVE: To assess the role of confirmatory prostate biopsy in the accurate risk assessment of patients with low risk prostate cancer eligible for active surveillance. METHODS: Patients electing active surveillance of their low grade, low volume prostate cancer with prostate-specific antigen <20 ng/mL, 2 core involvement or Gleason 7 disease on subsequent biopsies. Prostate specific antigen, total number of cores on initial and rebiopsy, the presence of high-grade prostatic intraepithelial neoplasia, and prostate-specific antigen density, when available, were assessed as predictors of biopsy progression. RESULTS: Sixty patients were included. Median time to rebiopsy was 2 months. Nineteen patients (31.7%) had findings that excluded them from active surveillance. Despite rebiopsy findings, 7 patients elected for active surveillance, all of which eventually underwent treatment for continued biopsy progression. Of the 41 patients eligible for active surveillance after rebiopsy, 8% elected treatment, 74% remained on active surveillance, and 13% experienced biopsy progression. No cancer on rebiopsy was associated with a reduced risk of progression to treatment on active surveillance (odds ratio 0.14, P = .011). A microfocus of Gleason 4 pattern (odds ratio 16.0, P = .04) and high-grade prostatic intraepithelial neoplasia (odds ratio 7.29, P = .03) on initial biopsy were independent predictors of immediate rebiopsy progression. Prostate-specific antigen, prostate-specific antigen density, and the total number of cores were not significant. CONCLUSION: Confirmatory rebiopsy aids in the accurate identification of low-risk patients for active surveillance as one-third are initially undergraded. Patients with high-grade prostatic intraepithelial neoplasia and any Gleason pattern 4 on initial biopsy are at highest risk and should be counseled regarding the risks of progression on active surveillance accordingly. PMID- 23107399 TI - Free prostate-specific antigen is a better tool than total prostate-specific antigen at predicting prostate volume in patients with lower urinary tract symptoms. AB - OBJECTIVE: To evaluate the relationships among age, total prostate-specific antigen level (PSA), free PSA level, and prostate volume. METHODS: A total of 656 patients complaining of lower urinary tract symptoms who attended our urology outpatient department were enrolled. The standard assessment for lower urinary tract symptoms was applied, including serum total and free PSA determinations and transabdominal prostate volume measurement. Patients with a history of transurethral surgery, prostate cancer, and conditions other than benign prostatic hyperplasia that could affect the PSA levels were excluded. A linear regression model was used to estimate the prostate volume. Receiver operating characteristic curves were constructed to evaluate the ability of serum PSA and free PSA to estimate threshold prostate volumes and to select the optimal serum PSA and free PSA cutoff values. RESULTS: The linear regression model included age (P < .000), total PSA (P < .006), and free PSA (P < .000) as independent predictors of prostate volume. Consequently, an easy to use equation was developed to estimate the prostate volume. Free PSA performed better than total PSA at predicting the prostate volume. An area under the curve of 0.668 +/- 0.022 at predicting prostate volume >40 cm(3) with total PSA increased to 0.721 +/- 0.021 with free PSA. Moreover, free PSA with a cutpoint of 0.495 ng/mL correctly estimated a prostate volume of >40 and <40 cm(3) in 71% and 66% of the cases, respectively. CONCLUSION: The prostate volume can be estimated using easily obtained serum PSA levels, and free PSA had a better performance. PMID- 23107400 TI - Metabolic syndrome associated with reduced lower urinary tract symptoms in middle aged men receiving health checkup. AB - OBJECTIVE: To investigate the impact of metabolic syndrome on lower urinary tract symptoms in a sample of middle-aged men receiving a health checkup. METHODS: Subjects aged 45 years or older who voluntarily underwent a medical checkup were enrolled. Participant demographics and health history were collected by a self administered questionnaire. All participants were stratified into 2 groups by the presence of metabolic syndrome, as defined according to the updated National Cholesterol Education Program's Adult Treatment Panel III. Prostate volume and prostate-specific antigen levels were used for subgroup analysis. RESULTS: During January through December of 2010, 708 subjects with a mean age of 55.6 +/- 9.72 years were enrolled into the study. Compared to the nonmetabolic syndrome group, the metabolic syndrome group had lower total international prostatic symptoms score (7.89 +/- 6.63 vs 6.85 +/- 6.52, P = .05) and lower severity of weak urinary stream (1.24 +/- 1.60 vs 0.95 +/- 1.50, P = .021). In the higher prostate volume group (prostate volume >= 30 mL), total international prostatic symptoms score, storage score, and urinary frequency, urgency and incomplete emptying were lower in men vs those without metabolic syndrome (all P < .05). The negative association between voiding score, severity of lower urinary tract symptoms, and metabolic syndrome became particularly pronounced as the number of metabolic syndrome factors increased (P for trend < .01). CONCLUSION: We confirmed that metabolic syndrome had favorable effects on lower urinary tract symptoms, including voiding and storage symptoms in healthy middle-aged men. This beneficial effect was most significant in men with enlarged prostate and/or high prostate specific antigen levels. PMID- 23107401 TI - Male sexual function outcome after three laser prostate surgical techniques: a single center perspective. AB - OBJECTIVE: To assess the change and predictors of sexual-related outcomes after laser prostate surgery. METHODS: This is a longitudinal study of 216 sexually active men who underwent laser prostatectomy between 2005 and 2010. The International Index of Erectile Function-15 questionnaire was used both preoperatively and during the first year of follow-up. Cases with unreliable answers or patients without interested partners were excluded. All relevant data of both groups were depicted and statistically analyzed. RESULTS: We identified 191 patients that met the inclusion criteria, 99 holmium laser enucleation of the prostate, 34 holmium laser ablation, and 58 photoselective vaporization of the prostate (GreenLight-532-mm laser photoselective vaporization of the prostate). There were significant differences among the 3 groups regarding the International Index of Erectile Function-15 direction of change at 1 year, being unchanged in (22.2%, 24.4%, and 29.3%), improved in (60.6%, 29.4%, and 41.4), and declined in (17.2%, 41.2%, and 29.3%) in the 3 groups, respectively (P < .05). After adjusting for clinical and perioperative variables, the independent risk factors for decline in the International Index of Erectile Function score were basal International Index of Erectile Function >= 55 and energy to prostate ratio. In holmium laser enucleation of the prostate group, there was significant improvement of the mean overall score, erectile function, desire, and intercourse satisfaction domains (P < .05). In holmium laser ablation and photoselective vaporization of the prostate groups, there were no significant changes between mean preopeative and postoperative scores (P > .05). The incidence of new onset retrograde ejaculation in the holmium laser enucleation of the prostate group was (77.3%) significantly different compared to (31.1%) in the holmium laser ablation group and (33.2%) in photoselective vaporization of the prostate group (P < .05). CONCLUSION: Laser prostate surgery using more size-related laser energy might have possible negative influence on sexual function. Patients with normal preoperative sexuality are more at risk. PMID- 23107402 TI - Timing of orchiopexy in the United States: a quality-of-care indicator. AB - OBJECTIVE: To investigate whether orchiopexies are occurring later than recommended by American Academy of Pediatrics 1996 guidelines (around age 1). Adherence to guidelines is poorly studied. METHODS: The main cohort consisted of 4103 boys insured from birth (Innovus i3, insurance claims database). The complementary cohort consisted of 17 010 insured and noninsured boys (Pediatric Health Information System, PHIS). The inclusion criteria was age <= 5 years at time of International Classification of Disease, 9th revision-defined cryptorchidism diagnosis. The primary outcome was timely surgery (orchiopexy by age 18 months). RESULTS: In Innovus, 87% of boys who underwent an orchiopexy had a timely orchiopexy. Of those who did not undergo surgery (n = 2738), 90% had at least 1 subsequent well-care visit. Those who underwent timely surgery were referred to a surgeon at a younger age compared with those who underwent late surgery (4.1 vs 16.1 months, P < .00005). Predictors of timely surgery were number of well-care visits (odds ratio 1.5, 95% confidence interval 1.3-1.7), continuity of primary care (odds ratio 1.9, 95% confidence interval 1.3-2.7), and use of laparoscopy (odds ratio 4.5, 95% confidence interval 1.4-14.9). Family/internal medicine as referring provider was predictive of delayed surgery (odds ratio 0.5, 95% confidence interval 0.3-0.8). In the Pediatric Health Information System, 61% of those with private insurance had timely surgery compared with 54% of those without private insurance (P < .0001). CONCLUSION: We found an unexpectedly high adherence to guidelines in our continuously insured since birth Innovus population. Primary care continuity and well-care visits were associated with timely surgery. Further studies can confirm these findings in nonprivately insured patients with the ultimate goal of instituting quality improvement initiatives. PMID- 23107404 TI - Re: Willihnganz-Lawson et al.: De Castro technique used to create neophallus: a case of aphallia (Urology 2012;79:1149-1151). PMID- 23107403 TI - Seromuscular grafts for bladder reconstruction: extra-luminal demucosalisation of the bowel. AB - OBJECTIVE: To develop a robust sterile, fully demucosalized and vascularized seromuscular patch for use as an adjunct to novel bioengineering techniques aimed at augmenting, reconstructing, or replacing the bladder because of endstage disease. To eliminate deep colonic epithelial crypts to prevent the possibility of colonocyte regrowth. To maintain sterility by excluding the possibility of contamination from the bowel contents. METHODS: Pilot studies were performed on euthanized pigs to optimize the technique, with tissue samples examined by immunohistochemistry. In vivo, vascularized seromuscular colonic flaps were created from the bowel exterior in 7 large white hybrid pigs. The dissection was facilitated by placing an inflated Foley catheter within the colonic lumen. The seromuscular ends were approximated with 5/0 Vicryl sutures and excess mucosa intussuscepted within the lumen. Demucosalized flaps were used to augment the bladder by composite cystoplasty and were examined immunohistochemically at 3 months. RESULTS: Pilot studies showed that the technique was successful in creating seromuscular segments with no epithelial remnants. When applied surgically, the seromuscular flaps survived and showed no evidence of colonocyte regrowth at 3 months. CONCLUSION: Extraluminal dissection creates robust seromuscular flaps and prevents both regrowth by colonic epithelial cells and contamination of the tissue by exposure to the bowel contents. This technique should find application in a range of bladder reconstruction techniques, including composite cystoplasty and autoaugmentation. PMID- 23107405 TI - Re: Penbegul et al.: Safety and efficacy of ultrasound-guided percutaneous nephrolithotomy for treatment of urinary stone disease in children (Urology 2012;79:1015-1019). PMID- 23107407 TI - Re: Humphreys et al. Natural orifice transluminal endoscopic radical prostatectomy: initial perioperative and pathologic results (Urology 2011;78:1211 1217). PMID- 23107410 TI - Re: Xu et al. Doppler ultrasound-guided percutaneous nephrolithotomy with two step tract dilation for management of complex renal stones (Urology 2012;79:1247 1251). PMID- 23107412 TI - Editorial comment. PMID- 23107414 TI - Primary carcinoid tumor of urinary bladder discovered on pelvic magnetic resonance imaging. AB - Pure primary carcinoid tumor of the urinary bladder is an exceedingly rare lesion with less than twenty cases reported in the English language literature. These tumors are typically small and rarely invade past the lamina propria. Amenable to transurethral resection alone, they are associated with a favorable prognosis. We present a case of pure primary carcinoid tumor of the bladder discovered on T2 weighted pelvic magnetic resonance imaging. PMID- 23107415 TI - Small cell cancer of the prostate. AB - De novo small cell cancer of the prostate is a rare tumor and has different presentation, behavior, and outcome compared with adenocarcinoma. A 66-year-old man presented with symptoms masquerading as a rectal tumor. Primary symptoms were intermittent constipation and diarrhea without any urinary symptoms. Initial staging showed only 2 large pelvic nodes. Prostate-specific antigen was 4.8 ng/L. A transrectal prostate biopsy confirmed small cell histology. After having no response to hormones and carboplatin-etoposide, a course of palliative radiotherapy, docetaxel chemotherapy, and defunctioning colostomy offered palliation. Liver and lytic bone metastases developed later; the patient died 9 months after the presentation. PMID- 23107416 TI - Solitary osteoclast-like giant cell tumor of the kidney: a case report. AB - Osteoclast-like giant cell tumors are very uncommon and originate in osseous and tendinous tissues. However, they are also very rarely found in visceral organs. The kidney is extremely rarely affected by this tumor entity; usually osteoclast like giant cell tumors are associated with papillary renal cell carcinoma. We present the third case in the literature of a solitary osteoclast-like giant cell tumor in the kidney of an 89-year-old man and give a short overview of the current literature. PMID- 23107417 TI - Genomic regions associated with bovine milk fatty acids in both summer and winter milk samples. AB - BACKGROUND: In this study we perform a genome-wide association study (GWAS) for bovine milk fatty acids from summer milk samples. This study replicates a previous study where we performed a GWAS for bovine milk fatty acids based on winter milk samples from the same population. Fatty acids from summer and winter milk are genetically similar traits and we therefore compare the regions detected in summer milk to the regions previously detected in winter milk GWAS to discover regions that explain genetic variation in both summer and winter milk. RESULTS: The GWAS of summer milk samples resulted in 51 regions associated with one or more milk fatty acids. Results are in agreement with most associations that were previously detected in a GWAS of fatty acids from winter milk samples, including eight 'new' regions that were not considered in the individual studies. The high correlation between the -log10(P-values) and effects of SNPs that were found significant in both GWAS imply that the effects of the SNPs were similar on winter and summer milk fatty acids. CONCLUSIONS: The GWAS of fatty acids based on summer milk samples was in agreement with most of the associations detected in the GWAS of fatty acids based on winter milk samples. Associations that were in agreement between both GWAS are more likely to be involved in fatty acid synthesis compared to regions detected in only one GWAS and are therefore worthwhile to pursue in fine-mapping studies. PMID- 23107418 TI - Next-generation peptide vaccines for advanced cancer. AB - Many clinical trials of peptide vaccines have been carried out since the first clinical trial of a melanoma antigen gene-1-derived peptide-based vaccine was reported in 1995. The earlier generations of peptide vaccines were composed of one to several human leukocyte antigen class I-restricted CTL-epitope peptides of a single human leukocyte antigen type. Currently, various types of next generation peptide vaccines are under development. In this review, we focus on the clinical trials of the following categories of peptide vaccines mainly published from 2008 to 2012: (i) multivalent long peptide vaccines; (ii) multi peptide vaccines consisting of CTL- and helper-epitopes; (iii) peptide cocktail vaccines; (iv) hybrid peptide vaccines; (v) personalized peptide vaccines; and (vi) peptide-pulsed dendritic cell vaccines. PMID- 23107419 TI - Co-presentation of unilateral femoral and bilateral sciatic nerve variants in one cadaver: A case report with clinical implications. AB - OBJECTIVE: To present a group of anatomical findings that may have clinical significance. DESIGN: This study is an anatomical case report of combined lumbo pelvic peripheral nerve and muscular variants. SETTING: University anatomy laboratory. PARTICIPANTS: One cadaveric specimen. METHODS: During routine cadaveric dissection for a graduate teaching program, unilateral femoral and bilateral sciatic nerve variants were observed in relation to the iliacus and piriformis muscle, respectively. Further dissection of both the femoral nerve and accessory slip of iliacus muscle was performed to fully expose their anatomy. RESULTS: Piercing of the femoral nerve by an accessory iliacus muscle combined with wide variations in sciatic nerve and piriformis muscle presentations may have clinical significance. CONCLUSIONS: Combined femoral and sciatic nerve variants should be considered when treatment for a lumbar disc herniation is refractory to care despite positive orthopedic testing. PMID- 23107420 TI - Nutritional supplementation: the additional costs of managing children infected with HIV in resource-constrained settings. AB - OBJECTIVE: To explore the financial implications of applying the WHO guidelines for the nutritional management of HIV-infected children in a rural South African HIV programme. METHODS: WHO guidelines describe Nutritional Care Plans (NCPs) for three categories of HIV-infected children: NCP-A: growing adequately; NCP-B: weight-for-age z-score (WAZ) <=-2 but no evidence of severe acute malnutrition (SAM), confirmed weight loss/growth curve flattening, or condition with increased nutritional needs (e.g. tuberculosis); NCP-C: SAM. In resource-constrained settings, children requiring NCP-B or NCP-C usually need supplementation to achieve the additional energy recommendation. We estimated the proportion of children initiating antiretroviral treatment (ART) in the Hlabisa HIV Programme who would have been eligible for supplementation in 2010. The cost of supplying 26-weeks supplementation as a proportion of the cost of supplying ART to the same group was calculated. RESULTS: A total of 251 children aged 6 months to 14 years initiated ART. Eighty-eight required 6-month NCP-B, including 41 with a WAZ <=-2 (no evidence of SAM) and 47 with a WAZ >-2 with co-existent morbidities including tuberculosis. Additionally, 25 children had SAM and required 10-weeks NCP-C followed by 16-weeks NCP-B. Thus, 113 of 251 (45%) children were eligible for nutritional supplementation at an estimated overall cost of $11 136, using 2010 exchange rates. These costs are an estimated additional 11.6% to that of supplying 26-week ART to the 251 children initiated. CONCLUSIONS: It is essential to address nutritional needs of HIV-infected children to optimise their health outcomes. Nutritional supplementation should be integral to, and budgeted for, in HIV programmes. PMID- 23107421 TI - Early life intervention with glucocorticoids has negative effects on motor development and neuropsychological function in 14-17 year-old adolescents. AB - OBJECTIVE: To reduce the risk of bronchopulmonary dysplasia, preterm infants receive neonatal treatment with glucocorticoids, mostly dexamethasone (DEX). Compared to current protocols, treatment regimens of the late 1980s - early 1990s prescribed high doses of DEX for an extensive period up to 6 weeks. Worldwide at least one million children have been treated with this dose regimen. Previous studies have shown adverse effects of neonatal treatment with the glucocorticoid dexamethasone (DEX) on outcome in children aged 7-10 years. On the other hand, treatment with another glucocorticoid, hydrocortisone (HC), was not related to adverse effects in childhood. In the current study we determined the consequences of early life intervention with DEX or HC in adolescents (age 14-17 years). Besides motor function and intellectual capacities, we also examined fundamental neuropsychological functions which have so far received little attention. METHODS: In an observational cohort study we compared 14-17 year-old adolescents who received DEX (.5 mg/kg/day tapering off to .1 mg/kg/day over 21 days, n=63), or HC (5 mg/kg/day tapering off to 1 mg/kg/day over 22 days, n=67), or did not receive neonatal glucocorticoids (untreated, n=71) after premature birth (gestational age<32 weeks). Because gestational age was shorter and duration of ventilation was longer in the DEX-treated group, all analyses were corrected for these potential confounders. Motor function, IQ, and neuropsychological functions were assessed. RESULTS: DEX-treated group participants scored lower on gross motor skill tasks than their HC-treated and untreated counterparts. A higher proportion of DEX-treated girls needed special education compared to the other groups. DEX-treated adolescents performed poorer on neuropsychological tasks measuring alertness, visuomotor coordination, and emotion recognition. The HC treated group did not differ from the untreated group. CONCLUSIONS: Even after 14 17 years, neonatal treatment with .5 mg/kg/day DEX was associated with adverse effects on motor function, school level, and neuropsychological functions, whereas treatment with the clinically equally effective dose of 5 mg/kg/day HC was not. Potential physiological mechanisms underlying the differences in dexamethasone and hydrocortisone effects are discussed. Based on the current findings, we recommend early identification of neuropsychological deficits after DEX treatment in order to specify extra educational needs. PMID- 23107422 TI - A therapeutic vaccine using Salmonella-modified tumor cells combined with interleukin-2 induces enhanced antitumor immunity in B-cell lymphoma. AB - Therapeutic vaccination holds potential as complementary treatment for non Hodgkin's lymphoma (NHL). B-NHL cells are antigen-presenting cells, but they cannot elicit proper antitumor responses because they lack expression of co stimulatory molecules. Here, we report a novel approach to design improved whole tumor cell vaccines for B-NHL. We demonstrated that Salmonella infection significantly up-regulates CD80, CD86, CD40 and MHC II expression in lymphoma cells, and that therapeutic vaccination with infected and then irradiated lymphoma cells combined with IL-2 elicits strong anti-tumor specific immunity and extended survival in lymphoma-bearing mice. This may represent the basis of an effective immunotherapy against B-NHL that could be easily translated into the clinics. PMID- 23107423 TI - Clinical evaluations of cell-free fetal DNA quantities in pre-eclamptic pregnancies. AB - AIM: Quantitative changes of cell-free fetal DNA in maternal plasma as an indicator for impending pre-eclampsia was reported in different studies. Cell free fetal nucleic acids can be detected in maternal circulation during pregnancy. Our aim was to determine the higher rate of fetal DNA levels in maternal blood in pre-eclampsia compared to normal pregnancies and the clinical use of real-time polymerase chain reaction (PCR) in the Turkish population as a marker. MATERIAL AND METHODS: According to their gestational ages, the plasma levels of 30 pre-eclamptic women at 26-40 weeks of pregnancy were matched with 18 healthy pregnant women. Cell-free fetal DNA levels in maternal plasma were compared using real-time PCR technology. For the quantitative measurement of fetal DNA from maternal blood, the relative quantification PCR process was applied to all samples, using SRY and GAPDH genes. These patients were classified as pre-eclamptic and control groups and were matched according to weeks of pregnancy. RESULTS: Free fetal DNA levels of 30 pre-eclamptic patients were compared to healthy pregnant women and an average 3.06-fold increase was observed. During the second trimester, free fetal DNA levels were 1.5 times higher in pre-eclamptic patients. This increase was 3.5-fold during the third trimester. The DNA increase of pre-eclamptic patients was 4.1-fold and 3.4-fold during 29th-33rd and 34th-40th weeks, respectively. CONCLUSIONS: Cell-free fetal DNA in maternal blood could be used as a marker for identifying subjects at increased risk of developing pre-eclampsia. PMID- 23107424 TI - High-resolution motion compensated MRA in patients with congenital heart disease using extracellular contrast agent at 3 Tesla. AB - BACKGROUND: Using first-pass MRA (FP-MRA) spatial resolution is limited by breath hold duration. In addition, image quality may be hampered by respiratory and cardiac motion artefacts. In order to overcome these limitations an ECG- and navigator-gated high-resolution-MRA sequence (HR-MRA) with slow infusion of extracellular contrast agent was implemented at 3 Tesla for the assessment of congenital heart disease and compared to standard first-pass-MRA (FP-MRA). METHODS: 34 patients (median age: 13 years) with congenital heart disease (CHD) were prospectively examined on a 3 Tesla system. The CMR-protocol comprised functional imaging, FP- and HR-MRA, and viability imaging. After the acquisition of the FP-MRA sequence using a single dose of extracellular contrast agent the motion compensated HR-MRA sequence with isotropic resolution was acquired while injecting the second single dose, utilizing the timeframe before viability imaging. Qualitative scores for image quality (two independent reviewers) as well as quantitative measurements of vessel sharpness and relative contrast were compared using the Wilcoxon signed-rank test. Quantitative measurements of vessel diameters were compared using the Bland-Altman test. RESULTS: The mean image quality score revealed significantly better image quality of the HR-MRA sequence compared to the FP-MRA sequence in all vessels of interest (ascending aorta (AA), left pulmonary artery (LPA), left superior pulmonary vein (LSPV), coronary sinus (CS), and coronary ostia (CO); all p < 0.0001). In comparison to FP-MRA, HR-MRA revealed significantly better vessel sharpness for all considered vessels (AA, LSPV and LPA; all p < 0.0001). The relative contrast of the HR-MRA sequence was less compared to the FP-MRA sequence (AA: p <0.028, main pulmonary artery: p <0.004, LSPV: p <0.005). Both, the results of the intra- and interobserver measurements of the vessel diameters revealed closer correlation and closer 95 % limits of agreement for the HR-MRA. HR-MRA revealed one additional clinical finding, missed by FP-MRA. CONCLUSIONS: An ECG- and navigator-gated HR-MRA protocol with infusion of extracellular contrast agent at 3 Tesla is feasible. HR MRA delivers significantly better image quality and vessel sharpness compared to FP-MRA. It may be integrated into a standard CMR-protocol for patients with CHD without the need for additional contrast agent injection and without any additional examination time. PMID- 23107425 TI - Functional clustering of time series gene expression data by Granger causality. AB - BACKGROUND: A common approach for time series gene expression data analysis includes the clustering of genes with similar expression patterns throughout time. Clustered gene expression profiles point to the joint contribution of groups of genes to a particular cellular process. However, since genes belong to intricate networks, other features, besides comparable expression patterns, should provide additional information for the identification of functionally similar genes. RESULTS: In this study we perform gene clustering through the identification of Granger causality between and within sets of time series gene expression data. Granger causality is based on the idea that the cause of an event cannot come after its consequence. CONCLUSIONS: This kind of analysis can be used as a complementary approach for functional clustering, wherein genes would be clustered not solely based on their expression similarity but on their topological proximity built according to the intensity of Granger causality among them. PMID- 23107426 TI - Orbital anatomy for the surgeon. AB - An anatomic description of the orbit and its contents and the eyelids directed toward surgeons is the focus of this article. The bone and soft tissue anatomic nuances for surgery are highlighted, including a section on osteology, muscles, and the orbital suspensory system. Innervation and vascular anatomy are also addressed. PMID- 23107428 TI - Traditional and contemporary surgical approaches to the orbit. AB - Traditional orbital approaches are nearly a century old and still comprise the foundation of techniques used today. Computer-assisted planning and intraoperative navigation have recently been reported with more prevalence in the literature. The purpose of this article was to review commonly used approaches to the orbit: old and new. PMID- 23107427 TI - Growth and development of the orbit. AB - Every surgeon operating on the face, and particularly around the eye, should possess a working knowledge of the critical details related to development of the human orbit and recognized changes that occur during the course of aging. The anatomy of the orbit and periorbital region is complex, and the diagnosis and treatment of patients with orbital/periorbital disease requires expertise in congenital differences and awareness of the changes that occur as individuals age. PMID- 23107429 TI - Biomaterials for reconstruction of the internal orbit. AB - Orbital floor injuries, alone or combination with other facial fractures, are one of the most commonly encountered midface fractures. Techniques for orbital reconstruction have migrated away from autogenous bone grafts to well-tolerated alloplasts, such as titanium and Medpor. Material for reconstructing the orbit can then be selected based on requirements of the defect matched to the mechanical properties of the material. Material selection is largely and ultimately dependent upon surgeon preference. PMID- 23107430 TI - Evaluation of Gafchromic(r) EBT3 films characteristics in therapy photon, electron and proton beams. AB - PURPOSE: To evaluate the uncertainties and characteristics of radiochromic film based dosimetry system using the EBT3 model Gafchromic((r)) film in therapy photon, electron and proton beams. MATERIAL AND METHODS: EBT3 films were read using an EPSON Expression 10000XL/PRO scanner. They were irradiated in five beams, an Elekta SL25 6 MV and 18 MV photon beam, an IBA 100 MeV 5 * 5 cm(2) proton beam delivered by pencil-beam scanning, a 60 MeV fixed proton beam and an Elekta SL25 6 MeV electron beam. Reference dosimetry was performed using a FC65-G chamber (Elekta beam), a PPC05 (IBA beam) and both Markus 1916 and PPC40 Roos ion chambers (60 MeV proton beam). Calibration curves of the radiochromic film dosimetry system were acquired and compared within a dose range of 0.4-10 Gy. An uncertainty budget was estimated on films irradiated by Elekta SL25 by measuring intra-film and inter-film reproducibility and uniformity; scanner uniformity and reproducibility; room light and film reading delay influences. RESULTS: The global uncertainty on acquired optical densities was within 0.55% and could be reduced to 0.1% by placing films consistently at the center of the scanner. For all beam types, the calibration curves are within uncertainties of measured dose and optical densities. The total uncertainties on calibration curve due to film reading and fitting were within 1.5% for photon and proton beams. For electrons, the uncertainty was within 2% for dose superior to 0.8 Gy. CONCLUSIONS: The low combined uncertainty observed and low beam and energy-dependence make EBT3 suitable for dosimetry in various applications. PMID- 23107431 TI - Music as an adjuvant therapy in control of pain and symptoms in hospitalized adults: a systematic review. AB - The objective of this review is to evaluate the evidence regarding the use of music as an adjuvant therapy for pain control in hospitalized adults. The search terms music, music therapy, pain, adults, inpatient, and hospitalized were used to search the Cochrane Library, Cinahl, Medline, Natural Standard, and Scopus databases from January 2005 to March 2011. (A systematic review conducted by the Cochrane Collaboration has extensively covered the time frame from 1966 to 2004.) Seventeen randomized controlled trials met criteria for review and inclusion. Seven of the research studies were conducted with surgical patients, three with medical patients, one with medical-surgical patients, four with intensive care patients, and two with pregnant patients. The combined findings of these studies provide support for the use of music as an adjuvant approach to pain control in hospitalized adults. The use of music is safe, inexpensive, and an independent nursing function that can be easily incorporated into the routine care of patients. PMID- 23107432 TI - Genetic interactions associated with 12-month atrophy in hippocampus and entorhinal cortex in Alzheimer's Disease Neuroimaging Initiative. AB - Missing heritability in late onset Alzheimer disease can be attributed, at least in part, to heterogeneity in disease status and to the lack of statistical analyses exploring genetic interactions. In the current study, we use quantitative intermediate phenotypes derived from magnetic resonance imaging data available from the Alzheimer's Disease Neuroimaging Initiative, and we test for association with gene-gene interactions within biological pathways. Regional brain volumes from the hippocampus (HIP) and entorhinal cortex (EC) were estimated from baseline and 12-month magnetic resonance imaging scans. Approximately 560,000 single nucleotide polymorphisms (SNPs) were available genome-wide. We tested all pairwise SNP-SNP interactions (approximately 151 million) within 212 Kyoto Encyclopedia of Genes and Genomes pathways for association with 12-month regional atrophy rates using linear regression, with sex, APOE epsilon4 carrier status, age, education, and clinical status as covariates. A total of 109 SNP-SNP interactions were associated with right HIP atrophy, and 125 were associated with right EC atrophy. Enrichment analysis indicated significant SNP-SNP interactions were overrepresented in the calcium signaling and axon guidance pathways for both HIP and EC atrophy and in the ErbB signaling pathway for HIP atrophy. PMID- 23107434 TI - Persistent pain, sensory disturbances and functional impairment after immediate or delayed axillary lymph node dissection. AB - BACKGROUND: Patients treated with 2-step axillary lymph node dissection (ALND) may be at increased risk of nerve damage due to more challenging surgery than an ALND immediately after a sentinel lymph node biopsy (SLNB), and thus more at risk for persistent pain after breast cancer treatment (PPBCT). The aim of this study was to examine PPBCT, sensory disturbances and functional impairment in patients treated with a 2-step ALND compared to patients with an SLNB followed by an immediate ALND, and patients with ALND without a prior SLNB. METHODS: The study is a cross-sectional questionnaire study, comparing 2847 women treated with ALND in Denmark in 2005-2008. 196 patients treated with a 2-step ALND were compared with 1558 patients treated with an ALND after SLNB and 1093 with an ALND without a prior SLNB. RESULTS: Overall prevalence of PPBCT and sensory disturbances was high, with about 55% reporting PPBCT and 77% reporting sensory disturbances in all groups. No differences were found between the groups on prevalence and intensity of PPBCT (p = 0.92), sensory disturbances (p = 0.32), and functional consequences (p = 0.35). CONCLUSIONS: A 2-step ALND does not modify the risk of developing PPBCT compared to an immediate ALND. PMID- 23107433 TI - Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians. AB - Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer's disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD. PMID- 23107435 TI - Hopeahainol A attenuates memory deficits by targeting beta-amyloid in APP/PS1 transgenic mice. AB - Increasing evidence demonstrates that amyloid beta (Abeta) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Abeta is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase-inhibitory and anti-oxidative in H(2)O(2)-treated PC12 cells. In this study, we reported that HopA might bind to Abeta(1-42) directly and inhibit the Abeta(1-42) aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Abeta(1-42) and Abeta-binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long-term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD. PMID- 23107436 TI - Effect of health contract intervention on renal dialysis patients in Korea. AB - This study is a randomized, controlled trial to examine the effect of the health contract intervention, based on the goal attainment theory, on the self-care behavior and physiological indices of renal dialysis patients in Korea. The experimental group (n = 21) underwent health contract intervention for 4 weeks, while the control group (n = 22) received routine care. The data were collected using questionnaires and measurement of physiological indices and analyzed using the SPSS WIN 12.0 program. A P value < 0.05 was considered statistically significant. Total score of self-care behavior (P = 0.011) and individual scores for behaviors, such as diet (P = 0.017), exercise and rest (P = 0.001), and blood pressure and body weight (P = 0.006) were higher in the experimental group. Serum potassium concentration and mean weight gain between dialysis sessions were significantly low in the experimental group (P = 0.002, P = 0.017). Therefore, the health contract intervention based on the goal attainment theory proved effective in improving self-care behavior and physiological indices (K, P, mean weight gain) in renal dialysis patients in Korea. PMID- 23107437 TI - Withaferin A suppresses tumor promoter 12-O-tetradecanoylphorbol 13-acetate induced decreases in isocitrate dehydrogenase 1 activity and mitochondrial function in skin epidermal JB6 cells. AB - Withaferin A (WA) is a bioactive compound derived from Withania somnifera. The antitumor activity of WA has been well studied in human cancer models; however, its chemopreventive potential is unclear. In the present study, we used the skin epidermal JB6 P+ cells, a well-established model for tumor promotion, and demonstrated that WA suppressed the tumor promoter 12-O-tetradecanoylphorbol 13 acetate (TPA)-induced cell transformation and cell proliferation. Interestingly, TPA inactivated isocitrate dehydrogenase 1 (IDH1), which was reversed by WA. Similar results were also observed in mouse skin tissue. Therefore, we focused on metabolism as the potential mechanism of action. We found that mitochondrial functions were downregulated by TPA treatment, as indicated by reduced mitochondrial membrane potential, complex I activity and mitochondrial respiration. However, all of these downregulations were inhibited by WA. In addition, we examined the levels of alpha-ketoglutarate, a product of IDH1, and WA blocked its reduction upon TPA treatment. Finally, we detected the lactate level as a glycolysis marker, and WA suppressed its elevation caused by tumor promoter treatment. Altogether, these results suggest that WA might exert its chemopreventive activity via inhibiting not only oncogenic activation, but also IDH1 inactivation and mitochondrial dysfunction in early tumorigenesis. PMID- 23107438 TI - Biomechanical and histomorphometric evaluation of osseointegration of fusion sputtered zirconia implants. AB - PURPOSE: The aim of this study was to evaluate osseointegration of fusion sputtered zirconia implants in comparison with sandblasted, acid-etched titanium implants in a biomechanical and histomorphometric study. MATERIALS AND METHODS: Sixty zirconia implants were manufactured using CAD/CAM. Half received fusion sputtering surface treatment through spraying the green body implants with a jet of zirconia suspension. Standard Ti implants of the same shape and dimensions served as control. Thirty adult New Zealand white male rabbits were used in this study. Each animal received one fusion-sputtered and one Ti implant in one femur site and control zirconia in the other, for a healing period of 4, 8, and 12 weeks. At each healing time, a removal torque (RTQ) test was used to assess implant stability, while histological and histometric analyses were used to evaluate osseointegration. RESULTS: Fusion-sputtered zirconia implants demonstrated a statistically higher mean RTQ than control zirconia. When compared to Ti, however, although still higher, the differences were not significant. Histomorphometric evaluation revealed significantly greater bone-implant contact for fusion-sputtered zirconia implants compared to Ti after 4 and 8 weeks of healing time; however, at 12 weeks, the difference did not reach statistical significance. There were no significant differences in the measured bone density between fusion-sputtered and Ti implants, although the difference was significant when compared to the control zirconia. CONCLUSION: Fusion-sputtered zirconia implants demonstrated a degree of osseointegration and interfacial biomechanical stability comparable to Ti implants. PMID- 23107439 TI - Haemorrhoids: 21st-century management. PMID- 23107440 TI - The use of research questionnaires with hearing impaired adults: online vs. paper and-pencil administration. AB - BACKGROUND: When evaluating hearing rehabilitation, it is reasonable to use self report questionnaires as outcome measure. Questionnaires used in audiological research are developed and validated for the paper-and-pencil format. As computer and Internet use is increasing, standardized questionnaires used in the audiological context should be evaluated to determine the viability of the online administration format.The aim of this study was to compare administration of questionnaires online versus paper- and pencil of four standardised questionnaires used in hearing research and clinic. We included the Hearing Handicap Inventory for the Elderly (HHIE), the International Outcome Inventory for Hearing Aids (IOI-HA), Satisfaction with Amplification in Daily Life (SADL), and the Hospital Anxiety and Depression Scale (HADS). METHODS: A cross-over design was used by randomly letting the participants complete the questionnaires either online or on paper. After 3 weeks the participants filled out the same questionnaires again but in the other format. A total of 65 hearing-aid users were recruited from a hearing clinic to participate on a voluntary basis and of these 53 completed both versions of the questionnaires. RESULTS: A significant main effect of format was found on the HHIE (p < 0.001), with participants reporting higher scores on the online format than in the paper format. There was no interaction effect. For the other questionnaires were no significant main or interaction effects of format. Significant correlations between the two ways of presenting the measures was found for all questionnaires (p<0.05). The results from reliability tests showed Cronbachs alpha's above .70 for all four questionnaires and differences in Cronbachs alpha between administration formats were negligible. CONCLUSIONS: For three of the four included questionnaires the participants' scores remained consistent across administrations and formats. For the fourth included questionnaire (HHIE) a significant difference of format with a small effect size was found. The relevance of the difference in scores between the formats depends on which context the questionnaire is used in. On balance, it is recommended that the administration format remain stable across assessment points. PMID- 23107441 TI - Antiviral therapy for hepatitis B virus-related decompensated cirrhosis. AB - Antiviral therapy is important in patients with hepatitis B virus (HBV)-related decompensated cirrhosis. This therapy is beneficial in most patients for the stabilization or improvement of liver disease; however, advanced cirrhosis with a high Child-Pugh or model for end-stage liver disease (MELD) score may have progressed and does not benefit from antiviral therapy. It is important to identify patients with severe decompensated cirrhosis who will not improve under antiviral therapy and who require liver transplantation as early as possible. Entecavir (ETV) or tenofovir disoproxil fumarate (TDF) is the first-line therapy for nucleos(t)ide analogue (NA)-naive patients with decompensated cirrhosis due to their potent and prompt HBV suppressive effect and low rate of drug-resistant mutations. Patients on antiviral therapy should be monitored for virological and clinical response, compliance, drug resistance and adverse effects as well as surveillance for hepatocellular carcinoma (HCC). Additional studies of TDF and ETV are necessary to determine the optimal agent(s) for treating naive patients and those with drug-resistant decompensated cirrhosis. In order to evaluate the effectiveness of NA for the treatment of decompensated cirrhotic patients in the real world, high quality observational studies such as registration studies of antiviral therapy for HBV-related cirrhosis and a long-term follow-up in China, where a large number of such patients are found, are recommended. PMID- 23107442 TI - Serum levels of tissue inhibitor of metalloproteinase-1 are correlated with liver fibrosis in patients with chronic hepatitis B. AB - OBJECTIVE: To investigate the relationship between tissue inhibitor of metalloproteinase-1 (TIMP-1) expression and the severity of liver fibrosis in chronic hepatitis B (CHB) patients, and to explore the diagnostic value of serum TIMP-1. METHODS: A total of 159 CHB patients underwent liver biopsy for the analysis of liver fibrosis stages and inflammation. Serum TIMP-1 was determined by ELISA. Hyaluronic acid (HA), procollagen type III (PCIII), collagen type IV (CIV), laminin (LN), and FIB-4 index were determined and calculated, and diagnostic accuracy was analyzed using receiver operating characteristic (ROC) curve. RESULTS: Serum levels of TIMP-1 were associated with the grade of liver inflammation in CHB patients (r = 0.695, P < 0.01), especially in those without fibrosis or with stage 1 fibrosis, and were also positively correlated with liver fibrosis in CHB patients (r = 0.854, P < 0.01), particularly in those with inflammation at grade 1, 2 and 3. The area under the ROC curve (AUROC) of serum TIMP-1 was 0.918 for significant liver fibrosis (>=stage 2), and a sensitivity of 89.4% and specificity of 83.6% were obtained with a cut-off value of >=174.5 ng/mL of serum TIMP-1, which were higher than that of HA, CIV and FIB-4 index. CONCLUSION: TIMP-1 is a valuable single biomarker for the evaluation of significant fibrosis in CHB patients. PMID- 23107443 TI - Distribution of hepatitis C virus genotypes in Chinese patients with chronic hepatitis C: correlation with patients' characteristics and clinical parameters. AB - OBJECTIVE: This study aimed to explore the most up-to-date distribution of hepatitis C virus (HCV) genotypes in China, especially the association between HCV genotypes and patients' characteristics and clinical parameters. METHODS: Sera from 483 HCV antibody-positive patients were genotyped using a HCV genotyping chip assay. The distribution of HCV genotypes, clinical parameters, modes of transmission and duration of infection were determined and the relationships among these parameters were analyzed. RESULTS: A total of 424 patients were successfully genotyped. HCV genotypes 1, 2, 3 and 6 were found with a constituent ratio of 72.1%, 12.3%, 10.6% and 5.0%, respectively, in which subtypes 1b (69.1%), 2a (11.6%) and 3a (7.5%) were prevalent. The mean age of patients with genotype 1 and 2 was significantly elder than those with genotype 3 and 6 (P < 0.05). The distribution of HCV genotypes in relation to the mode of HCV transmission was remarkable (P < 0.001). Transfusion of blood and blood products was the main mode of transmission. Most genotype 1 infection (53.1%) was found in the group with a duration of HCV infection of 10-20 years. Genotype 1b was independently associated with age (P = 0.001) and mode of HCV transmission (P = 0.007). CONCLUSIONS: The main HCV subtype was genotype 1b in Chinese patients. The prevalence of HCV genotypes was correlated with age and the mode of HCV transmission. Genotype 3a and 6 may become an increasing threat in the future. PMID- 23107444 TI - Hematopoietic stem cell mobilization into the peripheral circulation in patients with chronic liver diseases. AB - OBJECTIVE: The present study was aimed to investigate and compare the kinetics of bone marrow-derived hematopoietic stem cells (BMHSC) migration in the peripheral blood and liver in response to liver injury in patients with chronic liver disease (CLD). METHODS: In all, 45 CLD patients staged with Child-Pugh A, B and C and 15 healthy participants were evaluated for the concentration of circulating BMHSC by a flow cytometric analysis of CD133(+) /CD34(+) cells. In addition, homing BMHSC and hepatic progenitors were assessed by the immunohistochemical detection of CD133(+) and OV6(+) cells in liver biopsy specimens from Child Pugh A and B patients. RESULTS: No significant difference in the percentage of circulating CD133(+) /CD34(+) cells was observed among all groups of patients. In liver tissues, OV6(+) cells increased significantly in Child-Pugh B cases (P < 0.05), while CD133(+) cells were distributed sparsely in the periportal region in Child-Pugh A and B patients. OV6(+) cells were significantly correlated with CD34(+) cells but not with CD133(+) cells in Child-Pugh A and B patients (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: Various degrees of severity in CLD neither evoked the mobilization of BMHSC into the circulation nor triggered their homing into liver tissue, thus excluding extrahepatic stem cell-mediated repair. The recovery process seems to be dependent on proliferating endogenous liver progenitors (OV6(+) cells). PMID- 23107446 TI - Suboptimal performance of simple noninvasive tests for advanced fibrosis in Chinese patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: To evaluate the diagnostic accuracy of some noninvasive fibrosis models in Chinese patients with nonalcoholic fatty liver disease (NAFLD). METHODS: Consecutive biopsy-proven NAFLD patients were recruited from a single center from January 2005 to December 2010. Advanced fibrosis (stage 3 and 4) was defined using Kleiner criteria. The area under the receiver operating characteristic curve (AUROC) was used to compare the diagnostic accuracy of the NAFLD fibrosis score (NFS), FIB-4 index, aspartate transaminase (AST)/platelet ratio index (APRI), AST/alanine transaminase (ALT) ratio (AAR) and body mass index (BMI)-AAR-Diabetes (BARD) score. RESULTS: Of the patients with NAFLD, 79.6% were males with a mean age of 37.1 years, mean BMI of 26.1 kg/m(2) and 41.4% of them had nonalcoholic steatohepatitis, and 24 (15.8%) had advanced fibrosis. The AUROC of the FIB-4 index, APRI, AAR, NFS and BARD score for advanced fibrosis were 0.756, 0.742, 0.670, 0.653 and 0.642 (P < 0.05 for all), respectively. A concordant negative predictive value of approximately 90% was indicated whereas the positive predictive values were modest for all tests, and only the FIB-4 index yielded a higher positive likelihood ratio of 7.65. Using these cut-off values of tests for excluding advanced fibrosis could reduce the use of liver biopsy in 56.6-74.3% of the patients, with a minor false negative rate of 5.3 9.9%. CONCLUSIONS: Although slightly less accurate than liver biopsy, simple noninvasive tests can reliably exclude advanced fibrosis in Chinese NAFLD patients in our center. FIB-4 index performs better than the other tests under examination. PMID- 23107445 TI - Pharmacogenetic selection of transplanted human hepatocytes in immunocompetent rats. AB - OBJECTIVE: To introduce a genetic survival advantage for transplanted human hepatocytes over host cells in rats. METHODS: Green fluorescent protein (GFP) was introduced into Huh-7 human hepatoma cells to create fluorescent GFP-Huh-7 cells. mRNA of CYP2E1, the enzyme that converts acetaminophen (APA) into hepatotoxic intermediates, was quantified by real-time polymerase chain reaction (PCR). The effects of APA on GFP-Huh-7 and control Huh-7 cells were determined in a cell culture. Immunological tolerance was induced by the injection of GFP-Huh-7 cells into fetal rats in utero. The GFP-Huh-7 cells were transplanted after birth of the rats into tolerant rats followed by APA treatment. Serum alanine aminotransferase (ALT) levels and liver histological data were obtained. GFP-Huh 7 cells were detected by quantitive PCR and microscopy. RESULTS: CYP2E1 mRNA levels in the GFP-Huh-7 cells were 2.7% of parental Huh-7 cells. In 1 mmol/L APA, parental Huh-7 cells decreased by 60% while GFP-Huh-7 cells increased to within 95% of untreated controls after 5 days. In rats in which GFP-Huh-7 cells were transplanted and treated with APA, serum ALT increased to a peak of 200 U/L on day 1 and returned to normal levels by day 3. Fluorescence microscopy of liver specimens from rats transplanted with GFP-Huh-7 cells showed substantial increases in GFP-Huh-7, but not Huh-7 cells by day 7 after APA treatment. Real time PCR confirmed a 10-fold increase of GFP mRNA in APA-treated rats, but not in those without APA treatment. CONCLUSIONS: The difference in CYP2E1 gene expression between GFP-Huh-7 and rat hepatocytes provides a convenient means for the enrichment of transplanted human cells in rat liver. PMID- 23107448 TI - Probable catastrophic antiphospholipid syndrome complicated with primary sclerosing cholangitis. PMID- 23107447 TI - Variceal recurrence, rebleeding rates and alterations in clinical and laboratory parameters following post-variceal obliteration using endoscopic sclerotherapy. AB - OBJECTIVE: To study the rates of variceal recurrence and rebleeding following sclerotherapy and its effect on clinical and laboratory parameters in patients with portal hypertension. METHODS: A total of 237 patients with portal hypertension together with esophageal variceal bleeding were included in the study. There were 138 patients with cirrhosis (group I), 42 with non-cirrhotic portal fibrosis (group II), and 57 with extrahepatic portal vein obstruction (group III). Baseline data and post-obliteration follow-up for rebleeding rates and changes in clinical and laboratory parameters were recorded. RESULTS: In all, 106 patients in group I, 31 in group II and 43 in group III experienced obliteration of varices. The recurrence of grade II varices occurred in 17 patients (9.4%) during a mean period of 9 months. Rebleeding from varices was observed in 4 patients (3.8%) in group I and 1 (3.2%) in group II, while none in group III experienced rebleeding. There was a significant improvement in ascites, jaundice, liver status, international normalized ratio and platelet count in group I patients after variceal eradication (P < 0.05). The main cause of death in the cirrhotic patients was active liver disease but not rebleeding. CONCLUSIONS: Following obliterative endoscopic sclerotherapy, rates of recurrence and rebleeding were significantly low when patients are kept under close observation. Disappearance of varices or reduction of variceal size improves the liver status in surviving cirrhotic patients. PMID- 23107449 TI - Effects of soybean isoflavones on reproductive parameters in Chinese mini-pig boars. AB - BACKGROUND: Soybean isoflavones are structurally similar to mammalian estrogens and therefore may act as estrogen agonists or antagonists. However, it has not been determined if they have any negative effects on reproductive parameters in male livestock. Therefore, the objective of this study was to evaluate the effects of soybean isoflavones on male reproduction using Chinese mini-pig boars as a model. Fifty Xiang boars were randomly divided into five groups and fed diets containing 0, 125, 250, or 500 ppm soybean isoflavones or 0.5 ppm diethylstilbestrol for 60 days. RESULTS: Dietary supplementation with 250 ppm of soy isoflavones markedly increased the testis index (P < 0.05), fructose content (P < 0.05), and alpha-glycosidase content in testicular tissue (P < 0.01), as well as increased the number of viable germ cells (P < 0.01) and the level of Bcl 2 protein (P < 0.01). However, 500 ppm of soybean isoflavones significantly reduced both testis and epididymis indexes (P < 0.05) and lactate dehydrogenase levels (P < 0.01), as well as reduced serum LH and testosterone levels (P < 0.05). High levels of soybean isoflavones also increased malondialdehyde levels (P < 0.05), as well as increased the numbers of early and late apoptotic germ cells (P < 0.01) and the level of Bax proteins (P < 0.05) in the testis. CONCLUSIONS: The results of this study indicate that consumption of soy isoflavones at dietary levels up to 250 ppm did not adversely affect reproductive parameters in Chinese mini-pig boars whereas higher levels of soy isoflavones may adversely affect male reproduction. PMID- 23107450 TI - Autologous G-CSF-mobilized peripheral blood CD34+ cell therapy for diabetic patients with chronic nonhealing ulcer. AB - Recently, animal studies have demonstrated the efficacy of endothelial progenitor cell (EPC) therapy for diabetic wound healing. Based on these preclinical studies, we performed a prospective clinical trial phase I/IIa study of autologous G-CSF-mobilized peripheral blood (PB) CD34(+) cell transplantation for nonhealing diabetic foot patients. Diabetic patients with nonhealing foot ulcers were treated with 2 * 10(7) cells of G-CSF-mobilized PB CD34(+) cells as EPC enriched population. Safety and efficacy (wound closure and vascular perfusion) were evaluated 12 weeks posttherapy and further followed for complete wound closure and recurrence. A total of five patients were enrolled. Although minor amputation and recurrence were seen in three out of five patients, no death, other serious adverse events, or major amputation was seen following transplantation. Complete wound closure was observed at an average of 18 weeks with increased vascular perfusion in all patients. The outcomes of this prospective clinical study indicate the safety and feasibility of CD34(+) cell therapy in patients with diabetic nonhealing wounds. PMID- 23107451 TI - Diffuse myocardial fibrosis in hypertrophic cardiomyopathy can be identified by cardiovascular magnetic resonance, and is associated with left ventricular diastolic dysfunction. AB - BACKGROUND: The presence of myocardial fibrosis is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) sequences can detect regional, but not diffuse myocardial fibrosis. Post-contrast T(1) mapping is an emerging CMR technique that may enable the non-invasive evaluation of diffuse myocardial fibrosis in HCM. The purpose of this study was to non-invasively detect and quantify diffuse myocardial fibrosis in HCM with CMR and examine its relationship to diastolic performance. METHODS: We performed CMR on 76 patients - 51 with asymmetric septal hypertrophy due to HCM and 25 healthy controls. Left ventricular (LV) morphology, function and distribution of regional myocardial fibrosis were evaluated with cine imaging and LGE. A CMR T(1) mapping sequence determined the post-contrast myocardial T(1) time as an index of diffuse myocardial fibrosis. Diastolic function was assessed by transthoracic echocardiography. RESULTS: Regional myocardial fibrosis was observed in 84% of the HCM group. Post-contrast myocardial T(1) time was significantly shorter in patients with HCM compared to controls, consistent with diffuse myocardial fibrosis (498 +/- 80 ms vs. 561 +/- 47 ms, p < 0.001). In HCM patients, post contrast myocardial T(1) time correlated with mean E/e' (r = -0.48, p < 0.001). CONCLUSIONS: Patients with HCM have shorter post-contrast myocardial T(1) times, consistent with diffuse myocardial fibrosis, which correlate with estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM. PMID- 23107452 TI - Penile length and girth restoration in severe Peyronie's disease using circular and longitudinal grafting. AB - OBJECTIVE: To report patient outcomes and satisfaction with our technique for penile length and girth restoration in severe Peyronie's disease (PD). PATIENTS AND METHODS: Between November 2006 and November 2011, 105 men with severe PD and erectile dysfunction (ED) underwent surgical correction using our new approach. The technique consists of penile prosthesis implantation with concomitant penile lengthening and girth restoration through circular and longitudinal incisions in the tunica albuginea according to geometric principles. RESULTS: The overall patient satisfaction rate was 89.4%. The mean (sd; range) functional penile length gain was 3.6 (0.7; 2-5) cm. Patient satisfaction with penile length gain was 95.2%. Three patients (2.9%) developed retraction with residual curvature of up to 30 degrees , but no re-operation was necessary. In one (1%) patient, the prosthesis had to be removed because of wound infection. At a mean (sd; range) follow-up of 18.2 (5.9; 6-46) months, 104 patients (99%) were able to have sexual intercourse. CONCLUSIONS: Our surgical approach for penile length and girth restoration leads to high patient satisfaction rates and excellent functional outcomes. Our surgical approach is a safe and valid therapeutic method for the treatment of severe PD associated with ED. PMID- 23107453 TI - The importance of geometry in mathematical models of developing systems. AB - Understanding the interaction between the spatial variation of extracellular signals and the interpretation of such signals in embryonic development is difficult without a mathematical model, but the inherent limitations of a model can have a profound impact on its utility. A central issue is the level of abstraction needed, and here we focus on the role of geometry in models and how the choice of the spatial dimension can influence the conclusions reached. A widely studied system in which the proper choice of geometry is critical is embryonic development of Drosophila melanogaster, and we discuss recent work in which 3D embryo-scale modeling is used to identify key modes of transport, analyze gap gene expression, and test BMP-mediated positive feedback mechanisms. PMID- 23107455 TI - Coordinated and evidence-based policy and practice for protecting children outside of family care. PMID- 23107454 TI - The transcriptional landscape of the deep-sea bacterium Photobacterium profundum in both a toxR mutant and its parental strain. AB - BACKGROUND: The deep-sea bacterium Photobacterium profundum is an established model for studying high pressure adaptation. In this paper we analyse the parental strain DB110 and the toxR mutant TW30 by massively parallel cDNA sequencing (RNA-seq). ToxR is a transmembrane DNA-binding protein first discovered in Vibrio cholerae, where it regulates a considerable number of genes involved in environmental adaptation and virulence. In P. profundum the abundance and activity of this protein is influenced by hydrostatic pressure and its role is related to the regulation of genes in a pressure-dependent manner. RESULTS: To better characterize the ToxR regulon, we compared the expression profiles of wt and toxR strains in response to pressure changes. Our results revealed a complex expression pattern with a group of 22 genes having expression profiles similar to OmpH that is an outer membrane protein transcribed in response to high hydrostatic pressure. Moreover, RNA-seq allowed a deep characterization of the transcriptional landscape that led to the identification of 460 putative small RNA genes and the detection of 298 protein-coding genes previously unknown. We were also able to perform a genome-wide prediction of operon structure, transcription start and termination sites, revealing an unexpected high number of genes (992) with large 5'-UTRs, long enough to harbour cis-regulatory RNA structures, suggesting a correlation between intergenic region size and UTR length. CONCLUSION: This work led to a better understanding of high-pressure response in P. profundum. Furthermore, the high-resolution RNA-seq analysis revealed several unexpected features about transcriptional landscape and general mechanisms of controlling bacterial gene expression. PMID- 23107456 TI - Relative benefits of on-plot water supply over other 'improved' sources in rural Vietnam. AB - OBJECTIVE: Access to improved water sources is rapidly expanding in rural central Vietnam. We examined one NGO-led piped water supply programme to assess the drinking water quality and health impacts of piped water systems where access to 'improved' water sources is already good. METHODS: This longitudinal, prospective cohort study followed 300 households in seven project areas in Da Nang province, Vietnam: 224 households who paid for an on-plot piped water connection and 76 control households from the same areas relying primarily on 'improved' water sources outside the home. The 4-month study was intended to measure the impact of the NGO-led water programmes on households' drinking water quality and health and to evaluate system performance. RESULTS: We found that: (i) households connected to a piped water supply had consistently better drinking water quality than those relying on other sources, including 'improved' sources and (ii) connected households experienced less diarrhoea than households without a piped water connection (adjusted longitudinal prevalence ratio: 0.57 (95% CI 0.39-0.86, P = 0.006) and households using an 'improved' source not piped to the plot: (adjusted longitudinal prevalence ratio: 0.59 (95% CI 0.39-0.91, P = 0.018). CONCLUSIONS: Our results suggest that on-plot water service yields benefits over other sources that are considered 'improved' by the WHO/UNICEF Joint Monitoring Programme. PMID- 23107457 TI - Significance of maternal screening for toxoplasmosis, rubella, cytomegalovirus and herpes simplex virus infection in cases of fetal growth restriction. AB - AIM: The objective of this study was to evaluate the significance of maternal toxoplasmosis, rubella, cytomegalovirus (CMV) and herpes simplex virus (TORCH) screening in cases of fetal growth restriction (FGR). MATERIAL AND METHODS: The medical records of women carrying fetuses with FGR who underwent TORCH screening over a 10-year period were retrospectively reviewed for maternal and congenital TORCH infection. Women carrying fetuses with FGR routinely underwent serologic TORCH tests and systematic ultrasound evaluation for congenital abnormalities. If a congenital CMV infection was suspected, amniotic fluid, placenta or neonatal urine was used for CMV DNA detection by polymerase chain reaction. RESULTS: In 319 patients, no cases of maternal or congenital infection with toxoplasma, rubella, or herpes simplex virus were found. Conversely, six cases (1.8%) were diagnosed with congenital CMV infection, two of which had no structural abnormalities other than FGR. CONCLUSIONS: A complete maternal TORCH screening for cases of FGR appears to be unnecessary. Although a maternal CMV test can be considered, the incidence of congenital CMV infection was found to be low in FGR cases. PMID- 23107458 TI - Evaluation of flavonoids and diverse antioxidant activities of Sonchus arvensis. AB - BACKGROUND: Sonchus arvensis is used in the treatment of various human aliments as a traditional medicine in Pakistan. In the study its various fractions are characterized for scavenging of diverse free radicals. RESULTS: Results of the present study revealed that various fractions of Sonchus arvensis significantly scavenged the free radicals (DPPH., ABTS.+, .OH, superoxide), however its methanolic fraction is more potent than other fractions. Significant correlation was found between DPPH., ABTS.+, superoxide radical and total antioxidant activity with total flavonoids and phenolics contents. Phytochmical analysis revealed the presence kaempferol, quercetin, orientin, rutin, hyperoside, catechin and myricetin. CONCLUSION: From the present data it is concluded that various fractions of Sonchus arvensis significantly scavenged the free radical, which might be due the presence of polyphenolic constituent. PMID- 23107459 TI - [The story of compensatory rest]. PMID- 23107460 TI - Psychosocial functioning and self-rated health in Japanese school-aged children: A cross-sectional study. AB - Emotional and behavioral disorders in children are school-health concerns; however, Japanese screening tools for such disorders are not yet available. We examined the association between psychosocial functioning as measured by the Pediatric Symptom Checklist (PSC) and self-rated health within school settings. A cross-sectional study was conducted for 2513 fifth and eighth graders from all of the primary and secondary schools in Shunan City, Japan. The Japanese PSC had high internal consistency (Cronbach's alpha = 0.90) and a factor structure similar to that of the English PSC. When the cut-off values were set to >= 28 and >= 17, 4-9% and 20-39% of our respondents, respectively, reported high PSC scores. A multiple ordinal logistic regression analysis showed that the odds ratio of a positive PSC score (>= 28) for poorer self-rated health among ratings of "very good," "good," "fair," and "poor" was 3.5 (95% confidence interval = 2.6 4.8). There was a clear association between psychosocial dysfunction identified by a PSC score >= 28 and poor self-rated health. We offer directions for further research on appropriate PSC cut-off values with Japanese samples. PMID- 23107461 TI - [Initial training in psychotherapy for psychiatrists in France: results of a national survey]. AB - INTRODUCTION: According to a recent change in the French legislation (2010) regarding the regulation of the use of the title of "psychotherapist", psychiatrists are now allowed to use this title at the end of their training, without any additional training. However, various publications from 2000 have shown that there is no specific training in psychotherapy at a professional level during the training of psychiatrists. GOALS: To study the current situation of the Academic training of French psychiatrists in psychotherapy during their residency, their interest for these therapies, their level of satisfaction regarding their training, and the importance of additional private training programs. METHODOLOGY: A survey was carried out among residents in psychiatry from October 2010 until January 2011. An anonymous questionnaire covering five domains (academic teaching, psychoanalysis, extra-academic training, interest in a more developed model of training, supervision) was sent by the French Federative Association of Psychiatrists Trainees (AFFEP) to all French psychiatrist trainees, through their local trainee associations (n=26). RESULTS: The questionnaire was answered by 869 of the 1334 psychiatry residents (65%). The vast majority of the trainees reported being interested in psychotherapy, but 75% thought that their training in psychotherapy (psychoanalysis, cognitive behavioral therapy [CBT] and systemic therapy) is insufficient. In 20 of the 26 universities, more than half of the trainees reported that their training was insufficient in the three fields; in four universities, more than half of the trainees were satisfied with at least one field. Yet, satisfaction rates were very different among universities: for example, 27% were satisfied with their psychoanalytic training in Paris and 87% in Strasbourg; 7% were satisfied with their CBT training in Strasbourg, but 65% in Nice. The vast majority (97%) believes that supervision about therapeutic relationship is necessary during residency rotations in the hospital. More than three quarters (78%) would like to have supervision at least twice a month. Yet, only 51% of respondents have such supervision. Once again, large disparities were observed between different Academies: for example 74% had supervision in Montpellier, but only 29% in Marseille. The vast majority (95%) of trainees would like a two-phase model of training (general theoretical teaching plus in-depth training in one or more methods), which is different to the current training model. CONCLUSION: Our results show a clear discrepancy between the importance of training in psychotherapy for psychiatrists, the interest of psychiatry students for these therapies, and the very high rate of dissatisfaction for the training received, as well as the rate of students supervised during their training period at the hospital. These results differ from what is observed in other countries, where satisfaction rates are much higher among students, and various psychotherapy training methods are proposed in a much more homogeneous manner. More research is required to understand the reasons for these difficulties with the psychotherapy training of psychiatrists in France, and to propose new models of training to improve this situation. PMID- 23107462 TI - [Adaptation of a questionnaire measuring representations related to work disability]. AB - BACKGROUND: Health, illness and treatment representations have been described as key factors for return to work. The Revised Illness Perception Questionnaire (IPQ R) is a quantitative tool available to assess these factors. However, an adaptation is necessary before its use with workers on prolonged work disability presenting musculoskeletal disorders (MSD). METHODS: Two distinct phases were carried out, firstly, by adapting the IPQ-R for a population of workers in prolonged work disability related to an MSD and, secondly, by conducting a pre test on the adapted questionnaire to assess item clarity. PHASE 1: The Technique for Research of Information by the Animation of a Group of Experts (TRIAGE) was selected to proceed with the adaptation. TRIAGE is an inductive and structured method aiming at the attainment of group consensus. Consensus was obtained in two steps: for the individual production, each expert had to judge the pertinence of the questioned elements and suggested new elements if needed; for the group production, all suggestions submitted were sorted according to TRIAGE systematic procedure, in order to retain the most pertinent ones by group consensus. Analysis was done simultaneously to data collection, by the attainment of group consensus. The group of experts consisted of six clinicians and two researchers. For the clinicians, selection criteria consisted of: being an occupational therapist or a psychologist and working for at least 2 years in a vocational rehabilitation setting for workers in prolonged work disability; for the researchers, being affiliated to a university and to have pursued a least one research project regarding prolonged work disability following MSD and development/validation of assessment tools. As a result of the adaptation process eight items were excluded because they were not considered pertinent by the experts. The label "illness" was changed for "current health condition" and 26 new items have been added to the questionnaire to better account for the work disability. The adapted questionnaire appears to present good content validity. PHASE 2: The assessment tool was then pre-tested using a widely known method for trans-cultural adaptation of questionnaires. This method adds a 7-point scale following each item in order to assess item clarity. When the questionnaire is filled, questions are asked to the respondent about items with low rating (4 or less on 7) in order to identify potential ambiguities. Inclusion criteria for the respondents consisted of: being between 18 and 64 of age, having more than 3 months of absence from work related to an MSD and being admitted in a rehabilitation program. Workers absent from work for more than a year, unable to understand and/or read French, suffering from an MSD related to a specific pathology, or presenting major psychiatric problems as indicated in their medical record were excluded. Nine workers were recruited using convenience sampling. Average clarity rating was above 4 for each item, suggesting that the adapted questionnaire was clear. Characteristics of participants seem to be representative of the target population. CONCLUSION: A questionnaire was adapted in order to better assess the representations of workers in a situation of work disability following an MSD. The rigorous process used in this study ensures the quality of the adaptation, but a validation study must be conducted before the implementation of the questionnaire in clinic and research. PMID- 23107463 TI - [Psychotherapy of chronic depression: contributions of CBASP by McCullough]. AB - INTRODUCTION: Chronic depression is a frequent disorder and is usually treated using traditional approaches. These approaches rarely take into account the psychopathological specificities of the chronic evolution of the disorder. OBJECTIVE: The present article aims at presenting the specific psychopathological nature of chronic depression and puts forward a treatment model that is particularly adapted to these specificities. TREATMENT MODEL: The treatment model, Cognitive Behavioral Analysis System of Psychotherapy (CBASP; according to McCullough) is based on two theoretical models: the developmental theory by J. Piaget and the interpersonal model by D. Kiesler. According to McCullough, the cognitive affective functioning of chronically depressed patients is comparable with the one of a child who has not reached the Piagetian stage of logical operations. Their thinking is global, pre-logical and presents with monologues, instead of internal dialogues. These patients are incapable of effective controlling and regulating of emotions and of constructive accommodation of established schemas, when confronted with novel experiences. Finally, these patients are unaware of their interpersonal effects on the environment they unwillingly have. The latter are conceptualized using Kiesler's conceptualization of psychopathology. According to this model, the patient sends implicit relational "messages" provoking interpersonal "pulls" in the interaction partner (e.g., the therapist). These pulls are assessed and may be graphically represented using a Circumplex Model, also called the Kiesler-circle, and is the basis of the case conceptualization in the psychotherapy with chronically depressed patients. CBASP has developed based on the clinical implications of these models and combines them in an original fashion. PRESENTATION OF MAIN THERAPEUTIC INTERVENTIONS: Two lines of intervention result from the models: (1) situational analysis, which analyzes the links between behavior in a particular situation and the person's goal or desire related to the particular situation, and (2) interpersonal techniques based on the notions of transference and counter transference. On one hand, situational analysis follows several steps linking the patient's behavior with his/her desired outcome, which is compared to the real outcome in the situation. The patient's interpretations are amended in a second step, using the desired outcome as an anchor. On the other hand, interpersonal techniques imply the therapist's stance of disciplined personal involvement, meaning a controlled way of therapist self-disclosure facing the patient, with the aim of experiencing by the patient, that his/her behavior does not remain without specific, immediate and authentic consequences in the environment. This experience by the patient should allow him/her to (re-)establish the perceived functionality of the patient's behavior in interpersonal encounters. DISCUSSION AND CONCLUSIONS: We underline the relevance of the approach by citing several empirical studies which have established the efficacy of the model, in specific clinical conditions that are the combined treatment with anti-depressant medication, a sufficient number of sessions and in the case of early trauma as etiological factor of the chronic depression. We discuss the application of CBASP to other clinical diagnoses, such as borderline and avoidant personality disorder as well as disorders related to substance abuse and thus argue in favor of CBASP as a central model in the treatment of various mental illnesses. PMID- 23107464 TI - Increased dosage of Ink4/Arf protects against glucose intolerance and insulin resistance associated with aging. AB - Recent genome-wide association studies have linked type-2 diabetes mellitus to a genomic region in chromosome 9p21 near the Ink4/Arf locus, which encodes tumor suppressors that are up-regulated in a variety of mammalian organs during aging. However, it is unclear whether the susceptibility to type-2 diabetes is associated with altered expression of the Ink4/Arf locus. In the present study, we investigated the role of Ink4/Arf in age-dependent alterations of insulin and glucose homeostasis using Super-Ink4/Arf mice which bear an extra copy of the entire Ink4/Arf locus. We find that, in contrast to age-matched wild-type controls, Super-Ink4/Arf mice do not develop glucose intolerance with aging. Insulin tolerance tests demonstrated increased insulin sensitivity in Super Ink4/Arf compared with wild-type mice, which was accompanied by higher activation of the insulin receptor substrate (IRS)-PI3K-AKT pathway in liver, skeletal muscle and heart. Glucose uptake studies in Super-Ink4/Arf mice showed a tendency toward increased (18)F-fluorodeoxyglucose uptake in skeletal muscle compared with wild-type mice (P = 0.079). Furthermore, a positive correlation between glucose uptake and baseline glucose levels was observed in Super-Ink4/Arf mice (P < 0.008) but not in wild-type mice. Our studies reveal a protective role of the Ink4/Arf locus against the development of age-dependent insulin resistance and glucose intolerance. PMID- 23107465 TI - Postprogression survival in patients with advanced non-small-cell lung cancer who receive second-line or third-line chemotherapy. AB - BACKGROUND: The increased availability of active agents has improved overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC). We previously showed that postprogression survival (PPS) is highly associated with OS in the first-line setting, but little is known about PPS in the salvage setting. In this study, we analyzed PPS in phase III trials in the second-line or third-line setting. PATIENTS AND METHODS: A literature search identified 18 trials for previously treated patients with advanced NSCLC. We partitioned OS into progression-free survival (PFS) and PPS and evaluated the association between OS and either PFS or PPS. Correlation analysis to examine whether a treatment benefit for PFS carried over to OS was performed by calculation of incremental gains in OS and PFS at the trial level. RESULTS: The average median PPS was longer than the average median PFS (5.4 and 2.6 months, respectively). The induction rate for subsequent chemotherapy after second-line or third-line treatment was related to the duration of PPS in linear regression analysis (r(2) = 0.4813). Median OS was highly associated with median PPS but not with PFS (r = 0.94 and 0.51, respectively), and only a weak association between the treatment benefits for PFS and OS was detected (r = 0.29). CONCLUSIONS: Treatment benefit for OS in patients with advanced NSCLC can be skewed by the effects of subsequent therapies in the second-line or third-line setting. Whether PFS or OS is the more appropriate endpoint for trials in the salvage setting should be considered. PMID- 23107466 TI - Detorque evaluation of dental abutment screws after immersion in a fluoridated artificial saliva solution. AB - PURPOSE: Implant-abutment connections still present failures in the oral cavity due to the loosening of mechanical integrity by detorque and corrosion of the abutment screws. The objective of this study was to evaluate the detorque of dental abutment screws before and after immersion in fluoridated solutions. MATERIALS AND METHODS: Five commercial implant-abutment assemblies were assessed in this investigation: (C) Conexao(r), (E) Emfils(r), (I) INP(r), (S) SIN(r), and (T) Titanium Fix(r). The implants were embedded in an acrylic resin and then placed in a holding device. The abutments were first connected to the implants and torqued to 20 Ncm using a handheld torque meter. The detorque values of the abutments were evaluated after 10 minutes. After applying a second torque of 20 Ncm, implant-abutment assemblies were withdrawn every 3 hours for 12 hours in a fluoridated solution over a period of 90 days. After that period, detorque of the abutments was examined. Scanning electronic microscopy (SEM) associated to energy dispersive spectroscopy (EDS) was applied to inspect the surfaces of abutments. RESULTS: Detorque values of systems C, E, and I immersed in the fluoridated solution were significantly higher than those of the initial detorque. ANOVA demonstrated no significant differences in detorque values between designs S and T. Signs of localized corrosion could not be detected by SEM although chemical analysis by EDS showed the presence of elements involved in corrosive processes. CONCLUSION: An increase of detorque values recorded on abutments after immersion in fluoridated artificial saliva solutions was noticed in this study. Regarding chemical analysis, such an increase of detorque can result from a corrosion layer formed between metallic surfaces at static contact in the implant-abutment joint during immersion in the fluoridated solutions. PMID- 23107467 TI - Diagnostic and prognostic value of plasma and tissue ubiquitin-like, containing PHD and RING finger domains 1 in breast cancer patients. AB - Ubiquitin-like, containing PHD and RING finger domains 1 (UHRF1) has been reported to play an important role in breast carcinogenesis. This work investigated the correlation of UHRF1 DNA level in plasma with clinical characteristics of breast cancer and its clinical significance in breast cancer diagnosis. The expression of UHRF1 in primary breast cancer tissue was examined by Western blot. The UHRF1 DNA levels in plasma and UHRF1 mRNA expression in tissues were determined by accurate real-time quantitative PCR. The associations of UHRF1 levels with clinical variables were evaluated using standard statistical methods. The UHRF1 DNA in plasma of 229 breast cancer patients showed higher expression than healthy controls, which showed high specificity up to 76.2% at a sensitivity of 79.2%, and was significantly associated with c-erbB2 positive status, cancer stage and lymph node metastasis. High UHRF1 DNA level in plasma was significantly associated with short progression-free survival. The UHRF1 DNA level in plasma is highly correlative with breast cancer and its status and stage, and may be a potential independent diagnostic and prognostic factor for both breast cancer and the survival of breast cancer patients. PMID- 23107468 TI - Identification of the internal anal opening and seton placement improves the outcome of deep postanal space abscess. AB - AIM: This study aimed to determine if successful seton placement at the initial drainage procedure improves outcomes in the management of deep postanal space abscesses. METHOD: A retrospective review was performed of all patients who underwent initial drainage of a DPA space abscess between December 2002 and August 2010. A seton was placed through the internal opening if it could be identified. RESULTS: Thirty-two patients of median age 41 (21-64) years formed the study group. Twenty-four (75.0%) had a seton inserted at the initial drainage procedure. The patients underwent a total of 56 operations. The median interval from the initial to the final operation was 5 (2-18) months with 17 (70.8%) patients having the final operation within 6 months. In the 8 (25.0%) patients whose internal opening could not be found, 26 operations were required with a median interval from the initial to the final surgery of 11 (3-24) months. Patients who had a seton successfully inserted at drainage underwent significantly earlier definitive surgery and required fewer operations (P < 0.038). CONCLUSION: Identification of an internal opening with placement of a seton at the initial drainage procedure is associated with earlier definitive surgery and fewer operations. PMID- 23107469 TI - Analysis of the MTHFR (methylenetetrahydrofolate reductase) 677 C>T and 1298 A>C polymorphisms in BCR-ABL-negative myeloproliferative neoplasms. PMID- 23107470 TI - Effects of comprehensive therapy based on traditional Chinese medicine patterns in stable chronic obstructive pulmonary disease: a four-center, open-label, randomized, controlled study. AB - BACKGROUND: Traditional Chinese medicine (TCM) has been used to treat chronic obstructive pulmonary disease (COPD) for many years. This study aimed to evaluate the efficacy and safety of the comprehensive therapy based on the three common TCM patterns in stable COPD patients. METHODS: A four-center, open-label randomized controlled method was conducted. A total of 352 patients were divided into the trial group (n = 176, treated with conventional Western medicine and Bu Fei Jian-Pi granules, Bu-Fei Yi-Shen granules, and Yi-Qi Zi-Shen granules based on the TCM patterns respectively) and the control group (n = 176, treated with conventional Western medicine). The frequency and duration of acute exacerbation, lung function, clinical symptoms, 6-minute walking distance (6MWD), dyspnea scale and quality of life were observed during a 6-month treatment period and at a further 12-month follow-up. RESULTS: A total of 306 patients completed the study fully. The full analysis set (FAS) population was 350 and the per-protocol analysis set (PPS) population was 306. After the 6-month treatment and 12-month follow-up, there were significant differences between the trial and control group in the following: frequency of acute exacerbation (FAS: P = 0.000; PPS: P = 0.000); duration of acute exacerbation (FAS: P = 0.000; PPS: P = 0.001); FEV1 (FAS: P = 0.007; PPS: P = 0.008); symptoms (FAS: P = 0.001; PPS: P = 0.001); 6MWD (FAS: P = 0.045; PPS: P = 0.042); dyspnea scale (FAS: P = 0.002; PPS: P = 0.004); and physical domain (FAS: P = 0.000; PPS: P = 0.000), psychological domain (FAS: P = 0.008; PPS: P = 0.011), social domain (FAS: P = 0.001; PPS: P = 0.000) and environment domain (FAS: P = 0.015; PPS: P = 0.009) of the WHOQOL-BREF questionnaire. There were no differences between the trial and control group in FVC, FEV1% and adverse events. CONCLUSIONS: Based on the TCM patterns, Bu-Fei Jian-Pi granules, Bu-Fei Yi-Shen granules and Yi-Qi Zi-Shen granules have beneficial effects on measured outcomes in stable COPD patients over the 6-month treatment and 12-month follow-up, with no relevant between-group differences in adverse events. TRIAL REGISTRATION: This trial was registered at Chinese Clinical Trial Register Center, ChiCTR-TRC-11001406. PMID- 23107471 TI - Chronic pain after carpal tunnel surgery: epidemiology and associated factors. AB - BACKGROUND: Chronic postoperative pain (CPOP) has been assessed after major orthopedic surgeries but not after carpal tunnel surgery (CTS). This study aimed at describing the evolution of nocturnal and diurnal pains during the year following CTS, and at looking for factors associated with CPOP. METHODS: Cohort of adult outpatients operated by one single surgeon, under regional anaesthesia (RA). Patients were questioned in the recovery room, and phoned 3 days and 12 months later. A multivariate analysis tested the association between CPOP and preoperative demographics, regional anaesthesia protocol, pain during RA, surgery and the first 3 postoperative days, postoperative complications. RESULTS: Between November 2006 and June 2010, 324 of 389 patients could be included. The nocturnal and diurnal pains disappeared on the evening of the procedure in 55% (180/324) and 50% (163/324) of patients respectively. At one year, 12% of patients (40/324) complained of pain which characteristic was similar to the preoperative one, and 22% (71/324) complained of a new pain (different from the preoperative one), which was therefore considered as CPOP. CPOP was associated with a decreased functional score (QuickDASH). After multivariate analysis, CPOP was associated with postoperative pain from D0 to D3 (p=0.02), minor postoperative complications (p<0.001) and absence of hypnotic approach during surgery (p=0.01). CONCLUSION: One year after CTS, 22% of patients have CPOP. This incidence is similar to the one observed after major surgeries. This study suggests for the first time that a hypnotic approach during the surgical procedure might decrease the CPOP incidence. PMID- 23107472 TI - [Glucose variability in intensive care unit]. AB - Hyperglycemia is significantly associated with increased mortality in critically ill patients and then, strict control of blood glucose (BG) concentration is important. Lowering of BG levels with intensive insulin therapy (IIT) was recommended in order to improve patient outcomes. But recently, some recent prospective trials failed to confirm the initial data, showing conflicting results (significantly increased mortality with IIT, more hypoglycemic episodes). So there is no consensus about efficiency and safety of IIT. Significant associations between glucose variability and mortality have been confirmed by several recent studies. A difference in variability of BG control could explain why the effect of IIT varied from beneficial to harmful. Managing and decreasing this BG variability could be an important goal of BG control in critically ill patients. Clinicians have to consider definitions, physiopathology and impacts of glucose variability, in order to improve patient outcomes. PMID- 23107473 TI - Predictive ability of the 2002 and 2010 versions of the Tumour-Node-Metastasis classification system regarding metastasis-free, cancer-specific and overall survival in a European renal cell carcinoma single-centre series. AB - OBJECTIVE: To compare the predictive ability of the Tumour-Node-Metastasis (TNM) classification systems for renal cell carcinoma (RCC) using three different endpoints: metastasis-free (MFS); overall (OS); and cancer-specific survival (CSS). PATIENTS AND METHODS: Data from 2739 consecutive patients with RCC, who underwent surgery at a single academic centre, were evaluated using multivariate Cox proportional models, Harrell's concordance (c)-index and by applying decision curve analysis (DCA) with regard to MFS, OS and CSS. RESULTS: According to TNM 2010, significant differences for MFS were observed for pT1a vs pT1b, pT1b vs pT2a, pT3a vs pT3b and pT3b vs pT3c stages, respectively (all P < 0.05). With regard to OS, significant differences could be observed in pT1a vs pT1b and pT3a vs pT3b stages, respectively (all P < 0.05). The c-index for CSS, OS and MFS was slightly higher for the 2002 than for the 2010 version of the TNM classification system. Non-inferiority of the 2002 TNM system is supported by the results of the DCA. CONCLUSION: According to our data, the predictive ability of the 2010 version of the TNM classification system regarding three different clinical endpoints is not superior to the 2002 version of this staging system. PMID- 23107474 TI - Mechanical properties of sintered meso-porous silicon: a numerical model. AB - : Because of its optical and electrical properties, large surfaces, and compatibility with standard silicon processes, porous silicon is a very interesting material in photovoltaic and microelectromechanical systems technology. In some applications, porous silicon is annealed at high temperature and, consequently, the cylindrical pores that are generated by anodization or stain etching reorganize into randomly distributed closed sphere-like pores. Although the design of devices which involve this material needs an accurate evaluation of its mechanical properties, only few researchers have studied the mechanical properties of porous silicon, and no data are nowadays available on the mechanical properties of sintered porous silicon. In this work we propose a finite element model to estimate the mechanical properties of sintered meso porous silicon. The model has been employed to study the dependence of the Young's modulus and the shear modulus (upper and lower bounds) on the porosity for porosities between 0% to 40%. Interpolation functions for the Young's modulus and shear modulus have been obtained, and the results show good agreement with the data reported for other porous media. A Monte Carlo simulation has also been employed to study the effect of the actual microstructure on the mechanical properties. PMID- 23107475 TI - Modular nanotransporters: a versatile approach for enhancing nuclear delivery and cytotoxicity of Auger electron-emitting 125I. AB - BACKGROUND: This study evaluates the potential utility of a modular nanotransporter (MNT) for enhancing the nuclear delivery and cytotoxicity of the Auger electron emitter 125I in cancer cells that overexpress the epidermal growth factor receptor (EGFR). METHODS: MNTs are recombinant multifunctional polypeptides that we have developed for achieving selective delivery of short range therapeutics into cancer cells. MNTs contain functional modules for receptor binding, internalization, endosomal escape and nuclear translocation, thereby facilitating the transport of drugs from the cell surface to the nucleus. The MNT described herein utilized EGF as the targeting ligand and was labeled with 125I using N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate (SGMIB). Membrane binding, intracellular and nuclear accumulation kinetics, and clonogenic survival assays were performed using the EGFR-expressing A431 epidermoid carcinoma and D247 MG glioma cell lines. RESULTS: [125I]SGMIB-MNT bound to A431 and D247 MG cells with an affinity comparable to that of native EGF. More than 60% of internalized [125I]SGMIB-MNT radioactivity accumulated in the cell nuclei after a 1-h incubation. The cytotoxic effectiveness of [125I]SGMIB-MNT compared with 125I-labeled bovine serum albumin control was enhanced by a factor of 60 for D247 MG cells and more than 1,000-fold for A431 cells, which express higher levels of EGFR. CONCLUSIONS: MNT can be utilized to deliver 125I into the nuclei of cancer cells overexpressing EGFR, significantly enhancing cytotoxicity. Further evaluation of [125I]SGMIB-MNT as a targeted radiotherapeutic for EGFR expressing cancer cells appears warranted. PMID- 23107477 TI - Elicitation of the most important structural properties of ionic liquids affecting ecotoxicity in limnic green algae; a QSAR approach. AB - Many ionic liquids are soluble in water and their impact on the aquatic environment has to be evaluated. However, due to the large number of ionic liquids and lack of experimental data, it is necessary to develop estimation procedures in order to reduce the materials and time consumption. In this study using multilayer perceptron neural network (MLP), ant colony optimization (ACO) and multiple linear regression (MLR) strategies, good predictive quantitative structure-activity relationships (QSAR) models were introduced and structural parameters affecting ecotoxicity of ionic liquids in limnic green algae (Scenedesmus vacuolatus) were revealed. Moreover, principal component analysis (PCA) and cluster analysis (CA) approaches were also applied to visualize any possible patterns or relationships among ionic liquids data. It was revealed that selected descriptors of the MLR model are also capable of clustering ionic liquids according to their four level of toxicity. PMID- 23107476 TI - Prevalence of single nucleotide polymorphism among 27 diverse alfalfa genotypes as assessed by transcriptome sequencing. AB - BACKGROUND: Alfalfa, a perennial, outcrossing species, is a widely planted forage legume producing highly nutritious biomass. Currently, improvement of cultivated alfalfa mainly relies on recurrent phenotypic selection. Marker assisted breeding strategies can enhance alfalfa improvement efforts, particularly if many genome wide markers are available. Transcriptome sequencing enables efficient high throughput discovery of single nucleotide polymorphism (SNP) markers for a complex polyploid species. RESULT: The transcriptomes of 27 alfalfa genotypes, including elite breeding genotypes, parents of mapping populations, and unimproved wild genotypes, were sequenced using an Illumina Genome Analyzer IIx. De novo assembly of quality-filtered 72-bp reads generated 25,183 contigs with a total length of 26.8 Mbp and an average length of 1,065 bp, with an average read depth of 55.9-fold for each genotype. Overall, 21,954 (87.2%) of the 25,183 contigs represented 14,878 unique protein accessions. Gene ontology (GO) analysis suggested that a broad diversity of genes was represented in the resulting sequences. The realignment of individual reads to the contigs enabled the detection of 872,384 SNPs and 31,760 InDels. High resolution melting (HRM) analysis was used to validate 91% of 192 putative SNPs identified by sequencing. Both allelic variants at about 95% of SNP sites identified among five wild, unimproved genotypes are still present in cultivated alfalfa, and all four US breeding programs also contain a high proportion of these SNPs. Thus, little evidence exists among this dataset for loss of significant DNA sequence diversity from either domestication or breeding of alfalfa. Structure analysis indicated that individuals from the subspecies falcata, the diploid subspecies caerulea, and the tetraploid subspecies sativa (cultivated tetraploid alfalfa) were clearly separated. CONCLUSION: We used transcriptome sequencing to discover large numbers of SNPs segregating in elite breeding populations of alfalfa. Little loss of SNP diversity was evident between unimproved and elite alfalfa germplasm. The EST and SNP markers generated from this study are publicly available at the Legume Information System ( http://medsa.comparative-legumes.org/) and can contribute to future alfalfa research and breeding applications. PMID- 23107478 TI - Synthesis and anti-microbial potencies of 1-(2-hydroxyethyl)-3-alkylimidazolium chloride ionic liquids: microbial viabilities at different ionic liquids concentrations. AB - Three 1-(2-hydroxyethyl)-3-alkylimidazolium chloride room temperature ionic liquids (ILs) [2OHimC(n)][Cl]; (n=0, 1, 4) have been synthesized from the appropriate imidazole precursors and characterized by IR and NMR spectroscopies and elemental analysis. Their anti-microbial activities were investigated using the well-diffusion method. The viabilities of Escherichia coli, Aeromonas hydrophila, Listeria monocytogenes and Salmonella enterica as a function of IL concentrations were studied. The minimal inhibitory concentrations (MICs) and EC50 values for the present ILs were within the concentration range from 60 to 125 mM and 23 to 73 mM. The anti-microbial potencies of the present ILs were compared to a standard antibiotic, gentamicin. The finding affords additional perspective on the level of ILs toxicity to aquatic lifeforms and yet, this characteristic can be readily harnessed to detect microbial growth and activity. PMID- 23107479 TI - Modification of a promiscuous inhibitor shifts the inhibition from gamma secretase to FLT-3. AB - The inhibition of FLT-3 activity is an interesting target for the treatment of acute myeloid leukemia (AML). The serendipitous identification of FLT-3 inhibitors from a CK1/gamma-secretase programme provided compounds with dual inhibitory activity. We analyzed the structure-activity relationship of these inhibitors and derivatized them to arrive at compounds with reduced impact on gamma-secretase activity and enhanced FLT-3 inhibition. PMID- 23107480 TI - Impact of protein binding cavity volume (PCV) and ligand volume (LV) in rigid and flexible docking of protein-ligand complexes. AB - The importance of protein binding cavity volume (PCV) and ligand volume (LV) in rigid and flexible docking has been studied in 48 protein-ligand complexes belonging to eight protein families. In continuation of our earlier study on protein flexibility in relationship to PCV and LV, this study analyzes the importance of PCV and LV in the scoring and ranking of ligands in docking experiments. Crystal structures of protein-ligand complexes with varied PCV were chosen for docking ligands of varied volume in each protein family. Docking and scoring accuracy have been evaluated by self and cross docking of ligands to the given protein conformation. Effect of PCV and LV in rigid and flexible docking has been studied both in apo and holo proteins. Rigid docking has performed well when appropriate protein conformation is used. Selecting the proteins with appropriate PCV based on the LV information is suggested for better results in ensemble docking. PMID- 23107481 TI - Synthesis and structure-activity relationship studies of cytotoxic vinorelbine amide analogues. AB - A series of 3-demethoxycarbonyl-3-acylamide methyl vinorelbine derivatives (compounds 7a-7z) were designed, synthesized, and evaluated for their inhibition activities against human non-small cell lung cancer cell line (A549). Most of the amide derivatives exhibited potent cytotoxicity, with the size of the introduced substituents being the foremost factor in determining the resultant cytotoxic activity. Test results in vivo against nude mice bearing A549 xenografts indicated that 7y showed comparable activities compared to the parent NVB. PMID- 23107482 TI - Structure-based discovery of C-2 substituted imidazo-pyrrolopyridine JAK1 inhibitors with improved selectivity over JAK2. AB - Herein we describe our successful efforts in obtaining C-2 substituted imidazo pyrrolopyridines with improved JAK1 selectivity relative to JAK2 by targeting an amino acid residue that differs between the two isoforms (JAK1: E966; JAK2: D939). Efforts to improve cellular potency by reducing the polarity of the inhibitors are also detailed. The X-ray crystal structure of a representative inhibitor in complex with the JAK1 enzyme is also disclosed. PMID- 23107483 TI - Synthesis and pharmacokinetic profile of rhein- boswellic acid conjugate. AB - Rhein, an active metabolite of diacerein, down-regulates the gene-expression and production of pro-matrix metalloproteinases and up-regulates the tissue inhibitors of metalloproteinase-1 production. The therapeutic effects of diacerein on osteoarthritis are, at least in part, due to the chondroprotective effect of rhein. Boswellic acid is a specific, non-redox inhibitor of leukotriene synthesis. It is claimed to possess good anti-inflammatory, anti-arthritic, analgesic, and anti-ulcer activities. It prevents the destruction of articular cartilage by decreasing degradation of glycosaminoglycans. Therefore, rhein and boswellic acid were linked chemically through a bioreversible ester linkage to synthesize their mutual prodrug by reported procedure. In vitro release profile of this prodrug was extensively studied in aqueous buffers of varied pH, upper GIT homogenates and 80% human plasma. In vivo release studies were undertaken in blood, urine and feces of rats. The prodrug was stable in HCl buffer (pH 1.2) and stomach homogenates of rats. However; in phosphate buffer (pH 7.4) and in intestinal homogenates the prodrug exhibited 91% and 96% release of rhein and 27.5% and 38% release of boswellic acid respectively over a period of 6h following first order kinetics. In 80% human plasma (in vitro) and rat blood (in vivo) also 96.35% and 91% release of rhein and 78% and 86.41% release of boswellic acid respectively was observed. The 24 h pooled samples of rat urine revealed presence of 6.2% intact prodrug, 7.1% of rhein and 8.9% of boswellic acid indicating their renal excretion. Samples of rat feces pooled over a period of 24 h showed absence of rhein and presence of 3.1% of intact boswellic acid and 4.6% of boswellic acid emphasizing their intestinal excretion. The in vivo release kinetics of prodrug in rat clearly indicated activation of prodrug to be occurring in blood, being catalyzed by the weak alkaline pH of blood (7.4) in combination with esterases present therein. PMID- 23107484 TI - Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. AB - Vitamin D status may influence the risk of developing metabolic diseases such as Type 2 diabetes (T2D), metabolic syndrome (MetS) and insulin resistance (IR). Several studies have assessed vitamin D in relationship with metabolic outcomes; however, results remain inconsistent. A systematic review and meta-analysis using multiple databases (MEDLINE, Web of Science and EMBASE), was performed up to 10 August 2012. Prospective studies reporting association of circulating or dietary vitamin D with incident T2D, MetS and IR outcomes were included. Relative risks (RR) were pooled using random effects and subgroup analysis by pertinent study level characteristics was performed. A total of seventeen articles based on eighteen unique prospective studies, and comprising 210 107 participants with 15 899 metabolic events, collected during a median follow up of 10 years (range 3-22 years), were included. RR for individuals in top v. bottom thirds of baseline vitamin D were 0.81 (95% CI 0.71, 0.92); 0.86 (95% CI 0.80, 0.92); and 0.84 (95% CI 0.64, 1.12) for T2D, MetS and IR outcomes, respectively. Moderate heterogeneity was found between fourteen studies (I 2 = 67%, P < 0.001) reporting on T2D. Findings were generally consistent across various study-level characteristics. In conclusion, vitamin D status at baseline in apparently healthy adults is inversely associated with future risks of T2D and MetS. Interventions aimed at maintaining adequate levels of vitamin D in addition to preventing deficiency may be a useful preventive measure for metabolic diseases. However, reliable evidence from carefully designed intervention studies, particularly those based on healthy populations, is needed to confirm observational findings. PMID- 23107485 TI - [Prostitution and public health in Valencia (Spain) in the 19th century]. PMID- 23107486 TI - Bile canalicular abnormalities in the early phase of a mouse model of sclerosing cholangitis. AB - BACKGROUND: The bile canaliculus is the smallest and first biliary channel and is formed by two or three adjacent hepatocytes. Previous studies of chronic cholangiopathies such as primary sclerosing cholangitis have focused on the bile ductules. However, little is known about the pathological alterations in bile canaliculi in the early phase of cholangiopathies. AIM: To characterize the bile canalicular morphology in the early phase of sclerosing cholangitis we used 3,5 diethoxycarbonyl-1,4-dihydrocollidine-induced mouse model of sclerosing cholangitis. METHODS: Mice were fed a diet with 3,5-diethoxycarbonyl-1,4 dihydrocollidine (0.1%). Serum biochemical, histological, immunohistochemical, and electron microscopic analyses were performed 1, 2, 4, and 7 days after feeding. RESULTS: All experimental groups showed significantly increased serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels. From day 1, bile canalicular abnormalities such as dilatation and meandering and loss of microvilli were observed. After bile canalicular abnormalities had appeared, substantial infiltration of inflammatory cells was observed amongst the necrotic cells and periductal region. After these inflammatory changes, cholangiocytes proliferated in the portal area and formed ductular reactions. Finally, periductal fibrosis appeared. CONCLUSION: This study provides novel evidence of the occurrence of bile canalicular abnormalities during the early phase of sclerosing cholangitis. PMID- 23107487 TI - Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD). AB - Most data regarding the natural history of inflammatory bowel diseases and their therapeutic management are from tertiary referral-centres. However, the patients followed in these centres represent a selected sample and extrapolation of these data to the general population is disputable. The EPIMAD Registry covers a large area of Northern France with almost 6 million inhabitants representing 9.3% of the entire French population. From 1988 to 2008, 18,170 incident patients were recorded in the registry including 8071 incident Crohn's disease, 5113 incident ulcerative colitis and 591 unclassified inflammatory bowel disease cases. The aim of this study was to review some of the most recent information obtained from this large population-based registry since its launch in 1988. PMID- 23107488 TI - Interobserver agreement among endoscopists on evaluation of polypoid colorectal lesions visualized with the Pentax i-Scan technique. AB - BACKGROUND AND AIMS: Advances in colonoscopy, such as the Pentax i-Scan electronic technique, have the potential to improve the early detection of colorectal cancer. The aim of this multicentre study was to assess the interobserver agreement in the visualization of the surface and margins of colorectal polyps and in distinguishing neoplastic from non-neoplastic polyps. PATIENTS AND METHODS: Eight expert endoscopists examined 400 mixed previously recorded images of polyps taken with different Pentax i-Scan settings in order to give an evaluation of the surface of the polyp and regular colonic mucosa, the pit-pattern and the nature of the lesion. RESULTS: A total of 400 mixed images of polyps with a diameter >5mm and <10mm were stored for analysis. Overall, there was a Kf agreement of 0.370 (p<0.001) and 0.306 (p<0.001) regarding pit-pattern and margins, respectively. The Kf agreement for the difference between neoplastic and non-neoplastic lesions was of 0.446 (p<0.001). CONCLUSIONS: We observed good interobserver agreement in the evaluation of neoplastic and non-neoplastic lesions and poor agreement in the evaluation of pit-pattern and margins. Adequate training is required in order to interpret images acquired with the i-Scan technique. PMID- 23107489 TI - Catheter-based endomyocardial delivery of mesenchymal precursor cells using 3D echo guidance improves cardiac function in a chronic myocardial injury ovine model. AB - The administration of bone marrow-derived stem cells may provide a new treatment option for patients with heart failure. Transcatheter cell injection may require multi-imaging modalities to optimize delivery. This study sought to evaluate whether endomyocardial injection of mesenchymal precursor cells (MPCs) could be guided by real-time 3D echocardiography (RT3DE) in treating chronic, postinfarction (MI) left ventricular (LV) dysfunction in sheep. Four weeks after induction of an anterior wall myocardial infarction in 39 sheep, allogeneic MPCs in doses of either 25 * 10(6) (n = 10), 75 * 10(6) (n = 9), or 225 * 10(6) (n = 10) cells or nonconditioned control media (n = 10) were administered intramyocardially into infarct and border zone areas using a catheter designed for combined fluoroscopic and RT3DE-guided injections. LV function was assessed before and after injection. Infarct dimension and vascular density were evaluated histologically. RT3DE-guided injection procedures were safe. Compared to controls, the highest dose MPC treatment led to increments in ejection fraction (3 ventricula 3% in 225M MPCs vs. -5 +/- 4% in the control group, p < 0.01) and wall thickening in both infarct (4 +/- 4% in 225M MPCs vs. -3 +/- 6% in the control group, p = 0.02) and border zones (4 +/- 6% in 225M MPCs vs. -8 +/- 9% in the control group, p = 0.01). Histology analysis demonstrated significantly higher arteriole density in the infarct and border zones in the highest dose MPC treated animals compared to the lower dose or control groups. Endomyocardial implantation of MPCs under RT3DE guidance was safe and without observed logistical obstacles. Significant increases in LV performance (ejection fraction and wall thickening) and neovascularization resulted from this technique, and so this technique has important implications for treating patients with postischemic LV dysfunction. PMID- 23107490 TI - Validation of a finite element model of a unilateral external fixator in a rabbit tibia defect model. AB - In case of large segmental defects in load-bearing bones, an external fixator is used to provide mechanical stability to the defect site. The overall stiffness of the bone-fixator system is determined not only by the fixator design but also by the way the fixator is mounted to the bone. This stiffness is an important factor as it will influence the biomechanical environment to which tissue engineering scaffolds and regenerating tissues are exposed. A finite element (FE) model can be used to predict the system stiffness. The goal of this study is to develop and validate a 3D anatomical FE model of a bone-fixator system which includes a previously developed unilateral external fixator for a large segmental defect model in the rabbit tibia. It was hypothesized that the contact interfaces between bone and fixator screws play a major role for the prediction of the stiffness. In vitro mechanical testing was performed in order to measure the axial stiffness of cortical bone from mid-shaft rabbit tibiae and of the tibia fixator system, as well as the bending stiffness of individual fixator screws, inserted in bone. MUCT-based case-specific FE models of cortical bone and SCREW BONE specimens were created to simulate the corresponding mechanical test set ups. The Young's modulus of rabbit cortical bone as well as appropriate screw bone contact settings were derived from those FE models. We then used the derived settings in an FE model of the tibia-fixator system. The difference between the FE predicted and measured axial stiffness of the tibia-fixator system was reduced from 117.93% to 7.85% by applying appropriate screw-bone contact settings. In conclusion, this study shows the importance of screw-bone contact settings for an accurate fixator stiffness prediction. The validated FE model can further be used as a tool for virtual mechanical testing in the design phase of new tissue engineering scaffolds and/or novel patient-specific external fixation devices. PMID- 23107492 TI - [Breast reconstruction after mastectomy]. AB - The mutilating surgery for breast cancer causes deep somatic and psychological sequelae. Breast reconstruction can mitigate these effects and permit the patient to help rebuild their lives. The purpose of this paper is to focus on breast reconstruction techniques and on factors involved in breast reconstruction. The methods of breast reconstruction are presented: objectives, indications, different techniques, operative risks, and long-term monitoring. Many different techniques can now allow breast reconstruction in most patients. Clinical cases are also presented in order to understand the results we expect from a breast reconstruction. Breast reconstruction provides many benefits for patients in terms of rehabilitation, wellness, and quality of life. In our mind, breast reconstruction should be considered more as an opportunity and a positive choice (the patient can decide to do it), than as an obligation (that the patient would suffer). The consultation with the surgeon who will perform the reconstruction is an important step to give all necessary informations. It is really important that the patient could speak again with him before undergoing reconstruction, if she has any doubt. The quality of information given by medical doctors is essential to the success of psychological intervention. This article was written in a simple, and understandable way to help gynecologists giving the best information to their patients. It is maybe also possible to let them a copy of this article, which would enable them to have a written support and would facilitate future consultation with the surgeon who will perform the reconstruction. PMID- 23107491 TI - Caenorhabditis elegans HSF-1 is an essential nuclear protein that forms stress granule-like structures following heat shock. AB - The heat shock transcription factor (HSF) is a conserved regulator of heat shock inducible gene expression. Organismal roles for HSF in physiological processes such as development, aging, and immunity have been defined largely through studies of the single Caenorhabditis elegans HSF homolog, hsf-1. However, the molecular and cell biological properties of hsf-1 in C. elegans are incompletely understood. We generated animals expressing physiological levels of an HSF-1::GFP fusion protein and examined its function, localization, and regulation in vivo. HSF-1::GFP was functional, as measured by its ability to rescue phenotypes associated with two hsf-1 mutant alleles. Rescue of hsf-1 development phenotypes was abolished in a DNA-binding-deficient mutant, demonstrating that the transcriptional targets of hsf-1 are critical to its function even in the absence of stress. Under nonstress conditions, HSF-1::GFP was found primarily in the nucleus. Following heat shock, HSF-1::GFP rapidly and reversibly redistributed into dynamic, subnuclear structures that share many properties with human nuclear stress granules, including colocalization with markers of active transcription. Rapid formation of HSF-1 stress granules required HSF-1 DNA-binding activity, and the threshold for stress granule formation was altered by growth temperature. HSF 1 stress granule formation was not induced by inhibition of IGF signaling, a pathway previously suggested to function upstream of hsf-1. Our findings suggest that development, stress, and aging pathways may regulate HSF-1 function in distinct ways, and that HSF-1 nuclear stress granule formation is an evolutionarily conserved aspect of HSF-1 regulation in vivo. PMID- 23107494 TI - [Relationship between the characteristics of the human sperm movement and their attachment to the zona pellucida]. AB - OBJECTIVE: Our objective was to study the relationships between the characteristics of the movement of sperm and their attachment to the zona pellucida. MATERIALS AND METHODS: Study related to 47 patients candidates with an IVF protocol. The puncture of the ovocytes was carried out under general anesthesia under echography control after stimulated cycles using association is the citrate of clomifene and the HMG or the busereline and the HMG. Study of the mobility of the spermatozoa was carried out thanks to a videomicrography computer assisted before and after treatment of sperm in Percoll. The setting in contact of the spermatozoa with the ovocytes having given failures of in vitro fertilization and beforehand preserved in a saline solution was carried out during 90 minutes with 37 degrees C, air-CO2 with 5%. After incubation, the spermatozoa fixed at the zona pellucida, are counted thanks to a meter with hand. RESULTS: The study of the test of fixing of the spermatozoa at the zona pellucida showed that the interaction spermatozoa/ovocytes is correlated positively with the parameters of the mobility analyzed by videomicrography computer-assisted: Vcl, Vsl and the ALH. CONCLUSION: The performance of the test requires a preliminary epididymal maturation of the spermatozoa in particular the ontogenesis of the spermatic sites of recognition for the zona pellucida. A deterioration of this stage of maturation led to failures of recognition and fixing at the zona pellucida. The test can predict the outcome of IVF and towards the good technique of medical assistance to procreation (AMP). PMID- 23107495 TI - Monitoring of bacterial load in terms of culturable and non-culturable cells on new materials placed in a delicatessen serve over counter. AB - The aim of this study was to determine how quickly the surface of a refrigerated supermarket serve over counter becomes loaded with bacteria. New material made of polyvinyl chloride or stainless steel was placed on the surface on which foodstuffs are displayed for sale. One to three samples per week for 7 weeks were collected on gauze pads. CFUs were counted and total cells were quantified by real-time PCR. "Viable" cells using real-time PCR following pre-treatment with ethidium monoazide were quantified on stainless steel. Attachment strengths were assessed at the end of the experiment by constructing detachment curves. Whatever the material, on day 1 the microbial load reached values near those observed in the following weeks i.e. 10(3)-10(4) log total cells/cm(2). The number of cells deposited in one week was compensated for by the small reduction obtained by cleaning and disinfection (C&D). The mean difference between total and viable cells was 0.54 log CFUs/cm(2). A big drop in CFUs following C&D was observed at the beginning of the experiment, despite no visible decrease in the number of viable cells, but the CFU reduction decreased over time. Nevertheless, the low efficiency of C&D on the dominant microbiota did not indicate the fate of pathogenic bacteria on these materials. Our data suggest that dead cells do not adhere quite so well as viable cells. Although no growth was observed and the attached bacterial community cannot therefore be considered a biofilm, attached cells shared certain properties attributed to biofilms i.e. their resistance to C&D increased over time and they followed a biphasic detachment curve. PMID- 23107496 TI - Salt at concentrations relevant to meat processing enhances Shiga toxin 2 production in Escherichia coli O157:H7. AB - Escherichia coli (E. coli) O157:H7 remains a major food safety concern associated with meat, especially beef products. Shiga toxins (Stx) are key virulence factors produced by E. coli O157:H7 that are responsible for hemorrhagic colitis and Hemolytic Uremic Syndrome. Stx are heat stable and can be absorbed after oral ingestion. Despite the extensive study of E. coli O157:H7 survival during meat processing, little attention is paid to the production of Stx during meat processing. The objective of this study was to elucidate the effect of salt, an essential additive to processed meat, at concentrations relevant to meat processing (0%, 1%, 2%, 3%, W/V) on Stx2 production and Stx2 prophage induction by E. coli O157:H7 strains. For both E. coli O157:H7 86-24 and EDL933 strains, including 2% salt in LB broth decreased (P<0.05) E. coli O157:H7 population, but increased (P<0.05) Stx2 production (as measured relative to Log(10)CFU) compared to that of the control (1% salt). Supplementing 3% salt decreased (P<0.05) both E. coli O157:H7 number and Stx2 production. Quantitative RT-PCR indicated that stx2 mRNA expression in culture media containing 2% salt was greatly increased (P<0.05) compared to other salt concentrations. Consistent with enhanced Stx2 production and stx2 expression, the 2% salt group had highest lambdoid phage titer and stx2 prophage induction among all salt treatments. RecA is a key mediator of bacterial response to stress, which mediates prophage activation. Quantitative RT-PCR further indicated that recA mRNA expression was higher in both 2% and 3% salt than that of 0% and 1% salt treatments, indicating that stress was involved in enhanced Stx2 production. In conclusion, salt at the concentration used for meat processing enhances Stx production, a process linked to bacterial stress response and lambdoid prophage induction. PMID- 23107497 TI - Survival of murine norovirus and F-RNA coliphage MS2 on pork during storage and retail display. AB - The existence of animal strains of norovirus (NV) that are closely related to human strains raises concerns about interspecies recombination and the potential for zoonotic transmission through undercooked meat products. Contamination of meat with NV can occur both via meat processing operations and poor food handler hygiene. There is a lack of knowledge on the survival of NV on raw meat because NV cannot be effectively cultivated and its detection is limited to molecular methods. The survival of murine norovirus (MNV) and MS2, as surrogates for NV, was determined on pork chops by plaque assay and real time RT-PCR. Both MNV and MS2 displayed very high survival rates on vacuum packaged raw pork chops that were stored at 2 degrees C for up to 7 weeks and numbers declined little during subsequent retail display for 7 days. Maximum reductions for MNV and MS2 were 1.0 log PFU/cm(2) and 0.6 log genome copies(GC)/cm(2) or 1.1 log PFU/cm(2) and 1.2 log GC/cm(2), respectively. The viability of MS2 and MNV was not affected by the proteolytic enzymes present in the meat nor by numbers of bacteria that increased with time during storage in vacuum packs and while on retail display. MNV and MS2 can be considered as good surrogates for NV on raw meat. The findings of this study indicate that potentially pathogenic NV will likely survive extremely well on fresh meat and consumers could potentially be at risk when consuming undercooked meat that is contaminated with NV. PMID- 23107498 TI - Evaluation of the control ability of five essential oils against Aspergillus section Nigri growth and ochratoxin A accumulation in peanut meal extract agar conditioned at different water activities levels. AB - Essential oils (EOs) from boldo [Peumus boldus Mol.], poleo [Lippia turbinata var. integrifolia (Griseb.)], clove [Syzygium aromaticum L.], anise [Pimpinella anisum] and thyme [Thymus vulgaris]) obtained by hydrodistillation were evaluated for their effectiveness against the growth of Aspergillus niger aggregate and A. carbonarius and accumulation of ochratoxin A (OTA). The evaluation was performed by compound dissolution at the doses of 0, 500, 1500 and 2500MUL/L in peanut meal extract agar (PMEA) and exposure to volatiles of boldo, poleo (0, 1000, 2000 and 3000MUL/L) and clove oils (0, 1000, 3000 and 5000MUL/L), taking into account the levels of the water activity of the medium (a(W) 0.98, 0.95, 0.93). Statistical analyses on growth of Aspergillus strains indicated that the major effect was produced by oil concentrations followed by substrate a(W), and that reductions in antifungal efficiency of the oils tested were observed in vapor exposure assay. At all a(W) levels, complete fungal growth inhibition was achieved with boldo EO at doses of 1500 and 2000MUL/L by contact and volatile assays, respectively. Contact exposure by poleo and clove EOs showed total fungal inhibition at the middle level tested of 1500MUL/L, regardless of a(W), while their antifungal effects in headspace volatile assay were closely dependent on medium a(W). The fumigant activity of poleo (2000MUL/L) and clove oils (3000MUL/L) inhibited growth rate by 66.0% and 80.6% at a(W) 0.98 and 0.93, respectively. OTA accumulation was closely dependent on a(W) conditions. The antiochratoxigenic property of the volatile fractions of boldo, poleo and clove EOs (1000MUL/L) was more significant at low a(W) levels, inhibition percentages were estimated at 14.7, 41.7 and 78.5% at a(W) 0.98, 0.95 and 0.93, respectively. Our results suggest that boldo, poleo and clove oils affect the OTA biosynthesis pathway of both Aspergillus species. This finding leaves open the possibility of their use by vapor exposure as effective non-toxic biopreservatives against OTA contamination in stored peanuts. PMID- 23107499 TI - Expression in Lactococcus lactis of functional genes related to amino acid catabolism and cheese aroma formation is influenced by branched chain amino acids. AB - Formation of cheese aroma compounds by Lactococcus lactis from amino acid catabolism depends on a complex network of reactions, which involve enzymes such as aminotransferases, dehydrogenases, lyases, and decarboxylases, among others. Based on the ability of some L. lactis strains to grow with low requirements of amino acids, we have studied in L. lactis IFPL730 the effect of the branched chain amino acid (BCAA) content on the expression of functional genes related to amino acid catabolism and aroma compound formation (araT, bcaT, kivD, ytjE and panE). L. lactis IFPL730 growth rate decreased under leucine, valine or isoleucine starvation but the strain reached similar viable counts at the stationary phase in all culture conditions studied. The level of expression of some genes encoding enzymes involved in amino acid catabolism changed significantly (P<0.05) when those conditions were compared. Specially, alpha ketoisovalerate decarboxylase (kivD), BCAA-specific aminotransferase (bcaT) and C S lyase (yjtE) gene expressions increased markedly by both isoleucine and valine starvation. In addition to gene expression, formation of volatile compounds was determined in all growth conditions. The results showed that BCAA starvation conditions caused a significant increase (P<0.05) in the formation of metabolic end products related to cheese aroma, such as 3-methylbutanal and 3 methylbutanol. PMID- 23107500 TI - Development and application of a loop-mediated isothermal amplification assay for rapid identification of aflatoxigenic molds and their detection in food samples. AB - Aflatoxins are the most thoroughly studied mycotoxins. They are produced by several members of the genus Aspergillus in section Flavi with Aspergillus flavus, Aspergillus parasiticus, and Aspergillus nomius being frequently isolated from contaminated food sources. In this work, we describe the development and evaluation of loop-mediated isothermal amplification (LAMP) assays for rapid detection of the three species in separate analyses. The acl1-gene of A. flavus and amy1-genes of A. nomius and A. parasiticus were used as target genes. The detection limits were 2.4, 7.6 and 20pg of pure DNA/reaction for A. flavus, A. nomius and A. parasiticus, respectively. For specificity testing, DNA extracted from mycelia of representative strains of 39 Aspergillus species, 23 Penicillium species, 75 Fusarium species and 37 other fungal species was used as a template for the specific LAMP primer sets developed for the three target species. The LAMP assay was combined with a DNA extraction method for the analysis of pure fungal cultures as well as artificially contaminated Brazil nuts, peanuts and green coffee beans. It is suggested that the developed LAMP assay is a promising tool in the prediction of a potential aflatoxin risk in food and food raw materials and may therefore be suitable for high throughput analysis in the food industry. PMID- 23107501 TI - Inactivation of Salmonella during cocoa roasting and chocolate conching. AB - The high heat resistance of Salmonella in foods with low water activity raises particular issues for food safety, especially chocolate, where outbreak investigations indicate that few colony-forming units are necessary to cause salmonellosis. This study evaluated the efficiency of cocoa roasting and milk chocolate conching in the inactivation of Salmonella 5-strain suspension. Thermal resistance of Salmonella was greater in nibs compared to cocoa beans upon exposure at 110 to 130 degrees C. The D-values in nibs were 1.8, 2.2 and 1.5-fold higher than those calculated for cocoa beans at 110, 120 and 130 degrees C. There was no significant difference (p>0.05) between the matrices only at 140 degrees C. Since in the conching of milk chocolate the inactivation curves showed rapid death in the first 180 min followed by a lower inactivation rate, and two D values were calculated. For the first time interval (0-180 min) the D-values were 216.87, 102.27 and 50.99 min at 50, 60 and 70 degrees C, respectively. The other D-values were determined from the second time interval (180-1440 min), 1076.76 min at 50 degrees C, 481.94 min at 60 degrees C and 702.23 min at 70 degrees C. The results demonstrated that the type of matrix, the process temperature and the initial count influenced the Salmonella resistance. PMID- 23107502 TI - Phylogenetic diversity, antibiotic resistance and virulence traits of Aeromonas spp. from untreated waters for human consumption. AB - It is well known that water constitutes an important contamination route for microorganisms. This is especially true for Aeromonas which are widespread in untreated and treated waters. In this study, Portuguese untreated waters not regularly monitored were screened for the presence and diversity of aeromonads. A total of 206 isolates were discriminated by RAPD-PCR and 80 distinct strains were identified by gyrB based phylogenetic analysis. The most frequently detected species were Aeromonas hydrophila, Aeromonas bestiarum and Aeromonas media. The antibiotic susceptibility profile of these strains was determined and showed a typical profile of the genus. Nonetheless, the percentage of resistant strains to tetracycline, chloramphenicol and/or trimethoprim/sulfamethoxazole was lower than that reported for clinical isolates and isolates recovered from aquacultures and other environments historically subjected to antibiotic contamination. This suggests that the existence of such pressures in those environments selects for resistant Aeromonas. A similar trend for integron presence was found. Genes coding for CphA and TEM, and tet(A), (E), (C) or (D) genes were found in 28%, 1%, and 10% of the strains, respectively. 10% of the strains contained an integron. Variable regions of seven class 1 integrons and one class 2 integron were characterised. Furthermore, strains displayed virulence related phenotypes such as extracellular lipolytic and proteolytic activities as well as aerolysin related genes (43% of strains). The ascV and aexT genes were found in 16% and 3% of strains respectively and, in some cases, concomitantly in the same specimen. This study shows that diverse Aeromonas spp. presenting distinct antibiotic resistance features and putative virulence traits are frequently present in waters for human and animal consumption in Portugal. Genes associated to antibiotic resistance and microbial virulence previously identified in organisms with human health significance were detected in these aeromonads, suggesting that these waters may act as a pivotal route for infections. PMID- 23107503 TI - Microbial ecology of sorghum sourdoughs: effect of substrate supply and phenolic compounds on composition of fermentation microbiota. AB - The choice of the cereal substrate determines sourdough microbiota, however, the substrate-associated ecological factors for this phenomenon have not been elucidated. This study investigated the competitiveness of Lactobacillus sanfranciscensis LTH 2590, a wheat sourdough isolate, and four isolates from sorghum sourdoughs (ting), Lactobacillus casei FUA3166, Lactobacillus harbinensis FUA3199, Lactobacillus parabuchneri FUA3169, and Lactobacillus coryniformis FUA3307, in sorghum sourdoughs, sorghum sourdoughs supplemented with maltose, or wheat sourdoughs. Fermentations were characterised by determination of cell counts, pH, and quantification of metabolites. Maltose was the main carbon source in wheat sourdoughs whereas glucose was the major carbon source in sorghum. L. coryniformis and L. parabuchneri produced 1,3- and 1,2-propanediol from glycerol and lactate, respectively, metabolites that were previously not observed in sourdough. To determine the competitiveness of strains, wheat and sorghum slurries were inoculated with equal cells counts of L. sanfranciscensis, L. parabuchneri, and L. casei fermented at 28 degrees C or 34 degrees C and propagated by back-slopping every 24h. Lactobacilli in sourdough were quantified by plating and species-specific quantitative PCR (qPCR). Generally, sorghum and wheat sourdoughs inoculated with isolates from ting gave no appreciable differences in the metabolites produced during the fermentation process. L. sanfranciscensis grew in wheat but not in sorghum sourdoughs, or sorghum sourdoughs supplemented with 2% maltose, 1% tryptone, 0.1% l-cysteine and 2% sucrose. Furthermore, L.sanfranciscensis decreased progressively during propagation of sorghum sourdoughs but ting isolates were overgrown by L. sanfranciscensis after three propagations in wheat sourdoughs independent of the incubation temperature. The anti-microbial activity of four different types of sorghum extracts was tested against L. sanfranciscensis, L. parabuchneri, and L. casei to correlate the resistance to phenolic compounds to growth in wheat or sorghum sourdoughs. L. sanfranciscensis was inhibited by phenolic extracts from sorghum flours whereas ting isolates were resistant. In conclusion, microbiota of sorghum sourdough differ from wheat and rye because sorghum contains active concentrations of antimicrobial phenolic compounds, and offers glucose as major carbon source. PMID- 23107504 TI - Efficacy of household washing treatments for the control of Listeria monocytogenes on salad vegetables. AB - The efficacy of household decontamination methods at reducing Listeria monocytogenes on fresh lettuce (Lactuca sativa), cucumber (Cucumis sativus) and parsley (Petroselinum sativum) was studied. Inoculated vegetable pieces were immersed in washing solutions and surviving L. monocytogenes enumerated. Parameters investigated were storage temperature prior to washing, dipping water temperature, agitation, acetic acid concentration and immersion time. The results indicated that the storage temperature significantly affects the efficacy of dipping vegetables in water for the control of L. monocytogenes, as the reduction in count was greatest when products had been stored at cooler temperatures. Decontamination with acetic acid (up to 2.0% v/v) was shown to have some effect in most cases, but the highest observed decrease in count was 2.6 log cfu/g. Experiments investigating the effect of exposure time to acetic acid (0.5% and 1.0% v/v, up to 30 min immersion) indicated that immersing the vegetables for more than 10 min is of minimal benefit. The most significant factor affecting washing and decontamination efficacy was the vegetable itself: L. monocytogenes colonizing cucumber epidermis was far more resistant to removal by washing and to acid treatment than that on the leafy vegetables, and L. monocytogenes on parsley was the most susceptible. This shows that published decontamination experiments (often performed with lettuce) cannot necessarily be extrapolated to other vegetables. PMID- 23107505 TI - Preservation of pears in water in the presence of Sinapis arvensis seeds: a Greek tradition. AB - In this research, the microbiological and physicochemical changes during preservation of pears in water in the presence of Sinapis arvensis seeds (PWS FL) according to the traditional Greek home food manufacture were studied. Pears preserved in water served as control (PW FL). The growth of lactic acid bacteria (LAB) coming from the pear surface was enhanced in the presence of Sinapis seeds, while Enterobacteriaceae and Gram-negative bacteria declined coincidently with the lower (P<0.05) pH of the PWS FL. LAB predominated over the other microbial groups in the fermentation liquids (FLs) of both systems. All the 49 LAB isolates from one fermentation experiment were identified as Leuconostoc mesenteroides subsp. cremoris by the SDS-PAGE of whole-cell proteins, while RAPD-PCR fingerprinting and partial 16S rRNA sequence determination of selected isolates did not discriminate them at the subspecies level. Fruit preserved in PWS FL had higher titratable or volatile acidity, phenolic compounds or antioxidant capacity as well as lower pH and firmness than the control fruit. All physicochemical parameters of the FLs increased except of the pH which decreased. Coincidently with higher population of LAB in PWS FL the levels of citric, lactic and acetic acid were higher than in control. Oxalic acid and related unknown substances were found at higher levels in PWS FL than the control and may be the agent(s) enhancing the growth of LAB and/or contributing partially to the decline of Enterobacteriaceae. The organoleptic test showed that fruit preserved in PWS FL had better overall acceptance than the control, and that it retained most of the positive traits. PMID- 23107506 TI - Antimicrobial resistance profiles among Escherichia coli strains isolated from commercial and cooked foods. AB - A total of 4330 food samples of which microbiological standard for Escherichia coli is negative in Korea were determined for the frequency of E. coli. Ninety six samples (2.2%) were positive for E. coli. Detection rate of E. coli varied significantly by food type and ranged from 0.3% to 10.9%. Seasoned raw meat (yukhoe) and cold bean-soup had the highest prevalence for E. coli (10.9%) followed by gimbap (5.2%), meat broth for cold noodle (2.9%) and sprout (2.1%). E. coli isolates (n=96) were investigated for their phenotypic and genotypic antimicrobial resistance patterns. Seventeen E. coli isolates (17.7%) were resistant to one or more antimicrobial agents tested. High rates of resistance to the following drugs were observed: tetracycline (15.6%), streptomycin (12.5%), ampicillin (10.4%), nalidixic acid (9.4%) and ticarcillin (9.4%). All ampicillin resistant isolates were screened for extended-spectrum beta-lactamase (ESBL) production by the combination disk test. None of the E. coli isolates produced ESBLs. Seventeen out of 96 E. coli isolates which were resistant to at least one antibiotic were investigated by PCR for the presence of 3 classes of antimicrobial resistance genes (tetracycline, aminoglycosides and beta-lactams). The tetracycline resistance genes tetA and tetB were found in 7 and 5 isolates, respectively. The aminoglycoside resistance genes, strA/B, aphA1, aadA and aac(3) IV were found in 9, 5, 2 and 2 isolates, respectively. The beta-lactam resistance gene, bla(TEM) was found in 7 isolates. Results of this study show that 13 E. coli isolates were multidrug resistant (to three or more antibiotics) and 12 isolates carried at least one antimicrobial resistance gene. These isolates can act as the reservoir for antimicrobial resistance genes and facilitate the dissemination of these genes to other pathogenic and commensal bacteria. Adequate intervention to reduce microbial contamination of these foods is strongly recommended. PMID- 23107507 TI - Susceptibility of Campylobacter to high intensity near ultraviolet/visible 395+/ 5nm light and its effectiveness for the decontamination of raw chicken and contact surfaces. AB - Campylobacter is an important cause of human gastroenteritis worldwide. Chicken meat is frequently contaminated with this organism and is considered to be a significant source of infection. It has been predicted that lowering the numbers of Campylobacter on chicken meat can reduce the risk to public health. The aims of the current study were to investigate the susceptibility of Campylobacter to high intensity near ultraviolet/visible (NUV-vis) 395+/-5nm light and to examine its potential for the microbiological decontamination of raw chicken and contact surfaces. Exposure of Campylobacter jejuni and Campylobacter coli to NUV-vis light of irradiances was assessed at three distances (3, 12 and 23 cm) from the light source for up to 10 min, corresponding to doses of 0.06 to 18J/cm(2). Overall, levels of inactivation in liquid and on raw chicken improved with longer exposure times and shorter distances from the light source. Reductions of more than 7log(10)CFU/mL were achieved for Campylobacter isolates in liquid following 2 min exposure at 3 cm. Exposure of skinless chicken fillet to NUV-vis light for 1 or 5 min at 3 cm distance reduced C. jejuni by 2.21 and 2.62 log(10)CFU/g, respectively. Increasing the treatment time to 10 min did not significantly increase the level of inactivation. In general, NUV-vis light treatment did not affect the colour of raw chicken. Excluding treatments which resulted in excessive heating (>50 degrees C) of chicken skin, a maximum reduction of 0.95 log(10)CFU/g was achieved for C. jejuni following 10 min exposure to NUV-vis light at 12 cm (P<0.05). For Enterobacteriaceae and total viable counts, significant reductions were achieved only on chicken fillet samples. Light treatments were significantly effective for decontaminating contact surfaces as there were no C. jejuni recovered from stainless steel or cutting board surfaces after NUV-vis light treatments from an initial inoculum of 2-4 log(10)CFU/cm(2) (P<0.05). The current study demonstrates potential for the use of NUV-vis light for the inactivation of Campylobacter spp. in liquids, on raw chicken and contact surfaces. The incorporation of this technology could be implemented in a commercial processing plant at various stages, for example to decontaminate carcasses during air chilling. It could also be applied at critical stages within the plant to control microbial contamination on equipment surfaces. PMID- 23107508 TI - Effects of nicotine on spinal cord injury pain vary among subtypes of pain and smoking status: results from a randomized, controlled experiment. AB - Smoking has been associated with increased pain severity in general chronic pain populations. Less is known about the effects of smoking and nicotine on the multifaceted and often complex subtypes of pain that frequently occur following spinal cord injury (SCI). The purpose of this study was to examine the effects of nicotine on self-reported pain among individuals with SCI and to determine if the effect of nicotine varied by pain subtype. A randomized, placebo-controlled crossover design was used to determine the effect of nicotine exposure on subtypes of SCI-related pain among smokers and nonsmokers. A complex relationship emerged, such that the degree of reported pain with exposure to 2 mg of nicotine compared to placebo varied according to pain type and smoking status of the subject. Pain sites that had characteristics of both neuropathic and musculoskeletal symptoms (deemed complex neuropathic pain sites) exhibited pain reduction after nicotine exposure in nonsmokers. In sharp contrast, smokers with this form of pain exhibited an increase in pain severity. Data were also examined descriptively to determine potentially unique factors associated with complex neuropathic pain that may explain trends associated with clinically relevant changes following nicotine exposure. In sum, smoking or tobacco use history may determine the analgesic (or enhanced pain perception) effect of nicotine on post SCI pain. PERSPECTIVE: Pain characterized by both neuropathic and musculoskeletal symptoms decreased in severity after nicotine exposure in nonsmokers with SCI but increased in severity among smokers with SCI. The analgesic (or enhanced nociceptive) effect of nicotine may depend on tobacco use history. PMID- 23107509 TI - Development and validation of a 'universal' HPLC method for pyrethroid quantification in long-lasting insecticidal mosquito nets for malaria control and prevention. AB - OBJECTIVES: To outline the development and validation of a universal method for quantifying deltamethrin, permethrin and alpha-cypermethrin levels in a variety of long-lasting insecticidal mosquito nets. METHODS: Using the HPLC conditions found in the CIPAC method for deltamethrin quantification, the method is based on a simple extraction technique for sample preparation (heating in isooctane at approximately 100 degrees C for 15 min). The method was validated for linearity, specificity, accuracy, precision, insecticide stability to extraction conditions and required extraction time for insecticide removal. RESULTS: The method was found valid for insecticide quantifications for various types of nets, namely for deltamethrin coated on polyester nets, deltamethrin incorporated into polyethylene nets, permethrin incorporated into polyethylene nets, alpha cypermethrin coated on polyester nets and alpha-cypermethrin incorporated into polyethylene nets. CONCLUSIONS: This method will provide a more simplified approach to testing a variety of nets (different types of fibre) containing deltamethrin, permethrin or alpha-cypermethrin. PMID- 23107510 TI - Clinical correlation between premature ovarian failure and a chromosomal anomaly in a 22-year-old Caucasian woman: a case report. AB - INTRODUCTION: Premature ovarian failure is defined as the cessation of ovarian activity before the age of 40 years. It is biochemically characterized by low levels of gonadal hormones (estrogens and inhibins) and high levels of gonadotropins (luteinizing hormone and follicle-stimulating hormone). CASE PRESENTATION: Our patient, a 22-year-old Caucasian woman under evaluation for infertility, had experienced secondary amenorrhea from the age of 18. No positive family history was noted regarding premature menopause. An examination of our patient's karyotype showed the presence of a reciprocal translocation, apparently balanced, which had the X chromosome long arm (q13) and the 14 chromosome short arm (p12) with consequent karyotype: 46, X, t(X; 14)(q13;p12). CONCLUSIONS: Our study has underlined that karyotyping is one of the fundamental investigations in the evaluation of amenorrhea. It highlighted a genetic etiology, in the form of a chromosomal abnormality, as the causal factor in amenorrhea. PMID- 23107511 TI - Cancer rehabilitation from the perspectives of oncology nurses in Korea. AB - The purpose of this study was to understand the perception of oncology nurses and how it is related to cancer rehabilitation in Korea. A qualitative study with three focus groups consisting of 6-8 Korean oncology nurses (n = 21) was conducted. The interviews were thematically analyzed. Two main themes for the attributes of cancer rehabilitation were "comprehensive activities of nurses" and "active involvement of survivors." Six subthemes from the oncology nurses' care experiences were identified: "incorporating partnership and sharing feelings," "fulfilling individualized needs," "providing timely and practical support," "enhancing internal strength with optimistic mindset," "regaining functional independence," and "getting family members in." The findings suggest that oncology nurses can play a key role in rehabilitation for cancer survivors. Nursing interventions focused on comprehensive activities of nurses as well as active involvement of survivors can be effective in enhancing cancer survivors' strength and resilience in order to lead a healthy life. Oncology nurses need to be taught a psychosocial intervention based on individualized assessment and family partnership for cancer survivors. PMID- 23107512 TI - Establishment and characterization of a new and stable collagen-binding assay for the assessment of von Willebrand factor activity. AB - INTRODUCTION: Laboratory diagnosis of von Willebrand disease (VWD) requires determination of both von Willebrand factor (VWF) protein levels and activity. Current VWF activity tests include the ristocetin cofactor assay and the collagen binding assay (VWF:CB). The goal of this investigation is to characterize a new collagen-binding assay and to determine its effectiveness in identifying VWD. METHODS: Analytical studies were carried out to characterize the performance of a new VWF:CB ELISA. Additionally, samples from a normal population were tested as were well-characterized type 1 and type 2 VWD samples. RESULTS: Repeatability and within-laboratory precision studies resulted in coefficients of variation (CVs) of <=11%. A linear range of 1-354% (0.01-3.54 IU/mL) was determined, along with a limit of detection and a lower limit of quantitation of 1.6% and 4.0% (0.016 and 0.04 IU/mL), respectively. Samples tested from apparently healthy individuals resulted in a normal range of 54-217% (0.54-2.17 IU/mL). Known VWD type 1 and type 2 samples were also analyzed by the ELISA, with 99% of samples having VWF:CB below the normal reference range and an estimated 96% sensitivity and 87% specificity using a VWF collagen-binding/antigen cutoff ratio of 0.50. CONCLUSION: This new VWF:CB ELISA provides an accurate measure of collagen binding activity that aids in the diagnosis and differentiation of type 1 from type 2 VWD. PMID- 23107513 TI - Comparative phylogenomics of Streptococcus pneumoniae isolated from invasive disease and nasopharyngeal carriage from West Africans. AB - BACKGROUND: We applied comparative phylogenomics (whole genome comparisons of microbes using DNA microarrays combined with Bayesian-based phylogenies) to investigate S. pneumoniae isolates from West Africa, with the aim of providing insights into the pathogenicity and other features related to the biology of the organism. The strains investigated comprised a well defined collection of 58 invasive and carriage isolates that were sequenced typed and included eight different S. pneumoniae serotypes (1, 3, 5, 6A, 11, 14, 19 F and 23 F) of varying invasive disease potential. RESULTS: The core genome of the isolates was estimated to be 38% and was mainly represented by gene functional categories associated with housekeeping functions. Comparison of the gene content of invasive and carriage isolates identified at least eleven potential genes that may be important in virulence including surface proteins, transport proteins, transcription factors and hypothetical proteins. Thirteen accessory regions (ARs) were also identified and did not show any loci association with the eleven virulence genes. Intraclonal diversity (isolates of the same serotype and MLST but expressing different patterns of ARs) was observed among some clones including ST 1233 (serotype 5), ST 3404 (serotype 5) and ST 3321 (serotype 14). A constructed phylogenetic tree of the isolates showed a high level of heterogeneity consistent with the frequent S. pneumoniae recombination. Despite this, a homogeneous clustering of all the serotype 1 strains was observed. CONCLUSIONS: Comparative phylogenomics of invasive and carriage S. pneumoniae isolates identified a number of putative virulence determinants that may be important in the progression of S. pneumoniae from the carriage phase to invasive disease. Virulence determinants that contribute to S. pneumoniae pathogenicity are likely to be distributed randomly throughout its genome rather than being clustered in dedicated loci or islands. Compared to other S. pneumoniae serotypes, serotype 1 appears most genetically uniform. PMID- 23107514 TI - Redundant effects of ketamine on the pathogenesis and severity of Brucella abortus infection. AB - Brucella abortus is an intracellular bacterium and leading to a serious debilitating disease known as brucellosis. Ketamine is an anesthetic and a sedative that affects the immunomodulatory activities of various immune cells. The current study was to elucidate the role of ketamine in B. abortus infection, focusing on the phagocytic activity and immune response of macrophages. Following incubation of murine macrophages with ketamine, the phagocytosis of B. abortus was markedly reduced compared with the unincubated control. Interestingly, ketamine-incubated cells displayed a decreased intensity of F-actin fluorescence compared with the B. abortus-induced amplification of intensity. Conversely, the intracellular replication of B. abortus within macrophages was notably enhanced by ketamine. Furthermore, the in vivo assessment using a mouse model revealed that continual injections with ketamine led to augmented bacterial burdens in the spleen, which was accompanied by decreased levels of mRNA expression of cytokines in the spleen. The elevations of serum cytokines such as IFN-gamma, IL-12 and IL 6, as well as the chemokine MCP-1, were also reduced by ketamine. These findings verify that ketamine suppresses the phagocytic activity and immune response during B. abortus infection. Therefore, the current study might provide novel insights into the potential influences of ketamine on infectious diseases caused by B. abortus, considering the host-pathogen interaction. PMID- 23107516 TI - [Acrodermatitis enteropathica associated with short bowel syndrome]. PMID- 23107515 TI - Fluorescence study for selecting specific ligands toward HER2 receptor: an example of receptor fragment approach. AB - Fluorescence titrations allowed us to study the interaction process between Herceptin (Fab)-derived peptides and a synthetic peptide mimicking a subdomain IV of the receptor HER2 (HER2-DIVMP). For some of the investigated peptide/HER2 DIVMP complexes a nanomolar dissociation constant was found. The performed interaction studies were completely immune from interferences of other receptor domains not covered by the design, thus decreasing the possibilities of selecting potential ligands able to bind other subtypes of HER2 receptor family. Our results demonstrate that the adopted receptor fragment approach represents an efficient methodology for selecting new molecules as lead structures specific for the receptor target. For these reasons the optimized compounds could be employed as delivery agents for the receptor-mediated anticancer therapy. PMID- 23107517 TI - [Passive leg raising test and fluid responsiveness in a child with multiple injuries]. PMID- 23107519 TI - In situ wet-cell TEM observation of gold nanoparticle motion in an aqueous solution. AB - In situ wet-cell transmission electron microscopy (TEM) technology enables direct observation of nanomaterials in a fully hydrated environment with high spatial and temporal resolution, which can be used to address a wide range of scientific problems. In this paper, the motions of approximately 5-nm sized gold nanoparticles in an aqueous solution are studied using the wet-cell TEM technology. It is observed that gold nanoparticles can be either in a single particle or cluster forms, and dynamic displacement and rotation motions are observed for both forms in the solution. Under electron beam irradiation, nanoparticles in some clusters gradually fused together; sometimes they also showed dramatic growth behavior. Mechanisms for the motion and growth of the particles/clusters are discussed. PMID- 23107518 TI - A survey of breast cancer physicians regarding patient involvement in breast cancer treatment decisions. AB - PURPOSE: Shared breast cancer treatment decision-making between patients and physicians increases patient treatment satisfaction and compliance and is influenced by physician-related factors. Attitudes and behaviors about patient involvement in breast cancer treatment decisions and treatment-related communication were assessed by specialty among breast cancer physicians of women enrolled in the Breast Cancer Quality of Care Study (BQUAL). RESULTS: Of 275 BQUAL physicians identified, 50.0% responded to the survey. Most physicians spend 46-60 min with the patient during the initial consult visit and 51.5% report that the treatment decision is made in one visit. Oncologists spend more time with new breast cancer patients during the initial consult (p = 0.021), and find it more difficult to handle their own feelings than breast surgeons (p = <0.001). CONCLUSION: Breast surgeons and oncologists share similar attitudes and behaviors related to patient involvement in treatment decision-making, yet oncologists report more difficulty managing their own feelings during the decision-making process. PMID- 23107520 TI - Dietary protein for human health. PMID- 23107521 TI - Dietary protein - its role in satiety, energetics, weight loss and health. AB - Obesity is a serious health problem because of its co-morbidities. The solution, implying weight loss and long-term weight maintenance, is conditional on: (i) sustained satiety despite negative energy balance, (ii) sustained basal energy expenditure despite BW loss due to (iii) a sparing of fat-free mass (FFM), being the main determinant of basal energy expenditure. Dietary protein has been shown to assist with meeting these conditions, since amino acids act on the relevant metabolic targets. This review deals with the effects of different protein diets during BW loss and BW maintenance thereafter. Potential risks of a high protein diet are dealt with. The required daily intake is 0.8-1.2 g/kg BW, implying sustaining the original absolute protein intake and carbohydrate and fat restriction during an energy-restricted diet. The intake of 1.2 g/kg BW is beneficial to body composition and improves blood pressure. A too low absolute protein content of the diet contributes to the risk of BW regain. The success of the so-called 'low carb' diet that is usually high in protein can be attributed to the relatively high-protein content per se and not to the relatively lower carbohydrate content. Metabolic syndrome parameters restore, mainly due to BW loss. With the indicated dosage, no kidney problems have been shown in healthy individuals. In conclusion, dietary protein contributes to the treatment of obesity and the metabolic syndrome, by acting on the relevant metabolic targets of satiety and energy expenditure in negative energy balance, thereby preventing a weight cycling effect. PMID- 23107522 TI - The metabolism of "surplus" amino acids. AB - For an adult in N balance, apart from small amounts of amino acids required for the synthesis of neurotransmitters, hormones, etc, an amount of amino acids almost equal to that absorbed from the diet can be considered to be "surplus" in that it will be catabolized. The higher diet-induced thermogenesis from protein than from carbohydrate or fat has generally been assumed to be due to increased protein synthesis, which is ATP expensive. To this must be added the ATP cost of protein catabolism through the ubiquitin-proteasome pathway. Amino acid catabolism will add to thermogenesis. Deamination results in net ATP formation except when serine and threonine deaminases are used, but there is the energy cost of synthesizing glutamine in extra-hepatic tissues. The synthesis of urea has a net cost of only 1.5 * ATP when the ATP yield from fumarate metabolism is offset against the ATP cost of the urea cycle, but this offset is thermogenic. In fasting and on a low carbohydrate diet as much of the amino acid carbon as possible will be used for gluconeogenesis - an ATP-expensive, and hence thermogenic, process. Complete oxidation of most amino acid carbon skeletons also involves a number of thermogenic steps in which ATP (or GTP) or reduced coenzymes are utilized. There are no such thermogenic steps in the metabolism of pyruvate, acetyl CoA or acetoacetate, but for amino acids that are metabolized by way of the citric acid cycle intermediates there is thermogenesis ranging from 1 up to 7 * ATP equivalent per mol. PMID- 23107523 TI - Effects of a high protein diet on body weight and comorbidities associated with obesity. AB - Red meat intake has been frequently associated with the development of coronary artery disease and type 2 diabetes but vegetable protein has been associated with protection from these diseases. Whether this is related to the protein per se or to the increased polyunsaturated fat or higher fibre levels associated with more vegetarian diets is not clear. High protein diets are associated with greater satiety and in some studies are associated with greater weight loss compared with high carbohydrate diets especially in an ad libitum design. These diets also lower plasma triglyceride and blood pressure and sometimes spare lean mass. There appear to be no harmful effects of high protein diets on bone density or renal function in weight loss studies. PMID- 23107524 TI - The role of high-protein diets in body weight management and health. AB - Studies examining the health benefits of high-protein diets typical of most affluent and many developing countries are not consistent. Prospective epidemiological studies relating dietary protein to clinical and metabolic endpoints suggest increased weight gain and increased risk of diabetes amongst those with a high protein intake and an increased risk of cancer with high intakes of red meat, but lower blood pressure and possibly a reduced risk of heart disease with higher protein intakes. The potential for high-protein diets to confer greater benefit than other diets has been examined using ad libitum and energy restricted diets. Of greatest interest have been the comparisons between high-protein and high-carbohydrate diets. Many trials have reported greater weight loss especially in the context of ad libitum diets over the short-to medium-term, sparing of lean body mass, lowering of triglyceride levels, improved HDL: total cholesterol ratio and improved glycaemic control. Limited data regarding insulin sensitivity are less consistent. A major difficulty in interpreting the results of these studies is that carbohydrate quality has not been taken into account. Furthermore, longer term comparisons of weight reducing diets differing in macronutrient composition have reported similar outcomes, suggesting that compliance is a more important consideration. Nevertheless dietary patterns with high-protein intakes are appropriate for weight reduction and weight maintenance and may be useful for those who have high triglyceride levels and other features of the metabolic syndrome. PMID- 23107526 TI - Food proteins as a source of bioactive peptides with diverse functions. AB - In addition to supplying essential nutrients, some food proteins can confer additional health benefits beyond nutrition. The presence of bioactive proteins and peptides in different foods is a factor not currently taken into consideration when assessing the dietary quality of food proteins. The range of described physiological benefits attributed to bioactive proteins and peptides is diverse. Multiple factors can potentially impact on the ability of a bioactive peptide or protein to elicit an effect. Although some food proteins act directly in their intact form to elicit their effects, generally it is peptides derived from digestion, hydrolysis or fermentation that are of most interest. The levels of bioactive peptides generated must be sufficient to elicit a response, but should not be so high as to be unsafe, thus causing negative effects. In addition, some peptides cause systemic effects and therefore must be absorbed, again in sufficient amounts to elicit their action. Many studies to date have been carried out in vitro; therefore it is important that further trials are conducted in vivo to assess efficacy, dose response and safety of the peptides, particularly if health related claims are to be made. Therefore, methods must be developed and standardised that enable the measurement of health benefits and also the level of bioactive peptides which are absorbed into the bloodstream. Once standardised, such methods may provide a new perspective and an additional mechanism for analysing protein quality which is currently not encompassed by the use of the protein digestibility-corrected amino acid score (PDCAAS). PMID- 23107527 TI - Dietary protein requirements and adaptive advantages in athletes. AB - Dietary guidelines from a variety of sources are generally congruent that an adequate dietary protein intake for persons over the age of 19 is between 0.8-0.9 g protein/kg body weight/d. According to the US/Canadian Dietary Reference Intakes, the RDA for protein of 0.8 g protein/kg/d is "...the average daily intake level that is sufficient to meet the nutrient requirement of nearly all [~98 %]... healthy individuals..." The panel also states that "...no additional dietary protein is suggested for healthy adults undertaking resistance or endurance exercise." These recommendations are in contrast to recommendations from the US and Canadian Dietetic Association: "Protein recommendations for endurance and strength trained athletes range from 1.2 to 1.7 g/kg/d." The disparity between those setting dietary protein requirements and those who might be considered to be making practical recommendations for athletes is substantial. This may reflect a situation where an adaptive advantage of protein intakes higher than recommended protein requirements exists. That population protein requirements are still based on nitrogen balance may also be a point of contention since achieving balanced nitrogen intake and excretion likely means little to an athlete who has the primary goal of exercise performance. The goal of the present review is to critically analyse evidence from both acute and chronic dietary protein-based studies in which athletic performance, or correlates thereof, have been measured. An attempt will be made to distinguish between protein requirements set by data from nitrogen balance studies, and a potential adaptive 'advantage' for athletes of dietary protein in excess of the RDA. PMID- 23107525 TI - Role of specific dietary amino acids in clinical conditions. AB - In a variety of chronic and acute disease states, alterations in protein synthesis, breakdown and protein turnover rates occur that are related to the loss of body protein and skeletal muscle wasting. A key observation is the stimulation of protein breakdown in muscle and the stimulation of protein synthesis in the splanchnic area; mainly liver. An altered splanchnic extraction of amino acids as well as an anabolic resistance to dietary protein, related to stress, disuse and aging play a key role in the pathogenesis of muscle wasting in these conditions. To overcome these factors, specific dietary protein and amino acid diets have been introduced. The main focus of these diets is the quantity and quality of dietary proteins and whether a balanced mixture or solely dietary essential amino acids are required with or without higher intake levels of specific amino acids. Specifically in cancer patients, stimulated muscle protein synthesis has been obtained by increasing the amount of protein in a meal and by providing additional leucine. Also in other chronic diseases such as chronic obstructive pulmonary disease and cystic fibrosis, meals with specific dietary proteins and specific combinations of dietary essential amino acids are able to stimulate anabolism. In acute diseases, a special role for the amino acid arginine and its precursor citrulline as anabolic drivers has been observed. Thus, there is growing evidence that modifying the dietary amino acid composition of a meal will positively influence the net balance between muscle protein synthesis and breakdown, leading to muscle protein anabolism in a variety of chronic and acute disease states. Specific amino acids with anabolic potential are leucine, arginine and citrulline. PMID- 23107528 TI - Background on international activities on protein quality assessment of foods. AB - The subject of protein quality assessment of foods and diets was addressed at the Codex Committee on Vegetable Proteins (1982-1989), FAO/WHO (1989, 2001) and WHO/FAO (2002) expert reviews. These international developments are summarized in this manuscript. In 1989, a Joint FAO/WHO Expert Consultation on Protein Quality Evaluation reviewed knowledge of protein quality assessment of foods, and specifically evaluated amino acid score corrected for protein digestibility, the method recommended by the Codex Committee on Vegetable Proteins. The report of the Consultation published in 1991 concluded that the Protein Digestibility corrected Amino Acid Score (PDCAAS) method was the most suitable approach for routine evaluation of protein quality for humans. The Consultation recognized that the amino acid scoring pattern proposed by FAO/WHO/UNU (1985) for preschool children was at that time the most suitable pattern for calculating PDCAAS for all ages except infants in which case the amino acid composition of human milk was recommended to be the basis of the scoring pattern. The rat balance method was considered as the most suitable practical method for predicting protein digestibility by humans. Since its adoption by FAO/WHO (1991), the PDCAAS method has been criticised for a number of reasons. The FAO/WHO (2001) Working Group on analytical issues related to protein quality assessed the validity of criticisms of the PDCAAS method. While recognizing a distinct regulatory use of protein quality data, the Working Group recommended that the PDCAAS method may be inappropriate for the routine prediction of protein quality of novel and sole source foods which contain high levels of anti nutritional factors; and that for regulatory purposes, the method should be revised to permit values of >100 for high quality proteins. In evaluating the recommendations of the Working Group, the WHO/FAO (2002) Expert Consultation on Protein and Amino Acid Requirements endorsed the PDCAAS method with minor modifications to the calculation method but also raised several issues. These included the calculation of scoring patterns; prediction of amino acid digestibility by faecal and ileal methods; reduced bioavailability of lysine in processed proteins; truncation of the amino acid score and consequent PDCAAS value; protein digestibility as a first limiting factor in determining the overall available dietary nitrogen; and the calculation of amino acid score for a dietary protein mixture. These concerns were considered particularly important in relation to the regulatory aspects of protein quality of foods, and their resolution was urgently recommended through a new separate expert review. PMID- 23107529 TI - Protein quality evaluation twenty years after the introduction of the protein digestibility corrected amino acid score method. AB - In 1989 the Joint FAO/WHO Expert Consultation on Protein Quality Evaluation recommended the use of the Protein Digestibility Corrected Amino Acid Score (PDCAAS) method for evaluating protein quality. In calculating PDCAAS, the limiting amino acid score (i.e., ratio of first limiting amino acid in a gram of target food to that in a reference protein or requirement) is multiplied by protein digestibility. The PDCAAS method has now been in use for 20 years. Research emerging during this time has provided useful data on various aspects of protein quality evaluation that has made a review of the current methods used in assessing protein quality necessary. This paper provides an overview of the use of the PDCAAS method as compared to other methods and addresses some of the key challenges that remain in regards to protein quality evaluation. Furthermore, specific factors influencing protein quality including the effects of processing conditions and preparation methods are presented. Protein quality evaluation methods and recommended protein intakes currently used in different countries vis a-vis the WHO/FAO/UNU standards are further provided. As foods are frequently consumed in complement with other foods, the significance of the PDCAAS of single protein sources may not be evident, thus, protein quality of some key food groups and challenges surrounding the calculation of the amino acid score for dietary protein mixtures are further discussed. As results from new research emerge, recommendations may need to be updated or revised to maintain relevance of methods used in calculating protein quality. PMID- 23107530 TI - The regulation of protein content and quality in national and international food standards. AB - Food regulation aims to protect public health through a safe and nutritious food supply produced by a compliant food industry. Food standards of developed countries generally do not regulate protein content or protein quality because the risk of dietary protein inadequacy in their national populations is very low. Protein is nevertheless regulated for reasons of product quality or protein labelling or to minimise assessed health risks associated with consumption of certain animal- and vegetable-protein foods; analogue products that extend or simulate commonly available animal-protein foods; and special purpose foods such as infant formula and foods, supplementary and medical foods, and foods for weight loss. The extent and approach to protein regulation varies greatly among jurisdictions but where it occurs, it is applied through minimum and sometimes maximum limits on protein content or quality measures or both using an inter related approach. Protein quality measures range from amino acid profiles and digestibility corrected scores to protein rating, a rat bioassay and reference proteins not further described. Regulatory methods for protein quality determination are referenced to the published scientific literature or developed nationally. Internationally, the Codex Alimentarius regulates the protein content and quality of some foods. The Codex approach varies according to the food but is similar to the approaches used in national and regional food regulation. This paper provides a comparison of the regulation of protein in foods using examples from the food regulations of Australia New Zealand, Canada, the European Union, the United States of America and the Codex Alimentarius. PMID- 23107531 TI - Recent advances in determining protein and amino acid requirements in humans. AB - During the past 25 years a significant amount of research has been conducted to determine amino acid requirements in humans. This is primarily due to advancements in the application of stable isotopes to examine amino acid requirements. The indicator amino acid oxidation (IAAO) method has emerged as a robust and minimally invasive technique to identify requirements. The IAAO method is based on the concept that when one indispensable dietary amino acid (IDAA) is deficient for protein synthesis, then the excess of all other IDAA, including the indicator amino acid, will be oxidized. With increasing intakes of the limiting amino acid, IAAO will decrease, reflecting increasing incorporation into protein. Once the requirement for the limiting amino acid is met there will be no further change in the indicator oxidation. The IAAO method has been systematically applied to determine most IDAA requirements in adults. The estimates are comparable to the values obtained using the more elaborate 24h-indicator amino acid oxidation and balance (24h-IAAO/IAAB) model. Due to its non-invasive nature the IAAO method has also been used to determine requirements for amino acids in neonates, children and in disease. The IAAO model has recently been applied to determine total protein requirements in humans. The IAAO method is rapid, reliable and has been used to determine amino acid requirements in different species, across the life cycle and in disease. The recent application of IAAO to determine protein requirements in humans is novel and has significant implications for dietary protein intake recommendations globally. PMID- 23107532 TI - Criteria and markers for protein quality assessment - a review. AB - Dietary proteins are found in animal products, plant products and single-cell organisms. Proteins are present in variable proportions in these different food sources and the different proteins also differ in their amino acid composition, dietary indispensable amino acid content and physico-chemical properties. Different criteria can be used to define dietary protein requirements and different markers can be used to assess nutritional protein quality according to the criteria used for protein requirement estimation. The current approach to determining protein requirements is related to nitrogen balance and the dietary indispensable amino acid score approach relates protein quality to the capacity of protein to allow reaching nitrogen balance by providing nitrogen and indispensable amino acids. A second approach considers more directly protein nitrogen utilization by the body and includes measurement of protein digestibility and of the efficiency of dietary nitrogen retention at maintenance or for protein deposition at the whole body level or in more specific body areas. Another approach is related to protein turnover and protein synthesis in relation to maintenance and/or efficiency for deposition or development (growth) at the whole body level or for different and more specific target tissues such as muscle or bone. Lastly, protein quality can also be evaluated from different markers used as risk factors for metabolic dysfunction and disorders related for instance to insulin resistance, diabetes and obesity or cardio-vascular disease. The accuracy and relevance of these different approaches is discussed regarding the capacity of the different protein sources (i.e. animal as meat, milk or eggs, legume as soya or pea, or cereal as wheat or rice) to satisfy protein requirements according to these different criteria and markers. PMID- 23107533 TI - Standardised methods for amino acid analysis of food. AB - Amino acids (AA) are essential nutritional components of a balanced diet and occur in foods in either the free AA form or as the building blocks of proteins. The analysis of AAs in foods is composed of a number of unit operations; the release of the AAs from the food matrix, the separation of the individual AAs and their quantification using calibration standards. Each of these steps has their own idiosyncrasies, e.g. different hydrolysis conditions are required for the optimal release of different AAs and there are a diverse number and type of food matrices, such that most laboratories adapt methods to best suit their applications. There is currently no official standardised method for AA analysis, although the Association of Analytical Communities (AOAC) has validated methods for a number of individual AA components. The established analytical techniques of HPLC (ion exchange or reversed phase) and GC-MS have recently been supplemented by a number of new methods. These include capillary electrophoresis MS and Ultra HPLC-MS, and LC with other detectors. This review will address the intricacies and concerns of the protein hydrolysis step, discuss what specifications or prerequisites need to be placed on the existing and new methods and laboratories using these methods, comment on whether one method can successfully satisfy the exacting requirements of the various unit operations, and finally pose the question 'Is there any merit in 'developing' a validated (e.g. AOAC) official method of analysis for AAs in food?' PMID- 23107534 TI - Determination of protein and amino acid digestibility in foods including implications of gut microbial amino acid synthesis. AB - To meet the protein and amino acid requirements of individuals and of populations requires information not only about their requirements but also about the capacity of available foods to meet those requirements. Most of our current knowledge of the digestibility of food proteins and the methods to estimate it has been derived from work with animals. Because the microbiota of the large intestine alter the amino acid composition of the digesta, and because only trivial quantities of amino acids are absorbed intact from the large intestine, the current method of choice for assessing amino acid digestibility is ileal digestibility corrected for basal endogenous losses, that is, standardized ileal digestibility. For protein as a whole, however, because nitrogen absorbed in forms other than as amino acids can contribute to the nitrogen economy, the absorption of nitrogen over the whole digestive tract is the more appropriate measure. Most of the methods developed for estimating ileal amino acid outflow in animals are not directly applicable to man: the exception is the use of volunteers with an ileostomy. The flow and composition of ileal digesta in human subjects can also be measured by the infusion of a marker and withdrawal of samples through a naso-intestinal tube. However, this method is too demanding for routine use and is likely to be restricted to validating the application to humans of digestibility data obtained either from animals, of which the pig seems most suitable, or in vitro methods. Microbial activity in the gastrointestinal (GI) tract is not confined to the large intestine: the numbers and metabolic activity of the upper GI microbiota lead to substantial amounts of microbial protein leaving the ileum. It appears however that a large proportion of the amino acids used by the upper GI microbiota are preformed - from the diet or from endogenous materials - rather than from de novo synthesis. Although there are still uncertainties about the impact of microbial activity in the upper GI tract, the amino acid composition of ileal digesta provides the best available basis for estimating the proportion of dietary amino acids available for metabolism. PMID- 23107535 TI - Ileal and faecal protein digestibility measurement in humans and other non ruminants - a comparative species view. AB - A comparative non-ruminant species view of the contribution of the large intestinal metabolism to inaccuracies in nitrogen and amino acid absorption measurements is provided to assess potential implications for the determination of crude protein/amino acid digestibility in adult humans consuming lower digestible protein sources. Most of the amino acids in the hindgut are constituents of the microorganisms and significant microbial metabolism of dietary and endogenous amino acids occurs. Bacterial metabolism of nitrogen containing compounds leads to a significant disappearance of nitrogen in the large intestine. Literature data show that some 79 % of the nitrogen entering the large intestine of the horse is absorbed. For dogs, sows, and growing pigs these estimates are 49, 34 and 16 %, respectively. The coefficient of gut differentiation of humans compares closely to that of dogs while the coefficient of fermentation in humans is the lowest of all non-ruminant species and closest to that of cats and dogs. Large intestinal digesta transit times of humans compare closest to adult dogs. Significant amino acid metabolism has been shown to occur in the large intestine of the adult dog. Use of the growing pig as an animal model is likely to underestimate the fermentation of amino acids in the human large intestine. Based on the significant degree of fermentation of nitrogen-containing components in the large intestine of several non-ruminant species, it can be expected that determination of amino acid digestibility at a faecal level in humans consuming low quality proteins would not provide accurate estimates of the amino acids absorbed by the intestine. PMID- 23107536 TI - Gut luminal endogenous protein: implications for the determination of ileal amino acid digestibility in humans. AB - The true ileal digestibility assay provides the most informative measure of digestibility to assess bioavailability of amino acids in foods for humans. To determine 'true' estimates of ileal amino acid digestibility, requires that endogenous amino acids present in digesta at the terminal ileum be quantified. The amounts of endogenous amino acids in ileal digesta can be determined after feeding an animal or human a protein-free diet (traditional approach) or by various methods after giving a protein-containing diet. When the protein-free method has been applied with adult human subjects an overall mean value (three separate studies) for endogenous ileal nitrogen flow of 800 mg N/d has been reported. This value is considerably lower than a comparable value obtained after feeding protein of 1852 mg N/d (mean of four separate studies), and thus endogenous ileal N and amino acids should be measured under conditions of protein alimentation. There is some confusion concerning the terminology used to define digestibility, with the term "true" digestibility having different adopted meanings. Here, true amino acid digestibility is defined as apparent amino acid digestibility corrected for the basal amino acid losses determined after giving either a protein-free or a protein-containing diet. Basal losses should be determined at a defined dry-matter and protein intake. The protein-free diet approach to determining endogenous amino acids is considered unphysiological and basal losses refer to ileal endogenous amino acid flows associated with digesta dry-matter flow, and not including "specific" effects of dietary factors such as non starch polysaccharides and anti nutritional factors. Arguments are advanced that the enzyme hydrolysed protein/ultra filtration method may be suitable for routine application with a cannulated pig model, to obtain physiologically-valid basal estimates of ileal endogenous amino acids to allow calculation of true ileal amino acid digestibility in the pig, and then prediction (via statistical relationships) of true coefficients of amino acid digestibility in humans. PMID- 23107537 TI - Evidence for validity of ileal digestibility coefficients in monogastrics. AB - Measures of amino acid (AA) digestibility are used widely to estimate bioavailability of AA in feed and food ingredients for monogastric animals. In principle, the digestibility assay is simpler than in vivo assessments of AA bioavailability and allows for simultaneous estimation of the bioavailability of all AA in an experimental diet. It is generally assumed that absorption of intact AA in the hindgut of monogastrics is minimal, even though colonocytes do contain AA transporters and have been shown to absorb AA. This assumption is supported by the observation that infusion of AA into the hindgut does not improve nitrogen balance in monogastrics. In addition, growth performance of monogastrics is more highly correlated with ileal than faecal AA digestibility. Therefore, ileal digestibility coefficients provide better estimates of AA bioavailability than faecal digestibility coefficients. Measures of apparent ileal digestibility (AID) of AA are confounded with endogenous gut AA losses (EAAL). The curvilinear increase in AID of AA with increasing dietary AA level has been attributed to the relatively large contribution of EAAL to total ileal AA flows at low dietary AA levels. Subtracting basal EAAL from total ileal AA flows yields standardized ileal digestibility (SID) coefficients that appear to be more additive than AID coefficients in mixtures of feed ingredients. An implicit assumption when using SID AA coefficients in diet formulation is that the post-absorptive utilization of AA is not influenced by the dietary protein source. This assumption appears inappropriate when using feed or food ingredients that have been over-heated, induce large amounts of EAAL, or contain substantial amounts of fermentable fibre. Improved understanding of processes that contribute to the discrepancy between bioavailability and ileal digestibility will allow a more effective use of AA digestibility coefficients in diet formulation. PMID- 23107538 TI - Animal models for determining amino acid digestibility in humans - a review. AB - Animal models have been commonly used for determining amino acid digestibility in humans. This allows digestibility assays to be undertaken more efficiently than those undertaken using humans directly. The laboratory rat, usually considered as a suitable animal model, has been widely used, especially as the rat is easy to raise and relatively inexpensive to house. Although more technically demanding, the pig has also been promoted as a useful model for human nutrition studies. It may be a better model than the rat, as it is a meal eater, its upper digestive tract is anatomically and physiologically closer to that of humans and it eats most foods consumed by humans. Amino acid digestibility may be determined either at the faecal or the ileal level, the latter being considered the most accurate. This contribution evaluates the suitability of the rat and pig as animal models for assessing ileal and faecal amino acid digestibility in humans. The drawbacks and advantages of using these animal models are discussed. The review is based mainly on results from controlled studies comparing both species; however, as the number of these studies is limited, data from indirect comparisons also provide insight. PMID- 23107539 TI - In vitro determination of dietary protein and amino acid digestibility for humans. AB - The development, refinement and validation of in vitro digestibility assays for dietary protein and amino acids for single stomached mammals are reviewed. The general principles of in vitro digestibility assays and their limitations are discussed. In vitro protein digestibility assays must be accurate, rapid, cheap, simple, robust, adaptable and relevant to the processes of digestion, absorption, and metabolism. Simple in vitro methods have the potential to give useful measures of in vivo amino acid and protein digestibility for humans. In vitro methods, including the complex multi-component models of digestion simulating the various physical and chemical processes, require independent validation with in vivo data from the target species or an acceptable animal model using the most appropriate in vivo measure of digestibility. For protein sources devoid of anti nutritional factors or plant fibre, true ileal digestibility is the recommended in vivo baseline, while for plant proteins the recommended in vivo assay is real ileal digestibility. More published comparative studies are required to adequately validate in vitro digestibility assays. PMID- 23107540 TI - Aspects of physical and chemical alterations to proteins during food processing - some implications for nutrition. AB - In this paper, we give an overview of our research exploring the impact of physical and chemical processing on food proteins. There are three themes, applied to the proteins of wheat, soya, egg and dairy foods. Firstly, the impact of the Maillard reaction on food proteins is discussed, with a particular focus on how the reactions might be harnessed to manipulate food texture. Secondly, the potential of enzymatic protein-protein crosslinking is considered, especially the enzyme transglutaminase. Thirdly, the broader question of how the aggregation of proteins within a food is altered by chemical and physical modification and how, in turn, this might impact on the overall nutritional quality of the food is considered. PMID- 23107541 TI - Available versus digestible dietary amino acids. AB - Available amino acids are those absorbed from the gastrointestinal tract in a form suitable for body protein synthesis. True ileal digestible amino acids are determined based on the difference between dietary amino acid intake and unabsorbed dietary amino acids at the terminal ileum. The accuracy of ileal digestible amino acid estimates for predicting available amino acid content depends on several factors, including the accuracy of the amino acid analysis procedure. In heat processed foods, lysine can react with compounds to form nutritionally unavailable derivatives that are unstable during the hydrochloric acid hydrolysis step of amino acid analysis and can revert back to lysine causing an overestimate of available lysine. Recently, the true ileal digestible reactive (available) lysine assay based on guanidination has provided a means of accurately determining available lysine in processed foods. Methionine can be oxidised during processing to form methionine sulphoxide and methionine sulphone and cysteine oxidised to cysteic acid. Methionine sulphoxide, but not methionine sulphone or cysteic acid, is partially nutritionally available in some species of animal. Currently, methionine and cysteine are determined as methionine sulphone and cysteic acid respectively after quantitative oxidation prior to acid hydrolysis. Consequently, methionine and cysteine are overestimated if methionine sulphone or cysteic acid are present in the original material. Overall, given the problems associated with the analysis of some amino acids in processed foodstuffs, the available amino acid content may not always be accurately predicted by true ileal amino acid digestibility estimates. For such amino acids specific analytical strategies may be required. PMID- 23107542 TI - Identifying recommended dietary allowances for protein and amino acids: a critique of the 2007 WHO/FAO/UNU report. AB - The WHO/FAO/UNU (2007) report examines dietary protein and amino acid requirements for all age groups, protein requirements during pregnancy, lactation and catch-up growth in children, the implications of these requirements for developing countries and protein quality evaluation. Requirements were defined as the minimum dietary intake which satisfies the metabolic demand and achieves nitrogen equilibrium and maintenance of the body protein mass, plus the needs for growth in children and pregnancy and lactation in healthy women. Insufficient evidence was identified to enable recommendations for specific health outcomes. A meta analysis of nitrogen balance studies identifies protein requirements for adults 10 % higher than previous values with no influence of gender or age, consistent with a subsequently published comprehensive study. A new factorial model for infants and children, validated on the basis of the adequacy of breast milk protein intakes and involving a lower maintenance requirement value, no provision for saltatory growth and new estimates of protein deposition identifies lower protein requirements than in previous reports. Higher values for adult amino acid requirements, derived from a re-evaluation of nitrogen balance studies and new stable isotope studies, identify some cereal-based diets as being inadequate for lysine. The main outstanding issues relate to the biological implausibility of the very low efficiencies of protein utilisation used in the factorial models for protein requirements for all population groups especially pregnancy when requirements may be overestimated. Also considerable uncertainty remains about the design and interpretation of most of the studies used to identify amino acid requirement values. PMID- 23107543 TI - Available versus digestible amino acids - new stable isotope methods. AB - The nutritive value of food protein sources is dependent on the amino acid composition and the bioavailability of the nutritionally indispensable amino acids. Traditionally the methods developed to determine amino acid bioavailability have focused on intestinal absorption or digestibility, which is calculated as the percent of amino acid intake that does not appear in digesta or faeces. Traditional digestibility based methods do not always account for gut endogenous amino acid losses or absorbed amino acids which are unavailable due to the effect of heat processing and the presence of anti-nutritional factors, though methods have been developed to address these issues. Furthermore, digestibility based methods require the use of animal models, thus there is a need to develop in vivo methods that can be applied directly in human subjects to identify the proportion of dietary amino acids which is bioavailable, or metabolically available to the body for protein synthesis following digestion and absorption. The indicator amino acid oxidation (IAAO) method developed in our laboratory for humans has been systematically applied to determine almost all indispensable amino acid requirements in adult humans. Oxidation of the indicator amino acid is inversely proportional to whole body protein synthesis and responds rapidly to changes in the bioavailability of amino acids for metabolic processes. Using the IAAO concept, we developed a new in vivo method in growing pigs, pregnant sows and adult humans to identify the metabolic availability of amino acids in foods. The stable isotope based metabolic availability method is suitable for rapid and routine analysis in humans, and can be used to integrate amino acid requirement data with dietary amino acid availability of foods. PMID- 23107544 TI - Amino acid scoring patterns for protein quality assessment. AB - The 1985 FAO/WHO/UNU protein report defined reference amino acid patterns for infants based on breast milk and for preschool children, schoolchildren and adults from age specific estimates of dietary indispensible amino acid requirements divided by the safe protein requirement for each age group. This report argued that the protein quality of a diet should be estimated from its digestibility adjusted by its amino acid score calculated from its limiting amino acid in comparison with the reference amino acid pattern. Subsequently a joint FAO/WHO expert consultation on protein quality evaluation (1991) endorsed this protein digestibility-corrected score approach. However it rejected the adult scoring pattern identified in the 1985 report arguing that the amino acid values for this pattern were too low. As an interim measure it suggested that the scoring pattern for preschool children should be used for all age groups apart from infants. The recent WHO/FAO/UNU (2007) report endorsed the 1985 report in recommending the amino acid content of breast milk as the best estimate of infant amino acid requirements. However it was only able to identify reliable requirement values for adults and adopted a factorial approach to derivation of age-related scoring patterns. This utilized the adult pattern for maintenance, and the pattern of human tissue protein for growth. Thus scoring patterns were derived for children aged 0.5, 1-2, 3-10, 11-14, 15-18 years and for adults. The total dietary amino acid requirements calculated for these age groups were divided by the mean protein requirement to give the scoring pattern which should be used to adjust digestible intakes to identify the available protein in specific diets. However because the adult values were determined in subjects at protein intakes much higher than the mean minimum protein requirement, i.e. at 1 g/kg/d rather than 0.66 g/kg/d, the pattern is likely to include higher values than the minimum requirement and should therefore be referenced against the safe allowance. PMID- 23107545 TI - Impact of antinutritional factors in food proteins on the digestibility of protein and the bioavailability of amino acids and on protein quality. AB - Dietary antinutritional factors have been reported to adversely affect the digestibility of protein, bioavailability of amino acids and protein quality of foods. Published data on these negative effects of major dietary antinutritional factors are summarized in this manuscript. Digestibility and the quality of mixed diets in developing countries are considerably lower than of those in developed regions. For example, the digestibility of protein in traditional diets from developing countries such as India, Guatemala and Brazil is considerably lower compared to that of protein in typical North American diets (54-78 versus 88-94 %). Poor digestibility of protein in the diets of developing countries, which are based on less refined cereals and grain legumes as major sources of protein, is due to the presence of less digestible protein fractions, high levels of insoluble fibre, and/or high concentrations of antinutritional factors present endogenously or formed during processing. Examples of naturally occurring antinutritional factors include glucosinolates in mustard and canola protein products, trypsin inhibitors and haemagglutinins in legumes, tannins in legumes and cereals, gossypol in cottonseed protein products, and uricogenic nucleobases in yeast protein products. Heat/alkaline treatments of protein products may yield Maillard reaction compounds, oxidized forms of sulphur amino acids, D-amino acids and lysinoalanine (LAL, an unnatural nephrotoxic amino acid derivative). Among common food and feed protein products, soyabeans are the most concentrated source of trypsin inhibitors. The presence of high levels of dietary trypsin inhibitors from soyabeans, kidney beans or other grain legumes have been reported to cause substantial reductions in protein and amino acid digestibility (up to 50 %) and protein quality (up to 100 %) in rats and/or pigs. Similarly, the presence of high levels of tannins in sorghum and other cereals, fababean and other grain legumes can cause significant reductions (up to 23 %) in protein and amino acid digestibility in rats, poultry, and pigs. Normally encountered levels of phytates in cereals and legumes can reduce protein and amino acid digestibility by up to 10 %. D-amino acids and LAL formed during alkaline/heat treatment of lactalbumin, casein, soya protein or wheat protein are poorly digestible (less than 40 %), and their presence can reduce protein digestibility by up to 28 % in rats and pigs, and can cause a drastic reduction (100 %) in protein quality, as measured by rat growth methods. The adverse effects of antinutritional factors on protein digestibility and protein quality have been reported to be more pronounced in elderly rats (20-months old) compared to young (5-weeks old) rats, suggesting the use of old rats as a model for assessing the protein digestibility of products intended for the elderly. PMID- 23107546 TI - Advantages and limitations of the protein digestibility-corrected amino acid score (PDCAAS) as a method for evaluating protein quality in human diets. AB - PDCAAS is a widely used assay for evaluating protein quality. It is a chemical score, which is derived from the ratio between the first limiting amino acid in a test protein and the corresponding amino acid in a reference amino acid pattern and corrected for true faecal N digestibility. Chemical scores exceeding 100 % are truncated to 100 %. The advantages of the PDCAAS are its simplicity and direct relationship to human protein requirements. The limitations are as follows: the reference pattern is based on the minimum amino acid requirements for tissue growth and maintenance and does not necessarily reflect the optimum intake. Truncated PDCAAS of high-quality proteins do not give any information about the power of these proteins to compensate, as a supplement, for low levels of dietary essential amino acids in low-quality proteins. It is likely that faecal N digestibility does not take into account the loss from the colon of indispensable amino acids that were not absorbed in the ileum. Anti-nutritional factors, such as lectins and trypsin inhibitors, in several plant protein sources can cause heightened endogenous losses of amino acids, an issue which is particularly relevant in animal feedstuffs. The assumption that amino acid supplementation can completely restore biological efficiency of the protein source is incorrect since the kinetics of digestion and absorption between supplemented free amino acids and amino acids present in dietary proteins, are different. PMID- 23107547 TI - Amino acid requirements in children and the elderly population. AB - The factorial approach is used to measure the dietary indispensable amino acid (IAA) requirements in children, although recent measurements based on the indicator amino acid oxidation (IAAO) method have begun to generate more direct evidence. Difficulties with the factorial method are that it depends on accurate estimates of the maintenance protein requirement, as well as of protein deposition during growth. Also, a value for the efficiency of utilizing dietary protein for deposition has to be selected, based on published Nitrogen (N) balance studies. In the recent 2007 WHO/FAO/UNU report, the amino acid requirement pattern for infants was taken to be similar to the amino acid composition of breast milk. For pre-school and older children, the factorial method gave values for the scoring pattern of protein that were fairly close to the earlier 1985 WHO/FAO/UNU report for children, since growth progressively became a smaller component of the factorial calculation as age progressed. However, given that there are several assumptions in the derivation of factorial estimates, direct experimental measurements of the amino acid requirement are desirable. The IAAO method, as it is non-invasive, as made it possible to measure the IAA requirements in children. Over the last decade, some of the IAA requirements have been determined by using the IAAO method in healthy school age children; however, the data on IAA requirements in developing country populations are still being conducted. In the elderly, there are not enough data to make a separate recommendation for IAA requirements from that of adults. PMID- 23107548 TI - Protein intakes in India. AB - Indian diets derive almost 60 % of their protein from cereals with relatively low digestibility and quality. There have been several surveys of diets and protein intakes in India by the National Nutrition Monitoring Board (NNMB) over the last 25 years, in urban and rural, as well as in slum dwellers and tribal populations. Data of disadvantaged populations from slums, tribals and sedentary rural Indian populations show that the protein intake (mainly from cereals) is about 1 gm/kg/day. However, the protein intake looks less promising in terms of the protein digestibility corrected amino acid score (PDCAAS), using lysine as the first limiting amino acid, where all populations, particularly rural and tribal, appear to have an inadequate quality to their protein intake. The protein: energy (PE) ratio is a measure of dietary quality, and has been used in the 2007 WHO/FAO/UNU report to define reference requirement values with which the adequacy of diets can be evaluated in terms of a protein quality corrected PE ratio. It is likely that about one third of this sedentary rural population is at risk of not meeting their requirements. These levels of risk of deficiency are in a population with relatively low BMI populations, whose diets are also inadequate in fruits and vegetables. Therefore, while the burden of enhancing the quality of protein intake in rural India exists, the quality of the diet, in general, represents a challenge that must be met. PMID- 23107549 TI - Available lysine and digestible amino acid contents of proteinaceous foods of India. AB - Cereals and legumes are staple foods in India and are limiting in lysine and sulphur amino acids, respectively. Available lysine loss, due to Maillard-type reactions that may occur during food preparation, exacerbates the problem of lysine deficiency particularly in cereals. Consequently, determining the contents of digestible essential amino acids, particularly lysine, is important. True ileal digestibilities of most amino acids (including total and reactive lysine) were determined for ten food ingredients and eleven foods commonly consumed in India. Semi-synthetic diets each containing either an ingredient or the prepared food as the sole protein source were formulated to contain 100 g kg(-1) protein (75 g kg(-1) for rice-based diets) and fed to growing rats. Titanium dioxide was included as an indigestible marker. Digesta were collected and the amino acid content (including reactive lysine) of diets and ileal digesta determined. Available (digestible reactive) lysine content ranged from 1.9-15.4 g kg(-1) and 1.8-12.7 g kg(-1) across the ingredients and prepared foods respectively. True ileal amino acid digestibility varied widely both across ingredients and prepared foods for each amino acid (on average 60-92 %) and across amino acids within each ingredient and prepared food (overall digestibility 31-96 %). Amino acid digestibility was low for many of the ingredients and prepared foods and consequently digestibility must be considered when assessing the protein quality of poorer quality foods. Given commonly encountered daily energy intakes for members of the Indian population, it is estimated that lysine is limiting for adults in many Indian diets. PMID- 23107550 TI - Dietary protein quality and malnutrition in Africa. AB - The WHO (2007) Technical Report on protein and amino acid requirements in human nutrition states that the best estimate for a population average requirement is 105 mg nitrogen/kg body weight per day, or 0.66 g protein/kg body weight per day. In many developing countries protein intake falls significantly short of these values. Apart from protein quantity, protein quality including bioavailability and digestibility, from different food sources, are currently on the global agenda. The 1st International Symposium on Dietary Protein for Human Health held in Auckland, in March 2011, and the consecutive Food and Agricultural Organization of the United Nations (FAO) Expert Consultation on Dietary Protein Quality, both highlighted the importance of assessing the quality of protein from different food sources through determination of amino acid content. Throughout the developed world, animal products and cereals are the two most important sources of protein; in developing countries this order is reversed. In low income countries only 3 % of total dietary energy, as an indicator of diet composition, is derived from meat and offal, 11 % from roots and tubers and 6 % from pulses, nuts and oilseeds. The remainder of the dietary energy is mainly derived from cereal-based staple food. Although the production of livestock has increased in developing countries, the consumption of protein in these countries with people consuming the most limited amounts of protein are continually decreasing. Undernutrition, including insufficient consumption of protein, remains a persistent problem in the developing world, and although many diets within these developing countries are deficient in the quantity of protein compared to recommendations, the quality of the protein also strongly comes into focus. PMID- 23107551 TI - Assessment of protein adequacy in developing countries: quality matters. AB - Dietary protein and amino acid requirement recommendations for normal "healthy" children and adults have varied considerably with 2007 FAO/WHO protein requirement estimates for children lower, but dietary essential AA requirements for adults more than doubled. Requirement estimates as presented do not account for common living conditions, which are prevalent in developing countries such as energy deficit, infection burden and added functional demands for protein and AAs. This study examined the effect of adjusting total dietary protein for quality and digestibility (PDCAAS) and of correcting current protein and AA requirements for the effect of infection and a mild energy deficit to estimate utilizable protein (total protein corrected for biological value and digestibility) and the risk/prevalence of protein inadequacy. The relationship between utilizable protein/prevalence of protein inadequacy and stunting across regions and countries was examined. Data sources (n = 116 countries) included FAO FBS (food supply), UNICEF (stunting prevalence), UNDP (GDP) and UNSTATS (IMR) and USDA nutrient tables. Statistical analyses included Pearson correlations, paired sample/non-parametric t-tests and linear regression. Statistically significant differences were observed in risk/prevalence estimates of protein inadequacy using total protein and the current protein requirements versus utilizable protein and the adjusted protein requirements for all regions (p < 0.05). Total protein, utilizable protein, GDP per capita and total energy were each highly correlated with the prevalence of stunting. Energy, protein and utilizable protein availability were independently and negatively associated with stunting (p < 0.001), explaining 41 %, 34 % and 40 % of variation respectively. Controlling for energy, total protein was not a statistically significant factor but utilizable protein remained significant explaining~45 % of the variance (p = 0.017). Dietary utilizable protein provides a better index of population impact of risk/prevalence of protein inadequacy than crude protein intake. We conclude that the increased demand for protein due to infections and mild to moderate energy deficits, should be appropriately considered in assessing needs of populations where those conditions still prevail. PMID- 23107552 TI - The role of dietary protein in optimizing muscle mass, function and health outcomes in older individuals. AB - The determination of whether increased dietary protein can positively affect health outcomes is hindered by the absence of prospective, randomized trials directly addressing this issue in which all pertinent variables are controlled. Consequently, we can only address the question deductively by considering the support for the rationale underlying the notion of a beneficial effect of increased dietary protein intake. With regard to health outcomes, we have focused on older individuals. Muscle mass and function are progressively lost with aging, so that by the age of 60 many individuals have reached a threshold where function begins to be affected. An association between reduced muscle mass and strength and unfavourable health outcomes is more likely to be revealed in individuals who have significant decrements in muscle mass and strength. In this article support for the rationale underlying the notion of a beneficial effect of increased dietary protein intake is considered. Dietary protein intake, and the resulting increased availability of plasma amino acids, stimulates muscle protein synthesis. If all other variables are controlled, increased muscle protein synthesis leads to improved muscle mass, strength and function over time. Increased muscle mass, strength and function are related to improved health outcomes in older individuals. Since adverse effects of reasonable increases in protein intake above the recommended dietary allowance (RDA) of 0.8 g protein/kg/day have not been reported, it is reasonable to conclude that the optimal protein intake for an older individual is greater than the RDA. PMID- 23107553 TI - New perspectives in the control of body protein metabolism. AB - Recent advances in elucidating the mechanisms that control body protein synthesis and degradation both expand and complicate our understanding of how these processes are regulated. This review presents an introduction to the multiple regulatory systems involved, emphasizing the number of potential controls. These include gene transcription, gene activation or suppression, activation or suppression of mRNA translation and activation or suppression of signaling pathways. The complexity of these interacting controls presents a challenge to our understanding of the overall coordinated regulation of protein synthesis and degradation and its response to any particular stimulus. Specific examples are used to illustrate regulatory mechanisms, including the ways in which protein metabolism is regulated by the amino acid leucine. In addition to regulation associated with gene expression and post-translational control, the expanding field of epigenetics adds another layer of complexity, including trans generational responses to nutrient intake, highlighting the potential for long term impact of nutritional experience on the metabolism of subsequent generations. PMID- 23107554 TI - Retrospective evaluation of the diagnostic accuracy of Parkinsonism in a UK community based movement disorders clinic. PMID- 23107555 TI - Fatigue in Parkinson's disease: motor or non-motor symptom? AB - Fatigue is one of the most disabling symptoms in patients with Parkinson's disease (PD), with a significant impact on patients' quality of life. Clinical studies using ad hoc questionnaires showed that in PD fatigue is associated with non-motor as well motor symptoms. Neurophysiological observations suggest that motor mechanisms play a role in the pathophysiology of fatigue but there is no clear correlation between fatigue measured with clinical instruments and fatigue assessed with neurophysiological tests. Neuroimaging studies show that fatigue is associated with an involvement of non-dopaminergic or extrastriatal dopaminergic pathways. It is conceivable that both motor and non-motor mechanisms underlie the pathophysiology of fatigue. PMID- 23107556 TI - TOR1A sequence variants and the association with early-onset primary dystonia in the Chinese Han population. PMID- 23107557 TI - Abnormal occipital event-related potentials in Parkinson's disease with concomitant REM sleep behavior disorder. AB - BACKGROUND: Rapid eye movement sleep behavior disorder is found in 33-46% of patients with Parkinson's disease and was shown to be associated with cognitive deficits. Our goal was to improve our understanding of the role of this sleep disorder in cerebral dysfunction occurring in Parkinson's disease using a visual cognitive task and event-related potentials. METHODS: Sixteen patients with Parkinson's disease and rapid eye movement sleep behavior disorder, 15 patients with Parkinson's disease without rapid eye movement sleep behavior disorder and 16 healthy control subjects were included. The amplitude and latency of event related potentials were compared between groups. RESULTS: No group differences were found for reaction times or accuracy. A Group effect was found for P2 wave amplitude; patients with rapid eye movement sleep behavior disorder had increased P2 in comparison with the control group (p < 0.05). Patients with Parkinson's disease alone were not different from the two other groups for this component. Prolonged novelty P3 latencies on Cz were associated with longer disease durations among patients with Parkinson's disease (p < 0.01). CONCLUSION: Co morbid Parkinson's disease and rapid eye movement sleep behavior disorder were associated with abnormal visual P2 component of event-related potentials. Although patients with Parkinson's disease alone were not significantly different from patients with combined Parkinson's disease and rapid eye movement sleep behavior disorder, their P2 amplitudes were not sufficiently abnormal to differ from that of control subjects. This study confirms that rapid eye movement sleep behavior disorder accentuates cerebral dysfunctions in Parkinson's disease. PMID- 23107558 TI - A metabolic signature predicts biological age in mice. AB - Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8 to 129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice. In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that overexpress telomerase, their metabolic score corresponded to younger ages than expected. Importantly, telomerase reactivation late in life by using a TERT-based gene therapy recently described by us significantly reverted the metabolic profile of old mice to that of younger mice, further confirming an anti-aging role for telomerase. Thus, the metabolomic signature associated with natural mouse aging accurately predicts aging produced by telomere shortening, suggesting that natural mouse aging is in part produced by presence of short telomeres. These results indicate that the metabolomic signature is associated with the biological age rather than with the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism. PMID- 23107559 TI - Understanding the role of scientific evidence in consumer evaluation of natural health products for osteoarthritis an application of the means end chain approach. AB - BACKGROUND: Over 30% of individuals use natural health products (NHPs) for osteoarthritis-related pain. The Deficit Model for the Public Understanding of Science suggests that if individuals are given more information (especially about scientific evidence) they will make better health-related decisions. In contrast, the Contextual Model argues that scientific evidence is one of many factors that explain how consumers make health-related decisions. The primary objective was to investigate how the level of scientific evidence supporting the efficacy of NHPs impacts consumer decision-making in the self-selection of NHPs by individuals with osteoarthritis. METHODS: The means-end chain approach to product evaluation was used to compare laddering interviews with two groups of community-dwelling Canadian seniors who had used NHPs to treat their osteoarthritis. Group 1 (n=13) had used only NHPs (glucosamine and/or chondroitin) with "high" scientific evidence of efficacy. Group 2 (n=12) had used NHPs (methylsulfonylmethane (MSM) and/or bromelain) with little or no scientific evidence supporting efficacy. Content analysis and generation of hierarchical value maps facilitated the identification of similarities and differences between the two groups. RESULTS: The dominant decision-making chains for participants in the two scientific evidence categories were similar. Scientific evidence was an important decision making factor but not as important as the advice from health care providers, friends and family. Most participants learned about scientific evidence via indirect sources from health care providers and the media. CONCLUSIONS: The Contextual Model of the public understanding of science helps to explain why our participants believed scientific evidence is not the most important factor in their decision to use NHPs to help manage their osteoarthritis. PMID- 23107560 TI - GMP-compliant isolation and expansion of bone marrow-derived MSCs in the closed, automated device quantum cell expansion system. AB - The estimated frequency of MSCs in BM is about 0.001-0.01% of total nucleated cells. Most commonly, one applied therapeutic cell dose is about 1-5 million MSCs/kg body weight, necessitating a reliable, fast, and safe expansion system. The limited availability of MSCs demands for an extensive ex vivo amplification step to accumulate sufficient cell numbers. Human platelet lysate (PL) has proven to be a safe and feasible alternative to animal-derived serum as supplement for MSC cultivation. We have investigated the functionally closed automated cell culture hollow fiber bioreactor Quantum cell expansion system as an alternative novel tool to conventional tissue flasks for efficient clinical-scale MSC isolation and expansion from bone marrow using PL. Cells expanded in the Quantum system fulfilled MSC criteria as shown by flow cytometry and adipogenic, chondrogenic, and osteogenic differentiation capacity. Cell surface expression of a variety of chemokine receptors, adhesion molecules, and additional MSC markers was monitored for several passages by flow cytometry. The levels of critical media components like glucose and lactate were analyzed. PDGF-AA, PDGF-AB/BB, bFGF, TGF-beta1, sICAM-1, sVCAM-1, RANTES, GRO, VEGF, sCD40L, and IL-6 were assessed using a LUMINEX platform. Originally optimized for the use of fetal calf serum (FCS) as supplement and fibronectin as coating reagent, we succeeded to obtain an average of more than 100*10(6) of MSCs from as little as 18.8-28.6 ml of BM aspirate using PL. We obtained similar yields of MSCs/ul BM in the FCS containing and the xenogen-free expansion system. The Quantum system reliably produces a cellular therapeutic dose in a functionally closed system that requires minimal manipulation. Both isolation and expansion are possible using FCS or PL as supplement. Coating of the hollow fibers of the bioreactor is mandatory when loading MSCs. Fibronectin, PL, and human plasma may serve as coating reagents. PMID- 23107561 TI - A multidisciplinary clinical treatment of locally advanced rectal cancer complicated with rectovesical fistula: a case report. AB - INTRODUCTION: Rectal cancer with rectovesical fistula is a rare and difficult to treat entity. Here, we describe a case of rectal cancer with rectovesical fistula successfully managed by multimodality treatment. To the best of our knowledge, this is the first such case report in the literature. CASE PRESENTATION: A 51 year-old Chinese man was diagnosed as having rectal cancer accompanied by rectovesical fistula. He underwent treatment with neoadjuvant radiochemotherapy combined with total pelvic excision and adjuvant chemotherapy, as recommended by a multimodality treatment team. Post-operative pathology confirmed the achievement of pathological complete response. CONCLUSIONS: This case suggests that a proactive multidisciplinary treatment is needed to achieve complete cure of locally advanced rectal cancer even in the presence of rectovesical fistula. PMID- 23107562 TI - Mass murder: causes, classification, and prevention. AB - This article discusses common psychological and social factors in mass murders and outlines a proposed classification system to coordinate future research efforts. The final communications of two mass murderers are analyzed to demonstrate that the forensic psycholinguistic approach may assist in providing an enhanced understanding of the motives, psychopathology, and classification of mass murderers whose offenses can seem similar from a purely behavioral perspective. PMID- 23107563 TI - Child murder by parents and evolutionary psychology. AB - This article explores the contribution of evolutionary theory to the understanding of causation and motive in filicide cases and also reviews special issues in the forensic evaluation of alleged perpetrators of filicide. Evolutionary social psychology seeks to understand the context in which our brains evolved, to understand human behaviors. The authors propose evolutionary theory as a framework theory to meaningfully appreciate research about filicide. Using evolutionary psychology as a theoretical lens, this article reviews the research on filicide over the past 40 years, and describes epidemiologic and typologic studies of filicide, and theoretical analyses from a range of disciplines. PMID- 23107564 TI - Evaluating amnesia for criminal behavior: a guide to remember. AB - This article provides a guide that is important to remember in evaluating a criminal defendant's amnesia claim. Important concepts to understand regarding memory formation, memory systems, proposed causes of amnesia, reasons why amnesia claims may be true or false, and important strategies to implement as part of the evaluation process are reviewed. Structured assessment approaches are critical components of amnesia evaluations and generally require detailed questioning, review of collateral records, medical and neurologic workups, psychological testing, neuropsychological testing, and specific malingering assessments. PMID- 23107565 TI - Child pornography and the internet. AB - The dramatic increase in child pornography offenses over the past 10 years is directly related to the availability of such material on the Internet. Child pornography can be found on the Web, in newsgroups, and on peer-to-peer networks (the most common source at present). Offenders are a heterogeneous group, with different motivations and levels of risk. The possibility of crossover to a contact sexual offense exists, depending on the presence of other risk factors. Possession of child pornography without a history of contact offenses does not appear to increase the risk of future contact reoffending. PMID- 23107566 TI - Juvenile offenders: competence to stand trial. AB - This article details the legal background and assists the reader in the preparation and practical conduct of evaluations regarding juvenile adjudicative competency. The material is presented to be useful as a guide to direct questions of competency and covers aspects of evaluation that include: legal standard for competency to stand trial, developmental immaturity, current practice in juvenile competency to stand trial, forensic evaluation of juvenile competency to stand trial, organizing the evaluation, collateral sources of information, psychiatric evaluation of juvenile adjudicative competency, assessment of mental disorder and intellectual disability, assessment of developmental status, assessment of functional abilities for adjudicative competence, and reaching the forensic opinion. PMID- 23107567 TI - Psychological testing and the assessment of malingering. AB - This article discusses the prevalence of feigning in both criminal and civil settings and various psychological assessments useful in detecting feigning. The focus of this information is on the various psychological assessments available to assist clinicians in making a determination of whether or not an individual is feigning and concludes with the recommendations that multiple assessments are necessary to improve the sensitivity of detection methods. PMID- 23107568 TI - Forensic aspects and assessment of school bullying. AB - This article describes school's obligations related to bullying behavior, the assessment of bullying students and their victims, the evaluation of claimed damages due to bullying, and potential interventions for both individuals and school systems to reduce the frequency of bullying behavior. This article assists evaluators when assessing youth who are involved in bullying behavior, either as victims or perpetrators. Key areas highlighted include an overview of bullying behaviors, legal issues related to a school's responsibility in preventing or curtailing bullying behaviors, important components of a bullying assessment, and proposed interventions to minimize bullying. PMID- 23107569 TI - Psychiatric consultation in problem employee situations. AB - This article focuses on psychiatric consultation in "problem employee situations," a broad term that refers to any situation in which there is conflict between an employee and the employer or coworkers. It summarizes key principles and observations that are common to psychiatric consultations in the workplace and then offers case examples that are representative of such consultations and highlights those principles. Although the focus is on psychiatric consultation to employers, an employee may seek consultation himself or herself, especially when prospects for adversarial proceedings arise. The principles described here apply in both sets of circumstances. PMID- 23107570 TI - Testamentary capacity and guardianship assessments. AB - This article discusses the ever-increasing opportunity for forensic mental health evaluators to provide assistance to the legal system in the areas of testamentary capacity and guardianship assessments. These areas of evaluation are defined, and a discussion of preparation and execution of effective evaluations is provided. The legal concepts of undue influence and insane delusion are defined and applied to the evaluator's interview. Common cognitive concerns such as dementia and delirium may affect an evaluee's capacity, and their presence and effect on the evaluee are considered. Evaluators are encouraged to carefully consider specific capacities related to the relevant legal questions posed. PMID- 23107571 TI - Forensic mental health professionals in the immigration process. AB - This article adds to the existing literature on the role of mental health professionals in assisting attorneys in the asylum and refugee determination process primarily in the United States. The authors describe the legal context for asylum and refugee processing, challenges in conducting evaluations, diagnostic considerations, and specific competencies needed for mental health evaluators. Various cases are presented to illustrate key points. These cases purposely do not include any identifying information of any specific client, yet they are representative of the range and scope of issues that arise in this context. PMID- 23107572 TI - Deposition dos and don'ts: strategies for the expert witness. AB - The deposition is an important stage in the legal process, which poses special challenges for the deponent. This article reviews those challenges from the standpoint of the expert witness, addressing the stages of the deposition, the deposing attorney's strategies, the role and goals of the expert witness serving as the deponent, the approach to answering the attorney's questions, strategies for clarifying or reframing those questions, and the approaches to reviewing the deposition after the transcript has been printed. The article emphasizes tricks and traps used by the deposing attorney and how to avoid them. PMID- 23107573 TI - Psychopharmacologic management of aggression. AB - This article is designed to provide an overview of the existing literature on pharmacologically managing aggression, with a specific focus on psychiatric diagnoses commonly associated with increased aggression. Self-injurious behaviors and suicide are sometimes classified as forms of aggression, but information presented here focuses primarily on aggression toward others (physical and/or verbal). PMID- 23107574 TI - Mental health and legal systems inextricably intertwined. PMID- 23107576 TI - Mini-Med School: promoting awareness of medicine as a career for suburban and rural high-school students. AB - BACKGROUND: There is a global shortage of medical manpower. One approach to resolve such deficiencies is to effectively promote health careers to high-school students. Summer programmes held by medical faculties provide ideal opportunities for pre-medical students to examine the possible career opportunities in medicine. METHODS: The Royal College of Surgeons in Ireland has recently launched a 'Mini-Medical School' (MMS) programme for suburban and rural high-school students in the South Eastern Region of Ireland. This paper illustrates the MMS project and describes the participants' reaction and evaluation of the programme and the factors influencing their desire to practise medicine in future. RESULTS: A total of 90 students completed the online survey (response rate 75%). Eighty two per cent of the students indicated definitive and strong desire to study medicine after secondary school. There was no difference in interest between male and female students (P-value 0.665). The main factors influencing this interest were personal. Forty-four per cent of participants attributed this to the opportunity to help others while 30% to the intellectual challenge, whereas family, friends and other factors accounted for the rest of influential factors to study medicine. The majority agreed (60%) that the programme was quite accessible and easy to have a place. Opinions about the content of the programme focussed mainly on the interactive sessions. Forty-seven per cent liked the live patient-doctor interaction session the most, and 43% found the live video session very informative. CONCLUSION: The MMS is a highly effective platform for both the medical specialties and the high-school students. PMID- 23107575 TI - Effective classification of the prevalence of Schistosoma mansoni. AB - OBJECTIVE: To present an effective classification method based on the prevalence of Schistosoma mansoni in the community. METHODS: We created decision rules (defined by cut-offs for number of positive slides), which account for imperfect sensitivity, both with a simple adjustment of fixed sensitivity and with a more complex adjustment of changing sensitivity with prevalence. To reduce screening costs while maintaining accuracy, we propose a pooled classification method. To estimate sensitivity, we use the De Vlas model for worm and egg distributions. We compare the proposed method with the standard method to investigate differences in efficiency, measured by number of slides read, and accuracy, measured by probability of correct classification. RESULTS: Modelling varying sensitivity lowers the lower cut-off more significantly than the upper cut-off, correctly classifying regions as moderate rather than lower, thus receiving life-saving treatment. The classification method goes directly to classification on the basis of positive pools, avoiding having to know sensitivity to estimate prevalence. For model parameter values describing worm and egg distributions among children, the pooled method with 25 slides achieves an expected 89.9% probability of correct classification, whereas the standard method with 50 slides achieves 88.7%. CONCLUSIONS: Among children, it is more efficient and more accurate to use the pooled method for classification of S. mansoni prevalence than the current standard method. PMID- 23107577 TI - International Early Psychosis Association. PMID- 23107578 TI - Prevalence, treatment, and outcomes of coexistent ocular surface squamous neoplasia and pterygium. AB - PURPOSE: The purpose of this study was to determine the prevalence of ocular surface squamous neoplasia (OSSN) coexisting with pterygia in South Florida and to study the treatment and related outcomes. DESIGN: Noninterventional retrospective study. PARTICIPANTS: A total of 2005 patients with surgically excised pterygia at the Bascom Palmer Eye Institute from 2000 to 2010. METHODS: Pathology reports of patients with pterygia were reviewed for evidence of OSSN. Patients were divided into the following groups: pterygium and no OSSN (group 1), clinically suspected OSSN with pterygium (group 2), and unexpected OSSN with pterygium found on histopathology (group 3). Clinical charts of patients in groups 2 and 3 were reviewed. MAIN OUTCOME MEASURES: Period prevalence, treatment, and outcome. RESULTS: In surgically excised pterygia, the prevalence of coexistent OSSN was 1.7% (n = 34), of which 41% (n = 14) were clinically suspected preoperatively (group 2) and 59% (n = 20) were unexpectedly found on histopathology (group 3). Clinically suspected OSSN with pterygia was generally treated with wide surgical margins and cryotherapy, whereas unexpected OSSN with pterygia was treated with simple excision, followed by adjuvant interferon treatment in 30% (n = 6). After a mean follow-up of 2 years, there were no recurrences in the suspected OSSN group and 2 recurrences in the unexpected OSSN group. The recurrence rate in the latter group was 11% at 1 year and 24% at 2 years. CONCLUSIONS: Ocular surface squamous neoplasia is uncommonly found to coexist with pterygium. The prognosis in suspected OSSN cases is excellent, with no recurrences noted despite positive margins in 50% of cases. The recurrence rates of unexpected OSSN mirrors that of OSSN not associated with pterygium, and thus vigilance for recurrence is important. PMID- 23107579 TI - Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation. AB - PURPOSE: To determine the types and frequency of ocular conditions that simulate retinoblastoma (pseudoretinoblastoma) based on age at presentation. DESIGN: Retrospective case series. PARTICIPANTS: Two thousand seven hundred seventy-five patients. METHODS: Chart review. MAIN OUTCOME MEASURES: Conditions simulating retinoblastoma. RESULTS: Of 2775 patients referred for management of retinoblastoma, 2171 patients (78%) had confirmed retinoblastoma and 604 patients (22%) had simulating lesions (pseudoretinoblastomas). In the pseudoretinoblastoma cohort, the mean patient age at presentation was 4 years (median, 2 years). There were 27 different pseudoretinoblastoma conditions, and the 10 most common included Coats' disease (n = 244; 40%), persistent fetal vasculature (PFV; n = 158; 28%), vitreous hemorrhage (n = 27; 5%), ocular toxocariasis (n = 22; 4%), familial exudative vitreoretinopathy (FEVR; n = 18; 3%), rhegmatogenous retinal detachment (n = 18; 3%), coloboma (n = 17; 3%), astrocytic hamartoma (n = 15; 2%), combined hamartoma of retina and retinal pigment epithelium (n = 15; 2%), and endogenous endophthalmitis (n = 10; 2%). Simulating lesions differed based on age at presentation, and children younger than 1 year were most likely to have PFV (49%), Coats' disease (20%), or vitreous hemorrhage (7%); those 2 to 5 years of age were most likely to have Coats' disease (61%), toxocariasis (8%), or PFV (7%); and those older than 5 years were most likely to have Coats' disease (57%), toxocariasis (8%), or FEVR (6%). CONCLUSIONS: The most common pseudoretinoblastomas include Coats' disease, PFV, and vitreous hemorrhage, but the spectrum varies depending on patient age. PMID- 23107580 TI - Implementation of a free cataract surgery program in rural China: a community based randomized interventional study. AB - PURPOSE: To identify effective methods to increase the number of cataract surgeries in a rural setting in Pucheng County of Shaanxi Province, northwestern China. DESIGN: Community-based randomized interventional study. PARTICIPANTS: Four hundred thirty-two patients 50 years of age or older with operable cataract who had not undergone surgery 3 months after participation in a cataract outreach screening program. METHODS: Three hundred fifty-five (82.2%) patients eligible for surgery, but not scheduling it on their own, were contacted and were assigned randomly into 4 groups. Participants in group 1 (n = 86) were given informative reminders by telephone or in person by a trained facilitator about undergoing low cost cataract surgery. Group 2 (n = 86) was offered free cataract surgery. Group 3 (n = 90) was offered free surgery and reimbursement of transportation expenses. Group 4 (n = 93) was provided with free rides from home to hospital in addition to the reminder and free surgery. MAIN OUTCOME MEASURES: Number of participants undergoing cataract surgery after interventions. RESULTS: In total, 94 patients (26.5%) underwent cataract surgery after interventions. In group 1, 13 patients (14.4%) underwent surgery, which was significantly lower than the number in group 2 (n = 25 [27.8%]; P = 0.027), group 3 (n = 28 [31.1%]; P = 0.012), and group 4 (n = 26 [28%]; P = 0.038). There were no significant differences between groups 2 and 3 (P = 0.768) or between groups 2 and 4 (P = 0.869). CONCLUSIONS: Provision of free cataract surgery was twice as effective as giving patients an informative reminder when it came to increasing the uptake of cataract surgery. However, offering reimbursement of transportation expenses or provision of free rides had minimal added impact on the response rate of participants to undergo cataract surgery. PMID- 23107581 TI - Descemet's stripping automated endothelial keratoplasty: three-year graft and endothelial cell survival compared with penetrating keratoplasty. AB - PURPOSE: To assess 3-year outcomes of Descemet's stripping automated endothelial keratoplasty (DSAEK) in comparison with penetrating keratoplasty (PKP) from the Cornea Donor Study (CDS). DESIGN: Prospective, multicenter, nonrandomized clinical trial. PARTICIPANTS: A total of 173 subjects undergoing DSAEK for a moderate risk condition (principally Fuchs' dystrophy or pseudophakic corneal edema) compared with 1101 subjects undergoing PKP from the CDS. METHODS: The DSAEK procedures were performed by 2 experienced surgeons using the same donor and similar recipient criteria as for the CDS PKP procedures, performed by 68 surgeons. Graft success was assessed by Kaplan-Meier survival analysis. Central endothelial cell density (ECD) was determined from baseline donor and postoperative central endothelial images by the reading center used in the CDS Specular Microscopy Ancillary Study. MAIN OUTCOME MEASURES: Graft clarity and ECD. RESULTS: The donor and recipient demographics were comparable in the DSAEK and PKP groups, except that the proportion of Fuchs' dystrophy cases was higher in the DSAEK cohort. The 3-year survival rate did not differ significantly between DSAEK and PKP procedures performed for either Fuchs' dystrophy (96% for both; P = 0.81) or non-Fuchs' cases (86% vs. 84%, respectively; P = 0.41). Principal causes of graft failure or regraft within 3 years after DSAEK and PKP were immunologic graft rejection (0.6% vs. 3.1%), endothelial decompensation in the absence of documented rejection (1.7% vs 2.1%), unsatisfactory visual or refractive outcome (1.7% vs. 0.5%), and infection (0% vs. 1.1%), respectively. The 3-year predicted probability of a rejection episode was 9% with DSAEK versus 20% with PKP (P = 0.0005). The median 3-year cell loss for DSAEK and PKP was 46% and 51%, respectively (P = 0.33), in Fuchs' dystrophy cases and 59% and 61%, respectively (P = 0.70), in the non-Fuchs' cases. At 3 years, use of a smaller DSAEK insertion incision was associated with significantly higher cell loss (60% vs. 33% for 3.2- and 5.0-mm incisions, respectively; P = 0.0007), but not with a significant difference in graft survival (P = 0.45). CONCLUSIONS: The graft success rate and endothelial cell loss were comparable at 3 years for DSAEK and PKP procedures. A 5-mm DSAEK incision width was associated with significantly less cell loss than a 3.2-mm incision. PMID- 23107582 TI - Optimization of intraocular lens constant improves refractive outcomes in combined endothelial keratoplasty and cataract surgery. AB - PURPOSE: To evaluate the accuracy of intraocular lens (IOL) power calculations with A-constant optimization in Descemet's stripping automated endothelial keratoplasty (DSAEK) combined with cataract extraction and intraocular lens implantation (DSAEK triple procedure). DESIGN: Retrospective case series. PARTICIPANTS: Thirty eyes of 22 patients with Fuchs' endothelial dystrophy who underwent the DSAEK triple procedure performed by a single surgeon. METHODS: Prediction errors were calculated retrospectively for consecutive DSAEK triple procedures. These prediction errors then were used to determine an IOL constant for this cohort of patients. The new optimized IOL constant subsequently was compared with the manufacturer's IOL constant, allowing evaluation and quantification of refractive benefits of optimization. MAIN OUTCOMES MEASURES: The error in diopters (D) of the predicted refraction with the manufacturer's and optimized IOL constants. RESULTS: Optimization of the A constant decreased the mean absolute error (MAE) from 1.09 +/- 0.63 D (range, 0.12-2.41 D) to 0.61 +/- 0.4 D (range, 0-1.58 D; P = 0.004). Comparing the intended and final postoperative refractions calculated with the original manufacturer's constant and the optimized constant, 20% versus 43% of all eyes were in the less than 0.5 D range and 50% versus 83% of all eyes were in the less than 1.0-D range of the target refraction. Furthermore, optimization decreased the number of eyes that were more than 1.0 D from the target refraction from 50% to 17%. CONCLUSIONS: Optimization of the IOL constant showed significantly improved accuracy of predicted postoperative refraction compared with the manufacturer's IOL constant, which may help improve the postoperative refractive outcomes in patients undergoing the DSAEK triple procedure. PMID- 23107583 TI - Internal cantholysis for repair of moderate and large full-thickness eyelid defects. AB - PURPOSE: To determine the safety and efficacy of internal cantholysis for closure of larger full-thickness eyelid defects. DESIGN: Retrospective review of a consecutive case series. PARTICIPANTS: Eighteen patients (18 eyelids) underwent internal cantholysis for repair of a moderate or large full-thickness eyelid defect during the study period. METHODS: Retrospective review of a consecutive case series of all patients undergoing transconjunctival lateral cantholysis for repair of moderate and large full-thickness eyelid defects between October 2008 and November 2010. Moderate was defined as >= 14 mm in horizontal length, and large was defined as >= 20 mm in horizontal length. MAIN OUTCOME MEASURES: Charts were reviewed for patient demographics; indication for surgery; defect size, type, and location; other concomitant repair; follow-up interval; and complications. RESULTS: Eighteen patients (18 eyelids) underwent internal cantholysis for repair of a moderate or large full-thickness eyelid defect during the study period. Average patient age was 73 years (range, 45-94 years), and there were 10 male and 8 female patients. Average defect size was 19.0 mm (range, 14-25 mm). Average follow-up interval was 4.6 months (range, 1-12 months). Complications included eyelid margin notch (3 cases), persistent canthal dystopia (3 cases), trichiasis (2 cases), pyogenic granuloma (2 cases), eyelid margin nodule (1 case), lower eyelid elevation of 1 mm (1 case), and mild resolving medial lagophthalmos (1 case). No patient requested or required further surgery on the operated eyelid for any reason during the study period. CONCLUSIONS: Internal cantholysis allows for closure of moderate and large full-thickness eyelid defects. Complications are acceptable in light of the morbidity of other therapeutic options, such as semicircular flap or shared eyelid flap procedures. PMID- 23107585 TI - Comparison of four teaching methods on Evidence-based Practice skills of postgraduate nursing students. AB - The aim of this study was to compare four teaching methods on the evidence-based practice knowledge and skills of postgraduate nursing students. Students enrolled in the Evidence-based Nursing (EBN) unit in Australia and Hong Kong in 2010 and 2011 received education via either the standard distance teaching method, computer laboratory teaching method, Evidence-based Practice-Digital Video Disc (EBP-DVD) teaching method or the didactic classroom teaching method. Evidence based Practice (EBP) knowledge and skills were evaluated using student assignments that comprised validated instruments. One-way analysis of covariance was implemented to assess group differences on outcomes after controlling for the effects of age and grade point average (GPA). Data were obtained from 187 students. The crude mean score among students receiving the standard+DVD method of instruction was higher for developing a precise clinical question (8.1+/-0.8) and identifying the level of evidence (4.6+/-0.7) compared to those receiving other teaching methods. These differences were statistically significant after controlling for age and grade point average. Significant improvement in cognitive and technical EBP skills can be achieved for postgraduate nursing students by integrating a DVD as part of the EBP teaching resources. The EBP-DVD is an easy teaching method to improve student learning outcomes and ensure that external students receive equivalent and quality learning experiences. PMID- 23107584 TI - Identifying breast cancer risk loci by global differential allele-specific expression (DASE) analysis in mammary epithelial transcriptome. AB - BACKGROUND: The significant mortality associated with breast cancer (BCa) suggests a need to improve current research strategies to identify new genes that predispose women to breast cancer. Differential allele-specific expression (DASE) has been shown to contribute to phenotypic variables in humans and recently to the pathogenesis of cancer. We previously reported that nonsense-mediated mRNA decay (NMD) could lead to DASE of BRCA1/2, which is associated with elevated susceptibility to breast cancer. In addition to truncation mutations, multiple genetic and epigenetic factors can contribute to DASE, and we propose that DASE is a functional index for cis-acting regulatory variants and pathogenic mutations, and that global analysis of DASE in breast cancer precursor tissues can be used to identify novel causative alleles for breast cancer susceptibility. RESULTS: To test our hypothesis, we employed the Illumina((r)) Omni1-Quad BeadChip in paired genomic DNA (gDNA) and double-stranded cDNA (ds-cDNA) samples prepared from eight BCa patient-derived normal mammary epithelial lines (HMEC). We filtered original array data according to heterozygous genotype calls and calculated DASE values using the Log ratio of cDNA allele intensity, which was normalized to the corresponding gDNA. We developed two statistical methods, SNP- and gene-based approaches, which allowed us to identify a list of 60 candidate DASE loci (DASE >= 2.00, P <= 0.01, FDR <= 0.05) by both methods. Ingenuity Pathway Analysis of DASE loci revealed one major breast cancer-relevant interaction network, which includes two known cancer causative genes, ZNF331 (DASE = 2.31, P = 0.0018, FDR = 0.040) and USP6 (DASE = 4.80, P = 0.0013, FDR = 0.013), and a breast cancer causative gene, DMBT1 (DASE=2.03, P = 0.0017, FDR = 0.014). Sequence analysis of a 5' RACE product of DMBT1 demonstrated that rs2981745, a putative breast cancer risk locus, appears to be one of the causal variants leading to DASE in DMBT1. CONCLUSIONS: Our study demonstrated for the first time that global DASE analysis is a powerful new approach to identify breast cancer risk allele(s). PMID- 23107586 TI - CC genotype donors for the interleukin-28B single nucleotide polymorphism are associated with better outcomes in hepatitis C after liver transplant. AB - BACKGROUND/AIMS: Interleukin-28B (IL-28B) polymorphism is the strongest pretreatment predictor of viral clearance in the hepatitis C (HCV) population. Donor and recipient IL-28B genomic background may play an important role in post transplant HCV recurrence. We sought to examine the role of IL-28B polymorphisms of donor and recipients in liver transplant patients with recurrent HCV and its impact on the response to interferon-based therapy. METHODS: The cohort study consisted of 135 adult liver transplant patients who received interferon-based therapy for recurrent HCV between 1996 and 2005 at the University of Florida. IL 28B single nucleotide polymorphism (rs. 12979860) was characterized using liver tissue from all donors and recipients. RESULTS: The CC genotype was observed in approximately 30% of donors and recipients. Sustained viral response (SVR) to HCV therapy was 100% if both recipient and donor were CC genotype, while the SVR was only 25% if neither donor nor recipient had a CC genotype. (Recipient, P = 0.025, Donor, P < 0.001). Recipients and donors with CC genotype had less fibrosis than recipients with genotypes CT and TT, but the difference was not statistically significant. IL-28B genotype did not seem to play a role in the overall survival in these patients. CONCLUSION: In conclusion, recipient and donor CC genotype is associated with a better treatment response to interferon-based therapy after liver transplant. Our study suggests that using CC genotype donor livers for HCV patients may improve the overall clinical outcome after liver transplantation. PMID- 23107587 TI - Chromatin roadblocks to reprogramming 50 years on. AB - A half century after John Gurdon demonstrated nuclear reprogramming, for which he was awarded the 2012 Nobel Prize in Physiology or Medicine, his group provides insights into the molecular mechanisms whereby chromatin remodeling is required for nuclear reprogramming. Among the issues addressed in Gurdon's latest work are the chromatin impediments to artificially induced reprogramming, discovered by Shinya Yamanaka, who shared the award with Gurdon. PMID- 23107588 TI - Student tutors for hands-on training in focused emergency echocardiography--a randomized controlled trial. AB - BACKGROUND: Focused emergency echocardiography performed by non-cardiologists has been shown to be feasible and effective in emergency situations. During resuscitation a short focused emergency echocardiography has been shown to narrow down potential differential diagnoses and to improve patient survival. Quite a large proportion of physicians are eligible to learn focused emergency echocardiography. Training in focused emergency echocardiography usually comprises a lecture, hands-on trainings in very small groups, and a practice phase. There is a shortage of experienced echocardiographers who can supervise the second step, the hands-on training. We thus investigated whether student tutors can perform the hands-on training for focused emergency echocardiography. METHODS: A total of 30 volunteer 4th and 5th year students were randomly assigned to a twelve-hour basic echocardiography course comprising a lecture followed by a hands-on training in small groups taught either by an expert cardiographer (EC) or by a student tutor (ST). Using a pre-post-design, the students were evaluated by an OSCE. The students had to generate two still frames with the apical five chamber view and the parasternal long axis in five minutes and to correctly mark twelve anatomical cardiac structures. Two blinded expert cardiographers rated the students' performance using a standardized checklist. Students could achieve a maximum of 25 points. RESULTS: Both groups showed significant improvement after the training (p < .0001). In the group taught by EC the average increased from 2.3+/-3.4 to 17.1+/-3.0 points, and in the group taught by ST from 2.7+/-3.0 to 13.9+/-2.7 points. The difference in improvement between the groups was also significant (p = .03). CONCLUSIONS: Hands-on training by student tutors led to a significant gain in echocardiography skills, although inferior to teaching by an expert cardiographer. PMID- 23107589 TI - Inhibition of the IL-6 signaling pathway: a strategy to combat chronic inflammatory diseases and cancer. AB - Interleukin (IL)-6 is a pro-inflammatory cytokine that produces multifunctional effects. Deregulated IL-6 production and signaling are associated with chronic inflammatory diseases, auto-immunity and cancer. On this basis, inhibition of IL 6 production, its receptors or the signaling pathways are strategies currently being widely pursued to develop novel therapies for a wide range of diseases. This survey aims to provide an updated account of why IL-6 inhibitors are shaping up to become an important class of drugs potentially useful in the treatment of ailments and in particular in inflammation and cancer. In addition we discuss the role of different agents in modulating IL-6 and also recent clinical studies targeting IL-6 in inflammation-mediated diseases and cancer. PMID- 23107590 TI - Long-term results of 2 adjuvant trials reveal differences in chemosensitivity and the pattern of metastases between colon cancer and rectal cancer. AB - Two identical randomized controlled trials designed to optimize adjuvant treatment of colon cancer (CC) (n =855) and rectal cancer (RC) (n = 796) were performed. Long-term evaluation confirmed that the addition of folinic acid (FA) to 5-fluorouracil (5-FU) improved 7-year overall survival (OS) in CC but not in RC and revealed different patterns of recurrence in patients with CC and those with RC. BACKGROUND: Our aim was to compare long-term results of adjuvant treatment of colon cancer (CC) and rectal cancer (RC). Adjuvant chemotherapy of CC improved overall survival (OS), whereas that of RC remained at the level achieved by 5-fluorouracil (5-FU). METHODS: We separately conducted 2 identically designed adjuvant trials in CC and RC. Patients were assigned to adjuvant chemotherapy with 5-FU alone, 5-FU + folinic acid (FA), or 5-FU + interferon alfa. The first study enrolled patients with stage IIb/III CC, and the second study enrolled patients with stage II/III RC. All patients with RC received postoperative irradiation. RESULTS: Median follow-up for all patients with CC (n = 855) and RC (n = 796) was 4.9 years. The pattern and frequency of recurrence differed significantly, especially lung metastases, which occurred more frequently in RC (12.7%) than in CC (7.3%; P < .001). Seven-year OS rates for 5 FU, 5-FU + FA, and 5-FU + IFN-alfa were 54.1% (95% confidence interval [CI], 46.5 61.0), 66.8% (95% CI, 59.4-73.1), and 56.7% (95% CI, 49.3-63.4) in CC and 50.6% (95% CI, 43.0-57.7), 56.3% (95% CI, 49.4-62.7), and 54.8% (95% CI, 46.7-62.2) in RC, respectively. A subgroup analysis pointed to a reduced local recurrence (LR) rate and an increased OS by the addition of FA in stage II RC (n = 271) but not in stage III RC (n = 525). CONCLUSION: FA increased 7-year OS by 12.7 percentage points in CC but was not effective in RC. Based on these results and the pattern of metastases, our results suggest that the chemosensitivity of CC and RC may be different. Strategies different from those used in CC may be successful to decrease the frequency of distant metastases in RC in the future. PMID- 23107591 TI - Randomized comparative study of the serum antihemagglutinin and antineuraminidase antibody responses to six licensed trivalent influenza vaccines. AB - BACKGROUND: Serum antibody to the hemagglutinin (HA) surface protein of influenza virus induced by influenza vaccination is a correlate of protection against influenza. The neuraminidase (NA) protein is also on the surface of the virus; antibody to it has been shown to impair virus release from infected cells and to reduce the intensity of influenza infections in animal models and in humans challenged with infectious virus. Recently we have shown that NA inhibiting antibody can independently contribute to immunity to naturally-occurring influenza immunity in the presence of antibody to the HA. PURPOSE: The present study was conducted to evaluate induction of antibody to the NA and the HA by commercially available influenza vaccines. METHODS: Healthy young adults were vaccinated with one of five commercially available trivalent inactivated vaccines or live influenza vaccine. Frequencies of serum antibody and fold geometric mean titer (GMT) increases four weeks later were measured to each of the three vaccine viruses (A/H1N1, A/H3N2, B) in hemagglutination-inhibition (HAI) and neutralization (neut) assays. Frequency and fold GMT increase in neuraminidase inhibition (NI) antibody titers were measured to the influenza A viruses (A/H1N1, A/H3N2). RESULTS: No significant reactogenicity occurred among the vaccinated subjects. The Fluvirin inactivated vaccine induced more anti-HA antibody responses and a higher fold GMT increase than the other inactivated vaccines but there were no major differences in response frequencies or fold GMT increase among the inactivated vaccines. Both the frequency of antibody increase and fold GMT increase were significantly lower for live vaccine than for any inactivated vaccine in HAI and neut assays for all three vaccine viruses. Afluria inactivated vaccine induced more N1 antibody and Fluarix induced more N2 antibody than the other vaccines but all inactivated vaccines induced serum NI antibody. The live vaccine failed to elicit any NI responses for the N2 NA of A/H3N2 virus and frequencies were low for the N1 of A/H1N1 virus. CONCLUSIONS: Trivalent inactivated influenza vaccines with similar HA dosage induce similar serum anti HA antibody responses in healthy adults. Current inactivated vaccines all induce serum anti-NA antibody to the N1 and N2 NA proteins but some are better than others for N1 or N2. The live vaccine, Flumist, was a poor inducer of either anti HA or anti-NA serum antibody compared to inactivated vaccine in the healthy adults. In view of the capacity for contributing to immunity to influenza in humans, developing guidelines for NA content and induction of NA antibody is desirable. PMID- 23107592 TI - Restoration of viral epithelial tropism improves immunogenicity in rabbits and rhesus macaques for a whole virion vaccine of human cytomegalovirus. AB - Maternal immunity to human cytomegalovirus (HCMV) prior to conception is ~70% protective against congenital transmission and in utero infection of HCMV. Both functional antibodies capable of neutralizing virus and effective T-cells are believed to be important for the protection. Previous HCMV vaccines have rarely been shown able to induce neutralizing antibody titers comparable to those seen in naturally infected HCMV seropositive subjects. Recent studies link a glycoprotein H (gH) complex to receptor-mediated viral entry of endothelial/epithelial cells and leukocytes. This pentameric gH complex, composed of five proteins (gH, gL, UL128, UL130 and UL131 proteins), is notably missing in all HCMV vaccine previously evaluated in clinic. Here we showed that a HCMV virus, with restored expression of the pentameric gH complex, can induce 10-fold higher neutralizing antibody titers than an attenuated AD169 virus or a recombinant glycoprotein B vaccine in multiple animal species in which viral replication is not expected. Encouragingly, the peak neutralizing titers post vaccination in rabbits and monkeys were within 2-4-fold of the levels determined in HCMV seropositive subjects. Functional antibodies by vaccination could further be improved when formulated with a novel adjuvant, and the titers of the antiviral antibodies were sustained in rabbits for over a year after vaccination. These results indicate that the pentameric gH complex is associated with greatly improved functional antibodies following vaccination, and support a vaccine concept based on a nonreplicating whole HCMV with the pentameric gH-associated epithelial tropism restored. PMID- 23107593 TI - Cost-effectiveness analysis of universal childhood hepatitis A vaccination in Brazil: regional analyses according to the endemic context. AB - OBJECTIVE: To conduct a cost-effectiveness analysis of a universal childhood hepatitis A vaccination program in Brazil. METHODS: An age and time-dependent dynamic model was developed to estimate the incidence of hepatitis A for 24 years. The analysis was run separately according to the pattern of regional endemicity, one for South+Southeast (low endemicity) and one for the North+Northeast+Midwest (intermediate endemicity). The decision analysis model compared universal childhood vaccination with current program of vaccinating high risk individuals. Epidemiologic and cost estimates were based on data from a nationwide seroprevalence survey of viral hepatitis, primary data collection, National Health Information Systems and literature. The analysis was conducted from both the health system and societal perspectives. Costs are expressed in 2008 Brazilian currency (Real). RESULTS: A universal immunization program would have a significant impact on disease epidemiology in all regions, resulting in 64% reduction in the number of cases of icteric hepatitis, 59% reduction in deaths for the disease and a 62% decrease of life years lost, in a national perspective. With a vaccine price of R$16.89 (US$7.23) per dose, vaccination against hepatitis A was a cost-saving strategy in the low and intermediate endemicity regions and in Brazil as a whole from both health system and society perspective. Results were most sensitive to the frequency of icteric hepatitis, ambulatory care and vaccine costs. CONCLUSIONS: Universal childhood vaccination program against hepatitis A could be a cost-saving strategy in all regions of Brazil. These results are useful for the Brazilian government for vaccine related decisions and for monitoring population impact if the vaccine is included in the National Immunization Program. PMID- 23107594 TI - Chimeric hepatitis E virus-like particle as a carrier for oral-delivery. AB - Oral delivery with virus-like particles (VLPs) is advantageous because of the inherited entry pathway from their parental viral capsids, which enables VLP to withstand the harsh and enzymatic environment associated with human digestive tract. However, the repeat use of this system is challenged by the self-immunity. In order to overcome this problem, we engineered the recombinant capsid protein of hepatitis E virus by inserting p18 peptide, derived from the V3 loop of HIV-1 gp120, into the antibody-binding site. The chimeric VLP resembled the tertiary and quaternary structures of the wild type VLP and specifically reacted with an HIV-1 antibody against V3 loop. Different from the wild type VLP, the chimeric VLP was vulnerable to trypsin cleavage although it appeared as intact particle, suggesting that the intermolecular forces of attraction between the recombinant capsid proteins are strong enough to maintain the VLP icosahedral arrangement. Importantly, this VLP containing the V3 loop did not react with anti-HEV antibodies, in correspondence to the mutation at its antibody-binding site. Therefore, the insertion of peptides at the surface antigenic site could allow VLPs to escape pre-existing anti-HEV humoral immunity. PMID- 23107595 TI - Effectiveness and cost-effectiveness of pediatric rotavirus vaccination in British Columbia: a model-based evaluation. AB - BACKGROUND: Rotavirus gastroenteritis (RVGE) is associated with widespread morbidity and mortality in children worldwide. In high-income countries, including Canada, the burden of RVGE relates largely to morbidity and healthcare utilization. Two live rotavirus vaccines (RotaTeq((r)) (Merck Frosst Canada Ltd.) and RotarixTM (GlaxoSmithKline Inc.)), are now approved for use in Canada, but their economic attractiveness has not been evaluated in the Canadian context. METHODS: We performed a model-based economic analysis using a Markov chain Monte Carlo simulation of RVGE in populations of British Columbia children. Models were parameterized based on best available data on disease natural history and epidemiology, vaccine effectiveness and cost, and healthcare costs, and calibrated such that projections of healthcare utilization and vaccine coverage closely matched empirical estimates. Robustness of projections was evaluated in deterministic and probabilistic sensitivity analyses. RESULTS: Based on the best available data, childhood immunization against RVGE was projected to prevent 63 81 infections per 100 children vaccinated, and to prevent substantial numbers of outpatient medical visits. It was projected that either vaccine would prevent 1-2 hospitalizations per 100 children immunized. Vaccination was projected to increase healthcare costs: immunization with RotarixTM would prevent incident infections at a cost of approximately $10 per infection prevented or $2400 per quality-adjusted life-year gained. Vaccination with RotaTeqTM would be more costly and less effective and would not be preferred. Projections were robust in the face of wide-ranging sensitivity analyses. INTERPRETATION: The use of currently available vaccines against RVGE in British Columbia children is projected to result in a substantial reduction in the burden of illness and healthcare utilization associated with RVGE, with a modest increase in healthcare costs. RVGE vaccination should be considered "highly cost-effective" relative to other commonly available health interventions. PMID- 23107596 TI - Do income inequality and social capital associate with measles-containing vaccine coverage rate? AB - OBJECTIVE: We investigated the association between income inequality and social capital with measles-containing vaccine (MCV) coverage rates in Japan. METHODS: MCV coverage data for all 1750 municipalities were collected from statistics publicized by the Ministry of Health, Labour and Welfare of Japan in 2010. Prefectural Gini coefficients in 2009 (an indicator of income inequality) and social capital indicators (including voting rates, volunteer rates at the prefectural level, and move-in ratios at the municipal level) were linked to MCV coverage using a multilevel analysis adjusting for covariates (population, age distribution, average income, average number of household members). RESULTS: Coverage of the first dose of MCV (MCV1), and second dose (MCV2), decreased by 3.98% (95% confidence interval [CI]: 0.26-7.71) and 4.28% (95% CI: 0.60-7.60) per each 0.1-unit increase in Gini coefficients within large municipalities (with a population 50,000 or more), respectively. Conversely, coverage of MCV2 increased by 0.26% (95% CI: 0.08-0.45) per 1% increase in voting rate within large municipalities. Volunteer rates were inversely associated with MCV2 coverage within large municipalities. Move-in ratios at the municipal level were inversely associated with MCV2 coverage within medium-sized municipalities (with a population between 10,000 and 50,000). CONCLUSIONS: While higher income inequality at a prefectural level was associated with lower MCV coverage rates, higher social capital was associated with higher coverage in large municipalities. To enhance MCV coverage in Japan, we recommend that income inequality be addressed and social capital boosted at the prefectural level. PMID- 23107597 TI - Field vaccination of sheep with a larval-specific antigen of the gastrointestinal nematode, Haemonchus contortus, confers significant protection against an experimental challenge infection. AB - The availability of effective vaccines would add a valuable tool to the management of gastrointestinal nematode infections in livestock. While some experimental vaccines have shown protection in laboratory trials, few have been tested in the field. In the present study, eight month old sheep kept on pasture were treated with anthelmintic 8 weeks before vaccination with a larval surface antigen of the nematode parasite, Haemonchus contortus, under a commercially acceptable protocol, i.e. 2 immunizations using a commercial adjuvant; they were then given a controlled challenge infection 4 weeks later in indoor pens. Vaccination of sheep with 4 increasing doses of antigen resulted in significant reductions of 61% and 27% in cumulative faecal egg counts in the two highest dose groups, and a 69% reduction in worm burden in the highest dose group. Blood loss, as determined by packed cell volume, was also significantly reduced in the highest dose group of sheep. One outlier sheep showed an unusual increase in egg count without a concomitant increase in worm burden compared to the control sheep, indicating a vaccine-induced stress response. Antigen-specific serum antibody levels steadily increased in sheep while on pasture and decreased when transported to indoor pens. No difference in antibody levels could be detected between vaccinated and unvaccinated sheep, but all showed increased antibody levels compared to uninfected control sheep kept in indoors pens for 2-3 months, suggesting sheep were sensitized to the larval antigen either from low dose pasture contamination or cross reaction with pasture-related antigens. The results of these studies confirm the protective properties of the larval surface antigen and its protective effect when vaccinations are performed in the field. PMID- 23107599 TI - Effect of ventilatory variability on occurrence of central apneas. AB - OBJECTIVE: To compare the influence of 2 ventilation strategies on the occurrence of central apneas. METHODS: This was a prospective, comparative, crossover study with 14 unsedated subjects undergoing weaning from mechanical ventilation in the medical ICU of Hopital du Sacre-Coeur, Montreal, Quebec, Canada. The subjects were ventilated alternately in neurally adjusted ventilatory assist (NAVA) and pressure support ventilation (PSV) modes. Inspiratory flow/time and pressure/time waveforms and diaphragmatic electrical activity were used to detect central apneas. Ventilatory variability and breathing pattern were evaluated in both modes. Breathing patterns just before central apneas, and associations between apneas and sleep patterns (electroencephalogram) were studied. RESULTS: Switching from PSV to NAVA did not change mean minute ventilation, tidal volume, or breathing frequency. However, tidal volume variability, defined as the coefficient of variability (standard error/mean), was significantly greater with NAVA than with PSV (17.2 +/- 8 vs 10.3 +/- 4, P = .045). NAVA induced a greater decrease in central apneas, compared to PSV (to 0 with NAVA vs 10.5 +/- 11 with PSV, P = .005). Central apneas during PSV were detected only during non-rapid-eye movement sleep. CONCLUSIONS: NAVA was associated with increased ventilatory variability, compared to constant-level PSV. With NAVA the absence of over assistance during sleep coincided with absence of central apneas, suggesting that load capacity and/or neuromechanical coupling were improved by NAVA and that this improvement decreased or abolished central apneas. PMID- 23107598 TI - Indirubin-3'-(2,3 dihydroxypropyl)-oximether (E804) is a potent modulator of LPS stimulated macrophage functions. AB - Indirubin is a deep-red bis-indole isomer of indigo blue, both of which are biologically active ingredients in Danggui Longhui Wan, an ancient Chinese herbal tea mixture used to treat neoplasia and chronic inflammation and to enhance detoxification of xenobiotics. Multiple indirubin derivatives have been synthesized and shown to inhibit cyclin-dependent kinases (CDKs) and glycogen synthase kinase (GSK-3beta) with varying degrees of potency. Several indirubins are also aryl hydrocarbon receptor (AhR) agonists, with AhR-associated activities covering a wide range of potencies, depending on molecular structure. This study examined the effects of indirubin-3'-(2,3 dihydroxypropyl)-oximether (E804), a novel indirubin with potent STAT3 inhibitory properties, on basal and LPS inducible activities in murine RAW264.7 macrophages. Using a focused commercial qRT-PCR array platform (SuperArray(r)), the effects of E804 on expression of a suite of genes associated with stress and toxicity were determined. Most genes up regulated by LPS treatment were suppressed by E804; including LPS-induced expression of pro-inflammatory cytokines and receptors, apoptosis control genes, and oxidative stress response genes. Using qRT-PCR as a follow up to the commercial arrays, E804 treatment suppressed LPS-induced COX-2, iNOS, IL-6 and IL 10 gene expression, though the effects on iNOS and COX-2 protein expression were less dramatic. E804 also inhibited LPS-induced secretion of IL-6 and IL-10. Functional endpoints, including iNOS and lysozyme enzymatic activity, phagocytosis of fluorescent latex beads, and intracellular killing of bacteria, were also examined, and in each experimental condition E804 suppressed activities. Collectively, these results indicate that E804 is a potent modulator of pro-inflammatory profiles in LPS-treated macrophages. PMID- 23107600 TI - Utilization of communication technology by patients enrolled in substance abuse treatment. AB - BACKGROUND: Technology-based applications represent a promising method for providing efficacious, widely available interventions to substance abuse treatment patients. However, limited access to communication technology (i.e., mobile phones, computers, internet, and e-mail) could significantly impact the feasibility of these efforts, and little is known regarding technology utilization in substance abusing populations. METHODS: A survey was conducted to characterize utilization of communication technology in 266 urban, substance abuse treatment patients enrolled at eight drug-free, psychosocial or opioid replacement therapy clinics. RESULTS: Survey participants averaged 41 years of age and 57% had a yearly household income of less than $15,000. The vast majority reported access to a mobile phone (91%), and to SMS text messaging (79%). Keeping a consistent mobile phone number and yearly mobile contract was higher for White participants, and also for those with higher education, and enrolled in drug free, psychosocial treatment. Internet, e-mail, and computer use was much lower (39-45%), with younger age, higher education and income predicting greater use. No such differences existed for the use of mobile phones however. CONCLUSIONS: Concern regarding the digital divide for marginalized populations appears to be disappearing with respect to mobile phones, but still exists for computer, internet, and e-mail access and use. Results suggest that mobile phone and texting applications may be feasibly applied for use in program-client interactions in substance abuse treatment. Careful consideration should be given to frequent phone number changes, access to technology, and motivation to engage with communication technology for treatment purposes. PMID- 23107601 TI - A 'giant' intraluminal lipoma presenting with intussusception in an adult: a case report. AB - INTRODUCTION: Intussusception is an uncommon cause of intestinal obstruction in adults. It usually presents with typical features of intestinal obstruction, and is associated with the presence of a 'lead point' for the invaginated portion. This 'lead point' is rarely an intraluminal, submucosal lipoma. CASE PRESENTATION: We describe the case of a 64-year-old African-Ugandan woman of Bantu ethnicity who presented with features of intestinal obstruction secondary to intussusception. She was treated operatively. A left colocolonic invagination was found with the interssusceptum having a giant polyp. A left hemicolectomy was performed. A histopathological examination revealed a polypoid, submucosal lipoma. CONCLUSIONS: In resource-rich countries, most cases of colonic intraluminal polyps are detected through colonoscopy during routine medical check ups. With limited resources in our region, many tumors present as intestinal obstructions secondary to intussusception. Even then, most are associated with adenomas and malignancies. Rarely are polypoid, submucosal lipomas found. In our patient's case a polyp of 9.5cm at its widest dimension is of particular interest. A lesson to learn is that the differential diagnosis for intussusceptions in resource-poor countries should be broadened to include submucosal lipomas. PMID- 23107603 TI - A new role for mucins in immunity: insights from gastrointestinal nematode infection. AB - The body's mucosal surfaces are protected from pathogens and physical and chemical attack by the gel-like extracellular matrix, mucus. The framework of this barrier is provided by polymeric, gel-forming mucins. These enormous O linked glycoproteins are synthesised, stored and secreted by goblet cells that are also the source of other protective factors. Immune regulation of goblet cells during the course of infection impacts on mucin production and properties and ultimately upon barrier function. The barrier function of mucins in protection of the host is well accepted as an important aspect of innate defence. However, it is becoming increasingly clear that mucins have a much more direct role in combating pathogens and parasites and are an important part of the coordinated immune response to infection. Of particular relevance to this review is the finding that mucins are essential anti-parasitic effector molecules. The current understanding of the roles of these multifunctional glycoproteins, and other goblet cell products, in mucosal defence against intestinal dwelling nematodes is discussed. PMID- 23107602 TI - Pharmacological treatment of neonatal pain: in search of a new equipoise. AB - Inadequate management of pain in early human life contributes to impaired neurodevelopmental outcome and alters pain thresholds, pain or stress-related behavior and physiological responses. However, there are also emerging animal experimental data on the impact of exposure to analgo-sedatives on the incidence and extent of neuro-apoptosis. Since this association has also been suggested in humans, the pharmacological treatment of neonatal pain is in search of a new equipoise since these 'conflicting' observations are the main drivers to further reconsider our current treatment regimens. This review focuses on new data concerning clinical pharmacology of morphine, followed by data on more recently introduced opioids like remifentanil and tramadol, locoregional anesthesia and minimally invasive techniques in neonates, and finally with data on intravenous paracetamol. Since the available data are still incomplete, priorities for both clinical management and future research will be proposed. PMID- 23107604 TI - Similarities and differences in the biogenesis, processing and lysosomal targeting between zebrafish and human pro-Cathepsin D: functional implications. AB - The lysosomal protease Cathepsin D (CD) plays a role in neurodegenerative diseases, cancer, and embryo-fetus abnormalities. It is therefore of interest to know how this protein is synthesized in animal species used for modeling human diseases. Zebrafish (Danio rerio) is emerging as a valuable 'in vivo' vertebrate model for several human diseases. We have characterized the biogenetic pathways of zebrafish and human CD transgenically expressed in both human SH-SY5Y cells and zebrafish PAC2 cells. Differently from human CD, zebrafish CD was synthesized as a mono-glycosylated precursor (pro-CD) that was eventually processed into a single-chain mature polypeptide. In PAC2 cells, ammonium chloride and chloroquine impaired the N-glycosylation, and greatly stimulated the secretion, of pro-CD; still, a portion of un-glycosylated pro-CD reached the lysosomes and was processed to mature CD. The treatment with tunicamycin, which abrogates N glycosylation, resulted in a similar effect. Zebrafish pro-CD was correctly processed when expressed in human cells, and its glycosylation, transport and maturation were not impaired by ammonium chloride. On the contrary, the transport and processing of human pro-CD expressed in zebrafish cells were profoundly altered: while the intermediate single-chain was not detectable, a small amount of double-chain mature CD still formed. This fact indicates that the enzyme machinery for single- to double-chain processing of mammal CD is present in zebrafish. Our data highlight the respective impact of the information imparted by the primary sequence and of the cellular transport and processing machineries in the biogenesis of lysosomal CD. PMID- 23107605 TI - Erythropoietin treatment is associated with an augmented immune response to the influenza vaccine in hematologic patients. AB - The objective of this study was to examine whether treatment with recombinant human erythropoietin (rHuEPO), previously found to be associated with a positive effect on cell-mediated immunity and humoral immunity (hepatitis B vaccine), is associated with an improved response to the seasonal influenza (flu) vaccine. Three groups received flu vaccine: healthy controls, hematologic patients not treated with rHuEPO ("No EPO" group), and hematologic patients receiving rHuEPO for their anemia ("EPO" group). Anti-flu Ab titer was measured (complement fixation test) from blood samples drawn before and approximately 3-4 weeks, 7-8 weeks and 4 months after vaccination. Nineteen healthy subjects were compared with 17 No EPO and 17 EPO patients. Mean ages were 59.5, 61.3, and 73.1 years, respectively (EPO patients were older; p = 0.005). In the healthy group, the percentage of those sustaining only a partial (twofold) response, a strong (fourfold or greater) response, and an overall response (combined partial and strong responses) were 31.6%, 57.9%, and 89.5%, respectively. In the No EPO group, values were 35.3%, 17.6%, and 52.9%, respectively. EPO group results were similar to those of the healthy controls: 23.5%, 58.8%, and 82.4% (p = 0.016, EPO vs. No EPO). In conclusion, hematologic patients (NoEPO group) respond poorly to the flu vaccine, compared with healthy subjects, and rHuEPO treatment is associated with an improved immune response to the flu vaccine in hematologic patients, with titers similar to those of healthy subjects. PMID- 23107607 TI - [Guidelines for care of patients at risk and/or suffering from pressure sores]. PMID- 23107606 TI - Synthesis and characterization of lithium oxonitrate (LiNO). AB - The oxonitrate(1-) anion (NO(-)), the one-electron reduction product of nitric oxide and conjugate base of HNO, has not been synthesized and isolated due to the inherent reactivity of this anion. The large scale synthesis and characterization of a stable NO(-) salt is described here. The lithium salt of oxonitrate (LiNO) was formed by the deprotonation of N-hydroxybenzenesulfonamide with phenyllithium in aprotic, deoxygenated conditions. LiNO exhibited antiferromagnetic paramagnetism as determined by SQUID magnetometry, consistent with a triplet ground state of NO(-). LiNO reacted with HCl to yield nitrous oxide consistent with HNO formation and dimerization. LiNO consumed O(2) in a pH-dependent manner to initially produce peroxynitrite and eventually nitrite. Consistent with the reduction potential of NO, LiNO exhibited an oxidation potential of approximately +0.80 V as determined by reactions with a series of viologen electron acceptors. LiNO also reacted with ferric tetraphenylporphyrin chloride (Fe(TPP)Cl), potassium tetracyanonickelate (K(2)Ni(CN)(4)) and nitrosobenzene in a manner that is identical to other HNO/NO(-) donors. We conclude that the physical and chemical characteristics of LiNO are indistinguishable from the experimentally and theoretically derived data on oxonitrate (1-) anion. The bulk synthesis and isolation of a stable (3)NO(-) salt described here allow the chemical and physical properties of this elusive nitrogen oxide to be thoroughly studied as this once elusive nitrogen oxide is now attainable. PMID- 23107608 TI - Pyoderma gangrenosum possibly triggered by adalimumab. PMID- 23107609 TI - Educational application for visualization and analysis of electric field strength in multiple electrode electroporation. AB - BACKGROUND: Electrochemotherapy is a local treatment that utilizes electric pulses in order to achieve local increase in cytotoxicity of some anticancer drugs. The success of this treatment is highly dependent on parameters such as tissue electrical properties, applied voltages and spatial relations in placement of electrodes that are used to establish a cell-permeabilizing electric field in target tissue. Non-thermal irreversible electroporation techniques for ablation of tissue depend similarly on these parameters. In the treatment planning stage, if oversimplified approximations for evaluation of electric field are used, such as U/d (voltage-to-distance ratio), sufficient field strength may not be reached within the entire target (tumor) area, potentially resulting in treatment failure. RESULTS: In order to provide an aid in education of medical personnel performing electrochemotherapy and non-thermal irreversible electroporation for tissue ablation, assist in visualizing the electric field in needle electrode electroporation and the effects of changes in electrode placement, an application has been developed both as a desktop- and a web-based solution. It enables users to position up to twelve electrodes in a plane of adjustable dimensions representing a two-dimensional slice of tissue. By means of manipulation of electrode placement, i.e. repositioning, and the changes in electrical parameters, the users interact with the system and observe the resulting electrical field strength established by the inserted electrodes in real time. The field strength is calculated and visualized online and instantaneously reflects the desired changes, dramatically improving the user friendliness and educational value, especially compared to approaches utilizing general-purpose numerical modeling software, such as finite element modeling packages. CONCLUSION: In this paper we outline the need and offer a solution in medical education in the field of electroporation-based treatments, e.g. primarily electrochemotherapy and non-thermal irreversible tissue ablation. We present the background, the means of implementation and the fully functional application, which is the first of its kind. While the initial feedback from students that have evaluated this application as part of an e-learning course is positive, a formal study is planned to thoroughly evaluate the current version and identify possible future improvements and modifications. PMID- 23107610 TI - Is maternal posturing during labor efficient in preventing persistent occiput posterior position? A randomized controlled trial. AB - OBJECTIVE: We sought to evaluate the efficacy of maternal posturing during labor on the prevention of persistent occiput posterior (OP) position. STUDY DESIGN: We conducted a randomized trial including 220 patients in labor with a single fetus in documented OP position. Main outcome was the proportion of anterior rotation from OP position. RESULTS: The rates of anterior rotation were, respectively, 78.2% and 76.4% in the intervention group and the control group without significant difference (P = .748). Rates of instrumental and cesarean section deliveries were not significantly different between intervention and control groups (18.2% vs. 19.1%, P = .89, and 19.1% vs. 17.3%, P = .73, respectively). In intervention and control groups, persistent OP position rates were significantly higher among women who had cesarean section (71.4% and 89.5%, respectively) and an instrumental delivery (25% and 33.3%, respectively) than among women who achieved spontaneous vaginal birth (5.8% and 2.8%, respectively). In multivariable analysis, body mass index and parity were found to have significant and independent impact on the probability of fetal head rotation. CONCLUSION: Our study failed to demonstrate any maternal or neonatal benefit to a policy of maternal posturing for the management of OP position during labor. PMID- 23107611 TI - Correlation of arterial fetal base deficit and lactate changes with severity of variable heart rate decelerations in the near-term ovine fetus. AB - OBJECTIVE: Recent guidelines classify variable decelerations without detail as to degree of depth. We hypothesized that variable deceleration severity is highly correlated with fetal base deficit accumulation. STUDY DESIGN: Seven near-term fetal sheep underwent a series of graded umbilical cord occlusions resulting in mild (30 bpm decrease), moderate (60 bpm decrease), or severe (decrease of 90 bpm to baseline <70 bpm) variable decelerations at 2.5 minute intervals. RESULTS: Mild, moderate, and severe variable decelerations increased fetal base deficit (0.21 +/- 0.03, 0.27 +/- 0.03, and 0.54 +/- 0.09 mEq/L per minute) in direct proportion to severity. During recovery, fetal base deficit cleared at 0.12 mEq/L per minute. CONCLUSION: In this model, ovine fetuses can tolerate repetitive mild and moderate variable decelerations with minimal change in base deficit and lactate. In contrast, repetitive severe variable decelerations may result in significant base deficit increases, dependent on frequency. Modified guideline differentiation of mild/moderate vs severe variable decelerations may aid in the interpretation of fetal heart rate tracings and optimization of clinical management paradigms. PMID- 23107613 TI - Accuracy of 18-F-FDG PET imaging in the follow up of endometrial cancer patients: systematic review and meta-analysis of the literature. AB - OBJECTIVES: We reviewed the available literature on the accuracy of 18-F-FDG PET imaging in the follow up of the endometrial cancer patients and presented the results in systematic review and meta-analysis format METHODS: Medline, SCOPUS, ISI web of knowledge, Springer, and Science direct were searched with "PET AND Endometr*" as key words. All studies that evaluated the accuracy of 18-F-FDG imaging in the follow up of treated endometrial carcinoma were included if enough data could be extracted for calculation of sensitivity and/or specificity. RESULTS: Eleven studies (541 patients in total) were included in the analysis. Pooled diagnostic indices (patient basis) for detection of overall recurrence were as follows: sensitivity 95.8% [92.2-98.1], specificity 92.5% [89.3-94.9], positive likelihood ratio (LR+) 9.53 [6.52-13.91], negative likelihood ratio (LR ) 0.075 [0.044-0.128], and diagnostic odds ratio (DOR) 204 [91.97-453.5]. 18-F FDG performance was better in studies conducted by PET/CT as compared to PET. The treatment plan changed in 22-35% of the studied patients. CONCLUSION: 18-F-FDG PET is an accurate method for detection and localization of recurrence in post therapy follow up of endometrial carcinoma. It can also change the treatment planning by localizing the recurrent lesions. PMID- 23107612 TI - Eeyarestatin causes cervical cancer cell sensitization to bortezomib treatment by augmenting ER stress and CHOP expression. AB - OBJECTIVE: The proteasome inhibitor bortezomib is currently being tested in clinical trials against refractory cervical cancer. However, high doses of bortezomib are associated with adverse effects, which may lead to treatment abrogation or to the use of lower, ineffective doses. We investigated combination drug treatments that could enhance the efficacy of low bortezomib concentrations on cervical cancer cells. METHODS: The cervical cancer cell lines CaSki, HeLa and SW756 were treated with various combinations of bortezomib and eeyarestatin. Treated cells were analyzed for cell viability by clonal assays and the MTT assay, and for expression of pro-apoptotic proteins and cell stress markers by immunofluorescence, immunoblots and RT-PCR analysis. RESULTS: Cotreatment of bortezomib with eeyarestatin markedly enhanced cell death in cervical cancer cells, allowing reduction of the bortezomib concentration necessary for efficient cell death to as low as 5 ng/ml. Combination of bortezomib with eeyarestatin resulted in a massive induction of the endoplasmic reticulum stress reaction, small and large heat shock protein activation, autophagy, and upregulation of pro apoptotic CHOP. CONCLUSION: Eeyarestatin is a small molecule recently shown to cause endoplasmic reticulum stress by inhibiting the endoplasmic reticulum associated degradation pathway, which directs misfolded cytotoxic proteins to proteasomal degradation. Concomitant inhibition of both pathways markedly enhances the efficacy of bortezomib against cervical cancer cells and thus may be applied to reduce the bortezomib dosage required for efficient cervical cancer treatment. PMID- 23107614 TI - The triangulation technique for intraoperative positioning of the nipple areola complex. PMID- 23107615 TI - The surgeon, the tattoo and the black lymph node. PMID- 23107616 TI - Late results following flap reconstruction for chest wall recurrent breast cancer. AB - INTRODUCTION: Locally extensive recurrent breast cancer usually portends a poor prognosis but certain cases can be treated surgically by wide soft-tissue resection as well as full-thickness chest wall resection (FTCWR). The resulting defect usually necessitates immediate flap coverage. The aim of this study was to assess local control, morbidity, choice of flap reconstruction, patient selection and overall long-term survival following surgical salvage of patients with chest wall recurrent breast cancer. MATERIALS AND METHODS: Forty patients were treated with wide soft-tissue resection and immediate flap reconstruction from 1984 to 2011 in a single institution. Demographic, treatment and mortality data were obtained from patients' files. RESULTS: Mean age at surgery was 54 years. FTCWR was performed in 19 cases including three extended forequarter amputations. Chest wall stabilisation involved a synthetic mesh in 12 patients, fascia lata in two patients, free rib grafts in one patient and synthetic mesh and free rib graft in one patient. Soft-tissue reconstruction consisted of microvascular free flaps in seven patients and pedicled flaps in 33 patients. In-hospital mortality was 0%, 30-day mortality was 5%; there were two re-operations, six minor wound complications and one pulmonary embolism. There were no flap losses. In patients operated on with curative intent (n=31) median disease-free interval was 31 months and median survival was 52 months. CONCLUSIONS: In selected cases wide resections for extensive chest wall recurrent breast cancer can result in reasonable local control and survival. Several flap options exist for soft-tissue reconstruction. PMID- 23107617 TI - Inguinal lymph node dissection: epidermal vacuum therapy for prevention of wound complications. AB - BACKGROUND: Inguinal lymph node dissection (LND) is often associated with wound complications. The aim of this study was to evaluate epidermal vacuum therapy for the prevention of wound complications following inguinal LND. METHODS: From January 2009 to March 2012, a total of 24 patients with penile cancer or cancer of the urethra received uni- or bilateral inguinal lymphadenectomy in our institution. Postoperative wound care consisted of conventional wound care (CWC) in 16 patients or epidermal vacuum dressings (VAC) in eight patients. Maximum drained fluid per day, duration of drainage, duration of hospitalisation and inguinal complications (formation of lymphocele, persistent lymphorrhoea or lymphoedema of the lower extremity) as well as rate of reinterventions were evaluated retrospectively. Mann-Whitney U-tests were performed to compare treatment groups for maximal drained fluid per day, duration of drainage and duration of hospitalisation. Binary data were compared with Fisher's exact test. Statistical calculations were performed on a patient level. RESULTS: Patients treated with CWC showed a slight tendency to higher values of maximum drained fluid per day (p=0.632), duration of drainage (p=0.496) and a significantly longer time of hospitalisation (p=0.049). Epidermal VAC treatment resulted in significantly fewer complications such as formation of lymphoceles (62% vs. 20%), persistent lymphorrhoea (45% vs. 7%) or lymphoedema of the lower extremity (46% vs. 0%) (p=0.032). Reinterventions had to be performed in 23% of inguinal wounds (four patients) treated with CWC and for 7% of inguinal wounds (one patient) treated with epidermal VAC (p=0.631). CONCLUSIONS: Epidermal VAC following inguinal LND might be advantageous for the prevention of postoperative wound complications. Prospective, controlled studies are warranted to further evaluate efficacy and cost-effectiveness. PMID- 23107618 TI - What do I do now? An electroencephalographic investigation of the explore/exploit dilemma. AB - To maximize reward, we are faced with the dilemma of having to balance the exploration of new response options and the exploitation of previous choices. Here, we sought to determine if the event-related brain potential (ERP) in the P300 time range is sensitive to decisions to explore or exploit within the context of a sequential risk-taking task. Specifically, the task we used required participants to continually explore their options-whether they should "push their luck" and keep gambling or "take the money and run" and collect their winnings. Our behavioral analysis yielded two distinct distributions of response times: a larger group of short-decision times and a smaller group of long-decision times. Interestingly, these data suggest that participants adopted one of two modes of control on any given trial: a mode where they quickly decided to keep gambling (i.e. exploit), and a mode where they deliberated whether to the take the money they had already won or continue gambling (i.e. explore). Importantly, we found that the amplitude of the ERP in the P300 time range was larger for explorative decisions than for exploitative decisions and, further, was correlated with decision time. Our results are consistent with a recent theoretical account that links changes in ERP amplitude in the P300 time range with phasic activity of the locus coeruleus-norepinephrine system and decisions to engage in exploratory behavior. PMID- 23107619 TI - Effect of a free radical scavenger on nitric oxide release in microvessels. AB - BACKGROUND: Superoxides impair nitric oxide (NO) bioactivity; however, the dynamics of NO release in the peripheral microcirculation remain unknown. We investigated the effect of a free-radical scavenger (edaravone) on dynamic NO release and the expression of eNOS and iNOS in microvessels. METHODS AND RESULTS: An electrochemical microsensor was positioned at the iliac artery bifurcation of the rat abdominal aorta, and NO release was measured in response to edaravone. A bio-imaging model was also used to obtain images of NO release from microvessels. Moreover, eNOS expression and iNOS expression were investigated in inflammatory and non-inflammatory models. NO was observed in association with microvessels in the mesentery. NO release in the aorta was significantly greater with edaravone than with placebo in the non-inflammatory model (P<0.05). Acetylcholine-induced NO release with edaravone was greater than with placebo in both models. Bio imaging showed greater NO release from arterioles than from venules. eNOS expression with edaravone was greater than with placebo with or without inflammation. iNOS expression was increased by inflammation, but edaravone inhibited this increase. CONCLUSION: These results support the critical role of NO in the microcirculation and suggest that free-radical scavenging increases the bioavailability of NO in the microcirculation via eNOS upregulation. PMID- 23107620 TI - Does the relationship between affect complexity and self-esteem differ in young old and old-old participants? AB - OBJECTIVES: This study examines whether the relationship between positive affect (PA) and negative affect (NA) is more complex among old-old than among young-old participants and whether the independence and potential co-occurrence of both PA and NA (affect complexity) is related to higher self-esteem (SE) among older participants. METHOD: A convenience sample of 311 participants was divided into 2 groups: young-old, aged 65-79 years (n = 212), and old-old, aged 80-93 years (n = 99), participants. PA and NA were measured by the Positive and Negative Affect Schedule and SE was measured by the Self-Esteem Questionnaire. RESULTS: The findings show that PA and NA are less strongly related and even positively related to each other among older people and that SE is higher among the young old compared with the old-old participants. Finally, affect complexity is positively related to a higher degree of SE among the old-old participants. DISCUSSION: These findings may imply that the affect complexity is associated with buffering the noxious effect of deteriorating SE in old age. Future studies should examine further the intrapersonal relationship between affect complexity and SE in late life. PMID- 23107621 TI - Reliability of airway occlusion pressure as an index of respiratory motor output. AB - BACKGROUND: Airway occlusion pressure 0.1 s after the start of inspiratory flow (P0.1) is used as an index of respiratory motor output; however, the reliability of P0.1 in this capacity has not been sufficiently investigated. Therefore, the aim of our study was to examine the reliability of P0.1. METHODS: Eleven healthy subjects (7 men and 4 women) participated in our study. Subjects were placed in a supine position, and P0.1 was measured every 30 s for 5 min, following a 1-min period during which ventilation and breathing frequency were measured. A total of 10 P0.1 values were obtained, and the intraclass correlation coefficient (ICC) was used to analyze reliability. ICC values from ICC (1, 2) to ICC (1, 10) were calculated following a number of measurements (k), where ICC (1, k) was increased sequentially from 2 to 10. RESULTS: The ICC (1, 2) through ICC (1, 10) values were found to be between 0.877 and 0.960 (95% CI 0.565-0.966 and 0.912-0.987, respectively). When the target coefficient was set at 0.9, the ICC (1, 1) from 10 measurements was calculated a minimum of 4 times. CONCLUSIONS: Although a single measurement of P0.1 was somewhat reliable, the 95% CIs indicated that it is necessary to determine the average value of 3 or more measurements. The minimum of 4 repeat measurements were required to obtain valid results, indicating that the current method of determining P0.1 by averaging the values from at least 4 repeated measurements is valid. PMID- 23107622 TI - Assessment of quality of life of patients with oral cavity cancer who have had defects reconstructed with free anterolateral thigh perforator flaps. AB - The aim of this study was to evaluate quality of life (QoL) in patients who have had resections of oral cancer and reconstruction by free anterolateral thigh perforator flaps. QoL was assessed by the 14-item Oral Health Impact Profile (OHIP-14) and the University of Washington Quality of Life (UW-QoL) questionnaires 12 months postoperatively. Fifty-one of the 69 questionnaires were returned (74%). In the UW-QoL the best-scoring domain was pain, whereas the lowest scores were for chewing, saliva, and taste. In the OHIP-14 the lowest scoring domain was handicap, followed by psychological disability, and social disability. Free anterolateral thigh perforator flaps for reconstruction of defects of the head and neck after resection for cancer significantly influenced the patients' quality of life. PMID- 23107623 TI - Oral submucous fibrosis: an overview of the aetiology, pathogenesis, classification, and principles of management. AB - Oral submucous fibrosis (OSMF) is a complex, debilitating, and precancerous condition. Formerly confined to the Indian subcontinent, it is now often seen in the Asian populations of the United Kingdom, USA, and other developed countries, and is therefore a serious problem for global health. The well-known causative agent of the disease, areca-nut is now recognised as a group one carcinogen. We review and discuss all components of OSMF, including the terminology, presentation, aetiology, and pathogenesis, and provide a brief overview of its management. PMID- 23107624 TI - Foot Type Biomechanics Part 2: are structure and anthropometrics related to function? AB - BACKGROUND: Many foot pathologies are associated with specific foot types. If foot structure and function are related, measurement of either could assist with differential diagnosis of pedal pathologies. HYPOTHESIS: Biomechanical measures of foot structure and function are related in asymptomatic healthy individuals. METHODS: Sixty-one healthy subjects' left feet were stratified into cavus (n=12), rectus (n=27) and planus (n=22) foot types. Foot structure was assessed by malleolar valgus index, arch height index, and arch height flexibility. Anthropometrics (height and weight), age, and walking speed were measured. Foot function was assessed by center of pressure excursion index, peak plantar pressure, maximum force, and gait pattern parameters. Foot structure and anthropometric variables were entered into stepwise linear regression models to identify predictors of function. RESULTS: Measures of foot structure and anthropometrics explained 10-37% of the model variance (adjusted R(2)) for gait pattern parameters. When walking speed was included, the adjusted R(2) increased to 45-77% but foot structure was no longer a factor. Foot structure and anthropometrics predicted 7-47% of the model variance for plantar pressure and 16 64% for maximum force parameters. All multivariate models were significant (p<0.05), supporting acceptance of the hypothesis. DISCUSSION AND CONCLUSION: Foot structure and function are related in asymptomatic healthy individuals. The structural parameters employed are basic measurements that do not require ionizing radiation and could be used in a clinical setting. Further research is needed to identify additional predictive parameters (plantar soft tissue characteristics, skeletal alignment, and neuromuscular control) and to include individuals with pathology. PMID- 23107625 TI - Foot type biomechanics part 1: structure and function of the asymptomatic foot. AB - BACKGROUND: Differences in foot structure are thought to be associated with differences in foot function during movement. Many foot pathologies are of a biomechanical nature and often associated with foot type. Fundamental to the understanding of foot pathomechanics is the question: do different foot types have distinctly different structure and function? AIM: To determine if objective measures of foot structure and function differ between planus, rectus and cavus foot types in asymptomatic individuals. METHODS: Sixty-one asymptomatic healthy adults between 18 and 77 years old, that had the same foot type bilaterally (44 planus feet, 54 rectus feet, and 24 cavus feet), were recruited. Structural and functional measurements were taken using custom equipment, an emed-x plantar pressure measuring device, a GaitMat II gait pattern measurement system, and a goniometer. Generalized Estimation Equation modeling was employed to determine if each dependent variable of foot structure and function was significantly different across foot type while accounting for potential dependencies between sides. Post hoc testing was performed to assess pair wise comparisons. RESULTS: Several measures of foot structure (malleolar valgus index and arch height index) were significantly different between foot types. Gait pattern parameters were invariant across foot types. Peak pressure, maximum force, pressure-time integral, force-time-integral and contact area were significantly different in several medial forefoot and arch locations between foot types. Planus feet exhibited significantly different center of pressure excursion indices compared to rectus and cavus feet. CONCLUSIONS: Planus, rectus and cavus feet exhibited significantly different measures of foot structure and function. PMID- 23107626 TI - Combined oral alitretinoin and narrowband UVB treatment of cutaneous T cell lymphoma: favourable response after multiple ineffective systemic therapies. PMID- 23107627 TI - Early detection of Candida albicans biofilms at porous electrodes. AB - We describe the development of an electrochemical sensor for early detection of biofilm using Candida albicans. The electrochemical sensor used the ability of biofilms to accept electrons from redox mediators relative to the number of metabolically active cells present. Cyclic voltammetry and differential pulse voltammetry techniques were used to monitor the redox reaction of K(3)Fe(CN)(6) at porous reticulated vitreous carbon (RVC) (238.7 cm(2)) working electrodes versus Ag/AgCl reference. A shift in the peak potential occurred after 12 h of film growth, which is attributed to the presence of C. albicans. Moreover, the intensity of the ferricyanide reduction peak first increased as C. albicans deposited onto the porous electrodes at various growth times. The peak current subsequently decreased at extended periods of growth of 48 h. The reduction in peak current was attributed to the biofilm reaching its maximum growth thickness, which correlated with the maximum number of metabolically active cells. The observed diffusion coefficients for the bare RVC and biofilm-coated electrodes were 2.2 * 10(-3) and 7.0 * 10(-6) cm(2)/s, respectively. The increase in diffusivity from the bare electrode to the biofilm-coated electrode indicated some enhancement of electron transfer mediated by the biofilm to the porous electrode. Verification of the growth of biofilm was achieved using scanning electron microcopy and laser scanning confocal imaging microscopy. Validation with conventional plating techniques confirmed that the correlation (R(2) = 0.9392) could be achieved between the electrochemical sensors data and colony forming units. PMID- 23107628 TI - On the road to unravelling the aetiology of non-tuberculous mycobacterial disease. PMID- 23107629 TI - Restrictive lung disease: not restricted to the lung? PMID- 23107630 TI - New tuberculosis technologies: challenges for retooling and scale-up. AB - The availability of new tools does not mean that they will be adopted, used correctly, scaled up or have public health impact. Experience to date with new diagnostics suggests that many national tuberculosis programmes (NTPs) in high burden countries are reluctant to adopt and scale up new tools, even when these are backed by evidence and global policy recommendations. We suggest that there are several common barriers to effective national adoption and scale-up of new technologies: global policy recommendations that do not provide sufficient information for scale-up, complex decision-making processes and weak political commitment at the country level, limited engagement of and support to NTP managers, high cost of tools and poor fit with user needs, unregulated markets and inadequate business models, limited capacity for laboratory strengthening and implementation research, and insufficient advocacy and donor support. Overcoming these barriers will require enhanced country-level advocacy, resources, technical assistance and political commitment. Some of the BRICS (Brazil, Russia, India, China, South Africa) countries are emerging as early adopters of policies and technologies, and are increasing their investments in TB control. They may provide the first opportunities to fully assess the public health impact of new tools. PMID- 23107631 TI - 2011: the year in review. Part II: tuberculosis and lung disease. PMID- 23107632 TI - Trend in tuberculosis infection prevalence in a rural area in South India after implementation of the DOTS strategy. AB - SETTING: Three tuberculin surveys were conducted at intervals of 5 years following the implementation of a DOTS-based programme in 1999 in Tiruvallur District, South India. OBJECTIVE: To estimate the trend in the prevalence of tuberculosis (TB) infection among children and to evaluate the impact of the DOTS strategy. METHODS: Children aged 1-9 years in the sample for each survey were registered and administered 1 tuberculin unit of purified protein derivative RT 23 with Tween 80 by intradermal injection on the volar aspect of the left forearm. The induration diameter of the reaction was measured in mm after 72 h (3 days) and the prevalence of TB infection estimated. RESULTS: The induration data of bacille Calmette-Guerin (BCG) vaccinated and non-vaccinated children were analysed using the mixture model. The estimated prevalence of TB infection among non-BCG-vaccinated children in the three tuberculin surveys were respectively 19.4%, 13.8% and 11.4%, with an average annual decline of 5.2% (95%CI 3.6-6.8). The prevalence of TB infection among BCG-vaccinated children decreased, with an average annual decline of 5.4% (95%CI 10.0-18.6). CONCLUSION: A significant declining trend in the prevalence of TB infection among children was observed following the implementation of the DOTS strategy in the area. PMID- 23107633 TI - Predictors of sputum culture conversion among patients treated for multidrug resistant tuberculosis. AB - OBJECTIVE: To identify predictors of initial sputum culture conversion, estimate the usefulness of persistent positive cultures at different time points in predicting treatment failure, and evaluate different definitions of culture conversion for predicting failure among patients with multidrug-resistant tuberculosis (MDR-TB) in five countries, 2000-2004. METHODS: Predictors of time to conversion were identified using multivariate Cox proportional hazards regression modeling. Receiver operating characteristic curves were plotted to visualize the effect of using different definitions of 'culture conversion' on the balance between sensitivity and specificity. RESULTS: Overall, 1209/1416 (85%) of patients with baseline positive cultures converted in a median of 3.0 months (interquartile range 2.0-5.0). Independent predictors of less likely conversion included baseline positive smear (hazard ratio [HR] 0.60, 95%CI 0.53 0.68), resistance to pyrazinamide (HR 0.82, 95%CI 0.70-0.96), fluoroquinolones (FQs; HR 0.65, 95%CI 0.51-0.83) or thioamide (HR 0.83, 95%CI 0.71-0.96), previous use of FQs (HR 0.71, 95%CI 0.60-0.83), poor outcome of previous anti tuberculosis treatment (HR 0.69, 95%CI 0.54-0.88) and alcoholism (HR 0.74, 95%CI 0.63-0.87). The maximum combined sensitivity (84%) and specificity (94%) in predicting treatment failure was based on lack of culture conversion at month 9 of treatment, assuming conversion is defined as five consecutive negative cultures. CONCLUSION: Patients with identified risk factors were less likely to achieve sputum culture conversion during MDR-TB treatment. PMID- 23107634 TI - Influence of previous tuberculosis treatment history on acid-fast bacilli smear and culture conversion. AB - SETTING: A teaching hospital in the Republic of Korea, 2003-2009. OBJECTIVE: To evaluate the effect of previous tuberculosis (TB) treatment history on sputum smear and culture conversion. DESIGN: Data, including sputum acid-fast bacilli (AFB) results at baseline and at weeks 2, 4, 8, 12, 16, 20 and 24, were collected from patients with AFB sputum smear-positive and culture-confirmed pulmonary TB. Patients with multidrug-resistant TB or those with poor adherence were excluded. AFB conversion was compared between patients with a previous history of anti-tuberculosis treatment and those without. RESULTS: The median age of the 208 patients was 49.0 years; 58.3% were male, while 43 (20.7%) had a history of previous anti-tuberculosis treatment. Patients with a history of previous treatment had significantly lower sputum smear-negative conversion at 2 weeks of treatment compared with patients without (70.0% vs. 44.8%, P = 0.005). However, the two groups did not differ in culture conversion and in smear conversion at 4, 8, 12, 16, 20 and 24 weeks of anti-tuberculosis treatment. CONCLUSION: Patients with a history of previous anti-tuberculosis treatment are more likely to have positive sputum AFB smear at 2 weeks of treatment. However, sputum culture conversion is not affected by previous treatment history. PMID- 23107636 TI - Association between the CD14 gene C-159T polymorphism and serum soluble CD14 with pulmonary tuberculosis. AB - BACKGROUND: Functional C-159T polymorphism in the promoter region of the CD14 lipopolysaccharide receptor has been reported to be associated with the development of tuberculosis (TB). OBJECTIVE: To assess the association of CD14 C 159T polymorphism and serum soluble CD14 (sCD14) levels with pulmonary tuberculosis (TB) in an Iranian population living in a TB-endemic area. DESIGN: A case-control study was performed prospectively on 120 newly diagnosed pulmonary TB patients and 131 healthy subjects. C-159T polymorphism was performed using amplification refractory mutation system polymerase chain reaction (ARMS-PCR). Concentrations of sCD14 were measured in serum samples using enzyme-linked immunosorbent assay. RESULTS: The genotype frequencies of C-159T polymorphism differed significantly between TB patients and controls (P = 0.006). The risk of TB was 2.3-fold greater in individuals with the T-allele (CT + TT) in comparison to those without (OR 2.3, 95%CI 1.2-4.3, P = 0.006). Mean total sCD14 was significantly increased in the serum of patients with newly diagnosed pulmonary TB (mean +/- SD = 3177 +/- 751 ng/ml) compared to healthy controls (mean +/- SD = 2955 +/- 424 ng/ml, P < 0.004). CONCLUSION: These data indicate that the C-159T polymorphism of the CD14 gene is associated with TB; serum sCD14 levels were higher in TB patients in a sample of the Iranian population. PMID- 23107635 TI - Treatment for tuberculosis-associated immune reconstitution inflammatory syndrome in 34 HIV-infected patients. AB - BACKGROUND: Paradoxical tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) frequently follows the initiation of antiretroviral therapy (ART) in patients with tuberculosis (TB) and human immunodeficiency virus (HIV) co infection. Treatment recommendations are nearly exclusively based on expert opinion. OBJECTIVE: To assess the clinical outcomes of patients treated using various strategies for TB-IRIS. METHODS: In a retrospective analysis of patients treated in Paris hospitals from 1996 to 2008, we describe TB-IRIS outcome, frequency of relapses and CD4 cell count changes after 12 months of ART for the following strategies: no treatment, interrupted ART and use of steroids. RESULT: Among 34 patients, TB-IRIS outcome was favourable in 10/10 with no treatment, 11/13 with ART interruption, 3/3 with ART interruption and simultaneous use of steroids and 8/8 with steroids alone. Relapses were observed in both the ART interruption (6/13, 46%) and steroids (4/8, 50%) groups, but were less frequent in the no-treatment group (1/10, 10%). Steroids were prescribed in 61% of the patients and had no significant side effects; steroid use was associated with a trend towards a lower median CD4 cell count at 12 months of ART compared to the others (230 vs. 322 cells/mm(3)), despite no baseline differences. CONCLUSION: TB IRIS outcome was favourable regardless of the therapeutic strategies employed. Although steroids were widely used and well-tolerated, an initial wait-and-see attitude in the case of non-severe IRIS remains an interesting strategy to be evaluated. PMID- 23107637 TI - Clinical significance of mycobacterial genotyping in Mycobacterium avium lung disease in Korea. AB - SETTING: A recent study in Japan found that mycobacterial genotyping was associated with disease progression and susceptibility to certain drugs in Mycobacterium avium lung disease. However, it is not known whether this association is true in other populations. OBJECTIVE: To investigate the association between mycobacterial genotype, clinical characteristics and the progression of M. avium lung disease in Korean patients. DESIGN: A total of 102 M. avium clinical isolates were genotyped using M. avium tandem repeats-variable number of tandem repeats (MATR-VNTR). RESULTS: MATR-VNTR typing demonstrated a high discriminatory power and genetic diversity for molecular epidemiological studies of M. avium. In the phylogenetic tree, the M. avium clinical isolates were divided into three major clusters: A, B and C. Cluster A was observed most frequently (64/102, 63%), whereas cluster C was found in a minor proportion of the isolates (8/102, 8%). However, there was no association between the clinical characteristics, disease progression and drug susceptibility and the phylogenetic tree based on VNTR genotyping. CONCLUSIONS: MATR-VNTR genotyping may be useful for epidemiological studies of M. avium lung disease; however, no association was found between the specific VNTR genotypes of M. avium and the clinical characteristics of Korean patients. PMID- 23107638 TI - Mycobacterium africanum, an emerging disease in high-income countries? AB - BACKGROUND: Mycobacterium africanum is a cause of tuberculosis (TB) that has mainly been described in Africa, but immigration and travel patterns have contributed to the spread of the disease to other countries. METHODS: We retrospectively reviewed TB cases due to M. africanum during 2000-2010 in seven Spanish hospitals. Selected clinical charts were reviewed using a predefined protocol that included demographical, clinical and microbiological data and outcome. RESULTS: Although 57 cases were diagnosed, only 36 clinical charts were available for review: 82.8% were men and the mean age was 31.6 years (range 12 81). Forty-four cases were from Africa, 1 from the Philippines, 1 from India, and 4 from Spain, while the country of origin was unknown in 7 cases. The most frequent site of infection was the lung (58.3%). Four cases (6.9%) were resistant to at least one first-line anti-tuberculosis drug. CONCLUSIONS: Disease due to M. africanum in industrialised countries is mainly associated with immigration from endemic areas, although some cases also occur among native-born populations. PMID- 23107639 TI - Declaration on palliative care for MDR/XDR-TB. PMID- 23107641 TI - Evaluation of the Amplified MTD(r) Test in respiratory specimens of human immunodeficiency virus patients. PMID- 23107642 TI - Intervertebral disc segmentation in MR images using anisotropic oriented flux. AB - This study proposes an unsupervised intervertebral disc segmentation system based on middle sagittal spine MR scans. The proposed system employs the novel anisotropic oriented flux detection scheme which helps distinguish the discs from the neighboring structures with similar intensity, recognize ambiguous disc boundaries, and handle the shape and intensity variation of the discs. Based on minimal user interaction, the proposed system begins with vertebral body tracking to infer the information regarding the positions and orientations of the target intervertebral discs. The information is employed in a set of image descriptors, which jointly constitute an energy functional describing the desired disc segmentation result. The energy functional is minimized by a level set based active contour model to perform disc segmentation. The proposed segmentation system is evaluated using a database consisting of 455 intervertebral discs extracted from 69 middle sagittal slices. It is demonstrated that the proposed method is capable of delivering accurate results for intervertebral disc segmentation. PMID- 23107644 TI - Effect of harmane, an endogenous beta-carboline, on learning and memory in rats. AB - Our aim was to investigate the effects of acute harmane administration upon learning and memory performance of rats using the three-panel runway paradigm and passive avoidance test. Male rats received harmane (2.5, 5, and 7.5mg/kg, i.p.) or saline 30 min. before each session of experiments. In the three panel runway paradigm, harmane did not affect the number of errors and latency in reference memory. The effect of harmane on the errors of working memory was significantly higher following the doses of 5mg/kg and 7.5mg/kg. The latency was changed significantly at only 7.5mg/kg in comparison to control group. Animals were given pre-training injection of harmane in the passive avoidance test in order to determine the learning function. Harmane treatment decreased the retention latency significantly and dose dependently, which indicates an impairment in learning. In this study, harmane impaired working memory in three panel runway test and learning in passive avoidance test. As an endogenous bioactive molecule, harmane might have a critical role in the modulation of learning and memory functions. PMID- 23107643 TI - Anorexic effects of intra-VTA leptin are similar in low-fat and high-fat-fed rats but attenuated in a subgroup of high-fat-fed obese rats. AB - Leptin is an adiposity hormone that plays an important role in regulating food intake and energy homeostasis. This study investigated the effects of a high-fat (HF) and a low-fat, high-carbohydrate/sugar (LF) diet on leptin sensitivity in the ventral tegmental area (VTA) in rats. The animals were exposed to a HF or LF diet for 16 weeks. Then the effects of intra-VTA leptin (150 and 500 ng/side, unilateral dose) on food intake and body weights were investigated while the animals were maintained on the HF or LF diet. Long-term exposure to the HF or LF diet led to similar body weight gain in these groups. The HF-fed animals consumed a smaller amount of food by weight than the LF-fed animals but both groups consumed the same amount of calories. The bilateral administration of leptin into the VTA decreased food intake (72 h) and body weights (48 h) to a similar degree in the HF and LF-fed animals. When the HF-fed animals were ranked by body weight gain it was shown that the diet-induced obese rats (HF-fed DIO, upper quartile for weight gain) were less sensitive to the effects of leptin on food intake and body weights than the diet-resistant rats (HF-fed DR, lower quartile for weight gain). A control experiment with fluorescent Cy3-labeled leptin showed that leptin did not spread beyond the borders of the VTA. This study indicates that leptin sensitivity in the VTA is the same in animals that are exposed to a HF or LF diet. However, HF-fed DIO rats are less sensitive to the effects of leptin in the VTA than HF-fed DR rats. Leptin resistance in the VTA might contribute to overeating and weight gain when exposed to a HF diet. PMID- 23107645 TI - New Zealand's unique maternity system. AB - This discussion paper describes New Zealand's maternity system. It includes a brief background of the country and its history, key aspects of the legislative and funding contexts and the framework for the woman centred and midwife-led maternity system itself. PMID- 23107646 TI - Inhibitory effects of levetiracetam on the high-voltage-activated L-type Ca2+ channels in hippocampal CA3 neurons of spontaneously epileptic rat (SER). AB - Levetiracetam (LEV) is a widely used antiepileptic agent for partial refractory epilepsy in humans. LEV has unique antiepileptic effects in that it does not inhibit electroshock- or pentylenetetrazol-induced convulsion, but does inhibit seizures in kindling animal and spontaneously epileptic rat (SER: zi/zi, tm/tm) that shows both tonic convulsion and absence-like seizures. LEV also has unique characteristics in terms of its antiepileptic mechanism; it has no activity on Na+ and K+ channels or on glutamate and GABA(A) receptors. Recently, we found that LEV inhibits the depolarization shift and accompanying repetitive firing induced by mossy fiber stimulation in CA3 neurons of SER hippocampal slices. Therefore, this study was performed to determine whether LEV could inhibit the voltage-activated L-type Ca2+ current of hippocampal CA3 neurons obtained from SER and the non-epileptic Wistar rat. As previously reported, SER CA3 neurons were classified into type 1 and type 2 neurons. The application of LEV (100 MUM) elevated the threshold for activation of the Ca2+ current, which was lowered in SER type 1 neurons and reduced the current size. Type 2 neurons of SER have a similar current-voltage relationship to Wistar rat neurons and the decay component of Ca2+ current during depolarization pulse in type 2 neurons was found to be smaller than that in Wistar rat neurons. LEV (100 MUM) also reduced Ca2+ current in SER type 2 neurons. The effects of LEV were examined on such type 2 SER hippocampal CA3 neurons, compared with those on Wistar rat CA3 neurons. Application of LEV (10 MUM) produced a significant decrease of amplitude of the Ca2+ current in SER neurons, although at this concentration of LEV there was no statistically significant decrease in the amplitude of Ca2+ current in Wistar rat neurons. Furthermore, LEV (100 nM-1 mM) reduced the Ca2+ current in a concentration-dependent manner in both SER and Wistar rat neurons, but the inhibition was much more potent in the former neurons than in the latter. Under the condition that the Ca2+ current had already been inhibited by LEV (10 MUM), the addition of nifedipine (10 MUM) did not cause further inhibition. Conversely, LEV had no effects on the current that had already been decreased by nifedipine (10 MUM) given before LEV treatment (10 MUM), indicating that LEV could act on the L-type Ca2+ channel. LEV elevated the threshold potential level for activation of the Ca2+ current and reduced the L-type Ca2+ current in type 1 neurons of SER, and the inhibitory action in type 2 neurons was much more potent than that in Wistar rat neurons, suggesting that these effects contribute, at least partly, to the antiepileptic action of LEV. PMID- 23107647 TI - A point mutation associated with episodic ataxia 6 increases glutamate transporter anion currents. AB - Episodic ataxia is a human genetic disease characterized by paroxysmal cerebellar incoordination. There are several genetically and clinically distinct forms of this disease, and one of them, episodic ataxia type 6, is caused by mutations in the gene encoding a glial glutamate transporter, the excitatory amino acid transporter-1. So far, reduced glutamate uptake by mutant excitatory amino acid transporter-1 has been thought to be the main pathophysiological process in episodic ataxia type 6. However, excitatory amino acid transporter-1 does not only mediate secondary-active glutamate transport, but also functions as an ion channel. Here, we examined the effects of a disease-associated point mutation, P290R, on glutamate transport, anion current as well as on the subcellular distribution of excitatory amino acid transporter-1 using heterologous expression in mammalian cells. P290R reduces the number of excitatory amino acid transporter 1 in the surface membrane and impairs excitatory amino acid transporter-1 mediated glutamate uptake. Cells expressing P290R excitatory amino acid transporter-1 exhibit larger anion currents than wild-type cells in the absence as well as in the presence of external l-glutamate, despite a lower number of mutant transporters in the surface membrane. Noise analysis revealed unaltered unitary current amplitudes, indicating that P290R modifies opening and closing, and not anion permeation through mutant excitatory amino acid transporter-1 anion channels. These findings identify gain-of-function of excitatory amino acid transporter anion conduction as a pathological process in episodic ataxia. Episodic ataxia type 6 represents the first human disease found to be associated with altered function of excitatory amino acid transporter anion channels and illustrates possible physiological and pathophysiological impacts of this functional mode of this class of glutamate transporters. PMID- 23107648 TI - Beyond the arcuate fasciculus: consensus and controversy in the connectional anatomy of language. AB - The growing consensus that language is distributed into large-scale cortical and subcortical networks has brought with it an increasing focus on the connectional anatomy of language, or how particular fibre pathways connect regions within the language network. Understanding connectivity of the language network could provide critical insights into function, but recent investigations using a variety of methodologies in both humans and non-human primates have provided conflicting accounts of pathways central to language. Some of the pathways classically considered language pathways, such as the arcuate fasciculus, are now argued to be domain-general rather than specialized, which represents a radical shift in perspective. Other pathways described in the non-human primate remain to be verified in humans. In this review, we examine the consensus and controversy in the study of fibre pathway connectivity for language. We focus on seven fibre pathways-the superior longitudinal fasciculus and arcuate fasciculus, the uncinate fasciculus, extreme capsule, middle longitudinal fasciculus, inferior longitudinal fasciculus and inferior fronto-occipital fasciculus-that have been proposed to support language in the human. We examine the methods in humans and non-human primate used to investigate the connectivity of these pathways, the historical context leading to the most current understanding of their anatomy, and the functional and clinical correlates of each pathway with reference to language. We conclude with a challenge for researchers and clinicians to establish a coherent framework within which fibre pathway connectivity can be systematically incorporated to the study of language. PMID- 23107650 TI - General medical care of the dialysis patient: Core Curriculum 2013. PMID- 23107649 TI - Adults with RRM2B-related mitochondrial disease have distinct clinical and molecular characteristics. AB - Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B are an important cause of familial mitochondrial disease in both adults and children and represent the third most common cause of multiple mitochondrial DNA deletions in adults, following POLG [polymerase (DNA directed), gamma] and PEO1 (now called C10ORF2, encoding the Twinkle helicase) mutations. However, the clinico pathological and molecular features of adults with RRM2B-related disease have not been clearly defined. In this multicentre study of 26 adult patients from 22 independent families, including five additional cases published in the literature, we show that extra-ocular neurological complications are common in adults with genetically confirmed RRM2B mutations. We also demonstrate a clear correlation between the clinical phenotype and the underlying genetic defect. Myopathy was a prominent manifestation, followed by bulbar dysfunction and fatigue. Sensorineural hearing loss and gastrointestinal disturbance were also important findings. Severe multisystem neurological disease was associated with recessively inherited compound heterozygous mutations with a mean age of disease onset at 7 years. Dominantly inherited heterozygous mutations were associated with a milder predominantly myopathic phenotype with a later mean age of disease onset at 46 years. Skeletal muscle biopsies revealed subsarcolemmal accumulation of mitochondria and/or cytochrome c oxidase-deficient fibres. Multiple mitochondrial DNA deletions were universally present in patients who underwent a muscle biopsy. We identified 18 different heterozygous RRM2B mutations within our cohort of patients, including five novel mutations that have not previously been reported. Despite marked clinical overlap between the mitochondrial maintenance genes, key clinical features such as bulbar dysfunction, hearing loss and gastrointestinal disturbance should help prioritize genetic testing towards RRM2B analysis, and sequencing of the gene may preclude performance of a muscle biopsy. PMID- 23107651 TI - Increasing survival rate from commotio cordis. AB - BACKGROUND: Commotio cordis events due to precordial blows triggering ventricular fibrillation are a cause of sudden death (SD) during sports and also daily activities. Despite the absence of structural cardiac abnormalities, these events have been considered predominantly fatal with low survival rates. OBJECTIVE: To determine whether expected mortality rates for commotio cordis have changed over time, associated with greater public visibility. METHODS: US Commotio Cordis Registry was accessed to tabulate frequency of reported SD or resuscitated cardiac arrest over 4 decades. RESULTS: At their commotio cordis event, 216 study patients were 0.2-51 years old (mean age 15+/-9 years); 95% were males. Death occurred in 156 individuals (72%), while the other 60 (28%) survived. Proportion of survivors increased steadily with concomitant decrease in fatal events. For the initial years (1970-1993), 6 of 59 cases survived (10%), while during 1994 2012, 54 of 157 (34%) survived (P = .001). The most recent 6 years, survival from commotio cordis was 31 of 53 (58%), with survivor and nonsurvivor curves ultimately crossing. Higher survival rates were associated with more prompt resuscitation (40%<3 minutes vs 5%>3 minutes; P<.001) and participation in competitive sports (39%; P<.001), but with lower rates in African Americans (1 of 24; 4%) than in whites (54 of 166; 33%; P = .004). Independent predictors of mortality were black race (P = .045) and participation in noncompetitive sports (P = .002), with an on-site automated external defibrillator use protective against SD (P = .01). CONCLUSIONS: Survival from commotio cordis has increased, likely owing to more rapid response times and access to defibrillation, as well as greater public awareness of this condition. PMID- 23107652 TI - Effect of left ventricular ejection fraction and QRS duration on the survival benefit of implantable cardioverter-defibrillators: meta-analysis of primary prevention trials. AB - BACKGROUND: Implantable cardioverter-defibrillators (ICDs) are recommended for the primary prevention of sudden cardiac death in patients with left ventricular dysfunction, but it is unclear whether treatment benefits are diminished in patients with very low baseline left ventricular ejection fraction (LVEF) (<25%) or increased in those with prolonged QRS duration (>120 ms). OBJECTIVE: To study the effects of very low LVEF and prolonged QRS duration on the mortality benefits of ICD therapy. METHODS: We performed a meta-analysis of primary prevention randomized controlled trials comparing ICD and standard medical therapy. All cause mortality hazard ratios (HRs) in subgroups according to thresholds of 25% for LVEF and 120 ms for QRS duration were extracted from published reports or contributed by trial investigators and synthesized. RESULTS: There was no significant difference of ICD effectiveness in LVEF subgroups of 25%-35% (random effects HR 0.81; 95% confidence interval [CI] 0.70-0.94) vs<25% (HR 0.71; 95% CI 0.55-0.93). Results were also similar in the narrow and wide QRS subgroups (HR 0.78; 95% CI 0.68-0.90 and HR 0.70; 95% CI 0.51-0.95, respectively). Within the LVEF<25% and wide QRS subgroups, there was large heterogeneity driven by the Defibrillator in Acute Myocardial Infarction Trial that included patients with early post-myocardial infarction and its results (HR 1.49; 95% CI 0.84-2.68 and HR 1.51; 95% CI 0.83-2.83, respectively) differed significantly from other trials (P = .008 and P = .01, respectively). CONCLUSIONS: LVEF values and QRS duration do not appear to directly modify the survival benefit of ICD in patients with baseline LVEF<35%. However, patients with a recent myocardial infarction do not benefit from ICD, especially when they have LVEF<25% and/or wide QRS. PMID- 23107653 TI - Use of electrical coupling information in AF catheter ablation: every lesion counts. PMID- 23107654 TI - Expanding the limits of epicardial mapping for ablation of ventricular tachycardia--the times they are a-changin'. PMID- 23107655 TI - n-3PUFA and Holter-derived autonomic variables in patients with heart failure: data from the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) Holter substudy. AB - BACKGROUND: n-3 Polyunsaturated fatty acid (n-3PUFA) supplementation in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) study reduced total mortality in patients with heart failure (HF), but the mechanism of action is still debated. The hypothesis of the present GISSI-HF substudy was that n-3PUFA may have beneficial effects on cardiac autonomic control. OBJECTIVE: To evaluate the effect of 1 g/day of n-3PUFA vs placebo on heart rate variability variables, deceleration capacity, and turbulence slope. METHODS: The GISSI-HF study enrolled patients with HF of any cause and severity. Twenty-four-hour (range 16-24 hours) Holter recordings were performed and analyzed in 388 patients at baseline, 3 months, and 12 months. Baseline characteristics were compared by using the chi(2) test, t test, or nonparametric Wilcoxon 2-sample test. Changes over time were tested by using the analysis of covariance adjusted by baseline values. RESULTS: At baseline, 36% of the patients were older than 70 years, 82% were men, 92% presented a left ventricular ejection fraction<40%, and 80% were in New York Heart Association class II. An increase in mean RR interval, standard deviation of all normal-to-normal RR intervals, very low frequency power (all P<.05), and turbulence slope (P = .05) was observed after 3 months in the n-3PUFA group compared to the placebo group, independently of the frequency of dietary fish consumption or beta-blocker treatment. These differences between study groups were no longer statistically significant at 12 months. A per-protocol analysis in patients compliant with study treatment showed similar results. CONCLUSIONS: n-3PUFA supplementation partially restored autonomic modulation in patients with chronic HF; this effect was maximal after 3 months of treatment. PMID- 23107656 TI - Characterization of an H3N2 canine influenza virus isolated from Tibetan mastiffs in China. AB - Ten 3-month-old Tibetan mastiffs became ill 2 days after they were bought from a Tibetan mastiff exhibition, and 4 of them died 2 weeks later. A canine influenza virus (ZJ0110) was isolated from the lung of a deceased Tibetan mastiff and was characterized in detail. Sequence analysis indicated that the 8 genes of the canine isolate were most similar to those of avian-origin canine influenza viruses (H3N2) isolated in South Korea in 2007, with which they shared >98% sequence identity. ZJ0110 could experimentally infect 6-month-old beagles by intranasal inoculation and by airborne transmission, causing severe respiratory syndrome. Moreover, ZJ0110 could replicate in the upper respiratory tracts of mice and guinea pigs, and the virus titer was comparable to that in the upper respiratory tracts of dogs. Although the virus was genetically of avian origin, ZJ0110 could not experimentally infect chicken or ducks by intranasal inoculation. These results suggest that dogs might be an intermediary host in which avian influenza viruses adapt to replicate in mammals. PMID- 23107657 TI - Porcine circovirus type 2 (PCV2) vaccination reduces PCV2 in a PCV2 and Salmonella enterica serovar Choleraesuis coinfection model. AB - We previously reported that prior porcine circovirus type 2 (PCV2) infection potentiates the severity of clinical signs, lung lesions, and fecal shedding and tissue dissemination of Salmonella enterica serovar Choleraesuis in infected pigs. Here, we evaluated whether PCV2 vaccination is effective in reducing fecal shedding and tissue dissemination of S. Choleraesuis and improving clinical signs associated with PCV2 and S. Choleraesuis infection in 15 Cesarean-derived, colostrum-deprived pigs randomly assigned to 3 groups (n=5/group). The vaccinated and co-infected (VAC-COINF) group received 2 ml of a commercial PCV2 vaccine at age 3 weeks. The VAC-COINF and co-infected (COINF) groups were inoculated intranasally with PCV2 and S. Choleraesuis at 5 and 7 weeks of age, respectively. The CONTROL group pigs received a similar volume of PBS for sham-vaccination and sham-inoculation. PCV2 vaccination clearly reduced PCV2 DNA load in the serum and postmortem tissue samples and decreased PCV2 antigen levels in tissue samples of the VAC-COINF group. After S. Choleraesuis infection, the incidence of several clinical signs increased in the VAC-COINF group compared to that in the COINF group. The microscopic lung lesions and weight gain, fecal shedding and tissue dissemination of S. Choleraesuis except in the spleen were not significantly different in the VAC-COINF and COINF groups. Thus, PCV2 vaccination reduced PCV2 in the S. Choleraesuis and PCV2 coinfection model and the effects on S. Choleraesuis were minimal. PMID- 23107658 TI - Disseminated intravascular coagulation does not play a major role in the pathogenesis of classical swine fever. AB - Classical swine fever (CSF) is a multi-systemic disease that can be accompanied by severe haemorrhagic lesions. The underlying pathogenetic mechanisms are still far from being understood, though disseminated intravascular coagulation (DIC) was discussed as a major factor. In the presented study, the direct thrombin inhibitor hirudin was used in an attempt to elucidate the role of the coagulation system in the pathogenesis of CSF-induced haemorrhagic lesions. Two groups of piglets (n=5) were infected with highly virulent CSF virus (CSFV) strain CSF0634. One group underwent daily treatment with hirudin, the other served as untreated challenge infection control. Assessment of clinical signs using a clinical score system, coagulation tests, and blood counts were performed daily. Both groups developed acute-lethal CSF with haemorrhagic lesions. Although changes in the coagulation system were seen in the late stages of CSFV infection, our results strongly suggest that DIC does not present the crucial event in the pathogenesis of haemorrhagic lesions. PMID- 23107659 TI - Evaluation of minocycline susceptibility of methicillin-resistant Staphylococcus pseudintermedius. AB - Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is an increasingly important cause of opportunistic infections in dogs and cats. Treatment options are often limited because of the high level of antimicrobial resistance. Doxycycline resistance is common, but variable mechanisms of doxycycline resistance exist, with some conferring resistance to doxycycline but not minocycline. However, there has been limited study of minocycline susceptibility in clinical MRSP isolates nor has the association of susceptibility and clonal complex been clearly established. The objective of this study was to evaluate the susceptibility of MRSP to tetracycline, doxycycline and minocycline, to determine the prevalence of tet(M) and tet(K) and to evaluate the impact of strain on minocycline susceptibility. One hundred seven MRSP isolates from dogs from Canada and the US were included; 79 from clinical infections and 28 from colonization sites. Thirty-nine (36%) isolates were susceptible to tetracycline, 41 (38%) to doxycycline and 70 (65%) to minocycline. Two main dru types, dt9a and dt11a, were present. When tetracycline or doxycycline resistant, dru type dt9a and related strains predominantly harboured tet(K) and were susceptible to minocycline. In contrast, dt11a and related strains tended to harbour tet(M), which confers resistance to all three tetracyclines. Minocycline might be a treatment option for some MRSP infections, even those that are doxycycline resistant; however, interpretive breakpoints may need to be re-assessed. Study of the pharmacokinetics and clinical efficacy of minocycline in dogs and cats is warranted. PMID- 23107660 TI - [18th "Actualites du Pharo" Marseille, September 13th and 14th 2012]. PMID- 23107661 TI - [Obstetrical vesicovaginal fistula for single visiting surgeons in Africa]. AB - Obstetrical vesicovaginal fistulas remain frequent in Africa. An isolated surgeon, making a short-term visit, must select cases with a good prognosis by thorough clinical examination. Surgery is the only treatment and is simple for these simple cases: debridement of both sides of the sclerotic fistula, making it possible to separate the vaginal and bladder walls and to suture each individually. This reproducible surgery must be effective to lead to the women's social reintegration. Accordingly, isolated surgeons must treat only simple cases. PMID- 23107662 TI - [Human rabies in Abidjan (Cote d'Ivoire): recent cases]. AB - OBJECTIVE: To present epidemiological and clinical aspects of human rabies in a hospital center. METHOD: We analyzed medical records of cases of rabies in humans treated at the infectious disease department of the Treichville University Hospital Center from January 2005 through December 2009. RESULTS: Seven cases of human rabies were reported during those five years, four in teenagers and three in adults. Five of the cases involved bites by stray dogs whose vaccine status was unknown. No patient had had a pre-exposure prophylactic vaccination, and only four post-exposure prophylaxis, all incomplete. All of the patients developed furious rabies and fever 21 to 96 days (mean: 47.7) after the dog bite, when the wounds had healed and scars formed. Death occurred 4 to 10 days after the onset of symptoms (mean: 4.7). Relatives refused autopsies in all cases. CONCLUSION: It is indispensable to increase population awareness of prevention by vaccination against human rabies, reduce the population of stray dogs, and promote mass vaccination of dogs in the Ivory Coast. PMID- 23107663 TI - [Esophageal variceal band ligation in Dakar, Senegal]. AB - After a preliminary study in the gastrointestinal endoscopy center of the Aristide-Le-Dantec Teaching Hospital in Dakar, Senegal, demonstrated the feasibility and effectiveness of endoscopic ligation of esophageal varices, this procedure entered regular use for management of patients admitted for upper digestive tract bleeding due to these varices. This study sought to assess its effectiveness. Patients and method. This study, conducted from July 2005 through January 2010, included all patients with upper digestive tract bleeding due to rupture of esophageal varices. Results. In all, 140 patients with a mean age of 36 years [range: 16-75] were admitted for this diagnosis and included in the study: 93 men and 47 women (sex-ratio = 1.98). The presence of at least one clinical sign of portal hypertension was noted in 72% of cases. Esophageal varices were graded as stage III in 75.7% of cases. The underlying cause of portal hypertension was cirrhosis in 94.3%, presumptively due to hepatitis B virus among 37.1%. The varices were successfully eradicated in 64 patients (45.7%). The mean number of sessions required was 2 [range: 2-4] in patients with stage II and 3.4 [range, 3-8] in patients with stage III varices, and the mean number of bands applied per session was 5.1 [range: 2-6] and 5.6 [range: 2-10], respectively. The interval between sessions was 4 weeks [range: 3 -12]. Bleeding recurred in 8 patients (5.7%) before eradication was achieved; 4 (2.8%) of them died. Conclusion. Esophageal variceal ligation is an effective therapeutic and prophylactic procedure for management of esophageal varices in Senegal. PMID- 23107664 TI - [Intestinal parasites in children in Biankouma, Ivory Coast (mountaineous western region): efficacy and safety of praziquantel and albendazole]. AB - Schistosomiasis and soil-transmitted helminthiasis are a global public health problem, especially among schoolchildren. The purpose of this study was to determine the overall and specific prevalences of intestinal helminth infection and to assess the clinical efficacy, tolerance, and safety of praziquantel and albendazole for treating it. A descriptive cross-sectional study based on random sampling with one degree of freedom was conducted from November 2006 to March 2007 in the primary schools of Biankouma, Cote d'Ivoire. Stool samples were collected from 386 children aged from 4 to 15 years and analyzed by direct examination, with both the simplified Ritchie and Kato techniques. Children infected by schistosomiasis and soil-transmitted helminthiasis eggs were treated with praziquantel (40 mg/kg in a single dose), albendazole (400 mg/kg in a single dose) or both, as deemed necessary. The prevalence rate of intestinal parasite infection was 55.2%, including overall 15.4% with more than one parasite: two in 14.2% and three in 1.2%. Infection was correlated with male gender and older age. The most frequent helminths were Schistosoma mansoni (35.5%) and Necator americanus (25.9%). The efficacy rate for praziquantel, defined as parasite-free stools, was 57.7% on day 14 and 80.9% on day 90. The efficacy rate for albendazole on day 7 was 96.1% for Ascaris lumbricoides, 93% for Necator americanus and 81.3% for Trichuris trichiura. Adverse effects were common (40.8%) but minor (abdominal pain, headache, and itching) within 2 to 4 hours after intake of praziquantel. PMID- 23107665 TI - [Adhesion of physicians to the national malaria policy: situation in Antananarivo (Madagascar), 5 years after the policy revision]. AB - Our goal was to evaluate and analyze physicians' adherence to the national malaria policy in Antananarivo, 5 years after its revision. This prospective descriptive study was conducted in public and private health centers in Antananarivo in 2010, from May 1 to June 30. Adhesion to the new policy included adoption of the rapid diagnostic test for malaria (RDT) and/or microscopy as diagnostic methods and prescription of artemisinin-based combination therapy (ACT) as first-line treatment for uncomplicated malaria. A questionnaire was used to collect data from 106 physicians. Their average age was 43.9 years (range: 26 to 59 years). The male-female sex-ratio was 0.59. Physicians trained in using RDTs were confident in this means of diagnosis (p < 10(-4)). Prescription of ACT by physicians was associated with their participation in malaria training (p = 0.02). Only 2/3 of the physicians adhered to the current policy. Adherence increased with trust (p < 10(-4)), availability of RDT (p < 10(-5)), and training about the policy. Physician adhesion, training and confidence are essential to this policy and to changing physician behavior. Improvement of the health system is also needed. PMID- 23107666 TI - Methods of administering superimposed high-frequency jet ventilation and the associated risk for aspiration in a model of tracheal bleeding. AB - BACKGROUND: To determine the suitability of different superimposed high-frequency jet ventilation (SHFJV) application methods during tracheal bleeding. OBJECTIVE: To determine the effect of SHFJV on the aspiration of blood during tracheal bleeding. METHODS: A test lung was ventilated using SHFJV via a rigid endoscope, a jet laryngoscope and a 4-lumen jet catheter. Packed red blood cells (PRBCs) were injected into the artificial trachea caudally to the rigid endoscope and jet laryngoscope ventilation, and both caudally and cranially during ventilation via the 4-lumen jet catheter, and the migration of PRBCs during ventilation was studied using continuous video recording. RESULTS: Migration of blood into the lower respiratory tract did not occur during SHFJV via the rigid endoscope and jet laryngoscope and via the 4-lumen jet catheter with the bleeding caudal to ventilation source. If the bleeding was cranial to the 4-lumen jet catheter ventilation, migration of blood into the lower respiratory tract was seen when reflux of blood reached the entrainment area. From this area, blood is transported within the jet stream into the lower respiratory tract. CONCLUSIONS: SHFJV protects the lower respiratory tract from blood aspiration in case of tracheal bleeding. During SHFJV via the 4-lumen jet catheter, aspiration of blood only occurs if bleeding is localized cranial to the 4-lumen jet catheter ventilation. In case of heavy tracheal bleeding, the jet sources should be positioned cranial to the site of bleeding. PMID- 23107667 TI - Peptidomimetic modification improves cell permeation of bivalent farnesyltransferase inhibitors. AB - Bivalent enzyme inhibitors, in which a surface binding module is linked to an active site binding module through a spacer, are a robust approach for site selectively delivering a minimally-sized agent to a protein surface to regulate its functions, such as protein-protein interactions (PPIs). Previous research revealed that these agents effectively disrupt the interaction between farnesyltransferase (FTase) and the C-terminal region of K-Ras4B protein. However, the whole cell activity of these peptide-based agents is limited due to their low membrane permeability. In this study, we tested a peptidomimetic modification of these bivalent agents using a previously developed inhibitor, FTI 249, and evaluated their cell permeability and biological activity in cells. Confocal cell imaging using fluorescently-labeled agents showed that the peptidomimetic 3-BODIPY penetrated cells, while the peptide-based 1-BODIPY did not. Cell-based evaluation demonstrated that peptidomimetic 3 at a concentration of 100MUM inhibited HDJ-2 processing in cells, indicating that this peptidomimetic modification improves cell permeability, thus leading to enhanced whole cell activity of the bivalent compounds. PMID- 23107668 TI - Influence of thiostrepton binding on the ribosomal GTPase associated region characterized by molecular dynamics simulation. AB - The thiostrepton antibiotic inhibits bacterial protein synthesis by binding to a cleft formed by the ribosomal protein L11 and 23S's rRNA helices 43-44 on the 70S ribosome. It was proposed from crystal structures that the ligand restricts L11's N-terminal movement and thus prevents proper translation factor binding. An exact understanding of thiostrepton's impact on the binding site's dynamics at atomistic resolution is still missing. Here we report an all-atom molecular dynamics simulations of the binary L11.rRNA and the ternary L11.rRNA.thiostrepton complex (rRNA = helices 43-44). We demonstrate that thiostrepton directly impacts the binding site's atomic and biomacromolecular dynamics. PMID- 23107669 TI - Improving the fitness and physical activity levels of primary school children: results of the Fit-4-Fun group randomized controlled trial. AB - OBJECTIVE: To evaluate the impact of a multi-component school-based physical activity intervention (Fit-4-Fun) on health-related fitness and objectively measured physical activity in primary school children. METHODS: Four Hunter primary schools were recruited in April, 2011 and randomized by school into treatment or control conditions. Participants included 213 children (mean age = 10.72 years +/- 0.6; 52.2% female) with the treatment group (n = 118) completing the 8-week Fit-4-Fun Program. Participants were assessed at baseline and 6-month follow-up, with a 91% retention rate. Cardio-respiratory fitness (CRF) (20 m shuttle run) was the primary outcome, and secondary outcomes included body composition (BMI, BMI(Z)), muscular fitness (7-stage sit-up test, push-up test, basketball throw test, Standing Jump), flexibility (sit and reach) and physical activity (7 days pedometry). RESULTS: After 6-months, significant treatment effects were found for CRF (adjusted mean difference, 1.14 levels, p < 0.001), body composition (BMI mean, -0.96 kg/m(2), p < 0.001 and BMI z-score mean -0.47 z scores, p < 0.001), flexibility (sit and reach mean, 1.52 cm, p = 0.0013), muscular fitness (sit-ups) (mean 0.62 stages, p = 0.003) and physical activity (mean, 3253 steps/day, p < 0.001). There were no group by time effects for the other muscular fitness measures. CONCLUSIONS: A primary school-based intervention focusing on fitness education significantly improved health-related fitness and physical activity levels in children. PMID- 23107670 TI - Biosynthesis of phenolic antioxidants in carrot tissue increases with wounding intensity. AB - Biosynthesis of phenolic antioxidants in three carrots cultivars (Navajo, Legend and Choctaw) were studied under different wounding intensities (A/W) during storage. Generated A/W of 4.2, 6.0 and 23.5 cm(2)/g, corresponded to slices, pies, and shreds, respectively. Soluble phenolics, antioxidant capacity (AOX), and PAL activity increased with A/W for all cultivars. Intense wounding (23.5 cm(2)/g) induced an ~2.5- and ~12.4-fold increase in soluble phenolics and AOX, respectively, after 4 days compared to whole carrots. Wounding induced the synthesis of mainly chlorogenic acid (5-CQA) and 3,5-dicaffeoylquinic acid. A higher proportion of 5-CQA in the phenolic mixture was responsible for an increasing specific AOX (809 and 1,619 MUg Trolox/mg phenolics for whole carrots and shreds, respectively, for Choctaw cultivar). Wounded carrots can be promoted as an inexpensive rich source of phenolic antioxidants for the regular diet. By simply increasing wounding stress intensity it is possible to enhance the biosynthesis of phenolic antioxidants. PMID- 23107671 TI - Extraction of phenolic compounds from grapes and their pomace using beta cyclodextrin. AB - Use of aqueous cyclodextrins (CD) for recovery of selected bioactive phenolic compounds from grapes and their pomace was evaluated. When alpha, beta and gamma forms of CD were compared, beta-CD was the most effective in recovering stilbenes, flavonols, and flavan-3-ols from grape pomace. The maximum quantified phenolics were obtained from the powder and the slurry of grape pomace when extracted with 2.5% (w/v) aqueous beta-CD solutions at 60 degrees C for 12-24h. With beta-CD, total quantified phenolics obtained from the dry powder were 123 mg/100g (DW) while from the slurry, they were 35.8 mg/100g (FW). Incorporation of beta-CD to grape mash prior to pressing for juice enhanced the recovery of phenolics in juice. Incorporation of beta-CD was more effective in recovering flavan-3-ols than flavonols. Aqueous CD can effectively be used in recovering phenolics from by-products of fruit processing and therefore for functional foods and nutraceutical applications. PMID- 23107672 TI - Influence of lipid composition on physicochemical properties of nanoliposomes encapsulating natural dipeptide antioxidant l-carnosine. AB - Natural dipeptide antioxidants (l-carnosine) are recieving increasing attention because of their noticeable potential as biopreservatives in food recent technology. Encapsulation of antioxidants by nanoliposomes could represent an ameliorative approach to overcome the problems related to the direct application of these antioxidant peptides in food. In this study, nanoliposomes prepared from different lipids (DOPC, POPC and DPPC) by thin film hydration method, were assessed by considering their size, zeta-potential, phase transition temperature and fluidity. One important parameter of interest in this article was to compare the encapsulation efficacy of l-carnosine in three different nanoliposomes using a rapid and precise approach (1)H NMR without the need for physical separation of entrapped and non-entrapped l-carnosine. Furthermore, the morphology of small unilamellar nanoliposomes with different compositions on mica surface was investigated using Atomic Force Microscopy. PMID- 23107673 TI - Phenolic extracts of brewers' spent grain (BSG) as functional ingredients - assessment of their DNA protective effect against oxidant-induced DNA single strand breaks in U937 cells. AB - Brewers' spent grain (BSG), a by-product of the brewing industry, contains high amounts of phenolic acids, which have antioxidant effects. The present study examined the ability of BSG extracts to protect against the genotoxic effects of oxidants, hydrogen peroxide (H(2)O(2)), 3-morpholinosydnonimine hydrochloride (SIN-1), 4-nitroquinoline 1-oxide (4-NQO) and tert-butylhydroperoxide (t-BOOH) in U937 cells. Four pale (P1-P4) and four black (B1-B4) BSG extracts were investigated. U937 cells were pre-incubated with BSG extracts, exposed to the oxidants and the DNA damage was measured by the Comet assay. The black BSG extracts (B1-B4) significantly protected against H(2)O(2)-induced DNA damage. Extract B2, which had the highest phenol content, provided the greatest protection. Extracts P2, B2, B3 and B4 provided significant protection against SIN-1-induced DNA damage. None of the extracts protected against DNA damage induced by t-BOOH and 4-NQO. The DNA protective effects of the BSG phenolic extracts may be related to iron chelation. PMID- 23107674 TI - Effects of ozone on functional properties of proteins. AB - The present study investigates whether the ozone treatment could be an alternative to improve some functional properties of proteins. Ozone treatment was applied on whey protein isolate and egg white proteins which have been extensively used in food products to improve textural, functional and sensory attributes. Ozone treatment of proteins was performed either in aqueous solutions or as gas ozonation of pure protein powders. Foam formation and foam stability of proteins were enhanced extensively. The solubility of proteins were reduced as influenced from the aqueous and gas ozonation medium. The reduction was more pronounced in egg white proteins. Ozone treatment affected emulsion activity of whey protein isolate negatively and reduced the emulsion stability. PMID- 23107675 TI - Characterisation of bound volatile compounds of a low flavour kiwifruit species: Actinidia eriantha. AB - Aroma compounds in fruit are known to occur in free and glycosidically bound forms. The bound volatile fraction of a low flavour kiwifruit species, Actinidia eriantha, was studied. The fruit have a bland and grassy flavour. Glycosidic precursors were isolated from juice by adsorption onto an Amberlite XAD-2 column. After enzymatic hydrolysis with Rapidase AR2000, the released aglycones were analysed by GC-MS. Alcohols, terpenoids and phenolics were the most numerously represented compound classes. Alcohols, benzenoids and phenolics showed the highest concentrations. Major compounds were 2-phenylethanol, furfuryl alcohol, (Z)-3-hexen-1-ol, coniferyl alcohol, isoamyl alcohol and linolenic acid. Several of the bound compounds found, including linoleic, linolenic and benzoic acids and coniferyl alcohol, are precursors of odorous volatiles. Many compounds detected as bound volatiles have not been previously reported as free volatiles in A. eriantha. The bound volatile composition of A. eriantha also showed differences with those of other kiwifruit species. PMID- 23107676 TI - Volatile fingerprinting of chestnut flours from traditional Emilia Romagna (Italy) cultivars. AB - The volatile profile of nine monocultivar chestnut flours, obtained from fruits grown in Italy (Parma province), was characterised by a head-space solid-phase microextraction (HS-SPME) coupled with GC-MS technique. The volatile fraction was composed of 44 main compounds belonging to different classes, mainly aldehydes, ketones, alcohols, furans and terpenes. Aldehydes, in particular hexanal, are the most abundant components. In order to better understand the origin of the different volatile compounds during the drying and milling processes, samples of fresh fruit were also analysed by the same technique and the data obtained were statistically and critically compared in order to get a picture of the volatile evolution in chestnut from fresh fruit to flour. Finally, the nine monocultivar flours were chemometrically classified on the basis of the main odour descriptors associated with the volatile fingerprinting. PMID- 23107677 TI - Antioxidant capacity, total phenolic and ascorbate content as a function of the genetic diversity of leek (Allium ampeloprasum var. porrum). AB - Extracts of the white shaft and green leaves of 30 leek cultivars were investigated for their antioxidant properties, total phenolic (TP) and l-ascorbic acid (AA) content. The measured antioxidant properties included free radical scavenging activities against peroxyl (ORAC) and 2,2-diphenyl-1-picrylhydrazyl radicals (DPPH) and their Fe(3+) reducing capacity (FRAP). The results from this study suggest that the green leek leaves generally have significantly stronger antioxidant properties than the white shaft. Correlation analysis between the TP and the AA content and the antioxidant activity showed that phenolics and ascorbic acid contribute significantly to the antioxidant activity of leek. The three antioxidant activity assays were all correlated for the extracts of the white shaft of the 30 leek cultivars. Principal component analysis (PCA) elucidated the influence of part and type of cultivar on the antioxidant capacity, TP, and l-ascorbic acid content, whilst the breeding strategy and seed company had no influence. PMID- 23107678 TI - Collagen characteristics of farmed Atlantic salmon with firm and soft fillet texture. AB - The possible role of collagen in texture variations among Atlantic salmon (Salmo salar L.) grown under commercial conditions at a Norwegian farm was studied. The texture was determined instrumentally as the breaking strength, and collagen and its salt (SSC), acid (ASC), pepsin (PSC) and insoluble (IF) fractions were analysed in order to determine the collagen aggregation degree. The collagen solubility and its overall amino acid (AA) composition showed no correlation to the breaking strength, but a positive correlation was observed between the breaking strength and glycine (r=0.74) and alanine (r=0.87) contents of the PSC fraction. Salmon with high breaking strength had higher T(peak) (temperature of transition) and DeltaH (enthalpy of transition), and the collagen seemed to have triple helix structures mainly stabilized by covalent associations as compared to salmon with low breaking strength. The glycosylation degree was also positively correlated to the breaking strength (r=0.88, p <= 0.05). It is concluded that firmness of salmon muscle was not related to the total amount of collagen in the muscle, but rather higher collagen stability. PMID- 23107679 TI - Characterisation of calamansi (Citrus microcarpa). Part I: volatiles, aromatic profiles and phenolic acids in the peel. AB - Volatile compounds in the peel of calamansi (Citrus microcarpa) from Malaysia, the Philippines and Vietnam were extracted with dichloromethane and hexane, and then analysed by gas chromatography-mass spectroscopy/flame ionisation detector. Seventy-nine compounds representing >98% of the volatiles were identified. Across the three geographical sources, a relatively small proportion of potent oxygenated compounds was significantly different, exemplified by the highest amount of methyl N-methylanthranilate in Malaysian calamansi peel. Principal component analysis and canonical discriminant analysis were applied to interpret the complex volatile compounds in the calamansi peel extracts, and to verify the discrimination among the different origins. In addition, four common hydroxycinnamic acids (caffeic, p-coumaric, ferulic and sinapic acids) were determined in the methanolic extracts of calamansi peel using ultra-fast liquid chromatography coupled to photodiode array detector. The Philippines calamansi peel contained the highest amount of total phenolic acids. In addition, p Coumaric acid was the dominant free phenolic acids, whereas ferulic acid was the main bound phenolic acid. PMID- 23107680 TI - Characterisation of calamansi (Citrus microcarpa). Part II: volatiles, physicochemical properties and non-volatiles in the juice. AB - Calamansi juices from three countries (Malaysia, the Philippines and Vietnam) were characterised through measuring volatiles, physicochemical properties and non-volatiles (sugars, organic acids and phenolic acids). The volatile components of manually squeezed calamansi juices were extracted using dichloromethane and headspace solid-phase microextraction, and then analysed using gas chromatography mass spectrometry/flame ionisation detector, respectively. A total of 60 volatile compounds were identified. The results indicated that the Vietnam calamansi juice contained the highest amount of volatiles. Two principal components obtained from principal component analysis (PCA) represented 89.65% of the cumulative total variations of the volatiles. Among the non-volatile components, these three calamansi juices could be, to some extent, differentiated according to fructose and glucose concentrations. Hence, this study of calamansi juices could lead to a better understanding of calamansi fruits. PMID- 23107681 TI - Microcapsules containing antioxidant molecules as scavengers of reactive oxygen and nitrogen species. AB - The antioxidant capacities of gum arabic and maltodextrin microcapsules containing antioxidant molecules (trolox, alpha-tocopherol, beta-carotene, apo-8' carotenal and apo-12'-carotenal) against reactive oxygen and nitrogen species were evaluated. The scavenging capacities were influenced by the wall material, the reactive species, namely ROO(), H(2)O(2), HO(), HOCl and ONOO(-), and the antioxidant molecule. In general, a more pronounced enhancement of the antioxidant capacity due to incorporation of antioxidant molecules was observed in gum arabic microcapsules. The empty microcapsules showed capacity to scavenge all the studied ROS and RNS, being gum arabic a more potent antioxidant than maltodextrin. Apo-8'-carotenal incorporation promoted the highest increase in the scavenging capacities among the evaluated antioxidants, varying from 50% to 132% and from 39% to 85% for gum arabic and maltodextrin microcapsules, respectively, suggesting that this carotenoid presented the best balance between the molecule localization inside the microcapsules and the reactivity against the specific reactive species. PMID- 23107682 TI - Heat treatment effect on polyphosphate chain length in aqueous and calcium solutions. AB - Polyphosphate blends are used in food such as meat and dairy products to improve their texture and stability by sequestering metal ions. This study aims to analyse the impact of high temperature treatments on the composition of polyphosphates with regards to phosphate chain length in aqueous solutions with or without calcium. Temperature treatments of 120 degrees C for 10 min led to the hydrolytic degradation of long-chain phosphates into orthophosphate and trimetaphosphate whereas heating the salts to 100 degrees C in aqueous solutions had little effect on their composition. The presence of calcium increased the hydrolysis rate of long-chain phosphates and led to more trimetaphosphate and pyrophosphate as end products. The evolution of emulsifying salts' composition under heat treatment may lead to a modification of their chelating properties since short-chain phosphates are less efficient to chelate calcium than long chain phosphates. PMID- 23107683 TI - Evaluation of the structure-activity relationship of flavonoids as antioxidants and toxicants of zebrafish larvae. AB - The antioxidant ability of an array of commercially available flavonoids was evaluated on the larvae of the zebrafish model organism, in order to find flavonoids with lower toxicities and higher radical oxygen-scavenging properties than flavone. Among the flavonoids tested, chrysin and morin possessed higher reactive oxygen species (ROS)-scavenging rates (-99% and -101%, respectively) and lower toxicity (LD(50)>100 ppm). Zebrafish fins in the UVB+chrysin group were 6.30 times more likely to grow to normal fin size than those in the UVB-only control group, while zebrafish fins in the UVB+morin group were 11.9 times more likely to grow to normal fin size than those in the UVB-only control group. These results were analysed by the QSAR method and were in accordance with predicted values. A new 4'-fluoroflavone was synthesised. The ROS-scavenging rate of 4' fluoroflavone was -54%, which corresponds well with the predicted value (-48%). We propose that a combination of QSAR prediction and the zebrafish model organism is efficient for evaluating new flavonoids. PMID- 23107684 TI - New insights into antioxidant activity of Brassica crops. AB - Antioxidant activity of six Brassica crops-broccoli, cabbage, cauliflower, kale, nabicol and tronchuda cabbage-was measured at four plant stages with DPPH and FRAP assays. Samples taken three months after sowing showed the highest antioxidant activity. Kale crop possessed the highest antioxidant activity at this plant stage and also at the adult plant stage, while cauliflower showed the highest antioxidant activity in sprouts and in leaves taken two months after sowing. Brassica by-products could be used as sources of products with high content of antioxidants. Phenolic content and composition varied, depending on the crop under study and on the plant stage; sprout samples were much higher in hydroxycinnamic acids than the rest of samples. Differences in antioxidant activity of Brassica crops were related to differences in total phenolic content but also to differences in phenolic composition for most samples. PMID- 23107685 TI - Antioxidant capacity of cornelian cherry (Cornus mas L.) - comparison between permanganate reducing antioxidant capacity and other antioxidant methods. AB - Ethanol extracts (80% in water) of 10 cornelian cherry (Cornus mas L.) genotypes were studied for antioxidant properties, using methods including DPPH(), ()NO, O(2)(-) and ()OH antiradical powers, FRAP, total phenolic and anthocyanin content (TPC and ACC) and also one relatively new, permanganate method (permanganate reducing antioxidant capacity-PRAC). Lipid peroxidation (LP) was also determined as an indicator of oxidative stress. The data from different procedures were compared and analysed by multivariate techniques (correlation matrix calculation and principal component analysis (PCA)). Significant positive correlations were obtained between TPC, ACC and DPPH(), ()NO, O(2)(-), and ()OH antiradical powers, and also between PRAC and TPC, ACC and FRAP. PCA found two major clusters of cornelian cherry, based on antiradical power, FRAP and PRAC and also on chemical composition. Chemometric evaluation showed close interdependence between PRAC method and FRAP and ACC. There was a huge variation between C. mas genotypes in terms of antioxidant activity. PMID- 23107686 TI - Anti-inflammatory activity of lipophilic epigallocatechin gallate (EGCG) derivatives in LPS-stimulated murine macrophages. AB - Epigallocatechin gallate (EGCG), the major polyphenol in green tea and the main bioactive compound responsible for the health benefits of tea consumption, has been proposed as a functional ingredient for food and natural health products. However, EGCG is hydrophilic with poor cellular absorption and thus compromised bioefficiency in vivo. In order to enhance the lipophilicity of EGCG for improved bioefficiency and to take advantage of the health beneficial omega 3 fatty acids, the EGCG molecule was esterified with docosapentaenoic acid (DPA), upon which a mixture of ester derivatives with different degrees of substitution was produced. The EGCG-DPA esters were evaluated for their anti-inflammatory activity in LPS (lipopolysaccharides)-stimulated murine RAW 264.7 macrophages. The production of pro-inflammatory mediators nitric oxide (NO) and prostaglandin (PGE(2)) was significantly inhibited by treatment of EGCG-DPA esters, and the inhibition was largely due to their down-regulatory effect on iNOS (inducible NO synthase) and COX (cyclooxygenase)-2 gene expression at transcriptional level. The EGCG-DPA esters effectively suppressed the expression of iNOS and COX -2 proteins as well as their mRNA, as observed with western blotting and RT-PCR analyses. Ester derivatives of EGCG with other fatty acids (stearic acid, SA; eicosapentaenoic acid, EPA; and docosahexaenoic acid, DHA) were also prepared in the form of pure tetraesters, which also exhibited anti-inflammatory effect in the macrophages. The results suggest that EGCG ester derivatives with anti-inflammatory potentials may be useful in preventing/treating inflammation-mediated diseases and health conditions. PMID- 23107687 TI - Impact of lemon oil composition on formation and stability of model food and beverage emulsions. AB - Lemon oil is a complex organic compound isolated from citrus peel, which is commonly used as a flavouring agent in beverages, foods, cosmetics, and household products. We have studied the influence of lemon oil fold (1*, 3*, 5* and 10*) on the formation and properties of oil-in-water emulsions. Initially, the composition, molecular characteristics, and physicochemical properties of the four lemon oils were established. The main constituents in single-fold lemon oil were monoterpenes (>90%), whereas the major constituents in 10-fold lemon oil were monoterpenes (~35%), sesquiterpenes (~14%) and oxygenates (~33%). The density, interfacial tension, viscosity, and refractive index of the lemon oils increased as the oil fold increased (i.e., 1*<3*<5*<10*). The stability of oil-in water emulsions produced by high pressure homogenisation was strongly influenced by lemon oil fold. The lower fold oils were highly unstable to droplet growth during storage (1*, 3*, and 5*) with the growth rate increasing with increasing storage temperature and decreasing oil fold. Droplet growth was attributed to Ostwald ripening, i.e., diffusion of lemon oil molecules from small to large droplets. The highest fold oil (10*) was stable to droplet growth, which was attributed to the presence of an appreciable fraction of constituents with very low water-solubility that inhibited droplet growth through a compositional ripening effect. This study provides important information about the relationship between lemon oil composition and its performance in emulsions suitable for use in food and beverage products. PMID- 23107688 TI - In vitro and in vivo protective effects of fermented preparations of dietary herbs against lipopolysaccharide insult. AB - Lipopolysaccharide (LPS) is known to produce endotoxic shock by triggering systemic inflammatory responses. Here, we evaluated the protective effects of three fermented/re-fermented herbs, Rhizoma Atractylodis Macrocephalae, Massa Medicata Fermentata, and Dolichoris Semen, in an LPS-mediated inflammatory insult, either individually in vitro using RAW264.7 cells or in combination in in vivo using rats. In general, each of the fermented herbs showed appreciable in vitro anti-inflammatory activity, although the degree of this activity varied with the herb used. Moreover, a mixture of fermented herbal extracts in combination with probiotics significantly attenuated the blood endotoxin and CRP levels, as well as the gut permeability, and significantly augmented the intestinal Lactobacillus spp. colonisation in LPS-treated rats. However, these effects were not observed following the administration of the corresponding mixture of unfermented herbal extracts. Thus, our results highlight the beneficial impacts of the use of fermented herb products with probiotics to combat LPS-mediated inflammatory insults. PMID- 23107689 TI - Antioxidant capacity and inhibitory effect of grape seed and rosemary extract in marinades on the formation of heterocyclic amines in fried beef patties. AB - The effect of oil-based marinades containing grape seed extract (Vitis vinifera L.; 0.2, 0.4, 0.6 and 0.8 g/100g) formulated in a water/oil emulsion or rosemary extract (Rosmarinus officinalis; 0.12, 0.2, 0.6, 1.0 and 1.5 g/100g) in oil on the formation of heterocyclic amines (HAs) in fried beef patties was examined. After application of marinades and frying, four HAs MeIQx (2-amino-3,8 dimethylimidazo[4,5-f]quinoxaline), PhIP (2-amino-1-methyl-6 phenylimidazo[4,5b]pyridine), Norharman, and Harman were found at low levels in all fried patties, MeIQx (0.3-1.0 ng/g), and PhIP (0.02-0.3 ng/g). The content of MeIQx and PhIP were significantly reduced by approx. 57% and 90% (p<0.05), respectively, after use of marinades containing the highest extract concentration. The antioxidant capacity of grape seed was about two-times greater than that of rosemary extract. A correlation between inhibition of HAs and Trolox equivalents (MeIQx, R(2)=0.85, p<0.001; PhIP, R(2)=0.83, p<0.001) was found. Sensory tests showed a high acceptance of flavour and colour for controls and samples. PMID- 23107690 TI - Phenolic profiles of cherry tomatoes as influenced by hydric stress and rootstock technique. AB - The aim of the present work was to evaluate the influence of genetic and technological factors (cultivar and grafting) combined with the abiotic stress (water stress) on the content of phenolic compounds (flavonoids and phenolic acids classes and total phenolics) in cherry tomato. The identification and contents of phenolic compounds and flavonoids were determined by HPLC-MS in fruits on reciprocal grafting between a drought-tolerant cultivar (Zarina) and drought-sensible cultivar (Josefina), compared with both self-grafted and non grafted plants. The results show how pre-harvest factors, such as grafting and water stress, can influence the phenolic content of tomato fruits. Phenolic compounds, including rutin that belongs to the group of flavonoids, display a remarkable array of biological and pharmacological activities. So, the richness of ZarxJos under water stress conditions with these compounds confirms its nutritional value and it can be used as a potential source of phenols. The results suggest that grafting on specific rootstocks more adapted to water stress conditions may be a tool to improve crop quality under artificially imposed mild water stress. PMID- 23107691 TI - (-)-Epigallocatechin-3-gallate stimulates both AMP-activated protein kinase and nuclear factor-kappa B signaling pathways. AB - We previously reported that (-)-epigallocatechin-3-gallate (EGCG) increased the level of SHARP-1 mRNA via a phosphoinositide 3-kinase/atypical protein kinase C lambda signaling pathway in rat H4IIE hepatoma cells. In the present study, we investigated other signaling pathway(s). Treating with either compound-C, BAY11 7082, or both, partially blocked the up-regulation of the SHARP-1 gene by EGCG. This suggests that AMP-activated protein kinase (AMPK)- and nuclear factor-kappa B (NF-kappaB)-signaling pathways were additively involved in the induction mediated by EGCG. Indeed, an AMPK activator induced a level of SHARP-1 mRNA. Although actinomycin D partially blocked the EGCG-induction of that SHARP-1 mRNA level, the nucleotide sequence between -1501 and -1 in the rat SHARP-1 gene did not positively respond to EGCG and NF-kappaB, respectively. Thus, we conclude that EGCG stimulates multiple signaling pathways in the SHARP-1 gene expression at the transcriptional and post-transcriptional levels and that there is no regulatory region susceptible to EGCG and NF-kappaB in the examined region. PMID- 23107692 TI - Retardation of myoglobin and haemoglobin-mediated lipid oxidation in washed bighead carp by phenolic compounds. AB - Antioxidative activities of phenolic compounds (caffeic acid, gallic acid and tannic acid; 200 ppm) in washed mince (pH 6), with added myoglobin (Mb) and haemoglobin (Hb), from bighead carp (Hypophthalmichthys nobilis), during 9 days of iced storage, were studied. Tannic acid exhibited the preventive effect on discolouration of washed mince containing Mb or Hb during storage (P<0.05). High peroxide value (PV) was found and large amount of, thiobarbituric acid-reactive substances (TBARS) and hexanal were formed in washed mince containing haem proteins, especially Hb. As determined by apo Streptococcal haem-associated protein, Hb had the lower haem affinity than Mb. Phenolic compounds, especially caffeic acid and gallic acid, could lower lipid oxidation induced by Mb or Hb throughout storage (P<0.05). Prevention of haem release, as well as inhibition of lipid oxidation induced by haem proteins with selected phenolic compounds, should be an alternative means in lowering discolouration and lipid oxidation in fish muscle. PMID- 23107693 TI - Production of dipeptidyl peptidase IV inhibitory peptides from defatted rice bran. AB - The insulinotropic hormone glucagon-like peptide-1 is metabolised extremely rapidly by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV). Therefore, human DPP-IV is a key regulator involved in the prevention and treatment of type 2 diabetes. To simplify the method of producing an inhibitory peptide against DPP IV, we focused on rice bran (RB) as a source and subjected proteins from defatted RB to enzymatic proteolysis using 2 commercial enzymes. The RB peptides produced with Umamizyme G exhibited 10 times the inhibitory activity as those produced with Bioprase SP. The half-maximal inhibitory concentration (IC(50)) value of the RB peptides was 2.3 +/- 0.1mg/ml. Leu-Pro and Ile-Pro were identified as the inhibitory peptides among the RB peptides produced with Umamizyme G. Ile-Pro was the strongest DPP-IV inhibitor among the 15 Xaa-Pro dipeptides and Pro-Ile tested. Ile-Pro competitively inhibited DPP-IV (K(i)=0.11 mM). Mass spectrometry indicated that the contents of Leu-Pro and Ile-Pro in the RB peptides were 2.91 +/- 0.52 MUg/mg. PMID- 23107694 TI - The choice of homogenisation equipment affects lipid oxidation in emulsions. AB - Milk proteins are often used by the food industry because of their good emulsifying properties. In addition, they can also provide oxidative stability to foods. However, different milk proteins or protein components have been shown to differ in their antioxidative properties, and their localisation in emulsions has been shown to be affected by the emulsification conditions. The objective of this study was to investigate the influence of homogenisation equipment (microfluidizer vs. two-stage valve homogeniser) on lipid oxidation in 10% fish oil-in-water emulsions prepared with two different milk proteins. Emulsions were prepared at pH 7 with similar droplet sizes. Results showed that the oxidative stability of emulsions prepared with sodium caseinate was not influenced by the type of homogeniser used. In contrast, the type of homogenisation equipment significantly influenced lipid oxidation when whey protein was used as emulsifier, with the microfluidizer resulting in lower levels of oxidation. PMID- 23107695 TI - Antiangiogenic activity of indole-3-carbinol in endothelial cells stimulated with activated macrophages. AB - The effect of indole-3-carbinol (I3C), a major indolic metabolite in cruciferous vegetables, on lipopolysaccharide (LPS)-activated macrophage-induced tube formation and its associated factors in endothelial EA hy926 cells was investigated. LPS significantly enhanced the capillary-like structure of endothelial cells (ECs) co-cultured with macrophages, but no such effect was observed in single-cultured ECs. I3C, on the other hand, suppressed such enhancement in concert with decreased secretions of vascular endothelial growth factor (VEGF), nitric oxide (NO), interleukin-6 (IL-6), and matrix metalloproteinases (MMPs). The results obtained from cultivating ECs with conditioned medium (CM) collected from macrophages suggested that both ECs and macrophages were inactivated by I3C. These results indicate that I3C from cruciferous vegetables may possess potential roles in preventing inflammation associated angiogenic diseases. PMID- 23107696 TI - Purification and identification of immunomodulating peptides from enzymatic hydrolysates of Alaska pollock frame. AB - To prepare immunomodulating peptides from Alaska pollock frame (APF) hydrolysates, trypsin was employed for enzymatic hydrolysis, and the immunomodulating activities of the hydrolysates were studied using splenic lymphocytes proliferation assay. The highest activity of the hydrolysates was reached when DH ranged from 15% to 18%. The peptide fractions which exhibited the highest activity were further purified using ion exchange chromatography, gel filtration chromatography, and RP-HPLC. The peptides were identified using nano LC-ESI mass spectrometry. Finally, three immunomodulating peptides were obtained, and the amino acid sequences were Asn-Gly-Met-Thr-Tyr, Asn-Gly-Leu-Ala-Pro, and Trp-Thr, respectively. The lymphocyte proliferation rates were 35.92%, 32.96%, and 31.35% in the presence of 20 MUg/ml purified peptides, respectively. Therefore, the results demonstrated that the APF proteins hydrolysates prepared by trypsin could serve as a source of peptides with immunomodulating activity. It provided a scientific basis for the preparation of immunomodulating peptides. PMID- 23107697 TI - Compositions and yield of lipids extracted from hepatopancreas of Pacific white shrimp (Litopenaeus vannamei) as affected by prior autolysis. AB - Compositions and yield of lipids extracted from hepatopancreas of Pacific white shrimp (Litopenaeus vannamei) subjected to autolysis at 60 degrees C for different times (0, 30, 60, 90 120 and 150 min) were investigated. Extraction yield increased from 7.4% to 8.8% as autolysis time increased from 0 to 150 min. Coincidental increase in total carotenoid content was obtained with increasing autolysis time (p<0.05). The increases in thiobarbituric acid-reactive substances (TBARS) and p-anisidine value (AV) of lipids were noticeable when autolysis time increased (p<0.05). However, no changes in free fatty acid (FFA) content were observed within the first 60 min of autolysis (p>0.05), but subsequently increased up to 150 min. (p<0.05). No differences in fatty acid profiles of lipids extracted from hepatopancreas without and with 60 min prior autolysis were observed. Lipids extracted contained docosahexaenoic acid (DHA; C22:6(n-3)) as the most abundant fatty acid, followed by eicosapentaenoic acid (EPA; C20:5(n 3)). Therefore, prior autolysis at 60 degrees C for 60 min increased the extraction yield without negative effect on lipid quality. PMID- 23107698 TI - Immunomodulatory effects of feruloylated oligosaccharides from rice bran. AB - Feruloylated oligosaccharides (FOs), the ferulic acid ester of oligosaccharides, can be released either by the enzymatic or mild acid hydrolysis of arabinoxylans present in cereal bran, and are usually considered as natural antioxidants. However, no related research is available to explain their immunomodulatory effects. This report elucidated their immunomodulatory effects through the variations of pro-inflammatory mediators in vitro. FOs were obtained from the mild acid hydrolysis of rice bran. We found that FOs (0.1-100 MUg/ml) induced tumour necrosis factor alpha (TNF-alpha), IL-1beta, IL-6, nitric oxide (NO) and PGE(2) production in unstimulated macrophages, RAW264.7 cells. Furthermore, pre- and post-treated FOs (0.1-100 MUg/ml) dose-dependently suppressed TNF-alpha, IL 1beta, IL-6 and NO production, and induced IL-10 production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells without exerting cytotoxicity. As a result anti inflammatory and therapeutic activities were revealed. It is noteworthy that prostaglandin E(2) (PGE(2)) production was significantly suppressed at an FO level of 100 MUg/ml. The in vitro assessment of inflammatory mediators should be useful in further characterising the effects of FOs on immunomodulation. Moreover, it will create the economical value of rice bran, which has long been considered as conventional agricultural wastes. PMID- 23107699 TI - Influence of deficit irrigation and kaolin particle film on grape composition and volatile compounds in Merlot grape (Vitis vinifera L.). AB - The effect of deficit irrigation and a kaolin-based, foliar reflectant particle film (PF) on grape composition and volatile compounds in Merlot grapes was investigated over two growing seasons in semi-arid, south-western Idaho. Vines were provided with differential amounts of water based on their estimated crop evapotranspiration (ET(c)) throughout berry development, and particle film was applied to half of the vines in each irrigation main plot. Free and bound volatile compounds in grapes were analyzed using stir bar sorptive extraction-gas chromatography-mass spectrometry (SBSE-GC-MS). The concentrations of free C(6) compounds (hexanal, trans-2-hexenal, and 1-hexanol) decreased, and bound terpene alcohols (nerol and geraniol) and C(13)-norisoprenoids (beta-damascenone, 3 hydroxy-beta-damascenone, 1,1,6-trimethyl-1,2-dihydronaphthalene, and 3-oxo-alpha ionol) increased in berries each year in response to severity of vine water stress. Concentrations of C(13)-norisoprenoids and bound forms of nerol and geraniol were positively correlated with their concentrations in the corresponding wines. Particle film application had minimum effect on free and bound volatile composition in the grapes, and there was no interactive effect between particle film and deficit irrigation. However, particle film application enhanced the total amount of berry anthocyanins. PMID- 23107700 TI - Impact of alternative technique to ageing using oak chips in alcoholic or in malolactic fermentation on volatile and sensory composition of red wines. AB - This paper reports on a complete study of the effect of wood, in the form of oak chips, on the volatile composition and sensory characteristics of Moravia Agria wines added at different stages of the fermentation process. Aroma compounds were analyzed by gas chromatography-mass spectrometry (GC-MS). Sensory profile was evaluated by experienced wine-testers. Oak chips were added to wines in two dose rates at different stages of the winemaking process: during alcoholic fermentation (AF), during malolactic fermentation (MLF) and in young, red Moravia Agria wine. Wines fermented with oak chips during AF showed higher concentrations of the ethyl esters of straight-chain fatty acids, ethyl, hexyl, isoamyl acetates and superior alcohols than the control wines. The higher concentrations of benzene compound, oak lactones and furanic compounds were found in wines in contact with oak chips during MLF. The use of oak chips gives rise to a different sensorial profile of wines depending of the point of addition. Higher intensities of woody, coconut, vanilla and sweet spices descriptors were obtained when a large dose rate of chips was employed. PMID- 23107701 TI - Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells. AB - In an attempt to understand the beneficial health effects of Artemisia annua other than its anti-malaria properties, extracts from different cultivars prepared as tea infusions were investigated using Caco-2 cells on the intestinal inflammation and cytochrome P450 (CYP) activities. The characterisation of their phenolic compound (PC) profile revealed rosmarinic and chlorogenic acids as the main PCs. The extracts, assayed on Caco-2 cells at a plausible intestinal concentration, significantly decreased the secretion of pro-inflammatory cytokines, IL-8 and IL-6. This effect could be attributable at least to their content in rosmarinic acid, detected as a potent anti-inflammatory compound. The extracts also inhibited the activity of CYP3A4, whose expression was induced by 1,25-dihydroxyvitamin D(3), and of CYP1A1, induced by benzo(a)pyrene. Our results highlight the advantage of drinking A. annua infusions for their potent anti inflammatory effect, linked to PC content, which could synergise their antimalarial activity. PMID- 23107702 TI - Fabrication of viscous and paste-like materials by controlled heteroaggregation of oppositely charged lipid droplets. AB - This study describes the formation of materials with novel textural characteristics by controlled heteroaggregation of oppositely charged protein coated lipid droplets. Heteroaggregation was induced by mixing a suspension of beta-lactoglobulin (beta-Lg)-coated lipid droplets (zeta=-51 mV, d(43)~0.35 MUm, 20 wt.%) with a suspension of lactoferrin (LF)-coated lipid droplets (zeta=+32 mV, d(43)~0.35 MUm, 20 wt.%) under conditions where the two proteins had opposite charges (pH 7). The mean particle size, flow behaviour, and shear modulus of the materials depended on positive-to-negative particle ratio (0-100%), pH (3-9), ionic strength (0-400 mM), and temperature (30-90 degrees C). The largest particle sizes, highest viscosities, and largest gel strengths were observed at intermediate particle ratios (40% LF:60% beta-Lg), which was attributed to a strong electrostatic attraction between oppositely charged droplets (0mM NaCl, pH 7, 25 degrees C). A reduction in particle aggregation, viscosity, and gel strength occurred at intermediate ionic strengths due to screening of the electrostatic attraction between oppositely charged droplets. However, increased aggregation, thickening, and gelation occurred at higher ionic strengths due to screening in electrostatic repulsion between similarly charged droplets. Thermal treatment of the samples (90 degrees C) promoted a substantial increase in gel strength due to protein denaturation and increased droplet attraction. This study has important implications for the utilisation of controlled particle aggregation to create novel structures in foods, cosmetics, personal care, and other products. PMID- 23107703 TI - Influence of sorghum flour addition on flat bread in vitro starch digestibility, antioxidant capacity and consumer acceptability. AB - Wheat flour (WF) flat bread was prepared with varying levels of wholegrain "white" sorghum flour (WSF) or "red" sorghum flour (RSF). Farinograph dough rheology indicated reduced water absorption and stability time and increased breakdown with increased sorghum flour addition. The total phenolic content and antioxidant capacity of the 40% RSF flat bread >40% WSF flat bread>control (100% WF) flat bread. The rapidly digestible starch (RDS) level was lower in the 40% WSF and 40% RSF flat breads than the control (100% WF). Hedonic sensory evaluation indicated that sorghum addition did not reduce the sensory preference for the flat breads. Human clinical studies are now required to determine if the lower levels of RDS and higher antioxidants observed in the sorghum containing flat breads translate into beneficial low glycemic index and reduced oxidative stress in vivo. PMID- 23107704 TI - Alpha-L-arabinofuranosidase 3 from Penicillium purpurogenum (ABF3): potential application in the enhancement of wine flavour and heterologous expression of the enzyme. AB - An alpha-l-arabinofuranosidase (ABF3) from Penicillium purpurogenum was purified and its possible biotechnological application in the enhancement of wine flavour combined with P. purpurogenum beta-glucosidase was studied. A must from Muscat of Alexandria was used to isolate the glycosides. The total monosaccharide (glucose, arabinose and xylose) levels in the glycosides were determined after acid hydrolysis, and were compared with the result of enzymatic hydrolysis. These results were analogous to those obtained in similar experiments using a commercial preparation, thus suggesting that the enzyme from P. purpurogenum may prove useful in this particular application. This prompted us to express the enzyme heterologously. The abf3 gene was thus expressed in Pichia pastoris. The recombinant enzyme was purified and it shows the same properties of the native ABF3 (substrate specificity, kinetic constants, pH and temperature optima and antibody cross-reactivity). PMID- 23107705 TI - Bauhinia forficata Link authenticity using flavonoids profile: relation with their biological properties. AB - HPLC-DAD-ESI/MS(n) was used to ascertain the authenticity of two certified and two commercial Bauhinia forficata Link samples. Different flavonoids profiles were obtained, involving 39 compounds. Just kaempferol-3-O-(2 rhamnosyl)rutinoside was found in all analysed samples. Five compounds were common to the certified samples of B. forficata Link and B. forficata Link subsp. pruinosa (Vogel) Fortunato & Wunderlin, being kaempferol derivatives the most representative ones. The phenolic composition of B. forficata Link subsp. pruinosa (Vogel) Fortunato & Wunderlin is described herein for the first time, accounting for eight compounds, while 10 new compounds were identified in B. forficata Link. Commercial B. forficata Link showed higher contents of quercetin derivatives, in addition to the presence of myricetin derivatives and flavonoids (galloyl)glycosides, for which the MS fragmentation pattern is reported for the first time. B. forficata Link and the two commercial samples were able to inhibit alpha-glucosidase, with EC(50) values lower than that found for acarbose. Mild effects on cholinesterases were observed with the certified samples, while commercial ones were more effective. The same behaviour was observed concerning the scavenging of DPPH, nitric oxide and superoxide radicals. The presence of high contents of quercetin derivatives in commercial samples seems to directly influence their biological properties. The differences between phenolic profiles and their relation with the authenticity of commercial samples are discussed. PMID- 23107706 TI - Hypoglycemic effects of cocoa (Theobroma cacao L.) autolysates. AB - Fat, alkaloid and polyphenol contents of two clones of cocoa (UIT1 and PBC 140) were removed and the remaining powder was autolyzed at pH 3.5 and 5.2. Based on the results, autolysates of UIT produced at pH 3.5 exhibited the highest ability to inhibit alpha-amylase activity. However, no alpha-glucosidase inhibition activity was observed under the conditions specified. Autolysates produced under pH 3.5 caused the highest amount of insulin secretion. In streptozotocin-diabetic rats, all cocoa autolysates significantly decreased blood glucose at 4h. To assure that the results from the assays were not due to the polyphenols of cocoa autolysates qualitative and quantitative tests were applied. According to their results cocoa autolysates were found to be free from polyphenols. Analysis of amino acid composition revealed that cocoa autolysates were abundant in hydrophobic amino acids. It can be suggested that besides other compounds of cocoa, its peptides and amino acids could contribute to its health benefits. PMID- 23107707 TI - Characterisation and functionality of fructo-oligosaccharides affecting water status of strawberry fruit (Fragraria vesca cv. Mara de Bois) during postharvest storage. AB - Water status and analyses of free sugars, sugar-alcohols and fructo oligosaccharides (FOS) were carried out in Fragaria x vesca treated with different high CO(2) concentrations applied to minimise damage caused by storage at 0 degrees C. The thermodynamic parameters such as the amount of unfrozen water (U(w)), T(g), T(g)('), and peak position of the O-H stretching vibration were determined in various saccharides including FOS (1-kestose, nystose and kestopentaose) by infrared spectroscopy studies and differential scanning calorimetry. Beneficial high CO(2) treatment (20%) avoided the reduction of unfreezable water fraction and increased endogenous FOS levels, in contrast to that observed in air-stored and in those exposed to higher CO(2) levels (40%). The direct FOS-water interaction, possibly within the hydrogen-bond network of cellular structures, could explain the maintenance of water status, cell integrity and the low water leakage levels in 20% CO(2)-treated fruit at values similar to those found in freshly harvested fruit. PMID- 23107708 TI - Comparative effects of tocotrienol-rich fraction, alpha-tocopherol and alpha tocopheryl acetate on inflammatory mediators and nuclear factor kappa B expression in mouse peritoneal macrophages. AB - The effects of tocotrienol-rich fraction (TRF), alpha-tocopherol (T) and alpha tocopheryl acetate (TA) on lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages were examined. Results showed that at 5 30 MUg/ml, all test compounds plus 1 MUg/ml LPS exhibited no cytotoxic effects on macrophage cells. Compared with T and TA, TRF showed the strongest anti inflammatory activity as demonstrated by its potency in inhibiting the LPS induced nitric oxide (NO), prostaglandin E(2) (PGE(2)), and proinflammatory cytokine (TNF-alpha, IFN-gamma, IL-1beta and IL-6) production. At 10 MUg/ml, it significantly blocked the LPS induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression, but has no effect on cyclooxygenase-1 (COX-1). Furthermore, TRF also showed a greater inhibition on the nuclear factor kappa B (NF-kappaB) expression than T and TA. These results suggest that TRF could be a better agent than T and TA for use in the prevention of chronic inflammatory diseases. PMID- 23107709 TI - Empirical, thermodynamic and quantum-chemical investigations of inclusion complexation between flavanones and (2-hydroxypropyl)-cyclodextrins. AB - The inclusion complexation of (2-hydroxypropyl)-cyclodextrins with flavanones was investigated by phase solubility measurements, as well as thermodynamic and quantum chemical methods. Inclusion complexes were formed between (2 hydroxypropyl)-alpha-cyclodextrin (HP-alpha-CD), (2-hydroxypropyl)-beta cyclodextrin (HP-beta-CD), (2-hydroxypropyl)-gamma-cyclodextrin (HP-gamma-CD) and beta-cyclodextrin (beta-CD) and four flavanones (naringenin, naringin, hesperetin and dihydromyricetin) in aqueous solutions and their phase solubility was determined. For all the flavanones, the stability constants of their complexes formed with different CDs followed the rank order: HP-beta-CD (MW 1540)>HP-beta CD (MW 1460)>HP-beta-CD (MW 1380)>beta-CD>HP-gamma-CD>HP-alpha-CD. Experimental results and quantum chemical calculations showed that the ability of flavanones to form inclusion complex with (2-hydroxypropyl)-cyclodextrins was determined by both the steric effect and hydrophobicity of the flavanones. For flavanones that have similar molecular volumes, the hydrophobicity of the molecule was the main determining factor of its ability to form inclusion complexes with HP-beta-CD, and the hydrophobicity parameter Log P is highly correlated with the stability constant of the complexes. Results of thermodynamic study demonstrated that hydrophobic interaction is the main driving force for the formation process of the flavanone-CD inclusion complexes. Quantum chemical analysis of the most active hydroxyl groups and HOMO (the highest occupied molecular orbital) showed that the B ring of the flavanones was most likely involved in hydrogen bonding with the side groups in the cavity of the CDs, through which the inclusion complex was stabilised. PMID- 23107710 TI - Redox effect on volatile compound formation in wine during fermentation by Saccharomyces cerevisiae. AB - Although redox state is a well-known key process parameter in microbial activity, its impact on wine volatile aroma compounds produced during fermentation has not been studied in detail. In this study we report the effect of reductive and microaerobic conditions on wine aroma compound production using different initial amounts of yeast assimilable nitrogen (YAN: 180 and 400 mg N/l) in a simil grape must defined medium and two S. cerevisiae strains commonly used in wine-making. In batch fermentation culture conditions, reductive conditions were obtained using flasks plugged with Muller valves filled with sulphuric acid; while microaerobic conditions were attained with defined cotton plugs. It was found that significant differences in redox potential were obtained using the different plugs, and with variation of over 100 mV during the main fermentation period. Significant differences in the final concentration of higher alcohols, esters and fatty acids were attributed to differences in the redox state in the medium in both strains. A consistent increase in esters and medium chain fatty acids, as well as a decrease of higher alcohols and isoacids, was seen under reductive fermentation conditions. Interestingly, 1-propanol, delta-butyrolactone and ethyl lactate concentrations, showed no significant variation under the different redox conditions. A better understanding of the influence of redox state of the fermentation medium on the composition of volatile compounds in wine could enable improvement of vinification management. From a microbiological standpoint results presented here will contribute to the standardization of data models for the application of metabolic footprinting methods for wine yeast strain phenotyping and characterization. PMID- 23107711 TI - Selective in vivo effect of chitosan on fatty acid, neutral sterol and bile acid excretion: a longitudinal study. AB - Chitosan, a deacetylated form of chitin, is a dietary fibre known for its hypolipidemic properties, which are mainly attributed to its unique cationic characteristics. We studied the selective in vivo effect of chitosan on fat excretion in order to elucidate its hypolipidemic mechanism. A 4-week longitudinal study was conducted in guinea pigs and the effect of chitosan on fat absorption was compared to that of a soluble fibre: digestion-resistant maltodextrin. Animals were fed with high-fat isocaloric diets containing 12/100g of cellulose, digestion-resistant maltodextrin or chitosan. Subsequently, the excretion of fatty acids, neutral sterols and bile acids was determined. Chitosan selectively reduced fat absorption in comparison to digestion-resistant maltodextrin. The excretion of lauric, myristic and palmitic fatty acids of animals fed with chitosan was more than 10-, 5- and 2-fold higher, respectively, than in the cellulose group, whereas stearic acid excretion was not significantly altered. Oleic, linoleic and alpha-linolenic acid excretion were also significantly higher (P<0.001). The n-6/n-3 ratio in faeces of the chitosan group was 23.68, compared to 13.95 in the cellulose group. Total neutral sterol excretion was increased by both dietary fibres, whereas bile acid excretion was only increased by chitosan. Nevertheless, chitosan inhibited the intestinal bioconversion of cholesterol and primary bile acids to secondary metabolites. Hence, these results reveal that chitosan and digestion resistant maltodextrin exert their hypolipidemic activity by different mechanisms. PMID- 23107712 TI - Enzymatic production of 5'-inosinic acid by a newly synthesised acid phosphatase/phosphotransferase. AB - 5'-Nucleotides including 5'-inosinic acid have characteristic taste and important application in various foods as flavour potentiators. The selective nucleoside acid phosphatase/phosphotransferase (AP/PTase) can catalyse the synthesis of 5' nucleotides by transfer of phosphate groups. In this study, a 747-bp gene encoding AP/PTase from Escherichia blattae was synthesised. After expression, the recombinant AP/PTase was purified using nickel-NTA. The optimal temperature and pH of this enzyme were 30 degrees C and 5.0, respectively. The activity was partially inhibited by metal ions such as Hg(2+), Ag(+) and Cu(2+), but not by chelating reagents such as EDTA. The values of K(m) and V(max) for inosine were 40 mM and 3.5 U/mg, respectively. Using this purified enzyme, 16.83 mM of 5'-IMP was synthesised from 37 mM of inosine and the molar yield reached 45.5%. Homology modelling and docking simulation were discussed. PMID- 23107713 TI - Study of the retention capacity of anthocyanins by wine polymeric material. AB - Red wine is an important source of dietary intake of phenolic compounds with antioxidant activity that are related to the prevention of cardiovascular diseases and cancer. However, information concerning their specific release from this food matrix, although necessary to predict their bioavailability along the digestive tract, is still not clear. In this work, the interactions that can occur between the red wine polymeric material and anthocyanins were studied. For this purpose, the diffusion performance of nine anthocyanins through a dialysis membrane was evaluated in the presence and absence of the wine polymeric material. For each anthocyanin, a retention coefficient was calculated. Although in different extents, all anthocyanins were retained by the wine polymeric material. The higher retention coefficient was observed for coumaroyl and acetyl derivatives when compared with the non acylated anthocyanins. It is suggested that these associations are ruled by hydrophobic interactions. These results allow the prediction of a continuous and gradual dosage of wine anthocyanins, contributing to an extension in beneficial health properties upon ingestion. PMID- 23107714 TI - Hypolipidaemic effects and mechanisms of the main component of Opuntia dillenii Haw. polysaccharides in high-fat emulsion-induced hyperlipidaemic rats. AB - The antihyperlipidaemic effects of ODP-Ia, one of the main components of Opuntia dillenii Haw. polysaccharides, were studied. Gavage administration of ODP-Ia was observed to significantly decrease serum lipid levels and to increase serum high density lipoprotein cholesterol level in hyperlipidaemic rats. Similar suppressive patterns were also seen in hepatic total cholesterol and triglyceride levels. Moreover, the ODP-Ia administration significantly increased serum lecithin:cholesterol acyltransferase activity, increased the production of serum NO, inhibited hepatic HMG-CoA reductase activity, augmented serum and hepatic superoxide dismutase activities and decreased the serum and hepatic malondialdehyde contents in hyperlipidaemic rats. In addition, a histopathological examination revealed that ODP-Ia administration significantly suppressed inflammatory cell infiltration and the expression of VCAM-1. Together, these results indicate that ODP-Ia is a potential natural product for the treatment of hyperlipidaemia-related diseases by improving antioxidant levels, modulating the activities of enzymes involved in cholesterol metabolism, promoting the production of NO and suppressing the expression of VCAM-1, thereby suppressing lipid accumulation and inflammatory cell infiltration. PMID- 23107715 TI - Evaluation of the anti-inflammatory effects of phloretin and phlorizin in lipopolysaccharide-stimulated mouse macrophages. AB - Many reports suggest that phloretin and phlorizin have antioxidant properties and can inhibit glucose transportation, the anti-inflammatory effects and mechanism of phloretin and phlorizin remain unclear. This study aims to evaluate the anti inflammatory effects of phloretin and phlorizin in LPS-stimulated murine RAW264.7 macrophages. RAW264.7 cells were pretreated with various concentrations of phloretin or phlorizin (3-100 MUM) and cell inflammatory responses were induced with LPS. Pretreated with 10 MUM phloretin significantly inhibited the levels of NO, PGE(2), IL-6, TNF-alpha, iNOS and COX-2. Furthermore, it was demonstrated that phloretin suppressed the nuclear translocation of NF-kappaB subunit p65 proteins, and decreased phosphorylation in MAPK pathways. Surprisingly, phlorizin did not suppress the inflammatory response in LPS-stimulated RAW264.7 cells. These results suggest that phloretin has an anti-inflammatory effect that reduces levels of proinflammatory cytokines and mediators in RAW264.7 cells. PMID- 23107716 TI - Oral administration of a nephrotoxic dose of potassium bromate, a food additive, alters renal redox and metabolic status and inhibits brush border membrane enzymes in rats. AB - The time dependent effect of orally administered KBrO(3) on redox status and enzymes of brush border membrane (BBM) and carbohydrate metabolism has been studied in rat kidney. Animals were given a single oral dose of KBrO(3) (100mg/kg body weight) and sacrificed at different times after this treatment; control animals were not given KBrO(3). The administration of KBrO(3) resulted in nephrotoxicity, a decline in the specific activities of several BBM marker enzymes and also induced oxidative stress in kidney. The specific activities of enzymes of carbohydrate metabolism were also altered and suggest a shift in energy metabolism from the aerobic to anaerobic mode. The renal effects of single oral dose of KBrO(3) appeared to be reversible; maximum changes in all the parameters were 48 h after administration of KBrO(3) after which recovery took place, in many cases almost to control values, after 168 h. These results suggest that the administration of a single nephrotoxic dose of KBrO(3) inhibits brush border membrane enzymes, induces oxidative stress and alters energy metabolism of the renal system in a reversible manner. PMID- 23107717 TI - Taurine-nitrite interaction as a precursor of alkylation mechanisms. AB - Taurine (2-aminoethanesulphonic acid) is an amino acid-like-compound widely used as an ingredient in some nutraceuticals and energy drinks. Here the interaction of taurine (Tau) with nitrite was investigated. The reactions were carried out mimicking the conditions of the stomach lumen. The conclusions drawn are as follows: (i) Nitrite showed nitrosating capacity on Tau. The rate equation was nu(N)=k(obs)[Tau](o)[nitrite](o)(2), this result suggesting that the yield of nitrosation products in the human stomach would increase sharply with higher nitrate/nitrite intakes; (ii) the experimental results suggest a mechanism for the nitrosation, whose rate-limiting step is bimolecular attack by N(2)O(3); (iii) the nitrosation of taurine affords ethanesultone (ES), which displays alkylating capacity on the nucleophile 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilic characteristics similar to those of DNA bases. Although the NBP alkylation rate for ethanesultone is much higher than those for carcinogenic four-membered ring lactones, resulting in the nitrosation of amino carboxylic acids, the fraction of ES-forming adduct with NBP is much smaller; (iv) in spite of the low risk to human health, since the stomach lumen conditions could be a favourable medium for Tau nitrosation, attention should be paid to potential situations of the concurrence of high contents of taurine and nitrite/nitrate in the diet. PMID- 23107718 TI - Physiochemical properties and prolonged release behaviours of chitosan-denatured beta-lactoglobulin microcapsules for potential food applications. AB - Chitosan (CS) and beta-lactoglobulin (betalg) double-wall coating was designed as a shell structure to achieve prolonged release of core material in the gastrointestinal tract (GI) for potential food applications. A model core material, brilliant blue (BB) dye, was incorporated into CS as the primary wall material, and subsequently, denatured betalg, a secondary wall material, was used to coat the outer layer. The strongest interaction occurred between 0.5% (w/v) betalg and 0.5% (w/v) CS at pH 5.5 +/- 0.1, where the opposite charges of CS and betalg formed a complex, which is especially favourable in acidic beverage systems. Under simulated stomach conditions, a denatured-betalg coat resisted acid conditions and pepsin hydrolysis for 2h. While mimicking small intestine conditions, betalg was degraded by pancreatin, causing the release of BB-loaded CS to the intestinal fluid at a constant rate. The sustained release of core material later in the GI tract provided an optimal absorption rate in the small intestine. PMID- 23107719 TI - Microwave-assisted methanolysis of green coffee oil. AB - Optimisation of a microwave-assisted methanolysis was performed to obtain cafestol and kahweol directly from green coffee oil (Coffea arabica). A two factor (the methanolysis period and temperature), three-level, factorial experimental design (3(2)) was adopted. The methanolysis procedure was performed under microwave irradiation, using closed vessel and accurate fast responding internal fibre-optic temperature probe. The effects on the responses were measured by HPLC. After 3 min of microwave irradiation (hold time) at 100 degrees C, with 500 mg of green coffee oil, a yield higher than 99% was obtained. The yield of this reaction is 26% after 2h when working under conventional heating. The methods described in the literature lead to long reaction times, poor yields and formation of side products. The microwave-assisted technique proved to be faster, avoided undesired side products and gave better conversion, when compared to conventional heating process. PMID- 23107720 TI - Aggregation and structural changes of silver carp actomyosin as affected by mild acidification with D-gluconic acid delta-lactone. AB - The structural changes and aggregation properties of silver carp actomyosin acidified with d-gluconic acid-delta-lactone (GDL) were investigated. Results showed that silver carp actomyosin underwent aggregation and formation of precipitate as indicated by turbidity and centrifugation coupled electrophoresis analysis. Circular dichroism indicated that myosin rod unfolded during acidification, resulting in a gradual decrease in alpha-helical content. The changes in tertiary structure of actomyosin under acidic conditions were demonstrated by second-derivative UV spectra and intrinsic fluorescence. Tyrosine residues were exposed to the surface of proteins when pH was decreased to 5.5, and were buried inside the protein aggregates with further reduction in pH. In contrast, more tryptophan residues were exposed to the polar environment with decreasing pH. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide crosslinking experiments showed that the intensity of myosin heavy chain (MHC) bands decreased sharply with decreasing pH and the actin bands decreased more slowly, suggesting that MHC is the major protein component involved in the non-covalent cross linking and formation of aggregates during acidification of silver carp actomyosin. PMID- 23107721 TI - Composition of native Australian herbs polyphenolic-rich fractions and in vitro inhibitory activities against key enzymes relevant to metabolic syndrome. AB - Polyphenolic-rich fractions obtained from three native Australian herbs: Tasmannia pepper leaf, anise myrtle and lemon myrtle were characterised with regards to their composition, antioxidant capacities and inhibitory activities against alpha-glucosidase, pancreatic lipase and angiotensin I-converting enzyme, using in vitro models. Ellagic acid and derivatives were the dominant compounds of anise myrtle and lemon myrtle fractions, accompanied by flavonoids (catechin, myricetin, hesperetin, and quercetin). Tasmannia pepper leaf fraction comprised chlorogenic acid and quercetin derivatives, exhibited the highest oxygen radical absorbance capacity and effectively inhibited alpha-glucosidase (IC(50): 0.83 mg/ml) and pancreatic lipase (IC(50): 0.60 mg/ml). Anise myrtle and lemon myrtle fractions had pronounced alpha-glucosidase-inhibitory activities (IC(50): 0.30 and 0.13 mg/ml, respectively) and were less effective against lipase. Enzyme inhibitory activities showed various levels of correlation with the levels of total phenolics and antioxidant capacities, indicating a specificity of individual phenolic compounds present in the isolated fractions to complex with proteins. PMID- 23107722 TI - Fertilisation and pesticides affect mandarin orange nutrient composition. AB - The effects of the application of foliar fertilisation and pesticide on nutritional quality of mandarin orange juices were evaluated using (1)H NMR metabolomics. Significant differences between the use of fertiliser and pesticides during fruit formation were observed, and included changes in sugar, amino acid and organic acid composition. To determine whether the difference in sugar concentration was enough for the consumer to detect, a sensory experiment was performed in which two orange juice samples were prepared to resemble the sweet/sour taste balance of juice from mandarin oranges in which foliar fertilisation was either applied or not. In a test using non-trained individuals, 68% could correctly identify which juice had a sourer, or less sweet, taste. The implications of this study could impact citrus growers, and ultimately aid in development of fruit with superior sensory quality. PMID- 23107723 TI - Sugar composition of French royal jelly for comparison with commercial and artificial sugar samples. AB - A gas chromatographic method was developed to quantify the major and minor sugars of 400 Royal Jellies (RJs). Their contents were compared in relation to the geographical origins and different production methods. A reliable database was established from the analysis of 290 RJs harvested in different French areas that took into account the diversity of geographical origin, harvesting season, forage sources available in the environment corresponding to natural food of the bees: pollen and nectar. Around 30 RJ samples produced by Italian beekeepers, about sixty-ones from French market, and around thirty-ones derived from feeding experiments were analysed and compared with our database. Fructose and glucose contents are in the range 2.3-7.8% and 3.4-7.7%, respectively, whatever the RJ's origin. On the contrary, differences in minor sugar composition are observed. Indeed sucrose and erlose contents in French RJs are lesser than 1.7% and 0.3%, respectively, whereas they reach 3.9% and 2.0% in some commercial samples and 5.1% and 1.7% in RJs produced from feeding experiments. This study could be used to discriminate different production methods and provide an additional tool for identifying unknown commercial RJs. PMID- 23107724 TI - The isolation and identification of two compounds with predominant radical scavenging activity in hempseed (seed of Cannabis sativa L.). AB - Forty samples were extracted from defatted kernels and hulls of two varieties of hempseed (Bama and Yunma No. 1) using 10 different polar solvent systems. The radical scavenging capacity of the extracts was evaluated using 2,2-diphenyl-1 pikrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assays and the total phenolic content was determined by Folin-Ciocalteu's phenol reagent. The correlation analysis indicated that the antioxidants in hempseed belonged to phenolic and DPPH() assay was suitable for evaluating the radical scavenging activity. Two compounds, with predominant antiradical activity, were isolated in 60% ethanol extract of hempseed hull using macroporous resin absorption, LH-20 gel chromatography, and high performance liquid chromatography methods, which were identified as N-trans-caffeoyltyramine and cannabisin B by high-resolution mass spectra, nuclear magnetic resonance spectra, and ultraviolet data. The two compounds exhibited significant high DPPH() scavenging activity and protective effect against in vitro oxidation of human low density lipoprotein compared with extracts from flaxseed, grape seed, and soybean. This suggests that hempseed hull extract is a potential source of natural antioxidants, which could be added to dietary supplements to help prevent oxidative stress. PMID- 23107725 TI - Effect of different fermentation parameters on L-lactic acid production from liquid distillery stillage. AB - Expansion of lactic acid applications, predominantly for the preparation of biodegradable polymers increased the research interest for new, economically favourable production processes. Liquid stillage from bioethanol production can be an inexpensive, valuable source of nutrients for growth of lactic acid bacteria. Utilisation of residual biomass with spent fermentation media as a functional animal feed can greatly influence the process value and its ecological aspect. In this paper, the kinetics of lactic acid and biomass production on liquid stillage by Lactobacillus rhamnosus ATCC 7469 was studied. In addition, the impact of temperature, inoculum concentration, shaking and pH control by addition of CaCO(3) was evaluated. Maximal lactic acid yield of 73.4%, as well as high biomass production (3*10(8) CFU ml(-1)) were achieved under selected conditions (41 degrees C, 5% (v/v) of inoculum, 1% (w/v) of CaCO(3), initial pH of 6.5 and shaking rate of 90 rpm). These results were achieved without supplementation of the stillage with nitrogen or mineral sources. PMID- 23107726 TI - In situ thermal denaturation of myofibre sub-type proteins studied by immunohistofluorescence and synchrotron radiation FT-IR microspectroscopy. AB - The thermal denaturation of proteins in skeletal muscle was studied and characterised for the first time taking into account the in situ metabolic and contractile fibre types. From serial histological sections, collagen, elastin, various type I, IIa and IIx fibres and type I-IIa and IIa-IIx hybrids were identified by immunohistofluorescence. Histological sections were incubated in buffer solutions at increasing temperatures (40, 50, 60, 70 and 80 degrees C). Protein secondary structure was investigated by synchrotron radiation FT-IR microspectroscopy on connective tissue and in muscle fibres rigorously identified for sub-type. Whatever the target protein components, increasing temperature resulted in a decrease in alpha-helix secondary structure and an increase in beta sheet structure. This phenomenon was more pronounced for intracellular proteins than for connective tissue. Although hybrid fibres were generally somewhat less sensitive to unfolding than the pure types, the amplitude of the thermal denaturation of intracellular proteins was practically independent of fibre type. PMID- 23107727 TI - Clarification and pasteurisation effects on monomeric anthocyanins and percent polymeric colour of black carrot (Daucus carota L.) juice. AB - Black carrots (BCs) are a rich source of stable anthocyanins (ACNs). The purpose of this study was to evaluate the effects of clarification and pasteurisation on ACNs of black carrot juice (BCJ). Monomeric ACNs, ACN profile and percent polymeric colour were determined during processing of BCJ. While depectinisation and bentonite treatments resulted in 7% and 20% increases in monomeric ACN content of BCJ, respectively, gelatine-kieselsol treatment and pasteurisation resulted in 10% and 3-16% reduction. Percent polymeric colour decreased after clarification, but substantially increased in samples subjected to heat. ACNs of BCJ samples were identified by HPLC-MS. Unclarified BCJ contained cyanidin-3 galactoside-xyloside-glucoside-ferulic acid as the major ACN, followed by cyanidin-3-galactoside-xyloside-glucoside-coumaric acid, and cyanidin-3 galactoside-xyloside-glucoside. After depectinisation, two more ACNs (cyanidin-3 galactoside-xyloside and cyanidin-3-galactoside-xyloside-glucoside-sinapic acid) were also identified. These results indicated that depectinisation and bentonite treatment had positive effect on the colour of BCJ, while gelatin-kieselsol treatment and pasteurisation had negative effect. PMID- 23107728 TI - Lipid oxidation of stored eggs enriched with very long chain n-3 fatty acids, as affected by dietary olive leaves (Olea europea L.) or alpha-tocopheryl acetate supplementation. AB - The antioxidant potential of dietary olive leaves or alpha-tocopheryl acetate supplementation on lipid oxidation of refrigerated stored hen eggs enriched with very long-chain n-3 fatty acids, was investigated. Ninety-six brown Lohmann laying hens, were equally assigned into three groups. Hens within the control group were given a typical diet containing 3% fish oil, whereas other groups were given the same diet further supplemented with 10 g ground olive leaves/kg feed or 200mg alpha-tocopheryl acetate/kg feed. Results showed that alpha-tocopheryl acetate or olive leaves supplementation had no significant effect on the fatty acid composition and malondialdehyde (MDA) levels of fresh eggs but reduced their lipid hydroperoxide levels compared to controls. Storage for 60 d decreased the proportions of polyunsaturated fatty acids (PUFAs) but increased those of monounsaturated fatty acids (MUFAs) in eggs from the control group, while had no effect on the fatty acid composition of the eggs from the other two groups, which showed decreased levels of lipid hydroperoxides and MDA. Therefore, the very long chain n-3 PUFAs in eggs were protected from undergoing deterioration partly by olive leaves supplementation and totally by alpha-tocopheryl acetate supplementation. In addition, incorporating tocopherols into eggs might also provide a source of tocopherols for the human diet. PMID- 23107729 TI - Nutritional and nutraceutical comparison of Jamaican Psidium cattleianum (strawberry guava) and Psidium guajava (common guava) fruits. AB - Psidium cattleianum (strawberry guava) is one of many underutilised edible fruits that grow wild in Jamaica, and could potentially be commercially exploited to yield health and economic benefits. In this study, the total phenolics, proximate contents, and antioxidant, anti-inflammatory, and antimicrobial activities of P. cattleianum and P. guajava (common guava), a well-known species, were compared. Strawberry guavas were found to be superior to common guavas in antioxidant and antimicrobial activities, total phenolics and vitamin C content. They also possessed relatively high fibre content (24.9%). The hexane and ethyl acetate extracts of strawberry guavas showed cyclooxygenase-2 enzyme inhibitory activities of 18.3% and 26.5%, respectively (250 MUg/mL), indicating anti inflammatory activity. The EtOAc and MeOH extracts of P. guajava showed 56.4% (COX-2) and 44.1% (COX-1) inhibitory activity, respectively. Additionally, nine compounds were isolated from strawberry guava fruits, some of which demonstrated anti-inflammatory activity. These results indicate that strawberry guavas are beneficial for health. PMID- 23107730 TI - Red mold dioscorea: a potentially safe traditional function food for the treatment of hyperlipidemia. AB - A study was undertaken to evaluate whether the interaction between Monascus fermented products and lovastatin contributes to increased risk of rhabdomyolysis. Rhabdomyolysis is a potentially dangerous side effect of statin drugs. In this study with hyperlipidemic hamsters fed lovastatin only, lovastatin with 1-fold red mold dioscorea (RMD), and lovastatin, the functional components of red mold fermented products, HMG-CoA reductase inhibitors, did not exacerbate pre-existing diseases, and actually helped in improving existing disease conditions, respectively, as compared with the control. Administration of RMD, alone or in combination with lovastatin did not cause significant rhabdomyolysis as assessed by measuring the levels of creatinine phosphokinase. Further, we did not find any study that clearly implicates the involvement of RMD, which have long been considered a food product, in liver and kidney toxicity. RMD alone or in combination with lovastatin, does not increase the risk of rhabdomyolysis, even when administered at a high dosage (including HMG-CoA reductase inhibitors >75 mg/day/adult). PMID- 23107731 TI - Tyrosinase inhibitory effects and antioxidative activities of novel cinnamoyl amides with amino acid ester moiety. AB - Nine cinnamoyl amides with amino acid ester (CAAE) moiety were synthesized by the conjugation of the corresponding cinnamic acids (cinnamic acid, 4-hydroxy cinnamic acid, ferulic acid and caffeic acid) with amino acid esters, and their inhibitory effects on the activities of mushroom tyrosinase were investigated, using l-3,4-dihydroxyl-phenylalanine (l-DOPA) as the substrate. Among these CAAE amides, ethyl N-[3-(4-hydroxy-3-methoxyphenyl)-1-oxo-2-propen-1-yl]-l phenylalaninate (b(4)) showed the strongest inhibitory activity; the IC(50) was 0.18 MUM. The IC(50) values, inhibition types, inhibition mechanisms and kinetics of all these CAAE amides were evaluated. A structure-activity relationship (SAR) study found that the inhibitory effects were potentiated with the increasing length of hydrocarbon chains at the amino acid esters and also influenced by the substituents at the styrene groups. Furthermore, the hydroxyl radical scavenging and anti-lipid peroxidation activities of four CAAE derivatives were also investigated. Among these compounds, b(3) (ethyl N-[3-(3,4-dihydroxyphenyl)-1-oxo 2-propen-1-yl]-l-phenylalaninate) and b(4) exhibited potential antioxidant activities. PMID- 23107732 TI - Lipid profiles of oil from trout (Oncorhynchus mykiss) heads, spines and viscera: trout by-products as a possible source of omega-3 lipids? AB - Lipid profiles of fish oil extracted from trout heads, spines and viscera using supercritical carbon dioxide and Randall extraction with hexane were measured. The amount of unsaturated fatty acids (as a percentage of total fatty acids) was within the range of 72.6-75.3% in all the substrates. A significant presence of the most important omega-3 fatty acids was detected. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content in oil from spines, heads and viscera resulted to be 8.7% and 7.3%, 7.9% and 6.3%, and 6.4% and 6.0%, respectively. A low (~3%), but worth noting, presence of lipids with omega-1 polyunsaturated fatty chains was observed in all the oils. Finally, significant differences were noticed in the relative amounts of triacylglycerides (TAG), diacylglycerides (DAG) and free fatty acids (FFA). Whereas oil from heads and spines was essentially composed of TAG (~98%), in viscera oil the molar distribution ratio became TAG:DAG:FFA=87:8:5. PMID- 23107733 TI - Metabolic pathways of the psychotropic-carboline alkaloids, harmaline and harmine, by liquid chromatography/mass spectrometry and NMR spectroscopy. AB - The beta-carboline alkaloids, harmaline and harmine, are present in hallucinogenic plants Ayahuasca and Peganum harmala, and in a variety of foods. In order to establish the metabolic pathway and bioactivities of endogenous and xenobiotic bioactive beta-carbolines, high-performance liquid chromatography, coupled with mass spectrometry, was used to identify these metabolites in human liver microsomes (HLMs) in vitro and in rat urine and bile samples after oral administration of the alkaloids. Three metabolites of harmaline and two of harmine were found in the HLMs. Nine metabolites for harmaline and seven metabolites for harmine, from the rat urine and bile samples, were identified. Among them, four in vivo metabolites were isolated and fully characterised by NMR analysis. For the first time, harmaline is shown transforming to harmine by oxidative dehydrogenation in rat. Five metabolic pathways were therefore proposed, namely, oxidative dehydrogenation, 7-O-demethylation, hydroxylation, O glucuronide conjugation and O-sulphate conjugation. PMID- 23107734 TI - Encapsulation of functional lipophilic components in surfactant-based colloidal delivery systems: vitamin E, vitamin D, and lemon oil. AB - The fabrication and stability of surfactant-based colloidal delivery systems (microemulsions and emulsions) suitable for encapsulation of lipophilic active agents (vitamins and flavours) was investigated. An emulsion titration method was used to study the influence of surfactant type (Tween 20, 60 and 80) and oil type (Vitamin E, vitamin D(3) and lemon oil) on the incorporation of lipophilic components into surfactant micelles. Oil-in-water emulsions were formed and then different amounts were titrated into surfactant micelle solutions. The influence of surfactant-to-oil ratio (SOR) and oil type on the formation of colloidal dispersions was examined using dynamic light scattering and turbidity measurements. SOR, oil type, and surfactant type had a pronounced influence on the nature of the colloidal dispersions formed. Microemulsions could not be formed using vitamin D or E in 1% Tween solutions, due to the relatively large size of the lipophilic molecules relative to the hydrophobic interior of the surfactant micelles. On the other hand, microemulsions could be formed from lemon oil at relatively high SORs. There was not a major impact of non-ionic surfactant type (Tween 20, 60 or 80) on the formation and properties of the colloidal dispersions. However, Tween 20 micelles did appear to be able to solubilise less lemon oil than Tween 60 or 80 micelles, presumably due to their smaller dimensions. This study provides useful information for the rational design of food grade colloidal delivery systems for encapsulating flavour oils, oil-soluble vitamins, and other functional lipids for application in foods and beverages. PMID- 23107735 TI - A beta-galactosidase from chick pea (Cicer arietinum) seeds: its purification, biochemical properties and industrial applications. AB - A beta-galactosidase from Cicer arietinum seeds has been purified to apparent electrophoretic homogeneity using a combination of various fractionation and chromatographic techniques, giving a final specific activity of 220 units mg(-1), with approximately 1840 fold purification. Analysis of the protein by SDS-PAGE revealed two subunits with molecular masses of 48 and 38 kDa, respectively. These bands were further confirmed with LC-MS/MS, indicating that Chick pea beta galactosidase (CpGAL) is a heterodimer. Molecular mass was determined to be 85 kDa by Superose-12 FPLC column, which is in agreement with the molecular mass suggested by mass spectroscopy to be 83 kDa. The optimum pH of the enzyme was 2.8 and it hydrolysed o-nitrophenyl beta-d galactopyranoside (ONPG) with a K(m) value of 1.73 mM at 37 degrees C. The energy of activation (E(a)) calculated in the range of 35 to 60 degrees C, using Arrhenius equation, was determined to be 11.32 kcal mol(-1). The enzyme could also hydrolyse lactose, with an optimum pH of 4.0 at 40 degrees C. K(m) and E(a) for lactose hydrolysis was found to be 10mM and 10.57 kcal mol(-1), respectively. The enzyme was found to be comparatively thermostable showing maximum activity at 60 degrees C for both ONPG and lactose. Galactose was found to be the competitive inhibitor. beta-Galactosidase also exhibited glycoproteineous properties when applied on Con-A Sepharose column. The enzyme was localised in germinated seeds with X-gal activity staining and shown to be expressed prominently at grown radical tip and seed coat. Sequence alignment of CpGAL with other known plant beta-galactosidase showed high amino acid sequence homology. PMID- 23107736 TI - Enrichment of mushrooms: an interesting strategy for the acquisition of lithium. AB - The capability of Pleurotus ostreatus mushroom to accumulate lithium (Li) and the accessibility of this Li compared with lithium carbonate (Li(2)CO(3)), often used as psychiatric medicine, were investigated. Mushrooms were produced on a substrate-based on coffee husk, with different added concentrations of lithium chloride (LiCl). Biological efficiency (BE), the crude protein content, the concentration of Li and other elements present in mushrooms were determined. The sequential extraction and in vitro test were used to verify the accessibility and the degree of solubility of this element. Li concentration in mushrooms was directly influenced by increasing LiCl concentration in the substrate (P<0.05). The BE was not affected by different concentrations of LiCl. Li present in enriched mushrooms showed greater accessibility than in Li(2)CO(3). Therefore, P. ostreatus mushrooms, enriched with lithium can be an alternative source of Li, as well as being a food with high nutritional value. PMID- 23107737 TI - Synthesis and structure-activity relationships and effects of phenylpropanoid amides of octopamine and dopamine on tyrosinase inhibition and antioxidation. AB - Phenylpropanoid amides of octopamine (OA) 1a-1e and dopamine (DA) 2a-2e were synthesised and the structure-activity relationships (SARs) for antioxidant and tyrosinase inhibition activities were analysed. Among synthesised compounds, 2c, which contains two catechol moieties, exhibited the most DPPH radical-scavenging activity (EC(50)=16.2 +/- 2.4 MUM), and 1d exhibited significant tyrosinase inhibitory activity (IC(50)=5.3 +/- 1.8 MUM). Interestingly, with the same acid moiety, OA derivatives showed more inhibitory effect on tyrosinase than did compounds derived from DA, whereas DA derivatives were found to have higher antioxidant activity than compounds derived from OA. The relationship between their structures and their potencies, demonstrated in the current study, will be useful for the design of optimal agents. PMID- 23107738 TI - A new hydroxytyrosol metabolite identified in human plasma: hydroxytyrosol acetate sulphate. AB - We report progress in the study of olive oil phenolic metabolites in humans and identify a new hydroxytyrosol metabolite called hydroxytyrosol acetate sulphate, which was determined using tandem MS, after ingestion of 30 ml of olive oil with a high phenolic content (500 mg/kg oil), reaching a maximum concentration of 1.63 MUM. In order to understand and explain the generation of this metabolite, two different pathways are proposed. PMID- 23107739 TI - Assessment of the ability of seaweed extracts to protect against hydrogen peroxide and tert-butyl hydroperoxide induced cellular damage in Caco-2 cells. AB - The ability of brown seaweed extracts, Ascophyllum nodosum, Laminaria hyperborea, Pelvetia canaliculata, Fucus vesiculosus and Fucus serratus to protect against tert-butyl hydroperoxide (tert-BOOH) induced stress in Caco-2 cells was investigated. Oxidative stress was determined by measuring alteration in the enzymatic activity of catalase (CAT) and superoxide dismutases (SOD) and cellular levels of glutathione (GSH). L. hyperborea, P. canaliculata and F. serratus significantly protected against tert-BOOH induced SOD reduction but did not protect against the reduction in CAT activity or the increased cellular levels of GSH. The ability of F. serratus and F. vesiculosus to protect against H(2)O(2) and tert-BOOH induced DNA damage was also assessed. The DNA protective effects of the two seaweed extracts was compared to those of three metal chelators; deferoxamine mesylate (DFO), 1,10-phenanthroline (o-phen) and 1,2-Bis(2 aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (BAPTA-AM). F. serratus and F. vesiculosus significantly protected (P<0.05) against H(2)O(2) (50 MUM) induced DNA damage but not tert-BOOH induced damage. PMID- 23107740 TI - Nitric oxide-mediated vasorelaxation effects of anti-angiotensin I-converting enzyme (ACE) peptide from Styela clava flesh tissue and its anti-hypertensive effect in spontaneously hypertensive rats. AB - In our previous study, an anti-angiotensin I converting enzyme (ACE) peptide (Ala His-Ile-Ile-Ile, MW: 565.3Da) was isolated from Styela clava flesh tissue. In this study the fractions obtained during the isolation process and the finally purified peptide were examined to see if they had vasorelaxation effects in isolated rat aortas, and then the peptide was investigated for anti-hypertensive effect in spontaneously hypertensive rats (SHRs). The induction of vasorelaxation in the rat aortas was observed with the isolated fractions and the peptide from the enzymatic hydrolysate of S. clava flesh tissue and could be markedly blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-l arginine methyl ester (l-NAME). In human endothelial cells, NO synthesis was found to be increased and eNOS phosphorylation was upregulated when the cells were cultured with the purified peptide. Furthermore, systolic blood pressure was reduced by administration of the potent vasorelaxation peptide in SHRs. PMID- 23107741 TI - Dioscin: a synergistic tyrosinase inhibitor from the roots of Smilax china. AB - In our study, we investigated the inhibition of mushroom tyrosinase in Smilax china. A methanol (MeOH) extract of S. china was partitioned into hexane, ethyl acetate (EtOAc) and water. Of the three fractions, EtOAc extract showed the strongest inhibition of tyrosinase activity with l-tyrosine or l-DOPA as a substrate. Two compounds were isolated from a final active fraction by activity guided column chromatography. These compounds were identified as dioscin and oxyresveratrol by comparing their mass, (1)H- and (13)C-NMR spectral data with those reported in the literature. Dioscin showed little inhibition activity of tyrosinase, whereas oxyresveratrol, a known tyrosinase inhibitor, showed a strong tyrosinase inhibitory activity. We discovered that a mixture of oxyresveratrol and dioscin (IC(50)=5.1 and 5.7 MUg/ml) highly increased the inhibition of tyrosinase activity with l-tyrosine or l-DOPA as the substrate as compared to either oxyresveratrol (IC(50)=7.8 and 10.9 MUg/ml) or dioscin (IC(50)>100 and 100 MUg/ml) alone. PMID- 23107742 TI - Validation of antibiotics in catfish by on-line solid phase extraction coupled to liquid chromatography tandem mass spectrometry. AB - For the first time automated on-line solid phase extraction coupled to liquid chromatography tandem mass spectrometry was developed for the simultaneous determination of 13 antibiotics (sulfonamides and tetracyclines) in catfish. The method proposed was validated according to Commission Decision 2002/657/EC, showing good linearity between 2 and 350 MUg kg(-1), high recovery (80-99%) and reproducibility (13-20%) values, lower detection limits than 0.1 MUg kg(-1), and quantification limits under 2.4 MUg kg(-1) (between 39 and 84 times lower than the MRL fixed by the EU). Moreover, the proposed method was also used to determine sulfonamides and tetracyclines in 16 out of 107 samples, all previously analysed by microbiological screening that gave positive results. Five out of 13 antibiotics were found, having tetracycline the higher occurrence (10 samples); in all cases the concentrations were lower than the MRL established. PMID- 23107743 TI - Liquid chromatography/mass spectrometry based fingerprinting analysis and mass profiling of Euterpe oleracea (acai) dietary supplement raw materials. AB - Chemical fingerprinting and mass profiling methods to identify biologically active compounds in botanical dietary supplements is gaining much attention in recent years. Euterpe oleracea (acai) has been reported to be rich in health beneficial chemical constituents. We have developed LC/MS based fingerprinting and mass profiling methods to identify fatty acids, anthocyanins and non anthocyanin polyphenols in three processed raw materials; non-organic acai powder (ADSR-1), raw-organic acai powder (ADSR-2) and freeze-dried acai powder (ADSR-3) that are used in the preparation of botanical dietary supplements. For LC/MS analysis of fatty acids and non-anthocyanin polyphenols, the acai samples were extracted sequentially with dichloromethane followed by methanol. To study fingerprinting analysis of anthocyanins, acai samples were extracted with acidic methanol-water. The LC separation of fatty acids, non-anthocyanin polyphenols and anthocyanins in acai raw materials was achieved using a C18 column with a gradient mobile phase consisting of solvents A (0.1% formic acid in water), and B (0.1% formic acid in methanol). MS experiments were carried out with negative and positive mode electrospray ionization. LC/MS analysis of dichloromethane extracts of (ADSR-1), (ADSR-2) and (ADSR-3) acai powders have shown to contain fatty acids, gamma-linolenic acid, linoleic acid, palmitic acid, and oleic acid. Whereas, the fingerprinting analysis of methanol extracts of ADSR-1, ADSR-2 and ADSR-3 led to the identification of phenolic acids, anthocyanin and non anthocyanin polyphenols. The results from our study may be useful for the authentication and quality assessment of acai dietary supplement raw materials. PMID- 23107744 TI - Feasibility of conventional and Roundup Ready(r) soybeans discrimination by different near infrared reflectance technologies. AB - Identification and proper labelling of genetically modified organisms is required and increasingly demanded by legislation and consumers worldwide. In this study, the feasibility of three near infrared reflectance technologies (a chemical imaging unit, a commercial diode array instrument, and a light tube non commercial instrument) were compared for discriminating Roundup Ready(r) and not genetically modified soybean seeds. Over 200 seeds of each class (Roundup Ready(r) and conventional) were used. Principal Component Analysis with Artificial Neural Networks (PCA-ANN) and Locally Weighted Principal Component Regression (LW-PCR) were used for creating the discrimination models. Discrimination accuracies when new tested seeds belonged to samples included in the training sets achieved accuracies over 90% of correctly classified seeds for LW-PCR models. The light tube performed the best, while the imaging unit showed the worse accuracies overall. Models validated with new seeds from samples not included in the training set had accuracies of 72-79%. PMID- 23107745 TI - Characterization and authentication of a novel vegetable source of omega-3 fatty acids, sacha inchi (Plukenetia volubilis L.) oil. AB - Consumption of omega-3 fatty acids (omega-3's), whether from fish oils, flax or supplements, can protect against cardiovascular disease. Finding plant-based sources of the essential omega-3's could provide a sustainable, renewable and inexpensive source of omega-3's, compared to fish oils. Our objective was to develop a rapid test to characterize and detect adulteration in sacha inchi oils, a Peruvian seed containing higher levels of omega-3's in comparison to other oleaginous seeds. A temperature-controlled ZnSe ATR mid-infrared benchtop and diamond ATR mid-infrared portable handheld spectrometers were used to characterize sacha inchi oil and evaluate its oxidative stability compared to commercial oils. A soft independent model of class analogy (SIMCA) and partial least squares regression (PLSR) analyzed the spectral data. Fatty acid profiles showed that sacha inchi oil (44% linolenic acid) had levels of PUFA similar to those of flax oils. PLSR showed good correlation coefficients (R(2)>0.9) between reference tests and spectra from infrared devices, allowing for rapid determination of fatty acid composition and prediction of oxidative stability. Oils formed distinct clusters, allowing the evaluation of commercial sacha inchi oils from Peruvian markets and showed some prevalence of adulteration. Determining oil adulteration and quality parameters, by using the ATR-MIR portable handheld spectrometer, allowed for portability and ease-of-use, making it a great alternative to traditional testing methods. PMID- 23107746 TI - Identification of antioxidants in Fructus aurantii and its quality evaluation using a new on-line combination of analytical techniques. AB - A new on-line method for simultaneous identification and monitoring of antioxidants in Fructus aurantii was established by coupling high performance liquid chromatography-diode array detector-electrospray ionisation-ion trap-time of flight-mass spectrometry with post-column derivatisation and luminol-potassium ferricyanide chemiluminescence (HPLC-DAD-ESI-IT-TOF-MS-PCD-LPFCL). While the HPLC fingerprint, structural identification and radical scavenging profile were rapidly obtained by an on-line assay using ultraviolet (UV) absorption, MS and LPFCL, details of the precise substitution patterns of various structures were achieved through UV absorption using PCD addition of shift reagents. Twenty-five flavonoids were identified by either their PCD and MS data or comparison with reference substances. Data collected both from chromatograms and activity profiles of 12 samples revealed significant differences among samples from different habitats. The results showed that this method was rapid and precise, and therefore would be an effective and sensitive method for biocompounds analysis and quality evaluation for complex food and medicinal samples. PMID- 23107747 TI - MALDI-TOF mass spectrometry detection of extra-virgin olive oil adulteration with hazelnut oil by analysis of phospholipids using an ionic liquid as matrix and extraction solvent. AB - The adulteration of extra virgin olive oil (EVOO) with hazelnut oil (HO) is frequent and constitutes a serious concern both for oil suppliers and consumers. The high degree of similarity between the two oils as regards triacylglycerol, total sterol and fatty acid profile, complicates the detection of low percentages of HO in EVOO. However, phospholipids (PLs) are usually present in seed oils at a concentration range of 10-20 g/kg, while the amounts of PLs in VOOs are 300-400 times lower. Thus, in this work a sample pretreatment procedure focused towards the selective PLs extraction was developed; the Bligh-Dyer extraction procedure was modified introducing the ionic liquid resulting from the combination of TBA (tributylamine) and CHCA (alpha-Cyano-4-hydroxycinnamic acid) as extraction solvent. The selective extraction and enrichment of phospholipids from EVOO and HO samples was then achieved. The relevant extracts were analyzed by matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) using the same ionic liquid TBA-CHCA as MALDI matrix, that was found to be very suitable for PLs analysis. In fact, a remarkable increase of the phospholipids signals, with a simultaneous decrease of those relevant to triacylglycerols and diacylglycerols, was observed in the relevant mass spectra. The applicability of the whole method to the individuation of the presence of HO in EVOO was demonstrated by the analysis of EVOO samples progressively adulterated with variable quantities of HO, that was still detectable at a 1% contamination level. PMID- 23107748 TI - Identification and quantification of constituents of Gardenia jasminoides Ellis (Zhizi) by HPLC-DAD-ESI-MS. AB - A simple, rapid and specific HPLC method was carried out for the analysis of characteristic constituents in Gardenia jasminoides Ellis (Zhizi), namely iridoids, caffeoyl quinic acid derivatives and crocins. The separation was successfully obtained using a C(18) column by gradient elution with mixtures of methanol and water as mobile phases; detection wavelength was set at 240 nm for iridoid glycosides, 315 nm for quinic acid derivatives and 438 nm for crocins. The analytical method was validated and the quantification of active compounds, namely iridoids, was performed. Linearity, precision, repeatability, stability, accuracy, limit of detection (LOD) and limit of quantification (LOQ) were also reported. This assay was successfully applied for qualitative and quantitative analysis of five commercial samples of G. jasminoides Ellis. PMID- 23107749 TI - A simple method for total quantification of mannoprotein content in real wine samples. AB - Mannoproteins released by yeast cells throughout the winemaking process contribute in several ways to improve wine quality. For this reason, some winemaking practices have been developed in order to increase the mannoprotein content of wine. However, monitoring of mannoprotein content of wine during these processes, or even mannoprotein quantification in the final wines, is an analytical problem not easily solved so far. Here, we report a simple and accurate method for mannoprotein quantification in wines. The method involves isolation of wine polysaccharides by size exclusion chromatography, acid hydrolysis, elimination of acid by weak anionic exchange solid phase extraction, and analysis of monosaccharides by ion exclusion HPLC. Advantages over previously existing methods include low sample volumes, possibility of parallel processing for multiple samples, absence of precipitation steps, and clear distinction between mannoproteins and other wine polysaccharides. PMID- 23107750 TI - Proteomic analysis of processing by-products from canned and fresh tuna: identification of potentially functional food proteins. AB - Proteomic approaches have been used to identify the main proteins present in processing by-products generated by the canning tuna-industry, as well as in by products derived from filleting of skeletal red muscle of fresh tuna. Following fractionation by using an ammonium sulphate precipitation method, three proteins (tropomyosin, haemoglobin and the stress-shock protein ubiquitin) were identified in the highly heterogeneous and heat-treated material discarded by the canning industry. Additionally, this fractionation method was successful to obtain tropomyosin of high purity from the heterogeneous starting material. By-products from skeletal red muscle of fresh tuna were efficiently fractionated to sarcoplasmic and myofibrillar fractions, prior to the identification based mainly on the combined searching of the peptide mass fingerprint (MALDI-TOF) and peptide fragment fingerprinting (MALDI LIFT-TOF/TOF) spectra of fifteen bands separated by 1D SDS-PAGE. Thus, the sarcoplasmic fraction contained myoglobin and several enzymes that are essential for efficient energy production, whereas the myofibrillar fraction had important contractile proteins, such as actin, tropomyosin, myosin or an isoform of the enzyme creatine kinase. Application of proteomic technologies has revealed new knowledge on the composition of important by-products from tuna species, enabling a better evaluation of their potential applications. PMID- 23107751 TI - Simultaneous determination of polymethoxyflavones in Citrus species, Kiyomi tangor and Satsuma mandarin, by high performance liquid chromatography. AB - The content of polymethoxyflavones (PMFs) in Kiyomi tangor (Citrus unshiu Marcov. forma miyagawa-wase*C. sinensis) and Satsuma mandarin (C. unshiu Marcov. forma miyagawa-wase) was determined by HPLC/UV. The major PMFs of Kiyomi tangor were determined as 3,6,7,4'-tetramethoxyflavone in the peels (10.1mg/g) and leaves (9.2mg/g), and 3-hydroxy-5,6,7,4'-tetramethoxyflavone in the stems (1.5mg/g). The major PMFs of Satsuma mandarin were determined as 5,6,7,8,4'-pentamethoxyflavone in the peels (2.2mg/g) and leaves (1.6 mg/g), and 5,6,7,3',4'-pentamethoxyflavone in the stems (1.4mg/g). Large amounts of Citrus by-products can ultimately provide a cheap and convenient source of PMFs. PMID- 23107752 TI - Electrochemical determination of theophylline in foodstuff, tea and soft drinks based on urchin-like CdSe microparticles modified glassy carbon electrode. AB - A simply electrochemical method based on CdSe microparticles modified glassy carbon electrode (GCE) was developed to determine theophylline using cyclic voltammetry and differential pulse voltammetry. Theophylline showed a well defined oxidation peak at the fabricated electrode in phosphate buffer solution and the oxidation peak current is much higher than that at the bare GCE, indicating that CdSe can effectively improve the oxidation of theophylline. Several effect factors on theophylline determination were optimised, such as CdSe amount, solution pH, scan rate and accumulation time. Under the optimal conditions, the oxidation peak current of theophylline was proportional to its concentration in the range of 1.0-40 and 40-700 MUM with a correlation coefficient of 0.9974 and 0.9956, respectively. The limit of detection was estimated to be 0.4 MUM (S/N=3). The developed method showed good reproducibility and excellent selectivity. The fabricated electrode was successfully used to determine theophylline in tea, carbonated cola drink, fruit juice drink, fermented milk drink and preserved fruit with acceptable recovery. PMID- 23107753 TI - Separation and identification of zinc-chelating peptides from sesame protein hydrolysate using IMAC-Zn2+ and LC-MS/MS. AB - The metal chelating peptides from sesame protein hydrolysates (SPH), treated by papain, alcalase and trypsin, respectively, were investigated. The hydrolysates treated by trypsin had the highest metal chelating ability. The metal chelating peptides were isolated from the trypsin hydrolysates using immobilized metal affinity chromatography (IMAC-Zn(2+)). Further, six zinc-chelating peptides were identified with reversed phase (RP)-HPLC and mass spectrometry (LC-MS/MS). Three of these metal-chelating peptides, Ser-Met, Leu-Ala-Asn and Asn-Cys-Ser, were synthesized and the metal-chelating ability of peptides was measured. The Asn-Cys Ser peptide showed the highest zinc and iron chelating ability, which was even higher than reduced glutathione (GSH). The results confirm that the zinc or iron chelating activity of these peptides, and provide further support to its feasibility as natural metal chelating agents from sesame protein. PMID- 23107754 TI - New voltammetric procedure for determination of thiamine in commercially available juices and pharmaceutical formulation using a lead film electrode. AB - A simple, reliable and reproducible method, based on adsorptive stripping voltammetry (AdSV), for determination of vitamin B(1) (thiamine) in pharmaceutical preparation and food is described in this paper. The in situ plated lead film electrode was used as a working electrode. The lead film was formed and thiamine was accumulated at -1.25 V (vs. Ag/AgCl) on a glassy carbon electrode. Then, the preconcentrated thiamine was reduced by scanning the potential of the electrode from -1.25 to -1.55V using a square-wave technique. The linear range was from 0.0133 to 0.265 mg L(-1) for vitamin B(1), with the regression coefficient of 0.999. The detection limit for vitamin B(1) was 0.0053 mg L(-1) for the accumulation time 120s. The method developed was applied to the determination of thiamine in certified reference material (BCR-485), pharmaceutical formulation and commercially available juices, and the assay results were satisfactory. PMID- 23107755 TI - Determination of supplemental feeding needs for astaxanthin and canthaxanthin in salmonids by supramolecular solvent-based microextraction and liquid chromatography-UV/VIS spectroscopy. AB - Development of simple and rapid analytical methods for predicting supplemental feeding requirements in aquaculture is a need to reduce production costs. In this article, a supramolecular solvent (SUPRAS) made up of decanoic acid (DeA) assemblies was proposed to simplify sample treatment in the total and individual determination of carotenoids (red-pink pigments) in farmed salmonids. The analytes were quantitatively extracted in a single step that spends a few minutes using a small volume of SUPRAS (i.e. 800 MUL) and directly determined in extracts without the interference from fats or other matrix components. The methods based on the combination of microextraction with SUPRAS and photometry or HPLC-UV/VIS spectroscopy were developed for the determination of total and individual carotenoids, respectively. The applicability of the methods was demonstrated by analysing non-fortified and fortified samples of farmed Atlantic salmons and rainbow trouts. Recoveries obtained by photometry and HPLC-UV/VIS spectroscopy were within the intervals 98-104% and 94-106%, respectively. PMID- 23107756 TI - Baseline respiratory parameters in panic disorder: a meta-analysis. AB - BACKGROUND: The presence of abnormalities in baseline respiratory function of subjects with panic disorder (PD) is expected according to PD respiratory theories. We aimed to meta-analyze results from studies comparing baseline respiratory and hematic parameters related to respiration between subjects with PD and controls. METHODS: A literature research in bibliographic databases was performed. Fixed-effects models were applied for all parameters while random effects models only when suitable (at least 10 independent studies). Several moderator analyses and publication bias diagnostics were performed. RESULTS: We found significantly higher mean minute ventilation and lower et-pCO(2) in subjects with PD than controls. Moreover we also found evidences of reduced HCO(3)(-) and PO(4)(-) hematic concentrations, higher indexes of respiratory variability/irregularity and higher rate of sighs and apneas. Evidence of heterogeneity was partly explained by moderator analyses. No relevant publication bias was found. LIMITATIONS: Several shortcomings affected the included studies, such as over-inclusive recruitment criteria, samples unbalanced for socio demographic characteristics, lack of statistical details and small number of studies available for several parameters. DISCUSSION: Our results support the idea of abnormalities in respiratory function of subjects with PD. Compared to controls, they showed baseline hyperventilation; the results from hematic parameters suggest that hyperventilation may be chronic and not simply caused by their high anxiety levels during respiratory assessment. Evidences of higher variability and irregularity in respiratory patterns of subjects with PD were also found. It is unclear to what extent the higher rate of sighs and apneas may explain the other baseline respiratory abnormalities found in PD. PMID- 23107757 TI - Smoking and other risk factors for pancreatic cancer: a cohort study in men in Lithuania. AB - BACKGROUND: Cancer of the pancreas is a relatively rare, but highly fatal cancer worldwide. Cigarette smoking has been recognized as an important risk factor, but the relation to other potential determinants is still inconsistent. We investigated the association between different lifestyle, biological and anthropometric factors and the risk of pancreatic cancer in a prospective population-based cohort study from Kaunas, Lithuania. METHODS: Our study included 7132 urban men initially free from any diagnosed cancer, followed for up to 30 years. 77 incident cases of pancreatic cancer were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). RESULTS: Compared to never smokers, current smokers had a significantly increased risk of pancreatic cancer, HR was 1.79 (95% CI 1.03-3.09) after adjustment for age, body mass index, education and alcohol consumption. Among smokers, a significant association with higher smoking intensity was shown (>= 20 cigarettes/day: HR = 2.60; 95% CI 1.42 4.76, P(trend) = 0.046). We also observed a significantly increased risk for >= 30 pack-years of smoking (HR = 2.24; 95% CI 1.12-4.49, P(trend) = 0.16) and for age at starting smoking < 18 years (HR = 2.29; 95% CI 1.11-4.70, P(trend) = 0.43) as compared to never smokers. Alcohol consumption, body mass index and total cholesterol level were not significantly associated with pancreatic cancer. CONCLUSIONS: Smoking significantly increases pancreatic cancer incidence and its high prevalence in Lithuania may partly explain high incidence of the disease. No convincing evidence was found that alcohol consumption, body mass index or serum cholesterol level were associated with pancreatic cancer risk, although the assessment was limited by the lack of statistical power. PMID- 23107758 TI - Tea consumption reduces ovarian cancer risk. AB - OBJECTIVE: To ascertain the relationship between tea drinking and the risk of ovarian cancer among southern Chinese women, a case-control study was conducted in southern China during 2006-2008. METHODS: Five hundred incident patients with histologically confirmed epithelial carcinoma of the ovary and 500 controls (mean age 59 years) were recruited from four public hospitals in Guangzhou. Information on frequency, quantity and duration of tea drinking, amount of dried tea leaves brewed, together with habitual diet and lifestyle characteristics, was obtained face-to-face from participants using a validated and reliable questionnaire. Logistic regression analyses were performed to assess the association between tea consumption variables and the ovarian cancer risk. RESULTS: The control subjects reported higher tea consumption levels and prevalence (78.8%) than the ovarian cancer patients (51.4%). Regular drinking of green tea, black tea and/or oolong tea was associated with a lower risk of ovarian cancer, the adjusted odds ratio being 0.29 (95% confidence interval 0.22-0.39) after accounting for confounding factors. When compared with non-drinkers, apparent inverse dose-response relationships were observed for years of drinking, number of cups and quantity of tea consumed, as well as amount of dried tea leaves brewed (p < 0.01). CONCLUSION: Regular tea consumption is associated with a reduced risk of ovarian cancer for southern Chinese women. PMID- 23107759 TI - Operative hysteroscopy in an office-based surgical setting: review of patient safety and satisfaction in 414 cases. AB - STUDY OBJECTIVE: To determine the safety and satisfaction among patients undergoing operative hysteroscopy in an office-based setting. DESIGN: Retrospective analysis (Canadian Task Force classification II-2). SETTING: Physician's private office. PATIENTS: Women undergoing operative hysteroscopy in an office setting. INTERVENTIONS: Three hundred eighty-seven women underwent a total of 414 operative hysteroscopic procedures, with use of parenterally administered moderate sedation, a 9-mm operative resectoscope, and sonographic guidance. All patients were American Society of Anesthesiologists class I-III. MEASUREMENTS AND MAIN RESULTS: A total of 305 primary operative hysteroscopic procedures were performed including endomyometrial resection, myomectomy, polypectomy, removal of a uterine septum, and adhesiolysis. One hundred nine (26.3%) repeat operative procedures were performed in women in whom previous endometrial ablation and resection had failed. The average procedure required a mean (SD) of 37.6 (13.5) minutes to complete, and produced 14.1 (10.2) g of tissue. Ninety-nine percent of all procedures were completed. Only 1 patient required a hospital transfer for evaluation of a uterine perforation necessitating diagnostic laparoscopy. There were 8 (1.9%) postoperative infections, and no complications attributable to use of conscious sedation. Two hundred fifty-five women (65.6%) responded to our telephone survey. Two hundred fifty-two (98.8%) respondents were either "very satisfied" or "satisfied." Two hundred forty-nine women (97.6%) preferred the office to a hospital setting, whereas 6 (2.4%) would have preferred a hospital setting. All but 5 respondents would recommend this procedure to a friend. CONCLUSION: Major operative hysteroscopic surgery can be performed in an office-based setting with a high degree of safety and patient satisfaction. PMID- 23107760 TI - Interactions of DMPC and DMPC/gemini liposomes with the cell membrane investigated by electrorotation. AB - The electrorotation technique was utilized to investigate the interactions between a mouse fibroblast cell line and zwitterionic liposomes formed by a natural phospholipid or cationic liposomes formulated with the same phospholipid and a cationic gemini surfactant. The application of this technique allowed an accurate characterization of the passive dielectric behavior of the plasma membrane by the determination of its specific capacitance and conductance. Changes of these parameters, upon interaction with the liposomes, are related to variations in the structure and or in the transport properties of the membrane. Cells were exposed to both types of liposomes for 1 or 4h. Electrorotation data show a dramatic reduction of the dielectric parameters of the plasma membrane after one hour treatment. After 4h of treatment the effects are still observed only in the case of the cationic liposomes. Surprisingly, these same treatments did not cause a relevant biological damage as assessed by standard viability tests. A detailed discussion to rationalize this phenomenon is presented. PMID- 23107761 TI - Characterization of the defense transcriptome responsive to Fusarium oxysporum infection in Arabidopsis using RNA-seq. AB - We analyzed the dynamic defense transcriptome responsive to Fusarium oxysporum infection in Arabidopsis using a strand-specific RNA-sequencing approach. Following infection, 177 and 571 genes were up-regulated, 30 and 125 genes were down-regulated at 1 day-post-inoculation (1DPI) and 6DPI, respectively. Of these genes, 116 were up-regulated and seven down-regulated at both time points, suggesting that most genes up-regulated at the early stage of infection tended to be constantly up-regulated at the later stage whereas the landscape of the down regulated genes differed significantly at the two time points investigated. In addition to genes known to be part of the defense network in various plant pathogen interactions, many novel disease responsive genes, including non-coding RNAs, were identified. Disease inoculation experiments with mutants of the AtROBH genes showed that AtROBHD and AtROBHF have opposite effects on disease development and provided new insights into the functions of the genes encoding NADPH oxidase in fungal disease resistance. PMID- 23107762 TI - Analysis of microRNA expression profile induced by AICAR in mouse hepatocytes. AB - AMP-activated protein kinase (AMPK) has been proposed to act as a key energy sensor mediating the metabolism of glucose and lipids, and pharmacological activation of AMPK may provide a new strategy for the management of type 2 diabetes. MicroRNAs (miRNAs) are a group of endogenous noncoding RNA that play important roles in many biological processes including energy metabolism. Whether miRNAs mediate AMPK action in regulating metabolic process is not clear. In this study, 0.5mM 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) was added to increase activation of AMPK in 8 week old C57BL/6 mice primary hepatocytes. MiRNA microarray was performed to compare the miRNA expression profiles of hepatocytes treated with or without AICAR. We discovered that 41 miRNAs were significantly altered in AICAR-treated sample (fold change: >2) compared with untreated control sample. Among them, 19 miRNAs were upregulated. MiRNA targets were predicted by TargetScan. Further bioinformatic analysis indicated that these predicted targets might be mainly involved in pathways of cellular metabolism and tumor pathogenesis. FUNDO analysis suggested that these predicted targets were enriched in cancer, diabetes mellitus, hypertension, obesity and heart failure (P<0.01). A series of miRNAs could be regulated by the activation of AMPK and might mediate the action of AMPK during metabolic processes and tumor pathogenesis. Predicted target genes discovered in this study and pathway analysis provide new insights into hepatic metabolism and tumor pathogenesis regulated by AMPK signaling and clues to the possible molecular mechanism underlying the effect of AMPK. PMID- 23107763 TI - Host genetic risk factors for community-acquired pneumonia. AB - This study was conducted to establish the contribution of genetic host factors in the susceptibility to community acquired pneumonia (CAP) in the Russian population. Patients with CAP (n=334), volunteers without a previous history of CAP, constantly exposed to infectious agents, control A group (n=141) and a second control group B consisted of healthy persons (n=314) were included in the study. All subjects were genotyped for 13 polymorphic variants in the genes of xenobiotics detoxification CYP1A1 (rs2606345, rs4646903, and rs1048943), GSTM1 (Ins/del), GSTT1 (Ins/del), ABCB1 rs1045642); immune and inflammation response IL 6 (rs1800795), TNF-a (rs1800629), MBL2 (rs7096206), CCR5 (rs333), NOS3 (rs1799983), angiotensin-converting enzyme ACE (rs4340), and occlusive vascular disease/hyperhomocysteinemia MTHFR (rs1801133). Seven polymorphic variants in genes CYP1A1, GSTM1, ABCB1, NOS3, IL6, CCR5 and ACE were associated with CAP. For two genes CYP1A1 and GSTM1 associations remained significant after correction for multiple comparisons. Multiple analysis by the number of all risk genotypes showed a highly significant association with CAP (P=2.4*10(-7), OR=3.03, 95% CI 1.98-4.64) with the threshold for three risk genotypes. Using the ROC-analysis, the AUC value for multi-locus model was estimated as 68.38. PMID- 23107764 TI - Inactivation of the serine proteinase operon (proMCD) of Staphylococcus warneri M: serine proteinase and cysteine proteases are involved in the autolysis. AB - Unlike other members of coagulase negative staphylococci (CNS), strain warneri has proMCD operon, a homologue of sspABC proteinase operon of S. aureus. The proM and proC encode serine glutamyl endopeptidase and cysteine protease respectively, whereas proD directs homologue of SspC, putative cytoplasmic inhibitor which protects the host bacterium from premature activation of SspB. We determined whole nucleotide sequence of proMCD operon of S. warneri M, succeeded in expression of these genes, and investigated their functions by gene inactivation and complementation experiments. In gelatin zymography of the culture supernatant, a 20-kDa band corresponding to PROC cysteine protease was detected. By Western blotting, PROD was also confirmed in the cytoplasmic protein fraction. PROC and PROD showed significant similarity to SspB and SspC of S. aureus (73% and 58%, respectively). Inactivation mutants of proMCD, proCD and proD genes were established, separately. In the proMCD mutant, degradation/processing of extracellular proteins was drastically reduced, suggesting that PROM was responsible for the cleavage of extracellular proteins. By the proD mutation, the growth profile was not affected, and secretion of PROC was retained. Extracellular protein profiles of the proCD and proD mutants were not so different each other, but autolysin profiles were slightly dissimilar, around 39 48 kDa and 20kDa bands in zymogram. Experiments in buffer systems showed that autolysis was significantly diminished in proMCD mutant, and was promoted by addition of purified PROM. The proC gene was cloned into a multicopy plasmid, and introduced into the proMCD mutant. Compared with the wild type, autolysis of the proC-complemented strain was definitely enhanced by addition of purified PROM. These results suggested that PROM and PROC affected the coccal autolysis, through processing of the autolysin. PMID- 23107765 TI - Chondrocyte BMP2 signaling plays an essential role in bone fracture healing. AB - The specific role of endogenous Bmp2 gene in chondrocytes and in osteoblasts in fracture healing was investigated by generation and analysis of chondrocyte- and osteoblast-specific Bmp2 conditional knockout (cKO) mice. The unilateral open transverse tibial fractures were created in these Bmp2 cKO mice. Bone fracture callus samples were collected and analyzed by X-ray, micro-CT, histology analyses, biomechanical testing and gene expression assays. The results demonstrated that the lack of Bmp2 expression in chondrocytes leads to a prolonged cartilage callus formation and a delayed osteogenesis initiation and progression into mineralization phase with lower biomechanical properties. In contrast, when the Bmp2 gene was deleted in osteoblasts, the mice showed no significant difference in the fracture healing process compared to control mice. These findings suggest that endogenous BMP2 expression in chondrocytes may play an essential role in cartilage callus maturation at an early stage of fracture healing. Our studies may provide important information for clinical application of BMP2. PMID- 23107766 TI - Association between IL-4 polymorphism and acute rejection of solid organ allograft: a meta-analysis. AB - BACKGROUND: Cytokines have been implicated in the acute rejection of solid organ transplantation. Many studies have investigated the association between recipient or donor IL-4 polymorphism and acute rejection, with different studies reporting inconclusive results. METHODS: We searched PUBMED and EMBASE until June 2012 to identify eligible studies investigating the association between IL-4 polymorphism with acute rejection after solid organ transplantation. Statistical analysis was performed using STATA10.0. RESULTS: A total of 12 studies were included. Pooled ORs suggested 1) no significant association was detected between recipient or donor IL-4 -590C/T polymorphism and acute rejection of solid allograft; 2) no significant association was detected between recipient IL-4 -33C/T polymorphism and acute rejection of solid allograft; 3) when stratified by transplantation type, IL-4 -590C/T polymorphism was associated with acute rejection of liver transplantation (T/T+C/T vs. C/C: OR=0.36, 95%CI=0.14-0.90); 4) significantly decreased risk of acute rejection was detected in recipient IL-4 -590*T negative/donor T-positive genotype pairs than all other recipient-donor IL-4 590T/C pairs (OR=0.14, 95%CI=0.03-0.66). CONCLUSIONS: Our meta-analysis suggested that recipient IL-4 -590C/T polymorphism was associated with acute rejection of liver transplantation, but nor renal or heart transplantation. It was also suggested that combined recipient IL-4 -590*T-negative/donor T-positive genotype may suffer decreased risk of acute rejection of solid allograft. Further well designed studies with larger sample size were required to verify our findings, with focus on the association of IL-4 polymorphism with acute rejection in patients with liver transplantation and studies investigating combined recipient donor genotype. PMID- 23107767 TI - The impact of GGH -401C>T polymorphism on cisplatin-based chemoradiotherapy response and survival in cervical cancer. AB - AIMS: Cervical cancer is the third most frequent cancer in women worldwide, mostly treated with cisplatin-based chemoradiotherapy. Since it is known that folate metabolism might interfere with cisplatin effectiveness, we intended to study the influence of the Gamma Glutamyl Hydrolase -401C>T polymorphism in treatment response in cervical cancer. METHODS: We retrospectively reviewed the clinical data of 167 patients with bulky cervical cancer submitted to cisplatin based chemoradiotherapy. The genotypes of GGH -401C>T SNP were determined by real time PCR and statistical analysis was performed by chi(2) test and survival analysis. RESULTS: The genotypes of GGH-401C>T were significantly associated with the response to platinum-based chemoradiotherapy. Treatment response was higher in patients carrying the CC genotype, who presented a significant increased chance of treatment response (survival time in months/genotype: 91 for CC Vs 72 for CT/TT; p=0.035, log rank test). A Cox regression analysis accordingly showed that the presence of the T allele was significantly linked to a worse treatment response (HR=3.036; CI 95% 1.032-8.934, p=0.044). CONCLUSIONS: The results of our study suggested the potential interest of GGH -401C>T as a predictive factor of the outcome of cervical carcinoma treated with cisplatin-based chemoradiotherapy. PMID- 23107768 TI - Relationship between GSTM1 and GSTT1 polymorphisms and schizophrenia: a case control study in a Tunisian population. AB - There is substantial evidence found in the literature that supports the fact that the presence of oxidative stress may play an important role in the pathophysiology of schizophrenia. The glutathione S-transferases (GSTs) forms one of the major detoxifying groups of enzymes responsible for eliminating products of oxidative stress. Interindividual differences observed in the metabolism of xenobiotics have been attributed to the genetic polymorphism of genes coding for enzymes involved in detoxification. Thus, in this study we investigated the association of glutathione S-transferase Mu-1 (GSTM1) and glutathione S transferase theta-1 (GSTT1) gene deletion polymorphisms and schizophrenia in a Tunisian population. A case-control study including 138 schizophrenic patients and 123 healthy controls was enrolled. The GSTM1 and GSTT1 polymorphisms were analyzed by multiplex polymerase chain reaction (PCR). No association was found between the GSTM1 genotype and schizophrenia, whereas the prevalence of the GSTT1 active genotype was significantly higher in the schizophrenic patients (57.2%) than in the controls (45.5%) with (OR=0.6, IC 0.37-0.99, p=0.039). Thus, we noted a significant association between schizophrenia and GSTT1 active genotype. Furthermore, the combination of the GSTM1 and GSTT1 null genotypes showed a non significant trend to an increased risk of schizophrenia. The present finding indicated that GSTT1 seems to be a candidate gene for susceptibility to schizophrenia in at least Tunisian population. PMID- 23107769 TI - Hypocholesterolemic effect of rice protein is due to regulating hepatic cholesterol metabolism in adult rats. AB - Aging is one of major risk factors for developing hypercholesterolemia. To elucidate the cholesterol-lowering mechanism exerted by rice protein (RP), the effects on hepatic cholesterol outputs and cholesterol metabolism related enzymes were investigated in adult rats, which were fed by casein (CAS) and RP without cholesterol in diets. After 2 weeks of feeding, the significant cholesterol lowering effect was observed in adult rats fed by RP compared to CAS. The hepatic total- and VLDL-cholesterol secretions into circulation were significantly depressed in RP group, whereas biliary outputs of bile acids and cholesterol were effectively stimulated by RP-feeding, causing an increase in fecal sterol excretion compared to CAS. As a result, the apparent cholesterol absorption was significantly inhibited by RP. RP-feeding significantly increased the activity and gene expression of cholesterol 7alpha-hydroxylase, whereas acyl CoA:cholesterol acyltransferase-2 activity and gene expression were significantly decreased by RP as compared with CAS. Neither activity nor gene expression of 3 hydroxy-3-methylglutaryl coenzyme A reductase of RP did differ from CAS in the liver. The present study demonstrates that rice protein can prevent hypercholesterolemia through modifying hepatic cholesterol metabolism under cholesterol-free dietary condition. The findings suggest that hypocholesterolemic action induced by rice protein is attributed in part to the inhibition of cholesterol absorption during the adult period. PMID- 23107770 TI - Influence of CYP3A4, CYP3A5 and MDR-1 polymorphisms on tacrolimus pharmacokinetics and early renal dysfunction in liver transplant recipients. AB - OBJECTIVES: Tacrolimus is a widely used immunosuppressive drug in organ transplantation. The oral bioavailability of tacrolimus varies greatly between individuals and depends largely on the activity of both the cytochrome P450 3A (CYP3A) subfamily and P-glycoprotein (P-gp). The possible influence of single nucleotide polymorphisms (SNPs) of CYP3A subfamily and P-gp (MDR-1) in liver transplant recipients has recently been indicated as one of the most important variables affecting the pharmacokinetics of tacrolimus and the renal injury induced by tacrolimus. METHODS: A total of 216 liver transplant recipients were enrolled in this study. The recipients' mean follow-up time was 52 mo (range from 16 to 96 mo). All liver transplant recipients were all in a stable stage with normal serum creatinine (SCr). All liver transplant recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), CYP3A4 intron 6 (CYP3A4*22), MDR 1 exon 26 (3435C>T) and exon 12 (1236 C>T) SNPs by HRM analysis (high-resolution melting curve analysis). Recipients were defined as the early renal injury by the elevation of different microproteins in the urine including microalbumin (MA), urine immunoglobulin G (IGU), urine transferrin (TRU) and alpha1-microglobulin (A1M). RESULTS: The daily dose of tacrolimus was higher for recipients with CYP3A5 1/1 (AA) genotype than those with CYP3A5 3/ 3 (GG) genotype [3.0 (2.0-4.0) versus 2.0 (1.5-2.5) mg/d, P<0.05]. The concentration/dose ratio of recipients with CYP3A5 1 homozygotes was lowest compared to recipients with CYP3A5 3/ 3 and CYP3A5 1/ 3 genotypes. Furthermore, the recipients carrying CYP3A5 3 allele were associated with increased risk of early renal glomerular injury compared to the recipients carrying CYP3A5 1 allele (P=0.01). MDR-1 polymorphisms were not related with tacrolimus pharmacokinetics and early renal injury. CONCLUSION: CYP3A5 6986A>G genetic polymorphism affected daily dose requirements, concentration and nephrotoxicity of tacrolimus. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression outcome. PMID- 23107771 TI - CHK2 1100delC, IVS2+1G>A and I157T mutations are not present in hepatocellular cancer cases from a Turkish population. AB - AIM: The cell cycle checkpoint kinase 2 (CHK2) protein participates in the DNA damage response in many cell types. Germline mutations in CHK2 (1100delC, IVS2+1G>A and I157T) have been associated with a range of cancer types. This study aimed to investigate whether CHK2 1100delC, IVS2+1G>A and I157T mutations play an important role in the development of hepatocellular carcinoma (HCC) in a Turkish population. METHODS: A total of 165 hepatocellular cancer cases and 446 cancer-free controls were genotyped for CHK2 mutations by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and allele specific polymerase chain reaction (AS-PCR) methods. RESULTS: We did not find CHK2 1100delC, IVS2+1G>A and I157T mutations in any of 611 Turkish subjects. CONCLUSION: Our results demonstrate for the first time that CHK2 1100delC, IVS2+1G>A and I157T mutations have not been a genetic susceptibility factor for HCC in the Turkish population. Overall, our data suggests that genotyping of CHK2 mutations in clinical settings in the Turkish population should not be recommended. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins. PMID- 23107772 TI - Protein-protein interaction and SNP analysis in intraductal papillary mucinous neoplasm. AB - Intraductal papillary mucinous neoplasm (IPMN) is a type of tumor that grows within the pancreatic ducts. It is a progress from hyperplasia to intraductal adenoma (IPMA), to noninvasive carcinoma, and ultimately to invasive carcinoma (IPMC). The objective of this study was to explore the molecular mechanism of the progression from IPMA to IPMC. By using the GSE19650 affymetrix microarray data accessible from Gene Expression Omnibus (GEO) database, we first identified the differentially expressed genes (DEGs) between IPMA and IPMC, followed by the protein-protein interaction and single-nucleotide polymorphism (SNP) analysis of the DEGs. Our study identified thousands of DEGs which involved regulation of cell cycle and apoptosis in this progression from IPMA to IPMC. Protein-protein interaction network construction found that MYC, IL6ST, NR3C1, CREBBP, GATA1 and LRP1 might play an important role in the progression. Furthermore, the SNP analysis confirmed the association between BRAC1 and pancreas cancer. In conclusion, our data provide a comprehensive bioinformatics analysis of genes and pathways which may be involved in the progression of IPMN from IPMA to IPMC. PMID- 23107773 TI - When the difference is in the details: a critique of Zentner and Mitura (2012) "Stepping out of the caveman's shadow: Nations' gender gap predicts degree of sex differentiation in mate preferences". AB - In a recent 10-nation study, Zentner and Mitura (2012) reported observing smaller sex differences in mate preferences within nations that have higher gender parity. As noted in previous research, and in a re-analysis of Zentner and Mitura's own data, sex differences in some mate preferences (e.g., long-term mate preferences for physical attractiveness) are either unrelated to or actually get larger with higher national gender parity. It is critically important to distinguish among mate preference domains when looking for patterns of sexual differentiation across nations. Indeed, for many psychological domains (e.g., attachment styles, Big Five traits, Dark Triad traits, self-esteem, personal values, depression, emotional expression, crying behavior, intimate partner violence, tested mental abilities, health indicators; see Schmitt, 2012), sex differences are demonstrably larger in nations with higher sociopolitical gender parity. By not distinguishing among mate preferences, Zentner and Mitura committed a form of the ecological fallacy-making false conclusions about individual mate preferences when looking only at associations among groups of mate preferences. PMID- 23107774 TI - Population dynamics of Glossina palpalis gambiensis symbionts, Sodalis glossinidius, and Wigglesworthia glossinidia, throughout host-fly development. AB - The tsetse fly (Diptera: Glossinidae), the vector of trypanosomes causing human and animal trypanosomiasis, harbors symbiotic microorganisms including the primary symbiont Wigglesworthia glossinidia, involved in the fly's nutrition and fertility, and the secondary symbiont Sodalis glossinidius, involved in the trypanosome establishment in the fly's midgut. Both symbionts are maternally transmitted to the intrauterine progeny through the fly's milk gland secretions. In this study, we investigated the population dynamics of these symbionts during fly development. Wigglesworthia and Sodalis densities were estimated using quantitative PCR performed on Glossina palpalis gambiensis at different developmental stages. The results showed that the density of the primary Wigglesworthia symbiont was higher than that of Sodalis for all host developmental stages. Sodalis densities remained constant in pupae, but increased significantly in adult flies. The opposite situation was observed for Wigglesworthia, whose density increased in pupae and remained constant during the female adult stage. Moreover, Wigglesworthia density increased significantly during the transition from the pupal to the teneral stage, while mating had a contradictory effect depending on the age of the fly. Finally, tsetse fly colonization by both symbionts appears as a continuous and adaptive process throughout the insect's development. Last, the study demonstrated both symbionts of G. p. gambiensis, the vector of the chronic form of human African trypanosomiasis, to be permanent inhabitants of the colony flies throughout their life span. This was expected for the primary symbiont, Wigglesworthia, but not necessarily for the secondary symbiont, S. glossinidius, whose permanent presence is not required for the fly's survival. This result is of importance as Sodalis could be involved in the tsetse fly vector competence and may constitute a target in the frame of sleeping sickness fighting strategies. PMID- 23107775 TI - Expression of CXCL10 (IP-10) and CXCL11 (I-TAC) chemokines during Mycobacterium tuberculosis infection and immunoprophylaxis with Mycobacterium indicus pranii (Mw) in guinea pig. AB - Mycobacterium indicus pranii (earlier known as Mycobacterium w) has been used as an immunmodulatory agent in leprosy and tuberculosis by mediating the release of various cytokines and chemokines. CXCL10 (IP-10) and CXCL11 (I-TAC) chemokines are involved in T-cell migration and stimulation of natural killer cells in Mycobacterium tuberculosis infection. In this study, the effect of heat killed M. indicus pranii (alone and in conjunction with chemotherapy) on disease progression was determined by colony forming units (CFUs) in guinea pig lung following their aerosol infection and the expression levels of CXCL10 and CXCL11 were studied by quantitative Reverse Transcriptase Polymerase Chain Reaction (qRT PCR) and in situ RT-PCR. Four groups of animals included; infection only (Rv), immunoprophylaxis (RvMw), chemotherapy (RvCh) and combination of immunoprophylaxis with chemotherapy (RvChMw). In the group where immunoprophylaxis was given in combination with chemotherapy, the CFU counts reduced significantly at 4th week post-infection as compared to animals that received immunoprophylaxis or chemotherapy alone. At the same time, all groups of animals had elevated expression of CXCL 10 which was significantly high only in animals that received Mw with or without chemotherapy. Unlike to CXCL 10, study demonstrated suppressed expression CXCL 11 in both immunoprophylaxis as well as chemotherapy groups that became up-regulated in synergistic response of immunoprophylaxis and chemotherapy. Taken together, data indicates that the expression of CXCL10 and CXCL11 positively correlates with anti-tubercular treatment (at least with combination of immunoprophylaxis and chemotherapy). Therefore, prior immunization with Mw appears to be a good immunomodulator for release of chemokines and augments the effect of chemotherapy. PMID- 23107776 TI - Protein damage, repair and proteolysis. AB - Proteins are continuously affected by various intrinsic and extrinsic factors. Damaged proteins influence several intracellular pathways and result in different disorders and diseases. Aggregation of damaged proteins depends on the balance between their generation and their reversal or elimination by protein repair systems and degradation, respectively. With regard to protein repair, only few repair mechanisms have been evidenced including the reduction of methionine sulfoxide residues by the methionine sulfoxide reductases, the conversion of isoaspartyl residues to L-aspartate by L-isoaspartate methyl transferase and deglycation by phosphorylation of protein-bound fructosamine by fructosamine-3 kinase. Protein degradation is orchestrated by two major proteolytic systems, namely the lysosome and the proteasome. Alteration of the function for both systems has been involved in all aspects of cellular metabolic networks linked to either normal or pathological processes. Given the importance of protein repair and degradation, great effort has recently been made regarding the modulation of these systems in various physiological conditions such as aging, as well as in diseases. Genetic modulation has produced promising results in the area of protein repair enzymes but there are not yet any identified potent inhibitors, and, to our knowledge, only one activating compound has been reported so far. In contrast, different drugs as well as natural compounds that interfere with proteolysis have been identified and/or developed resulting in homeostatic maintenance and/or the delay of disease progression. PMID- 23107777 TI - Laparoscopic ventral mesh rectopexy in the management of solitary rectal ulcer syndrome: a cause for optimism? AB - AIM: The treatment of solitary rectal ulcer syndrome (SRUS) is notoriously difficult. Laparoscopic ventral mesh rectopexy (LVMR) is a nonresectional technique for patients with full thickness external rectal prolapse and internal prolapse with obstructed defaecation syndrome (ODS), features associated in the pathogenesis of SRUS. Our aim was to assess the short- and long-term efficacy of LVMR in treating SRUS. METHOD: Forty-eight patients with SRUS who underwent LVMR over a 15-year period (December 1996 to July 2012) were identified from a prospectively maintained electronic database. RESULTS: Forty-eight patients, 38 (79%) women, median age 43 (18-80) years, median body mass index 26 (21-40) kg/m(2) underwent LVMR for SRUS after initial biofeedback. The median follow-up was 33 months (95% CI 31-55, range 1-186 months); 52% were followed for more than 3 years and 13 (27%) for more than 5 years. Five (10%) had relapsed following a response to stapled transanal rectal resection (STARR; 10 additional patients have had a continued response to STARR). Eleven (23%) had intermittent reducible external prolapse. Epithelial ulcer healing was reported in all patients at 3 months. The ODS scores improved by 68% (P < 0.0001) and quality of life (QoL; Birmingham Bowel and Urinary Symptoms Questionnaire-22) scores improved by 45% (P < 0.0001). There was a significant improvement in bowel visual analogue scale (VAS) scores at 3 and 12 months (P = 0.0007). Sustained improvement in QoL and VAS scores was maintained at 2 years and continued in the 52% followed up for between 3 and 15 years. There were four (8%) symptomatic ODS recurrences: posterior rectal wall prolapse successfully treated by STARR (3) and one symptom free for 2 years following a temporary loop ileostomy. There were two recurrences (4%). CONCLUSION: LVMR appears to provide a sustained improvement in QoL, VAS and patient satisfaction in patients with SRUS. Morbidity, recurrence and safety profiles are low. PMID- 23107778 TI - Oleanane glycosides from Astragalus tauricolus: isolation and structural elucidation based on a preliminary liquid chromatography-electrospray ionization tandem mass spectrometry profiling. AB - As a part of our ongoing research for bioactive compounds from Turkish Astragalus species, the investigation of Astragalus tauricolus has been carried out. An approach based on HPLC-ESIMS(n) experiments has been used to profile the triterpene glycosides occurring in the butanol extract of the whole plant. On the basis of the results of the online screening by HPLC-ESIMS(n), 22 oleanane-type triterpene glycosides, including ten compounds never reported before, were isolated, and their structures were established by the extensive use of 1D and 2D NMR experiments along with ESIMS and HRMS analysis. Noteworthy, cycloartane-type triterpene glycosides, the main constituents of Astragalus spp., were not found. This peculiar feature characterizes a very limited group of Astragalus spp. The antiproliferative activity of the isolated compounds 1-12, 15, 17-19 was evaluated against a small panel of cancer cell lines. Only compound 11 showed an IC(50) of 22 MUM against human leukemia cell line (U937). The other tested compounds, in a range of concentrations between 1 and 50 MUM, did not cause any significant reduction of the cell number. PMID- 23107779 TI - Integrative epigenomic analysis identifies biomarkers and therapeutic targets in adult B-acute lymphoblastic leukemia. AB - Genetic lesions such as BCR-ABL1, E2A-PBX1, and MLL rearrangements (MLLr) are associated with unfavorable outcomes in adult B-cell precursor acute lymphoblastic leukemia (B-ALL). Leukemia oncoproteins may directly or indirectly disrupt cytosine methylation patterning to mediate the malignant phenotype. We postulated that DNA methylation signatures in these aggressive B-ALLs would point toward disease mechanisms and useful biomarkers and therapeutic targets. We therefore conducted DNA methylation and gene expression profiling on a cohort of 215 adult patients with B-ALL enrolled in a single phase III clinical trial (ECOG E2993) and normal control B cells. In BCR-ABL1-positive B-ALLs, aberrant cytosine methylation patterning centered around a cytokine network defined by hypomethylation and overexpression of IL2RA(CD25). The E2993 trial clinical data showed that CD25 expression was strongly associated with a poor outcome in patients with ALL regardless of BCR-ABL1 status, suggesting CD25 as a novel prognostic biomarker for risk stratification in B-ALLs. In E2A-PBX1-positive B ALLs, aberrant DNA methylation patterning was strongly associated with direct fusion protein binding as shown by the E2A-PBX1 chromatin immunoprecipitation (ChIP) sequencing (ChIP-seq), suggesting that E2A-PBX1 fusion protein directly remodels the epigenome to impose an aggressive B-ALL phenotype. MLLr B-ALL featured prominent cytosine hypomethylation, which was linked with MLL fusion protein binding, H3K79 dimethylation, and transcriptional upregulation, affecting a set of known and newly identified MLL fusion direct targets with oncogenic activity such as FLT3 and BCL6. Notably, BCL6 blockade or loss of function suppressed proliferation and survival of MLLr leukemia cells, suggesting BCL6 targeted therapy as a new therapeutic strategy for MLLr B-ALLs. SIGNIFICANCE: We conducted the first integrative epigenomic study in adult B-ALLs, as a correlative study to the ECOG E2993 phase III clinical trial. This study links for the first time the direct actions of oncogenic fusion proteins with disruption of epigenetic regulation mediated by cytosine methylation. We identify a novel clinically actionable biomarker in B-ALLs: IL2RA (CD25), which is linked with BCR-ABL1 and an inflammatory signaling network associated with chemotherapy resistance. We show that BCL6 is a novel MLL fusion protein target that is required to maintain the proliferation and survival of primary human adult MLLr cells and provide the basis for a clinical trial with BCL6 inhibitors for patients with MLLr. PMID- 23107780 TI - Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study. AB - INTRODUCTION: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer's disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. METHODS: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex((r)) with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Abeta1-40 and Abeta1-42 in plasma and levels of Abeta1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. RESULTS: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex((r)) was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). CONCLUSIONS: Curcumin was generally well tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex((r)) in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00099710. PMID- 23107781 TI - A common connexion between gap junctions, single nucleotide polymorphisms, and atrial fibrillation? PMID- 23107782 TI - Reply to Post and Sabin. PMID- 23107784 TI - Aspartate aminotransferase-to-platelet ratio index is a powerful predictor of mortality among HIV-positive patients. PMID- 23107783 TI - Heterovariant cross-reactive B-cell responses induced by the 2009 pandemic influenza virus A subtype H1N1 vaccine. AB - BACKGROUND: The generation of heterovariant immunity is a highly desirable feature of influenza vaccines. The goal of this study was to compare the heterovariant B-cell response induced by the monovalent inactivated 2009 pandemic influenza A virus subtype H1N1 (A[H1N1]pdm09) vaccine with that induced by the 2009 seasonal trivalent influenza vaccine (sTIV) containing a seasonal influenza A virus subtype H1N1 (A[H1N1]) component in young and elderly adults. METHODS: Plasmablast-derived polyclonal antibodies (PPAb) from young and elderly recipients of A(H1N1)pdm09 vaccine or sTIV were tested for binding activity to various influenza antigens. RESULTS: In A(H1N1)pdm09 recipients, the PPAb titers against homotypic A(H1N1)pdm09 vaccine were similar to those against the heterovariant seasonal A(H1N1) vaccine and were similar between young and elderly subjects. The PPAb avidity was higher among elderly individuals, compared with young individuals. In contrast, the young sTIV recipients had 10-fold lower heterovariant PPAb titers against the A(H1N1)pdm09 vaccine than against the homotypic seasonal A(H1N1) vaccine. In binding assays with recombinant head and stalk domains of hemagglutinin, PPAb from the A(H1N1)pdm09 recipients but not PPAb from the sTIV recipients bound to the conserved stalk domain. CONCLUSION: The A(H1N1)pdm09 vaccine induced production of PPAb with heterovariant reactivity, including antibodies targeting the conserved hemagglutinin stalk domain. PMID- 23107785 TI - Superparamagnetic iron oxide-enhanced magnetic resonance imaging in a case of spleen hamartoma. AB - OBJECTIVE: To emphasize the contribution of superparamagnetic iron oxide (SPIO) contrast agent in the diagnosis of the splenic hamartoma. CLINICAL PRESENTATION AND INTERVENTION: A 63-year-old female was admitted to our hospital with diffuse abdominal pain. An ultrasound examination revealed a 5 * 4 cm solid lesion in the spleen. Dynamic gadolinium-enhanced magnetic resonance imaging (MRI) of the abdominal findings was consistent with a splenic hamartoma. SPIO-enhanced MRI was then performed and it confirmed the diagnosis. The lesion showed a decrease of signal intensity on T2-weighted images. CONCLUSION: This case showed that SPIO enhanced MRI was useful for establishing a noninvasive diagnosis of the splenic hamartomas. PMID- 23107786 TI - The intraoperative mini gamma camera in primary hyperparathyroidism surgery. AB - INTRODUCTION AND OBJECTIVES: The evolution of primary hyperparathyroidism surgical treatment has been improved by the arrival of new techniques that allow for better parathyroid gland tracking. A mini gamma camera has recently been developed that makes it possible to take intraoperative parathyroid gammagraphies. The objective of this study was to evaluate the utility of this technique. METHOD: We prospectively studied 29 patients with primary hyperparathyroidism, comparing the diagnostic effectiveness of the MGP with the results obtained with preoperative techniques (ultrasound scan plus Tc(99m) sestamibi gammagraphy). RESULTS: The sensitivity and specificity of the mini gamma camera was superior to those of the preoperative techniques, applied to the lateral neck as well as to the face of the neck (lateral: 89.6% sensitivity and 96.15% specificity compared to 79.31% and 92.59% respectively; and neck face: sensitivity and specificity 83.33% and 90.91% against 48.39% and 72.73%). CONCLUSIONS: The portable mini gamma camera accurately tracks pathologic parathyroid glands. In that sense, it could be useful when considering a radio guided surgery with minimal parathyroid invasion. PMID- 23107787 TI - Societal solutions to childhood origins of coronary artery disease. AB - Childhood obesity and associated risks result in premature cardiovascular damage and disease with a consequent, large burden to society. There are causes for childhood obesity that are rooted in the socioeconomic milieu. Interventions that are population-based, and aimed towards prevention as opposed to treatment, are likely to be most effective in curtailing childhood obesity. Reforms to federal and state managed social welfare programs provide a compelling opportunity to affect the course and consequences of childhood obesity. PMID- 23107788 TI - Integrative analysis of prognostic factors in Chinese core binding factor leukemia. AB - The characteristics of core binding factor (CBF) leukemia appear to differ between Chinese and Caucasian patients. In this study, we analyzed the biological and clinical characteristics of 76 Chinese CBF leukemia patients out of 425 newly diagnosed acute myeloid leukemia (AML) patients. The frequency of CBF AML was 17.9%. Patients harboring t(8;21) were predominant in CBF AML. The incidence of c kit mutation in CBF AML was 28.9%. The N822K mutation appeared to be more prevalent in Chinese CBF AML patients. Multivariate analysis showed that c-kit mutation and high white blood cell count could negatively impact overall survival (OS) (HR=2.74 and 6.24, P=0.007 and 0.022, respectively) but did not affect relapse-free survival (RFS). Kaplan-Meier analysis showed a significant difference in both OS and RFS between wild-type and mutated c-kit patients. Although we had included recently reported prognostic indicators in our analysis, our results demonstrated that only c-kit mutation and high white blood cell count had prognostic impact on Chinese CBF AML patients. PMID- 23107789 TI - The Australian public's beliefs about the harmfulness of antipsychotics: associated factors and change over 16 years. AB - Negative views of psychiatric medications are common in many countries. Relatively little is known about beliefs about antipsychotic medications. A 2011 national survey of 2024 Australian adults assessed beliefs about their helpfulness or harmfulness for a person with either early or chronic schizophrenia and the associations with sociodemographic characteristics, exposure to schizophrenia, recognition of schizophrenia, and beliefs about other interventions, long-term outcomes, causes, and stigmatising attitudes. Changes since previous surveys (conducted in 1995 and 2003/4) were also assessed. Results showed that 19% of Australian adults believe that antipsychotics would be harmful for a person with early schizophrenia and 14% for chronic schizophrenia. This group was more likely to be male, born overseas, have less exposure to schizophrenia, show poorer schizophrenia recognition, have less positive views about other standard interventions, be less pessimistic about long-term outcomes and have greater stigmatising attitudes. Comparison with previous surveys showed that overall belief in the harmfulness of antipsychotics for schizophrenia decreased between 1995 and 2003/4 and between 1995 and 2011. The higher proportions of males and those from non-English speaking backgrounds believing in harmfulness suggest that education about the role of antipsychotics in the treatment of schizophrenia should focus on these groups. PMID- 23107790 TI - Determining severity subtypes of depression with a self-report questionnaire. AB - The American Psychiatric Association's recently revised guidelines for the treatment of major depressive disorder indicated that it is important to consider symptom severity in initial treatment selection. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we conducted two studies of psychiatric outpatients examining the correlates of severity classification based on a self-report depression scale. The first sample consisted of 470 depressed outpatients who completed the Clinically Useful Depression Outcome Scale (CUDOS) and measures of psychosocial morbidity at the time of presentation. The second sample consisted of 112 depressed outpatients who completed the CUDOS and were evaluated with the Hamilton Depression Rating Scale at baseline and after 3 months of treatment. Compared to mildly depressed patients, moderately depressed patients reported significantly more psychosocial morbidity across all functional domains. The same differences were found between moderately and severely depressed patients. Greater severity of depression was associated with lower rates of response and remission. The results of the present studies suggest that a self-report depression questionnaire can validly subtype depressed patients according to gradations of severity. PMID- 23107791 TI - The study of candidate genes related to the neurodevelopmental hypothesis of anorexia nervosa: classical association study versus decision tree. AB - In this research, we conducted a study of genes connected with the neurodevelopmental hypothesis of anorexia nervosa, using classical statistical and data-mining methods to establish a relationship with disease risk and algorithms to identify the best genetic predictors of anorexia nervosa. PMID- 23107792 TI - Predictors of self-reported psychosocial outcomes in individuals with dementia. AB - PURPOSE: Little is known about the illness experience from the perspective of individuals with dementia (IWDs), as most quantitative research has focused on IWDs' psychosocial issues from proxy reports. The primary aim of this study was to better understand the impact of the illness experience on well-being from the perspective of the IWD through the framework of the Stress Process Model for Individuals with Dementia (SPM for IWDs). DESIGN AND METHODS: Guided by the SPM for IWDs, self-report data were collected from IWDs (N = 131) about their illness experience, including primary objective and subjective stressors, secondary role and intrapsychic strains, and well-being outcomes. Using multiple linear regression, primary stressors, secondary strains, and background and context characteristics were entered into 3 prediction models for each outcome: anxiety, depression, and quality of life (QoL). RESULTS: Three distinct prediction patterns emerged for each of the outcome measures. Embarrassment about memory loss was the unique predictor of anxiety, whereas physical health strain and role captivity uniquely predicted depression. Unique predictors for QoL included lower perceived instrumental activities of daily living (IADL) difficulty and higher self-efficacy. IMPLICATIONS: This study provided valuable insight into the illness experience from the perspective of the IWD and identified key areas amenable to interventions, such as managing embarrassment about memory problems as well as improving self-efficacy and inner strength. Moreover, this study provided additional support for the inclusion of IWDs in the research process and highlighted the need for further research regarding clinical application of findings, testing of hypotheses, and analyzing efficacy of interventions. PMID- 23107793 TI - French clinical guidelines on perioperative nutrition. Update of the 1994 consensus conference on perioperative artificial nutrition for elective surgery in adults. AB - Surgical patient is a stressed patient. Aggression is more intense and prolonged as surgery is important. Surgery induces secretion of stress hormones, inflammatory mediators and metabolic changes resulting in significant catabolic phenomena. The presence of malnutrition is an independent risk factor for postoperative complications. Malnutrition increases morbidity (infections, delayed healing), mortality, length of stay and costs and impacts human quality of life for patients. It has been shown that the management of perioperative malnutrition reduces the additional risk generated by it. Perioperative nutritional support should not be systematically provided. Since 1994, recommendations on perioperative nutrition, the care of patients and the available resources have changed dramatically. An update of these recommendations was needed. In 2010, an expert panel of the French society of Anesthesiology (SFAR) and the French-speaking society of Clinical Nutrition and Metabolism (SFNEP) has made recommendations for good clinical practice of perioperative nutrition. They are presented. Thus, the perioperative nutritional management must be integrated in a process to reduce the operative risk: risk reduction due to preoperative malnutrition, reduced risk of postoperative malnutrition which may compromise the following treatments, reduction of postoperative metabolic complications, reducing the postoperative morbidity, especially infectious, through the use of pharmaconutrients either preoperatively or postoperatively in some patients. PMID- 23107794 TI - Miscibility of eudragit/chitosan polymer blend in water determined by physical property measurements. AB - The interest in the preparation and application of polymeric blends is growing since they can exhibit properties of great industrial interest. The current study focuses on the preparation of polymeric blends of varying compositions of eudragit and chitosan and their miscibility studies. The preparation was carried out by using ethanol and 1% acetic acid in water. FT-IR spectra reveal the possibilities of chemical interactions between eudragit/chitosan. The miscibility of polymeric blend at different composition has been investigated by viscosity, ultrasonic velocity, density, refractive index and adiabatic compressibility values measured at two different temperatures 30 degrees C and 40 degrees C. The interaction parameters DeltaB, MU and alpha, were determined from viscosity data. From the values observed, it is found that the blend is miscible in all compositions at 30 degrees C whereas at 40 degrees C, it seems to be immiscible in certain compositions. It is found that the blend is miscible, when the chitosan concentration is more than 70% (v/v) at both the temperatures and also observed that variation of temperature has no effect on the miscibility of eudragit/chitosan blend. PMID- 23107795 TI - Formulation and in vitro absorption analysis of Rhizoma paridis steroidal saponins. AB - Rhizoma paridis steroidal saponins (RPS) have been prepared and identified as the active compounds for antitumor activity in our previous study. However, the low oral bioavailability of the steroidal saponins restricted its using. In the present research, solid dispersion (SD) and phytosome (PHY) formulation of RPS were prepared, and the physicochemical parameters as well as the intestinal absorption in rat everted gut sac model were investigated. Seven agents were selected as the carriers of SD, and poloxamer 407 (P 407) was the most suitable one. SD reduced the particle size of saponins in the water solution, enhanced the solubility of the saponins by about 3.5 folds, and significantly improved the absorption transport of saponins from 48 to 104 MUg in everted gut sac of the rat system. PHY significantly enhanced the hydrophilic of saponins but showed little effect on the absorption in small intestine. Jejunum and ileum part absorbed more absolute contents of total saponins than duodenum parts. Six saponins, the main contents of RPS, used as the index of comparing the three forms, were also further investigated in the physico-chemical properties and the absorption tests. n-Octanol/water partition coefficients of the six saponins ordered in RPS, SD and PHY were Chonglouoside H>Dioscin>Polyphyllin D>Gracillin>Paris-VII>Formosanin C. All the saponins possessed the higher absorptive characteristics in SD formulation. The absorption rate of diosgenyl saponins in intestine was more than the pennogenyl saponins. PMID- 23107796 TI - Strong fiber-reinforced hydrogel. AB - In biological hydrogels, the gel matrix is usually reinforced with micro- or nanofibers, and the resulting composite is tough and strong. In contrast, synthetic hydrogels are weak and brittle, although they are highly elastic. The are many potential applications for strong synthetic hydrogels in medical devices, including as scaffolds for tissue growth. This work describes a new class of hydrogel composites reinforced with elastic fibers, giving them a cartilage-like structure. A three-dimensional rapid prototyping technique was used to form crossed "log-piles" of elastic fibers that are then impregnated with an epoxy-based hydrogel in order to form the fiber-reinforced gel. The fibrous construct improves the strength, modulus and toughness of the hydrogel, and also constrains the swelling. By altering the construct geometry and studying the effect on mechanical properties, we will develop the understanding needed to design strong hydrogels for biomedical devices and soft machines. PMID- 23107797 TI - Subcutaneous tissue response and osteogenic performance of calcium phosphate nanoparticle-enriched hydrogels in the tibial medullary cavity of guinea pigs. AB - In the current study, oligo(poly(ethylene glycol) fumarate) (OPF)-based hydrogels were tested for the first time as injectable bone substitute materials. The primary feature of the material design was the incorporation of calcium phosphate (CaP) nanoparticles within the polymeric matrix in order to compare the soft tissue response and bone-forming capacity of plain OPF hydrogels with CaP enriched OPF hydrogel composites. To that end, pre-set scaffolds were implanted subcutaneously, whereas flowable polymeric precursor solutions were injected in a tibial ablation model in guinea pigs. After 8 weeks of implantation, histological and histomorphometrical evaluation of the subcutaneous scaffolds confirmed the biocompatibility of both types of hydrogels. Nevertheless, OPF hydrogels presented a loose structure, massive cellular infiltration and extensive material degradation compared to OPF-CaP hydrogels that were more compact. Microcomputed tomography and histological and histomorphometrical analyses showed comparable amounts of new trabecular bone in all tibias and some material remnants in the medial and distal regions. Particularly, highly calcified areas were observed in the distal region of OPF-CaP-treated tibias, which indicate a heterogeneous distribution of the mineral phase throughout the hydrogel matrix. This phenomenon can be attributed to either hindered gelation under highly perfused in vivo conditions or a faster degradation rate of the polymeric hydrogel matrix compared to the nanostructured mineral phase, resulting in loss of entrapment of the CaP nanoparticles and subsequent sedimentation. PMID- 23107798 TI - Prediction of equibiaxial loading stress in collagen-based extracellular matrix using a three-dimensional unit cell model. AB - Mechanical signals are important factors in determining cell fate. Therefore, insights as to how mechanical signals are transferred between the cell and its surrounding three-dimensional collagen fibril network will provide a basis for designing the optimum extracellular matrix (ECM) microenvironment for tissue regeneration. Previously we described a cellular solid model to predict fibril microstructure-mechanical relationships of reconstituted collagen matrices due to unidirectional loads (Acta Biomater 2010;6:1471-86). The model consisted of representative volume elements made up of an interconnected network of flexible struts. The present study extends this work by adapting the model to account for microstructural anisotropy of the collagen fibrils and a biaxial loading environment. The model was calibrated based on uniaxial tensile data and used to predict the equibiaxial tensile stress-stretch relationship. Modifications to the model significantly improved its predictive capacity for equibiaxial loading data. With a comparable fibril length (model 5.9-8MUm, measured 7.5MUm) and appropriate fibril anisotropy the anisotropic model provides a better representation of the collagen fibril microstructure. Such models are important tools for tissue engineering because they facilitate prediction of microstructure mechanical relationships for collagen matrices over a wide range of microstructures and provide a framework for predicting cell-ECM interactions. PMID- 23107799 TI - Reactive magnetic poly(divinylbenzene-co-glycidyl methacrylate) colloidal particles for specific antigen detection using microcontact printing technique. AB - Epoxy-functionalized magnetic poly(divinylbenzene-co-glycidyl methacrylate) colloidal particles (mPDGs) were prepared by co-polymerization of 1,4 divinylbenzene and glycidyl methacrylate monomers. The reaction was conducted by batch emulsion polymerization in the presence of an oil in water magnetic emulsion as a seed. The chemical composition, morphology, iron oxide content, magnetic properties, particle size and colloidal stability of the prepared magnetic polymer particles were characterized using Fourier transform infrared spectroscopy, transmission electron microscopy, thermal gravimetric analysis, vibrating sample magnetometry, dynamic light scattering, and zeta potential determination, respectively. The prepared mPDGs were immobilized on a self assembled monolayer of 3-aminopropyltriethoxysilane (APTES)/octadecyltrichlorosilane (OTS), which were patterned on glass using microcontact printing technique, forming mPDGs-APTES/OTS reactive surface. This construction (mPDGs-APTES/OTS) was used as a solid support for immunoassay. The immobilized magnetic particles were bioconjugated with monoclonal anti-human IL 10 antibody to provide specific and selective recognition sites for the recombinant human IL-10 protein (antigen). Fluorescence microscopic examination was carried out to follow this immunoassay using fluorescently labeled anti-human IL-10 antibody. The results obtained proved the successful use of mPDGs-APTES/OTS microcontact printed surfaces in an immunoassay, which can be exploited and integrated into microsystems in order to elaborate medical devices (e.g. biosensors) which could provide rapid analysis at high sensitivity with low volumes of analyte. PMID- 23107800 TI - The smallest active carbamoyl phosphate synthetase was identified in the human gut archaeon Methanobrevibacter smithii. AB - The genome of the major intestinal archaeon Methanobrevibacter smithii contains a complex gene system coding for carbamoyl phosphate synthetase (CPSase) composed of both full-length and reduced-size synthetase subunits. These ammonia metabolizing enzymes could play a key role in controlling ammonia assimilation in M. smithii, affecting the metabolism of gut bacterial microbiota, with an impact on host obesity. In this study, we isolated and characterized the small (41 kDa) CPSase homolog from M. smithii. The gene was cloned and overexpressed in Escherichia coli, and the recombinant enzyme was purified in one step. Chemical cross-linking and size exclusion chromatography indicated a homodimeric/tetrameric structure, in accordance with a dimer-based CPSase activity and reaction mechanism. This small enzyme, MS-s, synthesized carbamoyl phosphate from ATP, bicarbonate, and ammonia and catalyzed the same ATP-dependent partial reactions observed for full-length CPSases. Steady-state kinetics revealed a high apparent affinity for ATP and ammonia. Sequence comparisons, molecular modeling, and kinetic studies suggest that this enzyme corresponds to one of the two synthetase domains of the full-length CPSase that catalyze the ATP dependent phosphorylations involved in the three-step synthesis of carbamoyl phosphate. This protein represents the smallest naturally occurring active CPSase characterized thus far. The small M. smithii CPSase appears to be specialized for carbamoyl phosphate metabolism in methanogens. PMID- 23107802 TI - Comparison of chitosan/starch composite film properties before and after cross linking. AB - Unmodified and cross-linked chitosan/starch composite films were prepared using the solvent evaporation method. The properties of the films were studied to obtain useful information about the possible applications of composite films. FT IR, SEM, and swelling property investigations show that the cross-linking agent glutaraldehyde reacts in the chitosan and starch blend. The compatibility of chitosan and starch blends before and after cross-linking was studied by UV-vis spectroscopy. The compatibility of the blends deteriorated after cross-linking. This finding was confirmed by the results of mechanical properties. The films show improved water barrier performance after cross-linking. The use of trace concentrations of glutaraldehyde in chitosan/starch films allows for possible application in the biomedical field. PMID- 23107801 TI - Assumed infectiousness, treatment adherence and sexual behaviours: applying the Swiss Statement on infectiousness to HIV-positive alcohol drinkers. AB - OBJECTIVES: The success of antiretroviral therapy (ART) for treating HIV infection is now being turned towards HIV prevention. The Swiss Federal Commission for HIV/AIDS has declared that HIV-positive persons who are treated with ART, have an undetectable viral load, and are free of co-occurring sexually transmitted infections (STIs) should be considered noninfectious for sexual transmission of HIV. This study examined the implications of these assumptions in a sample of HIV-positive individuals who drink alcohol. METHODS: People living with HIV/AIDS (n = 228) were recruited through community sampling. They completed confidential computerized interviews and underwent monthly unannounced pill counts for ART adherence. HIV viral loads were obtained from medical records. RESULTS: One hundred and eighty-five HIV-positive drinkers were currently receiving ART and 43 were untreated. Among those receiving ART, one in three were not virally suppressed and one in five had recently been diagnosed with an STI. Adherence was generally suboptimal, including among those assumed to be less infectious. As many as one in four participants reported engaging in unprotected intercourse with an HIV-uninfected partner in the past 4 months. There were few associations between assumed infectiousness and sexual practices. CONCLUSIONS: Less than half of people who drank alcohol and took ART met the Swiss criteria for noninfectiousness. Poor adherence and prevalent STI threaten the long-term potential of using ART for prevention. In the absence of behavioral interventions, the realities of substance use and other barriers call into question the use of ART as prevention among alcohol drinkers. PMID- 23107803 TI - Antibacterial activity evaluation of quaternary chitin against Escherichia coli and Staphylococcus aureus. AB - Water-soluble quaternary chitin/chitosan derivatives, O-[(2-hydroxy-3 trimethylammonium)propyl chitin (OHT-chitin), N-[(2-hydroxy-3 trimethylammonium)propyl chitosan (NHT-chitosan), and N,N,N-trimethylchitosan (TMC), having identical molecular weight and same anion, were prepared, and their antibacterial activities against Escherichia coli and Staphylococcus aureus were evaluated. Their minimum inhibitory concentration (MIC) values varied from 0.04 mg/mL to 20.48 mg/mL, and the minimum bactericidal concentration (MBC) values varied from 0.16 mg/mL to 40.96 mg/mL against E. coli and S. aureus, respectively. Transmission electron microscopy (TEM) clearly showed that there was serious damage on the bacterial walls, whereas there was some dissimilarity between TMC-treated E. coli and S. aureus. PMID- 23107804 TI - An insight into the properties of Aegle marmelos pectin-chitosan cross-linked films. AB - Pectin of Aegle marmelos (AP) ripe fruits processed in equal proportion with chitosan (CH) formed films that exhibited minimum swelling index and volume index on exposure to buffers of acidic and alkaline pH. Highest contact angle and spreading coefficient coupled with lowest work of adhesion in all buffers for this film suggested availability of limited number of functional groups for interaction with water molecules due to optimum cross-linking between -NH(3)(+) groups of CH and -COO(-) groups of AP. This contention was substantiated by the presence of almost negligible charge on this film. The endothermic transition DeltaH characteristic of -NH(3)(+)-COO(-) cross-linking between groups in this film was observed to decrease by only 1% after its sequential exposure to pH 1.2 (3 h) and pH 7.4 (6 h). Furthermore, the absence of pores or erosion in the scanning electron photomicrograph suggested the versatility of this film due to its resistance to acidic and alkaline pH. PMID- 23107805 TI - Influence of molecular mass of lignosulfonates on the resulting surface charges of solid particles. AB - Different lignosulfonate (LS) samples were prepared via a three-step method and were characterized by FT-IR, UV, GPC and functional groups measurement. FT-IR and UV spectra confirmed the prepared samples had typical characteristics of lignin materials. GPC and functional groups measurement results indicated the samples had different molecular mass (M(w)), but same quantities of sulfonic groups (S). The influence of M(w) of LS on the resulting surface charges of dimethomorph particles via adsorption was further investigated. The results indicated that the adsorption isotherms of LS on dimethomorph surfaces belonged to L-type and the adsorption capacity (q(m)) increased with increasing M(w). However, the non linear correlation between zeta potentials with the products of S and adsorption amount (SA) indicated SA did not positively improve the surface charges expectedly. Based on the analysis, an adsorption confirmation was proposed allowing prediction of the relation between M(w) and surface charge efficiency of LS for solid particles. PMID- 23107806 TI - Equilibrium studies of cellulase aggregates in presence of ascorbic and boric acid. AB - The aggregate formation of cellulase was detected at 300 and 10 mM ascorbic and boric acid respectively. These aggregates showed reduced enzyme activity, loss in near-UV signal, decrease tryptophan and ANS fluorescence. They possess increase in non-native beta-sheet structure as evident from far-UV CD and FTIR spectra, large hydrodynamic radii, increase thioflavin T fluorescence and shift in Congo red. Cellulase at 90 mM ascorbic acid exists as molten globule with retention of secondary structure, altered tryptophan environment, high ANS binding and loss in tertiary structure. Ascorbic acid acts as an antioxidant up to 90 mM and beyond this as a pro-oxidant. PMID- 23107807 TI - Characterization of chymotrypsin-iota-carrageenan complex in aqueous solution: a solubility and thermodynamical stability study. AB - The aim of this study is to report the results of research work on the molecular mechanism of complex formation between chymotrypsin and a negatively charged natural strong polyelectrolyte, iota-carrageenan, using spectroscopy techniques. The carrageenan-chymotrypsin complex showed a maximal non-solubility at pH around 4.50 with a stoichiometric ratio between 8 and 33 g of chymotrypsin per g of carrageenan. These values were depended on the enzyme concentration, pH and ionic strength medium. The insoluble complex was redissolved by modifying the pH and by a NaCl concentration around 0.2 M in agreement with a coulombic mechanism of complex formation. The non-soluble complex formation showed biphasic kinetics. A fast step was carried out around 10 s and a coulombic mechanism takes place, and a slower step of around 120 s, where participate only Van der Waals forces. The enzymatic activity of chymotrypsin was maintained even in the presence of carrageenan (0.005%, w/v). PMID- 23107808 TI - Amphiphilic conjunct of methyl cellulose and well-defined polyvinyl acetate. AB - Tailor-made conjunct of methyl cellulose (MC) and polyvinyl acetate (PVAc) was synthesized through the combination of reversible addition-fragmentation chain transfer (RAFT) polymerization and thiol-ene click reaction. MC was firstly transferred into unsaturated MC (UMC), and then covalently connected with well defined PVAc obtained by RAFT polymerization of vinyl acetate. The structure of the conjunct polymer (MCV) was confirmed with Fourier transform infrared spectra (FTIR) and proton nuclear magnetic resonance ((1)H NMR). Well-defined MCV was amphiphilic and able to self-assemble into size controllable micelles, which was verified with transmission electron microscopy (TEM) and size distribution analysis. It was found that the mean diameters of the micelles in aqueous solution were 105.6, 96.0 and 75.9 nm when the number average molecular weights of PVAc segments of MCV were 49,300, 32,500 and 18,200, respectively. PMID- 23107809 TI - Effect of chitooligosaccharides on mice hematopoietic stem/progenitor cells. AB - Chitooligosaccharides (COSs) is a kind of polysaccharide scaffolds used to enhance cartilage repair during treatments involving bone marrow stimulation, angiogenesis and osteogenesis increase in vivo. Capabilities of COSs in promoting the proliferation and differentiation of hematopoietic stem cells/hematopoietic progenitor cells were mainly explored in the paper. The results showed that a high concentration of COSs significantly proliferate the mice marrow cells and induced CD34+ cells into megakaryocyte progenitor cells. However, COSs could not enhance the proliferation of CD19+ and CD4+ and promote CD34+ cells to differentiate into lymphoid progenitor cells. It suggested that COSs can promote hematopoietic stem/progenitor cells hyperplasia, and the mechanism may be that COSs promote stromal cell secretion of hematopoietic growth factors. PMID- 23107810 TI - Peri-articular steroid injection in total knee arthroplasty: a prospective, double blinded, randomized controlled trial. AB - Total knee arthroplasty is a painful operation. Peri-articular local anesthetic injections reduce post-operative pain and assist recovery. It is inconclusive whether intra-operative injections of peri-articular corticosteroids are of benefit. Therefore our clinical question was: in patients with osteoarthritis who are undergoing TKA, does the addition of high or low dose corticosteroid to peri articular injections of local anesthetic and adrenaline improve post-operative pain and range of motion? We performed a prospective, double-blinded, randomized controlled trial of two different doses of triamcinolone acetate (N = 42 in each group) added to local anesthetic in TKA for osteoarthritis. There were no significant differences in pain scores or ROM between the control and corticosteroid groups. Differences in secondary outcomes were also non significant. Peri-articular corticosteroids do not appear to be of benefit in TKA. PMID- 23107811 TI - Leflunomide increases the risk of silent liver fibrosis in patients with rheumatoid arthritis receiving methotrexate. AB - INTRODUCTION: We identified silent liver fibrosis in patients with rheumatoid arthritis (RA) using transient elastography, and investigated medication that correlated with abnormal liver stiffness measurement (LSM) values. METHODS: We consecutively enrolled 105 patients with RA taking methotrexate over 24 weeks with normal liver functions and no history of underlying chronic liver disease. Blood tests were performed, and body mass index and metabolic syndrome were assessed. We checked LSM values, and adopted 5.3 kPa as the cutoff for abnormal LSM values. The cumulative doses of medications including methotrexate, leflunomide, sulfasalazine, hydroxychloroquine, prednisolone, meloxicam, and celecoxib were calculated. RESULTS: The median age of patients (20 men and 85 women) was 52.4 years. The median LSM value was 4.7 kPa and 24 (22.9%) patients had abnormal LSM values. Gamma-glutamyltranspeptidase levels and the cumulative doses of leflunomide and prednisolone significantly correlated with LSM values (P<0.05). The cumulative dose of leflunomide, but not methotrexate, was significantly higher in patients with abnormal LSM values than that in patients with normal LSM values (P = 0.008). When RA patients receiving leflunomide plus methotrexate were classified into two groups according to the optimal cutoff cumulative dose of leflunomide (19,170 mg), abnormal LSM values were more frequently identified in patients with high cumulative dose of leflunomide (odds ratio, 12.750; P<0.001). CONCLUSIONS: The cumulative dose of leflunomide was the only independent predictor of abnormal LSM values in patients with RA who had received methotrexate for more than six months. PMID- 23107812 TI - [Labor pain worries future fathers more than the mothers]. AB - OBJECTIVE: To evaluate the concerns of the future father about labor pain and another 9 items which could be important to the well-being of the mother during delivery. To investigate any possible differences in opinion between the future father and mother. PATIENTS AND METHODS: An anonymous and voluntary questionnaire was offered to the father and the pregnant patient during the last month of pregnancy. They had to answer the questionnaire separately, scoring 10 items in a 0-10 point ordinal scale, according to their concerns and the importance for the good development of the delivery (0= not concerned about/insignificant to 10=concerned about/great importance). The items included were: 1) esthetic aftermath, 2) embarassment, 3) continous information, 4) walking during labor, 5) drinking during labor, 6) companionship, 7) labor pain, 8) keeping composure, 9) kindness, 10) room comfortability. Data on age, education, parity and nationality were recorded. RESULTS: A total of 147 questionnaires were completed, 99 by mothers, and 48 by fathers. Pain was the most important concern for the future fathers scoring a mean (SD) of 8.15 (2), while continuous information 7.71 (2.5), kindness 7.9 (2.1), and companionship 8.21 (2.3) were more important than pain for mothers. A statistically significant difference was found between fathers and mothers regarding labor pain (P=.001), walking during labor (P=.003), and drinking during labor (P=.009). CONCLUSIONS: The result of our study suggests that increasing the presence of the father during the delivery process, and taking care of the emotional aspects and the quality of the information given could be very important for the perception of satisfaction. PMID- 23107813 TI - [Transversus abdominis plane (TAP) block for post-operative analgesia after a cesarean in a morbid obese patient with medial allergies]. PMID- 23107814 TI - Pheochromocytoma mimicking both acute coronary syndrome and sepsis: a case report. AB - OBJECTIVE: To present an atypical manifestation in a patient with pheochromocytoma. CLINICAL PRESENTATION AND INTERVENTION: A 48-year-old man presented with chest pain, fever and leukocytosis. Elevated cardiac biomarkers and diffuse ST-T abnormalities on electrocardiography suggested myocardial infarction. However, coronary angiography showed normal coronary arteries. Abdominal computed tomography revealed a left adrenal tumor of 6.7 * 6.8 cm. Paroxysmal fluctuation of blood pressure raised the suspicion of pheochromocytoma, which was further supported by elevated urine catecholamine levels. He underwent left adrenalectomy and pathological findings confirmed the diagnosis. CONCLUSION: Pheochromocytoma should be considered as part of the differential diagnosis in a patient with symptoms suggestive of both acute coronary syndrome and sepsis. PMID- 23107815 TI - The design of microfluidic affinity chromatography systems for the separation of bioanalytes. AB - The analytical (numerical) design of planar microfluidic affinity chromatography devices, which consist of multiple separation lanes and multiple, different surface-immobilised receptor patterns in each lane, is described. The model is based on the analytical solution of the transport-reaction equations in microfluidic systems of low Gratz number and for injection of small analyte plugs. The results reveal a simple approach for the design of microfluidic affinity chromatography devices tailored to the separation of bioanalytes, where receptors with high binding affinity are available. These devices have been designed for bioanalytical applications in mind, most notably for the proteomics field; the results are illustrated with an example using beta-Amyloid binding peptides. PMID- 23107816 TI - Frailty and mortality, disability and mobility loss in a Spanish cohort of older adults: the FRADEA study. AB - BACKGROUND: Original Fried's frailty criteria have not demonstrated their prognostic validity of mortality, disability and mobility loss in European cohorts. OBJECTIVES: To analyze whether frailty implies increased risk of death, incident disability in basic (BADL) or instrumental (IADL) activities of daily living, or mobility impairment. DESIGN: Concurrent cohort study. SETTING: Albacete City, Spain. PARTICIPANTS: 993 participants over age 70 from the FRADEA Study. MEASUREMENTS: Mortality, BADL and mobility using the Barthel Index, and IADL using the Lawton IADL Index, were recorded. BADL disability was defined as loss of the ability to perform bathing, grooming, dressing, toilet use, or feeding, while deterioration of mobility was defined as loss of ability to perform transfers, walk, or use stairs, and IADL disability as losing any of the activities included in the Lawton Index. The risk of presenting adverse events was determined by Cox and Kaplan-Meier proportional hazard analysis and logistic regression adjusted for age, sex, function, and comorbidity. RESULTS: Mean follow up was 534 days (SD 153), during which 105 participants (10.6%) died. Mean time to death was 363 days (SD 218), while 192 (25.4%) lost at least one BADL, 492 (60%) at least one IADL, and 222 (28.9%) lost mobility. Frail subjects had a greater adjusted risk of death (HR 5.5, CI 95% 1.5-20.2), of losing BADL (HR 2.5, CI 95% 1.3-4.8), of losing mobility (HR 2.7, CI 95% 1.5-5.0), and of losing IADL (HR 1.9, CI 95% 1.1-3.3) than non-frail patients. CONCLUSION: Fried's frailty criteria are associated with death, incident disability, and mobility impairment in a Spanish cohort of older adults. PMID- 23107817 TI - Clinical characteristics and genetic analysis in women with premature ovarian insufficiency. AB - OBJECTIVE: Premature ovarian insufficiency (POI) is defined as a primary ovarian defect characterized by absent menarche (primary amenorrhea) or premature depletion of ovarian follicles before the age of 40 (secondary amenorrhea) with hypergonadotropism and hypoestrogenism. METHODS: We studied the clinical, biological, and genetic data related to 50 POI patients with a mean age of menopause of 29 years (94% with secondary amenorrhea, 6% with primary amenorrhea and 15% with a family history of POI). Seventeen patients were affected by endocrine autoimmune diseases, antral follicles were observed in 31 patients by ultrasonography. RESULTS: Karyotype analysis did not show any abnormality of the X chromosome. No mutation in FSH receptor and GDF-9 genes was reported, while in one patient a variant of BMP-15 gene (A180T) was found. Four patients had fragile X mental retardation 1 gene (FMR1) premutation and one an intermediate sized CGG repeats of the same gene. Two patients with FMR1 premutation were sister and developed secondary amenorrhea at the age of 34 and 37 years. The other two patients presented with oligoamenorrhea at the age of 39 and 34 years. The patient harboured the intermediate sized CGG repeats developed secondary amenorrhea at the age of 33 years. CONCLUSIONS: The genetic analysis performed on a cohort of patients with POI revealed that 8% had FMR1 premutation and only one patient a previously known variant of BMP-15 gene. No alteration of the karyotype and FSH receptor and GDF-9 genes was evidenced. PMID- 23107818 TI - Autophagy upregulation promotes survival and attenuates doxorubicin-induced cardiotoxicity. AB - This study evaluated whether the manipulation of autophagy could attenuate the cardiotoxic effects of doxorubicin (DXR) in vitro as well as in a tumour-bearing mouse model of acute doxorubicin-induced cardiotoxicity. We examined the effect of an increase or inhibition of autophagy in combination with DXR on apoptosis, reactive oxygen species (ROS) production and mitochondrial function. H9C2 rat cardiac myoblasts were pre-treated with bafilomycin A1 (autophagy inhibitor, 10 nM) or rapamycin (autophagy inducer, 50 MUM) followed by DXR treatment (3 MUM). The augmentation of autophagy with rapamycin in the presence of DXR substantially ameliorated the detrimental effects induced by DXR. This combination treatment demonstrated improved cell viability, decreased apoptosis and ROS production and enhanced mitochondrial function. To corroborate these findings, GFP-LC3 mice were inoculated with a mouse breast cancer cell line (EO771). Following the appearance of tumours, animals were either treated with one injection of rapamycin (4 mg/kg) followed by two injections of DXR (10 mg/kg). Mice were then sacrificed and their hearts rapidly excised and utilized for biochemical and histological analyses. The combination treatment, rather than the combinants alone, conferred a cardioprotective effect. These hearts expressed down-regulation of the pro apoptotic protein caspase-3 and cardiomyocyte cross-sectional area was preserved. These results strongly indicate that the co-treatment strategy with rapamycin can attenuate the cardiotoxic effects of DXR in a tumour-bearing mouse model. PMID- 23107820 TI - Propensity score analysis evaluating preoperative glucocorticoid administration in elective colectomy. AB - BACKGROUND: Preoperative glucocorticoid (GC) administration attenuates the physiological response to surgery and improves clinical outcomes. However, GC use is not yet universally implemented. A propensity score analysis was performed to evaluate preoperative GC use in elective colectomy. METHODS: A retrospective review of prospectively collected data was conducted for all patients who had undergone elective colectomy within an established Enhanced Recovery After Surgery (ERAS) programme at our institution from January 2006 to 2010. Demographic data, surgery type, glucocorticoid administration and clinical outcomes including complication rates and length of hospital stay (LOS) were investigated. Univariate and propensity score analyses were conducted with statistical significance identified as p <= 0.05. RESULTS: There were 253 patients included in the analysis, of which 146 received preoperative GC. There were significant baseline differences between those who received GC and those who did not in male gender (GC: 56 (38%); non-GC: 58 (54%); p = 0.02) and American Society of Anesthesiologists (ASA) III (GC: 40 (27%); non-GC: 43 (40%); p = 0.04). On univariate analysis, there were no significant differences in the incidence of total complications, major complication, anastomotic leak and infectious complication. On propensity score analysis, preoperative GC administration was found to be independently associated with a reduction in LOS (GC: 5; Non-GC: 6; p = 0.04). CONCLUSION: Preoperative GC administration is associated with a reduction in LOS without an increase in postoperative complications. PMID- 23107819 TI - Stuck in the middle: structural insights into the role of the gH/gL heterodimer in herpesvirus entry. AB - Enveloped viruses enter cells by fusing the viral and cellular membranes, and most use a single viral envelope protein that combines receptor-binding and fusogenic functions. In herpesviruses, these functions are distributed among multiple proteins: the conserved fusion protein gB, various non-conserved receptor-binding proteins, and the conserved gH/gL heterodimer that curiously lacks an apparent counterpart in other enveloped viruses. Recent structural studies of gH/gL from HSV-2 and EBV revealed a unique complex with no structural or functional similarity to other viral proteins. Here we analyzed gH/gL structures and highlighted important functional regions. We propose that gH/gL functions as an adaptor that transmits the triggering signals from various non conserved inputs to the highly conserved fusion protein gB. PMID- 23107821 TI - Toxicity, antimicrobial and anthelmintic activities of Vernonia guineensis Benth. (Asteraceae) crude extracts. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study examined the antibacterial, antifungal, and anthelmintic properties of extracts obtained from the plant Vernonia guineensis, a plant commonly used in traditional Cameroonian medicine. MATERIALS AND METHODS: For in vitro studies, 10 g of leaf and tuber powder from V. guineensis was extracted separately using dichloromethane, methanol and distilled water. The extracts were dried in vacuo and used for antimicrobial and anthelmintic activity studies. In the antimicrobial assay, extracts were tested against bacterial and fungal organisms including; Staphylococcus aureus, Staphylococcus epidermidis, Acinetobacter baumannii, Aspergillus fumigatus, Candida albicans and Trichophyton mentagrophytes. In the anthelmintic assay, larval and adult stages of the hookworm Ancylostoma ceylanicum and the mouse nematode Trichuris muris were used. For the acute toxicity test, male and female rats of 150-200 g body weight were used in the experiment. The aqueous extract of V. guineensis tubers was administered in 4 doses of 500, 1000, 2000 and 4000 mg/kg per group (n=6), respectively, and the control group received distilled water. RESULTS: The crude extracts exhibited weak antibacterial and antifungal activity except for the dichloromethane extract, which showed moderate activity against A. fumigatus (MIC=200 MUg/ml). In the anthelmintic assay, the organic extracts of the tubers had 100% killing efficacy against T. muris at 2mg/ml in 48 h, while the aqueous extract showed no activity. The organic leaf extracts demonstrated potent activity killing 100% of the adult worms 1mg/ml in 24h. The aqueous leaf extract was active at 2mg/ml in 72 h, killing 100% of the adult worms. In the acute toxicity test, V. guineensis did not produce any toxic signs or death at the maximum concentration of 4000 mg/kg. CONCLUSION: Crude extracts from V. guineensis possess anthelmintic activity against T. muris with only weak antibiotic activity. Acute administration of aqueous extract from V. guineensis tubers did not produce toxic effects in rats. The absence of acute toxicity at the highest concentration tested indicates that the tea decoction from V. guineensis extract is safe at concentrations <= 4000 mg/kg. PMID- 23107822 TI - Biological activities of Pseudevernia furfuracea (L.) Zopf extracts and isolation of the active compounds. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pseudevernia furfuracea (L.) Zopf (Parmeliaceae) is a common epiphytic lichen in the conifer-hardwood forest of Anatolia. This species is used in traditional medicine in Turkey as a treatment for wounds, eczema and hemorrhoids. AIM OF THE STUDY: The present study was designed to investigate the active compounds from Pseudevernia. furfuracea, and the isolation studies yielded atraric acid (Aslan et al., 2006) as the major compound and a mixture of methyl hematommate (Baumann, 1960) and methyl chlorohematommate (Bayir et al., 2006). Furthermore, methanolic extract from thalli of Pseudevernia. furfuracea and its fractions and isolates (Aslan et al., 2006; Baumann, 1960; Bayir et al., 2006) were investigated for in vitro antimicrobial and antioxidant activities, and in vivo antinociceptive, anti-inflammatory and wound healing activities. MATERIAL AND METHODS: Antimicrobial activities of the samples were determined by using the disc diffusion technique. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay was used as a rapid TLC screening method to evaluate the antioxidant activity of Pseudevernia. furfuracea. The thiobarbituric acid (TBA) test was used to assess the efficacy of the extracts in protecting liposomes from lipid peroxidation. In vivo inhibitory effect of the extracts on the carrageenan induced hind paw edema model in mice was studied for the assessment of anti inflammatory activity. p-Benzoquinone-induced abdominal constriction test was used to explore the antinociceptive effects of the extracts. Moreover, the wound healing potential of the plant extracts that were evaluated by using in vivo incision and excision wound models on rats and mice, were comparatively assessed with a reference ointment Madecassol((r)). RESULTS: Significant antimicrobial activities were observed against Gram (+) microorganisms and Candida krusei and Candida. dubliniensis in dichloromethane (DCM) and ethyl acetate (EtOAc) extracts and isolates. The methanol (MeOH), DCM and EtOAc extracts of the lichen were found to possess moderate inhibitory activity on lipid peroxidation. Methanolic extract of the lichen was found to possess significant inhibitory activity on the carrageenan-induced hind paw edema model in mice whereas the other fractions did not show any activity. While DCM and EtOAc extracts and fractions showed notable anti-inflammatory activity on carrageenan-induced hind paw edema model without inducing any apparent acute toxicity or gastric damage. Moreover, topical application of the ointment prepared with MeOH extract and EtOAc fraction onto the incised wounds exerted remarkable wound healing activity. CONCLUSION: The results of these experimental studies exhibited that nonpolar fractions of Pseudevernia. furfuracea have significant antimicrobial activity against especially Candida species and polar fractions (especially MeOH) display antioxidant, anti-inflammatory, antinociceptive and wound healing activities. PMID- 23107823 TI - Repeated administration of an aqueous spray-dried extract of the leaves of Passiflora alata Curtis (Passifloraceae) inhibits body weight gain without altering mice behavior. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Passiflora alata is a Southern American species that constitutes many traditional remedies as well as phytomedicines used for sedative and anxiolytic purposes in Brazil. However studies on repeated treatment effects are scarce. AIM OF THE STUDY: To evaluate behavioral, physiological and biochemical effects of the repeated treatment with an aqueous spray-dried extract of Passiflora alata leaves containing 2.5% (w/v) of flavonoids (PA) in mice. MATERIAL AND METHODS: Male adult CF1 mice were treated (p.o.) for 14 days with PA (2.5; 25 or 250 mg/kg). The feeding behavior was evaluated at the beginning (1h after the first administration) and at the end of the treatment (15th day). The body weight gain and food consumption were monitored along the days. On day 15 mice were evaluated on plus maze, spontaneous locomotor activity, catalepsy and barbiturate sleeping time tests. Serum glucose, lipids, ALT and AST enzymes were determined. Liver, kidney, perirenal fat, epididymal and peritoneal fat were analyzed. RESULTS: The repeated treatment with the highest dose tested (250 mg/kg) did not alter the mice behavior on open field, elevated plus maze, catalepsy and barbiturate sleeping time tests. Repeated administration of PA 250 decreased mice feeding behavior and weight gain. PA 25 and PA 250 reduced mice relative liver weight and caused mild hepatic hydropic degeneration as well as a decrease in alanine aminotransferase (ALT) serum level. CONCLUSIONS: These results indicate that Passiflora alata does not present central cumulative effects and point to the needs of further studies searching for its hepatotoxicity as well as potential anorexigenic. PMID- 23107824 TI - Effect of the fungal immunomodulatory protein FIP-fve on airway inflammation and cytokine production in mouse asthma model. AB - The allergy is dependent on the balance between Th1 and Th2. The fungal immunodulatory protein (FIP-fve) was isolated from Flammulina velutipes. FIP-fve has been demonstrated to skew the response to Th1 cytokine production. We investigated whether oral administrations of FIP-fve inhibited allergen (OVA) induced chronic airway inflammation in the mouse asthma model. After intranasal challenge with OVA, the airway inflammation and hyperresponsiveness were determined by bronchoalveolar lavage fluid (BALF) analysis and ELISA assay. Both pre-treated and post-treated with FIP-fve suppressed the airway hyperresponsiveness by methacholine challenge and significantly decreased the number of infiltrating inflammatory cells and Th2 cytokines in bronchoalveolar lavage fluid (BALF) and serum compared with the OVA sensitized mice. In addition, FIP-fve reduced OVA-specific IgE levels in serum. FIP-fve markedly alleviated the OVA-induced airway hyperresponsiveness (AHR) to inhaled methacholine. Based on lung histopathological studies using hematoxylin and Liu's staining, FIP-fve inhibited inflammatory cell infiltration compared with the OVA-sensitized mice. Oral FIP-fve had an anti-inflammatory effect on OVA-induced airway inflammations and might posses the potential for alternative therapy for allergic airway diseases. PMID- 23107825 TI - Reactivation of latent viruses is associated with increased plasma cytokines in astronauts. AB - Success of long duration space missions will depend upon robust immunity. Decreased immunity has been observed in astronauts during short duration missions, as evident by the reactivation of latent herpes viruses. Seventeen astronauts were studied for reactivation and shedding of latent herpes viruses before, during, and after 9-14 days of 8 spaceflights. Blood, urine, and saliva samples were collected 10 days before the flight (L-10), during the flight (saliva only), 2-3h after landing (R+0), 3 days after landing (R+3), and 120 days after landing (R+120). Values at R+120 were used as baseline levels. No shedding of viruses occurred before flight, but 9 of the 17 (designated "virus shedders") shed at least one or more viruses during and after flight. The remaining 8 astronauts did not shed any of the 3 target viruses (non-virus shedders). Virus shedders showed elevations in 10 plasma cytokines (IL-1alpha, IL-6, IL-8, IFNgamma, IL-4, IL-10, IL-12, IL-13, eotaxin, and IP-10) at R+0 over baseline values. Only IL-4 and IP-10 were elevated in plasma of non-virus shedders. In virus shedders, plasma IL-4 (a Th2 cytokine) was elevated 21-fold at R+0, whereas IFNgamma (a Th1 cytokine) was elevated only 2-fold indicating a Th2 shift. The inflammatory cytokine IL-6 was elevated 33-fold at R+0. In non-shedding astronauts at R+0, only IL-4 and IP-10 levels were elevated over baseline values. Elevated cytokines began returning to normal by R+3, and by R+120 all except IL-4 had returned to baseline values. These data show an association between elevated plasma cytokines and increased viral reactivation in astronauts. PMID- 23107826 TI - Expression of IL-32 modulates NF-kappaB and p38 MAP kinase pathways in human esophageal cancer. AB - BACKGROUND: Esophageal cancer is the seventh leading cause of cancer death in males in USA, and there is a strong link has been demonstrated between inflammation and esophageal cancer, interleukin (IL)-32 is a recently described pro-inflammatory cytokine characterized by the induction of nuclear factor NF kappaB activation, the p38MAPK also plays an important role in key cellular processes related to inflammation and cancer. We investigated whether the IL-32 expression may be involved in esophageal carcinogenesis through modulates the activity of NF-kappaB and p-p38 MAPK. METHOD: Malignant esophageal tissue and blood samples were obtained from 65 operated untreated patients, normal samples was obtained from 35 patients operated for other reasons as control. IL-32 expression visualized by immunohistochemistry, Real time RT-PCR for IL-32 mRNA expression, NF-kappaB phosphorylation and phosphorylated p38mapk were analyzed by immunoblotting, ELISA for further detection IL-32 and cytokines (TNF-alpha, IL 1beta, IL-6 and IL-8) concentration in the patient's sera. RESULTS: IL-32 expression was increased in immunohistochemical staining for malignant esophageal tissue and it's correlated with the relative expression level of IL-32 mRNA P=0.007, the P-NF-kappaB level elevated in tumor tissue compared with control and no difference in the total NF-kappaB level P=0.003 while the IL-32 up-regulated the P-pNF-kappaB in the esophageal tumor P=0.005. There is increase in p-p38MAPK activation underlying IL-32 expression in tumor P=0.004, but no change in total p38 MAPK in malignant esophagus. The plasma level of IL-32 expression was increased in malignant esophageal patients P=0.01, with increased in the levels of the cytokines TNF-alpha, IL-6, and IL-1betaP<0.05. CONCLUSIONS: Understanding the pathway of IL-32 expression to stimulate the secretion cytokines via the activation of NF-kappaB and up-regulation of p-p38MAPK may or may not prove to be a therapeutic target, or a biomarker, and future studies will finally answer this hypothesis generated. PMID- 23107827 TI - Inflammatory intestinal damage induced by 5-fluorouracil requires IL-4. AB - BACKGROUND: 5-Fluorouracil (5-FU) induces intestinal mucositis, which is characterized by epithelial ulcerations in the mucosa and clinical manifestations, such as pain and dyspeptic symptoms. Cytokines participate in the inflammatory and functional events of intestinal mucositis. IL-4 is an important mediator of intestinal inflammation, with either anti-inflammatory or pro inflammatory functions, depending on the model of intestinal inflammation. This study aimed to evaluate the role of IL-4 in 5-FU-induced intestinal mucositis. METHODS: IL-4+/+ or IL-4-/- mice (25-30 g) were intraperitoneally injected with 5 FU (450 mg/Kg) or saline (C). After 3 days, the mice were sacrificed and the duodenum was evaluated for epithelial damage, MPO activity and cytokine concentration. RESULTS: 5-FU induced significant damage in the intestinal epithelium of IL-4+/+ mice (reduction in the villus/crypt ratio: control=3.31+/ 0.21 MUm, 5-FU=0.99+/-0.10 MUm). However, the same treatment did not induce significant damage in IL-4-/- mice (5-FU=2.87+/-0.19 MUm) compared to wild-type mice. 5-FU-induced epithelial damage increased the MPO activity (neutrophil number) and the level of pro-inflammatory cytokines (IL-4, TNF-alpha, IL-1beta and CXCL-8) in the duodenum. These results were not observed in IL-4-/- mice treated with 5-FU. CONCLUSION: Our data suggest that IL-4 participates as a pro inflammatory cytokine in a 5-FU-induced intestinal damage model and suggests that IL-4 antagonists may be novel therapeutics for this condition. PMID- 23107828 TI - TWEAK signals through JAK-STAT to induce tumor cell apoptosis. AB - The TWEAK receptor Fn14 (TNFRSF12), a member of the TNF Receptor superfamily, can mediate many processes, including apoptosis. Fn14 agonists have therefore been the subject of interest as potential cancer therapeutics. In cell culture experiments, interferon gamma (IFNgamma) is typically required for induction of apoptotic activity by either TWEAK or Fn14 agonistic antibodies in most cell lines. We have investigated the mechanism of IFNgamma signaling and the role of JAK-STAT signaling in TWEAK/Fn14-mediated tumor cell killing. We found that IFNgamma-mediated enhancement of tumor cell killing is JAK-STAT dependent, as JAK inhibitors block IFNgamma-dependent TWEAK induced apoptosis. Exposure of tumor cells to IFNgamma results in an increase in Fn14 expression on the cell surface, which may be a mechanism by which IFNgamma induces sensitivity to TWEAK. In a reciprocal fashion, we observed that IFNgamma receptor levels increase in response to TWEAK treatment in WiDr cells. Significantly, we found that TWEAK alone can induce STAT1 phosphorylation in WiDr tumor cells. Moreover, TWEAK induction of tumor cell apoptosis in WiDr cells in the absence of IFNgamma is mediated by the JAK-STAT pathway. Correspondingly, we show that treatment of tumor bearing mice with mBIIB036, an Fn14 agonistic antibody, results in STAT1 phosphorylation in the tumors. Notably, the level of STAT1 phosphorylation appears to correlate with the degree of tumor growth inhibition by BIIB036 in vivo. Additionally, in WiDr cells, TWEAK induces a soluble factor, which we have identified as IFNbeta, capable of independently inducing STAT1 phosphorylation when transferred to naive cells. Finally, either IFNalpha or IFNbeta can partially substitute for IFNgamma in sensitizing tumor cells to Fn14 agonists. In summary, we show that TWEAK/Fn14 can signal through the JAK-STAT pathway to induce IFNbeta, and that the ability of TWEAK to induce tumor cell apoptosis is mediated by JAK-STAT signaling. We also demonstrate that IFNgamma enhancement of TWEAK/FN14-mediated tumor cell death is JAK-dependent and may occur by IFNgamma dependent upregulation of Fn14 on tumor cells. These findings may have implications for the appropriately targeted clinical development of Fn14 agonists as anti-cancer therapy. PMID- 23107829 TI - Does treatment with corticosteroids and cyclosporine reduce transglutaminase type 2 expression in the renal tissue of patients with membranous nephropathy? AB - BACKGROUND/AIMS: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults. Transglutaminase type 2 (TG2) contributes to renal scarring through altering extracellular matrix homeostasis. In this study we hypothesized that immunosuppressive treatment would downregulate TG2 expression leading to reduced fibrosis, and subsequently TG2 would have value as a biomarker of progression of MN. METHODS: TG2 expression was studied by immunofluorescence in kidney biopsy sections from 32 patients with MN and was compared to control biopsies. All patients were subsequently treated by a combination of cyclosporine and prednisolone for at least 24 months with a repeat biopsy taken in 14 patients. RESULTS: Twenty-two out of 32 patients showed stable renal function, whereas 10 showed doubling of baseline serum creatinine and 5 of them reached end stage renal disease during the 5-year follow-up. At the end of the follow-up, 22 out of 32 patients were in remission of nephrotic syndrome. TG2 immunostaining was increased in sections from patients with MN compared to healthy controls (p = 0.0002). TG2 at diagnosis was more intense in patients with severer interstitial fibrosis and advanced glomerular sclerosis. TG2 significantly increased in most patients in the repeat biopsies after treatment (p < 0.0001), whereas patients who showed a marked increase in interstitial fibrosis in the repeat biopsy had significantly more TG2 expression in the first biopsy (p = 0.02). CONCLUSION: TG2 expression is increased in MN patients and continues to increase despite immunosuppressive treatment. However, early detection of TG2 might be of value in MN since increased TG2 production seems to precede extensive interstitial fibrosis. PMID- 23107830 TI - The local implementation of a chronic disease management model for childhood overweight and obesity. AB - BACKGROUND: The aim of this study is to determine opportunities and barriers regarding the management of overweight and obese children in daily practice, and to show the value of using focus groups when developing an action plan for childhood overweight management in a local context. METHODS: Seven focus groups and four semi-structured interviews were conducted with 29 professionals from nine different care disciplines and 7 parents of overweight and obese children aged 4-19 years. RESULTS: After thorough analysis of the focus groups, issues concerning finding the most appropriate care and realising a long-term weight management in daily practice have become clear. Some examples of these issues are: lack of awareness, reluctance to discuss and refer, mutual cooperation, contradictory advice and expectations of treatment and lack of effective support strategies. CONCLUSION: Focus groups deliver important information on local issues that are important for the development and implementation of a childhood overweight management action plan. And, besides delivering necessary information, focus groups lead to an increased awareness and willingness to improve childhood overweight management in a local context. PMID- 23107831 TI - Impact of performance-based financing on primary health care services in Haiti. AB - To strengthen Haiti's primary health care (PHC) system, the country first piloted performance-based financing (PBF) in 1999 and subsequently expanded the approach to most internationally funded non-government organizations. PBF complements support (training and technical assistance). This study evaluates (a) the separate impact of PBF and international support on PHC's service delivery; (b) the combined impact of PBF and technical assistance on PHC's service delivery; and (c) the costs of PBF implementation in Haiti. To minimize the risk of facilities neglecting potential non-incentivized services, the incentivized indicators were randomly chosen at the end of each year. We obtained quantities of key services from four departments for 217 health centres (15 with PBF and 202 without) from 2008 through 2010, computed quarterly growth rates and analysed the results using a difference-in-differences approach by comparing the growth of incentivized and non-incentivized services between PBF and non-PBF facilities. To interpret the statistical analyses, we also interviewed staff in four facilities. Whereas international support added 39% to base costs of PHC, incentive payments added only 6%. Support alone increased the quantities of PHC services over 3 years by 35% (2.7%/quarter). However, support plus incentives increased these amounts by 87% over 3 years (5.7%/quarter) compared with facilities with neither input. Incentives alone was associated with a net 39% increase over this period, and more than doubled the growth of services (P < 0.05). Interview findings found no adverse impacts and, in fact, indicated beneficial impacts on quality. Incentives proved to be a relatively inexpensive, well accepted and very effective complement to support, suggesting that a small amount of money, strategically used, can substantially improve PHC. Haiti's experience, after more than a decade of use, indicates that incentives are an effective tool to strengthen PHC. PMID- 23107832 TI - Evaluation of corneal elevation and thickness indices in pellucid marginal degeneration and keratoconus. AB - PURPOSE: To determine and compare corneal elevation and thickness indices, thereby formulating a reliable index to distinguish eyes with pellucid marginal degeneration (PMD) from keratoconus eyes and normal (control) eyes. SETTING: LV Prasad Eye Institute, Hyderabad, India. DESIGN: Initial model-building retrospective study. METHODS: Anterior and posterior corneal elevations and thickness indices were obtained from the Orbscan IIz topographer. These values were analyzed and compared between PMD patients, keratoconus patients, and control subjects. RESULTS: Of the indices, the mean values of anterior elevation (AE), ratio of the AE to the anterior best-fit sphere, ratio of the average power values of nasal quadrant to the average power values of inferior quadrant, and difference between maximum keratometry (K) and minimum K were significantly different between the 3 groups (P<.05). The highest area under the receiver operating-characteristic (AROC) curve in discriminating PMD from keratoconus was for asphericity (0.974; cutoff >=-0.07; sensitivity 93.3%; specificity 90.6%) followed by the ratio of average power values of the nasal and temporal quadrants to the average power values of the inferior and superior quadrants (Avg NT((D))/IS((D))) (0.959; cutoff >=1.005; sensitivity 96.7%; specificity 90.6%). The PMD index (AROC curve, 0.935), with a cutoff of 3.45 or higher had 90% sensitivity and 93.7% specificity to distinguish PMD from keratoconus and had 100% sensitivity and 100% specificity to distinguish PMD from control eyes, with a cutoff of 2.46 or higher (AROC curve, 1.000). CONCLUSIONS: The PMD index appeared to be highly sensitive and specific for diagnosing PMD. Asphericity and Avg NT((D))/IS((D)) were clinically relevant in discriminating PMD from other groups. PMID- 23107833 TI - Design and validity of a miniaturized open-field aberrometer. AB - PURPOSE: To design and validate a new miniaturized open-field wavefront device that can be attached to an ophthalmic surgical microscope or slitlamp. SETTING: Solihull Hospital and Aston University, Birmingham, United Kingdom. DESIGN: Comparative noninterventional study. METHODS: The dynamic range of the Aston aberrometer was assessed using a calibrated model eye. The validity was compared with that of a conventional desk-mounted Hartmann-Shack aberrometer (Topcon KR1W) in dilated eyes. The instruments were used in random order, with measurements repeated 5 times to assess intrasession repeatability. RESULTS: The open-field aberrometer had a large dynamic range of at least +21.0 diopters (D) to -25.0 D. It gave similar measurements to the conventional aberrometer for mean spherical equivalent (SE) (mean difference 0.02 D +/- 0.49 [95% confidence interval]; correlation r = 0.995; P<.001), astigmatic components (J0: 0.02 +/- 0.15 D; r = 0.977, P<.001; J45: 0.03 +/- 0.28, r = 0.666, P<.001), and higher-order aberration (HOA) root mean square (RMS) (0.02 +/- 0.20 D, r = 0.620, P<.001). Intraclass correlation coefficient assessments of intrasession repeatability were excellent (SE = 1.000, P<.001; J0 = 0.998, P<.001; J45 = 0.980, P<.01; HOA RMS = 0.961, P<.001). CONCLUSIONS: The new aberrometer gave valid, repeatable measurements of refractive error and HOAs over a large range. It can measure continuously, thus providing direct feedback on the optical status of the visual system to surgeons during intraocular lens implantation and corneal surgery. PMID- 23107835 TI - 68Ga-DOTA-NOC PET and peptide receptor radionuclide therapy in management of bilateral ovarian metastases from gastrointestinal carcinoid. AB - The management of neuroendocrine tumours is challenging when curative surgery is ruled out because of distant metastases. We report a case of gastrointestinal carcinoid with bilateral ovarian metastases in a 50-year-old female who received octreotide therapy followed by peptide receptor radionuclide therapy and surgery thereafter. Somatostatin receptor expression on neuroendocrine tumours has implications in diagnosis and therapy. (68)Ga-DOTA-NOC PET is a recent advancement in the field of somatostatin receptor imaging. The lesions which demonstrate tracer uptake on positron emission tomographic studies can be further planned for treatment with octreotide and (177)Lu-DOTA-TATE. The case in discussion responded well to non-invasive treatment options before proceeding to definitive surgical management. PMID- 23107834 TI - Muscle-fiber transdifferentiation in an experimental model of respiratory chain myopathy. AB - INTRODUCTION: Skeletal muscle fiber composition and muscle energetics are not static and change in muscle disease. This study was performed to determine whether a mitochondrial myopathy is associated with adjustments in skeletal muscle fiber-type composition. METHODS: Ten rats were treated with zidovudine, an antiretroviral nucleoside reverse transcriptase inhibitor that induces a myopathy by interfering with mitochondrial functions. Soleus muscles were examined after 21 weeks of treatment. Ten untreated rats served as controls. RESULTS: Zidovudine induced a myopathy with mitochondrial DNA depletion, abnormalities in mitochondrial ultrastructure, and reduced cytochrome c oxidase activity. Mitochondrial DNA was disproportionally more diminished in type I compared with type II fibers, whereas atrophy predominated in type II fibers. Compared with those of controls, zidovudine-exposed soleus muscles contained an increased proportion (256%) of type II fibers, whereas neonatal myosin heavy chains remained repressed, indicating fiber-type transformation in the absence of regeneration. Microarray gene-expression analysis confirmed enhanced fast-fiber isoforms, repressed slow-fiber transcripts, and reduced neonatal fiber transcripts in the mitochondrial myopathy. Respiratory chain transcripts were diminished, whereas the enzymes of glycolysis and glycogenolysis were enhanced, indicating a metabolic adjustment from oxidative to glycolytic capacities. A coordinated regulation was found of transcription factors known to orchestrate type II fiber formation (upregulation of MyoD, Six1, Six2, Eya1, and Sox6, and downregulation of myogenin and ERRgamma). CONCLUSIONS: The type I to type II fiber transformation in mitochondrial myopathy implicates mitochondrial function as a new regulator of skeletal muscle fiber type. PMID- 23107836 TI - Bevacizumab-containing chemotherapy is safe in patients with unresectable metastatic colorectal cancer and a synchronous asymptomatic primary tumor. AB - OBJECTIVE: Surgical resection of asymptomatic primary colorectal cancer in patients presenting with synchronous unresectable metastatic disease is controversial. Concerns and controversies remain over combining cytotoxic chemotherapy with bevacizumab in this patient population. METHODS: We identified medical records of 99 patients with synchronous metastatic primary colorectal cancer who received chemotherapy with bevacizumab as their initial treatment. The incidence of subsequent use of surgery and surgical outcomes were recorded. Patients were also assessed for overall survival. RESULTS: Patients who received bevacizumab-containing chemotherapy for synchronous metastatic primary colorectal cancer were divided into the non-surgery and surgery groups according to the resection status of their asymptomatic primary tumor. In the non-surgery group, two patients (4.4%) underwent additional surgery, while three patients (5.7%) required surgery for rectovesical fistula in the surgery group. The median overall survival was 17 months for the non-surgery group (95% CI: 10.6-23.3 months) and 23 months for the surgery group (95% CI: 21.3-24.6 months; P = 0.322). CONCLUSIONS: This study utilizing chemotherapy with bevacizumab did not result in an increased rate of morbidity related to the unresected primary tumor. Survival is not compromised by leaving the primary colon tumor intact. PMID- 23107837 TI - Seroepidemiology of Saffold cardiovirus (SAFV) genotype 3 in Japan. PMID- 23107838 TI - Recalling, reporting, and thinking about diagnoses. PMID- 23107840 TI - Parenthood, host resistance to the common cold, and impaired fertility. PMID- 23107839 TI - Psychosocial stress and cardiovascular disease risk: the role of physical activity. AB - Chronic stress and depression are associated with increased risk of cardiovascular disease and poorer prognosis, and physical (in)activity may be a key underlying biobehavioral mechanism. Physical activity has antidepressant effects, and physically fitter, more active individuals seem to be more biologically resilient to psychosocial stressors. This article will present data from a series of population cohort studies and laboratory-based psychophysiological studies to explore the role of physical activity as a protective factor against the effects of psychosocial stress on cardiovascular disease. These mechanisms may improve the treatment and prevention of stress related illnesses and, thus, has important implications for public health and clinical care of high-risk patients. PMID- 23107841 TI - Association between panic disorder and risk of atrial fibrillation:a nationwide study. AB - OBJECTIVE: The aim of the present study was to investigate the association between panic disorder (PD) and atrial fibrillation (AF). METHODS: We used a nationwide population-based data set from Taiwan. A total of 3888 patients with PD and without a diagnosis of AF from a sampled cohort data set of 1,000,000 were included in the study group. Ten people without PD and AF were selected for every 1 patient in the study group, matched by propensity score matching according to time of enrollment, age, sex, and comorbidities. We performed log-rank tests to analyze differences in accumulated AF-free survival rates between the two groups. Cox proportional hazard regressions were performed to evaluate the independent factors determining the longitudinal hazard of AF. RESULTS: During a maximal 7 year follow-up, 48 patients from the study group (1.2% of the patients with PD) and 358 from the control group (0.9% of the patients without PD) were newly diagnosed as having AF. Patients with PD had a significantly higher incidence of AF (hazard ratio [HR] = 1.54 [1.14-2.09]; log-rank test, p = .004). After Cox model adjustment for risk factors and comorbidities, PD (HR = 1.73, 95% confidence interval [CI] = 1.26-2.37), age (HR = 1.07, 95% CI = 1.06-1.08), male sex (HR = 1.26, 95% CI = 1.03-1.55), hypertension (HR = 2.00, 95% CI = 1.55 2.56), history of coronary artery disease (HR = 1.45, 95% CI = 1.15-1.82), congestive heart failure (HR = 2.46; 95% CI, 1.84-3.30), and valvular heart disease (HR = 2.83, 95% CI = 1.85-4.42) were independently associated with increased risk of AF. CONCLUSIONS: PD is independently associated with higher incidence of AF to be diagnosed in the future. Larger prospective studies or meta analysis are suggested to confirm the findings. PMID- 23107842 TI - Implicit racial bias as a moderator of the association between racial discrimination and hypertension: a study of Midlife African American men. AB - OBJECTIVES: Empirical findings on racial discrimination and hypertension risk have been inconsistent. Some studies have found no association between self reported experiences of discrimination and cardiovascular health outcomes, whereas others have found moderated or curvilinear relationships. The current cross-sectional study examined whether the association between racial discrimination and hypertension is moderated by implicit racial bias among African American midlife men. METHODS: This study examined the data on 91 African American men between 30 and 50 years of age. Primary variables were self-reported experiences of racial discrimination and unconscious racial bias as measured by the Black-White Implicit Association Test. Modified Poisson regression models were specified, examining hypertension, defined as a mean resting systolic level of at least 140 mm Hg or diastolic level of at least 90 mm Hg, or self-reported history of cardiovascular medication use with a physician diagnosis of hypertension. RESULTS: No main effects for discrimination or implicit racial bias were found, but the interaction of the two variables was significantly related to hypertension (chi(2)(1) = 4.89, p < .05). Among participants with an implicit antiblack bias, more frequent reports of discrimination were associated with a higher probability of hypertension, whereas among those with an implicit problack bias, it was associated with lower risk. CONCLUSIONS: The combination of experiencing racial discrimination and holding an antiblack bias may have particularly detrimental consequences on hypertension among African American midlife men, whereas holding an implicit problack bias may buffer the effects of racial discrimination. Efforts to address both internalized racial bias and racial discrimination may lower cardiovascular risk in this population. PMID- 23107844 TI - Nocturnal cardiovascular activity in essential hypotension: evidence of differential autonomic regulation. AB - OBJECTIVE: Essential hypotension represents a form of chronic low blood pressure (BP) not explained by medical or orthostatic conditions. The pathogenesis of essential hypotension may involve sympathetic hypoactivation and other forms of autonomic dysregulation. The aim of the current study was to investigate autonomic and cardiovascular activity during sleep in individuals with essential hypotension. METHODS: A case-control study was conducted in 14 individuals with essential hypotension (mean [standard error] = 23.4 [0.6] years, all women) and 14 controls (mean [standard error] age = 22.2 [0.4] years, all women). The following measures were collected over a night of sleep: BP, heart rate (HR), stroke volume, cardiac output (CO), preejection period (PEP), total peripheral resistance, and time-domain measures of HR variability. RESULTS: Hypotensive participants had consistently lower BP, HR, and CO than did normotensives. Cardiac autonomic variables revealed enhanced parasympathetic tone (proportion of adjacent normal-to-normal intervals that differed in length by more than 50 milliseconds = 40.8 [6.3] versus 23.4 [4.5], p = .03) and reduced sympathetic drive in hypotensives (PEP = 99.4 [3.6] versus 86.1 [4.3], p = .02). Analysis of temporal profiles showed that HR, stroke volume, and CO decreased throughout the night in both groups, whereas PEP and HR variability increased. Unlike controls, BP remained essentially unchanged in hypotensives, as the decrease in CO was counterbalanced by a parallel rise in total peripheral resistance. CONCLUSIONS: These findings suggest that nocturnal cardiac sympathetic withdrawal combined with vagal hyperactivity is a characteristic of the autonomic regulation in essential hypotension. PMID- 23107843 TI - Multilevel modeling in psychosomatic medicine research. AB - The primary purpose of this study is to provide an overview of multilevel modeling for Psychosomatic Medicine readers and contributors. The article begins with a general introduction to multilevel modeling. Multilevel regression modeling at two levels is emphasized because of its prevalence in psychosomatic medicine research. Simulated data sets based on some core ideas from the Familias Unidas effectiveness study are used to illustrate key concepts including communication of model specification, parameter interpretation, sample size and power, and missing data. Input and key output files from Mplus and SAS are provided. A cluster randomized trial with repeated measures (i.e., three-level regression model) is then briefly presented with simulated data based on some core ideas from a cognitive-behavioral stress management intervention in prostate cancer. PMID- 23107845 TI - [Marionette fold treatment by depressor anguli oris section: technical note]. AB - Marionette folds are typical signs of facial aging. They result from contraction of depressor anguli oris (DAO) muscle, which tracts the corner of the mouth inferiorly and laterally. Marionette folds express sadness, contrary to the real mood of patient, and constitute a purpose of consultation. A systematic classification of facial aging types has been developed by Glogau in 1994. It differentiates four types of wrinkles according to their severity. Type IV of marionette folds resists to treatment with filler injection or botulinum toxin type A. Some authors, like Le louarn C., have developed surgery techniques to correct those types IV of marionette folds. In this article, we describe the DAO section technique we use. Intervention occurs under local anaesthesia, by intrabuccal approach. Horizontal mucosal incision is performed 1cm long, at the vestibular projection of DAO insertion. Orbicularis oris and buccinator muscles are retracted horizontally to let appear the DAO fibers, which are cut until subdermal fat is seen. This technique must be completed by botulinum toxin type A injection in the inferior part of the DAO to avoid muscular regeneration. DAO section is an easy, quick and efficient surgery, which allows perennial correction in marionette folds treatment. It completes other less invasive techniques to enlarge therapeutic possibilities available for surgeons and patients. PMID- 23107846 TI - Change equals opportunity. PMID- 23107847 TI - Preventing plagiarism. PMID- 23107848 TI - Von Hippel-Lindau syndrome: implications for nursing care. PMID- 23107849 TI - Quality of life, uncertainty, and perceived involvement in decision making in patients with head and neck cancer. AB - PURPOSE/OBJECTIVES: To explore the relationship among perceived involvement in decision making, uncertainty, and quality of life (QOL) in patients with head and neck cancer in pre- and post-treatment periods using Mishel's Uncertainty in Illness Theory. DESIGN: A prospective, correlational design. SETTING: Six outpatient clinics at urban hospitals in New York, NY. SAMPLE: A convenience sample of 52 adults newly diagnosed with head and neck cancer. METHODS: Data were collected by a self-administered questionnaire containing a demographic datasheet, the Functional Assessment of Cancer Therapy-Head and Neck, Mishel Uncertainty in Illness Scale (Adult), and Perceived Involvement in Care Scale, at pretreatment (Time 1) and six weeks post-treatment (Time 2). MAIN RESEARCH VARIABLES: QOL, uncertainty, perceived involvement in decision making. FINDINGS: Post-treatment QOL was lower than pretreatment. QOL was associated with uncertainty and employment status at Time 1 and Time 2. Uncertainty and QOL at the time of pretreatment were predictors of post-treatment QOL after controlling for unemployment, chemoradiation, and physician. Perceived involvement in decision making was not associated with uncertainty or QOL. CONCLUSIONS: The higher a patient's pretreatment QOL, the more likely QOL remains sound after treatment. IMPLICATIONS FOR NURSING: Additional studies, including interventional evaluations to decrease uncertainty and to maintain employment and better income, are needed. Antecedents of Mishel's Uncertainty in Illness Theory may need to be refined for patients with head and neck cancer. PMID- 23107850 TI - Nighttime sleep disruptions, the hospital care environment, and symptoms in elementary school-age children with cancer. AB - PURPOSE/OBJECTIVES: To describe nighttime sleep-wake patterns during a 12-hour night shift among school-age children with cancer receiving inpatient chemotherapy and relationships among nighttime sleep, environmental stimuli, medication doses, and symptoms during that shift. DESIGN: Exploratory, descriptive, multiple-case study. SETTING: Inpatient pediatric oncology unit at a tertiary pediatric hospital in the western United States. SAMPLE: 15 elementary school-age children with cancer receiving inpatient chemotherapy. METHODS: Wrist actigraphs measured sleep-wake patterns. Data loggers and sound pressure level meters measured bedside light, temperature, and sound levels. Medication doses and occurrences of pain, nausea, and vomiting were identified through chart review. MAIN RESEARCH VARIABLES: Minutes of sleep. FINDINGS: Sleep varied based on time of night (F = 56.27, p < 0.01), with sleep onset delayed past 10 pm. A basic mixed linear model identified significant fixed effects for sound (F = 50.87, p < 0.01) and light (F = 7.04, p < 0.01) on minutes of sleep. A backward regression model including sound, light, medication doses, pain, and nausea accounted for about 57% of the variance in sleep minutes (F = 62.85, p < 0.01). CONCLUSIONS: Sleep was marked by frequent awakenings, limiting children's ability to experience full sleep cycles. Multiple factors-in particular, excessive sound levels-compromise sleep quantity and quality throughout the night. IMPLICATIONS FOR NURSING: Efforts to develop and test individualized and system-based interventions to modify the hospital care environment to promote nighttime sleep are needed. Oncology nurses have the opportunity to influence the care environment at an individual level and to influence unit-based practices to promote a healthy nighttime sleep environment. PMID- 23107851 TI - Health-related quality-of-life outcomes: a reflexology trial with patients with advanced-stage breast cancer. AB - PURPOSE/OBJECTIVES: To evaluate the safety and efficacy of reflexology, a complementary therapy that applies pressure to specific areas of the feet. DESIGN: Longitudinal, randomized clinical trial. SETTING: Thirteen community based medical oncology clinics across the midwestern United States. SAMPLE: A convenience sample of 385 predominantly Caucasian women with advanced-stage breast cancer receiving chemotherapy and/or hormonal therapy. METHODS: Following the baseline interview, women were randomized into three primary groups: reflexology (n = 95), lay foot manipulation (LFM) (n = 95), or conventional care (n = 96). Two preliminary reflexology (n = 51) and LFM (n = 48) test groups were used to establish the protocols. Participants were interviewed again postintervention at study weeks 5 and 11. MAIN RESEARCH VARIABLES: Breast cancer specific health-related quality of life (HRQOL), physical functioning, and symptoms. FINDINGS: No adverse events were reported. A longitudinal comparison revealed significant improvements in physical functioning for the reflexology group compared to the control group (p = 0.04). Severity of dyspnea was reduced in the reflexology group compared to the control group (p < 0.01) and the LFM group (p = 0.02). No differences were found on breast cancer-specific HRQOL, depressive symptomatology, state anxiety, pain, and nausea. CONCLUSIONS: Reflexology may be added to existing evidence-based supportive care to improve HRQOL for patients with advanced-stage breast cancer during chemotherapy and/or hormonal therapy. IMPLICATIONS FOR NURSING: Reflexology can be recommended for safety and usefulness in relieving dyspnea and enhancing functional status among women with advanced-stage breast cancer. PMID- 23107852 TI - Peer-based models of supportive care: the impact of peer support groups in African American breast cancer survivors. AB - PURPOSE/OBJECTIVES: To examine the impact of support groups among African American breast cancer survivors (BCSs). RESEARCH APPROACH: A qualitative research study. SETTING: Community health and cancer centers and churches. PARTICIPANTS: 62 African American BCSs. METHODOLOGIC APPROACH: Focus groups were conducted with African American BCSs to share their experiences with peer-based support groups. A brief questionnaire was administered and assessed demographics, medical history, and support group impact. FINDINGS: Survivors emphasized that a culturally embedded focus was essential for their participation in a cancer support group. The survivors underscored that cultural-based groups are rooted in the spiritual, linguistic, experiential, and historical contexts of the intended constituents. The peer-based support groups provided multilevel functions, including emotional, social, spiritual, informational, and financial support, as well as patient navigation. The groups' activities fostered personal development and a call to community advocacy that included prevention education and research engagement. CONCLUSIONS: The unique strengths of grassroots community-based support groups are that they are culturally consonant, peer-based, and responsive to cancer-related and personal needs. The contribution and value of those multifaceted peer-based groups expand the paradigm of supportive care, extending the net of psychosocial care to underserved and underrepresented cancer survivors. INTERPRETATION: Research provides the critical foundation to lead and articulate the studies necessary to bridge peer- and professional-based care to ensure the psychosocial needs of increasingly diverse survivors are met. PMID- 23107853 TI - The impact on sexuality after diagnosis and treatment for a hematologic malignancy: findings from Australia. AB - PURPOSE/OBJECTIVES: To present findings on the impact of diagnosis and treatment on sexuality for those diagnosed with a hematologic malignancy. RESEARCH APPROACH: A qualitative design based on a series of open-ended interviews and one focus group. SETTING: Queensland, Australia. PARTICIPANTS: 50 participants representing the major hematologic diagnostic groups. METHODOLOGIC APPROACH: Interviews were recorded, transcribed verbatim, and then coded and thematically analyzed for the research. FINDINGS: The impact of the disease and treatment on sexuality ranged from participants experiencing no problems or having a brief impact that passes over time, to those who reported serious problems that significantly affected their life satisfaction. Some concerns were raised about the taboo nature of sexuality and the lack of discussion on the topic. CONCLUSIONS: The findings contradict prior research that all patients with cancer will experience an impact on their sexuality by diagnosis and treatment. The current study indicates that a small subgroup of individuals diagnosed with hematologic malignancies are acutely distressed about issues regarding sexuality and require follow-up. INTERPRETATION: Individuals diagnosed with a hematologic malignancy may have difficulties with their sexuality and will, therefore, require follow-up or assistance. A subset of individuals will require understanding, support, and, for some, referral to follow-up with a specialist. As major obstacles still exist for patients accessing appropriate professional support and advice on sexuality, oncology nursing can provide leadership in this area. PMID- 23107854 TI - Purposeful interaction: ways Latino men communicate about prostate cancer. AB - PURPOSE/OBJECTIVES: To develop a descriptive framework of the communication processes used by Latinos with prostate cancer to communicate about their diagnosis. RESEARCH APPROACH: A constructivist grounded theory approach was used to analyze and build a descriptive framework from semistructured interviews. SETTING: A university-affiliated urban hospital in southern California. PARTICIPANTS: 30 Latinos treated for prostate cancer, who had at least one first degree male relative (FDMR), and who lived near the medical center. METHODOLOGIC APPROACH: Semistructured interviews with bilingual Latinos were conducted in participants' homes in the language they preferred. Individual and collaborative analyses of translated transcripts were guided by constructivist grounded theory. FINDINGS: Analysis uncovered an overarching process of purposeful interacting. Components of the process included occasionally overlapping spheres of communication, which were connected to purposes and content. Balanced in and influenced by the spheres were cross-cutting processes of respectful silence and selective disclosure. CONCLUSIONS: Men communicated different content about their prostate cancer to people representing different reference groups. Respectful silence and selective disclosure could be viewed as men's enactment of social interaction-using and choosing words based on the symbolic meaning the men perceived would have their intended meaning for the people in each of the spheres. INTERPRETATION: Culturally sensitive educational interventions should be targeted at Latinos with prostate cancer to understand risk and encourage disclosure to FDMRs. PMID- 23107855 TI - Predictors of survival in patients with non-small cell lung cancer. AB - PURPOSE/OBJECTIVES: To examine how routine laboratory biomarkers and clinical parameters available within medical records related to overall survival in patients with non-small cell lung cancer (NSCLC). DESIGN: Retrospective chart review. SETTING: University-based cancer center in rural West Virginia. SAMPLE: 110 patients from the U.S. Appalachian region with a primary diagnosis of NSCLC at initial hospitalization. METHODS: Electronic medical records were reviewed for one year after discharge or until death. The Kaplan-Meier method was used to compare survival curves for each prognostic factor. Cox proportional hazards model was used for multivariate analyses. MAIN RESEARCH VARIABLES: Total white blood cell, neutrophil, lymphocyte, and platelet counts; hemoglobin level; body mass index (BMI); performance status; and cancer stage. FINDINGS: Low BMI (lower than 18.5 lb/in2), advanced cancer stage (IIIB or IV), and elevated neutrophil (higher than 8 x 103/mcl) and platelet (300-826 x 1012/L) counts were significant, independent prognostic factors for shorter survival time in NSCLC. BMI (hazard ratio [HR] = 2.15, 95% confidence interval [CI] [0.94, 4.9]) and neutrophil (HR = 2.93, 95% CI [1.53, 5.59]) and platelet (HR = 2.65, 95% CI [1.25, 5.62]) counts were overall prognostic predictors for patients with advanced NSCLC and remained in the multivariate survival model. CONCLUSIONS: This study detected two known clinical parameters, cancer stage and nutritional status (i.e., BMI and neutrophil and platelet counts), as having independent prognostic significance for shorter survival in NSCLC. Research on survival in patients with NSCLC should include those identified laboratory biomarkers and clinical parameters for screening patients at risk for shorter survival time following hospitalization. Investigation of whether treatments tailored to address neutrophil and platelet counts and BMI can improve survival outcomes also is warranted. IMPLICATIONS FOR NURSING: Attention to common biomarkers recorded in patient charts (e.g., neutrophil and platelet counts) as well as BMI could allow nurses to identify patients at risk for low survival. Interventions should be identified and initiated. Longitudinal studies in clinical settings that follow the survival of patients with NSCLC are essential. PMID- 23107856 TI - Oncology update. PMID- 23107858 TI - Reduced-intensity conditioning allogeneic stem cell transplantation in pediatric patients and subsequent supportive care. AB - PURPOSE/OBJECTIVES: To determine if children undergoing reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC-AlloHSCT) have lower incidence of acute toxicities and, subsequently, require less supportive care than is required with myeloablative conditioning (MAC)-AlloHSCT. An additional purpose is to examine later outcomes by comparing 100-day transplantation-related mortality (TRM). DESIGN: Retrospective chart and electronic medical records review. SETTING: A pediatric care center in the northeastern United States. SAMPLE: 86 patients who underwent AlloHSCT from January 2004 through March 2008. METHODS: Charts were retrospectively reviewed. The comparison between groups was done by t test (continuous variables) and chi square test (categorical variables). The logistic regressions, Kaplan-Meier product-limit estimator, log rank test, and Cox proportional hazards model were used. MAIN RESEARCH VARIABLES: Days requiring total parenteral nutrition (TPN), patient-controlled analgesia (PCA), incidence of mucositis, days with fevers, number of infections, transfers to pediatric intensive care unit (PICU), blood product infusions, and 100-day TRM, all for 30 days post-transplantation. FINDINGS: When comparing pediatric patients undergoing RIC-AlloHSCT (n = 43) versus MAC-AlloHSCT (n = 43) in the first 30 days post-transplantation, a statistically significant decreased incidence was noted for mucositis, infections, transfers to PICU, days on TPN and PCA, and days with fever, as well as 100-day TRM. CONCLUSIONS: For pediatric patients, RIC-AlloHSCT is associated with significantly lower acute post-transplantation toxicities and TRM than MAC AlloHSCT. IMPLICATIONS FOR NURSING: For nurses to correctly educate their patients and family members, and to aid nurses in anticipating patient's needs, an understanding of the potential different acute toxicities and supportive care between pediatric patients undergoing RIC- versus MAC-AlloHSCT is vital. PMID- 23107859 TI - Relative dose intensity--improving treatment and outcomes in early-stage breast cancer: a retrospective study. AB - PURPOSE/OBJECTIVES: To determine the amount of chemotherapy delivered compared to amount of chemotherapy scheduled by calculating relative dose intensity (RDI) and to identify factors associated with nonadherence of scheduled treatment regimens for patients with early-stage breast cancer (ESBC). DESIGN: Retrospective, descriptive, correlational study. SETTING: Two community hospital cancer centers in northern Michigan. SAMPLE: 77 patients with ESBC receiving adjuvant chemotherapy. METHODS: The RDI CalculatorTM was used for data collection. A worksheet was developed for each patient and included characteristics, treatment information, and RDI calculations. SAS(r), version 19.2, was used for multivariate analyses based on logistical regression analyzing relationships among dependent and independent variables. MAIN RESEARCH VARIABLES: Dependent variables were RDI prescribed and RDI received. Independent variables included chemotherapy regimen, clinical characteristics, planned dose, and schedule. FINDINGS: The average RDI was 86.6%. The average RDI was 86.7% for patients younger than age 65, and 85.5% for those 65 and older. The most common reasons for dose reduction or dose delay were treatment toxicity, chronic disease risk factors, age, unplanned versus planned treatment dose, institution (different standards of care), patient preference, and weight. CONCLUSIONS: Meeting treatment goals of RDI for patients with ESBC has been shown to increase the disease-free survival rate and positively affects overall survival. IMPLICATIONS FOR NURSING: Nurses have the unique opportunity to case manage patients with ESBC throughout the spectrum of care. One of the key areas of focus is education of the patient and her family members from the time of diagnosis throughout treatment and rehabilitation. PMID- 23107860 TI - Symptom clusters in Chinese patients with primary liver cancer. AB - PURPOSE/OBJECTIVES: To derive symptom clusters and their clinical meanings in Chinese patients with primary liver cancer (PLC), to examine the factors related to the identified symptom clusters, and to validate the impact of the identified symptom clusters on patients' quality of life (QOL). DESIGN: Cross-sectional. SETTING: Inpatient departments at a medical center for hepatobiliary disease in China. SAMPLE: 277 patients with PLC, aged 18-77 years. METHODS: Data were collected from a number of measures, including demographic and disease characteristics, the MD Anderson Symptom Inventory, six additional symptom items specific to PLC, and the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire. Factor analysis was used to derive symptom clusters, independent samples t test or one-way analysis of variance was performed to identify the factors related to each symptom cluster, and multivariate regression models were applied to examine the predictive impact of the identified symptom clusters on PLC. MAIN RESEARCH VARIABLES: Demographic and medical variables, symptom clusters, and QOL. FINDINGS: Three symptom clusters were identified: gastrointestinal sickness, neuropsychological, and liver dysfunction. Patients who received liver protection treatment, received more than one kind of treatment, and had poorer physical performance, worse liver function, and more advanced cancer scored higher in severity across all three symptom clusters. All of the symptom clusters explained 48% of the QOL variance, and the liver dysfunction symptom cluster (adjusted R2 = 0.425) showed a superior influence. CONCLUSIONS: The liver dysfunction symptom cluster may be unique to Chinese patients with PLC. Patients with certain demographic and disease characteristics could be at risk for experiencing severe symptom clusters. In addition, a differential impact of the symptom clusters on QOL was noted in these patients. IMPLICATIONS FOR NURSING: The factors related to severity should be considered when managing symptom clusters. Because the predictive impacts of the three individual symptom clusters on QOL were varied and ordered in magnitude, healthcare providers should first alleviate the primary symptom cluster. This approach could be cost-effective and improve QOL. PMID- 23107861 TI - The meaning of life intervention for patients with advanced-stage cancer: development and pilot study. AB - PURPOSE/OBJECTIVES: To develop the Meaning of Life Intervention in response to the need for brief and meaning-focused interventions in palliative care and to establish potential effect sizes for future full-scale randomized, controlled trials. DESIGN: A randomized, controlled trial conducted to pilot test the Meaning of Life Intervention. SETTING: A 68-bed oncology inpatient ward in an urban acute general hospital in Hong Kong. SAMPLE: 84 patients with advanced stage cancer. Fifty-eight completed the study. METHODS: Assessments of outcome variables were conducted at baseline and one day and two weeks after the intervention. Patients were randomly allocated to the intervention group or the control group. Repeated measures analysis of covariance were conducted to assess the impact of the Meaning of Life Intervention on participants' quality of life. MAIN RESEARCH VARIABLES: The primary outcome was quality of life and was measured by the Quality-of-Life Concerns in the End-of-Life (QOLC-E) questionnaire and with a single-item scale on global quality of life. The eight subscales of the QOLC-E served as secondary outcomes. FINDINGS: Statistically significant main effects were noted for the group in the QOLC-E questionnaire total score, the single-item scale on global quality of life, and the existential distress subscale of the QOLC-E questionnaire. The effects represented a medium effect size. CONCLUSIONS: The results of this pilot study show that the Meaning of Life Intervention can improve quality of life, particularly existential distress. IMPLICATIONS FOR NURSING: The Meaning of Life Intervention represents a potentially effective and efficient intervention that is feasible for implementation by nursing staff for patients with advanced-stage cancer in a palliative care setting. PMID- 23107862 TI - Development of a postsurgical patient-reported outcome instrument for women with vulvar neoplasia. AB - PURPOSE/OBJECTIVES: To (a) develop the Women With Vulvar Neoplasia-Patient Reported Outcome (WOMAN-PRO) instrument as a measure of women's post-vulvar surgery symptom experience and informational needs, (b) examine its content validity, (c) describe modifications based on pilot testing, and (d) examine the content validity of the revised instrument. DESIGN: Mixed-methods research project. SETTING: One Swiss and two German university hospitals. SAMPLE: 10 patients and 6 clinicians participated in the pilot test. METHODS: The instrument was developed based on literature searches, clinician feedback, and patient interviews. Thirty-seven items were first pilot tested by patients and clinicians. The revised 36 items were pilot tested by patients. The content validity index (CVI) for each item and the entire instrument was calculated. MAIN RESEARCH VARIABLES: Symptom experience and informational needs of patients with vulvar neoplasia. FINDINGS: The initial pilot test showed excellent scale CVI based on feedback from patients (CVI = 0.98) and clinicians (CVI = 0.92). After revising six items based on low individual CVIs and participant comments, the revised WOMAN-PRO showed excellent item and scale content validity (CVI = 1). CONCLUSIONS: The newly developed WOMAN-PRO instrument can guide patients and clinicians in assessing symptoms, informational needs, and related distress. IMPLICATIONS FOR NURSING: Use of the WOMAN-PRO instrument in clinical practice can offer patients guidance in self-assessment and early recognition of symptoms. The instrument also can provide clinicians with systematic information about key symptoms from a patient perspective, as well as women's unmet informational needs. If the results of additional psychometric testing are promising, the WOMAN PRO tool may provide an outcome measure for clinical trials. PMID- 23107863 TI - Adaptation of the illness trajectory framework to describe the work of transitional cancer survivorship. AB - PURPOSE/OBJECTIVES: To examine and refine the Illness Trajectory Framework, and to address transitional cancer survivorship. DATA SOURCES: CINAHL(r), PubMed, and relevant Institute of Medicine reports were searched for survivors' experiences during the year following treatment. DATA SYNTHESIS: Using an abstraction tool, 68 articles were selected from the initial search (N > 700). Abstracted data were placed into a priori categories refined according to recommended procedures for theory derivation, followed by expert review. CONCLUSIONS: Derivation resulted in a framework describing the work of transitional cancer survivorship, defined as survivor tasks, performed alone or with others, to carry out a plan of action for managing one or more aspects of life following primary cancer treatment. Theoretically, survivors engage in three reciprocally interactive lines of work: (a) illness-related, (b) biographical, and (c) everyday life work. Adaptation resulted in refinement of these domains and the addition of survivorship care planning under "illness-related work." IMPLICATIONS FOR NURSING: Understanding this process of work may allow survivors and those who support them to better prepare for the post-treatment period. This adaptation provides a framework for future testing and development. Validity and utility of this framework within specific survivor populations also should be explored. PMID- 23107866 TI - Systemic fungal infections in patients with human inmunodeficiency virus. AB - Histoplasmosis is a systemic infection caused by the dimorphic fungus Histoplasma capsulatum. In immunocompromised patients, primary pulmonary infection can spread to the skin and meninges. Clinical manifestations appear in patients with a CD4(+) lymphocyte count of less than 150 cells/MUL. Coccidioidomycosis is a systemic mycosis caused by Coccidioides immitis and Coccidioides posadasii. It can present as diffuse pulmonary disease or as a disseminated form primarily affecting the central nervous system, the bones, and the skin. Cryptococcosis is caused by Cryptococcus neoformans (var. neoformans and var. grubii) and Cryptococcus gattii, which are members of the Cryptococcus species complex and have 5 serotypes: A, B, C, D, and AD. It is a common opportunistic infection in patients with human immunodeficiency virus (HIV)/AIDS, even those receiving antiretroviral therapy. Histopathologic examination and culture of samples from any suspicious lesions are essential for the correct diagnosis of systemic fungal infections in patients with HIV/AIDS. PMID- 23107867 TI - Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus doxorubicin and dexamethasone as induction therapy in previously untreated multiple myeloma patients. AB - We conducted a retrospective study to compare thalidomide, bortezomib and dexamethasone (VTD) with thalidomide plus doxorubicin and dexamethasone (TAD). Until now, first-line treatment with these combinations has not been reported in any comparative study. The principal objective of this study was to determine whether VTD would improve the complete response (CR) and CR plus very good partial response rates compared with TAD. Second, using additional methods, such as flow cytometric assays and polymerase chain reaction technology, we evaluated the molecular residual disease in the subgroup of patients that obtained CR. Our study shows that VTD is a superior induction regimen compared with TAD, with a higher response rate after induction, translating into greater CR plus very good partial response. PMID- 23107869 TI - The pharmacological differences in anti-anginal effects of long-lasting calcium channel blockers: azelnidipine and amlodipine. AB - ABSTRACT: We examined anti-anginal effects of azelnidipine and amlodipine in an arginine vasopressin (AVP)-induced rat anginal model. Oral administration of azelnidipine or amlodipine produced long-lasting inhibition of AVP-induced ST segment depression in ECG. The degrees of inhibition with azelnidipine at doses of 1 and 3 mg/kg were comparable to those with amlodipine at 3 and 10 mg/kg. Both drugs lowered mean blood pressure in a dose related manner, while only azelnidipine decreased heart rate. Azelnidipine at 3 mg/kg and amlodipine at 10 mg/kg produced a similar decrease in the rate pressure product, an index for cardiac oxygen consumption. Their inhibitory effects on calcium-induced vascular contraction were compared in isolated porcine coronary arteries. Both drugs produced a slow-developing inhibition of calcium-induced contraction. Although their inhibitory effects were similar, the way the both drugs inhibited calcium induced contraction differed with each other. After removing the drug from bathing solution, the inhibitory effects of azelnidipine were not blunted but were sustained for a long time which indicates that azelnidipine has high vascular affinity. On the other hand, those of amlodipine were rapidly blunted. These results suggest that the mechanisms underlying anti-anginal effects of azelnidipine differ from those of amlodipine. The anti-anginal effect with azelnidipine may be accounted for by its high affinity to the coronary blood vessels and the heart rate slowing effect, both of which are not shared with amlodipine. PMID- 23107868 TI - Vascular KCNQ (Kv7) potassium channels as common signaling intermediates and therapeutic targets in cerebral vasospasm. AB - Cerebral vasospasm after subarachnoid hemorrhage (SAH) is characterized by prolonged severe constriction of the basilar artery, which often leads to ischemic brain damage. Locally elevated concentrations of spasmogenic substances induce persistent depolarization of myocytes in the basilar artery, leading to continuous influx of calcium (Ca) through voltage-sensitive Ca channels and myocyte contraction. Potassium (K) channel openers may have therapeutic utility to oppose membrane depolarization, dilate the arteries, and reduce ischemia. Here, we examined the involvement of vascular Kv7 K channels in the pathogenesis of cerebral vasospasm and tested whether Kv7 channel openers are effective therapeutic agents in a rat model of SAH. Patch-clamp experiments revealed that 3 different spasmogens (serotonin, endothelin, and vasopressin) suppressed Kv7 currents and depolarized freshly isolated rat basilar artery myocytes. These effects were significantly reduced in the presence of a Kv7 channel opener, retigabine. Retigabine (10 MUM) also significantly blocked L-type Ca channels, reducing peak inward currents by >50%. In the presence of a selective Kv7 channel blocker, XE991, the spasmogens did not produce additive constriction responses measured using pressure myography. Kv7 channel openers (retigabine or celecoxib) significantly attenuated basilar artery spasm in rats with experimentally induced SAH. In conclusion, we identify Kv7 channels as common targets of vasoconstrictor spasmogens and as candidates for therapeutic intervention for cerebral vasospasm. PMID- 23107870 TI - Carvedilol is effective and safe in combination with bepridil for persistent atrial fibrillation and decreases the QT prolongation induced by bepridil therapy. AB - INTRODUCTION: We investigated the efficacy of carvedilol for preventing the recurrence of atrial fibrillation and reducing QT prolongation induced by bepridil. METHODS: We assigned 144 subjects with persistent atrial fibrillation. The subjects were divided into 3 groups: carvedilol plus bepridil, candesartan plus bepridil, and bepridil alone. The primary endpoint was length of time to the recurrence of atrial fibrillation. All subjects were followed up for 3 years. Electrocardiographic parameters were measured for QT interval, QTc, heart rate, and QRS duration. RESULTS: The pharmacological conversion rate by carvedilol plus bepridil was 77%, candesartan plus bepridil was 63%, and bepridil alone was 57%. The significant difference was between carvedilol plus bepridil and bepridil alone (P = 0.03). The maintenance of SR at 3 years was 60% in carvedilol plus bepridil, 59% in candesartan plus bepridil, and 40% in bepridil alone. The difference between carvedilol plus bepridil and bepridil alone was statistically significant (P = 0.04). QTc and QT interval were significantly prolonged in candesartan plus bepridil and bepridil alone but not in carvedilol plus bepridil. CONCLUSIONS: The authors demonstrated that the combination therapy with carvedilol plus bepridil is more effective for maintaining SR than bepridil alone therapy and carvedilol reduced QT prolongation by bepridil therapy. PMID- 23107871 TI - Daily dosing of vismodegib to steady state does not prolong the QTc interval in healthy volunteers. AB - INTRODUCTION: Vismodegib was assessed as being of low risk for QT interval prolongation based on prior nonclinical and clinical experience. A dedicated study was conducted to further assess the potential for vismodegib to prolong the QTc interval. METHODS AND RESULTS: Given the nonlinear pharmacokinetics of vismodegib, a thorough QTc study as is typically designed was not possible, and an innovative design was employed. This dedicated QTc study was powered to exclude a 20-millisecond change from the baseline QTc interval. The subjects were administered daily oral 150 mg of vismodegib for 7 days, or a single dose of 400 mg of moxifloxacin, with corresponding matching placebos. The upper limits of the 90% confidence intervals for the difference in DeltaQTcF between vismodegib and placebo at steady state were <20 milliseconds at all timepoints with a maximum of 10 milliseconds at 12 hours postdose. Exposure-response analysis yielded an estimated slope equal to 0.11 ms/MUM, which was not statistically significant. After a single dose of moxifloxacin was administered, the lower limits of the 90% confidence interval of the difference in DeltaQTcF between moxifloxacin and placebo were >5 milliseconds from 1-12 hours postdose, thereby establishing assay sensitivity. CONCLUSIONS: There was no effect of vismodegib on the QTc interval when dosed daily at 150 mg to steady state. PMID- 23107872 TI - Inhibition of suicidal erythrocyte death by probucol. AB - Probucol, an antioxidant and anti-inflammatory agent counteracting atherosclerosis and restenosis, is partially effective by influencing suicidal cell death or apoptosis. In analogy to apoptosis of nucleated cells, suicidal death of erythrocytes or eryptosis is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the erythrocyte surface. Eryptosis is stimulated by increase in cytosolic Ca(2+) activity, for example, after energy depletion or oxidative stress. The present study explored whether probucol influences eryptosis. Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter (FSC), and cytosolic Ca(2+) concentration from fluo-3 fluorescence in flow cytometry. As a result, energy depletion (48-hour glucose removal) increased annexin-V-binding, decreased FSC, and increased fluo-3 fluorescence. Probucol (<=30 MUM) did not significantly modify annexin-V-binding, FSC, or fluo-3 fluorescence in the presence of glucose but (at >=5 MUM) blunted the effect of glucose depletion on annexin-V-binding. Probucol (>=20 MUM) only slightly blunted the effects of glucose depletion on FSC and fluo-3 fluorescence. Ca(2+) ionophore ionomycin (1 MUM) and oxidative stress (30-minute exposure to 0.3 mM of tert-butylhydroperoxide) increased annexin-V binding, effects again blunted by 30 MUM of probucol. In conclusion, probucol blunts cell membrane scrambling after energy depletion and oxidative stress, effects primarily because of interference with the scrambling effects of increased cytosolic Ca(2+) concentration. PMID- 23107873 TI - No implication of thromboxane prostanoid receptors in reactive hyperemia of skin and skeletal muscle in human forearm. AB - There is evidence that reactive hyperemia (ie, the transient increase of blood flow above resting level after a short period of ischemia) could be negatively modulated by vasoconstrictor prostanoids. The present study tested whether pharmacological blockade of the thromboxane prostanoid receptors with the specific antagonist S18886 (terutroban) would amplify reactive hyperemia in human skin and skeletal muscle. Twenty healthy young male volunteers were enrolled in a randomized, blinded, crossover trial of oral S18886 30 mg/d for 5 days versus placebo. Reactive hyperemia was evaluated in forearm skin and skeletal muscle, after occlusion of the brachial artery with a pneumatic cuff inflated at suprasystolic pressure. Blood flow was measured with laser Doppler imaging (skin) and strain gauge venous occlusion plethysmography (muscle). On the first and last day of each treatment period, recordings of reactive hyperemia were obtained immediately before and 2 hours after drug intake. Whether in forearm muscle or skin, S18886 had no discernible effect on peak postocclusion blood flow, nor on the global hyperemic response as quantified by the area under curve. These results do not support that thromboxane prostanoid receptor activation could exert a moderating influence on reactive hyperemia in human skin and skeletal muscle, at least in young subjects. PMID- 23107874 TI - Platelet function in ischemic heart disease. AB - Blood platelets (PLTs) play a key role in atherothrombosis due to their ability of thrombus formation after rupture of an atherosclerotic plaque. Numerous clinical trials have established the efficacy of PLT function blockade in the prevention of acute coronary syndromes. Meanwhile, nearly all patients undergoing cardiopulmonary bypass grafting present with anti-PLT therapy. PLTs interact also with endothelial cells, leukocytes, and smooth muscle cells and are involved in vascular inflammation. This may result in an excessive fibroproliferative response after vessel dilatation. Furthermore, many PLT blockers are associated with response variability up to nonresponsiveness leading to increased reintervention and transfusion rates both identified as independent risk factors for an adverse clinical outcome after coronary interventions. Summarizing the role of PLTs for normal hemostasis and the pathophysiology of atherothrombosis, this review describes the current status of anti-PLT therapy and highlights some new anti-PLT drugs in the prevention of serious cardiovascular events. PMID- 23107875 TI - Inhibition of p38 MAPK during ischemia, but not reperfusion, effectively attenuates fatal arrhythmia in ischemia/reperfusion heart. AB - The mitogen-activated protein kinases (MAPKs) play an important role in ischemia/reperfusion (I/R) injury. Previous evidence suggests that p38 MAPK inhibition before ischemia is cardioprotective. However, whether p38 MAPK inhibition during ischemia or reperfusion provides cardioprotection is not well known. We tested the hypothesis that p38 MAPK inhibition at different times during I/R protects the heart from arrhythmias, reduces the infarct size, and attenuates ventricular dysfunction. Adult Wistar rats were subject to a 30-minute left anterior descending coronary artery occlusion, followed by a 120-minute reperfusion. A p38 MAPK inhibitor, SB203580, was given intravenously before left anterior descending coronary artery occlusion, during ischemia, or at the onset of reperfusion. The results showed that SB203580 given either before or during ischemia, but not at the onset of reperfusion, decreased the ventricular tachycardia/ventricular fibrillation (VT/VF) incidence and heat shock protein 27 phosphorylation, and increased connexin 43 phosphorylation. The infarct size and cytochrome c level was decreased in all SB203580-treated rats, without the alteration of the total Bax/Bcl-2 expression. The ventricular function was improved only in SB203580-pretreated rats. These findings suggest that timing of p38 MAPK inhibition with respect to onset of ischemia is an important determinant of therapeutic efficacy. PMID- 23107878 TI - Recommendations for the diagnosis and management of typical childhood spinal muscular atrophy. AB - Typical childhood spinal muscular atrophy is a disease that affects the anterior horn of the spinal cord related to SMN1 gene defects. Since no etiological treatment is currently available, its management is necessarily symptomatic and involves multidisciplinary care. The national plan on rare diseases for 2005-2008 developed by the French Ministry of Health resulted in the creation of 12 reference centres for neuromuscular diseases, mainly to improve their diagnosis and management. During the first one-day clinical research meeting on neuromuscular disorders, organized by the French Association to fight myopathies (AFM) in May 2007, clinicians from the 12 national reference centers led workshops for each of the main neuromuscular diseases. Concerning spinal muscular atrophy, discussions involving specialists from medical and allied professions were led by clinicians in charge of the workshop sessions. This paper reports the final version of their recommendation regarding the diagnosis, monitoring and management of typical infantile spinal muscular atrophy, which is necessarily multidisciplinary, including orthopedic, pulmonary, gastroenterology and nutrition care. PMID- 23107876 TI - Endothelial small-conductance and intermediate-conductance KCa channels: an update on their pharmacology and usefulness as cardiovascular targets. AB - Most cardiovascular researchers are familiar with intermediate-conductance KCa3.1 and small-conductance KCa2.3 channels because of their contribution to endothelium-derived hyperpolarization. However, to immunologists and neuroscientists, these channels are primarily known for their role in lymphocyte activation and neuronal excitability. KCa3.1 is involved in the proliferation and migration of T cells, B cells, mast cells, macrophages, fibroblasts, and dedifferentiated vascular smooth muscle cells and is, therefore, being pursued as a potential target for use in asthma, immunosuppression, and fibroproliferative disorders. In contrast, the 3 KCa2 channels (KCa2.1, KCa2.2, and KCa2.3) contribute to the neuronal medium afterhyperpolarization and, depending on the type of neuron, are involved in determining firing rates and frequencies or in regulating bursting. KCa2 activators are accordingly being studied as potential therapeutics for ataxia and epilepsy, whereas KCa2 channel inhibitors like apamin have long been known to improve learning and memory in rodents. Given this background, we review the recent discoveries of novel KCa3.1 and KCa2.3 modulators and critically assess the potential of KCa activators for the treatment of diabetes and cardiovascular diseases by improving endothelium derived hyperpolarizations. PMID- 23107877 TI - TRPV4 and the regulation of vascular tone. AB - Recent studies have introduced the importance of transient receptor potential vanilloid subtype 4 (TRPV4) channels in the regulation of vascular tone. TRPV4 channels are expressed in both endothelium and vascular smooth muscle cells and can be activated by numerous stimuli including mechanical (eg, shear stress, cell swelling, and heat) and chemical (eg, epoxyeicosatrienoic acids, endocannabinoids, and 4alpha-phorbol esters). In the brain, TRPV4 channels are primarily localized to astrocytic endfeet processes, which wrap around blood vessels. Thus, TRPV4 channels are strategically localized to sense hemodynamic changes and contribute to the regulation of vascular tone. TRPV4 channel activation leads to smooth muscle cell hyperpolarization and vasodilation. Here, we review recent findings on the cellular mechanisms underlying TRPV4-mediated vasodilation; TRPV4 channel interaction with other proteins including transient receptor potential channel 1, small conductance (K(Ca)2.3), and large conductance (K(Ca)1.1) calcium-activated potassium-selective channels; and the importance of caveolin-rich domains for these interactions to take place. PMID- 23107879 TI - [2011: What's new in dysimmune neuropathies]. AB - There are strong research activities in the field of dysimmune neuropathies. In Guillain-Barre syndrome, new pathophysiological mechanisms have been demonstrated with the potential development of new therapies, a clinical prediction model is applicable early in the course of disease, and under investigation are new treatment strategies with adapted intravenous Ig dosages. In chronic inflammatory demyelinating polyneuropathies, current diagnostic tests are discussed but biomarkers are needed, such as histological changes or differential gene expression in nerve or skin biopsies. The exploration of novel therapeutic approaches including monoclonal antibodies and oral immunosuppressants, known from multiple sclerosis studies, suggests new approaches to treatment. Changes of the peripheral nerves on MR imaging are better known and the usefulness of serum antibodies is reviewed. PMID- 23107880 TI - [Identification of emotions in patients with low-grade gliomas versus cerebrovascular accidents]. AB - INTRODUCTION: Facial and vocal emotions contribute to sustain efficient social relationships. Brain disease may impair their identification. In the case of slow growth tumors (Low Grade Gliomas [LGG]) or sudden stroke (cerebrovascular accidents [CVA]), the lesions induce contrasted plasticity and reorganisation processes. METHODS: We compared the facial, vocal and intermodal identification of six emotions (happiness, fear, angriness, sadness, disgust and neutral) of three groups: patients with LGG before and after tumor resection, patients with CVA and control subjects. RESULTS: In LGG patients, the results revealed less efficient performances after tumor resection and in CVA patients weak performances regarding negative emotions. The intermodal condition (simultaneous visual and vocal association) improved performances in all groups and enabled equivalent performance in CVA subjects compared with control subjects. CONCLUSION: The intergroup differences may be related to variable brain plasticity as a function of type and rapidity of brain injury. Intermodal processing appears to be a compensatory condition. PMID- 23107881 TI - [What's new concerning the chemobrain?]. AB - Chemobrain, a subtle cognitive decline after chemotherapy in non-cerebral cancer, remains a debated issue, which has nevertheless been widely described for more than 15 years in the international literature. This phenomenon is almost unknown in France to experts, neurologists and oncologists. Experimental evidence from animal models and from human functional imagery is reliable but contrasts with the observations made during clinical studies. Indeed, in clinical practice, the difficulty in proving the occurrence of chemobrain may be explained by a large number of methodological skews. However, considering the International Cognition and Cancer Task Force (ICCTF) guidelines, we propose a methodology applicable in daily practice and capable of improving awareness of this phenomenon. PMID- 23107882 TI - [Peripheral nerve damage in patients with leprosy]. AB - Leprosy is one of the six diseases that the WHO considers as the major threat in developing countries. Damage to nerves can occur before, during, and after treatment and can result in disabilities and long-term disfigurement, which is associated with stigma. Considered exotic and rare in European countries, it is important for neurologists to be able to make the diagnosis of leprosy early in order to rapidly alleviate patient suffering and prevent and reverse nerve damage. Leprosy must be considered in the differential diagnosis of peripheral neuropathy, even in the absence of skin lesions and especially when present in a patient from an endemic country. Immune response and mechanisms involved in nerve damage are not clearly understood. There is no predictive test for the extent of nerve damage and no good evidence on the best treatment. PMID- 23107883 TI - [Metabolic neuropathies: overview in 2011]. AB - Metabolic diseases constitute a frequent etiologic group of axonal and small fiber neuropathies. Recent works in this field are dominated by diabetic neuropathy (clinical presentation, prognostic factors) because of its prevalence. Vitamin B12 deficiency aroused several studies in 2011. This renewed interest for this well known entity ensues from the lack of sensibility of its biological markers underestimating its prevalence, its clinical spectrum and therefore, access to its therapy. Finally, 2011 highlighted the growing interest of the measure of the intra-epidermic nerve fibers density by skin biopsy for some metabolic disorders such as infra-clinical hypothyroidism, chronic renal failure or Fabry disease. PMID- 23107884 TI - [Conduction block: a notion to let through]. AB - Historical study of electrodiagnosis indicates that nerve conduction block is an old notion, used as early as the second century by Galien and then early in the 19th by physiologists such as Muller and Mateucci. Although introduced into the field of human pathology by Mitchell in 1872, who used it to study nerve injuries, and then by Erb in 1874 to study radial palsy, the contribution of nerve conduction blocks to electrodiagnosis was not exploited until the 1980s. At that time, attempts to improve early diagnosis of Guillain-Barre syndrome showed that among the electrophysiological consequences of demyelination, conduction block was the most appropriate to account for the paralysis. At the same time, descriptions of neuropathies characterized by conduction blocks led to considering conduction block as a major electrophysiological sign. Why was it so difficult for this sign to be retained for electrodiagnosis? Since the notion is not always associated with anatomical lesions, it doesn't fit easily into anatomoclinical reasoning, but has to be thought of in functional terms. Understanding how an uninjured axon could fail to conduct action potentials leads to an examination of the intimate consequences of demyelinations and axonal dysfunctions. But some of the difficulty encountered in adding this new old sign to the armamentarium of electrophysiological diagnosis was related to the technical precautions required to individualize a block. Several pitfalls have to be avoided if a conduction block is to be afforded real diagnostic value. Similar precautions and discussions are also needed to establish an opposing sign, the "excitability block" or "inverse block". PMID- 23107885 TI - Autosomal insertional translocation mimicking an X-linked mode of inheritance. AB - Unbalanced insertional translocations are a rare cause of intellectual disability. An unbalanced insertional translocation is a rare chromosomal imbalance, which may result from a balanced insertional translocation present in a phenotypically normal parent. We report here three brothers with intellectual disability, short stature, microcephaly, craniofacial anomalies and small testes. Since their parents and their sister were all phenotypically normal, the pattern of the family suggested an X-linked mode of inheritance. Surprisingly, we identified by array comparative genomic hybridization (aCGH) and fluorescent in situ hybridization (FISH) in the three brothers an 8q22.3q23.2 deletion resulting from a balanced insertional translocation present in their healthy father. The deletion encompassed the ZFPM2 gene known to be involved in gonadal development, which is consistent with the small testes and abnormal endocrine dosages in the affected brothers. The present report also illustrates that parental analyses by aCGH or qPCR methods are not sufficient when a de novo deletion or duplication is identified in an affected child and that FISH analysis should be performed on metaphase spreads in both parents to deliver an accurate genetic counseling. PMID- 23107892 TI - Targeting DNA repair mechanisms in cancer. AB - Preservation of genomic integrity is an essential process for cell homeostasis. DNA-damage response (DDR) promotes faithful transmission of genomes in dividing cells by reversing the extrinsic and intrinsic DNA damage, and is required for cell survival during replication. Radiation and genotoxic drugs have been widely used in the clinic for years to treat cancer but DNA repair mechanisms are often associated with chemo- and radio-resistance. To increase the efficacy of these treatments, inhibitors of the major components of the DDR such as ATM (ataxia telangiectasia mutated), ATR (ATM and Rad3-related), DNA-PK (DNA-dependent protein kinase, catalytic subunit), Chk1 (checkpoint protein 1) and Chk2 (checkpoint protein 2) have been used to confer radio- and/or chemosensitivity upon cancer cells. The elucidation of the molecular mechanisms of DNA repair and the discovery that tumors are frequently repair-deficient provide a therapeutic opportunity to selectively target this deficiency. Genetic mutations in the DNA repair genes constitute not only the initiating event of the cancer cell but also its weakness since the mutated gene is often needed by the cancer cell to maintain its own survival. This weakness has been exploited to specifically kill the tumor cells while sparing the normal ones, a concept known as 'synthetic lethality'. Recent efforts in the design of cancer therapies are directed towards exploiting synthetic lethal interactions with cancer-associated mutations in the DDR. In this review, we will discuss the latest concepts in targeting DNA repair mechanisms in cancer and the novel and promising compounds currently in clinical trials. PMID- 23107886 TI - Excitatory and inhibitory synaptic function in the rostral nucleus of the solitary tract in embryonic rat. AB - The embryonic development of synapses in the rostral nucleus of the solitary tract (rNST) was investigated in rat to determine when synapses begin to function. Using a brain slice preparation we studied appearance of synaptic receptors on second order rNST neurons and investigated the development of postsynaptic responses elicited by afferent nerve stimulation. Prenatal excitatory and inhibitory synaptic responses were recorded as early as E14. Glutamatergic and GABAergic postsynaptic responses were detected as early as E16. Both NMDA and AMPA receptors contributed to glutamatergic postsynaptic responses. GABAergic postsynaptic responses resulted primarily from activation of GABA(A) receptors. However, functional GABA(C) receptors were also demonstrated. A glycinergic postsynaptic response was not found although functional glycine receptors were demonstrated at E16. Solitary tract (ST) stimulation-evoked EPSCs, first detected at E16, were eliminated by glutamate receptor antagonists. ST evoked IPSPs, also detected at E16, were eliminated by GABA(A) receptor antagonist. Thus, considerable prenatal development of rNST synaptic connections occurs and this will ensure postnatal function of central taste processing circuits. PMID- 23107893 TI - Inhibition of MCP-1/CCR2 signaling pathway is involved in synergistic inhibitory effects of irbesartan with rosuvastatin on vascular remodeling. AB - Additional beneficial effects of angiotensin II type 1 (AT(1)) receptor blockers beyond AT(1) receptor blockade have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2). We examined the possible synergistic effects of the combination of irbesartan with rosuvastatin on preventing vascular remodeling focusing on the MCP-1/CCR2 pathway. We observed that administration of irbesartan and CCR2 antagonist, propagermanium, at noneffective doses, decreased the neointima with a decrease in PCNA labeling index in the injured mouse femoral artery induced by cuff placement. We also observed that administration of a noneffective dose of rosuvastatin with propagermanium decreased the neointima area, suggesting that the inhibitory effect of rosuvastatin on neointima formation is at least partly attributable to blockade of the MCP-1/CCR2 pathway. Moreover, we demonstrated that the combination of irbesartan with rosuvastatin decreased neointima formation. MCP-1 mRNA level was significantly increased in injured femoral arteries, and administration of irbesartan with rosuvastatin decreased the mRNA levels of MCP-1, TNFalpha, and IL-1beta, and increased PPARgamma mRNA expression. These results suggest that the synergistic inhibitory effects of irbesartan with rosuvastatin on neointima formation may involve attenuation of MCP-1/CCR2 signaling. PMID- 23107894 TI - Differences in mean and variability of heart rate and ambulatory rate-pressure product when valsartan or carvedilol is added to lisinopril. AB - Guidelines recommend combining beta-blockers and angiotensin-converting enzyme (ACE) inhibitors in high-risk heart disease but not in the initial treatment of hypertension. The mechanism of this benefit has not been determined. After 3 weeks of lisinopril (L, 40 mg/day) run-in, 30 subjects entered a single-blinded, forced-titration, crossover study in which carvedilol (C, 20 then 40 mg/day) or a control renin-angiotensin blocker, valsartan (V, 160 then 320 mg/day) were added to L. Ambulatory blood pressure (ABP) and heart rate monitoring was performed at the end of each period. Rate-pressure product (RPP, systolic BP * heart rate, an indicator of cardiac oxygen consumption) was measured over 24 hours, daytime (6 am to midnight), and nighttime (midnight to 6 am) periods. Variability (standard deviation and range) of RPP, BP, and heart rate was also investigated. After 4 weeks, mean 24-hour systolic BP was about 8 mm Hg lower when either V or C was added to L (P < .01 each). Heart rate was consistently lower with C (8 beats/min over 24 hours, P < .000) but was slightly increased with V (about 2 beats/min, P = NS). Consequently, C lowered RPP to a greater degree than V over 24 hours (about 8% vs. 2%, P < .000) and during daytime and nighttime periods (P < .000 each). In addition, RPP variability (SD but not range) was consistently lower on C than V. When added to L, C reduces the mean and variability (SD) of 24-hour heart rate and cardiac workload to a greater degree than valsartan. These effects may contribute to the outcome benefits observed with beta-blocker-ACE inhibitor combinations. PMID- 23107895 TI - Human renalase: a review of its biology, function, and implications for hypertension. AB - Renalase is a novel flavoprotein, highly expressed in kidney and heart, which metabolizes catecholamines and catecholamine-like substances via a superoxide (O2(-))-dependent mechanism using nicotinamide adenine dinucleotide (NADH) as a cofactor. Its mechanism of action is distinct from that of monoaminooxidases A and B, because it oxidizes catecholamines (epinephrine>>L-DOPA>dopamine = norepinephrine) to aminochrome, and the reaction rate increases ~4- to 6-fold in presence of NADH. Tissue and plasma renalase levels are decreased in animal models of chronic kidney disease, and renalase deficiency is associated with increased blood pressure and elevated circulating catecholamines. Renalase plasma levels, measured by enzyme-linked immunosorbent assay, are reported to be ~ 5 fold higher in patients with end-stage renal disease than in normal control subjects. They were also increased in kidney and heart transplant recipients, and inversely correlated with estimated glomerular filtration rate. Renalase has potential therapeutic applications. Experimental models demonstrate that the chronic administration of renalase decreases ambulatory blood pressure and prevents the development of cardiac hypertrophy in rats, and that its acute administration decreases ischemic acute kidney injury in mice. Here we provide a detailed review of renalase biology including its mechanism of action, secretion into blood, interaction with the renal dopamine and epinephrine system, and early studies evaluating its association with outcomes related to hypertension and target-organ injury. PMID- 23107896 TI - Urinary arginine methylation index associated with ambulatory blood pressure abnormalities in children with chronic kidney disease. AB - Arginine (ARG) metabolites are interrelated and are involved in chronic kidney disease (CKD) and cardiovascular disease. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) appears to correlate with cardiovascular outcomes. We investigated the relationship between ARG metabolites, and their combined ratios in urine, and the ABPM profiles of children and adolescents with CKD. This cross sectional study included 45 children and adolescents (age, 5-18 years) with stage 1 to 4 CKD. Each child underwent office blood pressure (BP) measurements, 24-hour ABPM, and urinary ARG metabolite determinations. Seventy percent of children with CKD had abnormal 24-hour ABPM profiles, including nocturnal hypertension, increased BP load, and nondipping nocturnal BP. The urinary ARG-to-asymmetric dimethylarginine (ADMA) ratio was lower, and the ADMA-to-symmetric dimethylarginine (SDMA) ratio was higher in children with advanced CKD (stages 2 4) than those with stage 1 CKD. CKD patients with BP abnormalities also had reduced urinary ARG and dimethylamine (DMA) levels. The higher urinary (ADMA+SDMA)-to-ARG ratios were correlated to ABPM abnormalities, including increased systolic BP load and non-dipping nocturnal BP. ABPM abnormalities were significantly associated with a high urinary (ADMA+SDMA)-to-ARG ratio, suggesting the possible involvement of methylated ARG in the development of hypertension among children with CKD. PMID- 23107897 TI - Early development of secondary hyperparathyroidism following renal transplantation. AB - BACKGROUND: Optimal levels of intact parathyroid hormone (iPTH) in the post transplant period are not known due to insufficient data. Therefore, we aimed to describe secondary hyperparathyroidism (SHPT) in Swedish renal transplant (RT) recipients and also report events of fractures and vascular events potentially related to levels of iPTH. METHODS: Medical charts from 132 RT recipients were retrospectively reviewed. Laboratory/clinical data were obtained at regular points up to 12 months post RT. Three groups were created based on pre-RT levels of iPTH based on KDOQI recommended levels of iPTH in CKD 5. RESULTS: One year post RT 69% had iPTH above levels recommended by KDOQI. A multiple regression analysis showed a strong relation between pre-transplant iPTH levels and iPTH levels at 12 months (beta coefficient = 0.323, p < 0.001). Patients with low pre transplant levels of iPTH had a higher rate of fractures during follow up compared to patients with higher pre-transplant levels of iPTH (P = 0.034) [corrected]. CONCLUSION: SHPT is common in Swedish RT recipients. Pre-transplant regulation of SHPT is of great importance to determine outcome post RT. Low levels of iPTH in the pre-transplant period could be associated with a high risk of fracture in the first post-transplant year. PMID- 23107898 TI - Resting energy expenditure in normal-weight and overweight/obese subjects was similar despite elevated sympathovagal balance. AB - OBJECTIVE: Alterations in the autonomic nervous system (ANS) may cause impairment in the metabolic processes that can lead to weight gain. The purpose of this study was to determine the difference between the resting energy expenditure (REE) and the resting ANS activity in overweight/obese and normal-weight healthy subjects. METHOD: Group 1 consisted of 18 subjects with BMI > 25 kg/m2, and 20 subjects with BMI ranging from 20 to 25 kg/m2 formed group 2. Measurements of low frequency (LF) and high-frequency (HF) power components expressed in normalized units (LFnu, HFnu) and LF/HF ratio were assessed for analysis of heart rate variability, and simultaneously REE measurement was performed. RESULTS: The mean LFnu (27.2% increased) and the LF/HF were higher and the mean HFnu was lower (29.9% decreased) in group 1 than in group 2 (p < 0.01). Although a statistical difference was observed in REE between groups, REE per kilogram corrected for fat free mass (REE(FFMcorr)) was 21.47 +/- 2.92 kcal/day/kg in group 1, and 21.56 +/- 1.90 kcal/day/kg in group 2, and this difference was not statistically significant (p > 0.05). CONCLUSION: We concluded that REE(FFMcorr) in overweight/obese and normal-weight subjects were similar despite elevated sympathovagal balance in overweight/obese individuals, and REE(FFMcorr) should be used to avoid misestimating the REE in obese and normal-weight subjects. PMID- 23107900 TI - Notes from the guest editor. PMID- 23107901 TI - Looking back 50 years in hospital administration. AB - Healthcare policy and hospital administration are dynamic and growing fields, oriented toward shaping the future. In an effort to understand where these fields have come from, as well as some of the re-occuring challenges faced, we conducted a retrospective analysis. Our research identified progress and major accomplishments, as well as issues that continue to challenge the field in five key areas: (1) the evolution of nursing, (2) funding and legislation, (3) hospital design, construction and technology, (4) patient care and infection control and (5) leadership. To explore these areas, a thematic content review was conducted on the 12 inaugural issues of Hospital Administration in Canada, a hospital administration periodical from 1962. All written content was reviewed, coded and categorized into major themes that represented the major hospital administration topics of 50 years ago. In this article, five prominent themes are explored and further illustrated using key stories and milestones from 1962. PMID- 23107902 TI - The more things change, the more they stay the same. AB - In "Looking Back 50 Years in Hospital Administration," Graham and Sibbald identify five principal themes in the 1962 issues of Hospital Administration in Canada: the evolution of nursing, funding and legislation, hospital design, patient care and infection control and leadership. These themes are of course consistent with thematic concerns regarding healthcare in 2012; in some ways, this consistency over 50 years is disappointing, but not surprising. This commentary examines some of the specific themes. PMID- 23107903 TI - 50 years of physical growth and impressive technological advances unmatched by health human resources reform and cultural change. AB - The year 1962 was pre-medicare. The public was concerned about access and individual affordability of care. Funding involved public or private responsibility and the role of government. Physicians, the most influential providers, were concerned that government funding would result in the loss of their independence and their becoming state employees. The retrospective analysis "Looking Back 50 Years in Hospital Administration" by Graham and Sibbald is arresting as it underlines just how much progress we have made in what could be termed "hardware" in support of healthcare policy and hospital administration. From this perspective, the progress has been eye opening, given the advent of universal healthcare, the advancement in our physical facilities, the development of high-quality diagnostic equipment, the explosion of new research centres and new and complex clinical procedures. The development of this hardware has given our providers better weapons and contributed to a remarkable improvement in life expectancy. But progress in health administration and policy management involves more than hardware. If the hardware constitutes the tools, then the "software" of the healthcare system involves the human resources and the culture change that must be positioned to make maximum use of the hardware. In 2062, looking back at the 2012 experience, the legacy test may be whether we dealt with health human resources and culture change at a rate that matched our progress in hardware. PMID- 23107904 TI - Nursing: not the problem, but leading solutions. AB - One of the major themes uncovered by Graham and Sibbald in their analysis of the 50-year-old issues of Hospital Administration in Canada (HAC) is the evolution of nursing. However, the HAC approach 50 years ago was that nursing was a problem to be solved, not a resource for health, the health system and the public, and that image would stay with nursing in Canada for many years to come. The recent commissioning by the Canadian Nurses Association of a National Expert Commission to examine sustainability of health and the healthcare system, and the resultant report, The Health of Our Nation, the Future of Our Health System: A Nursing Call to Action, released in June 2012, reflect a significantly different expectation about nurses and the nursing profession - they are not problems to be addressed, but are leading the solutions to better health, better care and better value. And patients are not passive recipients of care decided on by professionals alone, but central team members - "CEOs of their own healthcare" - in an inter professional patient-/family-focused team that collectively supports people in their health journey. A number of examples of potential articles about and from nursing, based on the findings of the National Expert Commission, are included to illustrate how nursing should be reflected in an issue of HAC in 2012. PMID- 23107905 TI - Fifty years of infection control and healthcare design. AB - The examination of 1962 perspectives on healthcare provided by Ross Graham and Shannon Sibbald in their article "Looking Back 50 Years in Hospital Administration" provides an opportunity to see not only what happened 50 years ago, but how modern attitudes and concerns both match and differ from those of the past. Focusing on infection prevention and hospital design, this commentary explores the changes in procedure, policy and attitudes since 1962, and how they are affecting healthcare today. PMID- 23107906 TI - Thoughts on "looking back on 50 years in hospital administration" from the perspectives of quality and safety. AB - The healthcare landscape has changed considerably over the past 50 years, with far greater emphasis on the quality of care. Although much progress has been made, there are many opportunities to improve quality and safety of care across Canada. The new Saskatchewan healthcare management system represents one whole system approach to achieving better health, better care, better value and better teams, using a Lean-based approach that reflects the dominant issues identified 50 years ago. PMID- 23107907 TI - Reflections on leadership in healthcare: the past 50 years. AB - Leadership in the hospital sector has been characterized by a state of change since the early 1960s. Heavily influenced by the emergence of the principles of the Canadian health system, leadership at the time was shaped in many ways by the post-World War II construction boom. It was significantly impacted by the developing professional unions in the clinical professions and the resultant and conflicted labour relations of the 60s and 70s. The environment of leadership was in those days predominantely a transactional style, and was frequently confrontational. But the many leaders of Canada's hospitals were also characterized by a caring cadre of often-colourful personalities who challenged, debated and strove to ensure adequate funding and a harmony among the diverse clinical, community and political interests confronting their organizations. The major restructuring of an ever-more expensive health system has set the stage for substantial innovation and reform as the leaders in the system integrate new technologies, personalized pharmaceuticals, devolving scopes of practice and entrepreneurial opportunities related to incentive funding. The development of leadership competencies such as the Leaders for Life framework across the health workforce will be essential to successfully guide our health delivery system into the future. PMID- 23107908 TI - On leadership and leaders. AB - Leadership is the vital ingredient to achieving organizational excellence and outstanding healthcare systems. There is so much to be celebrated when reflecting on the evolution of healthcare leadership over the past 50 years. However, in 50 years, we have created silos of care, of funding and of social policy that have undermined our progress in improving the care process, shifting away from health and toward healthcare, and we have lost the opportunity to promote streamlined care through the continuum of health needs. Exemplary healthcare leaders of tomorrow will need sophisticated business skills, balanced with the capacity to inspire innovation, in order to manage an ever-growing complex environment. PMID- 23107909 TI - Laparoscopic liver resection for hepatocellular carcinoma: a three-year study of 57 Patients. AB - BACKGROUND/AIMS: Laparoscopic liver resection has become an increasingly popular operation but is still in relatively limited use. Here we evaluate the intermediate-term results of laparoscopic liver resection. METHODOLOGY: Fifty seven patients with HCC underwent laparoscopic liver resection at the Asan Medical Center. Data for all resections were recorded and analyzed retrospectively. Patient gender, age, preoperative laboratory data, presence of cirrhosis, blood loss, hospital stay length, pathology report, tumor site and size, resection type, resection margin, morbidity and mortality were assessed. RESULTS: The mean patient age ranged from 35-74 years and the mean tumor size from 0.8-5.5 cm. Tumors were located in the left lateral lobe, left medial lobe and right lobe. Left lateral sectionectomy was performed in 32 cases, partial hepatectomy in 11, left hepatectomy in 6, right hepatectomy in 2, laparoscopy assisted right hepatectomy in 2 and laparoscopy-assisted right posterior sectionectomy in 4. Median operation time ranged from 95-380 min while median blood loss ranged from 150-800 mL. The mean resection margin was 2.08+/-1.68 cm with no in-hospital mortalities. Return to normal diet was achieved on average at 1.83+/-0.8 days; mean hospital stay ranged from 3 to 17 days. The 3-year overall and disease-free survival rates were 81% and 71%, respectively. CONCLUSIONS: Laparoscopic liver resection for HCC is feasible, safe and promising for a select group of patients. Its benefits include short hospital stays, rapid return to normal diet, full mobility and minimal morbidity with acceptable oncological parameters. PMID- 23107910 TI - Factor X inhibitor: a fulminant presentation and fatal course of a rare syndrome in a 59-year-old male. AB - Factor X inhibitors are rare. The few cases documented in the literature have occurred after viral prodromes, in association with cancer, or after exposure to antibiotics. Acquired factor X deficiencies are also rare and their etiology is largely unknown. We report a new case of a factor X inhibitor and review prior cases of both factor X inhibitors and non-amyloidosis-related acquired factor X deficiencies. PMID- 23107911 TI - Muscle activation history at different vertical jumps and its influence on vertical velocity. AB - In the present study we investigated displacement, time, velocity and acceleration history of center of mass (COM) and electrical activity of knee extensors to estimate the dominance of the factors influencing the vertical velocity in squat jumps (SJs), countermovement jumps (CMJs) and drop jumps (DJs) performed with small (40 degrees ) and large (80 degrees ) range of joint motion (SROM and LROM). The maximum vertical velocity (v4) was 23.4% (CMJ) and 7.8% (DJ) greater when the jumps were performed with LROM compared with SROM (p < 0.05). These differences are considerably less than it could be expected from the greater COM and knee angular displacement and duration of active state. This small difference can be attributed to the greater deceleration during eccentric phase (CMJ:32.1%, DJ:91.5%) in SROM than that in LROM. v4 was greater for SJ in LROM than for SJ in SROM indicating the significance of the longer active state and greater activation level (p < 0.001). The difference in v4 was greater between SJ and CMJ in SROM (38.6%) than in LROM (9.0%), suggesting that elastic energy storage and re-use can be a dominant factor in the enhancement of vertical velocity of CMJ and DJ compared with SJ performed with SROM. PMID- 23107912 TI - von Hippel-Lindau disease-associated solid microcystic serous adenomas masquerading as pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Patients with von Hippel-Lindau disease (VHL) commonly develop pancreatic cysts and neuroendocrine neoplasms (PNENs or PNETs). Solid microcystic serous adenoma (SMSA), a rare neoplasm described in VHL patients, can be mistaken for PNEN on imaging. METHODS: Clinical, pathologic, and radiologic data were reviewed on VHL patients who underwent surgery for a preoperative diagnosis of PNEN since 1994 at 1 institution. Blinded to the pathologic diagnoses, radiologists reassessed available imaging. RESULTS: For 55 patients, 79 pancreatectomies were performed for presumed PNENs. Ten (18%) patients underwent 12 (15%) resections for neoplasms diagnosed as SMSA on final pathology. The average size of a SMSA leading to operation was 3.6 +/- 0.4 cm. Four out of 11 SMSAs were still mistaken for PNENs when imaging was reassessed. The mean FDG positron emission tomography (PET) standardized uptake value was greater for 17 PNENs (12.1 +/- 1.2) compared with 6 SMSAs (4.2 +/- 0.5; P = .002). The mean doubling time of SMSAs and PNENs was similar. Seven (15%) patients with pathologically proven PNENs had malignant disease. CONCLUSION: SMSAs can mimic PNENs on nonfunctional imaging; FDG-PET may help to differentiate them. A high index of suspicion is needed to minimize operations performed for SMSA and to counsel VHL patients of their risks of undergoing operation for a lesion with no known malignant potential. PMID- 23107913 TI - Interactive relations of blood pressure and age to subclinical cerebrovascular disease. AB - OBJECTIVE: To examine interactive relations of blood pressure (BP) and age to MRI indices of subclinical cerebrovascular disease in middle-aged to older adults. METHODS: One hundred and thirteen stroke-free and dementia-free, community dwelling adults (ages 54-81 years; 65% men; 91% white) engaged in (1) clinical assessment of resting SBP and DBP; (2) MRI rated for periventricular white matter hyperintensities (WMH) and deep WMH silent brain infarction (SBI) and brain atrophy (i.e. ventricular enlargement and sulcal widening ). Principal components analysis of the MRI ratings yielded a two-component solution--(1) periventricular and deep WMH SBI; and (2) ventricular enlargement, sulcal widening. RESULTS: Relations of SBP, DBP and pulse pressure (PP) (and their interactions with age) to each MRI component were examined in multiple regression analyses adjusted for age, sex, fasting plasma glucose and cholesterol, and antihypertensives. For component 1, results indicated significant interactions of SBP and PP with age (P < 0.05); higher levels of SBP and PP were associated with greater white matter disease and brain infarction at younger ages (<= 68 years). Significant interactions of SBP and DBP with age were also noted for component 2 (P < 0.05); higher levels of BP were associated with greater brain atrophy at younger ages (<= 63 years). CONCLUSION: : Higher BP and PP are associated with greater subclinical cerebrovascular disease most prominently in the 'young old'. Appropriate management of hypertension and arterial stiffening may be critical to the preservation of brain structure with ageing. PMID- 23107914 TI - Association of elevated plasma aldosterone-to-renin ratio with future cardiovascular events in patients with essential hypertension. AB - BACKGROUND: We investigated the relationship between the renin/aldosterone profiles of patients with essential hypertension and their prognosis using a long term follow-up study design. METHODS: The cohort consisted of 125 Japanese patients with essential hypertension whose plasma-renin activity (PRA) (ng/ml per h), plasma-aldosterone concentration (PAC) (ng/dl), and ratio of PAC to PRA [aldosterone-renin ratio (ARR)] were determined under hospitalization from 1984 to 1993. The patients were divided into two groups according to their ARRs relative to the 50th percentile of the ARR value (ARR = 5.5); the low-ARR group (ARR <5.5, n = 66) and high-ARR group (ARR > 5.5, n = 59). Their clinical outcomes were monitored during follow-up by the attending physicians. RESULTS: Ninety-six patients with essential hypertension (77% of the original cohort) were eligible for the analyses. The mean follow-up time was 18.6 +/- 5.2 years. The cardiovascular morbidity was significantly higher in the high-ARR group than in the low-ARR group 3.2 vs. 2.4 per 100 patient-years, respectively (P = 0.014 by Kaplan-Meier analysis). Among the cardiovascular events, the incidence of stroke was 2.7-fold higher in the high-ARR group than in the low-ARR group. High ARR was an independent risk marker for cardiovascular events by Cox proportional hazards model analysis. CONCLUSION: : High ARR was an independent risk marker for cardiovascular events in patients with essential hypertension. PMID- 23107916 TI - Rapidity and quality of response to steroid-based induction therapy, without the addition of novel agents, does not affect post transplant outcomes in multiple myeloma. AB - BACKGROUND: The goal of induction in younger MM patients is to improve performance status and symptoms, enabling autologous stem cell transplantation (ASCT). It is unclear whether intensification of induction regimens improves post transplant outcomes. PATIENTS AND METHODS: We studied 178 MM patients who received conservative steroid-based induction therapy without novel agents before ASCT between 2000 and 2006 and correlated induction parameters (rapidity of response, need for salvage induction therapy, depth of response) with transplant outcomes. RESULTS: Fifty-three percent of patients achieved at least a partial response by cycle 2 (early responders). Rapidity of induction response did not translate into a significant difference in post transplant progression-free survival (PFS) (20.7 vs. 20.0 months; P = .24) or overall survival (OS) (64.4 vs. 51.3 months, respectively; P = .13). In 41 patients (23%) the first induction regimen failed, but they responded to salvage and proceeded to ASCT. They had inferior PFS (15.6 vs. 21.8 months; P = .008) and OS (43.5 vs. 69.4 months; P = .0004) post transplant compared with those requiring 1 regimen. CONCLUSION: Rapid response to induction therapy does not correlate with PFS or OS post ASCT when using a conservative steroid-based induction regimen. Patients in whom this initial induction fails have worse post transplant outcomes, thus the upfront use of intensive therapies with novel agents should be considered. PMID- 23107915 TI - Intensive induction chemotherapy followed by early high-dose therapy and hematopoietic stem cell transplantation results in improved outcome for patients with hepatosplenic T-cell lymphoma: a single institution experience. AB - INTRODUCTION: Hepatosplenic T-cell lymphoma is a rare form of extranodal non Hodgkin lymphoma, first recognized as a distinct entity in the Revised European American Lymphoma classification. Typical presentation includes lymphomatous infiltration of spleen and liver, and peripheral lymphadenopathy is rarely seen. The prognosis is almost uniformly poor, and there are no prospective studies of treatment of HSTCL. PATIENTS AND METHODS: For this report, we conducted a retrospective review of all pts who underwent treatment for HSTCL at our institution. Individual chart review was performed to report clinical presentation, management, and outcome. RESULTS: We identified 14 pts with HSTCL managed at our center, 7 of which remain alive with median follow-up of 65.6 months. Six of 7 received alternative induction chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide) or IVAC (ifosfamide, etoposide, high-dose cytarabine) as opposed to CHOP and all surviving pts had proceeded to undergo either autologous or allogeneic SCT. CONCLUSION: Our results suggest that use of non-CHOP induction regimen and early use of high dose therapy and SCT consolidation may translate to improved survival for pts with HSTCL. PMID- 23107917 TI - Advances in genetics and molecular breeding of three legume crops of semi-arid tropics using next-generation sequencing and high-throughput genotyping technologies. AB - Molecular markers are the most powerful genomic tools to increase the efficiency and precision of breeding practices for crop improvement. Progress in the development of genomic resources in the leading legume crops of the semi-arid tropics (SAT), namely, chickpea (Cicer arietinum), pigeonpea (Cajanus cajan) and groundnut (Arachis hypogaea), as compared to other crop species like cereals, has been very slow. With the advances in next-generation sequencing (NGS) and high throughput (HTP) genotyping methods, there is a shift in development of genomic resources including molecular markers in these crops. For instance, 2,000 to 3,000 novel simple sequence repeats (SSR) markers have been developed each for chickpea, pigeonpea and groundnut. Based on Sanger, 454/FLX and Illumina transcript reads, transcriptome assemblies have been developed for chickpea (44,845 transcript assembly contigs, or TACs) and pigeonpea (21,434 TACs). Illumina sequencing of some parental genotypes of mapping populations has resulted in the development of 120 million reads for chickpea and 128.9 million reads for pigeonpea. Alignment of these Illumina reads with respective transcriptome assemblies have provided more than 10,000 SNPs each in chickpea and pigeonpea. A variety of SNP genotyping platforms including GoldenGate, VeraCode and Competitive Allele Specific PCR (KASPar) assays have been developed in chickpea and pigeonpea. By using above resources, the first-generation or comprehensive genetic maps have been developed in the three legume speciesmentioned above. Analysis of phenotyping data together with genotyping data has provided candidate markers for drought-tolerance-related root traits in chickpea, resistance to foliar diseases in groundnut and sterility mosaic disease (SMD) and fertility restoration in pigeonpea. Together with these traitassociated markers along with those already available, molecular breeding programmes have been initiated for enhancing drought tolerance, resistance to fusarium wilt and ascochyta blight in chickpea and resistance to foliar diseases in groundnut. These trait-associated robust markers along with other genomic resources including genetic maps and genomic resources will certainly accelerate crop improvement programmes in the SAT legumes. PMID- 23107918 TI - Large SNP arrays for genotyping in crop plants. AB - Genotyping with large numbers of molecular markers is now an indispensable tool within plant genetics and breeding. Especially through the identification of large numbers of single nucleotide polymorphism (SNP) markers using the novel high-throughput sequencing technologies, it is now possible to reliably identify many thousands of SNPs at many different loci in a given plant genome. For a number of important crop plants, SNP markers are now being used to design genotyping arrays containing thousands of markers spread over the entire genome and to analyse large numbers of samples. In this article, we discuss aspects that should be considered during the design of such large genotyping arrays and the analysis of individuals. The fact that crop plants are also often autopolyploid or allopolyploid is given due consideration. Furthermore, we outline some potential applications of large genotyping arrays including high-density genetic mapping, characterization (fingerprinting) of genetic material and breeding related aspects such as association studies and genomic selection. PMID- 23107919 TI - Application of large-scale sequencing to marker discovery in plants. AB - Advances in DNA sequencing provide tools for efficient large-scale discovery of markers for use in plants. Discovery options include large-scale amplicon sequencing, transcriptome sequencing, gene-enriched genome sequencing and whole genome sequencing. Examples of each of these approaches and their potential to generate molecular markers for specific applications have been described. Sequencing the whole genome of parents identifies all the polymorphisms available for analysis in their progeny. Sequencing PCR amplicons of sets of candidate genes from DNA bulks can be used to define the available variation in these genes that might be exploited in a population or germplasm collection. Sequencing of the transcriptomes of genotypes varying for the trait of interest may identify genes with patterns of expression that could explain the phenotypic variation. Sequencing genomic DNA enriched for genes by hybridization with probes for all or some of the known genes simplifies sequencing and analysis of differences in gene sequences between large numbers of genotypes and genes especially when working with complex genomes. Examples of application of the above-mentioned techniques have been described. PMID- 23107920 TI - Diversity in global maize germplasm: characterization and utilization. AB - Maize (Zea mays L.) is not only of worldwide importance as a food, feed and as a source of diverse industrially important products, but is also a model genetic organism with immense genetic diversity. Although it was first domesticated in Mexico, maize landraces are widely found across the continents. Several studies in Mexico and other countries highlighted the genetic variability in the maize germplasm. Applications of molecular markers, particularly in the last two decades, have led to new insights into the patterns of genetic diversity in maize globally, including landraces as well as wild relatives (especially teosintes) in Latin America, helping in tracking the migration routes of maize from the centers of origin, and understanding the fate of genetic diversity during maize domestication. The genome sequencing of B73 (a highly popular US Corn Belt inbred) and Palomero (a popcorn landrace in Mexico) in the recent years are important landmarks in maize research, with significant implications to our understanding of the maize genome organization and evolution. Next-generation sequencing and high-throughput genotyping platforms promise to further revolutionize our understanding of genetic diversity and for designing strategies to utilize the genomic information for maize improvement. However, the major limiting factor to exploit the genetic diversity in crops like maize is no longer genotyping, but high-throughput and precision phenotyping. There is an urgent need to establish a global phenotyping network for comprehensive and efficient characterization of maize germplasm for an array of target traits, particularly for biotic and abiotic stress tolerance and nutritional quality. 'Seeds of Discovery' (SeeD), a novel initiative by CIMMYT with financial support from the Mexican Government for generating international public goods, has initiated intensive exploration of phenotypic and molecular diversity of maize germplasm conserved in the CIMMYT Gene Bank; this is expected to aid in effective identification and use of novel alleles and haplotypes for maize improvement. Multi-institutional efforts are required at the global level to systematically explore the maize germplasm to diversify the genetic base of elite breeding materials, create novel varieties and counter the effects of global climate changes. PMID- 23107921 TI - Divergence of flowering genes in soybean. AB - Soybean genome sequences were blasted with Arabidopsis thaliana regulatory genes involved in photoperioddependent flowering. This approach enabled the identification of 118 genes involved in the flowering pathway. Two genome sequences of cultivated (Williams 82) and wild (IT182932) soybeans were employed to survey functional DNA variations in the flowering-related homologs. Forty genes exhibiting nonsynonymous substitutions between G. max and G. soja were catalogued. In addition, 22 genes were found to co-localize with QTLs for six traits including flowering time, first flower, pod maturity, beginning of pod, reproductive period, and seed filling period. Among the genes overlapping the QTL regions, two LHY/CCA1 genes, GI and SFR6 contained amino acid changes. The recently duplicated sequence regions of the soybean genome were used as additional criteria for the speculation of the putative function of the homologs. Two duplicated regions showed redundancy of both flowering-related genes and QTLs. ID 12398025, which contains the homeologous regions between chr 7 and chr 16, was redundant for the LHY/CCA1 and SPA1 homologs and the QTLs. Retaining of the CRY1 gene and the pod maturity QTLs were observed in the duplicated region of ID 23546507 on chr 4 and chr 6. Functional DNA variation of the LHY/CCA1 gene (Glyma07g05410) was present in a counterpart of the duplicated region on chr 7, while the gene (Glyma16g01980) present in the other portion of the duplicated region on chr 16 did not show a functional sequence change. The gene list catalogued in this study provides primary insight for understanding the regulation of flowering time and maturity in soybean. PMID- 23107922 TI - Molecular markers in management of ex situ PGR-a case study. AB - Worldwide germplasm collections contain about 7.4 million accessions of plant genetic resources for food and agriculture. One of the 10 largest ex situ genebanks of our globe is located at the Leibniz Institute of Plant Genetics and Crop Plant Research in Gatersleben, Germany. Molecular tools have been used for various gene bank management practices including characterization and utilization of the germplasm. The results on genetic integrity of longterm- stored gene bank accessions of wheat (self-pollinating) and rye (open-pollinating) cereal crops revealed a high degree of identity for wheat. In contrast, the out-pollinating accessions of rye exhibited shifts in allele frequencies. The genetic diversity of wheat and barley germplasm collected at intervals of 40 to 50 years in comparable geographical regions showed qualitative rather than a quantitative change in diversity. The inter- and intraspecific variation of seed longevity was analysed and differences were detected. Genetic studies in barley, wheat and oilseed rape revealed numerous QTL, indicating the complex and quantitative nature of seed longevity. Some of the loci identified were in genomic regions that co-localize with genes determining agronomic traits such as spike architecture or biotic and abiotic stress response. Finally, a genome-wide association mapping analysis of a core collection of wheat for flowering time was performed using diversity array technology (DArT) markers. Maker trait associations were detected in genomic regions where major genes or QTL have been described earlier. In addition, new loci were also detected, providing opportunities to monitor genetic variation for crop improvement. PMID- 23107923 TI - Genetic mapping and coccidial parasites: past achievements and future prospects. AB - Coccidial parasites including Cryptosporidium parvum, Cyclospora cayetanensis, Neospora caninum, Toxoplasma gondii and the Eimeria species can cause severe disease of medical and veterinary importance. As many as one-third of the human population may carry T. gondii infection, and Eimeria are thought to cost the global poultry production industry in excess of US$2 billion per annum. Despite their significance, effective vaccines are scarce and have been confined to the veterinary field. As sequencing and genotyping technologies continue to develop, genetic mapping remains a valuable tool for the identification of genes that underlie phenotypic traits of interest and the assembly of contiguous genome sequences. For the coccidian, cross-fertilization still requires in vivo infection, a feature of their life cycle which limits the use of genetic mapping strategies. Importantly, the development of population-based approaches has now removed the need to isolate clonal lines for genetic mapping of selectable traits, complementing the classical clone-based techniques. To date, four coccidial species, representing three genera, have been investigated using genetic mapping. In this review we will discuss recent progress with these species and examine the prospects for future initiatives. PMID- 23107924 TI - Molecular-based rapid inventories of sympatric diversity: a comparison of DNA barcode clustering methods applied to geography-based vs clade-based sampling of amphibians. AB - Molecular markers offer a universal source of data for quantifying biodiversity. DNA barcoding uses a standardized genetic marker and a curated reference database to identify known species and to reveal cryptic diversity within wellsampled clades. Rapid biological inventories, e.g. rapid assessment programs (RAPs), unlike most barcoding campaigns, are focused on particular geographic localities rather than on clades. Because of the potentially sparse phylogenetic sampling, the addition of DNA barcoding to RAPs may present a greater challenge for the identification of named species or for revealing cryptic diversity. In this article we evaluate the use of DNA barcoding for quantifying lineage diversity within a single sampling site as compared to clade-based sampling, and present examples from amphibians. We compared algorithms for identifying DNA barcode clusters (e.g. species, cryptic species or Evolutionary Significant Units) using previously published DNA barcode data obtained from geography-based sampling at a site in Central Panama, and from clade-based sampling in Madagascar. We found that clustering algorithms based on genetic distance performed similarly on sympatric as well as clade-based barcode data, while a promising coalescent-based method performed poorly on sympatric data. The various clustering algorithms were also compared in terms of speed and software implementation. Although each method has its shortcomings in certain contexts, we recommend the use of the ABGD method, which not only performs fairly well under either sampling method, but does so in a few seconds and with a user-friendly Web interface. PMID- 23107925 TI - Exploring the correlations between sequence evolution rate and phenotypic divergence across the Mammalian tree provides insights into adaptive evolution. AB - Sequence evolution behaves in a relatively consistent manner, leading to one of the fundamental paradigms in biology, the existence of a 'molecular clock'. The molecular clock can be distilled to the concept of accumulation of substitutions, through time yielding a stable rate from which we can estimate lineage divergence. Over the last 50 years, evolutionary biologists have obtained an in depth understanding of this clock's nuances. It has been fine-tuned by taking into account the vast heterogeneity in rates across lineages and genes, leading to 'relaxed' molecular clock methods for timetree reconstruction. Sequence rate varies with life history traits including body size, generation time and metabolic rate, and we review recent studies on this topic. However, few studies have explicitly examined correlates between molecular evolution and morphological evolution. The patterns observed across diverse lineages suggest that rates of molecular and morphological evolution are largely decoupled. We discuss how identifying the molecular mechanisms behind rapid functional radiations are central to understanding evolution. The vast functional divergence within mammalian lineages that have relatively 'slow' sequence evolution refutes the hypotheses that pulses in diversification yielding major phenotypic change are the result of steady accumulation of substitutions. Patterns rather suggest phenotypic divergence is likely caused by regulatory alterations mediated through mechanisms such as insertions/deletions in functional regions. These can rapidly arise and sweep to fixation faster than predicted from a lineage's sequence neutral substitution rate, enabling species to leapfrog between phenotypic 'islands'. We suggest research directions that could illuminate mechanisms behind the functional diversity we see today. PMID- 23107926 TI - Complex genetic origin of Indian populations and its implications. AB - Indian populations are classified into various caste, tribe and religious groups, which altogether makes them very unique compared to rest of the world. The long term firm socio-religious boundaries and the strict endogamy practices along with the evolutionary forces have further supplemented the existing high-level diversity. As a result, drawing definite conclusions on its overall origin, affinity, health and disease conditions become even more sophisticated than was thought earlier. In spite of these challenges, researchers have undertaken tireless and extensive investigations using various genetic markers to estimate genetic variation and its implication in health and diseases. We have demonstrated that the Indian populations are the descendents of the very first modern humans, who ventured the journey of out-of-Africa about 65,000 years ago. The recent gene flow from east and west Eurasia is also evident. Thus, this review attempts to summarize the unique genetic variation among Indian populations as evident from our extensive study among approximately 20,000 samples across India. PMID- 23107927 TI - A transgenic Plasmodium falciparum NF54 strain that expresses GFP-luciferase throughout the parasite life cycle. AB - Plasmodium falciparum is the pathogenic agent of the most lethal of human malarias. Transgenic P. falciparum parasites expressing luciferase have been created to study drug interventions of both asexual and sexual blood stages but luciferase-expressing mosquito stage and liver stage parasites have not been created which has prevented the easy quantification of mosquito stage development (e.g. for transmission blocking interventions) and liver stage development (for interventions that prevent infection). To overcome this obstacle, we have created a transgenic P. falciparum NF54 parasite that expresses a GFP-luciferase transgene throughout the life cycle. Luciferase expression is robust and measurable at all life cycle stages, including midgut oocyst, salivary gland sporozoites and liver stages, where in vivo development is easily measurable using humanized mouse infections in conjunction with an in vivo imaging system. This parasite reporter strain will accelerate testing of interventions against pre-erythrocytic life cycle stages. PMID- 23107928 TI - Influence of parental overweight on the association of birth weight and fat distribution later in childhood. AB - OBJECTIVE: To examine whether the association between birth weight and fat distribution in childhood is modified by parental overweight. METHODS: Cross sectional study of 728 Danish children aged 8-10 and 14-16 years. The main outcomes were waist circumference, waist-to-height ratio, subscapular skinfold, and subscapular-to-triceps skinfold ratio. Analyses were stratified by parental overweight status (none vs. >=1 overweight parent) for each dependent variable, expressed as z-scores. RESULTS: Birth weight z-score was negatively associated with waist circumference (beta -0.08 SD; 95% CI -0.15, -0.02), waist-to-height ratio (beta -0.15 SD; 95% CI -0.22, -0.07), and subscapular-to-triceps ratio (beta -0.28 SD; 95% CI -0.44, -0.12) after adjustment for sex, age, puberty, preterm birth, BMI, height, socio-economic status, mother's age at delivery, parity, breastfeeding, energy intake, and aerobic fitness in the group with >=1 overweight parent. Birth weight was negatively associated with subscapular skinfold in groups with (beta -0.16 SD; 95% CI -0.24, -0.06) and without overweight parents (beta -0.09 SD; 95% CI -0.16, -0.02), but the magnitude of the association was greater in the former group. CONCLUSION: The association between birth weight and fat distribution seems to be influenced by parental overweight. Lower birth weights are associated with central adiposity among offspring of overweight parents. PMID- 23107929 TI - The impact of antibody selection on the detection of cardiac troponin I. AB - BACKGROUND: Cardiac troponin I (cTnI) is the current standard biomarker for diagnosing acute myocardial infarction and for risk-stratification of acute coronary syndromes in patients. However, it remains unclear how the epitope specificity of antibodies in immunoassays influences the detection of various modified forms of cTnI. METHODS: Four mouse anti-human cTnI monoclonal antibodies targeting different regions of human cTnI were chosen for immunoaffinity purification of cTnI from human and swine cardiac tissue. High-resolution intact protein mass spectrometry was employed to assess the comparative performance of these four antibodies in detecting modified forms of cTnI. RESULTS: Our data revealed that antibody selection significantly impacts the relative protein yield of cTn from immunoaffinity purification. Remarkably, a single amino acid variation in cTnI (G->S) in the epitope region completely abolished the binding between monoclonal antibody 560 and swine cTnI in solution. Moreover, proteolytic degradation around the epitope region severely compromised the detection of proteolytic fragment forms of cTnI by monoclonal antibodies. In contrast, the phosphorylation status near the epitope region did not significantly affect the antibody recognition of cTnI. CONCLUSION: Caution needs to be taken in the interpretation of the data produced by immuno-assays with monoclonal antibodies against various epitopes of cTnI. PMID- 23107931 TI - Factors associated with use of automated smoking cessation interventions: findings from the eQuit study. AB - The aim was to better understand structural factors associated with uptake of automated tailored interventions for smoking cessation. In a prospective randomized controlled trial with interventions only offered, not mandated, participants were randomized based on the following: web-based expert system (QuitCoach); text messaging program (onQ); both as an integrated package; the choice of using either or both; or a control condition informed of a static website (not considered here). Participants were 3530 smokers or recent quitters recruited from two sources; those seeking smoking cessation information, mostly recruited over the phone, and a cold-contacted group recruited from an Internet panel. More participants (60.1%) initially accepted the intervention they had been offered than used it (42.5%). Uptake of each intervention differed substantially by both recruitment source and modality (phone or web). onQ was a little more popular overall, especially in the information seeker sample. Highest overall intervention uptake occurred in the choice condition. A web-based intervention is most attractive if the offer to use is made by web, whereas a phone-based intervention is more likely to be used if the offer is made over the phone. Providing automated interventions on multiple platforms allows for maximal choice and greatest overall use of some form of help. PMID- 23107932 TI - Is school community readiness related to physical activity before and after the Ready for Recess intervention? AB - The purpose of this study was to determine: (i) the effect of schools' baseline community readiness (CR) on youth physical activity (PA) at recess prior to the Ready for Recess intervention; (ii) if changes in PA due to the intervention were explained by baseline CR and (iii) if specific components of the intervention altered an association between baseline CR and changes in youth PA. Methods that were employed included: six informants from each of 17 schools participated in CR interviews at baseline (N = 101). CR scores were calculated based on the CR model's nine stages. Direct observation was used to measure PA. Poisson models evaluated the association between baseline CR and PA. Results were that seven schools were in denial, eight in vague awareness and two in pre-planning stages. CR marginally predicted pre-intervention PA. When compared with youth at schools in denial, youth at schools in vague awareness and pre-planning demonstrated significant increases in moderate/vigorous PA. Ready for Recess strengthened this association. This is the first study to demonstrate that school CR may explain changes in PA at recess after a school-based PA intervention. Low CR levels may contraindicate interventions. Efforts to increase school CR a priori may be critical to increasing PA among youth. PMID- 23107930 TI - Carotid plaque, carotid intima-media thickness, and coronary calcification equally discriminate prevalent cardiovascular disease in kidney disease. AB - BACKGROUND: Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease (CKD) population. We examined the discriminative ability of noninvasive measures of atherosclerosis, including carotid intima media thickness (cIMT), carotid plaque, coronary artery calcification (CAC) and ascending and descending thoracic aorta calcification (TCAC), and Framingham risk score (FRS) to predict self-reported prevalent CVD. METHODS AND RESULTS: Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort (CRIC) study and also had all of the above measures within an 18-month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n = 220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate >=60, 45-59, 30-44, and <30 ml/min/1.73 m(2) was 21, 41, 28, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (C-statistic 0.70, 95% CI: 0.62-0.78; C-statistic 0.68, 95% CI: 0.60-0.75, and C-statistic 0.64, CI: 0.56-0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self reported prevalent CVD (C-statistic 0.58). CONCLUSIONS: There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD. PMID- 23107933 TI - More on the Liang Bua finds and modern human cretins. AB - Brown (2012: LB1 and LB6 Homo floresiensis are not modern human (Homo sapiens) cretins, Journal of Human Evolution) makes errors of fact, omission and interpretation. Brown's comments refer, among others, to (1) delayed growth and development indicated by unfused epiphyses, (2) postcranial limb proportions: limbs to trunk, between limbs, and within limbs, (3) postcranial bone torsions and angles, (4) postcranial robusticity, real and apparent, (5) skull features, and (6) cretinism on Flores. In each of these areas, much information about cretins is incorrect and much information (Oxnard et al., 2010) comparing the Liang Bua remains with cretins is ignored. PMID- 23107934 TI - Molybdate templated assembly of Ln12Mo4-type clusters (Ln = Sm, Eu, Gd) containing a truncated tetrahedron core. AB - Three heterometallic cluster complexes {Ln(12)Mo(4)} featuring an Ln(12) core of a distorted truncated tetrahedron were synthesized with the assistance of four MoO(4)(2-) anions as ancillary ligands. Magnetic studies of the {Gd(12)Mo(4)} cluster revealed a large magnetocaloric effect due to the presence of the large number of weakly coupled Gd(III) ions. PMID- 23107935 TI - Carbon dioxide (CO2) ablation as a remedy for hepatocellular carcinoma. AB - BACKGROUND/AIMS: The purpose of this research was to investigate the application of carbon dioxide (CO2) ablation and determine if carbon dioxide plays a role in treating hepatocellular carcinoma. METHODOLOGY: Twelve mice with subcutaneous xenografts of a hepatocellular cancer cell line were randomly separated into 2 groups. One group underwent CO2 ablation with their liver tumor in vivo while the other group in vitro, respectively. All mice were killed on day 28. Hematoxylin eosin (HE) staining was performed on the mice to estimate the pathological change. RESULTS: Just after 4 weeks, no significant difference in tumor size was detected between the two groups. The dimensions of the principal tumor varied from 2-3 cm with an average size of 2.2 cm in the greatest dimension. HE staining demonstrated an array of construct damage and necrosis in both groups. CONCLUSIONS: CO2 ablation could be an important treatment in the management of cancer. PMID- 23107936 TI - Why be nice? Better not think about it. AB - Are people more likely to be cooperative if they must act quickly or if they have more time to mull it over? The results of a recent series of studies suggest that peoples' initial impulse is to cooperate, but that with more time and reflection they become more selfish. PMID- 23107937 TI - Examination of fluorination effect on physical properties of saturated long-chain alcohols by DSC and Langmuir monolayer. AB - Partially fluorinated long-chain alcohols have been newly synthesized from a radical reaction, which is followed by a reductive reaction. The fluorinated alcohols have been investigated by differential scanning calorimetry (DSC) and compression isotherms in a Langmuir monolayer state. Their melting points increase with an increase in chain length due to elongation of methylene groups. However, the melting points for the alcohols containing shorter fluorinated moieties are lower than those for the typical hydrogenated fatty alcohols. Using the Langmuir monolayer technique, surface pressure (pi)-molecular area (A) and surface potential (DeltaV)-A isotherms of monolayers of the fluorinated alcohols have been measured in the temperature range from 281.2 to 303.2K. In addition, a compressibility modulus (Cs(-1)) is calculated from the pi-A isotherms. Four kinds of the alcohol monolayers show a phase transition (pi(eq)) from a disordered to an ordered state upon lateral compression. The pi(eq) values increase linearly with increasing temperatures. A slope of pi(eq) against temperature for the alcohols with shorter fluorocarbons is unexpectedly larger than that for the corresponding fatty alcohols. Generally, fluorinated amphiphiles have a greater thermal stability (or resistance), which is a characteristic of highly fluorinated or perfluorinated compounds. Herein, however, the alcohols containing perfluorobutylated and perfluorohexylated chains show the irregular thermal behavior in both the solid and monolayer states. PMID- 23107938 TI - Protein-mediated synthesis, pH-induced reversible agglomeration, toxicity and cellular interaction of silver nanoparticles. AB - Casein, a milk protein, is used to produce biotolerable and highly stable silver nanoparticles with a fair control over their size without using any additional reducing agent. These silver nanoparticles undergo reversible agglomeration to form protein-silver nanoparticle composite agglomerates as pH approaches to the isoelectric point of casein protein (pI=4.6). These agglomerates can then easily be re-dispersed in alkaline aqueous media with no obvious change in their optical properties. The nanoparticles can withstand high salt concentration (~0.5M), and can also be freeze-dried, stored as dry powder and then dispersed in aqueous media whenever required. More interestingly, by controlling the concentration of casein protein and pH, it was also possible to control the self-assembly of silver nanoparticles to produce fairly uniform spherical agglomerates. The nanoparticles and their agglomerates were thoroughly characterized using UV visible and FTIR spectroscopy, TEM, SEM and DLS, etc. Cytotoxicity of the hybrid materials was examined using a Resazurin based cytotoxicity assay. After determining the LD(50) using NIH/3T3 fibroblast cells, the cellular interaction of these hybrid nanoparticles was studied to examine the behavior of casein coated nanoparticles for their potential bio-applications. PMID- 23107939 TI - A free-standing, sheet-shaped, "hydrophobic" biomaterial containing polymeric micelles formed from poly(ethylene glycol)-poly(lactic acid) block copolymer for possible incorporation/release of "hydrophilic" compounds. AB - Sheet-shaped materials with a large contact area relative to the drug targeting site lead to advantages over conventional particle-shaped drug carriers and have several advantages for their biomedical applications. The present study proposes a methodology for preparing a novel sheet-shaped "hydrophobic" and biocompatible biomaterial in which polymeric micelles are uniformly dispersed for the incorporation of "hydrophilic" compounds into the sheet. The methoxy-terminated poly(ethylene glycol)-block-poly(lactic acid) block copolymer (CH(3)O-PEG-b-PLA) was successfully synthesized by means of the anionic ring-opening polymerization of both ethylene oxide and dl-lactide. CH(3)O-PEG-b-PLA was self-assembled and formed stable micelle-like w/o emulsion with a hydrophilic inner core in organic solvents. A sheet-shaped material containing a hydrophilic inner space for incorporating hydrophilic compounds was obtained by spin-coating both the micelle solution and a sheet-forming polymer. Fluorescent images of the sheet proved that polymeric micelles providing hydrophilic spaces were uniformly dispersed in the hydrophobic sheet. The facile technique presented in this paper can be a tool for fabricating sheet-shaped biomaterials that have a hydrophilic inner core and, consequently, that are suitable for the sustained release of hydrophilic compounds. PMID- 23107940 TI - In vitro and in vivo evaluation of riccardin D nanosuspensions with different particle size. AB - Riccardin D (RD) is a novel compound extracted from Chinese liverwort Marchantia polymorpha L. It exhibits various anticancer activities and can be used during lung cancer treatment. However, the compound's low solubility hinders its development. Recently nanosuspension has been developed as one of the most promising formulations for poorly water-soluble drugs. In order to understand the dissolution behavior of riccardin D in vitro and in vivo, two nanosuspensions of riccardin D with markedly different sizes were prepared. The particle size of nanosuspension A prepared by bottom-up method was 184.1+/-3.15 nm, while that of nanosuspension B prepared by top-down method was 815.4+/-9.65 nm. The main purpose of this study was to investigate the effects of particle size on pharmacokinetics and tissue distribution after intravenous administration. Riccardin D dissolving in organic solution was studied as control group. In pharmacokinetics study in Wistar rats, nanosuspension A showed properties similar to the control group, while nanosuspension B exhibited rather different properties. In tissue distribution research on Kunming strain mice, nanosuspension A had a multi-peak phenomenon because of reticulate endothelial system (RES) while nanosuspension B showed a high uptake in RES organs that passively target to the lungs. In conclusion, particle size of riccardin D nanosuspensions had obvious effects on pharmacokinetics and tissue distribution. PMID- 23107941 TI - In situ biosynthesis of Ag, Au and bimetallic nanoparticles using Piper pedicellatum C.DC: green chemistry approach. AB - The synthesis of Ag, Au and Ag-Au bimetallic nanoparticles using Piper pedicellatum C.DC leaf extract is demonstrated here. The rapid formation of stable Ag and Au nanoparticles has been found using P. pedicellatum C.DC leaf extract in aqueous medium at normal atmospheric condition. Competitive reduction of Ag(+) and Au(3+) ions present simultaneously in solution during exposure to P. pedicellatum C.DC leaf extract leads to the synthesis of bimetallic Ag-Au nanoparticles in solution. Transmission electron microscopy (TEM) analysis revealed that the Ag nanoparticles predominantly form spherical in shape with the size range of 2.0+/-0.5-30.0+/-1.2 nm. In case of Au nanoparticles, the particles are spherical in shape along with few triangular, hexagonal and pentagonal shaped nanoparticles also observed. X-ray diffraction (XRD) studies revealed that the nanoparticles were face centered cubic (fcc) in shape. Fourier transform infrared spectroscopy (FTIR) showed nanoparticles were capped with plant compounds. The chemical constituents, viz. catechin, gallic acid, courmaric acid and protocatechuic acid of the leaf extract were identified which may act as a reducing, stabilizing and capping agent. The expected reaction mechanism in the formation of Ag and Au nanoparticles is also reported. PMID- 23107942 TI - Air jet spinning of hydroxyapatite/poly(lactic acid) hybrid nanocomposite membrane mats for bone tissue engineering. AB - The technique for the production of multifunctional scaffolds from bioactive ceramics and biodegradable polymers for use in tissue scaffolds remains challenging. Here, the goal was to fabricate 3D nanocomposite nanofiber scaffolds of nanohydroxyapatite/poly(lactic acid) (nHA/PLA) prepared by air jet spinning (AJS) as a novel and facile composite fabrication process. The characteristics of the fabricated 3D scaffolds were investigated using SEM, water contact angle, DSC, FTIR, XRD analyses and tensile tests. The surface morphology exhibited highly interconnected bonded fibers due to the high fabrication rates. It was also found that the nHA particles were effectively embedded in the fibers' surface due to the difference in the kinetic energies between the nHA particles and polymer molecules. The as-received PLA film showed a low crystallinity value of about 19%, which was expected with the casting process. The crystallinities of the plain PLA and nHA/PLA membrane scaffolds were about 31.78% and 32.21%, respectively. This reveals that HA nanoparticles could engage in a beneficial interaction with the PLA chain molecules during the AJS process. The tensile strength of the membrane PLA mats, particularly the hybrid nanocomposite samples with low nHA contents, was considerably improved compared to that of the PLA casted film. Biological in vitro cell cultures of MC3T3-E1 osteoblast-like cells on the fabricated scaffolds were studied for up to seven days. The nanocomposite membrane mats of nHA/PLA, fabricated by AJS, had highly interconnected fibers. This facile technique has a high production rate and is a new concept of potential interest for bone tissue engineering applications. PMID- 23107943 TI - Impact of osmotic pressure and gelling in the generation of highly stable single core water-in-oil-in-water (W/O/W) nano multiple emulsions of aspirin assisted by two-stage ultrasonic cavitational emulsification. AB - The present investigation focuses in investigating the effect of osmotic pressure, gelling on the mean droplet diameter, polydispersity index, droplet size stability of the developed novel Aspirin containing water-in-oil-in-water (W/O/W) nano multiple emulsion. The aspirin-loaded nano multiple emulsion formulation was successfully generated using two-stage ultrasonic cavitational emulsification which had been reported in author's previous study. The osmotic behavior of ultrasonically prepared nano multiple emulsions were also examined with different glucose concentrations both in the inner and outer aqueous phases. In addition, introducing gelatin into the formulation also observed to play an important role in preventing the interdroplet coalescence via the formation of interfacial rigid film. Detailed studies were also made on the possible mechanisms of water migration under osmotic gradient which primarily caused by the permeation of glucose. Besides, the experimental results have shown that the interfacial tension between the two immiscible phases decreases with varying the composition of organic phase. Although the W/O/W emulsion prepared with the inner/outer glucose weight ratio of 1-0.5% (w/w) showed an excellent droplet stability, the formulation containing 0.5% (w/w) glucose in the inner aqueous phase appeared to be the most stable with minimum change in the mean droplet size upon one-week storage period. Based on the optimization, nano multiple emulsion droplets with the mean droplet diameter of around 400 nm were produced using 1.25% (w/w) Span 80 and 0.5% Cremophore EL. Overall, our investigation makes a pathway in proving that the use of ultrasound cavitation is an efficient yet promising approach in the generation of stable and uniform nano multiple emulsions and could be used in the encapsulation of various active pharmaceutical ingredients in the near future. PMID- 23107944 TI - Effects of gemini amphiphilic pseudopeptides on model lipid membranes: a Langmuir monolayer study. AB - Monolayers formed with 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, 1,2 dipalmitoyl-sn-glycero-3-phosphoethanolamine, 1,2-dimyristoyl-sn-glycero-3 [phospho-rac-(1-glycerol)] and 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1 glycerol)] at the air/water interface were used as model membranes for studying a potential biological activity of four newly synthesized gemini amphiphilic pseudopeptides (GAPs); some of the GAPs studied showed interesting self-assembly properties. The capacity of GAPs to self-assemble in different environments let us think that these molecules may find biomedical applications in, e.g., drug delivery or transfection. The surface pressure-area and surface potential-area compression isotherms, as well as Brewster angle microscopy and polarization modulation infrared reflection-absorption spectroscopy were used to study monolayers formed with pure GAPs, pure lipids and lipid/GAPs mixtures. The results obtained show that all four GAPs studied can be incorporated in lipid monolayers. The monolayers containing GAPs are expanded and more liquid-like compared to pure lipids. The overall results indicate that the important changes of the properties induced in the model membranes by GAPs are related to their intrinsic conformational flexibility. This feature of GAPs can be easily adjusted by engineering the structure of the spacer present in the polar head, with the aim to modify lipid membranes in a controlled way. PMID- 23107945 TI - The effect of culture condition and ionic strength on proton adsorption at the surface of the extreme thermophile Acidianus manzaensis. AB - Some previously published studies have used surface complexation theory to model proton adsorption in mesophilic bacteria. However, few experiments, to date, have investigated the effects of cultivation conditions and ionic strength on proton interactions among extreme thermophile archaea. In this study, we characterize proton adsorption of the extreme thermophile Acidianus manzaensis by performing acid-base titrations and electrophoretic mobility measurements in NaNO(3) solution (0.001-0.1M), as well as Attenuated Total Reflection Fourier Transformed Infrared Spectroscopy (ATR-FTIR) with pH 2-10. Equilibrium thermodynamics (Donnan model) were applied to predict trends of ion adsorption at the archaea-water interface. We observed that the acidic properties of the A. manzaensis surface were significantly related to culture conditions and ionic strength. The buffering capacity of A. manzaensis cultivated with pyrite was much less than that of A. manzaensis cultured with sulfur. Furthermore, with increasing pH value, the buffering capacity increased and the surface charge became increasingly negative. To our knowledge, A. manzaensis has the highest buffering capacity of per unit wet biomass among all microbes studied. In conclusion, based on our model, the acid-base properties of the cell wall of A. manzaensis can be characterized by invoking three distinct types of cell wall functional groups: Carboxyl, phosphoryl, and amide groups, which were also verified by ATR-FTIR. PMID- 23107946 TI - Electrospun Chitosan-graft-PLGA nanofibres with significantly enhanced hydrophilicity and improved mechanical property. AB - This work reported a novel poly(lactic-co-glycolic acid) (PLGA) composite nanofibres, Chitosan-graft-PLGA (CS-graft-PLGA), produced by the electrospinning technique. CS was grafted onto the PLGA surface via the cross-linking agents reacting with the PLGA with reactive carboxyl groups on its surfaces introduced from the alkali treatment. The CS grafting ratios of the electrospun CS-graft PLGA nanofibres were about 2.43%, 4.34%, 16.97% and 39.4% after cross-linked for 12 h, 16 h, 20 h and 24 h, respectively. The electrospun CS-graft-PLGA nanofibres were significantly uniform and highly smooth without the occurrence of bead defects, even at high CS grafting ratio. The electrospun CS-graft-PLGA nanofibres not only possessed the improved hydrophilicity and the protein absorption property, but also maintained the good mechanical property. In addition, the CS grafting can be conducive to accelerate degradation rate of PLGA. PMID- 23107947 TI - Multiwall carbon nanotubes decorated with NiFe2O4 magnetic nanoparticles, a new catalyst for voltammetric determination of cefixime. AB - Multiwall carbon nanotubes were decorated with synthesized NiFe(2)O(4) magnetic nanoparticles. The new materials were characterized with different techniques such as transform infrared spectroscopy, transmission electron microscopy, atomic force microscopy and electrochemical impedance spectroscopy. The multiwall carbon nanotubes decorated with NiFe(2)O(4) magnetic nanoparticles was used as a new mediator for the voltammetric determination of cefixime. Under the optimum conditions at pH 8.0, the oxidation of cefixime was occurred at 850 mV at the surface of the modified electrode. Linear sweep voltammetry exhibited two wide linear dynamic ranges of 0.1-100 and 100-600 MUmol L(-1) cefixime. The detection limit was found to be 0.02 MUmol L(-1) cefixime. Finally, the modified electrode showed good sensitivity, selectivity and stability for the determination of cefixime in real samples. PMID- 23107948 TI - Synthesis and characterization of biosheet impregnated with Macrotyloma uniflorum extract for burn/wound dressings. AB - Developing biomaterials having wound healing properties within the search of a common man is the need of hour, particularly in developing and third world countries. Keeping this objective in view we have developed a wound dressing material, in sheet form, containing fish scale collagen (FSC) and physiologically clotted fibrin (PCF), both are by products of aqua food and meat industries respectively. To impart antimicrobial properties to the composite sheet, it was incorporated with Macrotyloma uniflorum plant extract (MPE). SEM pictures have shown that FSC:PCF:MPE composite has fibrous and porous surface which helps in transportation of oxygen as well as absorbing wound fluids and their evaporation. The biomaterials have shown 100% biocompatibility and the percentage cell viability was found to be above 89%. The FSC:PCF:MPE biocomposite film with required mechanical strength, biocompatibility and antimicrobial properties can be tried as a burn/wound dressing material. PMID- 23107949 TI - Dielectric characterization of hepatocytes in suspension and embedded into two different polymeric scaffolds. AB - The dielectric and conductometric properties of hepatocytes in two different environments (in aqueous suspension and embedded into polymeric scaffolds) have been investigated in the frequency range from 1 kHz to 2 GHz, where the interfacial electrical polarization gives rise to marked dielectric relaxation effects. We analyzed the dielectric behavior of hepatocytes in complete medium aqueous suspensions in the light of effective medium approximation for heterogeneous systems and hepatocytes cultured into two different highly porous and interconnected polymeric structures. In the former case, we have evaluated the passive electrical parameters associated with both the plasmatic and nuclear membrane, finding a general agreement with the values reported elsewhere, based on a partially different analysis of the experimental spectra. In the latter case, we have evaluated the cell growth into two different polymeric scaffolds made of alginate and gelatin with a similar pore distribution and similar inter connectivity. Based on a qualitative analysis of the dielectric spectra, we were able to provide evidence that alginate scaffolds allow an overall survival of cells better than gelatin scaffold can do. These indications, confirmed by biological tests on cell viability, suggest that hepatocytes embedded in alginate scaffolds are able to perform liver specific functions even over on extended period of time. PMID- 23107950 TI - Silver-doped calcium phosphate nanoparticles: synthesis, characterization, and toxic effects toward mammalian and prokaryotic cells. AB - Spherical silver-doped calcium phosphate nanoparticles were synthesized in a co precipitation route from calcium nitrate/silver nitrate and ammonium phosphate in a continuous process and colloidally stabilized by carboxymethyl cellulose. Nanoparticles with 0.39 wt% silver content and a diameter of about 50-60 nm were obtained. The toxic effects toward mammalian and prokaryotic cells were determined by viability tests and determination of the minimal inhibitory and minimal bactericidal concentrations (MIC and MBC). Three mammalian cells lines, i.e. human mesenchymal stem cells (hMSC) and blood peripheral mononuclear cells (PBMC, monocytes and T-lymphocytes), and two prokaryotic strains, i.e. Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were used. Silver-doped calcium phosphate nanoparticles and silver acetate showed similar effect toward mammalian and prokaryotic cells with toxic silver concentrations in the range of 1-3 MUg mL(-1). PMID- 23107951 TI - Extracellular matrix protein patterns guide human chondrocytes adhesion and alignment characterized by vimentin and matrilin-3. AB - The main purpose of the present study is to investigate the influences of collagen VI (col-VI) patterns on human chondrocytes behaviors. To this end, col VI stripes with varying width and interstripe spacing are created on polystyrene (PS) surfaces by microcontact printing (MUCP). Human chondrocytes are then seeded on these protein patterns and the cell adhesion and alignment are investigated by staining the vimentin and matrilin-3 secreted by seeded chondrocytes. The results indicate that the cells preferentially attach onto the protein areas, rendering cell patterns and the elongated cell shapes. The pattern dimensions can significantly influence cell adhesion, spreading and orientation. The stripe protein patterns can guide cell adhesion and alignment. The cell morphologies can be controlled by carefully designing the pattern shapes and sizes. Our results suggest that the protein patterns can be used to modify biomaterials' surfaces for selective cell-binding and cell alignment. It could provide some cues for the development of novel implantable biomaterials, such as tissue-engineered scaffolds for cartilage replacement, where specific cell alignment is needed. PMID- 23107952 TI - Coaxial electrospinning with acetic acid for preparing ferulic acid/zein composite fibers with improved drug release profiles. AB - This study investigated drug/zein composite fibers prepared using a modified coaxial electrospinning process. With unspinnable acetic acid as sheath liquid and an electrospinnable co-dissolving solution of zein and ferulic acid (FA) as core fluid, the modified coaxial process could run smoothly and continuously without any clogging. Compared with those from the single-fluid electrospinning process, the FA-loaded zein fibers from the modified process were rounder and possessed higher quality in terms of diameter and distribution, as verified by scanning electron microscopic observations of their surface and cross-section. Differential scanning calorimetry and X-ray diffraction showed that fibers from both processes similarly formed a composite with the FA present in the zein matrix in an amorphous state. The driving force of encapsulation of FA into zein fibers was hydrogen bonding, as evidenced by the attenuated total reflectance Fourier transform infrared spectra. However, in vitro dissolution tests demonstrated that the fibers from the coaxial process exhibited better sustained release profiles with a smaller initial burst effect and less tailing-off release compared with those from the single process. The modified coaxial electrospinning process is a useful tool for generating nanofibers with higher quality and improved functional performance. PMID- 23107953 TI - Fabrication of biofunctional stents with endothelial progenitor cell specificity for vascular re-endothelialization. AB - Endothelial progenitor cells (EPCs) have been identified as a crucial factor for re-endothelialization after stenting, resulting in the prevention of stent thrombosis and neointimal hyperplasia. Because EPCs can be introduced by antibody antigen interactions, the suitable choice of antibody and the biocompatible surface modification technology including antibody immobilization are essential for developing an EPC-capturing stent. In this study, we fabricated a biofunctional stent with EPC specificity by grafting a hydrophilic polymer and consecutively immobilizing the antibody against vascular endothelial cadherin (VE cadherin) which is one of the specific EPC surface markers. The surface of a stainless steel stent was sequentially modified by acid-treatment, silanization and covalent attachment of polymers not only to improve biocompatibility but also to introduce functional groups on the stent surface. The surface-modified stent immobilized anti-VE-cadherin antibodies, and the EPCs were remarkably captured whereas THP-1s, human acute monocytic leukemia cells, were not adsorbed on the stent. Furthermore, we confirmed that the recruited EPCs developed the endothelial cell layers on the antibody-conjugated stent. These positive in vitro results will encourage the extensive application of biofunctional surface modification technology for a variety of medical devices. PMID- 23107954 TI - Preparation of tadpole-shaped calcium alginate microparticles with sphericity control. AB - Monosized sodium alginate microdroplets are prepared using a flow-focusing microdevice by adjusting the flow rate of the continuous phase (soybean oil) and the dispersed phase (sodium alginate solution). The gelation process of the semi product, sodium alginate microdroplets, occurs outside the channel in a calcium chloride solution to form tadpole-shaped calcium alginate microparticles. The microparticles prepared are in the range of 100-250 MUm in diameter, depending on the experimental conditions. The shape, size and size distribution of these calcium alginate microparticles depend strongly on the calcium solution concentration and the stirring mode. The shaping mechanism of the microparticles and the impact of the experimental conditions on particle shape and size are investigated. PMID- 23107955 TI - Microbial reduction of graphene oxide by Escherichia coli: a green chemistry approach. AB - Graphene and graphene related materials are an important area of research in recent years due to their unique properties. The extensive industrial application of graphene and related compounds has led researchers to devise novel and simple methods for the synthesis of high quality graphene. In this paper, we developed an environment friendly, cost effective, simple method and green approaches for the reduction of graphene oxide (GO) using Escherichia coli biomass. In biological method, we can avoid use of toxic and environmentally harmful reducing agents commonly used in the chemical reduction of GO to obtain graphene. The biomass of E. coli reduces exfoliated GO to graphene at 37 degrees C in an aqueous medium. The E. coli reduced graphene oxide (ERGO) was characterized with UV-visible absorption spectroscopy, particle analyzer, high resolution X-ray diffractometer, scanning electron microscopy and Raman spectroscopy. Besides the reduction potential, the biomass could also play an important role as stabilizing agent, in which synthesized graphene exhibited good stability in water. This method can open up the new avenue for preparing graphene in cost effective and large scale production. Our findings suggest that GO can be reduced by simple eco friendly method by using E. coli biomass to produce water dispersible graphene. PMID- 23107956 TI - Novel biocompatible nanoreactor for silica/gold hybrid nanoparticles preparation. AB - A new approach to the preparation of PEGylated [PEG: poly(ethylene glycol)] SiO(2)/Au hybrid nanoparticles was investigated. The synthesis of a PEGylated nanogel containing SiO(2)/Au hybrid nanoparticles was performed using matrix catalyzed hydrolysis of tetraethyl orthosilicate, followed by the reduction of HAuCl(4). UV-vis absorption of the prepared hybrid particles was obtained at 618 nm, which is a much longer wavelength than that of a nanogel containing only Au nanoparticles (523 nm). High-angle annular dark field images of the prepared particles observed using transmission electron microscopy and energy-dispersive X ray spectroscopy confirmed the coexistence of Si and Au in the same particle. The presence of Si and Au in the prepared particles was also confirmed by inductively coupled plasma atomic emission spectroscopy. Dynamic light-scattering measurements of the particles in a highly ionic medium showed that they have high stability in both acidic and basic regions. PMID- 23107957 TI - Inverted colloidal crystal scaffolds with induced pluripotent stem cells for nerve tissue engineering. AB - The development of biomaterials for regenerating neurons from induced pluripotent stem (iPS) cells is crucial to the potential therapy for traumatic injury to nervous system. This study aims to guide differentiation of iPS cells into neuron lineage cells in inverted colloidal crystal (ICC) scaffolds containing alginate, poly(gamma-glutamic acid), and surface CSRARKQAASIKVAVSADR (peptide). The differentiation of iPS cells in ICC constructs was characterized by staining of embryonic and neuronal markers. The results indicated that hexagonal crystals of polystyrene microspheres shaped hydrogels into ICC scaffolds with interconnected pores. CSRARKQAASIKVAVSADR slightly enhanced the adhesion of iPS cells in ICC constructs and yielded no variation in the viability of iPS cells. Cultured ICC constructs with CSRARKQAASIKVAVSADR reduced the expression of stage-specific embryonic surface antigen-1 and raised the expression of beta III tubulin of differentiating iPS cells. The induction with CSRARKQAASIKVAVSADR in ICC topography can improve the differentiation of iPS cells toward neurons for nerve tissue engineering. PMID- 23107958 TI - Novel silicificated PVAc/POSS composite nanofibrous mat via facile electrospinning technique: potential scaffold for hard tissue engineering. AB - This study presents the fabrication of novel porous silicificated PVAc/POSS composite nanofibers by facile electrospinning technique and the interaction of synthesized mats with simulated body fluid (SBF). The physicochemical properties of the electrospun composites were determined by scanning electron microscopy, energy dispersive X-ray spectroscopy, transmission electron microscopy, electron probe micro-analysis, X-ray diffraction and thermogravimetry analysis. To examine the in vitro cytotoxicity, mouse myoblast C2C12 cells were treated with pristine and composite nanofibrous mats and the viability of cells was analyzed by cell counting kit-8 assay at regular time intervals. Our results indicated the enhanced nucleation and the formation of apatite-like structures at the surface of silicificated PVAc/POSS during the incubation of electrospun mats in SBF solution. Cytotoxicity experiments designated that the myoblasts could attach to the composite after being cultured. We observed in the present study that PVAc/POSS nanofibrous mat could support cell adhesion and guide the spreading behavior of myoblasts. We conclude that the new electrospun silicificated PVAc/POSS composite scaffold with unique porous morphology have excellent biocompatibility. Consequently, our investigation results showed that the as-spun porous PVAc/POSS composite nanofibrous scaffold could be a potential substrate for the proliferation and mineralization of osteoblasts, enhancing bone regeneration. The biocomposite mats represent a promising biomaterial to be exploited for various tissue engineering applications such as guided bone regeneration. PMID- 23107959 TI - Doxorubicin loaded magneto-niosomes for targeted drug delivery. AB - In chemotherapy the magnetic drug targeting to a specific organ or tissue is proposed on the assumption that magnetic fields are harmless to biological systems. In this light we have vehiculated doxorubicin as model drug by novel magneto-niosomes in order to evaluate the physico-chemical properties of the obtained formulations and the in vitro release profile. Tween 60 and Pluronic L64 have been used as surfactants and the formulation cytotoxicity has been performed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolum bromide and trypan blue dye esclusion tests. Results show that niosome dimensions and doxorubicin entrapment efficiencies are influenced by bilayer composition. In addition, formulations are able to control the deliver and release of the drug active form in a retarded manner. No additional toxicity, due to the encapsulation of ferrofluid into niosomes core, has been detected. PMID- 23107960 TI - The extra cellular synthesis of gold and silver nanoparticles and their free radical scavenging and antibacterial properties. AB - The bio reduction of chloro auric acid (HAuCl(4)) and silver nitrate (AgNO(3)) is achieved extracellularly by using the aqueous extract of Solanum torvum (S. torvum) fruit. The nanoparticle formation was screened by UV-visible spectroscopy through color conversion due to surface plasma resonance bands at 560 nm and 430 nm for gold and silver nanoparticles respectively. The spherical shapes with smooth surface of gold and silver nanoparticles were analyzed through scanning electron microscope and its presence was confirmed by energy dispersive X-ray spectroscopy (SEM/EDX). The functional groups in the gold and silver salts and the bio interactive functional groups present in the S. torvum extract were characterized by employing Fourier transform infra-red spectroscopy (FTIR). The biomedical properties of gold and silver nanoparticles were premeditated as free radical scavenging activity and antibacterial static agents. Gold and silver nanoparticles serve as strong hydroxyl, superoxide, nitric oxide and DPPH radical scavengers in contrast to their corresponding metal oxides. The radical quenching properties of gold and silver nanoparticles were found to correlate with in vitro DNA protective effect. The silver nanoparticles show strong zone of inhibition against Escherichia coli, Pseudomonas and Bacillus whereas, gold nanoparticles exhibit fair zone of inhibition. To our knowledge this is the first report that S. torvum extract can reduce metal acids to nano materials. PMID- 23107961 TI - Electrocatalytic oxidation of NADH using a pencil graphite electrode modified with quercetin. AB - In the present study, the electrocatalytic oxidation of reduced beta nicotinamide adenine dinucleotide (NADH) was investigated using a pencil graphite electrode modified with quercetin (PGE/QH(2)). The PGE/QH(2) was prepared through two steps: (i) the pre-treatment of PGE at 1.40 V vs. Ag|AgCl|KCl((sat.)) in pH 7.0 phosphate buffer containing 0.1 M KCl for 60s and (ii) adsorption of QH(2) on the PGE via immersion of PGE into a 1.0mM QH(2) solution (in ethanol) for 60s. Cyclic voltammetric studies show that the peak potential of NADH oxidation shifts from +500 mV at bare PGE to +300 mV at PGE/QH(2). The electrocatalytic currents obtained from amperometric measurements at +300 mV vs. Ag|AgCl|KCl((sat.)) and in phosphate buffer solution at pH 7.0 containing 0.1M KCl were linearly related to the concentration of NADH. Linear calibration plots are obtained in the concentration range from 0.5 MUM to 100 MUM. The limit of detection was found to be 0.15 MUM. PMID- 23107962 TI - Construction of amphiphilic copolymer nanoparticles based on gelatin as drug carriers for doxorubicin delivery. AB - Novel biodegradable amphiphilic copolymer nanoparticles based on gelatin, poly(lactide) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE) (gelatin-co-PLA-DPPE) have been successfully fabricated. In order to estimate the feasibility as drug carriers, an anti-tumor model drug doxorubicin hydrochloride salt (DOX) was incorporated into polymeric nanoparticles by double emulsion or nanoprecipitation method. The nanoparticle size, size distribution and encapsulation efficiency (EE) were influenced by the feed weight ratio of the copolymer to DOX and different fabrication methods of nanoparticles. In addition, in vitro release experiments exhibited the release behavior was affected by pH of release media. The DOX-loaded nanoparticles showed that faster release at pH 5.0 than their release at pH 7.4 buffer. The DOX-loaded copolymer nanoparticles showed comparable anticancer efficacy with the free drug in vitro and in vivo. These results demonstrate a feasible application of the gelatin derivative as a promising nanocarrier for delivery of anti-tumor drugs. PMID- 23107963 TI - A novel cell-based microfluidic multichannel setup-impact of hydrodynamics and surface characteristics on the bioadhesion of polystyrene microspheres. AB - Carboxylated polystyrene microspheres with 1 MUm in diameter were surface modified either by coating with poly(ethyleneimine) (PEI) as cationic polyelectrolyte leading to a conversion of the surface charge from negative to positive, or by covalent immobilization of wheat germ agglutinin (WGA) via a carbodiimide method to obtain a carbohydrate specific biorecognitive surface. To characterize the impact of the binding mechanism on the particle-cell interaction, the binding efficiencies to Caco-2 cells were investigated for both, the biorecognitive WGA-grafted particles and the positively charged PEI microspheres, and compared to the unmodified negatively charged polystyrene particles. As a result, WGA-grafted particles exhibited the highest binding rates to single cells as well as monolayers as compared to positive and negative particles under stationary conditions. Concerning ionic interactions, PEI-coated particles suffered from a critical agglomeration tendency leading to a high variance in cell binding. Furthermore, in order to elucidate the bioadhesive properties under flow conditions, an acoustically-driven microfluidic multichannel system was applied. Using different setups, it could be demonstrated that the hydrodynamics exerted almost no impact on cell-bound particles with a size of 1 MUm at a flow velocity of 2000 MUm s(-1). Using this novel microfluidic system, it was thus possible to prove that the omnipresent hydrodynamic drag in vivo is mostly negligible for microparticulate drug delivery systems in the size range of 1 MUm or below. PMID- 23107964 TI - Redox phospholipid polymer microparticles as doubly functional polymer support for immobilization of enzyme oxidase. AB - We prepared redox phospholipid polymer microparticles for immobilizing an enzyme in order to maintain activity for a long time and obtain highly effective electron transfer to a gold substrate as an electrode. To achieve these double functions, an amphiphilic redox phospholipid polymer, poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co-p-nitrophenyloxycarbonyl oligo(ethylene glycol) methacrylate (MEONP)-co-vinylferrocene (VFc)) (PMBNF) was synthesized. The polystyrene (PS) microparticles were modified by employing a simple solution dip-coating technique to form the PMBNF layer on the surface. As one of the model enzyme oxidases, a glucose oxidase (GO(x)) was immobilized on the PMBNF/PS microparticles by the reaction between the MEONP units in the PMBNF layer and the amino group in the GO(x). The activity of immobilized GO(x) is maintained well; for example, activity of more than 80% of the initial activity was observed even after storage at both 4 degrees C and 25 degrees C (ionic strength: 0.10 mol/L, phosphate buffer solution, pH 7.0) for at least one month. The GO(x)/PMBNF/PS microparticles were arrayed on a gold substrate in a monolayer, and then, crosslinked to each other with a polymeric diamine compound. The PMBNF/PS microparticles demonstrated an efficient electron transfer from immobilized GO(x) to the gold surface. From these results, we concluded that the PMBNF layer on the PS microparticles possessed double functions such as stable enzyme immobilization ability and efficient electron transfer ability. PMID- 23107965 TI - Electrophoresis of a charge-regulated soft sphere: importance of effective membrane charge. AB - The importance of the effective membrane charge on the electrophoretic behavior of a soft spherical particle comprising a rigid core and a charge-regulated membrane layer, mimicking both inorganic and biological colloids, is investigated. The mobility of the particle is simulated under various conditions by varying the double layer thickness, the bulk solution pH, and the charged conditions of the membrane layer. Several interesting electrophoretic behaviors that are of practical significance, are observed. For example, the particle mobility can be controlled by adjusting its properties such as the ratios of (acidic equilibrium constant/basic equilibrium constant) and (concentration of acidic functional groups/that of basic functional groups). Double layer polarization (DLP) is found to render the soft particle having behaviors different from those of the corresponding rigid particle. For instance, DLP can either be intensified or weakened, depending upon the strength of the hydrodynamic force and the electric force acting on the membrane layer. As the bulk electrolyte concentration increases in a certain range, because double layer shrinks into the membrane layer, its effective charge density increases, so is the particle mobility. PMID- 23107966 TI - Novel thermo/pH sensitive nanogels composed from poly(N-vinylcaprolactam) for controlled release of an anticancer drug. AB - A series of novel nanogels (NGs) with both pH and thermoresponsive properties were synthesised by free radical emulsion polymerisation of N-vinyl caprolactam (VCL) and acrylamidoglycolic acid (AGA). 5-Flurouracil, an anti cancer drug, was successfully loaded into these nanogels via equilibrium swelling method. The encapsulation efficiency of 5-FU was found up to 61%. Here we present the novel potential drug delivery system showing both pH and temperature release of 5-FU. Fourier transforms infrared spectroscopy (FTIR), and differential scanning calorimetric (DSC) examined the structure and morphology of the NGs. Transmission electron microscopy (TEM) indicates the diameter of the NGs to be about 50 nm. The size distribution of NGs was investigated using dynamic light scattering (DLS), the average diameter and polydispersity is 57 nm and 0.194. Interestingly, the in vitro release studies of 5-FU demonstrated the dual nature (pH and temperature) of NGs. The cumulative release data were analysed using an emperical equation to compute the diffusion exponent (n); whose values suggest Fickian diffusion. PMID- 23107967 TI - Comparison of bacterial cells and amine-functionalized abiotic surfaces as support for Pd nanoparticle synthesis. AB - An increasing demand for catalytic Pd nanoparticles has motivated the search for sustainable production methods. An innovative approach uses bacterial cells as support material for synthesizing Pd nanoparticles by reduction of Pd(II) with e.g. hydrogen or formate. Nevertheless, drawbacks of microbially supported Pd catalysts are the low catalytic activity compared to conventional Pd nanocatalysts and the possible poisoning of the catalyst surface by sulfur originating from bacterial proteins. A recent study showed that amine groups were a key component in surface-supported synthesis of Pd nanoparticles, and that abiotic surfaces could support the Pd particle synthesis as efficiently as bacteria. In this study, we explore the possibility of replacing bacteria with amine-functionalized materials, and we compare different functionalization strategies. Pd nanoparticles formed on the support materials were visualized by transmission electron microscopy, and their activity was evaluated by catalysis of p-nitrophenol reduction. Surfaces functionalized with 3 aminopropyltriethoxysilane and chitosan were interesting alternatives to bacterial cells, as the catalytic activity of Pd particles formed on these surfaces was higher than for Pd particles formed on Shewanella oneidensis cells. Smaller Pd nanoparticles generally have better catalytic properties, and previous studies have shown that the particle size can be lowered by increasing the amount of support material used during Pd particle formation. However, increasing the concentration of S. oneidensis cells beyond a certain threshold lead to deactivation of the Pd catalyst. This was not observed for the sulfur-free support materials, implying that such amine-rich materials can provide an excellent support for environmentally friendly synthesis of surface-immobilized Pd nanoparticles. PMID- 23107968 TI - Endoscopic versus open resection of tuberculum sellae meningiomas: a decision analysis. AB - BACKGROUND/AIMS: Tuberculum sellae meningiomas (TSMs) are challenging tumors for surgical resection. Endoscopic endonasal (EE) approaches to these lesions have not been directly compared to open craniotomy in a controlled trial. METHODS: We searched Medline and Embase online databases for English-language articles containing key words related to TSMs. Data were pooled, including 5 of our own patients reported here for the first time. Metaregression was used and a decision analytical model was constructed to compare outcomes between open microsurgery and EE approaches. RESULTS: The overall quality of life (QOL) was not significantly different between the approaches (p = 0.410); however, there were large differences in individual complication rates. The Monte Carlo simulation yielded an overall average QOL in craniotomy patients of 0.915 and in endoscopic patients of 0.952. Endoscopy had a higher CSF leak rate (26.8 vs. 3.5%, p < 0.001) but a lower rate of injury to the optic apparatus (1.4 vs. 9.2%, p < 0.001) compared with craniotomy. The 3-year recurrence rates were not statistically different (p = 0.529). CONCLUSION: EE resection of TSMs appears to be a comparable alternative to traditional open microsurgical resection with respect to overall QOL based on available publications. A meaningful comparison of recurrence rates will require a longer follow-up. PMID- 23107970 TI - Low-dose gemcitabine in long infusion: when less is more. PMID- 23107969 TI - Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. AB - BACKGROUND/AIMS: A decrease in glomerular podocyte number in membranous nephropathy and focal segmental glomerulosclerosis (FSGS) ultimately underlines glomerulosclerosis and the decrease in kidney function. Recent studies have shown that in these diseases, glomerular parietal epithelial cells begin to express proteins considered unique to podocytes, and that these glomerular epithelial transition cells might serve as podocyte progenitors. Because retinoids improve many forms of experimental glomerular disease characterized by podocyte injury and loss, we asked if all-trans retinoic acid (ATRA) induces parietal epithelial cells to express podocyte proteins. METHODS: ATRA or vehicle was administered to rats with experimental membranous nephropathy (passive Heymann nephritis model) and mice with experimental FSGS (anti-glomerular antibody model) following the onset of proteinuria. Immunohistochemistry staining of PAX2 (parietal epithelial cell marker), WT-1 (podocyte cell marker), and Ki-67 (proliferation marker) were performed on kidney tissues. RESULTS: Compared to diseased animals receiving vehicle, ATRA statistically significantly increased the number of glomerular transition cells, defined as cells double-staining for PAX2 and WT-1, in membranous nephropathy at weeks 2, 5 and 16, and in FSGS at weeks 1 and 2. This was accompanied by an increase in the number of podocytes compared to diseased controls receiving vehicle. CONCLUSION: ATRA increases the number of glomerular epithelial transition cells in experimental proteinuric glomerular diseases. Thus, ATRA may provide a useful pharmacologic approach to decipher the mechanisms underlying the possible progenitor role of parietal epithelial cells. PMID- 23107971 TI - Gemcitabine in brief versus prolonged low-dose infusion, both combined with carboplatin for advanced non-small cell lung cancer. AB - PURPOSE: Gemcitabine in low-dose prolonged infusion is a treatment with documented activity against a variety of tumors. The present study was conducted to evaluate the efficacy and safety of the combination of gemcitabine at a low dose prolonged infusion in comparison with standard dose gemcitabine with carboplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Sixty chemonaive patients with stage IIIB or IV NSCLC were included. Patients were randomly assigned 1:1 to receive 350 mg/m 2 gemcitabine in a 6-h infusion on days 1 and 8 and carboplatin area under the serum concentration time curve (AUC) 5 on day 1 versus gemcitabine 1,000 mg/m 2 on days 1 and 8 and carboplatin AUC 5 on day 1 (3-week cycle both). A total of 118 chemotherapy cycles, with a median of 4 cycles per patient (range 2-6), and 134 chemotherapy cycles, with a median of 4.47 cycles per patient (range 3-6) were administered in standard and low infusional dose arm, respectively. RESULTS: Among patients in the standard arm, 40% had overall response rate (ORR), 33.3% had stable disease and 26.6% had progressive disease, while in low-dose infusional arm, 36.6% had ORR, 36.3% had stable disease and 26.6% had progressive disease (P = 0.992). Median progression-free survival was 5.5 months and 5.4 months, median overall survival was 9.7 months and 10.7 months, and 1-year survival was 33.7% and 36.6% in standard arm and low-dose infusion arm, respectively. Grade 3/4 toxicity was rare. CONCLUSION: In NSCLC, gemcitabine low dose prolonged infusion with carboplatin has low toxicity, especially thrombocytopenia, and has an activity comparable with gemcitabine given in higher dose in standard infusion. PMID- 23107972 TI - Preservation of palatal mucoperiosteum for oronasal separation after total maxillectomy. AB - BACKGROUND: Oronasal communication occurs after total maxillectomy for advanced sinonasal cancers. This results in feeding, breathing and cosmetic impairment. Various methods have been described to close off the palatal defect from the oral cavity to improve the function of speech and deglutition. AIMS: The object of this article is to describe our experience of preservation of palatal mucoperiosteum for oronasal separation. MATERIALS AND METHODS: Retrospective review of clinical and operative records of 31 total maxillectomy patients where oronasal separation was achieved by the conventional technique of applying a maxillary obturator. The postoperative complications arising from the use of maxillary obturator for oronasal communication after total maxillectomy in these 31 patients were analysed. To avoid the complications encountered in these 31 patients we preserved and used the ipsilateral palatal mucoperiosteum for oronasal separation. This new technique was applied in 12 patients. The results are presented and compared. RESULTS: A total of 43 patients underwent total maxillectomy for advanced sinonasal tumors. In 31 patients the conventional maxillary obturator was used for oronasal separation. Among these patients, 30 had crustation of the maxillary cavity, nasal regurgitation and cheek skin retraction in 15 each, trismus in eight, infection of skin graft donor site in seven, cheek movement during respiration in five and ill-fitting prosthesis in three. In 12 patients palatal mucoperiosteum was preserved and used for oronasal separation. The complications encountered in oronasal separation by palatal prosthesis were avoided in the modified procedure. CONCLUSIONS: We found that oronasal separation by preservation of palatal mucoperiosteum following total maxillectomy allowed excellent palatal function, prompt rehabilitation and minimal complications without compromising the prognosis. PMID- 23107973 TI - Risk factor profiles of head and neck cancer patients of Andhra Pradesh, India. AB - OBJECTIVE: To define the demographic risk profile and stage at diagnosis among the head and neck cancer (HNC) patients reported in two hospital-based cancer registries in Andhra Pradesh. MATERIALS AND METHODS: A cross-sectional study was conducted in patients with histologically confirmed diagnosis of squamous cell carcinoma of the head and neck during 2002-2006. Data on the demographic profile and clinical information were obtained from hospital and clinical records. Staging was based on the American Joint Committee on Cancer and included primary tumor size (T), regional neck status (N), and group stage. The site of cancer was classified based on the International Classification of Disease for oncology (ICD 02). RESULTS: A total of 5458 cases of HNC were included in this study. Majority of the subjects were in the age range of 40-69 years with a significant male preponderance in all the age groups (P<0.001). The most common habit was the combination of smoking, alcohol, and chewing in both males and females (20.1 and 35.1%, respectively) (P<0.001). Tongue and buccal mucosa were the most common sites of cancer in both males (26.8 and 12.8%, respectively) and females (22.9 and 19.8%, respectively) (P<0.001). Tongue was the commonest site of cancer occurrence with respect to all the habits (both singly and in combination) except for chewing tobacco where buccal mucosa was the most common site. Males were more likely to be diagnosed in stage 3 (37.6%) and 4 (20.6%), while females were diagnosed in stage 1 (36.3%) and 2 (32.7%) (P<0.001). CONCLUSION: A male preponderance of cancer occurrence and combination of all the three habits (smoking, alcohol, and chewing) were found to be the significant risk factors. Males were more likely to be diagnosed later than females. PMID- 23107974 TI - Carcinoma base of tongue: single institution 15 year experiences. AB - AIMS: To report the outcome with radiotherapy and concomitant chemoradiotherapy in patients with locally advanced squamous cell carcinoma base of tongue treated and followed up at single institution over a period of 15 years. MATERIALS AND METHODS: This study was carried out by auditing the medical records of 103 patients treated at our institution between 1991 and 2006. Mean age with standard deviation of patients in the Radiotherapy only (group I) and chemoradiotherapy (group II) was 55.26 +/- 14.16 and 49.81 +/- 12.16 years. 46 patients were treated with radiotherapy alone and 57 patients were treated with concurrent chemo radiotherapy using infusion cisplatinum 3 weekly and 5 fluorouracil twice weekly. Mean follow up was 13.35 months. All the patients characteristic and treatment characteristics were recorded. RESULTS: There were 81 men and 22 women in the study. Group I contains 15 and 31 cases of stage III and IV tumors while group II contains 19 and 38 cases of stage III and IV respectively. Group II has shown improved loco regional control rate for the T3 and T4 tumors as compared to group I. Disease free survival and overall survival in the group II is 25.51 months and 22.53 months while group I has 8.67 months and 6.74 months respectively. Grade III mucosal toxicity incidence was higher in group II as compared to group I. CONCLUSIONS: In locally advanced squamous cell carcinoma of base of tongue tumors concomitant chemoradiotherapy with infusional cisplatinum and 5 fluorouracil results in higher disease free and overall survival as compared to radiotherapy as single modality. This better tumor response with chemoradiotherapy comes at cost of higher incidence of mucosal toxicity. PMID- 23107975 TI - Optimizing multimodality treatment for head and neck cancer in rural India. AB - BACKGROUND: Multimodality treatment of head and neck cancer in rural India is not always feasible due to lack of infrastructure and logistics. AIM: To demonstrate the feasibility of multimodality treatment for head and neck cancer in a community setting in rural India. SETTING AND DESIGN: Community cancer center, retrospective review. MATERIALS AND METHODS: This article focuses on practice environment in a cancer clinic in rural India. We evaluated patient profile, treatment protocols, infrastructure availability, factors impacting treatment decisions, cost estimations, completion of treatment, and major treatment-related complications for the patient population treated in our clinic for a 2-year period. RESULTS: A total of 230 head and neck cancer patients were treated with curative intent. Infrastructure support included basic operating room facility (cautery machine, suction, drill system, microscope, and anesthesia machine without ventilator support), blood bank, histopathology laboratory, and computerized tomography machine. Radiation therapy (RT) facility was available in a nearby city, about 75 km away. One hundred and fifty-four (67%) patients presented at an advanced stage, with 138 (60%) receiving multimodality treatment. One hundred and eighty-four (80%) patients underwent primary surgery and 167 (73%) received radiotherapy. Two hundred and twelve (92%) patients completed the treatment, 60 (26%) were lost to follow-up at 18-month median follow-up (range 12 26 months), with 112 patients (66%) being alive, disease free. Totally 142 were major head neck surgeries with 25 free flap reconstructions and 41 regional flaps. There were 15 (6%) major post-op complications and two perioperative mortalities. Average cost of treatment for single modality treatment was approximately 40,000 INR and for multimodality treatment was 80,000 INR. CONCLUSIONS: This study demonstrates that it is feasible to provide basic multimodality treatment to head and neck cancer patients in the community. PMID- 23107976 TI - The effect of intraarterial high-dose cisplatin on lymph nodes in oral and oropharyngeal cancer. AB - AIM OF STUDY: To assess the effect of strictly local treatment [intraarterial chemotherapy (iaCHT) with high-dose cisplatin and parallel neutralization] in the primary oral and oropharyngeal cancer (OOSCC) on the dependent cervical lymph nodes. PATIENTS AND METHODS: Seventeen consecutive patients with OOSCC and clinically positive necks underwent a prospective blinded comparison of two pre surgical fluor18-deoxyglucose (FDG)-positron emission tomography (PET) examinations: baseline examination 1 week before and follow-up examination 3 weeks after iaCHT. Maximal standardized uptake (SUVmax) values of lymph nodes were measured and compared with each other and histopathology. RESULTS: The SUVmax value of the primary and all neck lymph nodes with uptake decreased significantly. Twelve/17 patients having metastases revealed significant decrease (P = 0.03), and benign lymph nodes showed non-significant decrease of the SUVmax. All neck lymph nodes with uptake and nodal metastases showed a significant reduction (P = 0.004) of standard uptake values (SUV). CONCLUSION: A regional effect of intraarterial cisplatin is proven. To date, it is not clear whether this is due to decreasing inflammatory reaction or a translymphatic anti neoplastic effect. PMID- 23107977 TI - Early stage squamous cell carcinoma of the pyriform sinus: a review of treatment options. AB - The purpose of this review of the literature was to present treatment options for early stage pyriform sinus cancer. Squamous cell carcinoma of the pyriform sinus, as the most frequent cancer arising from the hypopharynx, is rarely diagnosed in its early stage. Based on evidence from retrospective studies, conservation surgery and definitive radiotherapy are considered the available treatment modalities for patients presenting with stage T1 and T2 pyriform sinus carcinomas without clinical evidence of neck lymph node metastases, offering similar results with respect to disease control and functional organ preservation. Also, the high risk of occult metastatic nodal disease even in the earliest stage of pyriform sinus cancer entails elective neck dissection or elective neck irradiation to be considered mandatory. However, for patients with early stage pyriform sinus cancer, no level 1 study exists in which conservation surgery is compared with radiotherapy alone for the evaluation of local control or survival. Randomized multicenter controlled trials evaluating efficacy of conservation surgery and definitive radiotherapy, and correctly interpreting functional outcome for each of the treatment procedures examined are necessary to obtain sufficient evidence to influence the decision in the choice of the most effective treatment for early pyriform sinus cancer. PMID- 23107978 TI - Risk factors and survival analysis of the esophageal cancer in the population of Jammu, India. AB - OBJECTIVE: To identify the risk factors of esophageal cancer and study their effect on the survival rates patients of Jammu region, India. MATERIALS AND METHODS: Detailed information was collected on socio-demographic, dietary and clinico-pathological parameters for 200 case control pairs. Discrete (categorical) data of 2 independent groups (control and cases) were summarized in frequency (%) and compared by using Chi-square (chi2 ) test. The mean age of two independent groups was compared by independent Student's t-test. To find out potential risk factor (s), the variable (s) found significant in univariate analysis were further subjected to multivariate logistic regression analysis. The association of potential risk factors with patients survival (3-year overall survival) was done by Kaplan-Meier survival curve analysis using Log-rank test. A 2-tailed (a = 2) P < 0.05 was considered statistically significant. RESULTS: Out of the 63 response parameters, seven were found highly significant on multivariate analysis. The mean (+/- SD) age was 56.74 +/- 10.76 years, the proportions of males were higher than females, mostly illiterate and lower income group. Among dietary characteristics, snuff was highest (OR = 3.86, 95% CI = 2.46 6.08) followed by salt tea (OR = 2.53, 95% CI = 1.49-4.29), smoking (OR = 1.97, 95% CI = 1.18-3.30), sundried food (OR = 1.77, 95% CI = 1.10-2.85) and red chilly (OR = 1.76, 95% CI = 1.07-2.89). Probability of survival lowered significantly (P < 0.05 or P < 0.01 or P < 0.001) in those consuming tobacco in the form of snuff (Log-rank c 2 = 24.62, P = 0.000) and smoking (Log-rank c 2 = 5.20, P = 0.023) as compared to those who did not take these. CONCLUSIONS: The analysis finally established snuff (smokeless tobacco) as the most powerful risk factor of esophageal cancer in Jammu region, followed by the salt tea, smoking and the sundried food. PMID- 23107979 TI - The feasibility and advantages of billroth-I reconstruction in distal gastric cancers following resection. AB - BACKGROUND: Gastric carcinomas are common malignancies in southern India and distal stomach remains the commonest site in low socio economic groups. Surgery still remains an important modality of treatment to achieve local control and also relieve obstructive symptoms. In this study we investigated the feasibility of performing a gastrectomy and billroth-1 type of anastomosis in a rural cancer center setting, with parameters like adequacy of margins, ease of anastomosis and its functional results were analysed. MATERIALS AND METHODS: Eight patients presenting to a rurally based cancer center underwent a distal gastrectomy and billroth-1 type of anastomosis for continuity restoration. RESULTS: All the patients had adequate proximal and distal marg. The surgical time varied between hrs. The anastomosis was constructed without any tension on bowel ends in all patients. The average time to start oral feeds varied between- None of the patients showed symptoms of bile reflux nor dumping. The average hospital stay varied between. CONCLUSIONS: Billroth-1 anastomosis is a physiologically more natural way of restoring continuity following a gastrectomy and it is a procedure which would be technically more simpler and decrease per and post operative complications and allow speedier post operative recovery following surgery on distal gastric cancers. PMID- 23107980 TI - An ultrastructural study of oogenesis and cell dynamics during cocoon shell secretion in the subterranean freshwater planarian Dendrocoelum constrictum (Platyhelminthes, Tricladida). AB - The ultrastructure of the ovary and the female atrium during cocoon formation was investigated in the subterranean freshwater planarian Dendrocoelum constrictum. In the peripheral portion of the ovary, the oogonia are recognized as undifferentiated germ cells, which are morphologically similar to neoblasts that have a high nucleus/cytoplasm ratio. Oocyte maturation is characterized by a marked growth of the cytoplasm because of the accumulation of cytoplasmic organelles and inclusions. The Golgi complexes begin to increase within the ooplasm and produce vesicles with an electron-dense content that fuse to produce larger spherical globules with homogeneous and electron-dense material. In the mature oocyte, the spherical globules migrate toward the cortical ooplasm, forming a continuous monolayer. We confirm that these spherical globules, which represent cortical granules rather than eggshell globules, vary in size up to 2MUm and their electron-dense content shows concentric thin bands. After leaving the ovary through the oviduct, the mature and fertilized oocytes reach the female atrium where they are packaged with thousands of vitelline cells in the cocoon shell. Based on our ultrastructural analysis, we demonstrate that the wall of the cocoon shell is composed of two layers, each of which has a different origin. The shell granules extruded from the vitelline cells are involved in the secretion of the inner layer of the cocoon shell, whereas the outer layer of the cocoon shell is synthesized by the epithelial cells in the genital atrium. PMID- 23107982 TI - Defined-size embryoid bodies formed in the presence of serum replacement increases the efficiency of the cardiac differentiation of mouse embryonic stem cells. AB - The pluripotent nature of embryonic stem (ES) cells makes them powerful tools in cell replacement therapy for severe degenerative diseases, such as heart failure. However, the development of strategies to increase the efficiency of cardiomyocyte (CMC) differentiation is still needed to produce a sufficient amount of cells for clinical applications. This paper evaluates the impact of the size and the aggregation of embryoid bodies (EBs) on the efficiency of ES cell differentiation into CMCs. ES cells were generated from RAP inbred mice. These cells expressed pluripotency markers and induced teratomas when injected into syngeneic mice, which made them suitable for differentiation into CMCs. We found that the EBs that were formed as a result of in vitro ES cell aggregation generated contractile tissue in direct correlation with the initial number of ES cells. Furthermore, the presence of knock-out serum replacement (KO-SR) during ES cell aggregation resulted in less compacted EBs and increased cell differentiation into CMCs compared to the presence of foetal bovine serum. In conclusion, cardiac differentiation of ES cells is dependent on the size and the degree of compaction of EBs, and the presence of KO-SR during initiation of EBs may lead to improved cardiogenic differentiation of ES cells. PMID- 23107981 TI - The role of ROS toxicity in spontaneous aneuploidy in cultured cells. AB - It is well known that the karyotype of animal cells cultured in vitro tends to become aneuploid as the culture ages. Aneuploidy can cause genetic instability, alter the biological properties of cells, and affect their application in genetic studies and cell engineering. Understanding the causes and mechanisms of aneuploidy is primary to control its occurrence in cultured cells, and is also helpful to understand the mechanisms of tumorigenesis because aneuploidy is a hallmark of tumor cells. This review underscores the potential role of reactive oxygen species (ROS) toxicity in spontaneous aneuploidy of cultured cells. The underlying mechanisms and possible sources of ROS are also discussed. PMID- 23107983 TI - Human placenta-derived mesenchymal stem cells suppress T cell proliferation and support the culture expansion of cord blood CD34+ cells: a comparison with human bone marrow-derived mesenchymal stem cells. AB - Human placenta-derived mesenchymal stem cells (hPMSCs) have been shown to possess immunosuppressive effects against T cells and support the expansion of hematopoietic stem/progenitor cells (HSPCs) from umbilical cord blood (UCB). However, the characteristics of hPMSCs compared with human bone marrow-derived mesenchymal stem cells (hBMSCs) are not fully understood. Here, we show that hPMSCs have similar regulatory effects on T cell activation, proliferation and cytokine secretion as hBMSCs and demonstrate that PDL1 and B7H4, negative co stimulatory molecules, are involved in the T cell immunosuppressive activities of hPMSCs and hBMSCs, respectively. hPMSCs efficiently enhanced the expansion of CD34+ cells from UCB compared with hBMSCs. Furthermore, hPMSCs maintained the expression of adhesion molecules (CD11a, CD44 and CD49e) in CD34+ cells. Similar effects were observed for both hPMSCs and hBMSCs on CD34+ cell chemotaxis and cytokine production, such as SDF-1alpha, IL-6 and SCF. Therefore, hPMSCs may be an ideal alternative source of hBMSCs for basic research and clinical applications, which may be significant in future efforts to explore the potential clinical utility of hPMSCs. PMID- 23107984 TI - WITHDRAWN: Compatibility of a blood collection tube that stabilizes cell-free DNA with a rapid fluorescence assay. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 23107985 TI - Enhanced expression and fucosylation of ficolin3 in plasma of RA patients. AB - OBJECTIVES: The aim of this work was to detect low abundant proteins, which may be potential biomarkers of rheumatoid arthritis (RA) at the early stage. We compared plasma protein profiles of RA patients with healthy individuals in two dimensional gel electrophoresis after removal of abundant proteins (albumin and IgG) using depletion kit and Aleuria aurantia lectin (AAL) affinity chromatography. DESIGN AND METHODS: Forty plasma samples each from healthy control individuals and RA patients were used in this study. RESULTS: We found ficolin 3, haptoglobin alpha chain, IgM chain, alpha-1-antitrypsin and hemopexin precursor to be up regulated in the plasma of RA patients. These proteins were identified by matrix assisted laser desorption ionization-time of flight (MALDI TOF) from several reproducible 2D gels. Ficolin 3, which was not at all visible in albumin and IgG depleted gels, but detected in AAL bound fractions, was further verified by immunobloting and enzyme immunoassay. Elevated fucosylation in ficolin 3 was detected using high performance anion exchange chromatography pulse amperometric detection (HPAEC-PAD), lectin blotting and enzyme linked lectin binding assay. CONCLUSIONS: Altered fucosylation and elevated level of Ficolin 3 might be exploited to be a potential marker for diagnosis of RA. PMID- 23107986 TI - Scope of nursing practice. PMID- 23107987 TI - Letter to editor response. PMID- 23107989 TI - The primacy of relationships: a study of public health nursing practice from a critical caring perspective. AB - Critical caring is a midrange theory proposed as a framework to guide public health nursing practice. This article reports findings of a study that examined the relevance of the theory to the practice of expert public health nurses (PHNs). Twenty-six PHNs participated in this study: 10 in interviews and 16 in 2 focus groups. Findings support the relevance of critical caring to PHN practice, explicated, and further refined the theory through the richness of participants' practice accounts As such, it has potential as a tool of resistance to forces that limit PHNs working to their full scope of practice. PMID- 23107988 TI - Hospital nurse force theory: a perspective of nurse fatigue and patient harm. AB - This article is focused on the primary finding of the 2010 Institute of Medicine report asserting that nurses practice to the full extent of their education and training. An evolving theoretical perspective for hospital nursing practice is proposed as a basis for reaching this goal. This article describes the background and current factors influencing professional hospital nursing practice, presents a theoretical model for future research designed to optimize the power of hospital nursing practice, using a newly evolved concept of "nurse force," and discusses the implications of nurse force theory on perspectives of hospital nurse fatigue and patient harm. PMID- 23107990 TI - Cultivating nursing leadership for our envisioned future. AB - Nurses have been called upon to lead and partner in the transformation of health care. Leadership is a component of the scope of nursing practice; however, the optimal approach to development of leadership competency has not been established. A metasynthesis of qualitative studies on leadership development was conducted to enhance an understanding of conditions that nurses reported to support or hinder their development as leaders. Noblit and Hare's approach was used for the metasynthesis process. Three overarching themes emerged. Opportunity structure, the relationship factor, and organizational culture are essential factors contributing to the successful cultivation of leadership competencies in nurses. PMID- 23107991 TI - The influence of social environmental factors on rehospitalization among patients receiving home health care services. AB - Guided by Orem's theory, this study examined the influence of social environmental factors on rehospitalization among home health care patients. Living arrangement, frequency of caregiving, and type of primary informal care were found to be related to functional ability. Measurable differences in clinical status and functional ability were related to the duration that patients received home health care services until rehospitalization, with the likelihood of rehospitalization increasing proportionately to the magnitude of the differences. Social environmental factors contributed to rehospitalization (self care deficit) through functional ability (self-care agency) by altering the balance between self-care demand (clinical status) and self-care agency. PMID- 23107993 TI - Dynamical systems modeling of physiological coregulation in dyadic interactions. AB - In this paper, we used a dynamical systems approach to examine the interrelations of the physiological signals in dyadic interactions. We introduced a system of differential equations developed for dyadic research (Felmlee and Greenberg, 1999) and applied it to time series of heart rate and respiration from individuals in 32 couples. The model included parameters representing self regulation and coregulation for each individual in the dyad. We applied the model directly to each dyad's data and then examined the distributions of the parameters, and compared such parameters across the three laboratory tasks. In the final step, we explored the associations between the parameter estimates extracted from the physiological data with those parameters from a similar model fitted to daily self-reports of affect. PMID- 23107992 TI - Development and testing of an intervention to improve outcomes for partners following receipt of an implantable cardioverter defibrillator in the patient. AB - The purpose of this article is to describe 3 foundational studies and how their results were used to formulate, design, and test a novel partner intervention for implementation in the immediate post-ICD (implantable cardioverter defibrillator) period after returning home. Nursing's expanding role into chronic illness management in the creation of evidence-based practice is highlighted. A randomized clinical trial comparing 2 intervention programs is being conducted with patients who receive an ICD for the first time and their intimate partners. Primary outcomes are physical functioning, psychological adjustment, relationship impact, and health care utilization. PMID- 23107994 TI - Heart rate and heart rate variability in panic, social anxiety, obsessive compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation. AB - It remains unclear if diminished high frequency heart rate variability (HF-HRV) can be found across anxiety disorders. HF-HRV and heart rate (HR) were examined in panic (PD), generalized anxiety (GAD), social anxiety (SAD), and obsessive compulsive disorder (OCD) relative to healthy controls at baseline and during anxiety stressors. All disorders evidenced diminished baseline HF-HRV relative to controls. Baseline HRV differences were maintained throughout relaxation. For hyperventilation, PD and GAD demonstrated greater HR than controls. Psychotropic medication did not account for HF-HRV differences except in OCD. Age and sex evidenced multiple main effects. Findings suggest that low baseline HF-HRV represents a common index for inhibitory deficits across PD, GAD, and SAD, which is consistent with the notion of autonomic inflexibility in anxiety disorders. Elevated HR responses to hyperventilation, however, are specific to PD and GAD. PMID- 23107995 TI - Culture moderates the cardiovascular consequences of anger regulation strategy. AB - PURPOSE: This research examined cultural differences in experiential and cardiovascular outcomes of three anger regulation strategies (expression, suppression and reappraisal). METHODS: Forty-five Chinese and 45 Caucasian females participated in a laboratory experiment in which role play was used to induce anger. During this role play participants were instructed to either express or suppress their feelings or engage in cognitive reappraisal. Emotional experience was measured before and after the role play. Cardiovascular indices were measured continuously during the experiment. RESULTS: Significant interactions were obtained such that Caucasians showed stronger cardiovascular responses to suppression than expression of anger whereas the opposite was true for Chinese. CONCLUSIONS: These results demonstrate that physiological consequences of emotion regulation strategies vary by cultural background. Possible reasons as well as implications of these findings are discussed. PMID- 23107996 TI - Neural mechanisms of selective exposure: an EEG study on the processing of decision-consistent and inconsistent information. AB - Decision makers tend to prefer decision-consistent information and/or neglect decision-inconsistent information (selective exposure). In the present EEG study the neural mechanisms of the classic selective exposure effect were examined by investigating oscillatory brain responses to consistent vs. inconsistent information. Twenty participants made an economic decision and subsequently were exposed to 45 consistent and 45 inconsistent images concerning their decision. EEG was recorded from 31 electrodes and differences between oscillatory brain responses towards consistent and inconsistent information were examined. The main result was an increase of induced theta power (5-8Hz, 0-0.7s) in the consistent compared to the inconsistent condition at right temporo-parietal electrodes, as well as a corresponding increase of evoked theta power at frontal electrodes. Since theta oscillations are often observed during memory formation, we conclude that decision-consistent information triggers memory formation, whereas decision inconsistent information seems not to do so. This finding supports the classic motivational perspective of Leon Festinger on the selective exposure effect. PMID- 23107998 TI - A commentary on "Suppurative osteomyelitis, bisphosphonate induced osteonecrosis, osteoradionecrosis: a blinded histopathologic comparison and its implications for the mechanism of each disease" by R.E. Marx and R. Tursun [Int. J. Oral Maxillofac. Surg. 41 (2012) 283-289]. PMID- 23107997 TI - Structural insight into inositol pyrophosphate turnover. AB - The diphosphoinositol polyphosphates ("inositol pyrophosphates"; PP-InsPs) regulate many cellular processes in eukaryotes, including stress responses, apoptosis, vesicle trafficking, cytoskeletal dynamics, exocytosis, telomere maintenance, insulin signaling and neutrophil activation. Thus, the enzymes that control the metabolism of the PP-InsPs serve important cell signaling roles. In order to fully characterize how these enzymes are regulated, we need to determine the atomic-level architecture of their active sites. Only then can we fully appreciate reaction mechanisms and their modes of regulation. In this review, we summarize published information obtained from the structural analysis of a human diphosphoinositol polyphosphate phosphohydrolase (DIPP), and a human diphosphoinositol polyphosphate kinase (PPIP5K). This work includes the analysis of crystal complexes with substrates, products, transition state analogs, and a novel phosphonoacetate substrate analog. PMID- 23107999 TI - Ex-vivo production of oral mucosa keratinocytes by the direct explant method. AB - The authors describe a simple and time saving technique for the ex-vivo production of oral mucosa keratinocytes by the direct explant method. PMID- 23108001 TI - A probabilistic account of exemplar and category generation. AB - People are capable of imagining and generating new category exemplars and categories. This ability has not been addressed by previous models of categorization, most of which focus on classifying category exemplars rather than generating them. We develop a formal account of exemplar and category generation which proposes that category knowledge is represented by probability distributions over exemplars and categories, and that new exemplars and categories are generated by sampling from these distributions. This sampling account of generation is evaluated in two pairs of behavioral experiments. In the first pair of experiments, participants were asked to generate novel exemplars of a category. In the second pair of experiments, participants were asked to generate a novel category after observing exemplars from several related categories. The results suggest that generation is influenced by both structural and distributional properties of the observed categories, and we argue that our data are better explained by the sampling account than by several alternative approaches. PMID- 23108000 TI - Association between kidney function and telomere length: the heart and soul study. AB - BACKGROUND: Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening. METHODS: The Heart and Soul Study is a longitudinal study of patients with stable coronary heart disease. Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFR(CKD-EPI)), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (n = 954) and 5 years later (n = 608). Linear regression models were used to test the association of kidney function with (i) baseline telomere length and (ii) change in telomere length over 5 years. RESULTS: At baseline, mean eGFR(CKD-EPI) was 72.6 (+/-21.5) ml/min/1.73 m(2), eGFRcys was 71.0 (+/-23.1) ml/min/1.73 m(2) and ACR was 8.6 (+/-12.3) mg/g. Only lower baseline eGFR(CKD-EPI) was associated with shorter baseline telomere length (9.1 (95% CI 1.2-16.9) fewer base pairs for every 5 ml/min/1.73 m(2) lower eGFR(CKD EPI)). Lower baseline eGFR(CKD-EPI) (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 (95% CI 4.3-17.3) decrease in base pairs over 5 years for every 5 ml/min/1.73 m(2) lower eGFR(CKD-EPI)). After adjustment for age, these associations were no longer statistically significant. CONCLUSIONS: In patients with coronary heart disease, reduced kidney function is associated with (i) shorter baseline telomere length and (ii) more rapid telomere shortening over 5 years; however, these associations are entirely explained by older age. PMID- 23108002 TI - Tribute to Bart Kamen. PMID- 23108003 TI - Back pain among long-term survivors of childhood leukemia. AB - BACKGROUND: The objectives of this study are to determine the prevalence and relative risk (RR) of back pain and identify possible mechanisms of back pain among childhood acute lymphoblastic leukemia (ALL) survivors. METHODS: Surveys were mailed to 5 + -year survivors of childhood ALL aged 13 to 25 years. Survivors' siblings were also invited to participate in the study. Prevalence of back pain and hip pain among ALL survivors was determined and compared with siblings. Sex, treatment with radiation therapy, obesity, and physical activity were examined for an association with back pain and hip pain. RESULTS: Forty-four of 99 (44.4%) ALL survivors reported back pain compared with 11 of 52 (21.2%) their siblings (P = 0.007; RR: 2.01; 95% confidence interval = 1.15-3.56). In contrast, 10 of 99 (10.1%) ALL survivors reported experiencing hip pain compared with 1 of 52 (2.0%) siblings experiencing hip pain [P = 0.07; RR: 4.95 (0.65 to 37.57)]. Twenty-six of 43 female survivors reported back pain compared with 18 of 56 male survivors who reported back pain (P = 0.005). Obesity, physical activity, and treatment with radiation therapy were not associated with back pain or hip pain. CONCLUSIONS: This is the first study demonstrating an increased frequency of back pain among survivors of childhood ALL. Future studies are needed to better define the causes of back pain among childhood ALL survivors. PMID- 23108004 TI - Premature atherosclerosis in children with beta-thalassemia major. AB - OBJECTIVES: In this study, we aimed to investigate the relationship between chronic hemolysis and increased body iron burden with development of premature atherosclerosis by carotid intima-media thickness (IMT), ferritin, serum lipid profile, homocysteine, nitrate/nitrite, and chitotriosidase enzyme activity in children with beta-thalassemia major. MATERIALS AND METHODS: A total of 31 children with a diagnosis of beta-thalassemia major between the ages of 4 to 16 years constituted the study group. Control group was consisted of 36 age-matched healthy children. Complete blood count, serum glucose, lipid profile, ferritin, homocysteine, calcium, chitotriosidase, and nitrate/nitrite levels were measured and electrocardiographic and echocardiographic investigation and carotid IMT measurement were performed. RESULTS: In study group serum total cholesterol, low density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were found to be significantly reduced, and very-low-density lipoprotein cholesterol levels were found to be significantly elevated. Plasma nitrate/nitrite levels were significantly reduced; chitotroisidase enzyme activity was significantly increased and carotid IMT was significantly increased in study group. Nitrate/nitrite was found to be the only variable that was statistically significantly related to carotid IMT. CONCLUSIONS: Subclinical atherosclerosis in children with beta-thalassemia major begins early in life, and these children are at risk for development of premature atherosclerosis. PMID- 23108005 TI - A natural tetrahydropyrimidine, ectoine, ameliorates ischemia reperfusion injury after intestinal transplantation in rats. AB - BACKGROUND/AIMS: Ischemia reperfusion (I/R) injury after small bowel transplantation leads to inflammatory reactions and loss of structural integrity with subsequent graft contractile dysfunction in the early postoperative phase. The natural tetrahydropyrimidine ectoine (1-,4-,5-,6-tetrahydro-2-methyl-4 pyrimidine carboxylic acid; THP) protects the ileal mucosa and muscularis against effects of I/R injury in an experimental model of isolated graft reperfusion. The effects of THP treatment were evaluated in an established experimental intestinal transplant model. METHODS: Isogenic, orthotopic small bowel transplantation was performed in Lewis rats (6 h cold ischemia time). Perioperative THP treatment (intraluminal/intravascular) groups were compared to vehicle-treated animals (after 3 and 24 h) and non-transplanted controls (n = 5/group). Park's score defined the effects of I/R injury. The infiltration of neutrophils, monocytes and macrophages, mRNA expression of IL-6 and TNF-alpha, serum levels of IL-6 and NO and smooth muscle contractility were evaluated. RESULTS: Improved graft outcome after intraluminal and intravascular THP treatment was defined by considerably ameliorated neutrophil infiltration and less histological signs of I/R injury (p <= 0.05). In the presence of THP, mRNA expression of IL-6 and TNF-alpha and IL-6 and NO serum levels were reduced and smooth muscle function was improved. CONCLUSION: THP treatment offers protection against the effects of I/R injury in intestinal transplantation in vivo, however, only as supplementary treatment option. PMID- 23108006 TI - Regenerative potential of the zebrafish corneal endothelium. AB - Corneal transparency, critical for clear vision, is maintained in part by the pump function of the corneal endothelial cells that are arrested in G(1) phase of the cell cycle in adult humans. Thus loss of endothelial cells leads to a decrease in endothelial cell density. A decrease below a critical threshold results in corneal edema and subsequent vision loss. Corneal edema due to endothelial dysfunction is a common indication for transplantation in developed countries. The zebrafish has emerged as a model for vertebrate regeneration due to its ease of genetic manipulation and remarkable regenerative capacity. The purpose of this study was to investigate the response and regenerative potential of the zebrafish corneal endothelium to pharmacological and mechanical injury. Similar to the human cornea, Na(+)/K(+) ATPase activity is necessary to maintain the pump function as intracameral injection of ouabain resulted in an increase in central corneal thickness. Surgical removal of the majority of the central corneal endothelium resulted in a similar increase in corneal thickness. Remarkably, by just one week post-injury the central corneal endothelium had largely re-formed. Immunofluorescence of phosphorylated histone H3 indicated that this recovery correlated with corneal endothelial cells re-entering the cell cycle. In conclusion, our results establish zebrafish as a useful model of corneal injury and repair that may offer insights into the mechanism of cell cycle arrest in human corneal endothelial cells. PMID- 23108007 TI - Comparison of subjective grading and objective assessment in meibography. AB - AIM: To analyse repeatability of subjective grading and objective assessment in non-contact infra-red meibography. METHODS: Meibography photographs of 24 subjects (female 14; mean age=46; range=19-69 years, upper-lid images=12, lower lid images=12) were classified in two sessions by three experienced observers (OI, OII, OIII). Relative area or portion affected by meibomian glands (MG) loss was classified applying three different grading scales in randomized order: a four-grade scale (4S) (degree 0=no partial glands; 1=<25% partial glands; 3=25 75% partial glands; 3=>75% partial glands), a pictorial five-grade scale (5S) (degree 0=no meibomian gland loss (MGL); 1=<25% MGL; 3=26-50% MGL; 3=51-75%; 4=>75% MGL) and objectively by a 100-grade scale (DA) applying ImageJ software. RESULTS: Observed MG loss ranged from 0% to 69%. Intra-observer agreement of the 5S (OI: kappa=0.80, p<0.001; OII: kappa=0.40, p=0.009; OIII kappa=0.81, p<0.001) was better than of the 4S (OI: kappa=0.79, p<0.001; OII: kappa=0.15, p=0.342; OIII kappa=0.50, p=0.0071). Intra-observer agreement of OI and OIII (+/-0.88 (95% confidence interval), +/-1.305) was better than of OII (+/-2.21) in 4S and 5S (+/ 0.99, +/-2.00 and +/-0.91; OI, OII and OIII, respectively) while it was relatively similar in DA (+/-18, +/-17 and +/-17). Inter-observer agreement was better in DA (OI-OII: +/-13, OI-OII: +/-19, OII-OIII: +/-26) than in 4S (OI-OII: +/-1.76; OI-OIII: +/-1.29 and OII-OIII: +/-1.31) or 5S (OI-OII: +/-1.49; OI-OIII: +/-0.91 and OII-OIII: +/-1.20). CONCLUSION: Intra-observer and inter-observer agreement was better in computerized grading followed by the subjective five grade scale and four-grade scale. PMID- 23108008 TI - Clinical performance and "ex vivo" dehydration of silicone hydrogel contact lenses with two new multipurpose solutions. AB - PURPOSE: To compare the performance of two novel multipurpose disinfecting solutions (MPDS) in preventing silicone hydrogel contact lens dehydration, provide higher scores of subjective comfort and stable optical quality during a month of lens wear in neophyte volunteers. METHOD: This is a prospective, double blind, contralateral and randomised study involving the contra lateral use of Complete RevitaLens and Biotrue MPDS. Twenty-five neophytes wore Air Optix Aqua for 1 month. Volunteers were evaluated on day 1 and day 30 at 2 and 10h after lens insertion. Tear film stability using Tearscope Plus (Keeler, UK), whole eye aberrations for 4.5mm pupil size (IRx3, ImaginEyes, France) and subjective comfort (0-10 score) along with the dehydration values obtained with a gravimetric method were collected at each follow-up visit. RESULTS: NIBUT values decreased significantly with both care systems from baseline to 10h visit on day 1 (p=0.032 and 0.016, mean difference=-6.7s and -7.0 s, for Complete Revitalens and Biotrue, respectively). Dehydration rates and ocular aberrations did not change significantly over the month of follow-up (p>0.05, ANOVA with Bonferroni post hoc corrections), nor between visits within the same day (p>0.05, paired sample T-test). End-of-day dryness sensation worsened similarly with both MPDS after 1 month (p=0.021 and 0.005, mean difference=-1.4 and -1.3, for Complete Revitalens and Biotrue, respectively). CONCLUSIONS: Regardless of their different chemical compositions in terms of moisture additives both MPDS solutions evaluated performed similarly regarding objective measures of dehydration, tear stability and optical quality but presented significant differences in subjective symptoms. PMID- 23108009 TI - Which soft contact lens power is better for piggyback fitting in keratoconus? AB - PURPOSE: To evaluate the impact of differente soft contact lens power in the anterior corneal curvature and regularity in subjects with keratoconus. METHODS: Nineteen subjects (30 eyes) with keratoconus were included in the study. Six corneal topographies were taken with Pentacam Eye System over the naked eye and successively with soft lens (Senofilcon A) powers of -3.00, -1.50, 0.00, +1.50 and +3.00 D. Corneal measurements of mean central keratometry (MCK), maximum tangential curvature (TK), maximum front elevation (MFE) and eccentricity (Ecc) at 6 and 8 mm diameters as well as anterior corneal surface high order aberrations (i.e. total RMS, spherical- and coma-like and secondary astigmatism) were evaluated. RESULTS: Negative- and plano-powered soft lenses flattened (p<0.05 in all cases), whereas positive-powered lenses did not induce any significant changes (p>0.05 in all cases) in MCK in comparison to the naked eye. The TK power decreased with negative lenses (p<0.05 in both cases) and increased with +3.00 D lenses (p=0.03) in comparison to the naked eye. No statistically significant differences were found in MFE with any soft lens power in comparison to the naked eye (p>0.05 in all cases). Corneal eccentricity increased at 8 mm diameter for all lens powers (p<0.05 in all cases). No statistically differences were found in HOA RMS and spherical-like aberration (both p>0.05). Statistically differences were found in coma-like and secondary astigmatism (both p<0.05). CONCLUSION: Negative-powered soft contact lenses provide a flatter anterior surface in comparison to positive-powered lenses in subjects with keratoconus and thus they might be more suitable for piggyback contact lens fitting. PMID- 23108010 TI - UVB-induced epidermal pigmentation in mice eyes with no contact lens wear and non UVB blocking and UVB blocking contact lens wear. AB - PURPOSE: Irradiation by ultraviolet (UV) B is known to increase the number of Dopa-positive melanocytes in the skin. This study examines the effectiveness of a contact lens for the defense of UVB eye irradiation-induced pigmentation. METHODS: A 2.5 kJ/m(2) dose of UVB radiation was delivered by a sunlamp to the eye of C57BL/6j male mice, and changes in the expression of Dopa-positive melanocytes in the epidermis and the plasma level of alpha-melanocyte-stimulating hormone (alpha-MSH) was analyzed. RESULTS: The degree of change in the Dopa positive melanocytes expression was reduced by UVB blocking contact lens using mice given UVB irradiation to the eye. The plasma level of alpha-MSH increased in the C57BL/6j mice after irradiation to the eye, but there was no increase in the UVB blocking contact lens mice given UVB irradiation to the eye. Both the increase of the expression of Dopa-positive melanocytes and the plasma level of alpha-MSH were strongly suppressed by an alignment fitting UVB blocking contact lens and only a slightly suspended UVB blocking contact lens. In addition, these changes were successfully inhibited by a UVB blocking contact lens but not by a non-UVB blocking contact lens with a similar absorbance. CONCLUSION: These observations suggest that the UVB blocking contact lens inhibits the pigmentation of the epidermis in mice by suppressing of the alpha-MSH. PMID- 23108011 TI - Near complete visual recovery and refractive stability in modern corneal transplantation: Descemet membrane endothelial keratoplasty (DMEK). AB - OBJECTIVE: To report the 6 months results of a large prospective study on Descemet membrane endothelial keratoplasty (DMEK) for management of corneal endothelial disorders. METHODS: DMEK was performed in 300 consecutive eyes with Fuchs endothelial dystrophy, bullous keratopathy or previous corneal transplant failure. Best spectacle corrected visual acuity (BSCVA), refractive outcome and endothelial cell density (ECD) were evaluated before and at 1, 3, and 6 months after surgery. Intra- and postoperative complications were documented. RESULTS: At 6 months, 98% of eyes reached a BCVA of >=20/40 (>=0.5), 79% >=20/25 (>=0.8), 46% >=20/20 (>=1.0), and 14% >=20/18 (>=1.2) (n=221). The pre- to 6 months postoperative spherical equivalent (SE) showed a +0.33D (+/-1.08D) hyperopic shift (P=0.0000). Refractive stability was shown at 3 months after DMEK, i.e. no significant change in SE (P=0.0822) or refractive cylinder (P=0.6182) at 3 versus 6 months follow-up. Donor ECD showed a decrease from 2561 (+/-198)cells/mm(2) before, to 1674 (+/-518)cells/mm(2) at 6 months after surgery (n=251) (P=0.0000). The main complication was (partial) graft detachment occurring in 31 eyes (10%). Secondary ocular hypertension was seen in 13 eyes (6%): 6 induced by air-bubble dislocation posterior to the iris and 4 induced by steroids. Secondary cataract requiring phaco-emulsification developed in 3 out of 63 (5%) phakic eyes. CONCLUSIONS: DMEK may provide a refractively neutral near complete, rapid visual rehabilitation with ECDs similar to earlier endothelial keratoplasty techniques. This combined with a relatively low complication rate, would indicate that DMEK is a safe and effective treatment for corneal endothelial disorders. PMID- 23108012 TI - Activation of AMP-activated protein kinase inhibits albumin-induced endoplasmic reticulum stress and apoptosis through inhibition of reactive oxygen species. AB - BACKGROUND: Endoplasmic reticulum (ER) stress induced by urinary albumin plays an important role in tubulointerstitial injury. We have shown that albumin-induced ER stress is regulated through reactive oxygen species (ROS)-c-Src kinase-mTOR signaling pathways. We postulated that peroxisome proliferator-activated receptor gamma (PPAR-gamma) might also act as an upstream signaling molecule between c-Src kinase and mTOR. It has been suggested that AMP-activated protein kinase (AMPK) is involved in attenuation of ER stress. We examined whether and how activation of AMPK suppressed the albumin-induced ER stress and apoptosis in tubular epithelial cells. METHOD: HK-2 cells, a proximal tubular cell line, were used. Protein expressions were measured by Western blot analysis. Intracellular ROS and apoptosis were analyzed by flow cytometry. RESULTS: Albumin-induced PPAR-gamma expression and PPAR-gamma inhibitor (GW9662) suppressed the albumin-induced ER stress. c-Src kinase inhibitor and GW9662 reduced the albumin-induced PPAR-gamma and mTOR, respectively. Metformin (the best known clinical activator of AMPK) and another AMPK activator (AICAR) suppressed the albumin-induced ER stress via inhibition of ROS through induction of endogenous antioxidant thioredoxin. AMPK inhibitor blocked the effect of metformin and AICAR. Our in vivo animal study showed that metformin reduced the renal cortical expression of ER stress protein (GRP78) in protein-overload proteinuria rats. Metformin also reduced the caspase 3-dependent apoptosis induced by albumin. CONCLUSION: PPAR-gamma was involved in albumin-induced ER stress as an upstream signaling molecule between c-Src kinase and mTOR. AMPK activation might be beneficial in attenuating the tubulointerstitial injury induced by albumin. PMID- 23108013 TI - Binuclear nickel complexes with an edge sharing bis(square-pyramidal) N3Ni(MU S2)NiN3 core: synthesis, characterization, crystal structure and magnetic properties. AB - The synthesis of the novel macrocyclic octadentate amino-thiophenolate ligand H(2)L2 (3,7,11,19,23,27-hexaaza-33,34-dithiol-15,31-di(tert-butyl) tricyclo[27,3,1(13.17)]-tetratriaconta-1(32),13,15,17(34),29,30-hexane) and its ability to support binuclear nickel(II) complexes with dithiolato-bridged square pyramidal Ni(II) ions are reported. H(2)L2 is obtained as the hexahydrobromide salt from a Schiff-base condensation reaction between 1,2-bis(4-tert-butyl-2,6 diformylphenylthio)ethane and bis(3-aminopropyl)amine followed by two successive reductions with NaBH(4) and Na/NH(3). The ligand forms a green, paramagnetic, binuclear nickel(II) complex dication [Ni(II)(2)L2](2+), which can be isolated as a ClO(4)(-) (4) or BPh(4)(-) salt (5). The binuclear nickel(II) complex contains a central N(3)Ni(MU-S)(2)NiN(3) core with two square-pyramidal coordinated Ni(II) ions. The [Ni(2)L2](2+) dication does not bind further coligands, in striking contrast to the behaviour of the parent [Ni(2)L1](2+) dication supported by the smaller (L1)(2-) macrocycle (containing diethylenetriamine in place of the dipropylenetriamine units) which readily binds a variety of other coligands (L') to form bisoctahedral [Ni(2)L1(L')](+) structures. The unusual behaviour of 4 relates to two different N configurations which leads to a steric shielding of the third bridging position by the CH(2)-groups of the dipropylenetriamine chains. An analysis of the temperature-dependent magnetic susceptibility data of 5 reveals the presence of a weak antiferromagnetic exchange interaction between the spins of the nickel(II) ions with a value for the magnetic exchange coupling constant J of -23.5 cm(-1) (H = -2JS(1)S(2)). These results are further substantiated by DFT calculations. PMID- 23108014 TI - Doping BiFeO3: approaches and enhanced functionality. AB - BiFeO(3) is one of the most studied multiferroic materials. Both its magnetic and ferroelectric properties can be influenced by doping. A large body of work on the doped material has been presented in the past couple of years. In this paper we provide a perspective on general doping concepts and their impact on the material's functionality. PMID- 23108016 TI - Enthesitis in psoriatic disease. AB - Enthesitis is increasingly recognized as an important component in psoriatic arthritis (PsA). Improved imaging techniques have expanded our understanding of the role of enthesitis in PsA and provided methods for earlier detection and assessment. Increased knowledge about the extent of tendon and ligament involvement has led to the theory that enthesitis may be the primary event in PsA. Given the historical difficulties in detecting and measuring enthesitis, its inclusion as an endpoint in PsA trials has been limited. Current trial data suggest that tumour necrosis factor inhibitors can successfully treat PsA-related enthesitis, which may have implications for the long-term prognosis of PsA. In this article, we review methods for detecting and assessing enthesitis, current thinking regarding the role of enthesitis in the pathogenesis of PsA, and trial evidence for the treatment of PsA and, therefore, enthesitis. PMID- 23108015 TI - Effect of music as nursing intervention for people diagnosed with fibromyalgia. AB - Primary fibromyalgia, a poorly understood chronic pain syndrome, is a disorder of uncertain etiology. The ultimate goal of fibromyalgia treatment is to develop a multimodal therapy. In recent years, the use of music as an intervention for the pain management and other symptoms has increased. The purpose of this study was to investigate the effects of music on pain and depression for people diagnosed with fibromyalgia using Rogers' theory of the unitary human being as the theoretical framework. An experimental 4-week longitudinal trial design was undertaken. Sixty patients diagnosed with fibromyalgia were randomly assigned to either a music intervention group or a control group. Music interventions consisted of listening to music once a day for 4 consecutive weeks using two types of CDs. Pain was measured with the McGill Pain Questionnaire Long Form and depression with the Beck inventory; a 100-mm visual analog scale was used to measure pain and depression. The treatment group reported a significant reduction in pain and depression at week 4 compared with the control group. Members of the control group reported no differences in pain. The findings of this pilot study suggest the importance of music therapy as a nursing intervention and justify further investigation into music as a self-management intervention to reduce pain and depression. PMID- 23108017 TI - Transitional cell-like morphology in ovarian endometrioid carcinoma: morphologic, immunohistochemical, and behavioral features distinguishing it from high-grade serous carcinoma. AB - Transitional cell-like growth has been reported as a morphologic variant of endometrioid adenocarcinoma in the uterus but is not well-described in the ovary. We report the clinicopathologic features of a series of ovarian endometrioid adenocarcinomas with transitional cell-like morphology, emphasizing the distinction from its mimics, including high-grade serous carcinoma, transitional cell carcinoma, and granulosa cell tumor. Among a cohort of 71 ovarian endometrioid adenocarcinomas surgically staged at our institution, 10 tumors (14%) exhibited transitional cell-like morphology. Patient age ranged from 39 to 79 years (mean, 52 y). Five tumors were stage I, 2 were stage II, and 3 stage III. The tumors ranged from 8.5 to 23 cm, and the transitional cell-like component occupied from 5% to 90% of the overall tumor, with the remainder being conventional endometrioid adenocarcinoma. The most compelling findings to support that this tumor pattern represents a morphologic variant of endometrioid adenocarcinoma are that the transitional cell-like components (1) merged directly and seamlessly with the conventional endometrioid component; (2) contained areas of mature or immature squamous differentiation; (3) lacked WT1 immunoexpression; (4) lacked the characteristic p53/p16 immunophenotype of high-grade serous carcinoma; and (5) did not appear to independently affect patient outcome. Two patients (20%) whose tumor contained transitional cell-like morphology died, whereas 14 patients (23%) lacking this morphology died. Although uncommon, transitional cell-like morphology appears to be a variant growth pattern of ovarian endometrioid adenocarcinoma that does not affect behavior and that should be distinguished from high-grade serous carcinoma and conventional ovarian transitional cell carcinoma. PMID- 23108018 TI - Venous invasion in colorectal cancer: impact of an elastin stain on detection and interobserver agreement among gastrointestinal and nongastrointestinal pathologists. AB - Venous invasion (VI) is an independent prognostic indicator in colorectal cancer and may prompt consideration for adjuvant chemotherapy in patients with stage II tumors. Recent evidence suggests that VI is underreported in colorectal cancer and that detection may be enhanced by an elastin stain. This study aimed (1) to determine the impact of an elastin stain on VI detection and on interobserver agreement between gastrointestinal (GI) and non-GI pathologists, and (2) to identify factors associated with increased VI detection. Forty hematoxylin and eosin (H&E)-stained slides were circulated to 6 GI and 6 non-GI pathologists who independently assessed the VI status as positive, negative, or equivocal. Six weeks later, 40 corresponding Movat-stained slides were recirculated together with the original H&E slides and reassessed for VI status. Detection of VI was >2 fold higher with a Movat stain compared with an H&E stain alone (46.4% vs. 19.6%, P=0.001). GI pathologists detected VI more frequently than non-GI pathologists on both H&E (30.0% vs. 9.2%, P=0.029) and Movat (58.3% vs. 34.6%, P=0.018) stains. There was higher interobserver agreement in the case of a Movat stain, particularly for extramural VI (H&E: kappa=0.23 vs. Movat: kappa=0.41). A poststudy survey indicated that GI pathologists and non-GI pathologists applied similar diagnostic criteria but that GI pathologists more frequently applied "orphan arteriole" and "protruding tongue" signs as diagnostic clues to VI. This study confirms that VI is underdetected on H&E and highlights the role of elastin staining in improving VI detection and interobserver agreement. Strategies to improve VI detection are warranted. PMID- 23108019 TI - Intrapulmonary solitary fibrous tumors: clinicopathologic and immunohistochemical study of 24 cases. AB - Solitary fibrous tumor (SFT) is a ubiquitous neoplasm that arises most commonly from the pleura. SFT arising within lung parenchyma (intrapulmonary SFT) has been rarely reported and is therefore not well recognized. We present a clinicopathologic and immunohistochemical study of 24 cases of primary intrapulmonary SFT. Patients' ages ranged from 44 to 83 years (mean, 58 y). None of the patients had evidence or history of a similar tumor elsewhere. Tumor size ranged from 2.3 to 22 cm (mean, 8.5 cm). On the basis of the degree of cytologic atypia, cellularity, mitotic activity, and areas of necrosis, the lesions were divided into low-grade, intermediate-grade, and high-grade histology. Twenty-one tumors showed the conventional features of SFT of low-grade histology (<5 mitoses per 10 high-power fields), with alternating bands of rope-like collagen flanked by a bland-appearing spindle cell proliferation. Hemangiopericytic, angiofibromatous, and a neural-like plexiform growth pattern were also observed. Five of 21 cases showed an "adenofibromatous" appearance imparted by entrapped normal airspaces at the advancing edges of the lesion. One intermediate-grade tumor showed overall increased cellularity with plump, pleomorphic nuclei, 5 to 10 mitoses per 10 high-power fields, and focal areas of classic SFT. Two cases showed high-grade features at initial presentation, with areas resembling a pleomorphic high-grade sarcoma admixed with foci of conventional, low-grade SFT. Immunohistochemical staining analyses performed in 13 cases showed positivity of the tumor cells for CD34, bcl-2, and CD99 in the majority of cases tested. Clinical follow-up was available in 18 patients, with long-term follow-up (>5 y) in 6. Fourteen (14/18) patients were alive and well without evidence of disease 1 month to 14 years after initial diagnosis. Three patients died of their tumors after 4, 5, and 7 years; in 2 of them the initial tumor was of low-grade histology, but the recurrence/metastases showed a high-grade histology; the third fatal case showed a tumor with high-grade histology at initial diagnosis. One patient with intermediate-grade histology also had chest wall metastases at 5 years but was subsequently lost to follow-up. The results of our study indicate that although tumors with overtly malignant histologic features can be expected to behave as high-grade sarcomas, tumors with bland-appearing morphologic features at presentation may also follow an aggressive behavior. Adequate excision with close clinical follow-up, thus, appears to be the most prudent course of action for the management of primary intrapulmonary fibrous tumors. PMID- 23108020 TI - Clinicopathologic characteristics of HER2 FISH-ambiguous breast cancer at a single institution. AB - BACKGROUND: : The typical algorithm for human epidermal growth factor-2 (HER2) testing is immunohistochemistry (IHC), followed by reflex HER2 fluorescence in situ hybridization (FISH) for HER2 IHC-ambiguous (2+) cases. At our institution, HER2 FISH testing is initially performed as part of routine breast cancer testing, with HER2 FISH-ambiguous (HER2:CEP17 ratio, 1.8 to 2.2) cases reflexed to HER2 IHC. This provides a unique dataset for lesions that may not routinely undergo FISH testing. The clinicopathologic characteristics of HER2 FISH ambiguous cases are described. DESIGN: : The electronic pathology database in our institution was searched for HER2 FISH-ambiguous cases from 2007 to December 2011. Review of clinical and pathologic characteristics was performed. RESULTS: : Sixty cases from 60 patients were reported as HER2 FISH ambiguous. Reflex HER2 IHC testing was performed on all 60 cases, of which 26 were HER2 IHC negative (0 to 1+), 18 were HER2 IHC ambiguous (2+), and 16 were HER2 IHC positive (3+). Of the 46 HER2 FISH-ambiguous patients with available clinical records, 13 (32%) pursued anti-HER2 treatment (10 IHC 3+, 1 IHC 2+, 2 IHC 0 to 1+). All were grade II or III ductal carcinomas, with 1 grade III metaplastic carcinoma. CONCLUSIONS: : Reflex HER2 IHC testing after initially ambiguous HER2 FISH testing provides definitive HER2 status in a majority of cases (70%). However, a substantial percentage (30%) of HER2 FISH-ambiguous cases is also HER2 IHC ambiguous, suggesting an intermediate HER2 biology. Most HER2 FISH-ambiguous patients who received trastuzumab were HER2 IHC 3+, grade III, and had associated high-grade ductal carcinoma in situ. Although not statistically significant and with only minimal follow-up, no recurrences have occurred in those patients treated with trastuzumab (P=0.5754). PMID- 23108021 TI - IMP3 and GLUT-1 immunohistochemistry for distinguishing benign from malignant mesothelial proliferations. AB - Distinguishing malignant mesotheliomas from benign mesothelial proliferations on hematoxylin and eosin-stained sections can be extremely challenging. Various immunohistochemical stains have been suggested to help in making this distinction, but all are controversial. Recently, IMP3 (insulin-like growth factor II mRNA binding protein 3) and GLUT-1 (glucose transporter protein 1) have been proposed as immunohistochemical markers that are positive in mesotheliomas but not in benign proliferations. We evaluated the performance of these markers on a tissue microarray containing 30 malignant mesotheliomas and 48 benign thoracic or abdominal mesothelial proliferations. IMP3 was positive in 53% of malignant and 27% of benign cases (P=0.03), whereas GLUT-1 was positive in 60% of malignant and 13% of benign cases (P=0.0003). Forty-three percent of malignant cases, but only 4% of benign cases, were positive for both IMP3 and GLUT-1 (P=0.00003). We conclude that, statistically, both IMP3 and GLUT-1 are more frequently positive in malignant compared with benign mesothelial processes; however, the frequency of positive staining in benign cases is too high to allow their diagnostic use as single stains. The combination of both markers may be of greater diagnostic value, but this hypothesis should be confirmed in further studies. PMID- 23108022 TI - The clinical significance of focally enhanced gastritis in children. AB - Focally enhanced gastritis (FEG) was initially described in patients with inflammatory bowel disease (IBD), but subsequent reports found this to be a nonspecific finding in adults. Initial reports suggest that FEG may be more predictive of IBD in pediatric patients, but this has yet to be confirmed. The aim of our study was to characterize and determine clinical correlates of FEG in pediatric patients. Gastric biopsies from pediatric patients who were diagnosed with FEG at a single tertiary care center over a 5-year period were reviewed (5-y cohort study). In a subsequent study, all gastric biopsies from pediatric patients in the single center over a 1-year period were reviewed. Biopsies were reviewed in a blinded manner by 2 pathologists, and histologic data of interest were recorded. Clinical data and follow-up data were recorded from review of the electronic medical records. Of the 25 patients with FEG in the 5-year cohort study, IBD was present in 19 (76%) patients. Crohn disease (CD) was more common than ulcerative colitis (UC) among these patients (68% vs. 16%). In the 1-year review study with 262 gastric biopsies, FEG was present in 31 (11%) cases. Patients with FEG were significantly more likely to have IBD than non-FEG patients (61.3% vs. 11.6%, P<=0.001). Of the 19 patients with FEG and IBD, 9 patients had CD, 9 patients had UC, and 1 had indeterminate colitis. The presence of FEG is highly associated with IBD in pediatric patients. The presence of FEG does not reliably distinguish between patients with CD and those with UC. PMID- 23108023 TI - Primary intrathoracic dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans (DFSP) is defined as a low-grade sarcoma derived from an uncertain cell of origin in the reticular dermis. We report a fibrosarcomatous variant of DFSP (FS-DFSP) that arose primarily in the deep thoracic soft tissue. The patient was a 9-year-old girl who presented with dyspnea and low-grade fevers without a clinically detectable mass or a history of skin lesion. Imaging studies revealed a 10-cm mass entirely confined within the thoracic cavity. Three years after a marginal excision with adjuvant chemotherapy and radiotherapy, the tumor recurred in the paraspinal region. Histologically, the primary and recurrent tumors comprised a high-grade spindle cell sarcoma, with a small component of storiform, low-grade, CD34-positive spindle cells, classic for an ordinary DFSP. The diagnosis of FS-DFSP was confirmed molecularly by the demonstration of a COL1A1-PDGFB fusion by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analyses. To our knowledge, this is the first documented case of a genetically confirmed deep seated DFSP without an associated superficial soft tissue or dermal component. The implication of this case on expanding the clinical spectrum of DFSP will have to be elucidated in future studies by applying molecular pathologic tools in deep seated sarcomas in the proper morphologic context. PMID- 23108024 TI - Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. AB - Follicular lymphoma (FL), a common lymphoma in adults, occurs rarely in pediatric and young adult patients. Most pediatric cases have been described as grade 3, but the criteria to distinguish the pediatric variant of FL (PFL) from usual FL (UFL) seen in adults are not well defined. We undertook a study of FL in patients under the age of 30. We identified 63 cases, which were analyzed by morphology, immunohistochemistry, and polymerase chain reaction analysis of IGH@ and IGK@ clonality. These data were correlated with clinical findings including stage, treatment, and outcome. Among the 63 cases, 34 cases were classified as PFL: 22 presenting in lymph nodes, 8 in the Waldeyer ring, and 4 in the testis. Clonal immunoglobulin gene rearrangement was detected in 97% of PFL cases, but fluorescence in situ hybridization analysis showed an absence of the BCL2/IGH@ translocation in all cases tested. Twenty-nine cases were classified as UFL, 28 of which presented in lymph nodes. The nodal PFLs were observed exclusively in male patients in both children and young adults with a median age of 15 years. They showed marked head/neck predilection, blastoid cytologic features with a high proliferation rate, lack of BCL2 protein and t(14;18), low clinical stage at presentation, and good prognosis. PFLs involving the Waldeyer ring were distinguished by MUM1 expression, 50% (3/6) of which carried IRF4 breaks. BCL2 expression was common (63%) in the absence of BCL2/IGH@ translocation. UFLs were more common in female patients, exclusively in young adults (median age, 24 y), with no cases reported in patients under the age of 18. Twenty-five of 29 cases were of grade 1-2, and 4 cases were classified as grade 3A. They exhibited a higher clinical stage at presentation. Eighty-three percent expressed BCL2. Our results indicate that histologic and immunophenotypic criteria can reliably separate PFL and UFL and that UFL is exceptionally rare in the pediatric age group. PFL associated with particular anatomic sites have distinctive features and should be evaluated separately in future clinical and biological studies. PMID- 23108025 TI - HNF4alpha as a marker for invasive mucinous adenocarcinoma of the lung. AB - A new lung adenocarcinoma classification was recently proposed by IASLC/ATS/ERS. In this classification, invasive mucinous adenocarcinoma (IMC) is placed in a new category because of its unique radiologic, morphologic, and genetic characteristics. Minimal cytologic atypia characterizes this tumor; thus, it is occasionally difficult to make a diagnosis with a biopsy specimen. We used immunohistochemistry to examine HNF4alpha expression in a tissue microarray consisting of 278 lung adenocarcinoma specimens. In addition, we analyzed the clinicopathologic features, including EGFR, KRAS, and ALK mutation status. HNF4alpha expression was detected in 33 of the 37 surgically resected IMCs. The tumor cells were uniformly labeled with the molecule in all of the corresponding biopsy specimens, whereas the normal cells were not. Although HNF4alpha was also expressed in other lung adenocarcinoma subtypes, those with HNF4alpha expression shared IMC features, including negative TTF-1 expression (P<0.001), positive CDX2 expression (P<0.001), positive KRAS mutation status (P=0.001), and negative EGFR mutation status (P<0.001). Although some ALK-positive adenocarcinomas showed IMC morphology, the tumors were negative for HNF4alpha, suggesting that they belonged to a different group of tumors. We found that HNF4alpha labeled all of the IMC tumors except the ALK-positive adenocarcinomas. Thus, HNF4alpha positivity could serve as a useful marker for overcoming the diagnostic difficulties caused by minimal nuclear atypia and sparse tumor cells in small biopsy samples. Because other adenocarcinoma subtypes with HNF4alpha expression share clinicopathologic features with IMC, these adenocarcinomas, especially the columnar cell type of acinar-predominant adenocarcinoma, might constitute a biological spectrum of IMC. PMID- 23108026 TI - Urinary miR-21, miR-29, and miR-93: novel biomarkers of fibrosis. AB - BACKGROUND: MicroRNAs (miRNAs) play important roles in the progression of renal fibrosis. We studied the urinary levels of miR-21, miR-29 family and miR-93, which are downstream mediators of the transforming growth factor-beta(1) (TGF beta(1)), in patients with immunoglobulin A (IgA) nephropathy. METHODS: We studied the urinary miRNA levels of 43 IgA nephropathy patients and 13 healthy controls. RESULTS: The IgA nephropathy group had significantly lower urinary miR 29b and miR-29c, but higher miR-93 levels than controls. Proteinuria significantly correlated with urinary levels of miR-29b (r = -0.388, p = 0.003) and miR-29c (r = -0.409, p = 0.002). Glomerular filtration rate significantly correlated with urinary levels of miR-21 (r = 0.338, p = 0.028), miR-29b (r = 0.333, p = 0.031) and miR-29c (r = 0.304, p = 0.050). Urinary miR-93 level significantly correlated with glomerular scarring (r = -0.392, p = 0.010). Urinary miRNA level of SMAD3, but not TGF-beta(1), correlated with urinary miR-21 (r = 0.624, p < 0.001), miR-29b (r = 0.566, p < 0.001), miR-29c (r = 0.619, p < 0.001) and miR-93 (r = 0.332, p = 0.032). CONCLUSIONS: Urinary miR-29b and miR 29c levels correlated with proteinuria and renal function, while urinary miR-93 level correlated with glomerular scarring. More importantly, urinary levels of these miRNA targets significantly correlated with urinary SMAD3 level. Our results suggest that these miRNA targets are regulated by the TGF-beta(1)/SMAD3 pathway and they may play important roles in the development of progressive renal fibrosis in IgA nephropathy. PMID- 23108028 TI - Specificity of Ocimum basilicum geraniol synthase modified by its expression in different heterologous systems. AB - Numerous aromatic plant species produce high levels of monoterpenols, using geranyl diphosphate (GPP) as a precursor. Sweet basil (Ocimum basilicum) geraniol synthase (GES) was used to evaluate the monoterpenol profiles arising from heterologous expressions in various plant models. Grapevine (Vitis vinifera) calli were transformed using Agrobacterium tumefasciens and the plants were regenerated. Thale cress (Arabidopsis thaliana) was transformed using the floral dip method. Tobacco (Nicotiana benthamiana) leaves were agro-infiltrated for transient expression. Although, as expected, geraniol was the main product detected in the leaves, different minor products were observed in these plants (V. vinifera: citronellol and nerol; N. benthamiana: linalool and nerol; A. thaliana: none). O. basilicum GES expression was also carried out with microbial system yeasts (Saccharomyces cerevisiae) and Escherichia coli. These results suggest that the functional properties of a monoterpenol synthase depend not only on the enzyme's amino-acidic sequence, but also on the cellular background. They also suggest that some plant species or microbial expression systems could induce the simultaneous formation of several carbocations, and could thus have a natural tendency to produce a wider spectrum of monoterpenols. PMID- 23108027 TI - Hijacking membrane transporters for arsenic phytoextraction. AB - Arsenic is a toxic metalloid and recognized carcinogen. Arsenate and arsenite are the most common arsenic species available for uptake by plants. As an inorganic phosphate (Pi) analog, arsenate is acquired by plant roots through endogenous Pi transport systems. Inside the cell, arsenate is reduced to the thiol-reactive form arsenite. Glutathione (GSH)-conjugates of arsenite may be extruded from the cell or sequestered in vacuoles by members of the ATP-binding cassette (ABC) family of transporters. In the present study we sought to enhance both plant arsenic uptake through Pi transporter overexpression, and plant arsenic tolerance through ABC transporter overexpression. We demonstrate that Arabidopsis thaliana plants overexpressing the high-affinity Pi transporter family members, AtPht1;1 or AtPht1;7, are hypersensitive to arsenate due to increased arsenate uptake. These plants do not exhibit increased sensitivity to arsenite. Co-overexpression of the yeast ABC transporter YCF1 in combination with AtPht1;1 or AtPht1;7 suppresses the arsenate-sensitive phenotype while further enhancing arsenic uptake. Taken together, our results support an arsenic transport mechanism in which arsenate uptake is increased through Pi transporter overexpression, and arsenic tolerance is enhanced through YCF1-mediated vacuolar sequestration. This work substantiates the viability of coupling enhanced uptake and vacuolar sequestration as a means for developing a prototypical engineered arsenic hyperaccumulator. PMID- 23108029 TI - Mullins' syndrome: a new gammopathy-related autoinflammatory syndrome resistant to anakinra. PMID- 23108030 TI - In praise of the literary eponym--Henry V sign. AB - The use of eponyms in medicine is often discouraged. However, the literary eponym should be an exception as it is not linked with many of the difficulties associated with conventional eponyms and offers descriptive brevity and accuracy. Here, we illustrate the point with Henry V sign, which will be familiar to many who have cared for patients in the terminal stage of illness. PMID- 23108031 TI - Osborn waves in a patient with hypothermia due to severe hypothyroidism. PMID- 23108032 TI - The delta wave in Wolff-Parkinson-White syndrome. PMID- 23108033 TI - Soft synthesis of isocyanate-functionalised metal-organic frameworks. AB - We have developed an original synthetic pathway for the conversion of a MIL 68(In)-NH(2) metal-organic framework into its corresponding isocyanate (-NCO) derivative. This two-step soft post-modification technique leads to highly porous isostructural materials. PMID- 23108034 TI - Nuclear spin Hall and Klein tunneling effects during oxidation with electric and magnetic field inductions in graphene. AB - The recent observation of the explosive oxidation of graphene with enhancement for decreasing temperature and the requirements for synchronizing oxidants for collective oxidation-reduction (redox) reactions presented a chemical scenario for the thermal harvesting by the magnetic spin Hall Effect. More experimental data are presented to demonstrate such spin Hall Effect by determining the influence of spins of so-called spectator fermionic cations. Furthermore, the so called spectator bosonic cations are discovered to cause a Klein tunneling effect during the redox reaction of graphene. The Na(+) and K(+), fermionic cations and the Mg(2+) and Ca(2+), bosonic cations were observed and compared under a variety of experimental conditions: adiabatic reactions with initial temperatures (18-22 degrees C); reactions toward infinite dilution; isothermal reactions under nonadiabatic conditions at low temperature of 18 degrees C; reactions under paramagnetic O(2) or diamagnetic N(2) atmospheres of different permeabilities; reactions in applied and no applied external magnetic field; and reactions toward excess concentrations of common and uncommon Na(+) and Mg(2+) cations. The observed reaction kinetics and dynamics under these various, diverse conditions are consistent with the spin Hall mechanism, energy harvesting and short time violation of Second Law of Thermodynamics for redox reactions of graphene by the Na(+)K(+) mixture and are consistent with the Klein tunnel mechanism for the redox reactions of graphene by the Mg(2+)Ca(2+) mixture. Mixed spin Hall and Klein tunnel mechanisms are discovered to slow and modulate explosive redox reactions. Such spin Hall Effect also gives explanation of recent tunneling of electrons through boron nitride. PMID- 23108035 TI - Lung function of infants with congenital lung lesions in the first year of life. AB - BACKGROUND: Several studies have evaluated short-term neonatal outcome in infants with congenital lung lesions (CLL) but clinical course and lung function in the longer term have not yet been documented. We hypothesized that clinical course and lung function would be negatively affected by surgical resection. OBJECTIVE: To evaluate respiratory symptoms and lung function longitudinally in the first year of life in infants with CLL, and to analyse differences herein between infants managed by observation only and infants whose affected lung parts were resected. METHODS: We evaluated respiratory symptoms and lung function at 6 and 12 months in 30 patients with CLL. Functional residual capacity (FRC(p)) and maximal expiratory flow at functional residual capacity (V'(max)FRC) were measured with body plethysmography. SD scores were calculated for V'(max)FRC. RESULTS: Prevalence of respiratory symptoms did not differ between the groups. Mean FRC(p) (95% CI) was 25.3 (23.3-27.3) in the group managed by observation versus 27.3 (25.1-29.6) in the group managed by surgery (p = 0.149). Mean (95% CI) SDS V'(max)FRC was -1.45 (-1.84 to -1.06) versus -1.41 (-1.90 to -0.91) (p = 0.892). Lung function did not change significantly over the 6-month period. CONCLUSION: Surgical resection did not seem to have negatively affected the clinical course and lung function. We recommend pulmonary follow-up of all CLL patients into adulthood to further identify any long-term effects of CLL and observation or surgery. PMID- 23108036 TI - Arsenic inhibits the adipogenic differentiation of mesenchymal stem cells by down regulating peroxisome proliferator-activated receptor gamma and CCAAT enhancer binding proteins. AB - Arsenic remains a top environmental concern in the United States as well as worldwide because of its global existence and serious health impacts. Apoptotic effect of arsenic in human mesenchymal stem cells (hMSCs) has been identified in our previous study; the effects of arsenic on hMSCs remain largely unknown. Here, we report that arsenic inhibits the adipogenic differentiation of human mesenchymal stem cells (hMSCs). Arsenic reduced the formation of lipid droplets and the expression of adipogenesis-related proteins, such as CCAAT enhancer binding protein-(C/EBPs), peroxisome proliferator-activated receptor-gamma (PPAR gamma), and adipocyte fatty acid-binding protein aP2 (aP2). Arsenic mediates this process by sustaining PPAR-gamma activity. In addition, inhibition of PPAR-gamma activity with T0070907 and up-regulation with its agonist troglitazone, showed the direct association of PPAR-gamma and arsenic-mediated inhibition of differentiating hMSCs. Taken together, these results indicate that arsenic inhibits adipogenic differentiation through PPAR-gamma pathway and suggest a novel inhibitory effect of arsenic on adipogenic differentiation in hMSCs. PMID- 23108038 TI - Urea-based constructs readily amplify and attenuate nonlinear optical activity in response to H-bonding and anion recognition. AB - Urea-based molecular constructs are shown for the first time to be nonlinear optically (NLO) active in solution. We demonstrate self-assembly triggered large amplification and specific anion recognition driven attenuation of the NLO activity. This orthogonal modulation along with an excellent nonlinearity transparency trade-off makes them attractive NLO probes for studies related to weak self-assembly and anion transportation by second harmonic microscopy. PMID- 23108037 TI - In vitro mutagenicity and blood compatibility of paclitaxel and curcumin in poly (DL-lactide-co-glicolide) films. AB - Curcumin is considered to be a potential component for drug-eluting stents due to its anti-inflammatory properties. In this study we compared the mutagenicity and blood compatibility of curcumin to first generation drug eluting stent components: paclitaxel and sirolimus. The Ames test was used to assess mutagenicity. Blood compatibility was tested by measuring platelet activation and fibrinogen adsorption on poly (DL-lactide-co-glycolide, PLGA) films. We discovered that there was no significant increase in the number of revertants/plate following treatment with curcumin (up to 0.5mg/plate) or sirolimus (up to 0.5 MUg/plate). However, a significant induction in the frequency of bacterial his(+) revertant colonies by paclitaxel at concentrations of 0.02, 0.05, 0.1, 0.2 and 0.5 MUg/plate was observed. We also discovered a significant reduction in platelet activation by PLGA films containing 30% and 50% by weight curcumin. A similar reduction in platelet activation was also observed for PLGA films containing 1% by weight paclitaxel. In addition, we observed an increase of fibrinogen adsorption to PLGA-films containing curcumin. This would compromise the potential use of curcumin as a component of drug-eluting stents. Moreover, our data challenges the current view that paclitaxel does not significantly induce mutagenesis. PMID- 23108039 TI - One-pot synthesis of responsive catalytic Au@PVP hybrid nanogels. AB - Responsive catalytic hybrid nanogels with Au nanoparticle cores and a polyvinylpyrrolidone (PVP) based gel shell are prepared through a novel one-pot approach. The embedded Au nanoparticles demonstrate both a pH-modulated catalytic activity and anti-aggregation properties upon recycling. PMID- 23108040 TI - Neural correlates of the modified Stroop effect in post-traumatic stress disorder: an event-related potential study. AB - Previous studies have provided electrophysiological evidence for attentional abnormalities in patients with post-traumatic stress disorder (PTSD). The present study examined the electrophysiological activity of trauma-exposed patients with or without a PTSD during a modified Stroop task. The PTSD group showed a reduced P2 and P3 amplitude relative to the non-PTSD group under both the earthquake related and earthquake-unrelated words conditions. Importantly, the earthquake related words elicited a greater P3 amplitude (350-450 ms after stimulus) than did unrelated words in the non-PTSD group, whereas no significant difference was found in the PTSD group. This indicates that PTSD patients had some attention deficits compared with non-PTSD individuals, and that these attention deficits were not just limited to earthquake-related words. PMID- 23108041 TI - Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions. AB - Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin+ cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin+ cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica. PMID- 23108042 TI - Prazosin differentially affects extinction of cocaine conditioned place preference on the basis of dose and initial preference. AB - Recent work has shown that alpha1-adrenergic receptor blockade impairs extinction in fear conditioning paradigms in rodents. However, studies of the role of alpha1 adrenergic receptors in extinction using other conditioning paradigms, such as those examining the conditioned effects of drug of abuse, have yielded inconsistent results. In this article, we reanalyze and extend previously reported findings of the effect of prazosin, an alpha1-adrenergic receptor antagonist, on the extinction of a cocaine-induced conditioned place preference in rats, using a median split of performance during the initial test for preference. This new reanalysis, which includes further extinction testing, indicated a paradoxical dose effect. A single post-test administration of a lower dose of prazosin, 0.3 mg/kg intraperitoneally, impaired extinction in rats that showed a below-median preference during initial testing, but had no effect on extinction in rats that showed an above-median preference during initial testing. In contrast, a single post-test administration of a higher dose of prazosin, 1.0 mg/kg intraperitoneally, enhanced extinction in rats that showed an above-median preference during initial testing, but had no effect on extinction in rats that showed a below-median preference during initial testing. Consistent with other studies of fear and drug conditioning, these results suggest the involvement of the alpha1-adrenergic receptor in the formation of extinction memories, but also indicate a potentially important differential effect on extinction on the basis of the dose of prazosin and the strength of the initial learning. PMID- 23108043 TI - A funny thing happened on the way to the scanner: humor detection correlates with gray matter volume. AB - The detection and appreciation of humor is a complex cognitive process that remains poorly understood. Although functional neuroimaging studies have begun to map the brain systems involved in humor appreciation, there are virtually no data on the structural correlates between gray matter volume and this capacity. Using voxel-based morphometry, the present study examined the association between gray matter volume and the ability to detect and appreciate humor. Fifty-nine healthy adults aged 18-45 years (30 men) underwent structural MRI and completed the University of Pennsylvania Humor Appreciation Test (HAT). After controlling for age and sex, gray matter volume of the left inferior frontal gyrus, left temporal pole, and left insula correlated positively with the appreciation of visual and verbal humor on the HAT, whereas the gray matter volume of the right inferior frontal gyrus correlated only with verbal humor appreciation scores. There were no negative correlations between gray matter volume and HAT performance. These data support a neurobiological basis for humor appreciation, particularly involving left-hemispheric cortical systems, and further suggest that individual differences in humor appreciation may be related to differences in regional gray matter volume. PMID- 23108044 TI - Frequency-dependent effects of repetitive transcranial magnetic stimulation on the human brain. AB - The aim of this study was to examine the effects of repetitive transcranial magnetic stimulation (rTMS) on human brain activity. The effects of low-frequency magnetic stimulation were evaluated by analyzing the P300 component of event related potentials (ERPs). A figure eight-shaped flat coil was used to stimulate the region over the left or the right supramarginal gyrus, which is considered to be the origin of the P300 component. We examined the effect of rTMS on the latency of the P300 component in 14 healthy individuals by applying 100 magnetic pulses for each stimulus point. Stimulus frequencies were 1.00, 0.75, 0.50, and 0.25 Hz rTMS. The auditory oddball task was used to elicit the P300s before and shortly after rTMS. We found that P300 latencies varied according to the stimulation frequency and the hemisphere of rTMS application. A 1.00 Hz rTMS pulse train over the left supramarginal gyrus shortened the P300 latencies by ~15 ms at Fz. A 0.5 Hz rTMS pulse train over the left supramarginal gyrus lengthened the P300 latencies by ~15 ms at Fz. In contrast, 0.75 and 0.25 Hz rTMS pulse trains over the left supramarginal gyrus and 1.00, 0.75, 0.50, and 0.25 Hz rTMS pulse trains over the right supramarginal gyrus did not alter P300 latencies. These results indicate that rTMS frequency affects cognitive processing. We suggest that the effects of rTMS vary according to the activity of excitatory and inhibitory synapses. In addition, the effects of rTMS over the left supramarginal gyrus are dependent on stimulus frequency. PMID- 23108045 TI - Ribavirin efficiently suppresses porcine nidovirus replication. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine epidemic diarrhea virus (PEDV) are porcine nidoviruses that represent emerging viral pathogens causing heavy economic impacts on the swine industry. Although ribavirin is a well-known antiviral drug against a broad range of both DNA and RNA viruses in vitro, its inhibitory effect and mechanism of action on porcine nidovirus replication remains to be elucidated. Therefore, the present study was conducted to determine whether ribavirin suppresses porcine nidovirus infection. Our results demonstrated that ribavirin treatment dose-dependently inhibited the replication of both nidoviruses. The antiviral activity of ribavirin on porcine nidovirus replication was found to be primarily exerted at early times post infection. Treatment with ribavirin resulted in marked reduction of viral genomic and subgenomic RNA synthesis, viral protein expression, and progeny virus production in a dose-dependent manner. Investigations into the mechanism of action of ribavirin against PRRSV and PEDV revealed that the addition of guanosine to the ribavirin treatment significantly reversed the antiviral effects, suggesting that depletion of the intracellular GTP pool by inhibiting IMP dehydrogenase may be essential for ribavirin activity. Further sequencing analysis showed that the mutation frequency in ribavirin-treated cells was similar to that in untreated cells, indicating that ribavirin did not induce error-prone replication. Taken together, our data indicate that ribavirin might not only be a good therapeutic agent against porcine nidovirus, but also a potential candidate to be evaluated against other human and animal coronaviruses. PMID- 23108046 TI - Transient kinetics of aminoglycoside phosphotransferase(3')-IIIa reveals a potential drug target in the antibiotic resistance mechanism. AB - Aminoglycoside phosphotransferases are bacterial enzymes responsible for the inactivation of aminoglycoside antibiotics by O-phosphorylation. It is important to understand the mechanism of enzymes in order to find efficient drugs. Using rapid-mixing methods, we studied the transient kinetics of aminoglycoside phosphotransferase(3')-IIIa. We show that an ADP-enzyme complex is the main steady state intermediate. This intermediate interacts strongly with kanamycin A to form an abortive complex that traps the enzyme in an inactive state. A good strategy to prevent the inactivation of aminoglycosides would be to develop uncompetitive inhibitors that interact with this key ADP-enzyme complex. PMID- 23108047 TI - FBXW7-mediated degradation of CCDC6 is impaired by ATM during DNA damage response in lung cancer cells. AB - CCDC6 is rearranged in approximately 20% of papillary thyroid carcinomas and some lung cancers participating in the formation of PTC1/ret proto-oncogene oncogene. CCDC6 is involved in the cellular response to DNA damage and is stabilized by ATM mediated phosphorylation at Thr434. However, the E3 ligase that targets CCDC6 for destruction is unknown. Here, we show that FBXW7 interacts with and targets CCDC6 for ubiquitin-mediated proteasomal degradation. Moreover, FBXW7-mediated CCDC6 degradation is impaired in response to DNA damage. Mechanistically, phosphorylation of CCDC6 at Thr434 by ATM during DNA damage response prevents FBXW6-CCDC6 interaction and FBXW7-mediated CCDC6 degradation. Our results suggest that the involvement of FBXW7 in targeting CCDC6 for destruction will be useful for the establishment of new therapeutic approaches for cancer treatment. PMID- 23108048 TI - Identification of a HAD superfamily phosphatase, HdpA, involved in 1,3 dihydroxyacetone production during sugar catabolism in Corynebacterium glutamicum. AB - Corynebacterium glutamicum produces 1,3-dihydroxyacetone (DHA) as metabolite of sugar catabolism but the responsible enzyme is yet to be identified. Using a transposon mutant library, the gene hdpA (cgR_2128) was shown to encode a haloacid dehalogenase superfamily member that catalyzes dephosphorylation of dihydroxyacetone phosphate to produce DHA. Inactivation of hdpA led to a drastic decrease in DHA production from each of glucose, fructose, and sucrose, indicating that HdpA is the main enzyme responsible for DHA production from sugars in C. glutamicum. Confirmation of DHA production via dihydroxyacetone phosphatase finally confirms a long-speculated route through which bacteria produce DHA. PMID- 23108049 TI - DUSP6 is a novel transcriptional target of p53 and regulates p53-mediated apoptosis by modulating expression levels of Bcl-2 family proteins. AB - p53 regulates various cellular responses through transcriptional regulation of distinct sets of target genes. Dual specificity phosphatase 6 (DUSP6) is a cytosolic phosphatase that inactivates the extracellular-signal-regulated kinase 1/2 (ERK1/2). This study demonstrates that p53 transactivates DUSP6 in human colorectal HCT116 cells to regulate ERK1/2 in p53-mediated cell death. DUSP6 is transactivated by p53 overexpression and genotoxic agents, and chromatin immunoprecipitation revealed two p53-binding sites in the DUSP6 promoter responsible for DUSP6 induction. Expression of shDUSP6 inhibited 5'-FU-induced cell death, whereas overexpression of DUSP6 increased susceptibility to 5'-FU. 5' FU treatment dephosphorylated ERK in a DUSP6-dependent manner, resulting in destabilization of Bcl-2 and stabilization of Bad. These results provide insights on the modulatory role of p53 in the survival pathway by up-regulating DUSP6. PMID- 23108050 TI - Novel function of transthyretin in pancreatic alpha cells. AB - Although transthyretin (TTR) is expressed in pancreatic alpha (glucagon) cells in the islets of Langerhans, the function of TTR in pancreatic alpha cells remains unknown. In this study, by using TTR knockout (TTR KO) mice, we determined the novel role of TTR in glucose homeostasis. We demonstrated that TTR KO mice evidenced impaired recovery of blood glucose and glucagon levels. Lack of TTR induced significantly lower levels of glucagon in the islets of Langerhans. These results suggest that TTR expressed in pancreatic alpha cells may play important roles in glucose homeostasis via regulating the expression of glucagon. PMID- 23108051 TI - Cdk1 interplays with Oct4 to repress differentiation of embryonic stem cells into trophectoderm. AB - Cdk1 plays an important role in undifferentiated ES cells, but the underlying mechanism remains unclear. This study explores how Cdk1 collaborates with Oct4 to inhibit differentiation in mouse ES cells. We show a direct interaction between Cdk1 and Oct4, whereas other Cdk members, including Cdk2 and Cdk4, fail to associate with Oct4. By immunocytochemistry we show that Cdk1 and Oct4 co localize in ES cells. The biological function of the Cdk1-Oct4 complex was also addressed. We found that Cdk1 enhances the binding of Oct4 on the trophectoderm marker Cdx2 and promotes Cdx2 repression. This regulation is independent of Cyclins and of the kinase activity of Cdk1. Our study explains how Cdk1 and Oct4 interplay to inhibit ES cell differentiation into trophectoderm and thereby maintain stemness. PMID- 23108052 TI - Signaling regulated endocytosis and exocytosis lead to mating pheromone concentration dependent morphologies in yeast. AB - Polarized cell morphogenesis requires actin cytoskeleton rearrangement for polarized transport of proteins, organelles and secretory vesicles, which fundamentally underlies cell differentiation and behavior. During yeast mating, Saccharomyces cerevisiae responds to extracellular pheromone gradients by extending polarized projections, which are likely maintained through vesicle transport to (exocytosis) and from (endocytosis) the membrane. We experimentally demonstrate that the projection morphology is pheromone concentration-dependent, and propose the underlying mechanism through mathematical modeling. The inclusion of membrane flux and dynamically evolving cell boundary into our yeast mating signaling model shows good agreement with experimental measurements, and provides a plausible explanation for pheromone-induced cell morphology. PMID- 23108053 TI - [A case of biochemical assay discrepancy: Interference with measurement of thyroid-stimulating hormone due to rheumatoid factor]. PMID- 23108054 TI - [Multifocal osteonecrosis in long-term corticoid treatment secondary to panhypopituitarism: a case report]. PMID- 23108055 TI - Optical imaging of arrhythmias in the cardiomyocyte monolayer. AB - In recent years, cultured cardiac cell monolayers have become a contemporary experimental preparation for the study of fundamental mechanisms that underlie normal and pathologic electrophysiology at the tissue level. Ion channels and gap junctions in the cardiomyocyte monolayer may be modulated using drugs that suppress or enhance certain channels/junctions, or by genetic silencing or overexpression. The cardiomyocyte monolayer is particularly well suited for studies of functional electrophysiologic properties of mixtures of cardiac and noncardiac cells (eg, myofibroblasts), which otherwise would be difficult to investigate. Optical mapping of monolayers has provided insight into mechanisms that can set the stage for arrhythmias, such as unidirectional conduction block, gap junction uncoupling, ischemia, alternans, and anisotropy, and continues to enhance our understanding of basic electrophysiologic mechanisms. PMID- 23108056 TI - Implantable cardioverter-defibrillator shock prevention does not reduce mortality: a systemic review. AB - BACKGROUND: Mortality is increased among implantable cardioverter-defibrillator (ICD) recipients who receive shocks; however, whether shocks cause this increase or are simply a marker of risk is unknown. Antiarrhythmic medications, catheter ablation, and enhanced ICD programming all may reduce ICD shocks, but whether shock reduction decreases mortality is unknown. OBJECTIVE: The purpose of this study was to conduct a meta-analysis to estimate the impact of ICD shock reduction on survival. METHODS: Two independent reviewers searched MEDLINE, EMBASE, and clinicaltrials.gov and extracted data from randomized controlled trials assessing the efficacy of interventions to prevent ICD shocks. RESULTS: Seventeen randomized trials were included in this analysis, including 5875 patients. Mean ejection fraction of all trial participants was 32%, and 25% of the patients received ICD therapy for primary prophylaxis. Antiarrhythmic medications (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.36-0.96, P = .03) and catheter ablation of ventricular tachycardia (OR 0.35, 95% CI 0.19-0.62, P = .0004) significantly reduced the proportion of patients receiving shocks. However, there was no significant reduction in mortality among trials of antiarrhythmic medications (OR 1.07, 95% CI 0.72-1.59, P = .73) or catheter ablation (OR 0.72, 95% CI 0.32-1.64, P = .44). The 5 ICD programming trials had sufficiently heterogeneous interventions that pooling of their results was not performed. However, only the PAINFREE-II (Pacing Fast Ventricular Tachycardia Reduces Shock Therapies) trial demonstrated a significant reduction in shocks (OR 0.38, 95% CI 0.22-0.65), but this was not associated with any significant reduction in mortality (OR 1.41, 95% CI 0.81-2.45). CONCLUSION: There is no compelling evidence that existing interventions that reduce ICD shocks significantly improve survival. PMID- 23108057 TI - Synthetic, structural, spectroscopic and theoretical study of a Mn(III)-Cu(II) dimer containing a Jahn-Teller compressed Mn ion. AB - The heterobimetallic complex [Cu(II)Mn(III)(L)(2)(py)(4)](ClO(4)).EtOH (1) built using the pro-ligand 2,2'-biphenol (LH(2)), contains a rare example of a Jahn Teller compressed Mn(III) centre. Dc magnetic susceptibility measurements on 1 reveal a strong antiferromagnetic exchange between the Cu(II) and Mn(III) ions mediated through the phenolate O-atoms (J = -33.4 cm(-1)), with magnetisation measurements at low temperatures and high fields suggesting significant anisotropy. Simulations of high-field and high frequency powder EPR data suggest a single-ion anisotropy D(Mn(III)) = +4.45 cm(-1). DFT calculations also yield an antiferromagnetic exchange for 1, though the magnitude is overestimated (J(DFT) = -71 cm(-1)). Calculations reveal that the antiferromagnetic interaction essentially stems from the Mn(d(x(2)-y(2)))-Cu(d(x(2)-y(2))) interaction. The computed single-ion anisotropy and cluster anisotropy also correlates well with experiment. A larger cluster anisotropy for the S = 3/2 state compared to the single-ion anisotropy of Mn(III) is rationalised on the basis of orbital mixing and various contributions that arise due to the spin-orbit interaction. PMID- 23108059 TI - Tissue composition of the vaginal wall in women with pelvic organ prolapse. AB - BACKGROUND/AIMS: To determine the composition of the vaginal wall and to explore the connective tissue layer, muscularis and basement membrane in relation to the pathogenesis of pelvic organ prolapse (POP). METHODS: We performed a histopathological study with respect to the composition of the vaginal wall of 33 patients and 9 controls. Tissue samples from the vaginal wall were analysed for collagens II and IV, desmin, elastin, fibronectin, smooth muscle actin (SMA) and transforming growth factor (TGF)-beta1 using (immuno)histochemistry. Morphometric analyses were also performed. RESULTS: Morphometric characteristics and expression of SMA, TGF-beta1, elastin and collagen II were significantly altered in women with POP. CONCLUSION: Our results suggest that there could be an altered tissue composition of the vaginal wall in women with POP. SMA expression could play a role in the pathogenesis of POP. The alterations in elastin and TGF-beta1 expression are likely a result of POP. PMID- 23108060 TI - Decreased hepatic phosphatidylinositol-3,4,5-triphosphate (PIP3) levels and impaired glucose homeostasis in type 1 and type 2 diabetic rats. AB - BACKGROUND/AIMS: Phosphatidylinositol-3,4,5-triphosphate (PIP3) and phosphatidylinositol-4,5-biphosphate (PIP2) are two well-known lipid second messengers. Polyphosphoinositides have been implicated in the regulation of the signal transduction pathways involved in glucose metabolism using cell culture studies. However, there are no in vivo studies in the literature investigating the status of PIP3 and PIP2 in any of the tissues of diabetic animals. The liver plays an important role in the regulation of whole body glucose homeostasis. This study investigated whether hepatic PIP3 and/or PIP2 levels are altered in diabetes. METHODS: Experiments were performed in streptozotocin-treated type 1 (T1D) and ZDF type 2 (T2D) diabetic rats. Blood glucose was determined utilizing glucose oxidase, glycosylated hemoglobin (GHb) using Glyco-Tek Affinity columns, and hepatic PIP3 and PIP2 concentrations by sandwich ELISA, and Akt phosphorylation and GLUT2 protein abundance by Western blotting. RESULTS: Blood glucose and GHb were higher in T1D and T2D rats compared to controls. As compared to control animals, in livers from T1D and T2D rats PIP3 levels were reduced, AKT phosphorylation downregulated, and GLUT2 protein expression increased. PIP2 levels were unchanged. CONCLUSION: PIP3 is decreased, AKT phosphorylation downregulated, GLUT2 protein expression increased and glucose homeostasis altered in livers of type 1 and type 2 diabetic rats. PMID- 23108066 TI - A rare case of primary extranodal marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix in the setting of endometriosis. AB - Extranodal marginal zone B-cell lymphomas are uncommon. Most occur in the gastrointestinal tract. Marginal zone B-cell lymphomas of the female genital tract are rare, and few cases exist of marginal zone B-cell lymphomas of the uterus, cervix, and fallopian tubes. We report the first marginal zone B-cell lymphoma of the ovary, fallopian tube, and appendix arising in endometriosis. PMID- 23108061 TI - PPARgamma activation prevents impairments in spatial memory and neurogenesis following transient illness. AB - The detrimental effects of illness on cognition are familiar to virtually everyone. Some effects resolve quickly while others may linger after the illness resolves. We found that a transient immune response stimulated by lipopolysaccharide (LPS) compromised hippocampal neurogenesis and impaired hippocampus-dependent spatial memory. The immune event caused an ~50% reduction in the number of neurons generated during the illness and the onset of the memory impairment was delayed and coincided with the time when neurons generated during the illness would have become functional within the hippocampus. Broad spectrum non-steroidal anti-inflammatory drugs attenuated these effects but selective Cox 2 inhibition was ineffective while PPARgamma activation was surprisingly effective at protecting both neurogenesis and memory from the effects of LPS produced transient illness. These data may highlight novel mechanisms behind chronic inflammatory and neuroinflammatory episodes that are known to compromise hippocampus-dependent forms of learning and memory. PMID- 23108062 TI - Childhood adversity and cell-mediated immunity in young adulthood: does type and timing matter? AB - Childhood adversity can have powerful effects on health over the life course. Persistent changes in cell-mediated immune function may be one pathway linking adverse childhood experiences with later disease risk. However, limited research has examined childhood adversity in relation to cell-mediated immune function, and in particular, immune response to latent viruses in adulthood. The present study investigated the association of two types of childhood adversity, socioeconomic disadvantage during adolescence and abuse prior to age 18, with Epstein-Barr Virus (EBV) antibody titers in a large nationally representative sample of young adults aged 24-32years. Data were drawn from the National Longitudinal Study on Adolescent Health, Wave 4 (n=13,162). We examined the associations of three indicators of adolescent SES (parental education, household income, and occupational status) and frequency and timing of physical and sexual abuse with EBV antibodies, controlling for age, sex, race/ethnicity, and presence of a smoker in the household during adolescence. Lower parental occupational status and some categories of lower education were associated with elevated EBV antibodies (p<.05), and individuals who reported sexual abuse that occurred more than 10times had elevated EBV antibodies relative to individuals who were not sexually abused (p=0.03). Among individuals exposed to physical abuse, those who were first abused at age 3-5years had heightened EBV antibodies relative to those first abused during adolescence (p=0.004). This study extends prior research linking early adversity and immune function, and provides initial evidence that childhood adversity has a persistent influence on immune responses to latent infection in adulthood. PMID- 23108067 TI - Effects of increased fetuin-A in human trophoblast cells and associated pregnancy outcomes. AB - OBJECTIVE: The purpose of this study was to determine whether fetuin-A affects trophoblast viability and invasion, whether growth factors that bind receptors that activate tyrosine kinase are impaired by fetuin-A, and whether elevated maternal serum fetuin-A levels are associated with adverse pregnancy outcomes. STUDY DESIGN: We studied viability and invasion in first-trimester extravillous trophoblast cells that were exposed to fetuin-A, insulin-like growth factor, and placental growth factor. Insulin receptor substrates expression was assessed. We compared serum fetuin-A levels in 111 preeclampsia cases and 95 controls. RESULTS: Fetuin-A reduced extravillous trophoblast cell viability and invasion in the presence or absence of growth factors. Fetuin-A reduced insulin receptor substrate-1 and tyrosine phosphorylated insulin receptor substrate-1 expression in extravillous trophoblast cells that had been treated with insulin-like growth factor. Elevated serum fetuin-A levels were more prevalent in preeclampsia cases than control subjects, even after we controlled for diabetes mellitus, hypertension, and obesity. CONCLUSION: Fetuin-A may decrease trophoblast viability and invasion caused by the inhibition of receptor tyrosine kinase activity. Elevated serum levels of fetuin-A may be associated with preeclampsia. PMID- 23108068 TI - Bacterial sensor triggering receptor expressed on myeloid cells-2 regulates the mucosal inflammatory response. AB - BACKGROUND AND AIMS: Triggering receptor expressed on myeloid cells (TREM)-2 is a surface receptor detected on macrophages, dendritic cells, and microglia that binds repeated anionic motifs on yeast and Gram-positive and Gram-negative bacteria. Little is known about TREM-2 expression and function in the intestine or its role in inflammatory bowel disease (IBD). We investigated the expression of TREM-2 in the intestinal lamina propria and its role in the development of colonic inflammation. METHODS: We measured levels of TREM-2 in lamina propria mononuclear cells from surgical specimens collected from patients with IBD or cancer (controls). We analyzed the development of colitis in TREM-2 knockout and wild-type mice. Colon samples were isolated from mice and analyzed for cytokine expression, phagocytosis of bacteria, proliferation in colonic crypts, lamina propria mononuclear cell function, and T-cell activation by ovalbumin. RESULTS: TREM-2 was virtually absent from colon samples of control patients, but levels were significantly higher in within the inflamed mucosa of patients with IBD; it was mainly expressed by CD11c(+) cells. Levels of TREM-2 increased as acute or chronic colitis was induced in mice. TREM-2 knockout mice developed less severe colitis than wild-type mice; the knockout mice lost less body weight, had a lower disease activity index, and had smaller mucosal lesions in endoscopic analysis. Colon dendritic cells from TREM-2 knockout mice produced lower levels of inflammatory cytokines and had reduced levels of bacterial killing and T-cell activation than cells from wild-type mice. CONCLUSIONS: TREM-2 contributes to mucosal inflammation during development of colitis in mice. Levels of TREM-2 are increased within the inflamed mucosa of patients with IBD, indicating its potential as a therapeutic target. PMID- 23108069 TI - Fabrication of n-type ZnO nanowire/graphene/p-type silicon hybrid structures and electrical properties of heterojunctions. AB - Compared to the p-n junction type device (Device A) with an n-type ZnO nanowire (n-ZnO)/p-type silicon (p-Si) hybrid structure, the newly designed device (Device B) with an n-ZnO/reduced graphene oxide sheet (rGO)/p-Si hybrid structure displays interesting electrical characteristics such as lower turn-on voltage and better current symmetry. The addition of rGO between n-ZnO and the p-Si substrate enables tuning of the p-n junctions into back-to-back Schottky junctions and lowering of the turn-on voltages, implying great potential applications in electronic and optoelectronic devices. The electrical characteristics and operating mechanism of these two devices are fully discussed. PMID- 23108071 TI - Hypoxia-inducible plasmid expressing both miSHP-1 and HO-1 for the treatment of ischemic disease. AB - Ischemic heart disease (IHD) is one of the leading causes of death worldwide. Unfortunately, current pharmacological treatments for ischemic heart disease do not reliably prevent the remodeling of the left ventricle and the progression to heart failure. Gene therapy offers a novel means to directly treat the pathophysiology underlying the long-term complications of ischemic heart disease. To date, gene therapies directed at single molecular targets have not been successful in the treatment of ischemic heart disease. In this study, we describe a gene therapy combination for inhibiting cardiomyocyte apoptosis under hypoxic conditions. This gene therapy combination utilizes a hypoxia-inducible plasmid expressing both heme oxygenase-1 (HO-1) and the Src homology domain-2 containing tyrosine phosphatase-1 microRNA (miSHP-1): pEpo-SV-miSHP-HO-1. This novel gene therapy construct demonstrated an enhanced expression of HO-1, production of miSHP-1, down-regulation of SHP-1, and inhibition of cardiomyocyte apoptosis under hypoxic compared to normoxic conditions. These results suggest that pEpo-SV miSHP-HO-1 may be a promising gene therapy combination construct for the clinical treatment of ischemic disease. PMID- 23108073 TI - Self-assembly between dicarboxylate ions and binuclear europium complexes: moving to water-pH dependence and effects of buffers. AB - Binuclear lanthanide complexes consisting of two lanthanide binding domains in kinetically stable DO3A binding pockets linked by a 3-functionalized meta-xylyl bridge form stable 1:1 adducts with isophthalate and dinicotinate in water. The influence of buffer, pH and ligand structure on the binding of dinicotinate has been investigated. PMID- 23108074 TI - Treatment of ipsilateral renal ureteral calculi by combining retroperitoneal laparoscopic surgery with tubeless mini-percutaneous nephrolithotomy. AB - OBJECTIVES: To report and discuss the role of the treatment of ipsilateral renal and upper middle ureteral stones in patients by combing retroperitoneal laparoscopic surgery with tubeless mini-percutaneous nephrolithotomy. PATIENTS AND METHODS: Eleven patients associated with ipsilateral renal and upper middle ureteral stones underwent combing retroperitoneal laparoscopic surgery with tubeless mini-percutaneous nephrolithotomy after failure of shockwave or ureteroscopy lithotripsy. Their data were analyzed retrospectively including stone burden, perioperative complications and outcomes. RESULTS: All the patients underwent retroperitoneal laparoscopic ureterolithotomy and tubeless mini percutaneous nephrolithotomy successfully. Surgical time ranged from 80 to 160 min with a mean of 118 min. The mean hospital stay was 4 days (3-7 days). The mean length of retroperitoneal urinary drainage was 3 days (2-6 days). There were minor complications in 3 (27.2%) patients. The stone-free rate was 82% (9 patients). Two patients had a residual calyceal fragment that was treated with shockwave lithotripsy. All of them were followed up for 3-24 months. Renal function was improved in different degree. CONCLUSION: In carefully selected patients, combining retroperitoneal laparoscopic surgery with tubeless mini percutaneous nephrolithotomy can treat ipsilateral renal and upper middle ureteral calculi by a single procedure with advantages of high stone-free rate, safety, reliability, rapid recovery and less complications. PMID- 23108075 TI - Analysis of the cercosporin polyketide synthase CTB1 reveals a new fungal thioesterase function. AB - The polyketide synthase CTB1 is demonstrated to catalyze pyrone formation thereby expanding the known biosynthetic repertoire of thioesterase domains in iterative, non-reducing polyketide synthases. PMID- 23108076 TI - Laparoscopic cholecystectomy in patients with a previous history of gastrectomy. AB - BACKGROUND/AIMS: Laparoscopic cholecystectomy (LC) in patients with a previous history of upper abdominal surgery is a difficult procedure with a high conversion rate. METHODOLOGY: Forty-two patients with a previous history of gastrectomy (gastrectomy group) were compared to patients without previous abdominal surgery (no surgery group, n=1375). Patients in the gastrectomy group were divided into two groups for comparison: first, an umbilicus-group (n=12, at the umbilicus) and a side-group (n=23, right of the umbilicus) by the location of the primary port insertion, second, a benign group (n=31) and a malignant group (n=11). RESULTS: Patients in the gastrectomy group had similar operative morbidity but a significantly higher conversion rate and a longer postoperative hospital stay than patients in the no-surgery group. Conversion was performed in four patients in the gastrectomy group (9.5%): 3 in the umbilicus-group and one in a side-group. Two patients in the umbilicus-group had adhesion only just around the primary port site. Patients in the malignant group had similar postoperative hospital stay and morbidity but a significantly longer operating time than patients in the benign group. CONCLUSIONS: Previous gastrectomy for benign or malignant diseases is no longer considered a relative contraindication for performance of safe LC. PMID- 23108077 TI - Radiofrequency ablation of metastatic liver masses: recurrence patterns and prognostic factors based on radiologic features. AB - BACKGROUND/AIMS: To investigate the therapeutic result of RFA and the factors predicting recurrence after RFA in patients with hepatic metastases. METHODOLOGY: We reviewed 33 patients who had hepatic metastases and underwent curative RFA. Statistical analysis of the determinants of tumor recurrence was done by sex, age, site and differentiation of the primary cancer, lesion size, location within the liver, ablative margin and presence of vessels contiguous to the mass and time from the initial liver metastasis to RFA. RESULTS: Marginal tumor recurrence was seen at the ablation margin in 13 (25%) of 52 lesions. Lesions with an ablative margin of 5mm or more had longer marginal recurrence-free interval compared to lesions with an ablative margin of less than 5mm. The patients with primary colorectal cancer had a significantly longer distant recurrence-free interval compared to patients with non-colorectal neoplasms. CONCLUSIONS: Percutaneous RFA is an effective alternative modality for the treatment of hepatic metastases from various primary cancers and has a relatively low recurrence rate. The presence of an ablative margin was a significant prognostic factor for marginal tumor recurrence. In addition, distant metastasis, a new hepatic lesion or extrahepatic was significantly influenced by the site of the primary cancer. PMID- 23108078 TI - Association of MHC class I expression and lymph node metastasis of gastric carcinoma. AB - BACKGROUND/AIMS: HLA gene encodes MHC, which could represent a common mechanism for enhanced antitumor immune response through T-cell cytotoxicity. Loss of HLA class I expression has been considered to be an important prognostic factor in many malignancies. We investigated the impact of HLA class I expression on lymph node metastasis in gastric carcinoma. METHODOLOGY: We examined HLA class I expression in clinical samples from 349 patients by immunohistochemistry and compared primary lesions and metastatic lymph nodes. We analyzed the expression of HLA class I antigen in gastric cancer cell lines using flow-cytometry and HLA A typed these cell lines using PCR. RESULTS: HLA class I expression was down regulated in metastatic lymph nodes compared with its expression in primary lesion. Patients with negative expression showed a significantly poorer prognosis. We observed down-regulation of HLA class I antigen in OCUM-2MLN cell line, which has a high potential for metastasizing to lymph node. PCR-SBT analysis indicated LOH of HLA-A gene in OCUM-2MLN. CONCLUSIONS: We showed that HLA class I expression was abrogated in tumor cells that had metastasized to lymph nodes. We further suggest that loss of HLA class I due to LOH was associated with lymph node metastasis. PMID- 23108079 TI - Management of occluded metallic stents in malignant hilar biliary stricture. AB - BACKGROUND/AIMS: Little is known about the management of occluded multiple metallic stent (MS) deployed in malignant hilar biliary strictures (HBS). The purpose of this study was to evaluate the endoscopic management of occluded multiple MSs deployed in HBS. METHODOLOGY: Fifty-five patients with unresectable biliary tract carcinoma had multiple MSs inserted due to HBS. The endoscopic intervention through the duodenal papilla was performed on 30 cases that had MS occlusion. The procedure success rate, the survival time after the procedure and the number of endoscopic interventions before death were analyzed, retrospectively. RESULTS: The causes of MS obstruction were tissue ingrowth (n=20), sludge (n=7), tumor overgrowth (n=2), and hemobilia (n=1). Endoscopic cleaning or deployment of plastic stents or metallic stents was performed on these patients and was successfully accomplished only via the transpapillary approach. The survival time after MS obstruction was 219 days. The median number of endoscopic interventions before death was 3. The median interval of endoscopic intervention after the first plastic stent occlusion was 84 days. CONCLUSIONS: Our long-term data regarding the endoscopic management of occluded MSs deployed in malignant hilar biliary strictures are acceptable although the patency time of plastic stents deployed after MS occlusion was relatively short. PMID- 23108080 TI - Helicobacter pylori eradication increases telomere length in gastric mucosa. AB - BACKGROUND/AIMS: Our purpose in this study was to analyze telomere length and telomerase activity before and after eradication treatment in gastric mucosa in patients positive for H. pylori. METHODOLOGY: There were two groups: a control group (n=17) and a study group (n=21). For H. pylori eradication, the patients were administrated proton pump inhibitor (PPI) + clarithromycin + amoxicillin or PPI + metronidazole + tetracycline + bismuth for 14 days. Telomere length was analyzed with RT-PCR and telomerase activity with PCR-ELISA on biopsy specimens from the antrum. The result p<0.05 was considered significant. RESULTS: Prior to eradication, there was no significant difference between telomere lengths of the patient and control groups (2481.2+/-1823 and 2958.9+/-1345.7 bp, p=0.11, respectively). The telomere length of the study group became longer after eradication (before 2481.2+/-1823bp, after 3766.3+/-1608.8bp, p=0.01). Telomerase activity was not detected in either the patient or the control group. CONCLUSIONS: An increase in telomere length was observed with H. pylori eradication. This finding may indicate the importance of H. pylori eradication to avoid the development of gastric cancer. PMID- 23108081 TI - The association between coronary artery calcification and colorectal adenoma. AB - BACKGROUND/AIMS: Both colorectal neoplasm and coronary artery disease are prevalent diseases worldwide and share several risk factors. The aim of this study was to investigate the association between coronary artery calcification and prevalence of colorectal adenoma. METHODOLOGY: We retrospectively evaluated 3,092 subjects who underwent colonoscopy and coronary artery calcium computed tomography (CT) on the same day or within a 3-month interval, during routine check-ups between January 2006 and June 2009 at the Center for Health Promotion of the Samsung Medical Center. Multivariate logistic regression analysis was used to calculate adjusted odds ratios (ORs). RESULTS: Colorectal adenomas were detected in 1,067 (34.5%) of the 3,092 subjects, including 536 (41.0%) individuals with and 531 (29.7%) without coronary calcification (p<0.001). Multiple logistic regression analysis showed that the presence of coronary artery calcification (OR=1.346; 95% confidence interval [CI]=1.122-1.614), age >=50 years (OR=1.516; 95% CI=1.256-1.829), waist circumference of 90-99cm (OR=1.364; 95% CI=1.008-1.844) and current smoker (OR=1.266; 95% CI=1.045-1.534) were associated with the prevalence of colorectal adenoma. CONCLUSIONS: The prevalence of colorectal adenoma is significantly higher in patients with coronary artery calcification. Our results support positive relationship between coronary artery disease and colorectal adenoma. PMID- 23108082 TI - Nutritional support in patients with colorectal cancer during chemotherapy: does it work? AB - BACKGROUND/AIMS: Early intervention with nutritional supplementation has been shown to halt malnutrition and may improve outcome in some patients with colorectal cancer. The aim of this study was to investigate whether dietary counseling, oral nutrition and megestrol acetate during chemotherapy affected nutritional status and survival in patients with advanced disease. METHODOLOGY: Six hundred and twenty-eight patients with colorectal advanced disease were included in the study from January 2000 through December 2009 and divided into one of two groups. Group I consisted of 315 patients who were monitored prospectively and were given nutritional support. Group II included 313 patients without nutritional counseling and support. After the completion of chemotherapy all patients were evaluated (BMI, NST, Appetite Loss Scale and ECOG). RESULTS: After the completion of chemotherapy, there were lower proportions of patients in Group I with a BMI<20, NST>=5, loss of appetite and decreased weight gain. Nutritional counseling and supplemental feeding temporarily halted weight loss and improved appetite. This improvement may have implications for patient survival. Patients with early nutritional support lived 19.1 months while patients in the control group had a survival of 12.4 months (p=0.022). CONCLUSIONS: This study demonstrated that concurrent individualized dietary counseling and nutritional support are effective in improving nutritional status thereby lessening chemotherapy-induced morbidity. PMID- 23108083 TI - The assessment of clinicopathological features, therapy pattern and survival benefit of 162 gastric cancers with liver metastases. AB - BACKGROUND/AIMS: This study investigated the influence of clinicopathological characteristics and different therapy patterns on overall survival of gastric cancer patients with liver metastases. METHODOLOGY: One hundred and sixty two patients were enrolled in this study. The data of clinicopathological characteristics, treatment methods and overall survival were collected. Univariate and multivariate analyses were performed using log-rank tests and Cox's proportional hazard model, respectively. RESULTS: Of all the patients enrolled, 27 (16.7%) had liver-only metastases and 48 patients (28.7%) received local treatment for liver metastases. The median overall survival of the 162 patients was 9.5 months (95%CI: 8.4-10.6). One- and two-year survival rates were 28.4% and 4.3%, respectively. There was no difference in the overall survival of patients who had received the different chemotherapy regimens. Multivariate analysis revealed that numbers of liver metastases 1-3, without extrahepatic metastases, receiving local treatment for liver metastases were better prognostic factors, and HR were 0.490, 0.479, 0.495. CONCLUSIONS: A smaller number of liver metastases, without extrahepatic metastases and local therapy for liver metastases are the independent survival factors for gastric cancer with liver metastases. PMID- 23108084 TI - Response failure to the treatment of Clostridium difficile infection and its impact on 30-day mortality. AB - BACKGROUND/AIMS: Few data are available on response failure and hospital mortality. This study aimed to evaluate the association between response failure to the treatment of CDI and 30-day mortality. METHODS: Medical records of patients diagnosed with CDI between March 2005 and March 2010 were reviewed. CDI diagnosis was considered in patients with diarrhea when the stool toxins assay was positive or pseudomembranous colitis (PMC) was confirmed by endoscopy. If there were no symptomatic improvements during 10 days of treatment, the case was regarded as response failure. Patients were stratified into a mild or severe disease group based on clinical criteria. RESULTS: Among 536 subjects (age 64+/ 14.12, mild 266, severe 270), 26 (4.9%) showed response failure, which occurred more frequently in the severe disease than mild disease group. Forty-eight (9%) patients died within 1 month and mortality rate in the failure group was higher than in the response group (42.3% vs. 7.3%, p<0.001). Malignancy, albumin <2.5 mg/dL, WBC >15,000 cells/mm3, ICU admission and response failure were independent risk factors associated with 30-day mortality after CDI. CONCLUSIONS: Response failure to the treatment negatively affects a patients' survival within 30 days after CDI. PMID- 23108085 TI - Laparoscopic spleen-preserving distal pancreatectomy (LSPDP). AB - BACKGROUND/AIMS: To study the feasibility and safety of laparoscopic spleen preserving distal pancreatectomy (LSPDP). METHODOLOGY: Four patients underwent attempted LSPDP from February 2008 to April 2010 in our department and their clinical data and outcome were reviewed retrospectively. RESULTS: A total of 4 laparoscopic distal pancreas resections were attempted for 3 female and 1 male patient. All of these operations were successful with an average operative time of 235 min (range 115-305 min) and average blood loss of 200mL (range 100-450mL). The mean hospital stay time was 12.8 days, ranging from 10 to 21 days. Pancreatic fistula occurred in 1 patient then cured by extending drainage. Postoperative pathological examination showed those 2 cases of serous cystadenoma, 1 case of mucinous cystadenoma and 1 case of insulinoma, respectively. CONCLUSIONS: LSPDP is minimally invasive, safe and feasible for the management of benign pancreatic tail tumors with the advantages of earlier recovery and less morbidity from complications. PMID- 23108086 TI - High expression of serum miR-17-5p associated with poor prognosis in patients with hepatocellular carcinoma. AB - BACKGROUND: MicroRNAs (miRNAs) have been shown to play pivotal roles in diverse biological processes. Altered expressions of miR-17-5p in several tumor types have been reported. However, the expression and clinical significance of serum miR-17-5p in patients with hepatocellular carcinoma (HCC) are unclear. METHODOLOGY: The expression of miR-17-5p was measured in the serum of paired pre operative and post-operative groups (n=96) as well as non-relapsed and relapsed groups (n=40) by qRT-PCR. Further study was performed to analyze the correlation of miR-17-5p expression with clinicopathologic variables and the relationship between miR-17-5p expression and the prognosis of HCC patients. RESULTS: The expression of serum miR-17-5p was significantly down-regulated in post-operative group and upregulated in relapsed group. Moreover, the expression of serum miR-17 5p was remarkably associated with the metastasis status and TNM stages (P<0.0001). Importantly, Kaplan-Meier curve analysis revealed that HCC patients with high expression of serum miR-17-5p had a significantly shortened overall survival (P=0.003). Univariate and Multivariable Cox regression analysis indicated that the expression of serum miR-17-5p was an independent risk factor for overall survival (P=0.005 and P=0.043, respectively). CONCLUSIONS: The level of serum miR-17-5p is associated with development of HCC and can serve as a non invasive biomarker for the prognostic prediction of HCC patients. PMID- 23108087 TI - Risk factors for survival after colorectal cancer resection. AB - BACKGROUND/AIMS: To describe survival rates and prognostic factors for colorectal cancer (CRC) operated in a district general hospital setting with a special focus on the number of lymph nodes examined. METHODOLOGY: Between December 2004 and December 2006, a total of 277 CRC patients who underwent surgical treatment in QHSU were included. All patients were followed up intensively from discharge until death or the end of the follow-up (December 31, 2010). RESULTS: The median follow-up period was 53 months (range, 1-72 months). Overall 3-year survival was 72.9%. In only 11.5% of the specimens were 12 or more lymph nodes retrieved, but this did not affect survival. A multivariate analysis identified that the significant prognostic factors were TNM stage III [adjusted hazard ratio (HR): 5.49; 95%CI: 1.64-18.41], TNM stage IV (adjusted HR: 7.55; 95%CI: 2.12-26.84), tumor histology (adjusted HR: 1.88; 95%CI: 1.16-3.04), hospital stay (adjusted HR: 1.03; 95%CI: 1.00-1.06) and lymph node ratio (LNR) (adjusted HR: 3.92; 95%CI: 1.79-8.55) for stage III. CONCLUSIONS: TNM stage, tumor histology and the length of hospital stay could prominently affect outcome overall. The lymph node count did not have a significant impact on survival, whereas the LNR proved significant for stage III. Nevertheless, a protocol using overall lymph node yield as a surrogate measure for more radical surgery seems warranted to improve the lymph node resected. PMID- 23108088 TI - Efficacy of chemoembolization for recurrent HCC after curative ablation therapy. AB - BACKGROUND/AIMS: Transarterial chemoembolization (TACE) is a widely applied standard treatment option for treatment-naive patients with multifocal hepatocellular carcinoma (HCC). However, the treatment strategy in patients with multi-nodular recurrences has not been well addressed. This retrospective cohort study aimed to evaluate the efficacy of TACE for recurrent HCC. METHODOLOGY: Two hundred seventeen consecutive patients who received curative ablation therapy for HCC were followed up. Forty-three of the 217 underwent TACE for recurrent HCC, and the treatment efficacy after TACE was compared with that in 99 treatment naive patients who underwent TACE for multifocal HCC during the same period. RESULTS: The overall survival rates of the patients after TACE for recurrent HCC were not different (P=0.136) from those of the treatment-naive patients after TACE. No serious adverse events related to TACE were observed in either group. Serum albumin levels (>3.5g/dL, p=0.001), alpha-fetoprotein levels (<300ng/mL, p=0.021), protein induced by vitamin K absence or antagonist II levels (<300ng/mL, p=0.045), and the number of recurrent tumors (<=3 nodules, p=0.047) were prognostic factors after TACE in patients with recurrent HCC. CONCLUSIONS: TACE for multifocal recurrent HCC is safe and effective, with good survival results, similar to those of initial TACE for treatment-naive patients with multifocal HCC. PMID- 23108089 TI - Clinical outcome of esophagogastrostomy after proximal gastrectomy for gastric cancer. AB - BACKGROUND/AIMS: In order to prevent reflux esophagitis after proximal gastrectomy, reconstruction by jejunal interposition (EJ) is often performed; however, this procedure is considered to be extremely complex. The purpose of this research is to consider the indication and usefulness of esophagogastrostomy (EG), as a less-invasive method of reconstruction. METHODOLOGY: From 1999, 64 proximal gastrectomy cases have been reviewed. In 46 cases, EG combined with a reflux prevention procedure was performed while in the remaining 18 cases, EJ was performed. An endoscopic examination was conducted 1 year after surgery in all cases. RESULTS: Compared to EJ, EG required less surgical time, thus resulting in less blood loss. Reflux esophagitis was frequently present in the EG cases (22 vs. 11%). In the EG group, 36 cases involving abdominal esophagus (AE) conservation due to the site of the cancer in comparison to the resection group (10), experienced a lower probability of reflux esophagitis (5.6 vs. 60%) and endoscopic examinations showed a lower severity (Grade B,C,D; 0 vs. 50%). CONCLUSIONS: EG combined with a reflux prevention procedure is simple and less invasive. In cases in which the conservation of AE is possible, less reflux esophagitis is observed and EG is therefore recommended as an appropriate reconstruction method. PMID- 23108090 TI - Human platelets can discriminate between various bacterial LPS isoforms via TLR4 signaling and differential cytokine secretion. AB - Platelets are currently acknowledged as cells of innate immunity and inflammation and play a complex role in sepsis. We examined whether different types of LPS have different effects on the release of soluble signaling/effective molecules from platelets. We used platelet-rich plasma from healthy volunteers and LPS from two strains of gram-negative bacteria with disparate LPS structures. We combined LPS-stimulated platelet supernatants with reporter cells and measured the PBMC cytokine secretion profiles. Upon stimulation of platelets with both Escherichia coli O111 and Salmonella minnesota LPS, the platelet LPS::TLR4 interaction activated pathways to trigger the production of a large number of molecules. The different platelet supernatants caused differential PBMC secretion of IL-6, TNFalpha, and IL-8. Our data demonstrate that platelets have the capacity to sense external signals differentially through a single type of pathogen recognition receptor and adjust the innate immune response appropriately for pathogens exhibiting different types of 'danger' signals. PMID- 23108095 TI - Reduction in body weight but worsening renal function with late ultrafiltration for treatment of acute decompensated heart failure. AB - OBJECTIVES: The safety, effectiveness and indications for ultrafiltration (UF) are not well established. We hypothesized that UF would not worsen renal function in patients with heart failure (HF) who were not responding to medical therapy. METHODS: Data was collected for patients who underwent UF between 2006 and 2010 (n = 72, median age 61 years, 54% males, 61% Caucasian, 54% left ventricular ejection fraction >= 40%). RESULTS: Baseline GFR was 38 ml/min/1.73 m2. All patients were initially treated with loop diuretics and 58% required a thiazide like diuretic or vasoactive agent. UF resulted in total fluid removal of 11.3 liters and weight loss was 9.7 kg. The median decrease in eGFR during UF was 4.5 ml/min/m2 (IQR--13, 0; p < 0.01) and 43% of patients experienced a >= 20% decrease in eGFR. Ten percent of patients required dialysis and 13% died, received a ventricular assist device/cardiac transplant or were discharged to hospice. CONCLUSIONS: In a cohort of HF patients who did not respond to medical therapy, UF was associated not only with a significant reduction of body weight and fluid removal, but also acute worsening of renal function. Further research to identify the appropriate population for UF, long-term outcomes and the intensity of treatment is required if UF is to gain wide acceptance for HF management. PMID- 23108091 TI - Fli-1 transcription factor affects glomerulonephritis development by regulating expression of monocyte chemoattractant protein-1 in endothelial cells in the kidney. AB - Expression of transcription factor Fli-1 is implicated in the development of glomerulonephritis. Fli-1 heterozygous knockout (Fli1(+/-)) NZM2410 mice, a murine model of lupus, had significantly improved survival and reduced glomerulonephritis. In this study, we found that infiltrated inflammatory cells were significantly decreased in the kidneys from Fli-1(+/-) NZM2410 mice. The expression of monocyte chemoattractant protein-1 (MCP-1) was significantly decreased in kidneys from Fli-1(+/-) NZM2410 mice. The primary endothelial cells isolated from the kidneys of Fli-1(+/-) NZM2410 mice produced significantly less MCP-1. In endothelial cells transfected with specific Fli-1 siRNA the production of MCP-1 was significantly reduced compared to cells transfected with negative control siRNA. By Chromatin Immunoprecipitation (ChIP) assay, we further demonstrated that Fli-1 directly binds to the promoter of the MCP-1 gene. Our data indicate that Fli-1 impacts glomerulonephritis development by regulating expression of inflammatory chemokine MCP-1 and inflammatory cell infiltration in the kidneys in the NZM2410 mice. PMID- 23108097 TI - TREM-1: intracellular signaling pathways and interaction with pattern recognition receptors. AB - TREM-1 is an important signaling receptor expressed on neutrophils and monocytes that plays an important role in systemic infections. Here, we review the intracellular signaling pathways that mediate the immunological effects of TREM 1. Because of the absence of signaling motifs, TREM-1 constitutively associates with DAP12 for induction of intracellular signals. After phosphorylation of DAP12, production of chemokines and cytokines is induced. Moreover, TREM-1 also modulates signaling pathways induced by known classes of PRRs, such as TLRs and NLRs. The exact mechanisms through which TREM-1 influences TLR and NLR pathways are still largely elusive. PMID- 23108096 TI - Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes. AB - Understanding the early pathogenesis of DR may uncover new therapeutic targets to prevent or slow the progression of this sight-threatening disorder. We investigated the role of leukocyte-mediated generation of LTs in regulation of retinal capillary degeneration and inflammation in the diabetic mouse. We generated (1) chimeric mice that lacked the ability to generate LTs by transplanting 5LO-/- bone marrow cells into ND.WT mice and into SD.WT mice and (2) "control" chimeric mice by transplanting WT bone marrow cells into 5LO-/- mice or into WT mice. Retinas from diabetic chimeric mice with WT marrow demonstrated capillary degeneration to the same extent as retinas from diabetic, nonchimeric WT mice. In contrast, retinas from diabetic chimeric mice with 5LO-/- marrow developed significantly less capillary degeneration and pericyte loss (P<0.05). In the retinas from chimeric mice with WT marrow, diabetes induced a rise in leukocyte adherence to the microvasculature, expression of the NF-kappaB p65 subunit, and ICAM1, superoxide generation, and retinal microvascular permeability, yet these characteristic responses were blunted by >50% in diabetic chimeras containing 5LO-/- leukocytes (P<0.05). Our data suggest the critical involvement of leukocytes and LTs in the regulation of inflammation and capillary degeneration in DR. PMID- 23108098 TI - Thrombin-induced CCN2 expression in human lung fibroblasts requires the c Src/JAK2/STAT3 pathway. AB - Thrombin is a multifunctional serine protease and an important fibrotic mediator that induces CCN2 expression. We previously showed that thrombin induces CCN2 expression via an ASK1-dependent JNK/AP-1 pathway in human lung fibroblasts. In this study, we further investigated the roles of c-Src, JAK2, and STAT3 in thrombin-induced CCN2 expression. Thrombin-induced CCN2 expression and CCN2-Luc activity were attenuated by a JAK inhibitor (AG490) and JAK2DN, STAT3DN, and the STAT decoy ODN. Moreover, transfection of cells with a CCN2-mtSTAT-Luc construct inhibited thrombin-induced CCN2-Luc activity. Treatment of cells with thrombin caused JAK2 phosphorylation at Tyr1007/1008 and STAT3 phosphorylation at Tyr705 in time-dependent manners. Thrombin-induced STAT3 phosphorylation was inhibited by AG490 and JAK2DN. Thrombin-induced STAT3 binding to the CCN2 promoter was analyzed by a DNA-binding affinity pull-down assay. In addition, thrombin-induced CCN2 expression and CCN2-Luc activity were inhibited by c-SrcDN and PP2 (an Src inhibitor). Transfection of cells with c-SrcDN also inhibited thrombin-induced JAK2 and STAT3 phosphorylation. Taken together, these results indicate that thrombin might activate c-Src to induce JAK2 activation, which in turn, causes STAT3 activation, and finally induces CCN2 expression in human lung fibroblasts. PMID- 23108099 TI - Selective inhibition of the gliadin-specific, cell-mediated immune response by transamidation with microbial transglutaminase. AB - CD is an immune-mediated enteropathy caused by the ingestion of wheat gluten. The modification of gluten by intestinal tTGase plays a crucial role in CD pathogenesis. In this study, we observed that extensive transamidation of wheat flour with K-C2H5 by mTGase yielded spf and K-gliadins fractions. By Western blot, we found that these modifications were associated with strongly reduced immune cross-reactivity. With the use of DQ8 tg mice as a model of gluten sensitivity, we observed a dramatic reduction in IFNgamma production in gliadin specific spleen cells challenged with spf and K-gliadins in vitro (n=12; median values: 813 vs. 29 and 99; control vs. spf and K-gliadins, P=0.012 for spf, and P=0.003 for K-gliadins). For spf, we also observed an increase in the IL 10/IFNgamma protein ratio (n=12; median values: 0.3 vs. 4.7; control vs. spf, P=0.005). In intestinal biopsies from CD patients challenged in vitro with gliadins (n=10), we demonstrated further that K-gliadins dramatically reduced the levels of antigen-specific IFNgamma mRNA in all specimens responsive to native gliadins (four of 10; P<0.05). As cytotoxic effects have been described for gliadins, we also studied GST and caspase-3 activities using the enterocytic Caco 2 cell line. We found that neither activities were modified by flour transamidation. Our results indicate that K-C2H5 cross-linking via mTGase specifically affects gliadin immunogenicity, reversing the inducible inflammatory response in models of gluten sensitivity without affecting other aspects of the biological activity of gliadins. PMID- 23108100 TI - The importance of the macrophage within the human endometrium. AB - The human endometrium is exposed to cyclical fluctuations of ovarian-derived sex steroids resulting in proliferation, differentiation (decidualization), and menstruation. An influx of leukocytes (up to 15% macrophages) occurs during the latter stages of the menstrual cycle, including menses. We believe the endometrial macrophage is likely to play an important role during the menstrual cycle, especially in the context of tissue degradation (menstruation), which requires regulated repair, regeneration, and phagocytic clearance of endometrial tissue debris to re-establish tissue integrity in preparation for fertility. The phenotype and regulation of the macrophage within the endometrium during the menstrual cycle and interactions with other cell types that constitute the endometrium are currently unknown and are important areas of study. Understanding the many roles of the endometrial macrophage is crucial to our body of knowledge concerning functionality of the endometrium as well as to our understanding of disorders of the menstrual cycle, which have major impacts on the health and well being of women. PMID- 23108101 TI - Influenza-induced, helper-independent CD8+ T cell responses use CD40 costimulation at the late phase of the primary response. AB - The helper-dependent pathway of priming CD8(+) T cells involves "licensing" of DCs by CD40L on CD4(+) T cells. The helper-independent ("helpless") pathways elicited by many viruses, including influenza, are less widely understood. We have postulated that CD40L can be up-regulated on DCs by such viruses, and this promotes priming of CD8(+) T cells via CD40. Most studies on costimulation have been performed in the presence of CD4(+) T cells, and so the role of CD40L costimulation under helpless circumstances has not been fully elucidated. Here, we investigated such a role for CD40L using CD40L KO mice. Although the number of influenza-specific CD8(+) T cells was unaffected by the absence of CD4(+) T cells, it was markedly decreased in the absence of CD40L. Proliferation (the number of CD44(+)BrdU(+) influenza-specific CD8(+) T cells) in the primary response was diminished in CD40L KO mice at Day 8 but not at Day 5 after infection. MLR studies indicated that CD40L expression on DCs was critical for CD8(+) T cell activation. Adoptive transfer of CD40 KO CD8(+) T cells compared with WT cells confirmed that CD40 on such cells was critical for the generation of primary anti-influenza CD8(+) T cell responses. The late effect also corresponded with the late expression of CD40 by influenza-specific CD8(+) T cells. We suggest that costimulation via CD40L on DCs and CD40 on CD8(+) T cells is important in optimizing primary CD8(+) T cell responses during influenza infection. PMID- 23108102 TI - Activation of TRPV4 strengthens the tight-junction barrier in human epidermal keratinocytes. AB - The transient receptor potential cation channel, subfamily V (TRPV), is expressed in the epidermis and considered to be a sensor of extrinsic stimuli such as temperature and other physical or chemical factors. In this study, we examined whether or not the activation of TRPVs by their agonists alters the epidermal tight junction (TJ) function in cultured human epidermal keratinocytes. Reverse transcription-polymerase chain reaction (RT-PCR) analyses showed that mRNA for TRPV1, 3 and 4 were expressed in differentiated keratinocytes in which TJs had formed. Stimulation of the keratinocytes with a TRPV4 agonist (4alpha-phorbol 12, 13-didecanoate, 4alpha-PDD) strengthened the TJ-associated barrier, analyzed by means of transepithelial electric resistance measurements and flux measurements of the paracellular tracer. Stimulation with TRPV1 and TRPV3 agonists did not have the same result. Simultaneously, the 4alpha-PDD-stimulated keratinocytes showed an upregulation of TJ structural proteins, occludin and claudin-4, and TJ regulatory factors, phospho-atypical PKCzeta/iota. It was also observed that the amounts of occludin and phospho-atypical PKCzeta/iota complex were higher in 4alpha-PDD stimulated keratinocytes. In conclusion, we demonstrated that the activation of TRPV4 strengthened the TJ-associated barrier of epidermal cells. It was also suggested that the upregulation of TJ structural proteins and/or the posttranslational modification of TJ structural proteins by phospho-atypical PKCzeta/iota are responsible for the enhancement of TJ function. Our study supports the hypothesis that TJs change their function in response to a change in the external environment sensed through TRPVs. PMID- 23108103 TI - Acute carbonyl stress induces occludin glycation and brain microvascular endothelial barrier dysfunction: role for glutathione-dependent metabolism of methylglyoxal. AB - We recently demonstrated that methylglyoxal (MG) induced apoptosis of brain microvascular endothelial cells (IHECs) that was preceded by glutathione (GSH) depletion. Here, we test the hypothesis that MG induces occludin glycation and disrupts IHEC barrier function, which is prevented by GSH-dependent MG metabolism. Exposure of IHECs to MG decreased transendothelial electrical resistance (TEER) in association with MG-adduct formation. A 65-kDa MG-glycated protein corresponded to occludin, which was confirmed by immunoprecipitation. Moreover, immunofluorescence staining showed that MG disrupted the architectural organization of ZO-1. Occludin glycation and ZO-1 disruption were prevented by N acetylcysteine (NAC). Accordingly, TEER loss was abrogated by NAC (via GSH synthesis) and exacerbated by buthionine sulfoximine (BSO; GSH synthesis inhibitor). BSO treatment attenuated D-lactate production, consistent with a role for GSH in glyoxalase I-catalyzed MG elimination. Although MG increased reactive oxygen species (ROS) generation, the ROS scavengers tempol and tiron did not block barrier disruption. This suggests that endogenously generated ROS were unlikely to be a major cause of or did not reach a threshold to elicit barrier failure as elicited by exogenous hydrogen peroxide (300-400 MUM). Immunohistochemistry revealed a lower percentage of microvessels stained with anti-occludin, but a higher percentage stained with anti-MG in diabetic rat brain compared to controls. Western analyses confirmed the decrease in diabetic brain occludin expression, but an increase in glycated occludin levels. These results provide novel evidence that reactive carbonyl species can mediate occludin glycation in cerebral microvessels and in microvascular endothelial cells that contribute to barrier dysfunction, a process that was prevented by GSH through enhanced MG catabolism. PMID- 23108104 TI - Urinary conjugated alpha-tocopheronolactone--a biomarker of oxidative stress in children with type 1 diabetes. AB - Increased oxidative stress has been implicated in both the onset and the progression of diabetes mellitus and its complications. The development of easy to measure biomarkers of oxidative stress would, therefore, help in determining in a prospective manner the impact of glycemic control on oxidative stress and macrovascular disease in patients with diabetes. We report the development and validation of a novel method to directly measure the urinary concentrations of the conjugated metabolites of vitamin E (alpha-tocopherol) and investigate whether the oxidized metabolite alpha-tocopheronolactone (alpha-TL) could be used as a biomarker of oxidative stress in children with type 1 diabetes. A novel method using liquid chromatography-tandem mass spectrometry was developed and used to measure directly and rapidly the urinary concentrations of the glucuronidated and sulfated metabolites of alpha-tocopherol in 32 young patients with type 1 diabetes and age-matched controls. The mean concentrations of the glucuronidated and sulfated conjugates of alpha-TL were all highly significantly increased in the children with type 1 diabetes (p<0.001). The results suggest that the measurement of the urinary concentrations of alpha-TL conjugates may provide a useful biomarker of oxidative stress in diabetes and possibly in other clinical conditions in which oxidative stress has been implicated. PMID- 23108105 TI - Characterisation and validation of an enzyme-immunoassay for the non-invasive assessment of faecal glucocorticoid metabolites in cheetahs (Acinonyx jubatus). AB - The non-invasive measurement of adrenocortical function in cheetahs is an important tool to assess stress in captive and free-ranging individuals, because stress has been suggested to be one of the causes of poor reproductive performance of captive cheetahs. We tested four enzyme immunoassays (EIA) in two captive cheetahs in Germany using adrenocorticotropic hormone (ACTH) challenges and identified the corticosterone-3-CMO EIA to be most sensitive to the increase in faecal glucocorticoid metabolite (fGCM) concentrations after the ACTH challenge. This EIA performed also well in five captive cheetahs in South Africa. The fGCM concentrations across all seven cheetahs increased within 24h by 681% compared to the baseline levels prior to ACTH. Storage of faecal samples at 0-4 degrees C did not strongly affect fGCM concentrations within 24h, simplifying sample collection when immediate storage at -20 degrees C is not feasible. The two cheetahs in Germany also received an injection of [(3)H]cortisol to characterise fGCMs in faecal extracts using high-performance liquid chromatography (HPLC) immunograms. HPLC fractions were measured for their radioactivity and immunoreactive fGCM concentrations with the corticosterone-3 CMO EIA, respectively. The results revealed a polar peak of radiolabelled cortisol metabolites co-eluting with the major peak of immunoreactive fGCMs. Thus, our EIA measured substantial amounts of fGCMs corresponding to the radioactive peaks. The peaks were of higher polarity than native cortisol and corticosterone, suggesting that the metabolites were conjugated, which was confirmed by solvolysis of the HPLC fractions. Our results show that the corticosterone-3-CMO EIA is a reliable tool to assess fGCMs in cheetahs. PMID- 23108106 TI - Low temperature synthesis of monodisperse nanoscaled ZrO2 with a large specific surface area. AB - Thermal decomposition of Zr(C(2)O(4))(2).4H(2)O within an autoclave or in a conventional tube furnace at temperatures below 380 degrees C resulted in nano- and micron-sized ZrO(2), respectively. Reactions under autogenic pressure yielded monodisperse monoclinic (m) and tetragonal (t) ZrO(2) nanoparticles with an average diameter of ~8 nm and interconnected t-ZrO(2) nanoparticles with diameters of ~4 nm, depending on the synthesis temperature. Samples were characterised by X-ray diffraction (XRD), small angle X-ray scattering (SAXS), scanning electron microscopy (SEM), transmission electron microscopy (TEM) associated with energy dispersive X-ray spectroscopy (EDS), Raman microspectroscopy and photoluminescence spectroscopy (PL). Nanostructured zirconia materials exhibited high specific areas of 276-385 m(2) g(-1) which make them promising candidates as catalysts and catalyst supports. Co-existence of m- and t-ZrO(2) nanoparticles with diameters of 6-9 nm, i.e. above the critical particle size of 6 nm for the formation of t-ZrO(2), demonstrated that the particle size is not the only factor for stabilisation of the t-ZrO(2) modification at room temperature. PMID- 23108108 TI - Electronic medical records: don't let the tail wag the dog. PMID- 23108109 TI - A six-bladed impeller-like Cu18 nanocluster with S6 symmetry constructed from simple inorganic linkers. AB - Eighteen Cu(II) ions are consolidated by simple inorganic linkers alone to construct an S(6)-symmetric six-bladed impeller-like Cu(18) nanocluster driven by the concomitant decomposition reaction of a Schiff base, which affords a typical high-nuclearity inorganic cluster and a representative synthetic strategy. The magnetic measurements reveal dominant antiferromagnetic interaction in this cluster. PMID- 23108110 TI - Oocyte developmental failure in response to elevated nonesterified fatty acid concentrations: mechanistic insights. AB - Elevated plasma nonesterified fatty acid (NEFA) concentrations are associated with negative energy balance and metabolic disorders such as obesity and type II diabetes. Such increased plasma NEFA concentrations induce changes in the microenvironment of the ovarian follicle, which can compromise oocyte competence. Exposing oocytes to elevated NEFA concentrations during maturation affects the gene expression and phenotype of the subsequent embryo, notably prompting a disrupted oxidative metabolism. We hypothesized that these changes in the embryo are a consequence of modified energy metabolism in the oocyte. To investigate this, bovine cumulus oocyte complexes were matured under elevated NEFA conditions, and energy metabolism-related gene expression, mitochondrial function, and ultrastructure evaluated. It was found that expression of genes related to REDOX maintenance was modified in NEFA-exposed oocytes, cumulus cells, and resultant blastocysts. Moreover, the expression of genes related to fatty acid synthesis in embryos that developed from NEFA-exposed oocytes was upregulated. From a functional perspective, inhibition of fatty acid beta oxidation in maturing oocytes exposed to elevated NEFA concentrations restored developmental competence. There were no clear differences in mitochondrial morphology or oxygen consumption between treatments, although there was a trend for a higher mitochondrial membrane potential in zygotes derived from NEFA exposed oocytes. These data show that the degree of mitochondrial fatty acid beta oxidation has a decisive impact on the development of NEFA-exposed oocytes. Furthermore, the gene expression data suggest that the resulting embryos adapt through altered metabolic strategies, which might explain the aberrant energy metabolism previously observed in these embryos originating from NEFA-exposed maturing oocytes. PMID- 23108111 TI - Embryo implantation failure and other reproductive defects in Ube2q1-deficient female mice. AB - The ubiquitination process is indispensable for proteome regulation. Three classes of ubiquitin (Ub)-related proteins can be distinguished: E1, E2 and E3. Proteins from the E2 class are responsible for the transfer of Ubls from E1 to the target protein. For this activity, interaction with class E3 ligases is usually required. Ub-conjugating enzyme E2Q 1 (UBE2Q1) belongs to the E2 class of Ub-related enzymes and is demonstrated to be involved in the regulation of membrane B4GALT1 protein. Here, we demonstrate that human UBE2Q1 and mouse Ube2q1 are widely expressed and highly conserved genes. To elucidate the function of UBE2Q1 protein, we generated knockout mouse model. No overt phenotype was detected in UBE2Q1-deficient males, but in mutant females, pleiotropic reproductive defects were observed including altered oestrus cycle, abnormal sexual behaviour and reduced offspring care. Moreover, in the uterus of mutant females, significantly increased embryonic lethality and decreased implantation capacity of homozygous mutant embryos were noticed. We found that Ube2q1 is not expressed in the uterus of non-pregnant females but its expression is up regulated during pregnancy. Taken together, Ube2q1 is involved in different aspects of female fertility. PMID- 23108114 TI - Carbene spacers in bis-porphyrinic scaffolds. AB - The preparation of two meso-imidazolylporphyrins was achieved in good yield by Ullmann coupling between a meso-bromotriarylporphyrin and imidazoles. Subsequent alkylation afforded the corresponding imidazolium functionalized porphyrins as direct precursors of the carbene. The complexation of these azolium salts with palladium led to trans-anti bis-porphyrin carbenic complexes. PMID- 23108112 TI - Multiple follicle culture supports primary follicle growth through paracrine acting signals. AB - In vitro follicle growth in alginate hydrogels is a unique and versatile method for studying ovarian and follicle biology that may also have implications for fertility preservation. Current culture systems support the development of isolated mouse follicles from the secondary stage onward. However, it has been a challenge to grow smaller follicles in vitro due to the dissociation of the oocyte from companion somatic cells. Recent work has demonstrated that coculturing primary follicles with mouse embryonic fibroblasts or ovarian stromal cells supports follicle survival and growth. In this study, we demonstrate that follicles themselves can exert a beneficial coculture effect. When primary follicles were cultured in groups of five or ten (multiple follicle culture), there was increased growth and survival. The multiple follicle culture approach maintained follicle integrity and resulted in the formation of antral stage follicles containing meiotically competent gametes. The growth and survival of primary follicles were highly number dependent, with the most significant enhancement observed when the largest number of follicles was grown together. Our data suggest that the follicle unit is necessary to produce the secreted factors responsible for the supportive effects of multiple follicle culture, as neither denuded oocytes, oocyte-secreted factors, nor granulosa cells alone were sufficient to support early follicle growth in vitro. Therefore, there may be signaling from both the oocyte and the follicle that enhances growth but requires both components in a feedback mechanism. This work is consistent with current in vivo models for follicle growth and thus advances the movement to recapitulate the ovarian environment in vitro. PMID- 23108113 TI - Psoriasis comorbidities: results from the National Psoriasis Foundation surveys 2003 to 2011. AB - BACKGROUND: Studies examining comorbidities among psoriasis patients with varying disease severities measured by body surface area (BSA) are lacking. OBJECTIVE: To examine the association between psoriasis severity and comorbid conditions, including rheumatologic, cardiovascular and other immune-mediated diseases. METHODS: From 2003 to 2011, the National Psoriasis Foundation conducted surveys among 5,604 psoriasis patients. The combined surveys represented the largest study to date that used BSA as a direct measure of psoriasis severity for comorbidity assessment. RESULTS: Over 86% of psoriatic arthritis (PsA) patients reported presenting with psoriasis prior to PsA; the diagnosis of psoriasis preceded that of PsA by a mean period of 14.6 years. Compared to those with mild psoriasis, patients with moderate-to-severe psoriasis had significantly increased adjusted odds of PsA (moderate: odds ratio, OR: 1.21, 95% confidence interval, CI: 1.04-1.41; severe: OR: 2.32, 95% CI: 1.98-2.70). Patients with severe psoriasis had increased adjusted odds of diabetes (OR: 1.5, 95% CI: 1.08-2.08) and cardiovascular disease (OR: 1.5, 95% CI: 1.01-2.24) compared to those with mild-to-moderate psoriasis. Odds of rheumatoid arthritis, ankylosing spondylitis, lupus, Crohn's disease and multiple sclerosis were not significantly increased in patients with severe psoriasis. CONCLUSION: Compared to those with mild-to moderate psoriasis, patients with severe psoriasis are at increased odds of PsA, diabetes and cardiovascular diseases. PMID- 23108115 TI - Pharmacological inhibition of adipocyte fatty acid binding protein alleviates both acute liver injury and non-alcoholic steatohepatitis in mice. AB - BACKGROUND & AIMS: Adipocyte fatty acid binding protein (A-FABP) is a key mediator of inflammatory response in macrophages. Increased hepatic expression and circulating levels of A-FABP have been observed in patients with non alcoholic fatty liver disease (NAFLD). Here, we investigated the role of A-FABP in both lipopolysaccaride (LPS)-induced acute liver injury and high fat high cholesterol (HFHC) diet-induced NAFLD in mice. METHODS: Mice with LPS-induced acute liver injury and HFHC diet-induced obesity were treated with the A-FABP inhibitor BMS309403. Liver tissues of the mice were analyzed by immunohistochemistry, Western blot or real-time PCR. RESULTS: A-FABP expression in Kupffer cells was significantly elevated in mice with LPS-induced acute liver injury and HFHC diet-induced obesity, as compared to their healthy controls. Pretreatment of mice with BMS309403 led to a diminished LPS-induced elevation in serum levels of alanine transaminase and hepatic production of pro-inflammatory cytokines. Likewise, chronic treatment of HFHC diet-induced obese mice with BMS309403 ameliorated hepatic steatosis, macrophage infiltration, and cellular ballooning of hepatocytes. Such improvements in liver function and morphology were accompanied by significantly decreased activation of both c-Jun and NF kappaB. Pretreatment with BMS309403 suppressed both LPS- and palmitate-induced pro-inflammatory responses in isolated rat Kupffer cells. Adenovirus-mediated ectopic expression of A-FABP alone was sufficient to induce liver injury and inflammation in mice. CONCLUSIONS: These findings suggest that A-FABP is an important contributor to both LPS-induced acute liver injury and diet-induced NAFLD by potentiating inflammation in Kupffer cells. Pharmacological inhibition of A-FABP may represent a promising modality for obesity-related non-alcoholic steatohepatitis. PMID- 23108116 TI - Treatment of infected soft tissue blast injury in swine by regulated negative pressure wound therapy. AB - OBJECTIVE: This study was designed to investigate the therapeutic potential of regulated negative pressure wound therapy (RNPT) in treating infected blast injuries in swine. BACKGROUND: Approximately 30% to 80% of blast injuries develop infection, which increases the morbidity and mortality of these casualties. RNPT has been used in US military operations in Iraq; however, no randomized controlled study has been conducted on the use of RNPT to treat infected war injuries. METHODS: Infected soft tissue blast injuries were treated with gauze dressings or RNPT with different pressures ranging from -5 to -35 kPa. To evaluate the wound healing process, the wound area, wound depth, the number of proliferative cells, and the vascular endothelial cells in the granulation tissue were measured at different time points. Furthermore, to evaluate the infection and inflammation of the blast injury, the bacterial load, bacterial species, and several inflammatory markers were detected. RESULTS: Compared with gauze dressing treatments, RNPT reduced bacterial load more efficiently, initiated granulation tissue formation earlier, and increased the inflammation faster. Negative pressures ranging from -10 to -25 kPa applied on the RNPT group showed beneficial effects in treating the infected soft tissue blast injury. RNPT did not significantly change both the aerobic and anaerobic bacterial composition compared with those of the gauze dressing group. CONCLUSIONS: RNPT clearly shows beneficial effects in treating the infected soft tissue blast injury in comparison with the gauze dressing therapy in swine. PMID- 23108117 TI - The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a retrospective analysis of 295 patients. AB - OBJECTIVES: T1 esophageal squamous cell carcinoma (ESCC) has a low, but still present, risk of lymph node (LN) metastasis. Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) is often applied for T1 ESCC. To achieve successful treatment by EMR/ESD, the risk of LN metastases, LN recurrence, and hematological recurrence need to be better understood. The aim of this study was to determine the precise risk for metastasis in T1 ESCC. METHODS: We divided 295 patients with T1 ESCC who underwent surgery and/or ESD/EMR into 6 categories (m1, m2, m3, sm1, sm2, and sm3). Their risks of LN metastasis, LN recurrence, hematological recurrence, and the outcome were determined. RESULTS: The rates of LN metastasis and LN recurrence were 0% in m1 and m2, 9% in m3, 16% in sm1, 35% in sm2, and 62% in sm3 cases. The incidence of hematological recurrence was 0% in m1, m2, m3, and sm1 cases; 9% in sm2 cases; and 13% in sm3 cases. The overall risk of metastasis was 9% in m3, 16% in sm1, 38% in sm2, and 64% in sm3 patients. The 5-year disease-specific survival rates were 100% in m1, m2, and m3; 90.9% in sm1; 78.8% in sm2; and 68.6% in sm3 patients. Statistically, both lymphatic and venous invasion were selected as predictive markers for metastasis. In m3 patients, positivity for either of these had an odds ratio for metastasis of 7.333 (P = 0.093). CONCLUSIONS: Our study provides a precise assessment of the comprehensive risk of metastasis and feasible predictive markers for T1 ESCC. PMID- 23108118 TI - A therapeutic strategy for metastatic malignant fibrous histiocytoma through mesenchymal stromal cell-mediated TRAIL production. AB - OBJECTIVE: To overcome the therapeutic limitations of malignant fibrous histiocytoma (MFH), we evaluated human adipose tissue-derived mesenchymal stromal cells (MSCs) that secrete tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on metastatic MFH. BACKGROUND: MFH is a highly malignant and metastatic type of sarcoma but surgical removal is the only effective method for treating MFH. MSCs are easily transduced to express a high level of transgene and can migrate toward cancer. For this reason, MSCs are a promising candidate for metastatic MFH therapies. METHODS: In vitro sustainability of MSC-TRAIL against MFH-ino was analyzed by apoptosis assay. For preclinical study, anti-MFH effects of MSC-TRAILs were validated in murine models for local tumorigenesis and metastasis. Furthermore, a time-interval metastasis model of MFH was applied to confirm antimetastatic ability of MSC-TRAIL for preestablished metastatic MFH. RESULTS: We found that MFH-ino is highly susceptible to recombinant TRAIL and MSC TRAIL, which selectively induce apoptosis via caspase-8 activation in vitro. Moreover, not only MFH-ino but xenograft explants were also significantly inhibited by MSC-TRAIL in local tumorigenesis. In particular, the metastatic ability of MFH-ino was considerably reduced by MSC-TRAIL in metastasis murine model, particularly for preestablished metastatic MFH. CONCLUSIONS: These results suggest that MSC-TRAIL is sufficiently effective in inhibiting MFH-ino metastasis and the application using MSC-TRAIL could be extended to other sarcomas and recurrent metastatic cancers for cell-mediated cancer therapy. PMID- 23108119 TI - Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease. AB - BACKGROUND: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184* higher in BE and 99* higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER. PMID- 23108120 TI - Alterations in gut hormones after laparoscopic sleeve gastrectomy: a prospective clinical and laboratory investigational study. AB - OBJECTIVE: To evaluate the effect of laparoscopic sleeve gastrectomy (LSG) on fasting and meal-stimulated release of the gut hormones ghrelin, pancreatic polypeptide (PP), peptide-YY (PYY), glucagon-like peptide-1 (GLP-1), and amylin and of the adipocytokine leptin. BACKGROUND: Mounting evidence suggests that the mechanisms of weight loss and the improvement in glucose metabolism seen after LSG are related not only to gastric restriction but also to neurohormonal changes. METHODS: : Fasting and postprandial levels at 60 and 120 minutes after a standard test meal of the above peptides and glucose metabolism indices were evaluated in 15 consecutive morbidly obese (MO) subjects before and 6 and 12 months after LSG. As study controls, 15 lean subjects matched for age and sex were also assessed. RESULTS: Body mass index values notably decreased at 6 and 12 months (P < 0.01), postoperatively. In addition, an overall improvement of the glycemic profile of MO patients was noted. After LSG, markedly decreased fasting and postprandial levels of ghrelin, amylin, and leptin were observed. A significant postprandial increase of PYY and GLP-1 levels was also noted postoperatively. Interestingly, significantly increased levels of PP were noted only at 60 minutes postprandially after LSG. CONCLUSIONS: LSG markedly improved glucose homeostasis and generated significant changes in ghrelin, PP, PYY, GLP-1, amylin, and leptin levels. These multiple hormonal actions may have several beneficial effects on the underlying mechanism of weight loss, demonstrating that LSG could be more than just a restrictive bariatric operation. PMID- 23108121 TI - Half-life of serum alpha-fetoprotein: an early prognostic index of recurrence and survival after hepatic resection for hepatocellular carcinoma. AB - OBJECTIVE: To explore the prognostic value of the postsurgical half-life (HL) of serum alpha-fetoprotein (AFP). BACKGROUND: There is still a paucity of early surrogate indicators of clinical endpoints after liver resection of hepatocellular carcinoma (HCC). METHODS: The analysis was based on cohorts of 225 (exploration set) and 117 (validation set) treatment-naive HCC patients undergoing curative liver resection. We defined 3 categories of AFP HL: early complete resolution of AFP, normal HL, and prolonged HL if the HL exceeded 7 days. Overall, probabilities of recurrence and survival were estimated and compared across the AFP HL categories. RESULTS: In the exploration cohort, 48 patients (21.3%) achieved early AFP complete resolution, 116 (51.6%) had normal HL, and 61 (27.1%) had prolonged HL. Long AFP HL was significantly associated with early postoperative recurrence (P < 0.001), as was microvascular invasion. Early recurrence within 2 years of resection was observed in 59% of the patients with prolonged AFP HL compared with only 29.3% of those with normal AFP HL (P < 0.001). A log-rank test followed by multivariate Cox analysis identified an independent function of prolonged AFP HL in predicting shorter recurrence-free survival and overall survival time after HCC resection (hazard ratios, 2.81 and 3.58; P < 0.001). When AFP HL analysis was applied to the validation cohort, the association between prolonged AFP HL and survival endpoints (hazard ratio, 11.63 and 16.39; P < 0.001) was confirmed. PMID- 23108122 TI - Ex vivo lung evaluation of prearrest heparinization in donation after cardiac death. AB - OBJECTIVE: To evaluate the effects of prearrest heparin administration on lung quality in a model of donation after cardiac death (DCD), and to assess the potential application of ex vivo lung perfusion (EVLP) in the identification of better grafts from the DCD donor pool. METHODS: Cardiac death was induced by electric shock in 10 pigs. One group received a prearrest heparin dose of 300 units/kg (H group, n = 5) and the other did not (NH group, n = 5). Animals remained at room temperature for 1 hour without ventilation, defining the warm ischemic time. After harvest, the lungs underwent 6 hours of cold ischemia before being evaluated with EVLP for 4 hours. RESULTS: Static compliance 28 +/- 3 versus 29 +/- 2 (Cstat-cm H2O), pulmonary vascular resistance (PVR) 593 +/- 127 versus 495 +/- 70 (PVR-dyn.s/cm), and oxygenation 327 +/- 32 versus 330 +/- 28 (DeltaPO2 mm Hg) remained stable from the beginning until the end of EVLP in the H group. In the NH group, Cstat started to decline after the first hour (25 +/- 2 vs 21 +/ 2), DeltaPO2 after hour 2 (265 +/- 44 vs 207 +/- 44), and PVR started to increase after hour 3 (765 +/- 132 vs 916 +/- 168). Significant differences between the groups were observed at the end of EVLP (P < 0.001). Parameters of lung quality after EVLP also showed significant differences between the groups: wet weight-to-dry weight ratio (P < 0.001), protein in the bronchial lavage (P < 0.01), Na + K-ATPase activity (P < 0.001), and E-selectin (P < 0.001) in the perfusate. CONCLUSIONS: Prearrest heparin administration improved organ function by preserving endothelial homeostasis. EVLP proved to be a useful platform for assessing DCD lungs, providing reliable means of discriminating injured grafts. PMID- 23108123 TI - Feasibility of split liver transplantation for 2 adults in the model of end-stage liver disease era. AB - OBJECTIVE: To examine the results of split liver transplantation for 2 adults in the model of end-stage liver disease (MELD) era. BACKGROUND: In the MELD era, liver allografts are first allocated to recipients with the highest MELD scores. However, the application of split liver transplantation for 2 adults in urgent condition has doubled and has become a matter of concern. METHODS: Twenty-one deceased liver grafts were split into full right and full left lobes for 42 adult recipients. One of the hemiliver grafts was allocated to the recipient with the highest MELD score in the waiting list. The results of split liver transplantation were examined and compared with those of living donor liver transplantation. RESULTS: Among 42 recipients, 24 (57.1%) had MELD scores higher than 20. The median (interquartile) MELD score for the recipients with split liver transplantation was 22 (15-30), which was higher than that for the recipients with living donor liver transplantation (P < 0.001). The 1-, 3-, and 5 year survival rates for split liver transplantation were comparable with those of living donor transplantation (P = 0.489). Nevertheless, 10 of 42 split liver recipients died within 3 months after transplantation. By receiver operating characteristic curve analysis, the safe graft-recipient weight ratio was better more than 1% to avoid early patient death for split liver transplantation. CONCLUSIONS: Although most of the recipients with split liver transplantation had high MELD scores, the results were comparable with those of living donor liver transplantation. Split liver transplantation for 2 adults is still feasible in the MELD era. PMID- 23108124 TI - Atlanta redux: revisiting the severity stratification system for acute pancreatitis. PMID- 23108125 TI - Resection or transplantation for early hepatocellular carcinoma in a cirrhotic liver: does size define the best oncological strategy? AB - BACKGROUND: Resection and liver transplantation (LT) are the only curative options for hepatocellular carcinoma in cirrhotic patients (HCC-cirr). OBJECTIVE: We tried to define the best primary intention-to-treat strategy in patients undergoing either resection or LT for early single HCC-cirr (<=5 cm). METHODS: From 1990 to 2010, 198 patients with early HCC-cirr underwent either resection (group R, n = 97) or LT (group T, n = 101) as the primary procedure. Our policy was to prioritize Childs A patients with peripheral lesions for resection rather than LT. Patient and tumor characteristics, and outcomes (recurrence-free survival [RFS] and overall survival [OS]), were studied. RESULTS: A longer diagnosis-to-surgery interval, more Child Pugh B/C patients, and more tumor nodules (on histopathological examination) were found in group T patients. The postoperative mortality (4.1% vs 3.0%, P = 0.72) and rate of major complications (19.1% vs 24.7%, P = 0.35) were similar in groups R and T, respectively, whereas tumor recurrence was higher in group R (62% vs 10% in group T, P < 0.0001). The 5 year OS (75% vs 52%, P = 0.0008) and RFS (72% vs 20%, P < 0.0001) were better in group T; similarly, more patients were disease free at last follow-up (27% vs 62%, P < 0.0001). Resection as the surgical procedure, tumor diameter 3 cm or more on histology, and microvascular tumor invasion were poor prognostic factors for OS and RFS. Including dropout patients from LT list in the analysis, the outcomes in group T were still better (70% and 61% vs 51% and 36% at 5 and 10 years, P = 0.01). CONCLUSIONS: On an intention-to-treat basis, LT is associated with the best survival outcomes in patients with early HCC-cirr. Resection may achieve comparable OS in patients with single HCC-cirr of size smaller than 3 cm; however, the RFS still remains lower than that in patients of group T. This study could serve as a guide for HCC-cirr patients who are candidates for either resection or LT. PMID- 23108126 TI - Resection versus transplantation for early hepatocellular carcinoma: more art than science. PMID- 23108127 TI - Reassessing the role of supplemental oxygen in the prevention of surgical site infection. PMID- 23108128 TI - Laparoscopic surgery compared with open surgery decreases surgical site infection in obese patients: a systematic review and meta-analysis. AB - OBJECTIVE: To compare surgical site infections rate in obese patients after laparoscopic surgery with open general abdominal surgery. BACKGROUND: In mixed surgical populations, surgical site infections are fewer in laparoscopic surgery than in open surgery. It is not clear if this is also the case for obese patients, who have a higher risk of surgical site infections than nonobese patients. METHODS: MEDLINE, Embase, and The Cochrane library (CENTRAL) were searched systematically for studies on laparoscopic surgery compared with open abdominal surgery. Randomized controlled trials (RCTs) and observational studies reporting surgical site infection in groups of obese patients (body mass index >= 30) were included. Separate meta-analyses with a fixed effects model for RCTs and a random effects model for observational studies were performed. Methodological quality of the included studies was assessed according to the Cochrane method and the Newcastle-Ottawa Scale. RESULTS: Eight RCTs and 36 observational studies on bariatric and nonbariatric surgery were identified. Meta-analyses of RCTs and observational studies showed a significantly lower surgical site infection rate after laparoscopic surgery (OR = 0.19; 95% CI [0.08-0.45]; P = 0.0002 and OR = 0.33; 95% CI [0.26-0.42]; P = 0.00001). Sensitivity analyses to assess the impact of selection and detection bias confirmed the significant estimates with acceptable heterogeneity. No publication bias was present for the observational studies. CONCLUSIONS: Laparoscopic surgery in obese patients reduces surgical site infection rate by 70%-80% compared with open surgery across general abdominal surgical procedures. Future efforts should be focused on further development of laparoscopic surgery for the growing obese population. PMID- 23108129 TI - An evaluation of a proactive geriatric trauma consultation service. AB - OBJECTIVE: To describe and evaluate an inpatient geriatric trauma consultation service (GTCS). BACKGROUND: Delays in recognizing the special needs of older trauma patients may result in suboptimal care. The GTCS is a proactive geriatric consultation model aimed at preventing and managing age-specific complications and discharge planning for all patients 60 years or older admitted to the St Michael's Hospital Trauma Service. METHODS: This was a before and after case series of patients admitted pre-GTCS (March 2005-August 2007) and post-GTCS (September 2007-March 2010). Study data were derived from a review of the medical records and from the St Michael's Hospital trauma registry. Abstracted data included demographics, type of geriatric issues addressed, rate of adherence to recommendations made by the GTCS, geriatric-specific clinical outcomes, trauma quality indicators, consultation requests, and discharge destinations. RESULTS: A total of 238 pre-GTCS patients and 248 post-GTCS patients were identified. The rate of adherence to recommendations made by the GTCS team was 93.2%. There were fewer consultation requests made to Internal Medicine and Psychiatry in the post GTCS group (N = 31 vs N = 18, P = 0.04; and N = 33 vs N = 18, P = 0.02; respectively). There were no differences in any of the prespecified complications except delirium (50.5% pre-GTCS vs 40.9% post- GTCS, P = 0.05). Among patients admitted from home, fewer were discharged to long-term care facilities among the post-GTCS group (6.5% pre-GTCS vs 1.7% post-GTCS, P = 0.03). CONCLUSIONS: A proactive geriatric consultation model for elderly trauma patients may decrease delirium and discharges to long-term care facilities. Future studies should include a multicenter randomized trial of this model of care. PMID- 23108130 TI - Extended or limited lymph node dissection? A gastric cancer surgical dilemma. PMID- 23108131 TI - Anastomotic leak and local recurrence in colorectal cancer. PMID- 23108132 TI - Surgical stress promotes the development of cancer metastases by a coagulation dependent mechanism involving natural killer cells in a murine model. AB - OBJECTIVE: To determine whether the postoperative hypercoagulable state is responsible for the increase in metastases observed after surgery. BACKGROUND: Surgery precipitates a hypercoagulable state and increases the formation of cancer metastases in animal models. Coagulation promotes metastases by facilitating the formation of microthrombi around tumor cell emboli (TCE), thereby inhibiting natural killer (NK) cell-mediated destruction. METHODS: Mice underwent surgery preceded by tumor cell inoculation to establish pulmonary metastases in the presence or absence of various perioperative anticoagulants. Pulmonary TCE were quantified and characterized using fluorescently labeled fibrinogen and platelets. The role of NK cells was evaluated by repeating these experiments after antibody depletion in a genetically deficient strain and by adoptively transferring NK cells into NK-deficient mice. RESULTS: Surgery resulted in a consistent and significant increase in metastases while a number of different anticoagulants and platelet depletion attenuated this effect. Impaired clearance of TCE from the lungs associated with an increase in peritumoral fibrin and platelet clot formation was observed in surgically stressed mice, but not in control mice or mice that received perioperative anticoagulation. The increase in TCE survival conferred by surgery and inhibited by perioperative anticoagulation was eliminated by the immunological or genetic depletion of NK cells. Adoptive transfer experiment confirms that surgery impairs NK cell function. CONCLUSIONS: Surgery promotes the formation of fibrin and platelet clots around TCE, thereby impairing NK cell-mediated tumor cell clearance, whereas perioperative anticoagulation attenuates this effect. Therapeutic interventions aimed at reducing peritumoral clot formation and enhancing NK cell function in the perioperative period will have important clinical implications in attenuating metastatic disease after cancer surgery. PMID- 23108133 TI - Enhancing the photocytotoxic potential of curcumin on terpyridyl lanthanide(III) complex formation. AB - Lanthanide(III) complexes [Ln(R-tpy)(cur)(NO3)2] (Ln = La(III) in 1, 2; Gd(III) in 5, 6) and [Ln(R-tpy)(scur)(NO3)2] (Ln = La(III) in 3, 4; Gd(III) in 7, 8), where R-tpy is 4'-phenyl-2,2':6',2''-terpyridine (ph-tpy in 1, 3, 5, 7), 4'-(1 pyrenyl)-2,2':6',2''-terpyridine (py-tpy in 2, 4, 6, 8), Hcur is curcumin (in 1, 2, 5, 6) and Hscur is diglucosylcurcumin (in 3, 4, 7, 8), were prepared and their DNA photocleavage activity and photocytotoxicity studied. Complexes [La(ph tpy)(cur)(NO3)2] (1) and [Gd(ph-tpy)(cur)(NO3)2] (5) were structurally characterized. The complexes in aqueous-DMF showed an absorption band near 430 nm and an emission band near 515 nm when excited at 420 nm. The complexes are moderate binders to calf-thymus DNA. They cleave plasmid supercoiled DNA to its nicked circular form in UV-A (365 nm) and visible light (454 nm) via (1)O2 and OH pathways. The complexes are remarkably photocytotoxic in HeLa cells in visible light (lambda = 400-700 nm) and are non-toxic in the dark. FACScan analysis of the HeLa cells treated with 2 and 4 showed cell death via an apoptotic pathway. Nuclear localization of 1-4 is evidenced from confocal imaging on HeLa cells. The hydrolytic instability of curcumin gets significantly reduced upon binding to the lanthanide ions while retaining its photocytotoxic potential. PMID- 23108134 TI - Preparation and evaluation of ionic liquid-gold nanoparticles functionalized silica monolithic column for capillary electrochromatography. AB - This paper describes the development of silica monolithic column modified with ionic liquids-gold nanoparticles (ILs-GNPs) for capillary electrochromatography (CEC). The novel ILs (1-methyl-2-mercapto-3-butylimidazolium bromide) were synthesized and used to modify GNPs functionalized silica monolithic column via the formation of a Au-S bond. The morphology of the GNPs and ILs-GNPs functionalized silica (ILs-GNPs-silica) monolithic column were characterized by transmission electron microscopy and scanning electron microscope, respectively. A cathodic electroosmotic flow was observed at pH above 6.4 on ILs-GNPs-silica monolithic column, which was reversed at acidic pH. The electrochromatographic performance of ILs-GNPs-silica monolithic column was evaluated by separation of different kinds of analytes such as hydrophobic, polar and basic compounds. The ILs-GNPs-silica monolithic column displayed enhanced hydrophobic retention characteristics in the separation of five hydrophobic n-alkylbenzenes when compared to the ILs bonded silica monolithic column. The column efficiencies for the n-alkylbenzenes were from 62,000 to 110,000 N m(-1). The ILs-GNPs-silica monolithic column exhibited reversed-phase electrochromatographic behavior toward neutral solutes. Separation of polar compounds was demonstrated on ILs-GNPs silica monolithic column in reversed-phase CEC mode using high aqueous mobile phases. The relatively good peak shape and high separation efficiency on ILs-GNPs silica monolithic column was obtained for basic solutes when compared to silica monolithic column modified GNPs. PMID- 23108135 TI - Topical treatment with basic fibroblast growth factor promotes wound healing and barrier recovery induced by skin abrasion. AB - It has been reported that basic fibroblast growth factor (bFGF) promotes the healing of skin ulceration by inducing fibroblast proliferation, yet the role of bFGF on epidermal barrier function, especially from the perspective of scratch induced skin abrasion, remains unknown. To this end, we initially developed an epidermal abrasion mouse model induced by scratching with a stainless-steel wire brush, and examined the effects of bFGF on the wound healing induced by skin abrasion. This procedure induced a significant elevation of transepidermal water loss (TEWL) in a scratch-count-dependent manner. This elevated TEWL was significantly decreased following topical application of bFGF to the skin. In addition, bFGF increased the expression of Ki67 in keratinocytes following mechanical scratching. These results suggest that bFGF enhances keratinocyte proliferation, which, in turn, repairs the skin barrier disruption and wounds caused by scratching in mice. Consistently, bFGF stimulated proliferation of normal human epidermal keratinocytes (NHEK). Intriguingly, the effect of bFGF and other growth factors on NHEK proliferation was additive. However, high cell density diminished the effect of bFGF on NHEK proliferation. This particular result can be explained by our observation that FGF receptor mRNA expression in NHEK was low under conditions of high cell density. Our findings suggest that bFGF stimulates keratinocyte proliferation, especially in a lower cell density environment, to repair skin wound in accord with skin barrier recovery. PMID- 23108136 TI - VEGFA-VEGFR pathway blockade inhibits tumor-induced regulatory T-cell proliferation in colorectal cancer. AB - Multitarget antiangiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and patients with metastatic renal carcinomas. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number, and proliferation were analyzed by flow cytometry in peripheral blood of patients with metastatic colorectal cancer (mCRC) treated with bevacizumab, a monoclonal antibody targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26 bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of patients with mCRCs. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in patients with mCRCs. VEGFR-2- but not VEGFR-1 specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR-2 blockade. Anti-VEGF-A therapies also have immunologic effects that may be used with a therapeutic goal in the future. PMID- 23108137 TI - A tumorigenic MLL-homeobox network in human glioblastoma stem cells. AB - Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behavior are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma. We found that MLL directly activates the Homeobox gene HOXA10. In turn, HOXA10 activates a downstream Homeobox network and other genes previously characterized for their role in tumorigenesis. The MLL-Homeobox axis we identified significantly contributes to the tumorigenic potential of glioblastoma stem cells. Our studies suggest a role for MLL in contributing to the epigenetic heterogeneity between tumor-initiating and non-tumor-initiating cells in glioblastoma. PMID- 23108138 TI - A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. AB - The relevance of many BRCA2 variants of uncertain significance (VUS) to breast cancer has not been determined due to limited genetic information from families carrying these alterations. Here, we classified six new variants as pathogenic or nonpathogenic by analysis of genetic information from families carrying 64 individual BRCA2 DNA binding domain (DBD) missense mutations using a multifactorial likelihood model of cancer causality. Next, we evaluated the use of a homology-directed DNA break repair (HDR) functional assay as a method for inferring the clinical relevance of VUS in the DBD of BRCA2 using 18 established nonpathogenic missense variants and all 13 established pathogenic missense mutations from the BRCA2 DBD. Compared with the known status of these variants based on the multifactorial likelihood model, the sensitivity of the HDR assay for pathogenic mutations was estimated at 100% [95% confidence interval (CI): 75.3%-100%] and specificity was estimated at 100% (95% CI: 81.5%-100%). A statistical classifier for predicting the probability of pathogenicity of BRCA2 DBD variants was developed using these functional results. When applied to 33 additional VUS, the classifier identified eight with 99% or more probability of nonpathogenicity and 18 with 99% or more probability of pathogenicity. Thus, in the absence of genetic evidence, a cell-based HDR assay can provide a probability of pathogenicity for all VUS in the BRCA2 DBD, suggesting that the assay can be used in combination with other information to determine the cancer relevance of BRCA2 VUS. PMID- 23108139 TI - A unique galectin signature in human prostate cancer progression suggests galectin-1 as a key target for treatment of advanced disease. AB - Galectins, a family of glycan-binding proteins, influence tumor progression by modulating interactions between tumor, endothelial, stromal, and immune cells. Despite considerable progress in identifying the roles of individual galectins in tumor biology, an integrated portrait of the galectin network in different tumor microenvironments is still missing. We undertook this study to analyze the "galectin signature" of the human prostate cancer microenvironment with the overarching goal of selecting novel-molecular targets for prognostic and therapeutic purposes. In examining androgen-responsive and castration-resistant prostate cancer cells and primary tumors representing different stages of the disease, we found that galectin-1 (Gal-1) was the most abundantly expressed galectin in prostate cancer tissue and was markedly upregulated during disease progression. In contrast, all other galectins were expressed at lower levels: Gal 3, -4, -9, and -12 were downregulated during disease evolution, whereas expression of Gal-8 was unchanged. Given the prominent regulation of Gal-1 during prostate cancer progression and its predominant localization at the tumor vascular interface, we analyzed the potential role of this endogenous lectin in prostate cancer angiogenesis. In human prostate cancer tissue arrays, Gal-1 expression correlated with the presence of blood vessels, particularly in advanced stages of the disease. Silencing Gal-1 in prostate cancer cells reduced tumor vascularization without altering expression of other angiogenesis-related genes. Collectively, our findings identify a dynamically regulated "galectin specific signature" that accompanies disease evolution in prostate cancer, and they highlight a major role for Gal-1 as a tractable target for antiangiogenic therapy in advanced stages of the disease. PMID- 23108140 TI - Nitric oxide-dependent downregulation of BRCA1 expression promotes genetic instability. AB - Elevated levels of nitric oxide (NO) and reactive nitrogen species (RNS) may link inflammation to the initiation, promotion, and progression of cancer. Traditionally, this link has been thought to be mediated by the effects of NO/RNS in generating DNA damage. However, this damage also stimulates DNA repair responses with subsequent blocks to cell proliferation and apoptosis, thereby preventing accumulation of NO/RNS-generated mutations. In addressing this conundrum, I describe here an alternative mechanism for understanding mutagenesis by NO/RNS. Moderate NO/RNS concentrations stimulated mutagenesis not directly by generating DNA damage but indirectly by modifying the activities of DNA repair and genome stability factors without affecting cell proliferation. NO/RNS at concentrations physiologically relevant to inflammation stimulated PP2A activity, leading to dephosphorylation of RBL2, its accumulation in the nucleus, and formation of RBL2/E2F4 complexes. RBL2/E2F4 formation in turn led to a shift in BRCA1 promoter occupancy from complexes containing activator E2F1 to complexes containing repressor E2F4, downregulating BRCA1 expression. By inhibiting BRCA1 expression, NO/RNS thereby reduces the ability of cells to repair DNA double strand breaks through homologous recombination repair, increasing the involvement of error-prone nonhomologous end joining (NHEJ). In summary, NO/RNS stimulates genetic instability by inhibiting BRCA1 expression and shifting DNA repair from high fidelity to error-prone mechanisms. PMID- 23108141 TI - Dose-dense chemotherapy improves mechanisms of antitumor immune response. AB - Dose-dense (DD) regimens of combination chemotherapy may produce superior clinical outcomes, but the basis for these effects are not completely clear. In this study, we assessed whether a DD combinatorial regimen of low-dose cisplatin and paclitaxel produces superior immune-mediated efficacy when compared with a maximum tolerated dose (MTD) regimen in treating platinum-resistant ovarian cancer as modeled in mice. Immune responses generated by the DD regimen were identified with regard to the immune cell subset responsible for the antitumor effects observed. The DD regimen was less toxic to the immune system, reduced immunosuppression by the tumor microenvironment, and triggered recruitment of macrophages and tumor-specific CD8(+) T-cell responses to tumors [as determined by interleukin (IL)-2 and IFN-gamma secretion]. In this model, we found that the DD regimen exerted greater therapeutic effects than the MTD regimen, justifying its further clinical investigation. Fourteen patients with platinum-resistant relapse of ovarian cancer received DD chemotherapy consisting of weekly carboplatin (AUC2) and paclitaxel (60-80 mg/m(2)) as the third- or fourth-line treatment. Serum was collected over the course of treatment, and serial IFN-gamma and IL-2 levels were used to determine CD8(+) T-cell activation. Of the four patients with disease control, three had serum levels of IL-2 and IFN-gamma associated with cytotoxic CD8(+) T-cell activity. The therapeutic effect of the DD chemotherapy relied on the preservation of the immune system and the treatment mediated promotion of tumor-specific immunity, especially the antitumor CD8(+) T cell response. Because the DD regimen controlled drug-resistant disease through a novel immune mechanism, it may offer a fine strategy for salvage treatment. PMID- 23108142 TI - Tissue damage-associated "danger signals" influence T-cell responses that promote the progression of preneoplasia to cancer. AB - T-cell responses may be shaped by sterile "danger signals" that are constituted by damage-associated molecular patterns (DAMP). However, whether and what type of adaptive immune responses are triggered in vivo by DAMPs induced by tumor progression are not well characterized. In this study, we report that the production of HMGB1, an established DAMP released by dying cells, was critical for tumor progression in an established mouse model of prostate cancer. HMGB1 was required for the activation and intratumoral accumulation of T cells that expressed cytokine lymphotoxinalpha(1)beta(2) (LT) on their surface. Intriguingly, these tumor-activated T cells recruited macrophages to the lesion and were essential to promote the preneoplasia to invasive carcinoma in an LTbeta receptor (LTbetaR)-dependent manner. Taken together, our findings suggest that the release of HMGB1 as an endogenous danger signal is important for priming an adaptive immune response that promotes malignant progression, with implications for cancer prevention and therapy. PMID- 23108143 TI - Immune-dependent and independent antitumor activity of GM-CSF aberrantly expressed by mouse and human colorectal tumors. AB - Granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) is a cytokine produced in the hematologic compartment that may enhance antitumor immune responses, mainly by activation of dendritic cells. Here, we show that more than one-third of human colorectal tumors exhibit aberrant DNA demethylation of the GM CSF promoter and overexpress the cytokine. Mouse engraftment experiments with autologous and homologous colon tumors engineered to repress the ectopic secretion of GM-CSF revealed the tumor-secreted GM-CSF to have an immune associated antitumor effect. Unexpectedly, an immune-independent antitumor effect was observed that depended on the ectopic expression of GM-CSF receptor subunits by tumors. Cancer cells expressing GM-CSF and its receptor did not develop into tumors when autografted into immunocompetent mice. Similarly, 100% of the patients with human colon tumors that overexpressed GM-CSF and its receptor subunits survived at least 5 years after diagnosis. These data suggest that expression of GM-CSF and its receptor subunits by colon tumors may be a useful marker for prognosis as well as for patient stratification in cancer immunotherapy. PMID- 23108144 TI - Vaccination with antigen-transfected, NKT cell ligand-loaded, human cells elicits robust in situ immune responses by dendritic cells. AB - Both innate and adaptive immunity are crucial for cancer immunosurveillance, but precise therapeutic equations to restore immunosurveillance in patients with cancer patients have yet to be developed. In murine models, alpha galactosylceramide (alpha-GalCer)-loaded, tumor antigen-expressing syngeneic or allogeneic cells can act as cellular adjuvants, linking the innate and adaptive immune systems. In the current study, we established human artificial adjuvant vector cells (aAVC) consisting of human HEK293 embryonic kidney cells stably transfected with the natural killer T (NKT) immune cell receptor CD1d, loaded with the CD1d ligand alpha-GalCer and then transfected with antigen-encoding mRNA. When administered to mice or dogs, these aAVC-activated invariant NKT (iNKT) cells elicited antigen-specific T-cell responses with no adverse events. In parallel experiments, using NOD/SCID/IL-2rgammac(null)-immunodeficient (hDC NOG) mouse model, we also showed that the human melanoma antigen, MART-1, expressed by mRNA transfected aAVCs can be cross-presented to antigen-specific T cells by human dendritic cells. Antigen-specific T-cell responses elicited and expanded by aAVCs were verified as functional in tumor immunity. Our results support the clinical development of aAVCs to harness innate and adaptive immunity for effective cancer immunotherapy. PMID- 23108145 TI - Genome-wide association study reveals novel genetic determinants of DNA repair capacity in lung cancer. AB - Suboptimal cellular DNA repair capacity (DRC) has been shown to be associated with enhanced cancer risk, but genetic variants affecting the DRC phenotype have not been comprehensively investigated. In this study, with the available DRC phenotype data, we analyzed correlations between the DRC phenotype and genotypes detected by the Illumina 317K platform in 1,774 individuals of European ancestry from a Texas lung cancer genome-wide association study. The discovery phase was followed by a replication in an independent set of 1,374 cases and controls of European ancestry. We applied a generalized linear model with single nucleotide polymorphisms as predictors and DRC (a continuous variable) as the outcome. Covariates of age, sex, pack-years of smoking, DRC assay-related variables, and case-control status of the study participants were adjusted in the model. We validated that reduced DRC was associated with an increased risk of lung cancer in both independent datasets. Several suggestive loci that contributed to the DRC phenotype were defined in ERCC2/XPD, PHACTR2, and DUSP1. In summary, we determined that DRC is an independent risk factor for lung cancer, and we defined several genetic loci contributing to DRC phenotype. PMID- 23108146 TI - Spatiotemporal assessments of dermal hyperemia enable accurate prediction of experimental cutaneous carcinogenesis as well as chemopreventive activity. AB - Field cancerization refers to areas of grossly normal epithelium that exhibit increased risk for tumor occurrence. Unfortunately, elucidation of the locoregional changes that contribute to increased tumor risk is difficult due to the inability to visualize the field. In this study, we use a noninvasive optical based imaging approach to detail spatiotemporal changes in subclinical hyperemia that occur during experimental cutaneous carcinogenesis. After acute inflammation from 10 weeks of UVB irradiation subsides, small areas of focal hyperemia form and were seen to persist and expand long after cessation of UVB irradiation. We show that these persistent early hyperemic foci reliably predict sites of angiogenesis and overlying tumor formation. More than 96% of the tumors (57 of 59) that developed following UVB or 7,12-dimethylbenz(a)anthracene/phorbol 12 myristate 13-acetate (DMBA/PMA) treatment developed in sites of preexisting hyperemic foci. Hyperemic foci were multifocal and heterogeneously distributed and represented a minor fraction of the carcinogen-treated skin surface (10.3% of the imaging area in vehicle-treated animals). Finally, we also assessed the ability of the anti-inflammatory agent, celecoxib, to suppress hyperemia formation during photocarcinogenesis. The chemopreventive activity of celecoxib was shown to correlate with its ability to reduce the area of skin that exhibit these hyperemic foci, reducing the area of imaged skin containing hyperemic foci by 49.1%. Thus, we propose that a hyperemic switch can be exploited to visualize the cancerization field very early in the course of cutaneous carcinogenesis and provides insight into the chemopreventive activity of the anti-inflammatory agent celecoxib. PMID- 23108147 TI - Insulin resistance predicts the effectiveness of different glycemic index diets on weight loss in non-obese women. AB - OBJECTIVE: The present study aimed to evaluate whether baseline insulin resistance (IR) modify weight change associated to glycemic index (GI) of the diet. METHOD: This is a secondary analysis of a randomized GI intervention according to baseline HOMA-IR. Middle-aged (25-45 years), non-obese (BMI 23-29.9 kg/m2) women were randomized to low or high GI diets matched on total energy, macronutrient composition, and fiber content. Both groups received dietary counseling based on a small energy restriction (100-300 kcal/day). Women were classified in two groups according to their baseline HOMA-IR: IR (n = 64) and non IR (n = 121). RESULTS: At baseline, IR and non-IR groups had similar BMI (26.7 vs. 26.3 kg/m2; p = 0.21), but the IR group presented with higher waist circumference (82.7 vs. 80.8 cm; p = 0.02) and showed greater weight loss after 12 months of follow-up (-1.6 vs. -1.1 kg; p = 0.01), mainly among those in a high GI diet (-2.1 vs. -1.0 kg; p = 0.005) compared to the non-IR group (-1.4 vs. -0.8 kg; p = 0.04). CONCLUSIONS: The high-GI group showed statistically significant higher reduction in body weight, mainly among those women with baseline IR . Low GI diet did not facilitate weight loss neither in IR women nor in non-IR women. PMID- 23108149 TI - Trends in exposure to television food advertisements in South Korea. AB - Given the increased concern about the impact of TV food advertisements (ads) on individual food choices, we provide important evidence on TV food ad exposure between 2004 and 2009 in South Korea. We used monthly targeted ratings data by age group as the number of ads seen daily from Korean Nielsen Media Research. We generated six food groups: beverages (milk, soda, fruit drinks, sports/energy drinks, water, coffee/tea products, and other); snacks/sweets (cookies/chips, candy, and chewing gum); fast food (Domino's pizza, Lotteria, McDonald's, Mr. Pizza, Pizza Hut, local chicken and pizza franchises, and other); instant noodle; full-service restaurants; and other. From 2004 to 2009, overall exposure to television food ads fell by 19.0% (from 6.8 to 5.5 ads daily), although exposure to full-service restaurant ads increased over that time period by 45.7%. While fast-food ad exposure fell overall, exposure to ads for local fried chicken franchises nearly doubled, making them the most commonly seen fast-food ads by 2009. Fast-food and instant noodle ads made up larger proportions of total ad exposure in 2009 than in 2004 in all age groups, with the largest increase among adolescents. Beverage ads continue to be the most prevalent food ads seen in South Korea. Differential trends found in exposure across and within food product categories and differences by age groups highlight the need for continued monitoring to help inform the regulatory policy debate on food advertising, particularly with regards to ads directed at children and adolescents. PMID- 23108150 TI - Control of appetite. Personal and departmental recollections. AB - This paper is partly a brief academic autobiography. It begins in 1942 when I volunteered for lifesaving research for the Royal Navy. This brought me to a Department headed by a very unusual Professor, R.A. McCance, an eccentric and a polymath. I have tried to say something about him and the Department. After the war, McCance gave me the Ph.D. project: The Effect of Ventromedial Lesions in the Hypothalamus in Rats in Parabiosis. It had recently been discovered that such lesions cause obesity, and energy balance was an active field. Parabiosis dates to the nineteenth century but had not previously been used in this context. The results were uniform and dramatic. I have briefly presented them, with a review of my own and others' subsequent work. This leads to a picture of a negative feedback system, which regulates food intake to maintain a near-constant proportion of fat in the body, and maintains energy balance with increasing precision as time progresses. The parabiotic effect strongly suggests that there must be a blood-borne link between body fat and the hypothalamus. I have tried to make the case as strongly as I can for further work to identify this link, which has obvious scientific and clinical importance. PMID- 23108151 TI - Metabolism by grasshoppers of volatile chemical constituents from Mangifera indica and Solanum paniculatum leaves. AB - The chemical volatiles from plant leaves and their biological activities have been extensively studied. However, no studies have addressed plant-chemical volatiles after undergoing the digestive process in host insects. Here we describe for the first time chemical profiles of volatile constituents from Solanum paniculatum and Mangifera indica leaves metabolized by grasshoppers. Both profiles were qualitatively and quantitatively different from the profiles of non metabolized leaves. The amount of nerolidol, the major constituent of S. paniculatum leaves, decreased and other sesquiterpenes, such as spathulenol, were formed during the digestive process of the grasshopper Chromacris speciosa. In M. indica, the presence of phenylpropanoids was observed (dillapiole, Z-asarone, E asarone and gamma-asarone) in the leaves metabolized by the grasshopper Tropidacris collaris, but these compounds were not found in the non-metabolized leaves. PMID- 23108152 TI - Colour in insect thermoregulation: empirical and theoretical tests in the colour changing grasshopper, Kosciuscola tristis. AB - Body colours can result in different internal body temperatures, but evidence for the biological significance of colour-induced temperature differences is inconsistent. We investigated the relationship between body colour and temperature in a model insect species that rapidly changes colour. We used an empirical approach and constructed a heat budget model to quantify whether a colour change from black to turquoise has a role in thermoregulation for the chameleon grasshopper (Kosciuscola tristis). Our study shows that colour change in K. tristis provides relatively small temperature differences that vary greatly with wind speed (0.55 degrees C at ms(-1) to 0.05 degrees C at 10 ms(-1)). The biological significance of this difference is unclear and we discuss the requirement for more studies that directly test hypotheses regarding the fitness effects of colour in manipulating body temperature. PMID- 23108153 TI - DFT study of the mechanism for methane hydroxylation by soluble methane monooxygenase (sMMO): effects of oxidation state, spin state, and coordination number. AB - The exact structure of the active site of intermediate Q, the methane-oxidizing species of soluble methane monooxygenase (sMMO), and the reaction mechanism of Q with methane molecule are still not fully clear. To gain further insights into the structure and reaction mechanism, five diiron models of Q that differ in shape, oxidation state, spin state, and coordination number of the two iron centers are studied. Different mechanisms in different spin states were explored. Density functional theory (DFT) calculations show that Fe(III)Fe(IV)(MU-O)(MU-OH) is more reactive than Fe(IV)(2)(MU-O)(2) in the oxygen-rich environment and that the reactivity of the active core of sMMO-Q is not enhanced by converting its oxo bridge into a terminal ligand. A four-coordinated diiron model is the most effective for methane hydroxylation. Both radical and non-radical intermediates are involved in the reactions for the four-coordinated diiron model. PMID- 23108148 TI - Microbial manipulation of the amyloid fold. AB - Microbial biofilms are encased in a protein, DNA, and polysaccharide matrix that protects the community, promotes interactions with the environment, and helps cells adhere together. The protein component of these matrices is often a remarkably stable, beta-sheet-rich polymer called amyloid. Amyloids form ordered, self-templating fibers that are highly aggregative, making them a valuable biofilm component. Some eukaryotic proteins inappropriately adopt the amyloid fold, and these misfolded protein aggregates disrupt normal cellular proteostasis, which can cause significant cytotoxicity. Indeed, until recently amyloids were considered solely the result of protein misfolding. However, research over the past decade has revealed how various organisms have capitalized on the amyloid fold by developing sophisticated biogenesis pathways that coordinate gene expression, protein folding, and secretion so that amyloid related toxicities are minimized. How microbes manipulate amyloids, by augmenting their advantageous properties and by reducing their undesirable properties, will be the subject of this review. PMID- 23108154 TI - Age-related aspects of cutaneous wound healing: a mini-review. AB - As the aging population in developed countries is growing in both numbers and percentage, the medical, social, and economic burdens posed by nonhealing wounds are increasing. Hence, it is all the more important to understand the mechanisms underlying age-related impairments in wound healing. The purpose of this article is to give a concise overview of (1) normal wound healing, (2) alterations in aging skin that have an impact on wound repair, (3) alterations in the repair process of aged skin, and (4) general factors associated with old age that might impair wound healing, with a focus on the literature of the last 10 years. PMID- 23108155 TI - The brave new world of coordination frameworks. AB - In 1994 the field of coordination frameworks was still in its infancy and yet to give birth to its offspring research field of metal-organic frameworks (MOFs). Studies by Zaworotko and Ciani served to illustrate both the simplicity and the complexity of these remarkable structures. PMID- 23108157 TI - Genome-wide copy number variation study in anorectal malformations. AB - Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2-5/10 000 live births) and carry significant chronic morbidity. ARMs present either as isolated or as part of the phenotypic spectrum of some chromosomal abnormalities or monogenic syndromes. The etiology is unknown. To assess the genetic contribution to ARMs, we investigated single-nucleotide polymorphisms and copy number variations (CNVs) at genome-wide scale. A total of 363 Han Chinese sporadic ARM patients and 4006 Han Chinese controls were included. Overall, we detected a 1.3 fold significant excess of rare CNVs in patients. Stratification of patients by presence/absence of other congenital anomalies showed that while syndromic ARM patients carried significantly longer rare duplications than controls (P = 0.049), non-syndromic patients were enriched with both rare deletions and duplications when compared with controls (P = 0.00031). Twelve chromosomal aberrations and 114 rare CNVs were observed in patients but not in 868 controls nor 11 943 healthy individuals from the Database of Genomic Variants. Importantly, these aberrations were observed in isolated ARM patients. Gene-based analysis revealed 79 genes interfered by CNVs in patients only. In particular, we identified a de novo DKK4 duplication. DKK4 is a member of the WNT signaling pathway which is involved in the development of the anorectal region. In mice, Wnt disruption results in ARMs. Our data suggest a role for rare CNVs not only in syndromic but also in isolated ARM patients and provide a list of plausible candidate genes for the disorder. PMID- 23108156 TI - p63 control of desmosome gene expression and adhesion is compromised in AEC syndrome. AB - Ankyloblepharon, ectodermal defects, cleft lip/palate (AEC) syndrome is a rare autosomal dominant disorder caused by mutations in the p63 gene, essential for embryonic development of stratified epithelia. The most severe cutaneous manifestation of this disorder is the long-lasting skin fragility associated with severe skin erosions after birth. Using a knock-in mouse model for AEC syndrome, we found that skin fragility was associated with microscopic blistering between the basal and suprabasal compartments of the epidermis and reduced desmosomal contacts. Expression of desmosomal cadherins and desmoplakin was strongly reduced in AEC mutant keratinocytes and in newborn epidermis. A similar impairment in desmosome gene expression was observed in human keratinocytes isolated from AEC patients, in p63-depleted keratinocytes and in p63 null embryonic skin, indicating that p63 mutations causative of AEC syndrome have a dominant-negative effect on the wild-type p63 protein. Among the desmosomal components, desmocollin 3, desmoplakin and desmoglein 1 were the most significantly reduced by mutant p63 both at the RNA and protein levels. Chromatin immunoprecipitation experiments and transactivation assays revealed that p63 controls these genes at the transcriptional level. Consistent with reduced desmosome function, AEC mutant and p63-deficient keratinocytes had an impaired ability to withstand mechanical stress, which was alleviated by epidermal growth factor receptor inhibitors known to stabilize desmosomes. Our study reveals that p63 is a crucial regulator of a subset of desmosomal genes and that this function is impaired in AEC syndrome. Reduced mechanical strength resulting from p63 mutations can be alleviated pharmacologically by increasing desmosome adhesion with possible therapeutic implications. PMID- 23108158 TI - Gene therapy provides long-term visual function in a pre-clinical model of retinitis pigmentosa. AB - Approximately 36 000 cases of simplex and familial retinitis pigmentosa (RP) worldwide are caused by a loss in phosphodiesterase (PDE6) function. In the preclinical Pde6alpha(nmf363) mouse model of this disease, defects in the alpha subunit of PDE6 result in a progressive loss of photoreceptors and neuronal function. We hypothesized that increasing PDE6alpha levels using an AAV2/8 gene therapy vector could improve photoreceptor survival and retinal function. We utilized a vector with the cell-type-specific rhodopsin (RHO) promoter: AAV2/8(Y733F)-Rho-Pde6alpha, to transduce Pde6alpha(nmf363) retinas and monitored its effects over a 6-month period (a quarter of the mouse lifespan). We found that a single injection enhanced survival of photoreceptors and improved retinal function. At 6 months of age, the treated eyes retained photoreceptor cell bodies, while there were no detectable photoreceptors remaining in the untreated eyes. More importantly, the treated eyes demonstrated functional visual responses even after the untreated eyes had lost all vision. Despite focal rescue of the retinal structure adjacent to the injection site, global functional rescue of the entire retina was observed. These results suggest that RP due to PDE6alpha deficiency in humans, in addition to PDE6beta deficiency, is also likely to be treatable by gene therapy. PMID- 23108160 TI - Mass spectrometry methods for intrinsically disordered proteins. AB - In the last ten years mass spectrometry has emerged as a powerful biophysical technique capable of providing unique insights into the structure and dynamics of proteins. Part of this explosion in use involves investigations of the most recently 'discovered' subset of proteins: the so-called 'Intrinsically Disordered' or 'Natively Unstructured' proteins. A key advantage of the use of mass spectrometry to study intrinsically disordered proteins (IDPs) is its ability to test biophysical assertions made about why they differ from structured proteins. For example, from the charge state distribution presented by a protein following nano-electrospray (n-ESI) it is possible to infer the range of conformations present in solution and hence the extent of disorder; n-ESI is highly sensitive to the degree of folding at the moment of transfer from the liquid to the gas phase. The combination of mass spectrometry with ion mobility (IM-MS) provides rotationally averaged collision cross-sections of molecular ions which can be correlated with conformation; this too can be applied to IDPs. Another feature which can be monitored by IM-MS is the tendency of disordered proteins to form amyloid fibrils, the protein aggregates involved in the onset of neurodegenerative diseases such as Parkinson's and Alzheimer's. IM-MS provides a useful insight into events that occur during the early stages of aggregation including delineating the structure of the monomer, identifying oligomer distributions, and revealing mechanistic details of the aggregation process. Here we will review the use of MS and IM-MS to study IDPs using examples from our own and other laboratories. PMID- 23108159 TI - Expression of DUX4 in zebrafish development recapitulates facioscapulohumeral muscular dystrophy. AB - Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy characterized by an asymmetric progressive weakness and wasting of the facial, shoulder and upper arm muscles, frequently accompanied by hearing loss and retinal vasculopathy. FSHD is an autosomal dominant disease linked to chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading candidate gene as causative of FSHD. However, DUX4 expression is extremely low in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in human FSHD. Here, we show that the misexpression of very low levels of human DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less pigmentation of the eyes, altered morphology of ears, developmental abnormality of fin muscle, disorganization of facial musculature and/or degeneration of trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant localization of myogenic cells marked with alpha-actin promoter-driven enhanced green fluorescent protein outside somite boundary, especially in head region. These abnormalities were rescued by coinjection of the short form of DUX4 (DUX4 s). Our results suggest that the misexpression of DUX4-fl, even at extremely low level, can recapitulate the phenotype observed in FSHD patients in a vertebrate model. These results strongly support the current hypothesis for a role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during development is important for the pathogenesis of FSHD. PMID- 23108161 TI - Large scale boron carbon nitride nanosheets with enhanced lithium storage capabilities. AB - Few-layered boron carbon nitride nanosheets are synthesized by a simple and environmentally friendly process. The BCN nanosheets have 2-6 atomic layers with high surface area and show enhanced storage performance in lithium batteries, as well as a stable capacity of ~100 mA h g(-1) at 2 A g(-1) for 5000 cycles. PMID- 23108163 TI - The identification of frail older adults in primary care: comparing the accuracy of five simple instruments. AB - BACKGROUND: many instruments are available to identify frail older adults who may benefit from geriatric interventions. Most of those instruments are time consuming and difficult to use in primary care. OBJECTIVE: to select a valid instrument to identify frail older adults in primary care, five simple instruments were compared. METHODS: instruments included clinical judgement of the general practitioner, prescription of multiple medications, the Groningen frailty indicator (GFI), PRISMA-7 and the self-rated health of the older adult. Fried's frailty criteria and a clinical judgement by a multidisciplinary expert panel were used as reference standards. Data were used from the cross-sectional Dutch Identification of Frail Elderly Study consisting of 102 people aged 65 and over from a primary care practice in Amsterdam. In this study, frail older adults were oversampled. We estimated the accuracy of each instrument by calculating the area under the ROC curve. The agreement between the instruments and the reference standards was determined by kappa. RESULTS: frailty prevalence rates in this sample ranged from 11.6 to 36.4%. The accuracy of the instruments ranged from poor (AUC = 0.64) to good (AUC = 0.85). CONCLUSION: PRISMA-7 was the best of the five instruments with good accuracy. Further research is needed to establish the predictive validity and clinical utility of the simple instruments used in this study. PMID- 23108165 TI - Molecular tectonics: zinc coordination networks based on centric and acentric porphyrins bearing pyridyl units. AB - Two new ligands, one symmetric 1 and the other acentric 2, based on a porphyrin backbone bearing either two ethynylpyridyl or one pyridyl and one ethynylpyridyl coordinating groups connected to the porphyrin at two opposite meso positions have been designed and prepared. In the presence of a Zn(II) cation, they lead to the formation of neutral metallatectons 1-Zn and 2-Zn which self-assemble into coordination networks in the crystalline phase. Whereas the metallatecton 1-Zn leads exclusively to the formation of grid type 2D networks, 2-Zn generates two types of crystals with rod and rhombic morphologies. The rod type crystals are composed of a 1D zigzag type arrangement whereas crystals with rhombic morphology are composed of directional 2D grid type architecture. The packing of the latter leading to the formation of the crystal occurs in a centrosymmetric fashion causing thus the loss of directionality. PMID- 23108164 TI - The assessment of cognition in visually impaired older adults. AB - BACKGROUND: visual and cognitive impairments are common in later life. Yet there are very few cognitive screening tests for the visually impaired. OBJECTIVE: to screen for cognitive impairment in the visually impaired. METHODS: case-control study including 150 elderly participants with visual impairment (n = 74) and a control group without visual impairment (n = 76) using vision-independent cognitive tests and cognitive screening tests (MMSE and clock drawing tests (CDT)) which are in part vision dependent. RESULTS: the scoring of the two groups did not differ in the vision-independent cognitive tests. Visually impaired patients performed poorer than controls in the vision-dependent items of the MMSE (T = 7.3; df: 148; P < 0.001) and in CDT (T = 3.1; df: 145; P = 0.003). No group difference was found when vision-independent items were added to MMSE and CDT. The test score gain by the use of vision-independent items correlated with the severity of visual impairment (P < 0.002). CONCLUSION: visually impaired patients benefit from cognitive tests, which do not rely on vision. The more visually impaired the greater the benefit. PMID- 23108166 TI - Ventricular fibrillation resulting from diaphragmatic stimulation during gastric bypass surgery. AB - OBJECTIVE: Gastric bypass operations are common and severely obese patients are prone to arrhythmias, particularly atrial fibrillation. Intraoperative ventricular arrhythmias during bariatric surgery have not been reported previously. CASE REPORT: A 35-year-old, severely obese, diabetic woman with no other prior medical history underwent thorough preoperative cardiovascular evaluation before having laparoscopic Roux-en-Y gastric bypass. Intraoperatively she developed sudden onset ventricular fibrillation during the use of unipolar electrocautery near the Angle of His. The procedure was aborted, and the patient underwent repeat cardiovascular assessment including coronary angiography and serial electrophysiology studies before being unremarkably re-operated 6 months later, at which time a harmonic scalpel was used for dissection. 12 months post operation, the patient remains asymptomatic. CONCLUSION: Owing to the proximity of the right ventricle overlying the diaphragm, far-field stimulation was likely responsible for inducing VF. PMID- 23108167 TI - Methotrexate-conjugated and hyperbranched polyglycerol-grafted Fe3O4 magnetic nanoparticles for targeted anticancer effects. AB - Superparamagnetic nanoparticles grafted with hyperbranched polyglycerol (HPG) and conjugated with methotrexate (MTX) (MNP-g-HPG-MTX) were synthesized via a sol-gel reaction followed by thiol-ene click chemistry and esterification reaction. The successful grafting of MTX and HPG onto the nanoparticles was confirmed by X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FT-IR) spectroscopy, and UV-visible spectroscopy. The HPG-graft layer confers the magnetic nanoparticles with good dispersibility and stability in aqueous medium and macrophage-evasive property while the MTX acts as a chemotherapeutic drug as well as a tumor targeting ligand. The dose-dependent targeting and anticancer effect of the MNP-g-HPG-MTX nanoparticles were evaluated, and the results showed that depending on the amount of conjugated MTX and the concentration of the incubated nanoparticles, the uptake of MNP-g-HPG-MTX nanoparticles by human head and neck cancer (KB) cells can be eight times or more higher than those by 3T3 fibroblasts and RAW macrophages. As a result, the MNP-g-HPG-MTX nanoparticles are capable of killing ~50% of the KB cells while at the same time exhibiting low cytotoxicity towards 3T3 fibroblasts and RAW macrophages. Thus, such nanoparticles can potentially be used as active targeting anticancer agents. PMID- 23108168 TI - Spontaneous intracranial hypotension secondary to anterior thoracic osteophyte: Resolution after primary dural repair via posterior approach. AB - INTRODUCTION: Spontaneous intracranial hypotension (SIH) is an uncommon syndrome widely attributed to CSF hypovolemia, typically secondary to spontaneous CSF leak. Although commonly associated with postural headache and variable neurological symptoms, one of the most severe consequences of SIH is bilateral subdural hematomas with resultant neurological deterioration. PRESENTATION OF CASE: We present the case of a patient diagnosed with SIH secondary to an anteriorly positioned thoracic osteophyte with resultant dural disruption, who after multiple attempts at nonsurgical management developed bilateral subdural hematomas necessitating emergent surgical intervention. The patient underwent a unilateral posterior repair of his osteophyte with successful anterior decompression. At 36months follow up, the patient reported completely resolved headaches with no focal neurological deficits. DISCUSSION: We outline our posterior approach to repair of the dural defect and review the management algorithm for the treatment of patients with SIH. We also examine the current hypotheses as to the origin, pathophysiology, diagnosis and treatment of this syndrome. CONCLUSION: A posterior approach was utilized to repair the dural defect caused by an anterior thoracic osteophyte in a patient with severe SIH complicated by bilateral subdural hematomas. This approach minimizes morbidity compared to an anterior approach and allowed for removal of the osteophyte and repair of the dural defect. PMID- 23108169 TI - The use of polytetrafluoroethylene to facilitate the vascular access in recurrent melanoma to limbs. AB - INTRODUCTION: Melanoma with recurrent loco-regional metastases to limbs often makes difficult a second surgical approach because of the adhesions affecting the vascular access. Our aim was to evaluate whether the placement of a polytetrafluoroethylene (PTFE) membrane around vessels might facilitate a surgical re-approach. PRESENTATION OF CASE: We reported a case of a 64-year-old male with a melanoma on the left foot who developed in transit metastases after LND. While performing the inguinopelvic LND we coated the iliac vessels with PTFE patch to facilitate the vascular access in case of re-intervention for a ILP. In the second surgical approach we made a cutaneous incision in the left iliac region and we proceeded through the subcutaneous tissue until detection of iliac vessels, more clearly visible because of the PTFE patch fixed around vascular walls to minimize adhesions. We removed the PTFE coating and easily performed arteriotomy and venotomy for the completion of the ILP. DISCUSSION: This case report seems to demonstrate the efficacy of a PTFE membrane applied in a patient around iliac vessels during inguinopelvic dissection, to reduce adhesion density. In fact this membrane provided a barrier to adhesions of the iliac vessels, decreasing the risk of vascular injury thereby facilitating a subsequent vascular access. Re-coating of the iliac vessels with PTFE could be preparatory to a better identification of the vascular structures in cases of a surgical re approach. CONCLUSION: The use of PTFE effectively simplifies the second approach to vessels in event of a melanoma metastasizing to limbs. PMID- 23108170 TI - Internal hernias in pregnant women with history of gastric bypass surgery: Case series and review of literature. AB - INTRODUCTION: Gastric bypass surgery is the most common obesity surgery procedure in women. Decreased weight loss favors fertility and leads to pregnancy sometimes just months after surgery, raising the risk of developing gastric bypass-related complications during pregnancy, including the formation of internal hernias. PRESENTATION OF CASE: The first patient presented at 37 weeks of gestation with abdominal pain, nausea and vomiting. X-ray revealed multiple air-fluid levels and absence of gas in colon. She underwent a cesarean section and exploratory laparotomy without complications. A Petersen's space internal hernia was found. The second patient presented at 25 weeks of gestation with abdominal pain and nausea. X-ray revealed multiple air-fluid levels and a "U-shaped" intestinal loop. She underwent exploratory laparotomy with reduction of an internal hernia also in Petersen's space. DISCUSSION: Pregnant patients with internal hernias after gastric bypass are usually of young age and with a several-day history of abdominal pain. Surgical exploration is safe and should not be delayed. The literature review showed that maternal death (9%) and fetal death (13.6%) rates are considerably high. CONCLUSION: The possibility of an internal hernia should always be considered in pregnant women with history of gastric bypass who present with abdominal pain, in order to prevent catastrophic outcomes such as maternal and/or fetal death. PMID- 23108171 TI - The ghost in the machine is the elephant in the room: souls, death, and harm at the end of life. AB - The idea that we human beings have souls that can continue to have conscious experiences after the deaths of our bodies is controversial in contemporary academic bioethics; this idea is obviously present whenever questions about harm at the end of life are discussed, but this idea is often ignored or avoided because it is more comfortable to do so. After briefly discussing certain types of experiences that lead some people to believe in souls that can survive the deaths of their bodies, I begin to answer the question, "If personal postmortem survival of some sort is real, then how should this alter the way we approach our bioethical discussions about death, the harm of death, and harming the dead?" The bioethics issues I briefly discuss in the remaining two sections are the debate about defining death and the decision whether to forego life-prolonging treatments. PMID- 23108172 TI - Harm, change, and time. AB - What is harm? I offer an account that involves the victim's either suffering some adverse intrinsic change or being prevented from enjoying some beneficial intrinsic change. No one is harmed, I claim, in virtue of relational changes alone. Thus (excepting for contrived cases), there are neither posthumous harms nor, in life, harms of the undiscovered betrayal, slander, reputation-damaging variety. Further, two widespread moves in the philosophy of death are rejected. First, death and posthumous are not to be assimilated--death does bring about adverse internal change and harms us straightforwardly. Second, Pitcher-type accounts of posthumous harm are criticized--posthumous events can thwart the satisfaction of my interests, but I am not harmed either just when this occurs or, earlier, when I first acquire or invest in those interests. We have other ways of describing what is going on. PMID- 23108173 TI - Visual detection of potassium by a cyanine dye supramolecular aggregate responsive to G-quadruplex motif transition. AB - A supramolecular probe is designed for visual detection of potassium based on a novel cyanine dye aggregate recognizing the motif transition of telomeric G quadruplexes under the Na(+) background. The practical application for colorimetric measurement of urine potassium has been tested. PMID- 23108175 TI - Boratabenzene-vanadium sandwich molecular wire and its properties. AB - Different from all reported sandwich molecular wires (SMWs), a novel class of SMW including vanadium boratabenzene (HBBz) clusters and their related one dimensional (1D) SMWs are explored by using a density functional theory approach. The uniqueness of this class of SMWs lies in the boron heterocycles, where they possess a reactive functional atom. These features may overcome the limitation of existing SMWs which are inert and are difficult to be absorbed stably on surfaces. Theoretical calculations of the novel vanadium boratabenzene clusters indicated that they are energetically stable, with the rings having a restricted degree of rotation. In addition, its metallic 1D analog shows great promise in the applications of molecular electronics and spintronics. PMID- 23108174 TI - Bacillus thuringiensis Cry1A toxin-binding glycoconjugates present on the brush border membrane and in the peritrophic membrane of the Douglas-fir tussock moth are peritrophins. AB - Bacillus thuringiensis (Bt) Cry1A toxin-binding sites in the Douglas fir tussock moth (DFTM) larval gut were localized using immunofluorescence microscopy. Cry1Aa, Cry1Ab and Cry1Ac all bound strongly to the DFTM peritrophic membrane (PM); weaker binding of the Cry1A toxins was observed along the apical brush border of the midgut epithelium. Comparative analysis of the Cry1A toxin-binding molecules in the PM and brush border membrane vesicles (BBMVs) showed that a similar toxin-binding complex was present in both. The Cry1A toxin-binding substance, a broad band with an apparent size of 180kDa, consisted of a closely spaced doublet. The doublet was present in peritrophins, proteins tightly bound to the PM. Lectin binding studies of the PM and BBMV toxin-binding components revealed that they are glyconjugates with terminal alpha-GalNAc residues comprised exclusively of O-linked oligosaccharides in their glycan structures. Mild periodate oxidation, release of O-linked glycans by beta-elimination, and enzymatic removal of terminal alpha-linked GalNAc residues with N-acetyl-alpha-D galactosaminidase digestion abolished Cry1A toxin-binding to the PM and BBMV components. These data provide strong evidence that O-linked glycans are the target structures on the toxin-binding glycoconjugates for the Cry1A class of insecticidal proteins in DFTM larvae. PMID- 23108176 TI - Realization of an efficient cholesterol biosensor using ZnO nanostructured thin film. AB - A zinc oxide (ZnO) nanostructured thin film synthesized by a vapour phase transport technique on a platinum coated silicon (Pt/Si) substrate has been successfully utilized for the detection of cholesterol. Amperometric and photometric studies reveal that the prepared bioelectrode ChOx/ZnO/Pt/Si is highly sensitive to the detection of cholesterol over a wide concentration range, 0.12-12.93 mM (5-500 mg dl(-1)). The higher sensitivity is attributed to the large surface area of ZnO thin film for effective loading of ChOx besides its high electron communication capability. A relatively low value of the enzyme's kinetic parameter (Michaelis-Menten constant, 1.08 mM) indicates an enhanced affinity of the enzyme (ChOx) towards the analyte (cholesterol). The prepared bioelectrode is found to exhibit a long shelf life of more than 10 weeks, having negligible interference from the presence of other biomolecules present in human serum indicating potential application of the ZnO nanostructured thin film for cholesterol sensing. PMID- 23108177 TI - Well-defined NHC-rhodium hydroxide complexes as alkene hydrosilylation and dehydrogenative silylation catalysts. AB - Alkene hydrosilylation and dehydrogenative silylation reactions, mediated by [Rh(cod)(NHC)(OH)] complexes (cod = 1,5-cyclooctadiene; NHC = N-heterocyclic carbene) are described. The study details a comparison of the catalytic activity and steric characteristics of four rhodium complexes bearing different NHC ligands. The novel [Rh(cod)(Ii-PrMe)(OH)] complex (Ii-PrMe = 1,3-diisopropyl-4,5 dimethylimidazol-2-ylidine) was designed to improve the reactivity of Rh(I) hydroxides and proved to be a successful promoter of hydrosilylation and dehydrogenative silylation, displaying good stereo- and regiocontrol. PMID- 23108180 TI - A ternary cathode composed of LSM, YSZ and Ce0.9Mn0.1O2-delta for the intermediate temperature solid oxide fuel cells. AB - The YSZ electrolyte fuel cell with a ternary cathode composed of LSM-YSZ Ce(0.9)Mn(0.1)O(2-delta) exhibits ca. 2.6 times higher current density than that with a binary cathode composed of LSM-YSZ at 600 degrees C. PMID- 23108182 TI - New tetrazole-based Cu(I) homo- and heteroleptic complexes with various P^P ligands: synthesis, characterization, redox and photophysical properties. AB - Four Cu(I) complexes with general formulas [Cu(N^N)(2)][BF(4)] and [(P^P)Cu(N^N)][BF(4)] were prepared, where N^N stands for 2-(2-tert-butyl-2H tetrazol-5-yl)pyridine and P^P is a chelating diphosphine, namely bis (diphenylphosphino)methane (dppm), bis-(diphenylphosphino)ethane (dppe) or bis[2 (diphenylphosphino)phenyl]ether (POP). In an acetonitrile medium, the Electro Spray Ionization Mass Spectrometry (ESI-MS) determination provided the preliminary evidence for the occurrence of the dppm-containing complex as a mixture of a cationic mononuclear [Cu(N^N)(dppm)](+) species and a bis-cationic dinuclear [Cu(2)(N^N)(2)(dppm)(2)](2+)-type compound. Definitive evidence of peculiar structural features came from X-ray crystallography, which showed both the dppm- and, unexpectedly, the dppe-based heteroleptic compounds to crystallize as diphosphine-bridged Cu(I) dimers, unlike [Cu(N^N)(2)](+) and [(POP)Cu(N^N)](+) which are mononuclear species. In solutions of non-coordinating solvents, (31)P NMR studies at variable temperatures and dilution titrations confirmed that the dppm-based complex undergoes a monomer-dimer dynamic equilibrium, while the dppe containing complex occurs as the bis-cationic dinuclear species, [Cu(2)(N^N)(2)(dppe)(2)](2+), within a concentration range comprised between 10( 2) and 10(-4) M. Differences among heteroleptic complexes might be related to the smaller natural bite angle displayed by dppm and dppe phosphine ligands (72 degrees and 85 degrees , respectively), with respect to that reported for POP (102 degrees ). The electrochemical features of the new species have been investigated by cyclic voltammetry. Despite the irreversible and complicated redox behaviour, which is typical for copper complexes, the reductions have been attributed to the tetrazole ligand whereas the oxidations are characterized as Cu(I/II) processes with a substantial contribution from the P^P-based ligands in the case of the heteroleptic species. All the four complexes are weakly or not luminescent in CH(2)Cl(2) solution, but heteroleptic complexes are bright green luminophores in a solid matrix, with quantum yields as high as 45% (dppm complex) even at room temperature. This makes them potential candidates as cheap emitting materials for electroluminescent devices. PMID- 23108183 TI - Prevalence of coronary artery disease before valvular surgery in patients with rheumatic valvular disease. AB - BACKGROUND: Although many patients with valvular heart disease have concomitant coronary artery disease (CAD), there are limited data on the association between rheumatic valvular disease (RVD) and CAD. In this study, we aimed to investigate the prevalence of CAD in a group of patients with RVD and undergoing coronary angiography before valvular surgery. METHODS: In this retrospective analysis, we enrolled a total of 1075 patients (658 women, 61.2%; mean age: 53.2 +/- 9.9 years) who underwent coronary angiography for the evaluation of CAD before valvular surgery between January 2003 and May 2010. RESULTS: The overall prevalence of significant CAD was 11.1%. Patients with significant CAD were older than patients without significant CAD (55.16 +/- 10.4 vs. 51.45 +/- 9.1; P<0.001). In addition, hypertension, smoking, diabetes mellitus, and dyslipidemia were more prevalent among patients with significant CAD (P<0.05). After adjustment for several risk factors, only aortic stenosis remained the predictor of significant CAD (odds ratio: 1.66; 95% confidence interval: 1.26-2.19; P<0.001). However, aortic regurgitation was inversely associated with the presence of CAD (odds ratio: 0.56; 95% confidence interval: 0.21-1.01; P<0.001). CONCLUSION: The overall prevalence of CAD in our population with RVD was low. Rheumatic aortic stenosis is associated with an increased prevalence of CAD, whereas the prevalence of CAD is lower in those patients with aortic regurgitation. PMID- 23108184 TI - Evaluation of intra-operative abdominal wall perfusion in post-bariatric abdominal dermolipectomy. AB - OBJECTIVE: Abdominal dermolipectomy after massive weight loss has become a standard procedure. However the complication rates such as wound necrosis or secondary healing complications are still high. In this context ischaemia or inadequate micro-perfusion are known as triggers of wound healing complications. Little is known about the regional perfusion patterns before and after post bariatric abdominal dermolipectomy. This study focuses on assessment of intraoperative micro-perfusion patterns of the abdominal tissue. METHODS: The perfusion of the abdominal wall flap was monitored intra-operatively in 17 patients with an average BMI of 29.2 +/- 3.7 kg/m2 after bariatric surgery. All patients underwent abdominal post-bariatric dermolipectomy after massive weight loss while applying the non-invasive O2C laser-spectrophotometer. The micro perfusion parameters oxygen saturation (SO2), relative haemoglobin content (rHB) and relative blood flow (BF) were intra-operatively measured. RESULTS: The results of this study show that the part of the abdominal fat typically resected during dermolipectomy has the lowest SO2 before surgery. Furthermore, the results demonstrate that previously well oxygenated parts in the median line of the abdominal fat undergo a significant decrease in oxygen saturation upon mobilisation and subsequent suturing, while the caudal wound edges show an increase of micro-perfusion parameters. CONCLUSION: Data show that micro perfusion is worst in the median line of the cranial wound edge and is significantly altered after mobilisation. In addition an intra-operative increase of micro-perfusion in the caudal part of the wound edge, especially in the mons pubis area, can be measured. PMID- 23108185 TI - Solid crystal suspensions containing griseofulvin--preparation and bioavailability testing. AB - The improvement of the bioavailability of poorly soluble drugs has been an important issue in pharmaceutical research for many years. Despite the suggestion of several other technologies in the past, drug particle size reduction is still an appropriate strategy to guarantee high bioavailability of various drugs. A few years ago, the Solid Crystal Suspension (SCS) technology was suggested, in which crystalline drug particles are ground and dispersed in a highly soluble crystalline carrier by a hot melt extrusion process. The current study demonstrates the scale-up of the SCS technology to standard, lab-scale extrusion equipment--a change from previous investigations, which used small batch sizes. A twin-screw extruder was modified to account for the rapid crystallization of the carrier. The screw speed and the barrel temperature were identified as critical process parameters and were varied systematically in several experimental designs. Finally, parameters were identified that produced extrudates with rapid dissolution rates. After extrusion, the extrudates were milled to granules and then tableted. These tablets were investigated with respect to their bioavailability in beagle dogs. It was found that drug particle size reduction in the hot melt extrusion led to 3.5-fold higher bioavailability in these dogs than occurred with the physical mixture of the used substances. The solid crystal suspension formulation had a slightly higher bioavailability than the marked product. In conclusion, the SCS technology was successfully scaled up to lab scale equipment, and the concept was confirmed by a bioavailability study. PMID- 23108186 TI - Cathepsin-mediated regulation of autophagy in saposin C deficiency. AB - Saposin C deficiency, a rare variant form of Gaucher disease, is due to mutations in the prosaposin gene (PSAP) affecting saposin C expression and/or function. We previously reported that saposin C mutations affecting one cysteine residue result in autophagy dysfunction. We further demonstrated that the accumulation of autophagosomes, observed in saposin C-deficient fibroblasts, is due to an impairment of autolysosome degradation, partially caused by the reduced amount and enzymatic activity of CTSB (cathepsin B) and CTSD (cathepsin D). The restoration of both proteases in pathological fibroblasts results in almost completely recovery of autophagic flux and lysosome homeostasis. PMID- 23108188 TI - Prospective short-term evaluation of transurethral needle ablation procedure in an ambulatory setting. AB - OBJECTIVE: To assess the results of transurethral needle ablation (TUNA) (Prostiva(r), Medtronic, France) performed in an ambulatory setting in men with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A multicenter open-label study was conducted. Short-term success was defined by ability to leave the hospital on the evening of the intervention, and absence of rehospitalization due to complications during the first postoperative month. Sexual and urinary functions were evaluated by validated questionnaires. RESULTS: The procedure was successful in 44/49 patients. Sexual and ejaculatory function was not affected or slightly improved in the majority of patients. Urinary parameters improved with a 32% decrease in the International Prostate Symptom Score. At 1 month postoperation, more than 80% of patients were satisfied, and 36/41 patients were prepared to undergo the procedure again if needed. Our study was limited by the short follow-up duration. CONCLUSIONS: TUNA can be successfully performed in an ambulatory setting under local and/or general anesthesia with a high level of patient satisfaction and a low short-term morbidity, especially on sexual function. Thus, the procedure is a suitable mini invasive option for patients who cannot/do not want to take medical therapy or undergo invasive surgical procedures, or want to preserve their sexual function. PMID- 23108187 TI - Store-dependent deactivation: cooling the chain-reaction of myocardial calcium signaling. AB - In heart cells, Ca(2+) released from the internal storage unit, the sarcoplasmic reticulum (SR) through ryanodine receptor (RyR2) channels is the predominant determinant of cardiac contractility. Evidence obtained in recent years suggests that SR Ca(2+) release is tightly regulated not only by cytosolic Ca(2+) but also by intra-store Ca(2+) concentration. Specifically, Ca(2+)-induced Ca(2+) release (CICR) that relies on auto-catalytic action of Ca(2+) at the cytosolic side of RyR2s is precisely balanced and counteracted by RyR2 deactivation dependent on a reciprocal decrease of Ca(2+) at the luminal side of RyR2s. Dysregulation of this inherently unstable Ca(2+) signaling is considered to be an underlying cause of triggered arrhythmias, and is associated with genetic and acquired forms of sudden cardiac death. In this article, we present an overview of recent advances in our understanding of the regulatory role luminal Ca(2+) plays in Ca(2+) handling, with a particular emphasis on the role of Ca(2+)release refractoriness in aberrant Ca(2+) release. PMID- 23108189 TI - The need for juvenile animal studies--a critical review. AB - With the introduction of specific pediatric legislation in the United States (US) and the European Union (EU) requiring the development of medicines for children the interest in juvenile animal studies (JAS) increased, but also the discussion about the value and necessity of such studies. Regulatory guidance regarding JAS is available from The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) M3(R2) guideline and from more specific guidance documents issued by the Food and Drug Administration (FDA) as well as the European Medicines Agency (EMA). This paper summarizes and discusses the regulatory requirements regarding the need for JAS, their design and timing as well as the current experience with such studies. The relevant guidance documents as well as several authors support a case-by-case approach regarding the need for and design of JAS. JAS should be considered, especially in cases when organ systems undergoing postnatal development, like the kidney, the skeleton or the central nervous system (CNS), have been identified as toxicity target organs, as developing organ systems usually are more sensitive to toxicity than mature organs. The relevance of the findings from JAS for human use will essentially depend on an appropriate study design, especially on the choice of species as well as the age of the juvenile animal at the start of study. As the available data from JAS show, the design of JAS seems to have improved since the introduction of specific guidance documents. However, so far, there is not enough experience to finally answer the question if JAS are useful. Interpretation of the results from JAS and their extrapolation to the pediatric population is hampered by the incomplete understanding of the animal models used in these studies as well as the lack of access to existing JAS data. Further data will be necessary to ultimately clarify the need for such studies. PMID- 23108190 TI - The calcium-sensing receptor is silenced by genetic and epigenetic mechanisms in unfavorable neuroblastomas and its reactivation induces ERK1/2-dependent apoptosis. AB - Neuroblastic tumors (NTs) include the neuroblastomas, ganglioneuroblastomas and ganglioneuromas. We have reported previously that the calcium-sensing receptor is expressed in differentiated, favorable NTs but almost undetectable in unfavorable neuroblastomas. We have now detected hypermethylation of a particular region within the CpG island encompassing the CaSR gene promoter 2 in neuroblastoma cell lines and 25% primary neuroblastomas. Hypermethylation of this region was associated with reduced CaSR messenger RNA expression and several predictors of poor outcome in neuroblastomas, including MYCN amplification. Treatment with 5'aza-2-deoxycitidine and/or trichostatin A restored CaSR expression in MYCN amplified cell lines. Following 5'aza-2-deoxycitidine exposure, decreased percentages of methylated CpG sites were observed at the above-mentioned region. By interphase fluorescence in situ hybridization, variable percentages of nuclei with monosomy of chromosome 3, where the human CaSR gene resides, were observed in more than 90% of primary NTs of all subgroups. Nuclei harboring this alteration were heterogeneously distributed among tumor cells. Ectopic overexpression of the calcium-sensing receptor in two MYCN-amplified neuroblastoma cell lines in which this gene is silenced by promoter hypermethylation significantly reduced their in vitro proliferation rates and almost abolished their capacity to generate xenografts in immunocompromised mice. Finally, upon acute exposure to calcium, the primary activator of this receptor, calcium-sensing receptor-overexpressing neuroblastoma cells underwent apoptosis, a process dependent on sustained activation of ERK1/2. These data would support the hypothesis that epigenetic silencing of the CaSR gene is neither an in vitro artefact in neuroblastoma cell lines nor an irrelevant, secondary event in primary NTs, but a significant mechanism for neuroblastoma survival. PMID- 23108191 TI - Silver(I) coordination complexes and extended networks assembled from S, Se, Te substituted acenaphthenes. AB - Six related organo-chalconium silver(I) coordination complexes, including two examples of rare organotellurium-silver coordination, have been prepared and structurally characterised by X-ray crystallography. The series of 5-bromo-6 (phenylchalcogeno)acenaphthene ligands L1-L3 [Acenap(Br)(EPh)] (Acenap = acenaphthene-5,6-diyl; E = S, Se, Te) were independently treated with silver(I) salts (AgBF4, AgOTf). In order to keep the number of variables to a minimum, all reactions were carried out using a 1:1 ratio of Ag/L and run in dichloromethane. The nature of the donor atoms and the coordinating ability of the respective counter-anion affects the structural architecture of the final silver(I) complex, generating a monomeric dinuclear complex {[(AgBF4(L1)2)2] 1}, monomeric, mononuclear, two-coordinate silver(I) complexes {[AgBF4(L)2] (2 L = L2; 3 L = L3)}, a monomeric three-coordinate silver(I) complex {[AgOTf(L2)2] 5}, a monomeric four-coordinate silver(I) complex {[AgOTf(L1)3] 4} and a 1D extended helical chain polymer {[AgOTf(L3)]n 6}. The organic acenaphthene ligands L1-L3 all adopt the same ligation mode with the central silver atom (classical monodentate coordination), which employs a variety of coordination geometries (linear, trigonal planar, see-saw, tetrahedral). PMID- 23108193 TI - Contribution of REN gene MBbo I polymorphism in conferring risk for essential hypertension: a case control study from South India. AB - BACKGROUND: Renin is a rate-limiting enzyme of the renin-angiotensin-aldosterone system (RAAS) that plays a crucial role in the regulation of blood pressure. The renin gene has been suggested as a marker for genetic predisposition to essential hypertension (EHT) in humans. The purpose of the study is to explore the association of a genetic marker of renin gene Mbo I polymorphism with EHT in the South Indian population. METHODS: A total of 279 hypertensive and 200 normotensive subjects were genotyped for REN Mbo I polymorphism (RFLP) using the PCR-restriction fragment length polymorphism method. RESULTS: There were no significant differences in the distribution of genotypes and alleles for REN gene Mbo I polymorphism between hypertensive cases and controls (p>0.05). The genotypic and allele frequencies were in Hardy-Weinberg equilibrium both in cases and controls. Females with Mbo I AA+GA genotypes had 1.87-fold higher risk to develop hypertension as compared with those with GG genotype (odds ratio 1.87; 95% confidence interval = 0.98-3.56, p = 0.057). CONCLUSIONS: Our results indicate that renin gene Mbo I site polymorphism is not associated with blood pressure levels and risk of hypertension. However, the present study demonstrates risk for females who are carriers of REN Mbo I A allele for developing essential hypertension. PMID- 23108194 TI - Levels of NT-proBNP, markers of low-grade inflammation, and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease. AB - Renin-angiotensin-aldosterone system (RAAS) blockade may reduce levels of biomarkers of chronic low-grade inflammation and endothelial dysfunction. We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies. MATERIALS AND METHODS: The studies were double-blind, randomised, placebo-controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro- or macroalbuminuria treated with angiotensin-converting enzyme inhibitor (ACE inhibitor) or angiotensin receptor blocker (ARB), and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days. OUTCOME MEASURES: Changes in inflammatory (hsCRP, s-ICAM, TNFalpha, IL-6, IL-8, Serum amyloid A, IL1beta), endothelial dysfunction (sE-selectin, s-ICAM1, s-VCAM1, VWF, p-selectin, s-thrombomodulin) and NT-proBNP after each treatment period. RESULTS: During spironolactone treatment, u-albumin excretion rate was reduced from 605 (411-890) to 433 (295-636) mg/24 h, as previously reported. Markers of inflammation and endothelial dysfunction did not change; only changes in NT-proBNP (reduced by 14%, p=0.05) and serum amyloid A (reduced by 62%, p=0.10) were borderline significant. DISCUSSIONS: Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti-inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment. PMID- 23108195 TI - A novel route for preparing highly proton conductive membrane materials with metal-organic frameworks. AB - Fe-MIL-101-NH(2) was prepared by a novel method. The MOFs adhered well to SPPO via chemical bonds, and yielded the mixed-matrix Fe-MIL-101-NH(2)-SPPO membrane for use in fuel cells. The proton conductivity of the membranes was as high as 0.10 S cm(-1) at room temperature and 0.25 S cm(-1) at 90 degrees C. PMID- 23108196 TI - Metastable beta-Bi2O3 nanoparticles with high photocatalytic activity from polynuclear bismuth oxido clusters. AB - The synthesis of nanoscaled beta-Bi(2)O(3) starting from the bismuth oxido clusters [Bi(6)O(4)(OH)(4)](NO(3))(6).H(2)O, [Bi(22)O(26)(OSiMe(2)(t)Bu)(14)], [Bi(38)O(45)(NO(3))(20)(DMSO)(28)](NO(3))(4).4DMSO and [Bi(38)O(45)(OMc)(24)(DMSO)(9)].2DMSO.7H(2)O (OMc = O(2)CC(3)H(5)) under ambient conditions is reported. The metal oxido clusters are regarded as ideal precursors for beta-Bi(2)O(3) due to their structural relationship with the latter. Nevertheless, different bismuth oxide polymorphs are accessible dependent on the hydrolysis protocol. Hydrolysis over a period of 18 h gave stable alpha-Bi(2)O(3) whereas after 3 min an amorphous material is observed. Annealing of the amorphous material at 370 degrees C gave nanoscaled beta-Bi(2)O(3). An unusual high reactivity of the beta-Bi(2)O(3) particles with SiO(2) and Al(2)O(3) is observed at temperatures above 400 degrees C. Powder X-ray diffraction studies, transmission electron microscopy, diffuse reflectance UV/Vis spectroscopy and nitrogen adsorption measurements are used for characterization of the as-prepared beta-Bi(2)O(3) nanoparticles. The properties of the beta-Bi(2)O(3) nanoparticles depend on the starting bismuth oxido clusters with regard to particle size and optical band gap. The beta-Bi(2)O(3) nanoparticles show excellent photocatalytic activity as demonstrated by dye decomposition (rhodamine B, methyl orange, methylene blue and orange G) under visible light. PMID- 23108197 TI - Hypophosphatemic rickets. AB - PURPOSE OF REVIEW: Description of the recent advances on the regulation of phosphate metabolism, gene mutations, and new approaches to treatment in patients with hypophosphatemic rickets. RECENT FINDINGS: Fibroblast growth factor 23 (FGF23) overproduction may be a primary cause of hypophosphatemic rickets. Inactivating mutations of phosphate-regulating gene with homologies to endopeptidases on the X chromosome, dentin matrix acidic phosphoprotein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1 are associated with X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets 1, and autosomal recessive hypophosphatemic rickets 2, respectively. Activating mutations of FGF23 gene is the cause of autosomal dominant hypophosphatemic rickets. Iron deficiency may affect autosomal dominant hypophosphatemic rickets phenotype by regulating FGF23 production.Current treatment with activated vitamin D metabolites and oral inorganic phosphate salts may partially correct skeletal lesions and linear growth in patients with hypophosphatemic rickets. However, some patients have poor improvement by the current treatment. SUMMARY: Identification of the causative mutation in patients with hypophosphatemic rickets may be useful to confirm the diagnosis and probably for prognosis. Inhibition of FGF23 overproduction by anti-FGF23 neutralizing antibodies could be a future approach for treatment of patients with FGF23-dependent hypophosphatemic rickets. PMID- 23108198 TI - Reproductive impact of polycystic ovary syndrome. AB - PURPOSE OF REVIEW: The purpose of this review is to highlight the impact of polycystic ovary syndrome (PCOS) on menstrual function, fertility and reproductive outcomes. Women with PCOS often present with anovulation, menstrual disturbances and hyperandrogenism. Management options for the reproductive disorders of PCOS will be discussed. RECENT FINDINGS: The role of metformin in treating PCOS is narrowing. New data show improved live birth rates by skipping a progestin withdrawal bleed and proceeding directly with a dose escalation of clomiphene for ovulation induction. The Pregnancy in PCOS trial II will determine the safety and efficacy of clomiphene citrate compared to letrozole, in achieving live birth in infertile women with PCOS. SUMMARY: Initial treatment for reproductive disorders in overweight and obese women with PCOS is weight loss. This helps menstrual disturbances, shortens the time to conception and reduces adverse obstetric risks. Clomiphene citrate is considered the first-line therapy for ovulatory infertility. Clomiphene citrate-resistant women may be offered aromatase inhibitors or laparoscopic ovarian surgery. Metformin does not improve live birth rate or reduce miscarriage rate and is no longer considered an option for ovulation induction. Women with PCOS need to be counseled about risks of multiple gestations with gonadotropin therapy. PMID- 23108199 TI - Clinical update on screening, diagnosis and management of metabolic disorders and cardiovascular risk factors associated with polycystic ovary syndrome. AB - PURPOSE OF REVIEW: Polycystic ovarian syndrome (PCOS) is the most common endocrinopathy in premenopausal women. This review discusses the screening, diagnosis and management of metabolic disorders and cardiovascular risk factors associated with PCOS, highlighting significant recent developments. RECENT FINDINGS: PCOS is a complex genetic disorder with multiple susceptibility genes as well as environmental factors influencing the expression of various PCOS phenotypes. The first genome-wide association study of PCOS identified susceptibility loci on chromosome 2 near the luteinizing hormone receptor gene LHCGR and chromosome 9 near the obesity gene DEEND1A. Women with PCOS are affected by a variety of metabolic disorders, including insulin resistance, metabolic syndrome, type-2 diabetes, dyslipidemia and obesity. Recently, it has been established that women with PCOS have a high risk of nonalcoholic fatty liver disease. These metabolic disturbances are associated with an increased risk of cardiovascular disease (CVD). Although women with PCOS have higher rates of cardiovascular risk factors and intermediate markers of CVD, studies definitively documenting increased CVD are lacking. SUMMARY: The high prevalence of metabolic disorders and CVD risk factors in women with PCOS highlights the need for early screening, diagnosis and treatment of these disorders to promote long-term health and possibly prevent CVD. PMID- 23108200 TI - Management of CAH during pregnancy: optimizing outcomes. AB - PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is one of the most common autosomal recessive disorders. In the past, pregnancy was considered to be unlikely for women with CAH, particularly the classical forms. The purpose of this review is to provide current information regarding the pathophysiology of CAH, factors relevant for female and male fertility, and recommendations for management during pregnancy. RECENT FINDINGS: Individuals with CAH, both female and male, have reduced fertility. For women, chronic anovulation, elevated progestin levels, and aberrant endometrial implantation have been identified as reasons for the subfertility. Testicular adrenal rest tumors, oligospermia, and hypogonadotropic hypogonadism are frequently associated with subfertility in men with all forms of CAH. SUMMARY: Adequate suppression of progesterone appears to be an essential aspect of preconception management for women. Most importantly, treatment needs to be individualized. Awareness of these factors and appropriate therapeutic interventions can lead to successful outcome defined as a healthy live born infant. PMID- 23108202 TI - Childhood obesity is associated with changes in the serum metabolite profile. AB - OBJECTIVE: The human serum metabolite profile is reflective of metabolic processes, including pathophysiological changes characteristic of diseases. Therefore, investigation of serum metabolite concentrations in obese children might give new insights into biological mechanisms associated with childhood obesity. METHODS: Serum samples of 80 obese and 40 normal-weight children between 6 and 15 years of age were analyzed using a mass spectrometry-based metabolomics approach targeting 163 metabolites. Metabolite concentrations and metabolite ratios were compared between obese and normal-weight children as well as between children of different pubertal stages. RESULTS: Metabolite concentration profiles of obese children could be distinguished from those of normal-weight children. After correction for multiple testing, we observed 14 metabolites (glutamine, methionine, proline, nine phospholipids, and two acylcarnitines, p < 3.8 * 10-4) and 69 metabolite ratios (p < 6.0 * 10-6) to be significantly altered in obese children. The identified metabolite markers are indicative of oxidative stress and of changes in sphingomyelin metabolism, in beta-oxidation, and in pathways associated with energy expenditure. In contrast, pubertal stage was not associated with metabolite concentration differences. CONCLUSION: Our study shows that childhood obesity influences the composition of the serum metabolome. If replicated in larger studies, the altered metabolites might be considered as potential biomarkers in the generation of new hypotheses on the biological mechanisms behind obesity. PMID- 23108204 TI - Synthesis, structure and reactivity of cyclopropenyl-1-ylidene stabilized S(II), Se(II) and Te(II) mono- and dications. AB - The syntheses and structural characterization of carbene-stabilized chalcogen centred mono- and dications employing a reverse electron demand onio-substitutent transfer strategy are reported. The electronic structures of these compounds were determined by density functional calculations and their reactivity towards Pd(0) centres was evaluated. PMID- 23108201 TI - Plasma 25-hydroxyvitamin D(3) and bladder cancer risk according to tumor stage and FGFR3 status: a mechanism-based epidemiological study. AB - BACKGROUND: Previous evidence suggests that 25-hydroxyvitamin D(3) [25(OH)D(3)] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D(3) and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes. METHODS: Plasma concentrations of 25(OH)D(3) in 1125 cases with UBC and 1028 control subjects were determined by a chemiluminescence immunoassay. FGFR3 mutational status and expression in tumor tissue were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression adjusting for potential confounders. Analyses were further stratified by tumor invasiveness and grade, FGFR3 expression, and smoking status. Cell proliferation was measured in human UBC cell lines cultured with 1alpha,25-dihydroxyvitamin D(3). RESULTS: A statistically significantly increased risk of UBC was observed among subjects presenting the lowest concentrations of 25(OH)D(3) (OR(adj) = 1.83; 95% CI = 1.19 to 2.82; P = .006), showing a dose-response effect (P (trend) = .004). The association was stronger for patients with muscle-invasive tumors, especially among low-FGFR3 expressers (OR(adj) = 5.94; 95% CI = 1.72 to 20.45; P = .005). The biological plausibility of these associations is supported by the fact that, in vitro, 1alpha,25-dihydroxyvitamin D(3) upregulates FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3. CONCLUSION: These findings support a role of vitamin D in the pathogenesis of UBC and show that 25(OH)D(3) levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D(3) may be at high risk of more aggressive forms of UBC. PMID- 23108205 TI - An insect trypsin-like serine protease as a target of microRNA: utilization of microRNA mimics and inhibitors by oral feeding. AB - MicroRNAs (miRNAs) are non-coding small RNAs (18-25 nt) that play crucial roles in various biological processes, including development, as gene regulators. In this study, we identified a miRNA, har-miR-2002b, that is specifically expressed during larval stages of Helicoverpa armigera (cotton bollworm). For the first time, we explored the possibility of utilizing synthetic inhibitor and mimic of a miRNA by oral feeding and confirmed that the inhibitor and mimic can successfully inhibit/oversupply har-miR-2002b in H. armigera larvae. Bioassays by oral feeding indicated 70% reduction in fecundity and 40% larval mortality in the presence of har-miR-2002b mimic. In addition, a large proportion of those larvae that made it to the pupal stage were deformed and only few moths emerged from them. This implied an important role of har-miR-2002b in larval development and adult fecundity. A trypsin-like serine protease (Ha-TLP) was identified as a target of har-miR-2002b. In vivo and in vitro studies revealed that in the presence of the miRNA mimic Ha-TLP transcript/protein levels and enzyme activity were significantly reduced. In contrast, inhibition of har-miR-2002b led to significant up-regulation of Ha-TLP transcript levels. This is the first study which shows the potential of utilization of miRNA mimics and inhibitors in pest control by targeting specific insect genes. PMID- 23108207 TI - Atg1 kinase regulates early and late steps during autophagy. AB - The notion that phosphorylation constitutes a major mechanism to induce autophagy was established 15 years ago when a conserved Atg1/ULK kinase family was identified as an essential component of the autophagy machinery. The key observation was that starved atg1Delta cells lack autophagosomes in the cytosol and fail to accumulate autophagic bodies in the vacuole. Although many studies have revealed important details of Atg1 activation and function, a cohesive model for how Atg1 regulates the autophagic machinery is lacking. Our recent findings identified conserved steps of temporal and spatial regulation of Atg1/ULK1 kinase at both the PAS and autophagosomal membranes, suggesting that Atg1 not only promotes autophagy induction, but may also facilitate late stages of autophagosome biogenesis. PMID- 23108208 TI - Differentiation of glioblastoma multiforme from metastatic brain tumor using proton magnetic resonance spectroscopy, diffusion and perfusion metrics at 3 T. AB - PURPOSE: To assess the contribution of (1)H-magnetic resonance spectroscopy (1H MRS), diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI) and dynamic susceptibility contrast-enhanced (DSCE) imaging metrics in the differentiation of glioblastomas from solitary metastasis, and particularly to clarify the controversial reports regarding the hypothesis that there should be a significant differentiation between the intratumoral and peritumoral areas. METHODS: Conventional MR imaging, (1)H-MRS, DWI, DTI and DSCE MRI was performed on 49 patients (35 glioblastomas multiforme, 14 metastases) using a 3.0-T MR unit. Metabolite ratios, apparent diffusion coefficient (ADC), fractional anisotropy (FA) and relative cerebral blood volume (rCBV) were measured in the intratumoral and peritumoral regions of the lesions. Receiver-operating characteristic analysis was used to obtain the cut-off values for the parameters presenting a statistical difference between the two tumor groups. Furthermore, we investigated the potential effect of the region of interest (ROI) size on the quantification of diffusion properties in the intratumoral region of the lesions, by applying two different ROI methods. RESULTS: Peritumoral N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, Cho/NAA and rCBV significantly differentiated glioblastomas from intracranial metastases. ADC and FA presented no significant difference between the two tumor groups. CONCLUSIONS: 1H-MRS and dynamic susceptibility measurements in the peritumoral regions may definitely aid in the differentiation of glioblastomas and solitary metastases. The quantification of the diffusion properties in the intratumoral region is independent of the ROI size placed. PMID- 23108210 TI - Excitability in the host-pathogen interactions of HIV infection and emergence of viral load blips. AB - HIV viral blips are characterized by intermittent episodes of detectable low level viraemia which return spontaneously to an undetectable level in patients with full suppression of viraemia (<50 copies/ml). The precise mechanisms responsible for viraemia blips and their clinical significance are not known. In this work, we analyze HIV blips using a mathematical model describing basic host pathogen interactions, in particular regulatory processes involving CD4+, CD8+ T cells and the virus. We show that under adequate conditions, this interaction system can be excitable and small perturbations of the system by external stimuli can generate robust viral load (VL) blips of regular or irregular frequency and peak amplitudes. Importantly, our analysis showed that direct perturbations of the viral load (by latent reservoirs or opportunistic diseases for example) more efficiently trigger VL blips on contrary to direct perturbations of the immune system, in particular the levels of uninfected CD4+ and cytotoxic CD8+ T-cells. This feature is shown to rely on specific stability properties in this interaction system. Our analysis moreover suggests that blips should be of low clinical significance since any other VL or immune system perturbations could trigger transient viraemia under adequate excitability conditions. PMID- 23108209 TI - Periodicity analysis of movement recursions. AB - Many animals adaptively use their environments by adjusting how long and how often they use specific areas of their home range. Whereas questions about residence times have been addressed for a long time, the study of movement recursions has only recently received due interest. A key question concerns the potential periodicity of such recursions, as many potential drivers of movement behaviour such as light, climate or plant-herbivore interactions can be periodic. We propose here to build upon well-established Fourier and wavelet analyses to extract periodic patterns from time-series of presence/absence, arrival or departure from areas of interest, and introduce reliable null models for assessing the statistical significance of the periods detected. We provide an illustrative example which shows how an impala (Aepyceros melampus) expressed periodic use of the main open area of its home range. The significant periods found (12 h using arrival times; 24h, 7 days, and 30 days using presence/absence records) were consistent with a use of this area linked to predation and disturbance, as the area was used more at night, closer to dark moon, and during week-days. Our approach is a further step towards building up a wider analytical framework for the study of movement ecology. PMID- 23108211 TI - Syntheses and structures of Zr4 tetrahedral clusters containing direct Zr-Zr bonds: the missing cluster in the series Zr(n) (n = 2-6). AB - The reduction of [(MU(2)-H)( MU(3)-H)(Cp*ZrCl)](4) by excess Na/Hg led to the isolation of the mixed-valence Zr(III)/Zr(IV) Zr(4) cluster [(MU(2)-H)(8)(MU(2) Cl)(2)(Cp*Zr)(4)], 1, and the Zr(II)/Zr(III) Zr(4) cluster [(MU(2) H)(6)(Cp*Zr)(4)], 2. The proton NMR data supports the diamagnetic property of both clusters in solution and the solid state structure of each cluster revealed a distorted tetrahedral skeleton comprised of four Zr atoms and the presence of direct Zr-Zr bonds. The hydride-bridged Zr-Zr bond distances are in the range of 3.0516(6)-3.0585(6) A in 1 and 3.0525(13)-3.0864(13) A in 2. The chloride-bridged Zr-Zr distances in 1 are 3.5514(6) and 3.5643(6) A. The existence of Zr-Zr bonds in both clusters was further confirmed by DFT calculations. 1 and 2 represent the first examples of Zr(4) tetrahedrons containing direct Zr-Zr bonds. PMID- 23108212 TI - Di(2-ethylhexyl)phthalate (DEHP) and di-n-butylphthalate (DBP) exposure through diet in hospital patients. AB - Ready-to-eat packed meals intended to hospital patients were studied over a two weeks period to measure the contents of di-(2-ethylhexyl) phthalate (DEHP) and di n-butylphthalate (DBP) and to evaluate their daily intake by total diet. The packaging consisted of polyethylene terephthalate (PET) dishes sealed with polypropylene (PP) foil. The DEHP mean concentrations in total meals varied from 0.061+/-0.028 to 0.307+/-0.138MUg/gwetweight (wet wt.); the DBP mean levels varied from 0.025+/-0.018 to 0.174+/-0.091MUg/gwetwt. Highest levels of concentration for DEHP and DBP were found in bread with mean values of 0.307+/ 0.138MUg/gwetwt. and 0.174+/-0.091MUg/gwetwt. for DEHP and DBP, respectively. The daily intake for DEHP was 3.1+/-0.9MUg/kgbw and 1.5+/-0.5MUg/kgbw for DBP. The mean+/-sd incidence of DEHP and DBP intake via hospital meals on the respective EFSA TDI was 6+/-2% (range 4-11%), and 15+/-5% (range 8-24%), respectively. Even if for hospital patients the major route of exposure may be represented by medical devices, the influence of the diet could have a significant value on TDI. PMID- 23108213 TI - Comment on "toxic hepatitis in a group of 20 male body-builders taking dietary supplements" by. PMID- 23108214 TI - Ameliorative effect of Drynaria quercifolia (L.) J. Sm., an ethnomedicinal plant, in arthritic animals. AB - Drynaria quercifolia (L.) J. Sm., is an ethnomedicinal plant used widely in Tamil Nadu to treat arthritis. The present study was aimed to evaluate the traditional claim of D. quercifolia rhizome water extract in adjuvant induced arthritic animals. Anti-arthritic effect was studied by assessing the levels of lysosomal enzymes, protein bound carbohydrates, urinary degradative collagen and serum cytokines on control and adjuvant induced arthritis. The paw swelling and body weight were also analyzed. The levels of ROS and lysosomal enzymes in neutrophils of control and adjuvant induced animals were also estimated. D. quercifolia rhizome water extract at doses of 100 and 200mg/kg reduced the paw thickness and elevated the mean body weight of arthritic rats. The treatment with extract showed a significant reduction in the levels of plasma and liver lysosomal enzymes as well as protein bound carbohydrates and urinary degradative collagen levels. The treatment reduced the levels of ROS and lysosomal enzymes in neutrophils significantly. The significant reduction in the levels of serum pro inflammatory cytokines (TNF-alpha and IL-1beta) and the increment in the levels of anti-inflammatory cytokine (IL-10) were also observed by the treatment. The present study supports the traditional claim of using D. quercifolia to treat rheumatism. PMID- 23108206 TI - Lignin-associated metagene expression in a lignocellulose-digesting termite. AB - Lignin is a component of plant biomass that presents a significant obstacle to biofuel production. It is composed of a highly stable phenylpropanoid matrix that upon degradation, releases toxic metabolites. Termites have specialized digestive systems that overcome the lignin barrier in wood lignocellulose to efficiently release fermentable simple sugars; however, how termites specifically degrade lignin and tolerate its toxic byproducts remains unknown. Here, using the termite Reticulitermes flavipes and its symbiotic (protozoan) gut fauna as a model system, we used high throughput Roche 454-titanium pyrosequencing and proteomics approaches to (i) experimentally compare the effects of diets containing varying degrees of lignin complexity on host-symbiont digestome composition, (ii) deeply sample host and symbiont lignocellulase diversity, and (iii) identify promising lignocellulase candidates for functional characterization. In addition to revealing over 9500 differentially expressed transcripts related to a wide range of physiological processes, our findings reveal two detoxification enzyme families not generally considered in connection with lignocellulose digestion: aldo-keto reductases and catalases. Recombinant versions of two host enzymes from these enzyme families, which apparently play no roles in cellulose or hemicellulose digestion, significantly enhance lignocellulose saccharification by cocktails of host and symbiont cellulases. These hypothesis-driven results provide important new insights into (i) dietary lignin as a xenobiotic challenge, (ii) the complex mechanisms used by termites to cope with their lignin-rich diets, and (iii) novel lignin-targeted enzymatic approaches to enhance biofuel and biomaterial production. PMID- 23108215 TI - Controversy over the use of creatine as a safe dietary supplement. PMID- 23108217 TI - L-shaped benzimidazole fluorophores: synthesis, characterization and optical response to bases, acids and anions. AB - Nine L-shaped benzimidazole fluorophores have been synthesized, computationally evaluated and spectroscopically characterized. These "half-cruciform" fluorophores respond to bases, acids and anions through changes in fluorescence that vary from moderate to dramatic. PMID- 23108218 TI - TICT fluorescence of N-borylated 2,5-diarylpyrroles: a gear like dual motion in the excited state. AB - A significantly red-shifted fluorescence and a high fluorescence quantum yield for the emission from the twisted intramolecular charge transfer (TICT) state are attained in new aminoboranes, N-borylated 2,5-diarylpyrroles. A gear like dual structural motion in the excited state is responsible for their large Stokes shifts. PMID- 23108216 TI - Promoting effect of polysaccharide isolated from Mori fructus on dendritic cell maturation. AB - Maturation of dendritic cells (DCs) is usually attenuated in the tumor microenvironment, which is an important immunological problem in DC-based immunotherapy of cancer. In this study, we report the effect of a Mori fructus polysaccharide (MFP) on DC maturation. MFP was treated to DCs generated from mouse BM cells. MFP induced phenotypic maturation of DCs, as proven by the increased expression of CD40, CD80/86, and MHC-I/II molecules. MFP induced functional maturation of DCs, in that MFP increased the expression of IL-12, IL 1beta, TNF-alpha, and IFN-beta, decreased antigen capture capacity, and enhanced allogenic T cell stimulation. MFP efficiently induced maturation of DCs from C3H/HeN mice having normal toll-like receptor4 (TLR4), but not DCs from C3H/HeJ mice having mutated TLR4, suggesting that TLR4 might be one of the membrane receptors of MFP. As a mechanism of action, MFP increased phosphorylation of mitogen-activated protein kinase (MAPKs), and nuclear translocation of NF-kappaB p65 subunit, which were important signal molecules downstream from TLR4. These data suggest that MFP induces DC maturation through TLR4 and MFP can be used as an adjuvant in DC-based cancer immunotherapy. PMID- 23108219 TI - Size-selective pH-operated megagates on mesoporous silica materials. AB - pH-responsive megagates have been fabricated around mesoporous silica material SBA-15 in order to mechanize the mesopores. These megagates remain closed in neutral conditions, but open at pH 5. The capping components of the megagates were designed to be capable of controlling pores up to 6.5 nm in diameter. Selectivity of payloads with different sizes can be achieved through the use of different capping components. The operation of the megagates was demonstrated by time-resolved fluorescence spectroscopy which is capable of monitoring the release of both the payload and the cap. This study opens up new possibilities in the field of controllable release. PMID- 23108220 TI - Guidelines for newborn screening of primary immunodeficiency diseases. AB - PURPOSE OF REVIEW: Technical possibilities to screen for inborn errors of immune function at the neonatal stage have been rapidly progressing, whereas the guidelines that apply for the evaluation of benefits and concerns on expanding screening panels have not been broadly discussed for primary immunodeficiency diseases (PID). This review reflects on the assessment of severe combined immunodeficiencies (SCID), primary agammaglobulinaemias (such as X-linked agammaglobulinaemia) and inherited haemophagocytic syndromes (such as familial haemophagocytic lymphohistiocytosis) to be included in newborn screening (NBS) programmes. RECENT FINDINGS: Screening programmes in several federal states in the United States have been supplemented with the T-cell receptor excision circle assay during the past few years to identify children with SCID. The reported experience indicates that an efficient and validated screening approach for SCID is feasible on a population-based scale. SUMMARY: In the light of recent advances, severe PID ought to be discussed for their rapid implementation in national NBS programmes based upon clinical, social and economical criteria as consolidated in the extended 22-item Wilson-Jungner framework. Although SCID currently most favourably fulfils these screening guidelines, other strong candidates can be identified among primary immunodeficiency disorders. Future efforts of healthcare professionals and policy makers are essential to improve the concept of neonatal screening for PID. PMID- 23108221 TI - Haematological manifestations and complications of Gaucher disease. AB - PURPOSE OF REVIEW: Gaucher disease is a rare inherited disorder of sphingolipid metabolism resulting in the accumulation of glucocerebroside substrate in cells throughout the reticuloendothelial system and clinical manifestations including cytopenias, organomegaly and bone disease. The clinical presentation is very variable and little has been understood of the determinants of heterogeneity or biological features that influence disease severity. RECENT FINDINGS: This review explores the haematological features of Gaucher disease in the context of new insights into the underlying cellular physiopathlogy. Careful examination of registry data has furthered understanding of individual risk factors for bone complications including fractures and osteonecrosis and for reduced or delayed response to enzyme replacement therapy. Analysis of substrates and their derivatives have added to possible biomarkers for assessment of disease burden and response to treatment and strikingly, in view of its rarity a genome-wide association study has identified a hitherto unsuspected gene as a potential modifier of severity. SUMMARY: Improved understanding of biological and clinical risk factors for severe manifestations of Gaucher disease will allow rational assessment of patients and suggests potential nonsubstrate directed adjuvant strategies to consider in the management of this condition. PMID- 23108222 TI - Ion mobility spectrometry for monitoring diamine oxidase activity. AB - The capability of IMS for the determination of kinetics in complex enzyme systems with reduced v(max) values has been demonstrated with the example of diamine oxidase (DAO). Michaelis-Menten and Lineweaver-Burk plots were obtained for the enzyme catalyzed putrescine oxidation and calculations of the kinetic parameters have been performed and compared with previously published values. The IMS procedure provided a limit of detection of 200 pg mL(-1) for putrescine, a limit of quantification of 667 pg mL(-1), a precision of 5.9%, and an analysis frequency of 40 s, which are analytical characteristics appropriate to perform label-free enzyme studies. Additionally, pseudo-competitive inhibition of the putrescine oxidation due to other diamines binding to the free enzyme has been evaluated. Moreover, the mass-mobility correlation curve of diamines based on the calculated mobilities of the studied analytes and data previously reported for cadaverine, serotonin and tryptamine was modelled. The analytical method could be used as an additional complementary tool for the existing drug discovery method, for the search of DAO activators; molecules that displace the substrate from the second site of DAO, but does not interfere with the catalytic function of the first site. PMID- 23108223 TI - Diffusion magnetic resonance imaging of chest tumors. AB - This review provides an overview of the current status of the published data on diffusion magnetic resonance (MR) imaging of chest tumors. Diffusion MR imaging is a non-invasive imaging technique that measures the differences in water mobility in different tissue microstructures and quantifies them based on the apparent diffusion coefficient. Diffusion MR imaging has been used for the characterization, grading and staging of lung cancer as well as for differentiating central tumors from post-obstructive consolidation. In addition, this technique helps in differentiating malignant from benign pulmonary and mediastinal tumors as well as in the characterization of pleural mesothelioma and effusion. Diffusion MR imaging can be incorporated into routine morphological MR imaging to improve radiologist confidence in image interpretation and to provide functional assessments of chest tumors during the same examination. Diffusion MR imaging could be used in the future as a functional imaging technique for tumors of the chest. PMID- 23108224 TI - Cathepsin C gene 5'-untranslated region mutation in papillon-lefevre syndrome. AB - BACKGROUND: Papillon-Lefevre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe form of generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). OBJECTIVE: To investigate the clinical and mutational characteristics of 6 PLS patients from 4 unrelated Slovenian families. METHODS: CTSC mutational and functional analyses were performed. RESULTS: In all patients, a novel homozygous substitution, c.-55C>A, in the CTSC 5'-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNA expression and CTSC activity. In silico analysis revealed the potential of the mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. CONCLUSION: Identification of a novel CTSC 5'-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS. PMID- 23108226 TI - Triphenylene derivatives: chemosensors for sensitive detection of nitroaromatic explosives. AB - New triphenylene derivatives 3 and 5, synthesized using a Suzuki-Miyaura coupling protocol and by a click reaction respectively, serve as potent chemosensors for various electron deficient nitroaromatic explosives, such as picric acid, trinitrotoluene, dinitrotoluene and dinitrobenzene. Derivative 5 exhibits a more sensitive response towards the nitroaromatics compared to derivative 3 due to its ordered organization. Furthermore, the solution coated strips of derivative 3 and gel coated strips of derivative 5 can detect picric acid in the range of 14 pg cm(-2), thus providing a simple and low cost method for the detection of picric acid in aqueous solution and in a contact mode. PMID- 23108225 TI - Characterization and optimization of vascular endothelial growth factor(165) (rhVEGF(165)) expression in Escherichia coli. AB - Vascular endothelial growth factors(165) (VEGF(165)) is the most potent and widely used pro-angiogenic factor. Here we determined optimal culture condition of recombinant human VEGF(165) (rhVEGF(165)) in Escherichia coli (E. coli). rhVEGF(165) expression was the highest in 0.25% of L-arabinose induction concentration, at 20 degrees C induction temperature, and for 5 h induction time under the control of araBAD promoter using pBADHisA vector. In biological activity test, rhVEGF(165) significantly increased the proliferative activity of CPAE cells (p<0.001) and upregulated the expressions of endothelial cell growth related genes, such as platelet endothelial cell adhesion molecule (PECAM-1), endothelial-specific receptor tyrosine kinase (TEK), kinase insert domain protein receptor (KDR), and tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) in calf pulmonary artery endothelial (CPAE) cells. PMID- 23108227 TI - PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. AB - Advanced glycation end products (AGEs) formed at an accelerated rate under diabetes, elicit oxidative and pro-apoptotic reactions in various types of cells, including podocytes, thus being involved in the development and progression of diabetic nephropathy. Recently, we, along with others, have found that pigment epithelium-derived factor (PEDF), a glycoprotein with potent neuronal differentiating activity, inhibits AGE-elicited mesangial and tubular cell damage through its anti-oxidative properties. However, the effects of PEDF on podocyte loss, one of the characteristic features of diabetic nephropathy remain unknown. In this study, we investigated whether and how PEDF could protect against AGE elicited podocyte apoptosis in vitro. AGEs decreased PEDF mRNA level in podocytes, which was blocked by neutralizing antibody raised against receptor for AGEs (RAGE-Ab). PEDF or RAGE-Ab was found to inhibit the AGE-induced up regulation of RAGE mRNA level, oxidative stress generation and resultant apoptosis in podocytes. All of the beneficial effects of PEDF on AGE-exposed podocytes were blocked by the treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-gamma (PPARgamma). Further, although PEDF did not affect protein expression levels of PPARgamma, it significantly restored the PPARgamma transcriptional activity in AGE-exposed podocytes. The present results demonstrated for the first time that PEDF could block the AGE-induced apoptotic cell death of podocytes by suppressing RAGE expression and subsequent ROS generation partly via PPARgamma activation. Our present study suggests that substitution of PEDF proteins may be a promising strategy for preventing the podocyte loss in diabetic nephropathy. PMID- 23108228 TI - Protein phosphorylation regulates in vitro spinach chloroplast petD mRNA 3' untranslated region stability, processing, and degradation. AB - RNA-binding proteins (RNPs) participate in diverse processes of mRNA metabolism, and phosphorylation changes their binding properties. In spinach chloroplasts, 24RNP and 28RNP are associated with polynucleotide posphorylase forming a complex on charge of pre-mRNA 3'-end maturation. Here, we tested the hypothesis that the phosphorylation status of 24RNP and 28RNP, present in a spinach chloroplast mRNA 3'-UTR processing extract (CPE), controls the transition between petD precursor stabilization, 3'-UTR processing, and RNA degradation in vitro. The CPE processed or stabilized petD precursor depending on the ATP concentration present in an in vitro 3'-UTR processing (IVP) assay. These effects were also observed when ATP was pre-incubated and removed before the IVP assay. Moreover, a dephosphorylated (DP)-CPE degraded petD precursor and recovered 3'-UTR processing or stabilization activities in an ATP concentration dependent manner. To determine the role 24/28RNP plays in regulating these processes a 24/28RNP-depleted (Delta24/28)CPE was generated. The Delta24/28CPE degraded the petD precursor, but when it was reconstituted with recombinant non-phosphorylated (NP)-24RNP or NP-28RNP, the precursor was stabilized, whereas when Delta24/28CPE was reconstituted with phosphorylated (P)-24RNP or P-28RNP, it recovered 3'-UTR processing, indicating that 24RNP or 28RNP is needed to stabilize the precursor, have a redundant role, and their phosphorylation status regulates the transition between precursor stabilization and 3'-UTR processing. A DP-Delta24/28CPE reconstituted or not with NP-24/28RNP degraded petD precursor. Pre-incubation of DP-Delta24/28CPE with NP 24/28RNP plus 0.03 mM ATP recovered 3'-UTR processing activity, and its reconstitution with P-24/28RNP stabilized the precursor. However, pre-incubation of DP-Delta24/28CPE with 0.03 mM ATP, and further reconstitution with NP-24/28RNP or P-24/28RNP produced precursor stability instead of RNA degradation, and RNA processing instead of precursor stability, respectively. Moreover, in vitro phosphorylation of CPE showed that 24RNP, 28RNP, and other proteins may be phosphorylated. Altogether, these results reveal that phosphorylation of 24RNP, 28RNP, and other unidentified CPE proteins mediates the in vitro interplay between petD precursor stability, 3'-UTR processing, and degradation, and support the idea that protein phosphorylation plays an important role in regulating mRNA metabolism in chloroplast. PMID- 23108229 TI - Azide-alkyne cycloaddition en route towards 1H-1,2,3-triazole-tethered beta lactam-ferrocene and beta-lactam-ferrocenylchalcone conjugates: synthesis and in vitro anti-tubercular evaluation. AB - A diverse range of triazoles were prepared following well established, Cu mediated azide-alkyne cycloaddition reactions with the aim of probing the anti tubercular structure-activity relationships (SAR) within the beta-lactam ferrocene-triazole conjugate family. The anti-tubercular evaluation studies of the synthesized conjugates revealed that none of the scaffolds exhibited any activity that restricted mycobacterial growth even at high doses. The introduction of various substituents onto the N-1 of the beta-lactam ring, introducing mono- or di-ferrocenylchalcone substituents at the C-3 position as well as introducing a spacer of varying chain length failed to produce any significant enhancement in the activity profiles. The described protocol was a successful attempt on the inclusion of a ferrocene nucleus in the beta-lactam family tethered via triazole linkers having metabolic stability and physicochemical favourability. PMID- 23108231 TI - Integrative neuroimaging in mood disorders. AB - PURPOSE OF REVIEW: Neuroimaging has become a central technique of biological psychiatry and is uniquely suited to assess functional and structural brain changes in psychiatric patients in vivo. In this review, we highlight several recent developments that may enable the transition of psychiatric neuroimaging from laboratory to clinic. RECENT FINDINGS: We describe recent trends in refining imaging techniques for brain microstructure (diffusion imaging) and neurochemistry (magnetic resonance spectroscopy of neurotransmitters and metabolites) and their application to patients with mood disorders and individuals at risk, such as first-degree relatives. We also survey recent progress in imaging-guided deep brain stimulation (DBS), imaging-based (neurofeedback) therapies and studies looking at their convergent anatomical targets. These new interventional techniques, which aim to modulate brain circuits of emotion and motivation highlighted by functional imaging studies, have shown promising effects in several small studies. SUMMARY: The mapping of brain patterns associated with risk to develop mood disorders may pave the way for diagnostic/prognostic applications of neuroimaging. The neuromodulation techniques of DBS and neurofeedback, which target dysfunctional or compensatory circuits identified by functional imaging, may take neuroimaging into a new, therapeutic domain. PMID- 23108232 TI - Fish oil as a management component for mood disorders - an evolving signal. AB - PURPOSE OF REVIEW: To overview the theoretical relevance of omega-3 and omega-6 fatty acids in the cause of mood disorders, and focus on evaluating the potential therapeutic role of omega-3 fatty acids. RECENT FINDINGS: Numerous studies have documented low omega-3 fatty acid levels in those with depressive disorders, and there are plausible biological explanations as to why reduced omega-3 status may predispose to mood disorders as well as to a range of other conditions. Although early studies evaluating the role of omega-3 preparations as treatments of depression were generally positive, the rate of negative or nondifferential studies has increased in recent years. Recent meta-analyses provide an explanation in suggesting that docosahexaenoic acid-weighted preparations may be ineffective while finding support for eicosapentaenoic acid (EPA)-weighted preparations. SUMMARY: There is sufficient indicative data favouring EPA-weighted omega-3 supplementation for those with a depressive mood disorder, particular when fish oil is viewed by patients as 'natural,' it has few side effects and is neuroprotective. Recent meta-analyses inform us that intervention studies should focus on EPA-weighted preparations. PMID- 23108235 TI - Performance of elite seated discus throwers in F30s classes: part I: does whole body positioning matter? AB - BACKGROUND: Studies on the relationship between performance and design of the throwing frame have been limited and therefore require further investigation. OBJECTIVES: The specific objectives were to provide benchmark information about performance and whole body positioning of male athletes in F30s classes. STUDY DESIGN: Descriptive analysis. METHODS: A total of 48 attempts performed by 12 stationary discus throwers in F33 and F34 classes during seated discus throwing event of 2002 International Paralympic Committee Athletics World Championships were analysed in this study. The whole body positioning included overall throwing posture (i.e. number of points of contact between the thrower and the frame, body position, throwing orientation and throwing side) and lower limb placements (i.e. seating arrangements, points of contact on the both feet, type of attachment of both legs and feet). RESULTS: Three (25%), five (42%), one (8%) and three (25%) athletes used from three to six points of contact, respectively. Seven (58%) and five (42%) athletes threw from a standing or a seated position, respectively. A straddle, a stool or a chair was used by six (50%), four (33%) or two (17%) throwers, respectively. CONCLUSIONS: This study provides key information for a better understanding of the interaction between throwing technique of elite seated throwers and their throwing frame. Clinical relevance This study aimed at improving the understanding of the relationship between athletic performance and the design of the throwing frame for seated discus throwers, with a particular emphasis on the description of whole body positioning. This knowledge is particularly important in the current debate around general principles underlying the design of throwing frames and classification of athletes with a disability, including those with lower limb amputation. PMID- 23108234 TI - Factors affecting stair-ascent patterns in unilateral transfemoral amputees. AB - BACKGROUND: Patterns and ease of stair ambulation influence amputees' level of satisfaction with their rehabilitation, confidence level, and motivation for continued rehabilitation, demonstrating the importance of stair-ascent data for rehabilitation. However, little is known about the determinants of stair-ascent patterns in unilateral transfemoral amputees. OBJECTIVES: To investigate the factors affecting stair-ascent patterns in transfemoral amputees. STUDY DESIGN: Cross-sectional survey. METHODS: Stair-ascent patterns were evaluated using the Stair Assessment Index. We collected Stair Assessment Index data as well as demographic and clinical data (sex, age, height, mass, amputation side, reason for amputation, time since amputation, and residual limb length) from 25 transfemoral amputees. RESULTS: Statistical analyses revealed that age was negatively correlated and time since amputation was positively correlated with Stair Assessment Index. In contrast, height, body mass, and residual limb lengths were not correlated with Stair Assessment Index. CONCLUSION: The results of this study suggest that in unilateral transfemoral amputee, (1) both age and time since amputation could affect stair-climbing patterns and (2) residual limb length should not be a limiting factor for stair climbing if the transfemoral amputee has a certain minimum residual limb length. CLINICAL RELEVANCE: Rehabilitation teams should carefully consider nonmodifiable predisposing factors such as age and time since amputation. However, they may be able to carry on stair-ascent rehabilitation for transfemoral amputees disregarding residual limb length (depending on the length). PMID- 23108236 TI - Autophagy activation ameliorates neuronal pathogenesis of FTLD-U mice: a new light for treatment of TARDBP/TDP-43 proteinopathies. AB - The administration of rapamycin, an MTOR-dependent autophagy activator, for the treatment of neurodegenerative diseases has been tested in several animal models. Thus, whether autophagy activation would lead to the clearance of abnormal accumulation of aggregated proteins in neurodegenerative diseases is worthy of exploration. We have recently shown that rapamycin administration at the early pathological stage of a mouse model with frontotemporal lobar dementia (FTLD-U) characterized with cytoplasmic TARDBP/TDP-43(+)/ubiquitin(+) inclusions (UBIs) in the diseased neurons could rescue the learning/memory deficiency and the abnormal motor function disorder of the mice. This was accompanied by a decreased level of CASP3/caspase-3 and a reduction of the neuronal loss in the mouse forehead. Moreover, autophagy activation at a late pathological stage also could improve motor function, which was accompanied by a reduction of the TARDBP(+) UBIs. This study has set the principal for therapy of neurodegenerative diseases with the TARDBP protein, i.e., amyotrophic lateral sclerosis (ALS)-TDP and FTLD-TDP43, with the use of autophagy activators. PMID- 23108237 TI - Glycerol inhibits water permeation through Plasmodium falciparum aquaglyceroporin. AB - Plasmodium falciparum aquaglyceroporin (PfAQP) is a multifunctional membrane protein in the plasma membrane of P. falciparum, the parasite that causes the most severe form of malaria. The current literature has established the science of PfAQP's structure, functions, and hydrogen-bonding interactions but left unanswered the following fundamental question: does glycerol modulate water permeation through aquaglyceroporin that conducts both glycerol and water? This paper provides an affirmative answer to this question of essential importance to the protein's functions. On the basis of the chemical-potential profile of glycerol from the extracellular bulk region, throughout PfAQP's conducting channel, to the cytoplasmic bulk region, this study shows the existence of a bound state of glycerol inside aquaglyceroporin's permeation pore, from which the dissociation constant is approximately 14MUM. A glycerol molecule occupying the bound state occludes the conducting pore through which permeating molecules line up in single file by hydrogen-bonding with one another and with the luminal residues of aquaglyceroporin. In this way, glycerol inhibits permeation of water and other permeants through aquaglyceroporin. The biological implications of this theory are discussed and shown to agree with the existent in vitro data. It turns out that the structure of aquaglyceroporin is perfect for the van der Waals interactions between the protein and glycerol to cause the existence of the bound state deep inside the conducting pore and, thus to play an unexpected but significant role in aquaglyceroporin's functions. PMID- 23108238 TI - Meta-analysis of the diagnostic performance of [18F]FDG-PET and PET/CT in renal cell carcinoma. AB - OBJECTIVES: Positron emission tomography (PET) using fluorodeoxyglucose (FDG) is useful for restaging renal cell carcinoma (RCC) and detecting metastatic diseases but is less satisfactory for detecting primary disease. We evaluated whether the integration of computed tomography (CT) scans with the PET system could increase the applicability of FDG-PET for RCC. METHODS: The MEDLINE databases were searched for relevant studies published since 2001. Two reviewers independently assessed the methodological quality of each study identified. We then performed a meta-analysis of the sensitivity and specificity of FDG-PET findings as reported in all the selected studies. RESULTS: Fourteen studies were eligible for inclusion. The pooled sensitivity and specificity of FDG-PET were 62% and 88% respectively, for renal lesions. For detecting extra-renal lesions, the pooled sensitivity and specificity of FDG-PET were 79% and 90%, respectively, based on the scans, and 84% and 91% based on the lesions. The use of a hybrid FDG-PET/CT to detect extra-renal lesions increased the pooled sensitivity and specificity to 91% and 88%, respectively, with good consistency. CONCLUSIONS: For RCC, combining the FDG-PET and CT systems is helpful for detecting extra-renal metastasis rather than renal lesions. The hybrid PET/CT system has comparable sensitivity and specificity with PET in detecting extra-renal lesions of RCC. ADVANCES IN KNOWLEDGE: The FDG-PET and PET/CT systems are both useful for detecting extra renal metastasis in renal cell carcinoma. PMID- 23108239 TI - Decoding twitter: Surveillance and trends for cardiac arrest and resuscitation communication. AB - AIM OF THE STUDY: Twitter has over 500 million subscribers but little is known about how it is used to communicate health information. We sought to characterize how Twitter users seek and share information related to cardiac arrest, a time sensitive cardiovascular condition where initial treatment often relies on public knowledge and response. METHODS: Tweets published April-May 2011 with keywords cardiac arrest, CPR, AED, resuscitation, heart arrest, sudden death and defib were identified. Tweets were characterized by content, dissemination, and temporal trends. Tweet authors were further characterized by: self-identified background, tweet volume, and followers. RESULTS: Of 62,163 tweets (15,324, 25%) included resuscitation/cardiac arrest-specific information. These tweets referenced specific cardiac arrest events (1130, 7%), CPR performance or AED use (6896, 44%), resuscitation-related education, research, or news media (7449, 48%), or specific questions about cardiac arrest/resuscitation (270, 2%). Regarding dissemination (1980, 13%) of messages were retweeted. Resuscitation specific tweets primarily occurred on weekdays. Most users (10,282, 93%) contributed three or fewer tweets during the study time frame. Users with more than 15 resuscitation-specific tweets in the study time frame had a mean 1787 followers and most self-identified as having a healthcare affiliation. CONCLUSION: Despite a large volume of tweets, Twitter can be filtered to identify public knowledge and information seeking and sharing about cardiac arrest. To better engage via social media, healthcare providers can distil tweets by user, content, temporal trends, and message dissemination. Further understanding of information shared by the public in this forum could suggest new approaches for improving resuscitation related education. PMID- 23108241 TI - Electrophysiological evidence of early word learning. AB - Around their first birthday infants begin to talk, yet they comprehend words long before. This study investigated the event-related potentials (ERP) responses of nine-month-olds on basic level picture-word pairings. After a familiarization phase of six picture-word pairings per semantic category, comprehension for novel exemplars was tested in a picture-word matching paradigm. ERPs time-locked to pictures elicited a modulation of the negative central (Nc) component, associated with visual attention and recognition. It was attenuated by category repetition as well as by the type-token ratio of picture context. ERPs time-locked to words in the training phase became more negative with repetition (N300-600), but there was no influence of picture type-token ratio, suggesting that infants have identified the concept of each picture before a word was presented. Results from the test phase provided clear support that infants integrated word meanings with (novel) picture context. Here, infants showed different ERP responses for words that did or did not align with the picture context: a phonological mismatch (N200) and a semantic mismatch (N400). Together, results were informative of visual categorization, word recognition and word-to-world-mappings, all three crucial processes for vocabulary construction. PMID- 23108240 TI - The neuroprotective effects of intraperitoneal injection of hydrogen in rabbits with cardiac arrest. AB - OBJECTIVE: The purpose of this study was to investigate the neuroprotective effects of intraperitoneal injection of hydrogen (H2) in rabbits with cardiac arrest (CA). METHODS: A rabbit model of CA was established by the delivery of alternating current between the esophagus and chest wall to induce ventricular fibrillation. Before CA, the animals were randomly divided into four groups: a sham group (no CA), a CA group, a CA + low dose (10 ml/kg) H2 group (CA + H2 group 1), and a CA + high dose (20 ml/kg) H2 group (CA + H2 group 2). In the first experiment, animals were observed for 72 h after the restoration of spontaneous circulation (ROSC). The neurological scores were assessed at 24, 48 and 72 h after ROSC. The rabbits that survived until 72 h were sacrificed using an overdose of anesthetic, and the brain tissues were collected and Nissl-stained to observe nerve cell damage in the hippocampal CA1 area. In addition, TUNEL assay was performed to detect apoptosis. In the second experiment, animals were observed for 6h after ROSC. Blood samples and brain hippocampal tissues were collected, and differences in oxidative stress indicators were compared among the four groups. RESULTS: Intraperitoneal injection of H2 improved the 72-h survival rate and neurological scores, reduced neuronal injury and inhibited neuronal apoptosis. Intraperitoneal injection of H2 reduced oxidative stress indicators in the plasma and hippocampal tissues and enhanced antioxidant enzyme activity. No significant difference was observed between the two CA groups treated with different doses of H2. CONCLUSIONS: Intraperitoneal injection of H2 is a novel hydrogen administration method and can reduce cerebral ischemia-reperfusion injury and improve the prognosis of cardiopulmonary cerebral resuscitation in a rabbit model of CA. PMID- 23108243 TI - Temperature-dependent assemblies from a 2-D triple-stranded meso-helical layer to a 3-D chain-layer metal-organic framework. AB - Two different crystal forms, namely {[Dy2(mpda)3(H2O)2].H2O}n (1) and [Dy2(mpda)3(H2O)4]n (2), were obtained from the reaction of multidentate 2,6 dimethylpyridine-3,5-dicarboxylic acid (H2mpda) with Dy2O3 at different temperatures. Structural analysis reveals that compound 1 is a 2-D triple stranded meso-helical layer, and 2 a 3-D chain-layer framework. The fluorescent measure shows that compound 1 is a promising luminescent probe for various metals with a remarkable "on-off" switch of emission, mainly deriving from many pairs of inversely arranged 4-aza bowl-like crown ethers distributed in the 2-D helical plane. Moreover, compound 1 presents noticeable hydrogen-sorption at medium pressure. PMID- 23108244 TI - Inherent grading characteristics of individual pathologists contribute to clinically and prognostically relevant interobserver discordance concerning Broders' grading of penile squamous cell carcinomas. AB - INTRODUCTION: We assessed the reproducibility and prognostic impact of the Broders' grading system (BGS) in a cohort of 147 patients with surgically treated penile squamous cell carcinomas. MATERIALS AND METHODS: Conventionally stained histology slides were graded according to the BGS in two rounds by two study pathologists. Reproducibility was assessed using K statistics. Multivariable analyses were calculated to predict cancer-specific survival (CSS). The 'mean grade' per pathologist per round was calculated by allocating grade points to each study case (G1-G4: 1-4 points) and dividing the sum of all grade points by the number of cases examined. RESULTS: The BGS showed substantial interobserver variation (59-87% with K = 0.38-0.69) but almost perfect intraobserver reproducibility (91% with K = 0.86 and 96% with K = 0.94, respectively). The 'mean grade' per pathologist remained nearly constant in both rounds of examination (differences <=0.05 grade points) but differed between the two pathologists (up to 0.4 grade points). In multivariable analyses, the prognostic impact of the BGS in terms of CSS was strongly pathologist-dependent. CONCLUSIONS: Clinically and prognostically relevant interobserver discordance concerning the BGS seems, at least in part, to be attributable to inherent 'aggressive' versus 'reserved' grading characteristics of individual pathologists. PMID- 23108246 TI - Pituitary tumors. AB - PURPOSE OF REVIEW: The aim of this article is to review current research in the treatment of pituitary tumors and summarize emerging medical, surgical and radiation-based therapies. RECENT FINDINGS: Existing medical agents such as dopamine agonists and somatostatin ligand receptors are being used in novel combinations to achieve biochemical remission for pituitary tumors and reduce tumor size. Advancements have also been made in surgery to improve tumor localization by use of intraoperative imaging and to reduce morbidities, such as cerebrospinal fluid leak, associated with transsphenoidal surgery. Finally, as radiation therapy and stereotactic radiosurgery for pituitary tumors gains more widespread use, long-term data is becoming available demonstrating its durability. SUMMARY: Although current therapeutics and treatment modalities have been in practice for several years, new applications of existing treatments continue to be developed and have potential to improve care for patients with pituitary tumors. PMID- 23108247 TI - Brain metastasis: opportunity for drug development? AB - PURPOSE OF REVIEW: Brain metastases are a common clinical problem, and only limited treatment options exist. We review recent advances in medical brain metastasis research with a focus on the most common tumor types associated with secondary brain colonization: melanoma, breast cancer and lung cancer. We speculate on opportunities for drug development in patients with brain metastases, both as a treatment of established disease and as an adjuvant and prophylactic strategy. RECENT FINDINGS: BRAF inhibitors and the immunomodulatory anticytotoxic T-lymphocyte-associated antigen 4 antibody ipilimumab have shown clinically meaningful activity in melanoma patients with brain metastases. In breast cancer, current studies on drug treatment of brain metastases are mainly focusing on human epidermal growth factor receptor 2 targeting agents such as lapatinib. Emerging data seem to implicate a potential role of targeted agents including antiangiogenic compounds, pazopanib, and epithelial growth factor receptor inhibitors for prevention of brain metastasis formation in breast cancer or nonsmall cell lung cancer. SUMMARY: Novel drugs are beginning to enter clinical practice for selected patients with brain metastases. The promising findings from recent studies may fuel more research on brain metastases and their optimal drug treatment. PMID- 23108249 TI - Disruption of motor network connectivity post-stroke and its noninvasive neuromodulation. AB - PURPOSE OF REVIEW: We review the latest evidence for the neural underpinnings of hand motor function recovery after stroke with particular emphasis on how the latter can be enhanced by noninvasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS). RECENT FINDINGS: New data from longitudinal studies in which rTMS of the lesioned or contralesional motor cortex was combined with motor training showed ambiguous effects: some patients improved whereas others did not show any rTMS effect (compared with control stimulation). In contrast, novel studies using tDCS point to a more consistent effect on distal upper limb function, especially for inhibitory (cathodal) tDCS applied over contralesional M1. Neuroimaging data reveal that the effects of rTMS/tDCS on the functional architecture of the motor system depend upon lesion location, degree of impairment and number of treatment sessions. Furthermore, analyses of regional brain activity and motor network connectivity allow prediction of the behavioural effects of brain stimulation. SUMMARY: rTMS and tDCS can be used to modulate stroke-induced changes of motor network activity and connectivity thereby improving hand motor function. The interindividual variability in response to brain stimulation calls for the identification of treatment-associated surrogate markers, which may be provided by neuroimaging. PMID- 23108248 TI - How can investigation of network function inform rehabilitation after traumatic brain injury? AB - PURPOSE OF REVIEW: Traumatic brain injury (TBI) often results in long-term cognitive impairments. This is often due to the disruption of brain networks that support cognition. Major advances have recently been made in our understanding of these networks. Here we review work that investigates the effect of TBI on brain networks, and discuss the potential importance of these findings for rehabilitation. RECENT FINDINGS: Large-scale brain networks, which we refer to as intrinsic connectivity networks (ICNs), have been identified. Traumatic axonal injury disrupts their white-matter connections, and altered brain activity within the networks is frequently observed after TBI. These changes relate to the pattern of cognitive impairment, and are useful for predicting clinical outcome. The effect of drugs such as methylphenidate, which can be used to augment rehabilitation, are beginning to be studied in the context of their effect on network function after TBI. SUMMARY: The assessment of brain network function after TBI provides insights into the pathophysiology of cognitive dysfunction and the mechanisms involved in recovery. These advances should provide the basis for a more detailed understanding of rehabilitation, and ultimately guide the development of targeted individualized therapy after TBI. PMID- 23108250 TI - Neuroimaging insights into network-based neurodegeneration. AB - PURPOSE OF REVIEW: Convergent evidence from a number of neuroscience disciplines supports the hypothesis that Alzheimer's disease and other neurodegenerative disorders progress along brain networks. This review considers the role of neuroimaging in strengthening the case for network-based neurodegeneration and elucidating potential mechanisms. RECENT FINDINGS: Advances in functional and structural MRI have recently enabled the delineation of multiple large-scale distributed brain networks. The application of these network-imaging modalities to neurodegenerative disease has shown that specific disorders appear to progress along specific networks. Recent work applying theoretical measures of network efficiency to in-vivo network imaging has allowed for the development and evaluation of models of disease spread along networks. Novel MRI acquisition and analysis methods are paving the way for in-vivo assessment of the layer-specific microcircuits first targeted by neurodegenerative diseases. These methodological advances coupled with large, longitudinal studies of subjects progressing from healthy aging into dementia will enable a detailed understanding of the seeding and spread of these disorders. SUMMARY: Neuroimaging has provided ample evidence that neurodegenerative disorders progress along brain networks, and is now beginning to elucidate how they do so. PMID- 23108251 TI - Rehabilitation of executive function and social cognition impairments after brain injury. AB - PURPOSE OF REVIEW: Brain injury is a major cause of long-term disability. Executive and social cognition sequelae are associated with poor outcome. This review examines recent evidence on the efficacy of rehabilitation in these areas. RECENT FINDINGS: Accumulating evidence shows that interventions that work with patients on developing insight and strategies to offset executive impairments can produce significant benefits. Training of specific capacities, such as working memory, holds some promise, but more needs to be known about effect generalization. Evidence on social cognition rehabilitation following brain injury is sparse. Although there are some encouraging early results, more information on the clinical significance of change for everyday function is required. SUMMARY: Rehabilitation in these areas is inherently difficult but vital if outcomes are to improve. Significant gains have been reported, and further work applying appropriate methods is urgently required. PMID- 23108252 TI - Cellular mechanisms of protein aggregate propagation. AB - PURPOSE OF REVIEW: New research on the mechanisms of neurodegeneration highlights parallels between prion disease pathogenesis and other, more common disorders not typically thought to be infectious. This involves propagation of protein misfolding from cell to cell by templated conformational change. This review focuses on the cell biology that underlies propagation of protein aggregation between cells, including a discussion of protein biochemistry and relevant mouse models. RECENT FINDINGS: Like the prion protein, several other proteins exhibit self-propagating fibrillar conformations in vitro. Multiple cellular studies have now implicated endocytic mechanisms in the uptake of aggregates into cells. Aggregates that enter cells somehow escape endocytic vesicles to contact cytosolic protein. The mechanism of release of protein monomers and aggregates from cells is not well understood. Animal models have confirmed that brain lysates and purified protein can accelerate brain pathology in a manner similar to prions. SUMMARY: Aggregate flux in and out of cells likely contributes to the progression of neuropathology in neurodegenerative diseases. A better understanding of these mechanisms is emerging and can help explain local spread of protein aggregation and the role of neural networks in disease. This will also inform new therapeutic strategies aimed at blocking this process. PMID- 23108254 TI - Establishing a cell line from Atlantic cod as a novel tool for in vitro studies. AB - The present work describes the generation of a cell line from newly hatched Atlantic cod (Gadus morhua) larvae (ACL cells). Primary cultures were initiated by explant outgrowth from partially minced tissues and subcultured cells were exposed to UV radiation. After a substantial period of growth lag, cells started to proliferate and different growth conditions were tested to establish the cell line. At present, the ACL cell line has been subcultured for more than 100 passages. ACL cells had a polygonal shape and the morphology appeared homogenous with epithelial-like cells. Cell growth was dependent on the presence of foetal bovine serum and cells proliferated in a wide temperature range with optimal growth at 15 degrees C. By exposure to a viral dsRNA mimic (poly I:C) the cells expressed high levels of a repertoire of genes comprising both inflammatory mediators and interferon stimulated genes. Infection studies with two different viruses showed that infectious pancreatic necrosis virus (IPNV) propagated efficiently, and induced low level expression of genes of both pathways before the cells rapidly died. No productive infection was obtained with nervous necrosis virus (NNV), but a transient increase in the viral RNA level, followed by a high increase in expression of selected ISGs, suggests that the virus enters the cells but is unable to complete its replication cycle. To our knowledge, ACL cells are at the moment the only existing cell line from Atlantic cod. Our results demonstrate that ACL cells can be a useful research tool for further exploration of host-pathogen interactions and it is believed that this cell line will serve as a valuable tool also for studies within other research areas. PMID- 23108255 TI - Truncated VP28 as oral vaccine candidate against WSSV infection in shrimp: an uptake and processing study in the midgut of Penaeus monodon. AB - Several oral vaccination studies have been undertaken to evoke a better protection against white spot syndrome virus (WSSV), a major shrimp pathogen. Formalin-inactivated virus and WSSV envelope protein VP28 were suggested as candidate vaccine components, but their uptake mechanism upon oral delivery was not elucidated. In this study the fate of these components and of live WSSV, orally intubated to black tiger shrimp (Penaeus monodon) was investigated by immunohistochemistry, employing antibodies specific for VP28 and haemocytes. The midgut has been identified as the most prominent site of WSSV uptake and processing. The truncated recombinant VP28 (rec-VP28), formalin-inactivated virus (IVP) and live WSSV follow an identical uptake route suggested as receptor mediated endocytosis that starts with adherence of luminal antigens at the apical layers of gut epithelium. Processing of internalized antigens is performed in endo-lysosomal compartments leading to formation of supra-nuclear vacuoles. However, the majority of WSSV-antigens escape these compartments and are transported to the inter-cellular space via transcytosis. Accumulation of the transcytosed antigens in the connective tissue initiates aggregation and degranulation of haemocytes. Finally the antigens exiting the midgut seem to reach the haemolymph. The nearly identical uptake pattern of the different WSSV antigens suggests that receptors on the apical membrane of shrimp enterocytes recognize rec-VP28 efficiently. Hence the truncated VP28 can be considered suitable for oral vaccination, when the digestion in the foregut can be bypassed. PMID- 23108253 TI - The bacterial second messenger c-di-GMP: probing interactions with protein and RNA binding partners using cyclic dinucleotide analogs. AB - The ability of bacteria to adapt to a changing environment is essential for their survival. One mechanism used to facilitate behavioral adaptations is the second messenger signaling molecule bis-(3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP). c-di-GMP is widespread throughout the bacterial domain and plays a vital role in regulating the transition between the motile planktonic lifestyle and the sessile biofilm forming state. This second messenger also controls the virulence response of pathogenic organisms and is thought to be connected to quorum sensing, the process by which bacteria communicate with each other. The intracellular concentration of c-di-GMP is tightly regulated by the opposing enzymatic activities of diguanlyate cyclases and phosphodiesterases, which synthesize and degrade the second messenger, respectively. The change in the intracellular concentration of c-di-GMP is directly sensed by downstream targets of the second messenger, both protein and RNA, which induce the appropriate phenotypic response. This review will summarize our current state of knowledge of c-di-GMP signaling in bacteria with a focus on protein and RNA binding partners of the second messenger. Efforts towards the synthesis of c-di-GMP and its analogs are discussed as well as studies aimed at targeting these macromolecular effectors with chemically synthesized cyclic dinucleotide analogs. PMID- 23108256 TI - The VP37-binding protein F1ATP synthase beta subunit involved in WSSV infection in shrimp Litopenaeus vannamei. AB - To investigate the interaction between white spot syndrome virus (WSSV)-VP37 and gill membrane proteins (GMPs) of Pacific white shrimp (Litopenaeus vannamei), the VP37 protein was expressed and purified, and a distinct 53 kDa VP37-binding protein band was identified in GMPs by virus overlay protein binding assay and GST pull-down assay. By electroelution, the VP37 binding protein was purified and identified as F(1)ATP synthase beta (F(1)ATPase beta) subunit by Mass Spectrometry. The purified F(1)ATPase beta subunit was used to immunize BALB/C mice to produce monoclonal antibodies (Mabs). After cell fusion, sixteen hybridomas secreting Mabs against F(1)ATPase beta subunit of L. vannamei were screened by enzyme-linked immunosorbant assay (ELISA), three of which designated as 1D5, 1E8 and 2H4 were cloned by limiting dilution and further characterized by indirect immunofluorescence assay (IIFA) and western blotting. The results of IIFA showed that specific fluorescence signals located at the peripheral zone of the gills of L. vannamei. Western blotting demonstrated that three Mabs reacted specifically with the 53 kDa protein band in GMPs of L. vannamei. By IIFA, the Mabs could also cross-react with the gill cells of three other WSSV-susceptible shrimps Fenneropenaeus chinensis, Penaeus monodon and Marsupenaeus japonicus. Furthermore, the three anti-F(1)ATPase beta subunit Mabs could partially block the binding of WSSV to GMPs by ELISA in vitro, and also exhibited direct anti WSSV activity in shrimp by neutralization assay in vivo. These findings suggested that F(1)ATPase beta subunit involved in WSSV infection in L. vannamei. PMID- 23108257 TI - Cloning and characterization of the SpLRR cDNA from green mud crab, Scylla paramamosain. AB - Infectious diseases have seriously inhibited the aquaculture of mud crab Scylla paramamosain in southeastern China. Identification of the immune molecules and characterization of the defense mechanisms will be pivotal to the reduction of these diseases. Available data show that leucine-rich repeat (LRR) proteins play a crucial role in protein-protein interactions, recognition processes or immune reactions in both invertebrates and vertebrates. In the present study, we cloned and characterized a LRR cDNA from the mud crab Scylla paramamosain (SpLRR) by using the RACE strategy. Bioinformatics analysis predicted that SpLRR contains one open reading frame of 1893 bp and encodes a LRR protein of 630 amino acids with 17 LRR domains and 5 potential N-glycosylation sites. Further, SpLRR and other arthropod LRR proteins could be clustered into one branch in a phylogenetic tree. SpLRR transcripts were detected using RT-PCR from examined tissues including heart, gill, stomach, intestine, muscle and hemocytes, whereas not from hepatopancreas. More importantly, the SpLRR mRNA expression was up-regulated after infection with Vibrio alginolyticus, Beta streptococcus or Poly I: C for 12 48 h, suggesting a novel LRR homolog in crab might be associated with the resistance to pathogens. The result could be important for future investigation of crab immune defense mechanisms. PMID- 23108259 TI - Primitive neuroectodermal tumor of the kidney: a single-institute series of six patients from China. AB - OBJECTIVE: Renal primitive neuroectodermal tumor (PNET) is a rare and highly malignant neoplasm. Our study aims to present the clinical findings and prognosis of 6 patients with renal PNET from China. MATERIAL AND METHODS: From January 2003 to February 2012, 6 patients with renal PNET confirmed by immunohistochemical staining and fluorescence in situ hybridization (FISH) treated in our institution were reviewed retrospectively and our data compared with the literature. RESULTS: There were 4 male and 2 female patients with a mean age of 35.0 years. The mean diameter was 13.3 cm. Five of the masses had renal vein thrombosis, and 3 extended into the inferior vena cava. A lymph node metastasis was detected in 1 patient and a liver metastasis in another patient. Radical nephrectomy was performed in all cases, with 5 patients following chemotherapy and 1 receiving Sutent treatment. Within a median follow-up of 7.5 months (range 1-71), median overall survival was 22.1 months. CONCLUSIONS: The diagnosis of renal PNET should be considered in young patients presenting with renal mass and venous thrombosis. It seems that Asian renal PNET patients had a higher rate of venous thrombosis than Caucasian populations. CD99 positivity on immunohistochemistry and EWS-FL1 chimera gene detected by FISH support the diagnosis. The prognosis is poor despite multimodal treatment. PMID- 23108260 TI - A-Z of malignant peripheral nerve sheath tumors. AB - This article reviews the typical and atypical locations, imaging findings, local recurrence, and metastatic pattern of malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are rare soft tissue sarcomas, commonly occur in extremities, and are often associated with neurofibromatosis. Distinction between benign and malignant tumors can be challenging on imaging. MPNSTs have a poor prognosis; however, rhabdomyoblastic differentiation (malignant triton tumor), which has imaging features similar to MPNSTs, is associated with even more aggressive behavior. PMID- 23108258 TI - Epigenetic biomarkers of T-cells in human glioma. AB - Immune factors are thought to influence glioma risk and outcomes, but immune profiling studies to further our understanding of the immune response are limited by current immunodiagnostic methods. We developed a new assay to capture glioma immune biology based on quantitative methylation specific PCR (qMSP) of two T cell genes (CD3Z: T-cells, and FOXP3: Tregs). Flow cytometry of T-cells correlated well with the CD3Z demethylation assay (r = 0.93; p < 2.2 * 10 (-16) ), demonstrating the validity of the assay. Furthermore, there was a high correlation between qMSP and immunohistochemistry (IHC) in quantifying tumor infiltrating T-cells (r = 0.85; p = 3.4 * 10 (-11) ). Applying our qMSP methods to archival whole blood from 65 glioblastoma multiforme (GBM) cases and 94 non diseased controls, GBM cases had highly statistically significantly lower T-cells (p = 1.7 * 10 (-9) ) as well as Tregs (p = 5.2 * 10 (-11) ) and a modestly lower ratio of Tregs/T-cells (p = 0.024). Applying the methods to 120 excised glioma tumors, we observed that tumor infiltrating CD3+ T-cells were positively correlated with glioma tumor grade (p = 5.7 * 10 (-7) ), and that Tregs were enriched in tumors compared with peripheral blood indicating active chemoattraction of suppressive Tregs into the tumor compartment. Poorer patient survival was correlated with higher levels of tumor infiltrating T-cells (p = 0.01) and Tregs (p = 0.04). DNA methylation based immunodiagnostics represent a new generation of powerful laboratory tools offering many advantages over conventional methods that will facilitate large clinical epidemiologic studies and capitalize on stored archival blood and tissue banks. PMID- 23108261 TI - Characteristics of methylcellulose acid gel lesions created in human and bovine enamel. AB - Acid gel caries lesions were created in 3,100 human and bovine enamel specimens and studied with transverse microradiography. Small, significant differences were found. Human enamel lesions were found to be less demineralized, shallower, had a higher ratio of integrated mineral loss (DeltaZ) to lesion depth (L), a lower degree of surface zone mineralization (SZ(max)) and showed less variability than those in bovine enamel. SZ(max) showed the highest variability. Between tissues, L differed the most, DeltaZ the least. Biological variation within bovine enamel is perhaps not only bigger than previously assumed, it may also overshadow any structural and chemical differences between tissues. PMID- 23108262 TI - A novel orange-yellow-emitting Ba3Lu(PO4)3:Eu2+,Mn2+ phosphor with energy transfer for UV-excited white LEDs. AB - Eu(2+)-Mn(2+) codoped orange-yellow-emitting Ba(3)Lu(PO(4))(3) phosphors were synthesized by a solid-state reaction. The synthesis, structure refinement, and luminescence properties of the obtained phosphor were first investigated in detail. The crystal structure was refined with a split-atom model, where the oxygen atoms are distributed over two partially occupied sites. The refinement confirmed that BLuP:0.005Eu(2+),0.06Mn(2+) has a cubic unit cell with space group I43d (no. 220), cell parameters a = b = c = 10.4025 A and Z = 4. The luminescent properties reveal that the developed phosphor can efficiently convert UV photons in a broad range from 230 to 430 nm into orange-yellow emission. On the basis of the luminescence spectra and fluorescence decay curves, we confirm that the energy transfer process from the Eu(2+) to Mn(2+) ions takes place in the codoped Ba(3)Lu(PO(4))(3):Eu(2+),Mn(2+) phosphor, and the energy transfer efficiency increases with an increase in the Mn(2+) content. The possible energy transfer mechanism was proposed in terms of the experimental results and analysis. In particular, our developed phosphor contains a larger amount of the red-emitting component, compared with the commercial YAG:Ce phosphor, possessing favorable properties for application in warm white LEDs with low correlated color temperature. PMID- 23108263 TI - Lifesaving, delayed deaths and cure in mortality modeling. AB - We generalize the lifesaving model to the case when the probability of lifesaving depends on the number of lifesavings in the past. We also suggest a new approach to analyzing the shape of mortality rates based on considering delays in deaths (and possible cure afterwards) which results in the decline of mortality rates. The derived lifetime distribution and the corresponding mortality rate can be used for a more flexible statistical analysis of mortality data. PMID- 23108264 TI - Oral anticoagulation and the risk of vitreous hemorrhage and retinal tears in eyes with acute posterior vitreous detachment. AB - PURPOSE: To determine if oral anticoagulation alters the association between vitreous hemorrhage (VH) and retinal tears in eyes with acute, posterior vitreous detachment (PVD). METHODS: In this retrospective chart review, the complete records of consecutive patients with spontaneous, symptomatic acute PVD from a single referral-based practice were reviewed. The use of oral anticoagulants, the presence of a VH, and the presence of a retinal tear or detachment were recorded. RESULTS: A total of 336 consecutive eligible patients (336 eyes) were included in the final analysis. Vitreous hemorrhage occurred in 118 (35%) eyes; in 43% of patients taking aspirin, clopidogrel, or warfarin versus 31% not taking these medications (P = 0.03). Retinal tears occurred in 46% of patients with VH versus 27% of patients without VH (P = 0.0007). Retinal tears occurred in 39% of patients with VH taking aspirin, clopidogrel, or warfarin compared with 52% of patients not taking these medications. (P = 0.20) A decreased proportion of patients with acute PVD taking one or more of the oral anticoagulant medications studied, regardless of the presence of VH, were diagnosed with a retinal tear (P = 0.0017) or retinal detachment (P = 0.0001). CONCLUSION: Retinal tears are commonly found (46%) in the eyes of patients who present with symptoms and signs of acute PVD and VH. Patients taking aspirin, clopidogrel, or warfarin who develop an acute PVD are more likely to present with VH. No statistically significant association was demonstrated between the use of oral anticoagulants in patients with acute PVD and VH and the presence of retinal tears or retinal detachment. PMID- 23108266 TI - Directional self-assembly of rare-earth hydroxocation nanosheets and paradodecatungstate anions. AB - Simply mixing layered rare-earth hydroxide colloidal solutions and paratungstate solution at pH > 7 led to directional self-assembly of rare-earth hydroxide nanosheets and paradodecatungstates. These hybrids exhibit efficient energy transfer from the OMCT band to rare-earth ions in the hydroxide layers as well as highly enhanced f-f transitions. PMID- 23108268 TI - Synthesis and evaluation of M. tuberculosis salicylate synthase (MbtI) inhibitors designed to probe plasticity in the active site. AB - Mycobacterium tuberculosis salicylate synthase (MbtI) catalyses the first committed step in the biosynthesis of mycobactin T, an iron-chelating siderophore essential for the virulence and survival of M. tuberculosis. Co-crystal structures of MbtI with members of a first generation inhibitor library revealed large inhibitor-induced rearrangements within the active site of the enzyme. This plasticity of the MbtI active site was probed via the preparation of a library of inhibitors based on a 2,3-dihydroxybenzoate scaffold with a range of substituted phenylacrylate side chains appended to the C3 position. Most compounds exhibited moderate inhibitory activity against the enzyme, with inhibition constants in the micromolar range, while several dimethyl ester variants possessed promising anti tubercular activity in vitro. PMID- 23108269 TI - Primary motor cortex and cerebellum are coupled with the kinematics of observed hand movements. AB - To find out in which detail the kinematics of observed movements is represented in the viewer's brain, we searched for brain areas displaying coherent magnetoencephalographic (MEG) activity with observed repetitive hand movements. Whole-scalp MEG signals were recorded from 10 right-handed young adults who observed repetitive 3-Hz right-hand flexion-extension movements performed by the experimenter. The coherence between the subject's MEG signals and the experimenter's index-finger acceleration was computed to index the level of actor observer coupling. The underlying cortical activity was identified with Dynamic Imaging of Coherent Sources. In all subjects, coherence spectra showed statistically significant peaks at movement frequency (F0) and its first harmonic (F1), strongest at visual areas. At F0, additional significant local coherence maxima, clearly distinct from the coherent visual areas, occurred in the primary motor (M1) cortices of both hemispheres and in the cerebellum (posterior vermis and hemispheres). Our results highlight the time-sensitive involvement of the M1 cortices and cerebellum in the kinematic representation of observed repetitive, non-goal directed motor actions. PMID- 23108270 TI - Neuromagnetic brain activity associated with anticipatory postural adjustments for bimanual load lifting. AB - During bimanual load lifting, the brain must anticipate the effects of unloading upon the load-bearing arm. Little is currently known about the neural networks that coordinate these anticipatory postural adjustments. We measured neuromagnetic brain activity with whole-head magnetoencephalography while participants performed a bimanual load-lifting task. Anticipatory adjustments were associated with reduction in biceps brachii muscle activity of the load bearing arm and pre-movement desynchronization of the cortical beta rhythm. Beamforming analyses localized anticipatory brain activity to the precentral gyrus, basal ganglia, supplementary motor area, and thalamus, contralateral to the load-bearing arm. To our knowledge this is the first human neuroimaging study to directly investigate anticipatory postural adjustments and to explicitly partition the anticipatory and volitional aspects of brain activity in bimanual load lifting. These data contribute to our understanding of the neural systems supporting anticipatory postural adjustments in healthy adults. PMID- 23108271 TI - Neural correlates of sound externalization. AB - When we listen to sounds through headphones without utilizing special transforms, sound sources seem to be located inside our heads. The sound sources are said to be lateralized to one side or the other to varying degree. This internal lateralization is different than sound source localization in the natural environment in which the sound is localized distal to the head. We used fMRI to investigate difference in neural responses between lateralization and localization. Individualized binaural recordings were used as externalized auditory stimuli and stereo recordings were used as internalized auditory stimuli. Brain activity was measured while 14 participants performed an active auditory localization task and while 12 participants performed a stimulus type identification task. Irrespective of the task condition, we observed enhanced activity in the bilateral posterior temporal gyri (pSTG) for the externalized stimuli relative to the internalized stimuli. Region of interest analysis indicated that both left and right pSTG were more sensitive to sound sources in contra- than ipsilateral hemifields. Moreover, greater back than front activity was also found in the left pSTG. Compared to impoverished spatial auditory stimuli, realistic spatial auditory stimuli enhance neural responses in the pSTG. This may be why we could observe contralateral hemifield preference in bilateral pSTG that many previous studies have failed to observe. Overall, the results indicate the importance of using ecologically valid stimuli for investigating neural processes in human cortex. PMID- 23108272 TI - Individual differences in left parietal white matter predict math scores on the Preliminary Scholastic Aptitude Test. AB - Mathematical skills are of critical importance, both academically and in everyday life. Neuroimaging research has primarily focused on the relationship between mathematical skills and functional brain activity. Comparatively few studies have examined which white matter regions support mathematical abilities. The current study uses diffusion tensor imaging (DTI) to test whether individual differences in white matter predict performance on the math subtest of the Preliminary Scholastic Aptitude Test (PSAT). Grades 10 and 11 PSAT scores were obtained from 30 young adults (ages 17-18) with wide-ranging math achievement levels. Tract based spatial statistics was used to examine the correlation between PSAT math scores, fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD). FA in left parietal white matter was positively correlated with math PSAT scores (specifically in the left superior longitudinal fasciculus, left superior corona radiata, and left corticospinal tract) after controlling for chronological age and same grade PSAT critical reading scores. Furthermore, RD, but not AD, was correlated with PSAT math scores in these white matter microstructures. The negative correlation with RD further suggests that participants with higher PSAT math scores have greater white matter integrity in this region. Individual differences in FA and RD may reflect variability in experience dependent plasticity over the course of learning and development. These results are the first to demonstrate that individual differences in white matter are associated with mathematical abilities on a nationally administered scholastic aptitude measure. PMID- 23108274 TI - The overlap of the EBA and the MT/V5 cluster. AB - The extrastriate body area (EBA) is located in the lateral occipito-temporal cortex, in the vicinity of the motion-sensitive region hMT/V5+. To investigate the relationship of EBA to the recently mapped retinotopic areas of the MT/V5 cluster (Kolster et al., 2010), we evaluated the proportion of voxels responsive to the presentation of static human bodies (EBA voxels) in each of the four areas of the MT/V5 cluster and neighboring LO and phPIT areas. We evaluated this proportion as both a function of the number of voxels in a given area and the total number of voxels in a broader lateral occipito-temporal cortex (LOTC) ROI. We observed that each of the four retinotopic areas of the MT/V5 cluster includes substantial fractions of EBA voxels, in contrast to the LO and phPIT areas. This proportion was slightly greater in the right than left hemisphere, and did not depend on the control condition. While most EBA voxels in MT/V5 were only body sensitive, those in pMSTv and pFST were also motion-sensitive. The main locus of EBA voxels outside the MT/V5 cluster was in the LOTC cortex just rostral to the MT/V5 cluster. Although this region contained more EBA voxels than the MT/V5 cluster, the proportion as a function of areal size was much reduced compared to the MT/V5 cluster. Our results show that EBA is not a single cortical area as EBA voxels are located in all four areas of the MT/V5 cluster, and that body sensitivity is a key feature of the MT/V5 cluster, in keeping with its exquisite sensitivity to observed actions of others. PMID- 23108273 TI - The effects of altered intrathoracic pressure on resting cerebral blood flow and its response to visual stimulation. AB - Investigating how intrathoracic pressure changes affect cerebral blood flow (CBF) is important for a clear interpretation of neuroimaging data in patients with abnormal respiratory physiology, intensive care patients receiving mechanical ventilation and in research paradigms that manipulate intrathoracic pressure. Here, we investigated the effect of experimentally increased and decreased intrathoracic pressures upon CBF and the stimulus-evoked CBF response to visual stimulation. Twenty healthy volunteers received intermittent inspiratory and expiratory loads (plus or minus 9cmH2O for 270s) and viewed an intermittent 2Hz flashing checkerboard, while maintaining stable end-tidal CO2. CBF was recorded with transcranial Doppler sonography (TCD) and whole-brain pseudo-continuous arterial spin labeling magnetic resonance imaging (PCASL MRI). Application of inspiratory loading (negative intrathoracic pressure) showed an increase in TCD measured CBF of 4% and a PCASL-measured increase in grey matter CBF of 5%, but did not alter mean arterial pressure (MAP). Expiratory loading (positive intrathoracic pressure) did not alter CBF, while MAP increased by 3%. Neither loading condition altered the perfusion response to visual stimulation in the primary visual cortex. In both loading conditions localized CBF increases were observed in the somatosensory and motor cortices, and in the cerebellum. Altered intrathoracic pressures, whether induced experimentally, therapeutically or through a disease process, have possible significant effects on CBF and should be considered as a potential systematic confound in the interpretation of perfusion based neuroimaging data. PMID- 23108275 TI - Neural correlates of prosocial behavior in infancy: different neurophysiological mechanisms support the emergence of helping and comforting. AB - The present study examined the neural processes related to different forms of prosocial behavior in infancy by means of a longitudinal study. At 14months, infants' resting state brain activation asymmetries were assessed by means of EEG. At 18months, we examined infants' instrumental helping, and at 24months infants' behavior in a comforting task. Behavioral analyses revealed a negative relation between infants' performances in the helping and comforting task. The EEG analysis showed that distinct neural patterns were related to each task. Greater left frontal cortical activation was associated with infants' understanding of the other's distress as well as empathic responding in the comforting task, whereas greater right temporal activation was related to infants' instrumental helping. These findings reveal the neural correlates of the earliest forms of prosocial action and show that different neurophysiological activation patterns are related to the emergence of instrumental helping and comforting in early development. PMID- 23108276 TI - Complementary attentional components of successful memory encoding. AB - Attention during encoding improves later memory, but how this happens is poorly understood. To investigate the role of attention in memory formation, we combined a variant of a spatial attention cuing task with a subsequent memory fMRI design. Scene stimuli were presented in the periphery to either the left or right of fixation, preceded by a central face cue whose gaze oriented attention to the probable location of the scene. We contrasted activity for scenes appearing in cued versus uncued locations to identify: (1) regions where cuing facilitated processing, and (2) regions involved in reorienting. We then tested how activity in these facilitation and reorienting regions of interest predicted subsequent long-term memory for individual scenes. In facilitation regions such as parahippocampal cortex, greater activity during encoding predicted memory success. In reorienting regions such as right temporoparietal junction, greater activity during encoding predicted memory failure. We interpret these results as evidence that memory formation benefits from attentional facilitation of perceptual processing combined with suppression of the ventral attention network to prevent reorienting to distractors. PMID- 23108277 TI - A non-linear mixed effect modelling approach for metabolite correction of the arterial input function in PET studies. AB - Quantitative PET studies with arterial blood sampling usually require the correction of the measured total plasma activity for the presence of metabolites. In particular, if labelled metabolites are found in the plasma in significant amounts their presence has to be accounted for, because it is the concentration of the parent tracer which is required for data quantification. This is achieved by fitting a Parent Plasma fraction (PPf) model to discrete metabolite measurements. The commonly used method is based on an individual approach, i.e. for each subject the PPf model parameters are estimated from its own metabolite samples, which are, in general, sparse and noisy. This fact can compromise the quality of the reconstructed arterial input functions, and, consequently, affect the quantification of tissue kinetic parameters. In this study, we proposed a Non Linear Mixed Effect Modelling (NLMEM) approach to describe metabolite kinetics. Since NLMEM has been developed to provide robust parameter estimates in the case of sparse and/or noisy data, it has the potential to be a reliable method for plasma metabolite correction. Three different PET datasets were considered: [11C] (+)-PHNO (54 scans), [11C]-PIB (22 scans) and [11C]-DASB (30 scans). For each tracer both simulated and measured data were considered and NLMEM performance was compared with that provided by individual analysis. Results showed that NLMEM provided improved estimates of the plasma parent input function over the individual approach when the metabolite data were sparse or contained outliers. PMID- 23108279 TI - Microautophagy in the visceral endoderm is essential for mouse early development. AB - During early embryogenesis, before the conceptus forms the placenta, maternal nutrients as well as signaling molecules must reach the embryo proper through a tightly sealed epithelial tissue, the visceral endoderm (VE). The VE serves as a signaling center for embryogenesis, where exocytic and endocytic processes integrate signal production, perception and termination. However, the endocytic process in this important tissue has not been well characterized. We show that endocytic delivery to the lysosomes occurs via RAB7-dependent microautophagy. This process is essential for early mammalian development. PMID- 23108280 TI - Afferent pathways arising from the lower urinary tract after complete spinal cord injury or cauda equina lesion: clinical observations with neurophysiological implications. AB - BACKGROUND: Afferents from the urinary tract transmit bladder sensations to the central nervous system. Spinal cord injury (SCI) may affect both efferent motor and afferent sensory pathways. Presence/absence of bladder sensations in patients with complete spinal cord, conus or cauda equina lesions was compared with neurologically unimpaired patients. METHODS: During urodynamics, bladder sensations were studied and compared in 59 patients: 21 patients with complete SCI below T6 and above Th12, 7 patients with a complete lesion of the conus medullaris, 11 patients with a complete lesion of the cauda equina, and 20 patients without neurological deficit. RESULTS: Two of 7 patients with complete conus lesion had a preserved filling sensation. Ten of 11 patients with complete lesion of the cauda equina reported a bladder filling sensation. Sensations are perceived at a similar pressure threshold but at a higher volume threshold. CONCLUSIONS: In patients with a complete cauda or a lower conus lesion, a sensory input from the bladder is preserved. These findings imply that the preserved bladder filling sensation in complete cauda or lower conus lesions is possibly transferred through the intact hypogastric plexus to the thoracolumbar segments of the spinal cord. PMID- 23108278 TI - Three-way (N-way) fusion of brain imaging data based on mCCA+jICA and its application to discriminating schizophrenia. AB - Multimodal fusion is an effective approach to better understand brain diseases. However, most such instances have been limited to pair-wise fusion; because there are often more than two imaging modalities available per subject, there is a need for approaches that can combine multiple datasets optimally. In this paper, we extended our previous two-way fusion model called "multimodal CCA+joint ICA", to three or N-way fusion, that enables robust identification of correspondence among N data types and allows one to investigate the important question of whether certain disease risk factors are shared or distinct across multiple modalities. We compared "mCCA+jICA" with its alternatives in a 3-way fusion simulation and verified its advantages in both decomposition accuracy and modal linkage detection. We also applied it to real functional Magnetic Resonance Imaging (fMRI)-Diffusion Tensor Imaging (DTI) and structural MRI fusion to elucidate the abnormal architecture underlying schizophrenia (n=97) relative to healthy controls (n=116). Both modality-common and modality-unique abnormal regions were identified in schizophrenia. Specifically, the visual cortex in fMRI, the anterior thalamic radiation (ATR) and forceps minor in DTI, and the parietal lobule, cuneus and thalamus in sMRI were linked and discriminated between patients and controls. One fMRI component with regions of activity in motor cortex and superior temporal gyrus individually discriminated schizophrenia from controls. Finally, three components showed significant correlation with duration of illness (DOI), suggesting that lower gray matter volumes in parietal, frontal, and temporal lobes and cerebellum are associated with increased DOI, along with white matter disruption in ATR and cortico-spinal tracts. Findings suggest that the identified fractional anisotropy changes may relate to the corresponding functional/structural changes in the brain that are thought to play a role in the clinical expression of schizophrenia. The proposed "mCCA+jICA" method showed promise for elucidating the joint or coupled neuronal abnormalities underlying mental illnesses and improves our understanding of the disease process. PMID- 23108283 TI - Rhodium-NHC complexes mediate diboration versus dehydrogenative borylation of cyclic olefins: a theoretical explanation. AB - In rhodium catalysed borylation of cyclic olefins, the synergy between bidentate NHC ligands, that modify cationic Rh(I) species, and the use of non-polar solvents, such as cyclohexane, is the key factor to favour a less energetically demanding route towards the formation of diborated products versus allyl boronate esters. PMID- 23108282 TI - Effect of dialyzed saliva on human enamel demineralization. AB - BACKGROUND: Saliva is supersaturated with respect to calcium and phosphate ions. Salivary ions may well play a role in the subsequent adsorption of proteins and consequently in the formation of the acquired enamel pellicle. Among several biological functions, the enamel pellicle forms a selectively permeable barrier that regulates demineralization processes. AIM: The aim of this study was to evaluate the importance of salivary proteins when adsorbed on enamel surface and the resultant protective effect against demineralization without the presence of salivary ions. METHODS: Enamel surfaces were coated with whole saliva, parotid saliva, dialyzed whole saliva or dialyzed parotid saliva (molecular weight cutoff 1 kDa). Adsorption was allowed to proceed for a period of 2 h. Enamel specimens were then washed with deionized water and immersed into a demineralization solution of pH 4.5 for 12 days. This solution was used to measure the amount of calcium and phosphate released from enamel specimens after the demineralization period. RESULTS: All coated specimen groups showed a significantly higher protection than those not coated with any type of saliva. In addition, undialyzed saliva (whole saliva and parotid saliva) was more effective in protecting the enamel against demineralization than dialyzed saliva. CONCLUSION: The present investigation indicates that the ionic composition of saliva can amplify the demineralization protection effect by reducing acid-induced enamel demineralization. Moreover, a protective effect of salivary proteins without presence of ions was demonstrated in this study. PMID- 23108284 TI - Time-series analyses of air pollution and mortality in the United States: a subsampling approach. AB - BACKGROUND: Hierarchical Bayesian methods have been used in previous papers to estimate national mean effects of air pollutants on daily deaths in time-series analyses. OBJECTIVES: We obtained maximum likelihood estimates of the common national effects of the criteria pollutants on mortality based on time-series data from <= 108 metropolitan areas in the United States. METHODS: We used a subsampling bootstrap procedure to obtain the maximum likelihood estimates and confidence bounds for common national effects of the criteria pollutants, as measured by the percentage increase in daily mortality associated with a unit increase in daily 24-hr mean pollutant concentration on the previous day, while controlling for weather and temporal trends. We considered five pollutants [PM10, ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2)] in single- and multipollutant analyses. Flexible ambient concentration response models for the pollutant effects were considered as well. We performed limited sensitivity analyses with different degrees of freedom for time trends. RESULTS: In single-pollutant models, we observed significant associations of daily deaths with all pollutants. The O3 coefficient was highly sensitive to the degree of smoothing of time trends. Among the gases, SO2 and NO2 were most strongly associated with mortality. The flexible ambient concentration-response curve for O3 showed evidence of nonlinearity and a threshold at about 30 ppb. CONCLUSIONS: Differences between the results of our analyses and those reported from using the Bayesian approach suggest that estimates of the quantitative impact of pollutants depend on the choice of statistical approach, although results are not directly comparable because they are based on different data. In addition, the estimate of the O3-mortality coefficient depends on the amount of smoothing of time trends. PMID- 23108285 TI - Design and use of performance measures to decrease low-value services and achieve cost-conscious care. AB - Improving quality of care while decreasing the cost of health care isa national priority. The American College of Physicians recently launched its High-Value Care Initiative to help physicians and patients understand the benefits, harms, and costs of interventions and to determine whether services provide good value. Public and private payers continue to measure underuse of high-value services(for example, preventive services, medications for chronic disease),but they are now widely using performance measures to assess use of low-value interventions (such as imaging for patients with uncomplicated low back pain) and using the results for public reporting and pay-for-performance. This paper gives an overview of performance measures that target low-value services to help physicians understand the strengths and limitations of these measures,provides specific examples of measures that assess use of low-value services, and discusses how these measures can be used in clinical practice and policy. PMID- 23108286 TI - The value of advocacy in obstetrics and maternal-fetal medicine. AB - PURPOSE OF REVIEW: To show that advocacy on behalf of an individual or organization has improved the practice of obstetrics and maternal-fetal medicine. RECENT FINDINGS: Advocacy by an individual or a large group aims to influence public policy and resource allocation decisions within political, economic, and social systems and institutions. For obstetrician-gynecologists and maternal fetal medicine physicians, there is a health policy medical practice intersection that may be often overlooked. In the areas of research, reimbursement, federal policies surrounding maternity care, and quality improvement, physician leaders have influenced the policymaking process and can improve upon it in the future. SUMMARY: Because of advocacy efforts by organizations whose members may include physicians and patients, pregnant women will have access to better quality of care, and physicians will be better off. Also, quality measures that will be implemented will make sense to those who must comply with them because of expert involvement. Advocacy is an investment for the future of the practice of obstetrics and maternal-fetal medicine - to ensure that the workforce is strengthened and that the care of women and their babies is the best it can be. PMID- 23108287 TI - Healthcare management strategies: interdisciplinary team factors. AB - PURPOSE OF REVIEW: Interdisciplinary team factors are significant contributors to clinical performance and associated patient outcomes. Quality of care and patient safety initiatives identify human factors associated with team performance as a prime improvement area for clinical patient care. RECENT FINDINGS: The majority of references to interdisciplinary teams in obstetrics and gynecology in the literature recommends the use of multidisciplinary approaches when managing complex medical cases. The reviewed literature suggests that interdisciplinary team development is important for achieving optimally efficient and effective performance; however, few reports provide specific recommendations for how to optimally achieve these objectives in the process of providing interdisciplinary care to patients. The absence of these recommendations presents a significant challenge for those tasked with improving team performance in the workplace. The prescribed team development programs cited in the review are principally built around communication strategies and simulation-based training mechanisms. Few reports provide descriptions of optimal team-based competencies in the various contexts of obstetric and gynecology teams. However, team-based evaluation strategies and empirical data documenting the transfer of team training to applied clinical care are increasing in number and quality. SUMMARY: Our findings suggest that research toward determining team factors that promote optimal performance in applied clinical practice requires definition of specific competencies for the variable teams serving obstetrics and gynecology. PMID- 23108288 TI - The role of nitrates in the prevention of preeclampsia: an update. AB - PURPOSE OF REVIEW: Defective nitric oxide synthesis and nitric oxide-mediated vasodilatation is widely documented in the pathophysiology of preeclampsia, a leading cause of maternal and perinatal morbidity and mortality worldwide. Several studies demonstrated the beneficial role of nitric oxide agents, especially glyceryl trinitrate and L-arginine in reducing the blood pressure and improving the uteroplacental blood flow velocities. However, there is insufficient evidence on the efficacy and safety of these agents in the prevention of preeclampsia and its complications, as there are very few randomized controlled trials with small number of women. The aim of this review is to summarize and evaluate the role of nitrates in the prevention of preeclampsia based on the available evidence in the literature till date and suggestions for future research. RECENT FINDINGS: Supplementation with L-arginine and antioxidant vitamins reduced the incidence of preeclampsia in women at high risk of preeclampsia [P < 0.001, absolute risk reduction 0.17 (confidence interval 0.12-0.21)]. SUMMARY: On the basis of the recent evidence, nitric oxide agents may be beneficial in the prevention of preeclampsia. Randomized controlled trials initiated in the first trimester and using long-acting nitrates are needed in high-risk women to validate these findings. PMID- 23108289 TI - Research and clinical applications of cancer genome sequencing. AB - PURPOSE OF REVIEW: To highlight the recent advances in cancer genome research and its clinical applications made possible by next-generation sequencing (NGS), with particular emphasis on gynecological and breast cancers is the purpose of the review. RECENT FINDINGS: Through advances in NGS technologies, whole-exome sequencing and whole-genome sequencing (WGS) have been performed on various cancers, identifying in the process numerous recurrent mutations and highly mutated genes. These cancers include uterine serous carcinomas, high-grade serous ovarian adenocarcinomas and breast cancer. In contrast to identifying somatic mutations in sporadic cancers, a far smaller number of studies using NGS have been conducted to identify new causal mutations or genes for hereditary cancer syndromes. In addition to research discovery, diagnostic applications of NGS have also become increasingly evident. Thus, WGS has been applied in a diagnostic context to identify a complex chromosomal rearrangement in a patient with acute myeloid leukemia of unclear subtype. Similarly, the targeted sequencing of panels of known cancer genes using NGS has demonstrated its robustness in the context of identifying known pathological mutations. SUMMARY: The research and clinical applications of cancer genome sequencing have progressed at an unprecedented pace over the last few years, and this promises to be accelerated with new developments of high-throughput NGS technologies and robust analytical tools. PMID- 23108290 TI - Antibiotic resistance genes in anaerobic bacteria isolated from primary dental root canal infections. AB - Fourty-one bacterial strains isolated from infected dental root canals and identified by 16S rRNA gene sequence were screened for the presence of 14 genes encoding resistance to beta-lactams, tetracycline and macrolides. Thirteen isolates (32%) were positive for at least one of the target antibiotic resistance genes. These strains carrying at least one antibiotic resistance gene belonged to 11 of the 26 (42%) infected root canals sampled. Two of these positive cases had two strains carrying resistance genes. Six out of 7 Fusobacterium strains harbored at least one of the target resistance genes. One Dialister invisus strain was positive for 3 resistance genes, and 4 other strains carried two of the target genes. Of the 6 antibiotic resistance genes detected in root canal strains, the most prevalent were blaTEM (17% of the strains), tetW (10%), and ermC (10%). Some as-yet-uncharacterized Fusobacterium and Prevotella isolates were positive for blaTEM, cfxA and tetM. Findings demonstrated that an unexpectedly large proportion of dental root canal isolates, including as-yet uncharacterized strains previously regarded as uncultivated phylotypes, can carry antibiotic resistance genes. PMID- 23108291 TI - Mechanisms and prospects of food protein hydrolysates and peptide-induced hypolipidaemia. AB - Hyperlipidaemia is an important risk factor for developing cardiovascular disease, a leading global health issue. While pharmaceutical interventions have proved efficacious in acute conditions, many hypolipidaemic drugs are known to induce adverse side effects. Due to a strong positive link between functional food components and human health, emerging research has explored the application of natural food-based strategies in disease management. One of such strategies involves the use of food proteins as precursors of peptides with a wide variety of beneficial health functions. Some plant, animal and marine-derived protein hydrolysates and peptides have shown promising hypolipidaemic properties when evaluated in vitro, in cultured mammalian cells and animal models. The products exert their functions via bile acid-binding and disruption of cholesterol micelles in the gastrointestinal tract, and by altering hepatic and adipocytic enzyme activity and gene expression of lipogenic proteins, which can modulate aberrant physiological lipid profiles. The activity of the protein hydrolysates and peptides depends on their physicochemical properties including hydrophobicity of amino acid residues but there is knowledge gap on detailed structure-function relationships and efficacy in hyperlipidaemic human subjects. Based on the prospects, commercial functional food products containing hypolipidaemic peptides have been developed for enhancement of cardiovascular health. PMID- 23108292 TI - Mitochondrial HSP90s and tumor cell metabolism. AB - The control of protein homeostasis, or proteostasis, has been traditionally viewed through the lenses of a general housekeeping function that all cells need, regardless of pathway specification or link to defined cellular responses. A more updated perspective considers proteostasis as an essential adaptive mechanism, taking place in specialized subcellular organelles, and maintaining the functionality of defined cellular networks. Fresh experimental evidence now identifies heat shock protein 90 (HSP90) chaperones as pivotal regulators of proteostasis in mitochondria, selectively in tumor cells. This function connects to a global network of cellular compensation, linking autophagy, endoplasmic reticulum (ER) stress and metabolic reprogramming in a single adaptive continuum, and offers prime opportunities for novel cancer therapeutics. PMID- 23108294 TI - Three-dimensional graphene-polypyrrole hybrid electrochemical actuator. AB - The advancement of mechanical actuators benefits from the development of new structural materials with prominent properties. A novel three-dimensional (3D) hydrothermally converted graphene and polypyrrole (G-PPy) hybrid electrochemical actuator is presented, which is prepared via a convenient hydrothermal process, followed by in situ electropolymerization of pyrrole. The 3D pore-interconnected G-PPy pillar exhibits strong actuation responses superior to pure graphene and PPy film. In response to the low potentials of +/-0.8 V, the saturated strain of 3D G-PPy pillar can reach a record of 2.5%, which is more than 10 times higher than that of carbon nanotube film and about 3 times that of unitary graphene film under an applied potential of +/-1.2 V. Also, the 3D G-PPy actuator exhibits high actuation durability with high operating load as demonstrated by an 11 day continuous measurement. Finally, a proof-of-concept application of 3D G-PPy as smart filler for on/off switch is also demonstrated, which indicates the great potential of the 3D G-PPy structure developed in this study for advanced actuator systems. PMID- 23108293 TI - Total ginsenosides of Radix Ginseng modulates tricarboxylic acid cycle protein expression to enhance cardiac energy metabolism in ischemic rat heart tissues. AB - To elucidate the underlying mechanism of cardio-protective activity of the total ginsenosides (TGS) of Radix Ginseng, proteomic analysis using two-dimensional gel electrophoresis (2-DE) and MALDI-TOF-TOF-MS techniques was employed for identifying the underlying targets of TGS on improvement of the energy metabolism of isolated rat heart tissues perfused in Langendorff system under ischemia reperfusion injury conditions. The image analysis results revealed 11 differentially expressed proteins in the TGS-treated heart tissues; these proteins, including LDHB and ODP-2, were found to be closely related to the function of tricarboxylic acid (TCA) cycle that plays pivotal roles in cardiac energy metabolism. It is thus concluded that improvement of cardiac energy metabolism via activating proteins in TCA cycle could be the major action pathway and targets of TGS activity against rat heart tissue injury. PMID- 23108295 TI - Quantitative DEMS study of ethanol oxidation: effect of surface structure and Sn surface modification. AB - Using the dual thin layer flow through cell, a semi-quantitative analysis of the volatile products during the electrooxidation of adsorbed and bulk solution of 0.01 M ethanol at polycrystalline platinum, smooth, roughened and Sn modified Pt(11,1,1), Pt(311) electrodes has been done by on-line differential electrochemical mass spectroscopy (DEMS). In addition to the current efficiency of CO(2), that of acetaldehyde was determined as a function of the flow rate. At polycrystalline platinum, ethanol oxidation produces only acetaldehyde; the amount of acetaldehyde further oxidized to acetic acid is negligible due to convection conditions. For comparison and for calibration purposes, i-propanol oxidation was examined for which acetone is the only oxidation product. At Pt(11,1,1), the main oxidation product is acetaldehyde. At Pt(311), in addition to acetaldehyde, acetic acid was also formed. Surface modification with Sn did not increase the reactivity of Pt(11,1,1) instead it led to inhibition of the ethanol oxidation. In the case of Pt(311), the onset potential of oxidation was shifted negatively by 0.2 V in the presence of Sn. The results of the potentiostatic measurements showed that this shift is not associated with the production of CO(2); rather acetic acid and acetaldehyde are the main oxidation products. PMID- 23108296 TI - Insight into the channel ion distribution and influence on the lithium insertion properties of hexatitanates A2Ti6O13 (A = Na, Li, H) as candidates for anode materials in lithium-ion batteries. AB - Li(2)Ti(6)O(13) and H(2)Ti(6)O(13) were easily synthesized from Na(2)Ti(6)O(13) by successive Na(+)-Li(+)-H(+) ion exchange. The crystal structures of Na(2)Ti(6)O(13), Li(2)Ti(6)O(13) and H(2)Ti(6)O(13) were investigated using neutron powder diffraction. Monovalent A(+) cations (Na, Li and H) have been located using difference Fourier analysis. Although monoclinic lattice parameters (space group C2/m) of the three titanates remain almost unchanged with retention of the basic [Ti(6)O(13)(2-)] network, monovalent Na, Li and H cations occupy different sites in the tunnel space. By comparing the structural details concerning the A(+) oxygen coordination, i.e. NaO(8) square prismatic coordination, LiO(4) square planar coordination and covalently bond H atoms, with results from (23)Na, (7)Li and (1)H NMR spectroscopy we were able to obtain a more detailed insight into the respective local distortions and anharmonic motions. We were able to show that the site that the A(+) cation occupies in the hexatitanate channel structure strongly influences the lithium insertion properties of these compounds and therefore their usefulness as electrode materials for energy storage. PMID- 23108297 TI - Early abdominal ectopic pregnancies: a systematic review of the literature. AB - OBJECTIVE: To define abdominal ectopic pregnancy outcomes by both location and treatment. METHODS: Literature review of abdominal pregnancies from 1965 to August of 2009. Ectopic pregnancy exclusions were interstitial, tubal, cervical, ovarian, or those beyond 20 weeks at diagnosis/treatment. RESULTS: There were 511 cases identified with 225 meeting the inclusion criteria. There were 7 maternal deaths (3.0%) with 18 (8%) of the early abdominal ectopic pregnancies occurring with an intrauterine device in place. Mean gestational age at the time of treatment was 10 weeks 0 days and mean maternal age was 29.7 years. The average blood loss associated with treatment was 1,450 ml. The top three sites of early abdominal ectopic pregnancies were pouches around the uterus (24.3%), serosal surface of the uterus and tubes (23.9%), and multiple sites (12.8%). Primary surgical management was performed in 208 cases (87.8%). Nonsurgical adjuvant or primary therapy included intramuscular methotrexate, intralesional methotrexate, intracardiac KCl, and artery embolization. CONCLUSION: Abdominal pregnancies should be considered in all patients until an intrauterine location can be confirmed. Understanding treatment options by pregnancy location may be helpful in the management of this potentially life-threatening condition. PMID- 23108299 TI - Preface. Inflammation and cancer. PMID- 23108300 TI - Promotion of hepatocellular carcinoma by hepatitis C virus. AB - Persistent infection with the hepatitis C virus (HCV) is a major global health problem. Around 2-3% of the world's population are chronically infected, and infected individuals are at high risk of developing steatosis, fibrosis, and liver cirrhosis. The latter is a major predisposing factor for the development of hepatocellular carcinoma (HCC). It is generally accepted that an inflammatory response triggered by persistent HCV infection leads to increased cell proliferation and fibrogenesis that in turn promotes cirrhosis and ultimately HCC development. This indirect mechanism of tumor induction would explain the long incubation period from primary HCV infection to HCC and the requirement for additional cofactors such as toxins or drugs (most notably alcohol), metabolic liver diseases, steatosis, nonalcoholic liver disease, or diabetes. With the advent of adequate cell culture systems for HCV it is, however, becoming increasingly clear that the virus also contributes directly to HCC formation. Examples are the continuous induction of stress response or the massive accumulation of intracellular lipids. Moreover, viral proteins can bind to and sequester cell cycle control factors such as the retinoblastoma protein or the tumor suppressor DDX3. Thus, HCV-associated liver cancer is most likely promoted by the combined action of long-term chronic inflammation and targeted perturbations of cellular key pathways involved in metabolic homeostasis as well as cell cycle control. PMID- 23108301 TI - Lymphotoxin, NF-KB, and cancer: the dark side of cytokines. AB - Cytokines have been implicated in a variety of physiological processes involving lymphoid tissue development, lymphocyte activation, and control of regenerative processes such as wound healing. The first characterization of a cytokine implicated in abolishing or killing tumor cells - the tumor necrosis factor (TNF) - fostered and boosted a completely new field of research that in addition to cancer research started to generate an overwhelming amount of knowledge in immunology, various pathological processes, and other fields of research. Due to the complex networks and versatile functions of cytokines, it soon became clear that cytokines can possess diametric functions in various biological processes. As for tumor research it was shown that some cytokines - depending on the type of organ, the time of action, gender, and the cellular environment - can have either pro- or anticarcinogenic action. For those cytokines reported to be procarcinogenic, this could be accomplished by directly acting as oncogenes or generating an inflammatory environment that is procarcinogenic. Here we review a novel role for TNF family members - in particular lymphotoxin (LT) alpha and beta - in physiology and in driving tumorigenesis, with special focus on the liver. We believe that recent findings on this particular cytokine might have strong implications for the therapy of liver cancer or other inflammation-induced cancer types. PMID- 23108302 TI - Colitis and colorectal cancer. AB - Inflammatory bowel diseases (IBD) are accompanied by an increased risk of developing colitis-associated carcinoma (CAC). These tumors are one of the most important causes of morbidity and mortality in patients with IBD and distinctly differ from sporadic colorectal cancer in their biology and underlying mechanisms. First, this review discusses risk factors for the development of CAC and summarizes some of the most important genetic alterations and molecular pathways involved in inflammatory carcinogenesis. Then, new endoscopic techniques, such as chromoendoscopy and confocal laser endomicroscopy, and their contribution to surveillance and early detection of CAC are presented. Last, we briefly address different types of concepts for prevention (i.e. anti inflammatory agents) and treatment (i.e. surgical resection) of CAC and give an outlook on this important aspect of IBD. PMID- 23108304 TI - Cellular immune responses to hepatocellular carcinoma: lessons for immunotherapy. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, with a continuously high mortality. Thus, the development of new therapeutic strategies is crucial to decrease recurrence rates and to improve the overall survival rates of HCC patients. The rationale for immunotherapy is based on the findings of several studies showing specific CD8(+) T-cell responses against various tumor associated antigens (TAAs) in HCC patients and a clinical benefit of T-cell infiltration in the tumor tissue. However, the impact of TAA-specific CD8(+) T cell responses on tumor control seems to be rather weak. Several different mechanisms contribute to the failure of the cellular immune response and will be summarized in this review. The aim of immune-based therapies is to overcome these mechanisms of T-cell failure and to induce or boost TAA-specific CD8(+) and CD4(+) T-cell responses. Several preclinical and clinical studies of immune-based therapeutic approaches show encouraging results and will be discussed in this review. PMID- 23108303 TI - Cellular immune suppressor mechanisms in patients with hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) has been shown to induce several immune suppressor mechanisms in patients. Our laboratory has been investigating different cellular mechanisms of immune suppression in patients with HCC. These suppressor mechanisms range from CD4(+) regulatory T cells, functionally impaired dendritic cells, neutrophils, and monocytes to myeloid-derived suppressor cells. In vitro as well as in vivo studies have demonstrated that abrogation of the suppressor cells enhances or unmasks tumor-specific anti-tumor immune responses. We performed a literature search for immune suppressor cells in HCC, and here we provide a comprehensive summary of the latest studies in this field. PMID- 23108305 TI - Interleukin-6 trans-signaling and colonic cancer associated with inflammatory bowel disease. AB - Interleukin-6 (IL-6) is a cytokine largely induced during infection, inflammation, and cancer. In the liver, IL-6 induces the synthesis of acute-phase proteins, which are believed to support the response of the body during infection and inflammation. Moreover, IL-6 has been reported to be a growth factor in multiple myeloma. IL-6 on cells binds to an IL-6 receptor (IL-6R) forming an IL 6/IL-6R complex, which associates with a homodimer of a second receptor subunit, gp130, to initiate signaling. Gp130 is present on all cells of the body, whereas IL-6R is only expressed on hepatocytes, some leukocytes, and some epithelial cells. Since gp130 has no measurable affinity for IL-6, cells which do not express IL-6R are unresponsive to the cytokine. A soluble form of IL-6R, which is found in the blood, can still bind IL-6 and the complex of IL-6/sIL-6R can bind to cellular gp130 also on cells without IL-6R expression. This signaling mechanism has been called trans-signaling. Interestingly, a soluble form of gp130 (sgp130) blocks IL-6 trans-signaling without affecting classic IL-6 signaling via the membrane-bound IL-6R. We used a dimerized version of sgp130 fused to the Fc portion of an IgG1 antibody (sgp130Fc) to discriminate between classic and trans signaling of IL-6. It turned out that proinflammatory activities of IL-6 are mediated via trans-signaling, whereas anti-inflammatory or regenerative activities are mediated via classic signaling. These results are important for strategies to inhibit IL-6 signaling in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and inflammation-associated colorectal cancer. PMID- 23108306 TI - TNF-dependent signaling pathways in liver cancer: promising targets for therapeutic strategies?. AB - Liver cancer represents a growing health burden worldwide, and treatment options are still limited. Hepatocellular carcinoma (HCC), the most frequent primary hepatic malignancy, arises in most instances in chronically inflamed and fibrotic livers. However, current systemic molecular therapies against HCC are mainly focusing on tyrosine kinases involved in angiogenic and oncogenic signaling pathways, whereas the knowledge on the unique association between inflammation and carcinogenesis in the liver has not yet translated into preventive or therapeutic concepts against HCC. Tumor necrosis factor (TNF) is a cytokine derived from monocytes and various other immunological and parenchymal cells. Upon binding to its receptors, TNF activates different signaling cascades including the pro-apoptotic caspase cascade as well as inflammatory and stress related pathways such as the NF-KB, p38MAPK, and Jun-(N)-terminal kinase (JNK) pathways. The role of TNF in cancer is controversial, since it was attributed both pro- and anti-carcinogenic functions. Its potential function in hepatocarcinogenesis has lately been investigated using genetically modified mouse models. These studies have highlighted that the various TNF-dependent signaling pathways withhold distinct functions in hepatocarcinogenesis, which are in part controversial and strongly depend on the experimental model system. Nevertheless, careful interpretation of findings in mouse models and critical consideration of their limitations might result in a new understanding of this complex pathway in hepatocarcinogenesis and thus might help identify the most promising targets in the TNF pathway and the appropriate clinical settings for future chemo-preventive or therapeutic strategies against HCC. PMID- 23108307 TI - Adipocytokines and hepatocellular carcinoma. AB - Adipocytokines are primarily adipocyte-derived products, although certain members are also synthesized by other cell types. These adipocytokines, similarly to classical cytokines, are characterized by very pleiotropic functions affecting biological processes throughout the body. An increasing number of adipocytokines has recently been recognized, such as adiponectin, leptin, pre-B cell colony enhancing factor/Nampt/visfatin, resistin, progranulin, and others. Adiponectin has emerged as the most abundant circulating adipocytokine, is produced almost exclusively by adipocytes, and has mainly anti-inflammatory and anti-diabetic functions. In contrast, leptin is produced by many cell types beyond adipocytes, regulates immunity and T cell functions, and acts in a more pro-inflammatory fashion. Adipocytokines play a fundamental role in adipose tissue homeostasis (i.e. health) and disease, especially in obesity-related disorders such as non alcoholic fatty liver diseases (NAFLD) and their complications, including hepatocellular carcinoma (HCC). Lack of adiponectin as observed in NAFLD drives steatosis and inflammation in the liver, and evidence is increasing that this adipocytokine has many anti-tumor properties and might play a rather protective role in HCC. The role of leptin in NAFLD is still unclear and this adipocytokine seems to have opposite effects in HCC, acting more as a tumor promoter. Evidence is increasing that HCC tissue produces various adipocytokines, and adiponectin expression in HCC seems to be decreased whereas leptin expression is rather increased. In conclusion, adipocytokines are increasingly recognized as pleiotropic molecules involved in the pathophysiology of HCC, which might lead to therapeutic approaches targeting these mediators. PMID- 23108308 TI - TGF-beta signaling in onset and progression of hepatocellular carcinoma. AB - Transforming growth factor (TGF)-beta is a central regulator in chronic liver disease, contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver damage-induced levels of active TGF-beta enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Further evidence points to a decisive role of cytostatic and apoptotic functions mediated on hepatocytes, which is critical for the control of liver mass, with loss of TGF-beta activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-beta with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-beta may turn from a tumor suppressor into a tumor promoter that exacerbates invasive and metastatic behavior. We have delineated this molecular switch of the pathway from cytostatic to tumor promoting in further detail and identify activation of survival signaling pathways in hepatocytes as a most critical requirement. Targeting the TGF-beta signaling pathway has been explored to inhibit liver disease progression. While interfering with TGF-beta signaling in various short-term animal models has demonstrated promising results, liver disease progression in humans is a process of decades with different phases in which TGF-beta or its targeting may have both beneficial and adverse outcomes. We emphasize that, in order to achieve therapeutic effects, targeting TGF-beta signaling in the right cell type at the right time is required. PMID- 23108309 TI - Epidermal growth factor receptor signaling in hepatocellular carcinoma: inflammatory activation and a new intracellular regulatory mechanism. AB - BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a chemoresistant tumor strongly associated with chronic hepatitis. Identification of molecular links connecting inflammation with cell growth/survival, and characterization of pro tumorigenic intracellular pathways is therefore of therapeutic interest. The epidermal growth factor receptor (EGFR) signaling system stands at a crossroad between inflammatory signals and intracellular pathways associated with hepatocarcinogenesis. We investigated the regulation and activity of different components of the EGFR system, including the EGFR ligand amphiregulin (AR) and its sheddase ADAM17, and the modulation of intracellular EGFR signaling by a novel mechanism involving protein methylation. METHODS: ADAM17 protein expression was examined in models of liver injury and carcinogenesis. Crosstalk between tumor necrosis factor (TNF)-alpha, AR and EGFR signaling was evaluated in human HCC cells and mouse hepatocytes. Modulation of EGFR signaling and biological responses by methylation reactions was evaluated in AML12 mouse hepatocytes. RESULTS: ADAM17 was upregulated in liver injury and hepatocarcinogenesis. TNF alpha triggered AR shedding and EGFR transactivation in HCC cells. AR was necessary for TNF-alpha activation of ERK1/2 and Akt signaling in hepatocytes. Inhibition of methylation reactions increased the ERK1/2 signal amplitude triggered by AR/EGFR and reduced DNA synthesis in AML12 cells. CONCLUSIONS: Increased ADAM17 in pre-neoplastic liver injury further supports its implication in hepatocarcinogenesis. AR release and EGFR transactivation by TNF-alpha constitutes a novel link between inflammatory signals and pro-tumorigenic mechanisms in liver cells. Finally, the identification of a new mechanism controlling growth factor signaling, and biological responses, involving methylation reactions within the RAS/RAF/MEK/ERK pathway, exposes a new target for antineoplastic intervention. PMID- 23108312 TI - Synthesis and properties of 1-(3'-dihydroxyboryl-2',3' dideoxyribosyl)pyrimidines. AB - Nucleoside analogues having a boronic acid in place of the 3-hydroxyl group of deoxyribose have been synthesized. The synthesis of 3'-dihydroxyboryl-2',3' dideoxyribose was based on asymmetric homologation of boronic esters with (dihalomethyl)lithium, beginning from a (silyloxymethyl)boronic ester. A change of chiral director is required before introduction of the second stereocenter, and the direct displacement of (S,S)-1,2-dicyclohexyl-1,2-ethanediol by (1S,2S,3R,5S)-pinanediol was used for this purpose. Coupling of the pinanediol ester of the 1-acetoxy-3-dioxyboryl-5-tert-butylsilyloxy deoxyribose analogue with silylated pyrimidine bases was accomplished with trimethylsilyl bromide. The boronic acid nucleoside analogues were not cytotoxic toward Hep G2 (human hepatocarcinoma) cells. Decomposition occurred over a period of several hours at 37 degrees C, pH 7.4, with liberation of free pyrimidine base. PMID- 23108313 TI - Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery. AB - The synthesis of various amides has been realised avoiding the use of any organic solvent from activation of carboxylic acids with CDI to isolation of the amides. Mechanochemistry was the key point of the process allowing rapid formation of the amide bond and efficient water-based purification of the final products. PMID- 23108314 TI - Socioeconomic disparities in cataract surgery. AB - PURPOSE OF REVIEW: As the elderly population continues to grow in the USA, an understanding of the increasing burden of cataract is pivotal. This review seeks to iterate the presence of this burden and to understand it better in the context of race, sex, and socioeconomic factors. RECENT FINDINGS: Although there have been multiple prevalence studies addressing the cataract burden in the USA, updated literature that directly elucidates the above issues has been sparse. Recent data support previous findings that the cataract burden among women is greater than that of men, likely predominantly due to greater longevity. With regard to race, there appears to be a slightly increased burden among Whites, although this increase may show regional variability and change over the next few decades, especially as the presently young Hispanic population continues to age and grow. It is likely that the significant divider responsible for unmet cataract surgery is socioeconomic, due to such factors as insurance coverage, income, and barriers to access such as transportation, service accessibility, and awareness. These latter barriers of income and access appear to be identical to those identified in developing countries. SUMMARY: The cataract burden in the USA is significant and is expected to continue to grow. Further studies are warranted to help us better understand barriers to access, particularly with regard to race and socioeconomic factors. Local efforts to address education and logistical barriers as well as nationwide policy efforts to address insurance coverage appear to be a crucial factor in surmounting an ongoing but treatable chronic disease. PMID- 23108315 TI - Free anterolateral thigh fascia lata flap for complex nasal lining defects. AB - OBJECTIVE: To introduce a novel technique for the reconstruction of complex nasal lining defects using the free vascularized anterolateral thigh fascia lata flap. METHODS: Free anterolateral thigh fascia lata flaps were used to replace nasal lining in 5 patients with total or subtotal rhinectomy defects. We performed a retrospective medical record review. RESULTS: No flap failure or lining loss was observed, and harvest site morbidity was negligible. Patients achieved satisfactory nasal form and patent nasal airways without a need for repeated revisions. In 2 patients, the anterolateral thigh flap was used simultaneously to restore the midface contour or to repair anterior skull base defects. CONCLUSIONS: In this case series, we demonstrate the novel use of vascularized fascia lata to provide viable nasal lining in total and subtotal nasal defect reconstruction. Potential advantages offered by this technique compared with more established methods include (1) single-stage replacement of nasal lining, structure, and skin coverage; (2) fewer additional stages of reconstruction to achieve functional and aesthetic results; (3) thin lining to allow for optimal airway contour; (4) less harvest site morbidity; and (5) development of composite soft tissue, cutaneous, and/or muscle flaps to repair adjacent defects. PMID- 23108316 TI - Antibodies enhance the infection of phorbol-ester-differentiated human monocyte like cells with coxsackievirus B4. AB - Coxsackievirus B4 (CV-B4), in presence of antibodies and through a specific viral receptor CAR and Fcgamma receptors II and III, can infect monocytes which results in interferon-alpha synthesis. The antibody-dependent enhancement of CV-B4 infection in the human monocytic-like THP-1 cell line has been investigated. The preincubation of CV-B4 with human plasma or human polyvalent immunoglobulins enhanced the infection of phorbol-myristate-acetate (PMA)-activated THP-1 cell cultures. CV-B4 replicated in these cells as demonstrated by the intracellular detection of infectious particles, viral protein VP1 (immunofluorescence), positive and negative viral RNA (RT-PCR). The viability of infected and control cell cultures was not different up to 20 days post-infection. Activated cell cultures inoculated with CV-B4 harbored intracellular RNA up to 14 days post infection and produced IFNalpha that was detected by intracellular immunofluorescence staining as soon as 4 h post-infection with a maximum at 48 h post-infection and by RT-PCR all along the experiment. Together, these data demonstrate that PMA-activated THP-1 cells can be infected with CV-B4, can produce IFNalpha as a result of interactions between the virus, antibodies and specific receptors. This cellular model can be used to investigate further the mechanism and the result of the antibody-dependent enhancement of CV-B4 infection. PMID- 23108317 TI - In vivo murine and in vitro M-like cell models of gastrointestinal anthrax. AB - Bacillus anthracis is the causative agent of anthrax and is acquired by three routes of infection: inhalational, gastrointestinal and cutaneous. Gastrointestinal (GI) anthrax is rare, but can rapidly result in severe, systemic disease that is fatal in 25%-60% of cases. Disease mechanisms of GI anthrax remain unclear due to limited numbers of clinical cases and the lack of experimental animal models. Here, we developed an in vivo murine model of GI anthrax where spore survival was maximized through the neutralization of stomach acid followed by an intragastric administration of a thiabendazole paste spore formulation. Infected mice showed a dose-dependent mortality rate and pathological features closely mimicking human GI anthrax. Since Peyer's patches in the murine intestine are the primary sites of B. anthracis growth, we developed a human M (microfold)-like-cell model using a Caco-2/Raji B-cell co culturing system to study invasive mechanisms of GI anthrax across the intestinal epithelium. Translocation of B. anthracis spores was higher in M-like cells than Caco-2 monolayers, suggesting that M-like cells may serve as an initial entry site for spores. Here, we developed an in vivo murine model of GI anthrax and an in vitro M-like cell model that could be used to further our knowledge of GI anthrax pathogenesis. PMID- 23108318 TI - Celiac disease. "To biopsy or not to biopsy. That is the question!". AB - Great progress has been made in the field of celiac disease (CD). During the past 50 years we have come to understand a great deal about the pathogenesis, clinical spectrum, and treatment. Great advances have been made in the technology of diagnosing CD. Heretofore, the gold standard used for diagnosis of CD is the small intestinal biopsy. The European Society for Pediatric Gastroenterology, Hepatology and Nutrition has recently issued guidelines that state that some patients do not require a biopsy for diagnosis. This review traces the history of CD with a particular attention to the evolution of the technology involved in the field. The question of the need for biopsy or not is discussed. PMID- 23108319 TI - Primary gastrointestinal motility disorders in childhood. AB - Pediatric gastrointestinal motility disorders are a heterogeneous group of conditions that can be particularly difficult to recognize and manage. Symptoms are typically chronic and have a significant impact on quality of life. Medical therapies are limited and definitive treatment often requires surgical intervention that can alleviate certain symptoms, but predispose the patients to other comorbidities. The goal of this review is to summarize the current understanding of the primary gastrointestinal motility disorders in childhood and their management. PMID- 23108320 TI - Diagnostic testing and management of gastroesophageal reflux disease (GERD) in children. AB - The diagnosis of gastroesophageal reflux disease (GERD) has evolved from reliance on history and fluoroscopy to continuous esophageal pH monitoring with catheter based pH probes and wireless pH probes to continuous impedance/pH monitoring. This review describes the currently employed diagnostic tests and the actual management of GERD in children. PMID- 23108321 TI - Autoimmune liver diseases. AB - Autoimmune liver diseases are characterized histologically by a dense mononuclear cell infiltrate in the portal tract and serologically by high levels of transaminases and immunoglobulin G (IgG) and positive autoantibodies, in the absence of a known etiology. In pediatrics, there are three liver disorders in which liver damage is likely to arise from an autoimmune attack: autoimmune hepatitis (AIH); autoimmune sclerosing cholangitis (ASC); and de novo autoimmune hepatitis after liver transplantation. The exact pathogenesis of AIH is still unknown, but it is known that unidentified environmental factors, and occasionally drugs, might trigger disease in genetically-susceptible individuals. The clinical spectrum of disease is very wide, ranging from asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical and histological parameters, and exclusion of other liver diseases. It is a relatively rare but devastating disease, which progresses rapidly unless immunosuppressive treatment is started promptly. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have intolerable side effects. The purpose of this review was to provide an overview of the current knowledge on pediatric autoimmune liver disease. PMID- 23108322 TI - Overview of the epidemiology and management of childhood obesity. AB - Pediatric obesity is rapidly emerging as a serious chronic disease affecting an increasing number of children worldwide. In this report, we review current aspects of pediatric obesity and obesity related management as it relates to the primary care provider who is often the first line of prevention in pediatric obesity. PMID- 23108323 TI - Overweight and obesity in male adolescent soccer players. AB - AIM: In spite of the increasing scientific interest in the epidemiology of overweight and obesity in children and adolescents, less attention was paid to the prevalence of these disorders in sport setting. The aim of this study was to investigate the prevalence of overweight and obesity in adolescent soccer players. METHODS: Male adolescent (N.=297 aged 12.01-20.98 y), classified in nine one-year age-groups, children (control group, N.=16 aged 7.34-11.97 y) and adult players (control group, N.=29 aged 21.01-31.59 y), all members of competitive soccer clubs, performed a series of anthropometric measures (body mass, height, skinfolds and circumferences), from which body mass index (BMI), percentage of fat (BF), fat mass (FM), fat free mass (FFM) and waist-to-hip ratio (WHR) were calculated. RESULTS: After having partitioned out the effect of age on the parameters of body composition, BMI was associated moderately to strongly with BF, FM and FFM (r=0.74, r=0.88 and r=0.68, P<0.001), while there was no corresponding relationship between WHR and BF (r=0.03, P=0.64). The prevalence of overweight/obese ranged 13.3-32.4%. Although there was no difference between adolescent age groups, the difference between adult and child control group (chi2=7.09, P<0.05; higher prevalence in children than in adults) indicated an attenuation of this prevalence with development. CONCLUSION: Based on these findings, the prevalence of overweight/obesity in adolescence was confirmed. However, what was novel was that this phenomenon was identified in adolescent sport setting and, consequently, exercise interventions with proper mode, duration and intensity, targeting this phenomenon, should be applied by coaches and fitness trainers. PMID- 23108324 TI - Prevalence of hyperinsulinism, type 2 diabetes mellitus and metabolic syndrome among Saudi overweight and obese pediatric patients. AB - AIM: Obesity and overweight among children and adolescents is increasing at an alarming rate, which lead to the increase in the incidence of their related co morbidities. Our objectives are to establish the following: 1) the prevalence of hyperinsulinism among overweight and obese pediatric patients. 2) The prevalence of type 2 diabetes mellitus (T2DM) among those with hyperinsulinism. 3) The prevalence of metabolic syndrome (MS) and its components among T2DM pediatric patients. METHODS: A retrospective cross-sectional study conducted on overweight and obese pediatric patients attending the pediatrics diabetes clinic at King Abdul-Aziz University Hospital, Jeddah, Saudi Arabia, from 2006 to 2010. Serum insulin level was measured for 387 patients (ages from 2 to 18 years). Those with hyperinsulinism underwent further investigations to assess the prevalence of T2DM and the prevalence of MS among T2DM patients. RESULTS: The overall prevalence of hyperinsulinism and T2DM were 44.7%, and 9.04%, respectively. Among children and adolescents with T2DM, 62.86% had a body mass index BMI>=85th percentile, 37.14% had a BMI >= 95th percentile, 14.29% had MS, 34.29% were hypertensive and 28.57% had dyslipidemia. CONCLUSION: Obesity and its co-morbidities were prevalent among Saudi pediatric patients. We recommend preventing excessive weight gain through the promotion of a healthy lifestyle, family educational seminars and the reinforcement of indoor exercises. PMID- 23108325 TI - Near-infrared spectroscopy measure of limb peripheral perfusion in neonatal arterial thromboembolic disease. AB - AIM: In critically ill neonates, peripheral perfusion and oxygenation assessment may provide indirect information on circulatory failure in limb arterial thromboembolic emergencies. Aims of our study were: 1) to evaluate the changes on tissue oxygenation index, oxyhemoglobin, deoxyhemoglobin and blood volume obtained by near-infrared spectroscopy (NIRS) on the infants legs; 2) to compare them with ultrasonographic data. METHODS: Tissue oxygenation index (TOI), oxyhemoglobin (O2Hb), deoxyhemoglobin (HHb) and blood volume (BV) differences were assessed by NIRS on the calf of 8 newborn infants (median weight 1995, range 585-3010 g; median gestational age 32.5, range 26-40 wks). An ultrasonographic scan of the arterial system was performed before the NIRS measurements, to validate the site of arterial occlusion. RESULTS: A t-test for independent samples showed lower values in the affected limb for all NIRS measurements. TOI measurements displayed lower values in the thromboembolic limb (mean 44.79+/-12%) versus unaffected (mean 47.95+/-17.08%) (P=0.0001). Mean (SD) peak systolic velocity in the patent artery below the occlusion decreased from 108+/-25 cm/s in the normal limb to 25.6+/-28 cm/s in the thrombus site (P=0.02). CONCLUSION: In neonatal intensive care units, measurement of limb peripheral perfusion and oxygenation seems to be clinically useful in arterial thromboembolic emergencies. PMID- 23108326 TI - Shaken baby syndrome: pathogenetic mechanism, clinical features and preventive aspects. AB - The shaken baby syndrome (SBS) is an extremely serious form of child abuse and a leading cause of death and disability in childhood. The syndrome usually occurs in infants younger than 1 year when a parent or a care-giver tries to stop the baby from crying by vigorous manual shaking. The repetitive oscillations with rotational acceleration of the head can result in injuries of both vascular and neuronal structures. The most frequent injuries associated with SBS include encephalopathy, retinal hemorrhages, and subdural hemorrhage. Fractures of the vertebrae, long bones, and ribs may also be associated with the syndrome. Victims of abuse have various presenting signs and symptoms ranging from irritability, decreased responsiveness and lethargy to convulsions, and death. Diagnosis is often difficult because usually parents or caregivers not tell the truth about what has happened to their child and because usually there is no external evidence of trauma. However, the syndrome might be suspected if the information provided are vague or changing and when the child presents with retinal hemorrhages, subdural hematoma, or fractures that cannot be explained by accidental trauma or other medical conditions. Of infants who are victims of SBS, approximately 15% to 38% die and 30% are at risk of long-term neurologic sequelae, including cognitive and behavioural disturbances, motor and visual deficits, learning deficits and epilepsy. Parents and caregivers must be warned about the dangers of shaking infants. PMID- 23108327 TI - Severe side effects of health migration: stress and anger. AB - A great deal of immigrants of very sick children treated in our country are unable to elaborate an effective coping strategy and a methodology of resilience. Their culture and communication difficulties do not allow them to build a strong self help system. Herein, we report five stories of mothers and children who were cared for in our Children's Hospital. Anger; this is quite a common emotion among many immigrant parents of sick children with high risk diseases who have been treated in our hospital for long periods of time. They live together in community housing with families from other countries, and of different religions and habits. Anger affects their personal and social well-being. Self-blame is a common expression of their condition, and they are unable to make helpful self sacrifices. They feel anger as a result of what has happened to them, and they do not have the abilities they need to activate a good defence mechanism. Resilience is completely unknown to them. In most cases, their relatives do not intend to help them. These mothers are far from their families and habits, they are alone with their child, they suffer but their relatives push them to go back home and to renounce to the hope of cure given by the physicians. They experience a loss in their self-monitoring ability to build a coping strategy and resilience. In these cases their display of anger is often exaggerated. The anger of the immigrants is an additional problem for physicians and other caregivers working in hospitals which treat immigrant children. PMID- 23108328 TI - Kinetics of the benzyl + O(3P) reaction: a quantum chemical/statistical reaction rate theory study. AB - The resonance stabilized benzyl radical is an important intermediate in the combustion of aromatic hydrocarbons and in polycyclic aromatic hydrocarbon (PAH) formation in flames. Despite being a free radical, benzyl is relatively stable in thermal, oxidizing environments, and is predominantly removed through bimolecular reactions with open-shell species other than O(2). In this study the reaction of benzyl with ground-state atomic oxygen, O((3)P), is examined using quantum chemistry and statistical reaction rate theory. C(7)H(7)O energy surfaces are generated at the G3SX level, and include several novel pathways. Transition state theory is used to describe elementary reaction kinetics, with canonical variational transition state theory applied for barrierless O atom association with benzyl. Apparent rate constants and branching ratios to different product sets are obtained as a function of temperature and pressure from solving the time dependent master equation, with RRKM theory for microcanonical k(E). These simulations indicate that the benzyl + O reaction predominantly forms the phenyl radical (C(6)H(5)) plus formaldehyde (HCHO), with lesser quantities of the C(7)H(6)O products benzaldehyde, ortho-quinone methide, and para-quinone methide (+H), along with minor amounts of the formyl radical (HCO) + benzene. Addition of O((3)P) to the methylene site in benzyl produces a highly vibrationally excited C(7)H(7)O* adduct, the benzoxyl radical, which can beta-scission to benzaldehyde + H and phenyl + HCHO. In order to account for the experimental observation of benzene as the major reaction product, a roaming radical mechanism is proposed that converts the nascent products phenyl and HCHO to benzene + HCO. Oxygen atom addition at the ortho and para ring sites in benzyl, which has not been previously considered, is shown to lead to the quinone methides + H; these species are less-stable isomers of benzaldehyde that are proposed as important combustion intermediates, but are yet to be identified experimentally. Franck Condon simulations of the benzaldehyde, o-quinone methide, and p-quinone methide photoelectron spectra suggest that these C(7)H(6)O isomers could be distinguished using tunable VUV photoionization mass spectrometry. PMID- 23108329 TI - Activation of autophagy in cells with abnormal karyotype. AB - The presence of even one extra chromosome severely impairs cellular growth. This effect of aneuploidy (a term describing chromosome numbers deviating from multiples of haploid chromosome content) has been observed in many different organisms, from yeast to humans. Accordingly, abnormal karyotypes are detected in nearly 30% of spontaneously aborted embryos. The rarely surviving infants, such as with trisomy of chromosome 21, are severely handicapped. The causes remain enigmatic, although recent studies exploiting yeast and mouse models provided first glimpses of the imbalanced inner life of aneuploid cells. Using comparative genomics, transcriptomics and proteomics we have analyzed the fate of the transcripts and proteins coded on the extra chromosomes as well as the general response to aneuploidy in human cells. PMID- 23108330 TI - Diffusion- and convection-based activation of Wnt/beta-catenin signaling in a gradient generating microfluidic chip. AB - Stem cells and developing tissues respond to long-range signaling molecules (morphogens), by starting different nuclear programs that decide about the cell fate. Cells sense the local morphogen concentration and the shape of the gradient. We developed a two-chambered microfluidic chip to reproduce the in vivo situation under shear stress free conditions. The gradient is generated in the lower part of our device and recognized by cells grown in the upper part in the microchamber. We tested our device by activating the Wnt/beta-catenin signaling pathway in HeLa cells as proven by nuclear beta-catenin accumulation in response to the Wnt pathway activator 6-bromoindirubin-3'-oxime (BIO). Applying the same readout system to a recombinant Wnt3a and Dkk-1 bipolar gradient we demonstrate that our microfluidic chip is suitable for morphogens as well as small molecules. More interestingly, our microfluidic device is highly flexible. While the generated gradients are stable for several hours and reproducible, we can change the kind and the shape of the gradient actively on demand. We also can switch from diffusion- to convection-based transport, thus applying the morphogen gradient either in a polarized or non-polarized manner. PMID- 23108331 TI - Nanofiber-net-binary structured membranes for highly sensitive detection of trace HCl gas. AB - This work describes the detection of trace hydrogen chloride (HCl) gas through analyses of the resonance frequency signal from quartz crystal microbalance (QCM) sensors coated with polyaniline (PANI) functionalized polyamide 6 (PA 6) (PANI-PA 6) nanofiber-net-binary (NNB) structured membranes. The PA 6 NNB substrate comprising nanofibers and spider-web-like nano-nets fabricated by a versatile electro-spinning/netting (ESN) process offered an ideal interface for the uniform PANI functionalization and enhanced sensing performance. Benefiting from the large specific surface area, high porosity, and strong adhesive force to the QCM electrode of the PANI-PA 6 NNB membranes, the developed HCl-selective sensors exhibited a rapid response, good reproducibility and stability, and low detection limit (7 ppb) at room temperature. Additionally, the PANI-PA 6 NNB sensing membranes presented visible color changes upon cycled exposure to HCl and ammonia, suggesting their potential application in the development of colorimetric sensors. The PANI-PA 6 NNB coated QCM sensors are considered to be a promising candidate for trace HCl gas detection in practical applications. PMID- 23108332 TI - Volume-related measurement error by three-dimensional ultrasound with a rotational multiplanar technique. AB - BACKGROUND: The goal of this study was to calculate the accuracy of three dimensional volume measurements with the rotational multiplanar technique VOCAL (Volume Organ Computer-aided AnaLysis). METHODS: An ultrasound phantom with 13 objects (volume 10.2-40.5 cm(3)) was created. After data acquisition, the volumes of the objects were measured with the VOCAL technique. RESULTS: A linear mixed model analysis showed a significant linear (B = -0.008, 95% CI -0.014, -0.002, p = 0.005) and a significant quadratic trend (B = 0.0001, 95% CI 0.000004, 0.0002, p = 0.040). The absolute error increases significantly with the increasing volume of interest with 0.044 cm(3) for each cm(3) rise of the volume of interest. The actual volume increased from an initial value of 10 cm(3) to values of 20, 30 and 40 cm(3), resulting in a decrease in the mean estimated percentage error from 15.4 to 10.6%, 8.0% and 7.5%. CONCLUSION: The results of this study showed that volume measurements with three-dimensional ultrasound and the VOCAL software can be used for volume measurements in vivo. However, it is important to assess the measurement error and to consider these error values when interpreting the results in daily practice. PMID- 23108333 TI - Rigid Mn(II) chelate as efficient MRI contrast agent for vascular imaging. AB - The aza-semi-crown pentadentate ligand rigidified by pyridine and piperidine rings was designed and synthesized. It can react with Mn(II) in water to form complex with improved longitudinal relaxivity, leading to efficient signal intensity enhancement of vascular vessels under a clinical magnetic resonance imaging scanner. PMID- 23108334 TI - Ortho-phenylenediamine-based open and macrocyclic receptors in selective sensing of H2PO4(-), ATP and ADP under different conditions. AB - Ortho-phenylenediamine-based open and macrocyclic receptors have been designed and synthesized. The open receptor 1 and the macrocyclic receptor 2 fluorimetrically distinguish H(2)PO(4)(-) from the other anions examined in CH(3)CN with appreciable binding constant values. As practical applications, they are also sensible to nucleotides in aq. CH(3)CN (1 : 1, v/v). The receptor 1 shows significant emission change upon complexation of ATP and ADP. ADP is selectively distinguished by a ratiometric change in emission. In contrast, the macrocyclic receptor 2, under similar conditions, shows good binding with ATP over the others. PMID- 23108335 TI - Immunological homeostasis of the eye. AB - Uveitis is a sight-threatening disease caused by autoimmune or infection-related immune responses. Studies in experimental autoimmune uveitis and in human diseases imply that activated CD4(+) T cells, Th1 and Th17 cells, play an effector role in ocular inflammation. The eye has a unique regional immune system to protect vision-related cells and tissues from these effector T cells. The immunological balance between the pathogenic CD4(+) T cells and regional immune system in the eye contributes to the maintenance of ocular homeostasis and good vision. Current studies have demonstrated that ocular parenchymal cells at the inner surface of the blood-ocular barrier, i.e. corneal endothelial (CE) cells, iris pigment epithelial (PE) cells, ciliary body PE cells, and retinal PE cells, contribute to the regional immune system of the eye. Murine ocular resident cells directly suppress activation of bystander T cells and production of inflammatory cytokines. The ocular resident cells possess distinct properties of immunoregulation that are related to disparate anatomical location. CE cells and iris PE cells, which are located at the anterior segment of the eye and face the aqueous humor, suppress activation of T cells via cell-to-cell contact mechanisms, whereas retinal PE cells suppress the activation of T cells via soluble factors. In addition to direct immune suppression, the ocular resident cells have another unique immunosuppressive property, the induction of CD25(+)Foxp3(+) Treg cells that also suppress the activation of bystander T cells. Iris PE cells convert CD8(+) T cells into Treg cells, while retinal PE cells convert CD4(+) T cells greatly and CD8(+) T cells moderately into Treg cells. CE cells also convert both CD4(+) T cells and CD8(+) T cells into Treg cells. The immunomodulation by ocular resident cells is mediated by various soluble or membrane-bound molecules that include TGF-beta TSP-1, B7-2 (CD86), CTLA-2alpha, PD-L1 (B7-H1), galectin 1, pigment epithelial-derived factor PEDF), GIRTL, and retinoic acid. Human retinal PE cells also possess similar immune properties to induce Treg cells. Although there are many issues to be answered, human Treg cells induced by ocular resident cells such as retinal PE cells and related immunosuppressive molecules can be applied as immune therapy for refractive autoimmune uveitis in humans in the future. PMID- 23108336 TI - Socioeconomic inequalities in childhood obesity in the United Kingdom: a systematic review of the literature. AB - Childhood obesity is a major public health challenge worldwide. There is a growing literature documenting socioeconomic inequalities in childhood obesity risk. Here we draw inference from the literature about inequalities in childhood obesity risk in the UK. We summarize and appraise the extant peer-reviewed literature about socioeconomic inequalities in childhood obesity in the UK. Common area-level indices of socioeconomic position, including the Carstairs Deprivation Index, the Index of Multiple Deprivation and the Townsend Deprivation Index, as well as common household and individual-level metrics of childhood socioeconomic position, including head-of-household social class and maternal education, were generally inversely associated with childhood obesity in the UK. We summarize key methodological limitations to the extant literature and suggest avenues for future research. PMID- 23108337 TI - [Rotator cuff]. PMID- 23108338 TI - Extending the health benefits of clean indoor air policies. PMID- 23108339 TI - Modeling colloid deposition on a protein layer adsorbed to iron-oxide-coated sand. AB - Our recent study reported that conformation change of granule-associated Bovine Serum Albumin (BSA) may influence the role of the protein controlling colloid deposition in porous media (Flynn et al., 2012). The present study conceptualized the observed phenomena with an ellipsoid morphology model, describing BSA as an ellipsoid taking a side-on or end-on conformation on granular surface, and identified the following processes: (1) at low adsorbed concentrations, BSA exhibited a side-on conformation blocking colloid deposition; (2) at high adsorbed concentrations, BSA adapted to an end-on conformation promoted colloid deposition; and (3) colloid deposition on the BSA layer may progressively generate end-on molecules (sites) by conformation change of side-on BSA, resulting in sustained increasing deposition rates. Generally, the protein layer lowered colloid attenuation by the porous medium, suggesting the overall effect of BSA was inhibitory at the experimental time scale. A mathematical model was developed to interpret the ripening curves. Modeling analysis identified the site generation efficiency of colloid as a control on the ripening rate (declining rate in colloid concentrations), and this efficiency was higher for BSA adsorbed from a more dilute BSA solution. PMID- 23108340 TI - Mechanisms for maintaining muscle. AB - PURPOSE OF REVIEW: The balance between the rates of protein synthesis and protein degradation governs the maintenance of muscle mass in the body. The main purpose of this review is to highlight the latest understanding of the various pathways that maintain this balance between muscle atrophy and hypertrophy. RECENT FINDINGS: The maintenance of muscle mass is an interplay between anabolic and catabolic pathways that are interconnected at several junctures. The insulin-like growth factor 1/IRS1/PI3K/Akt pathway along with the ubiquitin-proteasome pathway, lysosomal/autophagy pathway and myostatin pathway maintain this homeostasis with the aid of various transcriptional and genetic factors, many of which continue to be discovered and studied in an ongoing fashion. SUMMARY: We tried to present, in this short review, a holistic view of the various players, old and new, responsible for the maintenance of this delicate equilibrium between muscle gain and loss. The development of novel therapeutics aimed at the activation or suppression of these described mediators may help the field of medicine in the management of a myriad of clinical conditions, thereby improving mobility and quality of life of affected patients. PMID- 23108341 TI - Advancing the science of hospice care: Coalition of Hospices Organized to Investigate Comparative Effectiveness. AB - PURPOSE OF REVIEW: There is very little high-quality evidence to guide clinical practice in hospice care. In the areas of medical therapy, patient-centered and family-centered outcomes, and patient safety, there are numerous high-impact questions for which answers are needed. Although randomized controlled trials are the gold standard for research, such trials are difficult, time consuming, and expensive to conduct in a hospice population. Moreover, they cannot examine the implementation of therapies in real-world settings. Therefore, there is a need for novel, complementary approaches to research in this unique population. RECENT FINDINGS: This article describes the initial experience of the Coalition of Hospices Organized to Investigate Comparative Effectiveness (CHOICE). CHOICE is a national network of hospices that use electronic health record-based data collection procedures to answer key questions relevant to clinical care and policy. By using a rich source of existing data to conduct observational studies, CHOICE is able to overcome many of the most significant challenges of randomized controlled trials in hospice. However, this approach also created unique challenges related to governance and privacy concerns. SUMMARY: CHOICE is a growing research network that has the potential to make a contribution to the science of palliative care in a hospice population. PMID- 23108342 TI - Symptom clusters in children. AB - PURPOSE OF REVIEW: Researchers have focused on identifying and describing symptom experiences among children with various diseases but symptoms can have a synergistic and/or an antecedent effect that must be evaluated. This review reports the current knowledge of symptoms among various pediatric diseases and highlights symptom cluster research. RECENT FINDINGS: Symptoms of depression and anxiety are the most prevalent variables studied across pediatric disease studies followed by pain, fatigue, and quality of life. Although previous pediatric symptom research provides a foundation for understanding the complexities of these symptoms, there is limited evidence on symptom cluster research in pediatrics. Pain and fatigue are the most common symptoms analyzed for correlations, and relationships among symptoms that have been evaluated in children with juvenile idiopathic arthritis, HIV, cancer, cardiac disease requiring an implantable cardioverter defibrillator, and at end of life. Pain and fatigue have been associated with sleep disturbances, anxiety, depression, anorexia, and nausea/vomiting. SUMMARY: Pediatric oncology researchers are leading the way with symptom cluster studies; however, this work remains in the early stages. There is great potential to advance the state of the science with cluster analysis. Future research work should focus on evaluating symptoms and their interactions. PMID- 23108343 TI - Preparation and characterization of CuInS2 nanocrystals for photovoltaic materials. AB - Copper indium disulphide (CIS) nanocrystals (NCs) were prepared using a one-pot synthesis. The stoichiometry was optimized based on its current density as measured by photoelectrochemical (PEC) experiments at interfaces between NC films deposited on ITO and 0.1 M methyl viologen dichloride (MV(2+)) solution. This method also offers insight into the kinetics of the photoreaction. A copper poor sulphur rich starting ratio was found to produce a copper-rich, indium-poor and slightly sulphur rich material. Further NC characterization was performed with SEM and TEM to investigate the morphology and crystallinity of the 30-70 nm NCs. The oxidation states of the individual elements were determined to be I, III, and 2- for Cu, In and S, respectively. Characteristics of optimal as-prepared NCs were found to be compatible among high functioning absorbing layers. PMID- 23108344 TI - Synthesis of superamphiphobic breathable membranes utilizing SiO2 nanoparticles decorated fluorinated polyurethane nanofibers. AB - Superamphiphobic nanofibrous membranes exhibiting robust water/oil proof and breathable performances were prepared by the combination of a novel synthesized fluorinated polyurethane (FPU) containing a terminal perfluoroalkane segment and incorporated SiO(2) nanoparticles (SiO(2) NPs). By employing the FPU/SiO(2) NPs incorporation, the hybrid membranes possess superhydrophobicity with a water contact angle of 165 degrees and superoleophobicity with an oil contact angle of 151 degrees . Surface morphological studies have indicated that the wettability of resultant membranes could be manipulated by tuning the surface composition as well as the hierarchical structures. The quantitative hierarchical roughness analysis using N(2) adsorption method has confirmed a major contribution of SiO(2) NPs on enhancing the porous structure, and a detailed correlation between the fractal dimension and amphiphobicity is proposed. Furthermore, a designed concept test shows that the as-prepared membranes could load 1.5 kg water or oil at the same time maintained an extremely high air permeability of 2 L min(-1), suggesting their use as promising materials for a variety of potential applications in protective clothing, bioseparation, water purification, tissue engineering, microfluidic systems, etc., and also provided new insight into the design and development of functional hybrid membranes based on FPU. PMID- 23108345 TI - Reply: HCG supplementation of controlled ovarian stimulation cycles. PMID- 23108346 TI - Preclinical report on allogeneic uterus transplantation in non-human primates. AB - STUDY QUESTION: Is it possible to perform allogeneic uterus transplantation (UTx) with a donation from a live donor in a non-human primate species and what immunosuppression is needed to prevent rejection? SUMMARY ANSWER: Allogeneic UTx in the baboon is a donor- and recipient-safe surgical procedure; immunosuppression with induction therapy and a triple protocol should be used. WHAT IS KNOWN ALREADY: UTx may become a treatment for absolute uterine factor infertility. Autologous UTx models have been developed in non-human primates with reports on long-term survival of the uterine grafts. STUDY DESIGN, SIZEAND DURATION: This experimental study included 18 female baboons as uterus donors and 18 female baboons as uterus recipients. The follow-up time was 5-8 weeks. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Uterus retrieval was performed with extended hysterectomy including bilateral uterine and internal iliac arteries and ovarian veins. After UTx, with vascular anastomoses unilateral to the internal iliac artery and the external iliac vein, the uterus recipients received one of the following: no immunosuppression (n = 4); monotherapy (oral slow release tacrolimus) (n = 4) or induction therapy (antithymocyte globulin) followed by triple therapy (tacrolimus, mycophenolate, corticosteroids; n = 10). Surgical parameters, survival, immunosuppression and rejection patterns were evaluated. MAIN RESULTS AND THE ROLE OF CHANCE: The durations of uterus retrieval and recipient surgery were around 3 and 3.5 h, respectively. The total ischemic time was around 3 h. All the recipients and the donors survived the surgery. All the recipients presented rejection to some extent within the first weeks following UTx. In one recipient, the uterus was of normal appearance at the end of the study period. In spite of occasional high (>60 ng/ml) blood levels of tacrolimus, there was no evidence of nephrotoxicity. LIMITATIONS AND REASONS FOR CAUTION: This initial non-human primate allogeneic UTx study indicates that further research is needed to optimize immunosuppression protocols in order to avoid uterine rejection. WIDER IMPLICATIONS OF THE FINDINGS: The findings suggest that allogeneic UTx in primate species is feasible but continued work on this issue is needed. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Swedish Research Council, ALF University of Gothenburg, Hjalmar Svensson Foundation and by Jane and Dan Olsson Research Foundation. The authors do not have any competing interest. PMID- 23108347 TI - HCG supplementation of controlled ovarian stimulation cycles. PMID- 23108348 TI - Pelvic pain in women with ovarian endometrioma is mostly associated with coexisting peritoneal lesions. AB - STUDY QUESTION: Is the occurrence of pelvic pain in women with ovarian endometrioma associated with coexisting peritoneal lesions (PLs)? SUMMARY ANSWER: Pelvic pain in women with ovarian endometrioma is usually associated with coexisting PLs. An increased tissue inflammatory reaction with elevated prostaglandin (PG) production may be responsible for the generation of pain. WHAT IS KNOWN ALREADY: Severe pelvic pain in women with ovarian endometrioma is reported to be associated with deeply infiltrating endometriosis. However, information on pelvic pain in women with ovarian endometriosis with and without coexistent peritoneal superficial lesions is limited. STUDY DESIGN, SIZE AND DURATION: Retrospective clinical study with case-controlled biological research using prospectively collected tissue samples derived from women with and without endometriosis and their retrospective evaluation. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a retrospective cohort study conducted in 2988 cases who had laparoscopic surgery for indications of ectopic pregnancy, tubal infertility and other benign gynecologic diseases. We analyzed the occurrence of pelvic pain in the cases with ovarian endometrioma according to the distribution of coexisting PLs and pattern of intrapelvic adhesions. Inflammatory reaction of eutopic and ectopic endometria was measured by immunoreaction to macrophage marker, CD68. The tissue expression of cyclooxygenase (COX) 2 was examined by immunohistochemistry and tissue concentrations of PG F2alpha were measured by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 2988 surgical cases, 350 (11.7%) were found to have ovarian endometrioma at laparoscopy. Coexisting PLs were present in 269 of these women and in this group 85.4% of cases experienced pelvic pain and 14.6% had no pain. In contrast, among the 81 women with ovarian endometrioma only, 38.3% cases experienced pelvic pain and 61.7% cases had no pain and the difference between the groups was statistically significant (P < 0.01). The infiltration of CD68-immunoreactive macrophages was significantly higher in the eutopic and ectopic endometria of women with peritoneal endometriosis than in ovarian endometrioma. The tissue expression of COX2 and levels of PGF2alpha were significantly higher in both the eutopic and ectopic endometria derived from women with peritoneal endometriosis than in similar tissues derived from women with ovarian endometrioma. LIMITATIONS, REASONS FOR CAUTIONS: Lack of evaluation in the detection of general or disseminated deeply infiltrating endometriosis in the pelvic cavity could be a bias or limitation in this study. Further multicenter prospective studies are needed to strengthen our current findings. WIDER IMPLICATIONS OF THE FINDINGS: Our findings may provide some new insights to understand the physiopathology of pelvic pain in women with ovarian cystic endometriosis and may hint at proper surgical manipulation to prevent the recurrence of pelvic pain in these women. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23108349 TI - Variation in mean human sperm length is linked with semen characteristics. AB - STUDY QUESTION: Are there any links between the length measurements of sperm components (head, midpiece, flagellum, total sperm length and the flagellum:head ratio) and data obtained during semen analysis? SUMMARY ANSWER: Both the mean measurement and the variation in the lengths of sperm components are related to characteristics of semen. WHAT IS KNOWN ALREADY: Studies in non-human species have shown that sperm morphology (size and shape) is associated with testes productivity and the consistency of sperm manufacture. However, no study to date has investigated whether there are relationships between the size and consistency of human sperm components, and measures of semen characteristics, including sperm numbers and how well they swim. STUDY DESIGN, SIZE AND DURATION: A retrospective laboratory study of the semen provided by 103 randomly selected men from a 500 man cohort who enrolled into the study between April and December 2006. PARTICIPANTS AND SETTING: Men attending Sheffield Teaching Hospital NHS Foundation Trust for semen analysis as part of investigations for infertility and whose ejaculates were found to contain sperm. MAIN RESULTS AND THE ROLE OF CHANCE: The mean flagellum length and the mean total sperm length were positively associated with semen characteristics measured manually, but were not associated with the sperm swimming speed measured by computer-aided sperm analysis. Ejaculates with a lower variation in the length of sperm components contained sperm that were more likely to be motile. The mean sperm length components accounted for up to 9% of the variance in semen characteristics, while the coefficient of variation accounted for up to 21%. LIMITATIONS AND REASONS FOR CAUTION: The sperm examined were obtained from men undergoing fertility investigations and so these results may not reflect men in the general population. WIDER IMPLICATIONS OF THE FINDINGS: Sperm length measurements may provide a useful insight into testis function and the efficiency of spermatogenesis. STUDY FUNDING AND COMPETING INTERESTS: This study was supported by funding from the University of Sheffield. The authors declare no conflicts of interest. PMID- 23108350 TI - Exceptionally high lactide polymerization activity of zirconium complexes with bridged diketiminate ligands. AB - A cyclohexanediyl-bridged, bis(N-xylyl) diketiminate ligand, (+/-) C6H10(nacnac(Xyl)H)2, LH2 (Xyl = 2,6-dimethylphenyl), was obtained from the reaction of [(2,6-dimethylphenyl)amino]-pent-3-en-2-one first with Meerwein's salt, then with (+/-)-cyclohexanediamine. The reaction of the ligand with Zr(NMe2)4 yielded LZr(NMe2)2. Protonation of the remaining diamide ligands with EtOH or [H2NMe2]Cl yielded LZr(OEt)2 and LZrCl2, respectively. The latter complex was also obtained by the reaction of LH2 first with nBuLi and then with ZrCl4(THF)2. The dichloride complex yielded LZr(OEt)2 and LZrMe2 upon reaction with NaOEt or MeLi/AlMe3, respectively. X-ray diffraction studies showed a trans configuration of the ancillary ligands in LZrCl2 and LZrMe2, and a cis configuration in LZr(NMe2)2 and LZr(OEt)2. LZr(OEt)2 was tested as a catalyst for the polymerization of rac-lactide. Kinetic investigations yielded a rate law first order in catalyst and monomer and a rate constant k = 14(1) L mol(-1) s( 1), the latter being orders of magnitude higher than typical activities for group 4 complexes in lactide polymerization. Analyses of the obtained polymer revealed an atactic polymer and broad polymer molecular weight distributions with sizeable fractions of cyclic oligomers. The influence of contaminants on the polymerization activity was examined: while lactic acid deactivates the catalyst, addition of up to 1 equiv. of water or para-toluenesulfonic acid revitalized catalysts not showing maximum activity. PMID- 23108351 TI - Electrochemical detection of pyocyanin in nanochannels with integrated palladium hydride reference electrodes. AB - Miniaturized and integrated components for electrochemical detection in micro- and nano-fluidic devices are of great interest as they directly yield an electrical signal and promise sensitive, label-free, real-time detection. One of the challenges facing electrochemical sensing is the lack of reliable reference electrode options. This paper describes the fabrication and characterization of a microscale palladium hydride reference electrode in a single microfabrication step. The reference electrode was integrated inside of a nanoscale constriction along with a gold working electrode to create a complete electrochemical sensor. After charging the palladium electrode with hydrogen, the device was used to detect pyocyanin concentrations from 1-100 MUM, with a 0.597 micromolar detection limit. This is the first time that a palladium hydride reference electrode has been integrated with a microfabricated electrochemical sensor in a nanofluidic setup. The device was then used over the course of 8 days to measure pyocyanin produced by four different Pseudomonas aeruginosa strains in growth media. By utilizing square wave and differential pulse voltammetry, the redox active molecule, pyocyanin, was selectively detected in a complex solution without the use of any electrode surface modification. PMID- 23108352 TI - Photoremovable protecting groups as controlled-release device for sex pheromone. AB - Photoremovable protecting groups (PRPGs) were demonstrated as a delivery device for controlled release of pheromone under both UV light (>=350 nm) and direct sunlight irradiation. In the present work, (Z)-11-hexadecen-1-ol (sex pheromone of Chilo infuscatellus Snellen) was chemically caged by four different photoremovable protecting groups (7-hydroxy-4-hydroxymethylcoumarin, 1 pyrenemethanol, 9-anthracenemethanol and 2-(hydroxymethyl)anthraquinone) individually. Photophysical studies showed that the caged pheromone with coumarin, pyrene and anthracene derivatives exhibited strong fluorescence. Controlled release of (Z)-11-hexadecen-1-ol was achieved by irradiating the caged compounds in aqueous ethanol both under UV and sunlight. Further, to mimic the environmental conditions, controlled release of (Z)-11-hexadecen-1-ol was also studied in soil medium under direct sunlight. Thermogravimetric analysis showed that caging of (Z)-11-hexadecen-1-ol by PRPGs significantly reduced its volatility. Bioassay experiments indicated that PRPGs are harmless to soil bacteria (Azotobacter sp. and Pseudomonas aeruginosa) and in vitro cytotoxicity studies on eukaryotic L929 cells showed that PRPGs are also non-toxic. Field bioassays were performed using caged pheromone against maize stalk borer (Chilo partellus) and the results showed that the caged alcohol is effective in a number of moths catches instead of free alcohol in a blend for a longer period of time. Our studies indicated that use of PRPGs as delivery device for controlled release of pheromone by sunlight holds great interest for field applications. PMID- 23108353 TI - Trust and the demand for autonomy may explain the low rates of immunizations among nurses. AB - Rates of vaccinations of healthcare workers with recommended vaccines are generally low in the developed countries. Our goals were to identify attitudes associated with self-reported vaccinations against pertussis and seasonal influenza among Israeli nurses in Mother and Child Healthcare Centers (MCHC) in the Haifa District. Over 100 nurses answered a self-administered questionnaire. Forty two percent of the nurses reported receiving the pertussis vaccine in the last five years and 44% reported receiving the influenza vaccine during the previous year. Attitudes toward the importance of vaccinating nurses, trust in the public health authorities and demand for autonomy were associated with receiving the pertussis vaccine. Attitudes toward the importance of vaccinating nurses and trust were associated with receiving the influenza vaccine in a bivariant analysis. However, in the logistic regression models only attitudes toward the importance of vaccinating nurses were associated with vaccinations [odds ratio (OR)- 3.66, 95% confidence interval (CI)- 1.4-9.6 for pertussis and OR- 4.53, CI-1.6-13.0 for influenza]. Jewish nurses reported more often receiving the influenza vaccine compared with the Arab nurses, whereas there was no difference between them in receiving the pertussis vaccine. Low levels of positive attitudes toward the importance of vaccinating nurses may inhibit nurses in MCHC from receiving vaccines. The demand for autonomy and low levels of trust may, in part, form these low levels of positive attitudes toward the importance of vaccinating nurses. PMID- 23108354 TI - Vaccine effectiveness evaluation during a varicella outbreak among children of primary schools and day-care centers in a region which adopted UMV. AB - This study describes an outbreak of varicella, in a small town in the region of Puglia, Southern Italy, in the period between February-March 2011. This outbreak presented the opportunity to assess varicella vaccine effectiveness and its determinants. The outbreak occurred in a small community in Puglia; parents of the children attending the schools of the community were contacted by telephone and information was gathered on current disease and varicella history. Varicella vaccination history was verified through the immunization registry of the Local Health Unit. Before the outbreak, immunization coverage was 86.6% of children attending preschool and 51.9% of children attending elementary school. In day care center where the outbreak was happened, the attack rate in vaccinated individuals was 32.1% and 80% in susceptible unvaccinated individuals. VE is therefore estimated as 59.9% (95% CI = 48.3-69.8). In the elementary school the VE can be calculated as 69.2% (95% CI = 50.5-88.1), since the attack rate in unvaccinated children was of 23.1% and in vaccinated of 7.1. The time between vaccination and the onset of the epidemic appears higher in children with a vaccine failure. The results of this study highlight the need for a reflection on the desirability of adopting a shorter schedule in Italy, with a minimum 1 mo interval between MMRV doses. PMID- 23108355 TI - The changing epidemiology of meningococcal disease in North America 1945-2010. AB - The epidemiology of Invasive Meningococcal Disease (IMD) is distinct in the United States and Canada compared with other countries. This review describes the incidence, mortality and vaccination strategies relevant to IMD in these countries over the past 65 y. The incidence of IMD has remained consistently low in both countries during this period. Serogroup B and serogroup C have been the most prominent disease-causing serogroups. Notably, serogroup Y has recently become an important cause of IMD in the USA, but has not been as prominent in Canada. Periodic rises in incidence have been characterized by local outbreaks that have raised public concern, especially those caused by serogroup C in Canada, and serogroup B in the USA. Case fatality rates have remained consistent at around 10-20%, but vary by age and serogroup. Recent outbreaks have led to the introduction of vaccination programs for both outbreak control and routine immunization. PMID- 23108356 TI - Mini-chaperones: potential immuno-stimulators in vaccine design. AB - The immunogenic properties of heat shock proteins (HSPs) have prompted investigations into their application as immuno-modulatory agents. HSPs have been used as potent adjuvants in immunotherapy of cancer and infectious diseases. Some studies showed that immune activities reside within N- or C-terminal fragments of HSPs. These small fragments are sufficient to link peptides, to bind and be taken up by the receptors CD91 and scavenger receptor type A on antigen presenting cells (APCs). Thus, these mini-chaperones can be used in immunotherapy of tumors and vaccine development. The data clearly demonstrated the potential of using HSP fragments as a possible adjuvant to augment CTL response against infectious diseases. Some HSP domains have been shown to inhibit endothelial cell growth, angiogenesis or tumor growth. In this review, we describe the immuno-stimulatory activities of various mini-chaperones in development of different vaccine strategies (DNA-based vaccine and protein/peptide-based vaccines). PMID- 23108358 TI - Vaccine research, adolescents and Africa. PMID- 23108357 TI - Transgenic tobacco expressed HPV16-L1 and LT-B combined immunization induces strong mucosal and systemic immune responses in mice. AB - BACKGROUND: Although there are two HPV vaccines have been used to prevent cervical cancer, the cost limits their application in developing countries. The aim of this study was to evaluate the potential value of plant-based HPV16L1 and LTB proteins as a high-efficiency, low-cost and easy-to-use HPV16L1 oral vaccine. RESULTS: Transgenic plant-derived HPV16L1 and LTB were identified, which display potent immunogenicity and biologic activity. Higher levels of specific IgG and IgA levels of HPV16L1 were induced when mice were immunized with L1 combined with LTB by the oral route. The stimulation index (SI) of spleen cells from the L1/LTB immunized group was significantly higher than that in the L1-immunized group (p < 0.05). The percentage of IFN-gamma (+) /IL-4 (+) CD4 (+) T cells from the L1/LTB group was clearly increased compared with that in the L1 and control groups (p < 0.05). METHODS: Plant-expressed HPV16L1 and LTB proteins were extracted from transgenic tobacco leaves, and their biologic characteristics and activity were examined with electron microscopy and GM1-binding assays respectively. Mice were immunized orally with either HPV16L1 or LTB alone or in combination. Induced mucosal and systemic immune responses were detected by ELISA, Hemagglutination inhibition (HAI), lymphocyte proliferation assays and flow cytometry analysis. CONCLUSION: Strong mucosal and systemic immune responses were induced by transgenic tobacco derived HPV16-L1 and LTB combined immunization. This study will lay the foundation for the development of a new type of vaccine to decrease HPV16 infections, which may lead to the prevention of cervical cancer. PMID- 23108359 TI - How can nanotechnology help membrane vesicle-based cancer immunotherapy development? AB - Exosomes are nanosized vesicles originating from endosomal compartments and secreted by most living cells. In the past decade, exosomes have emerged as potent tools for cancer immunotherapy due to their important roles in modulation of immune responses, and promising results have been achieved in exosome-based immunotherapy. The recent rapid progress of nanotechnology, especially on tailored design of nanocarriers for drug delivery based on both passive and active targeting strategies, sheds light on re-engineering native membrane vesicles for enhanced immune regulation and therapy. Applications of nanotechnology toolkits might provide new opportunity not only for value-added therapeutic or diagnostic strategies based on exosomes in cancer immunotherapy, but also new insights for biogenesis and biological relevance of membrane vesicles. This commentary focuses on the recent development and limitations of using exosomes in cancer immunotherapy and our perspectives on how nanomaterials with potential immune regulatory effects could be introduced into exosome-based immunotherapy. PMID- 23108360 TI - Human papilloma virus vaccines: need to be introduced in India. AB - Human papilloma viruses (HPVs) infect the skin and mucosal epithelium of both men and women. There are about 100 types of HPVs, which are differentiated by the genetic sequence of the outer capsid protein L1. More than 30 types of HPVs are sexually transmitted. Most cases of carcinoma of the cervix are caused by HPV. Cervical cancer is one of the most common forms of cancer in women is the second biggest cause of female cancer mortality worldwide. The worldwide incidence of cervical carcinoma is 529,000 per year, and mortality is 275,000, of which an estimated 88% of deaths occur in developing countries. At least 20 million people worldwide are already chronically infected. Over 80% of cases of cervical carcinoma occurs in developing countries, with 25% estimated to occur in India. At least 50% of sexually active men and women encounter genital HPV at some time in their lives. Cervical cancer is ranked as the most frequent cancer in women in India. India has a population of approximately 366 million women above 15 y of age, who are at risk of developing cervical cancer. The current estimates indicate approximately 132,000 new cases diagnosed and 74,000 deaths annually in India, accounting for nearly one-third of the global cervical cancer deaths. HPV can be prevented by vaccination. Two types of HPV vaccines are available, as Gardasil and Cervarix, both of which are highly effective at preventing HPV infection. HPV vaccine is administered in a three-dose series administered by intramuscular injection, either in the deltoid muscle or in the antero-lateral thigh. The second and third doses should be administered 2 and 6 mo after the first dose respectively. The minimum interval between the first and second doses should be 4 weeks, between the second and third dose should be 12 weeks. PMID- 23108362 TI - Diagnostic and prognostic role of laparoscopic staging for gallbladder carcinoma. AB - BACKGROUND: The aim of this study was to evaluate the diagnostic and prognostic role of staging laparoscopy in gallbladder carcinoma (GBC). METHODS: From January 2007 through December 2010, 79 GBC patients without evidence of metastatic disease on preoperative imaging underwent staging laparoscopy. Peritoneal and liver metastases were assessed by a single surgeon in a systematic manner. Resection rate, safety, and survival analysis were compared between the laparoscopy group and no laparoscopy group. RESULTS: Disseminated disease was detected in 27 patients and no further surgery was performed; the overall accuracy for detecting unresectable disease was 67.5% (27/40), with 39 (75%) and 27 (51.9%) receiving resection and curative resection. In 203 GBC patients undergoing laparotomy, 90 (44.3%) and 53 (26.1%) patients received resection and curative resection; therefore, the resection rate and curative resection rate were significantly much higher in the laparoscopy group (p < 0.000). CONCLUSIONS: Staging laparoscopy in GBC is sensitive in detecting disseminated disease and increases the curative resection rate, shortens the recovery time, and has no negative implications on overall survival; therefore, we suggest the routine use of staging laparoscopy in patients with GBC without evidence of disseminated disease on preoperative imaging. PMID- 23108361 TI - Nicotine vaccines to treat tobacco dependence. AB - Tobacco smoking is globally far more widespread than use of any other substance of abuse. Nicotine is an important tobacco constituent that is responsible for addictive properties of smoking. The currently available medications for the treatment of nicotine addiction have limited efficacy. A challenging novel therapeutic concept is vaccination against nicotine. An efficient vaccine would generate antibodies that sequester nicotine in the blood and prevent its access to the brain. The vaccine would have great potential for treating nicotine addiction and for relapse prevention. We reviewed the current status of vaccines against nicotine addiction that are undergoing clinical trials or are in preclinical development. We discuss problems associated with the development of nicotine vaccines, their efficacy in addiction treatment, challenges and ethical concerns. Existing evidence indicates that nicotine vaccination is well tolerated and capable of inducing an immune response but its effectiveness in increasing smoking abstinence has not been shown so far. PMID- 23108363 TI - Design, synthesis and biological evaluation of benzo[e][1,2,4]triazin-7(1H)-one and [1,2,4]-triazino[5,6,1-jk]carbazol-6-one derivatives as dual inhibitors of beta-amyloid aggregation and acetyl/butyryl cholinesterase. AB - Alzheimer's disease (AD) onset and progression are associated with the dysregulation of multiple and complex physiological processes and a successful therapeutic approach should therefore address more than one target. Two new chemical entities, the easily accessible heterocyclic scaffolds 1,3 diphenylbenzo[e][1,2,4]triazin-7(1H)-one (benzotriazinone I) and 2-phenyl-6H [1,2,4]triazino[5,6,1-jk]carbazol-6-one (triazafluoranthenone II), were explored for their multitarget-directed inhibition of beta-amyloid (Abeta) fibrillization and acetyl- (AChE) and/or butyryl- (BChE) cholinesterase, three valuable targets for AD therapy. Introduction of appropriate amine substituents at positions 6 and 5 on scaffold I and II, respectively, allowed the preparation of a series of compounds that were tested as Abeta(1-40) aggregation and cholinesterase inhibitors. Potent inhibitors of Abeta self-aggregation were discovered and among them benzotriazinone 7 exhibited an outstanding IC(50) equal to 0.37 MUM. Compounds bearing a basic amine linked to the heterocyclic scaffold through a linear alkyl chain of varying length also afforded good ChE inhibitors. In particular, benzotriazinone 24 and triazafluoranthenone 38 were endowed with an interesting multiple activity, the former displaying IC(50) values of 1.4, 1.5 and 1.9 MUM on Abeta aggregation and AChE and BChE inhibition, respectively, and the latter showing IC(50) values of 1.4 and an outstanding 0.025 MUM in the Abeta aggregation and BChE inhibition, respectively. Benzotriazinone 24 and triazafluoranthenone 29, selected owing to their suitable aqueous solubility and Abeta aggregation inhibition, were submitted to a time course kinetic assay followed with thioflavin T (ThT) spectrofluorimetry, circular dichroism (CD) and transmission electron microscopy (TEM). Experimental data indicated that 24 acted at a low concentration ratio (10 MUM 24 vs. 50 MUM Abeta), stabilizing the unstructured Abeta peptide and inhibiting fibrillogenesis, and that 29 also acted as fibrillization inhibitor, but likely enhancing and stabilizing the beta-sheet arrangement of Abeta to yield protofibrillar species as detected by TEM. PMID- 23108364 TI - Narrow band ultraviolet B irradiations cause alteration in interleukin-31 serum level in psoriatic patients. AB - Scientific communications indicate the disturbed expression of neuropeptides in the skin and serum in psoriasis vulgaris (PsV) patients. Narrow-band ultraviolet radiation (NB-UVB) is one of the systemic therapies of PsV. The aim of the study was to evaluate the influence of NB-UVB therapy on substance P (SP), calcitonin gene-related peptide (CGRP), brain-derived neurotrophic factor (BDNF), corticotropin-releasing factor (CRF) and interleukin-31 (IL-31) serum concentrations in PsV patients. 59 psoriatic patients with mean PASI (psoriasis area and severity index) 14.3 were treated with NB-UVB (20 exposures). The control group consisted of 50 healthy subjects, whose age and sex matched. In all patients, serum concentration of BDNF, CRF, IL-31 substance P and CGRP was analyzed by ELISA before the treatment and in psoriatic group the analysis was also done after 10 and 20 irradiations. In patients there was found a significantly higher concentration of IL-31 (215.3 vs. 748.6 ng/ml; p < 0.0001), SP (25.7 vs. 67.2 pg/ml; p < 0.01), CGRP (31.4 vs. 44.15 pg/ml; p < 0.01) and a lower concentration of CRF (0.89 vs. 0.426 ng/ml; p < 0.0001) and BDNF (16.39 vs. 14.15 ng/ml; p = 0.1216) in comparison with the controls. 20 NB-UVB exposures caused a significant decrease in IL-31 level (748.6 vs. 631.7 ng/ml; p < 0.0001). The NB-UVB therapy had no major effect on neuropeptides serum levels regardless of a number of irradiations. On the basis of our study it can be suggested that IL-31 is involved in pathogenesis of psoriasis and the NB-UVB therapy causes alterations in its level. PMID- 23108365 TI - Minocycline modulates cytokine and chemokine production in lipopolysaccharide stimulated THP-1 monocytic cells by inhibiting IkappaB kinase alpha/beta phosphorylation. AB - Minocycline, which is a member of the broad-spectrum bacteriostatic tetracycline antibiotics group, has also recently been shown to have additional effects that are separate from their antimicrobial function; however, the detailed mechanisms involved remain unknown. We examined the effects of minocycline on cytokine and chemokine production and the expression levels of intracellular phosphorylated proteins in a lipopolysaccharide (LPS)-induced cytokine response model in vitro. In the present study, 3 cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6, and interferon [IFN]-gamma) and 7 chemokines (IL-8, interferon inducible protein [IP]-10, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, regulated upon activation normal T cell expressed secreted [RANTES], and eotaxin) were suppressed by minocycline in a dose-dependent manner. Moreover, the phosphorylation of inhibitor of nuclear factor-kappaB alpha (IkappaBalpha) and IkappaB kinase (IKK)alpha/beta, which is located upstream from IkappaBalpha, was significantly suppressed by minocycline, whereas the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, c Jun N-terminal kinase (JNK), p38, and TGF-beta-activated kinase (TAK)1 were not affected. Thus, minocycline appears to inhibit the signaling pathway at the level of IKKalpha/beta phosphorylation. In conclusion, minocycline was found to reduce the production of multiple cytokines and chemokines by inhibiting LPS-induced IKKalpha/beta phosphorylation. That is, minocycline appears to be a potent inhibitor of IKKalpha/beta phosphorylation. From a clinical and translational significance point-of view, these findings suggest that the use of minocycline offers the advantage of providing both antimicrobial and anti-inflammatory effects, which may be key in treating certain types of infectious diseases, particularly those that lead to hypercytokinemia and chronic inflammatory disorders. PMID- 23108366 TI - Shear induced formation of carbon and boron nitride nano-scrolls. AB - A 'top down' synthesis of carbon and hexagonal boron nitride (h-BN) nano-scrolls has been developed using the shear forces within dynamic thin films of N-methyl-2 pyrrolidone (NMP) generated on a rapidly rotating spinning disc processor (SDP), along with a theoretical understanding of the formation of the scrolls. PMID- 23108368 TI - The influence of stimulus duration on visual illusions and simple reaction time. AB - Target detection is affected by stimulus intensity. For instance, participants respond faster to larger objects than to smaller objects. In order to compute an object's size, the brain integrates contextual information, for example object distance. Accordingly, the perceived size of an object can be altered via depth cues which modulate perceived object distance. Recently, it has been demonstrated that reaction times are influenced by the perceived rather than by the retinal size of an object, thus indicating that manual responses are generated after the perceptual integration of distance and retinal size. However, the timing aspects of these integration processes to date remain largely unclear. Therefore, the present study investigated the influence of stimulus duration on size-distance integration by means of a simple reaction time paradigm and the well-known Ponzo illusion. In experiment 1, participants responded faster to perceptually longer lines within an illusion-inducing background, whereas no such effect was associated with a neutral background. Experiment 2 revealed that this effect depended on stimulus duration. Stimuli were reliably perceived even with the shortest durations. However, illusion-induced modulations of response times were not observed for stimulus durations shorter than 40 ms. The findings indicate that the integration of context and object information requires visual input to last for at least 40 ms. The data furthermore show that as long as the visual system has not enough time to integrate context and object information, size perception is formed on the basis of lower-level representations. PMID- 23108367 TI - Positive natural selection of TRIB2, a novel gene that influences visceral fat accumulation, in East Asia. AB - Accumulation of visceral fat increases cardiovascular mortality in industrialized societies. However, during the evolution of the modern human, visceral fat may have acted as energy storage facility to survive in times of famine. Therefore, past natural selection might contribute to shaping the variation of visceral fat accumulation in present populations. Here, we report that the gene encoding tribbles homolog 2 (TRIB2) influenced visceral fat accumulation and was operated by recent positive natural selection in East Asians. Our candidate gene association analysis on 11 metabolic traits of 5,810 East Asians revealed that rs1057001, a T/A transversion polymorphism in 3'untranslated region (UTR) of TRIB2, was strongly associated with visceral fat area (VFA) and waist circumference adjusted for body mass index (P = 2.7 * 10(-6) and P = 9.0 * 10( 6), respectively). rs1057001 was in absolute linkage disequilibrium with a conserved insertion-deletion polymorphism in the 3'UTR and was associated with allelic imbalance of TRIB2 transcript levels in adipose tissues. rs1057001 showed high degree of interpopulation variation of the allele frequency; the low-VFA associated A allele was found with high frequencies in East Asians. Haplotypes containing the rs1057001 A allele exhibited a signature of a selective sweep, which may have occurred 16,546-27,827 years ago in East Asians. Given the predominance of the thrifty gene hypothesis, it is surprising that the apparently non-thrifty allele was selectively favored in the evolution of modern humans. Environmental/physiological factors other than famine would be needed to explain the non-neutral evolution of TRIB2 in East Asians. PMID- 23108369 TI - Evidence against the facilitation of the vergence command during saccade-vergence interactions. AB - Combined saccade-vergence movements result when gaze shifts are made to targets that differ both in direction and in depth from the momentary fixation point. Currently, there are two rivaling schemes to explain these eye movements. According to the first, such eye movements are due to a combination of a conjugate saccadic command and a symmetric vergence command; the two commands are not taken to be independent but instead are suggested to interact in a nonlinear manner, which leads to an intra-saccadic facilitation of the vergence command. According to the second scheme, the saccade generator is disconjugate, thus encoding vergence information in the saccadic commands themselves, and the remaining vergence requirement is provided by an asymmetric mechanism. Here, we test the scheme that suggests an intra-saccadic facilitation of the vergence command. We analyze this scheme and show that it has two fundamental properties. The first is that the vergence command is always symmetric, even during the intra saccadic facilitation. The second is that the facilitated (and symmetric) vergence command sums linearly with the conjugate saccadic command at the final common pathway. Taking these properties together, this scheme predicts that the total magnitude of the saccadic component of combined saccade-vergence movements can be decomposed into a conjugate part and a symmetric part. When we tested this prediction in combined saccade-vergence movements of humans, we found that it was not confirmed. Thus, our results are incompatible with the facilitation of the vergence command hypothesis. Although these results do not directly verify the rivaling hypothesis, which suggests a disconjugate saccade generator, they do provide it with indirect support. PMID- 23108371 TI - Influence of high levels of cloud cover on vitamin D effective and erythemal solar UV irradiances. AB - The solar irradiances for the initiation of vitamin D synthesis (UV(D3)) have been measured concurrently with the amount of cloud cover to investigate the influence of high cloud cover fraction. The cases of 6.5 and more octa cloud cover were considered for five solar zenith angle (SZA) ranges up to 80 degrees . For each of the SZA ranges, the UV(D3) reduced due to the high cloud cover. The average of the ratios of the UV(D3) irradiances on a cloudy day to those on a clear day with the corresponding ozone and SZA are 0.71 for the 6.5-7.5 octa cloud and 0.45 for the more than 7.5 octa cloud ranges. The exposure times necessary to receive 1/3 MED to a horizontal plane were found to increase as the amount of cloud cover increased. For each cloud cover category, the range of values increased with cloud cover and with SZA. This research shows that the current public recommendations on the times of solar UV exposures required to produce adequate vitamin D are inappropriate for situations of more than 6.5 octa cloud. PMID- 23108370 TI - A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms? AB - Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group. PMID- 23108372 TI - Both BMI and waist circumference are associated with coronary vasoreactivity in overweight and obese men. AB - OBJECTIVE: Guidelines differ about the value of assessment of adiposity measures for cardiovascular disease risk prediction. Reduced coronary vasoreactivity appears to be one of the earliest abnormalities in the development of coronary artery disease. We studied the associations of BMI, waist circumference, waist-to hip ratio (WHR) and percentage of fat with coronary vasoreactivity. METHODS: Myocardial blood flow was quantitated in 14 overweight or obese non-smoking men (age 32 +/- 7 years, BMI 32 +/- 3 kg/m2, waist circumference 106 +/- 9 cm, WHR 0.96 +/- 0.04, %fat 27.2 +/- 3.7) using positron emission tomography and oxygen 15-labelled water. The measurements were performed basally and during adenosine infusion (140 ug/kg/min) to measure coronary vasoreactivity. RESULTS: Adenosine infusion induced significant increase in myocardial blood flow (from 0.8 +/- 0.2 to 3.5 +/- 0.9 ml/g/min). After adjustment for LDL-cholesterol, HbA(1c), systolic blood pressure and age, hyperaemic myocardial blood flow was inversely associated with BMI (r = -0.87, p = 0.001), waist circumference (r = -0.84, p = 0.003), WHR (r = -0.79, p = 0.007) and %fat (r = -0.65, p = 0.04). CONCLUSIONS: Both BMI and waist circumference are associated with coronary vasoreactivity in overweight and obese men. PMID- 23108373 TI - Random nanowires of nickel doped TiO2 with high surface area and electron mobility for high efficiency dye-sensitized solar cells. AB - Mesoporous TiO(2) with a large specific surface area (~150 m(2) g(-1)) is the most successful material in dye-sensitized solar cells so far; however, its inferior charge mobility is a major efficiency limiter. This paper demonstrates that random nanowires of Ni-doped TiO(2) (Ni:TiO(2)) have a dramatic influence on the particulate and charge transport properties. Nanowires (dia ~60 nm) of Ni:TiO(2) with a specific surface area of ~80 m(2) g(-1) were developed by an electrospinning technique. The band gap of the Ni:TiO(2) shifted to the visible region upon doping of 5 at% Ni atoms. The Mott-Schottky analysis shows that the flat band potential of Ni:TiO(2) shifts to a more negative value than the undoped samples. The electrochemical impedance spectroscopic measurements showed that the Ni:TiO(2) offer lower charge transport resistance, higher charge recombination resistance, and enhanced electron lifetime compared to the undoped samples. The dye-sensitized solar cells fabricated using the Ni:TiO(2) nanowires showed an enhanced photoconversion efficiency and short-circuit current density compared to the undoped analogue. The transient photocurrent measurements showed that the Ni:TiO(2) has improved charge mobility compared with TiO(2) and is several orders of magnitude higher compared to the P25 particles. PMID- 23108374 TI - A fourth-generation carbazole-phenylazomethine dendrimer as a size-selective host for fullerenes. AB - A fourth generation carbazole-phenylazomethine dendrimer with a porphyrin core was investigated as a new host for fullerenes (C(60), C(70), and C(84)). This dendrimer has a significantly higher association constant compared to the lower generation dendrimers, and the encapsulation is achieved by the cooperation of the dendron and the core. PMID- 23108375 TI - SOCS-3 is downregulated in progressive CKD patients and regulates proliferation in human renal proximal tubule cells in a STAT1/3 independent manner. AB - Proliferation and the sequence of epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), called epithelial-mesenchymal epithelial (EME) cycling are pivotal mechanisms of kidney repair and fibrosis. Furthermore, data suggest that dedifferentiation (EMT) is a prerequisite for proliferation of tubule cells. These processes have been shown to be regulated by STAT1/3 signaling. Suppressor of cytokine signaling-3 (SOCS-3) is a negative regulator of STAT1/3 signaling. Using a transcriptomics data set of patients with proteinuric kidney diseases we found that low levels of SOCS-3 RNA were associated with high-serum creatinine values in the long-term follow-up, which suggested a role of SOCS-3, regulated signaling in progression of chronic kidney disease. This result was validated in an independent cohort of patients with proteinuric nephropathies on protein level. In addition ~60% of STAT target genes were differentially expressed in relation to stable kidney disease patients. Using two renal cellular models and SOCS-3 knockdown by short interfering RNA we investigated SOCS-3 effects on oncostatin M-induced STAT activation, differentiation and proliferation. SOCS-3 knockdown resulted in enhanced pSTAT1/3 phosphorylation and epithelial differentiation. The latter effect was only slightly enhanced by OSM treatment. Cellular proliferation was inhibited after SOCS-3 knockdown. This effect could not be further stimulated by OSM. Effects of SOCS-3 knockdown were not enhanced by downregulation of STAT1/3, suggesting a STAT independent effect on cell cycle regulators. Indeed, knockdown and overexpression of SOCS-3 were associated with decrease and increase of cyclin D1, -E and proliferation, respectively. In summary, SOCS-3 inhibits phosphorylation of pSTAT1/3 in renal tubule cells. Additionally, we show for the first time that in vivo-loss of SOCS-3 is associated with unfavorable prognosis. In vitro, downregulation of SOCS-3 inhibits dedifferentiation (EMT) and cellular proliferation in kidney proximal tubule cells. PMID- 23108376 TI - OPA1 downregulation is involved in sorafenib-induced apoptosis in hepatocellular carcinoma. AB - Sorafenib has been used to treat advanced hepatocellular carcinoma (HCC), but the underlying molecular mechanisms remain controversial and why some patients do not respond to this therapy is poorly understood. In this study, we show that sorafenib triggers cell growth inhibition and apoptosis in HCC cells by directly targeting the mitochondria. Treatment with sorafenib induces rapid mitochondrial fragmentation, which is associated with the deregulation of mitochondria fusion related protein optic atrophy 1 (OPA1). Exposure of cells or isolated mitochondria to sorafenib substantially induces cytochrome c release. Our data indicate that siRNA-mediated OPA1 knockdown significantly sensitizes HCC cells to sorafenib-induced apoptosis. Furthermore, sorafenib has no apparent apoptotic toxicity to normal human primary hepatocytes. Sorafenib inhibits HCC xenograft tumor growth in vivo and murine xenograft tumor tissue analysis reveals mitochondria fusion protein. OPA1 expression levels are strongly downregulated by sorafenib treatment. Western blotting evaluation of patient HCC with matched non tumor tissue samples demonstrates that OPA1 expression is decreased in up to 40% of HCC patients. Taken together, we have shown that sorafenib suppresses the tumorigenesis of HCC through the induction of mitochondrial injury via OPA1. Our results provide new insights into the pathogenesis of HCC and suggest that OPA1 is a novel therapeutic target in patients with HCC. PMID- 23108377 TI - The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner. AB - Mucous metaplasia (MM) is an aberrant secretory phenotype that arises during Helicobacter-induced gastric carcinogenesis. HSPA5, a key modulator of the unfolded protein response (UPR) activated by endoplasmic reticulum (ER) stress is overexpressed in gastric cancer (GC). We studied activation of the UPR in MM and GC in humans and mice. We assessed RNA and protein levels of ER stress markers (HSPA5, XBP1, and CHOP) in human GC, and correlated with Helicobacter pylori (H. pylori) status, then surveyed HSPA5 in normal gastric mucosa and gastric pre neoplasia including gastritis and intestinal metaplasia (IM). The role of H. pylori infection in the UPR was assessed by co-culture with AGS GC cells. ER stress markers in metaplasia and dysplasia from transgenic K19-Wnt1/C2mE mice and C57Bl/6 mice with chronic Helicobacter felis (H. felis) infection were compared. HSPA5 was overexpressed in 24/73 (33%) of human GC. Induction of HSPA5 and XBP1 splicing was associated with H. pylori-associated GC (P=0.007 for XBP1 splicing). HSPA5 was overexpressed in MM but not gastritis in patients with H. pylori infection. Stimulation of AGS cells with CagA-positive H. pylori suppressed HSPA5 expression and XBP1 splicing. In the normal gastric mucosa of human and mouse, HSPA5 was constitutively expressed in MIST1-positive chief cells. Increased Hspa5 and Chop expression were found in dysplasia of C57Bl/6 mice with chronic H. felis infection but was absent in spontaneous gastric dysplasia in K19-Wnt1/C2mE mice with concomitant loss of Mist1 expression, similar to that observed in H. pylori associated human GC. Induction of the UPR in the milieu of Helicobacter-induced chronic inflammation and MM may promote neoplastic transformation of Helicobacter infected gastric mucosa. PMID- 23108378 TI - Role of pelvic floor muscle exercises in the prevention of stress urinary incontinence during pregnancy and the postpartum period. AB - OBJECTIVE: The aim of this study was to determine the role of pelvic floor muscle exercises (PFME) in the prevention of stress urinary incontinence (SUI) during pregnancy and the postpartum period. METHODS: A total of 102 women was included in the study. Data, collected through forms, included characteristics of the women, follow-up data during the pregnancy and postpartum period and a three-day urinary diary. Both groups were evaluated in terms of SUI at the 14th-20th, 28th and 32nd weeks of gestation and at 12 weeks postpartum. RESULTS: As shown by the pad test, SUI developed in 5.8, 17.3 and 1.9% of the subjects in the intervention group at the 28th and 32nd gestational week and the 12th postpartum week, respectively. The relevant ratios in the control group were 30, 48 and 18%, respectively. A statistically significant difference was found between the intervention and control groups in terms of SUI development at the 28th and 32nd weeks of gestation and the 12th postpartum week (p < 0.05). CONCLUSION: PFME are effective for prevention of SUI development during pregnancy and in the postpartum period. Health care providers are therefore recommended to provide education and counseling to pregnant women about SUI prevention. PMID- 23108379 TI - Fabrication of cone-shaped CNF/SiC-coated Si-nanocone composite structures and their excellent field emission performance. AB - Novel cone-shaped carbon nanofiber (CNF)/silicon carbide (SiC)-coated Si-nanocone (Si-NC) composite structures with excellent field emission (FE) performance have been fabricated by a simple microwave plasma chemical vapour deposition process. Transmission electron microscopy analyses reveal that the newly developed cone shaped composite structures are composed of bamboo-like herringbone CNFs grown vertically on the tips of conical SiC layers with a flat-top Si cone embedded underneath. For this CNF/SiC-coated Si-NC composite array, a ultra-low threshold field of 0.32 V MUm(-1) (at 10 mA cm(-2)), a large emission current density of 668 mA cm(-2) at 1.05 V MUm(-1), and a field enhancement factor as high as ~48,349 are obtained. In addition, the FE lifetime test performed at a large emission current density of 200 mA cm(-2) under an applied field of 1 V MUm(-1) shows no discernible decay during a period of over 260 minutes. We deduce that this superior FE performance can be attributed to the specific bamboo-like herringbone CNFs with numerous open graphitic edges and a faceted top end, and the conical base SiC/Si structures with sufficient adhesion to the substrate surface. Such a novel structure with promising emission characteristics makes it a potential material for electron field emitters. PMID- 23108380 TI - Bioimpedance rise in response to histone deacetylase inhibitor is a marker of mammary cancer cells within a mixed culture of normal breast cells. AB - Detection of a few cancer cells within a complex cellular mixture is a key challenge presented by clinical human biopsy samples. We have designed and tested a microfabricated bioimpedance device that can detect a few human MDA-MB-231 breast cancer cells in a mixed cell culture model of a breast tissue sample. The normal tissue components were modelled using non-cancerous MCF10A human breast epithelial cells and normal human HS68 fibroblasts. The sensor is a silicon chip 0.5 cm in diameter that contains one counter electrode and four 40 MUm-wide multi branched sensing electrodes. The cells' bioimpedances were characterized in pure monocultures and in mixed cell cultures following a brief cultivation on the sensor. After cell seeding, a stable bioimpedance signal was achieved indicative of cell attachment. A cancer-selective bioimpedance signal was elicited by addition of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor with selective actions on the cytoskeleton in breast cancer cells. SAHA elicited a 50% rise in peak bioimpedance in MDA-MB-231 breast cancer cells by 15 h. In mixed cultures of MDA-MB-231, MCF10A, and HS68 cells, the contribution of cancer cells present in the mixture dominated impedance response to SAHA. A single adherent cancer cell on any one of four electrodes in a background of ~100 normal cells resulted in >=5% increase in bioimpedance. The estimated sensitivity of this device is therefore one cancer cell among a background of 400 normal cells or the equivalent of 25 cancer cells in a biopsy sample of 10 000 cells. PMID- 23108381 TI - The value of the clinical impression in recognizing and treating sepsis patients in the emergency department. AB - OBJECTIVES: Immediate bedside recognition of sepsis in the emergency department (ED) enables early treatment. This study aims to investigate whether the clinical impression score of different health care providers (a) is a good predictor of the severity of sepsis, (b) is mutually agreed, and (c) correlates with the treatment provided in the ED. METHODS: We performed a prospective observational study in the ED of a tertiary teaching hospital over a 3-month period. The vital signs of all patients of at least 18 years presenting with suspected infection or sepsis were measured on arrival at the ED. In patients with at least one of the 'Systemic Inflammatory Response Syndrome' criteria, the nurse, resident, and attending physician assigned a clinical impression score for the degree of acute illness, ranging from 1 (not ill) to 10 (extremely ill). Additional information collected included demographic and treatment data. RESULTS: We included 123 patients with sepsis and 11 patients with a (suspected) infection with one 'Systemic Inflammatory Response Syndrome' criterion. The clinical impression scores of all health care providers increased significantly between the infection without sepsis, mild sepsis, and severe sepsis groups. The agreement between the health care providers ranged from moderate to good (weighted kappa 0.54-0.62). The clinical impression score correlated with time to antibiotics (R=-0.33, P=0.001), amount of volume therapy (R=0.61-0.64, P<=0.001), and amount of oxygen therapy (R=0.58-0.63, P<=0.001). CONCLUSION: The clinical impression score is associated with the severity of sepsis, is mutually agreed between the different health care providers and is correlated with sepsis treatment provided in the ED. PMID- 23108384 TI - Sleep disturbances in myotonic dystrophy type 2. AB - Sleep disorders in myotonic dystrophy type 1 (DM1) are common and include sleep disordered breathing, hypersomnia, and fatigue. Little is known regarding the occurrence of sleep disturbance in myotonic dystrophy type 2 (DM2). We hypothesized that DM2 patients may frequently harbor sleep disorders. We reviewed medical records of all genetically confirmed cases of DM2 seen at our sleep center between 1997 and 2010 for demographic, laboratory, overnight oximetry, and polysomnography (PSG) data. Eight patients (5 women, 3 men) with DM2 were identified. Excessive daytime sleepiness was seen in 6 patients (75%), insomnia in 5 (62.5%), and excessive fatigue in 4 (50%). Obstructive sleep apnea was diagnosed in 3 of 5 patients (60%) studied with PSG. Respiratory muscle weakness was present in all 6 patients (100%) who received pulmonary function testing. Four of 8 (50%) met criteria for diagnosis of restless legs syndrome. The clinical spectrum of DM2 may include a wide range of sleep disturbances. Although respiratory muscle weakness was frequent, sustained sleep-related hypoxia suggestive of hypoventilation was not seen in our patients. Further prospective studies are needed to examine the frequency and scope of sleep disturbances in DM2. PMID- 23108383 TI - HDAC isoenzyme expression is deregulated in chronic lymphocytic leukemia B-cells and has a complex prognostic significance. AB - Histone deacetylases (HDACs) play a crucial role in chromatin structure and, consequently, gene expression. Their deregulation has been reported in various cancers. We performed a complete and comprehensive study of the expression of 18 HDACs (including Sirtuin; SIRT) by real-time PCR in a cohort of 200 chronic lymphocytic leukemia (CLL) patients with a median follow-up of 77 mo, and compared it with the results obtained from normal B cells. We also compared HDAC expression at diagnosis and after relapse. We observed significant deregulation (mostly upregulation) of HDACs in CLL. In terms of clinical significance, only HDAC6 was significantly correlated with treatment-free survival (TFS), whereas HDAC3 and SIRT2, 3 and 6 were correlated with overall survival (OS). A multivariate Cox regression stepwise analysis indicated that HDAC6, 7 and 10 and SIRT3 were TFS independent predictors. Interestingly, poor prognosis was associated with an overexpression of HDAC7 and 10 but an underexpression of HDAC6 and SIRT3. Therefore, these factors were combined in a TFS score: patients with a score of 0-1-2, 3 and 4 had a median TFS of 107, 57 and 26 mo, respectively (HR = 4.03, p < 0.0001). For OS, SIRT5 and 6 allowed stratification into 3 groups, with a median OS of > 360, 237 and 94 mo (HR = 6.38, p < 0.0001). However, we could not find statistical differences in HDAC expression after relapse. These results, validated by a 5-fold cross-validation, highlight the complex impact of HDAC expression in CLL clinical course. PMID- 23108385 TI - [Database supported electronic retrospective analyses in radiation oncology: establishing a workflow using the example of pancreatic cancer]. AB - PURPOSE: Especially in the field of radiation oncology, handling a large variety of voluminous datasets from various information systems in different documentation styles efficiently is crucial for patient care and research. To date, conducting retrospective clinical analyses is rather difficult and time consuming. With the example of patients with pancreatic cancer treated with radio chemotherapy, we performed a therapy evaluation by using an analysis system connected with a documentation system. MATERIALS AND METHODS: A total number of 783 patients have been documented into a professional, database-based documentation system. Information about radiation therapy, diagnostic images and dose distributions have been imported into the web-based system. RESULTS: For 36 patients with disease progression after neoadjuvant chemoradiation, we designed and established an analysis workflow. After an automatic registration of the radiation plans with the follow-up images, the recurrence volumes are segmented manually. Based on these volumes the DVH (dose volume histogram) statistic is calculated, followed by the determination of the dose applied to the region of recurrence. All results are saved in the database and included in statistical calculations. CONCLUSION: The main goal of using an automatic analysis tool is to reduce time and effort conducting clinical analyses, especially with large patient groups. We showed a first approach and use of some existing tools, however manual interaction is still necessary. Further steps need to be taken to enhance automation. Already, it has become apparent that the benefits of digital data management and analysis lie in the central storage of data and reusability of the results. Therefore, we intend to adapt the analysis system to other types of tumors in radiation oncology. PMID- 23108386 TI - [Radical prostatectomy versus observation for localized prostate cancer]. PMID- 23108387 TI - Clinical characteristics, metabolic features, and phenotype of Chinese women with polycystic ovary syndrome: a large-scale case-control study. AB - AIM: The Rotterdam criteria extend the phenotypic spectrum of polycystic ovary syndrome (PCOS). The study was to investigate the clinical and biochemical features of a large-scale clinic based on the samples of Chinese women and to evaluate the value of Rotterdam criteria on Chinese PCOS women. METHODS: One thousand four hundred and four Chinese women were involved in our study, among whom, 719 cases were diagnosed as PCOS based on 2003 Rotterdam criteria, and 685 women without history of hyperandrogenism and with regular menstrual cycles were recruited as control. Clinical features, ultrasonographic (ovarian follicle number and volume), hormonal and metabolic parameters were commenced as outcome measures. RESULTS: Among 719 PCOS women, 6.1 % had hirsutism, 13.3 % had acne, 21.1 % had hyperandrogenism, 94.2 % had polycystic ovaries on ultrasonographic examination, and 88.6 % had menstrual abnormality. About one-third of the total PCOS patients were insulin resistant. The most frequent PCOS phenotype is the non hyperandrogenic phenotype (O + P). Total testosterone, LH/FSH ratio, body mass index (BMI), and Ferriman and Gallwey scores (F-G) were all significantly higher in PCOS groups compared with non-PCOS group. Women with PCOS and obesity had higher serum testosterone, fasting insulin, longer menstrual cycle and larger ovarian follicle number, and LH/FSH ratio, estradiol or ovarian volume were similar between obese and normal BMI women. The LH level was statistically lower in the obese PCOS group. CONCLUSIONS: Rotterdam criteria are generally applicable to Chinese population. Chinese women with PCOS showed lower rates of hyperandrogenemia, hirsutism, obesity, and insulin resistance. Obesity aggravates menstrual irregularity and increases the follicle number and serum total testosterone level. PMID- 23108388 TI - Sacral nerve stimulation for faecal incontinence secondary to congenital imperforate anus. AB - After treatment in infancy, patients with imperforate anus can develop bowel dysfunction in adult life. Low anorectal malformations are often associated with congenital deformity of the sacrum and coccyx (sacrococcygeal agenesis). Sacral nerve stimulation (SNS) is an effective treatment for incontinent patients with an accompanying acquired sphincter defect. We report two patients treated by SNS for faecal incontinence secondary to congenital imperforate anus. Two adults presented with faecal incontinence. Both had a congenital imperforate anus. The first, a female 36 years old, suffered from lifelong incontinence. She had daily passive soiling, a sensation of incomplete emptying and urgency (less than 5 min). The second, a male 35 years old, had had incontinence since adulthood. He had urgency (2 min) and daily soiling. Both had undergone coloanal pull-through procedures in infancy. Anal manometry showed a low resting pressure in both patients (30 and 33 cm H2O) and a reduced peak squeeze pressure increment (15 and 40 cm H2O). Endoanal ultrasonography demonstrated a complete ring of muscle around the neo-anus in both patients. The patients underwent peripheral nerve evaluation (PNE). Both had partial sacral agenesis, which made this technically difficult. After 3 weeks of PNE, the female patient showed no improvement, but the male patient had no further episodes of incontinence and urgency improved from 2 to 15 min. Accordingly, he underwent implantation of a permanent pulse generator. SNS may be effective for some incontinent patients with imperforate anus even in the presence of partial sacral agenesis. The clinician should be aware of any associated sacral agenesis and the technical difficulty this may cause. Alternative methods of neuromodulation, such as pudendal nerve stimulation, could be considered in such cases. PMID- 23108389 TI - Hide and seek: tell-tale signs of breast cancer lurking in the blood. AB - Breast cancer treatment is improving due to the introduction of new drugs, guided by molecular testing of the primary tumour for mutations/oncogenic drivers (e.g. HER2 gene amplification). However, tumour tissue is not always available for molecular analysis, intra-tumoural heterogeneity is common and the "cancer genome" is known to evolve with time, particularly following treatment as resistance develops. After resection, those patients with only residual micrometastases are likely to be cured but those with radiologically detectable overt disease are not. Thus, the discovery of blood test(s) that could (1) alert clinicians to early primary or recurrent disease and (2) monitor response to treatment could impact significantly on mortality. Towards this, we and others have focused on molecular profiling of circulating nucleic acids isolated from plasma, both cell-free DNA (cfDNA) and microRNAs, and the relationship of these to circulating tumour cells (CTCs). This review considers the utility of each as circulating biomarkers in breast cancer with particular emphasis on the bioinformatic tools available to support molecular profiling. PMID- 23108390 TI - Neurofibromatosis 1-related osteopenia often progresses to osteoporosis in 12 years. AB - The current study is based on our earlier investigation carried out in 1999, where bone mineral density (BMD) of 35 neurofibromatosis type 1 (NF1) patients was measured and osteoporosis was shown to be common in NF1. The findings have been confirmed by a number of later publications. The purpose of the current longitudinal study was to assess the bone health of these 35 NF1 patients 12 years after the initial study. A total of 28 patients were reached, and BMD of 19 patients was subsequently remeasured. Fracture history of 28/35 NF1 patients who were reached was verified from the medical records. Six NF1 patients had osteoporosis in 1999, and three of them had an osteoporotic fracture between 1999 and 2011, showing an increased fracture risk compared to NF1 patients without osteoporosis. BMD of 19 patients was remeasured in 2011, and four patients who had osteopenia in 1999 had osteoporosis in 2011. The decrease in BMD was not explained by changes in smoking habits, physical activity, sunlight exposure, body mass index, or laboratory parameters, even though secondary hyperparathyroidism was common. Osteoporosis was found in 2011 in patients aged 37 years or older, both men and women. The results showed that NF1-related osteopenia often progresses to osteoporosis since BMD decreases with aging even in young patients. Even though our sample size was 19 patients, we recommend follow-up of NF1 patients with osteopenia and consideration of prophylactic measures to prevent osteoporosis and associated fracture risk. PMID- 23108391 TI - Obesity is an independent determinant of ischemia-modified albumin. AB - OBJECTIVE: We have measured ischemia-modified albumin (IMA), total antioxidant status (TAS), total oxidant status (TOS) and high-sensitivity C-reactive protein (hsCRP) levels in obese and normal-weight subjects to investigate if IMA can be used as a biomarker of oxidative stress and inflammation and if IMA was an independent determinant of obesity or not. METHODS: The study was performed on 92 obese subjects (20 male, 72 female) aged 38 +/- 11 years and 78 normal-weight controls (19 male, 59 female) aged 37 +/- 11 years. Serum lipids, IMA, TAS, TOS, and hsCRP levels of the subjects were measured. RESULTS: IMA (p < 0.05), TOS (p < 0.001), and hsCRP (p < 0.001) levels of the obese subjects were significantly higher, whereas TAS levels were significantly lower (p < 0.05) than those of the controls after adjustment for age and gender. In the linear regression analysis, waist circumference (r2 = 0.139, p < 0.01), BMI (r2 = 0.136, p < 0.01) and insulin (r2 = 0.120, p < 0.05) were shown to be significant independent determinants of IMA levels. CONCLUSIONS: We have found that oxidative stress and inflammation were increased and antioxidative defense was decreased, which resulted in increased levels of IMA, a biomarker of ischemia, in obese subjects. Also, obesity and insulin were found to be independent determinants of IMA. Thus, obese subjects are under high risk of ischemia, and IMA may be used as a biomarker of oxidative stress and ischemia. Further larger investigations are needed to confirm this opinion. PMID- 23108392 TI - V6O13 films by control of the oxidation state from aqueous precursor to crystalline phase. AB - An aqueous deposition process for V(6)O(13) films is developed whereby the vanadium oxidation state is continuously controlled throughout the entire process. In the precursor stage, a controlled wet chemical reduction of the vanadium(V) source with oxalic acid is achieved and monitored by (51)Vanadium Nuclear Magnetic Resonance ((51)V-NMR) and Ultraviolet-Visible (UV-Vis) spectroscopy. The resulting vanadium(IV) species in the aqueous solution are identified as mononuclear citrato-oxovanadate(IV) complexes by Electron Paramagnetic Resonance (EPR) and Fourier Transform Infra-Red (FTIR) spectroscopy. This precursor is successfully employed for the deposition of uniform, thin films. The optimal deposition and annealing conditions for the formation of crystalline V(6)O(13), including the control of the vanadium oxidation state, are determined through an elaborate study of processing temperature and O(2) partial pressure. To ensure a sub 100 nm adjustable film thickness, a non-oxidative intermediate thermal treatment is carried out at the end of each deposition cycle, allowing maximal precursor decomposition while still avoiding V(IV) oxidation. The resulting surface hydrophilicity, indispensable for the homogeneous deposition of the next layer, is explained by an increased surface roughness and the increased availability of surface vanadyl groups. Crystalline V(6)O(13) with a preferential (002) orientation is obtained after a post deposition annealing in a 0.1% O(2) ambient for thin films with a thickness of 20 nm. PMID- 23108393 TI - Sgk1 enhances RANBP1 transcript levels and decreases taxol sensitivity in RKO colon carcinoma cells. AB - The serum- and glucocorticoid-regulated kinase (Sgk1) is essential for hormonal regulation of epithelial sodium channel-mediated sodium transport and is involved in the transduction of growth factor-dependent cell survival and proliferation signals. Growing evidence now points to Sgk1 as a key element in the development and/or progression of human cancer. To gain insight into the mechanisms through which Sgk1 regulates cell proliferation, we adopted a proteomic approach to identify up- or downregulated proteins after Sgk1-specific RNA silencing. Among several proteins, the abundance of which was found to be up- or downregulated upon Sgk1 silencing, we focused our attention of RAN-binding protein 1 (RANBP1), a major effector of the GTPase RAN. We report that Sgk1-dependent regulation of RANBP1 has functional consequences on both mitotic microtubule activity and taxol sensitivity of cancer cells. PMID- 23108394 TI - The Forkhead Box M1 protein regulates BRIP1 expression and DNA damage repair in epirubicin treatment. AB - FOXM1 is implicated in genotoxic drug resistance but its role and mechanism of action remain unclear. Here, we establish that gammaH2AX foci, indicative of DNA double-strand breaks (DSBs), accumulate in a time-dependent manner in the drug sensitive MCF-7 cells but not in the resistant counterparts in response to epirubicin. We find that FOXM1 expression is associated with epirubicin sensitivity and DSB repair. Ectopic expression of FOXM1 can increase cell viability and abrogate DSBs sustained by MCF-7 cells following epirubicin, owing to an enhancement in repair efficiency. Conversely, alkaline comet and gammaH2AX foci formation assays show that Foxm1-null cells are hypersensitive to DNA damage, epirubicin and gamma-irradiation. Furthermore, we find that FOXM1 is required for DNA repair by homologous recombination (HR) but not non-homologous end joining (NHEJ), using HeLa cell lines harbouring an integrated direct repeat green fluorescent protein reporter for DSB repair. We also identify BRIP1 as a direct transcription target of FOXM1 by promoter analysis and chromatin immunoprecipitation assay. In agreement, depletion of FOXM1 expression by small interfering RNA downregulates BRIP1 expression at the protein and mRNA levels in MCF-7 and the epirubicin-resistant MCF-7 Epi(R) cells. Remarkably, the requirement for FOXM1 for DSB repair can be circumvented by reintroduction of BRIP1, suggesting that BRIP1 is an important target of FOXM1 in DSB repair. Indeed, like FOXM1, BRIP1 is needed for HR. These data suggest that FOXM1 regulates BRIP1 expression to modulate epirubicin-induced DNA damage repair and drug resistance. PMID- 23108396 TI - H2A.Z-dependent crosstalk between enhancer and promoter regulates cyclin D1 expression. AB - H2A.Z association with specific genomic loci is thought to contribute to a chromatin structure that promotes transcription activation. Acetylation of H2A.Z at promoters of oncogenes has been linked to tumorigenesis. The mechanism is unknown. Here, we show that in triple negative breast cancer cells, H2A.Z bound to the promoter of the constitutively, weakly expressed cyclin D1 oncogene (CCND1), a key regulator of cellular proliferation. Depleting the pool of H2A.Z stimulated transcription of CCND1 in the absence of its cognate transcription factor, the estrogen receptor (ER). During activation of CCND1, H2A.Z was released from the transcription start site (TSS) and downstream enhancer (enh2) sequences. Concurrently, acetylation of H2A.Z, H3 and H4 at the TSS was increased but only H2A.Z was acetylated at enh2. Acetylation of H2A.Z required the Tip60 acetyltransferase to be associated with the activated CCND1 on both TSS and enh2 sites. Depletion of Tip60 prevented CCND1 activation. Chromosome conformation capture experiments (3C) revealed specific contacts between the TSS and enh2 chromatin regions. These results suggest that release of a histone H2A.Z-mediated repression loop activates CCND1 for transcription. Our findings open new avenues for controlling and understanding aberrant gene expression associated with tumorigenesis. PMID- 23108395 TI - DDX5 is a positive regulator of oncogenic NOTCH1 signaling in T cell acute lymphoblastic leukemia. AB - Notch signaling is a highly conserved cell-cell communication pathway regulating normal development and tissue homeostasis. Aberrant Notch signaling represents an important oncogenic mechanism for T cell acute lymphoblastic leukemia (T-ALL), an aggressive subset of the most common malignant childhood cancer ALL. Therefore, understanding the molecular regulation of Notch signaling is critical to identify new approaches to block aberrant Notch oncogenic activity. The family of three MAML transcriptional coactivators is crucial for Notch signaling activation. The prototypic member MAML1 is the major coactivator that regulates Notch oncogenic activities in leukemic cells. However, the molecular basis underlying MAML1 coactivator function that contributes to Notch signaling remains unclear. In this study, we performed proteomic studies and identified DDX5, an ATP-dependent DEAD box RNA helicase, as a component of the MAML1 protein complex. DDX5 interacts with MAML1 in vitro and in vivo, and is associated with the endogenous NOTCH1 transcription activation complex in human T-ALL leukemic cells. Lentivirus mediated short-hairpin RNA knock-down of DDX5 resulted in decreased expression of Notch target genes, reduced cell proliferation and increased apoptosis in cultured human leukemic cells with constitutive activation of Notch signaling. Also, DDX5 depletion inhibited the growth of human leukemia xenograft in nude mice. Moreover, DDX5 is highly expressed in primary human T-ALL leukemic cells based on the analyses of Oncomine and GEO databases, and Immunohistochemical staining. Our overall findings revealed a critical role of DDX5 in promoting efficient Notch-mediated transcription in leukemic cells, suggesting that DDX5 might be critical for NOTCH1-mediated T-ALL pathogenesis and thus is a potential new target for modulating the Notch signaling in leukemia. PMID- 23108397 TI - A human monoclonal antibody 264RAD targeting alphavbeta6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. AB - alphavbeta6 integrin expression is upregulated on a wide range of epithelial tumours, and is thought to play a role in modulating tumour growth. Here we describe a human therapeutic antibody 264RAD, which binds and inhibits alphavbeta6 integrin function. 264RAD cross-reacts with human, mouse and cynomolgus monkey alphavbeta6, and inhibits binding to all ligands including the latency-associated peptide of TGF-beta. Screening across a range of integrins revealed that 264RAD also binds and inhibits the related integrin alphavbeta8, but not the integrins alpha5beta1, alphavbeta3, alphavbeta5 and alpha4beta1. In vitro 264RAD inhibited invasion of VB6 and Detroit 562 cells in a Matrigel invasion assay and alphavbeta6 mediated production of matrix metalloproteinase-9 in Calu-3 cells. It inhibited TGF-beta-mediated activation of dermal skin fibroblasts by preventing local activation of TGF-beta by NCI-H358 tumour cells in a tumour cell-fibroblast co-culture assay. In vivo 264RAD showed dose dependent inhibition of Detroit 562 tumour growth, regressing established tumours when dosed at 20 mg/kg once weekly. The reduction in growth associated with 264RAD was related to a dose-dependent inhibition of Ki67 and phospho-ERK and a reduction of alphavbeta6 expression in the tumour cells, coupled to a reduction in fibronectin and alpha smooth muscle actin expression in stromal fibroblasts. 264RAD also reduced the growth and metastasis of orthotopic 4T1 tumours. At 20 mg/kg growth of both the primary tumour and the number of metastatic deposits in lung were reduced. The data support the conclusion that 264RAD is a potent inhibitor of alphavbeta6 integrin, with some activity against alphavbeta8 integrin, that reduces both tumour growth and metastasis. PMID- 23108398 TI - PKCdelta-mediated phosphorylation of BAG3 at Ser187 site induces epithelial mesenchymal transition and enhances invasiveness in thyroid cancer FRO cells. AB - Protein kinase C delta (PKCdelta) is a serine (Ser)/threonine kinase, which regulates numerous cellular processes, including proliferation, differentiation, migration and apoptosis. In the current study, Chinese hamster ovary cells were transfected with either a constitutively activated PKCdelta or a dominant negative PKCdelta, phosphoprotein enrichment, two-dimensional difference gel electrophoresis and mass spectrometry was combined to globally identified candidates of PKCdelta cascade. We found that Bcl-2 associated athanogene 3 (BAG3) was one of the targets of PKCdelta cascade, and BAG3 interacted with PKCdelta in vivo. In addition, we clarified that BAG3 was phosphorylate at Ser187 site in a PKCdelta-dependent manner in vivo. BAG3 has been implicated in multiple cellular functions, including proliferation, differentiation, apoptosis, migration, invasion, macroautophagy and so on. We generated wild-type (WT)-, Ser187Ala (S187A)- or Ser187Asp (S187D)-BAG3 stably expressing FRO cells, and noticed that phosphorylation state of BAG3 influenced FRO morphology. Finally, for the first time, we showed that BAG3 was implicated in epithelial-mesenchymal transition (EMT) procedure, and phosphorylation state at Ser187 site had a critical role in EMT regulation by BAG3. Collectively, the current study indicates that BAG3 is a novel substrate of PKCdelta, and PKCdelta-mediated phosphorylation of BAG3 is implicated in EMT and invasiveness of thyroid cancer cells. PMID- 23108399 TI - Loss of MUTYH function in human cells leads to accumulation of oxidative damage and genetic instability. AB - The DNA glycosylase MUTYH (mutY homolog (Escherichia coli)) counteracts the mutagenic effects of 8-oxo-7,8-dihydroguanine (8-oxodG) by removing adenine (A) misincorporated opposite the oxidized purine. Biallelic germline mutations in MUTYH cause the autosomal recessive MUTYH-associated adenomatous polyposis (MAP). Here we designed new tools to investigate the biochemical defects and biological consequences associated with different MUTYH mutations in human cells. To identify phenotype(s) associated with MUTYH mutations, lymphoblastoid cell lines (LCLs) were derived from seven MAP patients harboring missense as well as truncating mutations in MUTYH. These included homozygous p.Arg245His, p.Gly264TrpfsX7 or compound heterozygous variants (p.Gly396Asp/Arg245Cys, p.Gly396Asp/Tyr179Cys, p.Gly396Asp/Glu410GlyfsX43, p.Gly264TrpfsX7/Ala385ProfsX23 and p.Gly264TrpfsX7/Glu480del). DNA glycosylase assays of MAP LCL extracts confirmed that all these variants were defective in removing A from an 8-oxoG:A DNA substrate, but retained wild-type OGG1 activity. As a consequence of this defect, MAP LCLs accumulated DNA 8-oxodG in their genome and exhibited a fourfold increase in spontaneous mutagenesis at the PIG-A gene compared with LCLs from healthy donors. They were also hypermutable by KBrO3--a source of DNA 8-oxodG- indicating that the relatively modest spontaneous mutator phenotype associated with MUTYH loss can be significantly enhanced by conditions of oxidative stress. These observations identify accumulation of DNA 8-oxodG and a mutator phenotype as likely contributors to the pathogenesis of MUTYH variants. PMID- 23108400 TI - The serologically defined colon cancer antigen-3 interacts with the protein tyrosine phosphatase PTPN13 and is involved in the regulation of cytokinesis. AB - Cytokinesis is the final step of cell division. Increasing evidence suggests failure of cytokinesis might contribute to the development of cancer. Here, we demonstrate that the serologically defined colon cancer antigen-3 (SDCCAG3) forms a complex with PTPN13, a protein tyrosine phosphatase known to be involved in the regulation of cytokinesis, carcinogenesis and tumor aggressiveness. We show that SDCCAG3 is a novel endosomal protein, primarily localized at the early/recycling endosomal compartment. SDCCAG3 undergoes dynamic localization during cell division with strong accumulation at the midbody during cytokinesis. Overexpression as well as downregulation correlates with the generation of multinucleate cells. Furthermore, we show interaction of SDCCAG3 with the Arf GTPase activating protein GIT1 (G protein-coupled receptor kinase interactor-1). Overexpression of an ArfGAP-negative version of GIT1 also results in an increased number of multinucleate cells suggesting regulation of Arf-mediated vesicular trafficking or signaling via SDCCAG3. Finally, we demonstrate that SDCCAG3 expression levels are elevated in colon cancers. In summary, we have established SDCCAG3 as a novel endosomal protein, which is involved in the regulation of cytokinesis. PMID- 23108402 TI - 5-Fluorouracil signaling through a calcium-calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells. AB - 5-Fluorouracil (5-FU) is an anti-metabolite that is in clinical use for treatment of several cancers. In cells, it is converted into three distinct fluoro-based nucleotide analogs, which interfere with DNA synthesis and repair, leading to genome impairment and, eventually, apoptotic cell death. Current knowledge states that in certain cell types, 5-FU-induced stress is signaling through a p53 dependent induction of tumor necrosis factor-receptor oligomerization required for death-inducing signaling complex formation and caspase-8 activation. Here we establish a role of calcium (Ca(2+)) as a messenger for p53 activation in response to 5-FU. Using a combination of pharmacological and genetic approaches, we show that treatment of colon carcinoma cells stimulates entry of extracellular Ca(2+) through long lasting-type plasma membrane channels, which further directs posttranslational phosphorylation of at least three p53 serine residues (S15, S33 and S37) by means of calmodulin (CaM) activity. Obstructing this pathway by the Ca(2+)-chelator BAPTA (1,2-bis(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid) or by inhibitors of CaM efficiently reduces 5-FU-induced caspase activities and subsequent cell death. Moreover, ectopic expression of p53 S15A in HCT116 p53(-/ ) cells confirmed the importance of a Ca(2+)-CaM-p53 axis in 5-FU-induced extrinsic apoptosis. The fact that a widely used therapeutic drug, such as 5-FU, is operating via this pathway could provide new therapeutic intervention points, or specify new combinatorial treatment regimes. PMID- 23108401 TI - BAG-1 suppresses expression of the key regulatory cytokine transforming growth factor beta (TGF-beta1) in colorectal tumour cells. AB - As colorectal cancer remains the second highest cause of cancer-related deaths in much of the industrialised world, identifying novel strategies to prevent colorectal tumour development remains an important challenge. BAG-1 is a multi functional protein, the expression of which is up-regulated at relatively early stages in colorectal tumorigenesis. Importantly, BAG-1 is thought to enhance colorectal tumour progression through promoting tumour cell survival. Here, we report for the first time a novel role for BAG-1, establishing it as a suppressor of transforming growth factor beta (TGF-beta1) expression in colorectal tumour cells. Microarray analysis first highlighted the possibility that BAG-1 may regulate TGF-beta1 expression, a key cytokine in normal colonic tissue homoeostasis. Q-RT-PCR and ELISA demonstrated TGFB1 mRNA and protein expression to be significantly increased when BAG1 levels were reduced by small interfering RNA; additionally, induction of BAG-1L caused suppression of TGFB1 mRNA in colorectal tumour cells. Using reporter and chromatin immunoprecipitation assays, a direct association of BAG-1 with the TGFB1 gene regulatory region was identified. Immunohistochemistry and Weiser fraction data indicated that the levels of BAG-1 and TGF-beta1 are inversely correlated in the normal colonic epithelium in vivo, consistent with a role for BAG-1-mediated repression of TGF beta1 production. In vitro studies showed that the change in TGF-beta1 production following manipulation of BAG-1 is functionally relevant; through induction of anchorage-independent growth in TGF-beta1-dependent normal rat kidney fibroblasts and regulation of SMAD2 phosphorylation in TGF-beta1-sensitive adenoma cells. Taken together, this study identifies the anti-apoptotic protein BAG-1 as a suppressor of the inhibitory growth factor TGF-beta1, suggesting that high expression of BAG-1 can impact on a number of the hallmarks of cancer, of potential importance in promoting the early stages of colorectal tumorigenesis. Establishing BAG-1 as a repressor of TGF-beta1 has important biological implications, and highlights a new role for BAG-1 in colorectal tumorigenesis. PMID- 23108403 TI - RSK promotes G2 DNA damage checkpoint silencing and participates in melanoma chemoresistance. AB - The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. This type of cancer is highly resistant to conventional DNA-damaging chemotherapeutics, and intense research has been dedicated for understanding the molecular pathways underlying chemoresistance. The Ras/mitogen-activated protein kinase (MAPK) signalling pathway is often deregulated in melanoma, which frequently harbours activating mutations in NRAS or BRAF. Herein, we demonstrate that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) contributes to melanoma chemoresistance by altering their response to chemotherapeutic agents. We find that RSK phosphorylates checkpoint kinase 1 (Chk1) at an inhibitory site, Ser280, both in vitro and in vivo. Our results indicate that RSK is the predominant protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and consistent with this, we find that RSK constitutively phosphorylates Chk1 in melanoma. We show that RSK inhibition increases Chk1 activity in response to DNA damaging agents, suggesting that the Ras/MAPK pathway modulates Chk1 function and the response to DNA damage. Accordingly, we demonstrate that RSK promotes G2 DNA damage checkpoint silencing in a Chk1-dependent manner, and find that RSK inhibitors sensitize melanoma cells to DNA-damaging agents. Together, our results identify a novel link between the Ras/MAPK pathway and the DNA damage response, and suggest that RSK inhibitors may be used to modulate chemosensitivity, which is one of the major obstacles to melanoma treatment. PMID- 23108405 TI - Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. AB - Evidence accumulates that the transcription factor nuclear factor E2-related factor 2 (Nrf2) has an essential role in cancer development and chemoresistance, thus pointing to its potential as an anticancer target and undermining its suitability in chemoprevention. Through the induction of cytoprotective and proteasomal genes, Nrf2 confers apoptosis protection in tumor cells, and inhibiting Nrf2 would therefore be an efficient strategy in anticancer therapy. In the present study, pancreatic carcinoma cell lines (Panc1, Colo357 and MiaPaca2) and H6c7 pancreatic duct cells were analyzed for the Nrf2-inhibitory effect of the coffee alkaloid trigonelline (trig), as well as for its impact on Nrf2-dependent proteasome activity and resistance to tumor necrosis factor related apoptosis-inducing ligand (TRAIL) and anticancer drug-induced apoptosis. Chemoresistant Panc1 and Colo357 cells exhibit high constitutive Nrf2 activity, whereas chemosensitive MiaPaca2 and H6c7 cells display little basal but strong tert-butylhydroquinone (tBHQ)-inducible Nrf2 activity and drug resistance. Trig efficiently decreased basal and tBHQ-induced Nrf2 activity in all cell lines, an effect relying on a reduced nuclear accumulation of the Nrf2 protein. Along with Nrf2 inhibition, trig blocked the Nrf2-dependent expression of proteasomal genes (for example, s5a/psmd4 and alpha5/psma5) and reduced proteasome activity in all cell lines tested. These blocking effects were absent after treatment with Nrf2 siRNA, a condition in which proteasomal gene expression and proteasome activity were already decreased, whereas siRNA against the related transcription factor Nrf1 did not affect proteasome activity and the inhibitory effect of trig. Depending on both Nrf2 and proteasomal gene expression, the sensitivity of all cell lines to anticancer drugs and TRAIL-induced apoptosis was enhanced by trig. Moreover, greater antitumor responses toward anticancer drug treatment were observed in tumor-bearing mice when receiving trig. In conclusion, representing an efficient Nrf2 inhibitor capable of blocking Nrf2-dependent proteasome activity and thereby apoptosis protection in pancreatic cancer cells, trig might be beneficial in improving anticancer therapy. PMID- 23108406 TI - A tumor suppressor role for srGAP3 in mammary epithelial cells. AB - srGAP3, a member of the Slit-Robo sub-family of Rho GTPase-activating proteins (Rho GAPs), controls actin and microtubule dynamics through negative regulation of Rac. Here, we describe a potential role for srGAP3 as a tumor suppressor in mammary epithelial cells. We show that RNAi-mediated depletion of srGAP3 promotes Rac dependent, anchorage-independent growth of partially transformed human mammary epithelial cells (HMECs). Furthermore, srGAP3 expression is absent, or significantly reduced in 7/10 breast cancer cell lines compared with normal HMECs. Re-expression of srGAP3 in a subset of these cell lines inhibits both anchorage-independent growth and cell invasion in a GAP-dependent manner, and this is accompanied by an increase in phosphorylation of the ezrin/radixin/moesin (ERM) family proteins and myosin light chain 2 (MLC2). Inhibition of the Rho regulated kinase, ROCK, reduces ERM and MLC2 phosphorylation and restores invasion. We conclude that srGAP3 has tumor suppressor-like activity in HMECs, likely through its activity as a negative regulator of Rac1. PMID- 23108404 TI - mTORC1 enhancement of STIM1-mediated store-operated Ca2+ entry constrains tuberous sclerosis complex-related tumor development. AB - The protein complex of tuberous sclerosis complex (TSC)1 and TSC2 tumor suppressors is a key negative regulator of mammalian target of rapamycin (mTOR). Hyperactive mTOR signaling due to the loss-of-function of mutations in either TSC1 or TSC2 gene causes TSC, an autosomal dominant disorder featured with benign tumors in multiple organs. As the ubiquitous second messenger calcium (Ca(2+)) regulates various cellular processes involved in tumorigenesis, we explored the potential role of mTOR in modulation of cellular Ca(2+) homeostasis, and in turn the effect of Ca(2+) signaling in TSC-related tumor development. We found that loss of Tsc2 potentiated store-operated Ca(2+) entry (SOCE) in an mTOR complex 1 (mTORC1)-dependent way. The endoplasmic reticulum Ca(2+) sensor, stromal interaction molecule 1 (STIM1), was upregulated in Tsc2-deficient cells, and was suppressed by mTORC1 inhibitor rapamycin. In addition, SOCE repressed AKT1 phosphorylation. Blocking SOCE either by depleting STIM1 or ectopically expressing dominant-negative Orai1 accelerated TSC-related tumor development, likely because of restored AKT1 activity and enhanced tumor angiogenesis. Our data, therefore, suggest that mTORC1 enhancement of store-operated Ca(2+) signaling hinders TSC-related tumor growth through suppression of AKT1 signaling. The augmented SOCE by hyperactive mTORC1-STIM1 cascade may contribute to the benign nature of TSC-related tumors. Application of SOCE agonists could thus be a contraindication for TSC patients. In contrast, SOCE agonists should attenuate mTOR inhibitors-mediated AKT reactivation and consequently potentiate their efficacy in the treatment of the patients with TSC. PMID- 23108407 TI - A non-cell-autonomous tumor suppressor role for Stat in eliminating oncogenic scribble cells. AB - Elucidating signaling events between tumor cells and their microenvironment is a major challenge in understanding cancer development. Drosophila melanogaster has emerged as an important tool for dissecting the genetic circuits tumors depend on because their imaginal discs, simple epithelia present in the larva, can be genetically manipulated to serve as models to study cancer mechanisms. Imaginal disc cells mutant for the tumor-suppressor gene scribble (scrib) lose apical basal polarity and have the potential to form large neoplastic tumors. Interestingly, when scrib mutant (scrib(-)) cells are surrounded by normal cells the scrib(-) population is eliminated. However, the signals and mechanisms that cause the elimination of clones of scrib(-) cells are poorly understood. Here, we analyzed the role of Stat, a component of the JAK/STAT signaling pathway, in tissues with clones of scrib(-) cells. We found that Stat activity is required in normal cells for the elimination of neighboring scrib(-) cells. Importantly, these competitive defects of stat mutant cells are not simply due to defects in cell proliferation because even stat(-) cells manipulated to hyperproliferate are unable to eliminate scrib(-) cells. These data identify Stat activity as a critical determinant of whether or not a tissue can eliminate abnormal cells and provide an important step forward in understanding the complex network of signals operating in and around tumorigenic cells. PMID- 23108408 TI - miRNA-145 is downregulated in atypical and anaplastic meningiomas and negatively regulates motility and proliferation of meningioma cells. AB - Meningiomas are frequent, mostly benign intracranial or spinal tumors. A small subset of meningiomas is characterized by histological features of atypia or anaplasia that are associated with more aggressive biological behavior resulting in increased morbidity and mortality. Infiltration into the adjacent brain tissue is a major factor linked to higher recurrence rates. The molecular mechanisms of progression, including brain invasion are still poorly understood. We have studied the role of micro-RNA 145 (miR-145) in meningiomas and detected significantly reduced miR-145 expression in atypical and anaplastic tumors as compared with benign meningiomas. Overexpression of miR-145 in IOMM-Lee meningioma cells resulted in reduced proliferation, increased sensitivity to apoptosis, reduced anchorage-independent growth and reduction of orthotopic tumor growth in nude mice as compared with control cells. Moreover, meningioma cells with high miR-145 levels had impaired migratory and invasive potential in vitro and in vivo. PCR-array studies of miR145-overexpressing cells suggested that collagen type V alpha (COL5A1) expression is downregulated by miR-145 overexpression. Accordingly, COL5A1 expression was significantly upregulated in atypical and anaplastic meningiomas. Collectively, our data indicate an important anti-migratory and anti-proliferative function of miR-145 in meningiomas. PMID- 23108409 TI - Efficient TGFbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase HAS2. AB - Epithelial-mesenchymal transition (EMT) is a developmental program, which can be adopted by cancer cells to increase their migration and ability to form metastases. Transforming growth factor beta (TGFbeta) is a well-studied inducer of EMT. We demonstrate that TGFbeta potently stimulates hyaluronan synthesis via upregulation of hyaluronan synthase 2 (HAS2) in NMuMG mammary epithelial cells. This stimulatory effect requires the kinase active type I TGFbeta receptor and is dependent on Smad signaling and activation of the p38 mitogen-activated protein kinase. Knockdown of HAS2 inhibited the TGFbeta-induced EMT by about 50%, as determined by the phase contrast microscopy and immunostaining using the EMT marker ZO-1. Furthermore, real-time PCR analysis of the EMT markers fibronectin, Snail1 and Zeb1 revealed decreased expressions upon HAS2 suppression, using specific small interfering RNA (siRNA) for HAS2. Removal of the extracellular hyaluronan by Streptomyces hyaluronidase or inhibiting the binding to its cell surface receptor CD44 by blocking antibodies, did not inhibit TGFbeta-induced EMT. Interestingly, HAS2 suppression completely abolished the TGFbeta-induced cell migration, whereas CD44 knockdown did not. These observations suggest that TGFbeta-dependent HAS2 expression, but not extracellular hyaluronan, has an important regulatory role in TGFbeta-induced EMT. PMID- 23108410 TI - Hepatitis C virus-induced activation of beta-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events. AB - Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of hepatocellular carcinoma (HCC), although the underlying mechanisms are unclear. The c-Myc oncogene contributes to the genesis of many types of cancers, including HCC, partly via the induction of genetic damage and the inhibition of the cellular response to genotoxic stress. Here, we show a previously undiscovered mechanistic link between HCV infection and enhanced c-Myc expression. c-Myc expression was augmented in non-tumoral liver tissues from HCV infected individuals with or without HCC and in hepatocyte cell lines harboring an HCV replicon and the infectious HCV strain JFH1. Increased c-Myc expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame, demonstrating a direct role for HCV protein expression in c-Myc induction. Mechanistically, activation of Akt by the HCV non-structural protein NS5A, and the subsequent stabilization of the transcription factor beta-catenin, was demonstrated to be responsible for activation of the c-Myc promoter, and for increased c-Myc transcription. beta-Catenin-dependent c-Myc expression in this context led to increased production of reactive oxygen species, mitochondrial perturbation, enhanced DNA damage and aberrant cell-cycle arrest. Together, these data provide a novel insight into the mechanisms involved in HCV-associated HCCs, strongly suggesting that c-Myc has a crucial contributory role in this process. PMID- 23108411 TI - MUC1 enhances hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors. AB - Pancreatic cancer is one of the most lethal malignancies due to its aggressive growth and rapid development of distant metastases. In this context, mucin 1 (MUC1) overexpression and hypoxia are frequently observed events. However, their functional relationship remains largely unknown. This study provides evidence that MUC1 is overexpressed by hypoxia and contributes to hypoxia-driven angiogenesis. Using the conditioned medium obtained from hypoxia-stressed AsPC1 cells treated with MUC1 siRNAs, we demonstrated that MUC1 enhanced the endothelial tube formation, proliferation and migration ability, which induced by hypoxia-conditioned medium (HCM). In addition, MUC1 was significantly induced by hypoxia, especially in the pancreatic cancer cells derived from metastatic tumors (AsPC1, HPAF2 or Capan1), and MUC1-cytoplasmic tail (MUC1-CT) accumulated in the nucleus under hypoxia. As noted in a previous report, MUC1-CT was recruited to genomic regions upstream of the connective tissue growth factor (CTGF) accompanied with beta-catenin and p53, resulting in the hypoxic induction of CTGF. Moreover, hypoxia-induced MUC1 partially regulated two other hypoxia inducible proangiogenic factors including vascular endothelial growth factor-A and platelet-derived growth factor-B. The neutralization assay revealed that endothelial tube formation induced by HCM was clearly suppressed by antibodies against these three factors, suggesting the importance of these factors in hypoxia-driven angiogenesis. In summary, this is the first report demonstrating a pivotal role of MUC1 in controlling the hypoxia-driven angiogenesis through the regulation of multiple proangiogenic factors in pancreatic cancer. Our findings provide the novel insights into the understanding of complex interactions between pancreatic cancer cells and tumor microenvironments. PMID- 23108412 TI - The influence of Pluronics(r) on dark cytotoxicity, photocytotoxicity, localization and uptake of curcumin in cancer cells: studies of curcumin and curcuminoids XLIX. AB - In order to apply curcumin as a photosensitizer in photodynamic therapy (PDT) one needs a formulation that can solubilize and stabilize the compound. Pluronics(r) (Pluronic) are reported to both solubilize and stabilize curcumin against hydrolytic degradation. The aim of the present work was therefore to investigate the influence of Pluronic formulation on the photocytotoxicity of curcumin. Interactions between curcumin and Pluronics were investigated by fluorescence emission and absorption spectroscopy. Cell survival was measured with the MTT assay. The location of curcumin in the cells was investigated with fluorescence microscopy, and the cellular uptake was measured with fluorescence emission spectroscopy. Pluronics P123 and F127 in contrast to Pluronic P85 and PEG 400 may solubilize curcumin under non-cytotoxic conditions. An inverse relationship between the concentration of Pluronic and the photocytotoxicity of curcumin was observed. Curcumin could rapidly translocate across the cell membrane by passive diffusion. The fluorescence from curcumin in the cells (in the cytoplasm) after 1 hour of incubation was lowered by the presence of Pluronics in the formulation. However, the absolute amount of cell-bound curcumin after 1 hour of incubation was independent of the presence of Pluronics. Curcumin was bound more strongly to cells when incubated with formulations without Pluronics compared to cells incubated with curcumin formulations with Pluronics. Incubation of WiDr cells with curcumin for 6 hours resulted in lysosomal accumulation of curcumin independent of the presence of Pluronics. Lysosomally located curcumin could not be observed in HT1080 cells after 6 hours of incubation. The Pluronics P123 and F127 were found to be suitable for solubilizing and stabilizing curcumin, but inhibited photocytotoxic effects of curcumin unless the Pluronic concentration during treatment of the cells was less than 5-10* above the critical micellar concentration. PMID- 23108413 TI - Changes in cerebral oxygenation in patients with pulmonary dysfunction after lung resection. AB - Lung resection would be associated with lower jugular bulb oxygen saturation (SjvO2) values in patients with moderate to severe pulmonary dysfunction. We aimed to study the effects of lung resections on the postoperative changes in SjvO2, incidence of SjvO2 < 50%, pulmonary functions, cerebral blood flow equivalent (CBFE), and arterial to jugular difference in oxygen content (AjvDO2) in the patients with pulmonary dysfunction. Fifty-three patients scheduled for lung resection were allocated on the basis of forced vital capacity (FVC %) and forced expiratory volume in 1 second (FEV(1)%) into the following: good FVC and FEV1 (n = 14), mild (n = 14), moderate (n = 13), and severe (n = 12) pulmonary dysfunction groups. After lung resections, patients with pulmonary dysfunctions had significantly lower SjvO2, CBFE, FEV1, and FVC (P < .001), higher AjvDO2 (P < .001), and frequent episodes with SjvO2 < 50% (P < .03). Perioperative changes in FEV1 had a significant negative correlation with SjvO2 desaturation (P < .002). Patients with pulmonary dysfunction showed significant SjvO2 < 50% after lung resection, which is correlated to the perioperative changes in FEV1. PMID- 23108414 TI - Surgery for tracheobronchomalacia. AB - Tracheobronchomalacia (TBM) refers to a weakening of the anterior tracheal rings leading to splaying and collapse of the central airways. In this report, we review the treatment of TBM, including preoperative workup, intraoperative anesthesia management, and surgical technique for posterior splinting tracheobronchoplasty. Imperative in the preoperative preparation is a stent trial in which an airway stent is placed to temporarily relieve the TBM and reassess for improvement in symptoms. Definitive therapy is then carried out with posterior splinting tracheoplasty or tracheobronchoplasty. Surgical results are generally excellent with the majority of patients having significant improvements in breathing. PMID- 23108415 TI - The impact of dexmedetomidine infusion in sparing morphine consumption in off pump coronary artery bypass grafting. AB - PURPOSE: Recovery from off-pump coronary artery bypass (OPCAB) has been reported to be more advantageous than conventional coronary artery bypass grafting with regard to both hospital and intensive care unit length of stay. Dexmedetomidine is a selective alpha-2 agonist that has been used successfully as an adjunct to narcotics in adult and pediatric cardiac surgery. The aim of this study was to assess the effect of dexmedetomidine on the recovery, total narcotic consumption, and total hospital and intensive care unit length of stay in patients undergoing OPCAB. METHODS: The recovery, hospital and intensive care unit length of stay, as well as total morphine consumption of patients receiving dexmedetomidine infusion (0.5 ug/kg/h; dexmedetomidine group), after induction of general anesthesia, were compared with those receiving placebo (saline group). RESULTS: The duration of intubation of patients in the dexmedetomidine group was significantly shorter than in the control group (289 +/- 44 minutes in the dexmedetomidine group vs 530 +/- 119 minutes in the control group). The total hospital and intensive care unit length of stay were significantly shorter in the dexmedetomidine group (P < .05). Also, total fentanyl and morphine consumptions were lower in the dexmedetomidine group than in the control group (P < .05). CONCLUSION: Our study showed that dexmedetomidine might be an effective adjuvant in reducing both total hospital and intensive care unit length of stay in patients undergoing OPCAB. Dexmedetomidine might play a role in reducing total morphine and fentanyl consumption in OPCAB. PMID- 23108416 TI - Ki67 proliferation index, hepatic tumor load, and pretreatment tumor growth predict the antitumoral efficacy of lanreotide in patients with malignant digestive neuroendocrine tumors. AB - BACKGROUND: An antiproliferative effect of somatostatin analogs was recently demonstrated. AIM: To identify factors associated with tumor control in a group of patients with well-differentiated malignant digestive neuroendocrine tumors treated with lanreotide. METHODS: A retrospective study was conducted in 68 patients treated with lanreotide alone, with progression-free survival as the primary endpoint. The role of the following factors was searched for by univariate and multivariate analyses: age, sex, mode of discovery, site of the primary tumor, metastatic spread, Ki67 proliferation index, uptake on somatostatin receptor scintigraphy, pretreatment tumor growth, extent of liver involvement, resection of primary tumor, previous treatments, and tumor markers. RESULTS: Tumor progression was observed in 39/68 patients (57.4%). Median progression-free survival was 29 months. On multivariate analysis, a Ki67 proliferation index of up to 5% [hazard ratio (HR)=0.262, P=0.009], pretreatment stability (HR=0.241, P=0.008), and hepatic tumor load of up to 25% (HR=0.237, P=0.004) were significantly associated with disease stability under lanreotide therapy. CONCLUSION: In patients with well-differentiated malignant digestive neuroendocrine tumors, Ki67 proliferation index of up to 5%, stable disease before treatment, and low-to-moderate hepatic tumor involvement (<= 25%) are associated with tumor control during lanreotide treatment. These data if confirmed in prospective trials will help in rationalizing the use of somatostatin analogs with antiproliferative intent. PMID- 23108417 TI - Fluidics in a dual pneumatic ultra high-speed vitreous cutter system. AB - BACKGROUND: Dual pneumatic systems use two separate air line tubes to open and close the cutter and can achieve high cut rates. The purpose of this study is to evaluate the influence of gauge size, cut rate and aspiration on the flow rate performance of ultra high-speed cutters operated with a commercially available dual pneumatic vitrectomy system. METHODS: Analysis of a high-speed video was used to determine duty cycle. Flow rates from 20-, 23- and 25-gauge cutters were calculated in predetermined conditions of aspiration levels and cut rates; water and fresh porcine vitreous samples were studied. RESULTS: For all three gauges of cutters, the duty cycle and water flow showed an inverse correlation with increasing cut rates and a direct correlation with increasing aspiration levels (p < 0.05). Vitreous flow rates from all gauges increased with increasing aspiration and cut rates (p < 0.05). CONCLUSION: Larger gauges of the cutters as well as higher aspiration and cut rate levels resulted in improvement of the vitreous flow rates. A good understanding of the different flow rate settings is essential for the surgeon and optimizes the safety of surgical procedures. PMID- 23108418 TI - Targeted isolation and analysis of single tumor cells with aptamer-encoded microwell array on microfluidic device. AB - Microfluidic-based single cells analysis has been of great interest in recent years, promising disease diagnosis and personalized medicine. Current technologies are challenging in bioselectively isolating specific single cells from complex matrices. Herein, a novel microfluidic platform integrated with cell recognizable aptamer-encoded microwells was specifically developed to isolate single tumor cells with satisfied single-cell occupancy and unique bioselectivity. In this work, the designed microwell-structures enable us to encourage strong 3D local topographic interactions of the target cell surface with biomolecules and regulate the single-cell resolution. Under the optimized size of microwells, the single-cell occupancy was significantly enhanced from 0.5% to 88.2% through the introduction of the aptamer. Analysis of the target cells was directly performed in short time periods (<5.0 min) with small volumes (4.5 MUL). Importantly, such an aptamer-enabled microfluidic device shows an excellent selectivity for target single cells isolation compared with three control cells. Subsequently, targeted isolation and analysis of single tumor cells were demonstrated by using artificial complex cell samples at simulated conditions, and various cellular carboxylesterases were studied by time-course measurements of cellular fluorescence kinetics at individual-cell level. Thus, our technique will open up a new opportunity in single-cell level-based disease diagnosis and personalize medicine screening. PMID- 23108419 TI - Primary intraosseous squamous cell carcinoma of the jaw: two new cases and review of the literature. AB - BACKGROUND: Primary intraosseous squamous cell carcinoma is very rare. We report two cases of primary intraosseous squamous cell carcinoma of the jaw, one arising from an odontogenic cyst and the other arising de novo. METHODS AND RESULTS: The first case was a 76-year-old man with right mandible pain. A panoramic radiography and computed tomography revealed a large mandibular radiolucency. A biopsy revealed squamous cell carcinoma, and radiotherapy and hemimandibulectomy were performed. The second case was a 50-year-old man with lymph node swelling on the left neck. Squamous cell carcinoma of the lymph node was suspected after fine needle biopsy. After left neck dissection, histological testing of the odontogenic cyst revealed squamous cell carcinoma, of which the mandible was thought to be the primary site. CONCLUSION: Our two cases have no recurrence, and panoramic radiography was a useful tool in the detection of mandible disease. PMID- 23108420 TI - Hyperventilation-induced nystagmus in vestibular schwannoma and unilateral sensorineural hearing loss. AB - We evaluated the incidence and characteristics of hyperventilation-induced nystagmus (HVN) in 49 patients with gadolinium-enhanced magnetic resonance imaging evidence of vestibular schwannoma and 53 patients with idiopathic unilateral sensorineural hearing loss and normal radiological findings. The sensitivity and specificity of the hyperventilation test were compared with other audio-vestibular diagnostic tests (bedside examination of eye movements, caloric test, auditory brainstem responses) in the two groups of patients. The hyperventilation test scored the highest diagnostic efficiency (sensitivity 65.3 %; specificity 98.1 %) of the four tests in the differential diagnosis of vestibular schwannoma and idiopathic unilateral sensorineural hearing loss. Small tumors with a normal caloric response or caloric paresis were associated with ipsilateral HVN and larger tumors and severe caloric deficits with contralateral HVN. These results confirm that the hyperventilation test is a useful diagnostic test for predicting vestibular schwannoma in patients with unilateral sensorineural hearing loss. PMID- 23108421 TI - Radical neck dissection: is it still indicated? PMID- 23108422 TI - Estimates of connectivity reveal non-equilibrium epiphyte occurrence patterns almost 180 years after habitat decline. AB - Habitat loss is a major cause of species decline and extinction. Immediately after habitat loss, species occurrences are not in equilibrium with the new landscape and more closely reflect the previous landscape structure. Species with slow colonisation-extinction dynamics may display long time-lags before reaching a new equilibrium. We investigated the importance of connectivity to current and historical dispersal sources with the aim of explaining the occurrence pattern of epiphytic lichens with different traits among 104 old oaks. We used oak survey data collected from 1830 and 2009 for a Swedish landscape where oak densities declined drastically shortly after 1830. We fitted a commonly used connectivity measure and estimated the confidence interval for the spatial scale parameter. Small differences in the spatial scale parameter resulted in large differences in model fit. Connectivity to trees in 1830 better explained the occurrence of three of the four species compared to the connectivity in 2009. The explanatory power of the historical landscape structure was highest for the species with traits that may result in a low colonisation rate--both a narrow niche (here few suitable trees) and large dispersal propagules. The results suggest that oak dependent epiphytic lichens have not reached equilibrium with the spatial landscape structure 180 years after the drastic decline in habitat. For the long term persistence of epiphytes associated with old trees, conservation efforts should focus on (1) protecting and restoring stands where specialised species with large dispersal propagules (i.e. with low colonisation rates) occur today and (2) promoting tree regeneration in their near vicinity. PMID- 23108423 TI - Inferring host specificity and network formation through agent-based models: tick mammal interactions in Borneo. AB - Patterns of host-parasite association are poorly understood in tropical forests. While we typically observe only snapshots of the diverse assemblages and interactions under variable conditions, there is a desire to make inferences about prevalence and host-specificity patterns. We studied the interaction of ticks with non-volant small mammals in forests of Borneo. We inferred the probability of species interactions from individual-level data in a multi-level Bayesian model that incorporated environmental covariates and advanced estimates for rarely observed species through model averaging. We estimated the likelihood of observing particular interaction frequencies under field conditions and a scenario of exhaustive sampling and examined the consequences for inferring host specificity. We recorded a total of 13 different tick species belonging to the five genera Amblyomma, Dermacentor, Haemaphysalis, Ixodes, and Rhipicephalus from a total of 37 different host species (Rodentia, Scandentia, Carnivora, Soricidae) on 237 out of 1,444 host individuals. Infestation probabilities revealed most variation across host species but less variation across tick species with three common rat and two tree shrew species being most heavily infested. Host species identity explained ca. 75 % of the variation in infestation probability and another 8-10 % was explained by local host abundance. Host traits and site specific attributes had little explanatory power. Host specificity was estimated to be similarly low for all tick species, which were all likely to infest 34-37 host species if exhaustively sampled. By taking into consideration the hierarchical organization of individual interactions that may take place under variable conditions and that shape host-parasite networks, we can discern uncertainty and sampling bias from true interaction frequencies, whereas network attributes derived from observed values may lead to highly misleading results. Multi-level approaches may help to move this field towards inferential approaches for understanding mechanisms that shape the strength and dynamics in ecological networks. PMID- 23108424 TI - Changing profile of 7,519 neurologic outpatients evaluated over 20 years. AB - INTRODUCTION: There is scarce information on the demographic profile and diseases affecting neurologic outpatients. METHODS: We evaluated 7,519 neurologic outpatients over 20 years at the outpatient clinic of the Department of Neurological Sciences, Hospital-Clinica Kennedy, Guayaquil, Ecuador. RESULTS: Mean age was 48 +/- 19.4 years, and 57.8% were women. Common reasons for consultation included headache (33.2%), focal deficits (10.7%), and seizures (9%). The most common categories of neurologic diseases were cerebrovascular (10.6%), degenerative (7.6%), and traumatic (7.1%). Diseases of uncertain/unknown etiology accounted for 50.2% of cases. Young patients were most often evaluated for headache and seizures, while elderly patients usually presented with focal deficits, movement disorders, or cognitive decline. We also found significant variations in the prevalence of neurologic diseases over the study years. While the prevalence of degenerative diseases increased from 5.7% in 1990-1994 to 10.2% in 2005-2009, that of infectious diseases steadily decreased from 3.7 to 2.1% over the study years. CONCLUSION: There was a dynamic pattern of neurologic diseases over the years. Nowadays, distribution of neurologic symptoms and diseases in our population is more similar to that reported from the developed world than it was 20 years ago. PMID- 23108425 TI - Electrokinetics of pH-regulated zwitterionic polyelectrolyte nanoparticles. AB - The electrokinetic behavior of pH-regulated, zwitterionic polyelectrolyte (PE) nanoparticles (NPs) in a general electrolyte solution containing multiple ionic species is investigated for the first time. The NPs considered are capable of simulating entities such as proteins, biomolecules, and synthetic polymers. The applicability of the model proposed is verified by the experimental data of succinoglycan nanoparticles available in the literature. We show that, in addition to their effective charge density, counterion condensation, double-layer polarization, and electro-osmotic flow of unbalanced counterions inside the double layer all significantly affect the electrophoretic behaviors of NPs. Our model successfully predicts many interesting electrophoretic behaviors, which qualitatively agree with experimental observations available in the literature. In contrast, because the effects of double-layer polarization and charge regulation are neglected, the existing theoretical models fail to explain the experimental results. The results gathered provide necessary information for the interpretation of relevant electrophoresis data in practice, and for nanofluidic applications such as biomimetic ion channels and nanopore-based sensing of single biomolecules. PMID- 23108426 TI - Diagnostic performance of interferon-gamma release assays in elderly populations in comparison with younger populations. AB - An understanding of the diagnostic performance of interferon-gamma release assays (in terms of parameters such as specificity, positive predictive value, and likelihood ratio) is important in the diagnosis of active tuberculosis in elderly Japanese patients because the high proportion of a prior history of tuberculosis among these patients can lead to misleading results. To elucidate the diagnostic performance of such assays, we examined the results of the QuantiFERON-TB Gold In Tube test (QFT-GIT) in 65 patients in a younger group, and 52 patients in an elderly group who were suspected of having active tuberculosis and who had received the QFT-GIT. The median ages of the younger patients and elderly patients were 54 and 78 years, respectively. Among patients with active tuberculosis, the number of those with positive results on the QFT-GIT was similar in the two age groups [15 out of 17 (88.2 %) in the younger patients compared with 7 out of 8 (87.5 %) in the elderly patients]. However, in the patients with other diseases the number of those with positive QFT-GIT results was significantly different in the younger and elderly groups, being 6.3 and 27.3 %, respectively (P = 0.01). Although the sensitivity, negative predictive value, and negative likelihood ratio were similar in the two groups, the specificity, positive predictive value, and positive likelihood ratio were significantly lower in the elderly patients, being 72.7% (95 % confidence interval [CI], 57.2-85.0) compared with 93.8% (95 % CI, 82.8-98.7), 36.8% (95 % CI, 16.3-61.6) compared with 83.8% (95 % CI, 58.6-96.4), and 3.21 (95 % CI, 1.85-5.56) compared with 14.12 (95 % CI, 4.66-42.81), respectively. In the elderly patients with positive results on the test, a comparison of clinical data between those with active tuberculosis and those with other diseases demonstrated that the only clinical parameter showing a significant difference between these two groups was the radiological finding of small nodules in the patients with active tuberculosis (P < 0.01). The QFT-GIT may be less accurate in elderly patients, and radiological findings can be helpful in the clinical evaluation of patients with positive results on the test. PMID- 23108427 TI - Antibiotic susceptibility in relation to genotype of Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae responsible for community acquired pneumonia in children. AB - Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae are the main pathogens causing community-acquired pneumonia (CAP). We identified S. pneumoniae (n = 241), H. influenzae (n = 123), and M. pneumoniae (n = 54) as causative pathogens from clinical findings and blood tests from pediatric CAP patients (n = 903) between April 2008 and April 2009. Identification of genes mediating antimicrobial resistance by real-time PCR was performed for all isolates of these three pathogens, as was antibiotic susceptibility testing using an agar dilution method or broth microdilution method. The genotypic (g) resistance rate was 47.7 % for penicillin-resistant S. pneumoniae (gPRSP) possessing abnormal pbp1a, pbp2x, and pbp2b genes, 62.6 % for beta-lactamase nonproducing, ampicillin-resistant (gBLNAR) H. influenzae possessing the amino acid substitutions Ser385Thr and Asn526Lys, and 44.4 % for macrolide-resistant M. pneumoniae (gMRMP) possessing a mutation of A2063G, A2064G, or C2617A. Serotype 6B (20.3 %) predominated in S. pneumoniae, followed by 19F (15.4 %), 14 (14.5 %), 23F (12.0 %), 19A (6.2 %), and 6C (5.4 %). Coverage for the isolates by heptavalent pneumococcal conjugate vaccine (PCV7) and PCV13, respectively, was calculated as 68.5 and 80.9 %. A small number of H. influenzae were identified as type b (6.5 %), type e (0.8 %), or type f (0.8 %); all others were nontypeable. Proper use of antibiotics based on information about resistance in CAP pathogens is required to control rapid increases in resistance. Epidemiological surveillance of pediatric patients also is needed to assess the effectiveness of PCV7 and Hib vaccines after their introduction in Japan. PMID- 23108428 TI - Isolation of an X-factor-dependent but porphyrin-positive Escherichia coli from urine of a patient with hemorrhagic cystitis. AB - An Escherichia coli isolate was recovered from a 92-year-old female patient with urinary tract infection. Gram-stained preparation of the urine sediment manifested some gram-negative rod-shaped cells, and the urine specimen culture yielded nonhemolytic colonies on sheep blood agar plate. However, no visible colonies appeared on modified Drigalski agar plate. The isolate was finally identified as an X-factor-dependent E. coli. The interesting finding was that the isolate revealed a positive reaction for porphyrin test despite the requirement of hemin. This finding suggested that some pyrrol-ring-containing porphyrin compounds or fluorescent porphyrins had been produced as chemical intermediates in the synthetic pathway from delta-amino-levulinic acid (ALA), although the isolate should be devoid of synthesizing hems from ALA. This was the first clinical isolation of such a strain, indicating that the E. coli isolate should possess incomplete synthetic pathways of hems from ALA. PMID- 23108429 TI - [Hyperbaric oxygenation for necrotizing soft tissue infections: pro]. AB - Necrotizing soft tissue infections are a complex pathological spectrum of symptoms and result in a significantly increased risk of mortality depending on the degree of dissemination as well as the underlying bacterial infection. Hyperbaric oxygen therapy (HBOT) can significantly improve the effectiveness of a multidisciplinary treatment concept consisting of surgical debridement, critical care and antibiotic treatment. HBOT itself assists solid wound healing by bactericidal and bacteriostatic effects and by increasing the oxygen supply up to the cellular level resulting in an optimization of oxygen-dependent metabolic processes. The efficacy of treatment in a centre of cooperating specialized departments can therefore be increased by utilizing HBOT as adjunct treatment. Nevertheless, if a HBOT facility is available, excluding HBOT is equivalent to omission of an effective therapy option to the disadvantage of patients. PMID- 23108430 TI - Intraoperative ultrasound examination is useful for monitoring transplanted islets: a case report. AB - A 39-y-old man, who had an episode of pancreatic bleeding due to chronic pancreatitis, received total pancreatectomy with islet autotransplantation (TP with IAT). Intraoperative ultrasound (US) examination was done to detect transplanted islets and evaluate the quality of US imaging. Islet isolation from the resected total pancreas was performed and approximately 230,000 islet equivalents (IEQ) (the tissue volume was 600 uL and the purity was 30%) were acquired. A double lumen catheter, used for transplantation and for monitoring the portal vein pressure, was inserted into the portal vein via the superior mesenteric vein, and the tip of the catheter was positioned at the bifurcation of the anterior and posterior branch of the portal vein to selectively infuse the islets into the right lobe of the liver in order to prevent total liver embolization. Intraoperative US examination (central frequency 7.5 MHz, NemioTM XG, Toshiba Medical System Co.) was started at the same time as the transplantation. US examination revealed the transplanted islets as hyperechoic clusters that flowed from the tip of the catheter to the periphery of the portal vein. There were no findings of portal thrombosis or bleeding in the US image, and also no increase of the portal vein pressure during transplantation. In conclusion, we succeeded in visualizing human islets using US, which enabled us to perform islet transplantation safely. The hyperechoic images were considered to be viable islets. Intraoperative US examination can be useful for detecting islets at transplantation in a clinical setting. PMID- 23108431 TI - Autophagy in adipose tissue. PMID- 23108432 TI - Pre-exposure to heavy metal pollution and the odor of predation decrease the ability of snails to avoid stressors. AB - Many organisms appear to exhibit adaptive cost-benefit behaviors that balance foraging, safety, and pollution avoidance. However, what if the cognitive facilities needed to make decisions are compromised by industrial pollutants? Are the resulting decisions altered? Similarly, does exposure to kairomones from predators alter an organism's ability to avoid toxicants? Furthermore, how long an exposure is necessary: A few minutes, hours, or even a lifetime? We wondered if there was an interaction between the ability to respond to a predatory event and the ability to avoid heavy metals. PMID- 23108434 TI - Cross talk between cancer and immune cells: exploring complex dynamics in a microfluidic environment. AB - The reconstitution of a complex microenvironment on microfluidic chips is one of the cornerstones to demonstrate the improved flexibility of these devices with respect to macroscale in vitro approaches. In this work, we realised an on-chip model to investigate the interactions between cancer and immune system. To this end, we exploited mice deficient (Knock Out, KO) for interferon regulatory factor 8 (IRF-8), a transcription factor essential for the induction of competent immune responses, to investigate how IRF-8 gene expression contributes to regulate immune and melanoma cells crosstalk. In vivo, IRF-8 KO mice are highly permissive to B16 melanoma growth due to failure of immune cells to properly exert immunosurveillance. B16 cells and immune cells isolated from the spleen of wild type (WT) and IRF-8 KO mice were co-cultured for one week in a PDMS platform and monitored by fluorescence microscopy and time-lapse recordings. We observed that WT spleen cells migrated through microchannels connecting the culturing chambers towards B16 cells and tightly interacted with tumor cells, forming clusters of activation. In contrast, IRF-8 KO immune cells poorly interacted with melanoma cells. In parallel, B16 cells were more attracted towards microchannels, acquiring a more invasive behaviour in the presence of IRF-8 KO spleen cells, with respect to WT cells. Our results strongly confirm the in vivo observations and highlight the value of on-chip co-culture systems as a useful in vitro tool to elucidate the reciprocal interactions between cancer cells and host immune system, with relevant impact in the development of more effective anti-tumor therapeutic strategies. PMID- 23108433 TI - Role of late sodium channel current block in the management of atrial fibrillation. AB - The anti-arrhythmic efficacy of the late sodium channel current (late I(Na)) inhibition has been convincingly demonstrated in the ventricles, particularly under conditions of prolonged ventricular repolarization. The value of late I(Na) block in the setting of atrial fibrillation (AF) remains poorly investigated. All sodium channel blockers inhibit both peak and late I(Na) and are generally more potent in inhibiting late vs. early I(Na). Selective late I(Na) block does not prolong the effective refractory period (ERP), a feature common to practically all anti-AF agents. Although the late I(Na) blocker ranolazine has been shown to be effective in suppression of AF, it is noteworthy that at concentrations at which it blocks late I(Na) in the ventricles, it also potently blocks peak I(Na) in the atria, thus causing rate-dependent prolongation of ERP due to development of post-repolarization refractoriness. Late I(Na) inhibition in atria is thought to suppress intracellular calcium (Ca(i))-mediated triggered activity, secondary to a reduction in intracellular sodium (Na(i)). However, agents that block late I(Na) (ranolazine, amiodarone, vernakalant, etc) are also potent atrial-selective peak I(Na) blockers, so that the reduction of Na(i) loading in atrial cells by these agents can be in large part due to the block of peak I(Na). The impact of late I(Na) inhibition is reduced by the abbreviation of the action potential that occurs in AF patients secondary to electrical remodeling. It stands to reason that selective late I(Na) block may contribute more to inhibition of Ca(i) mediated triggered activity responsible for initiation of AF in clinical pathologies associated with a prolonged atrial APD (such as long QT syndrome). Additional studies are clearly needed to test this hypothesis. PMID- 23108435 TI - Factors predicting the long-term illness course in a cohort of depressed inpatients. AB - Depressed psychiatric inpatients show particularly high rates of recurrence and chronicity. To identify predictors of their long-term illness course is of high importance for tertiary prevention. We followed up 68 unipolarly depressed psychiatric inpatients 1, 6, 42, and 66 months after discharge. Outcomes included time spent in episodes, time to relapse/recurrence, and psychosocial functioning during the prospective 5.5-year interval. Predictors included demographic, clinical, cognitive vulnerability, and social support variables assessed at baseline. During the total observation period, 12 % of patients spent <50 % of time in remission, and 55 % of those remitted at post-discharge baseline suffered a relapse or recurrence. Mean psychosocial functioning was below normal functioning at all assessments. Depression levels after discharge and unsatisfactory relationships within the support network predicted all outcomes. Furthermore, early onset, longer episode duration prior to study entry, and state orientation predicted time spent in episodes. Further predictors of time to recurrence included number of previous hospitalizations and lack of psychotherapy after discharge. Long-term psychosocial functioning was additionally predicted by previous hospitalizations, duration of index episode, and state orientation. Our results demonstrate a highly recurrent and chronic illness course in depressed psychiatric inpatients. Identified predictors point to the need of treating depressive episodes to full remission. Psychological interventions should explicitly address patients' interpersonal needs and possible deficits. PMID- 23108436 TI - Effects of core instability strength training on trunk muscle strength, spinal mobility, dynamic balance and functional mobility in older adults. AB - BACKGROUND: Age-related postural misalignment, balance deficits and strength/power losses are associated with impaired functional mobility and an increased risk of falling in seniors. Core instability strength training (CIT) involves exercises that are challenging for both trunk muscles and postural control and may thus have the potential to induce benefits in trunk muscle strength, spinal mobility and balance performance. OBJECTIVE: The objective was to investigate the effects of CIT on measures of trunk muscle strength, spinal mobility, dynamic balance and functional mobility in seniors. METHODS: Thirty-two older adults were randomly assigned to an intervention group (INT; n = 16, aged 70.8 +/- 4.1 years) that conducted a 9-week progressive CIT or to a control group (n = 16, aged 70.2 +/- 4.5 years). Maximal isometric strength of the trunk flexors/extensors/lateral flexors (right, left)/rotators (right, left) as well as of spinal mobility in the sagittal and the coronal plane was measured before and after the intervention program. Dynamic balance (i.e. walking 10 m on an optoelectric walkway, the Functional Reach test) and functional mobility (Timed Up and Go test) were additionally tested. RESULTS: Program compliance was excellent with participants of the INT group completing 92% of the training sessions. Significant group * test interactions were found for the maximal isometric strength of the trunk flexors (34%, p < 0.001), extensors (21%, p < 0.001), lateral flexors (right: 48%, p < 0.001; left: 53%, p < 0.001) and left rotators (42%, p < 0.001) in favor of the INT group. Further, training-related improvements were found for spinal mobility in the sagittal (11%, p < 0.001) and coronal plane (11%, p = 0.06) directions, for stride velocity (9%, p < 0.05), the coefficient of variation in stride velocity (31%, p < 0.05), the Functional Reach test (20%, p < 0.05) and the Timed Up and Go test (4%, p < 0.05) in favor of the INT group. CONCLUSION: CIT proved to be a feasible exercise program for seniors with a high adherence rate. Age-related deficits in measures of trunk muscle strength, spinal mobility, dynamic balance and functional mobility can be mitigated by CIT. This training regimen could be used as an adjunct or even alternative to traditional balance and/or resistance training. PMID- 23108437 TI - A microporous metal-organic framework containing an exceptional four-connecting 4(2)6(4) topology and a combined effect for highly selective adsorption of CO2 over N2. AB - Reported here is a new microporous metal-organic framework, namely [Zn(2)(L)(btc)(Hbtc)] [NH(2)(CH(3))(2)].(DMF)(2)(H(2)O)(4) (1), which is synthesized solvo(hydro)thermally by the self-assembly of Zn(NO(3))(2), N(4),N(4) di(pyridin-3-yl)-[1,1'-biphenyl]-4,4'-dicarboxamide (L) and 1,3,5 benzenetricarboxylate acid (H(3)btc). Its topology can be described as a four connecting 4(2)6(4) matrix containing both tetrahedral metal and ligand nodes. Interestingly, such a matrix has the same topology symbol as that observed in the well known sodalite (SOD) net, but the td10 of 434 is different from the td10 of 791 for the SOD net, indicative of an exceptional four-connecting 4(2)6(4) net. Another outstanding point is the highly selective adsorption of CO(2) over N(2), possibly contributed by a combined effect from the charged skeleton, the existence of functional groups of -CONH- and -COOH in 1. PMID- 23108438 TI - Streptococcal infections in patients with chronic granulomatous disease: case report and review of the literature. PMID- 23108439 TI - Factors associated with low self-esteem in children with overweight. AB - OBJECTIVE: Low self-esteem is one of the main psychosocial factors related to childhood overweight. Yet not all overweight children are affected. Little is known about what characterises the group of overweight children with the lowest self-esteem. Our aim was to identify factors related to low domain-specific self esteem in children with overweight/obesity. METHODS: Children (aged 10-13; N = 5,185) and parents from a large population-based sample completed the Eating Disturbance Scale, the Self-Perception Profile for Children, and questions about bullying and socio-economic status (SES). Parents reported the child's weight and height. 545 children with overweight/obesity were identified in the overall sample and selected for the current analyses. Self-esteem scores from this group were compared to scores from children with normal weight. Factors examined in relation to self-esteem in children with overweight/obesity were: age, gender, SES, disturbed eating, bullying, parents' evaluation of weight status and degree of overweight. RESULTS: Children with overweight scored significantly lower than normal-weight children on all self-esteem domains. Athletic competence and physical appearance were most impaired. Disturbed eating and bullying were related to low physical appearance as well as scholastic, social and athletic self-esteem. Being female, a pre-teen, having a higher BMI and being evaluated as overweight by parents were associated with lower satisfaction with physical appearance. CONCLUSIONS: Disturbed eating and bullying are significantly related to low self-esteem in the overweight group. PMID- 23108440 TI - Hydrogen production by immobilized Chlorella vulgaris: optimizing pH, carbon source and light. AB - The effects of light, pH and organic carbon sources were investigated on hydrogen production by algae. An optical fiber was examined as an internal light source. The optical fiber rendered prolonged lag time and total time of hydrogen production. The optimal pH to produce hydrogen for Chlorella sp. was 8.0. Glucose, fructose, sucrose and malt extract were compared as organic carbon sources. The optimal dose of each carbon source was 5 g/L for maximum hydrogen yield. Sucrose produced the largest hydrogen volume (1,315 ml/L), while the highest production rate (24 ml/L/h) was observed in the presence of fructose. PMID- 23108441 TI - An oxidoreduction potential shift control strategy for high purity propionic acid production by Propionibacterium freudenreichii CCTCC M207015 with glycerol as sole carbon source. AB - The effects of oxidoreduction potential (ORP) regulation on the process of propionic acid production by Propionibacterium freudenreichii CCTCC M207015 have been investigated. Potassium ferricyanide and sodium borohydride were determined as ORP control agents through serum bottle experiment. In batch fermentation, cell growth, propionic acid and by-products distribution were changed with ORP levels in the range of 0-160 mV. Based on these analysis results, an ORP-shift control strategy was proposed: at first 156 h, ORP was controlled at 120 mV to obtain higher cell growth rate and propionic acid formation rate, and then it was shifted to 80 mV after 156 h to maintain the higher propionic acid formation rate. By applying this strategy, the optimal parameters were obtained as follows: the propionic acid concentration 45.99 g L(-1), productivity 0.192 g L(-1) h(-1), the proportion of propionic acid to total organic acids 92.26 % (w/w) and glycerol conversion efficiency 76.65 %. The mechanism of ORP regulation was discussed by the ratio of NADH/NAD(+), ATP levels, and metabolic flux analysis. The results suggest that it is possible to redistribute energy and metabolic fluxes by the ORP-shift control strategy, and the strategy could provide a simple and efficient tool to realize high purity propionic acid production with glycerol as carbon source. PMID- 23108442 TI - Impact of phosphate concentration on docosahexaenoic acid production and related enzyme activities in fermentation of Schizochytrium sp. AB - Docosahexaenoic acid (DHA) is an important and widely used infant food additive. In this study, the effects of phosphate concentration on lipid and especially DHA synthesis in the oleaginous fungi Schizochytrium sp. HX-308 have been investigated in batch cultures. The maximum DHA yield (8.9 g/L) and DHA productivity (148.3 mg/L h) in 0.1 g/L KH2PO4 concentration were higher than the DHA yield (6.2 g/L) and DHA productivity (86.1 mg/L h) in 4 g/L KH2PO4 concentration. Furthermore, differences in related enzyme activities (malic enzyme, glucose-6-phosphate dehydrogenase and NAD(+)-isocitrate dehydrogenase) between phosphate-sufficient and phosphate-limitation conditions were assayed. The results showed that the phosphate-limitation condition could maintain higher activities of malic enzyme and glucose-6-phosphate dehydrogenase in addition to lower activity of NAD(+)-isocitrate dehydrogenase. In addition, glucose-6 phosphate dehydrogenase might be the main supplier of NADPH at the early stage of fermentation while malic enzyme might be the provider at the late stage. This information might explain the regulation mechanism of phosphate limitation for lipid production and be useful for further DHA production enhancement. PMID- 23108444 TI - Diagnostic and therapeutic intervention approaches to acquired neurogenic language and communication disorders in adults. PMID- 23108445 TI - Assessment and treatment of aphasia in czech. AB - Intervention approaches to aphasia differ in different countries. The aim of this paper is to give an overview of the situation in the Czech Republic. The following topics are summarized: (1) Czech logopedics in aphasiology; (2) the assessment of aphasia; (3) the treatment of aphasia; (4) Czech aphasiologic material; (5) the qualification of clinical logopedists, and (6) regulations of aphasiologic care. Czech is a very intricate language, both phonetically and grammatically. The prevalence of consonants appearing in long sequences (a whole sentence can be constructed purely of consonants) makes it difficult to pronounce. The strong inflecting character with hundreds of grammatical forms for each inflected word makes it difficult to use correct morphology and syntax. These facts make Czech a real challenge both for aphasics and logopedists. An overview of aphasia tests and treatment methods used in the Czech Republic, as well as conditions of logopedic care are given. The paper will allow comparison with the situation in other countries. PMID- 23108446 TI - Current clinical practices in Aphasia Therapy in Finland: challenges in moving towards national best practice. AB - AIMS: The objective of this article is to discover and document the state of clinical practices for aphasia therapy in Finland and to gather information for developing national best practice. METHODS: Two surveys were administered in Finland that explored current clinical practices in aphasia rehabilitation and the resources available to speech and language therapists (SLTs). We integrated and compared the results of these surveys. The results are based on the responses of the 88 (45 + 43) returned questionnaires from SLTs. RESULTS: Four principle themes were identified: planning the aphasia therapy, measures and assessment methods, current therapy service provision, and development suggestions and barriers to change. The results of this study showed considerable consistency in clinical practices among the respondents to the surveys. However, we noticed that there are some discrepancies between the recent research findings and present clinical practices. CONCLUSIONS: The findings from this study indicate that there are many challenges in clinical decision-making at the moment in Finland. The article helps clinicians to evaluate the practices they use and to execute justified modifications in order to implement more effective models of practice. It is evident that national best practice guidelines for aphasia therapy would support SLTs in clinical decision-making. PMID- 23108447 TI - Quality of life after stroke: evaluation of the Greek SAQOL-39g. AB - BACKGROUND/AIMS: Stroke and aphasia rehabilitation aims to improve people's quality of life. Yet, scales for measuring health-related quality of life in stroke typically exclude people with aphasia. They are also primarily available in English. An exception is the 39-item generic version of the Stroke and Aphasia Quality of Life Scale (SAQOL-39g). This scale has been tested with people with aphasia; it has been adapted for use in many countries including Greece. The aim of this study was to examine the psychometric properties of the Greek SAQOL-39g. METHODS: An interview-based psychometric study was carried out. Participants completed: receptive subtests of the Frenchay Aphasia Screening Test, the Greek SAQOL-39g, the 12-item General Health Questionnaire, the Frenchay Activities Index, the Montreal Cognitive Assessment and the Barthel Index. RESULTS: 86 people took part; 26 provided test-retest reliability data. The Greek SAQOL-39g demonstrated excellent acceptability (minimal missing data; no floor/ceiling effects), test-retest reliability [intraclass correlation coefficient = 0.96 (overall scale), 0.83-0.99 (domains)] and internal consistency [Cronbach's alpha = 0.96 (overall scale), 0.92-0.96 (domains)]. There was strong evidence for convergent [r = 0.53-0.80 (overall scale), 0.54-0.89 (domains)] and discriminant validity [r = 0.52 (overall scale), 0.04-0.48 (domains)]. CONCLUSION: The Greek SAQOL-39g is a valid and reliable scale. It is a promising measure for use in stroke and aphasia treatment prioritization, outcome measurement and service evaluation. PMID- 23108448 TI - The effects of age and education on executive functioning and oral naming performance in greek cypriot adults: the neurocognitive study for the aging. AB - BACKGROUND/AIMS: Age, educational experiences, language and culture can affect linguistic-cognitive performance. This is the first systematic study investigating linguistic-cognitive aging in Greek Cypriot adults focusing on executive functioning (EF) and oral naming performance. METHOD: Three hundred and fifty-nine participants were included, a group of young-old, aged 60-75 years (n = 231), and a group of old-old participants, aged 76 years and older (n = 128). Participants in each age group were divided into three education groups: 0-4 years (n = 50), 5-9 years (n = 198), and 10 years of education and higher (n = 111). Participants were administered 5 measures of EF along with measures of receptive vocabulary and confrontational naming. RESULTS: There was a significant relationship between the EF composite score and all language measures. MANOVA (alpha = 0.05) indicated significant age and education effects on most measures of EF and language. Performance on receptive vocabulary and cognitive shift remained stable across age groups, but was mediated by education. CONCLUSION: Education plays a significant role on all measures requiring semantic organization, speed of information processing, cognitive shift, mental flexibility, receptive vocabulary and confrontational naming. Furthermore, strategic thinking has a role in semantic knowledge, word retrieval and semantic access in healthy aging. We conclude with clinical implications and assessment considerations in aphasia. PMID- 23108449 TI - Communicative clusters after a right-hemisphere stroke: are there universal clinical profiles?. AB - OBJECTIVE: The current research aimed at classifying communication profiles among right-brain-damaged adults with an intercultural perspective, and so begins to fill in a long-standing gap in the literature. METHOD: The sample was made up of 112 right-brain-damaged individuals from three nationalities (Canadians, Brazilians and Argentineans). They were assessed using 13 language tasks from the Protocol MEC in Spanish, Brazilian Portuguese and French. RESULTS: A hierarchical cluster analysis led to four distinct clinical profiles of communication. Since only a few distinctions between nationalities were observed, the results suggest that there probably is a partial universality of clinical profiles of communication impairments after a right brain damage. CONCLUSIONS: This study proposes a preliminary taxonomy of communication disorders among right-brain damaged individuals with cross-cultural implications. The exploration of associated stroke sites and neuropsychological concomitant deficits would contribute to the eventual development of a more accurate clinical intervention. PMID- 23108451 TI - Light fractionated ALA-PDT enhances therapeutic efficacy in vitro; the influence of PpIX concentration and illumination parameters. AB - Light fractionation, with a long dark interval, significantly increases the response to ALA-PDT in pre-clinical models and in non-melanoma skin cancer. We investigated if this increase in efficacy can be replicated in PAM 212 cells in vitro. The results show a significant decrease in cell survival after light fractionation which is dependent on the PpIX concentration and light dose of the first light fraction. This study supports the hypothesis that an underlying cellular mechanism is involved in the response to light fractionation in which a first light fraction leads to sub-lethally damaged cells that are sensitised to a second light fraction 2 hours later. The current study reveals the in vitro circumstances under which we can investigate the cellular pathways involved. PMID- 23108452 TI - Evaluation of hepatotoxicity of chemicals using hepatic progenitor and hepatocyte like cells derived from mouse embryonic stem cells: effect of chemicals on ESC derived hepatocyte differentiation. AB - Embryonic stem cell testing is an alternative model system to assess drug and chemical toxicities because of its similar developmental characteristics with in vivo embryogenesis and organogenesis. This study evaluated the toxicity of chemicals at specific developmental stages of mouse embryonic stem cell (ESC) derived hepatic differentiation; hepatic progenitor cells (HPCs), and hepatocyte like cells (HCs). The toxic effects of carbon tetrachloride (CCl(4)), 5 fluorouracil (5-FU), and arsanilic acid (Ars) were evaluated by measuring the expressions of Cytokeratin (CK18) and GATA binding protein 4 (GATA-4) and the activities of aspartate transaminase (AST), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) during the hepatic differentiation process. Non-toxic doses of three chemicals at a range of 25 to 500 MUM for CCl(4), 12.5 to 800 nM for 5-FU and 6.25 to 400 mM for Ars were treated. In the CCl(4)-treated group, significant decreases (P < 0.05) of the marker expression were observed by more than 300 MUM from day 10 in CK18 and by more than 400 MUM of CCl(4) from day 22 in GATA-4, respectively. However, both markers were decreased (P < 0.01) by treatments of all doses at day 40. In the 5-FU-treated group, the expressions of two proteins were not affected by any of the doses at day 10 and 22, whereas the GATA-4 expression was decreased (P < 0.05) by more than 400 nM of 5-FU at days 28 and 40. In the Ars-treated group, the CK18 expression was inhibited (P < 0.05) by more than 100 mM of Ars at day 22 but showed a tendency to recover. Although the GATA-4 was inhibited by all doses at day 22, the inhibition of GATA-4 recovered at days 28 and 40. ALP activities of three chemicals were significantly increased (P < 0.05) by a dose-dependent manner. The activities of AST and LDH were prone to be increased by more than 300 MUM of CCl(4,) but not affected by all doses of 5-FU except for 800 nM of 5-FU in AST activities. In the Ars, the enzyme activities were significantly increased (P < 0.05) by more than 50 MUM of Ars in AST and more than 6.25 MUM of Ars in LDH. The present results indicate that CCl(4) has a more toxic effect on HCs, whereas Ars is more toxic to HPCs. Additionally, in vitro alternative testing using ESC-derived HPCs and HCs could provide useful information on chemical toxicity during the hepatic differentiation process and could be a useful model system for assessing chemical hepatotoxicity. PMID- 23108453 TI - An ascorbic acid sensor based on protein-modified Au nanoclusters. AB - A simple fluorescence sensor for sensitive turn-off detection of ascorbic acid (AA) was developed by using protein-modified Au nanoclusters in aqueous media. The sensing mechanism is originated from the oxidation state change of Au nanoclusters controlled by AA. Under optimal experimental conditions, a good linear relationship between the relative fluorescence quenching intensity and the concentration of AA can be obtained in the range of 1.5 to 10 MUM, with a detection limit as low as 0.2 MUM. The proposed method is simple, efficient and reliable for monitoring of AA in some biological samples. PMID- 23108455 TI - Centrifugo-dynamic inward pumping of liquids on a centrifugal microfluidic platform. AB - We present a method to pump liquids in a centrifugal microfluidic spinning disk from a radial outward position to a radial inward position. Centrifugal forces are applied to compress air in a cavity, this way storing pneumatic energy. The cavity is connected to an outlet channel having a lower hydraulic resistance compared to the inlet channel. The stored pneumatic energy is quickly released by fast reduction of rotational frequency. This way liquid is transported mainly through the channel with lower resistance, directing the liquid radially inwards. Pump efficiencies of >75% per pump cycle have been demonstrated for water, ethanol, a highly viscous lysis buffer and whole blood. By employing three pump cycles, water has been pumped radially inwards with an efficiency of >90%. The inward pumping requires centrifugation only, which is intrinsically available on every centrifugal microfluidic platform. PMID- 23108454 TI - Autophagy genes function in apoptotic cell corpse clearance during C. elegans embryonic development. AB - Efficient apoptotic corpse clearance is essential for metazoan development and adult tissue homeostasis. Several autophagy proteins have been previously shown to function in apoptotic cell clearance; however, it remains unknown whether autophagy genes are essential for efficient apoptotic corpse clearance in the developing embryo. Here we show that, in Caenorhabditis elegans embryos, loss-of function mutations in several autophagy genes that act at distinct steps in the autophagy pathway resulted in increased numbers of cell corpses and delayed cell corpse clearance. Further analysis of embryos with a null mutation in bec- 1, the C. elegans ortholog of yeast VPS30/ATG6/mammalian beclin 1 (BECN1), revealed normal phosphatidylserine exposure on dying cells. Moreover, the corpse clearance defects of bec- 1(ok691) embryos were rescued by BEC-1 expression in engulfing cells, and bec- 1(ok691) enhanced corpse clearance defects in nematodes with simultaneous mutations in the engulfment genes, ced- 1, ced- 6 or ced- 12. Together, these data demonstrate that autophagy proteins play an important role in cell corpse clearance during nematode embryonic development, and likely function in parallel to known pathways involved in corpse removal. PMID- 23108456 TI - TRAIL death receptor 4 signaling via lysosome fusion and membrane raft clustering in coronary arterial endothelial cells: evidence from ASM knockout mice. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor, death receptor 4 (DR4), have been implicated in the development of endothelial dysfunction and atherosclerosis. However, the signaling mechanism mediating DR4 activation leading to endothelial injury remains unclear. We recently demonstrated that ceramide production via hydrolysis of membrane sphingomyelin by acid sphingomyelinase (ASM) results in membrane raft (MR) clustering and the formation of important redox signaling platforms, which play a crucial role in amplifying redox signaling in endothelial cells leading to endothelial dysfunction. The present study aims to investigate whether TRAIL triggers MR clustering via lysosome fusion and ASM activation, thereby conducting transmembrane redox signaling and changing endothelial function. Using confocal microscopy, we found that TRAIL induced MR clustering and co-localized with DR4 in coronary arterial endothelial cells (CAECs) isolated from wild-type (Smpd1 (+/+)) mice. Furthermore, TRAIL triggered ASM translocation, ceramide production, and NADPH oxidase aggregation in MR clusters in Smpd1 ( +/+ ) CAECs, whereas these observations were not found in Smpd1 (-/-) CAECs. Moreover, ASM deficiency reduced TRAIL-induced O(2) (-[Symbol: see text]) production in CAECs and abolished TRAIL-induced impairment on endothelium-dependent vasodilation in small resistance arteries. By measuring fluorescence resonance energy transfer, we found that Lamp-1 (lysosome membrane marker protein) and ganglioside G(M1) (MR marker) were trafficking together in Smpd1 (+/+) CAECs, which was absent in Smpd1 (-/-) CAECs. Consistently, fluorescence imaging of living cells with specific lysosome probes demonstrated that TRAIL-induced lysosome fusion with membrane was also absent in Smpd1 (-/-) CAECs. Taken together, these results suggest that ASM is essential for TRAIL-induced lysosomal trafficking, membrane fusion and formation of MR redox signaling platforms, which may play an important role in DR4-mediated redox signaling in CAECs and consequently endothelial dysfunction. PMID- 23108457 TI - Novel dating method to distinguish between forensic and archeological human skeletal remains by bone mineralization indexes. AB - The fast, high-throughput distinction between paleoanthropological remains and recent forensic/clinical bone samples is of vital importance in the field of medicolegal science. In this paper, a novel screening method has been described, using the crystallinity index (C.I.) and carbonate-phosphate index (C/P) as a means to distinguish between archeological and forensic anthropological skeletal findings. According to the Fourier transform infrared spectroscopy analyses, the archeological bone samples are characterized by a range of C.I. between 2.84 and 3.78 and by low C/P values of 0.10-0.33, while the C.I. and C/P ranges of forensic skeletal remains are 2.55-3.18 and 0.38-0.88, respectively. Significant (p < 0.05) changes were observed in C/P as well as C.I. values between the groups of forensic and archeological skeletal samples. The suggested dating method needs only a few milligramms of bone tissue; thus, it can be extremely useful for distiguishing ancient and recent bone fragments. PMID- 23108459 TI - The K-P algorithm: a new first-trimester growth model - comparison with other formulae and correlations with recorded embryonic lengths. AB - OBJECTIVE: To generate and validate individually fitted first-trimester growth curves using a new growth model. Secondary aims were to compare this new model with actual recorded embryonic measurements and validate its predictive accuracy. METHODS: A prospective study of women presenting to the Early Pregnancy Unit in the first trimester. Women with viable singleton pregnancies at the end of the first trimester who had had at least two crown-rump length (CRL) measurements were selected. An individual power function of CRL was derived from serial CRL measurements. Individual curves were fitted using computer software to estimate a dating adjustment factor ('k'), and a growth coefficient ('P') for each case. The predictive accuracy of the growth curves was then tested in a validation subset of the population that had a third CRL measurement. The population average curve from the developed model was also extrapolated to day 27 menstrual age (Carnegie stage 6), day 30 menstrual age (Carnegie stage 7) and day 84 menstrual age, and values were compared to previously reported measurements. RESULTS: 326 viable pregnancies were selected for CRL growth curve development. The mean time interval between CRL measurements was 20.5 days (range 2-44). The mean value for 'P' was 2.058, and for 'k' 24.6. Testing the model on a subset of 81 cases showed that the average error in predicting a third CRL measurement was 1% (SD 9.1%). CONCLUSIONS: These new, individually fitted growth curves for the first trimester correlate more closely with the recorded embryonic lengths than other standards. PMID- 23108458 TI - Apparent versus true gene expression changes of three hypoxia-related genes in autopsy derived tissue and the importance of normalisation. AB - The aim of our work was to show how a chosen normal-isation strategy can affect the outcome of quantitative gene expression studies. As an example, we analysed the expression of three genes known to be upregulated under hypoxic conditions: HIF1A, VEGF and SLC2A1 (GLUT1). Raw RT-qPCR data were normalised using two different strategies: a straightforward normalisation against a single reference gene, GAPDH, using the 2(-DeltaDeltaCt) algorithm and a more complex normalisation against a normalisation factor calculated from the quantitative raw data from four previously validated reference genes. We found that the two different normalisation strategies revealed contradicting results: normalising against a validated set of reference genes revealed an upregulation of the three genes of interest in three post-mortem tissue samples (cardiac muscle, skeletal muscle and brain) under hypoxic conditions. Interestingly, we found a statistically significant difference in the relative transcript abundance of VEGF in cardiac muscle between donors who died of asphyxia versus donors who died from cardiac death. Normalisation against GAPDH alone revealed no upregulation but, in some instances, a downregulation of the genes of interest. To further analyse this discrepancy, the stability of all reference genes used were reassessed and the very low expression stability of GAPDH was found to originate from the co regulation of this gene under hypoxic conditions. We concluded that GAPDH is not a suitable reference gene for the quantitative analysis of gene expression in hypoxia and that validation of reference genes is a crucial step for generating biologically meaningful data. PMID- 23108460 TI - Conjugated metallorganic macrocycles: opportunities for coordination-driven planarization of bidentate, pyridine-based ligands. AB - Two conjugated systems that can be constrained to planarity via metal coordination have been generated and their metal complexes studied. The potential for these architectures to be incorporated into metal-sensing arylene ethynylene/vinylene oligomers and polymers was probed by verifying that these ligands (1) bind strongly to Ag(I) and Pd(II) cations, and (2) that this event leads to complexes that are planar. Single crystal structures confirm that introduction of Ag(I) or Pd(II) cations enforces planarity in the newly formed macrocycles. Likewise, (1)H-NMR titration studies reveal stoichiometric binding of Pd(II) and strong binding of Ag(I) (K(a (Ligand 1)) = 1.3 * 10(2) M(-1); K(a (Ligand 2)) = 5.4 * 10(2) M(-1)) for each conjugated ligand. PMID- 23108461 TI - Characterization of 12 polymorphic microsatellite markers in the liverwort Marchantia inflexa (Marchantiaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Marchantia inflexa, a haploid liverwort with unisexual individuals, to identify clonal genotypes and measure population genetic variability. METHODS AND RESULTS: Twelve polymorphic primer sets were developed from three enriched genomic libraries. Primers were fluorescently labeled, and alleles were identified by fragment analysis. These primers were tested in four natural populations and revealed a moderate level of genetic variation within four populations, as indicated by the number of alleles per locus (range = 1-5). CONCLUSIONS: Development of polymorphic markers is crucial to the identification of individuals and will allow additional research into this species, particularly on its population genetics and metapopulation dynamics. PMID- 23108462 TI - Characterization of 39 novel EST-SSR markers for Liriodendron tulipifera and cross-species amplification in L. chinense (Magnoliaceae). AB - PREMISE OF THE STUDY: A novel set of simple sequence repeat (SSR) markers were developed and characterized from the expressed sequence tag (EST) database of Liriodendron tulipifera for application in population genetic studies of Liriodendron. METHODS AND RESULTS: Thirty-nine polymorphic EST-SSR loci were identified among 27 individuals sampled from a cultivated population of L. tulipifera. The number of alleles per locus ranged from three to 18. The average observed heterozygosity and expected heterozygosity were 0.684 and 0.778, respectively. Of the 39 loci, 32 showed interspecific transferability and polymorphism in a related species, L. chinense. The number of alleles per locus ranged from two to 11, and the average observed heterozygosity and expected heterozygosity were 0.475 and 0.736, respectively. CONCLUSIONS: The developed EST SSR markers will be useful for investigating adaptive genetic differentiation in Liriodendron. PMID- 23108463 TI - Eleven microsatellite markers for the mountain clover Trifolium montanum (Fabaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed in Trifolium montanum to investigate pollen dispersal patterns at landscape scale with a pollen-pool analysis (indirect parentage analysis) as well as in an experimental set-up with a direct paternity analysis. METHODS AND RESULTS: Screening 46 microsatellites developed for T. repens yielded four markers usable in T. montanum. Seven additional ones have been developed specifically for the target species using a 454-sequencing approach. All markers were polymorphic, with an allele number ranging from two to 45 based upon 254 individuals sampled from four populations, and an exclusion probability of 0.999. CONCLUSIONS: These markers proved a useful and reliable molecular tool for use in population genetics and parentage studies of this common grassland herb. PMID- 23108464 TI - Identifying multiple origins of polyploid taxa: a multilocus study of the hybrid cloak fern (Astrolepis integerrima; Pteridaceae). AB - PREMISE OF THE STUDY: Molecular studies have shown that multiple origins of polyploid taxa are the rule rather than the exception. To understand the distribution and ecology of polyploid species and the evolutionary significance of polyploidy in general, it is important to delineate these independently derived lineages as accurately as possible. Although gene flow among polyploid lineages and backcrossing to their diploid parents often confound this process, such post origin gene flow is very infrequent in asexual polyploids. In this study, we estimate the number of independent origins of the apomictic allopolyploid fern Astrolepis integerrima, a morphologically heterogeneous species most common in the southwestern United States and Mexico, with outlying populations in the southeastern United States and the Caribbean. METHODS: Plastid DNA sequence and AFLP data were obtained from 33 A. integerrima individuals. Phylogenetic analysis of the sequence data and multidimensional clustering of the AFLP data were used to identify independently derived lineages. KEY RESULTS: Analysis of the two datasets identified 10 genetic groups within the 33 analyzed samples. These groups suggest a minimum of 10 origins of A. integerrima in the northern portion of its range, with both putative parents functioning as maternal donors, both supplying unreduced gametes, and both contributing a significant portion of their genetic diversity to the hybrids. CONCLUSIONS: Our results highlight the extreme cryptic genetic diversity and systematic complexity that can underlie a single polyploid taxon. PMID- 23108465 TI - Eleven diverse nuclear-encoded phylogenetic markers for the subfamily Panicoideae (Poaceae). AB - PREMISE OF THE STUDY: Polyploidy is common in the grasses and low-copy nuclear loci are needed to further our understanding of phylogenetic relationships. METHODS AND RESULTS: Genetic and genomic resources were combined to identify loci known to influence plant and inflorescence architecture. Degenerate primers were designed and tested to amplify regions of 11 nuclear-encoded loci across the panicoid grasses. CONCLUSIONS: The primers designed in this study amplify regions of a diverse set of genes within the panicoid grasses. Properly employed, these markers will allow the identification of allopolyploid taxa and their diploid progenitors. PMID- 23108466 TI - Development of microsatellite markers for Pimenta pseudocaryophyllus (Myrtaceae), a wild South American species. AB - PREMISE OF THE STUDY: We developed the first set of microsatellite markers for Pimenta pseudocaryophyllus to support further studies on genetic diversity and to inform conservation strategies. METHODS AND RESULTS: The microsatellite-enriched library approach was used to isolate and characterize 12 new molecular markers. It was possible to detect 11 polymorphic microsatellite loci and one monomorphic locus. The polymorphism information content ranged from 0.317 to 0.869. CONCLUSIONS: These molecular markers will be valuable tools to aid in understanding the biology of P. pseudocaryophyllus and to detect ongoing consequences of its exploitation, in the context of conservation genetics. PMID- 23108467 TI - Microsatellite primers for the endangered beech tree, Fagus hayatae (Fagaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed for the endangered species Fagus hayatae (Fagaceae) to investigate the genetic diversity of the population and to investigate species delimitation within Fagus. METHODS AND RESULTS: Ten polymorphic simple sequence repeat markers were developed for F. hayatae using a magnetic bead enrichment method. The primers amplified trinucleotides, hexanucleotides, and complex repeats with six to 16 alleles per locus. The observed and expected heterozygosities across loci varied, with a range of 0.05-0.71 and 0.63-0.91, respectively. Most of the primers also amplified DNA from F. crenata, F. grandifolia, F. japonica, F. longipetiolata, F. lucida, F. orientalis, and F. sylvatica. CONCLUSIONS: These results indicate that these polymorphic loci of F. hayatae will be potentially useful for future studies of the population genetic diversity within the species. In addition, the interspecific amplification indicates that these transferable microsatellite markers will also be useful for future phylogeographic and speciation studies among close Fagus species. PMID- 23108468 TI - Isolation and characterization of microsatellite markers for an important tropical tree, Aquilaria malaccensis (Thymelaeaceae). AB - PREMISE OF THE STUDY: Aggressive collections and trade activities in recent decades have resulted in heavy pressure on the natural stands of Aquilaria malaccensis and concerns over its long-term survival potential. To aid DNA profiling and assessment of its genetic diversity, microsatellite markers were developed for the species. METHODS AND RESULTS: Seventeen polymorphic microsatellite markers were developed for A. malaccensis using an enrichment protocol. The markers were screened on 24 samples from a natural population. The number of alleles ranged from two to 11, and the observed heterozygosity ranged from 0.042 to 0.957. No significant deviation from Hardy-Weinberg equilibrium was detected after conservative Bonferroni correction. CONCLUSIONS: This is the first report on the development of microsatellite markers in A. malaccensis. The markers will be used to establish a DNA profiling database and to estimate the genetic diversity and population genetic structure of the species. PMID- 23108469 TI - Microsatellite primers for an Amazonian lowland tropical tree, Protium subserratum (Burseraceae). AB - PREMISE OF THE STUDY: The first microsatellite primers were developed for Protium subserratum, a widespread Amazonian tree, to investigate genetic differentiation between populations found on clay, brown-sand, and white-sand soils. * METHODS AND RESULTS: Seventeen primer pairs were identified from two individuals of P. subserratum found on white-sand and brown-sand soil types. Polymorphism was analyzed in 63 individuals from a total of three populations, each found on a different soil type. The primers amplified tetra-, tri-, and dinucleotide repeats with three to 24 alleles per locus. Excluding monomorphic loci, observed and expected heterozygosities ranged from 0 to 0.852 and 0.036 to 0.901, respectively. * CONCLUSIONS: These new microsatellite markers will be useful in studies of genetic diversity, population differentiation, and gene flow across habitat types in P. subserratum. PMID- 23108470 TI - Characterization of 21 microsatellite markers from cogongrass, Imperata cylindrica (Poaceae), a weed species distributed worldwide. AB - PREMISE OF THE STUDY: Microsatellite loci were developed from Imperata cylindrica, a traditional medicinal herb in Asia and among the top 10 worst invasive weeds in the world, to aid in the identification of the limits of asexual clonal individuals. METHODS AND RESULTS: A total of 21 microsatellite markers, including 18 polymorphic and three monomorphic loci, were developed from I. cylindrica using a magnetic bead enrichment protocol. The primers amplified dinucleotide, trinucleotide, and complex repeats. The number of alleles ranged from one to 19 per locus, with an observed heterozygosity ranging from 0.09 to 1.00. Several loci deviated significantly from the within-population Hardy Weinberg equilibrium as a result of asexual clonal reproduction. CONCLUSIONS: These polymorphic markers should be useful tools in further studies on the identification of the range of clonal reproduction units and the selection and classification of the medicinal cultivar. PMID- 23108471 TI - Comprehensive report of primary immunodeficiency disorders from a tertiary care center in India. AB - OBJECTIVES: There is paucity of data on Primary immunodeficiency disorders (PID) from India. Here we describe the frequency of different primary immunodeficiency disorders, their clinical features and disease complications of 159 patients with PID diagnosed in a tertiary care center from India over the last 3 years. METHODS: We retrospectively reviewed the records of all the patients identified to have specific PID from 2008 to 2011. The diagnosed patients were classified according to guidelines of International Union of Immunological Society (IUIS) into eight different sub groups. RESULTS: The distribution pattern was as follows: diseases of immune dysregulation (29 %), phagocytic defects (29 %), predominant antibody deficiency (13 %), combined T and B cell deficiency (19 %) and other well defined diseases (10 %). CONCLUSION: The distribution pattern of PID varied significantly from those reported by western studies. This study highlights the need for development of more advanced facilities for diagnosis and management of PID in India and also the need for establishing population and hospital based registries. PMID- 23108472 TI - Association between inflammatory and obesity markers in a Swiss population-based sample (CoLaus Study). AB - OBJECTIVE: To assess the associations between obesity markers (BMI, waist circumference and %body fat) and inflammatory markers (interleukin-1beta (IL 1beta); interleukin-6 (IL-6); tumor necrosis factor-alpha (TNF-alpha) and high sensitivity C-reactive protein (hs-CRP)). METHODS: Population sample of 2,884 men and 3,201 women aged 35-75 years. Associations were assessed using ridge regression adjusting for age, leisure-time physical activity, and smoking. RESULTS: No differences were found in IL-1beta levels between participants with increased obesity markers and healthy counterparts; multivariate regression showed %body fat to be negatively associated with IL-1beta. Participants with high %body fat or abdominal obesity had higher IL-6 levels, but no independent association between IL-6 levels and obesity markers was found on multivariate regression. Participants with abdominal obesity had higher TNF-alpha levels, and positive associations were found between TNF-alpha levels and waist circumference in men and between TNF-alpha levels and BMI in women. Obese participants had higher hs-CRP levels, and these differences persisted after multivariate adjustment; similarly, positive associations were found between hs-CRP levels and all obesity markers studied. CONCLUSION: Obesity markers are differentially associated with cytokine levels. %Body fat is negatively associated with IL 1beta; BMI (in women) and waist circumference (in men) are associated with TNF alpha; all obesity markers are positively associated with hs-CRP. PMID- 23108473 TI - When clinicians telling the truth is de facto discouraged, what is the family's attitude towards disclosing to a relative their cancer diagnosis? AB - PURPOSE: This study evaluated the attitudes of cancer patients' family members regarding disclosure of a cancer diagnosis to the patient and justifications for their attitudes. METHODS: Family members were invited to complete a questionnaire to evaluate their attitudes towards disclosure of a cancer diagnosis to a relative as well as reasons for their point of view. Data were analyzed to evaluate factors influencing attitudes. RESULTS: One hundred eighty-six completed surveys were returned. Of them, 44.1 % (82/186) indicated that the patient should be informed of the diagnosis, and 55.9 % (104/186) stated emphatically that the patient should not be told the truth. The main reason given for concealing the truth was fear that awareness of a cancer diagnosis might cause psychological morbidity. The justifications for disclosing the bad news were as follows: (1) obtaining the patient's cooperation during treatment, (2) the impossibility of concealment, and (3) believing the patient was psychologically strong enough to accept the truth. Patients' educational status and awareness of disease as well as family members' age were the factors that influenced attitudes toward disclosure. CONCLUSIONS: Telling the truth to a cancer patient is often de facto discouraged in clinicians. Family members often support nondisclosure, especially when they have experience with a relative who is unaware of the truth. The education level of family members does not appear to influence decisions regarding disclosure. These findings can be helpful in the development of policies and/or programs to assist medical professionals and family members engage in truthful disclosure to a patient who has cancer. PMID- 23108474 TI - Quality of life (QOL), supportive care, and spirituality in hematopoietic stem cell transplant (HSCT) patients. AB - For many patients, a hematopoietic stem cell transplant (HSCT) can be challenging to physical and emotional health. Supportive care needs can be overwhelming for many patients and families. The purpose of this study was to evaluate the effect of quality of life (QOL), spiritual well-being, and supportive care resources post-HSCT. This descriptive, repeated-measures study included people over the age of 18 years undergoing HSCT for any cancer diagnosis. The Functional Assessment in Cancer Therapy--Bone Marrow Transplant scale, the Functional Assessment of Chronic Illness Therapy--Spiritual--12 scale, and a resource questionnaire were administered prior to HSCT and following HSCT at 30, 60, 90, and 180 days. Three groups of HSCT patients were examined: allogeneic, autologous, and overall. Data analysis included descriptive statistics and correlations. In the sample (n = 159), the autologous HSCT group reported the highest QOL scores. Spirituality scores increased for the autologous HSCT group at 90 days, but decreased for the overall and allogeneic groups. The type of supportive care resources most used were information from the physician and nurse, the Leukemia and Lymphoma Society Support as the most used form of support group, and Faith, Prayer and Spiritual Healing. QOL and spiritual well-being scores correlated best at 180 days (6 months) for autologous and allogeneic patients. PMID- 23108475 TI - Hypnotic drug use among 0-17 year olds during 2004-2011: a nationwide prescription database study. AB - AIMS: To (a) describe the prevalence, trend, and amount of hypnotic drug use, (b) determine the prevalence of chronic diseases among hypnotic drug users, and (c) determine levels of recurrent hypnotic drug use (2007-2011), among 0-17 year old Norwegians. METHODS: Data were obtained from the nationwide Norwegian Prescription Database (NorPD) in the period 2004-2011. RESULTS: Hypnotic drug use in 0-17 year olds increased during the period, from 8.9 to 12.3 per 1000, mainly owing to doubling of melatonin use. Hypnotic drug use peaked at 15 per 1000 among those aged 1-2 years. Melatonin use increased steadily from 6 to 12 years of age, most pronounced in males. Among females, hypnotic drug use increased threefold from 13 to17 years of age. Melatonin was dispensed in the highest annual amount of all hypnotic drugs; accounting up to a median of 360 defined daily doses in 9 13 year old boys. A total of 62% and 52% of all male and female hypnotic drug users were co-medicated with reimbursable drugs for chronic diseases. Levels of recurrent use (2007-2011) were 12% in boys and 8% in girls, of whom 76-77% were co-medicated with drugs reimbursed for chronic diseases. CONCLUSIONS: There is a trend of increasing use of hypnotic drugs among 0-17 year olds, mainly owing to increasing use of melatonin, used in high amounts. Still, melatonin is not recommended in Norway for use in this age group because of insufficient data on safety and efficacy. A threefold increase in hypnotic drugs among females from 13 to 17 years of age warrants attention. PMID- 23108476 TI - Growth measures among preschool-age Inuit children living in Canada and Greenland. AB - AIM: The present study reports findings from a study of preschool-age Inuit children living in the Arctic regions of Canada and Greenland. METHODS: We compare stature and obesity measures using cutoffs from the Centers for Disease Control and the International Obesity Task Force references. The sample is comprised of 1121 Inuit children (554 boys and 567 girls) aged 3-5 years living in Nunavut (n=376) and Nunavik (n=87), Canada, in the capital city of Nuuk, Greenland (n=86), and in Greenland's remaining towns and villages (n=572). RESULTS: Greenland Inuit children were significantly taller than their Canadian counterparts, with greatest height and weight observed among children from Nuuk. Overall prevalence of stunting was low with the three cutoffs yielding similar values for height-for-age z-scores. Obesity prevalence was higher among Canadian Inuit children than their Greenland counterparts. CONCLUSIONS: Inuit children have stature values consistent with those of the Centers for Disease Control reference and low prevalence of stunting, though geographic variability in mean stature values between Canadian and Greenlandic samples likely reflects differences in both socioeconomic status and genetic admixture. Obesity prevalence is high among both Canadian and Greenland Inuit preschoolers, with children living in the city of Nuuk exhibiting lower obesity prevalence than children living in either Nunavut or Nunavik, Canada or Greenland's towns and villages. Varying obesity prevalence may reflect varying degrees of food security in remote locations as well as the influence of stature and sitting height which have not been well studied in young Inuit children. PMID- 23108478 TI - Erratun. PMID- 23108477 TI - Design of the OPUS School Meal Study: a randomised controlled trial assessing the impact of serving school meals based on the New Nordic Diet. AB - INTRODUCTION: Danish children consume too much sugar and not enough whole grain, fish, fruit, and vegetables. The Nordic region is rich in such foods with a strong health-promoting potential. We lack randomised controlled trials that investigate the developmental and health impact of serving school meals based on Nordic foods. AIM: This paper describes the rationale, design, study population, and potential implications of the Optimal well-being, development and health for Danish children through a healthy New Nordic Diet (OPUS) School Meal Study. METHODS: In a cluster-randomised cross-over design, 1021 children from 3rd and 4th grades (8-11 years old) at nine Danish municipal schools were invited to participate. Classes were assigned to two 3-month periods with free school meals based on the New Nordic Diet (NND) or their usual packed lunch (control). Dietary intake, nutrient status, physical activity, cardiorespiratory fitness, sleep, growth, body composition, early metabolic and cardiovascular risk markers, illness, absence from school, wellbeing, cognitive function, social and cultural features, food acceptance, waste, and cost were assessed. RESULTS: In total, 834 children (82% of those invited) participated. Although their parents were slightly better educated than the background population, children from various socioeconomic backgrounds were included. The proportion of overweight and obese children (14%) resembled that of earlier examinations of Danish school children. Drop out was 8.3%. CONCLUSIONS: A high inclusion rate and low drop out rate was achieved. This study will be the first to determine whether school meals based on the NND improve children's diet, health, growth, cognitive performance, and early disease risk markers. PMID- 23108480 TI - A modular approach to create a neurovascular unit-on-a-chip. AB - In this work, we describe the fabrication and working of a modular microsystem that recapitulates the functions of the "Neurovascular Unit". The microdevice comprised a vertical stack of a poly(dimethylsiloxane) (PDMS) neural parenchymal chamber separated by a vascular channel via a microporous polycarbonate (PC) membrane. The neural chamber housed a mixture of neurons (~4%), astrocytes (~95%), and microglia (~1%). The vascular channel was lined with a layer of rat brain microvascular endothelial cell line (RBE4). Cellular components in the neural chamber and vascular channel showed viability (>90%). The neural cells fired inhibitory as well as excitatory potentials following 10 days of culture. The endothelial cells showed diluted-acetylated low density lipoprotein (dil-a LDL) uptake, expressed von Willebrand factor (vWF) and zonula occludens (ZO-1) tight junctions, and showed decreased AlexafluorTM-conjugated dextran leakage across their barriers significantly compared with controls (p < 0.05). When the vascular layer was stimulated with TNF-alpha for 6 h, about 75% of resident microglia and astrocytes on the neural side were activated significantly (p < 0.05 compared to controls) recapitulating tissue-mimetic responses resembling neuroinflammation. The impact of this microsystem lies in the fact that this biomimetic neurovascular platform might not only be harnessed for obtaining mechanistic insights for neurodegenerative disorders, but could also serve as a potential screening tool for central nervous system (CNS) therapeutics in toxicology and neuroinfectious diseases. PMID- 23108479 TI - High expression of TNF alpha is associated with -308 and -238 TNF alpha polymorphisms in knee osteoarthritis. AB - Knee osteoarthritis (OA) is a common chronic degenerative disease characterized by the loss of articular cartilage components due to an imbalance between extracellular matrix destruction and repair. The proinflammatory cytokines involved in OA, TNFalpha and IL1beta, are considered the major implicated. The aim of this study was to investigate the relationship between TNFalpha -308 and 238 polymorphisms with messenger RNA (mRNA) and soluble TNFalpha expression in knee OA patients and healthy subjects (HS). Case-control study involved 50 knee OA patients classified according to 1986 ACR Classification Criteria, as well as 100 HS. The Western Ontario and McMaster Universities Osteoarthritis Index and Lequesne disability index were applied to OA patients. The -308 and -238 polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism technique. The TNFalpha mRNA expression was quantified by real-time PCR using TaqMan method. The sTNFalpha levels were measured by enzyme linked immunosorbent assay. The TNFalpha mRNA expression in knee OA patients was higher than in HS (1.56-fold). In addition, the TNFalpha mRNA expression was higher in carriers of G allele in the knee OA group for both polymorphisms. The sTNFalpha levels were increased in G/G versus G/A genotypes in both studied polymorphisms (p < 0.05). However, the TNFalpha -308 and -238 genotypes did not show statistical differences between groups. The G allele of TNFalpha -308 and 238 polymorphisms is associated with high mRNA and soluble expression in knee OA patients. However, it is not a marker of susceptibility in Western Mexico. Further studies are necessary to confirm these findings. PMID- 23108481 TI - Ligand field effect tuned magnetic behaviors of two chain compounds based on Mn(III)3O units: from slow magnetic relaxation to metamagnetism. AB - Two chain compounds built with anti-anti acetate bridged Mn(III)(3)O units, [Mn(3)O(Clppz)(3)(EtOH)(4)(OAc)](n) (1) and [Mn(3)O(Clppz)(3)(EtOH)(2)(OAc)](n) (2), were synthesized and characterized. The magnetic studies indicate that 1 is a single-chain magnet with two slow magnetization relaxation processes which has for the first time been found in this type of chain complex, while 2 shows a field-induced metamagnetic behavior. The quite different magnetic behaviors resulted from the different number of coordinated ethanol molecules on the Mn(III)(3)O unit, four ethanol molecules for 1, and two ethanol molecules for 2. The best fittings to the experimental magnetic susceptibilities gave J(1) = -2.72 cm(-1), J(2) = -4.34 cm(-1), zJ = 1.24 cm(-1) for 1 and J(1) = -5.91 cm(-1), J(2) = -0.98 cm(-1), zJ = 1.71 for 2 above 30 K. The positive zJ values indicate the presence of weak ferromagnetic interactions between the trinuclear units via acetate bridges in 1 and 2. PMID- 23108482 TI - The effect of carvedilol treatment on chronic heart failure in pediatric patients with dilated cardiomyopathy: a prospective, randomized-controlled study. AB - This study aimed to evaluate the clinical efficacy and safety of carvedilol for pediatric patients with chronic heart failure caused by dilated cardiomyopathy. Seven pediatric medical centers participated in this prospective study. Pediatric patients (n = 89) were randomly divided into an experimental group (carvedilol treatment) and a control group (conventional treatment). The analysis excluded 12 patients lost during the follow-up period. Carvedilol was added to the therapy of the experimental group after at least 1 month of basic treatment with digoxin, an angiotensin-converting-enzyme inhibitor, and diuretics. The control patients received the same basic treatment but did not receive carvedilol. The initial dose of carvedilol was 0.1 (mg/kg day), and the dose was doubled every 2 weeks until the maximum tolerated dose or 0.8 (mg/kg day) was achieved. The tolerated dose was maintained for 6 months. The Ross scales and echocardiographic parameters including left ventricular diastolic diameter, left ventricular systolic diameter, left ventricular ejection fraction, left ventricular fractional shortening, and serous brain natriuretic peptide (BNP) concentration, as well as clinical progress were compared between the two groups. The Ross scales decreased by 11.94% in the experimental group, which was more than in the control group (2.81%). In addition, changes to other echocardiographic parameters in the experimental group also were superior to those in the control group. The serous BNP concentration in the experimental group decreased by 30.1%, which also was more than the decrease (22.2%) observed in the control group. Clinical improvement was demonstrated by 40%, no change by 35%, and clinical deterioration by 25% of the patients in the experimental group, and by respectively 37.8, 27, and 35.2% of the patients in the control group. These differences were not statistically significant. Only one patient demonstrated a severe adverse event, severe pulmonary infection, and complete atrioventricular block. None of the other carvedilol-treated patients experienced drug-related side effects. Carvedilol can be safely used for treatment of chronic heart dysfunction in pediatric patients with dilated cardiomyopathy. The results in this study showed an apparent improvement in the cardiac function of these patients. Additional clinical studies are required to determine the most favorable dosing levels and regimens of carvedilol before its safety and efficacy for the pediatric population can be determined conclusively. PMID- 23108483 TI - Validation of the Innocor device for noninvasive measurement of oxygen consumption in children and adults. AB - Outpatient measurements of oxygen consumption (VO2) and cardiac output (CO) are valuable in the management of pediatric cardiac disease. Current methods are inaccurate and cumbersome or require invasive procedures. New devices to measure these variables in adults have not been rigorously tested for children. The Innocor system uses a photoacoustic analyzer to measure gas content for noninvasive measurement of VO2 and CO. This study sought to validate Innocor derived VO2 measurements in children and adults by comparing them against the gold standard Douglas bag method. Subjects were tested in an outpatient setting. Adaptations were made for pediatric patients based on weight. Resting VO2 measurements were obtained simultaneously by the Innocor system and Douglas bag during 3 min. The study enrolled 31 children (mean age, 12.2 years; range, 7-17 years, 17 girls) and 29 adults (mean age, 36.7 years; range, 19-57 years; 17 women). Strong correlation between the two techniques was seen for both the adults (R (2) = 0.88) and the children (R (2) = 0.82). The average discrepancy between the Innocor and Douglas bag measurements was 1.7 % (range, 0.6-19.1 %) for the adults, and 5.4 % (range, 0.1-32.2 %) for the children. The discrepancy was more than 15 % for 17 % of the adults and 22 % of the children, with the Innocor device tending to overestimate VO2 in children compared with the Douglas bag. This trend was not seen in adults. The Innocor system has excellent correlation with the Douglas bag and shows promise for noninvasive measurement of VO2 and CO in the school-age pediatric population. PMID- 23108484 TI - Aortopulmonary window with pulmonary atresia: a very rare association. PMID- 23108485 TI - Spermatic cord sarcoma: our experience and review of the literature. AB - INTRODUCTION: Spermatic cord tumors represent 4% of scrotal tumors. The most common neoplasms are lipomas. Spermatic cord sarcomas (SCS) of the genitourinary tract account for 2% of all urological tumors. Herein we presented our experience in the treatment of these tumors and a review of the literature. PATIENTS AND METHODS: A review of the literature was performed using the Medline database with no restriction on language and date of published papers. The literature search used the following terms: epidemiology, surgery, chemotherapy, radiotherapy and spermatic cord sarcomas. Four cases treated from December 2009 to May 2010 are described. RESULTS: All patients were treated with radical orchiectomy. The final pathological report showed different types of sarcomas. Two of the patients were treated with adjuvant chemotherapy. 12 months after surgery, 2/4 patients were alive without signs of relapse. CONCLUSION: SCS are very rare tumors with a poor prognosis. SCS's prognostic factors have been identified in grading, size, depth of invasion and surgical margin status. Age and performance status of the patient are however very important. Lymphatic and hematogenous dissemination is uncommon. Surgery is the most important treatment both in the first approach and in local relapse. The role of adjuvant chemotherapy and radiation therapy is still debated. PMID- 23108486 TI - Scavenger receptor A deficiency accelerates cerebrovascular amyloidosis in an animal model. AB - Cerebrovascular amyloidosis caused by amyloid accumulation in blood vessel walls may lead to hemorrhagic stroke and cognitive impairment. Expression of TGF-beta1 under glial fibrillary acidic protein promoter in mice leads to age-related deposition of amyloid, including beta-amyloid (Abeta), around cerebral blood vessels, leading to vascular pathology starting at age of 7 months. We have recently shown the important role of macrophages in clearing cerebrovascular amyloid. Scavenger receptor A (SRA) is a multi-ligand and multifunctional receptor expressed on macrophages, and it has been suggested to play a role in meditating phagocytosis of different types of antigens. We investigated the role of SRA in mediating cerebrovascular amyloid clearance. We bred TGF-beta1 mice with SRA(-/-) mice and discovered that TGF-beta1/SRA(-/-) mice showed cerebrovascular pathology at an earlier age (3 months) compared with TGF-beta1 mice. Furthermore, SRA deficiency in macrophages led to impaired clearing of congophilic cerebrovascular amyloid from amyloid precursor protein mouse model and led to reduced phagocytosis of both soluble and insoluble Abeta in vivo as compared with macrophages from wild-type mice. Our findings demonstrate the important role of SRA in cerebrovascular amyloid pathology and suggest targeting SRA for future diagnostic and therapeutic approaches for cerebral amyloid angiopathy. PMID- 23108487 TI - Changes in the BAG1 expression of Schwann cells after sciatic nerve crush. AB - Bcl-2-associated athanogene-1 (BAG1), a co-chaperone for Hsp70/Hsc70, is a multifunctional protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. However, the expression and roles of BAG1 in peripheral system lesions and repair are still unknown. In this study, we investigated the dynamic changes in BAG1 expression in an acute sciatic nerve crush model in adult rats. Western blot analysis revealed that BAG1 was expressed in normal sciatic nerves. BAG1 expression increased progressively after sciatic nerve crush, reached a peak 2 weeks post-injury, and then returned to the normal level 4 weeks post-injury. Spatially, we observed that BAG1 was mainly expressed in Schwann cells and that BAG1 expression increased in Schwann cells after injury. In vitro, we found that BAG1 expression increased during the cyclic adenosine monophosphate (cAMP)-induced Schwann cell differentiation process. BAG1-specific siRNA inhibited cAMP-induced Schwann cell differentiation. In conclusion, we speculated that BAG1 was upregulated in the sciatic nerve after crush, which was associated with Schwann cell differentiation. PMID- 23108488 TI - Formaldehyde impairs learning and memory involving the disturbance of hydrogen sulfide generation in the hippocampus of rats. AB - Formaldehyde (FA), a well-known indoor and outdoor pollutant, has been implicated as the responsible agent in the development of neurocognitive disorders. Hydrogen sulfide (H(2)S), the third gasotransimitter, is an endogenous neuromodulator, which facilitates the induction of hippocampal long-term potentiation, involving the functions of learning and memory. In the present study, we analyzed the effects of intracerebroventricular injection of FA on the formation of learning and memory and the generation of endogenous H(2)S in the hippocampus of rats. We found that the intracerebroventricular injection of FA in rats impairs the function of learning and memory in the Morris water maze and novel object recognition test and increases the formation of apoptosis and lipid peroxidation in the hippocampus. We also showed that FA exposure inhibits the expression of cystathionine beta-synthase, the major enzyme responsible for endogenous H(2)S generation in hippocampus and decreases the production of endogenous H(2)S in hippocampus in rats. These results suggested that FA-disturbed generation of endogenous H(2)S in hippocampus leads to the oxidative stress-mediated neuron damage, ultimately impairing the function of learning and memory. Our findings imply that the disturbance of endogenous H(2)S generation in hippocampus is a potential contributing mechanism underling FA-caused learning and memory impairment. PMID- 23108489 TI - Pregnancy in congenital myasthenic syndrome. AB - Some case reports have suggested possible worsening of the clinical condition of patients with congenital myasthenic syndromes (CMS) during pregnancy. However, this risk has not yet been quantified in a significant number of patients. Using a standardized report form, we reviewed the gynecological and obstetrical medical history of all patients with CMS listed in the French Registry. The data were reviewed with the assistance of the patients to insure accuracy. We report on 17 pregnancies in eight patients with CMS with mutations in CHRNA1, CHRNE, CHRND, GFPT1, COLQ, or DOK7. Symptoms worsened for six patients during at least one of their pregnancies, and one patient required hospitalization in an intensive care unit during the post-partum period. One patient never recovered to the level of her pre-pregnancy clinical condition. Only one caesarean section was performed. The outcome for children was excellent, with the exceptions of a pulmonary artery atresia in the offspring of a mother on pyridostigmin and a newborn with a severe neonatal congenital myasthenic syndrome (an autosomic dominant slow channel transmission). Our study argues in favor of frequent clinical worsening of symptoms during pregnancy in patients with CMS. These patients should be closely followed by neurologists during the course of pregnancy. However, the overall clinical prognosis is good since the vast majority of patients recovered their pre-pregnancy clinical status six months after the delivery. PMID- 23108490 TI - The frequency of spinocerebellar ataxia type 23 in a UK population. AB - Spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative diseases characterised by progressive cerebellar ataxia, dysarthria and oculomotor abnormalities. Recently the prodynorphin (PDYN) gene was identified as the cause of SCA23 in four Dutch families displaying progressive gait and limb ataxia. In this study we aimed to assess the frequency of PDYN gene defects and extend the phenotype of SCA23 patients in a UK ataxia series and also in patients from Greece, Egypt and India. We sequenced the coding and flanking intronic regions of the PDYN gene in a total of 852 ataxia patients, of which 356 were sporadic with no family history, 320 had a positive family history, and 176 probands had a positive family history and at least one family member had also been investigated. We also analysed 190 patients with multiple system atrophy with cerebellar features (MSA-C), a phenocopy of SCA23. We identified a novel putative pathogenic heterozygous missense variant in the PDYN gene in an early onset SCA patient with an unknown family history. This variant was not present in 570 matched British controls. This is the first study to screen for SCA23 in UK patients and confirms that PDYN mutations are a very rare cause of spinocerebellar ataxia, accounting for ~ 0.1 % of ataxia cases but perhaps with a higher frequency in pure cerebellar ataxia. Given the rarity of PDYN mutations, front-line diagnostic evaluation of UK familial and early onset pure spinocerebellar ataxia patients should focus on other known ataxia genes. PMID- 23108491 TI - Environmental dependency behaviours in frontotemporal dementia: have we been underrating them? AB - Environmental dependency (ED) behaviours, such as imitation behaviour (IB) and incidental utilization behaviour (UB), are considered pathognomonic of a frontal lesion and can play a unique role in diagnosing behavioural variant frontotemporal dementia (bvFTD). However, with only few focused observations of ED behaviour reported in earlier studies, their roles in the diagnosis of bvFTD have so far remained supportive. In this observational study, conducted in the cognitive clinic of a tertiary-care hospital, we explored the hypotheses that a focused and systematic search could uncover more ED behaviours in patients with bvFTD, and that the presence of ED behaviours such as incidental UB and IB should allow us to cleanly differentiate bvFTD from AD. Forty-one bvFTD patients and 75 probable AD patients, all diagnosed using accepted criteria, were seen by a neurologist and a neuropsychologist. Information regarding ED behaviour was obtained from the caregiver's history, observations for spontaneous behaviour and induction of the behaviour in the clinic. All ED behaviours were significantly more frequent in bvFTD compared with AD. UB (78 %; 66 % incidental) and IB (59 %) occurred exclusively in bvFTD. Multi-pronged and focused clinical assessment contributed to the high frequency of ED behaviours. Nearly two-thirds of bvFTD patients, but none with AD, showed three or more ED behaviours. We concluded that ED behaviours are more common in bvFTD than is currently recognized. UB, IB or three ED behaviours, if present, could clearly differentiate bvFTD from AD. A focused search should consistently uncover ED behaviours in bvFTD patients. PMID- 23108492 TI - ATL1 and REEP1 mutations in hereditary and sporadic upper motor neuron syndromes. AB - SPAST mutations are the most common cause of autosomal dominant hereditary spastic paraplegias (AD-HSPs), but many spastic paraplegia patients are found to carry no mutations in this gene. In order to assess the contribution of ATL1 and REEP1 in AD-HSP, we performed mutational analysis in 27 SPAST-negative AD-HSP families. We found three novel ATL1 mutations and one REEP1 mutation in five index-patients. In 110 patients with sporadic adult-onset upper motor neuron syndromes, a novel REEP1 mutation was identified in one patient. Apart from a significantly younger age at onset in ATL1 patients and restless legs in some, the clinical phenotype of ATL1 and REEP1 was similar to other pure AD-HSPs. PMID- 23108493 TI - Weight change and workplace absenteeism in the HealthWorks study. AB - OBJECTIVE: Little is known about the relationship between weight change and workplace absenteeism. The purpose of this study was to examine the degree to which weight change predicted 2-year absenteeism. METHODS: A longitudinal analysis of 1,228 employees enrolled in a worksite-randomized controlled trial was performed. Participants were all working adults in the Minneapolis, MN, area (USA). RESULTS: The final model indicated a significant interaction between weight change and baseline BMI. The difference in absenteeism ranged from (mean +/- SE) 3.2 +/- 1.2 days among healthy weight employees who maintained their weight to 6.6 +/- 1.1 days among obese employees who gained weight (and slightly higher among healthy weight employees who lost weight). The adjusted model also indicated that participants who were male, not depressed, nonsmokers, and had lower baseline absenteeism had significantly less workplace absenteeism relative to participants who were female, depressed, smokers, and had higher baseline absenteeism. CONCLUSION: Absenteeism was generally low in this sample, but healthy weight employees who maintained their body weight over 2 years had the fewest number of sick days. More research is needed in this area, but future workforce attendance interventions may be improved by focusing on the primary prevention of weight gain in healthy weight employees. PMID- 23108494 TI - Clinical application of sepsis biomarkers. AB - Sepsis is one of the leading causes of death in the critically ill. Early diagnosis is important to avoid delay in instituting appropriate treatment. However, diagnosis can be delayed because of difficulty in interpreting clinical features. Sepsis biomarkers can aid early diagnosis. This article reviews the application of readily available biomarkers for diagnosis of sepsis, for predicting prognosis, and for antibiotic stewardship. 178 biomarkers are described in the literature--ranging from specimen cultures, which lack sensitivity and specificity for early diagnosis of sepsis, to biomarkers such as C-reactive protein, procalcitonin, and genetic biomarkers, which have their own limitations. Future research will mainly focus on use of more than one biomarker, but the main problem in sepsis biomarker research seems to be a lack of a recommended biomarker. PMID- 23108495 TI - [Impressive sonogram of appendicitis]. PMID- 23108496 TI - The effect of atropine on the bispectral index response to endotracheal intubation during propofol and remifentanil anesthesia. AB - Atropine has been reported to increase the propofol requirements for the induction of anesthesia during continuous infusion of propofol. We investigated the influence of atropine on the bispectral index (BIS) response to endotracheal intubation during anesthetic induction with propofol and remifentanil target controlled infusion (TCI). Fifty-six patients aged 18-50 years undergoing general anesthesia, were enrolled. For induction of anesthesia, propofol TCI was set at a target effect-site concentration of 4.0 MUg/ml. Two minutes later, remifentanil was started at an effect-site concentration of 4.0 ng/ml. Four minutes after the start of propofol TCI, patients received either atropine (10 MUg/kg) or an equal volume of normal saline. Tracheal intubation was performed 10 min after anesthetic induction. Mean arterial pressure, HR, SpO2, and BIS were recorded during the 15 min-anesthesia induction. From 2 to 5 min after tracheal intubation, BIS was significantly higher in the atropine group than in the control group (p = 0.043, 0.033, 0.049, and 0.001, respectively). When compared with baseline values (immediately before intubation), BIS showed a significant increase at 1 min after intubation in both groups, without intergroup differences, whereas it decreased significantly from 4 to 5 min after intubation only in the control group. This study demonstrated that atropine maintained BIS increases in response to endotracheal intubation during anesthetic induction with propofol and remifentanil TCI, although the maximal response did not differ between the groups. PMID- 23108497 TI - Comparison of the diagnostic performance of three natriuretic peptides in hemodialysis patients: which is the appropriate biomarker?. AB - BACKGROUND: Plasma concentrations of natriuretic peptides are often elevated in chronic hemodialysis patients and difficult to interpret due to accumulation, high incidence of cardiac disease and changes in volume status. Mid-regional pro ANP is a newly developed assay whereas BNP and its fragment NT-pro-BNP are available for a longer time. In this cross-sectional study, we compared the plasma concentration of MR-pro-ANP, BNP and NT-pro-BNP in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors such as residual diuresis, cardiac status and interdialytic weight gain and with mortality. METHODS AND RESULTS: In all patients enrolled, the plasma concentration of all natriuretic peptides were largely elevated with a median concentration of 337 pg/ml (interquartile range 146-684) for BNP, 4435 pg/ml (1687-16228) for NT-proBNP and 907 pmol/L (650-1298) for MR-pro-ANP. Plasma concentration of all natriuretic peptides correlated independently with age, degree of systolic dysfunction and negatively with residual diuresis. Dependency on residual renal clearance was strongest for the fragments MR-pro-ANP and NT-pro BNP. The plasma concentration of all natriuretic peptides was associated with mortality within 2 years of follow-up. Receiver-operated curves revealed a low sensitivity (32-45%), but high specificity for all natriuretic peptides (85-93%) resulting in a high negative predictive (82-87%). Best cut-off values obtained from were 18 611 pg/ml for NT-pro-BNP, 958 pg/ml for BNP and 1684 pmol/L for MR pro-ANP. CONCLUSIONS: In hemodialysis patients, the fragments NTproBNP and MR-pro ANP are largely elevated compared to BNP which is explained by accumulation. The prognostic performance of MR-pro-ANP is similar to that of NT-pro-BNP or BNP. PMID- 23108498 TI - Molecular and functional aspects of menstruation in the macaque. AB - Much of our understanding of the molecular control of menstruation arises from laboratory models that experimentally recapitulate some, but not all, aspects of uterine bleeding observed in women. These models include: in vitro culture of endometrial explants or isolated endometrial cells, transplantation of human endometrial tissue into immunodeficient mice and the induction of endometrial breakdown in appropriately pretreated mice. Each of these models has contributed to our understanding of molecular and cellular mechanisms of menstruation, but nonhuman primates, especially macaques, are the animal model of choice for evaluating therapies for menstrual disorders. In this chapter we review some basic aspects of menstruation, with special emphasis on the macaque model and its relevance to the clinical issues of irregular and heavy menstrual bleeding (HMB). PMID- 23108500 TI - Anxiety and aggression in rural youth: baseline results from the rural adaptation project. AB - There is little research on the prevalence of and risk factors for mental health disorders, including anxiety and aggression, for low income, rural youth. The research that does exist suggests that rural youth may be at increased risk for negative outcomes, including low educational achievement, drug use and possession of weapons among gang members, and alcohol use. Using multilevel logistic regression, we examined individual, family, and school risk and protective factors for adolescent anxiety and aggression in a large, racially diverse sample of 4,321 middle school students who came from two impoverished, rural counties in a Southeastern state. Parent-child conflict, negative peer relationships, and negative friend behaviors were key risk factors associated with both anxiety and aggressive behaviors. The teacher turnover rate at school was also associated with both anxiety and aggression. Significant direct effects, cross-level moderation effects, and implications for prevention programming were discussed. PMID- 23108499 TI - Unusual titration of the membrane-bound artificial hemagglutinin fusion peptide. AB - E5 is a 20-residue-long analog of the fusion peptide from influenza hemagglutinin (GLFEAIAEFIEGGWEGLIEG). It has been suggested that two of its five glutamates, Glu11and Glu15, are critical in its pH-dependent membrane perturbation. To reveal their specific involvement, a pair of analogs with substitution of either Glu11 or Glu15 for Ala were synthesized. By analysis of the pH-dependence of the chemical shifts of protons of these peptides bound to dodecylphosphocholine micelles we found: (1) the peptides adopt an amphiphilic alpha-helical structure within residues 2-18, similar to the parent peptide; (2) the helix is significantly more disordered at neutral pH than at acidic pH for E5 peptide only; and (3) in E5 and mutant peptides the Glu11 and 15 residues have similar pK (a) values, higher than those of the other glutamates. This excludes their mutual interaction in E5, being a source of the elevated pK (a) values. We attribute this phenomenon to the presence of minor states caused by deepening of the Glu11 and 15 side-chains in the hydrophobic environment of the membrane. As the mid-pH of membrane-perturbation activity of E5 matches the pK (a) value of these glutamates, we conclude their presence contributes to the plasticity of the peptide and determines the pH-dependence of membrane perturbation caused by E5. PMID- 23108501 TI - Autonomic testing in healthy subjects: preliminary observations. AB - INTRODUCTION: Autonomic testing is used clinically. Yet, the prevalence of "abnormal" variants in the healthy population has not been reported. RESULTS: We report the results of autonomic testing in healthy females >18 years, in whom we found decrease or absent sudomotor function in 1-2 locations. CONCLUSIONS: These findings should caution physicians in the interpretation of autonomic testing. This report underscores the need of larger studies to determine the prevalence of these findings. PMID- 23108502 TI - Effects of different suture materials used for the repair of hypospadias: a stereological study in a rat model. AB - INTRODUCTION: Repair of the penile urethra in hypospadias is done with different suture materials. The aim of this study was to quantify the impact of different suture threads on histological parameters of the penis and urethra following hypospadias repair in rats. MATERIALS AND METHODS: Six groups of the rats, except for the control group, underwent incision and repair of the penis and urethra in the ventral line using different suture materials including Chromic, Vicryl (polyglactic acid), PDS (polydioxanone), Rapid Vicryl (polyglactin 910), Monocryl (poliglecaprone 25) and control groups. After 3 weeks the body of the penis was excised and histological sections were studied using stereological methods. RESULTS: Monocryl (poliglecaprone 25) was associated with a higher percentage of vessel density, higher volume of urethral lumen and lower lymphocyte infiltration. Volume of urethral epithelium was highest in the PDS group compared to the other operated groups. There was no significant difference regarding collagen deposition and fibroblast infiltration among the operated groups. CONCLUSIONS: The Monocryl and PDS groups showed better results. PMID- 23108503 TI - Cost control in a parallel universe: Medicare spending in the United States and Canada. PMID- 23108504 TI - Adsorption of organic dyes on TiO2 surfaces in dye-sensitized solar cells: interplay of theory and experiment. AB - First-principles computer simulations can contribute to a deeper understanding of the dye/semiconductor interface lying at the heart of Dye-sensitized Solar Cells (DSCs). Here, we present the results of simulation of dye adsorption onto TiO(2) surfaces, and of their implications for the functioning of the corresponding solar cells. We propose an integrated strategy which combines FT-IR measurements with DFT calculations to individuate the energetically favorable TiO(2) adsorption mode of acetic acid, as a meaningful model for realistic organic dyes. Although we found a sizable variability in the relative stability of the considered adsorption modes with the model system and the method, a bridged bidentate structure was found to closely match the FT-IR frequency pattern, also being calculated as the most stable adsorption mode by calculations in solution. This adsorption mode was found to be the most stable binding also for realistic organic dyes bearing cyanoacrylic anchoring groups, while for a rhodanine-3 acetic acid anchoring group, an undissociated monodentate adsorption mode was found to be of comparable stability. The structural differences induced by the different anchoring groups were related to the different electron injection/recombination with oxidized dye properties which were experimentally assessed for the two classes of dyes. A stronger coupling and a possibly faster electron injection were also calculated for the bridged bidentate mode. We then investigated the adsorption mode and I(2) binding of prototype organic dyes. Car Parrinello molecular dynamics and geometry optimizations were performed for two coumarin dyes differing by the length of the pi-bridge separating the donor and acceptor moieties. We related the decreasing distance of the carbonylic oxygen from the titania to an increased I(2) concentration in proximity of the oxide surface, which might account for the different observed photovoltaic performances. The interplay between theory/simulation and experiments appears to be the key to further DSCs progress, both concerning the design of new dye sensitizers and their interaction with the semiconductor and with the solution environment and/or an electrolyte upon adsorption onto the semiconductor. PMID- 23108505 TI - Efficacy and safety of metformin for treatment of overweight and obesity in adolescents: an updated systematic review and meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of using metformin in overweight and obese adolescents without related morbidity. METHODS: We conducted a systematic review and meta-analysis of randomized clinical trials published until June 2011, comparing metformin to placebo or other interventions. Our primary variables were baseline BMI changes and development of adverse effects. RESULTS: Nine studies (498 participants, mean age 14.2 years; mean BMI 36.4 kg/m2 met the inclusion criteria. In all but one study, metformin was combined with lifestyle modification and was compared to placebo combined with changes in lifestyle. Analysis showed that metformin reduced mean BMI by 1.42 kg/m2 (95% CI -2.18, 0.66), fasting insulin by 9.9 uU/ml (95% CI -13.8, -6.06) and the HOMA index by 1.78 (95% CI -3.32, -0.23). No changes in any other parameter were observed. No statistical differences were found in the rate of adverse events (33% metformin, 32% placebo).The withdrawal rates due to side effects in the metformin and placebo groups were 2.7% and 2.5%, respectively. CONCLUSIONS: The available evidence indicates that, in the short term, administration of metformin in addition to lifestyle modification is relatively effective for reducing BMI and hyperinsulinemia among obese adolescents without related morbidity, and displays an acceptable safety pattern. Nevertheless, its long-term impact is unknown. PMID- 23108506 TI - Effects of T-2 toxin on testosterone biosynthesis in mouse Leydig cells. AB - OBJECTIVE: To investigate the effects of T-2 toxin on testosterone biosynthesis in mouse Leydig cells. METHODS: Leydig cells isolated from clean and healthy Kunming male mice, whose concentration was adjusted to 5 * 10(5)/mL and the purity identified by the modified 3beta-hydroxysteroid dehydrogenase staining method, were used to establish a primary Leydig cell culture model. Blank control group (treated with 0 ng/mL human chorionic gonadotropin (hCG) and 0 mol/L T-2 toxin), inductive control group (treated with 10 ng/mL hCG and 0 mol/L T-2 toxin), low-dose T-2-toxin-exposure group (treated with 10 ng/mL hCG and 10(-9) mol/L T-2 toxin), middle-dose T-2 toxin-exposure group (treated with 10 ng/mL hCG and 10(-8) mol/L T-2 toxin) and high-dose T-2-toxin-exposure group (treated with 10 ng/mL hCG and 10(-7) mol/L T-2 toxin) were designed. The testosterone level was measured after 24 h incubation. RESULTS: After 24 h culture in liquid medium containing serum, the fresh isolated Leydig cells grew well and the purity exceeded 90%. By inducing 10 ng/mL hCG, the testosterone level of Leydig cells increased significantly and the difference compared with the blank control was of statistical sense. Compared with the inductive control group, the testosterone level of Leydig cells decreased, and the difference was of statistical sense in all T-2-toxin-exposure groups. Furthermore, the decrease was due to the increase in the dosage of T-2 toxin. CONCLUSIONS: T-2 toxin can directly decrease the testosterone biosynthesis in the primary Leydig cells derived from the mouse testis. PMID- 23108507 TI - Balancing confidentiality and collaboration within multidisciplinary health care teams. AB - As multidisciplinary perspectives are increasingly integrated into the treatment of health problems, opportunities for clinical psychologists in medical settings are expanding. Although cross-discipline collaboration is at the core of multidisciplinary treatment models, psychologists must be particularly cautious about information sharing due to their profession's ethical standards regarding patient confidentiality. Psychologists' ethical obligations require them to achieve a delicate balance between contributing to the treatment team and protecting patient confidentiality. In the current review, relevant ethical standards and federal guidelines are applied to everyday practices of clinical psychologists in medical settings. Additionally, recommendations for individual psychologists, health care organizations, and graduate training programs are presented. PMID- 23108509 TI - A systematic review of the literature exploring illness perceptions in mental health utilising the self-regulation model. AB - Psychologists have utilised a range of social cognition models to understand variation in physical health and illness-related behaviours. The most widely studied model of illness perceptions has been the Self-Regulation Model (SRM, Leventhal, Nerenz, & Steele, 1984). The illness perceptions questionnaire (IPQ) and its revised version (IPQ-R) have been utilised to explore illness beliefs in physical health. This review examined 13 quantitative studies, which used the IPQ and IPQ-R in mental health in their exploration of illness perceptions in psychosis, bipolar disorder, eating disorders, depression and adolescents experiencing mood disorders. Across these studies the SRM illness dimensions were largely supported. Mental illnesses were commonly viewed as cyclical and chronic, with serious negative consequences. Perceptions regarding chronicity, controllability and negative consequences were associated with coping and help seeking, while engagement with services and help seeking were also related to illness coherence beliefs. Treatment adherence was linked to beliefs that treatment could control one's illness. Whilst a major limitation of the reviewed studies was the use of cross-sectional designs, overall the applicability of the SRM to mental health was supported. The IPQ and IPQ-R were shown to be valuable measures of illness perceptions in mental health, offering implications for clinical practice. PMID- 23108511 TI - The role of accountable care organizations in delivering value. AB - The goal of Accountable Care Organizations is to improve patient outcomes while maximizing the value of the services provided. This will be achieved through the use of performance and quality measures that facilitate efficient, cost effective, evidence-based care. By creating a network connecting primary care physicians, specialists, rehabilitation facilities and hospitals, patient care should be maximized while at the same time delivering appropriate value for those services provided. The Medicare Shared Savings Program will financially reward ACOs that meet performance standards while at the same time lowering costs. The orthopaedic surgeon can only benefit by understanding how to participate in and negotiate the complexities of these organizations. PMID- 23108510 TI - Influence of sutureless 23-gauge sclerotomy architecture on postoperative intraocular pressure decrease: results of a multivariate analysis. AB - PURPOSE: To evaluate the factors affecting the postoperative intraocular pressure (IOP) decrease in 23-gauge (23-G) sutureless vitrectomy, including incision architecture evaluated by anterior segment spectral-domain optical coherence tomography (SD-OCT). METHODS: A prospective cohort study of 43 patients who underwent primary transconjunctival 23-G pars plana vitrectomy. All sclerotomy wounds were imaged 1 day after surgery using the anterior segment module of SD OCT (OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany). 23-G sclerotomy architecture, preoperative and postoperative medical data were also prospectively collected. RESULTS: Multivariate logistic regression analysis, with backward elimination, found that surgery duration (adjusted OR = 9.17, p = 0.020) and loss of wound apposition (adjusted OR = 15.12, p = 0.022) were risk factors for significant postoperative IOP decrease (>=3 mmHg) 1 day after surgery; while age, gender, myopia, and gas tamponade were not risk or protective factors for postoperative IOP decrease. CONCLUSIONS: In 23-G pars plana vitrectomy, the early postoperative decrease in IOP is mainly influenced by surgery duration and the self-sealing nature of the sclerotomy. The IOP decrease was not influenced by the presence or the absence of gas tamponade. PMID- 23108508 TI - The role of attachment style and depression in patients with hepatitis C. AB - Patients infected with chronic hepatitis C virus (HCV) commonly suffer from the triad of depression, pain and fatigue. This symptom triad in HCV is likely influenced by additional psychological and interpersonal factors, although the relationship is not clearly understood. This retrospective study aimed to characterize the relationship between attachment style and depressive and physical symptoms in the HCV-infected population. Over 18 months, 99 consecutively referred HCV infected patients were assessed with the Hamilton Depression Rating Scale (HDRS), Fatigue Severity Scale, Patient Health Questionnaire-15 for physical symptoms and the Relationship Questionnaire for attachment style. An ANOVA was used to identify differences between attachment styles and Pearson correlations were used to evaluate the association between depression, fatigue and physical symptoms. Approximately 15 % of patients in the sample had a fearful attachment style. Patients with fearful attachment style had significantly higher depressive symptoms compared to a secure attachment style (p = .025). No differences in physical and fatigue symptoms were observed between attachment styles. Further, HDRS scores were significantly associated with fatigue scores (p < .001) and physical symptoms (p < .001), reinforcing the relationship between these symptom domains in HCV-infected patients. Although depressive, physical and fatigue symptoms are inter-related in HCV-infected patients, our study results suggest that only depressive symptoms were influenced by the extremes of attachment style. Screening of relationship styles may identify at-risk HCV-infected individuals for depression who may have difficulty engaging in care and managing physical symptoms. PMID- 23108512 TI - Intraoperative fluorescence lymphography using indocyanine green in a patient with chylothorax after esophagectomy: report of a case. AB - We report a case of chylothorax treated successfully by a new diagnostic tool: indocyanine green (ICG) fluorescence lymphography. The patient, a 65-year-old man with adenocarcinoma of the esophagogastric junction, underwent radical esophagectomy, which was followed by the development of chylothorax. On postoperative day 10, we performed transabdominal ligation of the thoracic duct. During the re-operation, we injected ICG into the mesentery of the small bowel. We then performed mass ligation of the tissue right and dorsal of the aorta, including the thoracic duct, after which a near-infrared camera system revealed a fluorescent stripe on the caudal part of the ligation. The remnant thoracic duct appeared to be dilated as a result of lymphatic stasis. The patient was discharged 35 days after his initial surgery. We report this case to demonstrate the usefulness of intraoperative ICG lymphography as a tool to identify and confirm ligation of the thoracic duct transabdominally. PMID- 23108513 TI - Interactions of coinage metal clusters with histidine and their effects on histidine acidity; theoretical investigation. AB - Understanding the nature of interaction between metal nanoparticles and biomolecules such as amino acids is important in the development and design of biosensors. In this paper, binding of M(3) clusters (M = Au, Ag and Cu) with neutral and anionic forms of histidine amino acid was studied using density functional theory (DFT-B3LYP). It was found that the interaction of histidine with M(3) clusters is governed by two major bonding factors: (a) the anchoring N M and O-M bonds and (b) the nonconventional N-H...M and O-H...M hydrogen bonds. The nature of these chemical bonds has been investigated based on quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses. In the next step, the effects of Au, Ag and Cu metal clusters on the gas-phase acidity of weak organic acid (histidine) have been explored. The acidity of isolated histidine was compared with the acidity of its Au(3)-, Ag(3)- and Cu(3)-complexed species. Results indicate that upon complexation with M(3) clusters (at 298 K), the gas-phase acidity (GPA) of histidine varies from 339.5 to 312.3, 315.0, and 313.7 kcal mol(-1) for Au(3)-, Ag(3)- and Cu(3)-His complexes, respectively (i.e., its dissociation becomes much less endothermic). These values indicate that a weak organic acid can be converted to a super acid when it is complexed with metal clusters. Also, in order to investigate the acidity value of the imidazole moiety in histidine, histidine methyl ester (His-OMe) was selected. Similarly, the acidity of this compound was compared with the acidity of their Au(3), Ag(3) and Cu(3)-complexed species. After complexation with M(3) clusters at 298 K, the gas-phase acidity (GPA) of His-OMe varies from 333.0 to 280.0, 304.2 and 291.5 kcal mol(-1), respectively. Moreover, pK(a) values were determined in water for isolated and complexed species of His and His-OMe. The resulting pK(a) values were found to decrease upon complexation with M(3) clusters. PMID- 23108514 TI - Cardiotoxicity of plants in South Africa. PMID- 23108515 TI - Doppler echocardiographic indices in aortic coarctation: a comparison of profiles before and after stenting. AB - BACKGROUND: Diagnosis of aortic coarctation is important as it is a difficult condition to evaluate, especially in adults. A Doppler echocardiographic index could provide a simple tool to evaluate coarctation. This study was performed to compare Doppler echocardiographic profiles before and after stenting and to assess the diagnostic value of a complete list of echocardiographic indices for detecting aortic coarctation. METHODS: This prospective study was conducted on 23 patients with a diagnosis of aortic coarctation based on angiography. Echocardiographic assessment was done twice for all patients before and after stenting. Each time, two-dimensional and Doppler echocardiographic imaging modalities were performed and complete lists of indices were recorded for each case. After comparing the values of indices before and after stenting, diagnostic values of each index were calculated in order to diagnose significant coarctation. RESULTS: Twenty-three patients, including 16 males and seven females with a mean age of 26.14 +/- 10.17 years, were enrolled in this study. Except for the mean velocity and mean pressure gradient of the abdominal aorta, the values of the other indices of the abdominal/descending aorta showed enough change after stenting to indicate significant diagnostic accuracy for detecting aortic coarctation. The velocity-time integral and the pressure half-time were among the indices with the highest accuracy rates for this purpose (all p < 0.001). CONCLUSION: Post-stenting echocardiographic profiles could provide a reliable reference value of the normal aortic haemodynamics as a unique identification of each patient and it is presumed that these indices could be used as reliable indicators of response to treatment. PMID- 23108516 TI - A comparative study of amoxicillin, clindamycin and chlorhexidine in the prevention of post-extraction bacteraemia. AB - We evaluated some of the regimens recommended for the antimicrobial prophylaxis of infective endocarditis prior to dental extraction in 160 patients. Group A patients served as the control group, group B subjects rinsed their mouths with chlorhexidene, group C subjects took 3 g amoxicillin orally and group D patients took 600 mg clindamycin orally. The proportion of patients who had post extraction bacteraemia in groups A, B, C and D was 35, 40, 7.5 and 20%, respectively. The differences between the control and amoxicillin groups (p = 0.003) and between the chlorhexidine and amoxicillin groups (p = 0.0006) were statistically significant. Streptococci were not isolated in any patients in the amoxicillin and clindamycin groups. In our study, none of the regimens were effective in preventing post-extraction bacteraemia. PMID- 23108517 TI - Comparison of outcomes in ST-segment depression and ST-segment elevation myocardial infarction patients treated with emergency PCI: data from a multicentre registry. AB - BACKGROUND: Traditionally, acute myocardial infarction (AMI) has been described as either STEMI (ST-elevation myocardial infarction) or non-STEMI myocardial infarction. This classification is historically related to the use of thrombolytic therapy, which is effective in STEMI. The current era of widespread use of coronary angiography (CAG), usually followed by primary percutaneous coronary intervention (PCI) puts this classification system into question. OBJECTIVES: To compare the outcomes of patients with STEMI and ST-depression myocardial infarction (STDMI) who were treated with emergency PCI. METHODS: This multicentre registry enrolled a total of 6 602 consecutive patients with AMI. Patients were divided into the following subgroups: STEMI (n = 3446), STDMI (n = 907), left bundle branch block (LBBB) AMI (n = 241), right bundle branch block (RBBB) AMI (n = 338) and other electrocardiographic (ECG) AMI (n = 1670). Baseline and angiographic characteristics were studied, and revascularisation therapies and in-hospital mortality were analysed. RESULTS: Acute heart failure was present in 29.5% of the STDMI vs 27.4% of the STEMI patients (p < 0.001). STDMI patients had more extensive coronary atherosclerosis than patients with STEMI (three-vessel disease: 53.1 vs 30%, p < 0.001). The left main coronary artery was an infract-related artery (IRA) in 6.0% of STDMI vs 1.1% of STEMI patients (p < 0.001). TIMI flow 0-1 was found in 35.0% of STDMI vs 66.0% of STEMI patients (p < 0.001). Primary PCI was performed in 88.1% of STEMI (with a success rate of 90.8%) vs 61.8% of STDMI patients (with a success rate of 94.5%) (p = 0.012 for PCI success rates). In-hospital mortality was not significantly different (STDMI 6.3 vs STEMI 5.4%, p = 0.330). CONCLUSION: These data suggest that similar strategies (emergency CAG with PCI whenever feasible) should be applied to both these types of AMI. PMID- 23108518 TI - Elevated salivary C-reactive protein predicted by low cardio-respiratory fitness and being overweight in African children. AB - INTRODUCTION: C-reactive protein (CRP) is a sensitive marker of systemic inflammation and is an independent risk factor for cardiovascular disease. The aim of the study was to examine the relationship between salivary CRP, cardio respiratory fitness and body composition in a paediatric population. METHODS: This was a cross-sectional study of 170 black South African children (age 9.41 +/ 1.55 years, 100 females, 70 males) in grades 3 to 7. Unstimulated whole saliva samples were obtained for the analysis of CRP. Height, mass, skin-fold thickness, resting blood pressure, and waist and hip circumference measurements were obtained. Cardio-respiratory fitness was assessed using a 20-m multi-stage shuttle run. Children were classified as overweight/obese according to the Center for Disease Control and Prevention (CDC) body mass index (BMI) percentile ranking, and meeting percentage body fat recommendations, if percentage body fat was <= 25% in boys and <= 32% in girls. The cut-off point for low cardio respiratory fitness was a predicted aerobic capacity value <= the 50th percentile for the group. Contributions of low cardio-respiratory fitness, overweight/obesity, and not meeting percentage body fat recommendations, to elevated salivary CRP (>= 75th percentile) concentration and secretion rate were examined using binary logistic regression analysis with a backward stepwise selection technique based on likelihood ratios. RESULTS: Poor cardio-respiratory fitness was independently associated with elevated salivary CRP concentration (OR 3.9, 95% CI: 1.7-8.9, p = 0.001). Poor cardio-respiratory fitness (OR 2.7, 95% CI: 1.2-6.1, p = 0.02) and overweight/obesity (BMI >= 85th percentile) (OR 2.5, 95% CI: 1.1-5.9, p = 0.03) were independent predictors of elevated salivary CRP secretion rate. CONCLUSION: The results suggest a strong association between poor cardio-respiratory fitness and/or overweight/obesity and inflammatory status in children, based on elevated salivary CRP levels. PMID- 23108520 TI - New ESC guidelines on atrial fibrillation accept reality of next generation of anti-coagulants. PMID- 23108521 TI - Renal denervation in Symplicity trials and real-life setting continue to show significant blood pressure reduction in all treatment groups. PMID- 23108519 TI - Obesity and its health impact in Africa: a systematic review. AB - Obesity and its association with co-morbidities in Africa are on the rise. This systematic review examines evidence of obesity and its association with co morbidities within the African continent. Comparative studies conducted in Africa on adults 17 years and older with mean body mass index (BMI) >= 28 kg/m(2) were included. Five electronic databases were searched. Surveys, case-control and cohort studies from January 2000 to July 2010 were evaluated. Of 720 potentially relevant articles, 10 met the inclusion criteria. Prevalence of obesity was higher in urban than rural subjects with significant increases in obesity rates among women. Inflammatory marker levels were significantly elevated among Africans compared with Caucasians. The co-relationship between obesity and chronic diseases was also highlighted. This systematic review demonstrates that while obesity remains an area of significant public health importance to Africans, particularly in urban areas, there is little evidence of proper diagnosis, treatment and/or prevention. PMID- 23108522 TI - Rivaroxaban in acute coronary syndromes and atrial fibrillation: rivaroxaban shown to reduce cardiovascular deaths in STEMI patients. PMID- 23108523 TI - Ivabradine reduces total hospital burden in heart failure. PMID- 23108524 TI - GARFIELD: a window on the real-life treatment of atrial fibrillation - South Africa joins the GARFIELD registry. PMID- 23108525 TI - [External beam radiotherapy in the treatment of prostate cancer]. AB - Prostate cancer represents the most frequently diagnosed malignant tumor in Germany. Primary radiotherapy is one of the two recommended curative treatment options for this disease. There are two types of radiotherapy: external beam radiotherapy and interstitial brachytherapy. Technical developments during the last two decades have made it possible to achieve improved chances of being cured of tumors and improved relief from disease-related symptoms for patients at all tumor stages. Moreover, treatment can be administered with a reduced rate of side effects. Results of classical 3D conformal radiotherapy as well as modern radiation therapy techniques are comprehensively presented including the concept of hypofractionation with results from available randomized trials. After comprehensive assessment of all relevant risk factors, recommendations for the type of treatment must be based on a multidisciplinary approach. PMID- 23108526 TI - Transfemoral aortic valve implantation: bleeding events, related costs and outcomes. AB - Although less invasive then SAVR, TAVI is associated with a significant rate of access site and non-access site bleeding. These complications are major determinants of therapy outcome, however, the economic consequences are not well defined. The purpose of this study was to determine the relationship between bleeding, in-hospital resource utilization and costs among patients undergoing transfemoral aortic valve implantation (TF-AVI) at a representative university hospital in Germany. Between February 2010 and December 2011, we prospectively enrolled 60 consecutive patients undergoing TAVI using a 18F transfemoral approach at our institution. The relationship between overt bleeding (OVB), defined according to the definitions provided by the Valve Academic Research Consortium, in-hospital resource utilization and in-hospital costs was investigated. The mean age was 82 (+/-6) years, 53% were female and the mean EuroScore was 17.2% (+/-8, 7). Thirty-eight percent (23/60) of the patients had an OVB following TF-AVI procedure. In-hospital mortality was 8.7% in the OVB patients (2/23) and 2.7% among patients without any OVB (1/37; NOVB), which was not statistically significant (p = 0.3). The total length of stay (LOS) of patients with and without bleeding complication were 15.0 +/- 6.4 and 10.4 +/- 5.1 days, respectively (p < 0.01). Time spent on ICU in the OVB group was twice as long as compared to the NOVB group (120.5 +/- 98.5 min vs. 63.6 +/- 26.5 min, p < 0.01). Consequently, in-hospital costs were statistically significant higher in OVB patients (40.051 +/- 9.293 vs. 33.625 +/- 4.368, p < 0.01). Bleeding is associated with increased resource use and in-hospital costs among TF AVI patients. Our data indicates that strategies reducing bleeding risk may have the potential to generate important in-hospital costs reductions in TF-AVI patients. PMID- 23108527 TI - Treatment of recurrent anterior uveitis with infliximab in patient with ankylosing spondylitis. AB - BACKGROUND: We describe a HLA-B27-positive Japanese man with recurrent severe anterior uveitis OU and ankylosing spondylitis (AS) who was successfully treated with infliximab. CASE: A 25-year-old HLA-B27-positive Japanese man presented with recurrent anterior uveitis OU. The symptoms were consistent with typical HLA-B27 associated uveitis, whereas the subsequent course, which consisted of frequent episodes of recurrent severe anterior uveitis, was atypical. Although the patient was treated with intensive topical corticosteroids, cycloplegic treatment, sub Tenon triamcinolone acetonide injections, systemic corticosteroids and immunosuppressive agents, recurrence of the anterior uveitis persisted. Over 8 years there were 14 documented episodes of recurrent anterior uveitis OD and 10 OSs. At age 33, the patient was diagnosed with AS after a radiographic examination. We began infusions of infliximab (2.5 mg/kg) at 0, 2 and 6 weeks, and then every 8 weeks thereafter. The recurrent uveitis disappeared, and the immunosuppressive agents and oral corticosteroids were tapered and discontinued without relapse. All drugs other than infliximab were successfully stopped in October 2010. During the follow-up period, there were no adverse events. CONCLUSION: A case of severe recurrent anterior uveitis OU in a patient with AS with infliximab was successfully treated. This is the first report describing the efficacy of infliximab in AS-associated uveitis in Japan. PMID- 23108529 TI - Effectiveness of arbuscular mycorrhizal fungi (AMF) for inducing the accumulation of major carotenoids, chlorophylls and tocopherol in green and red leaf lettuces. AB - Previous studies demonstrated that arbuscular mycorrhizal fungi (AMF) can induce the accumulation of carotenoids, phenolics, anthocyanins and some mineral nutrients in leaves of lettuce (Lactuca sativa L.) thus enhancing its nutritional quality. Our objectives were to know which carotenoids were the most accumulated in leaves of mycorrhizal lettuces and to assess the effect of AMF on tocopherols' levels in leaves of lettuce plants. AMF always enhanced growth and, in most cases, increased the levels of all major carotenoids, chlorophylls and tocopherols in green and red leaf lettuces. Since these molecules are also important nutraceuticals, mycorrhization emerges as reliable technique to enhance the nutritional value of edible vegetables. These results are compared with other methods developed to improve nutritional quality. PMID- 23108528 TI - Diversity, abundance, and activity of ammonia-oxidizing bacteria and archaea in Chongming eastern intertidal sediments. AB - Ammonia oxidation plays a pivotal role in the cycling and removal of nitrogen in aquatic sediments. Certain bacterial groups and a novel group of archaea, which is affiliated with the novel phylum Thaumarchaeota, can perform this initial nitrification step. We examined the diversity and abundance of ammonia-oxidizing beta-Proteobacteria (beta-AOB) and ammonia-oxidizing archaea (AOA) in the sediments of Chongming eastern tidal flat using the ammonia monooxygenase-alpha subunit (amoA) gene as functional markers. Clone library analysis showed that AOA had a higher diversity of amoA gene than beta-AOB. The beta-Proteobacterial amoA community composition correlated significantly with water soluble salts in the sediments, whereas the archaeal amoA community composition was correlated more with nitrate concentrations. Quantitative PCR (qPCR) results indicated that the abundance of beta-AOB amoA gene (9.11 * 10(4)-6.47 * 10(5) copies g(-1) sediment) was always greater than that of AOA amoA gene (7.98 * 10(3)-3.51 * 10(5) copies g(-1) sediment) in all the samples analyzed in this study. The beta Proteobacterial amoA gene abundance was closely related to organic carbon, while no significant correlations were observed between archaeal amoA gene abundance and the environmental factors. Potential nitrification rates were significantly greater in summer than in winter and correlated strongly with the abundance of amoA genes. Additionally, a greater contribution of single amoA gene to potential nitrification occurred in summer (1.03-5.39 pmol N copy(-1) day(-1)) compared with winter (0.16-0.38 pmol N copy(-1) day(-1)), suggesting a higher activity of ammonia-oxidizing prokaryotes in warm seasons. PMID- 23108531 TI - Agricultural subsidies: are they a contributing factor to the American obesity epidemic? PMID- 23108530 TI - Association between swallow perception and esophageal bolus clearance in patients with globus sensation. AB - BACKGROUND: Globus sensation is common, but its pathogenesis is not yet clear. AIMS: Our purpose was to investigate subjective perception of swallowing and esophageal motility by combined multichannel intraluminal impedance and manometry (MII-EM) for patients with globus sensation. METHODS: Combined MII-EM was performed for 25 globus patients and 15 healthy controls. Swallows were abnormal if hypocontractivity or simultaneous contractions occurred. Esophageal bolus transit was incomplete if bolus exit was not found at one or more of all measurement sites. Perception of each swallow was assessed by use of a standardized scoring system, and was enhanced if the score was >1. RESULTS: Few globus patients reported enhanced perception during viscous or solid swallows. Incomplete bolus transit and enhanced perception occurred similarly between viscous and solid boluses. Agreement between enhanced perception and proximal bolus clearance was greater during solid swallows (kappa = 0.45, 95 % CI: 0.32 0.58) than during viscous swallows (kappa = 0.13, 95 % CI: 0-0.25) (P < 0.05). Similarly, agreement between enhanced perception and total bolus clearance was greater during solid swallows (kappa = 0.46, 95 % CI: 0.34-0.58) than during viscous swallows (kappa = 0.11, 95 % CI: 0-0.22) (P < 0.05). CONCLUSIONS: Enhanced swallow perception is uncommon in patients with globus sensation, although there is a significant association between enhanced esophageal perception and solid bolus clearance. Application of a solid bolus may help better delineation of the interrelationship between the subjective perception of bolus passage and the objective measurement of bolus clearance. PMID- 23108532 TI - Block-adaptive quantum mechanics: an adaptive divide-and-conquer approach to interactive quantum chemistry. AB - We present a novel Block-Adaptive Quantum Mechanics (BAQM) approach to interactive quantum chemistry. Although quantum chemistry models are known to be computationally demanding, we achieve interactive rates by focusing computational resources on the most active parts of the system. BAQM is based on a divide-and conquer technique and constrains some nucleus positions and some electronic degrees of freedom on the fly to simplify the simulation. As a result, each time step may be performed significantly faster, which in turn may accelerate attraction to the neighboring local minima. By applying our approach to the nonself-consistent Atom Superposition and Electron Delocalization Molecular Orbital theory, we demonstrate interactive rates and efficient virtual prototyping for systems containing more than a thousand of atoms on a standard desktop computer. PMID- 23108533 TI - Ion adsorption on the inner surface of single-walled carbon nanotubes used as electrodes for electric double-layer capacitors. AB - In the present study, ion adsorption on the outer and inner surfaces of single walled carbon nanotubes (SWCNTs) in different aqueous and organic electrolytes was analysed. It was found that the fundamental properties of tube size and electronic structure, particularly the transition between van Hove singularities (the band gap), reflected by the shape of the cyclic voltammogram and increase in the number of charge carriers upon doping, apparently provided additional energy for ion adsorption inside open-end SWCNTs. In addition, when cyclic voltammograms recorded at different potential scan rates were observed, the outer surface of the tubes demonstrated the behaviour of a flat electrode with less dependence on the potential scan rate when compared to the inner surface, which acts as a porous electrode showing an ohmic drop and a distorted voltammogram at high scan rates. Mathematical analysis showed that opening the inner channel of the tubes increases electrode resistance, and that the magnitude of variation in the resistance depends on the type of electrolyte. PMID- 23108534 TI - Seaweed allelopathy against coral: surface distribution of a seaweed secondary metabolite by imaging mass spectrometry. AB - Coral reefs are in global decline, with seaweeds increasing as corals decrease. Although seaweeds inhibit coral growth, recruitment, and survivorship, the mechanism of these interactions is poorly understood. Here, we used field experiments to show that contact with four common seaweeds induces bleaching on natural colonies of Porites rus. Controls in contact with inert, plastic mimics of seaweeds did not bleach, suggesting seaweed effects resulted from allelopathy rather than shading, abrasion, or physical contact. Bioassay-guided fractionation of the hydrophobic extract from the red alga Phacelocarpus neurymenioides revealed a previously characterized antibacterial metabolite, neurymenolide A, as the main allelopathic agent. For allelopathy of lipid-soluble metabolites to be effective, the compounds would need to be deployed on algal surfaces where they could transfer to corals on contact. We used desorption electrospray ionization mass spectrometry (DESI-MS) to visualize and quantify neurymenolide A on the surface of P. neurymenioides, and we found the molecule on all surfaces analyzed, with highest concentrations on basal portions of blades. PMID- 23108535 TI - Current and future management of follicular lymphoma. AB - Follicular lymphoma is usually considered as incurable, but patient's outcome has been steadily improving over the last decade. The introduction of anti-CD20 monoclonal antibodies represented a major step. Treatment of patients should take into account accurate staging results, symptoms related to lymphoma, tumor burden, age and comorbidities. Several options are still available for patients with localized or asymptomatic low risk disease, and randomized studies should be developed for those patients. When a systemic therapy is needed, the combination of rituximab with a few of the available cytotoxic regimens clearly provides the best results. Rituximab maintenance appears to further improve the progression free interval. Since most patients will likely survive for many years, the quality and duration of response as well as the short- and long-term side effects of the treatments should be carefully weighted during this prolonged therapeutic management. PMID- 23108536 TI - Guest editorial: Management of malignant lymphoma is continuously improving. PMID- 23108537 TI - An efficient and novel approach for the synthesis of substituted N-aryl lactams. AB - A quick, efficient, one-pot method for the synthesis of substituted N-aryl lactams through the reaction of various kinds of corresponding substituted arenes with a variety of omega-azido alkanoic acid chlorides using a Lewis acid (i.e. EtAlCl(2)) at room temperature, through the in situ involvement of a Friedel Crafts reaction followed by intramolecular Schimdt rearrangement was developed, and afforded good to excellent yields. PMID- 23108538 TI - Caregiving and coping in carers of people with anorexia nervosa admitted for intensive hospital care. AB - OBJECTIVE: The aim of the study was to examine how carers cope practically and emotionally with caring for individuals with anorexia nervosa who require intensive hospital care. METHOD: This study explores objective burden (time spent with caregiving and number of tasks), subjective burden (psychological distress), and social support in a sample of parents (n = 224) and partners (n = 28) from a consecutive series of patients (n = 178) admitted to inpatient units within the United Kingdom. RESULTS: Most time was spent providing emotional support and less with practical tasks. Time spent with caregiving was associated with carer distress and was fully mediated by carer burden. This was ameliorated by social support. Partners received minimal support from others, and we found similar levels of burden and distress for mothers and partners. DISCUSSION: The data indicate that professional and social support alleviates carer distress and may be of particular value for partners who are more isolated than parents. The data also suggest that time spent with practical support may be of more value than emotional support. PMID- 23108539 TI - Endocannabinoids in nervous system health and disease: the big picture in a nutshell. AB - The psychoactive component of the cannabis resin and flowers, delta9 tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related 'phytocannabinoid' compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the 'endocannabinoids' and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness. PMID- 23108540 TI - The evolution and comparative neurobiology of endocannabinoid signalling. AB - CB(1)- and CB(2)-type cannabinoid receptors mediate effects of the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide in mammals. In canonical endocannabinoid-mediated synaptic plasticity, 2-AG is generated postsynaptically by diacylglycerol lipase alpha and acts via presynaptic CB(1) type cannabinoid receptors to inhibit neurotransmitter release. Electrophysiological studies on lampreys indicate that this retrograde signalling mechanism occurs throughout the vertebrates, whereas system-level studies point to conserved roles for endocannabinoid signalling in neural mechanisms of learning and control of locomotor activity and feeding. CB(1)/CB(2)-type receptors originated in a common ancestor of extant chordates, and in the sea squirt Ciona intestinalis a CB(1)/CB(2)-type receptor is targeted to axons, indicative of an ancient role for cannabinoid receptors as axonal regulators of neuronal signalling. Although CB(1)/CB(2)-type receptors are unique to chordates, enzymes involved in biosynthesis/inactivation of endocannabinoids occur throughout the animal kingdom. Accordingly, non-CB(1)/CB(2)-mediated mechanisms of endocannabinoid signalling have been postulated. For example, there is evidence that 2-AG mediates retrograde signalling at synapses in the nervous system of the leech Hirudo medicinalis by activating presynaptic transient receptor potential vanilloid-type ion channels. Thus, postsynaptic synthesis of 2 AG or anandamide may be a phylogenetically widespread phenomenon, and a variety of proteins may have evolved as presynaptic (or postsynaptic) receptors for endocannabinoids. PMID- 23108541 TI - Why do cannabinoid receptors have more than one endogenous ligand? AB - The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Delta(9) tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2 arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis. PMID- 23108542 TI - Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development. AB - During brain development, neurogenesis is precisely regulated by the concerted action of intrinsic factors and extracellular signalling systems that provide the necessary niche information to proliferating and differentiating cells. A number of recent studies have revealed a previously unknown role for the endocannabinoid (ECB) system in the control of embryonic neuronal development and maturation. Thus, the CB(1) cannabinoid receptor in concert with locally produced ECBs regulates neural progenitor (NP) proliferation, pyramidal specification and axonal navigation. In addition, subcellularly restricted ECB production acts as an axonal growth cone signal to regulate interneuron morphogenesis. These findings provide the rationale for understanding better the consequences of prenatal cannabinoid exposure, and emphasize a novel role of ECBs as neurogenic instructive cues involved in cortical development. In this review the implications of altered CB(1)-receptor-mediated signalling in developmental disorders and particularly in epileptogenesis are briefly discussed. PMID- 23108543 TI - Functional diversity on synaptic plasticity mediated by endocannabinoids. AB - Endocannabinoids (eCBs) act as modulators of synaptic transmission through activation of a number of receptors, including, but not limited to, cannabinoid receptor 1 (CB1). eCBs share CB1 receptors as a common target with Delta(9) tetrahydrocannabinol (THC), the main psychoactive ingredient in marijuana. Although THC has been used for recreational and medicinal purposes for thousands of years, little was known about its effects at the cellular level or on neuronal circuits. Identification of CB1 receptors and the subsequent development of its specific ligands has therefore enhanced our ability to study and bring together a substantial amount of knowledge regarding how marijuana and eCBs modify interneuronal communication. To date, the eCB system, composed of cannabinoid receptors, ligands and the relevant enzymes, is recognized as the best-described retrograde signalling system in the brain. Its impact on synaptic transmission is widespread and more diverse than initially thought. The aim of this review is to succinctly present the most common forms of eCB-mediated modulation of synaptic transmission, while also illustrating the multiplicity of effects resulting from specializations of this signalling system at the circuital level. PMID- 23108544 TI - Cellular and intracellular mechanisms involved in the cognitive impairment of cannabinoids. AB - Exogenous cannabinoids, such as delta9-tetrahydrocannabinol (THC), as well as the modulation of endogenous cannabinoids, affect cognitive function through the activation of cannabinoid receptors. Indeed, these compounds modulate a number of signalling pathways critically implicated in the deleterious effect of cannabinoids on learning and memory. Thus, the involvement of the mammalian target of rapamycin pathway and extracellular signal-regulated kinases, together with their consequent regulation of cellular processes such as protein translation, play a critical role in the amnesic-like effects of cannabinoids. In this study, we summarize the cellular and molecular mechanisms reported in the modulation of cognitive function by the endocannabinoid system. PMID- 23108545 TI - The diacylglycerol lipases: structure, regulation and roles in and beyond endocannabinoid signalling. AB - The diacylglycerol lipases (DAGLs) hydrolyse diacylglycerol to generate 2 arachidonoylglycerol (2-AG), the most abundant ligand for the CB(1) and CB(2) cannabinoid receptors in the body. DAGL-dependent endocannabinoid signalling regulates axonal growth and guidance during development, and is required for the generation and migration of new neurons in the adult brain. At developed synapses, 2-AG released from postsynaptic terminals acts back on presynaptic CB(1) receptors to inhibit the secretion of both excitatory and inhibitory neurotransmitters, with this DAGL-dependent synaptic plasticity operating throughout the nervous system. Importantly, the DAGLs have functions that do not involve cannabinoid receptors. For example, 2-AG is the precursor of arachidonic acid in a pathway that maintains the level of this essential lipid in the brain and other organs. This pathway also drives the cyclooxygenase-dependent generation of inflammatory prostaglandins in the brain, which has recently been implicated in the degeneration of dopaminergic neurons in Parkinson's disease. Remarkably, we still know very little about the mechanisms that regulate DAGL activity-however, key insights can be gleaned by homology modelling against other alpha/beta hydrolases and from a detailed examination of published proteomic studies and other databases. These identify a regulatory loop with a highly conserved signature motif, as well as phosphorylation and palmitoylation as post translational mechanisms likely to regulate function. PMID- 23108546 TI - Hub and switches: endocannabinoid signalling in midbrain dopamine neurons. AB - The last decade has provided a wealth of experimental data on the role played by lipids belonging to the endocannabinoid family in several facets of physiopathology of dopamine neurons. We currently suggest that these molecules, being intimately connected with diverse metabolic and signalling pathways, might differently affect various functions of dopamine neurons through activation not only of surface receptors, but also of nuclear receptors. It is now emerging how dopamine neurons can regulate their constituent biomolecules to compensate for changes in either internal functions or external conditions. Consequently, dopamine neurons use these lipid molecules as metabolic and homeostatic signal detectors, which can dynamically impact cell function and fitness. Because dysfunctions of the dopamine system underlie diverse neuropsychiatric disorders, including schizophrenia and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Particularly, because dopamine neurons are critical in controlling incentive-motivated behaviours, the involvement of endocannabinoid molecules in fine-tuning dopamine cell activity opened new avenues in both understanding and treating drug addiction. Here, we review recent advances that have shed new light on the understanding of differential roles of endocannabinoids and their cognate molecules in the regulation of the reward circuit, and discuss their anti-addicting properties, particularly with a focus on their potential engagement in the prevention of relapse. PMID- 23108547 TI - Modulation of neuropathic-pain-related behaviour by the spinal endocannabinoid/endovanilloid system. AB - Neuropathic pain refers to chronic pain that results from injury to the nervous system. The mechanisms involved in neuropathic pain are complex and involve both peripheral and central phenomena. Although numerous pharmacological agents are available for the treatment of neuropathic pain, definitive drug therapy has remained elusive. Recent drug discovery efforts have identified an original neurobiological approach to the pathophysiology of neuropathic pain. The development of innovative pharmacological strategies has led to the identification of new promising pharmacological targets, including glutamate antagonists, microglia inhibitors and, interestingly, endogenous ligands of cannabinoids and the transient receptor potential vanilloid type 1 (TRPV1). Endocannabinoids (ECs), endovanilloids and the enzymes that regulate their metabolism represent promising pharmacological targets for the development of a successful pain treatment. This review is an update of the relationship between cannabinoid receptors (CB1) and TRPV1 channels and their possible implications for neuropathic pain. The data are focused on endogenous spinal mechanisms of pain control by anandamide, and the current and emerging pharmacotherapeutic approaches that benefit from the pharmacological modulation of spinal EC and/or endovanilloid systems under chronic pain conditions will be discussed. PMID- 23108548 TI - Dynamic changes to the endocannabinoid system in models of chronic pain. AB - The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2 AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling. PMID- 23108551 TI - Endocannabinoids in neuroendopsychology: multiphasic control of mitochondrial function. AB - The endocannabinoid system (ECS) is a construct based on the discovery of receptors that are modulated by the plant compound tetrahydrocannabinol and the subsequent identification of a family of nascent ligands, the 'endocannabinoids'. The function of the ECS is thus defined by modulation of these receptors-in particular, by two of the best-described ligands (2-arachidonyl glycerol and anandamide), and by their metabolic pathways. Endocannabinoids are released by cell stress, and promote both cell survival and death according to concentration. The ECS appears to shift the immune system towards a type 2 response, while maintaining a positive energy balance and reducing anxiety. It may therefore be important in resolution of injury and inflammation. Data suggest that the ECS could potentially modulate mitochondrial function by several different pathways; this may help explain its actions in the central nervous system. Dose-related control of mitochondrial function could therefore provide an insight into its role in health and disease, and why it might have its own pathology, and possibly, new therapeutic directions. PMID- 23108549 TI - Mast cell-glia axis in neuroinflammation and therapeutic potential of the anandamide congener palmitoylethanolamide. AB - Communication between the immune and nervous systems depends a great deal on pro inflammatory cytokines. Both astroglia and microglia, in particular, constitute an important source of inflammatory mediators and may have fundamental roles in central nervous system (CNS) disorders from neuropathic pain and epilepsy to neurodegenerative diseases. Glial cells respond also to pro-inflammatory signals released from cells of immune origin. In this context, mast cells are of particular relevance. These immune-related cells, while resident in the CNS, are able to cross a compromised blood-spinal cord and blood-brain barrier in cases of CNS pathology. Emerging evidence suggests the possibility of mast cell-glia communication, and opens exciting new perspectives for designing therapies to target neuroinflammation by differentially modulating the activation of non neuronal cells normally controlling neuronal sensitization-both peripherally and centrally. This review aims to provide an overview of recent progress relating to the pathobiology of neuroinflammation, the role of glia, neuro-immune interactions involving mast cells and the possibility that glia-mast cell interactions contribute to exacerbation of acute symptoms of chronic neurodegenerative disease and accelerated disease progression, as well as promotion of pain transmission pathways. Using this background as a starting point for discussion, we will consider the therapeutic potential of naturally occurring fatty acid ethanolamides, such as palmitoylethanolamide in treating systemic inflammation or blockade of signalling pathways from the periphery to the brain in such settings. PMID- 23108550 TI - The endocannabinoid system in normal and pathological brain ageing. AB - The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing. PMID- 23108555 TI - Validation of the Mexican Spanish version of the EORTC QLQ-H&N35 instrument to measure health-related quality of life in patients with head and neck cancers. AB - BACKGROUND: Health-related quality of life (HRQL) is an important outcome measurement in oncology. Our aim was to validate the Mexican Spanish version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-H&N35 questionnaire to measure HRQL in patients with head and neck cancers. METHODS: The QLQ-C30 and QLQ-H&N35 instruments were applied to Mexican patients with head and neck cancer at a cancer referral center. Reliability and validity tests were performed. Test-retest was carried out in selected patients. RESULTS: One hundred ninety-three patients were included in this cohort; tumor locations included the following: oral cavity 45 (23.3 %); larynx 35 (18.1 %); thyroid carcinoma invasive to aerodigestive tract 32 (16.6 %); oropharynx 17 (8.8 %); hypopharynx 12 (6.2 %); nasal cavity and paranasal sinuses 11 (5.7 %); salivary glands 11 (5.7 %); nasopharynx 8 (4.1 %); eye and adnexa 7 (3.6 %); cervical metastases of unknown origin 5 (2.6 %); primary sarcoma of the head and neck region 5 (2.6 %); maxillary antrum carcinoma 4 (2.1 %); and retinoblastoma 1 (0.5 %). Questionnaire compliance rates were high, and the instrument was well accepted; the internal consistency tests demonstrated good convergent and divergent validity. Cronbach's alpha coefficients of 8 of 9 multi-item scales of the QLQ-C30 and 6 of 8 scales of the QLQ-H&N35 instruments were >0.7 (range 0.22-0.89). Scales of the QLQ-C30 and QLQ-H&N35 instruments distinguished among clinically distinct groups of patients; some were highly sensitive to change over time. CONCLUSIONS: The Mexican Spanish version of the QLQ-H&N35 questionnaire is reliable and valid for the assessment of HRQL in patients with head and neck cancers and can be used in clinical trials in Mexican communities. PMID- 23108554 TI - Nuclear E-cadherin expression is associated with the loss of membranous E cadherin, plasmacytoid differentiation and reduced overall survival in urothelial carcinoma of the bladder. AB - BACKGROUND: Loss of E-cadherin represents a hallmark of plasmacytoid differentiation. We analyzed the effect of membranous E-cadherin loss and its nuclear accumulation in patients with locally advanced conventional urothelial carcinoma (UC) who were treated with radical cystectomy and adjuvant chemotherapy. METHODS: A total of 247 formalin-fixed, paraffin-embedded tumor samples were reviewed to detect histological variants of UC. Immunohistochemical staining of E-cadherin was performed and analyzed for membranous and nuclear expression. The correlation between E-cadherin expression and histology was assessed, and overall survival (OS) was analyzed with univariate and multivariate Cox regression and Kaplan-Meier analyses. Correlation of nuclear E-cadherin to tumor stage (pT), lymph node metastasis (pN), histologic subtype, and chemotherapy was performed by Fisher's exact test. RESULTS: Membranous and nuclear E-cadherin expression was strongly correlated to plasmacytoid urothelial carcinoma (PUC) (p < 0.001). Complete loss of membranous E-cadherin expression was observed in 76.2 % of PUCs, 11.1 % of conventional UCs, and 0 % of micropapillary urothelial carcinoma (MPCs). Nuclear accumulation was found in 47.6 % of PUCs, 10 % of MPCs, and 1.8 % of UCs. Sixty-two percent of all tumors with negative membranous E-cadherin expression and nuclear accumulation were PUCs (p = 0.035). In a Kaplan-Meier analysis, mean survival with nuclear E-cadherin expression was 31.9 months [95 % confidence interval (CI) 16.1-47.6] of patients without nuclear staining 61 months (95 % CI 53.5-67.7; p = 0.045). A univariate Cox regression analysis showed that nuclear E-cadherin accumulation was associated with a 2-fold increase in risk of death (95 % CI 1.03-4.06; p = 0.04). In multivariate Cox regression analysis adjusted to type of chemotherapy, tumor stage, and tumor grade, the hazard ratio for patients with nuclear E-cadherin was 2.03 (95 % CI 1.00-4.121; p = 0.050). CONCLUSIONS: Nuclear E-cadherin is associated with PUCs and is suggested to be an independent prognostic factor in advanced UC. PMID- 23108553 TI - Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. AB - Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Delta(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARgamma receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects. PMID- 23108552 TI - Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. AB - Human tissues express cannabinoid CB(1) and CB(2) receptors that can be activated by endogenously released 'endocannabinoids' or exogenously administered compounds in a manner that reduces the symptoms or opposes the underlying causes of several disorders in need of effective therapy. Three medicines that activate cannabinoid CB(1)/CB(2) receptors are now in the clinic: Cesamet (nabilone), Marinol (dronabinol; Delta(9)-tetrahydrocannabinol (Delta(9)-THC)) and Sativex (Delta(9) THC with cannabidiol). These can be prescribed for the amelioration of chemotherapy-induced nausea and vomiting (Cesamet and Marinol), stimulation of appetite (Marinol) and symptomatic relief of cancer pain and/or management of neuropathic pain and spasticity in adults with multiple sclerosis (Sativex). This review mentions several possible additional therapeutic targets for cannabinoid receptor agonists. These include other kinds of pain, epilepsy, anxiety, depression, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, stroke, cancer, drug dependence, glaucoma, autoimmune uveitis, osteoporosis, sepsis, and hepatic, renal, intestinal and cardiovascular disorders. It also describes potential strategies for improving the efficacy and/or benefit-to-risk ratio of these agonists in the clinic. These are strategies that involve (i) targeting cannabinoid receptors located outside the blood-brain barrier, (ii) targeting cannabinoid receptors expressed by a particular tissue, (iii) targeting upregulated cannabinoid receptors, (iv) selectively targeting cannabinoid CB(2) receptors, and/or (v) adjunctive 'multi-targeting'. PMID- 23108556 TI - Toxic nodular goiter and cancer: a compelling case for thyroidectomy. AB - BACKGROUND: Recent American Thyroid Association guidelines call for thyroidectomy or (131)I (Recommendation 31) in managing hyperthyroidism due to toxic nodular goiter (TNG). Concern for concomitant malignancy favors surgery. A 3 % thyroid cancer incidence in TNG patients has been reported, yet recent studies suggest this rate is underestimated. This multi-institutional study examined cancer incidence in TNG patients referred to surgery. METHODS: Patients referred for thyroidectomy at three tertiary-care institutions were included (2002-2011). Patients with concurrent indeterminate or malignant diagnosis by fine-needle aspiration (FNA) were excluded. Cancer incidence in TNG patients was determined. Fisher's exact and chi-square tests and nonparametric t tests were used. RESULTS: Among 2,551 surgically treated patients, 164 had TNG (6.4 %). Median age at presentation was 49.7 years, and 86 % were female. Overall cancer incidence was 18.3 % (30 of 164), and rates were not significantly different between institutions. A significantly greater cancer rate was noted in toxic multinodular goiter versus single toxic nodule patients (21 vs. 4.5 %, P < 0.05). Mean tumor size was 0.71 cm (range 0.1-1.5 cm; 23 % >=1 cm). Most patients underwent total or near-total thyroidectomy. There were no significant differences in tumor sizes among institutions (P > 0.05). No significant cancer association was noted with age, preoperative dominant nodule size, lymphocytic thyroiditis or preoperative FNA (P > 0.05). CONCLUSIONS: These data demonstrate a higher than expected incidental cancer rate in TNG patients compared to historical reports (18.3 vs. 3 %). This higher cancer incidence may alter the risk/benefit analysis regarding TNG treatment. This information should be provided to TNG patients before decision making regarding treatment. PMID- 23108558 TI - Endoglin (CD105) is not a specific selection marker for endothelial cells in human islets of Langerhans. Reply to Wheeler-Jones CPD, Clarkin CE, Farrar CE et al [letter]. PMID- 23108557 TI - A plant derived multifunctional tool for nanobiotechnology based on Tomato bushy stunt virus. AB - Structure, size, physicochemical properties and production strategies make many plant viruses ideal protein based nanoscaffolds, nanocontainers and nano-building blocks expected to deliver a multitude of applications in different fields such as biomedicine, pharmaceutical chemistry, separation science, catalytic chemistry, crop pest control and biomaterials science. Functionalization of viral nanoparticles through modification by design of their external and internal surfaces is essential to fully exploit the potentiality of these objects. In the present paper we describe the development of a plant derived multifunctional tool for nanobiotechnology based on Tomato bushy stunt virus. We demonstrate the ability of this system to remarkably sustain genetic modifications and in vitro chemical derivatizations of its outer surface, which resulted in the successful display of large chimeric peptides fusions and small chemical molecules, respectively. Moreover, we have defined physicochemical conditions for viral swelling and reversible viral pore gating that we have successfully employed for foreign molecules loading and retention in the inner cavity of this plant virus nanoparticles system. Finally, a production and purification strategy from Nicotiana benthamiana plants has been addressed and optimized. PMID- 23108559 TI - Establishing the efficacy of Gliadel wafers: progress towards a Phase III trial. PMID- 23108560 TI - The case for mini-craniotomy in the management of chronic subdural hematoma. PMID- 23108561 TI - Remote peritentorial hemorrhage complicating supratentorial aneurysmal surgery: a report of three cases and literature review. AB - We herein coin the term "remote peritentorial hemorrhage (RPTH)" and present three cases with "RPTH" after supratentorial aneurysmal surgeries, including two with remote cerebellar hemorrhage (RCH) and one with remote temporobasal hemorrhage. The RCH may result from rupture of the superior cerebellar veins due to excessive cerebrospinal fluid (CSF) loss. The mechanism behind the remote temporobasal hemorrhage may be similar to that of RCH. It can be explained by tearing of the temporobasal veins as a result of brain shift owing to intracranial hypotension stemming from intensive loss of CSF. As far as we know, this is the first report of such a bleeding pattern of probable venous origin. The results of this study could shed light on the "RPTH" physiopathology. PMID- 23108562 TI - Endoscopic biopsies of lesions associated with a thickened pituitary stalk. AB - BACKGROUND: Lesions associated with a thickened pituitary stalk (TPS lesions) revealed by magnetic resonance imaging have a diverse pathology. Accordingly, for clinical decision-making, it is necessary to make a diagnosis based on histopathological examination of the TPS lesions. The objectives of this study were to review endoscopic biopsies of TPS lesions and to assess the surgical strategy for treating these lesions. METHODS: Eleven patients (four males and seven females) aged from 6 to 75 years underwent endoscopic biopsy of a TPS lesion between 2006 and 2011 at University of Niigata. The relationships of the extent of lesions with surgical approaches were retrospectively examined. RESULTS: Among the 11 patients, a biopsy was performed via an endoscopic transsphenoidal approach for five with intrasellar lesions; via an endoscopic extended transsphenoidal approach for two with localized TPS lesions; and via an endoscopic intraventricular approach for four with the lesion protruding from the infundibulum. Histopathological examinations of all the lesions confirmed diagnoses of germinoma in four patients, hypophysitis in three, Langerhans cell histiocytosis in two, craniopharyngioma in one, and cancer metastasis in one. None of the 11 patients had further deterioration of pituitary function postoperatively. CONCLUSIONS: Endoscopic biopsy of TPS lesions is a less invasive alternative to open biopsy requiring transcranial surgery. The endoscopic transsphenoidal approach is most suitable for biopsies of TPS lesions associated with intrasellar lesions. Otherwise, the endoscopic intraventricular approach seems reasonable for intraventricular lesions protruding from the infundibulum, and the endoscopic extended transsphenoidal approach appears appropriate for localized TPS lesions. PMID- 23108563 TI - Adult moyamoya after revascularization. AB - BACKGROUND: Although cerebral revascularization is an accepted treatment for moyamoya, the precise impact of direct or indirect bypass methods on subsequent event rates is infrequently addressed in adult cohorts. METHODS: We reviewed 45 consecutive adults with 69 hemispheres affected by moyamoya. We evaluated stroke and hemorrhage rates prior to and following revascularization. RESULTS: Direct revascularization was performed for 35 hemispheres (51 %) in 29 patients (64 %). The annual stroke, hemorrhage and overall event rates in this cohort diminished from 8.9 %, 2.0 %, and 11 % per hemisphere-year to 4.5 %, 0 %, and 4.5 % per hemisphere-year after treatment, respectively (p = 0.06). Excluding perioperative events, no events occurred over 41.1 hemisphere-years of follow-up (p = 0.0017). After a mean clinical follow-up period of 1.3 years, 72 % of patients were improved, 24 % the same, and 3 % worse in this cohort. Indirect revascularization was performed for 18 hemispheres (26 %) in 13 patients (29 %). The annual stroke, hemorrhage and overall event rates were 13 %, 0 %, and 13 % per hemisphere-year prior to treatment, and 6.8 %, 4.5 %, and 11 % per hemisphere-year after treatment, respectively (p = 0.67). Excluding perioperative events, the overall annual event rate was 7.1 % (p = 0.69). After a mean clinical follow-up of 2.7 years, 46 % of patients were improved, 38 % were the same and 15 % were worse. CONCLUSION: Direct revascularization is the optimal choice to prevent subsequent events in adult patients with moyamoya. A favorable impact of indirect revascularization was less clear in this cohort, and should be reserved for patients with an inadequate donor vessel. PMID- 23108564 TI - Detection of TFPI2 methylation in the serum of hepatocellular carcinoma patients. AB - BACKGROUND: DNA methylation plays a key role in hepatocellular carcinogenesis and progression. Analysis of aberrant methylation in serum DNA might provide a strategy for noninvasive detection of hepatocellular carcinoma (HCC). METHODS: To explore the feasibility of this approach, we compared TFPI2 methylation status in serum samples of HCC, chronic hepatitis B (CHB) patients and normal control groups using methylation-specific polymerase chain reaction. RESULTS: Our results showed that the percentage of serum TFPI2 promoter methylation was significantly higher in the HCC group (46.5 %, 20/43) compared with the CHB group (16.7 %, 4/24; p = 0.015) and the normal control group (19.2 %, 5/26; p = 0.022), respectively, indicating that TFPI2 methylation frequently existed in the serum of HCC patients. In our study, the detection rate of HCC using serum TFPI2 methylation was 46.5 % (20/43), which was quite close to the reported detection rate of alpha-fetoprotein (54 %). In cases where we combined both markers, the detection rate was 61.0 %, suggesting that serum TFPI2 methylation could be used as a potential marker for noninvasive detection of HCC. Then, we evaluated the correlation between the serum TFPI2 methylation status of HCC patients and their clinicopathological parameters. Patients with advanced TNM stage (III-IV) showed a significantly elevated serum methylation percentage of TFPI2 in comparison with those with early TNM stage (I-II) (p = 0.025). Moreover, TFPI2 methylation was observed more frequently according to the progression of TNM stage. CONCLUSIONS: Our present study suggested that TFPI2 methylation in serum tended to be detected more easily in patients with advanced HCC and might be used as a predictor of HCC progression. PMID- 23108565 TI - Chronic Helicobacter pylori infection and DNA-damaged stem cells: a recipe for disaster. PMID- 23108566 TI - Image-enhanced endoscopy with I-scan technology for the evaluation of duodenal villous patterns. AB - BACKGROUND: I-scan technology is the newly developed endoscopic tool that works in real time and utilizes a digital contrast method to enhance endoscopic image. AIMS: We performed a feasibility study aimed to determine the diagnostic accuracy of i-scan technology for the evaluation of duodenal villous patterns, having histology as the reference standard. METHODS: In this prospective, single center, open study, patients undergoing upper endoscopy for an histological evaluation of duodenal mucosa were enrolled. All patients underwent upper endoscopy using high resolution view in association with i-scan technology. During endoscopy, duodenal villous patterns were evaluated and classified as normal, partial villous atrophy, or marked villous atrophy. Results were then compared with histology. RESULTS: One hundred fifteen subjects were recruited in this study. The endoscopist was able to find marked villous atrophy of the duodenum in 12 subjects, partial villous atrophy in 25, and normal villi in the remaining 78 individuals. The i-scan system was demonstrated to have great accuracy (100 %) in the detection of marked villous atrophy patterns. I-scan technology showed quite lower accuracy in determining partial villous atrophy or normal villous patterns (respectively, 90 % for both items). CONCLUSIONS: Image-enhancing endoscopic technology allows a clear visualization of villous patterns in the duodenum. By switching from the standard to the i-scan view, it is possible to optimize the accuracy of endoscopy in recognizing villous alteration in subjects undergoing endoscopic evaluation. PMID- 23108567 TI - The usability of allele-specific PCR and reverse-hybridization assays for KRAS genotyping in Serbian colorectal cancer patients. AB - BACKGROUND: Colorectal cancers (CRCs) with wild-type KRAS respond to EGFR targeted antibody treatment. Analysis of the hotspot clustered mutations in codons 12 and 13 is compulsory before therapy and no standardized methodology for that purpose has been established so far. Since these mutations may have different biological effects and clinical outcome, reliable frequency and types of KRAS mutations need to be determined for individual therapy. AIMS: The purpose of this study was to describe the KRAS mutation spectrum in a group of 481 Serbian mCRC patients and to compare the general performances of allele-specific PCR and reverse-hybridization assays. METHODS: KRAS testing was performed with two diagnostic analyses, DxS TheraScreen K-RAS PCR Kit and KRAS StripAssayTM. RESULTS: KRAS mutations in codons 12 and 13 were present in 37.6 % of analyzed formalin-fixed paraffin-embedded (FFPE) DNA samples. The seven most frequent mutation types were observed with both assays: p.G12D 34.6 %, p.G12V 24.9 %, p.G12A 10.3 %, p.G12C 8.1 %, p.G12S 5.4 %, p.G12R 1.6 %, and p.G13D 15.1 %. Regarding double mutants, 0.8 % of them were present among all tested samples and 2.2 % among KRAS mutated ones. CONCLUSIONS: Two screening approaches that were used in this study have been shown as suitable tests for detecting KRAS mutations in diagnostic settings. In addition, they appear to be good alternatives to methods presently in use. In our experience, both methods showed capacity to detect and identify double mutations which may be important for potential further subgrouping of CRC patients. PMID- 23108568 TI - Viscosity and temperature effects on the rate of oxygen quenching of tris-(2,2' bipyridine)ruthenium(II). AB - We compare the bimolecular quenching rate constant (k2) of luminescent tris(2,2' bipyridine)ruthenium(II) by oxygen in water, ethylene glycol and glycerol as a function of temperature and viscosity to several theoretical models. The Smoluchowski equation with experimentally determined diffusion coefficients produced calculated values that were in the best agreement with experiment. For the less viscous solvent, water, this equation produced a value that was approximately an order of magnitude larger than the experimental value. With an increase in solvent viscosity, the Smoluchowski value approached the experimental value. Using the Smoluchowski equation with calculated diffusion coefficients based on the known radii of the reacting species produced deviations an order of magnitude larger in water and a factor of two or three lower in ethylene glycol and glycerol. If an assumption is made that the radii of both molecules are equal, we have the Stokes Einstein equation, and the only parameters become temperature and viscosity. Using this relationship, the calculated values for water are about a factor of two larger and with ethylene glycol and glycerol about a factor of 6 smaller than experimental data. These results show that bimolecular quenching is a more complex process affected by many parameters such as solvent cage effects in addition to viscosity and temperature. PMID- 23108569 TI - Astrocytes shed large membrane vesicles that contain mitochondria, lipid droplets and ATP. AB - Various cells types, including stem and progenitor cells, can exchange complex information via plasma membrane-derived vesicles, which can carry signals both in their limiting membrane and lumen. Astrocytes, traditionally regarded as mere supportive cells, play previously unrecognized functions in neuronal modulation and are capable of releasing signalling molecules of different functional significance. In the present study, we provide direct evidence that human fetal astrocytes in culture, expressing the same feature as immature and reactive astrocytes, release membrane vesicles larger than the microvesicles described up to now. We found that these large vesicles, ranging from 1-5 to 8 MUm in diameter and expressing on their surface beta1-integrin proteins, contain mitochondria and lipid droplets together with ATP. We documented vesicle content with fluorescent specific dyes and with the immunocytochemistry technique we confirmed that mitochondria and lipid droplets were co-localized in the same vesicle. Scanning electron microscopy and transmission electron microscopy confirmed that astrocytes shed from surface membrane vesicles of the same size as the ones detected by fluorescence microscopy. Our results report for the first time that cultured astrocytes, activated by repetitive stimulation of ATP released from neighboring cells, shed from their surface large membrane vesicles containing mitochondria and lipid droplets. PMID- 23108570 TI - The plant strengthening root endophyte Piriformospora indica: potential application and the biology behind. AB - The successful conversion of plant production systems from conventional resource exhausting to sustainable strategies depends on knowledge-based management of environmental factors. Root-inhabiting fungi came more and more into focus because their hyphae connect in ideal manner resources and challenges of the surrounding with the plant. A paradigm for such root endophytes is presented by the basidiomycete Piriformospora indica. This fungus possesses a broad host spectrum and positively affects different aspects of plant performance. This so far unique combination of attributes makes P. indica and its close relatives among the Sebacinales very interesting tools for cultivation of various crops. This review will outline the different aspects required to apply this root endophyte in agri- and horticulture concerning plant growth, plant nutrition and plant defence or tolerance thereby explaining what is known about the biological basis for the observed effects. Open questions and challenges for successful inoculum production and application will be discussed. PMID- 23108572 TI - Acute anterior myocardial infarction in an 85-year-old male patient, complicated by the deadly duo: ventricular septal rupture and pseudoaneurysm. AB - Ventricular septal rupture and ventricular pseudoaneurysm formation are rare complications of acute myocardial infarction. Immediate intervention is mandatory in these circumstances. Our case is a unique presentation of an anterior myocardial infarction in an 85-year-old male, complicated by ventricular septal rupture and ventricular pseudoaneurysm formation. PMID- 23108571 TI - Myocardial infarction and sudden cardiac death in Olmsted County, Minnesota, before and after smoke-free workplace laws. AB - BACKGROUND: Reductions in admissions for myocardial infarction (MI) have been reported in locales where smoke-free workplace laws have been implemented, but no study has assessed sudden cardiac death in that setting. In 2002, a smoke-free restaurant ordinance was implemented in Olmsted County, Minnesota, and in 2007, all workplaces, including bars, became smoke free. METHODS: To evaluate the population impact of smoke-free laws, we measured, through the Rochester Epidemiology Project, the incidence of MI and sudden cardiac death in Olmsted County during the 18-month period before and after implementation of each smoke free ordinance. All MIs were continuously abstracted and validated, using rigorous standardized criteria relying on biomarkers, cardiac pain, and Minnesota coding of the electrocardiogram. Sudden cardiac death was defined as out-of hospital deaths associated with coronary disease. RESULTS: Comparing the 18 months before implementation of the smoke-free restaurant ordinance with the 18 months after implementation of the smoke-free workplace law, the incidence of MI declined by 33% (P < .001), from 150.8 to 100.7 per 100,000 population, and the incidence of sudden cardiac death declined by 17% (P = .13), from 109.1 to 92.0 per 100,000 population. During the same period, the prevalence of smoking declined and that of hypertension, diabetes mellitus, hypercholesterolemia, and obesity either remained constant or increased. CONCLUSIONS: A substantial decline in the incidence of MI was observed after smoke-free laws were implemented, the magnitude of which is not explained by community cointerventions or changes in cardiovascular risk factors with the exception of smoking prevalence. As trends in other risk factors do not appear explanatory, smoke-free workplace laws seem to be ecologically related to these favorable trends. Secondhand smoke exposure should be considered a modifiable risk factor for MI. All people should avoid secondhand smoke to the extent possible, and people with coronary heart disease should have no exposure to secondhand smoke. PMID- 23108573 TI - Giant pseudoaneurysm of the left axillary artery following a stab wound. AB - Axillary artery pseudoaneurysms are rare. We report on a 30-year-old patient with a 6.5-cm post-traumatic pseudoaneurysm of the left axillary artery two months after a knife stab wound of the shoulder. The patient showed axillary fullness and signs of severe brachial plexus compression. A surgical repair was undertaken. The aneurysm was excluded and a saphenous vein interposition was performed. The early and late postoperative periods were uneventful. This is probably not only the largest axillary artery pseudoaneurysm ever reported, but also the first secondary to a stab wound. PMID- 23108574 TI - Acute ST-elevation inferior myocardial infarction in a patient with a non obstructive mechanical mitral valve thrombosis. AB - The risk of systemic embolisation in patients with prosthetic heart valves who are receiving anticoagulation therapy is 0.5 to 1.7% per patient year and most cases present with cerebrovascular events. Here we report the case of a 42-year old woman who was uneventfully treated with a low dose, prolonged infusion of tissue plasminogen activator because of non-obstructive prosthetic mitral valve thrombosis. It presented as coronary embolism and resulted in acute ST-elevation inferior myocardial infarction. PMID- 23108576 TI - Morphological stability of organic solar cells based upon an oligo(p phenylenevinylene)-C70 dyad. AB - An oligo(p-phenylenevinylene)-C(70) dyad achieves the highest power conversion efficiency (1.92%) in dyad-based organic solar cells to date. Covalent attachment in the dyad prevents large phase separation, resulting in good morphological and device stability at high temperatures as compared with mixed bulk heterojunction devices. PMID- 23108575 TI - Prolonged coagulopathy related to coumarin rodenticide in a young patient: superwarfarin poisoning. AB - Superwarfarins (brodifacoum, difenacoum, bromodialone and chlorphacinone) are anticoagulant rodenticides that were developed in 1970s to overcome resistance to warfarin in rats. A 26-year-old previously healthy man was admitted to the emergency department with epigastric pain, severe upper and lower gastrointestinal haemorrhage, gingival bleeding and melena. The patient stated that he had been healthy with no prior hospital admissions and no personal or family history of bleeding diathesis. The patient, who later admitted attempted suicide, stated that he had taken 400 g rodenticide including brodifacoum orally for five days prior to admission to hospital. He had oral mucosal bleeding, numerous bruises over the arms, legs and abdomen, and an abdominal tenderness, together with melena. Laboratory tests revealed a haemoglobin level of 12.3 g/dl, leucocyte count of 9.1 * 10(9) /l, haematocrit of 28% and platelet count of 280 * 10(9) /l. The prothrombin time (PT) was > 200 s (normal range 10.5-15.2 s) and the activated partial thromboplastin time (aPTT) was 91 s (normal range 20-45 s). The INR (International normalised ratio) was reported to be > 17 (normal range 0.8-1.2). The thrombin time and plasma fibrinogen levels were in the normal range. The results showed the presence of brodifacoum at a concentration of 61 ng/ml, detected by reversed-phase liquid chromatography. PMID- 23108577 TI - Complete nucleotide sequences of two isolates of cherry green ring mottle virus from peach (Prunus persica) in China. AB - Two complete nucleotide sequences of cherry green ring mottle virus (CGRMV) isolated from peach in Hebei (Hs10) and Fujian (F9) Provinces, China, were determined. Five open reading frames (ORFs) were found in the genomes of both isolates. The F9 and Hs10 isolates shared 82.2 % and 83.4-94.4 % nucleotide sequence identity, respectively, with two CGRMV isolates from cherry. Analysis of the nucleotide and amino acid sequences from the five ORFs of both isolates showed that Hs10 shares the greatest sequence identity with P1A (GenBank AJ291761) from cherry. Phylogenetic analysis indicated that CGRMV isolates from peach and cherry are closely related to members of the genus Foveavirus. PMID- 23108578 TI - Population structure of blackberry chlorotic ringspot virus in the United States. AB - Blackberry chlorotic ringspot virus is a subgroup 1 ilarvirus, detected in several rosaceous hosts exhibiting disease symptoms in Europe and the United States. The population structure of the virus was studied using isolates collected from wild and cultivated plants from six states in the United States. The results suggest a homogeneous virus population in the United States, similar to what observed within single orchards for other ilarviruses. Given the lack of evidence for host or geography-driven adaptation, it is hypothesized that the virus was recently introduced into the New World. PMID- 23108579 TI - Dietary tin intake and association with canned food consumption in Japanese preschool children. AB - OBJECTIVES: Dietary intake of tin has seldom been studied in children although they probably have a high intake. This study was initiated to investigate dietary tin intake (Sn-D) of children in Japan. METHODS: In this study, 24-h food duplicate samples were collected from 296 preschool children in Miyagi prefecture, Japan. Sn in the samples were analyzed by inductively coupled-plasma mass spectrometry, after homogenization and wet digestion. RESULTS: Sn-D by the children was low, with 4.2 MUg/day as a median. The distribution was however wide, from 0.4 MUg/day up to >3 MUg/day. Canned foods were the major dietary Sn source, whereas rice contributed essentially little. Sn-D among canned food consumers was 30.2 MUg/day as a geometric mean (10.6 MUg/day as a median), whereas Sn-D among the non-consumers of canned foods was distributed log normally, with 3.3 MUg/day as a geometric mean (2.5 MUg/day as a median). Sn levels in urine did not differ between children who consumed canned foods on the day previous to urine collection and those who did not. The Sn-D was far below the provisional tolerable weekly intake (14 mg/kg body weight/week) set by the 2001 Joint FAO/WHO Expert Committee. Nevertheless, children took more Sn than adults when compared on a body-weight basis. CONCLUSIONS: Canned foods were the major source of dietary Sn intake for preschool children studied. Thus, median Sn D was higher for the canned food consumers (10.6 MUg/day) than for non-consumers of canned foods (2.5 MUg/day). Sn-D by canned food-consuming children was, however, substantially lower than the provisional tolerable weekly intake. No difference was detected in Sn levels in urine between canned food-consuming and non-consuming children. PMID- 23108580 TI - A detailed investigation on the global minimum structures of mixed rare-gas clusters: geometry, energetics, and site occupancy. AB - We performed a global minimum search of mixed rare-gas clusters by applying an evolutionary algorithm (EA), which was recently proposed for binary atomic systems (Marques and Pereira, Chem. Phys. Lett. 2010, 485, 211). Before being applied to the potentials used in this work, the EA was further tested against results previously reported for the Ar(N)Xe(38-N) clusters and several new putative global minima were discovered. We employed either simple Lennard-Jones (LJ) potentials or more realistic functions to describe pair interactions in Ar(N)Kr(38-N), Ar(N)Xe(38-N), and Kr(N)Xe(38-N) clusters. The long-range tail of the pair-potentials shows some influence on the energetic features and shape of the structure of clusters. In turn, core-shell type structures are mostly observed for global minima of the binary rare-gas clusters, for both accurate and LJ potentials. However, the long-range tail of the potential may have influence on the type of atoms that segregate on the surface or form the core of the cluster. While relevant differences for the preferential site occupancy occur between the two potentials for Ar(N)Kr(38-N) (for N > 21), the type of atoms that segregate on the surface for Ar(N)Xe(38-N) and Kr(N)Xe(38-N) clusters is unaffected by the accuracy of the long-range part of the interaction in almost all cases. Moreover, the global minimum search for model-potentials in binary systems reveals that the surface-site occupancy is mainly determined by the combination of two parameters: the size ratio of the two types of particles forming the cluster and the minimum-energy ratio corresponding to the pair interactions between unlike atoms. PMID- 23108581 TI - N-acetyl-4-aminophenol and musculoskeletal adaptations to resistance exercise training. AB - N-acetyl-4-aminophenol (ACET) may impair musculoskeletal adaptations to progressive resistance exercise training (PRT) by inhibiting exercise-induced muscle protein synthesis and bone formation. To test the hypothesis that ACET would diminish training-induced increases in fat-free mass (FFM) and osteogenesis, untrained men (n = 26) aged >=50 years participated in 16 weeks of high-intensity PRT and bone-loading exercises and were randomly assigned to take ACET (1,000 mg/day) or placebo (PLAC) 2 h before each exercise session. Total body FFM was measured by DXA at baseline and week 16. Serum bone-specific alkaline phosphatase (BAP) and C-terminal crosslinks of type-I collagen (CTX) were measured at baseline and week 16. Vastus lateralis muscle biopsies were performed at baseline and weeks 3 and 16 for prostanoid, anabolic, and catabolic gene expression by RT-PCR. In exercise-compliant men (ACET, n = 10; PLAC, n = 7), the increase in FFM was not different between groups (p = 0.91). The changes in serum BAP and CTX were not different between groups (p > 0.7). There were no significant changes in any of the target genes at week 3. After 16 weeks of PRT, the mRNA expressions of the anabolic marker p70S6K (p = 0.003) and catabolic marker muscle-atrophy F-box (MAFbx) (p = 0.03) were significantly reduced as compared to baseline in ACET. The mRNA expression of the prostanoids were unchanged (all p >= 0.40) in both groups. The administration of ACET (1,000 mg) prior to each exercise session did not impair PRT-induced increases in FFM or significantly alter bone formation markers in middle aged and older men. PMID- 23108582 TI - Shoulder and forearm oxygenation and myoelectric activity in patients with work related muscle pain and healthy subjects. AB - We tested hypotheses of (a) reduced oxygen usage, oxygen recovery, blood flow and oxygen consumption; and (b) increased muscle activity for patients diagnosed with work-related muscle pain (WRMP) in comparison to healthy controls. Oxygenation was measured with near infrared spectroscopy (NIRS), and muscle activity with EMG for the extensor carpi radialis (ECR) and trapezius descendens (TD) muscles. Eighteen patients with diffuse neck-shoulder-arm pain and 17 controls (matched in age and sex) were equipped with NIRS and EMG probes. After determining an individual's maximum voluntary contraction (MVC) force, short-term (20 s) isometric contractions for the ECR and TD of 10, 30, 50 and 70 % MVC generated ?StO2 and StO2% recovery (Rslope) from NIRS, and RMS%max from EMG signals. In addition, upper arm venous (VO) and arterial (AO) occlusions generated slopes of total hemoglobin (HbTslope) and deoxyhemoglobin (HHbslope) for the resting ECR as surrogates of blood flow and oxygen consumption, respectively. Mixed model analyses, t tests, and Mann-Whitney test were used to assess differences between groups. There was no significant difference in MVC between groups for either muscle. Also, ?StO2%, Rslope for either muscle, and ECR-HbTslope were not different between groups, thus our hypotheses of reduced oxygen use, recovery, and blood flow for patients were not confirmed. However, patients had a significantly lower ECR-HHbslope confirming our hypothesis of reduced consumption. Further, there was no difference in RMS%max during contractions meaning that the hypothesis of increased activity for patients was not confirmed. When taking into account the number of NIRS variables studied, differences we found between our patient group and healthy controls (i.e., in forearm oxygen consumption and shoulder oxygen saturation level) may be considered modest. Overall our findings may have been impacted by the fact that our patients and controls were similar in muscle strength, which is in contrast to previous studies. PMID- 23108583 TI - Low-volume exercise training attenuates oxidative stress and neutrophils activation in older adults. AB - The purpose of this study was to investigate the effects of low-volume exercise training (100 min/week) on oxidative stress and neutrophils activation markers in older adults. Twenty-eight older adults (age range 65-78 years) were assigned into control (n = 14) or exercise (n = 14) groups. The exercise program consisted of walking 30-60 min/session, 2 days each week for 12 weeks. Blood samples were taken before starting the sessions (baseline) and when they ended. Fasting plasma and serum oxidative stress and inflammatory markers were measured using commercial kits. Cell surface expression of adhesion molecules on circulating leukocytes (CD66b and CD62L) was determined using flow cytometry. The concentrations of derivatives of reactive oxygen metabolites tended to be lower than the baseline values only in the exercise group (P = 0.05). The biological antioxidant potential, thioredoxin concentrations, and glutathione peroxidase activities significantly increased only in the exercise group (P < 0.05 for all). While CD66b expression tended to decrease only in the exercise group, CD62L expression significantly increased (P < 0.05). Our findings indicate that exercise training below the current recommended level of at least 150 min/week attenuates basal oxidative stress and neutrophil activation in older adults. Thus, our findings may encourage more people to incorporate a small amount of physical activity into their lives. PMID- 23108584 TI - Ventricular and autonomic benefits of exercise training persist after detraining in infarcted rats. AB - We evaluate the effects of detraining (DT, for 1 month) on the left ventricular (LV) remodeling and function, hemodynamic and baroreflex sensitivity (BRS), as well as on mortality rate of infarcted (MI) rats after 3 months of exercise training (ET, 50-70 % of VO2max). Male Wistar rats were divided into five groups: control (C, n = 10), untrained-infarcted (UI, n = 15), trained-infarcted (TI, n = 12), untrained-infarcted plus 1 month (UI-1, n = 15) and detrained-infarcted 1 month (DI-1, n = 15). LV function was evaluated by echocardiography at the initial and final of the protocols. After following, ET and/or DT protocols, hemodynamic and BRS [by tachycardic (TR) and bradycardic (BR) responses] were assessed. TI group displayed increased VO2max in comparison with UI and DI-1 groups; however, DI-1 values remained increased compared to UI-1 group. MI area was reduced by ET and maintained after DT. Ejection fraction (TI = 60 +/- 2 and DI-1 = 61 +/- 2 % vs. UI = 41 +/- 1 and UI-1 = 37 +/- 3 %), E/A ratio (TI = 1.6 +/- 0.1 and DI-1 = 1.9 +/- 0.1 vs. UI = 2.9 +/- 0.2 and UI-1 = 2.9 +/- 0.3), TR (TI = 3.3 +/- 0.3 and DI-1 = 3.3 +/- 0.4 vs. UI = 1.7 +/- 0.1 and UI-1 = 1.6 +/- 0.1 bpm/mmHg) and BR (TI = -2.2 +/- 0.1 and DI-1 = -2.0 +/- 0.1 vs. UI = -1.3 +/- 0.09 and UI-1 = -1.2 +/- 0.09 bpm/mmHg) were improved by ET and maintained after DT in comparison with untrained rats. These changes resulted in mortality reduction in the TI (8 %) and DI-1 groups (13 %) compared with the UI (46 %) and UI-1 (53 %) groups. These findings indicate that ET is not only an effective tool in the management of cardiovascular and autonomic MI derangements, but also that these positive changes were maintained even after 1 month of DT in rats. PMID- 23108586 TI - Trypanosomosis: a priority disease in tsetse-challenged areas of Burkina Faso. AB - Trypanosomosis is an important disease affecting humans as well as animals. It remains a big constraint to livestock productions in tropical areas. The objective of this study was to assess the importance of trypanosomosis among cattle diseases in Burkina Faso, mainly in tsetse-challenged areas, and to capture information on how farmers apply available methods for controlling the disease. A survey has been carried out in 29 villages of Burkina Faso in three regions (north, southwest, and west regions). One hundred and thirty-four cattle breeders were interviewed individually with a questionnaire. The results indicate that among the 16 diseases mentioned by cattle breeders, trypanosomosis is the most important one in tsetse-challenged areas. Overall, 76.12 % of the breeders mentioned it as the most important disease, while 54.55 % of the farmers in the southwest region and 70.91 % of the farmers in the west region ranked it as a priority disease. Chemoprophylaxis/chemotherapy is widely used as a control method. Isometamidium chloride and diminazene aceturate were used by 53.49 and 46.52 % of the responders, respectively. Among farmers, 85.55 % ranked diminazene aceturate as the less efficient while 14.45 % ranked isometamidium chloride as the most efficient trypanocid. Trypanocidal drug quality and drug resistance were raised as a major concern by 30.77 and 50 % of the respondents, respectively. According to them, zebu cattle are more susceptible to trypanosomosis than taurine Baoule cattle and their crosses with zebu, emphasizing that crossing susceptible breeds with trypanotolerant ones, could be used as part of an integrated control strategy. PMID- 23108585 TI - Toll-like receptor 4 is required for alpha-synuclein dependent activation of microglia and astroglia. AB - Alpha-synucleinopathies (ASP) are neurodegenerative disorders, characterized by accumulation of misfolded alpha-synuclein, selective neuronal loss, and extensive gliosis. It is accepted that microgliosis and astrogliosis contribute to the disease progression in ASP. Toll-like receptors (TLRs) are expressed on cells of the innate immune system, including glia, and TLR4 dysregulation may play a role in ASP pathogenesis. In this study we aimed to define the involvement of TLR4 in microglial and astroglial activation induced by different forms of alpha synuclein (full length soluble, fibrillized, and C-terminally truncated). Purified primary wild type (TLR4(+/+)) and TLR4 deficient (TLR4(-/-)) murine microglial and astroglial cell cultures were treated with recombinant alpha synuclein and phagocytic activity, NFkappaB nuclear translocation, cytokine release, and reactive oxygen species (ROS) production were measured. We show that TLR4 mediates alpha-synuclein-induced microglial phagocytic activity, pro inflammatory cytokine release, and ROS production. TLR4(-/-) astroglia present a suppressed pro-inflammatory response and decreased ROS production triggered by alpha-synuclein treatment. However, the uptake of alpha-synuclein by primary astroglia is not dependent on TLR4 expression. Our results indicate the C terminally truncated form as the most potent inductor of TLR4-dependent glial activation. The current findings suggest that TLR4 plays a modulatory role on glial pro-inflammatory responses and ROS production triggered by alpha-synuclein. In contrast to microglia, the uptake of alpha-synuclein by astroglia is not dependent on TLR4. Our data provide novel insights into the mechanisms of alpha synuclein-induced microglial and astroglial activation which may have an impact on understanding the pathogenesis of ASP. PMID- 23108587 TI - Evaluation of Petrifilms(TM) as a diagnostic test to detect bovine mastitis organisms in Kenya. AB - The study purpose was to validate Petrifilms(TM) (3M Microbiology, 2005) against standard culture methods in the diagnosis of bovine mastitis organisms in Kenya. On 128 smallholder dairy cattle farms in Kenya, between June 21, 2010 and August 31, 2010, milk samples from 269 cows that were positive on California Mastitis Test (CMT) were cultured using standard laboratory culture methods and Petrifilms(TM) (Aerobic Count and Coliform Count -3M Microbiology, 2005), and results were compared. Staphylococcus aureus was the most common bacterium isolated (73 % of samples). Clinical mastitis was found in only three cows, and there were only two Gram-negative isolates, making it impossible to examine the agreement between the two tests for Gram-negative- or clinical mastitis samples. The observed agreement between the standard culture and Petrifilm(TM) (3M Microbiology, 2005) results for Gram-positive isolates was 85 %, and there was fair agreement beyond that expected due to chance alone, with a kappa (kappa) of 0.38. Using culture results as a gold standard, the Petrifilms(TM) had a sensitivity of 90 % for Gram-positive samples and specificity of 51 %. With 87 % of CMT-positive samples resulting in Gram-positive pathogens cultured, there was a positive predictive value of 93 % and a negative predictive value of 43 %. Petrifilms(TM) should be considered for culture of mastitis organisms in developing countries, especially when Gram-positive bacteria are expected. PMID- 23108588 TI - Body mass index in 1.2 million adolescents and risk for end-stage renal disease. AB - BACKGROUND: The relationship between adolescent body mass index (BMI) and future risk for end-stage renal disease (ESRD) is not fully understood, nor is it known the extent to which this association is limited to diabetic ESRD. We evaluated the association between BMI in adolescence and the risk for all-cause, diabetic, and nondiabetic ESRD. METHODS: Medical data about 1 194 704 adolescents aged 17 years who had been examined for fitness for military service between January 1, 1967, and December 31, 1997, were linked to the Israeli ESRD registry in this nationwide population-based retrospective cohort study. Incident cases of treated ESRD between January 1, 1980, and May 31, 2010, were included. Cox proportional hazards models were used to estimate the hazard ratio (HR) for treated ESRD among study participants for their BMI at age 17 years, defined in accord with the US Centers for Disease Control and Prevention BMI for age and sex classification. RESULTS: During 30 478 675 follow-up person-years (mean [SD], 25.51 [8.77] person years), 874 participants (713 male and 161 female) developed treated ESRD, for an overall incidence rate of 2.87 cases per 100 000 person-years. Compared with adolescents of normal weight, overweight adolescents (85th to 95th percentiles of BMI) and obese adolescents (>=95th percentile of BMI) had an increased future risk for treated ESRD, with incidence rates of 6.08 and 13.40 cases per 100 000 person-years, respectively. In a multivariate model adjusted for sex, country of origin, systolic blood pressure, and period of enrollment in the study, overweight was associated with an HR of 3.00 (95% CI, 2.50-3.60) and obesity with an HR of 6.89 (95% CI, 5.52-8.59) for all-cause treated ESRD. Overweight (HR, 5.96; 95% CI, 4.41-8.06) and obesity (HR, 19.37; 95% CI, 14.13-26.55) were strong and independent risk factors for diabetic ESRD. Positive associations of overweight (HR, 2.17; 95% CI, 1.71-2.74) and obesity (HR, 3.41; 95% CI, 2.42 4.79) with nondiabetic ESRD were also documented. CONCLUSIONS: Overweight and obesity in adolescents were associated with significantly increased risk for all cause treated ESRD during a 25-year period. Elevated BMI constitutes a substantial risk factor for diabetic and nondiabetic ESRD. PMID- 23108589 TI - Regulation of amantadine hydrochloride binding with IIA subdomain of human serum albumin by fatty acid chains. AB - Human serum albumin (HSA) is a major protein component of blood plasma that has been exploited to bind and transport a wide variety of endogenous and exogenous organic compounds. Although anionic drugs readily associate with the IIA subdomain of HSA, most cationic drugs poorly associate with HSA at this subdomain. In this study, we propose to improve the association between cationic drugs and HSA by modifying HSA with fatty acid chains. For our experiments, we tested amantadine hydrochloride, a cationic drug with antiviral and antiparkinsonian effects. Our results suggest that extensive myristoylation of HSA can help stabilize the interaction between amantadine and HSA in vitro. Our X ray crystallography data further elucidate the structural basis of this regulation. Additionally, our crystallography data suggest that anionic drugs, with a functional carboxylate group, may enhance the association between amantadine and HSA by a mechanism similar to myristoylation. Ultimately, our results provide critical structural insight into this novel association between cationic drugs and the HSA IIA subdomain, raising the tempting possibility to fully exploit the unique binding capacity of HSA's IIA subdomain to achieve simultaneous delivery of anionic and cationic drugs. PMID- 23108590 TI - Identification of soluble CD146 as a regulator of trophoblast migration: potential role in placental vascular development. AB - Both vasculogenesis and angiogenesis occur during normal placental vascular development. Additionally, the placenta undergoes a process of vascular mimicry (pseudo-vasculogenesis) where the placental extravillous trophoblast (EVT) that invade the spiral arteries convert from an epithelial to an endothelial phenotype during normal pregnancy. As soluble CD146 (sCD146) constitutes a new physiological factor with angiogenic properties, we hypothesized that it could be involved in the regulation of placental vascular development by acting on EVT. Using placental villous explants, we demonstrated that sCD146 inhibits EVT outgrowth. Consistently, we showed that sCD146 inhibits the ability of EVT cells (HTR8/SVneo) to migrate, invade and form tubes in Matrigel, without affecting their proliferation or apoptosis. The involvement of sCD146 in human pregnancy was investigated by evaluation of sCD146 levels in 50 pregnant women. We observed physiological down-regulation of sCD146 throughout pregnancy. These results prompted us to investigate the effect of prolonged sCD146 administration in a rat model of pregnancy. Repeated systemic sCD146 injections after coupling caused a significant decrease of pregnancy rate and number of embryos. Histological studies performed on placenta evidenced a reduced migration of glycogen cells (analogous to EVT in rat) in sCD146-treated rats. We propose that in human, sCD146 could represent both an attractive biomarker of placental vascular development and a therapeutic target in pregnancy complications associated with pathological angiogenesis. PMID- 23108591 TI - High DLL4 expression in tumour-associated vessels predicts for favorable radiotherapy outcome in locally advanced squamous cell head-neck cancer (HNSCC). AB - INTRODUCTION: Expression of the DLL4 (a notch pathway ligand) by tumor-associated endothelium is a postulated marker of vascular maturity and functionality. As vascular functionality is an important parameter defining chemotherapy and oxygen intra-tumoral distribution, we investigated the role of DLL4 expression in tumour vasculature in the efficacy of radio-chemotherapy for HNSCC patients. MATERIALS AND METHODS: Sixty-five biopsy specimens from HNSCC patients with inoperable disease were immunohistochemically examined using anti-CD31 (pan-endothelial cell marker) and anti-DLL4 antibodies and the vascular density (VD) was recorded. Patients were treated with platinum based hypofractionated accelerated conformal radiotherapy. The median follow-up period was 24 months (4-80 months). RESULTS: Using the 33rd and 66th percentiles cases were grouped in three categories of low, medium and high CD31+ or DLL4+ VD. The percentage of vessels expressing DLL4 (DLL4-ratio) ranged from 17 to 100 % (mean 71 %), showing substantial variation among cases. In accordance with previous published studies, a biphasic pattern of association of CD31+ VD with poor outcome was noted. Cases with a medium VD had a significantly better local relapse free survival (LRFS) compared to cases of high VD (p = 0.0005, HR 0.15) and of low VD (p = 0.02, HR 0.28). High DLL4/CD31 ratio defined improved LRFS in both these subgroups of poor prognosis. CONCLUSIONS: The expression of DLL4 is associated with reduced radio-resistance, presumably by reducing hypoxia and improving chemotherapy accessibility. Using the combination of CD31 and DLL4 staining, a classification is suggested so that HNSCCs are categorized in sub-groups to be targeted by different anti-angiogenic and hypoxia targeting agents. PMID- 23108592 TI - An empirical study on the matrix-based protein representations and their combination with sequence-based approaches. AB - Many domains have a stake in the development of reliable systems for automatic protein classification. Of particular interest in recent studies of automatic protein classification is the exploration of new methods for extracting features from a protein that enhance classification for specific problems. These methods have proven very useful in one or two domains, but they have failed to generalize well across several domains (i.e. classification problems). In this paper, we evaluate several feature extraction approaches for representing proteins with the aim of sequence-based protein classification. Several protein representations are evaluated, those starting from: the position specific scoring matrix (PSSM) of the proteins; the amino-acid sequence; a matrix representation of the protein, of dimension (length of the protein) *20, obtained using the substitution matrices for representing each amino-acid as a vector. A valuable result is that a texture descriptor can be extracted from the PSSM protein representation which improves the performance of standard descriptors based on the PSSM representation. Experimentally, we develop our systems by comparing several protein descriptors on nine different datasets. Each descriptor is used to train a support vector machine (SVM) or an ensemble of SVM. Although different stand-alone descriptors work well on some datasets (but not on others), we have discovered that fusion among classifiers trained using different descriptors obtains a good performance across all the tested datasets. Matlab code/Datasets used in the proposed paper are available at http://www.bias.csr.unibo.it?nanni?PSSM.rar. PMID- 23108594 TI - Experiential avoidance mediates the association between thought suppression and mindfulness with problem gambling. AB - Experiential avoidance (EA) has been shown to be an important etiological and maintenance factor in a wide range psychopathology that includes addictive, anxiety, depressive and impulse control disorders. One common form of EA is thought suppression. Problem gambling causes enormous problems for afflicted individuals and has major social costs for their families and the community. Despite increasing interest in the contribution of EA to a broad range of psychological problems, its association with problem gambling has not previously been empirically investigated. The purpose of this cross-sectional study was to investigate the relationship between EA, thought suppression, and mindfulness among a group of 103 treatment seeking problem gamblers. Of particular interest was the extent to which EA accounted for the relationships between problem gambling and the two theoretically opposing constructs: thought suppression and mindfulness. Results showed EA was predictive of problem gambling. Thought suppression was positively associated and mindfulness negatively associated with problem gambling, and these relationships were mediated by EA. Directions for future research are suggested which include the application of treatments for problem gambling that undermine EA, such as acceptance and mindfulness based therapies. PMID- 23108595 TI - Dose-dependent effects of a genistein-enriched diet in the heart of ovariectomized mice. AB - The isoflavone genistein is used as a pharmacological compound and as a food supplement. The duration and the level of exposure of humans to genistein are considerable. However, the magnitude of genistein-supplemented dietary interventions necessary to induce any changes in the heart has not been studied so far. The aim of this study was to investigate the dose-dependent effects of dietary genistein in the disease- and stress-free mouse heart. Female C57BL/6J mice at the age of 2 months were ovariectomized and randomly assigned to feed on diets with seven different genistein doses (0.01, 0.03, 0.1, 0.3, 1, 3 and 10 g genistein/kg food) for 3 months. Mice with intact ovaries or ovariectomized fed on soy-free diets were used as controls. Ovariectomy led to an increase in body weight, while the two highest genistein doses prevented this increase. Absolute uterus weight was decreased in the ovariectomized group and all genistein groups except for the 10 g/kg food group compared with the intact ovaries/soy-free group. Considering cardiac mass, although the 3 and 10 g/kg food groups had significantly lower absolute heart weight than all other groups, heart-to-body weight ratios did not differ between these two groups and the intact ovaries/soy free group, while all remaining groups had smaller ratios. Next, we observed dose dependent effects of genistein on cardiac gene expression. The present findings indicate that exposure of female mice to the soy isoflavone genistein influences body weight and cardiac mass and gene expression in a dose-dependent manner. Human exposure to dietary genistein supplements may influence cardiac function. PMID- 23108593 TI - Cationic membrane peptides: atomic-level insight of structure-activity relationships from solid-state NMR. AB - Many membrane-active peptides, such as cationic cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs), conduct their biological functions by interacting with the cell membrane. The interactions of charged residues with lipids and water facilitate membrane insertion, translocation or disruption of these highly hydrophobic species. In this review, we will summarize high resolution structural and dynamic findings towards the understanding of the structure-activity relationship of lipid membrane-bound CPPs and AMPs, as examples of the current development of solid-state NMR (SSNMR) techniques for studying membrane peptides. We will present the most recent atomic-resolution structure of the guanidinium-phosphate complex, as constrained from experimentally measured site-specific distances. These SSNMR results will be valuable specifically for understanding the intracellular translocation pathway of CPPs and antimicrobial mechanism of AMPs, and more generally broaden our insight into how cationic macromolecules interact with and cross the lipid membrane. PMID- 23108596 TI - Hollow-core magnetic colloidal nanocrystal clusters with ligand-exchanged surface modification as delivery vehicles for targeted and stimuli-responsive drug release. AB - The fabrication of hierarchical magnetic nanomaterials with well-defined structure, high magnetic response, excellent colloidal stability, and biocompatibility is highly sought after for drug-delivery systems. Herein, a new kind of hollow-core magnetic colloidal nanocrystal cluster (HMCNC) with porous shell and tunable hollow chamber is synthesized by a one-pot solvothermal process. Its novelty lies in the "tunability" of the hollow chamber and of the pore structure within the shell through controlled feeding of sodium citrate and water, respectively. Furthermore, by using the ligand-exchange method, folate modified poly(acrylic acid) was immobilized on the surface of HMCNCs to create folate-targeted HMCNCs (folate-HMCNCs), which endowed them with excellent colloidal stability, pH sensitivity, and, more importantly, folate receptor targeting ability. These assemblages exhibited excellent colloidal stability in plasma solution. Doxorubicin (DOX), as a model anticancer agent, was loaded within the hollow core of these folate-HMCNCs (folate-HMCNCs-DOX), and drug release experiments proved that the folate-HMCNCs-DOX demonstrated pH-dependent release behavior. The folate-HMCNCs-DOX assemblages also exhibited higher potent cytotoxicity to HeLa cells than free doxorubicin. Moreover, folate-HMCNCs-DOX showed rapid cell uptake apart from the enhanced cytotoxicity to HeLa cells. Experimental results confirmed that the synthesized folate-HMCNCs are smart nanovehicles as a result of their improved folate receptor-targeting abilities and also because of their combined pH- and magnetic-stimuli response for applications in drug delivery. PMID- 23108598 TI - Gemcitabine alone and/or containing chemotherapy is efficient in refractory or relapsed NK/T-cell lymphoma. AB - Extranodal natural killer/T-cell lymphoma (ENKL) has a dismal prognosis. Although L-asparaginase has shown promising efficacy as a frontline therapy, currently there are no treatment options after progression to an L-asparaginase-containing regimen. We report the results of gemcitabine-containing therapy in patients with relapsed or refractory ENKL. We retrospectively reviewed 20 patients with refractory or relapsed ENKL who received a gemcitabine-containing regimen between 2005 and 2011. The overall response rate was 40% (8 of 20 patients) with a complete response (CR) rate of 20% (n = 4) and a partial response (PR) rate of 20% (n = 4). Four complete responders had a disease-free status for more than 7 months including two patients received autologous stem cell transplantation consolidation and L-aspraginase maintenance, respectively. The median progression free survival of the 20 patients was 2.3 months; however, it was 7.3 months for eight responders (CR and PR). The median overall survival of the eight responders had not been reached at the time of analysis. Gemcitabine was effective in a subset of pretreated ENKL patients and can be considered as a salvage option. PMID- 23108599 TI - Analysis of atmospheric dispersion factors for building wakes at the Wolsung nuclear site in Korea. AB - The characteristics of atmospheric dispersion considering the building effects in the Wolsung nuclear site in Korea were studied using ISC-PRIME and ARCON96 models. The maximum 2-h average atmospheric dispersion factor (ADF) was six times larger when the building geometry was considered in ISC-PRIME and two times larger in the exclusion area boundary. Owing to different adjustments for wind speed by the stability class, the ADFs calculated using ARCON96 were smaller than those calculated using ISC-PRIME. Strategies for locating buildings need to be considered to maximise dispersion when planning for constructing several reactors and accessory buildings at the Wolsung nuclear site. PMID- 23108601 TI - Hydrogen adsorption on and spillover from Au- and Cu-supported Pt3 and Pd3 clusters: a density functional study. AB - Motivated by the use of electrodes modified at the nanoscale by supported metal species, we studied computationally how the reactivity changes in such a composite system compared to the reactivity of the individual systems, metal clusters and metal surfaces. Specifically, we examined hydrogen adsorption on and hydrogen spillover from Au- and Cu-supported Pt(3) and Pd(3) clusters, using a method based on Density Functional Theory. Two distinctive types of sites were found for the adsorption of atomic hydrogen: (i) on the supported clusters and (ii) at the cluster-substrate interfaces. The adsorption energy of hydrogen on the supported clusters is ~20 kJ mol(-1) smaller when the cluster is supported by Cu instead of Au. In contrast, the substrate has no effect on hydrogen adsorbed at the cluster-substrate interfaces. Adsorbed Pt(3) and Pd(3) clusters locally modify the reactivity of the substrates as quantified by the reduced adsorption energy of hydrogen compared to the corresponding clean substrate. Hydrogen dissociative adsorption followed by spillover is thermodynamically and kinetically favored for clusters supported on a Cu surface, but not on Au. Moreover, spillover of hydrogen is more likely from metal-supported Pd than Pt clusters as revealed by barriers that are calculated 40-50 kJ mol(-1) lower in energy. PMID- 23108602 TI - Use of off-label and unlicensed drugs in the neonatal intensive care unit and its association with severity scores. AB - OBJECTIVE: To analyze the frequency of unlicensed (UL) and off-label (OL) prescriptions in neonates admitted to the neonatal intensive care unit of a tertiary care hospital and to determine their association with patients' severity. METHODS: Observational cohort study including drugs prescribed during hospitalization of neonates over a 6-week period between July and August 2011. The drugs were classified as UL and OL for dose, frequency, presentation, age group, or indication, according to an electronic list of drugs approved by the Food and Drug Administration. Patients were followed until hospital discharge or 31 days of hospitalization, with daily records of the Neonatal Therapeutic Intervention Scoring System (NTISS). RESULTS: We identified 318 prescription items for 61 patients (average of five items/patient); there were only 13 patients with appropriate use of medications (21%). A prevalence of 7.5% was identified for UL prescriptions and 27.7% for OL, and the most prevalent OL use was that related to age group - 19.5%. Fifty-seven medications were computed - one patient received 10 UL/OL drugs during hospitalization. The prevalence of OL uses was higher in preterm infants < 35 weeks and in those with higher severity scores (p = 0.00). CONCLUSIONS: The prevalence of neonates exposed to UL/OL drugs during hospitalization was high, especially for those with higher NTISS scores. Although there is general appreciation that neonates, especially preterm infants, have a high rate of drug use, an assessment including different cultures and countries is still needed to prioritize areas for future research in the pharmacotherapy of this vulnerable population. PMID- 23108603 TI - Epithelial toxicity of alkylglycoside surfactants. AB - Alkylglycoside surfactants have been proposed as drug delivery excipients with the potential to enhance mucosal drug absorption of therapeutic macromolecules. Previous work reported their drug absorption-promoting potential by demonstrating that several compounds within this class of surfactants improve mucosal absorption of peptides, proteins and other macromolecules. However, detailed investigation of their toxicity has not been conducted. Using Calu-3 epithelial cell layers as a model of the airway mucosa, and liposomes as models of cell membranes, this work investigates the cytotoxicity of dodecylmaltoside, tridecylmaltoside and tetradecylmaltoside, as representative alkylglycosides. A combination of different toxicity assays and other tests indicating cell membrane disruption were used to assess cytotoxicity. The alkylglycosides tested induced a dramatic reduction in cell viability, cell membrane and liposome-disruptive effects, as well as abrogation of transepithelial electrical resistance that did not recover completely. Importantly, these phenomena were noted at concentrations markedly lower than those typically used in the literature studies demonstrating the absorption-enhancing properties of alkylglycosides. This work therefore demonstrates that alkylglycosides exhibit significant toxicity towards airway epithelial cells, most likely resulting from a membrane-damaging effect, highlighting a need for further evaluation of their safety as absorption enhancing excipients. PMID- 23108605 TI - Insights into the dynamics of evaporation and proton migration in protonated water clusters from large-scale Born-Oppenheimer direct dynamics. AB - Large-scale on-the-fly Born-Oppenheimer molecular dynamics simulations using recent advances in linear scaling electronic structure theory and trajectory integration techniques have been performed for protonated water clusters around the magic number (H(2)O)(n)H(+) , for n = 20 and 21. Besides demonstrating the feasibility and efficiency of the computational approach, the calculations reveal interesting dynamical details. Elimination of water molecules is found to be fast for both cluster sizes but rather insensitive to the initial geometry. The water molecules released acquire velocities compatible with thermal energies. The proton solvation shell changes between the well-known Eigen and Zundel motifs and is characterized by specific low-frequency vibrational modes, which have been quantified. The proton transfer mechanism largely resembles that of bulk water but one interesting variation was observed. PMID- 23108604 TI - Urodynamic effects of the combination of tamsulosin and daily tadalafil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia: a randomized, placebo-controlled clinical trial. AB - OBJECTIVES: To evaluate the effect of association of tamsulosin/tadalafil taken daily compared with tamsulosin/placebo in the lower urinary tract with urodynamic study (UDS). METHODS: All patients underwent baseline UDS before randomization to tamsulosin 0.4 mg/tadalafil 5 mg (Group 1; n = 20) or tamsulosin 0.4 mg/placebo (Group 2; n = 20) once daily for 30 days. End-of-study UDS were performed on completion of the treatment period. The primary end point was to demonstrate changes in urodynamic variables in the voiding phase, detrusor pressure at maximum flow (PdetQmax), and maximum flow rate (Qmax), from baseline to week four. RESULTS: The primary outcome measure of this clinical trial, PdetQmax, showed a significant reduction in tamsulosin/tadalafil group (13 +/- 17.0) compared to tamsulosin/placebo (-1.2 +/- 14.35) group (P = 0.03). Qmax increased in both groups, tamsulosin/tadalafil (1.0 +/- 2.4) and tamsulosin/placebo (1.4 +/ 2.4), but the difference was not significant between treatment groups (P = 0.65). Total IPSS, storage, and voiding sub-score improved significantly in tamsulosin/tadalafil compared with tamsulosin/placebo group. CONCLUSIONS: The association of tamsulosin/tadalafil reduces detrusor pressure at maximum flow without changing the maximum flow rate during micturition and significantly improves lower urinary tract symptoms compared with the isolated use of tamsulosin. PMID- 23108606 TI - Synthesis and chiral recognition of nickel(II) macrocyclic complex with (R) naphthylethyleneamine pendant groups and its self-assembled framework. AB - A novel nickel(II) hexaaza macrocyclic complex, [Ni(L(R,R))](ClO(4))(2) (1), containing chiral pendant groups was synthesized by an efficient one-pot template condensation and characterized (L(R,R) ?1,8-di((R)-alpha-methylnaphthyl) 1,3,6,8,10,13-hexaazacyclotetradecane). The crystal structure of compound 1 was determined by single-crystal X-ray analysis. The complex was found to have a square-planar coordination environment for the nickel(II) ion. Open framework [Ni(L(R,R))](3) [C(6)H(3)(COO)(3)](2) (2) was constructed from the self-assembly of compound 1 with deprotonated 1,3,5-benzenetricarboxylic acid, BTC(3-). Chiral discrimination of rac-1,1'-bi-2-naphthol and rac-2,2,2-trifluoro-1-(9 anthryl)ethanol was performed to determine the chiral recognition ability of the chiral complex (1) and its self-assembled framework (2). Binaphthol showed a good chiral discrimination on the framework (2). The optimum experimental conditions for the chiral discrimination were examined by changing the weight ratio between the macrocyclic complex 1 or self-assembled framework 2 and racemates. The detailed synthetic procedures, spectroscopic data including single-crystal X-ray analysis, and the results of the chiral recognition for the compounds are described. PMID- 23108607 TI - Not all G-quadruplexes are created equally: an investigation of the structural polymorphism of the c-Myc G-quadruplex-forming sequence and its interaction with the porphyrin TMPyP4. AB - G-quadruplexes, DNA tertiary structures highly localized to functionally important sites within the human genome, have emerged as important new drug targets. The putative G-quadruplex-forming sequence (Pu27) in the NHE-III(1) promoter region of the c-Myc gene is of particular interest as stabilization of this G-quadruplex with TMPyP4 has been shown to repress c-Myc transcription. In this study, we examine the Pu27 G-quadruplex-forming sequence and its interaction with TMPyP4. We report that the Pu27 sequence exists as a heterogeneous mixture of monomeric and higher-order G-quadruplex species in vitro and that this mixture can be partially resolved by size exclusion chromatography (SEC) separation. Within this ensemble of configurations, the equilibrium can be altered by modifying the buffer composition, annealing procedure, and dialysis protocol thereby affecting the distribution of G-quadruplex species formed. TMPyP4 was found to bind preferentially to higher-order G-quadruplex species suggesting the possibility of stabilization of the junctions of the c-Myc G-quadruplex multimers by porphyrin end-stacking. We also examined four modified c-Myc sequences that have been previously reported and found a narrower distribution of G-quadruplex configurations compared to the parent Pu27 sequence. We could not definitively conclude whether these G-quadruplex structures were selected from the original ensemble or if they are new G-quadruplex structures. Since these sequences differ considerably from the wild-type promoter sequence, it is unclear whether their structures have any actual biological relevance. Additional studies are needed to examine how the polymorphic nature of G-quadruplexes affects the interpretation of in vitro data for c-Myc and other G-quadruplexes. The findings reported here demonstrate that experimental conditions contribute significantly to G-quadruplex formation and should be carefully considered, controlled, and reported in detail. PMID- 23108609 TI - Fatal strongyloidiasis in an immunocompromised HTLV-I infected patient. PMID- 23108608 TI - Prophylactic protective ventilation: lower tidal volumes for all critically ill patients? AB - High tidal volumes have historically been recommended for mechanically ventilated patients during general anesthesia. High tidal volumes have been shown to increase morbidity and mortality in patients suffering from acute respiratory distress syndrome (ARDS). Barriers exist in implementing a tidal volume reduction strategy related to the inherent difficulty in changing one's practice patterns, to the current need to individualize low tidal volume settings only for a specific subgroup of mechanically ventilated patients (i.e., ARDS patients), the difficulty in determining the predicated body weight (requiring the patient's height and a complex formula). Consequently, a protective ventilation strategy is often under-utilized as a therapeutic option, even in ARDS. Recent data supports the generalization of this strategy prophylactically to almost all mechanically ventilated patients beginning immediately following intubation. Using tools to rapidly and reliably determine the predicted body weight (PBW), as well as the use of automated modes of ventilation are some of the potential solutions to facilitate the practice of protective ventilation and to finally ventilate our patients' lungs in a more gentle fashion to help prevent ARDS. PMID- 23108610 TI - The skinny on obesity and end-stage renal disease. PMID- 23108612 TI - An overview of lectins purification strategies. AB - Lectins hold great promise not only as reagents for diagnostics and drug discovery but also as a novel class of biopharmaceutical products. In fact, new research directions in the last years have led to major developments in the uses of plant lectins as therapeutic agents against numerous diseases in an ageing society. It is even expected that lectins may occupy an important place in the biopharmaceutical industry next to monoclonal antibodies. All these new trends are placing a tremendous emphasis on the development of new approaches for faster lectins development, selection, and optimization, including alternatives methods of purification. This article reviews the isolation and purification methods used for lectins purification. Origins and applications of lectins are described, highlighting the special features of this class of proteins, such as the carbohydrated-binding domains and their importance in the development of affinity methodologies to increase and facilitate lectins purification. Published strategies for the purification of lectins from different sources are analyzed in relation to the purification methods used, their sequence, and the number of times they are used in a purification procedure. The purity of lectins is analyzed in relation to the average overall yield and purification factors obtained for each purification scheme for these proteins and the purification steps necessary. New directions are described for improving lectins separation and purification. PMID- 23108613 TI - Study of catalase adsorption on two mixed-mode ligands and the mechanism involved therein. AB - Mixed-mode chromatography sorbents n-hexylamine HyperCelTM (HEA) and phenylpropylamine HyperCelTM (PPA) were evaluated for the study of adsorption of catalase from two different sources. Various parameters such as buffer composition, ionic strength and pH were investigated to study the mechanism of interaction of commercially available pre-purified catalase from Bovine liver, purified catalase from black gram (Vigna mungo) and crude extract of black gram containing catalase with these mixed-mode ligands. A simple and economical screening protocol for identifying optimal buffer conditions for adsorption and desorption of catalase was established with micro volumes of the sorbent in batch mode. With HEA HyperCel, it was observed that pre-purified catalase from both bovine liver and black gram was completely retained at pH 7.0, irrespective of the presence or absence of NaCl in the adsorption buffer, whereas the catalase from crude extract of black gram was completely retained only in the presence of 0.2 M salt in the adsorption buffer. The elution of catalase from both the sources was accomplished by lowering the pH to 4.5 in absence of salt. In case of PPA HyperCel, catalase from both the sources was very strongly adsorbed under different buffer conditions studied, and elution did not yield a significant catalase activity. From the screening experiments, it could be concluded that the interaction of catalase with HEA HyperCel could be dominated by hydrophobic forces with minor contributions from ionic interaction and with PPA HyperCel, it could be a combination of different non-covalent interactions acting on different loci on the surface of the protein. PMID- 23108614 TI - Purification of urease from jack bean (Canavalia ensiformis) with copper (II) chelated poly(hydroxyethyl methacrylate-N-methacryloyl-(L)-histidine methyl ester) cryogels. AB - Jack bean (Canavalia ensiformis) is the source of interesting proteins that contribute to modern biochemistry, and urease is the primary of these proteins. Owing to its role and occurrence in nature, urease has become a part of extensive studies. In this study, jack bean urease (JBU) was purified by immobilized metal affinity chromatography using Cu(2+) chelated poly(hydroxyethyl methacrylate-N methacryloyl-(L)-histidine methyl ester) [PHEMAH-Cu(2+)]-based cryogels. PHEMAH Cu(2+) cryogel was synthesized and characterized for swelling degree, morphology (by SEM), N-methacryloyl-(L)-histidine methyl ester and Cu(2+) incorporation (by elemental analysis and atomic absorption spectrophotometry). The binding of JBU to PHEMAH-Cu(2+) cryogel was optimized by examining the effect of pH, flow rate and JBU concentration on binding. The maximal binding of JBU was 23.2 mg/dry gram of adsorbent. The maximal binding of JBU extracted from jack bean meal was 67.8 mg/dry gram of adsorbent. The elution of JBU from cryogel column was accomplished by 1.0 M NaCl in 20 mM phosphate buffer (pH 8.0). Molecular weight and purity of JBU from jack bean meal was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. It was observed that JBU could be repeatedly bound and eluted from (PHEMAH)-Cu(2+) cryogel with less than 10% loss in column capacity. PMID- 23108615 TI - Molecularly imprinted composite cryogel for albumin depletion from human serum. AB - A new composite protein-imprinted macroporous cryogel was prepared for depletion of albumin from human serum prior to use in proteom applications. Polyhydroxyethyl-methacylate-based molecularly imprinted polymer (MIP) composite cryogel was prepared with high gel fraction yields up to 83%, and its morphology and porosity were characterized by Fourier transform infrared, scanning electron microscopy, swelling studies, flow dynamics, and surface area measurements. Selective binding experiments were performed in the presence of competitive proteins human transferrin (HTR) and myoglobin (MYB). MIP composite cryogel exhibited a high binding capacity and selectivity for human serum albumin (HSA) in the presence of HTR and MYB. The competitive adsorption amount for HSA in MIP composite cryogel is 722.1 mg/dL in the presence of competitive proteins (HTR and MYB). MIP composite cryogel column was successfully applied in the fast protein liquid chromatography system for selective depletion of albumin in human serum. The depletion ratio was highly increased by embedding beads into cryogel (85%). Finally, MIP composite cryogel can be reused many times with no apparent decrease in HSA adsorption capacity. PMID- 23108616 TI - Engineering Candida albicans glucosamine-6-phosphate synthase for efficient enzyme purification. AB - Rationally designed muteins of Candida albicans glucosamine-6-phosphate synthase, an enzyme known as a promising target for antifungal chemotherapy, were constructed, overexpressed in Escherichia coli and purified to near homogeneity. To facilitate and to optimize the purification of the enzyme, three recombinant versions containing internal oligoHis fragments were constructed: (i) by substituting residues 343-348 of the interdomain undecapeptide linker with hexaHis, (ii) by replacing solvent-exposed residues 655-660 of the isomerase domain with hexaHis, and (iii) by replacing amino acids at positions 568 and 569 with His residues to generate the three-dimensional hexaHis microdomain in the enzyme quaternary structure. The resulting constructs were effectively purified to near homogeneity by rapid, one-step immobilized metal-ion affinity chromatography and demonstrated activity and catalytic properties comparable with that of the wild-type enzyme. The construct containing the 655-660 hexaHis insert was found to be a homodimeric protein, which is the first reported example of such quaternary structure of glucosamine-6-phosphate synthase of eukaryotic origin. PMID- 23108617 TI - Elution relationships to model affinity chromatography using a general rate model. AB - Different mathematical models with different degrees of complexity have been proposed to model affinity chromatography. In this work, in particular, a general rate model has been studied that considers axial dispersion, external film mass transfer, intraparticle diffusion, and kinetic effects investigating the influence in the simulations of two different relationships between the properties of the mobile phase and the affinity of different proteins to the ligand bound to the matrix. Two systems were used: Blue Sepharose and Protein A. With Blue Sepharose, an increasing linear salt gradient was used, and with Protein A, a decreasing semi-linear pH gradient. The kinetic parameters obtained in each of the two elution (adsorption/desorption) relationships studied (a power law type and an exponential type) led to very good agreements between experimental and simulated elution curves of mixtures of proteins finding that for more symmetrical peaks, the preferred elution relationship should be the exponential one, in contrast to the more asymmetrical peaks which shapes are better simulated by the power law relationship. PMID- 23108618 TI - High-affinity water-soluble system for efficient naringinase immobilization in polyvinyl alcohol-dimethyl sulfoxide lens-shaped particles. AB - Polyvinyl alcohol (PVA) is a water-soluble, biocompatible and biodegradable synthetic polymer whose application in the immobilization of biological agents for use in biocatalysis has shown promising results. This study aimed to investigate and optimize the immobilization of naringinase from Penicillium decumbens in PVA networks, targeting for the hydrolysis of naringin. Variables such as the most suitable cross-linker, catalyst, inorganic salt, co-solvents and solidification process were identified as key issues for PVA-based methods to form lens-shaped particles, while retaining high enzyme activity and stability. Major improvements were established for better and more reproducible immobilization conditions, namely, by designing a new immobilization apparatus to produce uniform lens-shaped particles. The common problems of PVA-based entrapment were significantly mitigated, through the use of selected cross linker, glutaraldehyde (GA), and co-solvent, dimethyl sulfoxide (DMSO), which decreased the toxicity of the immobilization process and allowed the control of membrane porosity, respectively. The relevance of DMSO and GA and their interaction and effect on the swelling ratio, encapsulation efficiency and residual activity of PVA biocatalysts were established. The immobilization of naringinase in PVA under a DMSO concentration of 60%, cross-linked with 1% GA, and particle lens size of 3.5-4.0 mm, width of 100-300 um and average particle volume of 12.5 +/- 0.92 uL, allowed an encapsulation efficiency of 98.6% and an average residual activity of 87% +/- 3.6%. The kinetic characterization of the immobilized naringinase showed no changes in pH profile, whereas hydrolytic activity increased up to 60 degrees C. Immobilization in PVA/DMSO/GA lens-shaped particles enhanced the storage stability of naringinase. Moreover, these naringinase bio-immobilizates retained a conversion rate higher than 78% after 23 runs. PMID- 23108619 TI - Hesperidinase encapsulation towards hesperitin production targeting improved bioavailability. AB - Hesperidin (hesperitin-7-O-rutinoside) and hesperitin (hesperitin-7-O-glucoside) show anti-inflammatory, antimicrobial, antioxidant, and anticarcinogenic effects and prevent bone loss. However, hesperidin has a low bioavailability compared to hesperitin due to the rutinoside moiety attached to the flavonoid. The removal of the rhamnose group to yield the corresponding flavonoid glucoside (hesperetin-7 glucoside) improved the bioavailability of the aglycone, hesperetin, in humans. In line with these assumptions, the aim of this work was the enzymatic production of hesperitin from hesperidin with hesperidinase. Despite the low hesperidin solubility in the reaction medium, the enzymatic bioconversion was carried with hesperidin soluble at lower concentrations (<=0.05 mg ml(-1)) and insoluble for high concentrations (>0.1-50 mg ml(-1)). A twofold increase in maximum reaction rates overtook the expected values, pointing to the enzyme ability to degrade insoluble hesperidin. To improve the bioprocess, hesperidinase was tested soluble and immobilized in calcium alginate (2%), k-carrageenan (2%), and chitosan (2%) beads. The immobilization was carried out by adsorption and encapsulation. Chitosan was cross-linked with glutaraldehyde (1% and 2%) and sodium sulfate (13.5% and 15%) in acetate buffer (0.02 M, pH 4.0). The relation between bioprocessing conditions and hesperidinase stability was studied. A residual activity of 193% was obtained with immobilized hesperidinase compared to the soluble form. A half-life of 770 min was attained with hesperidinase encapsulated in calcium alginate beads. The results presented in this work highlight the potential of hesperidinase encapsulation towards hesperitin production with insoluble substrate. To our knowledge, this work presents for the first time the potential of hesperidinase encapsulation on hydrogels for hesperitin production. This is an important achievement for pharmaceutical and nutraceutical applications of hesperitin because this compound presents a higher bioavailability compared to hesperidin. PMID- 23108620 TI - Towards a better understanding of the specificity of protein-protein interaction. AB - In order to predict interaction interface for proteins, it is crucial to identify their characteristic features controlling the interaction process. We present analysis of 69 crystal structures of dimer protein complexes that provides a basis for reasonable description of the phenomenon. Interaction interfaces of two proteins at amino acids level were localized and described in terms of their chemical composition, binding preferences, and residue interaction energies utilizing Amber empirical force field. The characteristic properties of the interaction interface were compared against set of corresponding intramolecular binding parameters for amino acids in proteins. It has been found that geometrically distinct clusters of large hydrophobic amino acids (leucine, valine, isoleucine, and phenylalanine) as well as polar tyrosines and charged arginines are signatures of the protein-protein interaction interface. At some extent, we can generalize that protein-protein interaction (seen through interaction between amino acids) is very similar to the intramolecular arrangement of amino acids, although intermolecular pairs have generally lower interaction energies with their neighbors. Interfaces, therefore, possess high degree of complementarity suggesting also high selectivity of the process. The utilization of our results can improve interface prediction algorithms and improve our understanding of protein-protein recognition. PMID- 23108622 TI - Autophosphorylation activation and inhibition by curcumin of the epidermal growth factor receptor reconstituted in liposomes. AB - The epidermal growth factor receptor (EGFR) is a 170-kDa transmembrane protein with intrinsic protein kinase activity. It is involved in the regulation of essential cellular processes such as proliferation, differentiation, survival, and migration. An increase in EGFR activity has been correlated to malignant evolution of the cells. We have used proteoliposomes as a platform to study the mechanism of activation and inhibition of EGFR. We have been able to reconstitute functional EGFR in liposomes through detergent removal by Bio-Beads and have measured the receptor dimerization and its autophosphorylation resulting from its inherent tyrosine kinase activity. In particular, we have studied the activation of autophosphorylation by the natural ligand epidermal growth factor and its inhibition by curcumin, a polyphenol from Curcuma longa. This artificial membrane model provides a convenient tool to both qualitatively and quantitatively elucidate the mechanism of activation and inhibition of EGFR. It allows studying the isolated receptor under well-defined conditions, which enables one to use a number of biochemical and physico-chemical techniques that are difficult to put into practice with living cells. We believe that this platform can be used as a systematic screening tool for membrane receptor modulators, which are potential drug candidates. PMID- 23108621 TI - Indirect ELISA-based approach for comparative measurement of high-affinity cohesin-dockerin interactions. AB - The interaction between the cohesin and dockerin modules serves to attach cellulolytic enzymes (carrying dockerins) to non-catalytic scaffoldin units (carrying multiple cohesins) in cellulosome, a multienzyme plant cell-wall degrading complex. This interaction is species-specific, for example, the enzyme borne dockerin from Clostridium thermocellum bacteria binds to scaffoldin cohesins from the same bacteria but not to cohesins from Clostridium cellulolyticum and vice versa. We studied the role of interface residues, contributing either to affinity or specificity, by mutating these residues on the cohesin counterpart from C. thermocellum. The high affinity of the cognate interactions makes it difficult to evaluate the effect of these mutations by common methods used for measuring protein-protein interactions, especially when subtle discrimination between the mutants is needed. We described in this article an approach based on indirect enzyme-linked immunosorbent assay (ELISA) that is able to detect differences in binding between the various cohesin mutants, whereas surface plasmon resonance and standard ELISA failed to distinguish between high-affinity interactions. To be able to calculate changes in energy of binding (DeltaDeltaG) and dissociation constants (K(d)) of mutants relative to wild type, a pre-equilibrium step was added to the standard indirect ELISA procedure. Thus, the cohesin-dockerin interaction under investigation occurs in solution rather than between soluble and immobilized proteins. Unbound dockerins are then detected through their interaction with immobilized cohesins. Because our method allows us to assess the effect of mutations on particularly tenacious protein-protein interactions much more accurately than do other prevalent methods used to measure binding affinity, we therefore suggest this approach as a method of choice for comparing relative binding in high-affinity interactions. PMID- 23108623 TI - Design of selective production of sophorolipids by Rhodotorula bogoriensis through nutritional requirements. AB - Rhodotorula bogoriensis is known as the producer of longer chain acidic sophorolipids (SLs) with a unique hydroxylation position where the sophorose unit is linked to the 13-hydroxydocosanoic acid. The influence of initial inoculum concentration, hydrophilic and hydrophobic carbon, and nitrogen sources on R. bogoriensis growth and SL production was evaluated to obtain a selective SL production. Experiments took place in microtiter plates, used as minireactors, after the verification of its suitability compared with shake flasks. The common structure of SLs is the 13-[2'-O-beta-d-glucopyranosyl-beta-d-glucopyranosyloxy] docosanoic acid SL. The analysis of the fermentation media using high-performance liquid chromatography with evaporative light scattering detector showed the production of four main SLs, respectively, in the following forms: (i) deacetylated (peak A) (C22:0 SL), (ii) 6"monoacetylated (peak B) (C22:0-6"Ac SL), (iii) 6'monoacetylated (peak C) (C22:0-6'Ac SL), and (iv) 6',6" diacetylated (peak D) (C22:0-6',6"Ac SL). The identification of compounds in SL mixtures was performed by liquid chromatography with electrospray ionization mass spectrometry analysis, and no differences were observed. Besides the four compounds detected using high-performance liquid chromatography with evaporative light scattering detector chromatograms, three other SLs was identified, corresponding to mono- and diacetylated C24:0 hydroxy fatty acid SLs. To our knowledge, this work presents for the first time the production and identification of C24:0 SLs. A longer hydrophobic tail on SLs had an important role in the improvement of surface active properties. The selection of a specific time for fermentation end and the use of different carbon (e.g. glucose, fructose, mannose, lactose, galactose, xylose) and nitrogen (e.g. peptone, (NH(4))(2)SO(4) and NaNO(3)) sources led to a selective production of de-, mono-, and diacetylated SLs by R. bogoriensis. PMID- 23108625 TI - Cytochrome P450 119 Compounds I Formed by Chemical Oxidation and Photooxidation Are the Same Species. AB - Compound I from cytochrome P450 119 prepared by the photooxidation method involving peroxynitrite oxidation of the resting enzyme to Compound II followed by photooxidation to Compound I was compared to Compound I generated by m chloroperoxybenzoic acid (MCPBA) oxidation of the resting enzyme. The two methods gave the same UV/Visible spectra, the same products from oxidations of lauric acid and palmitic acid and their (omega-2,omega-2,omega-3,omega-3) tetradeuterated analogues, and the same kinetics for oxidations of lauric acid and caprylic acid. The experimental identities between the transients produced by the two methods leave no doubt that the same Compound I species is formed by the two methods. PMID- 23108626 TI - The androgen receptor: a biologically relevant vaccine target for the treatment of prostate cancer. AB - The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. However, while it has long been the primary molecular target of metastatic prostate cancer therapies, it has not been explored as an immunotherapeutic target. In particular, the AR ligand-binding domain (LBD) is a potentially attractive target, as it has an identical sequence among humans as well as among multiple species, providing a logical candidate for preclinical evaluation. In this report, we evaluated the immune and anti-tumor efficacy of a DNA vaccine targeting the AR LBD (pTVG-AR) in relevant rodent preclinical models. We found immunization of HHDII-DR1 mice, which express human HLA-A2 and HLA-DR1, with pTVG-AR augmented AR LBD HLA-A2-restricted peptide specific, cytotoxic immune responses in vivo that could lyse human prostate cancer cells. Using an HLA-A2-expressing autochthonous model of prostate cancer, immunization with pTVG-AR augmented HLA-A2-restricted immune responses that could lyse syngeneic prostate tumor cells and led to a decrease in tumor burden and an increase in overall survival of tumor-bearing animals. Finally, immunization decreased prostate tumor growth in Copenhagen rats that was associated with a Th1 type immune response. These data show that the AR is as a prostate cancer immunological target antigen and that a DNA vaccine targeting the AR LBD is an attractive candidate for clinical evaluation. PMID- 23108628 TI - Beneficial effect of methylprednisolone after mandibular third molar surgery: a randomized, double-blind, placebo-controlled split-mouth trial. AB - OBJECTIVES: Third molar (M3) removal is the model most frequently used for pain trials in oral surgery. Corticosteroids are frequently administered to reduce trismus and swelling after dentoalveolar surgical procedures. The purpose of this investigation was to evaluate the influence of a single, preoperative oral application of methylprednisolone on postoperative trismus, pain intensity, and the subjective need for analgesic medication after surgical removal of impacted mandibular M3 (LM3). MATERIALS AND METHODS: Sixteen healthy patients requiring similar bilateral surgical LM3 removal were included in a prospective, randomized, placebo-controlled, double-blind study in a split-mouth design. At random, each patient received either weight-dependent methylprednisolone (40-80 mg) or a placebo orally 1 h prior to surgery. In each case, the right and left LM3 were treated in independent visits. Trismus, swelling, pain measured on a 100 mm visual analog scale, and the postoperative demand of analgesics were assessed. RESULTS: Statistical analysis indicates a significant reduction of trismus, swelling, pain intensity, and patient-controlled intake of analgesics during the whole postsurgical period of investigation (first to seventh day). CONCLUSIONS: The results of this study suggest that a single preoperative weight-dependent administration of methylprednisolone is a safe and effective concept for diminishing postoperative discomfort, pain intensity, and the total intake of analgesics after wisdom tooth extractions. CLINICAL RELEVANCE: In case of missing contraindications, the preoperative administration of methylprednisolone is recommended, a routine medication for more extended procedures in oral surgery. PMID- 23108629 TI - Pathological responses and survival of patients with human epidermal growth factor receptor 2-positive breast cancer who received neoadjuvant chemotherapy including trastuzumab. AB - BACKGROUND: The effectiveness of neoadjuvant chemotherapy is evaluated on the basis of pathological responses and survival outcome, because achievement of a pathological complete response (pCR) is a good predictor of long-term survival. However, few studies have assessed the survival of breast cancer patients who received neoadjuvant chemotherapy including trastuzumab. METHODS: The records of 161 breast cancer patients who received neoadjuvant chemotherapy between January 2006 and December 2011 were retrospectively reviewed. The patients were categorized into 4 subgroups on the basis of the status of the estrogen receptor (ER), the progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). HER2-positive patients received trastuzumab-based regimens. Pathological responses and survival were analyzed on the basis of breast cancer subtypes. RESULTS: The pCR results obtained were: luminal A and B (ER and/or PR positive, HER2-negative), 6.3 % (5/79 cases); luminal-HER2 hybrid (ER and/or PR positive, HER2-positive), 25.0 % (5/20 cases); HER2-enriched (ER and PR-negative, HER2-positive), 63.0 % (17/27 cases); and triple-negative (ER and PR-negative, HER2-negative), 25.7 % (9/35 cases). Achievement of pCR was a good predictor of disease-free survival in the HER2-enriched group. Overall survival of patients with pCR was slightly, but not significantly, better in the HER2-enriched and triple-negative subgroups. CONCLUSION: Responses and survival after neoadjuvant chemotherapy including trastuzumab of patients with HER2-positive tumors differed among disease subtypes. Our findings suggest that disease subtype is an important determinant of the efficacy of neoadjuvant chemotherapy. PMID- 23108630 TI - Primary intestinal-like adenocarcinoma of major salivary glands: 2 instances of previously undocumented phenotype. AB - BACKGROUND: Primary intestinal-like adenocarcinoma of the major salivary glands has not previously been reported. METHODS: The clinical and radiological findings of 2 patients with primary submandibular and sublingual tumors are presented. Histopathologic and immunohistochemical examinations of tumor sections were performed. Metastatic workup for distant occult primary was carried out. RESULTS: The light-optic and the immunomarkers revealed intestinal-like adenocarcinoma consistent with upper respiratory tract origin. Metastatic workup of both patients was negative for primary gastro-intestinal primary. CONCLUSION: Primary intestinal-like adenocarcinoma can develop in major salivary glands and should be considered in the differential diagnosis. PMID- 23108631 TI - Safety and immunogenicity of recombinant human thrombin: a pooled analysis of results from 10 clinical trials. AB - STUDY OBJECTIVE: To evaluate the safety and immunogenicity of recombinant human thrombin (rThrombin), an active topical stand-alone hemostatic agent. DESIGN: Analysis of pooled data from 10 rThrombin clinical trials. PATIENTS: A total of 644 adult and pediatric patients treated with rThrombin; 609 patients were included in the immunogenicity analysis. MEASUREMENTS AND MAIN RESULTS: In all studies, rThrombin was applied during a single surgical procedure (day 1); the procedures consisted of spinal procedures, major hepatic resection, peripheral arterial bypass, arteriovenous graft formation for hemodialysis access, and synchronous burn wound excision and skin grafting. A dosage of 1000 IU/ml of rThrombin was administered for more than 99% of patients. Adverse events and clinical laboratory values were monitored through day 29. Blood samples were obtained for immunogenicity analyses before the procedure and on day 29. Adverse events were mild or moderate in severity for the majority of patients; no patients discontinued from an rThrombin study due to adverse events. The most commonly reported adverse events in the 644 patients were incision site pain (305 patients [47.4%]), procedural pain (215 patients [33.4%]), and nausea (170 patients [26.4%]). Five patients (0.8%) died during the studies; all deaths were considered unrelated to rThrombin treatment. Antibodies to the rThrombin product developed in 5 (0.8%, 95% confidence interval 0.4-2.8%) of 609 patients by day 29, approximately 1 month after treatment; these antibodies did not neutralize the activity of native human thrombin. The development of antibodies did not appear to differ substantively by type of surgical procedure, amount of rThrombin administered, or patient age. CONCLUSION: Recombinant human thrombin was well tolerated, and adverse events were consistent with those reported in the postoperative setting in the surgical populations studied. Approximately 1 month after treatment, less than 1% of the patients had developed antibodies to the rThrombin product, and these antibodies did not neutralize the activity of native human thrombin. These results support the safety of rThrombin when used as a topical aid to hemostasis in numerous surgical settings and for patients of differing ages. PMID- 23108632 TI - Contribution of salivary gland ultrasonography to the diagnosis of Sjogren's syndrome: toward new diagnostic criteria? AB - OBJECTIVE: To determine the accuracy of salivary gland ultrasonography (SGUS) for diagnosing primary Sjogren's syndrome (SS) and to suggest modifications of the American-European Consensus Group (AECG) classification criteria. METHODS: We conducted a cross-sectional study in a prospective cohort of patients with suspected primary SS that was established between 2006 and 2011. The echostructure of the bilateral parotid and submandibular glands was graded from 0 to 4, and the gland size was measured; blood flow to the parotid gland was assessed using Doppler waveform analysis. The reference standard was a clinical diagnosis of primary SS as determined by a group of experts blinded to the results of SGUS. Receiver operating characteristic (ROC) curve analysis was performed to compare the diagnostic value of the 0-4-point echostructure grade for each of the 4 major salivary glands, the sum of the grades for the 4 glands, and the highest grade among the 4 glands. RESULTS: Of the 158 patients in the study, 78 had a diagnosis of primary SS according to the experts, including 61 patients (78.2%) who met the AECG criteria. Doppler waveform analysis and gland size measurement showed poor diagnostic performance. The results of ROC curve analysis showed that the highest grade among the 4 glands provided the best diagnostic value. The optimal grade cutoff was 2 (62.8% sensitivity and 95.0% specificity). A weighted score was constructed using scores for the 5 variables selected by logistic regression analysis, as follows: (salivary flow*1.5)+(Schirmer's test*1.5)+(salivary gland biopsy*3)+(SSA/SSB*4.5)+(SGUS*2). According to ROC curve analysis, a score of >=5 of 12.5 had 85.7% sensitivity and 94.9% specificity, compared with 77.9% sensitivity and 98.7% specificity for the AECG criteria. The addition of SGUS to the AECG criteria increased sensitivity to 87.0% but did not change specificity. CONCLUSION: Modifications of the AECG criteria, including the addition of a SGUS score, notably improved diagnostic performance. PMID- 23108633 TI - Polymorphic transformation of anhydrous caffeine upon grinding and hydrostatic pressurizing analyzed by low-frequency raman spectroscopy. AB - Low-frequency Raman investigations were carried out upon pressurizing and grinding both crystalline forms of anhydrous caffeine at room temperature. These investigations have led to the detection of metastable states under stress. Upon moderated hydrostatic compression, only form I transform into a metastable state characterized by a Raman band-shape resembling that of form II. Above 2 GPa, both pressurized forms convert into an identical disordered state, suggesting a pressure-induced amorphization. In contrast to hydrostatic compression, grinding induces transformation of each phase into the other, leading to an intermediate state only stabilized under long enough grinding. The origin of these metastable states induced by stress was related to the disordered nature of both crystalline forms of caffeine and the stability conditions at room temperature of form I. PMID- 23108634 TI - The effect of glenohumeral internal rotation deficit due to posterior capsular contracture on passive glenohumeral joint motion. AB - BACKGROUND: To date, no study has investigated the biomechanical consequences of glenohumeral internal rotation deficit (GIRD) at values seen in symptomatic athletes. Hypothesis/ PURPOSE: The purpose of this study was to determine the biomechanical changes that occur with a full spectrum of GIRD in a cadaveric model with passive loading. We hypothesized that there is a critical percentage of GIRD that will result in a decrease in posterior glenohumeral translation and shift of the humeral head apex at the extreme ranges of motion. STUDY DESIGN: Controlled laboratory study. METHODS: Six specimens were tested using the following conditions: (1) native state ("intact"); (2) after external rotation (ER) stretch ("stretched"); and (3) GIRD of 5%, 10%, 15%, and 20%. For each condition, maximum ER, maximum internal rotation (IR), and total range of motion were measured. Kinematic data were obtained to determine the position of the humeral head apex (HHA), the highest point on the articular surface of the humeral head, relative to the geometric center of the glenoid. The amount of translation was measured in the anterior, posterior, superior, and inferior directions. RESULTS: External rotation significantly increased compared with the intact condition for the stretched and 5% GIRD states, and IR decreased significantly beginning with 5% GIRD. At maximum ER, the HHA shifted significantly in the superior direction compared with the intact condition for all GIRD states, and at maximum IR, the HHA shifted significantly in the inferior direction compared with the intact and stretched conditions starting at 10% GIRD. The amount of posterior translation decreased significantly starting at 10% GIRD, and the amount of inferior translation decreased significantly starting at 20% GIRD. CONCLUSION: Biomechanical changes of passive glenohumeral joint motion occur in the glenohumeral joint with as little as 5% GIRD. CLINICAL RELEVANCE: Biomechanical changes of passive glenohumeral joint motion are noted with as little as 5% GIRD in this cadaveric model, and as the amount of GIRD increases, more substantial effects are noted. PMID- 23108635 TI - Ability to return to sports 5 years after matrix-associated autologous chondrocyte transplantation in an average population of active patients. AB - BACKGROUND: Cartilage injuries often occur during sports activities, and return to sports after cartilage surgery is an important outcome parameter for different treatment methods in the competitive as well as the recreationally active population. HYPOTHESIS: At the time of midterm follow-up after matrix-associated autologous chondrocyte transplantation (MACT), return to recreational sports at the preinjury level will be possible. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventy patients (51 men, 19 women; age [mean +/- standard deviation], 34.9 +/- 8.6 y; range, 18-55 y) were clinically evaluated 5 years after MACT through subjective clinical scores such as the Knee Injury and Osteoarthritis Outcome Score (KOOS) sport and recreation subscales, the Tegner activity scale, and the Noyes sports activity rating scale. The level of sports participation was included in the investigation. RESULTS: The results 5 years after MACT showed mean values of 60.1 for the KOOS-sport, 67.4 for the Noyes, and 3.8 for the Tegner scores, meaning that regular sports activity such as cycling or running on flat ground, as well as medium-level manual labor, is possible. We noted that 74.3% of our patients returned to at least their preinjury sports level. CONCLUSION: Midterm postoperative results after MACT show that in a moderately active population, participation in regular sports is possible for most patients, at least at their preinjury recreational level and intensity, and there is a good rate of return to sports. PMID- 23108636 TI - Arthroscopic repair of concomitant type II SLAP lesions in large to massive rotator cuff tears: comparison with biceps tenotomy. AB - BACKGROUND: There are no studies examining superior labrum anterior and posterior (SLAP) repair combined with repair of large to massive rotator cuff tears, and it is unclear whether a combined SLAP repair would lead to better outcomes than biceps tenotomy. HYPOTHESIS: Tenotomy and rotator cuff repair would lead to better outcomes compared with those of combined SLAP and rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Our study population consisted of 36 patients who had undergone either combined SLAP and rotator cuff repair (when the biceps was too healthy to cut; group R = 16 patients) or tenotomy and rotator cuff repair (when any fraying or partial tear existed in the biceps tendon; group T = 20 patients) for concomitant type II SLAP lesions and large to massive rotator cuff tears. The cuff repair was performed in a single row for both groups. Outcomes were assessed by comparing range of motion as well as Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), and University of California, Los Angeles (UCLA) scores between the 2 groups. RESULTS: At the 2-year follow-up, both groups demonstrated significant improvements in functional shoulder scores and range of motion. However, group T had better SST scores (group T, 9.3 +/- 1.6; group R, 7.8 +/- 1.9; P = .012), ASES scores (group T, 88.6 +/- 8.9; group R, 80.4 +/-8.9; P = .009), UCLA scores (group T, 29.6 +/- 3.0; group R, 26.0 +/- 4.2; P = .007), and forward flexion (group T, 145.9 degrees +/- 13.0 degrees ; group R, 132.5 degrees +/- 15.3 degrees ; P = .008). The mean tear size and the degree of preoperative muscle atrophy and fatty infiltration on magnetic resonance imaging were similar between the groups. CONCLUSION: For patients with concomitant type II SLAP lesions and large to massive rotator cuff tears, the outcomes of simultaneous arthroscopic SLAP and rotator cuff repair were inferior to those of arthroscopic biceps tenotomy and cuff repair in terms of functional shoulder scores and range of motion. Biceps tenotomy and rotator cuff repair may be a more reliable method to address concomitant type II SLAP lesions and large to massive rotator cuff tears in patients, although a randomized controlled trial is needed to confirm the results. PMID- 23108638 TI - Sports hernia in National Hockey League players: does surgery affect performance? AB - BACKGROUND: Athletic pubalgia is a complex injury that results in loss of play in competitive athletes, especially hockey players. The number of reported sports hernias has been increasing, and the importance of their management is vital. There are no studies reporting whether athletes can return to play at preinjury levels. PURPOSE: The focus of this study was to evaluate the productivity of professional hockey players before an established athletic pubalgia diagnosis contrasted with the productivity after sports hernia repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Professional National Hockey League (NHL) players who were reported to have a sports hernia and who underwent surgery from 2001 to 2008 were identified. Statistics were gathered on the players' previous 2 full seasons and compared with the statistics 2 full seasons after surgery. Data concerning games played, goals, average time on ice, time of productivity, and assists were gathered. Players were divided into 3 groups: group A incorporated all players, group B were players with 6 or fewer seasons of play, and group C consisted of players with 7 or more seasons of play. A control group was chosen to compare player deterioration or improvement over a career; each player selected for the study had a corresponding control player with the same tenure in his career and position during the same years. RESULTS: Forty-three hockey players were identified to have had sports hernia repairs from 2001 to 2008; ultimately, 80% would return to play 2 or more full seasons. Group A had statistically significant decreases in games played, goals scored, and assists. Versus the control group, the decreases in games played and assists were supported. Statistical analysis showed significant decreases in games played, goals scored, assists, and average time on ice the following 2 seasons in group C, which was also seen in comparison with the control group. Group B (16 players) showed only statistical significance in games played versus the control group. CONCLUSION: Players who undergo sports hernia surgeries return to play and often perform similar to their presurgery level. Players with over 7 full seasons return but with significant decreases in their overall performance levels. Less veteran players were able to return to play without any statistical decrease in performance and are likely the best candidates for repair once incurring injury. PMID- 23108637 TI - Infrared fiber optic probe evaluation of degenerative cartilage correlates to histological grading. AB - BACKGROUND: Osteoarthritis (OA), a degenerative cartilage disease, results in alterations of the chemical and structural properties of tissue. Arthroscopic evaluation of full-depth tissue composition is limited and would require tissue harvesting, which is inappropriate in daily routine. Fourier transform infrared (FT-IR) spectroscopy is a modality based on molecular vibrations of matrix components that can be used in conjunction with fiber optics to acquire quantitative compositional data from the cartilage matrix. PURPOSE: To develop a model based on infrared spectra of articular cartilage to predict the histological Mankin score as an indicator of tissue quality. STUDY DESIGN: Comparative laboratory study. METHODS: Infrared fiber optic probe (IFOP) spectra were collected from nearly normal and more degraded regions of tibial plateau articular cartilage harvested during knee arthroplasty (N = 61). Each region was graded using a modified Mankin score. A multivariate partial least squares algorithm using second-derivative spectra was developed to predict the histological modified Mankin score. RESULTS: The partial least squares model derived from IFOP spectra predicted the modified Mankin score with a prediction error of approximately 1.4, which resulted in approximately 72% of the Mankin scored tissues being predicted correctly and 96% being predicted within 1 grade of their true score. CONCLUSION: These data demonstrate that IFOP spectral parameters correlate with histological tissue grade and can be used to provide information on tissue composition. CLINICAL RELEVANCE: Infrared fiber optic probe studies have significant potential for the evaluation of cartilage tissue quality without the need for tissue harvest. Combined with arthroscopy, IFOP analysis could facilitate the definition of tissue margins in debridement procedures. PMID- 23108639 TI - The effect of medial opening wedge proximal tibial osteotomy on patellofemoral contact. AB - BACKGROUND: It has been suggested that patellofemoral contact pressures and contact forces may be altered secondary to an opening wedge high tibial osteotomy, yet few data are available that quantify the effect of varying degrees of medial opening wedge osteotomy on the patellofemoral joint contact characteristics. HYPOTHESIS: Opening wedge medial proximal tibial osteotomy will increase patellofemoral contact force and pressure. STUDY DESIGN: Controlled laboratory study. METHODS: Nine human cadaver knees were used. Pressure-sensitive film was placed in the suprapatellar pouch, leaving the patellar tendon and medial and lateral retinacula intact. The quadriceps tendon was attached to a materials testing machine along the axis of the femur, whereby a pulley mechanism generated 950 N of force. Patellofemoral contact characteristics were measured with pressure-sensitive film at 30 degrees , 60 degrees , 90 degrees , and 120 degrees of flexion for the native knee and after subsequent 10-mm and 15-mm medial opening wedge proximal tibial osteotomies. The film was analyzed with imaging software. RESULTS: There was a statistically significant increase (P < .05) in mean contact pressure at 30 degrees and 120 degrees between the 10-mm osteotomy and native knee and across all flexion angles between the 15-mm osteotomy and native knee. Furthermore, a significant difference was seen in peak pressures when native knees were compared with 10-mm and 15-mm opening wedge osteotomies at all flexion angles. CONCLUSION: There was a significant increase in patellofemoral pressures at varying degrees of knee flexion after medial opening wedge proximal tibial osteotomies of only 10 mm; a larger osteotomy resulted in a greater increase. CLINICAL RELEVANCE: When performing a medial opening wedge proximal tibial osteotomy, the surgeon should consider the negative effects of increased patellofemoral peak pressure. PMID- 23108640 TI - Rate of torque and electromyographic development during anticipated eccentric contraction is lower in previously strained hamstrings. AB - BACKGROUND: The effect of prior strain injury on myoelectrical activity of the hamstrings during tasks requiring high rates of torque development has received little attention. PURPOSE: To determine if recreational athletes with a history of unilateral hamstring strain injury will exhibit lower levels of myoelectrical activity during eccentric contraction, rate of torque development (RTD), and impulse (IMP) at 30, 50, and 100 milliseconds after the onset of myoelectrical activity or torque development in the previously injured limb compared with the uninjured limb. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: Twenty-six recreational athletes were recruited. Of these, 13 athletes had a history of unilateral hamstring strain injury (all confined to biceps femoris long head), and 13 had no history of hamstring strain injury. Following familiarization, all athletes undertook isokinetic dynamometry testing and surface electromyography (integrated EMG; iEMG) assessment of the biceps femoris long head and medial hamstrings during eccentric contractions at -60 and -180 deg.s(-1). RESULTS: In the injured limb of the injured group, compared with the contralateral uninjured limb, RTD and IMP was lower during -60 deg.s(-1) eccentric contractions at 50 milliseconds (RTD: injured limb, 312.27 +/- 191.78 N.m.s(-1) vs uninjured limb, 518.54 +/- 172.81 N.m.s(-1), P = .008; IMP: injured limb, 0.73 +/- 0.30 N.m.s vs uninjured limb, 0.97 +/- 0.23 N.m.s, P = .005) and 100 milliseconds (RTD: injured limb, 280.03 +/- 131.42 N.m.s(-1) vs uninjured limb, 460.54 +/- 152.94 N.m.s(-1), P = .001; IMP: injured limb, 2.15 +/- 0.89 N.m.s vs uninjured limb, 3.07 +/- 0.63 N.m.s, P < .001) after the onset of contraction. Biceps femoris long head muscle activation was lower at 100 milliseconds at both contraction speeds (-60 deg.s(-1), normalized iEMG activity [*1000]: injured limb, 26.25 +/- 10.11 vs uninjured limb, 33.57 +/- 8.29, P = .009; -180 deg.s(-1), normalized iEMG activity [*1000]: injured limb, 31.16 +/- 10.01 vs uninjured limb, 39.64 +/- 8.36, P = .009). Medial hamstring activation did not differ between limbs in the injured group. Comparisons in the uninjured group showed no significant between limbs difference for any variables. CONCLUSION: Previously injured hamstrings displayed lower RTD and IMP during slow maximal eccentric contraction compared with the contralateral uninjured limb. Lower myoelectrical activity was confined to the biceps femoris long head. Regardless of whether these deficits are the cause of or the result of injury, these findings could have important implications for hamstring strain injury and reinjury. Particularly, given the importance of high levels of muscle activity to bring about specific muscular adaptations, lower levels of myoelectrical activity may limit the adaptive response to rehabilitation interventions and suggest that greater attention be given to neural function of the knee flexors after hamstring strain injury. PMID- 23108641 TI - Overweight, elevated blood pressure, acanthosis nigricans and adherence to recommended dietary and physical activity guidelines among Hmong and white middle school students. AB - This cross-sectional study was conducted among low-income middle-school students (N = 426) in rural northern California to compare rates of overweight, elevated blood pressure and acanthosis nigricans (AN) between Hmong and white students. Associations among rates of overweight, elevated blood pressure, AN, and scores for adherence to recommended dietary guidelines were also examined. Fifty-two percent (52%) of white students were overweight/obese compared to 38% of Hmong students. Higher fruit consumption was associated with a lower BMI among white, but not Hmong students. Whereas 7% of white students were classified as pre hypertensive/hypertensive, the rate for Hmong students was 17%. Additionally, at 13 versus 2%, six-fold more Hmong students had an elevated blood pressure with a normal BMI compared to white students, respectively. Ethnicity was also an independent predictive factor for AN. Hmong students appear to be at higher risk for both hypertension and AN than white students irrespective of BMI. PMID- 23108642 TI - Rosuvastatin and ciprofibrate in the treatment of dyslipidemia in patients with HIV. AB - BACKGROUND: Dyslipidemia secondary to highly active antiretroviral therapy in patients with HIV is associated with a significant increase in cardiovascular morbidity and mortality due to atherosclerotic disease, requiring, thus, immediate and effective treatment. OBJECTIVE: To demonstrate the effectiveness and safety of rosuvastatin and ciprofibrate in the treatment of dyslipidemia associated with highly active antiretroviral therapy in patients with HIV. METHODS: Three hundred and forty-six patients with dyslipidemia underwent pharmacological treatment as follows: 200 patients with hypertriglyceridemia received ciprofibrate (Group I); 79 patients with hypercholesterolemia received rosuvastatin (Group II); and 67 patients with mixed dyslipidemia received ciprofibrate associated with rosuvastatin (Group III). The lipid profile was assessed before and after the lipid-lowering treatment, and the Wilcoxon test was used for statistical comparison. Liver transaminases and creatine phosphokinase were measured to assess liver and muscle toxicity. RESULTS: The serum concentrations of triglycerides and total cholesterol were significantly lower than those obtained before the lipid-lowering treatment in the three experimental groups (p < 0.002). A significant increase in HDL-cholesterol was observed in Groups I and III (p < 0.002). In Groups I and II, LDL-cholesterol was significantly lower (p < 0.001). None of the patients experienced elevations in transaminases or creatine phosphokinase to significantly toxic levels. CONCLUSION: The results of this study show that ciprofibrate and rosuvastatin or a combination of both can be considered an effective, safe and well-tolerated lipid-lowering treatment for patients with AIDS on highly active antiretroviral therapy. PMID- 23108643 TI - Postmenopausal therapy reduces catalase activity and attenuates cardiovascular risk. AB - BACKGROUND: Menopause can lead to alterations in women's health, with changes in the oxidative status of postmenopausal women in whom information regarding the influence of hormone therapy (HT) on antioxidant enzyme activities is limited. OBJECTIVE: To evaluate the influence of HT on catalase activity; concentrations of lipids and lipoprotein, cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, nitrates, high-sensitivity C-reactive protein and carotid thickness in postmenopausal women. METHODS: Ninety-four consecutive women were allocated to one of four groups, without HT and with HT. The latter group was subdivided into women using estrogen and those using estrogen plus progestogen therapy. Plasma biochemical parameters and common carotid intima media thickness measurements were performed. RESULTS: HT antagonized the decrease in catalase activity after menopause, but had no effect on the levels of cholesteryl ester transfer protein, thiobarbituric acid-reactive substances, lipid peroxide, nitrate, high-sensitivity C-reactive protein, or on the common carotid intima-media thickness. Multivariate analysis showed that estrogen-based HT attenuated the relationship between cardiovascular risk factors and the intima media thickness of the common carotid. CONCLUSION: This study indicates that HT in postmenopausal women produces beneficial antioxidant and anti-atherosclerotic effects by ameliorating the plasma lipid and lipoprotein profiles, increasing plasma catalase activity and attenuating the association between cardiovascular risk factors and early atherosclerosis. PMID- 23108644 TI - Ventricular repolarization in diabetic patients: characterization and clinical implications. AB - BACKGROUND: Diabetes mellitus is a chronic and very common condition, and there has been lately a considerable increase in its prevalence and incidence. Diabetic patients have increased cardiovascular mortality, in which malignant ventricular arrhythmias seem to be implicated. OBJECTIVE: To study the effects of diabetes on ventricular repolarization parameters responsible for an increased susceptibility to malignant ventricular arrhythmias and/or sudden death. METHODS: We selected a group of 110 diabetic patients and a group of 110 controls with the same distribution of age, gender and race. We evaluated the following parameters of ventricular repolarization: QT(max), QT(mean), QT(min), QTc(max), QTc(mean), QTc(min), QT and QTc dispersions, T(peak)-T(end) and jT(peak)-jT(end) intervals (D(II), V(2) and V(5)), T(peak)-T(end) and jT(peak)-jT(end) dispersions. The electrocardiograms (ECG) were performed by the same operator and reviewed by the same observers. QT intervals were corrected according to Bazzet's formula. RESULTS: We found significantly higher values of QTc(max) (p < 0.001), QTc(mean) (p < 0.001), QT dispersion (p < 0.001), QTc dispersion (p < 0.001), T(peak) T(end) dispersion ( p < 0.001), and jT(peak)-jT(end) dispersion (p < 0.001) in diabetic patients than in controls. In diabetic patients, we observed prolonged values of QTc interval (5.5%), QT dispersion (0.9%), QTc dispersion (0%), T(peak) T(end) interval (7.3%), jT(peak)-jT(end) interval (6.4%), T(peak)-T(end) dispersion (16.4%), and jT(peak)-jT(end) dispersion (12.7%). In the controls there were no prolonged values of any of the parameters. CONCLUSION: We concluded that diabetes causes prolongation and spatial dispersion of repolarization, and it may contribute to a greater ventricular electrical instability, whose expected clinical expression may be malignant ventricular arrhythmias. PMID- 23108645 TI - Hyperphosphorylation of Na-K-2Cl cotransporter in thick ascending limbs of Dahl salt-sensitive rats. AB - Salt-sensitive hypertension involves a renal defect preventing the kidney from eliminating excess NaCl. The thick ascending limb of Henle loop reabsorbs ~ 30% of filtered NaCl via the apical Na-K-2Cl cotransporter (NKCC2). Higher NKCC2 activity and Cl reabsorption have been reported in the thick ascending limbs from Dahl salt-sensitive rats (DSS) fed normal salt. NKCC2 activity is primarily regulated by protein trafficking and phosphorylation at Thr(96)/Thr(101) via STE20- and SPS1-related proline and alanine-rich kinases and oxidative stress responsive kinase 1. However, the mechanism for enhanced NKCC2 activity in DSS is unclear. We hypothesized that DSS exhibit enhanced NKCC2 trafficking and higher NKCC2 phosphorylation compared with Dahl salt-resistant rats on normal salt diet. We measured steady state surface NKCC2 expression and phosphorylation at Thr(96) and Thr(101) by surface biotinylation and Western blot. In DSS, the surface:total NKCC2 ratio was enhanced by 25% compared with Dahl salt-resistant rats (P<0.05) despite lower NKCC2 expression. Total NKCC2 phosphorylation at Thr(96) and Thr(101) was enhanced ~5-fold in DSS thick ascending limbs. Moreover, total STE20 and SPS1-related proline and alanine-rich kinases expression, kidney-specific STE20- and SPS1-related proline and alanine-rich kinases, and oxidative stress responsive kinase 1 were not different between strains, although STE20- and SPS1 related proline and alanine-rich kinases/oxidative stress-responsive kinase 1 phosphorylation was enhanced by 60% (P<0.05) in DSS rats, suggesting increased activity. We concluded that phosphorylation of NKCC2 Thr(96) and Thr(101) and surface:total NKCC2 ratio are enhanced in DSS rats. These differences in NKCC2 may be, in part, responsible for higher NKCC2 activity and abnormally enhanced thick ascending limb NaCl reabsorption in DSS rats. PMID- 23108646 TI - Cardiomyocyte mineralocorticoid receptors are essential for deoxycorticosterone/salt-mediated inflammation and cardiac fibrosis. AB - Because the role of mineralocorticoid receptors in specific cell types in cardiac remodeling remains unknown, we have compared cardiac responses with deoxycorticosterone/salt in cardiomyocyte mineralocorticoid receptor-null (MyoMRKO) and wild-type (WT) mice at 8 days and 8 weeks. No differences in cardiac function between untreated WT and MyoMRKO mice were found, whereas profibrotic markers were reduced in MyoMRKO hearts at baseline. At 8 days, MyoMRKO showed monocyte/macrophage recruitment equivalent to WT mice in response to deoxycorticosterone/salt but a suppression of markers of fibrosis compared with WT. At 8 weeks, MyoMRKO mice showed no deoxycorticosterone/salt-induced increase in inflammatory cell infiltration and collagen deposition or in proinflammatory gene expression. Although some profibrotic markers were equivalently increased in both genotypes, MyoMRKO mice also showed increased baseline levels of mRNA and protein for the transforming growth factor beta/connective tissue growth factor inhibitor decorin compared with WT that was accompanied by higher levels of matrix metalloproteinase 2/matrix metalloproteinase 9 activity. These data point to a direct role for cardiomyocyte mineralocorticoid receptor in both deoxycorticosterone/salt-induced tissue inflammation and remodeling and suggest potential mechanisms for the cardioprotective effects of selective mineralocorticoid receptor blockade in cardiomyocytes that may involve regulation of matrix metalloproteinase 2/matrix metalloproteinase 9 activity and the transforming growth factor-beta-connective tissue growth factor profibrotic pathway. PMID- 23108647 TI - Adipocyte deficiency of angiotensinogen prevents obesity-induced hypertension in male mice. AB - Previous studies demonstrated that diet-induced obesity increased plasma angiotensin II concentrations and elevated systolic blood pressures in male mice. Adipocytes express angiotensinogen and secrete angiotensin peptides. We hypothesize that adipocyte-derived angiotensin II mediates obesity-induced increases in systolic blood pressure in male high fat-fed C57BL/6 mice. Systolic blood pressure was measured by radiotelemetry during week 16 of low-fat or high fat feeding in Agt(fl/fl) and adipocyte angiotensinogen-deficient mice (Agt(aP2)). Adipocyte angiotensinogen deficiency had no effect on diet-induced obesity. Basal 24-hour systolic blood pressure was not different in low fat-fed Agt(fl/fl) compared with Agt(aP2) mice (124 +/- 3 versus 128 +/- 3 mm Hg, respectively). In Agt(fl/fl) mice, high-fat feeding significantly increased systolic blood pressure (24 hours; 134 +/- 2 mm Hg; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit an increase in systolic blood pressure (126 +/- 2 mm Hg). Plasma angiotensin II concentrations were increased by high-fat feeding in Agt(fl/fl) mice (low fat, 32 +/- 14; high fat, 219 +/- 58 pg/mL; P<0.05). In contrast, high fat-fed Agt(aP2) mice did not exhibit elevated plasma angiotensin II concentrations (high fat, 18 +/- 7 pg/mL). Similarly, adipose tissue concentrations of angiotensin II were significantly decreased in low fat- and high fat-fed Agt(aP2) mice compared with controls. In conclusion, adipocyte angiotensinogen deficiency prevented high fat-induced elevations in plasma angiotensin II concentrations and systolic blood pressure. These results suggest that adipose tissue serves as a major source of angiotensin II in the development of obesity hypertension. PMID- 23108648 TI - Peroxisome proliferator-activated receptor-gamma ameliorates pulmonary arterial hypertension by inhibiting 5-hydroxytryptamine 2B receptor. AB - An elevated plasma level of 5-hydroxytryptamine (5-HT) or upregulation of 5-HT receptor signaling or both is implicated in vascular contraction and remodeling in pulmonary arterial hypertension (PAH). Recently, peroxisome proliferator activated receptor-gamma (PPARgamma) agonists have been shown to ameliorate PAH. However, their effects on the 5-HT-induced contraction of pulmonary arteries remain unknown. Here, we examined the role of PPARgamma in inhibiting 5-HT2B receptor (5-HT2BR) to ameliorate PAH. Pulmonary arteries from PAH rats induced by monocrotaline or chronic hypoxia showed an enhanced vasoconstriction in response to BW723C86, a specific agonist for 5-HT2BR. Expression of 5-HT2BR was also increased in pulmonary arteries from the PAH rats, accompanied by vascular remodeling and right ventricular hypertrophy. Treatment with the PPARgamma agonist rosiglitazone in vivo reversed the expression and the vasocontractive effect of 5-HT2BR as well as the thickening of pulmonary arteries. In pulmonary artery smooth muscle cells, 5-HT induced the gene expression of 5-HT2BR, which was inhibited by rosiglitazone, pioglitazone, or adenovirus-mediated overexpression of constitutively activated PPARgamma. The pharmacological effect of PPARgamma was through the suppression of the 5-HT-induced activator protein-1 activity. These results demonstrated the beneficial effect of PPARgamma on 5 HT2BR-mediated vasocontraction, providing a new mechanism for the potential use of PPARgamma agonists in PAH. PMID- 23108649 TI - Pressure overload regulates expression of cytokines, gammaH2AX, and growth arrest and DNA-damage inducible protein 153 via glycogen synthase kinase-3beta in ischemic-reperfused hearts. AB - The growth arrest- and DNA-damage inducible protein 153 (GADD153) regulates both apoptosis and inflammatory response. Importantly, glycogen synthase kinase-3beta (GSK-3beta) may provide a mechanistic link for cellular expression of GADD153, inflammatory response, and cell death. We previously showed that pressure overload exacerbates myocardial ischemia reperfusion injury associated with significant reduction in phosphorylated (inactive) GSK-3beta. This raises the possibility that pressure overload, through a GSK-3beta-dependent mechanism, increases GADD153 expression, thereby upregulating inflammatory cytokine production and contributing to worsening of myocardial ischemia reperfusion injury. Accordingly, Langendorff-perfused rat hearts were subjected to global ischemia reperfusion protocol in the absence or presence of the GSK-3beta inhibitor, lithium chloride (1 mmol/L), with perfusion pressure set at 80 or 160 cmH(2)O; normoxic hearts served as controls. Compared with normoxia, an ischemia reperfusion insult increased expressions of proinflammatory cytokines, gammaH2AX, and GADD153 in association with increased cell death. In the ischemic-reperfused hearts, pressure overload did the following: (1) reduced interleukin-10 but increased interleukin-17 (cardiomyocytes), without affecting interleukin-23; (2) increased expressions of gammaH2AX and GADD153; (3) decreased 5,5',6,6' tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1) aggregates but increased JC-1 monomers (suggestive of reduced mitochondrial membrane potential, psi(m)); and (4) increased annexin V immunostaining as well as apoptotic and necrotic cell death. Treatment with lithium chloride caused a robust increase in interleukin-10, preserved psi(m), and markedly decreased all other parameters with the effect being most prominent for hearts perfused at the high pressure. In conclusion, pressure overload, via a GSK-3beta-dependent mechanism, exacerbates cell death in the isolated ischemic-reperfused heart involving regulation of inflammatory response, DNA injury, and GADD153 expression. PMID- 23108650 TI - Ablation points of renal sympathetic denervation: the more, the better? PMID- 23108651 TI - Interferon-gamma signaling inhibition ameliorates angiotensin II-induced cardiac damage. AB - Angiotensin (Ang) II induces vascular injury in part by activating innate and adaptive immunity; however, the mechanisms are unclear. We investigated the role of interferon (IFN)-gamma and interleukin (IL)-23 signaling. We infused Ang II into IFN-gamma receptor (IFN-gammaR) knockout mice and wild-type controls, as well as into mice treated with neutralizing antibodies against IL-23 receptor and IL-17A. Ang II-treated IFN-gammaR knockout mice exhibited reduced cardiac hypertrophy, reduced cardiac macrophage and T-cell infiltration, less fibrosis, and less arrhythmogenic electric remodeling independent of blood pressure changes. In contrast, IL-23 receptor antibody treatment did not reduce cardiac hypertrophy, fibrosis, or electric remodeling despite mildly reduced inflammation. IL-17A antibody treatment behaved similarly. In the kidney, IFN gammaR deficiency reduced inflammation and tubulointerstitial damage and improved glomerular filtration rate. Nonetheless, albuminuria was increased compared with Ang II-treated wild-type controls. The glomeruli of Ang II-treated IFN-gammaR knockout mice exhibited fewer podocytes, less nephrin and synaptopodin staining, and impaired podocyte autophagy. Thus, IFN-gamma blockade, but not IL-23 receptor antibody treatment, protects from Ang II-induced cardiac damage and electric remodeling. In the kidney, IFN-gamma signaling acts in a cell type-specific manner. Glomerular filtration rate is preserved in the absence of the IFN-gammaR, whereas podocytes may require the IFN-gammaR in the presence of Ang II for normal integrity and function. PMID- 23108652 TI - One miR level of control: microRNA-155 directly regulates endothelial nitric oxide synthase mRNA and protein levels. PMID- 23108653 TI - Modulation of bulbospinal rostral ventral lateral medulla neurons by hypoxia/hypercapnia but not medullary respiratory activity. AB - Although sympathetic vasomotor discharge has respiratory modulation, the site(s) responsible for this cardiorespiratory interaction is unknown. One likely source for this coupling is the rostral ventral lateral medulla (RVLM), where presympathetic neurons originate in close apposition to respiratory neurons. The current study tested the hypothesis that RVLM bulbospinal neurons are modulated by medullary respiratory network activity using whole-cell patch-clamp electrophysiological recordings of RVLM neurons while simultaneously recording fictive respiratory bursting activity from the hypoglossal rootlet. Additionally, we examined whether challenges to cardiorespiratory function, mainly hypoxia/hypercapnia, alter the activity of bulbospinal neurons and, secondarily, whether changes in synaptic input mediate these responses. Surprisingly, our results indicate that inspiratory-related activity did not modulate glutamatergic, gamma-aminobutyric acid-ergic, or glycinergic synaptic events or spontaneous action potential firing in these RVLM neurons. However, hypoxia/hypercapnia reversibly decreased the frequency of gamma-aminobutyric acid and glycine inhibitory postsynaptic currents. Glycinergic inhibitory postsynaptic current frequency was depressed from the fifth through the 10th minute, whereas the depression of gamma-aminobutyric acid-ergic events became significant only at the 10th minute of hypoxia/hypercapnia. On the basis of spontaneous firing activity, there were 2 populations of RVLM bulbospinal neurons. The firing frequency of low-discharging RVLM neurons was facilitated by hypoxia/hypercapnia, and this increase depended on reduced inhibitory neurotransmission. The firing frequency in RVLM neurons with high-discharge rates was inhibited, independent of synaptic input, by hypoxia/hypercapnia. This article demonstrates that sympathetic-respiratory coupling is not active in the neonatal brain stem slice, and reductions in inhibitory neurotransmission to low spontaneously active bulbospinal RVLM neurons are responsible for hypoxia/hypercapnia-elicited increases in activity. PMID- 23108654 TI - Cytochrome P450 1B1 gene disruption minimizes deoxycorticosterone acetate-salt induced hypertension and associated cardiac dysfunction and renal damage in mice. AB - Previously, we showed that the cytochrome P450 1B1 inhibitor 2,3',4,5' tetramethoxystilbene reversed deoxycorticosterone acetate (DOCA)-salt-induced hypertension and minimized endothelial and renal dysfunction in the rat. This study was conducted to test the hypothesis that cytochrome P450 1B1 contributes to cardiac dysfunction, and renal damage and inflammation associated with DOCA salt-induced hypertension, via increased production of reactive oxygen species and modulation of neurohumoral factors and signaling molecules. DOCA-salt increased systolic blood pressure, cardiac and renal cytochrome P450 1B1 activity, and plasma levels of catecholamines, vasopressin, and endothelin-1 in wild-type (Cyp1b1(+/+)) mice that were minimized in Cyp1b1(-/-) mice. Cardiac function, assessed by echocardiography, showed that DOCA-salt increased the thickness of the left ventricular posterior and anterior walls during diastole, the left ventricular internal diameter, and end-diastolic and end-systolic volume in Cyp1b1(+/+) but not in Cyp1b1(-/-) mice; stroke volume was not altered in either genotype. DOCA-salt increased renal vascular resistance and caused vascular hypertrophy and renal fibrosis, increased renal infiltration of macrophages and T lymphocytes, caused proteinuria, increased cardiac and renal nicotinamide adenine dinucleotide phosphate-oxidase activity, caused production of reactive oxygen species, and increased activities of extracellular signal regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src; these were all reduced in DOCA-salt-treated Cyp1b1(-/-) mice. Renal and cardiac levels of eicosanoids were not altered in either genotype of mice. These data suggest that, in DOCA-salt hypertension in mice, cytochrome P450 1B1 plays a pivotal role in cardiovascular dysfunction, renal damage, and inflammation, and increased levels of catecholamines, vasopressin, and endothelin-1, consequent to generation of reactive oxygen species and activation of extracellular signal regulated kinase 1/2, p38 mitogen-activated protein kinase, and cellular-Src independent of eicosanoids. PMID- 23108655 TI - Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults. AB - Vascular endothelial dysfunction develops with aging, as indicated by impaired endothelium-dependent dilation, and is related to increased cardiovascular disease risk. We hypothesized that short-term treatment with fenofibrate, a lipid lowering agent with potential pleiotropic effects, would improve endothelium dependent dilation in middle-aged and older normolipidemic adults by reducing oxidative stress. Brachial artery flow-mediated dilation, a measure of endothelium-dependent dilation, was assessed in 22 healthy adults aged 50 to 77 years before and after 7 days of fenofibrate (145 mg/d; n=12) or placebo (n=10). Brachial flow-mediated dilation was unchanged with placebo, but improved after 2 and 7 days of fenofibrate (5.1 +/- 0.7 versus 2 days: 6.0 +/- 0.7 and 7 days: 6.4 +/- 0.6%delta; both P<0.005). The improvements in flow-mediated dilation after 7 days remained significant (P<0.05) after accounting for modest changes in plasma total and low-density lipoprotein cholesterol. Endothelium-independent dilation was not affected by fenofibrate or placebo (P>0.05). Intravenous infusion of the antioxidant vitamin C improved brachial flow-mediated dilation at baseline in both groups and during placebo treatment (P<0.05), but not after 2 and 7 days of fenofibrate (P>0.05). Fenofibrate treatment also reduced plasma-oxidized low density lipoprotein, a systemic marker of oxidative stress, compared with placebo (P<0.05). In vascular endothelial cells sampled from peripheral veins of the subjects, endothelial nitric oxide synthase protein expression was unchanged with placebo and after 2 days of fenofibrate, but was increased after 7 days of fenofibrate (0.54 +/- 0.03 versus 2 days: 0.52 +/- 0.04 and 7 days: 0.76 +/- 0.11 intensity/human umbilical vein endothelial cell control; P<0.05, 7 days). Short term treatment with fenofibrate improves vascular endothelial function in healthy normolipidemic middle-aged and older adults by reducing oxidative stress and induces an increase in endothelial nitric oxide synthase. PMID- 23108656 TI - Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. AB - Nitric oxide generated by endothelial nitric oxide synthase (eNOS) plays an important role in maintaining cardiovascular homeostasis. Under various pathological conditions, abnormal expression of eNOS contributes to endothelial dysfunction and the development of cardiovascular diseases. A variety of pathological stimuli has been reported to decrease eNOS expression mainly through decreasing eNOS mRNA stability by regulating the binding of several cytosolic proteins to the cis-acting sequences within eNOS mRNA 3' untranslated regions. However, the detailed mechanisms remain elusive. Because microRNAs inhibit gene expression through binding to the 3' untranslated regions of their target mRNAs, microRNAs may be the important posttranscriptional modulators of eNOS expression. Here, we provided evidence that eNOS is a direct target of miR-155. Overexpression of miR-155 decreased, whereas inhibition of miR-155 increased, eNOS expression and NO production in human umbilical vein endothelial cells and acetylcholine-induced endothelium-dependent vasorelaxation in human internal mammary arteries. Inflammatory cytokines including tumor necrosis factor-alpha increased miR-155 expression. Inhibition of miR-155 reversed tumor necrosis factor-alpha-induced downregulation of eNOS expression and impairment of endothelium-dependent vasorelaxation. Moreover, we observed that simvastatin attenuated tumor necrosis factor-alpha-induced upregulation of miR-155 and ameliorated the effects of tumor necrosis factor-alpha on eNOS expression and endothelium-dependent vasodilation. Simvastatin decreased miR-155 expression through interfering mevalonate-geranylgeranyl-pyrophosphate-RhoA signaling pathway. These findings indicated that miR-155 is an essential regulator of eNOS expression and endothelium-dependent vasorelaxation. Inhibition of miR-155 may be a new therapeutic approach to improve endothelial dysfunction during the development of cardiovascular diseases. PMID- 23108657 TI - Antihypertensive and laxative effects by pharmacological inhibition of sodium proton-exchanger subtype 3-mediated sodium absorption in the gut. AB - High intestinal sodium absorption is one mechanism of hypertension and constipation. The sodium-proton-exchanger subtype 3 (NHE3) is an important mediator of sodium absorption in the gut. SAR218034 (SAR) is an orally nonabsorbable specific NHE3 inhibitor. The effect of SAR (1 mg/kg per day in chow) on feces sodium excretion, systolic blood pressure via tail cuff, and gene expression of NHE3 in the gut were studied in senescent lean hypertensive rats (spontaneously hypertensive rats-lean, loaded with NaCl 0.7% in drinking water) and in hypertensive, obese, and hyperinsulinemic rats (spontaneously hypertensive rats-obese, not loaded with NaCl). In spontaneously hypertensive rats-lean, inhibition of intestinal NHE3 by SAR increased feces sodium excretion and reduced urinary sodium excretion, whereas absolute sodium balance and serum sodium concentration were not changed. This suggests reduced intestinal sodium absorption in SAR-treated animals and was associated with increased feces water content (58% versus 42% in placebo treated animals; P=0.0001) and reduction in systolic blood pressure from 222 +/- 7 to 198 +/- 2 mm Hg (P=0.0001). Angiotensin converting enzyme inhibition by ramipril plus NHE3 inhibition resulted in an additive blood pressure-lowering effect. In spontaneously hypertensive rats obese, SAR lowered systolic blood pressure but did not modify serum insulin or cholesterol levels. Gene expression of NHE3 was upregulated in the ileum and colon but not in the jejunum of SAR-treated rats. Reduction of intestinal sodium absorption by selective NHE3 inhibition in the gut reduces high blood pressure and increases feces water excretion. Intestinal NHE3 blockade could be a new treatment strategy for elderly patients suffering from high blood pressure and constipation. PMID- 23108658 TI - Medullary respiratory network drives sympathetic overactivity and hypertension in rats submitted to chronic intermittent hypoxia. PMID- 23108659 TI - The adipose/circulating renin-angiotensin system cross-talk enters a new dimension. PMID- 23108660 TI - Blood pressure tracking over the adult life course: patterns and correlates in the Framingham heart study. AB - The extent to which select vascular risk factors differentially influence blood pressure (BP) is incompletely understood. Thus, we used multilevel modeling to analyze serial BP measurements using 21 732 person-observations obtained on Framingham Heart Study participants (mean age, 38 years, 52% women; 4993 unique individuals) over a 28-year period. We related longitudinal tracking of each BP measure (systolic BP, diastolic BP, mean arterial pressure, and pulse pressure) to age, sex, body mass index, smoking, diabetes mellitus, total/high-density lipoprotein cholesterol ratio, and heart rate. In multivariable-adjusted analyses, we observed that older age, male sex, greater body mass index, and higher heart rate were positively associated with increase in all BP measures (P<0.0001). Notably, higher total/high-density lipoprotein cholesterol ratio was associated with greater mean arterial pressure (P<0.01). Conversely, diabetes mellitus and smoking were associated with higher pulse pressure (P<0.01). We also observed effect modification by sex: the increase in pulse pressure with age and body mass index was more pronounced in women compared with men (P<0.0001). All BP measures tracked at higher levels in both men and women with multiple vascular risk factors. Taken together, our longitudinal observations in a large community based sample demonstrate a greater pulsatile load in women than in men with increasing age. We also observed a differential impact of select vascular risk factors on the individual components of BP, underscoring distinct regulation of these measures over the life course. PMID- 23108661 TI - Immunolocalization of 8-5' and 8-8' linked structures of lignin in cell walls of Chamaecyparis obtusa using monoclonal antibodies. AB - Mouse monoclonal antibodies were generated against dehydrodiconiferyl alcohol- or pinoresinol-p-aminohippuric acid (pAHA)-bovine serum albumin (BSA) conjugate as probes that specifically react with 8-5' or 8-8' linked structure of lignin in plant cell walls. Hybridoma clones were selected that produced antibodies that positively reacted with dehydrodiconiferyl alcohol- or pinoresinol-pAHA-BSA and negatively reacted with pAHA-BSA and guaiacylglycerol-beta-guaiacyl ether-pAHA BSA conjugates containing 8-O-4' linkage. Eight clones were established for each antigen and one of each clone that positively reacted with wood sections was selected. The specificity of these antibodies was examined by competitive ELISA tests using various lignin dimers with different linkages. The anti dehydrodiconiferyl alcohol antibody reacted specifically with dehydrodiconiferyl alcohol and did not react with other model compounds containing 8-O-4', 8-8', or 5-5' linkages. The anti-pinoresinol antibody reacted specifically with pinoresinol and syringaresinol and did not react with the other model compounds containing 8-O-4', 8-5', or 5-5' linkages. The antibodies also did not react with dehydrodiconiferyl alcohol acetate or pinoresinol acetate, indicating that the presence of free phenolic or aliphatic hydroxyl group was an important factor in their reactivity. In sections of Japanese cypress (Chamaecyparis obtusa), labeling by the anti-dehydrodiconiferyl alcohol antibody was found in the secondary walls of phloem fibers and in the compound middle lamellae, and secondary walls of tracheids. Weak labeling by the anti-pinoresinol antibody was found in secondary walls of phloem fibers and secondary walls and compound middle lamellae of developed tracheids. These labelings show the localization of 8-5' and 8-8' linked structure of lignin in the cell walls. PMID- 23108662 TI - What remains after 2 months of starvation? Analysis of sequestered algae in a photosynthetic slug, Plakobranchus ocellatus (Sacoglossa, Opisthobranchia), by barcoding. AB - The sacoglossan sea slug, Plakobranchus ocellatus, is a so-called long-term retention form that incorporates chloroplasts for several months and thus is able to starve while maintaining photosynthetic activity. Little is known regarding the taxonomy and food sources of this sacoglossan, but it is suggested that P. ocellatus is a species complex and feeds on a broad variety of Ulvophyceae. In particular, we analysed specimens from the Philippines and starved them under various light conditions (high light, low light and darkness) and identified the species of algal food sources depending on starvation time and light treatment by means of DNA-barcoding using for the first time the combination of two algal chloroplast markers, rbcL and tufA. Comparison of available CO1 and 16S sequences of specimens from various localities indicate a species complex with likely four distinct clades, but food analyses do not indicate an ecological separation of the investigated clades into differing foraging strategies. The combined results from both algal markers suggest that, in general, P. ocellatus has a broad food spectrum, including members of the genera Halimeda, Caulerpa, Udotea, Acetabularia and further unidentified algae, with an emphasis on H. macroloba. Independent of the duration of starvation and light exposure, this algal species and a further unidentified Halimeda species seem to be the main food source of P. ocellatus from the Philippines. It is shown here that at least two (or possibly three) barcode markers are required to cover the entire food spectrum in future analyses of Sacoglossa. PMID- 23108663 TI - Diversity of culturable root-associated/endophytic bacteria and their chitinolytic and aflatoxin inhibition activity of peanut plant in China. AB - A total of 72 isolates of root-associated/endophytic (RAE) bacteria were isolated from peanut plants grown in the main producing areas of 6 provinces in China. The 16S rRNA gene sequences of these isolates were determined and phylogenetic analyses revealed that 72 isolates belonged to the classes Bacilli (49 isolates) and Gammaproteobacteria (23 isolates). The majority of RAE bacteria in Bacilli belonged to 2 genera, Bacillus and Lysinibacillus (48 and 1) while those in Gammaproteobacteria belonged to the genera Enterobacter, Serratia, Stenotrophomonas, and Pseudomonas (7, 11, 3 and 2 isolates, respectively). This is the first report of Lysinibacillus xylanilyticus isolate as biocontrol agent against AFs. All of the selected RAE bacteria showed inhibitory activities against Aspergillus parasiticus (A. parasiticus) growth and/or aflatoxins (AFs) production by visual agar plate assay and tip culture method. Most of the RAE bacteria strains (96 % strains) were determined to have decreased mycelia growth or AFs production levels by >50 % (p < 0.05). Bacterial isolates were further characterized for chitinolytic activity and 22 strains (30 % strains) of identified RAE bacteria degraded colloidal chitin on the chitin medium plate. Ten selected chitinolytic RAE bacteria were tested for antifungal activity on peanuts and most of them significantly decreased mycelial growth and AFs production levels by >90 %. These results showed a wide distribution of biological control bacteria against AFs in Chinese peanut main producing areas and the selected RAE bacteria could potentially be utilized for the biocontrol of toxicogenic fungi. PMID- 23108664 TI - The microbial degradation of azo dyes: minireview. AB - The removal of dyes in wastewater treatment plants still involves physical or chemical processes. Yet numerous studies currently exist on degradation based on the use of microbes-which is a well-studied field. However progress in the use of biological methods to deal with this environmentally noxious waste is currently lacking. This review focuses on the largest dye class, that is azo dyes and their biodegradation. We summarize the bacteria identified thus far which have been implicated in dye decolorization and discuss the enzymes involved and mechanisms by which these colorants are broken down. PMID- 23108665 TI - Biodegradation of lindane using a novel yeast strain, Rhodotorula sp. VITJzN03 isolated from agricultural soil. AB - Lindane is a notorious organochlorine pesticide due to its high toxicity, persistence in the environment and its tendency to bioaccumulate. A yeast strain isolated from sorghum cultivation field was able to use lindane as carbon and energy source under aerobic conditions. With molecular techniques, it was identified and named as Rhodotorula strain VITJzN03. The effects of nutritional and environmental factors on yeast growth and the biodegradation of lindane was investigated. The maximum production of yeast biomass along with 100 % lindane mineralization was noted at an initial lindane concentration of 600 mg l(-1) within a period of 10 days. Lindane concentration above 600 mg l(-1) inhibited the growth of yeast in liquid medium. A positive relationship was noted between the release of chloride ions and the increase of yeast biomass as well as degradation of lindane. The calculated degradation rate and half life of lindane were found to be 0.416 day(-1) and 1.66 days, respectively. The analysis of the metabolites using GC-MS identified the formation of seven intermediates including gamma-pentachlorocyclohexane(gamma-PCCH), 1,3,4,6-tetrachloro-1,4 cyclohexadiene(1,4-TCCHdiene), 1,2,4-trichlorobenzene (1,2,4 TCB), 1,4 dichlorobenzene (1,4 DCB), chloro-cis-1,2-dihydroxycyclohexadiene (CDCHdiene), 3 chlorocatechol (3-CC) and maleylacetate (MA) derivatives indicating that lindane degradation follows successive dechlorination and oxido-reduction. Based on the results of the present study, the possible pathway for lindane degradation by Rhodotorula sp. VITJzN03 has been proposed. To the best of our knowledge, this is the first report on lindane degradation by yeast which can serve as a potential agent for in situ bioremediation of medium to high level lindane-contaminated sites. PMID- 23108666 TI - Sirtuin-3 modulates Bak- and Bax-dependent apoptosis. AB - Sirtuin-3 exhibits properties of a tumor suppressor partly emanating from its ability to control the state of mitochondrial metabolism, with depletion of sirt 3 increasing tumor cell survival. In the present study we demonstrate that depletion of sirtuin-3 brings about an anti-apoptotic phenotype via stimulating cyclophilin-D activity, which promotes the binding of hexokinase II to the mitochondria, thereby preventing Bak/Bax dependent mitochondrial injury and cell death. By contrast, increased expression of sirtuin-3 decreases cyclophilin-D activity, resulting in detachment of hexokinase II from the mitochondria and potentiation of Bak- and Bax-induced mitochondrial injury and loss of cell viability. PMID- 23108668 TI - The RAD51 paralogs ensure cellular protection against mitotic defects and aneuploidy. AB - The interplay between homologous DNA recombination and mitotic progression is poorly understood. The five RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) are key enzymes for DNA double-strand break repair. In our search for specific functions of the various RAD51 paralogs, we found that inhibition of XRCC3 elicits checkpoint defects, while inhibition of RAD51B or RAD51C induces G2/M cell cycle arrest in HeLa cells. Using live-cell microscopy we show that in XRCC3-knockdown cells the spindle assembly checkpoint persists and there is a higher frequency of chromosome misalignments, anaphase bridges, and aneuploidy. We observed centrosome defects in the absence of XRCC3. While RAD51B and RAD51C act early in homologous recombination, XRCC3 functions jointly with GEN1 later in the pathway at the stage of Holliday junction resolution. Our data demonstrate that Holliday junction resolution has critical functions for preventing aberrant mitosis and aneuploidy in mitotic cells. PMID- 23108667 TI - Direct mobilisation of lysosomal Ca2+ triggers complex Ca2+ signals. AB - Accumulating evidence implicates acidic organelles of the endolysosomal system as mobilisable stores of Ca(2+) but their relationship to the better-characterised endoplasmic reticulum (ER) Ca(2+) store remains unclear. Here we show that rapid osmotic permeabilisation of lysosomes evokes prolonged, spatiotemporally complex Ca(2+) signals in primary cultured human fibroblasts. These Ca(2+) signals comprised an initial response that correlated with lysosomal disruption and secondary long-lasting spatially heterogeneous Ca(2+) oscillations that required ER-localised inositol trisphosphate receptors. Electron microscopy identified extensive membrane contact sites between lysosomes and the ER. Mobilisation of lysosomal Ca(2+) stores is thus sufficient to evoke ER-dependent Ca(2+) release probably through lysosome-ER membrane contact sites, and akin to the proposed mechanism of action of the Ca(2+) mobilising messenger nicotinic acid adenine dinucleotide phosphate (NAADP). Our data identify functional and physical association of discrete Ca(2+) stores important for the genesis of Ca(2+) signal complexity. PMID- 23108669 TI - Antibodies binding the ADAM10 substrate recognition domain inhibit Eph function. AB - The ADAM10 transmembrane metalloprotease cleaves a variety of cell surface proteins that are important in disease, including ligands for receptor tyrosine kinases of the erbB and Eph families. ADAM10-mediated cleavage of ephrins, the ligands for Eph receptors, is suggested to control Eph/ephrin-mediated cell-cell adhesion and segregation, important during normal developmental processes, and implicated in tumour neo-angiogenesis and metastasis. We previously identified a substrate-binding pocket in the ADAM10 C domain that binds the EphA/ephrin-A complex thereby regulating ephrin cleavage. We have now generated monoclonal antibodies specifically recognising this region of ADAM10, which inhibit ephrin cleavage and Eph/ephrin-mediated cell function, including ephrin-induced Eph receptor internalisation, phosphorylation and Eph-mediated cell segregation. Our studies confirm the important role of ADAM10 in cell-cell interactions mediated by both A- and B-type Eph receptors, and suggest antibodies against the ADAM10 substrate-recognition pocket as promising therapeutic agents, acting by inhibiting cleavage of ephrins and potentially other ADAM10 substrates. PMID- 23108670 TI - Neisseria gonorrhoeae infection causes DNA damage and affects the expression of p21, p27 and p53 in non-tumor epithelial cells. AB - The constant shedding and renewal of epithelial cells maintain the protection of epithelial barriers. Interference with the processes of host cell-cycle regulation and barrier integrity permits the bacterial pathogen Neisseria gonorrhoeae to effectively colonize and invade epithelial cells. Here, we show that a gonococcal infection causes DNA damage in human non-tumor vaginal VK2/E6E7 cells with an increase of 700 DNA strand breaks per cell per hour as detected by an alkaline DNA unwinding assay. Infected cells exhibited elevated levels of DNA double-strand breaks, as indicated by a more than 50% increase in cells expressing DNA damage-response protein 53BP1-positive foci that co-localized with phosphorylated histone H2AX (gammaH2AX). Furthermore, infected cells abolished their expression of the tumor protein p53 and induced an increase in the expression of cyclin-dependent kinase inhibitors p21 and p27 to 2.6-fold and 4.2 fold of controls, respectively. As shown by live-cell microscopy, flow cytometry assays, and BrdU incorporation assays, gonococcal infection slowed the host cell cycle progression mainly by impairing progression through the G2 phase. Our findings show new cellular players that are involved in the control of the human cell cycle during gonococcal infection and the potential of bacteria to cause cellular abnormalities. PMID- 23108671 TI - Fission yeast TORC1 prevents eIF2alpha phosphorylation in response to nitrogen and amino acids via Gcn2 kinase. AB - Serine 51 phosphorylation of the eukaryotic initiation factor-2alpha (eIF2alpha) is an important mechanism involved in blocking general protein synthesis in response to diverse types of stress. In fission yeast, three kinases (Hri1, Hri2 and Gcn2) can phosphorylate eIF2alpha at serine 51. In this study, we show that Tor2, as part of the TORC1 complex, prevents the phosphorylation of eIF2alpha in cells growing in the presence of nitrogen and amino acids. Inhibition of TORC1, either by rapamycin treatment, mutation of Tor2 or nitrogen deprivation, induces Gcn2-dependent phosphorylation of eIF2alpha. PMID- 23108672 TI - Active involvement of micro-lipid droplets and lipid-droplet-associated proteins in hormone-stimulated lipolysis in adipocytes. AB - The regulation of lipolysis in adipocytes involves coordinated actions of many lipid droplet (LD)-associated proteins such as perilipin, hormone sensitive lipase (HSL), adipose triglyceride lipase (ATGL), and its activator protein, CGI 58. Here, we describe the cellular origin and physiological significance of micro LDs (mLDs) that emerge in the cytoplasm during active lipolysis, as well as the roles of key lipolytic proteins on mLDs in differentiated 3T3-L1 adipocytes. Multiplex coherent anti-Stokes Raman scattering (CARS) microscopy demonstrated that mLDs receive the fatty acid (FA) moiety of triglyceride from pre-existing LDs during lipolysis. However, when FA re-esterification was blocked, mLDs did not emerge. Time-lapse imaging of GFP-tagged LD-associated proteins and immunocytochemical analyses showed that particulate structures carrying LD associated proteins emerged throughout the cells upon lipolytic stimulation, but not when FA re-esterification was blocked. Overall lipolysis, as estimated by glycerol release, was significantly lowered by blocking re-esterification, whereas release of free FAs was enhanced. ATGL was co-immunoprecipitated with CGI 58 from the homogenates of lipolytically stimulated cells. Following CGI-58 knockdown or ATGL inhibition with bromoenol lactone, release of both glycerol and FA was significantly lowered. AICAR, an activator of AMP-activated protein kinase, significantly increased FA release, in accordance with increased expression of ATGL, even in the absence of CGI-58. These results suggest that, besides on the surface of pre-existing central LDs, LD-associated proteins are actively involved in lipolysis on mLDs that are formed by FA re-esterification. Regulation of mLDs and LD-associated proteins may be an attractive therapeutic target against lipid-associated metabolic diseases. PMID- 23108673 TI - Exploring the effect of aminoglycoside guanidinylation on ligands for Tau exon 10 splicing regulatory element RNA. AB - We describe the effect of guanidinylation of the aminoglycoside moiety on acridine-neamine-containing ligands for the stem-loop structure located at the exon 10-5'-intron junction of Tau pre-mRNA, an important regulatory element of tau gene alternative splicing. On the basis of dynamic combinatorial chemistry experiments, ligands that combine guanidinoneamine and two different acridines were synthesized and their RNA-binding properties were compared with those of their amino precursors. Fluorescence titration experiments and UV-monitored melting curves revealed that guanidinylation has a positive effect both on the binding affinity and specificity of the ligands for the stem-loop RNA, as well as on the stabilization of all RNA sequences evaluated, particularly some mutated sequences associated with the development of FTDP-17 tauopathy. However, this correlation between binding affinity and stabilization due to guanidinylation was only found in ligands containing a longer spacer between the acridine and guanidinoneamine moieties, since a shorter spacer produced the opposite effect (e.g. lower binding affinity and lower stabilization). Furthermore, spectroscopic studies suggest that ligand binding does not significantly change the overall RNA structure upon binding (circular dichroism) and that the acridine moiety might intercalate near the bulged region of the stem-loop structure (UV-Vis and NMR spectroscopy). PMID- 23108674 TI - Conventional strain energies of azetidine and phosphetane: can density functional theory yield reliable results? AB - The conventional strain energies for azetidine and phosphetane are determined within the isodesmic, homodesmotic, and hyperhomodesmotic models. Optimum equilibrium geometries, harmonic vibrational frequencies, and corresponding electronic energies and zero-point vibrational energies are computed for all pertinent molecular systems using self-consistent field theory, second-order perturbation theory, and density functional theory and using the correlation consistent basis sets cc-pVDZ, cc-pVTZ, and cc-pVQZ. Single point fourth-order perturbation theory, CCSD, and CCSD(T) calculations using the cc-pVTZ and the cc pVQZ basis sets are computed using the MP2/cc-pVTZ and MP2/cc-pVQZ optimized geometries, respectively, to ascertain the contribution of higher order correlation effects and to determine if the quadruple-zeta valence basis set is needed when higher order correlation is included. In the density functional theory study, eight different functionals are used including B3LYP, wB97XD, and M06-2X to determine if any functional can yield results similar to those obtained at the CCSD(T) level. PMID- 23108675 TI - The power to block the Affordable Care Act: what are the limits? PMID- 23108678 TI - Management of acute lateral ankle ligament injury in the athlete. AB - PURPOSE: Inversion injuries involve about 25 % of all injuries of the musculoskeletal system and about 50 % of these injuries are sport-related. This article reviews the acute lateral ankle injuries with special emphasis on a rationale for treatment of these injuries in athletes. METHODS: A narrative review was performed using Pubmed/Medline, Ovid and Embase using key words: ankle ligaments, injury, lateral ligament, ankle sprain and athlete. Articles related to the topic were included and reviewed. RESULTS: It is estimated that one inversion injury of the ankle occurs for every 10,000 people each day. Ankle sprains constitute 7-10 % of all admissions to hospital emergency departments. Inversion injuries involve about 25 % of all injuries of the musculoskeletal system, and about 50 % of these injuries are sport-related. The lateral ankle ligament complex consists of three ligaments: the anterior talofibular ligament, the calcaneofibular ligament and the posterior talofibular ligament. The most common trauma mechanism is supination and adduction (inversion) of the plantar flexed foot. CONCLUSION: Delayed physical examination provides a more accurate diagnosis. Ultrasound and MRI can be useful in diagnosing associated injury and are routine investigations in professional athletes. Successful treatment of grade II and III acute lateral ankle ligament injuries can be achieved with individualized aggressive, non-operative measures. RICE therapy is the treatment of choice for the first 4-5 days to reduce pain and swelling. Initially, 10-14 days of immobilization in a below the knee cast/brace is beneficial followed by a period in a lace-up brace or functional taping reduces the risk of recurrent injury. Acute repair of the lateral ankle ligaments in grade III injuries in professional athletes may give better results. PMID- 23108679 TI - A biomechanical analysis of the soft tissue and osseous constraints of the hip joint. AB - PURPOSE: The goal of this study was to determine the role of soft tissue and osseous constraints in hip biomechanics using a unique robotic testing apparatus. METHODS: Four fresh-frozen human cadaveric hemi-pelvises without degenerative changes or dysplasia were stripped of all soft tissue except the ligamentous capsule and the intra-articular structures. All hips were tested using a robotic manipulator/universal force-moment sensor testing system to measure and compare end-range of motion (ROM) and kinematic translations in "capsule vented" (a small hole in the capsule) and "capsule separated" (capsular ligaments separated from each other) states. Then, the "capsule vented" state was compared to the condition in which the capsule and labrum were removed to calculate bone and soft tissue forces with 40 N of load applied in six different directions along three axes. RESULTS: There were no significant differences in end-ROM or kinematic translations between the "capsule vented" and "capsule separated" states. Bone forces significantly increased with loads applied in the anterior, posterior and superior directions. Soft tissue forces increased significantly with loads applied in the medial, lateral and inferior directions. CONCLUSION: The individual hip capsular ligaments act independently of each other to resist end ROM. Both osseous and soft tissue constraints are important to hip biomechanics depending upon the direction of applied force. The clinical relevance is that surgical management for hip disorders should preserve the soft tissue constraints in the hip when possible to maintain normal hip biomechanics. PMID- 23108680 TI - Cartilage repair using mesenchymal stem cell (MSC) sheet and MSCs-loaded bilayer PLGA scaffold in a rabbit model. AB - PURPOSE: The integration of regenerated cartilage with surrounding native cartilage is a major challenge for the success of cartilage tissue-engineering strategies. The purpose of this study is to investigate whether incorporation of the power of mesenchymal stem cell (MSC) sheet to MSCs-loaded bilayer poly (lactic-co-glycolic acid) (PLGA) scaffolds can improve the integration and repair of cartilage defects in a rabbit model. METHODS: Rabbit bone marrow-derived MSCs were cultured and formed cell sheet. Full-thickness cylindrical osteochondral defects (4 mm in diameter, 3 mm in depth) were created in the patellar groove of 18 New Zealand white rabbits and the osteochondral defects were treated with PLGA scaffold (n = 6), PLGA/MSCs (n = 6) or MSC sheet-encapsulated PLGA/MSCs (n = 6). After 6 and 12 weeks, the integration and tissue response were evaluated histologically. RESULTS: The MSC sheet-encapsulated PLGA/MCSs group showed significantly more amounts of hyaline cartilage and higher histological scores than PLGA/MSCs group and PLGA group (P < 0.05). In addition, the MSC sheet encapsulated PLGA/MCSs group showed the best integration between the repaired cartilage and surrounding normal cartilage and subchondral bone compared to other two groups. CONCLUSIONS: The novel method of incorporation of MSC sheet to PLGA/MCSs could enhance the ability of cartilage regeneration and integration between repair cartilage and the surrounding cartilage. Transplantation of autologous MSC sheet combined with traditional strategies or cartilage debris might provide therapeutic opportunities for improving cartilage regeneration and integration in humans. PMID- 23108681 TI - One-year clinical and MR imaging outcome after partial meniscal replacement in stabilized knees using a collagen meniscus implant. AB - PURPOSE: The purpose of the study was to evaluate the clinical and radiological outcomes after medial/lateral collagen meniscus substitution (CMI) at 12 months postoperatively. METHODS: Sixty-seven patients (m:f = 47:20, mean age 36 +/- 10 years) underwent arthroscopic CMI after previous subtotal medial (n = 55) or lateral meniscectomy (n = 12) due to persistent joint line pain (n = 25) or to prophylactic reasons (n = 42). Clinical follow-up consisted of IKDC score, Tegner score, Lysholm score, and visual analog scale for pain and satisfaction (preinjury, preoperatively, and 12 months postoperatively; follow-up rate 90 %). MRI scans were analyzed according to the Genovese criteria. RESULTS: Nineteen patients (29 %) showed a normal (A), 35 nearly normal (B), 5 abnormal (C), and 1 patient severely abnormal total IKDC score (D). The median Tegner preinjury score was 7 (range 2-10) and at follow-up 6 (range 2-10). The mean Lysholm score before surgery was 68 +/- 20 and 93 +/- 9 at follow-up. Preoperatively, the mean VAS pain was 4.4 +/- 3.1 and 2.0 +/- 1.0 at follow-up. Clinical failure of the CMI occurred in 3 patients (n = 1 infection, n = 1 failure of the implant, n = 1 chronic synovitis). On MRI, the CMI was completely resorbed in 3 patients (5 %), partially resorbed in 55 (92 %), and entirely preserved in 3 (5 %) patients. In 5 patients (8 %) the CMI was isointense, in 54 (90 %) slightly and 1 (2 %) highly hyperintense. 43 (72 %) patients showed an extrusion of the CMI implant of more than 3 mm. CONCLUSIONS: Significant pain relief and functional improvement throughout all scores at 1 year was noted. The CMI undergoes significant remodeling, degradation, resorption, and extrusion in most of the patients. No difference in outcomes between the medial and lateral CMI was observed. LEVEL OF EVIDENCE: Prospective therapeutic study, Level IV. PMID- 23108682 TI - Roles of ACL remnants in knee stability. AB - PURPOSE: This study evaluated knee laxity in anterior tibial translation and rotation following removal of anterior cruciate ligament (ACL) remnants using a computer navigation system. METHODS: This prospective study included 50 knees undergoing primary ACL reconstruction using a navigation system. ACL remnants were classified into four morphologic types: Type 1, bridging between the roof of the intercondylar notch and tibia; Type 2, bridging between the posterior cruciate ligament and tibia; Type 3, bridging between the anatomical insertions of the ACL on the lateral wall of the femoral condyle and the tibia; and Type 4, no bridging of ACL remnants. Anterior tibial translation and rotatory laxity were measured before and after remnant resection using a navigation system at 30 degrees , 60 degrees , and 90 degrees of knee flexion. The amount of change in anterior tibial translation and rotatory laxity of each type was compared among the types. RESULTS: The different morphologic types of ACL remnants were as follows: Type 1, 15 knees; Type 2, 9 knees; Type 3, 6 knees; and Type 4, 20 knees. The amount of change in anterior tibial translation and rotatory laxity at 30 degrees knee flexion in Type 3 was significantly larger than in the other types. There were no significant differences in either tibial translation or rotatory laxity at 60 degrees and 90 degrees knee flexion among the types. CONCLUSIONS: In Type 3, ACL remnants contributed to anteroposterior and rotatory knee laxity evaluated at 30 degrees knee flexion. The bridging point of the remnants is important to knee laxity. The Type 3 remnant should be preserved as much as possible when ACL reconstruction surgery is performed. LEVEL OF EVIDENCE: Prognostic study, level II. PMID- 23108683 TI - Does the severity of preoperative varus deformity influence postoperative alignment in both conventional and computer-assisted total knee arthroplasty? AB - PURPOSE: The postoperative alignment was compared according to the severity of preoperative varus deformity in computer-assisted and conventional total knee arthroplasty (CAS-TKA). METHODS: The study reviewed 127 consecutive CAS-TKA and 236 conventional TKA, retrospectively. In CAS-TKA, 77 knees with a varus deformity <=15.0 degrees were classified in group CAS-A and 50 knees with a varus deformity >15.0 degrees were classified in group CAS-B. In conventional groups, 204 knees with a varus deformity <=15.0 were classified in group Conventional-A and 32 knees with a varus deformity >15.0 degrees were classified in group Conventional-B. The postoperative mechanical axis (MA) was compared among groups CAS-A, CAS-B, Conventional-A and Conventional-B. RESULTS: The average postoperative MA was 0.7 degrees varus in group CAS-A, 2.8 degrees varus in group CAS-B, 1.1 degrees varus in group Conventional-A and 3.2 degrees varus in group Conventional-B (p < 0.001). The postoperative MA was within 3 degrees in 81.8, 62.0, 58.8 and 37.5 % of group CAS-A, CAS-B, Conventional-A and Conventional-B, respectively. CONCLUSIONS: The severity of preoperative varus deformity influences postoperative alignment despite using CAS. More careful correction of the alignment is required, especially in TKA performed on patients with a greater varus deformity. LEVEL OF EVIDENCE: III. PMID- 23108684 TI - Medial patellofemoral ligament reconstruction for patellar maltracking following total knee arthroplasty is effective. AB - PURPOSE: Maltracking of the patella after total knee arthroplasty (TKA) remains a well-recognized problem. The medial patellofemoral ligament (MPFL) has shown to be important for patellar stabilization and reconstructions of the MPFL have already shown excellent functional outcomes for patellar instability of the native knee. Nevertheless, there is only limited literature on using an MPFL reconstruction for correction of patellar maltracking after TKA. In this retrospective study, a consecutive case series was evaluated. METHODS: Between 2007 and 2010, nine patients (nine knees) with anterior knee pain and symptomatic (sub)luxations of the patella after primary or revision TKA were treated by reconstruction of the MPFL in combination with a lateral release. In two cases, an additional tibial tuberosity transfer was performed, due to insufficient per operative correction. Pre-operative work-up included a CT scan to rule out component malrotation and disorders in limb alignment. Pre- and post-operative patellar displacement and lateral patellar tilt were measured on axial radiographs. Clinical outcome was evaluated using the visual analogue scale (VAS) satisfaction, VAS pain, dislocation rate and Bartlett patella score. RESULTS: Median patellar displacement improved from 29 mm (0-44) to 0 mm (0-9) post operatively. Median lateral patellar tilt was 45 degrees (23-62) pre-operative and changed to a median 15 degrees (-3 to 21) post-operative. Median VAS satisfaction was 8 (5-9) and only one patient reported a subluxing feeling afterwards. The Bartlett patella score displayed a diverse picture. CONCLUSIONS: Patellar maltracking after primary or revision TKA without malrotation can effectively be treated by MPFL reconstruction in combination with a lateral release. Only in limited cases, an additional tibial tuberosity transfer is needed. LEVEL OF EVIDENCE: IV. PMID- 23108685 TI - Efficacy of interscalene block combined with multimodal pain control for postoperative analgesia after rotator cuff repair. AB - PURPOSE: The aim of the study reported here was to compare the efficacy and safety of postoperative analgesia provided by interscalene block with multimodal pain control (IB-MPC) versus that provided by multimodal pain control (MPC) alone after arthroscopic rotator cuff repair. METHODS: Sixty consecutive patients were assigned to either the IB-MPC group (30 patients) or the MPC group (30 patients). Visual analogue scale (VAS) pain scores before surgery and through day 5 after surgery, consumption of rescue analgesic, adverse effects and complications were evaluated. RESULTS: Mean VAS pain scores immediately after surgery and on days 1 through 5 after surgery were 3.9 +/- 2.6, 4.4 +/- 1.5, 3.4 +/- 1.3, 2.7 +/- 1.3, 2.4 +/- 1.2, and 2.0 +/- 1.0, respectively, in the IB-MPC group and 6.2 +/- 1.8, 4.1 +/- 1.7, 3.2 +/- 1.9, 2.7 +/- 1.4, 2.5 +/- 1.3, and 2.0 +/- 1.2, respectively, in the MPC group. The IB-MPC group had significantly lower VAS pain score immediately after surgery than the MPC group did (P < 0.001). There were no statistically significant differences regarding consumption of rescue analgesic or adverse effects between the two groups (n.s.). In the IB-MPC group, complications related to interscalene block included tingling of the hand in three patients and numbness of the neck and ear in two. However, these symptoms resolved spontaneously within a few days. No patients had major complications related to interscalene block. CONCLUSIONS: IB-MPC achieved better pain control immediately after surgery than MPC alone, without major complications related to interscalene block. It is an effective and safe method for providing postoperative analgesia after arthroscopic rotator cuff repair. LEVEL OF EVIDENCE: Prospective Comparative Study, Prognosis Study, Level II. PMID- 23108686 TI - The role of the peroneal tendons in passive stabilisation of the ankle joint: an in vitro study. AB - PURPOSE: Peroneal tendons are known as active stabilizer in acute ankle sprain while an intact ankle mortise and intact lateral ligaments are required for passive stability of the ankle joint. The goal of this study is to determine the peroneal tendons as passive stabilizer in case of lateral ligament instability. METHODS: Twelve (12) human lower leg cadaver specimens underwent a torsion simulation in the testing system, 858 Mini Bionix((r)) (MTS((r)) Systems Corporation, Eden Prairie, MN, USA) and a specially designed mounting platform for the specimens. The preset torsion between tibia and calcaneus was primarily set at 30 degrees of internal rotation during plantar flexion and hindfoot inversion. The resisting torque around mechanical tibial axis was recorded which ensures stability in ankle sprain trauma. The first series of measurements were performed on healthy specimens and the following after transecting structures in following order: ATFL (anterior talofibular ligament) in combination with CFL (calcaneofibular ligament), followed by peroneus longus tendon and finally peroneus brevis tendon. RESULTS: The combined lateral ATFL and CFL instability shows a decrease of the resisting torque which ensures stability in ankle sprain trauma. Only a transection of PLT with existing lateral dual-ligament instability results in a significant decrease in torque (p < 0.0001). CONCLUSION: The PLT has a substantial effect on passive stability at a present lateral ligament lesion in ankle sprain trauma. A deficiency in viscoelastic properties of the peroneus longus tendon must be considered in diagnostic and treatment for ankle instability. PMID- 23108688 TI - A response to "Bridging the gender gap in communication skills" by Wu and McLaughlin (2012). PMID- 23108689 TI - Bridging the gender gap in communication skills. PMID- 23108690 TI - Making the horse drink: use of mini-CEX in an assessment for learning view. PMID- 23108693 TI - Preparation and characterization of poly(epsilon-caprolactone) nanospheres containing the local anesthetic lidocaine. AB - The objective of this work was to develop a modified release system for the local anesthetic lidocaine (LDC), using poly(epsilon-caprolactone) (PCL) nanospheres (NSs), to improve the pharmacological properties of the drug when administered by the infiltration route. In vitro experiments were used to characterize the system and investigate the release mechanism. The NSs presented a polydispersion index of 0.072, an average diameter of 449.6 nm, a zeta potential of -20.1 mV, and an association efficiency of 93.3%. The release profiles showed that the release of associated LDC was slower than that of the free drug. Atomic force microscopy analyses showed that the spherical structure of the particles was preserved as a function of time, as well as after the release experiments. Cytotoxicity and pharmacological tests confirmed that association with the NSs reduced the toxicity of LDC, and prolonged its anesthetic action. This new formulation could potentially be used in applications requiring gradual anesthetic release, especially dental procedures. PMID- 23108694 TI - Ultrasonic nebulisation extraction: extraction column coupled with liquid phase microextraction for analysis of the volatile organic compounds in Foeniculum vulgare Mill. as a model. AB - INTRODUCTION: As the concentrations of the volatile organic compounds are always low and their matrix is complex, it is necessary to pre-concentrate the volatile organic compounds before analysis. Ultrasonic nebulisation extraction with a self made extraction column coupled with liquid phase microextraction is developed for the extraction of active constituents from spices. OBJECTIVE: To develop an environmentally compatible extraction technique for the preparation and analysis of the volatile organic compounds from spices. METHOD: The sample is placed into the nebulisation vessel of a nebulisation humidifier and a purging gas is blown through the vessel continuously. When the nebuliser is switched on, a ultrasonic fountain is formed by ultrasonic vibration and the target analytes are transferred from the sample solution to the vapour phase and then concentrated on the extraction solvent in the extraction column. After extraction for 3 min and allowed to stand upright for 5 min, the extract is analysed by GC and GC-MS. Different methods of comparison can then be carried out. RESULTS: Optimum conditions were found to be: 30 MUL of n-tetradecane as the extraction solvent, a flow rate for the purging gas of 40 mL/min, a purging time of 3 min and a standing time was 5 min. The contents of constituents in the extract obtained by the proposed method were close to those obtained by hydrodistillation (HD). Moreover, the proposed method achieves higher enrichment efficiency. CONCLUSION: A method was developed for the extraction of volatile organic compounds from spices. The study has shown that it is a fast and environmentally sustainable technique. PMID- 23108695 TI - Hemoglobin levels triggering erythropoiesis-stimulating agent therapy in patients with cancer: the shift after United States Food and Drug Administration policy changes. AB - STUDY OBJECTIVE: To determine whether the hemoglobin level at which health care providers prescribed erythropoiesis-stimulating agent (ESA) therapy (trigger hemoglobin level) for their patients receiving chemotherapy was lower after the United States Food and Drug Administration (FDA) mandated a black-box warning in March 2007. DESIGN: Retrospective analysis. DATA SOURCE: U.S. Department of Veterans Affairs Healthcare System (VA) national databases. PATIENTS: A total of 7450 patients who were diagnosed with cancer between 2002 and 2009, were undergoing chemotherapy, and who received an ESA within 12 months after their cancer diagnosis. MEASUREMENTS AND MAIN RESULTS: Data were collected on patients' demographic, clinical, environmental, and treatment-related factors. After controlling for these factors, multivariable regression analyses were used to compare the trigger hemoglobin level before and after the FDA-mandated labeling change. The average trigger hemoglobin level was 0.73 g/dl lower after the labeling change (95% confidence interval [CI] -0.84 to -0.63). Moreover, the decline in trigger hemoglobin levels began in mid-2006, when the average trigger hemoglobin level fell from 10.50 g/dl in early 2006 (95% CI 10.36-10.63) to 9.30 g/dl by late 2009 (95% CI 9.10-9.49). CONCLUSION: Even before the 2007 FDA mandated changes in ESA product labeling, hemoglobin levels that triggered ESA treatment began declining for patients receiving cancer care within the VA. This highlights the critical importance of dissemination of postmarketing safety data to impact shifts in ESA use for anemia management. PMID- 23108696 TI - Incidence of atypical acute nerve hyperexcitability symptoms in oxaliplatin treated patients with colorectal cancer. AB - CONTEXT: Peripheral, acute or chronic, neurotoxicity is one of the main dose limiting adverse effects of oxaliplatin (OXA). Acute neurotoxicity is typically characterized by distal and perioral cold-induced paresthesias and dysesthesias, but other uncommon symptoms might also be present. OBJECTIVES: The aim of this post hoc analysis of data extracted from a prospective, multicenter study was to assess the incidence of uncommon acute OXA neurotoxicity symptoms in patients undergoing OXA-based chemotherapy. METHODS: One hundred chemotherapy-naive patients (62 males, 38 females, aged 64.7 +/- 8.7 years) with colorectal cancer scheduled to receive OXA-based therapy (FOLFOX-4, FOLFOX-6, and XELOX) underwent neurologic evaluation after the 1st infusion and then after 3 and 6 months of OXA based chemotherapy (after 6th or 4th and 12th or 8th cycles, respectively, according to regimen). At evaluation, patients were asked to report the presence and characteristics of acute hyperexcitability symptoms. RESULTS: Eighty-two patients presented typical symptoms of acute OXA neurotoxicity in the form of cold-induced paresthesias and dysesthesias. In 45/82 (54.9 %) of patients, uncommon symptoms were also present; shortness of breath (32 %), jaw spasm (26 %), fasciculations (25 %), cramps (20 %), and difficulty in swallowing (18 %) were more frequently reported, while voice (4 %) and visual changes, ptosis and pseudolaryngospasm (1 %) occurred rarely. No significant correlation was disclosed between acute OXA neurotoxicity and chemotherapy regimen, cumulative dose of OXA or patients' age. CONCLUSIONS: A high percentage of patients treated with OXA-based chemotherapy develop acute neurotoxicity also with uncommon manifestations. Since OXA acute neurotoxicity might be related to the onset of chronic neurotoxicity, these patients should be closely monitored to avoid this dose-limiting adverse effect. PMID- 23108697 TI - Sunitinib combined with pemetrexed and cisplatin: results of a phase I dose escalation and pharmacokinetic study in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer and mesothelioma. AB - PURPOSE: To determine the maximum tolerated dose (MTD), safety and tolerability of sunitinib plus pemetrexed and cisplatin for advanced solid malignancies. METHODS: Using a 3 + 3 dose-escalation design, patients received oral sunitinib (37.5 or 50 mg) qd on a continuous daily dosing (CDD) schedule or Schedule 2/1 (2 weeks on, 1 week off treatment) plus pemetrexed (400 or 500 mg/m(2) IV) and cisplatin (75 mg/m(2) IV) q3w up to 6 cycles. RESULTS: Sunitinib 37.5 mg/pemetrexed 400 mg/m(2)/cisplatin 75 mg/m(2) CDD (n = 5) was not tolerated. Lower doses on this schedule were not explored. The Schedule 2/1 MTD (n = 15) was sunitinib 37.5 mg/pemetrexed 500 mg/m(2)/cisplatin 75 mg/m(2), based on one dose limiting toxicity (myocardial infarction) out of six patients. The MTD was further studied in an expansion cohort of 10 non-small cell lung cancer (NSCLC) patients and one mesothelioma patient. There were no clinically significant drug drug interactions. Cumulative myelosuppression was problematic: the median relative dose intensity (% actual/intended) across all cycles was 61 % for sunitinib, 78 % for pemetrexed, and 74 % for cisplatin. Four of eight NSCLC patients in the dose-escalation and expansion cohorts at the Schedule 2/1 MTD who were evaluable for efficacy had stable disease >= 8 weeks, and the one patient with mesothelioma had a partial response. CONCLUSIONS: In patients with advanced solid malignancies, sunitinib was not tolerated at 37.5 mg CDD with standard pemetrexed and cisplatin doses. Dose reductions were often needed due to cumulative myelosuppression following cycle 1. The MTD showed modest antitumor activity. PMID- 23108692 TI - A randomized, double-blind, placebo-controlled study of latrepirdine in patients with mild to moderate Huntington disease. AB - BACKGROUND Latrepirdine is an orally administered experimental small molecule that was initially developed as an antihistamine and subsequently was shown to stabilize mitochondrial membranes and function, which might be impaired in Huntington disease. OBJECTIVE To determine the effect of latrepirdine on cognition and global function in patients with mild to moderate Huntington disease. DESIGN Randomized, double-blind, placebo-controlled study. SETTING Sixty four research centers in Australia, Europe, and North America. PATIENTS Four hundred three patients with mild to moderate Huntington disease and baseline cognitive impairment (Mini-Mental State Examination score, 10-26). INTERVENTION Latrepirdine (20 mg) vs matching placebo administered orally 3 times daily for 26 weeks. MAIN OUTCOME MEASURES The co-primary outcome measures were cognition as measured by the change in Mini-Mental State Examination score from baseline to week 26 and global function at week 26 as measured by the Clinician Interview Based Impression of Change, plus carer interview, which ranges from 1 (marked improvement) to 7 (marked worsening). Secondary efficacy outcome measures included behavior, daily function, motor function, and safety. RESULTS The mean change in Mini-Mental State Examination score among participants randomized to latrepirdine (1.5-point improvement) did not differ significantly from that among participants randomized to placebo (1.3-point improvement) (P=.39). Similarly, the distribution of the Clinician Interview-Based Impression of Change, plus carer interview did not differ significantly among those randomized to latrepirdine compared with placebo (P=.84). No significant treatment effects were detected on the secondary efficacy outcome measures. The incidence of adverse events was similar between those randomized to latrepirdine (68.5%) and placebo (68.0%). CONCLUSION In patients with mild to moderate Huntington disease and cognitive impairment, treatment with latrepirdine for 6 months was safe and well tolerated but did not improve cognition or global function relative to placebo. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00920946. PMID- 23108698 TI - A phase I trial of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer. AB - PURPOSE: Platelet-derived growth factor receptor (PDGFR) inhibition by reducing tumoral interstitial fluid pressure might increase the efficacy of chemotherapy. Imatinib inhibits PDGFR kinase activity at therapeutically relevant doses. This phase I study aimed to assess the maximal tolerated dose (MTD) of imatinib in combination with mFOLFOX6-bevacizumab in patients with advanced colorectal cancer and to identify pharmacokinetic (PK) interactions and toxicities. METHODS: Eligible patients had measurable disease and adequate organ function. On day-14, patients commenced imatinib daily plus bevacizumab (5 mg/kg/2 weekly). Two weeks later (day 1), patients were also treated with full dose mFOLFOX6-bevacizumab for 12 cycles. Blood samples were taken for PK. DLTs defined in the first 6 weeks. Standard dose escalation of imatinib, with 3 patient cohorts: planned dose levels (DL): DL1; 400 mg, DL2; 600 mg, DL3; 800 mg daily. RESULTS: Ten patients enrolled. DL1 3 patients, DL2 7 patients. DLTs observed in 3 of 6 patients in DL2: febrile neutropenia (2); Grade 3 infection and Grade 4 neutropenia (1). Neutropenia was most frequent AEs: Grade 3/4 in >60 % of patients overall. In DL2 pts, imatinib clearance was reduced post-chemotherapy (P < 0.05). Oxaliplatin and 5FU PK unchanged by imatinib. CONCLUSIONS: MTD was imatinib 400 mg plus full dose mFOLFOX-bevacizumab. Dose escalation of imatinib limited by neutropenia. Further study is warranted as imatinib can be delivered at levels that inhibit PDGFR. PMID- 23108699 TI - In vitro cytotoxicity, pharmacokinetics, tissue distribution, and metabolism of small-molecule protein kinase D inhibitors, kb-NB142-70 and kb-NB165-09, in mice bearing human cancer xenografts. AB - PURPOSE: Protein kinase D (PKD) mediates diverse biological responses including cell growth and survival. Therefore, PKD inhibitors may have therapeutic potential. We evaluated the in vitro cytotoxicity of two PKD inhibitors, kb-NB142 70 and its methoxy analogue, kb-NB165-09, and examined their in vivo efficacy and pharmacokinetics. METHODS: The in vitro cytotoxicities of kb-NB142-70 and kb NB165-09 were evaluated by MTT assay against PC-3, androgen-independent prostate cancer cells, and CFPAC-1 and PANC-1, pancreatic cancer cells. Efficacy studies were conducted in mice bearing either PC-3 or CPFAC-1 xenografts. Tumor-bearing mice were euthanized between 5 and 1,440 min after iv dosing, and plasma and tissue concentrations were measured by HPLC-UV. Metabolites were characterized by LC-MS/MS. RESULTS: kb-NB142-70 and kb-NB165-09 inhibited cellular growth in the low-mid MUM range. The compounds were inactive when administered to tumor-bearing mice. In mice treated with kb-NB142-70, the plasma C (max) was 36.9 nmol/mL, and the PC-3 tumor C (max) was 11.8 nmol/g. In mice dosed with kb-NB165-09, the plasma C (max) was 61.9 nmol/mL, while the PANC-1 tumor C (max) was 8.0 nmol/g. The plasma half-lives of kb-NB142-70 and kb-NB165-09 were 6 and 14 min, respectively. Both compounds underwent oxidation and glucuronidation. CONCLUSIONS: kb-NB142-70 and kb-NB165-09 were rapidly metabolized, and concentrations in tumor were lower than those required for in vitro cytotoxicity. Replacement of the phenolic hydroxyl group with a methoxy group increased the plasma half-life of kb-NB165-09 2.3-fold over that of kb-NB142-70. Rapid metabolism in mice suggests that next-generation compounds will require further structural modifications to increase potency and/or metabolic stability. PMID- 23108700 TI - The immune microenvironment of human tumors: general significance and clinical impact. AB - Human cancers grow in a microenvironment of stromal, inflammatory and immunocompetent cells which is variable from tumor to tumor. The characterization of the immune contexture, i.e. the type, density and functional orientation of immunocompetent cells, the presence or absence of tertiary lymphoid structures is a major prognostic factor for patients survival and represent a guide and a target for innovative cancer therapies. PMID- 23108701 TI - Direct ab initio study on the rate constants of radical C2(A 3Pi(u)) + C3H8 reaction. AB - The mechanism and kinetics of the radical (3)C(2) + C(3)H(8) reaction have been investigated theoretically by direct ab initio kinetics over a wide temperature range. The potential energy surfaces have been constructed at the CCSD(T)/B3//UMP2/B1 levels of theory. The electron transfer was also analyzed by quasi-restricted orbital (QRO) in detail. It was shown that all these channels proceed exclusively via hydrogen abstraction. The overall ICVT/SCT rate constants are in agreement with the available experimental results. The prediction shows that the secondary hydrogen of C(3)H(8) abstraction by (3)C(2) radical is the major pathway at low temperatures (below 700 K), while as the temperature increases, the primary hydrogen of C(3)H(8) abstraction becomes more important and more favorable. A negative temperature dependence of the rate constants for the reaction of (3)C(2) + C(3)H(8) was observed. The three-(k (3)) and four parameter (k (4)) rate-temperature expressions were also provided within 243-2000 K to facilitate future experimental studies. PMID- 23108702 TI - In silico characterization of a novel beta-1,3-glucanase gene from Bacillus amyloliquefaciens--a bacterial endophyte of Hevea brasiliensis antagonistic to Phytophthora meadii. AB - We report the molecular characterization of beta-1,3-glucanase-producing Bacillus amyloliquefaciens-an endophyte of Hevea brasiliensis antagonistic to Phytophthora meadii. After cloning and sequencing, the beta-1,3-glucanase gene was found to be 747 bp in length. A homology model of the beta-1,3-glucanase protein was built from the amino acid sequence obtained upon translation of the gene. The target beta-1,3-glucanase protein and the template protein, endo beta-1,3-1,4-glucanase protein (PDB ID: 3o5s), were found to share 94% sequence identity and to have similar secondary and tertiary structures. In the modeled structure, three residues in the active site region of the template-Asn52, Ile157 and Val158-were substituted with Asp, Leu and Ala, respectively. Computer-aided docking studies of the substrate disaccharide (beta-1, 3-glucan) with the target as well as with the template proteins showed that the two protein-substrate complexes were stabilized by three hydrogen bonds and by many van der Waals interactions. Although the binding energies and the number of hydrogen bonds were the same in both complexes, the orientations of the substrate in the active sites of the two proteins were different. These variations might be due to the change in the three amino acids in the active site region of the two proteins. The difference in substrate orientation in the active site could also affect the catalytic potential of the beta-1,3 glucanase enzyme. PMID- 23108703 TI - Boron-doped tri(9,10-anthrylene)s: synthesis, structural characterization, and optoelectronic properties. AB - The reaction of 9,10-dibromo-9,10-dihydro-9,10-diboraanthracene (9,10-dibromo DBA, 3) with two equivalents of 9-lithio-2,6- or 9-lithio-2,7-di-tert butylanthracene gave the corresponding 9,10-dianthryl-DBAs featuring two (4) or four (5) inward-pointing tert-butyl groups. Compound 4 exists as two atropisomers, 4 and 4', due to hindered rotation about the exocyclic B-C bonds. X ray crystallography of 5 suggests that the overall interactions between facing tert-butyl groups are attractive rather than repulsive. Even in solution, 4/4' and 5 are stable toward air and moisture for several hours. Treatment of 3 with 10-lithio-9-R-2,7-di-tert-butylanthracenes carrying phenyl (R=Ph), dimesitylboryl (R=Mes(2)B), or N,N-di(p-tolyl)amino (R=Tol(2)N) groups gave the corresponding 9,10-dianthryl-DBA derivatives 9-11 in moderate to good yields. In these molecules, all four solubilizing tert-butyl groups are outward pointing. The solid-state structures of 4, 5, 9, and 10 reveal twisted conformations about the exocyclic B-C bonds with dihedral angles of 70-90 degrees . A significant electron-withdrawing character was proven for the Mes(2)B moiety, but no appreciable +M effect was evident for Tol(2)N. Compounds 5, 9, and 11 show two reversible DBA-centered reduction waves in the cyclic voltammogram. In the case of 10, a third reversible redox transition can be assigned to the Mes(2)B-anthryl substituents. The UV/Vis absorption spectrum of 5 is characterized by a very broad band at lambda(max)=510 nm, attributable to a twisted intramolecular charge transfer interaction from the anthryl donors to the DBA acceptor. The corresponding emission band shows pronounced positive solvatochromism (lambda(em)=567 nm, C(6)H(12); 680 nm, CH(2)Cl(2)) in line with a highly polar excited state. The charge-transfer bands of 10 and 11, as well as the emission bands of 9 and 10, are redshifted relative to those of 5. The Tol(2)N derivative 11 is essentially nonfluorescent in solution, but emits bright wine-red light in the solid state. PMID- 23108704 TI - Nd(2)Fe(14)B/FeCo anisotropic nanocomposite films with a large maximum energy product. AB - Anisotropic Nd(2) Fe(14) B/Fe(67) Co(33) nanocomposite thin films are successfully fabricated. The multilayer composite films comprise Nd-rich shell enveloped Nd(2) Fe(14) B grains and a Fe(67) Co(33) phase. The strong (001) texture of the Nd(2) Fe(14) B grains and the presence of exchange-coupled Fe(67) Co(33) lead to a high remanence and the presence of the Nd-rich shell gives rise to a high coercivity. The unique nanocomposite microstructure provides hints for developing rare-earth-lean high-performance magnets. PMID- 23108705 TI - One-pot synthesis of pillar[n]arenes catalyzed by a minimum amount of TfOH and a solution-phase mechanistic study. AB - A practical and effective trifluoromethanesulfonic acid (TfOH)-catalyzed cyclooligomerization strategy was developed for the synthesis of functionalized pillar[n]arenes and copillar[5]arenes from 1,4-dialkoxybenzenes with paraformaldehyde under mild reaction conditions, and the reaction mechanism of solution-phase catalytic synthesis of pillararenes was investigated by room temperature X-band ESR spectroscopy, mass spectroscopy, NMR and control experiments, suggesting a free radical process initially and a Friedel-Crafts alkylation process during the consequent coupling and ring-closure stage. PMID- 23108706 TI - Toward new classification criteria for Sjogren's syndrome? PMID- 23108707 TI - Benefits of educational attainment on adult fluid cognition: international evidence from three birth cohorts. AB - BACKGROUND: Educational attainment is highly correlated with social inequalities in adult cognitive health; however, the nature of this correlation is in dispute. Recently, researchers have argued that educational inequalities are an artefact of selection by individual differences in prior cognitive ability, which both drives educational attainment and tracks across the rest of the life course. Although few would deny that educational attainment is at least partly determined by prior cognitive ability, a complementary, yet controversial, view is that education has a direct causal and lasting benefit on cognitive development. METHODS: We use observational data from three birth cohorts, with cognition measured in adolescence and adulthood. Ordinary least squares regression was used to model the relationship between adolescent cognition and adult fluid cognition and to test the sensitivity of our analyses to sample selection, projection and backdoor biases using propensity score matching. RESULTS: We find that having a university education is correlated with higher fluid cognition in adulthood, after adjustment for adolescent cognition. We do not find that adolescent cognition, gender or parental social class consistently modify this effect; however, women benefited more in the 1946 sample from Great Britain. CONCLUSIONS: In all three birth cohorts, substantial educational benefit remained after adjustment for adolescent cognition and parental social class, offsetting an effect equivalent of 0.5 to 1.5 standard deviations lower adolescent cognition. We also find that the likelihood of earning a university degree depends in part on adolescent cognition, gender and parental social class. We conclude that inequalities in adult cognition derive in part from educational experiences after adolescence. PMID- 23108708 TI - Effects of the use of oral contraceptives on hip and knee kinematics in healthy women during anterior stair descent. AB - PURPOSE: Our aim was to evaluate the effects of the use of oral contraceptives (OC) on the hip and knee kinematics of healthy women during anterior stair descent. METHODS: Forty volunteers aged from 18 to 26 years were divided into two groups: 1-Group of women who had used OC for at least 3 months prior to evaluation (n = 20) and 2-Group of women who did not use OC (n = 20). The knee flexion/extension and abduction/adduction, hip flexion/extension, abduction/adduction and medial/lateral rotation excursions (degrees) were calculated for the dominant (supporting) limb during anterior stair descent. T tests for independent samples were used to compare the kinematic differences between the groups (alpha = 0.05). RESULTS: No significant difference was verified between the groups regarding the maximum excursion of knee flexion (n.s.) and abduction (n.s.) or hip flexion (n.s.), adduction (n.s.) and medial rotation (n.s.). When considering the knee flexion at 50 degrees , no significant difference was verified between the groups regarding the excursion of knee abduction (n.s.) or hip flexion (n.s.) adduction (n.s.) and medial/lateral rotation (n.s.). CONCLUSION: These results suggest that the use of OC does not influence the hip and knee kinematics during anterior stair descent. Therefore, the role of this medication as a protective factor against anterior cruciate ligament injuries remains questionable. PMID- 23108709 TI - Evaluation of confocal laser scanning microscopy for enumeration of virus-like particles in aquatic systems. AB - Abundances of virus-like particles (VLPs, mostly bacteriophages) are high in aquatic environments; therefore, techniques for precise enumeration are essential in ecological monitoring. VLPs were determined after staining with SYBR Gold by conventional epifluorescence microscopy and compared to enumerations performed by confocal laser scanning microscopy (CLSM). In order to assess the potential of CLSM for viral direct counts (VDCs), we processed samples from different freshwater and marine systems. Optical sectioning by CLSM and production of an overlay picture of multiple scans enables the often uneven whole investigated filter area to be brought to the plane of focus. This allows for subsequent image analysis of digitally created high-quality images. Another advantage using the CLSM was that the short spot excitation of the stain via laser beam minimized fading of the stain. The VDC results show that there is no significant difference between the two methods. Regarding the known difficulties of viral abundance estimates on particulate material, CLSM was further applied to enumerate VLPs on a small set of marine transparent exopolymeric particles sampled from the Atlantic Ocean. Our data suggest that CLSM is a useful tool to count viruses in water samples as well as attached to certain types of aquatic aggregates. PMID- 23108710 TI - Simultaneous quantification of Bi(III) and U(VI) in environmental water samples with a complicated matrix containing organic compounds. AB - Trace amounts of bismuth(III) and uranium(VI) can be simultaneously determined in a single scan by adsorptive cathodic stripping voltammetry in the presence of cupferron as a complexing agent. Optimal conditions were found to be: 0.1 mol L( 1) acetate buffer (pH 5.3), 5 * 10(-5) mol L(-1) cupferron, accumulation potential of -0.25 V, and accumulation time of 30 s. The linear range of Bi(III) and U(VI) was observed over the concentration range from 2 * 10(-9) to 2 * 10(-7) mol L(-1) and from 1 * 10(-8) to 5 * 10(-7) mol L(-1), respectively. The influence of the main components of real water samples such as foreign ions and organic substances (surface active substances, humic substances) was precisely investigated. The method was applied to the simultaneous measurements of bismuth and uranium in natural water samples. PMID- 23108711 TI - Seasonal effect on trace metal elements behaviour in a reservoir of northern Thailand. AB - Trace metal elements (TME) can be real threats for living organisms. However, few studies dealt with TME in reservoirs in rural areas where farming practises could induce negative effects. Mae Thang reservoir (northern Thailand) has been studied for 3 years to understand the seasonal behaviour of dissolved TME: Fe, Mn, Cd, Al, Pb, V, Cr, Co, Ni, Cu, Zn, Mo, U and As and associated physicochemical parameters. In situ measurements of these parameters were done during the dry and the wet seasons as well as water samples along the water column for further analyses and TME determination by inductively coupled plasma-mass spectrometry (ICP-MS). In the dry season, the water column was characterized by a strong stratification and anoxic conditions in the hypolimnion. High rain and water input from the watershed during the wet season induced mixing of the water. All TME, except Ni, Co and Cr were less concentrated in the wet season indicating a dilution effect by water input. There was thus no important dissolved pollution coming from the watershed. The anoxic conditions in the dry season enhanced the reduction of Fe and Mn and the desorption processes. Depth, and thus oxic-anoxic conditions were the main drivers of TME in the dry season, while in the wet season, dissolution processes from parent rocks of watershed were favoured. The average concentrations of TME in the reservoir were in the limit of the international and Thai standards. Only localized values in the bottom of the reservoir for Fe and Mn were higher than the limits. PMID- 23108712 TI - Development and application of microwave assisted extraction (MAE) for the extraction of five polycyclic aromatic hydrocarbons in sediment samples in Johannesburg area, South Africa. AB - A microwave-assisted extraction (MAE) method was verified and applied for the extraction of polycyclic aromatic hydrocarbons (PAHs) in sediment samples. Soxhlet extraction was used as the reference method. The optimum MAE was carried out with 20 mL of hexane/acetone (1:1, v/v) mixture in a 1-g sample at 250 W for 20 min. Soxhlet extraction was carried out with 250 mL of dichloromethane:hexane (1:1, v/v) mixture in a 15-g sample for 24 h in a water bath maintained at 60 degrees C. The collected extracts were both cleaned up, reduced to 1 mL under nitrogen and then injected into an HPLC fluorescence. To increase the sample throughput, simultaneous MAE was performed. The obtained percentage recoveries ranged from 61 to 93 and 88-98 for MAE and SE, respectively. The optimised MAE method was validated using certified reference material. It was then applied to real sediment samples from in and around the greater Johannesburg area. The sediments from Jukskei River were found to be the most polluted while Hartbeespoort Dam sediments were found to be least polluted. The overall order of concentrations for the studied PAHs per site was as follows: Jukskei River > Kempton Park > Centurion Dams > Natalspruit River (PIT) > Hartbeespoort Dam. PMID- 23108713 TI - Emergy-based evaluation of system sustainability and ecosystem value of a large scale constructed wetland in North China. AB - Constructed wetland has been widely adopted to deal with degraded natural wetlands and water bodies; thus, more attention should be focused on ecological economic sustainability and ecological efficiency of these projects for long-term success. Emergy accounting was conducted to investigate the energy and resource flows in constructed wetlands during the restoration process. Emergy-based indexes were adopted to evaluate the sustainability of a pilot large-scale constructed wetland in a large wetland restoration project in North China, carried out to enhance the river water quality and offset the degradation of natural wetland. Emergy and emdollar values for ecosystem services and natural capital were also calculated. The results showed that when outflow was considered as the product, the studied large-scale constructed wetland was more self supporting and could be operated with lesser financial investment, although the waste treatment efficiency and the sustainability index were lower than conventional small-scale treatment constructed wetlands. Compared with natural wetlands, more visits from tourists and lesser financial investment coming in as feedback into the wetland would reduce system environment loading and promote system self-support ability, ultimately generating sustainability. In addition, the studied large-scale constructed wetland can effectively simulate energy and resource flows of natural wetland ecosystem and contribute a roughly equal value of ecosystem services in term of gross primary production. The studied large scale constructed wetland can successfully achieve ecosystem functions as replacement for natural wetland and hasten the restoration process, although the restoration effectiveness of ecosystem structures in terms of living biomass and water using emergy-value accounting is still inconclusive. PMID- 23108714 TI - Perchlorate contamination of groundwater from fireworks manufacturing area in South India. AB - Perchlorate contamination was investigated in groundwater and surface water from Sivakasi and Madurai in the Tamil Nadu State of South India. Sensitive determination of perchlorate (LOQ = 0.005 MUg/L) was achieved by large-volume (500 MUL) injection ion chromatography coupled with tandem mass spectrometry. Concentrations of perchlorate were <0.005-7,690 MUg/L in groundwater (n = 60), <0.005-30.2 MUg/L in surface water (n = 11), and 0.063-0.393 MUg/L in tap water (n = 3). Levels in groundwater were significantly higher in the fireworks factory area than in the other locations, indicating that the fireworks and safety match industries are principal sources of perchlorate pollution. This is the first study that reports the contamination status of perchlorate in this area and reveals firework manufacture to be the pollution source. Since perchlorate levels in 17 out of 57 groundwater samples from Sivakasi, and none from Madurai, exceeded the drinking water guideline level proposed by USEPA (15 MUg/L), further investigation on human health is warranted. PMID- 23108715 TI - Quantitative detection of nitrate in water and wastewater by surface-enhanced Raman spectroscopy. AB - The presence of inorganic nitrogen species in water can be unsuitable for drinking and detrimental to the environment. In this study, a surface-enhanced Raman spectroscopy (SERS) method coupled with a commercially available gold nanosubstrate (a gold-coated silicon material) was evaluated for the detection of nitrate and nitrite in water and wastewater. Applications of SERS coupled with gold nanosubstrates resulted in an enhancement of Raman signals by a factor of ~10(4) compared to that from Raman spectroscopy. The new method was able to detect nitrate with linear ranges of 1-10,000 mg NO3(-)/L (R(2)= 0.978) and 1-100 mg NO3(-)/L (R(2)= 0.919) for water and wastewater samples, respectively. Among the common anions, phosphate appeared to be the major interfering anion affecting nitrate measurement. Nevertheless, the percentage error of nitrate measurement in wastewater by the proposed SERS method was comparable to that by ion chromatography. The nitrate detection limits in water and wastewater samples were about 0.5 mg/L. The SERS method could simultaneously detect sulfate, which may serve as a reference standard in water. These results suggested that the SERS coupled with nanosubstrates is a promising method to determine nitrate concentrations in water and wastewater. PMID- 23108716 TI - The hypothalamus-adipose axis is a key target of developmental programming by maternal nutritional manipulation. AB - Epidemiological studies initially demonstrated that maternal undernutrition leading to low birth weight may predispose for energy balance disorders throughout life. High birth weight due to maternal obesity or diabetes, inappropriate early post-natal nutrition and rapid catch-up growth may also sensitise to increased risk of obesity. As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of foetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set point. The hypothalamus-adipose axis plays a pivotal role in the maintenance of energy homoeostasis controlling the nutritional status and energy storage level. The perinatal period largely corresponds to the period of brain maturation, neuronal differentiation and active adipogenesis in rodents. Numerous dams and/or foetus/neonate dietary manipulation models were developed to investigate the mechanisms underlying perinatal programming in rodents. These models showed several common offspring hypothalamic consequences such as impaired neurogenesis, neuronal functionality, nuclei structural organisation and feeding circuitry hardwiring. These alterations led to a persistent reprogrammed appetite system that favoured the orexigenic pathways, leptin/insulin resistance and hyperphagia. Impaired hypothalamic sympathetic outflow to adipose tissue and/or reduced innervation may also account for modified fat cell metabolism. Thus, enhanced adipogenesis and/or lipogenesis capacities may predispose the offspring to fat accumulation. Abnormal hypothalamus-adipose axis circadian rhythms were also evidenced. This review mainly focuses on studies in rodents. It highlights hormonal and epigenetic mechanisms responsible for long-lasting programming of energy balance in the offspring. Dietary supplementation may provide a therapeutic option using a specific regimen for reversing adverse programming outcomes in humans. PMID- 23108717 TI - Mycorrhizal technology and phosphorus in the production of primary and secondary metabolites in cebil (Anadenanthera colubrina (Vell.) Brenan) seedlings. AB - BACKGROUND: The application of arbuscular mycorrhizal fungi (AMF) can increase the growth and concentration of primary and secondary metabolites in several plant species. Cebil (Anadenanthera colubrina), a medicinal plant, benefits from mycorrhizal association, but the influence of the symbiosis on the production of its bioactive compounds is unknown. In this study the effect of mycorrhizal inoculation and phosphorus (P) supply on the production of primary and secondary metabolites in cebil seedlings was determined. RESULTS: The production of proteins and carbohydrates in terms of both concentration and content was enhanced by inoculation with AMF, but this benefit was mitigated at higher levels of P (30 and 50 mg dm(-3) soil). The concentration of phenols, flavonoids and total tannins was favoured by mycorrhizal inoculation even at the highest levels of P (30 and 50 mg dm(-3) soil). CONCLUSION: The production of primary and secondary metabolites in leaves of A. colubrina can be maximised by mycorrhization, with the benefit depending on supplementation of soil phosphate. PMID- 23108718 TI - Noninvasive prenatal aneuploidy testing of chromosomes 13, 18, 21, X, and Y, using targeted sequencing of polymorphic loci. AB - OBJECTIVE: This study aims to develop a noninvasive prenatal test on the basis of the analysis of cell-free DNA in maternal blood to detect fetal aneuploidy at chromosomes 13, 18, 21, X, and Y. METHODS: A total of 166 samples from pregnant women, including 11 trisomy 21, three trisomy 18, two trisomy 13, two 45,X, and two 47,XXY samples, were analyzed using an informatics-based method. Cell-free DNA from maternal blood was isolated, amplified using a multiplex polymerase chain reaction (PCR) assay targeting 11,000 single nucleotide polymorphisms on chromosomes 13, 18, 21, X, and Y in a single reaction, and sequenced. A Bayesian based maximum likelihood statistical method was applied to determine the chromosomal count of the five chromosomes interrogated in each sample, along with a sample-specific calculated accuracy for each test result. RESULTS: The algorithm correctly reported the chromosome copy number at all five chromosomes in 145 samples that passed a DNA quality test, for a total of 725/725 correct calls. The average calculated accuracy for these samples was 99.92%. Twenty-one samples did not pass the DNA quality test. CONCLUSIONS: This informatics-based method noninvasively detected fetuses with trisomy 13, 18, and 21, 45,X, and 47,XXY with high sample-specific calculated accuracies for each individual chromosome and across all five chromosomes. PMID- 23108719 TI - Comparison of prescription drug costs in the United States and the United Kingdom, part 3: methylphenidate. AB - STUDY OBJECTIVE: To compare the annual cost of methylphenidate in the United States and the United Kingdom. DESIGN: Matched-cohort cost analysis. DATA SOURCES: The U.K. General Practice Research Database (GPRD) and MarketScan Commercial Claims and Encounters Database, a large, U.S. self-insured medical claims database. STUDY POPULATION: We initially identified 1.6 million people in the GPRD who were younger than 65 years of age in 2005. These people were then matched by year of birth and sex with 1.6 million people in the U.S. database. From this matched pool, we estimated that 98,000 boys aged 5-14 years from each country in 2005 were prescribed at least one drug. Of these, 6485 (6.6%) in the U.S. were prescribed methylphenidate compared with 1405 (1.4%) in the U.K. After excluding those who did not receive methylphenidate continuously, there remained 2298 boys in the U.S. and 939 in the U.K. who were prescribed methylphenidate continuously during 2005 (annual methylphenidate users). We estimated and compared drug costs (presented in 2005 U.S. dollars) for continuous users separately in the two countries. MEASUREMENTS AND MAIN RESULTS: Estimated drug costs were determined by random sampling. Estimated annual costs/patient in the U.S. ranged from $402 for doses of 5-10 mg to $821 for doses greater than 20 mg. In the U.K., costs ranged from $146 for doses of 5-10 mg to $661 for doses greater than 20 mg. The total annual cost of the continuous receipt of methylphenidate in the U.S. was $170,199 compared with $39,393 in the U.K. CONCLUSION: The cost of methylphenidate for boys aged 5-14 years paid by private insurance companies in the U.S. was more than 4 times higher than comparable costs paid by the government in the U.K. PMID- 23108720 TI - Ischemic stroke and transient ischemic attack in young adults: risk factors, diagnostic yield, neuroimaging, and thrombolysis. AB - BACKGROUND: Approximately 10% to 14% of ischemic strokes occur in young adults. OBJECTIVE: To investigate the yield of diagnostic tests, neuroimaging findings, and treatment of ischemic strokes in young adults. DESIGN: We retrospectively reviewed data from our Get with the Guidelines-Stroke database from 2005 through 2010. SETTING: University hospital tertiary stroke center. PATIENTS: A total of 215 consecutive inpatients aged 18 to 45 years with ischemic stroke/transient ischemic attack. The mean (SD) age was 37.5 (7) years; 51% were male. RESULTS: There were high incidence rates of hypertension (20%), diabetes mellitus (11%), dyslipidemia (38%), and smoking (34%). Relevant abnormalities were shown on cerebral angiography in 136 of 203 patients, on cardiac ultrasonography in 100 of 195, on Holter monitoring in 2 of 192; and on hypercoagulable panel in 30 of 189 patients. Multiple infarcts were observed in 31% and were more prevalent in individuals younger than age 35 years. Relevant arterial lesions were frequently detected in the middle cerebral artery (23%), internal carotid artery (13%), and vertebrobasilar arteries (13%). Cardioembolic stroke occurred in 47% (including 17% with isolated patent foramen ovale), and 11% had undetermined stroke etiology. The median National Institutes of Health Stroke Scale score was 3 (interquartile range, 0-9) and 81% had good outcome at hospital discharge. Of the 29 patients receiving thrombolysis (median National Institutes of Health Stroke Scale score, 14; interquartile range, 9-17), 55% had good outcome at hospital discharge and none developed symptomatic brain hemorrhage. CONCLUSIONS: This study shows the contemporary profile of ischemic stroke in young adults admitted to a tertiary stroke center. Stroke etiology can be determined in nearly 90% of patients with modern diagnostic tests. The causes are heterogeneous; however, young adults have a high rate of traditional vascular risk factors. Thrombolysis appears safe and short-term outcomes are favorable. PMID- 23108722 TI - Safety and efficacy of therapeutic endoscopic interventions in the management of biliary leak. AB - Endoscopic procedures which reduce the trans-papillary pressure gradient are the treatment of choice for management of biliary leaks. We analyzed the data of 102 patients with biliary leak managed by various endoscopic procedures like endoscopic sphincterotomy (ES), ES with stenting, stenting alone or nasobiliary drainage (NBD) alone; 90 of these patients had developed a leak after cholecystectomy. In the post-cholecystectomy group, cannulation was successful in 79 patients; therapeutic intervention was not possible in 14 of them due to complete transection of common bile duct in 6, and leak proximal to ligature in 8. In the remaining 65 patients, ES with stenting was done in 52, stent alone in 6, ES alone in 5 and NBD alone in 2. All 12 patients in other etiology group were treated with ES plus stenting. The leak closed in a mean of 3 (1-10) days in all patients. Stents were removed after 6-8 weeks. Endoscopic procedures are effective in managing biliary leaks. PMID- 23108723 TI - Prevalence of gastrointestinal symptoms among the residents of Alamadhi village. PMID- 23108721 TI - Evaluation of the single-item self-rating adherence scale for use in routine clinical care of people living with HIV. AB - The self-rating scale item (SRSI) is a single-item self-report adherence measure that uses adjectives in a 5-point Likert scale, from "very poor" to "excellent," to describe medication adherence over the past 4 weeks. This study investigated the SRSI in 2,399 HIV-infected patients in routine care at two outpatient primary HIV clinics. Correlations between the SRSI and four commonly used adherence items ranged from 0.37 to 0.64. Correlations of adherence barriers, such as depression and substance use, were comparable across all adherence items. General estimating equations suggested the SRSI is as good as or better than other adherence items (p's <0.001 vs. <0.001-0.99) at predicting adherence-related clinical outcomes, such as HIV viral load and CD4(+) cell count. These results and the SRSI's low patient burden suggest its routine use could be helpful for assessing adherence in clinical care and should be more widespread, particularly where more complex instruments may be impractical. PMID- 23108725 TI - Fetal fraction in maternal plasma cell-free DNA at 11-13 weeks' gestation: relation to maternal and fetal characteristics. AB - OBJECTIVE: To examine the possible effects of maternal and fetal characteristics on the fetal fraction in maternal plasma cell-free (cf) DNA at 11-13 weeks' gestation and estimate the proportion of pregnancies at high risk of non-invasive prenatal testing (NIPT) failure because the fetal fraction is less than 4%. METHODS: In 1949 singleton pregnancies at 11-13 weeks' gestation cf-DNA was extracted from maternal plasma. Chromosome-selective sequencing of non polymorphic and polymorphic loci, where fetal alleles differ from maternal alleles, was used to determine the proportion of cf-DNA that was of fetal origin. Multivariable regression analysis was used to determine significant predictors of the fetal fraction among maternal and fetal characteristics. RESULTS: The fetal fraction decreased with increased maternal weight, it was lower in women of Afro Caribbean origin than in Caucasians and increased with fetal crown-rump length, serum pregnancy-associated plasma protein-A, serum free beta-human chorionic gonadotropin, smoking and trisomy 21 karyotype. The median fetal fraction was 10.0% (interquartile range, 7.8-13.0%) and this decreased with maternal weight from 11.7% at 60 kg to 3.9% at 160 kg. The estimated proportion with fetal fraction below 4% increased with maternal weight from 0.7% at 60 kg to 7.1% at 100 kg and 51.1% at 160 kg. CONCLUSIONS: Fetal fraction in maternal plasma cf-DNA is affected by maternal and fetal characteristics. PMID- 23108726 TI - The synthesis of organometallic coordination polymer flowers of Prussian blue with ultrathin petals by using crystallization-assisted interface coordination polymerization (CAICP). PMID- 23108727 TI - Room-temperature electron spin amplifier based on Ga(In)NAs alloys. AB - The first experimental demonstration of a spin amplifier at room temperature is presented. An efficient, defect-enabled spin amplifier based on a non-magnetic semiconductor, Ga(In)NAs, is proposed and demonstrated, with a large spin gain (up to 2700% at zero field) for conduction electrons and a high cut-off frequency of up to 1 GHz. PMID- 23108728 TI - Prevalence of pubovisceral muscle avulsion in a general gynecology cohort: a computed tomography (CT) study. AB - AIMS: To calculate the prevalence of pubovisceral muscle (PM) avulsion in a cohort of women presenting at a university hospital for non-urogynecological conditions. METHODS: Women with or without symptoms of PFD were studied in a tertiary referral urogynecology center between February and October 2010. Women were recruited from the Department of Radiology, where they were referred for a CT pelvis scan due to various pathologies. Assessment of participants included a detailed clinical interview, completion of King's Health and Prolapse-Quality of Life (P-QOL) questionnaires and spiral CT scan of the pelvis. Bilateral attachments of the PM to the pubic rami were identified in the plane of minimal hiatal dimensions, when present, and measurement of the levator symphysis gap (LSG) was taken in cases with PM complete detachment. Bivariate analysis between the PM maximum thickness and different obstetric variables was performed by using Spearman's correlation test (P < 0.05). RESULTS: One hundred ten women were included in the analysis. The overall prevalence of PM avulsion was 6.4% (7/110). In cases with confirmed avulsion, the levator sympysis gap (LSG) ranged from 17.30 to 25.40 mm. The left PM was found to be significantly thinner in parous women and in those with a history of prolonged second stage of labor. CONCLUSIONS: The prevalence of pubovisceral muscle avulsion using CT scanning in a general gynecology cohort is 6.4%. Thinning of the pubovisceral muscle occurs with parity and protracted labor and is more prominent on the left portion of the muscle. PMID- 23108730 TI - The influence of a line with fast diffusion on Fisher-KPP propagation. AB - We propose here a new model to describe biological invasions in the plane when a strong diffusion takes place on a line. We establish the main properties of the system, and also derive the asymptotic speed of spreading in the direction of the line. For low diffusion, the line has no effect, whereas, past a threshold, the line enhances global diffusion in the plane and the propagation is directed by diffusion on the line. It is shown here that the global asymptotic speed of spreading in the plane, in the direction of the line, grows as the square root of the diffusion on the line. The model is much relevant to account for the effects of fast diffusion lines such as roads on spreading of invasive species. PMID- 23108729 TI - A mixture theory model of fluid and solute transport in the microvasculature of normal and malignant tissues. II: Factor sensitivity analysis, calibration, and validation. AB - The treatment of cancerous tumors is dependent upon the delivery of therapeutics through the blood by means of the microcirculation. Differences in the vasculature of normal and malignant tissues have been recognized, but it is not fully understood how these differences affect transport and the applicability of existing mathematical models has been questioned at the microscale due to the complex rheology of blood and fluid exchange with the tissue. In addition to determining an appropriate set of governing equations it is necessary to specify appropriate model parameters based on physiological data. To this end, a two stage sensitivity analysis is described which makes it possible to determine the set of parameters most important to the model's calibration. In the first stage, the fluid flow equations are examined and a sensitivity analysis is used to evaluate the importance of 11 different model parameters. Of these, only four substantially influence the intravascular axial flow providing a tractable set that could be calibrated using red blood cell velocity data from the literature. The second stage also utilizes a sensitivity analysis to evaluate the importance of 14 model parameters on extravascular flux. Of these, six exhibit high sensitivity and are integrated into the model calibration using a response surface methodology and experimental intra- and extravascular accumulation data from the literature (Dreher et al. in J Natl Cancer Inst 98(5):335-344, 2006). The model exhibits good agreement with the experimental results for both the mean extravascular concentration and the penetration depth as a function of time for inert dextran over a wide range of molecular weights. PMID- 23108731 TI - On the concept of individual in ecology and evolution. AB - Part of the art of theory building is to construct effective basic concepts, with a large reach and yet powerful as tools for getting at conclusions. The most basic concept of population biology is that of individual. An appropriately reengineered form of this concept has become the basis for the theories of structured populations and adaptive dynamics. By appropriately delimiting individuals, followed by defining their states as well as their environment, it become possible to construct the general population equations that were introduced and studied by Odo Diekmann and his collaborators. In this essay I argue for taking the properties that led to these successes as the defining characteristics of the concept of individual, delegating the properties classically invoked by philosophers to the secondary role of possible empirical indicators for the presence of those characteristics. The essay starts with putting in place as rule for effective concept engineering that one should go for relations that can be used as basis for deductive structure building rather than for perceived ontological essence. By analysing how we want to use it in the mathematical arguments I then build up a concept of individual, first for use in population dynamical considerations and then for use in evolutionary ones. These two concepts do not coincide, and neither do they on all occasions agree with common intuition-based usage. PMID- 23108732 TI - Different episiotomy techniques, postpartum perineal pain, and blood loss: an observational study. AB - INTRODUCTION AND HYPOTHESIS: The lateral episiotomy technique has been postulated to cause more postpartum perineal pain and blood loss compared to the midline and mediolateral episiotomy technique. The aim of the study was to explore the association with postpartum perineal pain and blood loss between different episiotomy techniques. METHODS: Clinical evaluation of episiotomy was performed 0 3 days after delivery on 300 participating women. Episiotomy technique was classified by millimeter distance from the incision point to the posterior fourchette and by angle from the sagittal plane in degrees. Postpartum perineal pain was scored on a visual analogue scale (VAS) the first day after delivery. Blood loss data were collected from medical charts. Different episiotomy techniques and different episiotomy incision point groups were compared in relation to perineal pain perception and blood loss. RESULTS: We found no difference between midline, mediolateral, and lateral episiotomy techniques in perineal pain perception the first postpartum day (p = 0.74) or in estimated blood loss (p = 0.38). No differences were found in perineal pain or blood loss between midline and lateral incision points. Mediolateral angles were significantly narrower than lateral angles (p < 0.005). Physicians performed longer episiotomies than midwives (p < 0.005), but episiotomy angle did not vary between professions (p = 0.075). CONCLUSIONS: No differences in perineal pain perception the first postpartum day and no differences in estimated blood loss were found when comparing different episiotomy techniques or when comparing midline and lateral incision points. PMID- 23108733 TI - The polymorphisms of the MMP-1 and the MMP-3 genes and the risk of pelvic organ prolapse. AB - INTRODUCTION AND HYPOTHESIS: To investigate the associations between single nucleotide polymorphism (SNP) type 1G/2G at position -1607/-1608 of the matrix metalloproteinase (MMP)-1 gene and SNP type 5A/6A at position -1612/-1617 of the MMP-3 gene and the development of pelvic organ prolapse (POP) in women. METHODS: 133 patients with symptomatic POP were included in the study group. The control group consisted of 132 women with a normal pelvic floor. 1G/2G MMP-1 and 5A/6A MMP-3 SNPs were determined by polymerase chain reaction (PCR) and restriction fragments length polymorphism analysis. RESULTS: When estimated individually none of the investigated SNPs were associated with POP. The combined MMP-1/MMP-3 SNP analysis showed that the following polymorphic pairs were overrepresented in women with POP: 1G/2G -5A/6A, 2G/2G -5A/6A, 2G/2G -5A/5A, 1G/1G -6A/6A, p=0.005. CONCLUSIONS: The combined effect of -1607/-1608 MMP-1 and -1612/-1617 MMP-3 SNPs may contribute to the development of POP in some women. PMID- 23108734 TI - Fetal pulmonary thrombosis. PMID- 23108736 TI - What will it take to maintain the maternal and child health gains made in Haiti prior to the 2010 earthquake?: an analysis of past progress, trends, and the prospects for the realization of the United Nations Millennium Development Goals 4 and 5. AB - This report assesses the commendable progress made in maternal and child mortality reductions in Haiti prior to the January 2010 earthquake. Suggested measures that the Haitian government and international donor community can take to maintain these gains are also made. With the Millennium Development Goals (MDGs) deadline of 2015 drawing nearer, the likelihood that Haiti will achieve MDG's 4 and 5 of reducing child and maternal mortality by two-thirds and three quarters, respectively, by the end of this target year, remain questionable. In particular, the destruction inflicted on the country's health care system and health infrastructure by the 2010 earthquake have already resulted in a slowing of these gains and could potentially threaten an actual reversal of these trends. The country's Soins Obstetricaux Gratuits and Soins Infantiles Gratuits schemes established in 2008 and 2010, which provide free health care to women, newborns and children under 5, represent examples of measures that will need to be sustained and scaled up if the country is to meet its MDG 4 and 5 targets. The Haitian government's endorsement of an increased continuum of care approach to maternal and newborn health will also be vital for future initiatives. Post-quake public health and social service reconstruction efforts will need to incorporate maternal and child health-friendly services into their designs. It also remains critical that international donors continue to meet their pledges to Haiti. The Haitian government should also take more strides to clearly delineate the maternal and child health interventions it implements, both in order to facilitate greater national learning, as well as to improve the likelihood of future replication. PMID- 23108735 TI - Developing a standard approach to examine infant mortality: findings from the State Infant Mortality Collaborative (SIMC). AB - States can improve pregnancy outcomes by using a standard approach to assess infant mortality. The State Infant Mortality Collaborative (SIMC) developed a series of analyses to describe infant mortality in states, identify contributing factors to infant death, and develop the evidence base for implementing new or modifying existing programs and policies addressing infant mortality. The SIMC was conducted between 2004 and 2006 among five states: Delaware, Hawaii, Louisiana, Missouri, and North Carolina. States used analytic strategies in an iterative process to investigate contributors to infant mortality. Analyses were conducted within three domains: data reporting (quality, reporting, definitional criteria, and timeliness), cause and timing of infant death (classification of cause and fetal, neonatal, and postneonatal timing), and maturity and weight at birth/maturity and birth weight-specific mortality. All states identified the SIMC analyses as useful for examining infant mortality trends. In each of the three domains, SIMC results were used to identify important direct contributors to infant mortality including disparities, design or implement interventions to reduce infant death, and identify foci for additional analyses. While each state has unique structural, political, and programmatic circumstances, the SIMC model provides a systematic approach to investigating increasing or static infant mortality rates that can be easily replicated in all other states and allows for cross-state comparison of results. PMID- 23108737 TI - Medication exposure in pregnancy risk evaluation program: the prevalence of asthma medication use during pregnancy. AB - Asthma is one of the most common chronic diseases in women of reproductive age, occurring in up to 8 % of pregnancies. The objective of this study is to assess the prevalence of asthma medication use during pregnancy in a large diverse cohort. We identified women aged 15-45 years who delivered a live born infant between 2001 and 2007 across 11 U.S. health plans within the Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP). Using health plans' administrative and claims data, and birth certificate data, we identified deliveries for which women filled asthma medications from 90 days before pregnancy through delivery. Prevalence (%) was calculated for asthma diagnosis and medication dispensing. There were 586,276 infants from 575,632 eligible deliveries in the MEPREP cohort. Asthma prevalence among mothers was 6.7 %, increasing from 5.5 % in 2001 to 7.8 % in 2007. A total of 9.7 % (n = 55,914) of women were dispensed asthma medications during pregnancy. The overall prevalence of maintenance-only medication, rescue only medication, and combined maintenance and rescue medication was 0.6, 6.7, and 2.4 % respectively. The prevalence of maintenance-only use doubled during the study period from 0.4 to 0.8 %, while rescue-only use decreased from 7.4 to 5.8 %. In this large population-based pregnancy cohort, the prevalence of asthma diagnoses increased over time. The dispensing of maintenance-only medication increased over time, while rescue-only medication dispensing decreased over time. PMID- 23108738 TI - Influenza and pertussis vaccination coverage among privately insured women of reproductive age. AB - An increasing number of vaccines are now designated as maternal vaccines, recommended prior to, during, or immediately following pregnancy. The influenza and pertussis (Tdap) vaccines have the potential to improve the health of women and their offspring. Among privately insured women of reproductive age, goals of this study were to describe influenza and Tdap vaccination coverage and to explore variation in coverage by age and race/ethnicity. This cross-sectional, observational study included women 18-44 years of age with continuous enrollment from 1 January 2007-31 March 2011 in a single, Midwestern health insurance plan and at least one visit to a plan affiliated practice. Data on vaccine coverage came from insurance claims, supplemented by electronic medical record data. Primary outcomes were: receipt of Tdap ever, receipt of Tdap or Tetanus vaccination (Td) in the past 10 years, and receipt of influenza vaccination during the 2010-2011 influenza season. Coverage was compared by race/ethnicity. Among 12,657 women with continuous private insurance, 45.5 % had received Tdap ever, 82.5 % had received Td or Tdap in the past 10 years, and 39.8 % received the influenza vaccine in the 2010-2011 season. Marked disparities in influenza vaccination coverage by race/ethnicity were observed, only 30.0 % of African American women received influenza vaccine compared to 40.7 % of white, non Hispanic women (p < .0001). Among insured women of reproductive age, there is a need for interventions to increase Tdap and influenza vaccination uptake. Further research is needed to understand and address disparities in influenza vaccination coverage in this population. PMID- 23108739 TI - Estimation of preterm birth rate, associated factors and maternal morbidity from a demographic and health survey in Brazil. AB - To determine the prevalence of preterm birth from self-reports by Brazilian women, to assess complications, interventions and outcomes, to identify factors associated with preterm birth, and to improve the preterm birth rates estimates. This is a secondary analysis of data from a Demographic Health Survey. It interviewed a sample of 4,743 Brazilian women who had 6,113 live births from 2001 to 2007. Estimates of preterm birth rates were obtained per region and per year according to self-reported gestational age. The prevalence rate and 95 % confidence interval (CI) for preterm was determined according to the characteristics of mothers and offspring. Odds ratios and 95 % CI were estimated for complications such as severe maternal morbidity. The preterm birth rate was 9.9 %, with regional variations. Preterm birth was more likely to be associated with neonatal death, low birth weight, and longer hospital stay. Maternal factors associated with preterm birth were: white ethnicity, living in an urban area, history of hypertension or heart disease, twin gestation, non-elective Cesarean section, medical insurance for delivery, low number of antenatal visits, and severe morbidity. A self-report survey has indicated that the preterm birth rate in Brazil is higher than official data suggest, with an increasing trend in more developed areas, and is associated with poor neonatal and maternal outcomes. PMID- 23108740 TI - Outcomes and factors associated with breastfeeding for <8 weeks among preterm infants: findings from 6 states and NYC, 2004-2007. AB - To examine breastfeeding outcomes and factors associated with breastfeeding <8 weeks among preterm infants. Pregnancy Risk Assessment Monitoring System (PRAMS) data for seven sites from 2004 to 2007 were used. Logistic regression was used to identify correlates of short breastfeeding duration among preterm infants. Among preterm infants, short breastfeeding duration (<8 weeks) was associated with maternal age <=19 years (OR 1.75; 95 % CI: 1.22, 2.50), infant birth weight between 1,500 and 2,499 g (OR 1.29; 95 % CI: 1.01, 1.65), maternal obesity (OR 1.52; 95 % CI: 1.17, 1.98), smoking (OR 2.61; 95 % CI: 1.87, 3.63), and hypertension (OR 1.34; 95 % CI: 1.06, 1.69). Receiving a phone number for breastfeeding help (OR 0.59; 95 % CI: 0.44, 0.78) and not receiving a gift pack with formula (OR 0.64; 95 % CI: 0.47, 0.87) were associated with decreased odds of short duration. Speaking with a provider about breastfeeding prenatally was associated with increased odds of short duration (OR 1.75; 95 % CI: 1.33, 2.30). These findings strengthen the hypothesis that infant and maternal health are determinants of breastfeeding preterm infants and suggest a need to provide additional support to smokers, obese and hypertensive women, and mothers of infants with birth weights between 1,500 and 2,499 g, to help them sustain breastfeeding. Support from hospitals, such as providing a telephone number for breastfeeding help, and not providing a gift pack with formula, can also make a difference. These practices should be adopted by hospitals. PMID- 23108741 TI - Factors associated with a patient-centered medical home among children with behavioral health conditions. AB - At some point in their lives, nearly one-half of all American children will have a behavioral health condition. Many will not receive the care they need from a fragmented health delivery system. The patient-centered medical home is a promising model to improve their care; however, little evidence exists. Our study aim was to examine the association between several behavioral health indicators and having a patient-centered medical home. 91,642 children's parents or guardians completed the 2007 National Survey of Children's Health. An indicator for patient-centered medical home was included in the dataset. Descriptive statistics, bivariate tests, and multivariate regression models were used in the analyses. Children in the sample were mostly Male (52 %), White (78 %), non Hispanic (87 %), and did not have a special health care need (80 %). 6.2 % of the sample had at least one behavioral health condition. Conditions ranged from ADHD (6 %) to Autism Spectrum Disorder (ASD) (1 %). Frequency of having a patient centered medical home also varied for children with a behavioral health condition (49 % of children with ADHD and 33 % of children with ASD). Frequency of having a patient-centered medical home decreased with multiple behavioral health conditions. Higher severity of depression, anxiety, and conduct disorder were associated with a decreased likelihood of a patient-centered medical home. Results from our study can be used to target patient-centered medical home interventions toward children with one or more behavioral health conditions and consider that children with depression, anxiety, and conduct disorder are more vulnerable to these disparities. PMID- 23108742 TI - Diastereoselective synthesis of the C17-C30 fragment of amphidinol 3. AB - The diastereoselective synthesis of the C17-C30 fragment of amphidinol 3 (AM3) 1 was achieved from the enantio-enriched aldehyde 20, Weinreb amide 14 and 2-bromo 3-(trimethylsilyl)propene, which was used as a bifunctional conjunctive reagent. The absolute configuration of the stereogenic centers, in both aldehyde 20 and Weinreb amide 14, were efficiently controlled by using (+)-(R)-methyl-p tolylsulfoxide as the unique source of chirality. PMID- 23108743 TI - Determination of peptide and protein disulfide linkages by MALDI mass spectrometry. AB - The disulfide bond is one of the most common post-translational modifications in proteins, of which determination is essential to the comprehensive understanding of protein structures. Disulfide bond analysis has undergone great improvement due to the development of matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS), especially in terms of speed and sensitivity. In general, the characterization of disulfide-containing peptides is achieved by the reduction of disulfide bonds followed by alkylation. In this review we focus on the analysis of disulfide-containing proteins/peptides by some unique methods in MALDI MS. The MALDI in-source decay (ISD) of disulfide bonds and adducts of the matrix and sulfhydryl-containing peptide are discussed in detail. The mechanism of each method is discussed so as to help the reader gain greater insight into it, and examples of its application are also presented. The goal of this review is to provide an understanding of these techniques for analysis of disulfide linked proteins/peptides in MALDI MS. PMID- 23108744 TI - Insulin analogues in the treatment of diabetes in pregnancy. AB - Pregnancy affects both maternal and fetal metabolism, and even in non-diabetic women, it exerts a diabetogenic effect. Among pregnant women, 2% to 14% develop gestational diabetes. Pregnancy can also occur in women with preexisting diabetes, which may predispose the fetus to many alterations in organogenesis, restrict growth, and the mother, to some diabetes-related complications, such as retinopathy and nephropathy, or to acceleration of the course of these complications, if they are already present. Women with gestational diabetes generally start their treatment with diet and lifestyle changes; when these changes are not enough for optimal glycemic control, insulin therapy must then be considered. Women with type 2 diabetes using oral hypoglycemic agents are advised to change to insulin therapy. Those with preexisting type 1 diabetes should start intensive glycemic control. As basal insulin analogues have frequently been used off-label in pregnant women, there is a need to evaluate their safety and efficacy. The aim of this review is to report the use of both short- and long acting insulin analogues during pregnancy and to enable clinicians, obstetricians, and endocrinologists to choose the best insulin treatment for their patients. PMID- 23108745 TI - [25-hydroxyvitamin D concentrations and blood pressure levels in hypertensive elderly patients]. AB - OBJECTIVE: To evaluate the prevalence of inadequate vitamin D status and its relationship with associated factors in 91 elderly hypertensive patients in Joao Pessoa, PB/BR. MATERIALS AND METHODS: In a cross-sectional study, levels of 25 hydroxyvitamin D of 91 elderly patients were compared with biochemical, anthropometric, and dietary data, type of skin, exposure to sunlight, and blood pressure. RESULTS: The prevalence of inadequate vitamin concentrations (25 hydroxyvitamin D < 29 ng/mL) was 33%. The concentration of serum 25 hydroxyvitamin D was inversely associated with systolic blood pressure and positively associated with weekly fish consumption. The other variables showed no significant association with 25-hydroxyvitamin D. CONCLUSION: The prevalence of inadequate vitamin D concentrations was related with higher blood pressure in elderly patients. Moreover, greater fish weekly consumption influenced greater 25 hydroxyvitamin D concentration. PMID- 23108746 TI - High prevalence of vitamin D deficiency among newly diagnosed youth-onset diabetes mellitus in north India. AB - OBJECTIVES: Vitamin D deficiency is common at all ages, and low levels of vitamin D have been associated with high incidence of type 1 diabetes. Similar results are not consistent for type 2 diabetes. The aim of the present study was to estimate vitamin D status in newly detected youth-onset diabetes in north India. SUBJECTS AND METHODS: This was a prospective case control study at a tertiary care hospital in north India. Seventy two newly detected youth-onset diabetes subjects (age < 25 years), and 41 age- and gender-matched healthy controls were studied. In addition to basic information and management regarding their diabetes, metabolic parameters and serum 25(OH)D were measured in both the groups. RESULTS: Vitamin D deficiency was seen in 91.1% of the subjects with diabetes, and 58.5% of the healthy controls. Mean +/-SD 25(OH)D was significantly low, 7.88 +/- 1.20 ng/mL in subjects with diabetes against 16.64 +/- 7.83 ng/mL in controls. Sixty percent of cases had severe Vitamin D deficiency compared with 8.3% in controls. Levels of vitamin D did not correlate with clinical parameters, such as gender, body mass index; or with biochemical parameters, such as serum calcium, phosphorus, alkaline phosphatase, fasting plasma glucose, and HbA1C. CONCLUSION: Vitamin D deficiency is common in people with youth-onset diabetes. PMID- 23108747 TI - Evaluation of plasma homocysteine level according to the C677T and A1298C polymorphism of the enzyme MTHRF in type 2 diabetic adults. AB - OBJECTIVE: To determine plasma homocysteine levels during fasting and after methionine overload, and to correlate homocysteinemia according to methylenetetrahydrofolate reductase (MTHFR) polymorphism in type 2 diabetic adults. SUBJECTS AND METHODS: The study included 50 type 2 diabetic adults (DM group) and 52 healthy subjects (Control group). Anthropometric data, and information on food intake, serum levels of vitamin B12, folic acid and plasma homocysteine were obtained. The identification of C677T and A1298C polymorphisms was carried out in the MTHFR gene. RESULTS: There was no significant difference in homocysteinemia between the two groups, and hyperhomocysteinemia during fasting occurred in 40% of the diabetic patients and in 23% of the controls. For the same polymorphism, there was not any significant difference in homocysteine between the groups. In the Control group, homocysteinemia was greater in those subjects with C677T and A1298C polymorphisms. Among diabetic subjects, those with the A1298C polymorphism had lower levels of homocysteine compared with individuals with C677T polymorphism. CONCLUSION: The MTHFR polymorphism (C677T and A1298C) resulted in different outcomes regarding homocysteinemia among individuals of each group (diabetic and control). These data suggest that metabolic factors inherent to diabetes influence homocysteine metabolism. PMID- 23108748 TI - [Analysis of the mRNA expression of the S100beta protein in adipocytes of patients with diabetes mellitus, type 2]. AB - OBJECTIVE: This study aims to explore the possible relationship between the expression level of S100beta protein mRNA with diabetes mellitus type 2 in adipocytes from patients with this disease in comparison with normoglycemic individuals. MATERIALS AND METHODS: Samples of adipose tissue of eight patients from the coronary section of the Institute Dante Pazzanese of Cardiology (IDPC), four in Group Diabetes and four of Normoglycemic group, were evaluated by RT-PCR real time. RESULTS: An increase around 15 times values, between the threshold cycle (DeltaCt), of mRNA expression of S100beta protein in adipocytes of the diabetes group was observed in comparison to the control group (p = 0.015). CONCLUSION: Our results indicate, for the first time, that there is coexistence of increased expression of the S100beta and the type 2 diabetes mellitus gene. PMID- 23108749 TI - Oxidative stress and interleukin-6 secretion during the progression of type 1 diabetes. AB - OBJECTIVE: To evaluate inflammatory, oxidizing, and reducing responses during the progression of type 1 diabetes mellitus (T1DM) in patients without chronic complications. SUBJECTS AND METHODS: Plasma antioxidant status, reactive oxygen species (ROS), and interleukin-6 (IL-6) were measured in 42 patients with T1DM and in 24 healthy subjects. RESULTS: Significant increases were detected in the median values of ROS and IL-6 in patients with T1DM compared with healthy subjects (ROS ~ 4,836 vs. 2,036 RLU/min, respectively; P < .05: IL-6 ~ 14.2 vs. 9.7 pg/mL, respectively; P = .002). No significant between-group differences (P > 0.05) were observed in oxidizing responses or in IL-6 concentrations when diabetic patients were grouped according to time after diagnosis (0 - 10, 10 - 20 and > 20 years). Plasma antioxidant responses were similar in patients with T1DM and in healthy subjects. CONCLUSIONS: Our results demonstrate that oxidizing and inflammatory responses are increased at the onset of T1DM, but remain unchanged during disease progression. These findings suggest that functional changes involved in diabetic complications may commence in the first years after diagnosis. PMID- 23108750 TI - Use of hemoglobin A1C to detect Haitian-Americans with undiagnosed Type 2 diabetes. AB - OBJECTIVE: To evaluate the validity of hemoglobin A1C (A1C) as a diagnostic tool for type 2 diabetes and to determine the most appropriate A1C cutoff point for diagnosis in a sample of Haitian-Americans. SUBJECTS AND METHODS: Subjects (n = 128) were recruited from Miami-Dade and Broward counties, FL. Receiver operating characteristics (ROC) analysis was run in order to measure sensitivity and specificity of A1C for detecting diabetes at different cutoff points. RESULTS: The area under the ROC curve was 0.86 using fasting plasma glucose >= 7.0 mmol/L as the gold standard. An A1C cutoff point of 6.26% had sensitivity of 80% and specificity of 74%, whereas an A1C cutoff point of 6.50% (recommended by the American Diabetes Association - ADA) had sensitivity of 73% and specificity of 89%. CONCLUSIONS: A1C is a reliable alternative to fasting plasma glucose in detecting diabetes in this sample of Haitian-Americans. A cutoff point of 6.26% was the optimum value to detect type 2 diabetes. PMID- 23108751 TI - [Serious jaundice and thyrotoxic myocardiopathy with atrial thrombus]. AB - Jaundice related to thyrotoxicosis and not as an effect of antithyroid drugs is a rare complication that usually occurs in the presence of heart failure (HF) or hepatitis. We report a case of a 54-year-old white woman with hyperthyroidism caused by Graves's disease and jaundice despite methimazole suspension. Bilirubin fluctuated at high values, between 30.0 and 52.3 mg/dL, transaminases were slightly increased, on admission ALT = 46 U/L and AST = 87 U/L; coagulation indices and serum proteins were on the lower limit of the normal range with PT 68% and albumin = 2.5 g/dL. Serology for hepatitis was negative. After the first radioiodine therapy (RT), bilirubin reached its maximum, which coincided with the worst period of HF exacerbation. Bilirubin normalized 4 weeks after the second RT, with the stabilization of HF and normalization of thyroid hormones. We discuss the possible etiologies of severe jaundice in hyperthyroid patients, as well as the difficult anticoagulant therapy with warfarin. PMID- 23108752 TI - Ectopic Cushing's syndrome caused by a pulmonary ACTH-secreting tumor in a patient treated with octreotide. AB - Ectopic ACTH syndrome is a rare disease often associated with severe hypercortisolism. When feasible, optimal management is surgical excision of the tumor. A 33-year-old male patient was admitted to the hospital in 1993 with clinical manifestations suggestive of Cushing's syndrome. He presented high plasma ACTH and markedly elevated urinary free cortisol excretion that was not suppressed with high-dose dexamethasone administration. Pituitary MRI scan was normal. No central-to-peripheral ACTH gradient was present in bilateral inferior petrosal sinus sampling. Thoracic CT scan showed a 1.7 cm nodule at the left lung. Pulmonary fine needle cytology and immunocytochemical and ultrastructural studies, together with the presence of bone metastases, led to the diagnosis of an ACTH-producing neuroendocrine carcinoma. He was initially submitted to chemotherapy and has been on treatment with octreotide LAR since 1998, having shown a favorable clinical, biochemical and imaging response. We highlight the excellent long-term response to medical therapy with octreotide LAR, without tachyphylaxis, probably due to its antiproliferative effect. PMID- 23108753 TI - [The glucose-fatty acid cycle during intense exercise: a contestable theory?]. PMID- 23108754 TI - [Regulation of glucose and fatty acid metabolism in the skeleton muscle during physics exercise]. PMID- 23108755 TI - Dilution of pollution? Processes affecting the water quality in the river-style Three Gorges Reservoir. PMID- 23108756 TI - Organochlorine pesticides and polychlorinated biphenyls in soils surrounding the Tanggu Chemical Industrial District of Tianjin, China. AB - The spatial distribution of persistent organic pollutants (POPs) was examined in soils surrounding the Tanggu Chemical Industrial District in Tianjin, China. The concentrations of hexachlorocyclohexanes (HCHs), dichlorodiphenyltrichloroethanes (DDTs), hexachlorobenzenes (HCBs), and polychlorinated biphenyls (PCBs) were determined in 70 surface soils using accelerated solvent extraction and gas chromatography with electron capture detection. The results showed that the ranges of ?HCH, ?DDT, SigmaHCB, and ?PCB concentrations in soils were 2.1-12,549 MUg kg(-1) (average, 965 MUg kg(-1)), n.d.-2,033 MUg kg(-1) (average, 88.4 MUg kg(-1)), n.d.-1,924 MUg kg(-1) (average, 349 MUg kg(-1)), and n.d.-373 MUg kg(-1) (average, 46.2 MUg kg(-1)), respectively. Of these, HCHs were the dominant POPs, accounting for 75 % of the total organochlorine pesticide (OCP) residues. Overall, the spatial distribution of OCP concentrations showed a decreasing trend from the center of the Tanggu District to the surrounding areas. Two major pollution sources were Tianjin Dagu Chemical Co., Ltd. in the district center and the Tianjin Chemical Plant in Hangu District. In contrast, PCB concentrations were relatively high in the Haihe estuary to the east and low to the west of the study area. Component analysis of OCPs in these soils showed that they mainly came from industrial point sources. Compared with soils in other regions, soil DDT pollution was at a medium level in the Tanggu Chemical Industrial District, but associated HCH, HCB, and PCB pollution was relatively heavy. By multivariate statistical analyses, Tianjin Dagu Chemical Co., Ltd. was recognized as the main source of POPs, and soil properties were clarified to play an important role on the distribution and composition of POPs, especially the organic carbon content. PMID- 23108757 TI - Evidence of population genetic effects in Peromyscus melanophrys chronically exposed to mine tailings in Morelos, Mexico. AB - Effects of environmental chemical pollution can be observed at all levels of biological organization. At the population level, genetic structure and diversity may be affected by exposure to metal contamination. This study was conducted in Huautla, Morelos, Mexico in a mining district where the main contaminants are lead and arsenic. Peromyscus melanophrys is a small mammal species that inhabits Huautla mine tailings and has been considered as a sentinel species. Metal bioaccumulation levels were examined by inductively coupled plasma mass spectrometry and genetic analyses were performed using eight microsatellite loci in 100 P. melanophrys individuals from 3 mine tailings and 2 control sites. The effect of metal bioaccumulation levels on genetic parameters (population and individual genetic diversity, genetic structure) was analyzed. We found a tissue concentration gradient for each metal and for the bioaccumulation index. The highest values of genetic differentiation (Fst and Rst) and the lowest number of migrants per generation (Nm) were registered among the exposed populations. Genetic distance analyses showed that the most polluted population was the most genetically distant among the five populations examined. Moreover, a negative and significant relationship was detected between genetic diversity (expected heterozygosity and internal relatedness) and each metal concentration and for the bioaccumulation index in P. melanophrys. This study highlights that metal stress is a major factor affecting the distribution and genetic diversity levels of P. melanophrys populations living inside mine tailings. We suggest the use of genetic population changes at micro-geographical scales as a population level biomarker. PMID- 23108758 TI - Implicit sequence learning in a continuous pursuit-tracking task. AB - Assessing implicit learning in the continuous pursuit-tracking task usually concerns a repeated segment of target displacements masked by two random segments, as referred to as Pew's paradigm. Evidence for segment learning in this paradigm is scanty and contrasts with robust sequence learning in discrete tracking tasks. The present study investigates this issue with two experiments in which participants (N = 56) performed a continuous tracking task. Contrary to Pew's paradigm, participants were presented with a training sequence that was continuously cycled during 14 blocks of practice, but Block 12 in which a transfer sequence was introduced. Results demonstrate sequence learning in several conditions except in the condition that was obviously the most similar to previous studies failing to induce segment learning. Specifically, it is shown here that a target moving too slowly combined with variable time at which target reversal occurs prevents sequence learning. In addition, data from a post experimental recognition test indicate that sequence learning was associated with explicit perceptual knowledge about the repetitive structure. We propose that learning repetition in a continuous tracking task is conditional on its capacity to (1) allow participants to detect the repeated regularities and (2) restrict feedback-based tracking strategies. PMID- 23108759 TI - Hypoxic preconditioning protects microvascular endothelial cells against hypoxia/reoxygenation injury by attenuating endoplasmic reticulum stress. AB - Endothelial cells (ECs) are directly exposed to hypoxia and contribute to injury during myocardial ischemia/reperfusion. Hypoxic preconditioning (HPC) protects ECs against hypoxia injury. This study aimed to explore whether HPC attenuates hypoxia/reoxygenation (H/R) injury by suppressing excessive endoplasmic reticulum stress (ERS) in cultured microvascular ECs (MVECs) from rat heart. MVECs injury was measured by lactate dehydrogenase (LDH) leakage, cytoskeleton destruction, and apoptosis. Expression of glucose regulating protein 78 (GRP78) and C/EBP homologous protein (CHOP), activation of caspase-12 (pro-apoptosis factors) and phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) were detected by western blot analysis. HPC attenuated H/R-induced LDH leakage, cytoskeleton destruction, and cell apoptosis, as shown by flow cytometry, Bax/Bcl-2 ratio, caspase-3 activation and terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling. HPC suppressed H/R-induced ERS, as shown by a decrease in expression of GRP78 and CHOP, and caspase-12 activation. HPC enhanced p38 MAPK phosphorylation but decreased that of protein kinase R-like ER kinase (PERK, upstream regulator of CHOP). SB202190 (an inhibitor of p38 MAPK) abolished HPC induced cytoprotection, downregulation of GRP78 and CHOP, and activation of caspase-12, as well as PERK phosphorylation. HPC may protect MVECs against H/R injury by suppressing CHOP-dependent apoptosis through p38 MAPK mediated downregulation of PERK activation. PMID- 23108760 TI - Fatty acid synthase inhibitor cerulenin inhibits topoisomerase I catalytic activity and augments SN-38-induced apoptosis. AB - Fatty acid synthase (FASN) is overexpressed in a wide variety of human cancers, making it an attractive target for anticancer therapy. One of the most widely used inhibitors of FASN, cerulenin, is a natural product of Cephalosporium caerulens. Cerulenin is selectively toxic to human cancer cells in vitro. However, the mechanism by which FASN inhibition causes apoptosis in tumor cells remains unclear. Because of the widespread clinical interest in combining cerulenin with other chemotherapeutic agents, we performed this study to gain insight into the downstream effects of FASN inhibition that lead to apoptosis. Here, we observed the increased antitumor effect of cerulenin when combined with the topoisomerase inhibitor SN-38. We identified topoisomerase I as a potential mediator of cerulenin-induced apoptosis, possibly by upregulating intracellular polyunsaturation. Finally, we show that suppressing topoisomerase I catalytic activity results in synergistic effects between cerulenin and LY294002. Our results suggest that topoisomerase I could participate in cerulenin-induced apoptosis by upregulating intracellular polyunsaturation. These results will help determine the molecular basis of the cerulenin and SN-38 drug combination. Further investigation of this pathway will provide new insight into cancer cell metabolism and may aid in the design of additional cancer chemotherapeutic agents. PMID- 23108761 TI - Screening of agro-industrial wastes for citric acid bioproduction by Aspergillus niger NRRL 2001 through solid state fermentation. AB - BACKGROUND: The citric acid (CA) industry is currently struggling to develop a sustainable and economical process owing to high substrate and energy costs. Increasing interest in the replacement of costly synthetic substrates by renewable waste biomass has fostered research on agro-industrial wastes and screening of raw materials for economical CA production. The food-processing industry generates substantial quantities of waste biomass that could be used as a valuable low-cost fermentation substrate. The present study evaluated the potential of different agro-industrial wastes, namely apple pomace (AP), brewer's spent grain, citrus waste and sphagnum peat moss, as substrates for solid state CA production using Aspergillus niger NRRL 2001. RESULTS: Among the four substrates, AP resulted in highest CA production of 61.06 +/- 1.9 g kg(-1) dry substrate (DS) after a 72 h incubation period. Based on the screening studies, AP was selected for optimisation studies through response surface methodology (RSM). Maximum CA production of 312.32 g kg(-1) DS was achieved at 75% (v/w) moisture and 3% (v/w) methanol after a 144 h incubation period. The validation of RSM optimised parameters in plastic trays resulted in maximum CA production of 364.4 +/- 4.50 g kg(-1) DS after a 120 h incubation period. CONCLUSION: The study demonstrated the potential of AP as a cheap substrate for higher CA production. This study contributes to knowledge about the future application of carbon rich agro-industrial wastes for their value addition to CA. It also offers economic and environmental benefits over traditional ways used to dispose off agro industrial wastes. PMID- 23108762 TI - Process indicators of quality clinical pharmacy services during transitions of care. AB - The American College of Clinical Pharmacy charged the Public and Professional Relations Committee to develop a short white paper describing quality measures of clinical pharmacists' patient care services in transitional care settings. Transitional care describes patient movement from one health care setting or service to another. Care transitions are associated with an increased risk of adverse events for patients. Pharmacists play an important role in ensuring that medication errors and adverse events are minimized during these transitions, largely through the reconciliation of medications and assurance of continuity of care. Quality measures are often divided into three domains: structure, process, and outcome. Given the typical nature of the pharmacist's role, process indicators are best suited to evaluate quality clinical pharmacist services. However, process indicators relevant to pharmacists' activities are not yet fully described in the literature. The committee searched available literature describing quality measures that are directly influenced by the pharmacist during care transitions. This white paper describes these process indicators as quality measures of clinical pharmacists' services, identifies the transitional settings and activities to which they are most applicable, and provides the published sources from which indicators were derived. For process indicators that could not be found in published sources, we propose relevant measures that can be adapted for use in a given setting. As pharmacists become more involved in diverse and emerging patient care areas such as transitional care, it will be critical that they use these types of measures to document the quality of new services and reinforce the need for pharmacist participation during transitions of care. PMID- 23108763 TI - Synthesis and characterization of Pd@M(x)Cu(1-x) (M = Au, Pd, and Pt) nanocages with porous walls and a yolk-shell structure through galvanic replacement reactions. AB - This paper describes the synthesis of Pd@M(x)Cu(1-x) (M = Au, Pd, and Pt) nanocages with a yolk-shell structure through galvanic replacement reactions that involve Pd@Cu core-shell nanocubes as sacrificial templates and ethylene glycol as the solvent. Compared with the most commonly used templates based on Ag, Cu offers a much lower reduction potential (0.34 versus 0.80 V), making the galvanic reaction more easily to conduct, even at room temperature. Our structural and compositional characterizations indicated that the products were hollow inside, and each one of them contained porous M-Cu alloy walls and a Pd cube in the interior. For the Pd@Au(x)Cu(1-x) yolk-shell nanocages, they displayed broad extinction peaks extending from the visible to the near-IR region. Our mechanistic study revealed that the dissolution of the Cu shell preferred to start from the slightly truncated corners and then progressed toward the interior, because the Cu {100} side faces were protected by a surface capping layer of hexadecylamine. This galvanic approach can also be extended to generating other hollow metal nanostructures by using different combinations of Cu nanostructures and salt precursors. PMID- 23108764 TI - Which point-of-care creatinine analyser for radiology: direct comparison of the i Stat and StatStrip creatinine methods with different sample types. AB - BACKGROUND: Availability of whole blood creatinine estimation for patients scheduled to undergo radiological contrast investigations can provide information to aid patient care by reducing adverse effects and improving departmental efficiencies. METHODS: We performed imprecision studies, different patient sample type comparison in 40 participants, and a limited interference study with dopamine and dobutamine on the i-Stat and StatStrip point-of-care enzymatic analysers with the Beckman DxC800 Jaffe assay. RESULTS: Imprecision results showed that the i-Stat performed better. Patient comparison data indicated that the i-Stat provided better correlation than the StatStrip for all the different sample types with correlation coefficients (r(2)) being 0.995-0.996 and 0.918 0.995, respectively. The i-Stat results had a small positive bias of 6-9% for the three different sample types, which required different reference intervals. The StatStrip method showed greater scatter and overall small negative bias of -6% for the whole blood samples and a 10% positive bias with the plasma samples. Dopamine caused significant positive interference with the i-Stat only while dobutamine caused a small negative bias with the StatStrip method only. CONCLUSIONS: The findings indicated there are differences offered by the two systems. The StatStrip requires a very small finger prick capillary sample, calculates estimation of the glomerular filtration rate and has an adjustment option to improve correlation with the local method. The i-Stat offers better analytical imprecision and patient comparison with the laboratory method with the three sample types but showed significant interference from dopamine. A final consideration was the availability of middleware to capture patient results with the i-Stat. Based on all the study data, the i-Stat was recommended. PMID- 23108765 TI - Iron autointoxication in a 16-year-old girl: a protective role for hepcidin? AB - Intentional iron overdose appears to be an increasingly common form of attempted suicide. We present a case of iron overdose in a 16-year-old girl who was found unconscious in her bed and brought to our emergency department. The most remarkable diagnostic findings were the patient's comatose condition, divergent eye position and positive Babinski foot pad reflexes. Laboratory tests showed hyperglycaemia and mild metabolic acidosis. A computed tomography scan of the cerebrum showed no signs of intracerebral haemorrhage or elevated intracerebral pressure. Toxicology screening showed no use of acetaminophen, ethanol or drugs of abuse. The patient was stabilized and monitored on the intensive care ward. When she woke up, she confessed to having taken Fero-Gradumet((r)). Retrospectively analysed, the serum iron concentration in the first blood sample (seven hours after ingestion) was 62 MUmol/L which corresponds with moderate iron intoxication. The patient received whole bowel irrigation with 2 L polyethyleneglycol solution and de-ironing treatment with intravenous deferoxamine 20 mg/kg in eight hours. She was discharged from the hospital after three days in a good clinical condition. Retrospectively, serum hepcidin concentrations were determined and evaluated in conjunction with serum iron concentrations and the installed treatment. Before medical de-ironing interventions were started, we saw that the serum iron concentration in our patient was already declining. At the same time, we observed a sharp increase in the serum hepcidin concentration. After normalization of serum iron concentrations, hepcidin normalized as well. PMID- 23108766 TI - A new accurate, simple formula for LDL-cholesterol estimation based on directly measured blood lipids from a large cohort. AB - BACKGROUND: Low-density lipoprotein cholesterol (LDL-c) is the major measured parameter for cardiovascular risk assessment. The generally accepted formula (LDL F) for estimating LDL-c developed by Friedewald and colleagues in 1972 using data from 448 individuals suffers from known inaccuracies at extremes of triglyceride (TG) and total cholesterol (TC) values. METHODS: We generated new formulas based on a large Brazilian database containing directly measured lipid values from 10,664 fasted individuals. This database LDL-c was measured by the LDL-C Select FS (DiaSys) system, a homogeneous method without centrifugation. The formulas were generated using linear and non-linear approaches, and the formula with the highest accuracy and simplicity for general clinical use was selected. RESULTS: The simple formula LDL-c = 3/4 (TC - HDL-c) provided an accurate estimate of LDL c, a higher correlation with directly measured LDL (r = 0.93) compared with LDL-F (r = 0.87), and also a higher accuracy. CONCLUSIONS: The new formula outperformed several other LDL-c formulas over a wide range of TC, HDL-c and TG values. The validation and application of this formula in other populations is warranted. PMID- 23108767 TI - Acute silent cerebral ischemic events in children with sickle cell anemia. AB - BACKGROUND: Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain. OBJECTIVE: To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient. DESIGN: Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial. SETTING: Clinical trial setting in tertiary care centers. PATIENTS: Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea. MAIN OUTCOME MEASURE: Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI). RESULTS: Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE. CONCLUSIONS: Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia. PMID- 23108768 TI - Now or later? Strategy for removing small colorectal polyps. PMID- 23108769 TI - Treatment of early colorectal cancers: too many choices? PMID- 23108770 TI - Prevalence of buried Barrett's metaplasia in patients before and after radiofrequency ablation. AB - BACKGROUND AND STUDY AIM: Radiofrequency ablation (RFA) to treat Barrett's esophagus is increasingly accepted. Description of the etiology, natural history, and prevalence of buried Barrett's metaplasia (BBM) following RFA is limited, although BBM continues to pose a clinical dilemma. We aimed to assess the prevalence, characteristics, and eradication rate of BBM in patients with both dysplastic and nondysplastic Barrett's esophagus, treated with RFA and followed over time. PATIENTS AND METHODS: The presence of Barrett's esophagus, dysplasia, and BBM, before and after RFA, was assessed by two gastrointestinal pathologists in a retrospective chart review of patients who had undergone RFA at our center and had completed appropriate follow-up. RESULTS: We identified 112 patients with completed treatment and no further planned RFA. In 108, no residual Barrett's esophagus was seen after RFA; 4 patients with persistent Barrett's tissue underwent surgery. Regarding BBM, 17/112 patients (15.2%) had evidence of BBM during evaluation. In 12/17 (70.5%) BBM was found during the RFA treatment, with 8 having previously undergone non-RFA therapy and RFA for Barrett's esophagus and 4 having no previous intervention. In 5/17 (29.4%), BBM was seen only after RFA monotherapy. All 17 showed no evidence of BBM at final evaluation and were classified in the complete remission group (108/112). CONCLUSION: Both Barrett's esophagus and BBM were completely eradicated in all patients with long-term follow-up after RFA. Almost half of the patients with BBM had a prior history of non-RFA therapy for Barrett's esophagus compared with 26% the non-BBM cohort. All patients with previously identified Barrett's esophagus and BBM were completely cleared of disease at final follow-up. PMID- 23108772 TI - Feasibility of duodenal balloon-assisted direct cholangioscopy with an ultrathin upper endoscope. AB - BACKGROUND AND STUDY AIMS: We have previously developed duodenal balloon-assisted direct cholangioscopy (DBA-DC) with an ultrathin endoscope (UTE). Here, we further evaluated the feasibility, safety, and diagnostic and therapeutic usefulness of DBA-DC using UTE. PATIENTS AND METHODS: 40 consecutive patients with biliary diseases were enrolled in a prospective observational feasibility study. We assessed the success rate, procedure time, durability of the UTE, and usefulness in diagnosis and therapy. We also evaluated safety, including cardiovascular alterations and biliary injury as complications of the procedure. RESULTS: DBA-DC was performed successfully in 37/40 patients (92.5%). The mean time to reach either biliary bifurcation or stricture was 11.8 +/- 6.3 minutes. The procedure revealed 26 biliary stones, 5 cholangiocarcinomas, and 3 benign biliary strictures. Therapeutic procedures were performed in 16 patients (10 biliary lithotomies, 3 holmium-YAG laser lithotripsies, and 3 intraductal stent placements). No significant clinical complications related to DBA-DC were observed. Changes in cardiovascular responses and biliary biochemical parameters were minimal, except for leukocytosis in 8 patients. CONCLUSIONS: DBA-DC appears to be sufficiently feasible and may be useful as an alternative technique in cases that elude successful diagnosis and/or therapy with conventional endoscopic retrograde cholangiopancreatography (ERCP). PMID- 23108773 TI - Secondary sclerosing cholangitis in critically ill patients: model of end-stage liver disease score and renal function predict outcome. AB - Secondary sclerosing cholangitis in critically ill patients (SSC - CIP) is an underdiagnosed emerging disease. The aim of this study was to characterize clinical features and prognostic factors for mortality in SSC - CIP. This retrospective study included 54 patients who were diagnosed via endoscopic retrograde cholangiopancreatography (ERCP) after cardiothoracic surgery (n = 21), sepsis (n = 13), polytrauma (n = 11), and others (n = 9). In total, 33 patients who either died (n = 27) or needed liver transplantation (n = 6) were compared with surviving patients (n = 21). The model for end-stage liver disease (MELD) score and need for renal replacement therapy were independent risk factors for mortality. Compared with ERCP, accuracy was 30% for ultrasound and 36 % for liver biopsies. As a result of microbiological bile analysis, 28 % of patients required a change in antibiotic treatment. SSC - CIP is frequently a fatal disease. ERCP should be considered in selected patients to establish the diagnosis and hence provide useful clinical information. PMID- 23108774 TI - Re: Endoscopic ultrasound staging in gastric cancer: does it help management decisions in the era of neoadjuvant treatment? PMID- 23108776 TI - Covered self-expanding metal stents for transmural drainage of infected pancreatic fluid collections: don't sell the skin till you have caught the bear or at least spotted the animal. PMID- 23108771 TI - Epidemiological and prognostic factors involved in upper gastrointestinal bleeding: results of a French prospective multicenter study. AB - BACKGROUND AND STUDY AIMS: The mortality rate from upper gastrointestinal bleeding (UGIB) remains high, at 5 % - 10 %. The aim of the current study was to describe the epidemiological characteristics, prognostic factors, and actual practice in a cohort of patients with UGIB admitted to French general hospitals. METHODS: From March 2005 to February 2006, a prospective multicenter study was conducted at 53 French hospitals. A total of 3298 patients admitted for UGIB were enrolled consecutively. Patient data were collected up to the date of discharge from hospital. RESULTS: Data were available for 2130 men and 1073 women (mean age 63 +/- 18 years), one-third of whom were taking drugs that would increase the risk of UGIB. The two main causes of bleeding were peptic ulcers (38 %) and esophagogastric varices (EGV) or portal hypertensive gastropathy (24.5 %). Mean Rockall score was 5.0 +/- 2.3. Endoscopy was performed on 96 % of patients (within 24 hours in 79 %), and 66 % of those with ulcers and 62.5 % of the EGV patients underwent hemostatic therapy when indicated. Rebleeding occurred in 9.9 % of the patients, and 8.3 % died. Independent predictors of rebleeding were: need for transfusion (odds ratio [OR] 19.1; 95 % confidence interval [95 %CI] 10.1 - 35.9); hemoglobin < 10 g/dL (OR: 1.7; 95 %CI 1.1 - 3.3); Rockall score (OR: 1.4 for each 1 point score increase; 95 %CI 1.0 - 1.9), systolic blood pressure < 100 mmHg (OR: 1.9; 95 %CI 1.4 - 2.5), and signs of recent bleeding (OR: 2.4; 95 %CI 1.7 - 3.5). Independent predictors of mortality were: Rockall score (OR: 2.8; 95 %CI 2.0 - 4.0), co-morbidities (OR: 3.6 for each additional co morbidity; 95 %CI 2.0 - 6.3), and systolic blood pressure < 100 mmHg (OR: 2.1; 95 %CI 1.8 - 2.8). Rockall score, blood pressure and co-morbidities were taken as continuous variables meaning that the OR was 1.4 for every point increase, it was the same for blood pressure. CONCLUSION: UGIB still occurs mainly as a result of peptic ulcers and portal hypertension in France, and causes significant rates of mortality. There is scope for improvement via better prevention (better use of UGIB-facilitating drugs), endoscopic therapy, and management of co-morbidities. PMID- 23108778 TI - ESGE/ESDO quality in endoscopy: colonoscopy and colonic neoplasms symposium reports. PMID- 23108779 TI - Coronary CT angiography and high-risk plaque morphology. AB - Computed tomography angiography (CTA) is commonly employed for exclusion of coronary artery disease and demonstration of the extent of coronary vascular involvement. It has been recently proposed that coronary artery plaques could be visualized noninvasively. This review article focused on the high risk plaque detected by CTA. Plaque characteristics of acute coronary syndrome (ACS) was compared to sable angina pectoris (SAP). The presence of positive remodeling (ACS 87 %, SAP 12 %, p < 0.0001), low attenuation plaque (LAP) (ACS 79 %, SAP 9 %, p < 0.0001), and spotty calcification (ACS 63 %, SAP 21 %, p = 0.0005) were significantly more frequent in the culprit ACS lesions. Furthermore, in asymptomatic patients, presence of positively remodeling and LAP portends a greater risk for development of acute coronary events (hazard ratio = 22.8, CI = 6.9-75.2, p < 0.001). Possibility of drug intervention to high risk plaque was also reported. Serial CTA assessment allows for evaluation of interval change in morphological plaque characteristics and can be employed for assessment of efficacy of therapeutic intervention. Use of statin results in substantial reduction in LAP volume (follow-up: 4.9 +/- 7.8 versus baseline: 1.3 +/- 2.3 mm(3), p = 0.02) forwards stabilization of plaques. Although not recommended currently as a population-based strategy, CT angiographic examination may help identify very high risk asymptomatic subjects. PMID- 23108780 TI - Effects of strontium on the quality of bone apatite crystals: a paired biopsy study in postmenopausal osteoporotic women. AB - In paired biopsies of osteoporotic women treated with either strontium ranelate or a placebo for 36 months, characteristics of bone apatite crystals were not influenced by the presence of strontium. The mean rate of substitutions of calcium by strontium ions was 4.5 %. INTRODUCTION: The potential effect of strontium (Sr) on bone apatite crystals was investigated in paired biopsies of osteoporotic women treated with either strontium ranelate (SrRan) or a placebo for 36 months. METHODS: In ten paired biopsies, crystallinity, apparent length and width/thickness of crystals, interplanar distances, and lattice parameters of unit cells were assessed by X-ray diffraction and selected area electron diffraction. RESULTS: All these parameters, reflecting crystal and unit cell characteristics, were not influenced by the presence of Sr and were similar in SrRan and placebo groups after 36 months of treatment. The mean rate of substitutions of calcium by Sr ions was 4.5 %. CONCLUSION: Overall, the quality of bone apatite crystals was maintained after 36 months of treatment with SrRan. PMID- 23108781 TI - Continuous decline in incidence of hip fracture: nationwide statistics from Finland between 1970 and 2010. AB - We determined the current trend in the number and incidence of hip fracture among persons 50 years of age or older in Finland between 1970 and 2010. After a clear rise until the late 1990s, the incidence of hip fracture has continuously declined. INTRODUCTION: Hip fractures are a major public health issue associated with excess morbidity and mortality. We determined the current trend in the number and incidence (per 100,000 persons) of hip fracture among older adults in Finland, an EU country with a well-defined Caucasian population of 5.4 million people. METHODS: We took into account all persons 50 years of age or older who were admitted to hospitals for primary treatment of hip fracture between 1970 and 2010. RESULTS: The number of hip fractures rose sharply till the end of 1990s (from 1,857 in 1970 to 7,122 in 1997), but since then, the rise has leveled off (7,594 fractures in 2010). Similarly, the age-adjusted incidence of hip fracture increased until 1997 but declined thereafter. The decline was especially clear in women whose age-adjusted incidence was 515.7 (per 100,000 persons) in 1997 but only 382.6 in 2010. In men, the corresponding incidence was 245.3 in 1997 and 210.7 in 2010. The number of hip fractures will increase 1.8-fold by 2030 even with the current 2010 incidence rates because the size of the 50-year-old or older population is likely to increase sharply in the near future. CONCLUSIONS: The declining trend in the incidence of hip fracture in Finland has continued through the entire first decade of the new millennium. Reasons for this development are uncertain, but possible explanations include increased average body weight, improved functional ability among elderly Finns, and specific measures to prevent bone loss and reduce the risk of falling. PMID- 23108782 TI - Can detection of late-onset PE at triage by sflt-1 or PlGF be improved by the use of additional biomarkers? AB - OBJECTIVE: Accurate identification of preeclampsia (PE) at triage is essential to reduce maternal and fetal morbidity and mortality. The use of maternal blood based biomarkers may facilitate the clinician's ability to assess high risk pregnancies at triage. METHODS: A prospective cross-sectional study was performed to investigate the value of soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng), placental growth factor (PlGF), sP-selectin, cell-free fetal DNA and total cell-free DNA in patients with late-onset PE versus gestational age matched controls. RESULTS: The diagnosis of late-onset PE (n = 21) at triage was significantly improved by altered levels of sFlt-1, sEng, PlGF and cffDNA as compared with controls (n = 42). Areas under the receiver operating characteristic curves [AUC, Standard error (SE)] for predicting PE were for marker measurements prior to the first stage of labor as follows: sFlt-1 0.97 (SE 0.02), sEng 0.91 (SE 0.04), PlGF 0.95 (SE 0.04), cell-free fetal DNA (DYS 14) 0.84 (SE 0.06), total cell-free DNA (glyceraldehyde 3-phosphate dehydrogenase) 0.61 (SE 0.07), sP-selectin 0.51 (SE 0.07). The discrimination could be slightly improved by using the slt1-PlGF ratio: 0.98 (SE 0.02). CONCLUSION: The sFlt-1 is a useful tool for the detection of late-onset PE at triage. This can be slightly improved using a sFlt-1/PIGF ratio. The addition of other biomarkers did not improve screening performance for late-onset PE. PMID- 23108783 TI - Birt-Hogg-Dube syndrome: from gene discovery to molecularly targeted therapies. AB - Since the hallmark dermatologic features of Birt-Hogg-Dube (BHD) syndrome were first described by three Canadian physicians in 1977, the clinical manifestations of BHD have been expanded to include hamartomas of the hair follicle, lung cysts, increased risk for spontaneous pneumothorax and kidney neoplasia. Twenty-five years later the causative gene FLCN was identified, and the mutation spectrum has now been defined to include mainly protein truncating mutations, but also rare missense mutations and large gene deletions/duplication. Second "hit" FLCN mutations in BHD kidney tumors and loss of tumorigenic potential of the FLCN-null UOK257 tumor cell line when FLCN is re-expressed underscore a tumor suppressor role for FLCN. The identification of novel FLCN interacting proteins FNIP1 and FNIP2/L and their interaction with 5'-AMP activated protein kinase (AMPK) has provided a link between FLCN and the AMPK-mTOR axis and suggested molecular targets for therapeutic intervention to treat BHD kidney cancer and fibrofolliculomas. The generation of FLCN-null cell lines and in vivo animal models in which FLCN (or FNIP1) has been inactivated have provided critical reagents to facilitate mechanistic studies of FLCN function. Research efforts utilizing these critical FLCN-deficient cell lines and mice have begun to uncover important signaling pathways in which FLCN and its protein partners may play a role, including TGF-beta signaling, TFE3 transcriptional regulation, PGC1-alpha driven mitochondrial biogenesis, apoptotic response to cell stress, and vesicular transport. As the mechanisms by which FLCN inactivation leads to BHD manifestations are clarified, we can begin to develop therapeutic agents that target the pathways dysregulated in FLCN-deficient fibrofolliculomas and kidney tumors, providing improved prognosis and quality of life for BHD patients. PMID- 23108784 TI - [New aspects of surgery for pancreatic cancer. Principles, results and evidence]. AB - Ductal adenocarcinoma is the most frequent malignant tumor of the pancreas and total resection of the pancreatic tumor is still the only curative treatment option. Most tumors are located in the pancreatic head, therefore, pylorus preserving pancreaticoduodenectomy (Whipple PPPD) is the oncological standard procedure. By concentrating pancreatic resections in specialized centers for pancreatic surgery perioperative mortality and morbidity has decreased in recent years. However, pancreatic resections remain complex and difficult operations and pancreatic anastomosis is particular challenging. To achieve complete resection (R0) resection and reconstruction of large venous vessels is often necessary. Resection of arterial vessels is rarely performed and usually does not lead to an R0 resection of the tumor. Currently adjuvant chemotherapy after total tumor resection is standard of care for all tumor stages but neoadjuvant regimes have recently been reported increasingly more often. Advances in translational research has led to a better understanding of tumor biology and new diagnostic options and therapies are expected in the near future. PMID- 23108785 TI - Effects of short-term administration of estradiol on reperfusion arrhythmias in rats of different ages. AB - Little is known about age-related differences in short-term effects of estradiol on ischemia-reperfusion (I/R) insults. The present study was designed to evaluate the effects of short-term treatment with estradiol on reperfusion arrhythmias in isolated hearts of 6-7-week-old and 12-14-month-old female rats. Wistar rats were sham-operated, ovariectomized and treated with vehicle or ovariectomized and treated with 17beta-estradiol (E2; 5 ug.100 g-1.day-1) for 4 days. Hearts were perfused by the Langendorff technique. Reperfusion arrhythmias, i.e., ventricular tachycardia and/or ventricular fibrillation, were induced by 15 min of left coronary artery ligation and 30 min of reperfusion. The duration and incidence of I/R arrhythmias were significantly higher in young rats compared to middle-aged rats (arrhythmia severity index: 9.4 +/- 1.0 vs 3.0 +/- 0.3 arbitrary units, respectively, P < 0.05). In addition, middle-aged rats showed lower heart rate, systolic tension and coronary flow. Four-day E2 treatment caused an increase in uterine weight. Although E2 administration had no significant effect on the duration of I/R arrhythmias in middle-aged rats, it induced a marked reduction in the rhythm disturbances of young rats accompanied by a decrease in heart rate of isolated hearts. Also, this reduction was associated with an increase in QT interval. No significant changes were observed in the QT interval of middle-aged E2-treated rats. These data demonstrate that short-term estradiol treatment protects against I/R arrhythmias in hearts of young female rats. The anti arrhythmogenic effect of estradiol might be related to a lengthening of the QT interval. PMID- 23108786 TI - Evaluation of N95 respirator use with a surgical mask cover: effects on breathing resistance and inhaled carbon dioxide. AB - OBJECTIVE: For pandemic influenza outbreaks, the Institute of Medicine has recommended using a surgical mask cover (SM) over N95 filtering facepiece respirators (FFRs) among healthcare workers as one strategy to avoid surface contamination of the FFR which would extend its efficacy and reduce the threat of exhausting FFR supplies. The objective of this investigation was to measure breathing air quality and breathing resistance when using FFRs with US Food and Drug Administration-cleared SM and without SM. METHODS: Thirty National Institute for Occupational Safety and Health (NIOSH)-approved FFR models with and without SM were evaluated using the NIOSH Automated Breathing and Metabolic Simulator (ABMS) through six incremental work rates. RESULTS: Generally, concentrations of average inhaled CO(2) decreased and average inhaled O(2) increased with increasing O(2) consumption for FFR+SM and FFR-only. For most work rates, peak inhalation and exhalation pressures were statistically higher in FFR+SM as compared with FFR-only. The type of FFR and the presence of exhalation valves (EVs) had significant effects on average inhaled CO(2), average inhaled O(2), and breathing pressures. The evidence suggests that placement of an SM on one type of FFR improved inhaled breathing gas concentrations over the FFR without SM; the placement of an SM over an FFR+EV probably will prevent the EV from opening, regardless of activity intensity; and, at lower levels of energy expenditure, EVs in FFR do not open either with or without an SM. CONCLUSIONS: The differences in inhaled gas concentrations in FFR+SM and FFR-only were significant, especially at lower levels of energy expenditure. The orientation of the SM on the FFR may have a significant effect on the inhaled breathing quality and breathing resistance, although the measurable inhalation and exhalation pressures caused by SM over FFR for healthcare users probably will be imperceptible at lower activity levels. PMID- 23108787 TI - Monochorionic quadruplet pregnancy without severe complications: sonographic work up and placental findings. PMID- 23108788 TI - Use of dynamic wound closure system in conjunction with vacuum-assisted closure therapy in delayed closure of open abdomen. AB - AIM: Definitive abdominal closure may not be possible for several days or weeks after laparotomy in damage-control surgery, abdominal compartment syndrome and intraabdominal sepsis, until the patient has stabilized. Vacuum-assisted closure (VAC therapy((r)), KCI, San Antonio, TX, USA) and abdominal re-approximation anchor system (ABRA, Canica, Almonte, Ontario, Canada) are novel techniques in delayed closure of open abdomen. Our aim is to present the use of these strategies in the management of 7 patients with open abdomen. METHODS: Between August 2010 and December 2011, 7 patients with severe peritonitis were stabilized by laparotomy and treated with either ABRA system or ABRA system in conjunction with VAC dressing. VAC dressing applied to 4 patients initially and followed by ABRA. ABRA was applied alone to remaining 3 patients. Demographic data and patient characteristics, timing of VAC dressing and ABRA system were recorded. ICU and hospital stay and development of incisional hernia were also recorded. Stage of open abdomen, width of abdominal defect, extent to damage to fascia, and pressure sores were staged. RESULTS: The mean duration with VAC dressing before ABRA application was 18 days. The mean duration of ABRA application was 53 days. The average width of the abdominal defect was 18 cm. The average length of defect was 20.8 cm. Delayed primary abdominal closure was accomplished in 6 patients without further surgery. Incisional hernia with a small abdominal defect developed in 2 patients. CONCLUSION: Abdominal re-approximation anchor system and VAC dressing can be used separately or in conjunction with each other for closure of delayed open abdomen successfully. PMID- 23108789 TI - Sex-dependent differences in rat brown adipose tissue mitochondrial biogenesis and insulin signaling parameters in response to an obesogenic diet. AB - Marked sex-dependent differences in mitochondrial function and redox status have been found in brown adipose tissue (BAT) of control rats. Insulin also plays a role in the development and maintenance of this tissue. The aim was to investigate sexual dimorphism in the effects of diet-induced obesity on BAT mitochondrial function, as well as on insulin signaling pathway. 10-week-old Wistar rats of both sexes were fed a control diet or a palatable high-fat diet for 26 weeks. Serum markers of insulin sensitivity were analyzed. Mitochondrial DNA (mtDNA) content, mitochondrial oxidative activities, PGC-1alpha mRNA levels, as well as the protein levels of insulin receptor subunit beta (IRbeta), glucose transporter GLUT4, beta(3)-adrenergic receptor (beta(3)-AR), phosphatidylinositol 3-kinase, mitochondrial transcription factor A (TFAM), cytochrome c oxidase subunit IV (COX IV), and uncoupling protein 1 (UCP1) were measured in BAT. Obese females showed impaired systemic insulin sensitivity accompanied by diminished IRbeta, GLUT4, and beta(3)-AR protein levels in BAT. In addition, TFAM and COX IV protein and PGC-1alpha mRNA levels decreased in obese females, whereas mtDNA levels increased. In obese males, oxidative and thermogenic capacities rose and no significant changes were observed in the insulin signaling pathway elements. The reduction of the insulin signaling pathway in BAT of obese females may be responsible, at least partially, for the impaired biogenesis process, which could favor the increase of body weight found in this sex. In contrast, the enhanced mitochondrial functionality in the BAT of males would avoid increased oxidative damage and the impairment of insulin signaling. PMID- 23108790 TI - Investigation of in vitro and in vivo antioxidant potential of secoisolariciresinol diglucoside. AB - The present study was designed to evaluate the in vitro and in vivo ameliorative antioxidant potential of secoisolariciresinol diglucoside (SDG). In vitro antioxidant activity of synthetic SDG was carried out using DPPH, reducing power potency, and DNA protection assays. Wistar albino rats weighing 180-220 g were used for in vivo studies and liver damage was induced in the experimental animals by a single intraperitoneal (I.P.) injection of CCl(4) (2 g/kg b.w.). Intoxicated animals were treated orally with synthetic SDG at (12.5 and 25 mg/kg b.w.) and Silymarin (25 mg/kg) for 14 consecutive days. The levels of catalase (CAT), superoxide dismutase (SOD), peroxidase (POX), and lipid peroxidase (LPO) were measured in liver and kidney homogenates. The synthetic SDG exerts high in vitro antioxidant potency as it could scavenge DPPH at a IC(50) value of 78.9 MUg/ml and has dose-dependent reducing power potency and protected DNA at 0.5 mg/ml concentration. Oral administration of synthetic SDG at 12.5 and 25 mg/kg b.w. showed significant protection compared to Silymarin (25 mg/kg) and the activities of CAT, SOD, and POX were markedly increased (P < 0.05), whereas LPO significantly decreased (P < 0.001) in a dose-dependent manner in liver and kidney in both pre- and post-treatment groups when compared to toxin-treated group. The results of in vitro and in vivo investigations revealed that synthetic SDG at 25 mg/kg b.w. is associated with beneficial changes in hepatic enzyme activities and thereby plays a key role in the prevention of oxidative damage in immunologic system. PMID- 23108791 TI - Effect of combination of renin inhibitor and Mas-receptor agonist in DOCA-salt induced hypertension in rats. AB - To investigate the combined effect of aliskiren, a renin inhibitor, and AVE 0991, a Mas-receptor agonist, in experimental hypertension (HT) in rats. HT was produced by administration of deoxycorticosterone acetate (DOCA) and mean arterial blood pressure (MABP) was assessed by tail-cuff method. Treatments were started from 4th week onwards and were continued for 9 days. A significant increase in MABP was noted after 1 week in DOCA control rats, as compared with the base line value. A stable HT developed after 4 weeks of DOCA administration. Treatments with aliskiren and AVE 0991 alone, dose-dependently decreased MABP in DOCA-treated rats. Further, combination of low doses of aliskiren and AVE 0991 significantly reduced MABP, as compared with DOCA control rats and with either drug alone in low doses. It may be concluded that treatment with aliskiren produced down-regulation of both harmful Ang II-AT1-receptor and survival Ang(1 7)/Mas-receptor axis of RAAS. Treatment with combination of low doses of aliskiren and AVE 0991, for the first time, has been shown to produce synergistic blood pressure lowering effect. Therefore, combination of renin inhibitor with Mas-receptor agonist may prove beneficial for the treatment of hypertensive patients. PMID- 23108792 TI - SASH1 regulates proliferation, apoptosis, and invasion of osteosarcoma cell. AB - SASH1, a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in breast and colon cancer. The SASH1 protein possesses both the SH3 and SAM domains, indicating that it may play an important role in intracellular signal transduction. Reduced expression of SASH1 is closely related to tumor growth, invasion, metastasis, and poor prognosis. However, the biological role of SASH1 remains unknown in osteosarcoma. To unravel the function of SASH1, we explored the expression of SASH1 in osteosarcoma tissues and its correlation to the clinical pathology of osteosarcoma and analyzed the relationship between SASH1 expression and cell cycle, apoptosis and invasion of osteosarcoma MG-63 cells, using the flow cytometry analysis and transwell invasion chamber experiments. Furthermore, the effect of SASH1 on the expression of cyclin D1, caspase-3, matrix metalloproteinase (MMP)-9 were observed by western blot. Our results showed that the expression rate of SASH1 mRNA in osteosarcoma tissues was significantly lower than that in normal bone tissue (p = 0.000), that the expression rate of SASH1 mRNA in the carcinoma tissues from patients with lung metastasis was significantly lower than that from patients without lung metastasis (p = 0.041), and that the expression rate of SASH1 mRNA also decreased with increasing Enneking stage (p = 0.032). However, the mRNA expression of SASH1 in osteosarcoma was independent of the patient's gender, age, and tumor size (p = 0.983, 0.343, 0.517, respectively). The SASH1 protein displayed a down-regulation in osteosarcoma tissues compared to normal bone tissue (p = 0.000), displayed a down-regulation in osteosarcoma tissues from patients with lung metastasis compared to from patients without lung metastasis (p = 0.000), and displayed a gradual decrease with increasing Enneking stage (p = 0.000). In addition, the MG-63 cells from pcDNA3.1-SASH1 group exhibited significantly reduced cell viability, proliferation, and invasive ability compared to the empty vector group and blank control group (p = 0.023, 0.001, respectively), and there was no difference between the empty vector group and blank control group. The pcDNA3.1-SASH1 group displayed significantly more apoptotic cells than the empty vector group and blank control group (p = 0.004). The expression of cyclin D1, MMP-9 displayed a down-regulation in MG-63 cells from pcDNA3.1-SASH1 group compared to the empty vector group and blank control group (p = 0.000, 0.001, respectively) and the expression levels of caspase-3 displayed an up-regulation in MG-63 cells from pcDNA3.1-SASH1 group compared to the empty vector group and blank control group (p = 0.000). Taken together, these data indicated that the overexpression of SASH1 might be associated with the inhibition of growth, proliferation, and invasion of MG-63 cells and the promotion of apoptosis of MG-63 cells. PMID- 23108793 TI - Hemispheric asymmetry in the fusiform gyrus distinguishes Homo sapiens from chimpanzees. AB - While the neural basis for linguistic communication has been linked to brain structural asymmetries found only in humans (wider connective spacing is found between the minicolumns of neurons in the left hemisphere language areas), it is unknown if the opposite microanatomical asymmetry exists in the fusiform gyrus which typically supports a right hemisphere bias for face processing. Unlike language, face processing is an ability shared with chimpanzees and, as Darwin observed, the widespread use of facial expressions in animal communication suggests a biological basis. We tested the principle that minicolumn asymmetry follows typical functional dominance in humans, and tested its evolutionary continuity, by measuring minicolumn width, neuronal size and density in the mid fusiform cortex in 14 humans and 14 chimpanzees. We found that microanatomical asymmetry distinguishes humans from chimpanzees although the direction of asymmetry is the same as in language areas-the right hemisphere contained narrower minicolumns and smaller pyramidal neurons, as in auditory language areas. Uniformly narrow minicolumns in chimpanzees and in the human right hemisphere are consistent with mechanistic predictions supporting the apparent bias towards holistic face processing. Wider minicolumns and larger neurons in the human left hemisphere may be consistent with a language function such as word form processing. Microanatomical asymmetry in the neocortex therefore provides a correlate of hemispheric specialisation. PMID- 23108794 TI - Isolation and genomic characterization of stem cells in head and neck cancer. AB - BACKGROUND: This study investigated the use of 3 different established cell sorting strategies to isolate and characterize stem cells from head and neck cancer cell lines. METHODS: Five low-passage cell lines were subjected to cell sorting based on Hoechst side population, Aldefluor, and CD44 expression. Isolated cell populations were studied for gene expression, radiosensitivity, and chemosensitivity to cisplatin and paclitaxel. RESULTS: Each sorting method identified a different set of genes associated with different gene ontology categories, with mitosis being the only common category. CD44-associated gene changes were almost exclusively associated with cell cycle and in particular mitosis. There were no significant differences in radiosensitivity or cisplatin sensitivity of stem or non-stem cells, but CD44-isolated stem cells were more resistant to paclitaxel. CONCLUSIONS: This study suggested that CD44 may be the most promising cell-sorting strategy to isolate and investigate the impact of stem cells in head and neck squamous cell cancer (HNSCC). PMID- 23108795 TI - Synthesis of N-alkyl and N-aryl isoquinolones and derivatives via Pd-catalysed C H activation and cyclization reactions. AB - Relatively less expensive Pd-catalysed oxidative coupling reactions for the preparation of N-alkyl and N-aryl substituted isoquinolones and their derivatives have been developed. A broad reaction scope has been demonstrated. In addition, studies of the reaction additives and mechanistic insights, as well as KIE studies for a better understanding of the reaction pathway, have been discussed. PMID- 23108796 TI - Introns in UTRs: why we should stop ignoring them. AB - Although introns in 5'- and 3'-untranslated regions (UTRs) are found in many protein coding genes, rarely are they considered distinctive entities with specific functions. Indeed, mammalian transcripts with 3'-UTR introns are often assumed nonfunctional because they are subject to elimination by nonsense mediated decay (NMD). Nonetheless, recent findings indicate that 5'- and 3'-UTR intron status is of significant functional consequence for the regulation of mammalian genes. Therefore these features should be ignored no longer. PMID- 23108797 TI - n-Doping of organic electronic materials using air-stable organometallics: a mechanistic study of reduction by dimeric sandwich compounds. AB - Several 19-electron sandwich compounds are known to exist as "2*18-electron" dimers. Recently it has been shown that, despite their air stability in the solid state, some of these dimers act as powerful reductants when co-deposited from either the gas phase or from solution and that this behavior can be useful in n doping materials for organic electronics, including compounds with moderate electron affinities, such as 6,13-bis[tri(isopropyl)silylethynyl]pentacene (3). This paper addresses the mechanisms by which the dimers of 1,2,3,4,5 pentamethylrhodocene (1 b(2)), (pentamethylcyclopentadienyl)(1,3,5 trialkylbenzene)ruthenium (alkyl=Me, 2 a(2); alkyl=Et, 2 b(2)), and (pentamethylcyclopentadienyl)(benzene)iron (2 c(2)) react with 3 in solution. Vis/NIR and NMR spectroscopy, and X-ray crystallography indicate that the products of these solution reactions are 3(.-) salts of the monomeric sandwich cations. Vis/NIR kinetic studies for the Group 8 dimers are consistent with a mechanism whereby an endergonic electron transfer from the dimer to 3 is followed by rapid cleavage of the dimer cation. NMR crossover experiments with partially deuterated derivatives suggest that the C-C bond in the 1 b(2) dimer is much more readily broken than that in 2 a(2); consistent with this observation, Vis/NIR kinetic measurements suggest that the solution reduction of 3 by 1 b(2) can occur by both the mechanism established for the Group 8 species and by a mechanism in which an endergonic dissociation of the dimer is followed by rapid electron transfer from monomeric 1 b to 3. PMID- 23108798 TI - Outcomes in children with hemorrhagic stroke. AB - OBJECTIVES: To determine if a specific intracerebral hemorrhage ratio predicts poor outcome; whether predictors of outcome in adults, specifically hemorrhage location, ventricular involvement, or initial Glasgow Coma Scale score, predict outcome in childhood hemorrhagic stroke; and whether the cause of hemorrhagic stroke predicts outcome. DESIGN: Retrospective case study. SETTING A single tertiary care pediatric hospital. PARTICIPANTS: Fifty-nine cases who had nontraumatic hemorrhages. MAIN OUTCOME MEASURES: We examined whether hemorrhage volume, location, initial Glasgow Coma Scale score, or associated diagnoses predicted outcomes. We contacted survivors and parents and assessed outcomes using measures of neurological function, quality of life, and caregiver stress. RESULTS: Twenty died of the hemorrhage or associated illnesses, and we obtained follow-up on 19 survivors. Most survivors had mild to moderate neurological deficits, but many reported impaired school or physical functioning. Increasing hemorrhage volume predicted poorer neurological outcomes and poorer quality-of life ratings among survivors. Subjects who had intracranial vascular anomalies had the best outcomes of the group. Associated diagnoses strongly predicted scores on the parent- and child-rated quality-of-life measures. In contrast to what has been reported in adult studies, initial Glasgow Coma Scale score, primary location of the hemorrhage, and ventricular hemorrhage did not significantly predict outcomes, although ventricular hemorrhage was associated with trends toward poorer outcomes. CONCLUSIONS: The mortality of hemorrhagic stroke in children is lower than that in adults. Childhood survivors tend to have mild to moderate physical deficits, but they may have significant impairment in other domains such as school functioning. PMID- 23108799 TI - The Igf2as transcript is exported into cytoplasm and associated with polysomes. AB - Murine insulin-like growth factor 2 antisense (Igf2as) transcripts originate from the opposite strand of the same Igf2 locus as the Igf2 sense mRNA. The Igf2, insulin 2 (Ins2), and H19 genes form a cluster of imprinted genes on chromosome 7. Loss of imprinting of IGF2 in humans is associated with Beckwith-Wiedemann syndrome and Silver-Russell syndrome, as well as with Wilm's tumor and colorectal cancer. We developed a RNA-FISH protocol to detect Igf2as and Igf2 transcripts. The results from the RNA-FISH were confirmed with quantitative real-time PCR and clearly indicate that the Igf2as transcripts are predominantly located in the cytoplasm of C2C12 cells. In a polysome association study, we showed that the Igf2as sedimented with polysomes in a sucrose gradient. The cellular localization of Igf2as transcripts together with polysome fractionation analysis provides compelling evidence that the Igf2as is protein coding. PMID- 23108800 TI - Prevalence and molecular identification of the mediterranean variant among G6PD deficient Sistani and Balouch males in Southeastern Iran. AB - To determine the prevalence of G6PD deficiency and a Mediterranean mutation among males in southeastern Iran, we studied 1,097 Sistani and Balouch schoolboys. A questionnaire was used to collect demographic data and a history of malaria infection; blood samples were evaluated for G6PD deficiency and the G6PD Mediterranean mutation. Of the 1,097 boys screened, 175 were G6PD deficient (5.8 % of the Sistani boys and 19.3 % of the Balouch boys). The malaria survey indicated that among Balouch subjects, malaria infection was about 14 times that of Sistani subjects. Molecular characterization of G6PD-deficient samples revealed a general frequency of 85.1 % for the Mediterranean variant among all subjects (75 % among Sistani and 86.2 % among Balouch cases). The high prevalence of G6PD deficiency among Balouch populations confirms the hypothesis that the distribution of G6PD deficiency is concordant with the geographic distribution of malaria. PMID- 23108801 TI - Large-area fabrication of periodic sub-15 nm-width single-layer graphene nanorings. AB - A periodically aligned array of graphene nanorings (GRNRs) with a sub-15 nm linewidth at a pitch of 450 nm is fabricated with a large area, 9 cm(2) , through conventional nanoimprint lithography coupled with sophisticated metal deposition and plasma-etching processes. The existence of the single-layer GRNRs is verified by various techniques. PMID- 23108803 TI - Changes in Cesarean section scar dimensions during pregnancy: a prospective longitudinal study. AB - OBJECTIVES: To describe changes in Cesarean section (CS) scars longitudinally throughout pregnancy, and to relate initial scar measurements, demographic variables and obstetric variables to subsequent changes in scar features and to final pregnancy outcome. METHODS: In this prospective observational study we used transvaginal sonography (TVS) to examine the CS scar of 320 consecutive pregnant women at 11-13, 19-21 and 32-34 weeks' gestation. For scars visible on TVS, the hypoechoic part was measured in three dimensions and the residual myometrial thickness (RMT) was also measured. Analyses were carried out using one-way repeated measures ANOVA and mixed modeling. The incidence of subsequent scar rupture was recorded. RESULTS: The CS scar was visible in 284/320 cases (89%). Concerning length and depth of the hypoechoic part of the scar and RMT, the larger the initial scar measurement, the larger the decrease observed during pregnancy. For the hypoechoic part of the scar, the width increased on average by 1.8 mm per trimester, while the depth and length decreased by 1.8 and 1.9 mm, respectively (false discovery rate P < 0.0001). Mean RMT in the first trimester was 5.2 mm and on average decreased by 1.1 mm per trimester. Two cases (0.62%) of uterine scar rupture were confirmed following a trial of vaginal delivery; these had a mean RMT of 0.5 mm at second scan and an average decrease of 2.6 mm over the course of pregnancy. CONCLUSION: This study establishes reference data and confirms that the dimensions of CS scars change throughout pregnancy. Scar rupture was associated with a smaller RMT and greater decrease in RMT during pregnancy. There is the potential to test absolute values and observed changes in CS scar measurements as predictors of uterine scar rupture and outcome in trials of vaginal birth after Cesarean section. PMID- 23108804 TI - Enhancement of reproductive performances of Gangetic leaffish, Nandus nandus through up regulation of serum Ca2+ concentration, improved morphological alteration of liver and ovary with dietary polyunsaturated fatty acids. AB - Incorporation of polyunsaturated fatty acids (PUFAs) as biofunctional compounds with feed is an effective way for gonadal maturation without any hazardous effects on animal health, and thus it is possible to save the vulnerable species from the danger of extinction. In the present study sperm quality, level of Ca(2+) concentration in serum, histological structure of the liver and developmental stages of ovary of an endangered fish species, Nandus nandus were investigated for the confirmation of the positive effects of PUFAs in reproduction and gonadal maturation. Fishes were collected from Brahmaputra River, Mymensingh, Bangladesh. Treated group was fed 1% squid extracted phospholipid supplemented diet that was mixed with silver carp fish muscle where as controlled group was fed the same except phospholipid. For histology of liver and gonads, samples were dehydrated, cleaned and infiltrated, embedded in paraffin wax and sectioned. After that, the samples were stained with hematoxylin and eosin. The photomicrographs of the stained samples were taken by using light microscope. In comparison with the control group, treated group exhibited higher gonadal maturation which resulted in spontaneous spawning. Treated female demonstrated advanced gonadal developmental stages in comparison with the controlled female during different months. During spawning season, lipid granules and normal morphological alteration were observed in case of treated fish liver, whereas less lipid granules with more histological alteration of liver were observed in control group. Serum Ca(2+) concentration in treated female was found significantly higher (P < 0.01) in contrast to the controlled female during the breeding season which was an indicator of the augment of estrogen secretion during ovarian maturation. Better sperm quality, early maturation of oocytes, less histological alteration of liver hepatocytes and spontaneous spawning performances of PUFA-treated fish were as a result of the efficiency of PUFAs in enhancing maturation. The experiment suggests that supplementation of dietary PUFAs improve the spawning performances of fish. PMID- 23108806 TI - Foreword: social justice for battered women. PMID- 23108805 TI - Molecular cloning of grass carp (Ctenopharyngodon idellus) T-bet and GATA-3, and their expression profiles with IFN-gamma in response to grass carp reovirus (GCRV) infection. AB - Both T-bet and GATA-3, Th1/Th2 lineage-specific transcription factors, play important roles in the development of T cells and Th1/Th2 differentiation. In this study, T-bet and GATA-3 genes were cloned from grass carp (Ctenopharyngodon idellus). The putative primary structure of the polypeptide deduced from the cDNA sequence of grass carp T-bet contained 608 aa, which possessed a T-box DNA binding domain. The putative primary structure of the polypeptide deduced from the cDNA sequence of grass carp GATA-3 contained 396 aa, which possessed two consensus zinc finger domains (C-X(2)-C-X(17)-C-X(2)-C). The YxKxHxxxRP motif, KRRLSA and LMEKs/n sequences were also conserved in this GATA-3. Phylogenetic analysis indicated that grass carp T-bet and GATA-3 group with their known counterparts with zebrafish T-bet and GATA-3 as the closest neighbor, respectively. RT-qPCR results showed that grass carp T-bet gene was highly expressed in head kidney, followed by spleen, and low expressed in gill, liver, kidney, and intestine, while GATA-3 gene was highly expressed in intestine, followed by spleen, and low expressed in gill, liver, kidney, and head kidney. Grass carp is one of the "four important domestic fish" in China and often infected by grass carp reovirus (GCRV). As yet, there is no evidence that T-bet and GATA-3 (Th1/Th2 subsets) are involved in anti-virus immune of teleost fish. In this study, by RT-qPCR, we analyzed the expression dynamics of grass carp T bet and GATA-3 genes with IFN-gamma gene in response to GCRV infection for the first time. The expression dynamics showed that three genes might be crucially modulated by in vivo GCRV infection: (1) GCRV mainly induced a T-bet expression profile comparing to the GATA-3 expression, while the higher expression profiles of IFN-gamma correlated with the up-regulation of T-bet; (2) T-bet/IFN-gamma and GATA-3 expression changes suggest that in GCRV-infected grass carp, the common immune state of head kidney further heightens, whereas the common physiological state of intestine transforms to an anti-virus immune state. From this finding, we realize that GCRV mainly induces a Th1 response, and Th1 cell-mediated recognition mechanisms play very important roles in anti-virus cellular immune of grass carp. PMID- 23108807 TI - South Asian battered women's use of force against intimate male partners: a practice note. AB - The purpose of this practice note is to explore issues that arise in Manavi's work with South Asian women who use nonfatal force in heterosexual intimate relationships. It provides a nuanced understanding of the contexts within which a South Asian woman uses physical force. It addresses the many barriers a South Asian woman faces in an abusive relationship that ultimately may lead her to use of force. The goal of the practice note is to act as a tool to strengthen advocacy and service provision made available to South Asian female survivors of violence and abuse. PMID- 23108808 TI - Risk factors for complications of ERCP in primary sclerosing cholangitis. AB - BACKGROUND AND STUDY AIMS: Endoscopic retrograde cholangiographic pancreatography (ERCP) is the most accurate technique for surveillance of patients with primary sclerosing cholangitis (PSC). Our aim was to evaluate risk factors for complications of ERCP in patients with PSC. PATIENTS AND METHODS: In 2007 - 2009 we performed 441 ERCPs in patients with PSC. The primary tools for ERCP were a guide wire and papillotomy knife to gain access into the biliary duct. If the primary cannulation failed, and the wire went only into the pancreatic duct, pancreatic sphincterotomy was performed. If necessary, a further oblique cut with a needle knife was done in order to expose the biliary duct. RESULTS: Primary cannulation was successful in 389 patients (88.2 %). Of these, 147 (37.8 %) had had biliary sphincterotomy performed previously. In the group with failed primary cannulation, access into the biliary duct was achieved after pancreatic sphincterotomy in 52 patients. In 11 of these, a further cut with a needle knife was performed. Post-ERCP pancreatitis (PEP) was diagnosed in 31 patients (7.0 %). Factors predicting PEP were female sex (odds ratio [OR] 2.6, P = 0.015) and a guide wire in the pancreatic duct (OR 8.2, P < 0.01). Previous biliary sphincterotomy was a protective factor (OR 0.28, P = 0.02). The risk of PEP increased with the number of times the wire accidentally passed into the pancreatic duct (P < 0.001). Cholangitis developed in 6 patients (1.4 %). CONCLUSIONS: In patients with PSC the incidence of ERCP complications remained relatively low. The complication risk increased with the complexity of cannulation. In a patient with PSC in whom follow-up ERCP is planned, biliary sphincterotomy should be considered, as it may protect against PEP. PMID- 23108809 TI - Radiofrequency ablation and endoscopic resection in a single session for Barrett's esophagus containing early neoplasia: a feasibility study. AB - BACKGROUND AND STUDY AIM: Endoscopic resection with radiofrequency ablation (RFA) 6 weeks later safely and effectively eradicates Barrett's esophagus with high grade dysplasia (HGD) and early cancer. After widespread endoscopic resection, related scarring may hamper balloon-based circumferential RFA (c-RFA). However c RFA immediately followed by endoscopic resection in the same session might avoid the impact of scarring and reduce laceration and stenosis risk. We aimed to assess the feasibility of such an approach. PATIENTS AND METHODS: Patients with Barrett's esophagus >= 3 cm and >= 1 visible lesion (HGD/early cancer) were included. Visible lesions were marked with cautery, and c-RFA (12 J/cm2) was delivered using two applications and a cleaning step, followed by resection of the delineated area. Outcome measures were surface regression of Barrett's esophagus at 3 months, need for subsequent c-RFA, complications, and quality of resection specimens. RESULTS: 24 patients (20 men, 4 women; mean age 68 years, standard deviation [SD] 12; Barrett's esophagus median length C6M8) underwent single-session c-RFA + endoscopic resection, providing a median of 4 (interquartile range [IQR] 2 - 6) resection specimens (early cancer 18 patients; HGD 6). Complications included 1 perforation, 4 bleedings, and 5 stenoses; all were managed endoscopically. Specimens allowed assessment of neoplasia depth, differentiation, and lymphatic/vascular invasion. Median Barrett's esophagus surface regression at 3 months was 95 %. No patient required a second c-RFA procedure and 40 % required repeat endoscopic resection for visible lesions. Complete response for neoplasia was achieved in 100 % and complete response for intestinal metaplasia (CR-IM) in 95 %. CONCLUSIONS: c-RFA followed by endoscopic resection in the same session is feasible, but technically demanding and associated with a substantial rate of complications and repeat endoscopic resection. This approach should be reserved for selected cases in expert centers, with endoscopic resection and RFA 6 - 8 weeks later remaining the standard combined approach. PMID- 23108810 TI - Improving care transitions: current practice and future opportunities for pharmacists. AB - During the past decade, patient safety issues during care transitions have gained greater attention at both the local and national level. Readmission rates to U.S. hospitals are high, often because of poor care transitions. Serious adverse drug events (ADEs) caused by an incomplete understanding of changes in complex drug regimens can be an important factor contributing to readmission rates. This paper describes the roles and responsibilities of pharmacists in ensuring optimal outcomes from drug therapy during care transitions. Barriers to effective care transitions, including inadequate communication, poor care coordination, and the lack of one clinician ultimately responsible for these transitions, are discussed. This paper also identifies specific patient populations at high risk of ADEs during care transitions. Several national initiatives and newer care transition models are discussed, including multi- and interdisciplinary programs with pharmacists as key members. Among their potential roles, pharmacists should participate on medical rounds where available, perform medication reconciliation and admission drug histories, apply their knowledge of drug therapy to anticipate and resolve problems during transitions, communicate changes in drug regimens between providers and care settings, assess the appropriateness and patient understanding of drug regimens, promote adherence, and assess health literacy. In addition, this paper identifies barriers and ongoing challenges limiting greater involvement of pharmacists from different practice settings during care transitions. Professional degree programs and residency training programs should increase their emphasis on pharmacists' roles, especially as part of interdisciplinary teams, in improving patient safety during care transitions in diverse practice settings. This paper also recommends that Accreditation Council for Pharmacy Education (ACPE) standards include specific language regarding the exposure of students to issues regarding care transitions and that students have several opportunities to practice the skills needed for effective care transitions. Moreover, reimbursement mechanisms that permit greater pharmacist involvement in providing medication assistance to patients going through care transitions should be explored. Although health information technology offers the potential for safer care transitions, pharmacists' use of information technology must be integrated into the national initiatives for pharmacists to be effectively involved in care transitions. This paper concludes with a discussion about the importance of recognizing and addressing health literacy issues to promote patient empowerment during and after care transitions. PMID- 23108813 TI - CT scan: a benefit that may be evil. PMID- 23108811 TI - Increased effects of ginsenosides on the expression of cholesterol 7alpha hydroxylase but not the bile salt export pump are involved in cholesterol metabolism. AB - An extract from red ginseng [steamed and dried roots of Panax ginseng C.A. Meyer (RGE)] has been shown to have various actions on physiological functions. The mechanisms by which RGE promotes cholesterol metabolism in the liver are unclear, but RGE decreases the plasma levels of cholesterol. We investigated whether RGE affected the mRNA expression of cholesterol metabolism-related proteins such as cytochrome P450 (CYP)7A1 and bile salt export pump (BSEP) in the liver in hypercholesterolemic rats and rat primary hepatocytes. In-vivo studies showed the upregulation of CYP7A1 mRNA in hypercholesterolemic rats treated with RGE. Treatment with RGE exhibited decreased ratios of low-density lipoprotein cholesterol to high-density lipoprotein-cholesterol compared with hypercholesterolemia without RGE. In-vitro studies also showed the upregulation of CYP7A1 mRNA and protein levels by the addition of RGE to rat primary hepatocytes. The mRNA levels of BSEP exhibited few changes. The sustained levels of the liver X receptor (LXR) in vivo and the increased levels of LXR in vitro on RGE treatment could be involved in the upregulation of CYP7A1. To clarify the effects of 11 ginsenosides including RGE on the mRNA levels of CYP7A1 and BSEP, we performed in-vitro experiments using rat primary hepatocytes. The ginsenosides Ro, Rg3, Re, Rg1, and Rg2 exhibited increased mRNA levels of CYP7A1. These results suggest that several ginsenosides including RGE promoted cholesterol metabolism due to upregulation of CYP7A1. PMID- 23108812 TI - Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells. AB - The anoikis-sensitization activity of imperatorin, an active furanocoumarin component of Angelica dahurica root, is reported herein for the first time. The present study demonstrated that the imperatorin treatment at sub-toxic concentrations enhanced human lung cancer H23 cell apoptosis after detachment. A Western blot analysis showed that imperatorin significantly enhanced the p53 protein level, which subsequently down-regulated Mcl-1 protein and up-regulated Bax, while it had a minimal effect on Bcl-2 expression. In addition, an anchorage independent growth assay was performed to support the anti-metastasis potential of imperatorin. Consistent with anoikis assay, imperatorin exhibited a strong inhibitory effect on the anchorage-independent growth of the cells. Further, this study demonstrated that imperatorin sensitizes anoikis in other lung cancer cells, namely, H292 and A549. Because anoikis was shown to be a critical hindrance in preventing cancer cell metastasis, the knowledge regarding such an activity and an underlying mechanism may lead to the development of this compound for a cancer therapy. PMID- 23108814 TI - A new approach to endoscopic DCR. AB - AIM: To compare a composite technique of endoscopic dacrocystorhinostomy with the conventional technique. METHODS: A randomised prospective study was carried in the department of Otolaryngology Maulana Azad Medical College. Thirty patient selected for Endoscopic DCR were divided into two groups, one of which underwent conventional endoscopic DCR and the other group were treated with a newer technique using cautery, cold instrumentation and laser at different steps of endoscopic DCR. The patients were followed up for nine months. RESULTS/CONCLUSION: By using cautery, cold instrumentation and laser at different steps of endoscopic DCR we were able to achieve a success rate of around 94% with this composite technique as compared to 83.3% in conventional endoscopic DCR surgery. PMID- 23108815 TI - Quality of life in children with sleep-disordered breathing. AB - Children may present sleep-disordered breathing (SDB) and suffer with adverse effects upon their quality of life. OBJECTIVE: This study assessed the quality of life of children with SDB, compared subjects with obstructive sleep apnea syndrome (OSAS) and primary snoring (PS), and identified which areas in the OSA 18 questionnaire are more affected. METHODS: This is a historical cohort cross sectional study carried out on a consecutive sample of children with history of snoring and adenotonsillar hyperplasia. The subject's quality of life was assessed based on the answers their caregivers gave in the OSA-18 questionnaire and on diagnostic polysomnography tests. RESULTS: A number of 59 children participated in this study with mean age of 6.7 +/- 2.26 years. The mean score of the OSA-18 was 77.9 +/- 13.22 and the area most affected were "caregiver concerns" (21.8 +/- 4.25), "sleep disturbance" (18.8 +/- 5.19), "physical suffering" (17.3 +/- 5.0). The impact was low in 6 children (10.2%), moderate in 33 (55.9%) and high in 20 (33.9%). PS was found in 44 children (74.6%), OSAS in 15 (25.6%). OSAS had higher score on "physical suffering" area than PS (p = 0.04). The AI (r = 0.22; p = 0.08) and AHI (r = 0.14; p = 0.26) were not correlated with OSA-18. CONCLUSION: Sleep disordered breathing in childhood cause impairment in quality of life and areas most affected the OSA-18 were: "caregiver concerns", "sleep disturbance" and "physical suffering". OSAS has the domain "physical suffering" more affected than primary snorers. PMID- 23108816 TI - Comparing the clinical profile of non obese children with sleep apnea and snoring. AB - Few studies in the literature have looked into the cardiovascular and metabolic effects of Obstructive Sleep Apnea Syndrome (OSAS) in children. OBJECTIVE: This study aims to evaluate the metabolic profile of non-obese children with OSAS. METHODS: Fifty-two children were enrolled in this study, 21 girls and 31 boys. Patients were divided into two groups: OSAS (28 children) and Snore (22 children) according to polysomnographic evaluation. All children were submitted to ENT examination, measurements of weight, height and blood pressure. Blood samples were tested for hemoglobin, hematocrit, fasting glucose, fasting insulin, triglycerides, total cholesterol, HDL, LDL, VLDL, TSH and T4. The gathered data sets were compared between groups and also within the OSAS group according to the severity of the syndrome. RESULTS: The children from both groups had no alterations in blood pressure levels. The results of the blood tests were normal for both groups. Results of hemoglobin, hematocrit, and HDL were all significantly higher in the Snore group when compared to the OSAS group; by their turn, VLDL levels were higher in the OSAS group. There was no statistical difference between the groups based on OSAS severity. CONCLUSION: Non-obese children with OSAS present no significant alterations in metabolic tests or blood pressure levels. PMID- 23108817 TI - Are parents aware of their children's hearing complaints? AB - The accuracy of parents' impressions about their child's hearing status is variable and may not correspond to the child's complaints. AIM: To investigate children's self-reported hearing symptoms and parents' impressions about it. METHODS: 477 children (2nd to 5th grades of elementary schools) were interviewed and parents answered a survey at home. There were 393 matches between the children's interview and the parent's survey. RESULTS: 29% of the children reported trouble in understanding what people said, 36.1% had history of 1-3 ear infections, 12.7% had four or more ear infections, 21.7% had continuous tinnitus (positive association with history of exposure to loud sounds, p = 0.0007), 3.8% had pulsatile tinnitus and 2.9% had auditory hallucinations. 28.5% of the children were annoyed by loud sounds (associated with tinnitus, p = 0.0142, and gender, p = 0.0029) 10.4% had had audiological tests, and the determinant factors were history of ear infections (p < 0.001) and parents' concern about their child's hearing (p = 0.043). Parents and their own child's responses were significantly different. CONCLUSIONS: Children's auditory complaints were prevalent and relevant, but most of them had never had an audiological evaluation and most parents were not aware of their child's complaints. Sound intolerances and auditory hallucinations should be considered in clinical and audiological examinations. PMID- 23108818 TI - Peripheral osteoma of the maxillofacial region: a study of 10 cases. AB - Peripheral osteoma is a benign neoplasm, with low recurrence rate. Its incidence is rare in the jaws and the mandible is more affected than the maxilla. In most cases it is discovered during routine radiographic examinations. OBJECTIVE: The aim of this study is to show the author's experience regarding the treatment of this neoplasm. METHODS: A retrospective study from January 2002 to December 2007 including ten cases of peripheral osteoma in the maxillofacial region which were treated surgically by removal of the lesion followed by histological confirmation. None of the cases were correlated with Gardner's syndrome. RESULTS: In this series the incidence of this neoplasm was higher in females (1.5:1) with a mean age of 39, without age preference. One of the patients had lesion recurrence two years after the first surgery, having been submitted to another intervention, with no signs of relapse after three years and six months of follow up. CONCLUSION: Surgical treatment is effective for peripheral osteoma with a low recurrence rate. PMID- 23108819 TI - The use of Mitomycin-C to reduce synechia in middle meatus in sinus surgery: preliminary results. AB - Synechia is the most frequent complication after sinus surgery and has been reported in up to 36% of cases. Several types of materials have been used to reduce the incidence of synechia, including Mitomycin C (MMC). OBJECTIVE: This prospective study aimed to assess the effectiveness of topical MMC in the prevention of synechia after sinus surgery in humans. METHODS: At the end of surgery, MMC solution (1.0 mg/ml) was topically applied randomly to one of the middle meatuses (MMC group) of 14 patients while saline solution was applied to the contralateral meatus (control group). The author remained blind to the medicated side. Synechiae were classified as partial or total. RESULTS: Three patients had middle meatus synechia in the MMC group (21.43%) versus nine (64.29%) in the control group (p = 0.054). In the MMC group, all three middle meatus synechia were partial, while in the control group there were four partial (28.57%) and five total (35.71%) cases of synechia (p = 0.025). CONCLUSIONS: Mitomycin C was not effective in preventing middle meatus synechia, but reduced the probability of total synechia formation. PMID- 23108820 TI - Software for subjective visual vertical assessment: an observational cross sectional study. AB - Spatial orientation in relation to the gravitational axis is significantly important for the maintenance of the posture, gait and for most of the human's motor activities. The subjective visual vertical exam evaluates the individual's perception of vertical orientation. OBJECTIVES: The aims of this study were (1) to develop a virtual system to evaluate the subjective visual vertical exam, (2) to provide a simple tool to clinical practice and (3) to assess the subjective visual vertical values of healthy subjects using the new software. STUDY DESIGN: observational cross-sectional study. METHODS: Thirty healthy volunteers performed the subjective visual vertical exam in both static and dynamic conditions. The exam consisted in adjusting a virtual line in the vertical position using the computer mouse. For the static condition, the virtual line was projected in a white background. For the dynamic condition, black circles rotated in clockwise or counterclockwise directions. Six measurements were taken and the mean deviations in relation to the real vertical calculated. RESULTS: The mean values of subjective visual vertical measurements were: static -0.372o; +/- 1.21; dynamic clockwise 1.53o +/- 1.80 and dynamic counterclockwise -1.11o +/- 2.46. CONCLUSION: This software showed to be practical and accurate to be used in clinical routines. PMID- 23108821 TI - Levels II and III neck dissection for larynx cancer with N0 neck. AB - The removal of level II, III, and IV metastases has gained importance in the treatment of squamous cell carcinomas (SCC) of the neck and larynx. This study assessed the possibility of removing level II and level III metastases only, given the low likelihood of occurrence of metastatic lymph nodes on level IV in SCCs of the larynx. OBJECTIVE: This study aimed to analyze the prevalence rates of metastatic lymph nodes on level IV in laryngeal SCC patients. METHODS: This prospective study enrolled consecutive patients with laryngeal SCC submitted to neck lymph node dissection. Neck levels were identified and marked for future histopathology testing. RESULTS: Six percent (3/54) of the necks had level IV metastatic lymph nodes. All cN0 necks (42) were free from level IV metastasis. Histopathology testing done in the cN (+) necks (12) revealed that 25% of the level IV specimens were positive for SCC. The difference between cN0 and cN (+) necks was statistically significant (p = 0.009). Level IV metastases never occurred in isolation, and were always associated with level II or level III involvement (p = 0.002). CONCLUSION: The prevalence rate for lymph node metastasis in cN0 necks was 0%. Level IV metastatic lymph nodes were correlated to cN (+) necks. Level IV metastasis was associated with the presence of metastatic lymph nodes in levels II or III. PMID- 23108822 TI - Interleukin-13 gene polymorphisms at -1055 C/T and +2044 G/A positions in patients with squamous cell carcinoma of head and neck. AB - Squamous cell carcinoma (SCC) is the most common malignancy that involves the upper aerodigestive tract. Interleukin-13 (IL-13) is an immunoregulatory cytokine that has been reported to have some polymorphisms in it gene associated with same disease especially asthma and allergy. The present study aimed to investigate whether the polymorphisms of IL-13 gene (at positions of 1055C/T in the promoter of1L-13 gene and +2044G/T exon-4) differ in patients with head and neck SCC from healthy controls. METHODS: This study was investigated in patient with head and neck SCC (n = 137) and age- and sex-matched healthy controls (n = 127). Genotyping of IL-13 gene polymorphism was performed using polymerase chain reaction-based restriction fragment length polymorphism method. RESULTS: No statistically significant differences were found in the frequencies of genotypes and alleles between patients and control group at both sites (p = 0.16). In addition, no association was observed between investigated genotypes and other potential prognostic factors such as age, sex, primary tumor site, tumor size and smoking. CONCLUSION: This study suggests that there is no association between IL 13 gene polymorphisms (at position -1055C/T and +2044GI A) and susceptibility of the patients to SCC of head and neck. PMID- 23108823 TI - Satisfaction of patients fit with a hearing aid in a high complexity clinic. AB - The process of selecting and fitting hearing aid devices is only effective and only bring about good outcomes if the individual makes effective use of the device. Therefore, the individuals need to be happy with the outcome. AIM: To check the satisfaction of adults and elderly patients concerning their hearing aid in a high complex care clinic accredited by the Unified Health System, and to correlate this outcome with the variables related to age, gender, fitting period, daily use, as well as the type of sound amplifying device. METHODS: This is a descriptive cross-sectional study in which 60 subjects were evaluated using the questionnaire: Satisfaction with Amplification in Daily Life, applied by means of oral presentation, in individual interviews by the researcher. This instrument is divided into subscales: positive effects, service and costs, negative factors and personal image. RESULTS: It was shown that the subjects of this study were very happy with the use of hearing aid devices. There was significant difference in relating the daily use of the devices with the overall satisfaction score and subscale of personal image. CONCLUSION: It was found that the subjects of the study were very happy with the use of hearing aids, although satisfaction was not related to the variables: age, gender, time of use and device type. In general, participants with higher daily use are happier. PMID- 23108824 TI - Applicability of immediate, late or serial intact parathyroid hormone measurement following total thyroidectomy. AB - Hypocalcemia is the most common complication after total thyroidectomy. Intact parathyroid hormone (i-PTH) testing is a proven effective method to detect patients at risk for postoperative symptomatic hypocalcemia. However, there is still uncertainty as to the timing of i-PTH testing in a clinical setting. OBJECTIVE: This study looked into the correlation between serum i-PTH levels measured at different times after total thyroidectomy and the risk of symptomatic hypocalcemia. METHODS: This retrospective case series studied a group of 110 consecutive for hypocalcemia and intact parathyroid hormone (PTHi) levels four and twelve hours following total thyroidectomy. Statistical analysis was used to evaluate the performance of isolated and serial i-PTH measurements to determine the likelihood of symptomatic hypocalcemia. RESULTS: I-PTH is highly sensitive (90.3%-96.8%) and specific (77.2%-87.3%) for symptomatic hypocalcemia. There was no significant difference in the sensitivity levels of the tests done four and twelve hours after surgery or in a serial fashion. However, the 12-hour i-PTH level was more specific (p < 0.0007). CONCLUSION: Single i-PTH testing done 12 hours after total thyroidectomy may be used as a screening test to detect patients at risk for symptomatic hypocalcemia. PMID- 23108825 TI - Correlation of the P300 evoked potential in depressive and cognitive aspects of aging. AB - The P300 is a long-latency auditory evoked potential highly dependent on cognitive skills. It is believed that cognitive changes caused or not by depressive symptoms may interfere with the P300. AIM: To investigate the influence of aging, cognitive and depression aspects of the P300 latency in elderly people. METHODS: Clinical and experimental study with 60 elderly patients with sensorineural hearing loss of mild to moderately severe level, 20 males and 40 females, average age of 71.1. Participants were submitted to the long latency auditory evoked potential, in which the P300 latency (milliseconds) was studied. The cognitive aspects were assessed using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale (ADAS-Cog). In the assessment of depressive symptoms the Geriatric Depression Scale (GDS-15) was applied. RESULTS: We found a significant positive correlation between latency and age (p = 0.031). There were no significant differences among the P300 latency and the ADAS-Cog (p = 0.584), MMSE (p = 0.199) and GDS (p = 0.541) categories. CONCLUSION: Aging caused an increase in the P300 latency; however, cognitive performance and the presence of depressive symptoms did not influence the P300 results in this elderly population. PMID- 23108826 TI - Brain stem evoked response audiometry of former drug users. AB - Illicit drugs are known for their deleterious effects upon the central nervous system and more specifically for how they adversely affect hearing. OBJECTIVE: This study aims to analyze and compare the hearing complaints and the results of brainstem evoked response audiometry (BERA) of former drug user support group goers. METHODS: This is a cross-sectional non-experimental descriptive quantitative study. The sample consisted of 17 subjects divided by their preferred drug of use. Ten individuals were placed in the marijuana group (G1) and seven in the crack/cocaine group (G2). The subjects were further divided based on how long they had been using drugs: 1 to 5 years, 6 to 10 years, and over 15 years. They were interviewed, and assessed by pure tone audiometry, acoustic impedance tests, and BERA. RESULTS: No statistically significant differences were found between G1 and G2 or time of drug use in absolute latencies and interpeak intervals. However, only five of the 17 individuals had BERA results with adequate results for their ages. CONCLUSION: Marijuana and crack/cocaine may cause diffuse disorders in the brainstem and compromise the transmission of auditory stimuli regardless of how long these substances are used for. PMID- 23108827 TI - Static posturography in addicted to illicit drugs and alcohol. AB - The use of illicit drugs and alcohol can affect body balance. AIM: To evaluate balance control with static posturography in individuals addicted to illicit drugs, with or without alcohol abuse. STUDY DESIGN: Case-control, prospective. METHODS: 47 users of illicit drugs, with or without alcohol abuse, and a homogeneous control group consisting of 47 healthy individuals were submitted to a neurotological evaluation including Balance Rehabilitation Unit posturography. RESULTS: The stability threshold mean values were significantly lower (p < 0.0001) in users of illicit drugs, with or without alcohol abuse when compared to the control group; the mean values for sway velocity and ellipse area in all evaluated conditions were significantly higher (p <0.05) in the experimental group when compared to the control group, except for the ellipse area in static force surface and opened eyes (p = 0.168). CONCLUSION: The balance control of individuals addicted to illicit drugs with or without alcohol abuse could present stability threshold, sway velocity and ellipse area abnormalities in static posturography. PMID- 23108828 TI - Evaluation of balance in fallers and non-fallers elderly. AB - Falls present a substantial health problem among the elderly population. Approximately one-third of community-dwelling people over 65 years of age will experience one or more each year. OBJECTIVE: The purpose of this study was to evaluate balance between fallers and non-fallers elderly. STUDY DESIGN: Clinical study. METHODS: We studied 30 subjects older than 65 years of age. 15 subjects had a history of falls within a year (Group I) and 15 subjects had no history of falls (Group II). The scores of Computerized Dynamic Posturography (CDP); Sensory Organization Test (SOT), Limits of Stability (LOS), Rhytmic Weight Shift (RWS) and Berg Balance Scale (BBS) findings gathered from the individuals from Group I and Group II, were compared. RESULTS: The SOT 3, 6, composite, BBS scores and left-right on-axis velocity score of RWS test of the Group I were found to be significantly lower the Group II (p < 0.05). A positive correlation between the SOT 3, 5, composite and BBS scores of Group I and the SOT 4, 5, 6, composite and BBS scores of Group II is determined (p < 0.05). CONCLUSION: The CDP and BBS scores in fallers were found to be significantly lower as compared to the non fallers elderly. PMID- 23108829 TI - Prevalence of beta-hemolytic Streptococcus in children with special health care needs. AB - Pharyngotonsillitis by beta-hemolytic Streptococcus mostly affects children and immunocompromised, being Streptococcus pyogenes (Group A) the most common agent in bacterial pharyngotonsillitis. AIM: This work targeted the research of beta hemolytic Streptococcus Group-A (SBHGA) and No-A (SBHGNA) in the oropharynx of individuals with special health needs from the APAE (Maceio-AL). METHOD: A prospective study with oropharynx samples from patients with Down syndrome and other mental disorders (test) and students from a private school (control) aged 5 15 years. Cultures in blood agar (5%) were identified through Gram/catalase tests and bacitracin/trimethoprim-sulfamethoxazole disk diffusion method, applying the chi-squared statistical analysis. RESULTS: A total of 222 bacterial colonies were isolated in 74 individuals from APAE and 65 in the control group. In the test group, previous episodes of pharyngotonsillitis were reported by 36.49% (27/74) and 9.46% (7/74) were diagnosed with symptoms and/or signs suggestive of oropharynx infection. No positive sample of S. pyogenes was confirmed at APAE, being all samples classified as SBHGNA, with 5 SBHGA in the control group. CONCLUSION: The early identification of beta-hemolytic Streptococcus is important for the fast treatment of pharyngotonsillitis and the absence of S. pyogenes avoid future suppurative or not-suppurative sequels in the group from APAE. PMID- 23108830 TI - Non syndromic cleft lip and palate: relationship between sex and clinical extension. AB - Cleft lip and/or palate represent the most common congenital anomaly of the face. AIM: To describe the correlation between non-syndromic cleft lip and/or palate and gender, and its severity in the Brazilian population. METHODS: Cross sectional study, between 2009 and 2011, in a sample of 366 patients. The data was analyzed with descriptive statistics and multinomial logistic regression with a 95% interval to estimate the likelihood of the types of cleft lip and/or palate affecting the genders. RESULTS: Among the 366 cases of non-syndromic cleft lip and/or palate, the more frequent clefts were cleft lip and palate, followed respectively by cleft lip and cleft palate. The cleft palates were more frequent in females, while the cleft lip and palate and cleft lips only predominated in males. The risk of cleft li in relation the cleft palate was 2.19 times in males when compared to females; while the risk of cleft lip and palate in relation to cleft palate alone was 2.78 times in males compared to females. CONCLUSION: This study showed that there were differences in the distribution of the non-syndromic cleft lip and/or palate between males and females. PMID- 23108831 TI - Videolaryngostroboscopy and voice evaluation in patients with rheumatoid arthritis. AB - Arthritis may affect the larynx and produce symptoms such as hoarseness and vocal fatigue. OBJECTIVE: This paper aimed to evaluate the laryngeal manifestations of rheumatoid arthritis. METHODS: This is prospective study assessed 27 patients with rheumatoid arthritis with the aid of videolaryngostroboscopy, auditory perceptual analysis of the speech using the GIRBAS scale, acoustic analysis and the Voice Handicap Index questionnaire. RESULTS: Nineteen patients had laryngeal complaints, the main ones being intermittent dysphonia and sensation of a foreign body in the throat. The most frequent laryngoscopical finding was overlapping arytenoids. Three patients had low pitch, nine patients had mild dysphonia and roughness. Median acoustic measures were: F0, 198.39 Hz; Jitter, 0.815; Shimmer, 4.915; and NHR, 0.144. Regarding the Voice Handicap Index, the median score was zero in all domains. There was a statistically significant correlation between voice complaints and the domains of this index. Functional classes were significantly correlated to: overlapping arytenoids (p = 0.001), PPQ (p = 0.0257), Shimmer (p = 0.0295), APQ (p = 0.0195), and the VHI physical (p = 0.0227) and total domains (p = 0.0425). CONCLUSION: Laryngeal complaints were reported by 70.4% of the patients and laryngoscopical alterations were observed in 48% of the subjects. Voice acoustic evaluation and self-perception were altered. PMID- 23108832 TI - Neurofibromatosis 2: hearing restoration options. AB - Neurofibromatosis 2 (NF2) is an autosomal dominant disease in which hearing loss is predominant. Auditory restoration is possible using cochlear implants (CI) or auditory brainstem implant (ABI). OBJECTIVE: To assess the auditory results of CI and ABI in NF2 patients and review the literature. METHODS: Four NF2 patients were prospectively evaluated. They were submitted to tumor resection followed by ipsilateral CI or ABI depending on cochlear nerve preservation. Long term auditory results were described for CI (12 months) and ABI (48 months). RESULTS: All patients achieved auditory perception improvements in their hearing thresholds. The CI patient does not recognize vowels or sentences. The 3 ABI patients discriminate 70% of vowels and 86% in the 4-choice test. One of them does not recognize sentences. The other two recognize 100% of closed sentences and 10% and 20% of open sentences. CONCLUSION: The choice of implant type to restore hearing to NF2 patients will relay on anatomical and functional cochlear nerve preservation during tumor resection surgery. Although our experience was different, the literature shows that if this condition is achieved, CI will offer better auditory results. If not, ABI is recommended. PMID- 23108833 TI - Clear cell sarcoma of the parotid region. PMID- 23108835 TI - Primary lesion of mucocutaneous leishmaniasis simulating external otitis. PMID- 23108834 TI - Nasal histoplasmosis without lung involvement in an immunocompromised patient. PMID- 23108836 TI - Adult rhabdomyoma at submandibular gland. PMID- 23108837 TI - Intermolecular dynamics and paramagnetic properties of ethylenediaminetetraacetate complexes with the yttrium subgroup rare earth elements using nuclear magnetic resonance. AB - (1)H nuclear magnetic resonance (NMR) measurements are reported for the D(2)O solutions of [Ln(3+)(EDTA(4-))](-) complexes, where EDTA(4-) is ethylenediaminetetraacetate anion, Ln(3+) = Tb(3+) (I), Ho(3+) (II), Tm(3+) (III), Yb(3+) (IV) and Lu(3+) (V). Temperature dependencies of the (1)H NMR spectra of paramagnetic I-IV have been analyzed using the dynamic NMR methods. It is found that the activation free energies (DeltaG(?)(298)) of the intermolecular EDTA ions exchange at [Ln(3+) (EDTA(4-))](-) complexes are 60+/-3 (I), 66+/-3 (II), 69+/-3 (III) and 74+/-3 (IV) kJ/mol (at pD = 7). A monotonic increase of the free energy of chemical exchange processes along the series of lanthanide [Ln(3+) (EDTA(4-))](-) complexes is probably related to the lanthanide contraction. The obtained results indicate that coordination compounds I-IV may be considered as thermometric NMR sensors and lanthanide paramagnetic probes for in situ temperature control in solution. PMID- 23108838 TI - Magnetically modified spent grain as a low-cost, biocompatible and smart carrier for enzyme immobilisation. AB - BACKGROUND: Food and feed technology and biotechnology benefit from the use of immobilised enzymes. New low-cost enzyme carriers exhibiting high biocompatibility and response to external magnetic field can substantially improve the application potential of immobilised enzyme systems. RESULTS: Ferrofluid-modified spent grain was used as a low-cost, biocompatible and magnetically responsive carrier for the immobilisation of Candida rugosa lipase. Several immobilisation procedures were tested using both native and poly(ethyleneimine)-modified magnetic spent grain. Activity of immobilised lipase per unit mass of carrier, operational stability, time stability and Michaelis constant were compared. In general, magnetic spent grain modified with poly(ethyleneimine) bound a smaller amount of active lipase than unmodified magnetic spent grain, but the operational and storage stabilities of enzyme immobilised on poly(ethyleneimine)-modified carrier were very high. CONCLUSION: Ferrofluid-modified spent grain can be a promising low-cost magnetic carrier for enzyme immobilisation, applicable e.g. in food and feed technology and biotechnology. PMID- 23108839 TI - Lower pole stones: prone PCNL versus supine PCNL in the International Cooperation in Endourology (ICE) group experience. AB - PURPOSE: To assess efficacy and safety of prone- and supine percutaneous nephrolithotomy (PCNL) for the treatment of lower pole kidney stones. METHODS: Data from patients affected by lower pole kidney stones and treated with PCNL between December 2005 and August 2010 were collected retrospectively by seven referral centres. Variables analysed included patient demographics, clinical and surgical characteristics, stone-free rates (SFR) and complications. Statistical analysis was conducted to compare the differences for SFRs and complication rates between prone- and supine PCNL. RESULTS: One hundred seventeen patients underwent PCNL (mean stone size: 19.5 mm) for stones harboured only in the lower renal pole (single stone: 53.6%; multiple stones: 46.4%). A higher proportion of patients with ASA score >= 3 and harbouring multiple lower pole stones were treated with supine PCNL (5.8 vs. 23.1%; p = 0.0001, and 25 vs. 81.5%; p = 0.0001, respectively, for prone- and supine PCNL). One-month SFR was 88.9%; an auxiliary procedure was needed in 6 patients; the 3-month SFR was 90.2%. There were 9 post operative major complications (7.7%). No differences were observed in terms of 1- and 3-month SFRs (90.4 vs. 87.7%; p = 0.64; 92.3 vs. 89.2%; p = 0.4) and complication rates (7.6 vs. 7.7%; p = 0.83) when comparing prone- versus supine PCNL, respectively. CONCLUSIONS: The results confirm the high success rate and relatively low morbidity of modern PCNL for lower pole stones, regardless the position used. Supine PCNL was more frequently offered in case of patients at higher ASA score and in case of multiple lower pole stones. PMID- 23108845 TI - Temporal changes in occurrence frequency of bowel sounds both in fasting state and after eating. AB - Food evaluation technology that takes into account the constitutional predisposition and health of an individual's digestive system should aid in the development of value-added foods for patients and people who require health care. Based on the assumption that the degree of bowel activity changes depending on each individual's constitutional predisposition, health, and tolerance of the consumed foods, we investigated bowel sounds as an index of bowel activity. We have developed a method for investigating changes in bowel activity by performing long-term continuous recording of bowel sounds and observing changes in the occurrence frequency of bowel sounds per unit of time. In order to obtain basic data, we made recordings of eight healthy adults. We observed that bowel sounds continued even after the most recently consumed food had been nearly completely digested. In addition, we found that the occurrence frequency of bowel sounds of normal intensity (stethoscope audible) did not synchronize with that of minimal intensity (amplifier audible) in the fasting state. In contrast, the former did synchronize with the latter during digestion. PMID- 23108846 TI - Images in pediatrics: the thymic sail sign and thymic wave sign. AB - The authors present a radiographic image portraying the "thymic sail sign" and the "thymic wave sign," both normal findings in infant radiographs and present a short description of these signs. These are distinguished from pathologic findings such as the "spinnaker-sail sign" in pneumomediastinum. PMID- 23108847 TI - Gender-specific prevalence and associated risk factors of prehypertension among rural children and adolescents in Northeast China: a cross-sectional study. AB - Little is known about the prevalence and risk profile of prehypertension among Chinese children and adolescents. The aim of the present study was to investigate the prehypertensive status and its associated risk factors among rural Chinese children and adolescents. We conducted a cross-sectional study including 5,245 children and adolescents (2,732 boys and 2,513 girls) aged 5-18 years in Northeast China. Main anthropometric data and related information were collected. The overall prevalence of prehypertension and hypertension was 15 % and 20.2 %, respectively. The prevalence of prehypertension among boys was 15.7 %, compared to that of 14.2 % among girls (P = 0.256). After adjusting for age, race, weight status, waist circumference, triceps skinfold, family income, smoking and drinking status, boys aged 12-14 and 15-18 years had a 2.86- and 5.97-fold risk of prehypertension, respectively, compared to those aged 5-8 years. Overweight and obese boys had an increased risk of prehypertension in comparison to those with normal weight (overweight: odds ratio [OR] = 1.837, 95 % confidence interval [CI] 1.321-2.556; obese: OR = 2.941, 95 % CI 1.783-4.851). A larger triceps skinfold (>=90th percentile) was significantly related to increased odds of prehypertension (OR = 2.32; 95 % CI, 1.516-3.55) among boys. For girls, only older age was found to be a risk factor for prehypertension. CONCLUSION: Pediatric prehypertension is highly prevalent in rural Northeast China. The risk factors for prehypertension differed among boys and girls. A more comprehensive risk profile of prehypertension among children and adolescents needs to be established for early prevention. PMID- 23108848 TI - Oral health and oral health-related behaviour in preschool children: evidence for a social gradient. AB - This study aims to investigate the social gradient in the reported oral health related behaviour and oral health status of preschool children. Participants were 1,057 children born between October 2003 and July 2004 in Flanders, Belgium. Oral health examinations were performed by trained dentists when the children were 3 and 5 years old (respectively, in 2007 and 2009); data on dietary habits, oral hygiene habits and dental attendance of the children were obtained through structured questionnaires completed by the parents. Maternal educational level, measured in four categories, was used as a proxy of socio-economic status. Logistic and ordinal regressions showed a social gradient for the oral health related behaviours: a lower educational level of the mother was related to a higher consumption of sugared drinks between meals and to a lower brushing frequency and dental attendance of the child. Children from low-educated mothers also had seven times more chance to present with caries experience than children from mothers with a bachelor degree. Contrary to the expectations, there was a deviation from the gradient in 3-year-olds from the highest educational group showing an increased risk for caries experience (OR = 3.84, 95 % CI = 1.08 13.65). Conclusion. Already in very young children, a graded relationship is observed between socio-economic position, oral health and related behaviours. The results suggest that different approaches are required to promote oral health during early childhood depending on the mother's educational background. As children from the highest social group also have an increased caries risk, specific techniques may be needed. PMID- 23108849 TI - A right-to-left shunt and prothrombotic disorders in pediatric patients presenting with transient ischemic attack. AB - Arterial ischemic stroke is an important cause of morbidity and mortality in pediatric population. A right-to-left shunt (RLS) across the patent foramen ovale was recently demonstrated as a possible risk factor for pediatric stroke. Prothrombotic disorders are frequently identified in pediatric patients with stroke. Data regarding RLS and prothrombotic disorders in pediatric patients presenting with transient ischemic attack (TIA) are lacking. The aims of the present study were (1) to compare the prevalence and grade of RLS in pediatric patients presenting with TIA vs. controls using contrast transcranial Doppler with Valsalva maneuver and (2) to identify prothrombotic disorders in pediatric patients presenting with TIA. Twenty-three consecutive pediatric patients presenting with TIA were included in the study. Logistic regression analysis showed that RLS was significantly associated with TIA (OR 4.75, 95 % CI 1.39 16.2, p = 0.013). The prevalence of RLS was significantly higher in patients in comparison to controls (p = 0.019). Significantly more microembolic signals (MES) were detected in patients than in controls (p = 0.003). Prothrombotic disorders were identified in 14 of the 23 patients. Both the prevalence of RLS and number of detected MES were significantly higher in pediatric patients presenting with TIA in comparison to controls. Prothrombotic disorders were identified in a high proportion of patients. These findings suggest that paradoxical embolism may be important in pediatric patients presenting with TIA. PMID- 23108850 TI - Milk oral immunotherapy-effective but still experimental. PMID- 23108851 TI - On the origin of chirality in nanoplasmonic gyroid metamaterials. AB - Metallic single gyroids, a new class of self-assembled nanoplasmonic metamaterials, are analyzed on the basis of a tri-helical metamaterial model. The physical mechanisms underlying the chiral optical behavior of the nanoplasmonic single gyroid are identified and it is shown that the optical chirality in this metallic structure is primarily determined by structural chirality and the connectivity of helices along the main cubic axes. PMID- 23108852 TI - Ruthenium-catalyzed asymmetric hydrogenation of 3-oxoglutaric acid derivatives: a study of unconventional solvent and substituent effects. AB - A series of 3-oxoglutaric acid derivatives have been hydrogenated in different solvents in the presence of [RuCl(benzene)(S)-SunPhos]Cl (SunPhos = (2,2,2',2' tetramethyl-[4,4'-bibenzo[d][1,3]dioxole]-5,5'-diyl)bis(diphenylphosphine)). Unlike simple beta-keto acid derivatives, these advanced analogues can be readily hydrogenated in uncommon solvents such as THF, CH(2)Cl(2), acetone, and dioxane with high enantioselectivities. Two possible catalytic cycles have been proposed to explain the different reactivities of these 1,3,5-tricarbonyl substrates in the tested solvents. The C-2 and C-4 substituents had notable but irregular influence on the reactivity and enantioselectivity of the reactions. More pronounced solvent effects were observed: the ee values increased from around 20% in EtOH or THF to 90% in acetone. Inversion of the product configuration was observed when the solvent was changed from EtOH to THF or acetone, and a mixed solvent system can lead to better enantioselectivity than a single solvent. PMID- 23108853 TI - Transcriptional evolution underlying vertebrate sexual development. AB - Explaining the diversity of vertebrate sex-determining mechanisms ranging from genotypic (GSD) to temperature-dependent (TSD) remains a developmental and evolutionary conundrum. Using a phylogenetic framework, we explore the transcriptional evolution during gonadogenesis of several genes involved in sexual development, combining novel data from Chrysemys picta turtles (TSD) and published data from other TSD and GSD vertebrates. Our novel C. picta dataset underscores Sf1 and Wt1 as potential activators of the thermosensitive period and uncovered the first evidence of Dax1 involvement in male development in a TSD vertebrate. Contrasting transcriptional profiles revealed male-biased Wt1 expression in fish while monomorphic expression is found in tetrapods but absent in turtles. Sf1 expression appears highly labile with transitions among testicular, ovarian, and non-sex-specific gonadal formation patterns among and within lineages. Dax1's dual role in ovarian and testicular formation is found in fish and mammals but is dosage-sensitive exclusively in eutherian mammals due to its X-linkage in this group. Contrastingly, Sox9 male-biased and Aromatase female biased expression appear ancestral and virtually conserved throughout vertebrates despite significant heterochronic changes in expression as other elements likely replaced their function in early gonadogenesis. Finally, research avenues are highlighted to further study the evolution of the regulatory network of sexual development. PMID- 23108854 TI - Cancer care in East and Central Harlem: community partnership needs assessment. AB - In the largely African American and Hispanic communities of East and Central Harlem in New York City (NYC), health inequities are glaring. Mortality from cancer is 20-30 % higher than in Manhattan and 30-40 % higher than rates in the general population in NYC. Despite advances in risk assessment, early detection, treatment, and survivorship, individuals in Harlem and similar urban communities are not benefiting equally. Guided by community-based participatory research, this study serves as an important step in understanding cancer care needs and the range of factors that impact the disparate rates of cancer in East and Central Harlem. Forty individual interviews were conducted with community leaders and residents. Major themes included: need for appropriate supportive services; health care access and financial challenges; beliefs related to stigma, trust, and accountability; and the impact of the physical environment on health. Education was seen as a critical area of need and intervention. PMID- 23108855 TI - Multiple craniocervical chordomas presenting as a parapharyngeal mass. AB - BACKGROUND: Chordomas are malignant neoplasms of the axial skeleton that have rarely been seen in the cervical area. METHODS: A 55-year-old woman presented to our department with a history of a left cervical mass protruding into the throat with the symptoms of dysphagia and hoarseness. RESULTS: The radiological examination revealed 3 polycyclic masses in the neck, 2 on the left side and 1 small mass on the right side. After the neurosurgical excision of the intraspinal parts of the tumor, we performed the surgical resection of the cervical tumors via a lateral collotomy. The histological examination showed a chordoma. Because of the advanced stage of the tumor, a postoperative radiotherapy was performed. CONCLUSIONS: Meticulous radiological workup is essential in order to identify the exact extension of the tumor and to reveal possible multifocal lesions. The current literature and treatment recommendations for this rare tumor at this localization are discussed. PMID- 23108856 TI - Response of severely obese children and adolescents to behavioral treatment. AB - OBJECTIVES: To investigate whether the degree of obesity predicts the efficacy of long-term behavioral treatment and to explore any interaction with age. DESIGN: A 3-year longitudinal observational study. Obese children were divided into 3 age groups (6-9, 10-13, and 14-16 years) and also into 2 groups (moderately obese, with a body mass index [BMI]-standard deviation [SD] score [or z score] of 1.6 to <3.5, and severely obese, with a BMI-SD score of >=3.5). SETTING: National Childhood Obesity Center, Stockholm, Sweden. PARTICIPANTS: Children 6 to 16 years of age who started treatment between 1998 and 2006. INTERVENTION: Behavioral treatment of obesity. MAIN OUTCOME MEASURE: Change in BMI-SD score during 3 years of treatment; a reduction in BMI-SD score of 0.5 units or more was defined as clinically significant. RESULTS: A total of 643 children (49% female children) met the inclusion criteria. Among the youngest moderately obese children, 44% had a clinically significant reduction in BMI-SD score (mean reduction, -0.4 [95% CI, -0.55 to -0.32]). Treatment was less effective for the older moderately obese children. Twenty percent of children who were 10 to 13 years of age and 8% of children who were 14 to 16 years of age had a reduction in BMI-SD score of 0.5 units or more; 58% of the severely obese young children showed a clinically significant reduction in BMI-SD score (mean reduction, -0.7 [95% CI, -0.80 to 0.54]). The severely obese adolescents showed no change in mean BMI-SD score after 3 years, and 2% experienced clinically significant weight loss. Age was found to be a predictor of a reduction in BMI-SD score (odds ratio, 0.68 units per year [95% CI, 0.60-0.77 units per year]). CONCLUSIONS: Behavioral treatment was successful for severely obese children but had almost no effect on severely obese adolescents. PMID- 23108857 TI - Eliminating tyrosine sequence variants in CHO cell lines producing recombinant monoclonal antibodies. AB - Amino acid sequence variants are defined as unintended amino acid sequence changes that contribute to product variation with potential impact to product safety, immunogenicity, and efficacy. Therefore, it is important to understand the propensity for sequence variant (SV) formation during the production of recombinant proteins for therapeutic use. During the development of clinical therapeutic products, several monoclonal antibodies (mAbs) produced from Chinese Hamster Ovary (CHO) cells exhibited SVs at low levels (<=3%) in multiple locations throughout the mAbs. In these examples, the cell culture process depleted tyrosine, and the tyrosine residues in the recombinant mAbs were replaced with phenylalanine or histidine. In this work, it is demonstrated that tyrosine supplementation eliminated the tyrosine SVs, while early tyrosine starvation significantly increased the SV level in all mAbs tested. Additionally, it was determined that phenylalanine is the amino acid preferentially misincorporated in the absence of tyrosine over histidine, with no other amino acid misincorporated in the absence of tyrosine, phenylalanine, and histidine. The data support that the tyrosine SVs are due to mistranslation and not DNA mutation, most likely due to tRNA(Tyr) mischarging due to the structural similarities between tyrosine and phenylalanine. PMID- 23108858 TI - How did bacterial ancestors reproduce? Lessons from L-form cells and giant lipid vesicles: multiplication similarities between lipid vesicles and L-form bacteria. AB - In possible scenarios on the origin of life, protocells represent the precursors of the first living cells. To study such hypothetical protocells, giant vesicles are being widely used as a simple model. Lipid vesicles can undergo complex morphological changes enabling self-reproduction such as growth, fission, and extra- and intravesicular budding. These properties of vesicular systems may in some way reflect the mechanism of reproduction used by protocells. Moreover, remarkable similarities exist between the morphological changes observed in giant vesicles and bacterial L-form cells, which represent bacteria that have lost their rigid cell wall, but retain the ability to reproduce. L-forms feature a dismantled cellular structure and are unable to carry out classical binary fission. We propose that the striking similarities in morphological transitions of L-forms and giant lipid vesicles may provide insights into primitive reproductive mechanisms and contribute to a better understanding of the origin and evolution of mechanisms of cell reproduction. Editor's suggested further reading in BioEssays Synthesizing artificial cells from giant unilamellar vesicles: State-of-the art in the development of microfluidic technology Abstract. PMID- 23108860 TI - PknE, a serine/threonine protein kinase from Mycobacterium tuberculosis has a role in adaptive responses. AB - Serine/threonine protein kinases (STPK) play a major role in the physiology and pathogenesis of Mycobacterium tuberculosis. Here, we have examined the role of pknE, a STPK in the adaptive responses of M. tuberculosis using a deletion mutant DeltapknE. The survival of DeltapknE was assessed in the presence of stress (pH, surfactant and cell wall-damaging agents) and anti-tuberculosis drugs. DeltapknE had a defective growth in pH 7.0 and lysozyme (a cell wall-damaging agent) with better survival in pH 5.5, SDS and kanamycin (a second-line anti-tuberculosis drug). Furthermore, DeltapknE was reduced in cell size during growth in liquid media and exhibited hypervirulence in a guinea pig model of infection. In conclusion, our data suggest that pknE plays a role in adaptive response of M. tuberculosis regulating cellular integrity and survival. PMID- 23108861 TI - Cutting edge advances in nanomedicine. PMID- 23108862 TI - Engineering imaging probes and molecular machines for nanomedicine. AB - Nanomedicine is an emerging field that integrates nanotechnology, biomolecular engineering, life sciences and medicine; it is expected to produce major breakthroughs in medical diagnostics and therapeutics. Due to the size compatibility of nano-scale structures and devices with proteins and nucleic acids, the design, synthesis and application of nanoprobes, nanocarriers and nanomachines provide unprecedented opportunities for achieving a better control of biological processes, and drastic improvements in disease detection, therapy, and prevention. Recent advances in nanomedicine include the development of functional nanoparticle based molecular imaging probes, nano-structured materials as drug/gene carriers for in vivo delivery, and engineered molecular machines for treating single-gene disorders. This review focuses on the development of molecular imaging probes and engineered nucleases for nanomedicine, including quantum dot bioconjugates, quantum dot-fluorescent protein FRET probes, molecular beacons, magnetic and gold nanoparticle based imaging contrast agents, and the design and validation of zinc finger nucleases (ZFNs) and TAL effector nucleases (TALENs) for gene targeting. The challenges in translating nanomedicine approaches to clinical applications are discussed. PMID- 23108864 TI - Au nanostructures: an emerging prospect in cancer theranostics. AB - Au nanoparticles have been used in biomedical applications since ancient times. However, the rapid development of nanotechnology over the past century has led to recognition of the great potential of Au nanoparticles in a wide range of applications. Advanced fabrication techniques allow us to synthesize a variety of Au nanostructures possessing physiochemical properties that can be exploited for different purposes. Functionalization of the surface of Au nanoparticles further eases their application in various roles. These advantages of Au nanoparticles make them particularly suited for cancer treatment and diagnosis. The small size of Au particles enables them to preferentially accumulate at tumor sites to achieve in vivo targeting after systemic administration. Efficient light absorption followed by rapid heat conversion makes them very promising in photothermal therapy. The facile surface chemistry of Au nanoparticles eases delivery of drugs, ligands or imaging contrast agents in vivo. In this review, we summarize recent development of Au nanoparticles in cancer theranostics including imaging-based detection, photothermal therapy, chemical therapy and drug delivery. The multifunctional nature of Au nanoparticles means they hold great promise as novel anti-cancer therapeutics. PMID- 23108863 TI - Microscale methods to assemble mammalian cells into tissue-like structures. AB - Different cell types make up tissues and organs hierarchically and communicate within a complex, three-dimensional (3D) environment. The in vitro recapitulation of tissue-like structures is meaningful, not only for fundamental cell biology research, but also for tissue engineering (TE). Currently, TE research adopts either the top-down or bottom-up approach. The top-down approach involves defining the macroscopic tissue features using biomaterial scaffolds and seeding cells into these scaffolds. Conversely, the bottom-up approach aims at crafting small tissue building blocks with precision-engineered structural and functional microscale features, using physical and/or chemical approaches. The bottom-up strategy takes advantage of the repeating structural and functional units that facilitate cell-cell interactions and cultures multiple cells together as a functional unit of tissue. In this review, we focus on currently available microscale methods that can control mammalian cells to assemble into 3D tissue like structures. PMID- 23108865 TI - Antineoplastic activities of Gd@C82(OH)22 nanoparticles: tumor microenvironment regulation. AB - Malignant tumors are complex organs consisting of tumor cells and their microenvironment. Increasing evidence has shown that the tumor microenvironment is critical to the initiation and progression of tumors. Rational design of tumor therapies via targeting the tumor microenvironment to inhibit tumor growth is thus becoming a consensus strategy. Gd@C(82)(OH)(22) nanoparticles, as novel endohedral hydroxylated metallofullerenes, have been demonstrated to be a potent antitumor nanomedicine via targeting multiple factors in the tumor microenvironment. Gd@C(82)(OH)(22) nanoparticles possess excellent biocompatibility and remarkable antineoplastic activity, as a result not of direct tumor cytotoxicity but of their diverse biological effects, including antioxidation, immune activation, angiogenesis inhibition, imprisoning cancer cells, and reversal of drug-resistance. In this article, we summarize the unique nanoscale physiochemical properties and the antineoplastic activities of Gd@C(82)(OH)(22) nanoparticles, and focus on the mechanisms underlying their regulation of the tumor microenvironment. PMID- 23108867 TI - Comparison of cellular responses across multiple passage numbers in Ba/F3-BCR-ABL cells induced by silver nanoparticles. AB - With the rapid development of nanotechnology and increasingly broad bio application of engineered nanomaterials, their biohazards have become a serious public concern. It is believed that the chemical nature, particle size, morphology, and surface chemistry of nanomaterials are key parameters that influence their toxicity. Although cultured cells have been widely used to evaluate nanomaterial toxicity, it remains unclear whether the passage of these cells affects the evaluation results. In the present study, Ba/F3 cells transfected with the BCR-ABL gene were subcultured to study the effect of passage number on cell stability and their cellular responses upon exposure to nanomaterials. The results demonstrated that proliferation, cellular senescence, BCR-ABL gene expression, cell cycle and apoptosis were stable across multiple passages. Senescence and BCR-ABL gene expression of cells from different passage cells were unchanged when treated with silver nanoparticles (AgNPs). In addition, the cells at multiple passage numbers were all arrested in the G(2)/M phase and apoptosis was induced by the AgNPs. These nanoparticles could enter cells via endocytosis and localize in the endosomes, which were also not influenced by passage number. These data suggest that short-term passage would not affect cultured cell stability and toxicity assessment using these cells would be consistent when maintained appropriately. PMID- 23108866 TI - The effect of cigarette smoke extract on thrombomodulin-thrombin binding: an atomic force microscopy study. AB - Cigarette smoking is a well-known risk factor for cardiovascular disease. Smoking can cause vascular endothelial dysfunction and consequently trigger haemostatic activation and thrombosis. However, the mechanism of how smoking promotes thrombosis is not fully understood. Thrombosis is associated with the imbalance of the coagulant system due to endothelial dysfunction. As a vital anticoagulation cofactor, thrombomodulin (TM) located on the endothelial cell surface is able to regulate intravascular coagulation by binding to thrombin, and the binding results in thrombosis inhibition. This work focused on the effects of cigarette smoke extract (CSE) on TM-thrombin binding by atomic force microscopy (AFM) based single-molecule force spectroscopy. The results from both in vitro and live-cell experiments indicated that CSE could notably reduce the binding probability of TM and thrombin. This study provided a new approach and new evidence for studying the mechanism of thrombosis triggered by cigarette smoking. PMID- 23108868 TI - The role and clinical implications of microRNAs in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is common and one of the most aggressive of all human cancers. Recent studies have indicated that miRNAs, a class of small noncoding RNAs that regulate gene expression post-transcriptionally, directly contribute to HCC by targeting many critical regulatory genes. Several miRNAs are involved in hepatitis B or hepatitis C virus replication and virus-induced changes, whereas others participate in multiple intracellular signaling pathways that modulate apoptosis, cell cycle checkpoints, and growth-factor-stimulated responses. When disturbed, these pathways appear to result in malignant transformation and ultimately HCC development. Recently, miRNAs circulating in the blood have acted as possible early diagnostic markers for HCC. These miRNA also could serve as indicators with respect to drug efficacy and be prognostic in HCC patients. Such biomarkers would assist stratification of HCC patients and help direct personalized therapy. Here, we summarize recent advances regarding the role of miRNAs in HCC development and progression. Our expectation is that these and ongoing studies will contribute to the understanding of the multiple roles of these small noncoding RNAs in liver tumorigenesis. PMID- 23108869 TI - Effects of elevated CO2 on the nutrient compositions and enzymes activities of Nilaparvata lugens nymphs fed on rice plants. AB - Elevated CO(2) may reduce the tolerance of Nilaparvata lugen (N. lugens) to adverse environmental factors through the biological and physiological degeneration of N. lugens. In an artificial climate box, under 375 and 750 MUL L( 1) CO(2) levels, the rice stems nutrient content, the nutrient content and enzyme activities of N. lugens nymph fed on rice seedlings exposed to ambient and elevated CO(2) were studied. The results showed that rice stems had significantly higher protein and total amino acid levels under ambient than elevated CO(2) levels. Nymphs had significantly higher protein levels in the ambient CO(2) treatment, while their glucose levels were significantly lower under ambient CO(2) conditions. Significantly higher trypsin activity was observed in nymphs grown in elevated CO(2). Significantly lower activities of the protective enzymes total superoxide dismutase and catalase were observed in the nymphs under ambient CO(2). Meanwhile, the activity of the detoxification enzyme glutathione S transferase was significantly higher in the ambient CO(2) treatment. Measuring how energy and resources were allocated to enzymes in N. lugens nymphs under elevated CO(2) conditions can provide a more meaningful evaluation of their metabolic tolerances to adverse climatic conditions. PMID- 23108870 TI - Progress in protein structure and function studies in China during 2010-2011. PMID- 23108871 TI - Self-reported sensory descriptors are associated with quantitative sensory testing parameters in patients with cervical radiculopathy, but not in patients with fibromyalgia. AB - BACKGROUND: The painDETECT questionnaire (PD-Q) has been used as a tool to characterize sensory abnormalities in patients with persistent pain. This study investigated whether the self-reported sensory descriptors of patients with painful cervical radiculopathy (CxRAD) and patients with fibromyalgia (FM), as characterized by responses to verbal sensory descriptors from PD-Q (sensitivity to light touch, cold, heat, slight pressure, feeling of numbness in the main area of pain), were associated with the corresponding sensory parameters as demonstrated by quantitative sensory testing (QST). METHODS: Twenty-three patients with CxRAD (eight women, 46.3 +/- 9.6 years) and 22 patients with FM (20 women, 46.1 +/- 11.5 years) completed the PD-Q. Standardized QST of dynamic mechanical allodynia, cold and heat pain thresholds, pressure pain thresholds, mechanical and vibration detection thresholds, was recorded from the maximal pain area. Comparative QST data from 31 age-matched healthy controls (HCs; 15 women) were obtained. RESULTS: Patients with CxRAD demonstrated a match between their self-reported descriptors and QST parameters for all sensory parameters except for sensitivity to light touch, and these matches were statistically significant compared with HC data (p <= 0.006). The FM group demonstrated discrepancies between the PD-Q and QST sensory phenotypes for all sensory descriptors, indicating that the self-reported sensory descriptors did not consistently match the QST parameters (p = <=0.017). CONCLUSION: Clinicians and researchers should be cautious about relying on PD-Q as a stand-alone screening tool to determine sensory abnormalities in patients with FM. PMID- 23108872 TI - Lived autonomy and chronic mental illness: a phenomenological approach. AB - In this paper, I develop a phenomenological description of lived autonomy and describe possible alterations of lived autonomy associated with chronic depression as they relate to specific psychopathological symptoms. I will distinguish between two types of lived autonomy, a pre-reflective type and a reflective type, which differ with respect to the explicitness of the action that is willed into existence; and I will relate these types to the classical distinction between freedom of intentional action and freedom of the will. I will then describe how a chronically depressed person habitually discloses her experiential workspace with an impaired scope of perceivable action-properties, and pre-reflectively values many of these perceived action-properties as demanding or devalues these properties as well as her own abilities and drive to perform the respective actions ('depressive habituality'). These alterations, typically experienced in a passive manner, imply an impairment of both types of lived autonomy. Drawing on first-hand accounts, I will then argue that small islands of lived autonomy, even of the reflective type, are possible if the afflicted identifies with at least some of her 'depressive disabilities' (i.e., her levelled amount of daily activities, her social retreat in certain periods). Lastly, I will compare this manner of life-conduct with the constellation of includence (Inkludenz), as described by Tellenbach, and discuss the limitations of this study. PMID- 23108873 TI - Increase in the production of beta-carotene in recombinant Escherichia coli cultured in a chemically defined medium supplemented with amino acids. AB - Escherichia coli DH5alpha strain was selected as the recombinant host, and a chemically defined medium supplemented with amino acids was used instead of a complex medium for the efficient production of beta-carotene. In a fed-batch culture using glycerol with a chemically defined medium supplemented with amino acids, the concentration, specific content, and productivity of beta-carotene were 2,470 mg/l, 72 mg/g cells, and 77 mg/l h after 32 h, respectively. These values were, respectively, 43, 33, and 26 % higher than those obtained using the complex medium. This is the highest beta-carotene production that has been reported among the recombinant cells to date. PMID- 23108874 TI - Biodegradation of amine waste generated from post-combustion CO(2) capture in a moving bed biofilm treatment system. AB - Nitrogen and organic matter removal from reclaimer waste of a monoethanolamine (MEA) based CO(2)-capture plant was demonstrated in a pre-denitrification biofilm system. The reclaimer waste was generated from a 30 % (w/w) MEA solvent used for capturing CO(2) from flue gas from a coal-fired power plant. MEA, N-(2 hydroxylethyl)glycine (HEGly) and 2-hydroxyethylformamide (HEF) were the major contaminants treated. Hydrolysis of MEA to ammonia and further oxidation of organic intermediates readily occurred in the pre-denitrification system with a hydraulic retention time of 7 h. The biofilm system achieved 98 +/- 1 % removal of MEA and 72 +/- 16 % removal of total nitrogen. This is the first demonstration of efficient biodegradation of real amine waste from a post-combustion CO(2) capture facility by pre-denitrification without external electron donor. PMID- 23108875 TI - A genome walking strategy for the identification of nucleotide sequences adjacent to known regions. AB - To identify the transposon insertion sites in a soil actinomycete, Saccharopolyspora spinosa, a genome walking approach, termed SPTA-PCR, was developed. In SPTA-PCR, a simple procedure consisting of TA cloning and a high stringency PCR, following the single primer-mediated, randomly-primed PCR, can eliminate non-target DNA fragments and obtain target fragments specifically. Using SPTA-PCR, the DNA sequence adjacent to the highly conserved region of lectin coding gene in onion plant, Allium chinense, was also cloned. PMID- 23108876 TI - Re-engineering of genetic circuit for 2-deoxystreptamine (2-DOS) biosynthesis in Escherichia coli BL21 (DE3). AB - Various approaches for monocistronic constructions of genetic circuits have been designed for metabolite production but there has been no attempt to apply such methodology for aminoglycosides biosynthesis. Here, a simple and commercially available bio-part, despite the current trend focusing on the standardized BioBricks bio-parts available in the registry, is used. A 181-bp nucleotide fragment was designed for the efficient construction of an expression vector for monocistronic assembly of genes. Furthermore, a single vector with multi monocistronic assembled genes for 2-deoxystreptamine (2-DOS) synthesis was constructed for production in engineered Escherichia coli. The working efficiency of model vector was concluded by reporter assay whereas the expressions of biosynthesis genes were confirmed by RT-PCR and SDS-PAGE. Production of 2-DOS was confirmed by TLC, LC-ELSD, and ESI-MS/MS. PMID- 23108877 TI - Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study. AB - Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL 2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate (gammadelta T-cell culture). In both culture conditions, NK cells were increased in both percentage and absolute number in the culture with dasatinib compared with control culture without dasatinib. The increase of NK cells was dose dependent of dasatinib in the range of 2-25 nM. NK cell cytotoxicity of cultured cells with dasatinib was demonstrated to be superior to control cells without dasatinib in cytotoxicity assay using EGFP-transfected K562 cells as target cells. The present study suggested that lymphocytosis in dasatinib-treated CML patients is at least partly associated with a direct effect of dasatinib to stimulate the proliferation of NK cells. Favourable prognosis in patients with dasatinib-induced lymphocytosis might be associated with the effects of dasatinib to potentiate NK cytotoxicity in vivo. PMID- 23108878 TI - Immunohistochemical analysis of connective tissue in patients with pelvic organ prolapse. AB - The uterosacral ligaments are an important part of the pelvic support system. The objective of this study was to compare the expression of collagen type I and collagen type III in the uterosacral ligament biopsies from women with and without pelvic organ prolapse (POP). The uterosacral ligament biopsies were obtained from women with POP (n = 29) and non-POP subjects (n = 35). Immunohistochemistry for collagen type I and collagen type III was performed on formalin-fixed and paraffin-embedded sections. The two groups were matched for age, body mass index, parity and postmenopausal status. The expression of collagen type I (p < 0.001) and collagen type III (p < 0.0001) differed between women with POP and non-POP subjects. There was decreased expression of collagen type I and increased expression of collagen type III in uterosacral ligaments of women with POP compared with non-POP subjects. This difference indicates a possible relationship between POP and the immunohistochemical expression of collagen type I and collagen type III in uterosacral ligaments. PMID- 23108879 TI - Systematic variations in microvilli banding patterns along fiddler crab rhabdoms. AB - Polarisation sensitivity is based on the regular alignment of dichroic photopigment molecules within photoreceptor cells. In crustaceans, this is achieved by regularly stacking photopigment-rich microvilli in alternating orthogonal bands within fused rhabdoms. Despite being critical for the efficient detection of polarised light, very little research has focused on the detailed arrangement of these microvilli bands. We report here a number of hitherto undescribed, but functionally relevant changes in the organisation of microvilli banding patterns, both within receptors, and across the compound eye of fiddler crabs. In all ommatidia, microvilli bands increase in length from the distal to the proximal ends of the rhabdom. In equatorial rhabdoms, horizontal bands increase gradually from 3 rows of microvilli distally to 20 rows proximally. In contrast, vertical equatorial microvilli bands contain 15-20 rows of microvilli in the distal 30 um of the rhabdom, shortening to 10 rows over the next 30 um and then increase in length to 20 rows in parallel with horizontal bands. In the dorsal eye, horizontal microvilli occupy only half the cross-sectional area as vertical microvilli bands. Modelling absorption along the length of fiddler crab rhabdoms suggests that (1) increasing band length assures that photon absorption probability per band remains constant along the length of photoreceptors, indicating that individual bands may act as units of transduction or adaptation; (2) the different organisation of microvilli bands in equatorial and dorsal rhabdoms tune receptors to the degree and the information content of polarised light in the environment. PMID- 23108880 TI - (1)H, (13)C and (15)N NMR assignments for N- and O-acylethanolamines, important family of naturally occurring bioactive lipid mediators. AB - The complete (1)H, (13)C and (15)N NMR signal assignments of some N- and O acylethanolamines, important family of naturally occurring bioactive lipid mediators, were achieved using one-dimensional and two-dimensional experiments (gs-HMQC and gs-HMBC). PMID- 23108881 TI - Are stents necessary after choanal atresia repair? PMID- 23108882 TI - Mentoring, networking, and leadership. PMID- 23108883 TI - The importance of ulceration of cutaneous melanoma of the head and neck: a comparison of ear (pinna) and nonear sites. AB - OBJECTIVES/HYPOTHESIS: To compare clinicopathologic and prognostic factors associated with ear melanomas and nonear melanomas of the head and neck (H&N). STUDY DESIGN: Post hoc analysis of the database from a multi-institutional, prospective, randomized study. METHODS: Clinicopathologic factors were assessed and correlated with survival and recurrence. Univariate and multivariate analysis of prognostic factors affecting disease-free survival (DFS) and overall survival (OS) were performed. RESULTS: Of 405 patients with H&N melanomas >= 1.0 mm Breslow thickness, 59 patients had melanomas of the ear. Most were Caucasian (96.6%) males (79.7%) with a mean age of 52 years. The mean Breslow thickness was 2.5 mm; 34.5% had signs of ulceration. Sentinel lymph node (SLN) positivity was seen in 7.1%. The incidence of locoregional and distant recurrence were similar. OS for ear melanoma was significantly impacted by ulceration status (P = .013), whereas both ulceration and SLN positivity predicted survival in nonear melanoma (P < .001 and P = .015, respectively). Thicker melanomas in the nonear group demonstrated significantly decreased DFS, whereas other factors in both groups lost their predictive value (P = .035). CONCLUSIONS: In the Sunbelt Melanoma Trial, ulceration was the strongest predictor of overall survival in melanoma of the ear. Ulceration and SLN status correlated with poorer OS in nonear melanoma of the H&N, whereas increasing depth correlated with poorer DFS in those same patients. Recurrence and survival were not impacted by anatomic site, but the prognostic significance of ulceration, thickness, and SLN status in the H&N may vary with the site of the melanoma. PMID- 23108885 TI - How long is long enough to follow up children after cholesteatoma surgery? A 29 year study. AB - OBJECTIVES/HYPOTHESIS: To identify an association between follow-up period and cholesteatoma recidivism. STUDY DESIGN: Retrospective review. METHODS: From 1982 to 2011, we retrospectively screened a consecutive series of children (<= 18 years) with acquired cholesteatomas after primary surgery. The cumulative recidivism rates were calculated using standard calculation methods and Kaplan Meier survival analysis. RESULTS: A total of 73 operations were performed on 71 patients. The mean age was 10.7 years, and the mean follow-up period was 15.4 years. The number of censored cases increased with the follow-up time. Sixty-four (88%) operations had a follow-up period of 5 years or longer, and 41 (56%) operations 15 years or longer. Cholesteatoma recidivism was observed in seven ears (five recurrent and two residual diseases). The mean detection time was 10.4 years (range 1.9-17.2 years). Five of the seven ears (71.4%) with recidivism were detected more than 10 years after surgery. The recidivism rate increased with the follow-up time. However, the rates at 5, 10, 15, 20, and 25 years as calculated by the standard calculation method (1.4%, 2.7%, 8.2%, 9.5% and 9.5%, respectively) were underestimated compared with that by Kaplan-Meier analysis (1.4%, 3.1%, 11.6%, 14.4% and 14.4%, respectively). CONCLUSIONS: The Kaplan-Meier survival analysis method should be used when discussing recidivism rates, because the number of censored cases inevitably increases with observation time. Due to the late occurrence of recidivism and because the recidivism rate increases as time goes on, children should be periodically followed up for as long as possible. PMID- 23108884 TI - Cognitive speed as an objective measure of tinnitus. AB - OBJECTIVES/HYPOTHESIS: Subjective, chronic tinnitus is a common but poorly understood condition. The heterogeneity within tinnitus has hindered the development of functional severity measures and effective treatment. Tinnitus at least partially results from maladaptive cortical processes that are associated with cognitive deficits. This study examined whether cognitive processing speed might serve as a novel objective measure of tinnitus severity, and whether the psychiatric comorbidities of depression and somatization are predictive of self reported tinnitus severity. STUDY DESIGN: Cross-sectional study of 92 chronic tinnitus participants. METHODS: The Tinnitus Handicap Inventory (THI) captured the self-reported severity of tinnitus. Cognitive processing speed was objectively measured by the Brain Speed Test (BST), a short computerized test from Posit Science. Somatization and depression were captured by the Whiteley-7 and Patient Health Questionnaire-9 scales. The results of these tests were combined into a Composite Psychiatric State (CPS) variable. The ability of BST z score and CPS level to predict THI was assessed. RESULTS: There was a significant correlation (r = 0.54, P < .001) between BST z scores and THI in those with bothersome tinnitus (THI >= 30). Additionally, BST z score was correlated with the validated neurocognitive tests. Multivariate analysis identified BST z score and CPS level as independent predictors of THI. CONCLUSIONS: In severe tinnitus, BST provides an objective measure of the functional impact of tinnitus. Cognitive processing speed and psychiatric state are independent predictors of self reported tinnitus severity. These measures help define clinical subgroups within tinnitus: one subgroup whose functional impact is primarily cognitive and another whose functional impact is primarily psychiatric. PMID- 23108886 TI - Management of persistent inflammatory large joint monoarthritis. AB - Persistent inflammatory monoarthritis is inflammation of one joint, with symptoms lasting beyond 3 months. Approximately 50 % of cases are self-limiting; others will transform into oligo- or polyarticular disease, but a significant minority remain as a persistent inflammatory monoarthritis, which are often resistant to standard therapies used for oligo- or polyarticular disease and constitute a difficult therapeutic problem. However, there are no clear guidelines for treatment of this category of patients or an evidence-based consensus view on best treatment. A literature search was done through PubMed using 'monoarthritis', 'chronic synovitis' and 'persistent inflammatory monoarthritis' as search terms. Reports were located using references to related articles; reports in humans and animals, published in English, were included. Persistent inflammatory monoarthritis has a variable disease course, generally with a better prognosis than polyarthritis. There is no clear evidence for the use of traditional DMARDS in monoarthritis, and treatment algorithms are extrapolated from oligo- or polyarticular disease. Intra-articular anti-tumour necrosis factor (TNF) has been used with similar efficacy to intra-articular corticosteroids, and as yet, there are no reported cases of systemic anti-TNF use in monoarthritis. Synovectomy may be of use, with lower risk of recurrent disease, in open synovectomy. There is paucity of evidence for best practice in the management of chronic monoarthritis. Questions remain concerning the indications for invasive procedures and the balance between toxicity of systemic therapies versus the intended benefits to prevent disability. There is a pressing need for further studies and randomised controlled trials to be performed in this subset of patients. PMID- 23108888 TI - Images in vascular medicine. Traumatic arteriovenous fistula in the forearm. PMID- 23108887 TI - Tocilizumab in the treatment of the adult-onset Still's disease: current clinical evidence. AB - This study aimed to review and analyze the effectiveness and safety of tocilizumab in the treatment of patients with adult-onset Still's disease (AOSD). We report on two patients with AOSD who were successfully treated with tocilizumab. All published information on the use of tocilizumab in this disease was also retrieved through a systematic review of the English-language literature. Including our cases, 35 patients were given tocilizumab for AOSD (8 mg/kg/month in 22 patients). The main clinical manifestations were arthritis in all 35 patients and systemic symptoms such as fever or skin rash in 28 (80 %). Thirty-three (94 %) patients had unsuccessfully tried other immunosuppressive agents such as methotrexate, tumor necrosis factor-alpha blockers, or anakinra. Most of the patients achieved a response with tocilizumab, such as a prompt articular improvement in 30/35 (86 %) patients and a disappearance of systemic symptoms in 27/28 (96 %). Twenty-eight (80 %) patients tapered their steroid intakes, including seven (20 %) who were able to discontinue them. Four (11 %) patients relapsed, and two were successfully retreated with tocilizumab. Regarding safety, tocilizumab is a well-tolerated treatment, but severe side effects such as macrophage activation syndrome or cytomegalovirus reactivation are possible and require ongoing vigilance. Our findings suggest that tocilizumab should probably be proposed in refractory AOSD, as it allows for remission to be induced and the dose of steroid intakes to be reduced. It is a well-tolerated treatment that can be administered according to the therapeutic sequence of rheumatoid arthritis. Further prospective studies are required to assess the better use of this treatment (dosage and duration) and its place among other conventional treatments. PMID- 23108889 TI - Iridium-catalyzed dehydrogenative decarbonylation of primary alcohols with the liberation of syngas. AB - A new iridium-catalyzed reaction in which molecular hydrogen and carbon monoxide are cleaved from primary alcohols in the absence of any stoichiometric additives has been developed. The dehydrogenative decarbonylation was achieved with a catalyst generated in situ from [Ir(coe)(2)Cl](2) (coe = cyclooctene) and racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP) in a mesitylene solution saturated with water. A catalytic amount of lithium chloride was also added to improve the catalyst turnover. The reaction has been applied to a variety of primary alcohols and gives rise to products in good to excellent yields. Ethers, esters, imides, and aryl halides are stable under the reaction conditions, whereas olefins are partially saturated. The reaction is believed to proceed by two consecutive organometallic transformations that are catalyzed by the same iridium(I)-BINAP species. First, dehydrogenation of the primary alcohol to the corresponding aldehyde takes place, which is then followed by decarbonylation to the product with one less carbon atom. PMID- 23108890 TI - Significance of cancer-associated fibroblasts in the regulation of gene expression in the leading cells of invasive lung cancer. AB - PURPOSE: Cancer-associated fibroblasts (CAFs) contribute to tumor progression through multiple pathways. However, the effect of CAFs on gene expression in lung cancer has been largely unknown. Here we systematically compared the gene expression changes in lung cancer cells induced by normal fibroblasts and CAFs. METHODS: Wound healing and cell proliferation assays were used to identify the property of CAFs used in this study. We used cDNA microarray analysis to compare gene expression in lung cancer cells cultured with either conditioned medium (CM) from lung CAFs or normal lung fibroblasts, the result of which was confirmed by RT-PCR and Western blot analysis. Immunohistochemistry on tissue sections from lung cancers was conducted to further confirm the results of cDNA microarray analysis. RESULTS: The expression of many genes was upregulated in cancer cells by CAF CM, particularly cell adhesion molecules, integrins, and anti-apoptotic protein Bcl-2. Expression of integrins appeared to be upstream from Bcl-2. We identified transforming growth factor-beta as a candidate factor that induced the expression of those genes in cancer cells. Immunohistochemical studies of clinical lung cancer tissues revealed that integrins and Bcl-2 were more highly expressed in the leading cells (LCs) than in the following cells, at the invasive front of cancer nests, which are adjacent to or in proximity to the stroma. Furthermore, the expression of integrins and Bcl-2 in LCs had a tendency to correlate with the clinical stage of cancer progression, including lymph node metastasis. CONCLUSIONS: Our results suggest that CAFs promote lung cancer progression partly through the direct regulation of gene expression in the LCs of invasive cancer nests. PMID- 23108891 TI - Surgical outcome and prognostic factors after treatment of osteoradionecrosis of the jaws. AB - PURPOSE: This prospective study attempts to identify prognostic factors for outcome in patients Classes 2 and 3 osteoradionecrosis (ORN) treated using individualized methods. METHODS: From 2005 to 2010, patients with Classes 2 and 3 osteoradionecrosis of the jaws were treated by the same surgical team using standard protocols. The patients were evaluated prospectively and followed up for a minimum of 12 months after completion of treatment. Two examinations were performed at least six months apart. RESULTS: A total of 94 patients were assessed. Local debridement was performed in 33 patients (35.1 %), a rim resection with the application of a reconstruction plate was performed in 35 patients (37.2 %), and continuity resection in 26 patients (27.7 %). Postoperative wound infections locally or at the neck were detected in 69 patients (70.2 %), failure to eradicate radionecrosis occurred in 50 patients (53.2 %). The location of the primary tumor (p = 0.023) and radiation dose (p = 0.049), were associated with a significant risk of development of ORN. Prognostic factors for failure of treatment were the extent of initial osteoradionecrosis (p = 0.049) surgical treatment (p < 0.0001), number of debridements (p < 0.0001), type of microvascular free flap with (p < 0.0001), and grossly infected ORN (p < 0.0001). CONCLUSIONS: Several factors affect the outcome of treatment of ORN. We confirm many of the intuitive factors influence outcome of treatment and add evidence that complete removal of affected bone and watertight well vascularized coverage is the most useful treatment strategy. PMID- 23108892 TI - High COL4A3 expression correlates with poor prognosis after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. AB - In this study, we investigated whether COL4A3 mRNA expression levels were associated with clinical outcomes after treatment with a combination of gemcitabine (Gem)/cis-diamminedichloroplatinum(II) (CDDP) regimen for patients with advanced stage non-small cell lung cancer (NSCLC). Response and survival were correlated with the level of COL4A3 expression in 58 patients with advanced (stage IIIb or IV) NSCLC treated as part of a multicenter randomized trial with Gem 1,250 mg/m(2) on days 1 and 8 plus CDDP 100 mg/m(2) on day 1 every 3 weeks. mRNA was isolated from paraffin-embedded pretreatment primary tumor specimens, and relative expression levels of COL4A3/beta-actin were measured using a quantitative reverse transcription-PCR (Taqman) system. COL4A3 expression was detectable in all tumors. There were no significant differences in COL4A3 levels by gender, age, performance status, weight loss, or tumor stage. The overall response rate was 45.8 %. There were no significant associations between COL4A3 expression and response. Median overall survival was significantly longer in patients with low COL4A3 expression tumors compared to patients with high expression tumors. COL4A3 expression, Eastern Cooperative Oncology Group performance status, and presence of weight loss were significant prognostic factors for survival in a Cox proportional hazards multivariable analysis. These data suggest that COL4A3 expression is a predictive factor for survival after CDDP/Gem therapy in advanced NSCLC. Although there was a trend toward decreased response with high COL4A3 mRNA levels, this difference failed to reach statistical significance. This result may reflect the impact of Gem and the requirement for COL4A3 expression for CDDP/Gem synergism or may be attributable to the relatively small patient sample size in this study. Prospective studies of COL4A3 as a predictive marker for activity of CDDP-based regimens in NSCLC are warranted. PMID- 23108893 TI - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy improves the survival of gastric cancer patients with ovarian metastasis and peritoneal dissemination. AB - The prognosis for ovarian metastasis of gastric cancer is poor. There is no currently available treatment for this disease. The purpose of this study was to evaluate the efficacy and safety of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery (CRS) in female gastric cancer patients with metachronous ovarian metastasis. From January 2000 to December 2010, 62 patients developed ovarian metastasis after undergoing gastrectomy with D2 lymphadenectomy. Thirty-two patients underwent CRS plus HIPEC, and 30 patients underwent CRS alone. The median age of all 62 patients was 44 years (range 19-71 years). Metastatic carcinoma involving bilateral ovaries was observed in 50 patients (80.6 %). The median survival time in the CRS + HIPEC group was 15.5 months (95 % confidence interval [CI] 12.1-18.9 months) but was only 10.4 months (95 % CI 8.5-12.2 months) in the CRS group (P = 0.018). Among the 32 patients with pelvic peritoneal metastasis, a stratified analysis revealed that the median survival period for the 15 patients treated with CRS + HIPEC was significantly higher than that for the patients treated with CRS alone (P = 0.046). Among the 30 patients who suffered from ovarian metastasis alone, the median survival times were similar in both groups (P = 0.141). A multivariate analysis revealed that CRS + HIPEC and a low Peritoneal Cancer Index (PCI) were independent predictors for improved survival. In conclusion, our study indicates that employing the HIPEC procedure after CRS could improve the survival time of patients with ovarian metastasis with few complications; however, we do not recommend HIPEC treatment for ovarian metastasis alone. PMID- 23108895 TI - Severe haemorrhage after liver biopsy of malignant B-cell lymphoma mimicking hepatic infection. PMID- 23108894 TI - Specific phobia among U.S. adolescents: phenomenology and typology. AB - BACKGROUND: Investigators have proposed the diagnostic value of a generalized subtype of specific phobia, with classification based upon the number of phobic fears. However, current and future typologies of specific phobia classify the condition by the nature of phobic fears. This study investigated the clinical relevance of these alternative typologies by: (1) presenting the prevalence and correlates of specific phobia separately by the number and nature of phobia types; and (2) examining the clinical and psychiatric correlates of specific phobia according to these alternative typologies. METHODS: The National Comorbidity Survey Replication-Adolescent Supplement (NCS-A) is a nationally representative face-to-face survey of 10,123 adolescents aged 13-18 years in the continental United States. RESULTS: Most adolescents with specific phobia met criteria for more than one type of phobia in their lifetime, however rates were fairly similar across DSM-IV/5 subtypes. Sex differences were consistent across DSM-IV/5 subtypes, but varied by the number of phobic types, with a female predominance observed among those with multiple types of phobias. Adolescents with multiple types of phobias exhibited an early age of onset, elevated severity and impairment, and among the highest rates of other psychiatric disorders. However, certain DSM-IV/5 subtypes (i.e. blood-injection-injury and situational) were also uniquely associated with severity and psychiatric comorbidity. CONCLUSIONS: Results indicate that both quantitative and DSM-IV/5 typologies of specific phobia demonstrate diagnostic value. Moreover, in addition to certain DSM-IV/5 subtypes, a generalized subtype based on the number of phobias may also characterize youth who are at greatest risk for future difficulties. PMID- 23108896 TI - [Manifestation of epithelioid sarcoma of proximal type of the vulva]. PMID- 23108897 TI - [Asymptomatic leiomyosarcoma of the inferior vena cava with pulmonary metastasis as an incidental finding]. PMID- 23108898 TI - [Polyostotic Fibrous dysplasia of the clivus: atypical CT and MRI imaging]. PMID- 23108899 TI - [Paraganglioma of the terminal filum]. PMID- 23108900 TI - [Prevertebral tendinitis - a rare differential diagnosis of parapharyngeal abscess]. PMID- 23108901 TI - [Computed tomography evaluation of human mandibles with regard to layer thickness and bone density of the cortical bone]. AB - PURPOSE: Application of function-restoring individual implants for the bridging of defects in mandibles with continuity separation requires a stable fixation with special use of the cortical bone stumps. MATERIALS AND METHODS: Five section planes each of 100 computed tomographies of poly-traumatized patients' jaws were used for measuring the thickness of the cortical layer and the bone density of the mandible. The CT scans of 28 female and 72 male candidates aged between 12 and 86 years with different dentition of the mandible were available. RESULTS: The computed tomographic evaluations of human mandibles regarding the layer thickness of the cortical bone showed that the edge of the mandible in the area of the horizontal branch possesses the biggest layer thickness of the whole of the lower jaws. The highest medians of the cortical bone layer thickness were found in the area of the molars and premolars at the lower edge of the lower jaws in 6-o'clock position, in the area of the molars in the vestibular cranial 10 o'clock position and in the chin region lingual-caudal in the 4-o'clock position. The measurement of the bone density showed the highest values in the 8-o'clock position (vestibular-caudal) in the molar region in both males and females. CONCLUSION: The average values available of the bone density and the layer thickness of the cortical bone in the various regions of the lower jaw, taking into consideration age, gender and dentition, are an important aid in practice for determining a safe fixation point for implants in the area of the surface layer of the mandible by means of screws or similar fixation elements. PMID- 23108902 TI - Performance of an automatic dose control system for CT: patient studies. AB - PURPOSE: To study the effect of an automatic dose control (ADC) system with adequate noise characteristic on the individual perception of image noise and diagnostic acceptance compared to objectively measured image noise and the dose reductions achieved in a representative group of patients. MATERIALS AND METHODS: In a retrospective study two matched cohorts of 20 patients each were identified: a manual cohort with exposure settings according to body size (small - regular - large) and an ADC cohort with exposure settings calculated by the ADC system (DoseRight 2.0TM, Philips Healthcare). For each patient, 12 images from 6 defined anatomic levels from contrast-enhanced scans of chest and abdomen/pelvis were analyzed by 4 independent readers concerning image noise and diagnostic acceptance on a five-point Likert scale and evaluated for objectively measured image noise. Radiation exposure was calculated from recorded exposure data. RESULTS: Use of the ADC system reduced the average effective dose for patients by 36 % in chest scans (3.2 vs. 4.9 mSv) and by 17 % in abdomen/pelvis scans (7.6 vs. 8.3 mSv). Average objective noise was slightly lower in the manual cohort (11.1 vs. 12.8 HU), correlating with a slightly better rating in subjective noise score (4.4 vs. 4.2). However, diagnostic acceptance was rated almost equal in both cohorts with excellent image quality (4.6 vs. 4.5). CONCLUSION: Use of an ADC system with adequate noise characteristic leads to significant reductions in radiation exposure for patients while maintaining excellent image quality. PMID- 23108903 TI - [Radiographic, MR or ultrasound contrast media in pregnant or breast-feeding women: what are the key issues?]. AB - The use and the safety of radiographic, MR- or ultrasound contrast media in the diagnostic work-up of pregnant or lactating patients is a frequently discussed question. As only sparse clinical data is available, a careful benefit-risk assessment must contain physico-chemical properties, preclinical data including teratogeneity and embryotoxicity, as well as maternal and foetal exposure. With consideration to the individual risks, iodinated contrast media, macrocyclic MR contrast media with increased stability or sulphur hexafluoride ultrasound contrast media may, if clinically justified, be administered in the smallest possible doses throughout pregnancy. After parental administration of an iodinated contrast medium after the 12th week of pregnancy, the neonate's thyroidal function should be checked during the first week after birth. After parental administration of iodinated, stable macrocyclic, gadolinium or ultrasound contrast media, lactation can be continued normally. In any case, contrast media should be used with caution and only if the benefits outweigh the risk. PMID- 23108904 TI - A general approach towards thermoplastic multishape-memory polymers via sequence structure design. AB - The chain sequence of a poly(styrene-co-methyl acrylate) copolymer is designed to form a V-shaped gradient sequence via controlled/living radical emulsion copolymerization. This specially designed chain sequence gives this common copolymer the capacity of multishape memory. The copolymer can sequentially recover to its permanent shape from three or more previously programmed temporary shapes with the stimulus of temperature. PMID- 23108905 TI - Childhood obesity: shifting the focus to early prevention. PMID- 23108906 TI - p16 expression in cutaneous squamous carcinomas with neck metastases: a potential pitfall in identifying unknown primaries of the head and neck. AB - BACKGROUND: Human papillomavirus (HPV) positivity (+) has been used to identify oropharyngeal squamous carcinomas (SCCs) presenting as unknown primaries in the neck. p16 overexpression correlates with HPV+ in the oropharynx; however, the use of p16 alone as a surrogate marker of oropharyngeal HPV+ tumors has not been validated. METHODS: We immunohistochemically analyzed p16 expression in surgically resected aggressive cutaneous head and neck SCC primaries and their nodal metastases from 24 patients to determine the potential overlap of p16 expression outside of the oropharynx. RESULTS: Five of 24 primary tumors (20.8%) and 3 lymph node metastases (12.5%) in levels II, III, and V, and the periparotid region diffusely expressed p16. HPV (high-risk types by in situ hybridization) was negative. CONCLUSIONS: p16 expression is relatively common in lymph node positive cutaneous head and neck SCCs; thus, p16 expression as an independent biomarker and mechanism to determine the oropharyngeal source of an unknown primary is not advised. PMID- 23108907 TI - mRNA display selection and solid-phase synthesis of Fc-binding cyclic peptide affinity ligands. AB - Cyclic peptides are attractive candidates for synthetic affinity ligands due to their favorable properties, such as resistance to proteolysis, and higher affinity and specificity relative to linear peptides. Here we describe the discovery, synthesis and characterization of novel cyclic peptide affinity ligands that bind the Fc portion of human Immunoglobulin G (IgG; hFc). We generated an mRNA display library of cyclic pentapeptides wherein peptide cyclization was achieved with high yield and selectivity, using a solid-phase crosslinking reaction between two primary amine groups, mediated by a homobifunctional linker. Subsequently, a pool of cyclic peptide binders to hFc was isolated from this library and chromatographic resins incorporating the selected cyclic peptides were prepared by on-resin solid-phase peptide synthesis and cyclization. Significantly, this approach results in resins that are resistant to harsh basic conditions of column cleaning and regeneration. Further studies identified a specific cyclic peptide--cyclo[Link-M-WFRHY-K]--as a robust affinity ligand for purification of IgG from complex mixtures. The cyclo[Link-M WFRHY-K] resin bound selectively to the Fc fragment of IgG, with no binding to the Fab fragment, and also bound immunoglobulins from a variety of mammalian species. Notably, while the recovery of IgG using the cyclo[Link-M-WFRHY-K] resin was comparable to a Protein A resin, elution of IgG could be achieved under milder conditions (pH 4 vs. pH 2.5). Thus, cyclo[Link-M-WFRHY-K] is an attractive candidate for developing a cost-effective and robust chromatographic resin to purify monoclonal antibodies (mAbs). Finally, our approach can be extended to efficiently generate and evaluate cyclic peptide affinity ligands for other targets of interest. PMID- 23108909 TI - Letter to "Mapping of ghrelin gene expression and cell distribution in the stomach of morbidly obese patients--a possible guide for efficient sleeve gastrectomy construction"--authors' reply. PMID- 23108908 TI - Overexpression of integrin-linked kinase (ILK) is associated with tumor progression and an unfavorable prognosis in patients with colorectal cancer. AB - Integrin-linked kinase (ILK), an intracellular serine-threonine kinase, has been reported to be overexpressed in multiple types of human malignancies, including colorectal cancer (CRC). The prognostic value of ILK in CRC, however, remains unknown. In the present study, expression of ILK in 25 paired primary CRC samples and adjacent noncancerous tissues were quantified using real-time PCR and Western blotting. ILK protein expression was analyzed in 102 archived, paraffin-embedded CRC samples using immunohistochemistry. The correlation between ILK expression and clinicopathological factors was evaluated by the chi(2) test. Patients' overall survival was analyzed by Kaplan-Meier method. We found that both ILK mRNA and protein expression levels were significantly up-regulated in primary CRC samples compared with their corresponding normal tissues. Immunohistochemical analysis revealed relative high expression of ILK in 43 of 102 (42.2 %) primary CRC samples. Statistical analysis showed a significant correlation of ILK expression with tumor differentiation, lymph node metastasis, tumor invasion, and tumor-node-metastasis stage. Patients with tumors displaying high-level ILK expression showed significantly shorter overall survival (P = 0.028, log-rank test). More importantly, multivariate analysis indicated that high ILK protein expression was an independent prognostic factor for CRC patients (P = 0.026). Taken together, our data suggest that ILK overexpression is associated with tumor progression and a poor prognosis in CRC patients and may represent a novel potential prognostic marker for patients with CRC. PMID- 23108910 TI - Tumour burden at diagnosis as the main clinical predictor of cell resistance in patients with early stage, favourable Hodgkin lymphoma treated with VBM chemotherapy plus radiotherapy. AB - We verified whether early resistance to treatment can be predicted in a subset of patients with very favourable, early stage Hodgkin lymphoma, treated with VBM (vinblastine, bleomycin and methotrexate) chemotherapy and involved-field radiotherapy, an effective combination with very low early and late toxicity. The relative tumour burden (rTB) was volumetrically measured from the staging computed tomography and analysed together with the parameters of pre-therapy evaluation in 61 patients enrolled into the protocol MH-1b of the Gruppo Italiano Studio Linfomi between 1996 and 2003. Early failure, codified by either less than complete remission (i.e. partial/null response or progression) or early relapse (within 12 months from the end of therapy), was considered as clinical expression of resistance to treatment. Logistic regression and failure-free survival were the statistical tools for the analysis. The rTB demonstrated to be the best predictor of early failure, outperforming every other pre-treatment parameter, International Prognostic Score included. With a mean rTB value of 44.964 +/- 34.788 cm(3)/m(2) in the 53 patients successfully treated and of 130.185 +/- 63.993 cm(3)/m(2) in the eight with early treatment failure, the risk of resistance showed fivefold and 10-fold increases at rTB of 52.002 and 74.497 cm(3)/m(2), respectively. Only two patients relapsed more than 12 months after the end of therapy; both had a high initial rTB. The rTB is the best predictor of resistance also in the subset of patients with very favourable, early stage disease. Safe rTB limits are proposed for successful administration of VBM chemotherapy plus involved-field radiotherapy. PMID- 23108911 TI - A graphene-based electrochemical competitive immunosensor for the sensitive detection of okadaic acid in shellfish. AB - A novel graphene-based voltammetric immunosensor for sensitive detection of okadaic acid (OA) was developed. A simple and efficient electrografting method was utilized to functionalize graphene-modified screen-printed carbon electrodes (GSPE) by the electrochemical reduction of in situ generated 4-carboxyphenyl diazonium salt in acidic aqueous solution. Next, the okadaic acid antibody was covalently immobilized on the carboxyphenyl modified graphene electrodes via carbodiimide chemistry. Square wave voltammetry (SWV) was used to investigate the stepwise assembly of the immunosensor. A competitive assay between OA and a fixed concentration of okadaic acid-ovalbumin conjugate (OA-OVA) for the immobilized antibodies was employed for the detection of okadaic acid. The decrease of the [Fe(CN)(6)](3-/4-) reduction peak current in the square wave voltammetry for various concentrations of okadaic acid was used for establishing the calibration curve. A linear relationship between the SWV peak current difference and OA concentration was obtained up to ~5000 ng L(-1). The developed immunosensor allowed a detection limit of 19 ng L(-1) of OA in PBS buffer. The matrix effect studied with spiked shellfish tissue extracts showed a good percentage of recovery and the method was also validated with certified reference mussel samples. PMID- 23108913 TI - The human bitumen study hits the headlines. PMID- 23108912 TI - When a domain is not a domain, and why it is important to properly filter proteins in databases: conflicting definitions and fold classification systems for structural domains make filtering of such databases imperative. AB - Membership in a protein domain database does not a domain make; a feature we realized when generating a consensus view of protein fold space with our consensus domain dictionary (CDD). This dictionary was used to select representative structures for characterization of the protein dynameome: the Dynameomics initiative. Through this endeavor we rejected a surprising 40% of the 1,695 folds in the CDD as being non-autonomous folding units. Although some of this was due to the challenges of grouping similar fold topologies, the dissonance between the cataloguing and structural qualification of protein domains remains surprising. Another potential factor is previously overlooked intrinsic disorder; predictions suggest that 40% of proteins have either local or global disorder. One thing is clear, filtering a structural database and ensuring a consistent definition for protein domains is crucial, and caution is prescribed when generalizations of globular domains are drawn from unfiltered protein domain datasets. PMID- 23108914 TI - MicroRNA-210 targets antiapoptotic Bcl-2 expression and mediates hypoxia-induced apoptosis of neuroblastoma cells. AB - MicroRNAs (miRNAs) can regulate cell survival and death by targeting apoptosis related gene expression. miR-210 is one of the most hypoxia-sensitive miRNAs. In this study, we evaluated the roles of miR-210 in hypoxia-induced insults to neural cells. Treatment of neuro-2a cells with oxygen/glucose deprivation (OGD) induced cell apoptosis in a time-dependent manner. In parallel, OGD time dependently increased cellular miR-210 levels. Knocking down miR-210 expression using specific antisenses significantly attenuated OGD-induced neural apoptosis. Concurrently, OGD increased hypoxia-inducible factor (HIF)-1alpha mRNA and protein syntheses. Pretreatment with YC-1, an inhibitor of HIF-1alpha, reduced OGD-caused cell death. Sequentially, OGD specifically decreased antiapoptotic Bcl 2 mRNA and protein levels in neuro-2a cells. A search by a bioinformatic approach revealed that miR-210-specific binding elements exist in the 3'-untranslated region of Bcl-2 mRNA. Application of miR-210 antisenses simultaneously alleviated OGD-involved inhibition of Bcl-2 mRNA expression. In comparison, overexpression of miR-210 synergistically diminished OGD-caused inhibition of Bcl-2 mRNA expression and consequently induced greater cellular insults. Taken together, this study shows that OGD can induce miR-210 expression through activating HIF 1alpha. And miR-210 can mediate hypoxia-induced neural apoptosis by targeting Bcl 2. PMID- 23108915 TI - Candida famata (Candida flareri). AB - Candida famata (Candida flareri) belongs to the group of so-called 'flavinogenic yeasts', capable of riboflavin oversynthesis under condition of iron starvation. Some strains of C. famata belong to the most flavinogenic organisms known and were used for industrial production of riboflavin for a long time in the USA. C. famata is characterized by high salt tolerance, growing at NaCl concentrations of up to 2.5 M. Development of basic tools for the metabolic engineering of C. famata, such as a transformation system, selective markers, insertional mutagenesis, a reporter system and others, are described. The developed tools were used for cloning and identification of structural and regulatory genes of riboflavin synthesis. The construction of improved yeast strains producing riboflavin, FMN and FAD, based on the industrial riboflavin-producing strain dep8 and its non-reverting analogue AF4, is also described. PMID- 23108916 TI - Dabigatran compared with warfarin for stroke prevention with atrial fibrillation: experience in Hong Kong. AB - BACKGROUND: Dabigatran is an oral direct thrombin inhibitor recently approved for stroke prevention in atrial fibrillation (AF) as an alternative to warfarin. The primary advantages of dabigatran are freedom from monitoring and less interaction with other drugs and food. It is ideal for patients who are unwilling to adhere to regular coagulation monitoring or whose therapeutic effect using warfarin is not optimal despite adequate monitoring and management. However, the impact of dabigatran on health-related quality of life (HRQoL) and drug compliance has been less evaluated. This study aimed to evaluate the clinical and humanistic outcomes of dabigatran use in Hong Kong. HYPOTHESIS: Dabigatran 110 mg twice daily was non inferior in stroke prophylaxis in AF patients compared to adjusted-dose warfarin; while dabigatran 150 mg twice daily was superior to adjusted-dose warfarin in the real world data in Hong Kong. METHODS: We retrospectively analyzed 244 patients with newly diagnosed AF and prescribed dabigatran (n = 122) or warfarin (n = 122) for stroke prophylaxis from the Prince of Wales Hospital between January 2010 to November 2011. Clinical outcomes including death, stroke, bleeding, and HRQoL using the EuroQol EQ-5D-5L were compared between patients on dabigatran and warfarin. RESULTS: The median duration of follow-up was 310 days. Stroke occurred in 2 patients (1.64%) in the dabigatran group and 4 in the warfarin group (3.28%) (adjusted hazard ratio [HR]: 0.53, P = 0.47). Bleeding of any degree occurred in 28 patients on dabigatran and 38 patients on warfarin (adjusted HR: 0.76, P = 0.28), with age over 70 years and renal impairment being significant positive predictors of bleeding (P = 0.01 and 0.02, respectively). Dyspepsia was the most common adverse event of dabigatran over warfarin (19.7% vs 8.2%, P = 0.01). Rate of discontinuation of dabigatran was 25.4%, with dyspepsia being the most common cause for discontinuation (6 patients, 4.92%). There was no significant difference in drug compliance or HRQoL at 1 year between the 2 groups (utility score 0.77 [dabigatran] vs 0.74 [warfarin], P = 0.28). CONCLUSIONS: In Hong Kong, the clinical efficacy and safety of dabigatran were comparable to that of warfarin, and drug compliance and HRQoL of using dabigatran and warfarin were similar after 1 year of use. PMID- 23108917 TI - Management of glioblastoma in an NF1 patient with moyamoya syndrome: a case report. AB - INTRODUCTION: Glioma and moyamoya syndrome are both potential complications of neurofibromatosis type 1 (NF1). Here, we report the first case of NF1 concomitantly presenting with glioblastoma 10 years after surgical treatment of moyamoya syndrome. CASE REPORT: A 14-year-old boy with NF1 was incidentally diagnosed by magnetic resonance imaging (MRI) with a thalamic tumor during a follow-up for moyamoya syndrome, which had been treated with surgery 10 years earlier. After observation for 36 months, he developed left hemiparesis, and MRI revealed an increase in tumor size and obstructive hydrocephalus due to the tumor. Needle biopsy was performed through small craniotomy, and the histological diagnosis was glioblastoma. After concurrent chemoradiotherapy with 23 cycles of temozolomide, partial response of the tumor was observed. However, 24 months after the start of the initial therapy, the tumor showed regrowth, and the patient died 30 months after the initial therapy. No cerebrovascular events associated with moyamoya syndrome and chemoradiotherapy were observed during the clinical course of glioblastoma. DISCUSSION: Glioblastoma is a fatal disease in children, and our patient successfully received chemoradiotherapy with temozolomide despite the diagnoses of NF1 and moyamoya syndrome. Although radiotherapy or chemotherapy potentially causes cerebrovascular complications, chemoradiotherapy might be feasible for glioblastoma treatment in patients with moyamoya syndrome and NF1. The following issues are discussed in the management of the present case: the indication of biopsy in NF1 cases, the method of surgery, and the treatment protocol for tumors concomitant with moyamoya disease or syndrome. PMID- 23108918 TI - C2/3 instability: unusual cause of cervical myelopathy in a child with Down syndrome. AB - We report a rare cause of cervical myelopathy (CM) in a 10-year-old Down syndrome (DS) girl. She presented with progressive CM over 1 year affecting her ability to ambulate or feed herself. The myelopathy was secondary to C2/3 instability. Surgical reduction and instrumented fusion have significantly improved her neurological status. This case emphasizes the importance of close follow-up of DS patients for early diagnosis and treatment of cervical spine abnormalities. PMID- 23108919 TI - Birth prevalence of neural tube defects: a population-based study in South Eastern Hungary. AB - PURPOSE: Primary prevention by periconceptional folic acid supplementation can significantly reduce the risk of neural tube defects. EUROCAT, the European network of population-based registries for the epidemiologic surveillance of congenital anomalies, lacks sufficient data on the birth prevalence of neural tube defects in Hungary before and after the promotion of primary prevention by folic acid. Our aims were to compare the birth prevalence of neural tube defects (myelomeningocele, anencephaly and encephalocele) over two 12-year periods in South-Eastern Hungary. Further aims were to compare our data to those ones in other areas in Europe. METHODS: Data were collected from the databases of the Department of Hungarian Congenital Abnormality Registry. The total and live birth prevalence rate of neural tube defects were calculated and compared over 1980 1991 and 1994-2005. In addition, the trends in the total birth prevalence, the number of live births and terminations for and stillbirths with neural tube defects were analysed throughout the period of 1994-2005. RESULTS: A significant decline was found in the total and live birth prevalence of myelomeningocele, anencephaly and encephalocele over 1994-2005 compared to the period of 1980-1991. The total birth prevalence of neural tube defects, however, showed a trend of increase after 1994, with declining number of live births and increasing number of terminations for neural tube defects. CONCLUSION: Public health measures are warranted in order to replace termination of pregnancy with primary prevention in South-Eastern Hungary. PMID- 23108920 TI - Nanosized poly(ethylene glycol) domains within reverse micelles formed in CO2. PMID- 23108921 TI - In vitro and in vivo antiplasmodial activity of the root extracts of Brucea mollis Wall. ex Kurz. AB - Malaria control is compromised worldwide by continuously evolving drug-resistant strains of the parasite demanding exploration of natural resources for developing newer antimalarials. The northeastern region of India is endemic for malaria characterized by high prevalence of drug-resistant Plasmodium falciparum strains. Many plants are used by the indigenous communities living in the northeast India in their traditional system of medicine for the treatment of malarial fever. Folklore claim of antimalarial property of one such plant Brucea mollis was evaluated in vitro and in vivo for antiplasmodial activity. Crude extracts from dried B. mollis root powder were prepared through soxhlet extraction using petroleum ether, methanol, and water sequentially. Methanol extract was further partitioned between chloroform and water. These extracts were tested in vitro against laboratory-adapted chloroquine-sensitive and chloroquine-resistant strains of P. falciparum. In in vitro evaluation, extracts were found more active on the chloroquine-sensitive strain. Methanolic-chloroform (IC(50) 5.1 MUg ml( 1)) and methanolic-aqueous (IC(50) 13.9 MUg ml(-1)) extracts recorded significant in vitro antiplasmodial activity which was also supported by their promising in vivo activity (ED(50) 72 and 30 mg kg(-1) bw day(-1), respectively) against chloroquine-resistant Plasmodium yoelli N-67 strain in Swiss albino mice. Methanolic-aqueous extract-treated mice survived on average for 14 days that was comparable to the reference drug chloroquine. This is the first report of antiplasmodial activity of B. mollis validating the traditional use of this plant as antimalarial in the northeast India and calls for further detailed investigations. PMID- 23108922 TI - Functionalized soft nanoporous materials through supramolecular assembly of end functionalized polymer blends. AB - Supramolecular assembly through complementary interaction between molecular subgroups belonging to phase-separating polymer species offers a great opportunity, not only for constructing nanoscale soft templates reminiscent of conventional block copolymer morphologies, but also for tailoring surface properties by facile removal of one of the structure components by cleaving complementary interactions. Herein we report the fabrication of a novel, organic, nanoporous film through supramolecular assembly of two complementarily, end interacting, mono-end-functionalized polymers under solvent annealing. The film of end-functionalized polymer blends under solvent annealing yielded phase separated nanodomains that resemble nanoscopically ordered structures of block copolymers, but that are more advantageous due to easily cleavable and exchangeable links between the phase-separated domains. The removal of one of the components of the precursor structure formed from the end-functionalized polymers through cleavage of complementary interactions allowed us to fabricate mono- or multilayered nanoporous structures in which the chemically useful end functionalities of the remnant polymers are rich on the surface of the pores. The resultant, organic, nanoporous films with tailored surface functionality offer a useful platform for various chemical and biological applications. PMID- 23108923 TI - The serotonin transporter gene and depression. AB - Psychiatric disorders such as depression are known to be under a degree of genetic influence, but the specific variants contributing to this heritability remain largely unknown. The serotonin transporter gene has received the most attention in relation to depression, either alone or in conjunction with exposure to stressful life events (i.e. a gene x environment interaction), whereas neuroimaging studies have suggested an association with amygdala activation. There is also some evidence that this gene may predict antidepressant response. However, each of these literatures has followed a similar course of initial promise giving way to an inconsistent pattern of replications and nonreplications. In parallel, whole genome approaches have begun to provide robust findings and novel insights into the mechanisms of common disease. One of these insights is that the genetic architecture of common disease phenotypes such as depression comprises a very large number of common variants of very small effect, possibly together with a smaller number of rare variants of larger effect. This is at odds with the apparently large effect of the serotonin transporter gene reported in some studies. Taken together, it is unlikely that the serotonin transporter gene plays a major role in depression. Future single locus analyses should be informed by more robust findings derived from whole genome methods. PMID- 23108924 TI - Fetal pulmonary venous flow and restrictive foramen ovale in hypoplastic left heart. AB - PURPOSE: Hypoplastic left heart (HLH) with intact or restrictive interatrial communication (HLH-IAS/RAS) is associated with high mortality rates. The object was to correlate pulmonary venous (PV) Doppler spectra and direct foramen ovale (FO) assessment with the neonatal need for early atrial septostomy (EAS) and neonatal outcome. MATERIALS AND METHODS: We reviewed all prenatal echocardiograms and outcomes of 51 fetuses with HLH and information about the interatrial communication between 1994 - 2011. IAS/RAS was defined as a small/absent interatrial shunt on 2-dimensional imaging. Three PV Doppler spectra were observed: type A: continuous forward flow with a small a wave reversal; type B: continuous forward flow with increased a-wave reversal; type C: brief to-and-fro flow. RESULTS: Three of 51 neonates with type C pulmonary venous flow pattern and suspicion of IAS/RAS on 2-dimensional (2-DE) evaluation required EAS. In one fetus pulmonary venous flow changed from type B to type C spectra throughout gestation. Fetuses with type C spectra showed a 71.4 % survival after 30 days compared to 92.3 % in fetuses with type A spectra. Short term survival after EAS was 33 %. CONCLUSION: Prenatal PV flow pattern and 2-DE of the FO size help in identifying the fetus at risk for neonatal EAS and patient selection for fetal cardiac intervention. Most late second trimester values will not change over time. PMID- 23108925 TI - Interobserver variability and diagnostic performance in US assessment of thyroid nodule according to size. AB - PURPOSE: To evaluate the interobserver variability for US assessments of thyroid nodules and analyze the diagnostic performances of US assessments in thyroid nodules according to nodule size. MATERIALS AND METHODS: This was an IRB-approved retrospective study with waiver of informed consent. A total of 400 surgically confirmed thyroid nodules were included. Nodules were divided into 4 groups by size; group 1 (nodule size < 5 mm), group 2 (5 mm <= nodule size < 10 mm), group 3 (10 mm <= nodule size < 20 mm), and group 4 (nodule size >= 20 mm). Three experienced (7 - 10 years) radiologists retrospectively reviewed the US images. Agreement of each US descriptor and final US assessment, and diagnostic performances were calculated in each group and compared. RESULTS: Composition represented substantial or good agreement (k = 0.719 - 0.89). Margin showed the lowest agreement (k = 0.322 - 0.365). Individual kappa values for final assessment according to nodule size were as follows: group 1 (k = 0.674), group 2 (k = 0.596), group 3 (k = 0.674), and group 4 (k = 0.673). Specificity, PPV, and accuracy were significantly different among the groups with different size (p value < 0.05) and lowest in group 1. NPV, specificity, PPV and accuracy except PPV of observer 3 increased with nodule size (p < 0.05). CONCLUSION: Interobserver agreements were relatively good (k = 0.637) in final US assessment regardless of nodule size in experienced radiologists. High false-positive rate was observed in US assessment in nodules less than 5 mm in maximum diameter. PMID- 23108926 TI - Differentiating between malignant and benign breast masses: factors limiting sonoelastographic strain ratio. AB - PURPOSE: We compared strain ratio vs. qualitative elastography for the further differentiation of focal breast lesions, with special focus on limiting factors. MATERIALS AND METHODS: 215 patients with 224 histologically proven breast masses (116 malignant, 108 benign) were prospectively examined using a high-end ultrasound system (Philips iU22) with serial elastography function. B-mode scans and available mammograms were reviewed according to the BIRADS classification, raw elastogram data was analyzed qualitatively using the Tsukuba score and semiquantitatively by calculating the strain ratio (fat to lesion ratio). For diagnostic performance, Receiver Operating Characteristic (ROC) curve analysis was obtained. A sub-group analysis regarding breast density, lesion size, lesion depth and histological subtypes was performed. RESULTS: Mean strain ratio values were 3.04 +/- 0.9 for malignant and 1.91 +/- 0.75 for benign lesions (p < 0,001). The areas under the ROC curve values were 0.832 (95 % CI 0.777; 0.888) for strain ratio, 0.869 (95 % CI 0.822; 0.917) for Tsukuba score, 0.822 (95 % CI 0.768; 0.876) for B-mode ultrasound and 0.853 (95 % CI 0.799; 0.907) for mammography. Sensitivity, specificity, positive predictive value and negative predictive value of the strain ratio were 90.7 %, 58.2 %, 70.3 % and 85.1 %, when a cutoff point of 2.0 was used. Only lesion depth <= 4 mm was associated with diagnostic failure in the multivariate analysis of factors influencing accuracy, whereas no significant correlation between breast density and lesion size and the accuracy of the strain ratio could be found. CONCLUSION: The addition of strain ratio to B mode ultrasound increases specificity without loss of sensitivity in differentiating between malignant and benign breast tumors. Strain ratio measurements should not be carried out on tumors with a lesion depth <= 4 mm. PMID- 23108927 TI - Flexible and stretchable polymers with embedded magnetic nanostructures. AB - A novel pathway is presented to transfer and embed functional patterned magnetic nanostructures into flexible and stretchable polymeric membranes. The geometrical and magnetic properties are maintained through the process, realized even directly inside a microfluidic channel. These results pave the way to the realization of smart biomedical systems and devices based on the integration of magnetic nanostructures into new classes of substrates. PMID- 23108929 TI - Influence of group 10 metals on the growth and subsequent Coulomb explosion of small silicon clusters under strong light pulses. AB - Growth and ionization patterns of small silicon clusters are studied using ultrafast pulses centered at 624 nm by varying the metal electron source for cluster formation using group 10 transition metals. The silicon-cluster size was observed to change as the electron source was varied from Pd=24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs. CONCLUSIONS: Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments. PMID- 23108950 TI - Adolescents with acute lymphoblastic leukemia treated at pediatric versus adult hospitals. AB - BACKGROUND: The objective was to compare 5-year overall survival (OS) between adolescent and young adult (AYA) patients (age 15-19) with acute lymphoblastic leukemia (ALL) treated at a pediatric versus an adult center. PATIENTS AND METHODS: This was a population-based analysis using administrative data of Ontario ALL AYA patients diagnosed between 1986-2009. We calculated predicted survival proportions (PSPs) and 95% confidence intervals (CI). We also surveyed sites to determine whether pediatric or adult-based protocols were used in each period. RESULTS: Overall, 290 patients between 15-19 years of age were diagnosed with ALL during the study period; 144 patients (49.7%) were treated at an adult center. When adjusted for gender, age, income quintile and time period, AYA patients treated at a pediatric center did not have a significantly different PSP (0.65, 95% CI: 0.56-0.75) in comparison to those treated at an adult center (0.62, 95% CI 0.52-0.73; P = 0.87). Most AYA patients treated at adult centers received pediatric protocols in the recent periods. CONCLUSIONS: Using population based data, AYA ALL patients had similar outcomes whether treated at a pediatric or an adult center. Early introduction of aggressive treatment protocols in adult centers may have negated differences in outcomes among AYA patients by site of care. PMID- 23108951 TI - Incidence and predictors of ovarian function recovery (OFR) in breast cancer (BC) patients with chemotherapy-induced amenorrhea (CIA) who switched from tamoxifen to exemestane. AB - BACKGROUND: Aromatase inhibitors (AIs) may promote ovarian function recovery (OFR). True incidence, predictors and impact on the outcome of OFR are unknown. PATIENTS AND METHODS: We carried out a prospective study to assess ovarian function in estrogen receptor (ER)-positive BC patients on tamoxifen who had at least 2 years of chemotherapy-induced amenorrhea (CIA) and postmenopausal E2 levels. Patients switched to exemestane and underwent a series of investigations including vaginal ultrasound, antimullerian hormone, follicle stimulating hormone (FSH), and E2. E2 measurements were made using a clinical assay (direct) and a highly sensitive (indirect) immunoassay for comparison. RESULTS: Both E2 assays (indirect versus direct) showed a similar incidence of OFR 32% (95% CI 19.5-44.5) versus 30% (95% CI 17.7-42.3) and median time to OFR 5.4 months (95% CI 1.2-9.6) versus 6.0 months (95% CI 4.8-7.1).On multivariate analysis, the mean age at the start of exemestane treatment was the only marker associated with probability of OFR (OR: 0.44, 0.24-0.78; P = 0.006). According to a receiver operating characteristic (ROC) analysis, age <48 years predicted for OFR (sensitivity: 59%; 1-specificity: 17%; AUC: 0.796; P = 0.001). Patients with OFR had higher mean E2 levels (43.6 versus 5.76 pmol/l; P = 0.001) and a reduced disease-free survival [DFS; HR 9.3 (95% CI 3.3-48.0; P = 0.04)] than those without it. CONCLUSION: Even with a clinical and biochemical profile compatible with menopause, switching from tamoxifen to an AI should be avoided in patients <48 with CIA. PMID- 23108952 TI - Bevacizumab with peri-operative epirubicin, cisplatin and capecitabine (ECX) in localised gastro-oesophageal adenocarcinoma: a safety report. AB - BACKGROUND: Peri-operative chemotherapy and surgery is a standard treatment of localised oesophagogastric adenocarcinoma; however, the outcomes remain poor. PATIENTS AND METHODS: ST03 is a multicentre, randomised, phase II/III study comparing peri-operative ECX with or without bevacizumab (ECX-B). The primary outcome measure of phase II (n = 200) was safety, specifically gastrointestinal (GI) perforation rates and cardiotoxicity. RESULTS: Two hundred patients were randomised between October 2007 and April 2010. Ninety-one/101 (90%) ECX and 86/99 (87%) ECX-B patients completed pre-operative chemotherapy; 7 ECX and 9 ECX B patients stopped due to toxicity. Gastrointestinal perforations (3 ECX, 1 ECX B), cardiac events (1 ECX, 4 ECX-B) and venous thromboembolic events (VTEs, 8 ECX, 7 ECX-B) were uncommon. Arterial thromboembolic events (ATEs, myocardial infarction (MI) or cerebrovascular accident) were more frequent with ECX-B (5 versus 1 with ECX). Delayed wound healing, anastomotic leaks and GI bleeding rates were similar. More asymptomatic left ventricular ejection fraction (LVEF) falls (>=15% and/or to <50%) occurred with ECX-B (21.2% versus 11.1% with ECX). Clinically significant falls (>=10% to below lower limit of normal, LLN) occurred in (15.3%) and (8.9%) respectively, with no associated cardiac failure (median 22 months follow-up). CONCLUSIONS: Addition of bevacizumab to peri-operative ECX chemotherapy is feasible with acceptable toxicity and no negative impact on surgical outcomes. PMID- 23108953 TI - Phase II randomized, double-blind, placebo-controlled study of AMG 386 (trebananib) in combination with cisplatin and capecitabine in patients with metastatic gastro-oesophageal cancer. AB - BACKGROUND: We evaluated AMG 386, an investigational peptibody that neutralizes the interaction between angiopoietins-1 and -2 and the Tie2 receptor, combined with cisplatin/capecitabine (CX) as first-line treatment for metastatic gastro oesophageal cancer. PATIENTS AND METHODS: Patients with metastatic gastric, gastro-oesophageal junction, or distal oesophageal adenocarcinoma were randomized 1:1:1 to CX (cisplatin 80 mg/m(2) IV Q3W; capecitabine 1000 mg/m(2) P.O. BID for 14 days Q3W) plus intravenous AMG 386 10 mg/kg QW (Arm A) or 3 mg/kg QW (Arm B), or placebo QW (Arm C). The primary end point was estimated progression-free survival (PFS). RESULTS: A total of 171 patients were enrolled. Median estimated PFS in Arms A, B, and C was 4.2, 4.9, and 5.2 months, respectively (hazard ratio for Arms A+B combined versus Arm C, 0.98; 95% CI 0.67-1.43; P = 0.92). Objective response rates were 27% (Arm A), 43% (Arm B), and 35% (Arm C). Incidence of grade >=3 adverse events was 80% in Arm A, 84% in Arm B, and 75% in Arm C. There was no evidence of pharmacokinetic interactions. CONCLUSIONS: In this study, PFS and ORR were estimated to be similar with AMG 386 plus CX and placebo plus CX treatment. Compared with placebo, toxicity of AMG 386 plus CX was greater but manageable. PREVIOUS PRESENTATION: The results of this study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 20-22, 2011. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT00583674. PMID- 23108954 TI - Pharmaco-modulations of induced edema and vascular permeability changes by Vipera lebetina venom: inflammatory mechanisms. AB - The inflammatory response induced by Vipera lebetina venom (VLV) in the mice hind paw was evaluated by paw edema value and vascular permeability changes. The edema was produced in a dose- and time-dependent manner. This response was maximal within 2 h and disappeared after 24 h The minimum edema-forming dose was estimated at 0.8 MUg/20 g body weight. Microscopic examination confirmed that VLV also induces skin structure alterations with collagen fiber dissociation and polynuclear infiltration, which is characteristic of edema formation. The induced edema with VLV (1 MUg/paw) could be due to the release of pharmacological active substances at the site of injection. Histamine, serotonine, and arachidonate metabolites may play important roles in the vasoactive and edematic effect of VLV since pretreatment of mice with cromoglycate, cyproheptadine, ibuprofen, loratidine, and indomethacin significantly reduced the edema formation (77, 63, 57, 45, and 43 %, respectively). The obtained results demonstrate that the induced edema and vasodilatation by this venom may be triggered and maintained by different pharmacological mechanisms, since cromoglycate and cyproheptadine were the most active inhibitors of the edema. The relationships between histamine and serotonin release from mast cells and arachidonate metabolites activation could be the main step in edema-forming and the induced vasodilatation by the venom. PMID- 23108955 TI - Association study of IFIH1 rs1990760 polymorphism with systemic lupus erythematosus in a Chinese population. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease arising from the action of multiple genetic and environmental risk factors. The aim of this study was to examine the association of a single-nucleotide polymorphism, rs1990760, of the interferon induced with helicase C domain 1 (IFIH1) gene with SLE in a Chinese population. A total of 877 SLE patients and 978 healthy control subjects were enrolled in the present study. The genotype of the IFIH1 rs1990760 polymorphism was determined by Sequenom MassARRAY technology. The IFIH1 rs1990760 T allele was significantly increased in patient group compared with control subjects (T versus C, Odds ratio = 1.20, 95 % confidence interval = 1.02-1.40). However, no significant difference in genotype distribution was found between cases and controls (P = 0.07). No significant evidence was detected for the association of the IFIH1 rs1990760 polymorphism with SLE under neither dominant nor recessive model (TT + TC versus CC, P = 0.06; TT versus TC + CC, P = 0.08). We also analyzed the association of the IFIH1 rs1990760 T allele with clinical features, whereas no significant signal was found. In conclusion, our study represents the first report demonstrating an association of the IFIH1 rs1990760 polymorphism with SLE susceptibility in a Chinese population. PMID- 23108956 TI - Mast cells in human stenotic aortic valves are associated with the severity of stenosis. AB - Aortic valve stenosis (AS) is characterized by extensive calcification of the aortic valve leaflets and infiltration of inflammatory cells. Activated mast cells (MCs) may participate in the induction of fibrosis and calcification with ensuing valve stiffening. We sought to investigate whether the number of MCs within stenotic aortic valves is associated with the severity of AS. We studied 43 patients (19 men, 24 women) with dominant AS (age, 64.2 +/- 5.9 years; mean transvalvular pressure gradient, 62.11 +/- 24.47 mmHg) without atherosclerotic vascular disease, undergoing elective aortic valve replacement. MCs were detected in the excised valves by immunostaining. Aortic valves from five healthy subjects obtained on autopsy served as negative controls. The number of tryptase- and chymase-positive MCs was increased in AS valves compared with the control valves (6.9 [2.3-18.9]/mm(2) vs. 0.7 [0-2.2]/mm(2), P = 0.0001 and 3.2 [2.1-9.4]/mm(2) vs. 0.3 [0-1.9]/mm(2), P = 0.002, respectively). MCs that colocalized with macrophages and neovessels were detected mainly in the calcified regions of the leaflets. The number of MCs positively correlated with maximal (r = 0.73, P < 0.0001) and mean (r = 0.78, P < 0.0001) gradients and maximal aortic jet velocity (r = 0.68, P = 0.0005). An inverse correlation with aortic valve area (r = -0.71, P = 0.0001) was also observed. Multivariate regression analysis revealed that MC number and valve thickness were significantly associated with mean transvalvular gradient (R (2) = 0.74, P < 0.000001) in AS patients. Increased MC number within human stenotic aortic valves is associated with the severity of AS. PMID- 23108957 TI - Baicalein inhibits DMBA/TPA-induced skin tumorigenesis in mice by modulating proliferation, apoptosis, and inflammation. AB - Baicalein, one of the four major flavanoids extracted from the root of Scutellaria baicalensis, has been shown to exert chemopreventive effect against several cancers, including skin cancer. However, the precise mechanisms remain to be elucidated. In the present study, we investigated the chemopreventive activity of baicalein against 7,12-dimethylbenz[a]anthracene (DMBA)/12-O tetradecanoylphorbol-13-acetate (TPA)-mediated skin tumorigenesis in C57BL/6 mice. We found that topical treatment with baicalein resulted in a significant inhibitory effect on DMBA/TPA-mediated tumor promotion. Furthermore, we observed that baicalein suppressed cell proliferation and promoted apoptosis in DMBA/TPA mediated group. Additionally, pretreatment with baicalein inhibited the production of inflammatory cells in DMBA/TPA-induced skin/tumors. Further experiments showed that baicalein reduced TPA-induced skin hyperplasia as well as infiltration of polymorphonuclear leukocytes in the dermis. In conclusion, our data suggest that baicalein inhibits DMBA/TPA-induced skin tumorigenesis by suppressing proliferation and inflammation and promoting apoptosis. PMID- 23108958 TI - Effects of organoselenium compound 2-(5-selenocyanato-pentyl) benzo[de]isoquinoline 1,3-dione on cisplatin induced nephrotoxicity and genotoxicity: an investigation of the influence of the compound on oxidative stress and antioxidant enzyme system. AB - Cisplatin is one of the most active cytotoxic agents used in the treatment of cancer. However, cisplatin therapy is also associated with severe side effects like nephrotoxicity and genotoxicity. Free oxygen radicals are known to play a major role in cisplatin induced toxicities. Selenium is believed to be an important trace element and dietary antioxidant because of its ability to scavenge free oxygen radicals, thereby preventing cells from oxidative stress. The purpose of this study is to evaluate the protective role of a novel naphthalimide based organoselenium compound 2-(5-selenocyanato-pentyl) benzo[de]isoquinoline 1,3-dione against cisplatin induced toxicities in Swiss albino mice. Cisplatin was administered intraperitoneally (5 mg/kg b.w.) and the organoselenium compound was given by oral gavages (3 mg/kg b.w.) in concomitant and pretreatment schedule. The results showed that the test compound substantially reduced cisplatin induced reactive oxygen species generation and lipid peroxidation in kidney as well as blood urea nitrogen and creatinine levels in serum. Treatment with organoselenium compound was also able to restore the renal antioxidant system by modulating the cisplatin induced depleted activities of glutathione S-transferase, thioredoxin reductase, superoxide dismutase, catalase, glutathione peroxidase and reduced glutathione level. In addition, the organoselenium compound could efficiently minimize cisplatin induced chromosomal aberrations in bone marrow cells and extent of DNA damage in lymphocytes. Furthermore, the chemoprotective efficacy of the compound against cisplatin induced toxicity was confirmed by histopathological evaluation. The results suggest that the organoselenium compound has the potential to protect against cisplatin induced nephrotoxicity and genotoxicity in part by scavenging reactive oxygen species and by up regulating the antioxidant enzyme system. PMID- 23108959 TI - UVB radiation variably affects n-3 fatty acids but elevated temperature reduces n 3 fatty acids in juvenile Atlantic Salmon (Salmo salar). AB - Temperature and ultraviolet B radiation (UVB 290-320 nm) are inextricably linked to global climate change. These two variables may act separately, additively, or synergistically on specific aspects of fish biochemistry. We raised Atlantic Salmon (Salmo salar) parr for 54 days in outdoor tanks held at 12 and 19 degrees C and, at each temperature, we exposed them to three spectral treatments differing in UV radiation intensity. We quantified individual fatty acid (FA) mass fractions in four tissues (dorsal muscle, dorsal and ventral skin, and ocular tissue) at each temperature * UV combination. FA composition of dorsal muscle and dorsal and ventral skin was not affected by UV exposure. Mass fractions of 16:0, 18:0, and saturated fatty acids (SFA) were greater in dorsal muscle of warm-reared fish whereas 18:3n-3, 20:2, 20:4n-6, 22:5n-3, 22:6n-3, n-3, n-6, polyunsaturated fatty acids (PUFA), and total FA were significantly higher in cold-reared fish. Mass fractions of most of the FA were greater in the dorsal and ventral skin of warm-reared fish. Cold-reared salmon exposed to enhanced UVB had higher ocular tissue mass fractions of 20:2, 20:4n-6, 22:6n-3, n-3, n-6, and PUFA compared to fish in which UV had been removed. These observations forecast a host of ensuing physiological and ecological responses of juvenile Atlantic Salmon to increasing temperatures and UVB levels in native streams and rivers where they mature before smolting and returning to the sea. PMID- 23108960 TI - An improved method for analysis of glucosylceramide species having cis-8 and trans-8 isomers of sphingoid bases by LC-MS/MS. AB - High-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) approaches have enabled high selectivity and sensitivity for the identification and quantification of glucosylceramide molecular species. Here we demonstrate that HPLC-ESI-MS/MS is an efficient method for characterizing plant glucosylceramide species having the cis-8 and trans-8 isomers of sphingoid bases. Complete baseline separation was achieved using a high-carbon-content octadecylsilyl column and a simple binary gradient comprising methanol and water. The result of 2-hydroxy fatty acid composition achieved by HPLC-ESI-MS/MS was compared with that achieved by gas chromatography with flame ionization detection (GC-FID), indicating that the two methods yield similar molar compositions. The current method should be applicable to seeking the active components of glucosylceramide species from plant materials in response to biological challenges. PMID- 23108962 TI - [Hereditary thrombophilias and placenta-mediated pregnancy complications in the second and third trimester--predominance of association studies and small "body of evidence" in terms of clinical implications]. PMID- 23108961 TI - In silico prediction of mRNA poly(A) sites in Chlamydomonas reinhardtii. AB - Accurately predicting polyadenylation [poly(A)] sites is important for defining the end of genes and understanding gene regulation mechanisms. Alternative polyadenylation (APA) has been demonstrated to play an important role in transcriptome diversity and regulating gene expression. To accurately predict poly(A) and APA sites in Chlamydomonas reinhardtii, a green alga that can be used to produce renewable energy, we proposed a novel model that integrated five methods for representing the features of these sites with a combined classifier. We presented a new grouping method based on pattern assembly to classify the poly(A) sites into four groups. We used five methods, involving the predicted RNA secondary structure, the term frequency-inverse document frequency weight, first order Markov chain, pentamer ratio and a position weight matrix, to generate the feature space. We then developed a heuristic method to form the combined classifier by weighting multiple classifiers to predict poly(A) sites in each group. The high specificity and sensitivity of this model were demonstrated by testing the four groups of poly(A) sites and the intronic APA sites. The average prediction performance was approximately 8 % higher than the performance of a previous prediction model. For the group without any conserved patterns, the prediction accuracy was 9 % higher than for the accuracy with the previous technique. However, the prediction efficiency of this group was still significantly lower than that of the other groups, indicating the importance of identifying additional signal patterns for poly(A) site prediction. We also predicted the alternative poly(A) sites in introns with good accuracy. This prediction model was designed to be easily expanded with new classifiers or new features. Therefore, this model is applicable to new data or other species. Our model will be useful both in genome annotation because it predicts the end of a mature transcript and in genetic engineering because it enables researchers to eliminate undesirable poly(A) sites. PMID- 23108963 TI - Pathophysiology of neonatal transition and meaningful measures for the initial stabilisation of extremely premature neonates. AB - This report discusses the physiological aspects of neonatal transition from breathing liquid to air. Further, we discuss reasonable medical interventions to actively assist a gentle transition, and focus on team aspects of preparing both the perinatal team and parents for the challenging situation of preterm labour and delivery. Our aim is to critically evaluate current concepts on the physiology of neonatal transition and the current assessment of the newborn infant, to present means to facilitate non-traumatic pulmonary aeration and ways to foster successful teamwork and professional parental guidance in the delivery room. The authors report on their own work and on that of other research groups, as recently published in peer reviewed medical journals. When born, the newborn needs to rapidly clear his/her lungs from fluid to establish breathing. Active fluid transport and passive resorption help to establish the pulmonary functional residual capacity (FRC). Prenatal administration of corticosteroids helps to form and maintain the FRC of the newborn. Many very low gestational age neonates (ELGAN) will breathe at birth but require medical assistance. This is best done by giving distending positive airway pressure at levels of 5 cmH(2)O, or greater. Monitoring of these infants should be by peripheral pulse oximetry. Some ELGANs may require non-invasive ventilation and/or exogenous Surfactant replacement, and even fewer may require intubation and mechanical ventilation. The obstetric and neonatal teams need to coordinate their joined efforts to secure a safe delivery for mother and child. Ways of communication between teams and parents are presented. Many neonatal teams use video recording as a tool to assess and improve their work. We give insights into the use of video as a means to improve teamwork and patient care alike. PMID- 23108964 TI - [Deep sedation in neonates and infants for diagnostic procedures]. AB - Many diagnostic and interventional procedures in neonates and infants need to be performed under sedation. Depending on the level of sedation this can lead to a total immobilisation of the children combined with a reduction of stress and pain and good diagnostic conditions. Therefore a deep sedation often is comparable with general anaesthesia. When performing sedations, established safety standards need to be observed. Apart from a skilled physician, well defined structures and procedures for pre- and postprocedural care are necessary. This includes standardised monitoring, medications and adapted medical engineering. The article gives an overview of the principle requirements for the working area, the monitoring and the physician him/herself. Furthermore after an illustration of the widely used medications, guidance for the practical proceeding in common procedures is given. With such a professional management. it is possible to increase the quality and safety of care for the children and not least the satisfaction of the parents even more. PMID- 23108965 TI - [Birth weight percentile values for girls and boys under consideration of maternal height]. AB - There is a linear relationship between maternal height and birth weight. For each 1 cm increase in maternal height, birth weight increases by 16.7 g. Birth weight percentiles should be calculated by taking maternal height into account. We present birth weight percentile values for girls and boys born after 23-43 completed weeks of gestation for 5 maternal height groups. With these percentiles "genetically" small and "genetically" large, but healthy, neonates can be classified more adequately. The calculations are based on data of about 2.2 million singleton pregnancies from the German Perinatal Survey of 1995-2000. PMID- 23108966 TI - [Determination of maternal and foetal serum lipid profile and placental oxidised low density lipoprotein accumulation in preeclampsia and normotensive pregnancies]. AB - BACKGROUND: Oxidised low density lipoproteins (oxLDL) are key players in the development of atherosclerotic cardiovascular diseases. Since there are similarities between the pathogenesis of preeclampsia and atherosclerosis we hypothesised an increased accumulation of oxLDL at the materno-foetal and foeto foetal interface within the placental tissue of preeclamptic women compared to women with normotensive pregnancies (controls). Moreover, we analysed maternal and foetal serum lipid parameters. PATIENTS AND METHODS: oxLDL was determined by immunohistochemistry in placental paraffin sections of 14 women suffering from preeclampsia (30th-39th week of gestation) and compared to 28 preterm and term deliveries (25th-40th week of gestation). 10 high power fields were chosen randomly by the newCAST software and oxLDL expression was analysed via standardised methods by 2 independent and blinded investigators. Maternal and foetal triglycerides, total cholesterol, LDL cholesterol and HDL cholesterol were measured. Statistical examination was carried out by the Mann-Whitney test. RESULTS: oxLDL was found in villous trophoblast and placental endothelium. No significant differences were observed in expression intensity between preeclampsia and controls. Maternal and foetal triglyceride levels were significantly increased in preeclampsia compared to controls (pre-eclampsia mothers: 293 [SD 87.4] mg/dL, controls: 214 [SD 89.4] mg/dL, p=0.0097; preeclampsia foetuses: 26 [SD 16.6] mg/dL, controls: 18 [SD 10.4] mg/dL, p=0.0463). No significant differences in other lipid concentrations were found. CONCLUSIONS: We could not confirm our initial hypothesis of an increased oxLDL accumulation in placental tissue of preeclampsia. However, preeclampsia is a condition of dyslipidaemia affecting both maternal and foetal serum with implications for development and programming of cardiovascular diseases in later life. PMID- 23108967 TI - [Atypical myometric fluid accumulation in graviditate--intramural pregnancy or degenerated fibroid?]. AB - We wish to discuss a case of suspected fluid accumulation within the anterior uterine wall in graviditate. The initial diagnosis of a rare intramural pregnancy could not be confirmed by 4+5 gestational weeks. Following removal of the fluid and establishing the diagnosis of degenerated fibroid(s), the advancing pregnancy was somewhat uneventful, whereas the uterine wall lesion showed continuing growth. Both during delivery (via Caesarean section) and on repeated sonographic scans post partum the clinical diagnosis of uterine wall fibroids could be confirmed. The present case illustrates the feasibility of expectant monitoring of atypical fybroids in pregnancy. Nevertheless, a thorough sonographic monitoring as well as comprehensive counselling of the gravida is mandatory. Potentially more serious differential diagnoses (intramural pregnancy, uterine sarcoma) should be born in mind. PMID- 23108968 TI - [Thyreotoxicosis in early pregnancy with partial cystic mole--a case report]. AB - INTRODUCTION: With an incidence of 1:2,000-1:3,000 in Europe, mole pregnancy is rare. Partial mole is a benign form of gestational trophoblastic disease in which triploidy is thought to be caused by the insemination of an ovum by 2 sperms. A vital embryo is often dystrophic and growth retarded. The disease can present with vaginal bleeding, secondary anaemia, jaundice, signs of gestosis, as well as hyperthyroidism. CASE HISTORY: A 29-year-old, 2G1P, visited our hospital in the 13+3 week of gestation for first -trimester screening of trisomy 21. The patient was re-appointed for an ultrasound scan at 16 weeks of gestation to follow-up the appearance of a -cystic, hyperplasic placenta and minimal foetal pericardial effusion. She appeared at the 15+1 week gestation with acute upper abdominal pain, -tachycardia, hypertension (up to 160/100 mmHg) and double elevated liver enzymes. The performed ultrasound scan revealed a hydratiform placenta along with symmetrical foetal intrauterine growth retardation (IUGR). A cytogenetic examination revealed a triploidy (69, XXY). beta-hCG-values approximated 2,225,000 IU/L. Due to the severe progression of hyperthyroid symptoms (TSH<0.1 mU/L and fT4 29.6 pmol/L) and the poor foetal prognosis, abortion was induced with intravaginal supplements of gemeprost after cervical priming with mifepriston. Hyperthyroidism symptoms were managed with methizol and propanolol. The clinical situation improved rapidly following the expulsion of all foetal tissues. Histopathology of all aborted specimens verified the suspected diagnosis of partial mole including a slightly dystrophic fetus. Patient follow-up did not reveal any further pathology of the thyroid nor of the cardiopulmonary situation. beta-hCH values sank to below detection levels after 12 weeks. CONCLUSIONS: Gestational trophoblastic disease should be considered in the differential diagnosis when acute onset of symptoms pointing to hyperthyroidism occurs in women of child-bearing age. PMID- 23108971 TI - Mikko Hallman--a major translator of basic science into neonatal medicine. PMID- 23108972 TI - Syntheses and applications of monofluorinated cyclopropanes. AB - The combination of a fluorine atom and a cyclopropane ring, which both possess unique structural and chemical features, can generate new relevant building blocks for the discovery of efficient fluorinated biologically active agents. In this review, we report the different strategies to access monofluorocyclopropanes and highlight some of their attractive biological applications. PMID- 23108973 TI - Expression of the male reproduction-related gene in spermatic ducts of the blue swimming crab, Portunus pelagicus, and transfer of modified protein to the sperm acrosome. AB - Expression of a sex-specific gene in Macrobrachium rosenbergii (Mr-Mrr), encoding a male reproduction-related (Mrr) protein, has been identified in the spermatic ducts (SDs) and postulated to be involved in sperm maturation processes. M. rosenbergii is the only decapod that the expression and fate of the Mrr protein has been studied. To determine that this protein was conserved in decapods, we firstly used cloning techniques to identify the Mrr gene in two crabs, Portunus pelagicus (Pp-Mrr) and Scylla serrata (Ss-Mrr). We then investigated expression of Pp-Mrr by in situ hybridization, and immunolocalization, as well as phosphorylation and glycosylation modifications, and the fate of the protein in the male reproductive tract. Pp-Mrr was shown to have 632 nucleotides, and a deduced protein of 110 amino acids, with an unmodified molecular weight of 11.79 kDa and a mature protein with molecular weight of 9.16 kDa. In situ hybridization showed that Pp-Mrr is expressed in the epithelium of the proximal, middle, distal SDs, and ejaculatory ducts. In Western blotting, proteins of 10.9 and 17.2 kDa from SDs were all positive using anti-Mrr, antiphosphoserine/threonine, and antiphosphotyrosine. PAS staining showed they were also glycosylated. Immunolocalization studies showed Pp-Mrr in the SD epithelium, lumen, and on the acrosomes of spermatozoa. Immunofluorescence staining indicated the acrosome of spermatozoa contained the Mrr protein, which is phosphorylated with serine/threonine and tyrosine, and also glycosylated. The Mrr is likely to be involved in acrosomal activation during fertilization of eggs. PMID- 23108974 TI - Psychotic symptoms in adolescence index risk for suicidal behavior: findings from 2 population-based case-control clinical interview studies. AB - CONTEXT Recent evidence from both clinical and population research has pointed to psychotic symptoms as potentially important markers of risk for suicidal behavior. However, to our knowledge, there have been no epidemiological studies to date that have reported data on psychotic symptoms and suicidality in individuals who have been clinically assessed for suicidal behavior. OBJECTIVES To explore associations between psychotic symptoms in nonpsychotic adolescents and risk for suicidal behavior in (1) the general population, (2) adolescents with psychiatric disorder, and (3) adolescents with suicidal ideation. DESIGN Two independently conducted case-control clinical interview studies. SETTING Population-based studies in Ireland. PARTICIPANTS Study 1 included 212 adolescents aged 11 to 13 years. Study 2 included 211 adolescents aged 13 to 15 years. Participants were recruited from schools. MAIN OUTCOME MEASURES Suicidal behavior and psychotic symptoms, assessed by semi-structured diagnostic clinical interview. RESULTS Psychotic symptoms were associated with a 10-fold increased odds of any suicidal behavior (ideation, plans, or acts) in both the early and middle adolescence studies (odds ratio [OR], 10.23; 95% CI, 3.25-32.26; P < .001 and OR, 10.5; 95% CI, 3.14-35.17; P < .001, respectively). Adolescents with depressive disorders who also experienced psychotic symptoms were at a nearly 14 fold increased odds of more severe suicidal behavior (suicide plans and suicide acts) compared with adolescents with depressive disorders who did not experience psychotic symptoms (OR, 13.7; 95% CI, 2.1-89.6). Among all adolescents with suicidal ideation, those who also reported psychotic symptoms had a nearly 20 fold increased odds of suicide plans and suicide acts compared with adolescents with suicidal ideation who did not report psychotic symptoms (OR, 19.6; 95% CI, 1.8-216.1). CONCLUSIONS Psychotic symptoms are strongly associated with increased risk for suicidal behavior in the general adolescent population and in adolescents with (nonpsychotic) psychiatric disorder. In both studies, an absolute majority of adolescents with more severe suicidal behavior (suicidal plans and acts) reported psychotic symptoms when directly questioned about this as part of a psychiatric interview. Assessment of psychotic symptoms should form a key part of suicide risk assessment. PMID- 23108975 TI - Plasma-enabled graded nanotube biosensing arrays on a Si nanodevice platform: catalyst-free integration and in situ detection of nucleation events. AB - Low-temperature plasmas in direct contact with arbitrary, written linear features on a Si wafer enable catalyst-free integration of carbon nanotubes into a Si based nanodevice platform and in situ resolution of individual nucleation events. The graded nanotube arrays show reliable, reproducible, and competitive performance in electron field emission and biosensing nanodevices. PMID- 23108976 TI - Fathers' mental health as a protective factor in the relationship between maternal and child depressive symptoms. AB - BACKGROUND: The relationship between parental and child depressive symptoms has been found to be stronger for mothers than for fathers. Does this mean that fathers' mental health is less important in the context of child depressive symptoms? The goal of the current study is to test whether the degree of fathers' depressive symptoms moderate the relationship between mothers' and children's depressive symptoms. Our knowledge about such interaction effects between mothers' and fathers' symptoms is limited. METHODS: We examined depressive symptoms in 190 children (age 7-13, 118 boys) referred to child community clinics and their parents. Mothers and fathers reported on their own and their child's depressive symptoms, whereas children only reported on their own symptoms. RESULTS: Structural equation modeling revealed significant interaction effects of mothers' and fathers' depressive symptoms on mother- and father-reported child depressive symptoms, while no effects were found for child reports. When fathers reported few depressive symptoms for themselves, no relationship between mothers' and children's depressive symptoms was observed. The more depressive symptoms in fathers, the stronger the relationship between mothers' and children's symptoms. CONCLUSIONS: Fathers' mental health may be a protective factor in the relationship between mothers' and children's depressive symptoms. Thus, researchers and practitioners would benefit from considering not only depressive symptoms in mothers, but also in fathers, when examining and working with child depressive symptoms. PMID- 23108977 TI - Immunolocalization of keratin-associated beta-proteins in developing epidermis of lizard suggests that adhesive setae contain glycine--cysteine-rich proteins. AB - The localization of specific keratin-associated beta-proteins (formerly referred to as beta-keratins) in the embryonic epidermis of lizards is not known. Two specific keratin-associated beta-proteins of the epidermis, one representing the glycine-rich subfamily (HgG5) and the other the glycine-cysteine medium-rich subfamily (HgGC10), have been immunolocalized at the ultrastructural level in the lizard Anolis lineatopus. The periderm and granulated subperiderm are most immunonegative for these proteins. HgG5 is low to absent in theOberhautchen layer while is present in the forming beta-layer, and disappears in mesos- and alpha layers. Instead, HgGC10 is present in the Oberhautchen, beta-, and also in the following alpha-layers, and specifically accumulates in the developing adhesive setae but not in the surrounding cells of the clear layer. Therefore, setae and their terminal spatulae that adhere to surfaces allowing these lizards to walk vertically contain cysteine-glycine rich proteins. The study suggests that, like in adult and regenerating epidermis, the HgGC10 protein is not only accumulated in cells of the beta-layer but also in those forming the alpha-layer. This small protein therefore is implicated in resistance, flexibility, and stretching of the epidermal layers. It is also hypothesized that the charges of these proteins may influence adhesion of the setae of pad lamellae. Conversely, glycine-rich beta proteins like HgG5 give rise to the dense, hydrophobic, and chromophobic corneous material of the resistant beta-layer. This result suggests that the differential accumulation of keratin-associated beta-proteins over the alpha-keratin network determines differences in properties of the stratified layers of the epidermis of lizards. PMID- 23108978 TI - Photoinduced fluorescence activation and nitric oxide release with biocompatible polymer nanoparticles. AB - A viable strategy to encapsulate a fluorophore/photochrome dyad and a nitric oxide photodonor within supramolecular assemblies of a cyclodextrin-based polymer in water was developed. The two photoresponsive guests do not interact with each other within their supramolecular container and can be operated in parallel under optical control. Specifically, the dyad permits the reversible switching of fluorescence on a microsecond timescale for hundreds of cycles, and the photodonor enables the irreversible release of nitric oxide. Furthermore, these supramolecular assemblies cross the membrane of human melanoma cancer cells and transport their cargo in the cytosol. The fluorescence of one component allows the visualization of the labeled cells, and its switchable character could, in principle, be used to acquire super-resolution images, while the release of nitric oxide from the other induces significant cell mortality. Thus, our design logic for the construction of biocompatible nanoparticles with dual functionality might evolve into the realization of valuable photoresponsive probes for imaging and therapeutic applications. PMID- 23108979 TI - Ethyl acetate: X-ray, solvent and computed structures. AB - Ethyl acetate (ethyl ethanoate) was crystallized in situ and the crystal structure was determined. In the solid, the molecule is flat with trans conformation. The geometric details of ethyl acetate as a solvate are analyzed statistically using the Cambridge Structural Database, uncovering a high degree of hidden disorder. Despite the disorder, they exhibit a preference of the trans over the gauche isomer, with a negligible contribution of the cis isomer. These results are compared to ab initio calculations on both solid-state and molecular level. For the molecular structures, the computed energy differences of the isomers match the statistics found as a solvent. Several DFT-D2 methods used to calculate the solid state yield results that differ significantly from the experiment. PMID- 23108980 TI - Determination of perfluorinated compounds in aquatic organisms: a review. AB - Bioaccumulation of PFAS in aquatic organisms is an environmental problem of growing concern around the world. This problem has been tackled by regulatory bodies by proposing EQS for biota in EU water bodies and tolerable daily intake for food. The introduction of regulatory limits requires the availability of harmonised and validated analytical methods of sufficient sensitivity. This paper reviews recent advances in analytical methods for analysis of PFAS in aquatic organisms. The methods available for biota analysis are mostly based on three extraction procedures: ion-pair extraction, solvent liquid extraction, and alkaline digestion. The resulting extracts are then subjected to different clean up or enrichment steps on solid adsorbents, for example graphitized carbon black, C(18), and WAX phases. All methods reviewed in this work give reliable results but are partially validated only, because of the lack of certified reference materials and regular interlaboratory exercises. The few interlaboratory exercises performed on real unspiked samples did not afford satisfactory results for PFAS other than PFOS, especially for matrices with high lipid content, for example mussels. The reasons for those partially negative results have been identified, and can mainly be attributed to calibration procedures and availability and purity of standards. The urgent need for certified reference materials for this type of analysis is emphasized. PMID- 23108981 TI - Comparing beneficial effects of inhaled nitric oxide to L-arginine in necrotizing enterocolitis model in neonatal rats. AB - OBJECTIVE: Necrotizing enterocolitis (NEC) is a common and devastating gastrointestinal condition of neonatal infants. The pathophysiology of NEC remains poorly understood. We tried to evaluate the effectiveness of inhaled NO compared to L-arginine usage in necrotizing enterocolitis model in rats. MATERIAL METHODS: 46 newborn pups from 4 time-mated Sprague-Dawley pregnant rats were divided equally into 4 groups as follows: NEC (subjected to NEC), NEC + L arginine, NEC + inhaled NO and control. RESULTS: SOD, GSH-Px and NOx levels were significantly higher and MDA levels were significantly lower in NEC + inhaled NO group compared to NEC + L-arginine group. There was significantly lower intestinal injury and apoptosis index scoring in NEC + inhaled NO group compared to NEC + L-arginine group. CONCLUSION: We think that inhaled NO can be used as a novel therapeutic agent like L-arginine in NEC, like using in pulmonary hypertention in newborns but much more studies are needed. PMID- 23108982 TI - Development of a novel approach to safely couple the intestine to a distraction induced device for intestinal growth: use of reconstructive tissue matrix. AB - BACKGROUND: Distraction-induced intestinal growth may be a novel treatment for short bowel syndrome. Longitudinal, distractive tension created by the application of force creates a significant challenge: to produce adequate force, yet not cause perforation at the fixation points. This paper describes our development of a coupling strategy to allow for successful bowel lengthening. METHODS: A curvilinear hydraulic device was implanted in an isolated Roux limb of small bowel in young Yorkshire pigs. Bowel was lengthened over a 2-week period. Study groups included: Group 1: Twelve silk transmural anchoring sutures into an engineered-coupling ring at the ends of each device. Group 2: Addition of felt pledgets to the coupling rings on the serosal surface of the small bowel. Group 3: Extraluminal use of either thin AlloDerm((r)), thick AlloDerm((r)), or StratticeTM mesh to anchor the device. RESULTS: Group 1 (suture-only) resulted in a gradual pulling through the suture with increasing tension and no lengthening. Felt pledgets eroded in a similar fashion, causing abdominal sepsis. Thin AlloDerm((r)) failed to prevent erosion; however, it protected against gross contamination. Animals in which either thick AlloDerm((r)) or StratticeTM mesh was used survived complication free to the study endpoint. Both thick AlloDerm((r)) and StratticeTM prevented erosion and perforation allowing for an average of 10.85 cm expansion. CONCLUSION: This study demonstrates the use of either thick AlloDerm((r)) or StratticeTM reconstructive tissue matrix which allows for safe and effective coupling. Further, we suggest this approach could be an adjunct to esophageal lengthening procedures. PMID- 23108983 TI - Simultaneous determination of sunitinib and its two metabolites in plasma of Chinese patients with metastatic renal cell carcinoma by liquid chromatography tandem mass spectrometry. AB - A simple and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of sunitinib and its two metabolites in plasma of Chinese patients with metastatic renal cell carcinoma (mRCC). After simple one-step protein precipitation with methanol-acetonitrile (1:1, v/v), all three analytes were separated on an Agilent Zorbax SB-C(18) column using a gradient mobile phase consisting of water (0.1% formic acid)-acetonitrile (0.1% formic acid) at a flow rate of 0.50 mL/min. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 399.0 -> 326.2, m/z 371.0 -> 283.1, m/z 343.0 -> 283.1 and m/z 386.3 -> 122.2 for sunitinib, M1, M2 and buspirone, respectively. The method was linear over the range of 0.10-100 ng/mL for all three analytes using only 50 MUL of plasma and the lower limit of quantifications for the three analytes were all 0.10 ng/mL. The intra-day and inter-day precisions were all less than 15% and the accuracies were within the range of +/-15%; recoveries were between 85.0 and 115%. The validated method was successfully applied to an explorative pharmacokinetic study of sunitinib in Chinese patients with mRCC following multi dose oral administration. PMID- 23108984 TI - Care of patients with apparently asymptomatic severe aortic valve stenosis. AB - Although most asymptomatic patients with aortic stenosis (AS) have an excellent prognosis with observation only, some patients with severely stenotic aortic valves in the absence of symptoms may benefit from early intervention. In this article, we will review the literature on the use of varied imaging modalities, clinical factors, and biomarker testing to risk stratify such patients. Additionally, we will review the role of medical therapy to modify the course in AS. PMID- 23108987 TI - Brief report: an unusual manifestation of diagnostic overshadowing of pervasive developmental disorder--not otherwise specified: a five year longitudinal case study. AB - Children with communication disorders present with a range of comorbid conditions. Occasionally one of the comorbid conditions manifests so strongly that the primary condition goes unnoticed by the clinician. This tendency to overlook comorbid health problems in the presence of a disability is referred to as diagnostic overshadowing. This is a five-year follow up case study of a 9-year old female child. The child was initially diagnosed to have Separation anxiety disorder (SAD), but during the course of follow up she began to exhibit features of pervasive developmental disorder-not otherwise specified (PDD-NOS). This case report throws light on the severity of SAD which overshadowed PDD-NOS. Importance of follow-up and the need for a multidisciplinary team to be sensitive to the phenomenon of diagnostic overshadowing is discussed. PMID- 23108985 TI - Suggestion of GLYAT gene underlying variation of bone size and body lean mass as revealed by a bivariate genome-wide association study. AB - Bone and muscle, two major tissue types of musculoskeletal system, have strong genetic determination. Abnormality in bone and/or muscle may cause musculoskeletal diseases such as osteoporosis and sarcopenia. Bone size phenotypes (BSPs), such as hip bone size (HBS), appendicular bone size (ABS), are genetically correlated with body lean mass (mainly muscle mass). However, the specific genes shared by these phenotypes are largely unknown. In this study, we aimed to identify the specific genes with pleiotropic effects on BSPs and appendicular lean mass (ALM). We performed a bivariate genome-wide association study (GWAS) by analyzing ~690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) followed by a replication study in 2,286 unrelated US Caucasians (558 males and 1,728 females). We identified 14 interesting single nucleotide polymorphisms (SNPs) that may contribute to variation of both BSPs and ALM, with p values <10(-6) in discovery stage. Among them, the association of three SNPs (rs2507838, rs7116722, and rs11826261) in/near GLYAT (glycine-N acyltransferase) gene was replicated in US Caucasians, with p values ranging from 1.89 * 10(-3) to 3.71 * 10(-4) for ALM-ABS, from 5.14 * 10(-3) to 1.11 * 10(-2) for ALM-HBS, respectively. Meta-analyses yielded stronger association signals for rs2507838, rs7116722, and rs11826261, with pooled p values of 1.68 * 10(-8), 7.94 * 10(-8), 6.80 * 10(-8) for ALB-ABS and 1.22 * 10(-4), 9.85 * 10(-5), 3.96 * 10( 4) for ALM-HBS, respectively. Haplotype allele ATA based on these three SNPs was also associated with ALM-HBS and ALM-ABS in both discovery and replication samples. Interestingly, GLYAT was previously found to be essential to glucose metabolism and energy metabolism, suggesting the gene's dual role in both bone development and muscle growth. Our findings, together with the prior biological evidence, suggest the importance of GLYAT gene in co-regulation of bone phenotypes and body lean mass. PMID- 23108988 TI - Assessing recollection and familiarity in low functioning autism. AB - Methods to assess recollection and familiarity separately in autism spectrum disorder were recently developed and piloted (Bigham et al. in J Autism Dev Disord 40:878-889, 2010). The preliminary data obtained via these methods showed that whereas recollection was mildly impaired in high functioning autism, familiarity was spared. The current study set out to replicate the methods of assessment for recollection and familiarity devised by Bigham and her colleagues with individuals diagnosed with low functioning autism (LFA). Three critical modifications to the original paradigms were made within the current study. The modifications and implications of the findings for individuals with LFA will be discussed. PMID- 23108989 TI - Rationalizing the 1.9 A crystal structure of photosystem II--A remarkable Jahn Teller balancing act induced by a single proton transfer. PMID- 23108991 TI - Current evidence on the relationship between three polymorphisms in the XRCC7 gene and cancer risk. AB - Inconsistency of the association of polymorphisms of XRCC7 with cancer is noted. Three commonly studied XRCC7 polymorphisms including rs7003908 (T>G), rs7830743 (A>G), and rs10109984 (T>C) were selected to explore their association with risk of development of cancer by meta-analysis of published case-control studies. The results showed that no significant associations with cancer risk were found in any model in terms of rs7003908, rs7830743 and rs10109984 when all studies were pooled into the meta-analysis. But when stratified by cancer type, statistically significantly elevated cancer risk was only found in prostate cancer for rs7003908 (GG vs. TT: OR = 1.845, 95 % CI = 1.178-2.888; dominant model: OR = 1.423, 95 % CI = 1.050-1.929; recessive model: OR = 1.677, 95 % CI = 1.133 2.482). In the subgroup analysis by ethnicity or study design, no significantly increased risks were found for all three polymorphisms. This meta-analysis suggests that XRCC7 rs7003908 polymorphism may contribute to cancer susceptibility for prostate cancer, which is recommended to be included in future large-sample studies and functional assays. PMID- 23108992 TI - Cloning, bioinformatics and the enzyme activity analyses of a phenylalanine ammonia-lyase gene involved in dragon's blood biosynthesis in Dracaena cambodiana. AB - Phenylalanine ammonia-lyase (PAL) is the key enzyme of the phenylpropanoid pathway, playing an important role in plant development and defence. We cloned a partial cDNA of PAL gene, DcPAL1, from Dracaena cambodiana seedlings using RT-PCR with degenerate primers that were designed based on a multiple sequence alignment of known PAL genes from other plant species. DcPAL1 shows highly homologous to other known PAL genes registered in GenBank, being closest to that of Musa acuminata. DcPAL1 has a relatively high GC content and most of the GC is in the third codon position. It has 768 bp in size with a maximum open reading frame (ORF) of 765 bp, encoding a 255 amino acid-polypeptide. The deduced PAL protein is a stable protein, having classical PAL domains and consisting of three major hydrophobic domains. Analysis of effective number of codons (ENC) shows that DcPAL1 codons are used at equal frequency. Relatively higher usage frequency appears randomly in codons ended with any of the four bases; six codons have no usage bias. There are 45 codons showing distinct usage preference between DcPAL1 and E. coli, 20 between DcPAL1 and yeast. Therefore, the yeast system may be more suitable for the expression of DcPAL1. Upon the elicitation of Fusarium proliferatum, a potent elicitor of dragon's blood, the PAL enzyme activity in the leaves and stems of D. cambodiana and other two Dracaena spp. significantly increased, accompanying with the formation of dragon's blood, indicating the involvement of PAL in the biosynthesis of dragon's blood, a precious traditional medicine. PMID- 23108993 TI - Effect of ischemia post-conditioning on skeletal muscle oxidative injury, mTOR, Bax, Bcl-2 proteins expression, and HIF-1alpha/beta-actin mRNA, IL-6/beta-actin mRNA and caveolin-3/beta-actin mRNA expression in ischemia-reperfusion rabbits. AB - This study is designed to investigate the effect of ischemia post-conditioning on IR-induced skeletal muscle injury in limbs of experimental rabbits. Rabbits are randomized to one of the following three groups: sham control, ischemic reperfusion, ischemic postconditioning. The lipid peroxidation level, antioxidant enzymes activities, skeletal muscle mammalian target of rapamycin (mTOR), Bax, Bcl-2 proteins expression and Bcl-2/Bax, and HIF-1alpha/beta-actin mRNA, interleukin-6 (IL-6)/beta-actin mRNA and caveolin-3/beta-actin mRNA expression were tested in the current study. The results suggested that ischemic postconditioning might decrease lipid peroxidation level, lactic dehydrogenase (LDH), creatine kinase (CK) activities, Bcl-2 proteins expression and Bcl-2/Bax, HIF-1alpha/beta-actin mRNA expression and increase skeletal muscle antioxidant enzymes activities, Bax protein expression and IL-6/beta-actin mRNA and caveolin 3/beta-actin mRNA expression. These indicated that protective effect of ischemic postconditioning against IR-induced skeletal muscle injury involve into a complex molecular mechanism. Our research results may offer a theoretical guidance for therapy of related clinical diseases. PMID- 23108994 TI - Endothelial nitric oxide synthase gene polymorphisms and the risk of acute myocardial infarction in a South Indian population. AB - Myocardial infarction (MI) is a complex multi-factorial, polygenic disorder which results from an interaction between a person's genetic makeup and various environmental factors. Nitric oxide (NO), a potent vasodilator produced by endothelial cells, plays an important role in the regulation of blood pressure, regional blood flow and also inhibits platelet aggregation, vascular smooth muscle cell proliferation and leukocyte adhesion to vascular endothelium. Our aim was to analyze the association of NOS3 (endothelial nitric oxide synthase 3) 894G>T and -786T>C gene polymorphisms and MI risk in the South Indian population. A total of 287 MI patients, 279 risk control patients and 321 healthy controls were recruited for the retrospective study. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). There was no significant association observed between NOS3 894G>T, -786T>C polymorphisms and MI. A significant difference was observed in the distribution of GT genotype of the NOS3 894G>T polymorphism between the cases and the risk controls (p = 0.05) but the odds ratio (0.6) did not show risk for MI. The present study showed lack of association between NOS3 gene polymorphisms and MI in South Indian population. PMID- 23108995 TI - MiR-26a regulates cell cycle and anoikis of human esophageal adenocarcinoma cells through Rb1-E2F1 signaling pathway. AB - Resistance to anoikis, the subtype of apoptosis induced by lack of matrix adhesion, contributes to malignant transformation and development of metastasis. MicroRNAs play key regulatory roles in tumorigenesis and metastasis. In this study, we described that miR-26a, which is usually downregulated in tumor cells, is involved in the acquisition of anoikis-resistance of human esophageal adenocarcinoma (EA) cells. Results of qRT-PCR in clinical samples showed that downregulated miR-26a expression is related to tumorigenesis and metastasis of EA. In vitro experiments determined that miR-26a directly participates in the regulation of cell cycle and anoikis of human EA OE33 cells. Further, we identified that Rb1 is the direct functional target of miR-26a, and revealed that the reduction of miR-26a expression leads to increased Rb1 protein level and thus inhibits the function of E2F1, by which it influences the phenotypes of cell cycle and anoikis. The findings we reported here presented the evidence that miR 26a may be involved in regulation of anoikis-resistance of EA cells. Targeting miR-26a may provide a novel strategy to inhibit metastasis. PMID- 23108996 TI - Amerindians show association to obesity with adiponectin gene SNP45 and SNP276: population genetics of a food intake control and "thrifty" gene. AB - Adiponectin gene polymorphisms SNP45 and SNP276 have been related to metabolic syndrome (MS) and related pathologies, including obesity. However results of associations are contradictory depending on which population is studied. In the present study, these adiponectin SNPs are for the first time studied in Amerindians. Allele frequencies are obtained and comparison with obesity and other MS related parameters are performed. Amerindians were also defined by characteristic HLA genes. Our main results are: (1) SNP276 T is associated to low diastolic blood pressure in Amerindians, (2) SNP45 G allele is correlated with obesity in female but not in male Amerindians, (3) SNP45/SNP276 T/G haplotype in total obese/non-obese subjects tends to show a linkage with non-obese Amerindians, (4) SNP45/SNP276 T/T haplotype is linked to obese Amerindian males. Also, a world population study is carried out finding that SNP45 T and SNP276 T alleles are the most frequent in African Blacks and are found significantly in lower frequencies in Europeans and Asians. This together with the fact that there is a linkage of this haplotype to obese Amerindian males suggest that evolutionary forces related to famine (or population density in relation with available food) may have shaped world population adiponectin polymorphism frequencies. PMID- 23108997 TI - Removal of user fees for caesareans and under-fives in northern Sudan: a review of policy implementation and effectiveness. AB - In 2008, the Government of Sudan launched a policy of free curative care for under-fives and caesareans. This paper presents the findings of a review of this policy, on the basis of research conducted in five focal states of northern Sudan in 2010. Policy implementation was assessed using four research tools: key informant interviews, exit interviews, a facility survey, and analysis of facility finances and the cost of the package of care. The findings point to important weaknesses in implementation, such as unclear specification of the exact target group and package of care and inadequate funding. Despite this, service utilisation appears to have responded, at least in the short term. The findings also highlight the urgent need for improved access to basic health care and financial protection against health care costs in northern Sudan (for those with and without national health insurance membership). This review contributes to the growing literature on the selective removal of user fees for priority services. It indicates the range of challenges to effective implementation (strategic, financial and organisational). Some of these are particular to Sudan, but many are shared, and indicate important lessons for improving access to and quality of care for women and children in Africa. PMID- 23108998 TI - An indium-free low work function window electrode for organic photovoltaics which improves with in-situ oxidation. AB - A low-cost window electrode for organic photovoltaics that simultaneously removes the requirement for conducting oxide and conventional low work function electrodes and functions as a sink for oxygen/water in the heart of the device. Remarkably the functionality of this electrode, which is based on a 7.8 nm nanostructured Cu:Al film, improves upon in situ oxidation as demonstrated in bulk heterojunction organic photovoltaics. PMID- 23108999 TI - Gape size, its morphological basis, and the validity of gape indices in western diamond-backed rattlesnakes (Crotalus atrox). AB - Maximum gape is important to the ecology and evolution of many vertebrates, particularly gape-limited predators, because it can restrict the sizes and shapes of prey that can be eaten. Although many cranial elements probably contribute to gape, it is typically estimated from jaw length or jaw width, or occasionally from a combination of these two measures. We measured maximum gape directly for 18 individuals of the western diamond-backed rattlesnake, Crotalus atrox. We measured each individual's body length, several external cranial dimensions, several cranial osteological dimensions from cleaned skeletons, and we calculated gape index values from two published gape indices (GI). Cranial bone lengths and gape circumference showed negative allometry with snout-vent length (SVL), indicating that small individuals have relatively larger heads and gapes than their larger conspecifics. We then used Akaike's Information Criterion to determine which external and osteological measurements were the best predictors of gape. Body size (SVL) was the best predictor of maximum gape overall; however, when SVL was excluded from the analysis, quadrate (QL) and mandible lengths (MdLs) were the best predictors of maximum gape using both external and osteological measurements. Quadrate length probably contributes directly to gape; however, the importance of MdL to gape is less clear and may be due largely to its allometric relationships with head length and SVL. The two published GI did not prove to be better indicators of actual gape than the jaw and QLs in this study, and the gape values they produced differed significantly from our empirically determined gapes. For these reasons, we urge caution with the use and interpretation of computed GI in future studies. The extensive variation in quadrate and mandible morphology among lineages suggest that these bones are more important to variation in gape among species and lineages than within a single species. PMID- 23109000 TI - Are the ADA hemoglobin A(1c) criteria relevant for the diagnosis of type 2 diabetes in youth? AB - Diagnostic criteria for diabetes in children have not been established with nearly the rigor as that employed in adults. Recently revised American Diabetes Association (ADA) criteria allowed utilization of hemoglobin A(1c) (HbA1c) >= 6.5 % for diagnosis of diabetes. A recent series of pediatric studies appear to show that HbA1c has lower sensitivity than Fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT). However, FPG and OGTT have themselves never been validated in children. Studies to validate diagnostic thresholds in children appear unlikely to take place. Thus, accepting the major ADA diagnostic criteria appears to be the best course of action for the pediatric community. One area in which correlation studies between HbA1c and FPG or OGTT might shed light is in the definition of criteria for intervention in 'pre-diabetes,' as the Diabetes Prevention Program Trial did not use HbA1c. However, such treatment, and the exact diagnostic thresholds at which it should be initiated in children, remains unproven. PMID- 23109001 TI - Oral biofilm formation on the titanium and zirconia substrates. AB - OBJECTIVE: The aim of this randomized crossover investigation was to assess the biofilm formation on two titanium and one zirconia substrates in relation to the topography and surface roughness of the materials. METHODS: Twenty-four discs specimens for each evaluated material (Machined pure titanium, Cast pure titanium, or Zirconia) were evaluated after oral cavity exposure in six healthy subjects. The study was conducted in 3 phases according to the material evaluated. Each subject was asked to use a removable splint containing 4 disks of the same tested substrate, 2 located in the anterior, and 2 in the posterior region. Participants were asked to use the intraoral splint during 24 h. The total biofilm covering on the discs was evaluated by 1% of neutral red staining. EMV and surface roughness was carried out to correlate with the biofilm found between different substrates. RESULTS: Data showed higher mean roughness values for zirconia (Zc) when compared with titanium specimens (MPT and CPT; P < 0.001). MPT and CPT presented no differences between them (P > 0.05). The mean percentage (%) of covering biofilm on substrates was 84.14 for MPT, 86.22 for CPT and 90.90 for Zc. CONCLUSION: There were no significant differences in the total area of formed biofilm among the tested groups. No correlation was found between surface roughness and the total amount of formed biofilm in the groups. PMID- 23109002 TI - The effect of draft DSM-V criteria on posttraumatic stress disorder prevalence. AB - BACKGROUND: This study was designed to examine the concordance of proposed DSM-V posttraumatic stress disorder (PTSD) criteria with DSM-IV classification rules and examine the impact of the proposed DSM-V PTSD criteria on prevalence. METHOD: The sample (N = 185) included participants who were recruited for studies focused on trauma and health conducted at an academic medical center and VA medical center in the southeastern United States. The prevalence and concordance between DSM-IV and the proposed DSM-V classifications were calculated based on results from structured clinical interviews. Prevalence rates and diagnostic efficiency indices including sensitivity, specificity, area under the curve (AUC), and Kappa were calculated for each of the possible ways to define DSM-V PTSD. RESULTS: Ninety-five percent of the sample reported an event that met both DSM-IV PTSD Criterion A1 and A2, but only 89% reported a trauma that met Criterion A on DSM V. Results examining concordance between DSM-IV and DSM-V algorithms indicated that several of the algorithms had AUCs above 0.90. The requirement of two symptoms from both Clusters D and E provided strong concordance to DSM-IV (AUC = 0.93; Kappa = 0.86) and a greater balance between sensitivity and specificity than requiring three symptoms in both Clusters D and E. CONCLUSIONS: Despite several significant changes to the diagnostic criteria for PTSD for DSM-V, several possible classification rules provided good concordance with DSM-IV. The magnitude of the impact of DSM-V decision rules on prevalence will be largely affected by the DSM-IV PTSD base rate in the population of interest. PMID- 23109004 TI - Antiretroviral molecules and cardiovascular diseases. AB - Antiretroviral therapy has effectively tackled HIV replication and prevented the development of AIDS-related complications in the majority of HIV-positive patients. This pharmacological approach has dramatically increased the life expectancy of HIV-positive subjects transforming HIV infection into a chronic disease. Notwithstanding this major improvement in HIV disease management, several HIV-positive patients show an earlier and significant onset of aging related chronic conditions such as cardiovascular disease, osteoporosis, diabetes and neoplasias with respect to uninfected individuals. In particular, cardiovascular diseases are associated with both HIV infection and antiretroviral treatment, and represent major clinical complications in HIV-positive patients. Here, we discuss the interaction between antiretroviral therapy and cardiovascular system in HIV-positive patients focusing on the antiretroviral related mechanisms involved in cardiovascular alterations. PMID- 23109003 TI - A flexible docking approach for prediction of T cell receptor-peptide-MHC complexes. AB - T cell receptors (TCRs) are immune proteins that specifically bind to antigenic molecules, which are often foreign peptides presented by major histocompatibility complex proteins (pMHCs), playing a key role in the cellular immune response. To advance our understanding and modeling of this dynamic immunological event, we assembled a protein-protein docking benchmark consisting of 20 structures of crystallized TCR/pMHC complexes for which unbound structures exist for both TCR and pMHC. We used our benchmark to compare predictive performance using several flexible and rigid backbone TCR/pMHC docking protocols. Our flexible TCR docking algorithm, TCRFlexDock, improved predictive success over the fixed backbone protocol, leading to near-native predictions for 80% of the TCR/pMHC cases among the top 10 models, and 100% of the cases in the top 30 models. We then applied TCRFlexDock to predict the two distinct docking modes recently described for a single TCR bound to two different antigens, and tested several protein modeling scoring functions for prediction of TCR/pMHC binding affinities. This algorithm and benchmark should enable future efforts to predict, and design of uncharacterized TCR/pMHC complexes. PMID- 23109005 TI - HIV-1 non-B subtypes in Italy: a growing trend. AB - Sequence analysis plays an important role in the management of patients chronically infected with HIV-1. Knowledge of the viral genotype and drug resistance mutations is crucial for the correct management of these patients. From this point of view, the experience of researchers in the HIV-1 field and the introduction of the HIV-1 genotyping resistance test has been fundamental. Several molecular tools are available to assist the provider in interpreting genotypic test results including phylogenetics. However, it should be remembered that antiretroviral drug designs, resistance studies and interpretation systems have been largely based on HIV-1 subtype B, which has been historically the most prevalent subtype in Western countries. Due to increased migration towards Europe, especially from Africa and South- East Asia, the molecular epidemiology of HIV-1 in Western Europe, including Italy, is changing. HIV-1 non-B subtypes have entered Europe and their prevalence has increased over the last years. In Italy, the estimated percentage of infection with non-B subtypes ranges from 2.4 % to 19.4%. However, the true prevalence of HIV-1 non-B subtypes in this country is still not well known and probably underestimated. This may have important clinical and diagnostic implications. A strict molecular epidemiological survey and a reinforced sequencing strategy are required. PMID- 23109006 TI - New therapeutic options for HCV infection in the monoclonal antibody era. AB - Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease and the most common indication for liver transplantation. Current therapies are ineffective in a relevant percentage of patients raising the urgent medical need to develop adequate therapies for this infection. Broadly neutralizing human monoclonal antibodies (mAbs) directed against the HCV E2 glycoprotein (HCV/E2), the major target of the neutralizing humoral immune response, are considered as a possible novel therapeutic strategy for this infection. In the last few years, several anti-HCV/E2 human mAbs have been described in literature to be possibly used for therapeutic or prophylactic purposes. In this review, we illustrate the best candidates for an anti-HCV mAb-based therapy, considering their cross neutralization profiles and their ability to overcome possible viral escape mechanisms. PMID- 23109007 TI - Broad-range neutralizing anti-influenza A human monoclonal antibodies: new perspectives in therapy and prophylaxis. AB - Broadly neutralizing monoclonal antibodies (mAbs) directed against different subtypes of influenza A viruses are novel tools for the potential development of effective anti-influenza prophylactic and therapeutic strategies. In both cases, the main candidates for passive transfer and new vaccine development are represented by protective mAbs directed against influenza hemagglutinin (HA). A large number of mAbs directed against influenza HA has been developed to date. However, even if they can be useful and contribute to develop new vaccinal strategies, only few of them can be a good candidate for human administration. In this review, we will describe the most relevant human mAb directed against influenza HA able to recognize highly divergent influenza isolates and possibly useful for human therapy and prophylaxis. PMID- 23109008 TI - Recent and long-lasting infections: the need for avidity testing in HIV-1 infected subjects. AB - Standard serological tests have reached high levels of sensitivity and reproducibility but do not indicate whether infection is recent or long-standing. Among the 59960 sera analyzed for HIV positivity at the Retrovirus Laboratory, Operative Unit of Microbiology, Bologna, Italy, from January 2010 to July 2011, 134 samples showed an initial positive result. Application of the avidity test, able to distinguish between recent or long-standing HIV infection, classified 59 subjects as recently infected and 75 as chronically infected. Besides all the public health implications, the distinction between acute and chronic infection might serve to establish the time of infection and therefore reach any potential partners who might have been infected in a specific period of time. Although our results are limited to subjects referred to our laboratory and hence represent only a limited part of the problem, the routine application of methods able to distinguish recent from long-lasting infection could help monitor disease incidence, identify high-risk groups, and enhance epidemiological conclusions. PMID- 23109009 TI - Molecular characterization analysis of the outer protein layer (VP7) from human rotavirus A genotype G1 isolate identified in Iran: implications for vaccine development. AB - The full open reading frame of the outer protein layer VP7 from an isolate of human rotavirus identified in 2010 in an Iranian child admitted to hospital with gastroenteritis was amplified from a clinical stool specimen and subjected to molecular characterization. Genetic and phylogenetic analyses indicated that the analyzed gene falls into the G1 genotype forming a sub-cluster with sequences recently identified in Iran and geographically distant countries. Such results were confirmed by protein sequence alignment, showing a highly conserved "G1 like?? amino acid sequence pattern within the known three main immunodominant regions. These results are extremely relevant in a perspective of vaccine development. Indeed, the present study confirms that the A group G1 genotype is the most prevalent Rotavirus circulating in Iran and supports the development of G1 genotype-based rotavirus vaccine for this country. PMID- 23109010 TI - Incidence and risk factors for central vascular catheter-related bloodstream infections in a tertiary care hospital. AB - This study evaluated the incidence of colonization and infection related to Central Vascular Catheters (CVC) in a tertiary care Greek hospital, as well as risk factors associated with catheter-related bloodstream infection (CRBSI). A total of 340 CVCs, were studied in relation to patient clinical and epidemiological data, CVC characteristics, and microbiological culture results. Risk factors were assessed. Pulsed field gel electrophoresis was used for the investigation of the clonal relationship of the isolates. The incidence for CRBSI and catheter colonization (CC) was 11.47 and 19.49 per 1,000 catheter days, respectively. Risk factors independently associated with CRBSI were use of corticosteroids, diabetes mellitus, solid organ neoplasm, long duration of catheterization, and changing the CVC dressing at intervals of 48 hours or more. Risk factors for CC were diabetes mellitus, hospitalization in ICU, and prolonged hospitalization. The predominant microorganisms isolated from CRBSI episodes were coagulase-negative staphylococci. All patients with CVC require constant infection surveillance and appropriate care by trained medical staff. Use of CVC for the shortest time possible, good hand hygiene and change of CVC dressing at intervals of less than 48 hours are infection prevention practices that need to be followed. PMID- 23109011 TI - Antibiotic susceptibility of vancomyin and nitrofurantoin in Staphylococcus aureus isolated from burnt patients in Sulaimaniyah, Iraqi Kurdistan. AB - Burns remain a significant public health problem in terms of morbidity and mortality throughout the world, especially in low and middle-income countries. Burning raptures the skin barriers that normally prevent invasion by microorganisms and infection is a major complication in burn patients. Methicillin resistant Staphylococcus aureus (MRSA) is the most important nosocomial pathogen. This retrospective analysis was conducted in the burn unit of the Department of Microbiology in the Sulamaini Plastic Surgery and Burns Hospital. The analysis is based on data collected from the medical records of 2938 burn patients, hospitalized between May 2008 and December 2011. The clinical samples were taken from various body sources for microbiological tests. Patients with a high percentage of total body surface area burnt (P<0.001) and a longer hospital stay (P<0.001) were more likely to have infection compared to other patients. In addition, among all tested antibiotics, vancomycin and nitrofurantion seem to be the most effective antibiotics for MR- SA. Furthermore there was a significant association between age and antibiotic resistance for all antibiotics except for vancomycin and nitrofurantoin. Resistance to antibiotics increased with advancing age. The wide use of antibiotics in the treatment of bacterial infections has probably led to the emergence and spread of resistant strains. Routine microbiological surveillance and careful in vitro testing prior to antibiotic use and strict adherence to hospital antibiotic policy may help in the prevention and treatment of antibiotic resistant pathogens in burn infections. PMID- 23109012 TI - Prediction of the pho regulon in Streptomyces clavuligerus DSM 738. AB - Negative control of clavulanic acid by phosphate in Streptomyces clavuligerus DSM 738 suggests that a pho regulon may exist in this bacterium. S. clavuligerus PhoP was expressed with a C-terminal His-tag in Escherichia coli and purified. Binding of PhoP-His 6 to promoter fragments of phoRP/phoU and pstS was demonstrated in gel retardation experiments. These fragments contained direct 11 bp repeats resembling PHO boxes. The tentative consensus sequence, GKTCRHBBNSV, was used to search other potential PhoP target genes in the genomic sequence of S. clavuligerus. In total, the putative PHO binding sequence was found in promoter regions of 31 S. clavuligerus genes. Binding of PhoP- His 6 to the PHO box present in the promoter region of the phosphate transporter gene SSCG_07547 of S. clavuligerus was demonstrated. Furthermore, it was shown by real time PCR that decreased concentrations of phosphate do affect increased expressions of genes to which PhoP binds. These findings confirm that a pho regulon exists in S. clavuligerus. PMID- 23109013 TI - Candidemia: species involved, virulence factors and antimycotic susceptibility. AB - We investigate the characteristics of the Candida species involved in BSI episodes in our Institute, their phospholipase and protease activity and the susceptibility pattern towards the main antifungal agents currently available. From January 2009 to December 2010 we documented a total of 59 episodes of candidemia. The incidence of candidemia was 32% in General Surgery, 22% in the Intensive Care Unit (ICU), 13% in Oncology and 10% in Gastroenterology. C. albicans was the most common species (32 cases=48%), followed by C. glabrata (17 cases=26%) and C. parapsilosis (12 cases=18%), a significant production of phospholipase in all strains of C. albicans was detected. Among Candida non albicans species, the production of this enzyme only occurred in 1/12 strains of C. parapsilosis. The expression acid protease production was detected in 48% of C. albicans and no strains of Candida non-albicans. All species of Candida were susceptible to amphotericin B. The rate of susceptibility to fluconazole was 100% for albicans and C. parapsilosis. Decreased susceptibility to fluconazole was mostly seen with C. glabrata, which was 76.5% susceptible in a dose-dependent manner. The echinocandins showed a good performance for C. albicans, and maintained a good MIC distribution in C. glabrata. PMID- 23109014 TI - HAART simplification with lopinavir/ritonavir monotherapy in HIV/HCV co-infected patients starting anti-HCV treatment: a randomised pilot study (KaMon study). AB - The aim of this randomised, prospective, open-label, multicentre pilot clinical trial was to compare the 48-week toxicity profile of lopinavir/ritonavir (LPV/r) monotherapy with LPV/r-based HAART (KaMon = Kaletra monotherapy) in HIV/HCV patients undergoing HCV treatment. The study involved 30 HIV/HCV co-infected patients naive to anti- HCV therapy. One patient in each arm (6.7%) discontinued anti-HCV therapy because of adverse events. There were no significant between group differences in terms of the proportion of patients experiencing AEs (p=0.999) or the number of grade 3-4 AEs (p=0.146). No HIV failure was observed. The safety profile of LPV/r monotherapy was similar to that of LPV/r-based HAART, thus encouraging HAART simplification in patients receiving anti-HCV treatment. PMID- 23109015 TI - Neutralization activity and kinetics of two broad-range human monoclonal IgG1 derived from recombinant Fab fragments and directed against Hepatitis C virus E2 glycoprotein. AB - Hepatitis C virus (HCV) is the major cause of chronic liver disease worldwide. There is evidence that neutralizing anti-HCV antibodies may find potential applications in novel prophylactic and therapeutic strategies. This paper describes the very high neutralization activity and unique biological features of two broadly cross-reactive and cross-neutralizing anti-HCV human monoclonal IgG1 derived from human monoclonal recombinant Fab fragments. PMID- 23109016 TI - Iron-mediated regulation of metalloprotease VvpE production in Vibrio vulnificus. AB - In Vibrio vulnificus, the production of metalloprotease VvpE is controlled by Crp (cAMP-receptor protein) and SmcR (a quorum sensing regulator) at the transcription level, and by PilD-mediated type II general secretion system (TTGSS) at the extracellular secretion level. Iron is known to stimulate VvpE production but the related mechanisms remain unidentified. Iron stimulated vvpE transcription and extracellular VvpE production even in the background with a crp and/or smcR mutation. Iron stimulated the transcription of pilD encoding an essential element of TTGSS. Therefore, iron seems to stimulate vvpE transcription through factor(s) other than Crp and SmcR, and to facilitate extracellular VvpE production by increasing the activity of TTGSS. PMID- 23109017 TI - The heptide repeat 2 and upstream region of TGEV induces potent cross neutralizing antibodies against group I coronaviruses. AB - The coronavirus heptide repeat (HR) region in the spike protein induces neutralizing antibodies that block the postfusion core formation and inhibit virus entry into target cells. The HR2 regions for coronaviruses of the same serogroup share high homology. We found that polyclonal antibodies derived from transmissible gastroenteritis coronavirus HR2 and upstream region were cross reactive with the S proteins of the same serogroup in western blotting. The polyclonal antibodies also potently cross-neutralized viruses from the same serogroup. This study provides new insight for designing vaccine and therapeutic reagents against coronavirus infections. PMID- 23109018 TI - Comparison of different methods for determining beta-lactam susceptibility in Pseudomonas aeruginosa. AB - This study compared the results of antimicrobial susceptibility testing of 77 clinical strains isolated for Pseudomonas aeruginosa to five beta-lactam agents: aztreonam, ceftazidime, imipenem, meropenem and piperacillin+tazobactam. Four different methods were employed: two automated systems (VITEK 2 and Sensititre) and two standardized manual methods (Kirby-Bauer and E-test). The concordances for the susceptibility categories were better for Kirby-Bauer (medium value =89.6%), followed by Sensititre (medium value =87.0%) and VITEK 2 (medium value =82.8%). The disk diffusion method did not present very major errors in comparison to the two automated systems. PMID- 23109019 TI - Lactococcus garvieae endocarditis in a patient with colonic diverticulosis: first case report in Italy and review of the literature. AB - Lactococcus garvieae is a human opportunistic pathogen with low virulence, but it is a well-known pathogen in aquaculture. A total of 21 human infections have been reported in the literature, mostly endocarditis. Automated methods can wrongly identify this microorganism as Enterococcus spp with a non-standard phenotype, leading to an underestimation of the incidence of this infection. The route of infection could be the ingestion of raw fish, grilled fish or fresh dairy products. We describe the first case of L. garvieae mitral valve endocarditis in Italy, in a patient with mitral valve repair with autologous pericardium, mechanic prosthetic aortic valve and colonic diverticulosis. PMID- 23109020 TI - Peritonitis due to Ralstonia mannitolilytica in a pediatric peritoneal dialysis patient. AB - Ralstonia mannitolilytica constitutes a rare isolate in clinical specimens and to date very few infections with this Gramnegative bacillus have been reported. The first case of peritonitis in a pediatric patient due to R. mannitolilytica in the setting of peritoneal dialysis is described. It is very important to view this organism as a pathogen rather than contaminant when isolated in children with peritonitis. PMID- 23109021 TI - First detection of Brucella canis infections in a breeding kennel in Austria. AB - Brucella canis occurs almost worldwide and is a potential danger to the health of dogs and humans. The pathogen was detected in the placenta and fetuses of a Standard Poodle by direct culture and immunohistochemistry. Further, Brucellae were also isolated from the blood samples of two asymptomatic female Medium Poodles. The isolates were identified as B. canis by conventional microbiological methods and a novel Bruce-ladder multiplex PCR. Genotyping was performed by multiple locus variable number tandem repeats analysis (MLVA). PMID- 23109022 TI - Density functional calculations of the anisotropic effects of borazine and 1,3,2,4-diazadiboretidine. AB - On the basis of the nucleus-independent chemical shift (NICS) concept, the anisotropic effects of two inorganic rings, namely, borazine and planar 1,3,2,4 diazadiboretidine, are quantitatively calculated and visualized as isochemical shielding surfaces (ICSSs). Dissection of magnetic shielding values along the three Cartesian axes into contributions from sigma and pi bonds by the natural chemical shielding-natural bond orbital (NCS-NBO) method revealed that their appearance is not a simple reflection of the extent of (anti)aromaticity. PMID- 23109023 TI - Comparative clinical trial between Ciaglia and Griggs techniques during tracheostomy performed in patients admitted to intensive care unit. AB - Percutaneous dilatation tracheostomy (PDT) is one of the most frequent interventions in ventilator dependant ICU patients. Ciaglia and Griggs are two common PDT techniques. Few studies are available comparing these two methods, but there is no data available to compare these two techniques in Iranian population. The aim of this study was to compare Ciaglia and Griggs technique in our population in order to recognize advantages and disadvantages of each technique in order to identify the most beneficial one. This study is a comparative clinical trial conducted on 100 consecutive ICU admitted patients who needed prolonged intubation; half of them underwent PDT with Ciaglia method and other half with Griggs method. Procedural time and short term complications including bleeding, vital signs instability and technical errors were compared in both two methods. Both groups were comparable in demographic characteristics. Griggs method performed significantly faster than Ciaglia method (P=0.001). Complications such as high grade bleeding (P=0.01) and cardiac dysrhythmias (P=0.07) were less in Ciaglia technique than Griggs. Skin incision smaller than required was reported more with Griggs method than Ciaglia (P=0.03). We conclude that PDT with Ciaglia method is safer with less complications than the Griggs method. We suggest use of Ciaglia for less experienced operators. PMID- 23109024 TI - A novel protocol for gastric lavage in patients with aluminum phosphide poisoning: a double-blind study. AB - Aluminum phosphide poisoning (ALPP) still has no efficient and approved antidote. Supportive care and hemodynamic monitoring are the only choices of treatment. We proposed a new lavage formulation in addition to evaluation of its efficacy and defining the impact of clinical characteristics of patients on their prognosis. During eight months period of time, 120 patients were enrolled to the study and randomly received two different gastric lavage protocols. Our new lavage protocol had positive impact on patients' survival and the P-value in comparison with the classic gastric lavage method was close to significant level (P=0.054). On hospital arrival indication for intubation-ventilation as well as sense of thirst, sore throat and absence of nausea indicate worse outcome. Using our novel approach, indication for intubation-ventilation as well as sense of thirst, sore throat and absence of nausea can be considered as applicable prognostic factors in survival of ALPP patients. Further studies are required to set this approach as preferred treatment. PMID- 23109025 TI - Efficacy of transarterial chemoembolization on lesion reduction in colorectal liver metastases. AB - Following failure of systemic chemotherapy, transarterial chemoembolization (TACE) is an available method to control unresectable liver metastases from colorectal carcinoma (CRC). The aim of present study was to evaluate the efficacy of chemoembolization for inoperable metastatic liver lesions from CRC. Forty-five CRC patients with liver metastases resistant to systemic chemotherapy were enrolled in our study. For each patient, three session of TACE were conducted with 45 days interval. A combination of mitomycin, doxorubicin, and lipiodol were used for TACE. A tri-phasic computed tomography scan and biochemical laboratory tests were performed for all patients at baseline and 30 days after each TACE. Image analysis included measurement of lesion diameters as well as contrast enhancement. Eleven patients deceased before completing three session and the final analyses were performed on the remaining 34 patients. Evaluation of a total 93 lesions in all patients after chemoembolization sessions revealed a 25.88% reduction in anteroposterior (AP) diameter, 33.92% transverse (T) diameter, and 42.22% in product of APxT diameter of lesions (P<0.001 for all instances). CT scan showed a total disappearance of 33% of lesions and evident reduction in contrast enhancement in 16% of them. There were no changes in contrast enhancement in 51% of lesions. Evaluation of single largest lesion in each patient revealed 57.32% reduction in AP diameter, 59.66% in T diameter, and 62.17% in product of APxT diameters (P<0.001 for all diameters). TACE offers a viable option for CRC patients with unresectable liver metastases by significantly reducing lesion size and contrast enhancement. PMID- 23109026 TI - The effect of fetal liver-derived cell suspension allotransplantation on patients with diabetes: first year of follow-up. AB - Stem cell-based therapies have recently opened up new horizons for treatment of various types of diseases including diabetes mellitus. However, long-term efficacy and safety of these novel modalities still remain a serious question. Hereby, we aim to report the one-year follow-up results in the diabetic patients who underwent fetal liver-derived hematopoietic stem cell allotransplantation. Fifty six patients with type one (n=30) and type two (n=26) diabetes, aged 10-58 years old (32.8 +/- 16.3) were divided into the intervention and placebo group. The patients in the intervention group underwent fetal liver-derived hematopoietic stem cell transplantation while the patients in the placebo group received 5 ml of normal saline both via an intravenous route. The patients were visited at regular intervals to evaluate the efficacy of transplantation in glycemic control as well as possible complications. In the 6th month of the follow-up, there was a significant decrease in HbA1c levels in all groups without any rise in the fasting c-peptide. However, none of the precipitants transiently or continuously became insulin free in the first year after transplantation. It can be concluded that, in this study, fetal liver-derived hematopoietic stem cell transplantation had no significant effects on glycemic control. The heterogeneity of our patients might account for the negative results. Hence, longer follow-up results will be reported in the near future. PMID- 23109027 TI - Effect of adenotonsillectomy on ADHD symptoms of children with adenotonsillar hypertrophy. AB - Adenotonsillar hypertrophy and obstructive sleep disordered breathing can lead to attention deficit/hyperactivity disorder (ADHD). The purpose of this study was to evaluate effect of adenotonsillectomy on improvement of ADHD symptoms in a quasi experimental (before and after) study. The efficacy of adenotonsillectomy on improvement of ADHD symptoms of 35 children aged 5-12 years with adenotonsillar hypertrophy and ADHD was evaluated six months after surgery. Diagnosis of ADHD was based on the DSM-IV criteria in three subtypes (predominantly inattentive type, predominantly hyperactive-impulsive type and combined type). Seventeen boys (49%) and eighteen girls (51%) with mean (+/- SD) age of 7.4 +/- 3.8 years (range: 1-10 years) were evaluated. Frequency of combined type of ADHD decreased significantly six months after adenotonsillectomy (54.3% versus 22.9%, P=0.003). ADHD inattention score (2.26 +/- 1.93 versus 0.96 +/- 0.45, P=0.005), hyperactivity score (4.23 +/-3.57 versus 3.57 +/-8, P=0.03) as well as ADHD combined score (9.66 +/-2.58 versus 7.2 +/-3.67, P=0.0001) improved significantly after surgery. Upper air way obstruction due to adenotonsillar hypertrophy might be an important and treatable cause of ADHD and should be considered in evaluation of affected children. Adenotonsillectomy in these children is associated with improvements in ADHD symptoms. PMID- 23109028 TI - Anatomical variations of the saphenofemoral junction in patients with varicose veins. AB - Varicose veins are an extremely common medical condition (present in 5-30% of adults). Surgery remains the gold standard of care in patients with varicose veins, however several newer interventions have been recently introduced which need to be evaluated. During the standard surgery it is imperative to demonstrate and ligate the tributaries of the saphenofemoral junction in combination with stripping of the great saphenous vein. We studied 228 patients with varicose veins who underwent surgery during two years. The number and name of tributaries at the saphenofemoral junction, presence of external pudendal artery and its relationship to the saphenofemoral junction were recorded. The number of tributaries varied from 2 to 7 at the first five centimeters of the great saphenous vein. The average number of branches was 3.87 and the most common branch was the superficial external pudendal vein. The external pudendal artery was identified during all surgical exploration. It crossed anterior to saphenofemoral junction in 39.5% and posterior in 60.5%. Anatomical variations in venous branches at the saphenofemoral junction are varied (from 2 to 7), so it is recommended to explore the location of varicose veins precisely to ensure appropriate surgical technique. PMID- 23109029 TI - EEG abnormalities in clinically diagnosed brain death organ donors in Iranian tissue bank. AB - Brain death is defined as the permanent, irreversible and concurrent loss of all brain and brain stem functions. Brain death diagnosis is based on clinical criteria and it is not routine to use paraclinical studies. In some countries, electroencephalogram (EEG) is performed in all patients for the determination of brain death while there is some skepticism in relying on EEG as a confirmatory test for brain death diagnosis. In this study, we assessed the validity of EEG and its abnormalities in brain death diagnosis. In this retrospective study, we used 153 EEGs from medical records of 89 brain death patients in organ procurement unit of the Iranian Tissue Bank admitted during 2002-2008. We extracted and analyzed information including EEGs, which were examined by a neurologist for waves, artifacts and EEG abnormalities. The mean age of the patients was 27.2+/-12.7 years. The most common cause of brain death was multiple traumas due to accident (65%). The most prevalent artifact was electrical transformer. 125 EEGs (82%) were isoelectric (ECS) and seven EEGs (5%) were depictive of some cerebral activity which upon repeat EEGs, they showed ECS patterns too. There was no relationship between cause of brain death and cerebral activity in EEGs of the patients. In this study, we could confirm ECS patterns in all brain death patients whose status had earlier been diagnosed clinically. Considering the results of this study, it seems sensible to perform EEG as a final confirmatory test as an assurance to the patients' families. PMID- 23109030 TI - Prevalence of different electrocardiographic patterns in Iranian athletes. AB - To explore the abnormalities in Iranian athletes' electrocardiogram and find any relation with body fat. 239 international athletes were involved in this cross sectional study. Body-fat percentage and resting 12-lead ECGs were recorded from all participants. Of 239 participant athletes, 212 were male and 27 female. 60% of participants had sinus bradycardia. A total of 84% of the athletes demonstrated at least 1 abnormal ECG finding. Average values for the PR, QRS and QT intervals, P-wave duration and QRS axis were in normal range. Frequencies of various ECG abnormal findings in all athletes were as follows: right axis deviation 4.2%, left ventricular hypertrophy 6.2%, sinus arrhythmia 5.8%, right bundle branch block (RBBB) 24.2% (incomplete RBBB 16.8%, complete RBBB 7.4%), ST elevation 72.5%, prolonged QT interval 1.7%, T inversion 3.1% and Mobitz type I 1.2%. The athletes' ECG response to treadmill stress test was normal with no ischemia or arrhythmia. The means of BMI and body-fat percentage were 24.04 +/- 3.5 kg/m2 and 9.15 +/- 2.12%, respectively. Pearson correlation coefficient between body-fat percentage and ST changes was 0.65 (P=0.008) in anterior leads and 0.198 (P=0.017) in lateral leads. Also, the correlation coefficient between the body fat percentage and right bundle branch block was 0.36 (P=0.013). The results of current study support the inclusion of ECG in athletes' cardiac screening before they engage in vigorous exercises in order to detect the potentially fatal arrhythmias. PMID- 23109031 TI - Molar ectopic pregnancy after tubectomy. AB - Tubal ectopic hydatidiform mole is an uncommon but very important complication of pregnancy. The clinical manifestation is the same as ectopic pregnancy and in all of the cases management was the same as tubal ectopic pregnancy. We present a case of tubal ectopic pregnancy that after laparotomy and salpingectomy, pathologic examination reported hydatidiform mole within ectopic gestational tissue. So, a high index of suspicious is necessary for prompt diagnosis and correct fallow up of the patient. PMID- 23109032 TI - Severe hypoglycemia following acute aluminum phosphide (rice tablet) poisoning; a case report and review of the literature. AB - Aluminum phosphide (AlP) as 3 g tablet is widely used in Iran to protect stored food grains from pests. Hyperglycemia following its ingestion has been already reported in the recent years but severe hypoglycemia is uncommon. Here, we report a 19 year old male who attempted suicide with one tablet of AlP and demonstrated severe hypoglycemia. Despite restoration of blood glucose concentration to normal, he failed to respond to supportive treatment and died. The possible mechanisms leading to severe hypoglycemia are discussed. Though severe hypoglycemia is rare following AlP poisoning, physicians managing such patients should be aware of it. PMID- 23109033 TI - Variant course of posterior circumflex humeral artery associated with the abnormal origin of radial collateral artery: could it mimic the quadrangular space syndrome? AB - Variations in the origin of axillary artery branches are common. But, distinctly abnormal course of its posterior circumflex humeral branch is rare. We are reporting a case of posterior circumflex humeral artery (PCHA) originating from the axillary artery, passing through lower triangular space to reach the scapular region where it accompanied the axillary nerve and posterior circumflex humeral vein to pass around surgical neck of humerus, deep to the fibers of deltoid. Other variations observed in this specimen were the radial collateral artery arising from the PCHA, middle collateral artery arising directly from the brachial artery and absence of profunda brachii artery. PCHA forming a hair pin loop, traversing through lower triangular space instead of quadrangular space taking a long course is being reported for the first time. Further, the clinical and surgical importance of this case especially in relation with quadrangular space syndrome and relevant literature is discussed. PMID- 23109034 TI - Hyperglycemia induced hemichoreoathetosis, an uncommon presenting symptom of diabetes mellitus. AB - Chorea is brief, quasi-purposeful, irregular muscle contractions, not repetitive or rhythmic, but flows from one muscle to the next and athetosis is slow, writhing, continuous, worm-like movements of distal extremities (chiefly the fingers) which show bizarre positioning without posturing. Metabolic causes have been documented earlier, note worthy of that being Diabetes. Choreoathetosis has been reported earlier in diabetes mostly in an elderly female, diagnosed most often by Brain MRI. We report a case of hemichoreoathetosis in a male diabetic, whose involuntary movement completely resolved with glycemic control and diagnosis was easily confirmed with just a Brain CT. PMID- 23109035 TI - Physical punishment, abuse, torture or revenge? A case report. AB - Child maltreatment happens in all countries and cultures. Children as the vulnerable part of the societies are subject to rage, abuse and maltreatment and need special multidisciplinary attention to get proper protection and care. Appropriate legislation, community education, advocacy in media and attention of care givers and children health providers may alter the trend of child abuse in communities. In order to raise awareness about child abuse for healthcare professionals, in this report we introduce a disastrous case of 4 years old boy who was attacked by his father which presented to Children's Medical Center in Tehran. The living environment of the victim was a dysfunctional family and an addict father as the risk factors of dangerous circumstances for a child. PMID- 23109036 TI - Cholesterol embolization of right colon, misdiagnosed as colon tumor. PMID- 23109037 TI - Immunomagnetic nanoscreening of circulating tumor cells with a motion controlled microfluidic system. AB - Combining the power of immunomagnetic assay and microfluidic microchip operations, we successfully detected rare CTCs from clinical blood samples. The microfluidic system is operated in a flip-flop mode, where a computer-controlled rotational holder with an array of microfluidic chips inverts the microchannels. We have demonstrated both theoretically and experimentally that the direction of red blood cell (RBC) sedimentation with regards to the magnetic force required for cell separation is important for capture efficiency, throughput, and purity. The flip-flop operation reduces the stagnation of RBCs and non-specific binding on the capture surface by alternating the direction of the magnetic field with respect to gravity. The developed immunomagnetic microchip-based screening system exhibits high capture rates (more than 90%) for SkBr3, PC3, and Colo205 cell lines in spiked screening experiments and successfully isolates CTCs from patient blood samples. The proposed motion controlled microchip-based immunomagnetic system shows great promise as a clinical tool for cancer diagnosis and prognosis. PMID- 23109038 TI - Cytomegalovirus: prophylaxis, preemption, or "wait and watch". PMID- 23109039 TI - Enzyme-substrate complementarity governs access to a cationic reaction manifold in the P450(BM3)-catalysed oxidation of cyclopropyl fatty acids. AB - The products of cytochrome P450(BM3)-catalysed oxidation of cyclopropyl containing dodecanoic acids are consistent with the presence of a cationic reaction intermediate, which results in efficient dehydrogenation of the rearranged probes by the enzyme. These results highlight the importance of enzyme substrate complementarity, with a cationic intermediate occurring only when the probes used begin to diverge from ideal substrates for this enzyme. This also aids in reconciling literature reports supporting the presence of cationic intermediates with certain cytochrome P450 enzyme/substrate pairs. PMID- 23109040 TI - Serial evaluations at an indium-tin oxide production facility. AB - BACKGROUND: We evaluated the effectiveness of workplace changes to prevent indium lung disease, using 2002-2010 surveillance data collected by an indium-tin oxide production facility. METHODS: We assessed pulmonary function using lower limits of normal. Blood indium concentration and personal air sampling data were used to estimate exposure. RESULTS: Abnormalities were uncommon at hire. After hire, prevalence of spirometric restriction was 31% (n = 14/45), about fourfold higher than expected. Excessive decline in FEV1 was elevated at 29% (n = 12/41). Half (n = 21/42) had blood indium >=5 ug/l. More recent hires had fewer abnormalities. There was a suggestion that abnormalities were more common among workers with blood indium >=5 ug/l, but otherwise an exposure-response relationship was not evident. Peak dust concentrations were obscured by time averaging. CONCLUSIONS: Evolving lung function abnormalities consistent with subclinical indium lung disease appeared common and merit systematic investigation. Traditional measures of exposure and response were not illustrative, suggesting fresh approaches will be needed. Workplace changes seemed to have had a positive though incomplete impact; novel preventive interventions are warranted. PMID- 23109041 TI - The safety and efficacy of enhanced external counterpulsation as a treatment for angina in patients with aortic stenosis. AB - BACKGROUND: Comorbid aortic stenosis (AS) has been considered a precaution when applying enhanced external counterpulsation (EECP) to individuals with angina due to concerns about treatment-related hemodynamic changes. HYPOTHESIS: The aim of this study was to determine whether EECP safely reduces symptoms of myocardial ischemia and improves hemodynamics in individuals with AS. METHODS: Forty-three patients with AS (average age, 73 years; 86% male) and 43 comparison patients without AS were chosen from a database of 1327 EECP patients. Canadian Cardiovascular Society (CCS) Functional Angina Classification, diastolic augmentation ratio, and blood pressure were measured at baseline and on completion of the course of EECP. RESULTS: Thirty-five of the 43 patients with AS (81%, 95% CI: 66.6% to 91.6%) and 38 of the 43 without AS (88%, 95% CI: 74.9% to 96.1%) improved in angina class (P < 0.0001). There was no statistical difference between the percentages in patients with and without AS (P = 0.54). CCS angina class outcome was not associated with AS severity (P = 0.55). The percentage of patients with diastolic augmentation ratio >=1.0 was 16.3% in both groups at baseline and improved to 39.5% in AS patients and 37.2% in non-AS patients after EECP (both P = 0.002). The average decreases in systolic blood pressure in subjects with AS (-15 mm Hg, 95% CI: 11 to 20, P < 0.0001) and without AS (-18 mm Hg, 95% CI: 14 to 22, P < 0.0001) were similar (P = 0.31). No major adverse cardiac events were reported. CONCLUSIONS: Angina patients with AS who undergo EECP had clinically important symptomatic and hemodynamic improvements comparable to their non-AS counterparts. PMID- 23109042 TI - Polymer-chain encoding: synthesis of highly complex monomer sequence patterns by using automated protocols. PMID- 23109043 TI - Study on effects of partial ossicular replacement prostheses with different materials on hearing restoration. AB - Numerical simulation method was used in this paper to study the effects of partial ossicular replacement prostheses (PORPs) with different materials on hearing restoration, from the biomechanical point of view. According to the CT scan imagery of the right ear from a normal human body, the CT data was digitalized and imported into PATRAN to establish a three dimension finite element model by self-compiling program, and then a frequency response analysis was made for the model. The calculated results were compared with experiment data to verify the correctness of the numerical model. Based on this, human numerical model of PORPs was established to make dynamic calculation of sound conduction and analyse the effects of PORPs with different materials on hearing restoration. The following conclusions are obtained : From the angle of dynamical behaviors in sound conduction process of human ear, in different frequency bands of the same sound pressure, PORPs with different materials have different effects on hearing restoration. A better sound transmission in low frequencies is obtained by PORPs with hydroxyapatite ceramics, stainless steel. In high frequencies, better sound transmission is gained by PORPs with porous polyethylene. In the 500-3,000 Hz range which is clinicians typically measure and pay attention to, better sound transmission is gained by PORPs with alumina ceramics, hydroxyapatite ceramics, EH composite materials and porous polyethylene. There are three materials which has an obvious potential to provide more hearing restoration than another between 500 and 3,000 Hz. The hearing restoration value of hydroxyapatite ceramics is 7.1 dB larger than that of stainless steel. The hearing restoration value of titanium is 4.9 dB larger than that of stainless steel. Hydroxyapatite ceramics has better effects on sound transmission than titanium and other materials. PMID- 23109044 TI - Comparison of ultrasound-guided core biopsy versus fine-needle aspiration biopsy in the evaluation of salivary gland lesions. AB - Ultrasound-guided core biopsy provides many benefits compared with fine-needle aspiration cytology and has begun to emerge as part of the diagnostic work-up for a salivary gland lesion. Although the increased potential for tumor-seeding and capsule rupture has been extensively discussed, the safety of this procedure is widely accepted based on infrequent reports of tumor-seeding. In fact, a review of the literature shows only 2 cases of salivary tumor seeding following biopsy with larger-gauge needle characteristics, with 2 reported cases of salivary tumor seeding following fine-needle aspiration cytology. However, the follow-up interval of such studies (<7 years) is substantially less than the 20-year follow up typically necessary to detect remote recurrence. Studies on tumor recurrence of pleomorphic adenoma, the most common salivary gland lesion, suggest that as many as 16% of tumor recurrences occur at least 10 years following initial surgery, with average time to recurrence ranging anywhere from 6.1 to 11.8 years postoperatively. Despite the benefits of ultrasound-guided core biopsy over fine needle aspiration biopsy, which include both improved consistency and diagnostic accuracy, current studies lack adequate patient numbers and follow-up duration to confirm comparable safety profile to currently accepted fine-needle aspiration cytology. In this report we: (1) compare the relative benefits of each procedure, (2) review evidence regarding tumor seeding in each procedure, (3) discuss time course and patient numbers necessary to detect tumor recurrence, and (4) describe how these uncertainties should be factored into clinical considerations. PMID- 23109045 TI - PTHrP regulates the modeling of cortical bone surfaces at fibrous insertion sites during growth. AB - The sites that receive ligament and tendon insertions (entheses) on the cortical surfaces of long bones are poorly understood, particularly regarding modeling and regulation. Entheses are classified as either fibrocartilaginous or fibrous based on their structures. Fibrous entheses typically insert into the metaphysis or diaphysis of a long bone, bear a periosteal component, and are modeled during long-bone growth. This modeling forms a root system by which the insertions attach to the cortical surface. In the case of the medial collateral ligament, modeling drives actual migration of the ligament along the cortical surface in order to accommodate linear growth, whereas in other sites modeling may excavate a deep cortical root system (eg, the teres major insertion) or a shallow root system with a large footprint (eg, the latissimus dorsi insertion). We report here that conditionally deleting parathyroid hormone-related protein (PTHrP) in fibrous entheses via Scleraxis-Cre targeting causes modeling to fail in these three iterations of osteoclast-driven enthesis excavation or migration. These iterations appear to represent formes frustes of a common modeling strategy, presumably differing from each other as a consequence of differences in biomechanical control. In sites in which PTHrP is not induced, either physiologically or because of conditional deletion, modeling does not take place and fibrocartilage is induced. These findings represent the initial genetic evidence that PTHrP regulates periosteal/intramembranous bone cell activity on cortical bone surfaces and indicate that PTHrP serves as a load-induced modeling tool in fibrous insertion sites during linear growth. PMID- 23109047 TI - Neuropsychological assessment of preschoolers. PMID- 23109046 TI - Assessing executive function in preschoolers. AB - Executive function develops at an unprecedented rate during the preschool period, yet few clinicians attempt to assess executive processes in young children. The primary objective of this article is to demonstrate that executive function can be assessed in preschoolers, and to highlight the importance of detecting executive dysfunction as early as possible. Following a description of executive function and the underlying neural systems, this article outlines some of the challenges in assessing executive function in young children. The various assessment paradigms used for assessing executive function in preschoolers are presented, and based on studies that have applied these measurement tools normal development of executive domains is described. Finally, the benefits and opportunities for executive function intervention in the preschool period are considered. PMID- 23109049 TI - Amplification of the stereochemistry of biomolecular adsorbates by deracemization of chiral domains in bent-core liquid crystals. AB - Assemblies of chiral phospholipids that form spontaneously at interfaces between aqueous phases and bent-core liquid crystals can deracemize mixtures of chiral domains that otherwise form in the liquid crystal phase. An enantiomeric excess of chiral domains is induced by adsorption of either L- or D-phospholipid with the same sense of optical rotation. PMID- 23109048 TI - Filamin C-related myopathies: pathology and mechanisms. AB - The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy. PMID- 23109050 TI - Matrix isolation-vibrational circular dichroism spectroscopy of 3-butyn-2-ol and its binary aggregates. AB - Vibrational circular dichroism (VCD) spectroscopy has a unique specificity to chirality and is highly sensitive to the conformational equilibria of chiral molecules. On the other hand, the matrix-isolation (MI) technique allows substantial control over sample compositions, such as the sample(s)/matrix ratio and the ratio among different samples, and yields spectra with very narrow bandwidths. We combined VCD spectroscopy with the MI technique to record MI-VCD and MI-vibrational absorption spectra of 3-butyn-2-ol at different MI temperatures, which allowed us to investigate the conformational distributions of its monomeric and binary species. Good mirror-imaged MI-VCD spectra of opposite enantiomers were achieved. The related conformational searches were performed for the monomer and the binary aggregate and their vibrational absorption and VCD spectra were simulated. The well-resolved experimental MI-VCD bands provide the essential mean to assign the associated vibrational absorption spectral features correctly to a particular conformation in case of closely spaced bands. By varying the matrix temperature, we show that one can follow the self-aggregation process of 3-butyn-2-ol and confidently correlate the MI-VCD spectral features with those obtained for a 0.1 M CCl(4) solution and as a neat liquid at room temperature. Comparison of the aforementioned experimental VCD spectra shows conclusively that there is a substantial contribution from the 3-butyn-2-ol aggregate even at 0.1 M concentration. This spectroscopic combination will be powerful for studying self-aggregation of chiral molecules, and chirality transfer from a chiral molecule to an interacting achiral molecule and in electron donor-acceptor chiral complexes. PMID- 23109052 TI - Electron paramagnetic resonance analysis of the vimentin tail domain reveals points of order in a largely disordered region and conformational adaptation upon filament assembly. AB - Very little data have been reported that describe the structure of the tail domain of any cytoplasmic intermediate filament (IF) protein. We report here the results of studies using site directed spin labeling and electron paramagnetic resonance (SDSL-EPR) to explore the structure and dynamics of the tail domain of human vimentin in tetramers (protofilaments) and filaments. The data demonstrate that in contrast to the vimentin head and rod domains, the tail domains are not closely apposed in protofilaments. However, upon assembly into intact IFs, several sites, including positions 445, 446, 451, and 452, the conserved "beta site," become closely apposed, indicating dynamic changes in tail domain structure that accompany filament elongation. No evidence is seen for coiled-coil structure within the region studied, in either protofilaments or assembled filaments. EPR analysis also establishes that more than half of the tail domain is very flexible in both the assembly intermediate and the intact IF. However, by positioning the spin label at distinct sites, EPR is able to identify both the rod proximal region and sites flanking the beta-site motif as rigid locations within the tail. The rod proximal region is well assembled at the tetramer stage with only slight changes occurring during filament elongation. In contrast, at the beta site, the polypeptide backbone transitions from flexible in the assembly intermediate to much more rigid in the intact IF. These data support a model in which the distal tail domain structure undergoes significant conformational change during filament elongation and final assembly. PMID- 23109051 TI - Pain in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is an inflammatory disease of synovial joints, and pain is the predominant problem for people with RA. Pain in RA is distressing in its own right and adversely affects disability and psychosocial outcomes. RA pain may be due to joint inflammation and also augmented by central sensitization and structural joint damage. Noninflammatory pain mechanisms may confound the assessment of disease activity in RA, and treatment should aim to both suppress inflammatory disease and relieve pain symptoms. Effective treatment stratification requires a full assessment of pain mechanisms by clinical history and examination, as well as objective assessment of synovitis and joint damage. Biologic therapies and joint replacement surgery have major impacts on RA pain, but may only be available to those with most severe or advanced disease. Holistic approaches to pain management are indicated, including pharmacologic analgesia where randomized controlled trials (RCTs) offer evidence of efficacy. PMID- 23109053 TI - The effects of various doses of bacterial lipopolysaccharide on the expression of CD63 and the release of histamine by basophils of atopic and non-atopic patients. AB - OBJECTIVE: We tested the effect of various doses of bacterial lipopolysaccharide (LPS, endotoxin) on the expression of CD63 and the in vitro release of histamine by basophils stimulated with ragweed allergen in patients with or without ragweed and mite allergies. METHODS: The peripheral blood of 11 patients with ragweed allergy, 10 patients with mite allergy and 14 control patients was incubated with ragweed allergen extract following pretreatment with varying doses of LPS. The expression of CD63 in basophils was measured by flow cytometry, and the release of histamine was determined by ELISA. RESULTS: In the samples of patients with ragweed allergy that were exposed to specific allergen, only high doses of LPS significantly elevated the expression of CD63 (200 ng/ml; 1,000 EU/ml) and the release of histamine (2,000 ng/ml; 10,000 EU/ml). There was no effect of LPS in any other cases. CONCLUSIONS: Bacterial LPS (endotoxin) concentrations higher than 200 ng/ml (1,000 EU/ml), which rarely occurs in nature, could only activate the basophils from atopic patients whilst in the presence of the specific allergen. Thus, the restoration of the urban, "microbe-poor" milieu with endotoxin (as LPS) can be a promising and harmless approach for allergy prevention. PMID- 23109054 TI - Comparative morphology of serotonergic-like immunoreactive elements in the central nervous system of kinorhynchs (Kinorhyncha, Cyclorhagida). AB - Cycloneuralian taxa exhibit similar organ system architectures, providing informative characters of metazoan evolution, yet very few modern comparative descriptions of cellular and molecular homologies within and among those taxa are available. We immunolabeled and characterized elements of the serotonergic nervous system in the kinorhynchs Echinoderes spinifurca, Antygomonas paulae, and Zelinkaderes brightae using confocal laser scanning microscopy. Fluorescent markers targeting DNA were combined with observations of auto-fluorescent structures to guide interpretations of the internal and external anatomy in each species. Results show a common pattern of the central nervous system with a circumenteric brain divided into ring-shaped anterior and posterior neuronal somata and a central neuropil connected to a multi-stringed, longitudinal ventral nerve cord. Structural similarities and differences in the nervous systems of these species were observed and described, stressing the incomplete ring nature of the anterior region of the kinorhynch brain, the functional relationship between the brain and the movable introvert, and the number and arrangement of nerve strings and somata of the ventral nerve cord. The ventral cord ends in two ventrolateral cell bodies in E. spinifurca, and forms a terminal loop associated with a midterminal spine in A. paulae and Z. brightae. The possible functional and phylogenetic significance of these features and arrangements are discussed. PMID- 23109055 TI - Prevalence of epicondylitis, rotator cuff syndrome, and low back pain in Latino poultry workers and manual laborers. AB - BACKGROUND: The goal of this study is to improve understanding of immigrant Latino manual workers' occupational health, focusing on upper body musculoskeletal injury. METHODS: Physical exams were conducted with a representative sample of 516 Latino poultry workers and manual laborers in western North Carolina; outcome measures were prevalence of epicondylitis, rotator cuff syndrome, and low back pain. RESULTS: Low back pain (n = 89; 17.2%) and rotator cuff syndrome (n = 76; 14.7%) indicated by physical exam was common. Epicondylitis was less common, but still frequent (n = 30; 5.8%). Prevalence of each outcome did not differ between poultry processing workers and other manual workers. Workers >40 years old had greater incidence of rotator cuff syndrome and epicondylitis. CONCLUSIONS: Epicondylitis, rotator cuff syndrome, and low back pain are common in immigrant Latino workers, and may negatively impact long-term health and contribute to occupational health disparities. PMID- 23109056 TI - Clinical predictors of long-term outcome in obsessive-compulsive disorder. AB - BACKGROUND: The purpose of this study was to investigate demographic and clinical factors associated with the long-term outcome of obsessive-compulsive disorder (OCD). METHODS: A hundred ninety-six previously untreated patients with DSM-IV criteria OCD completed a 12-week randomized open trial of group cognitive behavioral therapy (GCBT) or fluoxetine, followed by 21 months of individualized, uncontrolled treatment, according to international guidelines for OCD treatment. OCD severity was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y BOCS) at different times over the follow-up period. Demographics and several clinical variables were assessed at baseline. RESULTS: Fifty percent of subjects improved at least 35% from baseline, and 21.3% responded fully (final Y-BOCS score < or = 8). Worse prognosis was associated with earlier age at onset of OCD (P = 0.045), longer duration of illness (P = 0.001) presence of at least one comorbid psychiatric disorder (P = 0.001), comorbidity with a mood disorder (P = 0.002), higher baseline Beck-Depression scores (P = 0.011), positive family history of tics (P = 0.008), and positive family history of anxiety disorders (P = 0.008). Type of initial treatment was not associated with long-term outcome. After correction for multiple testing, the presence of at least one comorbid disorder, the presence of a depressive disorder, and duration of OCD remained significant. CONCLUSIONS: Patients under cognitive-behavioral or pharmacological treatment improved continuously in the long run, regardless of initial treatment modality or degree of early response, suggesting that OCD patients benefit from continuous treatment. Psychiatric comorbidity, especially depressive disorders, may impair the long-term outcome of OCD patients. PMID- 23109057 TI - Molecular characterization, expression profiles, and association analysis with hematologic parameters of the porcine HPSE and HPSE2 genes. AB - Heparan sulfate (HS), which consists of repeating disaccharide units, plays an essential role in inflammation and viral infections. Heparanase (encoded by the HPSE gene) can cleave the HS chains of heparan sulfate proteoglycans (HSPGs), which are known to be important participants in immune responses. HPSE2 (heparanase 2) is a homologous gene of HPSE. To investigate the functions of HS, which is the primary receptor of the porcine reproductive and respiratory syndrome virus (PRRSV), the two genes involved in the metabolic process of HS were studied. Here, we present a study of tissue expression profiles, polymorphisms of the HPSE and HPSE2 genes, and the changes of their mRNA levels in porcine alveolar macrophages (PAMs) induced by PRRSV. Both genes are preferentially expressed in porcine immune or immune-related organs under normal conditions, e.g., in the lung, spleen, and lymph node. Moreover, a synonymous mutation c.750A>G located in exon5 of the HPSE gene was detected, and was significantly associated with the white blood cell (WBC) count, red blood cell (RBC) count, hemoglobin (HGB), and hematocrit (HCT) in the peripheral blood (p < 0.05). A single nucleotide polymorphism (SNP) c.2073A>G was found in the HPSE2 gene and association analysis showed that it was significantly associated with the WBC content in the blood (p < 0.05). Upon stimulation in healthy piglets with PRRSV, the HPSE mRNA was obviously up-regulated, while the HPSE2 mRNA did not induce a prominent change in PAMs. PMID- 23109058 TI - Low-dose steroids associated with milder histological changes after pediatric liver transplantation. AB - Controversy remains about the role of protocol liver biopsy for symptom-free recipients and about the long-term use of low-dose steroids after pediatric liver transplantation (LT). We conducted a national cross-sectional study of pediatric recipients who underwent LT between 1987 and 2007. Liver biopsy samples were taken from 54 patients (82% of survivors) after a median posttransplant follow-up of 11 years, and they were reviewed by 2 pathologists blinded to the clinical data. Biopsy samples from 18 patients (33%) showed nearly normal histology with no inflammation, fibrosis, or steatosis. Portal inflammation was detected in 14 samples (26%), showed no correlation with anti-nuclear antibodies, and was less frequent in the 35 patients whose immunosuppression included steroids (14% versus 47% of patients not using steroids, P = 0.008). Fibrosis was present in 21 biopsy samples (39%). According to the Metavir classification, 16 were stage 1, 3 were stage 2, and 2 were stage 3. The fibrosis stage correlated negatively with serum prealbumin levels (r = -0.364, P = 0.007) and positively with chronic cholestasis (cytokeratin 7 staining; r = 0.529, P < 0.001) and portal inflammation (r = 0.350, P = 0.01). Microvesicular steatosis was found in 23 biopsy samples (43% of patients in 5%-80% of hepatocytes), and it correlated with the body mass index (r = 0.458, P < 0.001) but not with steroid use. The age of the allograft (donor age plus follow-up time) correlated with higher serum gamma-glutamyltransferase (r = 0.472, P < 0.001) and conjugated bilirubin levels (r = 0.420, P = 0.002) as well as chronic cholestasis (r = 0.299, P = 0.03). The biopsy findings led to treatment changes in 10 patients (19%), whereas only 1 complication (subcapsular hematoma) was encountered. In conclusion, continuing low-dose steroids indefinitely after pediatric LT may have a positive effect on the long-term histological state of the liver graft. Allograft aging may lead to chronic cholestasis and thus contribute to the development of liver fibrosis. PMID- 23109060 TI - Lyso-globotriaosylsphingosine (lyso-Gb3) levels in neonates and adults with the Fabry disease later-onset GLA IVS4+919G>A mutation. AB - Lyso-globotriaosylsphingosine (lyso-Gb3) is a useful biomarker in the diagnosis and monitoring of treatment for Fabry disease. However, it is unclear whether lyso-Gb3 is elevated in patients with later-onset Fabry disease. Thus, we measured lyso-Gb3 levels from dried blood spots (DBS) from male newborns with the Fabry disease later-onset phenotype, IVS4+919G>A mutation, and their family members. The lyso-Gb3 levels were below the detection limit in normal control newborns and were slightly higher in adults. In males of all ages with the IVS4+919G>A mutation, lyso-Gb3 levels were elevated and were higher than in age matched controls. The elevation of lyso-Gb3 levels in males with the IVS4+919G>A mutation was only slightly elevated compared with patients with the classical Fabry phenotype. The measurement of lyso-Gb3 levels is useful in the diagnosis of Fabry disease, including the later-onset phenotype. The DBS lyso-Gb3 level was not elevated in IVS4+919G>A heterozygotes, and is not useful for their diagnosis. Since lyso-Gb3 levels are elevated from birth in Fabry disease males, "an elevated lyso-Gb3 level" may be of little values for deciding when to begin enzyme replacement therapy. PMID- 23109059 TI - Ammonia toxicity to the brain. AB - Hyperammonemia can be caused by various acquired or inherited disorders such as urea cycle defects. The brain is much more susceptible to the deleterious effects of ammonium in childhood than in adulthood. Hyperammonemia provokes irreversible damage to the developing central nervous system: cortical atrophy, ventricular enlargement and demyelination lead to cognitive impairment, seizures and cerebral palsy. The mechanisms leading to these severe brain lesions are still not well understood, but recent studies show that ammonium exposure alters several amino acid pathways and neurotransmitter systems, cerebral energy metabolism, nitric oxide synthesis, oxidative stress and signal transduction pathways. All in all, at the cellular level, these are associated with alterations in neuronal differentiation and patterns of cell death. Recent advances in imaging techniques are increasing our understanding of these processes through detailed in vivo longitudinal analysis of neurobiochemical changes associated with hyperammonemia. Further, several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase. Magnetic resonance imaging and spectroscopy will ultimately be a powerful tool to measure the effects of these neuroprotective approaches. PMID- 23109061 TI - Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. AB - Maple syrup urine disease (MSUD) is a neurometabolic disorder that leads to the accumulation of branched-chain amino acids (BCAAs) and their alpha-keto branched chain by-products. Because the neurotoxic mechanisms of MSUD are poorly understood, this study aimed to evaluate the effects of chronic administration of a BCAA pool (leucine, isoleucine and valine). This study examined the effects of BCAA administration on spatial memory and the levels of brain-derived neurotrophic factor (BNDF). We examined both pro-BDNF and bdnf mRNA expression levels after administration of BCAAs. Furthermore, this study examined whether antioxidant treatment prevented the alterations induced by BCAA administration. Our results demonstrated an increase in BDNF in the hippocampus and cerebral cortex, accompanied by memory impairment in spatial memory tasks. Additionally, chronic administration of BCAAs did not induce a detectable change in pro-BDNF levels. Treatment with N-acetylcysteine and deferoxamine prevented both the memory deficit and the increase in the BDNF levels induced by BCAA administration. In conclusion, these results suggest that when the brain is chronically exposed to high concentrations of BCAA (at millimolar concentrations) an increase in BDNF levels occurs. This increase in BDNF may be related to the impairment of spatial memory. In addition, we demonstrated that antioxidant treatment prevented the negative consequences related to BCAA administration, suggesting that oxidative stress might be involved in the pathophysiological mechanism(s) underlying the brain damage observed in MSUD. PMID- 23109062 TI - Expression of the Nrf2-system at the blood-CSF barrier is modulated by neonatal inflammation and hypoxia-ischemia. AB - Transcription factor NF-E2-related factor-2 (Nrf2) is a key regulator of endogenous anti-oxidant systems shown to play a neuroprotective role in the adult by preserving blood-brain barrier function. The choroid plexus, site for the blood-CSF barrier, has been suggested to be particularly important in maintaining brain barrier function in development. We investigated the expression of Nrf2- and detoxification-system genes in choroid plexus following systemic LPS injections, unilateral cerebral hypoxia-ischemia (HI) as well as the combination of LPS and HI (LPS/HI). Plexuses were collected at different time points after LPS, HI and LPS/HI in 9-day old mice. mRNA levels of Nrf2 and many of its target genes were analyzed by quantitative PCR. Cell death was analyzed by caspase-3 immunostaining and TUNEL. LPS caused down-regulation of the Nrf2-system genes while HI increased expression at earlier time points. LPS exposure prior to HI prevented many of the HI-induced gene increases. None of the insults resulted in any apparent cell death to choroidal epithelium. These data imply that the function of the inducible anti-oxidant system in the choroid plexus is down regulated by inflammation, even if choroid cells are not structurally damaged. Further, LPS prevented the endogenous antioxidant response following HI, suggesting the possibility that the choroid plexus may be at risk if LPS is united with an insult that increases oxidative stress such as hypoxia-ischemia. PMID- 23109063 TI - Diagnosis of Barth syndrome using a novel LC-MS/MS method for leukocyte cardiolipin analysis. AB - Barth syndrome (BTHS) is an X-linked disorder characterised by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia and 3-methylglutaconic aciduria. It is caused by mutations in the TAZ gene which codes for tafazzin, a protein with acyl transferase activity involved in synthesis of cardiolipin. Monolysocardiolipin (MLCL) is an intermediate in this process. Diagnosis of BTHS is difficult, as clinical and biochemical features are variable and numerous TAZ mutations have been described. These factors, together with lack of a straightforward diagnostic test are thought to have contributed to under diagnosis of the condition. A novel method for cardiolipin analysis by reversed phase ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS) is reported which is less complicated and faster than previously described methods and uses a readily available sample type. The equipment, reagents and expertise required are found in most clinical laboratories performing metabolic investigations. Leukocytes were prepared from whole blood, phospholipids extracted and tetralinoleyl cardiolipin (CL4) and MLCL analysed by UPLC-MS/MS. Reference values were derived from analysis of 76 control and 23 BTHS samples as follows: CL4 in controls >132 (95 % CI 100-169), BTHS <30.2 (21.3-40.4) pmol/mg protein; MLCL/CL4 ratio in controls <0.006 (0.004-0.009) and >2.52 (1.51-4.22) in BTHS patients. We describe an improved method for CL4 and MLCL/CL4 analysis which can be incorporated into the routine work of a clinical biochemistry laboratory. It shows 100 % sensitivity and specificity for BTHS, making it a suitable diagnostic test. PMID- 23109065 TI - Characterization of some tin-contained ancient glass beads found in China by means of SEM-EDS and raman spectroscopy. AB - A total of nine tin-contained ancient glass beads were characterized by a combination of scanning electron microscopy coupled with energy-dispersive X-ray spectrometry and Raman spectroscopy. These glass beads dated from 1st century BC to 10th century AD were excavated from the Xinjiang and Guangxi provinces of China. Two kinds of tin-based opacifiers/colorants included crystalline cassiterite (SnO(2)) and lead-tin yellow types II were first found in these soda lime glass beads. The tentative chronology of the tin-based opacifiers/colorants used in ancient glasses from China and the West was compared. In addition, several transition metal ions colorants were also found in these beads. The detailed study of the glassy matrices, crystalline inclusions, and the microstructural heterogeneities for these glass beads has revealed some valuable information to trace the possible making technology and provenances. PMID- 23109066 TI - A DNA-based and electrochemically transduced keypad lock system with reset function. AB - Try your lock: A resettable DNA-based keypad lock system with electrochemical current as output signal has been successfully developed as proof of concept (see scheme). The system is triggered to ON only when the inputs are adopted with an appropriate combination and exact sequence. The reset function can be facilely realized. PMID- 23109064 TI - Effects of hypoglycaemia on neuronal metabolism in the adult brain: role of alternative substrates to glucose. AB - Hypoglycaemia is characterized by decreased blood glucose levels and is associated with different pathologies (e.g. diabetes, inborn errors of metabolism). Depending on its severity, it might affect cognitive functions, including impaired judgment and decreased memory capacity, which have been linked to alterations of brain energy metabolism. Glucose is the major cerebral energy substrate in the adult brain and supports the complex metabolic interactions between neurons and astrocytes, which are essential for synaptic activity. Therefore, hypoglycaemia disturbs cerebral metabolism and, consequently, neuronal function. Despite the high vulnerability of neurons to hypoglycaemia, important neurochemical changes enabling these cells to prolong their resistance to hypoglycaemia have been described. This review aims at providing an overview over the main metabolic effects of hypoglycaemia on neurons, covering in vitro and in vivo findings. Recent studies provided evidence that non-glucose substrates including pyruvate, glycogen, ketone bodies, glutamate, glutamine, and aspartate, are metabolized by neurons in the absence of glucose and contribute to prolong neuronal function and delay ATP depletion during hypoglycaemia. One of the pathways likely implicated in the process is the pyruvate recycling pathway, which allows for the full oxidation of glutamate and glutamine. The operation of this pathway in neurons, particularly after hypoglycaemia, has been re-confirmed recently using metabolic modelling tools (i.e. Metabolic Flux Analysis), which allow for a detailed investigation of cellular metabolism in cultured cells. Overall, the knowledge summarized herein might be used for the development of potential therapies targeting neuronal protection in patients vulnerable to hypoglycaemic episodes. PMID- 23109067 TI - Comparable clinical safety and efficacy of biodegradable versus durable polymer paclitaxel eluting stents despite shorter dual antiplatelet therapy: insights from a multicenter, propensity score-matched registry. AB - BACKGROUND: The biodegradable polymer drug-eluting stents have been proposed as an alternative to durable polymer DES, theoretically improving vessel healing and reducing the need for prolonged double anti platelet therapy (DAPT), however clinical significance of this technology is under debate. Therefore, we sought to compare the clinical outcomes of two Paclitaxel eluting stents (PES) containing different polymer-based eluting matrices. METHODS: In this multicenter registry of 392 consecutive patients who underwent PCI between June 2006 and September 2008, we included patients with stable angina or NSTE-ACS displaying at least one significant lesion (>50% diameter stenosis) in native coronary arteries. RESULTS: Biodegradable polymer PES (BP-PES, LUC Chopin(2) , Balton, Poland) was implanted in 206 patients, whereas durable polymer PES (DP-PES, Taxus, Boston Scientific, USA) was implanted in 186 patients. There were no significant differences in baseline characteristics between groups with the exception of increased diabetes and number of lesions for BP-PES. In risk-unadjusted analysis at 1-year follow up, there were no significant differences in TLR (BP-PES: 8.4% vs. DP-PES: 6%; P = 0.36), TVR (BP-PES: 11.1% vs. DP-PES: 8.4%; P = 0.36) and incidence of stent thromboses (BP-PES: 2.15% vs. DP-PES: 3.4%; P = 0.42) between groups. There was also no difference in MACCE between groups (17.6% vs. 14.4%, P = 0.49). The mean dual antiplatelet therapy (DAPT) compliance at 1 year was 77% for BP-PES versus 92% for DP-PES (P = 0.03). Kaplan-Meier analysis showed a significantly higher long-term stroke free survival in BP-PES (P = 0.04). After adjustment, this was sustained with an additional tendency toward higher MI free survival for BP-PES (P = 0.059). CONCLUSIONS: In this observational analysis, BP-PES were comparable to DP-PES, with regard to incidence of repeated revascularizations, stent thromboses and MACCE despite earlier DAPT discontinuation. PMID- 23109069 TI - Why do Australian registered pharmacists leave the profession? a qualitative study. AB - BACKGROUND: Understanding why people choose to leave their professions is important to inform workforce planning to meet community needs. Poor job satisfaction has been linked to health practitioners expressing intentions to leave in other professions such as nursing, occupational therapy and medicine, but little is known about the reasons why pharmacists leave their profession. OBJECTIVE: To explore reasons why Australian pharmacists leave the profession. SETTING: As part of a survey of the Australian pharmacist workforce, a questionnaire was mailed to all registered pharmacists (n = 7,764) on the registers of the Pharmacy Boards of Victoria and South Australia; 1,627 (21 %) responded. Participants, who were registered but no longer working as a pharmacist, were asked to provide contact details if they were willing to be interviewed for this study; 89 (5.5 %) pharmacists accepted an invitation. A proportionate sample of 20 was selected for the interview. METHOD: A semi structured interview schedule was developed with probe options which encouraged participants to further explore their responses to questions. De-identified audio records of interviews were transcribed verbatim and thematically analysed. MAIN OUTCOME MEASURE: Reasons why pharmacists leave the pharmacy profession. RESULTS: Five themes emerged: (1) Dissatisfaction with the professional environment; (2) lack of career paths and opportunities; (3) under-utilisation of pharmacists' knowledge and skills; (4) wanting a change; and (5) staying connected with pharmacy. CONCLUSION: These findings provide insights to the pharmacy sector, previously unexplored in Australia, and informs future pharmacist workforce planning. To retain experienced, mid-career pharmacists in the profession, strategies to increase opportunities for career progression, better use of pharmacists' knowledge and skills and involvement in patient care are required to increase job satisfaction and improve retention rates. PMID- 23109068 TI - Proximal femoral density distribution and structure in relation to age and hip fracture risk in women. AB - Hip fracture risk rises exponentially with age, but there is little knowledge about how fracture-related alterations in hip structure differ from those of aging. We employed computed tomography (CT) imaging to visualize the three dimensional (3D) spatial distribution of bone mineral density (BMD) in the hip in relation to age and incident hip fracture. We used intersubject image registration to integrate 3D hip CT images into a statistical atlas comprising women aged 21 to 97 years (n = 349) and a group of women with (n = 74) and without (n = 148) incident hip fracture 4 to 7 years after their imaging session. Voxel-based morphometry was used to generate Student's t test statistical maps from the atlas, which indicated regions that were significantly associated with age or with incident hip fracture. Scaling factors derived from intersubject image registration were employed as measures of bone size. BMD comparisons of young, middle-aged, and older American women showed preservation of load-bearing cortical and trabecular structures with aging, whereas extensive bone loss was observed in other trabecular and cortical regions. In contrast, comparisons of older Icelandic fracture women with age-matched controls showed that hip fracture was associated with a global cortical bone deficit, including both the superior cortical margin and the load-bearing inferior cortex. Bone size comparisons showed larger dimensions in older compared to younger American women and in older Icelandic fracture women compared to controls. The results indicate that older Icelandic women who sustain incident hip fracture have a structural phenotype that cannot be described as an accelerated pattern of normal age-related loss. The fracture-related cortical deficit noted in this study may provide a biomarker of increased hip fracture risk that may be translatable to dual-energy X-ray absorptiometry (DXA) and other clinical images. PMID- 23109070 TI - Synthetic bioabsorbable hernia plug for plug and patch inguinal herniorrhaphy implantation technique. AB - New products have led the way in advancements of inguinal hernia repair. None is more impressive than the evolution of the plug patch. In 1968 Irving Lichtenstein introduced the first Marlex mesh plug repair when he rolled a piece of flat polypropylene into the shape of a cigarette to fill a femoral defect. He later expanded his use of the "cigarette plug" to repair recurrent hernias. Today, a wide array of mesh plugs, ranging from nonabsorbable to partially and fully absorbable biomaterials, are available from manufacturers. While some surgeons have used the plug alone for repair, most believe the overlay patch is of greater importance for the durability of the repair. With larger overlays, it is questionable whether a plug should be a permanent, nonabsorbable material. Heavyweight plugs have been reported to erode, migrate, or cause vocational limiting inguinodynia. Using a fully absorbable plug in inguinal hernia repair minimizes the risk of these complications. This article focuses on the technical refinements associated with using the completely absorbable GORE BIO-A Hernia Plug (W.L. Gore & Associates, Inc, Elkton, MD) in combination with macroporous polypropylene or polyester. Additionally, this paper describes the use of GORE BIO-A Tissue Reinforcement as an alternative for repair following removal of prior polypropylene plug-patch herniorrhaphy that cause inguinodynia. PMID- 23109071 TI - Calcium sulfate cement in contained traumatic metaphyseal bone defects. AB - The aim of this study was to evaluate prospective patients with periarticular fractures where a meta physeal bone defect was grafted with high compressive calcium sulfate cement. The calcium sulfate cement MIIG X3, (Wright Medical Technology, Inc, Arlington, TN) was used in 45 patients with periarticular fractures--distal radial, tibial plateau, humeral head, and calcaneal fractures- to fill the metaphyseal defect. All fractures were treated either with open or closed reduction, fracture fixation, and the cement was applied openly or closed. Radiographs were evaluated for fracture reduction, joint line gap, and step, as well as for rate of graft replacement by bone. All fractures united without an additional procedure. There were no wound infections or other complications attributed to the graft. At three-month follow-up, a complete graft replacement by bone was observed in all fractures. Joint line step was not developed in any patient, but a joint line gap of 3 mm was observed postoperatively in one patient with a tibial plateau fracture. Loss of reduction occurred in one patient with an extra-articular distal radial fracture treated with closed reduction and k-wire fixation. Cement that escaped into the joint or the surrounding soft tissues was not visible at the six-week follow-up. In conclusion, the results of this study confirm the safety and the efficacy of this cement when it is used as graft with the appropriate fixation method in traumatic metaphyseal bone defects. PMID- 23109072 TI - The dual radius hemispherical 'Trident" cup: results based on 150 consecutive cases. AB - INTRODUCTION: Initial stability with press-fit cups can be achieved in a number of ways based on the design of the cup. With line-to-line fit, screws fixation, press-fit of 1 to 2 mm which is obtained by an oversized hemispherical cup, initial stability can be achieved with the dual-radius press-fit cups, which have an equatorial diameter 1 to 2 mm greater than that of the polar diameter, to ensure a good press-fit and to provide adequate initial stability for bone ingrowth to occur reliably. METHODS: Between January 2002 and January 2008, 400 total hip replacements (THRs) were carried out. We examined the first 150 consecutive primary THRs. In all hips, the acetabular component was the dual radius Trident AD shell (Stryker Orthopaedics, Mahwah, New Jersey). RESULTS: The median duration of follow-up was 6,2 yrs (range, 5 to 7 yrs). The median post operative Harris Hip Score for 150 hips was 90.5 (range, 51 to 98). At the time of the latest follow-up, there was a bony incorporation of all components; we found no definite evidence of radiographic loosening and no signs of radiolucency. CONCLUSION: According to the encouraging results of the present study we conclude that the Trident cup is a valid choice for acetabular replacement. PMID- 23109073 TI - Single-use cutting blocks and trials lower costs in primary total knee arthroplasty. AB - Because total knee arthroplasty is one of the most common orthopaedic procedures, it is important that the medical community continually strive for cost reductions. This prospective controlled trial aimed to determine if cost decreases could be achieved in non-navigated and navigated procedures by replacing traditional saws, cutting blocks, and trials with a specialized single use system. Costs were lowered by an estimated $140.00-220.00 per surgery as a result of fewer instrument trays being reprocessed, and an estimated $75.00 330.00 per instrument case due to a 10-24-minute time savings during tray rewrapping. This study has positive financial implications for patients, hospitals, institutions, and third-party carriers. PMID- 23109074 TI - Reducing postoperative pain: the use of Tisseel for mesh fixation in inguinal hernia repair. AB - INTRODUCTION: The new objective in primary hernia surgery should be the reduction of disabling chronic pain. This article will discuss the safety, efficacy, and reduction of pain of a sutureless glue mesh procedure for primary uncomplicated inguinal hernia repair. METHODS: We began performing sutureless glue mesh repairs in 2004 for primary uncomplicated inguinal hernias with good results. After reduction of the hernia sac, polypropylene medium-weight preshaped flat mesh is fixed to the posterior inguinal wall with 0.5 mL of fibrin glue on the pubic tubercle; another 1.5 mL is sprayed on the entire mesh surface. The cord is positioned in subcutaneous space. The TI.ME.LI (Tissucol/Tisseel for MEsh fixation in LIchtenstein hernia repair) trial was planned and conducted based on this experience. RESULTS: In two years, we treated more than 600 primary inguinal hernias with fibrin glue mesh fixation repair. At follow-up (2 to 96 months after surgery), no patients presented with severe pain, 2.7% of patients complained of moderate pain. CONCLUSION: Fibrin sealant for mesh fixation in open repair is well tolerated and it should be considered as a first-line option for mesh fixation in open inguinal hernia repair. PMID- 23109075 TI - New surgical technique for treatment of stress urinary incontinence TVT-ABBREVO from development to clinical experience. AB - Tension-free suburethral tapes have revolutionized the surgical treatment of female stress urinary incontinence (SUI). These tapes are inserted by way of a retropubic or transobturator route. The inside-out tension-free vaginal tape transobturator approach, or TVT-Obturator system (TVT-O, Ethicon Women's Health and Urology, Somerville, NJ), was developed ten years ago with the aim of minimizing the risk of urinary tract injuries associated with retropubic and outside-in transobturator tapes while reproducibly ensuring minimal tissue dissection. Cadaveric studies have shown that the anatomical trajectory of the TVT-O tape is strictly perineal and courses away from neighboring obturator and pudendal neurovascular structures. Several meta-analyses have shown similar SUI cure rates after retropubic and transobturator tape procedures. Yet, the transobturator route may be associated with less voiding dysfunction, blood loss, bladder perforation, and shorter operating time. The original TVT-O procedure was modified with the aim of reducing the incidence of postoperative groin pain as well as the rather theoretical risk of obturator nerve injury. This modified procedure, named TVT-ABBREVO (Ethicon Women's Health and Urology, Somerville, NJ), utilizes a shortened, 12-cm-long polypropylene tape. In addition, perforation of the obturator membrane with the scissors and guide is avoided in order to reduce the depth of lateral dissection, and consequently, to maximize securing of the tape within the obturator muscular/aponeurotic structures. In a comparative anatomical study, it was indeed observed that the shorter tape traversed less muscular structures (with no or only a minimal amount of tape lying in the adductor muscles) than its original counterpart, while still consistently anchoring in the obturator membrane at a similarly safe distance from the obturator canal. In a single-center randomized clinical trial, after a 3 year minimum follow-up, the modified TVT-O procedure with a shorter tape and reduced dissection was found to be as safe and efficient as the primal procedure for treating female SUI, with less severe and frequent groin pain in the immediate postoperative period. PMID- 23109082 TI - Frontal theta is a signature of successful working memory manipulation. AB - It has been proposed that working memory (WM) is updated/manipulated via a fronto basal-ganglia circuit. One way that this could happen is via the synchronization of neural oscillations. A first step toward testing this hypothesis is to clearly establish a frontal scalp EEG signature of WM manipulation. Although many EEG studies have indeed revealed frontal EEG signatures for WM, especially in the theta frequency band (3-8 Hz), few of them required subjects to manipulate WM, and of those that did, none specifically tied the EEG signature to the manipulation process per se. Here we employed a WM manipulation task that has been shown with imaging to engage the prefrontal cortex and the striatum. We adapted this task to titrate the success of WM manipulation to approximately 50 %. Using time-frequency analysis of EEG, we showed that theta power increased over frontal cortex for successful versus failed WM manipulation, specifically at the time of the manipulation event. This establishes a clear-cut EEG signature of WM manipulation. Future studies could employ this to test the fronto-basal ganglia hypothesis of WM updating/manipulation. PMID- 23109083 TI - A right hemisphere dominance for bimanual grasps. AB - To find points on the surface of an object that ensure a stable grasp, it would be most effective to employ one area in one cortical hemisphere. But grasping the object with both hands requires control through both hemispheres. To better understand the control mechanisms underlying this "bimanual grasping", here we examined how the two hemispheres coordinate their control processes for bimanual grasping depending on visual field. We asked if bimanual grasping involves both visual fields equally or one more than the other. To test this, participants fixated either to the left or right of an object and then grasped or pushed it off a pedestal. We found that when participants grasped the object in the right visual field, maximum grip aperture (MGA) was larger and more variable, and participants were slower to react and to show MGA compared to when they grasped the object in the left visual field. In contrast, when participants pushed the object we observed no comparable visual field effects. These results suggest that grasping with both hands, specifically the computation of grasp points on the object, predominantly involves the right hemisphere. Our study provides new insights into the interactions of the two hemispheres for grasping. PMID- 23109084 TI - Differential effects of absent visual feedback control on gait variability during different locomotion speeds. AB - Healthy persons exhibit relatively small temporal and spatial gait variability when walking unimpeded. In contrast, patients with a sensory deficit (e.g., polyneuropathy) show an increased gait variability that depends on speed and is associated with an increased fall risk. The purpose of this study was to investigate the role of vision in gait stabilization by determining the effects of withdrawing visual information (eyes closed) on gait variability at different locomotion speeds. Ten healthy subjects (32.2 +/- 7.9 years, 5 women) walked on a treadmill for 5-min periods at their preferred walking speed and at 20, 40, 70, and 80 % of maximal walking speed during the conditions of walking with eyes open (EO) and with eyes closed (EC). The coefficient of variation (CV) and fractal dimension (alpha) of the fluctuations in stride time, stride length, and base width were computed and analyzed. Withdrawing visual information increased the base width CV for all walking velocities (p < 0.001). The effects of absent visual information on CV and alpha of stride time and stride length were most pronounced during slow locomotion (p < 0.001) and declined during fast walking speeds. The results indicate that visual feedback control is used to stabilize the medio-lateral (i.e., base width) gait parameters at all speed sections. In contrast, sensory feedback control in the fore-aft direction (i.e., stride time and stride length) depends on speed. Sensory feedback contributes most to fore aft gait stabilization during slow locomotion, whereas passive biomechanical mechanisms and an automated central pattern generation appear to control fast locomotion. PMID- 23109085 TI - Spatial attention modulates tactile change detection. AB - People often fail to detect changes between successively presented tactile patterns, a phenomenon known as tactile change blindness. In this study, we investigated whether changes introduced to tactile patterns are detected better when a participant's attention is focused on the location where the change occurs. Across two experiments, participants (N = 55) were instructed to detect changes between two consecutively presented tactile patterns. In half of the trials, the stimulated body sites in the two patterns were identical. In the other half of the trials, one of the stimulated body locations differed between the two patterns. Endogenous (or voluntary) attention was manipulated by instructing participants which new bodily location was most likely to be stimulated. We found that changes at the attended location were detected more accurately than changes at bodily locations that were unattended. This finding demonstrates that attention can effectively modulate tactile change detection. We discuss the value of this experimental paradigm for investigating excessive attentional focus or hypervigilance to particular regions of the body in various clinical populations. PMID- 23109086 TI - Discrimination is not impaired when more cortical space between two electro tactile markers increases perceived duration. AB - The purpose of the present study was to examine how duration processing is affected by space between two electro-tactile stimuli marking inter-stimulus time intervals. The results of two experiments, where the method of constant stimuli was used, indicated that discrimination remained at the same level when delivering two markers to different fingers (of the same hand) resulted in longer perceived duration than delivering them to the same finger. Indeed, in Experiment 1, intervals were overestimated while discrimination remained at the same level when the leading and tailing markers were delivered to the index and ring fingers, respectively, compared with when both markers were delivered to the index finger. In Experiment 2, while there were individual differences in spatial effect on perceived duration when the leading and tailing markers were delivered to the middle and little fingers, respectively, discrimination remained at the same level even with participants overestimating intervals. This indicates that variability in duration processing is constant within the same cortical hemisphere when more space between two stimuli marking time results in longer perceived duration. PMID- 23109087 TI - Coordination of degrees of freedom and stabilization of task variables in a complex motor skill: expertise-related differences in cello bowing. AB - Stringed instrument bowing is a complex sensorimotor skill, involving fine regulation of bow orientation and motion relative to the string. In this study, we characterize this skill in terms of stabilization of specific bow parameters as well as the underlying use and coordination of the degrees of freedom (DOF) of the right bowing arm. Age-matched samples of 10 advanced cellists and 10 cello novices took part in the study. Kinematic bow movement data were analyzed with respect to task variables suggested by the cello teaching literature: position and orientation of the bow relative to the string, bow velocity, and timing. Joint motion of the bowing arm was analyzed in terms of movement amplitude and inter-joint coordination (principal component analysis). As expected, novices showed poorer control of bowing parameters. In addition, novices differed markedly from advanced players in the use and coordination of the DOF of the bowing arm, with the elbow and wrist showing less overall movement and a reduced proportion of variance explained by the first principal component (PC1). In contrast, larger amounts of shoulder variance were explained by PC1 in novices compared to experts. Our findings support Bernstein's theory of graded skill acquisition, according to which early stages of motor skill learning are characterized by a "freezing" of movement DOF, while later learning stages exploit the DOF, possibly following a proximal-to-distal sequence, for improved task performance. PMID- 23109088 TI - Phosphine-based redox catalysis in the direct traceless Staudinger ligation of carboxylic acids and azides. PMID- 23109089 TI - Family-based association study of ADHD and genes increasing the risk for smoking behaviours. AB - OBJECTIVE: To investigate five top single nucleotide polymorphisms (SNPs) located in different genes and loci (CHRNA3, BDNF, DBH and LOC100188947) that were highly associated with different dimensions of smoking behaviour, in relation to attention-deficit hyperactivity disorder (ADHD). DESIGN: Cohort study consisting of a clinical sample of children with ADHD. SETTING: Douglas Institute ADHD Clinic, Montreal, Canada. PATIENTS: Families of 454 children with ADHD aged 6-12 years old. INTERVENTIONS: Family-based association tests used to study the transmission of risk alleles within these five genetic markers. MAIN OUTCOME MEASURES: Clinical diagnosis of ADHD, and a number of behavioural and neurocognitive phenotypes relevant to the disorder. RESULTS: One SNP (rs1329650) from a non-coding RNA (LOC100188947) was significantly associated with overall ADHD diagnosis with the C* risk allele being over-transmitted from parents to children with ADHD (p=0.02). It was also over-transmitted to children with higher scores on Conners' Parents (p=0.01) and Conners' Teacher (p=0.002) index scores, and Child Behaviour Checklist withdrawn (p=0.001) and aggressive (p=0.007) behaviours. Children with poorer performances on executive and attention tasks were more likely to inherit the risk allele. CONCLUSIONS: The C* allele of rs1329650 may be increasing the risk for ADHD and smoking behaviour through a common mechanism, possibly externalising behaviours and specific cognitive deficits that manifest as ADHD in childhood and are the gateway to smoking behaviour later in life. This exploratory study illustrates the use of comorbid disorders to investigate ADHD genetics. In spite of its relatively large sample size, replication in future studies is warranted. PMID- 23109091 TI - Shared biological risks that influence brain and behaviour. PMID- 23109090 TI - Systematic review and meta-analyses of risk factors for childhood overweight identifiable during infancy. AB - OBJECTIVE: To determine risk factors for childhood overweight that can be identified during the first year of life to facilitate early identification and targeted intervention. DESIGN: Systematic review and meta-analysis. SEARCH STRATEGY: Electronic database search of MEDLINE, EMBASE, PubMed and CAB Abstracts. ELIGIBILITY CRITERIA: Prospective observational studies following up children from birth for at least 2 years. RESULTS: Thirty prospective studies were identified. Significant and strong independent associations with childhood overweight were identified for maternal pre-pregnancy overweight, high infant birth weight and rapid weight gain during the first year of life. Meta-analysis comparing breastfed with non-breastfed infants found a 15% decrease (95% CI 0.74 to 0.99; I(2)=73.3%; n=10) in the odds of childhood overweight. For children of mothers smoking during pregnancy there was a 47% increase (95% CI 1.26 to 1.73; I(2)=47.5%; n=7) in the odds of childhood overweight. There was some evidence associating early introduction of solid foods and childhood overweight. There was conflicting evidence for duration of breastfeeding, socioeconomic status at birth, parity and maternal marital status at birth. No association with childhood overweight was found for maternal age or education at birth, maternal depression or infant ethnicity. There was inconclusive evidence for delivery type, gestational weight gain, maternal postpartum weight loss and 'fussy' infant temperament due to the limited number of studies. CONCLUSIONS: Several risk factors for both overweight and obesity in childhood are identifiable during infancy. Future research needs to focus on whether it is clinically feasible for healthcare professionals to identify infants at greatest risk. PMID- 23109093 TI - Lower limb alignment in the frontal plane: analysis from long standing radiographs and computer tomography scout views: an experimental study. AB - OBJECTIVES: A profound knowledge of physiologic lower limb alignment is essential to understand deformities and to plan surgical correction. The gold standard in radiographic assessment is the long standing radiograph with a forward directed patella. The advantage of computed tomography (CT) is that its cutting-edge image technique can visualize the femur condyles. Study purpose was to determine if the CT-scout view has the potential to replace the standing radiograph. MATERIALS AND METHODS: We compared the geometric data obtained from long standing radiograph and CT-scout views both with patella forward position. Furthermore, we developed a method of positioning the lower extremity stable on the CT table, where the femoral condyles became the new orientation criterion. Finally, we evaluated differences in the data ascertainment between the long standing radiograph with patella facing forward and the CT-scout view with the posterior edge of femoral condyles orientated parallel to the radiographic cassette. RESULTS: The geometric data of long standing radiograph and CT-scout views are comparable if the leg is in the same rotational position. We developed a CT positioning jig to adjust the femur condyles parallel to the radiographic cassette. In 80 % of the cases, the deviation was 5 degrees or less. These scout views showed statistically significant differences when compared with data from standing radiograph with a forward centered patella. CONCLUSION: No evidence was found clearly excluding the possibility of an exclusive use of the CT-scout view for the analysis of the leg geometry. However, advantages of the long standing radiograph became obvious. PMID- 23109092 TI - The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. AB - Human sulfatase 2 (SULF2) functions as an oncoprotein in hepatocellular carcinoma (HCC) development by promoting tumor growth and metastasis via enhancement of fibroblast growth factor-2/extracellular signal-regulated kinase and WNT/beta catenin signaling. Recent results implicate that SULF2 activates the transforming growth factor beta (TGFB) and Hedgehog/GLI1 pathways in HCC. OKN-007 is a novel phenyl-sulfonyl compound that inhibits the enzymatic activity of SULF2. To investigate the antitumor effect of OKN-007 in HCC, we treated Huh7 cells, which express high levels of SULF2, with OKN-007 and found that it significantly promoted tumor cell apoptosis and inhibited cell proliferation, viability, and migration. To understand the action of OKN-007 on SULF2, we used Huh7 cells which normally express SULF2 and Hep3B cells that do not normally express SULF2. Utilizing Huh7 cells transfected with short hairpin RNA targeting SULF2 and transfection of Hep3B cells with a SULF2 plasmid to enhance SULF2 expression, we showed that the antitumor activity of OKN-007 was more pronounced in cells expressing SULF2. Furthermore, in vivo experiments verified that OKN-007 repressed tumor growth significantly. These results identify SULF2 as an important target of the antitumor effect of OKN-007. To determine the molecular mechanism of the antitumor effect of OKN-007, both TGFB1/SMAD and Hedgehog/GLI1 signaling pathway activity were measured by Western blot and SMAD- or GLI reporter luciferase assays. We found that both signaling pathways were inhibited by OKN-007. Together, these results show that OKN-007 can suppress TGFB1/SMAD and Hedgehog/GLI1 signaling via its inhibition of SULF2 enzymatic activity. We conclude that OKN-007 or more potent derivatives may be promising agents for the treatment of HCC. PMID- 23109094 TI - Which posterior instrumentation is better for two-level anterior lumbar interbody fusion: translaminar facet screw or pedicle screw? AB - PURPOSE: To determine whether translaminar facet screws can provide stability equivalent to pedicle screws and whether the two posterior instrumentations have the same influence on the adjacent segments in two-level anterior lumbar interbody fusion. METHODS: In a biomechanical study conducted, we used 12 fresh human lumbar spines and tested an intact spine with a stand-alone two-level anterior lumbar interbody fusion and anterior fusion augmented with pedicle screws or translaminar facet screws, under 400 N compressive preloads and 7.5 N m moments in flexion, extension, axial rotation and lateral bending, and measured the stiffness of the operated level, range of motion and intradiscal pressure at the adjacent levels. RESULTS: We found a significant increase in the stiffness of the segments operated, range of motion and intradiscal pressure at the adjacent superior segment in the stand-alone two-level anterior lumbar interbody fusion during flexion, axial rotation and lateral bending, but a decrease in extension, when compared with the intact spine. The stiffness of operated segments, range of motion and intradiscal pressure in the adjacent segment are significantly higher in the two-level anterior lumbar interbody fusion augmented with posterior instrumentation than in the stand-alone two-level anterior lumbar interbody fusion. There was no significant difference between the two augmented constructs except that, at the adjacent superior segment, the intradiscal pressure was more in the construction augmented with a pedicle screw than with a translaminar facet screw in flexion. CONCLUSIONS: Translaminar facet screws can provide stability equivalent to pedicle screws, but their influence on the adjacent segments is relatively lower; therefore, we suggest that translaminar facet screws be the choice in the optimal posterior instrumentation in a two-level anterior lumbar interbody fusion. PMID- 23109095 TI - A non-randomized controlled clinical trial on autologous chondrocyte implantation (ACI) in cartilage defects of the medial femoral condyle with or without high tibial osteotomy in patients with varus deformity of less than 5 degrees . AB - PURPOSE: High tibial osteotomy (HTO) is a recommended concomitant surgery when treating cartilage lesions of the medial femoral condyle (MFC). Varus deformities of 5 degrees and more were considered an indication for HTO in patients with cartilage defects. This study compares clinical outcome in patients with ACI and concomitant varus deformity of <5 degrees with or without additional HTO. METHODS: 43 patients with isolated cartilage defect of the MFC and varus deformity between 1 degrees and 5 degrees (mean age 39.14 +/- 8.35 years; mean varus deformity 2.84 +/- 1.19 degrees ) were included (follow-up 71.88 +/- 23.99 months). Group A (n = 19) was treated with ACI and additional HTO; group B (n = 24) received ACI only. Survival rate in terms of absence of the need of reintervention was defined as main outcome parameter. In the subgroup without reintervention, functional outcome (KOOS and WOMAC) was evaluated. RESULTS: Overall rate of reintervention was 12 (27.9 %). Survival was significantly higher in group A (group A 89.5 %, group B 58.33 %; p = 0.023). Although a trend for better clinical outcome was observed for group A in the subgroup without reintervention, this observation lacked statistical significance (KOOS(symptoms) group A 73.23, group B 59.64; p = 0.274). CONCLUSION: While there is general consensus for treating varus deformities of >5 degrees in patients with cartilage lesions of the medial femoral condyle, HTO also leads to a reduced rate of reinterventions and longer survival rates in patients with varus deformities of <5 degrees . PMID- 23109096 TI - Microstructural changes in the hippocampus and posterior cingulate in mild cognitive impairment and Alzheimer's disease: a diffusion tensor imaging study. AB - Diffusion tensor imaging (DTI) is a sensitive MRI technique in the detection of white matter degeneration. We sought to demonstrate microstructural changes in normal controls, patients with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) and to determine which DTI parameters could be a reliable tool for the early diagnosis of AD. In total, 90 participants (35 normal, 20 aMCI, 35 AD) were recruited. We included early AD patients with clinical dementia rating scores of 0.5 and 1. The fractional anisotropy and mean diffusivity values, DTI parameter, were measured with the regions of interest method in the bilateral hippocampal body and posterior cingulate. Clinical history, neurological examination, and neuropsychological assessments were conducted. The DTI parameters in the bilateral hippocampus and posterior cingulate in aMCI and AD were different from those in normal controls. No difference was found in DTI parameters of the posterior cingulate between aMCI and AD. However, hippocampal DTI parameters were different between aMCI and AD. Cognitive summary measures were significantly correlated with DTI parameters, especially FA values in the hippocampus. The DTI analysis technique demonstrated significant microstructural alterations in the hippocampus and posterior cingulate already in prodromal stage of AD. DTI parameters in the hippocampus may be a more sensitive method to determine microstructural changes in early AD states and more correlated with cognition than DTI parameters in the posterior cingulate. PMID- 23109097 TI - Sleep disturbances in patients with multiple sclerosis. AB - Sleep disturbances constitute one of the important yet underestimated aspects of functioning of patients with multiple sclerosis (MS). The objective of this study was to evaluate sleep disturbances in patients with MS, with regard to demographic factors, disease-related variables, co-existing conditions and fatigue. In 100 MS patients, Epworth Sleepiness Scale (ESS) and a questionnaire about sleep disturbances (SlD) were implemented. ESS and SlD results were analyzed with regard to age, gender, duration of MS, type of its course, degree of disability in Expanded Disability Status Scale (EDSS), MS therapies, coexisting diseases, results of Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS). ESS score indicated increased daytime sleepiness in 19 patients. In SlD, 49 subjects reported sleep disturbances and 35 more than one of their kind (most commonly terminal and middle insomnia). No relationships were found between ESS and SlD scores and age, gender, MS duration, type of its course, EDSS or coexisting diseases. In 36 patients, somatic complaints interfered with sleep. The patients with depression had significantly lower ESS result and those currently treated with immunomodulation had significantly lower SlD score. SlD score correlated positively with FSS and MFIS. Sleep disturbances in MS patients may occur independently from demographic and disease-related variables, but they are often influenced by the symptoms of MS and therapies used. Sleep disturbances may contribute to fatigue in the course of MS. PMID- 23109098 TI - Preparation of photoactive polymers and postmodification via nitroxide trapping under UV irradiation. AB - New types of photoactive homo and block copolymers bearing alpha hydroxyalkylphenylketone (2-hydroxy-2-methyl-1-phenylpropan-1-one) moieties as backbone substituents are prepared using nitroxide-mediated radical polymerization (NMP). Such polymers can be readily activated via the Norrish-type I photoreaction to give polymeric acyl radicals. Photolysis in the presence of a persistent nitroxide, which serves as a C- radical trapping reagent, leads to chemically modified polymers conjugated with nitroxide moieties. The number average molecular weight (M(n)) of the prepolymers and the chemically modified polymers was determined by gel permeation chromatography (GPC). Structures were further confirmed by NMR spectroscopy and by attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy. PMID- 23109100 TI - Functional interaction between calsequestrin and ryanodine receptor in the heart. AB - Evidence obtained in the last two decades indicates that calsequestrin (CSQ2), as the major Ca(2+)-binding protein in the sarcoplasmic reticulum of cardiac myocytes, communicates changes in the luminal Ca(2+) concentration to the cardiac ryanodine receptor (RYR2) channel. This review summarizes the major aspects in the interaction between CSQ2 and the RYR2 channel. The single channel properties of RYR2 channels, discussed here in the context of structural changes in CSQ2 after Ca(2+) binding, are particularly important. We focus on five important questions concerning: (1) the method for reliable detection of CSQ2 on the reconstituted RYR2 channel complex; (2) the power of the procedure to strip CSQ2 from the RYR2 channel complex; (3) structural changes in CSQ2 upon binding of Ca(2+) which cause CSQ2 dissociation; (4) the potential role of CSQ2-independent regulation of the RYR2 activity by luminal Ca(2+); and (5) the vizualization of CSQ2 dissociation from the RYR2 channel complex on the single channel level. We discuss the potential sources of the conflicting experimental results which may aid detailed understanding of the CSQ2 regulatory role. Although we mainly focus on the cardiac isoform of the proteins, some aspects of more extensive work carried out on the skeletal isoform are also discussed. PMID- 23109102 TI - "Pollical palmar interosseous muscle" (musculus adductor pollicis accessorius): attachments, innervation, variations, phylogeny, and implications for human evolution and medicine. AB - Most atlases and textbooks dealing with human anatomy do not refer to the "pollical palmar interosseous" (PPI) muscle of Henle. In order to undertake a fresh and detailed study of this muscle and to thus better understand human comparative anatomy and evolution, we: 1) analyze the frequency of the PPI in a large sample of human hands; 2) describe the attachments, innervation and varieties of the PPI in these hands; 3) compare the data obtained with the information available in the literature; and 4) discuss the phylogenetic origin of the PPI and the implications of our observations and comparisons for medicine and for the understanding of human evolutionary history. Within the 72 hands dissected by us, the PPI is present in 67 hands (93%), commonly having a single muscular branch, originating from the medial side of the base of metacarpal I only, inserting onto the medial side of the base of the pollical proximal phalanx and/or surrounding structures (e.g., ulnar sesamoid bone, wing tendon of extensor apparatus), and passing at least partially, and usually mainly, medial to the princeps pollicis artery. A careful study of the human PPI, as well as a detailed comparison with other mammals, strongly suggest that the muscle is evolutionarily derived from the adductor pollicis, and namely from its oblique head. Therefore, we propose that PPI should be designated by the name musculus adductor pollicis accessorius, which indicates that the muscle is most likely a de novo structure derived from the adductor pollicis. PMID- 23109103 TI - Safety, incentives, and the reporting of work-related injuries among union carpenters: "you're pretty much screwed if you get hurt at work". AB - BACKGROUND: In the high-risk construction industry little is known about the prevalence or effects of programs offering rewards for workers and/or their supervisors for improved safety records or those that punish workers in some way for injury. METHODS: We conducted an anonymous survey of 1,020 carpenter apprentices in three union training programs to document prevalence of their exposure to such efforts. We explored associations between perceptions of the reporting of work-related injury and elements of these programs. RESULTS: Fifty eight percent (58%; n = 592) reported some safety incentive or negative consequence of work-related injuries on their current jobsite. Reporting of work related injuries was 50% less prevalent when workers were disciplined for injury experiences. Otherwise, we saw minimal evidence of association between injury reporting practices and safety incentive programs. However, considerable evidence of fear of reprisal for reporting injuries was revealed. Less than half (46.4%) reported that work-related injuries were reported in their current workplace all or most of the time; over 30% said they were almost never or rarely reported. CONCLUSIONS: There are multiple layers of disincentives to the reporting of work related injuries that hamper understanding of risk and pose threats to workplace safety and productivity. These pressures do not arise in a vacuum and are likely influenced by a host of contextual factors. Efforts that help us understand variation across jobsites and time could be enlightening; such inquiries may require mixed methodologies and should be framed with consideration for the upper tiers of the public health hierarchy of hazard control. PMID- 23109101 TI - Anti-infective properties of bacteriocins: an update. AB - Bacteriocin production is a widespread phenomenon among bacteria. Bacteriocins hold great promise for the treatment of diseases caused by pathogenic bacteria and could be used in the future as alternatives to existing antibiotics. The anti infective potential of bacteriocins for inhibiting pathogens has been shown in various food matrices including cheese, meat, and vegetables. However, their inhibition of pathogens in vivo remains unclear and needs more investigation, due mainly to difficulties associated with demonstrating their health benefits. Many bacteriocins produced by established or potential probiotic organisms have been evaluated as potential therapeutic agents and interesting findings have been documented in vitro as well as in a few in vivo studies. Some recent in vivo studies point to the efficacy of bacteriocin-based treatments of human and animal infections. While further investigation remains necessary before the possibilities for bacteriocins in clinical practice can be described more fully, this review provides an overview of their potential applications to human and veterinary health. PMID- 23109104 TI - High-throughput printing via microvascular multinozzle arrays. AB - Microvascular multinozzle arrays are designed and fabricated for high-throughput printing of functional materials. Ink-flow uniformity within these multigeneration, bifurcating microchannel arrays is characterized by computer modeling and microscopic particle image velocimetry (micro-PIV) measurements. Both single and dual multinozzle printheads are produced to enable rapid printing of multilayered periodic structures over large areas (~1 m(2)). PMID- 23109106 TI - Selective cell recruitment and spatially controlled cell attachment on instructive chitosan surfaces functionalized with antibodies. AB - Bioactive constructs to guide cellular mobilization and function have been proposed as an approach for a new generation of biomaterials in functional tissue engineering. Adult mesenchymal stem cells have been widely used as a source for cell based therapeutic strategies, namely tissue engineering. This is a heterogeneous cell population containing many subpopulations with distinct regenerative capacity. Thus, one of the issues for the effective clinical use of stem cells in tissue engineering is the isolation of a highly purified, expandable specific subpopulation of stem cells. Antibody functionalized biomaterials could be promising candidates to isolate and recruit specific cell types. Here we propose a new concept of instructive biomaterials that are able to recruit and purify specific cell types from a mixed cell population. This biomimetic concept uses a target-specific chitosan substrate to capture specific adipose derived stem cells. Specific antibodies were covalently immobilized onto chitosan membranes using bis[sulfosuccinimidyl] suberate (BS3). Quartz crystal microbalance (QCM) was used to monitor antibody immobilization/adsorption onto the chitosan films. Specific antibodies covalently immobilized, kept their bioactivity and captured specific cell types from a mixed cell population. Microcontact printing allowed to covalently immobilize antibodies in patterns and simultaneously a spatial control in cell attachment. PMID- 23109105 TI - Layer-by-layer assembled films composed of "charge matched" and "length matched" polysaccharides: self-patterning and unexpected effects of the degree of polymerization. AB - The functionalization of chitosan with carboxymethyl groups allows zwitterionic or anionic chitosan derivatives to be obtained as a function of the degree of substitution. Here, we show that polyelectrolyte multilayers of chitosan and carboxymethylchitosan can be assembled by "dipping" or "spraying" to form strongly hydrated films in which both the polyanion and polycation possess the same polymer backbone ("matched chemistries"). Such films grow rapidly to fairly large thickness in very few assembly steps, especially in the case of "matched" charge densities, and atomic force microscopy reveals the formation of surface patterns that are dependent on the deposition conditions and on the number of layers. Interestingly, the influence of the molar masses of the polyelectrolyte pairs on the complex formation is somewhat counterintuitive, the stronger complexation occurring between polyanions and polycations of different ("non matching") lengths. PMID- 23109107 TI - How to control the recombinant prion protein adhesion for successful storage through modification of surface properties. AB - Depletion of neuroproteins on the inner walls of storage tubes influences the accuracy of tests used for identification of various neurodegenerative disorders. In this paper, a strategy is described for surface modification of Eppendorf tubes leading to non-adhesive properties towards the recombinant human prion proteins (PrPrec(hum)). Tubes were pre-activated by helium plasma and grafted with three diverse coatings: pure poly(N-isopropylacrylamide) (PNIPAM), PNIPAM admixed with either neutral PEG(20)sorbitan monolaurate (PEG(20)) or positively charged cetyl trimethylammonium bromide (CTAB) at varying plasma activation times and polymer to surfactant ratios. New functionalized surfaces were analyzed by goniometry, streaming potential measurement and X-ray photoelectron spectroscopy, whereas the protein adhesion was monitored by enzyme linked immunosorbent assays and confocal microscopy. The mapping of PrPrec(hum) adhesion associated with surface analyses enabled us to determine that no or negligible depletion of PrPrec(hum) can be obtained by surfaces possessing basic component in the range between 50 and 60 mJ m(-2) and streaming potential zeta(7.4) - -50 mV. PMID- 23109108 TI - Transsynaptic inhibition of spinal transmission by A2 botulinum toxin. AB - Type A botulinum toxin blocks not only ACh release from motor nerve terminals but also central synaptic transmission, including glutamate, noradrenaline, dopamine, ATP, GABA and glycine. Neurotoxins (NTXs) are transported by both antero- and retrogradely along either motor or sensory axons for bidirectional delivery between peripheral tissues or the CNS. A newly developed type A2 NTX (A2NTX) injected into one rat foreleg muscle was transported to the contralateral muscle. This finding was consistent with the NTX traveling retrogradely via spinal neurons and then transsynaptically through motor neurons to the contralateral motor neurons within the spinal cord and on to the soleus muscle. In the present study we found that toxin injection into the rat left soleus muscle clearly induced bilateral muscle relaxation in a dose-dependent fashion, although the contralateral muscle relaxation followed the complete inhibition of toxin injected ipsilateral muscles. The toxin-injected ipsilateral muscle relaxation was faster and stronger in A2NTX-treated rats than A1LL (BOTOX). A1LL was transported almost equally to the contralateral muscle via neural pathways and the bloodstream. In contrast, A2NTX was mainly transported to contralateral muscles via the blood. A1LL was more successfully transported to contralateral spinal neurons than A2NTX. We also demonstrated that A1LL and A2NTX were carried from peripheral to CNS and vice versa by dual antero- and retrograde axonal transport through either motor or sensory neurons. PMID- 23109109 TI - alpha2-containing GABAA receptors expressed in hippocampal region CA3 control fast network oscillations. AB - GABA(A) receptors are critically involved in hippocampal oscillations. GABA(A) receptor alpha1 and alpha2 subunits are differentially expressed throughout the hippocampal circuitry and thereby may have distinct contributions to oscillations. It is unknown which GABA(A) receptor alpha subunit controls hippocampal oscillations and where these receptors are expressed. To address these questions we used transgenic mice expressing GABA(A) receptor alpha1 and/or alpha2 subunits with point mutations (H101R) that render these receptors insensitive to allosteric modulation at the benzodiazepine binding site, and tested how increased or decreased function of alpha subunits affects hippocampal oscillations. Positive allosteric modulation by zolpidem prolonged decay kinetics of hippocampal GABAergic synaptic transmission and reduced the frequency of cholinergically induced oscillations. Allosteric modulation of GABAergic receptors in CA3 altered oscillation frequency in CA1, while modulation of GABA receptors in CA1 did not affect oscillations. In mice having a point mutation (H101R) at the GABA(A) receptor alpha2 subunit, zolpidem effects on cholinergically induced oscillations were strongly reduced compared to wild-type animals, while zolpidem modulation was still present in mice with the H101R mutation at the alpha1 subunit. Furthermore, genetic knockout of alpha2 subunits strongly reduced oscillations, whereas knockout of alpha1 subunits had no effect. Allosteric modulation of GABAergic receptors was strongly reduced in unitary connections between fast spiking interneurons and pyramidal neurons in CA3 of alpha2H101R mice, but not of alpha1H101R mice, suggesting that fast spiking interneuron to pyramidal neuron synapses in CA3 contain alpha2 subunits. These findings suggest that alpha2-containing GABA(A) receptors expressed in the CA3 region provide the inhibition that controls hippocampal rhythm during cholinergically induced oscillations. PMID- 23109110 TI - Effects of in vivo injury on the neuromuscular junction in healthy and dystrophic muscles. AB - The most common and severe form of muscular dystrophy is Duchenne muscular dystrophy (DMD), a disorder caused by the absence of dystrophin, a structural protein found on the cytoplasmic surface of the sarcolemma of striated muscle fibres. Considerable attention has been dedicated to studying myofibre damage and muscle plasticity, but there is little information to determine if damage from contraction-induced injury occurs at or near the nerve terminal axon. We used alpha-bungarotoxin to compare neuromuscular junction (NMJ) morphology in healthy (wild-type, WT) and dystrophic (mdx) mouse quadriceps muscles and evaluated transcript levels of the post-synaptic muscle-specific kinase signalling complex. Our focus was to study changes in NMJs after injury induced with an established in vivo animal injury model. Neuromuscular transmission, electromyography (EMG), and NMJ morphology were assessed 24 h after injury. In non-injured muscle, muscle specific kinase expression was significantly decreased in mdx compared to WT. Injury resulted in a significant loss of maximal torque in WT (39 +/- 6%) and mdx (76 +/- 8%) quadriceps, but significant changes in NMJ morphology, neuromuscular transmission and EMG data were found only in mdx following injury. Compared with WT mice, motor end-plates of mdx mice demonstrated less continuous morphology, more disperse acetylcholine receptor aggregates and increased number of individual acetylcholine receptor clusters, an effect that was exacerbated following injury. Neuromuscular transmission failure increased and the EMG measures decreased after injury in mdx mice only. The data show that eccentric contraction-induced injury causes morphological and functional changes to the NMJs in mdx skeletal muscle, which may play a role in excitation-contraction coupling failure and progression of the dystrophic process. PMID- 23109111 TI - Heterogeneous properties of central lateral and parafascicular thalamic synapses in the striatum. AB - To understand the principles of operation of the striatum it is critical to elucidate the properties of the main excitatory inputs from cortex and thalamus, as well as their ability to activate the main neurons of the striatum, the medium spiny neurons (MSNs). As the thalamostriatal projection is heterogeneous, we set out to isolate and study the thalamic afferent inputs to MSNs using small localized injections of adeno-associated virus carrying fusion genes for channelrhodopsin-2 and YFP, in either the rostral or caudal regions of the intralaminar thalamic nuclei (i.e. the central lateral or parafascicular nucleus). This enabled optical activation of specific thalamic afferents combined with whole-cell, patch-clamp recordings of MSNs and electrical stimulation of cortical afferents, in adult mice. We found that thalamostriatal synapses differ significantly in their peak amplitude responses, short-term dynamics and expression of ionotropic glutamate receptor subtypes. Our results suggest that central lateral synapses are most efficient in driving MSNs to depolarization, particularly those of the direct pathway, as they exhibit large amplitude responses, short-term facilitation and predominantly express postsynaptic AMPA receptors. In contrast, parafascicular synapses exhibit small amplitude responses, short-term depression and predominantly express postsynaptic NMDA receptors, suggesting a modulatory role, e.g. facilitating Ca(2+)-dependent processes. Indeed, pairing parafascicular, but not central lateral, presynaptic stimulation with action potentials in MSNs, leads to NMDA receptor- and Ca(2+) dependent long-term depression at these synapses. We conclude that the main excitatory thalamostriatal afferents differ in many of their characteristics and suggest that they each contribute differentially to striatal information processing. PMID- 23109113 TI - Structural characterization of the capybara (Hydrochaeris hydrochaeris) tongue by light, scanning, and transmission electron microscopy. AB - Capybara is the largest rodent in the world and displays a seasonally dependent herbivore feeding behavior. Here, we present an anatomical contribution for understand this fact, by light, scanning, and transmission electron microscopy methodologies for tongue tissue analysis. The histological preparations revealed filiform, fungiform, vallate, and foliate papillae on the dorsal mucosa of the capybara tongue. The epithelial layer exhibited a lining of keratinized stratified squamous epithelial cells. The lamina propria was characterized by a dense connective tissue composed of the primary and secondary papillar projections. We also revealed the original aspects of the connective papillae. The shapes of the papillae varied by region of the tongue, and filiform, fungiform, vallate, and foliate papillae and subjacent layers of muscular fibers were observed. Pyriform taste buds occupying the epithelial layer of fungiform, vallate and foliate papillae were identified and the intracellular components of the taste buds and the intracorpuscular amyelinated nerve fibers were observed. The taste buds were characterized by the distribution of granular endoplasmic reticulum throughout the perinuclear area, the Golgi apparatus, and mitochondrial assemblies of various distinct diameters. Mitochondrial accumulation was also observed in the collagen bundle-surrounded amyelinated nerve fibers beside the basal cells. Therefore, these peculiar anatomical descriptions may contribute to understanding the adaptation of the feeding behavior of capybaras in a seasonally changing environment. PMID- 23109112 TI - The association between neonatal thyroxine and craniosynostosis, Texas, 2004 2007. AB - BACKGROUND: Craniosynostosis (CS), a structural anomaly characterized by premature fusion of cranial sutures, occurs in 1 in 2000 live births. Associations of CS with the thyroid have been reported. Neonatal thyroid hormone (T4) is evaluated nationally at birth by the Newborn Screening Program (NBS). This study evaluated the relationship between NBS T4 levels and craniosynostosis. METHODS: Live-born singleton babies born in 2004 through 2007 were identified through the Texas Birth Defects Registry (499 cases) and Texas Bureau of Vital Statistics (3570 controls) and successfully linked to analyte data available in the Texas NBS Database. Cases were classified based on the absence of other major defects (isolated cases, n = 382) and suture(s) involved. Mean T4 levels were compared between controls and cases (overall and stratified by classification). T4 levels were stratified by quintiles to evaluate differences between cases and controls within quintiles. The diagnostic utility of NBS T4 was evaluated using receiver operator characteristic (ROC) curves. RESULTS: Mean T4 levels were lower in isolated cases (16.89 MUg/dl) than in controls (17.77 MUg/dl; p = 0.0004). This trend persisted for sagittal (16.69 MUg/dl; p = 0.002) and metopic (16.83 MUg/dl; p = 0.042) CS. When stratified by quintiles, 54% of isolated lambdoid CS were in the first quintile compared to controls (p = 0.012). ROC area under the curve (AUC) was approximately 0.55 for all classifications except lambdoid (AUC = 0.73). CONCLUSION: NBS T4 levels were slightly lower among cases with nearly half of all lambdoid CS having T4 levels in the lowest quintile. However, overall NBS T4 levels are not suitable for potential screening or diagnostic application. PMID- 23109114 TI - Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus results in increased risk of fracture and delayed fracture healing. ZDF fa/fa rats are an established model of type 2 diabetes mellitus with low bone mass and delayed bone healing. We tested whether a sclerostin-neutralizing antibody (Scl-AbVI) would reverse the skeletal deficits of diabetic ZDF rats. Femoral defects of 3 mm were created in 11-week-old diabetic ZDF fa/fa and nondiabetic ZDF +/+ rats and stabilized by an internal plate. Saline or 25 mg/kg Scl-AbVI was administered subcutaneously (s.c.) twice weekly for 12 weeks (n = 9-10/group). Bone mass and strength were assessed using pQCT, micro-computed tomography (uCT), and biomechanical testing. Bone histomorphometry was used to assess bone formation, and the filling of the bone defect was analyzed by uCT. Diabetic rats displayed lower spinal and femoral bone mass compared to nondiabetic rats, and Scl-AbVI treatment significantly enhanced bone mass of the femur and the spine of diabetic rats (p < 0.0001). Scl-AbVI also reversed the deficit in bone strength in the diabetic rats, with 65% and 89% increases in maximum load at the femoral shaft and neck, respectively (p < 0.0001). The lower bone mass in diabetic rats was associated with a 65% decrease in vertebral bone formation rate, which Scl-AbVI increased by sixfold, consistent with a pronounced anabolic effect. Nondiabetic rats filled 57% of the femoral defect, whereas diabetic rats filled only 21% (p < 0.05). Scl-AbVI treatment increased defect regeneration by 47% and 74%, respectively (p < 0.05). Sclerostin antibody treatment reverses the adverse effects of type 2 diabetes mellitus on bone mass and strength, and improves bone defect regeneration in rats. PMID- 23109119 TI - DNA-modification of eukaryotic cells. AB - A novel bioorthogonal method for the modification of cells with single-stranded DNA oligomers is compared to five alternative methods with respect to labeling efficacy, specificity, and effects on cell viability. The new method is based on oxime ligation of aminooxybiotin to aldehyde groups installed by periodate cleavage of cell-surface glycans, followed by the coupling of preformed DNA streptavidin conjugates. As compared with two literature-reported methods based on direct coupling of N-hydroxysuccinimidyl (NHS)-DNA or NHS-biotinylation as well as with techniques based on strain-promoted alkyne-azide cycloaddition, this method shows the highest labeling densities and is sufficiently mild to avoid cell damage. Functionality of the DNA tags is demonstrated by DNA-directed immobilization on solid substrates and assembly of small cell aggregates. PMID- 23109117 TI - What we have learned from inherited platelet disorders. AB - Identifying the molecular basis of inherited platelet disorders has contributed to our understanding of normal platelet physiology. Many of these conditions are rare, but close observation of clinical and laboratory phenotype, and subsequent identification of the abnormal protein and mutated gene, have provided us with unique opportunities to examine specific aspects of platelet biogenesis and function. Phenotype-genotype association studies are providing a detailed understanding of the structure and function of platelet membrane receptors, the biogenesis and release of platelet granules, and the assembly of the cytoskeleton. Genetic polymorphisms contributing to decreased or increased platelet adhesion and activation may translate into increased clinical risks for bleeding or thrombosis. More recently, genome wide association studies have identified new genes contributing to the variation in normal platelet function. PMID- 23109120 TI - Steady-state and time-resolved fluorescence of tetramethylrhodamine attached to DNA: correlation with DNA sequences. AB - Time-resolved fluorescence as well as steady-state absorption and fluorescence were detected in order to study the interactions between tetramethylrhodamine (TAMRA) and DNA when TAMRA was covalently labeled on single- and double-stranded oligonucleotides. Fluorescence intensity quenching and lifetime changes were characterized and correlated with different DNA sequences. The results demonstrated that the photoinduced electron transfer interaction between guanosine residues and TAMRA introduced a short lifetime fluorescence component when guanosine residues were at the TAMRA-attached terminal of the DNA sequences. The discrepancy of two-state and three-state models in previous studies was due to the DNA sequence selection and sensitivity of techniques used to detect the short lifetime component. The results will help the design of fluorescence-based experiments related to a dye labeled probe. PMID- 23109121 TI - Copper/titanium catalysis forms fully substituted carbon centers from the direct coupling of acyclic ketones, amines, and alkynes. PMID- 23109122 TI - Urinary hydrophilic and hydrophobic metabolic profiling based on liquid chromatography-mass spectrometry methods: Differential metabolite discovery specific to ovarian cancer. AB - Discovery of novel metabolite biomarker(s) for improved ovarian cancer diagnosis is of great importance. In this paper, the differences of urinary hydrophilic and hydrophobic metabolic profiling between healthy women, benign ovarian tumor, and ovarian cancer patients were studied by metabolomics strategy. Metabolites in urine were analyzed on hydrophilic interaction chromatography (HILIC) and reversed-phase liquid chromatography (RPLC) coupled to MS. Data from HILIC or RPLC, positive or negative ion detection mode were found to be complementary. Data were filtered by orthogonal signal correction (OSC) method, and the three groups were discriminated by partial least squares discrimination analysis (PLS DA) models. By combining the four datasets, maximum information can be collected, and a PLS-DA model was built after OSC filtering. The model based on combined dataset is superior to the ones based on the separate dataset, and important metabolites were screened based on the combined dataset model. Five metabolites were found to be specific to ovarian cancer and ten metabolites were considered commonly related to ovarian cancer and benign ovarian tumor. Combination of RPLC and HILIC separation, as well as positive and negative ion detection in metabolomic studies show advantages in collecting various metabolites information that helps us better understand the metabolic event. PMID- 23109124 TI - [Depressive disorders]. PMID- 23109123 TI - What should we do about Hypertriglyceridemia in Coronary Artery Disease Patients? AB - OPINION STATEMENT: Triglycerides are routinely obtained with standard lipid testing, but their role in cardiovascular risk is controversial. An excess of triglycerides is commonly encountered in patients with the metabolic syndrome or diabetes, and represents an excess burden of small, dense low-density lipoproteins (LDLs), which confers additive risk for cardiovascular disease. Current guidelines prioritize LDL targets first, but treatment of triglycerides once LDL targets are achieved bears consideration. Beyond lifestyle modification, potential pharmacologic therapies include statins, fibrates, niacin, omega-3 fatty acids and antidiabetic drugs. There are few trials to date comparing these agents directly in the management of hypertriglyceridemia, but available data seems to demonstrate that the greatest benefit of triglyceride lowering is experienced in a subgroup of patients with an atherogenic lipid profile (elevated triglycerides, low high-density lipoprotein (HDL), elevated small, dense LDL particles). Here, we discuss the current understanding of how triglyceride elevations impart cardiovascular risk, current therapies and the data supporting their use, and ongoing studies to elucidate the degree to which treatment of triglycerides modifies risk of future cardiovascular events. PMID- 23109125 TI - [The psychopharmacological treatment of depressive disorders in childhood and adolescence - developments and standards since the "black box" warning]. AB - Depending on symptom severity, psychopharmacological treatment can be a valuable option in the treatment of depressive disorders in childhood and adolescence. This review provides recommendations for clinical treatment, focusing on suicidality and treatment-resistant patients. The quality of studies regarding the psychopharmacological therapy of depressive disorders in childhood and adolescence has improved since the "black box" warning of the FDA concerning the occurrence of suicidality under treatment with selective serotonin reuptake inhibitors (SSRIs). In Germany, there is proof for a trend toward a more evidence based psychopharmacological treatment approach within recent years. PMID- 23109126 TI - [Cognitive behavior therapy for depression in children and adolescents - procedure, effects, and developments]. AB - Cognitive behavior therapy offers a theoretically and empirically valid therapeutic approach for children and adolescents suffering from depression. It can be recommended according to present guidelines and efficacy studies. Further research and conceptual development, however, is necessary especially regarding the small to moderate effect sizes as well as the lack of long-term efficacy and effect factors. This article gives a short overview of the basics and contents of cognitive behavior therapy for depressive children and adolescents. It furthermore presents the latest findings and an assessment of its efficacy and relevant developments and perspectives. PMID- 23109127 TI - [Efficacy of universal and selective prevention on depression in children and adolescents. A systematic review]. AB - OBJECTIVE: Unipolar depressive disorder often begins in childhood, making it essential to prevent the development of depressive disorders early on. The current review describes the evidence of selective, indicated, and universal prevention of depression in children and adolescents based on published, systematic reviews, and metaanalyses. METHOD: Scientific databases were electronically searched for prevention studies done between 1990 and 2012 with children and adolescents and written in German and English. Ten systematic reviews and metaanalyses were identified as eligible for review. These reviews in turn investigated a total of 121 controlled studies, 52 of which were universal, 46 selective, and 19 targeted prevention studies. Four studies combined selective and indicated prevention. RESULTS: Evidence was found for selective, indicated, and universal prevention in comparison to untreated control groups for efficacy in reducing depressive symptoms in children and adolescents. This was still evident for the follow-up at 3 to 9 months. Evidence for efficacy of selective prevention was still evident at 12 months post-intervention. The effect sizes were mostly low. Compared with placebo the efficacy is considerably lower or no evidence was found. CONCLUSIONS: The results of the single reviews were quite heterogeneous. For further research there is an urgent need to identify the factors responsible for effective programs and to test these under real-world conditions. PMID- 23109128 TI - Prevalence and comorbidities of adolescent depression in Germany. An analysis of Health Insurance Data. AB - OBJECTIVE: Data on the prevalence of depressive disorders in adolescents are scarce. We aimed to examine the administrative prevalence of depressive disorders and related comorbidities in German adolescents. A second objective of was to assess potential regional (East vs. West Germany) differences in depression prevalence. METHOD: Data of a statutory health insurance company were analysed and outpatients from 12 to 18 years of age with diagnosed depression during a one year-period (2009) were identified. RESULTS: The population at risk consisted of 140,563 adolescents. Of these, 4,295 (41.2% male; mean age: 15.5 years) had a diagnosis of depression. This equates to a prevalence of 3.1% (females: 3.7%, males: 2.5%). There were no significant differences between East and West Germany. Of all adolescents with depression, 62.5% had at least one comorbid psychiatric diagnosis, with anxiety and emotional disorders (23.7%), somatoform disorders (16.8%), hyperkinetic disorders (16.2%) and posttraumatic stress disorder (10.0%) being most frequently diagnosed. CONCLUSIONS: The depression prevalence in this sample was lower than that in studies of clinical samples. There was a marked prevalence of psychiatric comorbidities, especially of internalizing disorders. In adolescents, the risk of depression seems to be comparable in both East and West Germany. PMID- 23109129 TI - [Agreement of clinical diagnosis, structured interviews, and self-report questionnaires for depression in children and adolescents]. AB - OBJECTIVE: The present study examines the agreement of structured child and parent interviews as well as clinical diagnosis for depressive episodes in children and adolescents. Moreover, it compares the accuracy and optimal cutoff scores of self-report questionnaires with reference to each of these diagnostic assessments. METHOD: 81 children (9-12 years) and 88 adolescents (13-16 years) in psychiatric care and their parents completed the structured diagnostic interview Kinder-DIPS. The children answered the German Children's Depression Inventory (CDI), and the adolescents answered the German Center for Epidemiologic Studies Depression Scale (CES-D). Kappa coefficients quantified the agreement. Receiver operating characteristic (ROC) curves were used to determine optimal cutoff scores, sensitivity, specificity, as well as positive and negative predictive values. RESULTS: The agreement between the child and parent interviews as well as between the interviews and clinical diagnosis was low to moderate. Clinicians diagnosed depressive episodes more frequently than the interviews. Cutoff scores and measures of accuracy varied between the reference standards, with less favorable results for clinical diagnosis. CONCLUSIONS: Clinicians may profit from conducting structured interviews. Strategies for dealing with conflicting information from children and parents should be tested empirically and described in detail. PMID- 23109132 TI - International environmental and occupational health: From individual scientists to networked science Hubs. AB - For the past 16 years, the International Training and Research in Environmental and Occupational Health program (ITREOH) has supported projects that link U.S. academic scientists with scientists from low- and middle-income countries in diverse research and research training activities. Twenty-two projects of varied duration have conducted training to enhance the research capabilities of scientists at 75 institutions in 43 countries in Asia, Africa, Eastern Europe, and Latin America, and have built productive research relationships between these scientists and their U.S. partners. ITREOH investigators and their trainees have produced publications that have advanced basic sciences, developed methods, informed policy outcomes, and built institutional capacity. Today, the changing nature of the health sciences calls for a more strategic approach. Data-rich team science requires greater capacity for information technology and knowledge synthesis at the local institution. More robust systems for ethical review and administrative support are necessary to advance population-based research. Sustainability of institutional research capability depends on linkages to multiple national and international partners. In this context, the Fogarty International Center, the National Institute of Environmental Sciences and the National Institute for Occupational Safety and Health, have reengineered the ITREOH program to support and catalyze a multi-national network of regional hubs for Global Environmental and Occupational Health Sciences (GEOHealth). We anticipate that these networked science hubs will build upon previous investments by the ITREOH program and will serve to advance locally and internationally important health science, train and attract first-class scientists, and provide critical evidence to guide policy discussions. PMID- 23109133 TI - Advantages of surface-initiated ATRP (SI-ATRP) for the functionalization of electrospun materials. AB - Surface-initiated atom transfer radical polymerization (SI-ATRP) is successfully applied to electrospun constructs of poly(L-lactide). ATRP macroinitiators are adsorbed through polyelectrolyte complexation following the introduction of negative charges on the polyester surface through its blending with a six-armed carboxy-terminated oligolactide. SI-ATRP of glycerol monomethacrylate (GMMA) or 2 (N,N-diethylamino)ethyl methacrylate (DEAEMA) allows then to grow surface films with controllable thickness, and in this way also to control the wetting and interactions of the construct. PMID- 23109134 TI - Professor Rolf C. Gaillard. PMID- 23109135 TI - Overexpression of insulin-like growth factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors. AB - Approximately 15% of gastrointestinal stromal tumors (GISTs) in adults and 85% in children lack mutations in KIT and PDGFRA and are known as wild-type GISTs. Wild type GISTs from adults and children express high levels of insulin-like growth factor 1 receptor (IGF1R) and exhibit stable genomes compared to mutant GISTs. Pediatric wild-type GISTs, GISTs from the multitumor Carney-Stratakis syndrome, and the Carney triad share other clinicopathological properties (e.g., early onset, multifocal GISTs with epitheliod cell morphology), suggesting a common etiology. Carney-Stratakis is an inherited association of GIST and paragangliomas caused by germline mutations in succinate dehydrogenase (SDH) genes. The connection between defective cellular respiration and GIST pathology has been strengthened by the utilization of SDHB immunohistochemistry to identify SDH deficiency in pediatric GISTs, syndromic GISTs, and some adult wild-type GISTs. SDHB and IGF1R expression was examined in 12 wild-type and 12 mutant GIST cases. Wild-type GISTs were screened for coding-region alterations in SDH genes and for chromosomal aberrations using genome-wide single-nucleotide polymorphism and MIP arrays. SDHB-deficiency, identified in 11/12 wild-type GIST cases, was tightly associated with overexpression of IGF1R protein and transcript. Biallelic inactivation of the SDHA gene was a surprisingly frequent event, identified in 5 of 11 SDHB-negative cases, generally due to germline point mutations accompanied by somatic SDHA allelic losses. As a novel finding, inactivation of the SDHC gene from a combination of a heterozygous coding-region mutation and hypermethylation of the wild-type allele was found in one SDHB-negative case. PMID- 23109137 TI - Five overlapping enterprise stents in the internal carotid artery-to-middle cerebral artery to treat a ruptured blood blister-like aneurysm. PMID- 23109136 TI - A sequential impairment of cortical astrocytes and GABAergic neurons during ischemia is improved by mGluR1,5 activation. AB - Ischemic brain cell death is presumably caused by excitotoxicity. In addition to an increase of glutamate release during ischemia, the deficiency of astrocytic glutamate-reuptake may cause glutamate accumulation, which results in GABAergic neurons being vulnerable to ischemia. To confirm this hypothesis, we studied the pathophysiological changes of cortical astrocytes and GABAergic neurons during ischemia as well as the prevention of their injuries. Ischemia led to the sequential impairments of astrocytic glutamate-transporter currents and GABAergic neuronal excitability. The changes were partially reversed by 3,5-DHPG, an agonist of type-I/V metabotropic glutamate receptors (mGluR). Thus, mGluR1,5 activation may be useful against the sequential impairment of cortical astrocytes and GABAergic neurons in an early stage of ischemia. PMID- 23109138 TI - Relative contributions of naturalistic and constructed support: two studies of women with type 2 diabetes. AB - Do distinct sources of social support have differential effects on health? Although previous research has contrasted family and friend support (naturalistic support), research on the relative effects of naturalistic support and constructed support (e.g., support groups) is extremely rare. Two studies of women with type 2 diabetes were conducted that assessed the independent effects of naturalistic and constructed support on physical activity and glycosylated hemoglobin (HbA1c). Participants were women diagnosed with type 2 diabetes from the intervention arms of two randomized controlled trials: primarily European American women (Study 1; N = 163) and exclusively Hispanic women (Study 2; N = 142). Measures assessed physical activity, HbA1c, and friend and family support at baseline and at 6 months, as well as group support after 6 months of intervention. In Study 1, only group support was related to increases in physical activity (DeltaR(2) = .036). In Study 2, group support and family support showed independent effects on increases in physical activity (DeltaR(2) = .047 and .060, respectively). Also, group support was related to decreases in HbA1c in Study 1 (DeltaR(2) = .031) and Study 2 (DeltaR(2) = .065). Overall, constructed (group) support was related to outcomes most consistently, but naturalistic (family) support showed some independent relation to physical activity improvement. PMID- 23109139 TI - Polymorphism of estrogen receptor alpha (ESR1) is associated with virological response to entecavir (ETV) in nucleoside-naive adult patients with chronic hepatitis B. AB - INTRODUCTION: Polymorphisms in estrogen receptor alpha (ESR1) are reported to be associated with the susceptibility to persistent HBV infection, HBV liver cirrhosis and HBV-related hepatocellular carcinoma (HCC). MATERIALS AND METHODS: To test the hypothesis that polymorphisms in estrogen receptor alpha (ESR1) might influence the virological response to entecavir (ETV) therapy, we examined two polymorphisms (PvuII and XbaI) in 76 nucleoside-naive chronic hepatitis B (CHB) patients. All of the patients (52 HBeAg-positive and 24 HBeAg-negative) were treated with ETV 0.5 mg daily and followed up for a median time of 96 weeks (range 48-96). Polymorphisms were determined using the polymerase chain reaction restriction fragment-length polymorphism (PCR-RFLP) method. RESULTS: Under an additive model, the univariate analysis showed that patients carrying the PvuII T/C genotype might have higher virological responders than those carrying the T/T and C/C genotypes at week 48 (87.7 vs. 57.1 vs. 58.3 %; P = 0.012) and week 96 (96.7 vs. 64.3 vs. 24 87.5 %; P = 0.018), although this difference disappeared with the multiple analysis at week 48 [95 % confidence interval (CI) 0.687-3.841; P = 0.269] and week 96 (95 % CI 0.861-18.016; P = 0.077). Conversely, the univariate analysis suggests statistical significance between the recessive model of PvuII (TT vs. TC/CC) and virological response at week 48 (57.1 vs. 81.1 %; P = 0.033) and week 96 (64.3 vs. 94.7 %; P = 0.017). Multiple regression analysis affirmed the significant and independent association between the recessive model of PvuII and virological response. In other words, patients carrying at least one PvuII C allele (TC/CC) had a better likelihood of achieving virological response compared with those carrying the T/T genotype at week 48 (95 % CI 1.026-14.785, P = 0.046) and week 96 (95 % CI 1.456-57.509; P = 0.018). XbaI polymorphisms were not significantly associated with virological response. CONCLUSION: Our results suggest that the PvuII polymorphism may play an important role in determining ETV efficacy after 48 and 96 weeks of treatment, at least in this study population. PMID- 23109141 TI - Fabrication of flexible, all-reduced graphene oxide non-volatile memory devices. AB - A flexible, all reduced graphene oxide non-volatile memory device, with lightly reduced GO as an active layer and highly reduced GO as both top and bottom electrodes, is fabricated by a full-solution process and its performance is characterized. It provides a convenient method to construct other all-carbon devices. PMID- 23109140 TI - Quantifying load-induced solute transport and solute-matrix interaction within the osteocyte lacunar-canalicular system. AB - Osteocytes, the most abundant cells in bone, are essential in maintaining tissue homeostasis and orchestrating bone's mechanical adaptation. Osteocytes depend upon load-induced convection within the lacunar-canalicular system (LCS) to maintain viability and to sense their mechanical environment. Using the fluorescence recovery after photobleaching (FRAP) imaging approach, we previously quantified the convection of a small tracer (sodium fluorescein, 376 Da) in the murine tibial LCS under intermittent cyclic loading. In the present study, we first expanded the investigation of solute transport using a larger tracer (parvalbumin, 12.3 kDa), which is comparable in size to some signaling proteins secreted by osteocytes. Murine tibiae were subjected to sequential FRAP tests under rest-inserted cyclic loading while the loading magnitude (0, 2.8, or 4.8 N) and frequency (0.5, 1, or 2 Hz) were varied. The characteristic transport rate k and the transport enhancement relative to diffusion (k/k0) were measured under each loading condition, from which the peak solute velocity in the LCS was derived using our LCS transport model. Both the transport enhancement and solute velocity increased with loading magnitude and decreased with loading frequency. Furthermore, the solute-matrix interaction, quantified in terms of the reflection coefficient through the osteocytic pericellular matrix (PCM), was measured and theoretically modeled. The reflection coefficient of parvalbumin (sigma = 0.084) was derived from the differential fluid and solute velocities within loaded bone. Using a newly developed PCM sieving model, the PCM's fiber configurations accounting for the measured interactions were obtained for the first time. The present study provided not only new data on the micro-fluidic environment experienced by osteocytes in situ but also a powerful quantitative tool for future study of the PCM, the critical interface that controls both outside-in and inside-out signaling in osteocytes during normal bone adaptation and in pathological conditions. PMID- 23109142 TI - Endoplasmic reticulum lipid rafts and upper motor neuron degeneration. PMID- 23109144 TI - The rocky road to translation in spinal cord repair. AB - Over the past 2 decades, the biological understanding of the mechanisms underlying structural and functional repair of the injured central nervous system has strongly increased. This has resulted in the development of multiple experimental treatment strategies with the collective aim of enhancing and surpassing the limited spontaneous recovery occurring in animal models and ultimately humans suffering from spinal cord or brain injuries. Several of these experimental treatments have revealed beneficial effects in animal models of spinal cord injury. With the exception of neurorehabilitative therapies, however, therapeutic interventions that enhance recovery are currently absent within the clinical realm of spinal cord injury. The present review surveys the prospects and challenges in experimental and clinical spinal cord repair. Major shortcomings in experimental research center on the difficulty of closely modeling human traumatic spinal cord injury in animals, the small number of investigations done on cervical spinal injury and tetraplegia, and the differences in lesion models, species, and functional outcome parameters used between laboratories. The main challenges in the clinical field of spinal cord repair are associated with the standardization and sensitivity of functional outcome measures, the definition of the inclusion/exclusion criteria for patient recruitment in trials, and the accuracy and reliability of an early diagnosis to predict subsequent neurological outcome. Research and clinical networks were recently created with the goal of optimizing animal studies and human trials. Promising clinical trials are currently in progress. The time has come to translate the biologic-mechanistic knowledge from basic science into efficacious treatments able to improve the conditions of humans suffering from spinal cord injury. PMID- 23109143 TI - Unintended effects of orphan product designation for rare neurological diseases. AB - Since the introduction of the Orphan Drug Act in 1983, designed to promote development of treatments for rare diseases, at least 378 orphan drugs have been approved. Incentives include financial support, tax credits, and perhaps most importantly, extended market exclusivity. These incentives have encouraged industry interest and accelerated research on rare diseases, allowing patients with orphan diseases access to treatments. However, extended market exclusivity has been associated with unacceptably high drug costs, both for newly developed drugs and for drugs that were previously widely available. We suggest that a paradoxical effect of orphan product exclusivity can be reduced patient access to existing drugs. In addition, the costs of each new drug are arguably unsustainable for patients and for the American health care system. Of all the specialties, neurology has the third highest number of orphan product designations, and neurological diseases account for at least one-fifth of rare diseases. Citing the use of tetrabenazine for chorea in Huntington disease, adrenocorticotropic hormone for infantile spasms, and enzyme replacement therapy with alglucosidase alpha for Pompe disease, we highlight these paradoxical effects. PMID- 23109145 TI - Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. AB - OBJECTIVE: Primary lateral sclerosis (PLS) is a motor neuron disorder that exclusively affects upper motor neurons leading to their degeneration. Mutations in the ALS2 gene encoding the protein Alsin have been described previously in the juvenile form of the disease. In this study, we identify mutation of the ERLIN2 gene in juvenile PLS patients and describe an in vitro model for loss of ERLIN2 function. METHODS: Single nucleotide polymorphism arrays were used for homozygosity mapping. DNA sequencing of candidate genes was used to detect the underlying mutation. Level of ERLIN2 mRNA was measured by quantitative real time polymerase chain reaction. Knocking down ERLIN2 in NSC34 cells was accomplished by short-hairpin RNA interference. RESULTS: We identified a splice junction mutation in the ERLIN2 gene-a component of the endoplasmic reticulum (ER) lipid rafts-that resulted in abnormal splicing of ERLIN2 transcript and nonsense mediated decay of ERLIN2 mRNA. Knocking down ERLIN2 in NSC34 cells suppressed their growth in culture. INTERPRETATION: Recently, we found that mutation of SIGMAR1, a component of ER lipid rafts, leads to juvenile amyotrophic lateral sclerosis. The identification of mutation in another component of the ER lipid rafts in juvenile PLS patients emphasizes their role in motor neuron function. Furthermore, the discovered effect of ERLIN2 loss on cell growth may advance understanding of the mechanism behind motor neuron degeneration in PLS. PMID- 23109146 TI - Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport. AB - OBJECTIVE: The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded alpha-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous alpha-synuclein to misfold. Here, we characterized and quantified the axonal transport of alpha-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport. METHODS: We grew primary cortical mouse neurons in microfluidic devices to separate somata from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent alpha-synuclein fibrils and their transfer to second-order neurons. RESULTS: Fibrillar alpha synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar alpha-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts. INTERPRETATION: These results support the hypothesis that the progression of Parkinson disease can be caused by neuron-to-neuron spread of alpha-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be trans-synaptic gives hope that alpha synuclein fibrils could be intercepted by drugs during the extracellular phase of their journey. PMID- 23109148 TI - Activation of microglial N-methyl-D-aspartate receptors triggers inflammation and neuronal cell death in the developing and mature brain. AB - OBJECTIVE: Activated microglia play a central role in the inflammatory and excitotoxic component of various acute and chronic neurological disorders. However, the mechanisms leading to their activation in the latter context are poorly understood, particularly the involvement of N-methyl-D-aspartate receptors (NMDARs), which are critical for excitotoxicity in neurons. We hypothesized that microglia express functional NMDARs and that their activation would trigger neuronal cell death in the brain by modulating inflammation. METHODS AND RESULTS: We demonstrate that microglia express NMDARs in the murine and human central nervous system and that these receptors are functional in vitro. We show that NMDAR stimulation triggers microglia activation in vitro and secretion of factors that induce cell death of cortical neurons. These damaged neurons are further shown to activate microglial NMDARs and trigger a release of neurotoxic factors from microglia in vitro, indicating that microglia can signal back to neurons and possibly induce, aggravate, and/or maintain neurologic disease. Neuronal cell death was significantly reduced through pharmacological inhibition or genetically induced loss of function of the microglial NMDARs. We generated Nr1 LoxP(+/+) LysM Cre(+/-) mice lacking the NMDAR subunit NR1 in cells of the myeloid lineage. In this model, we further demonstrate that a loss of function of the essential NMDAR subunit NR1 protects from excitotoxic neuronal cell death in vivo and from traumatic brain injury. INTERPRETATION: Our findings link inflammation and excitotoxicity in a potential vicious circle and indicate that an activation of the microglial NMDARs plays a pivotal role in neuronal cell death in the perinatal and adult brain. PMID- 23109147 TI - Isoflurane-induced apoptosis of oligodendrocytes in the neonatal primate brain. AB - OBJECTIVE: Previously we reported that exposure of 6-day-old (P6) rhesus macaques to isoflurane for 5 hours triggers a robust neuroapoptosis response in developing brain. We have also observed (unpublished data) that isoflurane causes apoptosis of cellular profiles in the white matter that resemble glia. We analyzed the cellular identity of the apoptotic white matter profiles and determined the magnitude of this cell death response to isoflurane. METHODS: Neonatal (P6) rhesus macaques were exposed for 5 hours to isoflurane anesthesia according to current clinical standards in pediatric anesthesia. Brains were collected 3 hours later and examined immunohistochemically to analyze apoptotic neuronal and glial death. RESULTS: Brains exposed to isoflurane displayed significant apoptosis in both the white and gray matter throughout the central nervous system. Approximately 52% of the dying cells were glia, and 48% were neurons. Oligodendrocytes (OLs) engaged in myelinogenesis were selectively vulnerable, in contrast to OL progenitors, astrocytes, microglia, and interstitial neurons. When adjusted for control rates of OL apoptosis, the percentage of OLs that degenerated in the forebrain white matter of the isoflurane-treated group was 6.3% of the total population of myelinating OLs. INTERPRETATION: Exposure of the infant rhesus macaque brain to isoflurane for 5 hours is sufficient to cause widespread apoptosis of neurons and OLs throughout the developing brain. Deletion of OLs at a stage when they are just beginning to myelinate axons could potentially have adverse long-term neurobehavioral consequences that might be additive to the potential consequences of isoflurane-induced neuroapoptosis. PMID- 23109150 TI - Acid-sensing ion channel 1: a novel therapeutic target for migraine with aura. AB - OBJECTIVE: Migraine with aura is a severe debilitating neurological disorder with few relatively specific therapeutic options. METHODS: We used amiloride, a blocker of epithelial sodium channels, to evaluate its pharmacological potential and explored the biology of a potential mechanism of action in well-established experimental models. RESULTS: Amiloride was shown to block cortical spreading depression, the experimental correlate of aura, and inhibited trigeminal activation in in vivo migraine models, via an acid-sensing ion channel 1 mechanism. Remarkably, amiloride then demonstrated good clinical efficacy in a small open-labeled pilot study of patients, reducing aura and headache symptoms in 4 of 7 patients with otherwise intractable aura. INTERPRETATION: The observations here identify an entirely novel treatment strategy for migraine. PMID- 23109149 TI - DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy. AB - OBJECTIVE: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry. METHODS: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum. RESULTS: Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum. Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2) -Man(5) . DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C). INTERPRETATION: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies. PMID- 23109151 TI - Pittsburgh compound B and the postmortem diagnosis of Alzheimer disease. AB - OBJECTIVE: Deposition of the amyloid-beta (Abeta) peptide in neuritic plaques is a requirement for the diagnosis of Alzheimer disease (AD). Although the continued development of in vivo imaging agents such as Pittsburgh compound B (PiB) is promising, the diagnosis of AD is still challenging. This can be partially attributed to our lack of a detailed understanding of the interrelationship between the various pools and species of Abeta and other common indices of AD pathology. We hypothesized that recent advances in our ability to accurately measure Abeta postmortem (for example, using PiB), could form the basis of a simple means to deliver an accurate AD diagnosis. METHODS: We conducted a comprehensive analysis of the amount of Abeta40 and Abeta42 in increasingly insoluble fractions, oligomeric Abeta, and fibrillar Abeta (as defined by PiB binding), as well as plaques (diffuse and neuritic), and neurofibrillary tangles in autopsy specimens from age-matched, cognitively normal controls (n = 23) and AD (n = 22) cases, across multiple brain regions. RESULTS: Both PiB binding and the amount of sodium dodecyl sulfate (SDS)-soluble Abeta were able to predict disease status; however, SDS-soluble Abeta was a better measure. Oligomeric Abeta was not a predictor of disease status. PiB binding was strongly related to plaque count, although diffuse plaques were a stronger correlate than neuritic plaques. INTERPRETATION: Although postmortem PiB binding was somewhat useful in distinguishing AD from control cases, SDS-soluble Abeta measured by standard immunoassay was substantially better. These findings have important implications for the development of imaging-based biomarkers of AD. PMID- 23109152 TI - Alzheimer disease family history impacts resting state functional connectivity. AB - OBJECTIVE: Offspring whose parents have Alzheimer disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) epsilon4 allele noncarriers. METHODS: We studied a cohort of 348 cognitively normal participants with or without family history of late onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging. RESULTS: A family history of late onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE epsilon4 allele noncarriers. INTERPRETATION: Unknown genetic factors, embodied in a family history of late onset AD, may affect DMN integrity prior to cognitive impairment. PMID- 23109153 TI - Amyloid deposition, hypometabolism, and longitudinal cognitive decline. AB - OBJECTIVE: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) population, we examined (1) cross-sectional relationships between amyloid deposition, hypometabolism, and cognition, and (2) associations between amyloid and hypometabolism measurements and longitudinal cognitive measurements. METHODS: We examined associations between mean cortical florbetapir uptake, mean (18) F fluorodeoxyglucose-positron emission tomography (FDG-PET) within a set of predefined regions, and Alzhiemer's Disease Assessment Scale (ADAS-cog) performance in 426 ADNI participants (126 normal, 162 early mild cognitive impairment [EMCI], 85 late MCI [LMCI], 53 Alzheimer disease [AD] patients). For a subset of these (76 normal, 81 LMCI) we determined whether florbetapir and FDG PET were associated with retrospective decline in longitudinal ADAS-cog measurements. RESULTS: Twenty-nine percent of normal subjects, 43% of EMCI patients, 62% of LMCI patients, and 77% of AD patients were categorized as florbetapir positive. Florbetapir was negatively associated with concurrent FDG and ADAS-cog in both MCI groups. In longitudinal analyses, florbetapir-positive subjects in both normal and LMCI groups had greater ongoing ADAS-cog decline than those who were florbetapir negative. However, in normal subjects, florbetapir positivity was associated with greater ADAS-cog decline than FDG, whereas in LMCI, FDG positivity was associated with greater decline than florbetapir. INTERPRETATION: Although both hypometabolism and beta-amyloid (Abeta) deposition are detectable in normal subjects and all diagnostic groups, Abeta showed greater associations with cognitive decline in normal participants. In view of the minimal cognitive deterioration overall in this group, this suggests that amyloid deposition has an early and subclinical impact on cognition that precedes metabolic changes. At moderate and later stages of disease (LMCI/AD), hypometabolism becomes more pronounced and more closely linked to ongoing cognitive decline. PMID- 23109154 TI - Relation of neuropathology to cognition in persons without cognitive impairment. AB - OBJECTIVE: A study was undertaken to examine the relation of Alzheimer disease (AD) pathology, cerebral infarcts, and Lewy body (LB) pathology to cognition in persons without cognitive impairment. METHODS: Persons without dementia from 2 cohort studies of aging, the Religious Orders Study and the Memory and Aging Project, agreed to annual clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed 5 cognitive domains. For 296 persons without cognitive impairment who died and underwent postmortem assessment, we quantified AD pathology as a global pathology score, and as amyloid load, paired helical filament tau-positive (PHFtau) tangle density, cerebral infarcts, and LB pathology. Linear regression was used to examine the relation of neuropathology to cognitive abilities, controlling for demographics. RESULTS: Nearly all persons had AD pathology with >3/4 exhibiting amyloid; 22% had macroscopic and 24% had microscopic infarctions, and 13% had LB pathology. The global measure of AD pathology was related to global cognition (p = 0.008), whereas infarcts and Lewy bodies were not. Amyloid load was related to global cognition (p < 0.05), with only a trend for tangles (p = 0.08). In analyses of cognitive domains, AD pathology (p = 0.006), PHFtau tangles (p = 0.03), and macroscopic infarctions (p = 0.02) were related to episodic memory, with a trend for amyloid load (p = 0.06); AD pathology (p = 0.02) and amyloid load (p = 0.03) were related to working memory. Findings for global cognition and episodic memory were stronger in additional analyses with neocortical amyloid and mesial temporal tangles. INTERPRETATION: AD pathology and macroscopic infarctions are common in older persons without cognitive impairment and are related to episodic and working memory. PMID- 23109155 TI - Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. AB - OBJECTIVE: Microvesicles (MVs) have been indicated as important mediators of intercellular communication and are emerging as new biomarkers of tissue damage. Our previous data indicate that reactive microglia/macrophages release MVs in vitro. The aim of the study was to evaluate whether MVs are released by microglia/macrophages in vivo and whether their number varies in brain inflammatory conditions, such as multiple sclerosis (MS). METHODS: Electron and fluorescence microscopy and flow cytometry were used to detect myeloid MVs in the cerebrospinal fluid (CSF) of healthy controls, MS patients, and rodents affected by experimental autoimmune encephalomyelitis (EAE), the animal model of MS. RESULTS: Myeloid MVs were detected in CSF of healthy controls. In relapsing and remitting EAE mice, the concentration of myeloid MVs in the CSF was significantly increased and closely associated with disease course. Analysis of MVs in the CSF of 28 relapsing patients and 28 patients with clinical isolated syndrome from 2 independent cohorts revealed higher levels of myeloid MVs than in 13 age-matched controls, indicating a clinical value of MVs as a companion tool to capture disease activity. Myeloid MVs were found to spread inflammatory signals both in vitro and in vivo at the site of administration; mice impaired in MV shedding were protected from EAE, suggesting a pathogenic role for MVs in the disease. Finally, FTY720, the first approved oral MS drug, significantly reduced the amount of MVs in the CSF of EAE-treated mice. INTERPRETATION: These findings identify myeloid MVs as a marker and therapeutic target of brain inflammation. PMID- 23109156 TI - Dabigatran and thrombolysis: A therapeutic dilemma. PMID- 23109158 TI - Cognition decline and saturated fat intake link questioned: confounders missed. PMID- 23109159 TI - Exome sequencing for gene discovery: time to set standard criteria. PMID- 23109160 TI - Exome sequencing for gene discovery: time does not stand still. PMID- 23109161 TI - Balanced anesthesia-baseline anesthesia. PMID- 23109162 TI - Anesthetics isoflurane and desflurane differently affect mitochondrial function, learning, and memory. PMID- 23109164 TI - Healthcare costs: Eden's apple? PMID- 23109165 TI - NerveCenter: October 2012. PMID- 23109166 TI - Novel approach to neurologic emergency research yields results. PMID- 23109167 TI - Symposium on congenital and acquired bleeding disorders in children (in honor of the lifetime accomplishments of Dr. Victor S. Blanchette in pediatric hematology). PMID- 23109168 TI - Histochemical characterization of the sialic acid residues in mouse colon mucins. AB - The mucins of colonic murine mucus are highly O-glycosilated sulfosialoglycoproteins. We have characterized the sialylation pattern of oligosaccharide chains of colonic murine mucins by conventional histochemical methods and by lectin histochemistry combined with chemical pretreatments and sialidase digestion. Oligosaccharide chains are strongly sulphated, with an increase of sulfation from the proximal toward the distal colon and a decrease of sialic acid expression and acetylation toward the distal colon. In the goblet cells of proximal colon, sialic acid bound alpha2,3 to Galbeta1,3GalNAc subterminal dimers is diacetylated at C7,C8;C7,C9;C8,C9 or triacetylated at C7,8,9. In the distal colon, sialic acid-linked alpha2,3 to Galbeta1,3GalNAc subterminal dimers shows reduced O-acetylation at C7 and/or C8, while acetyl substituents at C9 and at C4 are almost absent. Sialic acid is involved in different essential physiological functions; thus, alterations of its expression and acetylation in oligosaccharide chains of intestinal mucins are generally associated with diseases, such as ulcerative colitis and cancer. Mice may represent a suitable animal model to study alterations of oligosaccharidic chains in colonic mucins and lectin histochemistry combined with chemical pretreatments, and enzyme digestion may be a valuable tool for this study. Our present work may represent a landmark for further lectin histochemical studies to evaluate alterations of mouse colon mucins under different physiological, pathological, or experimental conditions, with possible translational value in humans. PMID- 23109169 TI - Spermatozoa motility and variation in the seminal plasma proteome of Eurasian perch (Perca fluviatilis) during the reproductive season. AB - This study evaluated physiological and functional sperm parameters and the seminal plasma proteome of Eurasian perch (Perca fluviatilis) over the course of their reproductive season. Spermatozoa velocity (169.56 +/- 6.53 to 158.5 +/- 7.4 um sec(-1)), percent motility (95.89 +/- 4.28% to 89.55 +/- 4.5%), and osmolality of seminal plasma (290 +/- 5 to 297 +/- 12 mOsmol kg(-1)) remained stable throughout the reproductive season. Milt volume and protein concentration of seminal plasma gradually increased and reached the highest values late in the reproductive period. Spermatozoa concentration peaked in the mid-reproductive season (66.90 +/- 13 * 10(9) spermatozoa ml(-1)) and decreased towards the end (54 +/- 10 * 10(9) spermatozoa ml(-1)). A proteomic analysis of seminal plasma using two-dimensional polyacrylamide gel electrophoresis revealed 10 protein spots significantly altered over the course of the reproductive season. Subsequent protein characterization suggested that time in the reproductive season predominantly affected proteins involved in membrane trafficking, organization, cell motility, and oxido-reductase activity. This study provides new data on physiological properties of sperm and protein patterns of seminal plasma over the course of the reproductive season that should be considered in the development of methods for artificial reproduction of perch. PMID- 23109170 TI - Dietary folate and folate vitamers and the risk of prostate cancer in The Netherlands Cohort Study. AB - PURPOSE: The aim of the present study was to examine the association between intake of folate, and specific folate vitamers, and the risk of advanced and total prostate cancer. METHODS: The association between dietary folate and prostate cancer risk was evaluated in The Netherlands Cohort Study (NLCS) on diet and cancer, conducted among 58,279 men ages 55-69 years at baseline. Information on diet was collected at baseline by means of food frequency questionnaires. Incident cases were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. After 17.3 years of follow up, 3,669 incident prostate cancer cases, of which 1,290 advanced cases, and 2,336 male subcohort members were available for case-cohort analyses. RESULTS: Dietary folate was not associated with prostate cancer risk, nor with the risk of advanced prostate cancer, among men in the NLCS cohort (HR = 1.05, 95 % CI: 0.87 1.26 and HR = 1.09, 95 % CI: 0.88-1.35, respectively, for the highest quintile of folate intake vs. the lowest quintile). Specific folate vitamers were neither associated with the risk of prostate cancer or risk of advanced prostate cancer. CONCLUSIONS: Our results do not support an association of dietary folate or specific folate vitamers on the risk of prostate cancer, or advanced prostate cancer. PMID- 23109171 TI - Comorbidities and endometrial cancer survival in Hispanics and non-Hispanic whites. AB - PURPOSE: We investigated comorbidities and endometrial cancer survival by ethnicity because Hispanic whites (HWs) have worse survival than non-Hispanic whites (NHWs). METHODS: An endometrial cancer cohort (1992-2004) established with the Surveillance, Epidemiology and End Results-Medicare-linked database (n = 3,286) was followed through 2007. Endometrial cancer-specific and other cause mortality were evaluated with multivariate hazard ratios (mHRs). RESULTS: HWs were more likely than NHWs to have regional/distant disease (31.7 vs. 24.8 %), diabetes (31.7 vs. 11.0 %), and hypertension (49.4 vs. 37.6 %). HWs had poorer endometrial cancer-specific survival than NHWs (age-adjusted HR = 1.28; 95% CI 1.01-1.61), but not after adjustment for tumor characteristics and treatment (mHR = 1.02; 95% CI 0.81-1.29). In contrast, even after adjustment for cancer-related factors, other cause mortality in HWs was elevated (mHR = 1.27; 95% CI 1.01 1.59), but not after further adjustment for comorbid conditions (mHR = 1.07; 95% CI 0.85-1.35). CONCLUSIONS: Comorbidities, particularly diabetes, were more common in HWs than in NHWs and impacted other cause mortality. Improving diabetes management may be an effective means of improving other cause mortality. This may be particularly true for HWs, given their particularly high prevalence of diabetes. PMID- 23109172 TI - A population-based analysis of the effect of marital status on overall and cancer specific mortality in patients with squamous cell carcinoma of the penis. AB - PURPOSE: The association between marital status and tumor stage and grade, as well as overall mortality (OM) and cancer-specific mortality (CSM) received little attention in patients with squamous cell carcinoma of the penis (SCCP). METHODS: We relied on the surveillance, epidemiology, and end results (SEER) 17 database to identify patients diagnosed with primary SCCP. Logistic and Cox regression models, respectively, addressed the effect of marital status on the rate of locally advanced disease and its effect on OM and CSM. Covariates consisted of age, race, socioeconomic status, year of surgery, and SEER registries. RESULTS: Between 1988 and 2006, 1,884 patients with SCCP were identified. At surgery, 1,192 (63.3 %) were married and 966 (51.3 %) had locally advanced disease. In multivariable logistic regression models predicting locally advanced disease at surgery, unmarried men had a 1.5-fold higher (p < 0.001) risk than others. In multivariable Cox models predicting CSM, marital status had no effect [hazard ratio (HR) = 1.3, p = 0.1]. Finally, in multivariable Cox models predicting OM, unmarried men had a 1.3-fold higher (p = 0.001) risk than others. CONCLUSION: Unmarried men tend to present with less favorable disease stage at SCCP. Moreover, unmarried men tend to live less long than their married counterparts. However, marital status has no effect on CSM. PMID- 23109173 TI - Light-triggered sequence-specific cargo release from DNA block copolymer-lipid vesicles. PMID- 23109174 TI - Bronchodilator activity of aerial parts of Polygonatum verticillatum augmented by anti-inflammatory activity: attenuation of Ca2+ channels and lipoxygenase. AB - Polygonatum verticillatum is commonly used for the treatment of asthma and inflammation. The current study was aimed to scrutinize the pharmacological profile of methanolic extract of the aerial parts (PA). Isolated tracheal preparations were used for the evaluation of bronchodilatory activity, whilst the in vivo carrageenan-induced paw oedema test and an in vitro lipoxygenase (LOX) inhibitory assay were used for the assessment of the anti-inflammatory profile of PA. When tested against carbachol and K+ (80 mM)-induced contractions, PA caused complete inhibition of isolated rabbit tracheal preparations in a dose-dependent mode, similar to verapamil. While elucidating possible mechanism, PA shifted the Ca2+ concentration-response curves to the right, analogous to that produced by verapamil, confirming a Ca2+ channel blocker-like activity. PA provoked profound reduction in paw oedema with a maximum protection of 60.87% at 200 mg/kg i.p. in a dose-dependent manner which was augmented by its prominent LOX inhibitory activity (IC50 : 125 ug/mL). These findings authenticated its therapeutic potential in the treatment of asthmatic and inflammatory conditions. PMID- 23109176 TI - Pharmacokinetics study of amoxycillin and clavulanic acid (8:1)--a new combination in healthy Chinese adult male volunteers using the LC-MS/MS method. AB - New oral granules of amoxicillin and clavulanic acid in 8:1 ratio have recently been developed and approved to conduct clinical trial in China. To date, there has been no report studying the pharmacokinetic characteristics of amoxicillin and clavulanic acid in man. Therefore, it is urgent to investigate the pharmacokinetic properties of amoxicillin and clavulanic acid in man. The aim of the study was to assess the pharmacokinetic properties of amoxicillin and clavulanic acid in 8:1 with different dosage in healthy volunteers and provide support for this drug to obtain marketing authorization in China. A liquid chromatography-tandem mass spectrometry method for determining the concentration of amoxicillin and clavulanic acid in human plasma was developed and applied to this open-label, single- and multiple-dose Pharmacokinetics study. Subjects were randomized to receive a single dose of 1, 2, and 4 pouches of the test granulation of amoxicillin and clavulanic acid in 8:1 ratio (amoxicillin is 250 mg and clavulanic acid is 31.25 mg per pouch). In the single-dose phase, blood samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 5, 8, 12, and 24 h after drug administration. In the multiple-dose phase, samples were obtained before drug administration on days 1, 2, 3, and 4 to determine the Cmin of amoxicillin and clavulanic acid. In the 4th day, samples were collected from 0.25 to 24 h after drug administration. Profiles of the concentration-time curves of amoxicillin and clavulanic acid were best fitted to two-compartment model. In this group of healthy Chinese subjects, the pharmacokinetics of amoxicillin fitted the linear dynamic feature at doses of 250,500 and 1,000 mg, and not obviously about clavulanic acid at doses of 31.25, 62.5, and 125 mg. The t 1/2 of single dose and multidoses were (1.45 +/- 0.12) and (1.44 +/- 0.26) h of amoxicillin and (1.24 +/- 0.23) and (1.24 +/- 0.17) of clavulanic acid, respectively; The AUC0-24 of single dose and multidoses were (27937.85 +/- 4265.59) and (24569.80 +/- 3663.63) ng h mL(-1) of amoxicillin and (891.45 +/- 194.30) and (679.61 +/- 284.05) ng h mL(-1) of clavulanic acid, respectively; The Cmax of single dose and multidoses were (8414.58 +/- 1416.78) and (7929.17 +/- 1291.54) ng mL(-1) of amoxicillin and (349.00 +/- 89.54) and (289.00 +/- 67.36) ng h mL(-1) of clavulanic acid, respectively. t 1/2, AUC0-24, and Cmax were similar after multiple-dose administration and after single-dose administration, suggesting that amoxicillin and clavulanic acid do not accumulate with multiple dose administration of 500 and 62.5 mg, respectively. PMID- 23109178 TI - Effects of homocysteine on ERK signaling and cell proliferation in fetal neural stem cells in vitro. AB - The aim of the present study was to determine if the excitatory amino acid homocysteine (Hcy) alters ERK signaling and cell proliferation in fetal neural stem cells (NSCs) in vitro. NSCs were isolated from fetal rats and grown in serum free suspension medium. The cells were identified as NSCs by their expression of immunoreactive Sox2. NSCs were assigned to one of four treatment groups: vehicle control, low-dose Hcy group (Hcy-L, medium contained 30 MUmol/L Hcy), middle-dose Hcy group (Hcy-M, 100 MUmol/L Hcy) and high-dose Hcy group (Hcy-H, 300 MUmol/L Hcy). Cell proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay. Protein expression levels of ERK1/2 and phosphorylated ERK1/2 were detected by Western blot. The effects of Hcy on NSC death, including apoptosis, were assessed by using flow cytometry and trypan blue exclusion. The results showed that NSCs grew as neurospheres in the serum-free medium. Hcy decreased ERK1/2 protein phosphorylation and NSC proliferation, but it did not induce cell death or apoptosis within the concentration from 30 to 300 MUmol/L. The above results are consistent with the hypothesis that Hcy decreases fetal NSC proliferation by inhibiting ERK signaling. PMID- 23109177 TI - Bumetanide hyperpolarizes madin-darby canine kidney cells and enhances cellular gentamicin uptake by elevating cytosolic Ca(2+) thus facilitating intermediate conductance Ca(2+)--activated potassium channels. AB - Loop diuretics such as bumetanide and furosemide enhance aminoglycoside ototoxicity when co-administered to patients and animal models. The underlying mechanism(s) is poorly understood. We investigated the effect of these diuretics on cellular uptake of aminoglycosides, using Texas Red-tagged gentamicin (GTTR), and intracellular/whole-cell recordings of Madin-Darby canine kidney (MDCK) cells. We found that bumetanide and furosemide dose-dependently enhanced cytoplasmic GTTR fluorescence by ~60 %. This enhancement was suppressed by La(3+), a non-selective cation channel (NSCC) blocker, and by K(+) channel blockers Ba(2+) and clotrimazole, but not by tetraethylammonium (TEA), 4 aminopyridine (4-AP) or glipizide, nor by Cl(-) channel blockers diphenylamine-2 carboxylic acid (DPC), niflumic acid (NFA), and CFTRinh-172. Bumetanide and furosemide hyperpolarized MDCK cells by ~14 mV, increased whole-cell I/V slope conductance; the bumetanide-induced net current I/V showed a reversal potential (V r) ~-80 mV. Bumetanide-induced hyperpolarization and I/V change was suppressed by Ba(2+) or clotrimazole, and absent in elevated [Ca(2+)]i, but was not affected by apamin, 4-AP, TEA, glipizide, DPC, NFA, or CFTRinh-172. Bumetanide and furosemide stimulated a surge of Fluo-4-indicated cytosolic Ca(2+). Ba(2+) and clotrimazole alone depolarized cells by ~18 mV and reduced I/V slope with a net current V r near -85 mV, and reduced GTTR uptake by ~20 %. La(3+) alone hyperpolarized the cells by ~-14 mV, reduced the I/V slope with a net current V r near -10 mV, and inhibited GTTR uptake by ~50 %. In the presence of La(3+), bumetanide-caused negligible change in potential or I/V. We conclude that NSCCs constitute a major cell entry pathway for cationic aminoglycosides; bumetanide enhances aminoglycoside uptake by hyperpolarizing cells that increases the cation influx driving force; and bumetanide-induced hyperpolarization is caused by elevating intracellular Ca(2+) and thus facilitating activation of the intermediate conductance Ca(2+)-activated K(+) channels. PMID- 23109179 TI - Cation-pi interactions in beta-lactamases: the role in structural stability. AB - beta-lactam group of antibiotics is the most widely used therapeutic molecules for treating bacterial infections. The main mode of bacterial resistance to beta lactams is by beta-lactamases. In the present study, we report our results on the role of cation-pi interactions in beta-lactamases and their environmental preferences. The number of interactions formed by arginine is higher than lysine in the cationic group, while tyrosine is comparatively higher than phenylalanine and tryptophan in the pi group. Our results indicate that cation-pi interactions might play an important role in the global conformational stability of beta lactamases. PMID- 23109180 TI - Bioaccumulation of chlorophacinone in strains of rats resistant to anticoagulants. AB - BACKGROUND: Anticoagulants are the only available compounds in the EU to control rat populations. Resistance to anticoagulant rodenticides (antivitamin K or AVK) is described and widespread across Europe. The present objective was to determine whether resistance was associated with an increased potential for bioaccumulation of AVK in the liver. Rats were selected from three major resistant genetically identified strains across Europe: Y139C (Germany), Y139F (France) and L120Q (United Kingdom). The rats were housed in individual cages and fed chlorophacinone wheat bait (50 mg kg(-1) ). Animals were assigned to groups for euthanasia either on day 1, 4, 9 or 14 (resistant rats) or on days 1 and 4 (susceptible rats). RESULTS: Chlorophacinone accumulated from day 1 to day 4 in all strains (maximum 160 ug liver(-1)) and remained stable thereafter. There was no significant difference between strains. Extensive metabolism of chlorophacinone was also found, and was similar (in nature and proportion of metabolites) across strains (3 OH-metabolites identified). Only the survival time differed significantly (L120Q > Y139C = Y139F > susceptible). CONCLUSIONS: Accumulation of chlorophacinone occurs from day 1 to day 4, and an equilibrium is reached, suggesting rapid elimination. Resistant and susceptible rats accumulate chlorophacinone to the same extent and only differ in terms of survival times. Resistant rats may then be a threat for non-target species for prolonged periods of time. PMID- 23109181 TI - ADAM: automated data management for research datasets. AB - Existing repositories for experimental datasets typically capture snapshots of data acquired using a single experimental technique and often require manual population and continual curation. We present a storage system for heterogeneous research data that performs dynamic automated indexing to provide powerful search, discovery and collaboration features without the restrictions of a structured repository. ADAM is able to index many commonly used file formats generated by laboratory assays and therefore offers specific advantages to the experimental biology community. However, it is not domain specific and can promote sharing and re-use of working data across scientific disciplines. AVAILABILITY AND IMPLEMENTATION: ADAM is implemented using Java and supported on Linux. It is open source under the GNU General Public License v3.0. Installation instructions, binary code, a demo system and virtual machine image and are available at http://www.imperial.ac.uk/bioinfsupport/resources/software/adam. PMID- 23109182 TI - Function of the HD-Zip I gene Oshox22 in ABA-mediated drought and salt tolerances in rice. AB - Oshox22 belongs to the homeodomain-leucine zipper (HD-Zip) family I of transcription factors, most of which have unknown functions. Here we show that the expression of Oshox22 is strongly induced by salt stress, abscisic acid (ABA), and polyethylene glycol treatment (PEG), and weakly by cold stress. Trans activation assays in yeast and transient expression analyses in rice protoplasts demonstrated that Oshox22 is able to bind the CAAT(G/C)ATTG element and acts as a transcriptional activator that requires both the HD and Zip domains. Rice plants homozygous for a T-DNA insertion in the promoter region of Oshox22 showed reduced Oshox22 expression and ABA content, decreased sensitivity to ABA, and enhanced tolerance to drought and salt stresses at the seedling stage. In contrast, transgenic rice over-expressing Oshox22 showed increased sensitivity to ABA, increased ABA content, and decreased drought and salt tolerances. Based on these results, we conclude that Oshox22 affects ABA biosynthesis and regulates drought and salt responses through ABA-mediated signal transduction pathways. PMID- 23109183 TI - Microfluidic investigation of BDNF-enhanced neural stem cell chemotaxis in CXCL12 gradients. AB - In vivo studies have suggested that gradients of CXCL12 (aka stromal cell-derived factor 1alpha) may be critical for neural stem cell (NSC) migration during brain development and neural tissue regeneration. However, traditional in vitro chemotaxis tools are limited by unstable concentration gradients and the inability to decouple cell migration directionality and speed. These limitations have restricted the reproducible and quantitative analysis of neuronal migration, which is required for mechanism-based studies. Using a microfluidic gradient generator, nestin and Sox-2 positive human embryonic NSC chemotaxis is quantified within a linear and stable CXCL12 gradient. While untreated NSCs are not able to chemotax within CXCL12 gradients, pre-treatment of the cells with brain-derived neurotrophic factor (BDNF) results in significant chemotactic, directional migration. BDNF pre-treatment has no effect on cell migration speed, which averages about 1 MUm min(-1). Quantitative analysis determines that CXCL12 concentrations above 9.0 nM are above the minimum activation threshold, while concentrations below 14.7 nM are below the saturation threshold. Interestingly, although inhibitor studies with AMD 3100 revealed that CXCL12 chemotaxis requires receptor CXCR4 activation, BDNF pre-treatment is found to have no profound effects on the mRNA levels or surface presentation of CXCR4 or the putative CXCR7 scavenger receptor. The microfluidic study of NSC migration within stable chemokine concentration profiles provides quantitative analysis as well as new insight into the migratory mechanism underlying BDNF-induced chemotaxis towards CXCL12. PMID- 23109184 TI - Nelfinavir is effective in inhibiting the multiplication and aspartic peptidase activity of Leishmania species, including strains obtained from HIV-positive patients. AB - OBJECTIVES: There is a general lack of effective and non-toxic chemotherapeutic agents for leishmaniasis and there is as yet no study about the effect of HIV peptidase inhibitors (HIV PIs) on Leishmania/HIV-coinfected patients. In the present work, we performed a comparative analysis of the spectrum of action of HIV PIs on different Leishmania spp., including strains obtained from HIV positive patients receiving or not receiving antiretroviral treatment. METHODS: The effects of nelfinavir and saquinavir on Leishmania proliferation were assessed by means of a colorimetric assay (MTT). Subsequently, the effect of nelfinavir on aspartic peptidase activity from Leishmania spp. was assessed by following the degradation of the fluorogenic substrate MCA-G-K-P-I-L-F-F-R-L-K DNP-Arg-NH(2). RESULTS: Nelfinavir was capable of significantly reducing the multiplication of many Leishmania reference strains and isolates obtained from HIV-positive patients receiving or not receiving antiretroviral treatment. Leishmania major growth was inhibited by ~ 50%, while all other flagellates were strongly inhibited (at least 94%), except for a Leishmania chagasi strain obtained from an HIV-positive patient under treatment with highly active antiretroviral therapy (HAART). Culture of this isolate in the presence of nelfinavir induced a considerable reduction in the aspartic peptidase activity. In addition, nelfinavir was also capable of inhibiting the aspartic peptidase activity of all Leishmania strains tested. CONCLUSIONS: The present data contribute to the study of the effect of HIV PIs on Leishmania infection and add new insights into the possibility of exploiting aspartic peptidases as promising targets in order to generate novel medications to treat leishmaniasis. PMID- 23109185 TI - Creatine kinase elevation in HIV-1-infected patients receiving raltegravir containing antiretroviral therapy: a cohort study. AB - OBJECTIVES: To evaluate the incidence and risk factors for significant creatine kinase elevation in HIV-1-infected patients who were prescribed a raltegravir containing antiretroviral therapy. DESIGN: A retrospective analysis of a prospectively collected cohort involving all consecutive patients who were prescribed a raltegravir-containing antiretroviral regimen between June 2005 and December 2010. METHODS: Significant creatine kinase elevation was defined as an elevation of at least 3-fold from the upper limit of normal (ULN) (grade 2, WHO classification) while receiving raltegravir. Blood analysis at each visit included at least creatine kinase, as well as plasma HIV-1 RNA and CD4 cell count. RESULTS: There were 475 patients who had been exposed to raltegravir for a median of 11.5 (IQR 8.2-15.2) months. An increase of creatine kinase >= 3-fold ULN was detected in 53 (11.2%) patients, representing an incidence of 3.8/100 person-years. Symptoms were reported by seven patients (1.5%), they showed either grade 1 (n = 3) or 2 (n = 4) creatine kinase increases. The median duration of raltegravir therapy before creatine kinase elevation was 5.9 (IQR 3.3-9.3) months. Evidence of creatine kinase elevation prior to raltegravir therapy [hazard ratio (HR) 3.30; 95% CI 1.59 +/- 6.86; P = 0.001], abnormal baseline creatine kinase (HR 3.24; 95% CI 1.63 +/- 6.45; P = 0.001) and male gender (HR 4.17; 95% CI 1.33 +/- 1.27; P = 0.001) were identified as independent risk factors for creatine kinase elevation during raltegravir treatment. CONCLUSIONS: Although ~ 1 in 10 patients on raltegravir therapy developed significant creatine kinase elevation as defined in this study, symptoms were uncommon, not severe and occurred in patients with easily identifiable risk factors. PMID- 23109186 TI - Partial protection against multiple RT-SHIV162P3 vaginal challenge of rhesus macaques by a silicone elastomer vaginal ring releasing the NNRTI MC1220. AB - OBJECTIVES: The non-nucleoside reverse transcriptase inhibitor MC1220 has potent in vitro activity against HIV type 1 (HIV-1). A liposome gel formulation of MC1220 has previously been reported to partially protect rhesus macaques against vaginal challenge with a simian HIV (SHIV). Here, we describe the pre-clinical development of an MC1220-releasing silicone elastomer vaginal ring (SEVR), including pharmacokinetic (PK) and efficacy studies in macaques. METHODS: In vitro release studies were conducted on SEVRs loaded with 400 mg of MC1220, using simulated vaginal fluid (SVF, n = 4) and 1 : 1 isopropanol/water (IPA/H(2)O, n = 4) as release media. For PK evaluation, SEVRs were inserted into adult female macaques (n = 6) for 30 days. Following a 1 week washout period, fresh rings were placed in the same animals, which were then challenged vaginally with RT SHIV162P3 once weekly for 4 weeks. RESULTS: SEVRs released 1.66 and 101 mg of MC1220 into SVF and IPA/H(2)O, respectively, over 30 days, the differential reflecting the low aqueous solubility of the drug. In macaque PK studies, MC1220 was consistently detected in vaginal fluid (peak 845 ng/mL) and plasma (peak 0.91 ng/mL). Kaplan-Meier analysis over 9 weeks showed significantly lower infection rates for animals given MC1220-containing SEVRs than placebo rings (hazard ratio 0.20, P = 0.0037). CONCLUSIONS: An MC1220-releasing SEVR partially protected macaques from vaginal challenge. Such ring devices are a practical method for providing sustained, coitally independent protection against vaginal exposure to HIV-1. PMID- 23109188 TI - Dust exposure and the risk of cancer in cement industry workers in Korea. AB - BACKGROUND: Cement is used widely in the construction industry, though it contains hazardous chemicals such as hexavalent chromium. Several epidemiological studies have examined the association between cement dust exposure and cancer, but these associations have proved inconclusive. In the present study, we examined the association between dust exposure and cancer in cement industry workers in Korea. METHODS: Our cohort consisted of 1,324 men who worked at two Portland cement manufacturing factories between 1997 and 2005. We calculated cumulative dust exposures, then categorized workers into high and low dust exposure groups. Cancer cases were identified between 1997 and 2005 by linking with the national cancer registry. Standardized incidence ratios (SIRs) were calculated for all workers and the high and low dust exposure groups, respectively. RESULTS: The SIR for overall cancers in all workers was increased (1.35, 95% CI: 1.01-1.78). The SIR for stomach cancer in the high dust exposure group was increased (2.18, 95% CI: 1.19-3.65), but there was no increased stomach cancer risk in the low dust exposure group. The SIR for rectal cancer in all workers was increased (3.05, 95% CI: 1.32-6.02). Rectal cancer risk was similar in the high and low exposure groups. CONCLUSIONS: Our findings suggest a potential association between exposure in the cement industry and an increased risk of stomach and rectal cancers. However, due to the small number of cases, this association should be further investigated in a study with a longer follow up period and adjustment for confounders. PMID- 23109196 TI - Fetal axillary cystic hygroma: a novel association with triple X syndrome. AB - BACKGROUND: Triple X syndrome is a relatively common sex chromosomal aneuploidy with an estimated incidence of one in every 1000 female births. There is considerable diversity in phenotypes among patients with triple X syndrome. Triple X syndrome has been shown to have associated abnormalities, with genitourinary malformations being the most consistent. Cystic hygroma (CH) is a lymphatic malformation that occurs because of the lack of development of communication between the lymphatic and the venous systems. CH has an incidence of 1 in every 6000-10,000 live births. CH is associated with a variety of conditions, including chromosomal aneuploidies and fetal malformations. CASE: We report a case of prenatally detected triple X syndrome with axillary CH as an isolated finding. The patient was referred because of a fetal cystic mass at the right axillary region. Amniocentesis revealed 47,XXX karyotype, and no additional abnormalities were detected prenatally or after abortion. CONCLUSION: This is a novel description of axillary CH associated with triple X syndrome. PMID- 23109189 TI - DNA sequencing and bar-coding using solid-state nanopores. AB - Nanopores have emerged as a prominent single-molecule analytic tool with particular promise for genomic applications. In this review, we discuss two potential applications of the nanopore sensors: First, we present a nanopore based single-molecule DNA sequencing method that utilizes optical detection for massively parallel throughput. Second, we describe a method by which nanopores can be used as single-molecule genotyping tools. For DNA sequencing, the distinction among the four types of DNA nucleobases is achieved by employing a biochemical procedure for DNA expansion. In this approach, each nucleobase in each DNA strand is converted into one of four predefined unique 16-mers in a process that preserves the nucleobase sequence. The resulting converted strands are then hybridized to a library of four molecular beacons, each carrying a unique fluorophore tag, that are perfect complements to the 16-mers used for conversion. Solid-state nanopores are then used to sequentially remove these beacons, one after the other, leading to a series of photon bursts in four colors that can be optically detected. Single-molecule genotyping is achieved by tagging the DNA fragments with gamma-modified synthetic peptide nucleic acid probes coupled to an electronic characterization of the complexes using solid-state nanopores. This method can be used to identify and differentiate genes with a high level of sequence similarity at the single-molecule level, but different pathology or response to treatment. We will illustrate this method by differentiating the pol gene for two highly similar human immunodeficiency virus subtypes, paving the way for a novel diagnostics platform for viral classification. PMID- 23109198 TI - [EUROPEAN COPD AUDIT in Poland--how do we treat the patients with COPD exacerbation?]. PMID- 23109199 TI - The UK Experience of COPD National Audit. PMID- 23109197 TI - Management of paediatric Lyme disease in non-endemic and endemic areas: data from the Registry of the Italian Society for Pediatric Infectious Diseases. AB - The purpose of this investigation was to determine how specialists in paediatric infectious diseases (PIDs) manage children with suspected Lyme disease (LD) by comparing their approaches in Italian endemic and non-endemic areas. A cross sectional survey of the PID specialists participating in the Italian Society for Pediatric Infectious Disease (SITIP) Registry of LD was carried out between 1 January and 30 April 2012. A total of 160 children (80 living in endemic areas and 80 living in non-endemic areas) were diagnosed as having LD between 1 January 2005 and 31 December 2011. The clinical manifestations were erythema migrans in 130 cases (81.3 %), arthritis in 24 (15.0 %) and neuroborreliosis in six (3.8 %). Significant differences from the recommendations concerning serology and the tests to undertake were mainly observed in the children with erythema migrans, especially those living in non-endemic areas (p < 0.05). The children with erythema migrans who lived in non-endemic areas were treated with antibiotics significantly less frequently than those living in endemic areas (p < 0.05), and significantly fewer children with erythema migrans or arthritis living in non endemic areas were treated with amoxicillin in comparison with those living in endemic regions (p < 0.05). The duration of antimicrobial therapy was significantly shorter than recommended in the children with erythema migrans or arthritis, especially those living in non-endemic areas (p < 0.05). Paediatric LD is also present in areas of Italy in which it is not considered endemic, but knowledge concerning its management is generally poor among PID specialists and characterised by enormous gaps in non-endemic areas. PMID- 23109200 TI - The European COPD Audit: a pilot experience of 16 European countries. PMID- 23109201 TI - Quality of care assessment in COPD. AUDIPOC: the Spanish audit experience. PMID- 23109202 TI - [Effects of biomass combustion and occupational exposures on lung function in random population sample of Malopolska inhabitants]. AB - INTRODUCTION: Risk factors other than tobacco smoking contribute to about 20% of chronic obstructive pulmonary disease cases. Exposure to these risk factors and their influence on lung function has not been adequately studied in the population of Malopolska. MATERIAL AND METHODS: In random population sample of adults at least forty years old, residents of 2 districts of Malopolska, data on exposure to known and probable respiratory risk factors were collected using questionnaire. All subjects without contraindications performed pre- and post bronchodilatator spirometry. RESULTS: We analyzed data from 618 subjects; 94,8% subjects lived for longer than 6 months in a dwelling where stove using coal or wood has been used for cooking and/or heating. At the time of study as many as 32.5% subjects were still using coal or wood for cooking or heating. Coal or wood were used as fuel on average for more than 30 years; 67% of subjects have ever worked in professions carrying a risk of exposure to potential respiratory risk factors. We have identified an independent relationship of farming with lower FEV1/FVC values as well as increased chronic obstructive pulmonary disease risk. CONCLUSIONS: Significant proportion of Malopolska inhabitants has been exposed to risks associated with cooking or heating with coal or wood. In the studied population farming was related to increased risk of chronic obstructive respiratory disease. PMID- 23109203 TI - [The evaluation of motivation and addiction to nicotine in smokers attempting to quit smoking]. AB - INTRODUCTION: Smoking cigarettes is a factor which increases the risk of developing many diseases, especially of the circulatory and respiratory systems. Quitting smoking is an essential element of prophylaxis and therapy. The effectiveness of treating the syndrome of nicotine addiction mostly depends on the motivation to give up the habit. The study aimed at evaluating the motivation and the strength of nicotine addiction as well as the factor which motivates smokers for giving up the habit. MATERIAL AND METHODS: Sixty-two smokers were included in the study. There were 31 males and 31 females. The mean age of the study subjects was 47.26 +/- 14.45. The study was performed using the author-made survey (including for example questions regarding sociodemographic data and motives for quitting smoking), Fagerstrom Tolerance Questionnaire (for analyzing degree of nicotine addiction) and Schneider Motivation Test (to evaluate the degree of motivation to quit smoking). RESULTS: Thirty-seven subjects out of the total number of 62 were the least addicted to nicotine. They were highly motivated to give up the habit of smoking. The mean value of motivation depended on the level of education of the subjects and was 7.71-8.50 scores. Health concerns were the reasons to make a decision to quit smoking for the majority of the subjects. CONCLUSIONS: Health concern is the most common reason for giving up the habit of smoking. The relationship between the motivation to quit smoking and the sex of the subjects was not observed. PMID- 23109204 TI - [Interstitial lung diseases among patients hospitalized in the Department of Respiratory Medicine in Radom District Hospital during the years 2000-2009]. AB - INTRODUCTION: There is little epidemiological data on interstitial lung diseases (ILDs) in Poland. The aim of the present study was to estimate the frequency of ILDs and frequency of the respiratory failure and the hospital mortality due to ILDs during the period 2000-2009 in Radom District Hospital. METHODS: Cases were identified through database of 20481 patients hospitalized in the Department of Respiratory Medicine in Radom District Hospital. The study encompassed the period from January 1, 2000 to December 31, 2009. According to national census data the total population of Radom region (former Radom Voivodeship) is about 630,000 adult (> 14 years) inhabitants. The population is mixed urban/rural and remained stable during the period 2000-2009. Diagnosis of ILD was based on: clinical data, laboratory examination, high resolution lung CT scan (HRCT), lung function tests and in some patients - the results of open or transbronchial lung biopsies. ILDs were recorded in the hospital database according to ICD-10 criteria. RESULTS: Between 2000 and 2009 a total of 554 patients were diagnosed with ILDs, in the course of 708 hospitalizations. The mean number of hospitalizations per patient was 1.3 (range 1-11). Admissions due to ILDs encompassed 3.5% of the total hospital admissions. A 20% increase in the annual rate of hospitalizations due to ILDs (from 10.7/100,000 between 2000- -2004 to 12.8/100,000 between 2005-2009) was recorded. Most frequent ILD diagnosis was interstitial pneumonia and fibrosis (J84) - 55.7% (including idiopathic pulmonary fibrosis [IPF] - J84.1-27.5%) and sarcoidosis (D86) - 25%. During the study period the increase in hospitalizations was observed in patients with sarcoidosis (+55%) and in the group of interstitial pneumonia and fibrosis (+39%), but the decrease (-38%) in the group of pneumoconiosis (J60-J68). Sex ratio (M/F) was 1.5/1 for all ILDs; ranging from 1.2/1 for D86 and J84 to 4.7/1 for radiotherapy and drug induced ILDs (J70) and 7.1/1 for J60-J68. Respiratory failure was found in over 50% of patients with IPF and pneumoconiosis but only occasionally in the course of sarcoidosis (7%). 6.3% of all ILDs patients died within 10 years, the mortality was the highest in interstitial pneumonia and fibrosis (4.3% of all ILDs patients died due to J84) and the lowest in sarcoidosis (only 1 patient - 0.18% died due to D86). Crude incidence rates were estimated to be 8.8/100,000 adults (> 14 years) for all ILDs; 5/100,000 for J84 (2.5/100 000 for J84.1, 0.3/100,000 for COP - cryptogenic organizing pneumonia and rare ILD's); 2.3/100,000 for D86, 1/100,000 for J60- J68, 0.2/100,000 for J70 and 0.3/100,000 for collagen tissue disease associated ILDs (J99). Ten years prevalence rates per 100,000 adults were: 87.7 for all ILDs; 50 for J84 (25.5 for J84.1; 3 for COP and rare ILDs); 23.1 for D86; 9.8 for J60-J68; 2.1 for J70 and 2.7 for J99. CONCLUSIONS: The incidence rates of ILDs found in our study are lower than that reported in recent European studies. Our study was based on data of single hospital center for respiratory medicine and probably underestimate the real incidence rates of ILDs. On the other hand, 10 years prevalence estimates are concordant with available epidemiological data. Comparisons of the relative frequencies are probably accurate and idiopathic pulmonary fibrosis and sarcoidosis appear to be the most frequent ILDs. PMID- 23109205 TI - [Socio-economic status and duration of TB symptoms in males treated at the Mazovian Treatment Centre of Tuberculosis and Lung Diseases in Otwock]. AB - INTRODUCTION: The incidence of tuberculosis depends on many factors, not only on health issues but also on socioeconomic factors. The aim of this study was to assess the duration of symptoms and the extent of radiological changes in men with bacteriologically confirmed pulmonary tuberculosis in relation to their socioeconomic status. MATERIAL AND METHODS: This was a retrospective study based on the analysis of 300 hospital records of patients hospitalised in 2004-2006 in the male ward of the Mazovian Treatment Centre of Lung Diseases and Tuberculosis in Otwock. In all patients, the diagnosis of tuberculosis was bacteriologically confirmed. We evaluated the duration of symptoms prior to hospitalisation, the extent of radiological changes and socioeconomic status. We also took into account the place of residence, professional activity, age and marital status. RESULTS: Among patients with TB hospitalised in the Mazovia Region, 74% were professionally inactive persons and 57% were unemployed. Patients population in cities and villages were similar, but as much as 10% of the patients hospitalised who were actively spreading bacilli in Mazovia Region were homeless. In the study group, 60% of the men were unmarried. In 63% of the patients symptoms of tuberculosis were present for more than two months. Chronic symptoms were reported more often in the unemployed (60%) and in single patients. As much as 81% of the patients at the initiation of treatment, had extensive radiological changes in 3 or more lung fields. Quite often sweeping pulmonary changes were observed in the homeless, unemployed and pensioners. Sputum smear-positive tuberculosis, was demonstrated in 87% of the examined patients. CONCLUSIONS: The incidence of tuberculosis observed in the Mazovia Region was especially observed in the unemployed, disabled and pensioners. Among these patients, many were homeless. The majority of patients in Mazovia Region at the start of treatment already had very extensive radiological changes and the symptoms were present with them for several weeks. PMID- 23109206 TI - [Pulmonary heart disease--cardiologist's point of view]. AB - This paper presents cardiologist's point of view on definition, diagnosis and treatment of pulmonary heart disease. Difficulties in interpretation of definition in clinical praxis and the role of medical history, physical examination, lung function tests, gasometry, chest X-ray and ECG in initial diagnosis of pulmonary heart disease are described. Author underlines the importance of echocardiographic study and pulmonary hemodynamics in confirmation of diagnosis and in differential diagnosis of "out of proportion" pulmonary hypertension. The current results of specific for pulmonary artery hypertension vasodilatory treatment in patients with pulmonary heart disease are discussed. PMID- 23109207 TI - [Pulmonary rehabilitation in patients with lung cancer]. AB - The paper presents current news on the possibilities of conducting rehabilitation of patients suffering from lung cancer. It presents the principles of conducting and contraindications for pulmonary rehabilitation for these patients according to current guidelines of American College of Sport Medicine. The methods of measuring exercise capacity for patients with lung cancer have been discussed. The value of ergospirometrial test with maximum oxygen consumption (VO(2peak)) in predicting not only the survival of patients with lung cancer, but also assessing the possibility of pulmonary rehabilitation programs has been highlighted. In the part devoted to physical training for patients before a surgery for lung cancer, current research results have been presented- these show that even a short, high intensity program of pulmonary rehabilitation for patients with lung cancer before surgery is effective and increases the safety of both- the safety of the surgery and extends survival time after operation for lung cancer. The paper describes difficulties in the implementation of rehabilitation programs after surgery conducted on patients with lung cancer resulting from dysfunction of cardiovascular and muscle atrophy - both skeletal and respiratory. The issue of patients with inoperable lung cancer treated with chemotherapy has been discussed so far in only one paper published in 2007. The results shown in it have been discussed as well. The authors demonstrated a significant improvement in the efficiency of respiratory-circulatory system assessed by six-minute walk test, although the rehabilitation program was graduated by small number of patients (44%). It was noted that patients with inoperable lung cancer now account for a large group of patients who use this type of medical intervention and can significantly improve the quality of life and the method shows positive impact on the survival rate. PMID- 23109208 TI - [Morbid obesity as a cause of respiratory failure]. AB - World epidemic of obesity reached Poland. Obesity may result in hypercapnic respiratory failure. This complication may be expected in morbidly obese subjects, with BMI > 35. Diagnosis is confirmed by arterial blood gas analysis showing PaO(2) < 60 mm Hg and PaCO(2) > 45 mm Hg. The most frequent cause of respiratoty failure is severe form of obstructive sleep apnea. In approximately 10% of patients obesity hypoventilation syndrome is diagnosed. Diagnosis is established during polysomnographic examination. Patients are treated with nocturnal ventilatory suport CPAP or BiPAP. Causative treatment is based on weight reduction. Low - calorie diet is ineffective. Bariatric surgery available in Poland is effective. PMID- 23109209 TI - Benign pulmonary metastasizing leiomyoma uteri. Case report and review of literature. AB - Benign metastasizing leiomyoma (BML) is a rare condition in middle-aged women with a history of uterine leiomyomata. It is characterized by the proliferation of, usually multiple, smooth muscle nodules. Approximately 100 cases have been reported in the literature, and the lungs were the most common site of metastases. We report a case of 52-year-old obese woman (BMI 31), hospital worker, smoker, admitted to the hospital with exertional dyspnoea, night sweats, loss of weight, and productive cough. Hysterectomy for a uterine leiomyoma was performed 9 years earlier. In addition, a history of two episodes of superficial vein thrombosis 3 and 2 years before admission was noted. Chest X-ray and subsequently CT chest examinations revealed multiple, non-calcified nodules within the middle and lower parts of both lungs. Specimens obtained by transbronchial biopsy (TBLB) and from open lung biopsy displayed benign muscle cell proliferation compatible with BML. The levels of sex hormones were characteristic for the menopause; therefore, observation was advised. Additionally, Streptococcus pneumoniae was cultured from bronchial washing, and bronchitis was diagnosed. Antibiotics, bronchodilators, and mucolytics were administered, and dyspnoea and cough with expectoration were diminished. Two years later pulmonary lesions have been stable; however, she has put on weight. Subsequently the patient has developed deep vein thrombosis with pulmonary embolism. Anticoagulant treatment was introduced, with some improvement. PMID- 23109210 TI - Pulmonary nocardiosis in a patient with chronic obstructive pulmonary disease- case report and literature review. AB - Nocardiosis is an infrequent but potentially serious pulmonary infection that typically affects patients with immune suppression or structural lung disease. We report a case of a 70-year-old patient with chronic obstructive pulmonary disease (COPD) treated with inhaled steroids, theophylline, short-acting beta agonists and anticholinergics, and long-term oxygen therapy, who presented with non-resolving pneumonia. Following a diagnosis of nocardiosis, made based on sputum culture, the patient was treated with trimethoprim/sulphamethoxazole and then, due to treatment side effects, with minocycline. We review the literature data on nocardiosis in COPD patients. PMID- 23109211 TI - Hypercalcemia and renal failure in the course of sarcoidosis--case report. AB - Disturbances of calcium metabolism such as hypercalcemia or/and hypercalciuria in the course of sarcoidosis can be a cause of renal failure in some patients. Life threatening hypercalcemia in sarcoidosis patients is not very frequent. Severe hypercalcemia leading to renal insufficiency is a very rare condition. We present a case of 53-year old man who was admitted to Department of Lung Diseases because of hypercalcemic syndrome and renal failure, and in whom diagnosis of sarcoidosis was made. He was successfully treated with systemic corticosteroids. In this article we present physiological mechanism of hypercalcemia in sarcoidosis patients, mechanism of renal damage and management of these difficult problems. PMID- 23109212 TI - [Pulmonary sclerosis in aspect of IgG4-related disease]. PMID- 23109213 TI - [Lung cancer. In 100 years of monograph by Issak Adler]. PMID- 23109214 TI - Inverse correspondence between hippocampal perfusion and verbal memory performance in older adults. AB - Understanding physiological changes that precede irreversible tissue damage in age-related pathology is central to optimizing treatments that may prevent, or delay, cognitive decline. Cerebral perfusion is a tightly regulated physiological property, coupled to tissue metabolism and function, and abnormal (both elevated and reduced) hippocampal perfusion has been reported in a range of cognitive disorders. However, the size and location of the hippocampus complicates perfusion quantification, as many perfusion techniques acquire data with spatial resolution on the order of or beyond the size of the hippocampus, and are thus suboptimal in this region (especially in the presence of hippocampal atrophy and reduced flow scenarios). Here, the relationship between hippocampal perfusion and atrophy as a function of memory performance was examined in cognitively normal healthy older adults (n = 20; age=67 +/- 7 yr) with varying genetic risk for dementia using a custom arterial spin labeling acquisition and analysis procedure. When controlling for hippocampal volume, it was found that hippocampal perfusion correlated inversely (P = 0.04) with memory performance despite absent hippocampal tissue atrophy or white matter disease. The hippocampal flow asymmetry (left hippocampus perfusion-right hippocampus perfusion) was significantly (P = 0.04) increased in APOE-epsilon4 carriers relative to noncarriers. These findings demonstrate that perfusion correlates more strongly than tissue volume with memory performance in cognitively normal older adults, and furthermore that an inverse trend between these two parameters suggests that elevation of neuronal activity, possibly mediated by neuroinflammation and/or excitation/inhibition imbalance, may be closely associated with minor changes in memory performance. PMID- 23109215 TI - Fetuin-a in the developing brain. AB - The serum protein fetuin-A is essential for mineral homeostasis and shows immunomodulatory functions, for example by binding to TGF superfamily proteins. It proved neuroprotective in a rat stroke model and reduced lethality after systemic lipopolysaccharide challenge in mice. Serum fetuin-A concentrations are highest during intrauterine life. Different species show intrauterine cerebral fetuin-A immunoreactivity, suggesting a contribution to brain development. We therefore aimed at specifying fetuin-A immunoreactivity in brains of newborn rats (age P0-P28) and human neonates (20-40 weeks of gestation). In humans and rats, fetuin-A was found in cortex, white matter, subplate, hippocampus, subventricular zone, and ependymal cells which supports a global role for brain function. In rats, overall fetuin-A immunoreactivity decreased with age. At P0 fetuin-A immunoreactivity affected most brain structures. Thereafter, it became increasingly restricted to distinct cells of the hippocampus, cingular gyrus, periventricular stem cell layer, and ependyma. In ependymal cells the staining pattern complied with active transependymal transport from cerebrospinal fluid. Double immunofluorescence studies revealed colocalization with NeuN (mature neurons), beta III tubulin (immature neurons), GFAP (astrocytes), and CD68 (activated microglia). This points to a role of fetuin-A in different brain functional systems. In human neonatal autopsy cases, frequently affected from severe neurological and non-neurological diseases, fetuin-A immunoreactivity was heterogeneous and much less associated with age than in healthy tissues studied earlier, suggesting an impact of exogeneous noxious factors on fetuin-A regulation. Further research on the role of fetuin-A in the neonatal brain during physiological and pathological conditions is recommended. PMID- 23109216 TI - Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. AB - These guidelines for the management of patients up to 18 years with Langerhans cell histiocytosis (LCH) have been set up by a group of experts involved in the Euro Histio Net project who participated in national or international studies and in peer reviewed publications. Existing guidelines were reviewed and changed where new evidence was available in the literature up to 2012. Data and publications have been ranked according to evidence based medicine and when there was a lack of published data, consensus between experts was sought. Guidelines for diagnosis, initial clinical work-up, and treatment and long-term follow-up of LCH patients are presented. PMID- 23109217 TI - Combining next-generation sequencing with microarray for transcriptome analysis in rainbow trout gonads. AB - Microarray technology is a powerful tool for studying genome-wide gene expression. As the genome of many fish has not yet been determined, however, cDNA microarrays can only be designed from limited expressed sequence tag data. In this study, we designed a microarray based on the sequencing data (337,466 reads) obtained by next-generation sequencing of RNA extracted from rainbow trout (Oncorhynchus mykiss) embryonic genital ridge, testis, and ovary. These data (307,264 reads) were assembled into 28,668 contigs; 3,298 reads could not be assembled and 26,904 reads were unique sequences that did not cluster with other reads. Based on this information, 55,928 microarray probes were designed for a microarray, which was validated by hybridization experiments with RNA extracted from type A spermatogonia (A-SG) and testicular somatic cells. Expression of known spermatogonial markers was confirmed to be higher in A-SG than in testicular somatic cells whereas supporting-cell markers were expressed at higher levels in testicular somatic cells. This microarray analysis revealed that 8,068 transcripts showed at least fourfold higher signal in A-SG than testicular somatic cells. Fourteen of 17 randomly selected transcripts were expressed at significantly higher-levels in A-SG than somatic cells, by quantitative RT-PCR. In addition, three transcripts analyzed with in situ hybridization showed A-SG specific signals in immature trout testis, with one of them exhibiting a heterogeneous expression pattern in A-SG. The rainbow trout gonad microarray developed in this study therefore appears to be a useful tool to understand gametogenesis in rainbow trout. PMID- 23109218 TI - Highly conductive and strain-released hybrid multilayer Ge/Ti nanomembranes with enhanced lithium-ion-storage capability. AB - Highly conductive and hybridized microtubes relying on strain-released ultrathin Ti/Ge bilayer nanomembranes are reported. These hybrid multilayer microtubes show a remarkably enhanced reversible capacity up to 1495 mA h g(-1) with a high first-cycle Coulombic efficiency of 85%, and demonstrate an excellent capacity of ~930 mA h g(-1) after 100 cycles. PMID- 23109220 TI - Synthesis and biological evaluation of new bischromone derivatives with antiproliferative activity. AB - The synthesis of new bischromone derivatives (4a-c and 5a-c) as potential anticancer drugs is described. The difference in the reactivity between 4-oxo-4H chromene-3-carboxylic acid 2 (or its methyl ester 3) and 4-oxo-4H-chromene-3 carbonyl chloride 1 with three different polyamines: 3,3'-diamino-N methyldipropylamine (a), 1,4-bis(3-aminopropyl)piperazine (b), 4,9-dioxa-1,12 dodecanediamine (c) resulted in the formation of two different groups of products, compounds 4a-c and 5a-c, designed in agreement with the bisintercalators' structural requirements. The transformation of 4-oxo-4H chromene-3-carboxylic acid into 2H-chromene-2,4(3H)-diones (5) was confirmed by the NMR and XRD experiments. Compounds 4a and 5a were evaluated in vitro in the highly aggressive melanoma cell line A375. An enhanced induction of apoptosis and cell cycle arrest clearly revealed that compound 5a was more potent than 4a. Compound 5a was also more active in diminishing the adhesive potential of melanoma cells. Current studies support the notion that small changes in the three-dimensional structure of molecules might have a substantial impact on their biological activity. PMID- 23109219 TI - Pharmacokinetics and safety of ezetimibe/simvastatin combination tablet: an open label, single-dose study in healthy Chinese subjects. AB - BACKGROUND AND OBJECTIVES: Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics. METHODS: This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10 mg and simvastatin 40 mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms. RESULTS: The pharmacokinetic parameters (mean +/- SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56 +/- 26.62 and 9.40 +/- 6.17 ng/mL; time to reach C(max) (t(max)) 0.93 +/- 0.30 and 1.25 +/- 1.27 h; elimination half-life (t(1/2)) 24.32 +/- 13.27 and 18.90 +/- 9.66 h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06 +/- 241.45 and 126.01 +/- 69.01 ng.h/mL, respectively. The pharmacokinetic parameters (mean +/- SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92 +/- 5.50 and 3.37 +/- 1.78 ng/mL, t(max) 0.98 +/- 0.28 and 3.73 +/- 1.68 h, t(1/2) 4.19 +/- 1.81 and 7.65 +/- 7.96 h, and mean AUC(last) 33.63 +/- 20.41 and 32.50 +/- 18.79 ng.h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(infinity)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study. CONCLUSION: Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid. PMID- 23109221 TI - Anti-inflammatory and PPAR transactivational properties of flavonoids from the roots of Sophora flavescens. AB - Anti-inflammatory and peroxisome proliferator-activated receptors (PPARs) transactivational effects of nine compounds (1 - 9) from the roots of Sophora flavescens were evaluated using NF-kappaB-luciferase, reverse transcriptase polymerase chain reaction, peroxisome proliferator response element (PPRE) luciferase, and GAL-4-PPAR chimera assays. Compounds 4 and 8 significantly inhibited TNFalpha-induced NF-kappaB transcriptional activity in HepG2 cells in a dose-dependent manner, with IC50 values of 4.0 and 4.4 MUM, respectively. Furthermore, the transcriptional inhibitory function of these compounds was confirmed by a decrease in cyclooxgenase 2 and inducible nitric oxide synthase gene expression levels in HepG2 cells. Compounds 1, 3, 5, 6, 8, and 9 significantly activated the transcription of PPARs in a dose-dependent manner, with EC50 values ranging from 1.1 to 13.0 MUM. Compounds 1, 3, 5, 6, 8, and 9 exhibited dose-dependent PPARalpha transactivational activity, with EC50 values in a range of 0.9 - 16.0 MUM. Compounds 1, 3, 8, and 9 also significantly upregulated PPARgamma activity in a dose-dependent manner, with EC50 values of 10.5, 6.6, 15.7, and 1.6 MUM, whereas compounds 1, 8, and 9 demonstrated transactivational PPARbeta(delta) effects with EC50 values of 11.4, 10.3, and 1.5 MUM, respectively. These results provide a scientific rationale for the use of the roots of S. flavescens and warrant further studies to develop new agents for the prevention and treatment of inflammatory and metabolic diseases. PMID- 23109222 TI - Insulin-like growth factor I, growth hormone, and insulin sensitivity: the effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects. AB - Both altered GH-IGF-I axis and low serum levels of 25-hydroxyvitamin D (25(OH)D) are linked to measures of metabolic syndrome. Our hypothesis was that there is a relation between GH, IGF-I, and 25(OH)D; and that vitamin D supplementation may have an effect on the levels of GH, IGF-I, and IGF-I/IGFBP-3 ratio. 318 overweight and obese subjects completed a one-year randomized intervention with either 40,000 or 20,000 IU cholecalciferol per week or placebo. GH, IGF-I, IGFBP 3 and measures of insulin resistance were evaluated at baseline and at the end of study. There was a significant relation between entities of GH-IGF-I axis and insulin resistance. Subjects with severe obesity had significantly lower serum 25(OH)D and had a significant linear decline in IGF-I/IGFBP-3 ratio with increasing serum 25(OH)D quartiles. Vitamin D status was an independent predictor of GH-IGF-I axis and supplementation with vitamin D decreased IGF-I/IGFBP-3 ratio in subjects without severe obesity. No corresponding effect of vitamin D supplementation on BMI or insulin resistance was observed. Adverse effects of GH IGF-I axis on glucose metabolism and the development of metabolic syndrome may be in part associated with the changes in vitamin D status. PMID- 23109224 TI - A biocompatible fluorescent ink based on water-soluble luminescent carbon nanodots. PMID- 23109223 TI - Rosiglitazone protects against palmitate-induced pancreatic beta-cell death by activation of autophagy via 5'-AMP-activated protein kinase modulation. AB - Promoting beta-cell survival is crucial for the prevention of beta-cell failure in diabetes. Thiazolidinediones, a widely used drug to improve insulin sensitivity in clinical practice, is found to have a protective effect on islet beta-cell. To date, the mechanism underlying the protective role of thiazolidinedione on beta-cell survival remain largely unknown. Activation of autophagy was detected by transmission electron microscopy, western blot, and GFP LC3 transfection. Cell viability was examined by WST-8. Cell apoptosis was demonstrated by DAPI and Annexin V/PI staining. Colony formation assay was used to detect long-term cell viability. We demonstrated that rosiglitazone-treated beta-cells were more resistant to palmitate-induced apoptosis. The conversion of LC3-I to LC3-II and accumulated autophagosomes were found to be upregulated in rosiglitazone-treated cells. Inhibition of autophagy augmented palmitate-induced apoptosis with rosiglitazone treatment, suggesting that autophagy plays an important role in the survival function of rosiglitazone on beta-cells. Furthermore, we showed that rosiglitazone could induce AMP-activated protein kinase (AMPK) phosphorylation and reduce p70S6 kinase phosphorylation. Inhibition of AMPK impaired autophagy activation and enhanced palmitate-induced apoptosis during rosiglitazone treatment. These findings reveal that rosiglitazone-induced autophagy contributes to its protective function on beta-cells during palmitate treatment. PMID- 23109225 TI - A combined atomic force microscopy and computational approach for the structural elucidation of breitfussin A and B: highly modified halogenated dipeptides from Thuiaria breitfussi. PMID- 23109226 TI - Frankliniella occidentalis (Pergande) integrated pest management programs for fruiting vegetables in Florida. AB - BACKGROUND: The spread of the western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), resulted in the worldwide destabilization of established integrated pest management programs for many crops. Efforts to control the pest and the thrips-vectored tospoviruses with calendar applications of broad-spectrum insecticides have been unsuccessful. The result has been a classic '3-R' situation: resistance to numerous insecticides; resurgence of the western flower thrips populations as a result of natural predators and native competitor thrips being eliminated; replacement by various other pests. This paper reports on integrated pest management programs for fruiting vegetables that are effective, economical, ecologically sound and sustainable. RESULTS: The components include the following: define pest status (economic thresholds); increase biotic resistance (natural enemies and competition); integrate preventive and therapeutic tactics (scouting, ultraviolet-reflective technologies, biological control, compatible insecticides, companion plants and fertility); vertically integrate the programs with other pests; continually communicate latest science-based management tactics with end-users. CONCLUSION: These programs have been widely implemented in Florida and have significantly improved the management of western flower thrips and thrips-transmitted viruses. PMID- 23109227 TI - The role of eating and emotion in binge eating disorder and loss of control eating. AB - OBJECTIVE: Binge eating, defined as the consumption of large amounts of food during which a sense of loss of control (LOC) is experienced, is associated with negative affect. However, there are no data on the experience of LOC after accounting for the effects of negative affect and caloric intake. METHOD: Nine adult patients with binge eating disorder (BED) and 13 obese nonbinge eating disorder (NBED) participants carried a palmtop computer for 7 days, rating momentary mood and sense of LOC multiple times each day. Electronic food logs were collected once daily. RESULTS: After removing the effects of caloric intake and negative affect, a significant group difference was observed for ratings of LOC between BED and NBED participants. DISCUSSION: These findings suggest the experience of LOC in adults with BED is a salient feature of binge episodes, beyond that explained by caloric intake and momentary affect. PMID- 23109228 TI - Binding structures of tri-N-acetyl-beta-glucosamine in hen egg white lysozyme using molecular dynamics with a polarizable force field. AB - Lysozyme is a well-studied enzyme that hydrolyzes the beta-(1,4)-glycosidic linkage of N-acetyl-beta-glucosamine (NAG)(n) oligomers. The active site of hen egg-white lysozyme (HEWL) is believed to consist of six subsites, A-F that can accommodate six sugar residues. We present studies exploring the use of polarizable force fields in conjunction with all-atom molecular dynamics (MD) simulations to analyze binding structures of complexes of lysozyme and NAG trisaccharide, (NAG)(3). MD trajectories are applied to analyze structures and conformation of the complex as well as protein-ligand interactions, including the hydrogen-bonding network in the binding pocket. Two binding modes (ABC and BCD) of (NAG)(3) are investigated independently based on a fixed-charge model and a polarizable model. We also apply molecular mechanics with generalized born and surface area (MM-GBSA) methods based on MD using both nonpolarizable and polarizable force fields to compute binding free energies. We also study the correlation between root-mean-squared deviation and binding free energies of the wildtype and W62Y mutant; we find that for this prototypical system, approaches using the MD trajectories coupled with implicit solvent models are equivalent for polarizable and fixed-charge models. PMID- 23109229 TI - Sclerostin antibody inhibits skeletal deterioration due to reduced mechanical loading. AB - Sclerostin, a product of the SOST gene produced mainly by osteocytes, is a potent negative regulator of bone formation that appears to be responsive to mechanical loading, with SOST expression increasing following mechanical unloading. We tested the ability of a murine sclerostin antibody (SclAbII) to prevent bone loss in adult mice subjected to hindlimb unloading (HLU) via tail suspension for 21 days. Mice (n = 11-17/group) were assigned to control (CON, normal weight bearing) or HLU and injected with either SclAbII (subcutaneously, 25 mg/kg) or vehicle (VEH) twice weekly. SclAbII completely inhibited the bone deterioration due to disuse, and induced bone formation such that bone properties in HLU SclAbII were at or above values of CON-VEH mice. For example, hindlimb bone mineral density (BMD) decreased -9.2% +/- 1.0% in HLU-VEH, whereas it increased 4.2% +/- 0.7%, 13.1% +/- 1.0%, and 30.6% +/- 3.0% in CON-VEH, HLU-SclAbII, and CON-SclAbII, respectively (p < 0.0001). Trabecular bone volume, assessed by micro computed tomography (uCT) imaging of the distal femur, was lower in HLU-VEH versus CON-VEH (p < 0.05), and was 2- to 3-fold higher in SclAbII groups versus VEH (p < 0.001). Midshaft femoral strength, assessed by three-point bending, and distal femoral strength, assessed by micro-finite element analysis (uFEA), were significantly higher in SclAbII versus VEH-groups in both loading conditions. Serum sclerostin was higher in HLU-VEH (134 +/- 5 pg/mL) compared to CON-VEH (116 +/- 6 pg/mL, p < 0.05). Serum osteocalcin was decreased by hindlimb suspension and increased by SclAbII treatment. Interestingly, the anabolic effects of sclerostin inhibition on some bone outcomes appeared to be enhanced by normal mechanical loading. Altogether, these results confirm the ability of SclAbII to abrogate disuse-induced bone loss and demonstrate that sclerostin antibody treatment increases bone mass by increasing bone formation in both normally loaded and underloaded environments. PMID- 23109230 TI - Radiological diagnosis of large-bowel obstruction: neoplastic etiology. AB - Large-bowel obstruction (LBO) is a relatively common abdominal emergency. The CT exam has become the most important imaging modality for the diagnosis of LBO, following abdominal ultrasound and plain radiography. The recent multi-detector CT (MD-CT) is able to clarify the etiology of LBO and to help in deciding how to treat LBO. Therefore, it is important for the radiologists to become familiar with the imaging findings of LBO, including plain radiograph and CT, due to various causes. In this article, we have shown the characteristics of the radiological findings including plain radiograph, barium study, and CT as well as their correlations with pathologic findings of LBO. The etiology of LBO is usually divided into neoplastic diseases and nonneoplastic diseases. However, the most common cause is the neoplastic etiology. Now, we can afford the critical information concerning the level of obstruction, its cause, the viability of the involved bowel loops, and a decision-making regarding the therapy for patients with LBO, using MD-CT high technology. PMID- 23109231 TI - Endothelial differentiation and vasculogenesis induced by three-dimensional adipose-derived stem cells. AB - Recently, an angiogenic therapy based on adipose-derived stem cells (ASCs) in an ischemic model has been reported. This study demonstrates the differentiation of human ASCs (hASCs) into endothelial cells clusters by culturing the cells in the form of three dimensional cell masses (3DCMs), which is based on the adherent activity of ASCs for a substrate. The 3DCM composed of hASCs induced hypoxic conditions and expressed angiogenic factors, such as vascular endothelial growth factor and interleukin-8. From immunochemical staining analysis, the 3DCMs of hASCs were CD31(+), KDR(+), and CD34(+), whereas monolayer-cultured hASCs were negative for the these markers. To evaluate the ability of vasculature to form within 3DCMs, the 3DCMs were mixed in Matrigel/fibrin gel and injected into mice. Mature tubular microvessels perfused with blood were observed in the 3DCM/gel 20 days after injection, but not in the gel alone or hASC/gel mixture. Vasculature formed in the 3DCM/gel was recognized by antibodies against human alpha-smooth muscle actin, KDR, CD31, and CD34, but not by antibodies against murine antigens. These results suggest that the vasculatures originated from the embedded human cells. The 3DCMs of hASCs could function as a source of vascular cells for neovascularization, and could also be co-implanted with other cell types for regenerative medicine. PMID- 23109232 TI - Peripheral blood stem-cell harvest using percutaneous arterial lines in children. AB - BACKGROUND: Autologous peripheral blood stem-cell collection (PBSCC) in children has become an integral part of contemporary treatment protocols, but the procedure is often complicated due to technical issues related to vascular access. Central line placement is often implemented to surmount this problem, but is associated with complications such as bleeding, thrombosis and pneumothorax. As an alternative we have introduced the use of radial arterial lines for PBSCC in children. PROCEDURE: Data from autologous stem cell collections performed from October 2002 to December 2011 using a radial arterial line were collected. RESULTS: A total of 372 PBSCC procedures were performed during the study period; an arterial line was used in 311 PBSCC's in 208 children. The average patient age and weight were 7.9 years (SD 5.4) and 28.3 kg (SD 20.4), respectively. The smallest patient was 9 months old and weighed 7 kg. The mean total volume processed was 8,593 cm(3) (SD 4,854), and the mean number of blood volumes processed was 4.3. Mean collection time for a single blood volume was 55 minutes (SD 15.5). The mean number of CD34+ cells collected per donation was 5.8 * 10(6) /kg. Ninety-seven patients (46%) required more than one collection to meet the requested CD34+ cell target. No serious adverse effects associated with vascular access occurred in this cohort. CONCLUSION: Percutaneous placement of radial artery catheters can be rapidly and safely performed in very small infants and in children with difficult venous access. This technique provides a reliable platform for efficient PBSCC. PMID- 23109233 TI - Modeling toxicity of binary metal mixtures (Cu(2+) -Ag(+) , Cu(2+) -Zn(2+) ) to lettuce, Lactuca sativa, with the biotic ligand model. AB - The biotic ligand model (BLM) was applied to predict metal toxicity to lettuce, Lactuca sativa. Cu(2+) had the lowest median effective activity (EA50(M) ), compared with Ag(+) and Zn(2+) (EA50(Cu) = 2.60 * 10(-8) M, EA50(Ag) = 1.34 * 10(-7) M, EA50(Zn) = 1.06 * 10(-4) M). At the 50% response level, the fraction of the total number of biotic ligands occupied by ions (f50(M) ) was lowest for Ag(+) among the metals (f50(Ag) = 0.22, f50(Cu) = 0.36, f50(Zn) = 0.42). Cu(2+) had the highest affinity for biotic ligands compared with Ag(+) and Zn(2+) , as shown by stability constants of the cation-biotic ligand binding, expressed as log K(MBL) (log K(CuBL) = 7.40, log K(AgBL) = 6.39, log K(ZnBL) = 4.00). Furthermore, the BLM was combined with the toxic equivalency factor approach in predicting toxicity of mixtures of Cu(2+) -Zn(2+) and Cu(2+) -Ag(+) . The fraction of biotic ligands occupied by ions was used to determine the relative toxic potency of metals and the toxic equivalency quotient (TEQ) of mixtures. This approach allowed for including interactions in estimating mixture toxicity and showed good predictive power (r(2) = 0.64-0.84). The TEQ at the 50% response level (TEQ50, Cu(2+) equivalents) for Cu(2+) -Zn(2+) mixtures was significantly lower than the value for Cu(2+) -Ag(+) mixtures. Joint toxicity depended on both TEQ and specific composition of the mixture. The present study supports the use of the accumulation of metal ions at the biotic ligands as a predictor of toxicity of single metals and mixtures. PMID- 23109234 TI - Elevated p66Shc is associated with intracellular redox imbalance in developmentally compromised bovine embryos. AB - The in vitro production of mammalian embryos suffers from low efficiency, with 50 70% of all fertilized oocytes failing to develop to the blastocyst stage. This high rate of developmental failure is due, in part, to the effects of oxidative stress generated by reactive oxygen species (ROS). The p66Shc adaptor protein controls oxidative stress response by regulating intracellular ROS levels through multiple pathways, including mitochondrial ROS generation and the repression of antioxidants. This study explored the relationship between p66Shc levels, redox state, and developmental potential in early bovine embryos. Embryo developmental potential was established based on observing their time of first cleavage. P66Shc, catalase, and mitochondrial-specific, manganese-superoxide dismutate (MnSOD) levels were compared between embryos with high and low developmental potentials. Additionally, p66Shc, catalase, and MnSOD content were assayed following a variety of oxidative stress-inducing and-alleviating conditions. Increased developmental potential correlated with significantly lower p66Shc content, significantly higher levels of catalase and MnSOD, and significantly lower intracellular ROS levels (MitoSOX staining) and reduced DNA damage (gamma H2A.X(phospho S139) immunostaining). p66Shc content was increased by either high (20%) O(2) culture or H(2)O(2) treatment, and significantly decreased by supplementing culture media with the antioxidant polyethylene glycol-conjugated catalase. While the abundance of p66Shc varied according to pro/anti-oxidant culture conditions, antioxidant content varied only according to developmental potential. This discrepancy has important implications regarding ongoing efforts towards maximizing in vitro embryo production. PMID- 23109235 TI - Colon adenocarcinoma metastatic to the distal extremity. PMID- 23109236 TI - Bupropion therapy in pregnancy and the occurrence of cardiovascular malformations in infants. PMID- 23109237 TI - Benfluorex-induced cardiac valve injury. PMID- 23109239 TI - Drug-related hazardous conditions to prevent injury and defining injury is also important. PMID- 23109240 TI - Skeletal variation among early Holocene North American humans: implications for origins and diversity in the Americas. AB - The movement of humans into the Americas remains a major topic of debate among scientific disciplines. Central to this discussion is ascertaining the timing and migratory routes of the earliest colonizers, in addition to understanding their ancestry. Molecular studies have recently argued that the colonizing population was isolated from other Asian populations for an extended period before proceeding to colonize the Americas. This research has suggested that Beringia was the location of this "incubation," though archaeological and skeletal data have not yet supported this hypothesis. This study employs the remains of the five most complete North American male early Holocene skeletons to examine patterns of human morphology at the earliest observable time period. Stature, body mass, body breadth, and limb proportions are examined in the context of male skeletal samples representing the range of morphological variation in North America in the last two millennia of the Holocene. These are also compared with a global sample. Results indicate that early Holocene males have variable postcranial morphologies, but all share the common trait of wide bodies. This trait, which is retained in more recent indigenous North American groups, is associated with adaptations to cold climates. Peoples from the Americas exhibit wider bodies than other populations sampled globally. This pattern suggests the common ancestral population of all of these indigenous American groups had reduced morphological variation in this trait. Furthermore, this provides support for a single, possibly high latitude location for the genetic isolation of ancestors of the human colonizers of the Americas. PMID- 23109241 TI - Sudden unexpected death in epilepsy. Potential role of antiepileptic drugs. AB - Among people with epilepsy, there is a 20-fold higher risk of dying suddenly and unexpectedly compared with the general population. This phenomenon is called sudden unexpected death in epilepsy (SUDEP) and the term is used when sudden death occurs in an otherwise reasonably healthy person with epilepsy and the autopsy is unrevealing. In most cases, SUDEP occurs during sleep and is unwitnessed. Risk factors for SUDEP include the presence or number of generalized tonic-clonic seizures (GTCS), nocturnal seizures, young age at epilepsy onset, longer duration of epilepsy, dementia, absence of cerebrovascular disease, asthma, male gender, symptomatic aetiology of epilepsy and alcohol abuse. Suggested factors predisposing to SUDEP have included long-QT-related mutations, impaired serotonergic brain stem control of respiration, altered autonomic control and seizures with a pronounced postictal suppression and respiratory compromise. Final events that may lead up to SUDEP are a postictal CNS shutdown with pronounced EEG suppression, ictal or postictal apnoea, and ictal cardiac arrhythmia. It is unknown whether antiepileptic drugs (AEDs) modify the risk for SUDEP. Studies have consistently found that the presence or number of GTCS is associated with an increased risk for SUDEP. Since continued presence of GTCS clearly necessitates the use of AEDs, both factors must be taken into account to determine whether one or both increases the risk for SUDEP. Some studies suggest that AEDs, such as lamotrigine and carbamazepine, may increase the risk of SUDEP, but rarely adjust for GTCS. Other studies, which have found that AEDs are associated with a decreased SUDEP risk, either adjust for the number of GTCS or are meta-analyses of randomized clinical trials. Studies assessing the impact of AEDs on the risk for SUDEP are limited because SUDEP is a rare event, making randomized clinical trials impossible to conduct. Observational studies focus on whether or not an AED was prescribed. When postmortem AED concentrations are assessed they are usually low or absent, perhaps due to sampling in deceased individuals, making it difficult to fully resolve whether AEDs increase or decrease SUDEP risk. Despite these caveats, the evidence suggests that AEDs are not associated with an increased risk for SUDEP on a population level, although some individuals may be susceptible to effects of AEDs. Recent evidence from a meta-analysis of randomized clinical trials of adjunctive AEDs at efficacious doses provides strong support for AED treatment as mono- or polytherapy to increase seizure control and protect against SUDEP in patients with refractory epilepsy. For patients for whom seizure control is unattainable, supervision or monitoring may prevent SUDEP, though this has never been formally tested. PMID- 23109242 TI - Catalytic asymmetric synthesis of substituted morpholines and piperazines. PMID- 23109244 TI - Statistical Raman spectroscopy: an method for the characterization of covalently functionalized single-walled carbon nanotubes. PMID- 23109245 TI - Triazole fungicides and the selection of resistance to medical triazoles in the opportunistic mould Aspergillus fumigatus. AB - Azole resistance is an emerging problem in the opportunistic mould Aspergillus fumigatus. The triazoles are the most important agents for the management of Aspergillus diseases in humans. Selection for acquired resistance may occur in the hospital setting through exposure to high doses of azoles during azole therapy, but evidence is accumulating that A. fumigatus may become resistant to medical triazoles through environmental exposure to fungicides. The recovery of A. fumigatus isolates resistant to the medical triazoles from azole-naive patients as well as from the environment strongly indicates an environmental route of resistance selection. Molecule alignment studies have identified five fungicides that share a very similar molecule structure with the medical triazoles, and thus may have selected for mechanisms that confer resistance to both groups of compounds. It is important to explore further the presumed fungicide-driven route of resistance selection in order to implement effective preventive measures as the prevalence of azole resistance in A. fumigatus continues to increase and causes major challenges in the management of azole resistant Aspergillus diseases. PMID- 23109243 TI - Acute toxicities of unrelated bone marrow versus peripheral blood stem cell donation: results of a prospective trial from the National Marrow Donor Program. AB - Although peripheral blood stem cells (PBSCs) have replaced bone marrow (BM) as the most common unrelated donor progenitor cell product collected, a direct comparison of concurrent PBSC versus BM donation experiences has not been performed. We report a prospective study of 2726 BM and 6768 PBSC donors who underwent collection from 2004 to 2009. Pain and toxicities were assessed at baseline, during G-CSF administration, on the day of collection, within 48 hours of donation, and weekly until full recovery. Peak levels of pain and toxicities did not differ between the 2 donation processes for most donors. Among obese donors, PBSC donors were at increased risk of grade 2 to 4 pain as well as grade 2 to 4 toxicities during the pericollection period. In contrast, BM donors were more likely to experience grade 2 to 4 toxicities at 1 week and pain at 1 week and 1 month after the procedure. BM donors experienced slower recovery, with 3% still not fully recovered at 24 weeks, whereas 100% of PBSC donors had recovered. Other factors associated with toxicity included obesity, increasing age, and female sex. In summary, this study provides extensive detail regarding individualized risk patterns of PBSC versus BM donation toxicity, suggesting donor profiles that can be targeted with interventions to minimize toxicity. PMID- 23109246 TI - Comparison of two simulation methods to compute solvation free energies and partition coefficients. AB - The thermodynamic integration (TI) and expanded ensemble (EE) methods are used here to calculate the hydration free energy in water, the solvation free energy in 1-octanol, and the octanol-water partition coefficient for a six compounds of varying functionality using the optimized potentials for liquid simulations (OPLS) all-atom (AA) force field parameters and atomic charges. Both methods use the molecular dynamics algorithm as a primary component of the simulation protocol, and both have found wide applications in fields such as the calculation of activity coefficients, phase behavior, and partition coefficients. Both methods result in solvation free energies and 1-octanol/water partition coefficients with average absolute deviations (AAD) from experimental data to within 4 kJ/mol and 0.5 log units, respectively. Here, we find that in simulations the OPLS-AA force field parameters (with fixed charges) can reproduce solvation free energies of solutes in 1-octanol with AAD of about half that for the solute hydration free energies using a extended simple point charge (SPC/E) model of water. The computational efficiency of the two simulation methods are compared based on the time (in nanoseconds) required to obtain similar standard deviations in the solvation free energies and 1-octanol/water partition coefficients. By this analysis, the EE method is found to be a factor of nine more efficient than the TI algorithm. For both methods, solvation free energy calculations in 1-octanol consume roughly an order of magnitude more CPU hours than the hydration free energy calculations. PMID- 23109247 TI - Developing a strong anion exchange/RP (SAX/RP) 2D LC system for high-abundance proteins depletion in human plasma. AB - Human plasma is dominated by high-abundance proteins which severely impede the detection of low-abundance proteins. Unfortunately, now there is no efficient method for large-scale depletion of high-abundance proteins in human plasma. In this study, we developed a new strategy, strong anion exchange (SAX)/RP 2D LC system, which has potential for large-scale depletion of high-abundance proteins in human plasma. Separation gradients of the system were optimized to ensure an extensive separation of plasma proteins. Plasma was fractionated into 67 fractions by SAX. All these fractions were subjected a thorough separation by the 2D RPLC and 66 peaks with high UV absorption (>20 mAU) at 215 nm were collected. Proteins in these peaks were identified by LC-MS/MS analysis. Results showed that 83 proteins could be identified in these peaks, 68 among them were reported to be high- or middle-abundance proteins in plasma. All these proteins had definite retention times and were mapped in the 2D SAX-RP system, which resulted in accurate depletion of high-abundance proteins with ease. Our studies provide a convenient and effective method for large-scale depletion of high-abundance proteins and in-depth research in human plasma proteomics. PMID- 23109248 TI - Dynamic evaluation of polypropylene capillary-channeled fibers as a stationary phase in high-performance liquid chromatography. AB - Polypropylene (PP) capillary-channeled polymer (C-CP) fiber stationary phases are investigated for applications in HPLC. Specifically, the roles that fiber size and shape, linear velocity, interstitial fraction, and column inner diameter play in separation efficiency were evaluated using a uracil and butylparaben mixture eluted under isocratic conditions. Four fiber types, having nominal diameters ranging from 30 to 65 MUm, were used in 250 mm * 2.1 mm columns. Optimum flow characteristics, as judged by plate height and resolution, were observed for 40 MUm diameter PP C-CP fibers packed at an interstitial fraction of ~0.63, over a broad range of linear velocities (~2 to 37 mm/s). The influence of column inner diameter was studied on 1.5, 2.1, and 4.6 mm columns packed at the optimal interstitial fraction. The best performing column in terms of plate height and resolution was the 2.1 mm inner diameter. C-CP columns were also evaluated for the separation of a protein mixture composed of ribonuclease A, cytochrome c, and transferrin. Results obtained with the biomacromolecules mixture validate the optimal structural and operative conditions determined with the small solutes, laying the groundwork towards biomacromolecule applications, focusing more on the chemical aspects of separations. PMID- 23109249 TI - Human prostate DU145 carcinoma cells implanted in nude mice remove the peritoneal mesothelium to invade and grow as carcinomas. AB - Implanted human, androgen-independent prostatic carcinoma cells (DU145) into athymic (NCr nu/nu) mice produce diverse tumors on the peritoneal surfaces of many organs. Light and ultrastructural observations show that the mesothelial covering these surfaces are typically microvilli-coated, squamous cells or secretory cuboidal cells. The peritoneal regions colonized by tumors lack mesothelial cells and are covered by actively replicating carcinoma cells that grow as poorly differentiated cell clusters made of cell aggregates to somewhat compact spheroids covered with pleiomorphic microvilli and containing an undifferentiated vascular supply. These xenografts clusters invade the diaphragm and develop into tumors with both a basal solid aspect and an upper region of cribriform morphology. Furthermore, each tumor contains two cell types: (1) a poorly differentiated clear cell type, which grows into intraperitoneal tumors and (2) a large, basophilic cell type, which invades the peritoneal stroma of organs, including of the diaphragm. PMID- 23109250 TI - Effects of Sun ginseng on memory enhancement and hippocampal neurogenesis. AB - Panax ginseng C.A. Meyer has been used in traditional herb prescriptions for thousands of years. A heat-processing method has been used to increase the efficacy of ginseng, yielding what is known as red ginseng. In addition, recently, a slightly modified heat-processing method was applied to ginseng, to obtain a new type of processed ginseng with increased biological activity; this new form of ginseng is referred to as Sun ginseng (SG). The aim of this study was to investigate the effect of SG on memory enhancement and neurogenesis in the hippocampal dentate gyrus (DG) region. The subchronic administration of SG (for 14 days) significantly increased the latency time in the passive avoidance task relative to the administration of the vehicle control (P < 0.05). Western blotting revealed that the levels of phosphorylated extracellular signal regulated kinase (pERK) and phosphorylated protein kinase B (pAkt) were significantly increased in hippocampal tissue after 14 days of SG administration (P < 0.05). Doublecortin and 5-bromo-2-deoxyuridine immunostaining revealed that SG significantly enhanced the neuronal cell proliferation and the survival of immature neurons in the subgranular zone of the hippocampal DG region. These results suggest that SG has memory-enhancing activities and that these effects are mediated, in part, by the increase in the levels of pERK and pAkt and by the increases in cell proliferation and cell survival. PMID- 23109251 TI - Discontinuation of denosumab and associated fracture incidence: analysis from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. AB - Osteoporosis is a chronic disease and requires long-term treatment with pharmacologic therapy to ensure sustained antifracture benefit. Denosumab reduced the risk for new vertebral, nonvertebral, and hip fractures over 36 months in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial. Whereas discontinuation of denosumab has been associated with transient increases in bone remodeling and declines in bone mineral density (BMD), the effect on fracture risk during treatment cessation is not as well characterized. To understand the fracture incidence between treatment groups after cessation of investigational product, we evaluated subjects in FREEDOM who discontinued treatment after receiving two to five doses of denosumab or placebo, and continued study participation for >=7 months. The off-treatment observation period for each individual subject began 7 months after the last dose and lasted until the end of the study. This subgroup of 797 subjects (470 placebo, 327 denosumab), who were evaluable during the off-treatment period, showed similar baseline characteristics for age, prevalent fracture, and lumbar spine and total hip BMD T-scores. During treatment, more placebo-treated subjects as compared with denosumab-treated subjects sustained a fracture and had significant decreases in BMD. During the off-treatment period (median 0.8 years per subject), 42% versus 28% of placebo- and denosumab-treated subjects, respectively, initiated other therapy. Following discontinuation, similar percentages of subjects in both groups sustained a new fracture (9% placebo, 7% denosumab), resulting in a fracture rate per 100 subject-years of 13.5 for placebo and 9.7 for denosumab (hazard ratio [HR] 0.82; 95% confidence interval [CI], 0.49-1.38), adjusted for age and total hip BMD T-score at baseline. There was no apparent difference in fracture occurrence pattern between the groups during the off treatment period. In summary, there does not appear to be an excess in fracture risk after treatment cessation with denosumab compared with placebo during the off-treatment period for up to 24 months. PMID- 23109252 TI - Dilemma in re-use and recycling of waste electrical and electronic equipment. PMID- 23109255 TI - Stereochemical studies on ovatoxin-a. AB - Ovatoxin-a is the main toxin produced by Ostreopsis ovata, a benthic dinoflagellate that has bloomed massively across the Mediterranean basin over the past years, inflicting both human and environmental suffering. Ovatoxin-a has recently been isolated from cultures of O. ovata and structurally identified as an analogue of palytoxin: in comparison with palytoxin, ovatoxin-a lacks three hydroxy groups at the 17-, 44- and 64-positions, but features an extra hydroxy functionality at the 42-position. Herein we report on the NMR-based elucidation of the stereochemistry of ovatoxin-a, which includes 7 stereogenic double bonds and 62 asymmetric carbon atoms. Understanding the full stereochemistry of ovatoxin-a is a step towards the elucidation of its mechanism of action on a molecular level. PMID- 23109256 TI - Effect of external variables on the performance of the geriatric comorbidity score derived from prescription claims in the community-dwelling elderly. AB - BACKGROUND: Comorbidity scores based on medical or prescription claims data are frequently used to control for confounding in pharmacoepidemiological studies. Performance of such scores in predicting the risk of death in community-dwelling elderly adults may be compromised by the absence of mental health and socioeconomic characteristics not captured in claims data. OBJECTIVE: The aim of the study was to assess the impact of adding mental health status and sociodemographic characteristics to the Geriatric Comorbidity Score (GCS), a score derived from prescription claims data in the Quebec community-dwelling elderly population. METHODS: We used the cohort study from the longitudinal Quebec Seniors' Health Survey (n = 1,494) conducted between 2005 and 2006. For each participant, we obtained mental health and socioeconomic characteristics through validated questionnaires, which we linked with the medical and prescription claims databases of the Quebec Health Insurance Agency [Regie de l'assurance maladie du Quebec (RAMQ)]. The main study outcome was death within 1 year, ascertained using the Quebec death registry. The GCS was calculated from prescription claims data, with the c statistic as a measure of performance. Using backward stepwise selection, external variables (marital status, region, family income, social support, daily hassles, perceived physical and mental health status, presence of mental health disorders) were added to the logistic regression model and the marginal effect assessed by comparing the c statistic with and without each covariate. RESULTS: Over 1 year, 77 deaths (5.15 %) were reported. The c statistic for the GCS was calculated as 0.67 (95 % confidence interval 0.64, 0.70). Addition of sex and age to the score yielded a 2.4 % increase. The variable with the greatest impact on the c statistic was marital status (6.1 % increase). Though important contributors, social support and perceived mental health status did not significantly improve performance of the score. CONCLUSIONS: While sex, age and marital status significantly improved performance of a predictive score in the community-dwelling elderly population, the absence of data on mental and physical health status did not appear to compromise the validity of claims-based scores. Combining comorbidity scores with other methods to control for confounding thus remains a useful tool in pharmacoepidemiological research. PMID- 23109253 TI - Health promotion for adolescent childhood leukemia survivors: building on prevention science and ehealth. AB - Teenage survivors of childhood acute lymphoblastic leukemia (ALL) have increased morbidity likely due to their prior multicomponent treatment. Habits established in adolescence can impact individuals' subsequent adult behaviors. Accordingly, healthy lifestyles, avoiding harmful actions, and appropriate disease surveillance are of heightened importance among teenage survivors. We review the findings from prevention science and their relevance to heath promotion. The capabilities and current uses of eHealth components including e-learning, serious video games, exergaming, behavior tracking, individual messaging, and social networking are briefly presented. The health promotion needs of adolescent survivors are aligned with those eHealth aspects to propose a new paradigm to enhance the wellbeing of adolescent ALL survivors. PMID- 23109257 TI - Perception of affect in biological motion cues in anorexia nervosa. AB - OBJECTIVE: Nonverbal motion cues (a clenched fist) convey essential information about the intentions of the actor. Individuals with anorexia nervosa (AN) have demonstrated impairment in deciphering intention from facial affective cues, but it is unknown whether such deficits extend to deciphering affect from body motion cues. METHOD: We examined the capacities of adults with AN (n = 21) or those weight restored for >=12 months (WR; n = 20) to perceive affect in biological motion cues relative to healthy controls (HC; n = 23). RESULTS: Overall, individuals with AN evidenced greater deficit in discriminating affect from biological motion cues than WR or HC. Follow-up analyses showed that individuals with AN differed especially across two of the five conditions--deviating most from normative data when discriminating sadness and more consistently discriminating anger relative to WR or HC. DISCUSSION: Implications of these findings are discussed in relation to some puzzling interpersonal features of AN. PMID- 23109258 TI - Effects of repeated pulsed herbicide exposures on the growth of aquatic macrophytes. AB - Many contaminants are released into aquatic systems intermittently in a series of pulses. Pulse timing and magnitude can vary according to usage, compound-specific physicochemical properties, and use area characteristics. Standard laboratory ecotoxicity tests typically employ continuous exposure concentrations over defined durations and thus may not accurately and realistically reflect the effects of certain compounds on aquatic organisms, resulting in potential over- or underestimation. Consequently, the relative effects of pulsed (2 and 4 d) and continuous exposures of the duckweed Lemna minor to isoproturon, metsulfuron methyl, and pentachlorophenol over a period of 42 d were explored in the present study. At the highest test concentrations, exposure of L. minor to pulses of metsulfuron-methyl resulted in effects on growth similar to those of an equivalent continuous exposure. For isoproturon, pulsed exposures had a lower impact than a corresponding continuous exposure, whereas the effect of pentachlorophenol delivered in pulses was greater. These differences may be explained by compound-specific uptake and degradation or dissipation rates in plants and the recovery potential that occurs following pulses for different pesticides. Given these results, use of a simple time-weighted average approach to estimate effects of intermittent exposures from short-term standard toxicity studies may not provide an accurate prediction that reflects realistic exposure scenarios. Development of mechanistic modeling approaches may facilitate better estimates of effects from intermittent exposures. PMID- 23109259 TI - Easy access to L-mannosides and L-galactosides by using C-H activation of the corresponding 6-deoxysugars. PMID- 23109261 TI - Coping and the biosocial consequences of food insecurity in the 21st century. AB - Food security occurs when all members of a household have reliable access to food in sufficient quantity and quality to maintain an active and healthy lifestyle. Given the important biological and social value of food for humans, food and food sufficiency have been traditional topics of study among biological anthropologists. The focus on food insecurity, however, has emerged within the past two decades and recent global events, including the food crisis of 2007/2008, have led to renewed interests in the topic of food insecurity and wellbeing. Here, we review current and novel threats to food security, current thinking on measurement and definitions, and then outline a model that links food insecurity to coping strategies and then to health outcomes. We suggest that coping strategies are typically context-specific and can be food and nonfood based. We further suggest that coping strategies may impact health quite broadly, not just through nutritional pathways. We then review available data on the relationship between food insecurity and nutritional status, chronic diseases, infectious diseases, and mental health. Our review highlights the far reaching consequences of food insecurity for human wellbeing but also the considerable variability in its effect and our limited empirical knowledge of the pathways through which food insecurity impacts health. We conclude by offering thoughts on how biological anthropologists might contribute to growing our understanding of food insecurity and human health and wellbeing. PMID- 23109262 TI - The non-target impact of spinosyns on beneficial arthropods. AB - Spinosyn-based products, mostly spinosad, have been widely recommended by extension specialists and agribusiness companies; consequently, they have been used to control various pests in many different cropping systems. Following the worldwide adoption of spinosad-based products for integrated and organic farming, an increasing number of ecotoxicological studies have been published in the past 10 years. These studies are primarily related to the risk assessment of spinosad towards beneficial arthropods. This review takes into account recent data with the aim of (i) highlighting potentially adverse effects of spinosyns on beneficial arthropods (and hence on ecosystem services that they provide in agroecosystems), (ii) clarifying the range of methods used to address spinosyn side effects on biocontrol agents and pollinators in order to provide new insights for the development of more accurate bioassays, (iii) identifying pitfalls when analysing laboratory results to assess field risks and (iv) gaining increasing knowledge on side effects when using spinosad for integrated pest management (IPM) programmes and organic farming. For the first time, a thorough review of possible risks of spinosad and novel spinosyns (such as spinetoram) to beneficial arthropods (notably natural enemies and pollinators) is provided. The acute lethal effect and multiple sublethal effects have been identified in almost all arthropod groups studied. This review will help to optimise the future use of spinosad and new spinosyns in IPM programmes and for organic farming, notably by preventing the possible side effects of spinosyns on beneficial arthropods. PMID- 23109263 TI - Solvent-driven symmetry of self-assembled nanocrystal superlattices--a computational study. AB - The preference of experimentally realistic sized 4-nm facetted nanocrystals (NCs), emulating Pb chalcogenide quantum dots, to spontaneously choose a crystal habit for NC superlattices (Face Centered Cubic (FCC) vs. Body Centered Cubic (BCC)) is investigated using molecular simulation approaches. Molecular dynamics simulations, using united atom force fields, are conducted to simulate systems comprised of cube-octahedral-shaped NCs covered by alkyl ligands, in the absence and presence of experimentally used solvents, toluene and hexane. System sizes in the 400,000-500,000-atom scale followed for nanoseconds are required for this computationally intensive study. The key questions addressed here concern the thermodynamic stability of the superlattice and its preference of symmetry, as we vary the ligand length of the chains, from 9 to 24 -CH(2) groups, and the choice of solvent. We find that hexane and toluene are "good" solvents for the NCs, which penetrate the ligand corona all the way to the NC surfaces. We determine the free energy difference between FCC and BCC NC superlattice symmetries to determine the system's preference for either geometry, as the ratio of the length of the ligand to the diameter of the NC is varied. We explain these preferences in terms of different mechanisms in play, whose relative strength determines the overall choice of geometry. PMID- 23109264 TI - Endothelium-independent vasorelaxation effects of Sigesbeckia glabrescens (Makino) Makino on isolated rat thoracic aorta. AB - The present study aimed to investigate the vasorelaxant effect of the methanol extract of Sigesbeckia glabrescens (Makino) Makino (MESG) on rat aortic rings and mechanism of action. MESG inhibited both noradrenaline bitartrate (NA)- and potassium chloride (KCl)-induced contraction of endothelium-intact aortic rings in a concentration-dependent manner. Removal of the endothelium did not influence the effect of MESG on NA-precontracted aortic rings. Pretreatment with MESG (250 ug/mL) inhibited calcium chloride-induced vasocontraction of NA- or KCl precontracted endothelium-denuded aortic rings. It also relaxed phorbol-12 myristate-13-acetate-induced contraction of aortic rings in a concentration dependent manner. In addition, Bay K8644 (an L-type calcium channel opener) vasocontracted in MESG pretreated aortic rings. On the other hand, the inositol 1,4,5-triphosphate receptor, the ryanodine receptor, the Rho-kinase inhibitor (Y 27632), a soluble guanylyl cyclase blocker (1-H-[1,2,4]-oxadiazolo-[4,3a] quinoxalin-1-one), and K+ channel blockers (glybenclamide, tetraethylammonium, and 4-aminopyridine) did not affect the effect of MESG. These results suggested that the mechanism underlying the vasorelaxant effect of MESG is mediated by endothelium-independent pathways. This specifically refers to blockade of the influx of extracellular Ca2+ via receptor-operative Ca2+ channels and voltage dependent Ca2+ channels and inhibition of a protein kinase C-mediated cellular pathway. PMID- 23109265 TI - Parental income and the dynamics of health inequality in early childhood- evidence from the UK. AB - Recent research documents that socioeconomic health inequality has its origins in early childhood, that is, children from high-income families have better health than their peers from low-income families. In this article, we investigate the determinants of the evolution of socioeconomic health inequality in the UK. We analyze the relation between household income and both the prevalence and the consequences of adverse health conditions by following up infants throughout early childhood. We find evidence for the hypothesis that parental income operates through two different channels: it reduces the likelihood of incurring certain illnesses and it cushions the consequences of health conditions. Our results also indicate that a higher household income increases the probability that children fully recover from some diseases within a given period. PMID- 23109266 TI - Effectiveness of abbreviated CBT for insomnia in psychiatric outpatients: sleep and depression outcomes. AB - OBJECTIVE: To test the efficacy of cogntive-behavioral therapy for insomnia (CBT I) as a supplement treatment for psychiatric outpatients. Comorbid insomnia is prevalent among individuals with varied psychiatric disorders and evidence indicates that CBT-I may be effective for reducing insomnia and other psychiatric symptoms. METHOD: The present study randomly assigned 30 psychiatric outpatients (mean duration of treatment = 3.6 years) with low sleep quality and residual depressive symptoms to two sessions of CBT-I or a treatment as usual control group. Assessment included the Pittsburgh Sleep Quality Index (PSQI) for insomnia and the Patient Health Questionnaire (PHQ-9) for depression at pretreatment and 4 and 8 weeks posttreatment. RESULTS: Patients who received CBT-I demonstrated within group changes in PSQI and the PHQ-9 scores at both 4 and 8 weeks posttreatment, but did not show between-group differences. Additionally, 38% of the treatment participants achieved normal sleep at follow-up compared with none in the control condition. CONCLUSIONS: This study provides preliminary evidence that abbreviated behavioral treatment has beneficial effects on residual insomnia and depression in long-term psychiatric outpatients. PMID- 23109267 TI - Identification and characterization of the "super-reduced" state of the H-cluster in [FeFe] hydrogenase: a new building block for the catalytic cycle? PMID- 23109268 TI - Comparative three-dimensional structure of the trabecular bone in the talus of primates and its relationship to ankle joint loads generated during locomotion. AB - The trabecular structure of the ankle bone in small to medium-bodied (60-5000 g) primates of distinct locomotor types was analyzed using high-resolution X-ray computed tomography. There are large inter-, intraspecific, and regional (medial vs. lateral) variations in the trabecular architecture of the talar body. Body mass has no effect on the bone volume fraction or on the fabric anisotropy. However, both the number and thickness of trabeculae seem to be body mass dependent. All taxa show anisotropic trabecular bone, but the degree of anisotropy and elongation values vary, notably across the locomotion categories. The fabric orientation in the talar body indicates that, practically, all taxa studied display a generally consistent pattern of orientation restricted primarily to a dorsoplantar direction. We have observed a mediolateral difference in the bone volume fraction in most primates who are proficient or frequent climbers. This could reflect a specific reinforcement of the trabecular structure in response to the loads engendered in habitually sustained foot inversion. In contrast, tali of primates who are proficient or frequent leapers rather exhibit a different three-dimensional distribution of the material, which consists of a more anisotropic trabecular structure. This could reflect stronger unidirectional and stereotypical-loading conditions generated at the ankle joints during a leap. Finally, it appears that the talar trabecular bone structure has a good potential for predicting locomotion in extinct species. We have analyzed the trabecular bone structure of the talus of some Eocene European primates (Adapis, Leptadapis, and Necrolemur) and compared the functional signal of the external versus internal talar anatomy in these fossils. PMID- 23109269 TI - Nutritional status of children during treatment for acute lymphoblastic leukemia in Guatemala. AB - BACKGROUND: Most children with cancer live in developing countries where the prevalence of malnutrition may reach 50% and influence the course of the disease. This study examined the prevalence and severity of malnutrition at diagnosis, as well as after 3 and 6 months of chemotherapy, in children with acute lymphoblastic leukemia (ALL) in Guatemala. METHODS: Triceps skin fold thickness (TSFT) and mid upper arm circumference (MUAC) provided measures of nutritional status (NS) in three categories: adequately nourished (A): TSFT and MUAC > 10th percentile; severely depleted (SD): TSFT or MUAC < 5th percentile; and moderately depleted (MD): all the remaining patients. RESULTS: Of 331 new patients, 241 had NS assessed at diagnosis. A = 113 (46.9%); MD = 28 (11.6%); SD = 100 (41.5%). At 3 months A = 106 (52.2%); MD = 25 (12.3%); SD = 72 (35.5%). At 6 months A = 146 (76.0%); MD = 12 (6.3%); SD = 34 (17.7%). In multivariate analysis, SD children at 6 months of treatment had a hazard of death that was 2.4-fold the hazard of those A or MD (95% CI: 1.3-4.7) CONCLUSIONS: Malnutrition is prevalent in newly diagnosed children with ALL in Guatemala and severe nutritional depletion is apparently predictive of abandonment of therapy and relapse of disease, but if children survive and improve their NS in the first 6 months after diagnosis, their chances of survival may improve significantly to approximate those in children not presenting with nutritional depletion. PMID- 23109271 TI - A novel strategy to increase performance of solid-phase microextraction fibers: electrodeposition of sol-gel films on highly porous substrate. AB - In the present work, the effect of substrate porosity for preparation of solid phase microextraction (SPME) fibers was investigated. The fibers were prepared by electrodeposition of sol-gel coatings using negative potentials on porous Cu wire and compared with previous reported technique for preparation of SPME fibers using positive potentials on smooth gold wire. Porous substrate was prepared by electrodeposition of a thin layer of Cu on a Cu wire. The extraction capability of prepared fibers was evaluated through extraction of some aromatic hydrocarbons from the headspace of aqueous samples. The effect of substrate porosity and some operating parameters on extraction efficiency was optimized. The results showed that extraction efficiency of SPME fibers highly depends on porosity of the substrate. The LOD ranged from 0.005 to 0.010 ng/mL and repeatability at the 1 ng/mL was below 12%. Electrodeposited films were characterized for their surface morphology and thermal stability using SEM and thermogravimetric analysis, respectively. SEM analysis revealed formation of porous substrate and subsequently porous coating on the wire surface and thermogravimetric analysis showed high thermal stability of the prepared fiber. PMID- 23109273 TI - New formulation of paraquat with lysine acetylsalicylate with low mammalian toxicity and effective herbicidal activity. AB - BACKGROUND: Currently, the commercial formulations of the herbicide paraquat are highly toxic to humans, and no effective antidote is available for paraquat poisoning. The aim of the present study was to develop a safe formulation, combining paraquat and the known antidote lysine acetylsalicylate. The toxicity of a mixture of Gramoxone(r) (20% paraquat) and lysine acetylsalicylate in adult Wistar male rats and the herbicidal efficacy against grass lawn (50% of Poa pratensis and 50% of Festuca arundinacea) were evaluated. This new formulation was administered to Wistar rats by gavage at 125 mg kg(-1) of paraquat ion and lysine acetylsalicylate at 79, 158 or 316 mg kg(-1) body weight, and the survival rate was observed for 30 days. RESULTS: The survival rate of the paraquat group was only 40%, while lysine acetylsalicylate provided effective protection, with full survival observed in the groups that received 125 mg kg(-1) of paraquat ion and 316 mg kg(-1) of lysine acetylsalicylate. Both formulations of paraquat, either in the absence or in the presence of lysine acetylsalicylate, provided the same herbicidal activity against the tested herbal species. CONCLUSIONS: The present formulation of paraquat containing lysine acetylsalicylate, significantly decreases mammalian toxicity while maintaining effective herbicidal activity. PMID- 23109272 TI - Subjective and objective binge eating in relation to eating disorder symptomatology, negative affect, and personality dimensions. AB - OBJECTIVE: The current study explored the clinical meaningfulness of distinguishing subjective (SBE) from objective binge eating (OBE) among individuals with threshold/subthreshold bulimia nervosa (BN). We examined relations between OBEs and SBEs and eating disorder symptoms, negative affect, and personality dimensions using both a group comparison and a continuous approach. METHOD: Participants were 204 adult females meeting criteria for threshold/subthreshold BN who completed questionnaires related to disordered eating, affect, and personality. RESULTS: Group comparisons indicated that SBE and OBE groups did not significantly differ on eating disorder pathology or negative affect, but did differ on two personality dimensions (cognitive distortion and attentional impulsivity). Using the continuous approach, we found that frequencies of SBEs (not OBEs) accounted for unique variance in weight/shape concern, diuretic use frequency, depressive symptoms, anxiety, social avoidance, insecure attachment, and cognitive distortion. DISCUSSION: SBEs in the context of BN may indicate broader areas of psychopathology. PMID- 23109274 TI - Revealing noncovalent interactions in quantum crystallography: taurine revisited. AB - The charge density distribution in taurine (2-aminoethane-sulfonic acid) is further studied with the molecular orbital occupation number refinement scheme. The recently proposed NCIPLOT scheme (Johnson et al., J. Am. Chem. Soc. 2010, 132, 6498) is applied to visualize the noncovalent interactions from experimentally refined charge densities. Herein, we demonstrate the evolution of the reduced density gradient isosurface during the charge density refinement process. PMID- 23109275 TI - Rhodium(III)-catalyzed oxidative C-H coupling of N-methoxybenzamides with aryl boronic acids: one-pot synthesis of phenanthridinones. PMID- 23109270 TI - Identification and function of proteolysis regulators in seminal fluid. AB - Proteins in the seminal fluid of animals with internal fertilization effect numerous responses in mated females that impact both male and female fertility. Among these proteins is the highly represented class of proteolysis regulators (proteases and their inhibitors). Though proteolysis regulators have now been identified in the seminal fluid of all animals in which proteomic studies of the seminal fluid have been conducted (as well as several other species in which they have not), a unified understanding of the importance of proteolysis to male fertilization success and other reproductive processes has not yet been achieved. In this review, we provide an overview of the identification of proteolysis regulators in the seminal fluid of humans and Drosophila melanogaster, the two species with the most comprehensively known seminal fluid proteomes. We also highlight reports demonstrating the functional significance of specific proteolysis regulators in reproductive and post-mating processes. Finally, we make broad suggestions for the direction of future research into the roles of both active seminal fluid proteolysis regulators and their inactive homologs, another significant class of seminal fluid proteins. We hope that this review aids researchers in pursuing a coordinated study of the functional significance of proteolysis regulators in semen. PMID- 23109276 TI - Antibacterial effects of ellagitannins from Acalypha wilkesiana var. macafeana hort.: surface morphology analysis with environmental scanning electron microscopy and synergy with antibiotics. AB - The present study served to gain further insight into the bactericidal effects of ellagitannins from Acalypha wilkesiana var. macafeana hort. against pathogenic bacteria. Ellagitannins from the aerial parts of A. wilkesiana var. macafeana hort. (EAW) inhibited the growth of Bacillus cereus (ATCC 11778), Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 11632) and Methicillin resistant Staphylococcus aureus (MRSA) clinical strain with inhibition zones equal to 11.01 +/- 1.53 mm, 16.63 +/- 0.11 mm, 11.40 +/- 1.10 mm and 8.22 +/- 0.19 mm, respectively. The minimal inhibition concentration and the minimal bactericidal concentration of ellagitannins from A. wilkesiana var. macafeana hort. (EAW) against MRSA were 750 ug/mL and 3000 ug/mL, respectively. We then examined the synergistic effect of EAW with three antibiotics, i.e. ampicillin, streptomycin and tetracycline, via the checkerboard assay and time-kill assay and observed that EAW is synergistic with ampicillin against S. aureus (ATCC 11632). Environmental electron scanning microscopy analysis showed cell lysis against S. aureus (ATCC 11632) upon treatment with the ellagitannin fraction. The ellagitannin fraction from A. wilkesiana var. macafeana hort. is bactericidal against gram-positive bacteria tested and works synergistically with ampicillin against S. aureus. Morphology analysis of the cell suggests that the bactericidal property of the ellagitannin fraction mechanism involves lysis of the cell wall. In summary, our studies demonstrate that A. wilkesiana var. macafeana hort. produces bactericidal ellagitannins of clinical and/or cosmetological value. PMID- 23109277 TI - SDS-PAGE-free protocol for comprehensive identification of cytochrome P450 enzymes and uridine diphosphoglucuronosyl transferases in human liver microsomes. AB - Comprehensive identification of cytochrome P450 enzymes (CYPs) and uridine diphosphoglucuronosyl transferases (UGTs) in human liver microsomes (HLMs) was performed with an SDS-PAGE-free protocol. HLMs were solubilized with 5% v/v ionic liquid, 1-butyl-3-methyl imidazolium tetrafluoroborate, followed by tryptic digestion, and 2D-SCX-RPLC-ESI-MS/MS (LTQ XL) analysis in triplicate. In total, 27 CYPs and 12 UGTs were confidently identified with average sequence coverage as 30.99 and 25.07%, average peptide number as 14 and 13, and average unique peptide number as 7 and 4, respectively. The highly similar isoforms of CYP3A, CYP2C, and CYP4F subfamilies could be unambiguously differentiated from each other, despite the fact that the sequence similarity of CYP2C9 and CYP2C19 is 91%. In addition, protein spectral count was used to approximately evaluate the relative abundance of identified CYPs and UGTs, and the results agreed with previous immunochemistry reports. PMID- 23109278 TI - Belousov-Zhabotinsky reaction in protic ionic liquids. PMID- 23109279 TI - Enantioselective toxicity and bioaccumulation of fipronil in fathead minnows (Pimephales promelas) following water and sediment exposures. AB - Fipronil is a widely used, broad-spectrum pesticide that is applied as an equal mixture of two enantiomers. As regulations on older pesticides become more stringent, production and application of fipronil is expected to grow, leading to increased inputs into aquatic environments and complex exposures to biota. To better understand the potential exposures introduced by fipronil contamination, we conducted subchronic toxicity tests with larval fathead minnows (Pimephales promelas) and waterborne fipronil and its enantiomers and exposed juvenile fathead minnows to fipronil-spiked sediment. Enantioselective toxicity was observed in fish after the 7-d subchronic exposure, with increased toxicity of the racemate and (+) enantiomer observed compared with the (-) enantiomer. Curiously, toxicities of the racemate and (+) enantiomer were not significantly different, even though the racemate contains 50% of the (+) enantiomer and 50% of the less toxic (-) enantiomer. During the sediment exposure, racemic fipronil in sediment was transformed primarily to fipronil sulfide, while exposed fish rapidly accumulated fipronil and/or fipronil sulfide and transformed the majority to fipronil sulfone. Using the results of the sediment-exposure experiment, the authors explored a mechanism that may contribute to the interesting trends in enantioselective toxicity observed during the waterborne exposures. In tandem, the aquatic toxicity experiment and the spiked sediment exposure demonstrate the potentially complex behavior of fipronil in sediment and fish. PMID- 23109280 TI - Field and laboratory methods in human milk research. AB - Human milk is a complex and variable fluid of increasing interest to human biologists who study nutrition and health. The collection and analysis of human milk poses many practical and ethical challenges to field workers, who must balance both appropriate methodology with the needs of participating mothers and infants and logistical challenges to collection and analysis. In this review, we address various collection methods, volume measurements, and ethical considerations and make recommendations for field researchers. We also review frequently used methods for the analysis of fat, protein, sugars/lactose, and specific biomarkers in human milk. Finally, we address new technologies in human milk research, the MIRIS Human Milk Analyzer and dried milk spots, which will improve the ability of human biologists and anthropologists to study human milk in field settings. PMID- 23109281 TI - Cognitive processing of trauma and attitudes toward disclosure in the first six months after military deployment. AB - OBJECTIVES: To examine the role of cognitive processing and attitudes toward trauma disclosure among newly returned veterans of the Iraq and Afghanistan wars. METHOD: In total, 110 veterans completed the Cognitive Processing of Trauma Scale, Disclosure of Trauma Questionnaire, and assessments of posttraumatic stress symptoms (PTSS), depression, and posttraumatic growth (PTG). RESULTS: Both maladaptive and adaptive processing were the strongest predictors of PTSS and depression, betas = .21 to .38. However, urge to discuss trauma was the main predictor of PTG, beta = .53. Correlational findings suggested that veterans' willingness to discuss their traumas and reactivity to doing so were related with their processing of these experiences, rs = .23 to .40. CONCLUSION: This study provides further support for the critical intersection between cognitive processing and disclosure, while also suggesting the need for more research on the intra- and inter-personal dimensions of these constructs in negative and constructive outcomes after trauma. PMID- 23109282 TI - Do cancer and treatment type affect distress? AB - OBJECTIVE: We examined differences in distress levels and Distress Thermometer (DT) cutoff scores between different cancer types. The effect of socio demographic and illness-related variables on distress was also examined. METHODS: One thousand three hundred fifty patients (response = 51%) completed questions on socio-demographic and illness-related variables, the Dutch version of the DT and Problem List, and the Hospital Anxiety and Depression Scale. Receiver operating characteristics analyses were performed to determine cancer specific cutoff scores. Univariate and multivariate effects of socio-demographic and illness related variables (including cancer type) on distress were examined. RESULTS: Prostate cancer patients reported significantly lower DT scores (M = 2.5 +/- 2.5) and the cutoff score was lower (>= 4) than in patients with most other cancer types (M varied between 3.4 and 5.1; cutoff >= 5). Multivariate analyses (F = 10.86, p < .001, R(2) = 0.08) showed an independent significant effect of four variables on distress: intensive treatment (beta = .10, any (combination of) treatment but surgery only and 'wait and see'); a non-prostate cancer type (beta = -.17); the interaction between gender and age (beta = -.12, highest distress in younger women as compared with older women and younger and older men); and the interaction between cancer type and treatment intensity (beta = .08, lowest scores in prostate cancer patients receiving non-intensive treatment as compared with their counterparts). CONCLUSIONS: Distress and cutoff score in prostate cancer patients were lower than in patients with other cancer types. Additionally, younger women and patients receiving treatment other than surgery only or 'wait and see' are at risk for higher distress. These results can help identify patients possibly in need of referral to professional psychosocial and/or allied health care. PMID- 23109283 TI - Synthesis and characterization of new 5-linked pinoresinol lignin models. AB - Pinoresinol structures, featuring a beta-beta'-linkage between lignin monomer units, are important in softwood lignins and in dicots and monocots, particularly those that are downregulated in syringyl-specific genes. Although readily detected by NMR spectroscopy, pinoresinol structures largely escaped detection by beta-ether-cleaving degradation analyses presumably due to the presence of the linkages at the 5 positions, in 5-5'- or 5-O-4'-structures. In this study, which is aimed at helping better understand 5-linked pinoresinol structures by providing the required data for NMR characterization, new lignin model compounds were synthesized through biomimetic peroxidase-mediated oxidative coupling reactions between pre-formed (free-phenolic) coniferyl alcohol 5-5'- or 5-O-4' linked dimers and a coniferyl alcohol monomer. It was found that such dimers containing free-phenolic coniferyl alcohol moieties can cross-couple with the coniferyl alcohol producing pinoresinol-containing trimers (and higher oligomers) in addition to other homo- and cross-coupled products. Eight new lignin model compounds were obtained and characterized by NMR spectroscopy, and one tentatively identified cross-coupled beta-O-4'-product was formed from a coniferyl alcohol 5-O-4'-linked dimer. It was demonstrated that the 5-5'- and 5-O 4'-linked pinoresinol structures could be readily differentiated by using heteronuclear multiple-bond correlation (HMBC) NMR spectroscopy. With appropriate modification (etherification or acetylation) to the newly obtained model compounds, it would be possible to identify the 5-5'- or 5-O-4'-linked pinoresinol structures in softwood lignins by 2D HMBC NMR spectroscopic methods. Identification of the cross-coupled dibenzodioxocin from a coniferyl alcohol 5-5' linked moiety suggested that thioacidolysis or derivatization followed by reductive cleavage (DFRC) could be used to detect and identify whether the coniferyl alcohol itself undergoes 5-5'-cross-linking during lignification. PMID- 23109284 TI - Pediatric autopsy consent: helping families create hope out of despair. PMID- 23109285 TI - The validity of multiple choice practical examinations as an alternative to traditional free response examination formats in gross anatomy. AB - Traditionally, an anatomy practical examination is conducted using a free response format (FRF). However, this format is resource-intensive, as it requires a relatively large time investment from anatomy course faculty in preparation and grading. Thus, several interventions have been reported where the response format was changed to a selected response format (SRF). However, validity evidence from those interventions has not proved entirely adequate for the practical anatomy examination, and thus, further investigation was required. In this study, the validity evidence of SRF was examined using multiple choice questions (MCQs) constructed according to different levels of Bloom's taxonomy in comparison with the traditional free response format. A group of 100 medical students registered in a gross anatomy course volunteered to be enrolled in this study. The experimental MCQ examinations were part of graded midterm and final steeplechase practical examination. Volunteer students were instructed to complete the practical examinations twice, once in each of two separate examination rooms. The two separate examinations consisted of a traditional free response format and MCQ format. Scores from the two examinations (FRF and MCQ) displayed a strong correlation, even with higher level Bloom's taxonomy questions. In conclusion, the results of this study provide empirical evidence that the SRF (MCQ) response format is a valid method and can be used as an alternative to the traditional FRF steeplechase examination. PMID- 23109286 TI - Development of an extraction method for the determination of avermectins in soil using supercritical CO2 modified with ethanol and liquid chromatography-tandem mass spectrometry. AB - The aim of the present study was to develop a multiresidue analytical method for determination of avermectins (abamectin, ivermectin, moxidectin, and doramectin) in soil samples using supercritical fluid extraction and LC-MS/MS. The optimal extraction conditions for supercritical fluid extraction were 80 degrees C for temperature, 300 kg/cm(2) for pressure, 40 min as an extraction time, and 30% of a modifier ratio. The linearity of the calibration curves was excellent and yielded the correlation coefficients (r(2) = 0.998-0.999, at a range of 1.5-500 ng/g). Soil samples were fortified with known quantities of the analytes at three different concentration levels (5, 10, and 50 ng/g) and the recoveries were in the range of 82.5-96.2% with relative standard deviation values ranging between 2.1 and 7.9%. The limits of detections and limits of quantitations were 1.5 and 5 ng/g, respectively. The developed method was successfully applied to analyze avermectin residues in soil samples collected from 13 sites in the Honam area, Republic of Korea. In sum, a combination of supercritical fluid extraction and LC MS/MS has been proven to be highly efficient as an environmentally friendly technique for the simultaneous determination of avermectins in soil samples. PMID- 23109287 TI - Diverse reactivity in a rhodium(III)-catalyzed oxidative coupling of N-allyl arenesulfonamides with alkynes. PMID- 23109288 TI - Development of new ecological long-lasting dispensers of semiochemicals for the control of Bactrocera oleae (Rossi). AB - BACKGROUND: A new controlled-release pheromone 1,7-dioxaspiro[5,5]undecane dispenser has been developed, which is useful for monitoring the population and controlling Bactrocera oleae (Rossi, 1790) (Diptera: Tephritidae). For this purpose, several kinds of dispensers based on attapulgite were designed and tested in this study. RESULTS: The designed dispensers, together with the commercial-brand olive fruit fly 'Long-Life Lure', which was used as a reference, were evaluated in the field, and in parallel were subjected to an accelerated ageing process in a chamber with a constant temperature and air speed. The residual pheromone content was periodically determined by liquid-gas chromatography in order to obtain the half-life of dispensers and the pheromone release rate. The mesoporous dispenser proved to have the best performance in the field, with a half-life of 5 months and an average emission speed of 0.6 mg day( 1) , parameters very close to those obtained with the commercial dispenser tested. In addition, to evaluate the effectiveness of the different dispensers in the field, a duplicate comparative study of captures was designed, and a colony monitoring study of the olive fruit fly was performed using various food and sex attractants. CONCLUSIONS: Although no significant differences in captures were found between the dispensers tested, the highest number of captures was obtained on average with the mesoporous dispensers demonstrating good pheromone emission characteristics. PMID- 23109289 TI - Metal-free oxidation/C(sp3)-H functionalization of unactivated alkynes using pyridine-N-oxide as the external oxidant. PMID- 23109290 TI - Accelerated high-frame-rate mouse heart cine-MRI using compressed sensing reconstruction. AB - We introduce a new protocol to obtain very high-frame-rate cinematographic (Cine) MRI movies of the beating mouse heart within a reasonable measurement time. The method is based on a self-gated accelerated fast low-angle shot (FLASH) acquisition and compressed sensing reconstruction. Key to our approach is that we exploit the stochastic nature of the retrospective triggering acquisition scheme to produce an undersampled and random k-t space filling that allows for compressed sensing reconstruction and acceleration. As a standard, a self-gated FLASH sequence with a total acquisition time of 10 min was used to produce single slice Cine movies of seven mouse hearts with 90 frames per cardiac cycle. Two times (2*) and three times (3*) k-t space undersampled Cine movies were produced from 2.5- and 1.5-min data acquisitions, respectively. The accelerated 90-frame Cine movies of mouse hearts were successfully reconstructed with a compressed sensing algorithm. The movies had high image quality and the undersampling artifacts were effectively removed. Left ventricular functional parameters, i.e. end-systolic and end-diastolic lumen surface areas and early-to-late filling rate ratio as a parameter to evaluate diastolic function, derived from the standard and accelerated Cine movies, were nearly identical. PMID- 23109291 TI - Carabin deficiency in B cells increases BCR-TLR9 costimulation-induced autoimmunity. AB - The mechanisms behind flares of human autoimmune diseases in general, and of systemic lupus in particular, are poorly understood. The present scenario proposes that predisposing gene defects favour clinical flares under the influence of external stimuli. Here, we show that Carabin is low in B cells of (NZB * NZW) F1 mice (murine SLE model) long before the disease onset, and is low in B cells of lupus patients during the inactive phases of the disease. Using knock-out and B-cell-conditional knock-out murine models, we identify Carabin as a new negative regulator of B-cell function, whose deficiency in B cells speeds up early B-cell responses and makes the mice more susceptible to anti-dsDNA production and renal lupus flare after stimulation with a Toll-like Receptor 9 agonist, CpG-DNA. Finally, in vitro analysis of NFkappaB activation and Erk phosphorylation in TLR9- and B-cell receptor (BCR)-stimulated Carabin-deficient B cells strongly suggests how the internal defect synergizes with the external stimulus and proposes Carabin as a natural inhibitor of the potentially dangerous crosstalk between BCR and TLR9 pathways in self-reactive B cells. PMID- 23109293 TI - Effects of bisphenol A on growth and nitrogen nutrition of roots of soybean seedlings. AB - Bisphenol A (BPA) is an environmental endocrine disruptor that seriously threatens ecological systems. Plants are the primary producers in ecological systems, but little information is available concerning the toxic effect of BPA on plants. In the present study, the effects of BPA on the growth and nitrogen nutrition of roots of soybean seedlings were investigated by using a root automatic scan apparatus and biochemical methods. It was found that when soybean seedlings were treated with 1.5 mg/L BPA, the growth of roots was improved, the content of nitrate in roots was increased, the content of ammonium in roots was decreased, and the activities of nitrate reductase and nitrite reductase in roots were not changed. The opposite effects were observed in roots treated with 17.2 mg/L and 50.0 mg/L BPA, except for an increase in the content of nitrate in roots treated with 17.2 mg/L BPA and a decrease in the activities of nitrate reductase and nitrite reductase in roots of soybeans seedlings. Statistical analysis indicated that the change in the nitrogen nutrition of roots of soybean seedlings treated with BPA was one reason why the growth of roots was changed. The authors suggest that the potential environmental and ecological risk of BPA to plants should receive more consideration. PMID- 23109292 TI - Tracking antigen-specific CD4+ T cells throughout the course of chronic Leishmania major infection in resistant mice. AB - Primary Leishmania major infection typically produces cutaneous lesions that not only heal but also harbor persistent parasites. While the opposing roles of CD4(+) T-cell-derived IFN-gamma and IL-10 in promoting parasite killing and persistence have been well established, how these responses develop from naive precursors has not been directly monitored throughout the course of infection. We used peptide:Major Histocompatibility Complex class II (pMHCII) tetramers to investigate the endogenous, parasite-specific primary CD4(+) T-cell response to L. major in mice resistant to infection. Maximal frequencies of IFN-gamma(+) CD4(+) T cells were observed in the spleen and infected ears within a month after infection and were maintained into the chronic phase. In contrast, peak frequencies of IL-10(+) CD4(+) T cells emerged within 2 weeks of infection, persisted into the chronic phase, and accumulated in the infected ears but not the spleen, via a process that depended on local antigen presentation. T helper type-1 (Th1) cells, not Foxp3(+) regulatory T cells, were the chief producers of IL-10 and were not exhausted. Therefore, tracking antigen-specific CD4(+) T cells revealed that IL-10 production by Th1 cells is not due to persistent T-cell antigen receptor stimulation, but rather driven by early antigen encounter at the site of infection. PMID- 23109294 TI - Preliminary evaluation of an observational measure of group cohesion for group psychotherapy. AB - OBJECTIVE: Group psychotherapy research would benefit from an observational measure of group cohesion to complement existing self-report measures. This study introduces the Therapy Process Observational Coding System-Group Cohesion scale (TPOCS-GC), which observationally assesses cohesion between each member and the group. METHOD: In total 27 parents participated in a group parent-training social competency intervention for children with attention deficit-hyperactivity disorder. Independent coders double-coded group cohesion and the alliance in 144 client-sessions. Parents, teachers, and children completed cognitive, behavioral, and therapy participation measures. RESULTS: The TPOCS-GC demonstrated modest to strong item-level interrater reliability and acceptable internal consistency. Group cohesion evidenced moderate stability over the course of treatment. Relations between TPOCS-GC and theoretically linked and unrelated variables provided some evidence for construct and predictive validity. CONCLUSIONS: This preliminary study suggests that the TPOCS-GC is a reliable instrument that may help fill an instrumentation gap in the field. PMID- 23109295 TI - Hollow-fiber liquid-phase microextraction and gas chromatography-mass spectrometry of barbiturates in whole blood samples. AB - Here, we present a method for measuring barbiturates (butalbital, secobarbital, pentobarbital, and phenobarbital) in whole blood samples. To accomplish these measurements, analytes were extracted by means of hollow-fiber liquid-phase microextraction in the three-phase mode. Hollow-fiber pores were filled with decanol, and a solution of sodium hydroxide (pH 13) was introduced into the lumen of the fiber (acceptor phase). The fiber was submersed in the acidified blood sample, and the system was subjected to an ultrasonic bath. After a 5 min extraction, the acceptor phase was withdrawn from the fiber and dried under a nitrogen stream. The residue was reconstituted with ethyl acetate and trimethylanilinium hydroxide. An aliquot of 1.0 MUL of this solution was injected into the gas chromatograph/mass spectrometer, with the derivatization reaction occurring in the hot injector port (flash methylation). The method proved to be simple and rapid, and only a small amount of organic solvent (decanol) was needed for extraction. The detection limit was 0.5 MUg/mL for all the analyzed barbiturates. The calibration curves were linear over the specified range (1.0 to 10.0 MUg/mL). This method was successfully applied to postmortem samples (heart blood and femoral blood) collected from three deceased persons previously exposed to barbiturates. PMID- 23109297 TI - Studies on the amination of aryl chlorides with a monoligated palladium catalyst: kinetic evidence for a cooperative mechanism. AB - Combined spectroscopic, crystallographic, and kinetic studies of the mechanism of aromatic amination with the efficient dinuclear Pd precatalyst [Pd(2)Cl(MU Cl)PtBu(2)(Bph-Me)] (Bph-Me = 2'-methyl-[1,1'-biphenyl]-2-yl) have revealed overlapping, yet cooperative, mechanistic scenarios, the relative weights of which are strongly influenced by the products formed as the reaction proceeds. The stability and evolution of the precatalyst in solution has been studied and several metalation pathways that point to a single monoligated intermediate have been identified. Our work sheds light on the nature of the catalytic species involved in the process and on the structure of the corresponding catalytic network. PMID- 23109296 TI - Chemotherapy and cognitive complaints in women with breast cancer. AB - BACKGROUND: Results of existing studies are inconclusive concerning the relationship between chemotherapy and subjective cognitive functioning (SCF). The aim of this study was to evaluate SCF of breast cancer (BC) patients and to find predictors of impaired SCF. Both satisfaction and frequency of complaints about SCF were measured. METHODS: BC patients who were about to receive chemotherapy (N = 74) and patients with a benign breast disease (BBD) (N = 63) participated. Before chemotherapy started (Time 1) and 3 months after ending chemotherapy (and at comparable moments for the BBD group) (Time 2), women completed validated questionnaires concerning the frequency of complaints and satisfaction with SCF, fatigue, perceived stress, anxiety, and depressive symptoms. RESULTS: No differences were found between the BBD and BC patients concerning the frequency of complaints about SCF across time. Satisfaction with SCF decreased across time in BC patients but remained stable across time in BBD patients (p < 0.001; p = 0.003 after controlling for state anxiety and perceived stress). Correlation coefficients between the satisfaction and the frequency of complaints about SCF ranged between -0.26 and -0.49. Depressive symptoms and satisfaction with SCF (Time 1) predicted the frequency of complaints about SCF (Time 2). Diagnosis, frequency of complaints about SCF, and state anxiety (Time 1) predicted satisfaction with SCF (Time 2). CONCLUSIONS: BC patients do not differ in the frequency of complaints about SCF compared with BBD patients, but their satisfaction with SCF decreased after treatment. Psychological factors predicted the frequency of complaints about SCF. Psychological factors and diagnosis predicted satisfaction with SCF. PMID- 23109298 TI - Adaptive response of low linear energy transfer X-rays for protection against high linear energy transfer accelerated heavy ion-induced teratogenesis. AB - BACKGROUND: Adaptive response (AR) of low linear energy transfer (LET) irradiations for protection against teratogenesis induced by high LET irradiations is not well documented. In this study, induction of AR by X-rays against teratogenesis induced by accelerated heavy ions was examined in fetal mice. METHODS: Irradiations of pregnant C57BL/6J mice were performed by delivering a priming low dose from X-rays at 0.05 or 0.30 Gy on gestation day 11 followed one day later by a challenge high dose from either X-rays or accelerated heavy ions. Monoenergetic beams of carbon, neon, silicon, and iron with the LET values of about 15, 30, 55, and 200 keV/MUm, respectively, were examined. Significant suppression of teratogenic effects (fetal death, malformation of live fetuses, or low body weight) was used as the endpoint for judgment of a successful AR induction. RESULTS: Existence of AR induced by low-LET X-rays against teratogenic effect induced by high-LET accelerated heavy ions was demonstrated. The priming low dose of X-rays significantly reduced the occurrence of prenatal fetal death, malformation, and/or low body weight induced by the challenge high dose from either X-rays or accelerated heavy ions of carbon, neon or silicon but not iron particles. CONCLUSIONS: Successful AR induction appears to be a radiation quality event, depending on the LET value and/or the particle species of the challenge irradiations. These findings would provide a new insight into the study on radiation-induced AR in utero. PMID- 23109299 TI - The willed body donor interview project: medical student and donor expectations. AB - The Anatomical Donations Program at the University of Michigan Medical School (UMMS) has begun a multiphase project wherein interviews of donors will be recorded and later shown to medical students who participate in the anatomical dissection course. The first phase of this project included surveys of both current UMMS medical students and donors concerning their perceptions of such a program. A five-question survey administered via Qualtrics software was electronically mailed to all current medical students at UMMS, and a survey was mailed to registered and potential donors requesting information from the UMMS on anatomical donations. A total of 224 medical student responses (response rate 33%) and 54 donor responses (response rate 27%) were received. Seventy-four percent of students and 81% of donors reported they would participate in this program if it existed. Students and donors supported the implementation of this program for varying reasons, though many felt strongly they would not want to participate in a donor interview program. These qualitative results support those of previous studies that show a majority of students desire a closer personal relationship with the donor, and these are the first results to be reported on donor perceptions of a donor interview program. Although many students and donors are in favor of instituting this program, others feel strongly that such an experience could be traumatic. The causes of these differing reactions need to be further explored, and the opinions of those who object to this study will be respected by maintaining voluntary participation in future phases of this study. PMID- 23109300 TI - 3D chemical image using TOF-SIMS revealing the biopolymer component spatial and lateral distributions in biomass. PMID- 23109301 TI - Central nervous system juvenile xanthogranuloma after langerhans cell histiocytosis. PMID- 23109302 TI - Contact and fumigant toxicity of Pinus densiflora needle hydrodistillate constituents and related compounds and efficacy of spray formulations containing the oil to Dermatophagoides farinae. AB - BACKGROUND: The toxicity of red pine needle hydrodistillate (RPN-HD), 19 RPN-HD constituents and another 12 structurally related compounds and the control efficacy of four experimental spray formulations containing RPN-HD (0.5. 1, 2 and 3% sprays) to adult Dermatophagoides farinae were evaluated. RESULTS: RPN-HD (24 h LC50 , 68.33 ug cm(-2) ) was toxic to mites. Menthol was the most toxic compound (12.69 ug cm(-2) ), and the toxicity of this compound and benzyl benzoate did not differ significantly. High toxicity was also produced by alpha terpineol, bornyl acetate, geranyl acetate, thymol, linalyl acetate, terpinyl acetate, citral, linalool and camphor (18.79-36.51 ug cm(-2) ). These compounds were more toxic than either deet or dibutyl phthalate. In vapour-phase mortality tests, these compounds were consistently more toxic in closed versus open containers, indicating that their mode of delivery was largely a result of vapour action. RPN-HD 3% experimental spray provided 95% mortality against adult D. farinae, whereas permethrin (cis:trans, 25:75) 2.5 g L(-1) spray treatment resulted in 0% mortality. CONCLUSION: In the light of global efforts to reduce the level of highly toxic synthetic acaricides in indoor environments, RPN-HD and the compounds described merit further study as potential biocides for the control of Dermatophagoides populations as fumigants with contact action. PMID- 23109303 TI - Proximal femoral replacement and allograft prosthesis composite in the treatment of periprosthetic fractures with significant proximal bone loss. AB - Femoral bone loss due to periprosthetic fracture, a challenging problem in total hip arthroplasty (THA), is increasingly encountered due to a rise in the number of revision THAs performed. Allograft prosthesis composite (APC) and proximal femoral replacement (PFR) are two available options for management of patients with difficult type-B3 Vancouver periprosthetic fractures. The treatment algorithm for patients with these fractures has been extensively studied and is influenced by the age and activity level of the patient. APC is often preferred in young and active patients in an attempt to preserve bone stock while older and less active patients are considered candidates for PFR. In spite of the high rate of overall complications with these two procedures, reported survivorship is acceptable. Treating patients with these complicated fractures is fraught with complications and, even with successful treatment, the outcomes are not as promising as those associated with primary hip replacement. In this paper, we aimed to review available published reports about PFR and APC for treatment of periprosthetic fractures around THAs. PMID- 23109304 TI - Total joint arthroplasty in human immunodeficiency virus positive patients. AB - Recent advances in the medical management of patients with human immunodeficiency virus (HIV) have led to improvement in their life expectancy. The growing numbers of HIV-positive patients are now living long enough to develop end-stage arthritis, as well as other long-term musculoskeletal complications of HIV infection and treatment. This has resulted in an increased demand for total joint arthroplasty among these individuals. However, the safety and outcomes of such procedures are frequently questioned in published reports. Although increased complication rates have often been reported, most studies have reported on joint arthroplasties in HIV patients with hemophilia. The most widely reported complications in both HIV-negative and positive hemophiliac patients are aseptic loosening and postoperative infection. A possible relationship between the rate of these complications and cluster of differentiation (CD4) lymphocyte count has also been proposed. In addition to hemophilia, other factors frequently comorbid with HIV infection, such as intravenous drug use, can further complicate the clinical outcomes of these individuals following total joint replacement procedures. Physicians treating HIV positive patients must remain aware of the risks and outcomes of total joint surgery in this group when counseling them on treatment options. PMID- 23109305 TI - Pelvic fractures at a new level 1 trauma centre: who dies from pelvic trauma? The Inkosi Albert Luthuli Central Hospital experience. AB - OBJECTIVE: To identify the incidence of pelvic trauma, causes of death and factors predicting death with pelvic fractures. METHODS: All pelvic fractures were retrospectively identified from a registry spanning from March 2007 to August 2009. Data was captured on a proforma. Data for survivors, non-survivors and a subgroup with pelvic injury as the underlying cause of death were compared. RESULTS: Pelvic fracture incidence was 16% of major trauma cases. Patient with pelvic fractures had 31% mortality and 9% pelvic fracture-induced mortality. Motor vehicle collisions were the commonest external cause of pelvic fractures (59%); however, the highest mortality was from falls >6 m. The Injury Severity Score (ISS) was 29 in survivors, 36 in non-survivors, and 54 in the pelvic death subgroup. Type C fracture was a predictor of mortality (P = 0.135). 53% of the cases required transfusion in the first 24 hours. The pelvic death subgroup received a mean of 10.7 units of blood, versus 4 units for survivors and 3.7 units for non-survivors (P = 0.259). CONCLUSION: The overall incidence of pelvic fracture and associated mortality were higher than previously reported. Fracture severity and falls from heights are associated with additional injuries (higher ISS) and mortality. More severe fractures cause deaths directly attributable to the pelvic injury. The requirement for major blood transfusions for pelvic fracture hemorrhage was related to mortality. Female patients appeared to fare worse than males. PMID- 23109306 TI - Does previous varicose vein surgery alter deep vein thrombosis risk after lower limb arthroplasty? AB - OBJECTIVE: To determine the rates of deep vein thrombosis (DVT) and pulmonary embolism (PE) after total knee arthroplasty (TKA) and total hip arthroplasty (THA) in patients who have had previous varicose vein (VV) surgery. METHODS: Data on 57,364 patients who had undergone THAs and 51,859 patients who had undergone TKAs were obtained from the Scottish Arthroplasty Project and cross-referenced with patients for whom DVT/PE events had been recorded (Scottish Morbidity Database). RESULTS: The THA DVT rate in patients who had previously undergone VV surgery was 0.8% (27/3478), and in those with no previous VV diagnosis or surgery was 0.8% (428/53,659). In patients with a previous VV diagnosis but no VV surgery, the THA DVT rate was 3.1% (7/227) (Pearson chi2 test, chi2 = 14.8, degrees of freedom = 2, P = 0.001). No significant difference was found for the corresponding data in the TKA cohort. The THA PE rate in patients who had previously undergone VV surgery was 0.7% (26/3478), and in those with no previous VV diagnosis or surgery 0.7% (376/53,659). No correlation was found between prior VV interventions and PE rates. CONCLUSION: Untreated VVs are associated with an increased risk of DVT after THA. Therefore, patients with VVs should consider having them treated prior to undergoing orthopedic interventions. PMID- 23109307 TI - Cage migration after transforaminal lumbar interbody fusion and factors related to it. AB - OBJECTIVE: To review and analyze cage migration and related risk factors in patients who have undergone transforaminal lumbar interbody fusion (TLIF). METHODS: A retrospective study was conducted to review the complications of cage migration in 512 patients who had undergone a TLIF procedure from January 2010 to June 2011 in five spinal centers. In all, 263 men and 249 women with a mean age of 54.7 years were included. All patients were followed up at 3, 6 and 12 months after the procedure. The clinical outcomes were evaluated by visual analogue scores, the Oswestry disability index, plain radiography and three-dimensional CT scanning to analyze the incidence of, and risk factors related to, cage migration. RESULTS: Cage migration was found in 6 of the 512 patients (1.17%). Significant differences were found between all pairs of centers. Different shapes and sizes of cages had different incidences of migration. Analysis showed that rectangular-shaped cages had a significantly greater incidence of cage migration (3.11%, 5/161) than did kidney-shaped cages (0.28%, 1/351; P < 0.05). Small cages had a tendency to more frequent post-operative cage migration (5.13%, 4/78) than did large cages (0.46%, 2/434; P < 0.05). Double segment TLIF cages migrated more frequently (5.75%, 5/87) than did mono-segment cages (0.24%, 1/425; P < 0.05)). Furthermore, when the adjacent endplates were of linear type, the cages migrated much more frequently (3.50%) than when they were of concave-concave type (0.27%; P < 0.05). CONCLUSION: Cage size, shape, number of fused segments and adjacent endplate shape might be risk factors for cage migration in addition to surgical technique, disc height and bone mineral density. PMID- 23109308 TI - A comparison between "sandwich" and conventional methods of repairing spinal dura rupture. AB - OBJECTIVE: To study the therapeutic efficacy of the "sandwich" method (medical glue + gelatin sponge + medical glue) of spinal dural repair for preventing cerebrospinal fluid (CSF) leaks during treatment of subdural tumors. METHODS: Fifty-four patients with spinal subdural tumors treated between April 2007 and June 2011 were retrospectively investigated. The patients were divided into two groups: a conventional group (group A) and a "sandwich" group (group B). The group A patients included 16 males and 7 females with an average tumor course of 11 months (range, 2-34 months). Four of their 23 tumors were in the cervical spine, eight thoracic, and eleven lumbar. The group B patients included 19 males and 12 females with an average tumor course of 12 months (range, 3-36 months). Five of their 31 tumors were in the cervical spines, 10 thoracic, and 16 lumbar. In group A, the dural repairs were performed with interlocking sutures and a gelatin sponge covering the dura; whereas in group B, they were performed with interlocking sutures, painting of medical glue around the dural incision, covering this with a gelatin sponge, and finally covering of the gelatin sponge with medical glue. The total volume of drainage after operation, incidence of CSF leaks, healing of the incision, and recovery of clinical performance were recorded. RESULTS: Compared to group A patients, group B patients had a significantly smaller total volume of drainage (P < 0.05) on the day of surgery, and the first, second, and third postoperative days. The incidence of CSF leakage in group B was also significantly less than in group A (P < 0.05). Before discharge, three patients in group A developd hydrops, which was successfully treated by aspiration, continuous pressure from sandbags, and the prone position. During the first 3 months of follow-up, five patients developed deep hydrops under their incisions but required no treatment. There were no obvious abnormalities in group B. CONCLUSION: After removal of subdural spinal tumors by incising the dura mater, or in related spinal surgery, application of the "sandwich" complex to the damaged spinal dura reduces the volume of drainage postoperatively and reduces the incidence of CSF leakage. PMID- 23109309 TI - Causes, treatment and prevention of esophageal fistulas in anterior cervical spine surgery. AB - OBJECTIVE: To evaluate the causes, treatment and prevention of esophageal fistulas after anterior cervical spine surgery. METHOD: Between January 2004 and December 2011, 5 of 2348 patients who underwent anterior cervical surgery in our hospital developed esophageal fistulas (three male and two female patients, average age 34 years). Their diagnoses were cervical injuries (three), cervical spondylosis (one) and cervical tuberculosis (one). Their esophageal fistulas were treated by debridement and exploratory surgery, primary suturing of the perforation and/or sternocleidomastoid myoplasty. If conservative treatment failed or esophageal fistula recurred, plate removal was offered. Postoperative treatment included esophageal rest, enteral nutrition, wound drainage, and antibiotics. Methylene blue was used to evaluate results. RESULT: An esophageal fistula was discovered during anterior cervical surgery in one patient and primary suturing performed. In four patients, fistulas were diagnosed after anterior cervical decompression and fusion. In one of these, only debridement and exploratory surgery were required. In another, a perforation was sutured during debridement and exploratory surgery. In the third, internal fixation was removed because of failure of prolonged conservative treatment. In the fourth, the esophageal fistula recurred repeatedly; he required removal of the hardware and reinforcement with a sternocleidomastoid muscle flap. At 6-48 months follow-up, all patients were in good condition, symptom free, and without cervical instability or infectious spondylitis. CONCLUSION: Successful management of esophageal fistula after anterior cervical spinal surgery depends on primary closure of the perforation with or without muscle flaps, surgical drainage, esophageal rest and nutritional support, and removal of hardware if necessary. Prevention consists of careful surgery and gentle tissue handling. PMID- 23109310 TI - Cerebrospinal fluid leakage during anterior approach cervical spine surgery for severe ossification of the posterior longitudinal ligament: prevention and treatment. AB - OBJECTIVE: The prevention and treatment of the common complication of cerebrospinal fluid leakage (CSFL) during anterior approach cervical spine surgery for severe ossification of the posterior longitudinal ligament (OPLL) is documented. METHOD: A retrospective analysis of 47 patients with severe cervical OPLL aged 39 to 73 years (average, 56.4 years) who underwent anterior operations was conducted. All patients were classified as local or segmental types based on the thickness of the ossified mass (>5 mm) and canal stenosis rates exceeding 50%. Fifteen cases underwent discectomy and fusion and 32 cases corpectomy and fusion. Preoperative CT images were analyzed for operation breakthrough and decompression range. During surgery, the ossified mass was excised or floated and the arachnoid reserved in order to reduce dural damage. Sutures coupled with gelatin sponge or muscle pedicle were applied to repair dural defects. After surgery, patients were confined to bed to allow for drainage or puncture. RESULTS: Fifteen cases of dural defects were recognized intraoperatively. Postoperatively, 5 patients developed CSFL. Partially cut dura with intact arachnoid occurred in one patient who developed a CSF pseudocyst. No cases required secondary operations or shunt placement and all exhibited good wound healing, with JOA scores increasing from 7.30 +/- 1.08 to 13.70 +/- 0.81 points and improvement rates of 65.98% +/- 7.35%. CONCLUSION: During anterior surgical treatment for severe OPLL, CSFL can be prevented and treated through careful analysis of CT images, meticulous operative technique, careful handling of the ossified mass, and intra-operative repair of dural damage. PMID- 23109311 TI - Surgical treatment of gastrocnemius muscle ruptures. AB - Rupture of the medial head of the gastrocnemius, known as "tennis leg", typically occurs when the muscle has been overstretched by dorsiflexion of the ankle with full knee extension. The classic clinical presentation is a middle-aged person who complains of sports-related acute pain in the mid portion of the calf, associated with a snapping sensation. Magnetic resonance imaging (MRI) or ultrasound is often required to evaluate patients with this condition. This injury is usually managed non-operatively, surgical treatment rarely being indicated according to published reports. One case of longstanding and one of recent rupture of the musculotendinous junction of the medial head of the gastrocnemius that were successfully treated by surgical repair are presented here and the MRI characteristics and indications for surgery are discussed. PMID- 23109312 TI - Atraumatic heterotopic ossification in the setting of prolonged intubation because of H1N1 influenza: a case report. PMID- 23109313 TI - Pulmonary embolism caused by cement leakage after percutaneous kyphoplasty: a case report. PMID- 23109314 TI - Isolated tuberculous pyomyositis of semimembranosus and adductor magnus: a case report. PMID- 23109315 TI - Giant subdeltoid tubercular bursitis: a case report. PMID- 23109316 TI - A general strategy for the synthesis of carbon nanofibers from solid carbon materials. PMID- 23109318 TI - Scarless integumentary wound healing in the mammalian fetus: molecular basis and therapeutic implications. AB - Adult mammals respond to injury of their skin/integument by forming scar tissue. Scar is useful in rapidly sealing an injured area, but can also lead to significant morbidity. Mammals in fetal life retain the ability to heal integumentary wounds regeneratively, without scar. The critical molecular mechanisms governing this remarkable phenomenon have been a subject of great interest, in the hopes that these could be dissected and recapitulated in the healing adult wound, with the goal of inducing scarless healing in injured patients. Multiple lines of investigation spanning decades have implicated a number of factors in distinguishing scarless from fibrotic wound healing, including most prominently transforming growth factor-beta and interleukin-10, among others. Therapeutic interventions to try to mitigate scarring in adult wounds have been developed out of these studies, and have reached the level of clinical trials in humans, although as yet no FDA-approved treatment exists. More recent expressomic studies have revealed many more genes that are differentially expressed in scarlessly healing fetal wounds compared with adult, and microRNAs have also been identified as participating in the fetal wound healing response. These represent an even greater range of potential therapeutics (or targets for therapy) to translate the promise of scarless fetal wound healing to the injured adult patient. PMID- 23109319 TI - Scarless fetal skin wound healing update. AB - Scar formation, a physiologic process in adult wound healing, can have devastating effects for patients; a multitude of pathologic outcomes, affecting all organ systems, stems from an amplification of this process. In contrast to adult wound repair, the early-gestation fetal skin wound heals without scar formation, a phenomenon that appears to be intrinsic to fetal skin. An intensive research effort has focused on unraveling the mechanisms that underlie scarless fetal wound healing in an attempt to improve the quality of healing in both children and adults. Unique properties of fetal cells, extracellular matrix, cytokine profile, and gene expression contribute to this scarless repair. Despite the great increase in knowledge gained over the past decades, the precise mechanisms regulating scarless fetal healing remain unknown. Herein, we describe the current proposed mechanisms underlying fetal scarless wound healing in an effort to recapitulate the fetal phenotype in the postnatal environment. PMID- 23109317 TI - Wound healing in development. AB - Wound healing is the inherent ability of an organism to protect itself against injuries. Cumulative evidence indicates that the healing process patterns in part embryonic morphogenesis and may result in either organ regeneration or scarring, phenomena that are developmental stage- or age-dependent. Skin is the largest organ. Its morphogenesis and repair mechanisms have been studied extensively due not only to its anatomical location, which allows easy access and observation, but also to its captivating structure and vital function. Thus, this review will focus on using skin as a model organ to illustrate new insights into the mechanisms of wound healing that are developmentally regulated in mammals, with special emphasis on the role of the Wnt signaling pathway and its crosstalk with TGF-beta signaling. Relevant information from studies of other organs is discussed where it applies, and the clinical impact from such knowledge and emerging concepts on regenerative medicine are discussed in perspective. PMID- 23109320 TI - Elastin signaling in wound repair. AB - Skin is an important organ to the human body as it functions as an interface between the body and environment. Cutaneous injury elicits a complex wound healing process, which is an orchestration of cells, matrix components, and signaling factors that re-establishes the barrier function of skin. In adults, an unavoidable consequence of wound healing is scar formation. However, in early fetal development, wound healing is scarless. This phenomenon is characterized by an attenuated inflammatory response, differential expression of signaling factors, and regeneration of normal skin architecture. Elastin endows a range of mechanical and cell interactive properties to skin. In adult wound healing, elastin is severely lacking and only a disorganized elastic fiber network is present after scar formation. The inherent properties of elastin make it a desirable inclusion to adult wound healing. Elastin imparts recoil and resistance and induces a range of cell activities, including cell migration and proliferation, matrix synthesis, and protease production. The effects of elastin align with the hallmarks of fetal scarless wound healing. Elastin synthesis is substantial in late stage in utero and drops to a trickle in adults. The physical and cell signaling advantages of elastin in a wound healing context creates a parallel with the innate features of fetal skin that can allow for scarless healing. PMID- 23109322 TI - Controlled preparation and reactive silver-ion sorption of electrically conductive poly(N-butylaniline)-lignosulfonate composite nanospheres. AB - Electroconductive poly(N-butylaniline)-lignosulfonate (PBA-LS) composite nanospheres were prepared in a facile way by in situ, unstirred polymerization of N-butylaniline with lignosulfonate (LS) as a dispersant and dopant. The LS content was used to optimize the size, structure, electroconductivity, solubility, and silver ion adsorptive capacity of the PBA-LS nanospheres. Uniform PBA-LS10 nanospheres with a minimal mean diameter of 375 nm and high stability were obtained when the LS content was 10 wt %. The PBA-LS10 nanospheres possess an increased electroconductivity of 0.109 S cm(-1) compared with that of poly(N butylaniline) (0.0751 S cm(-1)). Furthermore, the PBA-LS10 nanospheres have a maximal silver-ion sorption capacity of 815.0 mg g(-1) at an initial silver ion concentration of 50 mmol L(-1) (25 degrees C for 48 h), an enhancement of 70.4% compared with PBA. Moreover, a sorption mechanism of silver ions on the PBA-LS10 nanospheres is proposed. TEM and wide-angle X-ray diffraction results showed that silver nanoparticles with a diameter size range of 6.8-55 nm was achieved after sorption, indicating that the PBA-LS10 nanospheres had high reductibility for silver ions. PMID- 23109323 TI - Elution behavior of shortened multiwalled carbon nanotubes in size exclusion chromatography. AB - We present a rigorous investigation on elution behaviors of ultrasonically shortened multiwalled carbon nanotubes in size-exclusion chromatography. The size separation of five carbon nanotube samples that underwent ultrasonic shortening for varying lengths of time revealed the existence of three kinds of carbon species: large nanotubes, small nanotubes, and amorphous carbon species. Separation of the three different carbon species was confirmed by SEM analyses on the fractionated eluates and also by light scattering/UV absorbance double detection. The chromatographic peak intensity ratio between the large and small nanotubes suggested an increased amount of small carbon nanotubes upon longer mechanical treatment time. The effect of the concentration of carbon nanotube dispersion on elution behavior was examined, and the elution volume of the shortened nanotubes was found to decrease upon dilution while that of the large nanotubes showed the opposite tendency. Unusual elution behaviors of the multiwalled carbon nanotubes were also observed by altering the flow rate, and these behaviors could be explained by the longer equilibration time taken for large nanotubes to access the pores of the packing materials and a possible morphology change of small carbon nanotubes. PMID- 23109324 TI - Attitudes of cancer patients in a university teaching hospital in southeast Nigeria on disclosure of cancer information. AB - OBJECTIVE: The attitudes of cancer patients from southeast Nigeria on disclosure of cancer information were studied to ascertain their information needs and what information was disclosed to them by their physicians. METHODS: Structured questionnaires were administered on all consenting cancer patients that were managed at the University of Nigeria Teaching Hospital Enugu between July and October 2011. The data collected were analysed with Statistical Package for Social Sciences version 18. RESULTS: Two hundred and forty-four patients participated in the study. Ninety-five per cent of the participants wanted to know the nature of their diagnosis, but 76.7% admitted to being informed of the diagnosis by their doctors. Nearly 54% of participants will like to be informed of a bad prognosis, but only 1.8% was informed. The word cancer was used to disclose the diagnosis to 69.4% of the patients, but 108 (44.3%) patients did not have any idea what cancer meant, 39.8% knew it as an incurable disease whereas 8.6% described it as a tumour or abnormal growth. Patient factors that significantly improved the disclosure of diagnostic information were education (p = 0.044) and site of the cancer (p = 0.043). CONCLUSIONS: Most of the surveyed cancer patients in University of Nigeria Teaching Hospital Enugu desire to know the truth about the diagnosis of their disease, and more than 50% of them desire to know when the disease becomes terminal and death is imminent. Physicians in southeast Nigeria should consider the information needs of the individual patients and tailor their disclosure practices to meet these individual needs. PMID- 23109321 TI - Embryonic wound healing: a primer for engineering novel therapies for tissue repair. AB - Scar is the default tissue repair used by the body in response to most injuries-a response that occurs in wounds ranging in seriousness from minor skin cuts to complete severance of the spinal cord. By contrast, before the third trimester of pregnancy embryonic mammals tend to heal without scarring due to a variety of mechanisms and factors that are uniquely in operation during development in utero. The goal of tissue engineering is to develop safe and clinically effective biological substitutes that restore, maintain, or improve tissue function in patients. This review provides a comparative overview of wound healing during development and maturation and seeks to provide a perspective on just how much the embryo may be able teach us in the engineering of new therapies for tissue repair. PMID- 23109325 TI - The benefits and limitations of using ultrasonography to supplement anatomical understanding. AB - Anatomical understanding is critical to medical education. With reduced teaching time and limited cadaver availability, it is important to investigate how best to utilize in vivo imaging to supplement anatomical understanding and better prepare medical graduates for the proliferation of point-of-care imaging in the future. To investigate whether using short sessions of in vivo imaging using ultrasonography could benefit students' anatomical knowledge and clinical application, we conducted a 2-hour session on abdominal anatomy using ultrasonography in small groups of five to six students, for both first- and second-year student cohorts. Individual feedback was collected to assess student perceptions. To measure retention and understanding, a short examination containing ultrasound images and questions and performance of a clinical skill (gastrointestinal' tract examination) were assessed. Ultrasonography sessions were highly valued by the students, with 90% of the students reporting their understanding was improved, and over 70% reporting increased confidence in their anatomical knowledge. However, the assessments showed no appreciable impact on skills or understanding related to abdominal anatomy and examination. We conclude that the risk associated with limited exposure increasing confidence without increasing skills remains real and that in vivo imaging is not effective when used as a short adjunct teaching tool. The widespread use of ultrasonography means finding the best way to incorporate ultrasound into medical education remains important. To this end, we are currently implementing an extended program including echocardiography and multiple anatomical sessions that will determine if frequency and repetition of use can positively impact on student performance and understanding. PMID- 23109326 TI - A woman with periodic chest pain. PMID- 23109327 TI - Marie Stopes: botany and birth control. PMID- 23109328 TI - Bright lights and big city health problems. PMID- 23109329 TI - Adults with advanced cancer still hope for cure. PMID- 23109330 TI - First line catheter ablation or drugs for paroxysmal atrial fibrillation? PMID- 23109331 TI - Contrast-induced nephropathy in patients with ST elevation myocardial infarction treated with primary percutaneous coronary intervention. AB - We assessed the relationship between contrast-induced nephropathy (CIN) and SYNTAX score (SS) and serum uric acid (SUA) levels in patients with ST elevation myocardial infarction (STEMI). A total of 835 STEMI patients in whom primary percutaneous coronary intervention was performed in our cardiology clinic were included in this study (615 male, 220 female; mean age 58.1 +/- 12.2 years). The patients were divided into 2 groups (CIN and non-CIN). Contrast-induced nephropathy was observed in 9.6% (80) of patients; SS (13.9 +/- 6.2/22.1 +/- 5.8) and SUA (5.1 +/- 0.9/6.2 +/- 0.9) values in the CIN group were higher compared with the non-CIN group (P < .001, for all). All SS (95% confidence interval [CI] = 1.136-1.250, P = .001), SUA (95% CI = 1.877-3.236, P = .002), and diabetes (95% CI = 0.998-1.039, P = .026) were independent predictors of CIN in logistic regression analysis. Procedures that can prevent CIN may be beneficial in patients at high risk as identified by the SS and SUA levels. PMID- 23109332 TI - Analysis of peptide secondary structures by photoactivatable amino acid analogues. AB - Photochemical cross-linking was applied to trap intramolecular interactions in peptides. The incorporation of diazirine-labeled amino acid analogues in combination with high-resolution mass spectrometry made it possible to catch reverse-turn conformations within peptides, exactly map their self-interacting surfaces, and discriminate between stable and transient interactions. PMID- 23109333 TI - Synthetic strategy for cyclic amines: a stereodefined cyclic N,O-acetal as a stereocontrol and diversity-generating element. PMID- 23109334 TI - Characterisation of field-evolved resistance to chlorantraniliprole in the diamondback moth, Plutella xylostella, from China. AB - BACKGROUND: Chlorantraniliprole and flubendiamide belong to the new chemical class of diamide insecticides. High levels of resistance to chlorantraniliprole rapidly evolved in field populations of Plutella xylostella from southern China. An investigation was made of diamide cross-resistance, as well as inheritance, stability and metabolic mechanisms of chlorantraniliprole resistance in field populations of P. xylostella from southern China. RESULTS: Three field populations of P. xylostella collected from southern China in 2011 showed high levels of cross-resistance between chlorantraniliprole (18-1150-fold) and flubendiamide (15-800-fold) when compared with a susceptible reference strain. Genetic analysis showed that chlorantraniliprole resistance in the ZC population was autosomal and incompletely recessive. In the absence of selection pressure, resistance to chlorantraniliprole in the ZC population declined from 2040-fold (G1 ) to 25-fold (G7 ). The ZC-R strain (derived by selection from ZC) exhibited 670-fold resistance to chlorantraniliprole, which is synergised by known metabolic inhibitors such as PBO, DEM and DEF at low levels. CONCLUSION: Field evolved resistance to chlorantraniliprole in P. xylostella confers strong cross resistance to flubendiamide, so both compounds should be well separated and not alternated in resistance management strategies. High-level resistance to chlorantraniliprole in the ZC population was incompletely recessive and not stable. Metabolic detoxification was involved in chlorantraniliprole resistance in the ZC-R strain to some extent, but target-site resistance could not be excluded. (c) 2012 Society of Chemical Industry. PMID- 23109335 TI - IgG Fab fragments forming bivalent complexes by a conformational mechanism that is reversible by osmolytes. AB - Generated by proteolytic cleavage of immunoglobulin, Fab fragments possess great promise as blocking reagents, able to bind receptors or other targets without inducing cross-linking. However, aggregation of Fab preparations is a common occurrence, which generates intrinsic stimulatory capacity and thwarts signal blockade strategies. Using a panel of biochemical approaches, including size exclusion chromatography, SDS-PAGE, mass spectrometry, and cell stimulation followed by flow cytometry, we have measured the oligomerization and acquisition of stimulatory capacity that occurs in four monoclonal IgG Fabs specific for TCR/CD3. Unexpectedly, we observed that all Fabs spontaneously formed complexes that were precisely bivalent, and these bivalent complexes possessed most of the stimulatory activity of each Fab preparation. Fabs composing bivalent complexes were more susceptible to proteolysis than monovalent Fabs, indicating a difference in conformation between the Fabs involved in these two different states of valency. Because osmolytes represent a class of compounds that stabilize protein folding and conformation, we sought to determine the extent to which the amino acid osmolyte l-proline might impact bivalent Fab complexation. We found that l-proline (i) inhibited the adoption of the conformation associated with bivalent complexation, (ii) preserved Fab monovalency, (iii) reversed the conformation of preformed bivalent Fabs to that of monovalent Fabs, and (iv) separated a significant percentage of preformed bivalent complexes into monovalent species. Thus, Fab fragments can adopt a conformation that is compatible with folding or packing of a bivalent complex in a process that can be inhibited by osmolytes. PMID- 23109336 TI - BACE1 protein endocytosis and trafficking are differentially regulated by ubiquitination at lysine 501 and the Di-leucine motif in the carboxyl terminus. AB - beta-Site amyloid precursor protein-cleaving enzyme (BACE1) is a membrane tethered member of the aspartyl proteases that has been identified as beta secretase. BACE1 is targeted through the secretory pathway to the plasma membrane and then is internalized to endosomes. Sorting of membrane proteins to the endosomes and lysosomes is regulated by the interaction of signals present in their carboxyl-terminal fragment with specific trafficking molecules. The BACE1 carboxyl-terminal fragment contains a di-leucine sorting signal ((495)DDISLL(500)) and a ubiquitination site at Lys-501. Here, we report that lack of ubiquitination at Lys-501 (BACE1K501R) does not affect the rate of endocytosis but produces BACE1 stabilization and accumulation of BACE1 in early and late endosomes/lysosomes as well as at the cell membrane. In contrast, the disruption of the di-leucine motif (BACE1LLAA) greatly impairs BACE1 endocytosis and produces a delayed retrograde transport of BACE1 to the trans-Golgi network (TGN) and a delayed delivery of BACE1 to the lysosomes, thus decreasing its degradation. Moreover, the combination of the lack of ubiquitination at Lys-501 and the disruption of the di-leucine motif (BACE1LLAA/KR) produces additive effects on BACE1 stabilization and defective internalization. Finally, BACE1LLAA/KR accumulates in the TGN, while its levels are decreased in EEA1 positive compartments indicating that both ubiquitination at Lys-501 and the di leucine motif are necessary for the trafficking of BACE1 from the TGN to early endosomes. Our studies have elucidated a differential role for the di-leucine motif and ubiquitination at Lys-501 in BACE1 endocytosis, trafficking, and degradation and suggest the involvement of multiple adaptor molecules. PMID- 23109337 TI - Crystal structure of calmodulin binding domain of orai1 in complex with Ca2+ calmodulin displays a unique binding mode. AB - Orai1 is a plasma membrane protein that in its tetrameric form is responsible for calcium influx from the extracellular environment into the cytosol in response to interaction with the Ca(2+)-depletion sensor STIM1. This is followed by a fast Ca(2+).calmodulin (CaM)-dependent inhibition, resulting from CaM binding to an Orai1 region called the calmodulin binding domain (CMBD). The interaction between Orai1 and CaM at the atomic level remains unknown. Here, we report the crystal structure of a CaM.Orai1-CMBD complex showing one CMBD bound to the C-terminal lobe of CaM, differing from other CaM-target protein complexes, in which both N- and C-terminal lobes of CaM (CaM-N and CaM-C) are involved in target binding. Orai1-CMBD binds CaM-C mainly through hydrophobic interactions, primarily involving residue Trp(76) of Orai1-CMBD, which interacts with the hydrophobic pocket of CaM-C. However, NMR data, isothermal titration calorimetry data, and pulldown assays indicated that CaM-N and CaM-C both can bind Orai1-CMBD, with CaM N having ~4 times weaker affinity than CaM-C. Pulldown assays of a Orai1 CMBD(W76E) mutant, gel filtration chromatography data, and NOE signals indicated that CaM-N and CaM-C can each bind one Orai1-CMBD. Thus our studies support an unusual, extended 1:2 binding mode of CaM to Orai1-CMBDs, and quantify the affinity of Orai1 for CaM. We propose a two-step mechanism for CaM-dependent Orai1 inactivation initiated by binding of the C-lobe of CaM to the CMBD of one Orai1 followed by the binding of the N-lobe of CaM to the CMBD of a neighboring Orai1. PMID- 23109338 TI - Multivalent pseudopeptides targeting cell surface nucleoproteins inhibit cancer cell invasion through tissue inhibitor of metalloproteinases 3 (TIMP-3) release. AB - Blockage of the metastasis process remains a significant clinical challenge, requiring innovative therapeutic approaches. For this purpose, molecules that inhibit matrix metalloproteinases activity or induce the expression of their natural inhibitor, the tissue inhibitor of metalloproteinases (TIMPs), are potentially interesting. In a previous study, we have shown that synthetic ligands binding to cell surface nucleolin/nucleophosmin and known as HB 19 for the lead compound and NucAnt 6L (N6L) for the most potent analog, inhibit both tumor growth and angiogenesis. Furthermore, they prevent metastasis in a RET transgenic mice model which develops melanoma. Here, we investigated the effect of N6L on the invasion capacity of MDA-MB-435 melanoma cells. Our results show that the multivalent pseudopeptide N6L inhibited Matrigel invasion of MDA-MB-435 cells in a modified Boyden chamber model. This was associated with an increase in TIMP-3 in the cell culture medium without a change in TIMP-3 mRNA expression suggesting its release from cell surface and/or extracellular matrix. This may be explained by our demonstrated N6L interaction with sulfated glycosaminoglycans and consequently the controlled bioavailability of glycosaminoglycan-bound TIMP 3. The implication of TIMP-3 in N6L-induced inhibition of cell invasion was evidenced by siRNA silencing experiments showing that the loss of TIMP-3 expression abrogated the effect of N6L. The inhibition of tumor cell invasion by N6L demonstrated in this study, in addition to its previously established inhibitory effect on tumor growth and angiogenesis, suggests that N6L represents a promising anticancer drug candidate warranting further investigation. PMID- 23109339 TI - Ubiquitination of neuronal nitric-oxide synthase in the calmodulin-binding site triggers proteasomal degradation of the protein. AB - Nitric-oxide synthase, a cytochrome P450-like hemoprotein enzyme, catalyzes the synthesis of nitric oxide, a critical signaling molecule in a variety of physiological processes. Our laboratory has discovered that certain drugs suicide inactivate neuronal nitric-oxide synthase (nNOS) and lead to the preferential ubiquitination of the inactivated nNOS by an Hsp70- and CHIP (C terminus of Hsc70 interacting protein)-dependent process. To further understand the process by which altered nNOS is recognized, ubiquitinated, and proteasomally degraded, we examined the sites of ubiquitination on nNOS. We utilized an in vitro ubiquitination system containing purified E1, E2 (UbcH5a), Hsp70, and CHIP that recapitulates the ability of the cells to selectively recognize and ubiquitinate the altered forms of nNOS. LC-MS/MS analysis of the tryptic peptides obtained from the in vitro ubiquitinated nNOS identified 12 ubiquitination sites. Nine of the sites were within the oxygenase domain and two were in the calmodulin-binding site, which links the oxygenase and reductase domains, and one site was in the reductase domain. Mutational analysis of the lysines in the calmodulin-binding site revealed that Lys-739 is a major site for poly-ubiquitination of nNOS in vitro and regulates, in large part, the CHIP-dependent degradation of nNOS in HEK293 cells, as well as in in vitro studies with fraction II. Elucidating the exact site of ubiquitination is an important step in understanding how chaperones recognize and trigger degradation of nNOS. PMID- 23109340 TI - The structure of Sec12 implicates potassium ion coordination in Sar1 activation. AB - Coat protein II (COPII)-coated vesicles transport proteins and lipids from the endoplasmic reticulum to the Golgi. Crucial for the initiation of COPII coat assembly is Sec12, a guanine nucleotide exchange factor responsible for activating the small G protein Sar1. Once activated, Sar1/GTP binds to endoplasmic reticulum membranes and recruits COPII coat components (Sec23/24 and Sec13/31). Here, we report the 1.36 A resolution crystal structure of the catalytically active, 38-kDa cytoplasmic portion of Saccharomyces cerevisiae Sec12. Sec12 adopts a beta propeller fold. Conserved residues cluster around a loop we term the "K loop," which extends from the N-terminal propeller blade. Structure-guided site-directed mutagenesis, in conjunction with in vitro and in vivo functional studies, reveals that this region of Sec12 is catalytically essential, presumably because it makes direct contact with Sar1. Strikingly, the crystal structure also reveals that a single potassium ion stabilizes the K loop; bound potassium is, moreover, essential for optimum guanine nucleotide exchange activity in vitro. Thus, our results reveal a novel role for a potassium stabilized loop in catalyzing guanine nucleotide exchange. PMID- 23109341 TI - Listeria monocytogenes triggers the cell surface expression of Gp96 protein and interacts with its N terminus to support cellular infection. AB - Listeria monocytogenes is an intracellular food-borne pathogen causing listeriosis in humans. This bacterium deploys an arsenal of virulence factors that act in concert to promote cellular infection. Bacterial surface proteins are of primary importance in the process of host cell invasion. They interact with host cellular receptors, inducing/modulating specific cellular responses. We previously identified Vip, a Listeria surface protein covalently attached to the bacterial cell wall acting as a key virulence factor. We have shown that Vip interacts with Gp96 localized at the surface of host cells during invasion and that this interaction is critical for a successful infection in vivo. To better understand the importance of Vip-Gp96 interaction during infection, we aimed to characterize this interaction at the molecular level. Here we demonstrate that, during infection, L. monocytogenes triggers the cellular redistribution of Gp96, inducing its exposure at the cell surface. Upon infection, Gp96 N-terminal domain is exposed to the extracellular milieu in L2071 fibroblasts and interacts with Vip expressed by Listeria. We identified Gp96 (Asp(1)-Leu(170)) as sufficient to interact with Vip; however, we also showed that the region Tyr(179)-Leu(390) of Gp96 is important for the interaction. Our findings unravel the Listeria-induced surface expression of Gp96 and the topology of its insertion on the plasma membrane and improve our knowledge on the Vip-Gp96 interaction during Listeria infection. PMID- 23109342 TI - RNase L induces autophagy via c-Jun N-terminal kinase and double-stranded RNA dependent protein kinase signaling pathways. AB - Autophagy is a tightly regulated mechanism that mediates sequestration, degradation, and recycling of cellular proteins, organelles, and pathogens. Several proteins associated with autophagy regulate host responses to viral infections. Ribonuclease L (RNase L) is activated during viral infections and cleaves cellular and viral single-stranded RNAs, including rRNAs in ribosomes. Here we demonstrate that direct activation of RNase L coordinates the activation of c-Jun N-terminal kinase (JNK) and double-stranded RNA-dependent protein kinase (PKR) to induce autophagy with hallmarks as accumulation of autophagic vacuoles, p62(SQSTM1) degradation and conversion of Microtubule-associated Protein Light Chain 3-I (LC3-I) to LC3-II. Accordingly, treatment of cells with pharmacological inhibitors of JNK or PKR and mouse embryonic fibroblasts (MEFs) lacking JNK1/2 or PKR showed reduced autophagy levels. Furthermore, RNase L-induced JNK activity promoted Bcl-2 phosphorylation, disrupted the Beclin1-Bcl-2 complex and stimulated autophagy. Viral infection with Encephalomyocarditis virus (EMCV) or Sendai virus led to higher levels of autophagy in wild-type (WT) MEFs compared with RNase L knock out (KO) MEFs. Inhibition of RNase L-induced autophagy using Bafilomycin A1 or 3-methyladenine suppressed viral growth in initial stages; in later stages autophagy promoted viral replication dampening the antiviral effect. Induction of autophagy by activated RNase L is independent of the paracrine effects of interferon (IFN). Our findings suggest a novel role of RNase L in inducing autophagy affecting the outcomes of viral pathogenesis. PMID- 23109344 TI - Sequential dispersive liquid-liquid microextraction for the determination of aryloxyphenoxy-propionate herbicides in water. AB - A novel dispersive liquid-liquid microextraction (DLLME) method followed by HPLC analysis, termed sequential DLLME, was developed for the preconcentration and determination of aryloxyphenoxy-propionate herbicides (i.e. haloxyfop-R-methyl, cyhalofop-butyl, fenoxaprop-P-ethyl, and fluazifop-P-butyl) in aqueous samples. The method is based on the combination of ultrasound-assisted DLLME with in situ ionic liquid (IL) DLLME into one extraction procedure and achieved better performance than widely used DLLME procedures. Chlorobenzene was used as the extraction solvent during the first extraction. Hydrophilic IL 1-octyl-3 methylimidazolium chloride was used as a dispersive solvent during the first extraction and as an extraction solvent during the second extraction after an in situ chloride exchange by bis[(trifluoromethane)sulfonyl]imide. Several experimental parameters affecting the extraction efficiency were studied and optimized with the design of experiments using MINITAB(r) 16 software. Under the optimized conditions, the extractions resulted in analyte recoveries of 78-91%. The correlation coefficients of the calibration curves ranged from 0.9994 to 0.9997 at concentrations of 10-300, 15-300, and 20-300 MUg L(-1). The relative SDs (n = 5) ranged from 2.9 to 5.4%. The LODs for the four herbicides were between 1.50 and 6.12 MUg L(-1). PMID- 23109343 TI - Na+/H+ exchanger regulatory factor 1 (NHERF1) directly regulates osteogenesis. AB - Bone formation requires synthesis, secretion, and mineralization of matrix. Deficiencies in these processes produce bone defects. The absence of the PDZ domain protein Na(+)/H(+) exchange regulatory factor 1 (NHERF1) in mice, or its mutation in humans, causes osteomalacia believed to reflect renal phosphate wasting. We show that NHERF1 is expressed by mineralizing osteoblasts and organizes Na(+)/H(+) exchangers (NHEs) and the PTH receptor. NHERF1-null mice display reduced bone formation and wide mineralizing fronts despite elimination of phosphate wasting by dietary supplementation. Bone mass was normal, reflecting coordinated reduction of bone resorption and formation. NHERF1-null bone had decreased strength, consistent with compromised matrix quality. Mesenchymal stem cells from NHERF1-null mice showed limited osteoblast differentiation but enhanced adipocyte differentiation. PTH signaling and Na(+)/H(+) exchange were dysregulated in these cells. Osteoclast differentiation from monocytes was unaffected. Thus, NHERF1 is required for normal osteoblast differentiation and matrix synthesis. In its absence, compensatory mechanisms maintain bone mass, but bone strength is reduced. PMID- 23109345 TI - A photoswitchable and photoluminescent organic semiconductor based on cation-pi and carboxylate-pyridinium interactions: a supramolecular approach. PMID- 23109346 TI - Decision making for borderline cases in pass/fail clinical anatomy courses: the practical value of the standard error of measurement and likelihood ratio in a diagnostic test. AB - Several studies have shown that the standard error of measurement (SEM) can be used as an additional "safety net" to reduce the frequency of false-positive or false-negative student grading classifications. Practical examinations in clinical anatomy are often used as diagnostic tests to admit students to course final examinations. The aim of this study was to explore the diagnostic value of SEM using the likelihood ratio (LR) in establishing decisions about students with practical examination scores at or below the pass/fail cutoff score in a clinical anatomy course. Two hundred sixty-seven students took three clinical anatomy practical examinations in 2011. The students were asked to identify 40 anatomical structures in images and prosected specimens in the practical examination. Practical examination scores were then divided according to the following cutoff scores: 2, 1 SEM below, and 0, 1, 2 SEM above the pass score. The positive predictive value (+PV) and LR of passing the final examination were estimated for each category to explore the diagnostic value of practical examination scores. The +PV (LR) in the six categories defined by the SEM was 39.1% (0.08), 70.0% (0.30), 88.9% (1.04), 91.7% (1.43), 95.8% (3.00), and 97.8% (5.74), respectively. The LR of categories 2 SEM above/below the pass score generated a moderate/large shift in the pre- to post-test probability of passing. The LR increased the usefulness and practical value of SEM by improving confidence in decisions about the progress of students with borderline scores 2 SEM above/below the pass score in practical examinations in clinical anatomy courses. PMID- 23109347 TI - The future of hemostasis management. AB - We are in the midst of an unprecedented period for the development of new therapeutic products to treat patients with bleeding diseases. While current hemostatic treatments are already very effective and safe, new agents to enhance convenience and further improve both short- and long-term efficacy of treatment are under development. Some of these products have already reached the clinic for early phase trials, and others will be available shortly. The strategies being evaluated for hemostatic enhancement range from gene and nucleic acid-based approaches, to the development of complex, naturally occurring molecules such as the non-anticoagulant polysaccharide, fucoidan. There is every likelihood that combinations of these treatment approaches will further improve the quality of bleeding disease management over the next 5 years and beyond. PMID- 23109348 TI - Effects of Cry34/35Ab1 corn on the survival and development of western corn rootworm, Diabrotica virgifera virgifera. AB - BACKGROUND: The western corn rootworm, Diabrotica virgifera virgifera LeConte, is a major agricultural pest that is managed with transgenic corn, Zea mays L., expressing genes from Bacillus thuringiensis Berliner (Bt). The effects of Bt corn producing Cry34/35Ab1 (event DAS-59122-7) and entomopathogens on the survival and development of larval D. v. virgifera were examined in laboratory, field and greenhouse experiments. RESULTS: Larvae preferred non-Bt over Bt corn in a laboratory experiment, and there was higher recovery from non-Bt corn than from Bt corn in a field experiment. In a greenhouse study, survival at 17 days did not differ significantly among non-Bt corn, Bt corn and a blend of Bt and non Bt corn, but development was delayed on Bt corn. Older larvae fed non-Bt corn had lower survival when entomopathogenic nematodes were added, but no other effects of pathogen were detected. CONCLUSION: Bt corn producing Cry34/35Ab1 delayed larval development of D. v. virgifera and deterred feeding. In a mixture of Bt and non-Bt corn, larval development and survival were similar to non-Bt corn alone, suggesting that non-Bt plants in a blended refuge or a pure stand may produce a similar number of adult insects, and that timing of adult emergence may also be similar. PMID- 23109350 TI - An Integrated "energy wire" for both photoelectric conversion and energy storage. PMID- 23109349 TI - Discovery of depsides and depsidones from lichen as potent inhibitors of microsomal prostaglandin E2 synthase-1 using pharmacophore models. AB - Nature in silico: Virtual screening using validated pharmacophore models identified lichen depsides and depsidones as potential inhibitors of mPGES-1, an emerging target for NSAIDs. Evaluation of the virtual hits in a cell-free assay revealed physodic acid and perlatolic acid as potent inhibitors of mPGES-1 (IC(50) = 0.4 and 0.43 MUM, respectively), indicating that these natural products have potential as novel anti-inflammatory agents. PMID- 23109351 TI - Quantitative determination of amphetamine in plasma using negative ion chemical ionization GC-MS of o-(pentafluorobenzyl-oxycarbonyl)-2,3,4,5-tetrafluorobenzoyl derivatives. AB - Quantitative determination of amphetamine in plasma by the use of a novel electrophoric derivatization reagent, o-(pentafluorobenzyloxycarbonyl)-2,3,4,5 tetrafluorobenzoyl chloride is described. Amphetamine can be quantitatively measured down to 49 pg/mL plasma using only 250 MUL of sample due to the extraordinary sensitivity of the derivatives under negative ion chemical ionization MS. Plasma samples were made alkaline with carbonate buffer and treated with n-hexane and reagent solution for 20 min, which, after concentration was measured by negative ion chemical ionization GC-MS. The method is rapid as extraction and derivatization occur in one single step. [(2)H(5)]-Amphetamine was used as an internal standard. Validation data are given to demonstrate the usefulness of the assay, including specificity, linearity, accuracy and precision, benchtop stability, freeze-thaw stability, autosampler stability, aliquot analysis, and prospective analytical batch size accuracy. PMID- 23109352 TI - ANK3 as a risk gene for schizophrenia: new data in Han Chinese and meta analysis. AB - Histological and neuroimaging evidence supports the hypothesis that neuronal disconnectivity may be involved in the pathogenesis of schizophrenia. A genome wide association study (GWAS) showed a single nucleotide polymorphism (SNP), rs10761482 in ankyrin 3 (ANK3), a major neuron-enriched gene, was associated with schizophrenia although inconsistent results had been reported. Two meta analyses reported another SNP rs10994336 in ANK3 gene confers risk to bipolar disorder (BD). Due to evidence of genetic overlap between schizophrenia and BD, we investigated common findings by analyzing the association of ANK3 polymorphisms (rs10761482, rs10994336, and two missenses, rs3808942 and rs3808943) with schizophrenia, using the Han Chinese population. A total of 516 schizophrenia cases, 400 controls, and 81 trios of early onset schizophrenia were recruited for association studies. Furthermore, the published datasets were combined with our results to determine the effect of the loci on schizophrenia. Our association study showed the frequencies of C allele of rs10761482 and T allele of rs10994336 were higher in patients than in controls. Furthermore, allele condition analyses indicated the association signal observed at rs10761482 and rs10994336 was independent. A haplotype analysis revealed the rs10761482-rs3808942-rs3808943 haplotype was associated with schizophrenia. The frequency of the T-T-T haplotype was higher in patients than in controls. In the transmission disequilibrium test analysis, the C allele of rs10761482 and the rs10761482-rs3808942-rs3808943 haplotype were preferentially transmitted in the trios. Meta analysis incorporating previous and current studies also showed rs10761482 and rs10994336 were associated with schizophrenia. We conclude that ANK3 gene has a major influence on susceptibility to schizophrenia across populations. PMID- 23109353 TI - Neglect subtypes, race, and poverty: individual, family, and service characteristics. AB - Recent child maltreatment research has highlighted the very different context of poverty for Black and White children. Neglect is the most common form of maltreatment and strongly associated with poverty. Neglect is, however, not a unitary construct. We lack an understanding of whether reporting of and responding to different types of neglect may vary by poverty, race, or the intersection of the two. Administrative census, child welfare, welfare, health, and education data were used to examine how family and community poverty factors associate with various subtypes of neglect and subsequent case dispositions for Black and White children. Black children reported to child welfare reside in far poorer communities than Whites, even after taking into account family income (Aid to Families with Dependent Children [AFDC]/Temporary Aid to Needy Families [TANF]). Black children were more commonly reported and substantiated for severe and basic needs neglect. Community poverty indicators had a different relationship to report disposition for Black as compared to White children after controlling for neglect subtypes, child and family characteristics. Implications for practice and policy are discussed. PMID- 23109354 TI - Generation of a conditional mouse model to target Acvr1b disruption in adult tissues. AB - Alk4 is a type I receptor that belongs to the transforming growth factor-beta (TGF-beta) family. It takes part in the signaling of TGF-beta ligands such as Activins, Gdfs, and Nodal that had been demonstrated to participate in numerous mechanisms ranging from early embryonic development to adult-tissue homeostasis. Evidences indicate that Alk4 is a key regulator of many embryonic processes, but little is known about its signaling in adult tissues and in pathological conditions where Alk4 mutations had been reported. Conventional deletion of Alk4 gene (Acvr1b) results in early embryonic lethality prior gastrulation, which has precluded study of Alk4 functions in postnatal and adult mice. To circumvent this problem, we have generated a conditional Acvr1b floxed-allele by flanking the fifth and sixth exons of the Acvr1b gene with loxP sites. Cre-mediated deletion of the floxed allele generates a deleted allele, which behaves as an Acvr1b null allele leading to embryonic lethality in homozygous mutant animals. A tamoxifen inducible approach to target disruption of Acvr1b specifically in adult tissues was used and proved to be efficient for studying Alk4 functions in various organs. We report, therefore, a novel conditional model allowing investigation of biological role played by Alk4 in a variety of tissue-specific contexts. PMID- 23109355 TI - Copper-mediated difluoromethylation of (hetero)aryl iodides and beta-styryl halides with tributyl(difluoromethyl)stannane. PMID- 23109356 TI - Medical use of cannabis. Cannabidiol: a new light for schizophrenia? AB - The medical properties of cannabis have been known for many centuries; its first documented use dates back to 2800 BC when it was described for its hallucinogenic and pain-relieving properties. In the first half of the twentieth century, a number of pharmaceutical companies marked cannabis for indications such as asthma and pain, but since then its use has sharply declined, mainly due to its unpredictable effects, but also for socio-political issues. Recently, great attention has been directed to the medical properties of phytocannabinoids present in the cannabis plant alongside the main constituent Delta9 Tetrahydrocannabinol (THC); these include cannabinoids such as cannabidiol (CBD), cannabigerol (CBG), and tetrahydrocannabivarin (THCV). Evidence suggests an association between cannabis and schizophrenia: schizophrenics show a higher use of marijuana as compared to the healthy population. Additionally, the use of marijuana can trigger psychotic episodes in schizophrenic patients, and this has been ascribed to THC. Given the need to reduce the side effects of marketed antipsychotics, and their weak efficacy on some schizophrenic symptoms, cannabinoids have been suggested as a possible alternative treatment for schizophrenia. CBD, a non-psychoactive constituent of the Cannabis sativa plant, has been receiving growing attention for its anti-psychotic-like properties. Evidence suggests that CBD can ameliorate positive and negative symptoms of schizophrenia. Behavioural and neurochemical models suggest that CBD has a pharmacological profile similar to that of atypical anti-psychotic drugs and a clinical trial reported that this cannabinoid is a well-tolerated alternative treatment for schizophrenia. PMID- 23109357 TI - The use of DDAVP in children with bleeding disorders. AB - Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) has been used in children with von Willebrand disease (VWD) and Hemophilia A for almost 35 years. This treatment has substantially lowered the number of children exposed to human plasma derived products, with a good safety profile, and at very low cost. The response to DDAVP has been shown to be associated with age, baseline factor level, and genetic mutations. A DDAVP challenge test is recommended. DDAVP has also been used to prevent and treat bleeding episodes in children with platelet function defects and other disorders associated with bleeding tendency. PMID- 23109358 TI - Receptor-based virtual screening and biological characterization of human apurinic/apyrimidinic endonuclease (Ape1) inhibitors. AB - The endonucleolytic activity of human apurinic/apyrimidinic endonuclease (AP endo, Ape1) is a major factor in maintaining the integrity of the genome. Conversely, as an undesired effect, Ape1 overexpression has been linked to resistance to radio- and chemotherapeutic treatments in several human tumors. Inhibition of Ape1 using siRNA or the expression of a dominant negative form of the protein has been shown to sensitize cells to DNA-damaging agents, including various chemotherapeutic agents. Therefore, inhibition of the enzymatic activity of Ape1 might result in a potent antitumor therapy. A number of small molecules have been described as Ape1 inhibitors; however, those compounds are in the early stages of development. Herein we report the identification of new compounds as potential Ape1 inhibitors through a docking-based virtual screening technique. Some of the compounds identified have in vitro activities in the low-to-medium micromolar range. Interaction of these compounds with the Ape1 protein was observed by mass spectrometry. These molecules also potentiate the cytotoxicity of the chemotherapeutic agent methyl methanesulfonate in fibrosarcoma cells. This study demonstrates the power of docking and virtual screening techniques as initial steps in the design of new drugs, and opens the door to the development of a new generation of Ape1 inhibitors. PMID- 23109360 TI - Visualization of latent fingermarks using an aptamer-based reagent. PMID- 23109361 TI - Train-the-trainer: implementation of cognitive behavioural guided self-help for recurrent binge eating in a naturalistic setting. AB - OBJECTIVE: The present study evaluated the feasibility and acceptability of cognitive behavioural guided self-help (CBTgsh) for recurrent binge eating using the train-the-trainer implementation strategy. METHOD: After receiving expert-led training in CBTgsh, a master's-level graduate student in clinical psychology subsequently trained and supervised less experienced graduate students to implement the treatment in an open clinical trial. Participants were 38 treatment seeking students at a university counselling centre with recurrent binge eating, featuring cases of bulimia nervosa, binge eating disorder, or eating disorder not otherwise specified. RESULTS: Intent-to-treat (ITT) analyses revealed 42.1% abstinence from binge eating at post-treatment and 47.4% at one-month follow-up. Participants reported significant pretreatment to post-treatment reductions on measures of specific eating disorder psychopathology, general psychopathology, and functional impairment and high levels of treatment acceptability. CONCLUSIONS: These results provide 'proof-of-concept' for the train-the-trainer implementation strategy and add to the evidence supporting the feasibility and effectiveness of CBTgsh in routine clinical care. PMID- 23109359 TI - The 4.1B cytoskeletal protein regulates the domain organization and sheath thickness of myelinated axons. AB - Myelinated axons are organized into specialized domains critical to their function in saltatory conduction, i.e., nodes, paranodes, juxtaparanodes, and internodes. Here, we describe the distribution and role of the 4.1B protein in this organization. 4.1B is expressed by neurons, and at lower levels by Schwann cells, which also robustly express 4.1G. Immunofluorescence and immuno-EM demonstrates 4.1B is expressed subjacent to the axon membrane in all domains except the nodes. Mice deficient in 4.1B have preserved paranodes, based on marker staining and EM in contrast to the juxtaparanodes, which are substantially affected in both the PNS and CNS. The juxtaparanodal defect is evident in developing and adult nerves and is neuron-autonomous based on myelinating cocultures in which wt Schwann cells were grown with 4.1B-deficient neurons. Despite the juxtaparanodal defect, nerve conduction velocity is unaffected. Preservation of paranodal markers in 4.1B deficient mice is associated with, but not dependent on an increase of 4.1R at the axonal paranodes. Loss of 4.1B in the axon is also associated with reduced levels of the internodal proteins, Necl-1 and Necl-2, and of alpha-2 spectrin. Mutant nerves are modestly hypermyelinated and have increased numbers of Schmidt-Lanterman incisures, increased expression of 4.1G, and express a residual, truncated isoform of 4.1B. These results demonstrate that 4.1B is a key cytoskeletal scaffold for axonal adhesion molecules expressed in the juxtaparanodal and internodal domains that unexpectedly regulates myelin sheath thickness. PMID- 23109362 TI - Evaluation of peptide fractionation strategies used in proteome analysis. AB - Peptide fractionation is extremely important for the comprehensive analysis of complex protein mixtures. Although a few comparisons of the relative separation efficiencies of 2-D methodologies using complex biological samples have appeared, a systematic evaluation was conducted in this study. Four different fractionation methods, namely strong-cation exchange, hydrophilic interaction chromatography, alkaline-RP and solution isoelectric focusing, which can be used prior to LC MS/MS analysis, were compared. Strong-cation exchange * RPLC was used after desalting the sample; significantly more proteins were identified, compared with the nondesalted sample (1990 and 1375). We also found that the use of a combination of analytical methods resulted in a dramatic increase in the number of unique peptides that could be identified, compared with only a small increase in protein levels. The increased number of distinct peptides that can be identified is especially beneficial, not only for unequivocally identifying proteins but also for proteomic studies involving posttranslational modifications and peptide-based quantification approaches using stable isotope labeling. The identification and quantification of more peptides per protein provide valuable information that improves both the quantification of, and confidence of protein identification. PMID- 23109363 TI - Regulating cell morphogenesis: the Drosophila Jun N-terminal kinase pathway. AB - The Jun-N-terminal Kinase pathway (JNK), known also as stress activated protein kinase pathway (SAPK), is an eukaryotic evolutionarily conserved signaling pathway. From a purported evolutionarily "ancient" function as stress mediator, it evolved in multicellular eukaryotes to permanent roles in development, without leaving its original function. In Drosophila melanogaster, it is required for follicle cell morphogenesis, embryonic dorsal closure, pupal thoracic closure and genital disc rotation closure, all processes with requisite cell shape changes. Besides, it is activated during wound healing and in response to stress (UV irradiation, oxidative stress) where it may signal cell death or proliferation. Despite these varied roles, it has a conserved core of molecules that follow the MAPKKK/MAPKK/MAPK logic of mitogen activated protein kinases pathways. Regulation of the JNK pathway appears majorly negative, with phosphatases, transcription factors and proteins of novel structure "holding back" on JNK activation in different tissues. This particular mode of regulation may hark back to the pathway's origin as stress detector and responder, implying readiness to respond, from which the developmental roles may have evolved as conditions demanding obligate and predicted stress responses (i.e., embryonic dorsal closure viewed as a "wound of development"). PMID- 23109364 TI - Facile assembly of graphene on anion exchange resin microspheres for electrochemical sensing and biosensing. AB - Graphene sheets were assembled on anion exchange resin (AER) microspheres based on the electrostatic interactions between graphene oxide and AER and subsequent chemical reduction. The prepared graphene-coated AER microspheres were characterized by scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. They were then embedded in the bores of pipette tips to fabricate disposable electrodes for electrochemical sensing. The workability and performance of the novel electrodes were examined by analyzing the electrochemical behavior of the electrodes for the sensing of ascorbic acid, dopamine, uric acid, acetaminophen, aniline, and glucose by cyclic voltammetry and amperometry. The advantages of the electrodes include ease of fabrication, low cost, pronounced electrocatalytic activity, and rapid response. Thus, they hold great promise for a wide range of applications. PMID- 23109366 TI - The rare inherited coagulation disorders. AB - The rare inherited coagulation disorders (RICD) are uncommon and thus not well defined in terms of severity or management. Inheritance is autosomal; in some of these disorders in the heterozygote state affected individuals may be mildly symptomatic. Severe deficiencies are more common in association with consanguinity. Factor X and factor XIII deficiency have the most severe manifestations, while factor XI deficiency is the least severe. Factor VII and factor XI deficiencies show a poor relationship between the factor level and bleeding risk. Unlike hemophilia, women are equally affected by these RICD and can have problems related to menstruation and childbirth. PMID- 23109367 TI - Reversible redox reconfiguration of secondary structures in a designed peptide. PMID- 23109368 TI - Proven in vitro evolution of protease cathepsin E-inhibitors and -activators at pH 4.5 using a paired peptide method. AB - Improving a particular function of molecules is often more difficult than identifying such molecules ab initio. Here, a method to acquire higher affinity and/or more functional peptides was developed as a progressive library selection method. The primary library selection products were utilized to build a secondary library composed of blocks of 4 amino acids, of which selection led to peptides with increased activity. These peptides were further converted to randomly generate paired peptides. Cathepsin E-inhibitors thus obtained exhibited the highest activities and affinities (pM order). This was also the case with cathepsin E-activating peptides, proving the methodological effectiveness. The primary, secondary, and tertiary library selections can be regarded as module finding, module-shuffling, and module-pairing, respectively, which resembles the progression of the natural evolution of proteins. The mode of peptide binding to their target proteins is discussed in analogy to antibodies and epitopes of an antigen. PMID- 23109369 TI - Spatial and developmental heterogeneity of calcium signaling in olfactory ensheathing cells. AB - Olfactory ensheathing cells (OECs) are specialized glial cells in the mammalian olfactory system supporting growth of axons from the olfactory epithelium into the olfactory bulb. OECs in the olfactory bulb can be subdivided into OECs of the outer nerve layer and the inner nerve layer according to the expression of marker proteins and their location in the nerve layer. In the present study, we have used confocal calcium imaging of OECs in acute mouse brain slices and olfactory bulbs in toto to investigate physiological differences between OEC subpopulations. OECs in the outer nerve layer, but not the inner nerve layer, responded to glutamate, ATP, serotonin, dopamine, carbachol, and phenylephrine with increases in the cytosolic calcium concentration. The calcium responses consisted of a transient and a tonic component, the latter being mediated by store-operated calcium entry. Calcium measurements in OECs during the first three postnatal weeks revealed a downregulation of mGluR(1) and P2Y(1) receptor mediated calcium signaling within the first 2 weeks, suggesting that the expression of these receptors is developmentally controlled. In addition, electrical stimulation of sensory axons evoked calcium signaling via mGluR(1) and P2Y(1) only in outer nerve layer OECs. Downregulation of the receptor-mediated calcium responses in postnatal animals is reflected by a decrease in amplitude of stimulation-evoked calcium transients in OECs from postnatal days 3 to 21. In summary, the results presented reveal striking differences in receptor responses during development and in axon-OEC communication between the two subpopulations of OECs in the olfactory bulb. PMID- 23109370 TI - Triple-decker Au3-Ag-Au3-Ag-Au3 ion cluster enclosed in a self-assembled cage. PMID- 23109371 TI - Detection of anti-yellow fever virus immunoglobulin m antibodies at 3-4 years following yellow fever vaccination. AB - The duration of anti-yellow fever (YF) virus immunoglobulin M (IgM) antibodies following YF vaccination is unknown, making it difficult to interpret positive IgM antibody results in previously vaccinated travelers. We evaluated the frequency and predictors of YF IgM antibody positivity 3-4 years following YF vaccination. Twenty-nine (73%) of 40 participants had YF IgM antibodies 3-4 years postvaccination. No demographic or exposure variables were predictive of YF IgM positivity. However, persons who were YF IgM positive at 3-4 years postvaccination had earlier onset viremia and higher neutralizing antibody geometric mean titers at 1 month and 3-4 years postvaccination compared with persons who were YF IgM negative. Detection of YF IgM antibodies several years postvaccination might reflect remote YF vaccination rather than recent YF vaccination or YF virus infection. PMID- 23109372 TI - Entomologic investigations during an outbreak of West Nile virus disease in Maricopa County, Arizona, 2010. AB - Entomologic investigations were conducted during an intense outbreak of West Nile virus (WNV) disease in Maricopa County, Arizona during July 31-August 9, 2010. The investigations compared the East Valley outbreak area, and a demographically similar control area in northwestern metropolitan Phoenix where no human cases were reported. Five mosquito species were identified in each area, and species composition was similar in both areas. Significantly more Culex quinquefasciatus females were collected by gravid traps at Outbreak sites (22.2 per trap night) than at control sites (8.9 per trap night), indicating higher Cx. quinquefasciatus abundance in the outbreak area. Twenty-eight WNV TaqMan reverse transcription-polymerase chain reaction-positive mosquito pools were identified, including 24 of Cx. quinquefasciatus, 3 of Psorophora columbiae, and 1 of Culex sp. However, Cx. quinquefasciatus WNV infection rates did not differ between outbreak and control sites. At outbreak sites, 30 of 39 engorged Cx. quinquefasciatus had fed on birds, 8 of 39 on humans, and 1 of 39 on a lizard. At control sites, 20 of 20 identified blood meals were from birds. Data suggest that Cx. quinquefasciatus was the primary enzootic and epidemic vector of this outbreak. The most important parameters in the outbreak were vector abundance and blood meal analysis, which suggested more frequent contact between Cx. quinquefasciatus and human hosts in the outbreak area compared with the control area. PMID- 23109373 TI - Ocular zoonotic onchocerca infection in a resident of Oregon. AB - A long, slender filarial nematode was removed from the left anterior chamber of a resident of Oregon after several days of pain and blurred vision. The worm was identified as an Onchocerca, but it could not be further identified. This worm is the third zoonotic Onchocerca removed from the anterior chamber and the second case reported from the United States. Cases of zoonotic onchocerciasis continue to garner attention, and those cases affecting the eye are of particular interest. PMID- 23109374 TI - Field evaluation of a PCR test for Schistosoma japonicum egg detection in low prevalence regions of China. AB - Sensitive Schistosoma japonicum detection methods are needed to progress from schistosomiasis control to elimination. The sensitivity of the Kato-Katz thick smear and miracidium hatching tests decrease with infection intensity and serological tests cannot always identify current infections. We evaluated a fecal polymerase chain reaction (PCR) assay to detect S. japonicum infection in 106 humans and 8 bovines in China. PCR was highly sensitive, detecting S. japonicum DNA at 0.5 eggs/g of stool. Comparing PCR examination of a single stool sample to the miracidium hatching test using three consecutive stool samples, more humans were hatching test positive (20%) than PCR positive (15%). However, two individuals were PCR positive in a village where no infections were detected by coprological methods. The sensitivity of PCR makes it a promising tool for schistosomiasis diagnostics and screening, although egg shedding variability and stool sample size present challenges for any detection method in low-transmission areas. PMID- 23109376 TI - Reaction of an "invisible" frustrated N/B Lewis pair with dihydrogen. AB - D-(+)-Camphor forms the enamine 2 with piperidine. Compound 2 adds HB(C(6)F(5))(2) at the enamine carbon atom C3 to form a Lewis acid/Lewis base adduct (exo-/endo-isomers of 3). Exposure of 3 to dihydrogen (2.5 bar, room temperature) leads to heterolytic splitting of H(2) to form the H(+)/H(-) addition products (4, two diastereoisomers) of the "invisible" frustrated Lewis pairs (5, two diastereoisomers) that were apparently generated in situ by enamine hydroboration under equilibrium conditions. PMID- 23109375 TI - Differentiating Schistosoma haematobium from related animal schistosomes by PCR amplifying inter-repeat sequences flanking newly selected repeated sequences. AB - In schistosomiasis elimination programs, successful discrimination of Schistosoma haematobium from the related animal Schistosoma parasites will be essential for accurate detection of human parasite transmission. Polymerase chain reaction assays employing primers from two newly selected repeated sequences, named Sh73 and Sh77, did not discriminate S. haematobium when amplifying Sh73-77 intra- or inter-repeats. However, amplification between Sh73 and the previously described DraI repeat exhibited discriminative banding patterns for S. haematobium and Schistosoma bovis (sensitivity 1 pg and 10 pg, respectively). It also enabled banding pattern discrimination of Schistosoma curassoni and Schistosoma intercalatum, but Schistosoma mattheei and Schistosoma margrebowiei did not yield amplicons. Similar inter-repeat amplification between Sh77 and DraI yielded amplicons with discriminative banding for S. haematobium, and S. bovis; however, S. mattheei was detected only at low sensitivity (1 ng). The Sh73/DraI assay detected snails infected with S. haematobium, S. bovis, or both, and should prove useful for screening snails where discrimination of S. haematobium from related schistosomes is required. PMID- 23109377 TI - Online desorption of molecularly imprinted stir bar sorptive extraction coupled to high performance liquid chromatography for the trace analysis of triazines in rice. AB - Based on a special homemade interface, the molecularly imprinted stir bar sorptive extraction was coupled to high performance liquid chromatography for the online desorption and analysis. During desorption, the analytes desorbed from stir bar were delivered to a sample loop and then was introduced into liquid chromatography for further analysis. The online desorption and introduction processes were real-time monitored by the ultraviolet detector of the liquid chromatography system. In this way, the method sensitivity and reproducibility was improved for the introduction timing of the desorption solvent with greatest concentration of the target analytes was accurately controlled. To demonstrate the feasibility of the method, terbuthylazine imprinted stir bar was synthesized and used for the analysis of nine triazines in rice. Under the optimized conditions, limits of detection of 0.02-0.11 MUg/L and precision within 4.3-7.2% were achieved. The new method was compared with other two traditional offline desorption procedures, i.e. ultrasonic-assisted desorption and static thermal desorption. The comparison results showed that the proposed method is accurate, precise, fast, and suitable for the trace analysis of complex samples. PMID- 23109379 TI - A model of axonal transport drug delivery: effects of diffusivity. AB - This paper investigates the effects of diffusivity on retrograde dynein-driven transport of pharmaceutical agent complexes (PACs) in axons. The model is designed with two goals in mind: (1) to capture results on axonal transport drug delivery reported in recent experimental research by Filler et al. (Filler AG, Whiteside GT, Bacon M, Frederickson M, Howe FA, Rabinowitz MD, Sokoloff AJ, Deacon TW, Abell C, Munglani R, Griffiths JR, Bell BA, Lever AML. Tri-partite complex for axonal transport drug delivery achieves pharmacological effect. BMC Neuroscience 2010; 11: 8) and (2) to produce analytically tractable equations. It is shown that the inclusion of a diffusion process in the model produces equations that can still be solved by Laplace transform, although the last step of the solution, finding the inverse Laplace transform, has to be accomplished numerically, thus leading to a hybrid analytical and numerical solution technique. The effects of diffusivity and the kinetic rates describing PAC transition between the dynein-driven and accumulated states on transport of PACs toward the neuron soma are investigated. PMID- 23109378 TI - Domain specific genetic mosaic system in the Drosophila eye. AB - Genetic mosaic approach is commonly used in the Drosophila eye by completely abolishing or misexpressing a gene within a subset of cells to unravel its role during development. Classical genetic mosaic approach involves random clone generation in all developing fields. Consequently, a large sample size needs to be screened to generate and analyze clones in specific domains of the developing eye. To address domain specific functions of genes during axial patterning, we have developed a system for generating mosaic clones by combining Gal4/UAS and flippase (FLP)/FRT system which will allow generation of loss-of-function as well as gain-of-function clones on the dorsal and ventral eye margins. We used the bifid-Gal4 driver to drive expression of UAS-FLP. This reagent can have multiple applications in (i) studying spatio-temporal function of a gene during dorso ventral (DV) axis specification in the eye, (ii) analyzing genetic epistasis of genes involved in DV patterning, and (iii) conducting genome wide screens in a domain specific manner. PMID- 23109380 TI - A near-infrared spectroscopy computational model for cerebral hemodynamics. AB - Near infrared spectroscopy (NIRS) is a technique used to detect and measure changes in the concentrations of oxygenated hemoglobin, deoxygenated hemoglobin, and water in tissues based on the differential absorption, scattering, and refraction of the near infrared light. In this imaging technique, the optical properties of tissues are reconstructed from the measurements obtained from the sensors located on the boundary. A computational method for the rapid noninvasive detection / quantification of cerebral hemorrhage is described using the above procedure. CFD Research Corporation's finite volume computational biology code was used to numerically mimic the NIRS procedure by (i) noninvasively 'numerically penetrating' the brain tissues and (ii) reconstructing the optical properties the presence of water, oxygenated, and deoxygenated blood. These numerical noninvasive measurements are then used to predict the extent and severity of the brain hemorrhage. The paper also discusses ideas to obtain the location and the severity of a localized injury. Two-dimensional and three dimensional simulations are performed as a proof of concept for the numerical formulation being feasible for the above mentioned detection/quantification. The results demonstrate that this numerical NIRS formulation can be used as a noninvasive technique for both qualitative and quantitative evaluation of cerebral hemodynamics. PMID- 23109381 TI - A dual neural network ensemble approach for multiclass brain tumor classification. AB - The present study is conducted to develop an interactive computer aided diagnosis (CAD) system for assisting radiologists in multiclass classification of brain tumors. In this paper, primary brain tumors such as astrocytoma, glioblastoma multiforme, childhood tumor-medulloblastoma, meningioma and secondary tumor metastases along with normal regions are classified by a dual level neural network ensemble. Two hundred eighteen texture and intensity features are extracted from 856 segmented regions of interest (SROIs) and are taken as input. PCA is used for reduction of dimensionality of the feature space. The study is performed on a diversified dataset of 428 post contrast T1-weighted magnetic resonance images of 55 patients. Two sets of experiments are performed. In the first experiment, random selection is used which may allow SROIs from the same patient having similar characteristics to appear in both training and testing simultaneously. In the second experiment, not even a single SROI from the same patient is common during training and testing. In the first experiment, it is observed that the dual level neural network ensemble has enhanced the overall accuracy to 95.85% compared with 91.97% of single level artificial neural network. The proposed method delivers high accuracy for each class. The accuracy obtained for each class is: astrocytoma 96.29%, glioblastoma multiforme 96.15%, childhood tumor-medulloblastoma 90%, meningioma 93.00%, secondary tumor metastases 96.67% and normal regions 97.41%. This study reveals that dual level neural network ensemble provides better results than the single level artificial neural network. In the second experiment, overall classification accuracy of 90.4% was achieved. The generalization ability of this approach can be tested by analyzing larger datasets. The extensive training will also further improve the performance of the proposed dual network ensemble. Quantitative results obtained from the proposed method will assist the radiologist in forming a better decision for classifying brain tumors. PMID- 23109382 TI - Smoothed particle hydrodynamics method applied to pulsatile flow inside a rigid two-dimensional model of left heart cavity. AB - This paper aims to extend the application of smoothed particle hydrodynamics (SPH), a meshfree particle method, to simulate flow inside a model of the heart's left ventricle (LV). This work is considered the first attempt to simulate flow inside a heart cavity using a meshfree particle method. Simulating this kind of flow, characterized by high pulsatility and moderate Reynolds number using SPH is challenging. As a consequence, validation of the computational code using benchmark cases is required prior to simulating the flow inside a model of the LV. In this work, this is accomplished by simulating an unsteady oscillating flow (pressure amplitude: A = 2500 N / m(3) and Womersley number: W(o) = 16) and the steady lid-driven cavity flow (Re = 3200, 5000). The results are compared against analytical solutions and reference data to assess convergence. Then, both benchmark cases are combined and a pulsatile jet in a cavity is simulated and the results are compared with the finite volume method. Here, an approach to deal with inflow and outflow boundary conditions is introduced. Finally, pulsatile inlet flow in a rigid model of the LV is simulated. The results demonstrate the ability of SPH to model complex cardiovascular flows and to track the history of fluid properties. Some interesting features of SPH are also demonstrated in this study, including the relation between particle resolution and sound speed to control compressibility effects and also order of convergence in SPH simulations, which is consistently demonstrated to be between first-order and second-order at the moderate Reynolds numbers investigated. PMID- 23109383 TI - Computational representation of a realistic head and brain volume conductor model: electroencephalography simulation and visualization study. AB - Computational head and brain volume conductor modeling is a practical and non invasive method to investigate neuroelectrical activity in the brain. Anatomical structures included in a model affect the flow of volume currents and the resulting scalp surface potentials. The influence of different tissues within the head on scalp surface potentials was investigated by constructing five highly detailed, realistic head models from segmented and processed Visible Human Man digital images. The models were: (1) model with 20 different tissues, that is, skin, dense connective tissue (fat), aponeurosis (muscle), outer, middle and inner tables of the scalp, dura matter, arachnoid layer (including cerebrospinal fluid), pia matter, six cortical layers, eye tissue, muscle around the eye, optic nerve, temporal muscle, white matter and internal air, (2) model with three main inhomogeneities, that is, scalp, skull, brain, (3) model with homogeneous scalp and remaining inhomogeneities, (4) model with homogeneous skull and remaining inhomogeneities, and (5) model with homogeneous brain matter and remaining inhomogeneities. Scalp potentials because of three different dipolar sources in the parietal-occipital lobe were computed for all five models. Results of a forward solution revealed that tissues included in the model and the dipole source location directly affect the simulated scalp surface potentials. The major finding indicates that significant change in the scalp surface potentials is observed when the brain's distinctions are removed. The other modifications, for example, layers of the scalp and skull are important too, but they have less effect on the overall results. PMID- 23109384 TI - Noncontact intraocular pressure reading prediction after Laser-assisted in situ Keratomileusis by the finite element method. AB - The finite element method with linear elastic assumption for predicting the intraocular pressure (IOP) readings after reshaping of the corneal structure is demonstrated in the present study. Twelve effective eye measurements in seven subjects were examined using the TOPCON LX-10, a noncontact intraocular pressure measurement technique, before and after laser-assisted in situ Keratomileusis surgery. A linear elastic model was introduced to reduce possible errors from a complicated anisotropic model with uncertain tissue parameters. Linear relationship between the simplified removal depth of laser-assisted in situ Keratomileusis and predicted IOP was expected, and the comparisons between measurements and the predicted model were made. The results indicated that the expected IOP readings are close to the measurement IOP values, while larger errors occur at smaller IOP conditions. In conclusion, the linear elastic finite element approach can already reveal parameters that influence measurement data the most, and the interaction between parameters was higher than we had expected. This helps us to build the confidence on implementing the anisotropic model. PMID- 23109385 TI - Von Willebrand disease. AB - Long-term prophylaxis is not as well known in Von Willebrand disease (VWD) as in hemophilia but attempts to evaluate prophylaxis scientifically in VWD have started. A few cohort studies have been reported. In an international effort the Von Willebrand disease prophylaxis network (VWD PN) has been formed to investigate the role of prophylaxis in clinically severe VWD (e.g., patients with type 3 VWD) that is nonresponsive to other treatments. Findings from the VWD PN studies will hopefully provide more robust evidence for which patients might best benefit from prophylaxis and for appropriate dosing regimens for prophylaxis in patients with VWD. PMID- 23109386 TI - Radical/anionic S(RN)1-type polymerization for preparation of oligoarenes. PMID- 23109387 TI - Performance of a new fluorescence-labeled MMP inhibitor to image tumor MMP activity in vivo in comparison to an MMP-activatable probe. AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade structural components of the extracellular matrix and participate in pathologies such as cancer and inflammatory disorders. The development of novel contrast agents for optical imaging of MMP activity in vivo is of great interest. The commonly used near-infrared fluorescence-compatible agents are dye-quenched probes that do not emit fluorescence until they interact with MMPs. In contrast, fluorescent synthetic low-molecular-weight MMP inhibitors have not been systematically employed. The aim of this study was to evaluate the performance of our recently developed Cy5.5-labeled MMP inhibitor to image MMP activity in tumors in vivo compared with activatable fluorescent MMP-sensing probes. The dynamic uptake of Cy5.5-AF489 into four different tumor entities was analyzed in xenografted mice by intravenous injection and subsequent fluorescence reflectance imaging. Tumors were characterized in regard to their MMP-2 and -9 mRNA expressions (qRT-PCR analysis), proteins (immunohistochemistry) and gelatinase/collagenase activities (in situ zymography). Cy5.5-AF489 was compared with MMPSenseTM 680 and MMPSenseTM 750 FAST, two commercially available MMP-activatable probes. Cy5.5-AF489 showed a specific tumor uptake, which was blocked by pre-injection of the unlabeled MMPI, and discriminated between tumors with high or low MMP-2/-9 expressions. Our optical probe facilitated faster visualization of MMP-active tumors accompanied by excellent tumor-to-background ratios when compared with activatable probes. The MMP inhibitor Cy5.5-AF489 permits fast in vivo imaging of MMP expression/activity in tumors. Given its small molecular weight and non-peptidic structure, translational imaging from a preclinical application to a diagnostic tool for MMP-related diseases seems feasible. PMID- 23109388 TI - Hindered diffusion of MRI contrast agents in rat brain extracellular micro environment assessed by acquisition of dynamic T1 and T2 maps. AB - The knowledge of brain tissues characteristics (such as extracellular space and tortuosity) represents valuable information for the design of optimal MR probes for specific biomarkers targeting. This work proposes a methodology based on dynamic acquisition of relaxation time maps to quantify in vivo MRI contrast agent concentration after intra-cerebral injection in rat brain. It was applied to estimate the hindered diffusion in brain tissues of five contrast agents with different hydrodynamic diameters (Dotarem((r)) ~ 1 nm, P846 ~ 4 nm, P792 ~ 7 nm, P904 ~ 22 nm and Gd-based emulsion ~ 170 nm). In vivo apparent diffusion coefficients were compared with those estimated in an obstacle-free medium to determine brain extracellular space and tortuosity. At a 2 h imaging timescale, all contrast agents except the Gd-based emulsion exhibited significant diffusion through brain tissues, with characteristic times compatible with MR molecular imaging (<70 min to diffuse between two capillaries). In conclusion, our experiments indicate that MRI contrast agents with sizes up to 22 nm can be used to perform molecular imaging on intra-cerebral biomarkers. Our quantification methodology allows a precise estimation of apparent diffusion coefficients, which is helpful to calibrate optimal timing between contrast agent injection and MRI observation for molecular imaging studies. PMID- 23109389 TI - Magnetic labeling of pancreatic beta-cells modulates the glucose- and insulin induced phosphorylation of ERK1/2 and AKT. AB - This study was undertaken to investigate the effect of a magnetic resonance imaging (MRI) contrast agent, superparamagnetic iron oxide nanoparticle (SPIO), on signal transduction by glucose and insulin in pancreatic beta-cells. INS-1 cells were labeled in culture medium containing clinically approved SPIO for 24 h. Labeled and unlabeled cells were stimulated with glucose (25 mM) or insulin (0.1-1 uM) for 12 h. The phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2) and protein kinase B (AKT) and intracellular insulin protein levels were assessed by Western blotting. After labeling with increasing amounts of SPIO, cytotoxicity was not observed, yet the intracellular iron concentration increased in a dose-dependent manner. SPIO labeling (200 ug Fe ml(-1)) induced a significant increase in ERK1/2 and AKT phosphorylation (labeled vs unlabeled, p < 0.05), but significantly reduced the glucose-stimulated phosphorylation of ERK1/2 and AKT and insulin-stimulated phosphorylation of AKT (labeled vs unlabeled, p < 0.05). The level of intracellular insulin protein was found to be lower in labeled cells than unlabeled cells (labeled vs unlabeled, p < 0.05). This study demonstrates that SPIO labeling alters some fundamental functional variables, at least in INS-1 cells, through modulation of the glucose- or insulin-induced activation of ERK1/2 and AKT, which leads to insulin biosynthesis. PMID- 23109390 TI - VCAM-1-targeting gold nanoshell probe for photoacoustic imaging of atherosclerotic plaque in mice. AB - The development of molecular probes and novel imaging modalities, allowing better resolution and specificity, is associated with an increased potential for molecular imaging of atherosclerotic plaques especially in basic and pre-clinical research applications. In that context, a photoacoustic molecular probe based on gold nanoshells targeting VCAM-1 in mice (immunonanoshells) was designed. The molecular probe was validated in vitro and in vivo, showing no noticeable acute toxic effects. We performed the conjugation of gold nanoshells displaying near infrared absorption properties with VCAM-1 antibody molecules and PEG to increase their biocompatibility. The resulting immunonanoshells obtained under different conditions of conjugation were then assessed for specificity and sensitivity. Photoacoustic tomography was performed to determine the ability to distinguish gold nanoshells from blood both in phantoms and in vivo. Ex vivo optical projection tomography of hearts and aortas from atherosclerotic and control mice confirmed the selective accumulation of the immunonanoshells in atherosclerotic prone regions in mice, thus validating the utility of the probe in vivo in small animals for pre-clinical research. These immunonanoshells represent an adequate mean to target atherosclerotic plaques in small animals, leading to new tools to follow the effect of therapies on the progression or regression of the disease. PMID- 23109391 TI - Amide conjugates of the DO3A-N-(alpha-amino)propionate ligand: leads for stable, high relaxivity contrast agents for MRI? AB - A novel synthetic methodology for preparing amide conjugates of the DO3A-N-(alpha amino)propionate chelator is described, using the synthesis of the DO3A-N-(alpha benzoylamido)propionate chelator as an illustrative example. The model Gd[DO3A-N (alpha-benzoylamido)propionate] chelate displays accelerated water exchange, stability in a wide pH range and inertness towards transmetallation by Zn(2+). The Gd[DO3A-N-(alpha-benzoylamido)propionate] complex is mainly excreted via the kidneys, producing a significant increase in the kidney medulla/cortex enhancement ratio in MR images of Wistar rats, reflecting probably its higher lipophilicity compared with Gd(DTPA). The results presented suggest that Gd[DO3A N-(alpha-amido)propionate] chelates can be valuable leads for preparing potentially safe high relaxivity MRI contrast agents. PMID- 23109392 TI - Rapid spectrophotometric technique for quantifying iron in cells labeled with superparamagnetic iron oxide nanoparticles: potential translation to the clinic. AB - Labeling cells with superparamagnetic iron oxide (SPIO) nanoparticles provides the ability to track cells by magnetic resonance imaging. Quantifying intracellular iron concentration in SPIO labeled cells would allow for the comparison of agents and techniques used to magnetically label cells. Here we describe a rapid spectrophotometric technique (ST) to quantify iron content of SPIO-labeled cells, circumventing the previous requirement of an overnight acid digestion. Following lysis with 10% sodium dodecyl sulfate (SDS) of magnetically labeled cells, quantification of SPIO doped or labeled cells was performed using commonly available spectrophotometric instrument(s) by comparing absorptions at 370 and 750 nm with correction for turbidity of cellular products to determine the iron content of each sample. Standard curves demonstrated high linear correlation (R(2) = 0.998) between absorbance spectra of iron oxide nanoparticles and concentration in known SPIO-doped cells. Comparisons of the ST with inductively coupled plasma-mass spectroscopy (ICP-MS) or nuclear magnetic resonance relaxometric (R(2)) determinations of intracellular iron contents in SPIO containing samples resulted in significant linear correlation between the techniques (R(2) vs ST, R(2) > 0.992, p < 0.0001; ST vs ICP-MS, R(2) > 0.995, p < 0.0001) with the limit of detection of ST for iron = 0.66 ug ml(-1) for 10(6) cells ml(-1). We have developed a rapid straightforward protocol that does not require overnight acid digestion for quantifying iron oxide content in magnetically labeled cells using readily available analytic instrumentation that should greatly expedite advances in comparing SPIO agents and protocols for labeling cells. PMID- 23109393 TI - Field dependence of T1 for hyperpolarized [1-13C]pyruvate. AB - In vivo metabolism of hyperpolarized pyruvate has been demonstrated to be an important probe of cellular glycolysis in diseases such as cancer. The usefulness of hyperpolarized (13)C imaging is dependent on the relaxation rates of the (13)C enriched substrates, which in turn depend on chemical conformation and properties of the dissolution media such as buffer composition, solution pH, temperature and magnetic field. We have measured the magnetic field dependence of the spin lattice relaxation time of hyperpolarized [1-(13)C]pyruvate using field-cycled relaxometry. [1-(13)C]pyruvate was hyperpolarized using dynamic nuclear polarization and then rapidly thawed and dissolved in a buffered solution to a concentration of 80 mmol l(-1) and a pH of ~7.8. The hyperpolarized liquid was transferred within 8 s to a fast field-cycling relaxometer with a probe tuned for detection of (13)C at a field strength of ~0.75 T. The magnetic field of the relaxometer was rapidly varied between relaxation and acquisition fields where the sample magnetization was periodically measured using a small flip angle. Data were recorded for relaxation fields varying between 0.237 mT and 0.705 T to map the T(1) dispersion of the C-1 of pyruvate. Using similar methods, we also determined the relaxivity of the triarylmethyl radical (OX063; used for dynamic nuclear polarization) on the C-1 of pyruvate at field strengths of 0.001, 0.01, 0.1 and 0.5 T using 0.075, 1.0 and 2.0 mmol l(-1) concentrations of OX063 in the hyperpolarized pyruvate solution. PMID- 23109394 TI - Contrast enhancement by lipid-based MRI contrast agents in mouse atherosclerotic plaques; a longitudinal study. AB - The use of contrast-enhanced MRI to enable in vivo specific characterization of atherosclerotic plaques is increasing. In this study the intrinsic ability of two differently sized gadolinium-based contrast agents to enhance atherosclerotic plaques in ApoE(-/-) mice was evaluated with MRI. We obtained a kinetic profile for contrast enhancement, as the literature data on optimal imaging time points is scarce, and assessed the longer-term kinetics. Signal enhancement in the wall of the aortic arch, following intravenous injection of paramagnetic micelles and liposomes, was followed for 1 week. In vivo T(1)-weighted MRI plaque enhancement characteristics were complemented by fluorescence microscopy of NIR(664) incorporated in the contrast agents and quantification of tissue and blood Gd DTPA. Both micelles and liposomes enhanced contrast in T(1)-weighted MR images of plaques in the aortic arch. The average contrast-to-noise ratio increased after liposome or micelle injection to 260 or 280% respectively, at 24 h after injection, compared with a pre-scan. A second wave of maximum contrast enhancement was observed around 60-72 h after injection, which only slowly decreased towards the 1 week end-point. Confocal fluorescence microscopy and whole body fluorescence imaging confirmed MRI-findings of accumulation of micelles and liposomes. Plaque permeation of contrast agents was not strongly dependent on the contrast agent size in this mouse model. Our results show that intraplaque accumulation over time of both contrast agents leads to good plaque visualization for a long period. This inherent intraplaque accumulation might make it difficult to discriminate passive from targeted accumulation. This implies that, in the development of targeted contrast agents on a lipid-based backbone, extensive timing studies are required. PMID- 23109395 TI - In vivo magnetic resonance imaging of glucose - initial experience. AB - A new noninvasive, nonradioactive approach for glucose imaging using spin hyperpolarization technology and stable isotope labeling is presented. A glucose analog labeled with (13)C at all six positions increased the overall hyperpolarized imaging signal; deuteration at all seven directly bonded proton positions prolonged the spin-lattice relaxation time. High-bandwidth (13)C imaging overcame the large glucose carbon chemical shift dispersion. Hyperpolarized glucose images in the live rat showed time-dependent organ distribution patterns. At 8 s after the start of bolus injection, the inferior vena cava was demonstrated at angiographic quality. Distribution of hyperpolarized glucose in the kidneys, vasculature, and heart was demonstrated at 12 and 20 s. The heart-to-vasculature intensity ratio at 20 s suggests myocardial uptake. Cancer imaging, currently performed with (18)F-deoxyglucose positron emission tomography (FDG-PET), warrants further investigation, and glucose imaging could be useful in a vast range of clinical conditions and research fields where the radiation associated with the FDG-PET examination limits its use. PMID- 23109396 TI - Evaluation of superparamagnetic iron oxide nanoparticles (Endorem(r)) as a photoacoustic contrast agent for intra-operative nodal staging. AB - Detection of tumor metastases in the lymphatic system is essential for accurate staging of malignancies. Commercially available superparagmagnetic nanoparticles (SPIOs) accumulate in normal lymph tissue after injection at a tumor site, whereas less or no accumulation takes place in metastatic nodes, thus enabling lymphatic staging using MRI. We verify for the first time the potential of SPIOs, such as Endorem((r)) as a novel photoacoustic (PA) contrast agent in biological tissue. We injected five Wistar rats subcutaneously with variable amounts of Endorem((r)) and scanned the resected lymph nodes using a tomographic PA setup. Findings were compared using histology, vibrating sample magnetometry (VSM) and 14 T MR-imaging. Our PA setup was able to detect the iron oxide accumulations in all the nodes containing the nanoparticles. The distribution inside the nodes corresponded with both MRI and histological findings. VSM revealed that iron quantities inside the nodes varied between 51 +/- 4 and 11 +/- 1 ug. Nodes without SPIO enhancement did not show up in any of the PA scans. Iron oxide nanoparticles (Endorem((r))) can be used as a PA contrast agent for lymph node analysis and a distinction can be made between nodes with and nodes without the agent. This opens up possibilities for intra-operative nodal staging for patients undergoing nodal resections for metastatic malignancies. PMID- 23109397 TI - Gd2O3 nanoparticles: size-dependent nuclear magnetic resonance. AB - In this communication, we demonstrate that there is an optimum gadolinium oxide (Gd(2)O(3)) nanoparticle size of 2.3 nm; in the presence of Gd(2)O(3) particles smaller and larger than this critical size, the spin-lattice relaxation rate (T(1) = 1/r(1)) of water protons at 7.0 T drastically decreases. Since r(1) is directly related to the quality of magnetic resonance imaging, the results presented here have significant implications for clinical diagnostics. PMID- 23109398 TI - In vivo real-time lymphatic draining using quantum-dot optical imaging in mice. AB - The lymphatic system is essential for fluid regulation and for the maintenance of host immunity. However, in vivo lymph flow is difficult to track in real time, because of the lack of an appropriate imaging method. In this study, we combined macro-zoom fluorescence microscopy with quantum-dot (Qdot) optical lymphatic imaging to develop an in vivo real-time optical lymphatic imaging method that allows the tracking of lymph through lymphatic channels and into lymph nodes. After interstitial injection of Qdots in a mouse, rapid visualization of the cervical lymphatics and cervical lymph nodes was achieved. Real-time monitoring of the injected Qdots revealed that the cortex of the node enhanced first followed by a net-like pattern in the central portion of the node. Histology revealed that the rim and net-like enhancing regions corresponded to the subcapsular sinuses and medullary sinuses respectively. Additionally, multiplexed two-color real-time lymphatic tracking was performed with two different Qdots. With this real-time imaging system, we successfully tracked microscopic lymphatic flow in vivo. This method could have a potential impact for lymphatic research in visualizing normal or abnormal functional lymphatic flows. PMID- 23109400 TI - Synthesis, radiolabeling, and preclinical evaluation of a new octreotide analog for somatostatin receptor-positive tumor scintigraphy. AB - Radiolabeled somatostatin analogs have become powerful tools in the diagnosis and staging of neuroendocrine tumors, which express somatostatin receptors. The aim of this study was to evaluate a new somatostatin analog, 6-hydrazinopyridine-3 carboxylic acid-Ser3-octreotate (HYNIC-SATE) radiolabeled with 99mTc, using ethylenediamine-N,N'-diacetic acid and tricine as coligands, to be used as a radiopharmaceutical for the in vivo imaging of somatostatin receptor subtype 2 (SSTR2)-positive tumor. Synthesis of the peptide was carried out on a solid phase using a standard Fmoc strategy. Peptide conjugate affinities for SSTR2 were determined by receptor binding affinity on rat brain cortex and C6 cell membranes. Internalization rate of 99mTc-HYNIC-SATE was studied in SSTR2 expressing C6 cells that were used for intracranial tumor studies in rat brain. A reproducible in vivo C6 glioma model was developed in Sprague-Dawley rat and confirmed by histopathology and immunohistochemical analysis. Biodistribution and imaging properties of this new radiopeptide were also studied in C6 tumor-bearing rats. Radiolabeling was performed at high specific activities, with a radiochemical purity of >96%. Peptide conjugate showed high affinity binding for SSTR2 (HYNIC-SATE IC50=1.60+/-0.05 n m) and specific internalization into rat C6 cells. After administration of 99mTc-HYNIC-SATE in C6 glioma-bearing rats, a receptor specific uptake of radioactivity was observed in SSTR-positive organs and in the implanted intracranial tumor and rapid excretion from nontarget tissues via kidneys. 99mTc-HYNIC-SATE is a new receptor-specific radiopeptide for targeting SSTR2-positive brain tumor and might be of great promise in the scintigraphy of SSTR2-positive tumors. PMID- 23109403 TI - Preparation of sub-10 nm AgI nanoparticles and a study on their phase transition temperature. PMID- 23109404 TI - Inhibitors in childhood hemophilia A: genetic and treatment-related risk factors for development and eradication. AB - The development of neutralizing antibodies remains a serious complication of hemophilia replacement therapy. Factor VIII inhibiting antibodies (inhibitors) occur commonly following replacement therapy in hemophilia A, creating a significant burden of clinical disease. This article will review our current understanding of risk factors and their known impact on inhibitor development in previously untreated or minimally treated children with severe and mild hemophilia A. It will also explore how the most recently elucidated immunology of inhibitor development might hold important clues to more effective inhibitor eradication and prevention in this heavily impacted patient population. PMID- 23109401 TI - Redundant roles of PRDM family members in zebrafish craniofacial development. AB - BACKGROUND: PRDM proteins are evolutionary conserved Zn-Finger transcription factors that share a characteristic protein domain organization. Previous studies have shown that prdm1a is required for the specification and differentiation of neural crest cells in the zebrafish. RESULTS: Here we examine other members of this family, specifically prdm3, 5, and 16, in the differentiation of the zebrafish craniofacial skeleton. prdm3 and prdm16 are strongly expressed in the pharyngeal arches, while prdm5 is expressed specifically in the area of the forming neurocranium. Knockdown of prdm3 and prdm16 results in a reduction in the neural crest markers dlx2a and barx1 and defects in both the viscerocranium and the neurocranium. The knockdown of prdm3 and prdm16 in combination is additive in the neurocranium, but not in the viscerocranium. Injection of sub-optimal doses of prdm1a with prdm3 or prdm16 Morpholinos together leads to more severe phenotypes in the viscerocranium and neurocranium. prdm5 mutants have defects in the neurocranium and prdm1a and prdm5 double mutants also show more severe phenotypes. CONCLUSIONS: Overall, our data reveal that prdm3, 5, and 16 are involved in the zebrafish craniofacial development and that prdm1a may interact with prdm3, 5, and 16 in the formation of the craniofacial skeleton in zebrafish. PMID- 23109405 TI - Establishment of a search library about benzylisoquinoline alkaloids based on selective separation on the binaphthyl column and standard analysis on C18 column. AB - A search library about benzylisoquinoline alkaloids was established based on preparation of alkaloid fractions from Rhizoma coptidis, Cortex phellodendri, and Rhizoma corydalis. In this work, two alkaloid fractions from each herbal medicine were first prepared based on selective separation on the "click" binaphthyl column. And then these alkaloid fractions were analyzed on C18 column by liquid chromatography coupled with tandem mass spectrometry. Many structure-related compounds were included in these alkaloids fractions, which led to easy separation and good MS response in further work. Therefore, a search library of 52 benzylisoquinoline alkaloids was established, which included eight aporphine, 19 tetrahydroprotoberberine, two protopine, two benzyltetrahydroisoquinoline, and 21 protoberberine alkaloids. The information of the search library contained compound names, structures, retention times, accurate masses, fragmentation pathways of benzylisoquionline alkaloids, and their sources from three herbal medicines. Using such a library, the alkaloids, especially those trace and unknown components in some herbal medicine could be accurately and quickly identified. In addition, the distribution of benzylisoquinoline alkaloids in the herbal medicines could be also summarized by searching the source samples in the library. PMID- 23109406 TI - Apolipoproteins do not add prognostic information beyond lipoprotein cholesterol measures among individuals with obesity and insulin resistance syndromes: the ARIC study. AB - AIMS: There are conflicting guidelines regarding the measurement of apolipoproteins (apoB, apoA-1), in addition to standard lipoprotein cholesterol measures, for cardiovascular risk assessment among individuals with obesity or insulin resistance syndromes. This study aims to assess whether apolipoprotein assessments add prognostic information regarding coronary heart disease (CHD) risk beyond standard lipoprotein cholesterol measurements among individuals with obesity, diabetes, and the metabolic syndrome. METHODS AND RESULTS: We followed 9026 participants in the Atherosclerosis Risk in Communities (ARIC) study without cardiovascular disease at baseline (visit 4, 1996-99). We compared the associations of apoB, apoA-1, and their respective lipoprotein cholesterol measures with incident CHD events among individuals with and without obesity, the metabolic syndrome, or diabetes. Over a median follow up of 10.1 years, there were 903 CHD events. Among participants with obesity, the top quintiles of apoB (HR 2.00, 95% CI 1.40-2.85 compared with the bottom quintile) and the apoB/apoA-1 ratio (HR 2.47, 95% CI 1.53-4.01) did not demonstrate stronger associations with CHD than the top quintiles of non-high-density-lipoprotein cholesterol (non-HDL C) (HR 2.54, 95% CI 1.65-3.89) and the ratio of non-HDL-C/HDL-C (HR 4.28, 95% CI 2.29-8.03). Analogous findings were seen among patients with diabetes and the metabolic syndrome. In models adjusted for non-HDL-C and HDL-C, apoB (p = 0.94) and apoA-1 (p = 0.55) were not significantly associated with CHD events among those with obesity, in contrast to non-HDL-C and HDL-C (p = 0.02 for both). CONCLUSIONS: Among individuals with obesity and insulin resistance syndromes, apolipoproteins did not provide prognostic information regarding CHD risk beyond that provided by non-HDL-C and HDL-C. PMID- 23109407 TI - An inpatient lifestyle-change programme improves heart rate recovery in overweight and obese children and adolescents (LOGIC Trial). AB - BACKGROUND: Impaired heart rate recovery (HRR) is a strong predictor of overall mortality and cardio-metabolic risk. This study aimed at investigating (1) the effect of participation in a lifestyle-change programme for weight loss on HRR in overweight and obese children and (2) potential associations between the changes in one minute HRR (HRR1) and fitness, weight loss and cardio-metabolic risk. METHODS: The analysis included 429 individuals (169 boys) aged 13.9 +/- 2.3 years who participated in an inpatient weight loss programme for four to six weeks. At baseline and the end of the programme clinical investigations were performed, including blood analyses, blood pressure, anthropometry and maximal cycle ergometer exercise testing with continuous heart rate (HR) monitoring. HRR was calculated as the difference between the highest exercising HR and HR at one, three and five minutes post-exercise. RESULTS: Average body weight decreased from 90.7 +/- 22.5 kg to 81.9 +/- 20.0 kg and peak exercise capacity increased from 1.66 +/- 0.38 W/kg to 2.05 +/- 0.45 W/kg (p < 0.001). Cardio-metabolic risk factors improved (waist circumference, LDL-cholesterol, HOMA insulin ratio, blood pressure; p < 0.05). HDL-cholesterol and triglyceride levels remained unchanged. Compared with baseline, at follow-up the decline in HR was more pronounced (+32%, +18% and +11% for HRR1, HRR3 and HRR5; p < 0.001). Improvements in HRR1 were weakly correlated with changes in exercise capacity (p < 0.05; r < 0.13), but not with changes in body weight and cardio-metabolic risk factors. CONCLUSIONS: HRR considerably improved after an inpatient weight loss programme in overweight and obese children. This was not associated with improvements in body weight and cardio-metabolic risk; hence HRR would be a valuable addition to cardiovascular risk assessment in this group. PMID- 23109408 TI - Post-treatment levels of stem cell factor and hs-CRP in serum and crevicular fluid of chronic periodontitis subjects with type 2 diabetes. AB - OBJECTIVE: The purpose of this study is to evaluate the stem cell factor (SCF) and high sensitive C reactive protein (hs-CRP) concentration in gingival crevicular fluid (GCF) and serum of chronic periodontitis subjects with type 2 diabetes, and to evaluate the effect of nonsurgical periodontal therapy on their GCF and serum concentrations. MATERIALS AND METHODS: A total of (age and gender matched) 22 subjects were evaluated. Pre- and post-treatment levels of SCF and hs CRP in GCF and serum were measured and compared using enzyme linked immunosorbant assay. Clinical parameters including probing depth and clinical attachment level were also measured. Paired t-test was used to compare the before- and after treatment levels of the two molecules. RESULTS: A highly significant difference (P < 0.001) was found in the GCF and serum concentrations of SCF and hs-CRP before and after treatment. CONCLUSION: Our observations indicated that short term nonsurgical therapy resulted in a significant improvement in periodontal indices and in a marked decrease of SCF and hs-CRP serum and GCF levels. PMID- 23109409 TI - Electron acceptors based on an all-carbon donor-acceptor copolymer. PMID- 23109410 TI - Genistein and daidzein, typical soy isoflavones, inhibit TNF-alpha-mediated downregulation of adiponectin expression via different mechanisms in 3T3-L1 adipocytes. AB - SCOPE: Previous reports suggest that soy isoflavones have multiple biological functions and may help to restore adiponectin expression and insulin sensitivity. However, little is known about whether soy isoflavones can inhibit the downregulation of adiponectin and their molecular mechanisms. In the present study, we demonstrate that genistein (Gen) or daidzein (Dai) can significantly inhibit the downregulation of adiponectin expression via unique and different molecular mechanisms. METHODS AND RESULTS: Pretreatment with Gen or Dai significantly inhibited the tumor necrosis factor-alpha (TNF-alpha)-mediated downregulation of adiponectin expression in 3T3-L1 adipocytes. Gen inhibited the TNF-alpha-induced c-Jun-NH(2) -terminal kinase (JNK) signaling that is involved in adiponectin expression. Molecular docking studies based on JNK1 with Gen or Dai clearly supported our experimental results. However, Dai did not significantly inhibit JNK signaling. Dai did, however, inhibit the TNF-alpha induced downregulation of forkhead box-containg protein O1, which is also involved in adiponectin expression. CONCLUSION: These data demonstrate that: (i) both Gen and Dai significantly inhibit the TNF-alpha-mediated downregulation of adiponectin in adipocytes; (ii) Gen is an effective inhibitor of JNK activation, thus inhibiting the TNF-alpha-mediated downregulation of adiponectin; and (iii) Dai can inhibit the downregulation of adiponectin by restoring the TNF-alpha mediated reduction of forkhead box-containg protein O1 protein expression. PMID- 23109411 TI - Linear bactenecin analogs with cell selectivity and anti-endotoxic activity. AB - Bactenecin (Bac) is a 12-residue disulfide-linked antimicrobial peptide isolated from the granules of bovine neutrophils. In this study, to develop novel linear Bac analogs with cell selectivity and anti-endotoxic activity, we designed and synthesized a series of linear Bac analogs with amino acid substitution in Cys3,11 and/or Val6,7 of Bac. Among Bac analogs, some analogs (Bac-W, Bac-KW, Bac L, Bac-KL, Bac-LW, and Bac-KLW) with higher hydrophobicity showed the amalgamated property of cell selectivity and anti-endotoxic activity. Furthermore, Bac-W, Bac KW, Bac-LW, and Bac-KLW showed serum stability comparable with that of disulfide bonded Bac. Therefore, these Bac analogs (Bac-W, Bac-KW, Bac-LW, and Bac-KLW) can serve as promising antibiotics for the development of therapeutic agents for treatment against endotoxic shock and bacterial infection. In addition, our results suggest that a little increase in hydrophobicity may be responsible for the decreased cell selectivity of the multiple Arg-containing peptides (Bac-W, Bac-L, and Bac-LW) over the multiple Lys-containing peptides (Bac-KW, Bac-KL, and Bac-KLW). PMID- 23109412 TI - Adnexal torsion in third trimester of pregnancy. AB - The authors report an unusual case of adnexal torsion in a patient in the third trimester of pregnancy. A 32-year-old woman, gravida 1, para 0, in the 32nd week of gestation initially presented with clinical signs of acute appendicitis. On laparotomy, it was identified that a necrotic mass of the right adnexa and performed a unilateral salpingo-oophorectomy. The postoperative period was uneventful. In the 37th week of gestation, the labour was induced by fetal intrauterine growth restriction. She delivered vaginally, a healthy baby, with 2085 g and an Apgar score of 9 and 10 at the first and fifth minute, respectively. PMID- 23109413 TI - Secondary spontaneous pneumothorax: a rare complication of pulmonary embolism. AB - An 85-year-old lady presented with a left middle cerebral artery territory infarct. Several days into her admission she became hypoxic and haemodynamically unstable. A CT pulmonary angiogram showed bilateral pulmonary emboli, right-sided parenchymal cavitation due to infarction and an associated large pneumothorax. She was treated successfully with an intercostal drain and anticoagulation. This case describes the rare phenomenon of secondary spontaneous pneumothorax due to pulmonary infarction from pulmonary embolism. The factors associated with the development of infarcts from pulmonary thromboemboli are poorly understood although a number of predisposing conditions and pathological features have been suggested. Pulmonary infarction occurs in around 10% of cases of pulmonary emboli but the complication of secondary spontaneous pneumothorax would appear to be much less common. One should consider pulmonary embolism as the cause of pneumothorax where there is significant clinical suspicion. PMID- 23109414 TI - Painful ophthalmoplegia with simultaneous orbital myositis, optic and oculomotor nerve inflammation and trigeminal nucleus involvement in a patient with herpes zoster ophthalmicus. AB - Viral infection is a rare cause of painful ophthalmoplegia. We report on a 67 year-old patient who developed painful double vision after a vesicular skin rash on the left forehead. MRI disclosed simultaneous inflammatory lesions in all extraocular muscles, the second and third cranial nerve, as well as pathological signal intensity along the spinal trigeminal tract and nucleus within the medulla oblongata and the pons. Cerebrospinal fluid and serum tests for varicella zoster were positive. The patient was treated effectively with intravenous acyclovir and methylprednisolone. Simultaneous lesions in various neighbouring neural structures may be characteristic for the highly neurotropic behaviour of the herpesviridae and should be considered as a cause of painful ophthalmoplegia that can be depicted by appropriate imaging. PMID- 23109415 TI - Electrocautery-induced gangrene of the glans penis in a child following circumcision. PMID- 23109416 TI - Vitreopapillary and vitreomacular traction in proliferative Eales' disease. AB - Vitreoretinal interface alterations leading to vitreopapillary and vitreomacular traction in a 29-year case of proliferative Eales' disease is described for the first time. On fundus examination, an ellipsoid area of vitreomacular traction was noted temporal to the optic disc. A triangular-shaped infolding of the retina was observed superior to the fovea. Epiretinal membrane was seen temporal to the disc involving the macula. Imaging by spectral domain optical coherence tomography in the papillomacular bundle region revealed retinoschisis at the level of the outer nuclear layer and confirmed the presence of retinal infolding and epiretinal membrane in the macular area. Three-dimensional imaging documented vitreoretinal interface alterations exquisitely. PMID- 23109417 TI - Remote spinal epidural haematoma after spinal anaesthesia presenting with a 'spinal lucid interval'. AB - An obstetric patient who had no significant risk factors developed a spinal epidural haematoma remote from the site of needle puncture (for administration of spinal anaesthesia). The clinical deficits were manifest after recovery from the motor blockade had started a phenomenon that we have termed as a 'spinal lucid interval'. The patient developed flaccid paraplegia with a sharp sensory level and urinary retention. The patient underwent emergency laminectomy and evacuation of the haematoma. She gradually recovered near normal power and was ambulant independently and had normal sphincter function at follow-up. PMID- 23109418 TI - A suspected malignancy in osteolytic bone tumour of the thumb. AB - A 75-year-old male patient was referred to our institution owing to a painful and gradually developing lesion of the thumb with suspicious malignancy. The patient was suffering from a swollen, red, tender left thumb for 3 months. An old scar at the finger pulp could be traced from an old minor trauma. The x-ray revealed an osteolytic lesion in the terminal phalanx of the non-dominant hand that raised concerns of malignancy. Additional investigations such as ultrasound, CT-scan and MRI have been performed to get better insight to the lesion. After performing a biopsy, no malignant cells were found. Owing to the local destroying effect of the lesion and the clinical signs of the patient, the lesion was excised in total. The histopathological evaluation confirmed the tumour as a rare intraosseous epidermoid cyst. A bone graft after resection was not needed. The postoperative follow-up of the patient was uneventful. PMID- 23109419 TI - Isolation of Leclercia adecarboxylata from a wound infection after exposure to hurricane-related floodwater. AB - A man in his early 80s presented to our emergency department with painless redness and swelling in his right leg. One week prior, he cleaned up floodwater in his basement after Hurricane Irene passed the Mid-Atlantic region of the USA in August 2011. Physical examination included large purple bullae and raised concern for necrotising fasciitis. Wound culture revealed a polymicrobial infection including Leclercia adecarboxylata. PMID- 23109420 TI - Tiam1 regulates the Wnt/Dvl/Rac1 signaling pathway and the differentiation of midbrain dopaminergic neurons. AB - Understanding the mechanisms that drive the differentiation of dopaminergic (DA) neurons is crucial for successful development of novel therapies for Parkinson's disease, in which DA neurons progressively degenerate. However, the mechanisms underlying the differentiation-promoting effects of Wnt5a on DA precursors are poorly understood. Here, we present the molecular and functional characterization of a signaling pathway downstream of Wnt5a, the Wnt/Dvl/Rac1 pathway. First, we characterize the interaction between Rac1 and Dvl and identify the N-terminal part of Dvl3 as necessary for Rac1 binding. Next, we show that Tiam1, a Rac1 guanosine exchange factor (GEF), is expressed in the ventral midbrain, interacts with Dvl, facilitates Dvl-Rac1 interaction, and is required for Dvl- or Wnt5a induced activation of Rac1. Moreover, we show that Wnt5a promotes whereas casein kinase 1 (CK1), a negative regulator of the Wnt/Dvl/Rac1 pathway, abolishes the interactions between Dvl and Tiam1. Finally, using ventral midbrain neurosphere cultures, we demonstrate that the generation of DA neurons in culture is impaired after Tiam1 knockdown, indicating that Tiam1 is required for midbrain DA differentiation. In summary, our data identify Tiam1 as a novel regulator of DA neuron development and as a Dvl-associated and Rac1-specific GEF acting in the Wnt/Dvl/Rac1 pathway. PMID- 23109421 TI - Fbw7alpha and Fbw7gamma collaborate to shuttle cyclin E1 into the nucleolus for multiubiquitylation. AB - Cyclin E1, an activator of cyclin-dependent kinase 2 (Cdk2) that promotes replicative functions, is normally expressed periodically within the mammalian cell cycle, peaking at the G(1)-S-phase transition. This periodicity is achieved by E2F-dependent transcription in late G(1) and early S phases and by ubiquitin mediated proteolysis. The ubiquitin ligase that targets phosphorylated cyclin E is SCF(Fbw7) (also known as SCF(Cdc4)), a member of the cullin ring ligase (CRL) family. Fbw7, a substrate adaptor subunit, is expressed as three splice-variant isoforms with different subcellular distributions: Fbw7alpha is nucleoplasmic but excluded from the nucleolus, Fbw7beta is cytoplasmic, and Fbw7gamma is nucleolar. Degradation of cyclin E in vivo requires SCF complexes containing Fbw7alpha and Fbw7gamma, respectively. In vitro reconstitution showed that the role of SCF(Fbw7alpha) in cyclin E degradation, rather than ubiquitylation, is to serve as a cofactor of the prolyl cis-trans isomerase Pin1 in the isomerization of a noncanonical proline-proline bond in the cyclin E phosphodegron. This isomerization is required for subsequent binding and ubiquitylation by SCF(Fbw7gamma). Here we show that Pin1-mediated isomerization of the cyclin E phosphodegron and subsequent binding to Fbw7gamma drive nucleolar localization of cyclin E, where it is ubiquitylated by SCF(Fbw7gamma) prior to its degradation by the proteasome. It is possible that this constitutes a mechanism for rapid inactivation of phosphorylated cyclin E by nucleolar sequestration prior to its multiubiquitylation and degradation. PMID- 23109422 TI - Hsp70 is a novel posttranscriptional regulator of gene expression that binds and stabilizes selected mRNAs containing AU-rich elements. AB - The AU-rich elements (AREs) encoded within many mRNA 3' untranslated regions (3'UTRs) are targets for factors that control transcript longevity and translational efficiency. Hsp70, best known as a protein chaperone with well defined peptide-refolding properties, is known to interact with ARE-like RNA substrates in vitro. Here, we show that cofactor-free preparations of Hsp70 form direct, high-affinity complexes with ARE substrates based on specific recognition of U-rich sequences by both the ATP- and peptide-binding domains. Suppressing Hsp70 in HeLa cells destabilized an ARE reporter mRNA, indicating a novel ARE directed mRNA-stabilizing role for this protein. Hsp70 also bound and stabilized endogenous ARE-containing mRNAs encoding vascular endothelial growth factor (VEGF) and Cox-2, which involved a mechanism that was unaffected by an inhibitor of its protein chaperone function. Hsp70 recognition and stabilization of VEGF mRNA was mediated by an ARE-like sequence in the proximal 3'UTR. Finally, stabilization of VEGF mRNA coincided with the accumulation of Hsp70 protein in HL60 promyelocytic leukemia cells recovering from acute thermal stress. We propose that the binding and stabilization of selected ARE-containing mRNAs may contribute to the cytoprotective effects of Hsp70 following cellular stress but may also provide a novel mechanism linking constitutively elevated Hsp70 expression to the development of aggressive neoplastic phenotypes. PMID- 23109423 TI - p38alpha mitogen-activated protein kinase depletion and repression of signal transduction to translation machinery by miR-124 and -128 in neurons. AB - The p38alpha to p38delta mitogen-activated protein kinases (MAPKs) are central regulatory nodes coordinating acute stress and inflammatory responses. Their activation leads to rapid adjustment of protein synthesis, for instance translational induction of proinflammatory cytokines. The only known direct link of p38 to translation machinery is the MAPK signal-integrating kinase Mnk. Only p38alpha and p38beta transcripts are ubiquitously expressed. These mRNAs encode highly conserved proteins that equally phosphorylate recombinant Mnk1 in vitro. We discovered that expression of the p38alpha protein, but not the p38beta isoform, is suppressed in the brain. This is due to p38alpha depletion by two neuron-selective microRNAs (miRNAs), miR-124 and -128. Suppression of p38alpha protein was reversed by miR-124/-128 antisense oligonucleotides in primary explant neuronal cultures. Targeted p38alpha depletion reduced Mnk1 activation, which cannot be compensated by p38beta. Our research shows that p38alpha alone controls acute stress and cytokine signaling from p38 MAPK to translation machinery. This regulatory axis is greatly diminished in neurons, which may insulate brain physiology and function from p38alpha-Mnk1-mediated signaling. PMID- 23109424 TI - Defective autophagy and mTORC1 signaling in myotubularin null mice. AB - Autophagy is a vesicular trafficking pathway that regulates the degradation of aggregated proteins and damaged organelles. Initiation of autophagy requires several multiprotein signaling complexes, such as the ULK1 kinase complex and the Vps34 lipid kinase complex, which generates phosphatidylinositol 3-phosphate [PtdIns(3)P] on the forming autophagosomal membrane. Alterations in autophagy have been reported for various diseases, including myopathies. Here we show that skeletal muscle autophagy is compromised in mice deficient in the X-linked myotubular myopathy (XLMTM)-associated PtdIns(3)P phosphatase myotubularin (MTM1). Mtm1-deficient muscle displays several cellular abnormalities, including a profound increase in ubiquitin aggregates and abnormal mitochondria. Further, we show that Mtm1 deficiency is accompanied by activation of mTORC1 signaling, which persists even following starvation. In vivo pharmacological inhibition of mTOR is sufficient to normalize aberrant autophagy and improve muscle phenotypes in Mtm1 null mice. These results suggest that aberrant mTORC1 signaling and impaired autophagy are consequences of the loss of Mtm1 and may play a primary role in disease pathogenesis. PMID- 23109425 TI - Systematic identification of functional residues in mammalian histone H2AX. AB - The histone variant H2AX is a principal component of chromatin involved in the detection, signaling, and repair of DNA double-strand breaks (DSBs). H2AX is thought to operate primarily through its C-terminal S139 phosphorylation, which mediates the recruitment of DNA damage response (DDR) factors to chromatin at DSB sites. Here, we describe a comprehensive screen of 67 residues in H2AX to determine their contributions to H2AX functions. Our analysis revealed that H2AX is both sumoylated and ubiquitylated. Individual residues defective for sumoylation, ubiquitylation, and S139 phosphorylation in untreated and damaged cells were identified. Specifically, we identified an acidic triad region in both H2A and H2AX that is required in cis for their ubiquitylation. We also report the characterization of a human H2AX knockout cell line, which exhibits DDR defects, including p53 activation, following DNA damage. Collectively, this work constitutes the first genetic complementation system for a histone in human cells. Finally, our data reveal new roles for several residues in H2AX and define distinct functions for H2AX in human cells. PMID- 23109426 TI - Molecular mechanisms of N-formyl-methionyl-leucyl-phenylalanine-induced superoxide generation and degranulation in mouse neutrophils: phospholipase D is dispensable. AB - Phospholipase D (PLD), which produces the lipid messenger phosphatidic acid (PA), has been implicated in superoxide generation and degranulation in neutrophils. The basis for this conclusion is the observation that primary alcohols, which interfere with PLD-catalyzed PA production, inhibit these neutrophil functions. However, off-target effects of primary alcohols cannot be totally excluded. Here, we generated PLD(-/-) mice in order to reevaluate the involvement of PLD in and investigate the molecular mechanisms of these neutrophil functions. Surprisingly, N-formyl-methionyl-leucyl-phenylalanine (fMLP) induced these functions in PLD(-/ ) neutrophils, and these functions were suppressed by ethanol. These results indicate that PLD is dispensable for these neutrophil functions and that ethanol nonspecifically inhibits them, warning against the use of primary alcohols as specific inhibitors of PLD-mediated PA formation. The calcium ionophore ionomycin and the membrane-permeative compound 1-oleoyl-2-acetyl-sn-glycerol (OADG) synergistically induced superoxide generation. On the other hand, ionomycin alone induced degranulation, which was further augmented by OADG. These results demonstrate that conventional protein kinase C (cPKC) is crucial for superoxide generation, and a Ca(2+)-dependent signaling pathway(s) and cPKC are involved in degranulation in mouse neutrophils. PMID- 23109427 TI - A discrete ubiquitin-mediated network regulates the strength of NOD2 signaling. AB - Dysregulation of NOD2 signaling is implicated in the pathology of various inflammatory diseases, including Crohn's disease, asthma, and sarcoidosis, making signaling proteins downstream of NOD2 potential therapeutic targets. Inhibitor-of apoptosis (IAP) proteins, particularly cIAP1, are essential mediators of NOD2 signaling, and in this work, we describe a molecular mechanism for cIAP1's regulation in the NOD2 signaling pathway. While cIAP1 promotes RIP2's tyrosine phosphorylation and subsequent NOD2 signaling, this positive regulation is countered by another E3 ubiquitin ligase, ITCH, through direct ubiquitination of cIAP1. This ITCH-mediated ubiquitination leads to cIAP1's lysosomal degradation. Pharmacologic inhibition of cIAP1 expression in ITCH(-/-) macrophages attenuates heightened ITCH(-/-) macrophage muramyl dipeptide-induced responses. Transcriptome analysis, combined with pharmacologic inhibition of cIAP1, further defines specific pathways within the NOD2 signaling pathway that are targeted by cIAP1. This information provides genetic signatures that may be useful in repurposing cIAP1-targeted therapies to correct NOD2-hyperactive states and identifies a ubiquitin-regulated signaling network centered on ITCH and cIAP1 that controls the strength of NOD2 signaling. PMID- 23109428 TI - Effects of the Paf1 complex and histone modifications on snoRNA 3'-end formation reveal broad and locus-specific regulation. AB - Across diverse eukaryotes, the Paf1 complex (Paf1C) plays critical roles in RNA polymerase II transcription elongation and regulation of histone modifications. Beyond these roles, the human and Saccharomyces cerevisiae Paf1 complexes also interact with RNA 3'-end processing components to affect transcript 3'-end formation. Specifically, the Saccharomyces cerevisiae Paf1C functions with the RNA binding proteins Nrd1 and Nab3 to regulate the termination of at least two small nucleolar RNAs (snoRNAs). To determine how Paf1C-dependent functions regulate snoRNA formation, we used high-density tiling arrays to analyze transcripts in paf1Delta cells and uncover new snoRNA targets of Paf1. Detailed examination of Paf1-regulated snoRNA genes revealed locus-specific requirements for Paf1-dependent posttranslational histone modifications. We also discovered roles for the transcriptional regulators Bur1-Bur2, Rad6, and Set2 in snoRNA 3' end formation. Surprisingly, at some snoRNAs, this function of Rad6 appears to be primarily independent of its role in histone H2B monoubiquitylation. Cumulatively, our work reveals a broad requirement for the Paf1C in snoRNA 3'-end formation in S. cerevisiae, implicates the participation of transcriptional proteins and histone modifications in this process, and suggests that the Paf1C contributes to the fine tuning of nuanced levels of regulation that exist at individual loci. PMID- 23109429 TI - Piccolo NuA4-catalyzed acetylation of nucleosomal histones: critical roles of an Esa1 Tudor/chromo barrel loop and an Epl1 enhancer of polycomb A (EPcA) basic region. AB - Piccolo NuA4 is an essential yeast histone acetyltransferase (HAT) complex that targets histones H4 and H2A in nucleosome substrates. While Piccolo NuA4's catalytic subunit Esa1 alone is unable to acetylate nucleosomal histones, its accessory subunits, Yng2 and Epl1, enable Esa1 to bind to and to act on nucleosomes. We previously determined that the Tudor domain of Esa1 and the EPcA homology domain of Epl1 play critical roles in Piccolo NuA4's ability to act on the nucleosome. In this work, we pinpoint a loop within the Esa1 Tudor domain and a short basic region at the N terminus of the Epl1 EPcA domain as necessary for this nucleosomal HAT activity. We also show that this Esa1 Tudor domain loop region is positioned close to nucleosomal DNA and that the Epl1 EPcA basic region is in proximity to the N-terminal histone H2A tail, the globular region of histone H4, and also to nucleosomal DNA when Piccolo NuA4 interacts with the nucleosome. Since neither region identified is required for Piccolo NuA4 to bind to nucleosomes and yet both are needed to acetylate nucleosomes, these regions may function after the enzyme binds nucleosomes to disengage substrate histone tails from nucleosomal DNA. PMID- 23109430 TI - The forkhead transcription factor FOXM1 controls cell cycle-dependent gene expression through an atypical chromatin binding mechanism. AB - There are nearly 50 forkhead (FOX) transcription factors encoded in the human genome and, due to sharing a common DNA binding domain, they are all thought to bind to similar DNA sequences. It is therefore unclear how these transcription factors are targeted to specific chromatin regions to elicit specific biological effects. Here, we used chromatin immunoprecipitation followed by sequencing (ChIP seq) to investigate the genome-wide chromatin binding mechanisms used by the forkhead transcription factor FOXM1. In keeping with its previous association with cell cycle control, we demonstrate that FOXM1 binds and regulates a group of genes which are mainly involved in controlling late cell cycle events in the G(2) and M phases. However, rather than being recruited through canonical RYAAAYA forkhead binding motifs, FOXM1 binding is directed via CHR (cell cycle genes homology region) elements. FOXM1 binds these elements through protein-protein interactions with the MMB transcriptional activator complex. Thus, we have uncovered a novel and unexpected mode of chromatin binding of a FOX transcription factor that allows it to specifically control cell cycle-dependent gene expression. PMID- 23109431 TI - New insights into structural determinants for prostanoid thromboxane A2 receptor- and prostacyclin receptor-G protein coupling. AB - G protein-coupled receptors (GPCRs) interact with heterotrimeric G proteins and initiate a wide variety of signaling pathways. The molecular nature of GPCR-G protein interactions in the clinically important thromboxane A2 (TxA(2)) receptor (TP) and prostacyclin (PGI(2)) receptor (IP) is poorly understood. The TP activates its cognate G protein (Galphaq) in response to the binding of thromboxane, while the IP signals through Galphas in response to the binding of prostacyclin. Here, we utilized a combination of approaches consisting of chimeric receptors, molecular modeling, and site-directed mutagenesis to precisely study the specificity of G protein coupling. Multiple chimeric receptors were constructed by replacing the TP intracellular loops (ICLs) with the ICL regions of the IP. Our results demonstrate that both the sequences and lengths of ICL2 and ICL3 influenced G protein specificity. Importantly, we identified a precise ICL region on the prostanoid receptors TP and IP that can switch G protein specificities. The validities of the chimeric technique and the derived molecular model were confirmed by introducing clinically relevant naturally occurring mutations (R60L in the TP and R212C in the IP). Our findings provide new molecular insights into prostanoid receptor-G protein interactions, which are of general significance for understanding the structural basis of G protein activation by GPCRs in basic health and cardiovascular disease. PMID- 23109434 TI - In vitro tendon tissue development from human fibroblasts demonstrates collagen fibril diameter growth associated with a rise in mechanical strength. AB - BACKGROUND: Collagen-rich tendons and ligaments are important for joint stability and force transmission, but the capacity to form new tendon is poorly understood. In the present study, we investigated mechanical strength, fibril size, and structure during development of tendon-like tissue from adult human tenocytes (termed tendon constructs) in vitro over 5 weeks in 3D tissue culture. RESULTS: The constructs displayed large elongated tendon cells aligned along the tendon axis together with collagen fibrils that increased in diameter by 50% from day 14 to 35, which approaches that observed in adult human tendon in vivo. The increase in diameter was accompanied by a 5-fold increase in mechanical strength (0.9+/ 0.1 MPa to 4.9+/-0.6 MPa) and Young's modulus (5.8+/-0.9 MPa to 32.3+/-4.2 MPa), while the maximal strain at failure (16%) remained constant throughout the 5-week culture period. CONCLUSIONS: The present study demonstrates that 3D tendon constructs can be formed by isolated human tendon fibroblasts, and when these constructs are subjected to static self-generated tension, the fibrils will grow in size and strength approaching that of adult human tendon in vivo. PMID- 23109432 TI - Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. AB - Molecular mechanisms underlying sarcopenia, the age-related loss of skeletal muscle mass and function, remain unclear. To identify molecular changes that correlated best with sarcopenia and might contribute to its pathogenesis, we determined global gene expression profiles in muscles of rats aged 6, 12, 18, 21, 24, and 27 months. These rats exhibit sarcopenia beginning at 21 months. Correlation of the gene expression versus muscle mass or age changes, and functional annotation analysis identified gene signatures of sarcopenia distinct from gene signatures of aging. Specifically, mitochondrial energy metabolism (e.g., tricarboxylic acid cycle and oxidative phosphorylation) pathway genes were the most downregulated and most significantly correlated with sarcopenia. Also, perturbed were genes/pathways associated with neuromuscular junction patency (providing molecular evidence of sarcopenia-related functional denervation and neuromuscular junction remodeling), protein degradation, and inflammation. Proteomic analysis of samples at 6, 18, and 27 months confirmed the depletion of mitochondrial energy metabolism proteins and neuromuscular junction proteins. Together, these findings suggest that therapeutic approaches that simultaneously stimulate mitochondrogenesis and reduce muscle proteolysis and inflammation have potential for treating sarcopenia. PMID- 23109435 TI - Synthesis and application of Nalpha-Fmoc-Npi-4-methoxybenzyloxymethylhistidine in solid phase peptide synthesis. AB - The 4-methoxybenzyloxymethyl (MBom) group was introduced at the Npi-position of the histidine (His) residue by using a regioselective procedure, and its utility was examined under standard conditions used for the conventional and the microwave (MW)-assisted solid phase peptide synthesis (SPPS) with 9 fluorenylmethyoxycarbonyl (Fmoc) chemistry. The Npi-MBom group fulfilling the requirements for the Fmoc strategy was found to prevent side-chain-induced racemization during incorporation of the His residue even in the case of MW assisted SPPS performed at a high temperature. In particular, the MBom group proved to be a suitable protecting group for the convergent synthesis because it remains attached to the imidazole ring during detachment of the protected His containing peptide segments from acid-sensitive linkers by treatment with a weak acid such as 1% trifluoroacetic acid in dichloromethane. We also demonstrated the facile synthesis of Fmoc-His(pi-MBom)-OH with the aid of purification procedure by crystallization to effectively remove the undesired tau-isomer without resorting to silica gel column chromatography. This means that the present synthetic procedure can be used for large-scale production without any obstacles. PMID- 23109433 TI - CRL4(CDT2) targets CHK1 for PCNA-independent destruction. AB - CDT2 targets proteins involved in replication licensing (CDT1), cell cycle control (p21), and chromatin modification (SET8) for destruction by the CUL4 based E3 ligase (CRL4). CRL4(CDT2) recruits these substrates through interactions with chromatin-bound PCNA and ubiquitinates them exclusively on chromatin. Rereplication and G(2) cell cycle arrest are observed in CDT2-depleted cells. The rereplication phenotype has been attributed to an inability to destroy CDT1, but the molecular target important for G(2) cell cycle arrest in CDT2-depleted cells has not been identified. Here we identify CHK1 as a novel CRL4(CDT2) substrate and demonstrate that CHK1 activity is required for maintaining G(2) arrest in CDT2-depleted cells. We demonstrate that CRL4(CDT2) targets the activated form of CHK1 for destruction in the nucleoplasm rather than on chromatin and that this occurs in a PCNA-independent manner. Although both CRL1 and CRL4 ubiquitinate CHK1, we report that they bind CHK1 in distinct cellular compartments. Our study provides insight into how elevated CDT2 expression levels may provide tumors with a proliferative advantage. PMID- 23109436 TI - Importance of pharmacokinetics in the management of hemophilia. AB - Hemophilia A and hemophilia B are caused by congenital deficiency of factor VIII and factor IX, respectively, and may lead to recurrent, spontaneous bleeding into the muscles and joints resulting in disabling arthropathy. Effective management is available in the form of prophylactic infusions of clotting factor concentrates which have been demonstrated to prevent bleeding episodes and greatly improve the quality of life of these patients. Prophylaxis is, however, expensive. Usual dosing regimens rely on weight based calculations but dosing with an understanding of an individual's pharmacokinetic response has been demonstrated to be more effective in predicting clotting factor levels that protect against bleeding episodes. Standard pharmacokinetic studies require a prohibitive number of time sampling points but recent population or Bayesian pharmacokinetics can be used to provide an accurate estimation of an individual's pharmacokinetic response using a limited number of sampling time points. The use of population pharmacokinetics has the potential to greatly increase the use of pharmacokinetic dosing regimens and optimize the use of clotting factor concentrates in patients with hemophilia. PMID- 23109441 TI - Determination of sertraline in rat plasma by HPLC and fluorescence detection and its application to in vivo pharmacokinetic studies. AB - A simple, rapid, and sensitive HPLC method based on 9H-fluoren-9-ylmethyl chloroformate derivatization for the quantification of sertraline in rat plasma has been developed, requiring a plasma sample of only 0.1 mL, which was deproteinized and derivatized for 5 min in two single steps. The obtained derivative was stable at room temperature and was determined by HPLC using a fluorescence detector. The analytical column was a C(18) column and the mobile phase was acetonitrile and water (80:20, v/v). Calibration curves were linear in the range of 10-500 ng/mL. The limit of detection was approximately 3 ng/mL, and the lower limit of quantification was established at 10 ng/mL. The bias of the method was lower than 10%, and the within day as well as between day, relative standard deviations were lower than 12%. This analytical method was successfully applied to characterize sertraline pharmacokinetics in rats following intravenous (t(1/2) = 213 +/- 48 min, Cl = 43.1 +/- 8.7 mL/min, V(d) = 11560 +/- 1861 mL) and oral (C(max) = 156 +/- 76 ng/mL, t(max) = 63.8 +/- 16.3 min) administration of 2 and 5 mg, respectively. PMID- 23109444 TI - Polycystic liver disease: a clinical review. AB - Polycystic liver disease rarely occurs in isolation as part of autosomal dominant polycystic liver disease, but more commonly, it exists as an extra-renal manifestation of autosomal dominant polycystic kidney disease. The pathogenesis of polycystic liver disease involves defects in the primary cilium of the cholangiocyte, with genetic mutations that impair key proteins integral to the complex functioning of cilia. While most patients are asymptomatic and require no intervention aside from reassurance and genetic counseling, in a minority of patients, polycystic liver disease creates a myriad of symptoms from the compressive effects of enlarged cysts, and can even cause malnutrition and liver decompensation in the severest of cases. In patients with symptomatic disease, a variety of interventional radiology or surgical techniques can be considered, including aspiration with sclerotherapy of a dominant cyst, fenestration, segmental hepatic resection, and even liver transplantation. Although there are no curative medical options for polycystic liver disease, somatostatin analogs hold promise and have shown minimal efficacy in human studies. However, further research is needed to develop more efficacious medical treatments. PMID- 23109445 TI - Genomic determinants of hepatitis C virus antiviral therapy outcomes: toward individualized treatment. AB - Hepatitis C virus (HCV) is an important global health problem with an estimated prevalence of more than 170 million infected individuals worldwide. Currently, the standard antiviral therapy, based on pegylated interferon alpha and ribavirin, can achieve a virological response in only nearly 50% of the patients infected with HCV genotype 1, the most widely distributed globally. During the last years, relevant data from genome-wide association studies (GWAS) about the impact and contribution of the patient genomics on viral infection outcomes has suggested the possibility that an individualized antiviral therapy can be considered. In this review, we analyze the existing information on single nucleotide polymorphisms (SNPs) of several host genes and viral factors that influence, as a whole, the outcome of the standard antiviral therapy, and that might be used to predict an individualized antiviral response. We also discuss the clinical data within the most recent context of the triple antiviral therapy. PMID- 23109446 TI - Greater Celandine hepatotoxicity: a clinical review. AB - Herbal hepatotoxicity is a rare and poorly described disease because reported cases are mostly scattered and lack an appropriate causality assessment. We now describe in detail the clinical picture of herbal hepatotoxicity by extracts of Greater Celandine (GC), syn. Chelidonium majus L. from the Papaveraceae family, which contain more than 20 ingredients including various biologically active isoquinoline alkaloids. For this purpose, we analyzed and reviewed published cases of 16 patients from various European countries. In all patients, herbal hepatotoxicity was of probable and highly probable causality for GC, using the original and updated scale of CIOMS (Council for International Organizations of Medical Sciences). GC associated hepatotoxicity usually has an acute clinical course exhibiting a hepatocellular pattern of injury and is correlated to an idiosyncratic reaction with its metabolic subtype. Jaundice combined with high values of serum aminotransferases was present in virtually all cases with favourable outcome despite severe clinical course. In conclusion, GC hepatotoxicity is a typical herbal hepatotoxicity with a sound causality track for GC, but there is uncertainty regarding the respective causative compound(s). The present detailed review of GC hepatotoxicity may serve as an example for clinical causality assessments of future cases of liver injury due to other herbs. PMID- 23109447 TI - Genotype/subgenotype distribution of hepatitis B virus among hemodialysis patients with chronical hepatitis B. AB - INTRODUCTION: Hepatitis B virus (HBV) infection in hemodialysis (HD) patients is a major concern, but limited information exists on the HBV genotyping in patients on maintenance HD in Turkey. AIM: To investigate the genotype and subgenotype distribution of HBV in Turkish HD patients with chronic hepatitis B. MATERIAL AND METHODS: A total of 248 HBsAg positive patients undergoing long-term HD from all regions of Turkey were included in this study. HBV genotypes were determined by phylogenetic analysis and by genotyping tools. RESULTS: HBV DNA was detected in 94/248 (38%) of the patients. Among the study patients, genotype D of HBV was predominant (99%) and one patient (1%) was infected with genotype G. The majority (82%) of HBV genotype D branched into subgenotype D1, and also in ayw2 HBsAg subtype clusters in the phylogenetic tree. However, 10% and 8% of the strains branched into subgenotype D2 (also in ayw3 HBsAg subtype cluster) and subgenotype D3 clusters, respectively. CONCLUSION: In conclusion, HBV genotyping should be routinely applied to HD patients to establish a baseline. Determination of genotypes/subgenotypes of HBV may provide robust epidemiological data related to their circulation as well as their transmissibility. PMID- 23109448 TI - Validation and comparison of simple noninvasive models for the prediction of liver fibrosis in chronic hepatitis C. AB - INTRODUCTION: Although it is standard procedure in the evaluation of liver diseases, biopsy is an invasive method subject to sampling error and intra or inter-observer variability. Thus, surrogate markers of liver fibrosis have been proposed, with variable availability and accuracy. AIM: Validate and compare the performance of APRI and FIB-4 as predictors of liver fibrosis in HCV patients. MATERIAL AND METHODS: Cross-sectional study including patients with HCV-RNA (+) who underwent liver biopsy. Significant fibrosis was defined as METAVIR stage >= 2. The diagnostic performance of the models in predicting significant fibrosis were evaluated and compared by ROC curves. RESULTS: The study included 119 patients, mean age 43.7 +/- 10.6 years and 62% males. Significant fibrosis was identified in 41 patients. The AUROCs observed were: APRI = 0.793 +/- 0.047, FIB 4 = 0.811 +/- 0.045 and AST/ALT = 0.661 +/- 0.055 (P = 0.054 for APRI vs. AST/ALT, and P = 0.014 for FIB-4 vs. AST/ALT). Considering classic cutoffs, the PPV and NPV for APRI and FIB-4 were, respectively, 77% and 92% and 83% and 81%. Thirteen (19%) patients were misdiagnosed by APRI and 16 (18%) by FIB-4. By restricting the indication of liver biopsy to patients with intermediate values, it could have been correctly avoided in 47% and 63% of the patients with APRI and FIB-4, respectively. CONCLUSION: The models APRI and FIB-4 were superior to AST/ALT ratio in the diagnosis of significant fibrosis in chronic HCV infection. Even though the overall performance of APRI and FIB-4 was similar, a higher proportion of patients may be correctly classified by FIB-4. PMID- 23109449 TI - Epidemiological, clinical and laboratory features of chronic hepatitis B infection in a cohort of immigrant and Italian patients from Ferrara, Italy. AB - BACKGROUND: Italy has recently become a land of immigration. Two hundred and fifty thousand carriers are immigrants and chronic HBV infection is the prevalent form. Considering the elevated number of foreigners resident in our province and the potential risk of transmission to local people, we retrospectively investigated the patterns of chronic hepatitis B (CHB) in 154 patients (76 foreigners, 78 Italians) observed in our Institution, with regard to demographic and clinical/laboratory characteristics. RESULTS: The immigrants were younger (mean age 31 years) compared to Italians (51.5) and mainly came from East Europe. Regarding exposure to HBV, the intra-familial risk factor was most frequently observed in foreigners, compared to Italians (p = 0.03). Foreigners also showed a higher prevalence of HBeAg positive forms, HDV co-infection (7.9%) and abnormal ALT and/or HBV-DNA values, compared to Italians. HBeAg positivity was more associated with increased ALT (OR = 36.6, p = 0.001) than with elevated HBV viremia (OR = 6.5, p = 0.049); age was a protective factor (OR = 0.1; p = 0.014). No significant association was found between increased ALT and foreign nationality. The simultaneous presence of increased ALT and viremia was more frequent among foreigners, (OR = 7.6, p = 0,014) and increased with age (OR = 1.06, p = 0.013). Antiviral therapy was given in 7.8% of foreign citizens. CONCLUSION: Immigrants constitute a vulnerable population subgroup that would benefit from a more active approach regarding doctor patient relationship for early recognition of HBV and treatment programmes. PMID- 23109450 TI - Occult HBV infection among anti-HBc positive HIV-infected patients in apex referral centre, Eastern India. AB - BACKGROUND: The prevalence of occult HBV, defined by the presence of HBV DNA in individuals with antibodies to HBV core antigen and with absence of HBV surface antigen, but its clinical significance and virological features in HIV-infected patients is still unclear. AIM: To investigate the prevalence, clinical significance and molecular characterization of occult hepatitis B virus infection in ART-Naive HIV-positive individuals. MATERIAL AND METHODS: Among the 1077 HIV infected patients with different risk factors for HIV infection, 297 were HBsAg ve ART-naive, of them 112 was randomly selected for the study. HBV DNA was tested by in-house PCR and quantified by qPCR. Molecular characterization was performed by sequencing the envelope and overlapping polymerase genes. RESULTS: We found the prevalence of occult HBV to be 10.7% among a randomly selected group of HBsAg ve/antiHBc+ve HIV-infected patients. Overall 33.9% (38 of 112) of the patients were antiHBc positive indicating exposure to HBV infection. HBV DNA was detected in 12/38 (31.5%) antiHBc positive samples and 50% of them had CD4 T cell count < 200 cells/mm(3). HCV coinfection was low (2.7%). No surrogate marker for OBI could be identified. Presence of antiHBs antibodies did not rule out OBI. Liver biopsy in six cases showed varying stages of chronic hepatitis. Several mutations were detected but not the common immune escape mutant G145R. CONCLUSION: In conclusion the prevalence of OBI was significantly high among HIV coinfected patients, which highlights the importance of HBV DNA testing in these patients and indicates need for further prospective studies in larger cohorts to assess its clinical significance. PMID- 23109451 TI - IL28B polymorphisms predict the response to chronic hepatitis C virus infection treatment in a Mexican population. AB - INTRODUCTION: The treatment of hepatitis C virus (HCV) genotype 1 with ribavirin (RBV) and pegylated-interferon alpha (peg-IFNalpha) provides a low-level sustained virological response (SVR). Single nucleotide polymorphisms (SNPs) in the interleukin 28B (IL28B) gene have been identified as SVR predictors. Our aim was to establish an association between three IL28B SNPs (rs8099917, rs12979860, and rs8103142) and the peg-IFNalpha/RBV treatment response in a Mexican population cohort with chronic HCV. MATERIAL AND METHODS: A cohort study was performed with 83 chronic HCV patients at the Fundacion Clinica Medica Sur in Mexico City. All patients were treated with peg-IFNalpha and RBV. The data were analyzed by logistic regression, with adjustments for age, gender, and viral genotype, to determine any associations between the SNPs and the treatment response. RESULTS: In the study group of 83 HCV patients, the main genotype was genotype 1 (70%, n = 58) and the overall SVR was 32.53% (n = 27). In the HCV-1 group, SVR was 27%, whereas SVR was 44% in the HCV-2 group. We found an association between rs12979860 CC and SVR in a codominant model (OR = 4.83, 95% CI = 1.12-20.8, P = 0.033). There was no statistically significant association between SVR and rs8099917 or rs8103142. rs12979860 polymorphisms of CC, CT, and TT, were present in 24%, 41%, and 35% of patients, respectively. CONCLUSION: A Mexican HCV-1-infected population treated with peg-IFNalpha and RVB had a low SVR rate, which was associated with the SNP rs12979860 (CC). SVR was not associated with the SNPs rs8099917 or rs8103142. PMID- 23109452 TI - Health-related quality of life in Egyptian patients after liver transplantation. AB - INTRODUCTION-AIM: Health-Related Quality of Life (HRQOL) has become an important focus of patient care and clinical outcomes research with the improvement in patient and graft survival after liver transplantation (LT). The current study was designed to evaluate the post-transplant HRQOL profiles using the Liver Disease Quality of Life 1.0 (LDQOL 1.0) Questionnaire and demonstrate the possible effect of peri-transplant clinical covariates on these profiles. MATERIAL AND METHODS: Participants included pre-transplant group (waiting-list patients n = 50) and post-transplant group (mean 5 +/- 4 years after deceased or living donor LT n = 103) who were recruited from 3 specialized centers in Egypt. We applied the LDQOL 1.0 questionnaire; a 111-item containing the Short Form-36 version 2.0 (SF-36v2) as a generic component supplemented by 75 disease-specific items. The etiology of cirrhosis, co-morbidities, model for end-stage liver disease (MELD), Child-Pugh class and post-operative complications were analyzed. RESULTS: All recipients had significant higher HRQOL scores than patients in waiting-list using both questionnaire components. Recipients with pre-LT MELD >= 15, Child-Pugh class C, history of hepatocellular carcinoma (HCC) demonstrated low HRQOL scores. Recipients without post-operative surgical complications had a statistically better HRQOL using the disease-specific, but not the SF-36v2 component. On the other hand, both components demonstrated non-significant lower scores in recipients with rejection episodes, cytomegalovirus (CMV) infection and hepatitis C recurrence had compared to those without medical complications. CONCLUSION: Generally HRQOL improves dramatically after LT as assessed by LDQOL questionnaire. Moreover, combined questionnaires can provide accurate information about the possible impaired HRQOL post-LT due to pre-transplant disease severity and post-operative complications. PMID- 23109453 TI - Steatotic livers. Can we use them in OLTX? Outcome data from a prospective baseline liver biopsy study. AB - INTRODUCTION: Steatotic livers have been associated with greater risk of allograft dysfunction in liver transplantation. Our aim was to determinate the prevalence of steatosis in grafts from deceased donors in Chile and to assess the utility of a protocol-bench biopsy as an outcome predictor of steatotic grafts in our transplant program. MATERIAL AND METHODS: We prospectively performed protocol bench graft biopsies from March 2004 to January 2009. Biopsies were analyzed and classified by two independent pathologists. Steatosis severity was graded as normal from absent to < 6%; grade 1: 6-33%; grade 2: > 33-66% and grade 3: > 66%. RESULTS: We analyzed 58 liver grafts from deceased donors. Twenty-nine grafts (50%) were steatotic; 9 of them (16%) with grade 3. Donor age (p < 0.001) and BMI over 25 kg/m 2 (p = 0.012) were significantly associated with the presence of steatosis. There were two primary non-functions (PNF); both in a grade 3 steatotic graft. The 3-year overall survival was lower among recipients with macrovesicular steatotic graft (57%) than recipients with microvesicular (85%) or non-steatotic grafts (95%) (p = 0.026). CONCLUSION: Macrovesicular steatosis was associated with a poor outcome in this series. A protocol bench-biopsy would be useful to identify these grafts. PMID- 23109454 TI - Evaluation of the C3435T polymorphism in the MDR1 gene in patients with hepatocellular carcinoma. AB - INTRODUCTION: Considering the high prevalence of liver tumors and the impact on patient survival, a greater understanding of the biological behavior of those tumors if of great importance. The multidrug resistance gene (MDR1) may present as single nucleotide polymorphism (SNP) which can affect the expression and activity of P-glycoprotein (Pgp), and high expression of Pgp has been associated with a worse prognosis in affected patients. OBJECTIVE: To correlate the C3435T polymorphism in the MDR1 gene with the immunohistochemical expression of Pgp. MATERIAL AND METHODS: A total of 67 samples from patients with diagnosis of hepatocellular carcinoma (HCC), collected in the period from 2000 to 2009, were analyzed. The polymorphism in the MDR1 gene was determined by the technique of allele-specific real time PCR using TaqMan assay, and the expression of protein Pgp was evaluated by immunohistochemistry. RESULTS: Among the samples evaluated, 56 (83.6%) were from male patients and 11 (16.4%) from females. Mean age was 60.6 years (+/- 8.8), ranging from 37 to 85 years. The etiology of the HCC was related to hepatitis C virus infection (HCV) in 31 (46.3%) of cases, followed by hepatitis C virus infection + alcohol in 24 cases (35.8%), alcohol in 4 cases (6)%, hepatitis B virus (HBV) in 4 cases (6%) and other factors in 4 cases (6%). Liver transplantation was performed in 48 cases (71.6%) and hepatectomia in 19 cases (28.4%). The genotypes CC, CT and TT showed frequencies of 25.4%, 41.8% and 32.8%, respectively, and the allele frequencies were 46.3% for allele C and 53.7% for allele T. The expression of Pgp in over 75% of the cells was significantly more frequent in tumor tissue. On the other hand, a low expression of Pgp, in less than 25% of the cells, was significantly more frequent in non-tumor tissue. The Pgp expression in more than 50% of tumor cells of individuals with genotypes CC, CT and TT was 15.7%, 51.0% and 33.3%, respectively, and was significantly higher when in the presence of allele T (p = 0.002). CONCLUSION: The presence of the polymorphic allele T is related to increased expression of Pgp protein in patients with HCC. PMID- 23109455 TI - Response to different therapeutic approaches in Wilson disease. A long-term follow up study. AB - BACKGROUND AND AIMS: There are certain areas of uncertainty regarding the best therapeutic approach in patients diagnosed with Wilson Disease (WD). Our aim was to assess treatment response to different therapies in a cohort of WD patients followed in a single center. MATERIAL AND METHODS: This is an observational, descriptive study in which clinical, laboratory and imaging data are reviewed in a series of 20 WD patients with a median follow-up of 14 years. Type of presentation, treatment used, biochemical and copper homeostasis parameters were elicited. RESULTS: Median age at diagnosis was 22 years. The most frequent form of presentation was hepatic (n = 10, 50%; mean age: 21.5 years), followed by neurological (25%; mean age: 34.5 years) and mixed (15%). The initial treatment in both symptomatic and asymptomatic patients at diagnosis was d-penicillamine in 90% and Zinc (Zn) in 10%, respectively. Patients who were maintained on d penicillamine for the whole period had complete biochemical normalization (baseline ALT: 220 IU/l; last follow up 38 IU/l). In contrast, patients in whom d penicillamine was switched to Zn, irrespective of the cause, did not show a complete biochemical remission (baseline ALT: 100 IU/l vs. 66 IU/l at last follow up). CONCLUSIONS: Treatment was found to be effective in most cases regardless of the drug used. However, side effects were common in those treated with d penicillamine agents, and required switching to zinc. Therapy with zinc was well tolerated and appeared to have a good efficacy. However, in 33%, a complete normalization of liver enzymes was never reached. PMID- 23109456 TI - Prognostic factors associated with in-hospital mortality in patients with spontaneous bacterial peritonitis. AB - INTRODUCTION: Spontaneous bacterial peritonitis (SBP) is associated with a high in-hospital mortality rate ranging from 20-40%. The model for end-stage liver disease (MELD) has been suggested as a predictor of in-hospital mortality in patients with SBP. However, the accuracy of the MELD has been questioned, and the integrated MELD (iMELD) score, which incorporates age and serum sodium to the previous model, has been proposed to improve prognostic accuracy. The iMELD has not yet been evaluated in patients with SBP. AIM: To evaluate the accuracy of iMELD and MELD scores in predicting in-hospital mortality in patients with SBP and to identify other prognostic factors of mortality in this group of patients. RESULTS: Of 40 patients analyzed, 65% were male, 50% had hepatitis C, and 27.5% had hepatocellular carcinoma. Mean age was 55.6 years; 25.7% were classified as Child-Pugh class B, and 74.3% as class C. Mean scores were 46.0 and 19.9 for iMELD and MELD, respectively. In-hospital mortality was 40%. Univariate analysis showed that total bilirubin, creatinine, MELD and iMELD scores were significantly associated with in-hospital mortality. The prognostic accuracy was 80% and 77% for iMELD and MELD scores, respectively. CONCLUSION: In conclusion, bilirubin, creatinine, MELD and iMELD were predictors of in-hospital mortality in cirrhotic patients with SPB. iMELD was slightly more accurate than MELD in this group of patients. PMID- 23109457 TI - Splenectomy in cirrhosis with hypersplenism: improvement in cytopenias, Child's status and institution of specific treatment for hepatitis C with success. AB - INTRODUCTION: Hypersplenism in cirrhosis is not infrequent and may compromise with quality of life and therapy. Splenectomy is a therapeutic option, but information on results of splenectomy is scarce. MATERIAL AND METHODS: Consecutive patients with cirrhosis who underwent splenectomy between 2001-2010 were included in the study. Safety, efficacy of splenectomy and subsequent influence on therapy were evaluated. RESULTS: Thirty three patients (mean age 30.9 +/- 11.6 years, 19 men, viral 48.5%, autoimmune 15.1%, cryptogenic 36.4%) underwent splenectomy. Twenty were Child's A, 13 Child's B. Twenty patients had > 6 months follow up. Common indications were inability to treat with interferon, transfusion-dependent anemia, recurrent mucosal bleeds, and large spleen compromising quality of life. Median hospital stay was 7 (4-24) days. There was no splenectomy related mortality. Twenty three (70%) patients had post-operative complications, most commonly infections. Two patients required percutaneous drainage of post-operative collections, and 1 needed re-exploration for intra abdominal bleed. Subsequent to splenectomy platelet count (44,000 to 151,000/mm 3 , p < 0.01) and TLC (2,500 to 13,400/mm 3 , p < 0.01) had sustained increase in all patients except one. Five HCV cirrhotics completed interferon and ribavirin therapy, 4 achieved sustained viral response. The quality of life improved and there was no recurrence of infections, mucosal bleed or anemia requiring transfusions in any patient. In patients on long term follow up (median duration 27 months), the median Child's score improved from 6 at baseline to 5 at follow up (p < 0.05). CONCLUSIONS: Splenectomy was safe and effective in patients with cirrhosis, and improved therapeutic options as well as Child's score. PMID- 23109458 TI - Protective role of standardized Feronia limonia stem bark methanolic extract against carbon tetrachloride induced hepatotoxicity. AB - OBJECTIVE: This study evaluates hepatoprotective potential of Feronia limonia stem bark (FSB) extracts and fractions using experimental models. MATERIALS AND METHODS: Activity levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and cell viability were evaluated in HepG2 cells treated with carbon tetrachloride (CCl4) in presence or absence of FL extracts or fractions. Also, plasma markers of hepatic damage, hepatic antioxidants, lipid peroxidation and histopathological alterations were assessed in rats treated with CCl4 alone or in combination with 200 or 400 mg/kg bodyweight (BW) of FSB-7 or 25 mg/kg BW of silymarin. RESULTS: In vitro co-supplementation of FSB extracts or fractions recorded varying degree of hepatoprotective potentials. Also, pre supplementation of FSB methanolic extract (FSB-7) followed by CCl4 treatment significantly prevented hepatic damage and depletion of cellular antioxidants. Also, CCl4+ FSB-7 group showed minimal distortion in the histoarchitecture of liver and results were comparable to that of CCl4+ silymarin treated rats. CONCLUSION: This inventory is the first scientific report on hepatoprotective potential of FSB methanolic extract. PMID- 23109459 TI - Alcohol effects on liver diseases: good or bad buddy?. PMID- 23109460 TI - An unusual cause of portal cavernomatosis. PMID- 23109462 TI - Spontaneous bacterial peritonitis caused by Listeria monocytogenes: a case report and literature review. AB - Spontaneous bacterial peritonitis (SBP) is a common and often serious complication of long standing ascites in the presence of advanced liver disease.1 We report a case of a 51- year-old man with alcoholic cirrhosis admitted to our department with jaundice, ascitis and lower limbs edema. A diagnosis of spontaneous bacterial peritonitis was made and empiric therapy with cefotaxime was prescribed with no response. Three days later Listeria monocytogenes was detected in peritoneal fluid culture and amoxicillin was initiated according to in vitro sensibility test. Despite adequate antibiotic therapy, the patient died one week later. PMID- 23109461 TI - Porphyria cutanea tarda in an HCV-positive liver transplant patient: a case report. AB - INTRODUCTION: Porphyria cutanea tarda (PCT) is the most common type of porphyria. The strong association between PCT and hepatitis C virus (HCV) infection is well established. Although antiviral treatment of chronic hepatitis C may improve PCT in some cases, de novo onset of PCT has been observed in patients under- going peginterferon/ribavirin treatment. We present a rare case of a genotype 3 HCV positive liver transplant recipient who developed PCT during antiviral treatment and discuss its probable etiopathogenesis. CASE PRESENTATION: A genotype 3 HCV positive liver transplant recipient, a 42-year-old man, was treated with peginterferon alfa-2a (180 ug/week) combined with ribavirin (1,200 mg/day) for recurrence of HCV infection after liver transplantation. He presented with hyperferritinemia but tested negative for genetic hemochromatosis (C282Y and H63D mutations). During antiviral therapy, he developed skin lesions on his hands characterized by vesicles and erosions consistent with PCT. PCT was confirmed by skin biopsy and elevated urinary uroporphyrin levels (1,469 mg/24 h). He was treated with chloroquine (200 mg) twice weekly, resulting in gradual regression of the skin lesions. Antiviral treatment was stopped after 48 weeks, and the patient achieved a sustained virological response. In conclusion, we report an extremely rare case of PCT in a genotype 3 HCV-positive liver transplant patient treated with antiviral therapy. We believe that the combination of HCV genotype 3 infection; hemolysis due to ribavirin treatment; and increased plasma levels of cytokines, such as IL-6 and TNFalpha, could have altered the patient's iron metabolism and thus caused PCT. PMID- 23109463 TI - Dorsal root ganglionopathy in a hepatitis C patient: a case report. AB - We report an unusual clinical presentation of dorsal root ganglionopathy in a hepatitis C patient with negative cryoglobulins characterized by both motor and sensory symptoms. This mixed clinical picture in a hepatitis C patient is rare but should be considered a potential complication of HCV infection. PMID- 23109464 TI - Thyroid-like cholangiocarcinoma of the liver: an unusual morphologic variant with follicular, trabecular and insular patterns. AB - We report the case of a 26-year-old woman with a 19 cm malignant hepatic neoplasm with morphological features that closely resembled a follicular thyroid carcinoma. Despite this, it was interpreted as a cholangiocarcinoma due to the absence of a primary thyroid tumor and the lack of thyroglobulin and TTF-1 immunoreactivity by the hepatic tumor. The left hepatic lobectomy specimen showed an encapsulated and multinodular gray-white mass with cystic and hemorrhagic areas. Microscopically, it displayed predominant macro and microfolicullar patterns with focal solid, trabecular and insular areas. The small and distended follicles contained a colloid-like secretion and were lined by low cuboidal cells with scant cytoplasm, round or oval hyperchromatic nuclei with fine chromatin. The solid areas, trabecular and insular structures were similar to those of follicular or papillary thyroid carcinomas. In addition, some of the neoplastic cells had clear nuclei with occasional grooves. The tumor was positive for cytokeratin (CK) 7, CK 19 and CD138, and negative for TTF-1, thyroglobulin, Hepar 1, Glypican-3, alpha-fetoprotein and neuroendocrine markers. A thyroid neoplasm was excluded clinically and by ultrasound and computed tomography. Although, the residual hepatic parenchyma was initially not cirrhotic, the patient eventually developed cryptogenic cirrhosis. The patient received adjuvant chemotherapy and died of metastatic disease 18 months after surgery. The thyroid-like pattern broadens the morphologic spectrum of cholangiocarcinoma. PMID- 23109465 TI - Elevated alanine aminotransferase levels are associated with impaired fasting glucose and type 2 diabetes in obese women. PMID- 23109466 TI - Increased mortality in chronic HCV infection. PMID- 23109467 TI - Molecular and immunological characterization of wheat Serpin (Tri a 33). AB - SCOPE: Several wheat proteins are responsible for food and respiratory allergies. Due to their large polymorphism, the allergenic potential of a number of them has not yet been precisely established. The aim of this work was to perform a thorough assessment of serpin (Tri a 33) allergenicity. METHODS AND RESULTS: Recombinant wheat Serpin-Z2B isoform (rSerpin-Z2B) was expressed in Escherichia coli. Synchrotron radiation circular dichroism data indicated that the recombinant serpin contains slightly more beta-strands than alpha-helix structures. IgE reactivity of sera from 103 patients with food allergy and 29 patients with Baker's asthma was evaluated using ELISA, a model of basophil activation and linear epitope mapping (Pepscan). Twenty percent of patients with food allergy to wheat and 31% of those with Baker's asthma displayed rSerpin-Z2B specific IgE in ELISA. The protein was able to induce IgE-dependent basophil degranulation. The Pepscan experiment identified four regions involved in IgE binding to serpin. Heating the protein induced its irreversible denaturation and impaired IgE binding, revealing the predominance of conformational epitopes. CONCLUSION: This study confirms wheat serpin allergenicity and shows that recombinant serpin may be a marker of a broad spectrum of sensitization to wheat proteins. PMID- 23109468 TI - Recommendations for the use of mechanical circulatory support: device strategies and patient selection: a scientific statement from the American Heart Association. PMID- 23109469 TI - How do you recruit and retain a prebirth cohort? Lessons learnt from growing up in New Zealand. AB - Growing Up in New Zealand, a longitudinal study following nearly 7,000 children, has faced some unique challenges in identifying, enrolling, and retaining a large and diverse antenatal cohort. Identification of a study region with population demographics that enabled enrollment of an appropriately diverse sample was required as was intensive community and participant engagement in order to promote the study. Complementary methods used included direct engagement with prospective participants and the community and indirect engagement via media. Thus far, retention rates above 95% have been achieved by maintaining a multimethod approach that includes valuing participants and building trusting relationships, strong brand recognition, community engagement, maintenance of participant contact and location records, ensuring high-quality interactions between the participants and the study, pretesting measures and methods prior to the main cohort, and using participant feedback to inform the measures and methods used in future waves of data collection. PMID- 23109470 TI - Determining the best graft-sealant combination for skull base repair using a soft tissue in vitro porcine model. AB - BACKGROUND: The purpose of this work was to compare the absolute breaking strength of various soft tissue skull base (SB) repairs in an in vitro porcine model. METHODS: A burst pressure (BP) testing system was designed using an axial loading force to create increasing hydraulic pressure. Defects measuring 0.5 * 0.5 cm were created in fascia lata samples. Defects were repaired using various grafts (pericranium and 2 different dural substitutes, Alloderm((r)) and Durasis((r))) measuring 1.0 * 1.0 cm to cover the deficient area. Grafts were further reinforced onto the fascia background with either fibrin glue (Tisseel((r))) or hydrogel sealant (DuraSealTM). Each combination of graft and sealant was conducted 6 times and tested 24 hours after the repair. RESULTS: The mean BP (+/-standard deviation [SD]) were as follows: DuraSealTM-Alloderm, 12.5 +/- 5.8 mmHg; DuraSealTM-Durasis, 21.8 +/- 20.7 mmHg; DuraSealTM-pericranium, 44.7 +/- 30.1 mmHg; Tisseel-Alloderm, 30.6 +/- 26.3 mmHg; Tisseel-Durasis, 15.8 +/- 18.6 mmHg; and Tisseel-pericranium, 95.5 +/- 86 mmHg. One-way analysis of variance showed that the strongest type of repair was Tisseel-pericranium when adjusting for the others (p < 0.0001). The difference in mean BP of repair with DuraSealTM vs Tisseel((r)) was not statistically significant (p = 0.22). Comparing sealants, the use of Alloderm((r)) or Durasis((r)) decreased the strength of the repair in comparison to pericranium (p < 0.0001). Bonferroni analysis showed a significant difference between pericranium and Alloderm((r)) (p < 0.05) and between pericranium and Durasis((r)) (p < 0.05) but not between Alloderm((r)) and Durasis((r)) (p > 0.05). CONCLUSION: In this model, the strongest type of repair (pressure 6 times higher than normal intracranial pressure) was the combination of Tisseel((r))-pericranium. Our data will help guide surgeons who repair SB defects to choose the best graft and sealant. PMID- 23109471 TI - Biodistribution of intact fluorescent CdSe/CdS/ZnS quantum dots coated by mercaptopropionic acid after intravenous injection into mice. AB - Semiconductor quantum dots (QD) have been widely used for fluorescent bioimaging. However their biosafety has attracted increasing attention, since the data about their in vivo behavior in biological systems are still limited. In this paper we have investigated the short- and long-term biodistribution of intact fluorescent CdSe/CdS/ZnS QD coated by 3-mercaptopropionic acid in mice. The results showed that intravenously injected QD accumulated mainly in the lungs, liver and spleen and were retained in these tissues for over 22 days. QD caused signs of acute toxicity in mice including death. The investigated QD possibly caused vascular thrombosis. The results of a toxicological assay indicated that some histopathological changes occurred in the lung tissue after the injection of QD. Our study highlights the need for careful evaluation of QD safety before their use in biological applications. PMID- 23109472 TI - Hemophilia and prophylaxis. AB - Clinical experience over decades and numerous retrospective and, recently, also prospective studies clearly demonstrate that prophylactic treatment, albeit much more expensive, is superior to on-demand treatment regardless of whether the outcome is number of joint- or life-threatening bleeds or arthropathy optimal prophylactic treatment should be started early (primary prophylaxis) but various opinions exist on the model. The optimal model should be to individualize prophylaxis taking into account the bleeding phenotype and the individual susceptibility to arthropathy and further develop monitoring by global coagulation assays and pharmacokinetic parameters. This review covers proof of concept of primary prophylaxis in children, comparisons between prophylaxis and on demand treatment, and future trends of prophylactic treatment of hemophilia. PMID- 23109473 TI - Development of a fast sample treatment for the analysis of free and bonded sterols in human serum by LC-MS. AB - The analysis of sterols in biological fluids allows the clinical study of cholesterol related diseases. This research is focused on reducing the sample processing time of the determination of free and bonded sterols in human serum. Ten sterols were studied: cholesterol precursors (desmosterol, lanosterol, and cholestanol); phytosterols (stigmasterol, campesterol, sitosterol, and sitostanol) and oxysterols (7-alpha-hydroxy-4-cholesten-3-one, 24 hydroxycholesterol, and 27-hydroxycholesterol). Ultrasound assistance was used to diminish the reaction time during the alkaline hydrolysis for determining total sterols. Different retention mechanisms of solid-phase extraction were compared, two reversed-phase sorbents DSC-18 and polymeric Oasis-HLB and a novel zirconia coated silica phase. DSC-18 and zirconia-coated silica were the most suitable sorbents to analyze these metabolites. The resulting extracts were analyzed by liquid chromatography coupled to mass spectrometry. The analytical parameters were determined and better values were observed with DSC-18 cartridges for most sterols. LOQ were in the low ng/mL level. Recoveries were in the range 85-99%. Average intermediate precision was 15%. Accuracy for both cartridges was more than 92%. Zirconia-coated silica showed better performance for the oxysterols, with recoveries around 90%. The procedure allows the determination of free and bonded sterol precursors, phytosterols, and oxysterols in human serum. PMID- 23109474 TI - Identification of the verruculogen prenyltransferase FtmPT3 by a combination of chemical, bioinformatic and biochemical approaches. AB - Previous studies showed that verruculogen is the end product of a biosynthetic gene cluster for fumitremorgin-type alkaloids in Aspergillus fumigatus and Neosartorya fischeri. In this study, we isolated fumitremorgin A from N. fischeri. This led to the identification of the responsible gene, ftmPT3, for O prenylation of an aliphatic hydroxy group in verruculogen. This gene was found at a different location in the genome of N. fischeri than the identified cluster. The coding sequence of ftmPT3 was amplified by fusion PCR and overexpressed in Escherichia coli. The enzyme product of the soluble His(8)-FtmPT3 with verruculogen and dimethylallyl diphosphate (DMAPP) was identified unequivocally as fumitremorgin A by NMR and MS analyses. K(M) values of FtmPT3 were determined for verruculogen and DMAPP at 5.7 and 61.5 MUM, respectively. Average turnover number (k(cat)) was calculated from kinetic parameters of verruculogen and DMAPP to be 0.069 s(-1). FtmPT3 also accepted biosynthetic precursors of fumitremorgin A, for example, fumitremorgin B and 12,13-dihydroxyfumitremorgin C, as substrates and catalyses their prenylation. PMID- 23109476 TI - Knowledge differentially supports memory for nutrition information in later life. AB - We examined the extent to which prior knowledge about nutrition moderates age differences in remembering newly learned nutrition information. Younger and older adults with varying levels of knowledge read an article on fats and cholesterol and then completed a memory task. Participants responded to statements that were or were not-presented in the text, which enabled us to examine memory accuracy overall as well as hits and memory errors. Results showed age differences were present in the low-knowledge group but not in the high-knowledge group. Findings illustrate the importance of knowledge for older adults' memory for health information. PMID- 23109475 TI - Isothiocyanate concentrations and interconversion of sulforaphane to erucin in human subjects after consumption of commercial frozen broccoli compared to fresh broccoli. AB - SCOPE: Sulforaphane (a potent anticarcinogenic isothiocyanate derived from glucoraphanin) is widely considered responsible for the protective effects of broccoli consumption. Broccoli is typically purchased fresh or frozen and cooked before consumption. We compared the bioavailability and metabolism of sulforaphane from portions of lightly cooked fresh or frozen broccoli, and investigated the bioconversion of sulforaphane to erucin. METHODS AND RESULTS: Eighteen healthy volunteers consumed broccoli soups produced from fresh or frozen broccoli florets that had been lightly cooked and sulforaphane thio-conjugates quantified in plasma and urine. Sulforaphane bioavailability was about tenfold higher for the soups made from fresh compared to frozen broccoli, and the reduction was shown to be due to destruction of myrosinase activity by the commercial blanching-freezing process. Sulforaphane appeared in plasma and urine in its free form and as several thio-conjugates forms. Erucin N-acetyl-cysteine conjugate was a significant urinary metabolite, and it was shown that human gut microflora can produce sulforaphane, erucin, and their nitriles from glucoraphanin. CONCLUSION: The short period of blanching used to produce commercial frozen broccoli destroys myrosinase and substantially reduces sulforaphane bioavailability. Sulforaphane was converted to erucin and excreted in urine, and it was shown that human colonic flora were capable of this conversion. PMID- 23109477 TI - Dozens of scientists quit Texas cancer agency review panels, claiming that business interests trumped merit. PMID- 23109478 TI - NHS in England paid out L3.1bn in compensation claims linked to maternity care in past decade. PMID- 23109480 TI - High Court upholds suspension of doctor whose failings as expert witness were "serious and dangerous". PMID- 23109481 TI - US firm accused of manipulating journal articles and paying millions to authors. PMID- 23109482 TI - Tamiflu: the battle for secret drug data. PMID- 23109483 TI - Clinical trial data for all drugs in current use. PMID- 23109484 TI - Open letter to Roche about oseltamivir trial data. PMID- 23109485 TI - Academics plea for politicians to tackle problem of missing data. PMID- 23109486 TI - Tailor-made anion-exchange membranes for salinity gradient power generation using reverse electrodialysis. AB - Reverse electrodialysis (RED) or blue energy is a non-polluting, sustainable technology for generating power from the mixing of solutions with different salinity, that is, seawater and river water. A concentrated salt solution (e.g., seawater) and a diluted salt solution (e.g., river water) are brought into contact through an alternating series of polymeric anion-exchange membranes (AEMs) and cation-exchange membranes (CEMs), which are either selective for anions or cations. Currently available ion-exchange membranes are not optimized for RED, whereas successful RED operation notably depends on the used ion exchange membranes. We designed such ion-exchange membranes and for the first time we show the performance of tailor-made membranes in RED. More specifically, we focus on the development of AEMs because these are much more complex to prepare. Herein we propose a safe and more environmentally friendly method and use halogenated polyethers, such as polyepichlorohydrin (PECH) as the starting material. A tertiary diamine (1,4-diazabicyclo[2.2.2]octane, DABCO) was used to introduce the ion-exchange groups by amination and for simultaneous cross-linking of the polymer membrane. Area resistances of the series of membranes ranged from 0.82 to 2.05 Omega cm2 and permselectivities from 87 to 90 %. For the first time we showed that tailor-made ion-exchange membranes can be applied in RED. Depending on the properties and especially membrane thickness, application of these membranes in RED resulted in a high power density of 1.27 W m-2, which exceeds the power output obtained with the commercially available AMX membranes. This shows the potential of the design of ion-exchange membranes for a viable blue energy process. PMID- 23109487 TI - Transferrin immunoextraction for determination of carbohydrate-deficient transferrin in human serum by capillary zone electrophoresis. AB - CZE-based assays for carbohydrate-deficient transferrin (CDT) in which serum is mixed with an Fe(III) ion-containing solution prior to analysis are effective approaches for the determination of CDT in patient samples. Sera of patients with progressed diseases, however, are prone to interferences comigrating with transferrin (Tf) that prevent the proper determination of CDT by CZE in these samples. The need of a simple and economic approach to immunoextract Tf from human serum prompted us to investigate the use of a laboratory-made anti-Tf spin column containing polyclonal rabbit anti-human Tf antibodies linked to Sepharose 4 Fast Flow beads. This article reports extraction column manufacturing and column characterization with sera having normal and elevated CDT levels. The developed procedure was applied to a number of relevant hepatology and dialysis patient samples and could thereby be shown to represent an effective method for extraction and concentration of all Tf isoforms. Furthermore, lipemic sera were delipidated using a mixture of diisopropyl ether and butanol prior to immunoextraction. CDT could unambiguously be determined in all pretreated samples. PMID- 23109488 TI - Positioning new treatments in the management of immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) is a syndrome characterized by low platelet counts and an increased risk of bleeding. For most children, ITP is a self-limiting disease; however, for some children and most adults, thrombocytopenia can become chronic. Newer therapies for ITP include rituximab and thrombopoietin (TPO) receptor agonists. Rituximab is a useful second-line therapy and may be splenectomy-sparing. Thrombopoeitin receptor agonists have demonstrated large treatment effects with respect to increasing platelet levels; however, they require maintenance dosing. This review summarizes how these new agents might be positioned in the management of patients with chronic ITP. PMID- 23109489 TI - Profiling of mercapturic acids of acrolein and acrylamide in human urine after consumption of potato crisps. AB - SCOPE: Acrolein (AC) and acrylamide (AA) are food contaminants generated by heat treatment. We studied human exposure after consumption of potato crisps by monitoring excretion of mercapturic acids (MAs) in urine. METHODS AND RESULTS: MA excretion was monitored in human urine collected up to 72 h after ingestion of a test meal of experimental (study 1: 1 mg AA/150 g) or commercially available (study 2: 44 MUg AA plus 4.6 MUg AC/175 g) potato crisps. MA contents were analysed after purification via SPE using HPLC-ESI-MS/MS. On the basis of the area under the curve values of MAs excreted in urine, the total excretion of AC related MAs exceeded that of AA-related MAs up to 12 times in study 1 and up to four times in study 2. Remarkably, AC content of potato crisps of study 2 was found to be only about 1/10 the AA content, as determined by isotope dilution headspace GC/MS. CONCLUSION: Our results indicate substantially higher exposure to AC from potato crisps than to AA. Total AC in such foods may encompass bioavailable AC forms not detected by headspace GC/MS. Both findings may also apply to other heat processed foods. PMID- 23109490 TI - Crystallinity-controlled titanium oxide-carbon nanocomposites with enhanced lithium storage performance. AB - Nanocomposites of crystalline-controlled TiO(2) -carbon are prepared by a novel one-step approach and applied in anodes of lithium ion batteries. In our nanocomposite anodes, the Li(+) capacity contribution from the TiO(2) phase was enormous, above 400 mAh g(-1) (Li(1+x) TiO(2) , x>0.2), and the volumetric capacity was as high as 877 mAh cm(-3) with full voltage utilization to 0 V versus Li/Li(+) , which resulted in higher energy density than that of state-of the-art titania anodes. For the first time, it was clearly revealed that the capacity at 1.2 and 2.0 V corresponded to Li(+) storage at amorphous and crystalline TiO(2) , respectively. Furthermore, improvements in the rate capability and cycle performance were observed; this was attributed to resistance reduction induced by higher electrical/Li(+) conduction and faster Li(+) diffusion. PMID- 23109491 TI - Modulation of lipid metabolism by polyphenol-rich grape skin extract improves liver steatosis and adiposity in high fat fed mice. AB - This study investigated the influence of polyphenol-rich grape skin extract (GSE) on adiposity and hepatic steatosis in mice fed a high fat diet (HFD) and its underlying mechanisms based on adipose and hepatic lipid metabolism. C57BL/6J mice were fed a normal diet or a HFD (20% fat, w/w) with or without GSE (0.15%, w/w) for 10 weeks. The supplementation of GSE significantly lowered body weight, fat weight, plasma free fatty acid level, and hepatic lipid accumulation compared to the HFD group. Plasma leptin level was significantly lower, while the plasma adiponectin level was higher in the GSE group than in the HFD group. GSE supplementation significantly suppressed the activities of lipogenic enzymes in both adipose and liver tissues, which was concomitant with beta-oxidation activation. Furthermore, GSE reversed the HFD-induced changes of the expression of genes involved in lipogenesis and beta-oxidation in the liver. These findings suggest that GSE may protect against diet-induced adiposity and hepatic steatosis by regulating mRNA expression and/or activities of enzymes that regulate lipogenesis and fatty acid oxidation in the adipose tissue and liver. PMID- 23109492 TI - SPE for the simultaneous determination of various isothiocyanates. AB - Several SPE sorbents were investigated for the extraction of a group of chemically diverse isothiocyanates (ITCs). They included bonded silica, carbon based, and polymer-based sorbents with various functional groups. Results showed large differences in the ability of these sorbents to simultaneously extract ITCs from standard solutions. Recovery rates were on average the highest with divinylbenzene (DVB) based polymeric sorbents, especially with a DVB/N vinylpyrrolidone copolymer that had recovery rates ranging between 86.7 and 95.6%. These sorbents achieved the most balanced extraction efficiency between aliphatic and aromatic, polar, and nonpolar ITCs. With graphitized carbon, C(18) bonded silica, and amide-containing sorbent, recovery levels were higher for the two least polar aromatic ITCs (benzyl ITC and phenylethyl ITC), whereas for the polar aliphatic ITCs levels were the lowest. The least retained one, was methyl ITC that is the most polar with recoveries between 0 and 31.5%. The presence of amide groups, especially in a polyamide sorbent, appeared to be particularly unsuitable for the extraction of aliphatic ITCs. A copolymer made up of DVB and N vinylpyrrolidone was therefore shown to be the most suited for the extraction of both aliphatic and aromatic ITCs. PMID- 23109493 TI - Update on the Intercontinental Cooperative ITP Study Group (ICIS) and on the Pediatric and Adult Registry on Chronic ITP (PARC ITP). AB - The Intercontinental Cooperative ITP Study Group (ICIS) was founded in 1997, when the American practice guidelines demonstrated that there is a substantial lack of clinical data. The aim of the group was to promote basic science and clinical research in the field of ITP. Clinical data and more recently DNA is collected to investigate children and adults with ITP. ICIS organizes regular meetings and opened several registries, the most recent being the Pediatric and Adult Registry on Chronic ITP (PARC-ITP), all of which will be briefly discussed. There are many unanswered questions in basic science and clinical research in ITP which need large collaborative studies. The international network of ICIS may be of value in better understanding ITP. PMID- 23109495 TI - Self-control, negative affect, and young driver aggression: an assessment of competing theoretical claims. AB - A large body of research reveals support for Agnew's general strain theory (GST) and Gottfredson and Hirschi's self-control theory, yet the two perspectives make decidedly different predictions concerning the relationships between self control, negative affect (e.g., anger), and criminal/deviant behavior. Where GST specifies indirect and conditioning effects of self-control and negative affect on criminal/deviant behavior, self-control theory states that the independent effect of indicators of anger would be spurious and should disappear on controlling for self-control. We test these propositions using survey data from a probability sample of young adults. The structural equation models indicate that, although anger is largely the consequence of self-control, self-control and negative affect exert significant direct effects on driving aggression. These results highlight the need to integrate GST and self-control theories to better explain this form of deviant behavior. PMID- 23109494 TI - Spontaneous formation of heterogeneous patches on polymer-lipid core-shell particle surfaces during self-assembly. AB - Spontaneous formation of heterogeneous patches on the surface of lipid-based nanoparticles (NPs) and microparticles (MPs) due to the segregation of two different functional groups. Patch formation is observed when tracing the functional groups with quantum dots, gold nanoparticles, and fluorescent dyes. This discovery could have important implications for the future design of self assembled NPs and MPs for different biomedical applications. PMID- 23109496 TI - Management of severe epistaxis after Young's procedure: a case report. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder affecting multiple organ systems, with epistaxis being the most common manifestation. Multiple procedures have been used for the management of epistaxis in the setting of HHT, including closure of the anterior nares via a Young's procedure. While this procedure results in loss of smell and permanent nasal obstruction, proponents note significant improvement in patient symptomatology. METHODS: Case report. RESULTS: A 70-year-old female with a history of HHT presented to an outside hospital with bleeding into the nasopharynx 2 months after undergoing a modified Young's procedure at an unaffiliated institution. She was transfused with 2 units of packed red blood cells (PRBCs) and transferred to our facility. Due to persistent epistaxis and need for airway protection, the patient was intubated and her throat was packed. She also developed aspiration pneumonia and hypotensive shock requiring vasopressors. Twenty-four hours following bilateral internal maxillary and sphenopalatine artery embolization, she developed significant epistaxis requiring reversal of the Young's procedure on the left and placement of an anterior-posterior pack at the bedside. Upon packing removal several days later in the operating room, she was noted to have significant bleeding that necessitated reversal of the Young's procedure on the right side to obtain adequate exposure and hemostasis. CONCLUSION: We report a case of significant, life-threatening epistaxis following a modified Young's procedure that requiring multiple transfusions, bilateral embolization, and ultimately reversal of the Young's procedure for control of epistaxis. Although recognized as a potential complication, to our knowledge this is the first report in the English literature of such a case. PMID- 23109501 TI - Auto-immune lymphoproliferative disorder and other secondary immune thrombocytopenias in childhood. AB - Primary immune thrombocytopenia (ITP) in childhood, typically presents as an acute self-limiting illness. However, secondary ITP is often a chronic disorder due to an underlying disease. Combined cytopenias in childhood, that is, secondary ITP occurring with auto-immune hemolytic anemia and/or auto-immune neutropenia, are often associated with disorders characterized by immune dysregulation. Such disorders include systemic lupus erythematosus, auto-immune lymphoproliferative syndrome, and common variable immune deficiency. Evans syndrome describes the combination of ITP, autoimmune hemolytic anemia, and/or autoimmune neutropenia. However, it is now clear that some patients with Evans syndrome have an underlying immunodeficiency. This report focuses on combined auto-immune cytopenias and highlights the challenges in their diagnosis and management. PMID- 23109502 TI - PDLA/PLLA and PDLA/PCL nanofibers with a chitosan-based hydrogel in composite scaffolds for tissue engineered cartilage. AB - Osteoarthritis (OA) is the most prevalent musculoskeletal disease in humans, causing pain, loss of joint motility and function, and severely reducing the standard of living of patients. Cartilage tissue engineering attempts to repair the damaged tissue of individuals suffering from OA by providing mechanical support to the joint as new tissue regenerates. The aim of this study was to create composite three dimensional scaffolds comprised of electrospun poly(D,L lactide)/poly(L-lactide) (PDLA/PLLA) or poly(D,L-lactide)/polycaprolactone (PDLA/PCL) with salt leached pores and an embedded chitosan hydrogel to determine the potential of these scaffolds for cartilage tissue engineering. PDLA/PLLA hydrogel scaffolds displayed the largest compressive moduli followed by PDLA/PCL hydrogel scaffolds. Dynamic mechanical tests showed that the PDLA/PLLA scaffolds had no appreciable recovery while PDLA/PCL scaffolds did exhibit some recovery. Primary canine chondrocytes produced both collagen type II and proteoglycans (primary components of extracellular matrix in cartilage) while being cultured on scaffolds composed of electrospun PDLA/PCL. As a result, a composite electrospun embedded hydrogel scaffold shows promise for treating individuals suffering from OA. PMID- 23109503 TI - Diffusion and interaction dynamics of individual membrane protein complexes confined in micropatterned polymer-supported membranes. AB - Micropatterned polymer-supported membranes (PSM) are established as a tool for confining the diffusion of transmembrane proteins for single molecule studies. To this end, a photochemical surface modification with hydrophobic tethers on a PEG polymer brush is implemented for capturing of lipid vesicles and subsequent fusion. Formation of contiguous membranes within micropatterns is confirmed by scanning force microscopy, fluorescence recovery after photobleaching (FRAP), and super-resolved single-molecule tracking and localization microscopy. Free diffusion of transmembrane proteins reconstituted into micropatterned PSM is demonstrated by FRAP and by single-molecule tracking. By exploiting the confinement of diffusion within micropatterned PSM, the diffusion and interaction dynamics of individual transmembrane receptors are quantitatively resolved. PMID- 23109504 TI - Use of nasopharyngeal culture to determine appropriateness of antibiotic therapy in acute bacterial rhinosinusitis. AB - BACKGROUND: Rhinosinusitis is one of the top 5 diagnoses for which an antibiotic is prescribed, often without a clear bacterial etiology. This study evaluated whether nasopharyngeal culture and gram stain could serve as a surrogate for endoscopically obtained middle meatal cultures in directing appropriate therapy for acute bacterial rhinosinusitis (ABRS). This study also investigated the utility of a rapid sinus test screen in differentiating bacterial from nonbacterial rhinosinusitis. METHODS: Thirty-one adult patients met inclusion criteria for ABRS. Samples were obtained from both the middle meatus and nasopharynx for Gram stain and culture. Nasal mucous samples were tested with a rapid sinus test strip measuring pH, levels of protein, nitrites, and leukocyte esterase. RESULTS: Sixty-one percent (61%) of nasopharyngeal and 48% of middle meatal samples grew pathogenic bacteria. The concordance rate was 84% between the 2 sites (p = 0.0006). The following pathogenic organisms were detected: Moraxella catarrhalis, Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas aeruginosa, and Staphylococcus aureus. For nasopharyngeal samples, reliance on Gram stain alone exhibited a sensitivity of 31% and specificity of 100% and, similarly, for middle meatus samples, 47% and 93%, respectively. The rapid sinus test revealed a sensitivity of 83% and specificity of 7%. CONCLUSION: Nasopharyngeal and middle meatal cultures exhibited high concordance for pathogenic bacteria. Gram stain exhibited moderate sensitivity and excellent specificity. Nasopharyngeal cultures could provide a viable method, especially in a primary care setting, for determining the appropriateness of antibiotic therapy. The rapid sinus test's lack of specificity precluded its utility in the differentiation between bacterial and nonbacterial rhinosinusitis. PMID- 23109506 TI - Oral challenge with increasing doses of LPS modulated the patterns of plasma metabolites and minerals in periparturient dairy cows. AB - We showed recently that repeated oral exposure to LPS stimulated humoral immune responses in periparturient dairy cows. Here, metabolic and mineral responses to repeated oral administration of LPS were investigated. Sixteen clinically healthy, pregnant Holstein cows were orally administered 3 ml of saline solution (control) or 3 ml of saline solution containing 3 increasing doses of LPS, at 07:00 h, as follows: (i) 0.01 ug/kg body mass (BM) on d -14 and -10, (ii) 0.05 ug/kg BM on d -7 and -3, and (iii) 0.1 ug/kg BM on d 3 and 7 relative to parturition. Blood samples were measured shortly before, and at 8 different time points after (up to 6 h), the first challenge of each LPS dosage to evaluate the post-challenge plasma profile, as well as weekly up to 4 wk postpartum. Results showed that oral administration of LPS lowered concentrations of non-esterified fatty acids (P < 0.01) and beta-hydroxy-butyrate (P < 0.01) in the plasma, particularly after the third LPS challenge. Also, after the third oral LPS challenge, treatment tended to increase plasma glucose. Plasma calcium did not change, but concentrations of insulin (P < 0.01) and zinc (P < 0.01) were greater, while that of copper was lower (P < 0.01) in the plasma of treated cows. This is the first report to indicate a potential role for repeated oral administration of LPS around parturition to modulate the profile of plasma metabolites and minerals postpartum. PMID- 23109507 TI - Manipulation of innate immunity by a bacterial secreted peptide: lantibiotic nisin Z is selectively immunomodulatory. AB - Innate immunity is triggered by a variety of bacterial molecules, resulting in both protective and potentially harmful pro-inflammatory responses. Further, innate immunity also provides a mechanism for the maintenance of homeostasis between the host immune system and symbiotic or non-pathogenic microorganisms. However, the bacterial factors that mediate these protective effects have been incompletely defined. Here, it was demonstrated that the lantiobiotic nisin Z is able to modulate host immune responses and mediate protective host immunity. Nisin Z induced the secretion of the chemokines MCP-1, IL-8 and Gro-alpha, and significantly reduced TNF-alpha induction in response to bacterial LPS in human PBMC. The results correlated with the ability of nisin Z to confer protection against both the Gram-positive organism Staphylococcus aureus, and the Gram negatives Salmonella enterica sv. Typhimurium and Escherichia coli in murine challenge models. Mechanistic studies revealed that nisin Z modulates host immunity through similar mechanisms as natural host defense peptides, engaging multiple signal transduction pathways and growth factor receptors. The results presented herein demonstrate that, in addition to nisin Z, other bacterial cationic peptides and, in particular, the lantibiotics, could represent a new class of secreted bacterial molecule with immunomodulatory activities. PMID- 23109508 TI - Bleeding severity as an important outcome in childhood immune thrombocytopenia. AB - Over the years pediatric hematologists have continued to debate whether pharmacotherapy or clinical observation should be employed as initial management in childhood immune thrombocytopenia (ITP). Delineating the fundamental elements of heterogeneity in bleeding manifestations in childhood ITP has proven to be a complicated task. Efforts to classify the impact of hemorrhage in ITP based on platelet count have been problematic. Factors beyond relying on a laboratory measurement as a surrogate marker of disease severity need to be considered. What is needed to better guide therapeutic decision-making is a clinically relevant and evidence-based measure of bleeding severity. In this special supplement, the history of therapeutic management in ITP and prior attempts to grade or quantify hemorrhage will be reviewed. PMID- 23109509 TI - Comparative effect of human and Trypanosoma cruzi calreticulin in wound healing. AB - In orthopaedics, the use of factors that enhance granulation tissue formation and prevent or delay new bone regeneration is sometimes desirable. Calreticulin (CRT), a unique endoplasmic reticulum luminal Ca(2+) -binding chaperone widely distributed in eukaryotic cells, is involved in many cellular functions. Among them, CRT has an important influence in cutaneous wound healing and diverse processes associated with cutaneous repair, inhibition of angiogenesis, promotion of cell adhesion and antitumour effect. One of the molecules involved in several aspects of the host-parasite interplay is Trypanosoma cruzi calreticulin (TcCRT), which is highly homologous to human calreticulin (HuCRT). Here, recombinant (r)HuCRT and rTcCRT are compared on their abilities to affect fibroblast behaviour in a scratch plate assay, and wound healing in in vivo skin rat models. In molar terms, rTcCRT is three orders of magnitude more efficient than rHuCRT in increasing proliferation and migration of human fibroblasts in vitro. A similar effect was observed in vivo on rat skin wounds and inhibition of bone gap bridging in rabbit unicortical bone osteotomies. PMID- 23109510 TI - Endoscopic endonasal anatomy of the nasopharynx in a cadaver model. AB - BACKGROUND: Nasopharyngectomy is an accepted treatment for recurrent nasopharyngeal carcinoma following radiation with or without chemotherapy. Traditionally, the nasopharynx has been approached through relatively invasive "open" techniques including transpalatal, maxillary swing, and trans-mandibular pterygoid approaches. Contemporary management has included the use of endoscopic techniques to exenterate tumors in this location. The purpose of the present study is to describe the endoscopic anatomy of this region through cadaveric dissection and to characterize the technical limitations of the approach. METHODS: Five fresh cadaveric heads were dissected to study the endoscopic anatomy of the nasopharynx and associated structures. RESULTS: Endoscopic dissection of the nasopharynx was completed in all 5 specimens. Nasopharyngeal anatomy including the buccopharyngeal fascia, pharyngobasilar fascia, superior constrictor, longus capitus, longus coli, fossa of Rosenmuller, basisphenoid, auditory torus, and internal carotid artery were characterized. CONCLUSION: Surgical access to the nasopharynx has posed significant challenges in the treatment of recurrent or persistent nasopharyngeal carcinoma. This study demonstrated that endoscopic dissection of this region is feasible and has the potential to completely exenterate these lesions. PMID- 23109511 TI - Vitamin MK-7 enhances vitamin D3-induced osteogenesis in hMSCs: modulation of key effectors in mineralization and vascularization. AB - The osteoblast is the bone-forming cell and is derived from mesenchymal stem cells (MSCs). Osteo-inductive substances could represent a useful therapeutic approach during the fracture repair process. The aim of this work was to evaluate the effects of vitamin MK-7, alone or in association with vitamin D3, in differentiating human MSCs (hMSCs) in vitro along the osteoblastic lineage. In particular, primary endpoints of the study include gene and protein markers of osteoblast differentiation. Considering genes involved in bone formation and mineralization, our data show that vitamin MK-7 enhances vitamin D3 gene induction of osteocalcin (OC). Among genes related to cell growth and differentiation, a specific effect of vitamin MK-7 was observed for growth differentiation factor-10 (GDF10) and insulin-like growth factor 1 (IGF1), the latter being also involved in the induction of vascular endothelial growth factors (VEGFA). Accordingly, vitamin co-supplementation greatly affected VEGFA and its receptor fms-related tyrosine kinase 1 (FLT1), a key factor in both angiogenic and osteogenic processes. These results stress the relevance of MK-7 and D3 co-supplementation in the bone-healing process as able to modulate the expression of genes involved in both mineralization and angiogenesis. Moreover, at the protein level co-association of vitamins might provide an optimal balance between induction and carboxylation of osteocalcin, essential for its functionality in the extracellular matrix (ECM). Our results may provide hints for therapeutic application of hMSCs in bone disease, clarifying mechanisms involved in stem cell-mediated bone development, and they also highlight the relevance of co-supplementation strategies, since single supplementations might result in a suboptimal effect. PMID- 23109513 TI - Freedom of movement across the EU: legal and ethical issues for children with chronic disease. AB - While freedom of movement has been one of the most highly respected human right across the EU, there are various aspects which come into play which still need to be resolved for this to be achieved in practice. One of these key issues is cross border health care. Indeed, there is an increasing awareness of standardisation of health service provision and cross border collaboration in the EU. However, certain groups particularly children may be at risk of suboptimal treatment as a result. We present the case of a child patient which highlights the complexity of this matter spanning family law, health law, social security law as well as ethical issues. EU legislation needs to ensure that children patients have access to high quality care across the EU borders. PMID- 23109515 TI - Natural history and management of aortocoronary saphenous vein graft aneurysms: a systematic review of published cases. PMID- 23109514 TI - Association between smoke-free legislation and hospitalizations for cardiac, cerebrovascular, and respiratory diseases: a meta-analysis. AB - BACKGROUND: Secondhand smoke causes cardiovascular and respiratory disease. Smoke free legislation is associated with a lower risk of hospitalization and death from these diseases. METHODS AND RESULTS: Random-effects meta-analysis was conducted by law comprehensiveness to determine the relationship between smoke free legislation and hospital admission or death from cardiac, cerebrovascular, and respiratory diseases. Studies were identified by using a systematic search for studies published before November 30, 2011 with the use of the Science Citation Index, Google Scholar, PubMed, and Embase and references in identified articles. Change in hospital admissions (or deaths) in the presence of a smoke free law, duration of follow-up, and law comprehensiveness (workplaces only; workplaces and restaurants; or workplaces, restaurants, and bars) were recorded. Forty-five studies of 33 smoke-free laws with median follow-up of 24 months (range, 2-57 months) were included. Comprehensive smoke-free legislation was associated with significantly lower rates of hospital admissions (or deaths) for all 4 diagnostic groups: coronary events (relative risk, 0.848; 95% confidence interval 0.816-0.881), other heart disease (relative risk, 0.610; 95% confidence interval, 0.440-0.847), cerebrovascular accidents (relative risk, 0.840; 95% confidence interval, 0.753-0.936), and respiratory disease (relative risk, 0.760; 95% confidence interval, 0.682-0.846). The difference in risk following comprehensive smoke-free laws does not change with longer follow-up. More comprehensive laws were associated with larger changes in risk. CONCLUSIONS: Smoke-free legislation was associated with a lower risk of smoking-related cardiac, cerebrovascular, and respiratory diseases, with more comprehensive laws associated with greater changes in risk. PMID- 23109516 TI - Cardiac hydatidosis: a follow-up with cardiovascular magnetic resonance. PMID- 23109517 TI - Favorable course of pericardial angiosarcoma under paclitaxel followed by pazopanib treatment documented by cardiovascular magnetic resonance imaging. PMID- 23109518 TI - Statins and risk of new-onset diabetes mellitus. PMID- 23109520 TI - Letter by Sharma et al regarding article, "impact of the presence and extent of incomplete angiographic revascularization after percutaneous coronary intervention in acute coronary syndromes: the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial". PMID- 23109537 TI - Comparison of pollution levels on the Mississippi Gulf Coast during the 2010 Gulf BP oil spill to ecological and health-based standards. AB - To evaluate the possible impact that the BP Deepwater Horizon Gulf oil spill might have had on pollution levels in the State of Mississippi, the Mississippi Department of Environmental Quality (MDEQ), and the US Environmental Protection Agency (EPA) analyzed surface water and ambient air quality pollutant data taken from MDEQ and EPA monitoring sites on the Mississippi Gulf Coast. The data were compared with acute, chronic, and human health air and water quality standards to determine whether the pollutant levels occurring during the oil spill could cause ecological and/or human health effects. The water quality data indicated levels of nickel, vanadium, volatile organic compounds (VOCs), and semivolatile organic compounds analyzed remained below acute and chronic levels for both aquatic life and human health. The air quality sampling data showed that the levels of VOCs and polycyclic aromatic hydrocarbons associated with the oil spill were well below EPA chronic and human health screening levels. A comparison of the air quality monitoring data taken before and after the oil spill showed that the concentrations of ozone and fine particulate matter were elevated for brief periods but remained below actionable levels. PMID- 23109538 TI - Benzene absorption in animals and man: an overview. AB - Benzene is a widespread, naturally occurring substance of environmental concern as systemic exposure in humans is proven to be carcinogenic. Dermal exposure is a common and significant route of systemic entry and percutaneous absorption is critical in exposure risk assessment. This article reviews the scientific principles, methodologies, and research behind the multiple steps of the percutaneous absorption of benzene in animals and man and the application of this information to optimize exposure risk assessments. A focus on occupational exposures to benzene is made with an exploration of the limitations of current preventative measures and hazard assessments. Finally, recommendations for future research to fill existing knowledge gaps are made. PMID- 23109539 TI - Misregulated inflammation as an outcome of early-life exposure to endocrine disrupting chemicals. AB - This review introduces a potential unifying concept involving the risk of chronic diseases in which early-life exposure to endocrine-disrupting chemicals (EDCs) can program host responses for misregulated inflammation. Inflammation is a part of host defense against pathogenic challenges and one of the processes necessary for normal tissue homeoregulation and for reproduction (e.g., implantation, labor). Deviations from tightly regulated inflammation present a significant health risk because unresolved inflammation can compromise tissue function and increase the risk for later-life cancer in the affected target tissue. The critical windows of innate immune vulnerability during prenatal and neonatal maturation are when developmental programming and the trajectory for childhood and adult inflammatory responses are largely established. Misregulated inflammation is a common thread that links most significant chronic diseases and conditions across all physiologic systems as well as the associated comorbid conditions. As a result, chronic diseases exist both as a myriad of conditions and as an integrated, dysfunctionally connected unit. Because the hormone microenvironment exerts a significant effect on resident innate immune cell function, endocrine disruption is likely to produce misregulated inflammation in tissues. Among the factors determining specific health risks and disease outcomes across a lifetime are the age of exposure, sex, genetic background, and transgenerational epigenetic experiences. Additional research into early-life EDC exposure and misregulation of inflammation appears to be a useful avenue for reducing environmental health risks. PMID- 23109540 TI - Structure and function of bacterial dynamin-like proteins. AB - Membrane dynamics are essential for numerous cellular processes in eukaryotic and prokaryotic cells. In eukaryotic cells, membrane fusion and fission are often catalyzed by large GTPases of the dynamin protein family. These proteins couple GTP hydrolysis to membrane deformation, which eventually leads to fusion or fission of the lipid bilayer. Mutations in eukaryotic dynamin-like proteins (DLPs) are associated with various diseases underscoring the importance to fully understand the biochemistry of these proteins. In recent years, a wealth of structural and biochemical data have been published that allow a detailed analysis of how dynamins or DLPs modulate biological membranes. However, less is known about the function of bacterial DLPs, although structural data exist. This review summarizes current knowledge about bacterial dynamins and discusses structural and functional properties in comparison to their eukaryotic counterparts. PMID- 23109541 TI - Functional relevance of transmembrane domains in membrane fusion. AB - Membrane fusion is ubiquitous in life. Fusion of biological membranes is mediated by specialized fusion proteins anchored to the bilayers destined to fuse. Here we describe these proteins as being instrumental in viral, intracellular and developmental fusion. Next, we review experimental and theoretical evidence that points to fusion in the different systems as following a common 'fusion through hemifusion' pathway. We also focus on the structure and dynamics of the transmembrane segment that anchors the fusion proteins to the bilayer, and its role in driving fusion. In particular, we highlight the influence of this single segment on the surrounding membrane lipids and on the overall shape of the membrane along the way to fusion. PMID- 23109542 TI - Mitofilin complexes: conserved organizers of mitochondrial membrane architecture. AB - Mitofilin proteins are crucial organizers of mitochondrial architecture. They are located in the inner mitochondrial membrane and interact with several protein complexes of the outer membrane, thereby generating contact sites between the two membrane systems of mitochondria. Within the inner membrane, mitofilins are part of hetero-oligomeric protein complexes that have been termed the mitochondrial inner membrane organizing system (MINOS). MINOS integrity is required for the maintenance of the characteristic morphology of the inner mitochondrial membrane, with an inner boundary region closely apposed to the outer membrane and cristae membranes, which form large tubular invaginations that protrude into the mitochondrial matrix and harbor the enzyme complexes of the oxidative phosphorylation machinery. MINOS deficiency comes along with a loss of crista junction structures and the detachment of cristae from the inner boundary membrane. MINOS has been conserved in evolution from unicellular eukaryotes to humans, where alterations of MINOS subunits are associated with multiple pathological conditions. PMID- 23109543 TI - The gateway to chloroplast: re-defining the function of chloroplast receptor proteins. AB - Chloroplast biogenesis often requires a tight orchestration between gene expression (both plastidial and nuclear) and translocation of ~3000 nuclear encoded proteins into the organelle. Protein translocation is achieved via two multimeric import machineries at the outer (TOC) and inner (TIC) envelope of chloroplast, respectively. Three components constitute the core element of the TOC complex: a beta-barrel protein translocation channel Toc75 and two receptor constituents, Toc159 and Toc34. A diverse set of distinct TOC complexes have recently been characterized and these diversified TOC complexes have evolved to coordinate the translocation of differentially expressed proteins. This review aims to describe the recent discoveries relating to the typical characteristics of these distinct TOC complexes, particularly the receptor constituents, which are the main contributors for TOC complex diversification. PMID- 23109544 TI - The sensor kinase DcuS of Escherichia coli: two stimulus input sites and a merged signal pathway in the DctA/DcuS sensor unit. AB - The membrane-integral sensor kinase DcuS of Escherichia coli consists of a periplasmically located sensory PAS(P) domain, transmembrane helices TM1 and TM2, a cytoplasmic PAS(C) domain and the kinase domain. Stimulus (C(4)-dicarboxylate) binding at PAS(P) is required to stimulate phosphorylation of the kinase domain, resulting in phosphoryl transfer to the response regulator DcuR. PAS(C) functions as a signaling device or a relay in signal transfer from TM2 to the kinase. Phosphorylated DcuR induces the expression of the target genes. Sensing by DcuS requires the presence of the C(4)-dicarboxylate transporter DctA during aerobic growth. DctA forms a sensor unit with DcuS, and a short C-terminal sequence of DctA forming the putative helix 8b is required for interaction with DcuS. Helix 8b contains a LDXXXLXXXL motif that is essential for function and interaction. DcuS requires the PAS(C) domain for signal perception from DctA. Thus, DcuS and DctA form a DctA/DcuS sensory unit, and DcuS perceives stimuli from two different sites (PAS(P) and DctA). The signal transfer pathways are supposed to merge at PAS(C). The fumarate/succinate antiporter DcuB takes over the role as a co-sensor of DcuS under anaerobic growth conditions. PMID- 23109545 TI - Intronic hammerhead ribozymes in mRNA biogenesis. AB - Small self-cleaving ribozymes are a group of natural RNAs that are capable of catalyzing their own and sequence-specific endonucleolytic cleavage. One of the most studied members is the hammerhead ribozyme (HHR), a catalytic RNA originally discovered in subviral plant pathogens but recently shown to reside in a myriad of genomes along the tree of life. In eukaryotes, most of the genomic HHRs seem to be related to short interspersed retroelements, with the main exception of a group of strikingly conserved ribozymes found in the genomes of all amniotes (reptiles, birds and mammals). These amniota HHRs occur in the introns of a few specific genes, and clearly point to a preserved biological role during pre-mRNA biosynthesis. More specifically, bioinformatic analysis suggests that these intronic ribozymes could offer a new form of splicing regulation of the mRNA of higher vertebrates. We review here the latest advances in the discovery and biological characterization of intronic HHRs of vertebrates, including new conserved examples in the genomes of the primitive turtle and coelacanth fish. PMID- 23109546 TI - Interaction between natural compounds and human topoisomerase I. AB - Eukaryotic topoisomerase I (Top1) is a monomeric enzyme that catalyzes the relaxation of supercoiled DNA during important processes including DNA replication, transcription, recombination and chromosome condensation. Human Top1 I is of significant medical interest since it is the unique cellular target of camptothecin (CPT), a plant alkaloid that rapidly blocks both DNA and RNA synthesis. In this review, together with CPT, we point out the interaction between human Top1 and some natural compounds, such us terpenoids, flavonoids, stilbenes and fatty acids. The drugs can interact with the enzyme at different levels perturbing the binding, cleavage, rotation or religation processes. Here we focus on different assays that can be used to identify the catalytic step of the enzyme inhibited by different natural compounds. PMID- 23109547 TI - beta-Barrel scaffolds for the grafting of extracellular loops from G-protein coupled receptors. AB - Owing to the difficulties in production and purification of G-protein-coupled receptors (GPCRs), relatively little structural information is available about this class of receptors. Here we aim at developing small chimeric proteins, displaying the extracellular ligand-binding motifs of a human GPCR, the Y receptor. This allows the study of ligand-receptor interactions in simplified systems. We present comprehensive information on the use of transmembrane (OmpA) and soluble (Blc) beta-barrel scaffolds. Whereas Blc appeared to be not fully compatible with our approach, owing to problems with refolding of the hybrid constructs, loop-grafted versions of OmpA delivered encouraging results. Previously, we described a chimeric construct based on OmpA displaying all three extracellular Y1 receptor loops in different topologies and showing moderate affinity to one of the natural ligands. Now, we present detailed data on the interaction of these constructs with several Y receptor ligands along with data on new constructs. Our findings suggest a common binding mode for all ligands, which is mediated through the C-terminal residues of the peptide ligand, supporting the functional validity of these hybrid receptors. The observed binding affinities, however, are well below those observed for the natural receptors, clearly indicating limitations in mimicking the natural systems. PMID- 23109548 TI - The GlycanBuilder and GlycoWorkbench glycoinformatics tools: updates and new developments. AB - During the EUROCarbDB project our group developed the GlycanBuilder and GlycoWorkbench glycoinformatics tools. This short communication summarizes the capabilities of these two tools and updates which have been made since the original publications in 2007 and 2008. GlycanBuilder is a tool that allows for the fast and intuitive drawing of glycan structures; this tool can be used standalone, embedded in web pages and can also be integrated into other programs. GlycoWorkbench has been designed to semi-automatically annotate glycomics data. This tool can be used to annotate mass spectrometry (MS) and MS/MS spectra of free oligosaccharides, N and O-linked glycans, GAGs (glycosaminoglycans) and glycolipids, as well as MS spectra of glycoproteins. PMID- 23109549 TI - Data reduction methods for ektacytometry in clinical hemorheology. AB - Laser-diffraction ektacytometry is a generally accepted technique for measuring RBC deformability induced by fluid shear stress (SS) and yields paired elongation index-SS data at several levels of stress. Unfortunately, comparison of results is hindered by the lack of simple indices that accurately characterize these data. Several mathematical models have been proposed, including those developed for analysis of enzyme kinetics (Lineweaver-Burk, Eadie-Hofstee) and curve fitting (Streekstra-Bronkhorst). All of these analytical approaches provide a value for cell deformation at infinite stress (EImax) and the shear stress required to achieve one-half of this deformation (SS1/2); the use of non-linear regression is essential when calculating these parameters. While the current models provide equivalent results for normal RBC if used with non-linear regression, EImax and SS1/2 are not always concordant for cells with abnormal mechanical behavior. This technical note examines such differences for three conditions: glutaraldehyde treatment, mechanical stress and non-isotonic media. It was found that none of the models yield completely satisfactory values for EImax and SS1/2, especially if there are large changes of EImax. However, the ratio of SS1/2 to EImax (SS1/2/EImax) is much less affected by these problems, has similar power (i.e., standardized difference) as SS1/2 and EImax and is more robust in reflecting alterations of deformability. We thus conclude that the SS1/2/EImax ratio can be used when reporting and comparing various populations of RBC or cells obtained from subjects having different clinical states. PMID- 23109550 TI - Association of hematological parameters with insulin resistance, insulin sensitivity, and asymptomatic cerebrovascular damage: the J-SHIP and Toon Health Study. AB - BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2+/-0.7, Q2: 2.0+/-0.7, Q3: 1.9+/-0.7, Q4: 1.8+/-0.6, p<0.001) and insulin resistance (1.0+/-0.6, 1.2+/-0.7, 1.3+/-0.8, 1.5+/-1.0, p<0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (beta=-0.074, p=0.019) and insulin resistance (beta=0.115, p<0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p=0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r=-0.250, p<0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p=0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance. PMID- 23109551 TI - Spacing between core recognition motifs determines relative orientation of AraR monomers on bipartite operators. AB - Transcription factors modulate expression primarily through specific recognition of cognate sequences resident in the promoter region of target genes. AraR (Bacillus subtilis) is a repressor of genes involved in L-arabinose metabolism. It binds to eight different operators present in five different promoters with distinct affinities through a DNA binding domain at the N-terminus. The structures of AraR-NTD in complex with two distinct operators (ORA1 and ORR3) reveal that two monomers bind to one recognition motif (T/ANG) each in the bipartite operators. The structures show that the two recognition motifs are spaced apart by six bases in cases of ORA1 and eight bases in case of ORR3. This increase in the spacing in the operators by two base pairs results in a drastic change in the position and orientation of the second monomer on DNA in the case of ORR3 when compared with ORA1. Because AraR binds to the two operators with distinct affinities to achieve different levels of repression, this observation suggests that the variation in the spacing between core recognition motifs could be a strategy used by this transcription modulator to differentially influence gene expression. PMID- 23109552 TI - MetaboLights--an open-access general-purpose repository for metabolomics studies and associated meta-data. AB - MetaboLights (http://www.ebi.ac.uk/metabolights) is the first general-purpose, open-access repository for metabolomics studies, their raw experimental data and associated metadata, maintained by one of the major open-access data providers in molecular biology. Metabolomic profiling is an important tool for research into biological functioning and into the systemic perturbations caused by diseases, diet and the environment. The effectiveness of such methods depends on the availability of public open data across a broad range of experimental methods and conditions. The MetaboLights repository, powered by the open source ISA framework, is cross-species and cross-technique. It will cover metabolite structures and their reference spectra as well as their biological roles, locations, concentrations and raw data from metabolic experiments. Studies automatically receive a stable unique accession number that can be used as a publication reference (e.g. MTBLS1). At present, the repository includes 15 submitted studies, encompassing 93 protocols for 714 assays, and span over 8 different species including human, Caenorhabditis elegans, Mus musculus and Arabidopsis thaliana. Eight hundred twenty-seven of the metabolites identified in these studies have been mapped to ChEBI. These studies cover a variety of techniques, including NMR spectroscopy and mass spectrometry. PMID- 23109553 TI - ECMDB: the E. coli Metabolome Database. AB - The Escherichia coli Metabolome Database (ECMDB, http://www.ecmdb.ca) is a comprehensively annotated metabolomic database containing detailed information about the metabolome of E. coli (K-12). Modelled closely on the Human and Yeast Metabolome Databases, the ECMDB contains >2600 metabolites with links to ~1500 different genes and proteins, including enzymes and transporters. The information in the ECMDB has been collected from dozens of textbooks, journal articles and electronic databases. Each metabolite entry in the ECMDB contains an average of 75 separate data fields, including comprehensive compound descriptions, names and synonyms, chemical taxonomy, compound structural and physicochemical data, bacterial growth conditions and substrates, reactions, pathway information, enzyme data, gene/protein sequence data and numerous hyperlinks to images, references and other public databases. The ECMDB also includes an extensive collection of intracellular metabolite concentration data compiled from our own work as well as other published metabolomic studies. This information is further supplemented with thousands of fully assigned reference nuclear magnetic resonance and mass spectrometry spectra obtained from pure E. coli metabolites that we (and others) have collected. Extensive searching, relational querying and data browsing tools are also provided that support text, chemical structure, spectral, molecular weight and gene/protein sequence queries. Because of E. coli's importance as a model organism for biologists and as a biofactory for industry, we believe this kind of database could have considerable appeal not only to metabolomics researchers but also to molecular biologists, systems biologists and individuals in the biotechnology industry. PMID- 23109554 TI - Building the repertoire of dispensable chromosome regions in Bacillus subtilis entails major refinement of cognate large-scale metabolic model. AB - The nonessential regions in bacterial chromosomes are ill-defined due to incomplete functional information. Here, we establish a comprehensive repertoire of the genome regions that are dispensable for growth of Bacillus subtilis in a variety of media conditions. In complex medium, we attempted deletion of 157 individual regions ranging in size from 2 to 159 kb. A total of 146 deletions were successful in complex medium, whereas the remaining regions were subdivided to identify new essential genes (4) and coessential gene sets (7). Overall, our repertoire covers ~76% of the genome. We screened for viability of mutant strains in rich defined medium and glucose minimal media. Experimental observations were compared with predictions by the iBsu1103 model, revealing discrepancies that led to numerous model changes, including the large-scale application of model reconciliation techniques. We ultimately produced the iBsu1103V2 model and generated predictions of metabolites that could restore the growth of unviable strains. These predictions were experimentally tested and demonstrated to be correct for 27 strains, validating the refinements made to the model. The iBsu1103V2 model has improved considerably at predicting loss of viability, and many insights gained from the model revisions have been integrated into the Model SEED to improve reconstruction of other microbial models. PMID- 23109555 TI - The UCSC Cancer Genomics Browser: update 2013. AB - The UCSC Cancer Genomics Browser (https://genome-cancer.ucsc.edu/) is a set of web-based tools to display, investigate and analyse cancer genomics data and its associated clinical information. The browser provides whole-genome to base-pair level views of several different types of genomics data, including some next generation sequencing platforms. The ability to view multiple datasets together allows users to make comparisons across different data and cancer types. Biological pathways, collections of genes, genomic or clinical information can be used to sort, aggregate and zoom into a group of samples. We currently display an expanding set of data from various sources, including 201 datasets from 22 TCGA (The Cancer Genome Atlas) cancers as well as data from Cancer Cell Line Encyclopedia and Stand Up To Cancer. New features include a completely redesigned user interface with an interactive tutorial and updated documentation. We have also added data downloads, additional clinical heatmap features, and an updated Tumor Image Browser based on Google Maps. New security features allow authenticated users access to private datasets hosted by several different consortia through the public website. PMID- 23109556 TI - Altered levels of homocysteine and serum natural antioxidants links oxidative damage to Alzheimer's disease. AB - Increasing evidence supports the theory that oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). Homocysteine (Hcy), uric acid (UA), bilirubin, and albumin are simple laboratory parameters that are related to oxidative stress. In this study we compared serum Hcy and antioxidant levels in patients with AD and normal cognitive function. In this cross-sectional study, 143 AD patients and 1,553 patients with normal cognitive function aged 65 years and over were enrolled. Mean values of UA and albumin levels of AD patients were significantly lower than normal cognitive function subjects (p: 0.003 versus p < 0.001, respectively). Mean value of Hcy levels of AD patients was significantly higher than normal cognitive function subjects (p = 0.031). Multivariate regression analysis revealed that Mini-nutritional assessment short form (OR: 0.905, 95% CI: 0.850-0.965, p = 0.002), hypertension (OR: 1.573, 95% CI: 1.148-2.155, p = 0.005), UA (OR: 0.879, 95% CI: 0.788-0.981, p = 0.021), Hcy (OR: 1.040, 95% CI: 1.022-1.059, p < 0.001), and albumin (OR: 0.505, 95% CI: 0.339-0.753, p < 0.001) were independent variables predicting the occurrence of AD. Our study supports the hypothesis that a decrease in antioxidants and an increase in oxidative damage are linked to AD. PMID- 23109557 TI - Mild cognitive impairment: same identity for different entities. AB - This study investigates whether different patterns of grey matter (GM) loss may account for the different neuropsychological profiles observed in patients with amnestic (a-) and non-amnestic (na-) mild cognitive impairment (MCI), and may predict patients' clinical evolution. Fifty-five consecutive individuals complaining of cognitive dysfunction (referred to specialist dementia clinics) were screened and included in the study if they met the diagnostic criteria for MCI on a neurodegenerative basis. After an extensive neuropsychological assessment, patients were classified as suffering from a-MCI or na-MCI. Twenty eight healthy individuals were also recruited and served as controls. All participants underwent magnetic resonance imaging at 3T, including conventional images and volumetric scans. Volumetric data were processed using voxel-based morphometry to assess between-group differences in regional GM volumes and correlations with neuropsychological performances. When compared to controls, a MCI patients showed prominent GM volume reductions in the medial temporal lobes, while those with na-MCI showed reduced GM volumes in the orbito-frontal cortex and basal ganglia. In a-MCI patients, significant associations were found between verbal long-term memory performance and GM volumes in the hippocampus. Conversely, in na-MCI patients, associations were found between scores at tests exploring executive functions and GM volumes in the orbito-frontal cortex. At one year follow-up, conversions were recorded exclusively toward Alzheimer's disease (AD) in the a-MCI group, and toward non-AD dementia in the na-MCI group. This study confirms that MCI is a heterogeneous clinical identity including different neurodegenerative entities; specific patterns of regional GM loss appear to account for specific neuropsychological features and are likely to predict patients' clinical evolution. PMID- 23109558 TI - Peroxisome proliferators reduce spatial memory impairment, synaptic failure, and neurodegeneration in brains of a double transgenic mice model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration of cognitive abilities, accumulation of the amyloid beta peptide (Abeta), increase of oxidative stress, and synaptic alterations. The scavenging of reactive oxygen species through their matrix enzyme catalase is one of the most recognized functions of peroxisomes. The induction of peroxisome proliferation is attained through different mechanisms by a set of structurally diverse molecules called peroxisome proliferators. In the present work, a double transgenic mouse model of AD that co-expresses a mutant human amyloid-beta protein precursor (AbetaPPswe) and presenilin 1 without exon 9 (PS1dE9) was utilized in order to assess the effect of peroxisomal proliferation on Abeta neurotoxicity in vivo. Mice were tested for spatial memory and their brains analyzed by cytochemical, electrophysiological, and biochemical methods. We report here that peroxisomal proliferation significantly reduces (i) memory impairment, found in this model of AD; (ii) Abeta burden and plaque-associated acetylcholinesterase activity; (iii) neuroinflammation, measured by the extent of astrogliosis and microgliosis; and (iv) the decrease in postsynaptic proteins, while promoting synaptic plasticity in the form of long-term potentiation. We concluded that peroxisomal proliferation reduces various AD neuropathological markers and peroxisome proliferators may be considered as potential therapeutic agents against the disease. PMID- 23109559 TI - Inflammation from dialysis, can it be removed? AB - Mortality among hemodialysis patients remains unacceptably high in the USA, especially among newly diagnosed end-stage renal disease patients. Chronic inflammation is a risk factor for cardiovascular disease among HD patients. It has been shown that complications of the arteriovenous (AV) access are not just limited to overt infectious complications but they may also pose a threat as a haven for occult infection and can aggravate the chronic inflammatory state. This inflammatory state is characterized by failure to thrive, erythropoietin resistant anemia, hypoalbuminemia, elevated plasma C-reactive protein levels, which are well-known risk factors for increased morbidity and mortality on dialysis. In this issue, Wasse et al. presents a paper that demonstrates in a large cohort that failed AV grafts are associated with increased chronic inflammatory markers. They have provided a mechanistic insight into the causes of the chronic inflammatory state among dialysis patients. Along this line, it has also been demonstrated that failed renal allografts are also harbors of a chronic inflammatory state and that the removal of a failed renal allograft will lead to resolution of both overt inflammation and subclinical inflammatory states. This suggests that in select dialysis patients the surgical removal of foci of chronic inflammation can have an impact on the overall inflammatory state and perhaps survival. PMID- 23109560 TI - Preface: physiopathology of vascular risk factors in Alzheimer's disease. PMID- 23109564 TI - A focus on pressure-driven membrane technology in olive mill wastewater reclamation: state of the art. AB - Direct disposal of the heavily polluted effluent from olive oil industry (olive mill wastewater, OMW) to the environment or to domestic wastewater treatment plants is actually prohibited in most countries, and conventional treatments are ineffective. Membranes are currently one of the most versatile technologies for environmental quality control. Notwithstanding, studies on OMW reclamation by membranes are still scarce, and fouling inhibition and prediction to improve large-scale membrane performance still remain unresolved. Consequently, adequately targeted pretreatment for the specific binomium membrane-feed, as well as optimized operating conditions for the proper membranes, is today's challenge to ensure threshold flux values. Several membrane materials, configurations and pore sizes have been elucidated, and also different pretreatments including sedimentation, centrifugation, biosorption, sieving, filtration and microfiltration, various types of flocculation as well as advance oxidation processes have been applied so far. Recovery of potential-value compounds, such as a variety of polyphenols highlighting oleuropein and hydroxytyrosol, has been attempted too. All this research should constitute the starting point to proceed with OMW purification beyond recycling for irrigation or depuration for sewer discharge, with the aim of complying with standards to reuse the effluent in the olive oil production process, together with cost-effective recovery of added value compounds. PMID- 23109566 TI - Mechanical pre-treatment (MPT) - revitalised by MBR process. AB - Since the mid-nineties membrane bioreactor (MBR) technology has been introduced to municipal wastewater treatment in Europe. The first MBR plants went into operation performing a conventional mechanical pre-treatment (MPT) without any advanced treatment units. After a short operation period, clogging caused by fibrous substances and hence module sludging was observed. Thus, MPT was upgraded introducing sieves. Several investigations had been carried out to determine the removal efficiency of different sieve units and entire MPT systems. Meanwhile experiences from long-term operation at different MBR sites indicate dependencies between different MPT units, especially between the aerated grit chamber/grease trap and the subsequent sieve unit. Usually the sieve is the final MPT unit and its performance depends on the performance of the upstream MPT units. This report describes and discusses results from a research project at MBR Kaarst-Nordkanal in Germany conducted in 2008 to 2010 by the Water Board of River Erft and the Department of Sanitary and Environmental Engineering. Main focus is addressed for the parameters SS (settable solids) and grease. One major experience is the confirmation of relevant interactions between the grit chamber and the downstream sieve unit. Stable operation of the grit chamber and grease trap is essential to achieve a constantly high removal performance of the sieve unit and therefore the entire MPT stage. In turn, negative impacts on the grit chamber performance from the return flow concept have to be avoided. Finally, it is shown that the appropriate two-dimensional sieve gap size should not go beyond 1 mm when operating hollow fibre membranes. PMID- 23109565 TI - Standard and new faecal indicators and pathogens in sewage treatment plants, microbiological parameters for improving the control of reclaimed water. AB - This study involved collaboration between three centres with expertise in viruses, bacteria and protozoa. The focus of the research was the study of the dissemination and removal of pathogens and faecal indicators in two sewage treatment plants (STP1 and STP2) using tertiary treatments. Samples were collected over a period of five months through the sewage treatment processes. Analysis of the samples revealed that the plants were not efficient at removing the faecal indicators and pathogens tested during the study. From entry point (raw sewage) to effluent level (tertiary treatment effluent water), the experimental results showed that the reduction ratios of human adenoviruses were 1.2 log10 in STP1 and 1.9 log10 in STP2. Whereas for Giardia spp. and Cryptosporidium spp. the reduction ratios were 2.3 log10 for both pathogens in STP1, and 3.0 and 1.7 log10 in STP2, respectively. Furthermore, the presence of faecal indicators and pathogens at different sampling points was evaluated revealing that the tested pathogens were present in reclaimed water. Human adenovirus and Arcobacter spp. showed positive results in infectivity assays for most of the tertiary effluent water samples that comply with current legislation in Spain. The pathogens detected must be evaluated using a risk assessment model, which will be essential for the development of improved guidelines for the re-use of reclaimed water. PMID- 23109567 TI - Electro-coagulation treatment of oily wastewater with sludge analysis. AB - Experiments were carried out in a batch reactor to treat the oily effluent by electro-coagulation. The influence of operating parameters such as applied current, type of electrode and electrolysis time on electro-coagulation efficiency has been critically examined. The maximum percentage removal of chemical oxygen demand (COD) was 94% under optimum experimental conditions of pH 6.7, current density 6 mA/cm2, electrolysis time 40 min, and using mild steel as anode. The remaining sludge in the reactor was analyzed by energy disperse analysis of X-rays (EDAX) and scanning electron microscope (SEM) analysis. The analysis confirms that the oily pollutant was removed by electroflotation and adsorption of the oily particles of precipitate during the electro-coagulation process. Electro-coagulation can be used as an efficient treatment technique for oily wastewater. PMID- 23109568 TI - Degradation of bromamine acid by nanoscale zero-valent iron (nZVI) supported on sepiolite. AB - Sepiolite, a natural nano-material, was chosen as a carrier to prepare supported nanoscale zero-valent iron (nZVI). The effects of preparation conditions, including mass ratio of nZVI and activated sepiolite and preparation pH value, on properties of the supported nZVI were investigated. The results showed that the optimal mass ratio of nZVI and sepiolite was 1.12:1 and the optimal pH value was 7. The supported nZVI was characterized by X-ray diffraction (XRD), transmission electron microscope (TEM) and energy dispersive spectrometer (EDS), and furthermore an analogy model of the supported nZVI was set up. Compared with the nZVI itself, the supported nZVI was more stable in air and possessed better water dispersibility, which were beneficial for the degradation of bromamine acid aqueous solution. The degradation characteristics, such as effects of supported nZVI dosage, initial concentration and initial pH value of the solution on the decolorization efficiency were also investigated. The results showed that in an acidic environment the supported nZVI with a dosage of 2 g/L showed high activity in the degradation of bromamine acid with an initial concentration of 1,000 mg/L, and the degree of decolorization could reach up to 98%. PMID- 23109569 TI - Removal of pharmaceutical residue in municipal wastewater by DAF (dissolved air flotation)-MBR (membrane bioreactor) and ozone oxidation. AB - Growing attention is given to pharmaceutical residue in the water environment. It is known that pharmaceuticals are able to survive from a series of wastewater treatment processes. Concerns regarding pharmaceutical residues are attributed to the fact that they are being detected in water and sediment environment ubiquitously. Pharmaceutical treatment using a series of wastewater treatment processes of the DAF (dissolved air flotation)-MBR (membrane bioreactor)-ozone oxidation was conducted in the study. DAF, without addition of coagulant, could remove COD(cr) (chemical oxygen demand by Cr) up to over 70%, BOD 73%, SS 83%, T N 55%, NH4(+) 23%, and T-P 65% in influent of municipal wastewater. Average removal rates of water quality parameters by the DAF-MBR system were very high, e.g. COD(cr) 95.88%, BOD5 99.66%, COD(mn) (chemical oxygen demand by Mn) 93.63%, T-N 69.75%, NH4-N 98.46%, T-P 78.23%, and SS 99.51%, which satisfy effluent water quality standards. Despite the high removal rate of the wastewater treatment system, pharmaceuticals were eliminated to be about 50-99% by the MBR system, depending on specific pharmaceuticals. Ibuprofen was well removed by MBR system up to over 95%, while removal rate of bezafibrate ranged between 50 and 90%. With over 5 mg/l of ozone oxidation, most pharmaceuticals which survived the DAF-MBR process were removed completely or resulted in very low survival rate within the range of few micrograms per litre. However, some pharmaceuticals such as bezafibrate and naproxen tended to be resistant to ozone oxidation. PMID- 23109570 TI - Ecophysiological role and function of uncultured Chloroflexi in an anammox reactor. AB - The coexistence of uncultured heterotrophic bacteria belonging to the phylum Chloroflexi has often been observed in anaerobic ammonium oxidation (anammox) reactors fed with synthetic nutrient medium without organic carbon compounds. To determine if coexisting Chloroflexi in anammox reactors scavenge organic matter derived from anammox bacterial cells, the present study was conducted to investigate the substrate uptake pattern of the uncultured Chloroflexi present in an anammox reactor and to clarify if they take up microbial products derived from anammox bacterial cells. To accomplish this, combined microautoradiography and fluorescence in situ hybridization (MAR-FISH) was conducted. Phylogenetic analysis revealed that 36% of the clones analyzed in this study were affiliated with Chloroflexi. The sequence similarities to Anaerolinea thermophila and Caldilinea aerophila within the phylum Chloroflexi were only 81.0-88.7% and 80.3 83.8%, respectively. The uncultured Chloroflexi were found to incorporate sucrose, glucose, and N-acetyl-glucosamine. The (14)C-tracing experiment revealed that the uncultured Chloroflexi were clearly MAR-positive, indicating the utilization of decaying anammox bacterial cell materials. Taken together, these results indicate that coexisting uncultured Chloroflexi in anammox reactors scavenge organic compounds derived from anammox bacterial cells. PMID- 23109571 TI - Occurrence of pharmaceuticals and endocrine disruptors in raw sewage and their behavior in UASB reactors operated at different hydraulic retention times. AB - This work investigated the occurrence of pharmaceuticals and endocrine disrupting compounds (EDCs) in raw sewage (from Belo Horizonte city, Minas Gerais state, Brazil) and assessed their behavior in demo-scale upflow anaerobic sludge blanket reactors (UASB reactors) operated at different hydraulic retention times (HRT). The dissolved concentration of the studied micropollutants in the raw and treated sewage was obtained using solid phase extraction (SPE) followed by analysis in a liquid chromatography system coupled to a hybrid high resolution mass spectrometer consisting of an ion-trap and time of flight (LC-MS-IT-TOF). The natural (estradiol) and synthetic (ethinylestradiol) estrogens were hardly detected; when present, however, their concentrations were lower than the method quantification limits. The concentrations of bisphenol A and miconazole in raw sewage were similar to that reported in the literature (around 200 ng L-1 and hardly detected, respectively). The antibiotics sulfamethoxazole (median 13.0 ng L-1) and trimethoprim (median 61.5 ng L-1), and the other pharmaceutical compounds (diclofenac and bezafibrate, with median 99.9 and 94.4 ng L-1, respectively) were found in lower concentrations when compared with reports in the literature, which might indicate a lower consumption of such drugs in Brazil. The UASB reactors were inefficient in the removal of bisphenol A, and led to an increased concentration of nonylphenol in the effluent. The anaerobic reactors were also inefficient in the removal of diclofenac, and led to a partial removal of bezafibrate; whereas, for sulfamethoxazole there seemed to be a direct relationship between the HRT and removal efficiencies. For trimethoprim the sludge retention time (SRT) seemed to play an important role, although it was only partially removed in the UASB reactors. PMID- 23109572 TI - Granular biomass selection in a double-stage biogas collection UASB reactor: effects on SMA, abundance and diversity of the methanogenic population. AB - The present work aimed at investigating biomass selection in a pilot-scale double stage biogas collection (DSBC) upflow anaerobic sludge bed (USAB) reactor treating domestic wastewater. Specific methanogenic activity (SMA) measurements and FISH countings were applied to sludge samples collected during 102 days of operation of the DSBC-UASB and of a control reactor. Results showed that both reactors presented similar SMA values in early stages of operation however the UASB-DSBC reactor showed much higher SMA after day 45, when the biomass was in granular stage. In terms of archaeal abundance, no statistical difference was observed between the reactors. Polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) revealed a similar composition of the archaeal communities in the two reactors and during the operational period, mainly constituted by Methanosaeta concilii. The results suggest that cell activity rather than archaeal abundance or diversity drive the methane production in the UASB reactors. PMID- 23109573 TI - The operation of two EGSB reactors under the application of different loads of oxytetracycline and florfenicol. AB - This study evaluated the effect of the antibiotics oxytetracycline (OTC) and florfenicol (FLO) on the operation of two EGSB (expanded granular sludge bed) reactors. The experiment was conducted for 210 d in reactor R1 and 245 d in reactor R2. The reactors were inoculated with granular sludge from a upflow anaerobic sludge blanket (UASB) reactor on a local dairy farm. The sludge had an average pellet size of 2.35 mm, good sedimentability and a high percentage of organic material. The antibiotic tolerance and the inhibitory action on the bacterial population were different for each antibiotic studied. The results showed a more severe inhibitory effect on microorganisms that were in contact with increases in loads of FLO than those that were in contact with increasing loads of OTC, a condition reflected in the chemical oxygen demand (COD) removal efficiency. PMID- 23109574 TI - Decontamination of synthetic textile wastewater by electrochemical processes: energetic and toxicological evaluation. AB - The treatment of a synthetic textile wastewater, prepared with several compounds used in the finishing of textile materials, was comparatively studied by electrochemical methods such as electrooxidation (EO) (titanium electrode) and electrocoagulation (EC) (with aluminum and iron electrodes). The influence of pH, current density and operating time on the treatment was assessed by the parameters used to measure the level of organic contaminants in the wastewater; i.e. color, toxicity and chemical oxygen demand (COD). The experimental results showed that an effective electrochemical oxidation was achieved in which the wastewater was decolorized and 92% of COD was completely eliminated. In particular, the mineralization took place by indirect oxidation, mediated by active chlorine, and the treatment efficiency was enhanced by the addition of NaCl to the wastewater and by increasing the applied current density. The toxicity, still higher than the toxicity of the raw effluent, indicated a presence of toxic products after EO. Good results were obtained with the Al and Fe electrodes, mainly with respect to the removal of color and toxicity. EC is more economical than EO and the toxicity evaluation with the Daphnia magna test shows a significant reduction after EC. PMID- 23109575 TI - The effect of sludge recirculation rate on a UASB-digester treating domestic sewage at 15 degrees C. AB - The anaerobic treatment of low strength domestic sewage at low temperature is an attractive and important topic at present. The upflow anaerobic sludge bed (UASB) digester system is one of the anaerobic systems to challenge low temperature and concentrations. The effect of sludge recirculation rate on a UASB-digester system treating domestic sewage at 15 degrees C was studied in this research. A sludge recirculation rate of 0.9, 2.6 and 12.5% of the influent flow rate was investigated. The results showed that the total chemical oxygen demand (COD) removal efficiency rose with increasing sludge recirculation rate. A sludge recirculation rate of 0.9% of the influent flow rate led to organic solids accumulation in the UASB reactor. After the sludge recirculation rate increased from 0.9 to 2.6%, the stability of the UASB sludge was substantially improved from 0.37 to 0.15 g CH4-COD/g COD, and the bio-gas production in the digester went up from 2.9 to 7.4 L/d. The stability of the UASB sludge and bio-gas production in the digester were not significantly further improved by increasing sludge recirculation rate to 12.5% of the influent flow rate, but the biogas production in the UASB increased from 0.37 to 1.2 L/d. It is recommended to apply a maximum sludge recirculation rate of 2-2.5% of the influent flow rate in a UASB digester system, as this still allows energy self-sufficiency of the system. PMID- 23109576 TI - Molecular weight distribution of organic matter by ozonation and biofiltration. AB - Molecular weight (MW) distribution of organic matter by ozonation and biofiltration was evaluated using gel chromatography. The MW distribution of organic matter by Sephadex G-25 was observed from groups 2 (MW = 1,029-7,031 g/mol) and 3 (MW = 303-1,029 g/mol) shifted to groups 2, 3 and 4 (MW < 303 g/mol) under ozone doses of 0.1 and 0.4 mg O3/mg total organic carbon (TOC). The shift in MW increases as ozone dosage increases. Biofiltration effectively degraded the organic molecule of group 2; however, the biofiltration only slightly degraded the organic molecule of group 4. Increased ozone dose destroyed functional groups C?C in phenolic and C-O in alcoholic compounds and increased UV-insensitive biodegradable organic carbon for subsequent biofiltration. Biofiltration effectively degraded organic compounds of alcohols and alkenes at an ozone dose of 0.1 mg O3/mg TOC. Experimental approaches in this study can be applied to evaluate and diagnose the function of a full-scale process combining ozonation and biofiltration in drinking water treatment plants. PMID- 23109577 TI - Lead isotopes as a tracer of Pb origin in the sediments from Beijiang River, South China. AB - Concentrations and enrichment of heavy metals were determined in sediments collected from Beijiang River, South China. The Pb isotopic compositions in these sediment samples were also employed to effectively identify metal pollution sources. According to the measured Pb concentrations, the total Pb concentrations in sediments varied from 62.1 to 1,152.5 MUg/g, with an average concentration of 249.6 MUg/g. The assessment by Geoaccumulation Index indicates that Pb is at the 'strongly contaminated' level, indicating that the Pb pollution was mainly due to anthropogenic inputs. The observed isotopic ratios varied from 1.174 to 1.204 for 206Pb/207Pb, 2.452 to 2.478 for 208Pb/207Pb, 18.404 to 18.937 for 206Pb/204Pb, 15.631 to 15.790 for 207Pb/204Pb, 38.455 to 39.121 for 208Pb/204Pb. The majority of these ratios are lower than those reported for natural geological sources, especially for sediments collected from a smelter. Significant correlation between Pb concentration and isotopic ratios suggested possible binary mixing of Pb. Combined with Pb concentration and enrichment levels, our results show that Pb pollution in the sediments of Beijiang River was mainly derived from anthropogenic sources. The mining activities and metal smelting processing was the main source of Pb pollution in this region. PMID- 23109578 TI - Bioaccumulation and primary risk assessment of persistent organic pollutants with various bivalves. AB - Field surveys on persistent organic pollutant (POP) bioaccumulation were conducted with oysters, clams and scallops whose consumption amount accounted for large shares in the total consumption of shellfish in Japan. There was no numerical difference in bioaccumulation characteristics between oysters, clams, scallops, Corbicula and Mytilus galloprovincialis. Therefore, it was clear that the bioaccumulation characteristics in oysters, clams and scallops, which are important for food, could be ascertained by using the monitoring results with Corbicula and M. galloprovincialis which are easily sampled in various water areas in the world. Non-cancer risk (hazard quotient, HQ) and cancer risk (excess cancer risk, DeltaR) via shellfish ranged from 10-8 to 10-4 and from 10-11 to 10 7, respectively, at sampling points, which showed the risks of POP exposure via shellfish to be low enough. However, concerning the intake of other food, the importance of dieldrin monitoring should be suggested in Japan. Based on these results, the effectiveness of primary risk assessment could be suggested for screening chemicals whose preferential monitoring is needed. PMID- 23109579 TI - Sustainable nitrogen removal by denitrifying anammox applied for anaerobic pre treated potato wastewater. AB - The feasibility of sustainable nitrogen removal was investigated in a two stage biofilm configuration consisting of a MBBR (Moving Bed Biofilm Reactor) and a Deamox reactor (Biobed-EGSB). The MBBR is used for nitrification and the denitrifying ammonium oxidation (Deamox) is aimed at a nitrogen removal process in which part of the required nitrite for the typical anammox reaction originated from nitrate. Anaerobic pre-treated potato wastewater was supplied to a MBBR and Deamox reactor operated in series with a bypass flow of 30%. The MBBR showed stable nitrite production at ammonium-loading rates of 0.9-1.0 kg NH4-N/m3 d with ammonium conversion rates of 0.80-0.85 kg NH4-N/m3 d. The nitrogen-loading rate and conversion rate of the Deamox reactor were 1.6-1.8 and 1.6 kg N/m3 d. The maximum ammonium removal capacity in the Deamox reactor was 0.6 kg NH4-N/m3 d. The removal efficiency of soluble total nitrogen reached 90%. The Deamox process performance was found to be negatively affected during decline of the operating temperature from 33 to 22 degrees C and by organic loading rates with a chemical oxygen demand (COD)/NO2-N ratio >1. PMID- 23109580 TI - Synthesization, characterization and adsorption properties of sulfonic cellulose. AB - The synthesization and characterization of a new environmental functional material-sulfonic cellulose - were studied in this paper. The preparation conditions were optimized through an orthogonal experiment. The modified cellulose was characterized by Fourier transform infrared spectroscopy (FTIR), X ray diffraction (XRD) and scanning electron microscope (SEM). The adsorption rules of cationic organic pollutants and heavy metal ions by this new material were discussed. Regeneration and recycling performances of the sulfonic cellulose were also investigated. At the temperature of 323 K, sulfonic cellulose was prepared by grafting 2-acrylamido-2-methylpropane sulfonic acid (AMPS) onto alkali-treated cellulose for 4 h with the employing of ceric ammonium nitrate as initiator. The mass ratio of AMPS to cellulose was 3:1 and the concentration of ceric ammonium nitrate was 63.8 mmol/L. The sulfur content of sulfonic cellulose was 7.32 wt%. The peaks of 1,303 and 1,159 cm-1 in IR suggested the existence of the sulfonic group in sulfonic cellulose. The XRD and SEM results showed that the crystallinity decreased while the specific surface area increased after modification. Batch adsorption results showed that sulfonic cellulose had a favorable adsorption capacity for model contaminants at pH 6.0-7.0. The adsorption process was endothermic and reached equilibrium in 180 min. The adsorption rules of cationic organic pollutants and heavy metal ions indicated that sulfonic cellulose had high adsorption capacity for the cationic dyes with a coplanar macromolecule structure and organic compounds carrying the amino group. Under room temperature, 1.0 mol/L HCl can be used as a desorption solution and the equilibrium adsorption capacity had little decrease (less than 7%) after six adsorption-desorption cycles. PMID- 23109581 TI - Enhancing oil-sorption performance of polypropylene fiber by surface modification via UV-induced graft polymerization of butyl acrylate. AB - In order to improve oil sorption performances, polypropylene (PP) fiber was modified through graft polymerization with butyl acrylate (BA) initiated by ultraviolet (UV) radiation in isopropanol/water mixture solution. Fourier transform infrared (FT-IR) spectra, scanning electron microscopy (SEM) and specific surface area were used to characterize the chemical and morphological changes of the PP fiber surface. Static contact angle (CA) measurements showed that the hydrophilicity of original PP fiber was enhanced after graft polymerization. The grafted fiber exhibited an excellent oil-sorption, oil retention performance, fast saturation-sorption rate and superior reusability of oil. When the grafting degree was 15.55%, the maximum oil-sorption capacity reached 18.35 g/g, while the oil-sorption capacity of original PP fiber was only 11.54 g/g. After the tenth cycle of reuse, the grafted fiber sorbent assembly only lost 30% of its virgin sorption capacity. PMID- 23109582 TI - Spectrophotometric determination of trace amounts of phosphate in water and soil. AB - A simple spectrophotometric method has been developed for the determination of phosphate dissolved in soil and water. The method is based on the formation of phosphomolybdate with added ammonium molybdate followed by reduction with hydrazine in acidic medium. Orthophosphate and molybdate ions condense in acidic solution to give molybdophosphoric (phosphomolybdic) acid, which upon selective reduction (perhaps with hydrazinium sulphate) produces a blue colour, due to molybdenum blue of uncertain composition. The intensity of blue colour is proportional to the amount of phosphate. If the acidity at the time of reduction is 0.5 M in sulphuric acid and hydrazinium sulphate is the reductant, the resulting blue complex exhibits maximum absorption at 830 nm. The system obeys Lambert-Beer's law at 830 nm in the concentration range of 0.5-5 MUg/mL of phosphate with a relative standard deviation (RSD) of 0.1% and correlation coefficient of 0.99. Molar absorptivity was determined to be 2.9 * 104 L mol-1 cm 1 at 830 nm. The method is also applicable for the determination of phosphate in nuclear reprocessing plants, medical science, clinical science, agriculture, metallurgy and environmental science. PMID- 23109583 TI - Modeling sewage leakage to surrounding groundwater and stormwater drains. AB - Underground sewage pipe systems deteriorate over time resulting in cracks and joint defects. Sewage thus leaks out and contaminates the surrounding groundwater and the surface water in stormwater drains. Many studies have investigated the problem of sewage leakage but no published studies, to the best knowledge of the authors, have examined the hydrologic interactions between leaky sewage pipes, groundwater and stormwater drains. This study numerically models such interactions using generic conditions in Singapore. It first develops accurate representations of weep holes and leaky sewage pipes, and further shows the long term and short-term system responses to rainfall events. Some of the implications include: (1) quality of water seeping into the drains tends to be low in dry years; (2) complete contaminant attenuation after pipe rehabilitation takes several years; (3) responses to rainfall events at weep holes are immediate but the effects on sewage leakage might only show up a few days later. The simulation results allow us to better understand the local-scale migration of sewage leakage from a sewage pipe to nearby stormwater drains. With calibrations and verifications with local field data, the modeling framework would be applicable and beneficial to the sewage leakage monitoring and sewage pipe rehabilitation worldwide. PMID- 23109584 TI - The impact of Pleurotus ostreatus on organic matter transformation processes. AB - This study showed the effect of Pleurotus ostreatus on the external organic matter (OM) transformation processes. The kinetics of these changes were determined. The experiment was conducted as 42-day pot experiment done in four combinations (with four replications). The four combinations of different substrates were: (1) organic, (2) composted hay, (3) organic soil + composted hay, (4) organic soil + composted hay + lead. The study results showed that P. ostreatus had the ability to transform external OM as well as metal-organic complexes. These transformations were reflected in the constant rate of characterized changes and correlation coefficients. The study also indicated the direction of the external OM transformation. The direction leads to the selective oxidation of aliphatic structures, and an increase in humic substances which are resistant to oxidation. The study also identified the negative impact of lead on the ability of P. ostreatus to transform humic substances. The impact of lead was expressed as the lower value of the rapid rate constant k1 in objects enriched with lead acetate. PMID- 23109585 TI - Faecal contamination of public water sources in informal settlements of Kisumu City, western Kenya. AB - High levels of environmental contamination, often associated with improper waste and excreta management, are widespread among informal settlements within urban areas in developing countries. We determined the level of faecal contamination in domestic water sources and evaluated the potential contribution of these water sources to intestinal helminthiases in seven informal settlements of Kisumu City, western Kenya. Membrane filtration technique was used for enumeration of total and faecal (Escherichia coli) coliform bacteria in water samples collected from dams, rivers, springs and wells. Out of the 80 water sources sampled, 76 (95%) were highly contaminated with E coli. All water samples from unprotected wells (26) and 92.6% of samples from protected wells (25) were positive for E. coli. The highest and lowest E. coli densities were observed in samples from dams (3,800 +/- 1,807 coliforms per 100 ml) and boreholes (419 +/- 223 coliforms per 100 ml), respectively (p = 0.0321). Distance from pit latrines was negatively associated with E. coli coliform density for wells (r = -0.34, n = 53, p = 0.0142). Untreated well-water may not be suitable for human consumption, and its continued use constitutes a major health risk for the inhabitants of these informal settlements. PMID- 23109586 TI - Surveillance of human viral contamination and physicochemical profiles in a surface water lagoon. AB - The present study evaluated the contamination of a surface water lagoon (Peri Lagoon) in Florianopolis, Santa Catarina, Brazil, by human adenovirus (HAdV), polyomavirus JC (JCPyV), hepatitis A virus (HAV) and rotavirus species A (RVA). Efforts were driven to determine the correlation between viral presence and the physicochemical parameters of the lagoon and measure the distribution of these viruses throughout the year (June 2010 to May 2011). A total of 48 samples were collected, concentrated and analyzed by qPCR (quantitative polymerase chain reaction). Approximately 96% of the samples were positive for HAdV (46/48), 65% were positive for RVA (31/48), 21% were positive for JCPyV (10/48) and 12% were positive for HAV (6/48). The presence of JCPyV was positively correlated with that of NO(2)(-)N, and also there was a positive correlation between the presence of each one of the viruses (HAdV, HAV and RVA) in winter. Samples from water dedicated for human consumption and recreation tested positive for HAdV by qPCR. These samples were also subjected to viral integrity and viability assays: 83% (10/12) contained intact viral particles and 66% (8/12) contained infectious particles. Our results demonstrate the release of human waste into water sources, justifying the urgent need to add viral parameters to water quality surveillance. PMID- 23109588 TI - Degradation of naproxen by combination of Fenton reagent and ultrasound irradiation: optimization using response surface methodology. AB - A central composite factorial design methodology was employed to optimize the degradation of naproxen (NPX) by the combination of Fenton reagent and ultrasound (US) irradiation. In this study, the variables considered for the process optimization were the hydrogen peroxide, ferrous ion and NPX initial concentrations, while ultrasonic power amplitude was adjusted at 90% and initial pH was 3. An appropriate quadratic model was developed in order to plot the response surface and contour curves. Optimum dosage of Fenton reagent for NPX removal was found to be hydrogen peroxide concentration = 9.98 mmol L-1, ferrous ion concentration = 4.83 mg L-1 while NPX concentration was equal to 20 mg L-1. A degradation efficiency of 100% was achieved within 10 min under US. PMID- 23109587 TI - Characteristics of various forms of phosphorus and their relationships in the sediments of Haizi Lake, China. AB - The phosphorus (P) distribution in the sediments of Haizi Lake from the middle reach of the Yangtze River region, China, was investigated using a sequential chemical extraction procedure. P forms and concentrations of sediment samples taken at 25 sites over the whole lake were measured. The relationships between various forms of P in sediments and dissolved P in the overlying water were also discussed. Results showed that the concentrations of total P (TP) in the sediments ranged from 404 to 670 mg kg-1, with an average of 503 mg kg-1. The exchangeable P (Ex-P), Al-bound P (Al-P), Fe-bound P (Fe-P), occluded P (Oc-P), authigenic carbonate fluorapatite + biogenic apatite + CaCO3-associated P (ACa P), detrital apatite + other inorganic P (De-P) and organic P (Or-P) accounted for, on average, 0.52, 0.04, 10.9, 32.0, 7.4, 20.1 and 29.0% of TP, respectively. Relevance analysis indicated that Oc-P, ACa-P and De-P, as the majority forms of inorganic P, were less correlated to others. The significant correlations between Ex-P, Al-P, Fe-P, Or-P and TP suggested the probability of reciprocal transformation. It was suggested that Ex-P, Al-P, Fe-P, Or-P and TP in the sediments might be released easily to the water interface, resulting in sustained lake eutrophication. PMID- 23109589 TI - Urban water infrastructure asset management - a structured approach in four water utilities. AB - Water services are a strategic sector of large social and economic relevance. It is therefore essential that they are managed rationally and efficiently. Advanced water supply and wastewater infrastructure asset management (IAM) is key in achieving adequate levels of service in the future, particularly with regard to reliable and high quality drinking water supply, prevention of urban flooding, efficient use of natural resources and prevention of pollution. This paper presents a methodology for supporting the development of urban water IAM, developed during the AWARE-P project as well as an appraisal of its implementation in four water utilities. Both water supply and wastewater systems were considered. Due to the different contexts and features of the utilities, the main concerns vary from case to case; some problems essentially are related to performance, others to risk. Cost is a common deciding factor. The paper describes the procedure applied, focusing on the diversity of drivers, constraints, benefits and outcomes. It also points out the main challenges and the results obtained through the implementation of a structured procedure for supporting urban water IAM. PMID- 23109590 TI - Characteristics and separation efficiencies of PPSU/PEI/PEG blend membranes with different compositions for water treatment. AB - To overcome the problems and constraints in the application of single organic membranes in wastewater treatment or water reuse processes, different blend membranes were prepared and modified to improve the separation efficiency of humic acids (HAs) and mitigate the fouling problems occurring during water purification. This study extends the results of our previous research and further investigates the relationships between the composition of polyphenylsulfone/polyetherimide/polyethylene glycol (PPSU/PEI/PEG) blend membranes and membrane characteristics and performance. The experimental results showed that the PEI and PEG component ratios of PPSU could significantly affect the blend membrane structure, morphology, and properties. With the increase in PEG concentration, the pore volume, pore size distribution, and permeability of the blend membranes was enhanced. The hydrophilic or hydrophobic properties of the blend membranes can be modified by changing the PPSU/PEI ratios. The optimum composition of the PPSU/PEI/PEG blend membrane was 35/5/6 wt%, and the corresponding permeability and HAs separation efficiency was 127 Lm-2h-1 and 83%, respectively. PMID- 23109591 TI - Effects of bubbling operations on a thermally stratified reservoir: implications for water quality amelioration. AB - Artificial thermal mixing of the water column is a common method of addressing water quality problems with the most popular method of destratification being the bubble curtain. The air or oxygen distribution along submerged multiport diffusers is based on similar basic principles as those of outfall disposal systems. Moreover, the disposal of sequestered greenhouse gases into the ocean, as recently proposed by several researchers to mitigate the global warming problem, requires analogous design criteria. In this paper, the influence of a bubble-plume is evaluated using full-scale temperature and water quality data collected in San Roque Reservoir, Argentina. A composite system consisting of seven separated diffusers connected to four 500 kPa compressors was installed at this reservoir by the end of 2008. The original purpose of this air bubble system was to reduce the stratification, so that the water body may completely mix under natural phenomena and remain well oxygenated throughout the year. By using a combination of the field measurements and modelling, this work demonstrates that thermal mixing by means of compressed air may improve water quality; however, if improperly sized or operated, such mixing can also cause deterioration. Any disruption in aeration during the destratification process, for example, may result in a reduction of oxygen levels due to the higher hypolimnetic temperatures. Further, the use of artificial destratification appears to have insignificant influence on reducing evaporation rates in relatively shallow impoundments such as San Roque reservoir. PMID- 23109592 TI - Co-governing decentralised water systems: an analytical framework. AB - Current discourses in urban water management emphasise a diversity of water sources and scales of infrastructure for resilience and adaptability. During the last 2 decades, in particular, various small-scale systems emerged and developed so that the debate has largely moved from centralised versus decentralised water systems toward governing integrated and networked systems of provision and consumption where small-scale technologies are embedded in large-scale centralised infrastructures. However, while centralised systems have established boundaries of ownership and management, decentralised water systems (such as stormwater harvesting technologies for the street, allotment/house scales) do not, therefore the viability for adoption and/or continued use of decentralised water systems is challenged. This paper brings together insights from the literature on public sector governance, co-production and social practices model to develop an analytical framework for co-governing such systems. The framework provides urban water practitioners with guidance when designing co-governance arrangements for decentralised water systems so that these systems continue to exist, and become widely adopted, within the established urban water regime. PMID- 23109593 TI - Assessment of the potential for biogas production from wheat straw leachate in upflow anaerobic sludge blanket digesters. AB - Wheat straw is a major potential source of waste biomass for renewable energy production, but its high salt content causes problems in combustion. The salts can be removed by washing, but this process also removes a proportion of the organic material which could potentially be recovered by anaerobic digestion of the washwater leachate. This approach would maximise the overall energy yield in an integrated process in which washwater could be recycled after further desalting. Leachate from cold water washing with a chemical oxygen demand (COD) of 1.2 g l-1 was fed to mesophilic upflow anaerobic sludge blanket (UASB) digesters at a loading rate of 1 g COD l-1 day-1 to determine the energy yield and any detrimental effects of the leached salts on the process. The specific methane production was 0.29 l CH4 g-1 COD(added), corresponding to a COD removal rate of 84%. Light metal cations in the leachate, especially potassium, were found to accumulate in the digesters and appeared to have a synergistic effect up to a concentration of ~6.5 mg K g-1 wet weight of the granular sludge, but further accumulation caused inhibition of methanogenesis. It was shown that gas production in the inhibited digesters could be restored within 12 days by switching the feed to a synthetic sewage, which washed the accumulated K out of the digesters. PMID- 23109594 TI - Estimates of methane loss and energy recovery potential in anaerobic reactors treating domestic wastewater. AB - This work aimed at developing a mathematical model that could estimate more precisely the fraction of chemical oxygen demand (COD) recovered as methane in the biogas and which, effectively, represented the potential for energy recovery in upflow anaerobic sludge blanket (UASB) reactors treating domestic wastewater. The model sought to include all routes of conversion and losses in the reactor, including the portion of COD used for the reduction of sulfates and the loss of methane in the residual gas and dissolved in the effluent. Results from the production of biogas in small- and large-scale UASB reactors were used to validate the model. The results showed that the model allowed a more realistic estimate of biogas production and of its energy potential. PMID- 23109595 TI - Anaerobic/aerobic treatment of a petrochemical wastewater from two aromatic transformation processes by fluidized bed reactors. AB - An integrated fluidized bed reactor (FBR) has been employed as the treatment for petrochemical industry wastewaters with high organic matter and aromatic compounds, under anaerobic and aerobic conditions. The system was operated at hydraulic residence time (HRT) of 2.7 and 2.2 h in the anaerobic and aerobic reactor, respectively. The degree of fluidization in the beds was 30%. This system showed a high performance on the removal of organic matter and aromatic compounds. At different organic loading rates (OLR), the chemical oxygen demand (COD) removal in the anaerobic reactor was close to 85% and removals of the COD up to 94% were obtained in the aerobic reactor. High removals of benzene, toluene, ethylbenzene, xylenes, styrene, 1,2,4-trimethylbenzene, 1,3,5 trimethylbenzene and naphthalene were achieved in this study. PMID- 23109596 TI - Worldwide surveys of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) in water environment in recent years. AB - Recently, perfluorinated compounds (PFCs) have been noted as causes of some of the important environmental problems in recent years due to their occurrences and properties. The most commonly used PFCs are perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), which have been used in many kinds of products. They have been found in surface water and tap water in both developed and developing countries around the world including in North America, Europe and Asia. In most countries, rivers are the source of tap water, which is one of the important pathways in which PFCs reach humans. It is essential to evaluate PFOS and PFOA contamination in the river basin. The purpose of this field study was to determine the presence of PFOS and PFOA in rivers around the world. The surveys were conducted in 15 countries during 2004 to 2010. In total, 539 samples were collected from the rivers in 41 cities. A solid phase extraction (SPE) coupled with HPLC-ESI-MS/MS were used for the analysis of these chemicals. PFOS and PFOA were detected in all 41 cities not only in industrialized areas but also in non industrialized areas, representing that these compounds undergo long-range transportation in the environment. The average concentration of PFOS in each city ranged from not detected to 70.1 ng/L. The average concentration of PFOA in each city was in the range 0.2-1,630.2 ng/L. The industrialized areas show higher contamination in both PFOS and PFOA concentrations than non-industrialized areas. Industrial activities are some of the major sources of PFCs contamination in rivers. PMID- 23109597 TI - Water treatment using activated carbon supporting silver and magnetite. AB - Recent efforts in water purification have led to the development of novel materials whose unique properties can offer effective biocidal capabilities with greater ease of use and at lower cost. In this study, we introduce a novel procedure for the preparation of activated carbon (charcoal) composite in which magnetite and silver are incorporated (MCAG); we also describe the use of this material for the disinfection of surface water. The formation process of magnetic MCAG composite was studied using ultraviolet-visible spectroscopy. The results demonstrated the high sorption efficiency of AgNO3 to magnetic activated carbon. The antimicrobial capabilities of the prepared MCAG were examined and the results clearly demonstrate their inhibitory effect on total river water bacteria and on Pseudomonas koreensis and Bacillus mycoides cultures isolated from river water. The bacterial counts in river water samples were reduced by five orders of magnitude following 30 min of treatment using 1 g l-1 of MCAG at room temperature. The removal of all bacteria from the surface water samples implies that the MCAG material would be a suitable disinfectant for such waters. In combination with its magnetic character, MCAG would be an excellent candidate for the simple ambulatory disinfection of surface water. PMID- 23109598 TI - Pilot plant study of alternative filter media for rapid gravity filtration. AB - Sand has been the main filter media used in rapid gravity filtration since its introduction. The dominance of sand has been due to its low cost and availability. Extensive experience has led to sand filters with a dependable and predictable performance. Sand remains the preferred filter medium but usually with a larger sized anthracite capping to reduce the onset of head loss. Other approved filter media are now commercially available and this paper compares sand with recycled glass, Filtralite((r)) and slate at pilot scale. The results have reaffirmed the basic importance of particle size on head loss and turbidity performance rather than surface activity or specific surface area. The results did suggest, however, that particle shape and packing exerted a stronger influence on performance than previously acknowledged. These could be used to improve the design and the contribution to sustainability made by rapid gravity filters. PMID- 23109599 TI - Performance and microbial characteristics of integrated fixed-film activated sludge system treating industrial wastewater. AB - Integrated fixed-film activated sludge (IFAS) is a modification of conventional activated sludge processes used for wastewater treatment consisting of biofilm attachment surfaces added to suspended-growth reactors, thereby creating hybrid suspended attached-growth systems. In this work, an IFAS system, with a total working volume of 560.7 L, was employed to investigate the performance of pollutants removal in industrial effluent. Microbial communities of suspended growth and attached-growth biomass were investigated by a combination of polymerase chain reaction-denaturing gradient gel electrophoresis (PCR-DGGE) and fluorescence in situ hybridization (FISH). In the system, suspended-growth and attached-growth biomass worked together to maintain a stable COD, NH4(+)-N and TN removal efficiency of 74, 93 and 76%, respectively. PCR-DGGE results showed that Proteobacteria was the dominant genera of bacteria in both the suspended and attached growth sludge. Some of the bacterial species (Firmicutes and Pseudomonas) may play an important role in the organic degradation of this water. Denitrifying bacteria were found to be accumulated in the biofilms. FISH results showed that there were more nitrifying bacteria in the suspended-growth biomass than the attached-growth biomass but fewer denitrifying bacteria in the former biomass. PMID- 23109600 TI - Application of the radiating effect concept to implement measures stipulated by the European Water Framework Directive. AB - Hydromorphological deficits of European rivers and creeks are a major reason for the fact that the good ecological status stipulated by the European Water Framework Directive has not been achieved. In order to overcome these deficits, the German state of North Rhine-Westphalia calls for the implementation of a radiating effect concept to facilitate the planning of cost-effective restoration measures. The radiating effect concept states that natural or near-natural sections of water bodies have a positive impact on adjacent hydromorphologically altered sections. Transforming this concept into concrete measures will contribute to creating and boosting such radiating effects. We have applied the radiating effect concept to 11 small streams in a low mountain range and assessed its efficiency by comparing the biological and hydromorphological data of 48 sampling sites. Our findings show that near-natural stream sections have a positive effect on the ecological status of adjacent hydromorphologically altered sections. This study provides an innovative approach to the implementation of Integrated River Basin Management at a local scale. Its results are potentially of major interest to water managers dealing with the challenge of prioritizing river restoration measures. Nevertheless, specific issues such as assessing the influence of artificial barriers limiting the radiating effects need to be further investigated. PMID- 23109601 TI - Nutrient retention in riparian floodplains on landscape scale, the necessity for a monthly retention approach. AB - This study analyses the computed nitrogen retention, the distribution and the extent of riparian floodplains of three German rivers, as input data and application of the retention model has not been carried out on landscape scale so far. The Software FLYS 2.1.3 was used for the calculation of the floodplain extent and depth at certain discharges. Thus a first empirical approach is suggested to quantify the share of load that enters the floodplain (incoming load) and the extent of floodplain as variables depending on discharge ratios. Measured loads have subsequently been applied to the presented approach to calculate incoming loads on a monthly and yearly basis for the years 1999 and 2002. Finally, linear and exponential yearly retention models were applied, obtained from the literature. Large variations in the retention results were found between the years and the models and between monthly and yearly calculations. In hydrologically average years, calculated retention rates are in the range of reported values (440-670 kg N ha-1 yr-1), whereas for wet years, retention values account for 1,400 kg N ha-1 yr-1. Consequently, this approach needs to be improved to reduce overestimation by considering more complex characteristics of the floodplain, but generally its application is possible on the landscape scale. PMID- 23109602 TI - Influence of flow velocity on the removal of faecal coliforms in horizontal subsurface flow constructed wetland. AB - In order to determine the influence of flow velocity on the removal of faecal coliforms (FC) in constructed wetlands (CWs), removal rate constants of FC (k(FC)) were studied at various flow velocities (u). Membrane filtration technique was used during analysis. Values of k(FC) were determined using Reed's equation of pathogen removal; the results were compared with the plug flow equation. According to Reed's equation, k(FC) values ranged from 1.6 day-1 at a velocity of 4 m/day to 34.5 day-1 at a velocity of 42.9 m/day. The removal rates correlated positively with flow velocity (r = 0.84, p < 0.05). On assuming a plug flow equation, removal rates constants ranged from 0.77 to 11.69 day-1; a more positive correlation (r = 0.93, p < 0.05) was observed. Optimum removal rate constants were observed for the velocity ranging 36 to 43 m/day. Generally, the increase of flow velocity improved FC removal rate constants: implying that pathogen removals are influenced by diffusion of the microorganisms into the biofilms on CW media. The velocity dependent approach together with the plug flow equation is therefore proposed for incorporation in the design of CW in a tropical climate where temperature variations are minor. PMID- 23109603 TI - Determination of the effect of wind velocity and direction changes on turbidity removal in rectangular sedimentation tanks. AB - In the present study, a pilot-scale sedimentation tank was used to determine the effect of wind velocity and direction on the removal efficiency of particles. For this purpose, a 1:20 scale pilot simulated according to Frude law. First, the actual efficiency of total suspended solids (TSS) removal was calculated in no wind condition. Then, the wind was blown in the same and the opposite directions of water flow. At each direction TSS removal was calculated at three different velocities from 2.5 to 7 m/s. Results showed that when the wind was in the opposite direction of water flow, TSS removal efficiency initially increased with the increase of wind velocity from 0 to 2.5 m/s, then it decreased with the increase of velocity to 5 m/s. This mainly might happen because the opposite direction of wind can increase particles' retention time in the sedimentation tank. However, higher wind velocities (i.e. 3.5 and 5.5 m/s) could not increase TSS removal efficiency. Thus, if sedimentation tanks are appropriately exposed to the wind, TSS removal efficiency increases by approximately 6%. Therefore, energy consumption will be reduced by a proper site selection for sedimentation tank unit in water and waste water treatment plants. PMID- 23109604 TI - Resolving Canada's jurisdictional health quagmire. PMID- 23109606 TI - Healthier doctors, healthier patients. PMID- 23109605 TI - Hypertrophic cardiomyopathy: diagnosis, risk stratification and treatment. PMID- 23109607 TI - The "physician personality" and other factors in physician health. PMID- 23109609 TI - Red capes and physician resilience. PMID- 23109610 TI - Feds must step up and restrict generic oxycodone, Ontario says. PMID- 23109611 TI - Pantoprazole-induced acute interstitial nephritis. PMID- 23109612 TI - Health care workers must protect patients from influenza by taking the annual vaccine. PMID- 23109613 TI - The perils of clerkships. PMID- 23109614 TI - Tinea corporis in a mixed martial arts fighter. PMID- 23109615 TI - Eponymy: make that Hippocrates-Janin-Neumann-Reis-Bluthe- ... -Behcet's disease. PMID- 23109616 TI - Rethinking education of deaf children in Zimbabwe: challenges and opportunities for teacher education. AB - The study explores the communication challenges faced by teacher trainees in teaching deaf learners and the opportunities that they present. A critical disabilities study approach within the qualitative paradigm was employed to collect interview data from 14 trainee teachers (6 were men and 8 women) and 5 of their specialist mentors (all of them were women) at 3 special schools in Zimbabwe. The trainees were aged 28-45. Data were analyzed using theme identification methods. Results showed that all the mentors and trainees without deaf assistants tended to teach using spoken language and even though they had no prior experience with them, they were suspicious of the use of deaf assistants, whom they saw as synonymous with sign language. Scepticism about using sign language was based on the idea that it was inadequate, would interfere with spoken language development, and would not enable learners to be included in a nondeaf world. It was also established that most of the mentors and trainees with deaf assistants used spoken language to teach, although this tended to be in combination with signs. Based on these challenges, opportunities to develop the education of deaf learners are discussed and recommendations made. PMID- 23109617 TI - Mental health triage tools for medically cleared disaster survivors: an evaluation by MRC volunteers and public health workers. AB - OBJECTIVE: Psychological assessment after disasters determines which survivors are acutely distressed or medically compromised and what kind of assistance is needed (whether practical or psychological). A mental health triage tool can help direct more people to the appropriate type of help. The purpose of this study was to determine the effectiveness of the Fast Mental Health Triage Tool (FMHT) and the Alsept-Price Mental Health Scale (APMHS) among public health workers and Medical Reserve Corps (MRC) volunteers in conducting mental health triage. Both tools screen for ability to follow simple commands, chronic medical conditions, mental health conditions and services, occult injuries, and traumatic events in the past year. Both were designed for use in disasters where mental health resources are scarce and survivors are already medically triaged. METHODS: Volunteers (n = 204) and workers (n = 66) were randomized into 3 groups, with 79 participating. Fifty-nine raters completed 20 each of 1180 mental health clinical vignettes of disaster survivors. RESULTS: The survey presenting the vignettes was highly reliable at 0.771; the study model was parallel between baseline and treatment; and the interclass correlation among the raters was high at 0.852. Each rater triaged the same cases, but the rater was randomly assigned to use FMHT, APMHS, or no tool or scale. Between-subject effect for the tools used was significant (P = .039). The FMHT was significantly better than no tool in correct mental health triage, 67.3% to 51.5% (P = .028). CONCLUSION: The incorporation of a temporal component should be evaluated for potential inclusion in existing mental health triage systems. PMID- 23109619 TI - The management of weakness caused by lumbar and lumbosacral nerve root compression. AB - Spinal stenosis and disc herniation are the two most frequent causes of lumbosacral nerve root compression. This can result in muscle weakness and present with or without pain. The difficulty when managing patients with these conditions is knowing when surgery is better than non-operative treatment: the evidence is controversial. Younger patients with a lesser degree of weakness for a shorter period of time have been shown to respond better to surgical treatment than older patients with greater weakness for longer. However, they also constitute a group that fares better without surgery. The main indication for surgical treatment in the management of patients with lumbosacral nerve root compression should be pain rather than weakness. PMID- 23109620 TI - The use of non-vascularised osteochondral autograft for reconstruction of articular surfaces in the hand and wrist. AB - Bone loss involving articular surface is a challenging problem faced by the orthopaedic surgeon. In the hand and wrist, there are articular defects that are amenable to autograft reconstruction when primary fixation is not possible. In this article, the surgical techniques and clinical outcomes of articular reconstructions in the hand and wrist using non-vascularised osteochondral autografts are reviewed. PMID- 23109621 TI - Defining peri-prosthetic infection: do we have a workable gold standard? AB - Peri-prosthetic infection remains a leading cause of revision surgery. Recent publications from the American Musculoskeletal Infection Society have sought to establish a definition of peri-prosthetic infection based on clinical findings and laboratory investigations. The limitations of their approach are discussed and an alternative definition is proposed, which it is felt may better reflect the uncertainties encountered in clinical practice. PMID- 23109622 TI - A review of rapid prototyped surgical guides for patient-specific total knee replacement. AB - Improvements in the surgical technique of total knee replacement (TKR) are continually being sought. There has recently been interest in three-dimensional (3D) pre-operative planning using magnetic resonance imaging (MRI) and CT. The 3D images are increasingly used for the production of patient-specific models, surgical guides and custom-made implants for TKR. The users of patient-specific instrumentation (PSI) claim that they allow the optimum balance of technology and conventional surgery by reducing the complexity of conventional alignment and sizing tools. In this way the advantages of accuracy and precision claimed by computer navigation techniques are achieved without the disadvantages of additional intra-operative inventory, new skills or surgical time. This review describes the terminology used in this area and debates the advantages and disadvantages of PSI. PMID- 23109623 TI - A prospective, randomised controlled trial comparing ceramic-on-metal and metal on-metal bearing surfaces in total hip replacement. AB - In a double-blinded randomised controlled trial, 83 patients with primary osteoarthritis of the hip received either a ceramic-on-metal (CoM) or metal-on metal (MoM) total hip replacement (THR). The implants differed only in the bearing surfaces used. The serum levels of cobalt and chromium and functional outcome scores were compared pre-operatively and at six and 12 months post operatively. Data were available for 41 CoM and 36 MoM THRs (four patients were lost to follow-up, two received incorrect implants). The baseline characteristics of both cohorts were similar. Femoral head size measured 36 mm in all but two patients who had 28 mm heads. The mean serum cobalt and chromium levels increased in both groups, with no difference noted between groups at six months (cobalt p = 0.67, chromium p = 0.87) and 12 months (cobalt p = 0.76, chromium p = 0.76) post-operatively. Similarly, the mean Oxford hip scores, Western Ontario and McMaster Universities Osteoarthritis index and University of California, Los Angeles activity scores showed comparable improvement at 12 months. Our findings indicate that CoM and MoM couplings are associated with an equivalent increase in serum cobalt and chromium levels, and comparable functional outcome scores at six and 12-months follow-up. PMID- 23109624 TI - Using a calliper to restore the centre of the femoral head during total hip replacement. AB - Restoration of leg length and offset is an important goal in total hip replacement. This paper reports a calliper-based technique to help achieve these goals by restoring the location of the centre of the femoral head. This was validated first by using a co-ordinate measuring machine to see how closely the calliper technique could record and restore the centre of the femoral head when simulating hip replacement on Sawbone femur, and secondly by using CT in patients undergoing hip replacement. Results from the co-ordinate measuring machine showed that the centre of the femoral head was predicted by the calliper to within 4.3 mm for offset (mean 1.6 (95% confidence interval (CI) 0.4 to 2.8)) and 2.4 mm for vertical height (mean -0.6 (95% CI -1.4 to 0.2)). The CT scans showed that offset and vertical height were restored to within 8 mm (mean -1 (95% CI -2.1 to 0.6)) and -14 mm (mean 4 (95% CI 1.8 to 4.3)), respectively. Accurate assessment and restoration of the centre of the femoral head is feasible with a calliper. It is quick, inexpensive, simple to use and can be applied to any design of femoral component. PMID- 23109625 TI - Comparison of the outcome following the fixation of osteotomies or fractures associated with total hip replacement using cables or wires: the results at five years. AB - There are no recent studies comparing cable with wire for the fixation of osteotomies or fractures in total hip replacement (THR). Our objective was to evaluate the five-year clinical and radiological outcomes and complication rates of the two techniques. We undertook a review including all primary and revision THRs performed in one hospital between 1996 and 2005 using cable or wire fixation. Clinical and radiological evaluation was performed five years post operatively. Cables were used in 51 THRs and wires in 126, and of these, 36 THRs with cable (71%) and 101 with wire (80%) were evaluated at follow-up. The five year radiographs available for 33 cable and 91 wire THRs revealed rates of breakage of fixation of 12 of 33 (36%) and 42 of 91 (46%), respectively. With cable there was a significantly higher risk of metal debris (68% vs. 9%; adjusted relative risk (RR) 6.6; 95% confidence interval (CI) 3.0 to 14.1), nonunion (36% vs. 21%; adjusted RR 2.0; 95% CI 1.0 to 3.9) and osteolysis around the material, acetabulum or femur (61% vs 19%; adjusted RR 3.9; 95% CI 2.3 to 6.5). Cable breakage increased the risk of osteolysis to 83%. There was a trend towards foreign-body reaction and increased infection with cables. Clinical results did not differ between the groups. In conclusion, we found a higher incidence of complications and a trend towards increased infection and foreign-body reaction with the use of cables. PMID- 23109626 TI - Revision total hip replacement using the cement-in-cement technique for the acetabular component: technique and results for 60 hips. AB - The technique of femoral cement-in-cement revision is well established, but there are no previous series reporting its use on the acetabular side at the time of revision total hip replacement. We describe the technique and report the outcome of 60 consecutive acetabular cement-in-cement revisions in 59 patients at a mean follow-up of 8.5 years (5 to 12). All had a radiologically and clinically well-fixed acetabular cement mantle at the time of revision. During the follow-up 29 patients died, but no hips were lost to follow-up. The two most common indications for acetabular revision were recurrent dislocation (46, 77%) and to complement femoral revision (12, 20%). Of the 60 hips, there were two cases of aseptic loosening of the acetabular component (3.3%) requiring re-revision. No other hip was clinically or radiologically loose (96.7%) at the latest follow-up. One hip was re-revised for infection, four for recurrent dislocation and one for disarticulation of a constrained component. At five years the Kaplan-Meier survival rate was 100% for aseptic loosening and 92.2% (95% CI 84.8 to 99.6), with revision for any cause as the endpoint. These results support the use of cement-in-cement revision on the acetabular side in appropriate cases. Theoretical advantages include preservation of bone stock, reduced operating time, reduced risk of complications and durable fixation. PMID- 23109627 TI - Femoroacetabular impingement after slipped upper femoral epiphysis: the radiological diagnosis and clinical outcome at long-term follow-up. AB - Deformity after slipped upper femoral epiphysis (SUFE) can cause cam-type femoroacetabular impingement (FAI) and subsequent osteoarthritis (OA). However, there is little information regarding the radiological assessment and clinical consequences at long-term follow-up. We reviewed 36 patients (43 hips) previously treated by in situ fixation for SUFE with a mean follow-up of 37 years (21 to 50). Three observers measured the femoral head ratio (FHR), lateral femoral head ratio (LFHR), alpha-angle on anteroposterior (AP) and frog leg lateral views, and anterior femoral head-neck offset ratio (OSR). A Harris hip score < 85 and/or radiologically diagnosed osteoarthritis (OA) was classified as a poor outcome. Patients with SUFE had significantly higher FHR, LFHR and alpha-angles and lower OSR than a control group of 22 subjects (35 hips) with radiologically normal hips. The interobserver agreement was less, with wider limits of agreement (LOA), in hips with previous SUFE than the control group. At long-term follow-up abnormal alpha-angles correlated with poor outcome, whereas FHR, LFHR and OSR did not. We conclude that persistent deformity with radiological cam FAI after SUFE is associated with poorer clinical and radiological long-term outcome. Although the radiological measurements had quite wide limits of agreement, they are useful for the diagnosis of post-slip deformities in clinical practice. PMID- 23109628 TI - Arthroscopic reconstruction of the ligamentum teres: technique and early outcomes. AB - Femoroacetabular impingement causes groin pain and decreased athletic performance in active adults. This bony conflict may result in femoroacetabular subluxation if of sufficient magnitude. The ligamentum teres has recently been reported to be capable of withstanding tensile loads similar to that of the anterior cruciate ligament, and patents with early subluxation of the hip may become dependent on the secondary restraint that is potentially provided by the ligamentum teres. Rupture of the ligamentum may thus cause symptomatic hip instability during athletic activities. An arthroscopic reconstruction of the ligamentum teres using iliotibial band autograft was performed in an attempt to restore this static stabiliser in a series of four such patients. Early clinical results have been promising. The indications, technique and early outcomes of this procedure are discussed. PMID- 23109629 TI - The radiological parameters correlated with the alignment of the femoral component after Oxford phase 3 unicompartmental knee replacement. AB - The purpose of this study was to measure the radiological parameters of femoral component alignment of the Oxford Phase 3 unicompartmental knee replacement (UKR), and evaluate their effect on clinical outcome. Multiple regression analysis was used to examine the relative contributions of the radiological assessment of femoral component alignment in 189 consecutive UKRs performed by a single surgeon. The American Knee Society scores were compared between groups, defined as being within or outside recommended tolerances of the position of the femoral component. For the flexion/extension position 21 UKRs (11.1%) lay outside the recommended limits, and for posterior overhang of the femoral component nine (4.8%) lay outside the range. The pre-operative hip/knee/ankle (HKA) angle, narrowest canal distance from the distal femoral entry point of the alignment jig and coronal entry-point position had significant effects on the flexion/extension position. Pre-operative HKA angle had a significant influence on posterior overhang of the femoral component. However, there was no significant difference in American Knee Society scores relative to the position of the femoral component. PMID- 23109630 TI - Is patient reporting of physical function accurate following total knee replacement? AB - The aim of this study was to determine the association between the Oxford knee score (OKS) and direct assessment of outcome, and to examine how this relationship varied at different time-points following total knee replacement (TKR). Prospective data consisting of the OKS, numerical rating scales for 'worst pain' and 'perceived mean daily pain', timed functional assessments (chair rising, stairs and walking ability), goniometry and lower limb power were recorded for 183 patients pre-operatively and at six, 26 and 52 weeks post operatively. The OKS was influenced primarily by the patient's level of pain rather than objective functional assessments. The relationship between report of outcome and direct assessment changed over time: R2 = 35% pre-operatively, 44% at six weeks, 57% at 26 weeks and 62% at 52 weeks. The relationship between assessment of performance and report of performance improved as the patient's report of pain diminished, suggesting that patients' reporting of functional outcome after TKR is influenced more by their pain level than their ability to accomplish tasks. PMID- 23109631 TI - Pain management protocols, peri-operative pain and patient satisfaction after total knee replacement: a multicentre study. AB - In a prospective multicentre study we investigated variations in pain management used by knee arthroplasty surgeons in order to compare the differences in pain levels among patients undergoing total knee replacements (TKR), and to compare the effectiveness of pain management protocols. The protocols, peri-operative levels of pain and patient satisfaction were investigated in 424 patients who underwent TKR in 14 hospitals. The protocols were highly variable and peri-operative pain levels varied substantially, particularly during the first two post-operative days. Differences in levels of pain were greatest during the night after TKR, when visual analogue scores ranged from 16.9 to 94.3 points. Of the methods of managing pain, the combined use of peri-articular infiltration and nerve blocks provided better pain relief than other methods during the first two post-operative days. Patients managed with peri-articular injection plus nerve block, and epidural analgesia were more likely to have higher satisfaction at two weeks after TKR. This study highlights the need to establish a consistent pain management strategy after TKR. PMID- 23109632 TI - Survivorship of high tibial osteotomy in the treatment of osteoarthritis of the knee: Finnish registry-based study of 3195 knees. AB - Previous studies from single centres or single-surgeon series report good early and mid-term results for high tibial osteotomy (HTO) in the treatment of osteoarthritis of the knee. However, the survivorship of HTO at a national level is unknown. This registry-based study included 3195 high HTOs performed between 1987 and 2008. Kaplan-Meier analysis revealed an overall survivorship of 89% (95% confidence interval (CI) 88 to 90) at five years and 73% (95% CI 72 to 75) at ten years, when conversion to total knee replacement was taken as the endpoint. Females and patients aged > 50 years had worse survivorship than males or patients aged <= 50 years (hazard ratio (HR) 1.26 (95% CI 1.11 to 1.43) and HR 1.41 (95% CI 1.23 to 1.64), respectively). The survivorship of HTOs performed between 1998 to 2008 was worse than for those performed between 1987 and 1997. PMID- 23109633 TI - Low prevalence of osteoarthritis in patients with congenital clubfoot at more than 60 years' follow-up. AB - We investigated 60 patients (89 feet) with a mean age of 64 years (61 to 67) treated for congenital clubfoot deformity, using standardised weight-bearing radiographs of both feet and ankles together with a functional evaluation. Talocalcaneal and talonavicular relationships were measured and the degree of osteo-arthritic change in the ankle and talonavicular joints was assessed. The functional results were evaluated using a modified Laaveg-Ponseti score. The talocalcaneal (TC) angles in the clubfeet were significantly lower in both anteroposterior (AP) and lateral projections than in the unaffected feet (p < 0.001 for both views). There was significant medial subluxation of the navicular in the clubfeet compared with the unaffected feet (p < 0.001). Severe osteoarthritis in the ankle joint was seen in seven feet (8%) and in the talonavicular joint in 11 feet (12%). The functional result was excellent or good (>= 80 points) in 29 patients (48%), and fair or poor (< 80 points) in 31 patients (52%). Patients who had undergone few (0 to 1) surgical procedures had better functional outcomes than those who had undergone two or more procedures (p < 0.001). There was a significant correlation between the functional result and the degree of medial subluxation of the navicular (p < 0.001, r2= 0.164), the talocalcaneal angle on AP projection (p < 0.02, r2 = 0.025) and extent of osteoarthritis in the ankle joint (p < 0.001). We conclude that poor functional outcome in patients with congenital clubfoot occurs more frequently in those with medial displacement of the navicular, osteoarthritis of the talonavicular and ankle joints, and a low talocalcaneal angle on the AP projection, and in patients who have undergone two or more surgical procedures. However, the ankle joint in these patients appeared relatively resistant to the development of osteoarthritis. PMID- 23109634 TI - The use of a ceramic talar body prosthesis in patients with aseptic necrosis of the talus. AB - The purpose of this study was to evaluate the clinical results of a newly designed prosthesis to replace the body of the talus in patients with aseptic necrosis. Between 1999 and 2006, 22 tali in 22 patients were replaced with a ceramic prosthesis. A total of eight patients were treated with the first generation prosthesis, incorporating a peg to fix into the retained neck and head of the talus, and the remaining 14 were treated with the second-generation prosthesis, which does not have the peg. The clinical results were assessed by the American Orthopaedic Foot and Ankle Society ankle/hindfoot scale. The mean follow-up was 98 months (18 to 174). The clinical results of the first generation prostheses were excellent in three patients, good in one, fair in three and poor in one. There were, however, radiological signs of loosening, prompting a change in design. The clinical results of the second-generation prostheses were excellent in three patients, good in five, fair in four and poor in two, with more favourable radiological appearances. Revision was required using a total talar implant in four patients, two in each group. Although the second-generation prosthesis produced better results, we cannot recommend the use of a talar body prosthesis. We now recommend the use of a total talar implant in these patients. PMID- 23109635 TI - Ultrasound evaluation of the distal migration of the long head of biceps tendon following tenotomy in patients undergoing arthroscopic repair of tears of the rotator cuff. AB - This study evaluates the position of the long head of biceps tendon using ultrasound following simple tenotomy, in patients with arthroscopically repaired rotator cuff tears. In total, 52 patients with a mean age of 60.7 years (45 to 75) underwent arthroscopic repair of the rotator cuff and simple tenotomy of the long head of biceps tendon. At two years post-operatively, ultrasound revealed that the tendon was inside the bicipital groove in 43 patients (82.7%) and outside in nine (17.3%); in six of these it was lying just outside the groove and in the remaining three (5.8%) it was in a remote position with a positive Popeye Sign. A dynamic ultrasound scan revealed that the tenotomised tendons had adhered to the surrounding tissues (autotenodesis).The initial condition of the tendon influenced its final position (p < 0.0005). The presence of a Popeye sign was statistically influenced by the pre-operative co-existence of supraspinatus and subscapularis tears (p < 0.0001). It appears that the natural history of the tenotomised long head of biceps tendon is to tenodese itself inside or just outside the bicipital groove, while its pre-operative condition and coexistent subscapularis tears play a significant role in the occurrence of a Popeye sign. PMID- 23109636 TI - Promising one- to six-year results with the Motec wrist arthroplasty in patients with post-traumatic osteoarthritis. AB - The Motec cementless modular metal-on-metal ball-and-socket wrist arthroplasty was implanted in 16 wrists with scaphoid nonunion advanced collapse (SNAC; grades 3 or 4) and 14 wrists with scapholunate advanced collapse (SLAC) in 30 patients (20 men) with severe (grades 3 or 4) post-traumatic osteoarthritis of the wrist. The mean age of the patients was 52 years (31 to 71). All prostheses integrated well radiologically. At a mean follow-up of 3.2 years (1.1 to 6.1) no luxation or implant breakage occurred. Two wrists were converted to an arthrodesis for persistent pain. Loosening occurred in one further wrist at five years post-operatively. The remainder demonstrated close bone-implant contact. The clinical results were good, with markedly decreased Disabilities of the Arm Shoulder and Hand (DASH) and pain scores, and increased movement and grip strength. No patient used analgesics and most had returned to work. Good short-term function was achieved using this wrist arthroplasty in a high-demand group of patients with post-traumatic osteoarthritis. PMID- 23109637 TI - Errors of level in spinal surgery: an evidence-based systematic review. AB - Wrong-level surgery is a unique pitfall in spinal surgery and is part of the wider field of wrong-site surgery. Wrong-site surgery affects both patients and surgeons and has received much media attention. We performed this systematic review to determine the incidence and prevalence of wrong-level procedures in spinal surgery and to identify effective prevention strategies. We retrieved 12 studies reporting the incidence or prevalence of wrong-site surgery and that provided information about prevention strategies. Of these, ten studies were performed on patients undergoing lumbar spine surgery and two on patients undergoing lumbar, thoracic or cervical spine procedures. A higher frequency of wrong-level surgery in lumbar procedures than in cervical procedures was found. Only one study assessed preventative strategies for wrong-site surgery, demonstrating that current site-verification protocols did not prevent about one-third of the cases. The current literature does not provide a definitive estimate of the occurrence of wrong-site spinal surgery, and there is no published evidence to support the effectiveness of site-verification protocols. Further prevention strategies need to be developed to reduce the risk of wrong site surgery. PMID- 23109638 TI - Is cauda equina syndrome linked with obesity? AB - No previous studies have examined the physical characteristics of patients with cauda equina syndrome (CES). We compared the anthropometric features of patients who developed CES after a disc prolapse with those who did not but who had symptoms that required elective surgery. We recorded the age, gender, height, weight and body mass index (BMI) of 92 consecutive patients who underwent elective lumbar discectomy and 40 consecutive patients who underwent discectomy for CES. On univariate analysis, the mean BMI of the elective discectomy cohort (26.5 kg/m2 (16.6 to 41.7) was very similar to that of the age-matched national mean (27.6 kg/m2, p = 1.0). However, the mean BMI of the CES cohort (31.1 kg/m2 (21.0 to 54.9)) was significantly higher than both that of the elective group (p < 0.001) and the age-matched national mean (p < 0.001). A similar pattern was seen with the weight of the groups. Multivariate logistic regression analysis was performed, adjusted for age, gender, height, weight and BMI. Increasing BMI and weight were strongly associated with an increased risk of CES (odds ratio (OR) 1.17, p < 0.001; and OR 1.06, p < 0.001, respectively). However, increasing height was linked with a reduced risk of CES (OR 0.9, p < 0.01). The odds of developing CES were 3.7 times higher (95% confidence interval (CI) 1.2 to 7.8, p = 0.016) in the overweight and obese (as defined by the World Health Organization: BMI >= 25 kg/m2) than in those of ideal weight. Those with very large discs (obstructing > 75% of the spinal canal) had a larger BMI than those with small discs (obstructing < 25% of the canal; p < 0.01). We therefore conclude that increasing BMI is associated with CES. PMID- 23109639 TI - Patient and implant survival following 4323 total hip replacements for acute femoral neck fracture: a retrospective cohort study using National Joint Registry data. AB - United Kingdom National Institute for Health and Clinical Excellence guidelines recommend the use of total hip replacement (THR) for displaced intracapsular fractures of the femoral neck in cognitively intact patients, who were independently mobile prior to the injury. This study aimed to analyse the risk factors associated with revision of the implant and mortality following THR, and to quantify risk. National Joint Registry data recording a THR performed for acute fracture of the femoral neck between 2003 and 2010 were analysed. Cox proportional hazards models were used to investigate the extent to which risk of revision was related to specific covariates. Multivariable logistic regression was used to analyse factors affecting peri-operative mortality (< 90 days). A total of 4323 procedures were studied. There were 80 patients who had undergone revision surgery at the time of censoring (five-year revision rate 3.25%, 95% confidence interval 2.44 to 4.07) and 137 patients (3.2%) patients died within 90 days. After adjusting for patient and surgeon characteristics, an increased risk of revision was associated with the use of cementless prostheses compared with cemented (hazard ratio (HR) 1.33, p = 0.021). Revision was independent of bearing surface and head size. The risk of mortality within 90 days was significantly increased with higher American Society of Anesthesiologists (ASA) grade (grade 3: odds ratio (OR) 4.04, p < 0.001; grade 4/5: OR 20.26, p < 0.001; both compared with grades 1/2) and older age (>= 75 years: OR 1.65, p = 0.025), but reduced over the study period (9% relative risk reduction per year). THR is a good option in patients aged < 75 years and with ASA 1/2. Cementation of the femoral component does not adversely affect peri operative mortality but improves survival of the implant in the mid-term when compared with cementless femoral components. There are no benefits of using head sizes > 28 mm or bearings other than metal-on-polyethylene. More research is required to determine the benefits of THR over hemiarthroplasty in older patients and those with ASA grades > 2. PMID- 23109640 TI - Malleolar fractures and their ligamentous injury equivalents have similar outcomes in supination-external rotation type IV fractures of the ankle treated by anatomical internal fixation. AB - It has previously been suggested that among unstable ankle fractures, the presence of a malleolar fracture is associated with a worse outcome than a corresponding ligamentous injury. However, previous studies have included heterogeneous groups of injury. The purpose of this study was to determine whether any specific pattern of bony and/or ligamentous injury among a series of supination-external rotation type IV (SER IV) ankle fractures treated with anatomical fixation was associated with a worse outcome. We analysed a prospective cohort of 108 SER IV ankle fractures with a follow-up of one year. Pre-operative radiographs and MRIs were undertaken to characterise precisely the pattern of injury. Operative treatment included fixation of all malleolar fractures. Post-operative CT was used to assess reduction. The primary and secondary outcome measures were the Foot and Ankle Outcome Score (FAOS) and the range of movement of the ankle. There were no clinically relevant differences between the four possible SER IV fracture pattern groups with regard to the FAOS or range of movement. In this population of strictly defined SER IV ankle injuries, the presence of a malleolar fracture was not associated with a significantly worse clinical outcome than its ligamentous injury counterpart. Other factors inherent to the injury and treatment may play a more important role in predicting outcome. PMID- 23109641 TI - The effects of rivaroxaban on the complications of surgery after total hip or knee replacement: results from the RECORD programme. AB - Post-operative complications after total hip or knee replacement can delay recovery, prolong hospitalisation, increase rates of re-admission and, in the most severe cases, lead to long-term disability or even death. In this analysis of pooled data from four large, randomised, phase III clinical trials that compared the oral, direct Factor Xa inhibitor rivaroxaban with subcutaneous enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement (n = 12,729), the incidence of complications, including bleeding and adverse events related to surgery (such as wound infection, wound dehiscence and haemarthrosis) are reported. Interventions and procedures relating to surgery are also compared between the groups. Bleeding events, including excessive wound haematoma and surgical-site bleeding, occurred at similar rates in the rivaroxaban and enoxaparin groups. Over the total study duration, adverse surgical events occurred at a similar rate in the rivaroxaban group compared with the enoxaparin group after total knee replacement (2.26% vs. 2.69%, respectively) and total hip replacement (1.48% vs. 1.65%, respectively). Blood loss, wound drainage and transfusion requirements were also similar between the two groups. This analysis shows that the incidence of adverse surgical events with rivaroxaban was similar to enoxaparin. PMID- 23109642 TI - Restoring shoulder abduction in children with Erb's palsy: when to add trapezius transfer to a teres major transfer. AB - A total of 35 children with Erb's palsy and shoulder abduction of < 90 degrees underwent transfer of teres major. In 18 cases (group 1) a trapezius transfer was added (combined procedure). In 17 cases (group 2) teres major transfer was carried out in isolation (single procedure). The mean gain in abduction was 67.2 degrees (60 degrees to 80 degrees ) in group 1 and 37.6 degrees (20 degrees to 70 degrees ) in group 2, which reached statistical significance (p < 0.001). Group 2 was further divided into those who had deltoid power of < M3 (group 2a) and those with deltoid power >= M3 (group 2b). The difference in improvement of abduction between groups 2a and group 2b was statistically significant (p < 0.001) but the difference between group 2b and group 1 was not (p = 0.07). We recommend the following protocol of management: in children with abduction >= 90 degrees a single procedure is indicated. In children with abduction < 90 degrees : a combined procedure is indicated if deltoid power is < M3 and a single procedure is indicated if deltoid power is >= M3. If no satisfactory improvement is achieved, the trapezius can be transferred at a later stage. PMID- 23109644 TI - Calcium and phosphate impact cardiovascular risk. AB - Non-traditional risk factors substantially contribute to cardiovascular (CV) disease. A deranged calcium-phosphate metabolism-first identified as a major non traditional CV risk factor in patients with chronic kidney disease-may be implicated in development and progression of CV disease even among individuals with intact renal function. This review thus summarizes epidemiological and experimental data on the role of calcium, phosphate, and its major regulating hormones-parathyroid hormone, calcitriol, and fibroblast growth factor 23-in CV medicine. PMID- 23109645 TI - Association between menstrual cycle irregularities and endocrine and metabolic characteristics of the polycystic ovary syndrome. AB - OBJECTIVE: Insulin resistance (IR) is frequent in polycystic ovary syndrome (PCOS) and contributes to the increased risk for type 2 diabetes mellitus and cardiovascular disease of this population. Several markers of IR are used but most are expensive or have limited sensitivity and specificity. Preliminary data suggest that the menstrual cycle pattern correlates with IR in PCOS but existing studies are small. We aimed to assess the relationship between the type of menstrual cycle irregularities and IR in PCOS. DESIGN: Prospective study. METHODS: We studied 1285 women with PCOS, divided according to the menstrual cycle pattern. RESULTS: Patients with isolated secondary amenorrhea and those with secondary amenorrhea alternating with regular menstrual cycles were more insulin resistant than patients with regular cycles (Group D). Patients with isolated oligomenorrhea were also more insulin resistant than Group D. However, patients with oligomenorrhea alternating with regular cycles, secondary amenorrhea, or polymenorrhea had comparable levels of markers of IR with Group D. Moreover, patients with oligomenorrhea alternating with regular cycles were less insulin resistant than patients with secondary amenorrhea alternating with regular cycles. Finally, patients with isolated polymenorrhea and those with polymenorrhea alternating with regular cycles had comparable levels of markers of IR with Group D. CONCLUSIONS: Amenorrhea is associated with more pronounced IR in PCOS, and oligomenorrhea portends a less excessive risk for IR than amenorrhea whereas polymenorrhea appears to be even more benign metabolically. Therefore, the type of menstrual cycle abnormality appears to represent a useful tool for identifying a more adverse metabolic profile in PCOS. PMID- 23109646 TI - Genes that characterize T3-predominant Graves' thyroid tissues. AB - OBJECTIVE: 3,5,3'-Triiodothyronine (T(3))-predominant Graves' disease is characterized by the increasing volume of thyroid goiter resulting in poor prognosis. Although type 1 and type 2 iodothyronine deiodinases (DIO1 and DIO2 respectively) are known to be overexpressed in the thyroid tissues of T(3) predominant Graves' disease, the pathogenesis of this disease is still unclear. The aim of our study is to identify genes that characterize T(3)-predominant Graves' disease tissue in order to clarify the molecular mechanism of this disease. DESIGN AND METHODS: mRNAs from two thyroid tissues of both typical T(3) predominant and common-type Graves' disease were analyzed with DNA microarrays with probes for 28 869 genes. Genes identified to be differentially expressed between the two groups were further analyzed in the second and third screenings using 70 Graves' thyroid tissues by real-time quantitative RT-PCR. RESULTS: Twenty-three candidate genes were selected as being differentially expressed in the first screening with microarrays. Among these, seven genes, leucine-rich repeat neuronal 1 (LRRN1), bone morphogenetic protein 8a (BMP8A), N-cadherin (CDH2), phosphodiesterase 1A (PDE1A), creatine kinase mitochondrial 2 (CKMT2), integrin beta-3 (ITGB3), and protein tyrosine phosphatase non-receptor type 4 (PTPN4), were confirmed to be differentially expressed in DIO1 or DIO2 over- and underexpressing Graves' tissues. CONCLUSIONS: These genes are related to the characteristics of T(3)-predominant Graves' disease, such as high titer level of serum anti-TSH receptor antibody, high free T(3) to free thyroxine ratio, and a large goiter size. They might play a role in the pathogenesis of T(3)-predominant Graves' disease. PMID- 23109647 TI - Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study. AB - AIMS: The aim of this study was to investigate myocardial 2D strain echocardiography and cardiac biomarkers in the assessment of cardiac function in children with acute lymphoblastic leukaemia (ALL) during and shortly after treatment with anthracyclines. METHODS AND RESULTS: Cardiac function of 60 children with ALL was prospectively studied with measurements of cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) and conventional and myocardial 2D strain echocardiography before start (T = 0), after 3 months (T = 1), and after 1 year (T = 2), and were compared with 60 healthy age-matched controls. None of the patients showed clinical signs of cardiac failure or abnormal fractional shortening. Cardiac function decreased significantly during treatment and was significantly decreased compared with normal controls. Cardiac troponin T levels were abnormal in 11% of the patients at T = 1 and were significantly related to increased time to global peak systolic longitudinal strain at T = 2 (P = 0.003). N-terminal-pro-brain natriuretic peptide levels were abnormal in 13% of patients at T = 1 and in 20% at T = 2, absolute values increased throughout treatment in 59%. Predictors for abnormal NT pro-BNP at T = 2 were abnormal NT-pro-BNP at T = 0 and T = 1, for abnormal myocardial 2D strain parameters at T = 2 cumulative anthracycline dose and z score of the diastolic left ventricular internal diameter at baseline. CONCLUSION: Children with newly diagnosed ALL showed decline of systolic and diastolic function during treatment with anthracyclines using cardiac biomarkers and myocardial 2D strain echocardiography. N-terminal-pro-brain natriuretic peptide levels were not related to echocardiographic strain parameters and cTnT was not a predictor for abnormal strain at T = 2.Therefore, the combination of cardiac biomarkers and myocardial 2D strain echocardiography is important in the assessment of cardiac function of children with ALL treated with anthracyclines. PMID- 23109648 TI - The role of imaging in acute aortic syndromes. AB - The classic entity of life-threatening aortic dissection represents one pathology of a spectrum of acute conditions coined the acute aortic syndrome comprising dissection, intramural haematoma, penetrating atherosclerotic ulcer, and contained aortic rupture of any cause. The common denominator is disruption of the aortic media layers associated with severe pain and a variety of other symptoms. Any clinical suspicion of acute aortic syndrome should prompt immediate action and confirmatory non-invasive imaging; with respect to sensitivity and specificity for acute aortic pathology modern contrast-enhanced CT technology, MR imaging and ultrasound techniques have similar diagnostic accuracy near 100%. Since the prognosis of most patients with acute aortic dissection is related to undelayed diagnosis and (often surgical) treatment swift diagnostic imaging should be the primary goal in the work-up of any patient with suspected acute aortic syndrome; transfer and in-hospital logistics and local expertise for the differential use of various imaging modalities should be constantly improved. PMID- 23109649 TI - Quadricuspid pulmonic valve: diagnosis by MRI. PMID- 23109650 TI - The benefits of using a heart failure management programme in Swedish primary healthcare. AB - AIM: Heart failure (HF) is a common condition with which high mortality, morbidity, and poor quality of life are associated. It has previously been shown that use of HF management programmes (HFMPs) in HF clinics can be beneficial. The purpose of this study was to evaluate if the use of HFMPs also has beneficial effects on HF patients in primary healthcare (PHC). METHODS AND RESULTS: This is a randomized, prospective, open-label study including 160 patients from five PHC centres with systolic HF and a mean age of 75 years (standard deviation 7.8). In the intervention group, an intensive follow-up was performed by HF nurses and physicians providing information and education about HF and the optimization of HF treatment according to recognized guidelines. There was a significant improvement of composite endpoints in the intervention group. Significantly more patients with reduced N-terminal pro brain natriuretic peptide (P = 0.012), improved cardiac function (P = 0.03), fewer healthcare contacts (P = 0.04), and fewer emergency room visits and admittances (P = 0.0002 and P = 0.03, respectively) could be seen in the intervention group when compared with the control group. CONCLUSIONS: The use of a HFMP in a PHC setting was found to have beneficial effects in terms of reducing the number of healthcare contacts and hospital admissions, and improving cardiac function in patients with systolic HF, even if the result should be interpreted with caution. It can therefore be recommended that HFMPs should be used in PHC. PMID- 23109651 TI - Three decades of heart transplantation in Scandinavia: long-term follow-up. AB - AIM: Heart transplantation (HTx) has become a standard treatment for patients with end-stage heart disease. The aim of this study was to report the long-term outcome after HTx in Scandinavia. METHODS AND RESULTS: During the period, 1983 2009, 2333 HTxs were performed in 2293 patients (mean age 45 +/- 16 years, range 0-70, 78% male). The main indications for HTx were non-ischaemic cardiomyopathy (50%), ischaemic cardiomyopathy (34%), valvular cardiomyopathy (3%), congenital heart disease (7%), retransplantation (2%), and miscellaneous (4%). The registry consists of pre-operative data from recipients and donors, data from pre operative procedures, and long-term follow-up data. Mean follow-up was 7.8 +/- 6.6 years (median 6.9, interquartile range 2.5-12.3, interval 0-27) and no patients were lost to follow-up. Long-term survival for HTx patients was 85, 76, 61, 43, and 30% at 1, 5, 10, 15, and 20 years of follow-up, respectively. Ten year survival in patients bridged with mechanical circulatory support, in children, after retransplantation, and after concomitant other organ transplantation was 56, 74, 38, and 43%, respectively. Older patients (age > 55 years) had a significantly worse survival (P < 0.001). Patients transplanted more recently had a significantly better survival (P < 0.001). In a multivariate Cox regression analysis, independent predictors of long-term survival were recipient age (P < 0.001), donor age (P < 0.001), diagnosis (P = 0.001), and era of transplantation (P < 0.001). CONCLUSIONS: HTx in Scandinavia proves to have a significantly better survival among patients transplanted in the last decade. HTxs from mechanical circulatory support, in children, after retransplantation, and with concomitant other organ transplantation were performed with acceptable results. PMID- 23109652 TI - Migraine and migraine subtypes in preadolescent children: association with school performance. AB - OBJECTIVES: To conduct a population-based study describing school performance in children with episodic migraine (EM), chronic migraine (CM), and probable migraine (PM), relative to controls. METHODS: Children (n = 5,671) from 87 cities and 18 Brazilian states were interviewed by their teachers (n = 124). First, teachers were asked to provide information on the performance of the students while at school, which consisted of the same information provided to the educational board, with measurements of the overall achievement of competencies for the school year. The MTA-SNAP-IV scale was then used to capture symptoms of attention-deficit/hyperactivity disorder, and to provide objective information on the performance of the students. Parents were interviewed using a validated headache questionnaire and the Strengths and Difficulties Questionnaire, which measures behavior in 5 domains. Multivariate models estimated determinants of school performance as a function of headache status. RESULTS: EM occurred in 9% of the children, PM in 17.6%, and CM in 0.6%. Poor performance at school was significantly more likely in children with EM and CM, relative to children without headaches, and was significantly influenced by severity (p < 0.001) and duration (p < 0.001) of headache attacks, by abnormal scores of mental health (p < 0.001), and by nausea (p < 0.001), as well as by headache frequency, use of analgesics, and gender. CONCLUSION: Children with migraine are at an increased risk of having impairments in their school performance and factors associated with impairment have been mapped. Future studies should address the directionality of the association and putative mechanisms to explain it. PMID- 23109654 TI - SWAN MRI revealing multiple microhemorrhages secondary to septic emboli from mucormycosis. PMID- 23109653 TI - Moving toward molecular classification of diffuse gliomas in adults. AB - Diffuse gliomas are a heterogenous group of neoplasms traditionally classified as grades II to IV based on histologic features, and with prognosis determined mainly by histologic grade and pretreatment clinical factors. Our understanding of the molecular basis of glioma initiation, tumor progression, and treatment failure is rapidly evolving. A molecular profile of diffuse gliomas is emerging. Studies evaluating gene expression and DNA methylation profile have found multiple glioma subtypes and an association between subtype and survival. The recent discovery of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma has provided reproducible prognostic biomarkers and novel therapeutic targets. Glioblastomas that exhibit CpG island hypermethylator phenotype, proneural gene expression, or IDH1 mutation identify a subset of patients with markedly improved prognosis. Accumulated evidence supports the stratification of both low-grade and anaplastic diffuse gliomas into prognostic groups using 1p/19q codeletion and IDH mutation status. A classification scheme incorporating clinical, pathologic, and molecular information may facilitate improved prognostication for patients treated in the clinic, the development of more effective clinical trials, and rational testing of targeted therapeutics. PMID- 23109655 TI - Subthalamic deep brain stimulation at individualized frequencies for Parkinson disease. PMID- 23109656 TI - Risk of fractures in patients with multiple sclerosis: a population-based cohort study. PMID- 23109657 TI - Clinical reasoning: a case of acute onset bilateral ptosis in a young child. PMID- 23109658 TI - Child neurology: benign nocturnal alternating hemiplegia of childhood. PMID- 23109660 TI - Mystery case: idiopathic bilateral stenosis of the foramina of Monro. PMID- 23109661 TI - The impact of migraine on school performance. PMID- 23109662 TI - The enigma of Russian waves and not so bad prospects. PMID- 23109663 TI - Psychosocial correlates of physical activity in school children aged 8-10 years. AB - BACKGROUND: Understanding correlates of physical activity (PA) among children in different populations may contribute to fostering active lifestyles. This study considered gender differences in relationships between biologic (body mass index, BMI), demographic (socioeconomic sport status, SES) and psychosocial correlates of PA and level of PA in Portuguese primary school children. METHODS: 683 children, aged 8-10 years, from 20 different elementary schools in northern Portugal were surveyed. Weight status was classified using International Obesity Task Force (IOTF) criteria for the BMI. Family SES was estimated from school records. PA level and psychosocial correlates (attraction to PA, perceived physical competence and parental socialization) were obtained with interview and standardized questionnaires, respectively. Sex-specific hierarchical multiple regression analyses (SPSS 18.0) were conducted and included two blocks of predictor variables (biologic and demographic, and psychosocial). RESULTS: Level of PA was significantly higher in boys than girls. Enjoyment of participation in vigorous PA was positively associated with level of PA. Perceived acceptance by peers in games and sports and parental encouragement were positively and significantly related to PA in girls. Perceived physical competence was positively and significantly related to PA in boys. Weight status and SES were not associated with PA. CONCLUSIONS: Boys and girls differed in perceived attractiveness of PA and perceived physical competence, both of which influenced level of PA. Differences in perceptions may be important aspects of motivation for PA in school children. PMID- 23109664 TI - Fumiyo Ikeda: ubiquitin lines up for action. Interview by Caitlin Sedwick. PMID- 23109665 TI - Discovering the first microRNA-targeted drug. AB - MicroRNAs (miRNAs) are important post-transcriptional regulators of nearly every biological process in the cell and play key roles in the pathogenesis of human disease. As a result, there are many drug discovery programs that focus on developing miRNA-based therapeutics. The most advanced of these programs targets the liver-expressed miRNA-122 using the locked nucleic acid (LNA)-modified antisense oligonucleotide miravirsen. Here, we describe the discovery of miravirsen, which is currently in phase 2 clinical trials for treatment of hepatitis C virus (HCV) infection. PMID- 23109666 TI - The discovery of natalizumab, a potent therapeutic for multiple sclerosis. AB - Multiple sclerosis (MS) is the major inflammatory demyelinating disease of the central nervous system. There is strong evidence that an immune response in the brain is a critical component of the disease. In 1992, in a collaboration between academia and biotechnology, my colleagues and I showed that alpha4 integrin was the critical molecule involved in the homing of immune cells into the inflamed brain. Was it sheer luck that these results led to the development of a drug for MS? PMID- 23109667 TI - Hypertrophic cardiomyopathy: translating cellular cross talk into therapeutics. AB - Hypertrophic cardiomyopathy (HCM) is a common inherited heart disease with serious adverse outcomes, including heart failure, arrhythmias, and sudden cardiac death. The discovery that mutations in sarcomere protein genes cause HCM has enabled the development of mouse models that recapitulate clinical manifestations of disease. Studies in these models have provided unexpected insights into the biophysical and biochemical properties of mutated contractile proteins and may help to improve clinical diagnosis and management of patients with HCM. PMID- 23109668 TI - Using force to visualize conformational activation of integrins. AB - The development of biophysical approaches to analyze integrin-ligand binding allows us to visualize in real time the conformational changes that shift the bond affinity between low- and high-affinity states. In this issue, Chen et al. (2012. J. Cell Biol. http://dx.doi.org/jcb.201201091) use these approaches to validate some aspects of the classical integrin regulation model; however, their data suggest that much of the regulation occurs after ligand binding rather than in preparation for ligand binding to occur. PMID- 23109669 TI - Local axonal function of STAT3 rescues axon degeneration in the pmn model of motoneuron disease. AB - Axonal maintenance, plasticity, and regeneration are influenced by signals from neighboring cells, in particular Schwann cells of the peripheral nervous system. Schwann cells produce neurotrophic factors, but the mechanisms by which ciliary neurotrophic factor (CNTF) and other neurotrophic molecules modify the axonal cytoskeleton are not well understood. In this paper, we show that activated signal transducer and activator of transcription-3 (STAT3), an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, acts locally in axons of motoneurons to modify the tubulin cytoskeleton. Specifically, we show that activated STAT3 interacted with stathmin and inhibited its microtubule destabilizing activity. Thus, ectopic CNTF-mediated activation of STAT3 restored axon elongation and maintenance in motoneurons from progressive motor neuronopathy mutant mice, a mouse model of motoneuron disease. This mechanism could also be relevant for other neurodegenerative diseases and provide a target for new therapies for axonal degeneration. PMID- 23109670 TI - Observing force-regulated conformational changes and ligand dissociation from a single integrin on cells. AB - As adhesion molecules, integrins connect a cell to its environment and transduce signals across the membrane. Their different functional states correspond to distinct conformations. Using a biomembrane force probe, we observed real-time reversible switches between bent and extended conformations of a single integrin, alpha(L)beta(2), on the surface of a living cell by measuring its nanometer-scale headpiece displacements, bending and unbending frequencies, and molecular stiffness changes. We determined the stabilities of these conformations, their dynamic equilibrium, speeds and rates of conformational changes, and the impact of divalent cations and tensile forces. We quantified how initial and subsequent conformations of alpha(L)beta(2) regulate the force-dependent kinetics of dissociation from intercellular adhesion molecule 1. Our findings provide new insights into how integrins function as nanomachines to precisely control cell adhesion and signaling. PMID- 23109671 TI - A longitudinal analysis of Hispanic youth acculturation and cigarette smoking: the roles of gender, culture, family, and discrimination. AB - INTRODUCTION: Risk for smoking initiation increases as Hispanic youth acculturate to U.S. society, and this association seems to be stronger for Hispanic girls than boys. To better understand the influence of culture, family, and everyday discrimination on cigarette smoking, we tested a process-oriented model of acculturation and cigarette smoking. METHODS: Data came from Project RED (Reteniendo y Entendiendo Diversidad para Salud), which included 1,436 Hispanic students (54% girls) from Southern California. We used data from 9th to 11th grade (85% were 14 years old, and 86% were U.S. born) to test the influence of acculturation-related experiences on smoking over time. RESULTS: Multigroup structural equation analysis suggested that acculturation was associated with increased familismo and lower traditional gender roles, and enculturation was linked more with familismo and respeto. Familismo, respeto, and traditional gender roles were linked with lower family conflict and increased family cohesion, and these links were stronger for girls. Familismo and respeto were further associated with lower discrimination. Conversely, fatalismo was linked with worse family functioning (especially for boys) and increased discrimination in both the groups. Discrimination was the only predictor of smoking for boys and girls. CONCLUSIONS: In all, the results of the current study indicate that reducing discrimination and helping youth cope with discrimination may prevent or reduce smoking in Hispanic boys and girls. This may be achieved by promoting familismo and respeto and by discouraging fatalistic beliefs. PMID- 23109672 TI - Effectiveness of motivational interviewing in influencing smoking cessation in pregnant and postpartum disadvantaged women. AB - INTRODUCTION: Systematic assessments of Motivational Interviewing (MI) in smoking behavior have been rare to date. This study aimed to determine whether an integrated approach, involving staff training in MI techniques, was sufficient to affect change in smoking status or intensity in low-income pregnant and postpartum women. METHODS: Overall, 500 consecutive smokers were recruited at first prenatal visit to public antenatal clinics. Following staff training, 500 more were recruited (intervention group). Data were recorded at 28-32 weeks gestation, after birth, at 3-4 and 7-9 months postpartum. The primary outcome measure was self-reported continued abstinence from smoking verified by urinary cotinine analysis. Changes in smoking intensity were also measured. RESULTS: There was no significant difference in the proportion of smokers in the intervention and control groups who reported stopping smoking at 28-32 weeks gestation (8.2% vs. 8.8%; p = .73), 1 week after birth (8.6% vs. 11.4%; p = .14), 3-4 months after birth (5.8% vs. 4.8%; p = .48), or 7-9 months after birth (5.2% vs. 4.0%; p = .36). Although more cases were nonsmoking at the second visit, 14.8% [95% CI = 11.8-18.5] vs. 13.1% controls [95% CI = 10.3-16.6], this was not statistically significant. CONCLUSIONS: MI delivered at a number of time points during pregnancy and up to 9 months postpartum failed to affect quit rates. It may have had a small effect in preventing relapse among spontaneous quitters in late pregnancy though the validity of this remains uncertain. PMID- 23109673 TI - Effect of sphingosine kinase 1 inhibition on blood pressure. AB - Accumulating evidence suggests that sphingosine kinase 1 (SphK1) plays a key role in carcinogenesis by regulating cyclooxygenase-2 (COX-2) expression. Recent clinical studies have revealed that COX-2 inhibitors cause adverse cardiovascular side effects, likely due to inhibition of prostacyclin (PGI(2)). In this work, we investigated the roles of SphK1 inhibition on blood pressure (BP). The results show that lack of SphK1 expression did not exacerbate angiotensin II (Ang II) induced acute hypertension, whereas celecoxib, a COX-2 inhibitor, augmented and sustained higher BP in mice. Interestingly, SphK1-knockout mice inhibited prostaglandin E(2) (PGE(2)) but not PGI(2) production in response to Ang II, whereas celecoxib blocked both PGE(2) and PGI(2) production. Mechanistically, SphK1 down-regulation by siRNA in human umbilical vein endothelial cells decreased cytokine-induced PGE(2) production primarily through inhibition of microsomal PGE synthase-1 (mPGES-1), not COX-2. SphK1 down-regulation also decreased MKK6 expression, which phosphorylates and activates P38 MAPK, which, in turn, regulates early growth response-1 (Egr-1), a transcription factor of mPGES 1. Together, these data indicate that SphK1 regulates PGE(2) production by mPGES 1 expression via the p38 MAPK pathway, independent of COX-2 signaling, in endothelial cells, suggesting that SphK1 inhibition may be a promising strategy for cancer chemoprevention with lack of the adverse cardiovascular side effects associated with coxibs. PMID- 23109674 TI - The transcription factor NF-E2-related factor 2 (Nrf2): a protooncogene? AB - The transcription factor Nrf2 is responsible for regulating a battery of antioxidant and cellular protective genes, primarily in response to oxidative stress. A member of the cap 'n' collar family of transcription factors, Nrf2 activation is tightly controlled by a series of signaling events. These events can be separated into the basal state, a preinduction response, gene induction, and finally a postinduction response, culminating in the restoration of redox homeostasis. However, despite the immensely intricate level of control the cellular environment imposes on Nrf2 activity, there are many opportunities for perturbations to arise in the signaling events that favor carcinogenesis and, therefore, implicate Nrf2 as both a tumor suppressor and a protooncogene. Herein, we highlight the ways in which Nrf2 is regulated, and discuss some of the Nrf2 inducible antioxidant (NQO1, NQO2, HO-1, GCLC), antiapoptotic (Bcl-2), metabolic (G6PD, TKT, PPARgamma), and drug efflux transporter (ABCG2, MRP3, MRP4) genes. In addition, we focus on how Nrf2 functions as a tumor suppressor under normal conditions and how its ability to detoxify the cellular environment makes it an attractive target for other oncogenes either via stabilization or degradation of the transcription factor. Finally, we discuss some of the ways in which Nrf2 is being considered as a therapeutic target for cancer treatment. PMID- 23109675 TI - Acid-sensing ion channels (ASICs) in mouse skeletal muscle afferents are heteromers composed of ASIC1a, ASIC2, and ASIC3 subunits. AB - Acid-sensing ion channels (ASICs) are expressed in skeletal muscle afferents, in which they sense extracellular acidosis and other metabolites released during ischemia and exercise. ASICs are formed as homotrimers or heterotrimers of several isoforms (ASIC1a, ASIC1b, ASIC2a, ASIC2b, and ASIC3), with each channel displaying distinct properties. To dissect the ASIC composition in muscle afferents, we used whole-cell patch-clamp recordings to study the properties of acid-evoked currents (amplitude, pH sensitivity, the kinetics of desensitization and recovery from desensitization, and pharmacological modulation) in isolated, labeled mouse muscle afferents from wild-type (C57BL/6J) and specific ASIC(-/-) mice. We found that ASIC-like currents in wild-type muscle afferents displayed fast desensitization, indicating that they are carried by heteromeric channels. Currents from ASIC1a(-/-) muscle afferents were less pH-sensitive and displayed faster recovery, currents from ASIC2(-/-) mice showed diminished potentiation by zinc, and currents from ASIC3(-/-) mice displayed slower desensitization than those from wild-type mice. Finally, ASIC-like currents were absent from triple null mice lacking ASIC1a, ASIC2a, and ASIC3. We conclude that ASIC1a, ASIC2a, and ASIC3 heteromers are the principle channels in skeletal muscle afferents. These results will help us understand the role of ASICs in exercise physiology and provide a molecular target for potential drug therapies to treat muscle pain. PMID- 23109676 TI - An alternative telomerase RNA in Arabidopsis modulates enzyme activity in response to DNA damage. AB - Telomerase replenishes telomere tracts by reiteratively copying its RNA template, TER. Unlike other model organisms, Arabidopsis thaliana harbors two divergent TER genes. However, only TER1 is required for telomere maintenance. Here we examine the function of TER2. We show that TER2 is spliced and its 3' end is truncated in vivo to generate a third TER isoform, TER2(S). TERT preferentially associates with TER2 > TER1 > TER2(S). Moreover, TER2 and TER2(S) assemble with Ku and POT1b (protection of telomeres), forming RNP (ribonucleoprotein) complexes distinct from TER1 RNP. Plants null for TER2 display increased telomerase enzyme activity, while TER2 overexpression inhibits telomere synthesis from TER1 and leads to telomere shortening. These findings argue that TER2 negatively regulates telomerase by sequestering TERT in a nonproductive RNP complex. Introduction of DNA double-strand breaks by zeocin leads to an immediate and specific spike in TER2 and a concomitant decrease in telomerase enzyme activity. This response is not triggered by replication stress or telomere dysfunction and is abrogated in ter2 mutants. We conclude that Arabidopsis telomerase is modulated by TER2, a novel DNA damage-induced noncoding RNA that works in concert with the canonical TER to promote genome integrity. PMID- 23109677 TI - Managing chronic inflammation in the aging diabetic patient with CKD by diet or sevelamer carbonate: a modern paradigm shift. AB - The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD. PMID- 23109678 TI - The role of metabolic syndrome, adiposity, and inflammation in physical performance in the Health ABC Study. AB - BACKGROUND: Metabolic syndrome (MetS) and functional limitation have been linked, but whether and how specific components of MetS and associated factors, such as inflammation, drive this relationship is unknown. METHODS: Data are from 2,822 men and women, aged 70-79 years, participating in the Health, Aging, and Body Composition (Health ABC) study and followed for 5 years. Presence of MetS at baseline was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Interleukin-6, C-reactive protein, and body fat mass were measured at baseline. Measures of physical performance, including 400-m walk time, 20-m walking speed, and the Health ABC physical performance battery (PPB) were obtained at baseline and examination years 2, 4, and 6. RESULTS: A total of 1,036 (37%) individuals met criteria for MetS. MetS was associated with poorer physical performance at baseline. Effect estimates between MetS and gait speed, and components of the Health ABC PPB (standing balance and repeated sit-to-stand performance) were modestly attenuated after adjustment for inflammation. All associations were attenuated to nonsignificance after adding total body fat mass to the model. Longitudinal analyses yielded similar results. Individual MetS component analysis revealed that abdominal obesity explained the largest fraction of the variation in physical performance. CONCLUSIONS: Although inflammatory biomarkers partially accounted for the relationship between MetS and aspects of physical performance, overall findings implicate adiposity as the primary factor explaining poorer physical performance in older adults with MetS. PMID- 23109680 TI - Growth and fat-free mass gain in preterm infants after discharge: a randomized controlled trial. AB - OBJECTIVE: To investigate whether the consumption of a nutrient-enriched formula after hospital discharge determines different growth and weight gain composition in preterm infants according to intra- and extrauterine growth pattern. METHODS: Two hundred seven preterm infants were randomized at term-corrected age to receive treatment A (term formula) or B (nutrient-enriched formula) up to 6 months of corrected age, using 2 computer-generated randomization lists, 1 for adequate for gestational age (AGA) and 1 for small for gestational age (SGA) infants. Infants were weaned according to our clinical practice after 6 months' corrected age. Anthropometric parameters and body composition by an air displacement plethysmography system were assessed at term and 1, 3, and 6 months' corrected age. Anthropometric parameters were also assessed at 12 months. RESULTS: Protein intakes were higher in infants receiving treatment B than in infants receiving treatment A at each study point. There were no differences between the feeding groups in weight and length SD scores in either the AGA and SGA group through the study. The mean head circumference values were higher in AGA infants receiving treatment B than in AGA infants receiving treatment A at 6 and 12 months, whereas at 6 months, the percentage of fat mass was lower. No difference in body composition was detected among SGA infants through the study. CONCLUSIONS: This randomized controlled trial demonstrates the beneficial effect of the consumption of a nutrient-enriched formula after hospital discharge by AGA infants both in terms of head circumference growth and fat-free mass gain. PMID- 23109679 TI - Instrument-based pediatric vision screening policy statement. AB - A policy statement describing the use of automated vision screening technology (instrument-based vision screening) is presented. Screening for amblyogenic refractive error with instrument-based screening is not dependent on behavioral responses of children, as when visual acuity is measured. Instrument-based screening is quick, requires minimal cooperation of the child, and is especially useful in the preverbal, preliterate, or developmentally delayed child. Children younger than 4 years can benefit from instrument-based screening, and visual acuity testing can be used reliably in older children. Adoption of this new technology is highly dependent on third-party payment policies, which could present a significant barrier to adoption. PMID- 23109681 TI - The role of the pediatrician in rural emergency medical services for children. AB - In rural America, pediatricians can play a key role in the development, implementation, and ongoing supervision of emergency medical services for children (EMSC). Pediatricians may represent the only source of pediatric expertise for a large region and are a vital resource for rural physicians (eg, general and family practice, emergency medicine) and other rural health care professionals (physician assistants, nurse practitioners, and emergency medical technicians), providing education about management and prevention of pediatric illness and injury; appropriate equipment for the acutely ill or injured child; and acute, chronic, and rehabilitative care. In addition to providing clinical expertise, the pediatrician may be involved in quality assurance, clinical protocol development, and advocacy, and may serve as a liaison between emergency medical services and other entities working with children (eg, school nurses, child care centers, athletic programs, and programs for children with special health care needs). PMID- 23109682 TI - Diagnostic value of procalcitonin in well-appearing young febrile infants. AB - BACKGROUND AND OBJECTIVE: Procalcitonin (PCT) has been introduced in many European protocols for the management of febrile children. Its value among young, well-appearing infants, however, is not completely defined. Our objective was to assess its performance in diagnosing serious bacterial infections and specifically invasive bacterial infections (IBIs) in well-appearing infants aged <3 months with fever without source (FWS). METHODS: Well-appearing infants aged <3 months with FWS admitted to 7 European pediatric emergency departments were retrospectively included. IBI was defined as the isolation of a bacterial pathogen in blood or cerebrospinal fluid culture. RESULTS: We included 1112 infants who had PCT measured and a blood culture performed. IBI was diagnosed in 23 cases (2.1%). In the multivariate analysis including clinical and laboratory data, PCT was the only independent risk factor for IBI (odds ratio 21.69; 95% confidence interval [CI] 7.93-59.28 for PCT >= 0.5 ng/mL). Positive likelihood ratios for PCT >= 2 ng/mL and C-reactive protein (CRP) >40 mg/L were 11.14 (95% CI 7.81-15.89) and 3.45 (95% CI 2.20-5.42), respectively. Negative likelihood ratios for PCT <0.5 ng/mL and CRP <20 mg/L were 0.25 (95% CI 0.12-0.55) and 0.41 (95% CI 0.22-0.76). Among patients with normal urine dipstick results and fever of recent onset, areas under the receiver operator characteristic curve for PCT and CRP were 0.819 and 0.563, respectively. CONCLUSIONS: Among well-appearing young infants with FWS, PCT performs better than CRP in identifying patients with IBIs and seems to be the best marker for ruling out IBIs. Among patients with normal urine dipstick results and fever of recent onset, PCT remains the most accurate blood test. PMID- 23109684 TI - Standards for health information technology to ensure adolescent privacy. AB - Privacy and security of health information is a basic expectation of patients. Despite the existence of federal and state laws safeguarding the privacy of health information, health information systems currently lack the capability to allow for protection of this information for minors. This policy statement reviews the challenges to privacy for adolescents posed by commercial health information technology systems and recommends basic principles for ideal electronic health record systems. This policy statement has been endorsed by the Society for Adolescent Health and Medicine. PMID- 23109683 TI - Relief of pain and anxiety in pediatric patients in emergency medical systems. AB - Control of pain and stress for children is a vital component of emergency medical care. Timely administration of analgesia affects the entire emergency medical experience and can have a lasting effect on a child's and family's reaction to current and future medical care. A systematic approach to pain management and anxiolysis, including staff education and protocol development, can provide comfort to children in the emergency setting and improve staff and family satisfaction. PMID- 23109685 TI - Human embryonic stem cell (hESC) and human embryo research. AB - Human embryonic stem cell research has emerged as an important platform for the understanding and treatment of pediatric diseases. From its inception, however, it has raised ethical concerns based not on the use of stem cells themselves but on objections to the source of the cells--specifically, the destruction of preimplantation human embryos. Despite differences in public opinion on this issue, a large majority of the public supports continued research using embryonic stem cells. Given the possible substantial benefit of stem cell research on child health and development, the American Academy of Pediatrics believes that funding and oversight for human embryo and embryonic stem cell research should continue. PMID- 23109687 TI - A protein kinase, calcineurin B-like protein-interacting protein Kinase9, interacts with calcium sensor calcineurin B-like Protein3 and regulates potassium homeostasis under low-potassium stress in Arabidopsis. AB - Potassium (K+) is an essential macronutrient for plant growth and development. Previous studies have demonstrated that Calcineurin B-Like Protein1 (CBL1) or CBL9 and CBL-Interacting Protein Kinase23 (CIPK23) regulate K+ uptake in Arabidopsis (Arabidopsis thaliana) roots by modulating K+ channel Arabidopsis K+ Transporter1. In this study, we show that the protein kinase CIPK9 interacts with the calcium sensor CBL3 and plays crucial roles in K+ homeostasis under low-K+ stress in Arabidopsis. Arabidopsis wild-type plants showed leaf chlorotic symptoms when grown for 10 d on low-K+ (100 MUM) medium. Here, we show that plants lacking CIPK9 displayed a tolerant phenotype to low-K+ stress, which still maintained green leaves when the wild-type plants showed typical K+-deficient symptoms. Overexpressing lines of CIPK9 resulted in a low-K+-sensitive phenotype compared with wild-type plants. Furthermore, CBL2 and CBL3 were identified as upstream regulators of CIPK9. Both CBL2- and CBL3-overexpressing lines displayed similar low-K+-sensitive phenotypes and K+ contents to CIPK9-overexpressing lines. However, only cbl3 mutant plants, but not cbl2 mutant plants, showed the low-K+-tolerant phenotype similar to cipk9 mutants. Taken together, these results demonstrate that CIPK9 and CBL3 work together and function in K+ homeostasis under low-K+ stress in Arabidopsis. PMID- 23109688 TI - Two GRAS proteins, SCARECROW-LIKE21 and PHYTOCHROME A SIGNAL TRANSDUCTION1, function cooperatively in phytochrome A signal transduction. AB - Photoreceptors, especially the far-red light-absorbing phytochrome A, play a crucial role in early seedling development, triggering the transition from etiolated to photomorphogenic growth. Here, we describe the biological functions of two GRAS proteins from Arabidopsis (Arabidopsis thaliana), SCARECROW-LIKE21 (SCL21) and PHYTOCHROME A SIGNAL TRANSDUCTION1 (PAT1), which are specifically involved in phytochrome A signal transduction. Loss-of-function mutants show an elongated hypocotyl under far-red light and are impaired in other far-red high irradiance responses. The SCL21 transcript itself is down-regulated by far-red light in a phytochrome A- and PAT1-dependent manner. Our results demonstrate that both SCL21 and PAT1 are positive regulators of phytochrome A signal transduction for several high-irradiance responses. Genetic and biochemical evidence suggest a direct interaction of the two proteins. PMID- 23109689 TI - Pemetrexed versus pemetrexed and carboplatin as second-line chemotherapy in advanced non-small-cell lung cancer: results of the GOIRC 02-2006 randomized phase II study and pooled analysis with the NVALT7 trial. AB - PURPOSE: To compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced NSCLC, in progression during or after first line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS). RESULTS: From July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). CONCLUSION: Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation. PMID- 23109690 TI - Imaging follicular lymphoma using positron emission tomography with [(18)F]fluorodeoxyglucose: to what purpose? PMID- 23109691 TI - Evaluating breast cancer risk with genome-wide association studies: is this approach patient ready? PMID- 23109692 TI - Results from a prospective, open-label, phase II trial of bendamustine in refractory or relapsed T-cell lymphomas: the BENTLY trial. AB - PURPOSE: To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. PATIENTS AND METHODS: Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m(2) per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). CONCLUSION: Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma. PMID- 23109693 TI - Palliative interventions in patients with peritoneal metastases and malignant bowel obstruction. PMID- 23109694 TI - Symptomatic treatment with lanreotide microparticles in inoperable bowel obstruction resulting from peritoneal carcinomatosis: a randomized, double-blind, placebo-controlled phase III study. AB - PURPOSE: To investigate the somatostatin analog lanreotide as symptomatic treatment for inoperable bowel obstruction due to peritoneal carcinomatosis. PATIENTS AND METHODS: In all, 80 patients with peritoneal carcinomatosis, inoperable malignant digestive obstruction, and two or more vomiting episodes per day or nasogastric tube (NGT) who were previously treated with intravenous corticosteroids and proton pump inhibitors were randomly assigned to one 30-mg injection of lanreotide microparticles (n = 43) or placebo (n = 37) in a 10-day, double-blind, parallel-group phase. The primary end point was the proportion of patients responding on day 7 (one or fewer episodes of vomiting per day or no vomiting recurrence after NGT removal [for >= 3 consecutive days in both cases]). Vomiting frequency/NGT secretion volumes, nausea, abdominal pain, well-being, and safety were also assessed. Patients could then enter an open-label lanreotide only phase. The study was conducted at 22 European hospitals. RESULTS: More patients receiving lanreotide than placebo were responders; this difference was not statistically significant for the intent-to-treat (ITT) population on the basis of diary cards (primary analysis; 41.9% [18 of 43] v 29.7% [11 of 37], respectively; odds ratio, 1.75; 95% CI, 0.68 to 4.49; P = .24) but was statistically significant for the corresponding supportive per protocol analysis (57.7% [15 of 26] v 30.4% [seven of 23]; P < .05) and ITT analysis, on the basis of investigators' assessments (50.0% [19 of 38] v 28.6% [10 of 35]; P < .05). Improvements in well-being were significantly greater with lanreotide on days 3, 6, and 7. No significant differences were observed for other secondary end points. Only two (mild/moderate) treatment-emergent adverse events were considered related to lanreotide. CONCLUSION: These results show that lanreotide has some efficacy and is safe in the symptomatic treatment of patients with inoperable bowel obstruction due to peritoneal carcinomatosis. PMID- 23109695 TI - Two drugs versus one drug in non-small-cell lung cancer: are we asking the right questions? PMID- 23109696 TI - Clinical outcome of the ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. AB - PURPOSE: The ACCORD 12 trial investigated the value of two different preoperative chemoradiotherapy (CT-RT) regimens in T3-4 Nx M0 resectable rectal cancer. Clinical results are reported after follow-up of 3 years. PATIENTS AND METHODS: Between November 2005 and July 2008, a total of 598 patients were randomly assigned to preoperative CT-RT with CAP45 (45-Gy RT for 5 weeks with concurrent capecitabine) or CAPOX50 (50-Gy RT for 5 weeks with concurrent capecitabine and oxaliplatin). Total mesorectal excision was planned 6 weeks after CT-RT. The primary end point was sterilization of the operative specimen, which was achieved in 13.9% versus 19.2% of patients, respectively (P = .09). Clinical results were analyzed for all randomly assigned patients according to the intention-to-treat principle. RESULTS: At 3 years, there was no significant difference between CAP45 and CAPOX50 (cumulative incidence of local recurrence, 6.1% v 4.4%; overall survival, 87.6% v 88.3%; disease-free survival, 67.9% v 72.7%). Grade 3 to 4 toxicity was reported in four patients in the CAP45 group and in two patients in the CAPOX50 group. Bowel continence, erectile dysfunction, and social life disturbance were not different between groups. In multivariate analysis, the sterilization rate (Dworak score) of the operative specimen was the main significant prognostic factor (hazard ratio, 0.32; 95% CI, 0.21 to 0.50). CONCLUSION: At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended. PMID- 23109698 TI - Misdiagnosis of non-hodgkin lymphoma as multiple myeloma. PMID- 23109697 TI - Initial molecular response at 3 months may predict both response and event-free survival at 24 months in imatinib-resistant or -intolerant patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase treated with nilotinib. AB - PURPOSE: The association between initial molecular response and longer-term outcomes with nilotinib was examined. PATIENTS AND METHODS: Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). RESULTS: BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to <= 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to <= 1%, > 1% to <= 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR-ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of <= 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to <= 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. CONCLUSION: Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of <= 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response. PMID- 23109699 TI - Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. AB - PURPOSE: [(18)F]Fluorodeoxyglucose positron emission tomography (PET) is widely used for the staging and restaging of patients with aggressive lymphoma, but less is known about the utility of PET in patients with follicular lymphoma (FL). In a prospective study, we evaluated the prognostic value of PET performed during treatment and at the end of treatment in 121 patients with FL treated with first line immunochemotherapy. PATIENTS AND METHODS: Patients with previously untreated high-tumor burden FL were treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) plus two cycles of rituximab, without rituximab maintenance. PET was performed before treatment, after four cycles of R-CHOP (interim PET), and at the end of treatment (final PET). PET scans were centrally reviewed. RESULTS: The total number of patients included was 121. Median age was 57 years. After central review, interim PET (n = 111) was negative in 76% of patients, and final PET (n = 106) was negative in 78%. With a median follow-up of 23 months, 2-year progression-free survival rates were 86% for interim PET-negative versus 61% for interim PET-positive patients (P = .0046) and 87% for final PET-negative versus 51% for final PET-positive patients (P < .001), respectively. Two-year overall survival also significantly differed according to final PET results: 100% versus 88% (P = .0128). CONCLUSION: PET performed either after four cycles of R-CHOP or at the end of therapy was strongly predictive of outcome in this prospective study. Therapeutic intervention based on PET results during or after inductive treatment should be evaluated. PMID- 23109700 TI - Acupuncture for cancer-related fatigue in patients with breast cancer: a pragmatic randomized controlled trial. AB - PURPOSE: We aimed to assess the effectiveness of acupuncture for cancer-related fatigue (CRF) in patients with breast cancer. PATIENTS AND METHODS: We conducted a pragmatic, randomized controlled trial comparing acupuncture with enhanced usual care. Three hundred two outpatients with breast cancer participated. We randomly assigned 75 patients to usual care and 227 patients to acupuncture plus usual care (random assignment of 1:3 respectively) with minimization controlling for baseline general fatigue and maintenance treatment. Treatment was delivered by acupuncturists once a week for 6 weeks through needling three pairs of acupoints. The usual care group received a booklet with information about fatigue and its management. Primary outcome was general fatigue at 6 weeks, measured with the Multidimensional Fatigue Inventory (MFI). Other measurements included the Hospital Anxiety and Depression Scale, Functional Assessment of Cancer Therapy General quality-of-life scale, and expectation of acupuncture effect. Analyses were by intention to treat. RESULTS: Two hundred forty-six of 302 patients randomly assigned provided complete data at 6 weeks. The difference in the mean General Fatigue score, between those who received the intervention and those who did not, was -3.11 (95% CI, -3.97 to -2.25; P < .001). The intervention also improved all other fatigue aspects measured by MFI, including Physical Fatigue and Mental Fatigue (acupuncture effect, -2.36 and -1.94, respectively; both at P < .001), anxiety and depression (acupuncture effect, -1.83 and -2.13, respectively; both at P < .001), and quality of life (Physical Well-Being effect, 3.30; Functional Well-Being effect, 3.57; both at P < .001; Emotional Well-Being effect, 1.93; P = .001; and Social Functioning Well-Being effect, 1.05; P < .05). CONCLUSION: Acupuncture is an effective intervention for managing the symptom of CRF and improving patients' quality of life. PMID- 23109701 TI - Opioid prescribing for cancer pain during the last 3 months of life: associated factors and 9-year trends in a nationwide United Kingdom cohort study. AB - PURPOSE: To determine time trends and characteristics associated with opioid analgesic prescribing to patients with cancer who are approaching the end of life. PATIENTS AND METHODS: This population-based cohort study used data on 29,825 patients diagnosed with five common cancers-lung (34.2%), colorectal (19.9%), female breast (21.6%), prostate (19.1%), and head and neck (5.2%)-in the United Kingdom General Practice Research Database (GPRD) who died between 2000 and 2008. Opioid prescription rates in the last 3 months of life were described. Characteristics associated with opioid prescribing were investigated by using generalized estimation equation models. RESULTS: In the last 3 months of life, 43.6% (95% CI, 43.0% to 44.2%) of patients received at least one prescription of opioids: morphine (33.4%; 95% CI, 32.8% to 33.9%), diamorphine (11.6%; 95% CI, 11.2% to 11.9%), and fentanyl family (10.2%; 95% CI, 9.8% to 10.5%). Over time, prescription rates increased for opioids predominant during specific time periods, especially oxycodone. Older patients (age > 60 years) had significantly lower chances of receiving opioids than their younger (age < 50 years) peers (prevalence ratio [PR] range, 0.14 to 0.78), even adjusted for comorbidity. Women were slightly more likely than men to receive any type of opioid (PR,1.07; 95% CI, 1.04 to 1.11). Morphine and diamorphine (PR range, 1.14 to 1.56) were more commonly prescribed for lung and colorectal cancers and fentanyl family for head and neck cancers (PR, 1.39; 95% CI, 1.19 to 1.62) compared with for prostate cancers. CONCLUSION: Morphine and diamorphine remain the stronghold for treating cancer pain in the United Kingdom. Opioid prescription rates are increasing over time. Prescription rates are lower for older people for all opioids, suggesting that this group needs attention. PMID- 23109702 TI - Treating cancer-related fatigue: the search for interventions that target those most in need. PMID- 23109703 TI - Recommendations for the return of research results to study participants and guardians: a report from the Children's Oncology Group. AB - PURPOSE: The Children's Oncology Group (COG) strongly supports the widely recognized principle that research participants should be offered a summary of study results. The mechanism by which to do so in a cooperative research group setting has not been previously described. METHODS: On the basis of a review of the available empirical and theoretic literature and on iterative, multidisciplinary discussion, a COG Return of Results Task Force (RRTF) offered detailed recommendations for the return of results to research study participants. RESULTS: The RRTF established guidelines for the notification of research participants and/or their parents/guardians about the availability of research results, a mechanism for and timing of sharing results via registration on the COG public Web site, the scope of the research to be shared, the target audience, and a process for creating and vetting lay summaries of study results. The RRTF recognized the challenges in adequately conveying complex scientific results to audiences with varying levels of health literacy and recommended that particularly sensitive or complex results be returned using direct personal contact. The RRTF also recommended evaluation of the cost, effectiveness, and impact of sharing results. CONCLUSION: These recommendations provide a framework for the offering and returning of results to participants. They can be used by individual investigators, multi-investigator research collaboratives, and large cooperative groups. PMID- 23109704 TI - A role for common genomic variants in the assessment of familial breast cancer. AB - PURPOSE: Genome-wide association studies have identified common genomic variants associated with increased susceptibility to breast cancer. In the general population, the risk associated with these known variants seems insufficient to inform clinical management. Their contribution to the development of familial breast cancer is less clear. PATIENTS AND METHODS: We studied 1,143 women with breast cancer who had completed BRCA1 and BRCA2 mutation screening as a result of a high risk for hereditary breast cancer. Genotyping of 22 breast cancer associated genomic variants was performed. A polygenic risk score (PRS), calculated as the sum of the log odds ratios for each allele, was compared with the same metric in 892 controls from the Australian Ovarian Cancer Study. The clinical features associated with the high and low ends of the polygenic risk distribution were compared. RESULTS: Women affected by familial breast cancer had a highly significant excess of risk alleles compared with controls (P = 1.0 * 10( 16)). Polygenic risk (measured by the PRS) was greater in women who tested negative for a BRCA1 or BRCA2 mutation compared with mutation carriers (P = 2.3 * 10(-6)). Non-BRCA1/2 women in the top quartile of the polygenic risk distribution were more likely to have had early-onset breast cancer (< 30 years of age, odds ratio [OR]= 3.37, P = .03) and had a higher rate of second breast cancer (OR 1.96, P = .02) compared with women with low polygenic risk. CONCLUSION: Genetic testing for common risk variants in women undergoing assessment for familial breast cancer may identify a distinct group of high-risk women in whom the role of risk-reducing interventions should be explored. PMID- 23109705 TI - Highlighting crypt necrosis by using confocal laser endomicroscopy for the in vivo and real-time diagnosis of GI graft-versus-host disease. PMID- 23109706 TI - CHEK2*1100delC heterozygosity in women with breast cancer associated with early death, breast cancer-specific death, and increased risk of a second breast cancer. AB - PURPOSE: We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. PATIENTS AND METHODS: From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. RESULTS: CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. CONCLUSION: Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer. PMID- 23109707 TI - Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Societe Francaise de Greffe de Moelle et de Therapie-Cellulaire and the Groupe-Francophone des Myelodysplasies. AB - PURPOSE: To investigate the impact of prior-to-transplantation azacitidine (AZA) on patient outcome after allogeneic stem-cell transplantation (alloSCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Of the 265 consecutive patients who underwent alloSCT for MDS between October 2005 and December 2009, 163 had received cytoreductive treatment prior to transplantation, including induction chemotherapy (ICT) alone (ICT group; n = 98), AZA alone (AZA group; n = 48), or AZA preceded or followed by ICT (AZA-ICT group; n = 17). At diagnosis, 126 patients (77%) had an excess of marrow blasts, and 95 patients (58%) had intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS). Progression to more advanced disease before alloSCT was recorded in 67 patients. Donors were sibling (n = 75) or HLA-matched unrelated (10/10; n = 88). They received blood (n = 142) or marrow (n = 21) grafts following either myeloablative (n = 33) or reduced intensity (n = 130) conditioning. RESULTS: With a median follow-up of 38.7 months, 3-year outcomes in the AZA, ICT, and AZA-ICT groups were 55%, 48%, and 32% (P = .07) for overall survival (OS); 42%, 44%, and 29% (P = .14) for event-free survival (EFS); 40%, 37%, and 36% (P = .86) for relapse; and 19%, 20%, and 35% (P = .24) for nonrelapse mortality (NRM), respectively. Multivariate analysis confirmed the absence of statistical differences between the AZA and the ICT groups in terms of OS, EFS, relapse, and NRM. CONCLUSION: With the goal of downstaging underlying disease before alloSCT, AZA alone led to outcomes similar to those for standard ICT. PMID- 23109708 TI - Referral practices of oncologists to specialized palliative care. AB - PURPOSE: To describe current referral practices of oncologists to specialized palliative care (SPC) and define demographic characteristics, practice situations, and opinions associated with referral. METHODS: Physician members of the Canadian Association of Medical Oncologists, Canadian Association of Radiation Oncologists, and Canadian Society of Surgical Oncology were invited to participate in an anonymous survey assessing SPC referral practices. Participants received two e-mailed and two mailed invitations. RESULTS: The response rate was 72% (603 of 839 physicians); 37% were medical oncologists/hematologists, 50% were radiation oncologists, and 12% were surgical oncologists. Ninety-four percent reported that SPC was available to them, but only 37% reported that these services accepted patients on chemotherapy. Eighty-four percent referred terminally ill patients usually/always, but generally for uncontrolled symptoms or discharge planning late in the disease course. One third would refer to SPC earlier if it was renamed supportive care. Predictors of higher referral frequency included comprehensiveness of available SPC services (P = .004), satisfaction with SPC availability (P < .001), SPC acceptance of patients receiving chemotherapy (P < .001), and oncologist ease with referring patients to a palliative care service before they were close to death (P < .001). Controlling for specialty, predictors of referral at diagnosis or during chemotherapy, rather than later, included satisfaction with SPC service availability (P < .001) and SPC service acceptance of patients on chemotherapy (P < .001). CONCLUSION: Oncologists referred patients frequently to SPC, but generally late in the disease course for patients with uncontrolled symptoms. Availability of comprehensive SPC, especially for patients receiving chemotherapy, and persisting definitional issues seem to be the main barriers preventing timely referral. PMID- 23109709 TI - Analysis of a wild mouse promoter variant reveals a novel role for FcgammaRIIb in the control of the germinal center and autoimmunity. AB - Genetic variants of the inhibitory Fc receptor FcgammaRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcgammaRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcgammaRIIb activation-induced up-regulation, mice developed more severe collagen induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcgammaRIIb in controlling affinity maturation, autoantibody production, and autoimmunity. PMID- 23109710 TI - Conditional deletion of cytokine receptor chains reveals that IL-7 and IL-15 specify CD8 cytotoxic lineage fate in the thymus. AB - The thymus generates T cells with diverse specificities and functions. To assess the contribution of cytokine receptors to the differentiation of T cell subsets in the thymus, we constructed conditional knockout mice in which IL-7Ralpha or common cytokine receptor gamma chain (gamma(c)) genes were deleted in thymocytes just before positive selection. We found that gamma(c) expression was required to signal the differentiation of MHC class I (MHC-I)-specific thymocytes into CD8(+) cytotoxic lineage T cells and into invariant natural killer T cells but did not signal the differentiation of MHC class II (MHC-II)-specific thymocytes into CD4(+) T cells, even into regulatory Foxp3(+)CD4(+) T cells which require gamma(c) signals for survival. Importantly, IL-7 and IL-15 were identified as the cytokines responsible for CD8(+) cytotoxic T cell lineage specification in vivo. Additionally, we found that small numbers of aberrant CD8(+) T cells expressing Runx3d could arise without gamma(c) signaling, but these cells were developmentally arrested before expressing cytotoxic lineage genes. Thus, gamma(c)-transduced cytokine signals are required for cytotoxic lineage specification in the thymus and for inducing the differentiation of MHC-I selected thymocytes into functionally mature T cells. PMID- 23109712 TI - Ascorbate as seen through plant evolution: the rise of a successful molecule? AB - Ascorbate is a widespread and efficient antioxidant that has multiple functions in plants, traditionally associated with the reactions of photosynthesis. This review aims to look at ascorbate from an evolutionary perspective. Cyanobacteria, algae, and bryophytes contain lower concentrations of ascorbate than higher plants, where the molecule accumulates in high concentrations in both photosynthetic and non-photosynthetic organs and tissues. This increase in ascorbate concentration is paralleled by an increase in the number of isoforms of ascorbate peroxidase and the ascorbate regenerating enzymes mono- and dehydroascorbate reductase. One way of understanding the rise in ascorbate concentrations is to consider ascorbate as a molecule among others that has been subject to selection pressures during evolution, due to its cost or benefit for the cell and the organism. Ascorbate has a low cost in terms of synthesis and toxicity, and its benefits include protection of the glutathione pool and proper functioning of a range of enzymes. The hypothesis presented here is that these features would have favoured increasing roles for the molecule in the development and growth of multicellular organisms. This review then focuses on this diversity of roles for ascorbate in both photosynthetic and non-photosynthetic tissues of higher plants, including fruits and seeds, as well as further functions the molecule may possess by looking at other species. The review also highlights one of the trade-offs of domestication, which has often reduced or diluted ascorbate content in the quest for increased fruit growth and yield, with unknown consequences for the corresponding functional diversity, particularly in terms of stress resistance and adaptive responses to the environment. PMID- 23109711 TI - Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression. AB - Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro-B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of >200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination. PMID- 23109713 TI - Taking a translational turn. PMID- 23109714 TI - Modeling-independent elucidation of inactivation pathways in recombinant and native A-type Kv channels. AB - A-type voltage-gated K(+) (Kv) channels self-regulate their activity by inactivating directly from the open state (open-state inactivation [OSI]) or by inactivating before they open (closed-state inactivation [CSI]). To determine the inactivation pathways, it is often necessary to apply several pulse protocols, pore blockers, single-channel recording, and kinetic modeling. However, intrinsic hurdles may preclude the standardized application of these methods. Here, we implemented a simple method inspired by earlier studies of Na(+) channels to analyze macroscopic inactivation and conclusively deduce the pathways of inactivation of recombinant and native A-type Kv channels. We investigated two distinct A-type Kv channels expressed heterologously (Kv3.4 and Kv4.2 with accessory subunits) and their native counterparts in dorsal root ganglion and cerebellar granule neurons. This approach applies two conventional pulse protocols to examine inactivation induced by (a) a simple step (single-pulse inactivation) and (b) a conditioning step (double-pulse inactivation). Consistent with OSI, the rate of Kv3.4 inactivation (i.e., the negative first derivative of double-pulse inactivation) precisely superimposes on the profile of the Kv3.4 current evoked by a single pulse because the channels must open to inactivate. In contrast, the rate of Kv4.2 inactivation is asynchronous, already changing at earlier times relative to the profile of the Kv4.2 current evoked by a single pulse. Thus, Kv4.2 inactivation occurs uncoupled from channel opening, indicating CSI. Furthermore, the inactivation time constant versus voltage relation of Kv3.4 decreases monotonically with depolarization and levels off, whereas that of Kv4.2 exhibits a J-shape profile. We also manipulated the inactivation phenotype by changing the subunit composition and show how CSI and CSI combined with OSI might affect spiking properties in a full computational model of the hippocampal CA1 neuron. This work unambiguously elucidates contrasting inactivation pathways in neuronal A-type Kv channels and demonstrates how distinct pathways might impact neurophysiological activity. PMID- 23109715 TI - Interactions of external K+ and internal blockers in a weak inward-rectifier K+ channel. AB - We investigated the effects of changing extracellular K(+) concentrations on block of the weak inward-rectifier K(+) channel Kir1.1b (ROMK2) by the three intracellular cations Mg(2+), Na(+), and TEA(+). Single-channel currents were monitored in inside-out patches made from Xenopus laevis oocytes expressing the channels. With 110 mM K(+) in the inside (cytoplasmic) solution and 11 mM K(+) in the outside (extracellular) solution, these three cations blocked K(+) currents with a range of apparent affinities (K(i) (0) = 1.6 mM for Mg(2+), 160 mM for Na(+), and 1.8 mM for TEA(+)) but with similar voltage dependence (zdelta = 0.58 for Mg(2+), 0.71 for Na(+), and 0.61 for TEA(+)) despite having different valences. When external K(+) was increased to 110 mM, the apparent affinity of all three blockers was decreased approximately threefold with no significant change in the voltage dependence of block. The possibility that the transmembrane cavity is the site of block was explored by making mutations at the N152 residue, a position previously shown to affect rectification in Kir channels. N152D increased the affinity for block by Mg(2+) but not for Na(+) or TEA(+). In contrast, the N152Y mutation increased the affinity for block by TEA(+) but not for Na(+) or Mg(2+). Replacing the C terminus of the channel with that of the strong inward-rectifier Kir2.1 increased the affinity of block by Mg(2+) but had a small effect on that by Na(+). TEA(+) block was enhanced and had a larger voltage dependence. We used an eight-state kinetic model to simulate these results. The effects of voltage and external K(+) could be explained by a model in which the blockers occupy a site, presumably in the transmembrane cavity, at a position that is largely unaffected by changes in the electric field. The effects of voltage and extracellular K(+) are explained by shifts in the occupancy of sites within the selectivity filter by K(+) ions. PMID- 23109716 TI - Distinct properties of Ca2+-calmodulin binding to N- and C-terminal regulatory regions of the TRPV1 channel. AB - Transient receptor potential (TRP) vanilloid 1 (TRPV1) is a molecular pain receptor belonging to the TRP superfamily of nonselective cation channels. As a polymodal receptor, TRPV1 responds to heat and a wide range of chemical stimuli. The influx of calcium after channel activation serves as a negative feedback mechanism leading to TRPV1 desensitization. The cellular calcium sensor calmodulin (CaM) likely participates in the desensitization of TRPV1. Two CaM binding sites are identified in TRPV1: the N-terminal ankyrin repeat domain (ARD) and a short distal C-terminal (CT) segment. Here, we present the crystal structure of calcium-bound CaM (Ca(2+)-CaM) in complex with the TRPV1-CT segment, determined to 1.95-A resolution. The two lobes of Ca(2+)-CaM wrap around a helical TRPV1-CT segment in an antiparallel orientation, and two hydrophobic anchors, W787 and L796, contact the C-lobe and N-lobe of Ca(2+)-CaM, respectively. This structure is similar to canonical Ca(2+)-CaM-peptide complexes, although TRPV1 contains no classical CaM recognition sequence motif. Using structural and mutational studies, we established the TRPV1 C terminus as a high affinity Ca(2+)-CaM-binding site in both the isolated TRPV1 C terminus and in full-length TRPV1. Although a ternary complex of CaM, TRPV1-ARD, and TRPV1-CT had previously been postulated, we found no biochemical evidence of such a complex. In electrophysiology studies, mutation of the Ca(2+)-CaM-binding site on TRPV1-ARD abolished desensitization in response to repeated application of capsaicin, whereas mutation of the Ca(2+)-CaM-binding site in TRPV1-CT led to a more subtle phenotype of slowed and reduced TRPV1 desensitization. In summary, our results show that the TRPV1-ARD is an important mediator of TRPV1 desensitization, whereas TRPV1-CT has higher affinity for CaM and is likely involved in separate regulatory mechanisms. PMID- 23109718 TI - Purinergic regulation of inflammasome activation after central nervous system injury. PMID- 23109719 TI - Clonal growth and fine-scale genetic structure in tanoak (Notholithocarpus densiflorus: Fagaceae). AB - The combination of sprouting and reproduction by seed can have important consequences on fine-scale spatial distribution of genetic structure (SGS). SGS is an important consideration for species' restoration because it determines the minimum distance among seed trees to maximize genetic diversity while not prejudicing locally adapted genotypes. Local environmental conditions can be expected to influence levels of clonal spread and SGS, particularly in the case of disturbance regimes such as fire. Here, we characterize fine-scale genetic structure and clonal spread in tanoak from drier upland sites and more mesic lowland woodlands. Clonal spread was a significant mode of stand development, but spread was limited on average to about 5-6 m. Gene dispersal was decomposed into clonal and sexual components. The latter varied according to whether it was estimated from all ramets with the clonal component removed or for a single ramet per genet. We used the difference in these 2 estimates of gene dispersal as a measure of the effect of clonality on effective population size in this species. Although upland sites had a greater number of ramets per genet, most of the other indices computed were not significantly different. However, they tended to show greater heterozygote excess and shorter gene dispersal distances than the lowland sites. The average distance among inferred sibships on upland sites was approximately at the scale of maximum clonal range. This was not the case on lowland sites, where sibs were more dispersed. We recommend minimum distances among seed trees to avoid selecting clones and to maximize genetic diversity for restoration. PMID- 23109717 TI - Cellular context and multiple channel domains determine cAMP sensitivity of HCN4 channels: ligand-independent relief of autoinhibition in HCN4. AB - Hyperpolarization-activated, cyclic nucleotide-sensitive (HCN) channels produce the I(f) and I(h) currents, which are critical for cardiac pacemaking and neuronal excitability, respectively. HCN channels are modulated by cyclic AMP (cAMP), which binds to a conserved cyclic nucleotide-binding domain (CNBD) in the C terminus. The unliganded CNBD has been shown to inhibit voltage-dependent gating of HCNs, and cAMP binding relieves this "autoinhibition," causing a depolarizing shift in the voltage dependence of activation. Here we report that relief of autoinhibition can occur in the absence of cAMP in a cellular context- and isoform-dependent manner: when the HCN4 isoform was expressed in Chinese hamster ovary (CHO) cells, the basal voltage dependence was already shifted to more depolarized potentials and cAMP had no further effect on channel activation. This "pre-relief" of autoinhibition was specific both to HCN4 and to CHO cells; cAMP shifted the voltage dependence of HCN2 in CHO cells and of HCN4 in human embryonic kidney (HEK) cells. The pre-relief phenotype did not result from different concentrations of soluble intracellular factors in CHO and HEK cells, as it persisted in excised cell-free patches. Likewise, it did not arise from a failure of cAMP to bind to the CNBD of HCN4 in CHOs, as indicated by cAMP dependent slowing of deactivation. Instead, a unique ~300-amino acid region of the distal C terminus of HCN4 (residues 719-1012, downstream of the CNBD) was found to be necessary, but not sufficient, for the depolarized basal voltage dependence and cAMP insensitivity of HCN4 in CHO cells. Collectively, these data suggest a model in which multiple HCN4 channel domains conspire with membrane associated intracellular factors in CHO cells to relieve autoinhibition in HCN4 channels in the absence of cAMP. These findings raise the possibility that such ligand-independent regulation could tune the activity of HCN channels and other CNBD-containing proteins in many physiological systems. PMID- 23109721 TI - Genetic diversity in the Homosporous Fern Ophioglossum vulgatum (Ophioglossaceae) from South Korea: inference of mating system and population history. AB - It is generally believed that the members of Ophioglossaceae have subterranean, potentially bisexual gametophytes, which favor intragametophytic selfing. In Ophioglossaceae, previous allozyme studies revealed substantial inbreeding within Botrychium species and Mankyua chejuense. However, little is known about the mating system in species of the genus Ophioglossum. Molecular marker analyses can provide insights into the relative occurrence of selfing versus cross fertilization in the species of Ophioglossum. We investigated allozyme variation in 8 Korean populations of the homosporous fern Ophioglossum vulgatum to infer its mating system and to get some insight into the population-establishment history in South Korea. We detected homozygous genotypes for alternative alleles at several loci, which suggest the occurrence of intragametophytic self fertilization. Populations harbor low within-population variation (% P = 7.2, A = 1.08, and H (e) = 0.026) and a high among-population differentiation (F (ST) = 0.733). This, together with the finding that alternative alleles were fixed at several loci, suggests that the number and size of populations of O. vulgatum might have been severely reduced during the last glaciation (i.e., due to its in situ persistence in small, isolated refugia). The combined effects of severe random genetic drift and high rates of intragametophytic selfing are likely responsible for the genetic structure displayed by this homosporous fern. Its low levels of genetic diversity in South Korea justify the implementation of some conservation measures to ensure its long-term preservation. PMID- 23109720 TI - Development and application of camelid molecular cytogenetic tools. AB - Cytogenetic chromosome maps offer molecular tools for genome analysis and clinical cytogenetics and are of particular importance for species with difficult karyotypes, such as camelids (2n = 74). Building on the available human-camel zoo fluorescence in situ hybridization (FISH) data, we developed the first cytogenetic map for the alpaca (Lama pacos, LPA) genome by isolating and identifying 151 alpaca bacterial artificial chromosome (BAC) clones corresponding to 44 specific genes. The genes were mapped by FISH to 31 alpaca autosomes and the sex chromosomes; 11 chromosomes had 2 markers, which were ordered by dual color FISH. The STS gene mapped to Xpter/Ypter, demarcating the pseudoautosomal region, whereas no markers were assigned to chromosomes 14, 21, 22, 28, and 36. The chromosome-specific markers were applied in clinical cytogenetics to identify LPA20, the major histocompatibility complex (MHC)-carrying chromosome, as a part of an autosomal translocation in a sterile male llama (Lama glama, LGL; 2n = 73,XY). FISH with LPAX BACs and LPA36 paints, as well as comparative genomic hybridization, were also used to investigate the origin of the minute chromosome, an abnormally small LPA36 in infertile female alpacas. This collection of cytogenetically mapped markers represents a new tool for camelid clinical cytogenetics and has applications for the improvement of the alpaca genome map and sequence assembly. PMID- 23109722 TI - Glutamine suppresses airway neutrophilia by blocking cytosolic phospholipase A(2) via an induction of MAPK phosphatase-1. AB - Neutrophils are inflammatory cells that may contribute in a crucial way to the pathophysiology of steroid-resistant severe asthma. We previously reported that the nonessential amino acid l-glutamine (Gln) suppressed the recruitment of neutrophils into the airway in a murine model of asthma. In this study, we investigated the mechanisms by which Gln exerts beneficial effects in airway neutrophilia. We used the model we previously developed, which is suitable for examining sequential early asthmatic events, including neutrophil infiltration. Gln suppressed airway neutrophilia in a CXC chemokine-independent way. Airway neutrophilia was associated with cytosolic phospholipase A(2) (cPLA(2)) and 5 lipoxygenase (5-LO) activities. p38 MAPK, the upstream pathway of cPLA(2) and 5 LO, played a key role in inducing airway neutrophilia. Gln inhibited not only the phosphorylation of cPLA(2) and p38 MAPK but also leukotriene B(4) levels in the airways. Gln induced the early induction of MAPK phosphatase-1 (MKP-1) protein, a negative regulator of p38. MKP-1 small interfering RNA abrogated all the effects of Gln. Our results suggest that pathways involving p38/cPLA(2)/5-LO have a major role in airway neutrophilia. Gln suppresses airway neutrophilia via inhibiting p38 MAPK and its downstream pathways in an MKP-1-dependent way, which may provide a novel therapeutic strategy for pulmonary neutrophilic inflammatory diseases. PMID- 23109724 TI - Neutrophil extracellular traps entrap and kill Borrelia burgdorferi sensu stricto spirochetes and are not affected by Ixodes ricinus tick saliva. AB - Lyme disease is caused by spirochetes of the Borrelia burgdorferi sensu lato complex. They are transmitted mainly by Ixodes ricinus ticks. After a few hours of infestation, neutrophils massively infiltrate the bite site. They can kill Borrelia via phagocytosis, oxidative burst, and hydrolytic enzymes. However, factors in tick saliva promote propagation of the bacteria in the host even in the presence of a large number of neutrophils. The neutrophil extracellular trap (NET) consists in the extrusion of the neutrophil's own DNA, forming traps that can retain and kill bacteria. The production of reactive oxygen species is apparently associated with the onset of NETs (NETosis). In this article, we describe NET formation at the tick bite site in vivo in mice. We show that Borrelia burgdorferi sensu stricto spirochetes become trapped and killed by NETs in humans and that the bacteria do not seem to release significant nucleases to evade this process. Saliva from I. ricinus did not affect NET formation by human neutrophils or its stability. However, it greatly decreased neutrophil reactive oxygen species production, suggesting that a strong decrease of hydrogen peroxide does not affect NET formation. Finally, round bodies trapped in NETs were observed, some of them staining as live bacteria. This observation could help contribute to a better understanding of the early steps of Borrelia invasion and erythema migrans formation after tick bite. PMID- 23109723 TI - Paneth cell-mediated multiorgan dysfunction after acute kidney injury. AB - Acute kidney injury (AKI) is frequently complicated by extrarenal multiorgan injury, including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of proinflammatory mediators drives multiorgan injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage-depleted mice decreased markedly. In addition, intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI. PMID- 23109725 TI - Differential expression of neurotensin and specific receptors, NTSR1 and NTSR2, in normal and malignant human B lymphocytes. AB - Neurotensin, a neuropeptide growth factor, and its two specific neurotensin receptors, NTSR1 and NTSR2, were shown to be expressed by human B cell lines. Another NTSR, sortilin, which is common to neurotensin and neurotrophins, was also detected as we have previously described. Neurotensin was functional in B cell lines; it induced their proliferation and inhibited apoptosis induced by serum deprivation or Fas activation. Quantitative study of gene expression in two malignant B cell diseases showed that NTSR2 was overexpressed, NTSR1 decreased, and neurotensin was unexpressed in B cell leukemia patient's cells, as compared with healthy B cells. However, these expressions did not significantly change in large diffuse B cell lymphoma lymph nodes compared with benign ones. This study points out that neurotensin and its two specific receptors are expressed in human B lymphocytes. Such expressions were not described, and their relationship in B cell diseases, especially in chronic B cell leukemia, needs to be considered further in regard to these findings. PMID- 23109726 TI - Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice. AB - CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement independent mechanism. PMID- 23109727 TI - 5-Lipoxygenase mediates RANKL-induced osteoclast formation via the cysteinyl leukotriene receptor 1. AB - 5-Lipoxygenase (5-LO) catalyzes the formation of two major groups of leukotrienes, leukotriene B4 and cysteinyl leukotrienes (CysLTs), and it has been implicated as a promising drug target to treat various inflammatory diseases. However, its role in osteoclastogenesis has not been investigated. In this study, we used mouse bone marrow-derived macrophages (BMMs) to show that 5-LO inhibitor suppresses RANKL-induced osteoclast formation. Inhibition of 5-LO was associated with impaired activation of multiple signaling events downstream of RANK, including ERK and p38 phosphorylation, and IkappaB degradation, followed by a decrease in NFATc1 expression. Ectopic overexpression of a constitutively active form of NFATc1 partly rescued the antiosteoclastogenic effect of 5-LO inhibitor. The knockdown of 5-LO in BMMs also resulted in a significant reduction in RANKL induced osteoclast formation, accompanied by decreased expression of NFATc1. Similar effects were shown with CysLT receptor (CysLTR)1/2 antagonist and small RNA for CysLTR1 in BMMs, indicating the involvement of CysLT and CysLTR1 in 5-LO mediated osteoclastogenesis. Finally, 5-LO inhibitor suppressed LPS-induced osteoclast formation and bone loss in the in vivo mouse experiments, suggesting a potential therapeutic strategy for treating diseases involving bone destruction. Taken together, the results of this study demonstrate that 5-LO is a key mediator of RANKL-induced osteoclast formation and possibly a novel therapeutic target for bone-resorption diseases. PMID- 23109729 TI - A sugar isomerization reaction established on various (betaalpha)8-barrel scaffolds is based on substrate-assisted catalysis. AB - In the course of tryptophan biosynthesis, the isomerization of phosphoribosylanthranilate (PRA) is catalyzed by the (betaalpha)8-barrel enzyme TrpF. The reaction occurs via a general acid-base mechanism with an aspartate and a cysteine residue acting as acid and base, respectively. PRA isomerase activity could be established on two (betaalpha)8-barrel enzymes involved in histidine biosynthesis, namely HisA and HisF, and on a HisAF chimera, by introducing two aspartate-to-valine substitutions. We have analyzed the reaction mechanism underlying this engineered activity by measuring its pH dependence, solving the crystal structure of a HisF variant with bound product analogue, and applying molecular dynamics simulations and mixed quantum and molecular mechanics calculations. The results suggest that PRA is anchored by the C-terminal phosphate-binding sites of HisA, HisF and HisAF. As a consequence, a conserved aspartate residue, which is equivalent to Cys7 from TrpF, is properly positioned to act as catalytic base. However, no obvious catalytic acid corresponding to Asp126 from TrpF could be identified in the three proteins. Instead, this role appears to be carried out by the carboxylate group of the anthranilate moiety of PRA. Thus, the engineered PRA isomerization activity is based on a reaction mechanism including substrate-assisted catalysis and thus differs substantially from the naturally evolved reaction mechanism used by TrpF. PMID- 23109728 TI - TRAF binding is required for a distinct subset of in vivo B cell functions of the oncoprotein LMP1. AB - EBV-encoded latent membrane protein 1 (LMP1) is important for EBV contributions to B cell transformation and many EBV-associated malignancies, as well as EBV mediated exacerbation of autoimmunity. LMP1 functionally mimics TNF receptor (TNFR) superfamily member CD40, but LMP1 signals and downstream effects are amplified and sustained compared with CD40. CD40 and LMP1 both use TNFR associated factor (TRAF) adaptor proteins, but in distinct ways. LMP1 functions require TRAFs 3, 5, and 6, which interact with LMP1. However, TRAFs can also contribute to signaling in the absence of direct interactions with cell surface receptors, so we investigated whether their roles in LMP1 in vivo functions require direct association. We show in this study that the LMP1 TRAF binding site was required for LMP1-mediated autoantibody production, the germinal center response to immunization, and optimal production of several isotypes of Ig, but not LMP1-dependent enlargement of secondary lymphoid organs in transgenic mice. Thus, LMP1 in vivo effects can be mediated via both TRAF binding-dependent and independent pathways. Together with our previous findings, these results indicate that TRAF-dependent receptor functions may not always require TRAF-receptor binding. These data suggest that TRAF-mediated signaling pathways, such as those of LMP1, may be more diverse than previously appreciated. This finding has significant implications for receptor and TRAF-targeted therapies. PMID- 23109731 TI - A Study of Shrinkage Stress Reduction and Mechanical Properties of Nanogel Modified Resin Systems. AB - A series of nanogel compositions were prepared from urethane dimethacrylate (UDMA) and isobornyl methacrylate (IBMA) in the presence of a thiol chain transfer agent. The linear oligomer of IBMA was synthesized by a similar solution polymerization technique. The nanogels were prepared with different crosslinker concentrations to achieve varied branching densities and molecular weights. The prepolymers were dispersed in triethylene glycol dimethacrylate at loading levels ranging from 10 wt% to 50 wt%. Photopolymerization reaction kinetics of all prepolymer modified systems were enhanced relative to the nanogel-free control during early stage polymerization while limiting conversion was similar for most samples. Volumetric polymerization shrinkage was reduced proportionally with the prepolymer content while the corresponding decrease in polymerization stress was potentially greater than an additive linear behavior. Flexural strength for inert linear polymer-modified systems decreased significantly with the increase in the prepolymer content; however, with an increase in the crosslinker concentration within the nanogel additives, and an increase in the concentration of residual pendant reactive sites, flexural strength was maintained or improved regardless of the nanogel loading level. This demonstrates that covalent attachment rather than just physical entanglement with the polymer matrix is important for effective polymer mechanical reinforcement by nanogel additives. Reactive nanogel additives can be considered as a practical, generic means to achieve substantial reductions in polymerization shrinkage and shrinkage stress in common polymers. PMID- 23109730 TI - Antibody affinity maturation using yeast display with detergent-solubilized membrane proteins as antigen sources. AB - Antigen preparations in the form of detergent-solubilized cell lysates could, in principle, render membrane proteins (MPs) compatible with in vitro antibody engineering technologies. To this end, detergent-solubilized cell lysates were coupled with the yeast surface display platform to affinity mature an anti transferrin receptor (TfR) single-chain antibody (scFv). Lysates were generated from TfR-expressing HEK293 cells by solubilization with detergent-containing buffer after undergoing plasma membrane-restricted biotinylation. Lysate-resident TfR was then combined with a mutagenic anti-TfR scFv library in a competitive, dissociation rate screen, and scFvs were identified with up to 4-fold improved dissociation rates on the surface of yeast. Importantly, although the lysates contained a complex mixture of biotinylated proteins, the engineered scFvs retained their TfR binding specificity. When secreted by yeast as soluble proteins, mutant scFvs bound to cell surface TfR with 3-7-fold improvements in equilibrium binding affinity. Although a known MP antigen was targeted for purposes of this study, employing biotin tagging as a means of antigen detection makes the lysate-based approach particularly flexible. We have previously shown that yeast display can be used to identify lead antibodies using cell lysate resident MP antigens, and combined with this work showing that antibodies can also be quantitatively engineered using cell lysates, these approaches may provide a high-throughput platform for generation and optimization of antibodies against MPs. PMID- 23109732 TI - Parallel-quadrature phase-shifting digital holographic microscopy using polarization beam splitter. AB - We present a digital holography microscopy technique based on parallel-quadrature phase-shifting method. Two pi/2 phase-shifted holograms are recorded simultaneously using polarization phase-shifting principle, slightly off-axis recording geometry, and two identical CCD sensors. The parallel phase-shifting is realized by combining circularly polarized object beam with a 45 degrees degree polarized reference beam through a polarizing beam splitter. DC term is eliminated by subtracting the two holograms from each other and the object information is reconstructed after selecting the frequency spectrum of the real image. Both amplitude and phase object reconstruction results are presented. Simultaneous recording eliminates phase errors caused by mechanical vibrations and air turbulences. The slightly off-axis recording geometry with phase-shifting allows a much larger dimension of the spatial filter for reconstruction of the object information. This leads to better reconstruction capability than traditional off-axis holography. PMID- 23109733 TI - A new approach to network heterogeneity: Polymerization Induced Phase Separation in photo-initiated, free-radical methacrylic systems. AB - Non-reactive, thermoplastic prepolymers (poly- methyl, ethyl and butyl methacrylate) were added to a model homopolymer matrix composed of triethylene glycol dimethacrylate (TEGDMA) to form heterogeneous networks via polymerization induced phase separation (PIPS). PIPS creates networks with distinct phase structure that can partially compensate for volumetric shrinkage during polymerization through localized internal volume expansion. This investigation utilizes purely photo-initiated, free-radical systems, broadening the scope of applications for PIPS since these processing conditions have not been studied previously.The introduction of prepolymer into TEGDMA monomer resulted in stable, homogeneous monomer formulations, most of which underwent PIPS upon photo irradiation, creating heterogeneous networks. During polymerization the presence of prepolymer enhanced autoacceleration, allowing for a more extensive ambient cure of the material. Phase separation, as characterized by dynamic changes in sample turbidity, was monitored simultaneously with monomer conversion and either preceded or was coincident with network gelation. Dynamic mechanical analysis shows a broadening of the tan delta peak and secondary peak formation, characteristic of phase-separated materials, indicating one phase rich in prepolymer and another depleted form upon phase separation. In certain cases, PIPS leads to an enhanced physical reduction of volumetric shrinkage, which is attractive for many applications including dental composite materials. PMID- 23109735 TI - Stockpiling oral cholera vaccine. PMID- 23109736 TI - Time for innovative dialogue on health systems research. PMID- 23109738 TI - Keeping kidneys. AB - Most countries struggle to meet the demand for transplant kidneys, but a few are reaping the benefits of systems dedicated to increasing the number of organ donations after death. Ben Jones and Mireia Bes report. PMID- 23109740 TI - Global cost of correcting vision impairment from uncorrected refractive error. AB - OBJECTIVE: To estimate the global cost of establishing and operating the educational and refractive care facilities required to provide care to all individuals who currently have vision impairment resulting from uncorrected refractive error (URE). METHODS: The global cost of correcting URE was estimated using data on the population, the prevalence of URE and the number of existing refractive care practitioners in individual countries, the cost of establishing and operating educational programmes for practitioners and the cost of establishing and operating refractive care facilities. The assumptions made ensured that costs were not underestimated and an upper limit to the costs was derived using the most expensive extreme for each assumption. FINDINGS: There were an estimated 158 million cases of distance vision impairment and 544 million cases of near vision impairment caused by URE worldwide in 2007. Approximately 47 000 additional full-time functional clinical refractionists and 18 000 ophthalmic dispensers would be required to provide refractive care services for these individuals. The global cost of educating the additional personnel and of establishing, maintaining and operating the refractive care facilities needed was estimated to be around 20 000 million United States dollars (US$) and the upper limit cost was US$ 28 000 million. The estimated loss in global gross domestic product due to distance vision impairment caused by URE was US$ 202 000 million annually. CONCLUSION: The cost of establishing and operating the educational and refractive care facilities required to deal with vision impairment resulting from URE was a small proportion of the global loss in productivity associated with that vision impairment. PMID- 23109739 TI - Rotavirus mortality in India: estimates based on a nationally representative survey of diarrhoeal deaths. AB - OBJECTIVE: To estimate the number of rotavirus-associated deaths among Indian children younger than five years. METHODS: We surveyed more than 23 000 child deaths from a nationally representative survey of 1.1 million Indian households during 2001-2003. Diarrhoeal deaths were characterized by region, age and sex and were combined with the proportion of deaths attributable to rotavirus, as determined by hospital microbiologic data collected by the Indian Rotavirus Strain Surveillance Network from December 2005 to November 2007. Rotavirus vaccine efficacy data from clinical trials in developing countries were used to estimate the number of deaths preventable by a national vaccination programme. Data were analysed using Stata SE version 10. FINDINGS: Rotavirus caused an estimated 113 000 deaths (99% confidence interval, CI: 86 000-155 000); 50% (54 700) and 75% (85 400) occurred before one and two years of age, respectively. One child in 242 died from rotavirus infection before five years of age. Rotavirus associated mortality rates overall, among girls and among boys were 4.14 (99% CI: 3.14-5.68), 4.89 (99% CI: 3.75-6.79) and 3.45 (99% CI: 2.58-4.66) deaths per 1000 live births, respectively. Rates were highest in Bihar, Uttar Pradesh and Madhya Pradesh, which together accounted for > 50% of deaths (64 400) nationally. Rotavirus vaccine could prevent 41 000-48 000 deaths among children aged 3-59 months. CONCLUSION: The burden of rotavirus-associated mortality is high among Indian children, highlighting the potential benefits of rotavirus vaccination. PMID- 23109741 TI - The impact of new tuberculosis diagnostics on transmission: why context matters. AB - OBJECTIVE: To estimate the impact of new tuberculosis diagnostics on tuberculosis transmission given the complex contextual factors that can lead to patient loss before diagnosis or treatment. METHODS: An epidemic model of tuberculosis specifying discrete steps along the tuberculosis diagnostic pathway was constructed. The model was calibrated to the epidemiology of tuberculosis and human immunodeficiency virus (HIV) infection in the United Republic of Tanzania and was used to assess the impact of a new diagnostic tool with 70% sensitivity for smear-negative pulmonary tuberculosis. The influence of contextual factors on the projected epidemic impact of the new diagnostic tool over the decade following introduction was explored. FINDINGS: With the use of smear microscopy, the incidence of tuberculosis will decline by an average of 3.94% per year. If the new tool is added, incidence will decline by an annual 4.25%. This represents an absolute change of 0.31 percentage points (95% confidence interval: 0.04 0.42). However, the annual decline in transmission with use of the new tool is less when existing strategies for the diagnosis of smear-negative cases have high sensitivity and when symptomatic individuals delay in seeking care. Other influential contextual factors include access to tuberculosis care, patient loss before diagnosis, initial patient default after diagnosis and treatment success rate. CONCLUSION: When implementing and scaling up the use of a new diagnostic tool, the operational context in which diagnosis and treatment take place needs to be considered. PMID- 23109742 TI - Population-level impact of hormonal contraception on incidence of HIV infection and pregnancy in women in Durban, South Africa. AB - OBJECTIVE: To estimate the potential impact of using hormonal contraceptives on rates of infection with human immunodeficiency virus type 1 (HIV-1) and pregnancy by theoretically removing the use of hormonal contraceptives from a study population. METHODS: A prospective cohort study included 3704 HIV-negative women who were enrolled in two biomedical trials that tested two vaginal microbicides (PRO 2000 and Carraguard(r)) for the prevention of HIV-1 in Durban, South Africa, in 2004-2009. Cox proportional hazards regression models along with partial population attributable risks (PARs) and their 95% confidence intervals (CIs) were calculated to assess the relative population-level impact of the use of hormonal contraceptives on HIV-1 seroconversion rates and on pregnancy rates. FINDINGS: Women who reported using hormonal contraceptives at enrolment in the trial had a higher risk of HIV-1 seroconversion (adjusted hazards ratio: 1.24; 95% CI: 0.97-1.58) than women who reported using other types of contraceptives at enrolment. At the population level, the use of hormonal contraceptives (pills or injectables) at baseline and during study follow-up accounted for approximately 20% (95% CI: 16-22) of HIV-1 seroconversions. However, the partial PAR indicated a relative impact of 12% (95% CI: 9.0-15.7). On the other hand, 72% (95% CI: 66 77) of the pregnancies could have been avoided if all women had used hormonal contraceptives. CONCLUSION: Women using hormonal contraceptives need comprehensive counselling on simultaneous prevention of HIV-1 infection. PMID- 23109743 TI - Estimated incidence of influenza-virus-associated severe pneumonia in children in El Salvador, 2008-2010. AB - OBJECTIVE: To estimate the incidence of influenza-virus-associated severe pneumonia among Salvadorian children aged < 5 years. METHODS: Data on children aged < 5 years admitted with severe pneumonia to a sentinel hospital in the western region were collected weekly. Nasal and oropharyngeal swab specimens were collected from a convenience sample of case patients for respiratory virus testing. A health-care utilization survey was conducted in the hospital catchment area to determine the proportion of residents who sought care at the hospital. The incidence of influenza-virus-associated severe pneumonia among all Salvadorian children aged < 5 years was estimated from surveillance and census data, with adjustment for health-care utilization. Influenza virus strains were characterized by the United States Centers for Disease Control and Prevention to determine their correspondence with northern and southern hemisphere influenza vaccine formulations. FINDINGS: Physicians identified 2554 cases of severe pneumonia. Samples from 608 cases were tested for respiratory viruses and 37 (6%) were positive for influenza virus. The estimated incidence of influenza-virus associated severe pneumonia was 3.2 cases per 1000 person-years (95% confidence interval, CI: 2.8-3.7) overall, 1.5 cases per 1000 person-years (95% CI: 1.0-2.0) during 2008, 7.6 cases per 1000 person-years (95% CI: 6.5-8.9) during 2009 and 0.6 cases per 1000 person-years (95% CI: 0.3-1.0) during 2010. Northern and southern hemisphere vaccine formulations matched influenza virus strains isolated during 2008 and 2010. CONCLUSION: Influenza-virus-associated severe pneumonia occurred frequently among young Salvadorian children during 2008-2010. Antigens in northern and southern hemisphere influenza vaccine formulations corresponded to circulating strains. PMID- 23109744 TI - Mortality measures from sample-based surveillance: evidence of the epidemiological transition in Viet Nam. AB - OBJECTIVE: To report methods and results from a national sample mortality surveillance programme implemented in Viet Nam in 2009. METHODS: A national sample of 192 communes located in 16 provinces and covering a population of approximately 2.6 million was selected using multi-stage cluster sampling. Deaths for 2009 were identified from several local data sources. Record reconciliation and capture-recapture methods were used to compile data and assess completeness of the records. Life tables were computed using reported and adjusted age specific death rates. Each death was followed up by verbal autopsy to ascertain the probable cause(s) of death. Underlying causes were certified and coded according to international guidelines. FINDINGS: A total of 9921 deaths were identified in the sample population. Completeness of death records was estimated to be 81%. Adjusted life expectancies at birth were 70.4 and 78.7 years for males and females, respectively. Stroke was the leading cause of death in both sexes. Other prominent causes were road traffic accidents, cancers and HIV infection in males, and cardiovascular conditions, pneumonia and diabetes in females. CONCLUSION: Viet Nam is undergoing the epidemiological transition. Although data are relatively complete, they could be further improved through strengthened local collaboration. Medical certification for deaths in hospitals, and shorter recall periods for verbal autopsy interviews would improve cause of death ascertainment. PMID- 23109745 TI - Factors associated with the safety of voluntary medical male circumcision in Nyanza province, Kenya. AB - OBJECTIVE: To determine factors associated with the incidence of adverse events associated with voluntary medical male circumcision (VMMC) for the prevention of HIV infection in Nyanza province, Kenya. METHODS: Males aged 12 years or older who underwent VMMC between November 2008 and March 2010 in 16 clinics in three districts were followed through passive surveillance to monitor the incidence of adverse events during and after surgery. A subset of clinic participants was randomly selected for active surveillance post-operatively and was monitored for adverse events through a home-based, in-depth interview and a genital exam 28 to 45 days after surgery. Performance indicators were assessed for 167 VMMC providers. FINDINGS: The adverse event rate was 0.1% intra-operatively and 2.1% post-operatively among clinic system participants (n = 3705), and 7.5% post operatively among participants under active surveillance (n = 1449). Agreement between systems was moderate (kappa: 0.20; 95% confidence interval, CI: 0.09 0.32). Providers who performed more than 100 procedures achieved an adverse event rate of 0.7% and 4.3% in the clinic and active surveillance systems, respectively, and had decreased odds of performing a procedure resulting in an adverse event. With provider experience, the mean duration of the procedure also dropped from 24.0 to 15.5 minutes. Among providers who had performed at least 100 procedures, nurses and clinicians provided equivalent services. CONCLUSION: To reduce the adverse event rate, one must ensure that providers achieve a desired level of experience before they perform unsupervised procedures. Adverse events observed by the provider as well as those perceived by the client should both be monitored. PMID- 23109746 TI - Oseltamivir storage, distribution and dispensing following the 2009 H1N1 influenza outbreak in Mexico. AB - PROBLEM: During an influenza outbreak or pandemic, timely access to antivirals is essential to reduce disease severity and transmission. Best practices in antiviral procurement, storage, distribution, prescription and dispensing must be followed for prompt drug delivery. APPROACH: Mexico implemented a national pandemic preparedness plan in 2006 and created a strategic antiviral stockpile. Oseltamivir powder was stored centrally in bulk for distribution to all 31 states and the capital district during an influenza outbreak. LOCAL SETTING: San Luis Potosi, in northern Mexico, was one of the states most intensely affected by the 2009 H1N1 influenza outbreak. RELEVANT CHANGES: The oseltamivir powder was meant to be reconstituted locally but had to be reconstituted centrally during the 2009 influenza outbreak. Doubts arose surrounding the shelf-life of the reconstituted product. As a result of these problems, the first supply of the drug reached San Luis Potosi 11 days after the influenza outbreak had begun. Furthermore, dispensing criteria at the state level had to be changed in conformity with the availability of oseltamivir. LESSONS LEARNT: Antiviral demand forecasts should be based on clearly defined distribution and dispensing criteria and decentralization of some of the medication stockpile should be considered. Mexico's national pandemic preparedness plan needs to be updated in accordance with the lessons learnt in 2009 to improve strategic stockpile management and ensure rapid delivery of oseltamivir to the population. PMID- 23109747 TI - A new entity for the negotiation of public procurement prices for patented medicines in Mexico. AB - PROBLEM: As countries expand health insurance coverage, their expenditures on medicines increase. To address this problem, WHO has recommended that every country draw up a list of essential medicines. Although most medicines on the list are generics, in many countries patented medicines represent a substantial portion of pharmaceutical expenditure. APPROACH: To help control expenditure on patented medicines, in 2008 the Mexican Government created the Coordinating Commission for Negotiating the Price of Medicines and other Health Inputs (CCPNM), whose role, as the name suggests, is to enter into price negotiations with drug manufacturers for patented drugs on Mexico's list of essential medicines. LOCAL SETTING: Mexico's public expenditure on pharmaceuticals has increased substantially in the past decade owing to government efforts to achieve universal health-care coverage through Seguro Popular, an insurance programme introduced in 2004 that guarantees access to a comprehensive package of health services and medicines. RELEVANT CHANGES: Since 2008, the CCPNM has improved procurement practices in Mexico's public health institutions and has achieved significant price reductions resulting in substantial savings in public pharmaceutical expenditure. LESSONS LEARNT: The CCPNM has successfully changed the landscape of price negotiation for patented medicines in Mexico. However, it is also facing challenges, including a lack of explicit indicators to assess CCPNM performance; a shortage of permanent staff with sufficient technical expertise; poor coordination among institutions in preparing background materials for the annual negotiation process in a timely manner; insufficient communication among committees and institutions; and a lack of political support to ensure the sustainability of the CCPNM. PMID- 23109749 TI - Neuropsychological differentiation of adaptive creativity and schizotypal cognition. AB - Both creativity and schizophrenia-spectrum disorders have been associated with activation of remote semantic concepts, but this activation results in innovative output in one case and communication disturbances in the other. The present study examined the relationship between monitoring semantic information (which relies on executive brain function), creativity, and characteristics of schizotypy in an undergraduate population. Results indicate that executive function differentiates the use of semantic information in creativity and schizotypy. Specification of the balance between executive monitoring and activation of semantic information is important for determining how communication disturbances manifest, and for the measurement of creativity and schizotypy in the general population. PMID- 23109750 TI - Chaos in the cockpit: a medical correlative. PMID- 23109748 TI - Perspectives on biomechanical growth and remodeling mechanisms in glaucoma(). AB - Glaucoma is a blinding diseases in which damage to the axons results in loss of retinal ganglion cells. Experimental evidence indicates that chronic intraocular pressure elevation initiates axonal insult at the level of the lamina cribrosa. The lamina cribrosa is a porous collagen structure through which the axons pass on their path from the retina to the brain. Recent experimental studies revealed the extensive structural changes of the lamina cribrosa and its surrounding tissues during the development and progression of glaucoma. In this perspective paper we review the experimental evidence for growth and remodeling mechanisms in glaucoma including adaptation of tissue anisotropy, tissue thickening/thinning, tissue elongation/shortening and tissue migration. We discuss the existing predictive computational approaches that try to elucidate the potential biomechanical basis of theses growth and remodeling mechanisms and highlight open questions, challenges, and avenues for further development. PMID- 23109751 TI - Implantation of left ventricular assist device complicated by undiagnosed thrombophilia. AB - A patient with dilated cardiomyopathy and no history of thromboembolic events received a surgically implanted axial-flow left ventricular assist device. After implantation, transesophageal echocardiography revealed a giant thrombus on the lateral and anterior aspects of the left ventricle. The inflow cannula inserted through the apex of the left ventricle was not obstructed, and the device generated satisfactory blood flow. Laboratory screening for thrombophilia showed protein S deficiency, heterozygous factor V Leiden mutation, and heterozygous MTHFR C667T mutation. During the entire duration of circulatory support, no significant suction events were detected, and the patient was listed for heart transplantation. Ventricular assist device implantation can unmask previously undiagnosed thrombophilia; therefore, it should be necessary to identify thrombophilic patients before cardiac support implantation. PMID- 23109752 TI - Aortic valve noncoronary cusp thrombosis after implantation of a nonpulsatile, continuous-flow pump. AB - Different institutions have different strategies for managing both native and prosthetic aortic valves in recipients of left ventricular assist devices (LVADs). Anticoagulation protocols and pump-flow algorithms remain nonstandardized. We describe our institutional experience with thrombotic complications and our evolving approach to this important clinical problem. We report the cases of 4 HeartMate II LVAD recipients in whom, despite an anticoagulative regimen, thrombus formed on the noncoronary cusp of the aortic valve. The management of the closed aortic valve in LVAD-supported patients remains problematic. PMID- 23109753 TI - Management of intra-aortic balloon pump entrapment: a case report and review of the literature. AB - An intra-aortic balloon pump is one of the most valuable tools in the cardiac surgeon's armament to assist in the management of the failing heart. Despite its widespread use, there are associated risks and complications, one of which is balloon rupture with associated entrapment. Numerous approaches for dealing with this complication have been described; here we review the previous experience with intra-aortic balloon pump entrapment and discuss potential management, with particular reference to a recent case of our own. PMID- 23109754 TI - Left ventricular assist device implantation combined with surgical ventricular reconstruction. AB - Nine months after sustaining a transmural anteroseptal myocardial infarction, a 45-year-old man presented with ischemic heart disease, severe mitral valve insufficiency, New York Heart Association functional class IV congestive heart failure, and a left ventricular aneurysm. Coronary angiography revealed 3-vessel disease. Echocardiography showed severe left ventricular impairment, pronounced thrombosis in the left ventricular apex, and low myocardial reserve. To reduce the high risk of performing left ventricular and mitral valve reconstruction concurrently with revascularization, we decided to perform ventricular reconstruction and to implant a Berlin Heart INCOR left ventricular assist device as a bridge to heart transplantation. The patient had an uncomplicated recovery, was discharged from the hospital with symptomatic improvement after 20 days, and was placed on the list for heart transplantation. We describe the patient's case, the surgical procedure, and the reasoning behind the chosen course of treatment. PMID- 23109756 TI - Extremely high-pressure dilation with a new noncompliant balloon. AB - Calcified nondilatable lesions remain a challenge for the interventional cardiologist, and they are becoming more frequent in the catheterization laboratory as the overall complexity of interventions increases. Stent underexpansion is the main risk factor for restenosis and thrombosis, which is the most feared complication for the interventionalist.In this report, we present our initial experience (8 patients) with a new noncompliant high-pressure balloon, the OPN NC balloon, a double-layered device. When we used this device at 40 atm, our rate of success was reasonable (75%) and our patients experienced no adverse sequelae. The OPN NC balloon appears to offer a new means of dilating lesions or underexpanded stents when other noncompliant balloons have failed. Safety seems reasonable, even at pressures as high as 40 atm. PMID- 23109755 TI - Simultaneous very late stent thrombosis in multiple coronary arteries. AB - We report 2 noteworthy cases of very late stent thrombosis presenting as ST segment-elevation myocardial infarction, with vastly different manifestations. Both patients were women who had histories of multivessel percutaneous coronary intervention with first-generation sirolimus-eluting stents, in 2005 and 2006. On the more recent occasions reported here, one underwent successful multivessel primary percutaneous coronary intervention, while the other underwent successful multivessel "plain old balloon angioplasty." Both were discharged from the hospital with advice to stop smoking and to follow a lifelong regimen of aspirin and clopidogrel.On the basis of these two cases and our review of the current literature, we ask whether it is now prudent to recommend lifelong dual antiplatelet therapy after drug-eluting stent deployment. Moreover, in order to account for cases of stent thrombosis that occur >= 5 years after drug-eluting stent implantation, should we perhaps suggest the addition of "extremely late stent thrombosis" to the existing Academic Research Consortium classification? PMID- 23109757 TI - Transcatheter retrieval and repositioning of embolized stent from the right ventricle in an infant. AB - Intracardiac stent embolization is a challenging complication in a small infant. A Palmaz stent was placed across the atrial septum in a 3-month-old boy to relieve symptoms of right-side heart failure. On routine chest radiography one week later, the stent was found to have embolized into the right ventricle. The stent was retrieved and repositioned by means of transcatheter technique, without subsequent complications. We found this method to be a viable alternative to surgery in a high-risk infant. To our knowledge, this is the first report of the successful transcatheter retrieval and repositioning of an expandable intravascular stent from an intraventricular position in an infant. PMID- 23109758 TI - Balloon-assisted retrieval of a broken stent-delivery system. AB - The breakage of a stent-delivery catheter at the shaft is a rare and dangerous complication during coronary intervention. We report a simple balloon technique for the successful retrieval, from within a guiding catheter, of both an unexpanded stent and its delivery system. PMID- 23109760 TI - Transcatheter retrieval of embolized AMPLATZER Septal Occluder. AB - In selected patients, transcatheter closure of atrial septal defects with the AMPLATZER Septal Occluder has yielded excellent results. However, there is a slight risk of device embolization after deployment. We report the case of a 26 year-old woman in whom an embolized AMPLATZER device was retrieved percutaneously from the right pulmonary artery. We also discuss important technical principles for managing this uncommon but potentially severe complication. PMID- 23109759 TI - AMPLATZER Septal Occluder failure resulting in paradoxical cerebral embolism. AB - Patent foramen ovale and atrial septal defect are risk factors for paradoxical embolism and subsequent cerebral ischemic events. The transseptal passage of emboli from the right to the left cardiac chambers appears to play an important role. The therapeutic options are medical therapy (anti-aggregation or anticoagulation), surgical closure, or transcatheter closure. Transcatheter closure of atrial septal defects affords the advantage of closing an atrial defect without the associated morbidity of open-heart surgery and the bleeding sequelae of oral anticoagulation. After closure, however, the presence of a residual shunt is independently associated with an increased risk of recurrent ischemic events. Newer devices, such as the AMPLATZER Septal Occluder, have decreased the risk of residual shunting and thromboembolic events. In addition, they have a very low risk of device dislodgement, migration, and embolization.We describe the case of a 60-year-old woman with Ebstein anomaly and recurrent ischemic strokes who presented with acute ischemic infarcts and paradoxical embolism 3 years after undergoing transcatheter closure of an atrial septal defect. A right-to-left shunt through a displaced AMPLATZER Septal Occluder was detected. Pulmonary hypertension and resultant right ventricular failure and right atrial dilation could have contributed to the persistent shunting and paradoxical embolism.To our knowledge, the delayed dysfunction of an AMPLATZER Septal Occluder has not been reported. In addition to describing the patient's case, we review the relevant medical literature. PMID- 23109761 TI - Mid-aortic syndrome in a 3-year-old girl successfully treated by aorto-aortic grafting and renal artery implantation into the graft. AB - Mid-aortic syndrome, an uncommon acquired or congenital condition characterized by segmental narrowing of the abdominal or distal descending thoracic aorta, is frequently accompanied by ostial stenosis of the aorta's branches. If left untreated, it can result in life-threatening complications secondary to severe hypertension.We report the case of a 3-year-old girl with congenital mid-aortic syndrome, who was diagnosed by chance in the course of a viral illness, and whose high blood pressure values were first dismissed as inaccurate. Attempts to achieve medical or endovascular control of her hypertension were unsuccessful. She was thereafter successfully treated by aorto-aortic bypass grafting, resection of the stenotic segments of both renal arteries, and implantation of the patent arterial segments into the graft. PMID- 23109762 TI - Hypoxia caused by persistent left superior vena cava connecting to the left atrium a rare clinical entity. AB - We relate the case of a 40-year-old man with a history of premature birth and dextroposition of the heart who presented for an evaluation of persistent hypoxia. An unrevealing pulmonary evaluation and agitated-saline echocardiogram led to cardiac magnetic resonance imaging. This revealed a very unusual finding: a persistent left superior vena cava with insertion into the left atrium and a small connecting vein between the right and left superior venae cavae. The implications, embryology, and pathogenesis of this rare condition are discussed. PMID- 23109763 TI - Intermittent cyanosis years after a Mustard repair for dextro-transposition of the great arteries. AB - A 28-year-old woman, who as an infant had undergone the Mustard atrial switch procedure for dextro-transposition of the great arteries, presented with a baffle leak and consequent intermittent cyanosis. In addition, an occlusive thrombus had formed in the systemic venous baffle after a failed attempt to remove infected pacemaker leads. Corrective surgery was successful. In addition to the case of our patient, we discuss long-term sequelae of the atrial switch procedure that present challenges in patient care. PMID- 23109764 TI - Tricuspid valve avulsion after blunt chest trauma. AB - Blunt cardiac trauma causing tricuspid regurgitation is rare and is most often associated with traffic accidents. Falling from a height can also cause such injuries, resulting in hemodynamic compromise and arrhythmias. The signs of traumatic tricuspid regurgitation can appear early or be delayed, depending upon the severity of injury. We present the case of a 68-year-old woman who fell from a height onto rocks during a hike. She sustained blunt cardiac injury with complete tricuspid valve avulsion, and underwent successful repair. In addition, we review the relevant medical literature. PMID- 23109765 TI - Transseptal mitral valve replacement after transcatheter aortic valve implantation. AB - We report a case of mitral valve replacement in a patient who had previously undergone transcatheter aortic valve implantation. A transseptal approach was used to avoid displacing the aortic prosthesis. Because of the small mitral annulus, a bioprosthetic aortic valve was used in reverse position for mitral valve replacement. The procedure did not interfere with the existing prosthesis, and a follow-up echocardiogram showed that both prosthetic valves were functioning well.To the best of our knowledge, this is the first report of mitral valve replacement in a patient who had a preceding transcatheter aortic valve implantation. We believe that the transseptal approach is promising for mitral valve replacement in such patients. Moreover, using a bioprosthetic aortic valve in reverse position is an option for mitral valve replacement when the mitral annulus is too small for placement of a standard bioprosthetic mitral valve. PMID- 23109766 TI - Early failure secondary to noncoronary leaflet prolapse in a stentless aortic bioprosthesis. AB - Structural degeneration is an important long-term disadvantage of biologic prostheses. However, early failure of these prostheses is uncommon and is usually caused by rapid calcification. We report the successful management of a rare case of early failure of a stentless aortic bioprosthesis (within 4 months of implantation). The patient presented with severe noncalcific aortic regurgitation secondary to prolapse of the noncoronary leaflet. In consideration of the acute nature of failure in this new-generation bioprosthesis and its unclear cause, we believe that this report, albeit of a single case, warrants some attention. PMID- 23109767 TI - Percutaneous closure of a left ventricular pseudoaneurysm in a high-risk surgical candidate. AB - Few cases of percutaneous device closure of a left ventricular pseudoaneurysm have been reported. We describe the case of a 67-year-old man with a history of coronary artery disease who presented with shortness of breath and chest pain. Computed tomographic angiography showed a left ventricular pseudoaneurysm that was filling from a small leak in the anterolateral aspect of the ventricle. The patient had undergone 3 previous sternotomies and was a high-risk candidate for surgical treatment of the pseudoaneurysm. Despite technical challenges, we closed the pseudoaneurysm percutaneously with use of a 6-mm AMPLATZER muscular ventricular septal defect occluder. The patient was released from the hospital the next day and was asymptomatic a year later.To our knowledge, this is the first report of the percutaneous closure of a left ventricular pseudoaneurysm via the femoral vein. We show that this manner of closure can be feasible in patients who have undergone multiple sternotomies and who are at high surgical risk. PMID- 23109768 TI - Spontaneous multiarterial dissection immediately after childbirth. AB - Spontaneous coronary artery dissection and vertebral artery dissection are rare, life-threatening conditions. The pathophysiology of spontaneous coronary artery dissection during the peripartum period is poorly understood. We present a case of spontaneous multivessel dissection in a 32-year-old postpartum woman who presented with neck and chest pain. The patient's coronary and vertebral artery dissections were diagnosed with use of multiple imaging methods, and dissection of the internal mammary artery was discovered during surgery. The patient underwent successful coronary artery bypass grafting and remained asymptomatic 2 years later. To our knowledge, this is the first report of simultaneous coronary, vertebral, and internal mammary artery dissection in a postpartum woman. Early recognition and treatment is crucial, given the high mortality rate associated with spontaneous dissection. PMID- 23109769 TI - Emergent repair of a complex dissecting aneurysm in the thoracic aorta. AB - Endovascular treatment of complex thoracic pathologic conditions involving the aortic arch can often be appropriate and safe; however, minimally invasive procedures are not always feasible, especially in emergent cases. We report the case of a 78-year-old woman who emergently presented in hemorrhagic shock with a ruptured chronic dissecting aneurysm that involved the aortic arch. Eight years earlier, she had undergone aortic valve replacement and plication of the ascending aorta, which was complicated a day later by Stanford type B dissection, malperfusion, and ischemia that required an axillobifemoral bypass. At the current admission, we successfully treated her surgically through a left thoracotomy, using moderate hypothermic extracorporeal circulation and advanced organ-protection methods. We discuss the surgical indications and our operative strategy in relation to open surgical repair versus endovascular treatment in patients with complex conditions. PMID- 23109770 TI - Mycotic aneurysms of the ascending aorta in the absence of endocarditis. AB - Mycotic aneurysm formation is a rare and potentially fatal sequela of bacteremia. We present the cases of 2 octogenarians who had surgically confirmed mycotic aneurysms that involved the ascending aorta, with contained rupture (pseudoaneurysm). Neither patient had evidence of valvular endocarditis. Patient 1, an 82-year-old man, had streptococcal bacteremia. Imaging confirmed a mycotic aneurysm of the ascending aorta, and resection was successful. Patient 2, an 83 year-old woman, had recurrent staphylococcal bacteremia and progressive widening of the mediastinum, and imaging revealed a mycotic pseudoaneurysm. She underwent surgical repair with use of a bovine pericardial patch, but she died 2 weeks later because of patch dehiscence.We did not initially suspect mycotic aneurysm in either patient. Despite the availability of accurate, noninvasive imaging techniques, strong clinical suspicion is required for the early diagnosis of mycotic aneurysm. PMID- 23109771 TI - Percutaneous thrombin injection of common carotid artery pseudoaneurysm without cerebral protection. AB - An 83-year-old man with sepsis sustained right common carotid artery injury during attempted central-line placement. A computed tomographic scan showed a large hematoma in the patient's neck and a carotid pseudoaneurysm. His clinical condition was such that transfer to the interventional suite was judged unsafe. Percutaneous thrombin injection was performed at the bedside under ultrasonographic guidance, but without protective temporary balloon occlusion. The procedure was successful, with no neurologic complications. At follow-up ultrasonographic evaluation, there was complete and sustained occlusion of the pseudoaneurysm.Emergent percutaneous treatment of common carotid artery pseudoaneurysm can be performed without temporary balloon occlusion for cerebral protection-in extreme circumstances, and at unknown risk. PMID- 23109772 TI - Successful coronary artery bypass in Ehlers-Danlos type IV syndrome case report and review of the literature. AB - Atherosclerotic coronary artery occlusive disease is very rare in cases of Ehlers Danlos type IV syndrome. We report what we believe is a unique case of successful coronary artery bypass grafting for atherosclerotic coronary artery disease in a patient with this syndrome and examine the possible implications for the natural progression of the disease through a review of the literature. Nevertheless, we reiterate previous investigators' advice that any invasive procedure on these patients should be approached with extreme caution and that surgery should be performed as a last resort, considering the significantly elevated risks. PMID- 23109773 TI - Spontaneous celiac artery dissection case report and literature review. AB - Symptomatic spontaneous celiac artery dissection is a rare condition that is being detected more often with the use of advanced imaging techniques. There is no consensus as to whether surgical or endovascular treatment is more appropriate.We describe the case of a 41-year-old hypertensive woman who presented with the sudden onset of sharp, persistent, right-upper-quadrant abdominal and epigastric pain. Magnetic resonance angiography of the abdomen revealed celiac artery dissection, with a flap compressing the lumen approximately 17 mm from the artery's origin at the aorta. Because of the patient's persistent epigastric pain, endovascular celiac artery stent implantation was performed with the use of 2 overlapping balloon-expandable stents. Twelve months after the procedure, the patient remained asymptomatic, and the stents were patent. This case and others in the medical literature suggest that endovascular treatment can be feasible in symptomatic patients with isolated spontaneous celiac artery dissection. PMID- 23109774 TI - Transseptal biopsy of a left atrial mass with 3-dimensional transesophageal echocardiographic guidance. AB - A 31-year-old man presented with a large cardiac mass that originated from the basal posterior left atrial wall and occupied most of the dilated atrium. Minimally invasive studies yielded inconclusive results, but the patient was considered at high risk for an open cardiac biopsy due to the size of the mass. To establish a tissue diagnosis for definitive treatment, we performed a transseptal cardiac biopsy guided by 3-dimensional transesophageal echocardiography. We thereby determined that the mass was a primary left atrial sarcoma. To the best of our knowledge, this is the first report concerning the use of 3-dimensional transesophageal echocardiography for biopsy of a left atrial mass. PMID- 23109775 TI - Paradoxical hemodynamic instability complicating pericardial window surgery for cardiac tamponade in a cancer patient. AB - Paradoxical hemodynamic instability is defined as unexpected hemodynamic compromise that develops in a patient after pericardial fluid drainage. The overall incidence of the condition is about 5%, and it has a high in-hospital mortality rate. The condition has been reported to occur regardless of the approach that is used to drain the fluid or the underlying cause of the disease. The pathophysiology of paradoxical hemodynamic instability and the appropriate intervention are not very clear, and further studies are needed to identify appropriate preventive measures.We report a rare manifestation of paradoxical hemodynamic instability in a 65-year-old woman who had a history of stage IV lung cancer. She presented with a one-week history of pleuritic chest pain and shortness of breath on exertion. Echocardiography revealed a large circumferential pericardial effusion with right atrial and ventricular collapse during diastole, suggesting a compressive effect of the pericardial fluid; however, left ventricular systolic function was well preserved. The patient underwent the scheduled creation of a subxiphoid pericardial window. Immediately after the pericardial fluid was evacuated, her heart began to beat more vigorously, but this was abruptly followed by an episode of asystole. Pacing and medical therapy were unsuccessful in preventing repeated episodes of asystole, and the patient died.To our knowledge, this is the 2nd report of unexpected asystole after the creation of a subxiphoid pericardial window, and it is the first report of a takotsubo-like contractile pattern associated with paradoxical hemodynamic instability. PMID- 23109776 TI - Primary endocardial fibroelastosis presenting in a young child as incessant ventricular tachycardia and dilated cardiomyopathy. AB - Endocardial fibroelastosis is a cardiomyopathy not commonly seen in the present age. We describe the case of a 4-year-old girl who presented with sustained incessant ventricular tachycardia, a severely dilated left ventricle, and cardiac dysfunction refractory to all medical management and even to ablation; she eventually underwent cardiac transplantation. The diagnosis was made only after histopathologic examination of the explanted heart showed clear evidence of endocardial fibroelastosis. Through this report, we would like to highlight the fact that primary endocardial fibroelastosis can masquerade as idiopathic dilated cardiomyopathy and that associated frequent premature ventricular contractions and nonsustained ventricular tachycardia require close monitoring. Progressive ventricular dilation and ventricular dysfunction can convey a poor prognosis. Sustained recalcitrant ventricular tachycardia in these patients can be a life threatening event that requires emergent mechanical support and heart transplantation. PMID- 23109777 TI - Biventricular assist device terminates polymorphic ventricular tachycardia in giant cell myocarditis. AB - We present the case of a 55-year-old woman with giant cell myocarditis who experienced a rapid deterioration in her condition. As her heart failure progressed, she developed more ventricular ectopic beats, which culminated in a polymorphic ventricular tachycardia that did not improve despite immunosuppressive and antiarrhythmic therapy. Emergent biventricular assist device placement, however, did eliminate her arrhythmia. PMID- 23109778 TI - Orthostatic hypotension as a manifestation of vitamin B12 deficiency. AB - A 90-year-old woman with orthostatic hypotension and near-syncope was found to have a low-normal level of vitamin B(12) and no other medical findings that could explain her orthostasis. Her symptoms responded to vitamin B(12) replacement therapy. This case shows that vitamin B(12) deficiency can induce orthostatic hypotension and syncope that are correctable by vitamin B(12) replacement. PMID- 23109779 TI - Conivaptan therapy in an infant with severe hyponatremia and congestive heart failure. AB - Conivaptan is a nonspecific arginine vasopressin receptor antagonist that has been used as therapy in adults who have hypervolemic hyponatremia due to congestive heart failure. Its use in children with congestive heart failure has not been reported. We describe the use of conivaptan in a 4-month-old infant girl with severe hypervolemic hyponatremia and heart failure. A therapeutic weight based dose was extrapolated from the adult dose. Conivaptan therapy was administered for 48 hours, after which the patient recovered from her hyponatremia without untoward effects. Arginine vasopressin receptor antagonists such as conivaptan may be useful as therapy for hyponatremia associated with heart failure. Further studies are required before conivaptan can be recommended for routine use in children. PMID- 23109780 TI - Fistula from right internal mammary artery to superior vena cava after use of a laser sheath to extract a pacemaker lead. AB - A 55-year-old woman presented with dyspnea on exertion due to a right internal mammary artery-to-superior vena cava arteriovenous fistula that occurred after pacemaker lead extraction with a laser sheath. The fistula was successfully repaired by placing a covered stent in the right internal mammary artery. In this unusual location, endovascular stenting is a reasonable alternative to coil embolization or surgical repair of an arteriovenous fistula resulting from laser lead extraction. PMID- 23109781 TI - Incidental papillary fibroelastoma multimodal: imaging and surgical decisions in 2 patients. AB - Papillary fibroelastoma is a rare, benign cardiac tumor typically found on the heart valves. It is usually discovered incidentally on echocardiography. The clinical presentation of cardiac papillary fibroelastoma varies from no symptoms to severe embolic sequelae. We report the incidental finding of papillary fibroelastoma in 2 patients. In each, we chose to excise the tumor. The relevant medical literature provides little guidance regarding whether to excise a small papillary fibroelastoma in an asymptomatic patient. Multimodal imaging, which we discuss in the context of our patients' cases, aids the cardiologist and cardiovascular surgeon in more accurately evaluating papillary fibroelastoma preoperatively. PMID- 23109782 TI - Ergotamine-associated valvulopathy with recurrent chylous pleural effusion. AB - We report a rare case of ergotamine-associated mitral stenosis in a 55-year-old woman who presented with recurrent chylous pleural effusion. Echocardiographic, gross, and microscopic features of the mitral valve were consistent with chronic ergotamine-induced valvulopathy. We conclude that medication-induced valvulopathy should be included in the differential diagnosis of valvular heart disease. In addition, cardiac function should be monitored before and during long-term therapy with ergotamine or ergotamine-derived dopamine agonists. PMID- 23109783 TI - Pressure wire used to measure gradient in chronic mesenteric ischemia. AB - Chronic mesenteric ischemia is a rare disorder in the United States. Frequently, its symptoms correlate poorly with the angiographically apparent degree of mesenteric artery stenosis. Measuring the pressure gradient with a small-caliber catheter is an established means of determining whether a particular stenosis is flow-limiting, thus guiding the interventional decision when stenoses are of indeterminate angiographic significance. Using a 0.014-in guidewire, however, is potentially more accurate because it eliminates any measurement error attributable to the use of a larger, potentially obstructive catheter. We present a case of chronic mesenteric ischemia in a 70-year-old woman who had abdominal pain with multiple possible causes. We used a 0.014-in pressure wire to calculate pressure gradients and guide our decision to stent tandem lesions in the superior mesenteric artery. After revascularization, the patient's symptoms improved dramatically. To the best of our knowledge, this is the first published case in which a pressure wire was used to measure a pressure gradient in chronic mesenteric ischemia. PMID- 23109784 TI - Bilateral pulmonary endarterectomy and Bentall procedure completed in one surgical session. AB - We describe the performance, in one surgical session, of bilateral pulmonary endarterectomy and a button-technique Bentall operation in a 68-year-old man. The patient had chronic thromboembolic pulmonary hypertension and an ascending aortic aneurysm with moderate aortic regurgitation. The procedures were concurrently completed during short periods of systemic circulatory arrest, with antegrade cerebral perfusion maintained through the brachiocephalic artery at a flow rate of 10 mL/min/kg. The patient's cerebral perfusion was monitored with use of near infrared spectroscopy, to prevent symmetric bilateral values from falling below 20% of the base value. The patient experienced no multiorgan failure or neurologic sequelae and, by the 6th postoperative day, improved from New York Heart Association functional class IV to class I.The reliable maintenance of continuous antegrade cerebral perfusion made the lengthy combined operation feasible, with low risk. The use of near-infrared spectroscopy enabled real-time monitoring of the patient's cerebral blood flow. Our experience shows the possibility of safely performing lengthy or multiple procedures in one surgical session. PMID- 23109785 TI - Apical hypertrophic cardiomyopathy. PMID- 23109786 TI - Apical hypertrophic cardiomyopathy: preliminary attempt at palliation with use of subselective alcohol ablation. AB - We report a case of severe apical hypertrophic cardiomyopathy in order to discuss the nature of this unusual condition and the possibility of using selective alcohol ablation to effectively treat symptomatic hypertrophic cardiomyopathy that presents with apical aneurysm. A 73-year-old woman with severe, progressive dyspnea and intermittent chest pain was found to have localized left ventricular apical dyskinesia distal to an obstructive mid-distal muscular ring. The ring caused total systolic obliteration of the apical left ventricular cavity. Apical cavity pressure was extremely high, up to 330 mmHg-200 mmHg above that in the main left ventricular cavity. Because of the danger of apical rupture and clot formation, we attempted the experimental use of alcohol ablation for effective palliation. We present our pilot experience, offer a novel interpretation of the nature of this obscure entity, and possibly justify a new catheter treatment. In addition, we discuss the developmental, pathophysiologic, and clinical implications of this unusual form of hypertrophic cardiomyopathy. To our knowledge, ours is the first reported use of subselective, modified-protocol alcohol septal ablation to treat an obstructive mid-apical muscular ring in a patient with apical hypertrophic cardiomyopathy. PMID- 23109787 TI - Incidental diagnosis of apical hypertrophic cardiomyopathy in an 18-year-old white man. PMID- 23109788 TI - Calcified aneurysm of left ventricular apex in apical cardiomyopathy. PMID- 23109789 TI - Secondary endocardial fibroelastosis in an adult: three-year follow-up by cardiac magnetic resonance imaging. PMID- 23109790 TI - Diastolic left main coronary flow reversal as a marker of severe aortic regurgitation. PMID- 23109791 TI - Coronary-coronary bypass with patency validated by 64-slice multidetector computed tomography. PMID- 23109792 TI - Intramyocardial hematoma from blunt trauma mimicking apical hypertrophic cardiomyopathy. PMID- 23109793 TI - Left main coronary artery dissection after valve replacement: role of coronary computed tomographic angiography. PMID- 23109794 TI - Three-dimensional transesophageal echocardiography shows dehiscence of mitral valve repair. PMID- 23109795 TI - Medical education on the brink. PMID- 23109796 TI - Medical education on the brink. PMID- 23109797 TI - Social Networking Site Use Predicts Changes in Young Adults' Psychological Adjustment. AB - This study examined youths' friendships and posted pictures on social networking sites as predictors of changes in their adjustment over time. Observational, self report, and peer report data were obtained from a community sample of 89 young adults interviewed at age 21 and again at age 22. Findings were consistent with a leveling effect for online friendships, predicting decreases in internalizing symptoms for youth with lower initial levels of social acceptance, but increases in symptoms for youth with higher initial levels over the following year. Across the entire sample, deviant behavior in posted photos predicted increases in young adults' problematic alcohol use over time. The importance of considering the interplay between online and offline social factors for predicting adjustment is discussed. PMID- 23109798 TI - Topical azithromycin or ofloxacin for endophthalmitis prophylaxis after intravitreal injection. AB - BACKGROUND: The number of patients who have undergone intravitreal injections has increased enormously in recent years, but a consensus is still lacking on prophylaxis for endophthalmitis. The aim of this prospective, observational study was to evaluate the prophylactic effect of azithromycin eye drops versus ofloxacin eye drops. METHODS: The study was conducted in five hospitals in Spain and included all patients undergoing intravitreal injections of triamcinolone, bevacizumab, ranibizumab, or pegaptanib over one year. Patients received azithromycin 15 mg/g eye drops (twice daily on the day prior to injection and for another 2 days) or ofloxacin 3 mg/g eye drops (every 6 hours on the day prior to injection and for another 7 days). RESULTS: In the azithromycin group, there were 4045 injections in 972 eyes of 701 patients. In the ofloxacin group, there were 4151 injections in 944 eyes of 682 patients. There were two cases of endophthalmitis (0.049%) in the azithromycin group and five (0.12%) in the ofloxacin group. The odds ratio of presenting with endophthalmitis in the ofloxacin group compared with the azithromycin group was 2.37 (95% confidence interval [CI] 1.32-3.72, P < 0.001). There were two cases of noninfectious uveitis after triamcinolone injection in the azithromycin group (0.049%) and two (0.048%) in the ofloxacin group; no significant differences were observed (odds ratio 0.902, 95% CI 0.622-1.407, P = 0.407). Conjunctival hyperemia was observed in 12 cases in the azithromycin group and none in the ofloxacin group. CONCLUSION: The risk of endophthalmitis was significantly greater with ofloxacin than with azithromycin. These findings provide a valuable addition to the ever increasing pool of information on endophthalmitis prophylaxis after intravitreal injection, although further large-scale studies are required to provide definitive conclusions. PMID- 23109799 TI - Topical intraocular pressure therapy effects on pregnancy. AB - PURPOSE: To assess the course of intraocular pressure (IOP), visual field progression, and adverse effects of antiglaucoma medication used during pregnancy. METHODS: Thirteen eyes of eight patients with glaucoma were examined. Their clinical records were reviewed to compare IOP, number of medications, and visual field indices (VFI) before, during, and after pregnancy using a two-tailed paired t-test. RESULTS: In seven (87.5%) of the eight patients, no disease progression was observed. IOP (mmHg) remained stable (baseline 17.3 +/- 3.6; first trimester 17.4 +/- 5.2, P = 0.930; second trimester 18.1 +/- 4.7, P = 0.519; third trimester 20.2 +/- 8.7, P = 0.344; and postpartum 21.5 +/- 7.6, P = 0.136). The mean number of glaucoma treatments fell from 1.7 +/- 0.52 before pregnancy to 0.83 +/- 0.75 (P = 0.04) in the second and third trimesters. In one patient, IOP increased during pregnancy and there was further visual field loss. In the only patient kept on fixed combination timolol-dorzolamide therapy throughout pregnancy, labor was induced because of delayed intrauterine growth. CONCLUSIONS: No changes in IOP and VFI were detected in most patients despite a reduction in the number of hypotensive agents required. Delayed intrauterine growth in one patient under fixed combination timolol-dorzolamide treatment was observed whereas no other adverse effects were detected. PMID- 23109800 TI - Two-year follow-up of ranibizumab combined with photodynamic therapy for polypoidal choroidal vasculopathy. AB - PURPOSE: We evaluated the 2-year efficacy of combined intravitreal ranibizumab (IVR) treatment and photodynamic therapy (PDT) for treatment-naive polypoidal choroidal vasculopathy (PCV). PATIENTS AND METHODS: Twenty-two eyes of 22 Japanese patients with treatment-naive PCV were prospectively recruited. All eyes had angiographic features of PCV according to indocyanine green angiography. The initial combination treatment regimen included a session of PDT with IVR. A total of three consecutive IVR treatments were given at 4-week intervals. Eyes were retreated with IVR or PDT at specific times. We evaluated the mean visual acuity and mean central retinal thickness (CRT) at 3, 6, 9, 12, 18, and 24 months after initial treatment. RESULTS: At month 9, visual acuity had improved by 5.7 letters (P = 0.10). Subsequently, mean visual acuity gradually decreased, and the difference from baseline was diminished to 2.9 letters at 24 months (P = 0.43). Mean CRT was significantly decreased from baseline over the 24-month follow-up (P < 0.05). CONCLUSION: With PDT combined with IVR for PCV, visual acuity improved during year 1, but the benefit decreased in year 2. PMID- 23109801 TI - Multiple spots of photodynamic therapy for the treatment of severe chronic central serous chorioretinopathy. AB - PURPOSE: To evaluate the efficacy and safety of fluorescein angiography (FA) guided photodynamic therapy (PDT) for the treatment of severe chronic central serous chorioretinopathy (CSC). METHODS: Patients presenting with chronic CSC with multiple areas of retinal pigment epithelium decompensation, with or without focal leaks, were treated with FA-guided full-fluence PDT. Best-corrected visual acuity (BCVA), optical coherence tomography (OCT), FA, indocyanine green angiography, and fundus autofluorescence were used to determine functional and anatomic outcomes. RESULTS: Twenty-one eyes (17 patients) were treated with PDT and followed for a median of 24 months (range, 12-73). In fourteen eyes (66.66%), two PDT spots were performed within the same session. In three eyes (14.28%), three PDT spots were performed, in two eyes (9.52%) four spots, and in two eyes (9.52%) five spots. In 17 eyes (80.95%), the leakage in FA and the subretinal fluid in OCT disappeared after only one session of PDT. In four eyes (19.05%), a second session - with only one spot - of PDT was required due to persistent or recurrent leakage and subfoveal SRF. Median BCVA improved significantly from 20/63 at baseline to 20/40 at 3 months (P = 0.0002) and 20/32 at 6 months (P < 0.0001), and remained improved until the last examination (20/25, P < 0.0001). Two patients complained of a transient central scotoma after the treatment. CONCLUSION: FA-guided full-fluence PDT with multiple PDT spots within the same session seems to be effective and safe for the treatment of chronic CSC cases with multiple areas of retinal pigment epithelium decompensation. PMID- 23109802 TI - Comparative study between trabeculectomy with photodynamic therapy (BCECF-AM) and trabeculectomy with antimetabolite (MMC) in the treatment of primary open angle glaucoma. AB - BACKGROUND: Various methods have been investigated to avoid postoperative scarring of the filtering bleb in modern glaucoma surgery. Most deal with the application of antimetabolic drugs such as mitomycin C (MMC). 2',7'-bis-(2 carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM) is a locally acting intracellular photosensitizer which could control and decrease postoperative fibrosis at the trabeculectomy site. PURPOSE: To compare the effect of photodynamic therapy in combination with trabeculectomy to the effect of MMC combined with the same procedure in controlling postoperative intraocular pressure (IOP) in patients with medically uncontrolled primary open angle glaucoma (1ry OAG). METHODS: A randomized controlled clinical trial was conducted on 76 eyes of 76 patients divided into three groups undergoing trabeculectomy, trabeculectomy with BCECF-AM (group A), trabeculectomy with MMC (group B), and trabeculectomy only as a control group (group C). Patients were reviewed postoperatively for clinical evaluation and photo documentation of the blebs with a fundus camera and ultrasonic biomicroscopy (UBM). The desirable effect of the adjunctive material was evaluated according to the clinical efficacy, tolerability, and safety by comparison with the control group. SETTING: Benha University Hospital, Benha, Egypt. RESULTS: After a mean follow-up of 24 months, all procedures succeeded in lowering IOP. The cumulative probability of complete success at the 24 month follow-up was 91% for group B, compared to 82% and 81.5% for group A and group C, respectively. The percentage of complete success was highest for group B, second highest for group A, and lowest for group C over the follow-up period; however, these differences were not statistically significant (P > 0.05). Regarding the bleb morphology and UBM reflectivity, the differences were not statistically significant (P > 0.05). The mean bleb height and breadth were larger in groups A and B in comparison to group C over the study period. The mean aqueous drainage route was similar in groups A and C, but less than in group B at 3 and 12 months postoperatively. Complications were generally mild and less marked in group A and C than group B. CONCLUSION: Cellular photoablation using BCECF-AM seems to be a feasible new method to use in combination with glaucoma filtration surgery. Although MMC might be considered a more potent adjunctive to trabeculectomy in promoting IOP reduction, photodynamic therapy carries relatively less risk of adverse effects and complications. Cellular photoablation using BCECF-AM could be considered efficient, tolerable and relatively safer in managing patients with 1ry OAG. Further studies are necessary to determine the safety and the reliability of this therapy. PMID- 23109803 TI - Laser in-situ keratomileusis in patients with diabetes mellitus: a review of the literature. AB - PURPOSE: A growing number of diabetic patients request laser in situ keratomileusis (LASIK) for elective vision correction each year. While the United States Food and Drug Administration considers diabetes a relative contraindication to LASIK surgery, there are several reports in the literature of LASIK being performed safely in this patient population. The purpose of this review was to examine whether diabetes should still be considered a contraindication to LASIK surgery by reviewing the ocular and systemic complications of diabetes, and examining the existing data on the outcomes of LASIK in diabetic patients. METHODS: A literature review was conducted through PubMed, Medline, and Ovid to identify any study on LASIK surgery in patients with diabetes mellitus. This search was conducted without date restrictions. The search used the Medical Subject Headings (MeSH((r))) term LASIK linked by the word "and" to the following MeSH and natural language terms: diabetes, diabetes mellitus, systemic disease, and contraindications. Abstracts for all studies meeting initial search criteria were reviewed for relevance. There were no prospective clinical studies identified. Three retrospective studies were identified. Key sources from these papers were identified, reviewed, and included as appropriate. An additional literature search was conducted to identify any study of ocular surgery on patients with diabetes using the MeSH terms refractive surgery, photorefractive keratectomy, radial keratotomy, cataract surgery, vitrectomy, and iridectomy linked by the word "and" to the following MeSH terms: diabetes, diabetes mellitus, and systemic disease. This search was conducted without date restrictions. Abstracts of studies meeting the initial search criteria were reviewed and articles deemed relevant to the subject were included in this review. CONCLUSION: LASIK may be safe in diabetic patients with tight glycemic control and no ocular or systemic complications. PMID- 23109804 TI - Neuropsychiatric Inventory data in a Belgian sample of elderly persons with and without dementia. AB - BACKGROUND/AIMS: This study assesses and compares prevalence of psychological and behavioral symptoms in a Belgian sample of people with and without dementia. METHODS: A total of 228 persons older than 65 years with dementia and a group of 64 non-demented persons were assessed using the Neuropsychiatric Inventory (NPI) in 2004. RESULTS: Within the group without dementia, the most frequent symptoms were depression, agitation, and irritability. Within the group with dementia, the most common symptoms were depression, irritability, apathy, and agitation. Prevalence of delusions (P < 0.05), hallucinations (P < 0.05), anxiety (P < 0.05), agitation (P < 0.05), apathy (P < 0.01), aberrant motor behavior (P < 0.01), and eating disorders (P < 0.05) were significantly higher in the group with dementia. CONCLUSION: Depression, elation, irritability, disinhibition, and sleeping disorders are not specific to dementia. Agitation, apathy, anxiety, and delusions are more frequent in dementia but were not specific to the dementia group because their prevalence rates were close to 10% in the group without dementia. Hallucinations, aberrant motor behavior, and eating disorders are specific to dementia. The distinction between specific and nonspecific symptoms may be useful for etiological research on biological, psychological, and environmental factors. PMID- 23109805 TI - Low admission Norton scale scores are associated with falls long after rehabilitation in the elderly with hip fractures. AB - BACKGROUND: In this study, we investigated if low admission Norton scale scores (ANSS) are associated with falls, fractures, hospitalizations, and death, after rehabilitation in the elderly with hip fractures. METHODS: This prospective historical study followed consecutive elderly patients (>=65 years) who were admitted for rehabilitation following hip fracture surgery during 2009 and followed up in January or February 2012. The incidence of falls, number of falls, incidence of fractures, number of hospitalizations, and death rates were compared between patients with low (<=14) and high (>=15) ANSS. RESULTS: The final cohort included 174 patients of mean age 83.6 +/- 6.2 years, with 133 (76.4%) being women. Fifty-seven (27.0%) patients died during follow-up. Of the remaining 127 patients, 44 (34.6%) fell at least once and 15 (11.8%) suffered fractures. Overall, 81 (46.6%) patients had a low ANSS. Relative to patients with a high ANSS, they had a higher incidence of falls (odds ratio 3.3, 95% confidence interval 1.5-7.1; P = 0.002) and fell more times (1.2 +/- 1.8 versus 0.6 +/- 1.7; P = 0.002). Regression analysis showed that ANSS (as a parametric variable) as well as a low ANSS (as a nonparametric variable) were independently associated with falls (P = 0.002 and P = 0.009, respectively). There were no differences between patients with low and high ANSS in terms of incidence of fractures, number of hospitalizations, and death rates. CONCLUSION: The Norton scoring system may be used for predicting falls long after rehabilitation in the elderly with hip fractures. PMID- 23109806 TI - Fluorescence excitation analysis by two-photon confocal laser scanning microscopy: a new method to identify fluorescent nanoparticles on histological tissue sections. AB - In the present study, we make use of the ability of two-photon confocal laser scanning microscopes (CLSMs) equipped with tunable lasers to produce spectral excitation image sequences. Furthermore, unmixing, which is usually performed on emission image sequences, is performed on these excitation image sequences. We use factor analysis of medical image sequences (FAMIS), which produces factor images, to unmix spectral image sequences of stained structures in tissue sections to provide images of characterized stained cellular structures. This new approach is applied to histological tissue sections of mouse aorta containing labeled iron nanoparticles stained with Texas Red and counterstained with SYTO13, to obtain visual information about the accumulation of these nanoparticles in the arterial wall. The possible presence of Texas Red is determined using a two photon CLSM associated with FAMIS via the excitation spectra. Texas Red and SYTO13 are thus differentiated, and corresponding factor images specify their possible presence and cellular localization. In conclusion, the designed protocol shows that sequences of images obtained by excitation in a two-photon CLSM enables characterization of Texas Red-stained nanoparticles and other markers. This methodology offers an alternative and complementary solution to the conventional use of emission spectra unmixing to localize fluorescent nanoparticles in tissue samples. PMID- 23109808 TI - Crosstalk between EGFR and integrin affects invasion and proliferation of gastric cancer cell line, SGC7901. AB - BACKGROUND/OBJECTIVE: To investigate the crosstalk between epidermal growth factor receptor (EGFR) and integrin-mediated signal transduction pathways in human gastric adenocarcinoma cells. METHODS: EGF was used as a ligand of EGFR to stimulate the gastric adenocarcinoma cell, SGC7901. Signal molecules downstream of the integrin, FAK(Y397) and p130cas(Y410) phosphorylation, were measured by immunoprecipitation and western blot. Fibronectin (Fn) was used as a ligand of integrin to stimulate the same cell line. Signal molecules downstream of EGFR and extracellular signal-regulated kinase (ERK) general phosphorylation were also measured. Focal adhesion kinase (FAK) small-interfering RNA was designed and transfected into SGC7901 cells to decrease the expression of FAK. Modified Boyden chambers and MTT assay were used to examine the effect of FAK inhibition on the invasiveness and proliferation of SGC7901. RESULTS: EGF activated FAK(Y397) and p130cas(Y410) phosphorylation, while Fn activated ERK general phosphorylation. Inhibition of FAK expression decreased p130cas(Y410) phosphorylation activated by EGF and ERK general phosphorylation activated by Fn, also decreased the invasiveness and proliferation of SGC7901 cells activated by EGF or Fn. CONCLUSION: There is crosstalk between EGFR and integrin signal transduction. FAK may be a key cross point of the two signal pathways and acts as a potential target for human gastric cancer therapy. PMID- 23109807 TI - Cerebral blood flow in Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) dementia is a consequence of heterogeneous and complex interactions of age-related neurodegeneration and vascular-associated pathologies. Evidence has accumulated that there is increased atherosclerosis/arteriosclerosis of the intracranial arteries in AD and that this may be additive or synergistic with respect to the generation of hypoxia/ischemia and cognitive dysfunction. The effectiveness of pharmacologic therapies and lifestyle modification in reducing cardiovascular disease has prompted a reconsideration of the roles that cardiovascular disease and cerebrovascular function play in the pathogenesis of dementia. METHODS: Using two-dimensional phase-contrast magnetic resonance imaging, we quantified cerebral blood flow within the internal carotid, basilar, and middle cerebral arteries in a group of individuals with mild to moderate AD (n = 8) and compared the results with those from a group of age-matched nondemented control (NDC) subjects (n = 9). Clinical and psychometric testing was performed on all individuals, as well as obtaining their magnetic resonance imaging-based hippocampal volumes. RESULTS: Our experiments reveal that total cerebral blood flow was 20% lower in the AD group than in the NDC group, and that these values were directly correlated with pulse pressure and cognitive measures. The AD group had a significantly lower pulse pressure (mean AD 48, mean NDC 71; P = 0.0004). A significant group difference was also observed in their hippocampal volumes. Composite z-scores for clinical, psychometric, hippocampal volume, and hemodynamic data differed between the AD and NDC subjects, with values in the former being significantly lower (t = 12.00, df = 1, P = 0.001) than in the latter. CONCLUSION: These results indicate an association between brain hypoperfusion and the dementia of AD. Cardiovascular disease combined with brain hypoperfusion may participate in the pathogenesis/pathophysiology of neurodegenerative diseases. Future longitudinal and larger-scale confirmatory investigations measuring multidomain parameters are warranted. PMID- 23109809 TI - Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology. AB - Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. PMID- 23109811 TI - System 3 diagnostic process: the lateral approach. AB - The process of obtaining diagnosis is described as a dual-process model, including the intuitive process, and the analytical process. The similarity between the two systems is that they both infer a diagnosis from patient-derived information. Here we present another process by which to elicit the diagnosis: asking direct questions of the patient themselves, such as "What do you think is the cause?" or "What do you suspect is wrong?" This simple method would enable us to elicit pivotal information for diagnosis. Asking patients direct questions allows them to think about the cause of their own problem and suggest their own diagnosis. This method of reasoning is completely different from the two above mentioned systems and may represent a third approach. We highlight this third process as an important strategy, thereby using this third effective method of inquiry to facilitate quick and effective diagnosis in conjunction with former two systems. PMID- 23109810 TI - Post-herpetic neuralgia. AB - BACKGROUND: In spite of the large body of evidence available in the literature, definition and treatment of Post-Herpetic Neuralgia (PHN) are still lacking a consistent and universally recognized standardization. Furthermore, many issues concerning diagnosis, prediction and prevention of PHN need to be clarified in view of recent contributions. OBJECTIVES: To assess whether PHN may be better defined, predicted, treated and prevented in light of recent data, and whether available alternative or adjunctive therapies may improve pain relief in treatment recalcitrant PHN. METHODS: Systematic reviews, meta-analyses, randomized controlled trials, cohort studies and protocols were searched; the search sources included PubMed, Cochrane Library, NICE, and DARE. More than 130 papers were selected and evaluated. RESULTS: Diagnosis of PHN is essentially clinical, but it can be improved by resorting to the many tools available, including some practical and accessible questionnaires. Prediction of PHN can be now much more accurate, taking into consideration a few well validated clinical and anamnestic variables. Treatment of PHN is presently based on a well characterized array of drugs and drug associations, including, among others, tricyclic antidepressants, gabapentinoids, opioids and many topical formulations. It is still unsatisfactory, however, in a substantial proportion of patients, especially those with many comorbidities and intense pain at herpes zoster (HZ) presentation, so that this frequent complication of HZ still strongly impacts on the quality of life of affected patients. CONCLUSION: Further efforts are needed to improve the management of PHN. Potentially relevant interventions may include early antiviral therapy of acute HZ, prevention of HZ by adult vaccination, as well as new therapeutic approaches for patients experiencing PHN. PMID- 23109812 TI - Moraxella osloensis: an unusual cause of central venous catheter infection in a cancer patient. AB - Moraxella osloensis is a rare causative organism of infections in humans, with most cases reported in cancer patients. We report the case of a 67-year-old Japanese man with advanced cancer of the pancreatic head and multiple liver metastases who developed fever with chills. Blood culture was found to be positive for Gram-negative bacilli that were aerobic, oxidase-positive, and catalase-positive. M. osloensis was identified by 16 rRNA gene sequencing. Prompt control of the infection was achieved by treatment with cefepime for 14 days, without the need for removal of the central venous catheter. PMID- 23109813 TI - Effect of milnacipran on body weight in patients with fibromyalgia. AB - BACKGROUND: The purpose of this study was to evaluate the effects of milnacipran on body weight in patients with fibromyalgia. METHODS: ANALYSES WERE CONDUCTED IN THE FOLLOWING GROUPS: patients from three double-blind, placebo-controlled milnacipran trials (3 months, n = 2096; 6 months, n = 1008); 354 patients receiving milnacipran in placebo-controlled trials and double-blind extension studies (total >= 12 months of treatment); and 1227 patients in a long-term (up to 3.25 years) open-label milnacipran study. RESULTS: In placebo-controlled trials, 77% of patients were overweight or obese at baseline (body mass index >= 25 kg/m(2)). Mean weight loss was found with milnacipran at 3 months (100 mg/day, -1.14 kg; 200 mg/day, -0.97 kg; placebo, -0.06 kg; P < 0.001) and 6 months (100 mg/day, -1.01 kg; 200 mg/day, -0.71 kg; placebo, -0.04 kg; P < 0.05). Approximately twice as many milnacipran-treated patients had >=5% weight loss from baseline compared with placebo (3 and 6 months, P < 0.01). In extension studies, mean weight loss in patients receiving >=12 months of milnacipran was 1.06 kg. In patients receiving >=3 years of treatment in the open-label study, mean changes at 12, 24, 30, and 36-38 months were -1.16, -0.76, -0.19, and +0.11 kg, respectively. Among milnacipran-treated patients, rates of nausea (the most common adverse event) were lower among patients who lost weight than among those who did not (3 months, P = 0.02). CONCLUSION: The majority of patients with fibromyalgia in the milnacipran studies were overweight or obese. Milnacipran was associated with mean weight loss at 3 and 6 months (P < 0.05 versus placebo) and at 12 and 24 months of treatment, with mean changes drifting back to baseline at 30 months (-0.19 kg) and 36-38 months (+0.11 kg, no placebo comparison). PMID- 23109814 TI - Youth Supervision While Mothers Work: A Daily Diary Study of Maternal Worry. AB - Using data from a daily diary study of hourly hotel employees in the U.S. and their children, this study examined links between youth supervision arrangements and maternal worry while at work, examining both differences between individuals and day-to-day variation within individuals. Multilevel model analyses revealed both between- and within-person effects linking youth supervision to maternal worry. Mothers' partner status functioned as moderator, and maternal knowledge also emerged as a protective factor when youth were in self-care, highlighting a potential target for future work-family interventions, particularly those for hourly employees with limited access to family-friendly workplace policies.En utilisant les donnees d'une etude de journal quotidien des employes horaires de l'hotel aux Etats-Unis et leurs enfants, cette etude a examine les liens entre les modalites de supervision des jeunes et l'inquietude maternelle pendant le travail, en examinant a la fois les differences inter individus et la variation intra individus au jour le jour. Analyses multi-niveaux ont revele a la fois des effets inter et intra reliant la supervision des jeunes a l'inquietude maternelle. Statut de partenaire des meres a fonctionne en tant que moderateur, et la connaissance maternelle est egalement apparue comme un facteur de protection lorsque les jeunes ont pris soins d'eux-memes, soulignant une cible potentielle pour des interventions de conciliation travail-famille, en particulier ceux concus pour des employes horaires avec un acces limite a des politiques favorables a la famille. PMID- 23109815 TI - Recent advances in intracellular and in vivo ROS sensing: focus on nanoparticle and nanotube applications. AB - Reactive oxygen species (ROS) are increasingly being implicated in the regulation of cellular signaling cascades. Intracellular ROS fluxes are associated with cellular function ranging from proliferation to cell death. Moreover, the importance of subtle, spatio-temporal shifts in ROS during localized cellular signaling events is being realized. Understanding the biochemical nature of the ROS involved will enhance our knowledge of redox-signaling. An ideal intracellular sensor should therefore resolve real-time, localized ROS changes, be highly sensitive to physiologically relevant shifts in ROS and provide specificity towards a particular molecule. For in vivo applications issues such as bioavailability of the probe, tissue penetrance of the signal and signal-to noise ratio also need to be considered. In the past researchers have heavily relied on the use of ROS-sensitive fluorescent probes and, more recently, genetically engineered ROS sensors. However, there is a great need to improve on current methods to address the above issues. Recently, the field of molecular sensing and imaging has begun to take advantage of the unique physico-chemical properties of nanoparticles and nanotubes. Here we discuss the recent advances in the use of these nanostructures as alternative platforms for ROS sensing, with particular emphasis on intracellular and in vivo ROS detection and quantification. PMID- 23109816 TI - Comparative proteomic analysis of Lactobacillus plantarum WCFS1 and DeltactsR mutant strains under physiological and heat stress conditions. AB - Among Gram-positive bacteria, CtsR (Class Three Stress gene Repressor) mainly regulates the expression of genes encoding the Clp ATPases and the ClpP protease. To gain a better understanding of the biological significance of the CtsR regulon in response to heat-shock conditions, we performed a global proteomic analysis of Lactobacillus plantarum WCFS1 and DeltactsR mutant strains under optimal or heat stress temperatures. Total protein extracts from bacterial cells were analyzed by two-dimensional gel fractionation. By comparing maps from different culture conditions and different L. plantarum strains, image analysis revealed 23 spots with altered levels of expression. The proteomic analysis of L. plantarum WCFS1 and ctsR mutant strains confirms at the translational level the CtsR-mediated regulation of some members of the Clp family, as well as the heat induction of typical stress response genes. Heat activation of the putative CtsR regulon genes at transcriptional and translational levels, in the DeltactsR mutant, suggests additional regulative mechanisms, as is the case of hsp1. Furthermore, isoforms of ClpE with different molecular mass were found, which might contribute to CtsR quality control. Our results could add new outlooks in order to determine the complex biological role of CtsR-mediated stress response in lactic acid bacteria. PMID- 23109818 TI - Immunomodulating activity of Nymphaea rubra Roxb. extracts: activation of rat dendritic cells and improvement of the T(H)1 immune response. AB - Polysaccharides play a key role in enhancing immune function and facilitating cellular communication. Here, we purified Nymphaea rubra Roxb. polysaccharides (NR-PS) by treating them with pullulanase. They were then cultured with immature dendritic cells (DCs) derived from rat bone marrow hematopoietic cells (BMHCs). After treatment with bioactive NR-PS with a degree of polymerization (DP) value of 359.8, we found that the DCs underwent morphological changes indicative of activation. CD80/86 (87.16% +/- 8.49%) and MHC class II (52.01% +/- 10.11%) expression levels were significantly up-regulated by this treatment compared to the controls (65.45% +/- 0.97% and 34.87% +/- 1.96%). In parallel, endocytosis was also reduced (167.94% +/- 60.59%) after treatment with 25 MUg/mL of NR-PS as measured by the medium fluorescence intensity compared to the control (261.67% +/ 47.26%). Furthermore, the DCs after treatment with 25 MUg/mL NR-PS showed increased IL-12 (102.09 +/- 10.16 to 258.78 +/- 25.26 pg/mL) and IFN-gamma (11.76 +/- 0.11 to 15.51 +/- 1.66 pg/mL) secretion together with reduced IL-10 secretion (30.75 +/- 3.35 to 15.37 +/- 2.35 pg/mL), which indicates a T(H)1 immune response. In conclusion, NR-PS exhibits stimulatory effects on rat DCs and promotes the secretion of T(H)1 cytokines. Taken together, our studies are the first to show that NR-PS is an immunomodulator affecting the maturation and functioning of DCs. PMID- 23109817 TI - Cell signaling through protein kinase C oxidation and activation. AB - Due to the growing importance of cellular signaling mediated by reactive oxygen species (ROS), proteins that are reversibly modulated by these reactant molecules are of high interest. In this context, protein kinases and phosphatases, which act coordinately in the regulation of signal transduction through the phosphorylation and dephosphorylation of target proteins, have been described to be key elements in ROS-mediated signaling events. The major mechanism by which these proteins may be modified by oxidation involves the presence of key redox sensitive cysteine residues. Protein kinase C (PKC) is involved in a variety of cellular signaling pathways. These proteins have been shown to contain a unique structural feature that is susceptible to oxidative modification. A large number of scientific studies have highlighted the importance of ROS as a second messenger in numerous cellular processes, including cell proliferation, gene expression, adhesion, differentiation, senescence, and apoptosis. In this context, the goal of this review is to discuss the mechanisms by which PKCs are modulated by ROS and how these processes are involved in the cellular response. PMID- 23109819 TI - Combined treatment with an oncolytic adenovirus and antitumor activity of vincristine against retinoblastoma cells. AB - Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in combination with vincristine (VCR) on retinoblastoma in vitro, the cell viability, cell cycle effects and apoptotic activity of HXO-RB(44) cells treated with SG600, VCR or SG600 plus VCR were measured using a cell counting kit-8-based procedure and flow cytometry. Western blot analysis for Akt, p-Akt, p-p53 and p-Rb protein was performed to investigate the underlying mechanisms of combined therapy. The combination therapy exerted a synergistic antitumor effect via a type of G(2)/M and S phase arrest rather than the induction of apoptosis. The combination of VCR and SG600 further reduced Akt phosphorylation compared with cells treated with VCR alone, suggesting that SG600 could overcome chemoresistance, perhaps by down regulating Akt in RB cells. An increase in the expression of p-p53 and decrease in p-Rb expression in HXO-RB(44) after co-treatment might be associated with cell cycle block. Western blot examination revealed that VCR might enhance SG600 replication. These results suggest that viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma. PMID- 23109820 TI - Application of novel polymorphic microsatellite loci identified in the Korean Pacific Abalone (Haliotis diversicolor supertexta (Haliotidae)) in the genetic characterization of wild and released populations. AB - The small abalone, Haliotis diversicolor supertexta, of the family Haliotidae, is one of the most important species of marine shellfish in eastern Asia. Over the past few decades, this species has drastically declined in Korea. Thus, hatchery bred seeds have been released into natural coastal areas to compensate for the reduced fishery resources. However, information on the genetic background of the small abalone is scarce. In this study, 20 polymorphic microsatellite DNA markers were identified using next-generation sequencing techniques and used to compare allelic variation between wild and released abalone populations in Korea. Using high-throughput genomic sequencing, a total of 1516 (2.26%; average length of 385 bp) reads containing simple sequence repeats were obtained from 86,011 raw reads. Among the 99 loci screened, 28 amplified successfully, and 20 were polymorphic. When comparing allelic variation between wild and released abalone populations, a total of 243 different alleles were observed, with 18.7 alleles per locus. High genetic diversity (mean heterozygosity = 0.81; mean allelic number = 15.5) was observed in both populations. A statistical analysis of the fixation index (F(ST)) and analysis of molecular variance (AMOVA) indicated limited genetic differences between the two populations (F(ST) = 0.002, p > 0.05). Although no significant reductions in the genetic diversity were found in the released population compared with the wild population (p > 0.05), the genetic diversity parameters revealed that the seeds released for stock abundance had a different genetic composition. These differences are likely a result of hatchery selection and inbreeding. Additionally, all the primer pair sets were effectively amplified in another congeneric species, H. diversicolor diversicolor, indicating that these primers are useful for both abalone species. These microsatellite loci may be valuable for future aquaculture and population genetic studies aimed at developing conservation and management plans for these two abalone species. PMID- 23109821 TI - Isolation and characterization of 13 microsatellite loci from a Korean Endemic Species, Sophora koreensis (Fabaceae). AB - To evaluate the population genetics structure as a means of devising conservation strategies, we developed microsatellite primers for Sophora koreensis, a narrowly endemic and endangered species in Korea. Thirteen polymorphic microsatellite markers were developed in Korean populations of S. koreensis. Genetic diversity was analyzed in 40 individuals from two populations. The number of alleles per locus ranged from 4 to 14, with observed and expected heterozygosities ranging from 0.200 to 1.000 and from 0.189 to 0.864, respectively. The microsatellite markers described here are valuable tools for the population genetics research of S. koreensis. They can be used to obtain information for creating suitable management strategies to conserve this endemic and endangered species. PMID- 23109823 TI - Analysis of genome survey sequences and SSR marker development for Siamese Mud Carp, Henicorhynchus siamensis, using 454 pyrosequencing. AB - Siamese mud carp (Henichorynchus siamensis) is a freshwater teleost of high economic importance in the Mekong River Basin. However, genetic data relevant for delineating wild stocks for management purposes currently are limited for this species. Here, we used 454 pyrosequencing to generate a partial genome survey sequence (GSS) dataset to develop simple sequence repeat (SSR) markers from H. siamensis genomic DNA. Data generated included a total of 65,954 sequence reads with average length of 264 nucleotides, of which 2.79% contain SSR motifs. Based on GSS-BLASTx results, 10.5% of contigs and 8.1% singletons possessed significant similarity (E value < 10(-5)) with the majority matching well to reported fish sequences. KEGG analysis identified several metabolic pathways that provide insights into specific potential roles and functions of sequences involved in molecular processes in H. siamensis. Top protein domains detected included reverse transcriptase and the top putative functional transcript identified was an ORF2-encoded protein. One thousand eight hundred and thirty seven sequences containing SSR motifs were identified, of which 422 qualified for primer design and eight polymorphic loci have been tested with average observed and expected heterozygosity estimated at 0.75 and 0.83, respectively. Regardless of their relative levels of polymorphism and heterozygosity, microsatellite loci developed here are suitable for further population genetic studies in H. siamensis and may also be applicable to other related taxa. PMID- 23109822 TI - Adaptive response, evidence of cross-resistance and its potential clinical use. AB - Organisms and their cells are constantly exposed to environmental fluctuations. Among them are stressors, which can induce macromolecular damage that exceeds a set threshold, independent of the underlying cause. Stress responses are mechanisms used by organisms to adapt to and overcome stress stimuli. Different stressors or different intensities of stress trigger different cellular responses, namely induce cell repair mechanisms, induce cell responses that result in temporary adaptation to some stressors, induce autophagy or trigger cell death. Studies have reported life-prolonging effects of a wide variety of so called stressors, such as oxidants, heat shock, some phytochemicals, ischemia, exercise and dietary energy restriction, hypergravity, etc. These stress responses, which result in enhanced defense and repair and even cross-resistance against multiple stressors, may have clinical use and will be discussed, while the emphasis will be on the effects/cross-effects of oxidants. PMID- 23109825 TI - Indoleamine 2,3-dioxygenase (IDO) downregulates the cell surface expression of the CD4 molecule. AB - Indoleamine 2,3-dioxygenase (IDO) has been implicated in preventing the fetus from undergoing maternal T cell-mediated immune responses, yet the mechanism underlying these kinds of IDO-mediated immune responses has not been fully elucidated. Since the CD4 molecule plays a central role in the onset and regulation of antigen-specific immune responses, and T cell is sensitive in the absence of tryptophan, we hypothesize that IDO may reduce cell surface CD4 expression. To test this hypothesis, an adenoviral vector-based construct IDO EGFP was generated and the effect of IDO-EGFP on CD4 expression was determined on recombinant adenoviral infected C8166 and MT-2 cells, by flow cytometry and/or Western blot analysis. The results revealed a significant downregulation of cell membrane CD4 in pAd-IDOEGFP infected cells when compared to that of mock-infected cells or infection with empty vector pAd-EGFP. Further experiments disclosed that either an addition of tryptophan or IDO inhibitor could partly restore CD4 expression in pAd-IDOEGFP infected C8166 cells. Our findings suggest that downregulation of CD4 by IDO might be one of the mechanisms through which IDO regulates T cell-mediated immune responses. PMID- 23109826 TI - Synthesis, structure optimization and antifungal screening of novel tetrazole ring bearing acyl-hydrazones. AB - Azoles are generally fungistatic, and resistance to fluconazole is emerging in several fungal pathogens. In an attempt to find novel azole antifungal agents with improved activity, a series of tetrazole ring bearing acylhydrazone derivatives were synthesized and screened for their in vitro antifungal activity. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and determination of the levels of ergosterol, a fungal-specific sterol. Propidium iodide rapidly penetrated a majority of yeast cells when they were treated with the synthesized compounds at concentrations just above MIC, implying that fungicidal activity resulted from extensive lesions of the plasma membrane. Target compounds also caused a considerable reduction in the amount of ergosterol. The results also showed that the presence and position of different substituents on the phenyl ring of the acylhydrazone pendant seem to play a role on the antifungal activity as well as in deciding the fungistatic and fungicidal nature of the compounds. PMID- 23109824 TI - Vectors for inhaled gene therapy in lung cancer. Application for nano oncology and safety of bio nanotechnology. AB - Novel aerosol therapeutic modalities have been investigated for lung cancer. Inhaled gene therapy has presented safety and effectiveness previously in cystic fibrosis. However, safety concerns have been raised regarding the safety of non viral vectors for inhaled gene therapy in lung cancer, and therefore small steps have been made towards this multifunctional treatment modality. During the last decade, numerous new nanocomplexes have been created and investigated as a safe gene delivery nano-vehicle. These formulations are multifunctional; they can be used as either local therapy or carrier for an effective inhaled gene therapy for lung cancer. Herein, we present current and future perspectives of nanocomplexes for inhaled gene therapy treatment in lung cancer. PMID- 23109827 TI - Neuroprotective effects of erucin against 6-hydroxydopamine-induced oxidative damage in a dopaminergic-like neuroblastoma cell line. AB - Oxidative stress (OS) contributes to the cascade leading to the dysfunction or death of dopaminergic neurons during Parkinson's disease (PD). A strategy to prevent the OS of dopaminergic neurons may be the use of phytochemicals as inducers of endogenous antioxidants and phase 2 enzymes. In this study, we demonstrated that treatment of the dopaminergic-like neuroblastoma SH-SY5Y cell line with isothiocyanate erucin (ER), a compound of cruciferous vegetables, resulted in significant increases of both total glutathione (GSH) levels and total antioxidant capacity at the cytosolic level. The increase of GSH levels was associated with an increase in the resistance of SH-SY5Y cells to neuronal death, in terms of apoptosis, induced by 6-hydroxydopamine (6-OHDA). The pretreatment of SH-SY5Y cells with ER was also shown to prevent the redox status impairment, in terms of intracellular ROS and O(2) (*-) formation, and loss of mitochondrial membrane potential, early events that are initiators of the apoptotic process, induced by 6-OHDA. Last, the antiapoptotic and antioxidant effects of ER were abolished by buthionine sulfoximine, supporting the main role of GSH in the neuroprotective effects recorded by ER. These results suggest that ER may prevent the oxidative damage induced by 6-OHDA. PMID- 23109828 TI - Prenatal vitamin D deficiency induces an early and more severe experimental autoimmune encephalomyelitis in the second generation. AB - In a previous study, we demonstrated that mouse adult F(1) offspring, exposed to a vitamin D deficiency during pregnancy, developed a less severe and delayed Experimental Autoimmune Encephalomyelitis (EAE), when compared with control offspring. We then wondered whether a similar response was observed in the subsequent generation. To answer this question, we assessed F(2) females whose F(1) parents (males or females) were vitamin D-deprived when developing in the uterus of F(0) females. Unexpectedly, we observed that the vitamin D deficiency affecting the F(0) pregnant mice induced a precocious and more severe EAE in the F(2) generation. This paradoxical finding led us to assess its implications for the epidemiology of Multiple Sclerosis (MS) in humans. Using the REFGENSEP database for MS trios (the patient and his/her parents), we collected the parents' dates of birth and assessed a potential season of birth effect that could potentially be indicative of the vitamin D status of the pregnant grandmothers. A trend for a reduced number of births in the Fall for the parents of MS patients was observed but statistical significance was not reached. Further well powered studies are warranted to validate the latter finding. PMID- 23109829 TI - Graphene nanoplatelets as novel reinforcement filler in poly(lactic acid)/epoxidized palm oil green nanocomposites: mechanical properties. AB - Graphene nanoplatelet (xGnP) was investigated as a novel reinforcement filler in mechanical properties for poly(lactic acid) (PLA)/epoxidized palm oil (EPO) blend. PLA/EPO/xGnP green nanocomposites were successfully prepared by melt blending method. PLA/EPO reinforced with xGnP resulted in an increase of up to 26.5% and 60.6% in the tensile strength and elongation at break of the nanocomposites respectively, compared to PLA/EPO blend. XRD pattern showed the presence of peak around 26.5 degrees in PLA/EPO nanocomposites which corresponds to characteristic peak of graphene nanoplatelets. However, incorporation of xGnP has no effect on the flexural strength and modulus. Impact strength of PLA/5 wt% EPO improved by 73.6% with the presence of 0.5 wt% xGnP loading. Mechanical properties of PLA were greatly improved by the addition of a small amount of graphene nanoplatelets (<1 wt%). PMID- 23109830 TI - Gamma irradiation of in-shell and blanched peanuts protects against mycotoxic fungi and retains their nutraceutical components during long-term storage. AB - Peanut samples were irradiated (0.0, 5.2, 7.2 or 10.0 kGy), stored for a year (room temperature) and examined every three months. Mycotoxic fungi (MF) were detected in non-irradiated blanched peanuts. A dose of 5.2 kGy was found suitable to prevent MF growth in blanched samples. No MF was detected in in-shell peanuts, with or without irradiation. The colors of the control in-shell and blanched samples were, respectively, 44.72 and 60.21 (L *); 25.20 and 20.38 (Chroma); 53.05 and 86.46 ( degrees Hue). The water activities (Aw) were 0.673 and 0.425. The corresponding fatty acids were 13.33% and 12.14% (C16:0), 44.94% and 44.92% (C18:1, omega9) and 37.10% and 37.63% (C18:2, omega6). The total phenolics (TP) were 4.62 and 2.52 mg GAE/g, with antioxidant activities (AA) of 16.97 and 10.36 MUmol TEAC/g. Storage time negatively correlated with Aw (in-shell peanuts) or L *, linoleic acid, TP and AA (in-shell and blanched peanuts) but positively correlated with Aw (blanched peanuts), and with oleic acid (in-shell and blanched peanuts). Irradiation positively correlated with antioxidant activity (blanched peanuts). No correlation was found between irradiation and AA (in-shell samples) or fatty acids and TP (in-shell and blanched peanuts). Irradiation protected against MF and retained both the polyunsaturated fatty acids and polyphenols in the samples. PMID- 23109831 TI - NAD(P)H:quinone oxidoreductase 1 (NQO1) P187S polymorphism and prostate cancer risk in Caucasians. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A "C" to "T" transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1(609)TT genotype, and low to intermediate activity was detected in NQO1(609)CT genotype compared with (609)CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy-Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis. PMID- 23109832 TI - Biocompatibility of genipin and glutaraldehyde cross-linked chitosan materials in the anterior chamber of the eye. AB - Chitosan is a naturally occurring cationic polysaccharide and has attracted much attention in the past decade as an important ophthalmic biomaterial. We recently demonstrated that the genipin (GP) cross-linked chitosan is compatible with human retinal pigment epithelial cells. The present work aims to further investigate the in vivo biocompatibility of GP-treated chitosan (GP-chi group) by adopting the anterior chamber of a rabbit eye model. The glutaraldehyde (GTA) cross-linked samples (GTA-chi group) were used for comparison. The 7-mm-diameter membrane implants made from either non-cross-linked chitosan or chemically modified materials with a cross-linking degree of around 80% were inserted in the ocular anterior chamber for 24 weeks and characterized by slit-lamp and specular microscopic examinations, intraocular pressure measurements, and corneal thickness measurements. The interleukin-6 expressions at mRNA level were also detected by quantitative real-time reverse transcription polymerase chain reaction. Results of clinical observations showed that the overall ocular scores in the GTA-chi groups were relatively high. In contrast, the rabbits bearing GP chi implants in the anterior chamber of the eye exhibited no signs of ocular inflammation. As compared to the non-cross-linked counterparts, the GP-chi samples improved the preservation of corneal endothelial cell density and possessed better anti-inflammatory activities, indicating the benefit action of the GP cross-linker. In summary, the intracameral tissue response to the chemically modified chitosan materials strongly depends on the selection of cross linking agents. PMID- 23109833 TI - A DFT study of pyrrole-isoxazole derivatives as chemosensors for fluoride anion. AB - The interactions between chemosensors, 3-amino-5-(4,5,6,7-tetrahydro-1H-indol-2 yl)isoxazole-4-carboxamide (AIC) derivatives, and different anions (F(-) Cl(-), Br(-), AcO(-), and H(2)PO(4) (-)) have been theoretically investigated using DFT approaches. It turned out that the unique selectivity of AIC derivatives for F(-) is ascribed to their ability of deprotonating the host sensors. Frontier molecular orbital (FMO) analyses have shown that the vertical electronic transitions of absorption and emission for the sensing signals are characterized as intramolecular charge transfer (ICT). The study of substituent effects suggests that all the substituted derivatives are expected to be promising candidates for fluoride chemosensors both in UV-vis and fluorescence spectra except for derivative with benzo[d]thieno[3,2-b]thiophene fragment that can serve as ratiometric fluorescent fluoride chemosensor only. PMID- 23109834 TI - Multiscale models of the antimicrobial peptide protegrin-1 on gram-negative bacteria membranes. AB - Antimicrobial peptides (AMPs) are naturally-occurring molecules that exhibit strong antibiotic properties against numerous infectious bacterial strains. Because of their unique mechanism of action, they have been touted as a potential source for novel antibiotic drugs. We present a summary of computational investigations in our lab aimed at understanding this unique mechanism of action, in particular the development of models that provide a quantitative connection between molecular-level biophysical phenomena and relevant biological effects. Our work is focused on protegrins, a potent class of AMPs that attack bacteria by associating with the bacterial membrane and forming transmembrane pores that facilitate the unrestricted transport of ions. Using fully atomistic molecular dynamics simulations, we have computed the thermodynamics of peptide-membrane association and insertion, as well as peptide aggregation. We also present a multi-scale analysis of the ion transport properties of protegrin pores, ranging from atomistic molecular dynamics simulations to mesoscale continuum models of single-pore electrodiffusion to models of transient ion transport from bacterial cells. Overall, this work provides a quantitative mechanistic description of the mechanism of action of protegrin antimicrobial peptides across multiple length and time scales. PMID- 23109835 TI - Damaged DNA binding protein 2 in reactive oxygen species (ROS) regulation and premature senescence. AB - Premature senescence induced by DNA damage or oncogene is a critical mechanism of tumor suppression. Reactive oxygen species (ROS) have been implicated in the induction of premature senescence response. Several pathological disorders such as cancer, aging and age related neurological abnormalities have been linked to ROS deregulation. Here, we discuss how Damaged DNA binding Protein-2 (DDB2), a nucleotide excision repair protein, plays an important role in ROS regulation by epigenetically repressing the antioxidant genes MnSOD and Catalase. We further revisit a model in which DDB2 plays an instrumental role in DNA damage induced ROS accumulation, ROS induced premature senescence and inhibition of skin tumorigenesis. PMID- 23109836 TI - Ultrasound-assisted extraction of carnosic acid and rosmarinic acid using ionic liquid solution from Rosmarinus officinalis. AB - Ionic liquid based, ultrasound-assisted extraction was successfully applied to the extraction of phenolcarboxylic acids, carnosic acid and rosmarinic acid, from Rosmarinus officinalis. Eight ionic liquids, with different cations and anions, were investigated in this work and [C(8)mim]Br was selected as the optimal solvent. Ultrasound extraction parameters, including soaking time, solid-liquid ratio, ultrasound power and time, and the number of extraction cycles, were discussed by single factor experiments and the main influence factors were optimized by response surface methodology. The proposed approach was demonstrated as having higher efficiency, shorter extraction time and as a new alternative for the extraction of carnosic acid and rosmarinic acid from R. officinalis compared with traditional reference extraction methods. Ionic liquids are considered to be green solvents, in the ultrasound-assisted extraction of key chemicals from medicinal plants, and show great potential. PMID- 23109837 TI - Tissue microarray-based evaluation of Chromatin Assembly Factor-1 (CAF-1)/p60 as tumour prognostic marker. AB - In this study we aimed to confirm the emerging role of Chromatin Assembly Factor 1 (CAF-1 p60) as a new proliferation and prognostic marker for cancer and to test the usefulness of the tissue microarray technique (TMA) for CAF-1 p60 rapid screening in several human malignancies. CAF-1 is a histone chaperone, regulating chromatin dynamics during DNA replication and repair in eukaryotics. TMA is a powerful high-throughput methodology in the study of cancer, allowing simultaneous assessment of different biomarkers within large numbers of tissue specimens. We generated TMA taking 3 mm diameter-core biopsies from oral squamous cell carcinoma, prostate cancer, salivary gland tumours and skin melanoma specimens, which had been previously tested for CAF-1 p60 on routine tissue sections. We also analysed, for the first time, 30 larynx and 30 skin squamous cell carcinomas. CAF-1 p60 resulted over-expressed in both the tissue sections and the TMA specimens, with the highest levels of expression in tumours which were more aggressive and metastasizing. Notably, a high degree of agreement was found between the CAF-1 p60 assessment on TMAs and on routine tissue sections. Our findings confirm the prognostic role of CAF-1 p60 and indicate TMA as a really advantageous method for CAF-1 p60 immunohistochemical screening, allowing savings on both tissue quantity and operator-time. PMID- 23109838 TI - Successful treatment of liver aspergilloma by caspofungin acetate first-line therapy in a non-immunocompromised patient. AB - Aspergillosis remains to be a life-threatening complication in immunocompromised patients. However, Aspergillus infection can be observed in non-immunocompromised individuals in rare cases. We report a case of liver aspergilloma in a chronic aplastic anemia patient under relatively intact immune status. Therapeutic strategy for this rare condition was extensively discussed and caspofungin acetate single agent first-line therapy was applied after careful consideration. Encouraging clinical and radiologic improvements were achieved in response to the antifungal salvage. Our long-term follow-up study also revealed a favorable prognosis. Based on this experience, we suggest caspofungin acetate as first-line therapy for treatment plans of liver aspergilloma. PMID- 23109839 TI - The dual role of inflammation in colon carcinogenesis. AB - Chronic inflammation characterizing patients with inflammatory bowel disease (IBD) represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either directly or indirectly stimulate the uncontrolled growth of cancer cells. Nevertheless, under specific inflammatory conditions, immune cells can boost an anti-tumor immune response with the down stream effect of eliminating dysplastic and cancerous cells. This review outlines the beneficial and detrimental role of inflammation in colon carcinogenesis. PMID- 23109840 TI - Dual targeting and retrograde translocation: regulators of plant nuclear gene expression can be sequestered by plastids. AB - Changes in the developmental or metabolic state of plastids can trigger profound changes in the transcript profiles of nuclear genes. Many nuclear transcription factors were shown to be controlled by signals generated in the organelles. In addition to the many different compounds for which an involvement in retrograde signaling is discussed, accumulating evidence suggests a role for proteins in plastid-to-nucleus communication. These proteins might be sequestered in the plastids before they act as transcriptional regulators in the nucleus. Indeed, several proteins exhibiting a dual localization in the plastids and the nucleus are promising candidates for such a direct signal transduction involving regulatory protein storage in the plastids. Among such proteins, the nuclear transcription factor WHIRLY1 stands out as being the only protein for which an export from plastids and translocation to the nucleus has been experimentally demonstrated. Other proteins, however, strongly support the notion that this pathway might be more common than currently believed. PMID- 23109842 TI - Electric field induced fluorescence modulation of single molecules in PMMA based on electron transfer. AB - We present a method to modulate the fluorescence of non-polar single squaraine derived rotaxanes molecules embedded in a polar poly(methyl methacrylate) (PMMA) matrix under an external electric field. The electron transfer between single molecules and the electron acceptors in a PMMA matrix contributes to the diverse responses of fluorescence intensities to the electric field. The observed instantaneous and non-instantaneous electric field dependence of single-molecule fluorescence reflects the redistribution of electron acceptors in PMMA induced by electronic polarization and orientation polarization of polar polymer chains in an electric field. PMID- 23109843 TI - Nucleotide excision repair in cellular chromatin: studies with yeast from nucleotide to gene to genome. AB - Here we review our development of, and results with, high resolution studies on global genome nucleotide excision repair (GGNER) in Saccharomyces cerevisiae. We have focused on how GGNER relates to histone acetylation for its functioning and we have identified the histone acetyl tranferase Gcn5 and acetylation at lysines 9/14 of histone H3 as a major factor in enabling efficient repair. We consider results employing primarily MFA2 as a model gene, but also those with URA3 located at subtelomeric sequences. In the latter case we also see a role for acetylation at histone H4. We then go on to outline the development of a high resolution genome-wide approach that enables one to examine correlations between histone modifications and the nucleotide excision repair (NER) of UV-induced cyclobutane pyrimidine dimers throughout entire genomes. This is an approach that will enable rapid advances in understanding the complexities of how compacted chromatin in chromosomes is processed to access DNA damage and then returned to its pre-damaged status to maintain epigenetic codes. PMID- 23109844 TI - Characterization of 15 polymorphic microsatellite loci for Cephalotaxus oliveri (Cephalotaxaceae), a conifer of medicinal importance. AB - Cephalotaxus oliveri is a scarce medicinal conifer endemic to the south central region of China and Vietnam. A small fragmented population presently exists due to anthropogenic disturbance. C. oliveri has been used for its alkaloids harringtonine and homoharringtonine, which are effective against leucocythemia and lymphadenosarcoma. Monoecious plants have been detected in nature, although they were understood to be dioecious. In order to study the mating system, population genetics and the genetic effects of habitat fragmentation on C. oliveri, 15 polymorphic and 12 monomorphic microsatellite loci were developed for C. oliveri by using the Fast Isolation by AFLP of Sequences Containing repeats (FIASCO) protocol. The polymorphisms were assessed in 96 individuals from three natural populations (32 individuals per population). The number of alleles per locus ranged from two to 33, the observed and expected heterozygosity per locus ranged from 0.000 to 1.000 and from 0.000 to 0.923, respectively. These loci would facilitate a comprehensive understanding of the genetic dynamics on C. oliveri, which will be useful for establishing effective conservation strategies for this species. PMID- 23109845 TI - Commercial bee pollen with different geographical origins: a comprehensive approach. AB - Since the primordial of humanity, pollen has been considered a good source of nutrients and energy. Its promising healing properties have also been referred to. The present study aimed to characterize, for the first time, eight commercial pollens from Portugal and Spain available on the market studying the legislation on labeling, pollinic origin, physicochemical and microbiological analyses and identification of yeasts. Eleven botanical families were found amongst the samples. The most abundant family and the most dominant pollen was Cistaceae. The moisture content, ash, a(w), pH, reducing sugars, carbohydrates, proteins, lipids and energy were analyzed and the specific parameters were within the specifications required by some countries with legislation regarding these parameters. Microbiologically commercial pollen showed acceptable safety for the commercial quality and hygiene. All samples showed negative results for toxigenic species. The microorganisms studied were aerobic mesophiles, yeasts and moulds, coliforms, Escherichia coli, Staphylococcus aureus, Salmonella and sulfite reducing Clostridium. During the work, six yeasts species were isolated from pollen, with Rhodotorula mucilaginosa being the most abundant, as it was present in four samples. PMID- 23109841 TI - Erythropoietin: new directions for the nervous system. AB - New treatment strategies with erythropoietin (EPO) offer exciting opportunities to prevent the onset and progression of neurodegenerative disorders that currently lack effective therapy and can progress to devastating disability in patients. EPO and its receptor are present in multiple systems of the body and can impact disease progression in the nervous, vascular, and immune systems that ultimately affect disorders such as Alzheimer's disease, Parkinson's disease, retinal injury, stroke, and demyelinating disease. EPO relies upon wingless signaling with Wnt1 and an intimate relationship with the pathways of phosphoinositide 3-kinase (PI 3-K), protein kinase B (Akt), and mammalian target of rapamycin (mTOR). Modulation of these pathways by EPO can govern the apoptotic cascade to control beta-catenin, glycogen synthase kinase-3beta, mitochondrial permeability, cytochrome c release, and caspase activation. Yet, EPO and each of these downstream pathways require precise biological modulation to avert complications associated with the vascular system, tumorigenesis, and progression of nervous system disorders. Further understanding of the intimate and complex relationship of EPO and the signaling pathways of Wnt, PI 3-K, Akt, and mTOR are critical for the effective clinical translation of these cell pathways into robust treatments for neurodegenerative disorders. PMID- 23109846 TI - Isolation and characterization of 13 new polymorphic microsatellite markers in the Phaseolus vulgaris L. (Common Bean) genome. AB - In this study, 13 polymorphic microsatellite markers were isolated from the Phaseolus vulgaris L. (common bean) by using the Fast Isolation by AFLP of Sequence COntaining Repeats (FIASCO) protocol. These markers revealed two to seven alleles, with an average of 3.64 alleles per locus. The polymorphic information content (PIC) values ranged from 0.055 to 0.721 over 13 loci, with a mean value of 0.492, and 7 loci having PIC greater than 0.5. The expected heterozygosity (H(E)) and observed heterozygosity (H(O)) levels ranged from 0.057 to 0.814 and from 0.026 to 0.531, respectively. Cross-species amplification of the 13 prime pairs was performed in its related specie of Vigna unguiculata L. Seven out of all these markers showed cross-species transferability. These markers will be useful for future genetic diversity and population genetics studies for this agricultural specie and its related species. PMID- 23109847 TI - Synthesis and antimicrobial activity of some novel cross-linked chitosan hydrogels. AB - Four novel hydrogels based on chitosan were synthesized via a cross-linking reaction of chitosan with different concentrations of oxalyl bis 4-(2,5-dioxo-2H pyrrol- 1(5H)-yl)benzamide. Their structures were confirmed by fourier transform infrared X-ray (FTIR), scanning electron microscopy (SEM) and X-ray diffraction. The antimicrobial activities of the hydrogels against two crop-threatening pathogenic fungi namely: Aspergillus fumigatus (A. fumigatus, RCMBA 06002), and Aspergillus niger (A. niger, RCMBA 06106), and five bacterial species namely: Bacillis subtilis (B. subtilis, RCMBA 6005), Staphylococcus aureus (S. aureus, RCMBA 2004), Streptococcus pneumoniae (S. pneumonia, RCMB 000101) as Gram positive bacteria, and Salmonella typhimurium (S. typhimurium, RCMB 000104), and Escherichia coli (E. coli, RCMBA 5003) as Gram negative bacteria have been investigated. The prepared hydrogels showed much higher antimicrobial activities than that of the parent chitosan. The hydrogels were more potent in case of Gram positive bacteria than Gram-negative bacteria. Increasing the degree of cross linking in the hydrogels resulted in a weaker antimicrobial activity. PMID- 23109848 TI - A combination of 3D-QSAR, molecular docking and molecular dynamics simulation studies of benzimidazole-quinolinone derivatives as iNOS inhibitors. AB - Inducible Nitric Oxide Synthase (iNOS) has been involved in a variety of diseases, and thus it is interesting to discover and optimize new iNOS inhibitors. In previous studies, a series of benzimidazole-quinolinone derivatives with high inhibitory activity against human iNOS were discovered. In this work, three-dimensional quantitative structure-activity relationships (3D QSAR), molecular docking and molecular dynamics (MD) simulation approaches were applied to investigate the functionalities of active molecular interaction between these active ligands and iNOS. A QSAR model with R(2) of 0.9356, Q(2) of 0.8373 and Pearson-R value of 0.9406 was constructed, which presents a good predictive ability in both internal and external validation. Furthermore, a combined analysis incorporating the obtained model and the MD results indicates: (1) compounds with the proper-size hydrophobic substituents at position 3 in ring C (R(3) substituent), hydrophilic substituents near the X(6) of ring-D and hydrophilic or H-bond acceptor groups at position 2 in ring-B show enhanced biological activities; (2) Met368, Trp366, Gly365, Tyr367, Phe363, Pro344, Gln257, Val346, Asn364, Met349, Thr370, Glu371 and Tyr485 are key amino acids in the active pocket, and activities of iNOS inhibitors are consistent with their capability to alter the position of these important residues, especially Glu371 and Thr370. The results provide a set of useful guidelines for the rational design of novel iNOS inhibitors. PMID- 23109849 TI - High mitochondrial DNA copy number and bioenergetic function are associated with tumor invasion of esophageal squamous cell carcinoma cell lines. AB - We previously reported a gradual increase of relative mitochondrial DNA (mtDNA) copy number during the progression of esophageal squamous cell carcinoma (ESCC). Because mitochondria are the intracellular organelles responsible for ATP production, we investigated the associations among mtDNA copy number, mitochondrial bioenergetic function, tumor invasion and the expression levels of epithelial mesenchymal transition (EMT) markers in a series of seven ESCC cell lines, including 48T, 81T, 146T, TE1, TE2, TE6 and TE9. Among them, TE1 had the highest relative mtDNA copy number of 240.7%. The mRNA of mtDNA-encoded ND1 gene (2.80), succinate-supported oxygen consumption rate (11.21 nmol/min/10(6) cells), ATP content (10.7 fmol/cell), and the protein level of mitochondrial transcription factor A (TFAM) were the highest and the lactate concentration in the culture medium (3.34 mM) was the lowest in TE1. These findings indicate that TE1 exhibited the highest bioenergetic function of mitochondria. Furthermore, TE1 showed the highest trans-well migration activity of 223.0 cells/field, the highest vimentin but the lowest E-cadherin protein expression levels, which suggest that TE1 had the highest invasion capability. We then conducted a knockdown study using pLKO.1-based lentiviral particles to infect TE1 cells to suppress the expression of TFAM. Molecular analyses of the parental TE1, control TE1-NT and TFAM knockdown TE1-sh-TFAM(97) cells were performed. Interestingly, as compared to the control TE1-NT, TE1-sh-TFAM(97) exhibited lower levels of the relative mtDNA copy number (p = 0.001), mRNA of mtDNA-encoded ND1 gene (p = 0.050), succinate-supported oxygen consumption rate (p = 0.065), and ATP content (p = 0.007), but had a higher lactate concentration in the culture medium (p = 0.010) and higher protein level of lactate dehydrogenase. A decline in mitochondrial bioenergetic function was observed in TE1-sh-TFAM(97). Significantly, compared to the control TE1-NT, TE1-sh-TFAM(97) had a lower trans well migration activity (p < 0.001), a higher E-cadherin level but a lower vimentin protein level, which indicates a decrease of invasiveness. Taken together, we suggest that high relative mtDNA copy number and bioenergetic function of mitochondria may confer an advantage for tumor invasion of ESCC. PMID- 23109850 TI - Bio-guided isolation of the cytotoxic terpenoids from the roots of Euphorbia kansui against human normal cell lines L-O2 and GES-1. AB - The dried roots of Euphorbia kansui (kansui) have been used for centuries in China as a herbal medicine for edema, ascites, and asthma. The 95% ethanol extract showed a significant inhibition of cell proliferation against human normal cell lines L-O2 and GES-1. Bioassay-guided separation of the 95% ethanol extract from the roots of E. kansui led to the isolation of 12 diverse terpenoids whose structures were identified by (1)H, (13)C NMR spectroscopy and ESI-MS as kansuinine A (1), kansuinine B (2), kansuinine C (3), kansuiphorin C (4), 3-O (2'E,4'Z-decadienoyl)-20-O-acetylingenol (5), 3-O-(2'E,4'Edecadienoyl)-20-O acetylingenol (6), 3-O-(2'E,4'Z-decadienoyl)-20-deoxyingenol (7), 3-O-benzoyl-20 deoxyingenol (8), 5-O-benzoyl-20-deoxyingenol (9), kansenone (10), epi-kansenone (11), euphol (12). All these 12 terpernoids were evaluated in vitro for cytotoxicity on L-O2 and GES-1 cell lines. Most ingenane-type diterpenoids and 8 ene-7-one triterpenoids (5-11) exhibited a relatively lower IC(50) value; therefore, these compounds had stronger cytotoxicity against human normal cell lines L-O2 and GES-1 with dose-dependent relationships. These results will be significantly helpful to reveal the mechanism of toxicity of kansui and to effectively guide safer clinical application of this herb. PMID- 23109851 TI - Quantification and purification of mangiferin from Chinese Mango (Mangifera indica L.) cultivars and its protective effect on human umbilical vein endothelial cells under H(2)O(2)-induced stress. AB - Mangiferin is a natural xanthonoid with various biological activities. Quantification of mangiferin in fruit peel, pulp, and seed kernel was carried out in 11 Chinese mango (Mangifera indica L.) cultivars. The highest mangiferin content was found in the peel of Lvpimang (LPM) fruit (7.49 mg/g DW). Efficient purification of mangiferin from mango fruit peel was then established for the first time by combination of macroporous HPD100 resin chromatography with optimized high-speed counter-current chromatography (HSCCC). Purified mangiferin was identified by both HPLC and LC-MS, and it showed higher DPPH(*) free-radical scavenging capacities and ferric reducing ability of plasma (FRAP) than by l ascorbic acid (Vc) or Trolox. In addition, it showed significant protective effects on human umbilical vein endothelial cells (HUVEC) under H(2)O(2)-induced stress. Cells treated with mangiferin resulted in significant enhanced cell survival under of H(2)O(2) stress. Therefore, mangiferin from mango fruit provides a promising perspective for the prevention of oxidative stress associated diseases. PMID- 23109852 TI - Determination and analysis of ustiloxins A and B by LC-ESI-MS and HPLC in false smut balls of rice. AB - Ustiloxins are cyclopeptide mycotoxins produced by the pathogenic fungus Villosiclava virens of rice false smut. Ustiloxins A and B as two main mycotoxins were determined conveniently by LC-ESI-MS in the water extract from rice false smut balls which were mostly composed of the chlamydospores and mycelia of the pathogen. Both ustiloxins A and B in the water extract were also quantitatively analyzed by HPLC. This is the first report on the determination and analysis of ustiloxins A and B simultaneously by LC-ESI-MS and HPLC in false smut balls of rice. PMID- 23109854 TI - Optimization of supercritical CO(2) extraction of fish oil from viscera of African Catfish (Clarias gariepinus). AB - Fish oil was extracted from the viscera of African Catfish using supercritical carbon dioxide (SC-CO(2)). A Central Composite Design of Response Surface methodology (RSM) was employed to optimize the SC-CO(2) extraction parameters. The oil yield (Y) as response variable was executed against the four independent variables, namely pressure, temperature, flow rate and soaking time. The oil yield varied with the linear, quadratic and interaction of pressure, temperature, flow rate and soaking time. Optimum points were observed within the variables of temperature from 35 degrees C to 80 degrees C, pressure from 10 MPa to 40 MPa, flow rate from 1 mL/min to 3 mL/min and soaking time from 1 h to 4 h. However, the extraction parameters were found to be optimized at temperature 57.5 degrees C, pressure 40 MPa, flow rate 2.0 mL/min and soaking time 2.5 h. At this optimized condition, the highest oil yields were found to be 67.0% (g oil/100 g sample on dry basis) in the viscera of catfish which was reasonable to the yields of 78.0% extracted using the Soxhlet method. PMID- 23109853 TI - Asymmetric dimethylarginine, endothelial dysfunction and renal disease. AB - l-Arginine (Arg) is oxidized to l-citrulline and nitric oxide (NO) by the action of endothelial nitric oxide synthase (NOS). In contrast, protein-incorporated Arg residues can be methylated with subsequent proteolysis giving rise to methylarginine compounds, such as asymmetric dimethylarginine (ADMA) that competes with Arg for binding to NOS. Most ADMA is degraded by dimethylarginine dimethyaminohydrolase (DDAH), distributed widely throughout the body and regulates ADMA levels and, therefore, NO synthesis. In recent years, several studies have suggested that increased ADMA levels are a marker of atherosclerotic change, and can be used to assess cardiovascular risk, consistent with ADMA being predominantly absorbed by endothelial cells. NO is an important messenger molecule involved in numerous biological processes, and its activity is essential to understand both pathogenic and therapeutic mechanisms in kidney disease and renal transplantation. NO production is reduced in renal patients because of their elevated ADMA levels with associated reduced DDAH activity. These factors contribute to endothelial dysfunction, oxidative stress and the progression of renal damage, but there are treatments that may effectively reduce ADMA levels in patients with kidney disease. Available data on ADMA levels in controls and renal patients, both in adults and children, also are summarized in this review. PMID- 23109855 TI - A novel collection of snRNA-like promoters with tissue-specific transcription properties. AB - We recently identified a novel dataset of snRNA-like trascriptional units in the human genome. The investigation of a subset of these elements showed that they play relevant roles in physiology and/or pathology. In this work we expand our collection of small RNAs taking advantage of a newly developed algorithm able to identify genome sequence stretches with RNA polymerase (pol) III type 3 promoter features thus constituting putative pol III binding sites. The bioinformatic analysis of a subset of these elements that map in introns of protein-coding genes in antisense configuration suggest their association with alternative splicing, similarly to other recently characterized small RNAs. Interestingly, the analysis of the transcriptional activity of these novel promoters shows that they are active in a cell-type specific manner, in accordance with the emerging body of evidence of a tissue/cell-specific activity of pol III. PMID- 23109856 TI - An imprinted cross-linked enzyme aggregate (iCLEA) of sucrose phosphorylase: combining improved stability with altered specificity. AB - The industrial use of sucrose phosphorylase (SP), an interesting biocatalyst for the selective transfer of alpha-glucosyl residues to various acceptor molecules, has been hampered by a lack of long-term stability and low activity towards alternative substrates. We have recently shown that the stability of the SP from Bifidobacterium adolescentis can be significantly improved by the formation of a cross-linked enzyme aggregate (CLEA). In this work, it is shown that the transglucosylation activity of such a CLEA can also be improved by molecular imprinting with a suitable substrate. To obtain proof of concept, SP was imprinted with alpha-glucosyl glycerol and subsequently cross-linked with glutaraldehyde. As a consequence, the enzyme's specific activity towards glycerol as acceptor substrate was increased two-fold while simultaneously providing an exceptional stability at 60 degrees C. This procedure can be performed in an aqueous environment and gives rise to a new enzyme formulation called iCLEA. PMID- 23109857 TI - Isolation and characterization of microsatellite markers for Passiflora contracta. AB - Passiflora contracta Vitta (Passifloraceae) is an endemic species of the Atlantic Rainforest, one of the most species-rich ecoregions in the world, although extremely endangered. We have developed an enriched microsatellite library in order to fine-scale studies of the genetic structure of P. contracta. Twelve pairs of microsatellite primers were designed, and seven loci were successfully amplified and characterized by genotyping two wild populations of P. contracta. All seven loci were polymorphic, with an average number of alleles found being 4.8 and 5 per population. The cross-species transferability was tested using sister species Passiflora ovalis Vell. Ex Roemer. The development of these markers will contribute to the studies of population genetics in P. contracta as well as future studies concerning diversity patterns in the Atlantic Rainforest, and may also help to establish strategies for the conservation of this species. PMID- 23109858 TI - Phenolic compounds from Halimodendron halodendron (Pall.) voss and their antimicrobial and antioxidant activities. AB - Halimodendron halodendron has been used as forage in northwestern China for a long time. Its young leaves and flowers are edible and favored by indigenous people. In this study, eleven phenolic compounds were bioassay-guided and isolated from the aerial parts of H. halodendron for the first time. They were identified by means of physicochemical and spectrometric analysis as quercetin (1), 3,5,7,8,4'-pentahydroxy-3'-methoxy flavone (2), 3-O-methylquercetin (3), 3,3'-di-O-methylquercetin (4), 3,3'-di-O-methylquercetin-7-O-beta-d glucopyranoside (5), isorhamentin-3-O-beta-d-rutinoside (6), 8-O-methylretusin (7), 8-O-methylretusin-7-O-beta-d-glucopyranoside (8), salicylic acid (9), p hydroxybenzoic acid (ferulic acid) (10), and 4-hydroxy-3-methoxy cinnamic acid (11). They were sorted as flavonols (1-6), soflavones (7 and 8), and phenolic acids (9-11). Among the compounds, flanools 1-4 revealed a strong antibacterial activity with minimum inhibitory concentration (MIC) values of 50-150 MUg/mL, and median inhibitory concentration (IC(50)) values of 26.8-125.1 MUg/mL. The two isoflavones (7 and 8) showed moderate inhibitory activity on the test bacteria. Three phenolic acids (9, 10 and 11) showed strong antibacterial activity with IC(50) values of 28.1-149.7 MUg/mL. Antifungal activities of the compounds were similar to their antibacterial activities. All these phenolic compounds showed significant antimicrobial activity with a broad spectrum as well as antioxidant activity based on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging and beta-carotene-linoleic acid bleaching assays. In general, the flavonol aglycones with relatively low polarity exhibited stronger activities than the glycosides. The results suggest the potential of this plant as a source of functional food ingredients and provide support data for its utilization as forage as well. PMID- 23109859 TI - Optimization of ligninolytic enzyme activity and production rate with Ceriporiopsis subvermispora for application in bioremediation by varying submerged media composition and growth immobilization support. AB - Response surface methodology (central composite design of experiments) was employed to simultaneously optimize enzyme production and productivities of two ligninolytic enzymes produced by Ceriporiopsis subvermispora. Concentrations of glucose, ammonium tartrate and Polysorbate 80 were varied to establish the optimal composition of liquid media (OLM), where the highest experimentally obtained activities and productivities were 41 U L(-1) and 16 U L(-1) day(-1) for laccase (Lac), and 193 U L(-1) and 80 U L(-1) day(-1) for manganese peroxidase (MnP). Considering culture growth in OLM on various types of immobilization support, the best results were obtained with 1 cm beech wood cubes (BWCM). Enzyme activities in culture filtrate were 152 U L(-1) for Lac and 58 U L(-1) for MnP, since the chemical composition of this immobilization material induced higher Lac activity. Lower enzyme activities were obtained with polyurethane foam. Culture filtrates of OLM and BWCM were applied for dye decolorization. Remazol Brilliant Blue R (RBBR) was decolorized faster and more efficiently than Copper(II)phthalocyanine (CuP) with BWCM (80% and 60%), since Lac played a crucial role. Decolorization of CuP was initially faster than that of RBBR, due to higher MnP activities in OLM. The extent of decolorization after 14 h was 60% for both dyes. PMID- 23109860 TI - Molecular cloning and functional analysis of Three FLOWERING LOCUS T (FT) homologous genes from Chinese Cymbidium. AB - The FLOWERING LOCUS T (FT) gene plays crucial roles in regulating the transition from the vegetative to reproductive phase. To understand the molecular mechanism of reproduction, three homologous FT genes were isolated and characterized from Cymbidium sinense "Qi Jian Bai Mo", Cymbidium goeringii and Cymbidium ensifolium "Jin Si Ma Wei". The three genes contained 618-bp nucleotides with a 531-bp open reading frame (ORF) of encoding 176 amino acids (AAs). Alignment of the AA sequences revealed that CsFT, CgFT and CeFT contain a conserved domain, which is characteristic of the PEBP-RKIP superfamily, and which share high identity with FT of other plants in GenBank: 94% with OnFT from Oncidium Gower Ramsey, 79% with Hd3a from Oryza sativa, and 74% with FT from Arabidopsis thaliana. qRT-PCR analysis showed a diurnal expression pattern of CsFT, CgFT and CeFT following both long day (LD, 16-h light/8-h dark) and short day (SD, 8-h light/16-h dark) treatment. While the transcripts of both CsFT and CeFT under LD were significantly higher than under SD, those of CgFT were higher under SD. Ectopic expression of CgFT in transgenic Arabidopsis plants resulted in early flowering compared to wild-type plants and significant up-regulation of APETALA1 (AP1) expression. Our data indicates that CgFT is a putative phosphatidylethanolamine binding protein gene in Cymbidium that may regulate the vegetative to reproductive transition in flowers, similar to its Arabidopsis ortholog. PMID- 23109861 TI - Diamondoid characterization in condensate by comprehensive two-dimensional gas chromatography with time-of-flight mass spectrometry: The Junggar Basin of Northwest China. AB - Diamondoids in crude oil are useful for assessing the maturity of oil in high maturation. However, they are very difficult to separate and accurately quantify by conventional geochemical methods due to their low abundance in oil. In this paper, we use comprehensive two-dimensional gas chromatography with time-of flight mass spectrometry (GC*GC-TOFMS) to study the compounds in condensates from the Junggar Basin of northwest China and address their geological and geochemical applications. GC*GC-TOFMS improves the resolution and separation efficiency of the compounds. It not only separates the compounds that coelute in conventional GC-MS (e.g., 4, 8-dimethyl-diamantane and trimethyl-diamantane) but also allows the identification of compounds that were not previously detected (e.g., trimethyl-diamantane (15A)). A reversed-phase column system improves the separation capabilities over the normal phase column system. The diamondoid indexes indicate that a representative condensate from Well DX 10 is highly mature with equivalent Ro being approximately 1.5%. PMID- 23109862 TI - Medium optimization for exopolysaccharide production in liquid culture of endophytic fungus Berkleasmium sp. Dzf12. AB - Berkleasmium sp. Dzf12, an endophytic fungus from Dioscorea zingiberensis, is a high producer of spirobisnaphthalenes with various bioactivities. The exopolysaccharide (EPS) produced by this fungus also shows excellent antioxidant activity. In this study, the experimental designs based on statistics were employed to evaluate and optimize the medium for EPS production in liquid culture of Berkleasmium sp. Dzf12. For increasing EPS yield, the concentrations of glucose, peptone, KH(2)PO(4), MgSO(4).7H(2)O and FeSO(4).7H(2)O in medium were optimized using response surface methodology (RSM). Both the fractional factorial design (FFD) and central composite design (CCD) were applied to optimize the main factors which significantly affected EPS production. The concentrations of glucose, peptone and MgSO(4).7H(2)O were found to be the main effective factors for EPS production by FFD experimental analysis. Based on the further CCD optimization and RSM analysis, a quadratic polynomial regression equation was derived from the EPS yield and three variables. Statistical analysis showed the polynomial regression model was in good agreement with the experimental results with the determination coefficient (adj-R(2)) as 0.9434. By solving the quadratic regression equation, the optimal concentrations of glucose, peptone and MgSO(4).7H(2)O for EPS production were determined as 63.80, 20.76 and 2.74 g/L, respectively. Under the optimum conditions, the predicted EPS yield reached the maximum (13.22 g/L). Verification experiment confirmed the validity with the actual EPS yield as 13.97 g/L, which was 6.29-fold in comparison with that (2.22 g/L) in the original basal medium. The results provide the support data for EPS production in large scale and also speed up the application of Berkleasmium sp. Dzf12. PMID- 23109863 TI - Antinociceptive action of isolated mitragynine from Mitragyna Speciosa through activation of opioid receptor system. AB - Cannabinoids and opioids systems share numerous pharmacological properties and antinociception is one of them. Previous findings have shown that mitragynine (MG), a major indole alkaloid found in Mitragyna speciosa (MS) can exert its antinociceptive effects through the opioids system. In the present study, the action of MG was investigated as the antinociceptive agent acting on Cannabinoid receptor type 1 (CB1) and effects on the opioids receptor. The latency time was recorded until the mice showed pain responses such as shaking, licking or jumping and the duration of latency was measured for 2 h at every 15 min interval by hot plate analysis. To investigate the beneficial effects of MG as antinociceptive agent, it was administered intraperitoneally 15 min prior to pain induction with a single dosage (3, 10, 15, 30, and 35 mg/kg b.wt). In this investigation, 35 mg/kg of MG showed significant increase in the latency time and this dosage was used in the antagonist receptor study. The treated groups were administered with AM251 (cannabinoid receptor-1 antagonist), naloxone (non-selective opioid antagonist), naltrindole (delta-opioid antagonist) naloxonazine (MU(1)-receptor antagonist) and norbinaltorpimine (kappa-opioid antagonist) respectively, prior to administration of MG (35 mg/kg). The results showed that the antinociceptive effect of MG was not antagonized by AM251; naloxone and naltrindole were effectively blocked; and norbinaltorpimine partially blocked the antinociceptive effect of MG. Naloxonazine did inhibit the effect of MG, but it was not statistically significant. These results demonstrate that CB1 does not directly have a role in the antinociceptive action of MG where the effect was observed with the activation of opioid receptor. PMID- 23109864 TI - Combining the physical adsorption approach and the covalent attachment method to prepare a bifunctional bioreactor. AB - Aminopropyl-functionalized SBA-15 mesoporous silica was used as a support to adsorb myoglobin. Then, in order to avoid the leakage of adsorbed myoglobin, lysozyme was covalently tethered to the internal and external surface of the mesoporous silica with glutaraldehyde as the coupling agent. The property of amino-functionalized mesoporous silica was characterized by N(2) adsorption desorption and thermogravimetric (TG) analysis. The feature of the silica-based matrix before and after myoglobin adsorption was identified by fourier transform infrared (FTIR) and UV/VIS measurement. With o-dianisidine and H(2)O(2) as the substrate, the peroxidase activity of adsorbed myoglobin was determined. With Micrococus lysodeilicus as the substrate, the antibacterial activity of covalently tethered lysozyme was measured. Results demonstrated that the final product not only presented peroxidase activity of the myoglobin but yielded antibacterial activity of the lysozyme. PMID- 23109865 TI - Maternal phylogeny of a newly-found yak population in china. AB - The Jinchuan yak is a new yak population identified in Sichuan, China. This population has a special anatomical characteristic: an additional pair of ribs compared with other yak breeds. The genetic structure of this population is unknown. In the present study, we investigated the maternal phylogeny of this special yak population using the mitochondrial DNA variation. A total of 23 Jinchuan yaks were sequenced for a 823-bp fragment of D-loop control region and three individuals were sequenced for the whole mtDNA genome with a length of 16,371-bp. To compare with the data from other yaks, we extracted sequence data from Genebank, including D-loop of 398 yaks (from 12 breeds) and 55 wild yaks, and whole mitochondrial genomes of 53 yaks (from 12 breeds) and 21 wild yaks. A total of 127 haplotypes were defined, based on the D-loop data. Thirteen haplotypes were defined from 23 mtDNA D-loop sequences of Jinchuan yaks, six of which were shared only by Jinchuan, and one was shared by Jinchuan and wild yaks. The Jinquan yaks were found to carry clades A and B from lineage I and clade C of lineage II, respectively. It was also suggested that the Jinchuan population has no distinct different phylogenetic relationship in maternal inheritance with other breeds of yak. The highly haplotype diversity of the Pali breed, Jinchuan population, Maiwa breed and Jiulong breed suggested that the yak was first domesticated from wild yaks in the middle Himalayan region and the northern Hengduan Mountains. The special anatomic characteristic that we found in the Jinchuan population needs further studies based on nuclear data. PMID- 23109867 TI - Characterization of Erysiphe necator-responsive genes in Chinese Wild Vitis quinquangularis. AB - Powdery mildew (PM), caused by fungus Erysiphe necator, is one of the most devastating diseases of grapevine. To better understand grapevine-PM interaction and provide candidate resources for grapevine breeding, a suppression subtractive hybridization (SSH) cDNA library was constructed from E. necator-infected leaves of a resistant Chinese wild Vitis quinquangularis clone "Shang-24". A total of 492 high quality expressed sequence tags (ESTs) were obtained and assembled into 266 unigenes. Gene ontology (GO) analysis indicated that 188 unigenes could be assigned with at least one GO term in the biological process category, and 176 in the molecular function category. Sequence analysis showed that a large number of these genes were homologous to those involved in defense responses. Genes involved in metabolism, photosynthesis, transport and signal transduction were also enriched in the library. Expression analysis of 13 selected genes by qRT-PCR revealed that most were induced more quickly and intensely in the resistant material "Shang-24" than in the sensitive V. pseudoreticulata clone "Hunan-1" by E. necator infection. The ESTs reported here provide new clues to understand the disease-resistance mechanism in Chinese wild grapevine species and may enable us to investigate E. necator-responsive genes involved in PM resistance in grapevine germplasm. PMID- 23109866 TI - Personalized targeted therapy for lung cancer. AB - Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients. PMID- 23109868 TI - New 14-membered cyclopeptide alkaloids from Zizyphus oxyphylla Edgew. AB - Two new 14-membered cyclopeptide alkaloids, Oxyphylline B (4) and Oxyphylline C (5), along with three known 13-membered cyclopeptide alkaloids, were isolated from stem and roots of Zizyphus oxyphylla Edgew. The compounds were tested for antibacterial activity. Oxyphylline B (4) showed comparatively better antibacterial activities against Escherichia coli (MIC, 5 MUg/mL) than other compounds. This compound also exhibited weak antimicrobial activities against Staphylococcus aureus (MIC, 25 MUg/mL), Pseudomonas aeruginosa (MIC, 50 MUg/mL) and Salmonella typhi (MIC, 50 MUg/mL). PMID- 23109869 TI - Effects of sorafenib on C-terminally truncated androgen receptor variants in human prostate cancer cells. AB - Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARDeltaLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARDeltaLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARDeltaLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARDeltaLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR positive PCa. PMID- 23109870 TI - alpha-Tocopherol at nanomolar concentration protects PC12 cells from hydrogen peroxide-induced death and modulates protein kinase activities. AB - The aim of this work was to compare protective and anti-apoptotic effects of alpha-tocopherol at nanomolar and micromolar concentrations against 0.2 mM H(2)O(2)-induced toxicity in the PC12 neuronal cell line and to reveal protein kinases that contribute to alpha-tocopherol protective action. The protection by 100 nM alpha-tocopherol against H(2)O(2)-induced PC12 cell death was pronounced if the time of pre-incubation with alpha-tocopherol was 3-18 h. For the first time, the protective effect of alpha-tocopherol was shown to depend on its concentration in the nanomolar range (1 nM < 10 nM < 100 nM), if the pre incubation time was 18 h. Nanomolar and micromolar alpha-tocopherol decreased the number of PC12 cells in late apoptosis induced by H(2)O(2) to the same extent if pre-incubation time was 18 h. Immunoblotting data showed that alpha-tocopherol markedly diminished the time of maximal activation of extracellular signal regulated kinase 1/2 (ERK 1/2) and protein kinase B (Akt)-induced in PC12 cells by H(2)O(2). Inhibitors of MEK 1/2, PI 3-kinase and protein kinase C (PKC) diminished the protective effect of alpha-tocopherol against H(2)O(2)-initiated toxicity if the pre-incubation time was long. The modulation of ERK 1/2, Akt and PKC activities appears to participate in the protection by alpha-tocopherol against H(2)O(2)-induced death of PC12 cells. The data obtained suggest that inhibition by alpha-tocopherol in late stage ERK 1/2 and Akt activation induced by H(2)O(2) in PC12 cells makes contribution to its protective effect, while total inhibition of these enzymes is not protective. PMID- 23109871 TI - Is DNA damage response ready for action anywhere? AB - Organisms are continuously exposed to DNA damaging agents, consequently, cells have developed an intricate system known as the DNA damage response (DDR) in order to detect and repair DNA lesions. This response has to be rapid and accurate in order to keep genome integrity. It has been observed that the condensation state of chromatin hinders a proper DDR. However, the condensation state of chromatin is not the only barrier to DDR. In this review, we have collected data regarding the presence of DDR factors on micronuclear DNA lesions that indicate that micronuclei are almost incapable of generating an effective DDR because of defects in their nuclear envelope. Finally, considering the recent observations about the reincorporation of micronuclei to the main bulk of chromosomes, we suggest that, under certain circumstances, micronuclei carrying DNA damage might be a source of chromosome instability. PMID- 23109872 TI - Possible alterations in beta-Synuclein, the non-amyloidogenic homologue of alpha Synuclein, during progression of sporadic alpha-synucleinopathies. AB - alpha-Synucleinopathies are neurodegenerative disorders that are characterized by progressive decline of motor and non-motor dysfunctions. alpha-Synuclein (alphaS) has been shown to play a causative role in neurodegeneration, but the pathogenic mechanisms are still unclear. Thus, there are no radical therapies that can halt or reverse the disease's progression. beta-Synuclein (betaS), the non amyloidogenic homologue of alphaS, ameliorates the neurodegeneration phenotype of alphaS in transgenic (tg) mouse models, as well as in cell free and cell culture systems, which suggests that betaS might be a negative regulator of neurodegeneration caused by alphaS, and that "loss of function" of betaS might be involved in progression of alpha-synucleinopathies. Alternatively, it is possible that "toxic gain of function" of wild type betaS occurs during the pathogenesis of sporadic alpha-synucleinopathies, since tg mice expressing dementia with Lewy bodies-linked P123H betaS develop progressive neurodegeneration phenotypes, such as axonal pathology and dementia. In this short review, we emphasize the aspects of "toxic gain of function" of wild type betaS during the pathogenesis of sporadic alpha-synucleinopathies. PMID- 23109873 TI - Use of biotinylated ubiquitin for analysis of rat brain mitochondrial proteome and interactome. AB - Applicability of in vitro biotinylated ubiquitin for evaluation of endogenous ubiquitin conjugation and analysis of ubiquitin-associated protein-protein interactions has been investigated. Incubation of rat brain mitochondria with biotinylated ubiquitin followed by affinity chromatography on avidin-agarose, intensive washing, tryptic digestion of proteins bound to the affinity sorbent and their mass spectrometry analysis resulted in reliable identification of 50 proteins belonging to mitochondrial and extramitochondrial compartments. Since all these proteins were bound to avidin-agarose only after preincubation of the mitochondrial fraction with biotinylated ubiquitin, they could therefore be referred to as specifically bound proteins. A search for specific ubiquitination signature masses revealed several extramitochondrial and intramitochondrial ubiquitinated proteins representing about 20% of total number of proteins bound to avidin-agarose. The interactome analysis suggests that the identified non ubiquitinated proteins obviously form tight complexes either with ubiquitinated proteins or with their partners and/or mitochondrial membrane components. Results of the present study demonstrate that the use of biotinylated ubiquitin may be considered as the method of choice for in vitro evaluation of endogenous ubiquitin-conjugating machinery in particular subcellular organelles and changes in ubiquitin/organelle associated interactomes. This may be useful for evaluation of changes in interactomes induced by protein ubiquitination under norm and various brain pathologies. PMID- 23109874 TI - Experimental aspects of colloidal interactions in mixed systems of liposome and inorganic nanoparticle and their applications. AB - In the past few years, growing attention has been devoted to the study of the interactions taking place in mixed systems of phospholipid membranes (for instance in the form of vesicles) and hard nanoparticles (NPs). In this context liposomes (vesicles) may serve as versatile carriers or as a model system for biological membranes. Research on these systems has led to the observation of novel hybrid structures whose morphology strongly depends on the charge, composition and size of the interacting colloidal species as well as on the nature (pH, ionic strength) of their dispersing medium. A central role is played by the phase behaviour of phospholipid bilayers which have a tremendous influence on the liposome properties. Another central aspect is the incorporation of nanoparticles into vesicles, which is intimately linked to the conditions required for transporting a nanoparticle through a membrane. Herein, we review recent progress made on the investigations of the interactions in liposome/nanoparticle systems focusing on the particularly interesting structures that are formed in these hybrid systems as well as their potential applications. PMID- 23109876 TI - Combination of oxyanion Gln114 mutation and medium engineering to influence the enantioselectivity of thermophilic lipase from Geobacillus zalihae. AB - The substitution of the oxyanion Q114 with Met and Leu was carried out to investigate the role of Q114 in imparting enantioselectivity on T1 lipase. The mutation improved enantioselectivity in Q114M over the wild-type, while enantioselectivity in Q114L was reduced. The enantioselectivity of the thermophilic lipases, T1, Q114L and Q114M correlated better with log p as compared to the dielectric constant and dipole moment of the solvents. Enzyme activity was good in solvents with log p < 3.5, with the exception of hexane which deviated substantially. Isooctane was found to be the best solvent for the esterification of (R,S)-ibuprofen with oleyl alcohol for lipases Q114M and Q114L, to afford E values of 53.7 and 12.2, respectively. Selectivity of T1 was highest in tetradecane with E value 49.2. Solvents with low log p reduced overall lipase activity and dimethyl sulfoxide (DMSO) completely inhibited the lipases. Ester conversions, however, were still low. Molecular sieves employed as desiccant were found to adversely affect catalysis in the lipase variants, particularly in Q114M. The higher desiccant loading also increased viscosity in the reaction and further reduced the efficiency of the lipase-catalyzed esterifications. PMID- 23109875 TI - Optimization to low temperature activity in psychrophilic enzymes. AB - Psychrophiles, i.e., organisms thriving permanently at near-zero temperatures, synthesize cold-active enzymes to sustain their cell cycle. These enzymes are already used in many biotechnological applications requiring high activity at mild temperatures or fast heat-inactivation rate. Most psychrophilic enzymes optimize a high activity at low temperature at the expense of substrate affinity, therefore reducing the free energy barrier of the transition state. Furthermore, a weak temperature dependence of activity ensures moderate reduction of the catalytic activity in the cold. In these naturally evolved enzymes, the optimization to low temperature activity is reached via destabilization of the structures bearing the active site or by destabilization of the whole molecule. This involves a reduction in the number and strength of all types of weak interactions or the disappearance of stability factors, resulting in improved dynamics of active site residues in the cold. Considering the subtle structural adjustments required for low temperature activity, directed evolution appears to be the most suitable methodology to engineer cold activity in biological catalysts. PMID- 23109877 TI - Cellular delivery of doxorubicin via pH-controlled hydrazone linkage using multifunctional nano vehicle based on poly(beta-l-malic acid). AB - Doxorubicin (DOX) is currently used in cancer chemotherapy to treat many tumors and shows improved delivery, reduced toxicity and higher treatment efficacy when being part of nanoscale delivery systems. However, a major drawback remains its toxicity to healthy tissue and the development of multi-drug resistance during prolonged treatment. This is why in our work we aimed to improve DOX delivery and reduce the toxicity by chemical conjugation with a new nanoplatform based on polymalic acid. For delivery into recipient cancer cells, DOX was conjugated via pH-sensitive hydrazone linkage along with polyethylene glycol (PEG) to a biodegradable, non-toxic and non-immunogenic nanoconjugate platform: poly(beta-l malic acid) (PMLA). DOX-nanoconjugates were found stable under physiological conditions and shown to successfully inhibit in vitro cancer cell growth of several invasive breast carcinoma cell lines such as MDA-MB-231 and MDA-MB- 468 and of primary glioma cell lines such as U87MG and U251. PMID- 23109878 TI - High yield of wax ester synthesized from cetyl alcohol and octanoic acid by lipozyme RMIM and Novozym 435. AB - Wax esters are long-chain esters that have been widely applied in premium lubricants, parting agents, antifoaming agents and cosmetics. In this study, the biocatalytic preparation of a specific wax ester, cetyl octanoate, is performed in n-hexane using two commercial immobilized lipases, i.e., Lipozyme((r)) RMIM (Rhizomucor miehei) and Novozym((r)) 435 (Candida antarctica). Response surface methodology (RSM) and 5-level-4-factor central composite rotatable design (CCRD) are employed to evaluate the effects of reaction time (1-5 h), reaction temperature (45-65 degrees C), substrate molar ratio (1-3:1), and enzyme amount (10%-50%) on the yield of cetyl octanoate. Using RSM to optimize the reaction, the maximum yields reached 94% and 98% using Lipozyme((r)) RMIM and Novozym((r)) 435, respectively. The optimum conditions for synthesis of cetyl octanoate by both lipases are established and compared. Novozym((r)) 435 proves to be a more efficient biocatalyst than Lipozyme((r)) RMIM. PMID- 23109879 TI - Mechanisms of ovarian cancer metastasis: biochemical pathways. AB - Ovarian cancer is the most lethal gynecologic malignancy. Despite advances in chemotherapy, the five-year survival rate of advanced ovarian cancer patients with peritoneal metastasis remains around 30%. The most significant prognostic factor is stage, and most patients present at an advanced stage with peritoneal dissemination. There is often no clearly identifiable precursor lesion; therefore, the events leading to metastatic disease are poorly understood. This article reviews metastatic suppressor genes, the epithelial-mesenchymal transition (EMT), and the tumor microenvironment as they relate to ovarian cancer metastasis. Additionally, novel chemotherapeutic agents targeting the metastasis related biochemical pathways are discussed. PMID- 23109882 TI - Protective effect of anthocyanin from Lonicera Caerulea var. Edulis on radiation induced damage in mice. AB - The radioprotective effect of anthocyanin extracted from Lonicera caerulea var. edulis (ALC), was studied in ICR mice. Different doses of ALC were intragastrically administered to mice once a day, prior to radiation. After two weeks, the mice received a one-time 5 Gy whole body (60)Cogamma radiation. The spleen index, thymus index, activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), malondialdehyde (MDA) content, and glutathione (GSH) content in liver tissue were measured. Compared with the radiation control group, the levels of MDA in all ALC treated groups decreased significantly (p < 0.05). Moreover, the GSH content, activities of SOD and GSH-Px in liver tissue were enhanced significantly (p < 0.05) in all ALC groups. These results demonstrate that ALC may be a potential radioprotector, and a further study of the molecular mechanism is needed for further application. PMID- 23109881 TI - Neuroprotection for stroke: current status and future perspectives. AB - Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY 059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade. PMID- 23109880 TI - Environmental risk factors for multiple sclerosis: a review with a focus on molecular mechanisms. AB - Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and oligodendrocyte loss. There is a global latitude gradient in MS prevalence, and incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in causation of disease. We have reviewed the evidence and potential mechanisms of action for three exposures: vitamin D, Epstein Barr virus and cigarette smoking. Recent advances supporting gene-environment interactions are reviewed. Further research is needed to establish mechanisms of causality in humans and to explore preventative strategies. PMID- 23109883 TI - Mechanisms of oxidative damage in multiple sclerosis and neurodegenerative diseases: therapeutic modulation via fumaric acid esters. AB - Oxidative stress plays a crucial role in many neurodegenerative conditions such as Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's as well as Huntington's disease. Inflammation and oxidative stress are also thought to promote tissue damage in multiple sclerosis (MS). Recent data point at an important role of anti-oxidative pathways for tissue protection in chronic progressive MS, particularly involving the transcription factor nuclear factor (erythroid-derived 2)-related factor 2 (Nrf2). Thus, novel therapeutics enhancing cellular resistance to free radicals could prove useful for MS treatment. Here, fumaric acid esters (FAE) are a new, orally available treatment option which had already been tested in phase II/III MS trials demonstrating beneficial effects on relapse rates and magnetic resonance imaging markers. In vitro, application of dimethylfumarate (DMF) leads to stabilization of Nrf2, activation of Nrf2 dependent transcriptional activity and abundant synthesis of detoxifying proteins. Furthermore, application of FAE involves direct modification of the inhibitor of Nrf2, Kelch-like ECH-associated protein 1. On cellular levels, the application of FAE enhances neuronal survival and protects astrocytes against oxidative stress. Increased levels of Nrf2 are detected in the central nervous system of DMF treated mice suffering from experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In EAE, DMF ameliorates the disease course and improves preservation of myelin, axons and neurons. Finally, Nrf2 is also up-regulated in the spinal cord of autopsy specimens from untreated patients with MS, probably as part of a naturally occurring anti-oxidative response. In summary, oxidative stress and anti-oxidative pathways are important players in MS pathophysiology and constitute a promising target for future MS therapies like FAE. PMID- 23109885 TI - Studies on the interactions of copper and zinc ions with beta-amyloid peptides by a surface plasmon resonance biosensor. AB - The aggregation of beta-amyloid peptide (Abeta) into fibrils plays an important role in the pathogenesis of Alzheimer's disease (AD). Metal ions including copper and zinc are closely connected to the precipitation and toxicity of Abeta. In this study, a surface plasmon resonance (SPR) biosensor was constructed to investigate the interactions between Abeta and metal ions. Abeta peptide was immobilized on the SPR chip surface through a preformed alkanethiol self assembled monolayer (SAM). Our observations indicate that the immobilized Abeta undergoes a conformational change upon exposure to the metal ions. A difference in metal binding affinity between Abeta(1-28) and Abeta(1-42) was also detected. The results suggest that SPR is an effective method to characterize the interactions between Abeta and metal ions. PMID- 23109884 TI - Modification by ubiquitin-like proteins: significance in apoptosis and autophagy pathways. AB - Ubiquitin-like proteins (Ubls) confer diverse functions on their target proteins. The modified proteins are involved in various biological processes, including DNA replication, signal transduction, cell cycle control, embryogenesis, cytoskeletal regulation, metabolism, stress response, homeostasis and mRNA processing. Modifiers such as SUMO, ATG12, ISG15, FAT10, URM1, and UFM have been shown to modify proteins thus conferring functions related to programmed cell death, autophagy and regulation of the immune system. Putative modifiers such as Domain With No Name (DWNN) have been identified in recent times but not fully characterized. In this review, we focus on cellular processes involving human Ubls and their targets. We review current progress in targeting these modifiers for drug design strategies. PMID- 23109887 TI - Microsatellite loci in the Gypsophyte Lepidium subulatum (Brassicaceae), and transferability to other Lepidieae. AB - Polymorphic microsatellite markers were developed for the Ibero-North African, strict gypsophyte Lepidium subulatum to unravel the effects of habitat fragmentation in levels of genetic diversity, genetic structure and gene flow among its populations. Using 454 pyrosequencing 12 microsatellite loci including di- and tri-nucleotide repeats were characterized in L. subulatum. They amplified a total of 80 alleles (2-12 alleles per locus) in a sample of 35 individuals of L. subulatum, showing relatively high levels of genetic diversity, H(O) = 0.645, H(E) = 0.627. Cross-species transferability of all 12 loci was successful for the Iberian endemics Lepidium cardamines, Lepidium stylatum, and the widespread, Lepidium graminifolium and one species each of two related genera, Cardaria draba and Coronopus didymus. These microsatellite primers will be useful to investigate genetic diversity, population structure and to address conservation genetics in species of Lepidium. PMID- 23109886 TI - The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. AB - Over recent decades, a deep understanding of pathways that repair DNA double strand breaks (DSB) has been gained from biochemical, structural, biophysical and cellular studies. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent the two major DSB repair pathways, and both processes are now well understood. Recent work has demonstrated that the chromatin environment at a DSB significantly impacts upon DSB repair and that, moreover, dramatic modifications arise in the chromatin surrounding a DSB. Chromatin is broadly divided into open, transcriptionally active, euchromatin (EC) and highly compacted, transcriptionally inert, heterochromatin (HC), although these represent extremes of a spectrum. The HC superstructure restricts both DSB repair and damage response signaling. Moreover, DSBs within HC (HC-DSBs) are rapidly relocalized to the EC-HC interface. The damage response protein kinase, ataxia telangiectasia mutated (ATM), is required for HC-DSB repair but is dispensable for the relocalization of HC-DSBs. It has been proposed that ATM signaling enhances HC relaxation in the DSB vicinity and that this is a prerequisite for HC-DSB repair. Hence, ATM is essential for repair of HC-DSBs. Here, we discuss how HC impacts upon the response to DSBs and how ATM overcomes the barrier that HC poses to repair. PMID- 23109888 TI - Polystyrene attached Pt(IV)-azomethine, synthesis and immmobilization of glucose oxidase enzyme. AB - Modified polystyrene with Pt(IV)-azomethine (APS-Sch-Pt) was synthesized by means of condensation and demonstrated to be a promising enzyme support by studying the enzymatic properties of glucose oxidase enzyme (GOx) immobilized on it. The characteristics of the immobilized glucose oxidase (APS-Sch-Pt-GOx) enzyme showed two optimum pH values that were pH = 4.0 and pH = 7. The insertion of stable Pt(IV)-azomethine spacers between the polystyrene backbone and the immobilized GOx, (APS-Sch-Pt-GOx), increases the enzymes' activity and improves their affinity towards the substrate even at pH = 4. The influence of temperature, reusability and storage capacity on the free and immobilized glucose oxidase enzyme was investigated. The storage stability of the immobilized glucose oxidase was shown to be eleven months in dry conditions at +4 degrees C. PMID- 23109889 TI - Encapsulation-induced stress helps Saccharomyces cerevisiae resist convertible Lignocellulose derived inhibitors. AB - The ability of macroencapsulated Saccharomyces cerevisiae CBS8066 to withstand readily and not readily in situ convertible lignocellulose-derived inhibitors was investigated in anaerobic batch cultivations. It was shown that encapsulation increased the tolerance against readily convertible furan aldehyde inhibitors and to dilute acid spruce hydrolysate, but not to organic acid inhibitors that cannot be metabolized anaerobically. Gene expression analysis showed that the protective effect arising from the encapsulation is evident also on the transcriptome level, as the expression of the stress-related genes YAP1, ATR1 and FLR1 was induced upon encapsulation. The transcript levels were increased due to encapsulation already in the medium without added inhibitors, indicating that the cells sensed low stress level arising from the encapsulation itself. We present a model, where the stress response is induced by nutrient limitation, that this helps the cells to cope with the increased stress added by a toxic medium, and that superficial cells in the capsules degrade convertible inhibitors, alleviating the inhibition for the cells deeper in the capsule. PMID- 23109890 TI - Chromatin dynamics during nucleotide excision repair: histones on the move. AB - It has been a long-standing question how DNA damage repair proceeds in a nuclear environment where DNA is packaged into chromatin. Several decades of analysis combining in vitro and in vivo studies in various model organisms ranging from yeast to human have markedly increased our understanding of the mechanisms underlying chromatin disorganization upon damage detection and re-assembly after repair. Here, we review the methods that have been developed over the years to delineate chromatin alterations in response to DNA damage by focusing on the well characterized Nucleotide Excision Repair (NER) pathway. We also highlight how these methods have provided key mechanistic insight into histone dynamics coupled to repair in mammals, raising new issues about the maintenance of chromatin integrity. In particular, we discuss how NER factors and central players in chromatin dynamics such as histone modifiers, nucleosome remodeling factors, and histone chaperones function to mobilize histones during repair. PMID- 23109891 TI - Ethyl gallate induces apoptosis of HL-60 cells by promoting the expression of caspases-8, -9, -3, apoptosis-inducing factor and endonuclease G. AB - Many phytochemicals have been recognized to have potential therapeutic efficacy in cancer treatment. In this study, we investigated ethyl gallate (EG) for possible proapoptotic effects in the human promyelocytic leukemia cell line, HL 60. We examined cell viability, morphological changes, DNA content and fragmentation, and expression of apoptosis-related proteins for up to 48 h after EG treatment. The results showed that EG induced morphological changes and DNA fragmentation and reduced HL-60 cell viability in a dose-dependent and time dependent manner. Western blotting analysis indicated that EG-mediated HL-60 apoptosis mainly occurred through the mitochondrial pathway, as shown by the release of cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (Endo G), as well as the upregulation of Bcl-2-associated X protein (Bax). EG also activated the death receptor-dependent pathway of apoptosis by enhancing the expression of caspases-8, -9, and -3 and the Bcl-2 interacting domain (Bid). Collectively, our results showed that EG induces apoptosis in HL-60 via mitochondrial-mediated pathways. PMID- 23109892 TI - A soluble receptor for advanced glycation end-products inhibits hypoxia/reoxygenation-induced apoptosis in rat cardiomyocytes via the mitochondrial pathway. AB - Severe myocardial dysfunction and tissue damage resulting from ischemia/reperfusion (I/R) is a common clinical scenario in patients with certain types of heart diseases and therapies such as thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting, and cardiac transplantation. The underlining mechanism of endogenous cardiac protection after I/R injury has been a focus of current research. Growing evidences suggests that soluble receptor for advanced glycation end-products (sRAGE) has a cardioprotective effect; however, its role in I/R injury remains unclear. We hypothesized that exogenous administration of sRAGE during hypoxia/reoxygenation (H/R) induces cardioprotection by inhibiting cardiomyocyte apoptosis via multiple signals, involving mitochondrial membrane potential (MMP), the mitochondrial permeability transition pore (mPTP), mitochondrial cytochrome c, caspase-3, Bcl-2 and Bax. Neonatal rat cardiomyocytes underwent hypoxia for 3-h followed by 2-h reoxygenation or were treated with sRAGE for 10 min before H/R. Compared with H/R alone, sRAGE pretreatment reduced H/R-induced cardiomyocyte apoptosis from 27.9% +/- 5.9% to 9.4% +/- 0.7% (p < 0.05). In addition, sRAGE treatment significantly inhibited H/R-induced mitochondrial depolarization and mPTP opening, reduced mitochondrial cytochrome c leakage, caspase-3 and caspase-9 activity, and decreased the ratio of Bax to Bcl-2. Therefore, we conclude that the exogenous administration of sRAGE during H/R is involved in cardioprotection by inhibiting apoptosis via the mitochondrial pathway, which, if further confirmed in vivo, may have important clinical implications during H/R. PMID- 23109893 TI - Room temperature radiolytic synthesized Cu@CuAlO(2)-Al(2)O(3) nanoparticles. AB - Colloidal Cu@CuAlO(2)-Al(2)O(3) bimetallic nanoparticles were prepared by a gamma irradiation method in an aqueous system in the presence of polyvinyl pyrrolidone (PVP) and isopropanol respectively as a colloidal stabilizer and scavenger of hydrogen and hydroxyl radicals. The gamma irradiation was carried out in a (60)Co gamma source chamber with different doses up to 120 kGy. The formation of Cu@CuAlO(2)-Al(2)O(3) nanoparticles was observed initially by the change in color of the colloidal samples from colorless to brown. Fourier transform infrared spectroscopy (FTIR) confirmed the presence of bonds between polymer chains and the metal surface at all radiation doses. Results of transmission electron microscopy (TEM), energy dispersive X-ray spectrometry (EDX), and X-ray diffraction (XRD) showed that Cu@CuAlO(2)-Al(2)O(3) nanoparticles are in a core shell structure. By controlling the absorbed dose and precursor concentration, nanoclusters with different particle sizes were obtained. The average particle diameter increased with increased precursor concentration and decreased with increased dose. This is due to the competition between nucleation, growth, and aggregation processes in the formation of nanoclusters during irradiation. PMID- 23109894 TI - The emerging roles of ATP-dependent chromatin remodeling enzymes in nucleotide excision repair. AB - DNA repair in eukaryotic cells takes place in the context of chromatin, where DNA, including damaged DNA, is tightly packed into nucleosomes and higher order chromatin structures. Chromatin intrinsically restricts accessibility of DNA repair proteins to the damaged DNA and impacts upon the overall rate of DNA repair. Chromatin is highly responsive to DNA damage and undergoes specific remodeling to facilitate DNA repair. How damaged DNA is accessed, repaired and restored to the original chromatin state, and how chromatin remodeling coordinates these processes in vivo, remains largely unknown. ATP-dependent chromatin remodelers (ACRs) are the master regulators of chromatin structure and dynamics. Conserved from yeast to humans, ACRs utilize the energy of ATP to reorganize packing of chromatin and control DNA accessibility by sliding, ejecting or restructuring nucleosomes. Several studies have demonstrated that ATP dependent remodeling activity of ACRs plays important roles in coordination of spatio-temporal steps of different DNA repair pathways in chromatin. This review focuses on the role of ACRs in regulation of various aspects of nucleotide excision repair (NER) in the context of chromatin. We discuss current understanding of ATP-dependent chromatin remodeling by various subfamilies of remodelers and regulation of the NER pathway in vivo. PMID- 23109896 TI - Anti-epidermal growth factor receptor (EGFR) antibodies overcome resistance of ovarian cancer cells to targeted therapy and natural cytotoxicity. AB - The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment. PMID- 23109895 TI - Common fragile sites: genomic hotspots of DNA damage and carcinogenesis. AB - Genomic instability, a hallmark of cancer, occurs preferentially at specific genomic regions known as common fragile sites (CFSs). CFSs are evolutionarily conserved and late replicating regions with AT-rich sequences, and CFS instability is correlated with cancer. In the last decade, much progress has been made toward understanding the mechanisms of chromosomal instability at CFSs. However, despite tremendous efforts, identifying a cancer-associated CFS gene (CACG) remains a challenge and little is known about the function of CACGs at most CFS loci. Recent studies of FATS (for Fragile-site Associated Tumor Suppressor), a new CACG at FRA10F, reveal an active role of this CACG in regulating DNA damage checkpoints and suppressing tumorigenesis. The identification of FATS may inspire more discoveries of other uncharacterized CACGs. Further elucidation of the biological functions and clinical significance of CACGs may be exploited for cancer biomarkers and therapeutic benefits. PMID- 23109898 TI - A computational study of calcium(II) and copper(II) ion binding to the hyaluronate molecule. AB - The hyaluronate molecule is a negatively charged polysaccharide that performs a plethora of physiological functions in many cell tissues depending on its conformation. In the present paper, molecular modeling at three levels of theory and two basis sets was used to gain a deeper insight in the complex molecular structure of calcium(II) and copper(II) hyaluronate. Simulation results were compared with the experimental data (EXAFS or X-ray). It was found that B3LYP does not properly reproduce the experimental data while the HF and M06 methods do. Simulation data confirm that the N-acetyl group of the N-acetylglucosamine residue does not participate in the coordination bonding to the calcium(II) or copper(II) ion, as evident from the experimental data. PMID- 23109897 TI - Inhibition of GTRAP3-18 may increase neuroprotective glutathione (GSH) synthesis. AB - Glutathione (GSH) is a tripeptide consisting of glutamate, cysteine, and glycine; it has a variety of functions in the central nervous system. Brain GSH depletion is considered a preclinical sign in age-related neurodegenerative diseases, and it promotes the subsequent processes toward neurotoxicity. A neuroprotective mechanism accomplished by increasing GSH synthesis could be a promising approach in the treatment of neurodegenerative diseases. In neurons, cysteine is the rate limiting substrate for GSH synthesis. Excitatory amino acid carrier 1 (EAAC1) is a neuronal cysteine/glutamate transporter in the brain. EAAC1 translocation to the plasma membrane promotes cysteine uptake, leading to GSH synthesis, while being negatively regulated by glutamate transport associated protein 3-18 (GTRAP3 18). Our recent studies have suggested GTRAP3-18 as an inhibitory factor for neuronal GSH synthesis. Inhibiting GTRAP3-18 function is an endogenous mechanism to increase neuron-specific GSH synthesis in the brain. This review gives an overview of EAAC1-mediated GSH synthesis, and its regulatory mechanisms by GTRAP3 18 in the brain, and a potential approach against neurodegeneration. PMID- 23109899 TI - Genetic diversity characterization of porcine reproductive and respiratory syndrome virus isolates in Romania, based on phylogenetic analysis. AB - Porcine reproductive and respiratory syndrome (PRRS) is a disease produced by the (PRRS) virus, characterized by endemic evolution in the majority of countries, which remains in actuality being a permanent threat to health and economic free farms, as well as for those infected. The aim of this study was to evaluate the genetic diversity of Romanian PRRSV isolates from the four most important pig farms in Romania by comparing the nucleotide sequences obtained for ORF5 and ORF7 with a wide range of sequences from GenBank belonging to the main types of PRRSV; the type 1. Eighteen different sequences were obtained for ORF5 gene and 10 for ORF7 gene. One Romanian isolate (Rom3) was found in three of the four different investigated farms. The phylogenetic analysis revealed that the Romanian PRRSV nucleotide sequences clustered in three groups within the subtype 1 of the virus. The analysis of amino acid sequences evidenced for GP5 and N-nucleocapsid proteins confirmed that the Romanian virus belonged to type 1. PMID- 23109900 TI - Several lipid-related gene polymorphisms interact with overweight/obesity to modulate blood pressure levels. AB - Little is known about the interactions of single nucleotide polymorphisms (SNPs) and overweight/obesity on blood pressure levels. The present study was undertaken to detect 10 lipid-related gene SNPs and their interactions with overweight/obesity on blood pressure levels. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low density lipoprotein receptor (LDL-R) AvaII hepatic lipase gene (LIPC) -250G > A, endothelial lipase gene (LIPG) 584C > T, methylenetetrahydrofolate reductase (MTHFR) 677C > T, the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP) rs3757354, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator activated receptor delta (PPARD) +294T > C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed in 978 normal weight and 751 overweight/obese subjects. The interactions were detected by factorial regression analysis. The genotypes of ACAT-1 AC, LIPC GA and AA, and SCARB1 TT; LDL-R A-A- and LIPC GA; and SCARB1 TT were interacted with overweight/obesity to increase systolic, diastolic blood pressure (SBP, DBP) and pulse pressure (PP) levels; respectively. The genotypes of ACAT-1 CC; ACAT-1 AA and CC were interacted with overweight/obesity to decrease SBP, PP levels (p < 0.01-0.001); respectively. The differences in blood pressure levels between normal weight and overweight/obese subjects might partly result from different interactions of several SNPs and overweight/obesity. PMID- 23109901 TI - Development of new microsatellite markers for Salvia officinalis L. and its potential use in conservation-genetic studies of narrow endemic Salvia brachyodon Vandas. AB - Nine new microsatellite markers (SSR) were isolated from Salvia officinalis L. A total of 125 alleles, with 8 to 21 alleles per locus, were detected in a natural population from the east Adriatic coast. The observed heterozygosity, expected heterozygosity, and polymorphic information content ranged from 0.46 to 0.83, 0.73 to 0.93 and 0.70 to 0.92, respectively. New microsatellite markers, as well as previously published markers, were tested for cross-amplification in Salvia brachyodon Vandas, a narrow endemic species known to be present in only two localities on the Balkan Peninsula. Out of 30 microsatellite markers tested on the natural S. brachyodon population, 15 were successfully amplified. To obtain evidence of recent bottleneck events in the populations of both species, observed genetic diversity (H(E)) was compared to the expected genetic diversity at mutation-drift equilibrium (H(EQ)) and calculated from the observed number of alleles using a two-phased mutation model (TPM). Recent bottleneck events were detected only in the S. brachyodon population. This result suggests the need to reconsider the current threat category of this endemic species. PMID- 23109902 TI - Microsatellite markers for the Chameleon grasshopper (Kosciuscola tristis) (Orthoptera: Acrididae), an Australian Alpine Specialist. AB - A set of polymorphic loci was characterised using an enrichment library for the Australian alpine specialist, the chameleon grasshopper (Kosciuscola tristis), an atypical grasshopper known for its remarkable temperature-controlled colour change. The number of alleles per locus ranged from three to 20 and observed heterozygosity from 0.16 to 0.76. These are the first microsatellite markers for a non-endangered Australian alpine animal and will inform questions of gene flow across the sky islands of this unique and threatened region. PMID- 23109903 TI - Photophysical behaviors of single fluorophores localized on zinc oxide nanostructures. AB - Single-molecule fluorescence spectroscopy has now been widely used to investigate complex dynamic processes which would normally be obscured in an ensemble averaged measurement. In this report we studied photophysical behaviors of single fluorophores in proximity to zinc oxide nanostructures by single-molecule fluorescence spectroscopy and time-correlated single-photon counting (TCSPC). Single fluorophores on ZnO surfaces showed enhanced fluorescence brightness to various extents compared with those on glass; the single-molecule time trajectories also illustrated pronounced fluctuations of emission intensities, with time periods distributed from milliseconds to seconds. We attribute fluorescence fluctuations to the interfacial electron transfer (ET) events. The fluorescence fluctuation dynamics were found to be inhomogeneous from molecule to molecule and from time to time, showing significant static and dynamic disorders in the interfacial electron transfer reaction processes. PMID- 23109905 TI - Serum autofluorescence, a potential serum marker for the diagnosis of liver fibrosis in rats. AB - Fluctuations in serum autofluorescence (AF) intensity have recently been widely used as markers of certain diseases such as cancer. To determine the diagnostic value of serum AF intensity for liver fibrosis in rats, we induced liver fibrosis by subcutaneous injection of carbon tetrachloride into rats. The rat serum AF intensities were detected at the excitation wavelength of 337 nm and the emission wavelength of 512 nm. The degree of liver fibrosis was evaluated by Van Gieson's staining. The relationship between serum AF intensity and the degree of liver fibrosis was analyzed by Spearman and Pearson Correlation. The diagnostic sensitivity and specificity of the serum AF was determined by analyzing the receiver operating characteristic (ROC) curves. Our results show that the serum AF intensity in the rat liver fibrosis model increased when compared with control rats eight weeks and twelve weeks post induction of liver fibrosis. However, there was no significant difference in serum AF intensity between fibrotic and control rats at four week post induction. Furthermore, serum AF intensity correlated positively with the severity of the degree of hepatic fibrosis. ROC analysis further suggested that serum AF intensity is a valid marker for staging fibrosis. Therefore, it may potentially be developed as a novel diagnostic tool for hepatic fibrosis. PMID- 23109904 TI - Gelam honey scavenges peroxynitrite during the immune response. AB - Monocytes and macrophages are part of the first-line defense against bacterial, fungal, and viral infections during host immune responses; they express high levels of proinflammatory cytokines and cytotoxic molecules, including nitric oxide, reactive oxygen species, and their reaction product peroxynitrite. Peroxynitrite is a short-lived oxidant and a potent inducer of cell death. Honey, in addition to its well-known sweetening properties, is a natural antioxidant that has been used since ancient times in traditional medicine. We examined the ability of Gelam honey, derived from the Gelam tree (Melaleuca spp.), to scavenge peroxynitrite during immune responses mounted in the murine macrophage cell line RAW 264.7 when stimulated with lipopolysaccharide/interferon-gamma (LPS/IFN gamma) and in LPS-treated rats. Gelam honey significantly improved the viability of LPS/IFN-gamma-treated RAW 264.7 cells and inhibited nitric oxide production similar to the effects observed with an inhibitor of inducible nitric oxide synthase (1400W). Furthermore, honey, but not 1400W, inhibited peroxynitrite production from the synthetic substrate 3-morpholinosydnonimine (SIN-1) and prevented the peroxynitrite-mediated conversion of dihydrorhodamine 123 to its fluorescent oxidation product rhodamine 123. Honey inhibited peroxynitrite synthesis in LPS-treated rats. Thus, honey may attenuate inflammatory responses that lead to cell damage and death, suggesting its therapeutic uses for several inflammatory disorders. PMID- 23109906 TI - Purification and characterization of a ginsenoside Rb(1)-hydrolyzing beta glucosidase from Aspergillus niger KCCM 11239. AB - Rb(1)-hydrolyzing beta-glucosidase from Aspergillus niger KCCM 11239 was studied to develop a bioconversion process for minor ginsenosides. The specific activity of the purified enzyme was 46.5 times greater than that of the crude enzyme. The molecular weight of the native enzyme was estimated to be approximately 123 kDa. The optimal pH of the purified enzyme was pH 4.0, and the enzyme proved highly stable over a pH range of 5.0-10.0. The optimal temperature was 70 degrees C, and the enzyme became unstable at temperatures above 60 degrees C. The enzyme was inhibited by Cu(2+), Mg(2+), Co(2+), and acetic acid (10 mM). In the specificity tests, the enzyme was found to be active against ginsenoside Rb(1), but showed very low levels of activity against Rb(2), Rc, Rd, Re, and Rg(1). The enzyme hydrolyzed the 20-C,beta-(1->6)-glucoside of ginsenoside Rb(1) to generate ginsenoside Rd and Rg(3), and hydrolyzed 3-C,beta-(1->2)-glucoside to generate F(2). The properties of the enzyme indicate that it could be a useful tool in biotransformation applications in the ginseng industry, as well as in the development of novel drug compounds. PMID- 23109908 TI - Vitamin supplements improve a model form of muscular dystrophy. PMID- 23109907 TI - NAD+ biosynthesis ameliorates a zebrafish model of muscular dystrophy. AB - Muscular dystrophies are common, currently incurable diseases. A subset of dystrophies result from genetic disruptions in complexes that attach muscle fibers to their surrounding extracellular matrix microenvironment. Cell-matrix adhesions are exquisite sensors of physiological conditions and mediate responses that allow cells to adapt to changing conditions. Thus, one approach towards finding targets for future therapeutic applications is to identify cell adhesion pathways that mediate these dynamic, adaptive responses in vivo. We find that nicotinamide riboside kinase 2b-mediated NAD+ biosynthesis, which functions as a small molecule agonist of muscle fiber-extracellular matrix adhesion, corrects dystrophic phenotypes in zebrafish lacking either a primary component of the dystrophin-glycoprotein complex or integrin alpha7. Exogenous NAD+ or a vitamin precursor to NAD+ reduces muscle fiber degeneration and results in significantly faster escape responses in dystrophic embryos. Overexpression of paxillin, a cell adhesion protein downstream of NAD+ in this novel cell adhesion pathway, reduces muscle degeneration in zebrafish with intact integrin receptors but does not improve motility. Activation of this pathway significantly increases organization of laminin, a major component of the extracellular matrix basement membrane. Our results indicate that the primary protective effects of NAD+ result from changes to the basement membrane, as a wild-type basement membrane is sufficient to increase resilience of dystrophic muscle fibers to damage. The surprising result that NAD+ supplementation ameliorates dystrophy in dystrophin-glycoprotein complex- or integrin alpha7-deficient zebrafish suggests the existence of an additional laminin receptor complex that anchors muscle fibers to the basement membrane. We find that integrin alpha6 participates in this pathway, but either integrin alpha7 or the dystrophin-glycoprotein complex is required in conjunction with integrin alpha6 to reduce muscle degeneration. Taken together, these results define a novel cell adhesion pathway that may have future therapeutic relevance for a broad spectrum of muscular dystrophies. PMID- 23109909 TI - Sequencing the connectome. AB - Connectivity determines the function of neural circuits. Historically, circuit mapping has usually been viewed as a problem of microscopy, but no current method can achieve high-throughput mapping of entire circuits with single neuron precision. Here we describe a novel approach to determining connectivity. We propose BOINC ("barcoding of individual neuronal connections"), a method for converting the problem of connectivity into a form that can be read out by high throughput DNA sequencing. The appeal of using sequencing is that its scale- sequencing billions of nucleotides per day is now routine--is a natural match to the complexity of neural circuits. An inexpensive high-throughput technique for establishing circuit connectivity at single neuron resolution could transform neuroscience research. PMID- 23109911 TI - More than just access: delivering on a network-enabled literature. PMID- 23109910 TI - The molecular basis for recognition of CD1d/alpha-galactosylceramide by a human non-Valpha24 T cell receptor. AB - CD1d-mediated presentation of glycolipid antigens to T cells is capable of initiating powerful immune responses that can have a beneficial impact on many diseases. Molecular analyses have recently detailed the lipid antigen recognition strategies utilized by the invariant Valpha24-Jalpha18 TCR rearrangements of iNKT cells, which comprise a subset of the human CD1d-restricted T cell population. In contrast, little is known about how lipid antigens are recognized by functionally distinct CD1d-restricted T cells bearing different TCRalpha chain rearrangements. Here we present crystallographic and biophysical analyses of alpha galactosylceramide (alpha-GalCer) recognition by a human CD1d-restricted TCR that utilizes a Valpha3.1-Jalpha18 rearrangement and displays a more restricted specificity for alpha-linked glycolipids than that of iNKT TCRs. Despite having sequence divergence in the CDR1alpha and CDR2alpha loops, this TCR employs a convergent recognition strategy to engage CD1d/alphaGalCer, with a binding affinity (~2 uM) almost identical to that of an iNKT TCR used in this study. The CDR3alpha loop, similar in sequence to iNKT-TCRs, engages CD1d/alphaGalCer in a similar position as that seen with iNKT-TCRs, however fewer actual contacts are made. Instead, the CDR1alpha loop contributes important contacts to CD1d/alphaGalCer, with an emphasis on the 4'OH of the galactose headgroup. This is consistent with the inability of Valpha24- T cells to respond to alpha glucosylceramide, which differs from alphaGalCer in the position of the 4'OH. These data illustrate how fine specificity for a lipid containing alpha-linked galactose is achieved by a TCR structurally distinct from that of iNKT cells. PMID- 23109912 TI - Strengthening medical product regulation in low- and middle-income countries. AB - In summary, the case studies exploring global product supply chains and diethylene glycol poisoning in Panama, clinical trials regulation through AVAREF, premarket assurance through PEPFAR tentative approval, post-market surveillance in sub-Saharan Africa through research on drug and vaccine safety systems, and regulatory science through the creation of a low-cost meningitis vaccine for low- and middle-income countries, demonstrate the essential value of regulatory systems to low- and middle-income countries. When they work, people live; when they fail, people die. As the challenges of globalization mount, and efforts to provide medical products to low- and middle-income countries scale up, there is no better time to put regulatory system strengthening squarely on the global health and development agenda. PMID- 23109913 TI - Research conducted using data obtained through online communities: ethical implications of methodological limitations. PMID- 23109914 TI - Associations between mode of HIV testing and consent, confidentiality, and referral: a comparative analysis in four African countries. AB - BACKGROUND: Recommendations about scaling up HIV testing and counseling highlight the need to provide key services and to protect clients' rights, but it is unclear to what extent different modes of testing differ in this respect. This paper examines whether practices regarding consent, confidentiality, and referral vary depending on whether testing is provided through voluntary counseling and testing (VCT) or provider-initiated testing. METHODS AND FINDINGS: The MATCH (Multi-Country African Testing and Counseling for HIV) study was carried out in Burkina Faso, Kenya, Malawi, and Uganda. Surveys were conducted at selected facilities. We defined eight outcome measures related to pre- and post-test counseling, consent, confidentiality, satisfactory interactions with providers, and (for HIV-positive respondents) referral for care. These were compared across three types of facilities: integrated facilities, where testing is provided along with medical care; stand-alone VCT facilities; and prevention of mother-to-child transmission (PMTCT) facilities, where testing is part of PMTCT services. Tests of bivariate associations and modified Poisson regression were used to assess significance and estimate the unadjusted and adjusted associations between modes of testing and outcome measures. In total, 2,116 respondents tested in 2007 or later reported on their testing experience. High percentages of clients across countries and modes of testing reported receiving recommended services and being satisfied. In the unadjusted analyses, integrated testers were less likely to meet with a counselor before testing (83% compared with 95% of VCT testers; p<0.001), but those who had a pre-test meeting were more likely to have completed consent procedures (89% compared with 83% among VCT testers; p<0.001) and pre test counseling (78% compared with 73% among VCT testers; p = 0.015). Both integrated and PMTCT testers were more likely to receive complete post-test counseling than were VCT testers (59% among both PMTCT and integrated testers compared with 36% among VCT testers; p<0.001). Adjusted analyses by country show few significant differences by mode of testing: only lower satisfaction among integrated testers in Burkina Faso and Uganda, and lower frequency of referral among PMTCT testers in Malawi. Adjusted analyses of pooled data across countries show a higher likelihood of pre-test meeting for those testing at VCT facilities (adjusted prevalence ratio: 1.22, 95% CI: 1.07-1.38) and higher satisfaction for stand-alone VCT facilities (adjusted prevalence ratio: 1.15; 95% CI: 1.06-1.25), compared to integrated testing, but no other associations were statistically significant. CONCLUSIONS: Overall, in this study most respondents reported favorable outcomes for consent, confidentiality, and referral. Provider-initiated ways of delivering testing and counseling do not appear to be associated with less favorable outcomes for clients than traditional, client-initiated VCT, suggesting that testing can be scaled up through multiple modes without detriment to clients' rights. Please see later in the article for the Editors' Summary. PMID- 23109915 TI - Removing the age restrictions for rotavirus vaccination: a benefit-risk modeling analysis. AB - BACKGROUND: To minimize potential risk of intussusception, the World Health Organization (WHO) recommended in 2009 that rotavirus immunization should be initiated by age 15 weeks and completed before 32 weeks. These restrictions could adversely impact vaccination coverage and thereby its health impact, particularly in developing countries where delays in vaccination often occur. METHODS AND FINDINGS: We conducted a modeling study to estimate the number of rotavirus deaths prevented and the number of intussusception deaths caused by vaccination when administered on the restricted schedule versus an unrestricted schedule whereby rotavirus vaccine would be administered with DTP vaccine up to age 3 years. Countries were grouped on the basis of child mortality rates, using WHO data. Inputs were estimates of WHO rotavirus mortality by week of age from a recent study, intussusception mortality based on a literature review, predicted vaccination rates by week of age from USAID Demographic and Health Surveys, the United Nations Children's Fund (UNICEF) Multiple Indicator Cluster Surveys (MICS), and WHO-UNICEF 2010 country-specific coverage estimates, and published estimates of vaccine efficacy and vaccine-associated intussusception risk. On the basis of the error estimates and distributions for model inputs, we conducted 2,000 simulations to obtain median estimates of deaths averted and caused as well as the uncertainty ranges, defined as the 5th-95th percentile, to provide an indication of the uncertainty in the estimates. We estimated that in low and low middle income countries a restricted schedule would prevent 155,800 rotavirus deaths (5th-95th centiles, 83,300-217,700) while causing potentially 253 intussusception deaths (76-689). In contrast, vaccination without age restrictions would prevent 203,000 rotavirus deaths (102,000-281,500) while potentially causing 547 intussusception deaths (237-1,160). Thus, removing the age restrictions would avert an additional 47,200 rotavirus deaths (18,700 63,700) and cause an additional 294 (161-471) intussusception deaths, for an incremental benefit-risk ratio of 154 deaths averted for every death caused by vaccine. These extra deaths prevented under an unrestricted schedule reflect vaccination of an additional 21%-25% children, beyond the 63%-73% of the children who would be vaccinated under the restricted schedule. Importantly, these estimates err on the side of safety in that they assume high vaccine-associated risk of intussusception and do not account for potential herd immunity or non fatal outcomes. CONCLUSIONS: Our analysis suggests that in low- and middle-income countries the additional lives saved by removing age restrictions for rotavirus vaccination would far outnumber the potential excess vaccine-associated intussusception deaths. Please see later in the article for the Editors' Summary. PMID- 23109916 TI - Viral evasion of a bacterial suicide system by RNA-based molecular mimicry enables infectious altruism. AB - Abortive infection, during which an infected bacterial cell commits altruistic suicide to destroy the replicating bacteriophage and protect the clonal population, can be mediated by toxin-antitoxin systems such as the Type III protein-RNA toxin-antitoxin system, ToxIN. A flagellum-dependent bacteriophage of the Myoviridae, PhiTE, evolved rare mutants that "escaped" ToxIN-mediated abortive infection within Pectobacterium atrosepticum. Wild-type PhiTE encoded a short sequence similar to the repetitive nucleotide sequence of the RNA antitoxin, ToxI, from ToxIN. The PhiTE escape mutants had expanded the number of these "pseudo-ToxI" genetic repeats and, in one case, an escape phage had "hijacked" ToxI from the plasmid-borne toxIN locus, through recombination. Expression of the pseudo-ToxI repeats during PhiTE infection allowed the phage to replicate, unaffected by ToxIN, through RNA-based molecular mimicry. This is the first example of a non-coding RNA encoded by a phage that evolves by selective expansion and recombination to enable viral suppression of a defensive bacterial suicide system. Furthermore, the PhiTE escape phages had evolved enhanced capacity to transduce replicons expressing ToxIN, demonstrating virus-mediated horizontal transfer of genetic altruism. PMID- 23109917 TI - Mechanisms of spectral and temporal integration in the mustached bat inferior colliculus. AB - This review describes mechanisms and circuitry underlying combination-sensitive response properties in the auditory brainstem and midbrain. Combination-sensitive neurons, performing a type of auditory spectro-temporal integration, respond to specific, properly timed combinations of spectral elements in vocal signals and other acoustic stimuli. While these neurons are known to occur in the auditory forebrain of many vertebrate species, the work described here establishes their origin in the auditory brainstem and midbrain. Focusing on the mustached bat, we review several major findings: (1) Combination-sensitive responses involve facilitatory interactions, inhibitory interactions, or both when activated by distinct spectral elements in complex sounds. (2) Combination-sensitive responses are created in distinct stages: inhibition arises mainly in lateral lemniscal nuclei of the auditory brainstem, while facilitation arises in the inferior colliculus (IC) of the midbrain. (3) Spectral integration underlying combination sensitive responses requires a low-frequency input tuned well below a neuron's characteristic frequency (ChF). Low-ChF neurons in the auditory brainstem project to high-ChF regions in brainstem or IC to create combination sensitivity. (4) At their sites of origin, both facilitatory and inhibitory combination-sensitive interactions depend on glycinergic inputs and are eliminated by glycine receptor blockade. Surprisingly, facilitatory interactions in IC depend almost exclusively on glycinergic inputs and are largely independent of glutamatergic and GABAergic inputs. (5) The medial nucleus of the trapezoid body (MNTB), the lateral lemniscal nuclei, and the IC play critical roles in creating combination sensitive responses. We propose that these mechanisms, based on work in the mustached bat, apply to a broad range of mammals and other vertebrates that depend on temporally sensitive integration of information across the audible spectrum. PMID- 23109918 TI - Dopaminergic modulation of synaptic transmission and neuronal activity patterns in the zebrafish homolog of olfactory cortex. AB - Dopamine (DA) is an important modulator of synaptic transmission and plasticity that is causally involved in fundamental brain functions and dysfunctions. We examined the dopaminergic modulation of synaptic transmission and sensory responses in telencephalic area Dp of zebrafish, the homolog of olfactory cortex. By combining anatomical tracing and immunohistochemistry, we detected no DA neurons in Dp itself but long-range dopaminergic input from multiple other brain areas. Whole-cell recordings revealed no obvious effects of DA on membrane potential or input resistance in the majority of Dp neurons. Electrical stimulation of the olfactory tracts produced a complex sequence of synaptic currents in Dp neurons. DA selectively decreased inhibitory currents with little or no effect on excitatory components. Multiphoton calcium imaging showed that population responses of Dp neurons to olfactory tract stimulation or odor application were enhanced by DA, consistent with its effect on inhibitory synaptic transmission. These effects of DA were blocked by an antagonist of D2 like receptors. DA therefore disinhibits and reorganizes sensory responses in Dp. This modulation may affect sensory perception and could be involved in the experience-dependent modification of odor representations. PMID- 23109919 TI - Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse. AB - Histamine H3 receptor (H3R) antagonists/inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS). Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/neurochemical evidences available so far following H3R antagonists in the pathophysiology of Alzheimer's disease (AD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3R inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits. PMID- 23109920 TI - The biophysical bases of will-less behaviors. AB - Are there distinctions at the neurophysiological level that correlate with voluntary and involuntary actions? Whereas the wide variety of involuntary behaviors (and here mostly the deviant or pathological ones will be considered) will necessarily be represented at some biophysical level in nervous system activity-for after all those cellular activity patterns manifest themselves as behaviors and thus there will be a multiplicity of them-there could be some general tendencies to be discerned amongst that assortment. Collecting observations derived from neurophysiological activity associated with several pathological conditions characterized by presenting will-less actions such as Parkinson's disease, seizures, alien hand syndrome and tics, it is proposed that a general neurophysiologic tendency of brain activity that correlates with involuntary actions is higher than normal synchrony in specific brain cell networks, depending upon the behavior in question. Wilful, considered normal behavior, depends on precise coordination of the collective activity in cell ensembles that may be lost, or diminished, when there are tendencies toward more than normal or aberrant synchronization of cellular activity. Hence, rapid fluctuations in synchrony is associated with normal actions and cognition while less variability in brain recordings particularly with regards to synchronization could be a signature of unconscious and deviant behaviors in general. PMID- 23109921 TI - Gastric calcifying fibrous tumor: a very rare case report. AB - Calcifying fibrous tumor is a very rare benign mesenchymal tumor which shows a predilection for soft tissue, mesentery and peritoneum. Up to date only 7 cases have been reported in the literature confined to the gastric wall. We report a rare case of a calcifying fibrous tumor of the stomach in a 60-year-old man who presented with dyspepsia, flatulence and feeling weight. A clinical and laboratory investigation was performed with normal results. Gastroscopy revealed a bulge in the gastric body measuring 1 cm with normal overlying mucosa, and mucosal biopsies showed chronic gastritis. Endoscopic ultrasound of the gastric bulge showed a 1 * 0.8 cm hypoechoic lesion involving the gastric wall. After the above finding a wedge resection of the stomach was performed. Microscopically the lesion consisted of well-circumscribed hypocellular hyalinized fibrosclerotic tissue with lympoplasmatic infiltrates, lymphoid aggregates and psammomatous calcifications. Lesional cells were positive for vimentin and factor XIII and negative for actin, desmin, S100p, CD117, CD34, CD31 and ALK-1. The lesion involved the muscularis propria with variable submucosal extension. Calcifying fibrous tumor has shown an excellent prognosis with recurrences being rare and showing the same morphology as the primary lesion. PMID- 23109922 TI - Thymic Neuroblastoma within a Thymic Cyst in an Adult. AB - CASE PRESENTATION: A 65-year-old female patient with no clinical manifestations was hospitalized for examination and treatment of an anterior mediastinal tumor found at the time of a regular health checkup. Enhanced computed tomography (CT) and magnetic resonance imaging revealed a cystic lesion containing a solid tumor. Positron emission tomography-CT demonstrated increased uptake in the solid lesion. Tumor resection with total thymectomy was performed. A pathological diagnosis of thymic neuroblastoma within a thymic cyst was made. Micorscopic examination revealed that tumor cells of the solid component were lined with thymic epithelial cells of the inner cyst wall. Furthermore, some tumor cells of the solid component had melanin granules. These findings suggest that this tumor arose from progenitors of the thymic epithelial cells with the potential to differentiate along neural lines. CONCLUSIONS: Neuroblastoma commonly occurs in children. However, the diagnosis of neuroblastoma in adults has been reported in several case reports. We report an adult case of histogenetically informative thymic neuroblastoma within a thymic cyst. There are no standard treatment strategies and chemotherapy protocols. Complete surgical resection might be important for a better outcome. PMID- 23109923 TI - Breast metastasis of a squamous cell carcinoma of the uterine cervix mimicking inflammatory breast cancer. AB - Breast metastases from distant carcinoma are infrequent, and cervix carcinoma is rarely the primary lesion. We describe the first case of a cervical squamous cell carcinoma with breast metastasis mimicking an inflammatory breast cancer in a 74 year-old woman. Seventeen months after the treatment of a primary tumor, the patient developed breast lesions looking like an inflammatory breast tumor. After a 1-year delay due to the patient's refusal, pathological examination and immunohistochemistry confirmed the diagnosis of breast metastasis from a poorly differentiated squamous cell carcinoma. The volume of the breast was huge, associated with axillary lymphadenopathies and multiple lung metastases. Despite platinum-based chemotherapy, the disease progressed and the patient died rapidly, 3 months after the first chemotherapy cycle and 15 months after the first mammary symptoms. We review the literature concerning breast metastases from gynecologic cancers and, particularly, from cervical squamous cell carcinoma. Differential diagnosis of such lesions may be problematic but is essential to avoid unnecessary mutilating surgery and to institute the appropriate systemic therapy. The prognosis is poor. PMID- 23109924 TI - Is primary pulmonary meningioma a giant form of a meningothelial-like nodule? A case report and review of the literature. AB - Minute pulmonary meningothelial-like nodules (PMNs) are asymptomatic, small nodules that are occasionally detected in surgical or autopsy specimens. Recent improvements in tumor imaging and the increased use of computed tomography (CT) scans of the chest have led to the early detection of these pulmonary nodules in various clinical settings, often before surgery or health examinations. However, large PMNs have rarely been observed. In this study, we report a patient with a large PMN, which was almost identical to so-called 'primary pulmonary meningioma'. A CT scan of his chest revealed a small, well-circumscribed nodule. Immunohistochemical analysis of the tumor revealed that the tumor cells were positive for CD56, epithelial membrane antigen, and progesterone receptor. Given the similarity of these results to the staining pattern of minute PMNs in previous reports, we suggest that the primary pulmonary meningiomas reported to date are, in fact, a giant form of PMN. PMID- 23109925 TI - Yttrium-90 microsphere radioembolization for treatment of lung cancer hepatic metastases. AB - Because stage 4 lung cancer is associated with dismal 5-year survival rates, new treatment approaches targeting extrapulmonary disease are necessary. Yttrium-90 microsphere radioembolization is an emerging treatment for metastatic hepatic malignancies that results in high tumor response rates and extended patient survival. To date, application of this therapy toward management of lung cancer hepatic metastases has not been extensively described. Herein, we present 2 cases of effective yttrium-90 radioembolization for treatment of lung cancer hepatic metastases, and emphasize the potential coadjuvant value of this procedure in patients with advanced-stage lung cancer and liver-dominant metastatic disease. PMID- 23109926 TI - Sympathetic limitation of exercise hyperemia: even hypoperfused muscle is not exempted. PMID- 23109927 TI - Predictive physiological anticipation preceding seemingly unpredictable stimuli: a meta-analysis. AB - This meta-analysis of 26 reports published between 1978 and 2010 tests an unusual hypothesis: for stimuli of two or more types that are presented in an order designed to be unpredictable and that produce different post-stimulus physiological activity, the direction of pre-stimulus physiological activity reflects the direction of post-stimulus physiological activity, resulting in an unexplained anticipatory effect. The reports we examined used one of two paradigms: (1) randomly ordered presentations of arousing vs. neutral stimuli, or (2) guessing tasks with feedback (correct vs. incorrect). Dependent variables included: electrodermal activity, heart rate, blood volume, pupil dilation, electroencephalographic activity, and blood oxygenation level dependent (BOLD) activity. To avoid including data hand-picked from multiple different analyses, no post hoc experiments were considered. The results reveal a significant overall effect with a small effect size [fixed effect: overall ES = 0.21, 95% CI = 0.15 0.27, z = 6.9, p < 2.7 * 10(-12); random effects: overall (weighted) ES = 0.21, 95% CI = 0.13-0.29, z = 5.3, p < 5.7 * 10(-8)]. Higher quality experiments produced a quantitatively larger effect size and a greater level of significance than lower quality studies. The number of contrary unpublished reports that would be necessary to reduce the level of significance to chance (p > 0.05) was conservatively calculated to be 87 reports. We explore alternative explanations and examine the potential linkage between this unexplained anticipatory activity and other results demonstrating meaningful pre-stimulus activity preceding behaviorally relevant events. We conclude that to further examine this currently unexplained anticipatory activity, multiple replications arising from different laboratories using the same methods are necessary. The cause of this anticipatory activity, which undoubtedly lies within the realm of natural physical processes (as opposed to supernatural or paranormal ones), remains to be determined. PMID- 23109928 TI - How to tackle tremor - systematic review of the literature and diagnostic work up. AB - BACKGROUND: Tremor is the most prevalent movement disorder in clinical practice. It is defined as involuntary, rhythmic, oscillatory movements. The diagnostic process of patients with tremor can be laborious and challenging, and a clear, systematic overview of available diagnostic techniques is lacking. Tremor can be a symptom of many diseases, but can also represent a distinct disease entity. OBJECTIVE: The objective of this review is to give a clear, systematic and step wise overview of the diagnostic work-up of a patient with tremor. The clinical relevance and value of available laboratory tests in patients with tremor will be explored. METHODS: We systematically searched through EMBASE. The retrieved articles were supplemented by articles containing relevant data or provided important background information. Studies that were included investigated the value and/or usability of diagnostic tests for tremor. RESULTS: In most patients, history and clinical examination by an experienced movement disorders neurologist are sufficient to establish a correct diagnosis, and further ancillary examinations will not be needed. Ancillary investigation should always be guided by tremor type(s) present and other associated signs and symptoms. The main ancillary examination techniques currently are electromyography and SPECT imaging. Unfortunately, many techniques have not been studied in large prospective, diagnostic studies to be able to determine important variables like sensitivity and specificity. CONCLUSION: When encountering a patient with tremor, history, and careful clinical examination should guide the diagnostic process. Adherence to the diagnostic work-up provided in this review will help the diagnostic process of these patients. PMID- 23109929 TI - Cancer stem cells, tumor dormancy, and metastasis. AB - Tumor cells can persist undetectably for an extended period of time in primary tumors and in disseminated cancer cells. Very little is known about why and how these tumors persist for extended periods of time and then evolve to malignancy. The discovery of cancer stem cells (CSCs) in human tumors challenges our current understanding of tumor recurrence, drug resistance, and metastasis, and opens up new research directions on how cancer cells are capable of switching from dormancy to malignancy. Although overlapping molecules and pathways have been reported to regulate the stem-like phenotype of CSCs and metastasis, accumulated evidence has suggested additional clonal diversity within the stem-like cancer cell subpopulation. This review will describe the current hypothesis linking CSCs and metastasis and summarize mechanisms important for metastatic CSCs to re initiate tumors in the secondary sites. A better understanding of CSCs' contribution to clinical tumor dormancy and metastasis will provide new therapeutic revenues to eradicate metastatic tumors and significantly reduce the mortality of cancer patients. PMID- 23109931 TI - A consideration of the relative contributions of different microbial subpopulations to the soil N cycle. AB - We examine and discuss literature targeted at identifying "active" subpopulations of soil microbial communities with regard to the factors that affect the balance between mineralization and immobilization/assimilation of N. Whereas a large fraction (>=50%) of soil microbial biomass can immediately respire exogenous substrates, it remains unclear what percentage of both bacterial and fungal populations are capable of expressing their growth potential. The factors controlling the relative amounts of respiratorily responsive biomass versus growth-active biomass will impact the balance between N mineralization and N immobilization. Stable isotope probing of de novo DNA synthesis, and pyrosequence analyses of rRNA:rDNA ratios in soils have identified both numerically dominant and rare microbial taxa showing greatest growth potential. The relative growth responses of numerically dominant or rare members of a soil community could influence the amount of N immobilized into biomass during a "growth" event. Recent studies have used selective antibiotics targeted at protein synthesis to measure the relative contributions of fungi and bacteria to ammonification and [Formula: see text] consumption, and of NH(3)-oxidizing archaea (AOA) and bacteria (AOB) to NH(3) oxidation. Evidence was obtained for bacteria to dominate [Formula: see text] assimilation and for fungi to be involved in both consumption of dissolved organic nitrogen (DON) and its ammonification. Soil conditions, phase of cropping system, [Formula: see text] availability, and soil pH influence the relative contributions of AOA and AOB to soil nitrification. A recent discovery that AOA can ammonify organic N sources and oxidize it to [Formula: see text] serves to illustrate roles for AOA in both the production and consumption of [Formula: see text]. Clearly, much remains to be learned about the factors influencing the relative contributions of bacteria, archaea, and fungi to processing organic and inorganic N, and their impact on the balance between mineralization and immobilization of N. PMID- 23109930 TI - Nitric oxide and nitrous oxide turnover in natural and engineered microbial communities: biological pathways, chemical reactions, and novel technologies. AB - Nitrous oxide (N(2)O) is an environmentally important atmospheric trace gas because it is an effective greenhouse gas and it leads to ozone depletion through photo-chemical nitric oxide (NO) production in the stratosphere. Mitigating its steady increase in atmospheric concentration requires an understanding of the mechanisms that lead to its formation in natural and engineered microbial communities. N(2)O is formed biologically from the oxidation of hydroxylamine (NH(2)OH) or the reduction of nitrite (NO(-) (2)) to NO and further to N(2)O. Our review of the biological pathways for N(2)O production shows that apparently all organisms and pathways known to be involved in the catabolic branch of microbial N-cycle have the potential to catalyze the reduction of NO(-) (2) to NO and the further reduction of NO to N(2)O, while N(2)O formation from NH(2)OH is only performed by ammonia oxidizing bacteria (AOB). In addition to biological pathways, we review important chemical reactions that can lead to NO and N(2)O formation due to the reactivity of NO(-) (2), NH(2)OH, and nitroxyl (HNO). Moreover, biological N(2)O formation is highly dynamic in response to N-imbalance imposed on a system. Thus, understanding NO formation and capturing the dynamics of NO and N(2)O build-up are key to understand mechanisms of N(2)O release. Here, we discuss novel technologies that allow experiments on NO and N(2)O formation at high temporal resolution, namely NO and N(2)O microelectrodes and the dynamic analysis of the isotopic signature of N(2)O with quantum cascade laser absorption spectroscopy (QCLAS). In addition, we introduce other techniques that use the isotopic composition of N(2)O to distinguish production pathways and findings that were made with emerging molecular techniques in complex environments. Finally, we discuss how a combination of the presented tools might help to address important open questions on pathways and controls of nitrogen flow through complex microbial communities that eventually lead to N(2)O build-up. PMID- 23109933 TI - Heterotrophic bacterial production and extracellular enzymatic activity in sinking particulate matter in the western North Pacific Ocean. AB - Heterotrophic activities on sinking particulate matter (SPM) play an important role in SPM fluxes in the ocean. To demonstrate regional differences in heterotrophic activities on SPM, we measured heterotrophic bacterial production (HBP) in seawater (HBP(SW)) and SPM (HBP(SPM)) as well as potential extracellular enzyme activity (EEA) in SPM on a transect along 155 degrees E in the western North Pacific Ocean in the subarctic (44 degrees N), the Kuroshio Extension area (35 degrees N), and the subtropical gyre (20 degrees N). Depth-integrated HBP(SW) from the surface to 500 m was comparable between the locations, whereas HBP(SPM) at 44 degrees N was substantially lower than at the other sites. We found the highest particulate organic carbon (POC) export flux and export efficiency to bathypelagic depths, and the lowest water temperatures, at 44 degrees N. We found significant correlations between leucine aminopeptidase (LAPase) activity, beta glucosidase (BGase) activity, POC flux and particulate organic nitrogen flux. LAPase activity was two orders of magnitude higher than BGase activity, with a BGase:LAPase activity ratio of 0.027. There were no significant correlations between HBP and EEA in SPM except for lipase, and lipase activity was significantly correlated with temperature. We propose that hydrographic conditions are an important factor controlling heterotrophic bacterial activity and export efficiency of organic carbon to the deep ocean, as are the sources and abundance of SPM produced in the euphotic zone via primary production. PMID- 23109932 TI - Pathways of cell-cell transmission of HTLV-1. AB - The deltaretroviruses human T cell lymphotropic virus type 1 (HTLV-1) and human T cell lymphotropic virus type 2 (HTLV-2) have long been believed to differ from retroviruses in other genera by their mode of transmission. While other retroviruses were thought to primarily spread by producing cell-free particles that diffuse through extracellular fluids prior to binding to and infecting target cells, HTLV-1 and HTLV-2 were believed to transmit the virus solely by cell-cell interactions. This difference in transmission was believed to reflect the fact that, relative to other retroviruses, the cell-free virions produced by HTLV-infected cells are very poorly infectious. Since HTLV-1 and HTLV-2 are primarily found in T cells in the peripheral blood, spread of these viruses was believed to occur between infected and uninfected, T cells, although little was known about the cellular and viral proteins involved in this interaction. Recent studies have revealed that the method of transmission of HTLV is not unique: other retroviruses including human immunodeficiency virus (HIV) are also transmitted from cell-to-cell, and this method is dramatically more efficient than cell-free transmission. Moreover, cell-cell transmission of HTLV-1, as well as HIV, can occur following interactions between dendritic cells and T cells, as well as between T cells. Conversely, other studies have shown that cell-free HTLV 1 is not as poorly infectious as previously thought, since it is capable of infecting certain cell types. Here we summarize the recent insights about the mechanisms of cell-cell transmission of HTLV-1 and other retroviruses. We also review in vitro and in vivo studies of infection and discuss how these finding may relate to the spread of HTLV-1 between individuals. PMID- 23109934 TI - The entry of fetal and amniotic fluid components into the uterine vessel circulation leads to sterile inflammatory processes during parturition. AB - Pro-inflammatory cytokines play an important role during the process of human parturition. The focus of this review was to explore the contribution of biological, biochemical, and genetic changes in the onset of term labor. This article reviews the English-language literature on inflammatory, hormonal, and immunological factors in an effort to identify the molecular basis of human parturition. The majority of the genes and proteins up-regulated in parturition at term are related to four functional categories, mechanical stretch-mediated damage-associated molecular patterns (DAMPs) activation, response to immunity, induction of inflammatory signaling, and progressive uterine myometrial contractility and resultant term birth. Mechanical stretch could promote the entry of amniotic fluid components into the uterine vessel circulation that is the common physiologic mechanism at term prior to labor. The fetal or amniotic fluid-derived DAMPs could activate the immune system. The inflammatory mediators are produced by infiltrating activated leukocytes and by the reproductive tissues themselves such as myometrium, and subsequently lead to uterine contractions. This review supports the sterile inflammation hypothesis that there are at least two phases of human parturition: the initial wave of the entry of amniotic fluid components into uterine vasculatures would be followed by the second big wave of subsequent myometrial contraction. PMID- 23109935 TI - How complex are intracellular immune receptor signaling complexes? AB - Nucleotide binding leucine-rich repeat proteins (NLRs) are the major class of intracellular immune receptors in plants. NLRs typically function to specifically recognize pathogen effectors and to initiate and control defense responses that severely limit pathogen growth in plants (termed effector-triggered immunity, or ETI). Despite numerous reports supporting a central role in innate immunity, the molecular mechanisms driving NLR activation and downstream signaling remain largely elusive. Recent reports shed light on the pre- and post-activation dynamics of a few NLR-containing protein complexes. Recent technological advances in the use of proteomics may enable high-resolution definition of immune protein complexes and possible activation-relevant post-translational modifications of the components in these complexes. In this review, we focus on research aimed at characterizing pre- and post-activation NLR protein complexes and the molecular events that follow activation. We discuss the use of new or improved technologies as tools to unveil the molecular mechanisms that define NLR-mediated pathogen recognition. PMID- 23109936 TI - Regulation of plant immune receptors by ubiquitination. AB - From pathogen perception and the activation of signal transduction cascades to the deployment of defense responses, protein ubiquitination plays a key role in the modulation of plant immunity. Ubiquitination is mediated by three enzymes, of which the E3 ubiquitin ligases, the substrate determinants, have been the major focus of attention. Accumulating evidence suggests that ubiquitination modulates signaling mediated by pattern recognition receptors and is important for the accumulation of nucleotide-binding leucine-rich repeat type intracellular immune sensors. Recent studies also indicate that ubiquitination directs vesicle trafficking, a function that has been clearly established for immune signaling in animals. In this mini review, we discuss these and other recent advances and highlight important open questions. PMID- 23109937 TI - Long non-coding RNAs in cancer progression. AB - Recent large-scale transcriptome analyses have revealed that transcription is spread throughout the mammalian genomes, yielding large numbers of transcripts, including long non-coding RNAs (lncRNAs) with little or no protein-coding capacity. Dozens of lncRNAs have been identified as biologically significant. In many cases, lncRNAs act as key molecules in the regulation of processes such as chromatin remodeling, transcription, and post-transcriptional processing. Several lncRNAs (e.g., MALAT1, HOTAIR, and ANRIL) are associated with human diseases, including cancer. Those lncRNAs associated with cancer are often aberrantly expressed. Although the underlying molecular mechanisms by which lncRNAs regulate cancer development are unclear, recent studies have revealed that such aberrant expression of lncRNAs affects the progression of cancers. In this review, we highlight recent findings regarding the roles of lncRNAs in cancer biology. PMID- 23109939 TI - Molecular Cloning and Expression of EG95 Gene of Iranian Isolates of Echinococcus granulosus. AB - BACKGROUND: Echinococcosis or hydatidosis is a chronic, zoonotic worldwide infection that occurs by the larval stages of taeniid cestodes of the genus Echinococcus. Iran is known as endemic region for this infection in the world. Vaccination has been considered as a good prevention method for this disease. Recombinant vaccines containing EG95 protein, against E. granulosus, has shown a high degree of protection against E. granulosus infection. In this study EG95 gene was extracted from Iranian isolates of E. granulosus and then cloned and expressed in expression vector. METHODS: Protoscoleces were collected from sheep hydatid cysts. Then DNA and RNA were extracted from protoscoleces, and amplified by PCR and RT-PCR with specific primer. Afterward the purified RT-PCR products were successfully ligated into pTZ57R/T plasmid vector. The pcDNA3 plasmid was used as expression vector and Eg95 fragment sub cloned into this plasmid. The pcEG95 plasmid was digested by restriction enzymes to confirm cloning of this gene in pcDNA3 plasmid. In last step, the subcloned gene was expressed in CHO as eukaryotic cell. RESULTS: EG95 fragment successfully was subcloned in pcDNA3 and EG95 protein was expressed by eukaryotic cell. The recombinant EG95 protein was confirmed by SDS-PAGE and Western blot. CONCLUSION: Recombinant plasmid of pcEG95 was constructed successfully and express of recombinant EG95 protein was confirmed. PMID- 23109938 TI - Transcription factories. AB - There is considerable evidence that transcription does not occur homogeneously or diffusely throughout the nucleus, but rather at a number of specialized, discrete sites termed transcription factories. The factories are composed of ~4-30 RNA polymerase molecules, and are associated with many other molecules involved in transcriptional activation and mRNA processing. Some data suggest that the polymerase molecules within a factory remain stationary relative to the transcribed DNA, which is thought to be reeled through the factory site. There is also some evidence that transcription factories could help organize chromatin and nuclear structure, contributing to both the formation of chromatin loops and the clustering of active and co-regulated genes. PMID- 23109940 TI - In vivo Susceptibility of Plasmodium vivax to Chloroquine in Southeastern Iran. AB - BACKGROUND: Plasmodium vivax is the predominant species causes of malaria with about 90% total annual reported malaria in Iran. This study conducted to determine the susceptibility of Plasmodium vivax isolates to chloroquine in Sistan and Balochistan Province, southeastern Iran. METHODS: A total 270 subjects with symptomatic malaria and confirmed P. vivax infection completed the designed 28-day in vivo study. The thick and thin film blood smears were screened for malaria parasites by microscopy. The nested PCR was applied using the Plasmodium 18 subunit ribosomal ribonucleic (Ssr RNA) genes for detecting mixed infections and diagnosis of parasites in the samples with low parasite on days 0, 5, 6, 7, and 28. RESULTS: P. vivax was cleared in 15%, 50%, 95%, and 100% of patients on days 1, 2, 3, 4 respectively by microscopy assessment. Six patients were exhibited specific P. vivax band in nested PCR on day 5. No recurrence was observed on days 7, 14 and 28. Mean (+/-standard deviation) parasite clearance time was 2.41 (+/-0.8) days. CONCLUSION: P. vivax is still susceptible to chloroquine in Southeatern Iran. This finding is compatible with results of neighboring countries Pakistan and Afghanistan. PMID- 23109941 TI - Seroprevalence of human fasciolosis in a new-emerging focus of fasciolosis in yasuj district, southwest of iran. AB - BACKGROUND: Fasciolosis is an important health and veterinary problem in Iran. The epidemiological pattern of disease has been changed markedly in recent years and there are regions that have potent capacity to be new focus of the disease. One of these areas is Yasuj district in southwest of Iran where animal fasciolosis has been quite common. The current study was conducted to determine the seroprevalence of human fasciolosis in this area and to reveal the epidemiological factors associated with the spreading of the disease in this region. METHODS: One thousand blood samples were randomly collected from five villages in Yasuj district. ELISA, using Fasciola somatic antigen (SA), was carried out to detect anti Fasciola antibodies in the collected sera. RESULTS: Anti-Fasciola antibodies were detected in serum of 18(1.86%) individuals by ELISA. Out of 18 seropositive people, 9 (0.9) were female and 9 (0.9%) were male. Most of people (99.8%) had a history of consuming wild freshwater plants mainly Nasturtium microphyllum (local name Bakaloo) and/or Mentha logifolia (local name Pooneh). No significant correlation was found between seropositivity to fasciolosis and sex, age, history of consumption of green leafy aquatic plants whereas correlation between seropositivity and abdominal pain was significant (P< 0.05). CONCLUSION: Results of this study showed that the seroprevalence rate of human fasciolosis in Yasuj district is relatively high and this area can be considered as a new emerging focus of the disease in Iran. PMID- 23109942 TI - Inhibition of Murine Systemic Leishmaniasis by Acetyl Salicylic Acid via Nitric Oxide Immunomodulation. AB - BACKGROUND: The purpose of this study was to evaluate antileishmanial effects of ASA via NO pathway in Leishmania major infected Balb/c mice. Moreover, toxicity and pathological consequences of ASA administration were investigated. METHODS: Balb/c mice were infected with L. major and ASA was inoculated orally after lesion appearance for its ability to modulate NO and to modify Leishmania infection in host, in order to evaluate the effects of NO production on size and lesion macroscopy, delay of lesion formation and proliferation of amastigotes inside macrophages. Liver, spleen, and lymph nodes were also studied as target organs to detect amastigotes. In addition, plasma was investigated for NO induction using Griess microassay. RESULTS: ASA increased NO production in plasma of both naive and Leishmania test groups at the ultimate of the experimental period. A decline was observed in proliferation of amastigotes inside macrophages of test group when compared with control one. ASA reduced lesion size, inhibited Leishmania visceralisation in spleen, lymph node, and decreased hepato/splenomegaly in ASA treated animals. CONCLUSIONS: Some antileishmanial effects of ASA by NO-modulation were indicated during systemic leishmaniasis in mice. Despite slight effects on lesion size, ASA decreased parasite visceralization in target organs and declined their proliferation inside macrophages. Therefore, ASA may be indicated to inhibit systemic leishmaniasis via NO pathway in mice model. PMID- 23109943 TI - Cloning, and Molecular Characterization of Polymorphic Iranian Isolate Theileria annulata Surface Protein (Tasp). AB - BACKGROUND: Because of the strong immunologic responses of surface protein TaSp in Theileria annulata infected host, we tried to characterize this protein in a T. annulata isolate from Iran. METHODS: The RNA prepared from T. annulata infected cells was used to produce SMART-DS-cDNA. The Double strand cDNA was then amplified with primers derived from TaSp mRNA sequences. The PCR product was cloned in pTZ57R/T vector, sequenced and registered under accession no. JQ003240 in GenBank. RESULTS: The sequence analysis showed 90%-94% nucleotide sequence identity and 68%-94% amino acid homology to the corresponding sequences of TaSp gene by T. annulata, T. sp. china I, T. sp. china and T. lestoquardi and three T. annulata reported from Iran respectively. Interestingly, the sequence analysis also showed small nucleotide sequence region near the 5' end in which the presented TaSp protein differed very strongly from the other known TaSp sequences. For the preparation of the recombinant protein, the cDNA was cloned in pQE-32 vector, the recombinant protein was prepared and assayed by Theileria infected bovine serum. CONCLUSION: The polymorphism in TaSp gene could be detected in intra- as well as inter species. The different characterized TaSp proteins had a common identic region, which may be helpful for development of broad band vaccine based on the recombinant proteins. The polymorphism in this gene, make this protein also interesting for the diagnostic purposes. PMID- 23109944 TI - Sequence Analysis of the Second Internal Transcribed Spacer (ITS2) Region of rDNA for Species Identification of Trichostrongylus Nematodes Isolated From Domestic Livestock in Iran. AB - BACKGROUND: Infectivity of herbivores with Trichostrongylus nematodes is widespread in many countries, having a major economic impact on breeding, survivability, and productivity of domestic livestock. This study was carried out on Trichostrongylus species isolated from domestic livestock in order to develop an easy-to-perform method for species identification. METHODS: Trichostrongylus isolates were collected from sheep, goat, cattle, and buffaloes in Khuzestan Province, southwest Iran. Primary species identification was carried out based on morphological characterization of male worms. PCR amplification of ITS2-rDNA region was performed on genomic DNA and the products were sequenced. Phylogenetic analysis of the nucleotide sequence data was conducted employing Bayesian Inference approach. Consequently, a restriction fragment length polymorphism (RFLP) profile was designed to differentiate Trichostrongylus species. RESULTS: A consensus sequence of 238 nucleotides was deposited in the GenBank for Iranian isolates of Trichostrongylus species including T. colubriformis, T. capricola, T. probolurus and T. vitrinus. The designated RFLP using restriction enzyme TasI could readily differentiate among species having different ITS2 sequence. The molecular analysis was in concordance with morphological findings. CONCLUSION: Phylogenetic analysis indicated a close relationship among the sequences obtained in this study and reference sequence of relevant species. ITS2-RFLP with TasI is recommended for molecular differentiation of common Trichostrongylus species. PMID- 23109945 TI - Occurrence of Thermotolerant Hartmannella vermiformis and Naegleria Spp. in Hot Springs of Ardebil Province, Northwest Iran. AB - BACKGROUND: Geothermal waters could be suitable niches for thermophilic free living amoebae including Naegleria and Hartmannella. Ardebil Province, northwest Iran is popular for having many hot springs for recreational and health purposes activity. The present research is the first molecular based investigation regarding the presence of Naegleria and Hartmannella in the hot springs of Ardebil Province in Iran. METHODS: Overall, 30 water samples were taken from waters of thermal hot springs in Ardebil Province, Iran during 2010-2011. All collected samples were transferred to Dept. of Parasitology and Mycology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Cultivation of concentrated water samples was performed using culture-enrichment method. Cloning of the target amoebae was obtained and morphological and molecular analysis was done using page key combined with two sets of primers, respectively. Sequence analysis and homology search was used for strains identification. RESULTS: Of 30 water samples, 8 (26.7%) were positive for thermotolerant Vahlkampfiids and Hartmannella based on morphological characteristics of vegetative form and double walled cysts. Cloning of the target amoebae were done successfully. Sequencing of the positive isolates revealed that the strains belonged to Naegleria (N. carteri and N. spp) and H. vermiformis. CONCLUSION: The result highlights a need for improved filtration and disinfection and periodic monitoring of recreational thermal waters in order to prevent disease related to free- living amoebae. This is the first comprehensive molecular study of thermophilic Naegleria and Hartmannella in hot springs of Iran. PMID- 23109946 TI - Interleukin-10 and Transforming Growth Factor-beta in Early and Late Lesions of Patients with Leishmania major induced Cutaneous Leishmaniasis. AB - BACKGROUND: Cutaneous leishmaniasis is a neglected parasitic disease, which imposes massive human distress and financial costs to the endemic countries. Better understanding of host immune response to the parasite leads to helpful strategies for disease control. Interleukin (IL)-10 and transforming growth factor (TGF)-beta are important immune regulatory cytokines, which appear to develop non-healing forms of leishmaniasis. However, there is little information about the function of IL-10 and TGF-beta in old world cutaneous leismaniasis. The aim of this study was to analyze the role of IL-10 and TGF-beta in human cutaneous leishmaniasis due to Leishmania major infection. METHODS: Biopsies were obtained from lesions of twenty proven cases of L. major induced cutaneous leishmaniasis. IL-10 and TGF-beta positive cells were detected by immunofluorescence staining of frozen sections and compared between two groups of patients with early and late lesions. RESULTS: The mean percentage of IL-10 positive cells were significantly (P= 0.035) higher in late lesions (0.51+/-0.24) than early ones (0.15+/-0.07). Similar results were obtained for TGF-beta with mean percentages of 0.16+/-0.05 and 0.53+/-0.28 in early and late lesions respectively (P= 0.008). CONCLUSION: IL-10 and TGF-beta are present in lesions of L. major induced cutaneous leishmaniasis and contribute to the pathogenesis of long lasting disease forms. PMID- 23109947 TI - Aspicularis tetraptera Induced Hematological Parameters in Infected and Vaccinated Mice. AB - BACKGROUND: The present study deals with the effect of helminthic infection as Nematode parasite like Aspiculuris tetraptera on the haematological parameters of infected and vaccinated mice. METHODS: Totally 15 mice were used. Five mice were used for positive control, 5 mice used for negative control and 5 mice used for experiment. The hematological parameters were studied viz. RBC, Hb, and serum protein values. RESULTS: The mice carrying heavy infection showed decrease in the Hb, RBC, and serum protein but in the vaccinated mice, all studied parameters were become on normal range. The level of immune response was assessed based on above studied hematological parameters in infected and vaccinated mice with Aspiculuris tetraptera. CONCLUSION: The increased value of RBC, Hb and Serum protein in infected and vaccinated mice compared to infected and non vaccinated suggested the involvement of blood parameters in immune response. This study also proves that somatic antigen of A. tetraptera was effective in imparting immunity in mice. PMID- 23109948 TI - Prevalence of Trichomonas vaginalis Infection in Hamadan City, Western Iran. AB - BACKGROUND: Infection with Trichomonas vaginalis is one of the most common sexually transmitted diseases (STDs) in humans. The prevalence of infection in Iran has been reported between 2 to 8%, depending on deferent socio-cultural conditions. This study aimed to determine the prevalence of T. vaginalis in women referred to gynecologic clinics in Hamadan city, West of Iran. METHODS: This descriptive cross-sectional study was conducted on 750 women who referred to Gynecologic clinics in Hamadan from November 2010 to July 2011. Vaginal samples were obtained from them and examined by wet mount and culture methods for the detection of T. vaginalis. RESULTS: Sixteen out of 750 vaginal swab specimens (2.1%) were culture positive for T. vaginalis and 13 of these positive specimens (1.7%) were wet mount positive. Only 12 of 42 patients who were clinically diagnosed as having T. vaginalis infection, confirmed by culture method. Five hundred and fifty of the participants women (73.3%) had at least one of signs and symptoms of trichomoniasis. No statistical correlation was observed between clinical manifestations and parasitological results (p>0.05). CONCLUSION: This study showed low prevalence of T. vaginalis infection in the study population. Since clinical signs of trichomonal vaginitis are the same of other STDs, a confirmatory laboratory diagnosis is necessary. Wet smear as well as culture are sensitive for detection of T. vaginalis. PMID- 23109949 TI - Phylogenetic Analysis of Theileria annulata Infected Cell Line S15 Iran Vaccine Strain. AB - BACKGROUND: Bovine theileriosis results from infection with obligate intracellular protozoa of the genus Theileria. The phylogenetic relationships between two isolates of Theileria annulata, and 36 Theileria spp., as well as 6 outgroup including Babesia spp. and coccidian protozoa were analyzed using the 18S rRNA gene sequence. METHODS: The target DNA segment was amplified by PCR. The PCR product was used for direct sequencing. The length of the 18S rRNA gene of all Theileria spp. involved in this study was around 1,400 bp. RESULTS: A phylogenetic tree was inferred based on the 18S rRNA gene sequence of the Iran and Iraq isolates, and other species of Theileria available in GenBank. In the constructed tree, Theileria annulata (Iran vaccine strain) was closely related to other T. annulata from Europe, Asia, as well as T. lestoquardi, T. parva and T. taurotragi all in one clade. CONCLUSION: Phylogenetic analyses based on small subunit ribosomal RNA gene suggested that the percent identity of the sequence of Iran vaccine strain was completely the same as Iraq sequence (100% identical), but the similarity of Iran vaccine strain with other T. annulata reported from China, Spain and Italy determined the 97.9 to 99.9% identity. PMID- 23109950 TI - Seroprevalence of Toxoplasma gondii in Pregnant Women and Bioassay of IgM Positive Cases in Zanjan, Northwest of Iran. AB - BACKGROUND: The aim of this study was to determine the Toxoplasma antibodies in pregnant women in Zanjan, by ELISA method. METHODS: Blood samples were taken from 500 pregnant women referred to the health centers of Zanjan City, North West Iran, IgM and IgG titers were primarily evaluated. The collected data were analyzed with SPSS 11.5 using Chi-Square test. RESULTS: Anti Toxoplasma IgM and IgG were positive in 1.4% and 37.2% respectively. Seropositive subjects were more frequently seen in those with >30 years old compared to younger women (<20 years old). No significant relationship was found between the seroprevalence of T. gondii infection and level of education, residence area, history of abortion and gestational age. CONCLUSION: The rate of IgM positive was low; however, a large number of the studied population were IgG positive, indicative of having a latent infection due to the past exposure to Toxoplasma parasite in this region. PMID- 23109951 TI - Pediatric hydatidosis in Iranian referral pediatrics center. AB - BACKGROUND: Hydatidosis is one of the major zoonotic diseases that cause considerable public health problems in Iran. The present study was designed to investigate pediatric hydatidosis in patients referred to the Children Medical Center Hospital in Tehran, Iran during 2005-2010. METHODS: Data were collected from the records of 17 patients referred to the center with hydatidosis. Data included demographic data; laboratory results, type, and site of cysts, clinical manifestations, and treatment. RESULTS: Nine patients were boys (52.9%) and eight (47.1%) were girls. Most patients referred from central areas of Iran (58.8%). Seven patients had cysts in their lungs (41.2%) and three cases (17.6%) in liver. Six cases (35.3%) had simultaneous lung and liver cysts, 3 patients (17.6%) had brain cysts (alone or in combination with other organs involvement) and 2 patients (11.7%) showed multi-organ involvement. All patients were treated by albendazole and underwent surgery, recurrence was seen in 4 (23.5%) of the cases and one patient died due to rupture of the cyst and anaphylactic shock. CONCLUSION: Multi-organ involvement seems to be on the rise in children, this has led to the necessity for physicians to be more aware of clinical features, search, and rule out other organs for involvement diagnosis once a cyst is detected in one organ. PMID- 23109952 TI - Introducing Alphitobius diaperinus, (Insecta: Tenebrionidae) as a New Intermediate Host of Hadjelia truncata (Nematoda). AB - BACKGROUND: Hadjelia truncata is a nematode that causes lesions in the gizzard lining of pigeons, which may even lead to death. The aim of this study was to introduce Alphitobius diaperinus as a new intermediate host for Hadjelia truncata. METHODS: H. truncata infection was identified in a pigeon flock in Ahvaz City, Khuzestan Province, Iran by performing fecal examination and autopsy. Adult and larval stages of beetles were collected from the litter of pigeon houses, and identified morphologically. The beetle larvae were cultured in a medium, containing feces of the infected pigeons. Nematode larval stages from naturally and experimentally (culturally) infected adult beetles were fed to two groups of pigeons RESULTS: The collected beetles were identified as Alphitobius diaperinus. Average length and width of the adult beetles were 6.31 mm and 2.88 mm respectively. Infection rates of naturally and experimentally infected beetles with larval stages of the nematode were 66.2% and 45.1% respectively. The adult nematodes collected from gizzards of experimentally infected pigeons were identified as H. truncata. Nematode infection rates in pigeons after feeding the infective larvae collected from naturally and experimentally infected beetles were 44.7% and 32.5% respectively. CONCLUSION: A. diaperinus can serve as a natural intermediate host for H. truncata. PMID- 23109953 TI - The Multiple Forms of Leishmania major in BALB/C Mice Lung in Iran. AB - Cutaneous leishmaniasis is one of the most important parasitic diseases, which are endemic in different parts of Iran. Leishmania major and L. tropica are the primary causative agents of this disease. The aim of the present study was to detect the multiple forms of L. major in lung. Ppromastigotes of L. major at stationary phase were injected to BALB/c mice. After 60 days, the different forms of Leishmania parasites were checked in lung tissue. Promastigote and amastigote forms of Leishmania parasites were detected. PMID- 23109954 TI - Histopathologic Effects of Dirofilaria immitis Microfilaria on Internal Organs of Dog Confirming by PCR Technique. AB - BACKGROUND: The heartworm disease is an infectious disease of dogs with Dirofilaria immitis combined with cardiovascular and circulatory abnormalities. The heartworm disease can become a serious health risk when associated with a severe infection. In this study, a male, 8 year-old dog that died suddenly was necropsied and all tissues were examined grossly. METHODS: Major organs including heart, lungs, liver, spleen, kidneys, brain, eyes, and testis were fixed in 10% neutral formalin, embedded in paraffin, sectioned at 5-um thickness, stained with hematoxylin and eosin, and examined with a light microscope. For each examined organ, paraffin-embedded tissues were cut and placed in eppendorf tubes for genomic DNA extraction. PCR was performed using two sets of primers for amplification of a 302 bp ITS-2 gene fragment and a 203 bp cytochrome oxidase subunit 1 (CO1) gene fragment of D. immitis. RESULTS: During the necropsy examination, 46 adult D. immitis were found in the portal vein, right ventricle, and atrium of the heart and pulmonary trunk. Microscopically, microfilarias were found throughout the vessels of different organs including lungs, kidneys, liver, heart, brain, and spleen. All tissues examined by PCR were positive for D. immitis ITS-2 and CO1. CONCLUSION: PCR technique now represents an effective method for identification of D. immitis from formalin-fixed samples. PMID- 23109955 TI - Production and Evaluation of Toxoplasma gondii Recombinant Surface Antigen 1 (SAG1) for Serodiagnosis of Acute and Chronic Toxoplasma Infection in Human Sera. AB - BACKGROUND: The assays currently available for the detection of specific anti Toxoplasma antibodies may vary in their abilities to detect serum immunoglobulins, due to the Lack of a purified standardized antigen. The aim of this study was evaluation the recombinant Toxoplasma gondii SAG1 antigen for the serodiagnosis of acute and chronic toxoplasmosis. METHODS: This study describes an ELISA using recombinant SAG1 for detection of IgM and IgG antibodies against Toxoplasma gondii in human sera. Genomic DNA of T. gondii (RH Strain) was isolated and PCR reaction was performed. Recovered DNA was cloned into PTZ57R cloning vector. The recombinant plasmid was detected by restriction analysis. The SAG1 gene was subcloned in the pET- 28a expression vector. Protein production was then induced with 1 mM isopropyl-D - thiogalactopyranoside (IPTG). A total of 204 sera were tested using a commercial IgG and IgM ELISA kit (Trinity, USA) as gold standard prior to testing them with the recombinant antigen. RESULTS: Tested sera were divided into the following groups:(a) The 74 T. gondii IgG positive (b) 70 T.gondii IgM positive (c) 60 sera who had no serological evidence of toxoplasmosis as negative sera.To determine the specificity of the test, we used other parasitic diseases including echinococusis (N=5), malaria (N=14), leishmaniasis (N=7),fasciolasis (N=4), sterengyloidiasis (N=1). Sensitivity and specificity of the generated recombinant IgG ELISA in comparison with commercial ELISA (Com ELISA) were 93% and 95%, and the sensitivity and specificity of the generated recombinant IgM ELISA were 87% and 95% respectively. CONCLUSION: The results acquired here show that this antigen is useful for diagnostic purposes and could be replaced by lysed, whole cell antigens for diagnosis of chronic toxoplasmosis. PMID- 23109956 TI - Seroprevalence of human hydatidosis using ELISA method in qom province, central iran. AB - BACKGROUND: The objective of this study was to determine the prevalence of cystic echinococcosis (CE) in Qom Province, central Iran using ELISA test. METHODS: Overall, 1564 serum samples (800 males and 764 females) were collected from selected subjects by randomized cluster sampling in 2011-2012. Sera were analyzed by ELISA test using AgB. Before sampling, a questionnaire was filled out for each case. Data were analyzed using Chi-square test and multivariate logistic regression for risk factors analysis. RESULTS: Seropositivity was 1.6% (25 cases). Males (2.2%) showed significantly more positivity than females (0.9%) (P= 0.03). There was no significant association between CE seropositivity and age group, occupation, and region. Age group of 30-60 years encompassed the highest rate of positivity. The seropositivity of CE was 2.1% and 1.2% for urban and rural cases respectively. Binary logistic regression showed that males were 2.5 times at higher risk for infection than females. CONCLUSION: Although seroprevalence of CE is relatively low in Qom Province, yet due to the importance of the disease, all preventive measures should be taken into consideration. PMID- 23109957 TI - Interleukin-10 and Transforming Growth Factor-beta in Early and Late Lesions of Patients with Leishmania major Induced Cutaneous Leishmaniasis. AB - BACKGROUND: Cutaneous leishmaniasis is a neglected parasitic disease, which imposes massive human distress and financial costs to the endemic countries. Better understanding of host immune response to the parasite leads to helpful strategies for disease control. Interleukin (IL)-10 and transforming growth factor (TGF)-beta are important immune regulatory cytokines, which appear to develop non-healing forms of leishmaniasis. However, there is little information about the function of IL-10 and TGF-beta in old world cutaneous leismaniasis. The aim of this study was to analyze the role of IL-10 and TGF-beta in human cutaneous leishmaniasis due to Leishmania major infection. METHODS: Biopsies were obtained from lesions of twenty proven cases of L. major induced cutaneous leishmaniasis. IL-10 and TGF-beta positive cells were detected by immunofluorescence staining of frozen sections and compared between two groups of patients with early and late lesions. RESULTS: The mean percentage of IL-10 positive cells were significantly (P= 0.035) higher in late lesions (0.51+/-0.24) than early ones (0.15+/-0.07). Similar results were obtained for TGF-beta with mean percentages of 0.16+/-0.05 and 0.53+/-0.28 in early and late lesions respectively (P= 0.008). CONCLUSION: IL-10 and TGF-beta are present in lesions of L. major induced cutaneous leishmaniasis and contribute to the pathogenesis of long lasting disease forms. PMID- 23109958 TI - Comparison of Resistant and Susceptible Strains of Trichomons vaginalis to Metronidazole Using PCR Method. AB - BACKGROUND: Metronidazole is drug of choice recommended by WHO for treatment of trichomoniasis, however, some reports claims drug resistance in Trichomonas vaginalis isolates recently. The objective of this study was to determine the minimum lethal concentration (MLC) of metronidazole in resistant and sensitive strains, as well as genetic patterns of these stains by PCR method. METHODS: From February 2006 to March 2007, in a cross sectional study, clinical and wet mount examination of vaginal smear along with culture were performed on 683 women attending to public and private outpatient clinics in Hamadan. Trichomoniasis marked based on major clinical symptoms. Diagnosis confirmed using wet mount microscopically and culture in Diamond medium. A serial concentration of metronidazole was provided and all isolated Trichomonas strains (resistant and sensitive) tested by standard method. Finally, all sensitive and resistant strains examined by PCR technique. RESULTS: Only 15/683, (2.2%) of patients clinically diagnosed trichomonal vaginitis were positive for T. vaginalis by wet smear and culture. The minimum lethal concentration (MLC) for clinically sensitive isolates was 25 ug/ml; however, this concentration for resistant isolates was 200 ug/ml after 24 h and 100 ug/ml after 50 h. The results of PCR examination of DNA from sensitive and resistant isolates had same pattern. The lanes appeared by two primers were 98 bp and 261 bp for both clinically sensitive and resistant strains. CONCLUSION: Resistance to metronidazole in T. vaginalis has not relation to genetic variations and might be related to some physiologic pathways of organism. PMID- 23109959 TI - Malaria and Anemia among Children in a Low Resource Setting In Nigeria. AB - BACKGROUND: This study aimed at determining the prevalence of malaria and anemia among children in rural community of Okada, Edo State Nigeria, as well as to assess the level of use of Insecticide treated bed nets and its impact on prevalence of malaria and anemia among study population. METHODS: Thick blood films from 226 children with signs and symptoms of malaria in Okada community were stained and examined for presence of malaria parasites. Hemoglobin concentration of all children was also determined using standard method. RESULT: A total of 185 (81.9%) children were infected with malaria parasite. Malaria parasitaemia was significantly affected by age (P =0.003). A significantly higher number of positive cases of malaria and anemia was observed in rainy season as compared to dry season (P<0.05). The prevalence of anemia in children was 47.3%. Malaria was a risk factor for development of anemia in children (OR=2.551; 95% CI=1.227, 5.305; P=0.015). Use of insecticide treated bed nets was recorded in 11(4.9%) of children studied, and did not significantly reduce the prevalence of malaria and anemia. However among malaria parasite infected children, its use significantly reduced the prevalence of anemia (OR=0.126; 95%CI=0.015, 1.047; P=0.031). CONCLUSION: Malaria and anemia among children was high malaria intervention progammes by relevant agencies is strongly advocated. PMID- 23109960 TI - Prevalence of Toxocara Spp. eggs in Public Parks in Tehran City, Iran. AB - BACKGROUND: The objective of the present research was to determine the frequency of Toxocara spp. eggs in soil samples of public parks, in the city of Tehran, Iran. METHODS: A total of 600 soil samples were taken from 120 parks between Aprils to November, 2008. Soil samples were collected from 5 distinct sites in the parks. The samples were washed with saline solution and the collected sediment from each park were equally divided and examined by floatation and Petri dish methods for Toxocara eggs. RESULTS: Ten percent were contaminated with Toxocara spp. eggs. The number of observed Toxocara eggs in each microscopic field was varied from 1-3. No significant differences were observed between floatation and Petri dish methods. CONCLUSION: Our public parks showed a high risk of toxocariasis and the need for preventive studies. PMID- 23109961 TI - Comparison of Agar Dilution, Broth Dilution, Cylinder Plate and Disk Diffusion Methods for Evaluation of Anti-leishmanial Drugs on Leishmania promastigotes. AB - BACKGROUND: Leishmaniases are a group of diseases caused by Leishmania parasites. Growing of drug unresponsiveness in leishmaniasis patients necessitates the development of new drugs and accordingly a suitable assay is needed for evaluation of any modalities. The aim of this study was to compare four drug assays methods, agar dilution, broth dilution, cylinder plate and disk diffusion, for evaluation of anti-leishmanial drugs on Leishmania promastigotes, using glucantime as a currently available drug for treatment of leishmaniasis. METHODS: For broth dilution method, different concentration of glucantime was added to the parasite culture (promastigotes of Leishmania), while in cylinder plate method wells were punched in agar gel and filled with different concentration of drug and zone of inhibition was measured in each well. In disk diffusion method, the parasites were cultivated on the surface of agar; filter paper disks were enriched with various concentration of glucantime and were placed on the surface of agar. In agar dilution method, various concentrations of drug were incorporated onto blood agar and the parasites were cultivated on the surface of the agar. RESULTS: A direct correlation was found between the drug concentration and size of inhibitory zones in cylinder plate and disk diffusion methods. These two drug assays methods provided much better performance in comparison with broth and agar dilution methods. CONCLUSION: Cylinder plate and disk diffusion methods seem to be acceptable methods for susceptibility testing of anti-leishmanial compounds on Leishmania promastigotes. PMID- 23109962 TI - Expression and Purification of P43 Toxoplasma gondii Surface Antigen. AB - BACKGROUND: Toxoplasma gondii is an obligate intracellular protozoan parasite, capable of infecting all species of mammals including man. Congenital toxoplasmosis is more important during pregnancy for the first time. In this study we expressed and purified P43 Toxoplasma gondii tachyzoite and bradyzoite specific surface antigen. METHODS: The recombinant pGEMEX-1 contained Toxoplasma P43 coding sequence was transformed into E. coli and mass cultured in LB medium contained 100 MUg/ml ampicillin at 37 degrees C over night. The T7 promoter was induced by 1mM isopropyl-1-thio-beta-D-galactopyranoside (IPTG. Recombinant protein was purified by affinity chromatography and confirmed by gel diffusion dot blot and western blot,-using specific anti Toxoplasma antibodies. RESULTS: Recombinant plasmid was induced by IPTG and analyzed by SDS-PAGE. Recombinant protein was confirmed by Western-blot and dot blot using anti human Toxoplasma antibody. CONCLUSION: Recombinant Toxoplasma P43 was produced successfully. PMID- 23109963 TI - In Vitro Trypanocidal Activity of Antibodies to Bacterially Expressed Trypanosoma brucei Tubulin. AB - BACKGROUND: There are only four drugs for treating African trypanosomiasis, a devastating disease in sub-Saharan Africa. With slow discovery of better drugs, vaccination is viewed as the best method of control. We previously showed that antibodies to native Trypanosoma brucei brucei tubulin inhibit the growth of trypanosomes in culture. Here, we aimed to determine the effect of antibodies to bacterially expressed trypanosome tubulin on T. brucei brucei growth. METHODS: T. brucei brucei alpha and beta tubulin genes were individually expressed in Escherichia coli under the tryptophan promoter. Monoclonal tubulin antibodies reacted specifically with the expressed tubulins with no cross-reaction with the opposite tubulin. Rabbits were immunized with 450ug each of the concentrated recombinant tubulin, and production of antibodies assessed by ELISA and Western blotting. The effect of polyclonal antibodies on trypanosome growth was determined by culturing bloodstream T. brucei brucei in up to 25% of antisera. RESULTS: Low antisera dilutions (25%) from the immunized rabbits inhibited trypanosome growth. The most cytotoxic antisera were from one rabbit immunized with a mixture of both alpha and beta tubulins. However, the result was not reproduced in other rabbits and there was no apparent effect on growth at higher antisera dilutions. CONCLUSION: Antibodies to bacterially expressed trypanosome tubulin are not effective at killing cultured bloodstream trypanosomes. PMID- 23109964 TI - Detection and Identification of Toxoplasma gondii Type One Infection in Sheep Aborted Fetuses in Qazvin Province of Iran. AB - BACKGROUND: The aim of this study was to apply the nested-PCR and bioassay methods in detection and genotyping of Toxoplasma gondii infection in provided sheep aborted fetus samples from Qazvin Province of Iran. METHODS: Eighteen sheep aborted fetal samples were studied by nested-PCR-RFLP, histopathological observation and microbiological assay. Bioassay in mice was carried out by inoculating the brain samples intraperitoneally. RESULTS: The results demonstrated the frequency of 66% infected sheep aborted fetal samples with T. gondii type one. Although we could not isolate any parasite from inoculated mice even after three passages, but it was confirmed histopathologically formation of cyst like bodies in prepared mice brain sections. CONCLUSION: The results of the performed nested-PCR and formation of brain cyst in inoculated mice exhibited that T. gondii type one infection might be considered as one of the major causative agents for abortion in ewes. PMID- 23109965 TI - Larva Migration and Eosinophilia in Mice Experimentally Infected With Gnathostoma spinigerum. AB - BACKGROUND: Gnathostoma spinigerum causes larva migran in human which is endemic in Southeast Asia. Information regarding larva migration is limited. In this study, we investigated the parasite migration by recovery of worms from the whole body of mouse after oral infection with advanced third stage larvae (AL3). The percentage of blood eosinophils was examined in parallel. METHODS: Mice were orally infected with AL3 and histological study of organs was investigated in order to study the migration of AL3, along with blood eosinophilia. RESULTS: At 1 hr post infection (PI), the larvae remained in the stomach, thereafter at 3, 5, 7, 10 and 24 hr PI; they were recovered from various organs including liver, mesentery, esophagus, diaphragm, lung, heart and dorsal fat. At day 15 PI, they were mostly found in muscles (76.47%). The average worm recovery (5 months) was 78.03%. The worms were found in the liver at every time point. Larva encystment was detected. There was a significant difference in blood eosinophils between the 8 larvae- (average 9.33% + 6.25%) and the 15 larvae-infected groups (average 22.66% + 11.03%). Surprisingly, the blood eosinophils (average 19.00% + 2.92%) were not higher in the higher infective dose- group (25 larvae). CONCLUSION: Liver was involved by G. spinigerum throughout the study. We detected larva encystment which had never been reported in human gnathostomiasis. The highest percentage of eosinophil occurred during the invasive stage. PMID- 23109966 TI - Malaria in mazandaran, northern iran: passive case finding during 1997-2012. AB - BACKGROUND: Malaria is one of the most important parasitic diseases in tropical and temperate regions. The aim of this study was to determine the trend of malaria in Mazandaran Province, northern Iran during 1997-2012. METHODS: This retrospective study was conducted from 1997 to 2012. The population's study was individuals who registered at health centers of Mazandaran Province. Peripheral blood smear were prepared for each case, stained with Giemsa and examined by light microscope. In addition to demographic data, other parameters including Slide Positive Rate (SPR), Annual Parasite Incidence (API) and Annual Blood Examination Rate (ABER) were analyzed. RESULTS: In total, 844 cases of malaria were reported. Plasmodium vivax was predominant species with 821 cases (97.4%). The number of malaria cases increased from 1997 to 2005 and then decreased to 3 cases in 2011. Some cities had not reported any cases during last three years. The highest infection rate, 163(20.07%), was seen in 2001-02. The SPR had the highest value (0.54%) in 2004-05. The maximum API and ABER were observed in 2001 02 and 1997-98. 641(75.9%) of cases were imported from hyperendemic areas such as Afghanistan and South-eastern Iran and 94 (11.1%) malaria patients were recorded as introduced cases. The highest infection rate of malaria (21.3%) was seen in Babolsar. CONCLUSION: Extensive malaria control should be continued to Mazandaran to become malaria-free region and in prevention of re-introduction stage. PMID- 23109967 TI - Comparison of a Commercial ELISA with the Modified Agglutination Test for Detection of Toxoplasma gondii Antibodies in Sera of Naturally Infected Dogs and Cats. AB - BACKGROUND: Toxoplasma gondii can infect all warm-blooded animals. Modified agglutination test (MAT) and ELISA are widely used for the detection of T. gondii antibodies. However, there is little information on their acceptability for detecting antibodies in companion animals. METHODS: This study compared ELISA and MAT for their ability to detect T. gondii infection in naturally infected dogs and cats. Blood samples were collected from dogs and cats in different areas of Beijing, China and analyzed by ELISA and MAT. The chi(2) test and kappa analysis were used to evaluate their efficiency and agreement. RESULTS: For dogs, the seroprevalence of T. gondii antibodies detected by ELISA was 34.7%, which was significantly higher than that detected by MAT (P<0.05). There was no significant difference between ELISA and MAT for detecting T. gondii antibodies in cats. Good agreements between MAT and ELISA were seen in both dogs and cats; however, inconsistent results were demonstrated by kappa analysis and in MAT titer assay. CONCLUSION: Serum-based ELISA may be more satisfactory for screening test of T. gondii infection in dogs, whereas both methods could be acceptable in cats. PMID- 23109968 TI - Urinary schistosomiasis with simultaneous bladder squamous cell carcinoma and transitional cell carcinoma. AB - This is a case report concerning a 60 years old man who lived for a short period in an endemic area of Khuzestan Province (neighboring province of Persian Gulf in Iran) for approximately 20 years ago. Recently he referred to the Urology Department of Kerman University of Medical Sciences with hematuria and dysuria. In the sonography a polypoid mass on the bladder floor was observed. In the cystoscopy and biopsy a bladder tumor (Simultaneous squamous cell carcinoma and Transitional Bladder Cell Carcinoma) and schistosomiasis (Schistosoma haematobium) was diagnosed. PMID- 23109969 TI - Fatal Case of Plasmodium vivax Malaria in a Splenectomized Patient. AB - Malaria is a major problem in tropical and sub-tropical countries, with high morbidity and mortality. Splenectomy makes patients more susceptible to serious bacterial and parasitic infections. We report for the first time in Iran a fatal case of Plasmodium vivax malaria, confirmed by microscopic and molecular (Semi nested multiplex PCR) tests in a patient who had undergone splenectomy due to hemolytic anemia. PMID- 23109970 TI - A Case of Sparganosis mansoni in the Thigh: Serological Validation of Cure Following Surgery. AB - Cases of Sparganum mansoni, caused by the plerocercoid larva of the tapeworm S. mansoni, occur throughout the world, particularly in Asian, Middle Eastern, and European countries. However, cases of infection with this parasite are rarely seen in Japan. Here, we present a case of a 61-year-old woman with a solitary subcutaneous nodule in left inner aspect of the thigh, from which a long, slender, whitish worm was surgically removed. The parasite was histopathologically identified as S. mansoni. Serological testing confirmed cure of the infection after surgical removal of the parasite. The authors advocate immunoserological examination in case of S. mansoni. PMID- 23109972 TI - Clinicopathologic features of q Fever patients with acute hepatitis. AB - BACKGROUND: Q fever caused by Coxiella burnetii presents with diverse clinical and pathological features including subclinical or cholestatic hepatitis. However, the pathological features of liver biopsies from patients with Q fever have not been well described. METHODS: Clinical features and pathological findings of liver biopsies were reviewed in seven cases of Q fever that were confirmed by serological, microbiological, or molecular tests. RESULTS: All cases presented with fever. Liver enzymes were mildly elevated except one case with marked hyperbilirubinemia. Characteristic fibrin ring granulomas were present in three cases, epithelioid granulomas with eosinophilic infiltration in two cases, extensive extravasated fibrins without ring configuration mimicking necrotizing granuloma in one case, and acute cholangitis without granuloma in one case. All cases were treated with antibiotics for 20 days. Six cases were completely cured, but one suffered from multiorgan failure. CONCLUSIONS: C. burnetii infection is uncommon, but should always be considered in patients with acute hepatitis and fever. Because variable-sized circumferential or radiating fibrin deposition was a consistent feature of the present cases, Q fever can be strongly suggested by pathological features and confirmed by serological and/or molecular tests. PMID- 23109971 TI - CpG island hypermethylation in gastric carcinoma and its premalignant lesions. AB - Gastric cancers arise through a multistep process characterized by the progressive accumulation of molecular alterations in which genetic and epigenetic mechanisms have been implicated. Gastric cancer is one of the human malignancies in which aberrant promoter CpG island hypermethylation is frequently found. Helicobacter pylori and Epstein-Barr virus, which are known carcinogens for gastric cancer, are closely associated with enhanced hypermethylation of CpG island loci in gastric non-neoplastic epithelial cells and cancer cells, respectively. Aberrant CpG island hypermethylation occurs early in the multistep cascade of gastric carcinogenesis and tends to increase with the step-wise progression of the lesion. Approximately 400 genes that are actively expressed in normal gastric epithelial cells are estimated to be inactivated in gastric cancers as a result of promoter CpG island hypermethylation. In this review, a variety of information is summarized regarding CpG island hypermethylation in gastric cancer. PMID- 23109973 TI - The ratio of atypical ductal hyperplasia foci to core numbers in needle biopsy: a practical index predicting breast cancer in subsequent excision. AB - BACKGROUND: Although core needle biopsy (CNB) is considered to be the standard technique for histological diagnosis of breast lesions, it is less reliable for diagnosing atypical ductal hyperplasia (ADH). We therefore assessed the characteristics of CNB-diagnosed ADH that are more likely to be associated with more advanced lesions on subsequent surgical excision. METHODS: We retrospectively examined 239 consecutive CNBs, 127 of which were diagnosed as ADH following surgical excision, performed at Asan Medical Center between 1995 and 2010. Archival slides were analyzed for the number of cores per specimen, the number of ADH foci, and the ratio of ADH foci to number of cores (FC ratio). RESULTS: We found that ADH foci in 3 or more cores (p=0.003) and the presence of ADH in 3 or more foci (p=0.002) were correlated with malignancy following excision lesion. Moreover, an FC>1.1 was significantly associated with malignancy in the subsequent excision (p=0.000). CONCLUSIONS: Including the number of ADH foci, the number of cores involved according to ADH, FC ratio, and histologic type in a pathology report of CNB may help in making clinical decisions about surgical excision. PMID- 23109974 TI - Chemotherapy-associated hepatopathy in korean colorectal cancer liver metastasis patients: oxaliplatin-based chemotherapy and sinusoidal injury. AB - BACKGROUND: Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed. METHODS: Hematoxylin eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure. RESULTS: Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044). CONCLUSIONS: Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection. PMID- 23109975 TI - TNF-alpha and TNF-beta Polymorphisms are Associated with Susceptibility to Osteoarthritis in a Korean Population. AB - BACKGROUND: The tumor necrosis factor (TNF) is believed to play an important role in the pathophysiology of osteoarthritis (OA). Evidence shows that genetic polymorphisms make substantial contributions to the etiology of OA. METHODS: We investigated the genotypes TNF-alpha and TNF-beta in 301 OA patients and 291 healthy subjects as controls. We employed a polymerase chain reaction-restriction fragment length polymorphism and a polymerase chain reaction-single strand conformation polymorphism assay to identify the genotypes TNFA -G308A and TNFB +G252A, respectively. RESULTS: For TNFA -G308A, the percentages of genotypes GG, AG, and AA were 26.3% (79/301), 62.5% (188/301), and 11.3% (34/301) in OA patients and 88.7% (258/291), 11.3% (33/291), and 0% (0/291) in controls. For TNFB +G252A, the percentages of genotypes GG, AG, and AA were 15.3% (46/301), 41.9% (126/301), and 42.9% (129/301) in OA patients and 12% (35/291), 52.6% (153/291), and 35.4% (103/291) in controls. There were significant differences in genotypes and alleles of TNFA -308 between OA patients and controls (p<0.0001) and in alleles of TNFB +252 (p=0.0325). The risk of OA was significantly higher for carriers of the TNFA -308A allele and the TNFB +252 AA homozygote (p=0.0224). CONCLUSIONS: The results suggest close relationships between TNFA -G308A and TNFB +G252A polymorphisms and individual susceptibility to OA in the Korean population. PMID- 23109976 TI - Nuclear image analysis study of neuroendocrine tumors. AB - BACKGROUND: There is a subjective disagreement about nuclear chromatin in the field of pathology. Objective values of red, green, and blue (RGB) light intensities for nuclear chromatin can be obtained through a quantitative analysis using digital images. METHODS: We examined 10 cases of well differentiated neuroendocrine tumors of the rectum, small cell lung carcinomas, and moderately differentiated squamous cell lung carcinomas respectively. For each case, we selected 30 representative cells and captured typical microscopic findings. Using an image analyzer, we determined the longest nuclear line profiles and obtained graph files and Excel data on RGB light intensities. We assessed the meaningful differences in graph files and Excel data among the three different tumors. RESULTS: The nucleus of hematoxylin and eosin-stained tumor cells was expressed as a combination of RGB light sources. The highest intensity was from blue, whereas the lowest intensity was from green. According to the graph files, green showed the most noticeable change in the light intensity, which is consistent with the difference in standard deviations. CONCLUSIONS: The change in the light intensity for green has an important implication for differentiating between tumors. Specific features of the nucleus can be expressed in specific values of RGB light intensities. PMID- 23109977 TI - Interobserver variability in diagnosing high-grade neuroendocrine carcinoma of the lung and comparing it with the morphometric analysis. AB - BACKGROUND: Distinguishing small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is difficult with little information about interobserver variability. METHODS: One hundred twenty-nine cases of resected SCLC and LCNEC were independently evaluated by four pathologists and classified according to the 2004 World Health Organization criteria. Agreement was regarded as "unanimous" if all four pathologists agreed on the classification. The kappa statistic was calculated to measure the degree of agreement between pathologists. We also measured cell size using image analysis, and receiver-operating-characteristic curve analysis was performed to evaluate cell size in predicting the diagnosis of high-grade neuroendocrine (NE) carcinomas in 66 cases. RESULTS: Unanimous agreement was achieved in 55.0% of 129 cases. The kappa values ranged from 0.35 to 0.81. Morphometric analysis reaffirmed that there was a continuous spectrum of cell size from SCLC to LCNEC and showed that tumors with cells falling in the middle size range were difficult to categorize and lacked unanimous agreement. CONCLUSIONS: Our results provide an objective explanation for considerable interobserver variability in the diagnosis of high-grade pulmonary NE carcinomas. Further studies would need to define more stringent and objective definitions of cytologic and architectural characteristics to reliably distinguish between SCLC and LCNEC. PMID- 23109978 TI - Biologic response to carbonated hydroxyapatite associated with orthopedic device: experimental study in a rabbit model. AB - BACKGROUND: Carbonated hydroxyapatite (CHA) and related calcium phosphates have been studied for many years as implant materials due to their similarity with the mineral phase of bone. The main limitation of CHA ceramics as well as other bioactive materials is that they have poor mechanical proprieties. It is thought that the mechanical device can cause an increase in metabolic activity and bone healing. In this study we investigated the reactivity and tissue behaviour of implanted CHA biomaterial reinforced by mini external fixator. METHODS: The evaluation of biomaterial biocompatibility and osteogenesis was performed on a rabbit model over a period of 6 weeks by radiological, histological and scanning electron microscopy (SEM) coupled with energy dispersive X-ray SEM-energy dispersive X-ray (EDX) analysis. RESULTS: While rabbits treated with CHA exhibited more bone formation, and fibrous tissue was observed when empty bone defects were observed. EDX analysis detected little calcium and phosphorus on the surface of the bone that was not implanted, while high content of calcium (62.7%) and phosphorus (38%) was found on the interface bone cement. CONCLUSIONS: Bone repairing showed that the mini external fixator stimulated the ossification which was pushed when grafted by CHA. This effect may play an important role in the prevention of implant loosening. PMID- 23109979 TI - Detection of Survivin and COX-2 in Thyroid Carcinoma: Anaplastic Carcinoma Shows Overexpression of Nuclear Survivin and Low COX-2 Expression. AB - BACKGROUND: Overexpression of survivin, a member of the inhibitors of apoptosis protein, has been reported in various carcinomas, and its interaction with cyclooxygenase 2 (COX-2) results in accelerated tumor progression. The purpose of this study is to investigate the immunohistochemical expression of survivin and COX-2 in benign and malignant thyroid tissues and to define its association with pathologic and clinical features. METHODS: We examined expression of survivin and COX-2 by immunohistochemistry in 334 benign and malignant thyroid tissues and evaluated their clinical significance. RESULTS: Expression of survivin showed an increase along the spectrum of thyroid carcinoma progression; rarely positive in adenomatous goiter, moderately positive in papillary carcinoma, and strongly positive in anaplastic carcinoma (AC). Papillary microcarcinoma revealed the highest COX-2 positivity and AC demonstrated the lowest positivity among thyroid cancers. Node negative carcinomas showed higher COX-2 expression than node positive tumors. Survivin expression did not correlate with COX-2. CONCLUSIONS: Our findings suggest that survivin overexpression may be related to the pathogenesis of AC and can be a predictor of disease progression. COX-2 may be involved in the early phase of thyroid carcinoma. PMID- 23109980 TI - Detection of BRAF(V600E) Mutations in Papillary Thyroid Carcinomas by Peptide Nucleic Acid Clamp Real-Time PCR: A Comparison with Direct Sequencing. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) of the thyroid is the most common endocrine malignancy. High prevalence of an activating point mutation of BRAF gene, BRAF(V600E), has been reported in PTC. We assessed the efficiency of peptide nucleic acid clamp real-time polymerase chain reaction (PNAcqPCR) for the detection of BRAF(V600E) mutation in PTC in comparison with direct sequencing (DS). METHODS: A total of 265 thyroid lesions including 200 PTCs, 5 follicular carcinomas, 60 benign lesions and 10 normal thyroid tissues were tested for BRAF(V600E) mutation by PNAcqPCR and DS. RESULTS: The sensitivity and accuracy of the PNAcqPCR method were both higher than those of DS for the detection of the BRAF(V600E) mutation. In clinical samples, 89% of PTCs harbored the BRAF(V600E) mutation, whereas 5 follicular carcinomas, 50 benign lesions and 10 normal thyroid tissues lacked the mutation. The mutation was associated with aggressive clinical behaviors as extrathyroid invasion (p=0.015), lymph node metastasis (p=0.002) and multiple tumor numbers (p=0.016) with statistical significance. CONCLUSIONS: The PNAcqPCR method is efficiently applicable for the detection of the BRAF(V600E) mutation in PTCs in a clinical setting. PMID- 23109981 TI - Evaluation of Urine Cytology in Urothelial Carcinoma Patients: A Comparison of CellprepPlus(r) Liquid-Based Cytology and Conventional Smear. AB - BACKGROUND: Urine cytology is an important test in the screening of urothlelial neoplasms. The conventional smear (CS) method of testing urine samples has a low sensitivity, approximately 50% result accuracy for detecting urothelial carcinomas, while liquid-based cytology (LBC) has much improved diagnostic accuracy, sensitivity, and specificity. The aim of this study was to compare the morphologic features and diagnostic efficacy of CellprepPlus(r) LBC with those of CS for urine cytology. METHODS: A total of 713 cases of urine specimens collected from November 2009 to September 2010 were included. All specimens were divided equally for the preparation of CellprepPlus(r) LBC and CS for each case. RESULTS: CellprepPlus(r) revealed more cellularity, a cleaner background and better cytomorphologic features, but it showed a less intact architectural pattern compared to that of CS. Of the 88 histologically confirmed cases, the diagnostic sensitivity for CellprepPlus(r) was 50% and higher than the 37.5% for CS. The specificity of both preparations was 100%. CONCLUSIONS: The CellprepPlus(r) showed an improved quality of slides and provided better diagnostic accuracy, thus CellprepPlus(r) could be a first-line screening tool in urinary tract cytology. PMID- 23109982 TI - A soft tissue perineurioma and a hybrid tumor of perineurioma and schwannoma. AB - Perineuriomas are composed of differentiated perineurial cells. Perineuriomas have been recently recognized by the immunoreactivity for epithelial membrane antigen (EMA). Microscopically, perineuriomas show proliferation of spindle cells with wavy nuclei and delicate elongated bipolar cytoplasmic processes. The tumor cells are usually negative for the S-100 protein. Ultrastructurally, perineurial cells reveal slender, nontapered processes containing pinocytic vesicles and discontinuous basal lamina. Interestingly, hybrid tumors of benign peripheral nerve sheath tumor (PNST) have been recently reported by using immunohistochemical and ultrastructural investigations. Herein, we report a case of soft tissue perineurioma arising in the skin of a 56-year-old female; another case of a hybrid tumor of perineurioma and schwannoma in the posterior mediastinum occurred in a 53-year-old male, which is the first case of the hybrid PNST tumor reported in Korea. PMID- 23109983 TI - Hyaline vascular castleman disease involving renal parenchyma and a lymph node: a case report. AB - Castleman disease is a rare lymphoproliferative lesion that is predominantly found in the mediastinum. Retroperitoneal and pararenal localizations are very rare. We describe a 36-year-old man with a hyaline vascular type of Castleman disease involving renal parenchyma and a paraaortic lymph node. Most reported renal Castleman disease was plasma cell type with systemic symptoms. Herein, we report the first Korean case of the hyaline vascular type of Castleman disease involving the renal parenchyma and the paraaortic lymph node simultaneously. PMID- 23109984 TI - Urachal mucinous tumor of uncertain malignant potential: a case report. AB - Urachal mucinous tumor of uncertain malignant potential is very rare and is characterized by a multilocular cyst showing the proliferation of atypical mucin secreting cells without stromal invasion. As in ovarian and appendiceal borderline tumors, it represents a transitional stage of mucinous carcinogenesis in the urachus. In addition, this tumor may recur locally and develop into pseudomyxoma peritonei. Due to its scarcity and diagnostic challenges, we report a mucinous tumor of uncertain malignant potential arising in the urachus. PMID- 23109985 TI - Mimicry of Minute Pulmonary Meningothelial-like Nodules to Metastatic Deposits in a Patient with Infiltrating Lobular Carcinoma: A Case Report and Review of the Literature. AB - Minute pulmonary meningothelial-like nodules (MPMNs) are incidentally found lesions in lung resection specimens and autopsies. MPMNs have been associated with neoplastic and non-neoplastic pulmonary conditions and occasionally with extrapulmonary diseases. We report a case of a female patient presenting with invasive lobular carcinoma of the breast and MPMNs, masquerading as metastatic deposits. We describe the morphological, immunohistochemical and ultrastructural features of MPMNs and emphasize the importance of their recognition for proper staging and treatment of patients. To our knowledge, this is the first case in the English literature describing this coexistence. PMID- 23109986 TI - Metaplastic thymoma: report of 4 cases. AB - Metaplastic thymoma (MT), accepted in the World Health Organization 2004 scheme, is a circumscribed tumor of the thymus exhibiting biphasic morphology. We herein describe the clinicopathologic features of four MTs and the differential diagnoses of this unusual tumor. There were three women and one man with mean age of 49.5 years. The patients were found to have mediastinal masses, and underwent surgical excision. One exhibited symptoms of myasthenia gravis, and the serum titer for anti-acetylcholine receptor antibody was positive. Grossly, the tumors were encapsulated, and showed vaguely multinodular, solid, tan-white to yellow cut surfaces. Histologically, they comprised epithelial islands intertwining with bundles of delicate spindle cells. The patients remained well after surgical excision at 5-55 months. Because of the distinctive histological appearance and benign clinical course, MT should be distinguished from other more aggressive mediastinal neoplasms displaying biphasic feature. PMID- 23109987 TI - Adenocarcinoma with intraductal papillary mucinous neoplasm arising in jejunal heterotopic pancreas. AB - A 74-year-old man suffered from jejunal perforation and adhesion to sigmoid colon due to adenocarcinoma associated with intraductal papillary mucinous neoplasm (IPMN) arising in a jejunal heterotopic pancreas. The jejunal lesion showed direct extension to the sigmoid colon, which was mistaken as sigmoid colon cancer by surgeons. Malignant transformation is a rare complication of a heterotopic pancreas. About half of malignancies in reported cases were ductal adenocarcinoma arising in the stomach, and the jejunal location is extremely rare. Furthermore, IPMN is also uncommon finding in a heterotopic pancreas. PMID- 23109988 TI - Fine needle aspiration cytology of metastatic adenocarcinoma of the gingiva from the lung: a case report. AB - Metastases of malignant tumors to the oral region from distant sites are uncommon. A 45-year-old man with painless gingival swelling was diagnosed with adenocarcinoma of the lung. On cytology, clusters of tumor cells on mucous background revealed enlarged nuclei, indistinct cell borders, and irregular nuclear membranes. Some cells showed nuclear inclusions, nuclear grooves and small nucleoli. These findings are indicative of metastatic adenocarcinoma. We present a case of gingival metastasis from a lung adenocarcinoma. PMID- 23109989 TI - Clinicopathologic Features of IgA-Dominant Postinfectious Glomerulonephritis. AB - BACKGROUND: IgA-dominant acute postinfectious glomerulonephritis (APIGN) is a recently recognized morphologic variant of APIGN, but its clinicopathologic features were not clearly characterized. We will present demographic, clinical and renal biopsy findings from seven patients with IgA-dominant APIGN with a literature review. METHODS: All renal biopsy specimens (n=1,119) processed by the Department of Pathology in Hanyang University Hospital from 2005 to 2009 were reviewed. Seven patients with IgA-dominant APIGN were identified, and their clinical data analyzed. RESULTS: All patients had renal failure, hematuria and proteinuria. One was diabetic, and none of the patients had previous renal diseases. Three had clinical infections at the time of presentation: 2 with methicillin-resistant Staphylococcus aureus and one with rickettsial infection. Light microscopically diffuse endocapillary proliferative and exudative glomerulonephritis was found in all cases. Immunofluorescence microscopy showed granular IgA deposits along peripheral capillary walls and in mesangium. Ultrastructurally, subepithelial 'humps' with mesangial deposits were noted. End stage renal disease developed in two patients, chronic renal failure was stationary in two, and azotemia improved in three. CONCLUSIONS: Various infections including rickettsiosis preceded IgA-dominant APIGN in both diabetics and nondiabetics. Because the prognosis of IgA-dominant APIGN is poor, early diagnosis based on renal biopsy is required. PMID- 23109990 TI - Diagnostic Value of MDM2 and DDIT3 Fluorescence In Situ Hybridization in Liposarcoma Classification: A Single-Institution Experience. AB - BACKGROUND: The amplification of murine double minutes (MDM2) is the primary feature of well-differentiated liposarcomas (WDLPS) and dedifferentiated liposarcomas (DDLPS), while DDIT3 rearrangement is the main one of myxoid liposarcomas (MLPS). Our aim was to evaluate the added value of MDM2 amplification and DDIT3 rearrangement in making a diagnosis and classifying lipogenic tumors. METHODS: Eighty-two cases of liposarcoma and 60 lipomas diagnosed between 1995 and 2010 were analysed for MDM2 amplification and DDIT3 rearrangement using a fluorescence in situ hybridization (FISH). The subtypes of liposarcoma were reclassified according to the molecular results, whose results were reviewed with an analysis of the relevant histologic and immunohistochemical findings. RESULTS: One case of lipoma (1.67%) was reclassified as a WDLPS. Of the liposarcomas, 13.4% (16/82) were reclassified after the molecular testing. Five cases of MLPS were reclassified as four cases of DDLPS and one case of myxoid lipoma. Two cases of WDLPS were reclassified as one case of spindle cell lipoma and another case of myxofibrosarcoma. Four cases of DDLPS were reclassified as two cases of leiomyosarcoma, one case of angiomyolipoma and another case of fibroinflammatory lesion. Of the six cases of pleomorphic liposarcoma, five were reclassified as DDLPS. CONCLUSIONS: In our series, a critical revision of diagnosis was found at a rate of 3.5% (5/142) after a review of the lipomatous lesions. The uses of molecular testing by MDM2 and DDIT3 FISH were valuable to make an accurate subtyping of liposarcomas as well as to differentiate WDLPS from benign lipomatous tumor. PMID- 23109991 TI - Difference of Genome-Wide Copy Number Alterations between High-Grade Squamous Intraepithelial Lesions and Squamous Cell Carcinomas of the Uterine Cervix. AB - BACKGROUND: About 10% of high-grade squamous intraepithelial lesions (HSILs) progress to invasive carcinomas within 2-10 years. By delineating the events that occur in the early stage of the invasion, the pathogenesis of cervical cancer could be better understood. This will also propose the possible methods for inhibiting the tumor invasion and improving the survival of patients. METHODS: We compared the genomic profiles between the HSIL and the invasive squamous cell carcinoma (SCC) using an array comparative genomic hybridization. Using recurrently altered genes, we performed a principal component analysis to see variation of samples in both groups. To find possibly affected pathways by altered genes, we analyzed genomic profiles with the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database and GOEAST software. RESULTS: We found 11q12.3 and 2p24.1 regions have recurrent copy number gains in both groups. 16p12 13 and 20q11-13 regions showed an increased copy number only in cases of HSIL. 1q25.3 and 3q23-29 regions showed copy number gains only in cases of SCC. Altered genes in the SCC group were related to the mitogen-activated protein kinase signaling pathway and the RNA transport. Altered genes in the HSIL group were related to the ubiquitin mediated proteolysis and cell adhesion molecules. CONCLUSIONS: Our results showed not only that gains in 11q12.3 and 2p24.1 were early events occurring in the premalignant lesions and then maintained in cases of SCC but also that gains in 1q25.3 and 3q23-29 were late events occurring after invasion in those of SCC. PMID- 23109992 TI - Markers for screening lynch syndrome are reliable and useful for identifying the specimen mislabeling. AB - BACKGROUND: During specimen processing in surgical pathology laboratories, specimen-related adverse events (SRAEs), such as mislabeling and specimen mixed up might occur. In these situations, molecular techniques using short tandem repeat (STR) loci are required to identify the personal identity. Microsatellite instability (MSI) test is widely used for screening the hereditary non-polyposis colon cancer (Lynch syndrome) in surgical pathologies using polymorphic STR markers. We tried to evaluate the applicability of the MSI test for SRAEs. METHODS: We obtained 253 MSI test results to analyze the allele frequencies. After calibrating the estimated nucleotide lengths, we calculated the allele frequencies, a random match probability, and a likelihood ratio (LR) of three dinucleotide STR markers (D5S349, D17S250, and D2S123). RESULTS: The distribution of LR was 136.38 to 5,606,213.10. There was no case of LR<100. In addition, there were 153 cases (60.5%) of LR ranging from 100 to 10,000 and 100 cases (39.5%) of LR>10,000. Furthermore, the combined probability of identity was 9.23*10(-4) and the combined power of exclusion was 0.99908. CONCLUSIONS: Using the three STR markers that are recommended for MSI test, all the cases were positively identified in 1% range and about one-third cases showed high LR (>10,000). These results showed that MSI tests are useful to screen the personal identity in case of SRAE in pathology laboratories. PMID- 23109993 TI - Significance of electron dense deposits in patients with minimal change nephrotic syndrome. AB - BACKGROUND: Minimal change nephritic syndrome (MCNS) is characterized by a lack of obvious abnormalities on light microscopy, but its electron microscopic findings include the negative immunofluorescence findings and the diffuse effacement of the epithelial cell foot processes. Rarely the presence of electron dense deposits (EDDs) has been reported, but its clinical significance remains obscure. METHODS: Eleven patients with MCNS who had the EDD deposited were enrolled in the current study. We compared the clinical characteristics, laboratory results and response to steroid treatment between the two group: the EDD group (n=11; the male-to-female ratio, 8:3) and the non-EDD group (n=13, 8:5). RESULTS: There were no significant differences in most of the laboratory results or response to steroid treatment between the two groups. The frequency of relapses per year was significantly higher in the EDD group (1.1+/-0.7 times vs. 0.5+/-0.6 times; p=0.023). These EDDs were found in the mesangium or paramesangium. With no respect to the characteristics of EDDs, our results showed that they did not cause poor treatment outcomes except for the annual frequency of relapse. CONCLUSIONS: Further large-scale studies are warrented to determine the immunologic and prognostic significance of EDDs in patients with MCNS. PMID- 23109994 TI - Expression of HAT1 and HDAC1, 2, 3 in Diffuse Large B-Cell Lymphomas, Peripheral T-Cell Lymphomas, and NK/T-Cell Lymphomas. AB - BACKGROUND: It has generally been proven that histone acetylation and deacetylation are involved in the malignant transformation. To date, however, this has rarely been studied in cases of malignant lymphoma. METHODS: We studied nine cases of reactive lymphoid hyperplasia, 78 cases of diffuse large B-cell lymphoma (DLBCL), 13 cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and 13 cases of extranodal NK/T-cell lymphoma, nasal type (NKTCL). Thus, we attempted to elucidate the associations of the degree of the expression of histone acetyltransferase 1 (HAT1), histone deacetylase (HDAC) 1, HDAC2, and HDAC3 with the clinical behaviors of above malignant lymphomas using the immunohistochemistry and a western blot analysis. RESULTS: The degree of the expression of HAT1 was higher in cases of DLBCL, PTCL-NOS or NKTCL as compared with reactive lymphoid hyperplasia (p<0.05). The degree of the expression of HAT1 was correlated with that of HDAC1 in cases of DLBCL or NKTCL (p<0.05). The degree of the expression of HAT1 and HDAC1 was correlated with a poor survival in cases of DLBCL or PTCL-NOS (p>0.05). CONCLUSIONS: HAT1, HDAC1, and HDAC2 play a critical role in the development of malignant lymphomas. Both HAT1 and HDAC1 might be indicators for a poor prognosis in cases of DLBCL as cooperating factors. PMID- 23109995 TI - Evaluation of Bronchiolar and Alveolar Cell Injuries Induced by Short- and Long term Exposure to Sidestream Smoke. AB - BACKGROUND: We investigated effects of short- and long-term exposure to sidestream smoke on the bronchiolar and alveolar cells in Sprague-Dawley rats. METHODS: RATS WERE DIVIDED INTO FIVE EXPERIMENTAL GROUPS: groups 1, 2, and 3 (1 month exposure to 3, 5, and 7 cigarettes a day, respectively), groups 4 and 5 (3- and 6 month exposure to five cigarettes a day, respectively). We examined the morphologic changes, the expressions of tumor necrosis factor alpha (TNF-alpha), tumor growth factor beta1 (TGF-beta1), interlekin (IL)-1alpha, IL-1beta, Ki-67, and cytokeratin 14 and in situ apoptosis in the bronchiolar and alveolar cells on light microscopy (LM) and electron microscopic (EM) terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. RESULTS: LM showed the respiratory bronchiolar dilatation and alveolar wall collapse. In groups 3, 4, and 5, EM showed loss of the cilia and Clara cells with irregular size, more prominent alveolar wall collapse and dilation of alveolar duct than those of groups 1 and 2. Bronchiolar and alveolar cells showed increased expressions of TNF-alpha and TGF-beta in groups 4 and 5. LM and EM TUNEL stains showed increased apoptosis in groups 3, 4, and 5. CONCLUSIONS: Sidestream smoke causes a bronchiolar and alveolar cell injury and the severity correlates strongly the volume and duration of exposure to sidestream smoke. PMID- 23109996 TI - Identifying Polymorphisms in IL-31 and Their Association with Susceptibility to Asthma. AB - BACKGROUND: Interleukin 31 (IL-31) is a T helper type 2 effector cytokine that plays an important role in the pathogenesis of atopic and allergic diseases. IL 31 may be involved in promoting allergic inflammation and in inducing airway epithelial responses such as allergic asthma. METHODS: Single-base extension analysis was used to detect the genotypes of IL-31 single nucleotide polymorphisms (SNPs), and we compared the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. RESULTS: There were no significant differences in the genotype and allele frequencies of the IL-31 SNPs between patients with asthma and healthy controls. Furthermore we compared the genotype and allele frequencies of IL-31 SNPs between patients with atopic asthma, those with non-atopic asthma and healthy controls. This showed that the SNPs were not associated with the susceptibility to atopic asthma. There were no significant differences in the haplotype frequencies of IL-31 SNPs between patients with asthma and healthy controls. In patients with asthma, the IL-31 SNPs were significantly correlated with total serum levels of IgE (p=0.035). CONCLUSIONS: Our results indicate that, the IL-31 SNPs may be associated with IgE production in patients with asthma. PMID- 23109997 TI - The clinicopathologic features of molecular apocrine breast cancer. AB - BACKGROUND: To elucidate the clinicopathologic features and their implications on the immunohistochemistry in cases of molecular apocrine breast cancer (MABC). METHODS: Immunohistochemical (IHC) staining for estrogen receptor (ER), human epidermal growth factor receptor 2 (HER-2), cytokeratin (CK) 5/6, epidermal growth factor receptor (EGFR), androgen receptor (AR), gamma-glutamyltrasferase 1 (GGT1) and Ki-67 was performed on tissue microarray breast cancer samples from 204 patients. Phenotypes of breast cancer were divided based on the IHC status of ER, AR and GGT1 into the following: luminal type, ER positive and AR and/or GGT1 positive; basal type, ER, AR, and GGT1 negative; non-basal type, ER positive and AR and GGT1 negative; and MABC type, ER negative and AR and/or GGT1 positive. RESULTS: In our series of patients (n=204), there were 26 cases of MABC. Besides, there were 18, 60, and 100 cases of luminal type, basal type and non-basal type, respectively. The MABC demonstrated apocrine histology and a higher prevalence of HER-2 positivity than other phenotypes. With the basal type, the MABC manifested a more frequent expression of CK5/6 and EGFR and a higher Ki-67 index than other phenotypes (p<0.001). There were no significant differences in patient prognosis between the phenotypes of breast cancer. CONCLUSIONS: MABC are distinguishable from other phenotypes based on the apocrine histology and a higher expression rate of HER-2. PMID- 23109998 TI - Expression of human papillomavirus-related proteins and its clinical implication in tonsillar squamous cell carcinoma. AB - BACKGROUND: Human papillomavirus (HPV) is known to cause of oropharyngeal squamous cell carcinoma (SqCC). HPV positive SqCCs overexpress p16 and are associated with better survival. Several markers of cell cycles and apoptosis have been reported as a prognostic value. We examined the prognostic value of HPV status, p16, cyclin D1, and Bcl-2 in patients with tonsillar SqCC. METHODS: Tissue microarrays were constructed in 56 cases of tonsillar SqCC for which we performed an immunohistochemistry and an in situ hybridization (ISH) of the HPV. RESULTS: Of the 56 cases, 31 (55.3%) were positive for p16 and 20 (35.7%) were positive for HPV ISH. The expressions of p16, cyclin D1, and Bcl-2 were not correlated with the clinicopathologic variables including smoking status, differentiation and pT- and pN-stages. The HPV ISH positive group showed a better overall survival than the HPV negative group (p=0.04), and the p16 positive group showed a better disease free survival (DFS) than the negative group (p=0.016). Cox regression analysis showed that only p16 positivity was an independent prognostic factor for DFS (p=0.03; hazard ratio, 10.1). CONCLUSIONS: Our results indicate that both p16 expression and HPV status are useful indicators for risk stratification in patients with tonsillar SqCC. PMID- 23109999 TI - Primary Monophasic Synovial Sarcoma Arising in the Mesentery: Case Report of an Extremely Rare Mesenteric Sarcoma Confirmed by Molecular Detection of a SYT-SSX2 Fusion Transcript. AB - Synovial sarcoma arises in the para-articular tissues, and it can also occur in various unexpected sites. We report a rare case of primary monophasic synovial sarcoma (MSS) arising in the mesentery. A 59-year-old man presented with a palpable abdominal mass. On microscopic examination, the entire tumor comprised a dense proliferation of the spindle cells without epithelial components. The tumor cells were positive for transducin-like enhancer of split 1, bcl-2, epithelial membrane antigen and CD99 but negative for CD34, CD117, alpha-smooth muscle actin, cytokeratin, and calretinin on immunohistochemistry. The reverse transcriptase-polymerase chain reaction revealed a single 151-bp fragment representing the SYT-SSX2 fusion transcript. Because mesenteric MSS is extremely rare and many cases display histologic findings that overlap with those of more frequently involved tumors such as hemangiopericytoma and gastrointestinal stromal tumor, there is a chance of making an incorrect diagnosis that can result in an inappropriate treatment. PMID- 23110000 TI - Ectomesenchymal chondromyxoid tumor in the anterior tongue: case report of a unique tumor. AB - Ectomesenchymal chondromyxoid tumor (ECMT) is a rare tumor, exclusively arising in the anterior tongue. Thirty-eight cases have been reported in the English literature. It usually presents as a sessile protrusion and shows round to spindle cells embedded in myxoid to chondroid stroma. Tumor cells are almost always positive for polyclonal glial fibrillary acidic protein (GFAP). We report our experience in the recent treatment of a case of ECMT, the third case in 3 years. The mass in the anterior tongue revealed characteristic morphologic features of ECMT and the expression of polyclonal GFAP. Although ECMT should be differentiated from other mesenchymal tumors including myoepithelioma, its clinical, morphological, and immunohistochemical features enable its diagnosis, especially when pathologists are aware of it. PMID- 23110001 TI - Parathyromatosis: critical diagnosis regarding surgery and pathologic evaluation. AB - Parathyromatosis, in which several nodules of hyperfunctioning parathyroid tissue form in the neck and mediastinum, is a rare cause of recurrent hyperparathyroidism. However, there are some theories regarding the origin of parathyromatosis, and seeding after rupture of the parathyroid gland capsule during surgical removal of a parathyroid lesions is the most regarded one. Herein, we report a 41-year-old man who presented with multiple parathyroid nodules in and around the left thyroid lobe 5 years after parathyroid surgery for secondary hyperparathyroidism that was finally diagnosed as parathyromatosis. We discuss the differential diagnosis of parathyromatosis from other parathyroid tumors, particularly from parathyroid carcinoma, which is important in the management of a suspected lesion. PMID- 23110002 TI - Melanotic oncocytic metaplasia of the nasopharynx: a report of three cases and review of the literature. AB - Melanotic oncocytic metaplasia of the nasopharynx is a rare condition which is characterized by the presence of usually a small, brown to black colored pigmented lesion around the Eustachian tube opening. Although it is a benign lesion, it may be clinically misdiagnosed as malignant melanoma. Microscopically, melanotic oncocytic metaplasia is a combination of oncocytic metaplasia of the epithelium of the gland and melanin pigmentation in its cytoplasm. In our present study, we report three cases of melanotic oncocytic metaplasia of the nasopharynx. All the three cases occurred in men and were presented as multiple black pigmented lesions around the torus tubarius. Microscopically, mucous glands with diffuse oncocytic metaplasia and numerous black pigments were observed. No cellular atypia was observed. Immunohistochemically, the scattering of S-100 protein-positive, and human melanoma black 45-negative dendritic melanocytes was evident. This is the first report of cases of melanotic oncocytic metaplasia of the nasopharynx in Korea. PMID- 23110003 TI - Invasive cribriform carcinoma arising in malignant phyllodes tumor of breast: a case report. AB - Phyllodes tumor is an uncommon fibroepithelial neoplasm of the breast. And it is characterized by expanded stroma with increased cellularity and elongated epithelium-lined clefts. Mammary carcinomas within phyllodes tumors have been rarely reported. To date, however, no reports have described the invasive cribriform carcinoma arising in malignant phyllodes tumor. Here, we report a 62 year-old woman who presented with a large breast mass. Microscopically, the mass was a typical malignant phyllodes tumor showing well developed leaf-like architecture and stromal overgrowth with high cellularity and nuclear pleomorphism. In a portion of the tumor, however, the epithelial component showed a cribriform pattern of proliferation in the absence of myoepithelial cells, suggestive of the invasive cribriform carcinoma. To our knowledge, this is rare and it is difficult to make a differential diagnosis of it. Here, we report our case with a review of literatures. PMID- 23110004 TI - Cytologic findings of clear cell adenocarcinoma of the urethra: a case report. AB - Clear cell adenocarcinoma of the urethra is a rare disease entity with an uncertain histogenesis. Here, we present a case of primary clear cell adenocarcinoma of the female urethra with its cytological findings. A 54-year-old woman presented with a painless gross hematuria lasting 3 months. On vaginal sonography, there was a sausage-like, elongated mass in the urethra, measuring 3.8*4.3 cm. The voided urine cytology revealed small clusters of rounded or papillary cells. The necrotic debris and inflammatory cells were present within some clusters of tumor cells. These tumor cells were enlarged and had abundant clear or granular cytoplasm with cytoplasmic vacuoles. The nucleus was granular and contained vesicular chromatin with prominent nucleoli. The hobnail cells and hyaline globules were also present as in a histologic section. The histologic findings were compatible with clear cell adenocarcinoma. The tumor showed distinctive cytological features. Cytologically, however, it is necessary to make a differential diagnosis from other adenocarcinoma or high-grade urothelial carcinoma. PMID- 23110005 TI - Liquid-based cytology of villoglandular adenocarcinoma of the cervix: a report of 3 cases. AB - Villoglandular adenocarcinoma (VGA) is a rare subtype of cervical adenocarcinoma with a more favorable prognosis compared to conventional adenocarcinomas. Although the tumors are usually recognized on colposcopic examination due to the mainly exophytic growth pattern, they may be underdiagnosed as benign lesions by cytology because of their minimal cytologic atypia. We report the liquid-based cytology (LBC) findings of three histologically confirmed VGAs which we have recently identified. They were characterized by hypercellular smears on low-power examination with smooth-bordered three-dimensional papillary fragments. The nuclei were relatively uniform with irregular nuclear membranes. Nucleoli were small but distinct and macronucleoli were also seen. The abnormal architectural patterns such as papillary structures and nuclear overlapping and nuclear hyperchromasia are important clues to the diagnosis of VGA. In addition, nuclear membrane irregularity and prominent nucleoli can be recognized on LBC specimens, further facilitating its diagnosis. PMID- 23110006 TI - Clinicopathological analysis of 21 thymic neuroendocrine tumors. AB - BACKGROUND: Thymic neuroendocrine carcinomas (NECs) are uncommon, for which there is no established information available because of a limited number of epidemiological study in Asia. METHODS: We reviewed 21 cases of surgically resected thymic NECs, and evaluated their pathological and clinical features. RESULTS: It showed male predominance (male/female ratio, 15/6) with wide age range from 20 to 72 years (mean age, 49 years). All 21 cases were divided into two types according to the World Health Organization criteria: atypical carcinoid (n=18) and large cell NEC (n=3). Three cases of atypical carcinoid (AC) were associated with ectopic Cushing's syndrome. All the patients (3/3) with large cell NEC (3/3) and 16.7% (3/18) of those with AC died of tumor progression. Common sites of metastasis included lung, lymph node, brain, lumbar spine, mediastinum, bone, and liver. CONCLUSIONS: In conclusion, thymic neuroendocrine tumors carry a poor prognosis. Regarding the tumor classification, our results showed that a vast majority of carcinoids in the thymus correspond to ACs. In addition, our results also indicate that typical carcinoid is a very rare entity. Some cases of AC exhibited a large size, solid pattern and they showed aggressive clinical behavior, which highlights the spectrum of histologic appearances of thymic NECs. PMID- 23110007 TI - Proposal for Creating a Guideline for Cancer Registration of Microinvasive Tumors of the Breast and Ovary (II). AB - BACKGROUND: Cancer registration in Korea has a longer than 30-years of history, during which time cancer registration has improved and become well-organized. Cancer registries are fundamental for cancer control and multi-center collaborative research. However, there have been discrepancies in assigning behavior codes. Thus, we intend to propose appropriate behavior codes for the International Classification of Disease Oncology, 3rd edition (ICD-O-3) for microinvasive tumors of the ovary and breast not only to improve the quality of the cancer registry but also to prevent conflicts. METHODS: As in series I, two pathology study groups and the Cancer Registration Committee of the Korean Society of Pathologists (KSP) participated. To prepare a questionnaire on provisional behavior code, the relevant subjects were discussed in the workshop, and consensus was obtained by convergence of opinion from members of KSP. RESULTS: Microinvasive tumor of the breast should be designated as a microinvasive carcinoma which was proposed as malignant tumor (/3). Serous borderline tumor with microinvasion of the ovary was proposed as borderline tumor (/1), and mucinous borderline tumor with microinvasion of the ovary as either borderline (/1) or carcinoma (/3) according to the tumor cell nature. CONCLUSIONS: Some issues should be elucidated with the accumulation of more experience and knowledge. Here, however, we present our second proposal. PMID- 23110008 TI - Urinary decoy cell grading and its clinical implications. AB - BACKGROUND: Examination of urine for decoy cells (DCs) is a useful screening test for polyomavirus (PV) activation. We explored the significance of the amount of DCs in persistent shedding, PV nephropathy and acute rejection. METHODS: A case controlled study was performed in 88 renal allograft patients who had DCs detected at least once in four or more urine samples. RESULTS: Fifty one patients were classified into the high-grade shedding group (HG) and 37 patients into the low-grade shedding group (LG) according to DC shedding (>=10 or <10 DCs/10 high power field [HPF]). DC shedding of more than three consecutive months was significantly more prevalent in the HG as compared with their LG counterparts (p<0.0001). Urinary DCs were present for more than one year in 29.4% of the HG and 8.1% of the LG. Real-time polymerase chain reaction for PV was higher in both urine (51.4% vs. 11.1%) and plasma (9.1% vs. 0%) of the HG than the LG. The prevalence of PV nephropathy was higher in the HG than the LG (p=0.019). However, there was no significant difference in the prevalence of acute rejection. CONCLUSIONS: Shedding of >=10 DCs/10 HPF is associated with sustained shedding, polymerase chain reaction positivity and PV nephropathy, but not a predictor of acute rejection. PMID- 23110009 TI - Cyclooxygenase-2 expression and its prognostic significance in clear cell renal cell carcinoma. AB - BACKGROUND: The prognostic value of cyclooxygenase-2 (COX-2) in human renal cell carcinoma (RCC) remains unclear. The purposes of this study are to elucidate the clinical significance of COX-2 in clear cell RCC (CCRCC) and to assess the treatment effect of COX-2 inhibition on CCRCC cell lines. METHODS: Using tumor samples obtained from 137 patients who had undergone nephrectomy at Seoul National University Hospital, we evaluated COX-2 expression on immunohistochemistry. Moreover, we performed the cell proliferation assay using 3 (4,5-dimethylthiazol-2yl)-2,5-diphenyl-2H tetrazolium bromide (MTT) and cell invasion assay. Thus, we evaluated the effect of meloxicam, an inhibitor of COX 2, in two human CCRCC cell lines. RESULTS: Cancer-specific survival (p=0.038) and progression-free survival (p=0.031) were shorter in the COX-2 high expression group. A multivariate logistic regression model showed that COX-2 expression was an independent risk factor for pTNM stage and Fuhrman nuclear grade. The MTT assay revealed that COX-2 inhibition led to the suppression of the proliferation of CCRCC cell lines. Moreover, it also reduced their invasion capacity. CONCLUSIONS: This study postulates that COX-2 is a poor prognostic indicator in human CCRCC, suggesting that COX-2 inhibition can be a potential therapy in CCRCC. PMID- 23110010 TI - Frequency of BRAF Mutation and Clinical Relevance for Primary Melanomas. AB - BACKGROUND: This study was conducted to clarify the frequency of the BRAF mutation in primary melanomas and its correlation with clinicopathologic parameters. METHODS: We analyzed the frequency of BRAF mutation in patients with primary cutaneous melanoma (n=58) or non-cutaneous one (n=27) by performing dual priming oligonucleotide-based multiplex real-time polymerase chain reaction to isolate and to purify the DNA from the formalin-fixed and paraffin-embedded tumors. RESULTS: The BRAF mutation was found in 17.2% (10/58) of patients with primary cutaneous melanoma and 11.1% (3/27) of those with non-cutaneous melanoma. The frequency of BRAF mutation was not correlated with any clinicopathologic parameters with the exception of the patient age. The frequency of the BRAF mutation was significantly higher in patients younger than 60 years as compared with those older than 60 years (p=0.005). CONCLUSIONS: Compared with previous reports, our results showed that the frequency of the BRAF mutation was relatively lower in patients with primary cutaneous melanoma. Besides, our results also showed that the frequency of the BRAF mutation had an inverse correlation with the age. Further studies are warranted to exclude methodological bias, to elucidate the difference in the frequency of the BRAF mutation from the previous reports from a Caucasian population and to provide an improved understanding of the molecular pathogenesis of malignant melanoma. PMID- 23110011 TI - The Utility of p16INK4a and Ki-67 as a Conjunctive Tool in Uterine Cervical Lesions. AB - BACKGROUND: Immunohistochemical staining for p16INK4a and Ki-67 has been used to improve the accuracy in making a diagnosis of the uterine cervix cancer on biopsy. This study was conducted to examine the usefulness of these markers in the pathological diagnosis based on cervical biopsy. METHODS: We selected a consecutive series of 111 colposcopically directed cervical punch biopsies. Using these biopsy samples, we performed an immunohistochemical staining for p16INK4a and Ki-67 to establish a diagnosis. The slides were circulated among four pathologists in a sequential order: the hematoxylin and eosin (H&E) slide, H&E slide and p16INK4a-stained slide, and H&E slide, p16INK4a- and Ki-67-stained slides. RESULTS: The overall rates of the concordance in the first, the second, and the third diagnoses were 77.5%, 82.0%, and 82.0%, respectively. The rate of the concordance in the diagnosis of cervical intraepithelial neoplasm (CIN) 2/3 was increased from 62.2% to 73.0%. But there was a variability in the rate of the revision of the diagnosis between the pathologists. With the application of criteria for interpreting the expressions of p16INK4a and Ki-67, benign and CIN 1 lesions showed a p16INK4a expression score of 0 or 1. But CIN 2 and CIN 3 lesions showed a p16INK4a expression score of 2 and 3, respectively. CONCLUSIONS: The immunostain for p16INK4a and Ki-67 might be useful in reducing an inter-observer variability. But criteria for interpreting both markers should be strictly applied. PMID- 23110012 TI - The expression of pigment epithelium-derived factor in bladder transitional cell carcinoma. AB - BACKGROUND: Pigment epithelium-derived factor (PEDF) is an anti-angiogenic factor. The purpose of this study is to examine the involvement of PEDF in the angiogenesis and biological behavior of bladder transitional cell carcinoma (TCC). METHODS: We examined the expression of PEDF in 99 bladder TCCs and ten non neoplastic tissues, and evaluated microvessel density (MVD). RESULTS: The positive immunoreactivity for PEDF was seen in normal urothelium in 60% (6/10) and TCC in 13% (13/99). The PEDF expression had a significant correlation with MVD, i.e., a low MVD in 42% (5/12), a middle MVD in 11% (8/76) and a high MVD 0% (0/11) of tumors. The PEDF expression was not significantly correlated with the differentiation and invasion of TCC, but the degree of MVD was significantly higher in both high grade TCC and the pT2 tumors. CONCLUSIONS: The degree of PEDF expression is significantly higher in normal bladder urothelium than bladder TCC; it is inversely correlated with the angiogenesis; and it is not related to the differentiation and progression of TCC. It can therefore be concluded that bladder TCC would initially occur if there is a lack of the PEDF expression. PMID- 23110013 TI - Metastatic carcinomas to the oral cavity and oropharynx. AB - BACKGROUND: Metastases to the oral/oropharynx are very rare and their diagnosis is challenging. METHODS: We reviewed pathologic data for malignant tumors of the oral/oropharynx that were diagnosed at the Asan Medical Center, Seoul, Korea from 1995 until 2010. RESULTS: Twenty-nine cases of oral/oropharyngeal metastases were retrieved, comprising 2.0% of 1,445 malignancies. The most common primary sites were the liver and lung, followed by the stomach, colon, breast, prostate, and kidney. The gingiva was the most common metastatic site, followed by the tonsil/pillar, mandible, tongue, tongue base, palate mucosa, mouth floor, and buccal mucosa. Intervals between detection of primary tumors and metastases were variable, from -1 month to 104 months. Ten patients with lung (7 cases), liver, stomach, and kidney carcinomas manifested with oral/oropharyngeal metastases as the first sign of systemic metastases. The majority of patients had died within one year of the onset of an oral/oropharyngeal metastasis, but exceptionally long lived cases were also present. The survival periods of patients with lung cancers were longer than those of patients with non-pulmonary tumors. CONCLUSIONS: An awareness of the incidence, common primary sites, metastatic subsites, and metastatic courses or patterns of oral/oropharyngeal metastases is helpful in the diagnosis of metastatic carcinomas. PMID- 23110014 TI - Tumor budding and recurrence in submucosal invasive colorectal cancers of favorable histology: case reports of two early colorectal cancers with advanced recurrences. AB - Complete resection of submucosal invasive colorectal cancer (SICC) showing favorable histology is regarded as curative. We report on two cases of SICC showing recurrence within 5 years despite complete resection. The first patient was a 68-year-old woman with well differentiated rectal adenocarcinoma invading the superficial submucosa, which recurred after 4.7 years. The second patient was a 53-year-old man with pT1N0 moderately differentiated colonic adenocarcinoma. He developed widespread tumor recurrence after 3.9 years. Retrospective pathologic review of the original tumors showed multiple foci of tumor budding at the invasive front. Immunohistochemical staining for D2-40 of deeper levels of the paraffin blocks showed rare foci of small lymphatic invasion. Tumor budding at the invasive front may be an important indicator for SICC aggressiveness or may reflect early lymphatic invasion. More aggressive pathologic examination and follow-up is required for patients with SICC showing tumor budding, even in the absence of unfavorable histologic findings. PMID- 23110015 TI - Squamoid eccrine ductal carcinoma of the scalp. AB - Squamoid eccrine ductal carcinoma (SEDC) is an exceedingly rare tumor that shows both squamous and adnexal ductal differentiation. We report a case of this unusual tumor occurring on the occiput of a 53-year-old man. A histopathological examination revealed a nodular lesion infiltrating the dermis and subcutaneous tissue with numerous duct-like structure and squamoid differentiation foci. Five months later, the patient presented with a palpable mass at the site of the previous excision and the right side of the neck. Sono-guided fine needle aspiration of the right neck mass was performed and was diagnosed as a metastastasis of a lymph node. A right neck node dissection and re-excision of the occiput was performed. The histopathological findings were similar, but squamoid differentiation was more prominent than that in the previous lesion. Because of the rarity of SEDC, little is known about its biological behavior and optimal treatment. PMID- 23110016 TI - Papillary carcinoma of thyroid metastatic to adenocarcinoma in situ of lung: report of an unusual case. AB - The tumor-to-tumor metastasis is a rare event. The lung tumors are the most common donor tumors in tumor-to-tumor metastasis, but are exceedingly rare as a recipient. Here, we report a case of papillary thyroid carcinoma (PTC) metastasizing to adenocarcinoma in situ (AIS, formerly bronchioloalveolar carcinoma) of the lung in a 44-year-old woman who underwent total thyroidectomy for PTC 8 years ago. To the best of our knowledge, the present case is the first case reporting on PTC metastasized to AIS. A review of the relevant literature is presented. PMID- 23110017 TI - Gastric adenocarcinoma of fundic gland type: report of three cases. AB - Recently, fundic gland type gastric adenocarcinoma (GA-FG) has been reported as a new entity. This report describes GA-FG among Koreans for the first time. From March 2008 to July 2010 we identified only three cases of GA-FG out of over 6,000 GAs resected by endoscopy or surgery. Cell differentiation by mucin proteins, pepsinogen-I, and H+/K+-ATPase was evaluated. All three cases were male patients and diagnosed as early stage GA. Histologically, GA-FGs were well-differentiated adenocarcinoma with pale gray-blue, basophilic columnar or cuboidal cells and mildly enlarged nuclei, resembling chief cells. All three cases were positive for pepsinogen-I and were classified as gastric mucin phenotype. Among three histologic subtypes of GA-FG, since tumors were mainly composed of chief cells, our three cases were classified as chief cell predominant type. In conclusion, GA FG is very rare among Koreans and pepsinogen-I and MUC6 expression are typical immunohistochemical findings in GA-FG suggesting differentiation toward fundic glands. PMID- 23110018 TI - Plexiform angiomyxoid myofibroblastic tumor of the stomach: report of two cases and review of the literature. AB - Plexiform angiomyxoid myofibroblastic tumor (PAMT) of the stomach is a recently recognized entity. Because of its rarity, only 22 cases have been reported in the English-language literature and most of these are single case reports. We report two cases of gastric PAMT. The tumor cells were bland and plexiform arranged in a myxoid stroma, which was positive for alcian blue. Immunohistochemically, the tumor cells were positive for smooth muscle actin, but negative for c-kit, CD34, desmin, S-100 protein, epithelial membrane antigen, neurofilament, and protein kinase C-theta. Mutation analyses for exon 9, 11, 13, and 17 of KIT genes and 12, 14, and 18 of the platelet-derived growth factor receptor alpha (PDGFRA) genes were performed and the tumors were wild-type for mutation. PMID- 23110019 TI - Osteoclast-like Giant Cell Tumor of Parotid Gland with a Carcinomatous Component: A Case Report. AB - The giant cell tumor of the salivary gland is very rare, and 20 cases have been reported in the English-language literature. We report an additional case. A 57 year old man had noticed a mass in the right parotid area for several weeks. The diagnosis using aspiration cytology was a giant cell tumor possibly with a carcinomatous component. Superficial parotidectomy was carried out. The resected parotid gland contained a 1.8 cm-sized well-circumscribed brownish tumor. Histologically the tumor consisted of evenly distributed osteoclast-like giant cells, mononuclear cells and two small foci of a carcinomatous component. The osteoclast-like giant cells and mononuclear cells were positive for vimentin and CD68, and the carcinomatous component was positive for cytokeratin and epithelial membrane antigen. There was no metastatic lesion in the cervical lymph nodes. We believe this is the first case in Korea of an osteoclast-like giant cell tumor of the parotid gland. PMID- 23110020 TI - Cytologic Findings of Thyroid Carcinoma Showing Thymus-like Differentiation: A Case Report. AB - Carcinoma showing thymus-like differentiation (CASTLE) is a rare carcinoma of the thyroid or adjacent soft tissue of the neck with a histologic resemblance to thymic epithelial tumors. Although the fine-needle aspiration (FNA) plays a central role in the initial evaluation of thyroid nodules, few reports about the cytologic findings of CASTLE have been found according to a review of literatures. We report cytologic findings of a case of CASTLE. A 34-year-old woman presented with a 2-month history of sore throat. The FNA showed that the smear was composed of three dimensional clusters and sheets. The tumor cells were round to ovoid with high nuclear : cytoplasmic ratios. The nuclei were vesicular with small nucleoli. There were some tumor cells showing keratinization. Some lymphocytes were found on the background and within clusters. The presence of poorly-differentiated tumor cells with a focal keratinization and a lymphocytic background on the FNA is suggestive of CASTLE. PMID- 23110021 TI - Extranodal follicular dendritic cell sarcoma with rapid growth in parapharynx: a case report. AB - Follicular dendritic cell sarcoma (FDCS) is a rare malignancy arising from the antigen-presenting cells in the lymph node and extranodal tissue. We describe a 31-year-old male patient who presented with a swelling of the left parapharynx. The radiologic findings showed a 4.7*4.5*1.9 cm-sized, ill-defined mass in the left parapharyngeal space. A fine-needle aspiration cytology was performed and it showed scattered, irregular, cohesive clusters of tumor cells with a spindle-to ovoid shape with irregular contours in a background of lymphocytes. Based on these findings, a diagnosis of spindle cell neoplasm was made. The surgically resected tumor was composed of elongated, ovoid or polygonal cells showing positive immunohistochemistry for CD21, CD23, and CD35. Postoperatively, the residual tumor was observed to undergo a rapidly growth. There is an overlap in the cytologic and histologic findings between FDCS of the parapharynx and other tumors. Pathologists should therefore be aware of its characteristics not only to provide an accurate diagnosis but also to recommend the appropriate clinical management. PMID- 23110022 TI - HDAC1 Expression in Invasive Ductal Carcinoma of the Breast and Its Value as a Good Prognostic Factor. AB - BACKGROUND: Histone deacetylase 1 (HDAC1) is associated with the expression and function of estrogen receptors and the proliferation of tumor cells, and has been considered a very important factor in breast tumor progression and prognosis. Several studies have reported an association between HDAC1 expression and poorer prognosis in cancers including breast cancer, with a few exceptions. However, because of the dearth of studies on HDAC1 expression in breast cancer, its significance for breast cancer prognosis has not been well defined. Therefore, we examined HDAC1 expression in invasive ductal carcinoma (IDC), the most common breast cancer, and investigated its potential prognostic significance. METHODS: We used 203 IDC tissue samples. Immunohistochemical stains for HDAC1 and real time polymerase chain reaction for HDAC1 mRNA were performed and the results were compared to generally well-established prognostic factors in breast cancer and patient survival rates. RESULTS: HDAC1 expression was significantly reduced in proportion to higher histologic grade, higher nuclear pleomorphism score, and higher mitotic counts, and with lower estrogen receptor expression. Furthermore, it was significantly associated with the survival rate. CONCLUSIONS: HDAC1 expression is a good prognostic indicator in IDC. PMID- 23110023 TI - Clinicopathologic Implications of PIWIL2 Expression in Colorectal Cancer. AB - BACKGROUND: There are no established reports about the expression of the Piwil gene, a subfamily of the Piwi gene involved in RNA silencing and self-renewal, in colorectal carcinomas. It is known that the degree of PIWIL2 expression is higher in colorectal carcinomas. But its clinicopathologic significance remains undetermined. This study reassessed the relationship between PIWIL2 expression and the clinicopathologic parameters in colorectal carcinomas. METHODS: An immunohistochemistry of PIWIL2 expression was done in 60 cases of colorectal carcinoma. This was followed by an analysis of the correlation between PIWIL2 expression and clinicopathologic features and a survival analysis. RESULTS: There were 44 cases (73.3%) where the degree of PIWIL2 expression was relatively higher. The high degree of PIWIL2 expression was significantly correlated with the lower degree of differentiation (p=0.039), deep invasion (p=0.019) and perineural invasion (p=0.027). The overall survival was longer in patients with the lower degree of PIWIL2 expression than in those with the higher degree of PIWIL2 expression. CONCLUSIONS: Our results showed that the degree of PIWIL2 expression was relatively higher in colorectal carcinomas and it was significantly correlated with variable clinicopathologic indicators for a poor prognosis. This indicates that PIWIL2-positive cells contribute to the progression of colorectal cancer. PMID- 23110024 TI - Expressional Difference of RHEB, HDAC1, and WEE1 Proteins in the Stromal Tumors of the Breast and Their Significance in Tumorigenesis. AB - BACKGROUND: Fibroadenoma (FA) and phyllodes tumor (PT) are stromal tumors of breast and are histologically similar. There are no established differences in tumorigenesis and oncogene expression among them. Ras homolog enriched in brain (RHEB) plays an important role in cell growth and cell-cycle control, histone deacetylase 1 (HDAC1) is an important factor in breast tumor progression and prognosis, and WEE1 homolog (WEE1) functions as a tumor suppressor. No studies on the expressional differences of these proteins in FA and PT have been reported to date. METHODS: The expression of these proteins in FA, PT, and normal breast was compared. We used 102 cases of FA and 25 cases of benign PT. RESULTS: In epithelial cells, the expression of RHEB, HDAC1, and WEE1 was lowest in PT, higher in FA, and most enhanced in normal breast. In addition, the expression of RHEB and HDAC1 was higher in the stromal cells of PT than in FA and normal breast. CONCLUSIONS: Both epithelial and stromal cells of FA and PT express these proteins, which indicates that epithelial cells play an important role in the development of stromal tumors. In addition, the expressional differences of these proteins may be associated with the tumorigenesis of breast stromal tumors. PMID- 23110025 TI - Expressions of E-cadherin, Cortactin and MMP-9 in Pseudoepitheliomatous Hyperplasia and Squamous Cell Carcinoma of the Head and Neck: Their Relationships with Clinicopathologic Factors and Prognostic Implication. AB - BACKGROUND: E-cadherin, cortactin, and matrix metalloproteinase (MMP)-9 have roles in tumor development or progression, but their expression has not been fully investigated in pseudoepitheliomatous hyperplasia (PEH) and squamous cell carcinoma (SCC) of the head and neck. METHODS: We evaluated the immunohistochemical expression of E-cadherin, cortactin, and MMP-9 in 29 cases of PEH and 97 cases of SCC. Additionally, we evaluated their relationship with clinicopathologic factors and prognostic implications in SCC. RESULTS: Thirty five cases of SCC showed reduced expression of E-cadherin, whereas none of the PEH did. A total of 20 cases and 11 cases of SCC were immunoreactive for cortactin and MMP-9, respectively, whereas none of the PEH did. In SCC, reduced expression of E-cadherin was correlated with cortactin expression and invasion depth. Cortactin expression was correlated with differentiation, T classification, and recurrence and/or metastasis. MMP-9 expression was correlated with invasion depth. Cortactin expression was correlated with poor overall survival and relapse-free survival and it was an independent prognostic factor. CONCLUSIONS: The reduced expression of E-cadherin and the expression of cortactin may be helpful for the differential diagnosis of PEH and SCC. Furthermore, cortactin expression in association with reduced E-cadherin expression is correlated with poor prognosis in SCC. PMID- 23110026 TI - Loss of E-cadherin and Acquisition of Vimentin in Epithelial-Mesenchymal Transition are Noble Indicators of Uterine Cervix Cancer Progression. AB - BACKGROUND: Epithelial-mesenchymal transition (EMT) has been known to play a key role in the stromal invasion of carcinoma in situ (CIS) lesion. Loss of E cadherin and acquisition of vimentin are two critical steps in EMT, that are induced by Snail-1 upregulation associated with overexpression of epidermal growth factor receptor (EGFR). However, roles of EMT-related proteins in human cervical tissues have not been fully elucidated. In this study, we investigated the immunoexpressions of EMT-related proteins in CIS, microinvasive squamous cell carcinoma (SCC), and invasive SCC to demonstrate their key roles in tumor progression. METHODS: Eighty one CIS, 17 microinvasive, and 21 invasive SCC cases were immunostained with primary antibodies for Snail-1, EGFR, E-cadherin, and vimentin on paraffin-embedded tissue microarray blocks. RESULTS: EGFR and Snail-1 proteins were highly expressed but the levels were not significantly different between the three groups. However, loss of E-cadherin and acquisition of vimentin were proven to occur significantly higher in microinvasive and invasive SCC cases than in CIS. CONCLUSIONS: E-cadherin and vimentin were found to be two useful indicators of EMT in evaluating stromal invasion of CIS. However, it was not demonstrated for Snail-1 and EGFR proteins to play any key role in the progression of cervix cancer. PMID- 23110027 TI - The Histologic Cut-off Point for Adjacent and Remote Non-neoplastic Liver Parenchyma of Hepatocellular Carcinoma in Chronic Hepatitis B Patients. AB - BACKGROUND: The molecular profile of peritumoral non-neoplastic liver parenchyma (PNLP) has recently been suggested as predictive factor of early and late recurrence of hepatocellular carcinoma (HCC). However, there is no definite cut off point for tumor-free PNLP in terms of either histological or molecular changes. Therefore, our aim is to determine the numerical cut-off point for separating adjacent PNLP and remote PNLP in histopathologic perspective. METHODS: Peritumoral tissues from 20 resected HCC patients were sampled from 0 to 40 mm distance from the tumor border (divided into 5-mm columns). Histopathologic parameters such as necroinflammatory activity, fibrosis, bile ductular reaction, hepatic venulitis, peliosis, and steatosis were compared between each column. RESULTS: The morphologic changes just adjacent to the tumor were notably severe and faded with distance. The parenchyma within 10 mm of the tumor showed significantly severe inflammation, fibrosis, peliosis and hepatic venulitis compared with those from farther areas. The histopathologic changes of the parenchyma became stable beyond 20 mm. CONCLUSIONS: Results of this study revealed that the parenchyma within 10 mm distance from the tumor, or adjacent PNLP, has histopathologic changes that are directly affected by the tumor, and the parenchyma beyond 20 mm as the remote PNLP without tumor effect. PMID- 23110028 TI - Outcome of "Atypical Squamous Cells" in Cervical Cytology: Follow-up Assessment by Loop Electrical Excision Procedure. AB - BACKGROUND: We have retrospectively assessed the incidence and outcome of women diagnosed during a hospital-based cytology screening program with "atypical squamous cells (ASC)" and followed-up with loop electrical excision procedure (LEEP). METHODS: We analyzed 173,947 cases of cervical smears' follow-up cytology and histology findings. Previous or archival cytology with LEEP results were retrieved for 390 women with ASC of undetermined significance (ASC-US) and 112 with ASC, cannot exclude high-grade squamous intraepithelial lesion (ASC-H). RESULTS: On the follow-up cytology, of the 390 women initially diagnosed with ASC US, 130 (33.3%) had no follow-up records of smears before LEEP; smears of 18 (4.6%) were negative for cytologic abnormalities, 193 (49.5%) were ASC-US, 24 (6.2%) were ASC-H, 111 (28.5%) were low grade squamous intraepithelial lesion (SIL), and 44 (11.4%) were high grade SIL. LEEP findings in these 390 women showed that 183 (46.9%) were negative, 73 (18.7%) were graded as cervical intraepithelial neoplasia (CIN) 1, 25 (6.4%) as CIN 2, 102 (26.2%) as CIN 3, and 7 (1.8%) had carcinoma. LEEP was performed in 112 women initially diagnosed with ASC-H; 36 (32.1%) were negative, 4 (3.6%) were graded as CIN 1, 7 (6.3%) as CIN 2, 60 (53.6%) as CIN 3, and 5 (4.5%) with carcinoma. CONCLUSIONS: Patients with ASC-H smears were at increased risk of SIL or carcnoma compared with patients with ASC-US. Careful follow-up is required in ASC patients. PMID- 23110029 TI - Comparison of diagnostic cytomorphology of atypical squamous cells in liquid based preparations and conventional smears. AB - BACKGROUND: The aims of this study were to compare the cytomorphologic features diagnostic of atypical squamous cells (ASC) in liquid-based preparations (LBPs) and conventional Pap (CP) smears and to cytomorphologically assess the performance of the Cell Scan 1500TM in cervical cytology practice. METHODS: Cervicovaginal smears were obtained from 938 women. Two smears were obtained simultaneously from each individual, one for an LBP and the other for a CP smear; the smears were independently examined. ASC was diagnosed in 24 patients, and their samples were cytomorphologically and semiquantitatively analyzed. RESULTS: A total of 24 of the 938 women (2.6%) were diagnosed with ASC by one or both methods. Results from LBPs and CP smears were in agreement in 13 of 24 cases of ASC diagnosis (absolute direct agreement, 54.2%; k<0.20; p-value from chi-square test=0.085). Diagnostic features of ASC in the LBPs included squamous cell atypia and atypical squamous metaplasia. CONCLUSIONS: The cellular features diagnostic of ASC present in one preparation can manifest themselves differently in the other. Changes in individual cells, particularly nuclear changes, are the most reliable features for diagnosing ASC. The Cell Scan 1500TM processor is more effective at detecting ASC than are CP smears. PMID- 23110030 TI - Granular cell astrocytoma: report of a case. AB - We report here a rare case of granular cell astrocytoma. A 75-year-old man was admitted to Inha University Hospital with a three-month history of language deterioration. In a magnetic resonance imaging, a 6.5 cm-sized heterogeneous enhancing mass was seen in both the frontal lobes and the anterior genu of the corpus callosum. A stereotactic biopsy was performed. The tumor was composed of large and small round cells with abundant intracytoplasmic granules. The nuclei were bland, round to oval, and often eccentrically located. The cytoplasm of the tumor cells was positive for glial fibrillary acidic protein and S-100 protein. PMID- 23110031 TI - Collision of adenocarcinoma and schwannoma of the stomach: a case report. AB - The simultaneous occurrence of an adenocarcinoma and schwannoma is extremely rare in the stomach, and only one such case has been previously reported, which presented as two separate masses. Indeed, the collision of these tumors has never been reported. We report the case of a 61-year-old male patient who was diagnosed with the synchronous development of a schwannoma and advanced mucinous adenocarcinoma of the stomach, in which the carcinoma cells focally invaded the schwannoma. PMID- 23110032 TI - Primary thymic mucinous adenocarcinoma: a case report. AB - Primary thymic mucinous adenocarcinoma is an extremely rare aggressive subtype of thymic carcinoma. With a review of literatures, only nine cases have been reported up to present. A 36-year-old woman was admitted for further evaluation and treatment of a mediastinal mass. The patient had no medical history of cancer. The clinicoradiological examination disclosed no tumor elsewhere. After the surgical excision of mediastinal mass, it was grossly a round semi-solid mass with mucin-filled cystic areas. Microscopically solid areas showed cords, small nests and dilated glands infiltrating the fibrotic parenchyma, while the cystic areas were lined by mucinous epithelium with tumor cells floating in extracellular-mucin pools. Some cystic walls underwent malignant transformation of the benign thymic epithelium. Immunohistochemically, the tumor cells were positive for cytokeratin (CK) 7, CK20, CD5, and CDX-2, and negative for thyroid transcription factor-1. In conclusion, the mucinous thymic adenocarcinoma should be recognized as a separate histopathological entity and considered in the differential diagnosis of mediastinal carcinomas. PMID- 23110033 TI - Multifocal renal cell carcinoma of different histological subtypes in autosomal dominant polycystic kidney disease. AB - Renal cell carcinoma (RCC) in autosomal dominant polycystic kidney (ADPKD) is rare. To date, 54 cases of RCC in ADPKD have been reported. Among these, only 2 cases have different histologic types of RCC. Here we describe a 45-year-old man who received radical nephrectomy for multifocal RCC with synchronous papillary and clear cell histology in ADPKD and chronic renal failure under regular hemodialysis. The case reported herein is another example of the rare pathological finding of RCC arising in a patient with ADPKD. PMID- 23110034 TI - Multifocal Adenocarcinomas Arising within a Gastric Inverted Hyperplastic Polyp. AB - We present herein the occurrence of multifocal adenocarcinomas with a minute signet ring cell carcinoma that arose within a gastric inverted hyperplastic polyp (IHP) in a 40-year-old woman. Endoscopic ultrasonography demonstrated a heterogeneous hypoechoic mass in the third layer of the gastric wall. The endoscopic submucosal dissection specimen measuring 3.5*3.2*1.8 cm was a well circumscribed protruding lesion that had a slit-shaped cavity. Histologically, the lesion consisted mainly of endophytic proliferation of hyperplastic columnar cells resembling normal foveolar epithelium. In addition, six foci of adenocarcinomas and a minute focus of signet ring cell carcinoma were randomly distributed in the superficial and deep regions. The adenocarcinoma was gradually transitioning from dysplasia, while the signet ring cell carcinoma was surrounded by hyperplastic foveolar epithelium. This is the first report of a gastric IHP with multifocal intramucosal adenocarcinomas and a signet ring cell carcinoma, and endoscopic submucosal dissection is used to completely resect it. PMID- 23110035 TI - Primary Pulmonary Myxoid Liposarcoma with Translocation t(12;16)(q13;p11) in a Young Female Patient: A Brief Case Report. AB - Primary liposarcoma of the lung is an extremely rare disease. To date, only 14 cases have been reported in the literature. We experienced a case of myxoid liposarcoma of the lung treated by surgery. The tumor was well-defined, solid, lobulated mass measuring 3.5*2 cm, involving the bronchus of the left lower lobe. Microscopically, myxoid liposarcoma was identified. The fluorescence in situ hybridization confirmed the presence of a reciprocal translocation involving DNA damage-inducible transcript 3 (DDIT3) and fused in sarcoma (FUS) genes. The patient is still alive with no recurrence or metastasis at the time of writing this report (on 20 months postoperatively). To our knowledge, this is the first cytogenetic case report of pulmonary myxoid liposarcoma. PMID- 23110036 TI - Primary endometrial squamous cell carcinoma: a case report and review of relevant literature on korean women. AB - Primary endometrial squamous cell carcinoma (PESCC) is an extremely rare tumor with unclear pathogenesis. A 54-year-old postmenopausal woman presented with a 6 month history of vaginal bleeding. The patient was provisionally diagnosed with uterine submucosal leiomyoma. This was followed by total hysterectomy with a bilateral salpingo-oophorectomy under the laparoscopic guidance. Histopathologically, the tumor was PESCC which was accompanied by a lack of the tumor in the uterine cervix. The tumor showed positive immunoreactivity for p(16INK4a). But there was no evidence of human papillomavirus (HPV) on in situ hybridization and HPV DNA chip analysis. We also present a review of the relevant literature on Korean women. PMID- 23110037 TI - Endoscopic ultrasound-guided fine needle aspiration cytology diagnosis of solid pseudopapillary neoplasm: three case reports with review of literature. AB - Solid pseudopapillary neoplasm of the pancreas (SPN) is relatively rare and it occurs almost exclusively in women. We recently experienced three cases of SPN diagnosed by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). These three cases were two male and one female patient whose age was 29, 37, and 44 years old. Radiological diagnosis was pancreatic endocrine tumor (PEN) showing solid with a heterogenous echogenicity. EUS-FNA cytology specimens consisted of single cells and aggregates of uniform cells, forming microadenoid structures, branching, papillary clusters with delicate fibrovascular cores. In conclusion, a single diagnosis of SPN based on clinical and radiological findings would be risky because there is a possibility of it being misdiagnosed as PEN or other malignancies. An EUS-FNA is therefore essential for establishing the diagnosis. In addition, the pathologists should recognize the characteristic cytologic findings with immunoprofiles of SPN to prevent misdiagnosis of SPN. PMID- 23110038 TI - Retraction: Antibiotics threaten wildlife: circulating quinolone residues and disease in avian scavengers. PMID- 23110039 TI - The effect of dietary adaption on cranial morphological integration in capuchins (order Primates, genus Cebus). AB - A fundamental challenge of morphology is to identify the underlying evolutionary and developmental mechanisms leading to correlated phenotypic characters. Patterns and magnitudes of morphological integration and their association with environmental variables are essential for understanding the evolution of complex phenotypes, yet the nature of the relevant selective pressures remains poorly understood. In this study, the adaptive significance of morphological integration was evaluated through the association between feeding mechanics, ingestive behavior and craniofacial variation. Five capuchin species were examined, Cebus apella sensu stricto, Cebus libidinosus, Cebus nigritus, Cebus olivaceus and Cebus albifrons. Twenty three-dimensional landmarks were chosen to sample facial regions experiencing high strains during feeding, characteristics affecting muscular mechanical advantage and basicranial regions. Integration structure and magnitude between and within the oral and zygomatic subunits, between and within blocks maximizing modularity and within the face, the basicranium and the cranium were examined using partial-least squares, eigenvalue variance, integration indices compared inter-specifically at a common level of sampled population variance and cluster analyses. Results are consistent with previous findings reporting a relative constancy of facial and cranial correlation patterns across mammals, while covariance magnitudes vary. Results further suggest that food material properties structure integration among functionally-linked facial elements and possibly integration between the face and the basicranium. Hard object-feeding capuchins, especially C. apella s.s., whose faces experience particularly high biomechanical loads are characterized by higher facial and cranial integration especially compared to C. albifrons, likely because morphotypes compromising feeding performance are selected against in species relying on obdurate fallback foods. This is the first study to report a link between food material properties and facial and cranial integration. Furthermore, results do not identify the consistent presence of cranial modules yielding support to suggestions that despite the distinct embryological imprints of its elements the cranium of placental mammals is not characterized by a modular architecture. PMID- 23110040 TI - The Feedback Intervention Trial (FIT)--improving hand-hygiene compliance in UK healthcare workers: a stepped wedge cluster randomised controlled trial. AB - INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10 13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards. CONCLUSION: Despite difficulties in implementation, intention-to treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN65246961. PMID- 23110041 TI - Enrichment of murine CD68+ CCR2+ and CD68+ CD206+ lung macrophages in acute pancreatitis-associated acute lung injury. AB - Acute lung injury (ALI) is an important cause of mortality in critically ill patients. Acute pancreatitis (AP) is one of the risk factors for developing this syndrome. Among the inflammatory cells, macrophages have a key role in determining the severity of the acute lung injury. In the lungs, macrophages constitute a heterogeneous cell population distributed in different compartments. Changes in not only the macrophage count, but also in their phenotype have been seen during the course of lung injury. A murine ductal ligation model of acute pancreatitis showed substantial morphological changes in the pancreas and lungs. Immunohistochemistry showed neutrophil recruitment into both organs after 9 hours and later on. F4/80(+) cells in the pancreas increased in the ligated animals, though there was not a significant difference in their number in the lungs as compared to sham operated animals. Flow cytometry analysis of lung macrophages demonstrated an enrichment of F4/80(-) CD68(+)CCR2(+) and F4/80(-) CD68(+)CD206(+) lung macrophages in ligated animals (AP) as compared to the sham operated group. The level of interleukin-6 in plasma increased 3 hours after ligation compared to the sham operated group, as a first indicator of a systemic inflammatory response.This study suggests a role for F4/80(-) CD68(+) macrophages in the pathogenesis of acute lung injury in acute pancreatitis. Studying lung macrophages for different phenotypic markers, their polarization, activation and recruitment, in the context of acute lung injury, is a novel area to potentially identify interventions which may improve the outcome of acute lung injury. PMID- 23110042 TI - Tat-dependent translocation of an F420-binding protein of Mycobacterium tuberculosis. AB - F(420) is a unique cofactor present in a restricted range of microorganisms, including mycobacteria. It has been proposed that F(420) has an important role in the oxidoreductive reactions of Mycobacterium tuberculosis, possibly associated with anaerobic survival and persistence. The protein encoded by Rv0132c has a predicted N-terminal signal sequence and is annotated as an F(420)-dependent glucose-6-phosphate dehydrogenase. Here we show that Rv0132c protein does not have the annotated activity. It does, however, co-purify with F(420) during expression experiments in M. smegmatis. We also show that the Rv0132c-F(420) complex is a substrate for the Tat pathway, which mediates translocation of the complex across the cytoplasmic membrane, where Rv0132c is anchored to the cell envelope. This is the first report of any F(420)-binding protein being a substrate for the Tat pathway and of the presence of F(420) outside of the cytosol in any F(420)-producing microorganism. The Rv0132c protein and its Tat export sequence are essentially invariant in the Mycobacterium tuberculosis complex. Taken together, these results show that current understanding of F(420) biology in mycobacteria should be expanded to include activities occurring in the extra-cytoplasmic cell envelope. PMID- 23110043 TI - ER stress activates NF-kappaB by integrating functions of basal IKK activity, IRE1 and PERK. AB - NF-kappaB, a transcription factor, becomes activated during the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress response pathway. NF-kappaB is normally held inactive by its inhibitor, IkappaBalpha. Multiple cellular pathways activate IKK (IkappaBalpha Kinase) which phosphorylate IkappaBalpha leading to its degradation and NF-kappaB activation. Here, we find that IKK is required for maximum activation of NF-kappaB in response to ER stress. However, unlike canonical NFkappaB activation, IKK activity does not increase during ER stress, but rather the level of basal IKK activity is critical for determining the extent of NF-kappaB activation. Furthermore, a key UPR initiator, IRE1, acts to maintain IKK basal activity through IRE1's kinase, but not RNase, activity. Inputs from IRE1 and IKK, in combination with translation repression by PERK, another UPR initiator, lead to maximal NF-kappaB activation during the UPR. These interdependencies have a significant impact in cancer cells with elevated IKK/NF kappaB activity such as renal cell carcinoma cells (786-0). Inhibition of IKK by an IKK inhibitor, which significantly decreases NF-kappaB activity, is overridden by UPR induction, arguing for the importance of considering UPR activation in cancer treatment. PMID- 23110044 TI - Structural basis of type 2A von Willebrand disease investigated by molecular dynamics simulations and experiments. AB - The hemostatic function of von Willebrand factor is downregulated by the metalloprotease ADAMTS13, which cleaves at a unique site normally buried in the A2 domain. Exposure of the proteolytic site is induced in the wild-type by shear stress as von Willebrand factor circulates in blood. Mutations in the A2 domain, which increase its susceptibility to cleavage, cause type 2A von Willebrand disease. In this study, molecular dynamics simulations suggest that the A2 domain unfolds under tensile force progressively through a series of steps. The simulation results also indicated that three type 2A mutations in the C-terminal half of the A2 domain, L1657I, I1628T and E1638K, destabilize the native state fold of the protein. Furthermore, all three type 2A mutations lowered in silico the tensile force necessary to undock the C-terminal helix alpha6 from the rest of the A2 domain, the first event in the unfolding pathway. The mutations F1520A, I1651A and A1661G were also predicted by simulations to destabilize the A2 domain and facilitate exposure of the cleavage site. Recombinant A2 domain proteins were expressed and cleavage assays were performed with the wild-type and single-point mutants. All three type 2A and two of the three predicted mutations exhibited increased rate of cleavage by ADAMTS13. These results confirm that destabilization of the helix alpha6 in the A2 domain facilitates exposure of the cleavage site and increases the rate of cleavage by ADAMTS13. PMID- 23110045 TI - Silencing of miR-370 in human cholangiocarcinoma by allelic loss and interleukin 6 induced maternal to paternal epigenotype switch. AB - Cholangiocarcinoma (CCA) is a highly lethal malignant tumor arising from the biliary tract epithelium. Interleukin-6 (IL-6) is a major mediator of inflammation and contributor to carcinogenesis within the biliary tree. Previous studies suggested that enforced IL-6 contributes to cholangiocarcinogenesis through hypermethylation of several genes implicated in CCA. However, the precise mechanisms of IL-6 effects in CCA remain unclear. We now demonstrate that microRNA (miR)-370 is underexpressed in a large cohort of human CCA vs. normal liver tissues. In addition, we show that IL-6 induces a time-dependent silencing of miR-370. In addition, demethylation of CCA cells results in upregulation of miR-370. Furthermore, we demonstrate that miR-370 is imprinted, and that the Intergenic Differentially Methylated Region (IG-DMR) responsible for imprinting regulation of this genomic locus is hypermethylated in response to IL-6 treatment. In addition, the IG-DMR is hypermethylated in human CCA specimens compared to normal matched controls, in the same location as the IL-6 induced hypermethylation. Finally, miR-370 was found to regulate WNT10B in luciferase as well as western blotting experiments. Our data indicate that the paternal allele of miR-370 is normally silenced through genomic imprinting and that the overexpression of IL-6 in CCA effectively suppresses the expression of miR-370 from the maternal allele, lending support to the theory that miR-370 silencing in human CCA follows a classic two-hit mechanism. PMID- 23110046 TI - Development, characterization and experimental validation of a cultivated sunflower (Helianthus annuus L.) gene expression oligonucleotide microarray. AB - Oligonucleotide-based microarrays with accurate gene coverage represent a key strategy for transcriptional studies in orphan species such as sunflower, H. annuus L., which lacks full genome sequences. The goal of this study was the development and functional annotation of a comprehensive sunflower unigene collection and the design and validation of a custom sunflower oligonucleotide based microarray. A large scale EST (>130,000 ESTs) curation, assembly and sequence annotation was performed using Blast2GO (www.blast2go.de). The EST assembly comprises 41,013 putative transcripts (12,924 contigs and 28,089 singletons). The resulting Sunflower Unigen Resource (SUR version 1.0) was used to design an oligonucleotide-based Agilent microarray for cultivated sunflower. This microarray includes a total of 42,326 features: 1,417 Agilent controls, 74 control probes for sunflower replicated 10 times (740 controls) and 40,169 different non-control probes. Microarray performance was validated using a model experiment examining the induction of senescence by water deficit. Pre-processing and differential expression analysis of Agilent microarrays was performed using the Bioconductor limma package. The analyses based on p-values calculated by eBayes (p<0.01) allowed the detection of 558 differentially expressed genes between water stress and control conditions; from these, ten genes were further validated by qPCR. Over-represented ontologies were identified using FatiScan in the Babelomics suite. This work generated a curated and trustable sunflower unigene collection, and a custom, validated sunflower oligonucleotide-based microarray using Agilent technology. Both the curated unigene collection and the validated oligonucleotide microarray provide key resources for sunflower genome analysis, transcriptional studies, and molecular breeding for crop improvement. PMID- 23110047 TI - Prediction of protein phosphorylation sites by using the composition of k-spaced amino acid pairs. AB - As one of the most widespread protein post-translational modifications, phosphorylation is involved in many biological processes such as cell cycle, apoptosis. Identification of phosphorylated substrates and their corresponding sites will facilitate the understanding of the molecular mechanism of phosphorylation. Comparing with the labor-intensive and time-consuming experiment approaches, computational prediction of phosphorylation sites is much desirable due to their convenience and fast speed. In this paper, a new bioinformatics tool named CKSAAP_PhSite was developed that ignored the kinase information and only used the primary sequence information to predict protein phosphorylation sites. The highlight of CKSAAP_PhSite was to utilize the composition of k-spaced amino acid pairs as the encoding scheme, and then the support vector machine was used as the predictor. The performance of CKSAAP_PhSite was measured with a sensitivity of 84.81%, a specificity of 86.07% and an accuracy of 85.43% for serine, a sensitivity of 78.59%, a specificity of 82.26% and an accuracy of 80.31% for threonine as well as a sensitivity of 74.44%, a specificity of 78.03% and an accuracy of 76.21% for tyrosine. Experimental results obtained from cross validation and independent benchmark suggested that our method was very promising to predict phosphorylation sites and can be served as a useful supplement tool to the community. For public access, CKSAAP_PhSite is available at http://59.73.198.144/cksaap_phsite/. PMID- 23110048 TI - Ablation of neurogenesis attenuates recovery of motor function after focal cerebral ischemia in middle-aged mice. AB - Depletion of neurogenesis worsens functional outcome in young-adult mice after focal cerebral ischemia, but whether a similar effect occurs in older mice is unknown. Using middle-aged (12-month-old) transgenic (DCX-TK((+))) mice that express herpes simplex virus thymidine kinase (HSV-TK) under control of the doublecortin (DCX) promoter, we conditionally depleted DCX-positive cells in the subventricular zone (SVZ) and hippocampus by treatment with ganciclovir (GCV) for 14 days. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery (MCAO) or occlusion of the distal segment of middle cerebral artery (dMCAO) on day 14 of vehicle or GCV treatment and mice were killed 24 hr or 12 weeks later. Increased infarct volume or brain atrophy was found in GCV- compared to vehicle-treated middle-aged DCX-TK((+)) mice, both 24 hr after MCAO and 12 weeks after dMCAO. More severe motor deficits were also observed in GCV treated, middle-aged DCX-TK((+)) transgenic mice at both time points. Our results indicate that ischemia-induced newborn neurons contribute to anatomical and functional outcome after experimental stroke in middle-aged mice. PMID- 23110049 TI - Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data. AB - BACKGROUND: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects. OBJECTIVE: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding. METHODS: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping. RESULTS: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression. CONCLUSION: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets. PMID- 23110050 TI - The ubiquitin ligase Nedd4-1 participates in denervation-induced skeletal muscle atrophy in mice. AB - Skeletal muscle atrophy is a consequence of muscle inactivity resulting from denervation, unloading and immobility. It accompanies many chronic disease states and also occurs as a pathophysiologic consequence of normal aging. In all these conditions, ubiquitin-dependent proteolysis is a key regulator of the loss of muscle mass, and ubiquitin ligases confer specificity to this process by interacting with, and linking ubiquitin moieties to target substrates through protein:protein interaction domains. Our previous work suggested that the ubiquitin-protein ligase Nedd4-1 is a potential mediator of skeletal muscle atrophy associated with inactivity (denervation, unloading and immobility). Here we generated a novel tool, the Nedd4-1 skeletal muscle-specific knockout mouse (myo(Cre);Nedd4-1(flox/flox)) and subjected it to a well validated model of denervation induced skeletal muscle atrophy. The absence of Nedd4-1 resulted in increased weights and cross-sectional area of type II fast twitch fibres of denervated gastrocnemius muscle compared with wild type littermates controls, at seven and fourteen days following tibial nerve transection. These effects are not mediated by the Nedd4-1 substrates MTMR4, FGFR1 and Notch-1. These results demonstrate that Nedd4-1 plays an important role in mediating denervation-induced skeletal muscle atrophy in vivo. PMID- 23110051 TI - K-134, a phosphodiesterase 3 inhibitor, prevents brain damage by inhibiting thrombus formation in a rat cerebral infarction model. AB - BACKGROUND: K-134 is a more potent antiplatelet drug with a selective inhibitory effect on phosphodiesterase 3 (PDE3) compared with its analogue, cilostazol. OBJECTIVES: This study was performed to compare the ameliorating effects of K-134 and cilostazol on brain damage in an experimental photothrombotic cerebral infarction model. METHODS AND RESULTS: We investigated the effects of oral preadministration of PDE3 inhibitors in a rat stroke model established by photothrombotic middle cerebral artery (MCA) occlusion. K-134 significantly prolonged MCA occlusion time at doses >10 mg/kg, and reduced cerebral infarct size at 30 mg/kg in the stroke model (n = 12, 87.5+/-5.6 vs. 126.8+/-7.5 mm(3), P<0.01), indicating its potent antithrombotic effect. On the other hand, the effects of cilostazol on MCA occlusion time and cerebral infarct size are relatively weak even at the high dosage of 300 mg/kg. Furthermore, K-134 blocked rat platelet aggregation more potently than cilostazol in vitro. Also in an arteriovenous shunt thrombosis model, K-134 showed an antithrombotic effect greater than cilostazol. CONCLUSIONS: These findings suggest that K-134, which has strong antithrombotic activity, is a promising drug for prevention of cerebral infarction associated with platelet hyperaggregability. PMID- 23110052 TI - Effectiveness of holistic interventions for people with severe chronic obstructive pulmonary disease: systematic review of controlled clinical trials. AB - BACKGROUND: Despite a well-recognised burden of disabling physical symptoms compounded by co-morbidities, psychological distress and social isolation, the needs of people with severe chronic obstructive pulmonary disease (COPD) are typically poorly addressed. AIM: To assess the effectiveness of interventions designed to deliver holistic care for people with severe COPD. METHODS: We searched 11 biomedical databases, three trial repositories (January 1990-March 2012; no language restrictions) and contacted international experts to locate published, unpublished and in-progress randomised controlled trials (RCTs), quasi RCTs and controlled clinical trials (CCTs) that investigated holistic interventions to support patients with severe COPD in any healthcare context. The primary outcome was health-related quality of life (HRQoL). Quality assessment and data extraction followed Cochrane Collaboration methodology. We used a piloted data extraction sheet and undertook narrative synthesis. RESULTS: From 2,866 potentially relevant papers, we identified three trials: two RCTs (from United States and Australia), and one CCT (from Thailand): total 216 patients. Risk of bias was assessed as moderate in two studies and high in the third. All the interventions were led by nurses acting in a co-ordinating role (e.g. facilitating community support in Thailand, providing case-management in the USA, or co-ordinating inpatient care in Australia). HRQoL improved significantly in the Thai CCT compared to the (very limited) usual care (p<0.001), in two sub domains in the American trial, but showed no significant changes in the Australian trial. Exercise tolerance, dyspnoea, and satisfaction with care also improved in the Thai trial. CONCLUSIONS: Some 15 years after reports first highlighted the unmet needs of people with severe COPD, we have been unable to find robust trial evidence about interventions that can address those needs. There is an urgent need to develop and evaluate holistic care interventions designed improve HRQoL for people with severe COPD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42012002430). PMID- 23110053 TI - Percutaneous transhepatic balloon dilation of biliary-enteric anastomotic strictures after surgical repair of iatrogenic bile duct injuries. AB - PURPOSE: To evaluate the efficacy of percutaneous balloon dilation of biliary enteric anastomotic strictures resulting from surgical repair of laparoscopic cholecystectomy-related bile duct injuries. MATERIAL AND METHODS: A total of 61 patients were referred to our institution from 1995 to 2010 for treatment of obstruction at the biliary-enteric anastomosis following surgical repair of laparoscopic cholecystectomy-related bile duct injuries. Of these 61 patients, 27 underwent surgical revision upon stricture diagnosis, and 34 patients were managed using balloon dilation. Of these 34 patients, 2 were lost to follow up, leaving 32 patients for analysis. The primary study objective was to determine the clinical success rate of balloon dilation of biliary-enteric anastomotic strictures. Secondary study objectives included determining anastomosis patency, rates of stricture recurrence following treatment, and morbidity. RESULTS: Balloon dilation of biliary-enteric anastomotic strictures was clinically successful in 21 of 32 patients (66%). Anastomotic stricture recurred in one of 21 patients (5%) after an average of 13.1 years of follow-up. Patients who were unsuccessfully managed with balloon dilation required significantly more invasive procedures (6.8 v. 3.4; p = 0.02) and were left with an indwelling biliary catheter for a significantly longer period of time (8.8 v. 2.0 months; p = 0.02) than patients whose strictures could be resolved by balloon dilation. No significant differences in the number of balloon dilations performed (p = 0.17) or in the maximum balloon diameter used (p = 0.99) were demonstrated for patients with successful or unsuccessful balloon dilation outcomes. CONCLUSION: Percutaneous balloon dilation of anastomotic biliary strictures following surgical repair of laparoscopic cholecystectomy-related injuries may result in lasting patency of the biliary-enteric anastomosis. PMID- 23110054 TI - Iron regulator hepcidin exhibits antiviral activity against hepatitis C virus. AB - Hepatitis C viral infection affects 170 million people worldwide. It causes serious chronic liver diseases. HCV infection has been implicated in iron accumulation in the liver and iron overload has been shown to be a potential cofactor for HCV associated hepatocellular carcinoma progression. The underlying mechanisms are not understood. Human hepcidin, a 25 amino acid peptide mainly produced by hepatocytes, is a key regulator of iron metabolism. Alteration of hepcidin expression levels has been reported in the setting of chronic HCV infection and hepatocellular carcinoma. In this study, we aim to examine the interactions between HCV infection and hepcidin expression in liver cells. We found that hepcidin expression was suppressed in HCV infected cells. The suppressive effect appears to be regulated by histone acetylation but not DNA methylation. Moreover, we found that hepcidin had a direct antiviral activity against HCV replication in cell culture. The antiviral effect is associated with STAT3 activation. In conclusion, hepcidin can induce intracellular antiviral state while HCV has a strategy to suppress hepcidin expression. This may be a novel mechanism by which HCV circumvents hepatic innate antiviral defense. PMID- 23110055 TI - Differing roles for TCF4 and COL8A2 in central corneal thickness and fuchs endothelial corneal dystrophy. AB - Fuchs endothelial corneal dystrophy (FECD) is the most common late-onset, vision threatening corneal dystrophy in the United States, affecting about 4% of the population. Advanced FECD involves a thickening of the cornea from stromal edema and changes in Descemet membrane. To understand the relationship between FECD and central corneal thickness (CCT), we characterized common genetic variation in COL8A2 and TCF4, genes previously implicated in CCT and/or FECD. Other genes previously associated with FECD (PITX2, ZEB1, SLC4A11), and genes only known to affect CCT (COL5A1, FOXO1, AVGR8, ZNF469) were also interrogated. FECD probands, relatives and controls were recruited from 32 clinical sites; a total of 532 cases and 204 controls were genotyped and tested for association of FECD case/control status, a 7-step FECD severity scale and CCT, adjusting for age and sex. Association of FECD grade with TCF4 was highly significant (OR= 6.01 at rs613872; p = 4.8*10(-25)), and remained significant when adjusted for changes in CCT (OR= 4.84; p = 2.2*10(-16)). Association of CCT with TCF4 was also significant (p = 6.1*10(-7)), but was abolished with adjustment for FECD grade (p = 0.92). After adjusting for FECD grade, markers in other genes examined were modestly associated (p ~ 0.001) with FECD and/or CCT. Thus, common variants in TCF4 appear to influence FECD directly, and CCT secondarily via FECD. Additionally, changes in corneal thickness due to the effect of other loci may modify disease severity, age-at-onset, or other biomechanical characteristics. PMID- 23110056 TI - Regular exercise is associated with a reduction in the risk of NAFLD and decreased liver enzymes in individuals with NAFLD independent of obesity in Korean adults. AB - BACKGROUND: We evaluated the association of regular physical exercise with the presence of non-alcoholic fatty liver disease (NAFLD) and liver enzymes in relation to obesity and insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional analysis was conducted in 72,359 healthy Korean adults without diabetes who participated in a comprehensive health check-up. Subjects who have been exercising regularly (more than 3 times per week, at least for 30 minutes each time and for consecutive 3 month) were categorized into exercise group. All subjects were categorized into deciles based on their body mass index (BMI) and we estimated the odds ratios (ORs) for having NAFLD according to exercise regularity in each decile. The diagnosis of NAFLD was based on ultrasonography findings. Individuals with NAFLD (n = 19,921) were analyzed separately to evaluate ORs for having elevated liver enzymes based on regularity of exercise. The risk for NAFLD was significantly reduced in exercise group with age- and sex adjusted ORs of 0.53-0.72 for all BMI deciles except at BMI categories of <19.6 and 20.7-21.6 kg/m(2). While no difference was seen in BMI between subjects in exercise and non-exercise group across the BMI deciles, the values of body fat percentage and metabolic risk factors differed. Among NAFLD patients, subjects in exercise group had a lower risk for having elevated liver enzymes with multivariable adjusted OR of 0.85 (95% CI 0.74-0.99, for AST) and 0.74 (95% CI 0.67-0.81, for ALT) than did subjects in non-exercise group. CONCLUSIONS/SIGNIFICANCE: Regular exercise was associated with a reduced risk for having NAFLD and decreased liver enzymes in patients with NAFLD, and this relationship was also independent of obesity. PMID- 23110057 TI - Genome-wide identification of reverse complementary microRNA genes in plants. AB - MicroRNAs (miRNAs) are ~21-nucleotide small RNAs (sRNAs) with essential regulatory roles in plants. They are generated from stem-loop-structured precursors through two sequential Dicer-like 1 (DCL1)-mediated cleavages. To date, hundreds of plant miRNAs have been uncovered. However, the question, whether the sequences reverse complementary (RC) to the miRNA precursors could form hairpin-like structures and produce sRNA duplexes similar to the miRNA/miRNA* pairs has not been solved yet. Here, we interrogated this possibility in 16 plant species based on sRNA high-throughput sequencing data and secondary structure prediction. A total of 59 RC sequences with great potential to form stem-loop structures and generate miRNA/miRNA*-like duplexes were identified in ten plants, which were named as RC-miRNA precursors. Unlike the canonical miRNAs, only a few cleavage targets of the RC-miRNAs were identified in Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), and none in Soybean (Glycine max) based on degradome data. Surprisingly, the genomic regions surrounding some of the RC-miRNA target recognition sites were observed to be specifically methylated in both Arabidopsis and rice. Taken together, we reported a new class of miRNAs, called RC-miRNAs, which were generated from the antisense strands of the miRNA precursors. Based on the results, we speculated that the mature RC-miRNAs might have subtle regulatory activity through target cleavages, but might possess short interfering RNA-like activity by guiding sequence specific DNA methylation. PMID- 23110058 TI - Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model. AB - BACKGROUND: Peripheral arterial disease (PAD) is a common disease accounting for about 12% of the adult population, and causes significant morbidity and mortality. Therapeutic angiogenesis using angiogenic factors has been considered to be a potential treatment option for PAD patients. In this study, we assessed the potential of a new angiogenic factor AGGF1 for therapeutic angiogenesis in a critical limb ischemia model in mice for PAD. METHODS AND RESULTS: We generated a unilateral hindlimb ischemia model in mice by ligation of the right common iliac artery and femoral artery. Ischemic mice with intrasmuscular administration of DNA for an expression plasmid for human AGGF1 (AGGF1 group) resulted in increased expression of both AGGF1 mRNA and protein after the administration compared with control mice with injection of the empty vector (control group). Color PW Doppler echocardiography showed that the blood flow in ischemic hindlimbs was significantly increased in the AGGF1 group compared to control mice at time points of 7, 14, and 28 days after DNA administration (n = 9/group, P = 0.049, 0.001, and 0.001, respectively). Increased blood flow in the AGGF1 group was correlated to increased density of CD31-positive vessels and decreased necrosis in muscle tissues injected with AGGF1 DNA compared with the control tissue injected with the empty vector. Ambulatory impairment was significantly reduced in the AGGF1 group compared to the control group (P = 0.004). The effect of AGGF1 was dose-dependent. At day 28 after gene transfer, AGGF1 was significantly better in increasing blood flow than FGF-2 (P = 0.034), although no difference was found for tissue necrosis and ambulatory impairment. CONCLUSIONS: These data establish AGGF1 as a candidate therapeutic agent for therapeutic angiogenesis to treat PAD. PMID- 23110059 TI - Fish and mammalian phagocytes differentially regulate pro-inflammatory and homeostatic responses in vivo. AB - Phagocytosis is a cellular mechanism that is important to the early induction of antimicrobial responses and the regulation of adaptive immunity. At an inflammatory site, phagocytes serve as central regulators for both pro inflammatory and homeostatic anti-inflammatory processes. However, it remains unclear if this is a recent evolutionary development or whether the capacity to balance between these two seemingly contradictory processes is a feature already displayed in lower vertebrates. In this study, we used murine (C57BL/6) and teleost fish (C. auratus) in vitro and in vivo models to assess the evolutionary conservation of this dichotomy at a site of inflammation. At the level of the macrophage, we found that teleost fish already displayed divergent pro inflammatory and homeostatic responses following internalization of zymosan or apoptotic bodies, respectively, and that these were consistent with those of mice. However, fish and mice displayed significant differences in vivo with regards to the level of responsiveness to zymosan and apoptotic bodies, the identity of infiltrating leukocytes, their rate of infiltration, and the kinetics and strength of resulting antimicrobial responses. Unlike macrophages, significant differences were identified between teleost and murine neutrophilic responses. We report for the first time that activated murine, but not teleost neutrophils, possess the capacity to internalize apoptotic bodies. This internalization translates into reduction of neutrophil ROS production. This may play an important part in the recently identified anti-inflammatory activity that mammalian neutrophils display during the resolution phase of inflammation. Our observations are consistent with continued honing of inflammatory control mechanisms from fish to mammals, and provide added insights into the evolutionary path that has resulted in the integrated, multilayered responses that are characteristic of higher vertebrates. PMID- 23110060 TI - Evaluation of different biomarkers to predict individual radiosensitivity in an inter-laboratory comparison--lessons for future studies. AB - Radiotherapy is a powerful cure for several types of solid tumours, but its application is often limited because of severe side effects in individual patients. With the aim to find biomarkers capable of predicting normal tissue side reactions we analysed the radiation responses of cells from individual head and neck tumour and breast cancer patients of different clinical radiosensitivity in a multicentric study. Multiple parameters of cellular radiosensitivity were analysed in coded samples of peripheral blood lymphocytes (PBLs) and derived lymphoblastoid cell lines (LCLs) from 15 clinical radio-hypersensitive tumour patients and compared to age- and sex-matched non-radiosensitive patient controls and 15 lymphoblastoid cell lines from age- and sex- matched healthy controls of the KORA study. Experimental parameters included ionizing radiation (IR)-induced cell death (AnnexinV), induction and repair of DNA strand breaks (Comet assay), induction of yH2AX foci (as a result of DNA double strand breaks), and whole genome expression analyses. Considerable inter-individual differences in IR induced DNA strand breaks and their repair and/or cell death could be detected in primary and immortalised cells with the applied assays. The group of clinically radiosensitive patients was not unequivocally distinguishable from normal responding patients nor were individual overreacting patients in the test system unambiguously identified by two different laboratories. Thus, the in vitro test systems investigated here seem not to be appropriate for a general prediction of clinical reactions during or after radiotherapy due to the experimental variability compared to the small effect of radiation sensitivity. Genome-wide expression analysis however revealed a set of 67 marker genes which were differentially induced 6 h after in vitro-irradiation in lymphocytes from radio hypersensitive and non-radiosensitive patients. These results warrant future validation in larger cohorts in order to determine parameters potentially predictive for clinical radiosensitivity. PMID- 23110061 TI - "The 3/3 strategy": a successful multifaceted hospital wide hand hygiene intervention based on WHO and continuous quality improvement methodology. AB - BACKGROUND: Only multifaceted hospital wide interventions have been successful in achieving sustained improvements in hand hygiene (HH) compliance. METHODOLOGY/PRINCIPAL FINDINGS: Pre-post intervention study of HH performance at baseline (October 2007-December 2009) and during intervention, which included two phases. Phase 1 (2010) included multimodal WHO approach. Phase 2 (2011) added Continuous Quality Improvement (CQI) tools and was based on: a) Increase of alcohol hand rub (AHR) solution placement (from 0.57 dispensers/bed to 1.56); b) Increase in frequency of audits (three days every three weeks: "3/3 strategy"); c) Implementation of a standardized register form of HH corrective actions; d) Statistical Process Control (SPC) as time series analysis methodology through appropriate control charts. During the intervention period we performed 819 scheduled direct observation audits which provided data from 11,714 HH opportunities. The most remarkable findings were: a) significant improvements in HH compliance with respect to baseline (25% mean increase); b) sustained high level (82%) of HH compliance during intervention; c) significant increase in AHRs consumption over time; c) significant decrease in the rate of healthcare-acquired MRSA; d) small but significant improvements in HH compliance when comparing phase 2 to phase 1 [79.5% (95% CI: 78.2-80.7) vs 84.6% (95% CI:83.8-85.4), p<0.05]; e) successful use of control charts to identify significant negative and positive deviations (special causes) related to the HH compliance process over time ("positive": 90.1% as highest HH compliance coinciding with the "World hygiene day"; and "negative":73.7% as lowest HH compliance coinciding with a statutory lay-off proceeding). CONCLUSIONS/SIGNIFICANCE: CQI tools may be a key addition to WHO strategy to maintain a good HH performance over time. In addition, SPC has shown to be a powerful methodology to detect special causes in HH performance (positive and negative) and to help establishing adequate feedback to healthcare workers. PMID- 23110062 TI - Tsetse salivary gland proteins 1 and 2 are high affinity nucleic acid binding proteins with residual nuclease activity. AB - Analysis of the tsetse fly salivary gland EST database revealed the presence of a highly enriched cluster of putative endonuclease genes, including tsal1 and tsal2. Tsal proteins are the major components of tsetse fly (G. morsitans morsitans) saliva where they are present as monomers as well as high molecular weight complexes with other saliva proteins. We demonstrate that the recombinant tsetse salivary gland proteins 1&2 (Tsal1&2) display DNA/RNA non-specific, high affinity nucleic acid binding with K(D) values in the low nanomolar range and a non-exclusive preference for duplex. These Tsal proteins exert only a residual nuclease activity with a preference for dsDNA in a broad pH range. Knockdown of Tsal expression by in vivo RNA interference in the tsetse fly revealed a partially impaired blood digestion phenotype as evidenced by higher gut nucleic acid, hematin and protein contents. PMID- 23110063 TI - Boundaries of the origin of replication: creation of a pET-28a-derived vector with p15A copy control allowing compatible coexistence with pET vectors. AB - During our studies involving protein-DNA interactions, we constructed plasmid pSAM to fulfill two requirements: 1) to facilitate transfer of cloned sequences from widely used expression vector pET-28a(+), and 2) to provide a vector compatible with pBR322-derived plasmids for use in cells harboring two different plasmids. Vector pSAM is a pET-28a(+)-derived plasmid with the p15A origin of replication (ori); pET-28a(+) contains the pBR322 replicon that is incompatible with other pBR322-derived plasmids. By replacing the original pET-28a(+) replicon comprising the ori, RNAI, RNAII, and Rom-with the p15A replicon, we generated pSAM, which contains the pET-28a(+) multiple cloning site and is now compatible with pBR322-derived vectors. Plasmid copy number was assessed using quantitative PCR: pSAM copy number was maintained at 18+/-4 copies per cell, consistent with that of other p15A-type vectors. Compatibility with pBR322-derived vectors was tested with pGEX-6p-1 and pSAM, which maintained their copy numbers of 49+/-10 and 14+/-4, respectively, when both were present within the same cell. Swapping of the ori is a common practice; however, it is vital that all regions of the original replicon be removed. Additional vector pSAMRNAI illustrated that incompatibility remains when portions of the replicon, such as RNAI and/or Rom, are retained; pSAMRNAI, which contains the intact RNAI but not ROM, lowered the copy number of pGEX-6p-1 to 18+/-2 in doubly transformed cells due to retention of the pET-28a(+)-derived RNAI. Thus, pSAMRNAI is incompatible with vectors controlled by the pBR322 replicon and further demonstrates the need to remove all portions of the original replicon and to quantitatively assess copy number, both individually and in combination, to ensure vector compatibility. To our knowledge, this is the first instance where the nascent vector has been quantitatively assessed for both plasmid copy number and compatibility. New vector pSAM provides ease of transferring sequences from commonly used pET-28a(+) into a vector compatible with the pBR322 family of plasmids. This essential need is currently not filled. PMID- 23110064 TI - GCN2 has inhibitory effect on human immunodeficiency virus-1 protein synthesis and is cleaved upon viral infection. AB - The reversible phosphorylation of the alpha-subunit of eukaryotic translation initiation factor 2 (eIF2alpha) is a well-characterized mechanism of translational control in response to a wide variety of cellular stresses, including viral infection. Beside PKR, the eIF2alpha kinase GCN2 participates in the cellular response against viral infection by RNA viruses with central nervous system tropism. PKR has also been involved in the antiviral response against HIV 1, although this antiviral effect is very limited due to the distinct mechanisms evolved by the virus to counteract PKR action. Here we report that infection of human cells with HIV-1 conveys the proteolytic cleavage of GCN2 and that purified HIV-1 and HIV-2 proteases produce direct proteolysis of GCN2 in vitro, abrogating the activation of GCN2 by HIV-1 RNA. Transfection of distinct cell lines with a plasmid encoding an HIV-1 cDNA clone competent for a single round of replication resulted in the activation of GCN2 and the subsequent eIF2alpha phosphorylation. Moreover, transfection of GCN2 knockout cells or cells with low levels of phosphorylated eIF2alpha with the same HIV-1 cDNA clone resulted in a marked increase of HIV-1 protein synthesis. Also, the over-expression of GCN2 in cells led to a diminished viral protein synthesis. These findings suggest that viral RNA produced during HIV-1 infection activates GCN2 leading to inhibition of viral RNA translation, and that HIV-1 protease cleaves GCN2 to overcome its antiviral effect. PMID- 23110065 TI - Dietary protein affects gene expression and prevents lipid accumulation in the liver in mice. AB - BACKGROUND AND AIMS: High protein (HP) diets are suggested to positively modulate obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease in humans and rodents. The aim of our study was to detect mechanisms by which a HP diet affects hepatic lipid accumulation. METHODS: To investigate the acute and long term effect of high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35 energy%) or low (10 energy%) fat and high (50 energy%) or normal (15 energy%) protein diets for 1 or 12 weeks. Effects on body composition, liver fat, VLDL production rate and the hepatic transcriptome were investigated. RESULTS: Mice fed the HP diets displayed a lower body weight, developed less adiposity and decreased hepatic lipid accumulation, which could be attributed to a combination of several processes. Next to an increased hepatic VLDL production rate, increased energy utilisation due to enhanced protein catabolic processes, such as transamination, TCA cycle and oxidative phosphorylation was found upon high protein ingestion. CONCLUSION: Feeding a HP diet prevented the development of NAFLD by enhancing lipid secretion into VLDL particles and a less efficient use of ingested calories. PMID- 23110066 TI - Role of gap junction protein connexin43 in astrogliosis induced by brain injury. AB - Astrogliosis is a process that involves morphological and biochemical changes associated with astrocyte activation in response to cell damage in the brain. The upregulation of intermediate filament proteins including glial fibrillary acidic protein (GFAP), nestin and vimentin are often used as indicators for astrogliosis. Although connexin43 (Cx43), a channel protein widely expressed in adult astrocytes, exhibits enhanced immunoreactivity in the peri-lesion region, its role in astrogliosis is still unclear. Here, we correlated the temporal and spatial expression of Cx43 to the activation of astrocytes and microglia in response to an acute needle stab wound in vivo. We found large numbers of microglia devoid of Cx43 in the needle wound at 3 days post injury (dpi) while reactive astrocytes expressing Cx43 were present in the peripheral zone surrounding the injury site. A redistribution of Cx43 to the needle site, corresponding to the increased presence of GFAP-positive reactive astrocytes in the region, was only apparent from 6 dpi and sustained until at least 15 dpi. Interestingly, the extent of microglial activation and subsequent astrogliosis in the brain of Cx43 knockout mice was significantly larger than those of wild type, suggesting that Cx43 expression limits the degree of microgliosis. Although Cx43 is not essential for astrogliosis and microglial activation induced by a needle injury, our results demonstrate that Cx43 is a useful marker for injury induced astrogliosis due to its enhanced expression specifically within a small region of the lesion for an extended period. As a channel protein, Cx43 is a potential in vivo diagnostic tool of asymptomatic brain injury. PMID- 23110067 TI - Lower prevalence of carotid plaque hemorrhage in women, and its mediator effect on sex differences in recurrent cerebrovascular events. AB - BACKGROUND AND PURPOSE: Women are at lower risk of stroke, and appear to benefit less from carotid endarterectomy (CEA) than men. We hypothesised that this is due to more benign carotid disease in women mediating a lower risk of recurrent cerebrovascular events. To test this, we investigated sex differences in the prevalence of MRI detectable plaque hemorrhage (MRI PH) as an index of plaque instability, and secondly whether MRI PH mediates sex differences in the rate of cerebrovascular recurrence. METHODS: Prevalence of PH between sexes was analysed in a single centre pooled cohort of 176 patients with recently symptomatic, significant carotid stenosis (106 severe [>=70%], 70 moderate [50-69%]) who underwent prospective carotid MRI scanning for identification of MRI PH. Further, a meta-analysis of published evidence was undertaken. Recurrent events were noted during clinical follow up for survival analysis. RESULTS: Women with symptomatic carotid stenosis (50%>=) were less likely to have plaque hemorrhage (PH) than men (46% vs. 70%) with an adjusted OR of 0.23 [95% CI 0.10-0.50, P<0.0001] controlling for other known vascular risk factors. This negative association was only significant for the severe stenosis subgroup (adjusted OR 0.18, 95% CI 0.067 0.50) not the moderate degree stenosis. Female sex in this subgroup also predicted a longer time to recurrent cerebral ischemic events (HR 0.38 95% CI 0.15-0.98, P = 0.045). Further addition of MRI PH or smoking abolished the sex effects with only MRI PH exerting a direct effect. Meta-analysis confirmed a protective effect of female sex on development of PH: unadjusted OR for presence of PH = 0.54 (95% CI 0.45-0.67, p<0.00001). CONCLUSIONS: MRI PH is significantly less prevalent in women. Women with MRI PH and severe stenosis have a similar risk as men for recurrent cerebrovascular events. MRI PH thus allows overcoming the sex bias in selection for CEA. PMID- 23110068 TI - Hepatitis C virus phylogenetic clustering is associated with the social-injecting network in a cohort of people who inject drugs. AB - It is hypothesized that social networks facilitate transmission of the hepatitis C virus (HCV). We tested for association between HCV phylogeny and reported injecting relationships using longitudinal data from a social network design study. People who inject drugs were recruited from street drug markets in Melbourne, Australia. Interviews and blood tests took place three monthly (during 2005-2008), with participants asked to nominate up to five injecting partners at each interview. The HCV core region of individual isolates was then sequenced and phylogenetic trees were constructed. Genetic clusters were identified using bootstrapping (cut-off: 70%). An adjusted Jaccard similarity coefficient was used to measure the association between the reported injecting relationships and relationships defined by clustering in the phylogenetic analysis (statistical significance assessed using the quadratic assignment procedure). 402 participants consented to participate; 244 HCV infections were observed in 238 individuals. 26 genetic clusters were identified, with 2-7 infections per cluster. Newly acquired infection (AOR = 2.03, 95% CI: 1.04-3.96, p = 0.037, and HCV genotype 3 (vs. genotype 1, AOR = 2.72, 95% CI: 1.48-4.99) were independent predictors of being in a cluster. 54% of participants whose infections were part of a cluster in the phylogenetic analysis reported injecting with at least one other participant in that cluster during the study. Overall, 16% of participants who were infected at study entry and 40% of participants with newly acquired infections had molecular evidence of related infections with at least one injecting partner. Likely transmission clusters identified in phylogenetic analysis correlated with reported injecting relationships (adjusted Jaccard coefficient: 0.300; p<0.001). This is the first study to show that HCV phylogeny is associated with the injecting network, highlighting the importance of the injecting network in HCV transmission. PMID- 23110069 TI - In situ mass spectrometry imaging and ex vivo characterization of renal crystalline deposits induced in multiple preclinical drug toxicology studies. AB - Drug toxicity observed in animal studies during drug development accounts for the discontinuation of many drug candidates, with the kidney being a major site of tissue damage. Extensive investigations are often required to reveal the mechanisms underlying such toxicological events and in the case of crystalline deposits the chemical composition can be problematic to determine. In the present study, we have used mass spectrometry imaging combined with a set of advanced analytical techniques to characterize such crystalline deposits in situ. Two potential microsomal prostaglandin E synthase 1 inhibitors, with similar chemical structure, were administered to rats over a seven day period. This resulted in kidney damage with marked tubular degeneration/regeneration and crystal deposits within the tissue that was detected by histopathology. Results from direct tissue section analysis by matrix-assisted laser desorption ionization mass spectrometry imaging were combined with data obtained following manual crystal dissection analyzed by liquid chromatography mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical composition of the crystal deposits was successfully identified as a common metabolite, bisulphonamide, of the two drug candidates. In addition, an un-targeted analysis revealed molecular changes in the kidney that were specifically associated with the area of the tissue defined as pathologically damaged. In the presented study, we show the usefulness of combining mass spectrometry imaging with an array of powerful analytical tools to solve complex toxicological problems occurring during drug development. PMID- 23110070 TI - A non-linear deterministic model for regulation of diauxic lag on cellobiose by the pneumococcal multidomain transcriptional regulator CelR. AB - When grown on glucose and beta-glucosides, S. pneumoniae shows sequential use of sugars resulting in diauxic growth with variable time extent of the lag phase separating the biphasic growth curve. The pneumococcal beta-glucoside uptake locus containing the PTS transporter spr0276-82, is regulated by a multi-domain transcriptional regulator CelR. In this work, we address the contribution of phosphorylation of the phosphorylable cysteine in the EIIB domain of CelR to diauxic lag. Utilising site-directed mutagenesis of the phosphorylable amino acids in the EIIB and EIIA domains of CelR, we show that the EIIB domain activation is linked to the duration of the lag phase. Analysis of mutants for other PTS systems indicates that a second beta-glucoside PTS (spr0505), not able to support growth on cellobiose, is responsible for the lag during diauxic growth. A mathematical model of the process is devised together with a nonlinear identification procedure which provides model parameter estimates characterizing the single phases of bacterial growth. Parameter identification performed on data recorded in appropriate experiments on mutants allows for establishing a relationship between a specific model parameter, the EIIB domain and the time extent of the diauxic lag. The experimental results and the related insights provided by the mathematical model provide evidence that the conflicting activation of the CelR regulator is at the origin of the lag phase during sequential growth on glucose and cellobiose. This data is the first description of diauxic lag regulation involving two PTS and a multidomain regulator and could serve as a promising approach for studying the S. pneumoniae growth process on complex carbon sources as possibly encountered in the human host. PMID- 23110071 TI - Quantitative linking hypotheses for infant eye movements. AB - The study of cognitive development hinges, largely, on the analysis of infant looking. But analyses of eye gaze data require the adoption of linking hypotheses: assumptions about the relationship between observed eye movements and underlying cognitive processes. We develop a general framework for constructing, testing, and comparing these hypotheses, and thus for producing new insights into early cognitive development. We first introduce the general framework--applicable to any infant gaze experiment--and then demonstrate its utility by analyzing data from a set of experiments investigating the role of attentional cues in infant learning. The new analysis uncovers significantly more structure in these data, finding evidence of learning that was not found in standard analyses and showing an unexpected relationship between cue use and learning rate. Finally, we discuss general implications for the construction and testing of quantitative linking hypotheses. MATLAB code for sample linking hypotheses can be found on the first author's website. PMID- 23110072 TI - The metabolic profile of long-lived Drosophila melanogaster. AB - We investigated the age-related changes in the metabolic profile of male Drosophila melanogaster and compared the metabolic profile of flies selected for increased longevity to that of control flies of equal age. We found clear differences in metabolite composition between selection regimes and among age groups. Contrary to results found in a previous study of the transcriptome of these lines the metabolic profile did not show a younger pattern in longevity selected (LS) flies than in same aged control (C) flies. Rather, many of the metabolites affected by age had levels common to older control individuals in the young LS flies. Furthermore, ageing affected the metabolome in a different LS specific direction. The selection induced difference increased with age. Some metabolites involved in oxidative phosphorylation changed with age highlighting the importance of mitochondrial function in the ageing process. However, these metabolites were not affected by selection for increased longevity, indicating that improvements of mitochondrial function were not involved in the increased lifespan of LS lines. Of the eight metabolites identified as having a significant difference in relative abundance between selection regimes in our study choline, lysine and glucose also show difference among lifespan phenotypes in C. elegans indicating that the correlation between the concentration of these metabolites and longevity was evolutionary conserved. Links between longevity and choline concentration is also found in mice making this metabolite an obvious target for further study. PMID- 23110073 TI - Modeling the contributions of Basal ganglia and Hippocampus to spatial navigation using reinforcement learning. AB - A computational neural model that describes the competing roles of Basal Ganglia and Hippocampus in spatial navigation is presented. Model performance is evaluated on a simulated Morris water maze explored by a model rat. Cue-based and place-based navigational strategies, thought to be subserved by the Basal ganglia and Hippocampus respectively, are described. In cue-based navigation, the model rat learns to directly head towards a visible target, while in place-based navigation the target position is represented in terms of spatial context provided by an array of poles placed around the pool. Learning is formulated within the framework of Reinforcement Learning, with the nigrostriatal dopamine signal playing the role of Temporal Difference Error. Navigation inherently involves two apparently contradictory movements: goal oriented movements vs. random, wandering movements. The model hypothesizes that while the goal directedness is determined by the gradient in Value function, randomness is driven by the complex activity of the SubThalamic Nucleus (STN)-Globus Pallidus externa (GPe) system. Each navigational system is associated with a Critic, prescribing actions that maximize value gradients for the corresponding system. In the integrated system, that incorporates both cue-based and place-based forms of navigation, navigation at a given position is determined by the system whose value function is greater at that position. The proposed model describes the experimental results of [1], a lesion-study that investigates the competition between cue-based and place-based navigational systems. The present study also examines impaired navigational performance under Parkinsonian-like conditions. The integrated navigational system, operated under dopamine-deficient conditions, exhibits increased escape latency as was observed in experimental literature describing MPTP model rats navigating a water maze. PMID- 23110074 TI - Risk factors associated with death in in-hospital pediatric convulsive status epilepticus. AB - OBJECTIVE: To evaluate in-patient mortality and predictors of death associated with convulsive status epilepticus (SE) in a large, multi-center, pediatric cohort. PATIENTS AND METHODS: We identified our cohort from the KID Inpatient Database for the years 1997, 2000, 2003 and 2006. We queried the database for convulsive SE, associated diagnoses, and for inpatient death. Univariate logistic testing was used to screen for potential risk factors. These risk factors were then entered into a stepwise backwards conditional multivariable logistic regression procedure. P-values less than 0.05 were taken as significant. RESULTS: We identified 12,365 (5,541 female) patients with convulsive SE aged 0-20 years (mean age 6.2 years, standard deviation 5.5 years, median 5 years) among 14,965,571 pediatric inpatients (0.08%). Of these, 117 died while in the hospital (0.9%). The most frequent additional admission ICD-9 code diagnoses in addition to SE were cerebral palsy, pneumonia, and respiratory failure. Independent risk factors for death in patients with SE, assessed by multivariate calculation, included near drowning (Odds ratio [OR] 43.2; Confidence Interval [CI] 4.4 426.8), hemorrhagic shock (OR 17.83; CI 6.5-49.1), sepsis (OR 10.14; CI 4.0 25.6), massive aspiration (OR 9.1; CI 1.8-47), mechanical ventilation >96 hours (OR9; 5.6-14.6), transfusion (OR 8.25; CI 4.3-15.8), structural brain lesion (OR7.0; CI 3.1-16), hypoglycemia (OR5.8; CI 1.75-19.2), sepsis with liver failure (OR 14.4; CI 5-41.9), and admission in December (OR3.4; CI 1.6-4.1). African American ethnicity (OR 0.4; CI 0.2-0.8) was associated with a decreased risk of death in SE. CONCLUSION: Pediatric convulsive SE occurs in up to 0.08% of pediatric inpatient admissions with a mortality of up to 1%. There appear to be several risk factors that can predict mortality. These may warrant additional monitoring and aggressive management. PMID- 23110075 TI - Chromosomal instability in BRAF mutant, microsatellite stable colorectal cancers. AB - The BRAF oncogene is mutated in 15% of sporadic colorectal cancers. Approximately half of these BRAF mutant cancers demonstrate frequent frameshift mutations termed microsatellite instability (MSI), but are diploid and chromosomally stable. BRAF wild type cancers are typically microsatellite stable (MSS) and instead acquire chromosomal instability (CIN). In these cancers, CIN is associated with a poor outcome. BRAF mutant cancers that are MSS, typically present at an advanced stage and have a particularly poor prognosis. We have previously demonstrated clinical and molecular similarities between MSS cancers with or without a BRAF mutation, and therefore hypothesised that CIN may also be frequent in BRAF mutant/MSS cancers. BRAF mutant/MSS (n = 60), and BRAF wild type/MSS CRCs (n = 90) were investigated for CIN using loss of heterozygosity analysis over twelve loci encompassing chromosomal regions 5q, 8p, 17p and 18q. CIN was frequent in BRAF mutant/MSS cancers (41/57, 72%), which was comparable to the rate found in BRAF wild type/MSS cancers (74/90, 82%). The greatest loss in BRAF mutant/MSS cancers occurred at 8p (26/44, 59%), and the least at 5q (19/49, 39%). CIN in BRAF mutant/MSS cancers correlated with advanced stage (AJCC III/IV: 15/17, 88%; p = 0.02); showed high rates of co-occurrence with the CpG Island Methylator Phenotype (17/23, 74%); and CIN at 18q and 8p associated with worse survival (p = 0.02, p<0.05). This study demonstrates that CIN commonly occurs in advanced BRAF mutant/MSS colorectal cancers where it may contribute to poorer survival, and further highlights molecular similarities occurring between these and BRAF wild type cancers. PMID- 23110076 TI - Smooth pursuit and visual occlusion: active inference and oculomotor control in schizophrenia. AB - This paper introduces a model of oculomotor control during the smooth pursuit of occluded visual targets. This model is based upon active inference, in which subjects try to minimise their (proprioceptive) prediction error based upon posterior beliefs about the hidden causes of their (exteroceptive) sensory input. Our model appeals to a single principle--the minimisation of variational free energy--to provide Bayes optimal solutions to the smooth pursuit problem. However, it tries to accommodate the cardinal features of smooth pursuit of partially occluded targets that have been observed empirically in normal subjects and schizophrenia. Specifically, we account for the ability of normal subjects to anticipate periodic target trajectories and emit pre-emptive smooth pursuit eye movements--prior to the emergence of a target from behind an occluder. Furthermore, we show that a single deficit in the postsynaptic gain of prediction error units (encoding the precision of posterior beliefs) can account for several features of smooth pursuit in schizophrenia: namely, a reduction in motor gain and anticipatory eye movements during visual occlusion, a paradoxical improvement in tracking unpredicted deviations from target trajectories and a failure to recognise and exploit regularities in the periodic motion of visual targets. This model will form the basis of subsequent (dynamic causal) models of empirical eye tracking measurements, which we hope to validate, using psychopharmacology and studies of schizophrenia. PMID- 23110077 TI - Expression of ethanol-induced behavioral sensitization is associated with alteration of chromatin remodeling in mice. AB - BACKGROUND: Ethanol-induced behavioral sensitization (EIBS) is proposed to play a role in early and recurring steps of addiction. EIBS does not occur uniformly in all animals even from the same inbred strain. Since recent data demonstrate that epigenetic mechanisms are likely to be involved in the development and the persistence of ethanol-related behaviors, we explored the involvement of epigenetic mechanisms in ethanol response after EIBS development. METHODOLOGY: DBA/2J mice were i.p. injected with saline or ethanol (2 g/kg) once a day for 10 consecutive days. At day 17, ethanol-treated mice were split in resistant and sensitized groups. Brains were then removed 30 min after a saline or 2 g/kg ethanol challenge to assess i) gene expression using PCR array targeting 84 epigenetic-related genes and ii) histone deacetylases (HDAC), histone acetylases (HAT) and DNA methyltransferases (DNMT) activities as well as H4K12 acetylation. PRINCIPAL FINDINGS: Acute ethanol administration decreased dnmt1, esco2 and rps6ka5 genes expression. These genes were similarly altered in sensitized but not in resistant mice after an ethanol challenge, suggesting that resistant mice were tolerant to the transcriptional outcomes of an ethanol challenge. Whereas global HAT or DNMT activity was not affected, global HDAC activity was reduced after an acute ethanol injection. HDAC inhibition occurred in all ethanol-treated mice but with a lesser extent in sensitized animals. As a consequence, H4 acetylation was specifically potentiated in the core of the Nac proportionally to the striatal HDAC activity decrease. CONCLUSIONS/SIGNIFICANCE: The present study highlights that the contrasted behavioral response to an ethanol challenge between resistant and sensitized mice may be mediated by epigenetic mechanisms occurring specifically in the striatum. Here we show that vulnerability to ethanol dependence and relapse could be, at least in part, due to individual variability in acute ethanol-induced epigenetic response. PMID- 23110078 TI - What an rRNA secondary structure tells about phylogeny of fungi in Ascomycota with emphasis on evolution of major types of ascus. AB - BACKGROUND: RNA secondary structure is highly conserved throughout evolution. The higher order structure is fundamental in establishing important structure function relationships. Nucleotide sequences from ribosomal RNA (rRNA) genes have made a great contribution to our understanding of Ascomycota phylogeny. However, filling the gaps between molecular phylogeny and morphological assumptions based on ascus dehiscence modes and type of fruitbodies at the higher level classification of the phylum remains an unfulfilled task faced by mycologists. METHODOLOGY/PRINCIPAL FINDINGS: We selected some major groups of Ascomycota to view their phylogenetic relationships based on analyses of rRNA secondary structure. Using rRNA secondary structural information, here, we converted nucleotide sequences into the structure ones over a 20-symbol code. Our structural analyses together with ancestral character state reconstruction produced reasonable phylogenetic position for the class Geoglossomycetes as opposed to the classic nucleotide analyses. Judging from the secondary structure analyses with consideration of mode of ascus dehiscence and the ability of forming fruitbodies, we draw a clear picture of a possible evolutionary route for fungal asci and some major groups of fungi in Ascomycota. The secondary structure trees show a more reasonable phylogenetic position for the class Geoglossomycetes. CONCLUSIONS: Our results illustrate that asci lacking of any dehiscence mechanism represent the most primitive type. Passing through the operculate and Orbilia-type asci, bitunicate asci occurred. The evolution came to the most advanced inoperculate type. The ascus-producing fungi might be derived from groups lacking of the capacity to form fruitbodies, and then evolved multiple times. The apothecial type of fruitbodies represents the ancestral state, and the ostiolar type is advanced. The class Geoglossomycetes is closely related to Leotiomycetes and Sordariomycetes having a similar ascus type other than it was originally placed based on nucleotide sequence analyses. PMID- 23110079 TI - Genome-wide identification and characterization of R2R3MYB family in Cucumis sativus. AB - BACKGROUND: The R2R3MYB proteins comprise one of the largest families of transcription factors in plants. Although genome-wide analysis of this family has been carried out in some species, little is known about R2R3MYB genes in cucumber (Cucumis sativus L.). PRINCIPAL FINDINGS: This study has identified 55 R2R3MYB genes in the latest cucumber genome and the CsR2R3MYB family contained the smallest number of identified genes compared to other species that have been studied due to the absence of recent gene duplication events. These results were also supported by genome distribution and gene duplication analysis. Phylogenetic analysis showed that they could be classified into 11 subgroups. The evolutionary relationships and the intron-exon organizations that showed similarities with Arabidopsis, Vitis and Glycine R2R3MYB proteins were also analyzed and suggested strong gene conservation but also the expansions of particular functional genes during the evolution of the plant species. In addition, we found that 8 out of 55 (~14.54%) cucumber R2R3MYB genes underwent alternative splicing events, producing a variety of transcripts from a single gene, which illustrated the extremely high complexity of transcriptome regulation. Tissue-specific expression profiles showed that 50 cucumber R2R3MYB genes were expressed in at least one of the tissues and the other 5 genes showed very low expression in all tissues tested, which suggested that cucumber R2R3MYB genes took part in many cellular processes. The transcript abundance level analysis during abiotic conditions (NaCl, ABA and low temperature treatments) identified a group of R2R3MYB genes that responded to one or more treatments. CONCLUSIONS: This study has produced a comparative genomics analysis of the cucumber R2R3MYB gene family and has provided the first steps towards the selection of CsR2R3MYB genes for cloning and functional dissection that can be used in further studies to uncover their roles in cucumber growth and development. PMID- 23110080 TI - Molecular pathway reconstruction and analysis of disturbed gene expression in depressed individuals who died by suicide. AB - Molecular mechanisms behind the etiology and pathophysiology of major depressive disorder and suicide remain largely unknown. Recent molecular studies of expression of serotonin, GABA and CRH receptors in various brain regions have demonstrated that molecular factors may contribute to the development of depressive disorder and suicide behaviour. Here, we used microarray analysis to examine the expression of genes in brain tissue (frontopolar cortex) of individuals who had been diagnosed with major depressive disorder and died by suicide, and those who had died suddenly without a history of depression. We analyzed the list of differentially expressed genes using pathway analysis, which is an assumption-free approach to analyze microarray data. Our analysis revealed that the differentially expressed genes formed functional networks that were implicated in cell to cell signaling related to synapse maturation, neuronal growth and neuronal complexity. We further validated these data by randomly choosing (100 times) similarly sized gene lists and subjecting these lists to the same analyses. Random gene lists did not provide highly connected gene networks like those generated by the differentially expressed list derived from our samples. We also found through correlational analysis that the gene expression of control participants was more highly coordinated than in the MDD/suicide group. These data suggest that among depressed individuals who died by suicide, wide ranging perturbations of gene expression exist that are critical for normal synaptic connectively, morphology and cell to cell communication. PMID- 23110081 TI - Flanking residues are central to DO11.10 T cell hybridoma stimulation by ovalbumin 323-339. AB - T cell activation requires formation of a tri-molecular interaction between a major histocompatibility complex (MHC), peptide, and T cell receptor. In a common model system, the ovalbumin epitope 323-339 binds the murine class II MHC, I A(d), in at least three distinct registers. The DO11.10 T cell recognizes the least stable of these, as determined by peptide-MHC dissociation rates. Using exogenous peptides and peptide insertions into a carrier protein in combination with IL-2 secretion assays, we show that the alternate registers do not competitively inhibit display of the active register four. In contrast, this weakly binding register is stabilized by the presence of n-terminal flanking residues active in MHC binding. The DO11.10 hybridoma is sensitive to the presence of specific wild-type residues extending to at least the P-3 peptide position. Transfer of the P-4 to P-2 flanking residues to a hen egg lysozyme epitope also presented by I-A(d) increases the activity of that epitope substantially. These results illustrate the inherent complexity in delineating the interaction of multiple registers based on traditional thermodynamic measurements and demonstrate the potential of flanking residue modification for increasing the activity of weakly bound epitopes. The latter technique represents an alternative to substitution of anchor residues within a weakly bound register, which we show can significantly decrease the activity of the epitope to a responding T cell. PMID- 23110083 TI - Latitudinal patterns in phenotypic plasticity and fitness-related traits: assessing the climatic variability hypothesis (CVH) with an invasive plant species. AB - Phenotypic plasticity has been suggested as the main mechanism for species persistence under a global change scenario, and also as one of the main mechanisms that alien species use to tolerate and invade broad geographic areas. However, contrasting with this central role of phenotypic plasticity, standard models aimed to predict the effect of climatic change on species distributions do not allow for the inclusion of differences in plastic responses among populations. In this context, the climatic variability hypothesis (CVH), which states that higher thermal variability at higher latitudes should determine an increase in phenotypic plasticity with latitude, could be considered a timely and promising hypothesis. Accordingly, in this study we evaluated, for the first time in a plant species (Taraxacum officinale), the prediction of the CVH. Specifically, we measured plastic responses at different environmental temperatures (5 and 20 degrees C), in several ecophysiological and fitness related traits for five populations distributed along a broad latitudinal gradient. Overall, phenotypic plasticity increased with latitude for all six traits analyzed, and mean trait values increased with latitude at both experimental temperatures, the change was noticeably greater at 20 degrees than at 5 degrees C. Our results suggest that the positive relationship found between phenotypic plasticity and geographic latitude could have very deep implications on future species persistence and invasion processes under a scenario of climate change. PMID- 23110082 TI - Genetic susceptibility factors on genes involved in the steroid hormone biosynthesis pathway and progesterone receptor for gastric cancer risk. AB - BACKGROUND: The objective of the study was to investigate the role of genes (HSD3B1, CYP17A1, CYP19A1, HSD17B2, HSD17B1) involved in the steroid hormone biosynthesis pathway and progesterone receptor (PGR) in the etiology of gastric cancer in a population-based two-phase genetic association study. METHODS: In the discovery phase, 108 candidate SNPs in the steroid hormone biosynthesis pathway related genes and PGR were analyzed in 76 gastric cancer cases and 322 controls in the Korean Multi-Center Cancer Cohort. Statistically significant SNPs identified in the discovery phase were re-evaluated in an extended set of 386 cases and 348 controls. Pooled- and meta-analyses were conducted to summarize the results. RESULTS: Of the 108 SNPs in steroid hormone biosynthesis pathway related genes and PGR analyzed in the discovery phase, 23 SNPs in PGR in the recessive model and 10 SNPs in CYP19A1 in the recessive or additive models were significantly associated with increased gastric cancer risk (p<0.05). The minor allele frequencies of the SNPs in both the discovery and extension phases were not statistically different. Pooled- and meta-analyses showed CYP19A1 rs1004982, rs16964228, and rs1902580 had an increased risk for gastric cancer (pooled OR [95% CI] = 1.22 [1.01-1.48], 1.31 [1.03-1.66], 3.03 [1.12-8.18], respectively). In contrast, all PGR SNPs were not statistically significantly associated with gastric cancer risk. CONCLUSIONS: Our findings suggest CYP19A1 that codes aromatase may play an important role in the association of gastric cancer risk and be a genetic marker for gastric cancer susceptibility. PMID- 23110084 TI - TGFbeta1-induced Baf60c regulates both smooth muscle cell commitment and quiescence. AB - Smooth muscle cells (SMCs) play critical roles in a number of diseases; however, the molecular mechanism underlying their development is unclear. Although the role of TGFbeta1 signaling in SMC development is well established, the downstream molecular signals are not fully understood. We used several rat multipotent adult progenitor cell ((r)MAPC) lines that express levels of Oct4 mRNA similar to hypoblast stem cells (HypoSC), and can differentiate robustly to mesodermal and endodermal cell types. TGFbeta1 alone, or with PDGF-BB, induces differentiation of rMAPCs to SMCs, which expressed structural SMC proteins, including alpha smooth muscle actin (alphaSMA), and contribute to the SMC coat of blood vessels in vivo. A genome-wide time-course transcriptome analysis revealed that transcripts of Baf60c, part of the SWI/SNF actin binding chromatin remodeling complex D-3 (SMARCD3/BAF60c), were significantly induced during MAPC-SMC differentiation. We demonstrated that BAF60c is a necessary co-regulator of TGFbeta1 mediated induction of SMC genes. Knock-down of Baf60c decreased SMC gene expression in rMAPCs whereas ectopic expression of Baf60c was sufficient to commit rMAPCs to SMCs in the absence of exogenous cytokines. TGFbeta1 activates Baf60c via the direct binding of SMAD2/3 complexes to the Baf60c promoter region. Chromatin- and co-immunoprecipitation studies demonstrated that regulation of SMC genes by BAF60c is mediated via interaction with SRF binding CArG box-containing promoter elements in SMC genes. We noted that compared with TGFbeta1, Baf60c overexpression in rMAPC yielded SMC with a more immature phenotype. Similarly, Baf60c induced an immature phenotype in rat aortic SMCs marked by increased cell proliferation and decreased contractile marker expression. Thus, Baf60c is important for TGFbeta-mediated commitment of primitive stem cells (rMAPCs) to SMCs and is associated with induction of a proliferative state of quiescent SMCs. The MAPC-SMC differentiation system may be useful for identification of additional critical (co-)regulators of SMC development. PMID- 23110085 TI - Prevalence of plasmid-mediated quinolone resistance and aminoglycoside resistance determinants among carbapeneme non-susceptible Enterobacter cloacae. AB - BACKGROUND: Simultaneous resistance to aminoglycosides and fluoroquinolones in carbapeneme non-susceptible (CNS) isolates will inevitably create problems. The present study was performed to characterize the prevalence of the plasmid mediated quinolone resistance determinants (QRDs) and aminoglycoside resistance determinants (ARDs) among the CNS Enterobacter cloacae (E. cloacae) isolates in a Chinese teaching hospital, and to acquire their molecular epidemiological characteristics. METHODS: The beta-lactamases genes (including class A carbapenemase genes bla(KPC) and bla(SME), metallo-beta-lactamase genes (MBLs) bla(IMP), bla(VIM) and bla(NDM), and extended spectrum beta-lactamases (ESBLs),bla(CTX-M), bla(TEM) and bla(SHV)), QRDs (including qnrA, qnrB, qnrS and aac(6')-Ib-cr) and ARDs (including aac(6')-Ib, armA and rmtB) of these 35 isolates were determined by PCR and sequenced bidirectionally. The clonal relatedness was investigated by pulsed-field gel electrophoresis (PFGE). RESULTS: Of the 35 isolates, 9 (25.7%) harbored a carbapenemase gene; 23 (65.7%) carried ESBLs; 24 (68.6%) were QRD positive; and 27 (77.1%) were ARD positive. Among the 5 bla(IMP-8) positive strains, 4 (80%) contained both ESBL and QRD genes, and all the 5 (100%) harbored ARD genes. Of the 23 ESBLs positive isolates, 6 (26.1%) were carbapenemase positive, 14 (60.9%) were QRD positive, and 18 (78.3%) were ARD positive. PFGE revealed genetic diversity among the 35 isolates, indicating that the high prevalence of CNS E. cloacae isolates was not caused by clonal dissemination. CONCLUSION: QRD and ARD genes were highly prevalent among the CNS E. cloacae isolates. Multiple resistant genes were co-expressed in the same isolates. The CNS E. cloacae isolate co-expressing bla(NDM-1), bla(IMP-26), qnrA1 and qnrS1 was first reported. PMID- 23110086 TI - Age-dependent changes in the sphingolipid composition of mouse CD4+ T cell membranes and immune synapses implicate glucosylceramides in age-related T cell dysfunction. AB - To determine whether changes in sphingolipid composition are associated with age related immune dysfunction, we analyzed the core sphingolipidome (i.e., all of the metabolites through the first headgroup additions) of young and aged CD4(+) T cells. Since sphingolipids influence the biophysical properties of membranes, we evaluated the compositions of immune synapse (IS) and non-IS fractions prepared by magnetic immuno-isolation. Broadly, increased amounts of sphingomyelins, dihydrosphingomyelins and ceramides were found in aged CD4(+) T cells. After normalizing for total sphingolipid content, a statistically significant decrease in the molar fraction of glucosylceramides was evident in both the non-IS and IS fractions of aged T cells. This change was balanced by less dramatic increases in the molar fractions of sphingomyelins and dihydrosphingomyelins in aged CD4(+) T cells. In vitro, the direct or enzymatic enhancement of ceramide levels decreased CD4(+) T cell proliferation without regard for the age of the responding T cells. In contrast, the in vitro inhibition of glucosylceramidase preferentially increased the proliferation of aged CD4(+) T cells. These results suggest that reductions in glucosylceramide abundance contribute to age-related impairments in CD4(+) T cell function. PMID- 23110087 TI - Ultrastructural observation and gene expression profiling of Schistosoma japonicum derived from two natural reservoir hosts, water buffalo and yellow cattle. AB - Water buffalo and yellow cattle are the two of the most important natural reservoir hosts for Schistosoma japonicum in endemic areas of China, although their susceptibility differs, with water buffalo being less conducive to the growth and development of S. japonicum. Results from the current study show that the general morphology and ultrastructure of adult schistosomes derived from the two hosts also differed. Using high-throughput microarray technology, we also compared the gene expression profiles of adult schistosomes derived from the two hosts. We identified genes that were differentially expressed in worms from the two natural hosts. Further analysis revealed that genes associated with protein kinase and phosphatase, the stimulus response, and lipid and nucleotide metabolism were overexpressed, whereas genes associated with reproduction, anatomical structure morphogenesis and multifunctional motif were underexpressed in schistosomes from water buffalo. These differentially expressed genes were mainly involved in nucleotide, energy, lipid metabolism, energy metabolism, transcription, transport and signaling pathway. This suggests that they are key molecules affecting the survival and development of schistosomes in different natural host species. The results of this study add to current understanding of the interplay between parasites and their natural hosts, and provide valuable information for the screening of vaccine candidates or new drug targets against schistosomiasis in the natural reservoir hosts in endemic areas. PMID- 23110088 TI - IS-98-ST1 West Nile virus derived from an infectious cDNA clone retains neuroinvasiveness and neurovirulence properties of the original virus. AB - Infectious clones of West Nile virus (WNV) have previously been generated and used to decipher the role of viral proteins in WNV virulence. The majority of molecular clones obtained to date have been derived from North American, Australian, or African isolates. Here, we describe the construction of an infectious cDNA clone of a Mediterranean WNV strain, IS-98-ST1. We characterized the biological properties of the recovered recombinant virus in cell culture and in mice. The growth kinetics of recombinant and parental WNV were similar in Vero cells. Moreover, the phenotype of recombinant and parental WNV was indistinguishable as regards viremia, viral load in the brain, and mortality in susceptible and resistant mice. Finally, the pathobiology of the infectious clone was examined in embryonated chicken eggs. The capacity of different WNV strains to replicate in embryonated chicken eggs closely paralleled their ability to replicate in mice, suggesting that inoculation of embryonated chicken eggs could provide a practical in vivo model for the study of WNV pathogenesis. In conclusion, the IS-98-ST1 infectious clone will allow assessment of the impact of selected mutations and novel genomic changes appearing in emerging European strains pathogenicity and endemic or epidemic potential. This will be invaluable in the context of an increasing number of outbreaks and enhanced severity of infections in the Mediterranean basin and Eastern Europe. PMID- 23110089 TI - Inhibition of cell division induced by external guide sequences (EGS Technology) targeting ftsZ. AB - EGS (external guide sequence) technology is a promising approach to designing new antibiotics. EGSs are short antisense oligoribonucleotides that induce RNase P mediated cleavage of a target RNA by forming a precursor tRNA-like complex. The ftsZ mRNA secondary structure was modeled and EGSs complementary to two regions with high probability of being suitable targets were designed. In vitro reactions showed that EGSs targeting these regions bound ftsZ mRNA and elicited RNase P mediated cleavage of ftsZ mRNA. A recombinant plasmid, pEGSb1, coding for an EGS that targets region "b" under the control of the T7 promoter was generated. Upon introduction of this plasmid into Escherichia coli BL21(DE3)(pLysS) the transformant strain formed filaments when expression of the EGS was induced. Concomitantly, E. coli harboring pEGSb1 showed a modest but significant inhibition of growth when synthesis of the EGSb1 was induced. Our results indicate that EGS technology could be a viable strategy to generate new antimicrobials targeting ftsZ. PMID- 23110090 TI - Cardiac atrial circadian rhythms in PERIOD2::LUCIFERASE and per1:luc mice: amplitude and phase responses to glucocorticoid signaling and medium treatment. AB - Circadian rhythms in cardiac function are apparent in e.g., blood pressure, heart rate, and acute adverse cardiac events. A circadian clock in heart tissue has been identified, but entrainment pathways of this clock are still unclear. We cultured tissues of mice carrying bioluminescence reporters of the core clock genes, period 1 or 2 (per1(luc) or PER2(LUC)) and compared in vitro responses of atrium to treatment with medium and a synthetic glucocorticoid (dexamethasone [DEX]) to that of the suprachiasmatic nucleus (SCN) and liver. We observed that PER2(LUC), but not per1(luc) is rhythmic in atrial tissue, while both per1(luc) and PER2(LUC) exhibit rhythmicity in other cultured tissues. In contrast to the SCN and liver, both per1(luc) and PER2(LUC) bioluminescence amplitudes were increased in response to DEX treatment, and the PER2(LUC) amplitude response was dependent on the time of treatment. Large phase-shift responses to both medium and DEX treatments were observed in the atrium, and phase responses to medium treatment were not attributed to serum content but the treatment procedure itself. The phase-response curves of atrium to both DEX and medium treatments were found to be different to the liver. Moreover, the time of day of the culturing procedure itself influenced the phase of the circadian clock in each of the cultured tissues, but the magnitude of this response was uniquely large in atrial tissue. The current data describe novel entrainment signals for the atrial circadian clock and specifically highlight entrainment by mechanical treatment, an intriguing observation considering the mechanical nature of cardiac tissue. PMID- 23110091 TI - Increased mutability of Staphylococci in biofilms as a consequence of oxidative stress. AB - OBJECTIVES: To investigate the development of mutational resistance to antibiotics in staphylococcal biofilms. METHODS: Mutation frequencies to resistance against mupirocin and rifampicin were determined for planktonic cultures and for biofilms generated using either a novel static biofilm model or by continuous flow. DNA microarray analysis was performed to detect differences in transcriptional profiles between planktonic and biofilm cultures. RESULTS: The mutability of biofilm cultures increased up to 60-fold and 4-fold for S. aureus and S. epidermidis, respectively, compared with planktonic cultures. Incorporation of antioxidants into S. aureus biofilms reduced mutation frequencies, indicating that increased oxidative stress underlies the heightened mutability. Transcriptional profiling of early biofilm cultures revealed up regulation of the superoxide dismutase gene, sodA, also suggestive of enhanced oxidative stress in these cultures. The addition of catalase to biofilms of S. aureus SH1000 reduced mutation frequencies, a finding which implicated hydrogen peroxide in increased biofilm mutability. However, catalase had no effect on biofilm mutability in S. aureus UAMS-1, suggesting that there is more than one mechanism by which the mutability of staphylococci may increase during the biofilm mode of growth. CONCLUSION: Our findings suggest that biofilms represent an enriched source of mutational resistance to antibiotics in the staphylococci. PMID- 23110092 TI - Anti-cancer drugs elicit re-expression of UDP-glucuronosyltransferases in melanoma cells. AB - The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the detoxification of carcinogens as well as clearance of anti-cancer drugs. In humans, 19 UGT family members have been identified and are expressed in a tissue specific manner throughout the body. However, the UGTs have not been previously characterized in melanocytes or melanoma. In the present study, UGT2B7, UGT2B10, and UGT2B15 were identified as being normally expressed in human melanocytes. The same three UGT family members were also expressed in the primary melanoma cell line WM115. No UGT expression was detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line examined. These results suggest that UGT expression is lost during melanoma progression. Treatment of WM3211 or metastatic melanoma cell lines with anti-cancer agents (including vemurafenib) induced expression of UGT2B7, UGT2B10 and UGT2B15 demonstrating that melanoma cells retain the ability to re-express these same three UGTs. The corresponding increase in glucuronidation activity in melanoma cells following anti-cancer treatment was also observed. Furthermore, knockdown of UGT2B7 in WM115 cells sensitized these cells to treatment by adriamycin and epirubicin indicating that UGT2B7 is involved in resistance to these drugs. However, knockdown of UGT2B7 had no effect on temozolomide toxicity. Taken together, these results clearly demonstrate a role for UGTs in melanoma etiology. Since the UGTs are drug metabolism enzymes, we propose that re-expression of the UGTs constitutes a previously unsuspected mechanism for intratumoral drug resistance in melanoma. PMID- 23110093 TI - Animal welfare in studies on murine tuberculosis: assessing progress over a 12 year period and the need for further improvement. AB - There is growing concern over the welfare of animals used in research, in particular when these animals develop pathology. The present study aims to identify the main sources of animal distress and to assess the possible implementation of refinement measures in experimental infection research, using mouse models of tuberculosis (TB) as a case study. This choice is based on the historical relevance of mouse studies in understanding the disease and the present and long-standing impact of TB on a global scale. Literature published between 1997 and 2009 was analysed, focusing on the welfare impact on the animals used and the implementation of refinement measures to reduce this impact. In this 12-year period, we observed a rise in reports of ethical approval of experiments. The proportion of studies classified into the most severe category did however not change significantly over the studied period. Information on important research parameters, such as method for euthanasia or sex of the animals, were absent in a substantial number of papers. Overall, this study shows that progress has been made in the application of humane endpoints in TB research, but that a considerable potential for improvement remains. PMID- 23110094 TI - Selection against aerial dispersal in ants: two non-flying queen phenotypes in Pogonomyrmex laticeps. AB - The South American seed-harvester ant Pogonomyrmex laticeps has dimorphic queens: ergatoid (permanently wingless) and brachypterous (short, non-functional wings). Surveys in western Argentina indicated that colonies near Chilecito, La Rioja Province, produced only ergatoid queens, while those near Punta Balasto, Catamarca Province (263 km away), produced only brachypterous queens. Brachypterous queens were significantly larger than ergatoid queens for 10 of 11 external characters, but both phenotypes had comparable reproductive potential, i.e., a spermatheca and a similar number of ovarioles. Using normal winged queens of the closely related P. uruguayensis for comparison, we determined that both queen phenotypes in P. laticeps had a full set of dorsal thoracic sclerites, albeit each sclerite was much reduced, whereas workers had a thorax without distinct dorsal sclerites. Sclerites were fused and immobile in ergatoid queens, while they were separable and fully articulated in brachypterous queens. Both phenotypes lacked the big indirect flight muscles, but brachypterous queens retained the tiny direct flight muscles. Overall, this dimorphism across populations indicates that there are alternative solutions to selective pressures against flying queens. We lack field data about colony founding strategy (independent or dependent) for either queen phenotype, but colonies at both sites produced numerous gynes, and we infer that all foundresses initiate colonies independently and are obligate foragers. PMID- 23110095 TI - Mediterranean species of Caulerpa are polyploid with smaller genomes in the invasive ones. AB - Caulerpa species are marine green algae, which often act as invasive species with rapid clonal proliferation when growing outside their native biogeographical borders. Despite many publications on the genetics and ecology of Caulerpa species, their life history and ploidy levels are still to be resolved and are the subject of large controversy. While some authors claimed that the thallus found in nature has a haplodiplobiontic life cycle with heteromorphic alternation of generations, other authors claimed a diploid or haploid life cycle with only one generation involved. DAPI-staining with image analysis and microspectrophotometry were used to estimate relative nuclear DNA contents in three species of Caulerpa from the Mediterranean, at individual, population and species levels. Results show that ploidy levels and genome size vary in these three Caulerpa species, with a reduction in genome size for the invasive ones. Caulerpa species in the Mediterranean are polyploids in different life history phases; all sampled C. taxifolia and C. racemosa var. cylindracea were in haplophasic phase, but in C. prolifera, the native species, individuals were found in both diplophasic and haplophasic phases. Different levels of endopolyploidy were found in both C. prolifera and C. racemosa var. cylindracea. Life history is elucidated for the Mediterranean C. prolifera and it is hypothesized that haplophasic dominance in C. racemosa var. cylindracea and C. taxifolia is a beneficial trait for their invasive strategies. PMID- 23110098 TI - Geology of the Early Arikareean sharps formation on the Pine Ridge Indian Reservation and surrounding areas of South Dakota and Nebraska. AB - Based on geologic mapping, measured sections, and lithologic correlations, the local features of the upper and lower type areas of the Early Arikareean (30.8 20.6 million years ago) Sharps Formation are revised and correlated. The Sharps Formation above the basal Rockyford Member is divided into two members of distinct lithotypes. The upper 233 feet of massive siltstones and sandy siltstones is named the Gooseneck Road Member. The middle member, 161 feet of eolian volcaniclastic siltstones with fluvially reworked volcaniclastic lenses and sandy siltstone sheets, is named the Wolff Camp Member. An ashey zone at the base of the Sharps Formation is described and defined as the Rockyford Ash Zone (RAZ) in the same stratigraphic position as the Nonpareil Ash Zone (NPAZ) in Nebraska. Widespread marker beds of fresh water limestones at 130 feet above the base of the Sharps Formation and a widespread reddish-brown clayey siltstone at 165 feet above the base of the Sharps Formation are described. The Brown Siltstone Beds of Nebraska are shown to be a southern correlative of the Wolff Camp Member and the Rockyford Member of the Sharps Formation. Early attempts to correlate strata in the Great Plains were slow in developing. Recognition of the implications of the paleomagnetic and lithologic correlations of this paper will provide an added datum assisting researchers in future biostratigraphic studies. Based on similar lithologies, the Sharps Formation, currently assigned to the Arikaree Group, should be reassigned to the White River Group. PMID- 23110096 TI - Transmission ecology of Sin Nombre hantavirus in naturally infected North American deermouse populations in outdoor enclosures. AB - Sin Nombre hantavirus (SNV), hosted by the North American deermouse (Peromyscus maniculatus), causes hantavirus pulmonary syndrome (HPS) in North America. Most transmission studies in the host were conducted under artificial conditions, or extrapolated information from mark-recapture data. Previous studies using experimentally infected deermice were unable to demonstrate SNV transmission. We explored SNV transmission in outdoor enclosures using naturally infected deermice. Deermice acquiring SNV in enclosures had detectable viral RNA in blood throughout the acute phase of infection and acquired significantly more new wounds (indicating aggressive encounters) than uninfected deermice. Naturally infected wild deermice had a highly variable antibody response to infection, and levels of viral RNA sustained in blood varied as much as 100-fold, even in individuals infected with identical strains of virus. Deermice that infected other susceptible individuals tended to have a higher viral RNA load than those that did not infect other deermice. Our study is a first step in exploring the transmission ecology of SNV infection in deermice and provides new knowledge about the factors contributing to the increase of the prevalence of a zoonotic pathogen in its reservoir host and to changes in the risk of HPS to human populations. The techniques pioneered in this study have implications for a wide range of zoonotic disease studies. PMID- 23110097 TI - Hugl1 and Hugl2 in mammary epithelial cells: polarity, proliferation, and differentiation. AB - Loss of epithelial polarity is described as a hallmark of epithelial cancer. To determine the role of Hugl1 and Hugl2 expression in the breast, we investigated their localization in human mammary duct tissue and the effects of expression modulation in normal and cancer cell lines on polarity, proliferation and differentiation. Expression of Hugl1 and Hugl2 was silenced in both MCF10A cells and Human Mammary Epithelial Cells and cell lines were grown in 2-D on plastic and in 3-D in Matrigel to form acini. Cells in monolayer were compared for proliferative and phenotypic changes while acini were examined for differences in size, ability to form a hollow lumen, nuclear size and shape, and localization of key domain-specific proteins as a measure of polarity. We detected overlapping but distinct localization of Hugl1 and Hugl2 in the human mammary gland, with Hugl1 expressed in both luminal and myoepithelium and Hugl2 largely restricted to myoepithelium. On a plastic surface, loss of Hugl1 or Hugl2 in normal epithelium induced a mesenchymal phenotype, and these cells formed large cellular masses when grown in Matrigel. In addition, loss of Hugl1 or Hugl2 expression in MCF10A cells resulted in increased proliferation on Matrigel, while gain of Hugl1 expression in tumor cells suppressed proliferation. Loss of polarity was also observed with knockdown of either Hugl1 or Hugl2, with cells growing in Matrigel appearing as a multilayered epithelium, with randomly oriented Golgi and multiple enlarged nuclei. Furthermore, Hugl1 knock down resulted in a loss of membrane identity and the development of cellular asymmetries in Human Mammary Epithelial Cells. Overall, these data demonstrate an essential role for both Hugl1 and Hugl2 in the maintenance of breast epithelial polarity and differentiated cell morphology, as well as growth control. PMID- 23110099 TI - Probing the putative active site of YjdL: an unusual proton-coupled oligopeptide transporter from E. coli. AB - YjdL from E. coli is an unusual proton-coupled oligopeptide transporter (POT). Unlike prototypical POTs, dipeptides are preferred over tripeptides, in particular dipeptides with a positively charged C-terminal residue. To further understand this difference in peptide specificity, the sequences of YjdL and YdgR, a prototypical E. coli POT, were compared in light of the crystal structure of a POT from Shewanella oneidensis. Several residues found in the putative active site were mutated and the activities of the mutated variants were assessed in terms of substrate uptake assays, and changes in specificity in terms of uptake inhibition. Most strikingly, changing the YjdL specific Asp392 to the conserved Ser in YjdL obliterated the preference for a positively charged C terminal residue. Based on this unique finding and previously published results indicating that the dipeptide N-terminus may interact with Glu388, a preliminary orientation model of a dipeptide in the YjdL cavity is presented. Single site mutations of particularly Ala281 and Trp278 support the presented orientation. A dipeptide bound in the cavity of YjdL appears to be oriented such that the N terminal side chain protrudes into a sub pocket that opens towards the extracellular space. The C-terminal side chain faces in the opposite direction into a sub pocket that faces the cytoplasm. These data indicated a stabilizing effect on a bulky N-terminal residue by an Ala281Phe variant and on the dipeptide backbone by Trp278. In the presented orientation model, Tyr25 and Tyr58 both appear to be in proximity of the dipeptide backbone while Lys117 appears to be in proximity of the peptide C-terminus. Mutational studies of these conserved residues highlight their functional importance. PMID- 23110100 TI - A novel mammal-specific three partite enhancer element regulates node and notochord-specific Noto expression. AB - The vertebrate organizer and notochord have conserved, essential functions for embryonic development and patterning. The restricted expression of developmental regulators in these tissues is directed by specific cis-regulatory modules (CRMs) whose sequence conservation varies considerably. Some CRMs have been conserved throughout vertebrates and likely represent ancestral regulatory networks, while others have diverged beyond recognition but still function over a wide evolutionary range. Here we identify and characterize a mammalian-specific CRM required for node and notochord specific (NNC) expression of NOTO, a transcription factor essential for node morphogenesis, nodal cilia movement and establishment of laterality in mouse. A 523 bp enhancer region (NOCE) upstream the Noto promoter was necessary and sufficient for NNC expression from the endogenous Noto locus. Three subregions in NOCE together mediated full activity in vivo. Binding sites for known transcription factors in NOCE were functional in vitro but dispensable for NOCE activity in vivo. A FOXA2 site in combination with a novel motif was necessary for NOCE activity in vivo. Strikingly, syntenic regions in non-mammalian vertebrates showed no recognizable sequence similarities. In contrast to its activity in mouse NOCE did not drive NNC expression in transgenic fish. NOCE represents a novel, mammal-specific CRM required for the highly restricted Noto expression in the node and nascent notochord and thus regulates normal node development and function. PMID- 23110101 TI - Probing the neural basis of perceptual phenomenology with the touch-induced visual illusion. AB - Using the touch-induced visual illusion we examine whether the brain regions involved in coding sensory information are dissociable from those that contain decision information. Activity in the intraparietal sulcus, as measured by functional magnetic resonance imaging, was associated with the illusion suggesting a sensory coding role whereas activity in the middle occipital gyrus differentially modulated activity according to the decisions made by subjects consistent with their reported perceptual phenomenology. PMID- 23110102 TI - Association of primary care characteristics with variations in mortality rates in England: an observational study. AB - BACKGROUND: Wide variations in mortality rates persist between different areas in England, despite an overall steady decline. To evaluate a conceptual model that might explain how population and service characteristics influence population mortality variations, an overall null hypothesis was tested: variations in primary healthcare service do not predict variations in mortality at population level, after adjusting for population characteristics. METHODOLOGY/PRINCIPAL FINDINGS: In an observational study of all 152 English primary care trusts (geographical groupings of population and primary care services, total population 52 million), routinely available published data from 2008 and 2009 were modelled using negative binomial regression. Counts for all-cause, coronary heart disease, all cancers, stroke, and chronic obstructive pulmonary disease mortality were analyzed using explanatory variables of relevant population and service-related characteristics, including an age-correction factor. The main predictors of mortality variations were population characteristics, especially age and socio economic deprivation. For the service characteristics, a 1% increase in the percentage of patients on a primary care hypertension register was associated with decreases in coronary heart disease mortality of 3% (95% CI 1-4%, p = 0.006) and in stroke mortality of 6% (CI 3-9%, p<0.0001); a 1% increase in the percentage of patients recalling being better able to see their preferred doctor was associated with decreases in chronic obstructive pulmonary disease mortality of 0.7% (CI 0.2-2.0%, p = 0.02) and in all cancer mortality of 0.3% (CI 0.1-0.5%, p = 0.009) (continuity of care). The study found no evidence of an association at primary care trust population level between variations in achievement of pay for performance and mortality. CONCLUSIONS/SIGNIFICANCE: Some primary healthcare service characteristics were also associated with variations in mortality at population level, supporting the conceptual model. Health care system reforms should strengthen these characteristics by delivering cost-effective evidence based interventions to whole populations, and fostering sustained patient provider partnerships. PMID- 23110103 TI - COPS: a sensitive and accurate tool for detecting somatic Copy Number Alterations using short-read sequence data from paired samples. AB - Copy Number Alterations (CNAs) such as deletions and duplications; compose a larger percentage of genetic variations than single nucleotide polymorphisms or other structural variations in cancer genomes that undergo major chromosomal re arrangements. It is, therefore, imperative to identify cancer-specific somatic copy number alterations (SCNAs), with respect to matched normal tissue, in order to understand their association with the disease. We have devised an accurate, sensitive, and easy-to-use tool, COPS, COpy number using Paired Samples, for detecting SCNAs. We rigorously tested the performance of COPS using short sequence simulated reads at various sizes and coverage of SCNAs, read depths, read lengths and also with real tumor:normal paired samples. We found COPS to perform better in comparison to other known SCNA detection tools for all evaluated parameters, namely, sensitivity (detection of true positives), specificity (detection of false positives) and size accuracy. COPS performed well for sequencing reads of all lengths when used with most upstream read alignment tools. Additionally, by incorporating a downstream boundary segmentation detection tool, the accuracy of SCNA boundaries was further improved. Here, we report an accurate, sensitive and easy to use tool in detecting cancer-specific SCNAs using short-read sequence data. In addition to cancer, COPS can be used for any disease as long as sequence reads from both disease and normal samples from the same individual are available. An added boundary segmentation detection module makes COPS detected SCNA boundaries more specific for the samples studied. COPS is available at ftp://115.119.160.213 with username "cops" and password "cops". PMID- 23110104 TI - E4orf1 improves lipid and glucose metabolism in hepatocytes: a template to improve steatosis & hyperglycemia. AB - Hepatic steatosis often accompanies obesity and insulin resistance. The cornerstones of steatosis treatment include reducing body weight and dietary fat intake, which are marginally successful over the long term. Ad36, a human adenovirus, may offer a template to overcome these limitations. In vitro and in vivo studies collectively indicate that via its E4orf1 protein, Ad36 improves hyperglycemia, and attenuates hepatic steatosis, despite a high fat diet and without weight loss. Considering that hepatic insulin sensitivity, or the synthesis, oxidation, or export of fatty acid by hepatocytes are the key determinant of hepatic lipid storage, we determined the role of E4orf1 protein in modulating these physiological pathways. For this study, HepG2 cells, or mouse primary hepatocytes were transfected with E4orf1 or the null vector. Glucose output by hepatocytes was determined under gluconeogenic conditions (cAMP and dexamethasone, or glucagon exposure). Also, de-novo lipogenesis, palmitate oxidation, and lipid export as determined by apoB secretion were measured 48 h post transfection. Results show that compared to null vector transfected cells, E4orf1 significantly reduced glucose output in basal and gluconeogenic conditions. E4orf1 reduced de-novo lipogenesis by about 35%, increased complete fatty acid oxidation 2-fold (p<0.0001), and apoB secretion 1.5 fold(p<0.003). Response of key signaling molecules to E4orf1 transfection was in agreement with these findings. Thus, E4orf1 offers a valuable template to exogenously modulate hepatic glucose and lipid metabolism. Elucidating the underlying molecular mechanism may help develop therapeutic approaches for treating diabetes or non alcoholic fatty liver disease(NAFLD). PMID- 23110105 TI - A hybrid wetland map for China: a synergistic approach using census and spatially explicit datasets. AB - Wetlands play important ecological, economic, and cultural roles in societies around the world. However, wetland degradation has become a serious ecological issue, raising the global sustainability concern. An accurate wetland map is essential for wetland management. Here we used a fuzzy method to create a hybrid wetland map for China through the combination of five existing wetlands datasets, including four spatially explicit wetland distribution data and one wetland census. Our results show the total wetland area is 384,864 km(2), 4.08% of China's national surface area. The hybrid wetland map also shows spatial distribution of wetlands with a spatial resolution of 1 km. The reliability of the map is demonstrated by comparing it with spatially explicit datasets on lakes and reservoirs. The hybrid wetland map is by far the first wetland mapping that is consistent with the statistical data at the national and provincial levels in China. It provides a benchmark map for research on wetland protection and management. The method presented here is applicable for not only wetland mapping but also for other thematic mapping in China and beyond. PMID- 23110107 TI - Convex non-negative matrix factorization for brain tumor delimitation from MRSI data. AB - BACKGROUND: Pattern Recognition techniques can provide invaluable insights in the field of neuro-oncology. This is because the clinical analysis of brain tumors requires the use of non-invasive methods that generate complex data in electronic format. Magnetic Resonance (MR), in the modalities of spectroscopy (MRS) and spectroscopic imaging (MRSI), has been widely applied to this purpose. The heterogeneity of the tissue in the brain volumes analyzed by MR remains a challenge in terms of pathological area delimitation. METHODOLOGY/PRINCIPAL FINDINGS: A pre-clinical study was carried out using seven brain tumor-bearing mice. Imaging and spectroscopy information was acquired from the brain tissue. A methodology is proposed to extract tissue type-specific sources from these signals by applying Convex Non-negative Matrix Factorization (Convex-NMF). Its suitability for the delimitation of pathological brain area from MRSI is experimentally confirmed by comparing the images obtained with its application to selected target regions, and to the gold standard of registered histopathology data. The former showed good accuracy for the solid tumor region (proliferation index (PI)>30%). The latter yielded (i) high sensitivity and specificity in most cases, (ii) acquisition conditions for safe thresholds in tumor and non-tumor regions (PI>30% for solid tumoral region; <=5% for non-tumor), and (iii) fairly good results when borderline pixels were considered. CONCLUSIONS/SIGNIFICANCE: The unsupervised nature of Convex-NMF, which does not use prior information regarding the tumor area for its delimitation, places this approach one step ahead of classical label-requiring supervised methods for discrimination between tissue types, minimizing the negative effect of using mislabeled voxels. Convex NMF also relaxes the non-negativity constraints on the observed data, which allows for a natural representation of the MRSI signal. This should help radiologists to accurately tackle one of the main sources of uncertainty in the clinical management of brain tumors, which is the difficulty of appropriately delimiting the pathological area. PMID- 23110106 TI - Bilateral theta-burst TMS to influence global gestalt perception. AB - While early and higher visual areas along the ventral visual pathway in the inferotemporal cortex are critical for the recognition of individual objects, the neural representation of human perception of complex global visual scenes remains under debate. Stroke patients with a selective deficit in the perception of a complex global Gestalt with intact recognition of individual objects - a deficit termed simultanagnosia - greatly helped to study this question. Interestingly, simultanagnosia typically results from bilateral lesions of the temporo-parietal junction (TPJ). The present study aimed to verify the relevance of this area for human global Gestalt perception. We applied continuous theta-burst TMS either unilaterally (left or right) or bilateral simultaneously over TPJ. Healthy subjects were presented with hierarchically organized visual stimuli that allowed parametrical degrading of the object at the global level. Identification of the global Gestalt was significantly modulated only for the bilateral TPJ stimulation condition. Our results strengthen the view that global Gestalt perception in the human brain involves TPJ and is co-dependent on both hemispheres. PMID- 23110108 TI - The inhibition of KCa3.1 channels activity reduces cell motility in glioblastoma derived cancer stem cells. AB - In the present study we evaluated the expression of the intermediate conductance calcium-activated potassium (KCa3.1) channel in human glioblastoma stem-like cells (CSCs) and investigated its role in cell motility. While the KCa3.1 channel is not expressed in neuronal- and glial-derived tissues of healthy individuals, both the KCa3.1 mRNA and protein are present in the glioblastoma tumor population, and are significantly enhanced in CSCs derived from both established cell line U87MG and a primary cell line, FCN9. Consistent with these data, voltage-independent and TRAM-34 sensitive potassium currents imputable to the KCa3.1 channel were recorded in the murine GL261 cell line and several primary human glioblastoma cells lines. Moreover, a significantly higher KCa3.1 current was recorded in U87MG-CD133 positive cells as compared to the U87MG-CD133 negative subpopulation. Further, we found that the tumor cell motility is strongly associated with KCa3.1 channel expression. Blockade of the KCa3.1 channel with the specific inhibitor TRAM-34 has in fact a greater impact on the motility of CSCs (reduction of 75%), which express a high level of KCa3.1 channel, than on the FCN9 parental population (reduction of 32%), where the KCa3.1 channel is expressed at lower level. Similar results were also observed with the CSCs derived from U87MG. Because invasion of surrounding tissues is one of the main causes of treatment failure in glioblastoma, these findings can be relevant for future development of novel cancer therapeutic drugs. PMID- 23110109 TI - Antibacterial activity of polymer coated cerium oxide nanoparticles. AB - Cerium oxide nanoparticles have found numerous applications in the biomedical industry due to their strong antioxidant properties. In the current study, we report the influence of nine different physical and chemical parameters: pH, aeration and, concentrations of MgSO(4), CaCl(2), KCl, natural organic matter, fructose, nanoparticles and Escherichia coli, on the antibacterial activity of dextran coated cerium oxide nanoparticles. A least-squares quadratic regression model was developed to understand the collective influence of the tested parameters on the anti-bacterial activity and subsequently a computer-based, interactive visualization tool was developed. The visualization allows us to elucidate the effect of each of the parameters in combination with other parameters, on the antibacterial activity of nanoparticles. The results indicate that the toxicity of CeO(2) NPs depend on the physical and chemical environment; and in a majority of the possible combinations of the nine parameters, non-lethal to the bacteria. In fact, the cerium oxide nanoparticles can decrease the anti bacterial activity exerted by magnesium and potassium salts. PMID- 23110110 TI - A large extension to HIV-1 Gag, like Pol, has negative impacts on virion assembly. AB - The GagPol protein of HIV-1 harbors viral enzymes, such as protease (PR), reverse transcriptase, and integrase, that are all crucial for virion infectivity. Previous studies have suggested that expression of GagPol alone does not produce viral particles and that the budding defect is caused by the presence of the Pol region. However, it has remained unknown why GagPol fails to produce viral particles. We show here that HIV-1 GagPol is incapable of membrane binding and subsequent particle assembly. Our confocal data indicated that, despite full N myristoylation, GagPol protein failed to target plasma membrane with diffuse distribution in the cytoplasm. Membrane flotation analysis confirmed these findings. Progressive C-terminal truncation of GagPol to give GagPR allowed for plasma membrane targeting but still not for particle production. Conversely, the C-terminal addition of a noncognate protein, such as beta-galactosidase or 4 tandem GFP, to Gag impaired the membrane affinity, indicating that the Pol region, a large extension to Gag, inhibits membrane binding in the context of GagPol. The addition of the 10 N-terminal amino acids of Fyn kinase [Fyn(10)], a tight membrane-binding signal, conferred plasma membrane targeting on GagPol, but the Fyn(10)GagPol did not produce viral particles. The defect in particle budding was not rescued by the introduction of the PTAP motif, which is responsible for a late stage of viral particle budding. Rather, electron microscopy suggested that the budding defect of GagPR occurred at an early stage of particle morphogenesis. Our data, which were consistent with previous observations, demonstrate the defects of GagPol in membrane binding and particle assembly. PMID- 23110111 TI - Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. AB - Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of alpha amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells. PMID- 23110112 TI - Immune modulation mediated by cryptococcal laccase promotes pulmonary growth and brain dissemination of virulent Cryptococcus neoformans in mice. AB - C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1Delta) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2- towards M1 type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1Delta or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1Delta-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase induced changes in polarization of CD4+ T cells contribute to CNS dissemination. PMID- 23110113 TI - Survival among patients with HIV infection and smear-negative pulmonary tuberculosis - United States, 1993-2006. AB - BACKGROUND: In patients with HIV and tuberculosis (TB) in resource-constrained settings, smear-negative disease has been associated with higher mortality than smear-positive disease. Higher reported mortality may be due to misdiagnosis, diagnostic delays, or because smear-negative disease indicates more advanced immune suppression. METHODS: We analyzed culture-confirmed, pulmonary TB among patients with TB and HIV in the United States from 1993-2008 to calculate prevalence ratios (PRs) for smear-negative disease by demographic and clinical characteristics. Allowing two years for treatment outcome to be reported, we determined hazard ratios (HRs) for survival by smear status, adjusted for significant covariates on patients before 2006. RESULTS: Among 16,710 cases with sputum smear results, 6,739 (39%) were sputum smear-negative and 9,971 (58%) were sputum smear-positive. The prevalence of smear-negative disease was lower in male patients (PR: 0.89, 95% confidence interval [CI]: 0.86-0.93) and in those who were homeless (PR: 0.92, CI: 0.87-0.97) or used alcohol excessively (PR: 0.91, CI: 0.87-0.95), and higher in persons diagnosed while incarcerated (PR: 1.20, CI: 1.13-1.27). Patients with smear-negative disease had better survival compared to patients with smear-positive disease, both before (HR: 0.82, CI: 0.75-0.90) and after (HR: 0.81, CI: 0.71-0.92) the introduction of combination anti-retroviral therapy. CONCLUSIONS: In the United States, smear-negative pulmonary TB in patients with HIV was not associated with higher mortality, in contrast to what has been documented in high TB burden settings. Smear-negative TB can be routinely and definitively diagnosed in the United States, whereas high-burden countries often rely solely on AFB-smear microscopy. This difference could contribute to diagnostic and treatment delays in high-burden countries, possibly resulting in higher mortality. PMID- 23110114 TI - Adipokine hormones and hand osteoarthritis: radiographic severity and pain. AB - INTRODUCTION: Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain. METHODS: In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain. RESULTS: The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m(2) for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R(2) = 0.00-0.04 unadjusted analysis, all p values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R(2) = 0.36 unadjusted analysis, p-values<=0.04). CONCLUSION: In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain. PMID- 23110115 TI - Noncanonical microRNAs and endogenous siRNAs in lytic infection of murine gammaherpesvirus. AB - MicroRNA (miRNA) and endogenous small interfering RNA (endo-siRNA) are two essential classes of small noncoding RNAs (sncRNAs) in eukaryotes. The class of miRNA is diverse and there exist noncanonical miRNAs that bypass the canonical miRNA biogenesis pathway. In order to identify noncanonical miRNAs and endo siRNAs responding to virus infection and study their potential function, we sequenced small-RNA species from cells lytically infected with murine gammaherpesvirus 68 (MHV68). In addition to three novel canonical miRNAs in mouse, two antisense miRNAs in virus and 25 novel noncanonical miRNAs, including miRNAs derived from transfer RNAs, small nucleolar RNAs and introns, in the host were identified. These noncanonical miRNAs exhibited features distinct from that of canonical miRNAs in lengths of hairpins, base pairings and first nucleotide preference. Many of the novel miRNAs are conserved in mammals. Besides several known murine endo-siRNAs detected by the sequencing profiling, a novel locus in the mouse genome was identified to produce endo-siRNAs. This novel endo-siRNA locus is comprised of two tandem inverted B4 short interspersed nuclear elements (SINEs). Unexpectedly, the SINE-derived endo-siRNAs were found in a variety of sequencing data and virus-infected cells. Moreover, a murine miRNA was up regulated more than 35 fold in infected than in mock-treated cells. The putative targets of the viral and the up-regulated murine miRNAs were potentially involved in processes of gene transcription and protein phosphorylation, and localized to membranes, suggesting their potential role in manipulating the host basal immune system during lytic infection. Our results extended the number of noncanonical miRNAs in mammals and shed new light on their potential functions of lytic infection of MHV68. PMID- 23110116 TI - NFAT1 C-terminal domains are necessary but not sufficient for inducing cell death. AB - The proteins belonging to the nuclear factor of activated T cells (NFAT) family of transcription factors are expressed in several cell types and regulate genes involved in differentiation, cell cycle and apoptosis. NFAT proteins share two conserved domains, the NFAT-homology region (NHR) and a DNA-binding domain (DBD). The N- and C-termini display two transactivation domains (TAD-N and TAD-C) that have low sequence similarity. Due to the high sequence conservation in the NHR and DBD, NFAT members have some overlapping roles in gene regulation. However, several studies have shown distinct roles for NFAT proteins in the regulation of cell death. The TAD-C shows low sequence similarity among NFAT family members, but its contribution to specific NFAT1-induced phenotypes is poorly understood. Here, we described at least two regions of NFAT1 TAD-C that confer pro-apoptotic activity to NFAT1. These regions extend from amino acids 699 to 734 and 819 to 850 of NFAT1. We also showed that the NFAT1 TAD-C is unable to induce apoptosis by itself and requires a functional DBD. Furthermore, we showed that when fused to NFAT1 TAD-C, NFAT2, which is associated with cell transformation, induces apoptosis in fibroblasts. Together, these results suggest that the NFAT1 TAD-C includes NFAT death domains that confer to different NFAT members the ability to induce apoptosis. PMID- 23110117 TI - How much is too little to detect impacts? A case study of a nuclear power plant. AB - Several approaches have been proposed to assess impacts on natural assemblages. Ideally, the potentially impacted site and multiple reference sites are sampled through time, before and after the impact. Often, however, the lack of information regarding the potential overall impact, the lack of knowledge about the environment in many regions worldwide, budgets constraints and the increasing dimensions of human activities compromise the reliability of the impact assessment. We evaluated the impact, if any, and its extent of a nuclear power plant effluent on sessile epibiota assemblages using a suitable and feasible sampling design with no 'before' data and budget and logistic constraints. Assemblages were sampled at multiple times and at increasing distances from the point of the discharge of the effluent. There was a clear and localized effect of the power plant effluent (up to 100 m from the point of the discharge). However, depending on the time of the year, the impact reaches up to 600 m. We found a significantly lower richness of taxa in the Effluent site when compared to other sites. Furthermore, at all times, the variability of assemblages near the discharge was also smaller than in other sites. Although the sampling design used here (in particular the number of replicates) did not allow an unambiguously evaluation of the full extent of the impact in relation to its intensity and temporal variability, the multiple temporal and spatial scales used allowed the detection of some differences in the intensity of the impact, depending on the time of sampling. Our findings greatly contribute to increase the knowledge on the effects of multiple stressors caused by the effluent of a power plant and also have important implications for management strategies and conservation ecology, in general. PMID- 23110118 TI - The effect of bioactive compounds on in vitro and in vivo antioxidant activity of different berry juices. AB - BACKGROUND: Berry fruit is known for its high contents of various bioactive compounds. The latter constitute of anthocyanins, flavonols and flavanols and posses high antioxidative activity. The highly dynamic antioxidant system can be evaluated in vitro and in vivo in several model organisms. These measurements represent a good approximation of the real potential of bioactive compounds in the cells of higher eucarions. The aim of the study was thus to determine in vitro and in vivo antioxidant activity of different berry juices, which reportedly contain high amounts of phenolics. METHODOLOGY/PRINCIPAL FINDINGS: Five different berry species were collected from several locations in central Slovenia and juice was extracted from each species separately. Juice was assessed for their in vitro and in vivo antioxidant activity. Phenolic profiles of berries were determined with the use of a HPLC/MS system, in vitro antioxidant activity with the DPPH radical scavenging method and in vivo antioxidative activity using Saccharomyces cerevisiae. The highest diversity of individual phenols was detected for bilberry juice. The highest in vitro antioxidant capacity was determined for blackcurrant juice. A decrease in intracellular oxidation compared to control was observed in the following order: blackcurrant < chokeberry = blueberry < bilberry. The results indicate important differences in antioxidant activity of berry juices between in vitro and in vivo studies. CONCLUSION/SIGNIFICANCE: In addition to the total content of phenolic compounds entering the cells, a key factor determining antioxidative activity of berry juices is also the ratio between the compounds. Where high content levels of anthocyanins and very low content levels of flavonols and hydroxycinnamic acids were measured a lower intracellular oxidation has been detected. Specifically, intracellular oxidation increased with higher consumption of hydroxycinnamic acids and lower consumption of anthocyanins in the cells. Antioxidative activity also increased when the consumption of analyzed phenols was rather low. PMID- 23110119 TI - An unaccounted fraction of marine biogenic CaCO3 particles. AB - Biogenic production and sedimentation of calcium carbonate in the ocean, referred to as the carbonate pump, has profound implications for the ocean carbon cycle, and relate both to global climate, ocean acidification and the geological past. In marine pelagic environments coccolithophores, foraminifera and pteropods have been considered the main calcifying organisms. Here, we document the presence of an abundant, previously unaccounted fraction of marine calcium carbonate particles in seawater, presumably formed by bacteria or in relation to extracellular polymeric substances. The particles occur in a variety of different morphologies, in a size range from <1 to >100 um, and in a typical concentration of 10(4)-10(5) particles L(-1) (size range counted 1-100 um). Quantitative estimates of annual averages suggests that the pure calcium particles we counted in the 1-100 um size range account for 2-4 times more CaCO(3) than the dominating coccolithophoride Emiliania huxleyi and for 21% of the total concentration of particulate calcium. Due to their high density, we hypothesize that the particles sediment rapidly, and therefore contribute significantly to the export of carbon and alkalinity from surface waters. The biological and environmental factors affecting the formation of these particles and possible impact of this process on global atmospheric CO(2) remains to be investigated. PMID- 23110120 TI - RNA interference of endochitinases in the sugarcane endophyte Trichoderma virens 223 reduces its fitness as a biocontrol agent of pineapple disease. AB - The sugarcane root endophyte Trichoderma virens 223 holds enormous potential as a sustainable alternative to chemical pesticides in the control of sugarcane diseases. Its efficacy as a biocontrol agent is thought to be associated with its production of chitinase enzymes, including N-acetyl-beta-D-glucosaminidases, chitobiosidases and endochitinases. We used targeted gene deletion and RNA dependent gene silencing strategies to disrupt N-acetyl-beta-D-glucosaminidase and endochitinase activities of the fungus, and to determine their roles in the biocontrol of soil-borne plant pathogens. The loss of N-acetyl-beta-D glucosaminidase activities was dispensable for biocontrol of the plurivorous damping-off pathogens Rhizoctonia solani and Sclerotinia sclerotiorum, and of the sugarcane pathogen Ceratocystis paradoxa, the causal agent of pineapple disease. Similarly, suppression of endochitinase activities had no effect on R. solani and S. sclerotiorum disease control, but had a pronounced effect on the ability of T. virens 223 to control pineapple disease. Our work demonstrates a critical requirement for T. virens 223 endochitinase activity in the biocontrol of C. paradoxa sugarcane disease, but not for general antagonism of other soil pathogens. This may reflect its lifestyle as a sugarcane root endophyte. PMID- 23110121 TI - Dual role for the O-acetyltransferase OatA in peptidoglycan modification and control of cell septation in Lactobacillus plantarum. AB - Until now, peptidoglycan O-acetyl transferases (Oat) were only described for their peptidoglycan O-acetylating activity and for their implication in the control of peptidoglycan hydrolases. In this study, we show that a Lactobacillus plantarum mutant lacking OatA is unable to uncouple cell elongation and septation. Wild-type cells showed an elongation arrest during septation while oatA mutant cells continued to elongate at a constant rate without any observable pause during the cell division process. Remarkably, this defect does not result from a default in peptidoglycan O-acetylation, since it can be rescued by wild type OatA as well as by a catalytic mutant or a truncated variant containing only the transmembrane domain of the protein. Consistent with a potential involvement in division, OatA preferentially localizes at mid-cell before membrane invagination and remains at this position until the end of septation. Overexpression of oatA or its inactive variants induces septation-specific aberrations, including asymmetrical and dual septum formation. Overproduction of the division inhibitors, MinC or MinD, leads to cell filamentation in the wild type while curved and branched cells are observed in the oatA mutant, suggesting that the Min system acts differently on the division process in the absence of OatA. Altogether, the results suggest that OatA plays a key role in the spatio temporal control of septation, irrespective of its catalytic activity. PMID- 23110122 TI - Prey selection by an apex predator: the importance of sampling uncertainty. AB - The impact of predation on prey populations has long been a focus of ecologists, but a firm understanding of the factors influencing prey selection, a key predictor of that impact, remains elusive. High levels of variability observed in prey selection may reflect true differences in the ecology of different communities but might also reflect a failure to deal adequately with uncertainties in the underlying data. Indeed, our review showed that less than 10% of studies of European wolf predation accounted for sampling uncertainty. Here, we relate annual variability in wolf diet to prey availability and examine temporal patterns in prey selection; in particular, we identify how considering uncertainty alters conclusions regarding prey selection.Over nine years, we collected 1,974 wolf scats and conducted drive censuses of ungulates in Alpe di Catenaia, Italy. We bootstrapped scat and census data within years to construct confidence intervals around estimates of prey use, availability and selection. Wolf diet was dominated by boar (61.5 +/- 3.90 [SE] % of biomass eaten) and roe deer (33.7 +/- 3.61%). Temporal patterns of prey densities revealed that the proportion of roe deer in wolf diet peaked when boar densities were low, not when roe deer densities were highest. Considering only the two dominant prey types, Manly's standardized selection index using all data across years indicated selection for boar (mean = 0.73 +/- 0.023). However, sampling error resulted in wide confidence intervals around estimates of prey selection. Thus, despite considerable variation in yearly estimates, confidence intervals for all years overlapped. Failing to consider such uncertainty could lead erroneously to the assumption of differences in prey selection among years. This study highlights the importance of considering temporal variation in relative prey availability and accounting for sampling uncertainty when interpreting the results of dietary studies. PMID- 23110123 TI - An operant conditioning method for studying auditory behaviors in marmoset monkeys. AB - The common marmoset (Callithrix jacchus) is a small New World primate that has increasingly been used as a non-human model in the fields of sensory, motor, and cognitive neuroscience. However, little knowledge exists regarding behavioral methods in this species. Developing an understanding of the neural basis of perception and cognition in an animal model requires measurement of both brain activity and behavior. Here we describe an operant conditioning behavioral training method developed to allow controlled psychoacoustic measurements in marmosets. We demonstrate that marmosets can be trained to consistently perform a Go/No-Go auditory task in which a subject licks at a feeding tube when it detects a sound. Correct responses result in delivery of a food reward. Crucially, this operant conditioning task generates little body movement and is well suited for pairing behavior with single-unit electrophysiology. Successful implementation of an operant conditioning behavior opens the door to a wide range of new studies in the field of auditory neuroscience using the marmoset as a model system. PMID- 23110124 TI - The glutamatergic neurons in the spinal cord of the sea lamprey: an in situ hybridization and immunohistochemical study. AB - Glutamate is the main excitatory neurotransmitter involved in spinal cord circuits in vertebrates, but in most groups the distribution of glutamatergic spinal neurons is still unknown. Lampreys have been extensively used as a model to investigate the neuronal circuits underlying locomotion. Glutamatergic circuits have been characterized on the basis of the excitatory responses elicited in postsynaptic neurons. However, the presence of glutamatergic neurochemical markers in spinal neurons has not been investigated. In this study, we report for the first time the expression of a vesicular glutamate transporter (VGLUT) in the spinal cord of the sea lamprey. We also study the distribution of glutamate in perikarya and fibers. The largest glutamatergic neurons found were the dorsal cells and caudal giant cells. Two additional VGLUT-positive gray matter populations, one dorsomedial consisting of small cells and another one lateral consisting of small and large cells were observed. Some cerebrospinal fluid-contacting cells also expressed VGLUT. In the white matter, some edge cells and some cells associated with giant axons (Muller and Mauthner axons) and the dorsolateral funiculus expressed VGLUT. Large lateral cells and the cells associated with reticulospinal axons are in a key position to receive descending inputs involved in the control of locomotion. We also compared the distribution of glutamate immunoreactivity with that of gamma-aminobutyric acid (GABA) and glycine. Colocalization of glutamate and GABA or glycine was observed in some small spinal cells. These results confirm the glutamatergic nature of various neuronal populations, and reveal new small-celled glutamatergic populations, predicting that some glutamatergic neurons would exert complex actions on postsynaptic neurons. PMID- 23110125 TI - Progression of oral squamous cell carcinoma accompanied with reduced E-cadherin expression but not cadherin switch. AB - The cadherin switch from E-cadherin to N-cadherin is considered as a hallmark of the epithelial-mesenchymal transition and progression of carcinomas. Although it enhances aggressive behaviors of adenocarcinoma cells, the significance and role of cadherin switch in squamous cell carcinomas (SCCs) are largely controversial. In the present study, we immunohistochemically examined expression of E-cadherin and N-cadherin in oral SCCs (n = 63) and its implications for the disease progression. The E-cadherin-positive carcinoma cells were rapidly decreased at the invasive front. The percentage of carcinoma cells stained E-cadherin at the cell membrane was reduced in parallel with tumor dedifferentiation (P<0.01) and enhanced invasion (P<0.01). In contrast, N-cadherin-positive cells were very limited and did not correlate with the clinicopathological parameters. Mouse tongue tumors xenotransplantated oral SCC cell lines expressing both cadherins in vitro reproduced the reduction of E-cadherin-positive carcinoma cells at the invasive front and the negligible expression of N-cadherin. These results demonstrate that the reduction of E-cadherin-mediated carcinoma cell-cell adhesion at the invasive front, but not the cadherin switch, is an important determinant for oral SCC progression, and suggest that the environments surrounding carcinoma cells largely affect the cadherin expression. PMID- 23110126 TI - CaMKKbeta is involved in AMP-activated protein kinase activation by baicalin in LKB1 deficient cell lines. AB - AMP-activated protein kinase (AMPK) plays an important role in mediating energy metabolism and is controlled mainly by two upstream kinases, LKB1 or Ca(2+)/calmodulin-dependent protein kinase kinase-beta (CaMKKbeta). Previously, we found that baicalin, one of the major flavonoids in a traditional Chinese herb medicine, Scutellaria baicalensis, protects against the development of hepatic steatosis in rats feeding with a high-fat diet by the activation of AMPK, but, the underlying mechanism for AMPK activation is unknown. Here we show that in two LKB1-deficient cells, HeLa and A549 cells, baicalin activates AMPK by alpha Thr 172 phosphorylation and subsequent phosphorylation of its downstream target, acetyl CoA carboxylase, at Ser-79, to a similar degree as does in HepG2 cells (that express LKB1). Pharmacologic inhibition of CaMKKbeta by its selective inhibitor STO-609 markedly inhibits baicalin-induced AMPK activation in both HeLa and HepG2 cells, indicating that CaMKKbeta is the responsible AMPK kinase. We also show that treatment of baicalin causes a larger increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), although the maximal level of [Ca(2+)](i) is lower in HepG2 cells compared to HeLa cells. Chelation of intracellular free Ca(2+) by EDTA and EGTA, or depletion of intracellular Ca(2+) stores by the endoplasmic reticulum Ca(2+)-ATPase inhibitor thapsigargin abrogates baicalin induced activation of AMPK in HeLa cells. Neither cellular ATP nor the production of reactive oxygen species is altered by baicalin. Finally, in HeLa cells, baicalin treatment no longer decreases intracellular lipid accumulation caused by oleic acid after inhibition of CaMKKbeta by STO-609. These results demonstrate that a potential Ca(2+)/CaMKKbeta dependent pathway is involved in the activation of AMPK by baicalin and suggest that CaMKKbeta likely acts as an upstream kinase of AMPK in response to baicalin. PMID- 23110127 TI - Alkannin, HSP70 inducer, protects against UVB-induced apoptosis in human keratinocytes. AB - Alkannin is an active constituent from the root extract of Alkanna tinctoria of the Boraginaceae family and it may have utility as a heat shock protein 70 (HSP70) inducer in living organisms. Here, the effects of alkannin-induced HSP70 on ultraviolet (UV) B (40 mJ/cm(2))-induced apoptosis were investigated in human keratinocyte HaCaT cells. Pretreatment of cells with alkannin (1 uM) caused significant inhibition of UVB-induced apoptosis and caspase-3 cleavage. On the other hand, the addition of KNK437 (HSP70 inhibitor) reversed the action of alkannin increasing UVB-induced apoptosis in a dose-dependent manner. In addition, differences in gene expression associated with the suppression of UVB induced apoptosis in the presence of alkannin were investigated using Gene Chip assay. Our results indicate that alkannin suppresses UVB-induced apoptosis through the induction of HSP70 in human keratinocytes, and therefore, we suggest the usefulness of using alkannin as an antiaging agent. PMID- 23110128 TI - Selenite stimulates mitochondrial biogenesis signaling and enhances mitochondrial functional performance in murine hippocampal neuronal cells. AB - Supplementation of selenium has been shown to protect cells against free radical mediated cell damage. The objectives of this study are to examine whether supplementation of selenium stimulates mitochondrial biogenesis signaling pathways and whether selenium enhances mitochondrial functional performance. Murine hippocampal neuronal HT22 cells were treated with sodium selenite for 24 hours. Mitochondrial biogenesis markers, mitochondrial respiratory rate and activities of mitochondrial electron transport chain complexes were measured and compared to non-treated cells. The results revealed that treatment of selenium to the HT22 cells elevated the levels of nuclear mitochondrial biogenesis regulators PGC-1alpha and NRF1, as well as mitochondrial proteins cytochrome c and cytochrome c oxidase IV (COX IV). These effects are associated with phosphorylation of Akt and cAMP response element-binding (CREB). Supplementation of selenium significantly increased mitochondrial respiration and improved the activities of mitochondrial respiratory complexes. We conclude that selenium activates mitochondrial biogenesis signaling pathway and improves mitochondrial function. These effects may be associated with modulation of AKT-CREB pathway. PMID- 23110129 TI - MicroRNA-450a-3p represses cell proliferation and regulates embryo development by regulating Bub1 expression in mouse. AB - Bub1 is a critical component of the spindle assembly checkpoint (SAC) and closely linked to cell proliferation and differentiation. We previously found that spontaneous abortion embryos contained a low level of Bub1 protein but normal mRNA level, while the knockdown of Bub1 leads to abnormal numerical chromosomes in embryonic cells. Here, we investigated the mechanism through which governs the post-transcriptional regulation of Bub1 protein expression level. We first conducted bioinformatics analysis and identified eight putative miRNAs that may target Bub1. Luciferase reporter assay confirmed that miR-450a-3p can directly regulate Bub1 by binding to the 3'-untranslated region of Bub1 mRNA. We found that the overexpression of miR-450a-3p in mouse embryonic fibroblast (MEF) cells down-regulated Bub1 protein level, repressed cell proliferation, increased apoptosis and restricted most cells in G1 phase of the cell cycle. Furthermore, when the fertilized eggs were microinjected with miR-450a-3p mimics, the cleavage of zygotes was effectively suppressed. Our results strongly suggest that an abnormally decreased Bub1 level regulated by miRNAs may be implicated in the pathogenesis of spontaneous miscarriage. Therefore, the blockade of miR-450a-3p may be explored as a novel therapeutic strategy for preventing spontaneous miscarriages. PMID- 23110131 TI - Information structure influences depth of syntactic processing: event-related potential evidence for the Chomsky illusion. AB - Information structure facilitates communication between interlocutors by highlighting relevant information. It has previously been shown that information structure modulates the depth of semantic processing. Here we used event-related potentials to investigate whether information structure can modulate the depth of syntactic processing. In question-answer pairs, subtle (number agreement) or salient (phrase structure) syntactic violations were placed either in focus or out of focus through information structure marking. P600 effects to these violations reflect the depth of syntactic processing. For subtle violations, a P600 effect was observed in the focus condition, but not in the non-focus condition. For salient violations, comparable P600 effects were found in both conditions. These results indicate that information structure can modulate the depth of syntactic processing, but that this effect depends on the salience of the information. When subtle violations are not in focus, they are processed less elaborately. We label this phenomenon the Chomsky illusion. PMID- 23110130 TI - Poor long-term outcome in second kidney transplantation: a delayed event. AB - BACKGROUND: Old studies reported a worse outcome for second transplant recipient (STR) than for first transplant recipient (FTR) mainly due to non-comparable populations with numbers confounding factors. More recent analysis, based on improved methodology by using multivariate regressions, challenged this generally accepted idea: the poor prognosis for STR is still under debate. METHODOLOGY: To assess the long-term patient-and-graft survival of STR compared to FTR, we performed an observational study based on the French DIVAT prospective cohort between 1996 and 2010 (N = 3103 including 641 STR). All patients were treated with a CNI, an mTOR inhibitor or belatacept in addition to steroids and mycophenolate mofetil for maintenance therapy. Patient-and-graft survival and acute rejection episode (ARE) were analyzed using Cox models adjusted for all potential confounding factors such as pre-transplant anti-HLA immunization. RESULTS: We showed that STR have a higher risk of graft failure than FTR (HR = 2.18, p = 0.0013) but that this excess risk was observed after few years of transplantation. There was no significant difference between STR and FTR in the occurrence of either overall ARE (HR = 1.01, p = 0.9675) or steroid-resistant ARE (HR = 1.27, p = 0.4087). CONCLUSIONS: The risk of graft failure following second transplantation remained consistently higher than that observed in first transplantation after adjusting for confounding factors. The rarely performed time-dependent statistical modeling may explain the heterogeneous conclusions of the literature concerning second transplantation outcomes. In clinical practice, physicians should not consider STR and FTR equally. PMID- 23110132 TI - Genetic modification of cancer cells using non-viral, episomal S/MAR vectors for in vivo tumour modelling. AB - The development of genetically marked animal tumour xenografts is an area of ongoing research to enable easier and more reliable testing of cancer therapies. Genetically marked tumour models have a number of advantages over conventional tumour models, including the easy longitudinal monitoring of therapies and the reduced number of animals needed for trials. Several different methods have been used in previous studies to mark tumours genetically, however all have limitations, such as genotoxicity and other artifacts related to the usage of integrating viral vectors. Recently, we have generated an episomally maintained plasmid DNA (pDNA) expression system based on Scaffold/Matrix Attachment Region (S/MAR), which permits long-term luciferase transgene expression in the mouse liver. Here we describe a further usage of this pDNA vector with the human Ubiquitin C promoter to create stably transfected human hepatoma (Huh7) and human Pancreatic Carcinoma (MIA-PaCa2) cell lines, which were delivered into "immune deficient" mice and monitored longitudinally over time using a bioluminometer. Both cell lines revealed sustained episomal long-term luciferase expression and formation of a tumour showing the pathological characteristics of hepatocellular carcinoma (HCC) and pancreatic carcinoma (PaCa), respectively. This is the first demonstration that a pDNA vector can confer sustained episomal luciferase transgene expression in various mouse tumour models and can thus be readily utilised to follow tumour formation without interfering with the cellular genome. PMID- 23110133 TI - Characterization and identification of subpopulations of mononuclear preosteoclasts induced by TNF-alpha in combination with TGF-beta in rats. AB - Osteoclasts are unique multinucleated cells formed by fusion of preosteoclasts derived from cells of the monocyte/macrophage lineage, which are induced by RANKL. However, characteristics and subpopulations of osteoclast precursor cells are poorly understood. We show here that a combination of TNF-alpha, TGF-beta, and M-CSF efficiently generates mononuclear preosteoclasts but not multinucleated osteoclasts (MNCs) in rat bone marrow cultures depleted of stromal cells. Using a rat osteoclast-specific mAb, Kat1, we found that TNF-alpha and TGF-beta specifically increased Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells but not Kat1(-)c fms(+) cells. Kat1(-)c-fms(+) cells appeared in early stages of culture, but Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells increased later. Preosteoclasts induced by TNF-alpha, TGF-beta, and M-CSF rapidly differentiated into osteoclasts in the presence of RANKL and hydroxyurea, an inhibitor of DNA synthesis, suggesting that preosteoclasts are terminally differentiated cells. We further analyzed the expression levels of genes encoding surface proteins in bone marrow macrophages (BMM), preosteoclasts, and MNCs. Preosteoclasts expressed itgam (CD11b) and chemokine receptors CCR1 and CCR2; however, in preosteoclasts the expression of chemokine receptors CCR1 and CCR2 was not up-regulated compared to their expression in BMM. However, addition of RANKL to preosteoclasts markedly increased the expression of CCR1. In contrast, expression of macrophage antigen emr-1 (F4/80) and chemokine receptor CCR5 was down-regulated in preosteoclasts. The combination of TNF-alpha, TGF-beta, and M-CSF induced Kat1(+)CD11b(+) cells, but these cells were also induced by TNF-alpha alone. In addition, MIP-1alpha and MCP-1, which are ligands for CCR1 and CCR2, were chemotactic for preosteoclasts, and promoted multinucleation of preosteoclasts. Finally, we found that Kat1(+)c fms(+) cells were present in bone tissues of rats with adjuvant arthritis. These data demonstrate that TNF-alpha in combination with TGF-beta efficiently generates preosteoclasts in vitro. We delineated characteristics that are useful for identifying and isolating rat preosteoclasts, and found that CCR1 expression was regulated in the fusion step in osteoclastogenesis. PMID- 23110134 TI - A New C-Xyloside induces modifications of GAG expression, structure and functional properties. AB - Proteoglycans (PGs) are critically involved in major cellular processes. Most PG activities are due to the large interactive properties of their glycosaminoglycan (GAG) polysaccharide chains, whose expression and fine structural features are tightly controlled by a complex and highly regulated biosynthesis machinery. Xylosides are known to bypass PG-associated GAG biosynthesis and prime the assembly of free polysaccharide chains. These are, therefore, attractive molecules to interfere with GAG expression and function. Recently, we have developed a new xyloside derivative, C-Xyloside, that shares classical GAG inducing xyloside activities while exhibiting improved metabolic stability. We have previously shown that C-Xyloside had beneficial effects on skin homoeostasis/regeneration using a number of models, but its precise effects on GAG expression and fine structure remained to be addressed. In this study, we have therefore investigated this in details, using a reconstructed dermal tissue as model. Our results first confirmed that C-Xyloside strongly enhanced synthesis of GAG chains, but also induced significant changes in their structure. C Xyloside primed GAGs were exclusively chondroitin/dermatan sulfate (CS/DS) that featured reduced chain size, increased O-sulfation, and changes in iduronate content and distribution. Surprisingly, C-Xyloside also affected PG-borne GAGs, the main difference being observed in CS/DS 4-O/6-O-sulfation ratio. Such changes were found to affect the biological properties of CS/DS, as revealed by the significant reduction in binding to Hepatocyte Growth Factor observed upon C Xyloside treatment. Overall, this study provides new insights into the effect of C-Xyloside on GAG structure and activities, which opens up perspectives and applications of such compound in skin repair/regeneration. It also provides a new illustration about the use of xylosides as tools for modifying GAG fine structure/function relationships. PMID- 23110135 TI - Dopaminergic modulation of effort-related choice behavior as assessed by a progressive ratio chow feeding choice task: pharmacological studies and the role of individual differences. AB - Mesolimbic dopamine (DA) is involved in behavioral activation and effort-related processes. Rats with impaired DA transmission reallocate their instrumental behavior away from food-reinforced tasks with high response requirements, and instead select less effortful food-seeking behaviors. In the present study, the effects of several drug treatments were assessed using a progressive ratio (PROG)/chow feeding concurrent choice task. With this task, rats can lever press on a PROG schedule reinforced by a preferred high-carbohydrate food pellet, or alternatively approach and consume the less-preferred but concurrently available laboratory chow. Rats pass through each ratio level 15 times, after which the ratio requirement is incremented by one additional response. The DA D(2) antagonist haloperidol (0.025-0.1 mg/kg) reduced number of lever presses and highest ratio achieved but did not reduce chow intake. In contrast, the adenosine A(2A) antagonist MSX-3 increased lever presses and highest ratio achieved, but decreased chow consumption. The cannabinoid CB1 inverse agonist and putative appetite suppressant AM251 decreased lever presses, highest ratio achieved, and chow intake; this effect was similar to that produced by pre-feeding. Furthermore, DA-related signal transduction activity (pDARPP-32(Thr34) expression) was greater in nucleus accumbens core of high responders (rats with high lever pressing output) compared to low responders. Thus, the effects of DA antagonism differed greatly from those produced by pre-feeding or reduced CB1 transmission, and it appears unlikely that haloperidol reduces PROG responding because of a general reduction in primary food motivation or the unconditioned reinforcing properties of food. Furthermore, accumbens core signal transduction activity is related to individual differences in work output. PMID- 23110136 TI - Flexibility of the N-terminal mVDAC1 segment controls the channel's gating behavior. AB - Since the solution of the molecular structures of members of the voltage dependent anion channels (VDACs), the N-terminal alpha-helix has been the main focus of attention, since its strategic location, in combination with its putative conformational flexibility, could define or control the channel's gating characteristics. Through engineering of two double-cysteine mVDAC1 variants we achieved fixing of the N-terminal segment at the bottom and midpoint of the pore. Whilst cross-linking at the midpoint resulted in the channel remaining constitutively open, cross-linking at the base resulted in an "asymmetric" gating behavior, with closure only at one electric field's orientation depending on the channel's orientation in the lipid bilayer. Additionally, and while the native channel adopts several well-defined closed states (S1 and S2), the cross-linked variants showed upon closure a clear preference for the S2 state. With native channel characteristics restored following reduction of the cysteines, it is evident that the conformational flexibility of the N-terminal segment plays indeed a major part in the control of the channel's gating behavior. PMID- 23110137 TI - Lack of association between NADPH quinone oxidoreductase 1 (NQO1) gene C609T polymorphism and lung cancer: a case-control study and a meta-analysis. AB - BACKGROUND: The association between NAD(P)H:quinone oxidoreductase 1 (NQO1) gene C609T polymorphism (rs1800566) and lung cancer has been widely evaluated, and a definitive answer so far is lacking. We first conducted a case-control study to assess this association in northeastern Han Chinese, and then performed a meta analysis to further address this issue. METHODOLOGY/PRINCIPAL FINDINGS: This case control study involved 684 patients clinically diagnosed as lung cancer and 602 age-matched cancer-free controls from Harbin city, Heilongjiang province, China. Genotyping was conducted using the PCR-LDR (ligase detection reactions) method. Meta-analysis was managed by STATA software. Data and study quality were assessed in duplicate. Our case-control association study indicated no significant difference in the genotype and allele distributions of C609T polymorphism between lung cancer patients and controls, consistent with the results of the further meta-analysis involving 7286 patients and 9167 controls under both allelic (odds ratio (OR) = 0.99; 95% confidence interval (CI): 0.92-1.06; P = 0.692) and dominant (OR = 0.98; 95% CI: 0.89-1.08; P = 0.637) models. However, there was moderate evidence of between-study heterogeneity and low probability of publication bias. Further subgroup analyses by ethnicity, source of controls and sample size detected no positive associations in this meta-analysis. CONCLUSIONS: Our study in northeastern Han Chinese, along with the meta-analysis, failed to confirm the association of NQO1 gene C609T polymorphism with lung cancer risk, even across different ethnic populations. PMID- 23110138 TI - Increasing the use of skilled health personnel where traditional birth attendants were providers of childbirth care: a systematic review. AB - BACKGROUND: Improved access to skilled health personnel for childbirth is a priority strategy to improve maternal health. This study investigates interventions to achieve this where traditional birth attendants were providers of childbirth care and asks what has been done and what has worked? METHODS AND FINDINGS: We systematically reviewed published and unpublished literature, searching 26 databases and contacting experts to find relevant studies. We included references from all time periods and locations. 132 items from 41 countries met our inclusion criteria and are included in an inventory; six were intervention evaluations of high or moderate quality which we further analysed. Four studies report on interventions to deploy midwives closer to communities: two studies in Indonesia reported an increase in use of skilled health personnel; another Indonesian study showed increased uptake of caesarean sections as midwives per population increased; one study in Bangladesh reported decreased risk of maternal death. Two studies report on interventions to address financial barriers: one in Bangladesh reported an increase in use of skilled health personnel where financial barriers for users were addressed and incentives were given to skilled care providers; another in Peru reported that use of emergency obstetric care increased by subsidies for preventive and maternity care, but not by improved quality of care. CONCLUSIONS: The interventions had positive outcomes for relevant maternal health indicators. However, three of the studies evaluate the village midwife programme in Indonesia, which limits the generalizability of conclusions. Most studies report on a main intervention, despite other activities, such as community mobilization or partnerships with traditional birth attendants. Many authors note that multiple factors including distance, transport, family preferences/support also need to be addressed. Case studies of interventions in the inventory illustrate how different countries attempted to address these complexities. Few high quality studies that measure effectiveness of interventions exist. PMID- 23110139 TI - Rotavirus viroplasm fusion and perinuclear localization are dynamic processes requiring stabilized microtubules. AB - Rotavirus viroplasms are cytosolic, electron-dense inclusions corresponding to the viral machinery of replication responsible for viral template transcription, dsRNA genome segments replication and assembly of new viral cores. We have previously observed that, over time, those viroplasms increase in size and decrease in number. Therefore, we hypothesized that this process was dependent on the cellular microtubular network and its associated dynamic components. Here, we present evidence demonstrating that viroplasms are dynamic structures, which, in the course of an ongoing infection, move towards the perinuclear region of the cell, where they fuse among each other, thereby gaining considerably in size and, simultaneously, explaining the decrease in numbers. On the viral side, this process seems to depend on VP2 for movement and on NSP2 for fusion. On the cellular side, both the temporal transition and the maintenance of the viroplasms are dependent on the microtubular network, its stabilization by acetylation, and, surprisingly, on a kinesin motor of the kinesin-5 family, Eg5. Thus, we provide for the first time deeper insights into the dynamics of rotavirus replication, which can explain the behavior of viroplasms in the infected cell. PMID- 23110140 TI - Polymorphisms in inflammasome genes and risk of coal workers' pneumoconiosis in a Chinese population. AB - BACKGROUND: Coal workers' pneumoconiosis (CWP), resulting from the inhalation of silica-containing coal mine dust, is characterized by fibrosing nodular lesions that eventually develop into progressive pulmonary fibrosis. Recently, it has been hypothesized that inflammasomes could have a crucial role in the host response to silica and recent studies show that the inflammasome contributes to inflammation and pulmonary fibrosis. NLRP3, CARD8 are components of the NLRP3 inflammasome, which triggers caspase 1-mediated IL-1beta and IL-18 release. In the present study, we investigated whether common single nucleotide polymorphisms (SNPs) in inflammasome genes are associated with CWP. METHODS: We performed an association study analyzing 3 NLRP3, 1 CARD8, 1 IL-1beta, 2 IL-18 SNPs in a case control study of 697 CWP and 694 controls. Genotyping was carried out by the TaqMan method. RESULTS: The NLRP3 rs1539019 TT genotype was associated with a significantly increased risk of CWP (adjusted odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.07-1.81), compared with the GG/GT genotype, in particular among smokers (adjusted OR = 1.67, 95%CI = 1.15-2.42). In addition, the polymorphism was significantly associated with risk of CWP patients with stage I. CONCLUSIONS: This is the first report showing an association between the NLRP3 rs1539019 polymorphism and CWP, and suggests that this polymorphism may confer increased risk for the development of the disease. Further studies are warranted to confirm our findings. PMID- 23110141 TI - Accurate prediction of protein catalytic residues by side chain orientation and residue contact density. AB - Prediction of protein catalytic residues provides useful information for the studies of protein functions. Most of the existing methods combine both structure and sequence information but heavily rely on sequence conservation from multiple sequence alignments. The contribution of structure information is usually less than that of sequence conservation in existing methods. We found a novel structure feature, residue side chain orientation, which is the first structure based feature that achieves prediction results comparable to that of evolutionary sequence conservation. We developed a structure-based method, Enzyme Catalytic residue SIde-chain Arrangement (EXIA), which is based on residue side chain orientations and backbone flexibility of protein structure. The prediction that uses EXIA outperforms existing structure-based features. The prediction quality of combing EXIA and sequence conservation exceeds that of the state-of-the-art prediction methods. EXIA is designed to predict catalytic residues from single protein structure without needing sequence or structure alignments. It provides invaluable information when there is no sufficient or reliable homology information for target protein. We found that catalytic residues have very special side chain orientation and designed the EXIA method based on the newly discovered feature. It was also found that EXIA performs well for a dataset of enzymes without any bounded ligand in their crystallographic structures. PMID- 23110142 TI - Recombination activating gene-2 regulates CpG-mediated interferon-alpha production in mouse bone marrow-derived plasmacytoid dendritic cells. AB - Using mice that lack recombination activating gene-2 (Rag2), we have found that bone marrow-derived plasmacytoid dendritic cells (pDCs) as main producers of interferon-alpha (IFNalpha) require Rag2 for normal development. This is a novel function for Rag2, whose classical role is to initiate B and T cell development. Here we showed that a population of common progenitor cells in the mouse bone marrow possessed the potential to become either B cells or pDCs upon appropriate stimulations, and the lack of Rag2 hindered the development of both types of progeny cells. A closer look at pDCs revealed that Rag2-/- pDCs expressed a high level of Ly6C and were defective at producing IFNalpha in response to CpG, a ligand for toll-like receptor 9. This phenotype was not shared by Rag1-/- pDCs. The induction of CCR7, CD40 and CD86 with CpG, however, was normal in Rag2-/- pDCs. In addition, Rag2-/- pDCs retained the function to promote antibody class switching and plasma cell formation through producing IL-6. Further analysis showed that interferon regulatory factor-8, a transcription factor important for both IFNalpha induction and pDC development, was dysregulated in pDCs lacking Rag2. These results indicate that the generation of interferon response in pDCs requires Rag2 and suggest the lymphoid origin of bone marrow-derived pDCs. PMID- 23110143 TI - Meningococcal factor H binding protein fHbpd184 polymorphism influences clinical course of meningococcal meningitis. AB - Factor H Binding protein (fHbp) is an important meningococcal virulence factor, enabling the meningococcus to evade the complement system, and a main target for vaccination. Recently, the structure of fHBP complexed with factor H (fH) was published. Two fHbp glutamic acids, E(283) and E(304), form salt bridges with fH, influencing interaction between fHbp and fH. Fifteen amino acids were identified forming hydrogen bonds with fH. We sequenced fHbp of 254 meningococcal isolates from adults with meningococcal meningitis included in a prospective clinical cohort to study the effect of fHbp variants on meningococcal disease severity and outcome. All fHbp of subfamily A had E304 substituted with T304. Of the 15 amino acids in fHbp making hydrogen bonds to fH, 3 were conserved, 11 show a similar distribution between the two fHbp subfamilies as the polymorphism at position 304. The proportion of patients infected with meningococci with fHbp of subfamily A with unfavorable outcome was 2.5-fold lower than that of patients infected with meningococci with fHbp of subfamily B (2 of 40 (5%) vs. 27 of 213 (13%) (P = 0.28). The charge of 2 of 15 amino acids (at position 184 and 306) forming hydrogen bonds was either basic or acidic. The affinity of fHbp(K184) and of fHbp(D184) for recombinant purified human fH was assessed by Surface Plasmon Resonance and showed average K(D) of 2.60*10(-8) and 1.74*10(-8), respectively (ns). Patients infected with meningococci with fHbp(D184) were more likely to develop septic shock during admission (11 of 42 [26%] vs. 19 of 211 [9%]; P = 0.002) resulting in more frequent unfavorable outcome (9 of 42 [21%] vs. 20 of 211 [10%]; P = 0.026). In conclusion, we dentified fHBP(D184) to be associated with septic shock in patients with meningococcal meningitis. PMID- 23110144 TI - Diverse small molecule inhibitors of human apurinic/apyrimidinic endonuclease APE1 identified from a screen of a large public collection. AB - The major human apurinic/apyrimidinic endonuclease APE1 plays a pivotal role in the repair of base damage via participation in the DNA base excision repair (BER) pathway. Increased activity of APE1, often observed in tumor cells, is thought to contribute to resistance to various anticancer drugs, whereas down-regulation of APE1 sensitizes cells to DNA damaging agents. Thus, inhibiting APE1 repair endonuclease function in cancer cells is considered a promising strategy to overcome therapeutic agent resistance. Despite ongoing efforts, inhibitors of APE1 with adequate drug-like properties have yet to be discovered. Using a kinetic fluorescence assay, we conducted a fully-automated high-throughput screen (HTS) of the NIH Molecular Libraries Small Molecule Repository (MLSMR), as well as additional public collections, with each compound tested as a 7-concentration series in a 4 uL reaction volume. Actives identified from the screen were subjected to a panel of confirmatory and counterscreen tests. Several active molecules were identified that inhibited APE1 in two independent assay formats and exhibited potentiation of the genotoxic effect of methyl methanesulfonate with a concomitant increase in AP sites, a hallmark of intracellular APE1 inhibition; a number of these chemotypes could be good starting points for further medicinal chemistry optimization. To our knowledge, this represents the largest-scale HTS to identify inhibitors of APE1, and provides a key first step in the development of novel agents targeting BER for cancer treatment. PMID- 23110145 TI - Physical, chemical and biological characteristics in habitats of high and low presence of anopheline larvae in western Kenya highlands. AB - BACKGROUND: Characteristics of aquatic habitats determine whether mosquitoes will oviposit, hatch, develop, pupate and successfully emerge into adults or not, thus influencing which mosquito species will occupy a habitat. This study determined whether physiochemical and biological characteristics differ between habitats with high and low presence of anopheline larvae. METHODS: Physical, chemical and biological characteristics were evaluated in selected habitats twice per month within three highland valleys in western Kenya. Aquatic macro-organisms were sampled using a sweep-net. Colorimetric methods were used to determine levels of iron, phosphate, nitrate, ammonium and nitrite in water samples. Generalized Estimating Equations (GEE) was used to compare parameters between the two categories of anopheline presence. RESULTS: Habitats with high anopheline presence had greater abundance of mosquito aquatic stages and tadpoles and two times more levels of nitrate in water, whereas habitats with low anopheline presence had wider biofilm cover and higher levels of iron in water. CONCLUSION: Habitats of high and low presence of anopheline larvae, which differed in a number of physical, chemical and biological characteristics, were identified in valleys within western Kenya highlands. Differences in habitat characteristics are critical in determining the number of anopheline larvae that will fully develop and emerge into adults. PMID- 23110146 TI - The analgesic effect on neuropathic pain of retrogradely transported botulinum neurotoxin A involves Schwann cells and astrocytes. AB - In recent years a growing debate is about whether botulinum neurotoxins are retrogradely transported from the site of injection. Immunodetection of cleaved SNAP-25 (cl-SNAP-25), the protein of the SNARE complex targeted by botulinum neurotoxin serotype A (BoNT/A), could represent an excellent approach to investigate the mechanism of action on the nociceptive pathways at peripheral and/or central level. After peripheral administration of BoNT/A, we analyzed the expression of cl-SNAP-25, from the hindpaw's nerve endings to the spinal cord, together with the behavioral effects on neuropathic pain. We used the chronic constriction injury of the sciatic nerve in CD1 mice as animal model of neuropathic pain. We evaluated immunostaining of cl-SNAP-25 in the peripheral nerve endings, along the sciatic nerve, in dorsal root ganglia and in spinal dorsal horns after intraplantar injection of saline or BoNT/A, alone or colocalized with either glial fibrillar acidic protein, GFAP, or complement receptor 3/cluster of differentiation 11b, CD11b, or neuronal nuclei, NeuN, depending on the area investigated. Immunofluorescence analysis shows the presence of the cl-SNAP-25 in all tissues examined, from the peripheral endings to the spinal cord, suggesting a retrograde transport of BoNT/A. Moreover, we performed in vitro experiments to ascertain if BoNT/A was able to interact with the proliferative state of Schwann cells (SC). We found that BoNT/A modulates the proliferation of SC and inhibits the acetylcholine release from SC, evidencing a new biological effect of the toxin and further supporting the retrograde transport of the toxin along the nerve and its ability to influence regenerative processes. The present results strongly sustain a combinatorial action at peripheral and central neural levels and encourage the use of BoNT/A for the pathological pain conditions difficult to treat in clinical practice and dramatically impairing patients' quality of life. PMID- 23110147 TI - PARP-1 modulation of mTOR signaling in response to a DNA alkylating agent. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is widely involved in cell death responses. Depending on the degree of injury and on cell type, PARP activation may lead to autophagy, apoptosis or necrosis. In HEK293 cells exposed to the alkylating agent N-methyl-N'-nitro-N'-nitrosoguanine (MNNG), we show that PARP-1 activation triggers a necrotic cell death response. The massive poly(ADP-ribose) (PAR) synthesis following PARP-1 activation leads to the modulation of mTORC1 pathway. Shortly after MNNG exposure, NAD+ and ATP levels decrease, while AMP levels drastically increase. We characterized at the molecular level the consequences of these altered nucleotide levels. First, AMP-activated protein kinase (AMPK) is activated and the mTORC1 pathway is inhibited by the phosphorylation of Raptor, in an attempt to preserve cellular energy. Phosphorylation of the mTORC1 target S6 is decreased as well as the phosphorylation of the mTORC2 component Rictor on Thr1135. Finally, Akt phosphorylation on Ser473 is lost and then, cell death by necrosis occurs. Inhibition of PARP-1 with the potent PARP inhibitor AG14361 prevents all of these events. Moreover, the antioxidant N-acetyl-L-cysteine (NAC) can also abrogate all the signaling events caused by MNNG exposure suggesting that reactive oxygen species (ROS) production is involved in PARP-1 activation and modulation of mTOR signaling. In this study, we show that PARP-1 activation and PAR synthesis affect the energetic status of cells, inhibit the mTORC1 signaling pathway and possibly modulate the mTORC2 complex affecting cell fate. These results provide new evidence that cell death by necrosis is orchestrated by the balance between several signaling pathways, and that PARP-1 and PAR take part in these events. PMID- 23110148 TI - Isoflavones, genistein and daidzein, regulate mucosal immune response by suppressing dendritic cell function. AB - Lipopolysaccharide (LPS), a component of gram-negative bacterial cell walls, has been shown to have a strong adjuvant effect towards inhaled antigens contributing to airway inflammation. Isoflavones are anti-inflammatory molecules present in abundant quantities in soybeans. We investigated the effect of isoflavones on human dendritic cell (DC) activation via LPS stimulation and subsequent DC mediated effector cell function both in vitro and in a mouse model of upper airway inflammation. Human monocyte-derived DCs (MDDC) were matured with LPS (or TNF-alpha) +/- isoflavones (genistein or daidzein). The surface expression levels of DC activation markers were analyzed by flow cytometry. Mature DCs +/- isoflavones were washed and cultured with freshly-isolated allogenic naive CD4+ T cells for 5 days or with autologous natural killer (NK) cells for 2 hours. The percentages of proliferating IFN-gamma+ CD4+ T cells and cytokine levels in culture supernatants were assessed. NK cell degranulation and DC cytotoxicity were measured by flow cytometry. Isoflavones significantly suppressed the activation-induced expression of DC maturation markers (CD83, CD80, CD86) and MHC class I but not MHC class II molecules in vitro. Isoflavone treatment inhibited the ability of LPS-DCs to induce IFN-gamma in CD4+ T cells. NK cell degranulation and the percentage of dead DCs were significantly increased in isoflavone-treated DC-NK co-culture experiments. Dietary isoflavones suppressed the mucosal immune response to intra-nasal sensitization of mice to ovalbumin. Similar results were obtained when isoflavones were co-administered during sensitization. These results demonstrate that soybean isoflavones suppress immune sensitization by suppressing DC-maturation and its subsequent DC-mediated effector cell functions. PMID- 23110149 TI - Transcutaneous immunization system using a hydrotropic formulation induces a potent antigen-specific antibody response. AB - BACKGROUND: Transcutaneous immunization (TCI) is a novel vaccination strategy, which is expected to have therapeutic applications. However, to develop effective TCI systems, a simple, non-invasive and safe transdermal formulation is required. This study developed a novel TCI system utilizing the co-administration of a liposoluble absorption enhancer, propylene glycol monocaprylate (PGMC) and hydrosoluble protein antigen without pretreatment of any typical adjuvants and disruption of the skin. Novel transdermal formulations were also prepared with sodium salicylate (NaSal) as a hydrotropic agent to improve the solubility of poorly water-soluble substances. METHODOLOGY/PRINCIPAL FINDINGS: The TCI system, which used a transdermal formulation containing hen lysozyme (HEL) and PGMC, solubilized with NaSal, resulted in a substantial HEL-specific antibody response in an HEL dose-dependent manner even in the absence of potent adjuvants, such as cholera toxin (CT). We also investigated whether NaSal activates antigen presenting cells in vitro to clarify the mechanisms of antibody production by the hydrotropic formulation. NaSal enhanced the expression of MHC class II molecules and increased the production of IL-12 and TNF-alpha in dendritic cells, which were stimulated by lipopolysaccharide in vitro, indicating that NaSal had an effective adjuvant-like property. Moreover, the use of NaSal in the TCI system did not induce an HEL-specific, IgE-dependent anaphylactic reaction. CONCLUSION/SIGNIFICANCE: Our TCI system using a hydrotropic formulation effectively and safely induced the intended immune response, and this system thus represents a new advantageous method that will result in improved TCI strategies. PMID- 23110150 TI - Changes in the diurnal rhythms during a 45-day head-down bed rest. AB - In spaceflight human circadian rhythms and sleep patterns are likely subject to change, which consequently disturbs human physiology, cognitive abilities and performance efficiency. However, the influence of microgravity on sleep and circadian clock as well as the underlying mechanisms remain largely unknown. Placing volunteers in a prone position, whereby their heads rest at an angle of 6 degrees below horizontal, mimics the microgravity environment in orbital flight. Such positioning is termed head-down bed rest (HDBR). In this work, we analysed the influence of a 45-day HDBR on physiological diurnal rhythms. We examined urinary electrolyte and hormone excretion, and the results show a dramatic elevation of cortisol levels during HDBR and recovery. Increased diuresis, melatonin and testosterone were observed at certain periods during HDBR. In addition, we investigated the changes in urination and defecation frequencies and found that the rhythmicity of urinary frequency during lights-off during and after HDBR was higher than control. The grouped defecation frequency data exhibits rhythmicity before and during HDBR but not after HDBR. Together, these data demonstrate that HDBR can alter a number of physiological processes associated with diurnal rhythms. PMID- 23110151 TI - Antibody phage display assisted identification of junction plakoglobin as a potential biomarker for atherosclerosis. AB - To date, no plaque-derived blood biomarker is available to allow diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. In this study, specimens of thrombendarterectomy material from carotid and iliac arteries were incubated in protein-free medium to obtain plaque and control secretomes for subsequent subtractive phage display. The selection of nine plaque secretome specific antibodies and the analysis of their immunopurified antigens by mass spectrometry led to the identification of 22 proteins. One of them, junction plakoglobin (JUP-81) and its smaller isoforms (referred to as JUP-63, JUP-55 and JUP-30 by molecular weight) were confirmed by immunohistochemistry and immunoblotting with independent antibodies to be present in atherosclerotic plaques and their secretomes, coronary thrombi of patients with acute coronary syndrome (ACS) and macrophages differentiated from peripheral blood monocytes as well as macrophage-like cells differentiated from THP1 cells. Plasma of patients with stable coronary artery disease (CAD) (n = 15) and ACS (n = 11) contained JUP 81 at more than 2- and 14-fold higher median concentrations, respectively, than plasma of CAD-free individuals (n = 13). In conclusion, this proof of principle study identified and verified JUP isoforms as potential plasma biomarkers for atherosclerosis. Clinical validation studies are needed to determine its diagnostic efficacy and clinical utility as a biomarker for diagnosis, prognosis or monitoring of atherosclerotic vascular diseases. PMID- 23110152 TI - Crystal structures of bovine CD1d reveal altered alphaGalCer presentation and a restricted A' pocket unable to bind long-chain glycolipids. AB - NKT cells play important roles in immune surveillance. They rapidly respond to pathogens by detecting microbial glycolipids when presented by the non-classical MHC I homolog CD1d. Previously, ruminants were considered to lack NKT cells due to the lack of a functional CD1D gene. However, recent data suggest that cattle express CD1d with unknown function. In an attempt to characterize the function of bovine CD1d, we assessed the lipid binding properties of recombinant Bos taurus CD1d (boCD1d) in vitro. BoCD1d is able to bind glycosphingolipids (GSLs) with fatty acid chain lengths of C18, while GSLs with fatty acids of C24 do not bind. Crystal structures of boCD1d bound to a short-chain C12-di-sulfatide antigen, as well as short-chain C16-alphaGalCer revealed that the A pocket of boCD1d is restricted in size compared to that of both mouse and human CD1d, explaining the inability of long chain GSL's to bind to boCD1d. Moreover, while di-sulfatide is presented similarly compared to the presentation of sulfatide by mouse CD1d, alphaGalCer is presented differently at the cell surface, due to an amino acid Asp151Asn substitution that results in loss of intimate contacts between the alphaGalCer headgroup and CD1d. The altered alphaGalCer presentation by boCD1d also explains its lack of cross-activation of mouse iNKT cells and raises the interesting question of the nature and function of bovine lipid-reactive T cells. PMID- 23110153 TI - Prediction of muscle activities from electrocorticograms in primary motor cortex of primates. AB - Electrocorticography (ECoG) has drawn attention as an effective recording approach for brain-machine interfaces (BMI). Previous studies have succeeded in classifying movement intention and predicting hand trajectories from ECoG. Despite such successes, however, there still remains considerable work for the realization of ECoG-based BMIs as neuroprosthetics. We developed a method to predict multiple muscle activities from ECoG measurements. We also verified that ECoG signals are effective for predicting muscle activities in time varying series when performing sequential movements. ECoG signals were band-pass filtered into separate sensorimotor rhythm bands, z-score normalized, and smoothed with a Gaussian filter. We used sparse linear regression to find the best fit between frequency bands of ECoG and electromyographic activity. The best average correlation coefficient and the normalized root-mean-square error were 0.92+/ 0.06 and 0.06+/-0.10, respectively, in the flexor digitorum profundus finger muscle. The delta (1.5~4Hz) and gamma2 (50~90Hz) bands contributed significantly more strongly than other frequency bands (P<0.001). These results demonstrate the feasibility of predicting muscle activity from ECoG signals in an online fashion. PMID- 23110154 TI - Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital-based series of German patients with triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is an aggressive form of breast carcinoma with a poor prognosis. Recent evidence suggests that some patients with TNBC harbour germ-line mutations in DNA repair genes which may render their tumours susceptible to novel therapies such as treatment with PARP inhibitors. In the present study, we have investigated a hospital-based series of 40 German patients with TNBC for the presence of germ-line mutations in BRCA1, BRCA2, PALB2, and BRD7 genes. Microfluidic array PCR and next-generation sequencing was used for BRCA1 and BRCA2 analysis while conventional high-resolution melting and Sanger sequencing was applied to study the coding regions of PALB2 and BRD7, respectively. Truncating mutations in BRCA1 were found in six patients, and truncating mutations in BRCA2 and PALB2 were detected in one patient each, whereas no truncating mutation was identified in BRD7. One patient was a double heterozygote for the PALB2 mutation, c.758insT, and a BRCA1 mutation, c.927delA. Our results confirm in a hospital-based setting that a substantial proportion of German TNBC patients (17.5%) harbour germ-line mutations in genes involved in homology-directed DNA repair, with a preponderance of BRCA1 mutations. Triple negative breast cancer should be considered as an additional criterion for future genetic counselling and diagnostic sequencing. PMID- 23110155 TI - Activity-based protein profiling reveals mitochondrial oxidative enzyme impairment and restoration in diet-induced obese mice. AB - High-fat diet (HFD) induced obesity and concomitant development of insulin resistance (IR) and type 2 diabetes mellitus have been linked to mitochondrial dysfunction. However, it is not clear whether mitochondrial dysfunction is a direct effect of a HFD, or if mitochondrial function is reduced with increased HFD duration. We hypothesized that the function of mitochondrial oxidative and lipid metabolism functions in skeletal muscle mitochondria for HFD mice are similar, or elevated, relative to standard diet (SD) mice; thereby, IR is neither cause nor consequence of mitochondrial dysfunction. We applied a chemical probe approach to identify functionally reactive ATPases and nucleotide-binding proteins in mitochondria isolated from skeletal muscle of C57Bl/6J mice fed HFD or SD chow for 2-, 8-, or 16-weeks; feeding time points known to induce IR. A total of 293 probe-labeled proteins were identified by mass spectrometry-based proteomics, of which 54 differed in abundance between HFD and SD mice. We found proteins associated with the TCA cycle, oxidative phosphorylation (OXPHOS), and lipid metabolism were altered in function when comparing SD to HFD fed mice at 2 weeks, however by 16-weeks HFD mice had TCA cycle, beta-oxidation, and respiratory chain function at levels similar to or higher than SD mice. PMID- 23110156 TI - A functional requirement for astroglia in promoting blood vessel development in the early postnatal brain. AB - Astroglia are a major cell type in the brain and play a key role in many aspects of brain development and function. In the adult brain, astrocytes are known to intimately ensheath blood vessels and actively coordinate local neural activity and blood flow. During development of the neural retina, blood vessel growth follows a meshwork of astrocytic processes. Several genes have also been implicated in retinal astrocytes for regulating vessel development. This suggests a role of astrocytes in promoting angiogenesis throughout the central nervous system. To determine the roles that astrocytes may play during brain angiogenesis, we employ genetic approaches to inhibit astrogliogenesis during perinatal corticogenesis and examine its effects on brain vessel development. We find that conditional deletion from glial progenitors of orc3, a gene required for DNA replication, dramatically reduces glial progenitor cell number in the subventricular zone and astrocytes in the early postnatal cerebral cortex. This, in turn, results in severe reductions in both the density and branching frequency of cortical blood vessels. Consistent with a delayed growth but not regression of vessels, we find neither significant net decreases in vessel density between different stages after normalizing for cortical expansion nor obvious apoptosis of endothelial cells in these mutants. Furthermore, concomitant with loss of astroglial interactions, we find increased endothelial cell proliferation, enlarged vessel luminal size as well as enhanced cytoskeletal gene expression in pericytes, which suggests compensatory changes in vascular cells. Lastly, we find that blood vessel morphology in mutant cortices recovers substantially at later stages, following astrogliosis. These results thus implicate a functional requirement for astroglia in promoting blood vessel growth during brain development. PMID- 23110157 TI - Ultra-brief intervention for problem drinkers: results from a randomized controlled trial. AB - BACKGROUND: There are a number of evidence-based, in-person clinical inteventions for problem drinkers, but most problem drinkers will never seek such treatments. Reaching the population of non-treatment seeking problem drinkers will require a different approach. Accordingly, this randomized clinical trial evaluated an intervention that has been validated in clinical settings and then modified into an ultra-brief format suitable for use as an indicated public health intervention (i.e., targeting the population of non-treatment seeking problem drinkers). METHODOLOGY/PRINCIPAL FINDINGS: Problem drinkers (N = 1767) completed a baseline population telephone survey and then were randomized to one of three conditions - a personalized feedback pamphlet condition, a control pamphlet condition, or a no intervention control condition. In the week after the baseline survey, households in the two pamphlet conditions were sent their respective interventions by postal mail addressed to 'Check Your Drinking.' Changes in drinking were assessed post intervention at three-month and six-month follow-ups. The follow-up rate was 86% at three-months and 76% at six-months. There was a small effect (p = .04) in one of three outcome variables (reduction in AUDIT-C, a composite measure of quantity and frequency of drinking) observed for the personalized feedback pamphlet compared to the no intervention control. No significant differences (p>.05) between groups were observed for the other two outcome variables - number of drinks consumed in the past seven days and highest number of drinks on one occasion. CONCLUSIONS/SIGNIFICANCE: Based on the results of this study, we tentatively conclude that a brief intervention, modified to an ultra-brief, public health format can have a meaningful impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT00688584. PMID- 23110158 TI - Evidence for a role of a cortico-subcortical network for automatic and unconscious motor inhibition of manual responses. AB - It is now clear that non-consciously perceived stimuli can bias our decisions. Although previous researches highlighted the importance of automatic and unconscious processes involved in voluntary action, the neural correlates of such processes remain unclear. Basal ganglia dysfunctions have long been associated with impairment in automatic motor control. In addition, a key role of the medial frontal cortex has been suggested by administrating a subliminal masked prime task to a patient with a small lesion restricted to the supplementary motor area (SMA). In this task, invisible masked arrows stimuli were followed by visible arrow targets for a left or right hand response at different interstimuli intervals (ISI), producing a traditional facilitation effect for compatible trials at short ISI and a reversal inhibitory effect at longer ISI. Here, by using fast event-related fMRI and a weighted parametric analysis, we showed BOLD related activity changes in a cortico-subcortical network, especially in the SMA and the striatum, directly linked to the individual behavioral pattern. This new imaging result corroborates previous works on subliminal priming using lesional approaches. This finding implies that one of the roles of these regions was to suppress a partially activated movement below the threshold of awareness. PMID- 23110159 TI - ReFlexIn: a flexible receptor protein-ligand docking scheme evaluated on HIV-1 protease. AB - For many targets of pharmaceutical importance conformational changes of the receptor protein are relevant during the ligand binding process. A new docking approach, ReFlexIn (Receptor Flexibility by Interpolation), that combines receptor flexibility with the computationally efficient potential grid representation of receptor molecules has been evaluated on the retroviral HIV-1 (Human Immunodeficiency Virus 1) protease system. An approximate inclusion of receptor flexibility is achieved by using interpolation between grid representations of individual receptor conformations. For the retroviral protease the method was tested on an ensemble of protease structures crystallized in the presence of different ligands and on a set of structures obtained from morphing between the unbound and a ligand-bound protease structure. Docking was performed on ligands known to bind to the protease and several non-binders. For the binders the ReFlexIn method yielded in almost all cases ligand placements in similar or closer agreement with experiment than docking to any of the ensemble members without degrading the discrimination with respect to non-binders. The improved docking performance compared to docking to rigid receptors allows for systematic virtual screening applications at very small additional computational cost. PMID- 23110160 TI - Cholesterol depletion inactivates XMRV and leads to viral envelope protein release from virions: evidence for role of cholesterol in XMRV infection. AB - Membrane cholesterol plays an important role in replication of HIV-1 and other retroviruses. Here, we report that the gammaretrovirus XMRV requires cholesterol and lipid rafts for infection and replication. We demonstrate that treatment of XMRV with a low concentration (10 mM) of 2-hydroxypropyl-beta-cyclodextrin (2OHpbetaCD) partially depleted virion-associated cholesterol resulting in complete inactivation of the virus. This effect could not be reversed by adding cholesterol back to treated virions. Further analysis revealed that following cholesterol depletion, virus-associated Env protein was significantly reduced while the virions remained intact and retained core proteins. Increasing concentrations of 2OHpbetaCD (>=20 mM) resulted in loss of the majority of virion associated cholesterol, causing disruption of membrane integrity and loss of internal Gag proteins and viral RNA. Depletion of cholesterol from XMRV-infected cells significantly reduced virus release, suggesting that cholesterol and intact lipid rafts are required for the budding process of XMRV. These results suggest that unlike glycoproteins of other retroviruses, the association of XMRV glycoprotein with virions is highly dependent on cholesterol and lipid rafts. PMID- 23110162 TI - Climate change impacts on the future distribution of date palms: a modeling exercise using CLIMEX. AB - Climate is changing and, as a consequence, some areas that are climatically suitable for date palm (Phoenix dactylifera L.) cultivation at the present time will become unsuitable in the future. In contrast, some areas that are unsuitable under the current climate will become suitable in the future. Consequently, countries that are dependent on date fruit export will experience economic decline, while other countries' economies could improve. Knowledge of the likely potential distribution of this economically important crop under current and future climate scenarios will be useful in planning better strategies to manage such issues. This study used CLIMEX to estimate potential date palm distribution under current and future climate models by using one emission scenario (A2) with two different global climate models (GCMs), CSIRO-Mk3.0 (CS) and MIROC-H (MR). The results indicate that in North Africa, many areas with a suitable climate for this species are projected to become climatically unsuitable by 2100. In North and South America, locations such as south-eastern Bolivia and northern Venezuela will become climatically more suitable. By 2070, Saudi Arabia, Iraq and western Iran are projected to have a reduction in climate suitability. The results indicate that cold and dry stresses will play an important role in date palm distribution in the future. These results can inform strategic planning by government and agricultural organizations by identifying new areas in which to cultivate this economically important crop in the future and those areas that will need greater attention due to becoming marginal regions for continued date palm cultivation. PMID- 23110161 TI - Exclusion of exon 2 is a common mRNA splice variant of primate telomerase reverse transcriptases. AB - Telomeric sequences are added by an enzyme called telomerase that is made of two components: a catalytic protein called telomerase reverse transcriptase (TERT) and an integral RNA template (TR). Telomerase expression is tightly regulated at each step of gene expression, including alternative splicing of TERT mRNA. While over a dozen different alternative splicing events have been reported for human TERT mRNA, these were all in the 3' half of the coding region. We were interested in examining splicing of the 5' half of hTERT mRNA, especially since exon 2 is unusually large (1.3 kb). Internal mammalian exons are usually short, typically only 50 to 300 nucleotides, and most long internal exons are alternatively processed. We used quantitative RT-PCR and high-throughput sequencing data to examine the variety and quantity of mRNA species generated from the hTERT locus. We determined that there are approximately 20-40 molecules of hTERT mRNA per cell in the A431 human cell line. In addition, we describe an abundant, alternatively spliced mRNA variant that excludes TERT exon 2 and was seen in other primates. This variant causes a frameshift and results in translation termination in exon 3, generating a 12 kDa polypeptide. PMID- 23110163 TI - Alteration of cellular behavior and response to PI3K pathway inhibition by culture in 3D collagen gels. AB - Most investigations into cancer cell drug response are performed with cells cultured on flat (2D) tissue culture plastic. Emerging research has shown that the presence of a three-dimensional (3D) extracellular matrix (ECM) is critical for normal cell behavior including migration, adhesion, signaling, proliferation and apoptosis. In this study we investigate differences between cancer cell signaling in 2D culture and a 3D ECM, employing real-time, live cell tracking to directly observe U2OS human osteosarcoma and MCF7 human breast cancer cells embedded in type 1 collagen gels. The activation of the important PI3K signaling pathway under these different growth conditions is studied, and the response to inhibition of both PI3K and mTOR with PI103 investigated. Cells grown in 3D gels show reduced proliferation and migration as well as reduced PI3K pathway activation when compared to cells grown in 2D. Our results quantitatively demonstrate that a collagen ECM can protect U2OS cells from PI103. Overall, our data suggests that 3D gels may provide a better medium for investigation of anti cancer drugs than 2D monolayers, therefore allowing better understanding of cellular response and behavior in native like environments. PMID- 23110164 TI - Consistent selection towards low activity phenotypes when catchability depends on encounters among human predators and fish. AB - Together with life-history and underlying physiology, the behavioural variability among fish is one of the three main trait axes that determines the vulnerability to fishing. However, there are only a few studies that have systematically investigated the strength and direction of selection acting on behavioural traits. Using in situ fish behaviour revealed by telemetry techniques as input, we developed an individual-based model (IBM) that simulated the Lagrangian trajectory of prey (fish) moving within a confined home range (HR). Fishers exhibiting various prototypical fishing styles targeted these fish in the model. We initially hypothesised that more active and more explorative individuals would be systematically removed under all fished conditions, in turn creating negative selection differentials on low activity phenotypes and maybe on small HR. Our results partly supported these general predictions. Standardised selection differentials were, on average, more negative on HR than on activity. However, in many simulation runs, positive selection pressures on HR were also identified, which resulted from the stochastic properties of the fishes' movement and its interaction with the human predator. In contrast, there was a consistent negative selection on activity under all types of fishing styles. Therefore, in situations where catchability depends on spatial encounters between human predators and fish, we would predict a consistent selection towards low activity phenotypes and have less faith in the direction of the selection on HR size. Our study is the first theoretical investigation on the direction of fishery-induced selection of behaviour using passive fishing gears. The few empirical studies where catchability of fish was measured in relation to passive fishing techniques, such as gill-nets, traps or recreational fishing, support our predictions that fish in highly exploited situations are, on average, characterised by low swimming activity, stemming, in part, from negative selection on swimming activity. PMID- 23110165 TI - A new real-time PCR for the detection of Plasmodium ovale wallikeri. AB - It has been proposed that ovale malaria in humans is caused by two closely related but distinct species of malaria parasites: P. ovale curtisi and P. ovale wallikeri. We have extended and optimized a Real-time PCR assay targeting the parasite's small subunit ribosomal RNA (ssrRNA) gene to detect both these species. When the assay was applied to 31 archival blood samples from patients diagnosed with P. ovale, it was found that the infection in 20 was due to P. ovale curtisi and in the remaining 11 to P. ovale wallikeri. Thus, this assay provides a useful tool that can be applied to epidemiological investigations of the two newly recognized distinct P. ovale species, that might reveal if these species also differ in their clinical manifestation, drugs susceptibility and relapse periodicity. The results presented confirm that P. ovale wallikeri is not confined to Southeast Asia, since the majority of the patients analyzed in this study had acquired their P. ovale infection in African countries, mostly situated in West Africa. PMID- 23110167 TI - Influence of spatial resolution on space-time disease cluster detection. AB - BACKGROUND: Utilizing highly precise spatial resolutions within disease outbreak detection, such as the patients' address, is most desirable as this provides the actual residential location of the infected individual(s). However, this level of precision is not always readily available or only available for purchase, and when utilized, increases the risk of exposing protected health information. Aggregating data to less precise scales (e.g., ZIP code or county centroids) may mitigate this risk but at the expense of potentially masking smaller isolated high risk areas. METHODS: To experimentally examine the effect of spatial data resolution on space-time cluster detection, we extracted administrative medical claims data for 122500 viral lung episodes occurring during 2007-2010 in Tennessee. We generated 10000 spatial datasets with varying cluster location, size and intensity at the address-level. To represent spatial data aggregation (i.e., reduced resolution), we then created 10000 corresponding datasets both at the ZIP code and county level for a total of 30000 datasets. Using the space-time permutation scan statistic and the SaTScanTM cluster software, we evaluated statistical power, sensitivity and positive predictive values of outbreak detection when using exact address locations compared to ZIP code and county level aggregations. RESULTS: The power to detect disease outbreaks did not largely diminish when using spatially aggregated data compared to more precise address information. However, aggregations negatively impacted the ability to more accurately determine the exact spatial location of the outbreak, particularly in smaller clusters (<800 km2). CONCLUSIONS: Spatial aggregations do not necessitate a loss of power or sensitivity; rather, the relationship is more complex and involves simultaneously considering relative risk within the cluster and cluster size. The likelihood of spatially over-estimating outbreaks by including geographical areas outside the actual disease cluster increases with aggregated data. PMID- 23110166 TI - Long-term culture of astrocytes attenuates the readily releasable pool of synaptic vesicles. AB - The astrocyte is a major glial cell type of the brain, and plays key roles in the formation, maturation, stabilization and elimination of synapses. Thus, changes in astrocyte condition and age can influence information processing at synapses. However, whether and how aging astrocytes affect synaptic function and maturation have not yet been thoroughly investigated. Here, we show the effects of prolonged culture on the ability of astrocytes to induce synapse formation and to modify synaptic transmission, using cultured autaptic neurons. By 9 weeks in culture, astrocytes derived from the mouse cerebral cortex demonstrated increases in beta galactosidase activity and glial fibrillary acidic protein (GFAP) expression, both of which are characteristic of aging and glial activation in vitro. Autaptic hippocampal neurons plated on these aging astrocytes showed a smaller amount of evoked release of the excitatory neurotransmitter glutamate, and a lower frequency of miniature release of glutamate, both of which were attributable to a reduction in the pool of readily releasable synaptic vesicles. Other features of synaptogenesis and synaptic transmission were retained, for example the ability to induce structural synapses, the presynaptic release probability, the fraction of functional presynaptic nerve terminals, and the ability to recruit functional AMPA and NMDA glutamate receptors to synapses. Thus the presence of aging astrocytes affects the efficiency of synaptic transmission. Given that the pool of readily releasable vesicles is also small at immature synapses, our results are consistent with astrocytic aging leading to retarded synapse maturation. PMID- 23110168 TI - Inflammation and Gli2 suppress gastrin gene expression in a murine model of antral hyperplasia. AB - Chronic inflammation in the stomach can lead to gastric cancer. We previously reported that gastrin-deficient (Gast-/-) mice develop bacterial overgrowth, inflammatory infiltrate, increased Il-1beta expression, antral hyperplasia and eventually antral tumors. Since Hedgehog (Hh) signaling is active in gastric cancers but its role in precursor lesions is poorly understood, we examined the role of inflammation and Hh signaling in antral hyperplasia. LacZ reporter mice for Sonic hedgehog (Shh), Gli1, and Gli2 expression bred onto the Gast-/- background revealed reduced Shh and Gli1 expression in the antra compared to wild type controls (WT). Gli2 expression in the Gast-/- corpus was unchanged. However in the hyperplastic Gast-/- antra, Gli2 expression increased in both the mesenchyme and epithelium, whereas expression in WT mice remained exclusively mesenchymal. These observations suggested that Gli2 is differentially regulated in the hyperplastic Gast-/- antrum versus the corpus and by a Shh ligand independent mechanism. Moreover, the proinflammatory cytokines Il-1beta and Il 11, which promote gastric epithelial proliferation, were increased in the Gast-/- stomach along with Infgamma. To test if inflammation could account for elevated epithelial Gli2 expression in the Gast-/- antra, the human gastric cell line AGS was treated with IL-1beta and was found to increase GLI2 but decrease GLI1 levels. IL-1beta also repressed human GAST gene expression. Indeed, GLI2 but not GLI1 or GLI3 expression repressed gastrin luciferase reporter activity by ~50 percent. Moreover, chromatin immunoprecipitation of GLI2 in AGS cells confirmed that GLI2 directly binds to the GAST promoter. Using a mouse model of constitutively active epithelial GLI2 expression, we found that activated GLI2 repressed Gast expression but induced Il-1beta gene expression and proliferation in the gastric antrum, along with a reduction of the number of G-cells. In summary, epithelial Gli2 expression was sufficient to stimulate Il-1beta expression, repress Gast gene expression and increase proliferation, leading to antral hyperplasia. PMID- 23110169 TI - Transforming growth factor Beta 3 is required for excisional wound repair in vivo. AB - Wound healing is a complex process that relies on proper levels of cytokines and growth factors to successfully repair the tissue. Of particular interest are the members of the transforming growth factor family. There are three TGF-beta isoforms-TGF- beta 1, 2, and 3, each isoform showing a unique expression pattern, suggesting that they each play a distinct function during development and repair. Previous studies reported an exclusive role for TGF-beta 3 in orofacial development and a potent anti-scarring effect. However, the role of TGF- beta 3 in excisional wound healing and keratinocyte migration remains poorly understood. We tested the effect of TGF-beta 3 levels on excisional cutaneous wounds in the adult mouse by directly injecting recombinant TGF-beta 3 or neutralizing antibody against TGF-beta 3 (NAB) in the wounds. Our results demonstrate that TGF-beta 3 does not promote epithelialization. However, TGF-beta 3 is necessary for wound closure as wounds injected with neutralizing antibody against TGF-beta 3 showed increased epidermal volume and proliferation in conjunction with a delay in keratinocyte migration. Wild type keratinocytes treated with NAB and Tgfb3 deficient keratinocytes closed an in vitro scratch wound with no delay, suggesting that our in vivo observations likely result from a paracrine effect. PMID- 23110170 TI - The ability to induce microtubule acetylation is a general feature of formin proteins. AB - Cytoplasmic microtubules exist as distinct dynamic and stable populations within the cell. Stable microtubules direct and maintain cell polarity and it is thought that their stabilization is dependent on coordinative organization between the microtubule network and the actin cytoskeleton. A growing body of work suggests that some members of the formin family of actin remodeling proteins also regulate microtubule organization and stability. For example, we showed previously that expression of the novel formin INF1 is sufficient to induce microtubule stabilization and tubulin acetylation, but not tubulin detyrosination. An important issue with respect to the relationship between formins and microtubules is the determination of which formin domains mediate microtubule stabilization. INF1 has a distinct microtubule-binding domain at its C-terminus and the endogenous INF1 protein is associated with the microtubule network. Surprisingly, the INF1 microtubule-binding domain is not essential for INF1-induced microtubule acetylation. We show here that expression of the isolated FH1 + FH2 functional unit of INF1 is sufficient to induce microtubule acetylation independent of the INF1 microtubule-binding domain. It is not yet clear whether or not microtubule stabilization is a general property of all mammalian formins; therefore we expressed constitutively active derivatives of thirteen of the fifteen mammalian formin proteins in HeLa and NIH3T3 cells and measured their effects on stress fiber formation, MT organization and MT acetylation. We found that expression of the FH1 + FH2 unit of the majority of mammalian formins is sufficient to induce microtubule acetylation. Our results suggest that the regulation of microtubule acetylation is likely a general formin activity and that the FH2 should be thought of as a dual-function domain capable of regulating both actin and microtubule networks. PMID- 23110171 TI - Environmental enrichment enhances episodic-like memory in association with a modified neuronal activation profile in adult mice. AB - Although environmental enrichment is well known to improve learning and memory in rodents, the underlying neuronal networks' plasticity remains poorly described. Modifications of the brain activation pattern by enriched condition (EC), especially in the frontal cortex and the baso-lateral amygdala, have been reported during an aversive memory task in rodents. The aims of our study were to examine 1) whether EC modulates episodic-like memory in an object recognition task and 2) whether EC modulates the task-induced neuronal networks. To this end, adult male mice were housed either in standard condition (SC) or in EC for three weeks before behavioral experiments (n = 12/group). Memory performances were examined in an object recognition task performed in a Y-maze with a 2-hour or 24 hour delay between presentation and test (inter-session intervals, ISI). To characterize the mechanisms underlying the promnesiant effect of EC, the brain activation profile was assessed after either the presentation or the test sessions using immunohistochemical techniques with c-Fos as a neuronal activation marker. EC did not modulate memory performances after a 2 h-ISI, but extended object recognition memory to a 24 h-ISI. In contrast, SC mice did not discriminate the novel object at this ISI. Compared to SC mice, no activation related to the presentation session was found in selected brain regions of EC mice (in particular, no effect was found in the hippocampus and the perirhinal cortex and a reduced activation was found in the baso-lateral amygdala). On the other hand, an activation of the hippocampus and the infralimbic cortex was observed after the test session for EC, but not SC mice. These results suggest that the persistence of object recognition memory in EC could be related to a reorganization of neuronal networks occurring as early as the memory encoding. PMID- 23110172 TI - Neuroligin-1 overexpression in newborn granule cells in vivo. AB - Adult-born dentate granule cells integrate into the hippocampal network, extend neurites and form synapses in otherwise mature tissue. Excitatory and inhibitory inputs innervate these new granule cells in a stereotyped, temporally segregated manner, which presents a unique opportunity to study synapse development in the adult brain. To examine the role of neuroligins as synapse-inducing molecules in vivo, we infected dividing neural precursors in adult mice with a retroviral construct that increased neuroligin-1 levels during granule cell differentiation. By 21 days post-mitosis, exogenous neuroligin-1 was expressed at the tips of dendritic spines and increased the number of dendritic spines. Neuroligin-1 overexpressing cells showed a selective increase in functional excitatory synapses and connection multiplicity by single afferent fibers, as well as an increase in the synaptic AMPA/NMDA receptor ratio. In contrast to its synapse inducing ability in vitro, neuroligin-1 overexpression did not induce precocious synapse formation in adult-born neurons. However, the dendrites of neuroligin-1 overexpressing cells did have more thin protrusions during an early period of dendritic outgrowth, suggesting enhanced filopodium formation or stabilization. Our results indicate that neuroligin-1 expression selectively increases the degree, but not the onset, of excitatory synapse formation in adult-born neurons. PMID- 23110173 TI - SEED servers: high-performance access to the SEED genomes, annotations, and metabolic models. AB - The remarkable advance in sequencing technology and the rising interest in medical and environmental microbiology, biotechnology, and synthetic biology resulted in a deluge of published microbial genomes. Yet, genome annotation, comparison, and modeling remain a major bottleneck to the translation of sequence information into biological knowledge, hence computational analysis tools are continuously being developed for rapid genome annotation and interpretation. Among the earliest, most comprehensive resources for prokaryotic genome analysis, the SEED project, initiated in 2003 as an integration of genomic data and analysis tools, now contains >5,000 complete genomes, a constantly updated set of curated annotations embodied in a large and growing collection of encoded subsystems, a derived set of protein families, and hundreds of genome-scale metabolic models. Until recently, however, maintaining current copies of the SEED code and data at remote locations has been a pressing issue. To allow high performance remote access to the SEED database, we developed the SEED Servers (http://www.theseed.org/servers): four network-based servers intended to expose the data in the underlying relational database, support basic annotation services, offer programmatic access to the capabilities of the RAST annotation server, and provide access to a growing collection of metabolic models that support flux balance analysis. The SEED servers offer open access to regularly updated data, the ability to annotate prokaryotic genomes, the ability to create metabolic reconstructions and detailed models of metabolism, and access to hundreds of existing metabolic models. This work offers and supports a framework upon which other groups can build independent research efforts. Large integrations of genomic data represent one of the major intellectual resources driving research in biology, and programmatic access to the SEED data will provide significant utility to a broad collection of potential users. PMID- 23110174 TI - Sequential grouping modulates the effect of non-simultaneous masking on auditory intensity resolution. AB - The presence of non-simultaneous maskers can result in strong impairment in auditory intensity resolution relative to a condition without maskers, and causes a complex pattern of effects that is difficult to explain on the basis of peripheral processing. We suggest that the failure of selective attention to the target tones is a useful framework for understanding these effects. Two experiments tested the hypothesis that the sequential grouping of the targets and the maskers into separate auditory objects facilitates selective attention and therefore reduces the masker-induced impairment in intensity resolution. In Experiment 1, a condition favoring the processing of the maskers and the targets as two separate auditory objects due to grouping by temporal proximity was contrasted with the usual forward masking setting where the masker and the target presented within each observation interval of the two-interval task can be expected to be grouped together. As expected, the former condition resulted in a significantly smaller masker-induced elevation of the intensity difference limens (DLs). In Experiment 2, embedding the targets in an isochronous sequence of maskers led to a significantly smaller DL-elevation than control conditions not favoring the perception of the maskers as a separate auditory stream. The observed effects of grouping are compatible with the assumption that a precise representation of target intensity is available at the decision stage, but that this information is used only in a suboptimal fashion due to limitations of selective attention. The data can be explained within a framework of object-based attention. The results impose constraints on physiological models of intensity discrimination. We discuss candidate structures for physiological correlates of the psychophysical data. PMID- 23110175 TI - Isolation of reovirus T3D mutants capable of infecting human tumor cells independent of junction adhesion molecule-A. AB - Mammalian Reovirus is a double-stranded RNA virus with a distinctive preference to replicate in and lyse transformed cells. On that account, Reovirus type 3 Dearing (T3D) is clinically evaluated as oncolytic agent. The therapeutic efficacy of this approach depends in part on the accessibility of the reovirus receptor Junction Adhesion Molecule-A (JAM-A) on the target cells. Here, we describe the isolation and characterization of reovirus T3D mutants that can infect human tumor cells independent of JAM-A. The JAM-A-independent (jin) mutants were isolated on human U118MG glioblastoma cells, which do not express JAM-A. All jin mutants harbour mutations in the S1 segments close to the region that encodes the sialic acid-binding pocket in the shaft of the spike protein. In addition, two of the jin mutants encode spike proteins with a Q336R substitution in their head domain. The jin mutants can productively infect a wide range of cell lines that resist wt reovirus T3D infection, including chicken LMH cells, hamster CHO cells, murine endothelioma cells, human U2OS and STA-ET2.1 cells, but not primary human fibroblasts. The jin-mutants rely on the presence of sialic acid residues on the cell surface for productive infection, as is evident from wheat germ agglutinin (WGA) inhibition experiments, and from the jin-reovirus resistance of CHO-Lec2 cells, which have a deficiency of sialic-acids on their glycoproteins. The jin mutants may be useful as oncolytic agents for use in tumors in which JAM-A is absent or inaccessible. PMID- 23110176 TI - The effect of insulin, TNFalpha and DHA on the proliferation, differentiation and lipolysis of preadipocytes isolated from large yellow croaker (Pseudosciaena Crocea R.). AB - Fish final product can be affected by excessive lipid accumulation. Therefore, it is important to develop strategies to control obesity in cultivated fish to strengthen the sustainability of the aquaculture industry. As in mammals, the development of adiposity in fish depends on hormonal, cytokine and dietary factors. In this study, we investigated the proliferation and differentiation of preadipocytes isolated from the large yellow croaker and examined the effects of critical factors such as insulin, TNFalpha and DHA on the proliferation, differentiation and lipolysis of adipocytes. Preadipocytes were isolated by collagenase digestion, after which their proliferation was evaluated. The differentiation process was optimized by assaying glycerol-3-phosphate dehydrogenase (GPDH) activity. Oil red O staining and electron microscopy were performed to visualize the accumulated triacylglycerol. Gene transcript levels were measured using SYBR green quantitative real-time PCR. Insulin promoted preadipocytes proliferation, stimulated cell differentiation and decreased lipolysis of mature adipocytes. TNFalpha and DHA inhibited cell proliferation and differentiation. While TNFalpha stimulated mature adipocyte lipolysis, DHA showed no lipolytic effect on adipocytes. The expressions of adipose triglyceride lipase (ATGL), fatty acid synthase (FAS), lipoprotein lipase (LPL) and peroxisome proliferator-activated receptor alpha, gamma (PPARalpha, PPARgamma) were quantified during preadipocytes differentiation and adipocytes lipolysis to partly explain the regulation mechanisms. In summary, the results of this study indicated that although preadipocytes proliferation and the differentiation process in large yellow croaker are similar to these processes in mammals, the effects of critical factors such as insulin, TNFalpha and DHA on fish adipocytes development are not exactly the same. Our findings fill in the gaps in the basic data regarding the effects of critical factors on adiposity development in fish and will facilitate the further study of molecular mechanism by which these factors act in fish and the application of this knowledge to eventually control obesity in cultured species. PMID- 23110178 TI - A new approach for assessing sleep duration and postures from ambulatory accelerometry. AB - Interest in the effects of sleeping behavior on health and performance is continuously increasing-both in research and with the general public. Ecologically valid investigations of this research topic necessitate the measurement of sleep within people's natural living contexts. We present evidence that a new approach for ambulatory accelerometry data offers a convenient, reliable, and valid measurement of both people's sleeping duration and quality in their natural environment. Ninety-two participants (14-83 years) wore acceleration sensors on the sternum and right thigh while spending the night in their natural environment and following their normal routine. Physical activity, body posture, and change in body posture during the night were classified using a newly developed classification algorithm based on angular changes of body axes. The duration of supine posture and objective indicators of sleep quality showed convergent validity with self-reports of sleep duration and quality as well as external validity regarding expected age differences. The algorithms for classifying sleep postures and posture changes very reliably distinguished postures with 99.7% accuracy. We conclude that the new algorithm based on body posture classification using ambulatory accelerometry data offers a feasible and ecologically valid approach to monitor sleeping behavior in sizable and heterogeneous samples at home. PMID- 23110177 TI - Microstructural damage of the posterior corpus callosum contributes to the clinical severity of neglect. AB - One theory to account for neglect symptoms in patients with right focal damage invokes a release of inhibition of the right parietal cortex over the left parieto-frontal circuits, by disconnection mechanism. This theory is supported by transcranial magnetic stimulation studies showing the existence of asymmetric inhibitory interactions between the left and right posterior parietal cortex, with a right hemispheric advantage. These inhibitory mechanisms are mediated by direct transcallosal projections located in the posterior portions of the corpus callosum. The current study, using diffusion imaging and tract-based spatial statistics (TBSS), aims at assessing, in a data-driven fashion, the contribution of structural disconnection between hemispheres in determining the presence and severity of neglect. Eleven patients with right acute stroke and 11 healthy matched controls underwent MRI at 3T, including diffusion imaging, and T1 weighted volumes. TBSS was modified to account for the presence of the lesion and used to assess the presence and extension of changes in diffusion indices of microscopic white matter integrity in the left hemisphere of patients compared to controls, and to investigate, by correlation analysis, whether this damage might account for the presence and severity of patients' neglect, as assessed by the Behavioural Inattention Test (BIT). None of the patients had any macroscopic abnormality in the left hemisphere; however, 3 cases were discarded due to image artefacts in the MRI data. Conversely, TBSS analysis revealed widespread changes in diffusion indices in most of their left hemisphere tracts, with a predominant involvement of the corpus callosum and its projections on the parietal white matter. A region of association between patients' scores at BIT and brain FA values was found in the posterior part of the corpus callosum. This study strongly supports the hypothesis of a major role of structural disconnection between the right and left parietal cortex in determining 'neglect'. PMID- 23110180 TI - Metacommunity composition of web-spiders in a fragmented neotropical forest: relative importance of environmental and spatial effects. AB - The distribution of beta diversity is shaped by factors linked to environmental and spatial control. The relative importance of both processes in structuring spider metacommunities has not yet been investigated in the Atlantic Forest. The variance explained by purely environmental, spatially structured environmental, and purely spatial components was compared for a metacommunity of web spiders. The study was carried out in 16 patches of Atlantic Forest in southern Brazil. Field work was done in one landscape mosaic representing a slight gradient of urbanization. Environmental variables encompassed plot- and patch-level measurements and a climatic matrix, while principal coordinates of neighbor matrices (PCNMs) acted as spatial variables. A forward selection procedure was carried out to select environmental and spatial variables influencing web-spider beta diversity. Variation partitioning was used to estimate the contribution of pure environmental and pure spatial effects and their shared influence on beta diversity patterns, and to estimate the relative importance of selected environmental variables. Three environmental variables (bush density, land use in the surroundings of patches, and shape of patches) and two spatial variables were selected by forward selection procedures. Variation partitioning revealed that 15% of the variation of beta diversity was explained by a combination of environmental and PCNM variables. Most of this variation (12%) corresponded to pure environmental and spatially environmental structure. The data indicated that (1) spatial legacy was not important in explaining the web-spider beta diversity; (2) environmental predictors explained a significant portion of the variation in web-spider composition; (3) one-third of environmental variation was due to a spatial structure that jointly explains variation in species distributions. We were able to detect important factors related to matrix management influencing the web-spider beta-diversity patterns, which are probably linked to historical deforestation events. PMID- 23110179 TI - Adenoviral vectors stimulate glucagon transcription in human mesenchymal stem cells expressing pancreatic transcription factors. AB - Viral gene carriers are being widely used as gene transfer systems in (trans)differentiation and reprogramming strategies. Forced expression of key regulators of pancreatic differentiation in stem cells, liver cells, pancreatic duct cells, or cells from the exocrine pancreas, can lead to the initiation of endocrine pancreatic differentiation. While several viral vector systems have been employed in such studies, the results reported with adenovirus vectors have been the most promising in vitro and in vivo. In this study, we examined whether the viral vector system itself could impact the differentiation capacity of human bone-marrow derived mesenchymal stem cells (hMSCs) toward the endocrine lineage. Lentivirus-mediated expression of Pdx-1, Ngn-3, and Maf-A alone or in combination does not lead to robust expression of any of the endocrine hormones (i.e. insulin, glucagon and somatostatin) in hMSCs. Remarkably, subsequent transduction of these genetically modified cells with an irrelevant early region 1 (E1) deleted adenoviral vector potentiates the differentiation stimulus and promotes glucagon gene expression in hMSCs by affecting the chromatin structure. This adenovirus stimulation was observed upon infection with an E1-deleted adenovirus vector, but not after exposure to helper-dependent adenovirus vectors, pointing at the involvement of genes retained in the E1-deleted adenovirus vector in this phenomenon. Lentivirus mediated expression of the adenovirus E4-ORF3 mimics the adenovirus effect. From these data we conclude that E1-deleted adenoviral vectors are not inert gene-transfer vectors and contribute to the modulation of the cellular differentiation pathways. PMID- 23110181 TI - Investigating cell-ECM contact changes in response to hypoosmotic stimulation of hepatocytes in vivo with DW-RICM. AB - Hepatocyte volume regulation has been shown to play an important role in cellular metabolism, proliferation, viability and especially in hepatic functions such as bile formation and proteolysis. Recent studies on liver explants led to the assumption that cell volume changes present a trigger for outside-in signaling via integrins, a protein family involved in mediating cellular response to binding to the extracellular matrix (ECM). However, it remains elusive how these volume change related signaling events are transducted on a single cell level and how these events are influenced and controlled by ECM interactions. One could speculate that an increase in cell volume leads to an increase in integrin/ECM contacts which causes activation of integrins, which act as mechano-sensors. In order to test this idea, it was an important issue to quantify the cell volume dependence of the contact areas between the cell and the surrounding ECM. In this study we used two wavelength reflection interference contrast microscopy (DW RICM) to directly observe the dynamics of cell-substrate contacts, mimicking cell ECM interactions, in response to a controlled and well-defined volume change induced by hypoosmotic stimulation. This is the first time a non-invasive, label free method is used to uncover a volume change related response of in vitro hepatocytes in real time. The cell cluster analysis we present here agrees well with previous studies on ex vivo whole liver explants. Moreover, we show that the increase in contact area after cell swelling is a reversible process, while the reorganisation of contacts depends on the type of ECM molecules presented to the cells. As our method complements common whole liver studies providing additional insight on a cell cluster level, we expect this technique to be particular suitable for further detailed studies of osmotic stimulation not only in hepatocytes, but also other cell types. PMID- 23110182 TI - Predictive modeling and mapping of Malayan Sun Bear (Helarctos malayanus) distribution using maximum entropy. AB - One of the available tools for mapping the geographical distribution and potential suitable habitats is species distribution models. These techniques are very helpful for finding poorly known distributions of species in poorly sampled areas, such as the tropics. Maximum Entropy (MaxEnt) is a recently developed modeling method that can be successfully calibrated using a relatively small number of records. In this research, the MaxEnt model was applied to describe the distribution and identify the key factors shaping the potential distribution of the vulnerable Malayan Sun Bear (Helarctos malayanus) in one of the main remaining habitats in Peninsular Malaysia. MaxEnt results showed that even though Malaysian sun bear habitat is tied with tropical evergreen forests, it lives in a marginal threshold of bio-climatic variables. On the other hand, current protected area networks within Peninsular Malaysia do not cover most of the sun bears potential suitable habitats. Assuming that the predicted suitability map covers sun bears actual distribution, future climate change, forest degradation and illegal hunting could potentially severely affect the sun bear's population. PMID- 23110183 TI - Quantitative 3.0T MR spectroscopy reveals decreased creatine concentration in the dorsolateral prefrontal cortex of patients with social anxiety disorder. AB - BACKGROUND: The brain biochemical changes of social anxiety have not been clarified although there have been a limited number of MR spectroscopic studies which utilized metabolite/creatine ratios. Present study aimed to explore the alteration of absolute metabolite concentration in social anxiety disorder using quantitative MR spectroscopy. MATERIALS AND METHODS: With a 3.0T MR scanner, single voxel MR spectroscopy (stimulated echo acquisition mode, TR/TE/TM = 2000/20/16 ms) was performed in the left dorsolateral prefrontal cortex and related regions of nine medication-free patients with social anxiety disorder and nine controls. Absolute metabolite concentration was calculated using tissue water as the internal reference and corrected for the partial volume of cerebrospinal fluid. RESULTS: In the left dorsolateral prefrontal cortex, the N acetyl aspartate/creatine ratio of patients was significantly higher than that of controls, and this was due to the decrease of creatine concentration instead of the increase of N-acetyl aspartate concentration. Furthermore, the creatine concentration of the left dorsolateral prefrontal cortex was negatively correlated with the scores of Liebowitz social anxiety scale. CONCLUSIONS: The alteration of creatine level in the left dorsolateral prefrontal cortex suggests abnormal energy metabolism and correlates with symptom severity in social anxiety disorder. And metabolite concentration is preferable to metabolite/creatine ratio for the investigation of individual, absolute metabolite changes in this region of social anxiety disorder. PMID- 23110184 TI - Natural transmission of Plasmodium berghei exacerbates chronic tuberculosis in an experimental co-infection model. AB - Human populations are rarely exposed to one pathogen alone. Particularly in high incidence regions such as sub-Saharan Africa, concurrent infections with more than one pathogen represent a widely underappreciated public health problem. Two of the world's most notorious killers, malaria and tuberculosis, are co-endemic in impoverished populations in the tropics. However, interactions between both infections in a co-infected individual have not been studied in detail. Both pathogens have a major impact on the lung as the prime target organ for aerogenic Mycobacterium tuberculosis and the site for one of the main complications in severe malaria, malaria-associated acute respiratory distress syndrome (MA-ARDS). In order to study the ramifications caused by both infections within the same host we established an experimental mouse model of co-infection between Mycobacterium tuberculosis and Plasmodium berghei NK65, a recently described model for MA-ARDS. Our study provides evidence that malaria-induced immune responses impair host resistance to Mycobacterium tuberculosis. Using the natural routes of infection, we observed that co-infection exacerbated chronic tuberculosis while rendering mice less refractory to Plasmodium. Co-infected animals presented with enhanced inflammatory immune responses as reflected by exacerbated leukocyte infiltrates, tissue pathology and hypercytokinemia accompanied by altered T-cell responses. Our results--demonstrating striking changes in the immune regulation by co-infection with Plasmodium and Mycobacterium--are highly relevant for the medical management of both infections in humans. PMID- 23110185 TI - Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. AB - Neutrophils (PMNs) and cytokines have a critical role to play in host defense and systemic inflammatory response syndrome (SIRS). Neutrophil extracellular traps (NETs) have been shown to extracellularly kill pathogens, and inflammatory potential of NETs has been shown. Microbial killing inside the phagosomes or by NETs is mediated by reactive oxygen and nitrogen species (ROS/RNS). The present study was undertaken to assess circulating NETs contents and frequency of NETs generation by isolated PMNs from SIRS patients. These patients displayed significant augmentation in the circulating myeloperoxidase (MPO) activity and DNA content, while PMA stimulated PMNs from these patients, generated more free radicals and NETs. Plasma obtained from SIRS patients, if added to the PMNs isolated from healthy subjects, enhanced NETs release and free radical formation. Expressions of inflammatory cytokines (IL-1beta, TNFalpha and IL-8) in the PMNs as well as their circulating levels were significantly augmented in SIRS subjects. Treatment of neutrophils from healthy subjects with TNFalpha, IL-1beta, or IL-8 enhanced free radicals generation and NETs formation, which was mediated through the activation of NADPH oxidase and MPO. Pre-incubation of plasma from SIRS with TNFalpha, IL-1beta, or IL-8 antibodies reduced the NETs release. Role of IL-1beta, TNFalpha and IL-8 thus seems to be involved in the enhanced release of NETs in SIRS subjects. PMID- 23110186 TI - Limited T cell receptor repertoire diversity in tuberculosis patients correlates with clinical severity. AB - BACKGROUND: The importance of CD4+ and CD8+ T cells in protection against tuberculosis (TB) is well known, however, the association between changes to the T cell repertoire and disease presentation has never been analyzed. Characterization of T-cells in TB patients in previous study only analyzed the TCR beta chain and omitted analysis of the Valpha family even though alpha chain also contribute to antigen recognition. Furthermore, limited information is available regarding the heterogeneity compartment and overall function of the T cells in TB patients as well as the common TCR structural features of Mtb antigen specific T cells among the vast numbers of TB patients. METHODOLOGY/PRINCIPAL FINDINGS: CDR3 spectratypes of CD4+ and CD8+ T cells were analyzed from 86 patients with TB exhibiting differing degrees of disease severity, and CDR3 spectratype complexity scoring system was used to characterize TCR repertoire diversity. TB patients with history of other chronic disease and other bacterial or viral infections were excluded for the study to decrease the likely contribution of TCRs specific to non-TB antigens as far as possible. Each patient was age-matched with a healthy donor group to control for age variability. Results showed that healthy controls had a normally diversified TCR repertoire while TB patients represented with restricted TCR repertoire. Patients with mild disease had the highest diversity of TCR repertoire while severely infected patients had the lowest, which suggest TCR repertoire diversity inversely correlates with disease severity. In addition, TB patients showed preferred usage of certain TCR types and have a bias in the usage of variable (V) and joining (J) gene segments and N nucleotide insertions. CONCLUSIONS/SIGNIFICANCE: Results from this study promote a better knowledge about the public characteristics of T cells among TB patients and provides new insight into the TCR repertoire associated with clinic presentation in TB patients. PMID- 23110187 TI - Seroprevalence of fecal-oral transmitted hepatitis A and E virus antibodies in Burkina Faso. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) infections occur chiefly as a result of unhygienic conditions. The purpose of this study was to assess the seroprevalence of antibodies to both viruses in central Burkina Faso in the absence of a recorded hepatitis epidemic. Serum samples from 178 blood donors (131 males and 47 females) and from 189 pregnant women were collected from November 2010 to March 2012, at blood banks and medical centers in Burkina Faso. An immunochromatography test was used to screen for Anti-HAV IgM and IgG in a subgroup of 91 blood donors and 100 pregnant women. The seroprevalence of anti HAV IgG was 14.3% [CI95, 7.1-21.4%] for all blood donors and 23% [CI95, 14.8 31.2%] for pregnant women. Anti-HEV IgG were detected using the ELISA kits Dia.pro and Wantai and were found in 19.1% [CI95, 13.3-24.9%] of the blood donors and 11.6% [CI95, 7.1-16.2%] of the pregnant women. The seroprevalences of anti HAV and anti-HEV IgGs did not differ significantly between men and women blood donors. Anti-HAV IgM was detected in 3.3% of the blood donors and in 2% of the pregnant women. These findings for asymptomatic individuals indicate that the HAV and HEV circulate at low but significant levels. This is the first evaluation of the acute hepatitis virus burden in Burkina Faso and the underlying epidemiologic status of the population. PMID- 23110188 TI - Processes underlying the nutritional programming of embryonic development by iron deficiency in the rat. AB - Poor iron status is a global health issue, affecting two thirds of the world population to some degree. It is a particular problem among pregnant women, in both developed and developing countries. Feeding pregnant rats a diet deficient in iron is associated with both hypertension and reduced nephron endowment in adult male offspring. However, the mechanistic pathway leading from iron deficiency to fetal kidney development remains elusive. This study aimed to establish the underlying processes associated with iron deficiency by assessing gene and protein expression changes in the rat embryo, focussing on the responses occurring at the time of the nutritional insult. Analysis of microarray data showed that iron deficiency in utero resulted in the significant up-regulation of 979 genes and down-regulation of 1545 genes in male rat embryos (d13). Affected processes associated with these genes included the initiation of mitosis, BAD mediated apoptosis, the assembly of RNA polymerase II preinitiation complexes and WNT signalling. Proteomic analyses highlighted 7 proteins demonstrating significant up-regulation with iron deficiency and the down-regulation of 11 proteins. The main functions of these key proteins included cell proliferation, protein transport and folding, cytoskeletal remodelling and the proteasome complex. In line with our recent work, which identified the perturbation of the proteasome complex as a generalised response to in utero malnutrition, we propose that iron deficiency alone leads to a more specific failure in correct protein folding and transport. Such an imbalance in this delicate quality-control system can lead to cellular dysfunction and apoptosis. Therefore these findings offer an insight into the underlying mechanisms associated with the development of the embryo during conditions of poor iron status, and its health in adult life. PMID- 23110189 TI - Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome. AB - Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment ("waitlist"), placebo treatment alone ("limited") and, placebo treatment "augmented" with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response. PMID- 23110190 TI - IL-4 haplotype -590T, -34T and intron-3 VNTR R2 is associated with reduced malaria risk among ancestral indian tribal populations. AB - BACKGROUND: Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between T(H)1 and T(H)2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases. METHODS: We have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese). RESULTS: The -590T, -34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for 590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r2>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (chi23 = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%). CONCLUSIONS: Our study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection. PMID- 23110191 TI - High risk HPV contamination of endocavity vaginal ultrasound probes: an underestimated route of nosocomial infection? AB - BACKGROUND: Endocavity ultrasound is seen as a harmless procedure and has become a common gynaecological procedure. However without correct disinfection, it may result in nosocomial transmission of genito-urinary pathogens, such as high-risk Human Papillomavirus (HR-HPV). We aimed to evaluate the currently recommended disinfection procedure for covered endocavity ultrasound probes, which consists of "Low Level Disinfection" (LLD) with "quaternary ammonium compounds" containing wipes. METHODS: From May to October 2011 swabs were taken from endovaginal ultrasound probes at the Gynecology Department of the Lyon University Hospital. During the first phase (May-June 2011) samples were taken after the ultrasound examination and after the LLD procedure. In a second phase (July-October 2011) swab samples were collected just before the probe was used. All samples were tested for the presence of human DNA (as a marker for a possible transmission of infectious pathogens from the genital tract) and HPV DNA with the Genomica DNA microarray (35 different HPV genotypes). RESULTS: We collected 217 samples before and 200 samples after the ultrasound examination. The PCR was inhibited in two cases. Human DNA was detected in 36 (18%) post-examination samples and 61 (28%) pre-examination samples. After the ultrasound LLD procedure, 6 (3.0%) samples contained HR-HPV types (16, 31, 2*53 and 58). Similarly, HPV was detected in 6 pre-examination samples (2.7%). Amongst these 4 (1.9%) contained HR-HPV (types 53 and 70). CONCLUSION: Our study reveals that a considerable number of ultrasound probes are contaminated with human and HR-HPV DNA, despite LLD disinfection and probe cover. In all hospitals, where LLD is performed, the endovaginal ultrasound procedure must therefore be considered a source for nosocomial HR-HPV infections. We recommend the stringent use of high-level disinfectants, such as glutaraldehyde or hydrogen peroxide solutions. PMID- 23110192 TI - Genome-wide SNP discovery from transcriptome of four common carp strains. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) have been used as genetic marker for genome-wide association studies in many species. Gene-associated SNPs could offer sufficient coverage in trait related research and further more could themselves be causative SNPs for traits. Common carp (Cyprinus carpio) is one of the most important aquaculture species in the world accounting for nearly 14% of freshwater aquaculture production. There are various strains of common carp with different economic traits, however, the genetic mechanism underlying the different traits have not been elucidated yet. In this project, we identified a large number of gene-associated SNPs from four strains of common carp using next generation sequencing. RESULTS: Transcriptome sequencing of four strains of common carp (mirror carp, purse red carp, Xingguo red carp, Yellow River carp) was performed with Solexa HiSeq2000 platform. De novo assembled transcriptome was used as reference for alignments, and SNP calling was done through BWA and SAMtools. A total of 712,042 Intra-strain SNPs were discovered in four strains, of which 483,276 SNPs for mirror carp, 486,629 SNPs for purse red carp, 478,028 SNPs for Xingguo red carp and 488,281 SNPs for Yellow River carp were discovered, respectively. Besides, 53,893 inter-SNPs were identified. Strain-specific SNPs of four strains were 53,938, 53,866, 48,701, 40,131 in mirror carp, purse red carp, Xingguo red carp and Yellow River carp, respectively. GO and KEGG pathway analysis were done to reveal strain-specific genes affected by strain-specific non-synonymous SNPs. Validation of selected SNPs revealed that 48% percent of SNPs (12 of 25) were tested to be true SNPs. CONCLUSIONS: Transcriptome analysis of common carp using RNA-Seq is a cost-effective way of generating numerous reads for SNP discovery. After validation of identified SNPs, these data will provide a solid base for SNP array designing and genome-wide association studies. PMID- 23110193 TI - Tin oxide nanowires suppress herpes simplex virus-1 entry and cell-to-cell membrane fusion. AB - The advent of nanotechnology has ushered in the use of modified nanoparticles as potential antiviral agents against diseases such as herpes simplex virus 1 and 2 (HSV-1) (HSV-2), human immunodeficiency virus (HIV), monkeypox virus, and hepatitis B virus. Here we describe the application of tin oxide (SnO(2)) nanowires as an effective treatment against HSV-1 infection. SnO(2) nanowires work as a carrier of negatively charged structures that compete with HSV-1 attachment to cell bound heparan sulfate (HS), therefore inhibiting entry and subsequent cell-to-cell spread. This promising new approach can be developed into a novel form of broad-spectrum antiviral therapy especially since HS has been shown to serve as a cellular co-receptor for a number of other viruses as well, including the respiratory syncytial virus, adeno-associated virus type 2, and human papilloma virus. PMID- 23110194 TI - Dimethylarginine dimethylaminohydrolase1 is an organ-specific mediator of end organ damage in a murine model of hypertension. AB - BACKGROUND: The endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) is an independent predictor of cardiovascular and overall mortality. Moreover, elevated ADMA plasma concentrations are associated with the extent of hypertension. However, data from small-sized clinical trials and experimental approaches using murine transgenic models have revealed conflicting results regarding the impact of ADMA and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) in the pathogenesis of hypertension. METHODOLOGY/PRINCIPAL FINDINGS: Therefore, we investigated the role of ADMA and DDAH1 in hypertension-induced end organ damage using the uninephrectomized, deoxycorticosterone actetate salt, and angiotensin II-induced hypertension model in human DDAH1 (hDDAH1) overexpressing and wild-type (WT) mice. ADMA plasma concentrations differed significantly between hDDAH1 and WT mice at baseline, but did not significantly change during the induction of hypertension. hDDAH1 overexpression did not protect against hypertension-induced cardiac fibrosis and hypertrophy. In addition, the hypertension-induced impairment of the endothelium dependent vasorelaxation of aortic segments ex vivo was not significantly attenuated by hDDAH1 overexpression. However, hDDAH1 mice displayed an attenuated hypertensive inflammatory response in renal tissue, resulting in less hypertensive renal injury. CONCLUSION/SIGNIFICANCE: Our data reveal that hDDAH1 organ-specifically modulates the inflammatory response in this murine model of hypertension. The lack of protection in cardiac and aortic tissues may be due to DDAH1 tissue selectivity and/or the extent of hypertension by the used combined model. However, our study underlines the potency of hDDAH1 overexpression in modulating inflammatory processes as a crucial step in the pathogenesis of hypertension, which needs further experimental and clinical investigation. PMID- 23110195 TI - Characterization of porcine aortic valvular interstitial cell 'calcified' nodules. AB - Valve interstitial cells populate aortic valve cusps and have been implicated in aortic valve calcification. Here we investigate a common in vitro model for aortic valve calcification by characterizing nodule formation in porcine aortic valve interstitial cells (PAVICs) cultured in osteogenic (OST) medium supplemented with transforming growth factor beta 1 (TGF-beta1). Using a combination of materials science and biological techniques, we investigate the relevance of PAVICs nodules in modeling the mineralised material produced in calcified aortic valve disease. PAVICs were grown in OST medium supplemented with TGF-beta1 (OST+TGF-beta1) or basal (CTL) medium for up to 21 days. Murine calvarial osteoblasts (MOBs) were grown in OST medium for 28 days as a known mineralizing model for comparison. PAVICs grown in OST+TGF-beta1 produced nodular structures staining positive for calcium content; however, micro-Raman spectroscopy allowed live, noninvasive imaging that showed an absence of mineralized material, which was readily identified in nodules formed by MOBs and has been identified in human valves. Gene expression analysis, immunostaining, and transmission electron microscopy imaging revealed that PAVICs grown in OST+TGF-beta1 medium produced abundant extracellular matrix via the upregulation of the gene for Type I Collagen. PAVICs, nevertheless, did not appear to further transdifferentiate to osteoblasts. Our results demonstrate that 'calcified' nodules formed from PAVICs grown in OST+TGF-beta1 medium do not mineralize after 21 days in culture, but rather they express a myofibroblast-like phenotype and produce a collagen-rich extracellular matrix. This study clarifies further the role of PAVICs as a model of calcification of the human aortic valve. PMID- 23110196 TI - Progression from high insulin resistance to type 2 diabetes does not entail additional visceral adipose tissue inflammation. AB - Obesity is associated with a low-grade chronic inflammation state. As a consequence, adipose tissue expresses pro-inflammatory cytokines that propagate inflammatory responses systemically elsewhere, promoting whole-body insulin resistance and consequential islet beta-cell exhaustation. Thus, insulin resistance is considered the early stage of type 2 diabetes. However, there is evidence of obese individuals that never develop diabetes indicating that the mechanisms governing the association between the increase of inflammatory factors and type 2 diabetes are much more complex and deserve further investigation. We studied for the first time the differences in insulin signalling and inflammatory pathways in blood and visceral adipose tissue (VAT) of 20 lean healthy donors and 40 equal morbidly obese (MO) patients classified in high insulin resistance (high IR) degree and diabetes state. We studied the changes in proinflammatory markers and lipid content from serum; macrophage infiltration, mRNA expression of inflammatory cytokines and transcription factors, activation of kinases involved in inflammation and expression of insulin signalling molecules in VAT. VAT comparison of these experimental groups revealed that type 2 diabetic-MO subjects exhibit the same pro-inflammatory profile than the high IR-MO patients, characterized by elevated levels of IL-1beta, IL-6, TNFalpha, JNK1/2, ERK1/2, STAT3 and NFkappaB. Our work rules out the assumption that the inflammation should be increased in obese people with type 2 diabetes compared to high IR obese. These findings indicate that some mechanisms, other than systemic and VAT inflammation must be involved in the development of type 2 diabetes in obesity. PMID- 23110197 TI - Which factors affect the success or failure of eradication campaigns against alien species? AB - Although issues related to the management of invasive alien species are receiving increasing attention, little is known about which factors affect the likelihood of success of management measures. We applied two data mining techniques, classification trees and boosted trees, to identify factors that relate to the success of management campaigns aimed at eradicating invasive alien invertebrates, plants and plant pathogens. We assembled a dataset of 173 different eradication campaigns against 94 species worldwide, about a half of which (50.9%) were successful. Eradications in man-made habitats, greenhouses in particular, were more likely to succeed than those in (semi-)natural habitats. In man-made habitats the probability of success was generally high in Australasia, while in Europe and the Americas it was higher for local infestations that are easier to deal with, and for international campaigns that are likely to profit from cross-border cooperation. In (semi-) natural habitats, eradication campaigns were more likely to succeed for plants introduced as an ornamental and escaped from cultivation prior to invasion. Averaging out all other factors in boosted trees, pathogens, bacteria and viruses were most, and fungi the least likely to be eradicated; for plants and invertebrates the probability was intermediate. Our analysis indicates that initiating the campaign before the extent of infestation reaches the critical threshold, starting to eradicate within the first four years since the problem has been noticed, paying special attention to species introduced by the cultivation pathway, and applying sanitary measures can substantially increase the probability of eradication success. Our investigations also revealed that information on socioeconomic factors, which are often considered to be crucial for eradication success, is rarely available, and thus their relative importance cannot be evaluated. Future campaigns should carefully document socioeconomic factors to enable tests of their importance. PMID- 23110198 TI - Search query data to monitor interest in behavior change: application for public health. AB - There is a need for effective interventions and policies that target the leading preventable causes of death in the U.S. (e.g., smoking, overweight/obesity, physical inactivity). Such efforts could be aided by the use of publicly available, real-time search query data that illustrate times and locations of high and low public interest in behaviors related to preventable causes of death. OBJECTIVES: This study explored patterns of search query activity for the terms 'weight', 'diet', 'fitness', and 'smoking' using Google Insights for Search. METHODS: Search activity for 'weight', 'diet', 'fitness', and 'smoking' conducted within the United States via Google between January 4(th), 2004 (first date data was available) and November 28(th), 2011 (date of data download and analysis) were analyzed. Using a generalized linear model, we explored the effects of time (month) on mean relative search volume for all four terms. RESULTS: Models suggest a significant effect of month on mean search volume for all four terms. Search activity for all four terms was highest in January with observable declines throughout the remainder of the year. CONCLUSIONS: These findings demonstrate discernable temporal patterns of search activity for four areas of behavior change. These findings could be used to inform the timing, location and messaging of interventions, campaigns and policies targeting these behaviors. PMID- 23110199 TI - Forkhead box M1 (FoxM1) gene is a new STAT3 transcriptional factor target and is essential for proliferation, survival and DNA repair of K562 cell line. AB - The forkhead box (Fox) M1 gene belongs to a superfamily of evolutionarily conserved transcriptional regulators that are involved in a wide range of biological processes, and its deregulation has been implicated in cancer survival, proliferation and chemotherapy resistance. However, the role of FoxM1, the signaling involved in its activation and its role in leukemia are poorly known. Here, we demonstrate by gene promoter analysis, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays that FoxM1 is a new target of the STAT3 transcriptional activator. Additionally, FoxM1 is transcriptionally dependent on STAT3 signaling activation. Furthermore, we verified that FoxM1 is crucial for K562 cell proliferation, cell cycle checkpoints and viability and could be related to chemotherapeutic resistance. By microarray analysis, we determined the signaling pathways related to FoxM1 expression and its role in DNA repair using K562 cells. Our results revealed new signaling involved in FoxM1 expression and its role in leukemic cells that elucidate cellular mechanisms associated with the development of leukemia and disease progression. PMID- 23110200 TI - Induced pluripotent stem cells generated from human adipose-derived stem cells using a non-viral polycistronic plasmid in feeder-free conditions. AB - Induced pluripotent stem cells (iPSCs) can be generated from somatic cells by ectopic expression of defined transcription factors (TFs). However, the optimal cell type and the easy reprogramming approaches that minimize genetic aberrations of parent cells must be considered before generating the iPSCs. This paper reports a method to generate iPSCs from adult human adipose-derived stem cells (hADSCs) without the use of a feeder layer, by ectopic expression of the defined transcription factors OCT4, SOX2, KLF4 and C-MYC using a polycistronic plasmid. The results, based on the expression of pluripotent marker, demonstrated that the iPSCs have the characteristics similar to those of embryonic stem cells (ESCs). The iPSCs differentiated into three embryonic germ layers both in vitro by embryoid body generation and in vivo by teratoma formation after being injected into immunodeficient mice. More importantly, the plasmid DNA does not integrate into the genome of human iPSCs as revealed by Southern blotting experiments. Karyotypic analysis also demonstrated that the reprogramming of hADSCs by the defined factors did not induce chromosomal abnormalities. Therefore, this technology provides a platform for studying the biology of iPSCs without viral vectors, and can hopefully overcome immune rejection and ethical concerns, which are the two important barriers of ESC applications. PMID- 23110201 TI - Increased expression of intranuclear matrix metalloproteinase 9 in atrophic renal tubules is associated with renal fibrosis. AB - BACKGROUND: Reduced turnover of extracellular matrix has a role in renal fibrosis. Matrix metalloproteinases (MMPs) is associated with many glomerular diseases, but the histological association of MMPs and human renal fibrosis is unclear. METHODS: This is a retrospective study. Institutional Review Board approval was obtained for the review of patients' medical records, data analysis and pathological specimens staining with waiver of informed consents. Specimens of forty-six patients were examined by immunohistochemical stain of MMP-9 in nephrectomized kidneys, and the association of renal expression of MMP-9 and renal fibrosis was determined. MMP-9 expression in individual renal components and fibrosis was graded as high or low based on MMP-9 staining and fibrotic scores. RESULTS: Patients with high interstitial fibrosis scores (IFS) and glomerular fibrosis scores (GFS) had significantly higher serum creatinine, lower estimated glomerular filtration rate (eGFR), and were more likely to have chronic kidney disease (CKD) and urothelial cell carcinoma. Univariate analysis showed that IFS and GFS were negatively associated with normal and atrophic tubular cytoplasmic MMP-9 expression and IFS was positively correlated with atrophic tubular nuclear MMP-9 expression. Multivariate stepwise regression indicated that MMP-9 expression in atrophic tubular nuclei (r = 0.4, p = 0.002) was an independent predictor of IFS, and that MMP-9 expression in normal tubular cytoplasm (r = -0.465, p<0.001) was an independent predictor of GFS. CONCLUSIONS: Interstitial fibrosis correlated with MMP-9 expression in the atrophic tubular nuclei. Our results indicate that renal fibrosis is associated with a decline of MMP-9 expression in the cytoplasm of normal tubular cells and increased expression of MMP-9 in the nuclei of tubular atrophic renal tubules. PMID- 23110202 TI - Peripheral blood invariant natural killer T cells of pig-tailed macaques. AB - In humans, invariant natural killer T (iNKT) cells represent a small but significant population of peripheral blood mononuclear cells (PBMCs) with a high degree of variability. In this study, pursuant to our goal of identifying an appropriate non-human primate model suitable for pre-clinical glycolipid testing, we evaluated the percentage and function of iNKT cells in the peripheral blood of pig-tailed macaques. First, using a human CD1d-tetramer loaded with alpha-GalCer (alpha-GalCer-CD1d-Tet), we found that alpha-GalCer-CD1d-Tet(+) CD3(+) iNKT cells make up 0.13% to 0.4% of pig-tailed macaque PBMCs, which are comparable to the percentage of iNKT cells found in human PBMCs. Second, we observed that a large proportion of Valpha24(+)CD3(+) cells are alpha-GalCer-CD1d-Tet(+)CD3(+) iNKT cells, which primarily consist of either the CD4(+) or CD8(+) subpopulation. Third, we found that pig-tailed macaque iNKT cells produce IFN-gamma in response to alpha-GalCer, as shown by ELISpot assay and intracellular cytokine staining (ICCS), as well as TNF-alpha, as shown by ICCS, indicating that these iNKT cells are fully functional. Interestingly, the majority of pig-tailed macaque iNKT cells that secrete IFN-gamma are CD8(+)iNKT cells. Based on these findings, we conclude that the pig-tailed macaques exhibit potential as a non-human animal model for the pre-clinical testing of iNKT-stimulating glycolipids. PMID- 23110203 TI - Efficient detection of Mediterranean beta-thalassemia mutations by multiplex single-nucleotide primer extension. AB - beta-Thalassemias and abnormal hemoglobin variants are among the most common hereditary abnormalities in humans. Molecular characterization of the causative genetic variants is an essential part of the diagnostic process. In geographic areas with high hemoglobinopathy prevalence, such as the Mediterranean region, a limited number of genetic variants are responsible for the majority of hemoglobinopathy cases. Developing reliable, rapid and cost-effective mutation specific molecular diagnostic assays targeting particular populations greatly facilitates routine hemoglobinopathy investigations. We developed a one-tube single-nucleotide primer extension assay for the detection of eight common Mediterranean beta-thalassemia mutations: Codon 5 (-CT); CCT(Pro)->C-, Codon 6 ( A); GAG(Glu)->G-G, Codon 8 (-AA); AAG(Lys)->-G, IVS-I-1 (G->A), IVS-I-6 (T->C), IVS-I-110 (G->A), Codon 39 (C->T), and IVS-II-745 (C->G), as well as the hemoglobin S variant beta 6(A3) Glu>Val. We validated the new assay using previously genotyped samples obtaining 100% agreement between independent genotyping methods. Our approach, applicable in a range of Mediterranean countries, offers a combination of high accuracy and rapidity exploiting standard techniques and widely available equipment. It can be further adapted to particular populations by including/excluding assayed mutations. We facilitate future modifications by providing detailed information on assay design. PMID- 23110204 TI - Soybeans grown in the Chernobyl area produce fertile seeds that have increased heavy metal resistance and modified carbon metabolism. AB - Plants grow and reproduce in the radioactive Chernobyl area, however there has been no comprehensive characterization of these activities. Herein we report that life in this radioactive environment has led to alteration of the developing soybean seed proteome in a specific way that resulted in the production of fertile seeds with low levels of oil and beta-conglycinin seed storage proteins. Soybean seeds were harvested at four, five, and six weeks after flowering, and at maturity from plants grown in either non-radioactive or radioactive plots in the Chernobyl area. The abundance of 211 proteins was determined. The results confirmed previous data indicating that alterations in the proteome include adaptation to heavy metal stress and mobilization of seed storage proteins. The results also suggest that there have been adjustments to carbon metabolism in the cytoplasm and plastids, increased activity of the tricarboxylic acid cycle, and decreased condensation of malonyl-acyl carrier protein during fatty acid biosynthesis. PMID- 23110205 TI - Molecular analysis of RNF213 gene for moyamoya disease in the Chinese Han population. AB - BACKGROUND: Moyamoya disease (MMD) is an uncommon cerebrovascular disorder characterized by progressive occlusion of the internal carotid artery causing cerebral ischemia and hemorrhage. Genetic factors in the etiology and pathogenesis of MMD are being increasingly recognized. Previous studies have shown that the RNF213 gene was related to MMD susceptibility in the Japanese population. However, there is no large scale study of the association between this gene and MMD in the Chinese Han population. Thus we designed this case control study to validate the R4810K mutation and to define the further spectrum of RNF213 mutations in Han Chinese. METHODOLOGY/PRINCIPAL FINDINGS: Genotyping of the R4810K mutation in the RNF213 gene was performed in 170 MMD cases and 507 controls from a Chinese Han population. The R4810K mutation was identified in 22 of 170 MMD cases (13%), including 21 heterozygotes and a single familial homozygote. Two of the 507 controls (0.4%) were heterozygous R4810K carriers. The R4810K mutation greatly increased the risk for MMD (OR = 36.7, 95% CI: 8.6~156.6, P = 6.1 E-15). The allele frequency of R4810K was significantly different between patients with ischemia and hemorrhage (OR = 5.4, 95% CI: 1.8~16.1, P = 0.001). Genomic sequencing covering RNF213 exon 40 to exon 68 also identified eight other non-R4810K variants; P4007R, Q4367L, A4399T, T4586P, L4631V, E4950D, A5021V and M5136I. Among them A4399T polymorphism was found in 28/170 cases (16.5%) and 45/507 controls (8.9%) and was associated with MMD (OR = 2.0, 95% CI: 1.2~3.3, P = 0.004), especially with hemorrhage (OR = 2.8, 95% CI: 1.2~6.5, P = 0.014). CONCLUSIONS: RNF213 mutations are associated with MMD susceptibility in Han Chinese. The ischemic type MMD is particularly related to the R4810K mutation. However, A4399T is also a susceptible variant for MMD, primarily associated with hemorrhage. Identification of novel variants in the RNF213 gene further highlights the genetic heterogeneity of MMD. PMID- 23110206 TI - Loss of RBPj in postnatal excitatory neurons does not cause neurodegeneration or memory impairments in aged mice. AB - Previous studies suggest that loss of gamma-secretase activity in postnatal mouse brains causes age-dependent memory impairment and neurodegeneration. Due to the diverse array of gamma-secretase substrates, it remains to be demonstrated whether loss of cleavage of any specific substrate(s) is responsible for these defects. The bulk of the phenotypes observed in mammals deficient for gamma secretase or exposed to gamma-secretase inhibitors are caused by the loss of Notch receptor proteolysis. Accordingly, inhibition of Notch signaling is the main cause for untoward effects for gamma-secretase inhibitors as therapeutics for Alzheimer's disease. Therefore, we wished to determine if loss of canonical Notch signaling is responsible for the age-dependent neurodegeneration observed upon gamma-secrectase deficiency in the mouse brain. We generated postnatal forebrain-specific RBPj conditional knockout (cKO) mice using the CamKII-Cre driver and examined behavior and brain pathology in 12-18 month old animals. Since all four mammalian Notch receptor homologues signal via this DNA binding protein, these mice lack canonical Notch signaling. We found that loss of RBPj in mature excitatory neurons was well tolerated, with no evidence for neurodegeneration or of learning and memory impairment in mice aged up to 18 months. The only phenotypic deficit we observed in the RBPj-deficient mice was a subtle abnormality in olfactory preferences, particularly in females. We conclude that the loss of canonical Notch signaling through the four receptors is not responsible for age-dependent neurodegeneration or learning and memory deficits seen in gamma-secretase deficient mice. PMID- 23110207 TI - Chronic activation of the G protein-coupled receptor 30 with agonist G-1 attenuates heart failure. AB - G protein-coupled receptor (GPR) 30 is a novel estrogen receptor. Recent studies suggest that activation of the GPR30 confers rapid cardioprotection in isolated rat heart. It is unknown whether chronic activation of GPR30 is beneficial or not for heart failure. In this study we investigated the cardiac effect of sustained activation or inhibition of GPR30. Female Sprague-Dawley rats were divided into 7 groups #2Q1: sham surgery (Sham), bilateral ovariectomy (OVX), OVX+estrogen (E(2)), OVX+isoproterenol (ISO), OVX+ISO+G-1, OVX+ISO+E(2)+G15, OVX+ISO+E(2). ISO (85 mg/kg*17 day, sc) was given to make the heart failure models. G-1(120 ug/kg.d*14 day) was used to activate GPR30 and G15 (190 ug/kg.d*14 day) was used to inhibit GPR30. Concentration of brain natriuretic peptide in serum, masson staining in isolated heart, contractile function and the expression of beta(1) and beta(2)- adrenergic receptor (AR) of ventricular myocytes were also determined. Our data showed that ISO treatment led to heart failure in OVX rats. G-1 or E(2) treatment decreased concentration of brain natriuretic peptide, reduced cardiac fibrosis, and enhanced contraction of the heart. Combined treatment with beta(1) (CGP20712A) and beta(2)-AR (ICI118551) antagonist abolished the improvement of myocardial function induced by G-1. We also found that chronic treatment with G-1 normalized the expression of beta(1)-AR and increased the expression of beta(2)-AR. Our results indicate that chronic activation of the GPR30 with its agonist G-1 attenuates heart failure by normalizing the expression of beta(1)-AR and increasing the expression of beta(2) AR. PMID- 23110208 TI - Uncertainties in measuring populations potentially impacted by sea level rise and coastal flooding. AB - A better understanding of the impact of global climate change requires information on the locations and characteristics of populations affected. For instance, with global sea level predicted to rise and coastal flooding set to become more frequent and intense, high-resolution spatial population datasets are increasingly being used to estimate the size of vulnerable coastal populations. Many previous studies have undertaken this by quantifying the size of populations residing in low elevation coastal zones using one of two global spatial population datasets available - LandScan and the Global Rural Urban Mapping Project (GRUMP). This has been undertaken without consideration of the effects of this choice, which are a function of the quality of input datasets and differences in methods used to construct each spatial population dataset. Here we calculate estimated low elevation coastal zone resident population sizes from LandScan and GRUMP using previously adopted approaches, and quantify the absolute and relative differences achieved through switching datasets. Our findings suggest that the choice of one particular dataset over another can translate to a difference of more than 7.5 million vulnerable people for countries with extensive coastal populations, such as Indonesia and Japan. Our findings also show variations in estimates of proportions of national populations at risk range from <0.1% to 45% differences when switching between datasets, with large differences predominantly for countries where coarse and outdated input data were used in the construction of the spatial population datasets. The results highlight the need for the construction of spatial population datasets built on accurate, contemporary and detailed census data for use in climate change impact studies and the importance of acknowledging uncertainties inherent in existing spatial population datasets when estimating the demographic impacts of climate change. PMID- 23110209 TI - Liver restores immune homeostasis after local inflammation despite the presence of autoreactive T cells. AB - The liver must keep equilibrium between immune tolerance and immunity in order to protect itself from pathogens while maintaining tolerance to food antigens. An imbalance between these two states could result in an inflammatory liver disease. The aims of this study were to identify factors responsible for a break of tolerance and characterize the subsequent restoration of liver immune homeostasis. A pro-inflammatory environment was created in the liver by the co administration of TLR ligands CpG and Poly(I:C) in presence or absence of activated liver-specific autoreactive CD8(+) T cells. Regardless of autoreactive CD8(+) T cells, mice injected with CpG and Poly(I:C) showed elevated serum ALT levels and a transient liver inflammation. Both CpG/Poly(I:C) and autoreactive CD8(+)T cells induced expression of TLR9 and INF-gamma by the liver, and an up regulation of homing and adhesion molecules CXCL9, CXCL10, CXCL16, ICAM-1 and VCAM-1. Transferred CFSE-labeled autoreactive CD8(+) T cells, in presence of TLR3 and 9 ligands, were recruited by the liver and spleen and proliferated. This population then contracted by apoptosis through intrinsic and extrinsic pathways. Up-regulation of FasL and PD-L1 in the liver was observed. In conclusion, TLR mediated activation of the innate immune system results in a pro-inflammatory environment that promotes the recruitment of lymphocytes resulting in bystander hepatitis. Despite this pro-inflammatory environment, the presence of autoreactive CD8(+) T cells is not sufficient to sustain an autoimmune response against the liver and immune homeostasis is rapidly restored through the apoptosis of T cells. PMID- 23110210 TI - Control of fingertip forces in young and older adults pressing against fixed low- and high-friction surfaces. AB - Mobile computing devices (e.g., smartphones and tablets) that have low-friction surfaces require well-directed fingertip forces of sufficient and precise magnitudes for proper use. Although general impairments in manual dexterity are well-documented in older adults, it is unclear how these sensorimotor impairments influence the ability of older adults to dexterously manipulate fixed, low friction surfaces in particular. 21 young and 18 older (65+ yrs) adults produced maximal voluntary contractions (MVCs) and steady submaximal forces (2.5 and 10% MVC) with the fingertip of the index finger. A Teflon covered custom-molded splint was placed on the fingertip. A three-axis force sensor was covered with either Teflon or sandpaper to create low- and high-friction surfaces, respectively. Maximal downward forces (F(z)) were similar (p = .135) for young and older adults, and decreased by 15% (p<.001) while pressing on Teflon compared to sandpaper. Fluctuations in F(z) during the submaximal force-matching tasks were 2.45* greater (p<.001) for older adults than in young adults, and reached a maximum when older adults pressed against the Teflon surface while receiving visual feedback. These age-associated changes in motor performance are explained, in part, by altered muscle activity from three hand muscles and out-of-plane forces. Quantifying the ability to produce steady fingertip forces against low friction surfaces may be a better indicator of impairment and disability than the current practice of evaluating maximal forces with pinch meters. These age associated impairments in dexterity while interacting with low-friction surfaces may limit the use of the current generation of computing interfaces by older adults. PMID- 23110211 TI - CEP90 is required for the assembly and centrosomal accumulation of centriolar satellites, which is essential for primary cilia formation. AB - Centriolar satellites are PCM-1-positive granules surrounding centrosomes. Proposed functions of the centriolar satellites include protein targeting to the centrosome, as well as communication between the centrosome and surrounding cytoplasm. CEP90 is a centriolar satellite protein that is critical for spindle pole integrity in mitotic cells. In this study, we examined the biological functions of CEP90 in interphase cells. CEP90 physically interacts with PCM-1 at centriolar satellites, and this interaction is essential for centrosomal accumulation of the centriolar satellites and eventually for primary cilia formation. CEP90 is also required for BBS4 loading on centriolar satellites and its localization in primary cilia. Our results imply that the assembly and transport of centriolar satellites are critical steps for primary cilia formation and ciliary protein recruitment. PMID- 23110212 TI - Comparative genome-wide transcriptional analysis of Al-responsive genes reveals novel Al tolerance mechanisms in rice. AB - Rice (Oryza sativa) is the most aluminum (Al)-tolerant crop among small-grain cereals, but the mechanism underlying its high Al resistance is still not well understood. To understand the mechanisms underlying high Al-tolerance, we performed a comparative genome-wide transcriptional analysis by comparing expression profiling between the Al-tolerance cultivar (Koshihikari) and an Al sensitive mutant star1 (SENSITIVE TO AL RHIZOTOXICITY 1) in both the root tips and the basal roots. Exposure to 20 uM AlCl(3) for 6 h resulted in up-regulation (higher than 3-fold) of 213 and 2015 genes including 185 common genes in the root tips of wild-type and the mutant, respectively. On the other hand, in the basal root, genes up-regulated by Al were 126 and 2419 including 76 common genes in the wild-type and the mutant, respectively. These results indicate that Al-response genes are not only restricted to the root tips, but also in the basal root region. Analysis with genes up- or down-regulated only in the wild-type reveals that there are other mechanisms for Al-tolerance except for a known transcription factor ART1-regulated one in rice. These mechanisms are related to nitrogen assimilation, secondary metabolite synthesis, cell-wall synthesis and ethylene synthesis. Although the exact roles of these putative tolerance genes remain to be examined, our data provide a platform for further work on Al-tolerance in rice. PMID- 23110213 TI - Clinical patterns and treatment outcome in patients with melancholic, atypical and non-melancholic depressions. AB - OBJECTIVE: To assess sociodemographic, clinical and treatment factors as well as depression outcome in a large representative clinical sample of psychiatric depressive outpatients and to determine if melancholic and atypical depression can be differentiated from residual non-melancholic depressive conditions. SUBJECTS/MATERIALS AND METHOD: A prospective, naturalistic, multicentre, nationwide epidemiological study of 1455 depressive outpatients was undertaken. Severity of depressive symptoms was assessed by the Hamilton Depression Rating Scale (HDRS) and the Self Rated Inventory of Depressive Symptomatology (IDS SR(30)). IDS-SR(30) defines melancholic and atypical depression according to DSM IV criteria. Assessments were carried out after 6-8 weeks of antidepressant treatment and after 14-20 weeks of continuation treatment. RESULTS: Melancholic patients (16.2%) were more severely depressed, had more depressive episodes and shorter episode duration than atypical (24.7%) and non-melancholic patients. Atypical depressive patients showed higher rates of co-morbid anxiety disorders and substance abuse. Melancholic patients showed lower rates of remission. CONCLUSION: Our study supports a different clinical pattern and treatment outcome for melancholic and atypical depression subtypes. PMID- 23110214 TI - Luminal localization of alpha-tubulin K40 acetylation by cryo-EM analysis of fab labeled microtubules. AB - The alphabeta-tubulin subunits of microtubules can undergo a variety of evolutionarily-conserved post-translational modifications (PTMs) that provide functional specialization to subsets of cellular microtubules. Acetylation of alpha-tubulin residue Lysine-40 (K40) has been correlated with increased microtubule stability, intracellular transport, and ciliary assembly, yet a mechanistic understanding of how acetylation influences these events is lacking. Using the anti-acetylated tubulin antibody 6-11B-1 and electron cryo-microscopy, we demonstrate that the K40 acetylation site is located inside the microtubule lumen and thus cannot directly influence events on the microtubule surface, including kinesin-1 binding. Surprisingly, the monoclonal 6-11B-1 antibody recognizes both acetylated and deacetylated microtubules. These results suggest that acetylation induces structural changes in the K40-containing loop that could have important functional consequences on microtubule stability, bending, and subunit interactions. This work has important implications for acetylation and deacetylation reaction mechanisms as well as for interpreting experiments based on 6-11B-1 labeling. PMID- 23110215 TI - Aspirin inhibits colon cancer cell and tumor growth and downregulates specificity protein (Sp) transcription factors. AB - Acetylsalicylic acid (aspirin) is highly effective for treating colon cancer patients postdiagnosis; however, the mechanisms of action of aspirin in colon cancer are not well defined. Aspirin and its major metabolite sodium salicylate induced apoptosis and decreased colon cancer cell growth and the sodium salt of aspirin also inhibited tumor growth in an athymic nude mouse xenograft model. Colon cancer cell growth inhibition was accompanied by downregulation of Sp1, Sp3 and Sp4 proteins and decreased expression of Sp-regulated gene products including bcl-2, survivin, VEGF, VEGFR1, cyclin D1, c-MET and p65 (NFkappaB). Moreover, we also showed by RNA interference that beta-catenin, an important target of aspirin in some studies, is an Sp-regulated gene. Aspirin induced nuclear caspase dependent cleavage of Sp1, Sp3 and Sp4 proteins and this response was related to sequestration of zinc ions since addition of zinc sulfate blocked aspirin mediated apoptosis and repression of Sp proteins. The results demonstrate an important underlying mechanism of action of aspirin as an anticancer agent and, based on the rapid metabolism of aspirin to salicylate in humans and the high salicylate/aspirin ratios in serum, it is likely that the anticancer activity of aspirin is also due to the salicylate metabolite. PMID- 23110216 TI - Protein dynamics governed by interfaces of high polarity and low packing density. AB - The folding pathway, three-dimensional structure and intrinsic dynamics of proteins are governed by their amino acid sequences. Internal protein surfaces with physicochemical properties appropriate to modulate conformational fluctuations could play important roles in folding and dynamics. We show here that proteins contain buried interfaces of high polarity and low packing density, coined as LIPs: Light Interfaces of high Polarity, whose physicochemical properties make them unstable. The structures of well-characterized equilibrium and kinetic folding intermediates indicate that the LIPs of the corresponding native proteins fold late and are involved in local unfolding events. Importantly, LIPs can be identified using very fast and uncomplicated computational analysis of protein three-dimensional structures, which provides an easy way to delineate the protein segments involved in dynamics. Since LIPs can be retained while the sequences of the interacting segments diverge significantly, proteins could in principle evolve new functional features reusing pre-existing encoded dynamics. Large-scale identification of LIPS may contribute to understanding evolutionary constraints of proteins and the way protein intrinsic dynamics are encoded. PMID- 23110217 TI - Increasing O-GlcNAcylation level on organ culture of soleus modulates the calcium activation parameters of muscle fibers. AB - O-N-acetylglucosaminylation is a reversible post-translational modification which presents a dynamic and highly regulated interplay with phosphorylation. New insights suggest that O-GlcNAcylation might be involved in striated muscle physiology, in particular in contractile properties such as the calcium activation parameters. By the inhibition of O-GlcNAcase, we investigated the effect of the increase of soleus O-GlcNAcylation level on the contractile properties by establishing T/pCa relationships. We increased the O-GlcNAcylation level on soleus biopsies performing an organ culture of soleus treated or not with PUGNAc or Thiamet-G, two O-GlcNAcase inhibitors. The enhancement of O GlcNAcylation pattern was associated with an increase of calcium affinity on slow soleus skinned fibers. Analysis of the glycoproteins pattern showed that this effect is solely due to O-GlcNAcylation of proteins extracted from skinned biopsies. We also characterized the O-GlcNAcylated contractile proteins using a proteomic approach, and identified among others troponin T and I as being O GlcNAc modified. We quantified the variation of O-GlcNAc level on all these identified proteins, and showed that several regulatory contractile proteins, predominantly fast isoforms, presented a drastic increase in their O-GlcNAc level. Since the only slow isoform of contractile protein presenting an increase of O-GlcNAc level was MLC2, the effect of enhanced O-GlcNAcylation pattern on calcium activation parameters could involve the O-GlcNAcylation of sMLC2, without excluding that an unidentified O-GlcNAc proteins, such as TnC, could be potentially involved in this mechanism. All these data strongly linked O GlcNAcylation to the modulation of contractile activity of skeletal muscle. PMID- 23110218 TI - Influence of acute jugular vein compression on the cerebral blood flow velocity, pial artery pulsation and width of subarachnoid space in humans. AB - PURPOSE: The aim of this study was to assess the effect of acute bilateral jugular vein compression on: (1) pial artery pulsation (cc-TQ); (2) cerebral blood flow velocity (CBFV); (3) peripheral blood pressure; and (4) possible relations between mentioned parameters. METHODS: Experiments were performed on a group of 32 healthy 19-30 years old male subjects. cc-TQ and the subarachnoid width (sas-TQ) were measured using near-infrared transillumination/backscattering sounding (NIR-T/BSS), CBFV in the left anterior cerebral artery using transcranial Doppler, blood pressure was measured using Finapres, while end-tidal CO(2) was measured using medical gas analyser. Bilateral jugular vein compression was achieved with the use of a sphygmomanometer held on the neck of the participant and pumped at the pressure of 40 mmHg, and was performed in the bend over (BOPT) and swayed to the back (initial) position. RESULTS: In the first group (n = 10) during BOPT, sas-TQ and pulse pressure (PP) decreased (-17.6% and 17.9%, respectively) and CBFV increased (+35.0%), while cc-TQ did not change (+1.91%). In the second group, in the initial position (n = 22) cc-TQ and CBFV increased (106.6% and 20.1%, respectively), while sas-TQ and PP decreases were not statistically significant (-15.5% and -9.0%, respectively). End-tidal CO(2) remained stable during BOPT and venous compression in both groups. Significant interdependence between changes in cc-TQ and PP after bilateral jugular vein compression in the initial position was found (r = -0.74). CONCLUSIONS: Acute bilateral jugular venous insufficiency leads to hyperkinetic cerebral circulation characterised by augmented pial artery pulsation and CBFV and direct transmission of PP into the brain microcirculation. The Windkessel effect with impaired jugular outflow and more likely increased intracranial pressure is described. This study clarifies the potential mechanism linking jugular outflow insufficiency with arterial small vessel cerebral disease. PMID- 23110219 TI - Sequence fingerprints of microRNA conservation. AB - It is known that the conservation of protein-coding genes is associated with their sequences both various species, such as animals and plants. However, the association between microRNA (miRNA) conservation and their sequences in various species remains unexplored. Here we report the association of miRNA conservation with its sequence features, such as base content and cleavage sites, suggesting that miRNA sequences contain the fingerprints for miRNA conservation. More interestingly, different species show different and even opposite patterns between miRNA conservation and sequence features. For example, mammalian miRNAs show a positive/negative correlation between conservation and AU/GC content, whereas plant miRNAs show a negative/positive correlation between conservation and AU/GC content. Further analysis puts forward the hypothesis that the introns of protein-coding genes may be a main driving force for the origin and evolution of mammalian miRNAs. At the 5' end, conserved miRNAs have a preference for base U, while less-conserved miRNAs have a preference for a non-U base in mammals. This difference does not exist in insects and plants, in which both conserved miRNAs and less-conserved miRNAs have a preference for base U at the 5' end. We further revealed that the non-U preference at the 5' end of less-conserved mammalian miRNAs is associated with miRNA function diversity, which may have evolved from the pressure of a highly sophisticated environmental stimulus the mammals encountered during evolution. These results indicated that miRNA sequences contain the fingerprints for conservation, and these fingerprints vary according to species. More importantly, the results suggest that although species share common mechanisms by which miRNAs originate and evolve, mammals may develop a novel mechanism for miRNA origin and evolution. In addition, the fingerprint found in this study can be predictor of miRNA conservation, and the findings are helpful in achieving a clearer understanding of miRNA function and evolution. PMID- 23110220 TI - The essential role of the 3' terminal template base in the first steps of protein primed DNA replication. AB - Bacteriophages phi29 and Nf from Bacillus subtilis start replication of their linear genomes at both ends using a protein-primed mechanism by means of which the DNA polymerase initiates replication by adding dAMP to the terminal protein, this insertion being directed by the second and third 3' terminal thymine of the template strand, respectively. In this work, we have obtained evidences about the role of the 3' terminal base during the initiation steps of phi29 and Nf genome replication. The results indicate that the absence of the 3' terminal base modifies the initiation position carried out by phi29 DNA polymerase in such a way that now the third position of the template, instead of the second one, guides the incorporation of the initiating nucleotide. In the case of Nf, although the lack of the 3' terminal base has no effect on the initiation position, its absence impairs further elongation of the TP-dAMP initiation product. The results show the essential role of the 3' terminal base in guaranteeing the correct positioning of replication origins at the polymerization active site to allow accurate initiation of replication and further elongation. PMID- 23110221 TI - Plasma concentrations of soluble endoglin versus standard evaluation in patients with suspected preeclampsia. AB - BACKGROUND: The purpose of this study was to compare plasma soluble endoglin (sEng) levels with standard clinical evaluation or plasma levels of other angiogenic proteins [soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PlGF)] in predicting short-term adverse maternal and perinatal outcomes in women with suspected preeclampsia presenting prior to 34 weeks. METHODS AND FINDINGS: Data from all women presenting at <34 weeks for evaluation of preeclampsia with singleton pregnancies (July 2009-October 2010) were included in this analysis and sEng levels were measured at presentation. Data was analyzed for 170 triage encounters and presented as median {25-75(th) centile}. Thirty three percent of patients (56 of 170) experienced an adverse outcome. sEng levels (ng/ml) were significantly elevated in patients who subsequently experienced adverse outcomes compared to those who did not (32.3 {18.1, 55.8} vs 4.8 {3.2, 8.6}, p<0.0001). At a 10% false positive rate, sEng had higher detection rates of adverse outcomes than the combination of highest systolic blood pressure, proteinuria and abnormal laboratory tests (80.4 {70.0, 90.8} vs 63.8 {51.4, 76.2}, respectively). Subjects in the highest quartile of sEng were more likely to deliver early compared to those in the lowest quartile (HR: 14.96 95% CI: 8.73 25.62, p<0.0001). Natural log transformed sEng correlated positively with log sFlt1 levels (r = 0.87) and inversely with log PlGF levels (r = -0.79) (p<0.0001 for both). Plasma sEng had comparable area under the curve for prediction of adverse outcomes as measurement of sFlt1/PlGF ratio (0.88 {0.81, 0.95} for sEng versus 0.89 {0.83, 0.95} for sFlt1/PlGF ratio, p = 0.74). CONCLUSIONS: In women with suspected preeclampsia presenting prior to 34 weeks of gestation, sEng performs better than standard clinical evaluation in detecting adverse maternal and fetal outcomes occurring within two weeks of presentation. Soluble endoglin was strongly correlated with sFlt1 and PlGF levels, suggesting common pathogenic pathways leading to preeclampsia. PMID- 23110222 TI - Candidate olfaction genes identified within the Helicoverpa armigera Antennal Transcriptome. AB - Antennal olfaction is extremely important for insect survival, mediating key behaviors such as host preference, mate choice, and oviposition site selection. Multiple antennal proteins are involved in olfactory signal transduction pathways. Of these, odorant receptors (ORs) and ionotropic receptors (IRs) confer specificity on olfactory sensory neuron responses. In this study, we identified the olfactory gene repertoire of the economically important agricultural pest moth, Helicoverpa armigera, by assembling the adult male and female antennal transcriptomes. Within the male and female antennal transcriptomes we identified a total of 47 OR candidate genes containing 6 pheromone receptor candidates. Additionally, 12 IR genes as well as 26 odorant-binding proteins and 12 chemosensory proteins were annotated. Our results allow a systematic functional analysis across much of conventional ORs repertoire and newly reported IRs mediating the key olfaction-mediated behaviors of H. armigera. PMID- 23110223 TI - Autophagy inhibitor chloroquine enhanced the cell death inducing effect of the flavonoid luteolin in metastatic squamous cell carcinoma cells. AB - BACKGROUND: Flavonoids are widely proposed as very interesting compounds with possible chemopreventive and therapeutic capacities. METHODS & RESULTS: In this study, we showed that in vitro treatment with the flavonoid Luteolin induced caspase-dependent cell death in a model of human cutaneous squamous cell carcinoma (SCC) derived cells, representing a matched pair of primary tumor and its metastasis. Notably, no cytotoxic effects were observed in normal human keratinocytes when treated with similar doses of Luteolin. Luteolin-induced apoptosis was accompanied by inhibition of AKT signaling, and sensitivity decreased with tumor progression, as the primary MET1 SCC cells were considerably more sensitive to Luteolin than the isogenic metastatic MET4 cells. Extensive intracellular vacuolization was observed in Luteolin-treated MET4 cells, which were characterized as acidic lysosomal vacuoles, suggesting the involvement of autophagy. Transmission electron microscopy, mRFP-GFP-LC3 assay and p62 protein degradation, confirmed that Luteolin stimulated the autophagic process in the metastatic MET4 cells. Blocking autophagy using chloroquine magnified Luteolin induced apoptosis in the metastatic SCC cells. CONCLUSION: Together, these results suggest that Luteolin has the capacity to induce selectively apoptotic cell death both in primary cutaneous SCC cells and in metastatic SCC cells in combination with chloroquine, an inhibitor of autophagosomal degradation. Hence, Luteolin might be a promising agent for the treatment of cutaneous SCC. PMID- 23110224 TI - Promotion of both proliferation and neuronal differentiation in pluripotent P19 cells with stable overexpression of the glutamine transporter slc38a1. AB - BACKGROUND: We previously demonstrated the functional expression in newborn rat neocortical astrocytes of glutamine transporter (GlnT = slc38a1) believed to predominate in neurons over astroglia in the brain. In order to evaluate the possible role of this transporter in neurogenesis, we attempted to establish stable transfectants of GlnT in mouse embryonal carcinoma P19 cells endowed to proliferate for self-renewal and differentiate into progeny cells such as neurons and astroglia, in addition to in vitro pharmacological profiling of the green tea ingredient theanine, which is shown to be a potent inhibitor of glutamine transport mediated by GlnT in cultured neurons and astroglia. METHODOLOGY/PRINCIPAL FINDINGS: The full-length coding region of rat GlnT was inserted into a vector for gene transfection along with selection by G418, followed by culture with all-trans retinoic acid under floating conditions and subsequent dispersion for spontaneous differentiation under adherent conditions. Stable overexpression of GlnT led to marked increases in the size of round spheres formed during the culture for 4 days and 3-(4,5-dimethyl-2-thiazolyl)-2,5 diphenyl-2H-tetrazolium bromide reduction, with concomitant promotion of subsequent differentiation into cells immunoreactive for a neuronal marker protein. In these stable GlnT transfectants before differentiation, drastic upregulation was seen for mRNA expression of several proneural genes with a basic helix-loop-helix domain such as NeuroD1. Although a drastic increase was seen in NeuroD1 promoter activity in stable GlnT transfectants, theanine doubled NeuroD1 promoter activity in stable transfectants of empty vector (EV), without affecting the promoter activity already elevated in GlnT transfectants. Similarly, theanine promoted cellular proliferation and neuronal differentiation in stable EV transfectants, but failed to further stimulate the acceleration of both proliferation and neuronal differentiation found in stable GlnT transfectants. CONCLUSIONS/SIGNIFICANCE: GlnT would promote both proliferation and neuronal differentiation through a mechanism relevant to the upregulation of particular proneural genes in undifferentiated P19 cells. PMID- 23110225 TI - Characterization of biofilm formation by Borrelia burgdorferi in vitro. AB - Borrelia burgdorferi, the causative agent of Lyme disease, has long been known to be capable of forming aggregates and colonies. It was recently demonstrated that Borrelia burgdorferi aggregate formation dramatically changes the in vitro response to hostile environments by this pathogen. In this study, we investigated the hypothesis that these aggregates are indeed biofilms, structures whose resistance to unfavorable conditions are well documented. We studied Borrelia burgdorferi for several known hallmark features of biofilm, including structural rearrangements in the aggregates, variations in development on various substrate matrices and secretion of a protective extracellular polymeric substance (EPS) matrix using several modes of microscopic, cell and molecular biology techniques. The atomic force microscopic results provided evidence that multilevel rearrangements take place at different stages of aggregate development, producing a complex, continuously rearranging structure. Our results also demonstrated that Borrelia burgdorferi is capable of developing aggregates on different abiotic and biotic substrates, and is also capable of forming floating aggregates. Analyzing the extracellular substance of the aggregates for potential exopolysaccharides revealed the existence of both sulfated and non-sulfated/carboxylated substrates, predominately composed of an alginate with calcium and extracellular DNA present. In summary, we have found substantial evidence that Borrelia burgdorferi is capable of forming biofilm in vitro. Biofilm formation by Borrelia species might play an important role in their survival in diverse environmental conditions by providing refuge to individual cells. PMID- 23110226 TI - Discovery of bla(OXA-199), a chromosome-based bla(OXA-48)-like variant, in Shewanella xiamenensis. AB - INTRODUCTION: bla(OXA-48) is a globally emerging carbapenemase-encoding gene. The progenitor of bla(OXA-48) appears to be a Shewanella species. The presence of the bla(OXA-48)-like gene was investigated for two Shewanella xiamenensis strains. METHODS: Strain WCJ25 was recovered from post-surgical abdominal drainages, while S4 was the type strain of S. xiamenensis. Species identification for WCJ25 was established by sequencing the 16S rDNA and gyrB genes. PCR was used to screen the bla(OXA-48)-like genes and to obtain their complete sequences. A phylogenetic tree of the bla(OXA-48)-like genes was constructed. The genetic context of the bla(OXA-48)-like gene in strain WCJ25 was investigated by inverse PCR using self ligated AseI- or RsaI-restricted WCJ25 DNA fragments as template, while that in strain S4 was determined by PCR mapping using that in WCJ25 as template. RESULTS: A new bla(OXA-48) variant, designated bla(OXA-48b), with four silent nucleotide differences from the bla(OXA-48) (designated bla(OXA-48a)) found in the Enterobacteriaceae was identified in strain S4. Strain WCJ25 had a new bla(OXA 48)-like variant, bla(OXA-199), with five nucleotide differences from bla(OXA 48)a and bla(OXA-48b). The OXA-199 protein has three amino acid substitutions (H37Y, V44A and D153G) compared with OXA-48. Both bla(OXA-48b) and bla(OXA-199) were found adjacent to genes encoding a peptidase (indicated as orf), a protein of unknown function (sprT), an endonuclease I (endA), and a ribosomal RNA methyl transferase (rsmE) upstream and to transcriptional regulator gene lysR and an acetyl-CoA carboxylase-encoding gene downstream. In addition, the insertion sequence ISShes2 was found inserted downstream of bla(OXA-199) but not of bla(OXA 48b). The 26 bp sequences upstream and 63 bp downstream of bla(OXA-48a), bla(OXA 48b) and bla(OXA-199) were identical. CONCLUSIONS: bla(OXA-48a), bla(OXA-48b) and bla(OXA-199) might have a common origin, suggesting that the bla(OXA-48a) gene found in the Enterobacteriaceae could have originated from the chromosome of S. xiamenensis. PMID- 23110227 TI - Autoinducers act as biological timers in Vibrio harveyi. AB - Quorum sensing regulates cell density-dependent phenotypes and involves the synthesis, excretion and detection of so-called autoinducers. Vibrio harveyi strain ATCC BAA-1116 (recently reclassified as Vibrio campbellii), one of the best-characterized model organisms for the study of quorum sensing, produces and responds to three autoinducers. HAI-1, AI-2 and CAI-1 are recognized by different receptors, but all information is channeled into the same signaling cascade, which controls a specific set of genes. Here we examine temporal variations of availability and concentration of the three autoinducers in V. harveyi, and monitor the phenotypes they regulate, from the early exponential to the stationary growth phase in liquid culture. Specifically, the exponential growth phase is characterized by an increase in AI-2 and the induction of bioluminescence, while HAI-1 and CAI-1 are undetectable prior to the late exponential growth phase. CAI-1 activity reaches its maximum upon entry into stationary phase, while molar concentrations of AI-2 and HAI-1 become approximately equal. Similarly, autoinducer-dependent exoproteolytic activity increases at the transition into stationary phase. These findings are reflected in temporal alterations in expression of the luxR gene that encodes the master regulator LuxR, and of four autoinducer-regulated genes during growth. Moreover, in vitro phosphorylation assays reveal a tight correlation between the HAI-1/AI-2 ratio as input and levels of receptor-mediated phosphorylation of LuxU as output. Our study supports a model in which the combinations of autoinducers available, rather than cell density per se, determine the timing of various processes in V. harveyi populations. PMID- 23110228 TI - Persistence of motor-equivalent postural fluctuations during bipedal quiet standing. AB - Theoretical and empirical work indicates that the central nervous system is able to stabilize motor performance by selectively suppressing task-relevant variability (TRV), while allowing task-equivalent variability (TEV) to occur. During unperturbed bipedal standing, it has previously been observed that, for task variables such as the whole-body center of mass (CoM), TEV exceeds TRV in amplitude. However, selective control (and correction) of TRV should also lead to different temporal characteristics, with TEV exhibiting higher temporal persistence compared to TRV. The present study was specifically designed to test this prediction. Kinematics of prolonged quiet standing (5 minutes) was measured in fourteen healthy young participants, with eyes closed. Using the uncontrolled manifold analysis, postural variability in six sagittal joint angles was decomposed into TEV and TRV with respect to four task variables: (1) center of mass (CoM) position, (2) head position, (3) trunk orientation and (4) head orientation. Persistence of fluctuations within the two variability components was quantified by the time-lagged auto-correlation, with eight time lags between 1 and 128 seconds. The pattern of results differed between task variables. For three of the four task variables (CoM position, head position, trunk orientation), TEV significantly exceeded TRV over the entire 300 s-period.The autocorrelation analysis confirmed our main hypothesis for CoM position and head position: at intermediate and longer time delays, TEV exhibited higher persistence than TRV. Trunk orientation showed a similar trend, while head orientation did not show a systematic difference between TEV and TRV persistence. The combination of temporal and task-equivalent analyses in the present study allow a refined characterization of the dynamic control processes underlying the stabilization of upright standing. The results confirm the prediction, derived from computational motor control, that task-equivalent fluctuations for specific task variables show higher temporal persistence compared to task-relevant fluctuations. PMID- 23110229 TI - Differential allocation by female zebrafish (Danio rerio) to different-sized males--an example in a fish species lacking parental care. AB - Organisms allocate resources to reproduction in response to the costs and benefits of current and future reproductive opportunities. According to the differential allocation hypothesis, females allocate more resources to high quality males. We tested whether a fish species lacking parental care (zebrafish, Danio rerio) expresses male size-dependent differential allocation in monogamous spawning trials. In addition, we tested whether reproductive allocation by females is affected by previous experience of different-quality males, potentially indicating plasticity in mate choice. To that end, females were conditioned to large, small or random-sized males (controls) for 14 days to manipulate females' expectations of the future mate quality. Females showed a clear preference for large males in terms of spawning probability and clutch size independent of the conditioning treatment. However, when females experienced variation in male size (random-sized conditioning treatment) they discriminated less against small males compared to females conditioned to large and small males. This might suggest that differential allocation and size-dependent sexual selection is of less relevance in nature than revealed in the present laboratory study. PMID- 23110230 TI - Constitutive type VI secretion system expression gives Vibrio cholerae intra- and interspecific competitive advantages. AB - The type VI secretion system (T6SS) mediates protein translocation across the cell membrane of Gram-negative bacteria, including Vibrio cholerae - the causative agent of cholera. All V. cholerae strains examined to date harbor gene clusters encoding a T6SS. Structural similarity and sequence homology between components of the T6SS and the T4 bacteriophage cell-puncturing device suggest that the T6SS functions as a contractile molecular syringe to inject effector molecules into prokaryotic and eukaryotic target cells. Regulation of the T6SS is critical. A subset of V. cholerae strains, including the clinical O37 serogroup strain V52, express T6SS constitutively. In contrast, pandemic strains impose tight control that can be genetically disrupted: mutations in the quorum sensing gene luxO and the newly described regulator gene tsrA lead to constitutive T6SS expression in the El Tor strain C6706. In this report, we examined environmental V. cholerae isolates from the Rio Grande with regard to T6SS regulation. Rough V. cholerae lacking O-antigen carried a nonsense mutation in the gene encoding the global T6SS regulator VasH and did not display virulent behavior towards Escherichia coli and other environmental bacteria. In contrast, smooth V. cholerae strains engaged constitutively in type VI-mediated secretion and displayed virulence towards prokaryotes (E. coli and other environmental bacteria) and a eukaryote (the social amoeba Dictyostelium discoideum). Furthermore, smooth V. cholerae strains were able to outcompete each other in a T6SS-dependent manner. The work presented here suggests that constitutive T6SS expression provides V. cholerae with an advantage in intraspecific and interspecific competition. PMID- 23110231 TI - Late-onset running biphasically improves redox balance, energy- and methylglyoxal related status, as well as SIRT1 expression in mouse hippocampus. AB - Despite the active research in this field, molecular mechanisms underlying exercise-induced beneficial effects on brain physiology and functions are still matter of debate, especially with regard to biological processes activated by regular exercise affecting the onset and progression of hippocampal aging in individuals unfamiliar with habitual physical activity. Since such responses seem to be mediated by changes in antioxidative, antiglycative and metabolic status, a possible exercise-induced coordinated response involving redox, methylglyoxal- and sirtuin-related molecular networks may be hypothesized. In this study, hippocampi of CD1 mice undergoing the transition from mature to middle age were analyzed for redox-related profile, oxidative and methylglyoxal-dependent damage patterns, energy metabolism, sirtuin1 and glyoxalase1 expression after a 2- or 4 mo treadmill running program. Our findings suggested that the 4-mo regular running lowered the chance of dicarbonyl and oxidative stress, activated mitochondrial catabolism and preserved sirtuin1-related neuroprotection. Surprisingly, the same cellular pathways were negatively affected by the first 2 months of exercise, thus showing an interesting biphasic response. In conclusion, the duration of exercise caused a profound shift in the response to regular running within the rodent hippocampus in a time-dependent fashion. This research revealed important details of the interaction between exercise and mammal hippocampus during the transition from mature to middle age, and this might help to develop non-pharmacological approaches aimed at retarding brain senescence, even in individuals unfamiliar with habitual exercise. PMID- 23110232 TI - Variation in craniomandibular morphology and sexual dimorphism in pantherines and the sabercat Smilodon fatalis. AB - Sexual dimorphism is widespread among carnivorans, and has been an important evolutionary factor in social ecology. However, its presence in sabertoothed felids remains contentious. Here we present a comprehensive analysis of extant Panthera and the sabertoothed felid Smilodon fatalis. S. fatalis has been reported to show little or no sexual dimorphism but to have been intraspecifically variable in skull morphology. We found that large and small specimens of S. fatalis could be assigned to male and female sexes with similar degrees of confidence as Panthera based on craniomandibular shape. P. uncia is much less craniomandibularly variable and has low levels of sexual size dimorphism. Shape variation in S. fatalis probably reflects sexual differences. Craniomandibular size-dimorphism is lower in S. fatalis than in Panthera except P. uncia. Sexual dimorphism in felids is related to more than overall size, and S. fatalis and the four large Panthera species show marked and similar craniomandibular and dental morphometric sexual dimorphism, whereas morphometric dimorphism in P. uncia is less. Many morphometric-sexually dimorphic characters in Panthera and Smilodon are related to bite strength and presumably to killing ecology. This suggests that morphometric sexual dimorphism is an evolutionary adaptation to intraspecific resource partitioning, since large males with thicker upper canines and stronger bite forces would be able to hunt larger prey than females, which is corroborated by feeding ecology in P. leo. Sexual dimorphism indicates that S. fatalis could have been social, but it is unlikely that it lived in fusion-fission units dominated by one or a few males, as in sub-Saharan populations of P. leo. Instead, S. fatalis could have been solitary and polygynous, as most extant felids, or it may have lived in unisexual groups, as is common in P. leo persica. PMID- 23110233 TI - Functional similarities between pigeon 'milk' and mammalian milk: induction of immune gene expression and modification of the microbiota. AB - Pigeon 'milk' and mammalian milk have functional similarities in terms of nutritional benefit and delivery of immunoglobulins to the young. Mammalian milk has been clearly shown to aid in the development of the immune system and microbiota of the young, but similar effects have not yet been attributed to pigeon 'milk'. Therefore, using a chicken model, we investigated the effect of pigeon 'milk' on immune gene expression in the Gut Associated Lymphoid Tissue (GALT) and on the composition of the caecal microbiota. Chickens fed pigeon 'milk' had a faster rate of growth and a better feed conversion ratio than control chickens. There was significantly enhanced expression of immune-related gene pathways and interferon-stimulated genes in the GALT of pigeon 'milk'-fed chickens. These pathways include the innate immune response, regulation of cytokine production and regulation of B cell activation and proliferation. The caecal microbiota of pigeon 'milk'-fed chickens was significantly more diverse than control chickens, and appears to be affected by prebiotics in pigeon 'milk', as well as being directly seeded by bacteria present in pigeon 'milk'. Our results demonstrate that pigeon 'milk' has further modes of action which make it functionally similar to mammalian milk. We hypothesise that pigeon 'lactation' and mammalian lactation evolved independently but resulted in similarly functional products. PMID- 23110234 TI - Selection of suitable housekeeping genes for real-time quantitative PCR in CD4(+) lymphocytes from asthmatics with or without depression. AB - OBJECTIVE: No optimal housekeeping genes (HKGs) have been identified for CD4(+) T cells from non-depressive asthmatic and depressive asthmatic adults for normalizing quantitative real-time PCR (qPCR) assays. The aim of present study was to select appropriate HKGs for gene expression analysis in purified CD4(+) T cells from these asthmatics. METHODS: Three groups of subjects (Non-depressive asthmatic, NDA, n = 10, Depressive asthmatic, DA, n = 11, and Healthy control, HC, n = 10 respectively) were studied. qPCR for 9 potential HKGs, namely RNA, 28S ribosomal 1 (RN28S1), ribosomal protein, large, P0 (RPLP0), actin, beta (ACTB), cyclophilin A (PPIA), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), phosphoglycerate kinase 1 (PGK1), beta-2-microglobulin (B2M), glucuronidase, beta (GUSB) and ribosomal protein L13a (RPL13A), was performed. Then the data were analyzed with three different applications namely BestKeeper, geNorm, and NormFinder. RESULTS: The analysis of gene expression data identified B2M and RPLP0 as the most stable reference genes and showed that the level of PPIA was significantly different among subjects of three groups when the two best HKGs identified were applied. Post-hoc analysis by Student-Newman-Keuls correction shows that depressive asthmatics and non-depressive asthmatics exhibited lower expression level of PPIA than healthy controls (p<0.05). CONCLUSIONS: B2M and RPLP0 were identified as the most optimal HKGs in gene expression studies involving human blood CD4(+) T cells derived from normal, depressive asthmatics and non-depressive asthmatics. The suitability of using the PPIA gene as the HKG for such studies was questioned due to its low expression in asthmatics. PMID- 23110235 TI - The tauCstF-64 polyadenylation protein controls genome expression in testis. AB - The tauCstF-64 polyadenylation protein (gene symbol Cstf2t) is a testis-expressed orthologue of CstF-64. Mice in which Cstf2t was knocked out had a phenotype that was only detected in meiotic and postmeiotic male germ cells, giving us the opportunity to examine CstF-64 function in an isolated developmental system. We performed massively parallel clonally amplified sequencing of cDNAs from testes of wild type and Cstf2t(-/-) mice. These results revealed that loss of tauCstF-64 resulted in large-scale changes in patterns of genome expression. We determined that there was a significant overrepresentation of RNAs from introns and intergenic regions in testes of Cstf2t(-/-) mice, and a concomitant use of more distal polyadenylation sites. We observed this effect particularly in intronless small genes, many of which are expressed retroposons that likely co-evolved with tauCstF-64. Finally, we observed overexpression of long interspersed nuclear element (LINE) sequences in Cstf2t(-/-) testes. These results suggest that tauCstF-64 plays a role in 3' end determination and transcription termination for a large range of germ cell-expressed genes. PMID- 23110236 TI - Antepartum depression and anxiety associated with disability in African women: cross-sectional results from the CDS study in Ghana and Cote d'Ivoire. AB - BACKGROUND: Common mental disorders, particularly unipolar depressive disorders, rank among the top 5 with respect to the global burden of disease. As a major public health concern, antepartum depression and anxiety not only affects the individual woman, but also her offspring. Data on the prevalence of common mental disorders in pregnant women in sub-Saharan Africa are scarce. We provide results from Ghana and Cote d'Ivoire. METHODS: We subsequently recruited and screened n = 1030 women in the third trimester of their pregnancy for depressed mood, general anxiety, and perceived disability using the Patient Health Questionnaire depression module (PHQ-9), the 7-item Anxiety Scale (GAD-7), and the World Health Organisation Disability Assessment Schedule II (WHO-DAS 2.0, 12-item version). In addition to estimates of means and prevalence, a hierarchical linear regression model was calculated to determine the influence of antepartum depression and anxiety on disability. RESULTS: In Ghana, 26.6% of women showed substantially depressed mood. In Cote d'Ivoire, this figure was even higher (32.9%). Clear indications for a generalized anxiety disorder were observed in 11.4% and 17.4% of pregnant women, respectively. Comorbidity of both conditions was common, affecting about 7.7% of Ghanaian and 12.6% of Ivorian participants. Pregnant women in both countries reported a high degree of disability regarding everyday activity limitations and participation restrictions. Controlled for country and age, depression and anxiety accounted for 33% of variance in the disability score. CONCLUSIONS: Antepartum depression and anxiety were highly prevalent in our sample and contributed substantially to perceived disability. These serious threats to health must be further investigated and more data are needed to comprehensively quantify the problem in sub-Saharan Africa. PMID- 23110237 TI - Incidence and predictors of end stage renal disease among low-income blacks and whites. AB - We evaluated whether black race is associated with higher incidence of End Stage Renal Disease (ESRD) among a cohort of blacks and whites of similar, generally low socioeconomic status, and whether risk factor patterns differ among blacks and whites and explain the poorly understood racial disparity in ESRD. Incident diagnoses of ESRD among 79,943 black and white participants in the Southern Community Cohort Study (SCCS) were ascertained by linkage with the United States Renal Data System (USRDS) from 2002 through 2009. Person-years of follow up were calculated from date of entry into the SCCS until date of ESRD diagnosis, date of death, or September 1, 2009, whichever occurred first. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for incident ESRD among black and white participants in relation to baseline characteristics. After 329,003 person-years of follow-up, 687 incident cases of ESRD were identified in the cohort. The age-adjusted ESRD incidence rate was 273 (per 100,000) among blacks, 3.5-fold higher than the rate of 78 among whites. Risk factors for ESRD included male sex (HR = 1.6; 95% CI 1.4-1.9), low income (HR = 1.5; 95% CI 1.2-1.8 for income below vs. above $15,000), smoking (HR = 1.2; 95% CI 1.02-1.4) and histories of diabetes (HRs increasing to 9.4 (95% CI 7.4 11.9) among those with >=20 years diabetes duration) and hypertension (HR = 2.9; 95% CI 2.3-3.7). Patterns and magnitudes of association were virtually identical among blacks and whites. After adjustment for these risk factors, blacks continued to have a higher risk for ESRD (HR = 2.4; 95% CI = 1.9-3.0) relative to whites. The black-white disparity in risk of ESRD was attenuated but not eliminated after control for known risk factors in a closely socioeconomically matched cohort. Further research characterizing biomedical factors, including CKD progression, in ESRD occurrence in these two racial groups is needed. PMID- 23110238 TI - The impact of cHS4 insulators on DNA transposon vector mobilization and silencing in retinal pigment epithelium cells. AB - DNA transposons have become important vectors for efficient non-viral integration of transgenes into genomic DNA. The Sleeping Beauty (SB), piggyBac (PB), and Tol2 transposable elements have distinct biological properties and currently represent the most promising transposon systems for animal transgenesis and gene therapy. A potential obstacle, however, for persistent function of integrating vectors is transcriptional repression of the element and its genetic cargo. In this study we analyze the insulating effect of the 1.2-kb 5'-HS4 chicken beta-globin (cHS4) insulator element in the context of SB, PB, and Tol2 transposon vectors. By examining transgene expression from genomically inserted transposon vectors encoding a marker gene driven by a silencing-prone promoter, we detect variable levels of transcriptional silencing for the three transposon systems in retinal pigment epithelium cells. Notably, the PB system seems less vulnerable to silencing. Incorporation of cHS4 insulator sequences into the transposon vectors results in 2.2-fold and 1.5-fold increased transgene expression levels for insulated SB and PB vectors, respectively, but an improved persistency of expression was not obtained for insulated transgenes. Colony formation assays and quantitative excision assays unveil enhanced SB transposition efficiencies by the inclusion of the cHS4 element, resulting in a significant increase in the stable transfection rate for insulated SB transposon vectors in human cell lines. Our findings reveal a positive impact of cHS4 insulator inclusion for SB and PB vectors in terms of increased transgene expression levels and improved SB stable transfection rates, but also the lack of a long-term protective effect of the cHS4 insulator against progressive transgene silencing in retinal pigment epithelium cells. PMID- 23110239 TI - A cancer vaccine induces expansion of NY-ESO-1-specific regulatory T cells in patients with advanced melanoma. AB - Cancer vaccines are designed to expand tumor antigen-specific T cells with effector function. However, they may also inadvertently expand regulatory T cells (Treg), which could seriously hamper clinical efficacy. To address this possibility, we developed a novel assay to detect antigen-specific Treg based on down-regulation of surface CD3 following TCR engagement, and used this approach to screen for Treg specific to the NY-ESO-1 tumor antigen in melanoma patients treated with the NY-ESO-1/ISCOMATRIXTM cancer vaccine. All patients tested had Treg (CD25(bright) FoxP3(+) CD127(neg)) specific for at least one NY-ESO-1 epitope in the blood. Strikingly, comparison with pre-treatment samples revealed that many of these responses were induced or boosted by vaccination. The most frequently detected response was toward the HLA-DP4-restricted NY-ESO-1(157-170) epitope, which is also recognized by effector T cells. Notably, functional Treg specific for an HLA-DR-restricted epitope within the NY-ESO-1(115-132) peptide were also identified at high frequency in tumor tissue, suggesting that NY-ESO-1 specific Treg may suppress local anti-tumor immune responses. Together, our data provide compelling evidence for the ability of a cancer vaccine to expand tumor antigen-specific Treg in the setting of advanced cancer, a finding which should be given serious consideration in the design of future cancer vaccine clinical trials. PMID- 23110241 TI - Dyslipidemia Management for Secondary Prevention in Women with Cardiovascular Disease: What Can We Expect From Non-pharmacologic Strategies? AB - Cardiovascular disease is the leading cause of death in women and the treatment of dyslipidemia is a cornerstone of secondary prevention. Pharmacologic therapy with statins can lower LDL-C by 30-50% and reduce the risk of recurrent coronary heart disease in both men and women. While significant reductions in LDL-C can be achieved with statin therapy, diet and lifestyle modification remain an essential part of the treatment regimen for cardiovascular disease. Moreover, a large proportion of the U.S. population is sedentary, overweight, and does not consume a heart-healthy diet. Non-pharmacologic treatment strategies also improve other cardiovascular risk factors and are generally easily accessible. In this review, we examine the effect of non-pharmacologic therapy on lipids as part of the secondary prevention strategy of cardiovascular disease in women. PMID- 23110240 TI - Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). AB - ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn(2+) and non-transferrin-bound Fe(2+) in vitro. Using a Zip14(-/-) mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14(-/-) mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14(-/-) mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14-/- mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14(-/-) phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL 6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14(-/-) mice and their phenotype shows defects in glucose homeostasis. PMID- 23110242 TI - Optimal lead time for dengue forecast. AB - BACKGROUND: A dengue early warning system aims to prevent a dengue outbreak by providing an accurate prediction of a rise in dengue cases and sufficient time to allow timely decisions and preventive measures to be taken by local authorities. This study seeks to identify the optimal lead time for warning of dengue cases in Singapore given the duration required by a local authority to curb an outbreak. METHODOLOGY AND FINDINGS: We developed a Poisson regression model to analyze relative risks of dengue cases as functions of weekly mean temperature and cumulative rainfall with lag times of 1-5 months using spline functions. We examined the duration of vector control and cluster management in dengue clusters > = 10 cases from 2000 to 2010 and used the information as an indicative window of the time required to mitigate an outbreak. Finally, we assessed the gap between forecast and successful control to determine the optimal timing for issuing an early warning in the study area. Our findings show that increasing weekly mean temperature and cumulative rainfall precede risks of increasing dengue cases by 4-20 and 8-20 weeks, respectively. These lag times provided a forecast window of 1-5 months based on the observed weather data. Based on previous vector control operations, the time needed to curb dengue outbreaks ranged from 1-3 months with a median duration of 2 months. Thus, a dengue early warning forecast given 3 months ahead of the onset of a probable epidemic would give local authorities sufficient time to mitigate an outbreak. CONCLUSIONS: Optimal timing of a dengue forecast increases the functional value of an early warning system and enhances cost-effectiveness of vector control operations in response to forecasted risks. We emphasize the importance of considering the forecast-mitigation gaps in respective study areas when developing a dengue forecasting model. PMID- 23110243 TI - A Comparison of Testing Parameters and the Implementation of a Group Sequential Design for Equivalence Studies Using Paired-sample Analysis. AB - We address the problem of establishing two-sided equivalence using paired-sample analysis of two treatments or two laboratory tests with a binary endpoint. Through real data examples and monte carlo simulations, we compare three commonly used testing parameters, namely, the difference of response probabilities, the ratio of response probabilities, and the ratio of discordant probabilities based on score test statistics for constructing equivalence hypothesis tests of paired binary data. We provide suggestions on the choice of these three testing parameters and proper equivalence margins in hypothesis formulation of equivalence testing. In addition, we describe the implementation of a group sequential design in the context of equivalence testing with early stopping to reject, as well as to declare equivalence. PMID- 23110244 TI - Coronary artery calcium score: Re-evaluation of its predictive value for coronary artery disease. AB - Coronary artery disease is the leading cause of death in advanced countries and its prevalence is increasing among the developing countries. Cardiac computed tomography (CT) has been increasingly used in the diagnosis of coronary artery disease due to its rapid improvements in multislice CT scanners over the last decade, and this less-invasive technique has become a potentially effective alternative to invasive coronary angiography. Quantifying the amount of coronary artery calcium with cardiac CT has been widely accepted as a reliable non invasive technique for predicting risk of future cardiovascular events. However, the main question that remains uncertain is whether routine, widespread coronary artery calcium scoring in an individual patient will result in an overall improvement in quality of care and clinical outcomes. In this commentary, we discuss a current issue of the clinical value of coronary artery calcium scoring with regard to its value of predicting adverse cardiac events. We also discuss the applications of coronary artery calcium scores in patients with different risk groups. PMID- 23110245 TI - Next generation sequencing in cardiovascular diseases. AB - In the last few years, the advent of next generation sequencing (NGS) has revolutionized the approach to genetic studies, making whole-genome sequencing a possible way of obtaining global genomic information. NGS has very recently been shown to be successful in identifying novel causative mutations of rare or common Mendelian disorders. At the present time, it is expected that NGS will be increasingly important in the study of inherited and complex cardiovascular diseases (CVDs). However, the NGS approach to the genetics of CVDs represents a territory which has not been widely investigated. The identification of rare and frequent genetic variants can be very important in clinical practice to detect pathogenic mutations or to establish a profile of risk for the development of pathology. The purpose of this paper is to discuss the recent application of NGS in the study of several CVDs such as inherited cardiomyopathies, channelopathies, coronary artery disease and aortic aneurysm. We also discuss the future utility and challenges related to NGS in studying the genetic basis of CVDs in order to improve diagnosis, prevention, and treatment. PMID- 23110246 TI - Low doses of intravenous epinephrine for refractory sustained monomorphic ventricular tachycardia. AB - We report three cases of sustained monomorphic ventricular tachycardia (VT) in the setting of coronary artery disease, resistant to beta-blockers in two patients and to amiodarone in all, successfully terminated by low doses of intravenous (IV) epinephrine. VT was the first manifestation of coronary artery disease in one patient, whereas the other two patients had a previous history of myocardial infarction and were recipients of an implantable cardioverter defibrillator (ICD). One of these two patients experienced an arrhythmic storm. All had hemodynamic instability at the time of epinephrine administration. A single slow administration of IV epinephrine (0.5 to 1 mg administered over 30 to 60 s) restored sinus rhythm after 30-90 s with only minor side effects. In the ICD patient with recurrent VT and several cardioversions due to transformation of VT to ventricular fibrillation, epinephrine injection led to the avoidance of further shocks. Although potentially harmful, low doses of IV epinephrine used alone or in combination with beta-blocker treatment and electrical cardioversion may be an alternative effective therapy for sustained monomorphic VT refractory to amiodarone. The role of epinephrine in the termination of VT should be studied further, especially in patients pre-treated with amiodarone in combination with beta-blockers. PMID- 23110247 TI - The effect of prolonged exposure to war-related stress among hospital personnel with different affect types: lessons from the Second Lebanon War and the Gaza "Cast Lead" operation. AB - Two studies examined peritraumatic symptoms due to war-related stress among hospital personnel with different affect types. In Study 1, we examined 80 Israeli hospital personnel during the period they were exposed to frequent missile attacks in the Second Lebanon War. In Study 2, we examined 67 and 74 Israeli hospital personnel during the time they were exposed and were not exposed, respectively, to missile attacks in the Gaza "Cast Lead" operation. In both studies, hospital personnel completed measures of posttraumatic stress disorder symptoms as well as of positive- and negative-affect items (PA and NA, respectively). Exposed personnel with a positive congruent (high PA and low NA) or a deflated incongruent (low PA and low NA) affective types had a lower level of peritraumatic symptoms compared to those with a negative congruent (low PA and high NA) or an inflated incongruent (high PA and NA) affective types. Study 2 further showed that among non-exposed personnel, only personnel with a negative congruent affective type had a higher level of peritraumatic symptoms compared to personnel with other affective types. Clinical implications and required future studies are discussed. PMID- 23110248 TI - Neutron diffraction studies of the interaction between amphotericin B and lipid sterol model membranes. AB - Over the last 50 years or so, amphotericin has been widely employed in treating life-threatening systemic fungal infections. Its usefulness in the clinic, however, has always been circumscribed by its dose-limiting side-effects, and it is also now compromised by an increasing incidence of pathogen resistance. Combating these problems through development of new anti-fungal agents requires detailed knowledge of the drug's molecular mechanism, but unfortunately this is far from clear. Neutron diffraction studies of the drug's incorporation within lipid-sterol membranes have here been performed to shed light on this problem. The drug is shown to disturb the structures of both fungal and mammalian membranes, and co-localises with the membrane sterols in a manner consistent with trans-membrane pore formation. The differences seen in the membrane lipid ordering and in the distributions of the drug-ergosterol and drug-cholesterol complexes within the membranes are consistent with the drug's selectivity for fungal vs. human cells. PMID- 23110249 TI - Non-randomized mtDNA damage after ionizing radiation via charge transport. AB - Although it is well known that there are mutation hot spots in mtDNA, whether there are damage hot spots remain elusive. In this study, the regional DNA damage of mitochondrial genome after ionizing radiation was determined by real-time quantitative PCR. The mtDNA damage level was found to be dose-dependent and regional unequal. The control region was the most susceptible region to oxidative damage. GGG, as an typical hole trap during charge transport, was found to be disproportionally enriched in the control region. A total of 107 vertebrate mitochondrial genomes were then analyzed to testify whether the GGG enrichment in control region was evolutionary conserved. Surprisingly, the triple G enrichment can be observed in most of the homeothermal animals, while the majority of heterothermic animals showed no triple G enrichment. These results indicated that the triple G enrichment in control region was related to the mitochondrial metabolism during evolution. PMID- 23110250 TI - Multiple mutations and mutation combinations in the sodium channel of permethrin resistant mosquitoes, Culex quinquefasciatus. AB - A previous study identified 3 nonsynonymous and 6 synonymous mutations in the entire mosquito sodium channel of Culex quinquefasciatus, the prevalence of which were strongly correlated with levels of resistance and increased dramatically following insecticide selection. However, it is unclear whether this is unique to this specific resistant population or is a common mechanism in field mosquito populations in response to insecticide pressure. The current study therefore further characterized these mutations and their combinations in other field and permethrin selected Culex mosquitoes, finding that the co-existence of all 9 mutations was indeed correlated with the high levels of permethrin resistance in mosquitoes. Comparison of mutation combinations revealed several common mutation combinations presented across different field and permethrin selected populations in response to high levels of insecticide resistance, demonstrating that the co existence of multiple mutations is a common event in response to insecticide resistance across different Cx. quinquefasciatus mosquito populations. PMID- 23110251 TI - Sequential origin in the high performance properties of orb spider dragline silk. AB - Major ampullate (MA) dragline silk supports spider orb webs, combining strength and extensibility in the toughest biomaterial. MA silk evolved ~376 MYA and identifying how evolutionary changes in proteins influenced silk mechanics is crucial for biomimetics, but is hindered by high spinning plasticity. We use supercontraction to remove that variation and characterize MA silk across the spider phylogeny. We show that mechanical performance is conserved within, but divergent among, major lineages, evolving in correlation with discrete changes in proteins. Early MA silk tensile strength improved rapidly with the origin of GGX amino acid motifs and increased repetitiveness. Tensile strength then maximized in basal entelegyne spiders, ~230 MYA. Toughness subsequently improved through increased extensibility within orb spiders, coupled with the origin of a novel protein (MaSp2). Key changes in MA silk proteins therefore correlate with the sequential evolution high performance orb spider silk and could aid design of biomimetic fibers. PMID- 23110252 TI - Molecular architecture of human polycomb repressive complex 2. AB - Polycomb Repressive Complex 2 (PRC2) is essential for gene silencing, establishing transcriptional repression of specific genes by tri-methylating Lysine 27 of histone H3, a process mediated by cofactors such as AEBP2. In spite of its biological importance, little is known about PRC2 architecture and subunit organization. Here, we present the first three-dimensional electron microscopy structure of the human PRC2 complex bound to its cofactor AEBP2. Using a novel internal protein tagging-method, in combination with isotopic chemical cross linking and mass spectrometry, we have localized all the PRC2 subunits and their functional domains and generated a detailed map of interactions. The position and stabilization effect of AEBP2 suggests an allosteric role of this cofactor in regulating gene silencing. Regions in PRC2 that interact with modified histone tails are localized near the methyltransferase site, suggesting a molecular mechanism for the chromatin-based regulation of PRC2 activity.DOI:http://dx.doi.org/10.7554/eLife.00005.001. PMID- 23110253 TI - Foggy perception slows us down. AB - Visual speed is believed to be underestimated at low contrast, which has been proposed as an explanation of excessive driving speed in fog. Combining psychophysics measurements and driving simulation, we confirm that speed is underestimated when contrast is reduced uniformly for all objects of the visual scene independently of their distance from the viewer. However, we show that when contrast is reduced more for distant objects, as is the case in real fog, visual speed is actually overestimated, prompting drivers to decelerate. Using an artificial anti-fog-that is, fog characterized by better visibility for distant than for close objects, we demonstrate for the first time that perceived speed depends on the spatial distribution of contrast over the visual scene rather than the global level of contrast per se. Our results cast new light on how reduced visibility conditions affect perceived speed, providing important insight into the human visual system.DOI:http://dx.doi.org/10.7554/eLife.00031.001. PMID- 23110254 TI - Sequence specific detection of bacterial 23S ribosomal RNA by TLR13. AB - Toll-like receptors (TLRs) detect microbial infections and trigger innate immune responses. Among vertebrate TLRs, the role of TLR13 and its ligand are unknown. Here we show that TLR13 detects the 23S ribosomal RNA of both gram-positive and gram-negative bacteria. A sequence containing 13 nucleotides near the active site of 23S rRNA ribozyme, which catalyzes peptide bond synthesis, was both necessary and sufficient to trigger TLR13-dependent interleukin-1beta production. Single point mutations within this sequence destroyed the ability of the 23S rRNA to stimulate the TLR13 pathway. Knockout of TLR13 in mice abolished the induction of interleukin-1beta and other cytokines by the 23S rRNA sequence. Thus, TLR13 detects bacterial RNA with exquisite sequence specificity.DOI:http://dx.doi.org/10.7554/eLife.00102.001. PMID- 23110255 TI - New ideas on how drivers perceive speed emerge from the fog. AB - Experiments with a driving simulator contradict previous results by showing that car drivers slow down in fog. However, other forms of reduced visibility can cause drivers to speed up. PMID- 23110256 TI - Drug release from nanomedicines: Selection of appropriate encapsulation and release methodology. AB - The characterization of encapsulation efficiency and in vitro drug release from nanoparticle-based formulations often requires the separation of nanoparticles from unencapsulated drug. Inefficient separation of nanoparticles from the medium in which they are dispersed can lead to inaccurate estimates of encapsulation efficiency and drug release. This study establishes dynamic light scattering as a simple method for substantiation of the effectiveness of the separation process. Colistin-loaded liposomes, as an exemplar nano-sized delivery particle, were diluted to construct a calibration curve relating the amount of light scattering to liposome concentration. Dynamic light scattering revealed that, in the case of ultracentrifugation and centrifugal ultrafiltration, approximately 2.9% of the total liposomes remained in supernatants or filtrates, respectively. In comparison, filtrates obtained using pressure ultrafiltration contained less than 0.002% of the total liposomes from the formulation. Subsequent release studies using dialysis misleadingly implied a slow release of colistin over >48 h. In contrast, pressure ultrafiltration revealed immediate equilibration to the equilibrium distribution of colistin between the liposome and aqueous phases upon dilution. Pressure ultrafiltration is therefore recommended as the optimal method of choice for studying release kinetics of drug from nanomedicine carriers. PMID- 23110257 TI - Racotumomab: an anti-idiotype vaccine related to N-glycolyl-containing gangliosides - preclinical and clinical data. AB - Neu-glycolyl (NeuGc)-containing gangliosides are attractive targets for immunotherapy with anti-idiotype mAbs, because these glycolipids are not normal components of the cytoplasmic membrane in humans, but their expression has been demonstrated in several human malignant tumors. Racotumomab is an anti-idiotype mAb specific to P3 mAb, an antibody which reacts to NeuGc-containing gangliosides, sulfatides, and other antigens expressed in tumors. Preparations containing racotumomab were able to induce a strong anti-metastatic effect in tumor-bearing mice. Different Phase I clinical trials have been conducted in patients with advanced melanoma, breast cancer, and lung cancer. The results of these clinical trials demonstrated the low toxicity and the high immunogenicity of this vaccine. The induced antibodies recognized and directly killed tumor cells expressing NeuGcGM3. A Phase II/III multicenter, controlled, randomized, double blind clinical trial was conducted to evaluate the effect of aluminum hydroxide-precipitated racotumomab vaccine in overall survival in patients with advanced non-small cell lung cancer. The clinical results of this study showed a significant clinical benefit in the patients who were treated with the anti idiotype vaccine. PMID- 23110258 TI - Teaching wilderness first aid in a remote First Nations community: the story of the Sachigo Lake Wilderness Emergency Response Education Initiative. AB - OBJECTIVE: To understand how community members of a remote First Nations community respond to an emergency first aid education programme. STUDY DESIGN: A qualitative study involving focus groups and participant observation as part of a community-based participatory research project, which involved the development and implementation of a wilderness first aid course in collaboration with the community. METHODS: Twenty community members participated in the course and agreed to be part of the research focus groups. Three community research partners validated and reviewed the data collected from this process. These data were coded and analysed using open coding. RESULTS: Community members responded to the course in ways related to their past experiences with injury and first aid, both as individuals and as members of the community. Feelings of confidence and self efficacy related access to care and treatment of injury surfaced during the course. Findings also highlighted how the context of the remote First Nations community influenced the delivery and development of course materials. CONCLUSIONS: Developing and delivering a first aid course in a remote community requires sensitivity towards the response of participants to the course, as well as the context in which it is being delivered. Employing collaborative approaches to teaching first aid can aim to address these unique needs. Though delivery of a first response training programme in a small remote community will probably not impact the morbidity and mortality associated with injury, it has the potential to impact community self-efficacy and confidence when responding to an emergency situation. PMID- 23110259 TI - Axitinib, a new therapeutic option in renal cell carcinoma. AB - Axitinib is a small-molecule protein-tyrosine kinase receptor inhibitor specifically targeting this family of receptors, in addition to platelet-derived growth factor receptor and proto-oncogene c-Kit. Improved knowledge of kidney cancer development, and specifically mutations in the VHL gene, has supported the targeting of angiogenesis pathways. Axitinib is the most recently approved agent for use in metastatic renal cell carcinoma. This review will focus on the preclinical pharmacology, pharmacokinetics and clinical activity of this agent, and describe its place in the current treatment of renal cell carcinoma. PMID- 23110260 TI - Linagliptin as add-on therapy for type 2 diabetes - an overview. AB - The pathogenesis of type 2 diabetes (T2D) can result in decreased levels of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which under normal circumstances increase insulin secretion and suppress glucagon release. A new form of drug therapy known as dipeptidyl peptidase 4 (DPP IV) inhibitors has focused on increasing the circulating levels of these "incretin" hormones in order to improve glycemic control in patients with T2D. The DPP IV inhibitors saxagliptin, vildagliptin, linagliptin, alogliptin and sitagliptin function by inhibiting the enzyme DPP IV, which breaks down GLP-1 and GIP, and have had significant success. However, with most DPP IV inhibitors being extensively excreted renally, this is a significant issue, as a large proportion of diabetic patients suffer from renal complications. Linagliptin is a novel DPP IV inhibitor that is excreted primarily by the hepatic route, with little need for dose adjustment in patients with renal impairment. It therefore represents a major advancement in the pharmacotherapy of patients with T2D. PMID- 23110261 TI - Mogamulizumab for the treatment of adult T-cell leukemia/lymphoma. AB - T-cell neoplasms, such as adult T-cell leukemia/lymphoma (ATL) and peripheral T cell lymphoma, are particularly aggressive and, despite novel combination chemotherapy regimens, still have extremely poor prognoses. As such, there is an unmet medical need for novel therapies and the anti-chemokine CCR4 receptor antibody mogamulizumab (KW-0761) may offer such an option for the treatment of ATL. Mogamulizumab is a humanized antibody, with a defucosylated Fc region, which enhances antibody-dependent cellular cytotoxicity. As a result, mogamulizumab demonstrates potent antitumor activity at much lower doses than other therapeutic monoclonal antibodies. Clinical testing indicates that mogamulizumab is effective and well tolerated, with a predictable pharmacokinetic profile in patients with relapsed/refractory ATL. This drug was recently granted regulatory approval in Japan for this indication and continues to be evaluated in clinical trials in both the U.S. and Europe. PMID- 23110262 TI - Revisiting thalidomide: fighting with caution against idiopathic pulmonary fibrosis. AB - Thalidomide is an infamous drug whose use by pregnant women in the middle of last century tragically resulted in serious birth defects. However, as a result of its potent immunomodulatory, anti-inflammatory and antiangiogenic properties, thalidomide may be a potential therapy in many diseases. In recent years, thalidomide has been used effectively to treat various malignancies, including multiple myeloma, myelodysplastic syndromes, renal cell cancer, glioblastoma multiforme and prostate cancer. In addition, thalidomide has also proven effective against other immune-related diseases, including erythema nodosum leprosum and sarcoidosis. Idiopathic pulmonary fibrosis (IPF) is a deadly fibrotic disease with no effective treatment options. However, there is data to suggest that thalidomide may be useful in treating the chronic, disabling cough that accompanies IPF. It remains to be seen whether the immunomodulatory and antiangiogenic properties of thalidomide will also make it a potential therapy against the clinical progression of IPF. PMID- 23110263 TI - New molecular methods for the diagnosis of Clostridium difficile infections. AB - Clostridium difficile is recognized as the major agent responsible for nosocomial diarrhea in hospitalized patients. Accurate diagnosis of C. difficile infection (CDI) is essential for optimal treatment and prevention but continues to be challenging. There are currently two reference assays for the diagnosis of CDI with different targets: the cytotoxicity assay that detects free toxins and the toxigenic culture which detects the organism with the potential to produce toxin. In 2009, nucleic acid amplification tests (NAATs) based on the detection of toxin genes became commercially available for the diagnosis of CDI. These methods have been compared to toxigenic culture (equivalent endpoint) and showed a good correlation. Results can be provided to clinicians within the same day as the stool sample. According to the different assays, the tests are amenable to both batch and on-demand testing. The cost of these assays is still prohibitive for many laboratories and their place among the different diagnostic options remains to be clarified. In particular, these tests again raise the crucial question of the clinical significance of the presence of a toxigenic strain without any free toxin in stools. PMID- 23110265 TI - Clinical decision making-the danger of confirmation bias. PMID- 23110264 TI - A report from the 37th Annual Meeting of the International Urogynecological Association (September 4-8 - Brisbane, Australia). AB - Urinary incontinence was one of the major topics discussed in Brisbane during the International Urogynecological Association (IUGA)'s 37th Annual Meeting. Brisbane Convention Center was the site of this year's meeting, wherein podium, oral poster and non-moderated poster sessions presented the latest advances in urogynecology. The following report summarizes state-of-the-art therapies for common urogynecological diseases as discussed in Brisbane during the beautiful pre-spring days in early September 2012. PMID- 23110266 TI - Topical review: sleep bruxism, headaches, and sleep-disordered breathing in children and adolescents. AB - Sleep bruxism, a well-known burden for dentists, is commonly observed in pediatric populations. Dentists are responsible for the detection and prevention of the detrimental consequences on the stomatognathic system that may occur in some patients with sleep bruxism. However, sleep bruxism is much more than tooth wear, since it is frequently associated with orofacial pain, headaches, and other more severe sleep disorders, such as sleep-disordered breathing. Although the mechanisms underlying the possible interactions among sleep bruxism, headaches, and sleep-disordered breathing need further research, these conditions are often concomitant. A literature search was performed to identify relevant publications related to the topic, which have been integrated in this topical review. The aim of this article was to provide a brief overview on sleep bruxism, headaches, and sleep-disordered breathing in pediatric patients and to promote a multispecialist approach (including dentists, sleep specialist physicians, and psychologists) in the diagnosis and management of these frequently associated disorders. PMID- 23110267 TI - The effects of capsaicin-induced intraoral mucosal pain on jaw movements in humans. AB - AIMS: To determine whether mucosal pain, evoked through a novel topical capsaicin model, has an effect on jaw movement and whether psychologic factors have an association with any pain-induced movement effects. METHODS: Mandibular movement was recorded from 26 asymptomatic subjects during free opening and closing, resistant opening jaw movements, and free and standardized chewing, at baseline and in test sessions while the subjects were wearing a custom maxillary mouthguard coated with either capsaicin cream (pain group, 13 subjects) or placebo cream (control group, an additional 13 subjects). All subjects completed the Depression Anxiety Stress Scales (DASS) and the Pain Catastrophizing Scale (PCS). Statistical analyses were made with independent t tests and bivariate correlation analyses. RESULTS: Capsaicin induced moderate pain in the pain group, but there were no significant differences between the two groups in the change of kinematic variables from baseline except for a significantly greater increase from baseline in the number of chewing cycles per second (chewing rate) for free (t = 2.74, P = .011) and standardized chewing (t = 2.10, P = .047) in the pain group compared with the control group. In the pain group, the DASS anxiety score was negatively correlated (r = -.70, P = .007), with the change of mean opening velocity from the baseline to the test session in the free opening task, and the DASS depression score was negatively correlated to the increase of chewing rate in the free chewing task from the baseline to the test session (r = -.56, P = .046). CONCLUSION: Capsaicin-induced mucosal pain resulted in a significant increase in chewing rate but had no effect on amplitude or velocity in opening/closing jaw movements and chewing. Anxiety and depression scores correlated negatively with velocity in free opening jaw movement and chewing rate, respectively. PMID- 23110268 TI - Lack of temporal summation but distinct aftersensations to thermal stimulation in patients with combined tension-type headache and myofascial temporomandibular disorder. AB - AIMS: To compare patients with combined tension-type headache and myofascial temporomandibular disorder (TMD) with control subjects on two measures of central processing-ie, temporal summation and aftersensations to heat stimulation in the trigeminal nerve and spinal nerve territories. METHODS: A novel heat stimulation protocol was used in which 13 females with tension-type headache/TMD and 20 female controls were exposed to 11 painful heat stimuli at a rate of 0.33 Hz. Two temperature ranges (low, 44 degrees C to 46 degrees C; high, 45 degrees C to 47 degrees C) were tested on the cheek and arm in separate trials. Perceived pain was rated on a 100-mm visual analog scale after the second, sixth, and eleventh stimulus presentation and every 15 seconds after the final stimulus presentation (aftersensations) for up to 3 minutes. The duration of aftersensations was compared using the student unpaired t test with Welch correction. RESULTS: Temporal summation was not observed in any of the groups, but aftersensations were consistently reported. The aftersensations lasted longer in tension-type headache/TMD patients (right cheek, 100.4 +/- 62.0 seconds; right arm, 115.4 +/- 64.0 seconds) than in controls (right cheek, 19.5 +/- 2.5 seconds; right arm, 20.3 +/- 2.7 seconds) (P < .05). A cutoff value (right cheek, 44.6 seconds; right arm, 41.5 seconds) provided a sensitivity and specificity of 0.77 and 0.95, respectively, with the high stimulus protocol. CONCLUSION: The results from this pilot study suggest that aftersensations to painful heat stimulation can appear without temporal summation. Furthermore, the developed test protocol has a good predictive value and may have the potential to discriminate between tension-type headache/TMD patients and control subjects. PMID- 23110269 TI - Quality and content of internet-based information on temporomandibular disorders. AB - AIMS: To use a range of evaluation instruments to assess the content and quality of websites about temporomandibular disorders (TMD) and thereby provide guidance regarding the actual accuracy and comprehensiveness of the information of the sites. METHODS: Sixty-seven websites resulting from an Internet search with the word "TMD" were evaluated using Journal of the American Medical Association (JAMA), DISCERN, and Health on the Net (HON) criteria, along with an evaluation method to assess the scientific quality of the website contents. Results were compared according to reviewer, website type, and presence of HON seal. One-way analysis of variance (ANOVA), Student t test, chi-square test, and Pearson correlation analysis were used as appropriate. RESULTS: The mean content, HON, and DISCERN scores were 38.9%, below 50%, and 53.9% of the maximum possible score, respectively. Fewer than 50% of the sites displayed the author or reference of the information according to the JAMA benchmarks criteria. Every evaluation criteria showed good agreement among reviewers. Commercial websites were the most common, while sites of nonprofit organizations showed the highest content scores. The overall quality was poor to moderate for all website types. CONCLUSION: Sites concerning TMD were poorly organized and maintained. Also, most sites contained insufficient or scientifically incorrect information that could have a negative effect on the treatment outcome and prognosis of TMD. Clinicians should guide patients to reputable sources of information that will enhance patient comprehension and better treatment outcomes. PMID- 23110270 TI - Women with Ehlers-Danlos syndrome experience low oral health-related quality of life. AB - AIMS: To investigate the perceived impact of oral health-related quality of life problems in individuals with Ehlers-Danlos syndrome. METHODS: Members of the Swedish Ehlers-Danlos Syndrome Association completed the Oral Health Impact Profile (OHIP-14). Of the 250 participating individuals, 223 were women, and they were the main focus of the analyses. The results were compared with a previous study of the oral health impact on quality of life in the Swedish population. Statistical methods used for comparison were the Student t and chi-square tests. RESULTS: The mean OHIP-14 value for the entire Ehlers-Danlos syndrome group was 11.1. The mean for women was 11.8, which was significantly higher than 6.8 of the comparison group. The OHIP-14 score varied among age groups, and the highest mean value was found in the age group between 56 and 65 years of age. The most statistically significant differences between the subjects with Ehlers-Danlos syndrome and the comparison group were found for OHIP items 3, 4, and 8: "I have had pain in the mouth," "I have had discomfort when eating," and "I have been forced to interrupt meals." CONCLUSION: It is well-known that Ehlers-Danlos syndrome has a considerable impact on health-related quality of life, and this study is the first to reveal that women with Ehlers-Danlos syndrome report a low oral health-related quality of life as measured with the OHIP-14. Dimensions that were particularly relevant were physical pain, psychologic discomfort, and handicap. PMID- 23110271 TI - The characteristics of autonomic nervous system disorders in burning mouth syndrome and Parkinson disease. AB - AIMS: To conduct a clinical electrophysiologic evaluation of autonomic nervous system functions in patients with burning mouth syndrome and Parkinson disease and estimate the type and intensity of the autonomic dysfunction. METHODS: The study involved 83 subjects-33 with burning mouth syndrome, 20 with Parkinson disease, and 30 controls. The BMS group included 27 women and 6 men (median age, 60.0 years), and the Parkinson disease group included 15 women and 5 men (median age, 66.5 years). In the control group, there were 20 women and 10 men (median age, 59.0 years). All patients were subjected to autonomic nervous system testing. In addition to the Low autonomic disorder questionnaire, heart rate variability (HRV), deep breathing (exhalation/inspiration [E/I] ratio), and sympathetic skin response (SSR) tests were performed in all cases. Parametric and nonparametric tests (ANOVA, Kruskal-Wallis, and Scheffe tests) were used in the statistical analysis. RESULTS: The mean values for HRV and E/I ratios were significantly lower in the burning mouth syndrome and Parkinson disease groups. Significant prolongation of SSR latency in the foot was revealed in both burning mouth syndrome and Parkinson disease patients, and lowering of the SSR amplitude occurred in only the Parkinson disease group. The autonomic questionnaire score was significantly higher in burning mouth syndrome and Parkinson disease patients than in the control subjects, with the Parkinson disease group having the highest scores. CONCLUSION: In patients with burning mouth syndrome, a significant impairment of both the sympathetic and parasympathetic nervous systems was found but sympathetic/parasympathetic balance was preserved. The incidence and intensity of autonomic nervous system dysfunction was similar in patients with burning mouth syndrome and Parkinson disease, which may suggest some similarity in their pathogeneses. PMID- 23110272 TI - The relationship between resting arterial blood pressure and acute postoperative pain in endodontic patients. AB - AIMS: To evaluate the relationship between preoperative resting arterial blood pressure and postoperative pain in patients undergoing nonsurgical root canal therapy. METHODS: Written informed consent was obtained from normotensive patients seeking treatment for teeth with a preoperative diagnosis of pulpal necrosis and periradicular periodontitis. Preoperative resting blood pressure was recorded, and nonsurgical root canal therapy was initiated using a standardized protocol. Patients recorded their pre- and postoperative pain intensity on a 100 mm visual analog scale (VAS) for 7 days after the procedure. A linear regression model to predict postoperative VAS intensity used preoperative pain and blood pressure values as covariates. Pearson correlations were calculated to assess the relationship between the measures of preoperative blood pressure and both pre- and postoperative pain. RESULTS: After controlling for preoperative pain, significant correlations were observed between preoperative systolic blood pressure and postoperative pain (P < .05), as well as between preoperative pulse pressure and postoperative pain (P < .005) on day 1. CONCLUSION: This study has provided further evidence of a functional interaction between the cardiovascular and trigeminal pain regulatory systems. Understanding this complex relationship may lead to enhanced pain management strategies. PMID- 23110273 TI - Effect of estrogen and dietary loading on condylar cartilage. AB - AIMS: To study the effect of estrogen deficiency and altered temporomandibular joint loading on the histomorphology of condylar cartilage and on the expression of types II and X collagen and matrix metalloproteinase-3 (MMP-3). METHODS: Thirty-six female rats were divided into four groups: ovariectomized rats on a normal diet, nonovariectomized control rats on a normal diet, ovariectomized rats on a soft diet, and nonovariectomized control rats on a soft diet. Ovariectomy was performed at the age of 60 days. Repeated-measures ANOVA was used to analyze the data. RESULTS: The condylar cartilage in the ovariectomized normal diet group showed a significantly higher number of cells than in the nonovariectomized control rats (P < .001). The proportional amount of MMP-3 expression was significantly higher in the ovariectomized rats than in the nonovariectomized control rats in both diet groups (P < .001). The area covered by types II and X collagen was significantly higher in the experimental groups than in the control groups (P < .01). CONCLUSION: Condylar cartilage is sensitive to both estrogen level and dietary loading. PMID- 23110274 TI - Validation of a novel rat-holding device for studying heat- and mechanical-evoked trigeminal nocifensive behavioral responses. AB - AIMS: To test the reliability and validity of a novel rat-holding device designed to be used in conjunction with the plantar test apparatus for studying nocifensive behavioral responses in an established model of temporomandibular joint (TMJ) pathology. METHODS: Thirty-five young adult male Sprague-Dawley rats were used. Withdrawal latencies in response to infrared 40 heat stimulation of the submandibular region in naive animals (n = 4) and animals injected with saline or complete Freund's adjuvant (CFA) in the TMJ (n > 9) were measured over a 2-week time period. Nocifensive responses to mechanical stimulation of the cutaneous tissue directly over the TMJ with von Frey filaments were investigated in animals injected with CFA in the TMJ (n = 6). The effect on nocifensive responses to heat and mechanical stimulation of subcutaneous administration of buprenorphine (0.05 mg/kg) into the hindquarter was assessed in CFA and cotreated animals (n = 6). Statistical analysis was performed using a nonparametric Mann Whitney U test. RESULTS: Under basal conditions, withdrawal latencies to heat stimulation of the orofacial region remained consistently around 15 seconds over 14 days. Unilateral CFA injection in the TMJ significantly decreased heat withdrawal latencies on days 1, 2, 7, and 14 in the ipsilateral side (P < .05), but not contralateral side, when compared with basal values. CFA also significantly decreased the nocifensive threshold to mechanical stimulation on days 1, 2, and 7 postinjection (P < .05). CFA-mediated changes in heat withdrawal and mechanical thresholds in the orofacial region were significantly suppressed by subcutaneous administration of buprenorphine into the hindquarter (P < .05). CONCLUSION: Findings from this study provide evidence to validate the use of this holding device for studying nocifensive behaviors in the orofacial region of rats in response to heat or mechanical orofacial stimulation. PMID- 23110275 TI - [Is Danish percutaneous coronary intervention too centralized?]. PMID- 23110276 TI - [Outpatient forced treatment - pros and cons]. PMID- 23110277 TI - Medical doodles: 30 minutes well spent. Interview by Carol Ann Courneya. PMID- 23110278 TI - Foot-and-mouth disease too dangerous to study on mainland. PMID- 23110279 TI - Lord Dorwin's reviews. PMID- 23110280 TI - Hollywood vet receives AVMA Award. Interview by Katie Burns. PMID- 23110281 TI - The ups and downs of pet demographics. PMID- 23110282 TI - For veterinary medicine, it's the best--and worst--of times: AVMA President Aspros on the state of the profession. PMID- 23110283 TI - Raw food policy draws debate: AVMA advises against feeding dogs, cats raw animal proteins. PMID- 23110284 TI - HOD wants better communication with nonveterinary pharmacies. PMID- 23110285 TI - Word about a good medical journal. PMID- 23110286 TI - To follow the right path... PMID- 23110287 TI - Contracting medical services of intensive therapy by NFZ in Poland, i.e. life saving services but only partially? PMID- 23110288 TI - Adult intensive therapy services contracted by the National Health Fund in 2012. AB - BACKGROUND: Limited financial resources of the National Health Fund (NHF) affect the extent of funding allocated for intensive therapy services. The objective of the study was to analyse the levels of funding the departments of anaesthesiology and intensive therapy are provided with by NHF regional branches in 2012. METHODS: Websites of NHF regional branches were surveyed to obtain the data about the therapeutic entities containing departments of anaesthesiology and intensive therapy, whose services were contracted by NHF in 2012. The contract value, number of contracted points and price of a point were determined for each department. Moreover, based on preliminary survey of the National Official Register of Economic Entities (REGON), the number of intensive therapy beds in the departments in question was calculated. RESULTS: The highest expenditure on adult intensive therapy per one citizen was found in the West Pomeranian, Podlasie and Lesser Poland provinces whereas the lowest one in Swietokrzyskie, Pomeranian and Lublin provinces. CONCLUSION: Funds allocated by NHF for services of departments of anaesthesiology and intensive therapy are insufficient. PMID- 23110289 TI - Paediatric intensive therapy services contracted by the National Health Fund in 2012. AB - BACKGROUND: Departments of paediatric anaesthesiology and intensive therapy are relevant elements of the healthcare system in Poland. The aim of the present study was to analyse the level of funding of departments of paediatric anaesthesiology and intensive therapy provided by regional branches of the National Health Fund (NHF) in 2012. METHODS: The survey of websites of regional branches of NHF provided data about therapeutic entities with departments of paediatric anaesthesiology and intensive therapy, whose services were contracted by NHF in 2012. The contract value for 2012, number of contracted points and price of a point were defined for each department. Moreover, using the Register of Therapeutic Entities, the number of intensive therapy beds in the departments of paediatric anaesthesiology and intensive therapy in these entities was determined. RESULTS: The highest expenditure for intensive therapy of children and teenagers under 17 years of age per one citizen was found in the Silesian, Opole and Lodz provinces; the lowest expenditure was observed in the Lubusz (no contracted departments), Swietokrzyskie and Podkarpacie provinces. CONCLUSION: The level of funding of departments of paediatric anaesthesiology and intensive therapy provided by NHF appears to be sufficient; however, the staff and equipment potential of many such departments is not fully exploited. PMID- 23110290 TI - Comparison of target controlled infusion and total intravenous anaesthesia with propofol and remifentanil for lumbar microdiscectomy. AB - BACKGROUND: Propofol is often combined with remifentanil for induction and maintenance of total intravenous anaesthesia. Target-controlled infusion (TCI) permits adapting infusion to pharmacokinetic models. In this study we compared depth of anaesthesia, haemodynamic variables and times to recovery in patients scheduled for lumbar microdiscectomy and receiving either manually controlled (group I) or target- controlled (group II) infusion of propofol and remifentanil for anaesthesia. METHODS: Twenty three patients (group I) received a bolus induction of propofol 2 mg kg(-1) and remifentanil 1 MUg kg(-1). Twenty five patients (group II) received propofol and remifentanil at an initial effect site concentration of 4 MUg mL(1) and 4 ng mL(-1) respectively. According to BIS and haemodynamics, propofol/remifentanil infusion rates (group I) or concentration of propofol/remifentanil at an effect-site were adjusted upwards or downwards. We monitored bispectral index (BIS), mean arterial pressure (MAP) and heart rate (HR) during subsequent stages of anaesthesia and operation (T1-T10). RESULTS: Induction and total doses of propofol and remifentanil, times to recovery were comparable in both groups. BIS was lower at T2-T10 in comparison to baseline values. At T4 and T5 BIS was lower in group II than in group I. In group I, mean HR values were lower at T7-T9 in comparison to baseline values. In exeption of MAP at T6 in group II, MAP was lower at T2-T9 in comparison to baseline values in both groups. CONCLUSION: There are no clinically important differences in haemodynamic variables, depth of anaesthesia, time to recovery and doses of propofol/remifentanil between manually controlled and target-controlled infusion of propofol and remifentanil. PMID- 23110291 TI - Emotional reactions and needs of family members of ICU patients. AB - INTRODUCTION: The aim of the study was to determine emotional reactions and needs of families of ICU patients. METHODS: The study group included 60 relatives of ICU patients, aged 18-80 years. The diagnostic questionnaire-based survey was conducted. The questionnaire contained questions regarding demographic data, emotions and needs as well as the Courtauld Emotional Control Scale (CECS). RESULTS: The major emotions of patients' families on ICU admission were anxiety, uncertainty, fear, depression, and nervousness (particularly among parents and adult offsprings). On second-third day of hospitalisation, the emotions became less severe (P < 0.001). The anxiety-related emotional reactions were better controlled by men (P < 0.01); most women experienced stronger negative emotions (P < 0.05) and their needs to receive information and to be involved in patient care were expressed more. CONCLUSIONS: Negative emotions of ICU patients' relatives were highly intense, especially amongst parents and adult children. Women were characterised by higher levels of emotions and needs compared to men. PMID- 23110292 TI - Liver procurement from a brain-dead kidney transplant recipient--a case report. AB - The shortage of organ donors has led to new strategies to increase the availability of allografts for transplantation, such as organ procurement from brain-dead organ transplant recipients. We present the case of a 26 year-old male brain-dead liver donor who had been a kidney transplant recipient six years previously. The liver donor described in this report, as the first in Poland, has paved a new, although as yet narrow, way in the field of organ donation. This is also the first case described in the medical literature of liver recovery from a brain-dead kidney transplant recipient on an immunosuppressive regimen with three immunosuppressive agents. Although transplant recipients represent an uncommon group of deceased organ donors, it is probable that situations when they may be considered as potential organ donors will occur more often. Therefore, although specific criteria for organ donors exist, each reported potential donor should be considered individually, and brain-dead solid organ recipients should not be excluded a priori as organ donors; both their native and allografted organs may be recovered and successfully transplanted. In this study, we also review the current state of knowledge on the reuse of organs. PMID- 23110293 TI - Multiple organ failure after a fall from heights complicated by cardiac rupture and subacute cardiac tamponade. AB - Accidents and posttraumatic injuries are one of the most important health and social problems. Most of them require immediate medico-surgical intervention. Accidents are the leading cause of death among young people under age of 40. In 25% of cases they lead to disability. Fall from height causes inter alia blunt chest trauma, and internal organs contusion (e.g. heart and lungs), and may be fatal to substantial number of trauma victims. Excluding criminal injuries, this kind of trauma may occur during accidental fall or deliberate suicide attempt. Paper describes polytrauma victim who fell down from the eight floor (suicide attempt). Subacute pericardial tamponade, caused by cardiac wall rupture,occurred several hours after accident. The patient survived politrauma with severe cardiac injury complication thanks to effective multidisciplinary and multistage surgical treatment. PMID- 23110294 TI - Pharmacokinetic-pharmacodynamic modelling of antibiotic therapy in severe sepsis. AB - The antibiotic treatment of severe sepsis poses an increasing challenge in ICU. The multidrug resistance and diverse pharmacokinetics of antibiotics requires a different approach on antibiotic therapy because of the inadequate serum antibiotic levels found in ICU patients. The current guidelines or recommendations of antibiotic treatment take into account the pharmacokinetic parameters in determining the proper dosage. The recommended antibiotic treatment of severe sepsis requires daily assessment and dosage adjustment based on measurements of antibiotic concentrations in order to optimize the treatment. PMID- 23110295 TI - Management of perioperative stress in children and parents. Part I--the preoperative period. AB - Hospitalisation and surgery are undoubtedly one of the most difficult experiences the children and their parents have to face. The lack of appropriately provided information about treatment and other hospitalization-related aspects increases anxiety and uncertainty. Besides showing sincere empathy, physicians working with paediatric patients should know the strategies to reduce perioperative stress in children and their families. The first part of our paper describes various well tried methods of preoperative management, some of which can be applied before hospitalization. The crucial elements of such a strategy are to dissipate the emerging doubts by providing children and parents with relevant and understandable information and to familiarise them with the hospital setting. PMID- 23110296 TI - Management of perioperative stress in children and parents. Part II--anaesthesia and postoperative period. AB - The majority of children, even those well prepared and with positive attitudes, experiences stress in the operating theatre and during the postoperative period. In some cases, the stress is even stronger for their parents. The role of anaesthetists is to minimize the unpleasant sensations by providing painless vein cannulation, uneventful induction of anaesthesia, suitably planned and timed analgesia, and prevention of postoperative vomiting. The effectiveness of combined analgesics, early administration of saturating doses and analgesia supplemented or based on methods of block anaesthesia - particularly on peripheral and local blocks, less appreciated in children, have been highlighted. Such a stress-reducing strategy should be initiated before hospitalisation and consistently continued to its completion or even longer, the example of which are one-day surgery patients who should receive prescriptions for or suitable drugs (mainly analgesics) on discharge for use in the home setting. Preparation of local programmes for management reducing surgery-associated stress in children is worth recommending. PMID- 23110298 TI - 1,8-naphthyridine-derived Ni(2+)/Cu(2+)-selective fluorescent chemosensor with different charge transfer processses. AB - A highly fluorescent chemosensor based on 1,8-naphthyridine with high sensitivity and selectivity toward Ni(2+)/Cu(2+) over other cations both in aqueous solution over a wide pH range (4-10) and in cellular environments was developed. Counteranions such as acetate, sulfate, nitrate, and perchlorate have no influence on the detection of such metal ions. Ethylenediamine showed high selectivity toward the in situ-prepared Cu(2+) complex over the Ni(2+) complex, which can be applied to distinguish Ni(2+) and Cu(2+). The Ni(2+)-induced fluorescence on-off mechanism was revealed to be mediated by intramolecular charge transfer from the metal to the ligand, while that by Cu(2+) involves intramolecular charge transfer from the ligand to the metal, as confirmed by picosecond time-resolved fluorescence spectroscopy and time-dependent density functional theory calculations. PMID- 23110297 TI - Synthesis of chamaecypanone C analogues from in situ-generated cyclopentadienones and their biological evaluation. AB - A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5 diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated o-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure. PMID- 23110299 TI - Proteomic profiling of breast tissue collagens and site-specific characterization of hydroxyproline residues of collagen alpha-1-(I). AB - In a quantitative proteomics-based breast cancer study of complementary normal and tumor biopsies, 22 collagen isoforms were detected by LC-MALDI TOF/TOF MS. By applying proline oxidation, representing hydroxyproline, in database search parameters a substantial increase in assigned MS/MS was achieved, boosting the average (three experiments) number of peptides from 306 to 8126 for collagen alpha-1(I). The plethora of peptide identities for alpha-1(I) was disproportionate with full length protein sequence coverage which only increased from 28.3 to 64.4%. The peptides, in fact, constituted an extensive two dimensional array of isomers exhibiting heterogeneity in degree and location of hydroxyproline residues. A total of 3433 peptides, scores>36 (p<0.01), constituting 94% of the triple helix region of collagen alpha-1(I) provided a census of proline hydroxylation levels defined as the rate of site occupancy for each peptide isomer (r) and the total site occupancy for each proline residue (t). MS/MS and MS/MS/MS analysis, by MALDI-QIT-TOF MS, was used to corroborate site-specific proline hydroxylation of the original data. In addition, iTRAQ data for each collagen isoform in each of 10 patients (grouped by disease) was determined and indicated an increase in fibrillar collagens in invasive carcinoma but little change in fibroadenoma or DCIS. PMID- 23110301 TI - Radioactive contamination of natural ecosystems: seeing the wood despite the trees. PMID- 23110300 TI - Molecular basis for membrane pore formation by Bax protein carboxyl terminus. AB - Bax protein plays a key role in mitochondrial membrane permeabilization and cytochrome c release upon apoptosis. Our recent data have indicated that the 20 residue C-terminal peptide of Bax (BaxC-KK; VTIFVAGVLTASLTIWKKMG), when expressed intracellularly, translocates to the mitochondria and exerts lethal effect on cancer cells. Moreover, the BaxC-KK peptide, as well as two mutants where the two lysines are replaced with glutamate (BaxC-EE) or leucine (BaxC-LL), have been shown to form relatively large pores in lipid membranes, composed of up to eight peptide molecules per pore. Here the pore structure is analyzed by polarized Fourier transform infrared, circular dichroism, and fluorescence experiments on the peptides reconstituted in phospholipid membranes. The peptides assume an alpha/beta-type secondary structure within membranes. Both beta-strands and alpha helices are significantly (by 30-60 deg) tilted relative to the membrane normal. The tryptophan residue embeds into zwitterionic membranes at 8-9 A from the membrane center. The membrane anionic charge causes a deeper insertion of tryptophan for BaxC-KK and BaxC-LL but not for BaxC-EE. Combined with the pore stoichiometry determined earlier, these structural constraints allow construction of a model of the pore where eight peptide molecules form an "alpha/beta-ring" structure within the membrane. These results identify a strong membranotropic activity of Bax C-terminus and propose a new mechanism by which peptides can efficiently perforate cell membranes. Knowledge on the pore forming mechanism of the peptide may facilitate development of peptide-based therapies to kill cancer or other detrimental cells such as bacteria or fungi. PMID- 23110302 TI - Giant vesicles as encapsulating matrix for stabilizing alcohol oxidase and as container for coupled enzymatic reactions. AB - Encapsulation of a multimeric alcohol oxidase (AOx) in giant vesicles (GVs) was prepared by rapid evaporation method. The specific activity (477 U/mg-protein) of the GV encapsulated AOx was 3.5 fold higher than the free AOx. The half-life (~59.4 hours) of the encapsulated AOx was 20-fold higher than the free enzyme at 30 degrees C. Further, the GV was used to encapsulate AOx and HRP together as coupled reaction catalyst for chromogen-based optical detection of alcohols. The results confirmed potential application of the GV as micro-dimensional container for enhancing stability, activity and biosensing applications of AOx. PMID- 23110303 TI - More on the losses of dissolved CO(2) during champagne serving: toward a multiparameter modeling. AB - Pouring champagne into a glass is far from being inconsequential with regard to the dissolved CO(2) concentration found in champagne. Three distinct bottle types, namely, a magnum bottle, a standard bottle, and a half bottle, were examined with regard to their loss of dissolved CO(2) during the service of successively poured flutes. Whatever the bottle size, a decreasing trend is clearly observed with regard to the concentration of dissolved CO(2) found within a flute (from the first to the last one of a whole service). Moreover, when it comes to champagne serving, the bottle size definitely does matter. The higher the bottle volume, the better its buffering capacity with regard to dissolved CO(2) found within champagne during the pouring process. Actually, for a given flute number in a pouring data series, the concentration of dissolved CO(2) found within the flute was found to decrease as the bottle size decreases. The impact of champagne temperature (at 4, 12, and 20 degrees C) on the losses of dissolved CO(2) found in successively poured flutes for a given standard 75 cL bottle was also examined. Cold temperatures were found to limit the decreasing trend of dissolved CO(2) found within the successively poured flutes (from the first to the last one of a whole service). Our experimental results were discussed on the basis of a multiparameter model that accounts for the major physical parameters that influence the loss of dissolved CO(2) during the service of a whole bottle type. PMID- 23110304 TI - Faulty analysis leads to erroneous conclusions. PMID- 23110305 TI - Influence of platform and abutment angulation on peri-implant bone. A three dimensional finite element stress analysis. AB - The aim of this study was to evaluate stress distribution on the peri-implant bone, simulating the influence of Nobel Select implants with straight or angulated abutments on regular and switching platform in the anterior maxilla, by means of 3-dimensional finite element analysis. Four mathematical models of a central incisor supported by external hexagon implant (13 mm * 5 mm) were created varying the platform (R, regular or S, switching) and the abutments (S, straight or A, angulated 15 degrees ). The models were created by using Mimics 13 and Solid Works 2010 software programs. The numerical analysis was performed using ANSYS Workbench 10.0. Oblique forces (100 N) were applied to the palatine surface of the central incisor. The bone/implant interface was considered perfectly integrated. Maximum (sigmamax) and minimum (sigmamin) principal stress values were obtained. For the cortical bone the highest stress values (sigmamax) were observed in the RA (regular platform and angulated abutment, 51 MPa), followed by SA (platform switching and angulated abutment, 44.8 MPa), RS (regular platform and straight abutment, 38.6 MPa) and SS (platform switching and straight abutment, 36.5 MPa). For the trabecular bone, the highest stress values (sigmamax) were observed in the RA (6.55 MPa), followed by RS (5.88 MPa), SA (5.60 MPa), and SS (4.82 MPa). The regular platform generated higher stress in the cervical periimplant region on the cortical and trabecular bone than the platform switching, irrespective of the abutment used (straight or angulated). PMID- 23110306 TI - Diagnosis and ablation of multiform fascicular tachycardia. AB - INTRODUCTION: Fascicular tachycardia (FT) is an uncommon cause of monomorphic sustained ventricular tachycardia (VT). We describe 6 cases of FT with multiform QRS morphologies. METHODS AND RESULTS: Six of 823 consecutive VT cases were retrospectively analyzed and found attributable to FT with multiform QRS patterns, with 3 cases exhibiting narrow QRS VT as well. All underwent electrophysiology study including fascicular potential mapping, entrainment pacing, and electroanatomic mapping. The first 3 cases describe similar multiform VT patterns with successful ablation in the upper mid septum. Initially, a right bundle branch block (RBBB) VT with superior axis was induced. Radiofrequency catheter ablation (RFCA) targeting the left posterior fascicle (LPF) resulted in a second VT with RBBB inferior axis. RFCA in the upper septum just apical to the LBB potential abolished VT in all cases. Cases 4 and 5 showed RBBB VT with alternating fascicular block compatible with upper septal dependent VT, resulting in bundle branch reentrant VT (BBRT) after ablation of LPF and left anterior fascicle (LAF). Finally, Cases 5 and 6 demonstrated spontaneous shift in QRS morphology during VT, implicating participation of a third fascicle. In Case 6, successful ablation was achieved over the proximal LAF, likely representing insertion of the auxiliary fascicle near the proximal LAF. CONCLUSIONS: Multiform FTs show a reentrant mechanism using multiple fascicular branches. We hypothesize that retrograde conduction over the septal fascicle produces alternate fascicular patterns as well as narrow VT forms. Ablation of the respective fascicle was successful in abolishing FT but does not preclude development of BBRT unless septal fascicle is targeted and ablated. PMID- 23110307 TI - Predicting mortality in microscopic polyangiitis with renal involvement: a survival analysis based on 64 patients. AB - BACKGROUND: To determine predictors of survival in patients with microscopic polyangiitis (MPA). METHODS: A cohort of 64 patients who met the Chapel Hill criteria for MPA with renal involvement participated in the study. All subjects received cytotoxic drugs. All of the diagnoses were biopsy proven. RESULTS: We retrospectively studied 64 patients (median age, 59 years; male/female ratio, 1.6:1). The mean follow-up was 38 months; 34 (53.13%) patients died or acquired end-stage renal disease. According to univariate analysis, a preliminary prognostic value was attributed to serum creatinine (Scr) > 459 MUmol/L (p < 0.001); erythrocyte sedimentation rate (ESR) > 99 mm/h (p < 0.001); serum albumin < 30 g/L (p < 0.001); and hemoglobin < 84 g/L (p < 0.001). Logistic regression analysis showed that Scr level (beta = 1.02, p = 0.0002) and ESR (beta = 1.02, p = 0.0002) at baseline were associated with poor prognosis, and Cox regression analysis further confirmed this result [Scr: beta = 1.004, 95% confidence interval (CI): 1.002-1.006, p < 0.001; ESR: beta = 1.018, 95% CI: 1.000-1.037, p = 0.046]. The receiver operating characteristic curve showed that Scr and ESR were predictors of MPA patient prognosis, their areas under the curves were 0.95 and 0.80, their sensitivities were 94.1% and 92.3%, and their specificities were 94% and 70%, respectively. CONCLUSION: Despite the small number of patients in this study, the prevalence of renal vasculitis was high in patients with MPA. The level of Scr and ESR may be a useful clinical biomarker for monitoring prognosis. PMID- 23110308 TI - Reliability of the pattern hair loss classifications: a comparison of the basic and specific and Norwood-Hamilton classifications. AB - Pattern hair loss (PHL) is the most common form of baldness in both sexes. The Norwood-Hamilton classification is the most commonly used classification worldwide, but it has many limitations. The basic and specific (BASP) classification was introduced as an improvement over the Norwood-Hamilton classification. Previous research was done to estimate the reliability of the Norwood-Hamilton classification and the result was unsatisfactory. However, the reliability of the BASP and Norwood-Hamilton classifications has not yet been compared. Eight dermatological specialists, 17 dermatological residents and 15 general physicians classified PHL in 100 sets of photographs using both the BASP and Norwood-Hamilton classifications. Intergroup reproducibility was evaluated by examining the match rate of the individual data in each group and the match rate between hair specialist and the other examiners. Intragroup repeatability was determined by calculating the match rate between the first and second studies. In terms of intergroup reproducibility of the match rate for individual data in each group, the basic type had the best agreement, the specific type had the second best, and the Norwood-Hamilton classification had the lowest match rate. In comparison, hair specialist and intragroup repeatability showed the same patterns. The BASP classification not only distinguishes all kinds of hair loss patterns, but also has better reproducibility and repeatability than the Norwood Hamilton classification. PMID- 23110309 TI - The gene expression signature associated with TP53 mutation/deletion in chronic lymphocytic leukaemia is dominated by the under-expression of TP53 and other genes on chromosome 17p. AB - In chronic lymphocytic leukaemia (CLL), TP53 mutation and deletion are strongly associated with one another and with adverse clinical outcome. Mutant TP53 protein typically accumulates to high levels and has been reported to have transcriptional regulatory activity distinct from that of wild-type TP53. To investigate whether such an effect is relevant to CLL, carefully balanced primary CLL samples with or without TP53 mutation/deletion were compared for their gene expression profiles using high-density DNA microarrays. Ninety-six and eight differentially expressed genes were identified, respectively, using two alternative statistical approaches with different stringencies. None of the differentially expressed genes were known to be regulated by mutant TP53, and only four of the 67 under-expressed genes were known transcriptional targets of wild-type TP53. Significantly, both approaches showed that gene under-expression was the dominant feature of TP53-mutant CLL samples. Furthermore, a disproportionate number of the under-expressed genes were located on chromosome 17p, the most significant being TP53 itself. Together, these results indicate that any transcriptional regulatory effects of mutant TP53 in CLL cells are overshadowed by the under-expression of co-deleted TP53 and other genes on chromosome 17p. Our findings have implications for emerging therapeutic strategies that target mutant TP53. PMID- 23110310 TI - Comparison of four different analgesic discogram protocols comparing the incidence of reported pain relief following local anesthetic injection into concordantly painful lumbar intervertebral discs. AB - OBJECTIVE: To compare the incidence of pain relief following injection of local anesthetic (LA) into lumbar discs that caused concordant pain during provocation testing. DESIGN: Prospective collected data review from two centers and compare with published results. OUTCOME MEASURES: We compared subjective reported pain relief following provocative testing using the following protocols at three separate facilities: 23 patients undergoing routine provocative discography using contrast alone (PD); 47 patients undergoing provocative discography performed using an equal combination of LA and contrast (CPD); 120 patients injected with LA following routine PD (ADPD); 33 patients undergoing stand-alone analgesic discography (SAAD); and 28 patients injected with LA through a catheter (FAD) placed during provocative discogaphy testing. RESULTS: Pressure-controlled PD showed a positive response rate of 34% per disc in patients with a clinical diagnosis of discogenic pain. None of the PD group without LA had pain relief and less than 10% of the CPD group reported pain relief. Forty percent of the SAAD group with positive pain reproduction reported >=50% relief and 20% reporting >=80% relief. Forty-six percent of the ADPD group reported >=50% relief and 30% reporting >=80% relief. The FAD group had a greater 80% patients reporting >=50% pain relief although fewer 26% reporting more convincing >=80% relief. CONCLUSIONS: If the criterion standard to confirm painful annular tears is concordant pain provocation and 80% or greater pain relief following LA injected into lumbar discs, the SAAD, ADPD, and FAD protocols show statistically similar 20% to 30% prevelance. PMID- 23110311 TI - The fluidity of disclosure: a longitudinal exploration of women's experience and understanding of HIV disclosure in the context of pregnancy and early motherhood. AB - HIV disclosure is emphasised as an important component of efforts to prevent HIV transmission, including those to prevent transmission from mother to child. Studies which approach disclosure as a dichotomous variable that is either present or absent have generated a significant body of research describing disclosure patterns, antecedents, barriers and consequences. This study joins a growing body of research which explores disclosure as a complex, selective and gradual process occurring within the context of relationships. Using a qualitative, longitudinal ethnographic approach, the study explores HIV-positive women's subjective experience of disclosure and how they make meaning and understand disclosure processes during pregnancy and early motherhood. An interpretative phenomenological analysis of field notes from participant observation and in-depth interview transcripts suggests that women may experience disclosure as a more fluid construct than previously assumed. In contrast to the traditional dichotomous and linear approach to understanding disclosure, the meaning ascribed to disclosure "events" and behaviours was changeable and even reversible over time. These shifts occurred alongside changes in women's internal, interpersonal and material worlds and served important psychological and social functions. The findings have important implications for HIV counsellors working to encourage disclosure in the context of prevention interventions. PMID- 23110312 TI - Fibermalt is well tolerated in healthy men and women at intakes up to 60 g/d: a randomized, double-blind, crossover trial. AB - In this randomized, double-blind crossover trial, the digestive tolerance of a novel dietary fibre (fibermalt, an indigestible maltose alternan oligosaccharide) was assessed in healthy men and women. Twenty-nine subjects consumed 0 (control), 45 or 60 g of fibre in two doses per day for 2-week treatment periods, each separated by a 2-week washout. Results indicated no differences between treatments in composite gastrointestinal (GI) symptom scores (sum of six GI symptom ratings), individual GI symptoms (nausea, bloating, GI rumbling, gas/flatulence, abdominal pain, diarrhoea), bowel characteristics (frequency, faecal consistency, faecal hardness, straining, discomfort and incomplete evacuation) or average daily faecal output. The symptom scores were consistently low for each treatment period with means averaging below 1 out of a possible range of 0-12 for the composite score. The results of this study suggest that fibermalt is well tolerated at intakes up to 60 g of fibre per day. PMID- 23110313 TI - A lifespan comparison of the reliability, test-retest stability, and signal-to noise ratio of event-related potentials assessed during performance monitoring. AB - The reliability, stability, and signal-to-noise ratio (SNR) of event-related potentials (ERPs) were investigated in children, adolescents, younger adults, and older adults in performance monitoring tasks. P2, N2, P3, and P2-N2 peak-to-peak amplitude showed high odd-even split reliabilities in all age groups, ranging from.70 to.90. Multigroup analyses showed that test-retest stabilities (across 2 weeks) of ERP amplitudes did not differ among the four age groups. In contrast, relative to adolescents and younger adults, SNRs were lower in children and older adults, with higher noise levels in children and lower signal power in older adults. We conclude that age differences in the SNR of stimulus-locked ERPs can be successfully compensated by the averaging procedure with about 40 trials in the average. However, age differences in baseline noise and split-half reliability should be considered when comparing age groups in single trial measures or time-varying processes with ERPs. PMID- 23110314 TI - De novo assembly of the pepper transcriptome (Capsicum annuum): a benchmark for in silico discovery of SNPs, SSRs and candidate genes. AB - BACKGROUND: Molecular breeding of pepper (Capsicum spp.) can be accelerated by developing DNA markers associated with transcriptomes in breeding germplasm. Before the advent of next generation sequencing (NGS) technologies, the majority of sequencing data were generated by the Sanger sequencing method. By leveraging Sanger EST data, we have generated a wealth of genetic information for pepper including thousands of SNPs and Single Position Polymorphic (SPP) markers. To complement and enhance these resources, we applied NGS to three pepper genotypes: Maor, Early Jalapeno and Criollo de Morelos-334 (CM334) to identify SNPs and SSRs in the assembly of these three genotypes. RESULTS: Two pepper transcriptome assemblies were developed with different purposes. The first reference sequence, assembled by CAP3 software, comprises 31,196 contigs from >125,000 Sanger-EST sequences that were mainly derived from a Korean F1-hybrid line, Bukang. Overlapping probes were designed for 30,815 unigenes to construct a pepper Affymetrix GeneChip(r) microarray for whole genome analyses. In addition, custom Python scripts were used to identify 4,236 SNPs in contigs of the assembly. A total of 2,489 simple sequence repeats (SSRs) were identified from the assembly, and primers were designed for the SSRs. Annotation of contigs using Blast2GO software resulted in information for 60% of the unigenes in the assembly. The second transcriptome assembly was constructed from more than 200 million Illumina Genome Analyzer II reads (80-120 nt) using a combination of Velvet, CLC workbench and CAP3 software packages. BWA, SAMtools and in-house Perl scripts were used to identify SNPs among three pepper genotypes. The SNPs were filtered to be at least 50 bp from any intron-exon junctions as well as flanking SNPs. More than 22,000 high-quality putative SNPs were identified. Using the MISA software, 10,398 SSR markers were also identified within the Illumina transcriptome assembly and primers were designed for the identified markers. The assembly was annotated by Blast2GO and 14,740 (12%) of annotated contigs were associated with functional proteins. CONCLUSIONS: Before availability of pepper genome sequence, assembling transcriptomes of this economically important crop was required to generate thousands of high-quality molecular markers that could be used in breeding programs. In order to have a better understanding of the assembled sequences and to identify candidate genes underlying QTLs, we annotated the contigs of Sanger EST and Illumina transcriptome assemblies. These and other information have been curated in a database that we have dedicated for pepper project. PMID- 23110315 TI - Pseudoangiomatous stromal hyperplasia (PASH) causing massive breast enlargement: MRI findings. PMID- 23110316 TI - Endogenous silencing of Puccinia triticina pathogenicity genes through in planta expressed sequences leads to the suppression of rust diseases on wheat. AB - Rust fungi are destructive plant pathogens. The draft genomes of several wheat infecting species have been released and potential pathogenicity genes identified through comparative analyses to fungal pathogens that are amenable to genetic manipulation. Functional gene analysis tools are needed to understand the infection process of these obligate parasites and to confirm whether predicted pathogenicity genes could become targets for disease control. We have modified an Agrobacterium tumefaciens-mediated in planta-induced transient gene silencing (PITGS) assay for use in Triticum spp. (wheat), and used this assay to target predicted wheat leaf rust fungus, Puccinia triticina (Pt) pathogenicity genes, a MAP kinase (PtMAPK1), a cyclophilin (PtCYC1) and calcineurin B (PtCNB), to analyze their roles in disease. Agroinfiltration effectively delivered hairpin silencing constructs in wheat, leading to the generation of fungal gene-specific siRNA molecules in infiltrated leaves, and resulting in up to 70% reduction in transcription of the endogenous target genes in superinfected Pt. In vivo silencing caused severe disease suppression, compromising fungal growth and sporulation, as viewed by confocal microscopy and measured by reductions in fungal biomass and emergence of uredinia. Interestingly, using the same gene constructs, suppression of infection by Puccinia graminis and Puccinia striiformis was also achieved. Our results show that A. tumefaciens-mediated PITGS can be used as a reverse-genetics tool to discover gene function in rust fungi. This proof-of-concept study indicates that the targeted fungal transcripts might be important in pathogenesis, and could potentially be used as promising targets for developing RNA interference-based resistance against rust fungi. PMID- 23110317 TI - Survey of n-3 and n-6 polyunsaturated fatty acids in fish and fish products. AB - BACKGROUND: The imbalance of the n-3/n-6 ratio in the Western diet is characterised by a low intake of n-3 long-chain (LC) PUFA and a concurrent high intake of n-6 PUFA. Fish, in particular marine fish, is a unique source of n-3 LC PUFA. However, FA composition of consumed fish changed, due to the increasing usage of n-6 PUFA-rich vegetable oils in aquaculture feed and in fish processing (frying) which both lead to a further shift in n-6 PUFA to the detriment of n-3 LC PUFA.The aim of this study was to determine the ratio of n-3/n-6 including the contents of EPA and DHA in fish fillets and fish products from the German market (n=123). Furthermore, the study focussed on the FA content in farmed salmon compared to wild salmon as well as in processed Alaska pollock fillet, e.g., fish fingers. RESULTS: Total fat and FA content in fish products varied considerably depending on fish species, feed management, and food processing. Mackerel, herring and trout fillets characteristically contained adequate dietary amounts of absolute EPA and DHA, due to their high fat contents. However, despite a lower fat content, tuna, pollock, and Alaska pollock can contribute considerable amounts of EPA and DHA to the human supply.Farmed salmon are an appropriate source of EPA and DHA owing to their higher fat content compared to wild salmon (12.3 vs. 2.1 wt %), however with elevated SFA, n-9 and n-6 FA contents representing the use of vegetable oils and oilseeds in aquaculture feed. The n 3/n-6 ratio was deteriorated (2.9 vs. 12.4) but still acceptable. Compared to pure fish fillets, breaded and pre-fried Alaska pollock fillet contained extraordinarily high fat and n-6 PUFA levels. CONCLUSIONS: Since fish species vary with respect to their n-3 LC PUFA contents, eating a variety of fish is advisable. High n-6 PUFA containing pre-fried fish support the imbalance of n-3/n 6 ratio in the Western diet. Thus, consumption of pure fish fillets is to be favoured. The lower n-3 PUFA portion in farmed fish can be offset by the higher fat content, however, with an unfavourable FA distribution compared to wild fellows. PMID- 23110318 TI - Self-assembled peptide nanofiber templated one-dimensional gold nanostructures exhibiting resistive switching. AB - An amyloid-like peptide molecule self-assembling into one-dimensional nanofiber structure in ethanol was designed and synthesized with functional groups that can bind to gold ions. The peptide nanofibers were used as templates for nucleation and growth of one-dimensional gold nanostructures in the presence of ascorbic acid as reducing agent. We performed multistep seed-mediated synthesis of gold nanoparticles by changing peptide/gold precursor and peptide/reducing agent ratios. Gold nanostructures with a wide range of morphologies such as smooth nanowires, noodle-like one-dimensional nanostructures, and uniform aggregates of spherical nanoparticles were synthesized by use of an environmentally friendly synthesis method. Nanoscale electrical properties of gold-peptide nanofibers were investigated using atomic force microscopy. Bias dependent current (IV) measurements on thin films of gold-peptide nanofiber hybrid revealed tunneling dominated transport and resistive switching. Gold-peptide nanofiber composite nanostructures can provide insight into electrical conduction in biomolecular/inorganic composites, highlighting their potential applications in electronics and optics. PMID- 23110319 TI - Estimation of protein requirements according to nitrogen balance for older hospitalized adults with pressure ulcers according to wound severity in Japan. AB - OBJECTIVES: To estimate protein requirements in older hospitalized adults with pressure ulcers (PrU) according to systemic conditions and wound severity. DESIGN: Secondary nitrogen balance study over 3 days. SETTING: Long-term care facility. PARTICIPANTS: Twenty-eight older adults with PrU using a urinary catheter. MEASUREMENTS: Nitrogen balance over 3 days was evaluated from habitual nitrogen intake measured using a food weighing record and nitrogen excretion from urine, feces and wound exudate. Nitrogen intake required to maintain nitrogen equilibrium was estimated as an average protein requirement using a linear mixed model. RESULTS: Nitrogen intake at nitrogen equilibrium was 0.151 gN/kg per day (95% confidence interval = 0.127-0.175 gN/kg per day) for all participants. The amount of protein loss from wound exudate contributed little to total nitrogen excretion. A Charlson comorbidity index of 4 or greater (the median value) was related to lower nitrogen intake at nitrogen equilibrium (P = .005). Severe PrU with heavy exudate amounts and measured wound areas of 7.9 cm(2) or greater (the median value) were related to higher nitrogen intake at nitrogen equilibrium in individuals with a Charlson comorbidity index of 3 or less (both P = .04). Larger wound area (correlation coefficient (r) = 0.55, P = .003) and heavier exudate volume (r = 0.53, P = .004) were associated with muscle protein hypercatabolism measured according to 3-methylhistidine/creatinine ratio. CONCLUSION: The average protein requirement is 0.95 g/kg per day for older hospitalized Japanese adults with PrU, but protein requirements depend on an individual's condition and wound severity and range from 0.75 to 1.30 g/kg per day. Severe PrU can require higher protein intakes because of muscle protein hypercatabolism rather than direct loss of protein from wound exudate. PMID- 23110320 TI - A randomized, controlled non-inferiority trial comparing A(H1N1)pmd09 vaccine antigen, with and without AS03 adjuvant system, co-administered or sequentially administered with an inactivated trivalent seasonal influenza vaccine. AB - BACKGROUND: At the time of the influenza A(H1N1)pmd09 pandemic it was not known if concurrent or sequential administration of seasonal trivalent influenza vaccine (TIV) with pandemic vaccine was preferred. METHODS: Immunogenicity and safety were assessed in 871 healthy subjects aged 19-40 years who were randomised into six groups to receive co-administration or sequential administration of TIV and two doses of A(H1N1)pmd09 vaccine (either unadjuvanted or adjuvanted with AS03, an alpha-tocopherol and squalene-based oil-in-water emulsion). RESULTS: Safety and immunogenicity data (by haemagglutination inhibition [HI] assay) after each dose and six months post-Dose 1 are reported here. Co-administration of A(H1N1)pmd09 vaccine with TIV reduced the HI immune responses to A(H1N1)pmd09 vaccine. However, serologic responses with both co-administration and sequential schedules met the European and US regulatory criteria for pandemic and seasonal influenza vaccines up to six months following the first vaccine dose. The AS03 adjuvanted formulation elicited higher immune responses at all time points. Prior administration or co-administration of A(H1N1)pmd09 vaccine did not affect immune responses to TIV. CONCLUSIONS: Co-administration of TIV and A(H1N1)pmd09 vaccine negatively influenced A(H1N1)pmd09 vaccine immunogenicity but had no effect on TIV responses. The non-adjuvanted and adjuvanted vaccines demonstrated strong immune responses against all vaccine strains for up to six months following the first vaccine dose. PMID- 23110321 TI - Prevalence and profiles of unmet healthcare need in Thailand. AB - BACKGROUND: In the light of the universal healthcare coverage that was achieved in Thailand in 2002, policy makers have raised concerns about whether there is still unmet need within the population. Our objectives were to assess the annual prevalence, characteristics and reasons for unmet healthcare need in the Thai population in 2010 and to compare our findings with relevant international literature. METHODS: A standard set of OECD unmet need questionnaires was used in a nationally-representative household survey conducted in 2010 by the National Statistical Office. The prevalence of unmet need among respondents with various socio-economic characteristics was estimated to determine an inequity in the unmet need and the reasons behind it. RESULTS: The annual prevalence of unmet need for outpatient and inpatient services in 2010 was 1.4% and 0.4%, respectively. Despite this low prevalence, there are inequities with relatively higher proportion of the unmet need among Universal Coverage Scheme members, and the poor and rural populations. There was less unmet need due to cost than there was due to geographical barriers. The prevalence of unmet need due to cost and geographical barriers among the richest and poorest quintiles were comparable to those of selected OECD countries. The geographical extension of healthcare infrastructure and of the distribution of health workers is a major contributing factor to the low prevalence of unmet need. CONCLUSIONS: The low prevalence of unmet need for both outpatient and inpatient services is a result of the availability of well-functioning health services at the most peripheral level, and of the comprehensive benefit package offered free of charge by all health insurance schemes. This assessment prompts a need for regular monitoring of unmet need in nationally-representative household surveys. PMID- 23110322 TI - The cost of first-ever stroke in Valle d'Aosta, Italy: linking clinical registries and administrative data. AB - BACKGROUND: Stroke is one of the most relevant reasons of death and disability worldwide. Many cost of illness studies have been performed to evaluate direct and indirect costs of ischaemic stroke, especially within the first year after the acute episode, using different methodologies. METHODS: We conducted a longitudinal, retrospective, bottom-up cost of illness study, to evaluate clinical and economic outcomes of a cohort of patients affected by a first cerebrovascular event, including subjects with ischaemic, haemorrhagic or transient episodes. The analysis intended to detect direct costs, within 1, 2 and 3 years from the index event. Clinical patient data collected in regional disease registry were integrated and linked to regional administrative databases to perform the analysis. RESULTS: The analysis of costs within the first year from the index event included 800 patients. The majority of patients (71.5%) were affected by ischaemic stroke. Overall, per patient costs were ?7,079. Overall costs significantly differ according to the type of stroke, with costs for haemorrhagic stroke and ischaemic stroke amounting to ?9,044 and ?7,289. Hospital costs, including inpatient rehabilitation, were driver of expenditure, accounting for 89.5% of total costs. The multiple regression model showed that sex, level of physical disability and level of neurological deficit predict direct healthcare costs within 1 year. The analysis at 2 and 3 years (per patient costs: ?7,901 and ?8,874, respectively) showed that majority of costs are concentrated in the first months after the acute event. CONCLUSIONS: This cost analysis highlights the importance to set up significant prevention programs to reduce the economic burden of stroke, which is mostly attributable to hospital and inpatient rehabilitation costs immediately after the acute episode. Although some limitation typical of retrospective analyses the approach of linking clinical and administrative database is a power tool to obtain useful information for healthcare planning. PMID- 23110325 TI - Developing nurse educator competency in the pedagogy of simulation. AB - Faculty development is needed for nurse educators to effectively use simulation as a learning tool. A synthesis of research evidence regarding current practices in preparing educators to use simulation provided a foundation for faculty development. Implementation of a two-pronged approach within a regional collaboration of four schools of nursing is described; results of the evaluation of the approaches are presented. Use of the National League for Nursing Core Competencies of Nurse Educators as the organizing framework and Roger's Diffusion of Innovations Model as the theoretical framework is discussed. An overview is provided of the two prongs: (a) a short course for novice educators, and (b) examples of continuing education programming for experienced faculty members new to simulation to enhance effective application of this pedagogy. Recommendations include designing faculty development for simulation within a framework for systems change, maintaining flexibility to meet diverse needs, and using existing online resources. PMID- 23110323 TI - Trends in lipid profiles in patients with psoriasis: a population-based analysis. AB - BACKGROUND: Psoriasis is associated with an atherogenic lipid profile but longitudinal changes in lipids around disease onset are unknown. The purpose of our study is to examine the effect of psoriasis onset on serum lipid profiles. METHODS: We compared changes in lipid profiles in a population based incident cohort of 689 patients with psoriasis and 717 non-psoriasis subjects. All lipid measures performed 5 years before and after psoriasis incidence/index date were abstracted. Random-effects models adjusting for age, sex and calendar year were used to examine trends in lipid profiles. RESULTS: There were significant declines in total cholesterol (TC) and low-density lipoprotein (LDL) levels during the 5 years before and after psoriasis incidence/index date in both the psoriasis and the non-psoriasis cohorts, with a greater decrease noted in the TC levels (p=0.022) and LDL (p=0.054) in the non-psoriasis cohort. High-density lipoprotein (HDL) levels increased significantly both before and after psoriasis incidence date in the psoriasis cohort. Triglyceride (TG) levels were significantly higher (p<0.001), and HDL levels significantly lower (p=0.013) in patients with psoriasis compared to non-psoriasis subjects. There were no differences in prescriptions for lipid lowering drugs between the two cohorts. CONCLUSIONS: Patients with psoriasis had a significant decrease in TC and LDL levels during the 5 years before psoriasis incidence. Higher mean TG and lower mean HDL levels were noted in the 5 years before psoriasis incidence. These changes are unlikely to be caused by lipid lowering treatment alone and require further exploration. PMID- 23110324 TI - Clinical evaluation of WT1 mRNA expression levels in peripheral blood and bone marrow in patients with myelodysplastic syndromes. AB - A study to evaluate WT1 mRNA expression levels in peripheral blood (PB) and bone marrow aspirate (BM) was conducted in 172 patients, including 115 with myelodysplastic syndromes (MDS), in Japan. The level of WT1 mRNA expression was evaluated according to the French-American-British (FAB) and World Health Organization (WHO) classifications (2001, 2008) and using the International Prognostic Scoring System and the WHO Prognostic Scoring System scales. WT1 mRNA expression levels in PB and BM were well correlated (r = 0.85), and they tended to increase with disease stage progression and in those at higher risk of leukemic transformation. WT1 mRNA expression can be a useful marker for the diagnosis and risk evaluation of MDS. PMID- 23110326 TI - Student-created scenarios in the high-fidelity simulation laboratory. AB - As an assignment in a pediatric theory class, small groups of nursing students created and implemented scenarios in the high-fidelity simulation (HFS) laboratory. The project's purpose was to determine whether senior nursing students could create HFS scenarios that increased their knowledge base of pediatric nursing and supported the use of evidence in identifying problems and planning nursing care. After completing the project, students wrote individual reflective papers. Qualitative analysis of these papers revealed the common themes of expanded understanding of pediatric nursing care and professional growth. Data supported achievement of the project objectives; however, this was attributed to the scenario-creation process rather than to the scenarios themselves. Challenges identified included lack of a mechanism to involve each student in every scenario and logistical issues, such as faculty time and laboratory scheduling. With attention to such issues, this project can be implemented successfully in a variety of clinical areas. PMID- 23110327 TI - Developmental evaluation of preschool children: a service-learning experience for nursing students. AB - Service-learning is a practice that is beneficial for both students and community participants. This article presents the service-learning experience of senior level undergraduate nursing students at a southeastern U.S. university. Nursing students were taught how to administer the Denver II Developmental Screening Test (DDST-II), and they then evaluated high-risk preschool children during a clinical nursing experience. A total of 1,030 children were screened between 2008 and 2012. Early detection of developmental delays promotes earlier intervention for concerns, and the implementation of this service-learning project using a valid and sensitive screening tool aids in the cost-effective identification of preschool children who are at risk for developmental delays. Student evaluations of the experience were positive, and examples of the knowledge acquired are provided. PMID- 23110328 TI - QCM biosensor for testing the inflammatory response to blood-contacting biomaterials. AB - Inflammation is the primary problem associated with blood-contacting artificial organs. Leucocytes play an essential role in the generation of the inflammatory response. Inflammation can be defined in a variety of ways. The goal of this research is to develop a biosensor system that is less complicated and faster responding than conventional methods. In this study, highly sensitive QCM crystals were chemically modified to measure changes in adsorbed mass on the surface and were used to detect activated neutrophils. Leucocyte activation was quantified by measuring the change in frequency of the QCM. QCM crystals with immobilized anti-C3a were tested in vitro using different concentrations of neutrophils. The measured frequency shifts were proportional to neutrophil number, indicating that activated neutrophils attach to the surface of the QCM. These results were supported by AFM surface topography measurements and SEM images. This method presents a rapid, inexpensive, and easy bioassay that tests the inflammatory response to blood-contacting artificial organs. PMID- 23110329 TI - Improved levothyroxine pharmacokinetics after bariatric surgery. AB - BACKGROUND: The absorption of levothyroxine (LT4) is affected by many factors. Bariatric surgery is recommended in severely obese patients. The aim of this study was to determine the consequences of bariatric surgery on LT4 pharmacokinetic parameters, and to identify the regions of the gastrointestinal tract where LT4 is absorbed in patients with severe obesity before and after surgery. METHODS: We studied 32 severely obese nonhypothyroid patients who underwent sleeve gastrectomy (SG; n=10), Roux-en-Y gastric bypass (RYGBP; n=7), or biliopancreatic diversion with long limbs (BPD-LL; n=15). Before surgery, from 8:00 a.m., blood samples were collected before and every 30 minutes after the oral administration of a solution of 600 MUg of LT4. The same procedure was repeated 35 days after surgery. We estimated the pharmacokinetic parameters of LT4 before and after surgery, including the area under the curve (AUC), the peak thyroxine concentration (Cmax), and the time to peak thyroxine concentration (Tmax). RESULTS: Following surgery, in the SG group, the mean AUC was higher than it was before surgery (18.97+/-6.01 vs. 25.048+/-6.47 [MUg/dL].h; p<0.01), whereas the values of Cmax and Tmax were similar to those before surgery. In the RYGBP group, mean AUC, Cmax, and Tmax were similar before and after surgery. In the BPD-LL group, mean AUC and Cmax were higher after surgery than before (14.18+/-5.64 vs. 25.51+/-9.1 [MUg/dL].h, p<0.001; 5.62+/-1.34 vs. 8.16+/-2.57 MUg/dL, p<0.001, respectively), whereas Tmax was similar. CONCLUSIONS: The pharmacokinetic parameters of LT4 absorption are improved following SG and BPD-LL types of bariatric procedures. We conclude that the stomach, the duodenum, and the upper part of the jejunum are not sites for LT4 absorption, because in the above-mentioned bariatric procedures these are bypassed or removed. PMID- 23110330 TI - Use of subepithelial connective tissue graft as a biological barrier: a human clinical and histologic case report. AB - The aim of the present study was to develop a method to study the healing process after gingival grafting and to observe the histologic results after use of the modified edentulous ridge expansion technique. A 47-year-old nonsmoking woman with a noncontributory past medical history affected by edentulism associated with a horizontal alveolar ridge defect was referred to the authors for surgical correction of the deficit to improve implant support and the final esthetics of an implant-borne prosthesis. At the 4-month follow-up visit, a biopsy was performed by a punch technique in the same sites of healing abutment connection. The tissue was elevated from the attached gingival. Clinically, the grafted tissues seemed to be attached to the bone surfaces. The histologic findings revealed dense grafted tissues, providing long-term stability to the area. No ligament or bone, characteristic for periodontal regeneration, were observed. The presence of thick attached keratinized tissue around implants may constitute a protective factor against marginal inflammation or trauma. PMID- 23110331 TI - N-acetylcysteine expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic acid-induced colitis in rats. AB - High free radical production, low antioxidant capacity and excessive inflammation are well known features in the pathogenesis of inflammatory bowel disease. N acetylcysteine (NAC) is a powerful antioxidant and a scavenger of hydroxyl radicals. Recently, NAC has also been shown to have anti-inflammatory activities in tissues. Our study objective was to investigate the effects of NAC on tissue inflammatory activities using an ulcerative colitis model induced by acetic acid (AA) in rats. Wistar rats (n = 32) were divided into four groups. AA-induced colitis was performed in two of the groups while the other two groups were injected with saline intrarectally. One of the AA-induced colitis groups and one of the control groups were administered NAC (500 mg/kg/day) intrarectally, and the other control groups were given saline. After 4 days, colonic changes were evaluated biochemically by measuring proinflammatory cytokines [tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6], myeloperoxidase (MPO), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD) levels in tissue homogenates and by histopathological examination. AA caused colonic mucosal injury, whereas NAC administration suppressed these changes in the AA induced colitis group (p < 0.001). AA-administration resulted in increased TNF alpha, IL-1beta, IL-6, MPO and MDA levels, and decreased GSH and SOD levels, whereas NAC reversed these effects (all p < 0.001). In conclusion, the present study proposes that intrarectal NAC therapy has a dual action as an effective anti-inflammatory and an antioxidant, and may be a promising therapeutic option for ulcerative colitis. PMID- 23110332 TI - Allergic reactions compared between BN and Wistar rats after oral exposure to ovalbumin. AB - There is currently no validated animal model for evaluating the potential allergenicity of food proteins. This study aimed to compare the allergic reactions between BN and Wistar rats after oral exposure to ovalbumin (OVA) by studying immune responses and clinical manifestations. Female BN and Wistar rats were orally exposed to OVA on days 1 and 14, and thereafter daily from day 15 to day 42. Sera and plasma were screened for OVA-specific antibodies and histamine. On day 49, all the OVA-sensitized animals were orally challenged with OVA before blood pressure was measured. One day later (on day 50), histopathology and differential cell counts were performed. The results indicate that oral exposure of BN rats to OVA yielded IgE, IgG, and IgG(2a) antibody responses that were generally of higher levels than those observed in Wistar rats (p < 0.05). However, the Wistar rats presented with more serious clinical manifestations and histopathologic changes that could have serious implications for any OVA-induced anaphylaxis. The studies here proved that OVA-sensitized BN and Wistar rats evinced different immune responses and clinical manifestations; these outcomes suggested that the two rat strains might differ in their immunologic mechanisms of allergy and that there was no correlation between immune responses and the severity of clinical symptoms. To be clear, the data from these studies should be viewed as 'preliminary', as only a single protein allergen was examined. Accordingly, further studies are needed to compare the allergic reactions between BN and Wistar rats by using purified strong-, weak-, and non-allergenic proteins based on the experiments reported here. PMID- 23110333 TI - The chemistry-glycobiology frontier. PMID- 23110334 TI - Chiral tripodal ligand containing three N-heterocyclic donor functions and its copper complexes: crystallization of [LCu(I)]2(2+)/[L2Cu(II)](2+) stereoisomers and tyrosinase activity. AB - A novel chiral ligand system L containing one pyridyl and two imidazolyl donor functions has been synthesized and investigated with respect to its Cu(I) and Cu(II) coordination chemistry. Reaction with [Cu(MeCN)4]PF6 and [Cu(MeCN)4]OTf led to the dimeric complexes [LCu]2X2 (1, X = PF6; 2, X = OTf) with the ligands L in different configurations (R,S). The ligand matrix formed in these complexes can also host a Cu(II) ion instead of two Cu(I) ions so that mixed crystals of [L2Cu]X2 and [LCu]2X2 can be produced. The pure compounds [L2Cu]X2 (3, X = PF6; 4, X = OTf) can be obtained by treatment of 1 and 2 with O2 in acetonitrile, respectively. From the corresponding solution 3 crystallizes with the two L molecules in different configurations, while 4 crystallizes with the ligands in (S,S) or (R,R) configurations, respectively. Crystals containing the analogous diastereomers of 3 were obtained, besides those isolated previously, when this compound was synthesized by reaction of 1 with AgPF6. On treating 2 with O2 as the oxidant in acetonitrile, besides formation of 4, additional evidence for oxygenation of L to L(ox), where one of the original phenyl units corresponds to a phenolate function, was found: The dinuclear complex [L(ox)Cu(OH)(OTf)CuL](OTf) (5) was isolated as the final product of O2 activation and conversion, which resembles the one of tyrosinase. In acetonitrile 5 reacts further to give 4 and [L(ox)2Cu2](OTf)2 (6), and hence, product mixtures are obtained. In CH2Cl2 decomposition can be avoided, and hence, changing the solvent from acetonitrile to CH2Cl2 leads to selective formation of 5. PMID- 23110335 TI - Impact of radiofrequency characteristics on acute pulmonary vein reconnection and clinical outcome after PVAC ablation. AB - OBJECTIVE: The objective was to study the impact of radiofrequency (RF) characteristics on acute pulmonary vein reconnection (PVR) and outcome after PVAC ablation. PVI with additional ablation of PVR (PVI + PVR) was compared to PVI only. METHODS: In 40 consecutive patients, after PVAC-guided PVI, adenosine and a 1-hour waiting time were used to unmask and ablate acute PVR (PVI + PVR group). RF-characteristics and 1-year AF freedom were compared post hoc to 40 clinically matched patients undergoing PVI only (PVI-only group). Custom-made software was used to assess RF characteristics of the PVAC applications needed to obtain baseline PVI. RESULTS: There was no difference in clinical characteristics or baseline RF-profile between both groups. Acute PVR was observed and ablated in 38 of 160 veins (24%). AF-freedom after PVI + PVR was higher than PVI (85% vs 65%, P < 0.05). Within the PVI group, comparing patients with and without AF-recurrence, the percentage of PVAC applications with high T degrees (>48 degrees ) but low power (<3W) was higher (28 +/- 18% vs 11 +/- 11%, P < 0.0001). Within the PVI + PVR group, when comparing PVs with and without PVR, the percentage of low power/high T degrees PVAC applications was also higher (27 +/- 13% vs 13 +/- 15%, P < 0.0001). CONCLUSIONS: (1) After PVAC ablation, 24% of PVs exhibit acute reconnection. Additional ablation of reconnection improves clinical outcome. (2) Acute reconnection as well as clinical recurrence of AF are characterized by PVAC ablation with a considerable number of applications with high temperature but low power. (3) If PV isolation is obtained with low power applications, a consistent use of both adenosine and waiting time is required. PMID- 23110336 TI - Assessing the long-term health impact of Q-fever in the Netherlands: a prospective cohort study started in 2007 on the largest documented Q-fever outbreak to date. AB - BACKGROUND: Between 2007 and 2011, the Netherlands experienced the largest documented Q-fever outbreak to date with a total of 4108 notified acute Q-fever patients. Previous studies have indicated that Q-fever patients may suffer from long-lasting health effects, such as fatigue and reduced quality of life. Our study aims to determine the long-term health impact of Q-fever. It will also compare the health status of Q-fever patients with three reference groups: 1) healthy controls, 2) patients with Legionnaires' disease and 3) persons with a Q fever infection but a-specific symptoms. METHODS/DESIGN: Two groups of Q-fever patients were included in a prospective cohort study. In the first group the onset of illness was in 2007-2008 and participation was at 12 and 48 months. In the second group the onset of illness was in 2010-2011 and participation was at 6 time intervals, from 3 to 24 months. The reference groups were included at only one time interval. The subjective health status, fatigue status and quality of life of patients will be assessed using two validated quality of life questionnaires. DISCUSSION: This study is the largest prospective cohort study to date that focuses on the effects of acute Q-fever. It will determine the long term (up to 4 years) health impact of Q-fever on patients and compare this to three different reference groups so that we can present a comprehensive assessment of disease progression over time. PMID- 23110337 TI - Influence of hospice on nursing home residents with advanced dementia who received Medicare-skilled nursing facility care near the end of life. AB - OBJECTIVES: To examine differences in outcomes according to hospice status of skilled nursing facility (SNF) care recipients. DESIGN: Retrospective cohort. SETTING: Three thousand three hundred fifty-three U.S. nursing homes (NHs). PARTICIPANTS: Four thousand three hundred forty-four persons with advanced dementia who died in NHs in 2006 and received SNF care within 90 days of death were studied, 1,086 of these also received hospice before death: 705 after SNF care, and 381 concurrent with SNF care. MEASUREMENTS: Treatments, persistent pain and dyspnea, and hospital death. RESULTS: Decedents with any hospice received fewer medications, injections, feeding tubes, intravenous fluids, and therapy services and more hypnotics than those without hospice (all P < .001). Decedents with hospice after SNF care received fewer antipsychotics and those with hospice concurrent with SNF care received more antipsychotics than those without (all P < .001). Multivariate logistic regressions showed that decedents with hospice after SNF had lower likelihood of persistent dyspnea (adjusted odds ratio (AOR) = 0.63, 95% confidence interval (CI) = 0.45-0.87) and hospital death (AOR = 0.02, 95% = CI 0.01, 0.07) than those without hospice. Decedents with hospice concurrent with SNF care had a higher likelihood of persistent pain (AOR = 1.65, 95% CI = 1.23, 2.19) and a lower likelihood of hospital death (AOR = 0.13, 95% CI = 0.07, 0.26) than those without hospice. CONCLUSION: Residents dying with advanced dementia who received SNF care in the last 90 days of life had fewer aggressive treatments and lower odds of hospital death if they also received hospice care at any point during that time. Associations between hospice and persistent pain or dyspnea differed according to whether hospice care was received concurrent with or after SNF care. PMID- 23110338 TI - A pre-steady state kinetic analysis of the alphaY60W mutant of trans-3 chloroacrylic acid dehalogenase: implications for the mechanism of the wild-type enzyme. AB - The bacterial degradation of the nematicide 1,3-dichloropropene, an isomeric mixture, requires the action of trans- and cis-3-chloroacrylic acid dehalogenase (CaaD and cis-CaaD, respectively). Both enzymes are tautomerase superfamily members and share a core catalytic mechanism for the hydrolytic dehalogenation of the respective isomer of 3-haloacrylate. The observation that cis-CaaD requires two additional residues raises the question of how CaaD conducts a comparable reaction with fewer catalytic residues. As part of an effort to determine the basis for the apparently simpler CaaD-catalyzed reaction, the kinetic mechanism was determined by stopped-flow and chemical-quench techniques using a fluorescent mutant form of the enzyme, alphaY60W-CaaD, and trans-3-bromoacrylate as the substrate. The data from these experiments as well as bromide inhibition studies are best accommodated by a six-step model that provides individual rate constants for substrate binding, chemistry, and a proposed conformational change occurring after chemistry followed by release of malonate semialdehyde and bromide. The conformational change and product release rates are comparable, and together they limit the rate of turnover. The kinetic analysis and modeling studies validate the alphaY60W-CaaD mutant as an accurate reporter of active site events during the course of the enzyme-catalyzed reaction. The kinetic mechanism for the alphaY60W-CaaD-catalyzed reaction is comparable to that obtained for the cis-CaaD catalyzed reaction. The kinetic model and the validated alphaY60W-CaaD mutant set the stage for an analysis of active site mutants to explore the contributions of individual catalytic residues and the basis for the simplicity of the reaction. PMID- 23110339 TI - Increased serum levels of lipogenic enzymes in patients with severe liver steatosis. AB - BACKGROUND: Lipid metabolism is altered in subjects with liver steatosis. FAS is a key enzyme in de novo lipogenesis and both FAS gene expression and enzymatic activity are primarily regulated by metabolic signals in the liver. Lipoprotein lipase (LPL), the rate-limiting enzyme for the hydrolysis of core triglycerides, plays a pivotal role in lipid metabolism. This study aims to investigate if circulating levels of FAS and LPL could be clinically associated with liver steatosis. METHODS: In this work, we present data obtained from a subsample of 94 subjects with liver steatosis enrolled by NUTRIEPA study, a nutritional trial in subjects with liver steatosis. Serum levels of FAS protein and LPL activity were evaluated by ELISA test and by a fluorescent method, respectively. The diagnosis and the degree of liver steatosis were based on laboratory and ecographic measurements. Statistical methods included Kruskal-Wallis analysis of variance and Wilcoxon signed-rank test, where appropriate. The chi2 test has been performed to analyse categorical variables. RESULTS: The subjects with severe steatosis had significantly higher serum levels of FAS protein and LPL activity compared to subjects with mild and moderate liver steatosis. Moreover, a positive trend in serum levels of FAS expression from lower to higher degree of steatosis was also detected. CONCLUSIONS: We describe a relationship between human liver steatosis and elevated levels of circulating lipogenic enzymes. Increased serum levels of FAS expression and LPL activity could be considered a marker of severe liver steatosis. PMID- 23110340 TI - Young women in the UAE have higher incidence of HER2 positive breast cancer. PMID- 23110341 TI - Metabolic sequences of anaerobic fermentation on glucose-based feeding substrates based on correlation analyses of microbial and metabolite profiling. AB - Degradation processes in various biomasses are managed by complex metabolic dynamics created by diverse and extensive interactions and competition in microbial communities and their environments. It is important to develop visualization methods to provide a bird's-eye view when characterizing the entire sequential metabolic process in an environmental ecosystem. Here, we describe an approach for the visualization of the metabolic sequences in anaerobic fermentation ecosystems, characterizing the entire metabolic dynamics using a combination of microbial community profiles and metabolic profiles. By evaluating their time-dependent variation, we found that microbial community profiles and metabolite production processes were characteristically affected by the feeding of different glucose-based substrates (glucose, starch, cellulose), although the compositions of the major microbial community and the metabolites detected were likely to be similar in all experiments. This combinatorial approach to variation in microbial communities and metabolic profiles was used successfully to visualize metabolic sequences in anaerobic fermentation ecosystems, in addition to mining candidate microbiota for cellulose degradation. Thus, this approach provides a powerful tool for visualizing and evaluating metabolic sequences within the biomass degradation process in an environmental ecosystem. This is the first report to visualize the entire metabolic dynamic in an anaerobic fermentation ecosystem as metabolic sequences. PMID- 23110342 TI - Frequent hospital admission of older people with chronic disease: a cross sectional survey with telephone follow-up and data linkage. AB - BACKGROUND: The continued increase in hospital admissions is a significant and complex issue facing health services. There is little research exploring patient perspectives or examining individual admissions among patients with frequent admissions for chronic ambulatory care sensitive (ACS) conditions. This paper aims to describe characteristics of older, rural patients frequently admitted with ACS conditions and identify factors associated with their admissions from the patient perspective. METHODS: Patients aged 65+ resident in North Coast NSW with three or more admissions for selected ACS chronic conditions within a 12 month period, were invited to participate in a postal survey and follow up telephone call. Survey and telephone data were linked to admission and health service program data. Descriptive statistics were generated for survey respondents; logistic regression models developed to compare characteristics of patients with 3 or with 4+ admissions; and comparisons made between survey respondents and non-respondents. RESULTS: Survey respondents (n=102) had a mean age of 77.1 years (range 66-95 years), and a mean of 4.1 admissions within 12 months; 49% had at least three chronic conditions; the majority had low socioeconomic status; one in five (22%) reported some difficulty affording their medication; and 35% lived alone. The majority reported psychological distress with 31% having moderate or severe psychological distress. While all had a GP, only 38% reported having a written GP care plan. 22% of those who needed regular help with daily tasks did not have a close friend or relative who regularly cared for them. Factors independently associated with more frequent (n=4+) relative to less frequent (n=3) admissions included having congestive heart failure (p=0.003), higher social isolation scores (p=0.040) and higher Charlson Comorbidity Index scores (p=0.049). Most respondents (61%) felt there was nothing that could have avoided their most recent admission, although some potential avoidability of admission was described around medication and health behaviours. Respondents were younger and less sick than non-respondents. CONCLUSIONS: This study provides a detailed description of older patients with multiple chronic conditions and a history of frequent admission in rural Australia. Our results suggest that programs targeting medication use, health behaviours and social isolation may help reduce multiple hospital admissions for chronic disease. PMID- 23110344 TI - Case of palisaded encapsulated neuroma involving the palm. PMID- 23110345 TI - Vibrational analysis of side chain model compounds of perfluorinated alkyl sulfonic Acid ionomers. AB - Perfluorinated sulfonic acid ionomers have been extensively studied in particular for application to polymer electrolyte fuel cells as they show high proton conductivity at relatively low humidity. While vibrational spectroscopic methods have been successfully applied to investigate dissociation and hydration of their acid sites, the bands in the measured spectra have still been empirically assigned to local vibrations. We performed vibrational analysis of model compounds of the side chains of perfluorinated sulfonic acid ionomers by hybrid DFT calculation. On the basis of mean absolute errors in bond lengths and vibrational frequencies of triflic acid (CF(3)SO(3)H) calculated with various hybrid functionals and basis sets, PBE0/6-311G* gave the best results within affordable computational times and was applied for the model compounds. Most of the observed bands in the ATR-IR spectra of the model compounds were successfully reproduced by calculation of their dissociated sulfonate anions. New assignments were proposed for characteristic two peaks at around 970 and 1060 cm(-1) as combinations of SO(3) symmetric stretch and adjacent CCO bend in two opposite phases. Vibrational bands of doubly hydrogen-bonded acid dimer were also identified in the IR spectrum of "as-received" PFEESA which was not hydrated. These results would provide a new basis for application of vibrational spectroscopy of perfluorinated sulfonic acid ionomers on their structural changes with degree of hydration. PMID- 23110343 TI - An integrative computational systems biology approach identifies differentially regulated dynamic transcriptome signatures which drive the initiation of human T helper cell differentiation. AB - BACKGROUND: A proper balance between different T helper (Th) cell subsets is necessary for normal functioning of the adaptive immune system. Revealing key genes and pathways driving the differentiation to distinct Th cell lineages provides important insight into underlying molecular mechanisms and new opportunities for modulating the immune response. Previous computational methods to quantify and visualize kinetic differential expression data of three or more lineages to identify reciprocally regulated genes have relied on clustering approaches and regression methods which have time as a factor, but have lacked methods which explicitly model temporal behavior. RESULTS: We studied transcriptional dynamics of human umbilical cord blood T helper cells cultured in absence and presence of cytokines promoting Th1 or Th2 differentiation. To identify genes that exhibit distinct lineage commitment dynamics and are specific for initiating differentiation to different Th cell subsets, we developed a novel computational methodology (LIGAP) allowing integrative analysis and visualization of multiple lineages over whole time-course profiles. Applying LIGAP to time course data from multiple Th cell lineages, we identified and experimentally validated several differentially regulated Th cell subset specific genes as well as reciprocally regulated genes. Combining differentially regulated transcriptional profiles with transcription factor binding site and pathway information, we identified previously known and new putative transcriptional mechanisms involved in Th cell subset differentiation. All differentially regulated genes among the lineages together with an implementation of LIGAP are provided as an open-source resource. CONCLUSIONS: The LIGAP method is widely applicable to quantify differential time-course dynamics of many types of datasets and generalizes to any number of conditions. It summarizes all the time course measurements together with the associated uncertainty for visualization and manual assessment purposes. Here we identified novel human Th subset specific transcripts as well as regulatory mechanisms important for the initiation of the Th cell subset differentiation. PMID- 23110346 TI - On the global stability of a generalized cholera epidemiological model. AB - In this paper, we conduct a careful global stability analysis for a generalized cholera epidemiological model originally proposed in [J. Wang and S. Liao, A generalized cholera model and epidemic/endemic analysis, J. Biol. Dyn. 6 (2012), pp. 568-589]. Cholera is a water- and food-borne infectious disease whose dynamics are complicated by the multiple interactions between the human host, the pathogen, and the environment. Using the geometric approach, we rigorously prove the endemic global stability for the cholera model in three-dimensional (when the pathogen component is a scalar) and four-dimensional (when the pathogen component is a vector) systems. This work unifies the study of global dynamics for several existing deterministic cholera models. The analytical predictions are verified by numerical simulation results. PMID- 23110347 TI - The effectiveness of lumbar transforaminal injection of steroids: a comprehensive review with systematic analysis of the published data. AB - OBJECTIVE: To determine the effectiveness of lumbar transforaminal injection of steroids in the treatment of radicular pain. DESIGN: Comprehensive review of the literature with systematic analysis of all published data. INTERVENTIONS: Four reviewers independently assessed 39 publications on the effectiveness of lumbar transforaminal injection of steroids. Each reviewer determined if a publication provided any valid information on effectiveness. Assessments were compared, and the data of each publication were evaluated in terms of the rigor with which they were produced and the evidence they provided of effectiveness. OUTCOME MEASURES: The primary outcome sought was the success rate for relief of pain. Improvement in secondary outcomes was noted if reported. RESULTS: For miscellaneous conditions, the available evidence is limited and is neither compelling nor conclusive. For disc herniation, the evidence is sufficiently abundant to show that lumbar transforaminal injection of steroids is not universally effective but, nevertheless, benefits a substantial proportion of patients, and is not a placebo. Success rates are higher in patients with contained herniations that cause only low-grade compression of the nerve. CONCLUSION: In a substantial proportion of patients with lumbar radicular pain caused by contained disc herniations, lumbar transforaminal injection of corticosteroids is effective in reducing pain, restoring function, reducing the need for other health care, and avoiding surgery. The evidence supporting this conclusion was revealed by comprehensive review of all published data and found to be much more compelling than it would have been if the literature review had been of the limited scope of a traditional "systematic review" of randomized, controlled trials only. PMID- 23110348 TI - Encapsulation of poly(3-hexylthiophene) J-aggregate nanofibers with an amphiphilic block copolymer. AB - Poly(3-hexylthiophene) (P3HT) nanofibers (NF) displaying J-aggregate exciton coupling behavior are encapsulated with the amphiphilic block copolymer (BCP), poly(3-hexyl-thiophene)-block-poly(ethylene-glycol), (PHT(20)-b-PEG(108)). Encapsulation results in the formation of hierarchical superstructures, and the BCP coating is expected to exert a mild chemical pressure on the periphery of the NFs. Photoluminescence from encapsulated NF superstructures show line shape distortions due to self-absorption of the 0-0 transition which is consistent with preservation of J-aggregate character (intrachain order). Detailed resonance Raman spectra of encapsulated BCP-NF structures show no discernible changes in the P3HT aggregation state, and overtone and combination bands involving the symmetric stretching C?C (~1450 cm(-1)) and C-C (~1380 cm(-1)) backbone modes are observed. These features permit quantitative estimates of vibrational mode specific excited state structural displacements using a time-dependent Raman intensity analysis which is not possible from conventional vibronic analysis of optical lineshapes. PMID- 23110349 TI - Evolution of phenolic compounds and astringency during aging of red wine: effect of oxygen exposure before and after bottling. AB - The aim of this study was to evaluate the effect of oxygen exposure of red wine, before (micro-oxygenation) and after (nano-oxygenation) bottling, on the phenolic composition and astringency of wine. The astringency was evaluated by sensory analysis and by a method based on the SDS-PAGE of salivary proteins after reaction of saliva with wine (SPI, saliva precipitation index). Micro-oxygenation caused a stabilization of color, but this effect disappeared after long aging. For the wine with the lower pH a decrease of wine astringency and SPI was observed 42 months after micro-oxygenation. Oxygen ingress through the closure postbottling was positively correlated with the decrease of SPI. Therefore, the astringency and reactivity of wines toward salivary proteins of a bottled red wine can be modulated by controlled oxygen exposure during aging. For both experiments the effect of oxygen exposure depended on wine composition. PMID- 23110350 TI - Pandemic influenza vaccine: characterization of A/California/07/2009 (H1N1) recombinant hemagglutinin protein and insights into H1N1 antigen stability. AB - BACKGROUND: The recent H1N1 influenza pandemic illustrated the shortcomings of the vaccine manufacturing process. The A/California/07/2009 H1N1 pandemic influenza vaccine or A(H1N1)pdm09 was available late and in short supply as a result of delays in production caused by low yields and poor antigen stability. Recombinant technology offers the opportunity to shorten manufacturing time. A trivalent recombinant hemagglutinin (rHA) vaccine candidate for seasonal influenza produced using the baculovirus expression vector system (BEVS) was shown to be as effective and safe as egg-derived trivalent inactivated vaccine (TIV) in human clinical studies. In this study, we describe the characterization of the A/California/07/2009 rHA protein and compare the H1N1 pandemic rHA to other seasonal rHA proteins. RESULTS: Our data show that, like other rHA proteins, purified A/California/07/2009 rHA forms multimeric rosette-like particles of 20-40 nm that are biologically active and immunogenic in mice as assayed by hemagglutination inhibition (HAI) antibody titers. However, proteolytic digest analysis revealed that A/California/07/2009 rHA is more susceptible to proteolytic degradation than rHA proteins derived from other seasonal influenza viruses. We identified a specific proteolytic site conserved across multiple hemagglutinin (HA) proteins that is likely more accessible in A/California/07/2009 HA, possibly as a result of differences in its protein structure, and may contribute to lower antigen stability. CONCLUSION: We conclude that, similar to the recombinant seasonal influenza vaccine, recombinant A(H1N1)pdm09 vaccine is likely to perform comparably to licensed A(H1N1)pdm09 vaccines and could offer manufacturing advantages. PMID- 23110351 TI - Thermotherapy to the facial region in and around the eyelids altered prefrontal hemodynamic responses and autonomic nervous activity during mental arithmetic. AB - To investigate neural mechanisms of local thermotherapy to reduce mental stress, participants were required to perform mental arithmetic after treatment by a heat and steam-generating sheet on the facial eyelid region while hemodynamic activity and ECGs were monitored. The results indicated that thermotherapy decreased hemodynamic activity in the anterior dorsomedial prefrontal cortex (aDMPFC) involved in sympathetic activity. Consistently, thermotherapy increased parasympathetic activity while it decreased sympathetic activity. Furthermore, thermotherapy increased hemodynamic activity in the dorsolateral prefrontal cortex (DLPFC) during mental arithmetic. These hemodynamic responses in the DLPFC during mental arithmetic were negatively correlated with that in the aDMPFC during thermotherapy. The results suggest that thermotherapy in the facial eyelid region is useful to ameliorate mental fatigue through its effects on the prefrontal cortex. PMID- 23110352 TI - Sudden onset bilateral deafness as a presentation of chronic myeloid leukaemia. PMID- 23110354 TI - Educator perceptions of the relationship between education innovations and improved health. AB - BACKGROUND: Education innovations by health professions faculty are shaped by faculty conceptualizations of the pathway between their innovations and changes in health of communities. AIMS: We aimed to explore how existing theories about the relationship between education and health are attended to, interpreted, and applied by faculty in different national contexts. METHODS: We compared existing theoretical frameworks to perceptions of "front line" faculty. Fellows in Brazil- and India-based FAIMER faculty development programs were asked via questionnaires about the contribution of their education innovation projects to health improvements. RESULTS: Faculty identified pathways to improved societal health via increased quality, and to a lesser extent relevance, of education. Relationships between increased quantity of education and improved health were focused on faculty development. Faculty from both countries noted the value for health outcomes of innovations that affect networks and partnerships with other institutions. Faculty from India identified pathways to improved societal health via changes to instructional more than institutional processes. CONCLUSIONS: Results indicate where there are gaps in existing theories, a need to raise awareness about potential pathways to improving health via education changes, and opportunities for more detailed understanding of mechanisms of change via in depth research. PMID- 23110355 TI - The effect of a short integrated study skills programme for first-year medical students at risk of failure: a randomised controlled trial. AB - BACKGROUND: There is a need for outcome-based studies on strategies for supporting at-risk medical students that use long-term follow-up and contemporaneous controls. AIM: To measure the effect of a short integrated study skills programme (SSP) on the study progress of at-risk medical students. METHODS: First-year students identified as at-risk of academic failure at 7 months after enrolment were invited to participate in the randomised controlled trial. Participants were randomly assigned to the SSP group or to a control group receiving standard academic support. Effects of SSP were measured on the short (passed first exam after intervention), medium (obtained enough credits to proceed to second year) and long term (completed first-year curriculum within 2 years). RESULTS: SSP participants (n=43) more often passed the first exam after the intervention than controls (n=41; 30% versus 12%; X2(1)=4.06, p<0.005, effect size=0.22), in particular those who had previously passed at least one exam. No medium or long-term effect was found. Participants who had attended four or five SSP sessions outperformed those who had attended fewer sessions on all outcome measures. CONCLUSION: A short, integrated SSP benefited some, but not all students. Our advice is to focus support efforts on at-risk students who have demonstrated commitment and academic potential. PMID- 23110356 TI - Musical mnemonics in health science: a first look. AB - Song, with its memory enhancement potential and ability to engage, has been employed as a learning tool in some academic settings. Of the countless learning environments, health science may seem the most atypical setting for the musical mnemonic, and yet it may be the most suitable for its application. With medicine's robust history of student-made mnemonics, it only seems natural that learners and instructors alike have begun to experiment with song meant to educate and entertain, primarily imparting them through popular media-sharing sites. This initial assessment of song in health science is meant to highlight notions of efficacy, audience, and use through an informal survey of 10 user-made YouTube musical mnemonics. Two of these mnemonics were co-created by the author, while the remaining eight were identified via select search terms and significant viewer numbers. Resulting YouTube data infers that instructors play a major role in the use of musical mnemonics in health science education. User comments indicate that some students have found value in mnemonic songs, helping them recall information during assessments. More robust research methods, like Q method, meta-analysis, and opinion mining, can further confirm the value and role of musical mnemonics as they pertain to medicine and healthcare. PMID- 23110353 TI - Geographical delimitation of a partial selective sweep in African Drosophila melanogaster. AB - Positive selection leaves characteristic footprints on DNA variation but detecting such patterns is challenging as the age, the intensity and the mode of selection as well as demography and evolutionary parameters (mutation and recombination rates) all play roles and these are difficult to disentangle. We recorded nucleotide variation in a sample of isogenic chromosomes from a western African population of Drosophila melanogaster at a locus (Fbp2) for which a partial selective sweep had previously been reported. We compared this locus to four other genes from the same chromosomes and from a European and an East African population. Then, we assessed Fbp2 variation in a sample of 370 chromosomes covering a comprehensive geographic sampling of 16 African localities. The signature of selection was tested while accounting for the demographic history of the populations. We found a significant signal of selection in two West African localities including Ivory Coast. Variation at Fpb2 would thus represent a case of an ongoing selective sweep in the range of this species. A weaker, nonsignificant, signal of selection was, however, apparent in some other populations, thus leaving open several possibilities: (i) the selective sweep originated in Ivory Coast and has spread to the rest of the continent; (ii) several African populations report the signature of a selective event having occurred in an ancestral population; (iii) this genome region is subject to independent selective events in African populations; and (iv) A neutral scenario with population subdivision and local bottleneck cannot be fully excluded to explain the molecular patterns observed in some populations. PMID- 23110357 TI - The design and utility of institutional teaching awards: a literature review. AB - BACKGROUND: Institutional teaching awards have been used widely in higher education since the 1970s. Nevertheless, a comprehensive review of the literature on such awards has not been published since 1997. AIM: We conducted a literature review to learn as much as possible about the design (e.g., formats, selection processes) and utility (e.g., impact on individuals and institutions) of teaching awards in order to provide information for use in designing, implementing, or evaluating award programs. METHODS: We searched electronic databases for English language publications on awards for exemplary teaching. Targeted publications included descriptions and/or investigations of award programs, their impact, and theoretical or conceptual models for awards programs. Screening was conducted by dual review; a third reviewer was assigned for disagreements. Data were analyzed qualitatively. Results were summarized descriptively. RESULTS: We identified 1302 publications for initial relevancy screening by title and abstract. We identified an additional 23 publications in a follow-up search. The full text of 126 publications was reviewed for further relevance. A total of 62 publications were identified as relevant, and of these 43 met our criteria for inclusion. Of the 43, 19 described the design features of 24 awards; 20 reports discussed award utility. Nomination and selection processes and benefits (e.g., plaques) varied as did perceived impact on individuals and institutions. CONCLUSION: Limited evidence exists regarding design and utility of teaching awards. Awards are perceived as having potential for positive impact, including promotions, but may also have unintended negative consequences. Future research should investigate the impact of awards on personal and professional development, and how promotion and tenure committees perceive awards. PMID- 23110358 TI - Perceived effects of sexually explicit media among men who have sex with men and psychometric properties of the pornography consumption effects scale (PCES). AB - INTRODUCTION: Researchers have proposed that consumption of Sexually Explicit Media (SEM) may not only adversely influence sexual attitudes and behaviors of Men Who Have Sex with Men (MSM) but (also) play a positive role in the development and sexual education of MSM, be a major source of sexual information for MSM, and provide validation, understanding, and confirmation of MSM's sexual orientation. However, such claims are in urgent need of empirical validation as is the development of psychometrically sound and easily implemented instruments able to reliably assist such validations. AIMS: To investigate how MSM who consume SEM self-perceive the impact of SEM on their sexually-transmitted infections-related sexual risk behaviors (i.e., anal intercourse), sexual knowledge, enjoyment of sex, interest in sex, attitudes toward sex, and understanding of their sexual orientation. Further, to provide a thorough psychometric validation of a reduced and reworked version of the Pornography Consumption Effects Scale (PCES). Main Outcome Measure. A revised version of the PCES by Hald and Malamuth. METHODS: Online cross-sectional survey study of 1,333 US adult Men Who Have Sex with Men. RESULTS: This study found that 97% of MSM reported positive effects of SEM consumption on their sexual knowledge, enjoyment of and interest in sex, attitudes toward sex, and understanding of their sexual orientation. Only 3% reported any negative effects of their SEM consumption. SEM consumption was found to significantly increase consumers' interest in having protected anal intercourse while not significantly influencing their interests in having unprotected anal intercourse. The revised version of the PCES showed excellent psychometric performance. CONCLUSION: The study found that MSM generally report positive effects of their consumption of sexually explicit materials in areas related to their sexual knowledge, attitudes, behaviors, and orientation. This finding could have important implications for the sexual health and well-being of MSM by suggesting that SEM-based education and intervention might hold considerable overall health potential for MSM. PMID- 23110359 TI - Expression of IL-24 and IL-24 receptors in human wound tissues and the biological implications of IL-24 on keratinocytes. AB - Interleukin (IL)-24, also known as melanoma differentiation-associated gene-7, is a cytokine initially identified from cancerous cells and expressed in a range of cell types. It is a regulator of cell differentiation, growth, and apoptosis, and a promising anticancer agent. IL-24 acts via its heterodimic receptors: the IL 20R1 and IL-20R2 complex and the IL-22R1 and IL-20R2 complex. There is limited information on the effect of IL-24 in wound healing. Human acute and chronic wound tissues were used to analyze the transcript levels and histological staining of IL-24 and the IL-24 receptors. The biological response of human keratinocytes to recombinant human IL-24 was evaluated using electric cell substrate impedance sensing-based methods in conjunction with inhibitors to candidate signaling pathways. IL-24 significantly slowed the migration of keratinocytes (p = 0.01), with only a marginal effect on cellular adhesion. The inhibitory effect of IL-24 on migration was completed reversed following addition of an AKT inhibitor (p = 0.004) but not an SMAD3 pathway inhibitor. Human chronic wound tissues showed raised levels of both IL-24 (p = 0.003) and its receptor (p = 0.0305) compared with acute wound tissues. We conclude that IL-24 appears to promote wound chronicity via its inhibitory effect on the migratory behavior of human keratinocytes, mediated through an AKT-dependent pathway. PMID- 23110360 TI - The fabrication of nanosensor-based surface plasmon resonance for IgG detection. AB - Poly(2-hydroxyethyl methacrylate)/3-(2-imidazoline-1-yl)propyl(triethoxysilane) (PHEMA/IMEO) nanoparticles were attached on surface plasmon resonance (SPR) sensor for the real-time detection of human immunoglobulin G (IgG) in human serum. The PHEMA/IMEO nanoparticles-attached SPR sensor was characterized by Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), and contact angle measurements. IgG detection studies were performed using aqueous IgG solutions at different concentrations. In order to show the selectivity and specificity of the SPR sensor, competitive kinetic analyses were performed using IgG, albumin, hemoglobin in singular and competitive manner. Finally, IgG detection in human serum was carried out. PMID- 23110361 TI - Cost-effectiveness of adding vaccination with the AS04-adjuvanted human papillomavirus 16/18 vaccine to cervical cancer screening in Hungary. AB - BACKGROUND: The cervical cancer screening program implemented in Hungary to date has not been successful. Along with screening, vaccination is an effective intervention to prevent cervical cancer. The aim of this study was to assess the cost-effectiveness of adding vaccination with the human papillomavirus 16/18 vaccine to the current cervical cancer screening program in Hungary. METHODS: We developed a cohort simulation state-transition Markov model to model the life course of 12-year-old girls. Eighty percent participation in the HPV vaccination program at 12 years of age was assumed. Transitional probabilities were estimated using data from the literature. Local data were used regarding screening participation rates, and the costs were estimated in US $. We applied the purchasing power parity exchange rate of 129 HUF/$ to the cost data. Only direct health care costs were considered. We used a 3.7% discount rate for both the cost and quality-adjusted life years (QALYs). The time horizon was 88 years. RESULTS: Inclusion of HPV vaccination at age 12 in the cervical cancer prevention program was predicted to be cost-effective. The incremental cost-effectiveness ratio (ICER) of adding HPV vaccination to the current national cancer screening program was estimated to be 27 588 $/QALY. The results were sensitive to the price of the vaccine, the discount rate, the screening participation rate and whether herd immunity was taken into account. CONCLUSIONS: Our modeling analysis showed that the vaccination of 12-year-old adolescent girls against cervical cancer with the AS04-adjuvanted human papillomavirus 16/18 vaccine would be a cost-effective strategy to prevent cervical cancer in Hungary. PMID- 23110362 TI - Myocardial infarction after hip fracture repair: a population-based study. AB - OBJECTIVES: To quantify the occurrence of myocardial infarction (MI) occurring in the early postoperative period after surgical hip fracture repair and estimate the effect on 1-year mortality. DESIGN: A population-based, historical cohort study of individuals who underwent surgical repair of a hip fracture that used the computerized medical record linkage system of the Rochester Epidemiology Project. SETTING: Academic and community hospitals, outpatient offices, and nursing homes in Olmsted County, Minnesota. PARTICIPANTS: Over the 15-year study period (1988-2002), 1,116 elderly adults underwent surgical repair of a hip fracture. MEASUREMENTS: At the end of the first 7 days after hip fracture repair, participants were classified into one of three groups: clinically verified MI (cv MI), subclinical myocardial ischemia, and no myocardial ischemia. One-year mortality was compared between these groups. Multivariate models assessed risk factors for early postoperative cv-MI and 1-year mortality. RESULTS: Within the first 7 days after hip fracture repair, 116 (10.4%) participants experienced cv MI and 41 (3.7%) subclinical myocardial ischemia. Overall 1-year mortality was 22%, with no difference between those with subclinical myocardial ischemia and those with no myocardial ischemia. One-year mortality for those with cv-MI (35.8%) was significantly higher than for the other two groups. Occurrence of early postoperative cv-MI, male sex, and history of heart failure or dementia were independently associated with greater 1-year mortality, whereas prefracture home residence and preoperative higher hemoglobin were protective. CONCLUSION: Rates of early postoperative, cv-MI after hip fracture repair exceed rates after other major orthopedic surgeries and are independently associated with greater 1 year mortality. PMID- 23110363 TI - Serratia entomophila bet gene induction and the impact of glycine betaine accumulation on desiccation tolerance. AB - AIMS: The genes involved in choline transport and oxidation to glycine betaine in the biopesticidal bacterium Serratia entomophila were characterized, and the potential of osmoprotectants, coupled with increased NaCl concentrations, to improve the desiccation tolerance of this species was investigated. METHODS AND RESULTS: Serratia entomophila carries sequences similar to the Escherichia coli betTIBA genes encoding a choline transporter and dehydrogenase, a betaine aldehyde dehydrogenase and a regulatory protein. Disruption of betA abolished the ability of Ser. entomophila to utilize choline as a carbon source. Quantitative reverse-transcriptase PCR analysis revealed that betA transcription was reduced compared to that of the upstream genes in the operon, and that NaCl and choline induced bet gene expression. Glycine betaine and choline increased the NaCl tolerance of Ser. entomophila, and osmotically preconditioned cultures survived better than control cultures following desiccation and immediately after application to agricultural soil. CONCLUSIONS: Addition of glycine betaine and NaCl to growth medium can greatly enhance the desiccation survival of Ser. entomophila, and its initial survival in soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Serratia entomophila is sensitive to desiccation and does not persist under low soil moisture conditions. Techniques described here for enhancing the desiccation survival of Ser. entomophila can be used to improve formulations of this bacterium, and allow its application under a wider range of environmental conditions. PMID- 23110364 TI - Quantitative proteomics analysis of the cAMP/protein kinase A signaling pathway. AB - To define the proteins whose expression is regulated by cAMP and protein kinase A (PKA), we used a quantitative proteomics approach in studies of wild-type (WT) and kin- (PKA-null) S49 murine T lymphoma cells. We also compared the impact of endogenous increases in the level of cAMP [by forskolin (Fsk) and the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX)] or by a cAMP analogue (8-CPT-cAMP). We identified 1056 proteins in WT and kin- S49 cells and found that 8-CPT-cAMP and Fsk with IBMX produced differences in protein expression. WT S49 cells had a correlation coefficient of 0.41 between DNA microarray data and the proteomics analysis in cells incubated with 8-CPT-cAMP for 24 h and a correlation coefficient of 0.42 between the DNA microarray data obtained at 6 h and the changes in protein expression after incubation with 8-CPT-cAMP for 24 h. Glutathione reductase (Gsr) had a higher level of basal expression in kin- S49 cells than in WT cells. Consistent with this finding, kin- cells are less sensitive to cell killing and generation of malondialdehyde than are WT cells incubated with H(2)O(2). Cyclic AMP acting via PKA thus has a broad impact on protein expression in mammalian cells, including in the regulation of Gsr and oxidative stress. PMID- 23110366 TI - A substantial increase of the impact factor. PMID- 23110365 TI - QTL mapping of the production of wine aroma compounds by yeast. AB - BACKGROUND: Wine aroma results from the combination of numerous volatile compounds, some produced by yeast and others produced in the grapes and further metabolized by yeast. However, little is known about the consequences of the genetic variation of yeast on the production of these volatile metabolites, or on the metabolic pathways involved in the metabolism of grape compounds. As a tool to decipher how wine aroma develops, we analyzed, under two experimental conditions, the production of 44 compounds by a population of 30 segregants from a cross between a laboratory strain and an industrial strain genotyped at high density. RESULTS: We detected eight genomic regions explaining the diversity concerning 15 compounds, some produced de novo by yeast, such as nerolidol, ethyl esters and phenyl ethanol, and others derived from grape compounds such as citronellol, and cis-rose oxide. In three of these eight regions, we identified genes involved in the phenotype. Hemizygote comparison allowed the attribution of differences in the production of nerolidol and 2-phenyl ethanol to the PDR8 and ABZ1 genes, respectively. Deletion of a PLB2 gene confirmed its involvement in the production of ethyl esters. A comparison of allelic variants of PDR8 and ABZ1 in a set of available sequences revealed that both genes present a higher than expected number of non-synonymous mutations indicating possible balancing selection. CONCLUSIONS: This study illustrates the value of QTL analysis for the analysis of metabolic traits, and in particular the production of wine aromas. It also identifies the particular role of the PDR8 gene in the production of farnesyldiphosphate derivatives, of ABZ1 in the production of numerous compounds and of PLB2 in ethyl ester synthesis. This work also provides a basis for elucidating the metabolism of various grape compounds, such as citronellol and cis-rose oxide. PMID- 23110367 TI - Direct surface analysis of time-resolved aerosol impactor samples with ultrahigh resolution mass spectrometry. AB - Aerosol particles in the atmosphere strongly influence the Earth's climate and human health, but the quantification of their effects is highly uncertain. The complex and variable composition of atmospheric particles is a main reason for this uncertainty. About half of the particle mass is organic material, which is very poorly characterized on a molecular level, and therefore it is challenging to identify sources and atmospheric transformation processes. We present here a new combination of techniques for highly time-resolved aerosol sampling using a rotating drum impactor (RDI) and organic chemical analysis using direct liquid extraction surface analysis (LESA) combined with ultrahigh-resolution mass spectrometry. This minimizes sample preparation time and potential artifacts during sample workup compared to conventional off-line filter or impactor sampling. Due to the high time resolution of about 2.5 h intensity correlations of compounds detected in the high-resolution mass spectra were used to identify groups of compounds with likely common sources or atmospheric history. PMID- 23110368 TI - NGX426, an oral AMPA-kainate antagonist, is effective in human capsaicin-induced pain and hyperalgesia. AB - BACKGROUND: Non-N-methyl-D-aspartate receptor subtypes modulate neurotransmitter release and mediate fast excitatory postsynaptic potentials. This study evaluated the effects of an oral prodrug to tezampanel, a selective alpha-amino-3-hydroxy-5 methly-4-isoxazole-proprionic acid/kainate receptor antagonist, on intradermal capsaicin-induced pain and hyperalgesia. METHODS: This was a randomized, double blind, crossover, placebo-controlled study. Eighteen subjects received 150 or 90 mg NGX426, or placebo, separated by a washout of 6 +/- 2 days. In each treatment period, two intradermal injections of capsaicin were given in the volar region of alternate forearms at 30- and 120-minute drug/placebo administration. Spontaneous pain, elicited pain, and area of hyperalgesia were determined at certain time points after each injection. Subjects were asked to rate the painfulness of a 1 minute long 45 degrees C heat stimulus (brief thermal stimulation [BTS]) applied to the anterior thigh at 4 hours and 30 minutes following drug administration, then every 30 minutes through 6 hours following drug administration. RESULTS: The 150-mg dose produced a statistically definitive reduction in spontaneous pain for all time points relative to placebo. The 90-mg dose produced a statistically significant reduction for the early time point and the entire time interval. Both doses significantly reduced elicited pain at all time points. For the BTS, the 150-mg group reached statistical significance compared with placebo at the 270 minute time point only. CONCLUSIONS: This study demonstrated that NGX426 reduces capsaicin-induced pain and hyperalgesia in human volunteers with low incidence of side effects that suggests that this class of drug may be effective in the treatment of clinical pain. PMID- 23110369 TI - Breast cancer in the octogenarian. PMID- 23110370 TI - Formulation development and in-vitro/in-vivo correlation for a novel Sterculia gum-based oral colon-targeted drug delivery system of azathioprine. AB - The present study was aimed at designing a microflora triggered colon-targeted drug delivery system (MCDDS) based on swellable polysaccharide, Sterculia gum in combination with biodegradable polymers with a view to target azathioprine (AZA) in the colon for the treatment of IBD with reduced systemic toxicity. The microflora degradation study of gum was investigated in rat cecal medium. The polysaccharide tablet was coated to different film thicknesses with blends of chitosan/Eudragit RLPO and over coated with Eudragit L00 to provide acid and intestinal resistance. Swelling and drug release studies were carried out in simulated gastric fluid (SGF) (pH 1.2), simulated intestinal fluid (SIF) (pH 6.8) and simulated colonic fluid (SCF) (pH 7.4 under anaerobic environment), respectively. Drug release study in SCF revealed that swelling force of the gum could concurrently drive the drug out of the polysaccharide core due to the rupture of the chitosan/Eudragit coating in microflora-activated environment. Chitosan in the mixed film coat was found to be degraded by enzymatic action of the microflora in the colon. Release kinetic data revealed that, the optimized MCDDS was fitted well into first order model and apparent lag time was found to be 6 h, followed by Higuchi spherical matrix release. The degradation of chitosan was the rate-limiting factor for drug release in the colon. In-vivo study in rabbit shows delayed T(max), prolonged absorption time, decreased C(max) and absorption rate constant (Ka) indicating reduced systemic toxicity of the drug as compared to other dosage forms. PMID- 23110371 TI - Triphenotypic multiple myeloma expressing kappa or lambda light chain or both. PMID- 23110372 TI - Q(ST) < F(ST) As a signature of canalization. AB - A key aim of evolutionary biology - inferring the action of natural selection on wild species - can be achieved by comparing neutral genetic differentiation between populations (F(ST)) with quantitative genetic variation (Q(ST)). Each of the three possible outcomes of comparisons of Q(ST) and F(ST) (Q(ST) > F(ST), Q(ST) = F(ST), Q(ST) < F(ST)) is associated with an inference (diversifying selection, genetic drift, uniform selection, respectively). However, published empirical and theoretical studies have focused on the Q(ST) > F(ST) outcome. We believe that this reflects the absence of a straightforward biological interpretation of the Q(ST) < F(ST) pattern. We here report recent evidence of this neglected evolutionary pattern, provide guidelines to its interpretation as either a canalization phenomenon or a consequence of uniform selection and discuss the significant importance this issue will have for the area of evolutionary biology. PMID- 23110374 TI - Nonfouling hydrophilic poly(ethylene glycol) engraftment strategy for PDMS/SU-8 heterogeneous microfluidic devices. AB - We report a novel nonfouling passivation method using poly(ethylene glycol) (PEG) engraftment on the surfaces of poly(dimethylsiloxane) (PDMS) microfluidic devices sealed with SU-8. To achieve bonding between the PDMS and SU-8 surfaces, the PDMS surface was first functionalized with amines by treatment with 3 aminopropyltrimethoxysilane (APTMS) for subsequent reaction with epoxide functional groups on SU-8 surfaces. To modify the heterogeneous surfaces of the resulting PDMS/SU-8 microfluidic device further, the remaining SU-8 surfaces were amino functionalized using ethylene diamine (EDA), followed by treating both amino-functionalized PDMS and SU-8 surfaces with mPEG-NHS (N-hydroxysuccinimide) through an amine-NHS reaction for facile PEG immobilizations, thus simultaneously modifying both PDMS and SU-8 surfaces in one reaction. Detailed surface analyses such as the water contact angle, X-ray photoelectron spectroscopy (XPS), and atomic force microscopy (AFM) were conducted to confirm the chemical reactions and characterize the resulting surface properties. To test the efficacy of this surface-modification strategy, we conducted nonspecific protein and particle binding tests using microfluidic devices with and without modifications. The PEG modified PDMS/SU-8 device surfaces showed a 64.5% reduction in nonspecific bovine serum albumin (BSA) adsorption in comparison to that of the unmodified surfaces and 92.0 and 95.8% reductions in microbead adhesion under both stagnant and flowing conditions, respectively. PMID- 23110373 TI - Fasting remnant lipoproteins can predict postprandial hyperlipidemia. AB - BACKGROUND: Hypertriglyceridemia and postprandial hyperlipidemia is thought to play an important role in atherosclerosis, but to select patients at high-risk for cardiovascular diseases is difficult with triglycerides (TG) alone in these patients. METHODS: To predict postprandial hyperlipidemia without inconvenient test meal loading, we examined lipid concentrations before and after test meal loading and fasting adiponectin, and investigated which of these other than TG were significant during the fasting period in 45 healthy individuals (men: women, 26:19). RESULTS: TG, remnant-like particle-cholesterol and -triglyceride (RemL-C, RLP-C, and RLP-TG), and TG/apolipoprotein(apo)B were significantly elevated after loading and fasting values significantly and positively correlated with incremental area under the curve (iAUC) (r=0.80, r=0.79, r=0.63, r=0.58, r=0.54; p<0.0001). Fasting adiponectin positively correlated with fasting high-density lipoprotein-cholesterol (r=0.43, p<0.005) and apoA-I (r=0.34, p<0.05), and negatively correlated with iAUC of TG, RemL-C, RLP-C, RLP-TG, and TG/apoB (r= 0.37, r=-0.41, r=-0.37, r=-0.36, r=-0.37; p<0.05). We constructed the model of multivariable linear regression analysis without fasting TG. In the sex-, BMI-, age-, and waist circumference-adjusted analysis of postprandial TG elevation 2 h after test meal loading in all participants, RemL-C, RLP-C, RLP-TG, and TG/apoB were significant factors, but adiponectin was not. CONCLUSION: Fasting triglyceride-rich lipoprotein-related values, especially RemL-C, RLP-C, RLP-TG, and TG/apoB are useful predictors of postprandial hyperlipidemia in young healthy individuals. Although fasting adiponectin concentration correlated with the iAUCs for TG, RemL-C, RLP-C, RLP-TG, and TG/apoB, it was not a significant predictor of postprandial hyperlipidemia in multivariable linear regression analysis. PMID- 23110375 TI - Acute kidney injury after ingestion of rhubarb: secondary oxalate nephropathy in a patient with type 1 diabetes. AB - BACKGROUND: Oxalosis is a metabolic disorder characterized by deposition of oxalate crystals in various organs including the kidney. Whereas primary forms result from genetic defects in oxalate metabolism, secondary forms of oxalosis can result from excessive intestinal oxalate absorption or increased endogenous production, e.g. after intoxication with ethylene glycol. CASE PRESENTATION: Here, we describe a case of acute crystal-induced renal failure associated with excessive ingestion of rhubarb in a type 1 diabetic with previously normal excretory renal function. Renal biopsy revealed mild mesangial sclerosis, but prominent tubular deposition of oxalate crystals in the kidney. Oxalate serum levels were increased. CONCLUSION: Acute secondary oxalate nephropathy due to excessive dietary intake of oxalate may lead to acute renal failure in patients with preexisting renal disease like mild diabetic nephropathy. Attention should be payed to special food behaviors when reasons for acute renal failure are explored. PMID- 23110377 TI - Update in clinical allergy and immunology. AB - In the recent years, a tremendous body of studies has addressed a broad variety of distinct topics in clinical allergy and immunology. In this update, we discuss selected recent data that provide clinically and pathogenetically relevant insights or identify potential novel targets and strategies for therapy. The role of the microbiome in shaping allergic immune responses and molecular, as well as cellular mechanisms of disease, is discussed separately and in the context of atopic dermatitis, as an allergic model disease. Besides summarizing novel evidence, this update highlights current areas of uncertainties and debates that, as we hope, shall stimulate scientific discussions and research activities in the field. PMID- 23110376 TI - A 5A's communication intervention to promote physical activity in underserved populations. AB - BACKGROUND: The present study protocol describes the trial design of a clinician training intervention to improve physical activity counseling in underserved primary care settings using the 5As. The 5As (Ask, Advise, Agree, Assist, Arrange) are a clinical tool recommended for health behavior counseling in primary care. METHODS/DESIGN: The study is a two-arm randomized pilot pragmatic trial to examine a primary care clinician communication intervention on use of the 5As in discussion of physical activity in audio-recorded office visits in an ethnically diverse, low-income patient population. The study setting consists of two federally qualified community health centers in Rochester, NY. Eligible clinicians (n=15) are recruited and randomized into two groups. Group 1 clinicians participate in the training intervention first; Group 2 clinicians receive the intervention six months later. The intervention and its outcomes are informed by self-determination theory and principles of patient-centered communication. Assessment of outcomes is blinded. The primary outcome will be the frequency and quality of 5As discussions as judged by evaluating 375 audio recorded patient visits distributed over baseline and in the post-intervention period (immediately post and at six months). Secondary outcomes will be changes in patients' perceived competence to increase physical activity (Aim 2) and patients and clinicians beliefs regarding whether pertinent barriers to promoting exercise have been reduced. (Aim 3). Exploratory outcomes (Aim 4) are potential mediators of the intervention's effect and whether the intervention affects actual enrollment in the community program recommended for exercise. The analysis will use repeated measures (in the form of recorded office visits) from each clinician at each time point and aggregate measures of Groups 1 and 2 over time. DISCUSSION: Results will help elucidate the role of 5As communication training for clinicians on counseling for physical activity counseling in primary care. Results will explore the effectiveness of the 5As model linked to community resources for physical activity promotion for underserved groups. PMID- 23110378 TI - Road test and naturalistic driving performance in healthy and cognitively impaired older adults: does environment matter? AB - OBJECTIVES: To relate the standardized road test to video recordings of naturalistic driving in older adults with a range of cognitive impairment. DESIGN: Cross-sectional observational study. SETTING: Academic medical center memory disorders clinic. PARTICIPANTS: One hundred three older drivers (44 healthy, 59 with cognitive impairment) who passed a road test. MEASUREMENTS: Error rate and global ratings of safety (pass with and without recommendations, marginal with restrictions or training, or fail) made by a professional driving instructor. RESULTS: There was fair agreement between global ratings on the road test and naturalistic driving. More errors were detected in the naturalistic environment, but this did not affect global ratings. Error scores between settings were significantly correlated, and the types of errors made were similar. History of crashes corrected for miles driven per week was related to road test error scores but not naturalistic driving error scores. Global cognition (Mini-Mental State Examination) was correlated with road test and naturalistic driving errors. In healthy older adults, younger age was correlated with fewer errors on the road test and more errors in naturalistic driving. CONCLUSION: Road test performance is a reasonable proxy for estimating fitness to drive in older individuals' typical driving environments, but differences between performance assessed using these two methods remain poorly understood and deserve further study. PMID- 23110379 TI - Controlling electronic product branching at conical intersections in the UV photolysis of para-substituted thiophenols. AB - H (Rydberg) atom photofragment translation spectroscopy and high-level ab initio electronic structure calculations are used to explore the photodissociation dynamics of three para-substituted thiophenols (p-YPhSH; Y = CH(3), F, and MeO). UV excitation in the wavelength range 305 > lambda(phot) > 240 nm results in S-H bond fission and formation of p-YPhS radicals in their ground (X(2)B(1)) and first excited (A(2)B(2)) electronic states; the X/A state product branching ratio, Gamma, varies with para-Y substituent and excitation wavelength. Excitation at lambda(phot) < 265 nm results in direct population of the dissociative 1(1)pisigma* potential energy surface (PES). Gamma falls across the series p-CH(3)PhSH > p-FPhSH > p-MeOPhSH. Branching is ultimately determined at the conical intersection (CI) formed by the 1(1)pisigma* and ground (S(0)) PESs at extended R(S-H) bond length but is sensitively dependent on the orientation of the S-H bond (relative to the ring plane) in the S(0) molecules prior to photoexcitation. Excitation at lambda(phot) > 265 nm populates quasi-bound levels of the respective 1(1)pipi* states, which predissociate rapidly by tunneling under the lower diabats of the 1(1)pipi*/1(1)pisigma* CI at short R(S-H). Less extreme X/A product branching ratios are measured, implicating intramolecular vibrational redistribution within the photoexcited 1(1)pipi* molecules prior to their sampling the region of the 1(1)pisigma*/S(0) CI. PMID- 23110380 TI - Overexpression of an isopentenyl diphosphate isomerase gene to enhance trans polyisoprene production in Eucommia ulmoides Oliver. AB - BACKGROUND: Natural rubber produced by plants, known as polyisoprene, is the most widely used isoprenoid polymer. Plant polyisoprenes can be classified into two types; cis-polyisoprene and trans-polyisoprene, depending on the type of polymerization of the isoprene unit. More than 2000 species of higher plants produce latex consisting of cis-polyisoprene. Hevea brasiliensis (rubber tree) produces cis-polyisoprene, and is the key source of commercial rubber. In contrast, relatively few plant species produce trans-polyisoprene. Currently, trans-polyisoprene is mainly produced synthetically, and no plant species is used for its commercial production. RESULTS: To develop a plant-based system suitable for large-scale production of trans-polyisoprene, we selected a trans polyisoprene-producing plant, Eucommia ulmoides Oliver, as the target for genetic transformation. A full-length cDNA (designated as EuIPI, Accession No. AB041629) encoding isopentenyl diphosphate isomerase (IPI) was isolated from E. ulmoides. EuIPI consisted of 1028 bp with a 675-bp open reading frame encoding a protein with 224 amino acid residues. EuIPI shared high identity with other plant IPIs, and the recombinant protein expressed in Escherichia coli showed IPI enzymatic activity in vitro. EuIPI was introduced into E. ulmoides via Agrobacterium mediated transformation. Transgenic lines of E. ulmoides overexpressing EuIPI showed increased EuIPI expression (up to 19-fold that of the wild-type) and a 3- to 4-fold increase in the total content of trans-polyisoprenes, compared with the wild-type (non-transgenic root line) control. CONCLUSIONS: Increasing the expression level of EuIPI by overexpression increased accumulation of trans polyisoprenes in transgenic E. ulmoides. IPI catalyzes the conversion of isopentenyl diphosphate to its highly electrophilic isomer, dimethylallyl diphosphate, which is the first step in the biosynthesis of all isoprenoids, including polyisoprene. Our results demonstrated that regulation of IPI expression is a key target for efficient production of trans-polyisoprene in E. ulmoides. PMID- 23110381 TI - Prescribing in pregnancy for women with diabetes: use of potential teratogenic drugs and contraception. AB - AIMS: To describe contraception use and the prescription of drugs that are either not recommended in pregnancy or are potentially teratogenic by diabetes type in women of child-bearing age. METHODS: Retrospective, cross-sectional chart review undertaken in 22 general practices in Warwickshire, UK. Demographic, anthropometric, medical history, medication and contraception data were extracted from women aged 14 to 49 years with pre-existing diabetes. Independent sample t test, Mann-Whitney test and chi(2) -test were used to test for univariable associations and multiple logistic regression was used to adjust for confounders. RESULTS: Four hundred and seventy eligible women were identified; the majority had a diagnosis of Type 2 diabetes (67%). Thirty-six per cent and 64% of women with Type 1 and Type 2 diabetes, respectively, were prescribed drugs not recommended for use in pregnancy (P < 0.001). Less than half were using concomitant contraception (P < 0.001). No significant difference of contraception use was observed between women who were and were not taking drugs not recommended for use in pregnancy (40 vs. 41%, P = 0.4). CONCLUSIONS: Use of drugs not recommended during pregnancy in women with diabetes of child-bearing age is common but is not associated with increased use of contraception. There is need to identify and overcome barriers to effective contraception use for this population group in order to facilitate optimal management of cardiovascular risk. PMID- 23110382 TI - Diabetes MILES--The Netherlands: rationale, design and sample characteristics of a national survey examining the psychosocial aspects of living with diabetes in Dutch adults. AB - BACKGROUND: As the number of people with diabetes is increasing rapidly worldwide, a more thorough understanding of the psychosocial aspects of living with this condition has become an important health care priority. While our knowledge has grown substantially over the past two decades with respect to the physical, emotional and social difficulties that people with diabetes may encounter, many important issues remain to be elucidated. Under the umbrella of the Diabetes MILES (Management and Impact for Long-term Empowerment and Success) Study International Collaborative, Diabetes MILES--The Netherlands aims to examine how Dutch adults with diabetes manage their condition and how it affects their lives. Topics of special interest in Diabetes MILES--The Netherlands include subtypes of depression, Type D personality, mindfulness, sleep and sexual functioning. METHODS/DESIGN: Diabetes MILES--The Netherlands was designed as a national online observational study among adults with diabetes. In addition to a main set of self-report measures, the survey consisted of five complementary modules to which participants were allocated randomly. From September to October 2011, a total of 3,960 individuals with diabetes (40% type 1, 53% type 2) completed the battery of questionnaires covering a broad range of topics, including general health, self-management, emotional well-being and contact with health care providers. People with self-reported type 1 diabetes (specifically those on insulin pump therapy) were over-represented, as were those using insulin among respondents with self-reported type 2 diabetes. People from ethnic minorities were under-represented. The sex distribution was fairly equal in the total sample, participants spanned a broad age range (19-90 years), and diabetes duration ranged from recent diagnosis to living with the condition for over fifty years. DISCUSSION: The Diabetes MILES Study enables detailed investigation of the psychosocial aspects of living with diabetes and an opportunity to put these findings in an international context. With several papers planned resulting from a pooled Australian-Dutch dataset and data collections planned in other countries, the Diabetes MILES Study International Collaborative will contribute substantially to identifying potentially unmet needs of those living with diabetes and to inform clinical research and care across the globe. PMID- 23110383 TI - Development of a feed additive to reduce caecal Campylobacter jejuni in broilers at slaughter age: from in vitro to in vivo, a proof of concept. AB - AIM: In vitro and in vivo challenge studies were undertaken to develop an in-feed additive of microencapsulated propionic, sorbic acids and pure botanicals to control Campylobacter jejuni in broilers at slaughter age. METHODS AND RESULTS: Organic acids (OA) and pure botanicals were tested in vitro against Camp. jejuni, whereas in vivo, chickens were fed either a control diet, or increasing doses of the additive for 42 days (experiment 1); in the second experiment, chickens received the additive at 0.1 or 0.3% from day 0 to 21 or from day 22 to 42. The additive consistently reduced Camp. jejuni caecal counts at any given dose (exp. 1) or inclusion plan (exp. 2). Moreover, it was able to reduce the number of goblet cells and modify mucin glycoconjugates biosynthesis pattern. CONCLUSIONS: We developed an additive that was effective in reducing Camp. jejuni in slaughter age chickens even at low doses (0.1%). That efficacy was the result of the synergistic action between OA and botanicals. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a strategy to reduce Camp. jejuni in broilers and, as a consequence, to improve the safety of the food chain. Moreover, data suggest that a treatment limited to the last weeks before slaughter would allow to save on inclusion of the additive throughout the whole production cycle. PMID- 23110384 TI - Regeneration and bioengineering of transplantable abdominal organs: current status and future challenges. AB - INTRODUCTION: The most critical issue to organ transplantation is the identification of new sources of organs. The present manuscript illustrates the state-of-the-art regenerative medicine (RM) investigations aiming to manufacturing abdominal organs for transplant purposes. AREAS COVERED: This manuscript focuses on research in the bioengineering and regeneration of kidneys, insulin-producing cells, livers and small bowel. The main technology currently under development exploits the seeding of cells on supporting scaffolding material. Despite favorable preliminary results obtained with relatively simple, hollow organs, when more complex organs are considered, the scenario changes dramatically. Investigations are still in early stages, and clinical translation is not yet foreseeable based on current knowledge and information. Obstacles are numerous but we believe the critical factor hampering success is lack of in-depth understanding of the extracellular matrix (ECM) and cell-ECM interactions, as well as the mechanisms with which organs develop in utero. EXPERT OPINION: The success of RM to generate transplantable abdominal organs relies heavily on progress in (stem) cell therapies, developmental and ECM biology, and in the thorough understanding of the intricate relationship and interplay between cells and the ECM. This will require enormous investments in financial and medical resources, which ideally should be embarked upon by governments, the private sector and academia. PMID- 23110385 TI - Comparison of total and cytoplasmic mRNA reveals global regulation by nuclear retention and miRNAs. AB - BACKGROUND: The majority of published gene-expression studies have used RNA isolated from whole cells, overlooking the potential impact of including nuclear transcriptome in the analyses. In this study, mRNA fractions from the cytoplasm and from whole cells (total RNA) were prepared from three human cell lines and sequenced using massive parallel sequencing. RESULTS: For all three cell lines, of about 15000 detected genes approximately 400 to 1400 genes were detected in different amounts in the cytoplasmic and total RNA fractions. Transcripts detected at higher levels in the total RNA fraction had longer coding sequences and higher number of miRNA target sites. Transcripts detected at higher levels in the cytoplasmic fraction were shorter or contained shorter untranslated regions. Nuclear retention of transcripts and mRNA degradation via miRNA pathway might contribute to this differential detection of genes. The consequence of the differential detection was further investigated by comparison to proteomics data. Interestingly, the expression profiles of cytoplasmic and total RNA correlated equally well with protein abundance levels indicating regulation at a higher level. CONCLUSIONS: We conclude that expression levels derived from the total RNA fraction be regarded as an appropriate estimate of the amount of mRNAs present in a given cell population, independent of the coding sequence length or UTRs. PMID- 23110386 TI - Predictive validity of granulation tissue color measured by digital image analysis for deep pressure ulcer healing: a multicenter prospective cohort study. AB - This multicenter prospective cohort study examined the predictive validity of granulation tissue color evaluated by digital image analysis for deep pressure ulcer healing. Ninety-one patients with deep pressure ulcers were followed for 3 weeks. From a wound photograph taken at baseline, an image representing the granulation red index (GRI) was processed in which a redder color represented higher values. We calculated the average GRI over granulation tissue and the proportion of pixels exceeding the threshold intensity of 80 for the granulation tissue surface (%GRI80) and wound surface (%wound red index 80). In the receiver operating characteristics curve analysis, most GRI parameters had adequate discriminative values for both improvement of the DESIGN-R total score and wound closure. Ulcers were categorized by the obtained cutoff points of the average GRI (<=80, >80), %GRI80 (<=55, >55-80, >80%), and %wound red index 80 (<=25, >25-50, >50%). In the linear mixed model, higher classes for all GRI parameters showed significantly greater relative improvement in overall wound severity during the 3 weeks after adjustment for patient characteristics and wound locations. Assessment of granulation tissue color by digital image analysis will be useful as an objective monitoring tool for granulation tissue quality or surrogate outcomes of pressure ulcer healing. PMID- 23110388 TI - Poly(hydroxyethyl methacrylate) based magnetic nanoparticles for lysozyme purification from chicken egg white. AB - The purpose of this article is to synthesize poly(hydroxyethyl methacrylate-N methacryloyl-(L)-tryptophan) [mPHEMATrp] magnetic nanoparticles for lysozyme purification from chicken egg white. mPHEMATrp nanoparticles (38 nm in diameter) were synthesized by surfactant-free emulsion polymerization. Specific surface area of the mPHEMATrp nanoparticles was calculated to be 896 m2/g. Elemental analysis of mPHEMATrp nanoparticles was estimated in the range of 5.7-48.3 umol MATrp/g. The maximum lysozyme adsorption capacity of the mPHEMATrp nanoparticles was 376.1 mg/g. The mPHEMATrp nanoparticles could be used five times without decreasing the lysozyme adsorption capacity significantly. The results indicate that the mPHEMATrp nanoparticles promise high selectivity for lysozyme purification. PMID- 23110387 TI - The association between cognitive function and white matter lesion location in older adults: a systematic review. AB - BACKGROUND: Maintaining cognitive function is essential for healthy aging and to function autonomously within society. White matter lesions (WMLs) are associated with reduced cognitive function in older adults. However, whether their anatomical location moderates these associations is not well-established. This review systematically evaluates peer-reviewed evidence on the role of anatomical location in the association between WMLs and cognitive function. METHODS: In accordance with the preferred reporting items for systematic reviews and meta analysis (PRISMA) statement, databases of EMBASE, PUBMED, MEDLINE, and CINAHL, and reference lists of selected papers were searched. We limited our search results to adults aged 60 years and older, and studies published in the English language from 2000 to 2011. Studies that investigated the association between cognitive function and WML location were included. Two independent reviewers extracted: 1) study characteristics including sample size, sample characteristic, and study design; 2) WML outcomes including WML location, WML quantification method (scoring or volume measurement), strength of the MRI magnet in Tesla, and MRI sequence used for WML detection; and 3) cognitive function outcomes including cognitive tests for two cognitive domains of memory and executive function/processing speed. RESULTS: Of the 14 studies included, seven compared the association of subcortical versus periventricular WMLs with cognitive function. Seven other studies investigated the association between WMLs in specific brain regions (e.g., frontal, parietal lobes) and cognitive function. Overall, the results show that a greater number of studies have found an association between periventricular WMLs and executive function/processing speed, than subcortical WMLs. However, whether WMLs in different brain regions have a differential effect on cognitive function remains unclear. CONCLUSIONS: Evidence suggests that periventricular WMLs may have a significant negative impact on cognitive abilities of older adults. This finding may be influenced by study heterogeneity in: 1) MRI sequences, WML quantification methods, and neuropsychological batteries; 2) modifying effect of cardiovascular risk factors; and 3) quality of studies and lack of sample size calculation. PMID- 23110389 TI - Long-term effects of copper nanoparticles on wastewater biological nutrient removal and N2O generation in the activated sludge process. AB - The increasing use of copper nanoparticles (Cu NPs) raises concerns about their potential toxic effects on the environment. However, their influences on wastewater biological nutrient removal (BNR) and nitrous oxide (N(2)O) generation in the activated sludge process have never been documented. In this study the long-term effects of Cu NPs (0.1-10 mg/L) on BNR and N(2)O generation were investigated. The total nitrogen (TN) removal was enhanced and N(2)O generation was reduced at any Cu NPs levels investigated, but both ammonia and phosphorus removals were not affected. The mechanism studies showed although most of the Cu NPs were absorbed to activated sludge, the activated sludge surface was not damaged, and the released copper ion from Cu NPs dissolution was the main reason for TN removal improvement and N(2)O reduction. It was also found that the transformation of polyhydroxyalkanoates and the activities of ammonia monooxygenase, nitrite oxidoreductase, exopolyphosphatase, and polyphosphate kinase were not affected by Cu NPs, whereas the decreased metabolism of glycogen and the increased activities of denitrification enzymes were observed. Further investigation revealed that Cu NPs increased the number of denitrifiers (especially N(2)O reducing denitrifiers) but decreased nitrite accumulation. All these observations were in correspondence with the enhancement of TN removal and reduction of N(2)O generation. PMID- 23110390 TI - Successful endocrine therapy for locally advanced mucinous carcinoma of the breast. PMID- 23110392 TI - The proteomics of feather development in pied flycatchers (Ficedula hypoleuca) with different plumage coloration. AB - The genetic theory of morphological evolution postulates that form evolves largely by changing the expression proteins that are functionally conserved. It follows that understanding the function of proteins during different phases of development as well as the mechanisms by which the functions are modified is a prerequisite for understanding evolutionary change. Male pied flycatchers exhibit marked phenotypic variation in their breeding plumage. This variation has repeatedly been shown to have adaptive significance, but the molecular basis of this variation is not known. Here, we characterize the proteome of developing pied flycatcher feathers from differently pigmented males and also introduce a new method for examining the effect sizes of expression differences in protein interaction networks. Approximately 300 proteins were identified in the developing feathers of males. Gene products associated with cellular transport, cell metabolism and protein synthesis formed a large part of the developing feather proteome. Sixty-five proteins associated with the development of the epidermis and/or pigmentation were detected in the data. The examination of expression level differences of protein-protein interaction networks revealed an immunological signalling-related network to exhibit significantly higher expression in black compared to brown males. Additionally, indications of differences in energy balance and oxidative stress related characteristics were detected. Together, these results provide new insight into the molecular mechanisms and evolutionary significance of plumage colour variation. PMID- 23110391 TI - The role of Odontella aurita, a marine diatom rich in EPA, as a dietary supplement in dyslipidemia, platelet function and oxidative stress in high-fat fed rats. AB - BACKGROUND: Dietary changes are a major factor in determining cardiovascular risk. n-3 polyunsaturated fatty acids modulate the risk factors for metabolic syndrome via multiple mechanisms, including the regulation of the lipid metabolism. We therefore investigated the effect of Odontella aurita, a microalga rich in EPA, which is already used as a food supplement, on the risk factors for high-fat diet induced metabolic syndrome in rats. METHODS: Male Wistar rats were divided into 4 groups and were fed with a standard diet (control); with the standard diet supplemented with 3% freeze-dried O. aurita (COA); with a high-fat diet (HF); or with the high-fat diet supplemented with 3% of freeze-dried O. aurita (HFOA) for 7 weeks. In this study we evaluated the impact of these different diets on the risk factors for metabolic syndrome, such as hyperlipidemia, platelet aggregation, thromboxane B2 production, and oxidative stress. RESULTS: After 7 weeks of treatment, high fat feeding had increased final body weight, glycemia, triacylglycerol, and total cholesterol levels in plasma and liver compared to the control diet. Collagen-induced platelet aggregation and basal platelet thromboxane B2 were also higher in the high-fat fed rats than in those in the control group. In the liver, oxidative stress was greater in the HF group than in the control group. O. aurita intake in HFOA-fed rats resulted in lower glycemia and lipid levels in the plasma and liver relative than in the HF group. Thus, in the HFOA group, n-3 polyunsaturated fatty acid levels in the tissues studied (plasma, liver, and platelets) were higher than in the HF group. Platelet hyper-aggregability tended to decrease in HFOA-fed rats as basal platelet thromboxane B2 production decreased. Finally, O. aurita reduced oxidative stress in the liver, with lower malondialdehyde levels and increased glutathione peroxidase activity. CONCLUSIONS: O. aurita is a marine diatom rich in EPA as well as in other bioactive molecules, such as pigments. The synergistic effect of these microalgal compounds, displayed a beneficial effect in reducing the risk factors for high-fat induced metabolic syndrome: hyperlipidemia, platelet aggregation, and oxidative stress. PMID- 23110393 TI - Expression of aquaporin proteins in vagina of diabetes mellitus rats. AB - INTRODUCTION: Aquaporins (AQPs) are membrane proteins that facilitate water movement across biological membranes. Vaginal lubrication may be mediated by blood flow and other potential mechanisms related to transudation of fluid. The most common female sexual dysfunction in diabetes is inadequate vaginal lubrication. AIM: To investigate the expression of AQP1-3 in vaginal tissue of diabetes mellitus rats. METHODS: Female Sprague-Dawley rats (N = 20) were randomly divided into group A (12-week-old nondiabetic control, N = 5), group B (16-week-old nondiabetes control, N = 5), group C (12-week-old diabetes mellitus rats, N = 5), and group D (16-week-old diabetes mellitus rats, N = 5). Vaginal fluid was measured by fluid weight absorbed by cotton swabs after pelvic nerve electrostimulation and anterior vaginal tissue was dissected for determining the expression of AQP1-3 by immunohistochemical study and Western blot. MAIN OUTCOME MEASURES: The expression of AQP1-3 was determined in the vagina of diabetes mellitus rats by Western blot. RESULTS: There are no significant differences in serum estradiol concentrations of rats among these groups (P > 0.05). Vaginal fluid was significantly lower in group C (2.7 +/- 0.67 mg) and group D (2.5 +/- 1.03 mg) than in group A (5.74 +/- 1.23 mg) and group B (5.5 +/- 1.08 mg) (P < 0.05), respectively. The protein expressions of AQP1-3 were significantly lower in group C (43.40 +/- 4.83, 60.60 +/- 12.80, and 59.60 +/- 6.95) and group D (20.81 +/- 2.86, 47.80 +/- 11.43, and 54.20 +/- 5.26) than in group A (116.62 +/- 3.21, 110.81 +/- 8.044, and 108.80 +/- 4.97) and group B (122.12 +/- 14.54, 111.21 +/- 15.07, and 106.40 +/- 4.16) (P < 0.05), respectively. CONCLUSIONS: Decreased vaginal fluid in diabetes mellitus rats after electrostimulation may be partly due to estrogen-independent decreases of AQP1-3 in vaginal tissue. PMID- 23110395 TI - Occurrence of nephrolithiasis in a population of longsnout seahorse, Hippocampus reidi Ginsburg, and analysis of a nephrolith. PMID- 23110394 TI - A functional relationship between trigeminal astroglial activation and NR1 expression in a rat model of temporomandibular joint inflammation. AB - OBJECTIVE: To examine the hypothesis that glial activation would regulate the expression of the N-methyl-D-aspartate receptor subunit 1 (NR1) in the trigeminal subnucleus caudalis (Sp5C) after temporomandibular joint (TMJ) inflammation. METHODS: Inflammation of TMJ was produced in rats by injecting 50 MUL complete Freund's adjuvant (CFA) into unilateral TMJ space. Sham control rats received incomplete Freund's adjuvant injection. Mechanical nociception in the affected and non-affected TMJ site was tested by using a digital algometer. Fractalkine, fluorocitrate, and/or MK801 were intracisternally administrated to examine the relationship between astroglial activation and NR1 upregulation. RESULTS: CFA TMJ injection resulted in persistent ipsilateral mechanical hyperalgesia 1, 3, and 5 days after CFA injection. The inflammation also induced significant upregulation of CX3C chemokine receptor 1 and glial fibrillary acidic protein (GFAP) beginning on day 1 and of NR1 beginning on day 3 within the ipsilateral Sp5C. Intracisternal administration of fluorocitrate for 5 days blocked the development of mechanical hyperalgesia as well as the upregulation of GFAP and NR1 in the Sp5C. Conversely, intracisternal injection of fractalkine for 5 days exacerbated the expression of NR1 in Sp5C and mechanical hyperalgesia induced by TMJ inflammation. Moreover, once daily intracisternal fractalkine administration for 5 days in naive rats induced the upregulation of NR1 and mechanical hyperalgesia. CONCLUSIONS: These results suggest that astroglial activation contributes to the mechanism of TMJ pain through the regulation of NR1 expression in Sp5C. PMID- 23110396 TI - Reduction of transplant arteriosclerosis after treatment with mycophenolate mofetil and ganciclovir in a mouse aortic allograft model. AB - OBJECTIVES: Transplant arteriosclerosis is a major obstacle for long-term allograft survival in heart transplant. The aim of this study was to investigate potential synergistic effects of combined treatment with mycophenolate mofetil and ganciclovir on the development of transplant arteriosclerosis, presence of regulatory T cells, and expression of donor specific alloantibodies. MATERIALS AND METHODS: Donor aortas from C57BL/6 (H2b) mice that were fully mismatched to the major histocompatibility complex were transplanted into CBA (H2k) mouse recipients. Groups of mice received mycophenolate mofetil (100 or 300 mg/kg, oral), ganciclovir (10 or 72 mg/kg, intraperitoneal), or a mycophenolate mofetil and ganciclovir combination. Grafts were analyzed by histology and morphometry on day 30 after transplant. Numbers of regulatory T cells and donor-specific alloantibodies were examined by fluorescence-activated cell sorting analysis of splenic tissue and peripheral blood. RESULTS: Mycophenolate mofetil (100 mg/kg) and ganciclovir (10 mg/kg and 72 mg/kg) did not show effects on transplant arteriosclerosis formation or alloantibody production. However, groups treated with mycophenolate mofetil (300 mg/kg) or a low- or high-dose mycophenolate mofetil and ganciclovir combination had significantly reduced transplant arteriosclerosis and alloantibody levels. Expression of regulatory T cells within the spleen was similar between all experimental groups and untreated controls. CONCLUSIONS: The combination of mycophenolate mofetil and ganciclovir significantly reduced the development of transplant arteriosclerosis in a mouse abdominal aortic allograft model. This effect may be a result of decreased alloantibody production. PMID- 23110397 TI - Rehabilitation time before disability pension. AB - BACKGROUND: The decision to grant a disability pension is usually the end of a long process of medical examinations, treatment and rehabilitation attempts. This study investigates to what extent the time spent on rehabilitation time prior to disability pension is associated with characteristics of the individual or the local employment and welfare office, measured as municipality variance. METHODS: A study of 2,533 40 to 42 year olds who received disability pension over a period of 18 years. The logarithm of the rehabilitation time before granting a disability pension was analysed with multilevel regression. RESULTS: The rehabilitation time before a disability pension was granted ranged from 30 to 5,508 days. Baseline health characteristics were only moderately associated with rehabilitation time. Younger people and people with unemployment periods had longer rehabilitation time before a disability pension was granted. There were only minor differences in rehabilitation time between men and women and between different levels of education. Approximately 2% of the total variance in rehabilitation time could be attributed to the municipality of residence. CONCLUSIONS: There is a higher threshold for granting a disability pension to younger persons and those who are expecting periods of unemployment, which is reflected in the extended rehabilitation requirements for these groups. The longer rehabilitation period for persons with psychiatric disorders might reflect a lack of common knowledge on the working capacity of and the fitted rehabilitation programs for people with psychiatric disorders. PMID- 23110398 TI - Live attenuated influenza viruses produced in a suspension process with avian AGE1.CR.pIX cells. AB - BACKGROUND: Current influenza vaccines are trivalent or quadrivalent inactivated split or subunit vaccines administered intramuscularly, or live attenuated influenza vaccines (LAIV) adapted to replicate at temperatures below body temperature and administered intranasally. Both vaccines are considered safe and efficient, but due to differences in specific properties may complement each other to ensure reliable vaccine coverage. By now, licensed LAIV are produced in embryonated chicken eggs. In the near future influenza vaccines for human use will also be available from adherent MDCK or Vero cell cultures, but a scalable suspension process may facilitate production and supply with vaccines. RESULTS: We evaluated the production of cold-adapted human influenza virus strains in the duck suspension cell line AGE1.CR.pIX using a chemically-defined medium. One cold adapted A (H1N1) and one cold-adapted B virus strain was tested, as well as the reference strain A/PR/8/34 (H1N1). It is shown that a medium exchange is not required for infection and that maximum virus titers are obtained for 1 * 10-6 trypsin units per cell. 1 L bioreactor cultivations showed that 4 * 106 cells/mL can be infected without a cell density effect achieving titers of 1 * 108 virions/mL after 24 h. CONCLUSIONS: Overall, this study demonstrates that AGE1.CR.pIX cells support replication of LAIV strains in a chemically-defined medium using a simple process without medium exchanges. Moreover, the process is fast with peak titers obtained 24 h post infection and easily scalable to industrial volumes as neither microcarriers nor medium replacements are required. PMID- 23110399 TI - Solvent polarity-induced conformational unlocking of asparagine. AB - Classical and Car-Parrinello molecular dynamics simulations are performed to study the solvent effect on the conformational distribution of asparagine. Conformational populations obtained from the simulations in gas phase and in nonpolar chloroform solvent are in agreement with the most probable single conformation of asparagine in the gas phase measured in recent laser ablation with molecular beam Fourier transform microwave spectroscopy experiments. We rationalize that intramolecular hydrogen bonding and dipole-dipole interactions between carbonyl groups dictate such a conformational locking to a single asparagine conformer. The solvent polarity induced interlocking or intermolecular hydrogen bonding with water solvent molecules destabilizes the (NH...O?C) bonding between side chain and terminal groups of asparagine, while not essentially affecting the (NH...O?C) intramolecular hydrogen bondings within the side chain nor within the terminal groups. Such a conformational unlocking or cage effect is observed in asparagine within aqueous solution. We observed a spontaneous conversion of neutral to zwitterionic isomer of asparagine in aqueous solution, which is in agreement with interpretation of Raman spectroscopy results. Using Moller-Plesset second order perturbation theory, we show that a tautomeric shift from neutral to zwitterionic occurs on asparagine in between DMSO and water solvents. The ramification of these findings for the conformational character of asparagine is briefly discussed. PMID- 23110400 TI - Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8 hydroxy-2'-deoxyguanosine) in ex vivo human skin. AB - UV radiation (UVR) induces serious structural and functional alterations in human skin leading to skin aging and carcinogenesis. Reactive oxygen species are key players in UVR-mediated photodamage and induce the DNA-base-oxidized, intermediate 8-hydroxy-2'-deoxyguanosine (8-OHdG). Herein, we report the protective action of melatonin against UVR-induced 8-OHdG formation and depletion of antioxidative enzymes using ex vivo human full-thickness skin exposed to UVR in a dose (0, 100, 300 mJ/cm(2))- and time-dependent manner (0, 24, 48 hr post UVR). Dynamics of depletion of antioxidative enzymes including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), or 8-OHdG formation were studied by real-time PCR and immunofluorescence/immunohistochemical staining. UVR-treated skin revealed significant and immediate (0 hr 300 mJ/cm(2)) reduction of gene expression, and this effect intensified within 24 hr post-UVR. Simultaneous increase in 8-OHdG-positive keratinocytes occurred already after 0 hr post-UVR reaching 71% and 99% up-regulation at 100 and 300 mJ/cm(2), respectively (P < 0.001). Preincubation with melatonin (10(-3) M) led to 32% and 29% significant reductions in 8-OHdG-positive cells and the prevention of antioxidative enzyme gene and protein suppression. Thus, melatonin was shown to play a crucial role as a potent antioxidant and DNA protectant against UVR induced oxidative damage in human skin. PMID- 23110401 TI - Antiepileptic drug monotherapy exposure and suicide-related behavior in older veterans. AB - OBJECTIVES: To examine the association between antiepileptic drug (AED) receipt and suicide-related behavior (SRB) in older veterans. DESIGN: Retrospective database analysis. SETTING: Veterans Health Administration (VHA) inpatient and outpatient care. PARTICIPANTS: Veterans aged 65 and older in 2004 to 2006. MEASUREMENTS: SRB was identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes, and new AED monotherapy was identified using the VHA product variable in pharmacy data. Comorbid conditions and medications were also identified as potential confounders using previously validated algorithms. Cox proportional hazards models controlling for the propensity to receive AEDs examined the association between any AED exposure, specific AEDs, and time to SRB. RESULTS: Within the eligible sample of 2.15 million individuals, 332 cases of SRB were found. Overall, 98% of participants were male, and 67% were non-Hispanic white. Affective disorders and severe psychiatric conditions were strongly associated with SRB and were included in the propensity score. AED exposure displayed a significant association with SRB (odds ratio = 4.10, 95% confidence interval (CI) = 3.85-6.63) after adjusting for propensity to receive AEDs. Stratified analyses found similar results for those with (hazard ratio (HR) = 4.00, 95% CI = 2.9-5.5) and without (HR = 4.57, 95% CI = 1.15-18.20) mental health comorbidities. Gabapentin, phenytoin, lamotrigine, levetiracetam, topiramate, and valproate were significantly associated with SRB. CONCLUSION: Exposure to five common AEDs was associated with SRB in older VHA beneficiaries. Given the strong associations between psychiatric comorbidity and SRB, clinicians treating elderly adults should weigh this potential adverse effect into their consideration for treatment of those receiving AEDs. Particular attention should be given to depression and suicidality screening in people prescribed AEDs. PMID- 23110402 TI - Resilience among asylum seekers living with HIV. AB - BACKGROUND: A small body of evidence demonstrates the challenges faced by migrant communities living with HIV but has yet to consider in-depth the experience of asylum seekers whose residency status is undetermined. The overall aim of our study was to explore the experiences of those who are both living with HIV and seeking asylum. This paper focuses on the stressors precipitated by the HIV diagnosis and by going through the asylum system; as well as participants' resilience in responding to these stressors and the consequences for their health and wellbeing. METHODS: We conducted an ethnographic study. Fieldwork took place in the UK between 2008-2009 and included: 350 hours of observation at voluntary services providing support to black and minority ethnic groups living with HIV; 29 interviews and four focus group discussions with those who were seeking asylum and living with HIV; and 15 interviews with their health and social care providers. Data were analysed using the constant comparative method. RESULTS: There were three main stressors that threatened participants' resilience. First, migration caused them to leave behind many resources (including social support). Second, stigmatising attitudes led their HIV diagnosis to be a taboo subject furthering their isolation. Third, they found themselves trapped in the asylum system, unable to influence the outcome of their case and reliant on HIV treatment to stay alive. Participants were, however, very resourceful in dealing with these experiences. Resilience processes included: staying busy, drawing on personal faith, and the support received through HIV care providers and voluntary organisations. Even so, their isolated existence meant participants had limited access to social resources, and their treatment in the asylum system had a profound impact on perceived health and wellbeing. CONCLUSIONS: Asylum seekers living with HIV in the UK show immense resilience. However, their isolation means they are often unable to deal with their treatment in the asylum system, with negative consequences for their perceived health and wellbeing. PMID- 23110403 TI - Characterization of a transcriptome from a non-model organism, Cladonia rangiferina, the grey reindeer lichen, using high-throughput next generation sequencing and EST sequence data. AB - BACKGROUND: Lichens are symbiotic organisms that have a remarkable ability to survive in some of the most extreme terrestrial climates on earth. Lichens can endure frequent desiccation and wetting cycles and are able to survive in a dehydrated molecular dormant state for decades at a time. Genetic resources have been established in lichen species for the study of molecular systematics and their taxonomic classification. No lichen species have been characterised yet using genomics and the molecular mechanisms underlying the lichen symbiosis and the fundamentals of desiccation tolerance remain undescribed. We report the characterisation of a transcriptome of the grey reindeer lichen, Cladonia rangiferina, using high-throughput next-generation transcriptome sequencing and traditional Sanger EST sequencing data. RESULTS: Altogether 243,729 high quality sequence reads were de novo assembled into 16,204 contigs and 49,587 singletons. The genome of origin for the sequences produced was predicted using Eclat with sequences derived from the axenically grown symbiotic partners used as training sequences for the classification model. 62.8% of the sequences were classified as being of fungal origin while the remaining 37.2% were predicted as being of algal origin. The assembled sequences were annotated by BLASTX comparison against a non redundant protein sequence database with 34.4% of the sequences having a BLAST match. 29.3% of the sequences had a Gene Ontology term match and 27.9% of the sequences had a domain or structural match following an InterPro search. 60 KEGG pathways with more than 10 associated sequences were identified. CONCLUSIONS: Our results present a first transcriptome sequencing and de novo assembly for a lichen species and describe the ongoing molecular processes and the most active pathways in C. rangiferina. This brings a meaningful contribution to publicly available lichen sequence information. These data provide a first glimpse into the molecular nature of the lichen symbiosis and characterise the transcriptional space of this remarkable organism. These data will also enable further studies aimed at deciphering the genetic mechanisms behind lichen desiccation tolerance. PMID- 23110404 TI - Dianthus superbus fructus suppresses airway inflammation by downregulating of inducible nitric oxide synthase in an ovalbumin-induced murine model of asthma. AB - BACKGROUND: Dianthus superbus has long been used as a herbal medicine in Asia and as an anti-inflammatory agent. In this study, we evaluated the anti inflammatory effects of Dianthus superbus fructus ethanolic extract (DSE) on Th2 type cytokines, eosinophil infiltration, and other factors in an ovalbumin (OVA) induced murine asthma model. To study the possible mechanism of the anti inflammatory effect of DSE, we also evaluated the expression of inducible nitric oxide synthase (iNOS) in the respiratory tract. METHODS: Mice were sensitized on days 0 and 14 by intraperitoneal injection of OVA. On days 21, 22 and 23 after initial sensitization, mice received an airway challenge with OVA for 1 h using an ultrasonic nebulizer. DSE was applied 1 h prior to OVA challenge. Mice were administered DSE orally at doses of 100 mg/kg or 200 mg/kg once daily from day 18 to 23. Bronchoalveolar lavage fluid (BALF) was collected 48 h after the final OVA challenge. Levels of interleukin (IL)-4, IL-13 and eotaxin in BALF were measured using enzyme-linked immunosorbent assays (ELISAs). Lung tissue sections were stained with hematoxylin and eosin for assessment of cell infiltration and mucus production with periodic acid shift staining, in conjunction with ELISA and western blot analyses for iNOS expression. RESULTS: DSE significantly reduced the levels of IL-4, IL-13, eotaxin, and immunoglobulin (Ig) E, number of inflammatory cells in BALF, and inflammatory cell infiltration and mucus production in the respiratory tract. DSE also attenuated the overexpression of iNOS protein induced by OVA challenge. CONCLUSION: Our results suggest that DSE effectively protects against allergic airway inflammation by downregulating of iNOS expression and that DSE has potential as a therapeutic agent for allergic asthma. PMID- 23110405 TI - Progression of specialized intestinal metaplasia at the cardia to macroscopically evident Barrett's esophagus: an entity of concern in the ProGERD study. AB - OBJECTIVES AND AIMS: Histological Barrett's esophagus, defined as specialized intestinal metaplasia (SIM+) at the cardia without endoscopic suspicion of columnar epithelium, is found frequently in biopsies at the gastro-esophageal junction although its clinical relevance is unknown. The authors aim was to evaluate prospectively the progression of SIM+ to macroscopically evident Barrett's esophagus (BE/SIM+), and to identify risk factors for this progression. METHODS: Data were obtained from a sub-group of patients (no visible BE at presentation, but SIM+) included in the ProGERD study, a prospective evaluation of the clinical course of GERD under routine clinical care. They had esomeprazole 20-40 mg/day for 2-8 weeks. Symptom assessment was performed annually, and endoscopy with biopsy was planned at baseline, after healing treatment and after 2 and/or 5 years. RESULTS: 128 of 171 (74.8%) patients with unequivocal SIM at the z-line after healing were biopsied again after 2 and/or 5 years. At follow up, 33 (25.8%) of these patients showed progression to BE/SIM+. Factors significantly associated with progression were smoking, a long history of GERD and severe esophagitis at baseline. Patients who had progressed to BE/SIM+ already at 2 years showed consistent findings at 5 years. CONCLUSION: More than 20% of GERD patients with SIM+ in this study were found to have BE/SIM+ within 2 5 years. This finding supports the hypothesis that SIM+ at the cardia could be the missing link explaining increased cancer risk in GERD patients without overt BE and merits further investigation in a prospective study. PMID- 23110406 TI - Leprosy diagnosed by bone marrow aspiration. PMID- 23110407 TI - Harvesting classification trees for drug discovery. AB - Millions of compounds are available as potential drug candidates. High throughput screening (HTS) is widely used in drug discovery to assay compounds for a particular biological activity. A common approach is to build a classification model using a smaller sample of assay data to predict the activity of unscreened compounds and hence select further compounds for assay. This improves the efficiency of the search by increasing the proportion of hits found among the assayed compounds. In many assays, the biological activity is dichotomized into a binary indicator variable; the explanatory variables are chemical descriptors capturing compound structure. A tree model is interpretable, which is key, since it is of interest to identify diverse chemical classes among the active compounds to serve as leads for drug optimization. Interpretability of a tree is often reduced, however, by the sheer size of the tree model and the number of variables and rules of the terminal nodes. We develop a "tree harvesting" algorithm to filter out redundant "junk" rules from the tree while retaining its predictive accuracy. This simplification can facilitate the process of uncovering key relations between molecular structure and activity and may clarify rules defining multiple activity mechanisms. Using data from the National Cancer Institute, we illustrate that many of the rules used to build a classification tree may be redundant. Unlike tree pruning, tree harvesting allows variables with junk rules to be removed near the top of the tree. The reduction in complexity of the terminal nodes improves the interpretability of the model. The algorithm also aims to reorganize the tree nodes associated with the interesting "active" class into larger, more coherent groups, thus facilitating identification of the mechanisms for activity. PMID- 23110408 TI - Atypical facial pain secondary to an unusual iatrogenic endonasal "contact point". PMID- 23110409 TI - Clinical and economic burden of community-acquired pneumonia in the Medicare fee for-service population. AB - OBJECTIVES: To estimate current community-acquired pneumonia (CAP) incidence and its associated economic burden in the Medicare fee-for-service (FFS) population. DESIGN: Retrospective. SETTING: The 2007/08 Medicare Standard Analytic Files, a nationally representative random sample (5%) of Medicare beneficiaries enrolled in the FFS program. PARTICIPANTS: Residents of one of the 50 U.S. states or the District of Columbia aged 18 and older on July 1, 2007, with continuous Part A and Part B coverage during calendar year 2007. MEASUREMENTS: Incidence, episode length, mortality, and costs were assessed. All-cause costs were assessed using three methodologies: costs during the episode, and incremental costs using CAP cases as self-control (before-after) and with matched controls (case-control). RESULTS: Sixty-five thousand eight hundred four CAP episodes (39% inpatient treated episodes) were identified. Average inpatient and outpatient episode lengths were 32.8 +/- 46.9 and 12.4 +/- 27.3 days, respectively, and overall incidence was 4,482/100,000 person-years. Thirty-day case fatality was 8.5% for inpatient and 3.8% for outpatient CAP. The average CAP episode cost was $8,606 ($18,670 for inpatient, $2,394 for outpatient). The incremental cost of a CAP episode in the before-and-after and case-control analyses was approximately $10,000. CONCLUSION: An estimated 1.3 million CAP cases and 74,000 CAP-related deaths were found, with an economic burden of $13 billion annually in the Medicare fee-for-service population. Preventing CAP in this population may substantially reduce healthcare costs. PMID- 23110410 TI - Duodenal involvement by breast cancer. PMID- 23110411 TI - Prevalence and antimicrobial resistance of Enterococcus species of food animal origin from Beijing and Shandong Province, China. AB - AIMS: To evaluate the prevalence and antimicrobial resistance of Enterococcus species from chickens and pigs in Beijing and Shandong Province, China. METHODS AND RESULTS: Swab samples were collected from four farms in Beijing and two in Shandong Province in 2009 and tested for Enterococcus. Minimum inhibitory concentrations of antimicrobial agents were determined using broth microdilution or agar screening methods. A total of 453 Enterococcus isolates were recovered, belonging to six different Enterococcus species. All isolates were sensitive to vancomycin. Resistance to tetracycline (92.5%), amikacin (89.4%), erythromycin (72.8%) and rifampin (58.1%), and high-level streptomycin resistance (HLSR, 50.3%) were prevalent, while resistance to penicillins (7.9% to penicillin and 4.2% to ampicillin) was rare. The resistance rates to phenicols (chloramphenicol and florfenicol) and enrofloxacin, and high-level gentamicin resistance (HLGR) were approximately 30%. The vast majority of the Enterococcus isolates were classified as multidrug-resistant organisms. CONCLUSIONS: Resistance of Enterococcus sp. to most antimicrobials was more prevalent in China than in European or other Asian countries. SIGNIFICANCE AND IMPACT OF THE STUDY: Our findings reveal a high level of antimicrobial resistance in Enterococcus isolates from food animals in China and underline the need for prudent use of antibiotics in chicken and pig production to minimize the spread of antibiotic-resistant enterococci. PMID- 23110413 TI - Accumulation and biotransformation of BDE-47 by zebrafish larvae and teratogenicity and expression of genes along the hypothalamus-pituitary-thyroid axis. AB - Accumulation and effects of BDE-47 and two analogues, 6-OH-BDE-47 and 6-MeO-BDE 47, on ontogeny and profiles of transcription of genes along the hypothalamus pituitary-thyroid (HPT) axis of zebrafish (Danio rerio) embryos exposed from 4 h post fertilization (hpf) to 120 hpf were investigated. The 96 h-LC(50) of the most toxic compound, based on teratogenicity, was 330 MUg of 6-OH-BDE-47/L. 6-OH BDE-47 significantly down-regulated expression of mRNA of thyroid stimulating hormone receptor (TSHR), thyroid hormone receptors (TRs, including TRalpha and TRbeta), sodium/iodide symporter (NIS), and transthyretin (TTR) while up regulating expression of thyroglobulin (TG) and thyrotropin-releasing hormone (TRH). Spontaneous movement was affected by 1 mg of 6-OH-BDE-47/L or 5 mg of 6 MeO-BDE-47/L. BDE-47 did not alter activity of larvae at any concentration tested. 6-MeO-BDE-47 significantly up-regulated expression of mRNA of TRH, TRalpha, TRbeta and NIS. Both 6-OH-BDE-47 and 6-MeO-BDE-47 affected the thyroid hormone pathway. BDE-47 and 6-MeO-BDE-47 were accumulated more than 6-OH-BDE-47. 6-MeO-BDE-47 was transformed into 6-OH-BDE-47, but BDE-47 was not transformed into it. In summary, the synthetic brominated flame retardant, BDE-47, did not elicit the adverse effects caused by the other two analogues and appeared to have less toxicological relevance than the two natural product analogues 6-OH- and 6 MeO-BDE-47. PMID- 23110412 TI - Hydroxyethyl starch 130/0.4 and sodium chloride injection as adjunctive therapy in patients with cerebral hypoperfusion. AB - BACKGROUND: Both severe stenosis and completed occlusion in internal carotid artery or its distal branches have been considered the main reasons of cerebral hypoperfusion, which contributes to the washout disturbances of embolism in low perfusion territories distal to stenosis. An aggravated hypoperfusion state in certain brain region may induce ischemic stroke and further cognitive decline. However, the effective medication for cerebral hypoperfusion is largely unsettled. METHODS/DESIGN: By using computed tomography perfusion (CTP) imaging, the trial will evaluate the effectiveness, safety and tolerability of hydroxyethyl starch (HES) 130/0.4 for patients with extra-/intra-cranial artery stenosis and cerebral hypoperfusion. From 5 neurological inpatient wards, 300 patients will be randomly recruited for administered routine medications plus intravascular volume therapies using the equal volume of HES 130/0.4 or 0.9% sodium chloride solution. Cerebral hypoperfusion state after 7-day intervention is the primary outcome measure. The secondary outcome measures includes, impaired renal function, abnormal heart function, hematological changes, neurological dysfunctions and cerebrovascular events in peri-intervention period and/or 3 month follow-up. The sample size will allow the detection of a two-sided 5% significance level between groups in the endpoint with a power of 80%. DISCUSSION: The trial would provide important efficacy and safety data on the intravascular administration of HES 130/0.4 in patients with unilateral cerebral hypoperfusion. The effects on kidney function, heart function, coagulation, neurological function and cerebralvascular events will be assessed. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT01192581). PMID- 23110414 TI - Aryl-heteroaryl derivatives as novel wake-promoting agents. AB - In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually. PMID- 23110415 TI - Canine intervertebral disc fenestration using a vacuum-assisted tissue resection device. AB - OBJECTIVE: Describe the use and feasibility of a novel vacuum-assisted tissue resection device (VRD) for canine intervertebral disc fenestration, and compare the effectiveness of manual fenestration to the VRD. STUDY DESIGN: Randomized prospective study. ANIMALS: Canine cadavers (n = 15). METHODS: A cadaveric lumbar spine study was performed to compare the use of manual fenestration to a novel VRD for intervertebral disc fenestration. Both fenestration groups were compared to a control group. Effectiveness of fenestration was assessed by calculating a ratio of remaining nuclear weight postfenestration to total nuclear volume. Fenestrated discs with lower ratios were indicative of greater removal of nucleus pulposus. RESULTS: There was a statistically significant reduction in mean ratio (+/-SD) of remaining nuclear weight to volume with both fenestration groups compared to controls (0.39 +/- 0.07; P < .001). There was an improved ratio using the VRD (0.23 +/- 0.09) compared to manual fenestration (0.30 +/- 0.10); this was not statistically significant (P = .069). It was technically difficult to fenestrate the disc spaces at L5-L6 and L6-L7 because of location and anatomy, resulting in a statistically significant increase in the median ratio of nuclear weight-to-volume ratios in both manual and VRD fenestration groups when compared to the more cranial L4-L5 disc spaces, 0.32 +/- 0.08, and 0.35 +/- 0.08 versus 0.25 +/- 0.13 at L4-L5 (P = .026 and P = .004, respectively). CONCLUSIONS: The VRD is a feasible instrument for canine intervertebral disc fenestration. It is at least as effective as manual fenestration, and provides additional safety features. PMID- 23110416 TI - Analysis of the daily changes of melatonin receptors in the rat liver. AB - Melatonin membrane (MT1 and MT2) and nuclear (RORalpha) receptors have been identified in several mammalian tissues, including the liver. The mechanisms regulating hepatic melatonin receptors are yet unknown. This study investigated whether these receptors exhibit daily changes and the effects of melatonin on their levels. Our results show that mRNAs for MT1/MT2 receptors exhibit circadian rhythms that were followed by rhythms in their respective protein levels; the acrophases for the two rhythms were reached at 04:00 and 05:00 hr, respectively. Pinealectomy blunted the rhythms in both mRNAs and protein levels. In contrast, mRNA and protein levels of nuclear receptor RORalpha increased significantly after pinealectomy. The cycles of the latter receptor also exhibited circadian rhythms which peaked at 03:00 and 03:45 hr, respectively. Melatonin administration (10-200 mg/kg) increased in a dose-dependent manner the protein content of MT1/MT2 receptors, with no effects on RORalpha. Lunzindole treatment, however, did not affect melatonin receptor expression or content of either the membrane or nuclear receptors. Together with previously published findings which demonstrated the intracellular distribution of melatonin in rat liver, the current results support the conclusion that the circadian rhythms of MT1/MT2 and RORalpha receptors are under the control of the serum and intracellular melatonin levels. Moreover, the induction of MT1/MT2 receptors after the administration of high doses of melatonin further suggests that the therapeutic value of melatonin may not be restricted to only low doses of the indoleamine. PMID- 23110417 TI - Diffuse near-infrared spectroscopy prediction of healing in diabetic foot ulcers: a human study and cost analysis. AB - Wound size reduction has been the standard benchmark for determination of efficacy for diabetic ulcer treatments but due to interclinician error and difficulty measuring irregular wound shapes, this method is unreliable with a positive predictive value of less than 60%. Diffuse near-infrared spectroscopy (DNIRS) uses 70-MHz modulated light in the diagnostic window (650-900 nm) noninvasively to quantify levels of oxy- and deoxy-hemoglobin in the wound bed, which when measured over time, can show a trend toward or away from healing based on the changes in oxy-hemoglobin concentration from week to week. In this study, DNIRS was used to monitor 24 human diabetic foot ulcers longitudinally over the course of 20 weekly or biweekly measurement sessions. In just 4 weeks, the DNIRS system has an 82% positive predictive value (sensitivity of 0.9 and specificity of 0.86; p < 0.002). These data indicate that it could be possible to predict healing in 4 weeks using DNIRS, which can provide objective guidance toward the continuation of costly treatments. Discontinuing ineffective treatments after 4 weeks could have potentially saved over $12,600 per patient, based on the treatment regimen of patients in this study. PMID- 23110418 TI - Prevalence of the metabolic syndrome in a rural population in Ghana. AB - BACKGROUND: The Metabolic syndrome (MS) which is a constellation of cardiometabolic risk factors including dyslipidaemia, hypertension, hyperglycaemia, central obesity, and endothelial dysfunction was hitherto relatively uncommon among Africans south of the Sahara. This study seeks to determine the prevalence of MS, its components and risk factors among a rural population in Ghana based on two popular international algorithms. METHODS: This was a cross-sectional survey of a rural population in Ghana conducted between November and December, 2007. Two hundred and twenty-eight (228) settler farmers, families and staff associated with the GOPDC Ltd, between the ages of 35 and 64 years, were randomly selected for the study; pregnant women were excluded. The prevalence of MS was estimated using the IDF and ATPIII criteria. RESULTS: The final subject pool included 102 males, and 104 females. The mean age of all subjects was 44.4 +/- 6.9 years. The overall prevalence of MS by the IDF and ATPIII criteria were 35.9% and 15.0%, respectively, but there was an alarming female preponderance by both criteria {IDF: males = 15.7%, females =55.8%; ATPIII: males = 5.9%, females = 24.0%; sex differences p<0.001 for both criteria}. The most important determinants for IDF-defined MS were central obesity (55.3%), low High Density Lipoprotein (42.7%) and high Blood Pressure (39.5%). CONCLUSION: The triad of central obesity, high blood pressure and low HDL were most responsible for the syndrome in this rural population. PMID- 23110419 TI - Inferences on population history of a seed chalcid wasp: invasion success despite a severe founder effect from an unexpected source population. AB - Most invasive species established in Europe originate from either Asia or North America, but little is currently known about the potential of the Anatolian Peninsula (Asia Minor) and/or the Near East to constitute invasion sources. Mediterranean forests are generally fragile ecosystems that can be threatened by invasive organisms coming from different regions of the Mediterranean Basin, but for which historical data are difficult to gather and the phylogeographic patterns are still poorly understood for most terrestrial organisms. In this study, we characterized the genetic structure of Megastigmus schimitscheki, an invasive seed-feeding insect species originating from the Near East, and elucidated its invasion route in South-eastern France in the mid 1990s. To disentangle the evolutionary history of this introduction, we gathered samples from the main native regions (Taurus Mountains in Turkey, Lebanon and Cyprus) and from the invaded region that we genotyped using five microsatellite markers and for which we sequenced the mitochondrial Cytochrome Oxidase I gene. We applied a set of population genetic statistics and methods, including approximate Bayesian computation. We proposed a detailed phylogeographic pattern for the Near East populations, and we unambiguously showed that the French invasive populations originated from Cyprus, although the available historical data strongly suggested that Turkey could be the most plausible source area. Interestingly, we could show that the introduced populations were founded from an extremely restricted number of individuals that realized a host switch from Cedrus brevifolia to C. atlantica. Evolutionary hypotheses are discussed to account for this unlikely scenario. PMID- 23110420 TI - Reactive sites for chiral selective growth of single-walled carbon nanotubes: a DFT study of Ni55-C(n) complexes. AB - The physical and electronic properties of single-walled carbon nanotubes (SWCNTs) are determined by their chirality. The chirality selection mechanism in SWCNT growth is not fully understood. In this study, the interaction between near armchair (n,5), where n = 6, 7, 8, and 9, zigzag (9,0), and armchair (5,5) nanotubes and a fully relaxed Ni(55) metal cluster during the early stage of growth is studied by density functional theory calculations. We found that kink sites at the end edge of (n,5) nanotubes are more reactive than other sites based on the charge transfer analysis at the Ni-C interface. The frontier orbitals of the (6,5) and (7,5) caps are localized on their kink-step sites, which stretch outward from the carbon cap surface, having typical 2p(z) orbital feature of carbon atom with high reactivity. Such favorable frontier orbital spatial orientation and location is ideal to incorporate more carbon species. These reactive sites may lead to the faster growth rate, resulting in the chirality selectivity toward the (6,5) and (7,5) nanotubes. In contrast, the frontier orbitals of (8,5) and (9,5) caps spread over the entire carbon cap surface. Adding carbon species at these sites may lead to the chirality change or formation of other carbon structures. Our results showed that the spatial distribution and orientation of frontier orbitals is useful in explaining the chiral selectivity. Engineering catalyst clusters to control these reactive sites has high potential to further improve chirality control in SWCNT synthesis. PMID- 23110421 TI - Mesoporous hollow sphere titanium dioxide photocatalysts through hydrothermal silica etching. AB - Robust, monodisperse, mesoporous titanium dioxide (TiO2) submicrometer hollow spheres were synthesized through a single step hydrothermal silica etching reaction under mild conditions. Efficient silica (SiO2) removal was achieved without the use of toxic reagents, and a unique controllable silica redeposition mechanism was identified, imparting the hollow spheres with excellent structural integrity. The parameters of the hydrothermal reaction affecting the etching process, including pH, temperature, and silica concentration, were systematically investigated and optimized for the production of silica-templated hollow structures. The resulting processing conditions yielded TiO2 hollow spheres with a surface area of ~300 m2 g-1 and anatase phase crystallization, which exhibited high adsorption capacity for methylene blue dye and good photocatalytic activity without requiring high-temperature calcination. PMID- 23110422 TI - Prevalence of MTHFR, Factor V, ACE and APOE gene polymorphisms among Muslims of Manipur, India. AB - BACKGROUND: Chronic metabolic disorders such as cardiovascular disease and diabetes have become an emerging public health problem in India, in both rural and urban settings. Genetic markers like MTHFR, FV, ACE and APOE are important candidates involved in the development of these disorders. AIM: The present study aims to understand the distribution of allele frequencies of the SNPs in the above-mentioned genes in Manipuri Muslims, an endogamous religious community constituting ~8% of the Manipur population. SAMPLE AND METHODS: Blood samples were collected from 107 unrelated healthy individuals. Genotyping were done by PCR (for ACE I/D and MTHFR A1298C) followed by restriction digestion (for MTHFR C677T, FV G1691A and APOE). RESULTS AND DISCUSSION: All four SNPs, with the exception of FVL, were found to be polymorphic, with allele frequencies of 15.1%, 17%, 36.1% and 7.7% for MTHFR 677T, MTHFR 1298C, ACE D and APOE E4, respectively. The D allele of ACE I/D polymorphism was found to be significantly higher among males and also among the young age group compared with females and the old age groups, respectively. This study has highlighted the necessity of looking at the clinical implications of these SNPs in future studies of Manipuri Muslims. PMID- 23110423 TI - Prioritizing strategies for comprehensive liver cancer control in Asia: a conjoint analysis. AB - BACKGROUND: Liver cancer is a complex and burdensome disease, with Asia accounting for 75% of known cases. Comprehensive cancer control requires the use of multiple strategies, but various stakeholders may have different views as to which strategies should have the highest priority. This study identified priorities across multiple strategies for comprehensive liver cancer control (CLCC) from the perspective of liver cancer clinical, policy, and advocacy stakeholders in China, Japan, South Korea and Taiwan. Concordance of priorities was assessed across the region and across respondent roles. METHODS: Priorities for CLCC were examined as part of a cross-sectional survey of liver cancer experts. Respondents completed several conjoint-analysis choice tasks to prioritize 11 strategies. In each task, respondents judged which of two competing CLCC plans, consisting of mutually exclusive and exhaustive subsets of the strategies, would have the greatest impact. The dependent variable was the chosen plan, which was then regressed on the strategies of different plans. The restricted least squares (RLS) method was utilized to compare aggregate and stratified models, and t-tests and Wald tests were used to test for significance and concordance, respectively. RESULTS: Eighty respondents (69.6%) were eligible and completed the survey. Their primary interests were hepatitis (26%), hepatocellular carcinoma (HCC) (58%), metastatic liver cancer (10%) and transplantation (6%). The most preferred strategies were monitoring at-risk populations (p<0.001), clinician education (p<0.001), and national guidelines (p<0.001). Most priorities were concordant across sites except for three strategies: transplantation infrastructure (p=0.009) was valued lower in China, measuring social burden (p=0.037) was valued higher in Taiwan, and national guidelines (p=0.025) was valued higher in China. Priorities did not differ across stakeholder groups (p=0.438). CONCLUSIONS: Priorities for CLCC in Asia include monitoring at-risk populations, clinician education, national guidelines, multidisciplinary management, public awareness and centers of excellence. As most priorities are relatively concordant across the region, multilateral approaches to addressing comprehensive liver cancer would be beneficial. However, where priorities are discordant among sites, such as transplantation infrastructure, strategies should be tailored to local needs. PMID- 23110424 TI - Identification of the factors associated with outcomes in a Condition Management Programme. AB - BACKGROUND: A requirement of the Government's Pathways to Work (PtW) agenda was to introduce a Condition Management Programme (CMP). The aim of the present study was to identify the differences between those who engaged and made progress in this telephone-based biopsychosocial intervention, in terms of their health, and those who did not and to determine the client and practitioner characteristics and programme elements associated with success in a programme aimed at improving health. METHODS: Data were obtained from the CMP electronic spreadsheets and clients paper-based case records. CMP standard practice was that questionnaires were administered during the pre- and post-assessment phases over the telephone. Each client's record contains their socio-demographic data, their primary health condition, as well as the pre- and post-intervention scores of the health assessment tool administered. Univariate and multivariate statistical analysis was used to investigate the relationships between the database variables. Clients were included in the study if their records were available for analysis from July 2006 to December 2007. RESULTS: On average there were 112 referrals per month, totalling 2016 referrals during the evaluation period. The majority (62.8%) of clients had a mental-health condition. Successful completion of the programme was 28.5% (575 "completers"; 144 "discharges"). Several factors, such as age, health condition, mode of contact, and practitioner characteristics, were significant determinants of participation and completion of the programme. The results showed that completion of the CMP was associated with a better mental-health status, by reducing the number of clients that were either anxious, depressed or both, before undertaking the programme, from 74% to 32.5%. CONCLUSIONS: Our findings showed that an individual's characteristics are associated with success in the programme, defined as completing the intervention and demonstrating an improved health status. This study provides some evidence that the systematic evaluation of such programmes and interventions could identify ways in which they could be improved. PMID- 23110425 TI - Histologic and biomechanical studies of tendon-to-bone healing after autologous and allogeneic bone transplants. AB - OBJECTIVES: Compare histologic and biomechanical differences of tendon-to-bone healing between autologous and allogeneic bone transplants. MATERIALS AND METHODS: Adult, healthy, New Zealand white rabbits were used to establish the extra-articular tendon-to-bone healing model with the left hind limb transplanted with allogeneic bone and the right hind limb transplanted with autologous bone. After 3, 6, and 12 weeks after the transplant, the rabbits were killed to collect tendon-to-bone specimens, and then the healing processes in tendon-to-bone interfaces were examined. RESULTS: All rabbits grew well after incision without infection and can freely move. Histologic observations 3 and 6 weeks after surgery and biomechanical test results 6 weeks after surgery were statistically different between the autologous and the allogeneic transplants (P < .05). After 12 weeks, histologic observations and biomechanical test results showed no difference between the 2 transplants (P > .05). CONCLUSIONS: Allogeneic bone transplant has a relatively slower tendon-to-bone healing than does autologous bone transplant, but finally allogeneic and autologous bone transplants have the same extent of tendon-to-bone healing. PMID- 23110426 TI - Response to letter: cilostazol and its emerging benefits in gastroenterology besides its attenuating effect on indomethacin-induced small intestinal injury. PMID- 23110427 TI - Pulmonary embolism in chronic kidney disease: a lethal, overlooked and research orphan disease. PMID- 23110430 TI - The defense response in Arabidopsis thaliana against Fusarium sporotrichioides. AB - BACKGROUND: Certain graminaceous plants such as Zea mays and Triticum aestivum serve as hosts for Fusarium sporotrichioides; however, molecular interactions between the host plants and F. sporotrichioides remain unknown. It is also not known whether any interaction between Arabidopsis thaliana and F. sporotrichioides can occur. To understand these interactions, we performed proteomic analysis. RESULTS: Arabidopsis leaves and flowers were inoculated with F. sporotrichioides. Accumulation of PLANT DEFENSIN1.2 (PDF1.2) and PATHOGENESIS RELATED1 (PR1) mRNA in Arabidopsis were increased by inoculation of F. sporotrichioides. Furthermore, mitogen-activated protein kinase 3 (MPK3) and mitogen-activated protein kinase 6 (MPK6), which represent MAP kinases in Arabidopsis, were activated by inoculation of F. sporotrichioides. Proteomic analysis revealed that some defense-related proteins were upregulated, while the expression of photosynthesis- and metabolism-related proteins was down regulated, by inoculation with F. sporotrichioides. We carried out the proteomic analysis about upregulated proteins by inoculation with Fusarium graminearum. The glutathione S-transferases (GSTs), such as GSTF4 and GSTF7 were upregulated, by inoculation with F. graminearum-infected Arabidopsis leaves. On the other hand, GSTF3 and GSTF9 were uniquely upregulated, by inoculation with F. sporotrichioides. CONCLUSIONS: These results indicate that Arabidopsis is a host plant for F. sporotrichioides. We revealed that defense response of Arabidopsis is initiated by infection with F. sporotrichioides. PMID- 23110431 TI - Management of bleeding in patients taking FXa and FIIa inhibitors. PMID- 23110428 TI - Bio-crude transcriptomics: gene discovery and metabolic network reconstruction for the biosynthesis of the terpenome of the hydrocarbon oil-producing green alga, Botryococcus braunii race B (Showa). AB - BACKGROUND: Microalgae hold promise for yielding a biofuel feedstock that is sustainable, carbon-neutral, distributed, and only minimally disruptive for the production of food and feed by traditional agriculture. Amongst oleaginous eukaryotic algae, the B race of Botryococcus braunii is unique in that it produces large amounts of liquid hydrocarbons of terpenoid origin. These are comparable to fossil crude oil, and are sequestered outside the cells in a communal extracellular polymeric matrix material. Biosynthetic engineering of terpenoid bio-crude production requires identification of genes and reconstruction of metabolic pathways responsible for production of both hydrocarbons and other metabolites of the alga that compete for photosynthetic carbon and energy. RESULTS: A de novo assembly of 1,334,609 next-generation pyrosequencing reads form the Showa strain of the B race of B. braunii yielded a transcriptomic database of 46,422 contigs with an average length of 756 bp. Contigs were annotated with pathway, ontology, and protein domain identifiers. Manual curation allowed the reconstruction of pathways that produce terpenoid liquid hydrocarbons from primary metabolites, and pathways that divert photosynthetic carbon into tetraterpenoid carotenoids, diterpenoids, and the prenyl chains of meroterpenoid quinones and chlorophyll. Inventories of machine assembled contigs are also presented for reconstructed pathways for the biosynthesis of competing storage compounds including triacylglycerol and starch. Regeneration of S-adenosylmethionine, and the extracellular localization of the hydrocarbon oils by active transport and possibly autophagy are also investigated. CONCLUSIONS: The construction of an annotated transcriptomic database, publicly available in a web-based data depository and annotation tool, provides a foundation for metabolic pathway and network reconstruction, and facilitates further omics studies in the absence of a genome sequence for the Showa strain of B. braunii, race B. Further, the transcriptome database empowers future biosynthetic engineering approaches for strain improvement and the transfer of desirable traits to heterologous hosts. PMID- 23110432 TI - Birth weight differences between preterm stillbirths and live births: analysis of population-based studies from the U.S. and Sweden. AB - BACKGROUND: Many stillbirths show evidence of fetal growth restriction, and most occur at preterm gestational age. The objective of this study is to compare birth weights at preterm gestational ages between live births and stillbirths, and between those occurring before or during labour. METHODS: Based on singleton births from the United States (U.S.) 2003-2005 (n=902,491) and Sweden 1992-2001 (n=946,343), we compared birth weights between singleton live births and stillbirths at 24-36 completed weeks of gestation from the U.S. and at 28-42 completed weeks from Sweden. RESULTS: In both the U.S. and Sweden, stillbirth weight-for-gestational-age z-scores were at least one standard deviation lower than live birth z-scores at all preterm gestational ages (GA). In Sweden, no birth weight difference was observed between antepartum and intrapartum stillbirths at preterm GAs, whereas birth weights among intrapartum stillbirths were similar to those among live births at 37-42 weeks. CONCLUSIONS: Birth weights observed at preterm gestation are abnormal, but preterm stillbirths appear to be more growth-restricted than preterm live birth. Similar birth weights among ante- and intrapartum preterm stillbirths suggest serious fetal compromise before the onset of labor. PMID- 23110433 TI - Gait and cognition: a complementary approach to understanding brain function and the risk of falling. AB - Until recently, clinicians and researchers have performed gait assessments and cognitive assessments separately when evaluating older adults, but increasing evidence from clinical practice, epidemiological studies, and clinical trials shows that gait and cognition are interrelated in older adults. Quantifiable alterations in gait in older adults are associated with falls, dementia, and disability. At the same time, emerging evidence indicates that early disturbances in cognitive processes such as attention, executive function, and working memory are associated with slower gait and gait instability during single- and dual-task testing and that these cognitive disturbances assist in the prediction of future mobility loss, falls, and progression to dementia. This article reviews the importance of the interrelationship between gait and cognition in aging and presents evidence that gait assessments can provide a window into the understanding of cognitive function and dysfunction and fall risk in older people in clinical practice. To this end, the benefits of dual-task gait assessments (e.g., walking while performing an attention-demanding task) as a marker of fall risk are summarized. A potential complementary approach for reducing the risk of falls by improving certain aspects of cognition through nonpharmacological and pharmacological treatments is also presented. Untangling the relationship between early gait disturbances and early cognitive changes may be helpful in identifying older adults at risk of experiencing mobility decline, falls, and progression to dementia. PMID- 23110434 TI - Fracture repair using a polyaxial locking plate system (PAX). AB - OBJECTIVES: To report outcomes and complications of dog and cat fractures treated with the polyaxial locking plate system (PAX). STUDY DESIGN: Case series. ANIMALS: Dogs (n = 60) and 2 cats. METHODS: Medical records (December 2009-March 2011) of dogs and cats with fractures treated with the PAX system were reviewed. Cases with adequate follow-up to document a functional union, had surgery performed by an author, had no prior treatment of the fracture(s), and with complete operative records were included. Signalment, body weight, bone(s) fractured, area of bone fractured, fracture classification, concurrent orthopedic injuries, complications, time to functional union, if minimally invasive plate osteosynthesis (MIPO) techniques were used, plate size, number of plates, bone graft use, and ancillary methods of fixation were recorded. Additionally, fracture segment: plate length, screw, number of plate holes, number of empty screw holes overlying/adjacent to the fractures, number of cortices engaged above/below the fracture was evaluated. Variables were evaluated statistically for effect on complications and functional union. RESULTS: Sixty-two animals were included. Mean time to functional union was 7.1 weeks. Complications occurred in 12 animals (19%) and plate failure occurred in 3 (5%). Statistically significant factors that affected time to functional union were the presence of multiple injuries and age. Those associated with complications were double plates and number of cortices engaged above and below fractures. CONCLUSIONS: The PAX system allows for multidirectional screw insertion with an overall complication rate and time to functional union similar to other fracture repair implant systems. PMID- 23110435 TI - Neighborhood deprivation and mortality in women with breast cancer: a multilevel analysis from Sweden. PMID- 23110436 TI - Melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia-reperfusion injury. AB - This study investigated whether melatonin-treated adipose-derived mesenchymal stem cells (ADMSC) offered superior protection against acute lung ischemia reperfusion (IR) injury. Adult male Sprague-Dawley rats (n = 30) were randomized equally into five groups: sham controls, lung IR-saline, lung IR-melatonin, lung IR-melatonin-normal ADMSC, and lung IR-melatonin-apoptotic ADMSC. Arterial oxygen saturation was lowest in lung IR-saline; lower in lung IR-melatonin than sham controls, lung IR-melatonin-normal ADMSC, and lung IR-melatonin-apoptotic ADMSC; lower in lung IR-melatonin-normal ADMSC than sham controls and lung IR-melatonin apoptotic ADMSC; lower in lung IR-melatonin-apoptotic ADMSC than sham controls (P < 0.0001 in each case). Right ventricular systolic blood pressure (RVSBP) showed a reversed pattern among all groups (all P < 0.0001). Changes in histological scoring of lung parenchymal damage and CD68+ cells showed a similar pattern compared with RVSBP in all groups (all P < 0.001). Changes in inflammatory protein expressions such as VCAM-1, ICAM-1, oxidative stress, TNF-alpha, NF kappaB, PDGF, and angiotensin II receptor, and changes in apoptotic protein expressions of cleaved caspase 3 and PARP, and mitochondrial Bax, displayed identical patterns compared with RVSBP in all groups (all P < 0.001). Numbers of antioxidant (GR+, GPx+, NQO-1+) and endothelial cell biomarkers (CD31+ and vWF+) were lower in sham controls, lung IR-saline, and lung IR-melatonin than lung IR melatonin-normal ADMSC and lung IR-melatonin-apoptotic ADMSC, and lower in lung IR-melatonin-normal ADMSC than lung IR-melatonin-apoptotic ADMSC (P < 0.001 in each case). In conclusion, when the animals were treated with melatonin, the apoptotic ADMSC were superior to normal ADMSC for protection of lung from acute IR injury. PMID- 23110437 TI - Improved dielectric properties of nanocomposites based on poly(vinylidene fluoride) and poly(vinyl alcohol)-functionalized graphene. AB - In this work, two series of nanocomposites of poly(vinylidene fluoride) (PVDF) incorporated with reduced graphene oxide (rGO) and poly(vinyl alcohol)-modified rGO (rGO-PVA) were fabricated using solution-cast method and their dielectric properties were carefully characterized. Infrared spectroscopy and atom force microscope analysis indicated that PVA chains were successfully grafted onto graphene through ester linkage. The PVA functionalization of graphene surface can not only prevent the agglomeration of original rGO but also enhance the interaction between PVDF and rGO-PVA. Strong hydrogen bonds and charge transfer effect between rGO-PVA and PVDF were determined by infrared and Raman spectroscopies. The dielectric properties of rGO-PVA/PVDF and rGO/PVDF nanocomposites were investigated in a frequency range from 102 Hz to 107 Hz. Both composite systems exhibited an insulator-to-conductor percolating transition as the increase of the filler content. The percolation thresholds were estimated to be 2.24 vol % for rGO-PVA/PVDF composites and 0.61 vol % for rGO/PVDF composites, respectively. Near the percolation threshold, the dielectric permittivity of the nanocomposites was significantly promoted, which can be well explained by interfacial polarization effect and microcapacitor model. Compared to rGO/PVDF composites, higher dielectric constant and lower loss factor were simultaneously achieved in rGO-PVA/PVDF nanocomposites at a frequency range lower than 1 * 103 Hz. This work provides a potential design strategy based on graphene interface engineering, which would lead to higher-performance flexible dielectric materials. PMID- 23110438 TI - Special features of RAD Sequencing data: implications for genotyping. AB - Restriction site-associated DNA Sequencing (RAD-Seq) is an economical and efficient method for SNP discovery and genotyping. As with other sequencing-by synthesis methods, RAD-Seq produces stochastic count data and requires sensitive analysis to develop or genotype markers accurately. We show that there are several sources of bias specific to RAD-Seq that are not explicitly addressed by current genotyping tools, namely restriction fragment bias, restriction site heterozygosity and PCR GC content bias. We explore the performance of existing analysis tools given these biases and discuss approaches to limiting or handling biases in RAD-Seq data. While these biases need to be taken seriously, we believe RAD loci affected by them can be excluded or processed with relative ease in most cases and that most RAD loci will be accurately genotyped by existing tools. PMID- 23110439 TI - Highly predictive ligand-based pharmacophore and homology models of ABHD6. AB - alpha/beta-Hydrolase domain-containing 6 (ABHD6) represents a potentially attractive therapeutic target for indirectly potentiating 2-arachidonoylglycerol signaling; however, the enzyme is currently largely uncharacterized. Here, we describe a five element, ligand-based pharmacophore model along with a refined homology model of ABHD6. Following a virtual screen of a modest database, both the pharmacophore and homology models were found to be highly predictive, preferentially identifying ABHD6 inhibitors over drug-like non-inhibitors. The models yield insight into the features required for optimal ligand binding to ABHD6 and the atomic structure of the binding site. In combination, the two models should be very helpful not only in high-throughput virtual screening, but also in lead optimization, and will facilitate the development of novel, selective ABHD6 inhibitors as potential drugs. PMID- 23110440 TI - Parental palliative cancer: psychosocial adjustment and health-related quality of life in adolescents participating in a German family counselling service. AB - BACKGROUND: Parental palliative disease is a family affair, however adolescent's well-being and coping are still rarely considered. The objectives of this paper were a) to identify differences in psychosocial adjustment and health-related quality of life (HRQoL) among adolescents and young adults with parents suffering from palliative cancer or cancers in other disease stages, b) to relate psychosocial adjustment and health-related quality of life to adolescent coping, and c) to explore significant mediator and predictor variables. METHODS: Cross sectional data were derived from a multi-site research study of families before child-centered counselling. N=86 adolescents and young adults were included, their mean age 13.78 years (sd 2.45), 56% being female. Performed analyses included ANCOVA, multiple linear regression, and mediation analysis. RESULTS: Adolescents with parents suffering from palliative cancers reported significantly less total psychosocial problems, and better overall HRQoL. There were no significant group differences regarding coping frequency and efficacy. Our set of coping items significantly mediated the effect of parental disease stage on psychosocial problems and HRQoL. Further, parental disease status and general family functioning predicted psychosocial problems (R2adj =.390) and HRQoL (R2adj =.239) best. CONCLUSION: The study indicates distress among adolescents throughout the entire parental disease process. Our analysis suggests that counselling services could offer supportive interventions which focus particularly on adolescent coping as well as family functioning. PMID- 23110441 TI - MS2 viruslike particles: a robust, semisynthetic targeted drug delivery platform. AB - We show that viruslike particles (VLPs) reassembled in vitro with the RNA bacteriophage MS2 coat protein and an RNA conjugate encompassing a siRNA and a known capsid assembly signal can be targeted to HeLa cells by covalent attachment of human transferrin. The siRNA VLPs protect their cargoes from nuclease, have a double-stranded conformation in the capsid and carry multiple drug and targeting ligands. The relative efficiency of VLP reassembly has been assessed, and conditions have been determined for larger scale production. Targeted VLPs have been purified away from unmodified VLPs for the first time allowing improved analysis of the effects of this synthetic virion system. The particles enter cells via receptor-mediated endocytosis and produce siRNA effects at low nanomolar concentrations. Although less effective than a commercial cationic lipid vector at siRNA delivery, the smaller amounts of internalized RNA with VLP delivery had an effect as good as if not better than the lipid transfection route. This implies that the siRNAs delivered by this route are more accessible to the siRNA pathway than identical RNAs delivered in complex lipid aggregates. The data suggest that the MS2 system continues to show many of the features that will be required to create an effective targeted drug delivery system. The fluorescence assays of siRNA effects described here will facilitate the combinatorial analysis of both future formulations and dosing regimes. PMID- 23110442 TI - Intersex in Scrobicularia plana: transcriptomic analysis reveals novel genes involved in endocrine disruption. AB - Intersex, the appearance of female characteristics in male gonads, has been identified in a wide range of aquatic species worldwide, yet the underpinning molecular etiology remains uncharacterized. The presence of intersex has been shown to be a widespread phenomenon in bivalve, S. plana, populations from the southwest coast of the U.K., as well as inducible in an experimental exposure regime using endocrine disrupting compounds (EDCs). Herein, we use the suppressive subtractive hybridization approach to isolate differentially expressed transcripts in S. plana males exhibiting intersex. Transcripts involved in cell signaling, cell cycle control, energy production/metabolism, microtubule assembly, and sperm physiology are all highlighted as differentially expressed in intersex male clams. These provide both an insight into the molecular mechanisms of action involved in the development of intersex, as well as facilitating potential molecular-level "early warning" biomarkers of the condition. PMID- 23110443 TI - Ultrasonography of the diaphragm in amyotrophic lateral sclerosis: clinical significance in assessment of respiratory functions. AB - Our objective was to evaluate diaphragm thicknesses during respiration by ultrasonography, and compare with conventional measurements of respiratory functions in patients with amyotrophic lateral sclerosis (ALS). Thirty-six consecutive ALS patients and 19 age-matched healthy volunteers participated. Ultrasonography of the diaphragm in the zone of apposition was performed. Maximal diaphragm thickness during the maximal inspiratory effort (DTmax) and minimum diaphragm thickness at the end expiratory position (DTmin) were measured using ultrasonography. The thickening ratio (TR), defined as the ratio of DTmin to DTmax, was calculated. All patients underwent conventional pulmonary function testing. Arterial blood gas analysis was also performed. The diaphragm was clearly identifiable by ultrasonography. DTmax, DTmin and the TR were all significantly decreased in ALS patients with %VC (vital capacity) < 80, compared with those in either ALS patients with %VC >= 80 or healthy controls. DTmax, DTmin and the TR were all significantly correlated with %VC. In addition, significant inverse correlations were found between all three parameters and pCO(2). The inter-observer reliability of measurements of diaphragm thickness was high. In conclusion, sonography of the diaphragm can provide additional or complementary information for assessing respiratory functions in patients with ALS. PMID- 23110444 TI - Clinically relevant pain relief with an ibuprofen-releasing foam dressing: results from a randomized, controlled, double-blind clinical trial in exuding, painful venous leg ulcers. AB - The objective of this 6-week, 120-patient, double-blind, randomized, controlled trial was to investigate if a foam dressing with ibuprofen provided clinically relevant pain relief (PAR) for exuding, painful venous leg ulcers in comparison with a similar foam dressing without ibuprofen. Primary outcome parameter was PAR compared with baseline pain during the first 5 days of the investigation. PAR was registered by the patient morning and evening. Main end point was proportion of patients reporting a summed PAR score of at least 50% of the total maximum PAR (i.e., responders) and the corresponding number needed to treat (NNT). Wound related parameters such as ulcer healing, ulcer area reduction, and peri-ulcer skin condition as well as adverse events were recorded during all 6 weeks of the investigation. PAR was significantly greater in the ibuprofen foam group than the comparator group (p = 0.0438). There were 34% responders in the ibuprofen foam group vs. 19% in the comparator group (NNT = 6.8). When evening data were analyzed separately to evaluate PAR over daytime, NNT was 5.3. Wound healing parameters and adverse events were comparable. In conclusion, in this study, the ibuprofen foam dressing provided clinically relevant PAR for patients with exuding, painful venous ulcers. PMID- 23110445 TI - Estimating length of stay in publicly-funded residential and nursing care homes: a retrospective analysis using linked administrative data sets. AB - BACKGROUND: Information about how long people stay in care homes is needed to plan services, as length of stay is a determinant of future demand for care. As length of stay is proportional to cost, estimates are also needed to inform analysis of the long-term cost effectiveness of interventions aimed at preventing admissions to care homes. But estimates are rarely available due to the cost of repeatedly surveying individuals. METHODS: We used administrative data from three local authorities in England to estimate the length of publicly-funded care homes stays beginning in 2005 and 2006. Stays were classified into nursing home, permanent residential and temporary residential. We aggregated successive placements in different care home providers and, by linking to health data, across periods in hospital. RESULTS: The largest group of stays (38.9%) were those intended to be temporary, such as for rehabilitation, and typically lasted 4 weeks. For people admitted to permanent residential care, median length of stay was 17.9 months. Women stayed longer than men, while stays were shorter if preceded by other forms of social care. There was significant variation in length of stay between the three local authorities. The typical person admitted to a permanent residential care home will cost a local authority over L38,000, less payments due from individuals under the means test. CONCLUSIONS: These figures are not apparent from existing data sets. The large cost of care home placements suggests significant scope for preventive approaches. The administrative data revealed complexity in patterns of service use, which should be further explored as it may challenge the assumptions that are often made. PMID- 23110446 TI - Social support and age influence distress outcomes differentially across urban, regional and remote Australia: an exploratory study. AB - BACKGROUND: The variation of determinants of mental health with remoteness has rarely been directly examined. The current research aims to examine whether the association of psychosocial factors with psychological distress outcomes varies with increasing remoteness. METHODS: Participants were persons aged 55 and over from two community cohorts sampling from across rural and urban New South Wales (N = 4219; mean age = 69.00 years; 46.1% male). Measures of social support from these studies were calibrated to facilitate comparison across the sample. Remoteness was assessed using a continuous measure, the Accessibility/Remoteness Index of Australia. The association between demographic characteristics, social support, remoteness, and their interactions with remoteness in the prediction of high psychological distress (cut-off > 21 on the Kessler 10) were examined using logistic regression. RESULTS: Not being in a married or defacto relationship (OR 0.69; 99% CI 0.51-0.94), lower education (OR 0.52; 99% CI 0.38-0.71) and decreased social support (OR 0.36; 99% CI 0.31-0.42) significantly predicted psychological distress. There was a significant interaction of age and remoteness (OR 0.84; 99% CI 0.67-1.00), indicating that as remoteness increases, older persons are less likely to be highly distressed, as well as a significant interaction of social support and remoteness (OR 1.22; 99% CI 1.04-1.44), indicating that as remoteness decreases, persons with low levels of social support are more likely to be highly distressed. CONCLUSIONS: Remoteness may moderate the influence of social support and age on psychological distress outcomes. PMID- 23110447 TI - Enhanced Ca2+ entry, ceramide formation, and apoptotic death of erythrocytes triggered by plumbagin. AB - Plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone, 1), a natural product from plants with potential anticancer potency, induces apoptosis. Mechanisms involved in 1-induced apoptosis include mitochondrial depolarization, inactivation of NF kappaB, and altered expression of anti- and proapoptotic Bcl proteins. Similar to nucleated cells, erythrocytes may undergo suicidal death or eryptosis, which, like apoptosis, results in cell shrinkage and cell membrane scrambling with phosphatidylserine exposure at the cell surface. Triggers of eryptosis include increase of cytosolic Ca(2+) activity ([Ca(2+)]i) and ceramide formation. The present study explored whether 1 stimulates eryptosis. Cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin-V-binding, hemolysis from hemoglobin release, [Ca(2+)]i from Fluo-3 fluorescence, and ceramide abundance utilizing antibodies. A 48 h exposure to 1 (2 MUM) decreased forward scatter and increased annexin-V-binding significantly, events paralleled by increased [Ca(2+)]i and ceramide formation. Exposure to 1 was followed by a slight but significant increase of hemolysis. Removal of extracellular Ca(2+) slightly, but significantly blunted the effect of 1 (2 MUM) on annexin-V-binding. The present observations demonstrate that 1 may trigger suicidal death of erythrocytes, cells devoid of mitochondria and nuclei. PMID- 23110448 TI - YeastIP: a database for identification and phylogeny of Saccharomycotina yeasts. AB - With the advances in sequencing techniques, identification of ascomycetous yeasts to the species level and phylogeny reconstruction increasingly require curated and updated taxonomic information. A specific database with nucleotide sequences of the most common markers used for yeast taxonomy and phylogeny and a user friendly interface allowing identification, taxonomy and phylogeny of yeasts species was developed. By 1 September 2012, the YeastIP database contained all the described Saccharomycotina species for which sequences used for taxonomy and phylogeny, such as D1/D2 rDNA and ITS, are available. The database interface was developed to provide a maximum of relevant information and data mining tools, including the following features: (1) the blast n program for the sequences of the YeastIP database; (2) easy retrieval of selected sequences; (3) display of the available markers for each selected group of species; and (4) a tool to concatenate marker sequences, including those provided by the user. The concatenation tool allows phylogeny reconstruction through a direct link to the Phylogeny.fr platform. YeastIP is thus a unique database in that it provides taxonomic information and guides users in their taxonomic analyses. YeastIP facilitates multigenic analysis to encourage good practice in ascomycetous yeast phylogeny (URL: http://genome.jouy.inra.fr/yeastip.). PMID- 23110449 TI - Giant pendulous fibroma of the breast associated with a locally advanced carcinoma of the breast. PMID- 23110450 TI - Reproducing natural spider silks' copolymer behavior in synthetic silk mimics. AB - Dragline silk from orb-weaving spiders is a copolymer of two large proteins, major ampullate spidroin 1 (MaSp1) and 2 (MaSp2). The ratio of these proteins is known to have a large variation across different species of orb-weaving spiders. NMR results from gland material of two different species of spiders, N. clavipes and A. aurantia , indicates that MaSp1 proteins are more easily formed into beta-sheet nanostructures, while MaSp2 proteins form random coil and helical structures. To test if this behavior of natural silk proteins could be reproduced by recombinantly produced spider silk mimic protein, recombinant MaSp1/MaSp2 mixed fibers as well as chimeric silk fibers from MaSp1 and MaSp2 sequences in a single protein were produced based on the variable ratio and conserved motifs of MaSp1 and MaSp2 in native silk fiber. Mechanical properties, solid-state NMR, and XRD results of tested synthetic fibers indicate the differing roles of MaSp1 and MaSp2 in the fiber and verify the importance of postspin stretching treatment in helping the fiber to form the proper spatial structure. PMID- 23110451 TI - Genome-wide DNA methylation profiling predicts relapse in childhood B-cell acute lymphoblastic leukaemia. PMID- 23110452 TI - Phosphoproteomic analysis reveals major default phosphorylation sites outside long intrinsically disordered regions of Arabidopsis plasma membrane proteins. AB - BACKGROUND: Genome-wide statistics established that long intrinsically disordered regions (over 30 residues) are predicted in a large part of proteins in all eukaryotes, with a higher ratio in trans-membrane proteins. At functional level, such unstructured and flexible regions were suggested for years to favour phosphorylation events. In plants, despite increasing evidence of the regulation of transport and signalling processes by phosphorylation events, only few data are available without specific information regarding plasma membrane proteins, especially at proteome scale. RESULTS: Using a dedicated phosphoproteomic workflow, 75 novel and unambiguous phosphorylation sites were identified in Arabidopsis plasma membrane. Bioinformatics analysis showed that this new dataset concerned mostly integral proteins involved in key functions of the plasma membrane (such as transport and signal transduction, including protein phosphorylation). It thus expanded by 15% the directory of phosphosites previously characterized in signalling and transport proteins. Unexpectedly, 66% of phosphorylation sites were predicted to be located outside long intrinsically disordered regions. This result was further corroborated by analysis of publicly available data for the plasma membrane. CONCLUSIONS: The new phosphoproteomics data presented here, with published datasets and functional annotation, suggest a previously unexpected topology of phosphorylation in the plant plasma membrane proteins. The significance of these new insights into the so far overlooked properties of the plant plasma membrane phosphoproteome and the long disordered regions is discussed. PMID- 23110453 TI - High likelihood of malignancy in young patients presenting with a thyroid nodule in Northern England. PMID- 23110455 TI - Structural basis of innate immune recognition of viral RNA. AB - Viral RNA is recognized by innate immune receptors from two different families. In endolysosomal compartments, Toll-like receptors (TLRs) 3, 7 and 8 recognize either double-stranded RNA (dsRNA) or single-stranded RNA. In the cytoplasm, viral genomic RNA or transcriptional intermediates are recognized by DExD/H-box helicases RIG-I and MDA5. Recent structural studies of these RNA sensors have provided atomic-level insight into the recognition mechanism of viral RNA. TLR3 dimerizes around a straight 45-bp stretch of dsRNA, explaining the length requirement of at least 40 bp for dsRNA recognition. RIG-I recognizes blunt ends of dsRNA with 5'-triphosphate caps. Ligand binding releases RIG-I from a closed autoinhibited state, exposing the CARD signalling domains. MDA5 recognizes long dsRNA by cooperatively assembling into helical filaments. RNA recognition by RIG I and MDA5 triggers assembly of their common downstream signalling adaptor MAVS from its inactive monomeric form into its active polymeric form. While RIG-I and MDA5 appear to activate MAVS via distinct oligomerization mechanisms, a common paradigm is emerging in innate immunity for signal transduction by oligomerization-dependent signalling platforms. Many open questions remain including the role of proteolytic activation in RNA recognition by TLR3 and how unanchored ubiquitin chains contribute to RNA recognition by RIG-I and MDA5. PMID- 23110454 TI - Escherichia coli RecG functionally suppresses human Bloom syndrome phenotypes. AB - Defects in the human BLM gene cause Bloom syndrome, notable for early development of tumors in a broad variety of tissues. On the basis of sequence similarity, BLM has been identified as one of the five human homologs of RecQ from Escherichia coli. Nevertheless, biochemical characterization of the BLM protein indicates far greater functional similarity to the E. coli RecG protein and there is no known RecG homolog in human cells. To explore the possibility that the shared biochemistries of BLM and RecG may represent an example of convergent evolution of cellular function where in humans BLM has evolved to fulfill the genomic stabilization role of RecG, we determined whether expression of RecG in human BLM deficient cells could suppress established functional cellular Bloom syndrome phenotypes. We found that RecG can indeed largely suppress both the definitive elevated sister chromatid exchange phenotype and the more recently demonstrated gene cluster instability phenotype of BLM-deficient cells. In contrast, expression of RecG has no impact on either of these phenotypes in human cells with functional BLM protein. These results suggest that the combination of biochemical activities shared by RecG and BLM fill the same evolutionary niche in preserving genomic integrity without requiring exactly identical molecular mechanisms. PMID- 23110456 TI - Protective effect of the methanol extract from Cryptotaenia japonica Hassk. against lipopolysaccharide-induced inflammation in vitro and in vivo. AB - BACKGROUND: In folk medicine, the aerial part of Crytotaenia japonica Hassk. (CJ), is applied for treatment of the common cold, cough, urinary problems, pneumonia, and skin rashes. In this paper, the in vitro and in vivo anti inflammatory activity of CJ methanol extract was tested using lipopolysaccharide (LPS)-induced inflammatory models. METHODS: We measured nitric oxide (NO), inducible NO synthase (iNOS), and inflammatory cytokine levels from LPS stimulated mouse peritoneal macrophages. Also, several cellular signaling molecules which regulate the expressions of these inflammatory markers were examined. Finally, we tested whether oral administration of CJ methanol extract might affect the serum cytokine levels in LPS-injected mice. RESULTS: CJ methanol extract reduced NO release via iNOS protein inhibition. The extract was also shown to decrease the secretions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-12. Analysis of signaling molecules showed that CJ inhibited the phosphorylation of STAT1, p38, JNK and ERK1/2 as well as IkappaBalpha degradation. Finally, CJ decreased the serum levels of TNF-alpha and IL-6 in LPS-injected mice. CONCLUSIONS: Our results demonstrated the anti inflammatory activity of CJ methanol extract and its possible underlying mechanisms that involve modulation of IkappaBalpha, MAPK, and STAT1 activities. PMID- 23110458 TI - Helping rural women in Pakistan to prevent postpartum hemorrhage: a quasi experimental study. AB - BACKGROUND: According to the Pakistan Demographic and Health Survey from 2006 2007, the maternal mortality ratio in rural areas is 319 per 100,000 live births. Postpartum hemorrhage is the leading cause of maternal deaths in Pakistan. The objectives of the study were to document the feasibility of distribution of misoprostol tablets by community-based providers mainly traditional birth attendants and acceptability and use of misoprostol by women who gave birth at home. METHODS: A quasi-experimental design, comprising intervention and comparison areas, was used to document the acceptability of providing misoprostol tablets to pregnant women to prevent postpartum hemorrhage in the rural community setting in Pakistan. Data were collected using structured questionnaires administered to women before and after delivery at home and their birth attendants. RESULTS: Out of 770 women who delivered at home, 678 (88%) ingested misoprostol tablets and 647 (84%) ingested the tablets after the birth of the neonate but prior to the delivery of the placenta. The remaining women took misoprostol tablets after delivery of the placenta. Side effects were experienced by 40% of women and were transitory in nature. Among women who delivered at home, 80% said that they would use misoprostol tablets in the future and 74% were willing to purchase them in the future. CONCLUSIONS: Self-administration of misoprostol in the home setting is feasible. Community-based providers, such as traditional birth attendants and community midwives with proper training and counseling, play an important role in reducing postpartum hemorrhage. Proper counseling and information exchange are helpful for introducing new practices in resource-constrained rural communities. Until such a time that skilled birth attendance is made more universally available in the rural setting, alternative strategies, such as training and using the services of traditional birth attendants to provide safe pregnancy care, must be considered. PMID- 23110457 TI - Theranostic magnetic core-plasmonic shell star shape nanoparticle for the isolation of targeted rare tumor cells from whole blood, fluorescence imaging, and photothermal destruction of cancer. AB - Cancer is one of the most life-threatening diseases, which causes 7.6 million deaths and around 1 trillion dollars economic loss every year. Theranostic materials are expected to improve early detection and safe treatment through personalized medicine. Driven by the needs, we report the development of a theranostic plasmonic shell-magnetic core star shape nanomaterial based approach for the targeted isolation of rare tumor cells from the whole blood sample, followed by diagnosis and photothermal destruction. Experimental data with whole blood sample spiked with SK-BR-3 cancer cell shows that Cy3 attached S6 aptamer conjugated theranostic plasmonic/magnetic nanoparticles can be used for fluorescence imaging and magnetic separation even in 0.001% mixtures. A targeted photothermal experiment using 1064 nm near-IR light at 2-3 W/cm(2) for 10 min resulted in selective irreparable cellular damage to most of the SK-BR-3 cancer cells. We discuss the possible mechanism and operating principle for the targeted imaging, separation, and photothermal destruction using theranostic magnetic/plasmonic nanotechnology. After the optimization of different parameters, this theranostic nanotechnology-driven assay could have enormous potential for applications as contrast agent and therapeutic actuators for cancer. PMID- 23110459 TI - A free lunch? No cost for acquiring defensive plant pyrrolizidine alkaloids in a specialist arctiid moth (Utetheisa ornatrix). AB - Many herbivorous insects sequester defensive chemicals from their host plants. We tested sequestration fitness costs in the specialist moth Utetheisa ornatrix (Lepidoptera: Arctiidae). We added pyrrolizidine alkaloids (PAs) to an artificial diet at different concentrations. Of all the larval and adult fitness components measured, only development time was negatively affected by PA concentration. These results were repeated under stressful laboratory conditions. On the other hand, the amount of PAs sequestered greatly increased with the diet PA concentration. Absence of a detectable negative effect does not necessarily imply a lack of costs if all individuals express the biochemical machinery of detoxification and sequestration constitutively. Therefore, we used qPCR to show that expression of the gene used to detoxify PAs, pyrrolizidine-alkaloid-N oxygenase (pno), increased 41-fold in our highest PA treatment. Nevertheless, fitness components were affected only slightly or not at all, suggesting that sequestration in this species does not incur a strong cost. The apparent lack of costs has important implications for our understanding of the evolution of ecological interactions; for example, it implies that selection by specialist herbivores may decrease the levels of certain chemical defences in plant populations. PMID- 23110460 TI - Aminoglycoside antibiotics in the 21st century. AB - Aminoglycoside antibiotics were among the first antibiotics discovered and used clinically. Although they have never completely fallen out of favor, their importance has waned due to the emergence of other broad-spectrum antibiotics with fewer side effects. Today, with the dramatically increasing rate of infections caused by multidrug-resistant bacteria, focus has returned to aminoglycoside antibiotics as one of the few remaining treatment options, particularly for Gram-negative pathogens. Although the mechanisms of resistance are reasonably well understood, our knowledge about the mode of action of aminoglycosides is still far from comprehensive. In the face of emerging bacterial infections that are virtually untreatable, it is time to have a fresh look at this old class to reinvigorate the struggle against multidrug-resistant pathogens. PMID- 23110461 TI - No evidence of substantial growth progression or complications of large focal nodular hyperplasia during pregnancy. AB - OBJECTIVE: Focal nodular hyperplasia (FNH) is a benign liver tumor considered to develop under the influence of estrogens. Whether women with known FNH are at higher risk of growth progression and complications during pregnancy is still controversially discussed. The authors investigated the growth pattern of FNH during pregnancy and possible related complications. MATERIALS AND METHODS: Twenty pregnant women with FNH were followed by the authors' center. Before pregnancy, diagnosis of FNH was usually established by contrast-enhanced ultrasound. During pregnancy, monitoring of FNH was performed by conventional ultrasound. Furthermore, a questionnaire was sent to all patients. RESULTS: Patient's age ranged from 24 to 36 years. Mean size of FNH before pregnancy was 58.5 +/- 22.7 mm. It did not vary significantly during pregnancy (fourth month of pregnancy: 58.1 +/- 23.0 mm; after pregnancy: 55.5 +/- 26.8 mm; -8%; n.s.). Only in three patients, growth of FNH by 18 +/- 6% was observed, while FNH size remained constant in 7 patients and even declined by -11 +/- 6% in 10 patients. There were no FNH-related complications. The questionnaire was sent back by 16 patients (80%). All responding patients took oral contraceptives in the past over a mean 12.4 +/- 4.4 years. Previous pregnancies were reported by 38% of patients. FNH-related fears were expressed by 63% of patients, but no FNH-related complications or symptoms during pregnancy were noted. CONCLUSIONS: This study demonstrates that women with FNH are not at risk of significant growth progression or FNH-related complications. Pregnancy should not be discouraged in these patients but careful advice and guidance are necessary. PMID- 23110462 TI - Palliative and therapeutic harmonization: a model for appropriate decision-making in frail older adults. AB - Frail older adults face increasingly complex decisions regarding medical care. The Palliative and Therapeutic Harmonization (PATH) model provides a structured approach that places frailty at the forefront of medical and surgical decision making in older adults. Preliminary data from the first 150 individuals completing the PATH program shows that the population served is frail (mean Clinical Frailty Score = 6.3), has multiple comorbidities (mean 8), and takes many medications (mean = 9). Ninety-two percent of participants were able to complete decision-making for an average of three current or projected health issues, most often (76.7%) with the help of a substitute decision-maker (SDM). Decisions to proceed with scheduled medical or surgical interventions correlated with baseline frailty level and dementia stage, with participants with a greater degree of frailty (odds ratio (OR) = 3.41, 95% confidence interval (CI) = 1.39 8.38) or more-advanced stage of dementia (OR = 1.66, 95% CI = 1.06-2.65) being more likely to choose less-aggressive treatment options. Although the PATH model is in the development stage, further evaluation is ongoing, including a qualitative analysis of the SDM experience of PATH and an assessment of the effectiveness of PATH in long-term care. The results of these studies will inform the design of a larger randomized controlled trial. PMID- 23110463 TI - Transient induction of melatonin biosynthesis in rice (Oryza sativa L.) during the reproductive stage. AB - The regulation of reproduction-stage inducible melatonin biosynthesis in rice (Oryza sativa cv. Dongjin) was investigated. The flag leaf and panicle (flower) were collected from field-grown rice at three different reproductive stages: the preflowering stage, flowering stage, and postflowering stage. Melatonin synthesis was induced in the panicle, whereas no induction was observed in the flag leaf during the reproductive stages. The panicle displayed a peak melatonin level of 0.4 ng/g fresh weight (fw), which was six times that found in the flag leaf. The induction of melatonin biosynthesis was paralleled by the induction of corresponding genes and proteins such as tryptophan decarboxylase, tryptamine 5 hydroxylase, and N-acetylserotonin methyltransferase. In addition, melatonin induction was preceded by the accumulation of its precursor, tryptophan, in the panicle. These results suggest that the induction of melatonin during flower development is regulated by the transcriptional control of its biosynthesis genes and that melatonin may participate in flower development. PMID- 23110464 TI - Venlafaxine and risk of upper gastrointestinal bleeding in elderly depression. AB - In the past 10 years there has been an emphasis on the risk of upper gastrointestinal bleeding in patients taking SSRI antidepressants. Few studies have concurrently examined the possible risk of traditional antidepressants or atypical antidepressants such as venlafaxine, classified as a serotonin norepinephrine reuptake inhibitor. In order to promote debate about possible risk of upper gastrointestinal bleeding in elderly patients taking antidepressants different from SSRIs, we report a case of venlafaxine-induced upper gastrointestinal bleeding in a 84 years old woman. Discussion about safer drugs and protective factors is provided. PMID- 23110466 TI - Increased arterial wall thickness - atherosclerosis or what? PMID- 23110467 TI - The Kallikrein-Kinin system. PMID- 23110468 TI - Bjorn Folkow (1921-2012). PMID- 23110469 TI - Genetic polymorphisms and drug interactions leading to clopidogrel resistance: why the Asian population requires special attention. AB - Ischemic heart disease and stroke are the two leading causes of death worldwide. Antiplatelet therapy plays the most significant role in the management of these cardiovascular and cerebrovascular occlusive events to prevent recurrent ischemic attack. Clopidogrel, an antiplatelet drug, is widely prescribed either alone or in combination with aspirin as dual antiplatelet therapy for the prevention of vascular occlusive events. The antiplatelet response to clopidogrel varies widely. Hyporesponders and nonresponders are likely to have adverse cardiovascular events during follow-up. Some drugs, such as proton pump inhibitors (omeprazole), calcium channel blockers, selective serotonin reuptake inhibitors (nefazadone), coumarin derivatives (phenprocoumon), benzodiazepines, sulfonylurea, erythromycin, and itraconazole, decrease the antiplatelet effect of clopidogrel when administered concomitantly. Decreased response to clopidogrel is common among Asians due to genetic polymorphisms associated with clopidogrel resistance, and it is nearly 70% in some of the Asian communities. It is necessary to study Asian populations, because there are a large number of Asians throughout the world due to increased migration. Current guidelines do not make genetic testing or platelet response testing mandatory prior to clopidogrel prescription. Therefore, it is important for clinicians treating Asian patients to keep in mind the interindividual variability in response to clopidogrel when prescribing the drug. PMID- 23110470 TI - Soft tissue response after Class III bimaxillary surgery. AB - OBJECTIVE: To analyze the impact of surgical change in anterior face height and skeletal relapse on the long-term soft tissue profile. MATERIALS AND METHODS: Cephalometric radiographs of 81 patients taken before surgery and at five time points during a 3-year follow-up period were analyzed. All patients had Le Fort I and bilateral sagittal split osteotomies. The patients were divided into three subgroups according to the change in anterior face height during surgery. Calculations of soft to hard tissue ratios were based on the long-term soft tissue response relative to the surgical repositioning. RESULTS: The horizontal surgical repositioning varied considerably, depending on whether anterior face height was increased or decreased. For upper lip prominence, the pattern of long term change was the same irrespective of change in face height. In all groups, upper lip thickness decreased in both the short term and the long term, particularly in patients with surgical increase in face height. Lower lip thickness increased in the short term but decreased during the follow-up period. There were significant associations between horizontal soft tissue and corresponding hard tissue changes, except for soft tissue A-point and upper lip, when face height was increased. The ratios were higher for mandibular variables than for maxillary variables, particularly for B-point and pogonion when anterior face height had decreased. CONCLUSION: A change in facial height influences the soft tissue response. The mandibular soft tissues closely follow skeletal relapse beyond 2 months postsurgery. The findings have clinical implications for the relative maxillary and mandibular repositioning when planning surgery. PMID- 23110472 TI - Natural organic matter alters biofilm tolerance to silver nanoparticles and dissolved silver. AB - Motivated by the need to understand environmental risks posed by potentially biocidal engineered nanoparticles, the effects of silver nanoparticle (AgNP) exposure on viability in single species Pseudomonas fluorescens biofilms were determined via dye staining methods. AgNP dispersions, containing both particles and dissolved silver originating from the particles, negatively impacted biofilm viability in a dose-dependent manner. No silver treatments (up to 100 ppm AgNPs) resulted in 100% biofilm viability loss, even though these same concentrations caused complete viability loss in planktonic culture, suggesting some biofilm tolerance to AgNP toxicity. Colloidally stable AgNP suspensions exhibited greater toxicity to biofilms than corresponding particle-free supernatants containing only dissolved silver released from the particles. This distinct nanoparticle specific toxicity was not observed for less stable, highly aggregated particles, suggesting that biofilms were protected against nanoparticle aggregate toxicity. In both the stable and highly aggregated dispersions, dissolved silver made a significant contribution to overall toxicity. Therefore, despite increased colloidal stability when humic acid adsorbed to AgNPs, the presence of humic acid mitigated the toxicity of AgNP suspensions because it bound to silver ions in solution. PMID- 23110471 TI - Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study. AB - BACKGROUND: Patients with hypertension and cardiovascular disease (CVD), diabetes, or chronic kidney disease (CKD) usually require two or more antihypertensive agents to achieve blood pressure (BP) goals. METHODS: The efficacy/safety of olmesartan (OM) 40 mg, amlodipine besylate (AML) 10 mg, and hydrochlorothiazide (HCTZ) 25 mg versus the component dual-combinations (OM 40/AML 10 mg, OM 40/HCTZ 25 mg, and AML 10/HCTZ 25 mg) was evaluated in participants with diabetes, CKD, or chronic CVD in the Triple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in Hypertensive Patients Study (TRINITY). The primary efficacy end point was least squares (LS) mean reduction from baseline in seated diastolic BP (SeDBP) at week 12. Secondary end points included LS mean reduction in SeSBP and proportion of participants achieving BP goal (<130/80 mm Hg) at week 12 (double-blind randomized period), and LS mean reduction in SeBP and BP goal achievement at week 52/early termination (open-label period). RESULTS: At week 12, OM 40/AML 10/HCTZ 25 mg resulted in significantly greater SeBP reductions in participants with diabetes ( 37.9/22.0 mm Hg vs -28.0/17.6 mm Hg for OM 40/AML 10 mg, -26.4/14.7 mm Hg for OM 40/HCTZ 25 mg, and -27.6/14.8 mm Hg for AML 10/HCTZ 25 mg), CKD (-44.3/25.5 mm Hg vs -39.5/23.8 mm Hg for OM 40/AML 10 mg, -25.3/17.0 mm Hg for OM 40/HCTZ 25 mg, and -33.4/20.6 mm Hg for AML 10/HCTZ 25 mg), and chronic CVD (-37.8/20.6 mm Hg vs -31.7/18.2 mm Hg for OM 40/AML 10 mg, -30.9/17.1 mm Hg for OM 40/HCTZ 25 mg, and 27.5/16.1 mm Hg for AML 10/HCTZ 25 mg) (P<0.05 for all subgroups vs dual component treatments). BP goal achievement was greater for participants receiving triple-combination treatment compared with the dual-combination treatments, and was achieved in 41.1%, 55.0%, and 38.9% of participants with diabetes, CKD, and chronic CVD on OM 40/AML 10/HCTZ 25 mg, respectively. At week 52, there was sustained BP lowering with the OM/AML/HCTZ regimen. Overall, the triple combination was well tolerated. CONCLUSIONS: In patients with diabetes, CKD, or chronic CVD, short-term (12 weeks) and long-term treatment with OM 40/AML 10/HCTZ 25 mg was well tolerated, lowered BP more effectively, and enabled more participants to reach BP goal than the corresponding 2-component regimens. TRIAL IDENTIFICATION NUMBER: NCT00649389. PMID- 23110473 TI - The use of syndromic surveillance for decision-making during the H1N1 pandemic: a qualitative study. AB - BACKGROUND: Although an increasing number of studies are documenting uses of syndromic surveillance by front line public health, few detail the value added from linking syndromic data to public health decision-making. This study seeks to understand how syndromic data informed specific public health actions during the 2009 H1N1 pandemic. METHODS: Semi-structured telephone interviews were conducted with participants from Ontario's public health departments, the provincial ministry of health and federal public health agency to gather information about syndromic surveillance systems used and the role of syndromic data in informing specific public health actions taken during the pandemic. Responses were compared with how the same decisions were made by non-syndromic surveillance users. RESULTS: Findings from 56 interviews (82% response) show that syndromic data were most used for monitoring virus activity, measuring impact on the health care system and informing the opening of influenza assessment centres in several jurisdictions, and supporting communications and messaging, rather than its intended purpose of early outbreak detection. Syndromic data had limited impact on decisions that involved the operation of immunization clinics, school closures, sending information letters home with school children or providing recommendations to health care providers. Both syndromic surveillance users and non-users reported that guidance from the provincial ministry of health, communications with stakeholders and vaccine availability were driving factors in these public health decisions. CONCLUSIONS: Syndromic surveillance had limited use in decision-making during the 2009 H1N1 pandemic in Ontario. This study provides insights into the reasons why this occurred. Despite this, syndromic data were valued for providing situational awareness and confidence to support public communications and recommendations. Developing an understanding of how syndromic data are utilized during public health events provides valuable evidence to support future investments in public health surveillance. PMID- 23110474 TI - Rapid identification of Saccharomyces eubayanus and its hybrids. AB - The Saccharomyces species Saccharomyces eubayanus was recently discovered in Patagonia. Genomic, genetic and phylogenetic data all suggest that it is one of the two parents of the hybrid yeast S. pastorianus (S. cerevisiae being the other). Saccharomyces eubayanus genomes can also be found in strains of the hybrid species S. bayanus. Here, we describe a novel pair of PCR primers targeted against the S. eubayanus FSY1 gene that will specifically detect S. eubayanus and hybrids containing this allele of the gene. The primer pair can be used to identify the species using a rapid, inexpensive colony PCR method suitable for a preliminary identification of wild isolates. PMID- 23110475 TI - Melittin suppresses VEGF-A-induced tumor growth by blocking VEGFR-2 and the COX-2 mediated MAPK signaling pathway. AB - Melittin (1) is a major polypeptide in honey bee venom that has been used traditionally against chronic inflammation and cancer. However, its molecular mechanism has not been determined. In this study, the antitumor effect of 1 was compared with that of NS398, a cyclooxygenase-2 (COX-2) inhibitor, in vivo and in vitro. Subcutaneous injection of 1 at 0.5 and 5 mg/kg suppressed significantly vascular endothelial growth factor (VEGF)-A-transfected highly metastatic Lewis lung cancer (VEGF-A-hm LLC) tumor growth by 25% and 57%, respectively. Also, 1 inhibited significantly the number of vessels around VEGF-A-hm LLC cells. The results were superior to those obtained in the mice treated with NS398. Compound 1 dose-dependently inhibited proliferation and tube formation in human umbilical vein endothelial cells (VEGF-A-HUVECs), without affecting cell viability in native HUVECs. In addition, 1 decreased the expression of VEGF receptor-2 (VEGFR 2), COX-2, and prostaglandin E2 (PGE2) in VEGF-A-transfected HUVECs. These effects were accompanied by a reduction of the phosphorylation of extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase, whereas it increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). SB203580 abolished the downregulation of COX-2 and VEGFR-2 and the inhibition of cell proliferation by 1. The antitumor activity of 1 may be associated with antiangiogenic actions via inhibiting VEGFR-2 and inflammatory mediators involved in the MAPK signaling pathway. PMID- 23110476 TI - pH-triggered aggregate shape of different generations lysine-dendronized maleimide copolymers with maltose shell. AB - Glycopolymers are promising materials in the field of biomedical applications and in the fabrication of supramolecular structures with specific functions. For tunable design of supramolecular structures, glycopolymer architectures with specific properties (e.g., controlled self-assembly) are needed. Using the concept of dendronized polymers, a series of H-bond active giant glycomacromolecules with maleimide backbone and lysine dendrons of different generations were synthesized. They possess different macromolecular size and functionality along the backbone. Their peripheral maltose units lead to solubility under physiological conditions and controlled aggregation behavior. The aggregation behavior was investigated depending on generation number, pH value, and concentration. A portfolio of complementary analytical tools give an insight into the influence of the different parameters in shaping a rod-, coil-, and worm-like molecular structure and their controlled aggregate formation. MD simulation helped us to understand the complex aggregation behavior of the linear polymer chain without dendritic units. PMID- 23110477 TI - Construction of drug-polymer thermodynamic phase diagrams using Flory-Huggins interaction theory: identifying the relevance of temperature and drug weight fraction to phase separation within solid dispersions. AB - Amorphous drug-polymer solid dispersions have the potential to enhance the dissolution performance and thus bioavailability of BCS class II drug compounds. The principle drawback of this approach is the limited physical stability of amorphous drug within the dispersion. Accurate determination of the solubility and miscibility of drug in the polymer matrix is the key to the successful design and development of such systems. In this paper, we propose a novel method, based on Flory-Huggins theory, to predict and compare the solubility and miscibility of drug in polymeric systems. The systems chosen for this study are (1) hydroxypropyl methylcellulose acetate succinate HF grade (HPMCAS-HF)-felodipine (FD) and (2) Soluplus (a graft copolymer of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol)-FD. Samples containing different drug compositions were mixed, ball milled, and then analyzed by differential scanning calorimetry (DSC). The value of the drug-polymer interaction parameter chi was calculated from the crystalline drug melting depression data and extrapolated to lower temperatures. The interaction parameter chi was also calculated at 25 degrees C for both systems using the van Krevelen solubility parameter method. The rank order of interaction parameters of the two systems obtained at this temperature was comparable. Diagrams of drug-polymer temperature-composition and free energy of mixing (DeltaG(mix)) were constructed for both systems. The maximum crystalline drug solubility and amorphous drug miscibility may be predicted based on the phase diagrams. Hyper-DSC was used to assess the validity of constructed phase diagrams by annealing solid dispersions at specific drug loadings. Three different samples for each polymer were selected to represent different regions within the phase diagram. PMID- 23110478 TI - Clinical effectiveness of dermal substitution in burns by topical negative pressure: a multicenter randomized controlled trial. AB - Previous research has shown clinical effectiveness of dermal substitution; however, in burn wounds, only limited effect has been shown. A problem in burn wounds is the reduced take of the autograft, when the substitute and graft are applied in one procedure. Recently, application of topical negative pressure (TNP) was shown to improve graft take. The aim of this study was to investigate if application of a dermal substitute in combination with TNP improves scar quality after burns. In a four-armed multicenter randomized controlled trial, a split-skin graft with or without a dermal substitute and with or without TNP was compared in patients with deep dermal or full-thickness burns requiring skin transplantation. Graft take and rate of wound epithelialization were evaluated. Three and 12 months postoperatively, scar parameters were measured. The results of 86 patients showed that graft take and epithelialization did not reveal significant differences. Significantly fewer wounds in the TNP group showed postoperative contamination, compared to other groups. Highest elasticity was measured in scars treated with the substitute and TNP, which was significantly better compared to scars treated with the substitute alone. Concluding, this randomized controlled trial shows the effectiveness of dermal substitution combined with TNP in burns, based on extensive wound and scar measurements. PMID- 23110479 TI - Glaucoma associated with uveal cysts and goniodysgenesis in American Bulldogs: a case series. AB - We present a series of three American Bulldogs with clinical signs of glaucoma and intraocular inflammation accompanied by bilateral uveal cysts and abnormal gonioscopic findings. All dogs proved refractory to medical management and were enucleated. Histopathologic findings were similar in all three and included significant preiridal fibrovascular membranes and mononuclear inflammatory infiltrates in the anterior uvea. On microscopic evaluation, cysts appeared to arise primarily from the ciliary body and iridociliary sulcus, with smaller cysts also budding from the posterior iris. Pigment dispersion was variable but consistent, involving deposition of a small number of pigment-laden cells in the dependent trabecular meshwork. Cataract formation was not noted. Glaucoma associated with uveal cysts has been described previously in Golden Retrievers and Great Danes, although clinical and histopathologic findings in those breeds are not identical to those described here. American Bulldogs with uveal cysts should have gonioscopy performed and should be monitored carefully for signs of increased intraocular pressure and intraocular inflammation. Furthermore, documentation of cyst-associated glaucoma in a third breed suggests clinicians should exercise caution in dismissing uveal cysts in dogs as incidental findings. PMID- 23110480 TI - Comprehensive and highly sensitive urinary steroid hormone profiling method based on stable isotope-labeling liquid chromatography-mass spectrometry. AB - Steroid hormones are crucial substances that mediate a wide range of vital physiological functions of the body. Determination of the levels of steroid hormones plays an important role in understanding the mechanism of the steroid hormone-related diseases. In this study, we present a novel targeted metabolic profiling method based on the introduction of an easily protonated stable isotope tag to a hydroxyl-containing steroid hormone with a synthesized derivatization reagent, deuterium 4-(dimethylamino)-benzoic acid (d(4)-DMBA), and liquid chromatography-mass spectrometry (LC-MS). Different from other reported derivatization reagents that have been used to enhance the sensitivities for estrogens or androgens, our method is comprehensive with the capability of covering hydroxyl-containing androgens, estrogens, corticoids, and progestogens. Furthermore, the nonderivatized steroid hormones (e.g., 17alpha hydroxyprogesterone, progesterone, and androstenedione) were not destroyed during the derivatization process, and their levels could still be obtained in one LC-MS run. We were able to detect 24 steroid hormones at subng/mL levels (the lower limit of detection could reach 5 pg/mL for estrone and 16alpha-hydroxy estrone, which is equivalent to 0.1 pg on column) with maximum sensitivity enhancement factors of more than 10(3)- to 10(4)-fold after derivatization. The method was successfully applied to the measurement of free (unconjugated) steroid hormones in urine samples of males, females, and pregnant women. Because the significant role the steroid hormone pathway plays in humans, a comprehensive, sensitive, specific, and accurate method for profiling the steroid hormone metabolome shall offer new insights into hormone-related diseases. PMID- 23110481 TI - Ablative fractionated CO2 laser treatment of photoaging: a clinical and histologic study. AB - BACKGROUND: Ablative fractional photothermolysis (AFP) has been reported to be effective for changes in skin pigmentation and texture associated with photoaging. METHODS: A prospective study for the treatment of photoaging using a fractionated ablative carbon dioxide laser in 10 subjects. Assessment of laser efficacy was made using two modalities: histologic examination of skin biopsies and blinded physician clinical photographic assessment. For the histologic portion of the study, patients were randomized to treatment with the device at settings of pulse durations of 500, 1,000, 1,500, and 1,800 MUs. Depth of injury was assessed based on histologic evaluation of depth of thermal coagulation. For the clinical portion of the study, treatment was administered to the face using a carbon dioxide laser at settings of 30 W, 500-MUm pitch (density of treatment equivalent to ablation of 25% of the skin), and variable pulse duration of 1,000 to 1,500 MUs. RESULTS: The mean score for dyschromia had improved 47.5% (95% confidence interval (CI) = 44.1-50.9%), for skin texture 56.0% (95% CI = 51.9 60.1%), for skin laxity 56.0% (95% CI = 51.3-60.7%), for rhytides 52.5% (95% CI = 48.3-56.7%) and for overall cosmetic outcome 61.5% (95% CI = 56.4%,66.6%) 6 months after treatment. Histologic data revealed a proportional increase in depth of thermal coagulation at each pulse duration. The mean ablation depth was 283 MUm for a pulse duration of 500 MUs, 375 MUm for 1,000 MUs, 767 MUm for 1,500 MUs, and 1.05 mm for 1,800 MUs. CONCLUSIONS: We present a histologic analysis documenting the correlation between longer pulse duration and ablation depth using an AFP device. We identified that pulse duration settings up to 1,800 MUs could be used safely with an ablation depth up to 1.1 mm, correlating with injury into the deep reticular dermis. PMID- 23110482 TI - Commentary: Ablative fractionated CO2 laser treatment of photoaging: a clinical and histologic study. PMID- 23110483 TI - Letter: Stereo-orientation of Mohs surgical specimens: a novel histologic pearl to reduce mental fatigue. PMID- 23110486 TI - Polarizable elements in scabies infestation: a clue to diagnosis. AB - The diagnosis of scabies infestation is straightforward in cases where mite parts are largely visible; however, mites are often not captured in a specimen's planes of section. Polariscopic examination is a fast and simple adjunctive diagnostic tool to light microscopy. We describe the unique polariscopic findings in scabies infestation. Two cases of crusted scabies and eight cases of typical scabies were subjected to polariscopic examination. Diagnostic mite parts were visualized in at least one section in all cases. Attached and detached spines as well as scybala (fecal material) are polarizable. Specifically, spines show a polarizable outer sheath with dark central core while scybala show peripherally concentrated, stippled birefringence. Similar stippled birefringence is visible within the gut of some mites whereas significant birefringence is not appreciated in other mite parts. These results suggest that polariscopic examination is a helpful clue in the diagnosis of scabies infestation, especially in cases where the body of the mite is not visualized. PMID- 23110485 TI - Antibacterial, antioxidant and tyrosinase-inhibition activities of pomegranate fruit peel methanolic extract. AB - BACKGROUND: This study evaluated, using in vitro assays, the antibacterial, antioxidant, and tyrosinase-inhibition activities of methanolic extracts from peels of seven commercially grown pomegranate cultivars. METHODS: Antibacterial activity was tested on Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli and Klebsiella pneumonia) using a microdilution method. Several potential antioxidant activities, including radical-scavenging ability (RSA), ferrous ion chelating (FIC) and ferric ion reducing antioxidant power (FRAP), were evaluated. Tyrosinase enzyme inhibition was investigated against monophenolase (tyrosine) and diphenolase (DOPA), with arbutin and kojic acid as positive controls. Furthermore, phenolic contents including total flavonoid content (TFC), gallotannin content (GTC) and total anthocyanin content (TAC) were determined using colourimetric methods. HPLC ESI/MSn analysis of phenolic composition of methanolic extracts was also performed. RESULTS: Methanolic peel extracts showed strong broad-spectrum activity against Gram-positive and Gram-negative bacteria, with the minimum inhibitory concentrations (MIC) ranging from 0.2 to 0.78 mg/ml. At the highest concentration tested (1000 MUg/ml), radical scavenging activities were significantly higher in Arakta (83.54%), Ganesh (83.56%), and Ruby (83.34%) cultivars (P< 0.05). Dose dependent FIC and FRAP activities were exhibited by all the peel extracts. All extracts also exhibited high inhibition (>50%) against monophenolase and diphenolase activities at the highest screening concentration. The most active peel extract was the Bhagwa cultivar against monophenolase and the Arakta cultivar against diphenolase with IC50 values of 3.66 MUg/ml and 15.88 MUg/ml, respectively. High amounts of phenolic compounds were found in peel extracts with the highest and lowest total phenolic contents of 295.5 (Ganesh) and 179.3 mg/g dry extract (Molla de Elche), respectively. Catechin, epicatechin, ellagic acid and gallic acid were found in all cultivars, of which ellagic acid was the most abundant comprising of more than 50% of total phenolic compounds detected in each cultivar. CONCLUSIONS: The present study showed that the tested pomegranate peels exhibited strong antibacterial, antioxidant and tyrosinase inhibition activities. These results suggest that pomegranate fruit peel could be exploited as a potential source of natural antimicrobial and antioxidant agents as well as tyrosinase inhibitors. PMID- 23110484 TI - Upregulated expression of brain enzymatic markers of arachidonic and docosahexaenoic acid metabolism in a rat model of the metabolic syndrome. AB - BACKGROUND: In animal models, the metabolic syndrome elicits a cerebral response characterized by altered phospholipid and unesterified fatty acid concentrations and increases in pro-apoptotic inflammatory mediators that may cause synaptic loss and cognitive impairment. We hypothesized that these changes are associated with phospholipase (PLA2) enzymes that regulate arachidonic (AA, 20:4n-6) and docosahexaenoic (DHA, 22:6n-6) acid metabolism, major polyunsaturated fatty acids in brain. Male Wistar rats were fed a control or high-sucrose diet for 8 weeks. Brains were assayed for markers of AA metabolism (calcium-dependent cytosolic cPLA2 IVA and cyclooxygenases), DHA metabolism (calcium-independent iPLA2 VIA and lipoxygenases), brain-derived neurotrophic factor (BDNF), and synaptic integrity (drebrin and synaptophysin). Lipid concentrations were measured in brains subjected to high-energy microwave fixation. RESULTS: The high-sucrose compared with control diet induced insulin resistance, and increased phosphorylated-cPLA2 protein, cPLA2 and iPLA2 activity and 12-lipoxygenase mRNA, but decreased BDNF mRNA and protein, and drebrin mRNA. The concentration of several n-6 fatty acids in ethanolamine glycerophospholipids and lysophosphatidylcholine was increased, as was unesterified AA concentration. Eicosanoid concentrations (prostaglandin E2, thromboxane B2 and leukotriene B4) did not change. CONCLUSION: These findings show upregulated brain AA and DHA metabolism and reduced BDNF and drebrin, but no changes in eicosanoids, in an animal model of the metabolic syndrome. These changes might contribute to altered synaptic plasticity and cognitive impairment in rats and humans with the metabolic syndrome. PMID- 23110487 TI - Cyclosporine in patients with severe steroid refractory ulcerative colitis in the era of infliximab. Review article. AB - Corticosteroids are the mainstay of therapy for severe ulcerative colitis. However, at least a third of patients fail to respond and face a colectomy. In these, rescue therapy with cyclosporine or infliximab (IFX), aimed at avoiding surgery, has been used in recent years. Of the two options, infliximab is largely preferred in both Sweden and Norway, whereas cyclosporine (CyA) is generally regarded as difficult to use, rather toxic and showing limited long-term efficacy. In light of some new recent data, herein, we provide an update of the literature in the field. It appears that there are theoretical and practical arguments on each side, and as of today, the choice between IFX or CyA for rescue therapy cannot be made on strong evidence. Thus, the best choice of medical rescue therapy will depend on the results of ongoing RCTs as well as future research in the field. PMID- 23110488 TI - Advancing the field of elder abuse: future directions and policy implications. AB - Elder abuse, sometimes called elder mistreatment or elder maltreatment, includes psychological, physical, and sexual abuse; neglect (caregiver neglect and self neglect); and financial exploitation. Evidence suggests that one in 10 older adults experiences some form of elder abuse, but only one in 25 cases is reported to social services agencies. At the same time, elder abuse is associated with significant morbidity and premature mortality. Despite these findings, there is a great paucity in research, practice, and policy addressing the pervasive issues of elder abuse. Through my experiences as a American Political Sciences Association Congressional Policy Fellow and Health and Aging Policy Fellow working with the Administration on Community Living (ACL) (previously known as the Administration on Aging) for the last 2 years, I will describe the major functions of the ACL and highlight two major pieces of federal legislation: The Older Americans Act and the Elder Justice Act. I will also highlight major research gaps and future policy relevant research directions for the field of elder abuse. PMID- 23110489 TI - Vibrational frequency fluctuation of ions in aqueous solutions studied by three pulse infrared photon echo method. AB - In liquid water, hydrogen bonds form three-dimensional network structures, which have been modeled in various molecular dynamics simulations. Locally, the hydrogen bonds continuously form and break, and the network structure continuously fluctuates. In aqueous solutions, the water molecules perturb the solute molecules, resulting in fluctuations of the electronic and vibrational states. These thermal fluctuations are fundamental to understanding the activation processes in chemical reactions and the function of biopolymers. In this Account, we review studies of the vibrational frequency fluctuations of solute molecules in aqueous solutions using three-pulse infrared photon echo experiments. For comparison, we also briefly describe dynamic fluorescence Stokes shift experiments for investigating solvation dynamics in water. The Stokes shift technique gives a response function, which describes the energy relaxation in the nonequilibrium state and corresponds to the transition energy fluctuation of the electronic state at thermal equilibrium in linear response theorem. The dielectric response of water in the megahertz to terahertz frequency region is a key physical quantity for understanding both of these frequency fluctuations because of the influence of electrostatic interactions between the solute and solvent. We focus on the temperature dependence of the three experiments to discuss the molecular mechanisms of both the frequency fluctuations in aqueous solutions. We used a biexponential function with sub-picosecond and picosecond time constants to characterize the time-correlation functions of both the vibrational and electronic frequency fluctuations. We focus on the slower component, with time constants of 1-2 ps for both the frequency fluctuations at room temperature. However, the temperature dependence and isotope effect for the time constants differ for these two types of fluctuations. The dielectric interactions generally describe the solvation dynamics of polar solvents, and hydrodynamic theory can describe the slow component for the electronic states. Compared with the slow component of the solvation dynamics, however, the picosecond component for the vibrational frequency fluctuations is less sensitive to temperature. Therefore, the slow component of the vibrational frequency fluctuation is determined by different underlying dynamics, which are important for the solvation dynamics of the electronic state. The time constant for the picosecond component for the vibrational frequency fluctuation does not significantly depend on the solute. We propose that the vibrational frequency fluctuates because of the constant structural changes in the hydrogen-bonding network of water molecules around the solute. PMID- 23110490 TI - From urothelial signalling to experiencing a sensation related to the urinary bladder. AB - The mechanisms underlying bladder sensation and the way we experience sensations during normal voiding and in pathology is complex and not well understood. During storage and emptying, mechanical changes occurring in number of cell types within the bladder wall (i.e. the uroepithelium and bladder afferents) can have a major influence on our sensory systems. In this review, we discuss bladder sensation with a focus on coding events in the periphery. PMID- 23110491 TI - Validation of the Spanish version of the Lawton IADL Scale for its application in elderly people. AB - BACKGROUND: The adequate information about the functional capacity of elderly populations is a key for the comprehensive assessment of their health status and autonomy. The Lawton IADL (instrumental activities of daily living) Scale is a very often used scale to assess independent living skills, but has never been validated for its use in Spanish-speaking populations. The purpose of this study was to assess the validity, the reliability, and responsiveness of this widely used scale. METHODS: The validation was based on a prospective cohort of 1,965 patients aged 65 or over who suffered an accidental fall with a hip or wrist fracture as a result. These patients were followed up six months after the production of the fracture. Cronbach's alpha was used to assess reliability, and exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) for the construct validity. Convergent and discriminant validity were examined by the correlation of the IADL Scale with the Barthel Index, SF-12, WOMAC short form, and QuickDASH questionnaires. Known-groups validity was also studied comparing IADL Scale according to different groups, and responsiveness was assessed by means of effect sizes. RESULTS: The mean age was 80.04 years (SD 8.04). The Cronbach alpha coefficient was 0.94. In the EFA, factor loadings ranged from 0.67 to 0.90, and CFA confirmed the homogeneity of the construct. Regarding the convergent validity, all correlation coefficients were higher than 0.40. Significant differences were found according to different groups, supporting known-groups validity. Responsiveness parameters showed moderate to large changes (effect sizes, 0.79 and 0.84 among patients classified as worsened). CONCLUSIONS: These results confirm that the Spanish version of the Lawton IADL Scale has excellent reliability and validity and a moderate to large sensitivity to change. This study provides a proper validation, not only of the Spanish version of the Lawton IADL Scale, but also of the original instrument. PMID- 23110492 TI - Academic achievement trajectories of homeless and highly mobile students: resilience in the context of chronic and acute risk. AB - Analyses examined academic achievement data across third through eighth grades (N = 26,474), comparing students identified as homeless or highly mobile (HHM) with other students in the federal free meal program (FM), reduced price meals (RM), or neither (General). Achievement was lower as a function of rising risk status (General > RM > FM > HHM). Achievement gaps appeared stable or widened between HHM students and lower risk groups. Math and reading achievement were lower, and growth in math was slower in years of HHM identification, suggesting acute consequences of residential instability. Nonetheless, 45% of HHM students scored within or above the average range, suggesting academic resilience. Results underscore the need for research on risk and resilience processes among HHM students to address achievement disparities. PMID- 23110493 TI - Elderly patients affected by glioblastoma treated with radiotherapy: the role of serum hemoglobin level. AB - OBJECTIVE: To investigate the role of serum hemoglobin level for elderly patients with glioblastoma treated with radiotherapy (RT). METHODS: Patients older than 65 years with glioblastoma, who underwent surgical resection/biopsy and RT, were evaluated. Total doses were 30 or 60 Gy:30 Gy in 10 or 5 fractions (palliative approach) and 60 Gy in 30 fractions (standard approach). In the standard approach, temozolomide was administered concomitantly and adjuvantly to RT. Before starting and weekly during RT, serum hemoglobin level was assessed for all patients. Recursive partitioning analysis (RPA) was used to classify patients. RESULTS: From 2005 to 2011, 45 patients (median age 71 years) were treated in our institution. Hemoglobin level less than 12 was confirmed in 11 patients. Median progression-free survival (PFS) and overall survival (OS) were 8 and 13 months, respectively. Only RPA class and extent of surgery correlated to PFS (p = .002, p = .04, respectively). RPA class, surgery, and RT dose affected OS (p = .003, p = .02, p = .03, respectively), whereas age (<70 vs. >=70 years) and hemoglobin level (<12 vs. >=12) did not influenced outcome (p = 0.2, p = 0.5, respectively). CONCLUSION: Our data suggested that extent of surgery and RPA class remain independent prognostic factor, whereas patients' anemia did not adversely affect prognosis in glioblastoma elderly patients. PMID- 23110495 TI - Organoindium reagents: the preparation and application in organic synthesis. PMID- 23110494 TI - Study and implementation of urogenital schistosomiasis elimination in Zanzibar (Unguja and Pemba islands) using an integrated multidisciplinary approach. AB - BACKGROUND: Schistosomiasis is a parasitic infection that continues to be a major public health problem in many developing countries being responsible for an estimated burden of at least 1.4 million disability-adjusted life years (DALYs) in Africa alone. Importantly, morbidity due to schistosomiasis has been greatly reduced in some parts of the world, including Zanzibar. The Zanzibar government is now committed to eliminate urogenital schistosomiasis. Over the next 3-5 years, the whole at-risk population will be administered praziquantel (40 mg/kg) biannually. Additionally, snail control and behaviour change interventions will be implemented in selected communities and the outcomes and impact measured in a randomized intervention trial. METHODS/DESIGN: In this 5-year research study, on both Unguja and Pemba islands, urogenital schistosomiasis will be assessed in 45 communities with urine filtration and reagent strips in 4,500 schoolchildren aged 9-12 years annually, and in 4,500 first-year schoolchildren and 2,250 adults in years 1 and 5. Additionally, from first-year schoolchildren, a finger-prick blood sample will be collected and examined for Schistosoma haematobium infection biomarkers. Changes in prevalence and infection intensity will be assessed annually. Among the 45 communities, 15 were randomized for biannual snail control with niclosamide, in concordance with preventive chemotherapy campaigns. The reduction of Bulinus globosus snail populations and S. haematobium-infected snails will be investigated. In 15 other communities, interventions triggering behaviour change have been designed and will be implemented in collaboration with the community. A change in knowledge, attitudes and practices will be assessed annually through focus group discussions and in-depth interviews with schoolchildren, teachers, parents and community leaders. In all 45 communities, changes in the health system, water and sanitation infrastructure will be annually tracked by standardized questionnaire-interviews with community leaders. Additional issues potentially impacting on study outcomes and all incurring costs will be recordedand monitored longitudinally. DISCUSSION: Elimination of schistosomiasis has become a priority on the agenda of the Zanzibar government and the international community. Our study will contribute to identifying what, in addition to preventive chemotherapy, needs to be done to prevent, control, and ultimately eliminate schistosomiasis, and to draw lessons for current and future schistosomiasis elimination programmes in Africa and elsewhere. TRIAL REGISTRATION: ISRCTN48837681. PMID- 23110496 TI - Landscape genetics of a top neotropical predator. AB - Habitat loss and fragmentation as a consequence of human activities is a worldwide phenomenon and one of the major threats to global biodiversity. Habitat loss and fragmentation is particularly a concern in the biodiverse tropics, where deforestation is occurring at unprecedented rates. Although insects are one of the most diverse and functionally important groups in tropical ecosystems, the quantitative effect of landscape features on their gene flow remains unknown. Here, we used a robust landscape genetics approach to quantify the effect of ten landscape features (deforestation, mature forests, other forest types, the River Chagres, streams, stream banks, roads, sea, lakes and swamps) and interactions between them, on the gene flow of a neotropical forest keystone species, the army ant Eciton burchellii. The influence of landscape on E. burchellii's gene flow reflected the different dispersal capability of its sexes; aerial for males and pedestrian for females, and the different depths of population history inferred from microsatellites and mitochondrial DNA. In contrast to the gene flow facilitating effect of mature forests, deforested areas were found to be strong barriers for E. burchellii's gene flow. Other forest types were found to be gene flow facilitators but only when interacting with mature secondary forests, therefore indicating the importance of mature forests for the survival of E. burchelii and its associate species. The River Chagres was identified as a major historical gene flow barrier for E. burchellii, suggesting that an important loss of connectivity may occur because of large artificial waterways such as the Panama Canal. PMID- 23110497 TI - Expression of ERBB3 binding protein 1 (EBP1) in salivary adenoid cystic carcinoma and its clinicopathological relevance. AB - BACKGROUND: ERBB3 binding protein 1 (EBP1) gene transfer into human salivary adenoid cystic carcinoma cells has been shown to significantly inhibit cell proliferation and reduce tumor metastasis in mouse models. In the current study, to evaluate if EBP1 is a novel biomarker capable of identifying patients at higher risk of disease progression and recurrence, we examined the EBP1 expression profile in adenoid cystic carcinoma (ACC) patients and analyzed its clinicopathological relevance. To understand the underlying anti-metastatic mechanism, we investigated if EBP1 regulates invasion-related molecules. METHODS: We performed immunohistochemical analysis on 132 primary adenoid cystic carcinoma and adjacent non-cancerous tissues using commercial EBP1, MMP9, E-cadherin and ICAM-1 antibodies. Results were correlated to clinicopathological parameters, long-term survival and invasion-related molecules by statistical analysis. Cell motility and invasiveness of vector or wild-type EBP1-transfected ACC-M cell lines were evaluated using wound healing and Boyden chamber assays. MMP9, E cadherin and ICAM-1 proteins in these cell lines were detected using western blot assay. RESULTS: The expression of EBP1 was significantly higher in non-cancerous adjacent tissues compared with corresponding cancer tissues. The intensity and percentage of cells that reacted with EBP1 antibodies were significantly higher in cases with tubular pattern than those with solid pattern (P<0.0001). We also found adenoid cystic carcinoma with local lymphatic metastasis had significantly lower EBP1 expression than ACC with no local lymphatic node metastasis (P<0.0001). Similar findings were observed in ACC with lung metastasis compared with cases with no lung metastasis (P<0.0001), in particular, in cases with perineural invasion compared with cases with no perineural invasion (P<0.0001). Furthermore, a decrease in EBP1 expression was positively associated with a reduction in overall survival of ACC patients. Of note, EBP1 inhibits migration and invasiveness of ACC cells by upregulating E-cadherin but downregulating MMP9. In clinical adenoid cystic carcinoma patients, higher EBP1 expression was positively correlated with E-cadherin levels (P<0.001) but negatively correlated with MMP9 expression (P=0.0002). CONCLUSIONS: EBP1 expression is reduced in adenoid cystic carcinoma, indicating unfavorable prognosis of ACC patients. Its regulation of MMP9 and E-cadherin protein levels suggests a critical therapeutic potential. PMID- 23110498 TI - The LIKE system, a novel protein expression toolbox for Bacillus subtilis based on the liaI promoter. AB - BACKGROUND: Bacillus subtilis is a very important Gram-positive model organism of high biotechnological relevance, which is widely used as a host for the production of both secreted and cytoplasmic proteins. We developed a novel and efficient expression system, based on the liaI promoter (PliaI) from B. subtilis, which is under control of the LiaRS antibiotic-inducible two-component system. In the absence of a stimulus, this promoter is kept tightly inactive. Upon induction by cell wall antibiotics, it shows an over 100-fold increase in activity within 10 min. RESULTS: Based on these traits of PliaI, we developed a novel LiaRS controlled gene expression system for B. subtilis (the "LIKE" system). Two expression vectors, the integrative pLIKE-int and the replicative pLIKE-rep, were constructed. To enhance the performance of the PliaI-derived system, site directed mutagenesis was employed to optimize the ribosome binding site and alter its spacing to the initiation codon used for the translational fusion. The impact of these genetic modifications on protein production yield was measured using GFP as a model protein. Moreover, a number of tailored B. subtilis expression strains containing different markerless chromosomal deletions of the liaIH region were constructed to circumvent undesired protein production, enhance the positive autoregulation of the LiaRS system and thereby increase target gene expression strength from the PliaI promoter. CONCLUSIONS: The LIKE protein expression system is a novel protein expression system, which offers a number of advantages over existing systems. Its major advantages are (i) a tightly switched-off promoter during exponential growth in the absence of a stimulus, (ii) a concentration dependent activation of PliaI in the presence of suitable inducers, (iii) a very fast but transient response with a very high dynamic range of over 100-fold (up to 1,000-fold) induction, (iv) a choice from a range of well-defined, commercially available, and affordable inducers and (v) the convenient conversion of LIKE-derived inducible expression strains into strong constitutive protein production factories. PMID- 23110500 TI - Diethylstilbestrol in castration-resistant prostate cancer. AB - What's known on the subject? and What does the study add? Diethylstilbestrol (DES) was the first hormone treatment used for prostate cancer and has also shown effectiveness in castration-resistant disease in small studies; however, concerns over thromboembolic toxicity have restricted its use in the past. Over 200 elderly men with castration-resistant prostate cancer were treated with 1-3 mg of DES, given with 75 mg aspirin and breast bud irradiation. Almost 30% of men showed a significant PSA response and the median time to PSA progression was 4.6 months. Almost 20% of patients with pain had a significant analgesic benefit. The most important toxicity was thromboembolism in 10% of men. Overall the drug has an acceptable toxicity profile and offers a palliative benefit in frail elderly men who may not be fit for chemotherapy. OBJECTIVE: * To assess the efficacy and toxicity of diethylstilbestrol (DES) in the management of castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS: * A total of 231 patients with CRPC received treatment with DES at the Royal Marsden Hospital between August 1992 and August 2000. * The median pre-treatment prostate-specific antigen (PSA) level was 221 ng/mL. * DES was used at a dose of 1-3 mg daily, with aspirin 75 mg. * The primary endpoint was PSA response rate. RESULTS: * The PSA response rate (using PSA Working Group criteria) was 28.9%. * The median time to PSA progression was 4.6 months. * Of patients with bone pain, 18% had an improvement in their European Organisation for the Research and Treatment of Cancer pain score. * Thromboembolic complications were seen in 9.9% of all patients. CONCLUSIONS: * DES has significant activity in CRPC and can be of palliative benefit. * DES has an acceptable toxicity profile in the management of patients with symptomatic CRPC when used at a dose of 1-3 mg, combined with aspirin and prophylactic breast bud radiotherapy. PMID- 23110501 TI - Ore grade decrease as life cycle impact indicator for metal scarcity: the case of copper. AB - In the life cycle assessment (LCA) of products, the increasing scarcity of metal resources is currently addressed in a preliminary way. Here, we propose a new method on the basis of global ore grade information to assess the importance of the extraction of metal resources in the life cycle of products. It is shown how characterization factors, reflecting the decrease in ore grade due to an increase in metal extraction, can be derived from cumulative ore grade-tonnage relationships. CFs were derived for three different types of copper deposits (porphyry, sediment-hosted, and volcanogenic massive sulfide). We tested the influence of the CF model (marginal vs average), mathematical distribution (loglogistic vs loglinear), and reserve estimate (ultimate reserve vs reserve base). For the marginal CFs, the statistical distribution choice and the estimate of the copper reserves introduce a difference of a factor of 1.0-5.0 and a factor of 1.2-1.7, respectively. For the average CFs, the differences are larger for these two choices, i.e. respectively a factor of 5.7-43 and a factor of 2.1-3.8. Comparing the marginal CFs with the average CFs, the differences are higher (a factor 1.7-94). This paper demonstrates that cumulative grade-tonnage relationships for metal extraction can be used in LCA to assess the relative importance of metal extractions. PMID- 23110502 TI - Intensive playing leads to non-monosymptomatic enuresis in children with low prepulse inhibition. AB - AIM: Parents of children suffering from non-monosymptomatic enuresis (nmE) report their child wetting itself during intensive playing. As children with enuresis are characterized by reduced bladder control (measured as prepulse inhibition (PPI) of startle reflex), the hypothesis suggests that intensive playing leads to further decrease in control and consecutive wetting. Two questions are important: Does PPI change while concentrating? Is this difference more explicit in children with daytime incontinence? METHODS: Forty-four healthy children, 40 children with nmE and 37 with monosymptomatic enuresis (mE) were examined. PPI was measured while watching DVD and while playing Nintendo's Wii((r)) , and calculated as percentage of the native startle response. RESULTS: All probands showed a relevant decrease in PPI: in relaxed state, the PPI of the controls was 54%; when concentrating, it fell to 34.5% (p = 0.014). The decrease in PPI in mE was from 66% to 51% (p = 0.008), and the decrease in PPI in nmE was from 29% to 21% (p = 0.125). CONCLUSION: While the decrease in PPI when playing was smallest in the group with nmE, overall PPI level was by far the lowest. The findings confirm the aetiology of enuresis through impaired 'sensori-motor gating' in children with nmE and provide a neurophysiologic correlate for wetting while playing. PMID- 23110503 TI - Novel, cysteine-modified chelation strategy for the incorporation of [M(I)(CO)(3)](+) (M = Re, (99m)Tc) in an alpha-MSH peptide. AB - Engineering peptide-based targeting agents with residues for site-specific and stable complexation of radionuclides is a highly desirable strategy for producing diagnostic and therapeutic agents for cancer and other diseases. In this report, a model N-S-N(Py) ligand (3) and a cysteine-derived alpha-melanocyte stimulating hormone (alpha-MSH) peptide (6) were used as novel demonstrations of a widely applicable chelation strategy for incorporation of the [M(I)(CO)(3)](+) (M = Re, (99m)Tc) core into peptide-based molecules for radiopharmaceutical applications. The structural details of the core ligand-metal complexes as model systems were demonstrated by full chemical characterization of fac-[Re(I)(CO)(3)(N,S,N(Py) 3)](+) (4) and comparative high-performance liquid chromatography (HPLC) analysis between 4 and [(99m)Tc(I)(CO)(3)(N,S,N(Py)-3)](+) (4a). The alpha-MSH analogue bearing the N-S-N(Py) chelate on a modified cysteine residue (6) was generated and complexed with [M(I)(CO)(3)](+) to confirm the chelation strategy's utility when applied in a peptide-based targeting agent. Characterization of the Re(I)(CO)(3)-6 peptide conjugate (7) confirmed the efficient incorporation of the metal center, and the (99m)Tc(I)(CO)(3)-6 analogue (7a) was explored as a potential single photon emission computed tomography (SPECT) compound for imaging the melanocortin 1 receptor (MC1R) in melanoma. Peptide 7a showed excellent radiolabeling yields and in vitro stability during amino acid challenge and serum stability assays. In vitro B16F10 melanoma cell uptake of 7a reached a modest value of 2.3 +/- 0.08% of applied activity at 2 h at 37 degrees C, while this uptake was significantly reduced by coincubation with a nonlabeled alpha-MSH analogue, NAPamide (3.2 MUM) (P < 0.05). In vivo SPECT/X-ray computed tomography (SPECT/CT) imaging and biodistribution of 7a were evaluated in a B16F10 melanoma xenografted mouse model. SPECT/CT imaging clearly visualized the tumor at 1 h post injection (p.i.) with high tumor-to-background contrast. Blocking studies with coinjected NAPamide (10 mg per kg of mouse body weight) confirmed the in vivo specificity of 7a for MC1R-positive tumors. Biodistribution results with 7a yielded a moderate tumor uptake of 1.20 +/- 0.09 percentage of the injected radioactive dose per gram of tissue (% ID/g) at 1 h p.i. Relatively high uptake of 7a was also seen in the kidneys and liver at 1 h p.i. (6.55 +/- 0.36% ID/g and 4.44 +/- 0.17% ID/g, respectively), although reduced kidney uptake was seen at 4 h p.i. (3.20 +/- 0.48% ID/g). These results demonstrate the utility of the novel [M(I)(CO)(3)](+) chelation strategy when applied in a targeting peptide. PMID- 23110504 TI - Physical activity and environmental enrichment regulate the generation of neural precursors in the adult mouse substantia nigra in a dopamine-dependent manner. AB - BACKGROUND: Parkinson's disease is characterized by a continuous loss of neurons within the substantia nigra (SN) leading to a depletion of dopamine. Within the adult SN as a non-neurogenic region, cells with mainly oligodendrocytic precursor characteristics, expressing the neuro-glial antigen-2 (NG2) are continuously generated. Proliferation of these cells is altered in animal models of Parkinson's disease (PD). Exercise and environmental enrichment re-increase proliferation of NG2+ cells in PD models, however, a possible mechanistic role of dopamine for this increase is not completely understood. NG2+ cells can differentiate into oligodendrocytes but also into microglia and neurons as observed in vitro suggesting a possible hint for endogenous regenerative capacity of the SN. We investigated the role of dopamine in NG2-generation and differentiation in the adult SN stimulated by physical activity and environmental enrichment. RESULTS: We used the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model for dopamine depletion and analysed newborn cells in the SN at different maturation stages and time points depending on voluntary physical activity, enriched environment and levodopa-treatment. We describe an activity- induced increase of new NG2-positive cells and also mature oligodendrocytes in the SN of healthy mice. Running and enriched environment refused to stimulate NG2 generation and oligodendrogenesis in MPTP-mice, an effect which could be reversed by pharmacological levodopa-induced rescue. CONCLUSION: We suggest dopamine being a key regulator for activity-induced generation of NG2-cells and oliogodendrocytes in the SN as a potentially relevant mechanism in endogenous nigral cellular plasticity. PMID- 23110505 TI - Effects of epidermal growth factor receptor and phosphatase and tensin homologue gene expression on the inhibition of U87MG glioblastoma cell proliferation induced by protein kinase inhibitors. AB - The aim of the present study was to analyse the antiproliferative effects and mechanisms of action of protein kinase inhibitors (PKIs) in human glioblastoma multiforme (GBM) cells with different epidermal growth factor receptor (EGFR) and phosphatase and tensin homologue (PTEN) status. The GBM cell models were established by transfection of plasmids carrying wild-type EGFR, mutated EGFRvIII or PTEN and clonal selection in U87MG cells. Phosphatidylinositol 3-kinase (PI3 K)/AKT pathway-focused gene profiles were examined by real-time polymerase chain reaction-based assays, protein expression was evaluated by western blotting and the antiproliferative effects of PKI treatment were determined by the 3-(4,5 dimethyl-2 thiazoyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay in GBM cells. The cell model with intact PTEN and low EGFR levels was the most sensitive to treatment with the EGFR inhibitor erlotinib, whereas the model with EGFRvIII was the most resistant to treatment with the mitogen-activated protein kinase kinase inhibitor U0126. The dual PI3-K and mammalian target of rapamycin (mTOR) inhibitor PI103 had the most potent antiproliferative effects against all GBM cells tested. Following simultaneous stimulation of AKT and extracellular signal regulated kinase, rapamycin concentrations > 0.5 nmol/L failed to exhibit a further growth inhibitory effect. Concurrent inhibition of mTOR and ribosomal protein s6 activity may underlie the inhibition of GBM proliferation by PKI. In conclusion, overexpression of EGFR or EGFRvIII, accompanied by a loss of PTEN, contributed to the activation of multiple intracellular signalling pathways in GBM cells. Rigorous examination of biomarkers in tumour tissues before and after treatment may be necessary to determine the efficacy of PKI therapy in patients with GBM. PMID- 23110506 TI - A pilot clinical study of hair grafting in chronic leg ulcers. AB - Epidermal sheets spread centrifugally postinjury from the hair follicle infundibulum to reepithelialize the wound bed. Healing progresses faster in skin areas rich in terminal hair follicles. These observations are consistent with the role of the hair follicle as a major reservoir for progenitor cells. To evaluate the feasibility and potential healing capacity of autologous scalp follicular grafts transplanted into the wound bed of chronic leg ulcers, 10 patients with ulcers of an average 36.8 cm(2) size and a 10.5-year duration were included in this pilot study. Within each ulcer we randomly assigned a 2 * 2 cm "experimental" square to receive 20 hair grafts and a nongrafted "control" square of equal size. The procedure seemed to be safe, although major unrelated complications occurred in two patients. At the 18-week end point, we observed a 27.1% ulcer area reduction in the experimental square as compared with 6.5% in the control square (p = 0.046) with a maximum 33.5% vs. 9.7% reduction at week 4 (p = 0.007). Histological analyses showed enhanced epithelialization, neovascularization, and dermal reorganization. We conclude that terminal hair follicle grafting into wound beds is feasible in an outpatient setting and represents a promising therapeutic alternative for nonhealing chronic leg ulcers. PMID- 23110508 TI - Enteric-coated mycophenolate sodium in combination with full dose or reduced dose cyclosporine, basiliximab and corticosteroids in Australian de novo kidney transplant patients. AB - AIM: Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. METHODS: Twelve-month, prospective, randomized, open label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. RESULTS: There was no significant difference in mean Cockcroft Gault CrCl (creatinine clearance) (60.2 +/- 17.6 mL/min per 1.73 m(2) vs 63.2 +/ 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. CONCLUSION: This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant. PMID- 23110507 TI - Epigallocathechin gallate, polyphenol present in green tea, inhibits stem-like characteristics and epithelial-mesenchymal transition in nasopharyngeal cancer cell lines. AB - BACKGROUND: Previous studies have demonstrated that the consumption of green tea inhibits the growth of various cancers. Most cancers are believed to be initiated from and maintained by a small population of cancer stem-like cells (CSC) or tumor-initiating cells (TIC) that are responsible for tumor relapse and chemotherapeutic resistance. Although epigallocathechin gallate (EGCG), the most abundant catechin in green tea, has been reported to induce growth inhibition and apoptosis in some cancer cells, its effect on CSC is undefined. In this study, we enriched CSC by the sphere formation, and provided an efficient model for further experiments. Using this method, we examined the effects of EGCG regulating the nasopharyngeal carcinoma (NPC) CSC and attempted to elucidate the possible mechanisms. METHODS: NPC TW01 and TW06 cell lines were enriched by sphere formation and characterized their phenotypical properties, such as invasion capacity, epithelial-mesenchymal transition (EMT) and gene expression were analyzed by quantitative real-time reverse transcription polymerase chain reaction (q-RT-PCR). EGCG-induced growth inhibition in the parental and sphere derived cells was determined by MTT and bromodeoxyuridine (BrdU) assay. EGCG induced apoptosis was analyzed by flow cytometry with Annexin V and PI staining. The effects of EGCG on sphere-derived cell tumorigenicity, migration and invasion were determined by soft agar assay, wound healing, and cell invasion assay. The alternation of protein expression regulated by EGCG on these sphere-derived cells was assessed by immunofluorescence staining and western blot. RESULTS: NPC sphere derived cells grown in serum-free non-adherent culture showed increased expression of stem cell markers and EMT markers compared to parental cells grown in conventional culture. Although EGCG induced growth inhibition and apoptosis in the parental cells in a dose-dependent manner, it was not as effective against spheres. However, EGCG potently inhibited sphere formation and can eliminate the stem cell characteristics of NPC and inhibit the epithelial-mesenchymal transition (EMT) signatures. CONCLUSIONS: Overall, these findings show that NPC cells with sphere formations possess the properties of CSC. Using this model, we found that EGCG regulated NPC CSC, their self-renewal capacity, and inhibited their invasive characteristics. It supports the pivotal role of EGCG as a dietary compound targeting NPC and may decrease recurrence and metastasis in nasopharyngeal carcinoma cells. PMID- 23110509 TI - Pathophysiological bases of eosinophilic esophagitis therapy. AB - Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of unknown etiology, presenting a dense mucosal infiltration of eosinophils that is not reversible with proton pump inhibitor therapy. Endoscopy has reported EoE commonly polymorphous disease with subtle mucosal changes, accompanied by variations in the caliber of the esophagus. The suggestion of EoE as an allergic disease is still short of evidence and recently, it has only been confirmed that the esophagus mucosal layer infiltrated by eosinophils may determine an association with allergy after exposure to allergens. A comprehensive review of symptoms, risk factors, diagnoses and mechanisms involved in the pathogenesis of EoE was carried out, with an analysis of the different treatment options available for this disease firmly maximizing in incidence and prevalence. The management of EoE is multidisciplinary and can involve gastroenterologists, pathologists, allergists and dietitians, particularly in pediatric patients, because dietary food restrictions appear to be more beneficial in children versus adults. EoE can successfully be treated with topical corticosteroids, which eliminate the clinical manifestations and histological lesions in most cases. Prolonged treatment is advised for EoE because it recurs frequently, particularly on discontinuation of therapy. Experimental treatments using immunotherapy are being investigated, but their safety and efficacy are yet to be defined. PMID- 23110510 TI - Propofol combined with traditional sedative agents versus propofol- alone sedation for gastrointestinal endoscopy: a meta-analysis. AB - OBJECTIVE: To assess the efficacy and safety of sedation of propofol combined with traditional sedative agents (PTSA) for gastrointestinal endoscopy, we conducted a meta-analysis of randomized controlled trials (RCTs) comparing PTSA with propofol-alone sedation. MATERIAL AND METHODS: RCTs comparing the effects of PTSA and propofol alone during gastrointestinal endoscopy were found on MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE. Cardiopulmonary complications (i.e., hypoxia, hypotension, arrhythmia, and apnea), total dose of propofol used and amnesia were assessed. RESULTS: Nine original RCTs investigating a total of 1,505 patients, of whom, 805 received PTSA sedation and 700 received propofol-alone sedation, met the inclusion criteria. Compared with propofol-alone sedation, the pooled relative risk with the use of PTSA sedation for developing hypoxia, hypotension, arrhythmias, and apnea for all the procedures combined was 0.93 (95% CI, 0.30-2.92), 1.32 (95% CI, 0.38-4.64), 2.61 (95% CI, 0.23-29.29) and 2.81 (95% CI, 0.27-29.07), with no significant difference between the groups. The pooled mean difference in total dose of propofol used was -40.01 (95% CI, -78.96 to -1.05), which showed a significant reduction with use of PTSA sedation. The pooled relative risk for amnesia was 0.97 (95% CI, 0.88-1.07), suggesting no significant difference between the groups. CONCLUSIONS: PTSA sedation during gastrointestinal endoscopy could significantly reduce the total dose of propofol, but without benefits of lower risk of cardiopulmonary complications compared with propofol-alone sedation. PMID- 23110511 TI - Use of organic precursors and graphenes in the controlled synthesis of carbon containing nanomaterials for energy storage and conversion. AB - The development of high-performance electrochemical energy storage and conversion devices, including supercapacitors, lithium-ion batteries, and fuel cells, is an important step on the road to alternative energy technologies. Carbon-containing nanomaterials (CCNMs), defined here as pure carbon materials and carbon/metal (oxide, hydroxide) hybrids with structural features on the nanometer scale, show potential application in such devices. Because of their pronounced electrochemical activity, high chemical and thermal stability and low cost, researchers are interested in CCNMs to serve as electrodes in energy-related devices. Various all-carbon materials are candidates for electrochemical energy storage and conversion devices. Furthermore, carbon-based hybrid materials, which consist of a carbon component with metal oxide- or metal hydroxide-based nanostructures, offer the opportunity to combine the attractive properties of these two components and tune the behavior of the resulting materials. As such, the design and synthesis of CCNMs provide an attractive route for the construction of high-performance electrode materials. Studies in these areas have revealed that both the composition and the fabrication protocol employed in preparing CCNMs influence the morphology and microstructure of the resulting material and its electrochemical performance. Consequently, researchers have developed several synthesis strategies, including hard-templated, soft-templated, and template-free synthesis of CCNMs. In this Account, we focus on recent advances in the controlled synthesis of such CCNMs and the potential of the resulting materials for energy storage or conversion applications. The Account is divided into four major categories based on the carbon precursor employed in the synthesis: low molecular weight organic or organometallic molecules, hyperbranched or cross-linked polymers consisting of aromatic subunits, self assembling discotic molecules, and graphenes. In each case, we highlight representative examples of CCNMs with both new nanostructures and electrochemical performance suitable for energy storage or conversion applications. In addition, this Account provides an overall perspective on the current state of efforts aimed at the controlled synthesis of CCNMs and identifies some of the remaining challenges. PMID- 23110512 TI - Strategies for implementing genomic selection in family-based aquaculture breeding schemes: double haploid sib test populations. AB - BACKGROUND: Simulation studies have shown that accuracy and genetic gain are increased in genomic selection schemes compared to traditional aquaculture sib based schemes. In genomic selection, accuracy of selection can be maximized by increasing the precision of the estimation of SNP effects and by maximizing the relationships between test sibs and candidate sibs. Another means of increasing the accuracy of the estimation of SNP effects is to create individuals in the test population with extreme genotypes. The latter approach was studied here with creation of double haploids and use of non-random mating designs. METHODS: Six alternative breeding schemes were simulated in which the design of the test population was varied: test sibs inherited maternal (Mat), paternal (Pat) or a mixture of maternal and paternal (MatPat) double haploid genomes or test sibs were obtained by maximum coancestry mating (MaxC), minimum coancestry mating (MinC), or random (RAND) mating. Three thousand test sibs and 3000 candidate sibs were genotyped. The test sibs were recorded for a trait that could not be measured on the candidates and were used to estimate SNP effects. Selection was done by truncation on genome-wide estimated breeding values and 100 individuals were selected as parents each generation, equally divided between both sexes. RESULTS: Results showed a 7 to 19% increase in selection accuracy and a 6 to 22% increase in genetic gain in the MatPat scheme compared to the RAND scheme. These increases were greater with lower heritabilities. Among all other scenarios, i.e. Mat, Pat, MaxC, and MinC, no substantial differences in selection accuracy and genetic gain were observed. CONCLUSIONS: In conclusion, a test population designed with a mixture of paternal and maternal double haploids, i.e. the MatPat scheme, increases substantially the accuracy of selection and genetic gain. This will be particularly interesting for traits that cannot be recorded on the selection candidates and require the use of sib tests, such as disease resistance and meat quality. PMID- 23110513 TI - Medical decision-making for older adults without family. AB - Each year in the United States, individuals who lack decision-making capacity because of acute or chronic cognitive impairment are in situations in which important medical decisions must be made for them, but tens of thousands of these individuals have no known family members or designated surrogates available to help with those decisions. Such individuals constitute 16% of patients in intensive care units, 3% of nursing home residents, and a large but unspecified number of individuals in a variety of settings who are facing end-of-life decisions. Several approaches are currently used to aid in medical decision making for people without families or designated surrogates, including hospital ethics committees, court-appointed surrogate agents, reliance on advance directives if they are available, and even the use of computer-based decision systems. These approaches all have limitations and often result in individuals receiving care that would not have been their preference. Additionally, because clinical care teams must wrestle with uncertainty about best approaches to care, lengths of hospital stay for individuals without family are longer, resulting in higher healthcare costs and potentially more-aggressive interventions than individuals with family experience. This article reviews medical decision-making for older adults without families or designated surrogates and proposes a solution: "health fiduciaries"--a new type of professional trained and certified to act as a surrogate decision-maker for individuals who are unable to make decisions for themselves. PMID- 23110514 TI - Developmental trajectories in children with and without autism spectrum disorders: the first 3 years. AB - Retrospective studies indicate 2 major classes of autism spectrum disorder (ASD) onset: early and later, after a period of relatively healthy development. This prospective, longitudinal study examined social, language, and motor trajectories in 235 children with and without a sibling with autism, ages 6-36 months. Children were grouped as: ASD identified by 14 months, ASD identified after 14 months, and no ASD. Despite groups' initial similar developmental level at 6 months, ASD groups exhibited atypical trajectories thereafter. Impairment from 14 to 24 months was greater in the Early-ASD than the Later-ASD group, but comparable at 36 months. Developmental plateau and regression occurred in some children with ASD, regardless of timing of ASD diagnosis. Findings indicate a preclinical phase of varying duration for ASD. PMID- 23110515 TI - Dengue vector management using insecticide treated materials and targeted interventions on productive breeding-sites in Guatemala. AB - BACKGROUND: In view of the epidemiological expansion of dengue worldwide and the availability of new tools and strategies particularly for controlling the primary dengue vector Aedes aegypti, an intervention study was set up to test the efficacy, cost and feasibility of a combined approach of insecticide treated materials (ITMs) alone and in combination with appropriate targeted interventions of the most productive vector breeding-sites. METHODS: The study was conducted as a cluster randomized community trial using "reduction of the vector population" as the main outcome variable. The trial had two arms: 10 intervention clusters (neighborhoods) and 10 control clusters in the town of Poptun Guatemala. Activities included entomological assessments (characteristics of breeding-sites, pupal productivity, Stegomyia indices) at baseline, 6 weeks after the first intervention (coverage of window and exterior doorways made of PermaNet 2.0 netting, factory treated with deltamethrin at 55 mg/m2, and of 200 L drums with similar treated material) and 6 weeks after the second intervention (combination of treated materials and other suitable interventions targeting productive breeding-sites i.e larviciding with Temephos, elimination etc.). The second intervention took place 17 months after the first intervention. The insecticide residual activity and the insecticidal content were also studied at different intervals. Additionally, information about demographic characteristics, cost of the intervention, coverage of houses protected and satisfaction in the population with the interventions was collected. RESULTS: At baseline (during the dry season) a variety of productive container types for Aedes pupae were identified: various container types holding >20 L, 200 L drums, washbasins and buckets (producing 83.7% of all pupae). After covering 100% of windows and exterior doorways and a small number of drums (where the commercial cover could be fixed) in 970 study households, tropical rains occurred in the area and lead to an increase of the vector population, more pronounced (but statistically not significant) in the control arm than in the intervention arm. In the second intervention (17 months later and six weeks after implementing the second intervention) the combined approach of ITMs and a combination of appropriate interventions against productive containers (Temephos in >200 L water drums, elimination of small discarded tins and bottles) lead to significant differences on reductions of the total number of pupae (P = 0.04) and the House index (P = 0.01) between intervention and control clusters, and to borderline differences on reductions of the Pupae per Person and Breteau indices (P = 0.05). The insecticide residual activity on treated curtains was high until month 18 but the chemical concentration showed a high variability. The cost per house protected with treated curtains and drum covers and targeting productive breeding-sites of the dengue vector was $ 5.31 USD. The acceptance of the measure was generally high, particularly in families who had experienced dengue. CONCLUSION: Even under difficult environmental conditions (open houses, tropical rainfall, challenging container types mainly in the peridomestic environment) the combination of insecticide treated curtains and to a less extent drum covers and interventions targeting the productive container types can reduce the dengue vector population significantly. PMID- 23110516 TI - [Actinic keratoses]. PMID- 23110519 TI - Changes of inflammatory cytokines and neurotrophins emphasized their roles in hypoxic-ischemic brain damage. AB - Inflammatory cytokines and neurotrophins play crucial roles in hypoxic-ischemic brain damage (HIBD), but the expression changes of these proteins had not been systematically studied. In this article, we compared the levels of tumor necrosis factor alpha (TNF-alpha), intercellular adhesion molecule-1 (ICAM-1), interleukin 1beta (IL-1beta), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) in the progression of HIBD and analyzed their correlations with apoptosis. Seven-day-old pups of Sprague Dawley rats (n = 120) were randomly divided into two groups: the sham-operated (control) group and the hypoxia ischemia (HI) group. To establish the hypoxic-ischemic encephalopathy model, the pups from the HI group were subjected to left common carotid artery ligation followed by exposure to 8% O2 and 92% N2 for 2.5 hr. Pups from both the groups were sacrificed at 6, 24, 48, 72 hr and 7 days after hypoxia. The levels of TNF alpha, ICAM-1, IL-1beta, NGF, and BDNF in the brain tissues were measured by enzyme-linked immunosorbent assay. The neuronal apoptosis was examined by flow cytometry. We found that the levels of TNF-alpha, ICAM-1, IL-1beta, NGF, BDNF, and neuronal apoptosis rate in neonatal rats with HIBD significantly increased at 6, 24, 48, and 72 hr after hypoxia compared to the control group (p < .05) and returned back to normal by 7 days. Furthermore, neuronal apoptosis rate was positively correlated with the levels of TNF-alpha, ICAM-1, and IL-1beta and negatively correlated with the levels of NGF and BDNF. In neonatal rats with HIBD, the brain reaches its peak levels of damage by 24-72 hr after the injury. Inflammatory cytokines such as TNF-alpha, ICAM-1, and IL-1beta contribute to neuronal apoptosis induced by HIBD, whereas neurotrophins NGF and BDNF antagonize it. PMID- 23110517 TI - Systemic inflammatory biomarkers and co-morbidities of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) can no longer be considered as a disease affecting only the lungs. Increasing evidence supports the presence of a systemic inflammatory component which is thought to provide the link between COPD and the co-morbidities commonly associated with this disease. These include cardiovascular disorders, skeletal muscle dysfunction, diabetes, and osteoporosis. The majority of current therapies for COPD have been developed to improve airway obstruction or to target airway inflammation, leaving an unmet medical need with respect to the systemic inflammatory component of COPD and its extra-pulmonary manifestations. This review describes systemic biomarkers in COPD and their relationship with both the local lung and systemic manifestations of the disease. A summary is provided of the most promising biomarkers that have been investigated in COPD and its co-morbidities. Such biomarkers may be used to assess and manage the systemic effects of COPD, and may guide future development of novel therapeutic interventions to provide a more holistic approach to treating this multi-faceted disease. PMID- 23110518 TI - Comparison of the OHIP-14 and GOHAI as measures of oral health among elderly in Lebanon. AB - BACKGROUND: The respective abilities of the GOHAI and OHIP-14 to discriminate between aged patients with different levels of oral diseases have rarely been studied in developing countries. The aim of this study was to compare the discriminative abilities of the OHIP-14 and the GOHAI in an elderly Lebanese population, and particularly to identify persons with different masticatory function. METHODS: A sample of elderly, aged 65 years or more, living independently was recruited in two primary care offices in Beirut, Lebanon. Data were collected by means of personal interview and clinical examination. The Arabic OHIP-14 and GOHAI questionnaires were used after cultural adaptation for use in Lebanon. The internal consistency, reproducibility and concurrent validity were verified. To test their discriminative abilities, the ADD (GOHAI and OHIP) and SC (GOHAI and OHIP) scores were dichotomized according to the 25th and 75th percentile respectively and logistic regressions were conducted using socio demographic, clinical and subjective explanatory variables. RESULTS: Two hundred and six participants were included; mean age was 72 years and 60% were women. Good psychometric properties were observed for both questionnaires for internal consistency (Cronbach's alpha>0.88), reproducibility (ICC>0.86) and concurrent validity. Strong correlations were found between GOHAI and OHIP-14 scores but a high prevalence of subjects with no impact was observed using the OHIP-14. Both questionnaires were able to discriminate between participants according to age, perception of temporomandibular joint (TMJ) pain or functional status as represented by the number of dental Functional Units (FU). GOHAI was more discriminant since it identified participants with high dental care needs: high numbers of decayed teeth, low numbers of teeth and socially deprived status. CONCLUSIONS: Lebanese elderly with high dental care needs and impaired oral health were identified more easily with the GOHAI. These results may guide the choice of dental indicators to use in a national geriatric survey. PMID- 23110520 TI - The Kid-Short Marfan Score (Kid-SMS) - an easy executable risk score for suspected paediatric patients with Marfan syndrome. AB - AIM: Due to age-dependent manifestations, diagnosis of Marfan syndrome (MFS) in children and adolescents is sophisticated. Although revised Ghent criteria is a major step forward, its utility in children is still restricted due to expensive and technically advanced diagnostics. As early diagnosis submits long-term benefits concerning prognosis, the need of an appropriate diagnostic tool for risk stratification of suspected paediatric patients with Marfan is justified. METHODS AND RESULTS: Sixty paediatric patients with Marfan were subject to a standardized diagnostic programme. All clinical symptoms of the revised Ghent nosology were analysed concerning age at first clinical manifestation, prevalence and likelihood ratio for MFS. Symptoms with early onset, high prevalence and high positive likelihood ratio were identified and combined for a risk score called Kid-Short Marfan Score (Kid-SMS). Three risk categories for suspicion of Marfan syndrome were developed. Finally, the Kid-SMS was operated in 130 paediatric patients with suspected MFS. Kid-SMS identified significantly more suspected patients with Marfan compared with Ghent nosology, revised Ghent and genetics alone without oversensitivity. CONCLUSION: Whereas diagnosis of MFS in childhood is sophisticated, Kid-SMS is a useful tool for risk stratification of suspected paediatric patients with Marfan by easy executable diagnostics, especially for paediatricians and paediatric cardiologists. PMID- 23110521 TI - Diethylstilbestrol in castration-resistant prostate cancer. PMID- 23110522 TI - Large-scale production of edge-selectively functionalized graphene nanoplatelets via ball milling and their use as metal-free electrocatalysts for oxygen reduction reaction. AB - Edge-selectively functionalized graphene nanoplatelets (EFGnPs) with different functional groups were efficiently prepared simply by dry ball milling graphite in the presence of hydrogen, carbon dioxide, sulfur trioxide, or carbon dioxide/sulfur trioxide mixture. Upon exposure to air moisture, the resultant hydrogen- (HGnP), carboxylic acid- (CGnP), sulfonic acid- (SGnP), and carboxylic acid/sulfonic acid- (CSGnP) functionalized GnPs readily dispersed into various polar solvents, including neutral water. The resultant EFGnPs were then used as electrocatalysts for oxygen reduction reaction (ORR) in an alkaline electrolyte. It was found that the edge polar nature of the newly prepared EFGnPs without heteroatom doping into their basal plane played an important role in regulating the ORR efficiency with the electrocatalytic activity in the order of SGnP > CSGnP > CGnP > HGnP > pristine graphite. More importantly, the sulfur-containing SGnP and CSGnP were found to have a superior ORR performance to commercially available platinum-based electrocatalyst. PMID- 23110524 TI - PAI-1 and t-PA/PAI-1 complex potential markers of fibrinolytic bleeding after cardiac surgery employing cardiopulmonary bypass. AB - BACKGROUND: Enhanced bleeding remains a serious problem after cardiac surgery, and fibrinolysis is often involved. We speculate that lower plasma concentrations of plasminogen activator inhibitor - 1 (PAI-1) preoperatively and tissue plasminogen activator/PAI-1 (t-PA/PAI-1) complex postoperatively might predispose for enhanced fibrinolysis and increased postoperative bleeding. METHODS: Totally 88 adult patients (mean age 66 +/- 10 years) scheduled for cardiac surgery, were enrolled into a prospective study. Blood samples were collected pre-operatively, on admission to the recovery and at 6 and 24 hours postoperatively. Patients with a surgical bleeding that was diagnosed during reoperation were discarded from the study. The patients were allocated to two groups depending on the 24-hour postoperative chest tube drainage (CTD): Group I > 500ml, Group II <= 500ml. Associations between CTD, PAI-1, t-PA/PAI-1 complex and D-dimer were analyzed with SPSS. RESULTS: Nine patients were excluded because of surgical bleeding. Of the 79 remaining patients, 38 were allocated to Group I and 41 to Group II. The CTD volumes correlated with the preoperative plasma levels of PAI-1 (r = - 0.3, P = 0.009). Plasma concentrations of preoperative PAI-1 and postoperative t-PA/PAI 1 complex differed significantly between the groups (P < 0.001 and P = 0.012, respectively). Group I displayed significantly lower plasma concentrations of fibrinogen and higher levels of D-dimer from immediately after the operation and throughout the first 24 hours postoperatively. CONCLUSIONS: Lower plasma concentrations of PAI-1 preoperatively and t-PA/PAI-1 complex postoperatively leads to higher plasma levels of D-dimer in association with more postoperative bleeding after cardiac surgery. PMID- 23110523 TI - Identification of PADI2 as a potential breast cancer biomarker and therapeutic target. AB - BACKGROUND: We have recently reported that the expression of peptidylarginine deiminase 2 (PADI2) is regulated by EGF in mammary cancer cells and appears to play a role in the proliferation of normal mammary epithelium; however, the role of PADI2 in the pathogenesis of human breast cancer has yet to be investigated. Thus, the goals of this study were to examine whether PADI2 plays a role in mammary tumor progression, and whether the inhibition of PADI activity has anti tumor effects. METHODS: RNA-seq data from a collection of 57 breast cancer cell lines was queried for PADI2 levels, and correlations with known subtype and HER2/ERBB2 status were evaluated. To examine PADI2 expression levels during breast cancer progression, the cell lines from the MCF10AT model were used. The efficacy of the PADI inhibitor, Cl-amidine, was tested in vitro using MCF10DCIS cells grown in 2D-monolayers and 3D-spheroids, and in vivo using MCF10DCIS tumor xenografts. Treated MCF10DCIS cells were examined by flow-cytometry to determine the extent of apoptosis and by RT2 Profiler PCR Cell Cycle Array to detect alterations in cell cycle associated genes. RESULTS: We show by RNA-seq that PADI2 mRNA expression is highly correlated with HER2/ERBB2 (p = 2.2 * 106) in luminal breast cancer cell lines. Using the MCF10AT model of breast cancer progression, we then demonstrate that PADI2 expression increases during the transition of normal mammary epithelium to fully malignant breast carcinomas, with a strong peak of PADI2 expression and activity being observed in the MCF10DCIS cell line, which models human comedo-DCIS lesions. Next, we show that a PADI inhibitor, Cl-amidine, strongly suppresses the growth of MCF10DCIS monolayers and tumor spheroids in culture. We then carried out preclinical studies in nude (nu/nu) mice and found that Cl-amidine also suppressed the growth of xenografted MCF10DCIS tumors by more than 3-fold. Lastly, we performed cell cycle array analysis of Cl-amidine treated and control MCF10DCIS cells, and found that the PADI inhibitor strongly affects the expression of several cell cycle genes implicated in tumor progression, including p21, GADD45alpha, and Ki67. CONCLUSION: Together, these results suggest that PADI2 may function as an important new biomarker for HER2/ERBB2+ tumors and that Cl-amidine represents a new candidate for breast cancer therapy. PMID- 23110525 TI - Risk trade-offs in fish consumption: a public health perspective. AB - Fish consumption advisories instruct vulnerable consumers to avoid high mercury fish and to limit total fish intake to reduce neurotoxic risk. Consumption data from the U.S. suggest that nontarget consumers also respond to such advice. These consumers reduce exposure to mercury and other toxicants at the cost of reduction in cardioprotective fatty acids. We present a probabilistic model to assess these risk trade-offs. We use NHANES consumption data to simulate exposure to contaminants and nutrients in fish, employ dose-response relationships to convert exposure to health end points, and monetize them using benefit transfer. Our results suggest that newborns gained on average 0.033 IQ points from their mothers' compliance with the prominent FDA/EPA advisory. The welfare gain for a birth cohort is estimated at $386 million. This gain could be fully offset by increments in cardiovascular risk if 0.6% of consumers aged 40 and older reduced fish intake by one monthly meal until they reached the age of 60 or if 0.1% of them permanently reduced fish intake. PMID- 23110526 TI - The effect of RAD allele dropout on the estimation of genetic variation within and between populations. AB - Inexpensive short-read sequencing technologies applied to reduced representation genomes is revolutionizing genetic research, especially population genetics analysis, by allowing the genotyping of massive numbers of single-nucleotide polymorphisms (SNP) for large numbers of individuals and populations. Restriction site-associated DNA (RAD) sequencing is a recent technique based on the characterization of genomic regions flanking restriction sites. One of its potential drawbacks is the presence of polymorphism within the restriction site, which makes it impossible to observe the associated SNP allele (i.e. allele dropout, ADO). To investigate the effect of ADO on genetic variation estimated from RAD markers, we first mathematically derived measures of the effect of ADO on allele frequencies as a function of different parameters within a single population. We then used RAD data sets simulated using a coalescence model to investigate the magnitude of biases induced by ADO on the estimation of expected heterozygosity and F(ST) under a simple demographic model of divergence between two populations. We found that ADO tends to overestimate genetic variation both within and between populations. Assuming a mutation rate per nucleotide between 10(-9) and 10(-8), this bias remained low for most studied combinations of divergence time and effective population size, except for large effective population sizes. Averaging F(ST) values over multiple SNPs, for example, by sliding window analysis, did not correct ADO biases. We briefly discuss possible solutions to filter the most problematic cases of ADO using read coverage to detect markers with a large excess of null alleles. PMID- 23110529 TI - Freely available software programs for drug discovery. PMID- 23110528 TI - Incorporation of natural uncultivable Legionella pneumophila into potable water biofilms provides a protective niche against chlorination stress. AB - Legionella pneumophila is a waterborne pathogen that has been isolated sporadically from drinking water distribution systems (DWDS). Resistance to disinfectants is mainly attributed to the association of cells with amoebae, but biofilms are also thought to provide some degree of protection. In the present work, a two-stage chemostat was used to form heterotrophic biofilms from drinking water to study the influence of chlorine on the presence of naturally occurring L. pneumophila. The pathogen was tracked in planktonic and sessile biofilm phases using standard culture recovery techniques for cultivable cells and a peptide nucleic acid fluorescence in situ hybridisation assay for total cells. The results showed that the total number of L. pneumophila cells in biofilms was not affected by the concentrations of chlorine tested, and the presence of L. pneumophila could not be detected by culturing. To restrict the outbreaks of disease caused by this bacterium, efforts need to be concentrated on preventing L. pneumophila from re-entering an infectious state by maintaining residual disinfectant levels through the entire DWDS network so that the resuscitation of cells via contact with amoebae is prevented. PMID- 23110527 TI - Regression of vascular calcification in chronic kidney disease - feasible or fantasy? a review of the clinical evidence. AB - The complex relationships between cardiovascular, renal, and bone disease are increasingly recognized but not yet clearly understood. Vascular calcification (VC) represents a common end point between these interlinked systems. It is highly prevalent in chronic kidney disease (CKD) and may be responsible for some of the excess cardiovascular events seen in this condition. There is much interest in developing therapeutic agents to stop its development or reverse its progression. Traditionally considered to be due to abnormalities in calcium and phosphate metabolism alone, VC is now known to be the product of active, dynamic processes within the vessel wall. Primary prevention of VC is possible through successful prevention or reversal of progressive renal dysfunction, hypertension and hyperlipidaemia, but is challenging given the increasing global prevalence of these risk factors. Secondary prevention of VC through tight control of calcium and phosphate, can be achieved by dietary or pharmacological means. Both the modification of haemodialysis duration or methods and the use of renal transplantation have an effect. Novel drugs such as cinacalcet were hoped to halt calcification but results have been mixed, and no intervention has yet been shown to reverse calcification reliably. A new range of experimental targets involved in the putative mediatory pathways between bone and vascular disease has emerged. Aiming to manipulate the active mechanisms involved in calcium deposition, these hold hope for reversal of calcification, but are still theoretical or in early animal or human experimentation. PMID- 23110531 TI - The use of the R language for medicinal chemistry applications. AB - This manuscript serves as a review of how the R language has been used in the last decade to address problems related to medicinal chemistry design. This includes the use of the R language for chemoinformatics applications and interfaces, as well as statistical modeling for ADMET and potency endpoints. Additionally, a few examples of R code are provided to demonstrate the ability of this language to make available cutting-edge statistical analysis to the medicinal chemistry design community. PMID- 23110530 TI - A survey of quantitative descriptions of molecular structure. AB - Numerical characterization of molecular structure is a first step in many computational analysis of chemical structure data. These numerical representations, termed descriptors, come in many forms, ranging from simple atom counts and invariants of the molecular graph to distribution of properties, such as charge, across a molecular surface. In this article we first present a broad categorization of descriptors and then describe applications and toolkits that can be employed to evaluate them. We highlight a number of issues surrounding molecular descriptor calculations such as versioning and reproducibility and describe how some toolkits have attempted to address these problems. PMID- 23110532 TI - Drug discovery applications for KNIME: an open source data mining platform. AB - Technological advances in high-throughput screening methods, combinatorial chemistry and the design of virtual libraries have evolved in the pursuit of challenging drug targets. Over the last two decades a vast amount of data has been generated within these fields and as a consequence data mining methods have been developed to extract key pieces of information from these large data pools. Much of this data is now available in the public domain. This has been helpful in the arena of drug discovery for both academic groups and for small to medium sized enterprises which previously would not have had access to such data resources. Commercial data mining software is sometimes prohibitively expensive and the alternate open source data mining software is gaining momentum in both academia and in industrial applications as the costs of research and development continue to rise. KNIME, the Konstanz Information Miner, has emerged as a leader in open source data mining tools. KNIME provides an integrated solution for the data mining requirements across the drug discovery pipeline through a visual assembly of data workflows drawing from an extensive repository of tools. This review will examine KNIME as an open source data mining tool and its applications in drug discovery. PMID- 23110533 TI - Open source drug discovery with bioclipse. AB - We present the open source components for drug discovery that has been developed and integrated into the graphical workbench Bioclipse. Building on a solid open source cheminformatics core, Bioclipse has advanced functionality for managing and visualizing chemical structures and related information. The features presented here include QSAR/QSPR modeling, various predictive solutions such as decision support for chemical liability assessment, site-ofmetabolism prediction, virtual screening, and knowledge discovery and integration. We demonstrate the utility of the described tools with examples from computational pharmacology, toxicology, and ADME. Bioclipse is used in both academia and industry, and is a good example of open source leading to new solutions for drug discovery. PMID- 23110534 TI - Chemical landscape analysis with the OpenTox framework. AB - The Structure-Activity Relationships (SAR) landscape and activity cliffs concepts have their origins in medicinal chemistry and receptor-ligand interactions modelling. While intuitive, the definition of an activity cliff as a "pair of structurally similar compounds with large differences in potency" is commonly recognized as ambiguous. This paper proposes a new and efficient method for identifying activity cliffs and visualization of activity landscapes. The activity cliffs definition could be improved to reflect not the cliff steepness alone, but also the rate of the change of the steepness. The method requires explicitly setting similarity and activity difference thresholds, but provides means to explore multiple thresholds and to visualize in a single map how the thresholds affect the activity cliff identification. The identification of the activity cliffs is addressed by reformulating the problem as a statistical one, by introducing a probabilistic measure, namely, calculating the likelihood of a compound having large activity difference compared to other compounds, while being highly similar to them. The likelihood is effectively a quantification of a SAS Map with defined thresholds. Calculating the likelihood relies on four counts only, and does not require the pairwise matrix storage. This is a significant advantage, especially when processing large datasets. The method generates a list of individual compounds, ranked according to the likelihood of their involvement in the formation of activity cliffs, and goes beyond characterizing cliffs by structure pairs only. The visualisation is implemented by considering the activity plane fixed and analysing the irregularities of the similarity itself. It provides a convenient analogy to a topographic map and may help identifying the most appropriate similarity representation for each specific SAR space. The proposed method has been applied to several datasets, representing different biological activities. Finally, the method is implemented as part of an existing open source Ambit package and could be accessed via an OpenTox API compliant web service and via an interactive application, running within a modern, JavaScript enabled web browser. Combined with the functionalities already offered by the OpenTox framework, like data sharing and remote calculations, it could be a useful tool for exploring chemical landscapes online. PMID- 23110536 TI - GAMESS as a free quantum-mechanical platform for drug research. AB - Driven by a steady improvement of computational hardware and significant progress in ab initio method development, quantum-mechanical approaches can now be applied to large biochemical systems and drug design. We review the methods implemented in GAMESS, which are suitable to calculate large biochemical systems. An emphasis is put on the fragment molecular orbital method (FMO) and quantum mechanics interfaced with molecular mechanics (QM/MM). The use of FMO in the protein-ligand binding, structure-activity relationship (SAR) studies, fragment- and structure based drug design (FBDD/SBDD) is discussed in detail. PMID- 23110535 TI - Rational prediction with molecular dynamics for hit identification. AB - Although the motions of proteins are fundamental for their function, for pragmatic reasons, the consideration of protein elasticity has traditionally been neglected in drug discovery and design. This review details protein motion, its relevance to biomolecular interactions and how it can be sampled using molecular dynamics simulations. Within this context, two major areas of research in structure-based prediction that can benefit from considering protein flexibility, binding site detection and molecular docking, are discussed. Basic classification metrics and statistical analysis techniques, which can facilitate performance analysis, are also reviewed. With hardware and software advances, molecular dynamics in combination with traditional structure-based prediction methods can potentially reduce the time and costs involved in the hit identification pipeline. PMID- 23110537 TI - Comparison of X-chromosome inactivation in Duchenne muscle/myocardium-manifesting carriers, non-manifesting carriers and related daughters. AB - Female carriers of Duchenne muscular dystrophy (DMD) are usually asymptomatic. However, 2.5-7.8% of them may present muscle symptoms and cardiomyopathy, attributed to a reduced production of dystrophin, probably because of skewed patterns of X-chromosome inactivation (XCI). To evaluate the role of XCI in symptomatic (at muscle or heart level) and asymptomatic DMD carriers, 44 subjects were selected from our database (12 manifesting, 21 non-manifesting, 11 healthy females), and XCI pattern determined in the lymphocytes by the androgen receptor methylation-based assay. The results showed that DMD-manifesting carriers had a preferential inactivation of the X-chromosome carrying the normal allele, while non-manifesting carriers and healthy females showed a random XCI pattern. Moreover, when comparing muscle with heart manifesting carriers, the former group showed a higher degree of skewing. No concordance in XCI was found between mothers and daughters, when symptomatic/asymptomatic mother-daughter pairs were analyzed. The results confirm that DMD clinical manifestations in carriers are associated with non-random patterns of X inactivation. PMID- 23110538 TI - Genome-wide association study of insect bite hypersensitivity in two horse populations in the Netherlands. AB - BACKGROUND: Insect bite hypersensitivity is a common allergic disease in horse populations worldwide. Insect bite hypersensitivity is affected by both environmental and genetic factors. However, little is known about genes contributing to the genetic variance associated with insect bite hypersensitivity. Therefore, the aim of our study was to identify and quantify genomic associations with insect bite hypersensitivity in Shetland pony mares and Icelandic horses in the Netherlands. METHODS: Data on 200 Shetland pony mares and 146 Icelandic horses were collected according to a matched case-control design. Cases and controls were matched on various factors (e.g. region, sire) to minimize effects of population stratification. Breed-specific genome-wide association studies were performed using 70 k single nucleotide polymorphisms genotypes. Bayesian variable selection method Bayes-C with a threshold model implemented in GenSel software was applied. A 1 Mb non-overlapping window approach that accumulated contributions of adjacent single nucleotide polymorphisms was used to identify associated genomic regions. RESULTS: The percentage of variance explained by all single nucleotide polymorphisms was 13% in Shetland pony mares and 28% in Icelandic horses. The 20 non-overlapping windows explaining the largest percentages of genetic variance were found on nine chromosomes in Shetland pony mares and on 14 chromosomes in Icelandic horses. Overlap in identified associated genomic regions between breeds would suggest interesting candidate regions to follow-up on. Such regions common to both breeds (within 15 Mb) were found on chromosomes 3, 7, 11, 20 and 23. Positional candidate genes within 2 Mb from the associated windows were identified on chromosome 20 in both breeds. Candidate genes are within the equine lymphocyte antigen class II region, which evokes an immune response by recognizing many foreign molecules. CONCLUSIONS: The genome-wide association study identified several genomic regions associated with insect bite hypersensitivity in Shetland pony mares and Icelandic horses. On chromosome 20, associated genomic regions in both breeds were within 2 Mb from the equine lymphocyte antigen class II region. Increased knowledge on insect bite hypersensitivity associated genes will contribute to our understanding of its biology, enabling more efficient selection, therapy and prevention to decrease insect bite hypersensitivity prevalence. PMID- 23110540 TI - Toward the development of decision supporting tools that can be used for safe production and use of nanomaterials. AB - Although researchers have intentionally produced and used nanomaterials for more than a century, nanotechnology has made its mark in most areas of daily life in the past 20 years. Now thousands of products contain nanoparticles, nanofibers, or nanostructured parts. Because some chemical products have caused severe problems to human health and to the environment, we should consider the overall biological and toxicological effects of nanomaterials as we decide whether to use them in various products. We should also reflect on the mechanisms for making these decisions, which may greatly influence the development, production, and use of such products. The preselection of appropriate materials during the early product design state should allow industry and applied researchers to mitigate the risks of these new materials. However, currently the human and ecological risks of the applied nanomaterials during their life cycle are unknown. A large set of physicochemical characteristics can determine the potential human and environmental exposure to and hazards from nanomaterials. Thus, researchers will need many years to gather and analyze all the data to perform a comprehensive risk assessment for engineered nanomaterials and to develop a sound decision making process. The ideal risk assessment approach would include cost-effective screening processes to target resources toward the risks of greatest concern. The outcome of the risk assessment is only as good as the quality of the data used. Unfortunately, the actual review process of most journals that publish on nanotoxicology focuses on "mechanistic studies and results" rather than a toxicologically relevant outcome. For example, journals often do not include studies that show no effect as worthy of publication ("no-effect-studies" dilemma), which can lead to misleading interpretations of toxicological data for hazard identification. However, even with insufficient data sets, researchers can produce a preliminary comparable risk assessment ("approximate" risk assessment). Researchers have already performed risk-based evaluations of nanomaterials grounded on the comparison of exposure concentrations with no-effect levels (as required for chemical risk assessment), examining generic nanomaterials such as "nano-TiO2" but not specific forms or modifications. Even though these data sets on hazard and exposure are incomplete, they already provide the basis to illustrate the current state of knowledge and uncertainties. Therefore industry and applied researchers can calculate the probability that an adverse effect might occur and begin to balance the benefits and potential risks of an innovation. Based on the increasing numbers of nanotoxicology publications and funding programs, this Account reviews the decision support approaches that already exist to safely implement engineered nanomaterials during an early phase of innovation. PMID- 23110539 TI - Fenugreek extract as an inducer of cellular death via autophagy in human T lymphoma Jurkat cells. AB - BACKGROUND: Drugs used both in classical chemotherapy and the more recent targeted therapy do not have cancer cell specificity and, hence, cause severe systemic side effects. Tumors also develop resistance to such drugs due to heterogeneity of cell types and clonal selection. Several traditional dietary ingredients from plants, on the other hand, have been shown to act on multiple targets/pathways, and may overcome drug resistance. The dietary agents are safe and readily available. However, application of plant components for cancer treatment/prevention requires better understanding of anticancer functions and elucidation of their mechanisms of action. The current study focuses on the anticancer properties of fenugreek, a herb with proven anti-diabetic, antitumor and immune-stimulating functions. METHOD: Jurkat cells were incubated with 30 to 1500 MUg/mL concentrations of 50% ethanolic extract of dry fenugreek seeds and were followed for changes in viability (trypan blue assay), morphology (microscopic examination) and autophagic marker LC3 transcript level (RT-PCR). RESULTS: Incubation of Jurkat cells with fenugreek extract at concentrations ranging from 30 to 1500 MUg/mL for up to 3 days resulted in cell death in a dose- and time-dependent manner. Jurkat cell death was preceded by the appearance of multiple large vacuoles, which coincided with transcriptional up-regulation of LC3. GC-MS analysis of fenugreek extract indicated the presence of several compounds with anticancer properties, including gingerol (4.82%), cedrene (2.91%), zingerone (16.5%), vanillin (1.52%) and eugenol (1.25%). CONCLUSIONS: Distinct morphological changes involving appearance of large vacuoles, membrane disintegration and increased expression of LC3 transcripts indicated that fenugreek extract induced autophagy and autophagy-associated death of Jurkat cells. In addition to the already known apoptotic activation, induction of autophagy may be an additional mechanism underlying the anticancer properties of fenugreek. This is the first report showing fenugreek as an inducer of autophagy in human cells and further work is needed to define the various intermediates of the autophagic pathway. PMID- 23110542 TI - Retraction: Surfactant lavage therapy for respiratory deterioration in extremely premature infants. PMID- 23110543 TI - Effect of aging and human immunodeficiency virus infection on cognitive abilities. AB - OBJECTIVES: To explore the combined effects of aging and human immunodeficiency virus (HIV) infection on cognitive decay. DESIGN: Cross-sectional, single-cohort study. SETTING: Institute of Clinical Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy. PARTICIPANTS: One hundred fifty-three asymptomatic HIV-positive (HIV+) outpatients (20% aged >= 60) and an age- and education matched control population of 39 HIV-negative individuals. MEASUREMENTS: A neuropsychological investigation was conducted to compare four groups of participants classified on the basis of HIV serostatus and age (<60 vs >= 60). The effects of age and HIV infection on neuropsychological performance were analyzed using a two-by-two factorial analysis of variance. Demographic and clinical variables associated with neuropsychological performance were identified using linear regression analysis in the HIV+ population. RESULTS: HIV infection and aging had significant negative effects on cognitive performance, but no significant interaction was observed between these two factors. Although older HIV+ participants had worse cognitive performance, they showed no distinct cognitive pattern from younger HIV+ participants. Moreover, younger HIV+ participants' performance on memory tasks was qualitatively and quantitatively comparable with that of older HIV- participants, despite the dramatic age difference. CONCLUSION: Aging and HIV might be additive factors in the expression of cognitive decline. As the HIV+ population ages, routine neuropsychological examinations could help clinicians better understand and manage the expression of cognitive impairment. PMID- 23110541 TI - The evidence-policy divide: a 'critical computational linguistics' approach to the language of 18 health agency CEOs from 9 countries. AB - BACKGROUND: There is an emerging body of literature suggesting that the evidence practice divide in health policy is complex and multi-factorial but less is known about the processes by which health policy-makers use evidence and their views about the specific features of useful evidence. This study aimed to contribute to understandings of how the most influential health policy-makers view useful evidence, in ways that help explore and question how the evidence-policy divide is understood and what research might be supported to help overcome this divide. METHODS: A purposeful sample of 18 national and state health agency CEOs from 9 countries was obtained. Participants were interviewed using open-ended questions that asked them to define specific features of useful evidence. The analysis involved two main approaches 1)quantitative mapping of interview transcripts using Bayesian-based computational linguistics software 2)qualitative critical discourse analysis to explore the nuances of language extracts so identified. RESULTS: The decision-making, conclusions-oriented world of policy-making is constructed separately, but not exclusively, by policy-makers from the world of research. Research is not so much devalued by them as described as too technical- yet at the same time not methodologically complex enough to engage with localised policy-making contexts. It is not that policy-makers are negative about academics or universities, it is that they struggle to find complexity-oriented methodologies for understanding their stakeholder communities and improving systems. They did not describe themselves as having a more positive role in solving this challenge than academics. CONCLUSIONS: These interviews do not support simplistic definitions of policy-makers and researchers as coming from two irreconcilable worlds. They suggest that qualitative and quantitative research is valued by policy-makers but that to be policy-relevant health research may need to focus on building complexity-oriented research methods for local community health and service development. Researchers may also need to better explain and develop the policy-relevance of large statistical generalisable research designs. Policy-makers and public health researchers wanting to serve local community needs may need to be more proactive about questioning whether the dominant definitions of research quality and the research funding levers that drive university research production are appropriately inclusive of excellence in such policy-relevant research. PMID- 23110544 TI - Incidental renal stones in potential live kidney donors: prevalence, assessment and donation, including role of ex vivo ureteroscopy. AB - WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Previously, donors with asymptomatic stones found incidentally on CT were not considered ideal donor candidates because of the presumed risk of morbidity to both the donor and recipient. Increasingly, studies show that these risks are low. This study aims to evaluate the long-term safety of using ex vivo ureteroscopy to remove the stones from the donor kidney on the bench before donation. Outcomes so far suggest that this technique can safely render a kidney stone-free before transplantation. This has led to 20 more transplants in our institution than would otherwise be possible. OBJECTIVES: To evaluate the prevalence of asymptomatic renal stones in our potential donor population. To assess the safety and success of ex vivo ureteroscopy (ExURS) to remove stones from explanted donor kidneys before transplantation. PATIENTS AND METHODS: We conducted a retrospective analysis of 377 computed tomography (CT) angiograms of potential kidney donors between October 2004 and May 2007 to assess the prevalence of asymptomatic renal stones in our donor population. Between October 2005 and October 2011, kidneys from suitable donors underwent ExURS. Stones were removed using basket extraction or were fragmented with holmium laser on bench before transplantation. Immediate and long-term complications of the transplanted recipients were recorded. Donors were followed with yearly ultrasonography of the remaining kidney in addition to standard follow-up protocol. RESULTS: Review of 377 CT angiograms between October 2004 to May 2007 showed a 5% prevalence of asymptomatic renal stones. Out of 55 potential donors (19 identified between October 2004 to May 2007 and a further 36 identified since May 2007), 20 donors with stones proceeded to donation, with stone size ranging from 2 to 12 mm. Of the patients, 17 proceeded to ExURS. Stones were removed in 10 patients; five with basket retrieval, four with laser fragmentation and one with both laser fragmentation and basket retrieval. There were no early or late allograft stone related complications and no evidence of stones on follow-up imaging at a mean (range) of 10 (1-24) months. There has been no reported stone recurrence in any of the donors to date and no stone on ultrasonography of eight donors with >1 year follow-up (mean 26 months, range 12-49 months). CONCLUSIONS: Asymptomatic renal stones are present in 5% of our donors. ExURS can be safely used to remove stones in these kidneys before transplantation, without the risk of subjecting the donor to an additional stone-removing procedure. Continued long-term follow up of donors and recipients is still required to ensure the safety of this approach. PMID- 23110546 TI - Population trends in Pacific Oceanic sharks and the utility of regulations on shark finning. AB - Accurate assessment of shark population status is essential for conservation but is often constrained by limited and unreliable data. To provide a basis for improved management of shark resources, we analyzed a long-term record of species specific catches, sizes, and sexes of sharks collected by onboard observers in the western and central Pacific Ocean from 1995 to 2010. Using generalized linear models, we estimated population-status indicators on the basis of catch rate and biological indicators of fishing pressure on the basis of median size to identify trends for blue (Prionace glauca), mako (Isurus spp.), oceanic whitetip (Carcharhinus longimanus), and silky (Carcharhinus falciformis) sharks. Standardized catch rates of longline fleets declined significantly for blue sharks in the North Pacific (by 5% per year [CI 2% to 8%]), for mako sharks in the North Pacific (by 7% per year [CI 3% to 11%]), and for oceanic whitetip sharks in tropical waters (by 17% per year [CI 14% to 20%]). Median lengths of silky and oceanic whitetip sharks decreased significantly in their core habitat, and almost all sampled silky sharks were immature. Our results are consistent with results of analyses of similar data sets. Combined, these results and evidence of targeted fishing for sharks in some regional fisheries heighten concerns for sustainable utilization, particularly for oceanic whitetip and North Pacific blue sharks. Regional regulations that prohibit shark finning (removal of fins and discarding of the carcass) were enacted in 2007 and are in many cases the only form of control on shark catches. However, there is little evidence of a reduction of finning in longline fisheries. In addition, silky and oceanic whitetip sharks are more frequently retained than finned, which suggests that even full implementation of and adherence to a finning prohibition may not substantially reduce mortality rates for these species. We argue that finning prohibitions divert attention from assessing whether catch levels are sustainable and that the need for management of sharks should not be addressed by measures that are simple to implement but complex to enforce and evaluate. PMID- 23110547 TI - Occupational therapy assessments used in acute physical care settings. AB - OBJECTIVE: The aim of this study was to identify the assessments used by occupational therapists in acute care practice, their purpose, and the role of home visits and standardized tests. METHODS: A cross-sectional survey containing closed and open questions was sent to therapists working in physical acute care settings using convenience sampling. This article reports on the responses of 70 New Zealand occupational therapists (response rate = 74%). RESULTS: The study found that informal assessments (i.e. interviews and observations) were commonly used to evaluate daily living skills and to provide information about the home environment, cognition, transferring, leisure, and upper limb function. When situations were particularly complex, cognitive assessments and home visits were used judiciously to further investigate assumptions related to safety in discharge procedures. Standardized assessments were not widely used but were typically considered when cognitive ability needed to be confirmed. CONCLUSIONS: Occupational therapists' expertise lies in interviewing clients and in skilled observations of function. Standardized ADL assessments could complement occupational therapy practice but further research is needed to determine their value. In the final analysis, assessments should ensure that that both safety and client/carer concerns are at the centre of decision-making. PMID- 23110545 TI - Immunoglobulin E and mast cell proteases are potential risk factors of impaired fasting glucose and impaired glucose tolerance in humans. AB - AIM: Mast cells are important in experimental diabetes. Plasma levels of immunoglobulin E (IgE), tryptases, and chymases are inflammatory markers of human diabetes. Whether they also correlate with the risk of pre-diabetes, however, remains unknown. METHODS AND RESULTS: A total of 260 subjects 55-75 years of age were grouped as normal glucose tolerance (NGT), isolated impaired fasting glucose (I-IFG), isolated impaired glucose tolerance (I-IGT), and mixed IFG/IGT. There were significant differences in plasma levels of high-sensitivity C-reactive protein (hsCRP) (P < 0.001) and IgE (P = 0.003) among all subgroups of pre diabetes, and chymase in I-IGT (P = 0.043) and mixed IFG/IGT (P = 0.037) subgroups compared with NGT group. High-sensitivity CRP was a risk factor in all subgroups of pre-diabetes; IgE was a risk factor of mixed IFG/IGT; and chymase was a risk factor of I-IGT and mixed IFG/IGT. Interactions between hsCRP and high waist circumference (WC), waist-to-hip ratio (WHR), or HOMA-beta index, and interactions between IgE and high WC or tryptase levels all increased further the risk of developing I-IFG, I-IGT, or mixed IFG/IGT. CONCLUSION: Plasma hsCRP, IgE, and chymase levels associate with pre-diabetes status. While hsCRP, IgE, and chymase are individual risk factors of pre-diabetes, interactions with metabolic parameters increased further the risk of pre-diabetes. PMID- 23110548 TI - Antibacterial and water purification activities of self-assembled honeycomb structure of aerosol deposited titania film. AB - A simple and rapid room-temperature aerosol deposition method was used to fabricate TiO(2) films for photokilling/photdegradation applications. TiO(2) particles were accelerated to supersonic speeds and fractured upon impacting a glass substrate to form a functional thin film, a process known as aerosol deposition. After deposition, the films were annealed at various temperatures, and their photokilling/photodegradation performances following ultraviolet (UV) exposure were evaluated by counting the number of surviving bacterial colonies, and by a methylene blue decolorization test. The photocatalytic performances of all TiO(2) films were obtained under weak UV exposure (0.6 mW/cm(2)). The film density, crystalline phase, and surface roughness (morphology) were measured by scanning electron microscopy, X-ray diffraction, UV-visible spectroscopy, and atomic force microscopy. The unique, self-assembled honeycomb structure of the aerosol deposited films contributed to the increase in surface area because of extreme roughness, which enhances the photokilling and photodegradation performance. Nonannealed films yielded the best photocatalytic performance due to their small crystalline sizes and large surface areas due to increased surface roughness. PMID- 23110549 TI - The type and concentration of milk increase the in vitro bioaccessibility of coffee chlorogenic acids. AB - Coffee with different types and concentrations of milk was digested with pepsin (2 h) and pancreatin (2 h) to simulate gastropancreatic digestion. Chlorogenic acids (CGAs) were determined by high-performance liquid chromatography electrospray ionization-tandem mass spectrometry in ultrafiltrate (cutoff 3 kDa) to evaluate their bioaccessibility. After digestion, bioaccessible CGAs decreased from 80.2 to 53.0 and 69.5 MUmol/200 mL in coffee without milk and coffee-whole milk, respectively. When whole, semiskimmed, skimmed, or diluted milk were present, the increase in bioaccessibility was dependent on fat content (r = 0.99, p < 0.001). No relationship was observed between bioaccessibility and proteins, carbohydrates, and calcium content. The addition of milk to coffee caused an immediate decrease in the bioaccessibility due to CGAs binding to proteins. After digestion, 86-94% of bound CGAs remained in the high molecular weight fraction. Casein bound 5-caffeoylquinic acid with high affinity (K(D) of 37.9 +/- 2.3 MUmol/L; n = 0.88 +/- 0.06). PMID- 23110550 TI - Phenotype-dependent effects of EpCAM expression on growth and invasion of human breast cancer cell lines. AB - BACKGROUND: The epithelial cell adhesion molecule (EpCAM) has been shown to be overexpressed in breast cancer and stem cells and has emerged as an attractive target for immunotherapy of breast cancer patients. This study analyzes the effects of EpCAM on breast cancer cell lines with epithelial or mesenchymal phenotype. METHODS: For this purpose, shRNA-mediated knockdown of EpCAM gene expression was performed in EpCAMhigh breast cancer cell lines with epithelial phenotype (MCF-7, T47D and SkBR3). Moreover, EpCAMlow breast carcinoma cell lines with mesenchymal phenotype (MDA-MB-231, Hs578t) and inducible overexpression of EpCAM were used to study effects on proliferation, migration and in vivo growth. RESULTS: In comparison to non-specific silencing controls (n/s-crtl) knockdown of EpCAM (E#2) in EpCAMhigh cell lines resulted in reduced cell proliferation under serum-reduced culture conditions. Moreover, DNA synthesis under 3D culture conditions in collagen was significantly reduced. Xenografts of MCF-7 and T47D cells with knockdown of EpCAM formed smaller tumors that were less invasive. EpCAMlow cell lines with tetracycline-inducible overexpression of EpCAM showed no increased cell proliferation or migration under serum-reduced growth conditions. MDA-MB-231 xenografts with EpCAM overexpression showed reduced invasion into host tissue and more infiltrates of chicken granulocytes. CONCLUSIONS: The role of EpCAM in breast cancer strongly depends on the epithelial or mesenchymal phenotype of tumor cells. Cancer cells with epithelial phenotype need EpCAM as a growth- and invasion-promoting factor, whereas tumor cells with a mesenchymal phenotype are independent of EpCAM in invasion processes and tumor progression. These findings might have clinical implications for EpCAM-based targeting strategies in patients with invasive breast cancer. PMID- 23110551 TI - A multifunctional in situ-forming hydrogel for wound healing. AB - In this study, a multifunctional in situ-forming hydrogel (MISG) was prepared as a wound dressing designed to stop bleeding, inhibit inflammation, relieve pain, and improve healing. A mixture of poloxamers 407 and 188 was used for the matrix of the MISG. Other ingredients include aminocaproic acid (to stop bleeding), povidone iodine (anti-infective), lidocaine (pain relief), and chitosan (to enhance wound healing and regeneration). The incipient gelation temperature of the MISG was modified by varying the poloxamer concentration. Poloxamer cytotoxicity was evaluated in addition to the effect of the MISG on hemostasis in rabbits, pain relief in mice, bacteriostasis in vitro, and wound healing. The optimal MISG matrix consisted of 30% (w/v) poloxamer (407/188, 1 : 1, w/w) solution and was able to change to a gel within 10 minutes at 37 degrees C. The poloxamer solution had no cytotoxicity in fibroblasts. Compared to sterile gauze alone, the MISG significantly shortened average hemostasis time and decreased bleeding. The hydrogel showed strong bacteriostatic action similar to povidone iodine solution. It markedly increased the pain threshold and accelerated wound healing compared to the gauze. The MISG is a promising formulation for wound healing in emergency situations. PMID- 23110552 TI - Experience and analysis of Delphian lymph node metastasis in patients with papillary thyroid carcinoma. AB - BACKGROUND: Recently, lymph node metastasis (LNM) has been regarded as an important factor influencing loco-regional recurrence and survival rate in papillary thyroid cancer (PTC) patients. The aims of this study were to investigate the detection rate and metastasis rate of the Delphian lymph node (DLN) and clinical patterns related to regional LNM, and to examine how DLN metastasis affects PTC treatment. METHODS: We reviewed the medical records of 413 patients with pathologically confirmed PTC from among 452 patients who underwent thyroid surgery between January 2010 and October 2010 in the Department of Endocrine Surgery at Kosin University Gospel Hospital in Busan, South Korea. RESULTS: Multivariate analyses revealed a significantly higher proportion of cases with lymphovascular invasion (56.6% vs. 12.5%, P <0.001), central neck node metastasis (88.6% vs. 34.5%, P <0.001) and lateral neck node metastasis (47.2% vs. 10.2%, P <0.005) among cases with DLN metastasis compared to those without. The negative predictive value (NPV) of DLN metastasis with regard to the presence of contralateral central LNM for cases with a tumor size 1 cm or smaller than 1 cm was found to be 93.3% (127/136). CONCLUSION: When DLN metastasis is not detected in papillary thyroid microcarcinomas (PTMC), thyroid lobectomy on the affected side and ipsilateral central neck lymph node dissection should be sufficient. In addition, even in cases where lateral neck LNM is not detected on preoperative examination, if DLN metastasis is detected postoperatively, more careful attention should be paid to the lateral neck nodes during follow-up. PMID- 23110553 TI - Regio- and stereoselective synthesis of cyclic imidates via electrophilic cyclization of 2-(1-alkynyl)benzamides. A correction. AB - The electrophilic cyclization of 2-(1-alkynyl)benzamides affords high yields of cyclic imidates, instead of the previously reported isoindolin-1-ones, where cyclization proceeds on the oxygen of the carbonyl group rather than the nitrogen of the amide functionality. X-ray crystallography and spectroscopic techniques have been used to characterize the products. A correction is hereby provided in order to rectify the previous misassignment of structure. PMID- 23110554 TI - Differentiation of steroidogenic cells in the developing adrenal gland of Testudo hermanni Gmelin, 1789 (chelonian reptiles). AB - The aim of this study was to investigate the development and differentiation of steroidogenic cells in the embryonic adrenal gland of Testudo hermanni using histological, histochemical, immunohistochemical and ultrastructural methods. The 26 developmental stages were divided into three periods: early (stages 1-18, up to 20 days of incubation), intermediate (stages 19-22, incubation days 21-35) and advanced (stages 23-26, from incubation day 36 to hatching). A small presumptive bud of steroidogenic cells was visible at the end of the early period, protruding into the coelom from the lateral wall of intermediate mesoderm. Ultrastructural characteristics suggested that young and scarcely differentiated cells could already be able to perform steroidogenic activity: lipid droplets, large amount of SER and RER, small rounded mitochondria with variously shaped cristae and dense matrix. The cell membrane showed microvilli and coated pits. During the intermediate period, the interrenal bud deepened into the haemopoietic tissue, close to the mesonephros and the newly formed metanephros. The ultrastructural, immunohistochemical and immunocytochemical characteristics pointed to enhanced steroidogenic activity. The contact with both kidney types (mesonephros and metanephros) continued in the advanced period, and chromaffin cells were also extensively mixed with steroidogenic cells. This is a peculiar feature of chelonian adrenal gland, in comparison with that of other reptiles. The variable cytological characteristics of embryonic steroidogenic cells in the advanced period suggest a four-phase cycle of steroidogenic activity. PMID- 23110556 TI - Discriminative separation of gases by a "molecular trapdoor" mechanism in chabazite zeolites. AB - Separation of molecules based on molecular size in zeolites with appropriate pore aperture dimensions has given rise to the definition of "molecular sieves" and has been the basis for a variety of separation applications. We show here that for a class of chabazite zeolites, what appears to be "molecular sieving" based on dimension is actually separation based on a difference in ability of a guest molecule to induce temporary and reversible cation deviation from the center of pore apertures, allowing for exclusive admission of certain molecules. This new mechanism of discrimination permits "size-inverse" separation: we illustrate the case of admission of a larger molecule (CO) in preference to a smaller molecule (N(2)). Through a combination of experimental and computational approaches, we have uncovered the underlying mechanism and show that it is similar to a "molecular trapdoor". Our materials show the highest selectivity of CO(2) over CH(4) reported to date with important application to natural gas purification. PMID- 23110555 TI - Anti-Plasmodium falciparum invasion ligand antibodies in a low malaria transmission region, Loreto, Peru. AB - BACKGROUND: Erythrocyte invasion by Plasmodium falciparum is a complex process that involves two families; Erythrocyte Binding-Like (EBL) and the Reticulocyte Binding-Like (PfRh) proteins. Antibodies that inhibit merozoite attachment and invasion are believed to be important in mediating naturally acquired immunity and immunity generated by parasite blood stage vaccine candidates. The hypotheses tested in this study were 1) that antibody responses against specific P. falciparum invasion ligands (EBL and PfRh) differ between symptomatic and asymptomatic individuals living in the low-transmission region of the Peruvian Amazon and 2), such antibody responses might have an association, either direct or indirect, with clinical immunity observed in asymptomatically parasitaemic individuals. METHODS: ELISA was used to assess antibody responses (IgG, IgG1 and IgG3) against recombinant P. falciparum invasion ligands of the EBL (EBA-175, EBA 181, EBA-140) and PfRh families (PfRh1, PfRh2a, PfRh2b, PfRh4 and PfRh5) in 45 individuals infected with P. falciparum from Peruvian Amazon. Individuals were classified as having symptomatic malaria (N=37) or asymptomatic infection (N=8). RESULTS: Antibody responses against both EBL and PfRh family proteins were significantly higher in asymptomatic compared to symptomatic individuals, demonstrating an association with clinical immunity. Significant differences in the total IgG responses were observed with EBA-175, EBA-181, PfRh2b, and MSP119 (as a control). IgG1 responses against EBA-181, PfRh2a and PfRh2b were significantly higher in the asymptomatic individuals. Total IgG antibody responses against PfRh1, PfRh2a, PfRh2b, PfRh5, EBA-175, EBA-181 and MSP119 proteins were negatively correlated with level of parasitaemia. IgG1 responses against EBA-181, PfRh2a and PfRh2b and IgG3 response for PfRh2a were also negatively correlated with parasitaemia. CONCLUSIONS: These data suggest that falciparum malaria patients who develop clinical immunity (asymptomatic parasitaemia) in a low transmission setting such as the Peruvian Amazon have antibody responses to defined P. falciparum invasion ligand proteins higher than those found in symptomatic (non-immune) patients. While these findings will have to be confirmed by larger studies, these results are consistent with a potential role for one or more of these invasion ligands as a component of an anti-P. falciparum vaccine in low-transmission malaria-endemic regions. PMID- 23110557 TI - Multiple capacitors for natural genetic variation in Drosophila melanogaster. AB - Cryptic genetic variation (CGV) or a standing genetic variation that is not ordinarily expressed as a phenotype is released when the robustness of organisms is impaired under environmental or genetic perturbations. Evolutionary capacitors modulate the amount of genetic variation exposed to natural selection and hidden cryptically; they have a fundamental effect on the evolvability of traits on evolutionary timescales. In this study, I have demonstrated the effects of multiple genomic regions of Drosophila melanogaster on CGV in wing shape. I examined the effects of 61 genomic deficiencies on quantitative and qualitative natural genetic variation in the wing shape of D. melanogaster. I have identified 10 genomic deficiencies that do not encompass a known candidate evolutionary capacitor, Hsp90, exposing natural CGV differently depending on the location of the deficiencies in the genome. Furthermore, five genomic deficiencies uncovered qualitative CGV in wing morphology. These findings suggest that CGV in wing shape of wild-type D. melanogaster is regulated by multiple capacitors with divergent functions. Future analysis of genes encompassed by these genomic regions would help elucidate novel capacitor genes and better understand the general features of capacitors regarding natural genetic variation. PMID- 23110559 TI - Measuring artificial recharge with fiber optic distributed temperature sensing. AB - Heat was used as a tracer to measure infiltration rates from a recharge basin. The propagation of diurnal oscillation of surface water temperature into the basin bed was monitored along a transect using Fiber Optic Distributed Temperature Sensing (FODTS). The propagation rate was related to downward specific discharge using standard theory of heat advection and dispersion in saturated porous media. An estimate of the temporal variation of heat propagation was achieved using a wavelet transform to find the phase lag between the surface temperature diurnal oscillation and the correlated oscillation at 0.33 and 0.98 m below the bed surface. The wavelet results compared well to a constant velocity model of thermal advection and dispersion during periods of relatively constant discharge rates. The apparent dispersion of heat was found to be due primarily to hydrodynamic mechanisms rather than thermal diffusion. Specific discharge estimates using the FODTS technique also compared well to water balance estimates over a four month period, although there were occasional deviations that have yet to be adequately explained. The FODTS technique is superior to water balance in that it produces estimates of infiltration rate every meter along the cable transect, every half hour. These high resolution measurements highlighted areas of low infiltration and demonstrated the degradation of basin efficiency due to source waters of high suspended solids. FODTS monitoring promises to be a useful tool for diagnosing basin performance in an era of increasing groundwater demand. PMID- 23110558 TI - The REFER (REFer for EchocaRdiogram) protocol: a prospective validation of a clinical decision rule, NT-proBNP, or their combination, in the diagnosis of heart failure in primary care. Rationale and design. AB - BACKGROUND: Heart failure is a major cause of mortality and morbidity. As mortality rates are high, it is important that patients seen by general practitioners with symptoms suggestive of heart failure are identified quickly and treated appropriately. Identifying patients with heart failure or deciding which patients need further tests is a challenge. All patients with suspected heart failure should be diagnosed using objective tests such as echocardiography, but it is expensive, often delayed, and limited by the significant skill shortage of trained echocardiographers. Alternative approaches for diagnosing heart failure are currently limited. Clinical decision tools that combine clinical signs, symptoms or patient characteristics are designed to be used to support clinical decision-making and validated according to strict methodological procedures. The REFER Study aims to determine the accuracy and cost-effectiveness of our previously derived novel, simple clinical decision rule, a natriuretic peptide assay, or their combination, in the triage for referral for echocardiography of symptomatic adult patients who present in general practice with symptoms suggestive of heart failure. METHODS/DESIGN: This is a prospective, Phase II observational, diagnostic validation study of a clinical decision rule, natriuretic peptides or their combination, for diagnosing heart failure in primary care. Consecutive adult primary care patients 55 years of age or over presenting to their general practitioner with a chief complaint of recent new onset shortness of breath, lethargy or peripheral ankle oedema of over 48 hours duration, with no obvious recurrent, acute or self-limiting cause will be enrolled. Our reference standard is based upon a three step expert specialist consensus using echocardiography and clinical variables and tests. DISCUSSION: Our clinical decision rule offers a potential solution to the diagnostic challenge of providing a timely and accurate diagnosis of heart failure in primary care. Study results will provide an evidence-base from which to develop heart failure care pathway recommendations and may be useful in standardising care. If demonstrated to be effective, the clinical decision rule will be of interest to researchers, policy makers and general practitioners worldwide. TRIAL REGISTRATION: ISRCTN17635379. PMID- 23110560 TI - Cabergoline as treatment of ovarian hyperstimulation syndrome: a review. AB - One of the most serious complications of assisted reproduction techniques is ovarian hyperstimulation syndrome (OHSS). OHSS not only increases morbidity and mortality in IFV cycles, but also causes significant other problems, as cancelled in vitro fertilization (IVF) cycles, prolonged hospitalization, causing emotional and sociofinancial consequences. Several treatments for OHSS have been proposed and among these Cabergoline (Cb2). Despite the above-mentioned beneficial effect, Cb2 has not been widely used in everyday's clinical practice. With our study, we try to review all studies with strong evidence examining Cb2 use for OHSS prevention. PMID- 23110562 TI - Improvement of cathode performance on Pt-CeO(x) by optimization of electrochemical pretreatment condition for PEFC application. AB - Pt-CeO(x)/C electrocatalysts for the improvement of oxygen reduction reaction (ORR) activity on cathode were prepared by a combined process of precipitation and co-impregnation methods. The Pt-CeO(x)/C electrocatalysts pretreated by the optimized electrochemical conditioning process showed high ORR activity as compared with homemade Pt/C electrocatalyst. Also, it showed high stability in the cyclic voltammetry (CV) test up to 1000 cycles into 0.5 M H(2)SO(4) aqueous solution. On the basis of the data of cyclic voltammogram of 30 cyclic sweeps, X ray photoelectron spectroscopy, electron energy loss spectroscopy, high resolution transmission electron microscope image, and selected area electron diffraction analysis, it is concluded that the Pt-CeO(x) heterointerface involving the defect cluster formed by using optimized electrochemical pretreatment conditions on Pt in Pt-CeO(x)/C electro-catalyst contributes to the promotion of ORR activity and retention of its stability in long CV tests up to 1000 cycles. PMID- 23110563 TI - Association between depressive and anxiety disorders and adherence to antihypertensive medication in community-living elderly adults. AB - OBJECTIVES: To identify the determinants of antihypertensive medication adherence in community-living elderly adults. DESIGN: Longitudinal observational study. SETTING: Population-based health survey in the province of Quebec, Canada. PARTICIPANTS: Data from a representative sample (N = 2,811) of community-dwelling adults in Quebec aged 65 and older participating in the Etude sur la Sante des Aines study. The final study sample analyzed consisted of 926 participants taking antihypertensive drugs during the 2 years of the study. MEASUREMENTS: Adherence to antihypertensive medication was measured using days of supply obtained during a specified time period. Depression and anxiety disorders were assessed using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, and physical health status was measured using the Charlson Comorbidity Index. Other factors considered were age, education, marital status, annual family income, and number of antihypertensive drugs that participants used. RESULTS: Mean antihypertensive proportion (percentage) of days supplied in was 92.5% in Year 1 and 59.4% in Year 2. The presence of depression and anxiety disorders and the number of antihypertensive medications significantly predicted medication adherence. The sex by depression and anxiety disorders interaction term was significant. CONCLUSION: Adherence to antihypertensive medication was significantly associated with depression and anxiety disorders in men but not women. The treatment of depression and anxiety disorders in individuals with hypertension may be helpful in improving medication adherence rates and healthcare outcomes. PMID- 23110564 TI - Glucagon: are we missing a (life-saving) trick? PMID- 23110561 TI - Impact of cellular autophagy on viruses: Insights from hepatitis B virus and human retroviruses. AB - Autophagy is a protein degradative process important for normal cellular metabolism. It is apparently used also by cells to eliminate invading pathogens. Interestingly, many pathogens have learned to subvert the cell's autophagic process. Here, we review the interactions between viruses and cells in regards to cellular autophagy. Using findings from hepatitis B virus and human retroviruses, HIV-1 and HTLV-1, we discuss mechanisms used by viruses to usurp cellular autophagy in ways that benefit viral replication. PMID- 23110565 TI - Letter to the editor. PMID- 23110566 TI - Letter to the editor. PMID- 23110567 TI - Measurement of intra-abdominal pressure in dogs and cats. AB - OBJECTIVE: To review and summarize the human and veterinary literature on intra abdominal pressure measurement techniques. DATA SOURCES: Human and veterinary clinical studies, research articles, reviews, and textbooks with no date restrictions with a focus on techniques for intra-abdominal pressure (IAP) measurement and their limitations. HUMAN DATA SYNTHESIS: Human literature has established the intravesicular method as the gold standard for indirect measurement of IAP. However, current research has explored the intragastric method as a valid alternative. Recently, debate has focused on the shortcomings of the various measurement methods. VETERINARY DATA SYNTHESIS: Early human literature using dogs as models contributed to the original data for IAP measurements in small animals. Since that time, a number of clinical studies and 1 case report have contributed to that original information. A reference interval for IAP measured by the intravesicular method has recently been determined in healthy cats. CONCLUSIONS: Further studies investigating IAP in critically ill veterinary patients are required to establish the optimal technique for this measurement in veterinary medicine. PMID- 23110568 TI - Metabolic and hormonal responses to subcutaneous glucagon in healthy beagles. AB - OBJECTIVE: To compare the effects of subcutaneous (SC) and intravenous (IV) glucagon on glucose concentrations, and insulin and cortisol secretion. DESIGN: Prospective randomized 3-way crossover study. SETTING: University teaching hospital. ANIMALS: Five healthy beagles. INTERVENTIONS: Diabetes mellitus and adrenal insufficiency were excluded by repeated glucose and fructosamine measurements, urinalysis, abdominal ultrasonography, and ACTH stimulation tests. Blood samples were collected before and after the SC and IV injection of 1 milligram (1 mg = 1 mL) commercially available synthetic glucagon and analyzed for insulin-like immunoreactivity (insulin-imr), glucose, ACTH and cortisol concentrations. The results were compared with those obtained after the SC injection of 1 mL saline (placebo). Measurements were performed over a period of up to 3 hours. MEASUREMENTS AND MAIN RESULTS: SC glucagon significantly increased glucose and insulin-imr (P < 0.001 and 0.043, respectively). Peak glucose concentrations were observed after 20 minutes and were lower than after IV injection (mean +/- SD: 6.5 +/- 1.1 mmol/L versus 9.3 +/- 0.8 mmol/L [117.1 +/- 19.8 mg/dL versus 167.6 +/- 14.4 mg/dL]; P = 0.001). The route of application had no significant effect on insulin-imr (peak concentration: median [range]: 83.3 [13.9-312.5] pmol/L versus 194.5 [118.1-284.7] pmol/L [12 [2-45] MUU/mL versus 28 [17-41] MUU/mL; P = 0.151). SC glucagon did not increase cortisol or ACTH concentrations at any time point of observation (P > 0.05). Aside from somnolence, no adverse events were recorded. CONCLUSIONS: SC glucagon has the potential to be used as a simple and safe test in diabetic animals, but is of little use in animals with suspected corticotrophic insufficiency. The hyperglycemic effects are significant, implying that the commercially available human emergency kit could be useful in the home treatment of canine hypoglycemic emergencies. PMID- 23110569 TI - Exogenous L-lactate clearance in adult horses. AB - OBJECTIVE: To determine endogenous production of L-lactate and the clearance of exogenous sodium L-lactate (ExLC) in healthy adult horses. DESIGN: A sodium L lactate solution (1 mmol/kg body weight qs to 500 mL final volume in 0.9% NaCl) was adminstered IV over 15 minutes. Blood samples for L-lactate concentration [LAC] measurement were collected immediately prior to infusion, at 5, 10, and 15 minutes during infusion and at 1 minute intervals for 15 minutes, at 30, 45, 60, 120, and 180 minutes postinfusion. Disposition modeling and pharmacokinetic analysis was performed using proprietary software. SETTING: University Teaching Hospital. ANIMALS: Six clinically healthy adult horses. MEASUREMENTS AND MAIN RESULTS: Median (range) baseline [LAC] was 0.43 (0.20-0.72) mmol/L for samples obtained every 3 hours over the 24 hours prior to ExLC and demonstrated variability primarily associated with horse. Median [LAC] immediately prior to ExLC was 0.43 (0.35-0.52) mmol/L. A 2-compartment model was used to specify the pharmacokinetic parameters. Median (range) ExLC was 1.05 (0.073-1.75) L.h(-1) .kg(-1) and t(1/2) beta was 29.54 (20.8-38.6) min. Median lactate production based on basal [LAC] immediately prior to ExLC was was 0.49 (0.31-0.93) mmol.h( 1) .kg(-1) . CONCLUSIONS: ExLC in healthy adult horses is greater than that of hyperlactemic human patients but similar to normolactemic-sick human patients examined using the same model, supporting development of species, and disease specific ExLC parameters. PMID- 23110570 TI - Serum protein concentrations as predictors of serum immunoglobulin G concentration in neonatal foals. AB - OBJECTIVE: To determine the predictive value of serum concentrations of total protein (sTP), albumin (sAlb), and globulin (sGlob) measured by automated calorimetric assays to estimate serum immunoglobulin G (sIgG) concentrations in neonatal foals and identify failure of transfer of passive immunity when compared to turbidoimmunometric assay determinations of sIgG. DESIGN: Retrospective and prospective analysis of laboratory data. SETTING: University tertiary care facility. ANIMALS: Group 1 (retrospective): foals (n = 45) <=7 days of age in which sIgG, sGlob, sAlb, and sTP concentrations were measured on an automated chemistry analyzer. Group 2 (prospective): foals (n = 31) <=7 days of age with same laboratory data collected used to validate equations generated from group 1 foals. INTERVENTIONS: Spearman rank correlations between measured sIgG and serum protein concentrations were performed. When significant correlation was found, sIgG was estimated using an sGlob simple linear regression and estimated using a sGlob, sTP, and sAlb multiple linear regression. Comparisons between estimated and measured sIgG was performed using Kruskal-Wallis testing. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to identify foals with sIgG < 8.0 g/L [<800 mg/dL]. MEASUREMENTS AND MAIN RESULTS: sIgG was correlated with sGlob, sTP, and sAlb (rho = 0.8, 0.6, and 0.3, respectively; P < 0.05). Estimated sIgG and measured sIgG were not different (P > 0.9). In group 1 foals, the sensitivity, specificity, positive predictive value, and negative predictive value were 73%, 76%, 73%, and 83%, respectively, for sGlob, and 90%, 76%, 75%, and 90%, respectively, for multiple proteins estimated sIgG identification of failure of transfer of passive immunity. Test qualities were improved in group 2 foals. CONCLUSIONS: Serum protein concentrations may be used to estimate sIgG concentrations in newborn foals. Further investigation using a larger sample size is needed to validate this methodology of assessing humoral immunity in neonatal foals. PMID- 23110571 TI - Plasma lactate measurements in healthy cats. AB - OBJECTIVES: The primary objective was to determine if venous plasma lactate is affected by struggling during venipuncture in clinically normal, healthy cats. Additional objectives were to evaluate the effects of venipuncture site, age, sex, and time (0-24 h) on plasma lactate concentrations in healthy cats. DESIGN: Prospective clinical study. SETTING: Private veterinary referral center. ANIMALS: Twenty-one healthy, privately owned, sexually altered, adult cats. INTERVENTIONS: Blood was collected via jugular or medial saphenous venipuncture at the time of study entry and at 6 and 24 hours later. MEASUREMENTS AND MAIN RESULTS: In healthy cats, there were no significant differences in lactate concentrations statified by degree of struggling at time 0 (P = 0.33), time 6 (P = 0.23), or at time 24 (P = 0.41), venipuncture site (P = 0.58), age (P = 0.62), sex (P = 0.06), or time (P = 0.13). Most cats had mild to moderate struggling scores. Venous plasma lactate concentrations for this group of healthy adult cats had a mean of 1.63 mmol/L; 95% CI: 1.34-1.92, SD: 0.62, and a minimum-maximum range of 0.37 2.81 mmol/L. CONCLUSIONS: The occurrence of mild to moderate struggling during venipuncture, venipuncture site, age, sex, and time did not affect plasma lactate concentrations in this group of healthy cats. Our results suggest that plasma lactate can be reliably measured in cats. Further studies are warranted in sick cats to determine if plasma lactate measurements can be utilized as a diagnostic or prognostic biomarker. PMID- 23110572 TI - Admission base excess as a predictor of transfusion requirement and mortality in dogs with blunt trauma: 52 cases (2007-2009). AB - OBJECTIVE: To evaluate the ability of admission base excess (ABE) to predict blood transfusion requirement and mortality in dogs following blunt trauma. DESIGN: Retrospective study 2007-2009. SETTING: University Veterinary Teaching Hospital. ANIMALS: Fifty-two dogs admitted to the intensive care unit for treatment following blunt trauma. MEASUREMENTS AND MAIN RESULTS: Animals requiring red blood cell transfusion (N = 8) had significantly lower ABE than those not requiring transfusion (N = 44; median base excess [BE] = -8.4 versus 4.7, P = .0034), while there was no difference in admission packed cell volume (PCV) or age. Animals that died or were euthanized due to progression of signs (N = 5) had lower median ABE than those that survived (N = 47; median BE = -7.3 versus -4.9, P = 0.018). Admission PCV and age were not significantly different between survivors and nonsurvivors. Receiver operator characteristic curve analysis showed an ABE cutoff of -6.6 was 88% sensitive and 73% specific for transfusion requirement (P < 0.001), and a cutoff of -7.3 was 81% sensitive and 80% specific for survival (P < 0.001). Multivariate logistic regression analysis demonstrated that ABE was a predictor of transfusion requirement that was independent of overall severity of injury as measured by the Animal Triage Trauma (ATT) score, but a similar analysis showed that only ATT was an independent predictor of survival. CONCLUSIONS: The ABE in dogs with blunt trauma was a predictor of mortality and blood transfusion requirement within 24 hours. PMID- 23110573 TI - Preoperative thoracic radiographic findings in dogs presenting for gastric dilatation-volvulus (2000-2010): 101 cases. AB - OBJECTIVE: To identify the incidence of clinically significant findings on preoperative thoracic radiographs in dogs with gastric dilatation-volvulus (GDV) and to determine if those findings are associated with survival. DESIGN: Retrospective study from 2000 to 2010. SETTING: Urban university small animal teaching hospital. ANIMALS: One hundred and one dogs diagnosed with GDV that had thoracic radiographs obtained preoperatively, and medical records available with the following information available: signalment, time of presentation, respiratory status, plasma lactate, presence of cardiac arrhythmias, reason for thoracic radiographs, radiographic findings, and outcome. INTERVENTIONS: None. RESULTS: Findings on preoperative thoracic radiographs included small vena cava (40%), esophageal dilation (39%), microcardia (34%), aspiration pneumonia (14%), cardiomegaly (5%), pulmonary nodule (4%), pulmonary edema (2%), sternal lymphadenopathy (1%), and pulmonary bullae (1%). Eighty-four percent of dogs (85 out of 101) survived to discharge. Dogs without cardiomegaly on presenting thoracic radiographs had a 10.2 greater odds of surviving to discharge. CONCLUSIONS: The most common findings on preoperative thoracic radiographs include esophageal dilation, microcardia, and a small vena cava while the incidence of pulmonary nodules was low. A negative association between survival and presence of cardiomegaly on preoperative thoracic radiographs in dogs with GDV supports the need to obtain these images for prognostic information in spite of the emergency surgical nature of the GDV. The main limitations of this study include the possibilities of type I and type II errors, the retrospective nature of the study, and the lack of well-defined criteria for obtaining thoracic radiographs. PMID- 23110574 TI - Characterization of dissolved organic matter in full scale continuous stirred tank biogas reactors using ultrahigh resolution mass spectrometry: a qualitative overview. AB - Dissolved organic matter (DOM) was characterized in eight full scale continuous stirred tank biogas reactors (CSTBR) using solid-phase extraction and electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS). An overview of the DOM molecular complexity in the samples from biogas reactors with conventional operational conditions and various substrate profiles is provided by assignments of unambiguous exact molecular formulas for each measured mass peak. Analysis of triplicate samples for each reactor demonstrated the reproducibility of the solid-phase extraction procedure and ESI-FT-ICR-MS which allowed precise evaluation of the DOM molecular differences among the different reactors. Cluster analysis on mass spectrometric data set showed that the biogas reactors treating sewage sludge had distinctly different DOM characteristics compared to the codigesters treating a combination of organic wastes. Furthermore, the samples from thermophilic and mesophilic codigesters had different DOM composition in terms of identified masses and corresponding intensities. Despite the differences, the results demonstrated that compositionally linked organic compounds comprising 28-59% of the total number of assigned formulas for the samples were shared in all the reactors. This suggested that the shared assigned formulas in studied CSTBRs might be related to common biochemical transformation in anaerobic digestion process and therefore, performance of the CSTBRs. PMID- 23110575 TI - Definitions and factors associated with subthreshold depressive conditions: a systematic review. AB - BACKGROUND: Subthreshold depressive disorders (minor and subthrehold depression) have been defined in a wide range of forms, varying on the number of symptoms and duration required. Disability associated with these conditions has also been reported. Our aim was to review the different definitions and to determine factors associated with these conditions in order to clarify the nosological implications of these disorders. METHODS: A Medline search was conducted of the published literature between January 2001 and September 2011. Bibliographies of the retrieved papers were also analysed. RESULTS: There is a wide heterogeneity in the definition and diagnostic criteria of minor and subthreshold depression. Minor depression was defined according to DSM-IV criteria. Regarding subthreshold depression, also called subclinical depression or subsyndromal symptomatic depression, between 2 and 5 depressive symptoms were required for the diagnosis, and a minimum duration of 2 weeks. Significant impairment associated with subthreshold depressive conditions, as well as comorbidity with other mental disorders, has been described. CONCLUSIONS: Depression as a disorder is better explained as a spectrum rather than as a collection of discrete categories. Minor and subthreshold depression are common conditions and patients falling below the diagnostic threshold experience significant difficulties in functioning and a negative impact on their quality of life. Current diagnostic systems need to reexamine the thresholds for depressive disorders and distinguish them from ordinary feelings of sadness. PMID- 23110576 TI - A general structure for legal arguments about evidence using Bayesian networks. AB - A Bayesian network (BN) is a graphical model of uncertainty that is especially well suited to legal arguments. It enables us to visualize and model dependencies between different hypotheses and pieces of evidence and to calculate the revised probability beliefs about all uncertain factors when any piece of new evidence is presented. Although BNs have been widely discussed and recently used in the context of legal arguments, there is no systematic, repeatable method for modeling legal arguments as BNs. Hence, where BNs have been used in the legal context, they are presented as completed pieces of work, with no insights into the reasoning and working that must have gone into their construction. This means the process of building BNs for legal arguments is ad hoc, with little possibility for learning and process improvement. This article directly addresses this problem by describing a method for building useful legal arguments in a consistent and repeatable way. The method complements and extends recent work by Hepler, Dawid, and Leucari (2007) on object-oriented BNs for complex legal arguments and is based on the recognition that such arguments can be built up from a small number of basic causal structures (referred to as idioms). We present a number of examples that demonstrate the practicality and usefulness of the method. PMID- 23110577 TI - Characteristics of myogenic response and ankle torque recovery after lengthening contraction-induced rat gastrocnemius injury. AB - BACKGROUND: Although muscle dysfunction caused by unfamiliar lengthening contraction is one of most important issues in sports medicine, there is little known about the molecular events on regeneration process. The purpose of this study was to investigate the temporal and spatial expression patterns of myogenin, myoD, pax7, and myostatin after acute lengthening contraction (LC) induced injury in the rat hindlimb. METHODS: We employed our originally developed device with LC in rat gastrocnemius muscle (n = 24). Male Wistar rats were anesthetized with isoflurane (aspiration rate, 450 ml/min, concentration, 2.0%). The triceps surae muscle of the right hindlimb was then electrically stimulated with forced isokinetic dorsi-flexion (180 degrees /sec and from 0 to 45 degrees ). Tissue contents of myoD, myogenin, pax7, myostatin were measured by western blotting and localizations of myoD and pax7 was measured by immunohistochemistry. After measuring isometric tetanic torque, a single bout of LC was performed in vivo. RESULTS: The torque was significantly decreased on days 2 and 5 as compared to the pre-treatment value, and recovered by day 7. The content of myoD and pax7 showed significant increases on day 2. Myogenin showed an increase from day 2 to 5. Myostatin on days 5 and 7 were significantly increased. Immunohistochemical analysis showed that myoD-positive/pax7-positive cells increased on day 2, suggesting that activated satellite cells play a role in the destruction and the early recovery phases. CONCLUSION: We, thus, conclude that myogenic events associate with torque recovery after LC-induced injury. PMID- 23110578 TI - A two-stage surgical approach to the treatment of severe peri-implant defect: a 30-month clinical follow-up report. AB - With the advance of dental implant technology and the consequential increase in its success rate, the implant has become a highly predictable treatment method. Despite this, related complications are on the rise, with peri-implant mucositis and peri-implantitis being the most commonly observed. As in the case of conventional periodontitis, many patients experience peri-implant mucositis and peri-implantitis. In this case presentation, extensive bone loss occurred around the implant due to peri-implantitis, and the infection was first treated by applying chlorhexidine-soaked gauze and topical antibiotics. Then the guided bone regeneration procedure was performed using a bovine bone material and a collagen membrane, which resulted in the recovery of the lesion. With follow-ups of the healing process for 30 months, a successful outcome was observed that is reported herein. PMID- 23110579 TI - Managing dental emergencies: a descriptive study of the effects of a multimodal educational intervention for primary care providers at six months. AB - BACKGROUND: Clinicians providing primary emergency medical care often receive little training in the management of dental emergencies. A multimodal educational intervention was designed to address this lack of training. Sustained competency in managing dental emergencies and thus the confidence to provide this care well after an educational intervention is of particular importance for remote and rural healthcare providers where access to professional development training may be lacking. METHODS: A descriptive study design with a survey instrument was used to evaluate the effectiveness of a brief educational intervention for primary care clinicians. The survey was offered immediately before and at six months following the intervention. A Wilcoxon signed rank test was performed on pre and six month post-workshop matched pair responses, measuring self-reported proficiency in managing dental emergencies. The level of significance was set at p < 0.001. Confidence intervals (CI) were calculated for participants who scored an improved proficiency. RESULTS: The educational intervention was associated with a significant and sustained increase in proficiency and confidence to treat, especially in oral local anaesthesia, management of avulsed teeth and dental trauma, as reported by clinicians at six months after the education. This was associated with a greater number of cases where dental local anaesthesia was utilised by the participants. Comments from participants before the intervention, noted the lack of dental topics in professional training. CONCLUSIONS: The sustained effects of a brief multimodal educational intervention in managing dental emergencies on practice confidence and proficiency demonstrates its value as an educational model that could be applied to other settings and health professional groups providing emergency primary care, particularly in rural and remote settings. PMID- 23110580 TI - Two-year clinical performance of self-etching adhesive systems in composite restorations of anterior teeth. AB - OBJECTIVE: The aim of this study was to evaluate the two-year clinical performance of Class III, IV, and V composite restorations using a two-step etch and-rinse adhesive system (2-ERA) and three one-step self-etching adhesive systems (1-SEAs). MATERIAL AND METHODS: Two hundred Class III, IV, and V composite restorations were placed into 50 patients. Each patient received four composite restorations (Amaris, Voco), and these restorations were bonded with one of three 1-SEAs (Futurabond M, Voco; Clearfil S3 Bond, Kuraray; and Optibond All-in-One, Kerr) or one 2-ERA (Adper Single Bond 2/3M ESPE). The four adhesive systems were evaluated at baseline and after 24 months using the following criteria: restoration retention, marginal integrity, marginal discoloration, caries occurrence, postoperative sensitivity and preservation of tooth vitality. After two years, 162 restorations were evaluated in 41 patients. Data were analyzed using the chi(2) test (p<0.05). RESULTS: There were no statistically significant differences between the 2-ERA and the 1-SEAs regarding the evaluated parameters (p>0.05). CONCLUSION: The 1-SEAs showed good clinical performance at the end of 24 months. PMID- 23110581 TI - Two-year interfacial bond durability and nanoleakage of repaired silorane-based resin composite. AB - OBJECTIVES: To investigate the effect of silane primer application, intermediate adhesive agent/repair composite, and storage period on the interfacial microtensile bond strength (MUTBS) of repaired silorane-based resin composite compared with unrepaired composites and on the nanoleakage. METHODS: Forty-eight 1-month-old substrate specimens from Filtek P90 were roughened, etched, and distributed over two groups (n=24) based on receiving silane (Clearfil Ceramic Primer) or not. Then, half of the specimens (n=12) were repaired with P90 System Adhesive/Filtek P90 and the other half with Adper Scotchbond Multipurpose adhesive/Filtek Z250 resin composite. Within each repair category, repaired specimens were stored in artificial saliva at 37 degrees C for either 24 hours (n=6) or two years before being serially sectioned into sticks (0.6 +/- 0.01 mm(2)). From each specimen, two sticks were prepared for nanoleakage determination and four sticks were used for MUTBS testing. Additional unrepaired specimens from each composite (n=12) were made to determine the cohesive strength at 24 hours and two years. Mean MUTBS were calculated and statistically analyzed. Modes of failure were also determined. RESULTS: General linear model analysis revealed no significant effect for the silane priming, intermediate adhesive agent/repair composite, and storage period or for their interactions on the MUTBS values of the repaired specimens. There was no significant difference between the cohesive strength of Filtek P90 and Filtek Z250; both were significantly higher than all repaired categories. At 24 hours, nanoleakage was not detected when silorane-based composite was repaired with the same material. However, after two years, all repair categories showed nanoleakage. CONCLUSIONS: Silane application has no effect on MUTBS and nanoleakage. Durability of the interfacial bond of repaired silorane-based resin composite appeared successful regardless of the chemistry of the intermediate adhesive agent/composite used for repair. However, nanoleakage was detected early when a different repair intermediate adhesive agent/composite was used. PMID- 23110582 TI - The evaluation of dentinal tubule occlusion by desensitizing agents: a real-time measurement of dentinal fluid flow rate and scanning electron microscopy. AB - The aims of this study were to examine changes in dentinal fluid flow (DFF) during the application of a desensitizing agent and to compare the permeability reduction levels among different types of desensitizing agents. A cervical cavity was prepared for the exposure of cervical dentin on an extracted human premolar connected to a subnanoliter fluid flow measuring device under 20 cm of water pressure. The cavity was acid-etched with 32% phosphoric acid to make dentin highly permeable. The different types of desensitizing agents that were applied on the cavity were Seal&Protect as the light-curing adhesive type, SuperSeal and BisBlock as oxalate types, Gluma Desensitizer as the protein-precipitation type, and Bi-Fluoride 12 as the fluoride type. DFF was measured from the time before the application of the desensitizing agent throughout the application procedure to five minutes after the application. The characteristics of dentinal tubule occlusion of each desensitizing agent were examined by scanning electron microscopy. The DFF rate after each desensitizing agent application was significantly reduced when compared to the initial DFF rate before application for all of the desensitizing agents (p<0.05). Seal&Protect showed a greater reduction in the DFF rate when compared to Gluma Desensitizer and Bi-Fluoride 12 (p<0.05). SuperSeal and BisBlock exhibited a greater reduction in DFF rate when compared to Bi-Fluoride 12 (p<0.05). The dentin hypersensitivity treatment effects of the employed desensitizing agents in this study were confirmed through real-time measurements of DFF changes. The light-curing adhesive and oxalate types showed greater reduction in the DFF rate than did the protein-precipitation and fluoride types. PMID- 23110583 TI - Influence of confined fluids on nanoparticle-to-surroundings energy transfer. AB - Energy transfer from photoexcited nanoparticles to their surroundings was studied for both hollow and solid gold nanospheres (HGNs and SGNs, respectively) using femtosecond time-resolved transient extinction spectroscopy. HGNs having outer diameters ranging from 17 to 78 nm and fluid-filled cavities were synthesized by a sacrificial galvanic replacement method. The HGNs exhibited energy transfer half times that ranged from 105 +/- 10 ps to 1010 +/- 80 ps as the total particle surface area increased from 1005 to 28,115 nm(2). These data showed behaviors that were categorized into two classes: energy transfer from HGNs to interior fluids that were confined to cavities with radii <15 nm and >=15 nm. Energy transfer times were also determined for solid gold nanospheres (SGNs) having radii spanning 9-30 nm, with a similar size dependence where the relaxation times increased from 140 +/- 10 to 310 +/- 15 ps with increasing nanoparticle size. Analysis of the size-dependent energy transfer half times revealed that the distinct relaxation rate constants observed for particle-to-surroundings energy transfer for HGNs with small cavities were the result of reduced thermal conductivity of confined fluids. These data indicate that the thermal conductivity of HGN cavity-confined fluids is approximately one-half as great as it is for bulk liquid water. For all HGNs and SGNs studied, energy dissipation through the solvent and transfer across the particle/surroundings interface both contributed to the energy relaxation process. The current data illustrated the potential of fluid-filled hollow nanostructures to gain insight into the properties of confined fluids. PMID- 23110584 TI - Biological templates for antireflective current collectors for photoelectrochemical cell applications. AB - Three-dimensional (3D) structures such as nanowires, nanotubes, and nanorods have the potential to increase surface area, reduce light reflection, and shorten charge carrier transport distances. The assembly of such structures thus holds great promise for enhancing photoelectrochemical solar cell efficiency. In this study, genetically modified Tobacco mosaic virus (TMV1cys) was used to form self assembling 3D nanorod current collectors and low light-reflecting surfaces. Photoactive CuO was subsequently deposited by sputtering onto these patterned nanostructures, and these structures were examined for photocurrent activity. CuO thicknesses of 520 nm on TMV1cys patterned current collectors produced the highest photocurrent density of 3.15 mA/cm(2) yet reported for a similar sized CuO system. Reflectivity measurements are in agreement with full-wave electromagnetic simulations, which can be used as a design tool for optimizing the CuO system. Thus the combined effects of reducing charge carrier transport distance, increasing surface area, and the suppression of light reflection make these virus-templated surfaces ideal for photoelectrochemical applications. PMID- 23110585 TI - Factors affecting exclusive breast-feeding during the first 6 months in Korea. AB - BACKGROUND: The aim of this study was to identify the status of exclusive breast feeding (EBF) in Korea and analyze the factors affecting exclusive breast-feeding at 6 months of age. METHOD: This study was based on data obtained from the Korea National Health and Nutrition Examination Survey (KNHANES) IV, conducted from January 2007 to December 2008. A total of 404 mother-infant pairs were recruited. Exclusive breast-feeding was defined according to the criteria established by the World Health Organization. RESULT: The rate of EBF was 60.9% for 1 month, 55.0% for 3 months, 35.4% for 6 months, 3.7% for 9 months and 1.2% for 12 months after birth. According to a stepwise logistic regression analysis, factors that were positively associated with EBF at 6 months were younger maternal age (odds ratio [OR] = 0.85, 95% confidence interval [CI]: 0.79-0.92), higher maternal education level (OR = 2.29, 95%CI: 1.17-4.46) and living in a capital city (OR = 2.64, 95%CI: 1.46-4.75). CONCLUSION: The rate of EBF in Korea is still suboptimal. To promote EBF, persistent and systematic education and campaigns for breast-feeding should be provided, particularly in vulnerable regions. PMID- 23110586 TI - Maggot excretions affect the human complement system. AB - The complement system plays an important role in the activation of the inflammatory response to injury, although inappropriate complement activation (CA) can lead to severe tissue damage. Maggot therapy is successfully used to treat infected wounds. In this study, we hypothesized that maggot excretions/secretions influence CA in order to modulate the host's inflammatory response. Therefore, the effect of maggot excretions on CA was investigated in preoperatively and postoperatively obtained sera from patients. Our results show that maggot excretions reduce CA in healthy and postoperatively immune-activated human sera up to 99.9%, via all pathways. Maggot excretions do not specifically initiate or inhibit CA, but break down complement proteins C3 and C4 in a cation independent manner and this effect proves to be temperature tolerant. This study indicates a CA-reducing substrate that is already successfully used in clinical practice and may explain part of the improved wound healing caused by maggot therapy. Furthermore, the complement activation-reducing substance present in maggot excretions could provide a novel treatment modality for several diseases, resulting from an (over)active complement system. PMID- 23110587 TI - Nasolabial flap reconstruction in oral cancer. AB - BACKGROUND: The nasolabial flap is a simple flap used for reconstructing small intraoral defects created after the excision of malignant tumors. METHODS: A retrospective analysis of 26 cases of oral cancer treated with primary excision and nasolabial flap reconstruction was carried out. In 22 cases, the excision was combined with neck dissection and facial artery ligation. RESULTS: Good cosmetic and functional results were obtained in almost all cases. Wound dehiscence developed in three patients, while one patient developed a persistent orocutaneous fistula. Disease recurrence occurred in one patient. CONCLUSIONS: The nasolabial flap is a good flap for the reconstruction of small oral defects after excision of primary tumors and results in good overall cosmetic and functional outcome. PMID- 23110588 TI - Australian and U.S. news media portrayal of sharks and their conservation. AB - Investigation of the social framing of human-shark interactions may provide useful strategies for integrating social, biological, and ecological knowledge into national and international policy discussions about shark conservation. One way to investigate social opinion and forces related to sharks and their conservation is through the media's coverage of sharks. We conducted a content analysis of 300 shark-related articles published in 20 major Australian and U.S. newspapers from 2000 to 2010. Shark attacks were the emphasis of over half the articles analyzed, and shark conservation was the primary topic of 11% of articles. Significantly more Australian articles than U.S. articles treated shark attacks (chi(2) = 3.862; Australian 58% vs. U.S. 47%) and shark conservation issues (chi(2) = 6.856; Australian 15% vs. U.S. 11%) as the primary article topic and used politicians as the primary risk messenger (i.e., primary person or authority sourced in the article) (chi(2) = 7.493; Australian 8% vs. U.S. 1%). However, significantly more U.S. articles than Australian articles discussed sharks as entertainment (e.g., subjects in movies, books, and television; chi(2) = 15.130; U.S. 6% vs. Australian 1%) and used scientists as the primary risk messenger (chi(2) = 5.333; U.S. 25% vs. Australian 15%). Despite evidence that many shark species are at risk of extinction, we found that most media coverage emphasized the risks sharks pose to people. To the extent that media reflects social opinion, our results highlight problems for shark conservation. We suggest that conservation professionals purposefully and frequently engage with the media to highlight the rarity of shark attacks, discuss preventative measures water users can take to reduce their vulnerability to shark encounters, and discuss conservation issues related to local and threatened species of sharks. When integrated with biological and ecological data, social-science data may help generate a more comprehensive perspective and inform conservation practice. PMID- 23110589 TI - The Malaria in Pregnancy Library: a bibliometric review. AB - BACKGROUND: The Malaria in Pregnancy (MiP) Library is a bibliographic database that was created by the MiP Consortium in 2005 and is updated every four months using a standardized search protocol. A bibliometric review was conducted of the contents of the Library to determine dynamics in the type, content and volume of literature on malaria in pregnancy over time. METHODS: Data on year of publication, type, language, country of first-author affiliation and content (topic) were extracted from entries in the MiP Library and plotted over time. RESULTS: By January 2012, the MiP Library contained 5,346 entries, consisting of 3,721 journal articles (69.6%), 697 reports (13.0%), 219 academic theses (4.1%), 92 books or book chapters (1.7%), 487 conference proceedings (9.1%), 68 registered studies (1.3%) and 62 'other' (1.2%). Most of the sources were in English language (87.3%), followed by French (7.5%) and Spanish (1.5%). Over 40% of source material was publicly available online (42.4%) and the remaining with restricted access (35.0%) or otherwise unavailable (22.7%). The number of journal articles related to malaria in pregnancy increased from 41 in the 1960s, to 708 in the 1990s, and 1,895 between 2000 and 2009, and the variety of themes has increased over time. English-language articles were sourced from 737 different journals. The top three journals were the American Journal of Tropical Medicine and Hygiene (184), Malaria Journal (158) and the Transactions of the Royal Society of Tropical Medicine and Hygiene (131). CONCLUSION: The last decade has seen a dramatic increase in publications related to malaria in pregnancy, and an increasing proportion of these are publically available online. The MiP Library is a useful, scholarly source for literature and systematic reviews related to malaria in pregnancy. PMID- 23110590 TI - Age-dependent interaction of apolipoprotein E gene with eastern birthplace in Finland affects severity of coronary atherosclerosis and risk of fatal myocardial infarction--Helsinki Sudden Death Study. AB - BACKGROUND: Mortality from coronary heart disease (CHD) has been constantly higher in eastern late settlement regions compared to western early settlements in Finland, unrelated to classical risk factors. In line with this, eastern birthplace was an age-dependent predictor of severe coronary atherosclerosis and pre-hospital sudden coronary death among male residents of Helsinki. We investigated a possible interaction of apolipoprotein E (APOE) gene with birthplace on the risk of myocardial infarction (MI) and coronary atherosclerosis. METHOD: APOE genotypes were analyzed in the Helsinki Sudden Death Study series comprising out-of-hospital deaths among males aged 33-70 years (n = 577), who were born in high (east, n = 273) or low (west, n = 304) CHD mortality area. RESULTS: Eastern-born men <= 55 years carried 30% more often (P = 0.017) and older men 40% less often (P = 0.022) the APOE epsilon4 allele compared to western-born men (P = 0.003 for birthplace-by-age interaction). In multivariate analysis, the epsilon4 allele associated with the risk of out-of hospital MI (odds ratio 2.58; 95% CI 1.20-5.55; P = 0.016) only in eastern-born men and with advanced atherosclerosis in both regions of origin, respectively. CONCLUSIONS: Birthplace-bound risk of CHD was age-dependently modified by APOE epsilon4 allele, suggesting genetic differences in CHD susceptibility between early and late settlement regions in Finland and providing one explanation for the eastern high mortality. PMID- 23110591 TI - Heteroaggregation between isomeric amido-ethynyl-amidohelicene tridomain oligomers. AB - Three isomers, i.e., P4M5P4-1, M4P5M4-1, and M4M5M4-1, of amido-ethynyl amidohelicene tridomain oligomers were synthesized. P4M5P4-1 formed four homoaggregate states, i.e., all-dimer, amido-dimer, ethynyl-dimer, and random coil states, by independent aggregation and disaggregation at the ethynyl and amido domains. Then, possible combinations of heteroaggregation were examined between the isomeric tridomain oligomers P4P5P4-1, P4M5P4-1, M4P5M4-1, and M4M5M4 1. When P4P5P4-1 and P4M5P4-1 were mixed in THF, to which trifluoromethylbenzene was added, heteroaggregates with an all-dimer structure were formed without forming homoaggregates. The heteroaggregation initially occurred at the central ethynyl domain, which was followed by the aggregation at the amido domains. Heteroaggregates were also formed using the combinations P4P5P4-1/M4M5M4-1 and P4M5P4-1/M4P5M4-1, and the results indicated an important role for the central ethynyl domain for heteroaggregation. PMID- 23110592 TI - Resprouting as a key functional trait: how buds, protection and resources drive persistence after fire. AB - Resprouting as a response to disturbance is now widely recognized as a key functional trait among woody plants and as the basis for the persistence niche. However, the underlying mechanisms that define resprouting responses to disturbance are poorly conceptualized. Resprouting ability is constrained by the interaction of the disturbance regime that depletes the buds and resources needed to fund resprouting, and the environment that drives growth and resource allocation. We develop a buds-protection-resources (BPR) framework for understanding resprouting in fire-prone ecosystems, based on bud bank location, bud protection, and how buds are resourced. Using this framework we go beyond earlier emphases on basal resprouting and highlight the importance of apical, epicormic and below-ground resprouting to the persistence niche. The BPR framework provides insights into: resprouting typologies that include both fire resisters (i.e. survive fire but do not resprout) and fire resprouters; the methods by which buds escape fire effects, such as thick bark; and the predictability of community assembly of resprouting types in relation to site productivity, disturbance regime and competition. Furthermore, predicting the consequences of global change is enhanced by the BPR framework because it potentially forecasts the retention or loss of above-ground biomass. PMID- 23110593 TI - Linking predator-prey interactions with exposure to a trophically transmitted parasite using PCR-based analyses. AB - Parasite transmission is determined by the rate of contact between a susceptible host and an infective stage and susceptibility to infection given an exposure event. Attempts to measure levels of variation in exposure in natural populations can be especially challenging. The level of exposure to a major class of parasites, trophically transmitted parasites, can be estimated by investigating the host's feeding behaviour. Since the parasites rely on the ingestion of infective intermediate hosts for transmission, the potential for exposure to infection is inherently linked to the definitive host's feeding ecology. Here, we combined epidemiological data and molecular analyses (polymerase chain reaction) of the diet of the definitive host, the white-footed mouse (Peromyscus leucopus), to investigate temporal and individual heterogeneities in exposure to infection. Our results show that the consumption of cricket intermediate hosts accounted for much of the variation in infection; mice that had consumed crickets were four times more likely to become infected than animals that tested negative for cricket DNA. In particular, pregnant female hosts were three times more likely to consume crickets, which corresponded to a threefold increase in infection compared with nonpregnant females. Interestingly, males in breeding condition had a higher rate of infection even though breeding males were just as likely to test positive for cricket consumption as nonbreeding males. These results suggest that while heterogeneity in host diet served as a strong predictor of exposure risk, differential susceptibility to infection may also play a key role, particularly among male hosts. By combining PCR analyses with epidemiological data, we revealed temporal variation in exposure through prey consumption and identified potentially important individual heterogeneities in parasite transmission. PMID- 23110594 TI - Multilayer formation of the fluoroalkanol-omega-hydrogenated fluorocarbon mixture at the hexane/water interface studied by interfacial tensiometry and X-ray reflection. AB - Novel multilayer formation of fluorocarbon compounds at the hexane/water interface was investigated from the viewpoint of intermolecular interaction and miscibility of molecules in the adsorbed film. The two kinds of mixed systems were employed: 1H,1H,2H,2H-perfluorododecanol (FC12OH)-1H-perfluorodecane (HFC10) (System A) and 1-icosanol (C20OH)-HFC10 (System B). The interfacial tension gamma between the hexane solution and water was measured as a function of total concentration m and the composition of HFC10 in the mixture X(2) at 298.15 K under atmospheric pressure. X-ray reflectivity (XR) measurement was performed at BL37XU in SPring-8 as a function of scattering vector Q(z). In both systems, the gamma vs m curves except for the pure HFC10 system have a break at low concentrations, which corresponds to the gaseous-condensed monolayer transition for System A and the expanded-condensed monolayer for System B. The remarkable difference between the two systems was that the curves in a limited bulk composition range (0.45 <= X(2) <= 0.9) of System A show another break at high concentrations close to the solubility limit. The total interfacial density above this break point was around 7-11 MUmol m(-2), suggesting the spontaneous molecular piling to form a multilayer. The phase diagrams of adsorption in the condensed monolayer indicated that the film composition of HFC10 is negative in System B but definitely positive above X(2) >= 0.45 in System A. This clearly shows that HFC10 molecules are miscible with FC12OH but immiscible with C20OH in the condensed monolayer. Thus, it is likely that the mixing of HFC10 with FC12OH in the condensed monolayer induces multilayer formation. The X-ray reflectivity normalized by Fresnel reflectivity R/R(F) vs Q(z) plot in the condensed monolayer of System A was fitted by a one-slab model with uniform electron density and thickness. The electron density profile was almost the same as that of the pure FC12OH system. The plot in the multilayer, on the other hand, was fitted well by the two-slab model with different electron densities and thicknesses. The electron density profile showed that the multilayer consists of two layers, one of which has slightly higher electron density than the bulk hexane phase and piles on the lower layer with almost the same electron density as the condensed FC12OH monolayer. PMID- 23110595 TI - Effect of maternal obesity and weight gain on gestational diabetes mellitus. AB - The aim of the study is to evaluate the association between gestational diabetes mellitus (GDM) and maternal obesity and weight gain during pregnancy. A prospective cohort study screened 614 consecutive gravid patients for GDM using 50 g glucose challenge test (GCT). The pregnant women were divided into 4 groups according to their prepregnancy body mass index (BMI). Group I, II, III and IV constituted when the BMI < 18.5 kg/m2 (n = 16), 18.5-24.9 kg/m2 (n = 455), 25 29.9 kg/m2 (n = 122), and >30 kg/m2 (n = 21) respectively. All the pregnant women were also evaluated in terms of their weight gain during pregnancy and these cases were recruited in 3 groups as low, ideal and high weight gain groups. Overall, a positive 50 g GCT result was identified in 106/614 (17.8%) women. GDM was further diagnosed in 12/614 (1.95%) of subjects. The prevalence of GDM in Group II, III and IV was 1.31%, 3.28% and 9.52% respectively (p < 0.05). The cases of Group II in first and second trimester and Group III only in second trimester showed statistically significant positive results of 50 g GCT when they had excess weight gain compared to the ones whose weight gain were in normal range. Women planning pregnancy should be educated about the disadvantages of obesity, being over-weight and should be advised to have an ideal prepregnancy BMI and ideal weight gain during pregnancy. PMID- 23110596 TI - ChopSticks: High-resolution analysis of homozygous deletions by exploiting concordant read pairs. AB - BACKGROUND: Structural variations (SVs) in genomes are commonly observed even in healthy individuals and play key roles in biological functions. To understand their functional impact or to infer molecular mechanisms of SVs, they have to be characterized with the maximum resolution. However, high-resolution analysis is a difficult task because it requires investigation of the complex structures involved in an enormous number of alignments of next-generation sequencing (NGS) reads and genome sequences that contain errors. RESULTS: We propose a new method called ChopSticks that improves the resolution of SV detection for homozygous deletions even when the depth of coverage is low. Conventional methods based on read pairs use only discordant pairs to localize the positions of deletions, where a discordant pair is a read pair whose alignment has an aberrant strand or distance. In contrast, our method exploits concordant reads as well. We theoretically proved that when the depth of coverage approaches zero or infinity, the expected resolution of our method is asymptotically equal to that of methods based only on discordant pairs under double coverage. To confirm the effectiveness of ChopSticks, we conducted computational experiments against both simulated NGS reads and real NGS sequences. The resolution of deletion calls by other methods was significantly improved, thus demonstrating the usefulness of ChopSticks. CONCLUSIONS: ChopSticks can generate high-resolution deletion calls of homozygous deletions using information independent of other methods, and it is therefore useful to examine the functional impact of SVs or to infer SV generation mechanisms. PMID- 23110598 TI - Ionic enhancement of silica surface nanowear in electrolyte solutions. AB - The nanoscale wear and friction of silica and silicon nitride surfaces in aqueous electrolyte solutions were investigated by using sharp atomic force microscope (AFM) cantilever tips coated with silicon nitride. Measurements were carried out in aqueous solutions of varying pH and in monovalent and divalent cation chloride and nitrate solutions. The silica surface was shown to wear strongly in solutions of high pH (~11.0), as expected, but the presence of simple cations, such as Cs(+) and Ca(2+), was shown to dramatically effect the wear depth and friction force for the silica surface. In the case of monovalent cations, their hydration enthalpies correlated well with the wear and friction. The weakest hydrated cation of Cs(+) showed the most significant enhancement of wear and friction. In the case of divalent cations, a complex dependence on the type of cation was found, where the type of anion was also seen to play an important role. The CaCl(2) solution showed the anomalous enhancement of wear depth and friction force, although the solution of Ca(NO(3))(2) did not. The present results obtained with an AFM tip were also compared with previous nanotribology studies of silica surfaces in electrolyte solutions, and possible molecular mechanisms as to why cations enhance the wear and friction were also discussed. PMID- 23110599 TI - New dinuclear cobalt(II) and zinc(II) complexes of a carboxylate-rich dinucleating ligand: synthesis, structure, spectroscopic characterization, and their interactions with sugars. AB - Sugar-metal ion interactions in aqueous medium are involved in many biochemical processes such as the transport and storage of metals, the function and regulation of sugar-metabolizing metalloenzymes, the mechanism of action of metal containing pharmaceuticals, and toxic metal metabolism. To understand such interactions we synthesized and fully characterized two new dinuclear cobalt(II) and zinc(II) complexes as carbohydrate binding models for xylose/glucose isomerases (XGI). Synthesis of the dicobalt complex, Na3[Co2(ccdp)(MU HCO2)]BF4.9H2O.2CH3OH (1), was performed in methanol with stoichiometric amounts of Co(BF4)2.6H2O and the dinucleating ligand, H5ccdp (H5ccdp = N,N'-bis[2 carboxybenzomethyl]-N,N'-bis[carboxymethyl]-1,3-diaminopropan-2-ol), in the presence of NaOH at ambient temperature in an argon glovebox. Similarly, the dizinc complex, [NMe4]2[Zn2(ccdp)(MU-OAc)].CH3OH (2), was synthesized from Zn(OAc)2.2H2O and H5ccdp in the presence of NMe4OH at ambient temperature in methanol. Binding of the complexes with carbohydrates was investigated under different reaction conditions. In aqueous alkaline media, complexes 1 and 2 showed chelating ability towards the biologically important sugars, d-glucose and d-xylose, and a polyalcohol enzyme inhibitor (xylitol). In solution, each complex forms a 1:1 complex-substrate bound product with specific binding constant values. Synthesis, characterization details, and substrate binding using spectroscopic techniques and single-crystal X-ray diffraction are reported. PMID- 23110600 TI - Transient hyperlipidemia in a litter of kittens. AB - OBJECTIVE: To describe an entire litter of kittens with severe hyperlipidemia and subsequent successful, low-cost treatment that included high protein enteral support and parasite control. Previous case studies of similarly affected kittens have focused on a genetic etiology and on advanced interventions. The role of negative energy balance and additional factors influencing hyperlipidemia, as well as treatment and prognosis are discussed. CASE SUMMARY: Three of 6 kittens died or were euthanized due to severe clinical signs attributable to multiorgan failure associated with subacute hyperlipidemia. The remaining 3 kittens, although subclinical, were found to have similar biochemical abnormalities, including severe anemia and hypertriglyceridemia. Flea treatment and weaning with assisted enteral support prevented the worsening of clinical signs and returned biochemical parameters to within reference intervals. UNIQUE INFORMATION PROVIDED: Transient hyperlipidemia in kittens has been previously reported and successfully treated with administration of oxygen, blood transfusion, and diet change; these treatment recommendations may not always be financially feasible, resulting in euthanasia of affected kittens. In contrast, this report describes a successful, low-cost, outpatient approach of flea control, weaning, and introduction of a high protein enteral diet. It also highlights the importance of screening and treating seemingly unaffected littermates, provides new, previously unreported biochemical and histopathology findings, and proposes that negative energy balance is a significant factor in the development of transient hyperlipidemia in kittens. PMID- 23110601 TI - Using a generalized additive model with autoregressive terms to study the effects of daily temperature on mortality. AB - BACKGROUND: Generalized Additive Model (GAM) provides a flexible and effective technique for modelling nonlinear time-series in studies of the health effects of environmental factors. However, GAM assumes that errors are mutually independent, while time series can be correlated in adjacent time points. Here, a GAM with Autoregressive terms (GAMAR) is introduced to fill this gap. METHODS: Parameters in GAMAR are estimated by maximum partial likelihood using modified Newton's method, and the difference between GAM and GAMAR is demonstrated using two simulation studies and a real data example. GAMM is also compared to GAMAR in simulation study 1. RESULTS: In the simulation studies, the bias of the mean estimates from GAM and GAMAR are similar but GAMAR has better coverage and smaller relative error. While the results from GAMM are similar to GAMAR, the estimation procedure of GAMM is much slower than GAMAR. In the case study, the Pearson residuals from the GAM are correlated, while those from GAMAR are quite close to white noise. In addition, the estimates of the temperature effects are different between GAM and GAMAR. CONCLUSIONS: GAMAR incorporates both explanatory variables and AR terms so it can quantify the nonlinear impact of environmental factors on health outcome as well as the serial correlation between the observations. It can be a useful tool in environmental epidemiological studies. PMID- 23110602 TI - Contact urticaria syndrome from eye drops: levofloxacin hydrate ophthalmic solution. PMID- 23110604 TI - Camel and bovine chymosin hydrolysis of bovine alpha(S1)- and beta-caseins studied by comparative peptide mapping. AB - In many cheese varieties, the general proteolytic activity of the coagulant is of great importance to the development of flavor and texture during ripening. This study used capillary electrophoresis and LC-MS/MS to compare the in vitro proteolytic behavior of camel and bovine chymosin (CC/BC) on bovine alpha(S1)- and beta-casein (CN) at pH 6.5 and 30 degrees C. beta-CN hydrolysis was also studied at pH 5.2 and in the presence of 0, 2, and 5% (w/v) NaCl. A total of 25 alpha(S1)- and 80 beta-CN peptides were identified, and initial rates of early peptide formation were determined. The modes of proteolytic action of CC and BC shared a high degree of similarity generally. However, except for a few peptide bonds, CC was markedly less active, the magnitude of which varied widely with cleavage site. Preferential alpha(S1)-CN (Phe23-Phe24) and beta-CN (Leu192 Tyr193) hydrolysis by CC proceeded at an estimated 36 and 7% of the initial rate of BC, respectively. The latter rate difference was largely pH and NaCl independent. Several cleavage sites appeared to be unique to CC and especially BC action, but qualitative differences were often predetermined by quantitative effects. In particular, negligible CC affinity to alpha(S1)-CN164/165 and beta CN189/190 prevented further exposure of the N-terminal products. beta-CN hydrolysis by either enzyme was always stimulated at the lower pH, yet either inhibited or stimulated by the presence of NaCl, depending mainly on the predominating type of molecular substrate interactions involved at the specific site of cleavage. The potential impact of this proteolytic behavior on cheese quality is discussed. PMID- 23110605 TI - The proactive treatment of atopic dermatitis with tacrolimus ointment in Korean patients: a comparative study between once-weekly and thrice-weekly applications. PMID- 23110606 TI - eMedOffice: a web-based collaborative serious game for teaching optimal design of a medical practice. AB - BACKGROUND: Preparing medical students for the takeover or the start-up of a medical practice is an important challenge in Germany today. Therefore, this paper presents a computer-aided serious game (eMedOffice) developed and currently in use at the RWTH Aachen University Medical School. The game is part of the attempt to teach medical students the organizational and conceptual basics of the medical practice of a general practitioner in a problem-based learning environment. This paper introduces methods and concepts used to develop the serious game and describes the results of an evaluation of the game's application in curricular courses at the Medical School. RESULTS: Results of the conducted evaluation gave evidence of a positive learning effect of the serious game. Educational supervisors observed strong collaboration among the players inspired by the competitive gaming aspects. In addition, an increase in willingness to learn and the exploration of new self-invented ideas were observed and valuable proposals for further prospective enhancements were elicited. A statistical analysis of the results of an evaluation provided a clear indication of the positive learning effect of the game. A usability questionnaire survey revealed a very good overall score of 4.07 (5=best, 1=worst). CONCLUSIONS: We consider web based, collaborative serious games to be a promising means of improving medical education. The insights gained by the implementation of eMedOffice will promote the future development of more effective serious games for integration into curricular courses of the RWTH Aachen University Medical School. PMID- 23110607 TI - Evaluation of radial distribution of cartilage degeneration and necessity of pre contrast measurements using radial dGEMRIC in adults with acetabular dysplasia. AB - BACKGROUND: The purpose of the present study was to investigate the radial distribution patterns of cartilage degeneration in dysplastic hips at different stages of secondary osteoarthritis (OA) by using radial delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), and to assess whether pre-contrast measurements are necessary. METHODS: Thirty-five hips in 21 subjects (mean age +/- SD, 27.6 +/- 10.8 years) with acetabular dysplasia (lateral CE angle < 25 degrees ) were studied. Severity of OA was assessed on radiographs using Tonnis grading. Pre- (T1pre) and post-contrast T1 (T1Gd) values were measured at 7 sub-regions on radial reformatted slices acquired from a 3 dimensional (3D) T1 mapping sequence using a 1.5 T MR scanner. Values of radial T1pre, T1Gd and DeltaR1 (1/T1Gd - 1/T1pre) of subgroups with different severity of OA were compared to those of the subgroup without OA using nonparametric tests, and bivariate linear Pearson correlations between radial T1Gd and DeltaR1 were analyzed for each subgroup. RESULTS: Compared to the subgroup without OA, the subgroup with mild OA was observed with a significant decrease in T1Gd in the anterosuperior to superior sub-regions (mean, 476 ~ 507 ms, p = 0.026 ~ 0.042) and a significant increase in DeltaR1 in the anterosuperior to superoposterior and posterior sub-regions (mean, 0.93 ~ 1.37 s-1, p = 0.012 ~ 0.042). The subgroup with moderate to severe OA was observed with a significant overall decrease in T1Gd (mean, 404 ~ 452 ms, p = 0.001 ~ 0.020) and an increase in DeltaR1 (mean, 1.17 ~1.69 s-1, p = 0.001 ~ 0.020). High correlations were observed between radial T1Gd and DeltaR1 for all subgroups (r = -0.869 ~ -0.944, p < 0.001). CONCLUSIONS: Radial dGEMRIC without pre-contrast measurements is useful for evaluating different patterns of cartilage degeneration in the entire hip joint of patients with hip dysplasia, particularly for those in early stages of secondary OA. PMID- 23110608 TI - Efficacy of an adjunctive brief psychodynamic psychotherapy to usual inpatient treatment of depression: rationale and design of a randomized controlled trial. AB - BACKGROUND: A few recent studies have found indications of the effectiveness of inpatient psychotherapy for depression, usually of an extended duration. However, there is a lack of controlled studies in this area and to date no study of adequate quality on brief psychodynamic psychotherapy for depression during short inpatient stay exists. The present article describes the protocol of a study that will examine the relative efficacy, the cost-effectiveness and the cost-utility of adding an Inpatient Brief Psychodynamic Psychotherapy to pharmacotherapy and treatment-as-usual for inpatients with unipolar depression. METHODS/DESIGN: The study is a one-month randomized controlled trial with a two parallel group design and a 12-month naturalistic follow-up. A sample of 130 consecutive adult inpatients with unipolar depression and Montgomery-Asberg Depression Rating Scale score over 18 will be recruited. The study is carried out in the university hospital section for mood disorders in Lausanne, Switzerland. Patients are assessed upon admission, and at 1-, 3- and 12- month follow-ups. Inpatient therapy is a manualized brief intervention, combining the virtues of inpatient setting and of time-limited dynamic therapies (focal orientation, fixed duration, resource-oriented interventions). Treatment-as-usual represents the best level of practice for a minimal treatment condition usually proposed to inpatients. Final analyses will follow an intention-to-treat strategy. Depressive symptomatology is the primary outcome and secondary outcome includes measures of psychiatric symptomatology, psychosocial role functioning, and psychodynamic-emotional functioning. The mediating role of the therapeutic alliance is also examined. Allocation to treatment groups uses a stratified block randomization method with permuted block. To guarantee allocation concealment, randomization is done by an independent researcher. DISCUSSION: Despite the large number of studies on treatment of depression, there is a clear lack of controlled research in inpatient psychotherapy during the acute phase of a major depressive episode. Research on brief therapy is important to take into account current short lengths of stay in psychiatry. The current study has the potential to scientifically inform appropriate inpatient treatment. This study is the first to address the issue of the economic evaluation of inpatient psychotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ACTRN12612000909820). PMID- 23110610 TI - The coming era of quadrivalent human influenza vaccines: who will benefit? AB - Influenza vaccines form the mainstay of public health and personal protection against infection with seasonal influenza viruses. These vaccines are designed to protect people against infection with the currently circulating influenza viruses. Since the late 1970s, this has required the use of a trivalent vaccine consisting of two influenza A viruses and one influenza B virus. However, since the early 2000s, a second lineage of B viruses has regularly circulated in many countries that is quite distinct, with only low levels of cross protection between the two lineages. Due to the difficulties in determining which B lineage will circulate, and matching this with the vaccine to be administered some 6-9 months later, there has been an increasing interest in the development of quadrivalent influenza vaccines, containing two influenza B viruses representing both lineages. Development has been rapid and we are now on the cusp of a new generation of influenza vaccines becoming available. This paper discusses the issues and rationale behind this welcome development and who is likely to benefit most. PMID- 23110611 TI - Low-energy extracorporeal shock wave therapy enhances skin wound healing in diabetic mice: a critical role of endothelial nitric oxide synthase. AB - Low-energy extracorporeal shock wave (LE-ESW) treatment has been shown to accelerate wound repair; however, the mechanisms of treatment remain unclear. In the present study, we addressed the role of endothelial nitric oxide synthase (eNOS). A single LE-ESW treatment accelerated the healing of wounds in diabetic mice caused by the injection of streptozotocin. This accelerated healing was accompanied by the increased expression of eNOS and vascular endothelial growth factor (VEGF) and the generation of new vessels at the wound tissues. These results raised the possibility that eNOS may be involved in the beneficial effects of LE-ESW treatment. To address this possibility, we compared the effects of this treatment between mice with a genetic disruption of eNOS knockout (eNOS KO mice) and wild-type (WT) control mice. Interestingly, the LE-ESW-induced acceleration of wound closure and the increase in VEGF expression and neovascularization was significantly attenuated in eNOS-KO mice compared with WT mice. Considered collectively, these results showed that eNOS was induced at the wound tissues by LE-ESW treatment and played a critical role in the therapeutic effects of this treatment by accelerating the wound healing by promoting VEGF expression and neovascularization. PMID- 23110609 TI - Insulin detemir: a review of its use in the management of diabetes mellitus. AB - Insulin detemir (Levemir(r)) is a long-acting insulin analogue indicated for use as basal insulin therapy in patients with type 1 or 2 diabetes mellitus. The protracted action of insulin detemir is explained by increased self-association and reversible binding to albumin, which slows its systemic absorption from the injection site. In glucose-clamp studies, less within-patient variability in glucose-lowering effect was seen with insulin detemir than with neutral protamine Hagedorn (NPH) insulin or insulin glargine in patients with type 1 or 2 diabetes. The beneficial effect of insulin detemir on glycaemic control was shown in numerous randomized, open-label, multicentre trials, including when used as basal bolus therapy in patients with type 1 or 2 diabetes and as basal therapy in addition to oral antidiabetic drugs in insulin-naive patients with type 2 diabetes. In terms of glycosylated haemoglobin (HbA(1c)).[primary endpoint in most trials], insulin detemir was generally at least as effective as NPH insulin, insulin glargine or insulin lispro protamine suspension in patients with type 1 or 2 diabetes, and at least as effective as biphasic insulin aspart in patients with type 2 diabetes. Less within-patient variability in blood glucose was also generally seen with insulin detemir than with NPH insulin in patients with type 1 or 2 diabetes. Significantly less weight gain was generally seen with insulin detemir than with NPH insulin in patients with type 1 diabetes or with insulin detemir than with NPH insulin, insulin glargine, insulin lispro protamine suspension or biphasic insulin aspart (in one study) in patients with type 2 diabetes (i.e. insulin detemir generally had a weight-sparing effect). The addition of insulin detemir to liraglutide plus metformin improved glycaemic control in insulin-naive patients with type 2 diabetes and inadequate glycaemic control, although a significantly greater reduction in bodyweight was seen in patients receiving liraglutide plus metformin than in those receiving add-on therapy with insulin detemir. Results of two trials in patients aged 2-16 or 6-17 years (and a subgroup analysis in children aged 2-5 years) indicate that a basal bolus insulin regimen incorporating insulin detemir appears to be a suitable option for use in paediatric patients with type 1 diabetes. Less within-patient variation in self-measured fasting plasma glucose was seen with insulin detemir than with NPH insulin in one of the studies. Insulin detemir was noninferior to NPH insulin in pregnant women with type 1 diabetes in terms of the HbA(1c) value achieved at 36 gestational weeks. In addition, maternal and neonatal outcomes with insulin detemir were similar to those seen with NPH insulin. Subcutaneous insulin detemir was generally well tolerated in the treatment of patients with type 1 or 2 diabetes, including in paediatric patients and pregnant women with type 1 diabetes. The majority of adverse events, including serious adverse events, reported in insulin detemir recipients were not considered to be related to the study drug. Insulin detemir was generally associated with a significantly lower risk of nocturnal hypoglycaemia than NPH insulin in patients with type 1 or 2 diabetes, particularly nocturnal minor hypoglycaemia. In conclusion, insulin detemir is a useful option for use as basal insulin therapy in patients with type 1 or 2 diabetes. PMID- 23110612 TI - The earliest records of internally stratified cyanobacterial and algal lichens from the Lower Devonian of the Welsh Borderland. AB - Lichenization is assumed to be a very ancient mode of fungal nutrition, but fossil records are rare. Here we describe two fragments of exceptionally preserved, probably charred, lichen thalli with internal stratification. Cyanolichenomycites devonicus has a cyanobacterial and Chlorolichenomycites salopensis a unicellular, presumably green algal photobiont. Fruiting bodies are missing. Cyanolichenomycites devonicus forms asexual spores in a pycnidium. All specimens were examined with scanning electron microscopy techniques. The fossils were extracted by maceration. Extant lichens and free-living cyanobacteria were either experimentally charcoalified for comparison or conventionally prepared. Based on their septate hyphal structure, both specimens are tentatively interpreted as representatives of the Pezizomycotina (Ascomycota). Their presence in 415 million yr (Myr) old rocks from the Welsh Borderland predates existing Late Cretaceous records of pycnidial conidiomata by some 325 Myr and Triassic records of lichens with broadly similar organization by some 195 Myr. These fossils represent the oldest known record of lichens with symbionts and anatomy as typically found in morphologically advanced taxa today. The latter does not apply to Winfrenatia reticulata, the enigmatic crustose lichen fossil from the Lower Devonian, nor to presumed lichen-like organisms such as the Cambrian Farghera robusta or to the Lower Devonian Spongiophyton minutissimum. PMID- 23110613 TI - Nordic walking decreased circulating chemerin and leptin concentrations in middle aged men with impaired glucose regulation. AB - BACKGROUND: Dysfunction of adipose tissue is one of the major factors leading to insulin resistance. Altered adipokine concentration is an early sign of adipose tissue dysfunction. The aim of this study was to assess the impact of exercise intervention on adipokine profile, glycemic control, and risk factors of the metabolic syndrome (MeS) in men with impaired glucose regulation (IGR). METHODS: Overweight and obese men with IGR (n =144) aged 40-65 years were studied at baseline and at 12 weeks in a randomized controlled multicenter intervention study. BMI varied from 25.1 to 34.9. The subjects were randomized into one of three groups: 1) a control group (C; n =47), 2) a Nordic walking group (NW; n =48), or 3) a resistance training group (RT; n =49). RESULTS: Leptin concentrations decreased in the NW group compared to both other groups. Both types of exercise intervention significantly decreased serum chemerin concentrations compared to the C group. In the NW group also body fat percentage, fatty liver index (FLI), and total and LDL cholesterol concentrations decreased compared to the RT group. CONCLUSIONS: Nordic walking intervention seems to decrease chemerin and leptin levels, and subjects in this intervention group achieved the most beneficial effects on components of MeS. PMID- 23110614 TI - Tandem sequence of phenol oxidation and intramolecular addition as a method in building heterocycles. AB - A tandem phenol oxidation-Michael addition furnishing oxo- and -aza-heterocycles has been developed. Dirhodium caprolactamate [Rh(2)(cap)(4)] catalyzed oxidation by T-HYDRO of phenols with alcohols, ketones, amides, carboxylic acids, and N-Boc protected amines tethered to their 4-position afforded 4-(tert butylperoxy)cyclohexa-2,5-dienones that undergo Bronsted acid catalyzed intramolecular Michael addition in one-pot to produce oxo- and -aza-heterocycles in moderate to good yields. The scope of the developed methodology includes dipeptides Boc-Tyr-Gly-OEt and Boc-Tyr-Phe-Me and provides a pathway for understanding the possible transformations arising from oxidative stress of tyrosine residues. A novel method of selective cleavage of O-O bond in hindered internal peroxide using TiCl(4) has been discovered in efforts directed to the construction of cleroindicin F, whose synthesis was completed in 50% yield over just 3 steps from tyrosol using the developed methodology. PMID- 23110616 TI - Global lack of flyway structure in a cosmopolitan bird revealed by a genome wide survey of single nucleotide polymorphisms. AB - Knowledge about population structure and connectivity of waterfowl species, especially mallards (Anas platyrhynchos), is a priority because of recent outbreaks of avian influenza. Ringing studies that trace large-scale movement patterns have to date been unable to detect clearly delineated mallard populations. We employed 363 single nucleotide polymorphism markers in combination with population genetics and phylogeographical approaches to conduct a population genomic test of panmixia in 801 mallards from 45 locations worldwide. Basic population genetic and phylogenetic methods suggest no or very little population structure on continental scales. Nor could individual-based structuring algorithms discern geographical structuring. Model-based coalescent analyses for testing models of population structure pointed to strong genetic connectivity among the world's mallard population. These diverse approaches all support the conclusion that there is a lack of clear population structure, suggesting that the world's mallards, perhaps with minor exceptions, form a single large, mainly interbreeding population. PMID- 23110615 TI - Laboratory markers of disease severity in Plasmodium knowlesi infection: a case control study. AB - BACKGROUND: Plasmodium knowlesi malaria causes severe disease in up to 10% of cases in Malaysian Borneo and has a mortality rate of 1 - 2%. However, laboratory markers with the ability to identify patients at risk of developing complications have not yet been assessed as they have for other species of Plasmodium. METHODS: A case control study was undertaken in two hospitals in Sarikei and Sibu, Malaysian Borneo. One hundred and ten patients with uncomplicated (n = 93) and severe (n = 17) P. knowlesi malaria were studied. Standardized pigment-containing neutrophil (PCN) count, parasite density and platelet counts were determined and analysed by logistic regression and receiver operating characteristic (ROC) analysis. RESULTS: The PCN count was strongly associated with risk of disease severity. Patients with high parasite density (>= 35,000/MUl) or with thrombocytopaenia (<= 45,000/MUl) were also more likely to develop complications (odds ratio (OR) = 9.93 and OR = 5.27, respectively). The PCN count yielded the highest area under the ROC curve (AUC) estimate among all markers of severity (AUC = 0.8561, 95% confidence interval: 0.7328, 0.9794). However, the difference between all parameter AUC estimates was not statistically significant (Wald test, p = 0.73). CONCLUSION: Counting PCN is labour-intensive and not superior in predicting severity over parasitaemia and platelet counts. Parasite and platelet counts are simpler tests with an acceptable degree of precision. Any adult patient diagnosed with P. knowlesi malaria and having a parasite count >= 35,000/MUl or >= 1% or a platelet count <= 45,000/MUl can be regarded at risk of developing complications and should be managed according to current WHO guidelines for the treatment of severe malaria. PMID- 23110617 TI - Electrophoresis and dielectric dispersion of spherical polyelectrolyte brushes. AB - Spherical polyelectrolyte brushes (SPBs) consist of a rigid core on which polyelectrolyte chains are grafted in such a way that in certain conditions (low ionic strength and high charge of the chains) the polymer chains extend radially toward the liquid medium. Because of the hairy-like structure of the polymer brushes, the typical soft-particle approach used for explaining the behavior of polyelectrolyte-coated particles must be modified, using the assumptions that the density of charged segments in the polymer chains decreases with the squared distance to the rigid core surface and that the same happens to the friction between the brushes and the surrounding fluid. Interest in clarifying the electrokinetics of these systems is not just academic. It has recently been found experimentally (Jimenez et al., Soft Matter 2011, 7, 3758-3762) that the response of concentrated suspensions of spherical polyelectrolyte brushes in the presence of alternating electric fields shows a number of unexpected features. Both dielectric and dynamic electrophoretic mobility spectra (respectively, dependences of the electric permittivity and the AC electrophoretic mobility on the frequency of the applied field) showed very special aspects, with giant values of the mobility and an unusually strong dielectric relaxation in the kHz region. In the present paper we give a full account of the electrodynamics of such systems, based on a cell model for describing the hydrodynamic and electrical interactions between the particles. It is found that the low-frequency dynamic mobility of SPBs is much higher than that of rigid particles of comparable size and charge, making any interpretation based on zeta potential estimations of very limited applicability. The very characteristic feature of SPBs in concentrated suspensions, namely, the enhanced alpha relaxation, can be explained by considering an adequate description of the field-induced perturbations in the counterion and co-ion concentrations, well developed both outside and inside the soft layer in the case of brush-coated particles. It can be also pointed out that the dynamic electrophoretic mobility of SPBs increases with the volume fraction of particles, as a consequence of the large thickness of the brush. Predictions are also shown for the effects of friction coefficient and charge of the polyelectrolyte layer. The results compare well with experimental spectra of the dynamic mobility and electric permittivity of moderately concentrated suspensions of SPBs consisting of a 50 nm polystyrene core with grafted poly(styrene sulfonate) chains some 140 nm in length. PMID- 23110618 TI - Sexual medicine reflects the light of knowledge. PMID- 23110619 TI - Axel Fugl-Meyer 1934-2012. PMID- 23110622 TI - Maternal and umbilical cord ischemia-modified albumin levels in nonreassuring fetal heart rate tracings regarding the mode of delivery. AB - OBJECTIVE: To evaluate umbilical cord blood ischemia-modified albumin (IMA) levels in cases of fetal distress (FD) and to explore fetal blood IMA levels regarding the route of delivery. METHODS: Umbilical cord and maternal serum IMA concentrations were assessed in term 40 cases with cesarean section (CS) due to FD, 76 cases with elective repeat CS and 85 cases with noncomplicated vaginal delivery. RESULTS: The maternal and umbilical cord IMA levels were significantly lower in vaginal deliveries when compared with CS cases either in FD or previous CS groups (p = 0.02). Although no statistically significant difference was found in IMA levels of CS groups (previous CS vs. FD), cord blood IMA levels tend to be higher in FD group. Neither demographic characteristics nor fetal outcome parameters were found to have any correlation with maternal IMA levels. However, umbilical cord IMA levels were found to be negatively correlated with 1th min Apgar scores (r = -0.143, p = 0.043). CONCLUSIONS: IMA seems to be responsive to hypoxic FD showing the highest levels in cases with severe fetal hypoxia. Higher levels of IMA in cases with elective repeat CS might indicate acute transient hypoxia and possible myocardial ischemia in these cases. PMID- 23110623 TI - Fluorescent mu selective opioid ligands from a mixture based cyclic peptide library. AB - A positional scanning cyclic peptide library was generated using a penta-peptide thioester scaffold. Glycine was fixed at position R(1). Diaminopropionic acid was fixed at position R(3), with its gamma-amino attaching to an anthraniloyl group. Positions R(2) and R(4) contained 36 L- and D- amino acids and position R(5) contained 19 L- amino acids. Cyclization was performed in a mixture of acetonitrile and 1.5 M aqueous imidazole solution (7:1 v/v) at room temperature for 5 days. No significant cross-oligomerization was detected under the cyclization conditions. The library was screened in a binding assay for mu opioid receptor, identifying the active amino acid mixture at each position. A total of 40 individual cyclic peptides were identified and synthesized by the combinations of the most active amino acid mixtures found at three positions 5 * 4 * 2. Two cyclic peptides exhibited high binding affinities to opioid receptor. The most active cyclic peptide in the library was yielded to have Tyr at R(2), D-Lys at R(4), and Tyr at R(5). Further investigation on this compound revealed the side chain-to-tail isomer to have greater binding affinity (14 nM) than the head-to tail isomer (39 nM). Both isomers were selective for the mu-opioid receptor. PMID- 23110624 TI - Female sex hormones and differentiated thyroid carcinoma. PMID- 23110625 TI - Inhibition of Jak-STAT3 pathway enhances bufalin-induced apoptosis in colon cancer SW620 cells. AB - BACKGROUND: The purpose of the research is to investigate the roles of Jak-STAT3 signaling pathway in bufalin-induced apoptosis in colon cancer SW620 cells. METHODS: The inhibitory effects of bufalin on cell proliferation were determined by MTT (Methyl thiazolyltetrazolium) assay. The morphological changes of cells were measured by Wright-Giemsa staining. The cell cycle arrest and apoptosis were tested by flow cytometry analysis. Western Blot was used to determine the protein expression of the apoptosis inhibitors livin and caspase-3, the apoptosis-related proteins Bax and Bcl-2, as well as the key protein kinases in the Jak-stat3 signaling pathway, stat3 and p-stat3. RESULTS: (1) Bufalin inhibited the proliferation of SW620 cells. IC50 at 24 h, 48 h and 72 h were 76.72 +/- 6.21 nmol/L, 34.05 +/- 4.21 nmol/L and 16.7 +/- 6.37 nmol/L. (2) Bufalin induced SW620 cell cycle arrest and apoptosis, indicated by the appearance of apoptotic bodies; (3) The results from flow cytometry demonstrated that there was cell cycle G2/M phase arrest in 20 nmol/L bufalin treatment group (36.29 +/- 2.11% vs 18.39 +/- 1.74%, P<0.01); there was a sub-diploid apoptosis peak in 80 nmol/L bufalin treatment group (19.69 +/- 1.63% vs 0.99 +/- 0.23%, P <0.01). The apoptosis rate was 34.63 +/- 2.57% (vs 19.69 +/- 1.63%, P = 0.002) in JAK kinase inhibitor AG490 plus bufalin treatment group. (4) During the process of bufalin-induced apoptosis in SW620 cells, transient activation of p-stat3 inhibited the activation of stat3, up-regulated Bax expression, down-regulated livin and Bcl-2 expression (P<0.01), and activated caspase-3. Inhibition of Jak-stat3 signaling pathway by pre-treatment with AG490 significantly enhanced the bufalin-induced apoptosis (P<0.01), further up-regulated Bax protein expression, down-regulated livin and Bcl-2 protein expression and enhanced caspase-3 activation. CONCLUSIONS: Bufalin not only inhibited the growth of colon cancer SW620 cells, but also induced apoptosis of SW620 cells. Activation of caspase-3, up-regulation of Bax, down regulation of livin and Bcl-2, as well as inhibition of Jak-stat3 signaling pathway might be the important mechanisms for the bufalin-induced apoptosis. PMID- 23110626 TI - The cost effectiveness of teriparatide as a first-line treatment for glucocorticoid-induced and postmenopausal osteoporosis patients in Sweden. AB - BACKGROUND: This paper presents the model and results to evaluate the use of teriparatide as a first-line treatment of severe postmenopausal osteoporosis (PMO) and glucocorticoid-induced osteoporosis (GIOP). The study's objective was to determine if teriparatide is cost effective against oral bisphosphonates for two large and high risk cohorts. METHODS: A computer simulation model was created to model treatment, osteoporosis related fractures, and the remaining life of PMO and GIOP patients. Natural mortality and additional mortality from osteoporosis related fractures were included in the model. Costs for treatment with both teriparatide and oral bisphosphonates were included. Drug efficacy was modeled as a reduction to the relative fracture risk for subsequent osteoporosis related fractures. Patient health utilities associated with age, gender, and osteoporosis related fractures were included in the model. Patient costs and utilities were summarized and incremental cost-effectiveness ratios (ICERs) for teriparatide versus oral bisphosphonates and teriparatide versus no treatment were estimated.For each of the PMO and GIOP populations, two cohorts differentiated by fracture history were simulated. The first contained patients with both a historical vertebral fracture and an incident vertebral fracture. The second contained patients with only an incident vertebral fracture. The PMO cohorts simulated had an initial Bone Mineral Density (BMD) T-Score of -3.0. The GIOP cohorts simulated had an initial BMD T-Score of -2.5. RESULTS: The ICERs for teriparatide versus bisphosphonate use for the one and two fracture PMO cohorts were ?36,995 per QALY and ?19,371 per QALY. The ICERs for teriparatide versus bisphosphonate use for the one and two fracture GIOP cohorts were ?20,826 per QALY and ?15,155 per QALY, respectively. CONCLUSIONS: The selection of teriparatide versus oral bisphosphonates as a first-line treatment for the high risk PMO and GIOP cohorts evaluated is justified at a cost per QALY threshold of ?50,000. PMID- 23110627 TI - Case of paraneoplastic pemphigus associated with retroperitoneal diffuse large B cell lymphoma and fatal bronchiolitis obliterans-like lung disease. PMID- 23110629 TI - High-throughput profiling of peptide-RNA interactions using peptide microarrays. AB - A rapid and quantitative method to evaluate binding properties of hairpin RNAs to peptides using peptide microarrays has been developed. The microarray technology was shown to be a powerful tool for high-throughput analysis of RNA-peptide interactions by its application to profiling interactions between 111 peptides and six hairpin RNAs. The peptide microarrays were also employed to measure hundreds of dissociation constants (K(d)) of RNA-peptide complexes. Our results reveal that both hydrophobic and hydrophilic faces of amphiphilic peptides are likely involved in interactions with RNAs. Furthermore, these results also show that most of the tested peptides bind hairpin RNAs with submicromolar K(d) values. One of the peptides identified by using this method was found to have good inhibitory activity against TAR-Tat interactions in cells. Because of their great applicability to evaluation of nearly all types of RNA-peptide interactions, peptide microarrays are expected to serve as robust tools for rapid assessment of peptide-RNA interactions and development of peptide ligands against RNA targets. PMID- 23110631 TI - Use of intravenous lipid therapy in three cases of feline permethrin toxicosis. AB - OBJECTIVE: To describe the use of intravenous lipid emulsion (IVLE) as an adjunctive therapy in 3 cats with permethrin toxicosis. CASE SERIES SUMMARY: Three cats with permethrin toxicosis were treated with IVLE in addition to the current accepted treatment regime. All 3 cats demonstrated a subjective rapid clinical improvement after the administration of IVLE, with no adverse reactions observed. NEW OR UNIQUE INFORMATION PROVIDED: This is the first reported use of IVLE for feline permethrin toxicosis, with encouraging results. A possible reduction in costs associated with treatment may contribute to a reduction in euthanasia. Further investigation of the use of IVLEs in permethrin toxicosis is warranted. PMID- 23110628 TI - Alcohol dehydrogenase- and rat liver cytosol-dependent bioactivation of 1-chloro 2-hydroxy-3-butene to 1-chloro-3-buten-2-one, a bifunctional alkylating agent. AB - 1,3-Butadiene (BD) is an air pollutant whose toxicity and carcinogenicity have been considered primarily mediated by its reactive metabolites, 3,4-epoxy-1 butene and 1,2,3,4-diepoxybutane, formed in liver and extrahepatic tissues by cytochromes P450s. A possible alternative metabolic pathway in bone marrow and immune cells is the conversion of BD to the chlorinated allylic alcohol 1-chloro 2-hydroxy-3-butene (CHB) by myeloperoxidase in the presence of hydrogen peroxide and chloride ion. In the present study, we investigated the in vitro bioactivation of CHB by alcohol dehydrogenases (ADH) under in vitro physiological conditions (pH 7.4, 37 degrees C). The results provide clear evidence for CHB being converted to 1-chloro-3-buten-2-one (CBO) by purified horse liver ADH and rat liver cytosol. CBO readily reacted with glutathione (GSH) under assay conditions to form three products: two CBO-mono-GSH conjugates [1-chloro-4-(S glutathionyl)butan-2-one (3) and 1-(S-glutathionyl)-3-buten-2-one (4)] and one CBO-di-GSH conjugate [1,4-bis(S-glutathionyl)butan-2-one (5)]. CHB bioactivation and the ratios of the three GSH conjugates formed were dependent upon incubation time, GSH and CHB concentrations, and the presence of ADH or rat liver cytosol. The ADH enzymatic reaction followed Michaelis-Menten kinetics with a K(m) at 3.5 mM and a k(cat) at 0.033 s(-1). After CBO was incubated with freshly isolated mouse erythrocytes, globin dimers were detected using SDS-PAGE and silver staining, providing evidence that CBO can act as a protein cross-linking agent. Collectively, the results provide clear evidence for CHB bioactivation by ADH and rat liver cytosol to yield CBO. The bifunctional alkylating ability of CBO suggests that it may play a role in BD toxicity and/or carcinogenicity. PMID- 23110632 TI - Prevalence of psychological distress and mental disorders, and use of mental health services in the epidemiological catchment area of Montreal South-West. AB - BACKGROUND: This report presents the initial results of the first Epidemiological Catchment Area Study in mental health in Canada. Five neighbourhoods in the South West sector of Montreal, with a population of 258,000, were under study. The objectives of the research program were: 1) to assess the prevalence and incidence of psychological distress, mental disorders, substance abuse, parasuicide, risky behaviour and quality of life; 2) to examine the links and interactions between individual determinants, neighbourhood ecology and mental health in each neighbourhood; 3) to identify the conditions facilitating the integration of individuals with mental health problems; 4) to analyse the impact of the social, economic and physical aspects of the neighbourhoods using a geographic information system. 5) to verify the adequacy of mental health services. METHOD: A longitudinal study in the form of a community survey was used, complemented by focused qualitative sub-studies. The longitudinal study included a randomly selected sample of 2,433 individuals between the ages of 15 and 65 in the first wave of data collection, and three other waves are projected. An overview of the methods is presented. RESULTS: The prevalence of psychological distress, mental disorders and use of mental health services and their correlates are described for the first wave of data collection. CONCLUSION: Several vulnerable groups and risk factors related to socio-demographic variables have been identified such as: gender, age, marital status, income, immigration and language. These results can be used to improve treatment services, prevention of mental disorders, and mental health promotion. PMID- 23110633 TI - "Snake-oil," "quack medicine," and "industrially cultured organisms:" biovalue and the commercialization of human microbiome research. AB - BACKGROUND: Continued advances in human microbiome research and technologies raise a number of ethical, legal, and social challenges. These challenges are associated not only with the conduct of the research, but also with broader implications, such as the production and distribution of commercial products promising maintenance or restoration of good physical health and disease prevention. In this article, we document several ethical, legal, and social challenges associated with the commercialization of human microbiome research, focusing particularly on how this research is mobilized within economic markets for new public health uses. METHODS: We conducted in-depth, semi-structured interviews (2009-2010) with 63 scientists, researchers, and National Institutes of Health project leaders ("investigators") involved with human microbiome research. Interviews explored a range of ethical, legal, and social dimensions of human microbiome research, including investigators' perspectives on commercialization. Using thematic content analysis, we identified and analyzed emergent themes and patterns. RESULTS: Investigators discussed the commercialization of human microbiome research in terms of (1) commercialization, probiotics, and issues of safety, (2) public awareness of the benefits and risks of dietary supplements, and (3) regulation. CONCLUSION: The prevailing theme of ethical, legal, social concern focused on the need to find a balance between the marketplace, scientific research, and the public's health. The themes we identified are intended to serve as points for discussions about the relationship between scientific research and the manufacture and distribution of over-the counter dietary supplements in the United States. PMID- 23110634 TI - Synthesis and structural characterization of new Cu(I) complexes with the antithyroid drug 6-n-propyl-thiouracil. study of the Cu(I)-catalyzed intermolecular cycloaddition of iodonium ylides toward benzo[b]furans with pharmaceutical implementations. AB - The reaction of copper(I) iodide with 6-n-propylthiouracil (ptu) in the presence or absence of the triphenylphosphine (tpp) or tri(p-tolyl)phosphine (tptp) in a 1:1:2 molar ratio forms the mixed ligand Cu(I) complex with formula [CuI(ptu)2](toluene) (1), [CuI(tpp)2(ptu)] (2), and [CuI(tptp)2(ptu)] (3). The complexes have been characterized by FT-IR, (1)H NMR, UV-vis, spectroscopic techniques, and single crystal X-ray crystallography. Two sulfur atoms from two ptu ligands and one iodide form a trigonal geometry around the metal center in 1. Intramolecular interactions through hydrogen bonds lead to a bend ribbon polymeric supramolecular architecture with zigzag conformation. Two phosphorus atoms from two arylphosphines, one sulfur atom, and one iodide anion form a tetrahedron around the copper ion in case of 2 and 3. Intramolecular hydrogen bonding interactions lead to dimerization. Complexes 1-3 and the already known ones with formulas, [(tpSb)2Cu(MU2-I)2Cu(tpSb)2] (4) (tbSb = triphenylstibine), [(tpp)Cu(MU2-I)2Cu(tpp)2] (5), [(tpp)Cu(MU2-Cl)2Cu(tpp)2] (6), [CuCl(tpp)3.(CH3CN)] (7), and [AuCl(tpp)] (8), were used to study their catalytic activity on the intermolecular cycloaddition of iodonium ylides toward benzo[b]furans formation. The results show that both the metal and the ligand type affect the catalytic affinity of the complexes. The highest yield of benzo[b]furan was derived when complexes 2, 3, and 4 were used as catalysts. The mechanism of the Cu(I)-catalyzed and uncatalyzed intramolecular cycloaddition of iodonium ylide has been also thoroughly explored by means of ab initio electronic structure calculation methods, and the results are compared with the experimental ones. PMID- 23110635 TI - Multi-scale RNA comparison based on RNA triple vector curve representation. AB - BACKGROUND: In recent years, the important functional roles of RNAs in biological processes have been repeatedly demonstrated. Computing the similarity between two RNAs contributes to better understanding the functional relationship between them. But due to the long-range correlations of RNA, many efficient methods of detecting protein similarity do not work well. In order to comprehensively understand the RNA's function, the better similarity measure among RNAs should be designed to consider their structure features (base pairs). Current methods for RNA comparison could be generally classified into alignment-based and alignment free. RESULTS: In this paper, we propose a novel wavelet-based method based on RNA triple vector curve representation, named multi-scale RNA comparison. Firstly, we designed a novel numerical representation of RNA secondary structure termed as RNA triple vectors curve (TV-Curve). Secondly, we constructed a new similarity metric based on the wavelet decomposition of the TV-Curve of RNA. Finally we also applied our algorithm to the classification of non-coding RNA and RNA mutation analysis. Furthermore, we compared the results to the two well-known RNA comparison tools: RNAdistance and RNApdist. The results in this paper show the potentials of our method in RNA classification and RNA mutation analysis. CONCLUSION: We provide a better visualization and analysis tool named TV-Curve of RNA, especially for long RNA, which can characterize both sequence and structure features. Additionally, based on TV-Curve representation of RNAs, a multi-scale similarity measure for RNA comparison is proposed, which can capture the local and global difference between the information of sequence and structure of RNAs. Compared with the well-known RNA comparison approaches, the proposed method is validated to be outstanding and effective in terms of non-coding RNA classification and RNA mutation analysis. From the numerical experiments, our proposed method can capture more efficient and subtle relationship of RNAs. PMID- 23110636 TI - Accelerating adaptation of natural resource management to address climate change. AB - Natural resource managers are seeking tools to help them address current and future effects of climate change. We present a model for collaborative planning aimed at identifying ways to adapt management actions to address the effects of climate change in landscapes that cross public and private jurisdictional boundaries. The Southwest Climate Change Initiative (SWCCI) piloted the Adaptation for Conservation Targets (ACT) planning approach at workshops in 4 southwestern U.S. landscapes. This planning approach successfully increased participants' self-reported capacity to address climate change by providing them with a better understanding of potential effects and guiding the identification of solutions. The workshops fostered cross-jurisdictional and multidisciplinary dialogue on climate change through active participation of scientists and managers in assessing climate change effects, discussing the implications of those effects for determining management goals and activities, and cultivating opportunities for regional coordination on adaptation of management plans. Facilitated application of the ACT framework advanced group discussions beyond assessing effects to devising options to mitigate the effects of climate change on specific species, ecological functions, and ecosystems. Participants addressed uncertainty about future conditions by considering more than one climate-change scenario. They outlined opportunities and identified next steps for implementing several actions, and local partnerships have begun implementing actions and conducting additional planning. Continued investment in adaptation of management plans and actions to address the effects of climate change in the southwestern United States and extension of the approaches used in this project to additional landscapes are needed if biological diversity and ecosystem services are to be maintained in a rapidly changing world. PMID- 23110637 TI - Going the distance: early results of a distributed medical education initiative for Royal College residencies in Canada. AB - BACKGROUND: There is a shortage of specialty physicians practising in rural Canada: only 2.4% of Canadian specialist physicians practise rurally. Numerous strategies have been proposed and attempted that aim to increase the number of rural physicians. These include undergraduate and postgraduate distributed medical education opportunities. The Distributed Royal College Initiative at the University of Calgary is increasing the exposure of specialty residents to rural medicine through regional rotations and electives. An assessment of the initial impacts of this programme was made. METHODS: Specialty residents were sent a voluntary survey following their regional rotation in academic year 2010-2011. The survey measured each resident's satisfaction with the experience, interest in undertaking another rotation and the impact of the rotation on potential rural practice location. The survey asked for written comments on the rotation. Data were analysed using descriptive statistics. RESULTS: A total of 73% (29) of the 40 eligible residents completed the survey that was distributed upon completion of the rotation. In the survey, 45% of respondents indicated they would have been likely to practise in a regional community prior to the experience. This changed to 76% following the rotation. Analysis of the comments revealed strong positive characteristics of the experience across all disciplines. CONCLUSIONS: Specialty based, rural distributed programmes were perceived by the residents as educationally valuable and may be crucial in helping shift attitudes towards rural practice. Specific successful characteristics of the rotations provide direction to increase their quality further. These findings need to be verified in a larger sample. PMID- 23110639 TI - The role of osteoprotegerin in cardiovascular disease. AB - Osteoprotegerin (OPG) is a 401 amino acid N-glycosylated protein, which is highly expressed in a large number of tissues. OPG mainly binds to two ligands, i.e. RANKL (receptor activator of nuclear factor kappaB ligand) and TRAIL (tumor necrosis factor- related apoptosis-inducing ligand). Upon binding to the former ligand, OPG inhibits the activation of osteoclasts and promotes apoptosis of osteoclasts, whereas the binding of OPG with TRAIL prevents apoptosis of tumor cells. There is now emerging evidence that OPG participates in the pathogenesis of atherosclerosis and cardiovascular diseases by amplifying the adverse effects of inflammation and several traditional risk factors such as hyperlipidemia, endothelial dysfunction, diabetes mellitus, and hypertension. Some epidemiological studies also showed a positive association between OPG levels and cardiovascular morbidity and mortality. The aim of this article is to provide an overview of the main biochemical, physiological, and pathological aspects of OPG biology in cardiovascular disease. PMID- 23110638 TI - Dietary total antioxidant capacity from different assays in relation to serum C reactive protein among young Japanese women. AB - BACKGROUND: The association between dietary total antioxidant capacity (TAC) from different assays and serum C-reactive protein (CRP) has not been assessed in non Western populations. We examined the association between dietary TAC and serum CRP concentration in young Japanese women using different four TAC assays. METHODS: The subjects were 443 young Japanese women aged 18-22 years. Dietary TAC was assessed with a self-administered diet history questionnaire and the TAC value of each food using the following four assays: ferric reducing ability of plasma (FRAP); oxygen radical absorbance capacity (ORAC); Trolox equivalent antioxidant capacity (TEAC); and total radical-trapping antioxidant parameter (TRAP). Serum CRP concentrations were measured by highly sensitive nephelometry. RESULTS: The major contributor to dietary TAC was green, barley, and oolong tea (FRAP: 53%, ORAC: 45%, TEAC: 36%, and TRAP: 44%). The prevalence of elevated CRP concentrations (>= 1 mg/L) was 5.6%. TAC from FRAP was inversely associated with serum CRP concentrations (adjusted odds ratio [OR] for elevated CRP concentration in high [compared with low] dietary TAC group: 0.39 [95% confidence interval (CI): 0.16-0.98]; P = 0.04). TAC from ORAC was inversely associated with CRP, although the association was not significant (OR: 0.48 [95% CI: 0.20-1.14]; P = 0.10). TAC from TEAC was inversely associated with CRP (OR: 0.32 [95% CI: 0.12 0.82]; P = 0.02), as was TAC from TRAP (OR: 0.31 [95% CI: 0.12-0.81]; P = 0.02). CONCLUSIONS: Dietary TAC was inversely associated with serum CRP concentration in young Japanese women regardless of assay. Further studies are needed in other populations to confirm these results. PMID- 23110641 TI - Parenteral nutrition in the intensive care unit. AB - Patients in the intensive care unit (ICU) are unable to nourish themselves orally. In addition, critical illness increases nutrient requirements as well as alters metabolism. Typically, ICU patients rapidly become malnourished unless they are provided with involuntary feeding either through a tube inserted into the GI tract, called enteral nutrition (EN), or directly into the bloodstream, called parenteral nutrition (PN). Between the 1960s and the 1980s, PN was the modality of choice and the premise was that if some is good, more is better, which led to overfeeding regimens called hyperalimentation. Later, the dangers of overfeeding, hyperglycemia, fatty liver, and increased sepsis associated with PN became recognized. In contrast, EN was not associated with these risks and it gradually became the modality of choice in the ICU. However, ICU patients in whom the gastrointestinal tract was nonfunctional (i.e., gut failure) required PN to avoid malnutrition. In addition, EN was shown, on average, to not meet nutrient requirements, and underfeeding was recognized to increase complications because of malnutrition. Hence, the balanced perspective has been reached of using EN when possible but avoiding underfeeding by supplementing with PN when required. This new role for PN is currently being debated and studied. In addition, the relative merits and needs for protein, carbohydrates, lipids, and micronutrients are areas of study. PMID- 23110640 TI - Integration of TGF-beta- and EGFR-based signaling pathways using an agent-based model of epithelial restitution. AB - Damage to an epithelial surface disrupts its mechanical and immunologic barrier function and exposes underlying tissues to a potentially hostile external environment. Epithelial restitution occurs quickly to reestablish the barrier and comprises a major part of the immediate host response to injured tissue. Pathways involving transforming growth factor beta and activation of epidermal growth factor receptor are both of critical importance, although cross-pathway interactions have been poorly characterized. Agent-based modeling has been showed to be useful in integrating disparate bodies of knowledge and showing the dynamic consequences of pathway structures and cellular population behavior and is used herein to create an in silico analog of an in vitro scratch assay. The In Vitro Scratch Agent-Based Model consists of agents representing individual epithelial cells in a simulated extracellular matrix. Agents sense signals from the damaged environment and produce effector molecules, leading to their healing behavior. The In Vitro Scratch Agent-Based Model qualitatively matched wound healing dynamics when compared against data from traditional experiments. Putative cross talk mechanisms were then instantiated into the In Vitro Scratch Agent-Based Model and their relative plausibility examined, suggesting interaction at the receptor tyrosine kinase level. This highlights the utility of dynamic knowledge representation in the integration of pathways previously studied in separate contexts. PMID- 23110642 TI - Is there a place for coenzyme Q in the management of metabolic disorders associated with obesity? AB - Coenzyme Q (CoQ), a lipophilic cofactor of the electron transport chain in the mitochondria, can be synthesized endogenously or provided by food. The aim of this review is to summarize the in vitro cell culture studies, the in vivo animal studies, and the human studies investigating the impact of CoQ supplementation on the occurrence of obesity and related disorders (diabetes, hypertension, lipemia, and atherosclerosis). The antioxidative properties of CoQ have been observed in different experimental models of atherosclerosis, obesity, and diabetes. The recent discovery of the anti-inflammatory effect of CoQ, mostly described in vitro, has generated increased interest in CoQ supplementation, but it needs to be confirmed in vivo in pathological situations. CoQ intervention studies in humans failed to show reproducible effects on body weight, fat mass, or glycemia, but CoQ supplementation does seem to have an antihypertensive effect. The molecular mechanism to explain this effect has only recently been discovered. PMID- 23110644 TI - Novel concepts of broccoli sulforaphanes and disease: induction of phase II antioxidant and detoxification enzymes by enhanced-glucoraphanin broccoli. AB - Consumption of broccoli has long been considered to play a role in a healthy diet. Broccoli accumulates significant amounts of the phytonutrient glucoraphanin (4-methylsulfinylbutyl glucosinolate), which is metabolized in vivo to the biologically active sulforaphane. The preponderance of evidence available from in vitro, animal, and human studies supports the association of sulforaphane with phase II enzyme induction. This has provided impetus for developing varieties of broccoli, both sprouts and whole heads, that are rich in glucoraphanin. The cancer-preventive properties of cruciferous vegetables, especially broccoli, have been studied for decades. However, evidence of broccoli directly affecting cancer incidence or progression is ambiguous, in part because of the presence of substantial polymorphisms in enzymes that metabolize sulforaphane. Since broccoli sulforaphane is one of the most potent inducers of phase II enzymes, exploration into broccoli's impact on other areas of human health, such as cardiovascular health and upper airway immunity, has been suggested. This review provides an update on evidence supporting phase II enzyme induction by sulforaphanes, with implications for breeding broccoli varieties with enhanced amounts of glucoraphanin. Early-stage human studies of consumption of broccoli with enhanced glucoraphanin are also discussed. PMID- 23110643 TI - Early childhood growth failure and the developmental origins of adult disease: do enteric infections and malnutrition increase risk for the metabolic syndrome? AB - Hypotheses regarding the developmental origins of health and disease postulate that developing fetuses - and potentially young children - undergo adaptive epigenetic changes that have longstanding effects on metabolism and other processes. Ongoing research explores whether these adaptations occur during early life following early childhood malnutrition. In the developing world, there remains a high degree of nutritional stunting, defined as linear growth failure caused by inadequate caloric intake, which may be exacerbated by inflammation from ongoing infections. In areas with poor sanitation, children experience vicious cycles of enteric infections and malnutrition, resulting in poor nutrient absorption as a result of changes in the intestinal mucosa, now termed "environmental enteropathy." Emerging evidence links early childhood diarrhea and/or growth failure with an increased occurrence of risk factors for cardiovascular disease in later life, including dyslipidemia, hypertension, and glucose intolerance. The mechanisms for these associations remain poorly understood and may relate to epigenetic responses to poor nutrition, increased inflammation, or both. Given the increased incidence of cardiovascular disease in developing areas of the world, associations between childhood malnutrition, early life infections, and the increased occurrence of risk factors for cardiovascular disease underscore further reasons to improve nutrition and infection-related outcomes for young children worldwide. PMID- 23110645 TI - Salt in bread in Europe: potential benefits of reduction. AB - Bread is widely considered to be the foodstuff that provides the most dietary salt to the diet. As such, it is one of the key public health targets for a salt reduction policy. In this respect, it has been shown that a reduction in the salt content of bread is possible, and an alternative approach involves partial replacement with other, mainly potassium-based salts, which also counteract the effects of sodium. This replacement should be undertaken on the basis of criteria that maintain the product's sensory profile, and it tends to be more successful in breads with more naturally flavorful taste. The present review was conducted to examine salt intake in Europe and the health problems associated with its excessive consumption; particular focus is placed on the salt content of bread and the effects of its possible reduction and/or correction. The beneficial effects of such changes are highlighted by way of a theoretical calculation in baguette-type wheat bread. European legislation in the field of nutrition and health claims allows the positive aspects of such salt reduction and replacement methods to be stated. PMID- 23110647 TI - Femtoliter-scale patterning by high-speed, highly scaled inverse gravure printing. AB - Pattern printing techniques have advanced rapidly in the past decade, driven by their potential applications in printed electronics. Several printing techniques have realized printed features of 10 MUm or smaller, but unfortunately, they suffer from disadvantages that prevent their deployment in real applications; in particular, process throughput is a significant concern. Direct gravure printing is promising in this regard. Gravure printing delivers high throughput and has a proven history of being manufacturing worthy. Unfortunately, it suffers from scalability challenges because of limitations in roll manufacturing and limited understanding of the relevant printing mechanisms. Gravure printing involves interactions between the ink, the patterned cylinder master, the doctor blade that wipes excess ink, and the substrate to which the pattern is transferred. As gravure-printed features are scaled, the associated complexities are increased, and a detailed study of the various processes involved is lacking. In this work, we report on various gravure-related fluidic mechanisms using a novel highly scaled inverse direct gravure printer. The printer allows the overall pattern formation process to be studied in detail by separating the entire printing process into three sequential steps: filling, wiping, and transferring. We found that pattern formation by highly scaled gravure printing is governed by the wettability of the ink to the printing plate, doctor blade, and substrate. These individual functions are linked by the apparent capillary number (Ca); the printed volume fraction (phi(p)) of a feature can be constructed by incorporating these basis functions. By relating Ca and phi(p), an optimized operating point can be specified, and the associated limiting phenomena can be identified. We used this relationship to find the optimized ink viscosity and printing speed to achieve printed polymer lines and line spacings as small as 2 MUm at printing speeds as high as ~1 m/s. PMID- 23110648 TI - Quality of life after pertrochanteric femoral fractures treated with a gamma nail: a single center study of 62 patients. AB - BACKGROUND: Intramedullary nailing of pertrochanteric femoral fractures has grown in popularity over the past 2 decades likely because this procedure is associated with a low risk for postoperative morbidity and a fast recovery of function. The evaluation of outcomes associated with pertrochanteric nailing has mainly been based on objective measures. The purpose of the present study is to correlate patients' health-related quality of life results after intramedullary nailing of pertrochanteric fractures with objective outcome measures. METHODS: We conducted a single-center study including 62 patients (mean age 80 +/- 10 years) with pertrochanteric fractures treated with a Gamma 3 Nail. Health related quality of life was measured using the Short Form-36. These results were compared to both US and Austrian age and sex-adjusted population norms. The objective outcome measures studied at one year postoperatively included Harris Hip Score, range of motion, leg length, body mass index, neck-shaft angle and grade of osteoarthritis. RESULTS: According to the Harris Hip Score 43 patients (67%) had excellent or good results. There was no significant difference in the average neck-shaft angle comparing affected hip to non-affected hip at 12 months postoperatively. The average osteoarthritis score, for both the injured and uninjured hip, did not differ significantly. We found significant differences between the bodily pain, social functioning and mental health subscales and two summary scores of the Short-Form 36 in comparison to Austrian population norms. Complication rate was 8%. CONCLUSIONS: The results of this study confirm that intramedullary nailing with the use of a Gamma Nail is a safe treatment option for stable and unstable pertrochanteric fractures. Despite good functional and radiographic results we noticed a substantial fall off in patients' quality of life up to 12 months after operation. PMID- 23110650 TI - Primary gastric cancer presenting with a metastatic embolus in the common carotid artery: a case report. AB - Although about 30% of gastric cancers have distant metastasis at the time of initial diagnosis, metastatic tumor embolus in the main blood vessels is not common, especially in the main artery. The report presents, for the first time, an extremely rare clinical case of a metastatic embolus in the common carotid artery (CCA) from primary gastric cancer. Metastatic embolus from the primary tumor should be considered when patients present with gastric cancer accompanied by intravascular emboli. The patient should be actively examined further so as to allow early detection and treatment. PMID- 23110652 TI - Repigmentation of the epidermis around the acrosyringium in piebald skin: an ultrastructural examination. PMID- 23110651 TI - Sprague-Dawley and Fischer female rats differ in acute effects of fluoxetine on sexual behavior. AB - INTRODUCTION: The selective serotonin reuptake inhibitor (SSRI), fluoxetine, leads to sexual dysfunction in a substantial proportion of women. In studies with the Fischer inbred rat, the 5-HT(1A) receptor has been implicated in this sexual dysfunction. Whether this association with 5-HT(1A) receptors holds for other rat strains is not known. AIM: The effects of acute fluoxetine on sexual behavior in two strains of rats that differ in their response to a 5-HT(1A) receptor agonist were examined. Whether the strain difference is comparable in naturally cycling and hormonally primed, ovariectomized rats was determined. METHODS: Proestrous rats and ovariectomized rats, hormonally primed with estradiol benzoate and progesterone, were treated with varying doses of fluoxetine. Sexual behavior was examined before and after treatment with the SSRI. MAIN OUTCOME MEASURES: Lordosis to mount ratios, lordosis quality, and proceptive behaviors were quantified. Sprague-Dawley and Fischer females were compared on each of these measures. The IC(50) for inhibition of lordosis behavior was determined. RESULTS: In both the intact and the hormonally primed, ovariectomized model, Sprague Dawley females were less sensitive to the effects of fluoxetine on sexual behavior. In both groups, fluoxetine showed dose dependency in behavioral inhibition, but a higher dose was required for Sprague-Dawley than for Fischer females. Naturally cycling, proestrous rats required a higher dose of fluoxetine than hormonally primed ovariectomized rats to produce significant inhibition of sexual behavior. Thus, the strain difference in the response to fluoxetine does not parallel strain differences in the response to a 5-HT(1A) receptor agonist. CONCLUSIONS: Acute treatment with fluoxetine inhibits lordosis behavior in both Fischer and Sprague-Dawley females and the strain difference cannot be explained by reported strain differences in the response to a 5-HT(1A) receptor agonist. Fluoxetine's inhibition of female rat sexual behavior may involve effects of the SSRI in addition to activation of the 5-HT(1A) receptor. PMID- 23110653 TI - Exchange coupling and magnetic blocking in bipyrimidyl radical-bridged dilanthanide complexes. AB - The synthesis and magnetic properties of three new bipyrimidyl radical-bridged dilanthanide complexes, [(Cp*(2)Ln)(2)(MU-bpym(*))](+) (Ln = Gd, Tb, Dy), are reported. Strong Ln(III)-bpym(*-) exchange coupling is observed for all species, as indicated by the increases in chi(M)T at low temperatures. For the Gd(III) containing complex, a fit to the data reveals antiferromagnetic coupling with J = -10 cm(-1) to give an S = (13)/(2) ground state. The Tb(III) and Dy(III) congeners show single-molecule magnet behavior with relaxation barriers of U(eff) = 44(2) and 87.8(3) cm(-1), respectively, a consequence of the large magnetic anisotropies imparted by these ions. Significantly, the latter complex exhibits a divergence of the field-cooled and zero-field-cooled dc susceptibility data at 6.5 K and magnetic hysteresis below this temperature. PMID- 23110654 TI - Retrospective evaluation of toxicosis from selective serotonin reuptake inhibitor antidepressants: 313 dogs (2005-2010). AB - OBJECTIVE: To evaluate a clinical population of dogs exposed to selective serotonin reuptake inhibitor (SSRI) antidepressant medications and describe the clinical findings, epidemiological characteristics, outcome, and prognosis. DESIGN: Retrospective study (February 1, 2005-August 31, 2010). SETTING: Animal poison control helpline. ANIMALS: Three hundred thirteen dogs with presumed SSRI toxicosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Dogs with presumptive SSRI medication toxicosis identified by a review of the electronic database of Pet Poison Helpline, an animal poison control center, were evaluated. No clinical signs were reported in 76.3% (239/313) of cases. The remaining 23.6% (74/313) of cases demonstrated the following clinical signs: neurological 79.7% (59/74), gastrointestinal 25.6% (19/74), cardiovascular 9.5% (7/74), respiratory 8.2% (6/74), and thermoregulatory 6.7% (5/74). Of the dogs exhibiting neurological signs, 62.7% (37/59) showed depression, 37.2% (22/59) showed hyperactivity, 10.1% (6/59) exhibited ataxia, and 1.7% (1/59) showed other miscellaneous signs (eg, hyperesthesia). There was a significant difference between the dose ingested by symptomatic and asymptomatic dogs for fluoxetine (P = 0.0039), but not with any other SSRI. Ninety-four patients were confirmed to have received veterinary care. In cases where duration of veterinary care was determined (55/313), 67.2% (37/55) of dogs were hospitalized and 32.7% (18/55) treated as outpatients. The average duration of hospitalization was 18.5 hours, excluding outpatient visits. Of those patients that had complete follow-up information available (136/313), overall survival was 100%. CONCLUSIONS: The overall prognosis for animals with SSRI toxicosis is excellent with veterinary attention. Central nervous system depression was the most common clinical sign associated with SSRI toxicosis. PMID- 23110655 TI - Case of simultaneous occurrence of papulonecrotic tuberculid and erythema induratum. PMID- 23110656 TI - Accuracy and precision of CPET equipment: a comparison of breath-by-breath and mixing chamber systems. AB - Cardiopulmonary exercise testing (CPET) has become an important diagnostic tool for patients with cardiorespiratory disease and can monitor athletic performance measuring maximal oxygen uptake [Formula: see text]Vo2(; max). The aim of this study is to compare the accuracy and precision of a breath-by-breath and a mixing chamber CPET system, using two methods. First, this study developed a (theoretical) error analysis based on general error propagation theory. Second, calibration measurements using a metabolic simulator were performed. Error analysis shows that the error in oxygen uptake ([Formula: see text]Vo2) and carbon dioxide production (Vco2[Formula: see text]) is smaller for mixing chamber than for breath-by-breath systems. In general, the error of the flow sensor [Formula: see text]deltaV, the error in temperature of expired air deltaT(B) and the delay time error deltat(delay) are significant sources of error. Measurements using a metabolic simulator show that breath-by-breath systems are less stabile for different values of minute ventilation than mixing chamber systems. PMID- 23110657 TI - From nature to the laboratory: the impact of founder effects on adaptation. AB - Most founding events entail a reduction in population size, which in turn leads to genetic drift effects that can deplete alleles. Besides reducing neutral genetic variability, founder effects can in principle shift additive genetic variance for phenotypes that underlie fitness. This could then lead to different rates of adaptation among populations that have undergone a population size bottleneck as well as an environmental change, even when these populations have a common evolutionary history. Thus, theory suggests that there should be an association between observable genetic variability for both neutral markers and phenotypes related to fitness. Here, we test this scenario by monitoring the early evolutionary dynamics of six laboratory foundations derived from founders taken from the same source natural population of Drosophila subobscura. Each foundation was in turn three-fold replicated. During their first few generations, these six foundations showed an abrupt increase in their genetic differentiation, within and between foundations. The eighteen populations that were monitored also differed in their patterns of phenotypic adaptation according to their immediately ancestral founding sample. Differences in early genetic variability and in effective population size were found to predict differences in the rate of adaptation during the first 21 generations of laboratory evolution. We show that evolution in a novel environment is strongly contingent not only on the initial composition of a newly founded population but also on the stochastic changes that occur during the first generations of colonization. Such effects make laboratory populations poor guides to the evolutionary genetic properties of their ancestral wild populations. PMID- 23110659 TI - Introduction to the special issue on physical therapy practice in the neonatal intensive care unit. PMID- 23110658 TI - Does limited virucidal activity of biocides include duck hepatitis B virucidal action? AB - BACKGROUND: There is agreement that the infectivity assay with the duck hepatitis B virus (DHBV) is a suitable surrogate test to validate disinfectants for hepatitis B virucidal activity. However, since this test is not widely used, information is necessary whether disinfectants with limited virucidal activity also inactivate DHBV. In general, disinfectants with limited virucidal activity are used for skin and sensitive surfaces while agents with full activity are more aggressive. The present study compares the activity of five different biocides against DHBV and the classical test virus for limited virucidal activity, the vaccinia virus strain Lister Elstree (VACV) or the modified vaccinia Ankara strain (MVA). METHODS: Virucidal assay was performed as suspension test according to the German DVV/RKI guideline. Duck hepatitis B virus obtained from congenitally infected Peking ducks was propagated in primary duck embryonic hepatocytes and was detected by indirect immunofluorescent antigen staining. RESULTS: The DHBV was inactivated by the use of 40% ethanol within 1-min and 30% isopropanol within 2-min exposure. In comparison, 40% ethanol within 2-min and 40% isopropanol within 1-min exposure were effective against VACV/MVA. These alcohols only have limited virucidal activity, while the following agents have full activity. 0.01% peracetic acid inactivated DHBV within 2 min and a concentration of 0.005% had virucidal efficacy against VACV/MVA within 1 min. After 2-min exposure, 0.05% glutardialdehyde showed a comparable activity against DHBV and VACV/MVA. This is also the case for 0.7% formaldehyde after a contact time of 30 min. CONCLUSIONS: Duck hepatitis B virus is at least as sensitive to limited virucidal activity as VACV/MVA. Peracetic acid is less effective against DHBV, while the alcohols are less effective against VACV/MVA. It can be expected that in absence of more direct tests the results may be extrapolated to HBV. PMID- 23110660 TI - Efficient reconstruction of biological networks via transitive reduction on general purpose graphics processors. AB - BACKGROUND: Techniques for reconstruction of biological networks which are based on perturbation experiments often predict direct interactions between nodes that do not exist. Transitive reduction removes such relations if they can be explained by an indirect path of influences. The existing algorithms for transitive reduction are sequential and might suffer from too long run times for large networks. They also exhibit the anomaly that some existing direct interactions are also removed. RESULTS: We develop efficient scalable parallel algorithms for transitive reduction on general purpose graphics processing units for both standard (unweighted) and weighted graphs. Edge weights are regarded as uncertainties of interactions. A direct interaction is removed only if there exists an indirect interaction path between the same nodes which is strictly more certain than the direct one. This is a refinement of the removal condition for the unweighted graphs and avoids to a great extent the erroneous elimination of direct edges. CONCLUSIONS: Parallel implementations of these algorithms can achieve speed-ups of two orders of magnitude compared to their sequential counterparts. Our experiments show that: i) taking into account the edge weights improves the reconstruction quality compared to the unweighted case; ii) it is advantageous not to distinguish between positive and negative interactions since this lowers the complexity of the algorithms from NP-complete to polynomial without loss of quality. PMID- 23110661 TI - Economic analysis of cloud-based desktop virtualization implementation at a hospital. AB - BACKGROUND: Cloud-based desktop virtualization infrastructure (VDI) is known as providing simplified management of application and desktop, efficient management of physical resources, and rapid service deployment, as well as connection to the computer environment at anytime, anywhere with any device. However, the economic validity of investing in the adoption of the system at a hospital has not been established. METHODS: This study computed the actual investment cost of the hospital-wide VDI implementation at the 910-bed Seoul National University Bundang Hospital in Korea and the resulting effects (i.e., reductions in PC errors and difficulties, application and operating system update time, and account management time). Return on investment (ROI), net present value (NPV), and internal rate of return (IRR) indexes used for corporate investment decision making were used for the economic analysis of VDI implementation. RESULTS: The results of five-year cost-benefit analysis given for 400 Virtual Machines (VMs; i.e., 1,100 users in the case of SNUBH) showed that the break-even point was reached in the fourth year of the investment. At that point, the ROI was 122.6%, the NPV was approximately US$192,000, and the IRR showed an investment validity of 10.8%. From our sensitivity analysis to changing the number of VMs (in terms of number of users), the greater the number of adopted VMs was the more investable the system was. CONCLUSIONS: This study confirms that the emerging VDI can have an economic impact on hospital information system (HIS) operation and utilization in a tertiary hospital setting. PMID- 23110662 TI - Apoptosis signal-regulating kinase-1 inhibitor as a potent therapeutic drug for the treatment of gastric cancer. AB - Aside from the human epidermal growth factor receptor-2 (HER2)-targeting agent trastuzumab, molecular targeting therapy for gastric cancer (GC) has not been established. We previously reported that apoptosis signal-regulating kinase-1 (ASK1) was upregulated in human GC and that overexpression of ASK1 promoted GC cell proliferation. Here, we investigated the effect of ASK1 inhibitor K811 on GC cells. K811 efficiently prevented cell proliferation in cell lines with high ASK1 expression and in HER2-overexpressing GC cells. Treatment with K811 reduced sizes of xenograft tumors by downregulating proliferation markers. These results indicate that ASK1 inhibition prevents GC cell growth in vitro and in vivo, suggesting that ASK1 inhibitors can be potent therapeutic drugs for GC. PMID- 23110663 TI - Two males with SRY-positive 46,XX testicular disorder of sex development. AB - The 46,XX testicular disorder of sex development (46,XX testicular DSD) is a rare phenotype associated with disorder of the sex chromosomes. We describe the clinical, molecular, and cytogenetic findings of a 16- and a 30-year-old male patient with sex-determining region Y (SRY)-positive 46,XX testicular DSD. Chromosomal analysis revealed 46,XX karyotype. Fluorescence in situ hybridization (FISH) showed the SRY region translocated to the short arm of the X chromosome. The presence of the SRY gene was also confirmed by polymerase chain reaction (PCR). The X chromosome inactivation (XCI) assay showed that both patients have a random pattern of X chromosome inactivation. This report compares the symptoms and features of the SRY-positive 46,XX testicular DSD patients. PMID- 23110664 TI - A shape-optimized framework for kidney segmentation in ultrasound images using NLTV denoising and DRLSE. AB - BACKGROUND: Computer-assisted surgical navigation aims to provide surgeons with anatomical target localization and critical structure observation, where medical image processing methods such as segmentation, registration and visualization play a critical role. Percutaneous renal intervention plays an important role in several minimally-invasive surgeries of kidney, such as Percutaneous Nephrolithotomy (PCNL) and Radio-Frequency Ablation (RFA) of kidney tumors, which refers to a surgical procedure where access to a target inside the kidney by a needle puncture of the skin. Thus, kidney segmentation is a key step in developing any ultrasound-based computer-aided diagnosis systems for percutaneous renal intervention. METHODS: In this paper, we proposed a novel framework for kidney segmentation of ultrasound (US) images combined with nonlocal total variation (NLTV) image denoising, distance regularized level set evolution (DRLSE) and shape prior. Firstly, a denoised US image was obtained by NLTV image denoising. Secondly, DRLSE was applied in the kidney segmentation to get binary image. In this case, black and white region represented the kidney and the background respectively. The last stage is that the shape prior was applied to get a shape with the smooth boundary from the kidney shape space, which was used to optimize the segmentation result of the second step. The alignment model was used occasionally to enlarge the shape space in order to increase segmentation accuracy. Experimental results on both synthetic images and US data are given to demonstrate the effectiveness and accuracy of the proposed algorithm. RESULTS: We applied our segmentation framework on synthetic and real US images to demonstrate the better segmentation results of our method. From the qualitative results, the experiment results show that the segmentation results are much closer to the manual segmentations. The sensitivity (SN), specificity (SP) and positive predictive value (PPV) of our segmentation result can reach 95%, 96% and 91% respectively; As well as we compared our results with the edge-based level set and level set with shape prior method by means of the same quantitative index, such as SN, SP, PPV, which have corresponding values of 97%, 88%, 78% and 81%, 91%, 80% respectively. CONCLUSIONS: We have found NLTV denosing method is a good initial process for the ultrasound segmentation. This initial process can make us use simple segmentation method to get satisfied results. Furthermore, we can get the final segmentation results with smooth boundary by using the shape prior after the segmentation process. Every step enjoy simple energy model and every step in this framework is needed to keep a good robust and convergence property. PMID- 23110666 TI - Secondary structural changes of homologous proteins, lysozyme and alpha lactalbumin, in thermal denaturation up to 130 degrees C and sodium dodecyl sulfate (SDS) effects on these changes: comparison of thermal stabilities of SDS induced helical structures in these proteins. AB - The thermal stability of two homologous proteins, lysozyme and alpha-lactalbumin, was examined by circular dichroism. The present study clearly showed two different aspects between the homologous proteins: (1) the original helices of lysozyme and alpha-lactalbumin were unchanged at heat treatments up to 60 and 40 degrees C, respectively, indicating a higher thermal stability of lysozyme, and (2) upon cooling to 25 degrees C, the original helices of lysozyme were never reformed after they were once disrupted, while those of alpha-lactalbumin, disrupted at a particular temperature range between 40 and 60 degrees C, were completely reformed. In addition, the structural changes were also examined in the coexistence of sodium dodecyl sulfate (SDS), which induced the formation of helical structures in these proteins at 25 degrees C. A distinct difference appeared in the thermal stabilities of the SDS-induced helices. All of the SDS induced helices of lysozyme were disrupted below 60 degrees C, while those of alpha-lactalbumin at 10 mM SDS were unchanged up to 130 degrees C. A similarity was also fixed. Not only the SDS-induced helices but also the original helices of the two proteins were reformed upon cooling to 25 degrees C after the thermal denaturation below 100 degrees C in the coexistence of 10 mM SDS. PMID- 23110665 TI - Resolvin D2 prevents secondary thrombosis and necrosis in a mouse burn wound model. AB - Deep partial thickness burns are subject to delayed necrosis of initially viable tissues surrounding the primary zone of thermally induced coagulation, which results in an expansion of the burn wound, both in area and depth, within 48 hours postburn. Neutrophil sequestration and activation leading to microvascular damage is thought to mediate this secondary tissue damage. Resolvins, a class of endogenous mediators derived from omega-3 polyunsaturated fatty acids, have been shown to regulate the resolution of inflammation. We hypothesized that exogenous resolvins could mitigate the deleterious impact of the inflammatory response in burn wounds. Using two different mouse burn injury models involving significant partial thickness injuries, we found that a systemically administered single dose of resolvin D2 (RvD2) as low as 25 pg/g bw given within an interval of up to 4 hours postburn effectively prevented thrombosis of the deep dermal vascular network and subsequent dermal necrosis. By preserving the microvascular network, RvD2 enhanced neutrophil access to the dermis, but prevented neutrophil-mediated damage through other anti-inflammatory actions, including inhibition of tumor necrosis factor-alpha, interleukin-1beta, and neutrophil platelet-endothelial cell adhesion molecule-1. In a clinical context, RvD2 may be therapeutically useful by reducing the need for surgical debridement and the area requiring skin grafting. PMID- 23110667 TI - Clinical utility of the Snaith-Hamilton-Pleasure scale in the Chinese settings. AB - BACKGROUND: The Snaith-Hamilton-Pleasure-Scale (SHAPS) is a self-reported scale evaluating anhedonia for neuropsychiatric disorders. It has demonstrated with impressive psychometric properties and advantages in its applicability over other similar instruments. However, very few studies have been conducted to examine the clinical utility of the SHAPS in the context of Chinese settings. The current study aimed to examine the clinical utility of the translated version of the SHAPS in the Chinese clinical settings. METHODS: A Chinese version of SHAPS was administered to 336 college students to examine the internal consistency and test retest reliability at a 4-week interval. Moreover, the translated SHAPS was also administered to 141 patients with major depression, 72 patients with schizophrenia, and 72 healthy controls to examine its clinical discrimination. RESULTS: The internal consistency of the SHAPS for the non-clinical sample and test-retest reliability at a 4- week interval were 0.85 and 0.64, respectively. Moreover, the SHAPS also showed an excellent internal consistency (alpha was 0.93) and a one-factor solution with the first factor accounted for 51.53% of the variance in the clinical psychiatric samples. ANOVA of the SHAPS total score indicated that the patients with depression scored significantly more anhedonia than the patients with schizophrenia and healthy controls (p<0.001), and the patients with schizophrenia scored significantly more anhedonia than the healthy controls (P<0.02). CONCLUSIONS: These findings suggest that the Chinese version of the SHAPS is a useful and promising instrument in assessing anhedonia for clinical patients and non-clinical individuals in the Chinese settings. PMID- 23110668 TI - Effects on steroid hormones secretion resulting from the acute stimulation of sectioning the superior ovarian nerve to pre-pubertal rats. AB - In the adult rat, neural signals arriving to the ovary via the superior ovarian nerve (SON) modulate progesterone (P4), testosterone (T) and estradiol (E2) secretion. The aims of the present study were to analyze if the SON in the pre pubertal rat also modulates ovarian hormone secretion and the release of follicle stimulating hormone (FSH) and luteinizing (LH) hormone. P4, T, E2, FSH and LH serum levels were measured 30 or 60 minutes after sectioning the SON of pre pubertal female rats. Our results indicate that the effects on hormone levels resulting from unilaterally or bilaterally sectioning the SON depends on the analyzed hormone, and the time lapse between surgery and autopsy, and that the treatment yielded asymmetric results. The results also suggest that in the pre pubertal rat the neural signals arriving to the ovaries via the SON regulate the enzymes participating in P4, T and E2 synthesis in a non-parallel way, indicating that the mechanisms regulating the synthesis of each hormone are not regulated by the same signals. Also, that the changes in the steroids hormones are not explained exclusively by the modifications in gonadotropins secretion. The observed differences in hormone levels between rats sacrificed 30 and 60 min after surgery reflect the onset of the compensatory systems regulating hormones secretion. PMID- 23110669 TI - GTP binding leads to narrowing of the conformer population while preserving the structure of the RNA aptamer: a site-specific time-resolved fluorescence dynamics study. AB - In this study, we employed a combination of steady-state and time-resolved fluorescence spectroscopy and studied the site-specific dynamics in a GTP aptamer using 2-aminopurine as a fluorescent probe. We compared the dynamics of the GTP bound aptamer with that of the free aptamer as well as when it is denatured. GTP binding leads to an overall compaction of structure in the aptamer. The general pattern of fluorescence lifetimes and correlation times scanned across several locations in the aptamer does not seem to change following GTP binding. However, a remarkable narrowing of the lifetime distribution of the aptamer ensues following its compaction by GTP binding. Interestingly, such a "conformational narrowing" is evident from the lifetime readouts of the nucleotide belonging to the stem as well as the "bulge" part of the aptamer, independent of whether it is directly interacting with GTP. Taken together, these results underscore the importance of an overall intrinsic structure associated with the free aptamer that is further modulated following GTP binding. This work provides strong support for the "conformational selection" hypothesis of ligand binding. PMID- 23110670 TI - Clonal heterogeneity of mantle cell lymphoma revealed by array comparative genomic hybridization. AB - Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14)(q13;q32). This lymphoma exhibits a poor prognosis and remains incurable with standard chemotherapy approaches. Recently, we have shown that a majority of patients with acute-type adult T-cell leukemia/lymphoma (ATLL) have multiple subclones that were likely produced in lymph nodes. We investigated whether MCL has multiple subclones as identified in ATLL by high-resolution oligo-array comparative genomic hybridization (CGH). Eleven of 20 (55%) evaluable MCL cases had a log2 ratio imbalance, suggesting the existence of multiple subclones in MCL. Based on the proportion of every subclone relative to the main clone, we were able to speculate clonal evolution in each MCL case with multiple subclones. Our analysis gave new insights into the clonal heterogeneity quantitatively and accurately. Furthermore, genomic copy number alterations are not hierarchical events and not necessarily the initial or later events for cells to become MCL. PMID- 23110671 TI - Characterization and modeling of the interactions between coffee storage proteins and phenolic compounds. AB - This study addresses the interactions of coffee storage proteins with coffee specific phenolic compounds. Protein profiles of Coffea arabica and Coffea canephora (var. robusta) were compared. Major phenolic compounds were extracted and analyzed with appropriate methods. The polyphenol-protein interactions during protein extraction have been addressed by different analytical setups [reversed phase high-performance liquid chromatography (RP-HPLC), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS), and Trolox equivalent antioxidant capacity (TEAC) assays], with focus directed toward identification of covalent adduct formation. The results indicate that C. arabica proteins are more susceptible to these interactions and the polyphenol oxidase activity seems to be a crucial factor for the formation of these addition products. A tentative allocation of the modification type and site in the protein has been attempted. Thus, the first available in silico modeling of modified coffee proteins is reported. The extent of these modifications may contribute to the structure and function of "coffee melanoidins" and are discussed in the context of coffee flavor formation. PMID- 23110672 TI - Insecure attachment is related to more anal sex and vibrator orgasm but less vaginal orgasm. PMID- 23110674 TI - Audiometric screening of a population with intellectual disability. AB - OBJECTIVE: Evaluation of pure-tone audiometry (PTA) in hearing screening of a population with mild to profound intellectual disability (ID). DESIGN: PTA was performed at six frequencies at the screening level 20 dB HL. Referral criteria were threshold levels >= 25 dB HL at two or more frequencies for one ear or both. STUDY SAMPLE: 1478 participants aged 7-91 years were included. RESULTS: 1470 (99.5%) people cooperated in screening of which 1325 (90%) could be tested on both ears at all six frequencies. A majority, 987 (66.8%), performed ordinary PTA, 234 (15.8%) conditioned play audiometry, and 249 (16.9%) behavioural observation audiometry. Six hundred and sixty-nine (45%) passed and 809 (55%) failed according to referral criteria. Of those failing, 441 (54.5%) accepted referral to clinical evaluation. CONCLUSIONS: PTA with slight modifications is applicable for screening of a population with mild to profound intellectual disability. The most challenging and time-consuming activity is to introduce the test procedure in a way that reduces anxiety and establishes trust. PMID- 23110675 TI - Amalgamation of nucleosides and amino acids in antibiotic biosynthesis: discovery of an L-threonine:uridine-5'-aldehyde transaldolase. AB - The lipopeptidyl nucleoside antibiotics represented by A-90289, caprazamycin, and muraymycin are structurally highlighted by a nucleoside core that contains a nonproteinogenic beta-hydroxy-alpha-amino acid named 5'-C-glycyluridine (GlyU). Bioinformatic analysis of the biosynthetic gene clusters revealed a shared open reading frame encoding a protein with sequence similarity to serine hydroxymethyltransferases, resulting in the proposal that this shared enzyme catalyzes an aldol-type condensation with glycine and uridine-5'-aldehyde to furnish GlyU. Using LipK involved in A-90289 biosynthesis as a model, we now functionally assign and characterize the enzyme responsible for the C-C bond forming event during GlyU biosynthesis as an l-threonine:uridine-5'-aldehyde transaldolase. Biochemical analysis revealed this transformation is dependent upon pyridoxal-5'-phosphate, the enzyme has no activity with alternative amino acids, such as glycine or serine, as aldol donors, and acetaldehyde is a coproduct. Structural characterization of the enzyme product is consistent with stereochemical assignment as the threo diastereomer (5'S,6'S)-GlyU. Thus this enzyme orchestrates C-C bond breaking and formation with concomitant installation of two stereocenters to make a new l-alpha-amino acid with a nucleoside side chain. PMID- 23110676 TI - Measurement of affective and activity pain interference using the Brief Pain Inventory (BPI): Cancer and Leukemia Group B 70903. AB - OBJECTIVE: The Brief Pain Inventory (BPI) was designed to yield separate scores for pain intensity and interference. It has been proposed that the pain interference factor can be further broken down into unique factors of affective (e.g., mood) and activity (e.g., work) interference. The purpose of this analysis was to confirm this affective/activity interference dichotomy. PATIENTS AND METHODS: A retrospective confirmatory factor analysis was completed for a sample of 184 individuals diagnosed with castrate-resistant prostate cancer (age 40-86, mean = 65.46, 77% White non-Hispanic) who had been administered the BPI as part of Cancer and Leukemia Group B trial 9480. A one-factor model was compared against two-factor and three-factor models that were developed based on the design of the instrument. RESULTS: Root mean squared error of approximation (0.075), comparative fit index (0.971), and change in chi-square, given the corresponding change in degrees of freedom (13.33, P < 0.05) values for the three factor model (i.e., pain intensity, activity interference, and affective interference), were statistically superior in comparison with the one- and two factor models. This three-factor structure was found to be invariant across age, mean prostate-specific antigen, and hemoglobin levels. CONCLUSIONS: These results confirm that the BPI can be used to quantify the degree to which pain separately interferes with affective and activity aspects of a patient's everyday life. These findings will provide clinical trialists, pharmaceutical sponsors, and regulators with confidence in the flexibility of the BPI as they consider the use of this instrument to assist with understanding the patient experience as it relates to treatment. PMID- 23110677 TI - Cascaded discrimination of normal, abnormal, and confounder classes in histopathology: Gleason grading of prostate cancer. AB - BACKGROUND: Automated classification of histopathology involves identification of multiple classes, including benign, cancerous, and confounder categories. The confounder tissue classes can often mimic and share attributes with both the diseased and normal tissue classes, and can be particularly difficult to identify, both manually and by automated classifiers. In the case of prostate cancer, they may be several confounding tissue types present in a biopsy sample, posing as major sources of diagnostic error for pathologists. Two common multi class approaches are one-shot classification (OSC), where all classes are identified simultaneously, and one-versus-all (OVA), where a "target" class is distinguished from all "non-target" classes. OSC is typically unable to handle discrimination of classes of varying similarity (e.g. with images of prostate atrophy and high grade cancer), while OVA forces several heterogeneous classes into a single "non-target" class. In this work, we present a cascaded (CAS) approach to classifying prostate biopsy tissue samples, where images from different classes are grouped to maximize intra-group homogeneity while maximizing inter-group heterogeneity. RESULTS: We apply the CAS approach to categorize 2000 tissue samples taken from 214 patient studies into seven classes: epithelium, stroma, atrophy, prostatic intraepithelial neoplasia (PIN), and prostate cancer Gleason grades 3, 4, and 5. A series of increasingly granular binary classifiers are used to split the different tissue classes until the images have been categorized into a single unique class. Our automatically extracted image feature set includes architectural features based on location of the nuclei within the tissue sample as well as texture features extracted on a per-pixel level. The CAS strategy yields a positive predictive value (PPV) of 0.86 in classifying the 2000 tissue images into one of 7 classes, compared with the OVA (0.77 PPV) and OSC approaches (0.76 PPV). CONCLUSIONS: Use of the CAS strategy increases the PPV for a multi-category classification system over two common alternative strategies. In classification problems such as histopathology, where multiple class groups exist with varying degrees of heterogeneity, the CAS system can intelligently assign class labels to objects by performing multiple binary classifications according to domain knowledge. PMID- 23110679 TI - Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis. AB - BACKGROUND: Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. OBJECTIVE: To determine periostin levels in association with severity of skin fibrosis in patients with SSc. METHODS: Expression of periostin was immunohistochemically examined in skin obtained from patients with SSc and healthy controls. Enzyme-linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc [diffuse cutaneous SSc (dSSc), n=16; and limited cutaneous SSc (lSSc), n=40] and 66 healthy controls. RESULTS: Periostin was strongly expressed in the affected dermis from patients with SSc. Periostin was colocalized in alpha-smooth muscle actin-positive myofibroblasts and platelet endothelial cell adhesion molecule-1-positive endothelial cells in SSc dermis. Serum levels of periostin in patients with dSSc were markedly elevated compared with those in patients with lSSc and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in patients with dSSc with disease duration <=5 years compared with those with disease duration >5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in patients with SSc. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some patients with dSSc as the disease progressed. CONCLUSION: An elevated periostin level in patients with SSc is associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc. PMID- 23110678 TI - Retrieval orientation and the control of recollection: an fMRI study. AB - This study used event-related fMRI to examine the impact of the adoption of different retrieval orientations on the neural correlates of recollection. In each of two study-test blocks, participants encoded a mixed list of words and pictures and then performed a recognition memory task with words as the test items. In one block, the requirement was to respond positively to test items corresponding to studied words and to reject both new items and items corresponding to the studied pictures. In the other block, positive responses were made to test items corresponding to pictures, and items corresponding to words were classified along with the new items. On the basis of previous ERP findings, we predicted that in the word task, recollection-related effects would be found for target information only. This prediction was fulfilled. In both tasks, targets elicited the characteristic pattern of recollection-related activity. By contrast, nontargets elicited this pattern in the picture task, but not in the word task. Importantly, the left angular gyrus was among the regions demonstrating this dissociation of nontarget recollection effects according to retrieval orientation. The findings for the angular gyrus parallel prior findings for the "left-parietal" ERP old/new effect and add to the evidence that the effect reflects recollection-related neural activity originating in left ventral parietal cortex. Thus, the results converge with the previous ERP findings to suggest that the processing of retrieval cues can be constrained to prevent the retrieval of goal-irrelevant information. PMID- 23110680 TI - Properties of immobilized glucose oxidase and enhancement of enzyme activity. AB - In this study; glucose oxidase (GOD) and MnO2 were immobilized in alginate gel beads using the entrapment method and effects of oxygen vectors on immobilized GOD activity were investigated. The specific activity of free enzyme was 1.3 units/mg protein whereas that of immobilized enzyme was 8.4 * 10(-1) units/mg protein. The Km values for free and immobilized enzyme were found to be 2.7 mM, 2.9 mM; Vmax values 3.64 * 10(-1) MUmol/min.mL, 2.61 * 10(-1) MUmol/min.mL, respectively. When 4% (v/v) silicone oil or soybean oil was used, the activity of immobilized GOD increased 1.7 times and 1.3 times, respectively, compared to media without these oils. PMID- 23110681 TI - Acute mesenteric ischemia and duodenal ulcer perforation: a unique double pathology. AB - BACKGROUND: Acute mesenteric ischaemia and duodenal perforation are surgical emergencies with serious consequences. Patients presenting with acute mesenteric ischaemia alone face a high mortality rate as high as 60% whereas those presenting with peptic ulcer perforation the mortality rates range from 6-14%. There are very few reported cases of patients presenting with this dual pathology. CASE PRESENTATION: We report a unique case of a 53 year old Italian lady who presented with acute mesenteric ischaemia and duodenal perforation. This is the first report of massive bowel ischaemia and duodenal perforation with no apparent underlying common pathophysiology leading to this presentation. CONCLUSION: Early management in the intensive care unit and appropriate surgical intervention maximised the patient's chances of survival despite the poor prognosis associated with her dual pathology. The rare pathology of the patient described can be explained by two possible hypotheses: peptic ulcer disease causing duodenal ulceration, which precipitated ischaemic infarction of the small bowel. The second hypothesis is the patient developed a stress related ulcer following ischaemic bowel infarction secondary to arterial thrombosis. PMID- 23110682 TI - Public preferences for government spending in Canada. AB - This study considers three questions: 1. What are the Canadian public's prioritization preferences for new government spending on a range of public health-related goods outside the scope of the country's national system of health insurance? 2. How homogenous or heterogeneous is the Canadian public in terms of these preferences? 3. What factors are predictive of the Canadian public's preferences for new government spending? Data were collected in 2008 from a national random sample of Canadian adults through a telephone interview survey (n=1,005). Respondents were asked to rank five spending priorities in terms of their preference for new government spending. Bivariate and multivariable logistic regression analyses were conducted. As a first priority, Canadian adults prefer spending on child care (26.2%), followed by pharmacare (23.1%), dental care (20.8%), home care (17.2%), and vision care (12.7%). Sociodemographic characteristics predict spending preferences, based on the social position and needs of respondents. Policy leaders need to give fair consideration to public preferences in priority setting approaches in order to ensure that public health related goods are distributed in a manner that best suits population needs. PMID- 23110683 TI - Sarpogrelate hydrochloride, a selective 5-HT(2A) receptor antagonist, improves skin perfusion pressure of the lower extremities in hemodialysis patients with peripheral arterial disease. AB - BACKGROUND: Peripheral arterial disease (PAD) frequently occurs in patients on hemodialysis (HD); however, little is known about the effectiveness of drugs. We compare the effects of sarpogrelate and cilostazol in HD patients with PAD. METHODS: We conducted a prospective, randomized, open-label, and multicenter trial for 24 weeks in HD patients with PAD. Thirty-five patients were divided into two groups: sarpogrelate (n = 17) and cilostazol (n = 18). We analyzed changes in skin perfusion pressure (SPP), levels of oxidative stress biomarkers, and adverse events. RESULTS: At 24 weeks, SPP was increased in both groups (sarpogrelate, 43 +/- 17 to 55 +/- 15 mmHg; cilostazol, 49 +/- 21 to 66 +/- 29 mmHg; p < 0.05), and no difference was observed between the groups. Plasma pentosidine levels decreased in both groups (sarpogrelate, 0.65 +/- 0.24 to 0.48 +/- 0.12 mg/mL; cilostazol, 0.58 +/- 0.22 to 0.47 +/- 0.17 mg/mL; p < 0.05), and there were no differences between the groups. Serum malondialdehyde-modified low density lipoprotein (MDA-LDL) levels significantly increased only in cilostazol group (p < 0.05). There were no clinically significant safety concerns linked to the both drugs. Although blood pressure did not differ in both groups, heart rate increased only in cilostazol group from 77 +/- 13 to 83 +/- 16 beats per minute (p < 0.05). CONCLUSION: Sarpogrelate improves SPP in HD patients with PAD without increasing heart rate and serum MDA-LDL levels. We demonstrated that sarpogrelate is an effective and safe drug for the treatment of HD patients with PAD. PMID- 23110684 TI - Avatars using computer/smartphone mediated communication and social networking in prevention of sexually transmitted diseases among North-Norwegian youngsters. AB - BACKGROUND: Sexually transmitted diseases (STDs), especially the Chlamydia trachomatis bacterial infection, a common cause of infertility, are highly prevalent in developed countries, and a worrying problem in North Norway, where the incidence of chlamydia twice the Norwegian average. Seventy percent of reported chlamydia cases are found in people below 25 years of age, and although its spread could be controlled with proper prevention, young people are more aware of the risks of unwanted pregnancy than their risk of acquiring a STD. Information and Communication Technologies, including, the Internet, social media and/or smartphones, should be valued for sexual health promotion for their potential to engage young audiences. And in these media, avatars guarantee anonymity to users when handling sensitive information. The main objective of this project is to achieve that North Norwegian youngsters become more aware of STDs through the use of popular technologies among young people. METHODS: A Virtual Clinic for Sexually Transmitted Diseases (VCSTD) will be developed. The VCSTD will provide early guidance and reliable information sources concerning reproductive health, delivered in a novel and innovative way to the younger population. The VCSTD consists of an "avatar" supported intervention in a serious gaming and e-learning environment, which will bypass direct physical access (in person) to reliable medical information, as well as allowing the youngsters to share that information in social media, and thus helping the VCSTD to be disseminated to more people.Data analyses will be conducted on publically available health data relevant to STDs in Troms and Finnmark, like the absolute number of chlamydia tests, the amount of emergency contraception medication sold, and the number of abortions. Also, usage data of the system and experiences of usefulness will be explored through participants' voluntary responses to a feedback form available in the VCSTD. DISCUSSION: This study will examine the usefulness of an online public health intervention that aims to promote healthy sexual practices among North-Norwegian youngsters. If shown to be effective, the intervention could prove to be an affordable and widely accessible intervention to decrease risky sexual practices in younger population. PMID- 23110685 TI - Lymphodepletion chemotherapy followed by donor leukocytes for post transplantation relapse of myelofibrosis after previous donor leukocyte infusion failure. AB - Treatment of relapse after allogenic stem cell transplantation (allo-SCT) is challenging. The efficacy of donor leukocyte infusions (DLI) is excellent in chronic phase chronic myeloid leukaemia but limited in other disorders. We present a patient who relapsed 10 months after reduced intensity conditioning allo-SCT for a myelodysplastic/ myeloproliferative neoplasm with myelofibrosis despite receiving escalating doses of DLI for incomplete chimerism. He finally achieved complete remission with full whole blood and T-cell donor chimerism after DLI preceded by lymphodepletion chemotherapy. This case demonstrates that chemotherapy prior to DLI is a useful approach for treating relapses of relatively slowly progressive diseases, such as myeloproliferative diseases or myelodysplastic syndromes. PMID- 23110686 TI - Fixed drug eruption caused by ornidazole and fluconazole but not isoconazole, itraconazole, ketoconazole and metronidazole. PMID- 23110687 TI - Metamorphic protein IscU changes conformation by cis-trans isomerizations of two peptidyl-prolyl peptide bonds. AB - IscU from Escherichia coli, the scaffold protein for iron-sulfur cluster biosynthesis and transfer, populates two conformational states with similar free energies and with lifetimes on the order of 1 s that interconvert in an apparent two-state reaction. One state (S) is structured, and the other (D) is largely disordered; however, both play essential functional roles. We report here nuclear magnetic resonance studies demonstrating that all four prolyl residues of apo IscU (P14, P35, P100, and P101) are trans in the S state but that two absolutely conserved residues (P14 and P101) become cis in the D state. The peptidyl-prolyl peptide bond configurations were determined by analyzing assigned chemical shifts and were confirmed by measurements of nuclear Overhauser effects. We conclude that the S ? D interconversion involves concerted trans-cis isomerization of the N13-P14 and P100-P101 peptide bonds. Although the D state is largely disordered, we show that it contains an ordered domain that accounts for the stabilization of two high-energy cis peptide bonds. Thus, IscU may be classified as a metamorphic protein. PMID- 23110688 TI - Coexistence and origin of trophic ecotypes of pygmy whitefish, Prosopium coulterii, in a south-western Alaskan lake. AB - Ecologically, morphologically and genetically distinct populations within single taxa often coexist in postglacial lakes and have provided important model systems with which to investigate ecological and evolutionary processes such as niche partitioning and ecological speciation. Within the Salmonidae, these species complexes have been well studied, particularly within the Coregonus clupeaformis C. laveratus (lake and European whitefish, respectively) group, but the phenomenon has been less well documented in the other whitefish genera, Prosopium and Stenodus. Here, we examined the morphology, feeding biology and genetic structure of three putative forms of the pygmy whitefish, Prosopium coulterii (Eigenmann & Eigenmann, 1892), first reported from Chignik Lake, south-western Alaska, over 40 years ago. Field collections and morphological analyses resolved a shallow water (< 5 m depth) low gill raker count form (< 15 first arch gill rakers), a deepwater (> 30 m), low gill raker form and a deepwater, high gill raker count (> 15 gill rakers) form. The two low gill raker count forms fed almost exclusively on benthic invertebrates (mostly chironomids), while the deepwater, high gill raker count form fed almost exclusively on zooplankton; differences in diet were also reflected in differences both in delta(13) C and delta(15) N stable isotopes. All three forms were characterized by the same major mitochondrial DNA clade that has been associated with persistence in, and postglacial dispersal from, a Beringian glacial refugium. Analysis of variation at nine microsatellite DNA loci indicated low, but significant differentiation among forms, especially between the two low gill raker count forms and the high gill raker count form. The extent of differentiation along phenotypic (considerable) and genetic (subtle) axes among the Chignik Lake forms is similar to that found among distinct taxa of Prosopium found in pre-glacial Bear Lake (Utah-Idaho, USA) which is probably at least ten times older than Chignik Lake. Our analyses illustrate the potential for the postglacial differentiation in traits subject to divergent natural selection across variable environments. PMID- 23110689 TI - Biosorption of heavy metal ions onto agricultural residues buckwheat hulls functionalized with 1-hydroxylethylidenediphosphonic acid. AB - Novel biosorbent materials obtained from agricultural residues buckwheat hulls (BH) were successfully developed through functionalization with 1 hydroxylethylidenediphosphonic acid (HEDP), and they were characterized. This paper reports the feasibility of using HEDP-BH for removal of heavy metals from stimulated wastewater, the experimental results revealed that the adsorption property of functionalized buckwheat hulls with 120 mesh 120-HEDP-BH for Au(III) was very excellent, and the monolayer maximum adsorption capacity for Au(III) calculated from the Langmuir isotherm models was up to 450.45 mg/g at 35 degrees C. The combined effect of initial solution pH, 120-HEDP-BH dosage, and initial Au(III) concentration was investigated using response surface methodology (RSM), and the result showed that biomass dosage exerted a stronger influence on Au(III) uptake than those of initial pH and initial Au(III) concentration. Analysis of variance (ANOVA) of the quadratic model demonstrated that the model was highly significant. Moreover, investigation on the adsorption selectivity showed that 120-HEDP-BH displayed strong affinity for gold in aqueous solutions and even exhibited 100% selectivity for Au(III) ions in the presence of Zn(II) and Co(II). Regeneration capacities of 120-HEDP-BH were studied using the eluent solutions of 0.0-5.0% thiourea in 0.1 mmol/L HCl, and it was found that the adsorption capability remains high after several cycles of adsorption-desorption process. PMID- 23110690 TI - Health worker perspectives on user fee removal in Zambia. AB - BACKGROUND: User fees for primary care services were removed in rural districts in Zambia in 2006. Experience from other countries has suggested that health workers play a key role in determining the success of a fee removal policy, but also find the implementation of such a policy challenging. The policy was introduced against a backdrop of a major shortage in qualified health staff. METHODS: As part of a larger study on the experience and effect of user fee removal in Zambia, a number of case studies at the facility level were conducted. As part of these, quantitative and qualitative data were collected to evaluate health workers' satisfaction and experiences in charging and non-charging facilities. RESULTS: Our findings show that health-care workers have mixed feelings about the policy change and its consequences. We found some evidence that personnel motivation was higher in non-charging facilities compared to facilities still charging. Yet it is unclear whether this effect was due to differences in the user fee policy or to the fact that a lot of staff interviewed in non-charging facilities were working in mission facilities, where we found a significantly higher motivation. Health workers expressed satisfaction with an apparent increase in the number of patients visiting the facilities and the removal of a deterring factor for many needy patients, but also complained about an increased workload. Furthermore, working conditions were said to have worsened, which staff felt was linked to the absence of additional resources to deal with the increased demand or replace the loss of revenue generated by fees. CONCLUSION: These findings highlight the need to pay attention to supply-side measures when removing demand-side barriers such as user fees and in particular to be concerned about the burden that increased demand can place on already over stretched health workers. PMID- 23110691 TI - Steroidogenic capacity of the placenta as a supplemental source of progesterone during pregnancy in domestic cats. AB - BACKGROUND: Until recently, the corpus luteum (CL) was considered to be the main source of progesterone (P4) during pregnancy in the domestic cat (Felis catus). However, other possible sources of P4 have not been ruled out. Although feline placental homogenates were found to be capable of synthesizing P4, expression of the respective steroidogenic enzymes has not been investigated at the molecular level. Therefore, in the present study, expression of the two major factors involved in the synthesis of P4 - 3beta-hydroxysteroid dehydrogenase (3betaHSD) and steroidogenic acute regulatory protein (StAR) - was investigated in the feline CL and placenta during the course of pseudopregnancy and pregnancy. METHODS: The mRNA levels of StAR and 3betaHSD were determined using Real Time PCR and their localizations were determined by immunohistochemistry. Placental P4 concentrations, after ethyl extraction, were measured by EIA. RESULTS: Luteal 3betaHSD and StAR mRNA levels were strongly time-dependent, peaking during mid pregnancy. The placental 3betaHSD mRNA level was significantly upregulated towards the end of pregnancy. In the CL, 3betaHSD and StAR protein were localized in the luteal cells whereas in the placenta they were localized to the maternal decidual cells. Placental P4 concentrations were low in early pregnant queens, but increased along with gestational age. CONCLUSIONS: These results confirm that the placenta is an additional source of P4 in pregnant queens and can thereby be considered as an important endocrine organ supporting feline pregnancy. PMID- 23110692 TI - Tissue engraftment of hypoxic-preconditioned adipose-derived stem cells improves flap viability. AB - Adipose-derived stem cells (ASCs) have the ability to release multiple growth factors in response to hypoxia. In this study, we investigated the potential of ASCs to prevent tissue ischemia. We found conditioned media from hypoxic ASCs had increased levels of vascular endothelial growth factor (VEGF) and enhanced endothelial cell tubule formation. To investigate the effect of injecting rat ASCs into ischemic flaps, 21 Lewis rats were divided into three groups: control, normal oxygen ASCs (10(6) cells), and hypoxic preconditioned ASCs (10(6) cells). At the time of flap elevation, the distal third of the flap was injected with the treatment group. At 7 days post flap elevation, flap viability was significantly improved with injection of hypoxic preconditioned ASCs. Cluster of differentiation-31-positive cells were more abundant along the margins of flaps injected with ASCs. Fluorescent labeled ASCs localized aside blood vessels or throughout the tissue, dependent on oxygen preconditioning status. Next, we evaluated the effect of hypoxic preconditioning on ASC migration and chemotaxis. Hypoxia did not affect ASC migration on scratch assay or chemotaxis to collagen and laminin. Thus, hypoxic preconditioning of injected ASCs improves flap viability likely through the effects of VEGF release. These effects are modest and represent the limitations of cellular and growth factor-induced angiogenesis in the acute setting of ischemia. PMID- 23110693 TI - Metabonomics approach to assessing the modulatory effects of St John's wort, ginsenosides, and clomipramine in experimental depression. AB - The protective effects of St John's Wort extract (SJ), ginsenosides (GS), and clomipramine (CPM) on chronic unpredictable mild stress (CUMS)-induced depression in rats were investigated by using a combination of behavioral assessments and metabonomics. Metabonomic analyses were performed using gas chromatography/mass spectrometry in conjunction with multivariate and univariate statistical analyses. During and at the end point of the chronic stress experiment, food consumption, body weight, adrenal gland, thymus and spleen indices, behavior scores, sucrose consumption, and stress hormone levels were measured. Changes in these parameters reflected characteristic phenotypes of depression in rats. Metabonomic analysis of serum, urine, and brain tissue revealed that CPM and SJ mainly attenuated the alteration of monoamine neurotransmitter metabolites, while GS affected both excitatory/inhibitory amino acids and monoamine neurotransmitter metabolites. GS also attenuated the stress-induced alterations in cerebrum and peripheral metabolites to a greater extent than CPM and SJ. These results provide important mechanistic insights into the protective effects of GS against CUMS induced depression and metabolic dysfunction. PMID- 23110694 TI - Large-area Bernal-stacked bi-, tri-, and tetralayer graphene. AB - Few-layer graphene, with Bernal stacking order, is of particular interest to the graphene community because of its unique tunable electronic structure. A synthetic method to produce such large area graphene films with precise thickness from 2 to 4 layers would be ideal for chemists and physicists to explore the promising electronic applications of these materials. Here, large-area uniform Bernal-stacked bi-, tri-, and tetralayer graphene films were successfully synthesized on a Cu surface in selective growth windows, with a finely tuned total pressure and CH(4)/H(2) gas ratio. On the basis of the analyses obtained, the growth mechanism is not an independent homoexpitaxial layer-by-layer growth, but most likely a simultaneous-seeding and self-limiting process. PMID- 23110695 TI - Phosphorylation of p68 RNA helicase by p38 MAP kinase contributes to colon cancer cells apoptosis induced by oxaliplatin. AB - BACKGROUND: We previously demonstrated that p68 phosphorylation at threonine residues correlates with cancer cell apoptosis under the treatments of TNF-alpha and TRAIL (Yang, L. Mol Cancer Res Vol 3, pp 355-63 2005). RESULTS: In this report, we characterized the role of p68 phosphorylation in apoptosis induction under the treatment of oxaliplatin in the colon cancer cells. Our data suggest that oxaliplatin treatment activates p38 MAP kinase, which subsequently phosphorylates p68 at T564 and/or T446. The phosphorylation of p68, at least partially, mediates the effects of the drug on apoptosis induction, as mutations at these two sites greatly reduce the cancer cell death. CONCLUSION: Our studies reveal an important molecular mechanism that mediates the effects of anti-cancer drug, providing a potential strategy for improving cancer treatment. PMID- 23110697 TI - Socioeconomic status and metabolic syndrome in the general population of China: a cross-sectional study. AB - BACKGROUND: Individual socioeconomic status (SES) has been found to be associated with cardiovascular diseases in developed countries, but the association between individual SES and metabolic syndrome (MetS) is still unclear in China. The objective of this study was to investigate the association between individual SES and MetS in China. METHODS: A cross-sectional study of 10054 community residents was performed from May to August 2007 using multistage stratified random sampling. SES was assessed in terms of education, personal monthly income, and household monthly income. The association between SES and MetS was determined by logistic regression models. RESULTS: After the adjustments regarding age, marital status, smoking, drinking, physical activity, body mass index (BMI), and community type, odds ratios (ORs) for MetS of individuals with education level of 7~12 years and >12 years were 0.87 (95% confidence interval [CI]: 0.75 to 0.99) and 0.83 (95% CI: 0.62 to 0.91) respectively compared with those with education level of <7 years in women. Following the adjustments as above, ORs for MetS of individuals with household monthly income level of middle and higher were 0.94 (95% CI: 0.86 to 0.97), and 0.72 (95% CI: 0.65 to 0.88) respectively compared with those with lower household monthly income level in women. The association between SES and MetS was not significant in men. CONCLUSIONS: Gender had an influence on the association between individual SES and MetS. Lower education and household monthly income level were associated with higher risk of MetS among community residents in women, while such association was not significant in men. PMID- 23110696 TI - The CARD plays a critical role in ASC foci formation and inflammasome signalling. AB - The ASC (apoptosis speck-like protein) is a key component of multimeric protein complexes that mediate inflammation and host defence. Comprising a PYD (Pyrin) domain and a CARD (caspase activation and recruitment domain), ASC functions downstream of NLRs (nucleotide-binding domain, leucine-rich repeat-containing receptors) and AIM2 (absent in melanoma 2) through the formation of supramolecular structures termed inflammasomes. However, the mechanism underlying ASC signalling and its dependency on oligomeric arrangements in inflammasome formation remain poorly understood. When expressed in cells, ASC forms discrete foci (called 'specks') typically with one speck per cell. We employed a BiFC (bimolecular fluorescence complementation) system to investigate and visualize ASC foci formation in living cells. We demonstrated that the CARD of ASC plays a central role in ASC inflammasome assembly, representing the minimal unit capable of forming foci in conjunction with the caspase 1 CARD. Mutational studies point to multiple surfaces on the ASC CARD and two predominant areas on the caspase 1 CARD mediating the formation of ASC/caspase 1 foci. The lack of foci formation for ASC CARD mutants correlates with a loss of IL-1beta (interleukin 1beta) processing in response to NLRP (NLR family, PYD domain-containing) 3 or AIM2 agonists in RAW264.7 cell reconstitution assays. Analogously, we show that productive formation of the Salmonella typhimurium-induced NLRC4 (NLR family CARD domain-containing protein 4) inflammasome is dependent on ASC-CARD-mediated platform formation. Thus the results of the present study depict a central role of CARDs in the formation of ASC signalling platforms and provide an important tool for investigation of CARD-dependent networks. PMID- 23110698 TI - Net toroidal magnetic moment in the ground state of a {Dy6}-triethanolamine ring. AB - A toroidal magnetic moment in the absence of conventional total magnetic moment is observed in a {Dy(6)} ring. The reason for the net toroidal arrangement of the local magnetic moments is the high symmetry of the complex in combination with strong intra-molecular dipolar interactions between Dy ions. The description of single-ion and inter-ion anisotropic magnetic interactions is achieved here for the first time fully ab initio, i.e., without use of phenomenological parameters. PMID- 23110699 TI - Transcriptomic markers meet the real world: finding diagnostic signatures of corticosteroid treatment in commercial beef samples. AB - BACKGROUND: The use of growth-promoters in beef cattle, despite the EU ban, remains a frequent practice. The use of transcriptomic markers has already proposed to identify indirect evidence of anabolic hormone treatment. So far, such approach has been tested in experimentally treated animals. Here, for the first time commercial samples were analyzed. RESULTS: Quantitative determination of Dexamethasone (DEX) residues in the urine collected at the slaughterhouse was performed by Liquid Chromatography-Mass Spectrometry (LC-MS). DNA-microarray technology was used to obtain transcriptomic profiles of skeletal muscle in commercial samples and negative controls. LC-MS confirmed the presence of low level of DEX residues in the urine of the commercial samples suspect for histological classification. Principal Component Analysis (PCA) on microarray data identified two clusters of samples. One cluster included negative controls and a subset of commercial samples, while a second cluster included part of the specimens collected at the slaughterhouse together with positives for corticosteroid treatment based on thymus histology and LC-MS. Functional analysis of the differentially expressed genes (3961) between the two groups provided further evidence that animals clustering with positive samples might have been treated with corticosteroids. These suspect samples could be reliably classified with a specific classification tool (Prediction Analysis of Microarray) using just two genes. CONCLUSIONS: Despite broad variation observed in gene expression profiles, the present study showed that DNA-microarrays can be used to find transcriptomic signatures of putative anabolic treatments and that gene expression markers could represent a useful screening tool. PMID- 23110700 TI - Lymphocyte transformation assay for C neoformans antigen is not reliable for detecting cellular impairment in patients with neurocryptococcosis. AB - BACKGROUND: Cryptococcus neoformans causes meningitis and disseminated infection in healthy individuals, but more commonly in hosts with defective immune responses. Cell-mediated immunity is an important component of the immune response to a great variety of infections, including yeast infections. We aimed to evaluate a specific lymphocyte transformation assay to Cryptococcus neoformans in order to identify immunodeficiency associated to neurocryptococcosis (NCC) as primary cause of the mycosis. METHODS: Healthy volunteers, poultry growers, and HIV-seronegative patients with neurocryptococcosis were tested for cellular immune response. Cryptococcal meningitis was diagnosed by India ink staining of cerebrospinal fluid and cryptococcal antigen test (Immunomycol-Inc, SP, Brazil). Isolated peripheral blood mononuclear cells were stimulated with C. neoformans antigen, C. albicans antigen, and pokeweed mitogen. The amount of 3H-thymidine incorporated was assessed, and the results were expressed as stimulation index (SI) and log SI, sensitivity, specificity, and cut-off value (receiver operating characteristics curve). We applied unpaired Student t tests to compare data and considered significant differences for p<0.05. RESULTS: The lymphotoxin alpha showed a low capacity with all the stimuli for classifying patients as responders and non-responders. Lymphotoxin alpha stimulated by heated-killed antigen from patients with neurocryptococcosis was not affected by TCD4+ cell count, and the intensity of response did not correlate with the clinical evolution of neurocryptococcosis. CONCLUSION: Response to lymphocyte transformation assay should be analyzed based on a normal range and using more than one stimulator. The use of a cut-off value to classify patients with neurocryptococcosis is inadequate. Statistical analysis should be based on the log transformation of SI. A more purified antigen for evaluating specific response to C. neoformans is needed. PMID- 23110701 TI - Open preperitoneal versus anterior approach for recurrent inguinal hernia: a randomized study. AB - BACKGROUND: Inguinal herniorrhaphy remains one of the most common general surgical operations, with approximately 15% performed for recurrence. The repair of the resulting recurrent hernia is a daunting task because of already weakened tissues and obscured and distorted anatomy. The aim of this study is to compare the posterior preperitoneal versus anterior tension-free approach for repair of unilateral recurrent inguinal hernia regarding complications and early recurrence. METHODS: 120 Patients in this study were divided randomly into 2 main groups; Group A patients were subjected to posterior preperitoneal approach and those of group B were subjected to conventional anterior tension-free repair. The primary end point was recurrence and the secondary end points were time off from work, postoperative pain, scrotal swelling and wound infections. RESULTS: The mean hospital stay was 1.2 days and 4.7, the mean time to return work was 8.2 and 11.2 days and the mean time off from work was 9.4 and 15.9 days in group A and B respectively. The maximum follow-up period was 48 months and the minimum was 14 months with a mean value as 37.11 +/- 5.14 months. Only 2 recurrences (3.3%) in group A and 4 cases (6.25%) in group B were seen. The final pain score per patient and the overall complication rate were higher in group B. CONCLUSIONS: The open preperitoneal repair offers the advantages of low recurrence rate and allows covering all potential defects with one piece of mesh and is far superior to the anterior approach. TRIAL REGISTRATION: ACTRN12611000337976. PMID- 23110702 TI - Lenalidomide treatment for patients with myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure. PMID- 23110703 TI - PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in myelodysplastic syndromes. AB - PRAME and WT1 transcript levels were simultaneously measured in 312 bone marrow samples collected from patients with newly diagnosed myelodysplastic syndromes (MDS) and 111 samples collected during the treatment of 17 patients. Both the positive rate and the > 1-log increase expression frequency of PRAME were similar to those of WT1 (74.4 % vs. 77.6%; 51.6% vs. 49.0%), and 88.1% of patients overexpressed at least one marker. Moreover, the frequencies of PRAME expression with higher degrees of increase were significantly higher compared with those of WT1 expression (> 2-log increase: 30.8% vs. 3.8%; > 3-log increase: 9.0% vs. 0%; all p < 0.001). PRAME had a higher log increase than WT1 in 53.3% of the patients with overexpressed WT1. Both PRAME and WT1 transcript levels generally fluctuated within the normal range after hematopoietic stem cell transplant in all 10 patients in continuous complete remission. Six out of seven patients were predicted relapse by the combined detection: sustained positivity, or significant increase to be positive for both WT1 and PRAME in three patients, earlier by PRAME than WT1 or by PRAME alone in three patients. Thus, PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in MDS. PMID- 23110707 TI - Periodic ice banding in freezing colloidal dispersions. AB - Concentrated colloidal alumina dispersions were frozen in a directional solidification apparatus that provides independent control of the freezing rate and temperature gradient. Two distinct steady-state modes of periodic ice banding were observed in the range of freezing rates examined. For each mode, the wavelength between successive bands of segregated ice decreases with increasing freezing rate. At low freezing rates (0.25-3 MUm s(-1)), the ice segregates from the suspension into ice lenses, which are cracklike in appearance, and there is visible structure in the layer of rejected particles in the unfrozen region ahead of the ice lenses. In this regime, we argue that compressive cryosuction forces lead to the irreversible aggregation of the rejected particles into a close packed cohesive layer. The temperature in the aggregated layer is depressed below the bulk freezing point by more than 2 degrees C before the ice lenses are encountered; moreover, this undercooled region appears as a light-colored layer. The magnitude of the undercooling and the color change in this region both suggest the presence of pore ice and the formation of a frozen fringe. The possibility of a frozen fringe is supported by a quantitative model of the freezing behavior. At intermediate freezing rates, around 4 MUm s(-1), the pattern of ice segregation is disordered, coinciding with the disappearance of the dark- and light-colored layers. Finally, at high freezing rates (5-10 MUm s( 1)), there is a new mode of periodic ice banding that is no longer cracklike and is absent of any visible structure in the suspension ahead of the ice bands. We discuss the implications of our experimental findings for theories of ice lensing. PMID- 23110706 TI - Titrating lovaza from 4 to 8 to 12 grams/day in patients with primary hypertriglyceridemia who had triglyceride levels >500 mg/dl despite conventional triglyceride lowering therapy. AB - BACKGROUND: Omega-3 fatty acids are important in treatment of severe primary hypertriglyceridemia (HTG). In 15 patients with severe primary HTG (TG >500 mg/dl despite conventional TG lowering therapy), we assessed efficacy-safety of sequential monthly treatment with Lovaza, 4 to 8 to 12 g/day. METHODS: With TG >500 mg/dl despite Type V diet, hyperinsulinemia and diabetes control, and fibric acids, Lovaza (4 g/d) was added for 1 month, and if TG remained >500 mg/dl, increased to 8 g/d for 1 month, and then to 12 g/d for 1 month, and subsequently reduced to 4 g/day for 4 months. RESULTS: Primary HTG, median TG 884 mg/dl, 14 men, 1 woman, all white, age 50 +/- 7 years, 12 non-diabetic, 3 with stable diabetes control. Weight and diet held stable throughout. In 5 patients, after 1, 2, and 3 months on 4 g/day, TG fell <500, mean 1390 to 234 (-83%, p<.0001), to 135 (-90%, p<.0001), and 158 mg/dl (-89%, p<.0001), with a negative TG slope, p=.0013. Non-HDLC fell from 320 to 177 (-45%, p=.001), to 152 (-53%, p=.0002), and to 163 (-49%, p=.0004), with a negative slope, p=.01. In 10 patients, with Lovaza increased from 4 to 8 to 12 g, 3 failed to respond. In 7 of these 10 patients, TG fell 37% from 1075 to 672 on 4 g (p=.006), to 577 on 8 g (-46%, p=.0009), and to 428 mg/dl (-60%, p<.0001) on 12 g/day, with a negative TG slope, p=.0018. TG on 12 g/day was lower than on 8 g/day, p =.03. Non-HDLC fell from 245 to 217 mg/dl (-11%) on 4 g/day, to 203 (-17%, p=.01) on 8 g/day, and to 192 ( 22%, p=.003) on 12 g/day, with a negative slope, p=.016. Compared to pre-Lovaza baseline, no abnormal measures developed in safety tests. The 4, 8, and 12 g/d Lovaza doses were well tolerated. CONCLUSION: Titration of Lovaza from 4 to 8 to 12 g/d safely offers an effective way to lower TG beyond conventional 4 g therapy. PMID- 23110705 TI - Impact of immune escape mutations on HIV-1 fitness in the context of the cognate transmitted/founder genome. AB - BACKGROUND: A modest change in HIV-1 fitness can have a significant impact on viral quasispecies evolution and viral pathogenesis, transmission and disease progression. To determine the impact of immune escape mutations selected by cytotoxic T lymphocytes (CTL) on viral fitness in the context of the cognate transmitted/founder (T/F) genome, we developed a new competitive fitness assay using molecular clones of T/F genomes lacking exogenous genetic markers and a highly sensitive and precise parallel allele-specific sequencing (PASS) method. RESULTS: The T/F and mutant viruses were competed in CD4+ T-cell enriched cultures, relative proportions of viruses were assayed after repeated cell-free passage, and fitness costs were estimated by mathematical modeling. Naturally occurring HLA B57-restricted mutations involving the TW10 epitope in Gag and two epitopes in Tat/Rev and Env were assessed independently and together. Compensatory mutations which restored viral replication fitness were also assessed. A principal TW10 escape mutation, T242N, led to a 42% reduction in replication fitness but V247I and G248A mutations in the same epitope restored fitness to wild-type levels. No fitness difference was observed between the T/F and a naturally selected variant carrying the early CTL escape mutation (R355K) in Env and a reversion mutation in the Tat/Rev overlapping region. CONCLUSIONS: These findings reveal a broad spectrum of fitness costs to CTL escape mutations in T/F viral genomes, similar to recent findings reported for neutralizing antibody escape mutations, and highlight the extraordinary plasticity and adaptive potential of the HIV-1 genome. Analysis of T/F genomes and their evolved progeny is a powerful approach for assessing the impact of composite mutational events on viral fitness. PMID- 23110708 TI - Serum chemerin is increased in patients with chronic plaque psoriasis and normalizes following treatment with infliximab. AB - BACKGROUND: Chronic plaque psoriasis is associated with obesity, which is a metabolic and inflammatory disorder. Adipokines are involved in the pathogenesis of psoriasis and they are biomarkers of obesity-related inflammation. OBJECTIVES: To measure serum adipokines in patients with chronic plaque psoriasis treated with infliximab. METHODS: Serum levels of chemerin, resistin, visfatin, C reactive protein (CRP), lipids, glycaemia and liver enzymes were measured in 40 patients with psoriasis and 40 controls matched by age, sex and body mass index (BMI). Adipokines were measured at baseline and after 2-12 months of treatment with infliximab 5 mg kg(-1). RESULTS: At baseline, levels of chemerin (195.9+/ 48.5 vs. 145.6+/-27.1 ng mL(-1)), resistin (2.03+/-0.9 vs. 1.4+/-0.5 ng mL(-1)) and CRP (5.5+/-7.3 vs. 1.9 +/-4.4 mg L(-1)) were higher (P<0.01) in patients with psoriasis compared with controls. Psoriasis was associated with elevated chemerin level independently of age, sex, BMI and levels of cholesterol and triglycerides. Chemerin was linearly correlated to CRP (r=0.4, P=0.01) and resistin (r=0.3, P=0.01). Chemerin levels were higher in patients affected by psoriatic arthritis than in patients with psoriasis without arthritis (195.5+/-49.1 vs. 158.1+/-37.5 ng mL(-1), P=0.01). After 2 months of infliximab treatment a significant reduction of chemerin, resistin and CRP levels was observed. CONCLUSIONS: Patients with psoriasis have higher blood levels of adipokines, which normalize during therapy with infliximab. Whether this reduction is a direct effect of infliximab or secondary to a reduction of inflammation should be further investigated. PMID- 23110709 TI - Hearing impairment in Stickler syndrome: a systematic review. AB - BACKGROUND: Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype. METHODS: English-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation. RESULTS: 313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%). CONCLUSIONS: Hearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired. PMID- 23110710 TI - Demonstration of early functional compromise of bone marrow derived hematopoietic progenitor cells during bovine neonatal pancytopenia through in vitro culture of bone marrow biopsies. AB - BACKGROUND: Bovine neonatal pancytopenia (BNP) is a syndrome characterised by thrombocytopenia associated with marked bone marrow destruction in calves, widely reported since 2007 in several European countries and since 2011 in New Zealand. The disease is epidemiologically associated with the use of an inactivated bovine virus diarrhoea (BVD) vaccine and is currently considered to be caused by absorption of colostral antibody produced by some vaccinated cows ("BNP dams"). Alloantibodies capable of binding to the leukocyte surface have been detected in BNP dams and antibodies recognising bovine MHC class I and beta-2-microglobulin have been detected in vaccinated cattle. In this study, calves were challenged with pooled colostrum collected from BNP dams or from non-BNP dams and their bone marrow hematopoietic progenitor cells (HPC) cultured in vitro from sternal biopsies taken at 24 hours and 6 days post-challenge. RESULTS: Clonogenic assay demonstrated that CFU-GEMM (colony forming unit granulocyte/erythroid/macrophage/megakaryocyte; pluripotential progenitor cell) colony development was compromised from HPCs harvested as early as 24 hour post challenge. By 6 days post challenge, HPCs harvested from challenged calves failed to develop CFU-E (erythroid) colonies and the development of both CFU-GEMM and CFU-GM (granulocyte/macrophage) was markedly reduced. CONCLUSION: This study suggests that the bone marrow pathology and clinical signs associated with BNP are related to an insult which compromises the pluripotential progenitor cell within the first 24 hours of life but that this does not initially include all cell types. PMID- 23110711 TI - Pulseless electrical activity and successful out-of-hospital resuscitation - long term survival and quality of life: an observational cohort study. AB - BACKGROUND: The aim of the study was to evaluate the long-term outcome of patients successfully resuscitated from pre-hospital cardiac arrest with initial pulseless electrical activity (PEA), because the long-term outcome of these patients is unknown. Survival, neurological status one year after cardiac arrest and self-perceived quality of life after five years were assessed. METHODS: This retrospective study included adult patients resuscitated from PEA between August 2001 and March 2003 in three urban areas in southern Finland. A validated questionnaire was sent to patients while neurological status according to the Cerebral Performance Category (CPC) -classification was assessed based on medical database notes recorded during follow-up evaluations. RESULTS: Out of 99 included patients in whom resuscitation was attempted, 41 (41%) were successfully resuscitated and admitted to hospital. Ten (10%) patients were discharged from hospital. Seven were alive after one year and six after five years following cardiac arrest. Five of the seven patients alive one year after resuscitation presented with the same functional level as prior to cardiac arrest. CONCLUSIONS: Patients with initial PEA have been considered to have poor prognosis, but in our material, half of those who survived to hospital discharge were still alive after 5 years. Their self-assessed quality of life seems to be good with only mild to moderate impairments in activities of daily life. PMID- 23110712 TI - Smartphone and medical related App use among medical students and junior doctors in the United Kingdom (UK): a regional survey. AB - BACKGROUND: Smartphone usage has spread to many settings including that of healthcare with numerous potential and realised benefits. The ability to download custom-built software applications (apps) has created a new wealth of clinical resources available to healthcare staff, providing evidence-based decisional tools to reduce medical errors.Previous literature has examined how smartphones can be utilised by both medical student and doctor populations, to enhance educational and workplace activities, with the potential to improve overall patient care. However, this literature has not examined smartphone acceptance and patterns of medical app usage within the student and junior doctor populations. METHODS: An online survey of medical student and foundation level junior doctor cohorts was undertaken within one United Kingdom healthcare region. Participants were asked whether they owned a Smartphone and if they used apps on their Smartphones to support their education and practice activities. Frequency of use and type of app used was also investigated. Open response questions explored participants' views on apps that were desired or recommended and the characteristics of apps that were useful. RESULTS: 257 medical students and 131 junior doctors responded, equating to a response rate of 15.0% and 21.8% respectively. 79.0% (n=203/257) of medical students and 74.8% (n=98/131) of junior doctors owned a smartphone, with 56.6% (n=115/203) of students and 68.4% (n=67/98) of doctors owning an iPhone.The majority of students and doctors owned 1-5 medical related applications, with very few owning more than 10, and iPhone owners significantly more likely to own apps (Chi sq, p<0.001). Both populations showed similar trends of app usage of several times a day. Over 24 hours apps were used for between 1-30 minutes for students and 1-20 minutes for doctors, students used disease diagnosis/management and drug reference apps, with doctors favouring clinical score/calculator apps. CONCLUSIONS: This study found a high level of smartphone ownership and usage among medical students and junior doctors. Both groups endorse the development of more apps to support their education and clinical practice. PMID- 23110713 TI - Perinatal role of hepcidin and iron homeostasis in full-term intrauterine growth restricted infants. AB - OBJECTIVES: To prospectively investigate iron homeostasis in full-term intrauterine growth-restricted (IUGR) and appropriate-for-gestational-age (AGA) infants at birth, by evaluating cord blood concentrations of hepcidin (a bioactive molecule, principal regulator of iron metabolism, downregulated by hypoxia/iron deficiency and upregulated by inflammation), erythropoietin (EPO, a marker of prolonged fetal hypoxia), soluble transferrin receptor (sTfR, a marker of increased erythropoiesis and tissue iron deficiency), iron, ferritin, and unsaturated iron-binding capacity (UIBC). METHODS: Serum cord blood samples from 47 well-defined IUGR and 104 AGA singleton, full-term infants were analyzed for concentrations of all the aforementioned parameters by enzyme immunoassays and spectrophotometry. RESULTS: Hepcidin concentrations were similar, while EPO concentrations were higher in IUGR cases than in AGA controls (P = 0.047). Cord blood sTfR concentrations were increased in IUGR, compared to AGA infants (P = 0.004), and negatively correlated with their customized centiles and birth weight (r = -0.238, P = 0.003 and r = -0.157, P = 0.050, respectively). Ferritin concentrations were lower in IUGR cases than in AGA controls (P = 0.039). In both groups, no correlations were observed between cord blood hepcidin concentrations and iron status indices. CONCLUSIONS: Cord blood hepcidin concentrations in term IUGRs may remain unaffected, possibly due to a balance between hepcidin downregulation by chronic fetal hypoxia (indicated by higher EPO concentrations) and impaired iron metabolism (indicated by lower ferritin and higher sTfR concentrations) on the one hand, and hepcidin upregulation by the inflammatory state characterizing IUGRs, on the other. Furthermore, our findings may possibly indicate the need for regular follow-up for detection of iron-deficient anemia, not only in preterm but also in full-term IUGR neonates. PMID- 23110714 TI - Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England. AB - BACKGROUND: Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources. METHODS: Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman's general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record. RESULTS: Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete. CONCLUSION: Hospital admission data in England provide diagnostic information for vascular disease of sufficient reliability for epidemiological analyses. PMID- 23110716 TI - Occurrence, costs and heritability of delayed selfing in a free-living flatworm. AB - Evolutionary theory predicts that in the absence of outcrossing opportunities, simultaneously hermaphroditic organisms should eventually switch to self fertilization as a form of reproductive assurance. Here, we report the existence of facultative self-fertilization in the free-living flatworm Macrostomum hystrix, a species in which outcrossing occurs via hypodermic insemination of sperm into the parenchyma of the mating partner. First, we show that isolated individuals significantly delay the onset of reproduction compared with individuals with outcrossing opportunities ('delayed selfing') as predicted by theory. Second, consistent with the idea of M. hystrix being a preferential outcrosser under natural conditions, we report likely costs of selfing manifested via reduced hatchling production and offspring survival. Third, we demonstrate that selfing propensity has a genetic basis in this species, with a heritability estimated at 0.43 +/- 0.11. Variation in selfing propensity could arise due to differing costs of inbreeding among families; despite marked inter-family variation in apparent costs of inbreeding, we found no evidence for such a link. Alternatively, selfing propensity might differ across families because of heritable variation in reproductive traits that determine the likelihood of selfing. We speculate that adaptations to hypodermic insemination under outcrossing, most notably a highly modified copulatory stylet (male copulatory organ) and reduced sperm complexity, could also facilitate facultative selfing in this species. PMID- 23110715 TI - Mechanistic diversity in the RuBisCO superfamily: RuBisCO from Rhodospirillum rubrum is not promiscuous for reactions catalyzed by RuBisCO-like proteins. AB - d-Ribulose 1,5-bisphosphate carboxylase/oxygenases (RuBisCOs) are promiscuous, catalyzing not only carboxylation and oxygenation of d-ribulose 1,5-bisphosphate but also other promiscuous, presumably nonphysiological, reactions initiated by abstraction of the 3-proton of d-ribulose 1,5-bisphosphate. Also, RuBisCO has homologues that do not catalyze carboxylation; these are designated RuBisCO-like proteins or RLPs. Members of the two families of RLPs catalyze reactions in the recycling of 5'-methylthioadenosine (MTA) generated by polyamine synthesis: (1) the 2,3-diketo-5-methylthiopentane 1-phosphate (DK-MTP 1-P) "enolase" reaction in the well-known "methionine salvage" pathway in Bacillus sp. and (2) the 5 methylthio-d-ribulose 1-phosphate (MTRu 1-P) 1,3-isomerase reaction in the recently discovered "MTA-isoprenoid shunt" that generates 1-deoxy-d-xylulose 5 phosphate for nonmevalonate isoprene synthesis in Rhodospirillum rubrum. We first studied the structure and reactivity of DK-MTP 1-P that was reported to decompose rapidly [Ashida, H., Saito, Y., Kojima, C., and Yokota, A. (2008) Biosci., Biotechnol., Biochem. 72, 959-967]. The 2-carbonyl group of DK-MTP 1-P is rapidly hydrated and can undergo enolization both nonenzymatically and enzymatically via the small amount of unhydrated material that is present. We then examined the ability of RuBisCO from R. rubrum to catalyze both of the RLP-catalyzed reactions. Contrary to a previous report [Ashida, H., Saito, Y., Kojima, C., Kobayashi, K., Ogasawara, N., and Yokota, A. (2003) Science 302, 286-290], we were unable to confirm that this RuBisCO catalyzes the DK-MTP 1-P "enolase" reaction either in vitro or in vivo. We also determined that this RuBisCO does not catalyze the MTRu 1-P 1,3-isomerase reaction in vitro. Thus, although RuBisCOs can be functionally promiscuous, RuBisCO from R. rubrum is not promiscuous for either of the known RLP-catalyzed reactions. PMID- 23110717 TI - Spectroscopic characterization of the active Fe(III)Fe(III) and Fe(III)Fe(II) forms of a purple acid phosphatase model system. AB - Two new dinucleating ligands (H3L(2) and HL(3)), derivatives of a well-known dinucleating ligand (HL(1)) with two bis-picolylamine sites connected to a bridging phenolate, with hydrogen-bonding donor groups at two of the pyridine moieties were designed and synthesized. Design of these ligands suggests that they will lead to dinuclear complexes with potential to stabilize phosphoester substrates as monodentate rather than bridging ligands. We report the diferric complexes [Fe(III)2(H2L(2))(OH)](4+) and [Fe(III)2(L(3))(OH)(OH2)2](4+), which have been characterized by spectrophotometric titrations, UV-vis, IR, NMR, EPR, and Mossbauer spectroscopy. The phosphatase activity of the diferric systems, in addition to the partially reduced heterovalent [Fe(III)Fe(II)(L(3))(OH)(OH2)2](3+) complex, has been investigated, and the complexes are shown to catalytically hydrolyze the activated phosphodiester substrate BDNPP (bis-dinitrophenylphosphate) as well as the corresponding phosphomonoester substrate DNPP (dinitrophenylphosphate). The results indicate that indeed the secondary interactions lead to an increase of the phosphatase activity and to active phosphomonoesterase catalysts. Interestingly, the heterovalent form of the HL(3)-based complex is more efficient than the diferric complex, and this is also discussed. PMID- 23110718 TI - What's in a loop? AB - DNAs and proteins are major classes of biomolecules that differ in many aspects. However, a considerable number of their members also share a common architectural feature that enables the assembly of multi-protein complexes and thereby permits the effective processing of signals: loop structures of substantial sizes. Here we briefly review a few representative examples and suggest a functional classification of different types of loop structures. In proteins, these loops occur in protein regions classified as intrinsically disordered. Studying such loops, their binders and their interactions with other loops should reveal much about cellular information computation and signaling network architectures. It is also expected to provide critical information for synthetic biologists and bioengineers. PMID- 23110719 TI - Clinical effectiveness of topical negative pressure for dermal substitutes in burns. PMID- 23110720 TI - Fast and accurate haplotype frequency estimation for large haplotype vectors from pooled DNA data. AB - BACKGROUND: Typically, the first phase of a genome wide association study (GWAS) includes genotyping across hundreds of individuals and validation of the most significant SNPs. Allelotyping of pooled genomic DNA is a common approach to reduce the overall cost of the study. Knowledge of haplotype structure can provide additional information to single locus analyses. Several methods have been proposed for estimating haplotype frequencies in a population from pooled DNA data. RESULTS: We introduce a technique for haplotype frequency estimation in a population from pooled DNA samples focusing on datasets containing a small number of individuals per pool (2 or 3 individuals) and a large number of markers. We compare our method with the publicly available state-of-the-art algorithms HIPPO and HAPLOPOOL on datasets of varying number of pools and marker sizes. We demonstrate that our algorithm provides improvements in terms of accuracy and computational time over competing methods for large number of markers while demonstrating comparable performance for smaller marker sizes. Our method is implemented in the "Tree-Based Deterministic Sampling Pool" (TDSPool) package which is available for download at http://www.ee.columbia.edu/~anastas/tdspool. CONCLUSIONS: Using a tree-based determinstic sampling technique we present an algorithm for haplotype frequency estimation from pooled data. Our method demonstrates superior performance in datasets with large number of markers and could be the method of choice for haplotype frequency estimation in such datasets. PMID- 23110721 TI - Programmable sub-nanometer sculpting of graphene with electron beams. AB - Electron beams in transmission electron microscopes are very attractive to engineer and pattern graphene toward all-carbon device fabrication. The use of condensed beams typically used for sequential raster imaging is particularly exciting since they potentially provide high degrees of precision. However, technical difficulties, such as the formation of electron beam induced deposits on sample surfaces, have hindered the development of this technique. We demonstrate how one can successfully use a condensed electron beam, either with or without C(s) correction, to structure graphene with sub-nanometer precision in a programmable manner. We further demonstrate the potential of the developed technique by combining it with an established route to engineer graphene nanoribbons to single-atom carbon chains. PMID- 23110722 TI - Alexithymia and psychological distress in fibromyalgia: prevalence and relation with quality of life. AB - OBJECTIVES: Fibromyalgia (FM) is a chronic syndrome characterised by widespread musculoskeletal pain associated with other symptoms like fatigue, stiffness, non restorative sleep and psychological distress that strongly affects the quality of life in FM patients. While the psychological distress has been widely explored in FM, only a few studies investigated alexithymia, an emotional dysregulation trait. AIMS: Evaluate the prevalence of alexithymia and psychological distress and their impact on patients quality of life. METHODS: A battery of tests assessing alexithymia, depression, anxiety, emotional distress symptoms and the health related quality of life (HRQoL) was filled out by 55 female FM patients. After having analysed their prevalence, two regression analyses were performed in order to evaluate the role that alexithymia, depression, anxiety, emotional distress and pain characteristics have on quality of life of FM patients. RESULTS: Results showed that a clinically relevant level of psychological distress was present in more than half of our sample, whereas alexithymic traits were present in 20% of the patients. Regression analyses showed that pain intensity, depression and current pain were the variables that best contribute to explain the physical component of the HRQoL while anxiety, depression and pain intensity were the variables that mainly contributed to explain the mental component of quality of life. CONCLUSIONS: These results underline the high prevalence of alexithymia in FM patients and the great impact of psychological symptoms on FM patients HRQoL. Wholistic care of FM patients which addresses both physical and psychological symptoms is needed. PMID- 23110723 TI - Understanding burnout according to individual differences: ongoing explanatory power evaluation of two models for measuring burnout types. AB - BACKGROUND: The classic determination of burnout is by means of the dimensions exhaustion, cynicism and inefficacy. A new definition of the syndrome is based on clinical subtypes, consisting of "frenetic" (involved, ambitious, overloaded), "underchallenged" (indifferent, bored, with lack of personal development) and "worn-out" (neglectful, unacknowledged, with little control). The dimensions of overload, lack of development and neglect form a shortened version of this perspective. The aims of this study were to estimate and to compare the explanatory power of both typological models, short and long, with the standard measurement. METHODS: This was a cross-sectional survey with a randomly sample of university employees (n=409). Multivariate linear regression models were constructed between the "Maslach Burnout Inventory General Survey" (MBI-GS) dimensions, as dependent variables, and the "Burnout Clinical Subtype Questionnaire" (BCSQ-36 and BCSQ-12) dimensions, as independent variables. RESULTS: The BCSQ-36 subscales together explained 53% of 'exhaustion' (p<0.001), 59% of 'cynicism' (p<0.001) and 37% of 'efficacy' (p<0.001), while BCSQ-12 subscales explained 44% of 'exhaustion' (p<0.001), 44% of 'cynicism' (p<0.001), and 30% of 'efficacy' (p<0.001). The difference in the explanatory power of both models was significant for 'exhaustion' (p<0.001), and for 'cynicism' (p<0.001) and 'efficacy (p<0.001). CONCLUSIONS: Both BCSQ-36 and BCSQ-12 demonstrate great explanatory power over the standard MBI-GS, while offering a useful characterization of the syndrome for the evaluation and design of interventions tailored to the characteristics of each individual. The BCSQ-36 may be very useful in mental health services, given that it provides a good deal of information, while the BCSQ-12 could be used as a screening measure in primary care consultations owing to its simplicity and functional nature. PMID- 23110724 TI - Human resources needs for universal access to antiretroviral therapy in South Africa: a time and motion study. AB - BACKGROUND: Although access to life-saving treatment for patients infected with HIV in South Africa has improved substantially since 2004, treating all eligible patients (universal access) remains elusive. As the prices of antiretroviral drugs have dropped over the past years, availability of human resources may now be the most important barrier to achieving universal access to HIV treatment in Africa. We quantify the number of HIV health workers (HHWs) required to be added to the current HIV workforce to achieve universal access to HIV treatment in South Africa, under different eligibility criteria. METHODS: We performed a time and motion study in three HIV clinics in a rural, primary care-based HIV treatment program in KwaZulu-Natal, South Africa, to estimate the average time per patient visit for doctors, nurses, and counselors. We estimated the additional number of HHWs needed to achieve universal access to HIV treatment within one year. RESULTS: For universal access to HIV treatment for all patients with a CD4 cell count of <=350 cells/MUl, an additional 2,200 nurses, 3,800 counselors, and 300 doctors would be required, at additional annual salary cost of 929 million South African rand (ZAR), equivalent to US$ 141 million. For universal treatment ('treatment as prevention'), an additional 6,000 nurses, 11,000 counselors, and 800 doctors would be required, at an additional annual salary cost of ZAR 2.6 billion (US$ 400 million). CONCLUSIONS: Universal access to HIV treatment for patients with a CD4 cell count of <=350 cells/MUl in South Africa may be affordable, but the number of HHWs available for HIV treatment will need to be substantially increased. Treatment as prevention strategies will require considerable additional financial and human resources commitments. PMID- 23110725 TI - Tropheryma whipplei aortic valve endocarditis, cured without surgical treatment. AB - BACKGROUND: Culture-negative endocarditis due to Tropheryma whipplei is a rare disease. Mostly the diagnosis is made by histologic examination of resected heart valve tissue. CASE PRESENTATION: In this case report, we described a patient with a classical Whipple's disease. Transesophageal echocardiography (TEE) showed a vegetation on noncoronary cusp of the aortic valve. Whipple's disease was confirmed by positive Tropheryma whipplei polymerase chain reaction (PCR) in EDTA blood and a duodenal biopsy with positive periodic acid-Schiff stain (PAS) macrophages. CONCLUSION: Due to timely diagnosis, our patient was treated with antibiotics without valve replacement. PMID- 23110727 TI - Thermophilic anaerobic digestion of sewage sludge: focus on the influence of the start-up. A review. AB - The thermophilic anaerobic digestion (TAD) of sewage sludge has often been found to be less stable than mesophilic treatment. In comparison to mesophilic digesters, thermophilic reactors treating sludge are generally characterized by relatively high concentrations of volatile fatty acids (VFA) in the effluent along with poor effluent quality, indicating a lower level of process stability. However, reviewing the literature related to the procedure for obtaining a thermophilic inoculum, it seems that most of the problems associated with the instability and the accumulation of organic intermediates are the result of the manner in which the thermophilic sludge has been obtained. In this paper, the different options available for obtaining an anaerobic digester operating at thermophilic temperature (55 degrees C) have been reviewed. In this light, rapid heating to the target temperature followed by the development of thermophilic microorganisms, which can be determined by VFA dropping to <= 500 mg acetic acid L(-1) before increasing the organic loading rate (OLR), has been determined the most suitable means of establishing TAD. PMID- 23110729 TI - Hemolysis from platelet transfusion: call to action for an underreported reaction. PMID- 23110726 TI - Identification of novel CDK9 and Cyclin T1-associated protein complexes (CCAPs) whose siRNA depletion enhances HIV-1 Tat function. AB - BACKGROUND: HIV-1 Tat activates RNA Polymerase II (RNAP II) elongation of the integrated provirus by recruiting a protein kinase known as P-TEFb to TAR RNA at the 5' end of nascent viral transcripts. The catalytic core of P-TEFb contains CDK9 and Cyclin T1 (CCNT1). A human endogenous complexome has recently been described - the set of multi-protein complexes in HeLa cell nuclei. We mined this complexome data set and identified 12 distinct multi-protein complexes that contain both CDK9 and CCNT1. We have termed these complexes CCAPs for CDK9/CCNT1 associated protein complexes. Nine CCAPs are novel, while three were previously identified as Core P-TEFb, the 7SK snRNP, and the Super-Elongation Complex. We have investigated the role of five newly identified CCAPs in Tat function and viral gene expression. RESULTS: We examined five CCAPs that contain: 1) PPP1R10/TOX3/WDR82; 2) TTF2; 3) TPR; 4) WRNIP1; 5) FBXO11/CUL1/SKP1. SiRNA depletions of protein subunits of the five CCAPs enhanced Tat activation of an integrated HIV-1 LTR-Luciferase reporter in TZM-bl cells. Using plasmid transfection assays in HeLa cells, we also found that siRNA depletions of TTF2, FBXO11, PPP1R10, WDR82, and TOX3 enhanced Tat activation of an HIV-1 LTR luciferase reporter, but the depletions did not enhance expression of an NF kappaB reporter plasmid with the exception of PPP1R10. We found no evidence that depletion of CCAPs perturbed the level of CDK9/CCNT1 in the 7SK snRNP. We also found that the combination of siRNA depletions of both TTF2 and FBXO11 sensitized a latent provirus in Jurkat cells to reactivation by sub-optimal amounts of alphaCD3/CD28 antibodies. CONCLUSIONS: Our results identified five novel CDK9/CCNT1 complexes that are capable of negative regulation of HIV-1 Tat function and viral gene expression. Because siRNA depletions of CCAPs enhance Tat function, it is possible that these complexes reduce the level of CDK9 and CCNT1 available for Tat, similar to the negative regulation of Tat by the 7SK snRNP. Our results highlight the complexity in the biological functions of CDK9 and CCNT1. PMID- 23110730 TI - Immunoglobulin therapy and thrombosis: coincidence or causation? PMID- 23110731 TI - Iron chelation therapy in patients with transfusion-dependent myelodysplastic syndrome. PMID- 23110732 TI - Transfusion Medicine Illustrated. The blood of a poet is irreplaceable. PMID- 23110734 TI - Emanuel Hackel: 1925-2012. PMID- 23110735 TI - Safety of leukoreduced, cytomegalovirus (CMV)-untested components in CMV-negative allogeneic human progenitor cell transplant recipients. PMID- 23110736 TI - Does modern combat still need fresh whole blood transfusions? PMID- 23110737 TI - Comparison of source plasma quality in three different apheresis protocols. PMID- 23110738 TI - Monitoring access to nationally commissioned services in England. AB - BACKGROUND: For over 20 years, the National Health Service in England has run a system of national planning for highly specialised healthcare services. The aim is to ensure that very rare diseases are treated, and very complex procedures performed, in only a few centres, each of which maintains a volume high enough to maintain excellent outcomes. The commissioning strategy for the provision of these national services in England is strongly centralising. Centralising does however create a duty to ensure that patients distant from the treatment centres are not thereby disadvantaged. The commissioning process ensures sufficient capacity to treat the entire national caseload of clinically eligible patients. The aim of this paper is to apply the Systematic Component of Variation (SCV) to study access to services commissioned by the National Specialised Commissioning Team (NSCT) in England. The discussion focuses on the potential explanations for a high level of systematic variation between areas and on the use of the SCV to support the monitoring and development of these nationally commissioned services. METHOD: Data from nationally commissioned services for the year ending 2011 were received from treating hospital. Mid year age and sex appropriate population estimates were then obtained to provide denominator data. Data were analysed at the geographic level of strategic health authority. RESULTS: 30 services met all requirements for analysis. There is no apparent relationship between SCV and number of locations from which the service is provided. On inspection high SCV is more common among recently commissioned services. DISCUSSION: The importance of the SCV lies in its ability to support the development of highly specialised services. Once the random variation has been accounted for, the reasons for a systematic component can be explored. While no absolute cut- off exists, the SCV can be used to gauge and explore services that are potentially not covering the national caseload. The reason for a high SCV may not be immediately apparent; thus the SCV can aid those responsible for commissioning the service to seek potential explanations and identify improvements. CONCLUSION: We have reviewed spatial variation in access to a set of highly specialised services in England. On inspecting our results, we believe that they suggest that equity of access can usually be achieved at about five years after establishing a service, and this is not dependent, within the geography of England, on the number of centres designated. PMID- 23110739 TI - A new, clinically oriented, unifying and simple placental classification system. AB - OBJECTIVE: At present there is no internationally accepted, clinically easy understandable, comprehensive morphological placental classification. This hampers international benchmarking and comparisons, and clinical research. STUDY DESIGN: Internationally published criteria on morphological placental pathology were collected, standardized and focused into a comprehensive diagnosis category system. The idea was to create a clinically relevant placental pathology scheme related to major pathological processes. A system of nine main diagnostic categories (normal placenta included) was constructed. Pathologists and obstetricians discussed the mutual understanding of the wording in the reporting. The previously published diagnostic criteria were merged, structured and standardized. Through an interobserver correlation study on 315 placentas from intrauterine deaths and 31 controls (placentas from live births) the microscopic criteria in this classification system were tested on user-friendliness and reproducibility. RESULTS: The clinical feedback has been very positive, focusing on the understandability and usefulness in patient follow-up. The interobserver agreement in the microscopic correlation study was in general good. The differences in agreement mainly reflected the degree of preciseness of the microscopic criteria, exemplified by excellent correlation in diagnosing acute chorioamnionitis. Maternal and fetal circulatory disorders need grading criteria and studies are needed to get more insight and clinical correlations of villitis and maturation disorders. CONCLUSION: The clinically oriented, unifying and simple placental pathology classification system may work as a platform for standardization and international benchmarking. Further research is needed to define diagnostic criteria in staging and grading of some main diagnostic categories. PMID- 23110740 TI - Contact heat thermal threshold testing in beagle dogs: baseline reproducibility and the effect of acepromazine, levomethadone and fenpipramide. AB - BACKGROUND: In this methodology article a thermal threshold testing device designed to test nociception in cats was assessed in six dogs. The purpose of this study was to investigate baseline reproducibility of thermal thresholds obtained by the contact heat testing device, to assess the influence of acepromazine and levomethadone and fenpipramide in dogs. The relationship between change in nociceptive thermal threshold and the opioid's plasma concentration was determined. Six adult beagle dogs received levomethadone (0.2 mg/kg), acepromazine (0.02 mg/kg) or saline placebo by intramuscular injection (IM) in a randomized cross-over design. Three baseline nociceptive thermal threshold readings were taken at 15 minutes intervals prior to treatment. Further readings were made at 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, 360, 420 and 480 minutes after injection. A sedation score was assigned at every reading. Four saline placebo treatments were performed to assess baseline reproducibility. Levomethadone serum concentrations were measured prior and 0.5, 1, 2, 4, 8, 12 and 24 hours after drug dosing in a separate occasion. RESULTS: Acepromazine did not seem to increase the thermal threshold at any time. After levomethadone there was a significant rise of the thermal threshold between 15 to 120 minutes at serum concentrations between 22.6-46.3 ng/mL. Baseline reproducibility was stable in adult beagle dogs. CONCLUSION: The thermal threshold testing system is a suitable device for nociceptive threshold testing in dogs. PMID- 23110741 TI - Aqueous uranium(VI) complexes with acetic and succinic acid: speciation and structure revisited. AB - We employed density functional theory (DFT) calculations, and ultraviolet-visible (UV-vis), extended X-ray absorption fine-structure (EXAFS), and attenuated total reflection Fourier-transform infrared (IR) spectroscopy analyzed with iterative transformation factor analysis (ITFA) to determine the structures and the pH speciation of aqueous acetate (ac) and succinate (suc) U(VI) complexes. In the acetate system, all spectroscopies confirm the thermodynamically predicted pH speciation by Ahrland (1951), with the hydrated uranyl ion and a 1:1, a 1:2 and a 1:3 U(VI)-ac complex. In the succinate system, we identified a new 1:3 U(VI)-suc complex, in addition to the previously known 1:1 and 1:2 U(VI)-suc complexes, and determined the pH-speciation for all complexes. The IR spectra show absorption bands of the antisymmetric stretching mode of the uranyl mojety (upsilon3(UO2)) at 949, 939, 924 cm(-1) and at 950, 938, 925 cm(-1) for the 1:1, 1:2 and 1:3 U(VI)-ac and U(VI)-suc complexes, respectively. IR absorption bands at 1535 and 1534 cm(-1) and at 1465 and 1462 cm(-1) are assigned to the antisymmetric upsilon3,as(COO) and symmetric upsilon3,s(COO) stretching mode of bidentately coordinated carboxylic groups in the U(VI)-ac and U(VI)-suc complexes. The assignment of the three IR bands (upsilon3(UO2), upsilon3,as(COO), upsilon3,s(COO)) and the stoichiometry of the complexes is supported by DFT calculations. The UV-vis spectra of the equivalent U(VI)-ac and U(VI)-suc complexes are similar suggesting common structural features. Consistent with IR spectroscopy and DFT calculations, EXAFS showed a bidentate coordination of the carboxylic groups to the equatorial plane of the uranyl moiety for all uranyl ligand complexes except for the newly detected 1:3 U(VI)-suc complex, where two carboxylic groups coordinate bidentately and one carboxylic group coordinates monodentately. All 1:1 and 1:2 complexes have a U-Owater distance of ~2.36 A, which is shorter than the U-Owater distance of ~2.40 A of the hydrated uranyl ion. For all complexes the U-Ocarboxyl distance of the bidentately coordinated carboxylic group is ~2.47 A, while the monodentately coordinated carboxylic group of the 1:3 U(VI)-suc complex has a U-Ocarboxyl distance of ~2.36 A, that is, similar to the short U-Owater distance in the 1:1 and 1:2 complexes. PMID- 23110743 TI - Spatially explicit models of divergence and genome hitchhiking. AB - Strong barriers to genetic exchange can exist at divergently selected loci, whereas alleles at neutral loci flow more readily between populations, thus impeding divergence and speciation in the face of gene flow. However, 'divergence hitchhiking' theory posits that divergent selection can generate large regions of differentiation around selected loci. 'Genome hitchhiking' theory suggests that selection can also cause reductions in average genome-wide rates of gene flow, resulting in widespread genomic divergence (rather than divergence only around specific selected loci). Spatial heterogeneity is ubiquitous in nature, yet previous models of genetic barriers to gene flow have explored limited combinations of spatial and selective scenarios. Using simulations of secondary contact of populations, we explore barriers to gene flow in various selective and spatial contexts in continuous, two-dimensional, spatially explicit environments. In general, the effects of hitchhiking are strongest in environments with regular spatial patterning of starkly divergent habitat types. When divergent selection is very strong, the absence of intermediate habitat types increases the effects of hitchhiking. However, when selection is moderate or weak, regular (vs. random) spatial arrangement of habitat types becomes more important than the presence of intermediate habitats per se. We also document counterintuitive processes arising from the stochastic interplay between selection, gene flow and drift. Our results indicate that generalization of results from two-deme models requires caution and increase understanding of the genomic and geographic basis of population divergence. PMID- 23110742 TI - A link between interferon and augmented plasmin generation in exocrine gland damage in Sjogren's syndrome. AB - Sjogren's syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFNgamma and to a lesser extent, IFNalpha, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction. PMID- 23110744 TI - Diversity and composition of dengue virus type 2 in Venezuela. AB - Dengue is a mosquito-borne disease caused by four closely related dengue virus (genus Flavivirus)serotypes (DENV-1-4). The clinical outcomes vary from mild febrile illness to life-threatening haemorrhagic manifestations. DENVs are endemic in the tropics and subtropics globally and currently no specific treatment or vaccines are available. In Venezuela, the American-Asian genotype of DENV-2 is the most prevalent and has been associated with severe disease outcomes.We aimed to follow-up the molecular epidemiology of DENV-2 in Venezuela to investigate if the evolution of the virus has remained the same throughout time or if the same dynamics documented in Brazil (hyperendemic co-circulation) also occurred. The results show that whereas the epidemiology of DENV in several endemic areas is characterized by serotype replacements through time, in Venezuela the American-Asian genotype DENV-2 has evolved into several genetic lineages and has remained in hyperendemic co-circulation with the other serotypes. PMID- 23110745 TI - A comparative assessment of alternatives to the full-leg radiograph for determining knee joint alignment. AB - BACKGROUND: The purpose of this study was to assess the concurrent validity of alternative measures of frontal plane knee alignment, namely the radiographic anatomic axis and two clinical measures in patients complaining of knee malalignment as compared with the mechanical axis on full-length radiograph of lower limbs. METHODS: The knee-alignment angle was measured in 100 knees of 50 subjects with the chief complaint of frontal knee malalignment according to the following methods: lower-limb mechanical axis on radiograph, lower-limb anatomic axis on radiograph, distance between medial femoral condyles or medial malleoli using a calliper and lower-limb alignment using a goniometer. Data were analyzed using Pearson's correlation coefficient and simple linear regression. RESULTS: The anatomic axis best correlated with the mechanical axis (r = 0.93, P<0.001), followed closely by the intercondylar/intermalleolar distance measured by calliper (r = 0.89, P<0.001). Significant correlation was also found between the mechanical-axis angle and the lower limb axis measured by goniometer (r = 0.67, P<0.001). CONCLUSIONS: The anatomic axis on radiograph, the calliper method and to a lesser extent the goniometer measurement appear to be valid alternatives to the mechanical axis on full-leg radiograph for determining frontal plane knee alignment. These alternative measures have the potential to provide useful information regarding knee alignment and may increase the assessment of this parameter by clinicians and researchers. PMID- 23110746 TI - Emergence agitation in children undergoing adenotonsillectomy: a comparison of sevoflurane vs. sevoflurane-remifentanil administration. AB - BACKGROUND: Sevoflurane is widely used in paediatric anaesthesia but frequently causes emergence agitation (EA). This study evaluated whether limiting the sevoflurane concentration by combining remifentanil with sevoflurane reduced the incidence of EA. METHODS: Eighty-four preschool children scheduled for adenotonsillectomy were randomly assigned to either the remifentanil or sevoflurane group. In the remifentanil group, anaesthesia was induced with thiopental, rocuronium, and 1% sevoflurane. It was maintained with 1% sevoflurane, 60% nitrous oxide in oxygen, and a continuous infusion of remifentanil. For the sevoflurane group, anaesthesia was induced with thiopental, rocuronium, and 8% sevoflurane, and was maintained with 2-3% sevoflurane. Both groups received ketorolac 1 mg/kg and dexamethasone 0.15 mg/kg. EA was measured using the paediatric anaesthesia emergence delirium (PAED) scale and a four-point EA scale in the post-anaesthesia care unit. RESULTS: The scores on the PAED scales were significantly lower in the remifentanil group than in the sevoflurane group [median (interquartile range); 6 (4.25-10.25) vs. 11 (7.75-14.0), P = 0.007], and the proportion of patients with PAED scores >= 10 was significantly lower in the remifentanil group than in the sevoflurane group [15 (35.7%) vs. 27 (64.2%), P = 0.009]. The incidence of EA evaluated using the four-point scale was also lower in the remifentanil group [11 (26.1%) vs. 21 (50%), respectively, P = 0.025]. CONCLUSION: The incidence of EA was lower in children undergoing adenotonsillectomy who received a lower concentration of sevoflurane combined with remifentanil than in those given a higher concentration of sevoflurane without remifentanil. PMID- 23110748 TI - Children's eating behavior, feeding practices of parents and weight problems in early childhood: results from the population-based Generation R Study. AB - BACKGROUND: Weight problems that arise in the first years of life tend to persist. Behavioral research in this period can provide information on the modifiable etiology of unhealthy weight. The present study aimed to replicate findings from previous small-scale studies by examining whether different aspects of preschooler's eating behavior and parental feeding practices are associated with body mass index (BMI) and weight status -including underweight, overweight and obesity- in a population sample of preschool children. METHODS: Cross sectional data on the Child Eating Behaviour Questionnaire, Child Feeding Questionnaire and objectively measured BMI was available for 4987 four-year-olds participating in a population-based cohort in the Netherlands. RESULTS: Thirteen percent of the preschoolers had underweight, 8% overweight, and 2% obesity. Higher levels of children's Food Responsiveness, Enjoyment of Food and parental Restriction were associated with a higher mean BMI independent of measured confounders. Emotional Undereating, Satiety Responsiveness and Fussiness of children as well as parents' Pressure to Eat were negatively related with children's BMI. Similar trends were found with BMI categorized into underweight, normal weight, overweight and obesity. Part of the association between children's eating behaviors and BMI was accounted for by parental feeding practices (changes in effect estimates: 20-43%), while children's eating behaviors in turn explained part of the relation between parental feeding and child BMI (changes in effect estimates: 33-47%). CONCLUSIONS: This study provides important information by showing how young children's eating behaviors and parental feeding patterns differ between children with normal weight, underweight and overweight. The high prevalence of under- and overweight among preschoolers suggest prevention interventions targeting unhealthy weights should start early in life. Although longitudinal studies are necessary to ascertain causal directions, efforts to prevent or treat unhealthy child weight might benefit from a focus on changing the behaviors of both children and their parents. PMID- 23110747 TI - Fell-Muir lecture: Connective tissue growth factor (CCN2) -- a pernicious and pleiotropic player in the development of kidney fibrosis. AB - Connective tissue growth factor (CTGF, CCN2) is a member of the CCN family of matricellular proteins. It interacts with many other proteins, including plasma membrane proteins, modulating cell function. It is expressed at low levels in normal adult kidney cells but is increased in kidney diseases, playing important roles in inflammation and in the development of glomerular and interstitial fibrosis in chronic disease. This review reports the evidence for its expression in human and animal models of chronic kidney disease and summarizes data showing that anti-CTGF therapy can successfully attenuate fibrotic changes in several such models, suggesting that therapies targeting CTGF and events downstream of it in renal cells may be useful for the treatment of human kidney fibrosis. Connective tissue growth factor stimulates the development of fibrosis in the kidney in many ways including activating cells to increase extracellular matrix synthesis, inducing cell cycle arrest and hypertrophy, and prolonging survival of activated cells. The relationship between CTGF and the pro-fibrotic factor TGFbeta is examined and mechanisms by which CTGF promotes signalling by the latter are discussed. No specific cellular receptors for CTGF have been discovered but it interacts with and activates several plasma membrane proteins including low-density lipoprotein receptor-related protein (LRP)-1, LRP-6, tropomyosin-related kinase A, integrins and heparan sulphate proteoglycans. Intracellular signalling and downstream events triggered by such interactions are reviewed. Finally, the relationships between CTGF and several anti-fibrotic factors, such as bone morphogenetic factor-4 (BMP4), BMP7, hepatocyte growth factor, CCN3 and Oncostatin M, are discussed. These may determine whether injured tissue heals or progresses to fibrosis. PMID- 23110749 TI - Meeting surgical necessities for sentinel lymph node biopsy in breast cancer: experience with methylene blue in a Colombian hospital. PMID- 23110750 TI - Family meals among New Zealand young people: relationships with eating behaviors and body mass index. AB - OBJECTIVE: To examine the relationship between family meals and nutrition behaviors of adolescents. DESIGN: Secondary analysis of Youth'07, a nationally representative survey. SETTING: Secondary schools in New Zealand. PARTICIPANTS: Randomly selected adolescents (aged 13-17 years, n = 9,107) completed a multimedia and anonymous survey about their health. VARIABLES MEASURED: Body mass index and eating behaviors. ANALYSIS: Multiple logistic regression equations were used to determine the associations between family meals and body size and dietary behaviors, controlling for demographic variables. RESULTS: Nearly 60% of young people shared a meal with their families 5 or more times in the previous week. Frequent family meals were associated with greater consumption of fruits and vegetables (P < .001), and breakfast (P < .001). Adolescents who frequently shared family meals were also more likely to report that what they ate in the past week was healthy than adolescents who did not (P < .001). There was no relationship between frequency of family meals and body mass index (P = .60). CONCLUSIONS AND IMPLICATIONS: Data from the current study suggest that family meals cannot be used as a single strategy for obesity prevention, but they may provide an important opportunity for young people to consume healthy food. PMID- 23110751 TI - A homologous series of first-row transition-metal complexes of 2,2'-bipyridine and their ligand radical derivatives: trends in structure, magnetism, and bonding. AB - The organometallic first-row transition-metal complexes [M(2,2'-bipy)(mes)2] (M = Cr (1), Mn (2), Co (4), Ni (5); 2,2'-bipy = 2,2'-bipyridine; mes = 2,4,6-Me3C6H2) were reacted with potassium and a suitable alkali-metal sequestering agent to yield salts of the anionic species [M(2,2'-bipy)(mes)2](-). The neutral parent compounds and their corresponding anionic congeners were characterized by single crystal X-ray diffraction in [Cr(2,2'-bipy)(mes)2].1.5C6H6, [Mn(2,2' bipy)(mes)2], [Co(2,2'-bipy)(mes)2].THF, [Ni(2,2'-bipy)(mes)2], [K(dibenzo-18 crown-6).THF][Cr(2,2'-bipy)(mes)2].2THF, [K(18-crown-6)][Mn(2,2' bipy)(mes)2].2THF, [K(18-crown-6)][Mn(2,2'-bipy)(mes)2].0.67py.0.67tol, [K(2,2,2 crypt)][Co(2,2'-bipy)(mes)2], and [K(2,2,2-crypt)][Ni(2,2'-bipy)(mes)2]. These species, along with the previously reported neutral and anionic iron complexes [Fe(2,2'-bipy)(mes)2](0/-) (3/3(-)), form a homologous series of compounds which allow for an in-depth study of the interactions between metals and ligands. Single-crystal X-ray diffraction data, DFT calculations, and various spectroscopic and magnetic measurements indicate that the anionic complexes (1(-) 5(-)) can be best formulated as M(II) complexes of the 2,2'-bipyridyl radical anion. These findings complement recent studies which indicate that bond metric data from single-crystal X-ray diffraction may be employed as an important diagnostic tool in determining the oxidation states of bipyridyl ligands in transition-metal complexes. PMID- 23110752 TI - Blood biomarkers role in acute ischemic stroke patients: higher is worse or better? AB - BACKGROUND: Thrombolytic therapy (TT) for acute ischemic stroke (AIS) can provoke bleeding's complication depending on the ischemic lesion (IL) dimension. Inflammation involved in the setting of acute ischaemic stroke, is associated with infarct size. We aimed to study the independent correlation and association between clinical panel of routinely identified biomarkers, including inflammatory parameters, and cerebral IL dimension and site. RESULTS: We evaluated eleven biomarkers in 105 unrelated patients during their hospitalization after acute stroke event. Our data indicate a significant association of: a) confluent IL size with 4th quartile of Erythrocyte Sedimentation Rate (ESR) (OR = 5.250; 95% CI, 1.002 to 27.514) and an independent correlation with sex; b) confluent IL size with 3rd quartile of fibrinogen (OR = 5.5; 95% CI, 1.027 to 29.451); c) confluent IL size with 3rd quartile of platelets (OR= 0.059; 95% CI, 0.003 to 1.175) and independent correlation with sex; d) smaller IL size (OR = 5.25; 95% CI, 1.351 to 20.396) with 3rd quartile of albumin levels and nodular and parenchimal IL size with 2nd (OR = 0.227; 95% CI, 0.053 to 0.981), 3rd (OR = 0.164; 95% CI, 0.038 to 0.711) and 4th (OR = 0.205; 95% CI, 0.048 to 0.870) quartiles albumin levels; e) smaller IL size with 3rd quartile triglycerides (TG) levels (OR = 9; 95% CI, 2.487 to 32.567) and an independent correlation with anterior location. Smaller IL size, anterior AIS turned out to be independently correlated with high serum albumin levels. Finally, high INR and PTT values were associated with worse NIHSS clinical outcomes in contrast to that observed with higher albumin level. CONCLUSIONS: We provide evidence of routine biomarkers levels correlation with acute IL size, independently of age and sex. In addition, we highlight the importance of differentiation of biomarkers normal interval levels for further improvement not only of the clinical decision making but also in post-acute clinical outcome management. PMID- 23110754 TI - Endothelial function and arterial stiffness assessment as early surrogate markers of vascular risk in patients with systemic lupus erythematosus. AB - Patients with systemic lupus erythematosus (SLE) are at risk of premature atherosclerosis. Conventional prediction risk equations do not adequately predict the cardiovascular risk of these patients because of the complex interaction of traditional and SLE specific risk factors and treatment effects, as well as, the dynamic insult to the vasculature. Non-invasive vascular assessment is able to evaluate the vascular damage accumulated over time. The aim of this review is to examine the role of non-invasive assessment of endothelial function and arterial stiffness as surrogate markers for vascular risk in SLE patients. PMID- 23110755 TI - Classification of potassium and chlorine ionic currents in retinal ganglion cell line (RGC-5) by whole-cell patch clamp. AB - Retinal ganglion cell line (RGC-5) has been widely used as a valuable model for studying pathophysiology and physiology of retinal ganglion cells in vitro. However, the electrophysiological characteristics, especially a thorough classification of ionic currents in the cell line, remain to be elucidated in details. In the present study, we determined the resting membrane potential (RMP) in RGC-5 cell line and then identified different types of ionic currents by using the whole-cell patch-clamp technique. The RMP recorded in the cell line was between -30 and -6 mV (-17.6 +/- 2.6 mV, n = 10). We observed the following voltage-gated ion channel currents: (1) inwardly rectifying Cl- current (I Cl,ir), which could be blocked by Zn2+; (2) Ca2+-activated Cl- current (I Cl,Ca), which was sensitive to extracellular Ca2+ and could be inhibited by disodium 4,4' diisothiocyanatostilbene-2,2'-disulfonate; (3) inwardly rectifying K+ currents (I K1), which could be blocked by Ba2+; (4) a small amount of delayed rectifier K+ current (I K). On the other hand, the voltage-gated sodium channels current (I Na) and transient outward potassium channels current (I A) were not observed in this cell line. These results further characterize the ionic currents in the RGC 5 cell line and are beneficial for future studies especially on ion channel (patho)physiology and pharmacology in the RGC-5 cell line. PMID- 23110753 TI - Erythrocyte pyruvate kinase deficiency mutation identified in multiple breeds of domestic cats. AB - BACKGROUND: Erythrocyte pyruvate kinase deficiency (PK deficiency) is an inherited hemolytic anemia that has been documented in the Abyssinian and Somali breeds as well as random bred domestic shorthair cats. The disease results from mutations in PKLR, the gene encoding the regulatory glycolytic enzyme pyruvate kinase (PK). Multiple isozymes are produced by tissue-specific differential processing of PKLR mRNA. Perturbation of PK decreases erythrocyte longevity resulting in anemia. Additional signs include: severe lethargy, weakness, weight loss, jaundice, and abdominal enlargement. In domestic cats, PK deficiency has an autosomal recessive mode of inheritance with high variability in onset and severity of clinical symptoms. RESULTS: Sequence analysis of PKLR revealed an intron 5 single nucleotide polymorphism (SNP) at position 304 concordant with the disease phenotype in Abyssinian and Somali cats. Located 53 nucleotides upstream of the exon 6 splice site, cats with this SNP produce liver and blood processed mRNA with a 13 bp deletion at the 3' end of exon 5. The frame-shift mutation creates a stop codon at amino acid position 248 in exon 6. The frequency of the intronic SNP in 14,179 American and European cats representing 38 breeds, 76 western random bred cats and 111 cats of unknown breed is 6.31% and 9.35% when restricted to the 15 groups carrying the concordant SNP. CONCLUSIONS: PK testing is recommended for Bengals, Egyptian Maus, La Perms, Maine Coon cats, Norwegian Forest cats, Savannahs, Siberians, and Singapuras, in addition to Abyssinians and Somalis as well an any new breeds using the afore mentioned breeds in out crossing or development programs. PMID- 23110756 TI - General practitioners' views on the acceptability and applicability of a web based intervention to reduce antibiotic prescribing for acute cough in multiple European countries: a qualitative study prior to a randomised trial. AB - BACKGROUND: Interventions to promote prudent antibiotic prescribing by general practitioners (GPs) have often only been developed for use in one country. We aimed to develop an intervention which would be appropriate to implement in multiple European countries in order to offer greater benefit to practice whilst using fewer resources. The INTRO (INternet TRaining for antibiOtic use) intervention needed to deliver training to GPs in the use of C-Reactive Protein (CRP) near patient tests to help diagnose acute cough and in communication skills to help explain prescribing decisions to patients. We explored GPs' views on the initial version of INTRO to test acceptability and potentially increase applicability for use in multiple countries before the start of a randomised trial. METHOD: 30 GPs from five countries (Belgium, England, the Netherlands, Poland and Spain), were interviewed using a "think aloud" approach. GPs were asked to work through the intervention and discuss their views on the content and format in relation to following the intervention in their own practice. GPs viewed the same intervention but versions were created in five languages. Data were coded using thematic analysis. RESULTS: GPs in all five countries reported the view that the intervention addressed an important topic, was broadly acceptable and feasible to use, and would be a useful tool to help improve clinical practice. However, GPs in the different countries identified aspects of the intervention that did not reflect their national culture or healthcare system. These included perceived differences in communication style used in the consultation, consultation length and the stage of illness at which patient typically presented. CONCLUSION: An online intervention to support evidence-based use of antibiotics is acceptable and feasible to implement amongst GPs in multiple countries. However, tailoring of the intervention to suit national contexts was necessary by adding local information and placing more emphasis on the fact that GPs could select the communication skills they wished to use in practice. Using think aloud methods to complement the development of interventions is a powerful method to identify regional contextual barriers to intervention implementation. PMID- 23110757 TI - Jointly creating digital abstracts: dealing with synonymy and polysemy. AB - BACKGROUND: Ideally each Life Science article should get a 'structured digital abstract'. This is a structured summary of the paper's findings that is both human-verified and machine-readable. But articles can contain a large variety of information types and contextual details that all need to be reconciled with appropriate names, terms and identifiers, which poses a challenge to any curator. Current approaches mostly use tagging or limited entry-forms for semantic encoding. FINDINGS: We implemented a 'controlled language' as a more expressive representation method. We studied how usable this format was for wet-lab biologists that volunteered as curators. We assessed some issues that arise with the usability of ontologies and other controlled vocabularies, for the encoding of structured information by 'untrained' curators. We take a user-oriented viewpoint, and make recommendations that may prove useful for creating a better curation environment: one that can engage a large community of volunteer curators. CONCLUSIONS: Entering information in a biocuration environment could improve in expressiveness and user-friendliness, if curators would be enabled to use synonymous and polysemous terms literally, whereby each term stays linked to an identifier. PMID- 23110758 TI - Antibody-free detection of phosphoserine/threonine containing peptides by homogeneous time-resolved fluorescence. AB - Protein phosphorylation is a critical signaling mechanism in cellular regulation and stress response, and more than 95% of the phosphorylations are targeted toward Ser or Thr amino-acid residues. The classical techniques for analyzing phospho-amino acid residues use radioisotopes or sequence-specific antibodies. However, both practical and economical limitations have prevented their development, and we here propose an original approach for the detection of phospho-Ser/Thr residues. It requires no antibody and exploits the patented homogeneous time-resolved fluorescence (HTRF) technology, in association with a 3 step chemical transformation of phospho-amino acids into fluorescent derivatives. The process involves: (i) alkaline beta-elimination of the phosphorylated group, (ii) Michael addition of a bifunctional group, and then (iii) introduction of cyanin-5 as fluorescent acceptor for HTRF. The donor fluorescent moiety at the N terminus of the phosphorylated peptide is a streptavidin europium cryptate conjugate. After its development, the detection system has been validated on synthetic peptide substrates of Chk2, a key protein kinase activated in response to DNA damage and involved in cell cycle arrest. The results showed a good correlation with known specificity profiles. Interestingly, the detection system is versatile, easy to implement, and suitable for multiple parallel analyses. PMID- 23110759 TI - International Congress on Transposable Elements (ICTE) 2012 in Saint Malo and the sea of TE stories. AB - An international conference on Transposable Elements (TEs) was held 21-24 April 2012 in Saint Malo, France. Organized by the French Transposition Community (GDR Elements Genetiques Mobiles et Genomes, CNRS) and the French Society of Genetics (SFG), the conference's goal was to bring together researchers from around the world who study transposition in diverse organisms using multiple experimental approaches. The meeting drew more than 217 attendees and most contributed through poster presentations (117), invited talks and short talks selected from poster abstracts (48 in total). The talks were organized into four scientific sessions, focused on: impact of TEs on genomes, control of transposition, evolution of TEs and mechanisms of transposition. Here, we present highlights from the talks given during the platform sessions. The conference was sponsored by Alliance pour les sciences de la vie et de la sante (Aviesan), Centre national de la recherche scientifique (CNRS), Institut national de la sante et de la recherche medicale (INSERM), Institut de recherche pour le developpement (IRD), Institut national de la recherche agronomique (INRA), Universite de Perpignan, Universite de Rennes 1, Region Bretagne and Mobile DNA. CHAIR OF THE ORGANIZATION COMMITTEE: Jean-Marc Deragon ORGANIZERS: Abdelkader Ainouche, Mireille Betermier, Mick Chandler, Richard Cordaux, Gael Cristofari, Jean-Marc Deragon, Pascale Lesage, Didier Mazel, Olivier Panaud, Hadi Quesneville, Chantal Vaury, Cristina Vieira and Clementine Vitte. PMID- 23110760 TI - Inflammation and neurovascular changes in amyotrophic lateral sclerosis. AB - Neuroinflammation in now established as an important factor in the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). At various time points, astrocytes and microglia are markedly activated, either producing neuroprotective or pro-inflammatory molecules, which can decrease or increase the rate of primary motor neuron degeneration respectively. Recent research has shown that this neuroinflammatory component is affected by the peripheral immune system; T lymphocytes in particular are able to cross into the brain and spinal cord parenchyma, where they interact with resident microglia, either inducing them to adopt an M1 (cytotoxic) or M2 (protective) phenotype, depending on the stage of disease. Clearly understanding the changes that occur to allow the interaction between peripheral and central immune responses will be essential in any attempt to manipulate the disease process via neuroinflammatory mechanisms. However, our understanding of the endothelial changes, which facilitate the infiltration of peripheral immune cells into the brain and spinal cord, is still in its infancy. There are suggestions, though, of up-regulation of cellular adhesion molecules, which are able to arrest circulating leukocytes and facilitate diapedesis into the brain parenchyma. In addition, tight junction proteins appear to be down-regulated, leading to an increase in vascular permeability, an effect that is amplified by vascular damage late in the disease process. This review summarises our current knowledge regarding neuroinflammation, peripheral immune involvement, and endothelial changes in ALS. This article is part of a Special Issue entitled 'Neuroinflammation in neurodegeneration and neurodysfunction'. PMID- 23110761 TI - The UPD3 cytokine couples environmental challenge and intestinal stem cell division through modulation of JAK/STAT signaling in the stem cell microenvironment. AB - In Drosophila, the replacement of spent enterocytes (ECs) relies on division of intestinal stem cells (ISCs) and differentiation of their progeny, the enteroblasts (EBs). Recent studies have revealed a role for JAK/STAT signaling in the modulation of the rate of ISC division in response to environmental challenge. Here, we demonstrate the critical role of the UPD3 cytokine in the JAK/STAT-dependent response to enteric infection. We show that upd3 expression is activated in ECs and in EBs that massively differentiate in response to challenge. We show that the UPD3 cytokine, which is secreted basally and accumulates at the basement membrane, is required for stimulation of JAK/STAT signaling in EBs and visceral muscles (VMs). We further show that stimulation of ISC division requires active JAK/STAT signaling in EBs and VMs, but apparently not in ISCs. Our results suggest that EBs and VMs modulate the rate of the EGFR dependent ISC division through upd3-dependent production of the EGF ligands Spitz and Vein, respectively. This study therefore supports the notion that the production of the UPD3 cytokine in stem cell progeny (ECs and EBs) stimulates intestinal stem cell division through modulation of JAK/STAT signaling in the stem cell microenvironment (EBs and VMs). PMID- 23110762 TI - Effects of personality traits on the manifestations of irritable bowel syndrome. AB - OBJECTIVE: Previous studies have reported that patients with irritable bowel syndrome (IBS) show high neuroticism. However, the precise association between the IBS subtypes and the degree of neuroticism in younger populations is largely unknown. We tested our hypothesis that subjects with diarrhea-predominant IBS may have a higher degree of neuroticism than subjects without IBS or those with other subtypes of IBS. We also verified the additional hypothesis that the severity of neuroticism might be correlated with the severity of IBS in younger populations. METHODS: We conducted a cross-sectional survey of 557 university students, ranging in age from 18 to 21 years. Presence/ absence of IBS and determination of the IBS subtype was by the Rome II Modular Questionnaire, while the severity of IBS was determined by the IBS severity index (IBS-SI). The degree of neuroticism was evaluated using the Maudsely Personality Inventory (MPI). The presence/absence of psychological distress was measured with the K6 scale. RESULTS: Neuroticism scores in the subjects with diarrhea-predominant IBS were significantly higher than those in the non-IBS subjects or subjects with constipation-predominant IBS. The neuroticism scores were significantly correlated with the IBS-SI scores in all subjects with IBS. CONCLUSION: These results suggest that neuroticism is involved in the pathophysiology of IBS in young subjects, especially in that of the diarrhea-predominant subtype. PMID- 23110763 TI - Lung squamous cell carcinoma arising in a patient with adult-onset recurrent respiratory papillomatosis. AB - A 75-year-old male was admitted to our hospital in December 2011 with a mass in the right upper pulmonary lobe. He was incidentally diagnosed as having tracheal papillomas 10 years ago. Bronchoscopy revealed multiple polypoid papillomas in the dorsal lesion of the trachea. Polymerase chain reaction amplification detected human papillomavirus type 11 DNA in the papilloma tissues. A computed tomography scan demonstrated the occlusion of the right superior segment bronchus with distal consolidation. Furthermore, F-18 fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography showed intense tracer uptake in the right superior segment of the lung. He underwent a right upper lobectomy. The tumor was seen as a rounded nodule, ~ 2 cm in diameter. Histological examination of the tumor revealed squamous papilloma with papillary and solid architecture surrounded by accumulation of acute inflammatory cells. Furthermore, in a part of the tumor, squamous cell carcinoma was also present. The lymph nodes were free of tumor. After the surgery, he continued to undergo endoscopic microwave resection. Recurrent respiratory papillomatosis is a rare disease that can cause life threatening airway compromise and malignant transformation. The present case indicates that F-18 fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography is indispensable for early detection of lung cancer arising in a patient with recurrent respiratory papillomatosis. PMID- 23110764 TI - Genetic and lifestyle predictors of 15-year longitudinal change in episodic memory. AB - OBJECTIVES: To reveal distinct longitudinal trajectories in episodic memory over 15 years and to identify demographic, lifestyle, health-related, and genetic predictors of stability or decline. DESIGN: Prospective cohort study. SETTING: The Betula Project, Umea, Sweden. PARTICIPANTS: One thousand nine hundred fifty four healthy participants aged 35 to 85 at baseline. MEASUREMENTS: Memory was assessed according to validated episodic memory tasks in participants from a large population-based sample. Data were analyzed using a random-effects pattern mixture model that considered the effect of attrition over two to four longitudinal sessions. Logistic regression was used to determine significant predictors of stability or decline relative to average change in episodic memory. RESULTS: Of 1,558 participants with two or more test sessions, 18% were classified as maintainers and 13% as decliners, and 68% showed age-typical average change. More educated and more physically active participants, women, and those living with someone were more likely to be classified as maintainers, as were carriers of the met allele of the catechol-O-methyltransferase gene. Less educated participants, those not active in the labor force, and men were more likely to be classified as decliners, and the apolipoprotein E ~4 allele was more frequent in decliners. CONCLUSION: Quantitative, attrition-corrected assessment of longitudinal changes in memory can reveal substantial heterogeneity in aging trajectories, and genetic and lifestyle factors predict such heterogeneity. PMID- 23110765 TI - Male mice that lack the G-protein-coupled receptor GPR41 have low energy expenditure and increased body fat content. AB - SCFA are produced in the gut by bacterial fermentation of undigested carbohydrates. Activation of the Galphai-protein-coupled receptor GPR41 by SCFA in beta-cells and sympathetic ganglia inhibits insulin secretion and increases sympathetic outflow, respectively. A possible role in stimulating leptin secretion by adipocytes is disputed. In the present study, we investigated energy balance and glucose homoeostasis in GPR41 knockout mice fed on a standard low-fat or a high-fat diet. When fed on the low-fat diet, body fat mass was raised and glucose tolerance was impaired in male but not female knockout mice compared to wild-type mice. Soleus muscle and heart weights were reduced in the male mice, but total body lean mass was unchanged. When fed on the high-fat diet, body fat mass was raised in male but not female GPR41 knockout mice, but by no more in the males than when they were fed on the low-fat diet. Body lean mass and energy expenditure were reduced in male mice but not in female knockout mice. These results suggest that the absence of GPR41 increases body fat content in male mice. Gut-derived SCFA may raise energy expenditure and help to protect against obesity by activating GPR41. PMID- 23110766 TI - Facilitating the implementation and efficacy of health-promoting schools via an action-research approach in Taiwan. AB - Taiwan launched its evidence-based health-promoting school (HPS) program via an action-research approach in 2010. The program featured a collaborative partnership between schools, local education authorities and university support networks. This study was focused on examining whether an HPS action-research approach was effective in advancing HPS implementation, perceived HPS impact and perceived HPS efficacy in Taiwan. In 2011, questionnaires were sent to 900 sample schools in Taiwan. A total of 621 schools returned the questionnaire, including 488 primary schools and 133 middle schools. The response rate was 69%. This study compared the difference in HPS implementation status, perceived HPS impact and perceived HPS efficacy between those schools that had implemented action-research HPS (138 schools) and those that had not (483 schools). The univariate analysis results indicated that the HPS implementation levels for components that included school health policies, physical environment, social environment, teaching activities and school-community relations were significantly higher in action research schools than in non-action-research schools. Teachers in action-research schools reported significantly higher levels of HPS impact and HPS efficacy than non-action-research schools. The multivariate analysis results indicated that after controlling for school level and HPS funding, the HPS action-research approach was significantly positively related to greater levels of HPS implementation, perceived HPS impact and perceived HPS efficacy. PMID- 23110767 TI - Glucocorticoid treatment of astrocytes results in temporally dynamic transcriptome regulation and astrocyte-enriched mRNA changes in vitro. AB - While general effects of glucocorticoids are well established, the specific cellular mechanisms by which these hormones exert tissue-dependent effects continue to be elaborated. Diseases that demonstrate altered glucocorticoid signaling have been associated with alterations in astrocytes, yet relatively little is known about the effects of glucocorticoids upon this cell type. We have analyzed mRNA expression patterns following glucocorticoid treatment of mouse primary astrocyte cultures. Microarray analysis of cortical astrocyte cultures treated with dexamethasone over an eight-point, 24 h time course identified 854 unique genes with >=twofold change in mRNA expression at one or more time points. Clustering analysis associated subsets of these mRNA expression changes with gene ontology categories known to be impacted by glucocorticoids. Numerous mRNAs regulated by dexamethasone were also regulated by the natural ligand corticosterone; all of the mRNAs regulated >=twofold by corticosterone were substantially attenuated by cotreatment with the glucocorticoid receptor antagonist RU486. Of the mRNAs demonstrating >=twofold expression change in response to both glucocorticoids, 33 mRNAs were previously associated with glucocorticoid regulation, and 36 mRNAs were novel glucocorticoid targets. All genes tested by qPCR for glucocorticoid regulation in cortical astrocyte cultures were also regulated by glucocorticoids in hippocampal astrocyte cultures (18/18). Interestingly, a portion of glucocorticoid-regulated genes were astrocyte enriched; the percentage of astrocyte-enriched genes per total number of regulated genes was highest for the early time points and steadily decreased over the time course. These findings suggest that astrocytes in vitro may initially deploy cell type-specific patterns of mRNA regulatory responses to glucocorticoids and subsequently activate additional cell type-independent responses. PMID- 23110769 TI - Optical measurement of creatinine in spent dialysate. AB - AIM: The aim of the study was to develop an optical method for the estimation of creatinine (Cr) removal during dialysis using UV-absorbance. MATERIAL AND METHODS: 29 hemodialysis patients on chronic 3-times-a-week hemodialysis were studied in 6 separate studies. Double-beam pectrophotometer was used for the determination of UV-absorbance in the collected spent dialysate samples. A single wavelength (SW) and a multi-wavelength (MW) model were developed using stepwise regression utilizing Cr values from the laboratory as the dependent parameter. The reduction ratio (RR) and total removed Cr (TRCr) were estimated. RESULTS: For blood-Cr RRb (mean +/- SD) was 60.9 +/- 5.0% (calibration set) and 58.1 +/- 6.0% (validation set), for SW UVabsorbance RR_SW was 61.5 +/- 5.9% and 57.3 +/- 6.0%, and for MW UV-absorbance RR_MW was 65.8 +/- 5.8% and 61.7 +/- 6.4% respectively. RR_SW and RRb were not statistically different. RR_MW was higher compared to RRb (p < 0.05). TRCr_lab was 13.8 +/- 3.8 mmol, TRCr_SW 14.5 +/- 2.5 mmol and TRCr_MW 13.8 +/- 2.6 mmol, being not statistically different. CONCLUSION: In summary, creatinine removal during dialysis can be estimated as reduction ratio and total removed creatinine with the UV-absorbance technique. PMID- 23110770 TI - Implication of combined urinary biomarkers in early diagnosis of acute kidney injury following percutaneous coronary intervention. AB - BACKGROUND: Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin 18 (IL-18) are three of the most promising biomarkers for the early detection of acute kidney injury. In the present study, to determine whether a combination of the three biomarkers enhances their predictive value, representing an ideal indicator for the early detection of Acute Kidney Injury (AKI) we examined 118 adults undergoing elective percutaneous coronary intervention (PCI). METHODS: We performed a single center, nested case control study. Urinary KIM-1, NGAL and IL-18 were measured by enzyme-linked immunosorbent assay before and 6 h, 24 h, 48 h postcontrast. Serum creatinine was measured before and 24 h, 48 h postcontrast. RESULTS: 12 patients (10.1%) were identified with AKI. 30 patients were selected as controls, matched with cases at an attempted 2.5 : 1 ratio. Compared to the non-AKI group, urinary NGAL were significantly higher at all the time-points. Urinary KIM-1 and IL-18 levels were significantly higher at 24 h and 48 h postcontrast. In the AKI group, Urinary NGAL peaked at 6 h postcontrast, and then decreased. Both KIM-1 and IL-18 peaked at 24 hours postcontrast, remained markedly elevated up to 48 h. By applying area under the receiver operator characteristic curve, the combination of KIM-1, NGAL and IL-18 had the most powerful diagnostic power (AUC = 0.99, (95%CI: 0.90 - 1.00), p = 0.0001) for diagnosis of AKI at 24 h postcontrast, superior to that for single detection and serum creatinine. CONCLUSIONS: KIM-1, NGAL and IL-18 were increased in tandem after PCI. The combination of urinary biomarkers may allow for early detection of AKI following PCI, better than serum creatinine, and the individual biomarkers. PMID- 23110768 TI - Future detection and monitoring of diabetes may entail analysis of both beta-cell function and volume: how markers of beta-cell loss may assist. AB - Disease heterogeneity is as major issue in Type II Diabetes Mellitus (T2DM), and this patient inter-variability might not be sufficiently reflected by measurements of glycated haemoglobin (HbA1c).Beta-cell dysfunction and beta-cell death are initiating factors in development of T2DM. In fact, beta-cells are known vanish prior to the development of T2DM, and autopsy of overt T2DM patients have shown a 60% reduction in beta-cell mass.As the decline in beta-cell function and mass have been proven to be pathological traits in T2DM, methods for evaluating beta-cell loss is becoming of more interest. However, evaluation of beta-cell death or loss is currently invasive and unattainable for the vast majority of diabetes patients. Serological markers, reflecting beta-cell loss would be advantageous to detect and monitor progression of T2DM. Biomarkers with such capacities could be neo-epitopes of proteins with high beta-cell specificity containing post translational modifications. Such tools may segregate T2DM patients into more appropriate treatment groups, based on their beta-cell status, which is currently not possible. Presently individuals presenting with adequately elevated levels of both insulin and glucose are classified as T2DM patients, while an important subdivision of those is pending, namely those patients with sufficient beta-cell capacity and those without. This may warrant two very different treatment options and patient care paths.Serological biomarkers reflecting beta-cell health status may also assist development of new drugs for T2DM and aid physicians in better characterization of individual patients and tailor individual treatments and patient care protocols. PMID- 23110771 TI - Analysis of 24-hour ambulatory blood pressure monitoring in patients with diabetic nephropathy: a hospital-based study. AB - BACKGROUND AND AIMS: The present study was designed to characterize and compare the ambulatory blood pressure changes of patients with Type 2 diabetic nephropathy (DN) and non-diabetic chronic kidney disease (CKD), and to investigate the features of ambulatory blood pressure in patients with Type 2 diabetic nephropathy (DN) in comparison with those of non-diabetic chronic kidney disease (CKD) in our medical center. MATERIALS AND METHODS: 62 patients with Type 2 diabetic nephropathy (DN) in compliance with the diagnosis criteria of CKD were enrolled in the study, without renal replacement therapy. Their 24-h ambulatory blood pressure monitoring (ABPM) results were observed and compared with the ambulatory blood pressure results of 152 non-diabetic CKD patients with matching age, sex, renal function and other aspects. RESULTS: Analysis of ABPM data from 62 patients with Type 2 DN and 152 patients with nondiabetic CKD indicated: 1. The average 24-h systolic blood pressure (SBP), daytime and nighttime systolic blood pressure (SBP) in the patients with DN were all significantly higher than those of patients with non-DN. 2. Blood pressure variability did not differ considerably between the two groups; nighttime blood pressure decline was small in both groups, but not significantly different. 3. The systolic blood pressure loads in the patients with DN were all significantly higher than those of patients with non-DN. 4. The prevalence of abnormal Circadian BP rhythm was 90.3% in patients with DN, which did not differ considerably from the patients with non DN represented by 81.6%. 5. The nighttime SBP was correlated with 24-h urinary protein in patients with both non-DN and DN. CONCLUSIONS: Systolic blood pressure control of patients with intermediate or advanced diabetic nephropathy was worse than that of patients with non-diabetic CKD, and non-dipping rhythm was quite common. The nighttime SBP correlated with 24-h urinary protein excretion. PMID- 23110772 TI - Rechallenge with intravenous recombinant human erythropoietin can be successful following the treatment of anti-recombinant erythropoietin associated pure red cell aplasia. AB - Anti recombinant human erythropoietin (r-HuEpo) associated pure red cell aplasia (PRCA) is an immunologic adverse effect of using subcutaneous r-HuEpo. Immunosuppressive agents have been suggested as treatment of this serious complication. After the reversal of anti-r-HuEpo antibody, the patients continue to have renal anemia and require long-term blood transfusion, albeit less frequently than when the antibody is positive. It is controversial whether re challenging the patients with r-HuEpo is appropriate because re-challenging may cause the reappearance of the antibody. To balance the risk of antir-HuEpo antibody reappearance and longterm blood transfusion complications, we re challenged r-HuEpo in five anti-r-HuEpo associated PRCA cases after a successful reversal of antibody using prednisolone in combination with cyclophosphamide. The rechallenge was performed intravenously since there were no reports of anti-r HuEpo associated PRCA cases using this administration route. The duration after the reversal of antibody was 2.4 months before the re-challenge. Two patients were immediately re-challenged as soon as the antibodies reversed. After rechallenge with intravenous r-HuEpo, all patients responded to r-HuEpo: target level of Hb was maintained, blood transfusion was not required, and anti-r-HuEpo was consistently negative. All patients were followed for at least 6 months after re-challenge. Our data suggest that re-challenge with intravenous r-HuEpo can successfully treat anti- r-HuEpo associated PRCA. PMID- 23110773 TI - Spontaneous bilateral perirenal hemorrhage following prolonged fever: an uncommon presentation of polyarteritis nodosa. AB - A 68-year-old man presented with a spontaneous bilateral perirenal hemorrhage following a 2-month fever of unknown origin. A renal biopsy for a pathologic diagnosis seemed very risky because of the patient's bilateral perirenal hemorrhage. Therefore, we diagnosed polyarteritis nodosa using an abdominal computed tomography scan, a renal angiogram, and American College of Rheumatology criteria. The patient's multiple symptoms then responded well to the prescribed immunosuppressive regimen. This case is an uncommon presentation of polyarteritis nodosa with fever of unknown origin before a spontaneous bilateral perirenal hemorrhage. PMID- 23110774 TI - Factors related to the glomerular size in renal biopsies of chronic kidney disease patients. AB - BACKGROUND: Glomerular enlargement is an important process that preserves the optimal surface area of glomerular capillaries under both physiological and pathological conditions. However, information is limited regarding how the glomerular size is defined, especially in chronic kidney disease (CKD) patients. METHODS: A total of 206 renal biopsy specimens obtained from two different patient cohorts with or without a diagnosis of glomerulonephritis (non-GN group and IgAN group) were examined. The mean glomerular volume was estimated from the outer capillary area of individual glomeruli, and the clinicopathological factors at biopsy that were associated with the mean glomerular volume were analyzed in each group. RESULTS: The mean glomerular volume showed maximal 5.8 and 7.9-fold variations between individuals in the non-GN and IgAN groups, respectively. In both groups, the body mass index and glomerular density (non-sclerotic glomerular number per renal cortical area of the biopsy) were consistently identified as independent factors that were associated with the mean glomerular volume. In addition, the multivariate analyses using the glomerular density/body mass index ratio showed a more close association with the mean glomerular volume than the analyses using each measure separately. CONCLUSION: These results suggest that factors presumably reflecting both body consumption and nephron number have close relationships with the glomerular size, regardless of mechanism(s) underlying the injury. The most relevant factor affecting glomerular size may be a balance between these two measures. PMID- 23110775 TI - Severe manifestation of Bartter syndrome Type IV caused by a novel insertion mutation in the BSND gene. AB - Bartter syndrome Type IV is a rare subtype of the Bartter syndromes that leads to both severe renal salt wasting and sensorineural deafness. This autosomal recessive disease is caused by mutations in the gene encoding barttin, BSND, an essential subunit of the ClC-K chloride channels expressed in renal and inner ear epithelia. Patients differ in the severity of renal symptoms, which appears to depend on the modification of channel function by the mutant barttin. To date, only a few BSND mutations have been reported, most of which are missense or nonsense mutations. In this study, we report the identification of the first insertion mutation, p.W102Vfs*7, in the BSND gene of a newborn girl with acute clinical symptoms including early-onset chronic renal failure. The results support previous data indicating that mutations that are predicted to abolish barttin expression are associated with a severe phenotype and early onset renal failure. PMID- 23110776 TI - Parasol cell mosaics are unlikely to drive the formation of structured orientation maps in primary visual cortex. AB - The receptive fields of on- and off-center parasol cell mosaics independently tile the retina to ensure efficient sampling of visual space. A recent theoretical model represented the on- and off-center mosaics by noisy hexagonal lattices of slightly different density. When the two lattices are overlaid, long range Moire interference patterns are generated. These Moire interference patterns have been suggested to drive the formation of highly structured orientation maps in visual cortex. Here, we show that noisy hexagonal lattices do not capture the spatial statistics of parasol cell mosaics. An alternative model based upon local exclusion zones, termed as the pairwise interaction point process (PIPP) model, generates patterns that are statistically indistinguishable from parasol cell mosaics. A key difference between the PIPP model and the hexagonal lattice model is that the PIPP model does not generate Moire interference patterns, and hence stimulated orientation maps do not show any hexagonal structure. Finally, we estimate the spatial extent of spatial correlations in parasol cell mosaics to be only 200-350 MUm, far less than that required to generate Moire interference. We conclude that parasol cell mosaics are too disordered to drive the formation of highly structured orientation maps in visual cortex. PMID- 23110777 TI - Adams-Stokes attack as the first symptom of acute rheumatic fever: report of an adolescent case and review of the literature. AB - BACKGROUND: Acquired complete heart block, in pediatric age is mainly the results of direct injury to conduction tissue during cardiac surgery or cardiac catheterisation. It can also be observed in different clinical settings as infectious diseases, neoplasia, and inflammatory diseases. It has a wide range of presentation and in some settings it can appear a dramatic event. Although a rare finding during acute rheumatic fever, with a transient course, it may need a specific and intensive treatment. CASE PRESENTATION: We report the case of an Adams-Stokes attack in an adolescent with acute rheumatic carditis and complete atrio-ventricular block. The attack was the first symptom of carditis.We reviewed the literature and could find 25 cases of complete atrio-ventricular block due to rheumatic fever. Ten of the 25 patients experienced an Adams-Stokes attack. Nineteen of the 25 patients were certainly in the pediatric age group. Seven of the 19 pediatric cases experienced an Adams-Stokes attack. In 16/25 cases, the duration of the atrio-ventricular block was reported: it lasted from a few minutes to ten days. Pacemaker implantation was necessary in 7 cases. CONCLUSION: Rheumatic fever must be kept in mind in the diagnostic work-up of patients with acquired complete atrio-ventricular block, particularly when it occurs in pediatric patients. The insertion of a temporary pacemaker should be considered when complete atrio-ventricular block determines Adams-Stokes attacks. Complete heart block during acute rheumatic fever is rare and is usually transient. Along with endocarditis, myocarditis and pericarditis, complete atrio-ventricular block has been recognized, rarely, during the course of acute rheumatic carditis. PMID- 23110779 TI - Electronic structure investigation of MoS2 and MoSe2 using angle-resolved photoemission spectroscopy and ab initio band structure studies. AB - Angle-resolved photoemission spectroscopy (ARPES) and ab initio band structure calculations have been used to study the detailed valence band structure of molybdenite, MoS(2) and MoSe(2). The experimental band structure obtained from ARPES has been found to be in good agreement with the theoretical calculations performed using the linear augmented plane wave (LAPW) method. In going from MoS(2) to MoSe(2), the dispersion of the valence bands decreases along both k(parallel) and k(perpendicular), revealing the increased two-dimensional character which is attributed to the increasing interlayer distance or c/a ratio in these compounds. The width of the valence band and the band gap are also found to decrease, whereas the valence band maxima shift towards the higher binding energy from MoS(2) to MoSe(2). PMID- 23110778 TI - Abnormal expression of GADD45B in human colorectal carcinoma. AB - BACKGROUND: GADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date. METHODS: The mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes. RESULTS: The mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (P<0.05). Up regulation of GADD45B was also correlated with relapse and death of CRC patients (P<0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients who showed GADD45B overexpression. A Cox multivariate analysis revealed that GADD45B overexpression and TNM stage were significant factors affecting patients' survival. On the other hand, as a tumor suppressor gene, GADD45B amplified from normal colorectal tissues could induce apoptosis in CRC cell lines and may be associated with the p53-mediated apoptotic pathways. CONCLUSION: GADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future. PMID- 23110780 TI - Primary hyperaldosteronism: challenges in subtype classification. AB - BACKGROUND: Primary hyperaldosteronism (PA) is a serious and potentially debilitating disease. Detailed guidelines have been written to guide endocrinologists in establishing the diagnosis of PA as well as in subtype classification of PA. The objective of this case report is to present a case where subtype classification of PA was challenging and repeated imaging of the adrenal glands helped establish the diagnosis in a patient with initial normal adrenal glands on CT and MRI images. CASE PRESENTATION: We report a case of a 29 year-old woman with an established diagnosis of PA, but unclear subtype, who presented to us for further management. She initially presented for medical evaluation of uncontrolled hypertension and spontaneous hypokalemia 4 years prior. In the investigation of secondary causes of hypertension, plasma aldosterone-to-plasma renin activity ratio was elevated on two separate occasions, and primary hyperaldosteronism was confirmed by saline infusion test. Also during this time, she had adrenal venous sampling done 3 times at multiple institutions yielding confusing results. Initially, imaging by CT and MRI showed normal adrenal glands. To help establish the subtype of PA, we reimaged this patient's adrenal glands one year later revealing a 2 cm left adrenal adenoma. Laparoscopic left adrenalectomy improved her hypertension and was curative of her hypokalemia. CONCLUSION: This case presents an unusual case where reimaging of the adrenal glands led to the discovery of a single adenoma, initially not observed on imaging studies. PMID- 23110781 TI - Analysis of the swine tracheobronchial lymph node transcriptomic response to infection with a Chinese highly pathogenic strain of porcine reproductive and respiratory syndrome virus. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is a major pathogen of swine worldwide. Emergence in 2006 of a novel highly pathogenic PRRSV (HP-PRRSV) isolate in China necessitated a comparative investigation into the host transcriptome response in tracheobronchial lymph nodes (TBLN) 13 days post-infection with HP-PRRSV rJXwn06, PRRSV strain VR-2332 or sham inocula. RNA from each was prepared for next-generation sequencing. Amplified library constructs were directly sequenced and a list of sequence transcripts and counts was generated using an RNAseq analysis pipeline to determine differential gene expression. Transcripts were annotated and relative abundance was calculated based upon the number of times a given transcript was represented in the library. RESULTS: Major changes in transcript abundance occurred in response to infection with either PRRSV strain, each with over 630 differentially expressed transcripts. The largest increase in transcript level for either virus versus sham-inoculated controls were three serum amyloid A2 acute-phase isoforms. However, the degree of up or down-regulation of transcripts following infection with HP-PRRSV rJXwn06 was greater than transcript changes observed with US PRRSV VR-2332. Also, of 632 significantly altered transcripts within the HP-PRRSV rJXwn06 library 55 were up-regulated and 69 were down-regulated more than 3-fold, whilst in the US PRRSV VR-2332 library only 4 transcripts were up-regulated and 116 were down-regulated more than 3-fold. CONCLUSIONS: The magnitude of differentially expressed gene profiles detected in HP-PRRSV rJXwn06 infected pigs as compared to VR-2332 infected pigs was consistent with the increased pathogenicity of the HP-PRRSV in vivo. PMID- 23110782 TI - Adherence to antiretroviral therapy and treatment outcomes among conflict affected and forcibly displaced populations: a systematic review. AB - BACKGROUND: Optimal adherence to highly active antiretroviral therapy (HAART) is required to promote viral suppression and to prevent disease progression and mortality. Forcibly displaced and conflict-affected populations may face challenges succeeding on HAART. We performed a systematic review of the literature on adherence to HAART and treatment outcomes in these groups, including refugees and internally-displaced persons (IDPs), assessed the quality of the evidence and suggest a future research program. METHODS: Medline, Embase, and Global Health databases for 1995-2011 were searched using the Ovid platform. A backward citation review of subsequent work that had cited the Ovid results was performed using the Web of Science database. ReliefWeb and Medecins Sans Frontieres (MSF) websites were searched for additional grey literature. RESULTS AND CONCLUSION: We screened 297 records and identified 17 reports covering 15 quantitative and two qualitative studies from 13 countries. Three-quarters (11/15) of the quantitative studies were retrospective studies based on chart review; five studies included <100 clients. Adherence or treatment outcomes were reported in resettled refugees, conflict-affected persons, internally-displaced persons (IDPs), and combinations of refugees, IDPs and other foreign-born persons. The reviewed reports showed promise for conflict-affected and forcibly displaced populations; the range of optimal adherence prevalence reported was 87 99.5%. Treatment outcomes, measured using virological, immunological and mortality estimates, were good in relation to non-affected groups. Given the diversity of settings where forcibly-displaced and conflict-affected persons access ART, further studies on adherence and treatment outcomes are needed to support scale-up and provide evidence-based justifications for inclusion of these vulnerable groups in national treatment plans. Future studies and program evaluations should focus on systematic monitoring of adherence and treatment interruptions by using facility-based pharmacy records, understanding threats to optimal adherence and timely linkage to care throughout the displacement cycle, and testing interventions designed to support adherence and treatment outcomes in these settings. PMID- 23110783 TI - Repetition counts: repeated exposure increases intake of a novel vegetable in UK pre-school children compared to flavour-flavour and flavour-nutrient learning. AB - Children are not consuming sufficient amounts of fruits and vegetables in their habitual diet. Methods derived from associative learning theories could be effective at promoting vegetable intake in pre-school children. The objective of the present study was to compare the effectiveness of different learning strategies in promoting the intake of a novel vegetable. Children aged between 9 and 38 months were recruited from UK nurseries. The children (n 72) were randomly assigned to one of three conditions (repeated exposure, flavour-flavour learning or flavour-nutrient learning). Each child was offered ten exposures to their respective version of a novel vegetable (artichoke). Pre- and post-intervention measures of artichoke puree and carrot puree (control vegetable) intake were taken. At pre-intervention, carrot intake was significantly higher than artichoke intake (P<0.05). Intake of both vegetables increased over time (P<0.001); however, when changes in intake were investigated, artichoke intake increased significantly more than carrot intake (P<0.001). Artichoke intake increased to the same extent in all three conditions, and this effect was persistent up to 5 weeks post-intervention. Five exposures were sufficient to increase intake compared to the first exposure (P<0.001). Repeated exposure to three variants of a novel vegetable was sufficient to increase intake of this vegetable, regardless of the addition of a familiar taste or energy. Repetition is therefore a critical factor for promoting novel vegetable intake in pre-school children. PMID- 23110784 TI - Predicting road test performance in adults with cognitive or visual impairment referred to a Veterans Affairs Medical Center driving clinic. AB - OBJECTIVES: To develop a screening battery for office-based clinicians that would assist with the prediction of impaired driving performance and deciding who should proceed to road testing in a sample of adults with cognitive or visual deficits. DESIGN: Prospective observational study. SETTING: Driving evaluation clinic at a Veterans Affairs Medical Center (VAMC) in St. Louis, Missouri. PARTICIPANTS: Seventy-seven individuals aged 23 to 91 with diagnoses of cognitive or visual impairment or both referred to an occupational therapy based driving clinic by VAMC providers because of concerns regarding driving safety. MEASUREMENTS: Predictor variables included tests of visual and cognitive functioning and activities of daily living. The major outcome was pass or fail on a standardized performance-based on-road driving test. RESULTS: Thirty percent of the referrals failed the road test. The best predictors of driving performance were the Trail-Making Test Part A and the Mazes Test from the Neuropsychological Assessment Battery. CONCLUSION: Measures of visual search, psychomotor speed, and executive functioning accurately predicted road test performance in a significant number of participants. These brief tests may assist clinicians in deciding who should proceed with a road test in a driver rehabilitation clinic or perhaps to whom it should be recommended to cease driving. PMID- 23110785 TI - Significant enhancement in the photocatalytic activity of N, W co-doped TiO2 nanomaterials for promising environmental applications. AB - In this work, a mesoporous N, W co-doped TiO(2) photocatalyst was synthesized via a one-step solution combustion method, which utilized urea as the nitrogen source and sodium tungstate as the tungsten source. The photocatalytic activity of the N, W co-doped TiO(2) photocatalyst was significantly enhanced by a facile UV pretreatment approach and was evaluated by measuring the rate of photodegradation of Rhodamine B under both UV and visible (lambda > 420) light. Following the UV pretreatment, the UV photocatalytic activity of the N, W co-doped TiO(2) was doubled. In terms of visible light activity, the UV pretreatment resulted in an extraordinary >12 fold improvement. In order to gain insight into this substantial enhancement, the N, W co-doped TiO(2) photocatalysts were studied using x-ray diffraction, transmission electron microscopy, N(2) physisorption, UV vis absorbance spectroscopy and x-ray photoelectron spectroscopy prior to and following the UV pretreatment. Our experimental results have revealed that this significant augmentation of photocatalytic activity may be attributed to several synergetic factors, including increase of the specific surface area, reduction of the band gap energy and the removal of carbon impurities. PMID- 23110786 TI - The effect of naltrexone on the perception and distress in tinnitus: an open label pilot study. AB - OBJECTIVE: Tinnitus is a perceived sensation of sound without actual acoustic stimulation. Currently there are no standardized drug therapies for the treatment of tinnitus patients. A potential novel treatment for chronic tinnitus is naltrexone. Tinnitus can be considered an auditory phantom phenomenon similar to phantom pain. Naltrexone acts predominantly on MU-opioid receptors which are present in multiple areas of the brain, including the thalamus, dorsal part of the anterior cingulate, insula, amygdala, nucleus accumbens, and ventromedial to orbitofrontal cortex. These areas overlap with the areas involved in tinnitus related distress. The aim of the present study is to investigate three doses of naltrexone, namely 5, 12.5, and 50 mg and determine their influence on tinnitus complaints. We conducted a 4-week single-center, open-label treatment study. SUBJECTS AND METHODS: 86 patients received the drug treatment, while 30 patients received no treatment. RESULTS: Overall tinnitus distress was significantly reduced for the drug treatment group, while for the waiting control group this was not the case. No significant effect could be obtained for tinnitus intensity. A closer look at the data indicates that this effect is mainly generated due to a significant difference in the 50 mg drug treatment group for tinnitus distress. CONCLUSION: our results indicate that naltrexone might have an effect on tinnitus distress and more particularly higher doses of naltrexone. PMID- 23110787 TI - Economic prescribing of corticosteroid nasal sprays in Germany: comparison of mometasone and budesonide nasal sprays on the basis of the DDD, the PDD and reference prices. AB - AIM: According to the German Social Security Code (SGB V), drugs should be prescribed on a cost-effective basis. An attempt is made to achieve this in Germany with the help of the DDD system and reference prices. Taking the example of the most frequently prescribed corticosteroid nasal sprays containing the active substances budesonide (BNS) or mometasone (MNS), we will show here that the DDD system is not necessarily suitable for tapping economic reserves. Despite the pharmacologic differences between the two substances, a uniformly defined daily dose (DDD) is assumed for both. Moreover, since 2006 they have formed a reference-price group of nasally administered medication with other active substances. Products were compared with regard to potential differences in patient populations and resulting treatment costs. The extent to which the two instruments are suitable for tapping economic reserves were estimated. METHODS: We analyzed longitudinal diagnostic and prescription data in the IMS(r) Disease Analyzer Database from the period 2006 to July 2010. RESULTS: In total we analyzed data from 16,163 MNS and 4,218 BNS patients from GP practices plus 11,103 MNS and 2,521 BNS patients from ENT practices. The average quantity prescribed per patient differed in favor of MNS by -111.5 (for first prescriptions) to -260.1 puffs (after 730 days) in GP practices and by -137.3 to 488.3 puffs in ENT practices (p < 0.001). The mean calculated treatment cost per year from the point of view of the statutory health insurer was 20.40 ? (GP practices) and 30.50 ? (ENT practices) for MNS compared to 22.40 ? (GP practices) and 32.10 ? (ENT practices) for BNS. Based on the price level after the 2011 referenceprice adjustment, the treatment costs are 16.40 ? (GP practices) and 24.20 ? (ENT practices) for MNS versus 21.20 ? (GP practices) and 32.30 ? (ENT practices) for BNS. CONCLUSION: The volumes of MNS actually prescribed are significantly lower than those of BNS in the compared patient populations. Based on the actual consumption of the substances, there is no treatment-cost advantage for BNS in comparison to MNS from the statutory health insurer's point of view. By contrast, the reference-price adjustment results in a greater reduction of treatment costs for mometasone, so that in this case the statutory health insurer is able to tap economic reserves. Both the comparative parameters used for calculating the reference price and the DDD system are only conditionally suitable for tapping economic reserves for drugs. PMID- 23110788 TI - Changes in gastric pH and in pharmacokinetics of ulipristal acetate - a drug-drug interaction study using the proton pump inhibitor esomeprazole. AB - OBJECTIVE: Ulipristal acetate is a novel selective progesterone receptor modulator for the treatment of benign gynecological conditions such as uterine myoma. As a Biopharmaceutical Classification System (BCS) II compound, it is highly soluble at low pH but has low solubility at neutral conditions. Esomeprazole, a proton pump inhibitor used widely for treatment of gastric and duodenal ulcers, efficiently increases gastric pH. Thus, the aim of this study was to determine the effects of esomeprazole on the pharmacokinetics of ulipristal acetate. MATERIALS AND METHODS: This was a nonrandomized, single sequence, 2 period, open, study in 18 healthy female subjects. Subjects received oral ulipristal acetate tablets (10 mg) once on Days 1 and 13 and daily esomeprazole administrations (20 mg) from Days 9 through 14. RESULTS: Co administration of esomeprazole decreased geometric mean Cmax of ulipristal acetate by 65% (geometric mean ratio point estimate (90% CI): 0.35 (0.28 - 0.42)), and delayed median tmax from 0.75 to 1.00 h (Hodges-Lehmann estimate of difference (90% CI): tmax 0.63 (0.25 - 1.25)) but had minor effects on AUCs of +15% and +11% (geometric mean ratio point estimates (90% CI): AUC0-t 1.15 (1.02 - 1.31) and AUC0-infinity (1.11 (0.98 - 1.27)), respectively. A total of 6 adverse events were reported by 4 subjects, none of them being serious. CONCLUSIONS: Concomitant use of ulipristal acetate with esomeprazole at therapeutic concentrations led to a modified absorption rate while exposure in terms of AUC remained close to bioequivalence limits. In the context of chronic administration of ulipristal acetate, no clinically significant effects are expected from co administration with drugs increasing gastric pH. PMID- 23110789 TI - Serosurvey of veterinary conference participants for evidence of zoonotic exposure to canine norovirus - study protocol. AB - BACKGROUND: Noroviruses have emerged as the leading cause of outbreaks and sporadic cases of acute gastroenteritis in humans worldwide. Person-to-person contact and consumption of contaminated food are considered the most important ways of transmission of noroviruses however zoonotic transmission has been suggested. Recently, noroviruses have been found in dogs which, unlike bovine and swine noroviruses, may present a higher risk of zoonotic transfer, given to the often close contacts between humans and pet dogs in many societies across the world. The present paper describes a seroepidemiologic study aiming to provide information on the exposure level of humans to canine norovirus. METHODS/DESIGN: A case-control study was designed to address the potential exposure to canine norovirus based on the presence of antibodies against canine norovirus. Sera from veterinarians (a population repeatedly in close contact with dogs) will be collected in an annual Veterinary Sciences Congress in Portugal. In addition, sera from general population will be obtained and used as controls for comparative purposes. All sera will be tested for the presence of canine norovirus antibodies using a virus-like particle-based enzyme immune assay. Risk factors for canine norovirus antibodies presence in veterinarians will be investigated through the delivery of an anonymized questionnaire to the participants. DISCUSSION: The present study aims to identify seropositive individuals to canine norovirus and to assess risk profiles among veterinary professionals with occupational exposure to dogs. To our knowledge this is the first study providing information on the potential zoonotic risk of canine norovirus, thus allowing the development of preventive measures and ascertaining potential risks for Public Health resulting from contact to dogs. PMID- 23110790 TI - Omega 3 Fatty acids and cardiovascular outcomes: systematic review and meta analysis. AB - BACKGROUND: Early trials evaluating the effect of omega 3 fatty acids (omega-3 FA) reported benefits for mortality and cardiovascular events but recent larger studies trials have variable findings. We assessed the effects of omega-3 FA on cardiovascular and other important clinical outcomes. METHODS AND RESULTS: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all randomized studies using dietary supplements, dietary interventions, or both. The primary outcome was a composite of cardiovascular events (mostly myocardial infarction, stroke, and cardiovascular death). Secondary outcomes were arrhythmia, cerebrovascular events, hemorrhagic stroke, ischemic stroke, coronary revascularization, heart failure, total mortality, nonvascular mortality, and end stage kidney disease. Twenty studies including 63030 participants were included. There was no overall effect of omega-3 FA on composite cardiovascular events (relative risk [RR]=0.96; 95% confidence interval [CI], 0.90-1.03; P=0.24) or on total mortality (RR=0.95; 95% CI, 0.86-1.04; P=0.28). omega-3 FA did protect against vascular death (RR=0.86; 95% CI, 0.75-0.99; P=0.03) but not coronary events (RR=0.86; 95% CI, 0.67-1.11; P=0.24). There was no effect on arrhythmia (RR=0.99; 95% CI, 0.85-1.16; P=0.92) or cerebrovascular events (RR=1.03; 95% CI, 0.92-1.16; P=0.59). Adverse events were more common in the treatment group than the placebo group (RR=1.18, 95% CI, 1.02-1.37; P=0.03), predominantly because of an excess of gastrointestinal side effects. CONCLUSIONS: omega-3 FA may protect against vascular disease, but the evidence is not clear-cut, and any benefits are almost certainly not as great as previously believed. PMID- 23110791 TI - Left and codominant coronary artery circulations are associated with higher in hospital mortality among patients undergoing percutaneous coronary intervention for acute coronary syndromes: report From the National Cardiovascular Database Cath Percutaneous Coronary Intervention (CathPCI) Registry. AB - BACKGROUND: Left or codominant coronary arterial circulation may represent less well-balanced myocardial perfusion and thus confer worse prognosis in acute coronary syndrome, especially for culprit lesions arising from the left coronary artery. METHODS AND RESULTS: We related left and codominance, relative to right dominance, with in-hospital mortality in 207 926 percutaneous coronary interventions (PCI) for acute coronary syndromes from July 1, 2009 through June 30, 2010 in the National Cardiovascular Data Registry Cath Percutaneous Coronary Intervention (CathPCI) Registry database version 4. Generalized estimating equations and logistic regression analyses were used in unadjusted and multivariable adjusted models. Models were adjusted using the validated National Cardiovascular Data Registry mortality risk model. We performed subgroup analyses and formally tested for effect modification by the epicardial coronary artery containing the culprit lesion. Left coronary dominance was associated with higher in-hospital mortality in unadjusted (odds ratio=1.29, 95% confidence interval [CI], 1.17-1.42) and adjusted models (1.19, 95% CI, 1.06-1.34). Codominance was associated with worsened mortality only in adjusted models (odds ratio=1.16, 95% CI, 1.01-1.34). Addition of coronary dominance to the National Cardiovascular Data Registry risk model did not materially change model discrimination or calibration. The odds of death for left versus right dominance among those with left circumflex or left main culprit lesions was 1.25 (95% CI, 1.02-1.53), for right coronary artery lesions was 1.19 (95% CI, 0.83-1.71), and for left anterior descending artery lesions was 1.09 (95% CI, 0.93-1.28). There was no statistical evidence for effect modification by culprit lesion vessel (P=0.8). CONCLUSIONS: Left and codominance are associated with modestly increased post-percutaneous coronary intervention in-hospital mortality in patients with acute coronary syndrome. Confirmation of these findings with angiographic core laboratory verification of coronary dominance and longer term follow-up will be desirable. PMID- 23110792 TI - Mechanism of autograft insufficiency after the Ross operation in children. AB - BACKGROUND: It is unclear how autografts grow and dilate after the Ross operation in children. We analysed autograft growth and dilatation in children who underwent the Ross operation and examined the relationship of these factors to autograft failure. METHODS: From our institutional database, we retrospectively identified 33 children who underwent the Ross operation without aortic root reinforcement (mean age 9.9 years) and had normal body measurements and echocardiographic data throughout follow-up. RESULTS: Autograft insufficiency developed in 10 patients 5.1 years after the Ross operation. The average Z score at the development of autograft insufficiency was -0.1 (range from -2.0 to 6.1). The proportions of patients who remained free of autograft insufficiency at 5 and 10 years were 87.2% and 55.7%, respectively. A consistent trend in the time course of Z score was not found in any age group studied. CONCLUSIONS: Autograft growth and dilation after the Ross operation varied widely among patients, and the incidence of autograft insufficiency was independent of annulus size. PMID- 23110793 TI - Poorly differentiated synovial sarcoma is associated with high expression of enhancer of zeste homologue 2 (EZH2). AB - BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a polycomb group (PcG) family protein. Acting as a histone methyltransferase it plays crucial roles in maintaining epigenetic stem cell signature, while its deregulation leads to tumor development. EZH2 overexpression is commonly associated with poor prognosis in a variety of tumor types including carcinomas, lymphomas and soft tissue sarcomas. However, although the synovial sarcoma fusion proteins SYT-SSX1/2/4 are known to interact with PcG members, the diagnostic and prognostic significance of EZH2 expression in synovial sarcoma has not yet been investigated. Also, literature data are equivocal on the correlation between EZH2 expression and the abundance of trimethylated histone 3 lysine 27 (H3K27me3) motifs in tumors. METHODS: Immunohistochemical stains of EZH2, H3K27me3, and Ki-67 were performed on tissue microarrays containing cores from 6 poorly differentiated, 39 monophasic and 10 biphasic synovial sarcomas, and evaluated by pre-established scoring criteria. Results of the three immunostainings were compared, and differences were sought between the histological subtypes as well as patient groups defined by gender, age, tumor location, the presence of distant metastasis, and the type of fusion gene. The relationship between EZH2 expression and survival was plotted on a Kaplan-Meier curve. RESULTS: High expression of EZH2 mRNA and protein was specifically detected in the poorly differentiated subtype. EZH2 scores were found to correlate with those of Ki-67 and H3K27me3. Cases with high EZH2 score were characterized by larger tumor size (>= 5cm), distant metastasis, and poor prognosis. Even in the monophasic and biphasic subtypes, higher expression of EZH2 was associated with higher proliferation rate, larger tumor size, and the risk of developing distant metastasis. In these histological groups, EZH2 was superior to Ki-67 in predicting metastatic disease. CONCLUSIONS: High expression of EZH2 helps to distinguish poorly differentiated synovial sarcoma from the monophasic and biphasic subtypes, and it is associated with unfavorable clinical outcome. Importantly, high EZH2 expression is predictive of developing distant metastasis even in the better-differentiated subtypes. EZH2 overexpression in synovial sarcoma is correlated with high H3K27 trimethylation. Thus, along with other epigenetic regulators, EZH2 may be a future therapeutic target. PMID- 23110795 TI - The dependence of Ni-Fe bioxide composites nanoparticles on the FeCl2 solution used. AB - BACKGROUND: Ni2O3- gamma-Fe2O3 composite nanoparticles coated with a layer of 2FeCl3.5H2O can be prepared by co-precipitation and processing in FeCl2 solution. Using vibrating sample magnetometer (VSM), X-ray diffraction (XRD), transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS) diffraction techniques, the dependence of the preparation on the concentration of the FeCl2 treatment solution is revealed. RESULTS: The magnetization of the as-prepared products varied non-monotonically as the FeCl2 concentration increased from 0.020 M to 1.000 M. The Experimental results show that for the composite nanoparticles, the size of the gamma-Fe2O3 phase is constant at about 8 nm, the Ni2O3 phase decreased and the 2FeCl3.5H2O phase increased with increasing concentration of FeCl2 solution. The magnetization of the as-prepared products mainly results from the gamma-Fe2O3 core, and the competition between the reduction of the Ni2O3 phase with the increase of the 2FeCl3.5H2O phase resulted in the apparent magnetization varying non-monotonically. CONCLUSIONS: When the concentration of FeCl2 treatment solution did not exceed 0.100 M, the products are spherical nanoparticles of size about 11 nm; their magnetization increased monotonically with increasing the concentration of FeCl2 solution due to the decreasing proportion of Ni2O3 phase. PMID- 23110794 TI - Identification of myeloid derived suppressor cells in the peripheral blood of tumor bearing dogs. AB - BACKGROUND: Myeloid derived suppressor cells (MDSCs) are a recently described population of immune cells that significantly contribute to the immunosuppression seen in cancer patients. MDSCs are one of the most important factors that limit the efficacy of cancer immunotherapy (e.g. cancer vaccines) and MDSC levels are increased in cancer in multiple species. Identifying and targeting MDSCs is actively being investigated in the field of human oncology and is increasingly being investigated in veterinary oncology. The treatment of canine cancer not only benefits dogs, but is being used for translational studies evaluating and modifying candidate therapies for use in humans. Thus, it is necessary to understand the immune alterations seen in canine cancer patients which, to date, have been relatively limited. This study investigates the use of commercially available canine antibodies to detect an immunosuppressive (CD11b low/CADO48 low) cell population that is increased in the peripheral blood of tumor-bearing dogs. RESULTS: Commercially available canine antibodies CD11b and CADO48A were used to evaluate white blood cells from the peripheral blood cells of forty healthy control dogs and forty untreated, tumor-bearing dogs. Tumor-bearing dogs had a statistically significant increase in CD11b low/CADO48A low cells (7.9%) as compared to the control dogs (3.6%). Additionally, sorted CD11b low/CADO48A low generated in vitro suppressed the proliferation of canine lymphocytes. CONCLUSIONS: The purpose of this study was aimed at identifying potential canine specific markers for identifying MDSCs in the peripheral blood circulation of dogs. This study demonstrates an increase in a unique CD11b low/CADO48A low cell population in tumor-bearing dogs. This immunophenotype is consistent with described phenotypes of MDSCs in other species (i.e. mice) and utilizes commercially available canine-specific antibodies. Importantly, CD11b low/CADO48A low from a tumor environment suppress the proliferation of lymphocytes. These results provide a useful phenotype of cells increased in canine cancer patients that may serve as a useful prognostic marker for assessing immune status and functional response to cancer immunotherapies in dogs. Understanding MDSCs in dogs will allow for increased effectiveness of cancer immunotherapy in both dogs and humans. PMID- 23110796 TI - Aortopexy for the treatment of tracheomalacia in children: review of the literature. AB - Severe tracheomalacia presents a significant challenge for Paediatricians, Intensivists, Respiratory Physicians, Otolaryngologists and Paediatric Surgeons. The treatment of tracheomacia remains controversial, but aortopexy is considered by most to be one of the best options. We conducted a review of the English literature relating to aortopexy.Among 125 papers, 40 have been included in this review. Among 758 patients (62% males) affected with tracheomalacia, 581 underwent aortopexy. Associated co-morbidities were reported in 659 patients. The most frequent association was with oesophageal atresia (44%), vascular ring or large vessel anomalies (18%) and innominate artery compression (16%); in 9% tracheomalacia was idiopathic. The symptoms reported were various, but the most important indication for aortopexy was an acute life-threatening event (ALTE), observed in 43% of patients. The main preoperative investigation was bronchoscopy. Surgical approach was through a left anterior thoracotomy in 72% of patients, while median approach was chosen in 14% and in 1.3% a thoracoscopic aortopexy was performed. At follow-up (median 47 months) more than 80% of the patients improved significantly, but 8% showed no improvement, 4% had a worsening of their symptoms and 6% died. Complications were observed in 15% of patients, in 1% a redo aortopexy was deemed necessary.In our review, we found a lack of general consensus about symptom description and evaluation, indications for surgery, though ALTE and bronchoscopy were considered by all an absolute indication to aortopexy and the gold standard for the diagnosis of tracheomalacia, respectively. Differences were reported also in surgical approaches and technical details, so that the same term "aortopexy" was used to describe different types of procedures. Whatever approach or technique was used, the efficacy of aortopexy was reported as high in the majority of cases (more than 80%). A subgroup of patients particularly delicate is represented by those with associated gastro-esophageal reflux, in whom a fundoplication should be performed. Other treatments of tracheomalacia, particularly tracheal stenting, were associated with a higher rate of failure, severe morbidity and mortality. PMID- 23110797 TI - HPV type distribution in invasive cervical cancers in Italy: pooled analysis of three large studies. AB - OBJECTIVE: The aim of this study is to describe the prevalence of HPV types in invasive cervical cancers in Italy from 1996 to 2008. METHODS: A pooled analysis of the three largest case series typed to date was performed. HPV typing was performed on paraffin-embedded slices. Molecular analyses were performed in four laboratories. Multivariate analyses were performed to test the associations between calendar time, age, and geographical area and the proportion of types 16/18. RESULTS: Out of 574 cancers, 24 (4.2%) were HPV negative. HPV 16 and 18 were responsible for 74.4% (378/508) and 80.3% (49/61) of the squamous cancers and adenocarcinomas, respectively. Other frequent types were 31 (9.5%), 45 (6.4%), and 58 (3.3%) for squamous cancers and 45 (13.3%), 31, 35, and 58 (5.0%) for adenocarcinomas. The proportion of HPV 16 and/or 18 decreased with age (p value for trend <0.03), while it increased in cancers diagnosed in more recent years (p-value for trend < 0.005). CONCLUSIONS: The impact of HPV 16/18 vaccine on cervical cancer will be greater for early onset cancers. In vaccinated women, screening could be started at an older age without reducing protection. PMID- 23110798 TI - Influence of a 23S ribosomal RNA mutation in Helicobacter pylori strains on the in vitro synergistic effect of clarithromycin and amoxicillin. AB - BACKGROUND: Clarithromycin (CLR) is the most commonly recommended antibiotic in Helicobacter pylori eradication regimens, but the prevalence of CLR-resistant H. pylori is increasing. CLR resistance is associated with mutations in the 23S rRNA gene. However, H. pylori eradication can still be achieved with triple therapy, and an additive effect may occur with multiple antibiotics. METHODS: Twenty-six CLR-resistant strains were examined. The MIC of clarithromycin was determined by agar-dilution-testing on Columbia agar, as described elsewhere. The conserved region of the H. pylori 23S rRNA gene between nucleotide positions 1445 and 2846 [GenBank: U27270] was amplified. RFLP and sequence analysis were performed with the 1402-bp PCR product. Synergy between clarithromycin and amoxicillin was assessed using the agar dilution checkerboard technique. To confirm the correlation between mutation and synergistic effect with subinhibitory concentrations of AMX, site-directed mutagenesis was performed in four CLR susceptible H. pylori isolates. RESULTS: Twenty-six clarithromycin-resistant strains were examined. The conserved region of the H. pylori 23S rRNA gene was amplified, and the purified PCR product was checked for mutations by restriction fragment length polymorphism (RFLP) analysis and sequencing. A synergistic effect was found in only three of the 12 H. pylori strains (25%) with the A2142G mutation and five of the 10 H. pylori strains (50%) with the A2143G mutation (fractional inhibitory concentration: FIC < 0.5, minimal inhibitory concentration: MIC<2 mg/L) was found. Site-directed mutagenesis was performed in four CLR-susceptible H. pylori isolates.Three of these isolates harboring a mutation in position A2143G grew under selection with CLR (MIC >16 mg/L), and all three strains showed the synergistic effect (FIC<0.5). In contrast, three of the same four strains transformed with DNA fragments with a mutation in position A2142G were resistant to CLR (MIC>16 mg/L) and showed no synergism with amoxicillin (FIC>2). CONCLUSIONS: Here we demonstrate that in 100% of the in vitro transformed strains, a mutation at position A2143G leads to a synergistic effect between clarithromycin and amoxicillin, whereas a mutation at position at A2142G had no discernible effect. PMID- 23110799 TI - Validation of the Diet Quality Index for Adolescents by comparison with biomarkers, nutrient and food intakes: the HELENA study. AB - Food-based dietary guidelines (FBDG) aim to address the nutritional requirements at population level in order to prevent diseases and promote a healthy lifestyle. Diet quality indices can be used to assess the compliance with these FBDG. The present study aimed to investigate whether the newly developed Diet Quality Index for Adolescents (DQI-A) is a good surrogate measure for adherence to FBDG, and whether adherence to these FBDG effectively leads to better nutrient intakes and nutritional biomarkers in adolescents. Participants included 1804 European adolescents who were recruited in the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) Study. Dietary intake was assessed by two, non-consecutive 24 h recalls. A DQI-A score, considering the components' dietary quality, diversity and equilibrium, was calculated. Associations between the DQI-A and food and nutrient intakes and blood concentration biomarkers were investigated using multilevel regression analysis corrected for centre, age and sex. DQI-A scores were associated with food intake in the expected direction: positive associations with nutrient-dense food items, such as fruits and vegetables, and inverse associations with energy-dense and low-nutritious foods. On the nutrient level, the DQI-A was positively related to the intake of water, fibre and most minerals and vitamins. No association was found between the DQI-A and total fat intake. Furthermore, a positive association was observed with 25-hydroxyvitamin D, holo-transcobalamin and n-3 fatty acid serum levels. The present study has shown good validity of the DQI-A by confirming the expected associations with food and nutrient intakes and some biomarkers in blood. PMID- 23110800 TI - Test-retest reliability and minimal detectable change of repeated sit-to-stand analysis using one body fixed sensor in geriatric patients. AB - A majority of geriatric patients experience difficulty in performing sit-to-stand (SiSt) transitions. A detailed assessment of SiSt ability is a prerequisite for successful rehabilitation. Body fixed sensors (BFSs) are increasingly used to assess functional performances. As to date there is no system which analyzes clinically relevant phases of SiSt, the aim of this study was to determine the reliability of an automated approach for quantifying durations and angular velocities of trunk flexion and extension during repeated SiSt transitions using one BFS (DynaPort(r) Hybrid). Forty multimorbid geriatric patients aged 84.1 +/- 6.6 years were included. Each patient participated in two test sessions with a 5 min rest period in between. Intra- and interrater reliability was assessed. Intraclass correlation coefficients (ICCs), absolute and relative standard measurement errors (SEMs, SEMs%) and minimal detectable changes (MDCs(95), MDCs(95)%) were calculated. ICCs were good to excellent for all variables in the total sample (0.80-0.94). The intraobserver group (50%) showed a higher number of excellent ICCs (>=.9) compared to the interobserver subgroup (10%). SEM% was low for all variables (6.9-12.7%). MDC(95)% ranged 19.2-34.4% and more variables <=30% were found in the intra- (80%) compared to the inter-observer group (60%). Study results demonstrate that the BFS system provides a reliable analysis of SiSt phases in geriatric patients, and is a substantial improvement over the stopwatch approach used in clinical practice today. PMID- 23110801 TI - Green light emission from terbium doped silicon rich silicon oxide films obtained by plasma enhanced chemical vapor deposition. AB - The effect of silicon concentration and annealing temperature on terbium luminescence was investigated for thin silicon rich silicon oxide films. The structures were deposited by means of plasma enhanced chemical vapor deposition. The structural properties of these films were investigated by Rutherford backscattering spectrometry, transmission electron microscopy and Raman scattering. The optical properties were investigated by means of photoluminescence and photoluminescence decay spectroscopy. It was found that both the silicon concentration in the film and the annealing temperature have a strong impact on the terbium emission intensity. In this paper, we present a detailed discussion of these issues and determine the optimal silicon concentration and annealing temperature. PMID- 23110803 TI - Theoretical analysis of oxygen vacancies in layered sodium cobaltate, Na(x)CoO(2 delta). AB - Sodium cobaltate with high Na content is a promising thermoelectric material. It has recently been reported that oxygen vacancies can alter the material properties, reducing its figure of merit. However, experimental data concerning the oxygen stoichiometry are contradictory. We therefore studied the formation of oxygen vacancies in Na(x)CoO(2) with first principles calculations, focusing on x = 0.75. We show that a very low oxygen vacancy concentration is expected at the temperatures and partial pressures relevant for applications. PMID- 23110802 TI - Receptor specificity and erythrocyte binding preferences of avian influenza viruses isolated from India. AB - INTRODUCTION: Hemagglutination (HA) and hemagglutination inhibition (HI) assays are conventionally used for detection and identification of influenza viruses. HI assay is also used for detection of antibodies against influenza viruses. Primarily turkey or chicken erythrocytes [red blood cells (RBCs)] are used in these assays, as they are large, nucleated, and sediment fast, which makes it easy to determine the titer. Human influenza viruses agglutinate RBCs from chicken, human, and guinea pig, but not from horse. Human influenza viruses bind preferentially to sialic acid (SA) linked to galactose (Gal) by alpha 2, 6 linkage (SA alpha 2, 6-Gal), whereas avian influenza (AI) viruses bind preferentially to SA alpha 2, 3-Gal linkages. With this background, the present study was undertaken to study erythrocyte binding preferences and receptor specificities of AI viruses isolated from India. MATERIALS AND METHODS: A total of nine AI virus isolates (four subtypes) from India and three reference AI strains (three subtypes) were tested in HA and HI assays against mammalian and avian erythrocytes. The erythrocytes from turkey, chicken, goose, guinea pig and horse were used in the study. The receptor specificity determination assays were performed using goose and turkey RBCs. The amino acids present at 190 helix, 130 and 220 loops of the receptor-binding domain of the hemagglutinin protein were analyzed to correlate amino acid changes with the receptor specificity. RESULTS: All tested highly pathogenic avian influenza (HPAI) H5N1 viruses reacted with all five types of RBCs in the HA assay; AI H9N2 and H5N2 viruses did not react with horse RBCs. For H5N1 viruses guinea pig and goose RBCs were best for both HA and HI assays. For H9N2 viruses, guinea pig, fowl and turkey RBCs were suitable. For other tested AI subtypes, avian and guinea pig RBCs were better. Eight isolates of H5N1, one H4N6 and one H7N1 virus showed preference to avian sialic acid receptors. Importantly, two isolates of HPAI H5N1, H9N2 and H11N1 viruses showed receptor specificity preference to both avian and mammalian sialic acid (alpha-2, 3 and alpha-2, 6) receptors. CONCLUSIONS: Use of different types of RBCs resulted in titer variations in HA and HI assays. This showed that RBCs giving optimum HA and HI titers would increase sensitivity of detection and would be more appropriate for identification and antigenic analysis of AI viruses. Analysis of 16 amino acids in the receptor-binding domain of the hemagglutinin of HPAI H5N1 viruses revealed that the only variation observed was in S221P amino acid position. Two H5N1 viruses showed S221P amino acid change, out of which only one H5N1 virus showed preference to alpha 2, 6 sialic acid receptor. One H5N1 virus isolate with amino acid S at 221 position, showed preference to alpha 2,3 as well as alpha 2,6 sialic acid receptors. This indicated that factor(s) other than S221P mutation in the hemagglutinin are probably involved in determining receptor specificity of H5N1 viruses. This is the first report of receptor specificity and erythrocyte binding preferences of AI viruses from India. PMID- 23110804 TI - Association between WHO cut-offs for childhood overweight and obesity and cardiometabolic risk. AB - OBJECTIVE: To examine the association between cardiovascular risk and childhood overweight and obesity using the BMI cut-offs recommended by the WHO. DESIGN: Children were classified as normal weight, overweight and obese according to the WHO BMI-for-age reference. Blood pressure, lipids, glucose, insulin, homeostasis model assessment-insulin resistance (HOMA-IR) and uric acid levels were compared across BMI groups. ANOVA and tests of linearity were used to assess overall mean differences across groups. Crude and adjusted odds ratios were calculated for adverse plasma levels of biochemical variables. SETTING: Paediatric care centres. SUBJECTS: Children (n 149) aged 8-18 years. RESULTS: About 37 %, 22 % and 41 % of children were classified respectively as normal weight, overweight and obese. There were significant linear mean differences between BMI groups in systolic blood pressure, HDL-cholesterol, TAG, insulin, HOMA-IR and uric acid. Obese children were 10.6 times more likely than normal-weight children to have hypertension; OR for other associations were 60.2 (high insulin), 39.5 (HOMA-IR), 27.9 (TAG), 16.0 (HDL-cholesterol), 4.3 (LDL-cholesterol) and 3.6 (uric acid). Overweight children were more likely than normal-weight children to have hypertension (OR = 3.5), high insulin (OR = 28.2), high HOMA-IR (OR = 23.3) and high TAG (OR = 16.1). Nearly 92 % and 57 % of the obese and overweight children, respectively, had one or more risk factor. CONCLUSIONS: Obesity and overweight defined using the WHO BMI-for-age cut-offs identified children with higher metabolic and vascular risk. These results emphasize the importance of prevention of overweight and obesity in childhood to reduce cardiovascular risk. PMID- 23110805 TI - Mevalonate kinase deficiency, a metabolic autoinflammatory disease. AB - Mevalonate kinase deficiency is a rare autosomal recessive inborn error of metabolism with an autoinflammatory phenotype. In this review we discuss its pathogenesis, clinical presentation and treatment. Mutations in both copies of the MVK-gene lead to a block in the mevalonate pathway. Interleukin-1beta mediates the inflammatory phenotype. Shortage of a non-sterol isoprenoid product of the mevalonate pathway, Geranylgeranylpyrophosphate leads to aberrant activation of the small GTPase Rac1, and inflammasome activation. The clinical phenotype ranges widely, depending on the severity of the enzyme defect. All patients show recurrent fevers, lymphadenopathy and high acute phase proteins. Severely affected patients have antenatal disease onset, dysmorphic features, growth retardation, cognitive impairment and progressive ataxia. Diagnosis relies on mutation analysis of the MVK-gene. There is no evidence based therapy. IL-1 blockade is usually effective. Severe cases require allogeneic stem cell transplantation. Targeted therapies are needed. PMID- 23110806 TI - Perinatal testosterone exposure and autistic-like traits in the general population: a longitudinal pregnancy-cohort study. AB - BACKGROUND: Increased prenatal testosterone exposure has been hypothesized as a mechanism underlying autism spectrum disorders (ASD). However, no studies have prospectively measured prenatal testosterone exposure and ASD. The current study sought to determine whether testosterone concentrations in umbilical cord blood are associated with a clinical diagnosis of ASD in a small number of children and with autistic-like traits in the general population. METHODS: Umbilical cord blood was collected from 707 children. Samples were analyzed for total (TT) and bioavailable (BioT) testosterone concentrations. Parent report indicated that five individuals had a clinical diagnosis of ASD. Those participants without a diagnosis were approached in early adulthood to complete the Autism-Spectrum Quotient (AQ), a self-report measure of autistic-like traits, with 184 males (M = 20.10 years; SD= 0.65 years) and 190 females (M = 19.92 years; SD=0.68 years) providing data. RESULTS: The BioT and TT concentrations of the five children diagnosed with ASD were within one standard-deviation of the sex-specific means. Spearman's rank-order coefficients revealed no significant correlations between TT levels and scores on any AQ scale among males (rho range: -.01 to .06) or females (rho value range: -.07 to .01). There was also no significant association between BioT or TT concentrations and AQ scores among males (rho value range: .07 to .08) or females (rho value range: -.06 to .12). Males were more likely than females to have 'high' scores (upper decile) on the AQ scale relating pattern and detail processing. However, the likelihood of a high score on this scale was unrelated to BioT and TT concentrations in both males and females. CONCLUSIONS: These findings indicate that testosterone concentrations from umbilical cord blood are unrelated to autistic-like traits in the general population. However, the findings do not exclude an association between testosterone exposure in early intrauterine life and ASD. PMID- 23110807 TI - Testicular cancer in Europe and the USA: survival still rising among older patients. AB - BACKGROUND: Despite high curability, some testicular cancer (TC) patient groups may have increased mortality. We provide a detailed age- and histology-specific comparison of population-based relative survival of TC patients in Europe and the USA. Design Using data from 12 European cancer registries and the USA Surveillance, Epidemiology and End Results 9 database, we report survival trends for patients diagnosed with testicular seminomas and nonseminomas between 1993 1997 and 2003-2007. Additionally, a model-based analysis was used to compare survival trends and relative excess risk (RER) of death between Europe and the USA adjusting for differences in age and histology. RESULTS: In 2003-2007, the 5 year relative survival of patients with testicular seminoma was at least 98% among those aged <50 years, survival of patients with nonseminoma remained 3%-6% units lower. Despite improvements in the relative survival of nonseminoma patients aged >= 50 years by 13%-18% units, survival remained markedly lower than the survival of seminoma patients of the same age. Model-based analyses showed increased RERs for nonseminomas, older, and European patients. CONCLUSIONS: There remains little room for survival improvement among testicular seminoma patients, especially for those aged <50 years. Older TC patients remain at increased risk of death, which seems mainly attributable to the lower survival among the nonseminoma patients. PMID- 23110808 TI - Seminars in clinical pharmacology: an introduction to MET inhibitors for the medical oncologist. AB - MET is a tyrosine kinase receptor for hepatocyte growth factor (HGF), primarily expressed on epithelial cells; the activation of MET induces several biological responses relevant for the development and growth of many human cancers. Several human malignancies present altered expression of MET and this is usually associated with poor prognosis and aggressive phenotype. The majority of MET inhibitors in clinical development target directly the receptor through the use of monoclonal antibodies (MAbs) or through small molecule inhibitors of MET kinase activity; small molecule inhibitors are very potent but less specific than MAbs. MET inhibitors are of great clinical interest because of the extensive crosstalk of the HGF/MET axis with many other signaling pathways, including growth factor-dependent pathways (like PI3K/AKT/mTOR,RAS/RAF/ERK) and vascular endothelial growth factor (VEGF) axis. In preclinical studies, the treatment with MET inhibitors could prevent or reverse resistance to inhibitors of growth factor dependent signaling; this hypothesis is currently tested in phase III trials with anti-epidermal growth factor receptor (EGFR) inhibitors in non-small-cell lung cancer (NSCLC). Based on preclinical and preliminary clinical results, a rational strategy for the clinical development of MET antagonists should include a selection of the tumors with MET overexpression, the identification of prognostic/predictive biomarkers, the evaluation of combinations with anti-VEGF compounds. PMID- 23110809 TI - Effect of complementary and alternative medicine on the survival and health related quality of life among terminally ill cancer patients: a prospective cohort study. AB - BACKGROUND: We evaluated whether complementary and alternative medicine (CAM) use influenced outcomes [survival and health-related quality of life (HRQOL)] of cancer patients whose condition had just been judged terminal. PATIENTS AND METHODS: From July 2005 to October 2006, we conducted a prospective cohort study of 481 terminally ill cancer patients at 11 university hospitals and the National Cancer Center in Korea. We assessed how the use of CAM affected HRQOL and survival. RESULTS: In a follow-up of 481 patients and 163.8 person-years, we identified 466 deceased cases. On multivariate analyses, CAM users did not have better survival compared with nonusers [adjusted hazard ratio (aHR), 0.91; 95% confidence interval (CI) 0.74-1.10]. Among mind-body interventions, prayer showed significantly worse survival (aHR, 1.56; 95% CI, 1.00-2.43). Clinically, CAM users reported significantly worse cognitive functioning (-11.6 versus -1.3; P < 0.05) and fatigue (9.9 versus -1.0; P < 0.05) than nonusers. Compared with nonusers in subgroup analysis, users of alternative medical treatments, prayer, vitamin supplements, mushrooms, or rice and cereal reported clinically significant worse changes in some HRQOL subscales. CONCLUSION: While CAM did not provide any definite survival benefit, CAM users reported clinically significant worse HRQOLs. PMID- 23110810 TI - A population-based cohort study in Taiwan--use of insulin sensitizers can decrease cancer risk in diabetic patients? AB - BACKGROUND: The purpose of the study was to explore the possible association between the use of insulin sensitizers (thiazolidinediones, TZDs) and the risk of cancer in Taiwanese diabetic patients. PATIENTS AND METHODS: From the National Health Insurance Research Database (NHIRD) of Taiwan, we identified 22 910 diabetic patients newly diagnosed from 2001 to 2009 and 91 636 non-diabetic comparisons frequency matched with age, sex, and calendar year, excluding those with cancer at the baseline. Among the diabetics, 4159 patients were treated with TZDs and the rest of 18 752 patients were on other anti-diabetic medications (non TZDs). RESULTS: In comparison to the non-diabetes group, the non-TZDs group had an increased risk of developing cancer [the adjusted hazard ratio (HR): 1.20 and 95% confidence interval (CI) = 1.11-1.30]. The TZDs group had a HR of 1.18 (95% CI = 0.98-1.42). Analysis of site-specific cancer risks showed that both TZDs and non-TZDs groups with elevated risks of colorectal and pancreatic cancer. However, the non-TZDs group had an increased risk of liver cancer when comparing with TZD and non-diabetes groups. CONCLUSION: This study suggests that patients with diabetes are at an elevated risk of cancer (especially in colorectal and pancreatic cancers), and the use of TZDs might decrease the liver cancer risk in diabetic patients. Further investigation using large samples and rigorous methodology is warranted. PMID- 23110811 TI - Quality of surgery and neoadjuvant combined therapy in the ISG-GEIS trial on soft tissue sarcomas of limbs and trunk wall. AB - BACKGROUND: To explore correlation between the quality of surgery and outcome in high-risk soft tissue sarcoma (STS) patients treated within a phase III randomized trial. PATIENTS AND METHODS: In the trial, all patients received three cycles of preoperative chemotherapy (CT) with epirubicin 120 mg/m(2) and ifosfamide 9 g/m(2) and were randomly assigned to receive two further postoperative cycles. Radiotherapy (RT) could be delivered in the preoperative or postoperative setting. The association between surgical margins and overall survival (OS) was studied in a univariate and multivariate fashion. RESULTS: Two hundred and fifty-two patients completed the whole treatment and were operated conservatively. At a median follow-up of 60 months (IQR, 45-74 months), the 5 year OS was 0.73, even in patients with positive and negative margins. The 5-year cumulative incidence (CI) of local recurrence (LR) in patients with positive and negative microscopic margins was 0.17 (standard error, SE, 0.08) and 0.03 (SE, 0.01), respectively. In the subgroup of patients receiving combined preoperative CT-RT and with positive surgical margins, the CI of LR was 0. CONCLUSIONS: In this setting of high-risk STS treated by preoperative CT or CT-RT, the negative impact of positive margins on the outcome was limited. When close margins can be anticipated preoperative CT-RT may be a reasonable option to maximize the chance of cure. PMID- 23110812 TI - SPIDIA-RNA: first external quality assessment for the pre-analytical phase of blood samples used for RNA based analyses. AB - The diagnostic use of in vitro molecular assays can be limited by the lack of guidelines for collection, handling, stabilization and storage of patient specimens. One of the major goals of the EC funded project SPIDIA (www.spidia.eu) is to develop evidence-based quality guidelines for the pre-analytical phase of blood samples used for molecular testing which requires intracellular RNA analytes. To this end, a survey and a pan-European external quality assessment (EQA) were implemented. This report is the summary of the results of that trial. With the European Federation of Laboratory Medicine (EFLM) support, 124 applications for participation in the trial were received from 27 different European countries, and 102 laboratories actually participated in the trial. Each participating laboratory described their respective laboratory policies and practices as well as blood collection tubes typically used in performing this type of testing. The participating laboratories received two identical blood specimens: in an EDTA tubes (unstabilized blood; n=67) or in tubes designed specifically for the stabilization of intracellular RNA in blood (PAXgene(r) Blood RNA tubes; n=35). Laboratories were requested to perform RNA extraction according to the laboratory's own procedure as soon as possible upon receipt of the tubes for one tube and 24h after the first extraction for the second tube. Participants (n=93) returned the two extracted RNAs to SPIDIA facility for analysis, and provided details about the reagents and protocols they used for the extraction. At the SPIDIA facility responsible for coordinating the study, the survey data were classified, and the extracted RNA samples were evaluated for purity, yield, integrity, stability, and the presence of interfering substances affecting RT-qPCR assays. All participants received a report comparing the performance of the RNA they submitted to that of the other participants. All the results obtained by participants for each RNA quality parameter were classified as "in control", "warning", "out of control" and "missing" by consensus mean analysis. From the survey data, the most variable parameters were the volume of blood collected and the time and storage temperature between blood collection and RNA extraction. Analyzing the results of quality testing of submitted RNA samples we observed a data distribution of purity, yield, and presence of assay interference in agreement with expected values. The RNA Integrity Number (RIN) values distribution was, on the other hand, much wider than the optimal expected value, which led to an "in control" classification, even for partly degraded RNA samples. On the other hand, RIN values below 5 significantly correlated with a reduction of GAPDH expression levels. Furthermore, the distribution of the values of the four transcripts investigated (c-fos, IL-1beta, IL-8, and GAPDH) was wide and the RNA instability between samples separated by 24h were similar. Assuming the presence of at least two quality parameters "out of control" as an indication of a critical performance of the laboratory, 33% of the laboratories were included in this group. The results of this study will be the basis for implementing a second pan-European EQA and the results of both EQAs will be pooled and will provide the basis for the implementation of evidence-based guidelines for the pre-analytical phase of RNA analysis of blood samples. PMID- 23110813 TI - Moving gapless indirect excitons in monolayer graphene. AB - : The existence of moving indirect excitons in monolayer graphene is theoretically evidenced in the envelope-function approximation. The excitons are formed from electrons and holes near the opposite conic points. The electron-hole binding is conditioned by the trigonal warping of the electron spectrum. It is stated that the exciton exists in some sectors of the exciton momentum space and has the strong trigonal warping of the spectrum. PMID- 23110814 TI - Neuronal circuits involving neuropeptide Y in hypothalamic arcuate nucleus mediated feeding regulation. AB - Neuropeptide Y (NPY) is a 36-amino-acid neuropeptide that was first discovered in porcine brain extracts and later in the porcine intestine. It is widely distributed in both the central and peripheral nervous systems and exerts a powerful orexigenic effect. NPY-producing neuronal cell bodies are abundantly localized in the medial arcuate nucleus of the hypothalamus, this being a brain center that integrates signals for energy homeostasis. Accumulated evidence shows that hypothalamic neuropeptides such as ghrelin, orexin, melanin-concentrating hormone (MCH), galanin-like peptide (GALP) and proopiomelanocortin (POMC) are involved in the regulation of feeding behavior and energy homeostasis via neuronal circuits in the hypothalamus. NPY also forms part of the feeding regulating neuronal circuitry in conjunction with other feeding-regulating peptide-containing neurons within the hypothalamus. We summarize here current knowledge of the neuronal interactions between NPY and the different types of feeding-regulating peptide-containing neurons in the hypothalamus based on evidence at the immunohistochemicl level and with calcium imaging techniques. PMID- 23110815 TI - Protective role of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats. AB - Hyperlipidemia is an associated complication of diabetes mellitus. The association of hyperglycemia with an alteration of lipid parameters presents a major risk for cardiovascular complications in diabetes. The present study was designed to examine the antihyperlipidemic effect of 20-OH ecdysone on lipid profile and tissue fatty acid changes in streptozotocin induced diabetic rats. The levels of blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, high density lipoprotein, lipoprotein lipase, lecithin cholesterol acyl transferase, 3 hydroxy 3-methylglutaryl coenzyme A reductase and fatty acid composition were estimated in plasma, liver and kidneys of control and experimental groups of rats. Oral administration of 20-OH ecdysone at a dose of 5mg/kg bodyweight per day to STZ-induced diabetic rats for a period of 30 days resulted in a significant reduction in fasting blood glucose, cholesterol, triglycerides, free fatty acids, phospholipids, low density lipoprotein, very low density lipoprotein, 3-hydroxy 3-methylglutaryl coenzyme A reductase and elevation of high density lipoprotein, lipoprotein lipase and lecithin cholesterol acyl transferasein comparison with diabetic untreated rats. Moreover, administration of 20-OH ecdysone to diabetic rats also decreased the concentrations of fatty acids, viz., palmitic, stearic (16:1) and oleic acid (18:1), whereas linolenic (18:3) and arachidonic acid (20:4) were elevated. The antihyperlipidemic effect of 20-OH ecdysone was compared with glibenclamide a well-known antihyperglycemic drug. The result of the present study indicates that 20-OH ecdysone showed an antihyperlipidemic effect in addition to its antidiabetic effect in experimental diabetes. PMID- 23110816 TI - Sagace: a web-based search engine for biomedical databases in Japan. AB - BACKGROUND: In the big data era, biomedical research continues to generate a large amount of data, and the generated information is often stored in a database and made publicly available. Although combining data from multiple databases should accelerate further studies, the current number of life sciences databases is too large to grasp features and contents of each database. FINDINGS: We have developed Sagace, a web-based search engine that enables users to retrieve information from a range of biological databases (such as gene expression profiles and proteomics data) and biological resource banks (such as mouse models of disease and cell lines). With Sagace, users can search more than 300 databases in Japan. Sagace offers features tailored to biomedical research, including manually tuned ranking, a faceted navigation to refine search results, and rich snippets constructed with retrieved metadata for each database entry. CONCLUSIONS: Sagace will be valuable for experts who are involved in biomedical research and drug development in both academia and industry. Sagace is freely available at http://sagace.nibio.go.jp/en/. PMID- 23110817 TI - Ultrasound-guided excision combined with intraoperative assessment of gross macroscopic margins decreases the rate of reoperations for non-palpable invasive breast cancer. AB - AIMS: The standard technique for intraoperative tumour localization of clinically occult tumours is wire-guided localization (WGL). This, however, this has several disadvantages. The aim of the present work is to report our single-centre experience with intraoperative ultrasound-guided (IOUS) excision, performed by surgeons, combined with intraoperative assessment of macroscopic pathologic and ultrasound margins in non-palpable invasive cancers indicated for conservative breast therapy. PATIENTS AND METHODS: Two-hundred and twenty-five non-palpable invasive breast cancers were subjected to excision with IOUS. The lesion was located in the operating room with a high-frequency ultrasound probe (8-12 MHz), which was then used to guide surgical removal. The specimen margins were estimated by ultrasonography and macroscopic pathologic examination. The sensitivity of IOUS and effectiveness in the characterization of the specimen margins were evaluated, assessing the need for reoperation. RESULTS: Pathologic tumour size was 12.0 +/- 6.7 mm and 13 lesions (6.4 %) were <5 mm. The sensitivity of IOUS localization was 99.6% (224/225 cases). Only one cancer of less than 5 mm was not localized. The average weight of the specimens was 26.1 g. A second operation was required to remove margins in the 4% of cases (9/225). In 5 cases remains of in situ or invasive carcinoma were found. In two cases, conservative surgery was converted to mastectomy. CONCLUSIONS: IOUS excision combined with the intraoperative assessment of the macroscopic margins of non palpable breast cancers is a safe, useful, and efficient technique. We obtained an excellent characterization of tumour margins with moderate removal of breast tissue and consequently a lower number of reoperations were required and good cosmetic results were obtained. We believe that use of this technique in conservative breast cancer surgery should be recommended. PMID- 23110819 TI - Metformin overdose: time to move on. AB - Does metformin-associated lactic acidosis really exist? Despite an old controversy, there is no doubt about it. But do we understand what is going on? Laboratory findings raised several hypotheses explaining the pathophysiology of this disease. The main cause could be an inhibition of either gluconeogenesis or mitochondrial respiratory chain complex I. From bench to bedside, one hypothesis is now confirmed in humans. Metformin poisoning involves, at least partially, a mitochondrial dysfunction. PMID- 23110818 TI - Thermodynamic and structural destabilization of apoE3 by hereditary mutations associated with the development of lipoprotein glomerulopathy. AB - Lipoprotein glomerulopathy (LPG) is a dominant inherited kidney disorder characterized by lipoprotein thrombi in glomerular capillaries. Single-amino-acid mutations in apoE have been associated with the development of the disease, although the mechanism is unknown. In an effort to gain mechanistic insight linking the presence of such mutations and the development of LPG, we evaluated the effects of three of the most common apoE3 variants associated with this disease, namely R145P(Sendai), R147P(Chicago), and R158P(Osaka or Kurashiki), on the structural and conformational integrity of the protein. All three variants were found to have significantly reduced helical content, to expose a larger portion of hydrophobic surface to the solvent, and to be significantly thermodynamically destabilized, often lacking functionally relevant unfolding intermediates. Furthermore, all variants were aggregation prone and had enhanced sensitivity to protease digestion. Finally, although the variants were able to form discoidal lipoprotein particles, discrete subpopulations of poorly formed or aberrant particles were evident. Furthermore, these lipoprotein particles were thermodynamically destabilized and aggregation prone. Overall, our data suggest that these mutations induce a generalized unfolding of the N-terminal domain of apoE3 toward a molten-globule-like structure. ApoE3 N-terminal domain unfolding due to mutation may constitute a common mechanism underlying the protein's association with the pathogenesis of LPG. PMID- 23110820 TI - Negative moods correlate with craving in female methamphetamine users enrolled in compulsory detoxification. AB - BACKGROUND: Methamphetamine (METH) use, especially in females, has become a growing public health concern in China. In this study, we aimed to characterize the factors that contributed to drug craving in female METH users under isolated compulsory detoxification. We characterized factors contributing to craving such as duration of detoxification, history of drug use and self-reported mood state. METHODS: Subjects (N=113) undergoing a 1- to 3-year METH detoxification program were recruited from the Zhejiang Compulsory Detoxification Center for Women. The Questionnaire of METH-use Urge (QMU) was used to evaluate the level of craving for METH. The Abbreviate Profile of Mood States (A-POMS) was applied as an assessment for the negative mood disturbances. RESULTS: The participants were at a mean age of 25.2, primarily lowly educated and unemployed, and single. Smoking was the only route of METH administration at an average dose of 0.5 g/day, and 4 times/week. The reported craving level was positively correlated with the negative mood disturbances and the weekly dose of METH, but independent of the duration of detoxification. Furthermore, all five aspects of negative mood disturbances, including fatigue, bewilderment, anxiety, depression and hostility, were shown to positively correlate to the self-reported craving level after controlling for weekly dose of METH. CONCLUSIONS: The data demonstrate a robust correlation between mood distress and craving for METH. Our results call for close evaluation of mood distress in treatment of METH users in China. PMID- 23110821 TI - Inertial sensor motion analysis of gait, sit-stand transfers and step-up transfers: differentiating knee patients from healthy controls. AB - Patients undergoing total knee replacement for end stage knee osteoarthritis (OA) become increasingly younger and more demanding. Consequently, outcome assessment tools need to evolve toward objective performance-based measures. We applied a novel approach toward ambulatory biomechanical assessment of physical function using a single inertial sensor located at the pelvis to derive various motion parameters during activities of daily living. We investigated the potential of a clinically feasible battery of tests to define relevant parameters of physical function. We compared preoperative measures of end stage knee OA patients to healthy subjects. Our results show that measures of time yield the highest discriminative capacity to differentiate between groups. Additionally we found disease-dependent and task-specific alterations of movement for inertial sensor derived motion parameters with good discriminative capacity. The inertial sensor's output quantities seem to capture another clinically relevant dimension of physical function that is supplementary to time. This study demonstrates the potential of inertial sensor-based motion analysis and provides a standardized test feasible for a routine clinical application in the longitudinal follow-up. PMID- 23110822 TI - Immunological programming by breast milk creates an anti-inflammatory cytokine milieu in breast-fed infants compared to formula-fed infants. AB - Breast milk provides important maturational stimuli to an infant's developing immune system. However, data concerning the role of breast-feeding in reducing the risk of allergic disease remain contradictory. Previous studies have centred on comparative analyses of breast milk and formula compositions. We chose a slightly different angle, whereby we focused on the effects of the chosen diet on the infant himself, comparing the immune development of formula-fed and breast fed children. The objective of the present study was to determine how the mode of feeding affects infant immunology. Altogether, eighteen formula-fed infants with limited breast-feeding for ,3 months and twenty-nine infants who were exclusively breast-fed for .3 months were included in the study. Concentrations of interferon g, TNF-a IL-10, IL-5, IL-4 and IL-2 were measured simultaneously from the same serum sample through use of a multiplexed flow cytometric assay at the ages of 1, 3, 6 and 12 months. Transforming growth factor beta2 (TGF-beta2) was measured using ELISA at the same time points. Serum TNF-a and IL-2 concentrations were significantly higher in formula-fed than in breast-fed infants during the first year of life (ANOVA, P=0.002). The serum concentrations of TGF-b were significantly lower in formula-fed than in breast-fed infants throughout the first year of life (ANOVA, P<=0.0001). Exclusive breast-feeding promotes an anti inflammatory cytokine milieu, which is maintained throughout infancy. Such an immunological environment limits hyper-responsiveness and promotes tolerisation, possibly prohibiting the onset of allergic disease. PMID- 23110823 TI - Altered Wnt signalling in the teenage suicide brain: focus on glycogen synthase kinase-3beta and beta-catenin. AB - Glycogen synthase kinase (GSK)-3beta and beta-catenin are important components of the Wnt signalling pathway, which is involved in numerous physiological functions such as cognition, brain development and cell survival. Their abnormalities have been implicated in mood disorders and schizophrenia. Teenage suicide is a major public health concern; however, very little is known about its neurobiology. In order to examine if abnormalities of GSK-3beta and beta-catenin are associated with teenage suicide, we determined the gene and protein expression of GSK-3beta and beta-catenin in the prefrontal cortex (PFC) and hippocampus obtained from 24 teenage suicide victims and 24 normal control subjects. Protein expression was determined using Western blot with specific antibodies and gene expression (mRNA levels) was determined using the real-time polymerase chain reaction method. No significant change was observed in the GSK-3beta protein levels either in the PFC or hippocampus of suicide victims compared to controls. However, protein levels of pGSK-3beta-ser(9) were significantly decreased in the PFC and hippocampus of suicide victims compared to normal controls. We also found that GSK-3beta mRNA levels were significantly decreased in the PFC but not in the hippocampus of teenage suicide victims compared to controls. Mean protein and mRNA levels of beta-catenin were significantly decreased in both the PFC and hippocampus of teenage suicide group compared to controls. The observation that there is a decrease in beta-catenin and pGSK-3beta-ser(9) in the PFC and hippocampus of teenage suicide victims does indicate a disturbance in the Wnt signalling pathway in teenage suicide. PMID- 23110825 TI - Persistent fever, neck swelling, and small vessel vasculitis following tonsillectomy in a patient with Behcet's disease: a case report. AB - INTRODUCTION: Behcet's disease commonly presents with recurrent oral and genital mucocutaneous ulcerations, uveitis and various skin manifestations. Other clinical symptoms include gastrointestinal ulcerations, arthritis, venous thrombosis, arterial aneurysms and central nervous system affection. Vasculitis underlies most clinical symptoms of Behcet's disease. CASE PRESENTATION: We report the case of a 62-year-old European Caucasian woman with Behcet's disease who presented with persistent fever and neck soft-tissue swelling, despite broad antibiotic treatment, two weeks after acute tonsillitis and a tonsillectomy. Diffuse epi- and mesopharyngeal swelling shown on a computed tomography scan of her neck and persistently elevated serum markers of inflammation initially prompted suspicion of an infectious etiology. Magnet resonance imaging of her neck and a neck tissue biopsy finally confirmed small vessel vasculitis involving skin, subcutaneous tissue and muscle. Considering the clinical presentation, past medical history and histological findings, we interpreted our patient's symptoms as a flare of Behcet's disease. Immunosuppressive treatment led to rapid clinical improvement. CONCLUSION: A patient with Behcet's disease developed small vessel vasculitis of the soft tissue of her neck after tonsillitis and a tonsillectomy. Infection and surgery probably triggered a flare of Behcet's disease. PMID- 23110826 TI - [Paracetamol: a promising ancestor]. AB - More than a century after its discovery, paracetamol remains the most widely used analgesic around the world. Despite elderly, its beneficial effects (analgesic, antipyretic), its undesirable effects and its toxicity are an inexhaustible source of publications. Indeed, mechanisms underlying these actions are unclear. A better understanding of its analgesic mechanism of action will highlight molecular(s) target(s) involved in its effect. This will allow the design of more efficient analgesics with equal safety than paracetamol. Several systems appear to be involved: the serotoninergic system and the prostaglandin one. Two other endogenous systems presently need to be added: the cannabinoidergic and vanilloidergic systems. Recent studies reveal a new vision of paracetamol: a pro drug which needs to be bio-transformed to exert its analgesic effect. These new data forebode that paracetamol did not finish surprising us. PMID- 23110827 TI - [In Process Citation]. PMID- 23110824 TI - Harnessing the power of metabolism for seizure prevention: focus on dietary treatments. AB - The continued occurrence of refractory seizures in at least one-third of children and adults with epilepsy, despite the availability of almost 15 conventional and novel anticonvulsant drugs, speaks to a dire need to develop novel therapeutic approaches. Cellular metabolism, the critical pathway by which cells access and utilize energy, is essential for normal neuronal function. Furthermore, mounting evidence suggests direct links between energy metabolism and cellular excitability. The high-fat, low-carbohydrate ketogenic diet has been used as a treatment for drug-refractory epilepsy for almost a century. Yet, the multitude of alternative therapies to target aspects of cellular metabolism and hyperexcitability is almost untapped. Approaches discussed in this review offer a wide diversity of therapeutic targets that might be exploited by investigators in the search for safer and more effective epilepsy treatments. PMID- 23110828 TI - Conflicts of interests in the area of healthcare products and technology. Current state of affairs and recommendations. AB - The handling of conflicts of interest in the area of healthcare products and technology has become a major issue for all of those involved in healthcare. Round Table N degrees 4 at the Giens Workshops 2011 has put forward concrete proposals to clarify and optimise the handling of conflicts of interest. Conflicts of interest cannot be defined by the individuals consulted or applying for funds since each institution, whether public or private, that puts out a call for projects or that requests advice, analyses or expert testimony in the healthcare field has different degrees of what it defines as a conflict of interest, depending on the context of the proposal or specific request that it puts out. In contrast, each individual has ties of personal interest that can and must be openly disclosed. The ties are much more diverse than what is commonly found in the conflict of interest statements of large institutions operating in the healthcare field and are not limited to financial and operational ties between companies and individuals. In addition, the statements are difficult to manage because of their sheer number. The Round Table recommends that each individual should openly disclose all of his or her ties of personal interest in a Single Statement of Ties of personal Interest (SSTI). The SSTI would be updated regularly and accessible on line. Each institution could then determine whether or not the reported ties represent a conflict in the context of the mission proposed. Each institution could publish in advance the conditions that would give rise to a conflict and, in this way, an individual could refrain from applying for the mission. Other practical approaches to handling conflicts of interest were put forward. PMID- 23110829 TI - [In Process Citation]. PMID- 23110830 TI - [In Process Citation]. PMID- 23110831 TI - Clinical evaluation of medical devices: main constraints and specificities. AB - The purpose of the Giens round table no. 1 was to make proposals and recommendations regarding the clinical evaluation of medical devices. First, the European and French regulatory rules were examined and compared with the US FDA approach. Thereafter, the main specificities and constraints of the MD sector were underlined and their impact in clinical evaluation described and analyzed. Two areas, cumulating most of these constraints, were consecutively analyzed for concrete case study. Considering a patient-centered approach, the RT issued eight recommendations directed to manufacturers, physicians and policymakers in order to improve clinical evaluation in the medical device field. PMID- 23110832 TI - [In Process Citation]. PMID- 23110833 TI - Monoclonal Antibodies for Therapeutic Use: Specific Characteristics of Clinical Development, Evaluation by the Agencies, and Long-term Monitoring of Safety. AB - Monoclonal antibodies (MoAb) are very different from other drugs. The Round Table aimed to determine whether the specific characteristics of MoAb have repercussions on their clinical development, evaluation by the health authorities, and long-term monitoring. As regards the structure-activity relationship of MoAb, classification according to mechanism of action (neutralising or agonist MoAb, cytolytic MoAb) is more relevant than to their degree of humanisation. Recommendations on their clinical development would be useful since the early phases give rise to a number of problems and are insufficiently codified. The pharmacokinetic profile is very different from that of other drugs. The concentration-effect relationship is difficult to study since the biomarkers may be apparently disconnected from the therapeutic effect. The methodology for evaluation of MoAb by the agencies, and postmarketing surveillance do not differ from the procedures used for other drugs; however, MoAb bring together a number of specific characteristics as compared with other drugs. PMID- 23110834 TI - [In Process Citation]. PMID- 23110835 TI - Personalized Medicine: how to Switch from the Concept to the Integration into the Clinical Development Plan to Obtain Marketing Authorization. AB - One of the challenges of the coming years is to personalize medicine in order to provide each patient with an individualized treatment plan. The three objectives of personalized medicine are to refine diagnosis, rationalize treatment and engage patients in a preventive approach. Personalization can be characterized by various descriptors whether related to the field, biology, imaging, type of lesion of the entity to be treated, comorbidity factors, coprescriptions or the environment As part of personalized medicine focused on biological markers including genetics or genomics, the integration of the clinical development plan to obtain marketing authorization may be segmented in 3 stages with a known descriptor identified before clinical development, a known descriptor discovered during clinical development or a known descriptor known after clinical development. For each stage, it is important to clearly define the technical optimization elements, to specify the expectations and objectives, to examine the methodological aspects of each clinical development phase and finally to consider the fast changing regulatory requirements in view of the few registered therapeutics complying with the definition of personalized medicine as well as the significant technological breakthroughs according to the screened and selected biomarkers. These considerations should be integrated in view of the time required for clinical development from early phase to MA, i.e. more than 10 years. Moreover, business models related to the economic environment should be taken into account when deciding whether or not to retain a biomarker allowing the selection of target populations in a general population. PMID- 23110836 TI - [In Process Citation]. PMID- 23110837 TI - Contribution of modeling approaches and virtual populations in transposing the results of clinical trials into real life and in enlightening public health decisions. AB - Modeling consists in aggregating separate pieces of knowledge, according to a given structure and rules. It allows studying the behavior of more or less complex systems by simulation techniques. Modeling is used in different state-of the-art technological domains (meteorology, aeronautics). Its use has grown for the evaluation of medicines and medical devices, from conception to prescription (marketing authorization, reimbursement, price setting and re-registrations). It follows a scientific approach and is the object of good practice recommendations. Coupling models to virtual populations allows obtaining realistic results at the population level, testing diagnostic or therapeutic strategies, as well as estimating the consequences of transposing the results of clinical trials to the population. Through examples, the participants of the Round Table analyzed the contributions of the coupling of models and realistic virtual populations, and proposed guidelines for their judicious and systematic use. PMID- 23110838 TI - [Not Available]. AB - A cohort is a group of individuals sharing some characteristics, followed longitudinally. Essential tools of epidemiology, these studies provide pieces of evidence of the relationship between an exposition and outcomes in order to guide public health policies. In France, many cohorts have been conducted over the past few years. Sometimes, initiated by independent research teams (e.g. E3N) but more often, either requested by health authorities in a global public health plan (e.g. MEMENTO in the Alzheimer plan) or conducted to investigate a safety issue (e.g. France Coag). Besides, post authorization studies often consist in prospective cohorts. Because of objectives, designs and governance arrangements diversity; participants questioned whether it was interesting for researchers, regulators and industrials to use this epidemiological tool. Some findings about difficulties met in cohorts' establishment have been shared by each other. In order to make cohorts more efficient, participants have made some recommendations. PMID- 23110839 TI - [Therapeutic drug monitoring of primidone and phenobarbital]. AB - Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended". PMID- 23110840 TI - [Therapeutic drug monitoring of ethosuximide]. AB - Ethosuximide is a minor antiepileptic drug, available in France since 1965, indicated in the epilepsy absence, whose interest was reassessed from recent clinical trials, showing that it was the first choice, in term of risk benefit relationship, in this indication. It is a chiral molecule that presents a high bioavailability, a lack of protein binding, hepatic metabolism and urinary excretion. Its elimination half-life is long, between 40 and 60 h in adults, 30 and 40 h in children. The therapeutic range is established at 40-100 mg/L (283 708 umol/L), but the upper limit is probably underestimated. The clinical studies of relation exposure effects, although ancient (from the 1970s) and realized with methodologies that do not meet current criteria, show concentration-efficacy and toxicity relationship and the risk of drug interactions is proven. It is a drug preponderantly prescribed in children, a vulnerable population with physiological change with age. To benefit at best of its effectiveness, it is necessary to have relatively high plasma concentrations. Despite these arguments and due to the lack of studies providing a sufficient level of evidence, the recommendation can only be "potentially useful", assessment probably underestimated. PMID- 23110841 TI - [General Practitioners' Contribution to Dependence Assessment: the OPEMA Programme]. AB - Aim. This study presents the OPEMA (Observation des pharmacodependances en medecine ambulatoire) programme and the main results of its last annual survey (november 2010). Method. Collected data concern mainly subjects' sociodemographic situation, their state of health and their current consumption of psychoactive substance. Results. In 2010, 1394 subjects have been included, describing 2 450 consumptions of psychoactive susbtance. Their mean age is 38,2+/-12,7 years. Eighty-six per cent have a stable accomodation and 52% are in employment. Fifty six percent of included subjects present a psychiatric comorbidity. Among included subjects, HIV and HVC prevalence is respectively 3% and 20%. Fourty-five percent of included subjects have been using intraveinous route, 6% of whom using it currently. Eighty-two percent consume opiate maintenance treatment and 29% benzodiazepines. Conclusion. The OPEMA programme supplement the french pharmacodependence assessment system with collecting data from general practitioners, and promotes a global knowledge of dependent subjects' state of health. PMID- 23110842 TI - [Lidocaine-induced Neurotoxicity in a Newborn: a Case Report]. PMID- 23110843 TI - Evidence for natural recombination between mink enteritis virus and canine parvovirus. AB - A virus was isolated from mink showing clinical and pathological signs of enteritis in China. This virus, designated MEV/LN-10, was identified as mink enteritis virus (MEV) based on its cytopathic effect in the feline F81 cell line, the hemagglutination (HA) and hemagglutination inhibition (HI) assay, electron microscopy (EM) and animal infection experiments. The complete viral genome was cloned and sequenced. Phylogenetic and recombination analyses on the complete MEV/LN-10 genome showed evidence of recombination between MEV and canine parvovirus (CPV). The genome was composed of the NS1 gene originating from CPV while the VP1 gene was of MEV origin. This is the first demonstration of recombination between a CPV and MEV in nature. Our findings not only provide valuable evidence indicating that recombination is an important genetic mechanism contributing to the variation and evolution of MEV, but also that heterogeneous recombination can occur in the feline parvovirus subspecies. PMID- 23110845 TI - First principles calculation on the adsorption of water on lithium montmorillonite (Li-MMT). AB - The interaction of water molecules and lithium-montmorillonite (Li-MMT) is theoretically investigated using density functional theory (DFT) based first principles calculation. The mechanism of water adsorption at two different water concentrations on Li-MMT as well as their structural and electronic properties are investigated. It is found that the adsorption stability in Li-MMT is higher in higher water concentration. It is also found that an adsorbed water molecule on Li-MMT causes the Li to protrude from the MMT surface, so it is expected that Li may be mobile on H(2)O/Li-MMT. PMID- 23110846 TI - Wetting layer evolution and its temperature dependence during self-assembly of InAs/GaAs quantum dots. AB - For InAs/GaAs(001) quantum dot (QD) system, the wetting layer (WL) evolution and its temperature dependence were studied using reflectance difference spectroscopy and were analyzed with a rate equation model. WL thicknesses showed a monotonic increase at relatively low growth temperatures but showed an initial increase and then decrease at higher temperatures, which were unexpected from a thermodynamic understanding. By adopting a rate equation model, the temperature dependence of QD formation rate was assigned as the origin of different WL evolutions. A brief discussion on the indium desorption was given. Those results gave hints of the kinetic aspects of QD self-assembly. PMID- 23110847 TI - Device-based monitoring in physical activity and public health research. AB - Measurement of physical activity is important, given the vital role of this behavior in physical and mental health. Over the past quarter of a century, the use of small, non-invasive, wearable monitors to assess physical activity has become commonplace. This review is divided into three sections. In the first section, a brief history of physical activity monitoring is provided, along with a discussion of the strengths and weaknesses of different devices. In the second section, recent applications of physical activity monitoring in physical activity and public health research are discussed. Wearable monitors are being used to conduct surveillance, and to determine the extent and distribution of physical activity and sedentary behaviors in populations around the world. They have been used to help clarify the dose-response relation between physical activity and health. Wearable monitors that provide feedback to users have also been used in longitudinal interventions to motivate research participants and to assess their compliance with program goals. In the third section, future directions for research in physical activity monitoring are discussed. It is likely that new developments in wearable monitors will lead to greater accuracy and improved ease of-use. PMID- 23110844 TI - Vldlr overexpression causes hyperactivity in rats. AB - BACKGROUND: Reelin regulates neuronal positioning in cortical brain structures and neuronal migration via binding to the lipoprotein receptors Vldlr and Lrp8. Reeler mutant mice display severe brain morphological defects and behavioral abnormalities. Several reports have implicated reelin signaling in the etiology of neurodevelopmental and psychiatric disorders, including autism, schizophrenia, bipolar disorder, and depression. Moreover, it has been reported that VLDLR mRNA levels are increased in the post-mortem brain of autistic patients. METHODS: We generated transgenic (Tg) rats overexpressing Vldlr, and examined their histological and behavioral features. RESULTS: Spontaneous locomotor activity was significantly increased in Tg rats, without detectable changes in brain histology. Additionally, Tg rats tended to show performance deficits in the radial maze task, suggesting that their spatial working memory was slightly impaired. Thus, Vldlr levels may be involved in determining locomotor activity and memory function. CONCLUSIONS: Unlike reeler mice, patients with neurodevelopmental or psychiatric disorders do not show striking neuroanatomical aberrations. Therefore, it is notable, from a clinical point of view, that we observed behavioral phenotypes in Vldlr-Tg rats in the absence of neuroanatomical abnormalities. PMID- 23110849 TI - Prospective evaluation of direct approach with a tablet device as a strategy to enhance survey study participant response rate. AB - BACKGROUND: Investigators conduct survey studies for a variety of reasons. Poor participant response rates are common, however, and may limit the generalizability and utility of results. The objective of this study was to determine whether direct approach with a tablet device enhances survey study participant response rate and to assess participants' experiences with this mode of survey administration. FINDINGS: An interventional study nested within a single center survey study was conducted at McMaster Children's Hospital. The primary outcome was the ability to achieve of a survey study response rate of 70% or greater. Eligible participants received 3 email invitations (Week 0, 2, 4) to complete a web-based (Survey Monkey) survey. The study protocol included plans for a two-week follow-up phase (Phase 2) where non-responders were approached by a research assistant and invited to complete an iPad-based version of the survey. The Phase 1 response rate was 48.7% (56/115). Phase 2 effectively recruited reluctant responders, increasing the overall response rate to 72.2% (83/115). On a 7-point Likert scale, reluctant responders highly rated their enjoyment (mean 6.0, sd 0.83 [95% CI: 5.7-6.3]) and ease of use (mean 6.7, sd 0.47 [95% CI: 6.5 6.9]) completing the survey using the iPad. Reasons endorsed for Phase 2 participation included: direct approach (81%), immediate survey access (62%), and the novelty of completing a tablet-based survey (54%). Most reluctant responders (89%) indicated that a tablet-based survey is their preferred method of survey completion. CONCLUSIONS: Use of a tablet-based version of the survey was effective in recruiting reluctant responders and this group reported positive experiences with this mode of survey administration. PMID- 23110850 TI - Comparison of catechin profiles in human plasma and urine after single dosing and regular intake of green tea (Camellia sinensis). AB - Green tea (Camellia sinensis) catechin profiles in plasma and urine following single dosing and regular ingestion of green tea are not clear. We performed a placebo-controlled intervention study with sixteen healthy volunteers to determine changes in total and free catechins after a single dose and following 1 week of twice-daily green tea. Blood and urine samples were collected before (fasting) and after (60 and 120 min for blood; 90 and 180 min for urine) drinking 200 ml of 1.5% (w/v) green tea or water (n 8 each), and fasting samples were again collected after 7 d of 150 ml of 1% (w/v) supplemental green tea or water twice daily. After a 4-week washout, subjects were crossed onto the other treatment and procedures repeated. Plasma results at 1 h post-ingestion showed elevated (P < 0.05) mean epigallocatechin gallate (EGCG; 310 (SD 117) nmol/l; all in free form), epigallocatechin (EGC; 192 (SD 67) nmol/l; 30% free) and epicatechin gallate (ECG; 134 (SD 51) nmol/l; 75% free). Fasting plasma after 7 d of regular intake showed increased (P < 0.05) EGCG (80 v. 15 nmol/l at baseline) and ECG (120 v. 40 nmol/l), with > or =90% of both in their conjugated forms. Total EGC was < 10 nmol/l. Post-ingestion conjugation and renal loss of EGC and epicatechin were rapid and high, but were negligible for EGCG and ECG. In the green tea consumed, the content was EGCG > EGC > ECG, and the acute plasma response mirrored this. However, after chronic consumption there was almost no EGC found in fasting plasma, some EGCG was present, but a rather high level of ECG was maintained. PMID- 23110848 TI - Human pigmentation genes under environmental selection. AB - Genome-wide association studies and comparative genomics have established major loci and specific polymorphisms affecting human skin, hair and eye color. Environmental changes have had an impact on selected pigmentation genes as populations have expanded into different regions of the globe. PMID- 23110851 TI - Tooth periodontal ligament: Direct 3D microCT visualization of the collagen network and how the network changes when the tooth is loaded. AB - The periodontal ligament (PDL), a soft tissue connecting the tooth and the bone, is essential for tooth movement, bone remodeling and force dissipation. A collagenous network that connects the tooth root surface to the alveolar jaw bone is one of the major components of the PDL. The organization of the collagenous component and how it changes under load is still poorly understood. Here using a state-of-the-art custom-made loading apparatus and a humidified environment inside a microCT, we visualize the PDL collagenous network of a fresh rat molar in 3D at 1 MUm voxel size without any fixation or contrasting agents. We demonstrate that the PDL collagen network is organized in sheets. The spaces between sheets vary thus creating dense and sparse networks. Upon vertical loading, the sheets in both networks are stretched into well aligned arrays. The sparse network is located mainly in areas which undergo compressive loading as the tooth moves towards the bone, whereas the dense network functions mostly in tension as the tooth moves further from the bone. This new visualization method can be used to study other non-mineralized or partially mineralized tissues, and in particular those that are subjected to mechanical loads. The method will also be valuable for characterizing diseased tissues, as well as better understanding the phenotypic expressions of genetic mutants. PMID- 23110853 TI - Structural characterization of a D-isomer specific 2-hydroxyacid dehydrogenase from Lactobacillus delbrueckii ssp. bulgaricus. AB - Hydroxyacid dehydrogenases, responsible for the stereospecific conversion of 2 keto acids to 2-hydroxyacids in lactic acid producing bacteria, have a range of biotechnology applications including antibiotic synthesis, flavor development in dairy products and the production of valuable synthons. The genome of Lactobacillus delbrueckii ssp. bulgaricus, a member of the heterogeneous group of lactic acid bacteria, encodes multiple hydroxyacid dehydrogenases whose structural and functional properties remain poorly characterized. Here, we report the apo and coenzyme NAD+ complexed crystal structures of the L. bulgaricusD isomer specific 2-hydroxyacid dehydrogenase, D2-HDH. Comparison with closely related members of the NAD-dependent dehydrogenase family reveals that whilst the D2-HDH core fold is structurally conserved, the substrate-binding site has a number of non-canonical features that may influence substrate selection and thus dictate the physiological function of the enzyme. PMID- 23110854 TI - Implantable cardioverter defibrillator shocks are prospective predictors of anxiety. AB - OBJECTIVES: To examine the temporal contingency of anxiety and implantable cardioverter defibrillator (ICD) therapy (anti-tachycardia-pacing and shocks to prevent ventricular tachycardia and/or fibrillation). BACKGROUND: It is under debate whether anxiety is a precursor and/or consequence of ICD-therapy. METHODS: In a prospective longitudinal study, fifty-four patients undergoing first-time ICD-implantation were assessed for anxiety, frequency of ICD-shocks and anti tachycardia-pacing up to two days before ICD-implantation (T0) and twelve months later (T1). RESULTS: Anxiety at T0 did not predict frequency of ICD-shocks at T1, but ICD-shocks significantly predicted increased anxiety at T1. In contrast, anxiety at T0 and T1 was unrelated to frequency of anti-tachycardia-pacing. Effects remained stable when we controlled for potentially confounding variables (e.g. age, sex, cardiac health and depression at T0). CONCLUSION: Our findings indicate that repeated ICD-shocks are a cause of anxiety in ICD-patients rather than a consequence, thus shock frequency should be minimized. PMID- 23110852 TI - A collaborative framework for 3D alignment and classification of heterogeneous subvolumes in cryo-electron tomography. AB - The limitation of using low electron doses in non-destructive cryo-electron tomography of biological specimens can be partially offset via averaging of aligned and structurally homogeneous subsets present in tomograms. This type of sub-volume averaging is especially challenging when multiple species are present. Here, we tackle the problem of conformational separation and alignment with a "collaborative" approach designed to reduce the effect of the "curse of dimensionality" encountered in standard pair-wise comparisons. Our new approach is based on using the nuclear norm as a collaborative similarity measure for alignment of sub-volumes, and by exploiting the presence of symmetry early in the processing. We provide a strict validation of this method by analyzing mixtures of intact simian immunodeficiency viruses SIV mac239 and SIV CP-MAC. Electron microscopic images of these two virus preparations are indistinguishable except for subtle differences in conformation of the envelope glycoproteins displayed on the surface of each virus particle. By using the nuclear norm-based, collaborative alignment method presented here, we demonstrate that the genetic identity of each virus particle present in the mixture can be assigned based solely on the structural information derived from single envelope glycoproteins displayed on the virus surface. PMID- 23110856 TI - Probing the influences of urea on the interaction of sinomenine with human serum albumin by steady-state fluorescence. AB - The binding of sinomenine to human serum albumin (HSA) in aqueous solution in the absence and presence of urea has been studied by fluorescence and the three dimensional (3D) fluorescence at pH 7.40. Subdomain IIA binding site of human serum albumin (HSA) was characterized by examining the change in HSA fluorescence. The quenching rate constants and binding constants were calculated in the absence and presence of the denaturant. The results point to a static quenching mechanism operating in the complexes. However, the binding ability of sinomenine to denatured HSA is weaker than that of sinomenine to native HSA. Denaturation of HSA in the presence of urea is almost complete at [urea]>= 8.0M. Upon unfolding, two fluorescence peaks were observed. One peak was assigned to the fluorescence of Trp-214 residue in a polar environment, and the other peak was assigned to the fluorescence of tyrosine residues. Compared to the free HSA, the HSA-sinomenine complex is more stable in the presence of urea. PMID- 23110855 TI - Reduced LTP and LTD in prefrontal cortex synapses in the nucleus accumbens after heroin self-administration. AB - Addiction changes prefrontal cortex regulation of the nucleus accumbens, including reduced ability to induce long-term potentiation (LTP) and long-term depression (LTD). This important potential mechanism of impaired prefrontal regulation of behaviour has been shown only for cocaine. Here we show that animals trained to self-administer heroin demonstrate impaired LTP and LTD in the core of the nucleus accumbens following in vivo stimulation of the prelimbic prefrontal cortex. These data indicate that compromised synaptic plasticity in prefrontal to accumbens projections is a common feature of at least two distinct classes of addictive drug. PMID- 23110857 TI - Implementing nutrition guidelines for older people in residential care homes: a qualitative study using Normalization Process Theory. AB - BACKGROUND: Optimizing the dietary intake of older people can prevent nutritional deficiencies and diet-related diseases, thereby improving quality of life. However, there is evidence that the nutritional intake of older people living in care homes is suboptimal, with high levels of saturated fat, salt, and added sugars. The UK Food Standards Agency therefore developed nutrient- and food-based guidance for residential care homes. The acceptability of these guidelines and their feasibility in practice is unknown. This study used the Normalization Process Theory (NPT) to understand the barriers and facilitators to implementing the guidelines and inform future implementation. METHODS: We conducted a process evaluation in five care homes in the north of England using qualitative methods (observation and interviews) to explore the views of managers, care staff, catering staff, and domestic staff. Data were analyzed thematically and discussed in data workshops; emerging themes were then mapped to the constructs of NPT. RESULTS: Many staff perceived the guidelines as unnecessarily restrictive and irrelevant to older people. In terms of NPT, the guidelines simply did not make sense (coherence), and as a result, relatively few staff invested in the guidelines (cognitive participation). Even where staff supported the guidelines, implementation was hampered by a lack of nutritional knowledge and institutional support (collective action). Finally, the absence of observable benefits to clients confirmed the negative preconceptions of many staff, with limited evidence of reappraisal following implementation (reflexive monitoring). CONCLUSIONS: The successful implementation of the nutrition guidelines requires that the fundamental issues relating to their perceived value and fit with other priorities and goals be addressed. Specialist support is needed to equip staff with the technical knowledge and skills required for menu analysis and development and to devise ways of evaluating the outcomes of modified menus. NPT proved useful in conceptualizing barriers to implementation; robust links with behavior-change theories would further increase the practical utility of NPT. PMID- 23110858 TI - Toxoplasma gondii: effects of exogenous nitric oxide on egress of tachyzoites from infected macrophages. AB - Toxoplasma gondii is an obligate intracellular parasite that can infect any nucleated cells of warm-blood vertebrates. Invasion and egress by this protozoan parasite, both of which are crucial for its life cycle, are rapid events that are dependent upon parasite motility. A variety of chemicals and molecules have been utilized to induce Toxoplasma early egress from host cells. Here, we aimed to determine whether nitric oxide (NO) could induce egress of T. gondii tachyzoites from infected cells. Infected macrophages were collected from C57BL/6 mice and treated with different doses of sodium nitroferricyanide (III) dihydrate (SNP) which releases nitric oxide into cell culture medium. The pattern of parasite egress was analyzed by flow cytometry. The results showed that exogenous NO released by SNP could trigger egress of T. gondii tachyzoites from infected peritoneal macrophages which then underwent necrosis after parasite egress. Our findings provided a novel approach to study the interactions between host immune responses and T. gondii. PMID- 23110859 TI - Oxysterol-induced soluble endoglin release and its involvement in hypertension. AB - BACKGROUND: Ischemia in the placenta is considered the base of the pathogenesis of preeclampsia, a pregnancy-specific syndrome in which soluble endoglin (sEng) is a prognostic marker and plays a pathogenic role. Here, we investigated the effects of hypoxia and the downstream pathways in the release of sEng. METHODS AND RESULTS: Under hypoxic conditions, the trophoblast-like cell line JAR showed an increase in sEng parallel to an elevated formation of reactive oxygen species. Because reactive oxygen species are related to the formation of oxysterols, we assessed the effect of 22-(R)-hydroxycholesterol, a natural ligand of the liver X receptor (LXR), and the LXR synthetic agonist T0901317. Treatment of JAR cells or human placental explants with 22-(R)-hydroxycholesterol or T0901317 resulted in a clear increase in sEng that was dependent on LXR. These LXR agonists induced an increased matrix metalloproteinase-14 expression and activity and a significant reduction of its endogenous inhibitor, tissue inhibitor of metalloproteinase-3. In addition, mice treated with LXR agonists underwent an increase in the plasma sEng levels, concomitant with an increase in arterial pressure. Moreover, transgenic mice overexpressing sEng displayed high blood pressure. Finally, administration of an endoglin peptide containing the consensus matrix metalloproteinase-14 cleavage site G-L prevented the oxysterol-dependent increase in arterial pressure and sEng levels in mice. CONCLUSIONS: These studies provide a clue to the involvement of the LXR pathway in sEng release and its pathogenic role in vascular disorders such as preeclampsia. PMID- 23110860 TI - Cardiovascular events as a function of serum bilirubin levels in a large, statin treated cohort. AB - BACKGROUND: Serum bilirubin is an endogenous antioxidant that is routinely measured before a statin is prescribed primarily to assess liver function, but the association with cardiovascular disease (CVD) in this population has not been explored. METHOD AND RESULTS: We identified patients from a United Kingdom primary care database (The Health Improvement Network) with measurements of serum total bilirubin levels recorded 3 months before the first statin treatment between January 1, 2000, and December 31, 2010, and no history of liver disease or CVD. In total, 130 052 patients met the inclusion criteria, and after a median follow-up of 43 months, there were 7850 CVD events. In men, the incidence of CVD in the lowest decile category of bilirubin (1-6 MUmol/L [0.06-0.35 mg/dL]) was 215 per 10 000 person-years compared with 163 per 10 000 person-years in the highest decile (19-40 MUmol/L [1.1-2.3 mg/dL]). Similar differences were seen for women. After conventional CVD risk factors were accounted for, the associations with bilirubin were nonlinear (L shaped), and the models predicted that, compared with patients with a bilirubin level of 10 MUmol/L (0.6 mg/dL), those with a similar CVD risk profile but a bilirubin level of 5 MUmol/L (0.3 mg/dL) had an 18% (95% confidence interval, 9-27) higher risk of any CVD event, a 34% (95% confidence interval, 13-56) higher risk of myocardial infarction, and a 33% (95% confidence interval, 21-46) higher risk of death resulting from any cause. CONCLUSIONS: Serum bilirubin level measured before a statin prescription to assess liver function is an independent risk factor for CVD and death in both men and women. PMID- 23110861 TI - Bilirubin, the gold within. PMID- 23110862 TI - Central trigeminocardiac reflex in pediatric neurosurgery: a case report and review of the literature. AB - INTRODUCTION: Trigeminocardiac reflex is a well-known phenomenon in neurosurgery, craniofacial surgery, ophthalmology and interventional neuroradiology. Even though the trigeminocardiac reflex has become an important factor in skull base surgery and neurosurgery, the central form of trigeminocardiac reflex has only been described in adult subpopulations until now. CASE PRESENTATION: We present a clear form of repetitive trigeminocardiac reflex expressed during revision surgery of a giant (110*61mm) right temporoparietal meningioma in an 18-month-old male Caucasian patient. After cessation of the surgical stimulus, his heart rate and mean arterial blood pressure returned to normal physiological levels. The further follow-up was uneventful. CONCLUSION: Our case demonstrates that the central trigeminocardiac reflex also exists in pediatric patients, especially if manipulating trigeminal innervated structures or around the nerve itself. Whether the incidence and the behavior of the trigeminocardiac reflex is similar in pediatric neurosurgery compared with adult patients has to be shown in further studies. PMID- 23110863 TI - Systematic review of the body of evidence for the use of biomarkers in the diagnosis of dementia. AB - BACKGROUND: Although recent diagnostic criteria for Alzheimer's disease propose the use of biomarkers, validation of these biomarkers by diagnostic test accuracy studies is a necessary first step, followed by the synthesis of the evidence from these studies in systematic reviews and meta-analyses. The quality of the resulting evidence depends on the number and size of the primary studies, their quality, and the adequacy of their reporting. This systematic review assesses the weight and quality of the evidence available from primary diagnostic test accuracy studies. METHODS: A MEDLINE search was performed in August 2011 to identify all potentially relevant publications relating to the biomarkers beta amyloid, tau, positron emission tomography ((18)F-fluorodeoxyglucose or ligands for amyloid), or magnetic resonance imaging (MRI). The reporting and methodology were assessed using the Standards for Reporting of Diagnostic Accuracy and Quality Assessment of Diagnostic Accuracy Studies assessment tools, respectively. Because clinical progression to dementia is the most commonly used reference standard, this review focuses on participants with objective cognitive impairment but no dementia at baseline. RESULTS: Of the 19,104 published references identified by the search, 142 longitudinal studies relating to the biomarkers of interest were identified, which included subjects who had objective cognitive impairment but no dementia at baseline. The highest number of studies (n = 70) and of participants (n = 4722) related to structural MRI. MRI also yielded the highest number of studies with extractable data for meta-analysis (n = 32 [46% of all structural MRI studies]), followed by cerebrospinal fluid tau (n = 24 [73%]). There were few studies on positron emission tomography ligands for amyloid having suitable data for meta-analysis (n = 4). There was considerable variation across studies in reporting outcomes, methods of blinding and selection, means of accounting for indeterminate or missing values, the interval between the test and assessments, and the determination of test thresholds. CONCLUSIONS: The body of evidence for biomarkers is not large and is variable across the different types of biomarkers. Important information is missing from many study reports, highlighting the need for standardization of methodology and reporting to improve the rigor of biomarker validation. PMID- 23110864 TI - Benefits of combined cholinesterase inhibitor and memantine treatment in moderate severe Alzheimer's disease. AB - BACKGROUND: Clinical studies and post hoc analyses have investigated the use of combination therapy for the treatment of Alzheimer's disease (AD). We review the evidence for the short- and long-term efficacy of combination therapy in AD. METHODS: The review is based on a search of the PubMed database to identify relevant articles concerning combination treatment with memantine and cholinesterase inhibitors (ChEIs). RESULTS: In patients with moderate-to-severe AD, combination treatment with the N-methyl-d-aspartate receptor antagonist memantine and the ChEI donepezil has produced significant benefits in cognition, function, behavior, global outcome, and care dependency, compared with donepezil treatment alone. Data from long-term observational studies support these findings. Compared with ChEI monotherapy, combination treatment slowed cognitive and functional decline (a 4-year sustained effect that appeared to increase over time) and reduced the risk of nursing home admission. Preclinically, the combination of N-methyl-d-aspartate receptor modulation and acetylcholinesterase inhibition has been shown to act synergistically, which may explain the observed clinical effects of combination treatment. CONCLUSION: Treatment with memantine/ChEI combination therapy in moderate-to-severe AD produces consistent benefits that appear to increase over time, and that are beyond those of ChEI treatment alone. PMID- 23110866 TI - Mild cognitive impairment in a community sample: the Sydney Memory and Ageing Study. AB - BACKGROUND: Mild cognitive impairment (MCI) is associated with an increased dementia risk. This study reports incidence of MCI subtypes, rates of progression to dementia, and stability of MCI classification. METHODS: We examined 873 community-dwelling adults aged 70 to 90 years over 2 years as part of an ongoing population-based longitudinal study, the Sydney Memory and Ageing Study. Neuropsychological testing assessed five cognitive domains, and a diagnosis of no cognitive impairment, MCI, or dementia (follow-up only) was made according to published criteria. RESULTS: The incidence of MCI was 104.6 (95% confidence interval: 81.6-127.7) per 1000 person-years, with higher incidence in men (men, 156.8; women, 70.3). Incidence rates for single-domain amnestic, multiple-domain amnestic, single-domain nonamnestic, and multiple-domain nonamnestic MCI were 47.7, 7.9, 45.0, and 3.9 per 1000 person-years, respectively. The 2-year rate of progression from MCI at baseline to dementia was 4.8%, being highest for multidomain amnestic MCI (9.1%). Of those with MCI at baseline, 28.2% reverted to no cognitive impairment at follow-up. Sensitivity analyses by redefining criteria for cognitive impairment did not affect stability of diagnosis, although changing the threshold of domain impairment reduced baseline MCI prevalence from 36.7% to 5.7% and incidence to 23.5, and increased 2-year progression rate from MCI to dementia to 14.3%. CONCLUSIONS: Incidence rates for MCI are higher than previously reported, particularly in men and for single-domain MCI; rates for amnestic and nonamnestic MCI were comparable. Multidomain amnestic MCI was the most likely subtype to progress to dementia, but overall, the diagnosis of MCI, particularly single-domain MCI, shows considerable instability. PMID- 23110867 TI - Discriminatory and predictive capabilities of enzyme-linked immunosorbent assay and multiplex platforms in a longitudinal Alzheimer's disease study. AB - BACKGROUND: Multiplex assays such as xMAP have been proposed for the assessment of Alzheimer's disease (AD) biomarkers amyloid beta 42 (Abeta42), tau (Tau), and phosphorylated tau (pTau) in cerebrospinal fluid (CSF). Here, we compared the traditional enzyme-linked immunosorbent assay (ELISA) and xMAP with respect to their: (1) absolute biomarker concentration, (2) ability to distinguish AD from nondemented subjects, (3) ability to monitor AD longitudinally, and (4) ability to predict progression from mild cognitive impairment (MCI) to AD. METHODS: We selected 68 AD, 62 MCI, and 24 nondemented subjects, performed clinical examinations, and obtained CSF at baseline and 2 years later. Abeta42, Tau, and pTau were measured with both ELISA and xMAP. RESULTS: Biomarker levels differed considerably between the two assays, and the differences were concentration dependent. No differences were observed in ability to distinguish nondemented subjects from AD patients between ELISA (area under curve of 0.84 for Abeta42, 0.79 for Tau, and 0.75 for pTau) and xMAP (area under curve of 0.82 for Abeta42, 0.75 for Tau, and 0.73 for pTau), all P < .05. Increased Abeta42 levels of AD patients at follow-up compared with baseline were detected with ELISA, whereas increased Tau levels for nondemented subjects and MCI patients were only detected with xMAP. The hazard ratios for progression from MCI to AD did not differ between the assays. CONCLUSION: Both ELISA and multiplex assays can be used to measure AD biomarker levels in CSF to support clinical diagnosis and predict progression from MCI to AD with similar accuracy. Importantly, the assays' output in absolute biomarker concentrations is remarkably different, and this discrepancy cannot be reconciled with simple correction factors. PMID- 23110868 TI - The influence of insulin infusion on the metabolism of amyloid beta peptides in plasma. AB - BACKGROUND: Accumulating body of evidence suggests pathophysiologic links between Alzheimer's disease and diabetes mellitus (DM). For example, the two crucial peptides playing a role in both degenerative disorders, amyloid beta (Abeta) and insulin, are metabolized by the same enzyme, insulin degrading enzyme. Euglycemic hyperinsulinemic clamp is a method of estimating insulin sensitivity, based on the assumption that during steady-state hyperinsulinemic euglycemia, glucose infusion rate equals tissue glucose uptake, that is, the higher the glucose infusion rate, the higher the insulin sensitivity. OBJECTIVE: The aim of this study was to analyze the influence of insulin on the plasma concentrations of Abeta peptides. METHODS: Blood samples were collected from 20 healthy young male volunteers before insulin infusion (clamp) and then at 120 and 360 minutes. In the second protocol, insulin was accompanied by Intralipid, which is mainly a mixture of triacylglycerols, and heparin, given as an activator of lipoprotein lipase, inducing insulin resistance. Analyses of plasma Abeta1-42, Abetax-42, Abeta1-40, and Abetax-40 were performed with multiplexing technology. Furthermore, concentrations of the Abeta peptides in healthy persons were compared with those in 16 type 1 DM patients receiving chronic insulin therapy. RESULTS: When applied alone (i.e., without Intralipid), insulin infusion increased concentrations of Abeta42 (full length and N-terminally shortened) but not of Abeta40. When combined with Intralipid, infusion of insulin resulted in increased concentrations of all peptides (nonsignificant tendency in case of Abetax-40). We did not observe differences between Abeta peptide concentrations in healthy subjects and those in type 1 DM patients. CONCLUSION: Infusion of insulin in nonphysiologic high doses increases plasma concentrations of Abeta peptides; in case of Abeta40, only when applied together with Intralipid, which perhaps might be explained by hypothetical shift of insulin degrading enzyme activity from degradation of Abeta peptides to the degradation of insulin. PMID- 23110869 TI - Surface adsorption and micelle formation of imidazolium-based zwitterionic surface active ionic liquids in aqueous solution. AB - A novel class of zwitterionic surface active ionic liquids (SAILs), N-alkyl-N' carboxymethyl imidazolium inner salts ([N-C(n), N'-CO(2)-Im], n=10, 12, 14), was synthesized. Their aggregation behavior in aqueous solution was investigated by surface tension, isothermal titration calorimetry, and steady-state fluorescence. Compared with the reported imidazolium-based cationic SAILs, 1-alkyl-3 methylimidazolium bromide ([C(n)mim]Br) and zwitterionic betaine surfactants, (C(n)H(2)(n)(+1)N(CH(3))(2)CH(2)COO(-)), [N-C(n), N'-CO(2)-Im] exhibits significantly lower critical micelle concentration (cmc) and surface tension at cmc (gamma(cmc)) values. It is attributed to the incorporation of a deprotonated carboxylic group into the head group, which weakens the electrostatic repulsion between head groups and favors micellization. The micellar aggregation number of [N-C(n), N'-CO(2)-Im] is larger than that of [C(n)mim]Br, while less than that of C(n)H(2)(n)(+1)N(CH(3))(2)CH(2)COO(-). Similar to the traditional zwitterionic surfactants, the surface activity and adsorption properties of [N-C(12), N'-CO(2) Im] at air/water interface have a slight variation with temperature, pH, and ionic strength. This indicates that the present zwitterionic SAILs display the aggregation behavior much similar to zwitterionic surfactants, distinctly different from imidazolium-based cationic SAILs. Sets in low sensitivity to the environmental conditions, superior surface activity and unique physicochemical properties of ionic liquids, [N-C(n), N'-CO(2)-Im] can be exploited for utilizing as a potential substitute for conventional surfactants in certain fields. PMID- 23110870 TI - Distribution of cooperative unit size of amphiphilic molecules in the phase coexistence region in Langmuir monolayers. AB - The dependence of the size of the cooperative unit (C.U.) of amphiphilic molecules on surface pressure (pi) in the liquid expanded (LE)-liquid condensed (LC) phase coexistence region of Langmuir monolayers has been formulated and calculated using measured isotherm data. The C.U. size changes largely depending on the surface pressure in the coexistence region: these submicroscopic molecular aggregates are not static objects, but dynamic ones characterized by large fluctuations in size. It has been found that the C.U. size distribution can be a natural consequence of the significant change of monolayer compressibility, which reflects large molecular area density fluctuations, in the coexistence region. PMID- 23110871 TI - Coagulation by multivalent counterions and the Schulze-Hardy rule. AB - Starting from a number of empirical papers by Matijevic et al., the issue of coagulation of hydrophobic colloids by multivalent inorganic counterions is revisited. More recent information is also considered, and some important trends are confirmed and made more quantitative. It can be concluded that the high coagulating power of multivalent ions is mostly not a direct result of their high valence but caused by their propensity of building complexes with water that adsorb specifically. This mechanism requires a revision of the Schulze-Hardy rule interpretations. In addition, this finding helps to define conditions where overcharging by multivalent counterions can be attributed to ion correlations. PMID- 23110865 TI - Standardization of analysis sets for reporting results from ADNI MRI data. AB - The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1 weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12 month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2 year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly. PMID- 23110872 TI - Comparisons of the iron deficient metabolic response in rats fed either an AIN-76 or AIN-93 based diet. AB - BACKGROUND: Previous studies examining the metabolic consequences of dietary iron deficiency have reported elevated serum glucose concentrations in iron deficient animals. Importantly, the majority of these findings were observed using an earlier version of a laboratory animal diet (AIN-76A) in which the primary carbohydrate source was sucrose - a disaccharide known to negatively impact both glucose and lipid homeostasis. The AIN-76A diet formula was improved in 1993 (AIN-93) to optimize animal nutrition with a major change being the substitution of cornstarch for sucrose. Therefore, we sought to examine the effects of iron deficiency on steady-state glucose homeostasis and the hepatic expression of glucose- and lipid-related genes in rats fed an iron-deficient diet based on either an AIN-76A or AIN-93 diet. METHODS: The study design consisted of 6 treatment groups: control (C; 40 mg Fe/kg diet), iron deficient (ID; <= 3 mg Fe/kg diet), or pair-fed (PF; 40 mg Fe/kg) fed either an AIN-76A or AIN-93 diet for 21 d. Hemoglobin and hematocrit were measured in whole blood. Serum insulin and cortisol were measure by ELISA. Serum glucose and triacylglycerols were measured by standard colorimetric enzyme assays. Alterations in hepatic gene expression were determined by real-time qPCR. RESULTS: Hemoglobin and hematocrit were significantly reduced in both ID groups compared to the C and PF groups. Similarly, animals in the both ID groups exhibited elevated steady-state levels of blood glucose and insulin, and significantly decreased levels of circulating cortisol compared to their respective PF controls. Serum triacyglycerols were only increased in ID animals consuming the AIN-76A diet. Hepatic gene expression analyses revealed a ~4- and 3-fold increase in the expression of glucokinase and pyruvate dehydrogenase kinase-4 mRNA, respectively, in the ID group on either diet compared to their respective PF counterparts. In contrast, the expression of lipogenic genes was significantly elevated in the AIN-76 ID group, while expression of these genes was unaffected by iron status in the AIN-93 ID group. CONCLUSIONS: These results indicate that an impaired iron status is sufficient to alter glucose homeostasis, though alterations in lipid metabolism associated with ID are only observed in animals receiving the AIN-76A diet. PMID- 23110873 TI - Event-based analysis of free-living behaviour. AB - The quantification of free-living physical activities is important in understanding how physical activity and sedentary behaviour impact on health and also on how interventions might modify free-living behaviour to enhance health. Quantification, and the terminology used, has in many ways been determined by the choice of measurement technique. The inter-related issues around measurement devices and terminology used are explored. This paper proposes a terminology and a systematic approach for the analysis of free-living activity information using event-based activity data. The event-based approach uses a flexible hierarchical classification of events and, dependent on the research question, analysis can then be undertaken on a selection of these events. The quantification of free living behaviour is therefore the result of the analysis on the patterns of these chosen events. The application of this approach is illustrated with results from a range of published studies by our group showing how event-based analysis provides a flexible yet robust method of addressing the research question(s) and provides a deeper insight into free-living behaviour. It is proposed that it is through event-based analysis we can more clearly understand how behaviour is related to health and also how we can produce more relevant outcome measures. PMID- 23110874 TI - Dependence of the NaCl/Au(111) interface state on the thickness of the NaCl layer. AB - We investigated the growth and the electronic properties of crystalline NaCl layers on Au(111) surfaces by means of cryogenic scanning tunneling microscopy and spectroscopy under ultra-high vacuum conditions. Deposition of NaCl on Au(111) at room temperature yields bilayer NaCl islands, which can be transformed into trilayer NaCl islands by post-annealing. Upon NaCl adsorption, the Au(111) Shockley surface state becomes an interface state (IS) at the NaCl/Au(111) interface. Using Fourier-transform images of maps of the local density of states, the energy versus wave vector dispersions of the IS and the Au(111) bulk states are determined. The dispersion of both states is found to depend strongly on the thickness of the adsorbed NaCl layer. PMID- 23110875 TI - Morphological evolution of Ge/Si(001) quantum dot rings formed at the rim of wet etched pits. AB - We demonstrate the formation of Ge quantum dots in ring-like arrangements around predefined {111}-faceted pits in the Si(001) substrate. We report on the complex morphological evolution of the single quantum dots contributing to the rings by means of atomic force microscopy and demonstrate that by careful adjustment of the epitaxial growth parameters, such rings containing densely squeezed islands can be grown with large spatial distances of up to 5 MUm without additional nucleation of randomly distributed quantum dots between the rings. PMID- 23110876 TI - Aldosterone and the mineralocorticoid receptor in the cerebral circulation and stroke. AB - Ischemic stroke is a leading cause of morbidity and mortality worldwide. Elevated plasma aldosterone levels are an independent cardiovascular risk factor and are thought to contribute to hypertension, a major risk factor for stroke. Evidence from both experimental and human studies supports a role for aldosterone and/or the mineralocorticoid receptor (MR) in contributing to detrimental effects in the cerebral vasculature and to the incidence and outcome of ischemic stroke. This article reviews the evidence, including the protective effects of MR antagonism. Specifically, the effects of aldosterone and/or MR activation on cerebral vascular structure and on immune cells will be reviewed. The existing evidence suggests that aldosterone and the MR contribute to cerebral vascular pathology and to the incidence and outcome of stroke. We suggest that further research into the signaling mechanisms underlying the effects of aldosterone and MR activation in the brain and its vasculature, especially with regard to cell specific actions, will provide important insight into causes and potential treatments for cerebrovascular disease and stroke. PMID- 23110877 TI - Does body mass index affect the outcome of unicompartmental knee replacement? AB - BACKGROUND: Obesity is considered to be a contraindication for unicompartmental knee replacement (UKR). The aim was to study the impact of BMI on failure rate and clinical outcome of the Oxford mobile bearing UKR. METHOD: Two thousand four hundred and thirty-eight medial Oxford UKRs were studied prospectively and divided into groups: BMI<25 (n=378), BMI 25 to <30 (n=856), BMI 30 to <35 (n=712), BMI 35 to <40 (n=286), and BMI 40 to <45 (n=126) and BMI>=45 (n=80). RESULTS: There was no significant difference in survival rate between groups. At a mean follow-up of 5years (range 1-12years) there was no significant difference in the Objective American Knee Society Score between groups. There was a significant (p<0.01) trend with the Oxford Knee Score (OKS) and Functional American Knee Society Scores decreasing with increasing BMI. As there was an opposite trend (p<0.01) in pre-operative OKS, the change in OKS increased with increasing BMI (p=0.048). The mean age at surgery was significantly (p<0.01) lower in patients with higher BMI. CONCLUSIONS: Increasing BMI was not associated with an increasing failure rate. It was also not associated with a decreasing benefit from the operation. Therefore, a high BMI should not be considered a contra-indication to mobile bearing UKR. LEVEL OF EVIDENCE: IV. PMID- 23110879 TI - Connective field modeling. AB - The traditional way to study the properties of visual neurons is to measure their responses to visually presented stimuli. A second way to understand visual neurons is to characterize their responses in terms of activity elsewhere in the brain. Understanding the relationships between responses in distinct locations in the visual system is essential to clarify this network of cortical signaling pathways. Here, we describe and validate connective field modeling, a model-based analysis for estimating the dependence between signals in distinct cortical regions using functional magnetic resonance imaging (fMRI). Just as the receptive field of a visual neuron predicts its response as a function of stimulus position, the connective field of a neuron predicts its response as a function of activity in another part of the brain. Connective field modeling opens up a wide range of research opportunities to study information processing in the visual system and other topographically organized cortices. PMID- 23110881 TI - Crossmodal bias of visual input on pain perception and pain-induced beta activity. AB - In our environment, acute pain is often accompanied by input from other sensory modalities, like visual stimuli, which can facilitate pain processing. To date, it is not well understood how these inputs influence the perception and processing of pain. Previous studies on integrative processing between sensory modalities other than pain have shown that multisensory response gains are strongest when the constituent unimodal stimuli are minimally effective in evoking responses. This finding has been termed the principle of inverse effectiveness (IE). In this high-density electroencephalography study, we investigated the influence of Gabor patches of low and high contrast levels on the perception and processing of spatially and temporally aligned painful electrical stimuli of low and high intensities. Subjective pain ratings, event related potentials (ERPs) and oscillatory responses served as dependent measures. In line with the principle of IE, stronger crossmodal biasing effects of visual input on subjective pain ratings were found for low compared to high intensity painful stimuli. This effect was paralleled by stronger bimodal interactions in right-central ERPs (150-200ms) for low compared to high intensity pain stimuli. Moreover, an enhanced suppression of medio-central beta-band activity (12-24Hz, 200-400ms) was found for low compared to high intensity pain stimuli. Our findings possibly reflect a facilitation of stimulus processing that serves to enhance response readiness of the sensorimotor system following painful stimulation. Taken together, our study demonstrates that multisensory processing between visual and painful stimuli follows the principle of IE and suggests a role for beta-band oscillations in the crossmodal modulation of pain. PMID- 23110880 TI - Measuring relative timings of brain activities using fMRI. AB - Functional MRI (fMRI) has previously been shown to be able to measure hundreds of milliseconds differences in timings of activities in different brain regions, even though the underlying blood oxygenation level-dependent (BOLD) response is delayed and dispersed on the order of seconds. This capability may contribute towards the study of communication within the brain by assessing the temporal sequences of various brain processes (mental chronometry). The practical limit of fMRI for detecting the relative timing of brain activity is not known. We aimed to detect fine differences in the timings of brain activities beyond those previously measured from fMRI data in human subjects. We introduced known delays between the onsets of visual stimuli in a controlled, sparse event-related design and investigated if the temporal shifts in the corresponding average BOLD signals were detectable. To maximize sensitivity, we used high spatial and temporal resolution fMRI at ultrahigh field (7 T), in conjunction with a novel data-driven technique for voxel selection using graph-based visualizations of self-organizing maps and Granger causality to measure relative timing. This approach detected timing differences as small as 28ms in visual cortex in individual subjects. For signal extraction, the self-organizing map approach outperformed other common techniques including independent component analysis, voxelwise univariate linear regression analysis and a separate localizer scan. For relative timing measurement, Granger causality outperformed time-to-peak calculations derived from an inverse logit curve fit. We conclude that high-resolution imaging at ultrahigh field, signal extraction via self-organizing map, and appropriate use of Granger causality permit the detection of small timing differences in fMRI data, despite the intrinsically slow hemodynamic response. PMID- 23110878 TI - Individual differences in amygdala reactivity following nicotinic receptor stimulation in abstinent smokers. AB - Hyperactive amygdala functioning may underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent ~17days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics. PMID- 23110883 TI - BootGraph: probabilistic fiber tractography using bootstrap algorithms and graph theory. AB - Bootstrap methods have recently been introduced to diffusion-weighted magnetic resonance imaging to estimate the measurement uncertainty of ensuing diffusion parameters directly from the acquired data without the necessity to assume a noise model. These methods have been previously combined with deterministic streamline tractography algorithms to allow for the assessment of connection probabilities in the human brain. Thereby, the local noise induced disturbance in the diffusion data is accumulated additively due to the incremental progression of streamline tractography algorithms. Graph based approaches have been proposed to overcome this drawback of streamline techniques. For this reason, the bootstrap method is in the present work incorporated into a graph setup to derive a new probabilistic fiber tractography method, called BootGraph. The acquired data set is thereby converted into a weighted, undirected graph by defining a vertex in each voxel and edges between adjacent vertices. By means of the cone of uncertainty, which is derived using the wild bootstrap, a weight is thereafter assigned to each edge. Two path finding algorithms are subsequently applied to derive connection probabilities. While the first algorithm is based on the shortest path approach, the second algorithm takes all existing paths between two vertices into consideration. Tracking results are compared to an established algorithm based on the bootstrap method in combination with streamline fiber tractography and to another graph based algorithm. The BootGraph shows a very good performance in crossing situations with respect to false negatives and permits incorporating additional constraints, such as a curvature threshold. By inheriting the advantages of the bootstrap method and graph theory, the BootGraph method provides a computationally efficient and flexible probabilistic tractography setup to compute connection probability maps and virtual fiber pathways without the drawbacks of streamline tractography algorithms or the assumption of a noise distribution. Moreover, the BootGraph can be applied to common DTI data sets without further modifications and shows a high repeatability. Thus, it is very well suited for longitudinal studies and meta studies based on DTI. PMID- 23110882 TI - fMRI reveals reciprocal inhibition between social and physical cognitive domains. AB - Two lines of evidence indicate that there exists a reciprocal inhibitory relationship between opposed brain networks. First, most attention-demanding cognitive tasks activate a stereotypical set of brain areas, known as the task positive network and simultaneously deactivate a different set of brain regions, commonly referred to as the task negative or default mode network. Second, functional connectivity analyses show that these same opposed networks are anti correlated in the resting state. We hypothesize that these reciprocally inhibitory effects reflect two incompatible cognitive modes, each of which may be directed towards understanding the external world. Thus, engaging one mode activates one set of regions and suppresses activity in the other. We test this hypothesis by identifying two types of problem-solving task which, on the basis of prior work, have been consistently associated with the task positive and task negative regions: tasks requiring social cognition, i.e., reasoning about the mental states of other persons, and tasks requiring physical cognition, i.e., reasoning about the causal/mechanical properties of inanimate objects. Social and mechanical reasoning tasks were presented to neurologically normal participants during fMRI. Each task type was presented using both text and video clips. Regardless of presentation modality, we observed clear evidence of reciprocal suppression: social tasks deactivated regions associated with mechanical reasoning and mechanical tasks deactivated regions associated with social reasoning. These findings are not explained by self-referential processes, task engagement, mental simulation, mental time travel or external vs. internal attention, all factors previously hypothesized to explain default mode network activity. Analyses of resting state data revealed a close match between the regions our tasks identified as reciprocally inhibitory and regions of maximal anti-correlation in the resting state. These results indicate the reciprocal inhibition is not attributable to constraints inherent in the tasks, but is neural in origin. Hence, there is a physiological constraint on our ability to simultaneously engage two distinct cognitive modes. Further work is needed to more precisely characterize these opposing cognitive domains. PMID- 23110884 TI - The effects of elevated endogenous GABA levels on movement-related network oscillations. AB - The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation-inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15-30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta ERD) and movement-related gamma synchronisation (MRGS) (60-90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated. PMID- 23110885 TI - Fear bradycardia and activation of the human periaqueductal grey. AB - Animal models of predator defense distinguish qualitatively different behavioral modes that are activated at increasing levels of predation threat. A defense mode observed at intermediate threat levels is freezing: a cessation of locomotion that is characterized by a parasympathetically dominated autonomic nervous system response that causes heart rate deceleration, or fear bradycardia. Studies in rodents have shown that freezing depends on amygdalar projections to the periaqueductal grey (PAG). In humans, freezing-like behaviors are implicated in development and maintenance of psychopathology, but neural mechanisms underlying freezing or its characteristic autonomic response profile have not been identified. Here, we combined event-related blood oxygenation level-dependent functional MRI (BOLD-fMRI) with autonomic response measures in a picture viewing paradigm to probe activity and interconnectivity within the amygdala-PAG pathway and test for an association with parasympathetic as opposed to sympathetic activation. In response to negatively arousing pictures, we observed parasympathetic (bradycardia) and sympathetic (pupil dilation) autonomic responses, BOLD responses in the amygdala and PAG, and effective connectivity between these regions. Critically, BOLD responses in the PAG to negative pictures correlated on a trial-by-trial basis with bradycardia but not pupil dilation. This correlation with bradycardia remained significant when partialling out pupil dilation. Additionally, activity in regions associated with motor planning and inhibition mirrored the PAG response. Thus, our findings implicate the human PAG in a parasympathetically dominated defense mode that subserves a state of attentive immobility. Mechanistic insight into this qualitatively distinct defense mode may importantly advance translational models of anxiety disorders. PMID- 23110887 TI - Segmentation of magnetization transfer ratio lesions for longitudinal analysis of demyelination and remyelination in multiple sclerosis. AB - We demonstrate a new technique to quantify longitudinal changes in magnetization transfer ratio (MTR) magnetic resonance imaging (MRI). These changes are indicative of demyelination and remyelination. This technique comprises a definition of DeltaMTR lesions, which are identified directly from the MTR images, and an automatic procedure for segmenting these lesions. We used this technique to analyze MTR changes in lesions of subjects with rapidly progressing multiple sclerosis before and after treatment with immunoablation and autologous stem cell transplant. Subjects who experienced clinical improvement after treatment showed significantly improved MTR recovery in lesions that were recovering during treatment (p<0.0001) while those who were clinically stable after treatment showed significantly poorer MTR recovery (p=0.002). The statistical power of this technique to detect treatment effects on MTR recovery was shown to be considerably better than previous methods. These results suggest that longitudinal measurements of MTR in DeltaMTR lesions may be an important technique for the assessment of treatment effects on remyelination in clinical trials. PMID- 23110886 TI - Spatial smoothing systematically biases the localization of reward-related brain activity. AB - Neuroimaging methods with enhanced spatial resolution such as functional magnetic resonance imaging (FMRI) suggest that the subcortical striatum plays a critical role in human reward processing. Analysis of FMRI data requires several preprocessing steps, some of which entail tradeoffs. For instance, while spatial smoothing can enhance statistical power, it may also bias localization towards regions that contain more gray than white matter. In a meta-analysis and reanalysis of an existing dataset, we sought to determine whether spatial smoothing could systematically bias the spatial localization of foci related to reward anticipation in the nucleus accumbens (NAcc). An activation likelihood estimate (ALE) meta-analysis revealed that peak ventral striatal ALE foci for studies that used smaller spatial smoothing kernels (i.e. <6mm FWHM) were more anterior than those identified for studies that used larger kernels (i.e. >7mm FWHM). Additionally, subtraction analysis of findings for studies that used smaller versus larger smoothing kernels revealed a significant cluster of differential activity in the left relatively anterior NAcc (Talairach coordinates: -10, 9, -1). A second meta-analysis revealed that larger smoothing kernels were correlated with more posterior localizations of NAcc activation foci (p<0.015), but revealed no significant associations with other potentially relevant parameters (including voxel volume, magnet strength, and publication date). Finally, repeated analysis of a representative dataset processed at different smoothing kernels (i.e., 0-12mm) also indicated that smoothing systematically yielded more posterior activation foci in the NAcc (p<0.005). Taken together, these findings indicate that spatial smoothing can systematically bias the spatial localization of striatal activity. These findings have implications both for historical interpretation of past findings related to reward processing and for the analysis of future studies. PMID- 23110888 TI - The NTSR1 gene modulates the association between hippocampal structure and working memory performance. AB - The genetic and neural basis of working memory (WM) has been extensively studied. Many dopamine (DA) related genes, including the NTSR1 gene (a DA modulator gene), have been reported to be associated with WM performance. The NTSR1 protein is predominantly expressed in the cerebral cortex and the hippocampus, the latter of which is closely involved in WM processing based on both lesion and fMRI studies. Thus far, however, no study has examined the joint effects of NTSR1 gene polymorphism and hippocampal morphology on WM performance. Participants of the current study were 330 healthy Chinese college students. WM performance was measured with a 2-back WM paradigm. Structural MRI data were acquired and then analyzed using an automated procedure with atlas-based FreeSurfer segmentation software (v 4.5.0) package. Linear regression analyses were conducted with a NTSR1 C/T polymorphism which was previously reported to be associated with WM (rs4334545), hippocampal volume, and their interaction as predictors of WM performance, with gender and intracranial volume (ICV) as covariates. Results showed a significant interaction between NTSR1 genotype and hippocampal volume (p<.05 for both the left and right hippocampi). Further analysis showed that the correlation between hippocampal volume and WM scores was significant for carriers of the NTSR1 T-allele (p<.05 for both hippocampi), but not for CC homozygotes. These results indicate that the association between hippocampal structure and WM performance was modulated by variation in the NTSR1 gene, and suggest that further studies of brain-behavior associations should take genetic background information into account. PMID- 23110889 TI - Fast optical signal in visual cortex: Improving detection by General Linear Convolution Model. AB - In this study we applied the General Linear Convolution Model to fast optical signals (FOS). We modeled the Impulse Response Function (IRF) as a rectangular function lasting 30ms, with variable time delay with respect to the stimulus onset. Simulated data confirmed the feasibility of this approach and its capability of detecting simulated activations in case of very unfavorable Signal to Noise Ratio (SNR), providing better results than the grand average method. The model was tested in a cohort of 10 healthy volunteers who underwent to hemi-field visual stimulation. Experimental data quantified the IRF time delay at 80-100ms after the stimulus onset, in agreement with classical visual evoked potential literature and previous optical imaging studies based on grand average approach and a larger number of trails. FOS confirmed the expected contralateral activation in the occipital region. Correlational analysis between hemodynamic intensity signal, phase and intensity FOS supports diffusive rather than optical absorption changes associated with neuronal activity in the activated cortical volume. Our study provides a feasible method for detecting fast cortical activations by means of FOS. PMID- 23110890 TI - Cabergoline therapy for macroprolactinoma during pregnancy: a case report. AB - BACKGROUND: We assessed the safety of Cabergoline therapy during pregnancy in a lady with hyperprolactinemia intolerant to Bromocriptine. CASE PRESENTATION: We report the case of a 31 year old lady who presented to us with uncontrolled hyperprolactinemia. A pituitary Macroadenoma was demonstrated by MRI. Due to intolerance to Bromocriptine, Cabergoline was started. The patient improved and subsequently conceived. MRI in the second trimester demonstrated further reduction in the tumor size. It was decided to continue Cabergoline throughout pregnancy to ensure further reduction in tumor size until delivery and to hold Cabergoline during postpartum period to allow for an adequate interval of breastfeeding. At 37 weeks of gestation, the patient delivered a healthy baby. CONCLUSION: We were able to safely treat macroprolactinemia in our patient during pregnancy with cabergoline. This case report contributes to the relatively meager data available which advocates the safety of cabergoline therapy in pregnant hyperprolactinemic patients. PMID- 23110891 TI - O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a rare event in soft tissue sarcoma. AB - BACKGROUND: Gene silencing of O6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation improves the outcome of glioblastoma patients after combined therapy of alkylating chemotherapeutic agents and radiation. The purpose of this study was to assess the frequency of MGMT promoter methylation in soft tissue sarcoma to identify patients eligible for alkylating agent chemotherapy such as temozolomide. FINDINGS: Paraffin tumor blocks of 75 patients with representative STS subtypes were evaluated. The methylation status of the MGMT promoter was assessed by methylation-specific polymerase-chain-reaction analysis (PCR). Furthermore, immunohistochemistry was applied to verify expression of MGMT. MGMT gene silencing was assumed if MGMT promoter methylation was present and the fraction of tumor cells expressing MGMT was 20% or less. Methylation specific PCR detected methylated MGMT promoter in 10/75 cases. Immunohistochemical staining of nuclear MGMT was negative in 15/75 cases. 6/75 tumor samples showed MGMT promoter methylation and negative immunohistochemical nuclear staining of MGMT. In none of the tested STS subtypes we found a fraction of tumors with MGMT silencing exceeding 22%. CONCLUSION: MGMT gene silencing is a rare event in soft tissue sarcoma and cannot be recommended as a selection criterion for the therapy of STS patients with alkylating agents such as temozolomide. PMID- 23110893 TI - Circadian rhythms require proper RNA splicing. PMID- 23110892 TI - Systems analysis of plant functional, transcriptional, physical interaction, and metabolic networks. AB - Physiological responses, developmental programs, and cellular functions rely on complex networks of interactions at different levels and scales. Systems biology brings together high-throughput biochemical, genetic, and molecular approaches to generate omics data that can be analyzed and used in mathematical and computational models toward uncovering these networks on a global scale. Various approaches, including transcriptomics, proteomics, interactomics, and metabolomics, have been employed to obtain these data on the cellular, tissue, organ, and whole-plant level. We summarize progress on gene regulatory, cofunction, protein interaction, and metabolic networks. We also illustrate the main approaches that have been used to obtain these networks, with specific examples from Arabidopsis thaliana, and describe the pros and cons of each approach. PMID- 23110894 TI - Arabidopsis chloroplast RNA binding proteins CP31A and CP29A associate with large transcript pools and confer cold stress tolerance by influencing multiple chloroplast RNA processing steps. AB - Chloroplast RNA metabolism is mediated by a multitude of nuclear encoded factors, many of which are highly specific for individual RNA processing events. In addition, a family of chloroplast ribonucleoproteins (cpRNPs) has been suspected to regulate larger sets of chloroplast transcripts. This together with their propensity for posttranslational modifications in response to external cues suggested a potential role of cpRNPs in the signal-dependent coregulation of chloroplast genes. We show here on a transcriptome-wide scale that the Arabidopsis thaliana cpRNPs CP31A and CP29A (for 31 kD and 29 kD chloroplast protein, respectively), associate with large, overlapping sets of chloroplast transcripts. We demonstrate that both proteins are essential for resistance of chloroplast development to cold stress. They are required to guarantee transcript stability of numerous mRNAs at low temperatures and under these conditions also support specific processing steps. Fine mapping of cpRNP-RNA interactions in vivo suggests multiple points of contact between these proteins and their RNA ligands. For CP31A, we demonstrate an essential function in stabilizing sense and antisense transcripts that span the border of the small single copy region and the inverted repeat of the chloroplast genome. CP31A associates with the common 3'-terminus of these RNAs and protects them against 3'-exonucleolytic activity. PMID- 23110895 TI - Systems analysis of shoot apical meristem growth and development: integrating hormonal and mechanical signaling. AB - The shoot apical meristem (SAM) is a small population of stem cells that continuously generates organs and tissues. This review covers our current understanding of organ initiation by the SAM in Arabidopsis thaliana. Meristem function and maintenance involves two major hormones, cytokinins and auxins. Cytokinins appear to play a major role in meristem maintenance and in controlling meristematic properties, such as cell proliferation. Self-organizing transport processes, which are still only partially understood, lead to the patterned accumulation of auxin at particular positions, where organs will grow out. A major downstream target of auxin-mediated growth regulation is the cell wall, which is a determinant for both growth rates and growth distribution, but feedbacks with metabolism and the synthetic capacity of the cytoplasm are crucial as well. Recent work has also pointed at a potential role of mechanical signals in growth coordination, but the precise mechanisms at work remain to be elucidated. PMID- 23110896 TI - Modeling regulatory networks to understand plant development: small is beautiful. AB - We now have unprecedented capability to generate large data sets on the myriad genes and molecular players that regulate plant development. Networks of interactions between systems components can be derived from that data in various ways and can be used to develop mathematical models of various degrees of sophistication. Here, we discuss why, in many cases, it is productive to focus on small networks. We provide a brief and accessible introduction to relevant mathematical and computational approaches to model regulatory networks and discuss examples of small network models that have helped generate new insights into plant biology (where small is beautiful), such as in circadian rhythms, hormone signaling, and tissue patterning. We conclude by outlining some of the key technical and modeling challenges for the future. PMID- 23110897 TI - Multiscale systems analysis of root growth and development: modeling beyond the network and cellular scales. AB - Over recent decades, we have gained detailed knowledge of many processes involved in root growth and development. However, with this knowledge come increasing complexity and an increasing need for mechanistic modeling to understand how those individual processes interact. One major challenge is in relating genotypes to phenotypes, requiring us to move beyond the network and cellular scales, to use multiscale modeling to predict emergent dynamics at the tissue and organ levels. In this review, we highlight recent developments in multiscale modeling, illustrating how these are generating new mechanistic insights into the regulation of root growth and development. We consider how these models are motivating new biological data analysis and explore directions for future research. This modeling progress will be crucial as we move from a qualitative to an increasingly quantitative understanding of root biology, generating predictive tools that accelerate the development of improved crop varieties. PMID- 23110898 TI - The spectrum and frequency of self-inflicted and host gene mutations produced by the transposon Ac in maize. AB - The autonomous transposon Activator (Ac) is a powerful mutagen. Ac-induced mutations range from small footprints of host sequences to large rearrangements of transposon or host sequences. These mutations arise by different repair mechanisms of the double-strand break produced by Ac excision: footprints by nonhomologous end joining and rearrangements by various mechanisms, including DNA replication repair. Footprints greatly outnumber other mutations, masking them because they usually share a nonfunctional phenotype. To determine the spectrum and frequencies of host and self-mutations generated by Ac, we used an allele harboring Ac in the 5' untranslated region bronze (bz). In this system, simple excisions produce purple revertants, whereas deletions of host or transposon sequences produce stable bronze (bz-s) mutants. Internal and terminal deletions of Ac predominated among the 72 bz-s derivatives. Most internal deletions (52 of 54) behaved as nonautonomous Dissociation (Ds) elements. All nine terminal deletions or fractured Ac (fAc) elements had rearrangements of adjacent host sequences. Most Ds and fAc deletion junctions displayed microhomologies and contained filler DNA from nearby sequences, suggesting an origin by DNA repair synthesis followed by microhomology-mediated end joining. All mutations occurred more frequently in pollen, where one in 200 grains carried new Ds or fAc elements. PMID- 23110900 TI - In silico plant biology comes of age. PMID- 23110899 TI - Mutation of Arabidopsis spliceosomal timekeeper locus1 causes circadian clock defects. AB - The circadian clock plays a crucial role in coordinating plant metabolic and physiological functions with predictable environmental variables, such as dusk and dawn, while also modulating responses to biotic and abiotic challenges. Much of the initial characterization of the circadian system has focused on transcriptional initiation, but it is now apparent that considerable regulation is exerted after this key regulatory step. Transcript processing, protein stability, and cofactor availability have all been reported to influence circadian rhythms in a variety of species. We used a genetic screen to identify a mutation within a putative RNA binding protein (spliceosomal timekeeper locus1 [STIPL1]) that induces a long circadian period phenotype under constant conditions. STIPL1 is a homolog of the spliceosomal proteins TFP11 (Homo sapiens) and Ntr1p (Saccharomyces cerevisiae) involved in spliceosome disassembly. Analysis of general and alternative splicing using a high-resolution RT-PCR system revealed that mutation of this protein causes less efficient splicing of most but not all of the introns analyzed. In particular, the altered accumulation of circadian-associated transcripts may contribute to the observed mutant phenotype. Interestingly, mutation of a close homolog of STIPL1, STIP-LIKE2, does not cause a circadian phenotype, which suggests divergence in function between these family members. Our work highlights the importance of posttranscriptional control within the clock mechanism. PMID- 23110902 TI - Evaluation of a breast cancer nomogram for predicting the likelihood of additional nodal metastases in patients with a positive sentinel node biopsy. AB - AIM: Completion axillary lymph node dissection (CALND) performed as a standard procedure after a positive sentinel node biopsy (SLNB) in breast cancer patients results, in almost 40-70% of cases, in no additional positive nodes. A nomogram has been developed at Memorial Sloan Kettering Cancer Center (MSKCC) to predict the likelihood of nonsentinel node metastases (NSLNM) after a positive SLNB. Aim of study was to assess the accuracy of MSKCC nomogram in our community breast cancer population. MATERIAL OF STUDY: From a retrospective database of 276 breast cancer patients we evaluated 62 consecutive cases who underwent CALND after a positive SLNB. Patient and tumor characteristics were collected and the nomogram was used to calculate the probability of NSLNM. The accuracy of MSKCC nomogram was tested by the Receiver Operating Characteristic (ROC) curve. The Area Under the Curve (AUC), sensitivity and specificity were calculated for a 10% cut-off value. RESULTS: Presence of macrometastases (p=0.03) and its extranodal extension (p=0.013) in sentinel node were associated with NSLNM, while other tumor and patient characteristics were not. The accuracy of MSKCC nomogram as measured by AUC was 0.67. The nomogram showed 95% sensitivity and 14% specificity. We revised the nomogram by incorporating the presence of extranodal extension and we obtained a new test with improved specificity (84%). DISCUSSION: The modified predictive model is a useful tool in predicting the likelihood of NSLNM in our cohort of patients and may help decision regarding the need of completion axillary lymph node dissection. PMID- 23110901 TI - Conserved noncoding sequences highlight shared components of regulatory networks in dicotyledonous plants. AB - Conserved noncoding sequences (CNSs) in DNA are reliable pointers to regulatory elements controlling gene expression. Using a comparative genomics approach with four dicotyledonous plant species (Arabidopsis thaliana, papaya [Carica papaya], poplar [Populus trichocarpa], and grape [Vitis vinifera]), we detected hundreds of CNSs upstream of Arabidopsis genes. Distinct positioning, length, and enrichment for transcription factor binding sites suggest these CNSs play a functional role in transcriptional regulation. The enrichment of transcription factors within the set of genes associated with CNS is consistent with the hypothesis that together they form part of a conserved transcriptional network whose function is to regulate other transcription factors and control development. We identified a set of promoters where regulatory mechanisms are likely to be shared between the model organism Arabidopsis and other dicots, providing areas of focus for further research. PMID- 23110903 TI - Cephalic traumas with lacrimal apparatus involvement. Our experience. AB - PURPOSE: The involvement of the lacrimal ducts in the extreme cephalic trauma is an infrequent condition. A correct diagnosis and appropriate management of injuries of the lacrimal system are essential to prevent the onset of post traumatic epiphora. METHODS: In the last 5 years, 37 patients were treated for lacrimal apparatus injury as a result of cephalic trauma: in 16 there was an isolated lacrimal injury and in 21 were documented fractures combined with lacrimal damage. RESULTS: In 16 patients who had only deep lesions, was performed a reconstruction after location lesion localization, and only in 4 cases, because of the gravity of the lesion, it was decided to perform a reconstruction in a second time. In the remaining 21 patients the facial fractures were treated before lacrimal injuries, whose reconstruction was carried out on a second time. CONCLUSIONS: The reconstruction of the cephalic district has to be based on the restoration of morpho-functional component and on the identification and treatment of lacrimal injuries. The reduction of fractures in our view should start from the lateral area (centripetal reconstruction) allowing to have a guide for alignment of the fracture lines. The objectives to be achieved in a facial trauma are therefore three: the maintenance of vital functions, the recovery of the function and the restoration of morphological and functional prior to the event. PMID- 23110904 TI - Laparoscopic resection of hepatocellular carcinoma. Considerations on lesions in the posterosuperior segments of the liver. AB - AIM: The aim of this study was to evaluate retrospectively our results for laparoscopic liver resection (LLR) of hepatocellular carcinoma (HCC) including lesions in the posterosuperior segments of the liver in terms of feasibility, outcome, recurrence and survival. MATERIAL OF STUDY: Between June 2005 and May 2009, we performed 22 LLR for HCC. The underlying cirrhosis was staged as Child A in 19 cases and Child B in 3. RESULTS: LLR included a non anatomic resection in 15 cases and an anatomic resection in 7. A conversion to laparotomy occurred in one (4.5%) patient for hemorrhage. Mortality and morbidity rates were 0% and 18.1% (4/20). Over a mean follow-up period of 29 months (range: 19-65 months), 11 (50%) patients presented recurrence, mainly at distance from the surgical site. DISCUSSION: A laparoscopic approach is more suitable when the lesion is located in the peripheral "laparoscopic" segments 2 to 6. Nevertheless, six resections were made in the posterosuperior segments. Although parenchymal-sparing resection is required by the presence of underlying liver disease, anatomic resection has always to be considered and pursued to reduce local recurrence. In our series the recurrence rate was similar to those reported for other laparoscopic studies and for open resection of HCC. CONCLUSIONS: LLR for HCC in selected patients is a safe procedure with good short-term results. It can also be proposed in tumor locations with a difficult surgical access maintaining a low morbidity rate and good oncologic adequacy. This approach could have an impact on the therapeutic strategy of HCC complicating cirrhosis as a treatment with curative intent or as a bridge to liver transplantation. PMID- 23110905 TI - Endovascular treatment of abdominal aortic anastomotic pseudoaneurysm. The experience of two centers. AB - INTRODUCTION: Abdominal aortic pseudoaneurysms are a rare but serious complication of aortic surgery. Treatment with traditional open surgery is associated with a high rate of perioperative mortality and morbidity. Endovascular treatment is less invasive and guarantees lower mortality and morbidity rates. The aim of this study was to evaluate the role of short-, medium and long-term endovascular treatment of these pseudoaneurysms. MATERIALS AND METHODS: Over the past 10 years, 14 patients with abdominal aortic aneurysms, which developed after prior aortic surgery, underwent endovascular treatment involving implantation of an endoprosthesis at our institutions. Exclusion criteria were emergency treatment and suspicion of an infected prosthesis. A Cheatham-platinum covered stent mounted on a balloon catheter was implanted in one patient and self-expandable stent-graft in the other 13. No fenestrated or custom-made prostheses were used. RESULTS: The procedure had a 100% technical success rate. There was no postoperative mortality. Two type I endoleaks, observed at aortography at the end of the procedure, were not seen on the CT scan taken one month later. Three patients (21.4%) had major perioperative complications which consisted of early occlusion of a branch of the endoprosthesis, (treated with a femoro-femoral crossover bypass graft), a transient ischemic attack, and jaundice. The long-term mortality rate, at an average follow-up of 37.4 months, was 21.4%. None of the deaths was related to the procedure. CONCLUSIONS: Endovascular treatment of patients who develop anastomotic pseudoaneurysm after surgery of the abdominal aorta is safe and effective both in the short and long term. In our opinion it is the treatment of choice for this category of patients. PMID- 23110906 TI - Jaw angiosarcoma. First case, with massive intraosseous localization, described in Italian literature. AB - Angiosarcoma (AS) is a rare non-epithelial malignant neoplasm arising from neoplastic vascular degeneration of endothelial cells. It usually occurs in soft tissue and skin. The incidence, according to American authors, is 1% of all soft tissue sarcomas. About 50% of AS is localized in head and neck region (scalp and face skin) and represents less than 1% of all malignancies of this district; the primitive intra- oral localization is rare, even rarer intraosseous development of AS in jaw bones. The Authors report a case of a mandibular intraosseus angiosarcoma with different peculiarities: the rarity of the location and mode of occurrence; in addition they have focused on clinical-histopathological and immunohistochemical charateristics. PMID- 23110907 TI - Management of AAA and late Type II EL in a patient with concomitant renal cell carcinoma. Report of a case and review of the literature. AB - PURPOSE: Detection of cancer in patients with AAA complicates the treatment of both diseases. AAA associated with RN are rare, with an incidence of 0.1-3% representing a challenge in defining the surgical timing and approach. We discuss the rational for the treatment in patients with concomitant patologies. CASE REPORT: A 65 years-old man was diagnosed with both AAA and Renal Cell Carcinoma. The patient underwent first EVAR followed by renal embolization and Radical Nefrectomy. Three months later a Type II Endoleak was diagnosed and treated successfully. At 1 year follow-up the patient is disease free with complete exclusion of aneurysm sac. CONCLUSION: AAA can be successfully repaired in patients with renal neoplasm with great results, either simultaneously or in two stages. EVAR is a good alternative for such complex patients. PMID- 23110908 TI - Acute afferent loop obstruction treated by endoscopic decompression. Case report and review of literature. AB - Afferent loop syndrome (ALS) is a rare complication of Billroth-II gastrojejunostomy. Most cases of ALS are caused by obstruction from adhesions, kinking at the anastomosis, internal hernia, stomal stenosis, malignancy, or inflammation surrounding the anastomosis. A 61-years old man, who had undergone gastric resection 30 years before, was admitted at emergency room with severe abdominal pain in acute onset, nausea and vomiting. Ultrasonography and multi detector computed tomography suggested acute ALS, due probably to adhesions or internal hernia. The patient was conducted to digestive endoscopy unit and successfully treated with endoscopic decompression of dilated afferent loop. Open surgery is actually considered the gold-standard in treatment of ALS. However, some surgeons report a few cases treated by laparoscopic surgery, interventional radiology techniques, endoscopic decompression. Authors suggest endoscopic decompression of acute ALS due to adhesions or internal hernia as the first treatment, especially in high-surgical-risk patients. PMID- 23110909 TI - Giant submucosal lipoma cause colo-colonic intussusception. A case report and review of literature. AB - BACKGROUND: Lipoma of the large intestine is rare, with a reported incidence ranging between 0.2% and 4.4%. We present a case of a giant colonic lipoma causing descending-colonic intussusception. AIMS: A 54-year-old woman visited our emergency room with sudden onset of intermittent abdominal cramps. She was nauseous and had rectal blood loss for three days. Physical examination showed a tender palpable mass in the left lower abdominal quadrant. Rectal examination showed little blood on the glove. A CT scan demonstrated a clear intussusception of the descending-colonic (Fig. 1). Since the clinical presentation was that of an imminent ileus a laparotomy was performed. The intussusception was found in the descending coloni (Fig. 2), en-bloc resection with left hemicolectomy and was performed with end-to-end anastomosis. DISCUSSION: Lipomas of the gastrointestinal tract are rare conditions first described by Baurer in 1757. Lipomas in the intestinal tract are still relatively rare, however, being present in only 0.2% of a large autopsy series of 60 000 cases reported in 1955. In 90% of cases, lipoma of the colon are localized at submucous level. Submucosal lipomas are usually asymptomatic but may cause bleeding, obstruction, intussusception, or abdominal pain. Accurate preoperative diagnosis is difficult and lipoma is often mistaken for adenomatous polyp or carcinoma. CONCLUSION: Differential diagnosis includes malignancy, diverticulosis, adenomatous polyps and previous anastomosis. CT is the examination of choice. Surgical approach remains the treatment of choice for large colon lipoma. PMID- 23110910 TI - Correction of an end colostomy prolapse with the Delorme technique. A case report. AB - INTRODUCTION: We report a case of correction of an end colostomy prolapse with Delorme technique in an advanced stage oncologic patient to emphasize the clinical implications and advantages of this procedure. CASE REPORT: A 51-year old male patient with a stage IV rectal adenocarcinoma underwent laparoscopy for a palliative end colostomy at our institution. Approximately 6 months later, a prolapse of the colostomy occurred during chemotherapeutic treatment. The patient complained of progressive onset of pain and bleeding during defecation as well as difficulty managing the pouch system. Given the stage of the disease and the on going chemotherapy, a minimally invasive approach was desirable for prolapse correction and we opted for the Delorme procedure under local anesthesia. The postoperative course was excellent with no complications, the symptoms regressed rapidly, and defecation was normal immediately after surgery. The patient was discharged on the second post-operative day. After discharge the stoma was periodically controlled, confirming the success of the procedure. The last clinical evaluation was performed 3 months after surgery and stability was observed. CONCLUSIONS: The Delorme technique is a minimally invasive procedure used to correct an end colostomy prolapse. This technique guarantees excellent results in selected patients and permits the avoidance of more invasive procedures. PMID- 23110911 TI - Two-step surgery for a unique case of idiopathic female pseudohermaphroditism. Surgical treatment in an exceptional combined uro-genital malformation. AB - A 15 years-old patient was brought to our attention in June 2010 with a complex genito-urinary malformation: fusion of the labia majora and a partial union of labia minora, common urinary and vaginal meatus and clitoromegaly. The patient had a normal sexual feminine hormonal development. After diagnostic iter the patient underwent surgery twice. No signs of hormonal deficency was shown authorizing us to approach the disease as a congenital malformation due to an abnormality of intrauterine development. So surgical treatment was carried out, considering it as the gold standard for this type of malformations. It's considerable to emphasize that the association between clitoromegaly and fusion of the lower third of the urethra with the vagina has not been previously reported in the literature. PMID- 23110912 TI - Use of the Z-plasty technique in nasal skin cancers. Two clinical cases. AB - Basal cell carcinoma (BCC) is the most common type of cancer in Europe, Australia and the U.S.A. After nasal skin cancer excision, especially if it is less than 1 2 cm in diameter, several surgical techniques can be used to reconstruct the lack of substance.In the management of our two patients we have chosen to utilize, instead, a well-known plastic surgery technique, Z-plasty, which is both easy to perform that effective to achieve excellent cosmetic results. As shown by our two clinical cases, the use of Z-plasty for lack of substance of the nose tip and bridge can be extremely effective in terms of cosmetic results. In comparison with the other reconstructive techniques, in fact, it is very easy to perform and allows to avoid or minimize the distortion of the nasal tip and wing, to orient the incision along the skin tension lines and, finally, to replace the lack with very similar structures regarding color, thickness and tissue architecture to those removed. PMID- 23110913 TI - Evaluation and management of the CRPS II. PMID- 23110914 TI - Our orientation regarding the ductal carcinoma in situ of the breast. AB - AIM: The ductal carcinoma in situ is a malignant proliferation of mammary ductal epithelial cells without invasion beyond the basement membrane. The management of patients with DCIS is complex, controversial and has undergone changes over time. MATERIAL OF STUDY: We treated 65 patients diagnosed with DCIS between 2002 and 2005. We surveyed women aged between 28 and 71 years (average age 51.4), the DCIS in 16 patients appeared as a palpable mass (about 2.2 cm) - group I and in 49 patients as microcalcifications detected on mammography - group II. RESULTS: The most frequent histological type was found to be the comedocarcinoma. After 3 years of follow-up, we had 3 cases of recurrence (4.6%) in patients undergoing conservative surgery, with Van Nuys Prognostic Index between 3 and 4. DISCUSSION: 15-25% of cases of breast cancer are DCIS. Most of these are comedocarcinomas. Comedo form DCIS is an insidious cancer. Surgical treatment ranges from mastectomy to excision of the lesion, often the latter, followed by radiotherapy. CONCLUSION: We prefer, with regard to surgical treatment, quadrantectomy with systematic control of the free margins. The search for the axillary sentinel node represents for us, too, the gold standard. PMID- 23110915 TI - Topoisomerase 1(TOP1) gene copy number in stage III colorectal cancer patients and its relation to prognosis. AB - PURPOSE: A Topoisomerase 1 (Top1) poison is frequently included in the treatment regimens for metastatic colorectal cancer (mCRC). However, no predictive biomarkers for Top1 poisons are available. We here report a study on the TOP1 gene copy number in CRC patients and its association with patient prognosis and tumor cell proliferation. EXPERIMENTAL DESIGN: The study included TOP1 and CEN-20 fluorescence in situ hybridization (FISH) analyses on formalin fixed paraffin embedded (FFPE) tissue sections from 154 stage III CRC chemonaive patients. The frequencies of aberration in the TOP1 gene copy number, the CEN-20 copy number and the TOP1/CEN-20 ratio were analyzed and associated with overall survival (OS), time to recurrence (TTR) and in a subgroup analysis of rectal cancer patients only with time to local recurrence (LR in RC). Moreover, the TOP1 and CEN-20 copy numbers were correlated with the tumor Ki67 proliferation index. RESULTS: 35.7% of the tumors had an increased TOP1 copy number above 4n gene copies per cell and 28.6% and 9.7% had a TOP1/CEN-20 ratio >=1.5 or >=2.0, respectively. The TOP1 copy number and the TOP1/CEN-20 ratios were separately added into multivariate analyses as continuous variables, in which also age, gender, primary tumor location and Ki67 status were added as covariates. In contrast to the TOP1/CEN-20 ratio, the TOP1 copy number was significantly associated with OS (HR: 0.62; 95% CI: 0.42-0.90; p = 0.01). Neither the TOP1 copy number nor the ratio was significantly associated with TTR and only the TOP1/CEN 20 ratio was significantly associated with LR in RC (HR: 0.25; 95% CI: 0.08-0.83; p = 0.02). No significant correlation was found between the TOP1 copy number and proliferation, while a weak and inverse correlation between the CEN-20 copy number and proliferation was observed. CONCLUSIONS: This study showed that increased TOP1 gene copy numbers are frequent findings in cancer cells in stage III CRC tumors but unrelated to the proliferative status of the tumors. The association with prognosis is important to consider when planning and analyzing future studies investigating TOP1 as a potential predictive biomarker for Top1 poisons. PMID- 23110916 TI - Dietary changes in obese patients undergoing gastric bypass or lifestyle intervention: a clinical trial. AB - We compared changes in the dietary patterns of morbidly obese patients undergoing either laparoscopic gastric bypass surgery or a comprehensive lifestyle intervention programme. The present 1-year non-randomised controlled trial included fifty-four patients in the lifestyle group and seventy-two in the surgery group. Dietary intake was assessed by a validated FFQ. ANCOVA was used to adjust for between-group differences in sex, age, baseline BMI and baseline values of the dependent variables. Intakes of food groups and nutrients did not differ significantly between the intervention groups at baseline. At 1-year follow-up, the lifestyle group had a significantly higher daily intake of fruits and vegetables (561 (sd 198) v. 441 (sd 213) g, P= 0.002), whole grains (63 (sd 24) v. 49 (sd 16) g, P< 0.001) and fibre (28 (sd 6) v. 22 (sd 6) g, P< 0.001) than the surgery group and a lower percentage of total energy intake of saturated fat (12 (sd 3) v. 14 (sd 3) %, P< 0.001). The intake of red meat declined significantly within both groups, vegetables and fish intake were reduced significantly in the surgery group and added sugar was reduced significantly in the lifestyle group. The lifestyle patients improved their dietary patterns significantly (compared with the surgery group), increasing their intake of vegetables, whole grains and fibre and reducing their percentage intake of saturated fat (ANCOVA, all P< 0.001). In conclusion, lifestyle intervention was associated with more favourable dietary 1-year changes than gastric bypass surgery in morbidly obese patients, as measured by intake of vegetables, whole grains, fibre and saturated fat. PMID- 23110917 TI - Malaysian Twin Registry. AB - The National Malaysian Twin Registry was established in Royal College of Medicine, Perak, University Kuala Lumpur (UniKL) in June 2008 through a grant provided by UniKL. The general objective is to facilitate scientific research involving participation of twins and their family members in order to answer questions of health and wellbeing relevant to Malaysians. Recruitment is done via mass media, poster, and pamphlets. We now have 266 adult and 204 children twins registered. Several research projects including reproductive health study of twins and the role of co-bedding on growth and development of children are carried out. Registry holds annual activities for twins and seeks to provide health-related information for twins. We seek international collaboration. PMID- 23110918 TI - Ambulatory monitoring and sedentary behaviour: a population-health perspective. AB - Opportunities for sedentary-behaviour research using device-based measures are proposed, addressing four main topics: first, there is an explanation of how sedentary behaviours can most usefully be understood, emphasizing how they are distinct from lack of moderate-to-vigorous physical activity (the major focus of current national and international public-health guidelines), together with an account of the evidence on the relationships of sedentary behaviour with risk biomarkers and health outcomes; this highlights how device-based measurement is leading to rapid research advances. Second, the case is made for the utility of a behavioural epidemiology framework and an ecological model of sedentary behaviour to guide measurement-development initiatives. Third, the main elements of such a research agenda and the logic of their interrelationships are described. Fourth, and in conclusion, novel research opportunities arising within this perspective and likely future benefits are outlined. PMID- 23110919 TI - Mucous membrane pemphigoid in a patient with hypertension treated with atenolol: a case report. AB - INTRODUCTION: Atenolol is commonly used by patients with hypertension, angina pectoris, or myocardial infarction. There have been reports of various adverse effects associated with the use of atenolol including bullous pemphigoid. To the best of our knowledge we present the first case report of atenolol-induced mucous membrane pemphigoid. CASE PRESENTATION: A 42-year-old Thai man presented to our faculty after developing generalized fiery red gingiva and ulcerations on the buccal and labial mucosa after beginning atenolol treatment. Drug-induced mucous membrane pemphigoid was diagnosed from his clinical presentation and histopathologic and direct immunofluorescence examinations, combined with a history of beginning, and withdrawal, from atenolol therapy, with the lesions resolving after the cessation of atenolol therapy. CONCLUSIONS: To the best of our knowledge this is the first case of atenolol-induced oral mucous membrane pemphigoid reported in the literature. The observed lesions responded to withdrawal of the offending drug with complete remission. While drug-induced mucous membrane pemphigoid is an uncommon condition, dentists or other health care workers should include this condition in the differential diagnosis when a patient uses drugs suspected to be involved with drug-induced pemphigoid. PMID- 23110921 TI - Correction: Inducible Cre transgenic mouse strain for skeletal muscle-specific gene targeting. PMID- 23110920 TI - Matrix Gla protein reinforces angiogenic resolution. AB - Matrix Gla Protein (MGP) is an ECM molecule commonly associated with dysfunctions of large blood vessels such as arteriosclerosis and atherosclerosis. However, the exact role of MGP in the microvasculature is not clear. Utilizing a mouse MGP knockout model we found that MGP suppresses angiogenic sprouting from mouse aorta restricts microvascular density in cardiac and skeletal muscle, and is an endogenous inhibitor of tumor angiogenesis. Similarly, morpholino based knockdown of MGP in zebrafish embryos caused a progressive loss of luminal structures in intersegmental vessels, a phenotype reminiscent of Dll4/Notch inhibition. Accordingly, MGP suppressed Notch-dependent Hes-1 promoter activity and expression of Jagged1 mRNA relative to Dll4 mRNA. However, inhibition of BMP but not Notch or VEGF signaling reversed the excessive angiogenic sprouting phenotype of MGP knockout aortic rings suggesting that MGP may normally suppress angiogenic sprouting by blocking BMP signaling. Collectively, these results suggest that MGP is a multi-functional inhibitor of normal and abnormal angiogenesis that may function by coordinating with both Notch and BMP signaling pathways. PMID- 23110922 TI - Ketogenic enteral nutrition as a treatment for obesity: short term and long term results from 19,000 patients. AB - BACKGROUND: Only protein diet has been used successfully to prevent loss of lean body mass first in post-surgical and then in obese patients. We studied overweight and obese patients receiving short treatments of an exclusively protein-based nutritional solution as 24-hour enteral infusion. METHODS: 19,036 patients (age 44.3 +/- 13, M:F = 2:5) with an initial body mass index of 36.5 +/- 7.1 underwent 10-day cycles of enteral nutrition through a fine nasogastric tube. The nutritional solution consisted solely of 50-65 g of proteins, plus vitamins and electrolytes. The 24-hour infusion was controlled with a small portable pump. Before and after each 10-day cycle body composition was checked with a Handy 3000 impedance analyzer. At the onset of treatment, average fat mass was 40.9 +/- 12.8 kg while body cell mass was 42.7 +/- 7.2 kg in males and 27.4 +/- 4.6 kg in females. RESULTS: After an average of 2.5 cycles the patients lost 10.2 +/- 7.0 kg of body weight, 5.8 +/- 5.5 kg of fat mass and 2.2 +/- 3.3 kg of body cell mass. No significant adverse effects were recorded except asthenia and constipation which were easily controlled with therapy. Long-term results were obtained from 15,444 patients and after an average of 362 +/- 296 days we found a mean weight regain of 15.4%. CONCLUSION: Ketogenic Enteral Nutrition treatment of over 19,000 patients induced a rapid 10% weight loss, 57% of which was Fat Mass. No significant adverse effects were found. The treatment is safe, fast, inexpensive and has good one-year results for weight maintenance. PMID- 23110923 TI - Graveyards under the sea. PMID- 23110924 TI - Temperature dependent tunneling spectroscopy in the heavy fermion CeRu2Si2 and in the antiferromagnet CeRh2Si2. AB - CeRu(2)Si(2) and CeRh(2)Si(2) are two similar heavy fermion stoichiometric compounds located on the two sides of a magnetic quantum critical phase transition. CeRh(2)Si(2) is an antiferromagnet below T(N) = 36 K with moderate electronic masses whereas CeRu(2)Si(2) is a paramagnetic metal with particularly heavy electrons. Here we present tunneling spectroscopy measurements as a function of temperature (from 0.15 to 45 K). The tunneling conductance at 0.15 K reveals V-shaped dips around the Fermi level in both compounds, which disappear in CeRu(2)Si(2) above the coherence temperature, and in CeRh(2)Si(2) above the Neel temperature. In the latter case, two different kinds of V-shaped tunneling conductance dips are found. PMID- 23110925 TI - Thirteen years of experience with the endoscopic midface lift. AB - BACKGROUND: Numerous techniques have been used to rejuvenate the aging midface. The Endotine midface technique involves an endoscopic temporal approach, including midface dissection and malar suspension with fixation. The Endotine device (Microaire, Charlottesville, Virginia) eliminates the intraoral incision and use of sutures, enabling multipoint fixation and fast, simple adjustability for optimal control of midface elevation and volume. OBJECTIVES: The authors describe their preferred technique for the endoscopic midface lift and summarize their 13 years of experience. METHODS: A retrospective chart review was conducted of 183 patients who underwent endoscopic midface surgery. Patients treated from 1998 to 2003 received direct needle fixation (n = 95). Those treated later underwent fixation with the Endotine device (n = 88). RESULTS: Most (90%) of the patient population was female, and the average age at the time of surgery was 46 years (range, 39-54 years). Needle fixation was used in 95 patients and Endotine fixation in 88. The average follow-up period was 7 years. The authors have observed many improvements in outcomes since the introduction of the Endotine device into their practice. These include reduced swelling and bruising, more symmetric elevation of the malar fat pad, mild improvement of tear trough deformity, softening of the nasolabial folds, and, in some cases, decreased "jowling." The asymmetry often associated with direct needle fixation has decreased, and no skin dimpling has occurred. Through their experience, the authors' preferred technique has become the temporal-only approach with Endotine fixation. CONCLUSIONS: The Endotine midface suspension device enhances soft tissue fixation, provides simple adjustability for optimal elevation and projection, and maintains mechanical fixation until biologic fixation becomes adequate. The 5 tines provide multiple points of contact for secure soft-tissue fixation. Elevation forces are evenly distributed over a wide area, which eliminates skin irregularities. Insertion and deployment are accomplished easily through temporal incision. PMID- 23110926 TI - Correction of the supratip deformity of the nose. AB - BACKGROUND: A supratip deformity can develop either congenitally or after a poorly executed rhinoplasty, as a result of fullness or convexity just above the nasal tip. OBJECTIVE: In this article, the authors describe the causes of the supratip deformity and present their technique for surgical correction. METHODS: A retrospective chart review was conducted for 62 consecutive patients (24 primary rhinoplasty and 38 secondary rhinoplasty) treated between January 2005 and February 2010. The authors' approach to managing supratip deformity included a combination of wide undermining of the nasal skin through the open technique; resection of excessive soft tissue and the bony, cartilaginous dorsum; suturing to advance the supratip; and augmentation of the nasal tip and dorsum with cartilage, crushed cartilage, silicone implants, and/or septal extension grafts. RESULTS: No infection or nasal bleeding was recorded during postoperative follow up. The supratip and tip projection showed adequate shape in all cases. To assess satisfaction, all patients and 2 independent plastic surgeons were asked to rate the result on a 5-point scale. The average patient satisfaction rating was 4.2 and the average independent rating was 4.4 points. CONCLUSIONS: Supratip deformities should be corrected according to their unique cause and shape. The authors' method of repairing these deformities has resulted in a low complication rate and yielded satisfactory results. PMID- 23110927 TI - Commentary on: Pain control following breast augmentation: a qualitative systematic review. PMID- 23110928 TI - Arm dynamic definition by liposculpture and fat grafting. AB - BACKGROUND: The contour of the arm is determined by muscular shape and volume. Liposuction in this area is challenging due to the difficulties of achieving symmetry and the high risk of contour irregularities due to fat structures in the region. OBJECTIVE: The authors describe a new technique to achieve muscular definition in the arm. METHODS: From January 2005 to December 2011, a total of 651 arm-sculpting procedures were performed in consecutive patients. Patients with body mass index (BMI) >30 kg/m(2) and/or severe skin laxity were excluded. Fat grafting was performed in the deltoid area in selected cases. The areas of fat extraction and grafting were specific to gender: in men, an athletic, muscular look was preferred, whereas in women, a slimmer and less-defined shape was desired. RESULTS: Of the 651 patients, 158 were men (24.3%) and 493 were women (75.7%). Most patients (98.3%) were satisfied with the results in arm dynamic definition. All patients underwent other body contouring procedures at the time of arm enhancement. Complications (n = 21) included 1 soft tissue abscess in the posterior arm, 2 unilateral hematomas, and 3 unilateral seromas that required puncture, along with 15 cases of minor asymmetry. Transitory hardening of the skin of the posterior arm was frequent (n = 104) due to superficial fat extraction, but all cases resolved within 6 months. CONCLUSION: The authors were able to achieve natural results with this new procedure in arm contouring. The technique is safe and effective with reproducible results when performed through multilayer fragmentation and liposuction with an anatomical extraction. Fat grafting can be performed for contouring with no additional complications. PMID- 23110929 TI - Commentary on: Arm dynamic definition by liposculpture and fat grafting. PMID- 23110930 TI - Does systemic isotretinoin inhibit healing in a porcine wound model? AB - BACKGROUND: Within the plastic surgery community, it is widely believed that waiting a minimum of 6 to 12 months after patient cessation of systemic retinoid therapy is necessary before proceeding with elective surgery. OBJECTIVE: The authors investigate partial- and full-thickness wound healing after treatment with systemic isotretinoin in a porcine model. METHODS: Following institutional approval, 2 Hanford miniature pigs were obtained. One pig received isotretinoin at a dose of 2 mg/kg/d, administered orally along with pig feed over a 60-day period; the other (control) pig received only pig feed over the same time period. After the treatment period ended, a total of 24 full-thickness wounds and 24 partial-thickness wounds were made on each pig. The wounds were evaluated by photographic and histological analysis at 7, 14, and 28 days. RESULTS: The average full-thickness wound size in the control animal was 0.4346 cm(2) at 14 days and 0.0689 cm(2) at 28 days. The average full-thickness wound size in the isotretinoin-treated animal was 0.4685 cm(2) at 14 days and 0.0363 cm(2) at 28 days. The differences were not statistically significant between the 2 animals at either time point. On histological analysis, the healing characteristics of partial- and full-thickness wounds were similar at 7, 14, and 28 days for both animals. CONCLUSIONS: Invasive surgery might be safely performed even in the presence of recent isotretinoin therapy. This finding challenges the current practice of waiting longer than 6 months after completion of therapy to perform surgery. PMID- 23110931 TI - Commentary on: Social networks uncovered: 10 tips every plastic surgeon should know. PMID- 23110932 TI - Operative techniques in Asian rhinoplasty. AB - Rhinoplasty in patients of Asian descent presents a different set of challenges for rhinoplasty surgeons. Most Asian noses are characterized by a thick skin envelope, low radix and dorsum, bulbous tip, weak lower lateral cartilages, and a short columella. In this article, the authors describe an autogenous approach to Asian rhinoplasty that achieves aesthetic results comparable to the use of silicone implants without the associated risks observed with alloplastic implants. The technique consists of the following: (1) harvesting of grafts, (2) an open approach with skin defatting, (3) septal harvest, (4) placement of a septocolumellar graft, (5) nasal tip refinement, (6) radix and dorsal augmentation, (7) osteotomies, (8) alar base modifications, and (9) closure and casting. PMID- 23110934 TI - Cytotoxicity, oxidative stress, and genotoxicity in human hepatocyte and embryonic kidney cells exposed to ZnO nanoparticles. AB - Traces of zinc oxide nanoparticles (ZnO NPs) used may be found in the liver and kidney. The aim of this study is to determine the optimal viability assay for using with ZnO NPs and to assess their toxicity to human hepatocyte (L02) and human embryonic kidney (HEK293) cells. Cellular morphology, mitochondrial function (MTT assay), and oxidative stress markers (malondialdehyde, glutathione (GSH) and superoxide dismutase (SOD)) were assessed under control and exposed to ZnO NPs conditions for 24 h. The results demonstrated that ZnO NPs lead to cellular morphological modifications, mitochondrial dysfunction, and cause reduction of SOD, depletion of GSH, and oxidative DNA damage. The exact mechanism behind ZnO NPs toxicity suggested that oxidative stress and lipid peroxidation played an important role in ZnO NPs-elicited cell membrane disruption, DNA damage, and subsequent cell death. Our preliminary data suggested that oxidative stress might contribute to ZnO NPs cytotoxicity. PMID- 23110935 TI - Significance of pre-Quaternary climate change for montane species diversity: insights from Asian salamanders (Salamandridae: Pachytriton). AB - Despite extensive focus on the genetic legacy of Pleistocene glaciation, impacts of earlier climatic change on biodiversity are poorly understood. Because amphibians are highly sensitive to variations in precipitation and temperature, we use a genus of Chinese montane salamanders (Salamandridae: Pachytriton) to study paleoclimatic change in East Asia, which experienced intensification of its monsoon circulation in the late Miocene associated with subsequent Pliocene warming. Using both nuclear and mitochondrial DNA sequences, we reconstruct the species tree under a coalescent model and demonstrate that all major lineages originated before the Quaternary. Initial speciation within the genus occurred after the summer monsoon entered a stage of substantial intensification. Heavy summer precipitation established temporary water connectivity through overflows between adjacent stream systems, which may facilitate geographic range expansion by aquatic species such as Pachytriton. Species were formed in allopatry likely through vicariant isolation during or after range expansion. To evaluate the influence of Pliocene warming on these cold-adapted salamanders, we construct a novel temperature buffer-zone model, which suggests widespread physiological stress or even extinction during the warming period. A significant deceleration of species accumulation rate is consistent with Pliocene range contraction, which affected P. granulosus and P. archospotus the most because they lack large temperature buffer zones. In contrast, demographic growth occurred in species for which refugia persist. The buffer-zone model reveals the Huangshan Mountain as a potential climatic refugium, which is similar to that found for other East Asian organisms. Our approach can incorporate future climatic data to evaluate the potential impact of ongoing global warming on montane species (particularly amphibians) and to predict possible population declines. PMID- 23110937 TI - The link between some alleles on human leukocyte antigen system and autism in children. AB - The reason behind the initiation of autoimmunity to brain in some patients with autism is not well understood. There is an association between some autoimmune disorders and specific alleles of human leukocyte antigen (HLA) system. Thus, we examined the frequency of some HLA-DRB1 alleles in 100 autistic children and 100 healthy matched-children by differential hybridization with sequence-specific oligonucleotide probes. The risk of association between acquisition or absence of these alleles and autism and also a history of autoimmune diseases in autistic relatives was studied. Autistic children had significantly higher frequency of HLA-DRB1*11 allele than controls (P<0.001). In contrast, autistic children had significantly lower frequency of HLA-DRB1*03 allele than controls (P<0.001). Acquisition of HLA-DRB1*011 and absence of HLA-DRB1*3 had significant risk for association with autism (odds ratio: 3.21 and 0.17, respectively; 95% CI: 1.65 6.31 and 0.06-0.45, respectively). HLA-DRB1*11 had a significant risk for association with a family history of autoimmunity in autistic children (odds ratio: 5.67; 95% CI: 2.07-16.3). In conclusions, the link of some HLA alleles to autism and to family history of autoimmunity indicates the possible contributing role of these alleles to autoimmunity in some autistic children. Despite a relatively small sample size, we are the first to report a probable protective association of HLA-DRB1*03 allele with autism. It warrants a replication study of a larger sample to validate the HLA-DRB1 genetic association with autism. This is important to determine whether therapeutic modulations of the immune function are legitimate avenues for novel therapy in selected cases of autism. PMID- 23110936 TI - Assessment of the genetic relationship between Dictyocaulus species from Bos taurus and Cervus elaphus using complete mitochondrial genomic datasets. AB - BACKGROUND: Dictyocaulus species are strongylid nematodes of major veterinary significance in ruminants, such as cattle and cervids, and cause serious bronchitis or pneumonia (dictyocaulosis or "husk"). There has been ongoing controversy surrounding the validity of some Dictyocaulus species and their host specificity. Here, we sequenced and characterized the mitochondrial (mt) genomes of Dictyocaulus viviparus (from Bos taurus) with Dictyocaulus sp. cf. eckerti from red deer (Cervus elaphus), used mt datasets to assess the genetic relationship between these and related parasites, and predicted markers for future population genetic or molecular epidemiological studies. METHODS: The mt genomes were amplified from single adult males of D. viviparus and Dictyocaulus sp. cf. eckerti (from red deer) by long-PCR, sequenced using 454-technology and annotated using bioinformatic tools. Amino acid sequences inferred from individual genes of each of the two mt genomes were compared, concatenated and subjected to phylogenetic analysis using Bayesian inference (BI), also employing data for other strongylids for comparative purposes. RESULTS: The circular mt genomes were 13,310 bp (D. viviparus) and 13,296 bp (Dictyocaulus sp. cf. eckerti) in size, and each contained 12 protein-encoding, 22 transfer RNA and 2 ribosomal RNA genes, consistent with other strongylid nematodes sequenced to date. Sliding window analysis identified genes with high or low levels of nucleotide diversity between the mt genomes. At the predicted mt proteomic level, there was an overall sequence difference of 34.5% between D. viviparus and Dictyocaulus sp. cf. eckerti, and amino acid sequence variation within each species was usually much lower than differences between species. Phylogenetic analysis of the concatenated amino acid sequence data for all 12 mt proteins showed that both D. viviparus and Dictyocaulus sp. cf. eckerti were closely related, and grouped to the exclusion of selected members of the superfamilies Metastrongyloidea, Trichostrongyloidea, Ancylostomatoidea and Strongyloidea. CONCLUSIONS: Consistent with previous findings for nuclear ribosomal DNA sequence data, the present analyses indicate that Dictyocaulus sp. cf. eckerti (red deer) and D. viviparus are separate species. Barcodes in the two mt genomes and proteomes should serve as markers for future studies of the population genetics and/or epidemiology of these and related species of Dictyocaulus. PMID- 23110938 TI - Autoimmune responses against photoreceptor antigens during retinal degeneration and their role in macrophage recruitment into retinas of RCS rats. AB - Autoimmunity may contribute to retinal degeneration. The studies examined the evolution of autoimmune responses against retina in naive dystrophic RCS rats over the course of retinal degeneration. We showed that anti-retinal autoantibodies and T cells are generated in response to the availability of antigenic material released from dying photoreceptor cells during retinal degeneration but with distinctive activation trends. Passive transfer of anti retinal antibodies enhanced disease progression by disrupting the BRB, upregulating MCP-1, attracting blood macrophages into retina, and augmenting apoptotic photoreceptor cell death. Our findings directly link anti-retinal autoantibodies to activated macrophage entry and their possible role in neurodegeneration. PMID- 23110939 TI - Type I IFN receptor controls activated TYK2 in the nucleus: implications for EAE therapy. AB - Recent studies have suggested that activated wild-type and mutant Janus kinase JAK2 play a role in the epigenetics of histone modification, where it phosphorylates histone H3 on tyrosine 41(H3pY41). We showed that type I IFN signaling involves activated TYK2 in the nucleus. ChIP-PCR demonstrated the presence of receptor subunits IFNAR1 and IFNAR2 along with TYK2, STAT1, and H3pY41 specifically at the promoter of the OAS1 gene in IFN treated cells. A complex of IFNAR1, TYK2, and STAT1alpha was also shown in the nucleus by immunoprecipitation. IFN treatment was required for TYK2 activation in the nucleus. The presence of IFNAR1, IFNAR2, and activated STAT1 and STAT2, as well as the type I IFN in the nucleus of treated cells was confirmed by the combination of Western blotting and confocal microscopy. Trimethylated histone H3 lysine 9 underwent demethylation and subsequent acetylation specifically in the region of the OAS1 promoter. Resultant N-terminal truncated IFN mimetics functioned intracellularly as antivirals as well as therapeutics against experimental allergic encephalomyelitis without the undesirable side effects that limit the therapeutic efficacy of IFNbeta in treatment of multiple sclerosis. The findings indicate that IFN signaling is complex like that of steroid signaling. PMID- 23110940 TI - EGFR mutations are associated with favorable intracranial response and progression-free survival following brain irradiation in non-small cell lung cancer patients with brain metastases. AB - BACKGROUND: The presence of epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) is associated with increased radiosensitivity in vitro. However, the results from clinical studies regarding the radiosensitivity in NSCLC with mutant EGFR are inconclusive. We retrospectively analyzed our NSCLC patients who had been regularly followed up by imaging studies after irradiation for brain metastases, and investigated the impact of EGFR mutations on radiotherapy (RT). METHODS: Forty-three patients with brain metastases treated with RT, together with EGFR mutation status, demographics, smoking history, performance status, recursive partitioning analysis (RPA) class, tumor characteristics, and treatment modalities, were included. Radiological images were taken at 1 to 3 months after RT, and 3 to 6 months thereafter. Radiographic response was evaluated by RECIST criteria version 1.1 according to the intracranial images before and after RT. Log-rank test and Cox regression model were used to correlate EGFR mutation status and other clinical features with intracranial radiological progression-free survival (RPFS) and overall survival (OS). RESULTS: The median follow-up duration was 15 months. Patients with mutant EGFR had higher response rates to brain RT than those with wild-type EGFR (80% vs. 46%; p = 0.037). Logistic regression analysis showed that EGFR mutation status is the only predictor for treatment response (p = 0.032). The median intracranial RPFS was 18 months (95% CI = 8.33-27.68 months). In Cox regression analysis, mutant EGFR (p = 0.025) and lower RPA class (p = 0.026) were associated with longer intracranial RPFS. EGFR mutation status (p = 0.061) and performance status (p = 0.076) had a trend to predict OS. CONCLUSIONS: Mutant EGFR in NSCLC patients is an independent prognostic factor for better treatment response and longer intracranial RPFS following RT for brain metastases. PMID- 23110941 TI - Two new species of Syphacia (Nematoda: Oxyuridae) in endemic murid rodents from Sulawesi, Indonesia. AB - Two new species of Syphacia (Nematoda: Oxyuridae) are described from endemic murids of Sulawesi, Indonesia: Syphacia (Syphacia) taeromyos sp. n. and S. (S.) paruromyos sp. n. parasitic in the caecum of Taeromys celebensis and Paruromys dominator, respectively. They are readily distinguished from all of the congeners recorded from Indonesia-Australian regions by having a round cephalic plate, vesicular lateral alae in the male, posteriorly positioned excretory pore in the male, and/or lacking cervical alae. Syphacia (S.) paruromyos differs from S. (S.) taeromyos by having a whip-like tail appendage in the male, longer relative distance between excretory pore and vulva, and larger eggs. The round cephalic plate in both sexes and developed vesicular lateral alae in the male are morphological traits common in endemic Syphacia species hitherto known from Sulawesi murids, suggesting that they have derived from a common ancestor and evolved with their hosts in the isolated insular environment. PMID- 23110943 TI - IA-2 autoantibody affinity in children at risk for type 1 diabetes. AB - Autoantibodies to insulinoma-associated protein 2 (IA-2A) are associated with increased risk for type 1 diabetes. Here we examined IA-2A affinity and epitope specificity to assess heterogeneity in response intensity in relation to pathogenesis and diabetes risk in 50 children who were prospectively followed from birth. At first IA-2A appearance, affinity ranged from 10(7) to 10(11)L/mol and was high (>1.0*10(9)L/mol) in 41 (82%) children. IA-2A affinity was not associated with epitope specificity or HLA class II haplotype. On follow-up, affinity increased or remained high, and IA-2A were commonly against epitopes within the protein tyrosine phosphatase-like IA-2 domain and the homologue protein IA-2beta. IA-2A were preceded or accompanied by other islet autoantibodies in 49 (98%) children, of which 34 progressed to diabetes. IA-2A affinity did not stratify diabetes risk. In conclusion, the IA-2A response in children is intense with rapid maturation against immunogenic epitopes and a strong association with diabetes development. PMID- 23110944 TI - Energy expenditure estimation during normal ambulation using triaxial accelerometry and barometric pressure. AB - Energy expenditure (EE) is an important parameter in the assessment of physical activity. Most reliable techniques for EE estimation are too impractical for deployment in unsupervised free-living environments; those which do prove practical for unsupervised use often poorly estimate EE when the subject is working to change their altitude by walking up or down stairs or inclines. This study evaluates the augmentation of a standard triaxial accelerometry waist-worn wearable sensor with a barometric pressure sensor (as a surrogate measure for altitude) to improve EE estimates, particularly when the subject is ascending or descending stairs. Using a number of features extracted from the accelerometry and barometric pressure signals, a state space model is trained for EE estimation. An activity classification algorithm is also presented, and this activity classification output is also investigated as a model input parameter when estimating EE. This EE estimation model is compared against a similar model which solely utilizes accelerometry-derived features. A protocol (comprising lying, sitting, standing, walking, walking up stairs, walking down stairs and transitioning between activities) was performed by 13 healthy volunteers (8 males and 5 females; age: 23.8 +/- 3.7 years; weight: 70.5 +/- 14.9 kg), whose instantaneous oxygen uptake was measured by means of an indirect calorimetry system (K4b(2), COSMED, Italy). Activity classification improves from 81.65% to 90.91% when including barometric pressure information; when analyzing walking activities alone the accuracy increases from 70.23% to 98.54%. Using features derived from both accelerometry and barometry signals, combined with features relating to the activity classification in a state space model, resulted in a VO(2) estimation bias of -0.00 095 and precision (1.96SD) of 3.54 ml min(-1) kg( 1). Using only accelerometry features gives a relatively worse performance, with a bias of -0.09 and precision (1.96SD) of 5.99 ml min(-1) kg(-1), with the largest errors due to an underestimation of VO(2) when walking up stairs. PMID- 23110942 TI - Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. AB - Previous studies have reported alterations in numbers or function of regulatory T (Treg) cells in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous "Treg" populations. In this study, we used surface CD4, CD25(high), and CD127(low/-) expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg mediated suppression of responder T (Tresp) cells was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target. PMID- 23110945 TI - Federal legislation and the advancement of neonatal drug studies. PMID- 23110946 TI - Exercise-induced bronchoconstriction in school-aged children who had chronic lung disease in infancy. AB - OBJECTIVES: To assess for exercise-induced bronchoconstriction in 8- to 12-year old children who had chronic lung disease (CLD) in infancy, and to evaluate the response of bronchoconstriction to bronchodilation with albuterol in comparison with preterm and term controls. STUDY DESIGN: Ninety-two children, including 29 with CLD, 33 born preterm at <=32 weeks' gestation, and 30 born at term, underwent lung spirometry before and after cycle ergometry testing and after postexercise bronchodilation with albuterol. RESULTS: Doctor-diagnosed asthma and exercise-induced wheeze were reported more frequently in the CLD group than in the preterm and term groups, but only 10% were receiving a bronchodilator. There were no differences among the groups in peak minute ventilation, oxygen uptake, or carbon dioxide output at maximum exercise. After maximal exercise, predicted forced expiratory volume in 1 second (FEV1) decreased from a mean baseline value of 81.9% (95% CI, 76.6-87.0%) to 70.8% (95% CI, 65.5-76.1%) after exercise in the CLD group, from 92.0% (95% CI, 87.2-96.8%) to 84.3% (95% CI, 79.1-89.4%) in the preterm group, and from 97.5% (95% CI, 92.5-102.6%) to 90.3% (95% CI, 85.1-95.5%) in the term group. After albuterol administration, FEV1 increased to 86.8% (95% CI, 81.7-92.0%) in the CLD group, 92.1% (95% CI, 87.3-96.9%) in the preterm group, and 97.1% (95% CI, 92.0-102.3%) in the term group. The decrease in predicted FEV1 after exercise and increase in predicted FEV1 after bronchodilator use were greatest in the CLD group (-11.0% [95% CI, -18.4 to -3.6%] and 16.0% [95% CI, 8.6-23.4%], respectively; P < .005 for both), with differences of <8% in the 2 control groups. CONCLUSION: School-age children who had CLD in infancy had significant exercise-induced bronchoconstriction that responded significantly to bronchodilation. Reversible exercise-induced bronchoconstriction is common in children who experienced CLD in infancy and should be actively assessed for and treated. PMID- 23110947 TI - The evidence that evidence-based medicine omits. AB - According to current hierarchies of evidence for EBM, evidence of correlation (e.g., from RCTs) is always more important than evidence of mechanisms when evaluating and establishing causal claims. We argue that evidence of mechanisms needs to be treated alongside evidence of correlation. This is for three reasons. First, correlation is always a fallible indicator of causation, subject in particular to the problem of confounding; evidence of mechanisms can in some cases be more important than evidence of correlation when assessing a causal claim. Second, evidence of mechanisms is often required in order to obtain evidence of correlation (for example, in order to set up and evaluate RCTs). Third, evidence of mechanisms is often required in order to generalise and apply causal claims. While the EBM movement has been enormously successful in making explicit and critically examining one aspect of our evidential practice, i.e., evidence of correlation, we wish to extend this line of work to make explicit and critically examine a second aspect of our evidential practices: evidence of mechanisms. PMID- 23110948 TI - Congenital diaphragmatic Bochdaleck hernia: case report. AB - Congenital diaphragmatic Bochdaleck hernia is an anatomical defect of the diaphragm, which allows protrusion of abdominal viscera into the chest, causing serious pulmonary and cardiac complications in the neonate. In this study we aimed to present a case of congenital Bochdaleck hernia. We investigated a 40 weeks old child, with a pregnancy carried out in a public hospital in Passo Fundo, Rio Grande do Sul, Brazil. We suggest that if diagnosis occurs in the prenatal period, the prognosis of this disease improves. As a consequence, it allows the parity of the fetus to occur in a higher complexity center, optimizing the chances of survival. PMID- 23110949 TI - Lentivirus-mediated chronic expression of dominant-negative CREB in the dorsal hippocampus impairs memory for place learning and contextual fear conditioning. AB - Extensive research has shown that the transcription factor CREB has an important role during memory formation. In the present study, we tested a new method for chronic, stable expression of a dominant-negative form of CREB (mCREB) in the dorsal hippocampus using lentiviral vectors. In specific, we tested whether lentivirus-mediated chronic expression of mutant CREB impairs memory for two hippocampus-dependent tasks - place training in the water maze and contextual fear conditioning. Two weeks following intra-hippocampal infusion, experimental (mCREB) and control (LacZ and saline) rats were trained for 30 trials in one session on a place task in a water plus-maze and tested for an additional 30 trials on day 2 and on day 7. On day 8, all rats were trained on a contextual fear conditioning task and tested 24h later. For place learning, there was no difference between treatment groups on day 1, indicating that treatment with the lentiviral vectors did not alter performance or acquisition of the task. In comparisons with controls, mCREB-treated rats were not significantly impaired on day 2, overall, but they showed significant impairment on day 7. Contextual fear memory was impaired in mCREB-infused rats in comparison with controls. At the end of the experiment, total CREB and phosphorylated CREB protein were measured by western blot. Levels of total CREB were increased by approximately 40% among mCREB-treated rats in comparisons with controls, whereas levels of pCREB did not differ between groups, suggesting that the treatment caused significant expression of mCREB. In addition, mCREB infused rats showed a significant reduction in the pCREB to CREB ratio in comparison with controls, suggesting that the memory deficit seen in mCREB rats is most likely due to disruption of gene regulation caused by expression of mutant CREB. Taken together, the present results show that lentivirus expressing mCREB can be used to effectively alter CREB function within the hippocampus and that the treatment impairs memory for hippocampus-dependent tasks. PMID- 23110950 TI - The diagnosis and prevalence of subclinical endometritis in cows evaluated by different cytologic thresholds. AB - The aims of our study were to determine (1) how the prevalence of cytologically determined subclinical endometritis varies when using three different cytological threshold ratios to categorize cows as either with or without endometritis, (2) how the number of animals categorized as having endometritis changes from the fourth to the sixth wk postpartum when using each threshold, (3) how subclinical endometritis influences the number of days open, and (4) how the results of cytological and bacterial examinations correlate. To answer these questions, 222 clinically healthy cows in two herds were examined in the fourth (Exam 1) and the sixth wk (Exam 2) postpartum, when endometrial surface scrapings for bacteriologic and cytologic examination were collected by cytobrush from their uterine horns. After each examination, all cows were categorized using three different thresholds: (1) > 18% polymorphonuclear leucocytes in Exam 1 and > 10% in Exam 2, (2) > 8% in both exams, and (3) > 5% in both exams. It was found that: (1) The number of cows categorized as having endometritis increased as the threshold was lowered, and ranged from 18.9% to 75.4% according to herd, time of examination, and the threshold used; (2) with all three thresholds and in both herds, the number of cows categorized as having endometritis in Exam 1 was approximately double that in Exam 2; whereas depending on the herd and the threshold used, 6.1% to 17.0% of the cows that were negative in the first exam were positive in the second, and 7.4% to 33.3% were positive in both exams; (3) cows were open for a significantly greater number of days if categorized as having endometritis with the first threshold in Exam 1 (mean +/- SEM 151.5 +/- 9.5 vs. 115.9 +/- 7.8; P < 0.01), or with either the first or the second threshold in Exam 2 (mean +/- SEM 155.0 +/- 15.0 vs. 125.1 +/- 6.6; P < 0.05); and (4) the most common bacteria were Streptococcus acidominimus and Escherichia coli, and the correlation between cytologic and bacteriologic findings was low (Phi = 0.08 to 0.17 for different tested thresholds). Subclinical endometritis seems to be associated more with the postpartum recovery of the endometrium than with bacterial infection. PMID- 23110951 TI - Stimulatory effect of PGF2alpha on PRL based on experimental inhibition of each hormone in mares. AB - During the luteolytic period in mares, the peak of 65% of pulses of a PGF2alpha metabolite (PGFM) and the peak of a pulse of PRL have been reported to occur at the same hour. It is unknown whether the synchrony reflects an effect of PGF2alpha on PRL or vice versa. Controls, a flunixin meglumine (FM)-treated group (to inhibit PGF2alpha), and a bromocriptine-treated group (to inhibit PRL), were used at 14 days postovulation in June and in September (n = 6 mares/group/mo). Blood samples were collected hourly from just before treatment (Hour 0) to Hour 10. Concentrations of PGFM in the FM group were lower (P < 0.05) at Hours 4 to 6 than in the controls in each month, but bromocriptine had no detected effects on PGFM. Concentrations of PGFM averaged over all groups and within each group did not differ between June and September. Compared to the controls, concentrations of PRL in June were lower (P < 0.05) in the FM group at Hours 4 to 8 and in the bromocriptine group at Hours 4 to 10. Concentration of PRL averaged over groups was lower (P < 0.0001) in September (0.9 +/- 0.05 ng/mL, mean +/- SEM) than in June (3.0 +/- 0.3 ng/mL). Results supported the hypothesis that the positive association between PGFM and PRL concentrations in mares represents an effect of PGF2alpha on PRL rather than an effect of PRL on PGF2alpha. PMID- 23110952 TI - Role of LH in the progesterone increase during the bromocriptine-induced prolactin decrease in heifers. AB - The luteotrophic effect of bromocriptine in heifers was studied to determine if the reported posttreatment increase in progesterone (P4) just before or at the beginning of luteolysis was attributable to loss of a luteolytic effect of prolactin (PRL) or to the stimulation of LH, a known luteotropin. Four treatment groups (n = 7) were used: control (Ct), bromocriptine (Bc; 16 mg/heifer), acyline (Ac; 3 MUg/kg), and bromocriptine and acyline combined (BcAc). Bromocriptine (inhibitor of PRL) and acyline (antagonist of GnRH and therefore blocker of LH) were given at Hour 0 on Day 16 postovulation, and blood samples were taken hourly at Hours 0 to 8. Concentration of P4 was greater (P < 0.05) in the Bc group than in the Ct group at each of Hours 1 to 8. Concentration of LH increased (P < 0.05) between Hours 0 to 2 in the Bc group but not in the other three groups. The peak of the first posttreatment LH pulse occurred earlier in the Bc group than in the Ct group. Average concentration of PRL was lower (P < 0.05) and number of PRL pulses was less (P < 0.05) in the Bc group than in the Ct group. Acyline inhibited LH in the Ac and BcAc groups as indicated by a decrease (P < 0.05) in concentration between Hours 0 and 2 and a decrease (P < 0.001) in number of pulses/heifer during the 8 h. A decrease in PRL but not an increase in P4 and LH occurred in the BcAc group. Results supported the hypothesis that the P4 increase associated with PRL suppression by bromocriptine treatment is attributable to an increase in LH. PMID- 23110953 TI - Ovarian fluid enhances sperm velocity based on relatedness in lake trout, Salvelinus namaycush. AB - Studying mate choice at the gamete level can provide valuable insights into proximate mechanisms that underlie the evolution of mating systems. The objective was to assess whether ovarian fluid enhances sperm performance based on relatedness of mates in lake trout, Salvelinus namaycush, an iteroparous salmonid. Twelve trios were used, each composed of a female and two male fish; one male was related (full sibling) to the female, whereas the other was unrelated. Sperm from each male was activated in hatchery water or ovarian fluid from each corresponding female. No significant difference in sperm velocity was detected between the related and unrelated male fish when activated in hatchery water. However, when sperm was activated in ovarian fluid, sperm velocity from the related male was significantly higher than that of the unrelated male fish. Overall, ovarian fluid enhanced sperm performance of related male fish and might act as part of a recognition system to select sperm of a specific genotype. PMID- 23110954 TI - Defined media optimization for in vitro culture of bovine somatic cell nuclear transfer (SCNT) embryos. AB - The objective was to establish an efficient defined culture medium for bovine somatic cell nuclear transfer (SCNT) embryos. In this study, modified synthetic oviductal fluid (mSOF) without bovine serum albumin (BSA) was used as the basic culture medium (BCM), whereas the control medium was BCM with BSA. In Experiment 1, adding polyvinyl alcohol (PVA) to BCM supported development of SCNT embryos to blastocyst stage, but blastocyst formation rate and blastocyst cell number were both lower (P < 0.05) compared to the undefined group (6.1 vs. 32.6% and 67.3 +/- 3.4 vs. 109.3 +/- 4.5, respectively). In Experiment 2, myo-inositol, a combination of insulin, transferrin and selenium (ITS), and epidermal growth factor (EGF) were added separately to PVA-supplemented BCM. The blastocyst formation rate and blastocyst cell number of those three groups were dramatically improved compared with that of PVA-supplemented group in Experiment 1 (18.5, 23.0, 24.1 vs. 6.1% and 82.7 +/- 2.0, 84.3 +/- 4.2, 95.3 +/- 3.8 vs. 67.3 +/- 3.4, respectively, P < 0.05), but were still lower compared with that of undefined group (33.7% and 113.8 +/- 3.4, P < 0.05). In Experiment 3, when a combination of myo-inositol, ITS and EGF were added to PVA-supplemented BCM, blastocyst formation rate and blastocyst cell number were similar to that of undefined group (30.4 vs. 31.1% and 109.3 +/- 4.4 vs. 112.0 +/- 3.6, P > 0.05). In Experiment 4, when blastocysts were cryopreserved and subsequently thawed, there were no significant differences between the optimized defined group (Experiment 3) and undefined group in survival rate and 24 and 48 h hatching blastocyst rates. Furthermore, there were no significant differences in expression levels of H19, HSP70 and BAX in blastocysts derived from optimized defined medium and undefined medium, although the relative expression abundance of IGF-2 was significantly decreased in the former. In conclusion, a defined culture medium containing PVA, myo-inositol, ITS, and EGF supported in vitro development of bovine SCNT embryos. PMID- 23110955 TI - Improved cryopreservation of domestic cat sperm in a chemically defined medium. AB - The objective was to compare a proprietary egg yolk-based cryopreservation medium with a chemically defined soy-based medium, as well as to examine effects of temperature of glycerol addition on sperm parameters and IVF after freezing and thawing of domestic cat sperm. Semen was collected from adult cats (four males and three ejaculates per male), divided in four equal aliquots, and extended in either egg yolk with 4% glycerol added before (EYG) or after (EY) cooling to 5 degrees C, or soy-lecithin with 4% glycerol added before (SLG) or after (SL) cooling to 5 degrees C. Extended sperm were frozen in straws over liquid nitrogen vapor. Sperm progressive motility (%) and rate of progressive movement (scale of 0-5) were evaluated at 0, 1, 3, 6, and 24 h post-thaw. Sperm capacitation, acrosome integrity, and DNA integrity were assessed at 15 min post thaw. Effects of media (EY or SL) on IVF success was also examined (three males and three ejaculates per male). Sperm motility was greater (P < 0.05) in soy based compared with egg yolk-based media at 3, 6, and 24 h post-thaw. A higher (P < 0.05) percentage of noncapacitated sperm (pattern F) were present in soy-based (SLG, 63.7 +/- 9.2%; and SL, 64.1 +/- 9.2%) compared with egg yolk-based (EYG, 49.9 +/- 7.9%; and EY, 52.4 +/- 18.6%) cryopreservation media, regardless of temperature of glycerol addition. Addition of glycerol at 5 degrees C increased (P < 0.05) percentage of sperm motility at 6 h (EYG 16.3 +/- 8.3% vs. EY, 24.0 +/ 11.7%; SLG, 36.7 +/- 6.5% vs. SL, 42.9 +/- 10.1%) and 24 h (EYG, 2.1 +/- 3.3% vs. EY, 8.3 +/- 3.9%; SLG, 11.3 +/- 8.3% vs. SL, 18.8 +/- 7.4%) post-thaw in both media. There were no differences (P > 0.05) between cryodiluents in embryo cleavage, percentage of embryos reaching blastocyst, or cell number per blastocyst. The chemically defined, soy-based medium resulted in better preservation of long-term motility and capacitation status of frozen-thawed domestic cat sperm compared with a commercial egg yolk-based extender, without compromising fertilizing ability. PMID- 23110956 TI - Suppression of superconductivity in the Hubbard model by buckling and breathing phonons. AB - We study the effect of buckling and breathing phonons, relevant for cuprate superconductors, on the d-wave superconductivity in the two-dimensional Hubbard model by employing dynamical cluster Monte Carlo calculations. The interplay of electronic correlations and the electron-phonon interaction produces two competing effects: an enhancement of the effective d-wave pairing interaction, which favors d-wave superconductivity, and a strong renormalization of the single particle propagator, which suppresses superconductivity. In the region of the parameter space relevant for cuprate superconductors, we find that the buckling and the breathing phonons suppress the superconductivity. PMID- 23110957 TI - VETSA: the Vietnam Era Twin Study of Aging. AB - The Vietnam Era Twin Study of Aging (VETSA) is a longitudinal behavioral genetic study with a primary focus on cognitive and brain aging in men. It comprises a subset of over 1,200 twins from the Vietnam Era Twin Registry. Like many other studies of aging, the VETSA includes many different phenotypes, but there are some key features that distinguish it from most other behavioral genetic aging studies. First, the initial assessment was conducted when all participants were middle-aged. Second, the age range of participants is narrow; all were in their 50s at the time of the initial recruitment. Third, the study includes an extensive and demanding neurocognitive test battery that was designed to provide good coverage of different cognitive abilities and avoid ceiling effects in middle-aged adults. Fourth, young adult cognitive test data (at an average age of 20 years) are available to provide a gauge of cognitive change. These features make the VETSA ideal for studying the heterogeneity of within-individual trajectories from midlife to old age, and for early detection of risk factors for cognitive decline. PMID- 23110959 TI - A flexible nanobrush pad for the chemical mechanical planarization of Cu/ultra low-k materials. AB - A new idea of polishing pad called flexible nanobrush pad (FNP) has been proposed for the low down pressure chemical mechanical planarization (CMP) process of Cu/ultra-low-k materials. The FNP was designed with a surface layer of flexible brush-like nanofibers which can 'actively' carry nanoscale abrasives in slurry independent of the down pressure. Better planarization performances including high material removal rate, good planarization, good polishing uniformity, and low defectivity are expected in the CMP process under the low down pressure with such kind of pad. The FNP can be made by template-assisted replication or template-based synthesis methods, which will be driven by the development of the preparation technologies for ordered nanostructure arrays. The present work would potentially provide a new solution for the Cu/ultra-low-k CMP process. PMID- 23110958 TI - EAACI: A European Declaration on Immunotherapy. Designing the future of allergen specific immunotherapy. AB - Allergy today is a public health concern of pandemic proportions, affecting more than 150 million people in Europe alone. In view of epidemiological trends, the European Academy of Allergy and Clinical Immunology (EAACI) predicts that within the next few decades, more than half of the European population may at some point in their lives experience some type of allergy.Not only do allergic patients suffer from a debilitating disease, with the potential for major impact on their quality of life, career progression, personal development and lifestyle choices, but they also constitute a significant burden on health economics and macroeconomics due to the days of lost productivity and underperformance. Given that allergy triggers, including urbanization, industrialization, pollution and climate change, are not expected to change in the foreseeable future, it is imperative that steps are taken to develop, strengthen and optimize preventive and treatment strategies.Allergen specific immunotherapy is the only currently available medical intervention that has the potential to affect the natural course of the disease. Years of basic science research, clinical trials, and systematic reviews and meta-analyses have convincingly shown that allergen specific immunotherapy can achieve substantial results for patients, improving the allergic individuals' quality of life, reducing the long-term costs and burden of allergies, and changing the course of the disease. Allergen specific immunotherapy not only effectively alleviates allergy symptoms, but it has a long term effect after conclusion of the treatment and can prevent the progression of allergic diseases.Unfortunately, allergen specific immunotherapy has not yet received adequate attention from European institutions, including research funding bodies, even though this could be a most rewarding field in terms of return on investments, translational value and European integration and, a field in which Europe is recognized as a worldwide leader. Evaluation and surveillance of the full cost of allergic diseases is still lacking and further progress is being stifled by the variety of health systems across Europe. This means that the general population remains unaware of the potential use of allergen specific immunotherapy and its potential benefits.We call upon Europe's policy-makers to coordinate actions and improve individual and public health in allergy by:Promoting awareness of the effectiveness of allergen specific immunotherapyUpdating national healthcare policies to support allergen specific immunotherapyPrioritising funding for allergen specific immunotherapy researchMonitoring the macroeconomic and health economic parameters of allergyReinforcing allergy teaching in medical disciplines and specialtiesThe effective implementation of the above policies has the potential for a major positive impact on European health and well-being in the next decade. PMID- 23110961 TI - Quality of life assessment following adenotonsillectomy for obstructive sleep apnoea in children under three years of age. AB - AIM: To investigate the effects of adenotonsillectomy on the quality of life of children under three years of age with obstructive sleep apnoea. To our knowledge, there have been no previously published studies on this topic. METHOD: Thirty-nine children under three years of age and treated with adenotonsillectomy for obstructive sleep apnoea met the inclusion criteria. A quality of life questionnaire was adapted from the validated, six-item instrument developed by de Serres et al. (2000). The questionnaire assessed improvement in specific domains following adenotonsillectomy. Carers scored each domain on a point scale ranging from 'none' (0) to 'couldn't be more' (6). RESULTS: The quality of life of all children improved after surgery. The greatest mean improvement scores were in the domains of care-giver concern, physical suffering and sleep disturbance. The modal questionnaire score was 4 and the overall mean questionnaire score was 4.2. CONCLUSION: Adenotonsillectomy provides measurable improvements in quality of life for children under three years of age with obstructive sleep apnoea. PMID- 23110960 TI - Synergistic effect of gamma glutamyltransferase and obesity on metabolic syndrome, independent of hepatic steatosis. AB - PURPOSE: Both obesity and gamma glutamyltransferase (GGT) are individually considered to be closely associated with metabolic syndrome (MetS). Whether the 2 factors synergistically associate with MetS is not yet confirmed. The purpose of this study was to investigate whether obesity and GGT are interactively associated with MetS. METHODS: A cross-sectional study of 7390 adults (age 32-62 years old) was conducted from 2009 to 2010. RESULTS: Our results showed that greater serum GGT quartiles were positively associated with all MetS components and fatty liver (P < .001). The odds ratio of MetS increased significantly along with quartiles of GGT and obesity. In comparison with subjects with normal body mass index and first quartile GGT, the odds ratio of MetS in obese groups with 1st, 2nd, 3rd, and 4th quartile GGT were 6.8, 14.5, 20.3, and 45.2, respectively, and it remained tenable after adjustment for fatty liver. The synergy index of GGT and obesity on MetS is 2.2 (95% confidence interval, 1.9-2.6). CONCLUSIONS: Serum GGT level in combination with obesity can be a simple but useful tool for risk stratification of developing MetS. Obese individuals with high-normal GGT levels require close monitoring for high risk of MetS. PMID- 23110962 TI - Defining parasite biodiversity at high latitudes of North America: new host and geographic records for Onchocerca cervipedis (Nematoda: Onchocercidae) in moose and caribou. AB - BACKGROUND: Onchocerca cervipedis is a filarioid nematode of cervids reported from Central America to boreal regions of North America. It is found primarily in subcutaneous tissues of the legs, and is more commonly known as 'legworm'. Blackflies are intermediate hosts and transmit larvae to ungulates when they blood-feed. In this article we report the first records of O. cervipedis from high latitudes of North America and its occurrence in previously unrecognized host subspecies including the Yukon-Alaska moose (Alces americanus gigas) and the Grant's caribou (Rangifer tarandus granti). METHODS: We examined the subcutaneous connective tissues of the metacarpi and/or metatarsi of 34 moose and one caribou for parasitic lesions. Samples were collected from animals killed by subsistence hunters or animals found dead in the Northwest Territories (NT), Canada and Alaska (AK), USA from 2005 to 2012. Genomic DNA lysate was prepared from nematode fragments collected from two moose. The nd5 region of the mitochondrial DNA was amplified by PCR and sequenced. RESULTS: Subcutaneous nodules were found in 12 moose from the NT and AK, and one caribou from AK. Nematodes dissected from the lesions were identified as Onchocerca cervipedis based on morphology of female and male specimens. Histopathological findings in moose included cavitating lesions with multifocal granulomatous cellulitis containing intralesional microfilariae and adults, often necrotic and partially mineralized. Lesions in the caribou included periosteitis with chronic cellulitis, eosinophilic and lymphoplasmacytic infiltrate, and abundant granulation associated with intralesional adult nematodes and larvae. Sequences of the nd5 region (471bp), the first generated for this species, were deposited with Genbank (JN580791 and JN580792). Representative voucher specimens were deposited in the archives of the United States National Parasite Collection. CONCLUSIONS: The geographic range of O. cervipedis is broader than previously thought, and extends into subarctic regions of western North America, at least to latitude 66 degrees N. The host range is now recognized to include two additional subspecies: the Yukon-Alaska moose and Grant's caribou. Accelerated climate change at high latitudes may affect vector dynamics, and consequently the abundance and distribution of O. cervipedis in moose and caribou. Disease outbreaks and mortality events associated with climatic perturbations have been reported for other filarioids, such as Setaria tundra in Fennoscandia, and may become an emerging issue for O. cervipedis in subarctic North America. PMID- 23110963 TI - Three uses of an extra length of jejunum in pharyngo-oesophageal reconstruction with free jejunal flap. AB - BACKGROUND: The free jejunal flap is a widely spread method of pharyngo oesophageal reconstruction and can also be used in patients presenting with aspiration tendency following treatment for head and neck cancers or caustic injury of the upper aero-digestive tract to create a separate food pathway, the free jejunal diversionary conduit. METHODS: Sixteen patients, 13 males and 3 females, aged between 32 and 66 years, undergoing pharyngo-oesophageal reconstruction with a free jejunal flap between October 2005 and July 2011, were included in this study. An extra length of jejunum was used in 10 patients for widening of the upper portion of a prefabricated free jejunal flap, in three patients who developed a leak at the jejuno-oesophageal junction during the follow-up for creation of a seromuscular flap that was used to seal off the leak and in three patients with aspiration tendency for simultaneous creation of a free jejunal diversionary conduit and a separate pharyngo-cutaneous fistula. RESULTS: All flaps survived completely. No complication was observed at the pharyngo-jejunal junction during the follow-up in patients reconstructed with the prefabricated free jejunal flap. No recurrence of the leak was observed in patients treated with a seromuscular flap during the follow-up period. Patients with a free jejunal diversionary conduit did not experience episodes of aspiration and no obstruction of the pharyngo-cutaneous fistula was noted in the postoperative period. CONCLUSIONS: We want to encourage the use of an extra length of jejunum in pharyngo-oesophageal reconstruction with a free jejunal flap because it helps to manage postoperative complications, such as leakage and stricture, and it does not increase the morbidity related to the reconstruction. Furthermore, we believe that the creation of a separate pharyngo-cutaneous fistula represents another step forward in the improvement of pharyngo oesophageal reconstruction with a free jejunal diversionary conduit. PMID- 23110964 TI - Modelling fat mass as a function of weekly physical activity profiles measured by actigraph accelerometers. AB - We show results on the Avon longitudinal study of parents and children (ALSPAC) using a new approach for modelling the relationship between health outcomes and physical activity assessed by accelerometers. The key feature of the model is that it uses the histogram of physical activity counts as a predictor function, rather than scalar summary measures such as average daily moderate to vigorous physical activity (MVPA). Three models are fitted: (1a) A regression of fat mass at age 12 (N = 4164) onto the histogram of accelerometer counts at age 12; (1b) A regression of fat mass at age 14 (N = 2403) onto the histogram of accelerometer counts at age 12 and (1c) a regression of fat mass at age 14 (N = 2413) onto the accelerometer counts at age 14. All three models significantly improve on models including MVPA instead of the histogram and improve the goodness of fit of models (2a), (2b) and (2c) from R(2) = 0.267, 0.248 and 0.230 to R(2) = 0.292, 0.263 and 0.258 for models (1a), (1b) and (1c) respectively. The proportion of time spent in sedentary and very light activity (corresponding to slow walking and similar activities) has a positive contribution towards fat mass and time spent in moderate to vigorous activity has a negative contribution towards fat mass. PMID- 23110965 TI - Sexual obsessions and suicidal behaviors in patients with mood disorders, panic disorder and schizophrenia. AB - BACKGROUND: The topic of sexual obsessions as a psychiatric symptom has not been well investigated. The aim of this study was twofold: 1) to explore the presence of sexual obsessions in patients with mood disorders (n=156), panic disorder (n=54) and schizophrenia (n=79), with respect to non-psychiatric subjects (n=100); 2) to investigate the relationship between sexual obsessions and suicidal behaviors, taking into account socio-demographic variables ad mental disorders. METHODS: 289 psychiatric patients with mood disorders, panic disorder or schizophrenia, were recruited at the Italian University departments of psychiatry along with 100 non-psychiatric subjects, who presented for a routine eye exam at the ophthalmology department of the same Universities. The assessments included: the Structured Clinical Interview for DSM-IV-TR, the Brief Psychiatric Rating Scale (BPRS), the Obsessive-Compulsive Spectrum Self-Report (OBS-SR), for sexual obsession, and the Mood Spectrum-Self Report lifetime version (MOODS-SR). Suicidality was assessed by means of 6 items of the MOODS-SR. RESULTS: Sexual obsessions were more frequent in schizophrenia (54.4%), followed by mood disorders (35.9%). Among schizophrenia patients, males reported more sexual obsessions than females (P<0.01). Subjects who were more likely to report suicidal behaviors (suicidal ideation, plans and attempts) were female (adjusted OR=1.99), patients with mental disorders, specifically mood disorders (adjusted OR=11.5), schizophrenia (adjusted OR=3.7) or panic disorder (adjusted OR=2.9), and subjects who reported lifetime sexual obsessions (adjusted OR= 3.6). Sexual obsessions remained independently associated with all aspects of suicidal behaviors. Age, education, marital and employment status were not related to suicidal behaviors. CONCLUSIONS: Special attention should be given to investigate and establish effective strategies of treatment for sexual obsessions, especially those with comorbid mood disorders or schizophrenia. PMID- 23110966 TI - Fractional versus ablative erbium:yttrium-aluminum-garnet laser resurfacing for facial rejuvenation: an objective evaluation. AB - BACKGROUND: Laser is one of the main tools for skin resurfacing. Erbium:yttrium aluminum-garnet (Er:YAG) was the second ablative laser, after carbon dioxide, emitting wavelength of 2940 nm. Fractional laser resurfacing has been developed to overcome the drawbacks of ablative lasers. OBJECTIVE: We aimed to objectively evaluate the histopathological and immunohistochemical effects of Er:YAG 2940-nm laser for facial rejuvenation (multiple sessions of fractional vs single session of ablative Er:YAG laser). METHODS: Facial resurfacing with single-session ablative Er:YAG laser was performed on 6 volunteers. Another 6 were resurfaced using fractional Er:YAG laser (4 sessions). Histopathological (hematoxylin-eosin, orcein, Masson trichrome, and picrosirius red stains) and immunohistochemical assessment for skin biopsy specimens were done before laser resurfacing and after 1 and 6 months. Histometry for epidermal thickness and quantitative assessment for neocollagen formation; collagen I, III, and VII; elastin; and tropoelastin were done for all skin biopsy specimens. RESULTS: Both lasers resulted in increased epidermal thickness. Dermal collagen showed increased neocollagen formation with increased concentration of collagen types I, III, and VII. Dermal elastic tissue studies revealed decreased elastin whereas tropoelastin concentration increased after laser resurfacing. Neither laser showed significant difference between their effects clinically and on dermal collagen. Changes in epidermal thickness, elastin, and tropoelastin were significantly more marked after ablative laser. LIMITATIONS: The small number of patients is a limitation, yet the results show significant improvement. CONCLUSION: Multiple sessions of fractional laser have comparable effects to a single session of ablative Er:YAG laser on dermal collagen but ablative laser has more effect on elastic tissue and epidermis. PMID- 23110967 TI - Prognostic factors for local control of stage I non-small cell lung cancer in stereotactic radiotherapy: a retrospective analysis. AB - BACKGROUND: The purpose of this study is to investigate the prognostic factors of stereotactic radiotherapy for stage I NSCLC to improve outcomes. METHODS: Stage I non-small cell lung cancer patients who were treated with stereotactic radiotherapy between 2005 and 2009 at our hospital were enrolled in this study. The primary endpoint was local control rate. Survival estimates were calculated from the completion date of radiotherapy using the Kaplan-Meier method. The prognostic factors including patients' characteristics and dose-volume histogram parameters were evaluated using Cox's proportional hazard regression model. RESULTS: Eighty patients (81 lesions) treated with 3 dose levels, 48 Gy/4 fractions, 60 Gy/8 fractions and 60 Gy/15 fractions, were enrolled in this study. Median follow-up was 30.4 months (range, 0.3 - 78.5 months). A Cox regression model showed T factor (p = 0.013), biological effective dose calculated from prescribed dose (BED10) (p = 0.048), and minimum dose for PTV (p = 0.013) to be prognostic factors for local control. Three-year overall survival rate and local control rate were 89.9% (T1: 86.8%, T2: 100%) and 89.0% (T1: 97.9%; T2: 64.8%), respectively. When the 3-year local control rates were examined by prescribed doses, they were 100% for the dose per fraction of 48 Gy /4 fractions (105.6 Gy BED10), 82.1% for 60 Gy/8 fractions (105 Gy BED10), and 57.1% for 60 Gy/15 fractions (84 Gy BED10). The median value of the minimum dose for PTV (%) was 89.88 (%), and the 3-year local control rates were 100% in those with the minimum dose for PTV (%) >= 89.88% and 79.2% in those with the minimum dose for PTV (%) < 89.88%. CONCLUSIONS: Our results suggest that T factor, BED10, and minimum dose for PTV influence the local control rate. Local control rate can be improved by securing the minimum dose for PTV. PMID- 23110968 TI - Dragon TIS Spotter: an Arabidopsis-derived predictor of translation initiation sites in plants. AB - SUMMARY: In higher eukaryotes, the identification of translation initiation sites (TISs) has been focused on finding these signals in cDNA or mRNA sequences. Using Arabidopsis thaliana (A.t.) information, we developed a prediction tool for signals within genomic sequences of plants that correspond to TISs. Our tool requires only genome sequence, not expressed sequences. Its sensitivity/specificity is for A.t. (90.75%/92.2%), for Vitis vinifera (66.8%/94.4%) and for Populus trichocarpa (81.6%/94.4%), which suggests that our tool can be used in annotation of different plant genomes. We provide a list of features used in our model. Further study of these features may improve our understanding of mechanisms of the translation initiation. AVAILABILITY AND IMPLEMENTATION: Our tool is implemented as an artificial neural network. It is available as a web-based tool and, together with the source code, the list of features, and data used for model development, is accessible at http://cbrc.kaust.edu.sa/dts. PMID- 23110969 TI - MP-T: improving membrane protein alignment for structure prediction. AB - MOTIVATION: Membrane proteins are clinically relevant, yet their crystal structures are rare. Models of membrane proteins are typically built from template structures with low sequence identity to the target sequence, using a sequence-structure alignment as a blueprint. This alignment is usually made with programs designed for use on soluble proteins. Biological membranes have layers of varying hydrophobicity, and membrane proteins have different amino-acid substitution preferences from their soluble counterparts. Here we include these factors into an alignment method to improve alignments and consequently improve membrane protein models. RESULTS: We developed Membrane Protein Threader (MP-T), a sequence-structure alignment tool for membrane proteins based on multiple sequence alignment. Alignment accuracy is tested against seven other alignment methods over 165 non-redundant alignments of membrane proteins. MP-T produces more accurate alignments than all other methods tested (deltaF(M) from +0.9 to +5.5%). Alignments generated by MP-T also lead to significantly better models than those of the best alternative alignment tool (one-fourth of models see an increase in GDT_TS of >=4%). AVAILABILITY: All source code, alignments and models are available at http://www.stats.ox.ac.uk/proteins/resources PMID- 23110970 TI - 13CFLUX2--high-performance software suite for (13)C-metabolic flux analysis. AB - SUMMARY: (13)C-based metabolic flux analysis ((13)C-MFA) is the state-of-the-art method to quantitatively determine in vivo metabolic reaction rates in microorganisms. 13CFLUX2 contains all tools for composing flexible computational (13)C-MFA workflows to design and evaluate carbon labeling experiments. A specially developed XML language, FluxML, highly efficient data structures and simulation algorithms achieve a maximum of performance and effectiveness. Support of multicore CPUs, as well as compute clusters, enables scalable investigations. 13CFLUX2 outperforms existing tools in terms of universality, flexibility and built-in features. Therewith, 13CFLUX2 paves the way for next-generation high resolution (13)C-MFA applications on the large scale. AVAILABILITY AND IMPLEMENTATION: 13CFLUX2 is implemented in C++ (ISO/IEC 14882 standard) with Java and Python add-ons to run under Linux/Unix. A demo version and binaries are available at www.13cflux.net. PMID- 23110971 TI - Retrospective study of sensitivity and specificity of EEG in the elderly compared with younger age groups. AB - Following a recommendation from a Good Practice Guide published in Scotland stating that EEG should not be routinely used in the diagnosis of epilepsy in the elderly, we conducted a retrospective study to ascertain the effects this recommendation had. We found that predating the recommendation, there had already been a decline in the use of EEG in people aged 65 and over. Detailed examination of a 3.5-year epoch which straddled 2 years before the recommendation and 1.5 years after its publication revealed no evidence of a change in the type of referrals but just in the number of referrals. Comparison with 2 younger cohorts showed that EEG in the elderly had the same specificity and sensitivity as in the younger age groups and was of particular use in picking up previously unsuspected non-convulsive status. We conclude the EEG remains an important diagnostic adjunct in the elderly. PMID- 23110972 TI - Blockade of the renin-angiotensin system improves the early stages of liver regeneration and liver function. AB - BACKGROUND: Partial hepatectomy is the preferred option for selected patients with colorectal cancer liver metastases (CRCLM). Sufficient liver regeneration (LR) is essential for a successful outcome in these patients. The blockade of the renin-angiotensin system (RAS) reduces the growth of several tumor types. The RAS also acts as a regulator of liver fibrosis and potentially LR. The angiotensin converting enzyme (ACE) inhibitor, captopril, significantly inhibits the growth of CRCLM, but its effect on LR remains undefined. METHODS: After 70% of partial hepatectomy, mice were randomly assigned to control or captopril-treated groups. LR was measured by liver-to-body weight ratio on days 1, 2, 4, 6, and 8. Hepatocyte proliferation, apoptosis and cell size, hepatic stellate cell (HSC) count, and sinusoidal endothelial cell density were quantified. Matrix metalloproteinase 9 (MMP-9) protein levels, liver injury markers, and RAS messenger RNA levels were also determined. RESULTS: At day 2, captopril increased liver-to-body weight ratio (56.5 +/- 1.7 captopril versus 49.3 +/- 2.4 control, P = 0.027). This was associated with increased HSC count (65.4 +/- 4.8 cells per 100,000 MUm(2), 48.7 +/- 2.3, P = 0.007) and MMP-9 levels (0.68 +/- 0.12 AU, 0.12 +/- 0.04, P = 0.014). The messenger RNA levels of angiotensin-converting enzyme (P = 0.045) and angiotensin 1 receptor (P = 0.039) were reduced by captopril at day 2. CONCLUSION: Captopril enhanced early LR. This effect was associated with increased HSC numbers and MMP-9 protein, whereas hepatocyte proliferation was lower than controls. Captopril may provide a beneficial treatment option for the management of patients with CRCLM. PMID- 23110973 TI - Need for subsequent fundoplication after gastrostomy based on patient characteristics. AB - BACKGROUND: Gastrostomy tube placement is common in children. Many of the conditions associated with need for gastrostomy are also associated with gastroesophageal reflux. It is not clear how many patients without complicated reflux will subsequently require a fundoplication or which conditions increase this risk. Therefore, we performed a two-center review to determine the disease specific propensity for fundoplication after gastrostomy tube placement. METHODS: The data set was retrospectively collected from two centers from 2000 to 2008. All patients underwent gastrostomy tube placement without fundoplication owing to the surgeon's discernment that fundoplication was not needed at the time. Pearson's correlation was used to evaluate the influence of patient variables and operative approach against the subsequent need for fundoplication. Significance was defined as two-tailed P <= 0.01. Logistic regression analysis was used to evaluate independence. RESULTS: A total of 684 patients underwent gastrostomy tube placement only, of which 124 were open, 282 laparoscopic, and 278 endoscopic (percutaneous endoscopic gastrostomy). The mean patient age was 2.9 years. Subsequent fundoplication was performed in 62 patients (9.1%). The mean interval to fundoplication was 20.7 months. Cerebral palsy and anoxic brain injury had the most significant correlation with subsequent fundoplication. These were also independent predictors. The laparoscopic approach had a negative correlation with the subsequent need for fundoplication. CONCLUSIONS: The low incidence of subsequent fundoplication in children who undergo gastrostomy tube placement justifies conservative use of fundoplication in the absence of complicated reflux. Those with cerebral palsy and anoxic brain injury appeared to have the greatest risk of the need for subsequent fundoplication. PMID- 23110975 TI - Manual Gene Ontology annotation workflow at the Mouse Genome Informatics Database. AB - The Mouse Genome Database, the Gene Expression Database and the Mouse Tumor Biology database are integrated components of the Mouse Genome Informatics (MGI) resource (http://www.informatics.jax.org). The MGI system presents both a consensus view and an experimental view of the knowledge concerning the genetics and genomics of the laboratory mouse. From genotype to phenotype, this information resource integrates information about genes, sequences, maps, expression analyses, alleles, strains and mutant phenotypes. Comparative mammalian data are also presented particularly in regards to the use of the mouse as a model for the investigation of molecular and genetic components of human diseases. These data are collected from literature curation as well as downloads of large datasets (SwissProt, LocusLink, etc.). MGI is one of the founding members of the Gene Ontology (GO) and uses the GO for functional annotation of genes. Here, we discuss the workflow associated with manual GO annotation at MGI, from literature collection to display of the annotations. Peer-reviewed literature is collected mostly from a set of journals available electronically. Selected articles are entered into a master bibliography and indexed to one of eight areas of interest such as 'GO' or 'homology' or 'phenotype'. Each article is then either indexed to a gene already contained in the database or funneled through a separate nomenclature database to add genes. The master bibliography and associated indexing provide information for various curator-reports such as 'papers selected for GO that refer to genes with NO GO annotation'. Once indexed, curators who have expertise in appropriate disciplines enter pertinent information. MGI makes use of several controlled vocabularies that ensure uniform data encoding, enable robust analysis and support the construction of complex queries. These vocabularies range from pick-lists to structured vocabularies such as the GO. All data associations are supported with statements of evidence as well as access to source publications. PMID- 23110974 TI - Recent advances in biocuration: meeting report from the Fifth International Biocuration Conference. AB - The 5th International Biocuration Conference brought together over 300 scientists to exchange on their work, as well as discuss issues relevant to the International Society for Biocuration's (ISB) mission. Recurring themes this year included the creation and promotion of gold standards, the need for more ontologies, and more formal interactions with journals. The conference is an essential part of the ISB's goal to support exchanges among members of the biocuration community. Next year's conference will be held in Cambridge, UK, from 7 to 10 April 2013. In the meanwhile, the ISB website provides information about the society's activities (http://biocurator.org), as well as related events of interest. PMID- 23110976 TI - The conjoint influence of home enriched environment and lead exposure on children's cognition and behaviour in a Mexican lead smelter community. AB - A range of studies has been conducted on the detrimental effects of lead in mining and smelting communities. The neurocognitive and behavioural health effects of lead on children are well known. This research characterized the conjoint influence of lead exposure and home enriched environment on neurocognitive function and behaviour for first-grade children living in a Mexican lead smelter community. Structural equation models were used for this analysis with latent outcome variables, Cognition and Behaviour, constructed based on a battery of assessments administered to the first-grade children, their parents, and teachers. Structural equation modelling was used to describe complex relationships of exposure and health outcomes in a manner that permitted partition of both direct and indirect effects of the factors being measured. Home Environment (a latent variable constructed from information on mother's education and support of school work and extracurricular activities), and child blood lead concentration each had a main significant effect on cognition and behaviour. However, there were no statistically significant moderation relationships between lead and Home Environment on these latent outcomes. Home Environment had a significant indirect mediation effect between lead and both Cognition and Behaviour (p-value<0.001). The mediation model had a good fit with Root Mean Square Error of Approximation <0.0001 and a Weighted Root Mean Square Residual of 0.895. These results were highly significant and suggest that Home Environment has a moderate mediation effect with respect to lead effects on Behaviour (beta=0.305) and a lower mediation effect on Cognition (beta=0.184). The extent of home enrichment in this study was most highly related to the mother's support of schoolwork and slightly less by the mother's support of extracurricular activities or mother's education. Further research may be able to develop approaches to support families to make changes within their home and child rearing practices, or advocate for different approaches to support their child's behaviour to reduce the impact of lead exposure on children's cognitive and behavioural outcomes. PMID- 23110977 TI - Sensitivity, specificity and predictive values of linear and nonlinear indices of heart rate variability in stable angina patients. AB - BACKGROUND: Decreased heart rate variability (HRV) is related to higher morbidity and mortality. In this study we evaluated the linear and nonlinear indices of the HRV in stable angina patients submitted to coronary angiography. METHODS: We studied 77 unselected patients for elective coronary angiography, which were divided into two groups: coronary artery disease (CAD) and non-CAD groups. For analysis of HRV indices, HRV was recorded beat by beat with the volunteers in the supine position for 40 minutes. We analyzed the linear indices in the time (SDNN [standard deviation of normal to normal], NN50 [total number of adjacent RR intervals with a difference of duration greater than 50ms] and RMSSD [root-mean square of differences]) and frequency domains ultra-low frequency (ULF) <= 0,003 Hz, very low frequency (VLF) 0,003 - 0,04 Hz, low frequency (LF) (0.04-0.15 Hz), and high frequency (HF) (0.15-0.40 Hz) as well as the ratio between LF and HF components (LF/HF). In relation to the nonlinear indices we evaluated SD1, SD2, SD1/SD2, approximate entropy (-ApEn), alpha1, alpha2, Lyapunov Exponent, Hurst Exponent, autocorrelation and dimension correlation. The definition of the cutoff point of the variables for predictive tests was obtained by the Receiver Operating Characteristic curve (ROC). The area under the ROC curve was calculated by the extended trapezoidal rule, assuming as relevant areas under the curve >= 0.650. RESULTS: Coronary arterial disease patients presented reduced values of SDNN, RMSSD, NN50, HF, SD1, SD2 and -ApEn. HF <= 66 ms2, RMSSD <= 23.9 ms, ApEn <=-0.296 and NN50 <= 16 presented the best discriminatory power for the presence of significant coronary obstruction. CONCLUSION: We suggest the use of Heart Rate Variability Analysis in linear and nonlinear domains, for prognostic purposes in patients with stable angina pectoris, in view of their overall impairment. PMID- 23110978 TI - Animal DNA diagnostics - personal genomics for our pets and livestock is at the horizon. PMID- 23110980 TI - Fossa ovalis tear causing right to left shunting in a Cavalier King Charles Spaniel. AB - Left atrial tear is an infrequent sequela of severe mitral regurgitation due to myxomatous mitral valve degeneration. Interatrial septal tear due to mitral regurgitation causing a left-to-right shunt is uncommon. Right to left shunting secondary to acute interatrial septal tear is very rarely reported in the human literature, and has not been reported in the veterinary literature in a dog. This case describes the clinical, radiographic, echocardiographic, gross pathologic, and histopathologic features of a dog presented in acute respiratory distress secondary to acute onset right to left shunting through the interatrial septum. This was later documented to be due to a tear in the septum secondary to tricuspid regurgitation and pulmonary hypertension. The presence of an acquired right to left shunting atrial septal defect is of clinical and prognostic significance, and should be considered in cases of acute respiratory distress. PMID- 23110981 TI - Wrist-worn accelerometers in assessment of energy expenditure during intensive training. AB - We assessed the ability of the Polar activity recorder (AR) to measure energy expenditure (EE) during military training. Twenty-four voluntary male conscripts participated in the study and wore an AR on the non-dominant wrist 24 h a day for 7 d. The AR analyzed and stored the frequency of hand movements (f_hand) into memory at 1 min intervals. The relationship between f_hand and EE was studied over a 7 d period of military training using the doubly labeled water (DLW) technique. In addition, the relationship between f_hand and EE was analyzed during walking and running on a treadmill with an indirect calorimeter (IC), and f_hand was measured during a supervised 45 min field march test where the conscripts carried combat gear. EE was expressed as physical activity level (PAL), total energy expenditure (TEE), and activity-induced energy expenditure adjusted for body mass (AEE/BM). Over the 7 d period, f_hand alone explained 46% of inter-individual variation in PAL(DLW). After inclusion of body height and mass in the model used to predict PAL(DLW) from f_hand, a very high positive correlation and a low standard error of estimate (SEE) were observed between the AR and DLW techniques: for TEE r = 0.86 (p < 0.001), the SEE was 6.3%, and for AEE/BM r = 0.84 (p < 0.001), the SEE was 12.8%. In the treadmill exercise, f_hand correlated highly with PAL(IC) (r = 0.97 +/- 0.02). In the 45 min field march test, the AR measured similar f_hand as on the treadmill at the same speed. In conclusion, the wrist-worn AR can be regarded as a reliable and valid method for assessing EE during intensive training. PMID- 23110979 TI - Detection of dengue group viruses by fluorescence in situ hybridization. AB - BACKGROUND: Dengue fever (DF) and dengue hemorrhagic fever (DHF) represent a global challenge in public health. It is estimated that 50 to 100 million infections occur each year causing approximately 20,000 deaths that are usually linked to severe cases like DHF and dengue shock syndrome. The causative agent of DF is dengue virus (genus Flavivirus) that comprises four distinct serotypes (DENV-1 to DENV-4). Fluorescence in situ hybridization (FISH) has been used successfully to detect pathogenic agents, but has not been implemented in detecting DENV. To improve our understanding of DENV infection and dissemination in host tissues, we designed specific probes to detect DENV in FISH assays. METHODS: Oligonucleotide probes were designed to hybridize with RNA from the broadest range of DENV isolates belonging to the four serotypes, but not to the closest Flavivirus genomes. Three probes that fit the criteria defined for FISH experiments were selected, targeting both coding and non-coding regions of the DENV genome. These probes were tested in FISH assays against the dengue vector Aedes albopictus (Diptera: Culicidae). The FISH experiments were led in vitro using the C6/36 cell line, and in vivo against dissected salivary glands, with epifluorescence and confocal microscopy. RESULTS: The three 60-nt oligonucleotides probes DENV-Probe A, B and C cover a broad range of DENV isolates from the four serotypes. When the three probes were used together, specific fluorescent signals were observed in C6/36 infected with each DENV serotypes. No signal was detected in either cells infected with close Flavivirus members West Nile virus or yellow fever virus. The same protocol was used on salivary glands of Ae. albopictus fed with a DENV-2 infectious blood-meal which showed positive signals in the lateral lobes of infected samples, with no significant signal in uninfected mosquitoes. CONCLUSION: Based on the FISH technique, we propose a way to design and use oligonucleotide probes to detect arboviruses. Results showed that this method was successfully implemented to specifically detect DENV in a mosquito cell line, as well as in mosquito salivary glands for the DENV-2 serotype. In addition, we emphasize that FISH could be an alternative method to detect arboviruses in host tissues, also offering to circumvent the discontinuity of antibodies used in immunofluorescent assays. PMID- 23110982 TI - Vertebral artery stump syndrome in acute ischemic stroke. AB - Although the carotid artery stump as an embolic source for ischemic stroke has been well described, there have been few systematic reports of a similar syndrome in the posterior circulation (PC) after vertebral artery (VA) origin occlusion. The aim of this study was to identify the incidence and characteristics of acute ischemic stroke with VA stump syndrome. Of 3463 consecutive patients who were admitted within 7 days after onset, 865 patients with acute ischemic stroke in the PC were enrolled. The diagnostic criteria of VA stump syndrome included: (1) acute ischemic stroke in the posterior circulation; (2) the VA origin occlusion identified on MRA, duplex ultrasound, CT angiography, and/or conventional angiography; (3) presence of distal antegrade flow in the ipsilateral VA; and (4) absence of other causes of ischemic stroke. Of the 865 patients with PC stroke, 12 (1.4%) were diagnosed as having VA stump syndrome. The ischemic lesions included the cerebellum in all patients. Nine patients had multiple ischemic lesions in the brain stem, thalamus, or posterior lobe other than cerebellum. On duplex ultrasound, a to-and-fro flow pattern was observed in the culprit VA in 10 patients. Three patients had recurrences of ischemic stroke in the PC during the acute phase. VA stump syndrome was not a rare mechanism of PC stroke, and there was a high rate of stroke recurrence during the acute phase. Vascular assessment by a multimodality approach can be used to promptly detect VA stump syndrome. PMID- 23110984 TI - New approaches in alternative donor transplantation. PMID- 23110983 TI - Characterization of residential pesticide use and chemical formulations through self-report and household inventory: the Northern California Childhood Leukemia study. AB - BACKGROUND: Home and garden pesticide use has been linked to cancer and other health outcomes in numerous epidemiological studies. Exposure has generally been self-reported, so the assessment is potentially limited by recall bias and lack of information on specific chemicals. OBJECTIVES: As part of an integrated assessment of residential pesticide exposure, we identified active ingredients and described patterns of storage and use. METHODS: During a home interview of 500 residentially stable households enrolled in the Northern California Childhood Leukemia Study during 2001-2006, trained interviewers inventoried residential pesticide products and queried participants about their storage and use. U.S. Environmental Protection Agency registration numbers, recorded from pesticide product labels, and pesticide chemical codes were matched to public databases to obtain information on active ingredients and chemical class. Poisson regression was used to identify independent predictors of pesticide storage. Analyses were restricted to 259 participating control households. RESULTS: Ninety-five percent (246 of 259) of the control households stored at least one pesticide product (median, 4). Indicators of higher sociodemographic status predicted more products in storage. We identified the most common characteristics: storage areas (garage, 40%; kitchen, 20%), pests treated (ants, 33%; weeds, 20%), pesticide types (insecticides, 46%; herbicides, 24%), chemical classes (pyrethroids, 77%; botanicals, 50%), active ingredients (pyrethrins, 43%) and synergists (piperonyl butoxide, 42%). Products could contain multiple active ingredients. CONCLUSIONS: Our data on specific active ingredients and patterns of storage and use will inform future etiologic analyses of residential pesticide exposures from self reported data, particularly among households with young children. PMID- 23110985 TI - Graft-versus-host disease: state of the science. PMID- 23110986 TI - Multi-institutional assessments of transplantation for metabolic disorders. PMID- 23110987 TI - Hematopoietic cell transplantation for thalassemia: a global perspective BMT tandem meeting 2013. AB - Hematopoietic cell transplantation (HCT) remains the sole available curative option for patients with beta-thalassemia major. Expanded and improved supportive therapies for thalassemia now routinely extend the life span of affected individuals well into adulthood. Consequently, in regions of the world where this care is readily available, HCT has been pursued infrequently, in part owing to concerns about an expected lack of balance between risks and benefits. More recently, however, recognition of significant health problems in older patients with thalassemia, along with recognition of increased risks of graft-versus-host disease (GVHD), graft rejection, and impaired organ function leading to inferior HCT outcomes in this particular group, seem to be turning the wheels and tipping the balance again in the direction of consideration for earlier HCTs. In contrast, in countries where thalassemia is most prevalent (>100,000 new children born each year in Middle East and southeast Asia), lack of supportive care standards together with often insufficient access to dedicated health care facilities, results in the majority of these children not reaching adulthood, further supporting the need for expanded access to HCT for these patients. The cost of HCT is equivalent to that of a few years of noncurative supportive care, such that HCT in low-risk young children with a compatible sibling is justified not only medically and ethically but also financially. International cooperation can play a major role in increasing access to safe and affordable HCT in countries where there is a considerable shortage of transplantation centers. In this article, we review the current status of bone marrow transplantation for thalassemia major, with particular emphasis on a global prospective. PMID- 23110988 TI - Weight loss and Alzheimer's disease: temporal and aetiologic connections. AB - The intermediate and advanced stages of Alzheimer's disease (AD) are frequently associated with weight loss (WL), but WL may even precede the onset of cognitive symptoms. This review focuses on the possible aetiologic and temporal relationships between AD and WL. When WL occurs some years before any signs of cognitive impairment, it may be a risk factor for dementia due to deficiency of several micronutrients, such as vitamins and essential fatty acids, and consequent oxidative tissue damage. The leptin reduction associated with WL may also facilitate cognitive decline. The mechanisms potentially inducing WL in AD include lower energy intake, higher resting energy expenditure, exaggerated physical activity, or combinations of these factors. A hypermetabolic state has been observed in animals with AD, but has not been confirmed in human subjects. This latter mechanism could involve amyloid assemblies that apparently increase the circulating cytokine levels and proton leakage in mitochondria. WL may be caused by patients' increased physical activity as they develop abnormal motor behaviour (restlessness and agitation) and waste energy while trying to perform daily activities. During the course of AD, patients usually find it increasingly difficult to eat, so they ingest less food. AD-related neurodegeneration also affects brain regions involved in regulating appetite. The caregiver has an important role in ensuring an adequate food intake and controlling behavioural disturbances. In conclusion, WL is closely linked to AD, making periodic nutritional assessments and appropriate dietary measures important aspects of an AD patient's treatment. PMID- 23110989 TI - Cancer registries in four provinces in Turkey: a case study. AB - BACKGROUND: The burden of cancer affects all countries; while high-income countries have the capacity and resources to establish comprehensive cancer control programs, low and middle-income countries have limited resources to develop such programs. This paper examines factors associated with the development of cancer registries in four provinces in Turkey. It looks at the progress made by these registries, the challenges they faced, and the lessons learned. Other countries with similar resources can benefit from the lessons identified in this case study. METHODS: A mix of qualitative case study methods including key informant interviews, document review and questionnaires was used. RESULTS: This case study showed that surveillance systems that accurately report current cancer-related data are essential components of a country's comprehensive cancer control program. At the initial stages, Turkey established one cancer registry with international support, which was used as a model for other registries. The Ministry of Health recognized the value of the registry data and its contribution to the country's cancer control program and is supporting sustainability of these registries as a result. CONCLUSIONS: This study demonstrates how Turkey was able to use resources from multiple sources to enhance its population based cancer registry system in four provinces. With renewed international interest in non-communicable diseases and cancer following the 2011 UN high-level meeting on NCDs, low- and middle- income countries can benefit from Turkey's experience. Other countries can utilize lessons learned from Turkey as they address cancer burden and establish their own registries. PMID- 23110990 TI - Morphological, compositional, structural, and optical properties of Si-nc embedded in SiOx films. AB - Structural, compositional, morphological, and optical properties of silicon nanocrystal (Si-nc) embedded in a matrix of non-stoichiometric silicon oxide (SiOx) films were studied. SiOx films were prepared by hot filament chemical vapor deposition technique in the 900 to 1,400 degrees C range. Different microscopic and spectroscopic characterization techniques were used. The film composition changes with the growth temperature as Fourier transform infrared spectroscopy, energy dispersive X-ray spectroscopy, and X-ray photoelectron spectroscopy reveal. High-resolution transmission electron microscopy supports the existence of Si-ncs with a diameter from 1 to 6.5 nm in the matrix of SiOx films. The films emit in a wide photoluminescent spectrum, and the maximum peak emission shows a blueshift as the growth temperature decreases. On the other hand, transmittance spectra showed a wavelength shift of the absorption border, indicating an increase in the energy optical bandgap, when the growth temperature decreases. A relationship between composition, Si-nc size, energy bandgap, PL, and surface morphology was obtained. According to these results, we have analyzed the dependence of PL on the composition, structure, and morphology of the Si-ncs embedded in a matrix of non-stoichiometric SiOx films. PMID- 23110992 TI - Scanning tunneling microscopy of interface properties of Bi2Se3 on FeSe. AB - We investigate the heteroepitaxial growth of Bi(2)Se(3) films on FeSe substrates by low-temperature scanning tunneling microscopy/spectroscopy. The growth of Bi(2)Se(3) on FeSe proceeds via van der Waals epitaxy with atomically flat morphology. A striped moire pattern originating from the lattice mismatch between Bi(2)Se(3) and FeSe is observed. Tunneling spectra reveal the spatially inhomogeneous electronic structure of the Bi(2)Se(3) thin films, which can be ascribed to the charge transfer at the interface. PMID- 23110991 TI - Kyasanur forest disease. AB - In the spring of 1957, an outbreak of severe disease was documented in people living near the Kyasanur forest in Karnataka state, India, which also affected wild nonhuman primates. Collection of samples from dead animals and the use of classical virological techniques led to the isolation of a previously unrecognized virus, named Kyasanur forest disease virus (KFDV), which was found to be related to the Russian spring-summer encephalitis (RSSE) complex of tick borne viruses. Further evaluation found that KFD, which frequently took the form of a hemorrhagic syndrome, differed from most other RSSE virus infections, which were characterized by neurologic disease. Its association with illness in wild primates was also unique. Hemaphysalis spinigera was identified as the probable tick vector. Despite an estimated annual incidence in India of 400-500 cases, KFD is historically understudied. Most of what is known about the disease comes from studies in the late 1950s and early 1960s by the Virus Research Center in Pune, India and their collaborators at the Rockefeller Foundation. A report in ProMED in early 2012 indicated that the number of cases of KFD this year is possibly the largest since 2005, reminding us that there are significant gaps in our knowledge of the disease, including many aspects of its pathogenesis, the host response to infection and potential therapeutic options. A vaccine is currently in use in India, but efforts could be made to improve its long-term efficacy. PMID- 23110993 TI - Access to regulatory data from the European Medicines Agency: the times they are a-changing. AB - Systematic reviewers are increasingly trying to obtain regulatory clinical study reports (CSRs) to correct for publication bias. For instance, our organization, the Institute for Quality and Efficiency in Health Care, routinely asks drug manufacturers to provide full CSRs of studies considered in health technology assessments. However, since cooperation is voluntary, CSRs are available only for a subset of studies analysed. In the case of the inhaled insulin Exubera, the manufacturer refused to cooperate and in 2007 we asked the European Medicines Agency (EMA) to provide the relevant CSRs, but EMA denied access. Other researchers have reported similar experiences.In 2010 EMA introduced a new policy on access to regulatory documents, including CSRs, and has also undertaken further steps. The new policy has already borne fruit: in 2011, by providing additional sections of relevant CSRs, EMA made an important contribution to a review of oseltamivir (Tamiflu).Unfortunately, speedy implementation of the new policy may be endangered. We define a CSR following the International Conference on Harmonisation (ICH) E3 guideline. Although this guideline requires individual patient data listings, it does not necessarily require that these listings be made available in a computer-readable format, as proposed by some regulators from EMA and other agencies. However, access to raw data in a computer-readable format poses additional problems; merging this issue with that of access to CSRs could hamper the relatively simple implementation of the EMA policy. Moreover, EMA plans to release CSRs only on request; we suggest making these documents routinely available on the EMA website.Public access to regulatory data also carries potential risks. In our view, the issue of patient confidentiality has been largely resolved by current European legislation. The risk of other problems, such as conflicts of interest (CoIs) of independent researchers or quality issues can be reduced by transparency measures, such as the implementation of processes to evaluate CoIs and the publication of methods and protocols.In conclusion, regulatory data are an indispensable source for systematic reviews. Because of EMA's policy change, a milestone for data transparency in clinical research is within reach; let's hope it is not unnecessarily delayed. PMID- 23110994 TI - Twins Early Development Study (TEDS): a genetically sensitive investigation of cognitive and behavioral development from childhood to young adulthood. AB - The Twins Early Development Study (TEDS) is a large longitudinal sample of twins born in England and Wales between 1994 and 1996. The focus of TEDS has been on cognitive and behavioral development, including difficulties in the context of normal development. TEDS began when multiple births were identified from birth records and the families were invited to take part in the study; 16,810 pairs of twins were originally enrolled in TEDS. More than 10,000 of these twin pairs remain enrolled in the study to date. DNA has been collected for more than 7,000 pairs, and genome-wide genotyping data for two million DNA markers are available for 3,500 individuals. The TEDS families have taken part in studies when the twins were aged 2, 3, 4, 7, 8, 9, 10, 12, 14, and 16 years of age. Data collection is currently underway to assess the adult destinations of the twins as they move from school to university and the workplace. Between January 2012 and December 2014, all of the TEDS twins will turn 18, and the study will transition to an adult sample. TEDS represents an outstanding resource for investigating the developmental effects of genes and environments on complex quantitative traits from childhood to young adulthood and beyond. PMID- 23110995 TI - X-radiation inhibits histone deacetylase 1 and 2, upregulates Axin expression and induces apoptosis in non-small cell lung cancer. AB - BACKGROUND: Histone deacetylase (HDAC) plays an important role in the deacetylation of histone, which can alter gene expression patterns and affect cell behavior associated with malignant transformation. The aims of this study were to investigate the relationships between HDAC1, HDAC2, clinicopathologic characteristics, patient prognosis and apoptosis, to clarify the mechanism of upregulation of the Axis inhibitor Axin (an important regulator of the Wnt pathway) by X-radiation and to elucidate the effect of siRNA on radiation therapy of non-small cell lung cancer (NSCLC). METHODS: HDAC1 and HDAC2 expression levels were measured by immunohistochemistry and reverse transcription PCR. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling and fluorescence activated cell sorting. BE1 cells expressing Axin were exposed to 2 Gy of X-radiation. RESULTS: Expression of HDAC1 and that of HDAC2 were correlated, and significantly higher in NSCLC tissues than in normal lung tissues (P < 0.05). HDAC1 and HDAC2 expression was correlated with pTNM stage and negatively correlated with differentiation of NSCLC and apoptotic index (P < 0.05). The prognosis of patients with low expression of HDAC1 and HDAC2 was better than that of those with high expression. X-radiation and siRNA inhibited HDAC1 and HDAC2 expression in NSCLC cells and Axin levels were significantly higher in BE1 cells. CONCLUSIONS: X-radiation and siRNA inhibit expression of HDAC1 and HDAC2, weaken the inhibitory effect of HDAC on Axin, upregulate Axin expression and induce apoptosis of lung cancer cells. Inhibition of HDAC1 and HDAC2 is a means of enhancing the radiosensitivity of NSCLC. PMID- 23110996 TI - Seroprevalence of hepatitis C virus infection among surgical nurses, their patients and blood donation candidates in Poland. AB - OBJECTIVES: To assess the prevalence of anti-hepatitis C virus (HCV) in surgical nurses and midwives, to compare the rate with other female groups (their patients from the same hospitals and blood donation candidates) in a cross-sectional serosurvey, and to evaluate the alleged risk factors for acquiring an occupational infection. METHODS: Between February 2008 and June 2009, participants from 16 hospitals selected at random in West Pomerania, Poland completed a written questionnaire detailing potential risk factors for HCV infection. Serum samples were assayed for anti-HCV using third-generation testing methods. RESULTS: Of 414 staff members, six were found to be anti-HCV positive [1.4%, 95% confidence interval (CI) 0.7-3.1%]. The seropositive status of staff was discovered during this one-off screening. A logistic regression model indicated that for anti-HCV seropositivity, only the length of employment was associated with increased odds of being infected [odds ratio (OR) 2.8; P < 0.006]. The prevalence of anti-HCV was 1.1% (12/1118, 95% CI 0.6-1.9%) in 1118 female patients, and 0% (0/801, 95% CI 0-1.1%) in 801 female blood donation candidates. A significant staff/patient difference in anti-HCV prevalence was observed among those aged >50 years (6.9% vs 1.0%; P < 0.007). For this age group, being a nurse was associated with higher odds (OR 8.8; P < 0.005) of being infected with HCV. CONCLUSIONS: Comparison of HCV prevalence rates pointed to a decreasing trend in the order: surgical nurses/midwives, patients and blood donation candidates; this may indicate occupational risk. The greatest risk factor for contracting HCV infection was length of employment, suggesting a possible effect of accumulated exposure to contaminated blood and other body fluids. There is a need for better recognition of HCV infection as a consequence of prolonged blood exposure among surgical and gynaecological staff. PMID- 23110997 TI - Correlations of gene expression with ratings of inattention and hyperactivity/impulsivity in Tourette syndrome: a pilot study. AB - BACKGROUND: Inattentiveness, impulsivity and hyperactivity are the primary behaviors associated with attention-deficit hyperactivity disorder (ADHD). Previous studies showed that peripheral blood gene expression signatures can mirror central nervous system disease. Tourette syndrome (TS) is associated with inattention (IA) and hyperactivity/impulsivity (HI) symptoms over 50% of the time. This study determined if gene expression in blood correlated significantly with IA and/or HI rating scale scores in participants with TS. METHODS: RNA was isolated from the blood of 21 participants with TS, and gene expression measured on Affymetrix human U133 Plus 2.0 arrays. To identify the genes that correlated with Conners' Parents Ratings of IA and HI ratings of symptoms, an analysis of covariance (ANCOVA) was performed, controlling for age, gender and batch. RESULTS: There were 1201 gene probesets that correlated with IA scales, 1625 that correlated with HI scales, and 262 that correlated with both IA and HI scale scores (P<0.05, |Partial correlation (r(p))|>0.4). Immune, catecholamine and other neurotransmitter pathways were associated with IA and HI behaviors. A number of the identified genes (n=27) have previously been reported in ADHD genetic studies. Many more genes correlated with either IA or HI scales alone compared to those that correlated with both IA and HI scales. CONCLUSIONS: These findings support the concept that the pathophysiology of ADHD and/or its subtypes in TS may involve the interaction of multiple genes. These preliminary data also suggest gene expression may be useful for studying IA and HI symptoms that relate to ADHD in TS and perhaps non-TS participants. These results will need to be confirmed in future studies. PMID- 23110998 TI - Heart failure performance measures: do they have an impact on 30-day readmission rates? AB - Congestive heart failure (CHF) accounts for more health care costs than any other diagnosis. Readmissions contribute to this expenditure. The authors evaluated the relationship between adherence to performance metrics and 30-day readmissions. This was a retrospective study of 6063 patients with CHF between 2001 and 2008. Data were collected for 30-day readmissions and compliance with CHF performance measures at discharge. Rates of readmission for CHF increased from 16.8% in 2002 to 24.8% in 2008. Adherence to performance measures increased concurrently from 95.8% to 99.9%. Except for left ventricular function (LVF) assessment, the 30-day readmission rate was not associated with adherence to performance measures. Readmitted patients had twice the odds of not having their LVF assessed (odds ratio = 2.0; P < .00005; 95% confidence interval = 1.45-2.63). CHF performance measures, except for the LVF assessment, have little relationship to 30-day readmissions. Further studies are needed to identify performance measures that correlate with quality of care. PMID- 23110999 TI - Commentary: health systems must strive for data maturity. PMID- 23111000 TI - Alternative NADH dehydrogenase (NDH2): intermembrane-space-facing counterpart of mitochondrial complex I in the procyclic Trypanosoma brucei. AB - The respiratory chain of the procyclic stage of Trypanosoma brucei contains the standard complexes I through IV, as well as several alternative enzymes contributing to electron flow. In this work, we studied the function of an alternative NADH : ubiquinone oxidoreductase (NDH2). Depletion of target mRNA was achieved using RNA interference (RNAi). In the non-induced and RNAi-induced cell growth, membrane potential change, alteration in production of reactive oxygen species, overall respiration, enzymatic activities of complexes I, III and/or IV and distribution of NADH : ubiquinone oxidoreductase activities in glycerol gradient fractions were measured. Finally, respiration using different substrates was tested on digitonin-permeabilized cells. The induced RNAi cell line exhibited slower growth, decreased mitochondrial membrane potential and lower sensitivity of respiration to inhibitors. Mitochondrial glycerol-3-phosphate dehydrogenase was the only enzymatic activity that has significantly changed in the interfered cells. This elevation as well as a decrease of respiration using NADH was confirmed on digitonin-permeabilized cells. The data presented here together with previously published findings on complex I led us to propose that NDH2 is the major NADH : ubiquinone oxidoreductase responsible for cytosolic and not for mitochondrial NAD+ regeneration in the mitochondrion of procyclic T. brucei. PMID- 23111001 TI - Powassan virus infection: case series and literature review from a single institution. AB - BACKGROUND: Powassan virus is a flavivirus related to eastern hemisphere's tick borne encephalitis viruses. It can cause a rare but potentially life-threatening disease including encephalitis. CASE PRESENTATION: We report four cases of POWV infection in Minnesota and North Dakota with known exposure to tick bites in 2011. Our first case was an 18-year-old male who dramatically presented with seizure and headache with positive serum analysis for Powassan virus immunoglobulin M. The second case was a 60 year old gentleman with intraparenchymal hemorrhage and was diagnosed via cerebrospinal fluid analysis. Thirdly, a 61 year old male developed altered mental status and encephalitis. Our fourth patient was a 69 year old male who had headache and non-focal weakness who was diagnosed with serum analysis. CONCLUSION: Symptoms of Powassan virus infection ranged from headaches to seizures and severe neurological symptoms. This study serves to highlight the increased detection of Powassan virus infection in the central north United States. This report focuses on the increasing incidence that can lead to increasing efforts for raising awareness regarding this infection. There is a need for clinician vigilance and public attention due to its increasing detection, westward progression and varied clinical presentations. PMID- 23111002 TI - The cytochromes P450 of Grosmannia clavigera: Genome organization, phylogeny, and expression in response to pine host chemicals. AB - Grosmannia clavigera is a fungal associate of the mountain pine beetle (Dendroctonus ponderosae) and a pathogen of lodgepole pine (Pinus contorta) that must overcome terpenoid oleoresin and phenolic defenses of host trees. G. clavigera responds to monoterpene influx with complementary mechanisms that include export and the use of these compounds as a carbon source. Cytochromes P450 (CYPs) may also be involved in the metabolism of host defense compounds. We have identified and phylogenetically classified G. clavigera CYPs (CYPome). We show that although the G. clavigera CYPome has contracted in evolution, certain CYP families have expanded by duplication. We analyzed RNA-seq data for CYP expression following treatment with terpenes and pine phloem extracts to identify CYPs potentially involved in detoxification of these pine defense compounds. We also used transcriptome analysis of G. clavigera grown on monoterpenes, triglycerides or oleic acid as a carbon source to identify up-regulated CYPs that may be involved in the utilization of these compounds to support fungal growth. Finally, we identify secondary metabolite biosynthetic gene clusters that contain CYPs, and CYPs in clusters that may be involved in conversion of host chemicals. PMID- 23111003 TI - Health and ageing: a cross-sectional study of body composition. AB - BACKGROUND & AIMS: The aim of this work was to provide a complete profile of body composition (BC) in healthy subjects and to investigate age and gender-related differences by dual-energy X-ray absorptiometry (DXA) and its latest developments. METHODS: Italian volunteers among blood donors were enrolled in 5 different age bands (from 18 to 70 years old) to reach the threshold of 25 males and 25 females per single band (total: 250 subjects). All non-obese subjects who satisfied selective inclusion criteria were measured for weight and height and submitted to DXA, to determine fat mass (FM), non-bone lean mass (LM), bone mineral content and density, at regional and whole-body level. Moreover, the assessment of android visceral FM was performed by a new software. RESULTS: A decrease in LM and increase in FM was observed with ageing, although the phenomenon was proved to be attenuated in women. The central and visceral redistribution of FM was also shown along lifetime, but women were not affected as men by this change. CONCLUSIONS: This paper is a report on the status of healthy Italian subjects in their adulthood, to be used as a reference for future investigations on physiology, pathological human conditions, and differences between countries. PMID- 23111004 TI - Effects of hypocaloric diets with different glycemic indexes on endothelial function and glycemic variability in overweight and in obese adult patients at increased cardiovascular risk. AB - BACKGROUND & AIMS: The role of glycemic index of the diet in glucose control and cardiovascular prevention is still not clear. The aim of this study was to determine the effects of hypocaloric diets with different glycemic indexes and glycemic loads on endothelial function and glycemic variability in nondiabetic participants at increased cardiovascular risk. METHODS: Forty nondiabetic obese participants were randomly assigned to a three-month treatment with either a low glycemic index (LGI; n=19) or high glycemic index (HGI; n=21) hypocaloric diet with similar macronutrient and fiber content. Endothelial function was measured as flow-mediated dilatation (FMD) of the brachial artery before and after dieting. In addition, 48-h continuous subcutaneous glucose monitoring was done before and after dieting in a subgroup of 24 participants. RESULTS: The amount of weight loss after dieting was similar in both groups. The glycemic index of the diet significantly influenced the FMD (P<0.005). In particular, the change of FMD was 2.3+/-2.6% following the LGI diet, and -0.9+/-3.6% after the HGI diet (P<0.005). The mean 48-h glycemia decreased significantly after dietary treatment (P<0.05), but no significant effect of the glycemic index of the diet on results was observed. The glycemic index of the diet significantly influenced the 48-h glycemic variability measured as coefficient of variability (CV%; P<0.001). The CV% decreased after the LGI diet (from 23.5 to 20.0%) and increased after the HGI diet (from 23.6 to 26.6%). The change in percentage of FMD was inversely correlated with the change in the 48-h glycemic CV% (r=-0.45; P<0.05). CONCLUSIONS: Endothelial function and glycemic variability ameliorate in association with the adherence to an LGI hypocaloric diet in nondiabetic obese persons. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN56834511. PMID- 23111005 TI - Validation of seat-off and seat-on in repeated sit-to-stand movements using a single-body-fixed sensor. AB - The identification of chair rise phases is a prerequisite for quantifying sit-to stand movements. The aim of this study is to validate seat-off and seat-on detection using a single-body-fixed sensor against detection based on chair switches. A single sensor system with three accelerometers and three gyroscopes was fixed around the waist. Synchronized on-off switches were placed under the chair. Thirteen older adults were recruited from a residential care home and fifteen young adults were recruited among college students. Subjects were asked to complete two sets of five trials each. Six features of the trunk movement during seat-off and seat-on were calculated automatically, and a model was developed to predict the moment of seat-off and seat-on transitions. The predictions were validated with leave-one-out cross-validation. Feature extraction failed in two trials (0.7%). For the optimal combination of seat-off predictors, cross-validation yielded a mean error of 0 ms and a mean absolute error of 51 ms. For the best seat-on predictor, cross-validation yielded a mean error of -3 ms and a mean absolute error of 127 ms. The results of this study demonstrate that seat-off and seat-on in repeated sit-to-stand movements can be detected semi-automatically in young and older adults using a one-body-fixed sensor system with an accuracy of 51 and 127 ms, respectively. The use of the ambulatory instrumentation is feasible for non-technically trained personnel. This is an important step in the development of an automated method for the quantification of sit-to-stand movements in clinical practice. PMID- 23111006 TI - Air pollution from industrial swine operations and blood pressure of neighboring residents. AB - BACKGROUND: Industrial swine operations emit odorant chemicals including ammonia, hydrogen sulfide (H2S), and volatile organic compounds. Malodor and pollutant concentrations have been associated with self-reported stress and altered mood in prior studies. OBJECTIVES: We conducted a repeated-measures study of air pollution, stress, and blood pressure in neighbors of swine operations. METHODS: For approximately 2 weeks, 101 nonsmoking adult volunteers living near industrial swine operations in 16 neighborhoods in eastern North Carolina sat outdoors for 10 min twice daily at preselected times. Afterward, they reported levels of hog odor on a 9-point scale and measured their blood pressure twice using an automated oscillometric device. During the same 2- to 3-week period, we measured ambient levels of H2S and PM10 at a central location in each neighborhood. Associations between systolic and diastolic blood pressure (SBP and DBP, respectively) and pollutant measures were estimated using fixed-effects (conditional) linear regression with adjustment for time of day. RESULTS: PM10 showed little association with blood pressure. DBP [beta (SE)] increased 0.23 (0.08) mmHg per unit of reported hog odor during the 10 min outdoors and 0.12 (0.08) mmHg per 1-ppb increase of H2S concentration in the same hour. SBP increased 0.10 (0.12) mmHg per odor unit and 0.29 (0.12) mmHg per 1-ppb increase of H2S in the same hour. Reported stress was strongly associated with BP; adjustment for stress reduced the odor-DBP association, but the H2S-SBP association changed little. CONCLUSIONS: Like noise and other repetitive environmental stressors, malodors may be associated with acute blood pressure increases that could contribute to development of chronic hypertension. PMID- 23111007 TI - The Texas Twin Project. AB - Socioeconomic position, racial/ethnic minority status, and other characteristics of the macro-environment may be important moderators of genetic influence on a wide array of psychosocial outcomes. Designed to maximize representation of low socioeconomic status families and racial/ethnic minorities, the Texas Twin Project is an ongoing study of school-age twins (preschool through 12th grade) enrolled in public schools in the Austin, Texas and Houston, Texas metropolitan areas. School rosters are used to identify twin families from a target population with sizable populations of African American (18%), Hispanic/Latino (48%), and non-Hispanic White (27%) children and adolescents, over half of whom meet US guidelines for classification as economically disadvantaged. Initial efforts have focused on a large-scale, family-based survey study involving both parent and child reports of personality, psychopathology, physical health, academic interests, parent-child relationships, and aspects of the home environment. In addition, the Texas Twin Project is the basis for an in-laboratory study of adolescent decision-making, delinquency, and substance use. Future directions include geographic expansion of the sample to the entire state of Texas (with a population of over 25 million) and genotyping of participating twins. PMID- 23111008 TI - The natural history of compensated HCV-related cirrhosis: a prospective long-term study. AB - BACKGROUND & AIMS: The natural history of HCV-related compensated cirrhosis has been poorly investigated in Latin-American countries. Our study evaluated mortality and clinical outcomes in compensated cirrhotic patients followed for 6 years. METHODS: Four hundred and two patients with compensated HCV-related cirrhosis were prospectively recruited in a tertiary care academic center. At the time of admission, patients were stratified as compensated (absence [stage 1] or presence [stage 2] of esophageal varices) as defined by D'Amico et al. Subjects were followed to identify overall mortality or liver transplantation and clinical complication rates. RESULTS: Among 402 subjects, 294 were categorized as stage 1 and 108 as stage 2. Over a median of 176 weeks, 42 deaths occurred (10%), of which 30 were considered liver-related (7%) and 12 non-liver-related (3%); eight individuals (2%) underwent liver transplantation; 30 patients (7%) developed HCC, 67 individuals in stage 1 (22%) developed varices and any event of clinical decompensation occurred in 80 patients (20%). The 6-year cumulative overall mortality or liver transplantation was 15% and 45%, for stages 1 and 2, respectively (p<0.001). The cumulative 6-year HCC incidence was significantly higher among patients with varices (29%) than those without varices (9%), p<0.001. Similarly, the cumulative 6-year incidence of any clinical liver-related complication was higher in patients with stage 2 (66%) as compared to 26% in those with stage 1, respectively (p<0.001). CONCLUSIONS: Our results indicate significant morbidity and mortality and clinical outcome rates in compensated cirrhotic patients with varices (stage 2). PMID- 23111009 TI - MicroRNA-29a-c decrease fasting blood glucose levels by negatively regulating hepatic gluconeogenesis. AB - BACKGROUND & AIMS: The expression levels of microRNA-29 (miR-29) family members (miR-29a, miR-29b, miR-29c, here denoted collectively as miR-29a-c) are increased in livers of Goto-Kakizaki diabetic rats and db/db diabetic mice. However, the functional consequences of miR-29a-c upregulation in diabetic livers are not explored. The objective of this study was to evaluate the roles of miR-29a-c in the regulation of hepatic glucose production and blood glucose levels using different mouse models. METHODS: db/m, db/db diabetic and diet-induced obese (DIO) mice were injected with adenovirus expressing miR-29a-c through the tail vein. Blood glucose levels were measured and glucose-tolerance tests and pyruvate tolerance tests were performed. To explore the molecular mechanism by which miR 29a-c regulate hepatic glucose metabolism, gain or loss of miR-29a-c function studies were performed in primary mouse hepatocytes and the direct effectors of miR-29-mediated effects on glucose metabolism were identified. RESULTS: Adenovirus-mediated overexpression of miR-29a-c in the livers of db/m, db/db, and DIO mice decreased fasting blood glucose levels and improved glucose tolerance. Overexpression of miR-29a-c in primary hepatocytes and mouse livers decreased the protein levels of PGC-1alpha and G6Pase, the direct targets of miR-29a-c, thereby reducing cellular, and hepatic glucose production. In contrast, loss of miR-29a-c function in primary hepatocytes increased the protein levels of PGC-1alpha and G6Pase and increased cellular glucose production. Finally, enforced expression of PGC-1alpha increased miR-29a-c expression levels in primary hepatocytes, thus forming a negative feedback regulation loop. CONCLUSIONS: miR-29a-c can regulate hepatic glucose production and glucose tolerance in mice. PMID- 23111010 TI - Efficacy and safety of a modified intravenous recombinant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke. AB - BACKGROUND: Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA; 0.90 mg/kg, with a maximum dose of 90 mg) has been recommended as the standard management for acute ischemic stroke (AIS) thrombolysis. However, the dose of IV rtPA in Asia remains controversial. METHODS: This study was designed to verify the safety and efficacy of IV rtPA treatment for AIS with a lower dosage (0.90 mg/kg, with a maximum dose of 50 mg). Patients were divided into 3 dosage groups according to body weight (BW): group 1, <55 kg for 0.90 mg/kg; group 2, 55 to 67 kg for 0.75 to 0.90 mg/kg; and group 3, >67 kg for <0.75 mg/kg. The following data were collected: patient demographics, vascular risk factors, neuroimaging results, time of rtPA administration, National Institutes of Health Stroke Scale score before treatment and at 24 hours, and a modified Rankin Scale (mRS) score at 3 months. RESULTS: Eighty-three AIS patients who were of Han Chinese descent were included in the study. The baseline characteristics of the 3 dosage groups were well matched. In group 1 (BW <55 kg for 0.90 mg/kg; n = 19), 57.1% had a favorable outcome at 3 months, compared with 61.2% of patients in group 2 (BW 55-67 kg for 0.75-0.90 mg/kg; n = 33) and 51.5% in group 3 (BW >67 kg for <0.75 mg/kg; n = 31; P = .362). There were no significantly statistical differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. CONCLUSIONS: This IV rtPA regimen (0.90 mg/kg, with a maximum dose of 50 mg) not only shows sufficient favorable outcome in clinical practice in Chinese patients with AIS but also good health economic savings. This regimen could be suitable for many developing countries. PMID- 23111011 TI - Intensive blood pressure-lowering treatment in patients with acute lacunar infarction. AB - BACKGROUND: The optimal management of high blood pressure (BP) during the acute stage of stroke has yet to be established. To test the extent to which BP can be lowered without causing adverse effects and to determine the safety or efficacy of administration of antihypertensive agents in acute ischemic stroke, we performed ambulatory BP monitoring (ABPM) before and after administration of angiotensin receptor blockers (ARBs) with and without diuretics to monitor the ABPM profile after acute lacunar infarction. Patients with lacunar infarcts are presumed to be less vulnerable to reduced cerebral perfusion pressure in the ischemic tissue because of BP lowering. METHODS: We prospectively performed ABPM during the acute stage and around 3 weeks after ictus for 59 patients with lacunar infarction. As a historical control group, we selected 60 consecutive patients with acute lacunar infarction who were admitted during the period of 1 year before the present study and treated according to the guidelines. RESULTS: Baseline data, prevalence of progressive motor deficits, and modified Rankin Scale scores 3 months after ictus were not significantly different between both groups. ARB with or without diuretics lowered 24-hour systolic BP and diastolic BP by 27.8 and 12.7 mm Hg, daytime systolic BP and diastolic BP by 26.8 and 12.0 mm Hg, and nighttime systolic BP and diastolic BP by 30.2 and 12.0 mm Hg. The incidence of dippers tended to increase in the second measurement from 11 (18.6%) to 20 (33.8%; P=.093). CONCLUSIONS: Considerable reduction in 24-hour BP levels was attained around day 21. The limit of BP level to which BP can be safely lowered appears to be lower than that was previously considered. PMID- 23111012 TI - Merging species? Evidence for hybridization between the eel parasites Anguillicola crassus and A. novaezelandiae (Nematoda, Anguillicolidea). AB - BACKGROUND: The eel parasitic nematodes Anguillicola crassus (originating from Asia) and Anguillicola novaezelandiae (originating from New Zealand) were both introduced to Europe, but occurred in sympatry only in Lake Bracciano in Italy, where they both infected the European eel (Anguilla anguilla). A. novaezelandiae was introduced to the lake in 1975 and disappeared soon after A. crassus was also found there in 1993. We tested the hypothesis if hybridization of the two species might be an explanation for the findings at Lake Bracciano. FINDINGS: After laboratory infection of one European eel with 10 third stage larvae of each parasite, two living female and 4 male adults of each species were found to co occur in the swim bladder after 222 days post exposure. In 9 out of 17 eggs, isolated in total from uteri of the two A. novaezelandiae females, alleles were detected by microsatellite analysis that are characteristic for A. crassus, suggesting the hybrid origin of these eggs. In contrast, none of the eggs isolated from A. crassus females possessed alleles different from those found in A. crassus adults, but it was revealed that one female can be inseminated by several males. CONCLUSION: Our results show that A. crassus and A. novaezelandiae can co-infect a single eel and can mature together in the same swim bladder. We also provide evidence for the possibility of hybridization of A. crassus males with A. novaezelandiae females. Therefore, hybridization might be an explanation for the disappearance of A. novaezelandiae from Lake Bracciano. PMID- 23111013 TI - Thousands of missed genes found in bacterial genomes and their analysis with COMBREX. AB - BACKGROUND: The dramatic reduction in the cost of sequencing has allowed many researchers to join in the effort of sequencing and annotating prokaryotic genomes. Annotation methods vary considerably and may fail to identify some genes. Here we draw attention to a large number of likely genes missing from annotations using common tools such as Glimmer and BLAST. RESULTS: By analyzing 1,474 prokaryotic genome annotations in GenBank, we identify 13,602 likely missed genes that are homologs to non-hypothetical proteins, and 11,792 likely missed genes that are homologs only to hypothetical proteins, yet have supporting evidence of their protein-coding nature from COMBREX, a newly created gene function database. We also estimate the likelihood that each potential missing gene found is a genuine protein-coding gene using COMBREX. CONCLUSIONS: Our analysis of the causes of missed genes suggests that larger annotation centers tend to produce annotations with fewer missed genes than smaller centers, and many of the missed genes are short genes <300 bp. Over 1,000 of the likely missed genes could be associated with phenotype information available in COMBREX. 359 of these genes, found in pathogenic organisms, may be potential targets for pharmaceutical research. The newly identified genes are available on COMBREX's website. REVIEWERS: This article was reviewed by Daniel Haft, Arcady Mushegian, and M. Pilar Francino (nominated by David Ardell). PMID- 23111014 TI - Prevention of poststernotomy wound infections in obese patients by negative pressure wound therapy. AB - OBJECTIVE: The majority of wound infections after median sternotomy in obese patients are triggered by the breakdown of skin sutures and subsequent seepage of skin flora. The purpose of this study was to evaluate negative pressure wound dressing treatment for the prevention of infection. We hypothesized that negative pressure wound dressing treatment for 6 to 7 days applied immediately after skin closure reduces the numbers of wound infections. METHODS: In a prospective study, 150 consecutive obese patients (body mass index >= 30) with cardiac surgery performed via median sternotomy were analyzed. In the negative pressure wound dressing treatment group (n = 75), a foam dressing (Prevena, KCI, Wiesbaden, Germany) was placed immediately after skin suturing, and negative pressure of 125 mm Hg was applied for 6 to 7 days. In the control group (n = 75), conventional wound dressings were used. The primary end point was wound infection within 90 days. Mann-Whitney U test and Fisher exact test were used. Freedom from infection was estimated by Kaplan-Meier analysis. RESULTS: Three of 75 patients (4%) with continuous negative pressure wound dressing treatment had wound infections compared with 12 of 75 patients (16%) with conventional sterile wound dressing (P = .0266; odds ratio, 4.57; 95% confidence interval, 1.23-16.94). Wound infections with Gram-positive skin flora were found in only 1 patient in the negative pressure wound dressing treatment group compared with 10 patients in the control group (P = .0090; odds ratio, 11.39; 95% confidence interval, 1.42 91.36). CONCLUSIONS: Negative pressure wound dressing treatment over clean, closed incisions for the first 6 to 7 postoperative days significantly reduces the incidence of wound infection after median sternotomy in a high-risk group of obese patients. PMID- 23111015 TI - Historical perspectives of The American Association for Thoracic Surgery: John W. Strieder (1901-1993). PMID- 23111016 TI - Assessment of a mitral valve replacement skills trainer: a simplified, low-cost approach. AB - OBJECTIVES: Simulated mitral valve replacement may aid in the assessment of technical skills required for adequate performance in the operating room. We sought to design and assess a mitral valve replacement training station that is low-cost, nonperishable, portable, and reproducible as a first step in developing a mitral valve surgical skills curriculum. METHODS: Nineteen physicians (7 general surgery residents, 8 cardiothoracic surgery residents, and 4 attending cardiothoracic surgeons) underwent simulated mitral valve replacement testing. Simulated mitral valve replacement was performed on a training station consisting of a replaceable "mitral annulus" inside a restrictive "left atrium." Eight components of performance were graded on a 5-point scale. A composite score (100 point maximum) was calculated by weighting the grades by procedural time. The effect of training level was evaluated using analysis of variance and post hoc Tukey honestly significant difference. RESULTS: The speed of simulated mitral valve replacement varied among general surgery residents, cardiothoracic surgery residents, and attending cardiothoracic surgeons (52.9 +/- 9.0 vs 32.8 +/- 4.7 vs 28.0 +/- 3.5 minutes, respectively; F = 25.3; P < .001). Level of training significantly affected all 8 evaluation components (P < .001). Composite scores increased with level of training (general surgery residents 32.9 +/- 11.4, cardiothoracic surgery residents 65.1 +/- 11.5, and attending cardiothoracic surgeons 88.3 +/- 7.8 of a possible 100 points; F = 35.7; P < .001). Cardiothoracic surgery residents who reported having performed 10 to 50 mitral valve replacements as the primary surgeon had a composite score of 65.0 +/- 2.8 (P < .01 compared with attending cardiothoracic surgeons). CONCLUSIONS: Simulated mitral valve replacement can be performed using this simple, affordable, portable setup. Performance scores correlate with level of training and experience, but residents who performed 10 to 50 mitral valve replacements still failed to reach attending-level proficiency. This training simulator may facilitate skills practice and evaluation of competency in cardiac surgery trainees. PMID- 23111017 TI - Contractile mitral annular forces are reduced with ischemic mitral regurgitation. AB - OBJECTIVE: Forces acting on mitral annular devices in the setting of ischemic mitral regurgitation are currently unknown. The aim of this study was to quantify the cyclic forces that result from mitral annular contraction in a chronic ischemic mitral regurgitation ovine model and compare them with forces measured previously in healthy animals. METHODS: A novel force transducer was implanted in the mitral annulus of 6 ovine subjects 8 weeks after an inferior left ventricle infarction that produced progressive, severe chronic ischemic mitral regurgitation. Septal-lateral and transverse forces were measured continuously for cardiac cycles reaching a peak left ventricular pressure of 90, 125, 150, 175, and 200 mm Hg. Cyclic forces and their rate of change during isovolumetric contraction were quantified and compared with those measured in healthy animals. RESULTS: Animals with chronic ischemic mitral regurgitation exhibited a mean mitral regurgitation grade of 2.3 +/- 0.5. Ischemic mitral regurgitation was observed to decrease significantly septal-lateral forces at each level of left ventricular pressure (P < .01). Transverse forces were consistently lower in the ischemic mitral regurgitation group despite not reaching statistical significance. The rate of change of these forces during isovolumetric contraction was found to increase significantly with peak left ventricular pressure (P < .005), but did not differ significantly between animal groups. CONCLUSIONS: Mitral annular forces were measured for the first time in a chronic ischemic mitral regurgitation animal model. Our findings demonstrated an inferior left ventricular infarct to decrease significantly cyclic septal-lateral forces while modestly lowering those in the transverse. The measurement of these forces and their variation with left ventricular pressure contributes significantly to the development of mitral annular ischemic mitral regurgitation devices. PMID- 23111019 TI - Excellent short- and long-term outcomes after concomitant aortic valve replacement and coronary artery bypass grafting performed by surgeons in training. AB - OBJECTIVE: No previous studies have specifically addressed the effect of training on outcomes after concomitant aortic valve replacement and coronary artery bypass grafting. This study evaluated the early and late outcomes after concomitant aortic valve replacement and coronary artery bypass grafting performed by surgeons in training. METHODS: A retrospective analysis of data collected prospectively by the Australian and New Zealand Society of Cardiac and Thoracic Surgeons Cardiac Surgery Database between June 2001 and December 2009 was performed. Concomitant aortic valve replacement and coronary artery bypass grafting was performed in 2540 patients; of these procedures, 290 (11.4%) were by trainees. Patient demographics, intraoperative characteristics, and early morbidity were compared between trainee and staff cases using chi-square analysis and t tests. Multivariate analyses were used to determine the independent association of training status with 30-day and late mortality. RESULTS: Compared with staff cases, trainee cases were younger (mean age, 73.0 vs 74.2 years; P = .025) and less likely to present with triple vessel disease (27.9% vs 38.3%, P = .001) or previous cardiac surgery (6.3% vs 2.8%, P = .016). Trainee cases had longer mean perfusion (160.4 vs 144.6 minutes, P < .001) and crossclamp (125.2 vs 114.6 minutes, P < .001) times. The incidence of early complications was similar between the 2 groups. On multivariate analysis, trainee status was not associated with an increased risk of 30-day mortality (2.4% vs 4.0%, P = .348). Moreover, there was no significant difference in long-term outcomes, and 5-year survival was comparable in both groups (79.6% vs 77.4%, P = .200). CONCLUSIONS: Concomitant aortic valve replacement and coronary artery bypass grafting can be safely and effectively performed by properly supervised trainees in the contemporary era. It is imperative to offer training opportunities to junior surgeons in this complex procedure to ensure quality patient outcomes in the future. PMID- 23111018 TI - Insights from the STICH trial: change in left ventricular size after coronary artery bypass grafting with and without surgical ventricular reconstruction. AB - OBJECTIVE: The present analysis of the Surgical Treatment for Ischemic Heart Failure randomized trial data examined the left ventricular volumes at baseline and 4 months after surgery to determine whether any magnitude of postoperative reduction in end-systolic volume affected survival after coronary artery bypass grafting alone compared with bypass grafting plus surgical ventricular reconstruction. METHODS: Of the 1000 patients randomized, 555 underwent an operation and had a paired imaging assessment with the same modality at baseline and 4 months postoperatively. Of the remaining 455 patients, 424 either died before the 4-month study or did not have paired imaging tests and were excluded, and 21 were not considered because they had died before surgery or did not receive surgery. RESULTS: Surgical ventricular reconstruction resulted in improved survival compared with coronary artery bypass grafting alone when the postoperative end-systolic volume index was 70 mL/m(2) or less. However, the opposite was true for patients achieving a postoperative volume index greater than 70 mL/m(2). A reduction in the end-systolic volume index of 30% or more compared with baseline was an infrequent event in both treatment groups and did not produce a statistically significant survival benefit with ventricular reconstruction. CONCLUSIONS: In patients undergoing coronary artery bypass grafting plus surgical ventricular reconstruction, a survival benefit was realized compared with bypass alone, with the achievement of a postoperative end systolic volume index of 70 mL/m(2) or less. Extensive ventricular remodeling at baseline might limit the ability of ventricular reconstruction to achieve a sufficient reduction in volume and clinical benefit. PMID- 23111020 TI - Transapical implantation of an Edwards Sapien valve into a failed prosthetic mitral valve 3 years after a transapical aortic valve implantation. PMID- 23111021 TI - Early postoperative changes in cerebral oxygen metabolism following neonatal cardiac surgery: effects of surgical duration. AB - OBJECTIVE: The early postoperative period following neonatal cardiac surgery is a time of increased risk for brain injury, yet the mechanisms underlying this risk are unknown. To understand these risks more completely, we quantified changes in postoperative cerebral metabolic rate of oxygen (CMRO(2)), oxygen extraction fraction (OEF), and cerebral blood flow (CBF) compared with preoperative levels by using noninvasive optical modalities. METHODS: Diffuse optical spectroscopy and diffuse correlation spectroscopy were used concurrently to derive cerebral blood flow and oxygen utilization postoperatively for 12 hours. Relative changes in CMRO(2), OEF, and CBF were quantified with reference to preoperative data. A mixed-effect model was used to investigate the influence of total support time and deep hypothermic circulatory arrest duration on relative changes in CMRO(2), OEF, and CBF. RESULTS: Relative changes in CMRO(2), OEF, and CBF were assessed in 36 patients, 21 with single-ventricle defects and 15 with 2-ventricle defects. Among patients with single-ventricle lesions, deep hypothermic circulatory arrest duration did not affect relative changes in CMRO(2), CBF, or OEF (P > .05). Among 2-ventricle patients, total support time was not a significant predictor of relative changes in CMRO(2) or CBF (P > .05), although longer total support time was associated significantly with greater increases in relative change of postoperative OEF (P = .008). CONCLUSIONS: Noninvasive diffuse optical techniques were used to quantify postoperative relative changes in CMRO(2), CBF, and OEF for the first time in this observational pilot study. Pilot data suggest that surgical duration does not account for observed variability in the relative change in CMRO(2), and that more comprehensive clinical studies using the new technology are feasible and warranted to elucidate these issues further. PMID- 23111024 TI - Resection and heated pleural chemoperfusion in patients with thymic epithelial malignant disease and pleural spread: a single-institution experience. AB - OBJECTIVE: Our objective was to evaluate whether resection and heated pleural chemoperfusion (HPCP) is an effective treatment for de novo stage IVa thymoma (DNT) and thymic carcinoma (TC) and for thymoma with pleural relapse (TPR). METHODS: A retrospective study was conducted of patients undergoing resection and HPCP in 1 center. HPCP with cisplatinum +/- doxorubicin (adriamycin) was performed for 60 minutes using a standard roller pump and a modified heat exchanger to a maximal intrapleural temperature of 43 degrees C. Follow-up included at least 1 annual computed tomographic scan until death or March 2012. RESULTS: Thirty-five patients, 17 DNT, 14 TPR, and 4 TC, completed 42 intended treatments and were followed up for 4 to 202 months (median, 62 months). Seven patients had repeated HPCP at an interval of 2 to 12 years. There was no systemic toxicity. Ninety-day mortality was 2.5%. Major and minor morbidity occurred in 12% each. Five-, 10-, and 15-year overall survivals for DNT, TPR, and TC were 81%, 73%, 58% (DNT), 67%, 56%, 28% (TPR), and 0%, 0%, 0% (TC). Five- and 10-year progression-free survival was 61%, 43% for DNT and 48%, 18% for TPR. Presently, 11 of 17 DNT patients are alive (6, no evidence of disease), and 8 of 14 TPR are alive (6, no evidence of disease). Median survival for thymoma was 157 months. Overall survival was unrelated to any preoperative or intraoperative variable. Progression-free survival was improved in R0 compared with R1-2 resection (P < .001). Local control achieved in 21 (57%) of 37 procedures in thymoma patients was related only to completeness of resection (P = .015). CONCLUSIONS: (1) Lung sparing resection and HPCP is feasible and safe. (2) In thymoma with pleural spread it offers excellent survival despite moderate pleural control. (3) Preliminary results with stage IVa TC are disappointing. PMID- 23111025 TI - Tracheal regeneration: evidence of bone marrow mesenchymal stem cell involvement. AB - OBJECTIVES: Recent advances in airway transplantation have shown the ability of ex vivo or in vivo tracheal regeneration with bioengineered conduits or biological substitutes, respectively. Previously, we established a process of in vivo-guided tracheal regeneration using vascular allografts as a biological scaffold. We theorized that tracheal healing was the consequence of a mixed phenomenon associating tracheal contraction and regeneration. The aim of the present study was to determine the role that bone marrow stem cells play in that regenerative process. METHODS: Three groups of 12 rabbits underwent a gender mismatched aortic graft transplantation after tracheal resection. The first group received no cells (control group), the second group had previously received autologous green fluorescent protein-labeled mesenchymal stem cell transplantation, and the third group received 3 labeled mesenchymal stem cell injections on postoperative days 0, 10, and 21. RESULTS: The clinical results were impaired by stent complications (obstruction or migration), but no anastomotic leakage, dehiscence, or stenosis was observed. The rabbits were killed, and the trachea was excised for analysis at 1 to 18 months after tracheal replacement. In all 3 groups, microscopic examination showed an integrated aortic graft lined by metaplastic epithelium. By 12 months, immature cartilage was detected among disorganized elastic fibers. Positive SRY gene detection served as evidence for engraftment of cells derived from the male recipient. EF-green fluorescent protein detection showed bone marrow-derived mesenchymal stem cell involvement. CONCLUSIONS: The results of the present study imply a role for bone marrow stem cells in tracheal regeneration after aortic allografting. Studies are necessary to identify the local and systemic factors stimulating that regenerative process. PMID- 23111026 TI - Well-width dependence of the emission linewidth in ZnO/MgZnO quantum wells. AB - Photoluminescence (PL) spectra were measured as a function of well width (LW) and temperature in ZnO/Mg0.1Zn0.9O single quantum wells (QWs) with graded thickness. The emission linewidth (full width at half maximum) was extracted from the emission spectra, and its variation as a function of LW was studied. The inhomogeneous linewidth obtained at 5 K was found to decrease with increasing LW from 1.8 to 3.3 nm due to the reduced potential variation caused by the LW fluctuation. Above 3.3 nm, however, the linewidth became larger with increasing LW, which was explained by the effect related with defect generation due to strain relaxation and exciton expansion in the QW. For the homogenous linewidth broadening, longitudinal optical (LO) phonon scattering and impurity scattering were taken into account. The LO phonon scattering coefficient GammaLO and impurity scattering coefficient Gammaimp were deduced from the temperature dependence of the linewidth of the PL spectra. Evident reduction of GammaLO with decreasing LW was observed, which was ascribed to the confinement-induced enhancement of the exciton binding energy. Different from GammaLO, a monotonic increase in Gammaimp was observed with decreasing LW, which was attributed to the enhanced penetration of the exciton wave function into the barrier layers. PMID- 23111027 TI - CACNA1H antibodies associated with headache with neurological deficits and cerebrospinal fluid lymphocytosis (HaNDL). AB - BACKGROUND: Patients with the syndrome of headache with neurological deficits and lymphocytosis (HaNDL) typically present with recurrent and temporary attacks of neurological symptoms and cerebrospinal fluid lymphocytosis. AIM AND METHODS: To identify potential HaNDL-associated antibodies directed against neuronal surface and/or synapse antigens, sera of four HaNDL patients and controls were screened with indirect immunohistochemistry, immunofluorescence, cell-based assay, radioimmunoassay, protein macroarray and enzyme-linked immunosorbent assay (ELISA). RESULTS: Although HaNDL sera did not yield antibodies to any of the well characterized neuronal surface or synapse antigens, protein macroarray and ELISA studies showed high-titer antibodies to a subunit of the T-type voltage-gated calcium channel (VGCC), CACNA1H, in sera of two HaNDL patients. CONCLUSION: Our results support the notion that ion channel autoimmunity might at least partially contribute to HaNDL pathogenesis and occurrence of neurological symptoms. PMID- 23111029 TI - Progress. PMID- 23111028 TI - Radiation exposure of eyes, thyroid gland and hands in orthopaedic staff: a systematic review. AB - BACKGROUND: Various procedures, especially minimal invasive techniques using fluoroscopy, pose a risk of radiation exposure to orthopaedic staff. Anatomical sites such as the eyes, thyroid glands and hands are more vulnerable to radiation considering the limited use of personal protective devices in the workplace. The objective of the study is to assess the annual mean cumulative and per procedure radiation dose received at anatomical locations like eyes, thyroid glands and hands in orthopaedic staff using systematic review. METHODS: The review of literature was conducted using systematic search of the database sources like PUBMED and EMBASE using appropriate keywords. The eligibility criteria and the data extraction of literature were based on study design (cohort or cross sectional study), study population (orthopaedic surgeons or their assistants), exposure (doses of workplace radiation exposure at hands/fingers, eye/forehead, neck/thyroid), language (German and English). The literature search was conducted using a PRISMA checklist and flow chart. RESULTS: Forty-two articles were found eligible and included for the review. The results show that radiation doses for the anatomical locations of eye, thyroid gland and hands were lower than the dose levels recommended. But there is a considerable variation of radiation dose received at all three anatomical locations mainly due to different situations including procedures (open and minimally invasive), work experience (junior and senior surgeons),distance from the primary and secondary radiation, and use of personal protective equipments (PPEs). The surgeons receive higher radiation dose during minimally invasive procedures compared to open procedures. Junior surgeons are at higher risk of radiation exposure compared to seniors. PPEs play a significant role in reduction of radiation dose. CONCLUSIONS: Although the current radiation precautions appear to be adequate based on the low dose radiation, more in-depth studies are required on the variations of radiation dose in orthopaedic staff, at different anatomical locations and situations. PMID- 23111030 TI - The carrot and the stick. PMID- 23111031 TI - APDS panel session IV: intersection of surgical outcomes and medical education. PMID- 23111032 TI - A novel cadaver-based educational program in general surgery training. AB - OBJECTIVE: To describe the development of a cadaver-based educational program and report our residents' assessment of the new program. DESIGN: An anatomy-based educational program was developed using fresh frozen cadavers to teach surgical anatomy and operative skills to general surgery (GS) trainees. Residents were asked to complete a voluntary, anonymous survey evaluating perceptions of the program (6 questions formulated on a 5-point Likert scale) and comparing cadaver sessions to other types of learning (4 rank order questions). SETTING: Large university teaching hospital. PARTICIPANTS: Medical students, residents, and faculty members were participants in the cadaver programs. Only GS residents were asked to complete the survey. RESULTS: Since its implementation, 150 residents of all levels participated in 13 sessions. A total of 40 surveys were returned for a response rate of 89%. Overall, respondents held a positive view of the cadaver sessions and believed them to be useful for learning anatomy (94% agree or strongly agree), learning the steps of an operation (76% agree or strongly agree), and increasing confidence in doing an operation (53% agree or strongly agree). Trainees wanted to have more sessions (87% agree or strongly agree), and believed they would spend free time in the cadaver laboratory (58% agree or strongly agree). Compared with other learning modalities, cadaver sessions were ranked first for learning surgical anatomy, followed by textbooks, simulators, web sites, animate laboratories, and lectures. Respondents also ranked cadaver sessions first for increasing confidence in performing a procedure and for learning the steps of an operation. Cost of cadavers represented the major expense of the program. CONCLUSIONS: Fresh cadaver dissections represent a solution to the challenges of efficient, safe, and effective general surgery education. Residents have a positive attitude toward these teaching sessions and found them to be more effective than other learning modalities. PMID- 23111033 TI - A six year head-to-head comparison of osteopathic and allopathic applicants to a university-based, allopathic general surgery residency. AB - OBJECTIVE: The number of osteopathic physicians is increasing as is the number applying to allopathic general surgery residency programs. A lack of knowledge of osteopathic schooling leads to a potential applicant bias in favor of allopathic applicants, but the 2 groups have not been compared head to head. DESIGN: Applications over a 6-year period to an allopathic general surgery residency program were reviewed. Demographics, examination scores, employment, education, and research experience were catalogued into a database. Allopathic applicants were compared with osteopathic applicants utilizing statistical analysis. SETTING: A university teaching hospital. PARTICIPANTS: Allopathic and osteopathic applicants to an allopathic general surgery residency program. RESULTS: A total of 1290 applications were reviewed; 1155 allopathic and 135 osteopathic applications. Other than race, the 2 cohorts are similar in age, gender, and citizenship. The groups are not significantly different with regard to the number of letter of recommendations, volunteer activities, scholarly works, and advanced degrees. Graduates of both proceed directly to residency. A significantly higher percentage of allopathic graduates reported their United States medical licensing examination (USMLE) scores, yet when osteopaths released their USMLE transcript, they scored significantly higher on the USMLE Step 1 examination and required fewer attempts to pass. These differences do not apply to the USMLE Step 2 examination. CONCLUSIONS: No single screening tool exists for selecting a successful general surgery resident. We are seeing increased numbers of osteopathic applicants. Many criteria used to evaluate applicants do not apply to osteopathic applicants, but our comparison of common selection variables on the Electronic Residency Application Service (ERAS) application did not demonstrate an overall difference. While our analysis demonstrated a statistically higher USMLE Step 1 score by osteopathic applicants, they may only self-report favorable data. PMID- 23111034 TI - Can we predict which residents are going to pass/fail the oral boards? AB - OBJECTIVE: Previously, we identified a positive correlation between administration of regularly structured mock oral examinations and successful first time pass rates on the American Board of Surgery Certifying Examination (ABSCE)/oral boards. In this study, we investigated factors associated with test results to determine whether residents at risk of not passing the ABSCE can be identified a priori. DESIGN: All general surgery chief residents who graduated from a large academic/community program between 2001 and 2010 were identified. Residents who did not pass the ABSCE on the first attempt were compared to a control group of chief residents who passed the examination on the first attempt. Evaluation metrics included "knowledge," "professional communication," and "spoken English" scores. Differences between groups were determined using one-way ANOVA and chi(2) calculations. RESULTS: Over the decade, 13 residents made more than 1 attempt to pass the ABSCE. The element of the "knowledge" score associated with ABSCE first-attempt pass rates included United States medical licensing examination (USMLE) Step 2 scores (p = 0.02), and not ABSITE, American Board of Surgery Qualifying examination (ABSQE)/written examination or USMLE Step 1 scores. "Professional communication" scores associated with first-attempt pass rates included in-house mock oral examination scores (p = 0.01) and Citywide mock oral examination scores (p = 0.02). ABSCE pass rates did not differ in native vs. non-native English speakers or graduation from a United States vs. International medical school. CONCLUSIONS: Compared with a control group of residents from the same program, residents who passed the ABSCE examination on the first attempt were more likely to have higher USMLE Step 2 and professional communication scores. USMLE Step 1 scores and English as a native language were not associated with certifying examination pass rates. These criteria may offer guidance for residents preparing to take the ABSCE and may aid in the selection of residents for residency programs. Larger studies to validate these findings and to investigate the role of improving communication skills and conducting interventions between the 1st and 2nd attempt are warranted. PMID- 23111035 TI - Comparing video games and laparoscopic simulators in the development of laparoscopic skills in surgical residents. AB - INTRODUCTION: The video game industry has become increasingly popular over recent years, offering photorealistic simulations of various scenarios while requiring motor, visual, and cognitive coordination. Video game players outperform nonplayers on different visual tasks and are faster and more accurate on laparoscopic simulators. The same qualities found in video game players are highly desired in surgeons. Our investigation aims to evaluate the effect of video game play on the development of fine motor and visual skills. Specifically, we plan to examine if handheld video devices offer the same improvement in laparoscopic skill as traditional simulators, with less cost and more accessibility. METHODS: We performed an Institutional Review Board-approved study, including categorical surgical residents and preliminary interns at our institution. The residents were randomly assigned to 1 of 3 study arms, including a traditional laparoscopic simulator, XBOX 360 gaming console, or Nintendo DS handheld gaming system. After an introduction survey and baseline timed test using a laparoscopic surgery box trainer, residents were given 6 weeks to practice on their respective consoles. At the conclusion of the study, the residents were tested again on the simulator and completed a final survey. RESULTS: A total of 31 residents were included in the study, representing equal distribution of each class level. The XBOX 360 group spent more time on their console weekly (6 hours per week) compared with the simulator (2 hours per week), and Nintendo groups (3 hours per week). There was a significant difference in the improvement of the tested time among the 3 groups, with the XBOX 360 group showing the greatest improvement (p = 0.052). The residents in the laparoscopic simulator arm (n = 11) improved 4.6 seconds, the XBOX group (n = 10) improved 17.7 seconds, and the Nintendo DS group (n = 10) improved 11.8 seconds. Residents who played more than 10 hours of video games weekly had the fastest times on the simulator both before and after testing (p = 0.05). Most residents stated that playing the video games helped to ease stress over the 6 weeks and cooperative play promoted better relationships among colleagues. CONCLUSIONS: Studies have shown that residents who engage in video games have better visual, spatial, and motor coordination. We showed that over 6 weeks, residents who played video games improved in their laparoscopic skills more than those who practiced on laparoscopic simulators. The accessibility of gaming systems is 1 of the most essential factors making these tools a good resource for residents. Handheld games are especially easy to use and offer a readily available means to improve visuospatial and motor abilities. PMID- 23111036 TI - Development and implementation of an interactive, objective, and simulation-based curriculum for general surgery residents. AB - OBJECTIVE: A Steering Committee of residents and faculty initiated a systematic approach to curriculum development, focusing on competency-based education and emphasizing both resident and faculty engagement in the didactic process. SETTING: Integrated General Surgery Residency Program at the University of Connecticut School of Medicine, Farmington, Connecticut. PARTICIPANTS: Postgraduate year (PGY) 1 through 5 general surgery categorical and preliminary residents. METHODS: A Core Curriculum consisting of 45-minute blocks and 2.5 hours of resident time per week was developed by a steering committee composed of faculty and residents. Each block is assigned a faculty and resident moderator, and has defined competency and knowledge-based objectives. An anonymous online evaluation tool collected residents' perceptions of value and satisfaction with the curriculum utilizing 15 5-point Likert items focusing on conferences, objectives, preparation, and quality of presentations, and materials. Measures were taken at the close of the previous academic year (baseline) and at 6 months and 1 year after implementation. The analysis focused on the percent responding in the 2 highest Likert categories (good/excellent, almost always/always, agree/strongly agree). The resulting dichotomous outcomes were compared with time point using chi(2)-tests of proportion; Kruskal-Wallis statistic was also used to compare the full distribution of responses. All analyses were done using SPSS v. 14 with alpha = 0.05. RESULTS: One hundred two surveys were completed on-line (42 at baseline, 38 at 6 months, and 22 at 1 year). All 15 items showed increases from baseline to 1-year follow-up; 9 of the 15 were statistically significant with conferences and presentation quality and interaction showing the greatest improvement. CONCLUSIONS: Resident satisfaction with the core curriculum, and their self-reported clinical and academic abilities showed improvement after a systematic collaborative faculty-resident approach to curriculum development and implementation. PMID- 23111037 TI - Does resident ranking during recruitment accurately predict subsequent performance as a surgical resident? AB - BACKGROUND: While the primary goal of ranking applicants for surgical residency training positions is to identify the candidates who will subsequently perform best as surgical residents, the effectiveness of the ranking process has not been adequately studied. METHODS: We evaluated our general surgery resident recruitment process between 2001 and 2011 inclusive, to determine if our recruitment ranking parameters effectively predicted subsequent resident performance. We identified 3 candidate ranking parameters (United States Medical Licensing Examination [USMLE] Step 1 score, unadjusted ranking score [URS], and final adjusted ranking [FAR]), and 4 resident performance parameters (American Board of Surgery In-Training Examination [ABSITE] score, PGY1 resident evaluation grade [REG], overall REG, and independent faculty rating ranking [IFRR]), and assessed whether the former were predictive of the latter. Analyses utilized Spearman correlation coefficient. RESULTS: We found that the URS, which is based on objective and criterion based parameters, was a better predictor of subsequent performance than the FAR, which is a modification of the URS based on subsequent determinations of the resident selection committee. USMLE score was a reliable predictor of ABSITE scores only. However, when we compared our worst residence performances with the performances of the other residents in this evaluation, the data did not produce convincing evidence that poor resident performances could be reliably predicted by any of the recruitment ranking parameters. Finally, stratifying candidates based on their rank range did not effectively define a ranking cut-off beyond which resident performance would drop off. CONCLUSIONS: Based on these findings, we recommend surgery programs may be better served by utilizing a more structured resident ranking process and that subsequent adjustments to the rank list generated by this process should be undertaken with caution. PMID- 23111038 TI - Does success on the American Board of Surgery general surgery qualifying examination guarantee certifying examination success? AB - OBJECTIVE: The purpose of this study was to explore the relationship between qualifying examination (QE) and certifying examination (CE) results and to determine whether an appropriate cut-point on the QE would predict success on the CE. DESIGN: The scaled American Board of Surgery (ABS) QE scores of all first time examinees from 2006 to 2010 were retrospectively matched to their first-time CE pass/fail decisions. Contingency tables illustrating the QE-CE relationship were constructed and appropriate correlational statistics were computed. A receiver operating characteristic (ROC) curve analysis was constructed, with sensitivity and 1-specificity calculated for each possible QE cut-point used to predicted CE pass/fail classifications. Additionally, the area under the curve (AUC) was calculated. PARTICIPANTS: All first-time American Board of Surgery examinees for the Surgery Qualifying Examination from 2006 to 2010. RESULTS: A total of 4385 surgeons were analyzed, with QE scores averaging 82.1 +/- 5.8 (range, 58-99) and 82.8% of surgeons passing the CE on their first attempt. Contingency tables suggest a moderate relationship between QE and CE performance, although correlation indexes are low (phi = 0.13, point-biserial = 0.23). For the ROC analysis, the AUC = 0.674 (95% CI; 0.654-0.695) provides a better than chance pass/fail classification (p < 0.001), yet does not meet the minimum threshold for acceptability as a predictive test. No QE cut-point accurately predicted CE pass/fail decisions. CONCLUSIONS: While a moderate relationship between QE scores and CE performance is evident, correlations suggest that the 2 examinations measure different abilities. The low AUC value on the ROC analysis, along with poor predictability at all possible cut-points, show that no appropriate cut point on the QE predicts success on the CE. These data add to the validity of both tests by providing evidence that distinct latent traits are being measured by both tests. PMID- 23111039 TI - Feasibility and value of a procedural workshop for surgery residents based on phase II of the APDS/ACS national skills curriculum. AB - OBJECTIVES: The Association of Program Directors in Surgery/American College of Surgeons national skills curriculum provides residency programs with a great educational tool for their residents. Our objective was to assess the feasibility, value, and cost required to administer a procedural workshop for general surgery residents based on phase II of the national skills curriculum. DESIGN, SETTING, AND PARTICIPANTS: Surgery faculty instructed residents on a variety of level-appropriate surgical procedures during a procedural workshop using 4 training models (2 cadaver torsos and 2 pigs). The educational value of the workshop, the quality of teaching, the instruction and feedback received, and the training models used were evaluated by participants on a 10-point Likert scale. Resident performance and workshop cost were also assessed. RESULTS: Seven faculty instructed 16 residents (postgraduate year 1-4) on 23 surgical procedures (median 4 procedures per resident). Participants rated the overall value of the workshop as 8 (range, 7-10). Residents rated the quality of teaching as 9 (range, 6-10) and the quality of instruction and feedback received as 8.5 (range, 6-10). Overall resident performance was rated as 8 (range, 5-10) by faculty. The factors most positively impacting the quality of the workshop were reported to be the close interaction between residents and faculty, the training models, and the protected time. Sixty-eight percent of participants indicated that both cadaver and pig models were necessary for this course, and all participants believed that such workshops should be part of the general surgery curriculum. Overall cost reached just under $10,000 excluding supplies and faculty time. CONCLUSIONS: The feasibility of a cadaveric and animal-based procedural workshop for surgery residents based on phase II of the national skills curriculum was demonstrated. While very resource-intensive and costly, the educational value of this workshop was rated highly by residents and faculty because of their close interaction in a relaxed environment. Such workshops should be incorporated into the surgical curriculum. PMID- 23111040 TI - General surgery vs fellowship: the role of the Independent Academic Medical Center. AB - OBJECTIVES: To compare career choices of residency graduates from Independent Academic Medical Center (IAMC) and University Academic Medical Center (UAMC) programs and evaluate program directors' perceptions of residents' motivations for pursuing general surgery or fellowships. DESIGN: From May to August 2011, an electronic survey collected information on program characteristics, graduates' career pursuits, and career motivations. Fisher's exact tests were calculated to compare responses by program type. Multivariate logistic regression was used to identify independent program characteristics associated with graduates pursuing general surgery. SETTING: Data were collected on graduates over 3 years (2009 2011). PARTICIPANTS: Surgery residency program directors. RESULTS: Seventy-four program directors completed the survey; 42% represented IAMCs. IAMCs reported more graduates choosing general surgery. Over one-quarter of graduates pursued general surgery from 52% of IAMC vs 37% of UAMC programs (p = 0.243). Career choices varied significantly by region: over one-quarter of graduates pursue general surgery from 78% of Western, 60% of Midwestern, 40% of Southern, and 24% of Northeastern programs (p = 0.018). On multivariate analysis, IAMC programs were independently associated with more graduates choosing general surgery (p = 0.017), after adjustment for other program characteristics. Seventy-five percent of UAMC programs reported over three-fourths of graduates receive first choice fellowship, compared with only 52% of IAMC programs (p = 0.067). Fellowships were comparable among IAMC and UAMC programs, most commonly MIS/Bariatric (16%), Critical Care/Trauma (16%), and Vascular (14%). IAMC and UAMC program directors cite similar reasons for graduate career choices. CONCLUSIONS: Most general surgery residents undergo fellowship training. Graduates from IAMC and UAMC programs pursue similar specialties, but UAMC programs report more first choice acceptance. IAMC programs may graduate proportionately more general surgeons. Further studies directly evaluating surgical residents' career choices are warranted to understand the influence of independent and university programs in shaping these choices and to develop strategies for reducing the general surgeon shortage. PMID- 23111041 TI - Impact of resident participation on laparoscopic inguinal hernia repairs: are residents slowing us down? AB - OBJECTIVE: The time it takes to complete an operation is important. Operating room (OR) time is costly and directly associated with infectious complications and length of stay. Intuitively, procedures take longer when a surgical resident is operating. How much extra time should we take to train residents? We examined the relationship between laparoscopic inguinal hernia repair (IHR) procedure duration and resident participation and its impact on the development of complications and hospital stay. METHODS: Data from patients undergoing laparoscopic IHR in participating institutions of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) from 2007 to 2009 were retrospectively reviewed. Patients with current procedural terminology (CPT) codes 49650 and 49651 (laparoscopic initial and recurrent IHR) comprised our patient cohort. Participation of staff surgeon and resident postgraduate year level (PGY) were used as the main predictors for operative outcomes. RESULTS: A total of 6223 patients underwent laparoscopic IHR as their main procedure with no additional or concurrent procedures; 92% were men, 21% of the repairs were bilateral. In total, there were 98 patients with at least 1 complication (1.6%). Resident involvement was present in 3565 cases (57%) broken down by PGY1: 12%, PGY2: 12%, PGY3: 21%, PGY4: 19%, PGY5 or above: 36%. Median operative time was 45 minutes for staff surgeons alone and 64 minutes when there was a resident present (p < 0.001). PGY level predicted operative duration: higher PGY levels correlated with greater operative times (PGY1 median time 58 min vs PGY >= 5 = 67 min, p < 0.001). Resident participation was not a significant predictor for the development of complications (p = 0.30). CONCLUSIONS: Laparoscopic IHR is performed faster by staff surgeons without residents. There was no difference in the complication rate when residents were involved. Teaching and mentoring residents in the OR for laparoscopic IHR is safe and laudable. PMID- 23111042 TI - Impact of implementation of a pediatric surgery fellowship on general surgery resident operative volume. AB - OBJECTIVE: The purpose of this study was to determine the impact of the initiation of a pediatric surgery fellowship on general surgery resident operative volume at 1 major academic institution. DESIGN: Retrospective review of operative records obtained from the Accreditation Council for Graduate Medical Education (ACGME) general surgery resident and pediatric surgery fellow case logs. Data collected included number and type of pediatric index cases per year, number of total pediatric surgery cases per year, and number of total cases logged as primary surgeon to date. SETTING: Vanderbilt University School of Medicine Department of Surgery, which has an accredited general surgery program, finishes 7 chief residents per year during the study period, and instituted a new pediatric surgery fellowship in 2007. PARTICIPANTS: Case logs submitted by third and fourth year general surgery residents and first and second year pediatric surgery fellows were studied. RESULTS: The number of pediatric attending surgeons, relative value units (RVUs), and hospital admissions increased from 2003 to 2011. The median number of pediatric index cases performed by a resident decreased after the onset of fellowship from 34 cases to 23.5 cases per year (p < 0.001). The median number of total cases that residents performed on the pediatric surgery rotation also decreased from 74 to 53 cases per year after onset of the fellowship (p < 0.001). CONCLUSIONS: Even with an increase in the number of attending surgeons, RVUs, and admissions, the fellowship resulted in a decrease in general surgery resident index and overall case volume in pediatric surgery. Although operative volume is only 1 measure of surgical educational value, these findings suggest that the addition of surgical fellowships affects the educational experience of general surgery residents. We recommend that residency programs establish goals and calculate any potential impact on general surgery resident case volume before initiating a new surgical fellowship. PMID- 23111043 TI - Managing a surgical exsanguination emergency in the operating room through simulation: an interdisciplinary approach. AB - OBJECTIVE: Operating room (OR) emergencies, such as fire, anaphylaxis, cardiac arrest, and exsanguination, are infrequent, but high-risk situations that can result in significant morbidity and mortality. An exsanguination scenario involving a pregnant trauma patient in the OR was developed for surgery residents with the objectives of improving overall team performance when activating an emergency response system, identifying a team leader, initiating an exsanguination protocol, following advanced cardiac life support guidelines, and recognizing the mother as the first patient. STUDY DESIGN: During 6 months, 171 OR staff members of the Hospital of the University of Pennsylvania participated in a prospective study in which randomly selected groups of surgery residents, anesthesia residents, and perioperative nurses were trained in a simulated exsanguination and cardiac arrest emergency. Upon arrival to the simulation center, groups of trainees were assigned to a simulated OR equipped with a SimMan 3G (Laerdal, Norway) and a session moderator. The scenario started with a pregnant patient in hemorrhagic shock, bleeding from a carotid injury, ultimately leading to cardiac arrest. Each group did an initial "cold" simulation without any prior training or knowledge of the scenario, followed by a didactic training session, and ending with a "warm" simulation. SETTING: Penn Medicine Clinical Simulation Center at 1800 Lombard Street, Philadelphia, Pennsylvania. RESULTS: Among 156 participants, 50% reported understanding their role in an OR exsanguination emergency pretraining, compared with 98% who understood it posttraining (p < 0.001). For activation of the exsanguination protocol, 50% understood how to do it pretraining, compared with 98% posttraining (p = 0.004). The time needed to complete 8 clinically significant tasks was documented pre- and posttraining, with a statistically significant improvement in all tasks. CONCLUSIONS: The results of this simulated exsanguination emergency demonstrate that team training using a high-fidelity mannequin is an effective way to train OR personnel, on how to manage exsanguinating traumatic patients in a high-risk surgical emergency. PMID- 23111044 TI - Objective differentiation of force-based laparoscopic skills using a novel haptic simulator. AB - BACKGROUND: There is a growing need for effective surgical simulators to train the novice resident with a core skill set that can be later used in advanced operating room training. The most common simulator-based laparoscopic skills curriculum, the Fundamentals of Laparoscopic Skills (FLS), has been demonstrated to effectively teach basic surgical skills; however, a key deficiency in current surgical simulators is lack of validated training for force-based or haptic skills. In this study, a novel haptic simulator was examined for construct validity by determining its ability to differentiate between the force skills of surgeons and novices. METHODS: A total of 34 participants enrolled in the study and were divided into two groups: novices, with no previous surgical experience and surgeons, with some level of surgical experience (including upper level residents and attendings). All participants performed a force-based task using grasping, probing, or sweeping motions with laparoscopic tools on the simulator. In the first session, participants were given 3 trials to learn specific forces associated with locations on a graphic; after this, they were asked to reproduce forces at each of the locations in random order. A force-based metric (score) was used to record performance. RESULTS: On probing and grasping tasks, novices applied significantly greater overall forces than surgeons. When analyzed by force levels, novices applied greater forces on the probing task at lower and mid range forces, for grasping at low-range forces ranges and, for sweeping at high range forces. CONCLUSIONS: The haptic simulator successfully differentiated between novice and surgeon force skill level at specific ranges for all 3 salient haptic tasks, establishing initial construct validity of the haptic simulator. Based on these results, force-based simulator metrics may be used to objectively measure haptic skill level and potentially train residents. Haptic simulator development should focus on the 3 salient haptic skills (grasping, probing, and sweeping) where precise force application is necessary for successful task outcomes. PMID- 23111045 TI - Performance improvement: getting an early start. AB - BACKGROUND: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) and the Surgical Care Improvement Program (SCIP) can be utilized to develop quality initiatives to improve surgical care. Understanding the fundamentals of quality measures provides insight to the six Accreditation Council on Graduate Medical Education (ACGME) competencies. Resident education needs a robust exposure to quality measures, such as NSQIP and SCIP to prepare surgeons for tomorrow's healthcare system. METHODS: The resident champion (RC) position is a dedicated research year between the PGY-2 and PGY-3 as a way to introduce residents to NSQIP and the importance of quality improvement. The resident partners with the NSQIP clinical reviewer to analyze data, develop quality improvement projects, implement these initiatives, and re examine quality performance. RESULTS: Over the last 24 months, there have been numerous performance improvement initiatives and projects implemented at our facility as a direct result of the RC's efforts and their participation within the performance improvement committees. In addition, the projects led to multiple presentations at national conferences. CONCLUSIONS: A dedicated year in performance improvement has benefited our residents with a working knowledge of quality measures and our institution with multiple projects that have yielded significant improvements in the quality of patient care. PMID- 23111046 TI - Proficiency of surgical faculty and residents with ethical dilemmas: is modeling enough? AB - OBJECTIVE: Professionalism, an Accreditation Commission for Graduate Medical Education (ACGME) competency, embraces the concept of adherence to ethical principles. Despite this, most surgical residencies do not currently include ethics as part of their core curriculum. Further, expertise in effectively managing ethical dilemmas is frequently obtained via modeling after the attending physician. This study evaluated surgical faculty (SF) and residents (SR) on their understanding of basic ethical principles and their overall confidence in translation of these principles into clinical practice. The objective was to determine if there are any differences in the overall levels of knowledge and confidence in ethics between SR and SF. DESIGN AND SETTING: Immediately before the first session of a Kamangar Grant supported monthly Ethics Forum, all SF and SR completed a Pre-Curriculum Questionnaire (PCQ) on their knowledge about ethical principles and their confidence in dealing with ethical issues. PQC contained 13 multiple-choice and true/false knowledge questions and 8 questions evaluating confidence rated on a 5-point Likert scale. PARTICIPANTS: Surgical faculty (SF) (n = 16) and SR (n = 36). Knowledge and confidence scores were compared between SR and SF, using Student t-test analysis to evaluate differences between groups. RESULTS: No significant differences were found in ethical knowledge scores between faculty and residents. Faculty confidence is higher than resident (p < 0.05). Further, female faculty confidence is higher than that of their male counterparts (p < 0.05). CONCLUSIONS: While SF are more confident in their ethical decision-making, their fundamental knowledge base in ethics is not different from that of SR. Female SF report greater self-confidence over their male counterparts. In total, SF may not possess the foundation to effectively mentor residents in appropriate ethical principles and their translation to clinical practice. This study supports the need for both SR and SF to engage in an integrated education program in ethics to promote on-going dialogue in this complex topic. PMID- 23111047 TI - Selection, mentorship, and subsequent placement of preliminary residents without a designated categorical position in an academic general surgery residency program. AB - BACKGROUND: Academic general surgery residency programs face a reduction in clinical hours for residents at a time of expanding educational material/clinical programs. To meet these challenges, clinical staffing includes additional faculty, physician extenders, or additional residents. Categorical resident expansion is difficult but there is an ample pool of preliminary first year resident (R1) candidates every match week, and this pool is projected to increase markedly as all medical schools have increased enrollment without any real change to the demographics of available categorical residency positions. Our experience with preliminary R1s without a designated categorical position over the last 8 academic years forms the basis of this report. METHODS: The University of Colorado-Denver general surgery residency program recruits 8-12 preliminary R1s annually. Most of these are recruited on scramble day, as we found that having individual interview dates for these positions was labor-intensive and did not yield better candidates. Preliminary R1s were mentored in a systematic fashion by the program during the year to focus on career planning. Files for preliminary R1s were reviewed for demographics, medical school of origin, original prematch career goal, successful completion of the intern year, and subsequent categorical residency placement/type. RESULTS: We recruited 64 preliminary R1s without a designated categorical position over the past 8 years (16 females and 48 males) with an average age of 30 years old (range 25-45 years). These preliminary R1s attended medical schools throughout the United States (West 24, South 18, Central 11, Northeast 4, or International 7). The average United States Medical Licensing Examination (USMLE) Step 1 test score was 213 (range 185-252). The majority (95%) completed their preliminary year of training or left for a categorical position during the year. Most preliminary R1s (79%) were successfully placed into categorical training programs at the end of the year, with 23% ultimately receiving categorical training at our institution. Four did not complete their preliminary training year due to medical leave or unsatisfactory performance. The categorical positions preliminary R1s obtained include general surgery (n = 7, 15%), surgical subspecialties (n = 31, 65%), and nonsurgical subspecialties (n = 10, 20%). Ultimately, 14 (29%) of preliminary R1s who matched after 1 year did so in their fields of original interest. CONCLUSIONS: A symbiotic relationship can exist between a general surgery residency program and preliminary R1s. An approach that focuses on scramble day recruitment, frequent mentorship meetings, and an active role in secondary placement results in successful placement into categorical positions for the vast majority. In that regard, we would argue that we have provided equal career mentorship to these graduated students in comparison with their medical schools of origin. PMID- 23111048 TI - Surgical residents' perception of competence and relevance of the clinical curriculum to future practice. AB - INTRODUCTION: General surgery residents maintain a case log throughout residency in order to achieve a targeted number of designated operations. Program directors must certify that each graduate is competent to enter general surgery practice without direct supervision. Our purpose was twofold, to determine: 1) graduates' perception of competence and relevance of specific operations to their practice; and 2) if case volume is related to competence. METHODS: Six classes from a general surgery residency program (n=26) were surveyed one year after graduation. The survey was piloted and revised base on findings. It listed 67 operations encompassing all facets of general surgery. Each operation corresponded to two four-point scales (strongly agree to strongly disagree). One scale was headed with "I was well prepared to work-up, independently perform the operation, and effectively care for the patient post-operatively" and the other "This operation is relevant to my current practice profile". A linear regression analysis was utilized to study the relationship between total case volume and overall competence. An unpaired T-test was utilized to study the relationship between volume of specific operations and perceptions of competence. RESULTS: Twenty-two graduates completed the survey (85% response rate). All respondents felt prepared to perform 24% (16/67) of the operations. Fifty percent or more of respondents felt prepared to perform 91% (61/67) of the operations. Fifty percent or more did not feel competent performing the surgical treatment of necrotizing enterocolitis, orchiopexy, transhiatal esophagectomy, adrenalectomy, and open/endovascular abdominal aortic aneurysm repair. Twenty-six operations were felt to be irrelevant to the practice of 50% or more of graduates. No operation was unanimously felt to be relevant. For 12% of operations (8/67) at least 10% of graduates felt the operation was relevant to their practice but were not comfortable performing it. These operations (abdominoperineal resection, transanal excision of tumor, transhiatal esophagectomy, superficial inguinal lymph node dissection, right hepatectomy, whipple, colonoscopy, and adrenalectomy) were considered to be in need of educational improvement at a program level. After analyzing individual case logs, increased case volume only correlated with competence for esophagectomy (5 vs. 1 p = .014), EGD (32 vs. 9 p = .018), orchiopexy (2.5 vs. 0 p = .03), and adrenalectomy (3 vs. 1 p = .001). Total major operations performed did not correlate with overall competence (p = .12). CONCLUSION: As program directors must document graduates' competency they must do so with confidence. Our results suggest graduates to not feel competent performing many operations, and several are relevant to their practice. Competence in all aspects of general surgery may be unrealistic, even with robust volume. These findings might help in the restructuring curricula of residency. PMID- 23111049 TI - The effect of positive and negative verbal feedback on surgical skills performance and motivation. AB - There is considerable effort and time invested in providing feedback to medical students and residents during their time in training. However, little effort has been made to measure the effects of positive and negative verbal feedback on skills performance and motivation to learn and practice. To probe these questions, first-year medical students (n = 25) were recruited to perform a peg transfer task on Fundamentals of Laparoscopic Surgery box trainers. Time to completion and number of errors were recorded. The students were then randomized to receive either positive or negative verbal feedback from an expert in the field of laparoscopic surgery. After this delivery of feedback, the students repeated the peg transfer task. Differences in performance pre- and post-feedback and also between the groups who received positive feedback (PF) vs negative feedback (NF) were analyzed. A survey was then completed by all the participants. Baseline task times were similar between groups (PF 209.3 seconds; NF 203 seconds, p = 0.58). The PF group averaged 1.83 first-time errors while the NF group 1 (p = 0.84). Post-feedback task times were significantly decreased for both groups (PF 159.75 seconds, p = 0.05; NF 132.08 seconds, p = 0.002). While the NF group demonstrated a greater improvement in mean time than the PF group, this was not statistically significant. Both groups also made fewer errors (PF 0.33 errors, p = 0.04; NF 0.38 errors, p = 0.23). When surveyed about their responses to standardized feedback scenarios, the students stated that both positive and negative verbal feedback could be potent stimulants for improved performance and motivation. Further research is required to better understand the effects of feedback on learner motivation and the interpersonal dynamic between mentors and their trainees. PMID- 23111050 TI - The surgical residency interview: a candidate-centered, working approach. AB - PURPOSE: The interview process is a pivotal, differentiating component of the residency match. Our bias is toward a working interview, producing better fulfillment of the needs of both parties, and a more informed match selection for the candidates and program. METHODS: We describe a "candidate-centered" approach for integrating applicant interviews into our daily work schedule. Applicants are informed upon accepting the interview of the working interview model. Our program offers 33 interview days over a 12-week period. A maximum of 5 applicants are hosted per day. Applicants are assigned to 1 of our general, thoracic, vascular, or plastic surgery teams. The interview day begins with the applicant changing into scrubs, attending a morning conference, and taking part in a program overview by a Chief Resident. Applicants join their host team where 4-8 hours are spent observing the operative team, on rounds and sharing lunch. The faculty and senior residents are responsible for interviewing and evaluating applicants though the Electronic Residency Application Service. RESULTS: A total of 13 surgeons are involved in the interview process resulting in broad-based evaluations. Each surgeon interviewed between 3 and 12 applicants. Faculty rate this interview approach highly because it allows them to maintain a rigorous operative schedule while interacting with applicants. Current residents are engaged in welcoming applicants to view the program. Faculty and residents believe cooperating in a real world manner aids their assessment of the applicant. Applicants routinely provide positive feedback, relaying this approach is informative, transparent, and should be the "standard." Applicants believe they are presented a realistic view of the program. Ultimately, this candidate centered process may be attributable to our resident cohort who exhibit high satisfaction, excellent resident morale, and very low dropout rate. CONCLUSIONS: We present a candidate-centered, working interview approach used in the selection of general surgery residents. While it may require more resources than the traditional approach, it harbors advantages for the applicant and the program. PMID- 23111051 TI - The use of a surgery-specific written examination in the selection process of surgical residents. AB - OBJECTIVE: Selection of surgical residents is a difficult task, and program directors are interested in identifying the best candidates. Among the qualities being sought after is the ability to acquire surgical knowledge, and eventually do well on their board examinations. During the interview process, many programs use results from the United States Medical Licensing Exam (USMLE) to identify residents they think will do well academically. The purpose of this study was to evaluate a different method of identifying such residents, through the use of a surgery-specific written exam (SSWE). DESIGN: A retrospective review of residents in our program between 2004 and 2012 was done. A 50-question SSWE was designed and administered to candidates on the day of their interview. Scores on the SSWE and the USMLE were compared with results on the American Board of Surgery In Training Exam (ABSITE). Correlation coefficients were calculated and compared. SETTING: Community based General Surgery residency program. PARTICIPANTS: Resident applicants. RESULTS: Forty-three residents had scores available from the SSWE, USMLE Part 1 (USMLE-1), and Part 2 (USMLE-2). There were ABSITE scores available for 38 in postgraduate year (PGY) 1. USMLE-1 had a statistically significant correlation (r = 0.327, p = 0.045) with the ABSITE score in PGY-1 (ABSITE-1), while with USMLE-2 had slightly less correlation (r = 0.314, p = 0.055) with ABSITE-1. However, the SSWE had a much stronger correlation (r = 0.656, p < 0.001) than either of them. CONCLUSIONS: An SSWE is a good method to identify residents who will later do well on the ABSITE. It is a better method than using the more general USMLE. Since the ABSITE has been shown to correlate with performance on board examinations, residency programs interested in identifying candidates that will do well on their board examinations, should consider incorporating an SSWE into their application process. PMID- 23111052 TI - Trimming the fat: optimizing overall educational value by defining factors associated with overall educational value and service-to-education ratio. AB - OBJECTIVE: The Accreditation Council for Graduate Medical Education work rules have forced programs to critically appraise the overall educational value (OEV) of rotations. Successful rotations must satisfy Residency Review Committee mandates and optimize the service-to-education ratio (SER). This study was designed to examine the relationship between the OEV and SER and identify rotation characteristics (RC) associated with both. DESIGN, SETTING, AND PARTICIPANTS: The Division of Surgery Education at the Hospital of the University of Pennsylvania administered a survey in FY2011 to all residents detailing resident perceptions regarding OEV, SER, and other RC. Responses were linked to additional rotation data. The relationship between OEV and SER was examined before and after controlling for significant RC identified in univariate analyses. Subgroup analyses by junior (CY1-2) and senior (CY3-5) resident status were performed. RESULTS: The survey was sent to 85 residents participating in 48 general surgery rotations, with an overall response rate of 87%. OEV was inversely proportional to SER. All RC were significant predictors of OEV in univariate models except rotation length, patient care participation and the presence of fellows. SER alone was a significant predictor of OEV (coefficient = 1.24, p < 0.001) and explained 68% of the variation in OEV. After including other RC, SER remained a significant predictor (coefficient = -1.08, p < 0.001) and the model explained 85% of the variation in OEV. In subgroup analysis, SER remained a significant predictor of OEV for junior residents (coefficient = -1.27, p = < 0.001), but not for senior residents (coefficient = -0.46, p = 0.15). CONCLUSIONS: The SER is inversely correlated with the OEV of general surgery rotations for the aggregate group of surgical residents, but this relationship appears to be attenuated by other factors in the senior resident group. Identification of the factors that affect junior surgical residents may provide the ability to improve the SER for junior residents and allow for significant improvements in perceived OEV for the resident body as a whole. PMID- 23111053 TI - Using NNAPPS (Nighttime Nurse and Physician Paging System) to Maximize Resident Call Efficiency within 2011 Accreditation Council for Graduate Medical Education (ACGME) work hour restrictions. AB - OBJECTIVES: To assess if implementing Nighttime Nurse and Physician Paging System (NNAPPS) would improve nurse and physician communication as well as reduce the number of nonurgent pages to residents taking overnight call. DESIGN: NNAPPS was implemented on the busiest General Surgery and Transplant wards at our University Hospital. We conducted 2 prospective studies that logged pages received by on call surgery residents for 2-month blocks. The logs captured time, source, reason, and action resulting from pages. Independent reviewers determined urgency of the pages. Primary outcome measures were comparison of average nonurgent pages, total pages and total pages per patient during a night shift between the NNAPPS ward and all other wards that care for surgical patients. SETTING: University teaching hospital. PARTICIPANTS: General surgery residents working overnight call shifts on nine surgical services. RESULTS: In both studies combined, there were a total of 107 night shifts during which 771 pages were received. Total census was 1179 patients. Nurses initiated most pages (67%). Eight percent of pages interrupted patient care, while 40% of pages interrupted resident sleep. Most pages resulted in either a "new order" (39%) or "patient assessment" (22%), while 36% resulted in "no action." Most pages (56%) were "urgent," 25% "nonurgent," and 19% "unable to determine urgency." Regarding the Transplant ward, significant differences (p < 0.05) existed between average nonurgent pages (0.46 vs 2.14), total pages (3.69 vs 6.14) and total pages/patient during a shift (0.38 vs 0.68) when comparing pre- and post-NNAPPS data. CONCLUSIONS: NNAPPS significantly reduced nonurgent pages, total pages and pages per patient during a night shift compared to services with conventional systems. Streamlined paging systems lead to more efficient communication between providers and decrease the nonurgent pages to residents. NNAPPS continued high standards of patient care and improved sleep patterns for residents. PMID- 23111054 TI - How tired is too tired? A case report. AB - We report a case involving a 32-year-old male presenting with acute delirium after completing the daily duties of his job. Though previously well, social history was positive for surgical residency. Symptom resolution was achieved with conservative treatment. We feel that this patient's clinical course represents an emerging disease entity known as "fatigue," which may have important implications for surgical training and practice. PMID- 23111055 TI - Increased stress reactivity: a mechanism specifically associated with the positive symptoms of psychotic disorder. AB - BACKGROUND: An increased reactivity to stress in the context of daily life is suggested to be an independent risk factor underlying the positive symptoms of psychotic disorder. The aim of this study was to investigate whether positive symptoms moderate the association between everyday stressful events and negative affect (NA), known as stress reactivity. This hypothesis was put to the test in patients with a diagnosis of psychotic disorder. Method The Comprehensive Assessment of Symptoms and History (CASH) and the Positive and Negative Syndrome Scale (PANSS) were used to assess positive and negative symptoms. The experience sampling method (ESM), a structured diary technique, was used to measure stress reactivity and psychotic symptoms in daily life. RESULTS: Higher levels of positive symptoms (CASH: B = 0.14, p = 0.005; PANSS: B = 0.05, p = 0.000; ESM: B = 0.03, p = 0.000) and lower levels of negative symptoms (PANSS: B = - 0.05, p = 0.001) significantly moderate the association between unpleasant events and NA. No significant moderating effect was found for CASH negative symptoms. Moreover, the moderating effect of lifetime and current symptoms on the stress-NA association was significantly larger for those patients with predominantly positive symptoms (CASH: B = 0.09, p = 0.000; PANSS: B = 0.08, p = 0.000; ESM: B = 0.13, p = 0.000). CONCLUSIONS: Patients with a 'psychotic syndrome' with high levels of positive symptoms and low levels of negative symptoms show increased reactivity to stress in daily life, indicating that stress reactivity is a possible risk factor underlying this syndrome. PMID- 23111056 TI - Localization and interaction effects in ultrathin epitaxial NbN superconducting films. AB - For epitaxial NbN films with thickness d, 2.0 nm <= d <= 20.5 nm, we observed a sharp superconducting transition, for which the transition temperature T(c) monotonically decreased with increasing 1/d. Regarding the suppression of T(c), the sheet resistance R(sq) dependence of T(c) closely fitted the Finkel'stein formula from localization theory, with a reasonable value of the electron mean free path comparable to atomic distance, which was used as a fitting parameter. On the other hand, the critical sheet resistance R(c), at which the superconducting-insulator transition was expected, was approximately one-third of the universal value R(q) = h/4e(2) suggested by the dirty boson model for self duality. It is concluded that T(c) depression in the present NbN system is determined by localization theory but not the dirty boson model. PMID- 23111057 TI - Diabetes impairs stem cell and proangiogenic cell mobilization in humans. AB - OBJECTIVE: Diabetes mellitus (DM) increases cardiovascular risk, at least in part, through shortage of vascular regenerative cells derived from the bone marrow (BM). In experimental models, DM causes morphological and functional BM alterations, but information on BM function in human DM is missing. Herein, we sought to assay mobilization of stem and proangiogenic cells in subjects with and without DM. RESEARCH DESIGN AND METHODS: In a prospective trial (NCT01102699), we tested BM responsiveness to 5 MUg/kg human recombinant granulocyte colony stimulating factor (hrG-CSF) in 24 individuals with DM (10 type 1 and 14 type 2) and 14 individuals without DM. Before and 24 h after hrG-CSF, we quantified circulating stem/progenitor cells and total and differential white blood cell counts. We also evaluated in vivo the proangiogenic capacity of peripheral blood mononuclear cells using the Matrigel plug assay. RESULTS: In response to hrG-CSF, levels of CD34(+) cells and other progenitor cell phenotypes increased in subjects without DM. Patients with DM had significantly impaired mobilization of CD34(+), CD133(+), and CD34(+)CD133(+) hematopoietic stem cells and CD133(+)KDR(+) endothelial progenitors, independently of potential confounders. The in vivo angiogenic capacity of peripheral blood mononuclear cells significantly increased after hrG-CSF in control subjects without DM, but not in patients with DM. DM was also associated with the inability to upregulate CD26/DPP-4 on CD34(+) cells, which is required for the mobilizing effect of granulocyte colony-stimulating factor. CONCLUSIONS: Stem and proangiogenic cell mobilization in response to hrG-CSF is impaired in DM, possibly because of maladaptive CD26/DPP-4 regulation. These alterations may hamper tissue repair and favor the development of cardiovascular complications. PMID- 23111058 TI - Lessons from the mixed-meal tolerance test: use of 90-minute and fasting C peptide in pediatric diabetes. AB - OBJECTIVE: Mixed-meal tolerance test (MMTT) area under the curve C-peptide (AUC CP) is the gold-standard measure of endogenous insulin secretion in type 1 diabetes but is intensive and invasive to perform. The 90-min MMTT-stimulated CP >=0.2 nmol/L (90CP) is related to improved clinical outcomes, and CP >=0.1 nmol/L is the equivalent fasting measure (FCP). We assessed whether 90CP or FCP are alternatives to a full MMTT. RESEARCH DESIGN AND METHODS: CP was measured during 1,334 MMTTs in 421 type 1 diabetes patients aged <18 years at 3, 9, 18, 48, and 72 months duration. We assessed: 1) correlation between mean AUC CP and 90CP or FCP; 2) sensitivity and specificity of 90CP >=0.2 nmol/L and FCP >= 0.1 nmol/L to detect peak CP >=0.2 nmol/L and the equivalent AUC CP; and 3) how the time taken to reach the CP peak varied with age of diagnosis and diabetes duration. RESULTS: AUC CP was highly correlated to 90CP (r(s) = 0.96; P < 0.0001) and strongly correlated to FCP (r(s) = 0.84; P < 0.0001). AUC CP >=23 nmol/L/150 min was the equivalent cutoff for peak CP >=0.2 nmol/L (98% sensitivity/97% specificity). A 90CP >=0.2 nmol/L correctly classified 96% patients using AUC or peak CP, whereas FCP >=0.1 nmol/L classified 83 and 85% patients, respectively. There was only a small difference seen between peak and 90CP (median 0.02 nmol/L). The CP peak occurred earlier in patients with longer diabetes duration (6.1 min each 1-year increase in duration) and younger age (2.5 min each 1-year increase). CONCLUSIONS: 90CP is a highly sensitive and specific measure of AUC and peak CP in children and adolescents with type 1 diabetes and offers a practical alternative to a full MMTT. PMID- 23111059 TI - Photon activated therapy (PAT) using monochromatic synchrotron X-rays and iron oxide nanoparticles in a mouse tumor model: feasibility study of PAT for the treatment of superficial malignancy. AB - BACKGROUND: X-rays are known to interact with metallic nanoparticles, producing photoelectric species as radiosensitizing effects, and have been exploited in vivo mainly with gold nanoparticles. The purpose of this study was to investigate the potential of sensitizing effect of iron oxide nanoparticles for photon activated therapy. METHODS: X-rays photon activated therapy (PAT) was studied by treating CT26 tumor cells and CT26 tumor-bearing mice loaded with 13-nm diameter FeO NP, and irradiating them at 7.1 keV near the Fe K-edge using synchrotron x rays radiation. Survival of cells was determined by MTT assay, and tumor regression assay was performed for in vivo model experiment. The results of PAT treated groups were compared with x-rays alone control groups. RESULTS: A more significant reduction in viability and damage was observed in the FeO NP-treated irradiated cells, compared to the radiation alone group (p < 0.04). Injection of FeO NP (100 mg/kg) 30 min prior to irradiation elevated the tumor concentration of magnetite to 40 MUg of Fe/g tissue, with a tumor-to-muscle ratio of 17.4. The group receiving FeO NP and radiation of 10 Gy showed 80% complete tumor regression (CTR) after 15-35 days and relapse-free survival for up to 6 months, compared to the control group, which showed growth retardation, resulting in 80% fatality. The group receiving radiation of 40 Gy showed 100% CTR in all cases irrespective of the presence of FeO NP, but CTR was achieved earlier in the PAT treated group compared with the radiation alone group. CONCLUSIONS: An iron oxide nanoparticle enhanced therapeutic effect with relatively low tissue concentration of iron and 10 Gy of monochromatic X-rays. Since 7.1 keV X-rays is attenuated very sharply in the tissue, FeO NP-PAT may have promise as a potent treatment option for superficial malignancies in the skin, like chest wall recurrence of breast cancer. PMID- 23111060 TI - Cutaneous squamous cell carcinoma (SCC) arising in stump of amputated finger in a patient with resected glossal SCC. AB - BACKGROUND: Cutaneous squamous cell carcinoma (SCC) of the hands and fingers are sometimes locally aggressive; with higher rates of regional metastasis than other cutaneous SCC, although distant metastasis is rare. CASE PRESENTATION: We present the case of a 62-year-old Japanese man with double cancers: a tongue SCC and a cutaneous SCC. Swelling of the finger lesion developed gradually around the entire remaining middle finger after accidental amputation at the proximal interphalangeal joint. Histopathological examination of the tumor on the stump of the amputated finger indicated a well-differentiated SCC. The past history indicated surgery for SCC of the tongue 3 years earlier; with histopathology of moderately-differentiated SCC. CONCLUSION: Since dedifferentiation is unlikely in metastatic tumors, the cutaneous SCC of the finger is unlikely to have originated from the tongue SCC. Alternatively, the double cancer may be two unrelated lesions or the tongue tumor could have originated from the cutaneous SCC. PMID- 23111061 TI - A comparison of the Actigraph GT1M and GT3X accelerometers under standardized and free-living conditions. AB - Prior to 2008, data collection from Actigraph accelerometers was only possible in the uniaxial mode. In 2009, Actigraph released the GT3X, which allows triaxial data collection. The purpose of this study was to determine if data collected by the GT3X in the uniaxial mode are comparable to its predecessor, the GT1M, under both standardized and free-living conditions. Thirty-four subjects (17 women and 17 men) provided complete data for this study. Subjects wore the accelerometers (one GT1M and one GT3X) on their waistband in line with the right and left anterior axillary lines. Each subject walked on a treadmill at speeds of 2.4, 3.2, 4.0, 4.8, 5.6 and 6.4 km h(-1) for 5 min each, and then continued to wear both accelerometers for all waking hours for three consecutive days. Mean steady state activity counts min(-1) for both accelerometers were not statistically different for the standardized treadmill walking speeds and for mean minutes/day and activity counts/day for intensity classifications under the free-living condition. Based on comparisons made from both standardized walking speeds and free-living conditions, it is reasonable to compare data derived from either the GT1M or GT3X when collected in the uniaxial mode. PMID- 23111062 TI - Parallel labeling experiments with [1,2-(13)C]glucose and [U-(13)C]glutamine provide new insights into CHO cell metabolism. AB - We applied a parallel labeling strategy using two isotopic tracers, [1,2 (13)C]glucose and [U-(13)C]glutamine, to determine metabolic fluxes in Chinese hamster ovary (CHO) cells. CHO cells were grown in parallel cultures over a period of six days with glucose and glutamine feeding. On days 2 and 5, isotopic tracers were introduced and (13)C-labeling of intracellular metabolites was measured by gas chromatography-mass spectrometry (GC-MS). Metabolites in glycolysis pathway reached isotopic steady state for [1,2-(13)C]glucose within 1.5h, and metabolites in the TCA cycle reached isotopic steady state for [U (13)C]glutamine within 3h. Combined analysis of multiple data sets produced detailed flux maps at two key metabolic phases, exponential growth phase (day 2) and early stationary phase (day 5). Flux results revealed significant rewiring of intracellular metabolism in the transition from growth to non-growth, including changes in oxidative pentose phosphate pathway, anaplerosis, amino acid metabolism, and fatty acid biosynthesis. At the growth phase, de novo fatty acid biosynthesis correlated well with the lipid requirements for cell growth. However, surprisingly, at the non-growth phase the fatty acid biosynthesis flux remained high even though no new lipids were needed for cell growth. Additionally, we identified a discrepancy in the estimated TCA cycle flux obtained using traditional stoichiometric flux balancing and (13)C-metabolic flux analysis. Our results suggested that CHO cells produced additional metabolites from glucose that were not captured in previous metabolic models. Follow-up experiments with [U-(13)C]glucose confirmed that additional metabolites were accumulating in the medium that became M+3 and M+6 labeled. PMID- 23111063 TI - Stress and diabetes in socioeconomic context: a qualitative study of urban Indians. AB - Type 2 diabetes has escalated in urban India in the past two decades. Historically a disease of the affluent, recent epidemiological evidence indicates rising diabetes incidence and prevalence in urban India's middle class and working poor. Although there is substantial qualitative data about people with diabetes from high-income countries, scant resources provide insight into diabetes experiences among those in India, and lower-income groups specifically. In this article, we use individual-level analysis of illness narratives to understand how people experience and understand diabetes across income groups in Delhi, India. We conducted in-depth qualitative interviews and administered the Hopkins Symptoms Check-List (HSCL-25) to evaluate depression among 59 people with diabetes in northeast Delhi between December 2011 and February 2012. We analyzed their responses to: 1) what caused your diabetes?; 2) what do you find most stressful in your daily life?; and 3) where do you seek diabetes care? We found few people held diabetes beliefs that were congruent with socio-spiritual or biomedical explanatory models, and higher income participants commonly cited "tension" as a contributor to diabetes. Stress associated with children's futures, financial security, and family dynamics were most commonly reported, but how these subjective stresses were realized in people's lives varied across income groups. Depression was most common among the poorest income group (55%) but was also reported among middle- (38%) and high-income (29%) participants. One quarter of respondents reported diabetes distress, but only those from the low income community reported co-occurring depression and these respondents often revealed poor access to diabetes care. These data suggest that lower-income populations not only have higher rates of depression but also may be more likely to delay health care and therefore develop diabetes complications. This research has many implications for public health care in India as diabetes prevalence shifts to affect lower income groups who concurrently experience higher rates of depression and poorer access to medical care. PMID- 23111064 TI - Genetics and ultrasound in rheumatoid arthritis. PMID- 23111065 TI - Targeted blockade in lethal West Nile virus encephalitis indicates a crucial role for very late antigen (VLA)-4-dependent recruitment of nitric oxide-producing macrophages. AB - Infiltration of Ly6C(hi) monocytes from the blood is a hallmark of viral encephalitis. In mice with lethal encephalitis caused by West Nile virus (WNV), an emerging neurotropic flavivirus, inhibition of Ly6C(hi) monocyte trafficking into the brain by anti-very late antigen (VLA)-4 integrin antibody blockade at the time of first weight loss and leukocyte influx resulted in long-term survival of up to 60% of infected mice, with subsequent sterilizing immunity. This treatment had no effect on viral titers but appeared to be due to inhibition of Ly6C(hi) macrophage immigration. Although macrophages isolated from the infected brain induced WNV-specific CD4(+) T-cell proliferation, T cells did not directly contribute to pathology, but are likely to be important in viral control, as antibody-mediated T-cell depletion could not reproduce the therapeutic benefit of anti-VLA-4. Instead, 70% of infiltrating inflammatory monocyte-derived macrophages were found to be making nitric oxide (NO). Furthermore, aminoguanidine-mediated inhibition of induced NO synthase activity in infiltrating macrophages significantly prolonged survival, indicating involvement of NO in the immunopathology. These data show for the first time the therapeutic effects of temporally targeting pathogenic NO-producing macrophages during neurotropic viral encephalitis. PMID- 23111066 TI - Histone deacetylases inhibitor sodium butyrate inhibits JAK2/STAT signaling through upregulation of SOCS1 and SOCS3 mediated by HDAC8 inhibition in myeloproliferative neoplasms. AB - Constitutive activation of Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) signaling has an important role in the oncogenesis of myeloproliferative neoplasms (MPNs) and leukemia. Histone deacetylases (HDACs) inhibitors have been reported to possess anticancer activity through different mechanisms. However, whether HDACs inhibitors suppress JAK2/STAT signaling in MPNs is still unknown. In this study, we show that the HDAC inhibitor sodium butyrate (SB) inhibited JAK2/STAT signaling and increased the expression of suppressors of cytokine signaling 1 (SOCS1) and SOCS3, both of which are the potent feedback inhibitors of JAK2/STAT signaling. SB upregulated the expression of SOCS1 and SOCS3 by triggering the promoter-associated histone acetylation of SOCS1 and SOCS3 in K562 and HEL cell lines. Importantly, we found that upon knockdown of each class I HDACs, only knockdown of HDAC8 resulted in the increased expression of SOCS1 and SOCS3. Moreover, overexpression of SOCS1 and SOCS3 significantly inhibited cell growth and suppressed JAK2/STAT signaling in K562 and HEL cells. Furthermore, SB increased the transcript levels of SOCS1 and SOCS3 and inhibited the clonogenic activity of hematopoietic progenitors from patients with MPNs. Taken together, these data establish a new anticancer mechanism that SB inhibits JAK2/STAT signaling through HDAC8-mediated upregulation of SOCS1 and SOCS3. Thus, HDACs inhibitors may have therapeutic potential for the treatment of MPNs. PMID- 23111067 TI - Givinostat and hydroxyurea synergize in vitro to induce apoptosis of cells from JAK2(V617F) myeloproliferative neoplasm patients. AB - We investigated whether clinically achievable concentrations of the histone deacetylase (HDAC) inhibitors givinostat and hydroxyurea induce synergistic cytotoxicity in Jak2(V617F) cells in vitro and through which possible mechanism. Givinostat and hydroxyurea at low doses potentiated the pro-apoptotic effects of each other in the Jak2(V617F) HEL and UKE1 cell lines. Givinostat induced 6.8% 20.8% and hydroxyurea (HU) 20.4%-42.4% cell death alone and 35.8%-75.3% in combination. The effect was statistically significant using the median effect Chou-Talalay method, resulting in a combination index less than 1, indicating synergy. Givinostat alone induced cell cycle arrest of the cell lines in G0/G1 and hydroxyurea in S phase, whereas both drugs together led to a G1 block. At the molecular level, hydroxyurea counteracted the induction of p21CDKN1A by Givinostat and potentiated caspase 3 activation, explaining at least in part the increased apoptosis observed in presence of both compounds. We also verified the effect of the same drugs in colony assays of freshly isolated Jak2(V617F) polycythemia vera cells. In this case, low doses of the compounds were additive to each other. These results suggest that combined treatment with givinostat and hydroxyurea is a potential strategy for the management of Jak2(V617F) myeloproliferative neoplasms. PMID- 23111068 TI - Darker nights and dirty electricity. PMID- 23111071 TI - Peep into policy, politics, parliament. PMID- 23111073 TI - Public inquiries: are you ready? PMID- 23111075 TI - A brief introduction to ... safer cycling. PMID- 23111076 TI - In practice: dietary behaviour: a public health issue. PMID- 23111077 TI - Micronutrient deficiencies and infant development: where next? PMID- 23111078 TI - Reducing risk through physical activity. PMID- 23111079 TI - The leadership challenge - is the NHS 'up to it'? PMID- 23111080 TI - Children's food. PMID- 23111081 TI - Osteoporosis prevention and motivation for weight-bearing physical activity and calcium consumption. PMID- 23111082 TI - Customers' perspectives on the impact of the Pathways to Work condition management programme on their health, well-being and vocational activity. AB - AIMS: Pathways to Work is a UK initiative aimed at supporting customers on incapacity benefits to return to work. This qualitative study complements previous evaluations of Pathways to Work by exploring customers' perceptions of the impact of the Condition Management Programme (CMP) offered to claimants with long-term health conditions. METHODS: 39 customers took part in focus groups held at the seven sites where Pathways was originally piloted. The main focus of the discussions was on perceptions of the ways in which participation had impacted on health, well-being and return to work. The discussions were audio-recorded and fully transcribed for analysis using a text analysis framework to enable the development and refinement of categories and overarching patterns in the data. RESULTS: Perceived impacts on health and well-being included a more positive outlook, social contact, changed perceptions of conditions and improvements in health. Some customers also reported an increase in their vocational activity and others felt ready to embark on new activities. Factors associated with positive outcomes included the extent and quality of contact with CMP staff and practical advice about condition management. Factors impeding positive employment outcomes related mainly to obstacles to returning to work. CONCLUSIONS: The results indicated that CMP can assist customers to learn about and manage their health conditions and increase their vocational activity, and that CMP therefore provides a promising means of enabling people with long-term health conditions to regain a fulfilling, productive life. PMID- 23111083 TI - Therapeutic lighting design for the elderly: a review. AB - AIMS: Research suggests that specialised lighting design is essential to cater for the elderly users of a building because of reduced visual performance with increased age. This review aims to document what is known of the physical and psychological aspects of lighting and their role in promoting a healthy and safe environment for the elderly. METHODS: A methodical review was carried out of published literature on the physical and psychological impacts of light on the elderly. Design standards and guides from professional organizations were evaluated to identify synergies and gaps between the evidence base and current practice. RESULTS: Lighting has been identified as a significant environmental attribute responsible for promoting physical and mental health of the elderly. The evidence related to visual performance was found to be robust. However, guides and standards appeared to have focused mostly on illumination requirements for specific tasks and have lacked detailed guidelines on vertical lighting and luminance design. This review has identified a growing body of evidence on the therapeutic benefits of lighting and its use in treating psychological disorders among the elderly. The experiments using light as a therapy have improved our understanding of the underlying principles, but the integration of therapeutic aspects of lighting in design practice and guidelines is lacking. CONCLUSIONS: While design guidelines discuss the physical needs of lighting for the elderly fairly well, they lack incorporation of photobiological impacts. Despite positive outcomes from research, the implementation of therapeutic aspects of lighting in buildings is still debatable due to insufficient relevant investigations and robustness of their findings. Collaborations between designers and physicians can contribute in delivering customised lighting solutions by considering disease types and needs. Further investigation needs to be carried out for translating therapeutic benefits to photometric units to implement them in building lighting design. PMID- 23111084 TI - A proposal for a computer-based framework of support for public health in the management of biological incidents: the Czech Republic experience. AB - AIMS: Biological incidents jeopardising public health require decision-making that consists of one dominant feature: complexity. Therefore, public health decision-makers necessitate appropriate support. METHODS: Based on the analogy with business intelligence (BI) principles, the contextual analysis of the environment and available data resources, and conceptual modelling within systems and knowledge engineering, this paper proposes a general framework for computer based decision support in the case of a biological incident. At the outset, the analysis of potential inputs to the framework is conducted and several resources such as demographic information, strategic documents, environmental characteristics, agent descriptors and surveillance systems are considered. RESULTS: Consequently, three prototypes were developed, tested and evaluated by a group of experts. Their selection was based on the overall framework scheme. Subsequently, an ontology prototype linked with an inference engine, multi-agent based model focusing on the simulation of an environment, and expert-system prototypes were created. CONCLUSIONS: All prototypes proved to be utilisable support tools for decision-making in the field of public health. Nevertheless, the research revealed further issues and challenges that might be investigated by both public health focused researchers and practitioners. PMID- 23111085 TI - Mobile telecommunications and health: report of an investigation into an alleged cancer cluster in Sandwell, West Midlands. AB - AIMS: Residents of one street expressed concern about the number of incident cancers, following the installation of a nearby mobile phone base station. The investigation explored whether the base station could be responsible for the cancers. METHODS: Data were collected from residents' medical records. GPs and oncologists provided further information. RESULTS: Ward-level cancer incidence and mortality data were also obtained, over four three-year time periods. A total of 19 residents had developed cancer. The collection of cancers did not fulfil the criteria for a cancer cluster. Standardized mortality ratios (SMRs) for all malignant neoplasms (excluding non-melanoma skin cancers) in females (1.38 (95% CI, 1.08-1.74)) and all persons (1.27 (CI, 1.06-1.51)) were significantly higher than in the West Midlands during 2001-3. There were no significant differences for colorectal, female breast and prostate cancers, for any time period. Standardized incidence ratios (SIRs) for non-melanoma skin cancers in males and all persons was significantly lower than in the West Midlands during 1999-2001, and significantly lower in males, females and all persons during 2002-4. CONCLUSIONS: We cannot conclude that the base station was responsible for the cancers. It is unlikely that information around a single base station can either demonstrate or exclude causality. PMID- 23111086 TI - Use of ethnographic approaches to the study of health experiences in relation to natural landscapes. AB - AIMS: This paper discusses the use of ethnographic approaches to explore how engagement with natural landscapes might benefit people's health. METHODS: Drawing on a selected review of empirical research we identified 30 relevant research papers that utilised qualitative methods to explore health issues and engagement with nature. Three examples of 'alternative' - i.e. non-mainstream qualitative approaches - are used to illustrate how different methods can be used to explore people's experiences of engaging with nature for health. RESULTS: While quantitative methods are dominant in health research, qualitative approaches are becoming more widely used. Approaches such as autoethnography can add value to nature and health studies by providing opportunities for researchers to be self-critical of their role as a researcher. Accompanied visits and visual ethnography can afford the researcher rich data about bodily movement, facial expressions and journeys, as well as dialogues associated with the meanings of nature for health. CONCLUSIONS: The paper concludes by suggesting that ethnographic methods can provide useful and important insights into why people engage with the natural environment and the range of health benefits they may gain from contact with nature. PMID- 23111087 TI - A perspective on the future public health: an integrative and ecological framework. AB - Modernity has brought health and social benefits to many societies, not least through the insights of science and technology. Yet, modernity has also been associated with a number of cultural characteristics, such as materialism, individualism, consumerism and an addiction to continuing economic growth, that seem potentially harmful to health and well-being and inimical to social equity. There is an emerging body of evidence that suggests that, in the affluent world, some of our most intractable contemporary health problems are, in fact, the product of modernity. This suggests that the tools of modernity (its science and its technology) are ill suited to finding solutions. This poses a problem for public health, as this discipline is itself a product of modernity and thus appears ill equipped to deal with the conditions and challenges of a rapidly changing and unstable world, one where the very sustainability of human society is now in question. This paper argues that a new paradigm for the future public health is needed. It presents an integrative, ecological framework as a starting point from which public health might grasp the opportunities for change inherent in the 'modern' threats we face. It suggests a number of features that will need to underpin such a paradigm shift in thinking and practice. However, as this paper is written from the perspective of an affluent, developed society (albeit from a perspective that is explicitly critical of the goals, trends and values that seem to characterise such societies), other voices from other places need to be heard. We hope that others will want to engage with our arguments and suggestions, whether to challenge and refute these, or to further their development. PMID- 23111089 TI - Key factors influencing canine heartworm, Dirofilaria immitis, in the United States. AB - An examination of the Companion Animal Parasite Council's (CAPC) canine heartworm data to clarify the spatial prevalence of heartworm in the United States. Factors thought to influence the spatial risk of disease, as identified in a recent CAPC workshop, are discussed. PMID- 23111090 TI - Single port/incision laparoscopic surgery compared with standard three-port laparoscopic surgery for appendicectomy - a randomised controlled trial. AB - BACKGROUND: Laparoscopic surgery has become the preferred approach for many procedures because of reduced post-operative pain, better recovery, shorter hospital stay and improved cosmesis. Single incision laparoscopic surgery is one of the many recent variants where either standard ports or a specially designed single multi-channel port is introduced through a single skin incision. While the cosmetic advantage of this is obvious, the evidence base for claims of reduced morbidity and better post-operative recovery is weak. This study aims to compare the effectiveness of single port/incision laparoscopic appendicectomy with standard three-port laparoscopic appendicectomy in adult patients at six weeks post-surgery. We also wish to assess the feasibility of a multicentre randomised controlled trial comparing single port/incision laparoscopic surgery with standard three-port laparoscopic surgery for other surgical techniques. METHODS AND DESIGN: Patients diagnosed with suspected appendicitis and requiring surgical treatment will be randomised to receive either standard three-port or single incision laparoscopic surgery. Data will be collected from clinical notes, operation notes and patient reported questionnaires. The following outcomes will be considered:1. Effectiveness of the surgical procedure in terms of:*patient reported outcomes*clinical outcomes*resource use2. Feasibility of conducting a randomised controlled trial (RCT) in the emergency surgical setting by quantifying:*patient eligibility*randomisation acceptability*feasibility of blinding participants to the intervention received*completion rates of case report forms and patient reported questionnaires TRIAL REGISTRATION: ISRCTN66443895 (assigned 10 March 2011, first patient randomised 09 January 2011). PMID- 23111091 TI - Identification of an intestine-specific promoter and inducible expression of bacterial alpha-galactosidase in mammalian cells by a lac operon system. AB - BACKGROUND: alpha-galactosidase has been widely used in animal husbandry to reduce anti-nutritional factors (such as alpha-galactoside) in feed. Intestine specific and substrate inducible expression of alpha-galactosidase would be highly beneficial for transgenic animal production. METHODS: To achieve the intestine-specific and substrate inducible expression of alpha-galactosidase, we first identified intestine-specific promoters by comparing the transcriptional activity and tissue specificity of four intestine-specific promoters from human intestinal fatty acid binding protein, rat intestinal fatty acid binding protein, human mucin-2 and human lysozyme. We made two chimeric constructs combining the promoter and enhancer of human mucin-2, rat intestinal trefoil factor and human sucrase-isomaltase. Then a modified lac operon system was constructed to investigate the induction of alpha-galactosidase expression and enzyme activity by isopropyl beta-D-1-thiogalactopyranoside (IPTG) and an alpha-galactosidase substrate, alpha-lactose.We declared that the research carried out on human (Zhai Yafeng) was in compliance with the Helsinki Declaration, and experimental research on animals also followed internationally recognized guidelines. RESULTS: The activity of the human mucin-2 promoter was about 2 to 3 times higher than that of other intestine-specific promoters. In the lac operon system, the repressor significantly decreased (P < 0.05) luciferase activity by approximately 6.5-fold and reduced the percentage of cells expressing green fluorescent protein (GFP) by approximately 2-fold. In addition, the expression level of alpha galactosidase mRNA was decreased by 6-fold and alpha-galactosidase activity was reduced by 8-fold. In line with our expectations, IPTG and alpha-lactose supplementation reversed (P < 0.05) the inhibition and produced a 5-fold increase of luciferase activity, an 11-fold enhancement in the percentage of cells with GFP expression and an increase in alpha-galactosidase mRNA abundance (by about 5 fold) and alpha-galactosidase activity (by about 7-fold). CONCLUSIONS: We have successfully constructed a high specificity inducible lac operon system in an intestine-derived cell line, which could be of great value for gene therapy applications and transgenic animal production. PMID- 23111092 TI - The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate. AB - The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy. PMID- 23111093 TI - Subsyndromal depression in the United States: prevalence, course, and risk for incident psychiatric outcomes. AB - BACKGROUND: Subsyndromal depression (SD) may increase risk for incident major depressive and other disorders, as well as suicidality. However, little is known about the prevalence, course, and correlates of SD in the US general adult population. Method Structured diagnostic interviews were conducted to assess DSM IV Axis I and II disorders in a nationally representative sample of 34 653 US adults who were interviewed at two time-points 3 years apart. RESULTS: A total of 11.6% of US adults met study criteria for lifetime SD at Wave 1. The majority (9.3%) had <5 total symptoms required for a diagnosis of major depression; the remainder (2.3%) reported ?5 symptoms required for a diagnosis of major depression, but denied clinically significant distress or functional impairment. SD at Wave 1 was associated with increased likelihood of developing incident major depression [odds ratios (ORs) 1.72-2.05], as well as dysthymia, social phobia, and generalized anxiety disorder (GAD) at Wave 2 (ORs 1.41-2.92). Among respondents with SD at Wave 1, Cluster A and B personality disorders, and worse mental health status were associated with increased likelihood of developing incident major depression at Wave 2. CONCLUSIONS: SD is prevalent in the US population, and associated with elevated rates of Axis I and II psychopathology, increased psychosocial disability, and risk for incident major depression, dysthymia, social phobia, and GAD. These results underscore the importance of a dimensional conceptualization of depressive symptoms, as SD may serve as an early prognostic indicator of incident major depression and related disorders, and could help identify individuals who may benefit from preventive interventions. PMID- 23111094 TI - Trypanosoma evansi kDNA minicircle found in the Venezuelan nectar-feeding bat Leptonycteris curasoae (Glossophaginae), supports the hypothesis of multiple origins of that parasite in South America. AB - Trypanosoma evansi is a mammal generalist protozoon which causes negative effects on health and productivity in bovine and equine herds in South America, Europe, Asia and Africa. By molecular methods, we screened the presence of that parasite together with other trypanosome species in 105 bats of 10 species collected in arid zones of northern Venezuela. The first molecular approach was fluorescent fragment length barcoding (FFLB), which relies on amplification of relative small regions of rRNA genes (four loci) and fluorescence detection. By FFLB, 17 samples showed patterns of possible trypanosomatid infections. These samples were used to test presence of trypanosomes by PCR using the following DNA markers: V7-V8 SSU rRNA, gGAPDH and kDNA minicircle regions. Only in one individual of the nectar feeding bat, Leptonycteris curasoae, we were able to amplify 1000bp of the trypanosome kDNA minicircle. That PCR product was sequenced and the parasite species was determined by NCBI-BLAST and phylogenetic analysis. Both analyses showed that the minicircle sequence corresponds to Trypanosoma evansi. The phylogenetic analysis of the sequence obtained in this study clustered with a T. evansi sequence obtained in a Venezuelan capybara, Hydrochoerus hydrochaeris, and distant of others two T. evansi sequences obtained in a Colombian capybara and horse. This result supports the hypothesis of multiple origins of T. evansi in South America. PMID- 23111095 TI - Hepatitis B virus (HBV) reactivation in rheumatic patients with hepatitis core antigen (HBV occult carriers) undergoing anti-tumor necrosis factor therapy. AB - OBJECTIVES: The aim of this study was to assess the effects of anti-tumour necrosis factor (TNF) agents on hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative and anti-hepatitis B core (HBc)-positive patients (HBV occult carriers) with rheumatic diseases. METHODS: Evidence of HBV reactivation after anti-TNF therapy in HBV occult carriers with a rheumatic disease was studied by summarising results and by performing meta-analysis analysis. RESULTS: A total of 468 HBsAg-negative and anti-HBc-positive patients with a rheumatic disease undergoing treatment with an anti-TNF agent were identified in nine studies. The anti-TNF agents used were etanercept in 269 cases, adalimumab in 95, and infliximab in 100 cases, and these were administered for rheumatoid arthritis (RA) in 327 patients, ankylosing spondylitis in 49, and psoriatic arthritis (PsA) in 73 patients. Follow-up periods ranged from 6 to 60 months. HBV reactivation in patients on an anti-TNF agent was reported in 8 cases (8/468 = 1.7%). Seven of these patients had RA and 1 had PsA. Seven patients received etanercept and one adalimumab. HBV-DNA was detectable in 7 of these 8 cases. Antiviral treatment was administered in 6 of the 8 (lamivudine in 2, entecavir in 4) and clinical outcomes were satisfactory in all 8 patients. CONCLUSIONS: HBV reactivation was found in 8 (1.7%) patients among 468 HBsAg negative and anti-HBc-positive patients with rheumatic diseases treated with anti TNF agents. Our data suggest that HBsAg-negative and anti-HBc-positive patients undergoing anti-TNF therapy need to be carefully monitored during anti-TNF therapy. PMID- 23111096 TI - MetabR: an R script for linear model analysis of quantitative metabolomic data. AB - BACKGROUND: Metabolomics is an emerging high-throughput approach to systems biology, but data analysis tools are lacking compared to other systems level disciplines such as transcriptomics and proteomics. Metabolomic data analysis requires a normalization step to remove systematic effects of confounding variables on metabolite measurements. Current tools may not correctly normalize every metabolite when the relationships between each metabolite quantity and fixed-effect confounding variables are different, or for the effects of random effect confounding variables. Linear mixed models, an established methodology in the microarray literature, offer a standardized and flexible approach for removing the effects of fixed- and random-effect confounding variables from metabolomic data. FINDINGS: Here we present a simple menu-driven program, "MetabR", designed to aid researchers with no programming background in statistical analysis of metabolomic data. Written in the open-source statistical programming language R, MetabR implements linear mixed models to normalize metabolomic data and analysis of variance (ANOVA) to test treatment differences. MetabR exports normalized data, checks statistical model assumptions, identifies differentially abundant metabolites, and produces output files to help with data interpretation. Example data are provided to illustrate normalization for common confounding variables and to demonstrate the utility of the MetabR program. CONCLUSIONS: We developed MetabR as a simple and user-friendly tool for implementing linear mixed model-based normalization and statistical analysis of targeted metabolomic data, which helps to fill a lack of available data analysis tools in this field. The program, user guide, example data, and any future news or updates related to the program may be found at http://metabr.r-forge.r project.org/. PMID- 23111097 TI - Evaluation of end-user satisfaction among employees participating in a web-based health risk assessment with tailored feedback. AB - BACKGROUND: Web technology is increasingly being used to provide individuals with health risk assessments (HRAs) with tailored feedback. End-user satisfaction is an important determinant of the potential impact of HRAs, as this influences program attrition and adherence to behavioral advice. OBJECTIVE: The aim of this study was to evaluate end-user satisfaction with a web-based HRA with tailored feedback applied in worksite settings, using mixed (quantitative and qualitative) methods. METHODS: Employees of seven companies in the Netherlands participated in a commercial, web-based, HRA with tailored feedback. The HRA consisted of four components: 1) a health and lifestyle assessment questionnaire, 2) a biometric evaluation, 3) a laboratory evaluation, and 4) tailored feedback consisting of a personal health risk profile and lifestyle behavior advice communicated through a web portal. HRA respondents received an evaluation questionnaire after six weeks. Satisfaction with different parts of the HRA was measured on 5-point Likert scales. A free-text field provided the opportunity to make additional comments. RESULTS: In total, 2289 employees participated in the HRA program, of which 637 (27.8%) completed the evaluation questionnaire. Quantitative analysis showed that 85.6% of the respondents evaluated the overall HRA positively. The free-text field was filled in by 29.7 % of the respondents (189 out of 637), who made 315 separate remarks. Qualitative evaluation of these data showed that these respondents made critical remarks. Respondents felt restricted by the answer categories of the health and lifestyle assessment questionnaire, which resulted in the feeling that the corresponding feedback could be inadequate. Some respondents perceived the personal risk profile as unnecessarily alarming or suggested providing more explanations, reference values, and a justification of the behavioral advice given. Respondents also requested the opportunity to discuss the feedback with a health professional. CONCLUSIONS: Most people were satisfied with the web-based HRA with tailored feedback. Sources of dissatisfaction were limited opportunities for providing additional health information outside of the predefined health and lifestyle assessment questionnaire and insufficient transparency on the generation of the feedback. Information regarding the aim and content of the HRA should be clear and accurate to prevent unrealistic expectations among end-users. Involving trusted health professionals in the implementation of web-based HRAs may enhance the use of and confidence in the HRA. PMID- 23111098 TI - Establishing a threshold for the number of missing days using 7 d pedometer data. AB - The purpose of this study was to examine the threshold of the number of missing days of recovery using the individual information (II)-centered approach. Data for this study came from 86 participants, aged from 17 to 79 years old, who had 7 consecutive days of complete pedometer (Yamax SW 200) wear. Missing datasets (1 d through 5 d missing) were created by a SAS random process 10,000 times each. All missing values were replaced using the II-centered approach. A 7 d average was calculated for each dataset, including the complete dataset. Repeated measure ANOVA was used to determine the differences between 1 d through 5 d missing datasets and the complete dataset. Mean absolute percentage error (MAPE) was also computed. Mean (SD) daily step count for the complete 7 d dataset was 7979 (3084). Mean (SD) values for the 1 d through 5 d missing datasets were 8072 (3218), 8066 (3109), 7968 (3273), 7741 (3050) and 8314 (3529), respectively (p > 0.05). The lower MAPEs were estimated for 1 d missing (5.2%, 95% confidence interval (CI) 4.4-6.0) and 2 d missing (8.4%, 95% CI 7.0-9.8), while all others were greater than 10%. The results of this study show that the 1 d through 5 d missing datasets, with replaced values, were not significantly different from the complete dataset. Based on the MAPE results, it is not recommended to replace more than two days of missing step counts. PMID- 23111099 TI - The effectiveness of acupuncture in treating chronic non-specific low back pain: a systematic review of the literature. AB - BACKGROUND: Low back pain is a common musculoskeletal disorder defined as pain and soreness, muscle tension, or stiffness in the lumbosacral area of the spine which does not have a specific cause. Low back pain results in high health costs and incapacity to work causing an economic burden to society. The optimal management of non-specific low back pain appears to be undecided. Recently published guidelines support the use of acupuncture for treating non-specific low back pain and it has become a popular alternative treatment modality for patients with low back pain. METHODS: A comprehensive systematic literature search was conducted through Medline using Ovid and Medical Subject Headings for randomized controlled trials published in the last 10 years. The outcomes scored were subjective pain scores and functional outcome scores. RESULTS: Eighty two randomized studies were identified, of which 7 met our inclusion criteria. Three studies found a significant difference in pain scores when comparing acupuncture, or sham acupuncture, with conventional therapy or no care. Two studies demonstrated a significant difference between acupuncture treatment and no treatment or routine care at 8 weeks and 3 months. Three studies demonstrated no significant difference between acupuncture and minimal/sham acupuncture with no difference in pain relief or function over 6 to 12 months. CONCLUSIONS: This review provides some evidence to support acupuncture as more effective than no treatment, but no conclusions can be drawn about its effectiveness over other treatment modalities as the evidence is conflicting. PMID- 23111101 TI - p-electron magnetism in CdS doped with main group elements. AB - On the basis of ab initio supercell calculations employing density functional theory (DFT) and post-DFT methods, we investigate the behavior of main group element impurities (B, C, N, Al, Si, P, Ga, Ge) in wurtzite (w) and zincblende (zb) CdS lattices. It is found that the impurities prefer the sulfur position and most of them, depending on the concentration, exhibit magnetic order. We find that for small concentrations (64zb and 72w supercells) a half-metallic behavior is found. For a 16-atom supercell for both the zb- and w-structure partly also unsaturated magnetic moments occur. The field dependence of the magnetic moments in these materials may lead to new technological applications of these magnetic semiconductors as tunable spin injection materials. PMID- 23111100 TI - Spatio-temporal occurrence of Culicoides biting midges in the climatic regions of Switzerland, along with large scale species identification by MALDI-TOF mass spectrometry. AB - BACKGROUND: Culicoides biting midges are incriminated as biological vectors of a number of viruses, e.g. bluetongue virus. In order to define vector-free periods/areas and to assess the vectorial role of the various Culicoides species, a comprehensive knowledge on their spatio-temporal occurrence is required. METHODS: Biting midges were monitored on farm sites with livestock in the defined climatic regions, including high altitudes, of Switzerland by overnight trapping at 12 locations once a week over three years using UV-light traps. Based on morphological features, they were separated into three groups (i.e. Obsoletus, Pulicaris, other Culicoides spp.), and identification to the species level was achieved by protein profiling using MALDI-TOF mass spectrometry. RESULTS: Around 550,000 biting midges in total were collected, revealing a dominance (82 to 99%) of the Obsoletus group species up to an altitude of 1,200 m and of the Pulicaris group species above 1,500 m (85% at the highest trapping site at 2,130 m). The maximum number of midges collected in a summer night (756 to 19,682) as well as the total number of midges caught over three years (from 6,933 to 149,439) varied highly among the sites, whereas the annual variation in total midge abundance at the locations was statistically insignificant. MALDI-TOF MS of 100 randomly selected individual biting midges per trapping site yielded high quality spectra for 1,187 of the 1,200 (98.9%) specimens of which 1,173 could be assigned to one of the 15 Culicoides species for which biomarker mass sets are available in the reference database. CONCLUSIONS: There are no biting midge-free zones in all of the agriculturally utilized areas (including alpine summer pastures) of Switzerland. Annual variations of midge numbers at the sampled locations were low, indicating that monitoring of midges should preferably be done by investigating a large number of sites for one season instead of few locations for extended periods of time. High throughput species identification of midges by MALDI-TOF MS is feasible, and this technique adds to other recently developed methods for the identification of midges (PCRs in various formats, interactive identification keys), facilitating epidemiological and biological in-depth studies of these important insects. PMID- 23111103 TI - MiR-429 is an independent prognostic factor in colorectal cancer and exerts its anti-apoptotic function by targeting SOX2. AB - Emerging evidence has demonstrated that microRNAs (miRNAs) can act as oncogenes or tumor suppressors to participate in cancer development. In this study, we found that miR-429 expression was up-regulated in human colorectal cancer (CRC) tissues, and the high miR-429 expression was significantly associated with tumor size, lymph node metastasis and poor prognosis. Functionally, miR-429 overexpression suppressed cell apoptosis by directly targeting SOX2 in HT-29 cells. Taken together, our data suggest for the first time that miR-429 could play an oncogenic role in the cellular processes of CRC and represent a novel prognostic biomarker for CRC. PMID- 23111102 TI - Pancreatic cancer chemoprevention by phytochemicals. AB - Pancreatic cancer is fourth leading cause of cancer-related deaths in the United States of America. In spite of recent advances in the current therapeutic modalities such as surgery, radiation and chemotherapy patients, the average five year survival rate remains still less than 5%. Recently, compounds from natural sources receive ample of attention as anti-cancer agents. Many epidemiological studies published over the past few decades provide a strong correlation between consumption of vegetables, fruits or plant derived products and reduced incidence of cancer. The present review focuses on the potential antitumor effects of various natural products. PMID- 23111104 TI - Cancer genome sequencing: understanding malignancy as a disease of the genome, its conformation, and its evolution. AB - Advances in cancer genomics have been propelled by the steady evolution of molecular profiling technologies. Over the past decade, high-throughput sequencing technologies have matured to the point necessary to support disease specific shotgun sequencing. This has compelled whole-genome sequencing studies across a broad panel of malignancies. The emergence of high-throughput sequencing technologies has inspired new chemical and computational techniques enabling interrogation of cancer-specific genomic and transcriptomic variants, previously unannotated genes, and chromatin structure. Finally, recent progress in single cell sequencing holds great promise for studies interrogating the consequences of tumor evolution in cancers presenting with genomic heterogeneity. PMID- 23111105 TI - Intraosseous inoculation of tumor cells into bone marrow promotes distant metastatic tumor development: A novel tool for mechanistic and therapeutic studies. AB - Bone marrow-derived cells have a potent impact on the formation and progression of tumor metastasis. This study demonstrates that bone marrow directly promotes metastasis to distant sites from tumor cells residing in the bone marrow in multiple types of tumors and multiple mouse strains. The bone marrow environment requires less tumor cells for inducing distant metastasis and overcomes the inhibition of metastasis resulting from engineering the tumor cells with reporter genes. This discovery provides an effective approach to generate spontaneous-like metastatic tumor models which will satisfy the urgent need for studying metastasis biology and discovering novel therapeutics. PMID- 23111106 TI - Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth. AB - Sorafenib leads to a survival benefit in patients with advanced hepatocellular carcinoma but its use is hampered by the occurrence of drug resistance. To investigate the molecular mechanisms involved we developed five resistant human liver cell lines in which we studied morphology, gene expression and invasive potential. The cells changed their appearance, lost E-cadherin and KRT19 and showed high expression of vimentin, indicating epithelial-to-mesenchymal transition. Resistant cells showed reduced adherent growth, became more invasive and lost liver-specific gene expression. Furthermore, following withdrawal of sorafenib, the resistant cells showed rebound growth, a phenomenon also found in patients. This cell model was further used to investigate strategies for restoration of sensitivity to sorafenib. PMID- 23111107 TI - Rod microglia: elongation, alignment, and coupling to form trains across the somatosensory cortex after experimental diffuse brain injury. AB - BACKGROUND: Since their discovery, the morphology of microglia has been interpreted to mirror their function, with ramified microglia constantly surveying the micro-environment and rapidly activating when changes occur. In 1899, Franz Nissl discovered what we now recognize as a distinct microglial activation state, microglial rod cells (Stabchenzellen), which he observed adjacent to neurons. These rod-shaped microglia are typically found in human autopsy cases of paralysis of the insane, a disease of the pre-penicillin era, and best known today from HIV-1-infected brains. Microglial rod cells have been implicated in cortical 'synaptic stripping' but their exact role has remained unclear. This is due at least in part to a scarcity of experimental models. Now we have noted these rod microglia after experimental diffuse brain injury in brain regions that have an associated sensory sensitivity. Here, we describe the time course, location, and surrounding architecture associated with rod microglia following experimental diffuse traumatic brain injury (TBI). METHODS: Rats were subjected to a moderate midline fluid percussion injury (mFPI), which resulted in transient suppression of their righting reflex (6 to 10 min). Multiple immunohistochemistry protocols targeting microglia with Iba1 and other known microglia markers were undertaken to identify the morphological activation of microglia. Additionally, labeling with Iba1 and cell markers for neurons and astrocytes identified the architecture that surrounds these rod cells. RESULTS: We identified an abundance of Iba1-positive microglia with rod morphology in the primary sensory barrel fields (S1BF). Although present for at least 4 weeks post mFPI, they developed over the first week, peaking at 7 days post-injury. In the absence of contusion, Iba1-positive microglia appear to elongate with their processes extending from the apical and basal ends. These cells then abut one another and lay adjacent to cytoarchitecture of dendrites and axons, with no alignment with astrocytes and oligodendrocytes. Iba1-positive rod microglial cells differentially express other known markers for reactive microglia including OX-6 and CD68. CONCLUSION: Diffuse traumatic brain injury induces a distinct rod microglia morphology, unique phenotype, and novel association between cells; these observations entice further investigation for impact on neurological outcome. PMID- 23111108 TI - Internet treatment for social anxiety disorder in Romania: study protocol for a randomized controlled trial. AB - BACKGROUND: Social anxiety disorder (SAD) is one of the most common anxiety disorders and is associated with marked impairments. However, a small proportion of individuals with SAD seek and receive treatment. Internet-administrated cognitive behavior therapy (iCBT) has been found to be an effective treatment for SAD. This trial will be the first Internet-delivered guided self-help intervention for SAD in Romania. METHODS: Participants with social anxiety disorder (N = 96) will be recruited via newspapers, online banners and Facebook. Participants will be randomized to either: a) an active treatment, or b) a waiting list control group.The treatment will have a guided iCBT format and will last for nine weeks. Self-report questionnaires on social phobia, anxiety, depression, treatment credibility and irrational thinking will be used. All assessments will be collected pre, post and at follow-up (six months after intervention). Liebowitz Social Anxiety Scale - Self-Report version (LSAS-SR) will be the primary outcome measure and will be administrated on a weekly basis in both conditions. DISCUSSION: The present randomized controlled trial investigates the efficacy of an Internet-administered intervention in reducing social anxiety symptoms in a culture where this form of treatment has not been tested. This trial will add to the body of knowledge on the efficacy of iCBT, and the results might lead to an increase of the accessibility of evidence-based psychological treatment in Romania. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01557894. PMID- 23111109 TI - Mind your p values. AB - In a medical study, the goal is to convince readers that a compelling argument has been made to prove the investigators' case. The logic of how this proof is provided in medical studies can be confusing, and is discussed here in simple terms. PMID- 23111110 TI - Five decades with oxysterols. AB - I have been involved in research on oxysterols since 1963 and this review is intended to cover some of the most important aspects of this work. The first project dealed with 7alpha-hydroxy-4-cholesten-3-one. My successful synthesis of this steroid with high specific radioactivity allowed a demonstration that it is a bile acid precursor. The mechanism of conversion of 7alpha-hydroxycholesterol into 7alpha-hydroxy-4-cholesten-3-one was investigated and I concluded that only one enzyme is required and that no isomerase is involved. Accumulation of 7alpha hydroxy-4-cholesten-3-one in patients with lack of sterol 27-hydroxylase (Cerebrotendinous xanthomatosis was shown to be an important pathogenetic factor. This disease is characterized by cholestanol-containing xanthomas in tendons and brain and we could show that most of this cholestanol is formed from 7alpha hydroxy-4-cholesten-3-one. We also showed that 7alpha-hydroxy-4-cholesten-3-one passes the blood-brain barrier. In contrast to cholesterol itself, side-chain oxidized oxysterols have a high capacity to pass lipophilic membranes. We demonstrated conversion of cholesterol into 27-hydroxycholesterol to be a significant mechanism for elimination of cholesterol from macrophages. We also showed that conversion of cholesterol into 24S-hydroxycholesterol is important for elimination of cholesterol from the brain. Side-chain oxidized oxysterols have a high capacity to affect critical genes in cholesterol turnover in vitro. Most of the published in vitro experiments with oxysteroids are highly unphysiological, however. Mouse models studied in my laboratory with high or low levels of 27-hydroxycholesterol have little or no disturbances in cholesterol homeostasis. 24S-hydroxycholesterol is an efficient ligand to LXR and suggested to be important for cholesterol homeostasis in the brain. We recently developed a mouse model with markedly increased levels of this oxysterol in circulation and brain. This overexpression had however only a very modest effect on cholesterol turnover. We concluded that oxysterols are not the master regulators of cholesterol homeostasis in vivo suggested previously. PMID- 23111111 TI - Nutritional privation in utero and adult cardiovascular disease risk: famine studies as natural experiments. PMID- 23111112 TI - Pre-hospital diagnosis, triage and treatment in patients with ST elevation myocardial infarction. PMID- 23111113 TI - The Family-School Success intervention improves some family and educational outcomes in children with attention deficit hyperactivity disorder more than a control psychosocial intervention. PMID- 23111114 TI - Laparoendoscopic single-site radical hysterectomy: the first report of LESS type III hysterectomy involves a woman with cervical cancer. AB - Laparoendoscopic single-site surgery is a logical advance in the evolution of minimally invasive surgery and is being utilized to perform increasingly complex procedures. We report its use for completion of radical hysterectomy as treatment for cervical cancer. PMID- 23111116 TI - Enhancing the production of S-adenosyl-L-methionine in Pichia pastoris GS115 by metabolic engineering. AB - S-adenosyl-L-methionine is an important bioactive molecule participating in a number of biochemical reactions including the transmethylation and transsulphuration reactions of proteins and the biosynthesis of aliphatic polyamines. Strategies of metabolic engineering were used to alter the metabolic flux for enhancing the production of S-adenosyl-L-methionine (SAM) in Pichia pastoris GS115. These strategies include the over-expression of Sam2 by knock-in technique and the disruption of Cbs by knock-out technique. Three strains, ZJGSU1 with knock- in of Sam2, ZJGSU2 with knock-out of Cbs and ZJGSU3 with both knock in of Sam2 and knock -out of Cbs, were constructed for the effective production of SAM. Yields of SAM in strains ZJGSU1 and ZJGSU2 were 32- and 5-fold higher than in the original strain P. pastoris GS115, respectively. The strain ZJGSU3 had a dramatic increase in the SAM yield, and it was 46-fold higher compared to the original strain. These results indicate that there is a strong synergistic effect on the production of SAM by combining knock-in with knock-out techniques. The yield of SAM in ZJGSU3 strain was 4.37 g/L in a 3 L fermentor. This study provides deep insight into the effective industrial production of SAM in future. PMID- 23111115 TI - Maternal azithromycin therapy for Ureaplasma intraamniotic infection delays preterm delivery and reduces fetal lung injury in a primate model. AB - OBJECTIVE: We assessed the efficacy of a maternal multidose azithromycin (AZI) regimen, with and without antiinflammatory agents to delay preterm birth and to mitigate fetal lung injury associated with Ureaplasma parvum intraamniotic infection. STUDY DESIGN: Long-term catheterized rhesus monkeys (n = 16) received intraamniotic inoculation of U parvum (10(7) colony-forming U/mL, serovar 1). After contraction onset, rhesus monkeys received no treatment (n = 6); AZI (12.5 mg/kg, every 12 h, intravenous for 10 days; n = 5); or AZI plus dexamethasone and indomethacin (n = 5). Outcomes included amniotic fluid proinflammatory mediators, U parvum cultures and polymerase chain reaction, AZI pharmacokinetics, and the extent of fetal lung inflammation. RESULTS: Maternal AZI therapy eradicated U parvum intraamniotic infection from the amniotic fluid within 4 days. Placenta and fetal tissues were 90% culture negative at delivery. AZI therapy significantly delayed preterm delivery and prevented advanced fetal lung injury, although residual acute chorioamnionitis persisted. CONCLUSION: Specific maternal antibiotic therapy can eradicate U parvum from the amniotic fluid and key fetal organs, with subsequent prolongation of pregnancy, which provides a therapeutic window of opportunity to effectively reduce the severity of fetal lung injury. PMID- 23111117 TI - Low-field MRI versus ultrasound: which is more sensitive in detecting inflammation and bone damage in MCP and MTP joints in mild or moderate rheumatoid arthritis? AB - OBJECTIVES: The aim of the present paper is to determine if the ultrasound of hands and feet is comparable to the MRI of the dominant hand to detect erosive disease and inflammation in mild or moderate rheumatoid arthritis (RA). METHODS: Twenty-six patients (14 females; mean age, 48 years) with active mild or moderate RA (mean DAS28, 3.9; mean disease duration, 19 months) were examined clinically, by ultrasound and by gadolinium-enhanced low-field MRI at baseline, after 6 and 12 months (78 examinations). Radiographs from hands and forefeet were taken at baseline and after 12 months. MRI was performed at the clinically most active (dominant) hand or forefoot evaluating the MCP 1-5 or MTP 1-5 joints. Ultrasound examination additionally included all other 2nd, 5th MCP and 5th MTP joints. RESULTS: MRI and ultrasound detected erosive disease in 67 and 56 of 78 examinations, respectively (p<0.01); radiography only in 8 of 52 examinations (p<0.001). MRI and ultrasound were equally sensitive to detect synovitis (in 64 and 66 examinations). Synovial power Doppler signals were present in 38 ultrasound examinations. Bone marrow oedema was present in 37 MRI examinations. Ultrasound was more sensitive than MRI to detect tenosynovitis (in 30 vs. 15 examinations; p=0.001). CONCLUSIONS: MRI of the dominant hand and bilateral ultrasound of MCP and MTP joints are superior to x-ray to detect erosive disease in mild and moderate RA. MRI is slightly, but significantly more sensitive than ultrasound for erosive disease, while ultrasound is more sensitive to detect tenosynovitis. Ultrasound and MRI are comparably sensitive to detect synovitis. PMID- 23111118 TI - Improvement of the low knowledge, attitude and practice of hepatitis B virus infection among Saudi national guard personnel after educational intervention. AB - BACKGROUND: Although the risk of hepatitis B virus (HBV) was reported to be higher in military personnel than the general population in Saudi Arabia (SA), there is lack of studies assessing HBV awareness among them. The objective was to evaluate the knowledge, attitude and practice (KAP) of HBV infection among military personnel. METHODS: An intervention design with pre- and post-education KAP questionnaire was completed among National Guard soldiers working in Jeddah during January 2009. Educational intervention was provided through educational leaflets, group and individual discussions, visual show, and a lecture. A score was created from the correct answers to 58 questions. RESULTS: A total of 400 male soldiers with mean age 30.7 +/- 6.1 years completed both questionnaires. The majority had school education (96.8%) and in the lower military ranks (66.0%). Only 19.5% of soldiers reported HBV vaccine intake. The low median and inter quartile range of the pre-intervention score (16, 6-26) markedly increased after education (to 53, 50-55, p<0.001). The overall improvement of mean KAP score (204%) was also observed in all its component scores; disease nature (272%), methods of transmission (206%), prevention and control (109%), attitude (155%), and practice (192%). The improvement was evident irrespective of socio demographic characteristics and history of HBV vaccine. KAP scores were significantly associated with higher educational levels, higher monthly income, administrative jobs, and higher job ranks. CONCLUSION: We are reporting a low level of HBV awareness among Saudi military population. The study confirms the need and effectiveness of focused multifaceted educational campaigns among the military population. PMID- 23111119 TI - Intervention time prediction from surgical low-level tasks. AB - OBJECTIVE: Effective time and resource management in the operating room requires process information concerning the surgical procedure being performed. A major parameter relevant to the intraoperative process is the remaining intervention time. The work presented here describes an approach for the prediction of the remaining intervention time based on surgical low-level tasks. MATERIALS AND METHODS: A surgical process model optimized for time prediction was designed together with a prediction algorithm. The prediction accuracy was evaluated for two different neurosurgical interventions: discectomy and brain tumor resections. A repeated random sub-sampling validation study was conducted based on 20 recorded discectomies and 40 brain tumor resections. RESULTS: The mean absolute error of the remaining intervention time predictions was 13 min 24s for discectomies and 29 min 20s for brain tumor removals. The error decreases as the intervention progresses. DISCUSSION: The approach discussed allows for the on line prediction of the remaining intervention time based on intraoperative information. The method is able to handle demanding and variable surgical procedures, such as brain tumor resections. A randomized study showed that prediction accuracies are reasonable for various clinical applications. CONCLUSION: The predictions can be used by the OR staff, the technical infrastructure of the OR, and centralized management. The predictions also support intervention scheduling and resource management when resources are shared among different operating rooms, thereby reducing resource conflicts. The predictions could also contribute to the improvement of surgical workflow and patient care. PMID- 23111120 TI - Prefrontal dysfunction during emotion regulation in generalized anxiety and panic disorders. AB - BACKGROUND: The mechanisms that contribute to emotion dysregulation in anxiety disorders are not well understood. Two common disorders, generalized anxiety disorder (GAD) and panic disorder (PD), were examined to test the hypothesis that both disorders are characterized by hypo-activation in prefrontal cortex (PFC) during emotion regulation. A competing hypothesis that GAD in particular is characterized by PFC hyper-activation during emotion regulation (reflecting overactive top-down control) was also evaluated. Method Twenty-two medication free healthy control (HC), 23 GAD, and 18 PD participants underwent functional magnetic resonance imaging (fMRI) during a task that required them to reappraise (i.e. reduce) or maintain emotional responses to negative images. RESULTS: GAD participants reported the least reappraisal use in daily life, and reappraisal use was inversely associated with anxiety severity and functional impairment in these participants. During fMRI, HCs demonstrated greater activation during both reappraisal and maintenance than either GAD or PD participants (who did not differ) in brain areas important for emotion regulation (e.g. dorsolateral and dorsomedial PFC). Furthermore, across all anxious participants, activation during reappraisal in dorsolateral and dorsomedial PFC was inversely associated with anxiety severity and functional impairment. CONCLUSIONS: Emotion dysregulation in GAD and PD may be the consequence of PFC hypo-activation during emotion regulation, consistent with insufficient top-down control. The relationship between PFC hypo-activation and functional impairment suggests that the failure to engage PFC during emotion regulation may be part of the critical transition from dispositionally high anxiety to an anxiety disorder. PMID- 23111121 TI - Knowledge of the HPV vaccine and its association with vaccine uptake among female higher-education students in Greece. AB - The aims of the study were to assess the awareness and knowledge of HPV vaccination among female university and technological institutes students, and their association with vaccine uptake, and to identify the variables associated with higher levels of knowledge. PMID- 23111122 TI - Challenges associated with the recent outbreaks of wild-type poliovirus in previously polio-free countries. PMID- 23111123 TI - Development of Toxoplasma gondii vaccine: A global challenge. AB - Toxoplasmosis is caused by the protozoan parasite T. gondii. Humans and other warm-blooded animals are its hosts. The infection has a worldwide distribution; one-third of the world's population has been exposed to this parasite. There are three primary ways of transmission: ingesting uncooked meat containing tissue cysts, ingesting food and water contaminated with oocysts from infected cat feces and congenitally. Those particularly at risk of developing clinical illness include pregnant women, given that the parasite can pose a serious threat to the unborn child if the mother becomes infected while pregnant, and immunosuppressed individuals such as tissue transplant subjects, AIDS subjects, those with certain types of cancer and those undergoing certain forms of cancer therapy. Maternal infections early in pregnancy are less likely to be transmitted to the fetus than infections later in pregnancy, but early fetal infections are more likely to be severe than later infections. In the absence of an effective human vaccine, prevention of zoonotic transmission might be the best way to approach the problem of toxoplasmosis and must be done by limiting exposure to oocysts or tissue cysts. Vaccine development to prevent feline oocyst shedding is ongoing, mostly with live vaccines. The S48 strain Toxovax is a live vaccine originally developed for use in sheep, but when used in cats inhibits sexual development of T. gondii. This vaccine is used in sheep to reduce tissue cyst development. The T-263 strain of T. gondii is a live mutant strain designed to reduce or prevent oocyst shedding by cats by developing only partial infection in the feline intestinal tract. PMID- 23111124 TI - Influence of local structure on magnetic properties of layered cobaltites PrBaCo2O(5+delta), delta > 0.5. AB - The effect of local structure on the magnetic and transport properties of the layered perovskites has been investigated. The samples PrBaCo(2)O(5+delta), (delta = 0.80 and 0.67) crystallize in the same 112 type tetragonal structure but have different magnetic ground states. Extended x-ray absorption fine structure (EXAFS) spectroscopy has been employed to explain the changes in magnetic interactions based on the rotation and tilting of CoO polyhedra in these oxygen rich double perovskites. PMID- 23111125 TI - Granulocyte-macrophage colony-stimulating factor enhances the humoral immune responses of mouse zona pellucida 3 vaccine strategy based on DNA and protein coadministration in BALB/c mice. AB - We recently demonstrated that co-administration of mouse zona pellucida 3 (mZP3) DNA and protein vaccine enhanced the contraception of mice by increasing humoral immune responses. In this study, we try to use granulocyte-macrophage colony stimulating factor (GM-CSF) to further improve the humoral immune responses induced by mZP3 DNA and protein co-administration. BALB/c mice were intranasally pre-injected with GM-CSF 4 days before co-administration. Compared to DNA and protein coadministration without GM-CSF, the combination of GM-CSF and coadministration significantly enhances humoral immune responses, especially the level of secretory immunoglobulin A (sIgA) in vaginal washes. The enhanced antibody responses are correlated with the upregulated level of interleukin 4 (IL 4) and enhanced maturation of dendritic cells (DCs). Thus, GM-CSF is a potential candidate adjuvant to be used for the development of a safe and effective contraceptive vaccine. PMID- 23111126 TI - Sensorimotor performance asymmetries predict hand selection. AB - Handedness is most often measured by questionnaires that assess an individual's preference for using a particular hand to perform a variety of tasks. While such assessments have proved reliable, they do not address the underlying neurobehavioral processes that give rise to the choice of which hand to use. Recent research has indicated that handedness is associated with hemispheric specializations for different aspects of sensorimotor performance. We now hypothesize that an individual's choice of which hand to use for a given task should result from an interaction between these underlying neurobehavioral asymmetries with task conditions. We test this hypothesis by manipulating two factors in targeted reaching movements: (1) region of workspace and (2) visual feedback conditions. The first manipulation modified the geometric and dynamic requirements of the task for each arm, whereas the second modified the sensorimotor performance asymmetries, an effect predicted by previous literature. We expected that arm choice would be reflected by an interaction between these factors. Our results indicated that removing visual feedback both improved the relative performance of the non-dominant arm and increased the choice to use this arm for targets near midline, an effect that was enhanced for targets requiring larger movement amplitudes. We explain these findings in the context of the dynamic dominance hypothesis of handedness and discuss their implications for the link between hemispheric asymmetries in neural control and hand preference. PMID- 23111128 TI - Sediment contamination assessment in urban areas based on total suspended solids. AB - Sediment represents an important compartment in surface waters. It constitutes a habitat or spawning site for many organisms and is an essential trophic resource for higher level organisms. It can be impacted by anthropogenic activities, particularly through urban wet-weather discharges like stormwater and combined sewer overflows. An approach was presented for assessing the risks caused by urban wet-weather discharges to the sediment compartment based on total suspended solids (TSS). TSS is routinely measured in field surveys and can be considered as a tracer for urban wet-weather contamination. Three assessment endpoints linked with TSS were proposed: a) siltation of the riverbed, b) oxygen demand due to organic matter degradation and c) accumulation of ecotoxic contaminants on the riverbed (heavy metals, PAHs). These criteria were translated in terms of the maximal TSS accumulation load and exposure time (percentage of time exceeding the accumulation criteria) to account for sediment accumulation dynamics and resuspension in streams impacted by urban wet-weather discharges. These assessment endpoints were implemented in a stochastic model that calculates TSS behavior in receiving waters and allows therefore an assessment of potential impacts. The approach was applied to three Swiss case studies. For each, good agreement was found between the risk predictions and the field measurements confirming the reliability of the approach. PMID- 23111127 TI - Effect of a Web-based intervention to promote physical activity and improve health among physically inactive adults: a population-based randomized controlled trial. AB - BACKGROUND: Many people in Western countries do not follow public health physical activity (PA) recommendations. Web-based interventions provide cost- and time efficient means of delivering individually targeted lifestyle modification at a population level. OBJECTIVE: To examine whether access to a website with individually tailored feedback and suggestions on how to increase PA led to improved PA, anthropometrics, and health measurements. METHODS: Physically inactive adults (n = 12,287) participating in a nationwide eHealth survey and health examination in Denmark were randomly assigned to either an intervention (website) (n = 6055) or a no-intervention control group (n = 6232) in 2008. The intervention website was founded on the theories of stages of change and of planned behavior and, apart from a forum page where a physiotherapist answered questions about PA and training, was fully automated. After 3 and again after 6 months we emailed participants invitations to answer a Web-based follow-up questionnaire, which included the long version of the International Physical Activity Questionnaire. A subgroup of participants (n = 1190) were invited to a follow-up health examination at 3 months. RESULTS: Less than 22.0% (694/3156) of the participants logged on to the website once and only 7.0% (222/3159) logged on frequently. We found no difference in PA level between the website and control groups at 3- and 6-month follow-ups. By dividing participants into three groups according to use of the intervention website, we found a significant difference in total and leisure-time PA in the website group. The follow-up health examination showed no significant reductions in body mass index, waist circumference, body fat percentage, and blood pressure, or improvements in arm strength and aerobic fitness in the website group. CONCLUSIONS: Based on our findings, we suggest that active users of a Web-based PA intervention can improve their level of PA. However, for unmotivated users, single-tailored feedback may be too brief. Future research should focus on developing more sophisticated interventions with the potential to reach both motivated and unmotivated sedentary individuals. TRIAL REGISTRATION: Clinicaltrials.gov NCT01295203; http://clinicaltrials.gov/ct2/show/NCT01295203 (Archived by WebCite at http://www.webcitation.org/6B7HDMqiQ). PMID- 23111129 TI - Community ecology and the evolution of molecules of keystone significance. AB - Molecules of keystone significance are vital in structuring ecological communities. Select bioactive compounds can cause disproportionately large effects by connecting such seemingly disparate processes as microbial loop dynamics and apex predation. Here, we develop a general theory and propose mechanisms that could lead to the evolution of keystone molecules. Introduced into a respective community by one, or only a few, autotrophic or microbial species, these compounds often originate as chemical defenses. When co-opted by resistant consumer species, however, they are used either in chemical defense against higher-order predators or as chemosensory cues that elicit courtship and mating, alarm, and predatory search. Requisite to these multifunctional properties, biosynthetic capacity evolves along with mechanisms for resistance and/or toxin storage in primary producers. Subsequently, consumers acquire resistances or tolerances, and the toxins are transferred through food webs via trophic interactions. In consumers, mechanisms eventually evolve for recognizing toxins as feeding cues and, ultimately, as signals or pheromones in chemical communication within or between species. One, or a few, active compounds can thus mediate a vast array of physiological traits, expressed differentially across many species in a given community. Through convergent evolution, molecules of keystone significance provide critical information to phylogenetically diverse species, initiate major trophic cascades, and structure communities within terrestrial, freshwater, coastal-ocean and open-ocean habitats. PMID- 23111130 TI - Signaling events during cyclic guanosine monophosphate-regulated pigment aggregation in freshwater shrimp chromatophores. AB - Crustacean color change results partly from granule aggregation induced by red pigment concentrating hormone (RPCH). In shrimp chromatophores, both the cyclic GMP (3', 5'-guanosine monophosphate) and Ca(2+) cascades mediate pigment aggregation. However, the signaling elements upstream and downstream from cGMP synthesis by GC-S (cytosolic guanylyl cyclase) remain obscure. We investigate post-RPCH binding events in perfused red ovarian chromatophores to disclose the steps modulating cGMP concentration, which regulates granule translocation. The inhibition of calcium/calmodulin complex (Ca(2+)/CaM) by N-(6-aminohexyl)-5 chloro-1-naphthalenesulphonamide (W7) induces spontaneous aggregation but inhibits RPCH-triggered aggregation, suggesting a role in pigment aggregation and dispersion. Nitric oxide synthase inhibition by Nomega-nitro-L-arginine methyl ester hydrochloride (L-NAME) strongly diminishes RPCH-induced aggregation; protein kinase G inhibition (by rp-cGMPs-triethylamine) reduces RPCH-triggered aggregation and provokes spontaneous dispersion, disclosing NO/PKG participation in aggregation signaling. Myosin light chain phosphatase inhibition (by cantharidin) accelerates RPCH-triggered aggregation, whereas Rho-associated protein kinase inhibition (by Y-27632, H-11522) reduces RPCH-induced aggregation and accelerates dispersion. MLCP (myosin light chain kinase) and ROCK (Rho associated protein kinase) may antagonistically regulate myosin light chain (MLC) dephosphorylation/phosphorylation during pigment dispersion/aggregation. We propose the following general hypothesis for the cGMP/Ca(2+) cascades that regulate pigment aggregation in crustacean chromatophores: RPCH binding increases Ca(2+)(int), activating the Ca(2+)/CaM complex, releasing NOS-produced nitric oxide, and causing GC-S to synthesize cGMP that activates PKG, which phosphorylates an MLC activation site. Myosin motor activity is initiated by phosphorylation of an MLC regulatory site by ROCK activity and terminated by MLCP mediated dephosphorylation. Qualitative comparison reveals that this signaling pathway is conserved in vertebrate and invertebrate chromatophores alike. PMID- 23111131 TI - Morphology of the cement apparatus and the cement of the buoy barnacle Dosima fascicularis (Crustacea, Cirripedia, Thoracica, Lepadidae). AB - Barnacles produce a proteinaceous adhesive called cement to attach permanently to rocks or to other hard substrata. The stalked barnacle Dosima fascicularis is of special interest as it produces a large amount of foam-like cement that can be used as a float. The morphology of the cement apparatus and of the polymerized cement of this species is almost unknown. The current study aims at filling these gaps in our knowledge using light and electron microscopy as well as x-ray microtomography. The shape of the cement gland cells changes from round to ovoid during barnacle development. The cytoplasm of the gland cells, unlike that of some other barnacles, does not have distinct secretory and storage regions. The cement canals, which transport the cement from the gland cells to the base of the stalk, end at different positions in juvenile and mature animals. With increasing size of the cement float, the exit of the cement canals shift from the centrally positioned attachment disk of the vestigial antennules to more lateral positions on the stalk. The bubbles enclosed in the foam-like float are most likely filled with CO(2) that diffuses from the hemolymph into the cement canal system and from there into the cement. PMID- 23111132 TI - Food and heat stress in the California mussel: evidence for an energetic trade off between survival and growth. AB - In response to thermal stress, many rocky shore organisms exhibit characteristic physiological changes associated with increased tolerance to subsequent high temperatures. Although presumably adaptive, activation of the heat-shock response requires a significant energetic investment and therefore may impose a trade-off between survival and other life-history traits. We investigated the effects of chronic heat stress and variation in food availability on the relative allocation of resources to competing demographic parameters in the California mussel, Mytilus californianus. Our data support the idea that acclimatory responses to temperature stress can drive trade-offs among traits, as predicted by theory. Chronic heat stress invoked a cost to individuals, expressed as a reduction in shell growth or size-specific tissue mass in the field and laboratory, respectively. At the same time, prior thermal conditioning resulted in higher proportional survival after acute exposure to more extreme temperatures. Overall, mussels receiving less food exhibited poor condition and survival relative to individuals fed more, suggesting that individuals with limited access to resources are at greater risk because they are less able to mitigate potential costs of thermal stress through physiological mechanisms. Accurately forecasting the effects of climate change in rocky intertidal ecosystems will therefore require understanding not just how organisms respond to different temperature regimes, but also how variation in local resource availability modifies those responses. PMID- 23111133 TI - Identification, characterization, and expression levels of putative adhesive proteins from the tube-dwelling polychaete Sabellaria alveolata. AB - The shelter of the tube-dwelling polychaete Sabellaria alveolata is composed of mineral particles assembled with spots of a proteinaceous cement. The adhesive proteins constituting the cement were identified on the basis of their sequence similarity with proteins of a phylogenetically related species, Phragmatopoma californica. Two positively charged proteins, Sa-1 and Sa-2, share common features: they both have a mass of 22 kDa; are rich in glycine, tyrosine and basic residues; and show repeated peptide motifs. The consensus repeat of Sa-1 is KGAYGAKGLGYGNKAGYGAYG (occurring 6-8 times), while Sa-2 displays the consensus heptapeptide VHKAAWG (5 times) and undecapeptide VHKAAGYGGYG (8 times). Two variants of a serine-rich protein, Sa-3A (22 kDa) and Sa-3B (21 kDa), were also identified. Their serine residues account for 75 mol% and are probably phosphorylated, meaning that Sa-3 is very acidic and negatively charged. Moreover, tyrosine residues of all adhesive proteins are presumably modified into DOPA. Although protein sequences are not well-conserved between S. alveolata and P. californica, their main characteristics (including amino acid composition, post-translational modifications, repeated patterns, isoelectric point, and mass) are shared by both species. This suggests that these features are more important for their function than the primary structure of the proteins. The mRNA abundance for each protein was estimated by quantitative real-time PCR, revealing relative expression levels of about 5, 11, 1.5, and 1 for Sa-1, -2, -3A, and -3B, respectively. These levels could be indicative of charge neutralization phenomena or could reflect their function (interface vs. bulk) in the cement. PMID- 23111134 TI - Photophysiological consequences of vertical stratification of Symbiodinium in tissue of the coral Porites lutea. AB - In comparison to some corals, massive Porites spp. is physiologically resilient to environmental assaults and is becoming more abundant on coral reefs. To evaluate the extent to which thick tissues contribute to this physiological resilience, we tested the hypothesis that the Symbiodinium in Porites lutea are phenotypically and genetically homogeneous with regard to their distribution vertically within the tissue, and in their response to temperature. Symbiodinium density, genetic identity, and photophysiology were compared between outer and inner tissues defined as adjacent layers ~2 mm thick and beneath the skeleton surface. Symbiodinium densities were 5-fold greater and their cells contained less chlorophyll a in outer versus inner tissue, but ITS2 sequence identities were genetically uniform between layers. Maximum photochemical efficiency (F(v)/F(m)) in inner and outer tissue from the top and sides of the corals differed 6%-7%, with F(v)/F(m) greater in inner versus outer tissue on the top of colonies. On the tops of colonies, the initial slopes of the rETR versus irradiance relationship were not different between tissue layers, although they tended to be less steep for inner tissue. When exposed for 12 h to 28 degrees C, 30 degrees C, or 32 degrees C at ~700 MUmol quanta m(-2) s(-1), there was a trend for F(v)/F(m) of the Symbiodinium in both tissue layers to be reduced at 32 degrees C. Our results do not conform well to shade acclimatization in inner versus outer tissue of P. lutea, and they imply within-tissue heterogeneity that may be an important determinant of physiological performance in perforate corals. PMID- 23111135 TI - Vulnerability of the paper Nautilus (Argonauta nodosa) shell to a climate-change ocean: potential for extinction by dissolution. AB - Shell calcification in argonauts is unique. Only females of these cephalopods construct the paper nautilus shell, which is used as a brood chamber for developing embryos in the pelagic realm. As one of the thinnest (225 MUm) known adult mollusc shells, and lacking an outer protective periostracum-like cover, this shell may be susceptible to dissolution as the ocean warms and decreases in pH. Vulnerability of the A. nodosa shell was investigated through immersion of shell fragments in multifactorial experiments of control (19 degrees C/pH 8.1; pCO(2) 419; Omega(Ca) = 4.23) and near-future conditions (24 degrees C/pH 7.8 7.6; pCO(2) 932-1525; Omega(Ca) = 2.72-1.55) for 14 days. More extreme pH treatments (pH 7.4-7.2; pCO(2) 2454-3882; Omega(Ca) = 1.20-0.67) were used to assess tipping points in shell dissolution. X-ray diffractometry revealed no change in mineralogy between untreated and treated shells. Reduced shell weight due to dissolution was evident in shells incubated at pH 7.8 (projected for 2070) after 14 days at control temperature, with increased dissolution in warmer and lower pH treatments. The greatest dissolution was recorded at 24 degrees C (projected for local waters by 2100) compared to control temperature across all low-pH treatments. Scanning electron microscopy revealed dissolution and etching of shell mineral in experimental treatments. In the absence of compensatory mineralization, the uncovered female brood chamber will be susceptible to dissolution as ocean pH decreases. Since the shell was a crucial adaptation for the evolution of the argonauts' holopelagic existence, persistence of A. nodosa may be compromised by shell dissolution in an ocean-change world. PMID- 23111136 TI - Within-colony migration of symbionts during bleaching of octocorals. AB - Octocorals compose a major part of cnidarian diversity. As with other symbiont containing cnidarians, octocorals are susceptible to a stress response and subsequent "bleaching," which typically involves the loss of photosynthetic dinoflagellate symbionts. Studies of bleaching often focus on hexacorals, including sea anemones and scleractinians. The extent to which these results can be generalized to octocorals remains unclear. Bleaching was examined using two representative species of the Holaxonia-Alcyoniina clade of alcyonacean octocorals, Phenganax parrini and Sarcothelia sp. Remarkably, colonies of both species showed the same pattern in response to perturbation: symbionts in the polyps detach or die, leaving the polyps entirely bleached, yet at the same time large numbers of symbionts accumulate in the stolons. These symbionts are contained in host cells, many of which appear to attach to the stolon tissue. A comparison of living and fixed specimens suggests that these cells are loosely bound to, but not actually in, the stolonal tissue. Since gastrovascular fluid in the stolons is driven by cilia, these accumulating cells may lower fluid velocities. The accumulation of symbionts in the stolons during perturbation may have considerable relevance to how octocoral colonies recover from bleaching. PMID- 23111137 TI - Implications of left bundle branch block in patient treatment. AB - Left bundle branch block (LBBB) causes an abnormal pattern of cardiac activation and affects regional myocardial function. Although recognition of LBBB on the surface electrocardiogram is straightforward, dissecting its effect on patient treatment and outcome can be more challenging. The altered pattern of cardiac activation in LBBB causes electrical and mechanical ventricular dyssynchrony, influences ischemia detection on the surface electrocardiogram, and affects stress testing and imaging modalities dependent on wall motion and thickening. Restoration of synchrony by biventricular pacing can improve symptoms and longevity in carefully selected patients. The diagnostic, prognostic, and therapeutic implications of LBBB across this spectrum are discussed in this review. PMID- 23111138 TI - Comparison of four single-drug regimens on ventricular rate and arrhythmia related symptoms in patients with permanent atrial fibrillation. AB - Rate control of atrial fibrillation (AF) is a main treatment modality. However, data are scarce on the relative efficacy of calcium channel blockers and beta blockers or between drugs within each class. The purpose of the present study was to compare the effect of 4 rate-reducing, once-daily drug regimens on the ventricular heart rate and arrhythmia-related symptoms in patients with permanent AF. We included 60 patients (mean age 71 +/- 9 years, 18 women) with permanent AF in an investigator-blind cross-over study. Diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, and carvedilol 25 mg/day were administered for 3 weeks in a randomized sequence. The 24-hour heart rate was measured using Holter monitoring, and arrhythmia-related symptoms were assessed using the Symptom Checklist questionnaire before randomization and on the last day of each treatment period. The 24-hour mean heart rate was 96 +/- 12 beats/min at baseline (no treatment), 75 +/- 10 beats/min with diltiazem, 81 +/- 11 beats/min with verapamil, 82 +/- 11 beats/min with metoprolol, and 84 +/- 11 beats/min with carvedilol. All drugs reduced the heart rate compared to baseline (p <0.001 for all). The 24-hour heart rate was significantly lower with diltiazem than with any other drug tested (p <0.001 for all). Compared to baseline, diltiazem significantly reduced both the frequency (p <0.001) and the severity (p = 0.005) of symptoms. In contrast, verapamil reduced symptom frequency only (p = 0.012). In conclusion, diltiazem 360 mg/day was the most effective drug regimen for reducing the heart rate in patients with permanent AF. Arrhythmia-related symptoms were reduced by treatment with the calcium channel blockers diltiazem and verapamil, but not by the beta blockers. PMID- 23111139 TI - Reclassification of cardiovascular risk in patients with normal myocardial perfusion imaging using heart rate response to vasodilator stress. AB - Previous studies have shown that patients with normal vasodilator myocardial perfusion imaging (MPI) findings remain at a greater risk of future cardiac events than patients with normal exercise MPI findings. The aim was to assess improvement in risk classification provided by the heart rate response (HRR) in patients with normal vasodilator MPI findings when added to traditional risk stratification. We retrospectively studied 2,000 patients with normal regadenoson or adenosine MPI findings. Risk stratification was performed using Adult Treatment Panel III framework. Patients were stratified by HRR (percentage of increase from baseline) into tertiles specific to each vasodilator. All-cause mortality and cardiac death/nonfatal myocardial infarction (MI) <=2 years from the index MPI were recorded. During follow-up, 11.8% patients died and 2.7% patients experienced cardiac death/nonfatal MI in the adenosine and regadenoson groups, respectively. The patients who died had a greater Framingham risk score (12 +/- 4 vs 11 +/- 4, p = 0.009) and lower HRR (22 +/- 16 vs 32 +/- 21, p <0.0001). In an adjusted Cox model, the lowest tertile HRR was associated with an increased risk of mortality (hazard ratio 2.1) and cardiac death/nonfatal MI (hazard ratio 2.9; p <0.01). Patients in the highest HRR tertile, irrespective of the Adult Treatment Panel III category, were at low risk. When added to the Adult Treatment Panel III categories, the HRR resulted in net reclassification improvement in mortality of 18% and cardiac death/nonfatal MI of 22%. In conclusion, a blunted HRR to vasodilator stress was independently associated with an increased risk of cardiac events and overall mortality in patients with normal vasodilator MPI findings. The HRR correctly reclassified a substantial proportion of these patients in addition to the traditional risk classification models and identified patients with normal vasodilator MPI findings, who had a truly low risk of events. PMID- 23111140 TI - Managing patients with an indication for anticoagulant therapy after transcatheter aortic valve implantation. AB - Patients who undergo transcatheter aortic valve implantation are generally discharged on dual-antiplatelet therapy. However, many of these patients also have indications for anticoagulant therapy, and it is unclear what the best antithrombotic strategy is in these cases. Data from 360 patients who underwent transcatheter aortic valve implantation were retrospectively analyzed, of whom 60 (16.7%) had indications for anticoagulant treatment, mainly because of atrial fibrillation. The antithrombotic regimen was decided according to clinical evaluation of thrombotic and hemorrhagic risk; most of these patients (n = 43) were discharged with warfarin plus a single antiplatelet drug. Their outcomes were compared to those in a group with no indications for anticoagulation (n = 300) treated with dual-antiplatelet therapy. During the follow-up period (median 11 months), 53 patients (15%) died; mortality was not associated with antithrombotic regimen. The incidence of cerebral events or intracranial hemorrhage (4.6% and 1.1%, respectively) was low in the study population, and no significant differences were detected between groups; the bleeding rate was also unaffected by antithrombotic therapy. In conclusion, when anticoagulation is indicated after transcatheter aortic valve implantation, many variables must be taken into account. The most frequent scenario in this study was patients in atrial fibrillation, most of whom were discharged with warfarin plus a single antiplatelet medication. When bleeding was a concern, especially in the absence of coronary disease, warfarin alone was prescribed. These results suggest that this approach is safe, but data from larger, randomized studies are needed. PMID- 23111141 TI - Characteristics and outcomes of patients with ST-segment elevation myocardial infarction excluded from the harmonizing outcomes with revascularization and stents in acute myocardial infarction (HORIZONS-AMI) trial. AB - Randomized controlled trials assessing new drugs and devices tend to exclude subjects who are at greatest risk. The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial incorporated broader inclusion criteria in an attempt to include a more representative spectrum of patients presenting with ST-segment elevation myocardial infarction (STEMI). To identify the differences between this modern trial and the real world, we analyzed the characteristics and outcomes of patients with STEMI who were screened but not enrolled at a high-volume recruiting center. Of 318 consecutive patients with STEMI who were screened, 200 (62.9%) were randomized, and 118 (37.1%) were excluded. The baseline characteristics and 30-day and 1-year clinical outcomes were compared in the 2 groups. The excluded patients had numerous high-risk features compared to those randomized, including being older (67.0 +/- 12.8 vs 63.0 +/- 11.4 years, p = 0.004), more often had had a previous MI (34.7% vs 8.0%, p <0.001), Killip class III-IV (27.4% vs 4.0%, p <0.001), and lower hemoglobin (13.4 +/- 2.3 vs 14.8 +/- 1.5 g/dl, p <0.001). The excluded patients had markedly greater 30-day and 1-year rates of all-cause mortality (17.4% vs 2.0%, p <0.001, and 27.6% vs 2.5%, p <0.001, respectively), major adverse cardiovascular events (death, MI, ischemia driven target vessel revascularization, and stroke), major bleeding, and net adverse clinical events (major adverse cardiovascular events or major bleeding). On multivariate analysis, Killip class III-IV at presentation, age, left ventricular ejection fraction, and final Thrombolysis In Myocardial Infarction flow grade 3 were independent predictors of outcome. In conclusion, despite the broadened entry criteria of the HORIZONS-AMI trial, 37.1% of all patients presenting with STEMI at a center with a high rate of enrollment were judged to be ineligible and were excluded. The excluded patients had a significantly greater risk profile and markedly increased mortality and adverse events compared to the trial-eligible group. PMID- 23111142 TI - Incidence and outcomes of no-reflow phenomenon during percutaneous coronary intervention among patients with acute myocardial infarction. AB - Previous studies describing the no-reflow phenomenon in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were largely confined to single-center studies or small registries. To better characterize the incidence, predictors, and outcomes of the no-reflow phenomenon in a large contemporary population, we analyzed patients with AMI who were undergoing PCI of native coronary artery stenoses in the CathPCI Registry from January 1, 2004 through September 5, 2008 (n = 291,380). The angiographic no reflow phenomenon was site reported using a standardized definition. No-reflow developed in 2.3% of the patients with AMI (n = 6,553) during PCI. Older age, ST segment elevation AMI, prolonged interval from symptom onset to admission, and cardiogenic shock were clinical variables independently associated with the development of no-reflow (p <0.001). The angiographic factors independently associated with no-reflow included longer lesion length, higher risk class C lesions, bifurcation lesions, and impaired preprocedure Thrombolysis In Myocardial Infarction flow (p <0.001). No-reflow was associated with greater in hospital mortality (12.6% vs 3.8%, adjusted odds ratio 2.20, 95% confidence interval 1.97 to 2.47, p <0.001) and unsuccessful lesion outcome (29.7% vs 6.6%, adjusted odds ratio 4.70, 95% confidence interval 4.28 to 5.17, p <0.001) compared to patients without no-reflow. In conclusion, the development of no reflow, although relatively uncommon during PCI for AMI, is associated with adverse clinical outcomes. Upfront strategies to reduce the incidence of no reflow could be considered for high-risk patients to improve outcomes. PMID- 23111143 TI - Local distribution analysis of cytotoxic molecules in liver allograft is helpful for the diagnosis of acute cellular rejection after orthotopic liver transplantation. AB - BACKGROUND: As it is often difficult for a transplant pathologist to make a definite diagnosis of acute cellular rejection (ACR) by routine morphological analysis of liver allograft biopsy, supplementary methods and objective markers are needed to facilitate this determination. METHODS: To evaluate the diagnostic value of cytotoxic molecules in ACR episodes, immunohistochemical staining for perforin, granzyme B and T-cell intracellular antigen-1 (TIA-1) were performed in liver allograft biopsies. The positive cells in the portal tract area and lobules were counted separately to investigate the distribution of the cytotoxic molecules. RESULTS: The immunohistochemical study showed that the overall positive rates for the three markers were not significantly different between the ACR and non-ACR groups. However, in the portal tract area, perforin-, granzyme B- and TIA-1-positive cells in the ACR group were significantly more than those in the non-ACR groups. In the lobules, perforin- and granzyme B-positive cells in the ACR group were significantly more than those in the biliary complication and opportunistic infection groups, while TIA-1-positive cells was significantly fewer than those in non-ACR groups. The numbers of positive cells in the portal tract area correlated with the rejection activity index of ACR. CONCLUSIONS: These results indicate that, though the overall positive rates have nonsense in ACR diagnosis, the quantification and local distribution analysis of cytotoxic molecule positive cells in liver tissue is helpful for differential diagnosis and severity evaluation of ACR following liver transplantation. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2292255038100487. PMID- 23111144 TI - TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis. AB - BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4(+) T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naive T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE. FINDINGS: Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE. CONCLUSIONS: DC are sufficient as APC to effectively drive the differentiation of naive myelin-responsive T cells into autoaggressive effector T cells. TLR-4 stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system. PMID- 23111145 TI - Mind bomb-1 is an essential modulator of long-term memory and synaptic plasticity via the Notch signaling pathway. AB - BACKGROUND: Notch signaling is well recognized as a key regulator of the neuronal fate during embryonic development, but its function in the adult brain is still largely unknown. Mind bomb-1 (Mib1) is an essential positive regulator in the Notch pathway, acting non-autonomously in the signal-sending cells. Therefore, genetic ablation of Mib1 in mature neuron would give valuable insight to understand the cell-to-cell interaction between neurons via Notch signaling for their proper function. RESULTS: Here we show that the inactivation of Mib1 in mature neurons in forebrain results in impaired hippocampal dependent spatial memory and contextual fear memory. Consistently, hippocampal slices from Mib1 deficient mice show impaired late-phase, but not early-phase, long-term potentiation and long-term depression without change in basal synaptic transmission at SC-CA1 synapses. CONCLUSIONS: These data suggest that Mib1 mediated Notch signaling is essential for long-lasting synaptic plasticity and memory formation in the rodent hippocampus. PMID- 23111146 TI - Dietary intake and blood lipid profile in overweight and obese schoolchildren. AB - BACKGROUND: The high blood lipid levels and obesity are one of the main risk factors for cardiovascular diseases, and the atherosclerotic process begins in childhood. Some environmental factors are supposed to be involved in this relationship, such as dietary factors. This study aimed to investigate the relationship between dietary intake and blood lipids levels in overweight and obese schoolchildren. METHODS: This is a cross-sectional study with 147 overweight and obese schoolchildren in Botucatu city, Brazil. The anthropometric measurements (body weight, height, body mass index, waist circumference and skinfolds), pubertal staging evaluation and biochemical tests were taken in all children. Three 24h-recall were applied in order to estimate the dietary intake and its relationship with blood lipid levels. The Student t test and multiple linear regression analysis were used for statistical analysis. Statistical significance was assessed at the level of 0.05. The data were processed in SAS software (version 9.1.3; SAS Institute). RESULTS: At this study, 63% of children were obese (body mass index higher than 95th percentile) and 80% showed high body fat percentage. The percentage of children with abnormal total cholesterol and triglycerides was 12% and 10%, respectively, and 28% presented at least one abnormal lipid levels. The average values of anthropometric measurements were higher in children with elevated lipid levels. Total cholesterol levels were positively related to full-fat dairy products and triglycerides levels to saturated fat percentage. CONCLUSIONS: Saturated fat was positively associated with elevated lipid levels in overweight and obese schoolchildren. These results reinforce the importance of healthy dietary habits since childhood in order to reduce the risks of cardiovascular diseases in adulthood. PMID- 23111147 TI - Recurrence of major depressive disorder and its predictors in the general population: results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). AB - BACKGROUND: Knowledge of the risk of recurrence after recovery from major depressive disorder (MDD) in the general population is scarce. METHOD: Data were derived from 687 subjects in the general population with a lifetime DSM-III-R diagnosis of MDD but without a current major depressive episode (MDE) or dysthymia. Participants had to be at least 6 months in remission, and were recruited from The Netherlands Mental Health Survey and Incidence Study (NEMESIS), using the composite international diagnostic interview (CIDI). Recency and severity of the last MDE were assessed retrospectively at baseline. Recurrence of MDD was measured prospectively during the 3-year follow-up. Kaplan Meier survival curves were used to measure time to recurrence. Determinants of time to recurrence were analyzed using proportional hazard models. RESULTS: The estimated cumulative recurrence of MDD was 13.2% at 5 years, 23.2% at 10 years and 42.0% at 20 years. In bivariate analysis, the following variables predicted a shorter time to recurrence: younger age, younger age of onset, higher number of previous episodes, a severe last depressive episode, negative youth experiences, ongoing difficulties before recurrence and high neuroticism. Multivariably, younger age, a higher number of previous episodes, a severe last depressive episode, negative youth experiences and ongoing difficulties remained significant. CONCLUSIONS: In this community sample, the long-term risk of recurrence was high, but lower than that found in clinical samples. Subjects who had had an MDE had a long-term vulnerability for recurrence. Factors predicting recurrence included illness- and stress-related factors. PMID- 23111148 TI - Medical-grade honey does not reduce skin colonization at central venous catheter insertion sites of critically ill patients: a randomized controlled trial. AB - INTRODUCTION: Catheter-related bloodstream infections (CRBSIs) associated with short-term central venous catheters (CVCs) in intensive care unit (ICU) patients are a major clinical problem. Bacterial colonization of the skin at the CVC insertion site is an important etiologic factor for CRBSI. The aim of this study was to assess the efficacy of medical-grade honey in reducing bacterial skin colonization at insertion sites. METHODS: A prospective, single-center, open label randomized controlled trial was performed at the ICU of a university hospital in The Netherlands to assess the efficacy of medical-grade honey to reduce skin colonization of insertion sites. Medical-grade honey was applied in addition to standard CVC-site dressing and disinfection with 0.5% chlorhexidine in 70% alcohol. Skin colonization was assessed on a daily basis before CVC-site disinfection. The primary end point was colonization of insertion sites with >100 colony-forming units at the last sampling before removal of the CVC or transfer of the patient from the ICU. Secondary end points were quantitative levels of colonization of the insertion sites and colonization of insertion sites stratified for CVC location. RESULTS: Colonization of insertion sites was not affected by the use of medical-grade honey, as 44 (34%) of 129 and 36 (34%) of 106 patients in the honey and standard care groups, respectively, had a positive skin culture (P = 0.98). Median levels of skin colonization at the last sampling were 1 (0 to 2.84) and 1 (0 to 2.70) log colony-forming units (CFUs)/swab for the honey and control groups, respectively (P = 0.94). Gender, days of CVC placement, CVC location, and CVC type were predictive for a positive skin culture. Correction for these variables did not change the effect of honey on skin-culture positivity. CONCLUSIONS: Medical-grade honey does not affect colonization of the skin at CVC insertion sites in ICU patients when applied in addition to standard disinfection with 0.5% chlorhexidine in 70% alcohol. TRIAL REGISTRATION: Netherlands Trial Registry, NTR1652. PMID- 23111149 TI - Comparison of flunarizine and topiramate for the prophylaxis of pediatric migraines. AB - The purpose of this study was to compare the efficacy and tolerability of topiramate and flunarizine for the prophylaxis of pediatric migraines. A retrospective medical-record review of patients who underwent prophylaxis after receiving a diagnosis of migraine with aura and without aura was performed. Only patients who completed at least 3 months of treatment were included in the analysis. Response to treatment was assessed as the total number of headache days/month. Patients with more than 50% reduction in headache days/month were classified as responders. Responder rate, retention rate, and adverse-event rates were also calculated from all patients who started on the prophylaxis. Further analyses were performed using different patient groups with a cut-off age of 12 years. The responder rate was 80% (89/111 patients) for flunarizine and 81% (122/150 patients) for topiramate, based on a comparison among 261 patients. The retention rate was 67% for flunarizine and 63% for topiramate and the adverse event rate was 6% for flunarizine and 10% for topiramate. The responder rate, the retention rate, and the adverse-event rate were not significantly different between flunarizine and topiramate. These findings were concordant between the preadolescent (6-12 years old) and adolescent (13-18 years old) groups. The efficacy and tolerability of topiramate were not inferior to those of flunarizine for the prophylaxis of pediatric migraines. These findings were observed in preadolescent and adolescent patients. PMID- 23111150 TI - The measurement of sedentary patterns and behaviors using the activPALTM Professional physical activity monitor. AB - Epidemiological studies have associated the negative effects of sedentary time and sedentary patterns on health indices. However, these studies have used methodologies that do not directly measure the sedentary state. Recent technological developments in the area of motion sensors have incorporated inclinometers, which can measure the inclination of the body directly, without relying on self-report or count thresholds. This paper aims to provide a detailed description of methodologies used to examine a range of relevant variables, including sedentary levels and patterns from an inclinometer-based motion sensor. The activPAL Professional physical activity logger provides an output which can be interpreted and used without the need for further processing and additional variables were derived using a custom designed MATLAB(r) computer program. The methodologies described have been implemented on a sample of 44 adolescent females, and the results of a range of daily physical activity and sedentary variables are described and presented. The results provide a range of objectively measured and objectively processed variables, including total time spent sitting/lying, standing and stepping, number and duration of daily sedentary bouts and both bed hours and non-bed hours, which may be of interest when making association between physical activity, sedentary behaviors and health indices. PMID- 23111151 TI - Development of a pre-notification leaflet to encourage uptake of cervical screening at first invitation: a qualitative study. AB - Cervical screening attendance among women aged 25-29 years in England is lower than at older ages. There is some evidence that pre-notification leaflets motivate women who have not yet considered their response to a health intervention. We aimed to identify key information to motivate young women at their first cervical screening invitation. Six focus groups were conducted, five with young women aged 17-25 registered with a General Practice in Manchester, UK, and one with Practice nurses. Some women took part in two further groups to discuss leaflet design. There was low awareness of the purpose or procedures of cervical screening, and most women were de-motivated by reports of bad experiences. Some intended to be screened, but not immediately after invitation. Screening was viewed as a test for a cancer that affected older women. Since none of the participants believed that they had cervical cancer, screening seemed unnecessary. We conclude that the perception that screening is unimportant when you are young needs to be challenged. Women also need to be better informed of screening procedures. A pre-notification leaflet incorporating key information was designed and will be tested in a randomized trial of complex interventions within the routine cervical screening programme. PMID- 23111153 TI - Implication of VEGFR2 in systemic lupus erythematosus: a combined genetic and structural biological approach. AB - OBJECTIVES: VEGFR2 gene polymorphisms have already been correlated with vascular diseases such as coronary heart disease (CHD) and may influence endothelial integrity, repair and function. In view of the premature atherosclerosis observed in SLE, we sought to clarify the structural/functional consequences of two common single nucleotide polymorphisms (SNPs) of VEGFR2 in SLE and determine whether they are associated with risk of SLE by influencing endothelial cells. METHODS: Three-dimensional (3D) homology modelling was applied for the localisation of the V297I and the Q472H polymorphisms. Genotyping of the V297I (rs2305948) and Q472H (rs1870377) SNPs was done through Taqman technology in 250 SLE patients and 241 healthy controls from a Greek population (Cretan). The replication sample set for the rs1870377 SNP consisted of 253, 184 and 77 patients with SLE and 301, 118 and 11 ethnically-matched controls of African-American, European-American and Hispanic-American origin, respectively. RESULTS: Modelling revealed that the V297I polymorphism may affect the efficiency of trans-autophosphorylation and cell signalling, while Q472H affects homotypic contacts of membrane proximal Ig like domains. No significant allelic and genotypic association was observed for both the SNPs with risk of SLE. CONCLUSIONS: Although structural data suggest that both VEGFR2 SNPs may contribute to SLE pathogenesis by impairing VEGF signalling, none of the SNPs analysed was associated with increased susceptibility to SLE. However, they still may be relevant to the vascular damage/atherosclerosis in SLE. PMID- 23111154 TI - Paediatric bullous dermatoses. Linear immunoglobulin A (IgA) dermatosis. Bullous impetigo. Bullous insect bite reaction. Neonatal Herpes simplex virus (HSV) infection. PMID- 23111152 TI - Midkine-A functions upstream of Id2a to regulate cell cycle kinetics in the developing vertebrate retina. AB - BACKGROUND: Midkine is a small heparin binding growth factor expressed in numerous tissues during development. The unique midkine gene in mammals has two paralogs in zebrafish: midkine-a (mdka) and midkine-b (mdkb). In the zebrafish retina, during both larval development and adult photoreceptor regeneration, mdka is expressed in retinal stem and progenitor cells and functions as a molecular component of the retina's stem cell niche. In this study, loss-of-function and conditional overexpression were used to investigate the function of Mdka in the retina of the embryonic zebrafish. RESULTS: The results show that during early retinal development Mdka functions to regulate cell cycle kinetics. Following targeted knockdown of Mdka synthesis, retinal progenitors cycle more slowly, and this results in microphthalmia, a diminished rate of cell cycle exit and a temporal delay of cell cycle exit and neuronal differentiation. In contrast, Mdka overexpression results in acceleration of the cell cycle and retinal overgrowth. Mdka gain-of-function, however, does not temporally advance cell cycle exit. Experiments to identify a potential Mdka signaling pathway show that Mdka functions upstream of the HLH regulatory protein, Id2a. Gene expression analysis shows Mdka regulates id2a expression, and co-injection of Mdka morpholinos and id2a mRNA rescues the Mdka loss-of-function phenotype. CONCLUSIONS: These data show that in zebrafish, Mdka resides in a shared Id2a pathway to regulate cell cycle kinetics in retinal progenitors. This is the first study to demonstrate the function of Midkine during retinal development and adds Midkine to the list of growth factors that transcriptionally regulate Id proteins. PMID- 23111155 TI - Roundtable discussion: status asthmaticus in a patient with an anterior mediastinal mass. PMID- 23111156 TI - Bottom-up engineering of the surface roughness of nanostructured cubic zirconia to control cell adhesion. AB - Nanostructured cubic zirconia is a strategic material for biomedical applications since it combines superior structural and optical properties with a nanoscale morphology able to control cell adhesion and proliferation. We produced nanostructured cubic zirconia thin films at room temperature by supersonic cluster beam deposition of nanoparticles produced in the gas phase. Precise control of film roughness at the nanoscale is obtained by operating in a ballistic deposition regime. This allows one to study the influence of nanoroughness on cell adhesion, while keeping the surface chemistry constant. We evaluated cell adhesion on nanostructured zirconia with an osteoblast-like cell line using confocal laser scanning microscopy for detailed morphological and cytoskeleton studies. We demonstrated that the organization of cytoskeleton and focal adhesion formation can be controlled by varying the evolution of surface nanoroughness. PMID- 23111157 TI - A large-scale protein phosphorylation analysis reveals novel phosphorylation motifs and phosphoregulatory networks in Arabidopsis. AB - Large-scale protein phosphorylation analysis by MS is emerging as a powerful tool in plant signal transduction research. However, our current understanding of the phosphorylation regulatory network in plants is still very limited. Here, we report on a proteome-wide profiling of phosphopeptides in nine-day-old Arabidopsis (Arabidopsis thaliana) seedlings by using an enrichment method combining the titanium (Ti(4+))-based IMAC and the RP-strong cation exchange (RP SCX) biphasic trap column-based online RPLC. Through the duplicated RPLC-MS/MS analyses, we identified 5348 unique phosphopeptides for 2552 unique proteins. Among the phosphoproteins identified, 41% of them were first-time identified. Further evolutionary conservation and phosphorylation motif analyses of the phosphorylation sites discovered 100 highly conserved phosphorylation residues and identified 17 known and 14 novel motifs specific for Ser/Thr protein kinases. Gene ontology and pathway analyses revealed that many of the new identified phosphoproteins are important regulatory proteins that are involved in diverse biological processes, particularly in central metabolisms and cell signaling. Taken together, our results provided not only new insights into the complex phosphoregulatory network in plants but also important resources for future functional studies of protein phosphorylation in plant growth and development. PMID- 23111158 TI - Isolation and molecular characterization of GmERF7, a soybean ethylene-response factor that increases salt stress tolerance in tobacco. AB - Ethylene-response factors (ERFs) play an important role in regulating gene expression in plant responses to biotic and abiotic stresses. In this study, a new ERF transcription factor, GmERF7, was isolated from soybean. Sequence analysis showed that GmERF7 contained an AP2/ERF domain with 58 amino acids, two putative nuclear localization signal (NLS) domains, an acidic amino acid-rich transcriptional activation domain and a conserved N-terminal motif [MCGGAI(I/L)]. The expression of GmERF7 was induced by drought, salt, methyl jasmonate (MeJA), ethylene (ETH) and abscisic acid (ABA) treatments. However, the expression of GmERF7 decreased under cold treatment. GmERF7 localized to the nucleus when transiently expressed in onion epidermal cells. Furthermore, GmERF7 protein bound to the GCC-box element in vitro and activated the expression of the beta glucuronidase (GUS) reporter gene in tobacco leaves. Activities of GmERF7 promoter (GmERF7P) upregulated in tobacco leaves with 10h drought, salt and ETH treatments. However, activities of GmERF7P decreased with 10h cold and ABA treatments. Overexpression of GmERF7 in tobacco plants led to higher levels of chlorophyll and soluble carbohydrates and a lower level of malondialdehyde compared with wild-type tobacco plants under salt stress conditions, which indicated that GmERF7 enhanced salt tolerance in transgenic plants. PMID- 23111159 TI - Genetic association between IL-17F gene polymorphisms and the pathogenesis of Graves' Disease in the Han Chinese population. AB - BACKGROUND: Graves' Disease (GD) is a common and complex disorder, with a strong hereditary component. IL-17F is a potent cytokine and a potential contributor to the etiology of various human autoimmune diseases. In the present study, we focused on the relationship between polymorphisms in the IL-17F gene and GD susceptibility through a case-control association study in two independent Chinese cohorts. METHODS: Our pilot study was performed on a cohort from Shanghai, which included 757 GD patients and 741 healthy controls. Our replication cohort was from Xiamen, consisting of 434 GD patients and 420 healthy controls. We selected four tag SNPs (rs763780, rs2397084, rs9463772 and rs761167) within the IL-17F gene to conduct a genotyping analysis. RESULTS: In the Shanghai cohort, the rs9463772 polymorphism showed a significant association with GD and Graves' Disease-associated Ophthalmopathy (GO) patients (P(allele)=7*10(-5) and 7.4*10(-3) for GD and GO patients, respectively). The rs763780 polymorphism was found to have only a difference in genotype distribution between GD individuals and healthy controls (P=0.017). In the replication study, we confirmed the association between the rs9463772 polymorphism and GD susceptibility. Haplotype analysis showed that the haplotype of the four SNPs (GCTT) was associated with a significant risk of GD in the Shanghai cohort (P=7.9*10(-3)). CONCLUSION: Our results suggest that polymorphisms in the IL-17F gene increase the risk of Graves' Disease and that IL-17F is therefore a good candidate gene for Graves' Disease prediction in the Han Chinese population. PMID- 23111161 TI - Screening for the presence of FMR1 premutation alleles in women with fibromyalgia. AB - Fibromyalgia is a chronic condition characterized by widespread pain, fatigue, non-restorative sleep and cognitive difficulties that affects 2-4% of the general population. Recently a possible relationship between the FMR1 premutation and fibromyalgia has been pointed out. In attempt to gather more data we screened for the FMR1 CGG expansion 700 DNA samples from unrelated fibromyalgia patients. This data might be useful for evaluating the incorporation of this test in rheumatologic procedures for women with fibromyalgia. The observed frequency of FMR1 premutation carriers (3 of 700, 0.4%) is not significantly different from the estimated rate in the general female population (1/250-1/400) (P=0.539, P=0.716). Clinical examination of the FMR1 premutation carriers identified revealed that all of them had important neurological symptoms with regard to muscular symptoms, neurocognitive alterations and neurovegetative impairments. With regard to other clinical aspects of the disease the cases apparently did not differ from the average fibromyalgia patients. On the basis of our results an FMR1 screening among fibromyalgia female patients would not be recommended. However it would be worthwhile to further evaluate the different clinical presentations that fibromyalgia patients might present based on their FMR1 premutation carrier status. PMID- 23111160 TI - Mitochondrial DNA haplogroup Y is associated to Leigh syndrome in Chinese population. AB - Although Leigh syndrome (LS) is a well characterized clinical mitochondrial disorder; the exact mutation is not found in all cases and it is not clear whether matrilineal background has contributed to this disease. To address this issue, we extensively studied and compared the haplogroup composition of a sample of 171 Chinese LS patients with that of 1597 controls. Our results show that haplogroup Y may increase the risk of LS in Chinese by 2.867 fold (95% CI=1.135 7.240, P=0.020). Haplogroup B5 has also this trend (1.737 fold, 95% CI=0.961 3.139), but with a borderline P-value (P=0.065). Both haplogroups belong to macro haplogroup N and share a common reverse mutation on nucleotide position 10398 (A10398G). In fact, the combined haplogroup N with 10398G is also associated with an increased risk for LS (OR=1.882, 95% CI=1.134-3.124, P=0.013). PMID- 23111162 TI - Uniparental disomy analysis in trios using genome-wide SNP array and whole-genome sequencing data imply segmental uniparental isodisomy in general populations. AB - Whole chromosomal and segmental uniparental disomy (UPD) is one of the causes of imprinting disorder and other recessive disorders. Most investigations of UPD were performed only using cases with relevant phenotypic features and included few markers. However, the diagnosis of cases with segmental UPD requires a large number of molecular investigations. Currently, the accurate frequency of whole chromosomal and segmental UPD in a normal developing embryo is not well understood. Here, we present whole chromosome and segmental UPD analysis using single nucleotide polymorphism (SNP) microarray data of 173 mother-father-child trios (519 individuals) from six populations (including 170 HapMap trios). For two of these trios, we also investigated the possibility of shorter segmental UPD as a consequence of homologous recombination repair (HR) for DNA double strand breaks (DSBs) during the early developing stage using high-coverage whole-genome sequencing (WGS) data from 1000 Genomes Project. This could be overlooked by SNP microarray. We identified one obvious segmental paternal uniparental isodisomy (iUPD) (8.2 mega bases) in one HapMap sample from 173 trios using Genome-Wide Human SNP Array 6.0 (SNP6.0 array) data. However, we could not identify shorter segmental iUPD in two trios using WGS data. Finally, we estimated the rate of segmental UPD to be one per 173 births (0.578%) based on the UPD screening for 173 trios in general populations. Based on the autosomal chromosome pairs investigated, we estimate the rate of segmental UPD to be one per 3806 chromosome pairs (0.026%). These data imply the possibility of hidden segmental UPD in normal individuals. PMID- 23111163 TI - A genome-wide analysis of the RNA helicase gene family in Solanum lycopersicum. AB - Helicases belong to a class of molecular motor proteins that are found in yeast, animals, and plants. The helicase family is divided into three subfamilies, including the DEAD-box, DEAH-box and DExD/H-box helicases, which are classified based on variations within a common motif, known as motif II. The RNA helicases are involved in every step of RNA metabolism, including nuclear transcription, pre-mRNA splicing, ribosome biogenesis, nucleocytoplasmic transport, translation, RNA decay, and organellar gene expression. The RNA helicase protein family plays a crucial role in plant growth and development as well as in response to biotic and abiotic stresses. However, unlike Arabidopsis, no detailed information regarding the RNA helicase family is currently available for tomato (Solanum lycopersicum) due to a limited number of whole-genome sequences. In this study, we identified a total of 157 RNA helicase genes in the tomato genome. According to the structural features of the motif II region, we classified the tomato RNA helicase genes into DEAD-box, DEAH-box and DExD/H-box helicase genes. But there are 27 RNA helicases not belonging to this three subfamilies, we called that "other helicase". We mapped the 157 RNA helicase genes onto the tomato chromosomes, which range from chr01 to chr12. Microarray and expressed sequence tag data showed that many of these RNA helicase proteins may be involved in diverse biological processes and responses to various stresses. To our knowledge, this is the first report of a genome-wide analysis of the tomato RNA helicase gene family. This study provides valuable information for understanding the classification and putative functions of the RNA helicase gene family in Solanaceae. PMID- 23111164 TI - Default mode network connectivity encodes clinical pain: an arterial spin labeling study. AB - Neuroimaging studies have suggested the presence of alterations in the anatomo functional properties of the brain of patients with chronic pain. However, investigation of the brain circuitry supporting the perception of clinical pain presents significant challenges, particularly when using traditional neuroimaging approaches. While potential neuroimaging markers for clinical pain have included resting brain connectivity, these cross-sectional studies have not examined sensitivity to within-subject exacerbation of pain. We used the dual regression probabilistic Independent Component Analysis approach to investigate resting state connectivity on arterial spin labeling data. Brain connectivity was compared between patients with chronic low back pain (cLBP) and healthy controls, before and after the performance of maneuvers aimed at exacerbating clinical pain levels in the patients. Our analyses identified multiple resting state networks, including the default mode network (DMN). At baseline, patients demonstrated stronger DMN connectivity to the pregenual anterior cingulate cortex (pgACC), left inferior parietal lobule, and right insula (rINS). Patients' baseline clinical pain correlated positively with connectivity strength between the DMN and right insula (DMN-rINS). The performance of calibrated physical maneuvers induced changes in pain, which were paralleled by changes in DMN-rINS connectivity. Maneuvers also disrupted the DMN-pgACC connectivity, which at baseline was anticorrelated with pain. Finally, baseline DMN connectivity predicted maneuver-induced changes in both pain and DMN-rINS connectivity. Our results support the use of arterial spin labeling to evaluate clinical pain, and the use of resting DMN connectivity as a potential neuroimaging biomarker for chronic pain perception. PMID- 23111165 TI - The diagnostic value of arginase-1 immunostaining in differentiating hepatocellular carcinoma from metastatic carcinoma and cholangiocarcinoma as compared to HepPar-1. AB - BACKGROUND: The ability to distinguish hepatocellular carcinoma (HCC) from metastatic carcinoma (MC) involving the liver and cholangiocarcinoma (CC) by immunohistochemistry has been limited by the lack of a reliable positive marker for hepatocellular differentiation. Arginase-1 is a marker for HCC recently described in some literature. AIM: To examine the immunohistochemical staining of arginase-1 in cases of HCC, MC involving the liver and CC as compared to hepatocyte paraffin antigen -1 (HepPar-1) in an attempt to further define the diagnostic utility of arginase-1 in differentiating these tumors. MATERIALS AND METHODS: A comparative immunohistochemical study of arginase-1 and HepPar 1expression was performed in 50 HCC cases, 38 cases of MC to the liver from varying sites, 12 cases of CC and 10 specimens of normal liver tissues. The predictive capacity of arginase-1 and HepPar-1 staining was determined using sensitivity, specificity, positive predictive value, and negative predictive value calculations. RESULTS: All normal liver tissues (no=10), non- neoplastic cirrhotic liver tissues adjacent to HCC (no=42) as well as those adjacent to MC (no= 9) showed diffuse and strong immunostaining for both arginase-1 and HepPar 1. Arginase-1 demonstrated positive immunoreactivity in 42 of 50 (84%) cases of HCC compared with 35 of 50 (70%) for HepPar-1. Only one of 38 (2.6%) cases of MC and one of 12 (8.3%) cases of CC showed positive immunoreactivity for arginase-1. In contrast, HepPar-1 immunoreactivity was detected in 6 of 38 (15.8%) cases of MC and in 2 of 12 (16.7%) cases of CC. Arginase -1 showed a significantly higher sensitivity for HCC diagnosis (84%) compared to HepPar -1(70%) (p=0.016). The specificity of arginase-1 for HCC diagnosis was higher (96%) than that of HepPar 1 (84%); nevertheless, this was not statistically significant (p=0.109). Howerver, the combination of both immunomarkers for the diagnosis of HCC, raised the specificity to 100%. CONCLUSION: Arginase-1 immunostaining has a higher sensitivity and specificity than HepPar-1 for HCC diagnosis. Furthermore, the combined use of arginase-1 and HepPar-1 can provide a potentially promising tool to improve the accuracy in distinguishing HCC from metastatic carcinoma and cholangiocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9991436558072434. PMID- 23111167 TI - DNA-based HIV vaccines do not induce generalized activation in mucosal tissue T cells. AB - HIV preferentially infects activated T cells, and activated mucosal CD4+ T cells are the primary sites of viral replication. One potential explanation for increased HIV acquisition rates in the STEP study is that vaccination with adenoviral (Ad) vectors increased CD4+ T cell activation levels at the site of infection, a concept that others and we continue to explore. Whether vaccination with HIV vaccine platforms increases the activation state of CD4+ T cells within peripheral tissues, such as the gastro-intestinal (GI) mucosa, is exceptionally important to determine as a vaccine safety measure, given the susceptibility of activated CD4+ T cells to HIV infection. In this study we examined whether vaccination with DNA plasmids and chemokine adjuvants alter the activation state of T cells within the GI mucosa, inguinal LN, and peripheral blood. T cell activation state was measured by expression of CD25, CD69, and HLA-DR over the course of the prime/boost study. DNA plasmid vaccination did not increase expression of any of these markers in the 3 tissues studied. Addition of the gut homing chemokine TECK during DNA plasmid vaccination did not alter activation levels of CD4+ T cells at any of these sites. These findings indicate that DNA vaccines do not elicit generalized mucosal T cell activation. Thus, DNA platforms may be especially suitable for HIV vaccine development, where bystander activation could promote increased HIV transmission. PMID- 23111168 TI - What you always needed to know about electroporation based DNA vaccines. AB - Vaccinations are increasingly used to fight infectious disease, and DNA vaccines offer considerable advantages, including broader possibilities for vaccination and lack of need for cold storage. It has been amply demonstrated, that electroporation augments uptake of DNA in both skin and muscle, and it is foreseen that future DNA vaccination may to a large extent be coupled with and dependent upon electroporation based delivery. Understanding the basic science of electroporation and exploiting knowledge obtained on optimization of DNA electrotransfer to muscle and skin, may greatly augment efforts on vaccine development. The purpose of this review is to give a succinct but comprehensive overview of electroporation as a delivery modality including electrotransfer to skin and muscle. As well, this review will speculate and discuss future uses for this powerful electrotransfer technology. PMID- 23111166 TI - Harnessing DNA-induced immune responses for improving cancer vaccines. AB - DNA vaccines have emerged as an attractive strategy to promote protective cellular and humoral immunity against the encoded antigen. DNA vaccines are easy to generate, inexpensive to produce and purify at large-scale, highly stable and safe. In addition, plasmids used for DNA vaccines act as powerful "danger signals" by stimulating several DNA-sensing innate immune receptors that promote the induction of protective adaptive immunity. The induction of tumor-specific immune responses represents a major challenge for DNA vaccines because most of tumor-associated antigens are normal non-mutated self-antigens. As a consequence, induction of potentially self-reactive T cell responses against such poorly immunogenic antigens is controlled by mechanisms of central and peripheral tolerance as well as tumor-induced immunosuppression. Although several DNA vaccines against cancer have reached clinical testing, disappointing results have been observed. Therefore, the development of new adjuvants that strongly stimulate the induction of antitumor T cell immunity and counteract immune suppressive regulation is an attractive approach to enhance the potency of DNA vaccines and overcome tumor-associated tolerance. Understanding the DNA-sensing signaling pathways of innate immunity that mediate the induction of T cell responses elicited by DNA vaccines represents a unique opportunity to develop novel adjuvants that enhance vaccine potency. The advance of DNA adjuvants needs to be complemented with the development of potent delivery systems, in order to step toward successful clinical application. Here, we briefly discuss recent evidence showing how to harness DNA-induced immune response to improve the potency of cancer vaccines and counteract tumor-associated tolerance. PMID- 23111169 TI - Co-expression of HIV-1 virus-like particles and granulocyte-macrophage colony stimulating factor by GEO-D03 DNA vaccine. AB - Here, we report on GEO-D03, a DNA vaccine that co-expresses non-infectious HIV-1 virus-like particles (VLPs) and the human cytokine, granulocyte-macrophage colony stimulating factor (GM-CSF). The virus-like particles display the native gp160 form of the HIV-1 Envelope glycoprotein (Env) and are designed to elicit antibody against the natural form of Env on virus and virus-infected cells. The DNA expressed HIV Gag, Pol and Env proteins also have the potential to elicit virus specific CD4 and CD8 T cells. The purpose of the co-expressed GM-CSF is to target a cytokine that recruits, expands and differentiates macrophages and dendritic cells to the site of VLP expression. The GEO-D03 DNA vaccine is currently entered into human trials as a prime for a recombinant modified vaccinia Ankara (MVA) boost. In preclinical studies in macaques using an SIV prototype vaccine, this vaccination regimen elicited both anti-viral T cells and antibody, and provided 70% protection against acquisition during 12 weekly rectal exposures with a heterologous SIV. Higher avidity of the Env-specific Ab for the native form of the Env in the challenge virus correlated with lower likelihood of SIV infection. PMID- 23111170 TI - DNA prime-protein boost using subtype consensus Env was effective in eliciting neutralizing antibody responses against subtype BC HIV-1 viruses circulating in China. AB - Previously, we have shown that DNA prime-protein boost is effective in eliciting neutralizing antibodies (NAb) against randomly selected HIV-1 isolates. Given the genetic diversity of HIV-1 viruses and the unique predominant subtypes in different geographic regions, it is critical to test the DNA prime-protein boost approach against circulating viral isolates in key HIV endemic areas. In the current study, the same DNA prime-protein boost vaccine was used as in previous studies to investigate the induction of NAb responses against HIV-1 clade BC, a major subtype circulating in China. A codon optimized gp120-BC DNA vaccine, based on the consensus envelope (Env) antigen sequence of clade BC, was constructed and a stable CHO cell line expressing the same consensus BC gp120 protein was produced. The immunogenicity of this consensus gp120-BC was examined in New Zealand White rabbits by either DNA prime-protein boost or protein alone vaccination approaches. High levels of Env-specific antibody responses were elicited by both approaches. However, DNA prime-protein boost but not the protein alone immune sera contained significant levels of NAb against pseudotyped viruses expressing HIV-1 BC Env antigens. Furthermore, high frequencies of CD4 binding site-targeted antibodies were found in the DNA prime- protein boost rabbit sera indicating that the positive NAb may be the result of antibodies against conformationally sensitive epitopes on HIV-1 Env. The findings support that DNA prime-protein boost was effective in eliciting NAb against a key HIV-1 virus subtype in China. This result may lead to the development of regional HIV vaccines through this approach. PMID- 23111171 TI - Aluminum can induce alterations in the cellular localization and expression of three major nucleolar proteins in root tip cells of Allium cepa var. agrogarum L. AB - A 50 MUM aluminum (Al) could induce nucleolar materials containing the argyrophilic proteins scattered in the nuclei and extruded from the nuclei into the cytoplasm in the root tip cells of Allium cepa. Unfortunately, what kinds of nucleolar proteins are affected has not been reported till now. In order to go deeper into the understanding of the cytological effects of Al on nucleolus and nucleolar proteins, alterations in the cellular localization and expression of three major nucleolar proteins: nucleophosmin, nucleolin, and fibrillarin were further examined under the treatment with Al in the root tip cells of A. cepa in the present study. Cytological effects of Al on nucleolus were observed by silver staining method and three major nucleolar proteins: nucleophosmin, nucleolin, and fibrillarin were examined by western blotting. The results indicated that in the presence of 50 MUM Al for 48 h the nucleolar proteins were translocated from nucleolus to nucleoplasm and cytoplasm. Western blotting data demonstrated the relatively higher expression of the three major nucleolar proteins when compared with control. Evidence from the present investigation indicated that Al had toxic effects on Ag-NOR proteins, nucleophosmin and nucleolin, and other kinds of nucleolar proteins, fibrillarin. PMID- 23111172 TI - Salt-marsh areas as copper complexing ligand sources to estuarine and coastal systems. AB - Dissolved copper levels, copper complexing capacities and conditional stability constants have been determined in the Tagus estuarine waters and one of the saltmarshes located in this estuary, the Rosario saltmarsh. Tagus estuarine waters show a constant and around 20 nM copper concentration during the estuarine mixing. Most of this copper is organically complexed by a strong ligand (L(1)) with a concentration that varies between 19 and 55 nM and a log K' between 14.14 and 15.75. In addition L(1)/Cu ratios are quite constants and close to 1 all through the estuary, indicating the same source. A second and weaker ligand (L(2)) was also detected in these waters in higher concentrations (36-368 nM) but with a lower log K' that varies between 12.06 and 13.13. The present work has demonstrated that salt-marsh areas are important and continuous sources of copper complexing ligands to the Tagus estuary. Noticeable, tidal induced transport continuously feed these waters with copper and ligands, mainly with the stronger one. This continuous input, together with the high residence times of this system results in a quite constant concentration along the salinity gradient. This input represents 95% of the ligand present in the estuary. PMID- 23111173 TI - Evidence that hippocampal-parahippocampal dysfunction is related to genetic risk for schizophrenia. AB - BACKGROUND: Abnormalities in hippocampal-parahippocampal (H-PH) function are prominent features of schizophrenia and have been associated with deficits in episodic memory. However, it remains unclear whether these abnormalities represent a phenotype related to genetic risk for schizophrenia or whether they are related to disease state. METHOD: We investigated H-PH-mediated behavior and physiology, using blood oxygenation level-dependent functional magnetic resonance imaging (BOLD fMRI), during episodic memory in a sample of patients with schizophrenia, clinically unaffected siblings and healthy subjects. RESULTS: Patients with schizophrenia and unaffected siblings displayed abnormalities in episodic memory performance. During an fMRI memory encoding task, both patients and siblings demonstrated a similar pattern of reduced H-PH engagement compared with healthy subjects. CONCLUSIONS: Our findings suggest that the pathophysiological mechanism underlying the inability of patients with schizophrenia to properly engage the H-PH during episodic memory is related to genetic risk for the disorder. Therefore, H-PH dysfunction can be assumed as a schizophrenia susceptibility-related phenotype. PMID- 23111174 TI - Clinical and microbiological profile of post-penetrating keratoplasty infectious keratitis in failed and clear grafts. AB - PURPOSE: To comparatively evaluate the clinical and microbiological profiles and treatment outcome of cases with post-penetrating keratoplasty (PK) infectious keratitis in failed and clear grafts. DESIGN: Retrospective, matched cohort study. METHODS: All cases of infectious keratitis following penetrating keratoplasty admitted to the Royal Victorian Eye and Ear Hospital, Melbourne, between January 1998 and December 2008 were identified through a retrospective medical chart review. Cases without any surface sutures were selected and divided into 2 groups, microbial keratitis with pre-existing graft failure and microbial keratitis in clear graft on presentation. Demographic, clinical, and microbiological profiles of cases in both groups were analyzed and compared. RESULTS: Patients in the failed-graft group were older (P = .004) and had an early onset of graft infection (P = .049), compared with patients in the clear graft group. All patients in the failed-graft group were on long-term corticosteroid drops at the time of presentation (vs 76% in clear-graft group; P = .005). Moraxella sp was more frequently isolated in the failed-graft group (30.4%) compared with the clear-graft group (8%). A higher number of cases in the clear-graft group required surgical intervention in the form of corneal gluing and therapeutic corneal transplantation compared with the failed-graft group (P = .03). CONCLUSIONS: Prolonged use of corticosteroid eye drops is a major risk factor for the occurrence of postkeratoplasty infectious keratitis in failed and clear grafts. Infections in failed grafts occur earlier as compared to clear grafts, and indolent organisms like Moraxella are prevalent in patients with failed grafts in Australia. PMID- 23111175 TI - The effect of lateral decubitus position on intraocular pressure in patients with untreated open-angle glaucoma. AB - PURPOSE: To investigate the effect of change of body posture from the supine to the lateral decubitus position on intraocular pressure (IOP) in patients with open-angle glaucoma. DESIGN: Prospective, observational case series. METHODS: Setting. Institutional. Participants. Forty-four eyes of 22 patients with newly diagnosed bilateral open-angle glaucoma. Observation procedures. IOP was measured using the Tono-Pen XL (Reichert Inc) in both eyes 10 minutes after assuming each position: sitting, supine, right lateral decubitus, supine, left lateral decubitus, and supine. By comparing the mean deviation (MD) of Humphrey visual field between both eyes of a patient, eyes were classified into either worse-MD eye or better-MD eye. Main outcome measures. Magnitude of IOP alterations by postural changes and intereye difference of IOP with each posture. RESULTS: The mean +/- SD IOP of the dependent eyes (eye on the lower side in the lateral decubitus position) increased after changing from the supine to the right lateral decubitus position (19.1 +/- 2.6 mm Hg vs 21.0 +/- 2.7 mm Hg; P = .019) or the left lateral decubitus position (18.6 +/- 2.9 mm Hg vs 20.6 +/- 3.1 mm Hg; P = .002). The mean IOP of the dependent eyes was significantly higher than that of the nondependent eyes in the lateral decubitus positions (right lateral decubitus, +1.2 mm Hg; left lateral decubitus, +1.6 mm Hg; both, P < .05). Compared with the better-MD eyes, the worse-MD eyes showed a tendency for greater IOP rise with positional change from the supine to lateral decubitus position (2.3 +/- 2.2 mm Hg vs 1.5 +/- 2.1 mm Hg; P = .065). CONCLUSIONS: The postural change from the supine to lateral decubitus position may increase the IOP of the dependent eyes in patients with open-angle glaucoma. PMID- 23111176 TI - Long-term outcomes in patients who received a corneal graft for keratoconus between 1980 and 1986. AB - PURPOSE: To estimate the probability of allograft rejection, graft failure, and recurrent keratoconus (KC) and to assess vision-specific quality of life 20 to 25 years after corneal transplantation for KC. DESIGN: Retrospective case series. METHODS: Two hundred nineteen eyes of 184 subjects were identified from the Michigan Corneal Transplantation Patient Registry as receiving corneal transplantation for KC from 1980 through 1986. Current ophthalmic examinations and the 25-item National Eye Institute Visual Function Questionnaire were obtained. Kaplan-Meier analyses were used to estimate the time-related probability of allograft rejection, graft failure, and KC recurrence. Cox regression was used to identify predictive factors of these outcomes. The 25-item National Eye Institute Visual Function Questionnaire scores were summarized with descriptive statistics. RESULTS: Follow-up was available up to 27 years after surgery (median, 10 years). Rejection occurred in 98 of 219 grafts. Most rejections occurred in the first 2 years (probability, 41%; standard error, 3%). KC recurrence was noted in 6 grafts 9 to 20 years after surgery, with a 20-year probability of 10% (standard error, 4%). Eighteen grafts failed, with a 20-year probability of 12% (standard error, 3%). Larger host trephine size, male donor gender, and nonwhite donor race were associated with increased rejection hazard. Worse astigmatism and nonwhite recipient race were associated with increased failure hazard. Twenty-eight subjects completed the 25-item National Eye Institute Visual Function Questionnaire at an average of 23 years after surgery (range, 18 to 26 years). Their mean composite score was 84.5 (standard deviation, 12.1). CONCLUSIONS: Allograft rejection is frequent in the 2 years after corneal graft for KC. However, the 20-year probabilities of graft failure and recurrent KC are low. Given the relative youth of KC graft recipients, these statistics should enhance the information they receive. PMID- 23111178 TI - Serologic factors in early relapse of IgG4-related orbital inflammation after steroid treatment. AB - PURPOSE: To determine whether serologic factors correlate with early relapse in cases of IgG4-related orbital inflammation, a lymphoproliferative disorder. DESIGN: Retrospective cohort study. METHODS: We examined the orbital images and serum data of 30 patients with (n=24) or without (n=6) corticosteroid treatment before and after corticosteroid treatment and 6 months after discontinuation of corticosteroid treatment. RESULTS: Seven patients (23%) (all with corticosteroid treatment) had elevated serum levels of rheumatoid factor. Of the 24 patients with corticosteroid treatment, 24 (100%) showed regression of the lesion, but 8 of the 24 (33%) showed relapse. The serum IgG4 levels before and after corticosteroid treatment were not significantly different between the relapsed and nonrelapsed groups (P=.5 and P=.2, respectively). However, the incidence of patients who were rheumatoid factor-positive was significantly higher in the relapsed group (P=.02). The 6 patients without corticosteroid treatment showed minor proliferation or regression of the lesion at the 6-month follow-up. CONCLUSIONS: The serum rheumatoid factor level may correlate with proliferative activity in IgG4-related orbital inflammation. PMID- 23111179 TI - Intravitreal bevacizumab for macular complications from retinal arterial macroaneurysms. AB - PURPOSE: To evaluate the anatomic and functional results of the treatment with intravitreal bevacizumab in complicated retinal arterial macroaneurysm (RAM). DESIGN: A multicenter interventional, prospective, nonrandomized study. METHODS: Thirty-eight macroaneurysms of 37 patients with foveal complications were evaluated. All patients underwent a comprehensive ophthalmologic examination, fluorescein angiography (FA), and spectral-domain optical coherence tomography (SD OCT) examination. Each patient underwent 3 monthly injections of bevacizumab 1.25 mg/0.05 mL; 3 follow-up visits were planned at week 2, 6, and 12. RESULTS: Both best-corrected visual acuity (BCVA), expressed in logarithm of minimal angle of resolution (logMAR), and central retinal thickness (CRT) significantly improved during the follow-up visits (0.57 +/- 0.21 vs 0.41 +/- 0.15 vs 0.23 +/- 0.13 vs 0.09 +/- 0.10 and 520.38 +/- 191.05 vs 396.24 +/- 136.18 vs 283.86 +/- 71.87 vs 214.84 +/- 26.86, respectively, Friedman test P < .0001 for all variables). At 6 weeks of follow-up, FA showed complete closure of the RAM in 36 of 38 cases (94.7%). Four weeks following the third injection, the macular edema had completely resolved and hard exudates regressed slowly in 100% of patients. CONCLUSIONS: Intravitreal bevacizumab is an effective therapy for complicated RAM, quickly improving BCVA and CRT. Anti-vascular endothelial growth factor (VEGF) drugs might actively close the involved pathologically permeabilized retinal artery and normalize the vessel wall formation by localized inhibition of VEGF. PMID- 23111177 TI - CDKN2B-AS1 genotype-glaucoma feature correlations in primary open-angle glaucoma patients from the United States. AB - PURPOSE: To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients. DESIGN: Retrospective observational case series. METHODS: We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. RESULTS: For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, 0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, 0.29; P = 6.55E-05). CONCLUSION: Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG. PMID- 23111180 TI - Computerized assessment of intraretinal and subretinal fluid regions in spectral domain optical coherence tomography images of the retina. AB - PURPOSE: To evaluate a new computerized segmentation technique for the quantification of intraretinal and subretinal fluid in spectral-domain optical coherence tomography (SD OCT) images of the retina. DESIGN: Prospective, cross sectional study. METHODS: Thirty-seven B-scan images of 37 patients with exudative age-related macular degeneration were chosen randomly from SD OCT volume scans (1 per volume scan). All hyporeflective areas in the image first were segmented automatically as candidate regions by the program. Researchers who were masked to the candidate region information selected each fluid region from the original image using a single mouse click. The program then delineated the boundary of each region selected and calculated quantitative parameters, including total area of fluid regions if multiple regions were selected. The performance of our technique was validated by comparing the results with the measurements obtained from boundaries manually delineated by 2 masked observers. Time efficiency, agreement with manual delineation, and intraobserver and interobserver agreement of using the program were evaluated. RESULTS: The proposed technique reduced the average processing time per image approximately 6 fold (15 seconds for computerized segmentation vs 90 seconds for manual delineation). There was good agreement between computerized segmentation and manual delineation measured by intraclass correlation coefficient (range, 0.897 to 0.979) and the Dice coefficient (range, 0.721 to 0.785). The proposed technique has excellent intraobserver and interobserver agreement (intraclass correlation coefficient range, 0.998 to 0.999; Dice coefficient range. 0.959 to 0.981). CONCLUSIONS: This computerized segmentation method allows for accurate and fast quantification of fluid in retinal SD OCT images and could assist in monitoring disease progression and evaluating therapeutic intervention. PMID- 23111181 TI - Argon laser with and without anti-vascular endothelial growth factor therapy for extrafoveal polypoidal choroidal vasculopathy. AB - PURPOSE: To describe the clinical characteristics and outcome of eyes with extrafoveal polypoidal choroidal vasculopathy (PCV) treated with argon laser. DESIGN: Prospective cohort, noninterventional study. METHODS: A prospective study of Asian patients with extrafoveal PCV, confirmed on indocyanine green angiography and treated with argon laser with and without anti-vascular endothelial growth factor (VEGF) therapy. Patients were followed-up over 12 months with visual, angiographic, and structural outcomes recorded. RESULTS: Of the 93 eyes with PCV at baseline, 33 eyes (35.5%) in 31 patients had extrafoveal involvement and were treated with argon laser. Foveal involvement with fluid or blood at baseline was apparent in 23 eyes (69.7%), despite the extrafoveal location of 1 or more polyps. Of these 33 eyes, 12 (36.4%) also received anti VEGF injections (median, 2.5 injections) over the 12-month period. Two eyes received photodynamic therapy rescue during subsequent follow-up and were excluded for visual outcome analysis. In the remaining 31 eyes, mean visual acuity improved from 0.57 logarithm of the minimal angle of resolution (logMAR) units (range, 0.00 to 2.0 logMAR; standard deviation, 0.51 logMAR) at baseline to 0.39 logMAR (range, 0.00 to 2.0 logMAR; standard deviation, 0.43 logMAR) at month 12 (P = .01), with a mean gain in visual acuity of 9.0 letters at month 12. Stable or improved vision (defined as losing 5 letters or fewer) was achieved in 28 eyes (90.3%). Use of anti-VEGF was associated with significantly thicker central subfield at baseline (347.6 vs 258.1 MUm; P = .02) and resulted in similar vision and OCT results at month 3 and 12 compared with eyes that did not receive anti-VEGF. CONCLUSIONS: Argon laser treatment with selected use of anti VEGF therapy achieves stable or improved visual outcome in most eyes with extrafoveal PCV, including eyes with fluid or blood affecting the fovea at presentation. PMID- 23111182 TI - Prevalence and genomic association of reticular pseudodrusen in age-related macular degeneration. AB - PURPOSE: To survey the prevalence of reticular pseudodrusen in late age-related macular degeneration (AMD) using multiple imaging methods, and to investigate the association between reticular pseudodrusen and polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genes. DESIGN: Retrospective case series. METHODS: This study included 216 consecutive patients with late AMD (typical AMD, polypoidal choroidal vasculopathy [PCV], retinal angiomatous proliferation [RAP], or geographic atrophy). Eyes were assessed for reticular pseudodrusen using the blue channel of color fundus photography, infrared reflectance, fundus autofluorescence, and spectral-domain optical coherence tomography. The major AMD-associated single nucleotide polymorphisms (CFH Y402 rs1061170, CFH I62V rs800292, and ARMS2 A69S rs10490924) were genotyped. RESULTS: Forty-nine eyes of 30 patients had a reticular pattern in >=2 imaging modalities and were diagnosed with reticular pseudodrusen. Of these, 16 had bilateral late AMD, whereas 32 of 186 patients without reticular pseudodrusen had bilateral late AMD (P < .001). The prevalence of reticular pseudodrusen was 83% in RAP, 50% in geographic atrophy, 9% in typical AMD, and 2% in PCV. The frequency of the T allele in ARMS2 A69S in patients with and without reticular pseudodrusen was 78.6% and 59.9%, respectively (P=.007). CONCLUSIONS: The prevalence of reticular pseudodrusen was low in PCV cases. About 50% of patients with reticular pseudodrusen had bilateral late AMD. The connection of ARMS2 risk allele and reticular pseudodrusen was confirmed in a Japanese population. PMID- 23111183 TI - Blepharoptosis repair outcomes from trainee versus experienced staff as the primary surgeon. AB - PURPOSE: To compare outcomes of conjunctival Mullerectomy with or without tarsectomy versus external levator advancement for correction of upper blepharoptosis when performed by trainee versus staff surgeons. DESIGN: Retrospective, nonrandomized, interventional, consecutive case series. METHODS: Charts of patients undergoing conjunctival Mullerectomy with or without tarsectomy and external levator advancement blepharoptosis repair from January 2006 through December 2009 were reviewed. Main outcome measures included age, gender, preoperative and postoperative use of artificial tears, preoperative and postoperative marginal reflex distance, surgical complications, surgeon (trainee or staff surgeon), and anesthesia time. The Student t test was used for statistical analysis. RESULTS: A total of 170 patients underwent 248 surgeries (154 conjunctival Mullerectomies with or without tarsectomy and 94 external levator advancements). There were 108 female and 62 male patients. Mean patient age was 62 years (range, 3 to 94 years). Forty-one (24%) patients (26 conjunctival Mullerectomies with or without tarsectomy and 15 external levator advancements) underwent concurrent eyelid surgery, such as blepharoplasty. Trainees performed surgery on a total of 88 (35%) eyelids in 60 patients (35%). There was no significant difference in the percentage of cases undergoing concomitant surgery between trainee and staff surgeons (P = .18). The mean postoperative marginal reflex distance difference was 0.53 and 0.59 for trainee and staff surgeons, respectively. Mean overall anesthesia time was 26.8 minutes and 30.3 minutes for trainee and staff surgeons, respectively. Complications, including increase in dry eye or irritative symptoms and reoperation, occurred in 8 (13%) of 60 patients undergoing surgery by a trainee surgeon and in 22 (20%) of 110 patients undergoing surgery by staff surgeon. There was no significant difference in eyelid symmetry (P = .55), mean anesthesia time (P = .14), complication rate (P = .26), or reoperation rate (P = .17) when surgery was performed by a trainee versus a staff surgeon. CONCLUSIONS: There is no significant difference in mean postoperative marginal reflex distance, mean anesthesia time, complication rate, or reoperation rate between either conjunctival Mullerectomy with or without tarsectomy or external levator advancement blepharoptosis repair performed by trainee versus staff surgeons. PMID- 23111185 TI - Pluripotent stem cells as a model to study oxygen metabolism in neurogenesis and neurodevelopmental disorders. AB - Reactive oxygen species (ROS) and oxygen (O2) have been implicated in neurogenesis and self-renewal of neural progenitor cells (NPCs). On the other hand, oxidative unbalance, either by an impairment of antioxidant defenses or by an intensified production of ROS, is increasingly related to risk factors of neurodevelopmental disorders, such as schizophrenia. In this scenario, human induced pluripotent stem cells (hiPSCs) emerged as an interesting platform for the study of cellular and molecular aspects of this mental disorder, by complementing other experimental models, with exclusive advantages such as the recapitulation of brain development. Herein we discuss the role of O2/ROS signaling for neuronal differentiation and how its unbalance could be related to neurodevelopmental disorders, such as schizophrenia. Identifying the role of O2/ROS in neurogenesis as well as tackling oxidative stress and its disturbances in schizophrenic patients' derived cells will provide an interesting opportunity for the study of neural stem cells differentiation and neurodevelopmental disorders. PMID- 23111184 TI - Length-dependent effects on cardiac contractile dynamics are different in cardiac muscle containing alpha- or beta-myosin heavy chain. AB - Actomyosin crossbridges (XBs) are the fundamental source of force generation and pressure development in the myocardium. Faster kinetics are imparted on XBs comprised of the fast, alpha-myosin heavy chain (MHC) isoform, whereas slower kinetics are imparted on XBs comprised of the slow, beta-MHC isoform. Other factors, such as sarcomere length (SL), influence XB formation, presumably acting through allosteric effects on the kinetics that regulate the XB cycle. We sought to determine whether the slower XB kinetics of beta-MHC were more sensitive to such length-dependent effects than those of alpha-MHC. We studied the SL effects on mechanical properties of demembranated muscle fibers from normal and propylthiouracil-treated mouse hearts, which expressed predominantly alpha-MHC or beta-MHC, respectively. Interestingly, XB detachment kinetics were more length sensitive in beta-MHC fibers, as estimated by tension cost and XB detachment rate constant (c), and as inferred by ktr. The nonlinearity in force responses to various-amplitude step-like changes in muscle length was more pronounced in beta MHC fibers. This phenomenon is attributed to a greater cooperative/allosteric mechanism in beta-MHC fibers, as estimated by model parameter gamma. These data suggest a mechanism whereby greater cooperative/allosteric effects impart an enhanced length-sensitivity of XB cycling kinetics in fibers containing the slower cycling beta-MHC. PMID- 23111187 TI - The prevalence of upright non-stepping time in comparison to stepping time in 11 13 year old school children across seasons. AB - Evidence suggests that behaviours such as standing are beneficial for our health. Unfortunately, little is known of the prevalence of this state, its importance in relation to time spent stepping or variation across seasons. The aim of this study was to quantify, in young adolescents, the prevalence and seasonal changes in time spent upright and not stepping (UNSt(time)) as well as time spent upright and stepping (USt(time)), and their contribution to overall upright time (U(time)). Thirty-three adolescents (12.2 +/- 0.3 y) wore the activPAL activity monitor during four school days on two occasions: November/December (winter) and May/June (summer). UNSt(time) contributed 60% of daily U(time) at winter (Mean = 196 min) and 53% at summer (Mean = 171 min); a significant seasonal effect, p < 0.001. USt(time) was significantly greater in summer compared to winter (153 min versus 131 min, p < 0.001). The effects in UNSt(time) could be explained through significant seasonal differences during the school hours (09:00-16:00), whereas the effects in USt(time) could be explained through significant seasonal differences in the evening period (16:00-22:00). Adolescents spent a greater amount of time upright and not stepping than they did stepping, in both winter and summer. The observed seasonal effects for both UNSt(time) and USt(time) provide important information for behaviour change intervention programs. PMID- 23111186 TI - Role of Trp19 and Tyr200 in catalysis by the gamma-class carbonic anhydrase from Methanosarcina thermophila. AB - Although widely distributed in Nature, only two gamma class carbonic anhydrases are reported besides the founding member (Cam). Although roles for active-site residues important for catalysis have been identified in Cam, second shell residues have not been investigated. Two residues (Trp19 and Tyr200), positioned distant from the catalytic metal, were investigated by structural and kinetic analyses of replacement variants. Steady-state k(cat)/K(m) and k(cat) values decreased 3- to 10-fold for the Trp19 variants whereas the Y200 variants showed up to a 5-fold increase in k(cat). Rate constants for proton transfer decreased up to 10-fold for the Trp19 variants, and an increase of ~2-fold for Y200F. The pK(a) values for the proton donor decreased 1-2 pH units for Trp19 and Y200 variants. The variant structures revealed a loop composed of residues 62-64 that occupies a different conformation than previously reported. The results show that, although Trp19 and Y200 are non-essential, they contribute to an extended active-site structure distant from the catalytic metal that fine tunes catalysis. Trp19 is important for both CO(2)/bicarbonate interconversion, and the proton transfer step of catalysis. PMID- 23111189 TI - Treating chemobrain: rehabilitation therapies emerge. PMID- 23111188 TI - Adiponectin, body mass index and hepatic steatosis are independently associated with IGF-I status in obese non-diabetic women. AB - OBJECTIVE: Low IGF-I levels have been associated with obesity, insulin resistance, hepatic steatosis, and were shown to predict cardiovascular mortality. Adiponectin, on the other hand, was proved to have an important protective role against metabolic and cardiovascular diseases. This study investigates the relation between hepatic steatosis, adiponectin and IGF-I levels in a group of non-diabetic obese Romanian women. DESIGN: This cross-sectional study included 201 obese non-diabetic women, with mean age of 41.1+/-11.9 years and mean body mass index (BMI) of 44.1+/-8.3 kg/m(2), consecutively admitted to the Endocrinology Department of a University Hospital to be evaluated as candidates for bariatric surgery. Main measured parameters included total adiponectin (detected by ELISA method), insulin, C reactive protein (CRP), and IGF-I (all by chemiluminescence methods). Insulin sensitivity was assessed using the Quantitative Insulin Sensitivity Check Index (QUICKI). Patients were considered IGF-deficient if IGF-I z score was <=2 standard deviations from mean for age. Hepatic ultrasound was used to determine the presence of significant steatosis (SS+). RESULTS: Significant steatosis was observed in 60.7% of our patients and this feature was associated with reduced total adiponectin levels (p<0.001) and lower IGF-I z scores (p<0.001). IGF-I z score negatively correlated with BMI (r=-0.283, p<0.001), alanine aminotransferase (ALT) (r=-0.130, p=0.032), gamma glutamyltransferase (GGT) (r=-0.158, p=0.018) and logarithmic transformed (log) CRP (r=-0.232, p=0.001) and positively correlated with QUICKI (r=0.148, p=0.023) and log adiponectin (r=0.216, p=0.003). The relationship between IGF-I z score and log adiponectin remained significant after adjusting for age, BMI, ALT, QUICKI and log CRP (r=0.183, p=0.012). IGF-I deficiency was present in 33.3% of these obese women. In multivariate logistic analysis, BMI (p<0.001), ALT (p=0.003), log adiponectin (p<0.001) and SS (p=0.043) proved to be independently associated with IGF-I deficiency. CONCLUSIONS: Adiponectin is significantly correlated with IGF-I z scores and, along with BMI, ALT and significant steatosis, is independently associated with IGF-I deficiency in obese non diabetic women. PMID- 23111190 TI - Circulating tumor cells in early-stage breast cancer. PMID- 23111192 TI - Myeloproliferative cancers: treatment prospects for rare diseases. PMID- 23111193 TI - Myelodysplastic syndrome and benzene exposure among petroleum workers: an international pooled analysis. AB - BACKGROUND: Benzene at high concentrations is known to cause acute myeloid leukemia (AML), but its relationship with other lymphohematopoietic (LH) cancers remains uncertain, particularly at low concentrations. In this pooled analysis, we examined the risk of five LH cancers relative to lower levels of benzene exposure in petroleum workers. METHODS: We updated three nested case-control studies from Australia, Canada, and the United Kingdom with new incident LH cancers among petroleum distribution workers through December 31, 2006, and pooled 370 potential case subjects and 1587 matched LH cancer-free control subjects. Quantitative benzene exposure in parts per million (ppm) was blindly reconstructed using historical monitoring data, and exposure certainty was scored as high, medium, or low. Two hematopathologists assigned diagnoses and scored the certainty of diagnosis as high, medium, or low. Dose-response relationships were examined for five LH cancers, including the three most common leukemia cell-types (AML, chronic myeloid leukemia [CML], and chronic lymphoid leukemia [CLL]) and two myeloid tumors (myelodysplastic syndrome [MDS] and myeloproliferative disease [MPD]). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression, controlling for age, sex, and time period. RESULTS: Cumulative benzene exposure showed a monotonic dose-response relationship with MDS (highest vs lowest tertile, >2.93 vs <=0.348 ppm-years, OR = 4.33, 95% CI = 1.31 to 14.3). For peak benezene exposures (>3 ppm), the risk of MDS was increased in high and medium certainty diagnoses (peak exposure vs no peak exposure, OR = 6.32, 95% CI = 1.32 to 30.2) and in workers having the highest exposure certainty (peak exposure vs no peak exposure, OR = 5.74, 95% CI = 1.05 to 31.2). There was little evidence of dose-response relationships for AML, CLL, CML, or MPD. CONCLUSIONS: Relatively low-level exposure to benzene experienced by petroleum distribution workers was associated with an increased risk of MDS, but not AML, suggesting that MDS may be the more relevant health risk for lower exposures. PMID- 23111194 TI - CDKN2A (p16) promoter hypermethylation influences the outcome in young lung cancer patients. AB - PURPOSE: Non-small cell lung cancer (NSCLC) occurs most frequently in individuals older than 60 years of age. Currently, no biological indicators associated with NSCLC in younger patients (30 to 60 y) have been identified. To explore epigenetic influences, promoter methylation of selected tumor suppressor genes was analyzed in early-stage NSCLC patients ranging in age from 30 to 87 years at diagnosis. EXPERIMENTAL DESIGN: The analysis was performed on formalin-fixed tumor tissue from 193 surgically treated NSCLC patients (127, older than 60 y; 66, 60 y and younger). Methylation was quantified in p16, MGMT, DAPK, RASSF1, CDH1, LET7-3-a, NORE1(RASSF5), and PTEN promoters by pyrosequencing. p16 protein expression was assessed by immunohistochemistry (IHC). Outcome, defined by time to recurrence and overall survival, was evaluated by Kaplan-Meier analysis. RESULTS: Promoter methylation levels were generally higher in patients older than 60 years of age than in patients 60 years or younger at diagnosis. Of the genes tested, methylation levels of the p16 promoter showed age-related differences. Although p16 promoter methylation was significantly lower using cut-points of 50 years or younger and 40 years or younger (P=0.001 to 0.012, respectively), p16 protein expression increased with age. Patients 60 years or younger with p16 promoter hypermethylation had a significantly shortened time to recurrence (P=0.002) and a shortened survival time (P=0.011). No effect of p16 hypermethylation was seen in patients older than 60 years. CONCLUSIONS: p16 promoter hypermethylation was associated with a worse outcome in patients with age at diagnosis of 60 years or younger, but was not associated with the outcome in the older than 60-year age group. Overall, these data support methylation dependent and methylation-independent age-related regulation of p16 expression with differential effects on the outcome after surgical resection for early-stage NSCLC. PMID- 23111195 TI - Clinical and molecular findings of ataxia with oculomotor apraxia type 2 (AOA2) in 5 Tunisian families. AB - Ataxia with oculomotor apraxia type 2 (AOA2) is a recently described autosomal recessive cerebellar ataxia caused by mutations in the SETX gene. It is a rare monogenic disease characterized by progressive cerebellar ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and an elevated serum alpha-fetoprotein level. To date, >100 AOA2 patients have been described and 75 different mutations in the SETX gene have been identified. We report here the clinical and genetic findings of 13 AOA2 patients from 5 unrelated Tunisian consanguineous families. DNA was collected from probands and available family members, and the 24 SETX exons were screened by direct sequencing. Four different homozygous SETX gene mutations were identified. The missense mutation 915G>T [W305C] has been described previously in Algeria. The 3 other SETX mutations are novel, including a missense mutation c.7231C>T [R 2380 W], a nonsense mutation c.6475 C>T [R2098X], and a deletion c.7180-7183delAAAA [D2332fsX2343]. More extensive screening by molecular genetic analysis of SETX in patients with Friedreich ataxia-like phenotype may show that AOA2 is more common in Tunisia than previously thought. PMID- 23111196 TI - Reduction in WT1 gene expression during early treatment predicts the outcome in patients with acute myeloid leukemia. AB - Wilms tumor gene 1 (WT1) expression has been suggested as an applicable minimal residual disease marker in acute myeloid leukemia (AML). We evaluated the use of this marker in 43 adult AML patients. Quantitative assessment of WT1 gene transcripts was performed using real-time quantitative-polymerase chain reaction assay. Samples from both the peripheral blood and the bone marrow were analyzed at diagnosis and during follow-up. A strong correlation was observed between WT1 normalized with 2 different control genes (beta-actin and ABL1, P<0.001). WT1 mRNA level at diagnosis was of no prognostic relevance (P>0.05). A>=1-log reduction in WT1 expression in bone marrow samples taken <1 month after diagnosis significantly correlated with an improved overall survival (P=0.004) and freedom from relapse (P=0.010) when beta-actin was used as control gene. Furthermore, a reduction in WT1 expression by >=2 logs in peripheral blood samples taken at a later time point significantly correlated with a better outcome for overall survival (P=0.004) and freedom from relapse (P=0.012). This result was achieved when normalizing against both beta-actin and ABL1. These results therefore suggest that WT1 gene expression can provide useful information for minimal residual disease detection in adult AML patients and that combined use of control genes can give more informative results. PMID- 23111197 TI - Multiplex ligation-dependent probe amplification (MLPA) in tumor diagnostics and prognostics. AB - The increasing knowledge about genetic alterations and molecular biomarkers in cancer initiation and progression opens new possibilities for the treatment of various types of cancer. This requires the inclusion of sensitive, and preferably multiplex, methods for the detection of molecular genetic alterations in the toolbox of classic pathology. Multiplex ligation-dependent probe amplification (MLPA) is a multiplex polymerase chain reaction-based method that can detect changes in the gene copy number status, DNA methylation, and point mutations simultaneously. MLPA probes recognize target sequences of only 50 to 100 nucleotides in length. This makes it possible to use MLPA even on highly fragmented DNA, and allows the detection of small deletions encompassing only a single exon. MLPA is a reliable, cost-effective, and robust method that can be performed using a standard thermocycler and capillary electrophoresis equipment, generating results within 24 hours with a short hands-on working time. Up to 50 different genomic locations can be tested in a single reaction, which can be sufficient to detect those genetic alterations that are of diagnostic and prognostic significance in a certain tumor entity. In the last years, MLPA has been used successfully in tumor diagnostics and in cancer research. This review gives an overview on the collected experience of MLPA applications on tumor DNA, about the advantages but also potential pitfalls and limitations of this technique. PMID- 23111198 TI - Pyrosequencing of IDH1 and IDH2 mutations in brain tumors and non-neoplastic conditions. AB - The molecular profiling of brain tumors, including testing for MGMT promoter methylation and chromosome 1p/19q deletion, can provide both diagnostic and prognostic information that may guide treatment. Isocitrate dehydrogenase (IDH) mutation testing is a recent addition to this armamentarium of molecular pathology tools that similarly provides both diagnostic (eg, glioma vs. gliosis) and prognostic information. Herein, we describe a pyrosequencing-based approach to IDH1 and IDH2 mutation testing and its application to 139 neoplastic and non neoplastic central nervous system specimens. Several technical issues encountered in the development of the assay, particularly with regard to the optimization of the sequencing reaction, are described. Mutations in IDH1 codon 132 or IDH2 codon 172 were identified in 31.2% of all screened cases and 46.2% of screened World Health Organization grade I to IV gliomas (n=93), with mutations arising exclusively in grade II to IV oligodendroglial, astrocytic, or mixed oligoastrocytic neoplasms. Examination of the relationship between the mutation status and other pertinent variables demonstrated a significant male predominance among IDH1-mutated gliomas, most notably in grade III to IV astrocytic neoplasms. A significant association between IDH1/IDH2 mutation and 1p/19q deletion was also seen (Kendall tau coefficient=0.26, P=0.018), although several cases with 1p/19q deletion were IDH1/IDH2 wild type. PMID- 23111199 TI - More breast cancer metastases found in nonsentinel lymph nodes using a novel molecular method. PMID- 23111200 TI - Biphasic papillary and lobular breast carcinoma with PIK3CA and IDH1 mutations. AB - Morphologic "special types" of breast carcinomas have been recognized for many years, and their molecular and genetic properties have not been specifically studied until recently. Lobular carcinoma lacks functional E-cadherin expression but shares molecular similarities with low-grade invasive ductal carcinomas. Papillary carcinoma is relatively rare, and molecular features are just being elucidated. We report a case of concurrent invasive lobular and papillary carcinoma, the latter with extensive nodal involvement. Multiplex screening for activating point mutations identified different point mutations in the distinct morphologic components: lobular PIK3CA H1047R, papillary; PIK3CA Q546P, and IDH1 R132H. These molecular data favor coincidental "collision tumors" over clonal evolution. The IDH1 R132H point mutation is common in gliomas and acute myelogenous leukemia, but this has not been previously reported in breast carcinoma. The characterization of activating point mutations in morphologic special types of breast carcinoma may suggest avenues amenable to targeted therapy. PMID- 23111201 TI - Mitochondria malfunctions as mediators of stem-cells' related carcinogenesis: a hypothesis that supports the highly conserved profile of carcinogenesis. AB - Cancer development is an evolutionary process that has been highly conserved among centuries within organisms. Based on this, the interest in cancer research focuses on cells, organelles and genes that possess a genetic conservatism from yeasts to human. Towards this thought, mitochondria, the highly conserved and responsible for the cellular bioenergetic activity organelles, might play crucial role in carcinogenesis. Interestingly, tumors with low bioenergetic signature have worse prognosis and show a decreased expression of ATPase protein. Furthermore, according to the stem-cell theory of carcinogenesis, aggressive tumors are characterized by an increase number of malignant stem-like cell population and their resistance to chemotherapy has been found to be mitochondrially driven. The above considerations triggered us to hypothesize that mitochondrial bioenergetic processes in stem-like cancer cells plays a crucial role in the highly conserved process of carcinogenesis. Specifically, we support that mitochondrial and/or nuclear DNA alterations that control stem cells' ATP production drive stem cells to "immortalization" (Otto Warburg theory) that mediates cancer initiation and progression. Substantiation of our hypothesis requires evidence that: (1) alterations in mitochondria bioenergetic metabolites and enzymes encoded either from the mtDNA or the nuclear DNA are linked to human cancer and (2) mitochondrial functions are regulated by highly conserved genes involved in cancer-related cellular processes such as apoptosis, aging and autophagy. Experimental approach on how this hypothesis might be tested and promising strategies in cancer therapeutics are also discussed. In case the hypothesis of stem-cell bioenergetic malformations' related carcinogenesis proves to be correct, it would contribute to the development of new prognostic, diagnostic and even more effective therapeutic interventions against various types of cancer. PMID- 23111202 TI - Does Restless Legs Syndrome increase cardiovascular risk in Attention Deficit/Hyperactivity Disorder? AB - Preliminary evidence suggests a possible association between Attention Deficit/Hyperactivity Disorder and Restless Legs Syndrome with or without Periodic Limb Movements during Sleep. When comorbid, Restless Legs Syndrome/Periodic Limb Movements during Sleep might aggravate Attention Deficit/Hyperactivity Disorder symptoms. Pharmacological treatment of Attention Deficit/Hyperactivity Disorder may be associated, at least in some cases, with adverse cardiovascular events, including clinically significant elevation in heart rate and systemic blood pressure. However, the characteristics of patients with Attention-Deficit/Hyperactivity Disorder at risk for cardiovascular events during pharmacological treatment are poorly understood. Here, we hypothesize that Restless Legs Syndrome and/or Periodic Limb Movements during Sleep comorbid with Attention-Deficit/Hyperactivity Disorder increase cardiovascular risk via imbalance in activity of the autonomic nervous system. Such an imbalance of the could be related to alterations of sleep microarchitecture also detected by cyclic alternating pattern analysis. If empirical studies confirm our hypothesis, the clinician would be advised to systematically screen for and effectively treat Restless Legs Syndrome/Periodic Limb Movements during Sleep even before starting treatment with Attention-Deficit/Hyperactivity Disorder drugs. The management of Restless Legs Syndrome/Periodic Limb Movements during Sleep might reduce cardiovascular risk during pharmacological treatment of Attention Deficit/Hyperactivity Disorder. PMID- 23111203 TI - Gold nanoparticles: emerging paradigm for targeted drug delivery system. AB - The application of nanotechnology in medicine, known as nanomedicine, has introduced a plethora of nanoparticles of variable chemistry and design considerations for cancer diagnosis and treatment. One of the most important field is the design and development of pharmaceutical drugs, based on targeted drug delivery system (TDDS). Being inspired by physio-chemical properties of nanoparticles, TDDS are designed to safely reach their targets and specifically release their cargo at the site of disease for enhanced therapeutic effects, thereby increasing the drug tissue bioavailability. Nanoparticles have the advantage of targeting cancer by simply being accumulated and entrapped in cancer cells. However, even after rapid growth of nanotechnology in nanomedicine, designing an effective targeted drug delivery system is still a challenging task. In this review, we reveal the recent advances in drug delivery approach with a particular focus on gold nanoparticles. We seek to expound on how these nanomaterials communicate in the complex environment to reach the target site, and how to design the effective TDDS for complex environments and simultaneously monitor the toxicity on the basis of designing such delivery complexes. Hence, this review will shed light on the research, opportunities and challenges for engineering nanomaterials with cancer biology and medicine to develop effective TDDS for treatment of cancer. PMID- 23111204 TI - Resseguier method and Qi Gong sequentially integrated in patients with fibromyalgia syndrome. AB - OBJECTIVES: In fibromyalgia syndrome (FMS), the Resseguier Method (RM) and Qi Gong (QG) can be efficacious. QG aims to improve posture, respiration, concentration, while RM aims to obtain patient awareness and control of pain perception. We evaluate 2 protocols integrating RM and QG in FMS. METHODS: Thirty FMS patients were assigned to Group 1, treated by RM and then by QG or Group 2, treated by QG and then by RM. In both protocols, patients are treated 7 weeks by each technique (with 1 week interval), and followed up for 12 weeks. Patients were assessed at T0, at end of 1st (T1) and 2nd intervention (T2), at follow-up (FU) by number rating scale (NRS) for sleep quality and pain, Regional Pain Scale (RPS),Tender Points (TPs), FIQ, HAQ, SF36, HADS for anxiety and depression (HADS a/d). RESULTS: In Group 1 at T1 (after RM), NRS for pain, RPS, FIQ, HAQ were reduced, HADS-a and SF36 ameliorated; at T2 (after QG) FIQ were further reduced and TPs and HADS-d improved; HADS-a and SF36 maintained. In Group 2 at T1 (after QG), NRS for pain, RPS, TPs, FIQ, HAQ, reduced with reduction maintained at T2 (after RM). HADS-a and -d and SF36 ameliorated at T1, with improvement confirmed at T2; sleep quality ameliorated only at T2. Effects of both protocols are similar at T2 and maintained at FU. CONCLUSIONS: In FMS, both protocols improve pain, disability, quality of life, tenderness, anxiety. RM also ameliorates sleep and QG improves depression. Sequential integration of RM and QG is efficacious in FMS. PMID- 23111205 TI - Accurate prediction of pregnancy viability by means of a simple scoring system. AB - STUDY QUESTION: What is the performance of a simple scoring system to predict whether women will have an ongoing viable intrauterine pregnancy beyond the first trimester? SUMMARY ANSWER: A simple scoring system using demographic and initial ultrasound variables accurately predicts pregnancy viability beyond the first trimester with an area under the curve (AUC) in a receiver operating characteristic curve of 0.924 [95% confidence interval (CI) 0.900-0.947] on an independent test set. WHAT IS KNOWN ALREADY: Individual demographic and ultrasound factors, such as maternal age, vaginal bleeding and gestational sac size, are strong predictors of miscarriage. Previous mathematical models have combined individual risk factors with reasonable performance. A simple scoring system derived from a mathematical model that can be easily implemented in clinical practice has not previously been described for the prediction of ongoing viability. STUDY DESIGN, SIZE AND DURATION: This was a prospective observational study in a single early pregnancy assessment centre during a 9-month period. PARTICIPANTS/MATERIALS, SETTING AND METHODS: A cohort of 1881 consecutive women undergoing transvaginal ultrasound scan at a gestational age <84 days were included. Women were excluded if the first trimester outcome was not known. Demographic features, symptoms and ultrasound variables were tested for their influence on ongoing viability. Logistic regression was used to determine the influence on first trimester viability from demographics and symptoms alone, ultrasound findings alone and then from all the variables combined. Each model was developed on a training data set, and a simple scoring system was derived from this. This scoring system was tested on an independent test data set. MAIN RESULTS AND THE ROLE OF CHANCE: The final outcome based on a total of 1435 participants was an ongoing viable pregnancy in 885 (61.7%) and early pregnancy loss in 550 (38.3%) women. The scoring system using significant demographic variables alone (maternal age and amount of bleeding) to predict ongoing viability gave an AUC of 0.724 (95% CI = 0.692-0.756) in the training set and 0.729 (95% CI = 0.684-0.774) in the test set. The scoring system using significant ultrasound variables alone (mean gestation sac diameter, mean yolk sac diameter and the presence of fetal heart beat) gave an AUC of 0.873 (95% CI = 0.850-0.897) and 0.900 (95% CI = 0.871-0.928) in the training and the test sets, respectively. The final scoring system using demographic and ultrasound variables together gave an AUC of 0.901 (95% CI = 0.881-0.920) and 0.924 (CI = 0.900-0.947) in the training and the test sets, respectively. After defining the cut-off at which the sensitivity is 0.90 on the training set, this model performed with a sensitivity of 0.92, specificity of 0.73, positive predictive value of 84.7% and negative predictive value of 85.4% in the test set. LIMITATIONS, REASONS FOR CAUTION: BMI and smoking variables were a potential omission in the data collection and might further improve the model performance if included. A further limitation is the absence of information on either bleeding or pain in 18% of women. Caution should be exercised before implementation of this scoring system prior to further external validation studies WIDER IMPLICATIONS OF THE FINDINGS: This simple scoring system incorporates readily available data that are routinely collected in clinical practice and does not rely on complex data entry. As such it could, unlike most mathematical models, be easily incorporated into normal early pregnancy care, where women may appreciate an individualized calculation of the likelihood of ongoing pregnancy viability. STUDY FUNDING/COMPETING INTEREST(S): Research by V.V.B. supported by Research Council KUL: GOA MaNet, PFV/10/002 (OPTEC), several PhD/postdoc & fellow grants; IWT: TBM070706-IOTA3, PhD Grants; IBBT; Belgian Federal Science Policy Office: IUAP P7/(DYSCO, 'Dynamical systems, control and optimization', 2012-2017). T.B. is supported by the Imperial Healthcare NHS Trust NIHR Biomedical Research Centre. TRIAL REGISTRATION NUMBER: Not applicable. PMID- 23111206 TI - Synoptic philosophy in a neurosurgical residency: a book and cinema club. AB - Introduction of a book and cinema club in a Department of Neurosurgery has helped combine an education in humanities with neurosurgical training. The authors believe the addition of teaching in humanities adds to the specialty and helps in fulfilling the six core competencies of the Accreditation Council for Graduate Medical Education. The goal is to encourage synoptic philosophy and impart creative ways of interacting with the world. Books and movies with a medical basis and nonmedical basis were selected and reviewed in an open forum. Efforts were made to integrate the Accreditation Council for Graduate Medical Education six core competencies into the discussions. Residents anonymously completed a questionnaire pertaining to the usefulness of the book club in residency. There were 13 residents who attended the sessions and responded to the questionnaire. Of residents, 61.5% believed the topics were pertinent to their everyday life, and 77% believed that the club had helped them somehow in residency. Most (7 of 13) believed the club should not be included as part of the curriculum in an 80 hour work week. Institution of a book and movie club seems to be an effective way of integrating humanities within a neurosurgical residency. PMID- 23111207 TI - Epidemiology and long-term mortality in subarachnoid hemorrhage. PMID- 23111208 TI - Surgical freedom: a challenging topic in endoscopic endonasal approaches. PMID- 23111209 TI - Trigeminal neuralgia: a new neuroimaging perspective. PMID- 23111210 TI - Decompressive craniectomies: time to discuss not the DECRA study but the comments to the DECRA study. PMID- 23111211 TI - Local African concerns on multi-institutional neurosurgical training initiative at a tertiary referral center in Mwanza, Tanzania. PMID- 23111212 TI - Stupid mistakes. PMID- 23111213 TI - Assessment of postoperative hypocortisolism after pituitary surgery: when and how? PMID- 23111214 TI - Hemodynamic derangements with hydrogen peroxide instillation in neurosurgery: need for awareness among anesthesiologists and surgeons. PMID- 23111215 TI - Reflections on stem cell research for spine applications. PMID- 23111216 TI - Considering the cost of spine surgeries: is it necessary? PMID- 23111217 TI - The above-and-below endonasal transsphenoidal corridor to the retroinfundibular area: how to spin around the pituitary gland. PMID- 23111218 TI - Treatment of synovial cysts: a matter of debate. PMID- 23111219 TI - Yes, we CAN! PMID- 23111220 TI - Which side tips the scale for recurrent craniopharyngiomas? PMID- 23111221 TI - A perspective on craniopharyngioma. PMID- 23111222 TI - Toward clarity of management options in spinal synovial cysts. PMID- 23111223 TI - In reply. PMID- 23111224 TI - Is preoperative detection of neurovascular conflict in cranial nerves neuralgia improving clinical results. PMID- 23111225 TI - Clip reconstruction of midbasilar aneurysms. PMID- 23111226 TI - Reconstructing the "skull base" divide. PMID- 23111227 TI - Laterosellar compartment or cavernous sinus? What's the correct term? PMID- 23111228 TI - Bone morphogenetic protein and complications in spinal fusion surgery. PMID- 23111229 TI - Stereotactic radiosurgery for cavernous malformations: is it effective? PMID- 23111230 TI - Deep brain stimulation for treatment-resistant depression. AB - BACKGROUND: Major depressive disorder is a common and disabling illness and is the leading cause of disability worldwide. Despite aggressive medical, behavioral, and electroconvulsive therapies, a significant number of patients remain refractory to treatment. Deep brain stimulation (DBS) has proven efficacy in neurobehavioral disorders and, in a general sense, works by modulation of corticostriatopallidothalamocortical circuits implicated in these disorders. METHODS: Current data, treatment rationales, and future directions are presented. RESULTS: The two targets most commonly used for DBS in treatment-resistant depression are the subgenual cingulate gyrus and the ventral capsule/ventral striatum. Data on DBS of these regions are preliminary, with promise shown in early studies. CONCLUSIONS: Early work suggests DBS may become a therapeutic option in treatment-resistant depression. Further study is justified given the immense burden of disease. PMID- 23111231 TI - Current situation of neurosurgery in Central America: an analysis and suggestions for improvement. PMID- 23111232 TI - Changing neurosurgical experiences: the Iran-Iraq war and operation Iraqi freedom. PMID- 23111233 TI - Endoscopic carpal tunnel release. PMID- 23111235 TI - Launching plasmonic Bloch waves with excited dye molecules. AB - In this paper, we will demonstrate that excited dye molecules can be used to launch the plasmonic Bloch waves (PBWs) propagating at multi-metal-dielectric interfaces. The properties of the PBWs, such as wavevectors, propagating bands, the interface and grating period effect, were characterized by a leakage radiation microscope. Theoretical simulations were also carried out to reveal the properties of the PBWs and were consistent with the experimental results. What is more, experimental results reveal an interesting phenomenon: the PBWs launched by the excited dye molecules present different optical behaviors from those launched by far-field laser beams through attenuated total reflection. The mechanism of this difference was analyzed based on the energy conversion between the optical near-field and far-field. Our work provides a new way to launch the PBWs. Further, the coupling between the dye molecules and PBWs also demonstrates a new method to manipulate the fluorescence emission from random to controllable. PMID- 23111234 TI - Rapid sequence magnetic resonance imaging in the assessment of children with hydrocephalus. AB - OBJECTIVE: Recent reports have shown the utility of rapid-acquisition magnetic resonance imaging (MRI) in the evaluation of children with hydrocephalus. Rapid sequence MRI (RS-MRI) acquires clinically useful images in seconds without exposing children to the risks of ionizing radiation or sedation. We review our experience with RS-MRI in children with shunts. METHODS: Overall image quality, cost, catheter visualization, motion artifact, and ventricular size were reviewed for all RS-MRI studies obtained at Seattle Children's Hospital during a 2-year period. Image acquisition time was 12-19 seconds, with sessions usually lasting less than 3 minutes. RESULTS: Image quality was very good or excellent in 94% of studies, whereas only one was graded as poor. Significant motion artifact was noted in 7%, whereas 77% had little or no motion artifact. Catheter visualization was good or excellent in 57%, poor in 36%, and misleading in 7%. Small ventricular size was correlated with poor catheter visualization (Spearman's rho = 0.586; P < 0.00001). RS-MRI imaging cost ~$650 more than conventional computed tomography (CT). CONCLUSIONS: Our study supports that RS-MRI is an adequate substitute that allows reduced use of CT imaging and resultant exposure to ionizing radiation. Catheter position visualization remains suboptimal when ventricles are small, but shunt malfunction can be adequately determined in most cases. The cost is significantly more than CT, but the potential for lifetime reduction in radiation exposure may justify this expense in children. Limitations include the risk of valve malfunction after repeated exposure to high magnetic fields and the need for reprogramming with many types of adjustable valves. PMID- 23111236 TI - Stevens-Johnson syndrome/toxic epidermal necrolysis mouse model generated by using PBMCs and the skin of patients. AB - BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous reactions caused by drugs or infections and exhibiting widespread epidermal necrosis. Currently, there is no animal model that reproduces SJS/TEN symptoms. OBJECTIVE: We sought to develop a novel mouse model of SJS/TEN by using PBMCs and skin from patients who had recovered from SJS/TEN. METHODS: For our mouse model, patients' PBMCs were injected intravenously into immunocompromised NOD/Shi-scid, IL-2Rgamma(null) (NOG) mice, followed by oral administration of a causative drug. Subsequently, to replace human skin, unaffected skin specimens obtained from patients who had recovered from SJS/TEN were grafted onto NOG mice, after which patient-derived PBMCs and the causative drug were applied. RESULTS: Mice injected with PBMCs from patients with SJS/TEN and given the causative drug showed marked conjunctival congestion and numerous cell death of conjunctival epithelium, whereas there were no symptoms in mice injected with PBMCs from patients with ordinary drug skin reactions. CD8(+) T lymphocyte-depleted PBMCs from patients with SJS/TEN did not elicit these symptoms. In addition, skin-grafted mice showed darkening of the skin-grafted areas. Cleaved caspase-3 staining showed that dead keratinocytes were more numerous in the skin-grafted mice than in the healthy control animals. CONCLUSION: We have established a novel human-oriented SJS/TEN mouse model and proved the importance of CD8(+) T lymphocytes in SJS/TEN pathogenesis. The mouse model promises to promote diagnostic and therapeutic approaches. PMID- 23111237 TI - TGF-beta1 polymorphisms and asthma severity, airway inflammation, and remodeling. PMID- 23111238 TI - Development of dendrite polarity in Drosophila neurons. AB - BACKGROUND: Drosophila neurons have dendrites that contain minus-end-out microtubules. This microtubule arrangement is different from that of cultured mammalian neurons, which have mixed polarity microtubules in dendrites. RESULTS: To determine whether Drosophila and mammalian dendrites have a common microtubule organization during development, we analyzed microtubule polarity in Drosophila dendritic arborization neuron dendrites at different stages of outgrowth from the cell body in vivo. As dendrites initially extended, they contained mixed polarity microtubules, like mammalian neurons developing in culture. Over a period of several days this mixed microtubule array gradually matured to a minus-end-out array. To determine whether features characteristic of dendrites were localized before uniform polarity was attained, we analyzed dendritic markers as dendrites developed. In all cases the markers took on their characteristic distribution while dendrites had mixed polarity. An axonal marker was also quite well excluded from dendrites throughout development, although this was perhaps more efficient in mature neurons. To confirm that dendrite character could be acquired in Drosophila while microtubules were mixed, we genetically disrupted uniform dendritic microtubule organization. Dendritic markers also localized correctly in this case. CONCLUSIONS: We conclude that developing Drosophila dendrites initially have mixed microtubule polarity. Over time they mature to uniform microtubule polarity. Dendrite identity is established before the mature microtubule arrangement is attained, during the period of mixed microtubule polarity. PMID- 23111239 TI - Collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma. AB - BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal neoplasia in the gastrointestinal tract, although they represent only a small fraction of total gastrointestinal malignancies in adults (<2%). GISTs can be located at any level of the gastrointestinal tract; the stomach is the most common location (60-70%), in contrast to the rectum, which is most rare (4%). When a GIST invades into the adjacent prostate tissue, it can simulate prostate cancer. In this study, we report on a case comprising the unexpected collision between a rectal GIST tumour and a prostatic adenocarcinoma. FINDINGS: We describe the complexity of the clinical, endoscopic and radiological diagnosis, of the differential diagnosis based on tumour biopsy, and of the role of neoadjuvant therapy using imatinib prior to surgical treatment. CONCLUSIONS: Although isolated cases of coexisting GISTs and prostatic adenocarcinomas have previously been described, this is the first reported case in the medical literature of a collision tumour involving a rectal GIST and prostatic adenocarcinoma components. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1238437468776331. PMID- 23111240 TI - Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women. AB - BACKGROUND: Recent attention has been given to subclinical hypothyroidism, defined as an elevation of TSH (4.5-10 uIU/L) with T4 and T3 levels still within the normal range. Controversy exists about the proper lower limit of TSH that defines patients in the subclinical hypothyroidism range and about if/when subclinical hypothyroidism should be treated. Additional data are needed to examine the relationship between markers of thyroid function in the subclinical hypothyroidism range, biomarkers of health and ultimately health outcomes. OBJECTIVE: We aimed to assess the relationship between serum TSH levels in the 0.5-10 uIU/L range and serum cortisol in a cohort of healthy young men and women without clinical evidence of hypothyroidism. Based on data in frank hypothyroidism, we hypothesized that serum TSH levels would be positively correlated with serum cortisol levels, suggesting derangement of the cortisol axis even in subclinical hypothyroidism. METHODS: We conducted a cross sectional study in 54 healthy, young (mean 20.98 +/- 0.37 yrs) men (19) and women (35). Lab sessions took place at 1300 hrs where blood was drawn via indwelling catheter for later assessment of basal serum TSH, free T3, free T4, and cortisol levels. RESULTS: All but 1 participant had free T3 levels within the normal reference intervals; free T4 levels for all participants were within the normal reference intervals. Linear regression modeling revealed that TSH levels in the 0.5-10 uIU/L were significantly and positively correlated with cortisol levels. This positive TSH-cortisol relationship was maintained below the accepted 4.5 uIU/L subclinical hypothyroid cutoff. Separate regression analyses conducted by systematically dropping the TSH cutoff by 0.50 uIU/L revealed that the TSH cortisol relationship was maintained for TSH levels (uIU/L) <=4.0, <=3.5, <=3.0, and <=2.5 but not <=2.0. Linear regression modeling did not reveal a relationship between free T3 or free T4 levels and cortisol levels. CONCLUSIONS: Results suggest a positive relationship between TSH and cortisol in apparently healthy young individuals. In as much as this relationship may herald a pathologic disorder, these preliminary results suggest that TSH levels > 2.0 uIU/L may be abnormal. Future research should address this hypothesis further, for instance through an intervention study. PMID- 23111241 TI - Beneficial effects of ginsenoside-Rg1 on ischemia-induced angiogenesis in diabetic mice. AB - Neovascularization and the formation of collateral vessels are often impaired in diabetes mellitus (DM) population compared with non-diabetics. Alterations in vascular endothelial growth factor (VEGF) signaling and endothelial nitric oxide synthase (eNOS) dysfunction have been confirmed to play a crucial role in impaired neovascularization in diabetic mice. Accumulating data have suggested that Rg1, a main component of Panax ginseng, has the ability to promote tubulogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and that the mechanism involves increased expression level of VEGF as well as increased eNOS activation. Thus, we speculated that Rg1 might also have therapeutic effects on the impairment of neovascularization in diabetic individuals. The aim of the present study was to investigate whether Rg1 could improve angiogenesis in ischemic hindlimb of diabetic mice in vivo. Our data demonstrated that Rg1 treatment resulted in improved angiogenesis in the diabetic ischemic hindlimb, and the potential mechanism might involve increased eNOS activation, upregulated VEGF expression, and inhibited apoptosis. Our results suggest that Rg1 may be used as a novel and useful adjunctive drug for the therapy of peripheral arterial disease in DM. PMID- 23111242 TI - The effect of changes in referral behaviour following NICE guideline publication on agreement of examination findings between professionals in an established glaucoma referral refinement pathway: the Health Innovation & Education Cluster (HIEC) Glaucoma Pathways project. AB - AIM: To investigate whether the publication of the National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines had an effect on the agreement of examination findings between professionals involved in an established glaucoma referral refinement pathway. METHODS: To report inter-professional agreement for the clinical examination findings of optometrists with a special interest in glaucoma (OSI), optometrists with no specialist interest in glaucoma (non-OSI) and a glaucoma consultant. Part 1 investigated agreement between an OSI and consultant and part 2 investigated agreement of clinical findings between the non OSI and a specialist clinician (OSI or consultant). RESULTS: Part 1: Agreement between OSI and consultant in determining an abnormal intraocular pressure (IOP) (>21 mm Hg) expressed as a percentage positive predictive value (PPPV) was no different pre-NICE (60.6%) and post-NICE (61.4%, p=0.51) guidelines. PPPV for identification of an abnormal optic disc was better pre-NICE (60.6%) than post NICE (42.7%, p=0.02). The appropriate referral rate for patients referred by an OSI was higher pre-NICE (69.6%) than post-NICE (61.2%) (p=0.07). Part 2: The PPPV between non-OSI and specialist clinician for an abnormal IOP was better pre-NICE (62.5%) than post-NICE (50.9%, p=0.12). This was also observed for abnormal optic discs, 70.0% pre-NICE and 52.9% post-NICE (p=0.04). CONCLUSIONS: The accuracy for detecting an abnormal IOP by the OSI has remained unchanged post-NICE, but there was a reduction in accuracy in detecting an abnormal optic disc as well as the appropriate referral rate. For the non-OSI, there was a decline in both IOP and optic disc assessment accuracy. PMID- 23111243 TI - Immediate removal of posteriorly dislocated lens fragments through sclerocorneal incision during cataract surgery. PMID- 23111245 TI - Realizing full potential. PMID- 23111244 TI - Co-regulation of polar mRNA transport and lifespan in budding yeast Saccharomyces cerevisiae. AB - Recent studies have uncovered the links between aging, rejuvenation and polar protein transport in the budding yeast Saccharomyces cerevisiae. Here, we examined a still unexplored possibility for co-regulation of polar mRNA transport and lifespan. To monitor the amount and distribution of mRNA-containing granules in mother and daughter cells, we used a fluorescent mRNA-labeling system, with MFA2 as a reporter gene. The results obtained showed that deletion of the selected longevity regulators in budding yeast had a significant impact on the polar mRNA transport. This included changes in the amount of mRNA-containing granules in cytoplasm, their aggregation and distribution between the mother and daughter cells. A significant negative correlation was found between strain specific longevity, amount of granules and total fluorescent intensity both in mother and daughter cells. As indicated by the coefficient of determination, approximately 50-75% of variation in yeast lifespan could be attributed to the differences in polar mRNA transport. PMID- 23111246 TI - The importance of testing medical students' knowledge of what is least likely. PMID- 23111249 TI - More about the future of psychiatry education. PMID- 23111252 TI - Electronic health records: can we maximize their benefits and minimize their risks? PMID- 23111254 TI - Commentary: diversity and inclusion in the 21st century: bridging the moral and excellence imperatives. AB - There is prolific evidence of a commitment to diversifying student and faculty populations in academic medicine, but far less evidence of its effectiveness. The social justice underpinning of this commitment is important and must continue to undergird diversity and inclusion efforts. In today's environment of pinched resources, however, moral arguments alone will not suffice. What the diversity and inclusion movement needs for the 21st century is to apply rigorous empirical methods to understanding the most effective and efficient interventions to contribute to institutional excellence.The collection of diversity and inclusion articles in this month's issue of Academic Medicine is quite comprehensive and speaks to a range of audiences, from those who consider themselves experts on diversity and inclusion to the casual and interested reader. This robust collection will afford diversity practitioners, institutional leaders, and policy influencers with greater insight into what defines an effective diversity strategy.The academic medicine community cannot derive top value from diversity efforts, however, until practitioners, deans, CEOs, and policy makers begin operating with a shared framework for success. The excellence imperative facing our medical schools and teaching hospitals calls for improved precision in decision making and resource deployment to drive sustainable outcomes, which in turn requires a strong degree of alignment among all involved parties. PMID- 23111255 TI - My hands. PMID- 23111256 TI - Commentary: reflections on diversity and inclusion in medical education. AB - The authors discuss how the strategy of fostering greater diversity and inclusion regarding minorities can help decrease health disparities and improve health outcomes. They propose that examining admission to medical school of qualified individuals with physical disabilities and fostering better communication with these individuals should be part of that strategy. Whereas people with disabilities constitute about 20% of the population, only between 2% and 10% are practicing physicians. The two major barriers to having more persons with disabilities as medical students are the cost of accommodating these persons and medical schools' technical standards. The authors offer suggestions for overcoming these barriers, and the additional barrier of communication with persons with various disabilities, such as deafness or visual impairment.The authors also discuss some of the issues involved in having greater representation of minorities in medicine. In addition, they stress the need for more training in cultural awareness for students and residents and for physicians well along in their careers. Medical educators will be increasingly called on to create new models designed to sensitize students and faculty to racial, ethnic, and other types of diversity, while documenting the efficacy and costs of extant ones, from the standpoint of both practitioner and consumer.The authors hope that the moves toward greater diversity and more training in cultural awareness will increase the efficacy of health care while reducing its cost. The demands of these efforts will require the commitment of diverse, intellectually capable, and compassionate people at many levels of academic medicine. PMID- 23111257 TI - Commentary: a ray of hope for medical school research funding. AB - Academic health centers are traditionally dependent on extramural agencies like the National Institutes of Health to fund medical research. The still-struggling U.S. economy has kept federal paylines stagnant in recent years even as research costs climb. Academic health center leaders need to find new funding sources to ensure that critical medical research continues. Myers and colleagues, in their report in this issue of Academic Medicine, found that scientific research funding by philanthropic nonprofit organizations rose 26% from 2006 to 2008. Even though the time frame for their study precedes the recent economic recession, their findings provide hope and guidance to academic health centers. Stable research portfolios should include a variety of sources, and Myers and colleagues suggest that partnership opportunities exist between federal and not-for-profit funding sources to focus on key disease areas. Seeking broader research funding may benefit at-risk groups like junior investigators, as the average age of a first time NIH grant recipient in 2008 was 42 years old. To foster the new discoveries and ideas that come from young scientists, academic health centers need to diversify their research funding sources.It is encouraging that high-visibility philanthropic organizations enhanced funding by 26% from 2006 to 2008. However, between 2008 and 2010, overall grant support from foundations declined 2.3%. Should federal and private funding continue to fall, there is an eminent threat of losing a generation of investigators. Thus, creative solutions and partnerships are needed to fund more high-priority research to cure disease and create the future of medicine. PMID- 23111258 TI - Commentary: recognizing and tracking philanthropy's critical support of health research. AB - Given the current fiscal climate limiting both government and industry support for health research, philanthropic support of health research is increasingly relevant because it provides some of the critical "risk capital" that stimulates innovation, helps translate basic research findings into clinical applications, helps support the career development of investigators, builds new infrastructure, and helps fill key funding gaps. Unfortunately, because of the philanthropic sector's diversity and scope, it is challenging to track the sector's health research investments. The authors briefly review the landscape of philanthropic organizations, identify several success stories resulting from philanthropic investments, and finally underscore the importance of gaining more knowledge about the sector through purposeful data collection efforts such as those of the Health Research Alliance (HRA), a consortium of nonprofit funders of biomedical research and training. Recent HRA efforts of this type are highlighted in this commentary and described in detail in the report by Myers et al in this issue of Academic Medicine. PMID- 23111259 TI - Autonomy-supportive medical education: let the force be within you! PMID- 23111260 TI - Fluency-not competency or expertise-is needed to incorporate evidence into practice. PMID- 23111261 TI - Focus on improving relational communication skills and discussing what matters most. PMID- 23111262 TI - Clinical excellence: make it a habit. PMID- 23111263 TI - Organizational performance and teamwork: achieving interactive excellence. PMID- 23111264 TI - Developing to full potential: medical education as a scientific discipline. PMID- 23111265 TI - What are you doing creatively these days? PMID- 23111266 TI - Discovering medical students' full potential: a science and an art. PMID- 23111267 TI - A student's perspective on reaching full potential in academic medicine. PMID- 23111268 TI - Finding potential in balance: navigating the competing discourses of diversity and standardization. PMID- 23111269 TI - ACGME competencies should be required of our residencies, not just our residents. PMID- 23111270 TI - PERMA: a model for institutional leadership and culture change. PMID- 23111271 TI - A culture of coaching: achieving peak performance of individuals and teams in academic health centers. PMID- 23111272 TI - Flow, deliberate practice, and renewal are the keys to peak performance. PMID- 23111273 TI - Beyond the biomedical feedlot. PMID- 23111276 TI - Medicine and the arts. Morning Song by Marcia F. Brown. Commentary. PMID- 23111277 TI - 2012 humanism in medicine essay contest: second place: words you use to map a body. PMID- 23111278 TI - AM Last Page: caring for women veterans. PMID- 23111279 TI - The debate on sentinel node biopsy in melanoma: any clue? PMID- 23111280 TI - Constraint-induced movement therapy for the lower extremities in multiple sclerosis: case series with 4-year follow-up. AB - OBJECTIVE: To evaluate in a preliminary manner the feasibility, safety, and efficacy of Constraint-Induced Movement therapy (CIMT) of persons with impaired lower extremity use from multiple sclerosis (MS). DESIGN: Clinical trial with periodic follow-up for up to 4 years. SETTING: University-based rehabilitation research laboratory. PARTICIPANTS: A referred sample of ambulatory adults with chronic MS (N=4) with at least moderate loss of lower extremity use (average item score <=6.5/10 on the functional performance measure of the Lower Extremity Motor Activity Log [LE-MAL]). INTERVENTIONS: CIMT was administered for 52.5 hours over 3 consecutive weeks (15 consecutive weekdays) to each patient. MAIN OUTCOME MEASURES: The primary outcome was the LE-MAL score at posttreatment. Secondary outcomes were posttreatment scores on laboratory assessments of maximal lower extremity movement ability. RESULTS: All the patients improved substantially at posttreatment on the LE-MAL, with smaller improvements on the laboratory motor measures. Scores on the LE-MAL continued to improve for 6 months afterward. By 1 year, patients remained on average at posttreatment levels. At 4 years, half of the patients remained above pretreatment levels. There were no adverse events, and fatigue ratings were not significantly changed by the end of treatment. CONCLUSIONS: This initial trial of lower extremity CIMT for MS indicates that the treatment can be safely administered, is well tolerated, and produces substantially improved real-world lower extremity use for as long as 4 years afterward. Further trials are needed to determine the consistency of these findings. PMID- 23111282 TI - Analysis of gene expression changes to elucidate the mechanism of chilling injury in precision-cut liver slices. AB - The exact mechanism of chilling injury (by a decrease of temperature to sub physiological values), especially in the intact organ, is yet unknown. Precision cut liver slices (PCLS), which closely resemble the organ from which they are derived, are an ideal in vitro model to study the mechanism of chilling injury in the intact organ. In the present study we were able to separate chilling injury from other damaging events such as cryoprotectant toxicity and ice-crystal injury and performed micro-array analysis of regulated genes. Pathway analysis revealed that different stress responses, lipid/fatty acid and cholesterol biosynthesis and metabolism were affected by chilling. This indicates that the cell-membrane might be the primary site and sensor for chilling, which may initiate and amplify downstream intracellular signaling events. Most importantly, we were able to identify gene expression responses from stellate cells and Kupffer cells suggesting the involvement of all liver cell types in the injury. In conclusion, a broad spectrum of previously unknown gene expression changes induced by chilling was identified in the tissue. This is the first report of a systematic investigation on the mechanism of chilling injury in integrated tissue by micro array analysis under conditions in which other sources of injury are minimal. PMID- 23111281 TI - Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes. AB - Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating beta cell duress. To identify genes/mechanisms involved with diabetogenesis at the beta cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of beta cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility. PMID- 23111283 TI - Toosendanin induces apoptosis through suppression of JNK signaling pathway in HL 60 cells. AB - Toosendanin (TSN), a triterpenoid isolated from Melia toosendan Sieb. et Zucc., has been found to suppress proliferation and induce apoptosis in a variety of human cancer cells. However, the mechanism how TSN induces apoptosis remains poorly understood. In this study, we examined the effects of TSN on the growth, cell cycle arrest, induction of apoptosis and the involved signaling pathway in human promyelocytic leukemia HL-60 cells. Proliferation of HL-60 cells was inhibited in a dose-dependent manner with the IC(50 (48 h)) of 28 ng/mL. The growth inhibition was due primarily to the S phase arrest and cell apoptosis. Cell apoptosis induced by TSN was confirmed by Annexin V-FITC/propidium iodide staining. The increase of the pro-apoptotic protein Bax, cleaved PARP and caspase 3, and the decrease of anti-apoptotic protein Bcl-2 were observed. Western blot analysis indicated that TSN inhibits the CDC42/MEKK1/JNK pathway. Taken together, our study suggested, for the first time, that the pro-apoptotic effects of TSN on HL-60 cells were mediated through JNK signaling pathway. PMID- 23111284 TI - Individual responsibility for healthcare financing: application of an analytical framework exploring the suitability of private financing of assistive devices. AB - OBJECTIVE: To operationalise and apply a conceptual framework for exploring when health services contain characteristics that facilitate individuals' ability to take individual responsibility for health care through out-of-pocket payment. In addition, we investigate if the levels of out-of-pocket payment for assistive devices (ADs) in Sweden are in line with the proposed framework. METHOD: Focus groups were used to operationalise the core concepts of sufficient knowledge, individual autonomy, positive externalities, sufficient demand, affordability, and lifestyle enhancement into a measurable and replicable rationing tool. A selection of 28 ADs were graded separately as having high, medium, or low suitability for private financing according to the measurement scale provided through the operationalised framework. To investigate the actual level of private financing, a questionnaire about the level of out-of-pocket payment for the specific ADs was administered to county councils in Sweden. RESULTS: Concepts were operationalised into three levels indicating possible suitability for private financing. Responses to the questionnaire indicate that financing of ADs in Sweden varies across county councils as regards co-payment, full payment, discretionary payment for certain healthcare consumer groups, and full reimbursement. According to the framework, ADs commonly funded privately were generally considered to be more suitable for private financing. CONCLUSIONS: Sufficient knowledge, individual autonomy, and sufficient demand did not appear to influence why certain ADs were financed out-of-pocket. The level of positive externalities, affordability, and lifestyle enhancement appeared to be somewhat higher for ADs that were financed out-of-pocket, but the differences were small. Affordability seemed to be the most influential concept. PMID- 23111285 TI - Experience of violation during the past 3 months, social capital, and self-rated health: a population-based study. AB - OBJECTIVE: The objective was to investigate the association between experience of violation during the past 3 months and self-rated health, taking trust (social capital), economic stress, and country of birth and parents' country of birth into account. DESIGN/SETTING/PARTICIPANTS/MEASUREMENTS: The 2008 public health survey in Skane is a cross-sectional study with 55% response rate. A random sample was approached using a postal questionnaire, and 28,198 persons aged 18-80 responded. Logistic regression models investigated associations between experience of violation during the past 3 months and self-rated health. RESULTS: A 27.4% proportion of the men and 30.0% of the women reported less than good health. Less than good health was significantly higher in older age groups, among persons born outside Sweden, with low education, economic stress, low trust in other people, and experience of violation during the past 3 months. The group with experience of violation at one occasion during the past 3 months had odds ratio 1.76 (95% CI 1.57-1.97) of less than good health among men and odds ratio 1.78 (95% CI 1.62-1.96) among women, while the group with experience of violation two or more times during the past 3 months had odds ratio 4.28 (95% CI 3.36-5.44) among men and 3.54 (95% CI 2.89-4.35) among women in the final multiple analyses. CONCLUSIONS: Experience of violation during the past 3 months is significantly associated with less than good health, which is a finding with important policy implications. PMID- 23111286 TI - The piezoresistive effect in n-type junctionless silicon nanowire transistors. AB - The piezoresistive effect in n-type silicon nanowires on silicon-on-insulator wafers, also called junctionless nanowire transistors (JNTs), is investigated. A marked change in the subthreshold drain current for strained JNTs is observed. This change can be attributed to strain-induced interface state modification, due to an increase in the interface state for tensile strain or a decrease in the trap activation energy for compressive strain. Through many long-time cycles of compressive and released strain, the electromechanical response of subthreshold I(DS) with time is found, thus supporting the widely reported giant piezoresistance effect. In addition, JNTs involving a back-gate and an additional top-gate electrode may become a new prospect for high-precision sensor applications and next-generation multigate transistors. PMID- 23111287 TI - Update on deep brain stimulation for Parkinson's disease. AB - Deep brain stimulation (DBS) has evolved from an experimental procedure to a major treatment option for Parkinson's disease (PD). Although its underlying mechanism is still not fully understood, a growing body of evidence supports the role of DBS as an effective treatment option for carefully selected patients. Over time, the ever-expanding DBS patient cohort has also revealed the risks and challenges of the surgery. Major goals of this approach include identifying and reaching the correct target of stimulation, as well as delivering electrical current to the appropriate location in an appropriate manner. The safety concerns and adverse outcomes continue to be addressed with ever-improving operative strategies. Imminent developments in biomedical engineering hold the promise of more sophisticated and intelligent DBS devices, and improved imaging technology is providing unprecedented anatomical and functional resolution. Further advances in our understanding of physiology and pathology of the deep brain structures- guided not in small part by experience and access gained with DBS surgery in PD- will shape the future of this field. PMID- 23111288 TI - An update on peripheral nerve stimulation. AB - Electrical stimulation of peripheral nerves is an established modality in treatment of chronic pain. Although introduced half a century ago, it has enjoyed rapid growth in popularity and acceptance over the last decade or so. The spectrum of clinical situations where peripheral nerve stimulation (PNS) has been successfully used includes chronic pain in extremities, neck, lower back, chest and abdominal wall, and head and face regions. Based on several multicenter studies, PNS has been recently approved for clinical use in Europe for treatment of chronic low back pain and intractable chronic migraines. Such administrative recognition of clinical value of PNS necessitates update on PNS status for interested readers. The goal of this article is to provide a comprehensive overview of the different types of peripheral neurostimulation that are used today and providing the most updated information on the current state of the modality. As clinical interest and experience with PNS continue to grow, we expected steady accrual of objective evidence in terms of safety, efficacy, best indications and optimal stimulation parameters, all of which will be necessary for worldwide regulatory approval of PNS and for the benefit of patients who are still suffering from chronic neuropathic pain. PMID- 23111289 TI - A review on spinal cord stimulation. AB - Spinal cord stimulation has evolved since its inception. It has been used as a treatment option since 1967 with a concentration on chronic pain syndromes. This review will focus on reviewing the literature and the most recent publications, as well as a focus on the advancements in technology. The most common indications will be discussed as well as psychological screening, trials, implantation technique, and programming. Focused attention is on evolving technology and the direction of the field. This focus leans on the technology to keep pace with the evolving clinical needs. PMID- 23111290 TI - Rehabilitation interventions for chronic motor deficits with repetitive transcranial magnetic stimulation. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive electrophysiological method to modulate cortical excitability. As such, rTMS can be used in conjunction with conventional physiotherapy or occupational therapy to facilitate rehabilitation of motor function in patients with focal brain lesions. This review summarizes the rationale for using rTMS in the rehabilitation of motor deficits as derived from imaging and electrophysiological studies of the human motor system. rTMS methodology and its various stimulation modalities are introduced and current evidence for rTMS as supportive therapy for the rehabilitation of chronic motor deficits is discussed. PMID- 23111291 TI - Occipital nerve stimulation for primary headaches. AB - Occipital nerve stimulation may be effective for primary headache disorders. Four studies, including two double-blind show, stimulation-controlled studies that were performed for chronic migraine showed evidence of benefit. A separate study suggested a benefit for combined supraorbital and greater occipital nerve stimulation. Anecdotal evidence suggests benefit in hemicrania continua. In chronic cluster headache, several case series have shown improvement, which, combined with the safety of occipital nerve stimulation relative to deep brain stimulation, have led to published reports supporting this as the preferred surgical technique for chronic cluster headache. A few case reports suggest a possible benefit in short-lasting unilateral neuralgiform headache attacks with conjunctival injection tearing and short-lasting unilateral neuralgiform headache. PMID- 23111292 TI - New devices and drugs on the horizon in pain management. AB - Chronic pain is a common condition that confers a substantial burden--physical, psychological, and economic--to individuals and society. There are a wide variety of interventions available for this condition. Chronic pain that is refractory to conventional treatment remains a challenge to physicians and patients alike. The purpose of this review is to describe recent developments for chronic pain management including pharmaceutical interventions and medical device therapy. For drug therapy, this review will focus on three classes of medications: antidepressants, opiates and antiepileptic medications. For device therapy, the utility of electrical stimulation to neural structures (dorsal column, peripheral nerve and deep brain) and intrathecal therapy for chronic pain will be described. PMID- 23111293 TI - Surgical brain modulation for tinnitus: the past, present and future. AB - Tinnitus treatment has traditionally been restricted to ENT surgeons, audiologists, psychologists and psychiatrists. Recently, both basic and clinical research has focused on the brain's involvement in the generation of tinnitus, opening the tinnitus field up to neurologists and neurosurgeons specialized in the field of tinnitus. Non-pulsatile tinnitus can be considered an auditory phantom phenomenon, analogous to phantom pain, both with regards to pathophysiological mechanisms, clinical characteristics, and treatment approaches. Thus the understanding of tinnitus has benefited a lot from translating available knowledge of the somatosensory (pain) system to the auditory system. A literature review of neuromodulatory approaches to tinnitus is integrated in a single center's experience with invasive neuromodulation treatments for tinnitus. This is compared to findings from neuromodulatory treatment of chronic pain syndromes. The past, present and future options for functional neurosurgical approaches are outlined. In the past only destructive approaches were used, consisting of nerve lesions and frontal lobotomies. Presently neurostimulation trials are ongoing evaluating the effect of auditory cortex stimulation, frontal cortex stimulation, thalamic (VIM) and caudate stimulation as well as amygdalohippocampal stimulation, yielding suppression rates between 10 and 70%. Further potentially promising targets include the anterior cingulate, the medial geniculate bodies (MGB), the periaqueductal gray/ tectal longitudinal column (PAG/TLC), the dorsal cochlear nucleus, as well as the C2 and trigeminal nerve. Understanding tinnitus and its potential neuromodulation treatments is relatively simple for a neurosurgeon specialized in pain or a pain physician, based on the pathophysiological and clinical analogies. Similarly to pain a multidisciplinary approach can be advocated, and in view of the epidemiology and amount of suffering associated with this enigmatic symptom further investment in possible neuromodulation treatments is warranted. PMID- 23111294 TI - Deep brain stimulation effects on memory. AB - As the population of many countries ages, disorders of cognition and memory-such as Alzheimer's Disease (AD) and dementia associated with Parkinson's Disease-will become a major societal burden. At present, few effective medical therapies against these conditions are available. Deep brain stimulation (DBS) may be a potential therapeutic option, because it can directly target and modulate the activity of structures implicated in circuits subserving memory function. In this article, we review the scientific literature to address some of the mechanisms by which DBS may impact memory and cognition. We then summarize the results of recent clinical experience with DBS in AD and Parkinsonian dementia. PMID- 23111295 TI - Surgical management and alternative strategies for neighboring intracranial aneurysms. AB - AIM: Neighboring aneurysms are misidentified or named as a single multi-lobulated aneurysm, despite the demonstration of angiographic cleavage, because of the close proximity and different size. During surgery, neighboring intracranial aneurysms represent an interesting subset of aneurysms that may pose unique management challenges. Meticulous preoperative radiological planning is necessary to properly appreciate the local anatomy. Intraoperative microsurgical dissection of these aneurysm complexes may be difficult if a plane cannot be created between the neighboring lesions with dissection of the aneurysm necks and preservation of blood flow becoming a challenging situation. METHODS: A retrospective review over a 10-year period, of all patients with intracranial aneurysms treated by our service was performed to identify those patients with neighboring aneurysms. RESULTS: We encountered 73 instances of neighboring aneurysms (MCA-22, PCOMMA/AChA-20, ACOMMA-15, paraclinoid-5, upper basilar-4, pericallosal-3, ICA bifurcation-2, VB junction-2). Most patients were managed with either microsurgery for both aneurysms or coiling for both. Seven patients with severe SAH underwent coiling of the presumed ruptured (much larger) aneurysm with subsequent microsurgery for the neighboring aneurysm which was not considered amenable to endovascular therapy. In the setting of neighboring lesions, microsurgery was sometimes deemed significantly more difficult than usual, particularly when the aneurysm domes were adherent precluding optimal visualization of the local vascular anatomy. Temporary vascular occlusion was often helpful to allow for proper inspection and identification of all perforating vessels initially hidden by the adherent sacs. CONCLUSION: Neighboring intracranial aneurysms represent an interesting subset of aneurysms that may pose unique management challenges. Careful evaluation of preoperative angiography is necessary to properly appreciate the local anatomy in these cases. Microsurgical dissection of these aneurysm complexes may be difficult if a plane cannot be created between the neighboring lesions. Because neighboring aneurysms tend to obscure the local anatomy, intraoperative angiography and innovative surgical strategies were useful in our experience. PMID- 23111296 TI - Surgical outcome of anterior decompression in cervical spondylotic myelopathy in patients with less cord derangement. AB - AIM: CSM patients caused by osteophytic ridge or intervertebral disc herniation underwent anterior decompression and fusion were prospectively enrolled. The purpose was to elucidate the effects of decompression (anterior cervical discectomy and fusion) on myelopathic cord in milder cases, younger patients, and in short duration of the disease. METHODS: Forty-three patients with CSM were examined comprising Cooper and mJOA scale before and after surgery and followed for 12 months. RESULTS: Patients included in the study were 30 males and 13 females. The mean age of men was 50.9+/-13.2, and that of women was 46.8+/-11.8. The mean interval from symptoms onset to hospital presentation was 10.78+/-7.3 months. In lower limbs, among 31 with preoperative functional impairment, 25 remained unchanged, three improved and three worsened, which is not significant, and of 39 patients with preoperative upper limb functional impairments using Cooper's scale, 20 improved, 15 remained unchanged and 4 became worse (P=0.001). Recovery rate for mJOA score was 24.5+/-17.7%, for Cooper lower extremity score was 32.2+/-40.56% and for Cooper upper extremity score was 7.8+/-16.8%. The mean gain in mJOA was 0.84 (+/-0.57). CONCLUSION: Patients with short duration of symptom onset respond remarkably to decompression surgery. In patients with good condition that myelopathy has not established yet, perhaps mJOA is not a perfect and powerful scale for pre and postoperative assessment of patient. PMID- 23111297 TI - Minimally invasive stabilization of vertebral compression fractures using balloon kyphoplasty. AB - AIM: Spinal trauma is a leading cause of destabilization of the vertebral column. Balloon kyphoplasty is one among several surgical treatment methods for restoring spinal stability. This series included 25 patients (10 [40%] males and 15 [60%] females) over the age of 50 years who had undergone balloon kyphoplasty for traumatic compression fracture and were retrospectively evaluated to determine the success of this technique in terms of restoration of spinal stabilization. METHODS: Preoperative and postoperative direct radiographic images were obtained in all cases. Vertebral body height in the anterior, middle and posterior coronal planes were estimated from the radiographs. RESULTS: The mean anterior vertebral body height in the coronal plane was 16.39+/-5.64 mm before and 23.17+/-5.93 mm after surgery. Compared with preoperative measurements, the restoration ratio was 43% in the anterior coronal plane, 35% in the mid-coronal plane, and 43% in the posterior coronal plane. CONCLUSION: The study results suggest that balloon kyphoplasty may be used in the surgical treatment of vertebral compression fractures in selected cases. PMID- 23111298 TI - Dexamethasone significantly attenuates sub-arachnoid hemorrhage-induced elevation in cerebrospinal fluid citrulline and leukocytes. AB - AIM: Cerebral vasospasm is a leading cause of death and disability following aneurysmal subarachnoid hemorrhage (SAH). Nitric oxide (NO) is a potent mediator of vasodilation, and citrulline is a known contributor to NO production. The leukocytosis inflammatory response can increase vasoconstrictive compounds that may also contribute to vasospasm. Dexamethasone is a glucocorticosteroid commonly administered after SAH, which may alter the production of leukocytes and citrulline. The goal of this project was to study the effects of dexamethasone on leukocytosis, citrulline, and angiographic vasospasm. METHODS: Experimental SAH was induced in 18 New Zealand white rabbits. Intravenous dexamethasone was administered to one group (N.=9) at 2 mg/kg/day. A placebo group (N.=9) was given a saline infusion with otherwise identical procedures. CSF citrulline, leukocytes, protein, and glucose, as well as plasma citrulline were measured at baseline and 3 days post-SAH in a blinded fashion. Basilar artery angiography was performed at baseline and repeated 3 days post-SAH. RESULTS: The change in CSF citrulline from day 0 to day 3 was significantly lower in the dexamethasone group compared to controls (P=0.002). The change in CSF white blood cells was also significantly lower (P=0.005). There was no significant change in plasma citrulline levels or angiographic vasospasm. CONCLUSION: Dexamethasone significantly decreases CSF citrulline and CSF leukocytosis after experimental SAH. It is possible this could lead to a relative vasoconstriction and vasodilation, respectively. These processes could cancel-out opposing effects of dexamethasone on cerebral vasospasm, partially contributing to the recognized, multifactorial, inconsistent effects of glucocorticoids on vasospasm. PMID- 23111299 TI - Thoracic spinal stenosis and myelopathy: report of two rare cases and review of the literature. AB - The authors report two cases of thoracic spinal canal stenosis (SCS) and myelopathy. One is extremely unusual because of degenerative changes occurred in the upper thoracic spine. The other because of its multiple etiology among which calcification and ossification of the ligamentum flavum (OLF) in a Caucasian man. Both patients presented with an history of slowly progressive spastic paraparesis. In the first case computed tomography (CT) scans and magnetic resonance (MR) images revealed hypertrophy of the legamentum flavum and laminae causing compression of the spinal cord at T2-T3. In the second case diagnostic imaging showed three levels of stenosis in the lower thoracic spine due to degenerative changes, calcification and OLF with cord damage at T9-T10. A decompressive laminectomy and medial facetectomy was performed in both patients. The ligamentum flavum, hypertrophied and infolded in the first case and calcified and ossified in the second, was removed with careful dissection of the dural adhesions. Both patients showed a rapid post-operative recovery and regained autonomous walking within 1 month of surgery. Thoracic spinal cord stenosis is a rare and complex disorder because of differential diagnosis, neuroimaging features and treatment options. Regardless of its cause, prompt surgical decompression plays a key role in improving the functional outcome of myelopathy. PMID- 23111300 TI - Long-term survival in cerebellar glioblastoma multiforme. Case report. AB - Primary cerebellar glioblastoma multiforme (GBM) is a rare tumor in adults that accounts for just 1% of all cases of GBM. Cerebellar GBMs are not yet completely understood also as far as the prognosis. We report a case of cerebellar GBM in a 27-year-old woman. Magnetic resonance imaging (MRI) showed a 3x3.6 cm-sized, ill defined, heterogeneously enhancing mass in the left cerebellum. GBM was histologically confirmed following radical surgery. Postoperative radiotherapy with concomitant and adjuvant temozolomide chemotherapy was subsequently administrated. She has no evidence of recurrence and is in good clinical conditions up-to date, three years after surgery. PMID- 23111301 TI - Objective measurement of posture and posture transitions in the pre-school child. AB - Recent evidence suggests that between-individual variation in posture and posture transitions may have important health consequences in adults. The early life development of between-individual variation in posture and posture transitions has not been studied, and the physiological consequences of such variations in childhood are unknown, largely because of the absence of objective methods for measuring posture and posture transitions in young children. This study aimed to examine the objective measurement of posture transitions in pre-school children with the activPALTM monitor (PAL Technologies, Glasgow). Single-unit activity monitors such as the activPALTM have a limited output, with data categorized as 'sit/lie', 'stand' or 'walk' and the consequences of this for measurement of posture transitions in young children are unknown. Thirty children (mean age 4.1 years) were videoed for 1 h in nursery while wearing an activPALTM. Video was analysed on a second-by-second basis, with all postures categorized. From direct observation, time spent was sit/lie 46%; stand 35%; walk/run 16%; 3% was spent in heterogeneous non-sit/lie/upright postures (crawl, crouch, and kneel up). Despite these 'non-standard' postures being responsible for a low proportion of time, posture transitions involving them contributed to 34% of total transitions. There was a significant rank-order correlation (r = 0.79, p < 0.0001) between the number of posture transitions measured by activPALTM and by direct observation. 'Non-standard' postures in young children are probably not a problem if the aim is to measure total time sedentary or active, and the activPALTM may measure between-individual variation in transitions adequately in young children. However, non-standard postures may present problems for the detailed characterization of posture transitions in early childhood. PMID- 23111302 TI - Affordable Care Act: implications for APRNs. PMID- 23111303 TI - Inhaled corticosteroid prescribing from the emergency department for children with asthma. AB - In the article "Frequency of Prescription of Inhaled Corticosteroids to Children With Asthma in U.S. Emergency Departments," the authors conducted a secondary data analysis from the National Hospital Ambulatory Medical Care Survey database to examine inhaled corticosteroid prescribing patterns of providers caring for children with asthma visiting emergency departments. We review and critique this article and use a case study module to illustrate the importance of the research findings and how they relate to practice in the emergency department in light of current national guidelines for managing asthma exacerbations. PMID- 23111304 TI - Scaphoid fractures. AB - The scaphoid is the most commonly fractured of the eight carpal wrist bones. The mechanism of injury is usually from a fall on the outstretched hand. Initial radiographs may not identify a scaphoid fracture. A high index of suspicion given to these biomechanics and the physical findings will assist in the identification of this fracture. Certain fractures of the scaphoid are at high risk of avascular necrosis and nonunion requiring splinting and orthopedic referral of suspected fractures to assist in preventing such complications. PMID- 23111305 TI - Management of acute agitation in the emergency department. AB - Acutely agitated and combative patients are commonly seen and evaluated by health care providers in the emergency department. Treatment options have evolved significantly in recent years with the advent of intramuscular atypical antipsychotics and an expanded repertoire of patient-friendly oral formulations. Selection of the ideal pharmacologic treatment of an acutely agitated patient strengthens the patient-prescriber relationship and promotes adherence to future therapy. In this article, advantages and disadvantages of various treatment modalities for undifferentiated, psychotic, and nonpsychotic agitation are reviewed, including alternatives to the commonly prescribed haloperidol and lorazepam combination. Atypical antipsychotics may be superior in certain patients, with the added benefit of easier conversion to maintenance therapy. Special consideration is given to the treatment of acutely agitated geriatric patients suffering from delirium and/or dementia. Management of these patients should be guided by etiology and patient characteristics to obtain maximum therapeutic benefit. Although emergency department providers may only see a given patient once, the health care team must have an evidence-based approach to the care that is provided in the emergency department, as it can significantly influence the patient's overall course of treatment in the outpatient setting. PMID- 23111307 TI - Concussion or benign paroxysmal torticollis? AB - This case report describes a patient who presented to the trauma service on 3 occasions over the course of 2 years, each time with symptoms typical of concussion (e.g., crying, change in mentation, and vomiting). On more in-depth evaluation, it was discovered that the child had torticollis, pallor, and brief dizziness or vertigo with each episode. Benign paroxysmal torticollis is a periodic, paroxysmal syndrome that may be mistaken for the more common concussion. In addition to illustrating a uniquely pediatric neurological syndrome, this case demonstrates the importance of taking a careful history and considering a full range of differential diagnoses when evaluating every patient, even those with seemingly routine injuries. PMID- 23111308 TI - An educational program to prevent, manage, and recover from workplace violence. AB - There exists a gap in the preparation of emergency department (ED) employees to prevent, manage, and recover from workplace violence (WPV). Thus, the purpose of this article is to evaluate learning outcomes following a 4-unit WPV educational program. A quasi-experimental study was used to evaluate learning outcomes with 315 employees from 3 EDs. Units 1-3 were web-based and included a pretest posttest. Unit 4 was classroom-based and allowed employees to apply the knowledge learned during the web-based program. A paired samples t tests reflected a significant increase in knowledge attainment (p < 0.001). There was no significant difference in knowledge attainment between employees who completed the web-based learning only and employees who completed the hybrid web based/classroom-based education (p = 0.136). A well-developed WPV educational program can achieve significant learning outcomes in ED employees. Web-based learning may be an effective alternative yielding learning outcomes equal to that of a hybrid educational program. PMID- 23111309 TI - Challenges in obtaining accurate home medication lists in emergency triage at an academic medical center: perceptions from nurses. AB - The goal of this project was to assess perceptions of medication reconciliation from health care professionals who perform this task. Specific areas of interest included the perceived amount of time spent on medication reconciliation; process complexity; and effectiveness of the current process. Opinions concerning the use of alternative processes were also solicited. This prospective qualitative study involved 4 focus group sessions at a tertiary referral teaching hospital in Tucson, AZ. Nurses involved in admission medication reconciliation in the emergency department were invited to participate, and their perceptions were categorized and summarized. Participants reported a range of times to complete the medication reconciliation from zero to more than 20 min. According to the participants, the time spent on each patient depended on patient's medication knowledge and the complexity of the regimens. Participants wanted the medication list entry screen to be easier to use, and they also suggested patient medication lists from previous visits and from outpatient clinics associated with the medical center be easily accessible. Participants felt that emergency triage may not be the most ideal time in which to perform medication reconciliation, and they expressed concerns about accuracy of these medication lists. Whereas some were interested in the possibility of using a patient medication database and expected that it would improve accuracy and save time, others were less open to a perceived additional step. Participants provided suggestions for changes in the current medication reconciliation process that they feel could improve patient satisfaction and increase efficiency. PMID- 23111310 TI - The differential diagnosis of syncope: a guide for emergency department advanced practice nurses. AB - Syncope is common in patients presenting in the emergency department, and it is essential that advanced practice nurses (APNs) be able to quickly and efficiently risk-stratify these patients. The importance of a thorough and accurate history and physical examination cannot be understated in diagnosing the pathology of syncope. Although vasovagal syncope is the most common cause of syncope, it is important to rule out the life-threatening causes of syncope first. APNs working in emergency departments can determine what pertinent diagnostic studies need to be ordered and which consults should be considered in patients presenting with syncope. APNs can also decide whether an inpatient admission is warranted or whether the patient can be safely discharged with outpatient follow-up. The importance of the history and physical examination as the best tool that APNs can use has been highlighted. Finally, implications for APNs in treating patients presenting with syncope are discussed. PMID- 23111311 TI - A needle in the neck: trigger point injections as headache management in the emergency department. AB - A review of recent research suggests that the use of trigger point injections are successful in relieving the acute pain of musculoskeletal headaches. Patients with the chief complaint of headache commonly present to the emergency department (ED) and are often treated with multiple intravenous medications including narcotics. The success of outpatient treatment with trigger point injections can be applied to the acute care setting for improved patient outcomes and decongestion of the ED. This article will address the problems of intravenous medication therapy and discuss the benefits of trigger point therapy as management for musculoskeletal headaches specifically in the ED. In addition, discussion aims to provide tools for the nurse practitioner to integrate this skill into clinical practice. PMID- 23111312 TI - Patients who presented to an Australian emergency department and did not wait or left against medical advice: a prospective cohort follow-up study. AB - This study aimed to describe characteristics, outcomes, and post-emergency department (ED) departure medical requirements of patients who did not wait (DNW) or left against medical advice (LAMA) after presenting to an Australian hospital ED over a 6-month period. This was a prospective cohort follow-up study. Children and adults were compared in terms of ED characteristics and outcomes. Of the 32,333 patient presentations, 3,293 (10.2%) were recorded as DNW and 470 (1.5%) as LAMA. Of the DNW/LAMA presentations, 1,303 (34.6%) received a telephone call. One in four of the DNW/LAMA patients were children (<16 years). Most (87%) waited longer than the recommended time before leaving the ED, the majority (56%) sought care elsewhere, and some (n = 174, 13%) re-presented to the ED within 7 days; 20 of those required hospital admission. Strategies addressing front-end ED systems are required to mitigate the proportion of patients who DNW/LAMA. PMID- 23111313 TI - Cortical and trabecular bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model. AB - The mouse tibial axial compression loading model has recently been described to allow simultaneous exploration of cortical and trabecular bone adaptation within the same loaded element. However, the model frequently induces cortical woven bone formation and has produced inconsistent results with regards to trabecular bone adaptation. The aim of this study was to investigate bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model, with the ultimate goal of revealing a load that simultaneously induced lamellar cortical and trabecular bone adaptation. Adult (16 weeks old) female C57BL/6 mice were randomly divided into three load magnitude groups (5, 7 and 9N), and had their right tibia axially loaded using a continuous 2-Hz haversine waveform for 360 cycles/day, 3 days/week for 4 consecutive weeks. In vivo peripheral quantitative computed tomography was used to longitudinally assess midshaft tibia cortical bone adaptation, while ex vivo micro-computed tomography and histomorphometry were used to assess both midshaft tibia cortical and proximal tibia trabecular bone adaptation. A dose response to loading magnitude was observed within cortical bone, with increasing load magnitude inducing increasing levels of lamellar cortical bone adaptation within the upper two thirds of the tibial diaphysis. Greatest cortical bone adaptation was observed at the midshaft where there was a 42% increase in estimated mechanical properties (polar moment of inertia) in the highest (9N) load group. A dose response to load magnitude was not clearly evident within trabecular bone, with only the highest load (9N) being able to induce measureable adaptation (31% increase in trabecular bone volume fraction at the proximal tibia). The ultimate finding was that a load of 9N (engendering a tensile strain of 1833 MUepsilon on medial surface of the midshaft tibia) was able to simultaneously induce measurable lamellar cortical and trabecular bone adaptation when using the mouse tibial axial compression loading model in 16 week old female C57BL/6 mice. This finding will help plan future studies aimed at exploring simultaneous lamellar cortical and trabecular bone adaptation within the same loaded element. PMID- 23111314 TI - Serum uric acid plays a protective role for bone loss in peri- and postmenopausal women: a longitudinal study. AB - OBJECTIVE: Oxidative stress has been linked to osteoporosis. Serum uric acid (UA), a strong endogenous antioxidant, has been associated with higher bone mineral density (BMD), lower bone turnover and lower prevalence of fractures in a large cross-sectional study of men. Whether this relationship is present in women and how UA relates to changes in BMD longitudinally has not been examined. METHODS: A sample of 356 peri- and postmenopausal women, mean age 60.5 years was studied. Each individual had baseline BMD and body composition measurements by dual energy x-ray absorptiometry (DXA) and at least one repeat measure, on average 9.7 years later. Annual rate of change in BMD (A%DeltaBMD) was calculated. UA was measured at each DXA visit. Calciotropic hormones and bone turnover markers were measured at the final visit only. RESULTS: Cross-sectional data analyses revealed that women with higher UA levels had significantly higher absolute BMD measures at all skeletal sites. These women also had higher measures of body weight and its components such as lean mass (LM) and fat mass (FM). Results of multiple regression analyses showed a positive association between UA and BMD that remained significant even after accounting for possible confounders including LM and FM. Regression analyses of the longitudinal BMD data demonstrated significant associations between serum UA levels and annual rates of change in BMD at all skeletal sites. After adjustment associations remained significant for lumbar spine, forearm and whole body BMD but not for hip BMD. CONCLUSION: Higher serum UA levels appear to be protective for bone loss in peri- and postmenopausal women and this relationship is not affected by changes in body composition measures. PMID- 23111315 TI - Coordinated time-dependent modulation of AMPK/Akt/mTOR signaling and autophagy controls osteogenic differentiation of human mesenchymal stem cells. AB - We investigated the role of AMP-activated protein kinase (AMPK), Akt, mammalian target of rapamycin (mTOR), autophagy and their interplay in osteogenic differentiation of human dental pulp mesenchymal stem cells. The activation of various members of AMPK, Akt and mTOR signaling pathways and autophagy was analyzed by immunoblotting, while osteogenic differentiation was assessed by alkaline phosphatase staining and real-time RT-PCR/immunoblot quantification of osteocalcin, Runt-related transcription factor 2 and bone morphogenetic protein 2 mRNA and/or protein levels. Osteogenic differentiation of mesenchymal stem cells was associated with early (day 1) activation of AMPK and its target Raptor, coinciding with the inhibition of mTOR and its substrate p70S6 kinase. The early induction of autophagy was demonstrated by accumulation of autophagosome-bound LC3-II, upregulation of proautophagic beclin-1 and a decrease in the selective autophagic target p62. This was followed by the late activation of Akt/mTOR at days 3-7 of differentiation. The RNA interference-mediated silencing of AMPK, mTOR or autophagy-essential LC3beta, as well as the pharmacological inhibitors of AMPK (compound C), Akt (10-DEBC hydrochloride), mTOR (rapamycin) and autophagy (bafilomycin A1, chloroquine and ammonium chloride), each suppressed mesenchymal stem cell differentiation to osteoblasts. AMPK knockdown prevented early mTOR inhibition and autophagy induction, as well as late activation of Akt/mTOR signaling, while Akt inhibition suppressed mTOR activation without affecting AMPK phosphorylation. Our data indicate that AMPK controls osteogenic differentiation of human mesenchymal stem cells through both early mTOR inhibition-mediated autophagy and late activation of Akt/mTOR signaling axis. PMID- 23111316 TI - Growth of Bi2Te3 quantum dots/rods in glass: a unique highly stable nanosystem with novel functionality for high performance magneto optical devices. AB - Magneto optical materials are currently of great interest, primarily for modern applications in optical isolation, modulation and switching in telecommunication. However, single crystals are the benchmark materials still used in these devices which are rather expensive and very difficult to fabricate. In this context, we are reporting herewith a stable and novel Bi(2)Te(3) quantum dot-glass nanosystem obtained using a controlled thermo-chemical method. The Q-dots of hexagonal Bi(2)Te(3) of size 4 to 14 nm were grown along the <1 1 3> direction. Surprisingly, we obtained quantum rods of Bi(2)Te(3) of size 6 * 10 nm for the first time. The strong quantum confinement in the nanosystem is clearly shown by the optical study. The band gap of the host glass was drastically reduced (from 4.00 to 1.88 eV) due to the growth of Bi(2)Te(3) quantum dots whereas photoluminescence showed a Stokes shift ~175 meV. Faraday Rotation (FR) investigations of the Bi(2)Te(3) quantum dot-glass nanosystem show a nonlinear response in Verdet constant with a decrease in the Bi(2)Te(3) dot sizes. The Bi(2)Te(3) Q-dot-glass nanosystem with ~4 nm dots shows significant enhancement (70 times) in Verdet constant compared to the host glass and more radically better than conventional single crystal (TGG). This is the first time that such a type of unique nanosystem has been architectured and has given extremely good magneto-optical performance. We strongly feel that this novel nanosystem has tremendous applications in magneto-optical devices. It is noteworthy that expensive single crystals can be replaced with this cost effective novel glass nanosystem. Interestingly, the present quantum dot-glass nanosystem can be transformed into optical fibers very easily, which will have an exceptionally high impact on the fabrication of high performance magneto optical devices. PMID- 23111317 TI - RFT1-CDG in adult siblings with novel mutations. AB - RFT1-CDG is a rare N-glycosylation disorder. Only 6 children with RFT1-CDG have been described, all with failure to thrive, feeding problems, hypotonia, developmental delay, epilepsy, decreased vision, deafness and thrombotic complications. We report on two young adult siblings with RFT1-CDG, compound heterozygotes for the novel missense mutations c.1222A>G (p.M408V) and c.1325G>A (p.R442Q) in RFT1 gene. Similar to the previously described patients, these siblings have profound intellectual disability but no feeding problems or failure to thrive. Their epilepsy is well controlled and coagulopathy is mild without clinical consequences. In addition, visual acuity is normal in both patients and hearing impairment is present only in one. Our findings extend the phenotype associated with RFT1-CDG. PMID- 23111318 TI - Recombinant snake venom prothrombin activators. AB - Three prothrombin activators; ecarin, which was originally isolated from the venom of the saw-scaled viper Echis carinatus, trocarin from the rough-scaled snake Tropidechis carinatus, and oscutarin from the Taipan snake Oxyuranus scutellatus, were expressed in mammalian cells with the purpose to obtain recombinant prothrombin activators that could be used to convert prothrombin to thrombin. We have previously reported that recombinant ecarin can efficiently generate thrombin without the need for additional cofactors, but does not discriminate non-carboxylated prothrombin from biologically active gamma carboxylated prothrombin. Here we report that recombinant trocarin and oscutarin could not efficiently generate thrombin without additional protein co-factors. We confirm that both trocarin and oscutarin are similar to human coagulation Factor X (FX), explaining the need for additional cofactors. Sequencing of a genomic fragment containing 7 out of the 8 exons coding for oscutarin further confirmed the similarity to human FX. PMID- 23111319 TI - Cell fusion and hybrids in Archaea: prospects for genome shuffling and accelerated strain development for biotechnology. AB - The ability to exchange DNA between cells is a molecular process that exists in different species in the domain Archaea. Such horizontal gene transfer events were shown to take place between distant species of archaea and to result in the transfer of large genomic regions. Here we describe recent progress in this field, discuss the potential use of natural gene exchange processes to perform genome shuffling and argue its possible biotechnological applications. PMID- 23111323 TI - A sample design for globally consistent biomass estimation using lidar data from the Geoscience Laser Altimeter System (GLAS). AB - BACKGROUND: Lidar height data collected by the Geosciences Laser Altimeter System (GLAS) from 2002 to 2008 has the potential to form the basis of a globally consistent sample-based inventory of forest biomass. GLAS lidar return data were collected globally in spatially discrete full waveform "shots," which have been shown to be strongly correlated with aboveground forest biomass. Relationships observed at spatially coincident field plots may be used to model biomass at all GLAS shots, and well-established methods of model-based inference may then be used to estimate biomass and variance for specific spatial domains. However, the spatial pattern of GLAS acquisition is neither random across the surface of the earth nor is it identifiable with any particular systematic design. Undefined sample properties therefore hinder the use of GLAS in global forest sampling. RESULTS: We propose a method of identifying a subset of the GLAS data which can justifiably be treated as a simple random sample in model-based biomass estimation. The relatively uniform spatial distribution and locally arbitrary positioning of the resulting sample is similar to the design used by the US national forest inventory (NFI). We demonstrated model-based estimation using a sample of GLAS data in the US state of California, where our estimate of biomass (211 Mg/hectare) was within the 1.4% standard error of the design-based estimate supplied by the US NFI. The standard error of the GLAS-based estimate was significantly higher than the NFI estimate, although the cost of the GLAS estimate (excluding costs for the satellite itself) was almost nothing, compared to at least US$ 10.5 million for the NFI estimate. CONCLUSIONS: Global application of model-based estimation using GLAS, while demanding significant consolidation of training data, would improve inter-comparability of international biomass estimates by imposing consistent methods and a globally coherent sample frame. The methods presented here constitute a globally extensible approach for generating a simple random sample from the global GLAS dataset, enabling its use in forest inventory activities. PMID- 23111320 TI - Improving health from the inside: Use of engineered intestinal microorganisms as in situ cytokine delivery system. AB - The anti-inflammatory cytokine interleukin-10 and its viral homologs were chosen as model proteins for the development of drug delivery systems based on probiotic carriers like E. coli Nissle 1917, E. coli G3/10, and Saccharomyces boulardii. Exterior cytokine secretion was achieved by a modified E. coli hemolysin transporter. Release of interleukin-10 transported to the periplasm via the OmpF signal peptide was enabled by a T4 phage lysis system under control of the araC PBAD activator-promoter. The yield of interleukin-10 delivered by the phage lysis system was too low for functional analysis whereas the fusion protein secreted by the hemolysin transporter proved to be biologically inactive. Moreover, partial processing of the fusion protein by the E. coli membrane protease OmpT had no effect on the protein's functionality. Using the alpha-mating factor signal sequence, the yeast S. boulardii proved to be suitable for secretory expression of biologically active viral interleukin-10. PMID- 23111324 TI - The logic of gene regulatory networks in early vertebrate forebrain patterning. AB - The vertebrate forebrain or prosencephalon is patterned at the beginning of neurulation into four major domains: the telencephalic, hypothalamic, retinal and diencephalic anlagen. These domains will then give rise to the majority of the brain structures involved in sensory integration and the control of higher intellectual and homeostatic functions. Understanding how forebrain pattering arises has thus attracted the interest of developmental neurobiologists for decades. As a result, most of its regulators have been identified and their hierarchical relationship is now the object of active investigation. Here, we summarize the main morphogenetic pathways and transcription factors involved in forebrain specification and propose the backbone of a possible gene regulatory network (GRN) governing its specification, taking advantage of the GRN principles elaborated by pioneer studies in simpler organisms. We will also discuss this GRN and its operational logic in the context of the remarkable morphological and functional diversification that the forebrain has undergone during evolution. PMID- 23111325 TI - Dll1/Notch activation contributes to bortezomib resistance by upregulating CYP1A1 in multiple myeloma. AB - One of the greatest challenges in multiple myeloma (MM) treatment is to overcome drug resistance. Many pathways are involved including Notch signaling. Notch receptors are expressed by MM cells and Notch ligand Dll1 is present on bone marrow (BM) stromal cells. In this study, we demonstrate that Dll1 can activate Notch signaling mostly through Notch2 receptor and can contribute to drug resistance to bortezomib, both in murine and human MM cells. Blocking the Notch pathway by DAPT (gamma secretase inhibitor) could reverse this effect and increased sensitivity to bortezomib. We describe the upregulation of CYP1A1, a Cytochrome P450 enzyme involved in drug metabolism, as a possible mechanism of Dll1/Notch induced bortezomib resistance. This was confirmed by inhibition experiments using alpha-Naphthoflavone or CYP1A1-siRNA that resulted in an increased sensitivity to bortezomib. In addition, in vivo data showed that combination treatment of DAPT with bortezomib was able to increase bortezomib sensitivity and prolonged overall survival in the 5T33MM mouse model. Our data provide a potential strategy to overcome bortezomib resistance by Notch inhibition in MM therapy. PMID- 23111326 TI - Transcription-dependent nuclear localization of DAZAP1 requires an N-terminal signal. AB - Deleted in Azoospermia Associated Protein 1 (DAZAP1) is a ubiquitous hnRNP protein required for normal development and spermatogenesis. It resides predominantly in the nucleus and moves between the nucleus and the cytoplasm via a ZNS shuttling signal at its C-terminus. DAZAP1 accumulates in the cytoplasm when RNA polymerase II activity is inhibited by actinomycin D. Here we report the mapping of a 42-amino acid segment (N42) at the N-terminus of DAZAP1 that is both necessary and sufficient for its transcription-dependent nuclear localization. In addition, using a yeast two-hybrid system, we have identified SLIRP as a N42 binding protein which may regulate DAZAP1 subcellular localization. PMID- 23111327 TI - GRK5 ablation contributes to insulin resistance. AB - The G-protein-coupled receptor kinase 5 (GRK5) is an important member of the threonine/serine kinase family that phosphorylates and regulates the G-protein coupled receptor (GPCR) signaling pathway. GRK5 is highly expressed in adipose tissue and may act as an adipogenetic factor under high-fat load [1]. Insulin resistance is associated with the pathogenesis of metabolic disorders such as type 2 diabetes and obesity; however, the potential role of GRK5 in insulin resistance is unknown. We characterized the biochemical and molecular alterations related to metabolic complications observed in GRK5(-/-) mice. These mice, which are partially resistant to obesity induced by a high-fat diet, had impaired glucose tolerance and insulin sensitivity, as well as disruption of AKT signaling transduction compared with their wild-type littermates. Further study showed that the decreased insulin sensitivity was not attributable to alterations in inflammatory status such as the NF-kappaB signaling pathway or inflammatory gene expression. Instead, hepatic steatosis and changes of mRNA in genes involved in hepatic glucose and lipid homeostasis were found. Overall, our data identified GRK5 as a positive regulator of insulin sensitivity. Our results showed that this protein is a potential therapeutic target in the treatment of insulin resistance and related disorders. PMID- 23111328 TI - Laminin peptide YIGSR induces collagen synthesis in Hs27 human dermal fibroblasts. AB - The dermal ECM is synthesized from fibroblasts and is primarily compromised of fibrillar collagen and elastic fibers, which support the mechanical strength and resiliency of skin, respectively. Laminin, a major glycoprotein located in the basement membrane, promotes cell adhesion, cell growth, differentiation, and migration. The laminin tyrosine-isoleucine-glycine-serine-arginine (YIGSR) peptide, corresponding to the 929-933 sequence of the beta1 chain, is known to be a functional motif with effects on the inhibition of tumor metastasis, the regulation of sensory axonal response and the inhibition of angiogenesis through high affinity to the 67kDa laminin receptor. In this study, we identified a novel function of the YIGSR peptide to enhance collagen synthesis in human dermal fibroblasts. To elucidate this novel function regarding collagen synthesis, we treated human dermal fibroblasts with YIGSR peptide in both a time- and dose dependent manner. According to subsequent experiments, we found that the YIGSR peptide strongly enhanced collagen type 1 synthesis without changing cell proliferation or cellular MMP-1 level. This YIGSR peptide-mediated collagen type 1 synthesis was modulated by FAK inhibitor and MEK inhibitor. This study clearly reveals that YIGSR peptide plays a novel function on the collagen type 1 synthesis of dermal fibroblasts and also suggests that YIGSR is a strong candidate peptide for the treatment of skin aging and wrinkles. PMID- 23111329 TI - Acid-activated prorenin binds to (pro)renin receptor in vitro. AB - Binding properties of acid-activated prorenin to (pro)renin receptor [(P)RR] was investigated in vitro to discuss possible roles of such reversibly acid-activated prorenin in the renin angiotensin (RA) system. Prorenin was acidified at pH 3.3, 4.5, 5.5, 6.5, and its activation level was measured at 1, 2, 4, 8, 12, and 25 h. Prorenin, activated non-proteolytically in time- and pH-dependent manners, was verified by Western blot analyses. Acidification of prorenin for 25 h at pH 3.3, 4.5, 5.5, and 6.5 showed 78%, 54%, 34%, and 20% activities, respectively when compared with the renin activity of trypsinized prorenin as 100%. Additionally, the binding properties of acidified prorenin to (P)RR were elucidated both at the equilibrium state and in the kinetic state using BIAcore. BIAcore assay showed that acidified prorenin at pH 3.3, 4.5, 5.5, and 6.5 had apparent K(D) of 1.57 * 10(4), 14.1, 8.29, and 8.04 nM, respectively while native prorenin at pH 7.4 had a K(D) of 7.8 nM. At equilibrium state, K(D) of native prorenin was 1.42 nM whereas apparent K(D) varied from 1.25 to 5.0 nM for the prorenin acidified at pH 4.5, 5.5, and 6.5. The K(m) values of free forms of acidified prorenin at different pH (0.33-0.5 MUM) was almost similar to those of (P)RR-bound forms of acidified prorenin (0.5-0.77 MUM). These in vitro data indicate that prorenin acidified in vivo possibly modulate RA system in receptor-dependent and/or independent manners which could ultimately lead to the pathogenesis of diseases. PMID- 23111330 TI - Activation of prokaryotic translation by antisense oligonucleotides binding to coding region of mRNA. AB - A few examples of translational activation by antisense small noncoding RNAs (sRNAs) have already been discovered in prokaryotic cells, and all of them are through a sense-antisense interaction at the 5'-untranslated region (5'-UTR) of target mRNAs. Here, we report a novel phenomenon of translational activation of prokaryotic gene expression with trans-acting antisense oligonucleotides targeting the coding region of mRNA. Screening of antisense oligonucleotides complementary to the coding sequences of GFP or ZsGreen identified antisense sequences that activate translation of the mRNAs in a concentration-dependent manner. We also found that the translational activation highly depends on the hybridization positions of the antisense strands. Translation-activating antisense oligonucleotides (TAOs) tended to bind to the 5'-region rather than the 3'-region of the mRNA coding region. RNA folding simulation suggested that TAOs may disrupt the structured elements around the translation initiation region (TIR) by pairing with complementary sequences in the mRNA coding region, resulting in an increase in translation efficiency. Further, we demonstrate that number and position of locked nucleic acid (LNA) bases in the antisense strands govern the tendency of up- or down-regulation. Our findings described here may lead to the discovery of a new class of antisense sRNA and the development of a tool for activating desired gene expression in the future. PMID- 23111331 TI - Soy milk suppresses cholesterol-induced inflammatory gene expression and improves the fatty acid profile in the skin of SD rats. AB - Recently, an elevation in skin cholesterol level has been implicated in skin inflammation. Given the potential therapeutic effects of soy on low grade inflammatory diseases, we hypothesized that a CHOL diet could promote an inflammatory response in skin and that soy milk (SM) or fermented soy milk (F.SM) could prevent this cholesterol-induced skin inflammation. To test this hypothesis, freeze-dried SM or F.SM was provided as a protein replacement for 20% of the casein in the diets of Sprague-Dawley (SD) rats. The animals were divided into the following groups: (1) control group (CTRL), AIN76A diet without cholesterol, (2) high cholesterol (CHOL) group, AIN76A with 1% (w/w) cholesterol, (3) SM group, CHOL diet with freeze-dried SM, and (4) F.SM group, CHOL diet with F.SM. In the CHOL group, the expression levels of pro-inflammatory genes, including IL-1beta, IL-1alpha, iNOS, and COX-2, were elevated. In comparison, the SM and F.SM groups displayed the lowered expression of IL-1beta, COX-2, F4/80, and Cd68, an increase of a n-3/n-6 ratio, and a reduction in the estimated desaturase activities of delta 5 desaturase (D5D) and steaoryl CoA desaturase (SCD-1). In particular, F.SM significantly increased the proportion of dihomo gamma-linolenic acid (DGLA) in skin fatty acid (FA) composition compared with the CHOL group. Here we present evidence that SM or F.SM could alleviate the inflammatory response in the skin that is triggered by excess dietary cholesterol by reducing the expression of pro-inflammatory genes. This response could be partly associated with a decreased in macrophages in skin and/or by modulation of the skin's FA composition. PMID- 23111332 TI - Neuroendocrine regulatory peptide-2 stimulates glucose-induced insulin secretion in vivo and in vitro. AB - Neuroendocrine regulatory peptide (NERP)-2, recently identified as a bioactive peptide involved in vasopressin secretion and feeding regulation in the central nervous system, is abundantly expressed in endocrine cells in peripheral tissues. To explore the physiological roles of NERP-2 in the pancreas, we examined its effects on insulin secretion. NERP-2 increased glucose-stimulated insulin secretion (GSIS) in a dose-dependent manner, with a lowest effective dose of 10( 7) M, from the pancreatic beta-cell line MIN6 and isolated mouse pancreatic islets. NERP-2 did not affect insulin secretion under the low-glucose conditions. Neither NERP-1 nor NERP-2-Gly (nonamidated NERP-2) stimulated insulin secretion. NERP-2 significantly augmented GSIS after intravenous administration to anesthetized rats or intraperitoneal injection to conscious mice. We detected NERP-2 in pancreatic islets, where it co-localized extensively with insulin. Calcium-imaging analysis demonstrated that NERP-2 increased the calcium influx in MIN6 cells. These findings reveal that NERP-2 regulates GSIS by elevating intracellular calcium concentrations. PMID- 23111333 TI - Training history, deliberate practice and elite sports performance: an analysis in response to Tucker and Collins review--what makes champions? PMID- 23111334 TI - Tissue engineered plant extracts as nanofibrous wound dressing. AB - Use of plant extracts for treatment of burns and wound is a common practice followed over the decades and it is an important aspect of health management. Many medicinal plants have a long history of curative properties in wound healing. Electrospun nanofibers provide high porosity with large surface area-to volume ratio and are more appropriate for cell accommodation, nutrition infiltration, gas exchange and waste excretion. Electrospinning makes it possible to combine the advantages of utilizing these plant extracts in the form of nanofibrous mats to serve as skin graft substitutes. In this study, we investigated the potential of electrospinning four different plant extracts, namely Indigofera aspalathoides, Azadirachta indica, Memecylon edule (ME) and Myristica andamanica along with a biodegradable polymer, polycaprolactone (PCL) for skin tissue engineering. The ability of human dermal fibroblasts (HDF) to proliferate on the electrospun nanofibrous scaffolds was evaluated via cell proliferation assay. HDF proliferation on PCL/ME nanofibers was found the highest among all the other electrospun nanofibrous scaffolds and it was 31% higher than the proliferation on PCL nanofibers after 9 days of cell culture. The interaction of HDF with the electrospun scaffold was studied by F-actin and collagen staining studies. The results confirmed that PCL/ME had the least cytotoxicity among the different plant extract containing scaffolds studied here. Therefore we performed the epidermal differentiation of adipose derived stem cells on PCL/ME scaffolds and obtained early and intermediate stages of epidermal differentiation. Our studies demonstrate the potential of electrospun PCL/ME nanofibers as substrates for skin tissue engineering. PMID- 23111335 TI - A gold nanoparticle platform for the delivery of functional microRNAs into cancer cells. AB - Lack of affordable technologies for delivering microRNAs and siRNAs into cells on a large scale has hindered our efforts to rapidly parse through hundreds of dysregulated genes/microRNAs in order to identify drivers of complex diseases. The instability and polyanionic nature of naked microRNAs impede efficient cellular uptake and reduce half-life. Viral delivery requires cloning, microRNA mimics/inhibitors require costly modifications, and both require toxic lipofection or electroporation. To address these challenges, we developed a robust method for delivering unmodified microRNAs into cells on cysteamine functionalized gold nanoparticles (AuNPs). We validated our method in two different tumor models and found that the best formulation of miR(1)-AuNP(10)-S PEG(0.5) had the highest payload (10-20 fold higher than lipofection), lowest toxicity (98% of cell viability following treatment), efficient uptake (96% of cells took it), fastest endosomal escape and increased half-lives (at least 5 days) impacting cell proliferation and patterns of target gene expression. PMID- 23111336 TI - Protective effects of cationic bovine serum albumin-conjugated PEGylated tanshinone IIA nanoparticles on cerebral ischemia. AB - Tanshinone IIA is a good candidate for treating cerebral ischemia, but its short half-life and poor permeability across the blood-brain-barrier (BBB) limit its curative efficacy. In this study, we successfully developed cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles (CBSA-PEG-TIIA-NPs). A cerebral ischemia rat model was established to evaluate the treatment efficacy and protective mechanism of CBSA-PEG-TIIA-NPs. CBSA-PEG-TIIA-NPs showed the mean particle size 118 +/- 14 nm with drug loaded ratio and encapsulation efficiency 5.69 +/- 0.6% and 83.2 +/- 2.6%, respectively. The pharmacokinetics demonstrated that CBSA-PEG-TIIA-NPs could significantly prolong circulation time and increase plasma concentration compared with intravenously administrated TIIA solution. The biodistribution and brain uptake study confirmed that CBSA-PEG-TIIA-NPs possessed better brain delivery efficacy with a high accumulation in brain. CBSA-PEG-TIIA NPs obviously ameliorated infarct volume, neurological deficit and histopathological severity. Treatment with CBSA-PEG-TIIA-NPs markedly inhibited the levels of the MPO, TNF-alpha, IL-1beta and IL-6. Furthermore, CBSA-PEG-TIIA NPs significantly decreased the mRNA expressions of iNOS and p38MAPK, upregulated PPARgamma expression, and inhibited the protein levels of iNOS, GFAP and p38MAPK phosphorylation. These results demonstrated that CBSA-PEG-TIIA-NPs possessed remarkable neuroprotective effects on ischemic stroke through modulation of inflammatory cascades and neuronal signal pathways involved in cerebral ischemia. PMID- 23111337 TI - Synthesis of nano-textured biocompatible scaffolds from chicken eggshells. AB - Cell adhesion, morphology and growth are influenced by surface topography at nano and micrometer scales. Nano-textured surfaces are prepared using photolithography, plasma etching and long polymer chemical etching which are cost prohibitive and require specialized equipment. This article demonstrates a simple approach to synthesize nano-textured scaffolds from chicken eggshells. Varieties of pattern are made on the eggshells like micro-needle forests and nanopores, giving very uniform nano-textures to the surfaces. The surfaces are characterized for chemical composition and crystal phase. The novel patterns are transferred to PDMS surfaces and the nano-textured PDMS surfaces are used to study the effect of texturing on human fibroblast cell growth and attachment. The effects of surface topographies, along with laminin coating on cell cultures, are also studied. We find an exciting phenomenon that the initial seeding density of the fibroblast cells affects the influence of the nano-texturing on cell growth. These nano textured surfaces give 16 times more fibroblast growth when compared to flat PDMS surfaces. The novel nano-textured patterns also double the laminin adsorption on PDMS. PMID- 23111338 TI - The association of frailty with serum 25-hydroxyvitamin D and parathyroid hormone levels in older European men. AB - BACKGROUND: the link between the vitamin D endocrine axis and frailty remains undefined, with few studies examining the joint effect of vitamin D and parathyroid hormone (PTH) levels. Our objective was to determine the association of frailty with serum 25-hydroxyvitamin D (25(OH)D) and PTH. SETTING: cross sectional analysis within the European Male Ageing Study (EMAS). PARTICIPANTS: a total of 1,504 community-dwelling men aged 60-79 years. METHODS: frailty was classified using a frailty phenotype (FP) and frailty index (FI). The association of frailty with 25(OH)D and PTH was examined using multinomial logistic regression; individual FP criteria with 25(OH)D and PTH using binary logistic regression. Results were expressed as relative odds ratios (ROR) and 95% confidence intervals (CIs) for multinomial; odds ratios (OR) and 95% CIs for binary models. RESULTS: using the FP, 5.0% of subjects were classified as frail and 36.6% as prefrail. Lower levels of 25(OH)D were associated with being prefrail (per 1 SD decrease: ROR = 1.45; 95% CI: 1.26-1.67) and frail (ROR = 1.89; 95% CI: 1.30-2.76), after adjusting for age, centre and health and lifestyle confounders (robust group = base category). Higher levels of PTH were associated with being frail after adjustment for confounders (per 1 SD increase: ROR = 1.24; 95% CI: 1.01-1.52). Comparable results were found using the FI. Among the five FP criteria only sarcopenia was not associated with 25(OH)D levels, while only weakness was associated with PTH. CONCLUSION: lower 25(OH)D and higher PTH levels were positively associated with frailty in older men. Prospective data would enable the temporal nature of this relationship to be explored further. PMID- 23111339 TI - Differential roles for caspase-mediated and calpain-mediated cell death in 1- and 3-week-old rat cortical cultures. AB - Necrosis and apoptosis are well established as two primary cell death pathways. Mixed neuroglial cultures are commonly used to study cell death mechanisms in neural cells. However, the ages of these cultures vary across studies and little attention has been paid to how cell death processes may change as the cultures mature. To clarify whether neuroglial culture age affects cell death mechanisms, we treated 1- and 3-week-old neuroglial cultures with either the excitotoxic stimulus, N-methyl-D-aspartate (NMDA), or with the oxidative stressor, hydrogen peroxide (H2O2). Although NMDA is known to be toxic only in cultures that are at least 2 weeks old, H2O2 is toxic in cultures of all ages. Here, we confirm that, in 1-week-old neuroglial cultures, NMDA does not induce toxicity, whereas H2O2 induces both calpain-mediated and caspase-mediated neuronal death. In 3-week-old cultures, both NMDA and H2O2 trigger calpain-mediated, but not caspase-mediated, neuronal death. Further, we observed a decrease in caspase-3 levels and an increase in calpain levels in untreated neuroglial cultures as they aged. The findings presented here show that neuronal cell death mechanisms vary with culture age and highlight the necessity of considering culture age when interpreting neural cell culture data. PMID- 23111340 TI - Images in vascular medicine. Spontaneous celiac artery dissection. PMID- 23111341 TI - Physical activity of moderately impaired elderly stroke patients during rehabilitation. AB - In older adults, physical activity (PA) is promoted for public health preventive effort. It is also a major target in the rehabilitation process. Existing assessment tools in the clinical routine do not include any aspects of PA or participation and are often prone to floor or ceiling effects. The aim of this study was to document the process of rehabilitation by activity monitoring without floor or ceiling effects. Ninety-two stroke patients of a geriatric rehabilitation unit (mean age 82 years, +/-6.21 years, 61% women) were included in an observational study to assess physical capacity (balance, chair rise, gait speed) and PA at admission and two weeks thereafter. PA was measured through an ambulatory activity monitor based on accelerometers and gyroscopes and showed no floor or ceiling effects. Floor effects were however documented for measures of physical capacity (admission 5-11%; follow-up 2-9%) and ceiling effects were registered for the balance test (admission 17.4%; follow-up 22.8%). Improvements were documented for measures of physical capacity as well as for PA (all p < 0.001). We conclude that the assessment of PA by activity monitoring is a valuable measure to document objectively the process of rehabilitation without floor or ceiling effects. PMID- 23111342 TI - Tunable band gap in gold intercalated graphene. AB - Quasi free-standing graphene with Dirac fermion behavior has been recently demonstrated through gold intercalated epitaxial graphene. Herein, we investigate the electronic characteristics of gold-intercepted epitaxial graphene under a perpendicularly applied electric field. Evolution of the band structure of intercalated epitaxial graphene as a function of the bias is investigated by means of density-functional theory including interlayer van der Waals interactions. Our results indicate that gold-intercalated epitaxial graphene can lead to tuneable band gap with the applied bias, which is important for future device applications. PMID- 23111343 TI - Sub-axillary access with the use of costal cartilages articulated bars for correction of pectus carinatum. AB - We describe an original technique for correction of pectus carinatum (PC) through a limited sub-axillary incision by chondrectomy and the use of costal cartilages articulated bars to stabilize the chest wall. We have developed this technique in order to improve the cosmetic results in the surgical treatment of even complex sterno-chondral deformities. The surgical incision is made along the lateral edge of the pectoralis major muscle in the sub-axillary region and its length is related to the number of costal cartilages to be treated. This technique is principally indicated for asymmetric PC with unilateral deformities of the costal cartilages, but its application can be extended to bilateral alteration of the parasternal cartilages by performing the sub-axillary incision bilaterally. When more than four cartilages are removed, the chest is stabilized by articulated bars made using cylindrical fragments obtained by the division of the removed costal cartilages. This thoracoplasty technique performed with a minimally invasive sub-axillary access is simple and safe. It allows the effective treatment of severe PC with either unilateral asymmetric or bilateral costal cartilages deformities, avoiding the median sternal incision and the use of the metallic bar. PMID- 23111344 TI - Coronary artery bypass graft surgery during heart transplantation. AB - We report the case of a patient who was submitted to coronary artery bypass graft surgery (CABG) during heart transplant as, during bench exploration, the donor heart presented a palpable atherosclerotic lesion in the anterior descending artery, not detected before harvesting. The patent internal thoracic artery from a previous CABG was used. PMID- 23111345 TI - Impact on quality of life by improving asthma control medication in patients with persistent asthma in a paediatric emergency department. AB - OBJECTIVE: To assess the impact of improving long-term control medications on quality of life in children with persistent asthma symptoms attended in a paediatric emergency department (PED). STUDY DESIGN/METHODS: Prospective study carried out in a Spanish PED from May to December 2010 including children 1-14 years of age with persistent asthma symptoms. At discharge, their long-term control medications was either initiated or improved on the basis of the National Asthma Education and Prevention Program. Three follow-up telephone interviews at 2 and 6 weeks and at 6 months after the PED visit were completed. Parents were asked about the presence of asthma symptoms and quality of life of the child, respectively, using a six-item paediatric asthma control tool and an eight-item asthma-related quality-of-life instrument. RESULTS: The study was completed in 124 patients. Asthma LCTM was initiated in 74 (59.7%), improved in the same step in 36 (29%) and stepped up in 14 (11.3%). Ninety-one (73.4%), 107 (86.3%) and 117 patients (94.4%) were free of persistent asthma symptoms at 2 and 6 weeks and 6 months at follow-up, respectively. Seventy-five (60.5%) and 93 patients (75%) experienced an improvement in their quality of life between 2 and 6 weeks and 6 months after the PED visit, respectively. The mean eight-item asthma-related quality-of-life scores at 6 weeks and 6 months were significantly higher than those registered at 2 weeks at follow-up (91.9 +/- 11 and 93 +/- 10 vs. 86.1 +/- 14.3; P < 0.001). CONCLUSION: Children attended for acute asthma in PED where LCTM were initiated or stepped up showed a decrease in asthma persistent symptoms and an improvement in their quality of life. PMID- 23111347 TI - A comparative study of febrile and afebrile seizures associated with mild gastroenteritis. AB - PURPOSE: Seizures associated with mild gastroenteritis have been increasingly reported. We analyzed the clinical characteristics of febrile and afebrile seizures associated with mild gastroenteritis, and attempted to determine the influence of fever in these two groups. METHODS: We reviewed the medical records of 59 children presenting with seizures during a mild gastroenteritis episode. They were classified into an afebrile group (n=27) and a febrile group (n=32). We compared the age of onset, sex, seizure semiology, frequency, duration, family history, and prior history of seizures between the two groups. RESULTS: The mean age, family history, seizure semiology, and frequency of seizures were not significantly different between the two groups. However, more patients in the afebrile group experienced >= 2 seizures/day than in the febrile group (63% vs. 38%, p=0.051). The febrile patients had a tendency of experiencing prolonged seizures lasting >= 5 min compared with the afebrile group (34% vs. 11%, p=0.063). Prior febrile seizures were noted in 5 of the 32 patients (15.6%) in the febrile group, while none of the 27 patients in the afebrile group had a history of prior seizures (p=0.056). CONCLUSIONS: It seems that the presence of fever may influence the clinical characteristics of seizures associated with mild gastroenteritis. We suggest that afebrile seizures associated with gastroenteritis may be regarded as a distinct condition from those associated with fever, and it needs to be clarified by a further large sample study. PMID- 23111346 TI - Injections of muscimol into the paraventricular thalamic nucleus, but not mediodorsal thalamic nuclei, induce feeding in rats. AB - The paraventricular thalamic nucleus (PVT) is a component of the midline thalamic group that is interconnected with several brain regions known to play important roles in the control of food intake, including the lateral hypothalamus and nucleus accumbens shell, suggesting that the PVT itself may be involved in mediating feeding behavior. In the current study, we examined whether inhibition of cells in the PVT with the GABA(A) agonist muscimol could alter food intake in non-deprived rats. To control for possible spread of the drug, we also observed food intake after injections of muscimol into the overlying ventricle or laterally adjacent mediodorsal thalamic nuclei (MD). We found that muscimol injections into the central PVT dose-dependently increased food intake. In contrast, intra-MD injections of muscimol resulted in a potent dose-dependent suppression of food intake, while those into the overlying ventricle had no effect. These results support the proposal that the PVT is a component of the neural circuitry controlling feeding behavior. PMID- 23111348 TI - Reversal of efflux mediated antifungal resistance underlies synergistic activity of two monoterpenes with fluconazole. AB - Thymol (THY) and carvacrol (CARV), the principal chemical components of thyme oil have long been known for their wide use in medicine due to antimicrobial and disinfectant properties. This study, however, draws attention to a possible synergistic antifungal effect of these monoterpenes with azole antimycotic fluconazole. Resistance to azoles in Candida albicans involves over-expression of efflux-pump genes MDR1, CDR1, CDR2 or mutations and over-expression of target gene ERG11. The inhibition of drug efflux pumps is considered a feasible strategy to overcome clinical antifungal resistance. To put forward this approach, we investigated the combination effects of these monoterpenes and FLC against 38 clinically obtained FLC-sensitive, and eleven FLC-resistant Candida isolates. Synergism was observed with combinations of THY-FLC and CARV-FLC evaluated by checkerboard microdilution method and nature of the interactions was calculated by FICI. In addition, antifungal activity was assessed using agar-diffusion and time-kill curves. The drug efflux activity was determined using two dyes, Rhodamine6G (R6G) and fluorescent Hoechst 33342. No significant differences were observed in dye uptakes between FLC-susceptible and resistant isolates, incubated in glucose free buffer. However, a significantly higher efflux was recorded in FLC-resistant isolates when glucose was added. Both monoterpenes inhibited efflux by 70-90%, showing their high potency to block drug transporter pumps. Significant differences, in the expression levels of CDR1 and MDR1, induced by monoterpenes revealed reversal of FLC-resistance. The selectively fungicidal characteristics and ability to restore FLC susceptibility in resistant isolates signify a promising candidature of THY and CARV as antifungal agents in combinational treatments for candidiasis. PMID- 23111349 TI - Induced morphology control of Ln-asparagine coordination polymers from the macro to nanoscopic regime in polar solvent-water mixtures. AB - A bottom-up approach is presented here for morphology control of Ln-asparagine (Asn) coordination polymers (CPs) from the macro to nanoscopic regime by tuning solvent polarity based on the pi* solvent polarity scale in polar solvent-water mixed solutions. By a simple hydrothermal treatment, large macroporous spheres with sizes up to millimeters were obtained in ethanol (pi*: 0.54)-water mixtures, and their formation mechanism was proved to be particle aggregation together with a hollowing process based on Ostwald ripening. Other solvents with increasing polarity were also used, and submicrometer spheres as well as fine nanoparticles were prepared in acetone (pi*: 0.71) and DMF (pi*: 0.88), respectively. When dioxane (pi*: 0.55) was used here, whose pi* value is similar to ethanol, large macroporous spheres were also prepared. Furthermore, with Ce- and La-Asn CPs large spheres as precursors, after calcination, ceria and lanthana large spheres with hierarchical structures were fabricated, respectively. Considering that many growth media of CPs are single solvent systems, designing certain solvents mixtures and tuning their polarity would bring us new opportunities to achieve morphology and composition control of CPs materials. PMID- 23111350 TI - Anomalous Staudinger reaction at intramolecular frustrated P-B Lewis pair frameworks. AB - The FLP-mesityl azide addition products 5, formed by FLP-addition to the terminal azide nitrogen atom, undergo N-N bond cleavage in an unusual variant of the Staudinger reaction upon thermolysis or photolysis to give an internally borane stabilized [P]=NH phosphinimine and a dimethylindazole derivative. PMID- 23111351 TI - Electrical pulse triggered reversible assembly of molecular adlayers. AB - Reversible adlattice assembly for alkoxy-decorated aromatics is controllable by short electrical pulses. PMID- 23111352 TI - Government makes up hospital bailout policies "on the hoof," say MPs. PMID- 23111353 TI - Comparison of the diagnostic and prognostic values of 99mTc-MDP-planar bone scintigraphy, 131I-SPECT/CT and 18F-FDG-PET/CT for the detection of bone metastases from differentiated thyroid cancer. AB - OBJECTIVE: The aim of this study was to compare the diagnostic and prognostic values of (99m)Tc-MDP-planar bone scintigraphy ((99m)Tc-MDP-BS), (131)I single photon emission computed tomography/computed tomography ((131)I-SPECT/CT) and (18)F-fluorodeoxyglucose ((18)F-FDG)-PET/CT for the detection of bone metastases from differentiated thyroid cancer (DTC). METHODS: Eighty patients with DTC with suspected bone metastases from DTC were retrospectively analysed. All patients were examined with (99m)(99m)Tc-MDP-BS, (131)I-SPECT/CT and (18)F-FDG-PET/CT, with a maximum interval of 2 months between scans. The diagnostic performances of (99m)Tc-MDP-BS, (131)I-SPECT/CT and (99m)F-FDG-PET/CT were investigated and compared. Univariate and multivariate analyses were carried out to evaluate the effects of variables on the survival of patients. RESULTS: Out of the 80 patients with 148 foci, 43 with 106 foci were diagnosed as being true positive for bone metastases from DTC. In patient-based analysis, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of (99m)Tc-MDP-BS were 79.07, 83.78, 85.00, 77.50 and 81.25%, respectively; those of (131)I-SPECT/CT were 93.02, 97.30, 97.56, 92.31 and 95.00%, and those of (18)F FDG-PET/CT were 86.05, 94.59, 94.87, 85.36 and 87.80%, respectively. In lesion based analysis, the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy of (99m)Tc-MDP-BS were 72.64, 73.81, 87.50, 51.67 and 72.97%, respectively; those of (131)I-SPECT/CT were 92.45, 97.62, 98.99, 83.67 and 93.92%, and those of (18)F-FDG-PET/CT were 85.85, 88.10, 94.50, 71.15 and 86.49%, respectively. Comparing the receiver-operating characteristic area using the McNemar test, both (131)I-SPECT/CT and (18)F-FDG PET/CT were found to be superior to (99m)Tc-MDP-BS for the detection of bone metastases from DTC in patient-based and lesion-based analyses (P<0.05). Patient based analysis showed that there were no significant differences between (131)I SPECT/CT and (18)F-FDG-PET/CT (P=0.087) but lesion-based analysis revealed that (131)I-SPECT/CT was superior to (18)F-FDG-PET/CT (P=0.002). For the association between these image patterns and the prognosis of DTC patients, (18)F-FDG positivity was the factor predicting a poor prognosis. CONCLUSION: (131)I SPECT/CT and (18)F-FDG-PET/CT demonstrated high diagnostic performance in detecting bone metastases from DTC. (99m)Tc-MDP-BS might be completely replaced by (131)I-SPECT/CT in combination with ((131)F-FDG-PET/CT in the management of DTC patients with bone metastases. (18)F-FDG-PET/CT positivity was an independent factor associated with poor prognosis. PMID- 23111354 TI - Simplified methods for assessment of renal function as the ratio of glomerular filtration rate to extracellular fluid volume. AB - BACKGROUND: Instead of scaling glomerular filtration rate (GFR) to a body surface area of 1.73 m(2), it has been suggested to scale GFR to extracellular fluid volume (ECV). The ratio GFR/ECV has physiological meaning in that it indicates how often 'that which is to be regulated' (i.e. ECV) comes into contact with the 'regulator' (i.e. the kidneys). AIM: The aim of the present study was as follows: to analyse two published calculation methods for determining ECV and GFR/ECV; to develop a new simple and accurate formula for determining ECV; and to compare and evaluate these methods. MATERIALS AND METHODS: GFR was determined as (51)Cr-EDTA clearance. The study comprised 128 individuals (35 women, 66 men and 27 children) with a full (51)Cr-EDTA plasma concentration curve, determined from injection until 4-5 h p.i. Reference values for GFR and ECV were calculated from the full curve. One-pool approximations C/(1) and V(1) were calculated using only the final-slope curve. Four calculation methods were compared: simple one-pool values; GFR/ECV according to Peters and colleagues; ECV according to Brochner Mortensen (BM); and ECV according to a new method (JBM): y=2x-1, where x=Cl(1)/Cl and y=V(1)/ECV. RESULTS: The new JBM method is accurate and can be explained theoretically. BM has a slight bias for high renal function. The Peters method had bias in our data. GFR/ECV had better precision than ECV alone, especially for BM and JBM, which were within -4% to +7% of the reference values (95% limits of agreement in adults). CONCLUSION: GFR/ECV can be precisely determined, especially with the BM and JBM methods. Expressing GFR/ECV in unit %/h gives a simple interpretation. Normal ranges for GFR/ECV need to be established. PMID- 23111355 TI - Outcome of female pediatric patients diagnosed with genital tract rhabdomyosarcoma based on analysis of cases registered in SEER database between 1973 and 2006. AB - OBJECTIVES: We analyzed outcomes of pediatric rhabdomyosarcoma (RMS) of the female genitourinary (GU) tract using the Surveillance Epidemiology and End Result database. MATERIALS AND METHODS: Females (0 to 19 years of age) diagnosed with RMS of GU sites between 1973 and 2006 were included in the analysis as 2 groups, 0 to 9 and 10 to 19-year-olds. They were compared for primary site distribution, stage, histology, and therapy. Kaplan-Meier method was used for survival analysis by histology, stage, and primary sites. RESULTS: Sixty-seven cases were identified. Twenty-six cases (38.8%) had localized disease, 11 (16.2%) had regional disease, 15 (28.4%) had distant spread, and 15 (28.4%) were unstaged. The majority (85%) had embryonal RMS. Twenty-eight tumors originated in the vagina, 26 in the cervix/uterus, and 13 in other sites including vulva, labia, ovaries. Age groups did not differ with respect to race, cancer stage, histologic type, percent of cases treated surgically, and the proportion receiving radiotherapy. Vaginal RMS was predominant in the younger age group (68.4%). In the older age group, 65.5% had RMS of the cervix or uterus. This age related prevalence of tumor sites was statistically significant (P<0.001). Survival of patients with embryonal and early-stage tumor was superior. There was no significant difference in survival by age or primary tumor site. CONCLUSIONS: This population-based study confirmed the significance of tumor histology and stage for female GU RMS patients. Tumor sites are strongly associated with age at diagnosis. PMID- 23111356 TI - Dose delivery analysis of weekly versus 3-weekly cisplatin concurrent with radiation therapy for locally advanced nasopharyngeal carcinoma (NPC). AB - OBJECTIVE: The purpose of this study was to analyze the dose delivery and toxicity of weekly cisplatin versus high-dose cisplatin given every 3 weeks in a tertiary oncology clinic. METHODS: From January 2000 to July 2009, patients with biopsy-proven nasopharyngeal carcinoma receiving concurrent cisplatin with curative-intent radiation therapy (RT) were included. Before 2005, most patients received cisplatin (Q3) (100 mg/m intravenously days 1, 22, and 43 of RT) and 3 dimensional conformal RT (66 Gy, 33 fractions). After 2005, most patients received weekly cisplatin (Q1) (40 mg/m intravenously weekly for 7 wk of RT) and intensity-modulated radiotherapy (70 Gy, 35 fractions). RESULTS: Seventy-three patients were analyzed: 45 for Q1 and 28 for Q3. Cumulative doses >=200 mg/m were achieved in 80% of Q1 and 86% of Q3 patients, respectively. Dose reduction due to toxicity was required in 2/45 (4%) of Q1 patients compared with 11/28 (39%) of Q3 patients (P=0.0003). Toxicities in Q1 and Q3 patients included: hospitalization for acute toxicity in 20% and 35.7%; mean weight loss 10.85% and 8.75%; percutaneous endoscopic gastrostomy tube placement in 25.6% and 29.6%; and grade 3 dehydration in 11.1% and 17.9%, respectively. Median follow-up time was 3 years for Q1 and 6 years for Q3 patients. Median disease-free survival was 46 months for the Q1 group and 53 months for the Q3 group (P=0.667). There was no difference in overall survival between Q1 and Q3. CONCLUSIONS: In this series, weekly 40 mg/m cisplatin and 3-weekly 100 mg/m cisplatin showed similar deliverability, toxicity profiles, and outcomes. At our center, weekly cisplatin is standard of care for patients with locally advanced nasopharyngeal carcinoma undergoing chemoradiotherapy. PMID- 23111357 TI - Use of intraoperative radiotherapy for upper-extremity soft-tissue sarcomas: analysis of disease outcomes and toxicity. AB - OBJECTIVES: To review outcomes for patients who received intraoperative radiotherapy (IORT) for upper-extremity sarcoma. METHODS: We identified patients with upper-extremity tumors who were treated with external beam radiotherapy, surgery, and IORT, with or without chemotherapy. Kaplan-Meier estimates for overall survival (OS), central control (CC), local control (LC), and distant control (DC) were obtained. RESULTS: Sixty-one patients were identified. Median age was 50 years (range, 13 to 95 y). Median follow-up was 5.9 years. Eleven patients had gross (R2; n=1) or microscopic (R1; n=10) disease at the time of IORT. IORT doses ranged from 7.50 to 20.00 Gy. External beam radiotherapy doses ranged from 19.80 to 54.00 Gy. OS at 5 and 10 years was 72% and 58%, respectively. LC at 5 and 10 years was 91% and 88%, respectively. DC at 5 and 10 years was 80% and 77%, respectively. Patients treated for recurrent disease had inferior 5-year OS compared with patients with first diagnoses (63% vs. 74%; P=0.02) and lower 5-year LC (67% vs. 94%; P<0.01). For patients with R1 or R2 resections, LC at 5 and 10 years was 100% and 86%, respectively; for patients with R0 resections, LC was 89% at both 5 and 10 years (P=0.98). Severe toxicity attributable to treatment was noted for 4 patients (7%). CONCLUSIONS: For upper extremity sarcoma, treatment including IORT was associated with excellent LC, limb preservation, and survival. LC rates were excellent for patients with positive margins after resection. Patients with recurrent disease had worse outcomes, but limb preservation was achievable for most patients. PMID- 23111358 TI - Lymph node ratio is an independent prognostic factor after resection of periampullary malignancies: data from a tertiary referral center in the middle East. AB - OBJECTIVE: The prognostic impact of nodal involvement in resected pancreatic carcinoma and biliary malignancy has been relatively well established. It has been suggested that lymph node ratio (LNR) may be a more informative way of stratifying patients with node positive disease. Our retrospective review aimed to investigate the significance of such variables and test for independent prognostic factors for survival. METHODS: One hundred eighty-three pancreatic and periampullary malignancy cases were registered at the American University of Beirut Medical Center from 1990 to 2004. Of those, 80 had complete data on lymph node status. We analyzed the impact of the number of lymph nodes resected, the number of positive lymph nodes retrieved and LNR using Kaplan-Meier and Cox proportional hazard models. The measured outcome in the KM model was the survival probability at 1, 3, and 5 years while the Cox model was used to measure the hazard ratio (HR) of the previously identified predictors on survival. RESULTS: For the 80 patients included in this analysis, overall survival rates were 65% (54 to 78), 32% (18 to 47), and 21% (8 to 34) were alive at 1, 3, and 5 years, respectively. The median number of resected lymph nodes was 9. In the node positive patients, those who had >12 nodes examined were found to have a significantly better survival (HR=0.24; P=0.013). On multivariate analysis, our model showed the following factors to be significant: age 60 years or older (HR=5.92; P=0.018), poorly differentiated tumors (HR=21.87; P=0.018), number of lymph nodes examined <12 LN (HR=6.77; P=0.022), 3 or more metastatic LN (HR=7.21; P=0.028), and LNR>=0.2 (HR=7.12; P=0.007). CONCLUSIONS: After pancreaticodudonectomy for adenocarcinoma of the pancreas and biliary malignancies, ratio-based lymph node staging is an independent and powerful prognostic factor. PMID- 23111359 TI - A phase II study of bevacizumab, oxaliplatin, and capecitabine in patients with previously untreated metastatic colorectal cancer: a prospective, multicenter trial of the Korean Cancer Study Group. AB - BACKGROUND: Bevacizumab plus doublet chemotherapy has become one of the standard treatments for patients with metastatic colorectal cancer (mCRC). We have investigated the efficacy and safety of bevacizumab plus capecitabine and oxaliplatin as first-line chemotherapy for Korean patients with mCRC. METHODS: Patients were treated with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m on day 1 and capecitabine 2000 mg/m/d on days 1 to 14. After 9 cycles, patients were entered into the maintenance treatment, consisting of bevacizumab and capecitabine. Treatment was repeated every 3 weeks and response was evaluated every 2 cycles. RESULTS: Of the 49 patients (median age, 57 y), 29 (59%) had primary tumors in the colon, and 31 (63%) had metastases in 2 or more organs. Overall response rate was 71.4% (95% confidence interval [CI], 58.7%-84.1%), median progression-free survival was 10.4 months (95% CI, 8.2-12.5 mo), and median overall survival was 20.0 months (95% CI, 16.7-23.4 mo). Frequent grade 3 toxicities included neuropathy (9, 18.4%), neutropenia (8, 16.3%), diarrhea (6, 12.2%), and thrombocytopenia (3, 6.1%). Bevacizumab-related grade 3 or 4 toxicities included proteinuria (1, 2.0%) and bowel perforation (1, 2.0%). CONCLUSIONS: Bevacizumab plus capecitabine and oxaliplatin was well tolerated and showed promising antitumor activity in Korean patients with mCRC. PMID- 23111360 TI - Prognostic value of positron emission tomography/computed tomography findings in limited-stage small cell lung cancer before chemoradiation therapy. AB - OBJECTIVES: Positron emission tomography/computed tomography (PET/CT) is increasingly used for disease staging and evaluation of treatment effectiveness in limited-stage small cell lung cancer (LS-SCLC). However, the prognostic value of PET/CT metrics in LS-SCLC is not clear. METHODS: Subjects in this retrospective study were 50 patients with LS-SCLC who had had PET/CT before definitive chemoradiation therapy in January 2003 to August 2009; 15 (29%) had also had induction chemotherapy. Median radiation dose was 45 Gy (range, 40.5 to 61.8 Gy). All scans were read and scored by 1 radiologist. Kaplan-Meier curves were used to estimate survival outcomes, and Cox regression analysis was used to evaluate the prognostic value of pretreatment standardized uptake values (SUVs) with regard to locoregional control (LRC) and overall survival (OS). RESULTS: At a median follow-up time of 18.2 months (range, 2.1 to 78 mo), LRC rates were 64% at 2 and 3 years; OS rates were 81% at 2 years and 61% at 3 years. None of the metrics assessed (receipt of induction chemotherapy, pretreatment SUVprimary, SUVnodal, meanSUVmax) was associated with LRC or OS, but patients with residual SUV<=5.5 after treatment had a 3-year OS rate of 69% versus 34% for those with SUV>5.5. CONCLUSIONS: Pretreatment PET/CT metrics had no prognostic significance for patients with LS-SCLC, perhaps because of the rapid proliferation of SCLC or other confounding factors affecting survival. PMID- 23111361 TI - Prognostic value of primary tumor FDG uptake for occult mediastinal lymph node involvement in clinically N2/N3 node-negative non-small cell lung cancer. AB - OBJECTIVES: The objective of this study was to identify predictive factors of occult mediastinal nodal involvement on staging positron emission tomography with F-fluorodeoxyglucose in patients with non-small cell lung cancer. METHODS: We performed a retrospective review of 665 patients with suspected non-small cell lung cancer who underwent staging positron emission tomography with F fluorodeoxyglucose from January 1, 2000 through August 31, 2010 at the Hospital of the University of Pennsylvania with clinical stage I or II disease and no evidence of N2 or N3 involvement on staging positron emission tomography (PET). A total of 201 of these patients underwent invasive pathologic staging of the mediastinum at the Hospital of the University of Pennsylvania with pathology reports available at the time of review. RESULTS: A total of 63 of the 201 patients were found to have N2 disease at the time of pathologic staging. The mean standardized uptake value (SUV) of the primary tumor for patients with occult N2 metastases was significantly higher than the node-negative patients (SUV 9.31 vs. 7.24, P=0.04). Histology, tumor location (central vs. peripheral), sex, and age were not predictive for occult N2 disease. A multivariate analysis was performed and identified primary tumor SUV>6 was the only significant predictor (P=0.02). An analysis by quartile identified a primary tumor SUV>10 to have an odds ratio of 1.72 compared with an SUV<4 of occult N2 involvement. CONCLUSIONS: Increased primary tumor SUV predicted for increased risk of mediastinal nodal disease. Tumor location was not predictive of PET-occult mediastinal nodal involvement, in contrast to previous publications. Pathologic staging of the mediastinum should be strongly considered in these patients even with a negative mediastinum on PET. PMID- 23111362 TI - Long-term outcomes and role of chemotherapy in adults with newly diagnosed medulloblastoma. AB - OBJECTIVE: To assess the survival and role of adjuvant chemotherapy in adult medulloblastoma. METHODS: We reviewed outcomes of 66 patients (aged 18 y or more; median age, 33 y) with medulloblastoma. Forty-four (67%) patients had M0 disease, 9 had M1-M4, and 13 had MX. Thirty-one patients each for whom risk stratification was available were classified as high risk or standard risk. Fifty-six patients had histologic results: classic histology was the most common (n=46 [84%]), followed by desmoplastic (n=9), and large cell/anaplastic (n=1). Overall survival (OS) and progression-free survival (PFS) were estimated with Kaplan-Meier curves and log-rank tests. Cox regression analysis was used to compare recurrences. RESULTS: Median follow-up was 6.7 years. The estimated 5-year OS and PFS were 74% and 59%, respectively. High-risk versus standard-risk classification was associated with worse OS (61% vs. 86%; P=0.03) and recurrence (hazard ratio, 2.56; P=0.05) and a trend for worse PFS (49% vs. 69%; P=0.13). Gross total resection was associated with improved OS (P=0.03) and a trend toward improved PFS (P=0.09). No chemotherapy benefit could be demonstrated for the group as a whole. For high-risk patients with classic histology (n=25), chemotherapy was associated with a trend for improvement in 5-year PFS from 36% to 71% (P=0.10) and in 5-year OS from 49% to 100% (P=0.08). CONCLUSIONS: In adult patients with medulloblastoma, the extent of resection and risk classification predicts the outcome. These results suggest a chemotherapy benefit for high-risk patients with classic histology. PMID- 23111363 TI - Phase II study of biweekly carboplatin, gemcitabine, and bevacizumab as first line treatment in patients with stage IIIB/IV NSCLC. AB - BACKGROUND: This study was initiated to assess the safety and efficacy of biweekly carboplatin and gemcitabine with bevacizumab in treatment-naive patients with advanced and metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: An open-label, nonrandomized phase II clinical trial was conducted. Treatment consisted of a biweekly cycle of gemcitabine, carboplatin, and bevacizumab for a maximum of 6 cycles. If no disease progression or intolerable side effects were observed, maintenance therapy with bevacizumab was continued until disease progressed. Progression-free survival, overall survival (OS), objective response rate, and the safety and tolerability of the therapy were assessed. RESULTS: Treatment was administered to 35 patients with stage IIIB/IV NSCLC. Median age of the patients was 64.5 years, with 58% being male. Median number of cycles of treatment was 6 (range, 4 to 28 cycles); median number of days of treatment was 117 days (range, 43 to 451 d). Sixty-six percent of patients experienced grade >=3 toxicities. Hypertension (19%) was the most common adverse event. Pulmonary hemorrhage (3%) and pulmonary abscess (3%) were the causes of treatment-related deaths. There were 48% patients with partial response, 23% with stable disease, and 29% with progressive disease. Median progression-free survival was 2.6 months [95% confidence interval (CI), 1.6-3.4], and median OS was 13.4 months (95% CI, 8.4-24). The 2-year OS rate was 30% (95% CI, 12%-51%). CONCLUSIONS: Biweekly therapy with combination of carboplatin, gemcitabine, and bevacizumab in advanced inoperable NSCLC provided limited benefit and was associated with excessive toxicity. Further testing of this regimen is not recommended. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT00400803. PMID- 23111364 TI - Conditional survival probabilities for patients with resected pancreatic adenocarcinoma. AB - BACKGROUND: The purpose of this study is to evaluate conditional survival probabilities for patients with resected pancreatic adenocarcinoma (PC). METHODS: Patients with resected PC from 1998 to 2008 were identified from the Surveillance, Epidemiology and End Results Database. Data on patient, tumor, and treatment characteristics were extracted. Overall survival (OS) rates were calculated using the Kaplan-Meier method. A multivariable analysis at different time points from survival was performed to determine independent prognostic factors associated with all-cause mortality hazard ratios using Cox proportional hazards models. RESULTS: A total of 4883 patients with resected PC were identified. The 1-, 3-, and 5-year survival estimates for patients at diagnosis were 67%, 29%, and 21%, respectively. The probability of surviving an additional 1-, 3-, or 5-year conditional upon already surviving 5 years after diagnosis were 89%, 76%, and 71%, respectively. Prognostic factors significantly correlated with improved OS at the time of diagnosis on multivariable analysis include: earlier stage, younger age, later year of diagnosis, white ethnicity, female sex, and residence in a high income district (P<0.05). Among those already surviving 3 years after diagnosis, younger age was the only prognostic factor statistically significantly correlated with improved OS (P<0.05). CONCLUSIONS: Conditional survival estimates provide additional prognostic information that may be used to counsel PC patients on how their prognosis may change over time. Further research using prospectively collected data is warranted to help determine recommended follow-up intervals and benchmarks for future clinical trials. PMID- 23111365 TI - Correlation between (in)commensurate domains of multilayer epitaxial graphene grown on SiC(0001) and single layer electronic behavior. AB - A systematic study of the evolution of the electronic behavior and atomic structure of multilayer epitaxial graphene (MEG) as a function of growth time was performed. MEG was obtained by sublimation of a 4H-SiC(0001(-)) substrate in an argon atmosphere. Raman spectroscopy and x-ray diffraction were carried out in samples grown for different times. For 30 min of growth the sample Raman signal is similar to that of graphite, while for 60 min the spectrum becomes equivalent to that of exfoliated graphene. Conventional x-ray diffraction reveals that all the samples have two different (0001) lattice spacings. Grazing incidence x-ray diffraction shows that thin films are composed of rotated (commensurate) structures formed by adjacent graphene layers. Thick films are almost completely disordered. This result can be directly correlated to the single layer electronic behavior of the films as observed by Raman spectroscopy. Finally, to understand the change in lattice spacings as a result of layer rotation, we have carried out first principles calculations (using density functional theory) of the observed commensurate structures. PMID- 23111366 TI - Surface-initiated polymerization from carbon nanotubes: strategies and perspectives. AB - Carbon nanotubes (CNTs) represent one of the most promising materials in nanoscience today, with their unique electronic, chemical and mechanical properties. Strong van der Waals interactions and poor solubility greatly affect their potential for applications in various fields. In the past decade, great efforts have been undertaken to modify CNTs into organophilic material via covalent and non-covalent grafting strategies. This review focuses on advances in various strategies used for the surface initiated polymerization and provides perspectives on grafting polymers covalently from CNTs. PMID- 23111367 TI - Diaphragmatic hernia repair using a rectus abdominis muscle pedicle flap in three dogs. AB - OBJECTIVE: To report the clinical use of a pedicle flap from the rectus abdominis muscle to repair extensive diaphragmatic tears in dogs with diaphragmatic hernia. MATERIALS AND METHODS: Three dogs with a combination of radial and circumferential diaphragmatic tears were studied. The circumferential tear was repaired by suturing the wound edge with the edge at the abdominal wall. A pedicle flap of the rectus abdominis muscle was used for repairing the radial tear. The dogs were examined radiographically for lung and diaphragm appearance and evidence of reherniation at 10 days, and at one, two, and four months after surgery, and fluoroscopically for paradoxical motion of the diaphragm at one and four months. RESULTS: The rectus abdominis muscle pedicle flap was successfully used in all three dogs. The animals recovered uneventfully without evidence of reherniation during the four follow-up months. Fluoroscopic examination revealed no paradoxical motion of the diaphragm. CLINICAL SIGNIFICANCE: A rectus abdominis muscle pedicle flap can be used for repairing large diaphragmatic defects in dogs. PMID- 23111368 TI - Effect of the pelvic compression belt on the hip extensor activation patterns of sacroiliac joint pain patients during one-leg standing: a pilot study. AB - As a means of external stabilization of the sacroiliac joint (SIJ), many clinicians have often advocated the use of the pelvic compression belt (PCB). The objective of this pilot study was to compare the effects of the PCB on hip extensor muscle activation patterns during one-leg standing in subjects with and without sacroiliac joint pain (SIJP). Sixteen subjects with SIJP and fifteen asymptomatic volunteers participated in this study. Surface electromyography (EMG) data [signal amplitude and premotor reaction time (RT)] were collected from the gluteus maximus and biceps femoris muscles of the supporting leg during one leg standing with and without the PCB. Compared to that of the asymptomatic individuals, the EMG amplitude of the biceps femoris was significantly decreased in individuals with SIJP upon the application of the PCB (p < 0.05). Furthermore, on using the PCB, in individuals with SIJP, the RT of the gluteus maximus was significantly decreased; however, the RT of the biceps femoris was increased (p < 0.05). Thus, our data support the use of the PCB to modify the activation patterns of the hip extensors among patients with SIJP. PMID- 23111369 TI - Access to antenatal care and children's cognitive development: a comparative analysis in Ethiopia, Peru, Vietnam and India. AB - OBJECTIVES: Early life interventions are considered essential for reducing the burden of health inequalities over the life course. This paper tests this issue empirically focusing on whether access to antenatal care can later reduce children's health and educational inequalities. METHODS: Data came from the Young Lives Project for Ethiopia, Peru, Vietnam, and the State of Andhra Pradesh in India. We selected children born in early 2001/2002 and who were followed longitudinally in 2006/2007. We used multilevel mixed effects linear regression models to estimate the parameters of interest. RESULTS: We found a positive and significant relationship between mothers' access to antenatal care and their children's cognitive development in all countries. In addition, we found a positive and significant relationship between antenatal care and children's cognitive development for stunted children but only in Peru and Vietnam. CONCLUSIONS: We conclude that (1) antenatal care has the potential to change the negative consequences of early nutritional deficiencies on later cognitive development in Peru and Vietnam; (2) differentials in the quality of antenatal care services could explain the cross-country differentials in the role of early life interventions found here. PMID- 23111370 TI - Evaluation of an intervention using a self-regulatory counselling aid: pre- and post- intervention results of the OPTIMAHL 60plus study. AB - OBJECTIVES: The study covers development and evaluation of an innovative counselling aid in an intervention study. The main purpose of the study was to establish whether improvements in nutrition and physical activity behaviour according to standard recommendations can be demonstrated. METHODS: OPTIMAHL 60plus is a quasi-experimental study in which participants were assigned in clusters to an intervention or control group. The study was conducted in low socio-economic-status districts in Bremen, Germany. 423 elderly participated at baseline and 369 after 3 months intervention. Face-to-face interviews (24-h recall and frequency questionnaire) were conducted at T0 and T1. chi (2)-tests, sign-test and logistic regression were used for statistical analyses. RESULTS: No significant differences could be shown when comparing the intervention versus control group at T1. Significant changes from T0 to T1 in the intervention group were identified for daily fruit and vegetable (chi (2)-test, p = 0.04), and for weekly fish consumption (chi (2)-test, p = 0.04). However, similar results could also be shown for the control group. CONCLUSIONS: A practical counselling aid for elderly was developed and evaluated. Changes in the health behaviour of elderly were identified, but effects could not be clearly traced to the intervention. PMID- 23111371 TI - Health co-benefits and risks of public health adaptation strategies to climate change: a review of current literature. AB - OBJECTIVES: Many public health adaptation strategies have been identified in response to climate change. This report reviews current literature on health co benefits and risks of these strategies to gain a better understanding of how they may affect health. METHODS: A literature review was conducted electronically using English language literature from January 2000 to March 2012. Of 812 articles identified, 22 peer-reviewed articles that directly addressed health co benefits or risks of adaptation were included in the review. RESULTS: The co benefits and risks identified in the literature most commonly relate to improvements in health associated with adaptation actions that affect social capital and urban design. Health co-benefits of improvements in social capital have positive influences on mental health, independently of other determinants. Risks included reinforcing existing misconceptions regarding health. Health co benefits of urban design strategies included reduced obesity, cardiovascular disease and improved mental health through increased physical activity, cooling spaces (e.g., shaded areas), and social connectivity. Risks included pollen allergies with increased urban green space, and adverse health effects from heat events through the use of air conditioning. CONCLUSIONS: Due to the current limited understanding of the full impacts of the wide range of existing climate change adaptation strategies, further research should focus on both unintended positive and negative consequences of public health adaptation. PMID- 23111372 TI - Mediterranean studies of cardiovascular disease and hyperglycemia: analytical modeling of population socio-economic transitions (MedCHAMPS)--rationale and methods. AB - OBJECTIVES: In response to the escalating epidemic of cardiovascular disease (CVD) in the Mediterranean Region (MR), an international collaboration aiming at understanding the burden of CVD and evaluating cost-effective strategies to combat it was recently established. This paper describes the rationale and methods of the project MedCHAMPS to disseminate this successful experience. METHODS: The framework of MedCHAMPS is exceptional in combining multiple disciplines (e.g. epidemiology, anthropology, economics), countries [Turkey, Syria, occupied Palestinian territory (oPt), Tunisia, UK, Ireland], research methods (situational and policy analysis, quantitative and qualitative studies, statistical modeling), and involving local stakeholders at all levels to assess trends of CVD/diabetes in the society and attributes of the local health care systems to provide optimal policy recommendations to reduce the burden of CVD/diabetes. RESULTS AND CONCLUSIONS: MedCHAMPS provides policy makers in the MR and beyond needed guidance about the burden of CVD, and best cost-effective ways to combat it. Our approach of building developed-developing countries collaboration also provides a roadmap for other researchers seeking to build research base into CVD epidemiology and prevention in developing countries. PMID- 23111374 TI - Syntheses and in vitro evaluations of uncharged reactivators for human acetylcholinesterase inhibited by organophosphorus nerve agents. AB - Organophosphorus nerve agents (OPNAs) are highly toxic compounds that represent a threat to both military and civilian populations. They cause an irreversible inhibition of acetylcholinesterase (AChE), by the formation of a covalent P-O bond with the catalytic serine. Among the present treatment of nerve agents poisoning, pyridinium and bis-pyridinium aldoximes are used to reactivate this inhibited enzyme but these compounds do not readily cross the blood brain barrier (BBB) due to their permanent cationic charge and thus cannot efficiently reactivate cholinesterases in the central nervous system (CNS). In this study, a series of seven new uncharged oximes reactivators have been synthesized and their in vitro ability to reactivate VX and tabun-inhibited human acetylcholinesterase (hAChE) has been evaluated. The dissociation constant K(D) of inhibited enzyme oxime complex, the reactivity rate constant kr and the second order reactivation rate constant k(r2) have been determined and have been compared to reference oximes HI-6, Obidoxime and 2-Pralidoxime (2-PAM). Regarding the reactivation of VX-inhibited hAChE, all compounds show a better reactivation potency than those of 2-PAM, nevertheless they are less efficient than obidoxime and HI-6. Moreover, one of seven described compounds presents an ability to reactivate tabun inhibited hAChE equivalent to those of 2-PAM. PMID- 23111375 TI - Iron-mediated direct arylation with arylboronic acids through an aryl radical transfer pathway. AB - A novel iron-mediated direct C-H arylation of quinones and pyridine analogues with arylboronic acids has been developed using dichloromethane and water as solvents at ambient temperature. FeS is employed and serves as an efficient catalyst. A detailed reaction mechanism is speculated and expounded. PMID- 23111376 TI - The incidence of secondary central nervous system involvement in patients with non-Hodgkin's lymphoma as detected by 18F-FDG PET/CT. AB - AIM: Secondary central nervous system (CNS) involvement is a devastating and usually fatal complication of non-Hodgkin's lymphoma (NHL). We aimed to evaluate the incidence of secondary CNS involvement and the value of (18)F-FDG PET/computed tomography (CT) imaging in the detection of secondary CNS involvement in patients with NHL. METHODS: A total of 123 immunocompetent patients (58 men, 65 women; mean age: 56.5+/-19.2) with biopsy-proven NHL who underwent (18)F-FDG PET/CT for primary staging (n=68) and restaging (n=55) of recurrent disease were reviewed retrospectively. Those with secondary CNS involvement as diagnosed on PET/CT were identified. CNS involvement was confirmed by MRI and cerebrospinal fluid cytology. RESULTS: The clinical Ann Arbor stages of the patient population were as follows: stage I - 10 patients; stage II - 44 patients; stage III - 32 patients, and stage IV - 37 patients. PET/CT detected CNS involvement in six patients. The ages of patients with CNS disease ranged from 23 to 68 (mean: 47.2) years. Three patients presented with CNS involvement associated with systemic disease manifestation at initial diagnosis; one patient had isolated CNS relapse and two had relapsed systemic NHL with progression to CNS involvement. Relapse interval was 8-12 months following initial diagnosis. The types of CNS involvement in patients were as follows: parenchymal (n=2), leptomeningeal (n=2), both parenchymal and leptomeningeal (n=1), and pituitary gland involvement (n=1), which is an uncommon manifestation. Median duration of survival was 2.5 months after the diagnosis of CNS involvement. CONCLUSION: The incidence of secondary CNS involvement was 4.4% at initial diagnosis and 5.4% among patients with relapse of lymphoma in our study. PET/CT is a sensitive, objective, and valuable method for the diagnosis of secondary CNS involvement in patients with NHL. In addition, pituitary gland involvement, as a very rare manifestation of secondary CNS lymphoma, has been shown. PMID- 23111377 TI - Comparison between F-18 fluorodeoxyglucose and Ga-68 DOTATOC in metastasized melanoma. AB - PURPOSE: Somatostatin binding to somatostatin receptors (SSTRs) is known to have an antiproliferative effect in neuroendocrine tumours. Melanoma cells are derived from the neural crest and thus express SSTR. Treatment options in metastasized melanomas are limited. Therefore, we aimed to investigate whether there is a relevant uptake of the SSTR analogue DOTATOC in metastasized melanoma patients, which could be used for therapy with radiolabelled SSTR analogues. MATERIALS AND METHODS: We investigated 18 patients (nine men and nine women; mean age 61 years) with metastasized melanoma using PET/CT, first with F-18 fluorodeoxyglucose ((18)F-FDG) and then with Ga-68 DOTATOC. The number of (18)F-FDG-positive or DOTATOC-positive lesions and the maximum standardized uptake value (SUV(max)) for an index lesion were determined for each patient. RESULTS: DOTATOC could reveal metastatic lesions in 11 of 18 patients (61%). However, on a lesion-by-lesion basis only 59 of 263 (22%) (18)F-FDG-avid metastases were seen with DOTATOC. Further, DOTATOC uptake was only faint. The mean SUV(max) was 3.1 (range, 1.2 4.2) for DOTATOC, in contrast to 28.2 (range, 2.3-115) for (18)F-FDG. CONCLUSION: Radiolabelled DOTATOC does not seem to be a promising agent for treatment of metastasized melanoma. PMID- 23111378 TI - Three-dimensional positron emission tomography image texture analysis of esophageal squamous cell carcinoma: relationship between tumor 18F fluorodeoxyglucose uptake heterogeneity, maximum standardized uptake value, and tumor stage. AB - OBJECTIVE: To explore the relationship of a new PET image parameter, (18)F fluorodeoxyglucose ((18)F-FDG) uptake heterogeneity assessed by texture analysis, with maximum standardized uptake value (SUV(max)) and tumor TNM staging. MATERIALS AND METHODS: Forty consecutive patients with esophageal squamous cell carcinoma were enrolled. All patients underwent whole-body preoperative (18)F-FDG PET/CT. Heterogeneity of intratumoral (18)F-FDG uptake was assessed on the basis of the textural features (entropy and energy) of the three-dimensional images using MATLAB software. The correlations between the textural parameters and SUV(max), histological grade, tumor location, and TNM stage were analyzed. RESULTS: Tumors with higher SUV(max) were seen to be more heterogenous on (18)F FDG uptake. Significant correlations were observed between T stage and SUV(max) (r(s)=0.390, P=0.013), entropy (rs=0.693, P<0.001), and energy (r(s)=-0.469, P=0.002). Correlations were also found between SUV(max), entropy, energy, and N stage (r(s)=0.326, P=0.04; r(s)=0.501, P=0.001; r(s)=-0.413, P=0.008). The American Joint Committee on Cancer stage correlated significantly with all metabolic parameters. The receiver-operating characteristic curve demonstrated an entropy of 4.699 as the optimal cutoff point for detecting tumors above stage II(b) with an areas under the ROC curve of 0.789 (P<0.001). CONCLUSION: This study provides initial evidence for the relationship between the new parameter of tumor uptake heterogeneity and the commonly used simplistic parameter of SUV and tumor stage. Our findings suggest a complementary role of these parameters in the staging and prognosis of esophageal squamous cell carcinoma. PMID- 23111379 TI - I-123-MIBG myocardial imaging in trastuzumab-based cardiotoxicity: the first experience. AB - INTRODUCTION: Cardiotoxicity related to trastuzumab anticancer treatment poses a diagnostic challenge at early stages. The aim of the present pilot study was to assess the value of iodine-123-metaiodobenzylguanidine (I-123-MIBG) scintigraphy in breast cancer patients treated with trastuzumab who showed a decrease in their cardiac function. MATERIALS AND METHODS: I-123-MIBG scintigraphy was performed in nine patients with decreased or significantly decreasing left ventricular ejection fraction (LVEF) during trastuzumab therapy. On the basis of planar images, 4 h heart-to-mediastinum (HMR) ratio and washout percentages (WR) were calculated. RESULTS: I-123-MIBG scintigraphy revealed abnormal 4 h HMR and increased WR in three patients. LVEF recovery was observed in none of these patients during 3, 6, and 13 months of follow-up. In two of five patients with normal 4 h HMR the washout rates were also normal, whereas in three patients slightly increased washout rates were found. All five patients demonstrated a recovery of their LVEF value during follow-up. One patient with a normal 4 h HMR and normal WR initially showed a significant decrease in LVEF, which decreased further during follow-up. However, the LVEF value remained at 53%, which was within normal limits, after trastuzumab administration. CONCLUSION: In this pilot study we have explored the role of I-123-MIBG scintigraphy in the assessment of trastuzumab-related cardiotoxicity and suggest that, in patients with a persistently decreasing LVEF, I-123-MIBG scintigraphy might indicate whether recovery will occur and, consequently, whether retreatment may be initiated. PMID- 23111380 TI - A retrospective study comparing contrast-enhanced computed tomography with 18F FDG-PET/CT in the early follow-up of patients with retroperitoneal sarcomas. AB - OBJECTIVE: To compare 18-fluorine-labeled 2-deoxy-2-fluoro-D-glucose PET/computed tomography ((18)F-FDG-PET/CT) with contrast enhancement computed tomography (CECT) in the early follow-up of patients who had undergone treatment for primitive retroperitoneal sarcomas (RS). METHODS: This is a retrospective study on 24 patients who underwent (18)F-FDG-PET/CT and CECT within 2 years after therapy for RS. (18)F-FDG-PET/CT and CECT results were compared with results of histological examination and clinical-instrumental follow-up. We calculated the sensitivity and specificity of CECT and (18)F-FDG-PET/CT for retroperitoneal recurrences and compared them with results of the McNemar test. Negative predictive values (NPVs) and positive predictive values (PPVs) were calculated and the positive percentage agreement and negative percentage agreement were evaluated. RESULTS: The sensitivity and specificity of (18)F-FDG-PET/CT were 66.7 and 100% and those for CECT were 58.3 and 50%, respectively. For (18)F-FDG PET/CT, PPV was 100% [95% confidence interval (CI): 67-100%] and NPV was 75% (95% CI: 58-75%); for CECT, PPV was 54% (95% CI: 33-73%) and NPV was 55% (95% CI: 30 78%). Positive percentage agreement and negative percentage agreement were, respectively, 38 and 72% for retroperitoneal lesions, 42.8 and 100% for liposarcomas, 40 and 50% for leiomyosarcomas, 14.2 and 94% for abdominal lymph nodes, and 16.6 and 100% for lung metastasis. Neither technique gave reliable results for liver metastasis. CONCLUSION: Our data show that (18)F-FDG-PET/CT has a higher overall specificity compared with CECT in identifying areas of recurrence, demonstrating its validity for early whole-body detection of lesions. In our hands (18)F-FDG-PET/CT seems to be a good tool in the early follow-up of patients experiencing recurrence of RS. PMID- 23111381 TI - A standardized dual-phase 18F-DOPA PET/CT protocol in the detection of medullary thyroid cancer. PMID- 23111382 TI - Assessing the utility of the ventilation phase in ventilation-perfusion imaging for acute pulmonary embolism. AB - PURPOSE: This study aims to identify patient characteristics that allow the exclusion of the ventilation phase in ventilation-perfusion imaging for the evaluation of acute pulmonary embolism (PE). MATERIALS AND METHODS: A total of 500 consecutive ventilation-perfusion reports with an indication for possible acute PE were retrospectively reviewed. Information on ventilation abnormalities, perfusion defects, PIOPED classification, age, sex, chest radiograph results, and presence of respiratory disease was recorded. Patients with moderate and large perfusion defects were analyzed to assess the utility of the ventilation phase on the final PIOPED classification. RESULTS: Moderate (n=39) or large (n=26) perfusion defects were seen in 65 (13%) studies. Of these, 46 studies (70.8%) had defects unmatched on ventilation and three (4.6%) had triple-match defects, resulting in 49 reports (75.4%) classified as intermediate (n=28) or high (n=21) probability for PE. There was a statistically significant association between unmatched defects and a clear chest radiograph (P=0.03) and an association approaching statistical significance with younger age (P=0.05). There was a strong association with respiratory disease (P=0.12) and no association with patient sex (P=0.82). The percentage of studies with unmatched defects increased from 70.8 to 76.7% (33/43, P=0.39) if patients with respiratory disease were excluded, to 82.4% (28/34, P=0.14) if abnormal chest radiographs were excluded, and to 95.7% (22/23, P=0.01) if both were excluded. CONCLUSION: There may be a subset of patients - younger patients with clear chest radiographs and no respiratory disease - for whom the ventilation phase can be excluded and the determination of a PE is based solely on perfusion abnormalities. PMID- 23111383 TI - Value of 18F-FDG PET versus iliac biopsy in the initial evaluation of bone marrow infiltration in the case of Hodgkin's disease: a meta-analysis. AB - OBJECTIVE: We carried out a meta-analysis to evaluate the performance of 2-deoxy 2-[(18)F]fluoro-D-glucose ((18)F-FDG) PET and PET/CT against bone marrow biopsy (BMB) in the initial diagnosis of bone marrow infiltration (BMI) in patients with Hodgkin's disease (HD). MATERIALS AND METHODS: Retrospective and prospective studies with direct comparison of (18)F-FDG PET with BMB in the initial evaluation of BMI in HD were included. Seven eligible studies were included in the meta-analysis comprising a total of 687 patients. RESULTS: Both (18)F-FDG PET and BMB had excellent specificity in detecting BMI. However, (18)F-FDG PET had excellent pooled sensitivity (94.5%; 95% confidence interval: 89.0-97.8%) in detecting BMI in the initial staging of HD patients, whereas the pooled sensitivity of iliac BMB was very poor (39.4%; 95% confidence interval: 30.8 48.4%). The diagnostic odds ratio, a measure of the overall diagnostic power of the test, was much higher for PET (pooled value of 1591) than for iliac BMB (pooled value of 137). CONCLUSION: (18)F-FDG PET significantly outperforms iliac BMB in the detection of BMI in the initial staging of HD patients and therefore should be used as a first-line study. Iliac BMB has low sensitivity and a high rate of false-negative findings. Thus, a negative BMB finding cannot rule out marrow involvement in HD patients on initial staging. PMID- 23111384 TI - Cardiovascular risk-factor profiles of normal and overweight children and adolescents: insights from the Canadian Health Measures Survey. AB - BACKGROUND: There is no cardiovascular disease (CVD) risk factor profile in a representative sample of Canadian children and adolescents according to weight status. The 2007-2009 Canadian Health Measures Survey, launched by Statistics Canada in partnership with Health Canada and the Public Health Agency of Canada, provides an opportunity to address this gap. METHODS: The Canadian Health Measures Survey collected information at 15 sites across Canada from March 2007 to March 2009 from Canadians aged 6 to 79 years living in private households. The survey consisted of a household interview and a visit to a mobile examination centre to perform physical measurements, including anthropometry, blood pressure, and biospecimen collection. The present analysis is based on data from 2087 children and adolescents aged 6 to 19 years. RESULTS: Children and adolescents who were overweight or obese had on average higher mean concentrations and higher prevalence of adverse levels of CVD risk factors (systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein B, C-reactive protein, homocysteine, and insulin levels) than did normal-weight children and adolescents. Adjustment for covariates (gender, age, household education, household income adequacy, and province of residence) and compliance with recommendations for daily steps, soft-drink intake, and sleep duration did not alter the differences in CVD risk factors between normal weight and overweight or obese children and adolescents. CONCLUSIONS: Results of this study underscore the importance of excess weight as an independent risk factor for CVD health in early life and call for primary prevention of overweight and obesity in childhood to reduce CVD risk. PMID- 23111386 TI - Prevalence and epidemiological pattern of gallstones in urban residents in China. PMID- 23111390 TI - The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia. AB - BACKGROUND: Mortality in pneumococcal pneumonia remains high despite early antibiotic eradication of bacteria. Most deaths occur within the first week, the time of peak inflammatory responses. Statins and macrolides have broad immunosuppressive activity; their impact, separately and together, on survival in patients with pneumococcal pneumonia was evaluated. METHODS: All patients with pneumococcal pneumonia seen at a single medical center from 2000 through 2010 were included in this retrospective cohort study. A multivariate-adjusted Cox proportional hazard model was used to evaluate survival. RESULTS: Of 347 patients with pneumococcal pneumonia, 90 (26%) were taking a statin at presentation and 126 (36%) were started on treatment with a macrolide. Thirty-two (9%) statin users were treated with a macrolide. Statin users were older than non-statin users, with a higher prevalence of diabetes, coronary artery disease and chronic kidney disease and a lower prevalence of alcohol consumption and liver disease. Statin users had higher mean Pneumonia Patient Outcomes Research Team scores. Patients treated with a macrolide were not different from those who received other antibiotics. The risk of mortality among statin users was reduced at 7, 14, 20 and 30 days after admission. Mortality was not reduced in patients treated with a macrolide or with a macrolide plus a statin compared with those who did not receive a macrolide. CONCLUSIONS: Patients who are receiving statins at the time of admission for pneumococcal pneumonia have better clinical outcomes than those who are not. Treatment with a macrolide does not appear to confer a survival benefit. PMID- 23111391 TI - Validating severity of illness scoring systems in the prediction of outcomes in Staphylococcus aureus bacteremia. AB - BACKGROUND: Severity of illness scores are helpful in predicting mortality; however, no standardized scoring system has been validated in patients with Staphylococcus aureus bacteremia (SAB). The modified Rapid Emergency Medicine Score (REMS), the CURB-65 (confusion, urea, respiratory rate, blood pressure and age 65) and the Charlson weighted index of comorbidity (CWIC) were compared in predicting outcomes at the onset of SAB. METHODS: All adult inpatients with SAB from July 15, 2008, to December 31, 2009, were prospectively assessed. The 3 scoring systems were applied: REMS, CURB-65 and CWIC. The end points were attributable and overall mortality. RESULTS: A total of 241 patients with SAB were reviewed during the study period. The all-cause mortality rate was 22.8% and attributable mortality 14.1%. Patients who died had higher mean CURB-65 score and REMS than those who lived, whereas the difference in the CWIC score was not significant. Two logistic regression models based on CURB-65 score or REMS, after controlling for CWIC, revealed that both scores were independent predictors of mortality, with an odds ratio of 3.38 (P < 0.0001) and 1.45 (P < 0.0001) for CURB 65 and REMS, respectively. Receiver operating characteristic analysis revealed that a cutoff point of 3.0 (CURB-65) and 6.0 (REMS) provided the highest sensitivity and specificity. The area under the curves for all-cause mortality were 0.832 and 0.806, and for attributable mortality 0.845 and 0.819, for CURB-65 and REMS, respectively. CONCLUSIONS: REMS and CURB-65 scores outperformed CWIC as predictors of mortality in SAB and may be effective in predicting the severity of illness at the onset of bacteremia. PMID- 23111389 TI - MiR-93 enhances angiogenesis and metastasis by targeting LATS2. AB - Here we report that miR-93, a miRNA in the miR-106B~25 cluster, a paralog of the miR-17-92 cluster, was significantly upregulated in human breast carcinoma tissues. We stably expressed miR-93 in the MT-1 human breast carcinoma cell line and found that tumors formed by the miR-93 cells contained more blood vessels than those formed by the control cells. Co-culture experiments indicated that the MT-1 cells displayed a high activity of adhesion with endothelial cells and could form larger and more tube-like structures with endothelial cells. Lung metastasis assays were performed in a mouse metastatic model, and it was found that expression of miR-93 promoted tumor cell metastasis to lung tissue. In cell culture, expression of miR-93 enhanced cell survival and invasion. We examined the potential target that mediated miR-93's effects and found that the large tumor suppressor, homology 2 (LATS2) was a target of miR-93. Higher levels of LATS2 were associated with cell death in the tumor mass. Silencing LATS2 expression promoted cell survival, tube formation and invasion, while ectopic expression of LATS2 decreased cell survival and invasion. These findings demonstrated that miR-93 promoted tumor angiogenesis and metastasis by suppressing LATS2 expression. Our results suggest that the inhibition of miR-93 function may be a feasible approach to repress tumor metastasis. PMID- 23111392 TI - Natural killer/T-cell lymphoma, nasal type, masquerading as recalcitrant periodontitis in a patient with a diagnosis of Wegener's granulomatosis. AB - Extranodal natural killer (NK)/T-cell lymphoma, nasal type, is a rare type of non Hodgkin's lymphoma with similar presentation to various benign inflammatory diseases. Adequate biopsy is required for a diagnosis because this lymphoma frequently coexists with large amount of necrosis and inflammation. In this study, a case of a 49-year-old woman presenting with a 3-week history of right maxillary alveolar ridge pain with a subsequent diagnosis of periodontitis is described. The patient's clinical condition deteriorated over a period of 6 weeks. Computed tomography delineated involvement of the right maxillary sinus, posterior part of the right pharynx and right nasal cavity. Immunohistopathology initially revealed Wegener's granulomatosis, followed by extranodal nasal-type NK/T-cell lymphoma. Severe refractory periodontitis in a background of Wegener's granulomatosis may be the initial presentation of extranodal NK/T-cell lymphoma, nasal type. In addition to careful examination, radiographic and laboratory testing, multiple large biopsies should be taken for immunohistochemical analysis to obtain an appropriate diagnosis. PMID- 23111393 TI - Severe leprosy reactions due to Mycobacterium lepromatosis. AB - Leprosy is caused by the well-known Mycobacterium leprae and the newly discovered M lepromatosis. Here, the authors describe 2 cases of leprosy with unusual clinical presentation caused by M lepromatosis. The patients, a 32-year-old man and a 50-year-old woman, both of Mexican origin, manifested high fever, lymphadenopathy and florid skin lesions in the form of erythema nodosum and Lucio's phenomenon as the first clinical presentation. Heavy infiltration of acid fast bacilli was identified in the tissues that led to the diagnosis of lepromatous leprosy or diffuse leprosy. The patients were treated with multidrug regimen and responded appropriately. From the lymph node tissue, the authors showed the bacillus to be M lepromatosis, not M leprae as presumed previously, by differential polymerase chain reactions and analysis of gene sequences. These cases add to the growing studies on this organism, expand its endemic regions in Mexico and provide more clinical insight. PMID- 23111394 TI - Controllable synthesis of carbon coated iron-based composite nanoparticles. AB - Different types of carbon coated iron (Fe) based nanoparticles were controllably synthesized by detonation decomposition of urea nitrate metal complex explosive precursors. In order to control the detonation synthesis of the Fe-based composite nanoparticles, the main components of the urea nitrate metal complex explosive precursors were optimally designed. The components, morphologies, structures and various Fe-based phase composition of the as-obtained composite nanoparticles were further investigated by x-ray diffraction, transmission electron microscopy, electron diffraction spectroscopy and energy dispersive x ray spectroscopy. The results show that discrete, spherical, uniformly sized (~55 nm) iron oxide nanocrystals and core-shell structural composite nanoparticles (graphite coated Fe) were effectively synthesized by adjusting the densities, oxygen balances and mole ratios of C:Fe of these compound explosive precursors. The formation mechanism of these carbon coated Fe-based composites during the instantaneous detonation reaction process is further discussed. PMID- 23111395 TI - New concepts and modeling strategies to design and evaluate photo-electro catalysts based on transition metal oxides. AB - Photocatalytic production of transportation fuels should be among our long term strategies to achieve energy and environmental sustainability for the planet, but the technology is hampered by a lack of sufficiently efficient catalysts. Although efficiency is ultimately determined by laboratory measurements, theory and computation have become powerful tools for examining underlying mechanisms and guiding avenues of inquiry. In this review, we focus on first principles calculations of transition metal oxide semiconductor photocatalysts. We discuss how theory can be applied to investigate various aspects of a photocatalytic cycle: light absorption, electron/hole transport, band edge alignments of semiconductors, and surface chemistry. Emphasis is placed on identifying accurate models for specific properties and theoretical insights into improving photocatalytic performance. PMID- 23111396 TI - Galvanic vestibular stimulation influences randomness of number generation. AB - Successful interaction with the external environment requires a balance between novel or exploratory and routine or exploitative behaviours. This distinction is often expressed in terms of location or orientation of the body relative to surrounding space: functions in which the vestibular system plays an important role. However, the distinction can also be applied to novel versus repetitive production of any behaviour or symbol. Here, we investigated whether vestibular inputs contribute to the balance between novel and routine behaviours, independently of their effects on spatial orienting, by assessing effects of galvanic vestibular stimulation (GVS) on a random number generation task. Right anodal/left-cathodal GVS, which preferentially activates the left cerebral hemisphere decreased the randomness of the sequence, while left-anodal/right cathodal GVS, which preferentially activates the right hemisphere increased it. GVS did not induce any spatial biases in locations chosen from the number line. Our results suggest that vestibular stimulation of each hemisphere has a specific effect on the balance between novel and routine actions. We found no evidence for effects of non-specific arousal due to GVS on random number generation, and no evidence for effects on number generation consistent with modulation of spatial attention due to GVS. PMID- 23111397 TI - Anders Retzius (1796-1860). PMID- 23111398 TI - Effects of Rhizophagus irregularis MUCL 41833 on the reproduction of Radopholus similis in banana plantlets grown under in vitro culture conditions. AB - The role of arbuscular mycorrhizal fungi (AMF) in the control of migratory endoparasitic nematodes is nowadays largely admitted. Most studies were conducted under greenhouse conditions and a few used in vitro cultures with transgenic root organs. Here, we reported, for the first time, on the interaction between an AMF, Rhizophagus irregularis MUCL 41833 and Radopholus similis in roots of banana plantlets grown under in vitro culture conditions. The banana plantlets were pre mycorrhized in an extraradical mycelium network arising from a Medicago truncatula donor seedling, before transfer to an autotrophic in vitro cultivation system and subsequent nematode inoculation. Both microorganisms were able to complete their life cycle in the absence as well as in presence of each other. The total R. similis population (i.e., summed over the roots and growth medium) as well as the surface of root necrosis was significantly reduced by 60 and 56 %, respectively, in the AMF-colonized banana plantlets. By contrast, nematodes had no visible impact on root colonization (i.e., percentage of arbuscules, intraradical spores/vesicles, and hyphae) by AMF and on the number of spores and hyphal length produced in the medium. These results clearly demonstrated that pre mycorrhized banana plants could outcompete R. similis, while root colonization was not affected by the nematodes. They underline the interest of the novel in vitro cultivation system as a promising tool to investigate the biochemical factors and molecular mechanisms involved in the bio-protection conferred by AMF to a major root pathogen of banana. PMID- 23111399 TI - An initial experience using transanal vacuum therapy in pelvic anastomotic leakage. AB - BACKGROUND: Treatment of the presacral cavity that forms after contained anastomotic leakage of a low pelvic anastomosis is challenging and often results in a permanent stoma. EndospongeTM therapy is a minimally invasive method of treating the presacral cavity which potentially avoids a permanent stoma. We report our initial experience of using EndospongeTM therapy. METHODS: All patients who underwent EndospongeTM treatment for low pelvic anastomotic leakage in our hospital over a 45-month period were identified and data collected from clinical, operative and endoscopic notes. RESULTS: Eight patients (seven males, one female) underwent EndospongeTM therapy for extraperitoneal pelvic anastomotic leak during the study period; all had had defunctioning ileostomies placed at their original surgery. Six out of eight patients had complete closure or a reduction in the size of the abscess cavity. Five patients have had their ileostomies reversed with good or reasonable bowel function after a median follow up of 41 months and four of these patients had EndospongeTM therapy instituted within 6 weeks of initial surgery. One patient had EndospongeTM therapy abandoned and conversion to a permanent end colostomy after accidental intraperitoneal placement of the sponge. CONCLUSIONS: Early use of EndospongeTM therapy appears to offer a minimally invasive and effective way of closing the presacral cavity after a pelvic anastomotic leak, reducing the risk of permanent stoma and resulting in acceptable bowel function. EndospongeTM-specific complications can occur. PMID- 23111400 TI - Robotic-assisted laparoscopic segmental resection with rectoanal anastomosis: a new approach for the management of complicated rectourethral fistula. AB - Various transanal and perineal surgical techniques have been described for the treatment of rectourethral fistula (RUF). However, these techniques are poorly suited for complicated fistulas. Here, we present a novel minimally invasive procedure: robotic-assisted laparoscopic segmental resection with rectoanal anastomosis for the management of difficult RUFs. This novel technique may be valuable in the treatment of recurrent or complex RUFs. PMID- 23111401 TI - The argon beam coagulator: a more effective and expeditious way to address presacral bleeding. AB - Presacral bleeding is a dreaded complication of pelvic surgery. Rapid and effective control of such bleeding is important to avoid potentially life threatening outcomes. Various methods for controlling presacral bleeding, all with only limited success, have been described in the literature. We report the alternative technique of using the argon beam coagulator (ABC) to control presacral bleeding. We demonstrate its efficacious use in both open surgery and a laparoscopic case. Our approach involved applying an argon beam at bone setting directly to the bleeders and using a "point and shoot" technique. We found that ABC is a simpler, equally effective and expeditious way of addressing presacral bleeding. To the best of our knowledge, there has been only one previously reported case in the literature of the use of ABC to control presacral bleeding. PMID- 23111402 TI - Rehabilitation of fecal incontinence: what is the influence of anal sphincter lesions? AB - BACKGROUND: The aim of this study was to evaluate the results of rehabilitative treatment of incontinent patients with anal sphincter lesions in order to verify whether these lesions influence the outcome of rehabilitation. METHODS: Between January 2008 and June 2011, 48 patients [36 women, age range 51-77 years; 12 men, age range 57-70 years] affected by fecal incontinence were included in the study. After a preliminary clinical evaluation, including the Fecal Incontinence Severity Index (FISI) score, all patients were studied by means of endoanal ultrasound and anorectal manometry. Two patients groups were identified: Group 1 comprised 27 patients with sphincter lesions and Group 2 had 21 patients without sphincter lesions. All 48 underwent a multimodal rehabilitation program. At the end of the rehabilitation program, all patients were reassessed by means of clinical evaluation and anorectal manometry and their data were analyzed. RESULTS: Although we obtained an overall significantly lower FISI score in all patients after rehabilitation (p < 0.001) when compared with pre-treatment values, our study revealed that patients with sphincter lesions had a significantly worse post-rehabilitative FISI score (p < 0.003) when compared with those patients with intact anal sphincters and that there is a linear relationship between post-rehabilitative FISI scores and severity of sphincter lesions (rho s 0.69). CONCLUSIONS: These data suggest that rehabilitation may be less effective in patients affected by sphincter defects. PMID- 23111403 TI - Fibroblast colonization of modified silicone films. AB - HYPOTHESIS: Development of silicone films with hydrophilic surface properties and with associated fibroblast colonization for tympanic membrane reconstruction. BACKGROUND: Silicone films are used in ear surgery for splinting fresh eardrum perforations. The cure rate is high if the perforation is small and fresh. Persistent eardrum perforations have been treated in tympanoplasty procedures by splinting the tympanic membrane with silicone film. Silicone has hydrophobic properties and is poorly populated by cells. METHODS: Silicone films with a thickness of 0.13 mm were treated in a low-pressure oxygen plasma for different times. Oxidation of the surface allowed hydroxyl groups to form. The altered surface properties of the film were measured using the method of contact angle against water. Treated and untreated films (d = 22 mm) were placed in 12-well culture plates with 50000 L929 fibroblasts and in a standard medium for different lengths incubated at 37 degrees C. The quantification of the vegetation was performed after 5 days using WST-1 Cell Proliferation Reagent. The resulting cell growth was visualized after different incubation times through the Live/Dead Assay by fluorescence microscopy and scanning electron microscopy. RESULTS: The treatment of the films with low-pressure oxygen plasma resulted in a hydrophilic film surface. There were significant differences in fibroblast colonization in treated compared with untreated films. The hydrophilic silicone films had a higher quantity and quality of fibroblasts. CONCLUSION: Further surface modifications could improve the film in respect of fibroblast vegetation. The effectiveness of the modified silicone sheets should be evaluated in vivo before clinical trials. PMID- 23111405 TI - Surgical rehabilitation of paralytic lagophthalmus by platinum chain lid loading: focusing on patient benefit and health-related quality of life. AB - OBJECTIVE: To evaluate patient benefit and health-related quality of life after lid loading with platinum chains in adult patients with facial palsy. STUDY DESIGN: Retrospective data collection. SETTING: Germany's largest university clinic for otorhinolaryngology, head and neck surgery. SUBJECTS AND METHODS: Thirty-five patients received validated questionnaires determining the effects of the operation on the patients' health-related quality of life (Glasgow Benefit Inventory). Scores can range from -100 (maximal adverse effect), through 0 (no effect), to 100 (maximal positive effect). Furthermore, satisfaction, complaints, and complications regarding the platinum chain implant were inquired. RESULTS: Twenty-two patients (63 %) returned a valid questionnaire. The mean follow-up time was 31.5 months. A complete coverage of the cornea was achieved in 95% of the patients after the first operation and in the remaining patients after a revision with implantation of a heavier weight. Complete symmetry to the nonaffected eye was perceived by 64%. Recurrent conjunctivitis was complained preoperatively by 18% and postoperatively only by a single patient. In 2 patients, a mild pseudoptosis was found postoperatively, and a single patient complained about blurred vision. The median total Glasgow Benefit Inventory score was 27.8 (p < 0.001). The health-related quality of life was raised in 91% of the patients; 87% were fully satisfied with the functional result, and 91% with the aesthetical result. 100% would again decide in favor of platinum chain lid loading. CONCLUSION: Platinum chain lid loading in facial palsy patients can significantly increase patients' health-related quality of life and leads to a high rate of patient satisfaction. PMID- 23111404 TI - Reprogramming of single-cell-derived mesenchymal stem cells into hair cell-like cells. AB - HYPOTHESIS: Adult mesenchymal stem cells (MSCs) can be converted into hair cell like cells by transdetermination. BACKGROUND: Given the fundamental role sensory hair cells play in sound detection and the irreversibility of their loss in mammals, much research has focused on developing methods to generate new hair cells as a means of treating permanent hearing loss. Although MSCs can differentiate into multiple cell lineages, no efficient means of reprogramming them into sensory hair cells exists. Earlier work has shown that the transcription factor Atoh1 is necessary for early development of hair cells, but it is not clear whether Atoh1 can be used to convert MSCs into hair cells. METHODS: Clonal MSC cell lines were established and reprogrammed into hair cell like cells by a combination of protein transfer, adenoviral based gene transfer, and co-culture with neurons. During transdetermination, inner ear molecular markers were analyzed using reverse transcriptase-polymerase chain reaction, and cell structures were examined using immunocytochemistry. RESULTS: Atoh1 overexpression in MSCs failed to convert MSCs into hair cell-like cells, suggesting that the ability of Atoh1 to induce hair cell differentiation is context dependent. Because Atoh1 overexpression successfully transforms VOT-E36 cells into hair cell-like cells, we modified the cell context of MSCs by performing a total protein transfer from VOT-E36 cells before overexpressing Atoh1. The modified MSCs were transformed into hair cell-like cells and attracted contacts from spiral ganglion neurons in a co-culture model. CONCLUSION: We established a new procedure, consisting of VOT-E36 protein transfer, Atoh1 overexpression, and co-culture with spiral ganglion neurons, which can transform MSCs into hair cell-like cells. PMID- 23111406 TI - Neurotology: past, present, and future--the 2012 William F. House Lecture. PMID- 23111407 TI - Subclinical coronary atherosclerosis in young adults: prevalence, characteristics, predictors with coronary computed tomography angiography. AB - The purpose of this study was to assess the characteristics and predictors of subclinical coronary atherosclerosis in young adults. The study also evaluated predictors of cardiac events. We retrospectively enrolled 914 self-referred asymptomatic subjects under the age of 45 (552 men, 362 women) who had undergone both coronary CT angiography (CCTA) and coronary artery calcium scoring. Two radiologists analyzed plaque composition and degree of stenosis. For all subjects, we evaluated clinical risk factors and investigated cardiac events. Subclinical coronary atherosclerosis was found in 86 subjects (9.4 %). Among them, 64 subjects (74.4 %) had a single coronary artery plaque. On analysis of individual segments, the most common type of plaque was non-calcified plaque (NCP) (58 %), which was found in 63 subjects (6.9 %). Significant coronary artery stenosis was found in 9 subjects (0.1 %). Predictors of subclinical coronary atherosclerosis were age, male gender, hypertension, and diabetes mellitus. Male gender, diabetes mellitus, and amount of smoking were independent predictors of NCP. High low density lipoprotein cholesterol and calcium scores were also significant predictors of stenosis. Myocardial infarction developed in 1 subject, unstable angina in 2, stable angina in 1, and death in 1 (2.45 cardiac events per 1,000 person-years of follow-up). Multivariate analysis revealed hazard ratios of 2.2 for subclinical coronary atherosclerosis, 49.17 for NCP, and 105.58 for significant stenosis. The prevalence of subclinical coronary atherosclerosis in asymptomatic young adults is not negligible. CCTA has the potential to enhance risk stratification and prediction for coronary artery disease in asymptomatic young adults. PMID- 23111410 TI - Calcium amido-bisoxazoline complexes in asymmetric hydroamination/cyclisation catalysis. AB - Calcium complexes bearing bis(oxazolinylphenyl)amine (BOPA) ligands have been prepared, and their redistribution chemistry studied. The complexes [Ca(R BOPA){N(SiMe(3))(2)}(THF)] (R = (i)Pr 1a, Ph 1b and Bn 1c) are active in hydroamination catalysis and give the highest enantioselectivity reported for a calcium complex. PMID- 23111408 TI - Ankle-brachial index (ABI), abdominal aortic calcification (AAC), and coronary artery calcification (CAC): the Jackson heart study. AB - To examine the associations of peripheral atherosclerosis, assessed by the ABI at baseline with the extent of AAC and with CAC measured by MDCT at follow-up examination in the Jackson Heart Study cohort. Four categories of ABI: <0.90, 0.90-0.99, 1.00-1.39; >1.40. Presence of CAC/AAC was defined as scoring above the 75th percentile among participants with non-zero CT calcium scores. We conducted multivariable log-binomial models for this analysis examining the relationship between ABI and the presence of CAC or AAC using normal ABI (1.0 <= ABI <= 1.39) as the reference group. We estimated prevalence ratios adjusted for age, smoking, HTN, DM, BMI, LDL, HDL, CRP, systolic and diastolic blood pressure, and use of lipid-lowering medication. There were 2,398 patients in this analysis (women: 65 %, average age 55 years). AAC scores were not significantly different between sex. CAC scores were significantly higher in males than females regardless of ABI groups. The prevalence of significant AAC was 1.7 times higher for ABI < 0.90 (PR = 1.70; 95 % CI = 1.26-2.28; p = 0.0004) and 1.57 times higher for ABI 0.90-0.99 (PR = 1.57; 95 % CI = 1.20-2.03; p = 0.0008) than the normal ABI; AAC prevalence did not differ between subjects with ABI > 1.40 compared to those with normal ABI. The prevalence of the significant CAC was higher for ABI < 0.90 (PR = 1.55; 95 % CI = 1.12-2.14; p value = 0.0081) and ABI 0.90-0.99 (PR = 1.60; 95 % CI = 1.05-2.46; p = 0.0402) compared to normal ABI; CAC prevalence did not differ between subjects with ABI > 1.40 compared to those with normal ABI. Lower ABI was significantly associated with the extent of AAC and CAC in this cohort. ABI can provide clinicians with an inexpensive additional tool to assess vascular health and cardiovascular risk without exposing the patient to ionizing radiation. PMID- 23111411 TI - Seeing is believing - reducing misconceptions about children's hospice care through effective teaching with undergraduate nursing students. AB - Children's palliative care has evolved in recent years and is now recognised as a distinct area of health and social care practice. Whilst children's hospices are viewed as central to quality care for these children and families, lack of knowledge regarding the exact nature of care they provide exists. Education can go part way to changing attitudes and knowledge about the key contribution of hospices, thus improving future care. Alternative and innovative strategies to stimulate meaningful learning are pivotal to children's nurse education and this paper examines one such innovation adopted with 2nd year children's nursing students. Aiming to help students explore the ethos of children's hospice an educational visit was arranged, followed by an on line discussion. Although some practical challenges were encountered, the visit heightened student awareness moving them from the readily held perception that children's hospices were exclusively for dying children and was viewed by students as more effective than a traditional classroom session. PMID- 23111413 TI - Management of degenerative lumbosacral disease in cats by dorsal laminectomy and lumbosacral stabilization. AB - In this case series we describe the diagnosis and surgical treatment of five cats affected by clinical cauda equina syndrome as a result of degenerative lumbosacral stenosis. Radiographic and magnetic resonance imaging findings confirmed the suspected diagnosis of disc-associated lumbosacral disease. Cauda equina decompression was achieved by dorsal laminectomy followed by dorsal annulectomy and nuclear extirpation. Dorsal stabilization was achieved using miniature positive-profile pins inserted into the vertebral body of L7 and the wings of S1 with the free ends of the pins being embedded in a bolus of gentamicin-impregnated polymethylmethacrylate. Reassessment two years postoperatively using a previously validated feline specific owner questionnaire indicated satisfactory outcome with complete return to normal activity and resolution of signs of pain in all cases. PMID- 23111414 TI - Determinants of fatigue in Crohn's disease patients. AB - OBJECTIVE: Crohn's disease (CD) is often associated with severe fatigue. Little is known about patients who may be at the highest risk for fatigue. Therefore, we assessed the disease phenotype and factors related to fatigue in the presence of CD in two different populations. METHODS: Patients presenting at the clinic of a referral hospital and a general hospital were included in the study. They completed questionnaires including the Checklist Individual Strength, the Hospital Anxiety and Depression Scale, a questionnaire on disease activity, and one on medication use. The Montreal classification and sociodemographics were obtained from medical records. Hemoglobin and C-reactive protein levels were measured at baseline. RESULTS: In total, 425 patients were included (276 women, mean age: 42 years). Compared with patients from the general hospital, patients at the referral hospital had worse disease activity, worse disease behavior, more bowel resections, and a higher percentage of side-effects to medication and use of anti-tumor necrosis factor (TNF). The prevalence of fatigue was significantly higher in the referral patients compared with the general patients (65.7 vs. 52.5%, respectively; P=0.01). Similar results were found in patients in remission (53.3 vs. 40.5%; P=0.061). Factors related to fatigue were the use of anti-TNF at baseline, side-effects to 5-aminosalicylic acid, disease activity, female sex, and shorter disease duration. Furthermore, we found improvement in fatigue and a trend toward lower disease activity after 1 year of anti-TNF use. CONCLUSION: A high percentage of CD patients suffer from fatigue. As a more aggressive phenotype seems to be associated with more severe fatigue and patients in remission still suffer from fatigue, a multidimensional approach for fatigue is warranted in these patients. PMID- 23111415 TI - Gastroesophageal reflux, dental erosion, and halitosis in epidemiological surveys: a systematic review. AB - In published studies, it has been suggested that dental wear is associated with gastroesophageal reflux disease (GERD). This systematic review was carried out to evaluate the association of GERD, dental erosion, and halitosis and to compare the indices adopted in epidemiological surveys. The Medline database (until October, 2011) was searched systematically to identify studies evaluating the prevalence of oral alterations, such as dental erosion and halitosis, in patients with GERD symptoms. Two reviewers analyzed all reports and the selected studies were evaluated according to the quality of evidence, using the validated Newcastle-Ottawa Quality Assessment Scale. Full-text copies of a total of 32 publications were obtained in duplicate. Sixteen publications were identified among the citations in the Bibliographic lists of studies that fulfilled the exclusion/inclusion criteria and quality of evidence. The relationship between dental erosion and GERD patients was significant in only seven studies. According to three studies, halitosis could be one of several extraesophageal symptoms or manifestations in GERD patients. In one study, it was found that the mucosa of GERD patients was significantly more acidic in comparison with that of the control group. This systematic review showed that there is a relationship between GERD and oral diseases (dental erosion and halitosis). The epidemiological surveys used different indices to analyze GERD and dental erosion. Further research could investigate the best method for assessing the two diseases. PMID- 23111416 TI - Chloroquine overcomes resistance of lung carcinoma cells to the dual PI3K/mTOR inhibitor PI103 by lysosome-mediated apoptosis. AB - On the basis of previous findings that certain lung carcinoma cell lines are resistant to the dual PI3K/mTOR inhibitor PI103, we searched for new strategies to overcome this resistance. Here, we report that the lysosomotropic agent chloroquine (CQ) reverses the resistance of lung carcinoma cells to PI3K/mTOR inhibition and primes cells for PI103-induced apoptosis. Investigations of the underlying mechanism of this cooperative interaction show that PI103 increases lysosomal volume and function, as indicated by upregulation of the lysosomal marker protein LAMP-1 and maturation of the lysosomal enzyme cathepsin B, whereas CQ destabilizes lysosomal membranes. Together, CQ and PI103 act in concert to trigger lysosomal membrane permeabilization, resulting in the activation of caspases and apoptosis. The broad-range caspase inhibitor zVAD.fmk significantly decreases PI103-induced and CQ-induced loss of cell viability, indicating that caspases are required for cell death induction. Importantly, inhibition of lysosomal enzymes by CA-074me significantly reduces PI103-mediated and CQ mediated loss of cell viability, showing that lysosomal enzymes are critical mediators of PI103/CQ-induced cytotoxicity. In conclusion, CQ overcomes resistance of lung carcinoma cells to PI103-induced apoptosis by cooperating with PI103 to trigger lysosome-mediated apoptosis. These findings have important implications for developing effective PI3K/mTOR inhibitor-based therapies for lung cancer. PMID- 23111418 TI - The changing course of aortic valve disease in Scotland: temporal trends in hospitalizations and mortality and prognostic importance of aortic stenosis. AB - AIMS: To investigate the contemporary clinical course of aortic valve disease types. METHODS AND RESULTS: We performed a retrospective population-level epidemiological study of hospitalized care in Scotland from 1 January 1997 to 31 December 2005 using electronic case identification of hospital admissions and deaths. Time-to-event analyses were performed using Cox Proportional-Hazards models. A total of 19 733 adults with an index hospitalization and a final diagnosis of non-congenital aortic valve disease were identified. Aortic stenosis, aortic insufficiency, mixed aortic valve disease, or unspecified aortic valve disease occurred in 13 220 (67.0%), 2807 (14.2%), 699 (3.5%), and 3007 (15.2%), individuals, respectively. The majority of hospitalizations occurred in elderly persons aged 80 and older. In total, 9981 (50.6%) patients had died by 31 December 2006. When compared with aortic stenosis, the risk of death was less with aortic insufficiency [hazard ratio (95% confidence interval) 0.79 (0.74, 0.84)] and mixed aortic valve disease [0.83 (0.74, 0.93)]. Female gender, admission year, and hypertension were associated with lower mortality in patients with aortic stenosis. Patients with aortic stenosis had increased risk of death or heart failure (adjusted P < 0.001). Of all, 3673 (19.4%) patients had a first aortic valve replacement of whom 73.2% had aortic stenosis, 11.9% aortic valve disease (unspecified),10.0% aortic insufficiency, and 4.9% aortic stenosis with insufficiency. Patients with aortic stenosis with insufficiency had increased likelihood of aortic valve replacement [1.19 (1.02, 1.38)]. Age, female gender, and co-morbidity reduced the likelihood of aortic valve replacement. CONCLUSION: The incidence of aortic valve stenosis has substantially increased in Scotland in recent years. Aortic stenosis predicts morbidity and mortality when compared with other types of aortic valve disease. PMID- 23111417 TI - Interleukin-6 receptor pathways in abdominal aortic aneurysm. AB - METHODS: We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach. RESULTS: Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 * 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 * 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL 6 stimulation in Ala358 carriers. CONCLUSIONS: A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management. PMID- 23111419 TI - Photosensitized electron transfer within a self-assembled norharmane-2' deoxyadenosine 5'-monophosphate (dAMP) complex. AB - Norharmane is a compound that belongs to a family of alkaloids called beta carbolines (betaCs). These alkaloids are present in a wide range of biological systems, playing a variety of significant photo-dependent roles. Upon UV-A irradiation, betaCs are able to act as efficient photosensitizers. In this work, we have investigated the photosensitized oxidation of 2'-deoxyadenosine 5' monophosphate (dAMP) by norharmane in an aqueous phase, upon UV-A (350 nm) irradiation. The effect of the pH was evaluated on both the interactions between norharmane and dAMP in the ground and electronic excited states, and on the dAMP photosensitized oxidation. A quite strong static interaction between norharmane and dAMP was observed, especially under those pH conditions where the protonated form of the alkaloid is present (pH < 7). Theoretical studies were performed to further characterize the static complex structure. The participation of reactive oxygen species (ROS) in the photosensitized reaction was also investigated and the photoproducts were characterized by means of UV-LDI-MS and ESI-MS. All the data provided herein indicate that electron transfer (Type I) within a self assembled norharmane-dAMP complex is the operative mechanism in the dAMP photosensitization. PMID- 23111421 TI - The functional G143E variant of carboxylesterase 1 is associated with increased clopidogrel active metabolite levels and greater clopidogrel response. AB - INTRODUCTION: Carboxylesterase 1 (CES1) is the primary enzyme responsible for converting clopidogrel into biologically inactive carboxylic acid metabolites. METHODS: We genotyped a functional variant in CES1, G143E, in participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) study (n=566) and in 350 patients with coronary heart disease treated with clopidogrel, and carried out an association analysis of bioactive metabolite levels, on-clopidogrel ADP stimulated platelet aggregation, and cardiovascular outcomes. RESULTS: The levels of clopidogrel active metabolite were significantly greater in CES1 143E-allele carriers (P=0.001). Consistent with these findings, individuals who carried the CES1 143E-allele showed a better clopidogrel response as measured by ADP stimulated platelet aggregation in both participants of the PAPI study (P=0.003) and clopidogrel-treated coronary heart disease patients (P=0.03). No association was found between this single nucleotide polymorphism and baseline measures of platelet aggregation in either cohort. CONCLUSION: Taken together, these findings suggest, for the first time, that genetic variation in CES1 may be an important determinant of the efficacy of clopidogrel. PMID- 23111423 TI - The combination of mitochondrial low enzyme-activity aldehyde dehydrogenase 2 allele and superoxide dismutase 2 genotypes increases the risk of hypertension in relation to alcohol consumption. AB - A cooperative role of mitochondrial aldehyde dehydrogenase 2 (ALDH2) and superoxide dismutase 2 (SOD2) to maintain the vascular function has recently been demonstrated in nitrate tolerance. The present study examined whether the combination of low enzyme-activity variants of ALDH2 and SOD2 increases the risk of hypertension in relation to alcohol consumption. A total of 444 Japanese participants in a health-screening program were evaluated. The risk of hypertension among the individuals harboring both the ALDH2*2 allele and the SOD2 Val/Val genotype was significantly higher in drinkers than in nondrinkers (adjusted odds ratio, 6.22; 95% confidence interval, 2.26-17.1; P<0.001). Among these individuals, the systolic/diastolic blood pressure also increased by 0.24/0.14 mmHg for each 1g/day increase in alcohol consumption (P<0.001/P=0.003). These associations were observed, but the degree was lower among those with the other genotype combinations (0.11/0.10 mmHg; P=0.012/P=0.001). Information about the genetic predisposition to alcohol-related diseases may thus be useful to promote lifestyle modifications for high-risk individuals. PMID- 23111422 TI - Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. AB - OBJECTIVES: Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals. MATERIALS AND METHODS: The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated. RESULTS: A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13-69%] and a 42% (95% CI: 17-68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8-38%) lower ETV CL. Co administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL. CONCLUSION: ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa. PMID- 23111425 TI - Iridium(III) azuliporphyrins. AB - Azuliporphyrins were reacted with [Ir(COD)Cl](2) in refluxing o- or p-xylene to give novel iridium(III) derivatives that regioselectively incorporated an oxidized solvent molecule. The iridium(III) is inserted within the porphyrinoid macrocycle and possesses an additional apical acyl unit. PMID- 23111424 TI - Functional outcome of pannexin-deficient mice after cerebral ischemia. AB - Pannexin (Px, Panx) channels have been implicated in several physiological and pathological processes. We recently studied the potential contribution of pannexins in ischemic brain damage using Px1(-/-) Px2(-/-) mice and provided evidence that (1) the release of IL-1beta and hemichannel function in astrocytes are, in contrast to published data, not affected by the absence of Px1 and Px2, (2) channel function in neurons lacking Px1 and Px2 is impaired and (3) Px1(-/-) Px2(-/-) mice had a better functional outcome and smaller infarcts than wild-type mice when subjected to ischemic stroke. Here, we further investigate the neurological outcome of wild-type and pannexin double-knockout mice 48 h after permanent occlusion of the distal middle cerebral artery (MCAO). Pannexin double knockout mice (Px1(-/-) Px2(-/-)) were less impaired in parameters such as exploration, anxiety, sensorimotor function and behavioral symmetry. PMID- 23111426 TI - Investigating a two causes theory of inhibition of return. AB - It has recently been demonstrated that there are independent sensory and motor mechanisms underlying inhibition of return (IOR) when measured with oculomotor responses (Wang et al. in Exp Brain Res 218:441-453, 2012). However, these results are seemingly in conflict with previous empirical results which led to the proposal that there are two mutually exclusive flavors of IOR (Taylor and Klein in J Exp Psychol Hum Percept Perform 26:1639-1656, 2000). The observed differences in empirical results across these studies and the theoretical frameworks that were proposed based on the results are likely due to differences in the experimental designs. The current experiments establish that the existence of additive sensory and motor contributions to IOR do not depend on target type, repeated spatiotopic stimulation, attentional control settings, or a temporal gap between fixation offset and cue onset, when measured with saccadic responses. Furthermore, our experiments show that the motor mechanism proposed by Wang et al. in Exp Brain Res 218:441-453, (2012) is likely restricted to the oculomotor system, since the additivity effect does not carry over into the manual response modality. PMID- 23111427 TI - Perception of smooth and perturbed vection in short-duration microgravity. AB - Successful adaptation to the microgravity environment of space and readaptation to gravity on earth requires recalibration of visual and vestibular signals. Recently, we have shown that adding simulated viewpoint oscillation to visual self-motion displays produces more compelling vection (despite the expected increase in visual-vestibular conflict experienced by stationary observers). Currently, it is unclear what role adaptation to gravity might play in this oscillation-based vection advantage. The vection elicited by optic flow displays simulating either smooth forward motion or forward motion perturbed by viewpoint oscillation was assessed before, during and after microgravity exposure in parabolic flight. During normal 1-g conditions subjects experienced significantly stronger vection for oscillating compared to smooth radial optic flow. The magnitude of this oscillation enhancement was reduced during short-term microgravity exposure, more so for simulated interaural (as opposed to spinal) axis viewpoint oscillation. We also noted a small overall reduction in vection sensitivity post-flight. A supplementary experiment found that 1-g vection responses did not vary significantly across multiple testing sessions. These findings: (i) demonstrate that the oscillation advantage for vection is very stable and repeatable during 1-g conditions and (ii) imply that adaptation or conditioned responses played a role in the post-flight vection reductions. The effects observed in microgravity are discussed in terms of the ecology of terrestrial locomotion and the nature of movement in microgravity. PMID- 23111428 TI - Do preparation or control processes result in the modulation to Fitts' law for movements to targets with placeholders? AB - It is remarkable that the movement time of a goal-directed movement, the result of complex coordination in the nervous system, can be predicted by a simple mathematical equation. That equation is Fitts' law, and it is one of only a few laws that capture human motor performance. It has recently been shown that reaches to targets with placeholders modulate Fitts' law (e.g. Adam et al. in Psychol Sci 17(9):794-798, 2006). The purpose of this study was to further test whether the modulation to Fitts' law is a result of processes related to movement preparation or movement execution. Preparation and control processes were isolated with trajectory analysis; specifically, the durations of the primary submovement and the secondary submovement were selected to reflect the preparation and control processes, respectively. The time available for movement preparation was also manipulated by precuing the target in some blocks. We found that the modulation to Fitts' law in total movement time with target placeholders occurred during the secondary submovement, suggesting that control processes were the locus of the modulation. However, extending the duration of preparation with a precue eliminated the modulation in total movement time, which suggests that preparation processes were the locus of the modulation. Based on these results, it is premature to isolate unequivocally the modulation to either preparation or control processes. The modulation to Fitts' law during the secondary submovement presents the possibility that facilitated online control may contribute to the modulation. PMID- 23111429 TI - Movement analysis and EEG recordings in children with hemiplegic cerebral palsy. AB - Impaired hand function is often the most disabling symptom in children with hemiplegic cerebral palsy (CP). Literature provides a wide number of studies dealing either with the kinematics or the cerebral correlates of the impairment. Nevertheless, few studies exist merging both aspects together. The aim of this study is the integrated analyses of time and spatial parameters of both the affected and less-affected sides and of the EEG signal, recorded during the movement execution, for the quantitative description of the pointing gesture in children with CP. The participants (pathological and control subjects) were asked to execute a pointing task simultaneously with the recording by an optoelectronic system and an electroencephalographer. Kinematic data were processed for the extraction of several synthetic indexes, to be correlated with parameters derived from frequency analysis of the electroencephalographic signal. Kinematic results showed statistical differences (1) between the affected and the less-affected arms in patients and (2) between the less-affected arm in patients and the normal arm in controls. Further differences were found in kinematics with respect to bilateral or ipsilateral motor control, extracted from EEG. Given the different behavior evidenced by either ipsilateral or contralateral reorganization, and considering the role of feedback and feed-forward contributions to motor programming, some hypotheses emerged about the motor control during pointing task in CP. PMID- 23111430 TI - Dynamical degrees of freedom and correlations in isometric finger force production. AB - Prior research has concluded that the correlations of isometric finger forces represent the extent to which the fingers are controlled as a single unit. If this is the case, finger force correlations should be consistent with estimates of the controlled (dynamical) degrees of freedom in finger forces. The present study examined the finger force correlations and the dynamical degrees of freedom in four isometric force tasks. The tasks were to produce a preferred level of force with the (a) Index, (b) Ring, (c) Both fingers and also to (d) Rest the fingers on the load cells. Dynamical degrees of freedom in finger forces were lowest in the Both finger force task and progressively higher in the Ring, Index and Resting finger force tasks. The finger force correlations were highest in the Resting and lowest in the Index and Ring finger tasks. The results for the dynamical degrees of freedom in finger forces were consistent with a reduction in degrees of freedom in response to the degrees of freedom problem and the task constraints. The results for the finger force correlations were inconsistent with a reduction in the dynamical degrees of freedom. These findings indicate that finger force correlations do not necessarily reflect the coupling of finger forces. The findings also highlight the value of time-domain analyses to reveal the organization of control in isometric finger forces. PMID- 23111431 TI - Interaction between vibration-evoked proprioceptive illusions and mirror-evoked visual illusions in an arm-matching task. AB - We studied the influence of false proprioceptive information generated by arm vibration and false visual information provided by a mirror in which subjects saw a reflection of another arm on perception of arm position, in a forearm position matching task in right-handed subjects (n = 17). The mirror was placed between left and right arms, and arranged so that the reflected left arm appeared to the subjects to be their unseen right (reference) arm. The felt position of the right arm, indicated with a paddle, was influenced by vision of the mirror image of the left arm. If the left arm appeared flexed in the mirror, subjects felt their right arm to be more flexed than it was. Conversely, if the left arm was extended, they felt their right arm to be more extended than it was. When reference elbow flexors were vibrated at 70-80 Hz, an illusion of extension of the vibrated arm was elicited. The illusion of a more flexed reference arm evoked by seeing a mirror image of the flexed left arm was reduced by vibration. However, the illusion of extension of the right arm evoked by seeing a mirror image of the extended left arm was increased by vibration. That is, when the mirror and vibration illusions were in the same direction, they reinforced each other. However, when they were in opposite directions, they tended to cancel one another. The present study shows the interaction between proprioceptive and visual information in perception of arm position. PMID- 23111432 TI - Impact of ankle muscle fatigue and recovery on the anticipatory postural adjustments to externally initiated perturbations in dynamic postural control. AB - The aim of this study was to determine whether and how young participants modulate their postural response to compensate for postural muscle fatigue during predictable but externally initiated continuous and oscillatory perturbations. Twelve participants performed ten postural trials before and after an ankle muscle fatigue protocol. Each postural trial was 1 min long and consisted of continuous backward and forward oscillations of the platform. Fatigue was induced by intermittent, bilateral isometric contractions of the ankle plantar- and dorsiflexors until the force production was reduced to 50 % of the pre-fatigue maximal voluntary contraction. Changes in the center of mass (COM) displacement, center of pressure (COP) displacement, and anterior-posterior location of the COP within the base of support were quantified as well as the activity of the tibialis anterior (TA), medial gastrocnemius (MG), quadriceps, and hamstring. All participants demonstrated postural stability post-fatigue by maintaining the displacement of their COM. Everyone also demonstrated a general forward shift in the anterior-posterior location of the COP within the base of support; however, two distinct postural modifications, corresponding to either an immediate fatigue induced increase or decrease in the COP displacement during the backward platform translation, were recorded immediately post-fatigue. The changes in muscle onset latencies lasted beyond the recovery of the force production of the fatigued postural muscles. By 10 min post-fatigue, the participants showed a decrease in the COP displacement as well as an earlier activation of the postural muscles and an increased TA/MG co-activation relative to pre-fatigue. Although different strategies were used, the participants were able to adjust to and overcome postural muscle fatigue and remain balanced during the postural perturbations regardless of the direction of the platform movement. These adjustments lasted beyond the recovery of the ankle muscle force production indicating that they may be part of a centrally mediated protective response as opposed to a peripherally induced limitation to performance. PMID- 23111433 TI - Testicular tuberculosis in multidrug-resistant pulmonary tuberculosis. AB - We report a rare case of multidrug-resistant pulmonary and testicular tuberculosis (TB) in a 25-year-old immunocompetent patient. The patient was suspected to have a testicular cancer. He underwent radical orchiectomy, and surgical pathology revealed a granuloma containing acid-fast bacilli in the testis. Bronchial washing fluid culture grew Mycobacterium tuberculosis resistant to isoniazid, rifampin, and ethambutol. To our knowledge, this patient represents the first case of testicular TB in multidrug-resistant pulmonary TB. PMID- 23111434 TI - Management of chronic rhinosinusitis. PMID- 23111435 TI - Smoking is just as lethal for women. PMID- 23111437 TI - Decompressive hemicraniectomy in patients with supratentorial intracerebral hemorrhage. AB - BACKGROUND AND PURPOSE: Decompressive craniectomy (DC) lowers intracranial pressure and improves outcome in patients with malignant middle cerebral artery stroke. Its usefulness in intracerebral hemorrhage (ICH) is unclear. The aim of this study was to analyze feasibility and safety of DC without clot evacuation in ICH. METHODS: We compared consecutive patients (November 2010-January 2012) with supratentorial ICH treated with DC without hematoma evacuation and matched controls treated by best medical treatment. DC measured at least 150 mm and included opening of the dura. We analyzed clinical (age, sex, pathogenesis, Glasgow Coma Scale, National Institutes of Health Stroke Scale), radiological (signs of herniation, side and size of hematoma, midline shift, hematoma expansion, distance to surface), and surgical (time to and indication for surgery) characteristics. Outcome at 6 months was dichotomized into good (modified Rankin Scale 0-4) and poor (modified Rankin Scale 5-6). RESULTS: Twelve patients (median age 48 years; interquartile range 35-58) with ICH were treated by DC. Median hematoma volume was 61.3 mL (interquartile range 37-83.5 mL) and median preoperative Glasgow Coma Scale was 8 (interquartile range 4.3-10). Four patients showed signs of herniation. Nine patients had good and 3 had poor outcomes. Three patients (25%) of the treatment group died versus 8 of 15 (53%) of the control group. There were 3 manageable complications related to DC. CONCLUSIONS: DC is feasible in patients with ICH. Based on this small cohort, DC may reduce mortality. Larger prospective cohorts are warranted to assess safety and efficacy. PMID- 23111438 TI - Density of thrombus on admission CT predicts revascularization efficacy in large vessel occlusion acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Can lysability of large vessel thrombi in acute ischemic stroke be predicted by measuring clot density on admission nonenhanced CT (NECT), postcontrast enhanced CT, or CT angiogram (CTA)? METHODS: We retrospectively studied 90 patients with acute large vessel ischemic strokes treated with intravenous (IV) tPA, intra-arterial (IA) tPA, and/or mechanical thrombectomy devices. Clot density [in Hounsfield unit (HU)] was measured on NECT, postcontrast enhanced CT, and CTA. Recanalization was assessed by the Thrombolysis in Cerebral Infarction grading system (TICI) on digital subtraction angiography. RESULTS: Thrombus density on preintervention NECT correlated with postintervention TICI grade regardless of pharmacological (IV tPA r=0.69, IA tPA r=0.72, P<0.0001) or mechanical treatment (r=0.73, P<0.0001). Patients with TICI>=2 demonstrated higher HU on NECT (mean corrected HU IV tPA=1.58, IA tPA=1.66, mechanical treatment=1.7) compared with patients with TICI<2 (IV tPA=1.39, IA tPA=1.4, mechanical treatment=1.3) (P=0.01, 0.006, <0.0001 respectively). There was no association between recanalization and age, sex, baseline National Institute of Health Stroke Scale, treatment method, time to treatment, or clot volume. CONCLUSIONS: Thrombi with lower HU on NECT appear to be more resistant to pharmacological lysis and mechanical thrombectomy. Measuring thrombus density on admission NECT provides a rapid method to analyze clot composition, a potentially useful discriminator in selecting the most appropriate reperfusion strategy for an individual patient. PMID- 23111440 TI - Obesity: a stubbornly obvious target for stroke prevention. PMID- 23111439 TI - Retinal microvascular signs and risk of stroke: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND PURPOSE: Small-vessel disease contributes to the pathophysiology of stroke, and retinal microvascular signs have been linked to the risk of stroke. We examined the relationship of retinal signs with incident stroke in a multiethnic cohort. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective cohort study that enrolled participants without clinical cardiovascular diseases from 6 US communities between 2000 and 2002. Of the participants, 4849 (71.2%) had fundus photography performed in 2002 to 2004. Retinopathy and retinal vessel caliber were assessed from retinal images. Stroke risk factors including high-sensitivity C-reactive protein, carotid artery intima media thickness, and coronary artery calcium were measured using standardized protocols. Incident stroke was confirmed from medical record review and death certificates. RESULTS: After 6 years of follow-up, there were 62 incident strokes. Narrower retinal arteriolar caliber was associated with increased risk of stroke after adjusting for conventional cardiovascular risk factors (adjusted incidence rate ratio, 2.83; 95% CI, 1.34-5.95; P=0.006; adjusted hazard ratio, 3.01; 95% CI, 1.29-6.99; P=0.011). Retinopathy in persons without diabetes was associated with increased risk of stroke (adjusted adjusted incidence rate ratio, 2.96; 95% CI, 1.50-5.84; P=0.002; adjusted hazard ratio, 3.07; 95% CI, 1.17-8.09; P=0.023). These associations remained significant after adjusting for high sensitivity C-reactive protein, carotid intima-media thickness, or coronary artery calcium. CONCLUSIONS: Narrower retinal arteriolar caliber and retinopathy in nondiabetic persons were associated with increased risk of stroke in this relatively healthy multiethnic cohort independent of traditional risk factors and measures of atherosclerosis. The association between narrower retinal arteriolar caliber and stroke warrants further investigation. PMID- 23111441 TI - [Influence of chronic, structural changes of the muscle-tendon unit on the indication and technique of rotator cuff reconstruction]. AB - Rotator cuff lesions are common and the incidence increases with age. After tendon rupture of the rotator cuff, the muscle-tendon unit retracts, which is accompanied by muscle fatty infiltration, atrophy, and interstitial fibrosis of the musculature, thus, fundamentally changing the muscle architecture. These changes are important prognostic factors for the operative rotator cuff reconstruction outcome. Selection of the correct time point for reconstruction as well as the optimal mechanical fixation technique are decisive for successful attachment at the tendon-to-bone insertion site. Thus, knowledge of the pathophysiological processes plays an important role. The goal of this article is to establish a relationship between currently existing evidence with respect to the preoperatively existing changes of the muscle-tendon unit and the choice of the time for the operation and the operative technique. PMID- 23111442 TI - [Recurrent defects of the rotary cuff : Causes and therapeutic strategies]. AB - Recurrent defects of the rotator cuff still represent the most common complication after rotator cuff repair. The etiology is multifactorial; however, predominantly biological determinants seem to influence the structural outcome. Basically, recurrent defects due to non-healing of the rotator cuff tendons have to be distinguished from true re-ruptures, which occur after primary successful osteofibroblastic integration. Different modes of failure are responsible for recurrent defects of the rotator cuff. The management of recurrent defects depends on the clinical symptoms of the patient, the objective function of the shoulder and the pathomorphological changes of the rotator cuff and the shoulder joint itself. Beside a skillful neglect and/or conservative management, arthroscopic revision of failed cuff repairs appears to be a promising procedure. Irreparable tears can be managed using extraanatomic tendon transfer (latissimus dorsi or pectoralis major transfer) or shoulder replacement procedures (reverse prosthesis) depending on the functional symptoms of the patient. The results after re-reconstruction or open revision using tendon transfers are inferior compared to primary intervention. PMID- 23111443 TI - [Arthrodesis of the first metatarsophalangeal joint]. AB - OBJECTIVE: Fusion of the first metatarsophalangeal joint and realignment of the great toe in patients with painful arthritis to achieve pain-free walking. INDICATIONS: Hallux rigidus grade 3/4, hallux valgus et rigidus, claw toe deformity of the great toe, salvage after endoprosthesis or cheilectomy, avascular necrosis of the first metatarsal head arthritis of the first metatarsophalangeal joint. CONTRAINDICATIONS: Infection, painful arthritis of the interphanageal joint (relative contraindication), and severe osteoporosis (relative contraindication). SURGICAL TECHNIQUE: Dorsal approach to the first metatarsophalangeal joint. Removal of all osteophytes and circumferential capsular release. Debridement of the sesamoids. Cartilage resection (flat cuts or "cup and cone" reaming) and multiple drilling of the subchondral layer. In case of osseous defects, interposition of a corticocancellous bone graft. Trial reduction and assessment of the toe alignment. Fixation with two screws, one lag screw and dorsal plating, or dorsal plating only. Wound closure in layers. POSTOPERATIVE MANAGEMENT: Full weight bearing in a postoperative shoe or partial weight bearing in a short cast for 4-6 weeks. If the X-ray reveals sufficient bone healing, patients are allowed to wear sneakers with a stiff sole for 3-6 months. Sport activities with impact loading are limited for at least 3 months. Final X-ray control after 6 months. RESULTS: A total of 70 feet with a fusion of the first metatarsophalangeal joint were followed up after 28 months. Postoperative complications (7.3%): 5 wound slough, 1 infection, and 6 painful delayed union. Modified AOFAS forefoot score (max. 85 points) was 43 (32-58) points preoperatively and 82 (71-85) points postoperatively. Great toe alignment was perfect in 57 feet. Nine toes showed a valgus (> 20 degrees ) and 4 toes a varus malalignment. Fifty-four attained full ground contact. Eight patients reached the ground by flexion of the interphalangeal joint and 8 patients presented with dorsiflexion of the great toe. X-ray showed consolidation of the arthrodesis in 64 feet (91.4%), while 8 feet (4 with interposition of a bone graft) revealed signs of incomplete healing. These patients were advised to have an annual clinical and radiological reassessment performed. PMID- 23111444 TI - The promise and paradox of cultural competence. AB - Cultural competence has become a ubiquitous and unquestioned aspect of professional formation in medicine. It has been linked to efforts to eliminate race-based health disparities and to train more compassionate and sensitive providers. In this article, I question whether the field of cultural competence lives up to its promise. I argue that it does not because it fails to grapple with the ways that race and racism work in U.S. society today. Unless we change our theoretical apparatus for dealing with diversity to one that more critically engages with the complexities of race, I suggest that unequal treatment and entrenched health disparities will remain. If the field of cultural competence incorporates the lessons of critical race scholarship, however, it would not only need to transform its theoretical foundation, it would also need to change its name. PMID- 23111445 TI - Solid variant of aneurysmal bone cyst on the cervical spine of a child: case report, differential diagnosis and treatment rationale. AB - INTRODUCTION: Despite numerous descriptive publications, the nature, character, differential diagnosis and optimal treatment of aneurysmal bone cysts (ABCs), remain obscure. The authors report a case of the solid variant of aneurysmal bone cyst (S-ABC) occurring in the posterior components and body of C7 vertebra focusing on the differential diagnosis and surgical treatment rationale. CASE REPORT: Right shoulder and neck pain were the presenting symptoms of 9-year-old boy. Torticollis developed later on but no neurological deficit was found. Imaging revealed an osteolytic lesion with significant extraosseous extension. Although diagnosis favoured an ABC, imaging studies did not provide clear diagnostic criteria. CT guided biopsy performed preoperatively was also not directly diagnostic. Given that differential diagnoses included S-ABC but also giant cell tumor (GCT) of bone, decision was made to proceed with a staged, back and front, complete resection of the affected bony elements of C7. Preoperative spinal angiography showed supply to the tumor from the right ascending and deep cervical artery territories. Particle embolization was not performed due to the presence of ipsilateral supply to the anterior spinal artery at the C6 level and contralateral supply at the C7 level. Intraoperatively, histology taken from posterior elements, although again not clearly diagnostic, favoured S-ABC variant rather than GCT. Thus, initial plan was revised and anterior surgery was postponed as the extent of the dissection would have been dependent on the presumed diagnosis. The final histological report confirmed the diagnosis of an S ABC. In view of this, it was decided to embolize the lesion to avoid a second stage anterior surgery. At embolization, repeat spinal angiography showed reduced tumor blush following the surgery. Distal branches of the deep cervical artery were occluded with platinum coils (avoiding the risks associated with the use of particles or liquid embolic agents). No further procedure was planned. CONCLUSION: Imaging and histological pattern of this specific type of ABC, differential diagnosis from GCT and the surgical protocol followed with the patient consist of an interesting case of revising the initial plan, according to the upcoming histological reports. PMID- 23111446 TI - Expert's comment concerning grand rounds case entitled "treatment strategies for severe C1C2 luxation due to congenital os odontoideum causing tetraplegia" (by C. M. Bach, D. Arbab and M. Thaler, doi:10.1007/s00586-012-2329-5). PMID- 23111450 TI - FDA research and classification initiatives. PMID- 23111447 TI - TRPV1 properties in thoracic dorsal root ganglia neurons are modulated by intraperitoneal capsaicin administration in the late phase of type-1 autoimmune diabetes. AB - Pharmacological therapies in type 1 diabetes for efficient control of glycemia and changes in pain alterations due to diabetic neuropathy are a continuous challenge. Transient receptor potential vanilloid type 1 (TRPV1) from dorsal root ganglia (DRG) neurons is one of the main pharmacological targets in diabetes, and its ligand capsaicin can be a promising compound for blood-glucose control. Our goal is to elucidate the effect of intraperitoneal (i.p.) capsaicin administration in type 1 diabetic mice against TRPV1 receptors from pancreatic DRG primary afferent neurons. A TCR(+/-)/Ins-HA(+/-) diabetic mice (dTg) was used, and patch-clamp and immunofluorescence microscopy measurements have been performed on thoracic T(9)-T(12) DRG neurons. Capsaicin (800 MUg/kg, i.p. three successive days) administration in the late-phase diabetes reduces blood-glucose levels, partly reverses the TRPV1 current density and recovery time constant, without any effect on TRPV1 expression general pattern, in dTg mice. A TRPV1 hypoalgesia profile was observed in late-phase diabetes, which was partly reversed to normoalgesic profile upon capsaicin i.p. administration. According to the soma dimensions of the thoracic DRG neurons, a detailed analysis of the TRPV1 expression upon capsaicin i.p. treatment was done, and the proportion of large A fiber neurons expressing TRPV1 increased in dTg capsaicin-treated mice. In conclusion, the benefits of low-dose capsaicin intraperitoneal treatment in late phase type-1 diabetes should be further exploited. PMID- 23111451 TI - The effect of contact lens materials on disinfection activity of polyquaternium-1 and myristamidopropyl dimethylamine multipurpose solution against Staphylococcus aureus. AB - OBJECTIVES: This study examined the interaction of seven different lens materials with a multipurpose solution (MPS) containing the disinfectants polyquaternium-1 (0.001%) and myristamidopropyl dimethylamine (0.0005%). The objective of this study was to determine whether the different lens materials affect the concentration of a disinfectant in this commercially available MPS and the efficacy of the disinfectant against Staphylococcus aureus. METHODS: Silicone hydrogel lenses (galyfilcon A, senofilcon A, comfilcon A, enfilcon A, balafilcon A, and lotrafilcon B) and a conventional hydrogel lens (etafilcon A) were soaked in polypropylene lens cases filled with commercially available MPS containing 0.001% polyquaternium-1 and 0.0005% myristamidopropyl dimethylamine for 6, 12, 24, 72, and 168 hours. Empty lens cases were also filled with MPS. After each time point, solutions from cases containing the seven types of lenses and controls were assayed for activity against S. aureus according to International Standards Organization 14729 standard with modifications. Test solutions were analyzed for polyquaternium-1 and myristamidopropyl dimethylamine concentration at each time point. RESULTS: The concentration of polyquaternium-1 and myristamidopropyl dimethylamine remaining in the lens cases was reduced only slightly over time. Storage with the lenses did not adversely affect biocidal efficacy of the solution, and in some cases, it was significantly better (P=0.0029). CONCLUSION: The efficacy of this polyquaternium-1 and myristamidopropyl dimethylamine MPS to kill S. aureus was not adversely affected by the presence of lens materials soaking in the cases. Thus, current methods for performing solution antimicrobial testing should be reevaluated. PMID- 23111452 TI - Cyclin D1 polymorphism and oral cancer: a meta-analysis. AB - Cyclin D1 (CCND1) plays a critical role in the G1 to S-phase cell cycle transition. Data on the association between the CCND1 A870G polymorphism and oral cancer are conflicting. To assess the relationship between the CCND1 A870G genotype and the risk of developing oral cancer, we performed a meta-analysis. We searched PubMed to December 1, 2011, for studies on this topic that had been published in the English. For each study, we calculated odds ratios (ORs) and 95 % confidence intervals (CIs), assuming the frequency of allele comparison, homozygote comparison, recessive and dominant genetic models. We then calculated pooled ORs and 95 % CIs. Seven studies were included in the meta-analysis. The CCND1 G allele was not associated with oral cancer in the frequency of allele comparison (G vs. A: OR = 0.882; 95 % CI = 0.684-1.137; p = 0.001 for heterogeneity). In the subgroup analysis, the CCND1 G allele was associated with a borderline significantly decreased risk of developing oral cancer in Asians in the frequency of allele comparison (G vs. A: OR = 0.800; 95 % CI = 0.636-1.006; p = 0.089 for heterogeneity), and the association between the GG genotype and oral cancer was significant in Asians with respect to both the homozygote comparison (GG vs. AA: OR = 0.644; 95 % CI = 0.491-0.843; p = 0.186 for heterogeneity) and the dominant genetic model (GG + AG vs. AA: OR = 0.713; 95 % CI = 0.584-0.870; p = 0.293 for heterogeneity). Our analysis provides evidence that genotypes for the CCND1 A870G polymorphism may be associated with an increased risk of developing oral cancer in the Asian population. PMID- 23111453 TI - The common SNP (rs9939609) in the FTO gene modifies the association between obesity and high blood pressure in Chinese children. AB - Previous studies have suggested that common variants in fat mass- and obesity associated (FTO) gene are associated with body mass index (BMI) and the risk of obesity. Since obesity plays an important role in the etiology of high blood pressure (HBP), we aim to investigate the association between obesity and HBP in a population with different variants of the FTO gene. A total of 3,494 children (1,775 boys, 50.8 %) aged 6-18 years were recruited for measuring pubertal status, BMI and systolic and diastolic blood pressure. The single nucleotide polymorphism rs9939609 of the FTO gene was genotyped. The blood pressure levels increased by 1.4, 1.5 and 1.8 mmHg for systolic blood pressure and 0.8, 0.9 and 1.2 mmHg for diastolic blood pressure per 1-unit BMI increase in subjects carrying TT, TA and AA genotypes, respectively. After stratifying for FTO rs9939609 genotypes (TT, TA and AA), the odds ratios (95 % confidence intervals) of HBP in obese versus non-obese children were 4.26 (3.18-5.71), 5.13 (2.96-8.90) and 10.37 (1.59-67.43), respectively, with adjustment for age, gender and pubertal status. The FTO rs9939609 SNP modifies the effect of obesity on HBP in Chinese children, with obese ones carrying the AA homozygous genotype of the FTO rs9939609 having the highest risk of developing HBP. PMID- 23111454 TI - Quantitative assessment of the effect of ABCA1 gene polymorphism on the risk of Alzheimer's disease. AB - ATP-binding cassette transporter A1 (ABCA1) is a membrane-associated protein which has attracted considerable attention as a candidate gene for Alzheimer's disease (AD) based on its function as a key factor in lipid metabolism by mediating cellular cholesterol efflux, the rate-limiting step in the production of nascent high-density lipoprotein (HDL) particles. The relationship between ABCA1 common variations (R219 K rs2230806, I883 M rs4149313 and R1587 K rs2230808) and AD has been reported in various ethnic groups; however, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of 13 studies involving a total of 12,248 subjects to evaluate the effect of ABCA1 on genetic susceptibility for AD. Overall, the summary OR of AD was 1.01 (95 % CI: 0.93-1.10; P = 0.77), 1.10 (95 % CI: 0.96 1.26; P = 0.16), and 1.08 (95 % CI: 0.96-1.23; P = 0.21) for R219 K, I883 M and R1587 K polymorphism, respectively. No significant results were observed in dominant and recessive when compared with wild genotype for these polymorphisms. In the stratified analyses by ethnicity and sample size, no evidence of any gene disease association was obtained. In conclusion, the present meta-analysis does not support the notion that common SNPs on ABCA1 is a major genetic risk factor for AD. PMID- 23111455 TI - Quantitative assessment of the influence of PSMA6 variant (rs1048990) on coronary artery disease risk. AB - The proteasome system is a proteolytic pathway that regulates the expression of genes involved in inflammation. Recently, an association of a functional sequence variation, -8C/G, in the human proteasome subunit a type 6 gene (PSMA6) with the susceptibility to coronary artery disease (CAD) was reported. After that, several validation studies have been conducted among various ethnic populations, but the results have been inconsistent. To investigate this inconsistency and derive a more precise estimation of the relationship, a meta-analysis of 15,991 cases and 16,784 controls from 10 case-control studies was performed. Potential sources of heterogeneity including ethnicity, sample size and HWE status of study were also assessed. In a combined analysis, the summary per-allele OR for CAD of the -8C/G polymorphism was 1.09 (95 % CI: 1.02-1.16; P = 0.006). In the subgroup analysis by ethnicity, significantly increased risks were found in East Asians for the polymorphism; while no significant associations were found among Caucasians and other ethnic population in all genetic models. When restricted to studies concerning myocardial infarction patients, significant associations were detected in all genetic models. Furthermore, significant difference of PSMA6 mRNA expression was found between genotypes. In conclusion, this meta-analysis suggests that G allele of PSMA6-8C/G polymorphism is a risk factor associated with increased CAD susceptibility, but these associations vary in different ethnic populations. PMID- 23111457 TI - Chryptochrome 2 variants, chronicity, and seasonality of mood disorders. PMID- 23111456 TI - Ellagic acid checks lymphoma promotion via regulation of PKC signaling pathway. AB - Protein Kinase C (PKC) isozymes are key components involved in cell proliferation and their over activation leads to abnormal tumor growth. PKC follows signalling pathway by activation of downstream gene NF-kB and early transcription factor c Myc. Over activation of NF-kB and c-Myc gene are also linked with unregulated proliferation of cancer cells. Therefore any agent which can inhibit the activation of Protein kinase C, NF-kB and c-Myc may be useful in reducing cancer progression. To investigate this hypothesis we have tested the effect of ellagic acid on these genes in Dalton's lymphoma bearing (DL). The role of ellagic acid was also tested in regulation of tumor suppressor gene Transforming growth factor beta1 (TGF-beta1). DL mice were treated with three different doses (40, 60 and 80 mg/kg body weight) of ellagic acid. Ascites cells of mice were used for the experiments. Ellagic acid administration to DL mice decreased oxidative stress by reducing lipid peroxidation. Ellagic acid also down regulates the expression of classical isozymes of PKC i.e. PKCalpha, PKCbeta, and PKCgamma as well as activity of total PKC and NF-kB, indicating its antitumor action. The anticarcinogenic action of ellagic acid was also confirmed by up regulation of TGF-beta1 and down regulation of c-Myc. Lymphoma prevention by ellagic acid is further supported by decrease in cell proliferation, cell viability, ascites fluid accumulation and increase in life span of DL mice. All these findings suggest that ellagic acid prevents the cancer progression by down regulation of PKC signaling pathway leading to cell proliferation. PMID- 23111458 TI - A highly active catalytic system for Suzuki-Miyaura cross-coupling reactions of aryl and heteroaryl chlorides in water. AB - An easily available Pd(OAc)(2)/(2 mesitylindenyl)dicyclohexylphosphine/Me(octyl)(3)N(+)Cl(-)/K(3)PO(4).3H(2)O catalytic system was developed and it shows high catalytic activity in the Suzuki Miyaura cross-coupling reaction of a diverse array of aryl and heteroaryl chlorides in water. Notably, this catalytic system also works with ultra-low loading of the catalyst with high turnover numbers. PMID- 23111460 TI - Thin films of metals, metal chalcogenides and oxides deposited at the water-oil interface using molecular precursors. AB - The interface between two immiscible liquids is emerging as a powerful medium for the growth and deposition of nanostructured thin films of metals and compound semiconductors. Materials obtained through this exceedingly simple route seem to often adopt fascinating forms and morphologies. In this article, we outline features unique to the interface that shape the striking deposits and highlight the nature and properties of nanostructured films obtained using this technique. PMID- 23111459 TI - MicroRNA target sites as genetic tools to enhance promoter-reporter specificity for the purification of pancreatic progenitor cells from differentiated embryonic stem cells. AB - Pluripotent cells hold great promise for cell replacement therapies in regenerative medicine. All known protocols for directed in vitro differentiation of pluripotent cells did not yield pure populations complicating the characterization of the derived cells. In addition, the risk of tumor formation due to residual undifferentiated cells is a serious unresolved problem. In the present study the tissue-specific mouse Pdx1 promoter was used to control the expression of the reporter gene GFP2 in mouse ES cells in order to purify them via FACS during in vitro differentiation. The background fluorescence of transduced ES cells hampered the purification of Pdx1-positive cells due to a contaminating population of partially undifferentiated cells. MicroRNAs (mir) are important regulators of gene expression and were used to enhance promoter specificity during differentiation towards pancreatic progenitor cells. The mouse mmu-mir-294 was found to be mainly expressed during pluripotency, whereas the expression of the mir-302 cluster was increased during early differentiation. Integration of a microRNA target site for the mmu-mir-294 into the lentiviral vector reduced the background fluorescence specifically during pluripotency and permitted re-occurrence of GFP2 expression upon differentiation. A combination of the microRNA target site with the Pdx1 promoter fragment allowed the purification of pancreatic progenitors from differentiated ES cells. This population reflected an early pancreatic progenitor population without other contaminating cell lineages. In conclusion, microRNA target sites are efficient regulatory elements to control transgene expression and to enhance tissue specificity as presented in this study facilitating the sorting and purification of Pdx1-positive pancreatic progenitor cells. PMID- 23111461 TI - Investigations of IgG4-related disease involving the skin. AB - OBJECTIVES: IgG4-related skin disease is not widely recognized. This prompted us to investigate the clinical and pathological features of five patients we encountered with IgG4-related disease (IgG4-RD) affecting the skin. METHODS: We investigated the clinical and pathological features of these five patients, including the distribution, onset, and morphology of eruptions, their pathological and immunohistochemical characteristics, and the occurrence of disease in other organs. RESULTS: The skin lesions were typically erythematous nodules and papules and brown papules like prurigo nodularis, which developed on the face or in the head and neck areas in four patients. Skin lesions were the first clinical manifestation in three patients. All five patients had sialadenitis and/or dacryoadenitis. The mean serum IgG4 concentration was 665.6 +/- 410.0 mg/dl. Infiltrations of IgG4-positive plasma cells were observed in both the dermis and subcutaneous tissue. Germinal center formations were seen in three patients. Mild to moderate fibrosis was observed in all patients, and focal obliterative phlebitis in one. The average count of IgG4-positive cells was 67.3/high-power field (23.0-128.6). Wide variation in the numbers of infiltrating IgG4-positive cells was noted. CONCLUSION: IgG4-RD appears to have a distinctive clinicopathological presentation in the skin, differentiating it from other cutaneous disorders. PMID- 23111462 TI - Expression of transient receptor potential vanilloid channels TRPV5 and TRPV6 in human blood lymphocytes and Jurkat leukemia T cells. AB - Regulation of Ca(2+) entry is a key process for lymphocyte activation, cytokine synthesis and proliferation. Several members of the transient receptor potential (TRP) channel family can contribute to changes in [Ca(2+)](in); however, the properties and expression levels of these channels in human lymphocytes continue to be elusive. Here, we established and compared the expression of the most Ca(2+)-selective members of the TRPs, Ca(2+) channels transient receptor potential vanilloid 5 and 6 (TRPV5 and TRPV6), in human blood lymphocytes (HBLs) and leukemia Jurkat T cells. We found that TRPV6 and TRPV5 mRNAs are expressed in both Jurkat cells and quiescent HBLs; however, the levels of mRNAs were significantly higher in malignant cells than in quiescent lymphocytes. Western blot analysis showed TRPV5/V6 proteins in Jurkat T cells and TRPV5 protein in quiescent HBLs. However, the expression of TRPV6 protein was switched off in quiescent HBLs and turned on after mitogen stimulation of the cells with phytohemagglutinin. Inwardly directed monovalent currents that displayed characteristics of TRPV5/V6 currents were recorded in both Jurkat cells and normal HBLs. In outside-out patch-clamp studies, currents were reduced by ruthenium red, a nonspecific inhibitor of TRPV5/V6 channels. In addition, ruthenium red downregulated cell-cycle progression in both activated HBLs and Jurkat cells. Thus, we identified TRPV5 and TRPV6 calcium channels, which can be considered new candidates for Ca(2+) entry into human lymphocytes. The correlation between expression of TRPV6 channels and the proliferative status of lymphocytes suggests that TRPV6 may be involved in the physiological and/or pathological proliferation of lymphocytes. PMID- 23111463 TI - Curatively resected isolated inguinal lymph node metastasis from cecum cancer: report of a case. AB - We herein report the case of a curatively resected solitary inguinal lymph node metastasis from cecum cancer. Our patient was a 67-year-old male with cecum cancer with abdominal wall invasion. Three years after surgery, inguinal lymph node swelling was detected by a computed tomography examination. Further examination revealed no other metastases. Surgical resection was performed to remove the lesion, and microscopic examination revealed that cancer cells had metastasized. No recurrence was detected 3 years after the salvage surgery. Inguinal lymph node metastasis of cecum cancer has not been reported in the literature, but in our case salvage surgery resulted in a good outcome. PMID- 23111464 TI - Ileocolonic anastomosis: preferred techniques in 999 patients. A multicentric study. AB - PURPOSE: There is no standard anastomosis technique for performing reconstruction after right hemicolectomy, and, in the literature, studies on ileocolonic anastomosis are rare. The aim of this retrospective work was to analyze the type of anastomosis techniques used and the related results in a multicentric enquiry. METHODS: A questionnaire was sent to the departments of surgery covering a 1.8 million inhabitant area to collect data concerning the anastomosis techniques used and the results related to complications. RESULTS: Data for 999 patients from 14 departments of surgery were collected. 95.8% of the patients were affected by cancer and 4.2% were affected by inflammatory bowel disease (IBD). The positioning of the anastomosing bowel was side-to-side in 60.5% of the patients, end-to-side (E-S) in 38.1% of the patients and end-to-end in 1.3% of the patients. 46.4% of the anastomoses were handsewn and 53.6% were stapled. The complication rate in the cancer group was 5.1% for handsewn techniques and 4.7% for stapled techniques. The rate of anastomotic leakage was higher in the handsewn group than that in the stapled group (P < 0.05). The data for the IBD group were not statistically relevant. CONCLUSIONS: This wide multicentric retrospective analysis showed that there remains variability in ileocolonic anastomosis techniques. Stapled anastomoses are associated with a lower incidence of leakage. In stapled anastomoses, the E-S configuration is also related to a lower incidence of leakage. PMID- 23111466 TI - DSM-5 field trials in the United States and Canada, Part II: test-retest reliability of selected categorical diagnoses. AB - OBJECTIVE: The DSM-5 Field Trials were designed to obtain precise (standard error,0.1) estimates of the intraclass kappa asa measure of the degree to which two clinicians could independently agree on the presence or absence of selected DSM-5 diagnoses when the same patient was interviewed on separate occasions, in clinical settings, and evaluated with usual clinical interview methods. METHOD: Eleven academic centers in the United States and Canada were selected,and each was assigned several target diagnoses frequently treated in that setting.Consecutive patients visiting a site during the study were screened and stratified on the basis of DSM-IV diagnoses or symptomatic presentations. Patients were randomly assigned to two clinicians for a diagnostic interview; clinicians were blind to any previous diagnosis. All data were entered directly via an Internet-based software system to a secure central server. Detailed research design and statistical methods are presented in an accompanying article. RESULTS: There were a total of 15 adult and eight child/adolescent diagnoses for which adequate sample sizes were obtained to report adequately precise estimates of the intraclass kappa. Overall, five diagnoses were in the very good range(kappa=0.60-0.79), nine in the good range(kappa=0.40-0.59), six in the questionable range (kappa = 0.20-0.39), and three in the unacceptable range (kappa values,0.20). Eight diagnoses had insufficient sample sizes to generate precise kappa estimates at any site. CONCLUSIONS: Most diagnoses adequately tested had good to very good reliability with these representative clinical populations assessed with usual clinical interview methods. Some diagnoses that were revised to encompass a broader spectrum of symptom expression or had a more dimensional approach tested in the good to very good range. PMID- 23111465 TI - Do proton pump inhibitors protect against cancer progression in GERD? AB - Gastro-duodenal content reflux from gastro-esophageal reflux disease (GERD) induces the inflammation-metaplasia-dysplasia-adenocarcinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. The effect of PPI therapy on esophageal carcinogenesis remains unclear. While some studies suggest PPIs result in a significant reduction in the risk of developing dysplasia and adenocarcinoma in patients with Barrett's esophagus, others suggest that PPIs have no effect. Recent studies have revealed that PPIs can exert anti-inflammatory effects such as anti-oxidant properties and immunomodulatory effects through their interactions with neutrophils, monocytes, endothelial and epithelial cells. In addition, PPIs have the ability to prevent adhesion molecule binding in malignant cells and suppress metastasis. This article reviews the role of PPIs in esophageal carcinogenesis and their use as antitumor agents. PMID- 23111467 TI - Differential expression and localization of dentin matrix protein 1 (DMP1) fragments in mouse submandibular glands. AB - It has been demonstrated that dentin matrix protein 1 (DMP1) is an essential regulator in the formation of bone and tooth. In addition to the mineralized tissues, DMP1 is also expressed in the non-mineralized tissues such as kidney, brain and salivary glands. Some studies have shown that the expression of DMP1 is significantly elevated in cancerous glands, while details about the expression and localization patterns of DMP1 in these glandular tissues still remain largely unknown. In this study, with multiple approaches, we systematically analyzed the expression and localization of DMP1 in mouse submandibular glands (SMGs). The results showed that although DMP1 was expressed in both female and male mouse SMGs, the mRNA levels of DMP1 in male mice were higher than those in female mice after the appearance of granular convoluted tubule (GCT). In mouse SMGs, DMP1 was primarily present as the 46 kDa C-terminal fragment and the 37 kDa N-terminal fragment. The C-terminal fragment was mainly localized in the nuclei of acinar and ductal cells, while the N-terminal fragment was restricted to the cytoplasm of ductal cells. This study showed the expression of DMP1 in the GCT of male mice, a novel finding different from the result of previous reports. Collectively, the differential localization patterns of DMP1 fragments indicate that different forms of DMP1 may play distinct roles in the SMGs. PMID- 23111468 TI - Prognostic factors and a survival score for patients with metastatic spinal cord compression from colorectal cancer. AB - BACKGROUND: This study aimed to identify independent prognostic factors and to create a survival score for patients with metastatic spinal cord compression (MSCC) from colorectal cancer (CRC). PATIENTS AND METHODS: Data from 121 patients irradiated for MSCC from CRC were retrospectively analyzed. Eleven potential prognostic factors were investigated including tumor type, age, gender, Eastern Cooperative Oncology Group performance status score (ECOG-PS), number of involved vertebrae, ambulatory status prior to radiotherapy (RT), other bone metastases, visceral metastases, interval from cancer diagnosis to RT of MSCC, time of developing motor deficits prior to RT, and the RT schedule. RESULTS: On multivariate analysis, improved motor function was significantly associated with an ECOG-PS of 1-2 (p = 0.011) and a slower development of motor deficits (p < 0.001). Improved local control was significantly associated with absence of visceral metastases (p = 0.043) and longer-course RT (p = 0.008). Improved survival was significantly associated with an ECOG-PS of 1-2 (p < 0.001), ambulatory status (p < 0.001), absence of visceral metastases (p < 0.001), and a slower development of motor deficits (p = 0.047). These four prognostic factors were included in a survival score. The score for each factor was determined by dividing the 6-month survival rate by 10. The prognostic score represented the sum of the factor scores. Four prognostic groups were designed; the 6-month survival rates were 0% for 8-12 points, 26% for 13-18 points, 62% for 20-23 points, and 100% for 24-27 points (p < 0.001). CONCLUSION: This study identified several independent prognostic factors for treatment outcomes in patients irradiated for MSCC from CRC. The survival prognosis of these patients can be estimated with a new score. PMID- 23111471 TI - [Screening of gene polymorphisms does not improve predictability of radiation toxicity]. PMID- 23111469 TI - Plasminogen activator inhibitor-1 (PAI-1) expression in relation to hypoxia and oncoproteins in clinical cervical tumors. AB - PURPOSE: Explore the role of plasminogen activator inhibitor-1 (PAI-1) in cervical cancer and its relationship to hypoxia and the expression of p53, Ku70/80, and cyclin D1. MATERIAL AND METHODS: The expression of PAI-1, cyclin D1, and p53, together with tumor oxygenation, were determined in 43 consecutive patients suffering from localized cervical carcinoma. Oncoprotein expression was determined by immunohistochemistry. Tumor oxygenation was measured using a polarographic probe system, "pO2 histography." RESULTS: PAI expression was considered negative in 32.6% and overexpressed in 18.6% of cases. Cyclin D1 showed a median expression of 5.0 (range 0-70). We observed a positive association between PAI expression and altered p53 (p = 0.049) and cyclin D1 (p = 0.020). An inverse association was detected between PAI and Ku70/80 expression (p = 0.042). Cyclin D1 staining increased according to tumor volume (r = 0.314, p = 0.009). We did not observe a significant association between PAI and hypoxia or other clinicopathological parameters. CONCLUSION: The present results show that PAI-1 overexpression is associated with nonhomologous end-joining DNA repair down regulation (low Ku70/80 expression) and with increased p53 and cyclin D1 expression, and they suggest that PAI-1 plays a role in the tumor behavior in cervical carcinoma. PMID- 23111470 TI - Expander/implant breast reconstruction before radiotherapy: outcomes in a single institute cohort. AB - BACKGROUND AND PURPOSE: Radiotherapy (RT) of reconstructed breasts was associated with major complications and poor cosmetic outcome. The present study assessed complication rates, the link between risk factors and prosthesis removal, as well as cosmetic outcomes. PATIENTS AND METHODS: From 1997 to 2009, 101 consecutive patients received RT after breast reconstruction because of risk factors for relapse (92) or because relapse had occurred (9). At RT, 90 patients had temporary tissue expanders and 11 had permanent implants. Twelve patients underwent neo-adjuvant chemotherapy; all patients received adjuvant chemo- and/or hormone therapy. RESULTS: At a median follow-up of 50 months, late toxicities occurred in 28 patients: pain in 7, lymphedema in 6, G1 cutaneous toxicity in 5, and subcutaneous toxicity in 19 (2G1, 9G2, 7G3, 1G4), with more than one side effect in 12. In 8 patients the prosthesis ruptured (3), was displaced (3), was displaced and ruptured (1), or lost shape (1). Capsular contracture was classified in 89 patients as IA in 14, IB in 47, II in 10, III in 11, and IV in 7. Twelve prostheses (11.9%) were removed. The only significant factor for prosthesis removal was age (p = 0.007). Judgments of cosmetic results were available from 81 physicians and 84 patients. Outcome was excellent/good in 58/81 physician judgments and in 57/84 patient evaluations. Overall inter-rater agreement on outcome was good (kappa-value 0.64; 95% CI: 0.48-0.79). CONCLUSION: RT to reconstructed breasts was associated with low rates of late toxicity and prosthesis removal. Cosmetic outcomes were, on the whole, good to excellent. PMID- 23111472 TI - Assessment of renal function after conformal radiotherapy and intensity-modulated radiotherapy by functional 1H-MRI and 23Na-MRI. AB - PURPOSE: Adjuvant radiochemotherapy (RCHT) improves survival of patients with locally advanced gastric cancer. Conventional three-dimensional conformal radiotherapy (3D-CRT) results in ablative doses to a significant amount of the left kidney, while image-guided intensity-modulated radiotherapy (IG-IMRT) provides excellent target coverage with improved kidney sparing. Few long-term results on IMRT for gastric cancer, however, have been published. Functional magnetic resonance imaging (fMRI) at 3.0 T including blood oxygenation-level dependent (BOLD) imaging, diffusion-weighted imaging (DWI) and, for the first time, (23)Na imaging was used to evaluate renal status after radiotherapy with 3D CRT or IG-IMRT. PATIENTS AND METHODS: Four disease-free patients (2 after 3D-CRT and 2 after IMRT; FU for all patients > 5 years) were included in this feasibility study. Morphological sequences, axial DWI images, 2D-gradient echo (GRE)-BOLD images, and (23)Na images were acquired. Mean values/standard deviations for ((23)Na), the apparent diffusion coefficient (ADC), and R2* values were calculated for the upper/middle/lower parts of both kidneys. Corticomedullary (23)Na-concentration gradients were determined. RESULTS: Surprisingly, IG-IMRT patients showed no morphological alterations and no statistically significant differences of ADC and R2* values in all renal parts. Values for mean corticomedullary (23)Na-concentration matched those for healthy volunteers. Results were similar in 3D-CRT patients, except for the cranial part of the left kidney. This was atrophic and presented significantly reduced functional parameters (p = 0.001-p = 0.033). Reduced ADC values indicated reduced cell density and reduced extracellular space. Cortical and medullary R2* values of the left cranial kidney in the 3D-CRT group were higher, indicating more deoxygenated hemoglobin due to reduced blood flow/oxygenation. ((23)Na) of the renal cranial parts in the 3D-CRT group was significantly reduced, while the expected corticomedullary (23)Na-concentration gradient was partially conserved. CONCLUSIONS: Functional MRI can assess postradiotherapeutic renal changes. As expected, marked morphological/functional effects were observed in high-dose areas (3D-CRT), while, unexpectedly, no alteration in kidney function was observed in IG-IMRT patients, supporting the hypothesis that reducing total/fractional dose to the renal parenchyma by IMRT is clinically beneficial. PMID- 23111474 TI - HER2 testing in breast cancer: an overview of current techniques and recent developments. AB - Testing for HER2 positivity in breast cancer carries implications for prognosis and therapeutic response in patients. In recent times there have been numerous developments and refinements in the available technologies for HER2 testing. In addition to this, guidelines have been developed and modified in an attempt to improve reliability and accuracy of testing. Immunohistochemistry and FISH testing have been the most widely used methodology, and the technique which has the largest knowledge base. Some of the inherent disadvantages have prompted the development of newer brightfield techniques which overcome some of these issues. There is gathering experience with these emerging technologies. Despite efforts to optimise and standardise procedures there remains a small percentage of cases that continue to be unresolved, whether this be due to issues of polysomy of chromosome 17, other complex genetic changes or analytical/interpretative issues. An ideal method for the resolution of these equivocal results should be considered in a specialised testing/referral centre, and this may include karyotyping studies of chromosome 17 or multiple probes for chromosome 17 using fluorescence in situ hybridisation or multiplex ligation-dependent probe amplification.It is timely to review of some of the newer techniques available for routine testing and approaches for cases which prove difficult to resolve using conventional testing methodology. PMID- 23111475 TI - Cadmium and lead in Hong Kong school children. AB - AIM: Cadmium (Cd) and lead (Pb) are toxic elements in our environment. This study is to determine the reference intervals of Cd and Pb in blood and urine from Hong Kong school children and to identify their determinants. METHODS: A total of 2209 secondary school children and 893 preschool children were recruited. Cd and Pb in blood and urine were measured by inductively-coupled plasma mass spectrometry. RESULTS: Blood Cd was affected by age, smoking and residential district, while urine Cd was influenced by age and blood Cd. Blood Cd was positively correlated with smoking as confirmed by urinary cotinine (rho = 0.183, p < 0.001, n = 2074). Blood Pb was dependent on gender and residential district, while urinary Pb was dependent on gender and blood Pb. Students from schools of lower academic grading had higher blood Cd and Pb than those from higher academic grading schools (p < 0.001, respectively). Urinary albumin was positively associated with urinary Cd and Pb. CONCLUSIONS: Using a non-occupationally exposed population, the reference ranges are: blood Cd < 21.9 nmol/L for smokers and < 8.8 nmol/L for non-smokers, and blood Pb < 203.8 nmol/L. Reference intervals for urinary Cd and Pb are also reported. PMID- 23111476 TI - Evaluation of (SD) MPT64 antigen rapid test, for fast and accurate identification of Mycobacterium tuberculosis complex. AB - AIM: To evaluate the SD MPT64 assay for rapid, preliminary identification of Mycobacterium tuberculosis complex (MTBC). METHODS: All specimens were processed using a standard methodology and inoculated into an automated liquid culture system (BD MGIT960). All signal positive cultures had a smear prepared and tested using a commercial molecular assay. From a carefully mixed MGIT960 vial, 100 MUL of broth was loaded into the sample well, and the result recorded after 15 min. Repeat isolates from patients were excluded as were positive cultures contaminated with non-mycobacteria. RESULTS: Fifty MTBC and 150 non-tuberculous mycobacteria were isolated during the study period. Test sensitivity was 98.04%, specificity (98.68%), positive predictive value (96.15%), and a negative predictive value (99.34%). There were two false positive results: Mycobacterium gastri and Mycobacterium fortuitum which were both identified by 16S rDNA and rpoB sequence analysis. CONCLUSIONS: The SD MPT64 assay showed excellent performance. The major advantages are: (1) simplicity of test procedure, (2) rapid turnaround time, and (3) relatively inexpensive. When used in conjunction with the presence of serpentine cording in a stained smear from culture, a preliminary identification of MTBC may be made with high confidence. PMID- 23111477 TI - Kupffer cell haemophagocytosis presenting as fulminant liver failure. PMID- 23111478 TI - Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial. AB - BACKGROUND: Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious. METHODS: This multicentre, randomised controlled, parallel, hospital based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status. RESULTS: Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components. CONCLUSIONS: In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk. PMID- 23111479 TI - Professionalism and social networking: can patients, physicians, nurses, and supervisors all be "friends?". AB - The purpose of this study was to examine the use of social networking (Facebook) among nurse anesthetists. We examined whether they would have concerns about their supervisor, patients, or physicians seeing their Facebook profile. We also examined their attitudes related to maintaining professional boundaries with regard to the initiation or receipt of Facebook "friend" requests from their supervisor, patients, or physicians they work with. Our respondents consisted of 103 nurses currently enrolled in a graduate-level nurse anesthetist program. All respondents had a minimum of 2 years of work experience in critical care nursing. Most respondents were found to be neutral about physicians and supervisors viewing their Facebook profiles but expressed concerns about patients seeing such information. A vast majority indicated they would accept a friend request from their supervisor and a physician but not a patient. Surprisingly, about 40% had initiated a friend request to their supervisor or physician they work with. Implications for health care managers are discussed. PMID- 23111480 TI - Hospital bed utilization by teaching and nonteaching medical services. AB - A study was undertaken to determine whether hospital bed utilization is different between teaching and nonteaching hospitalist services. During a 2-year period, the average length of stay (ALOS), case-mix index, readmissions within 30 days of discharge, and percentage of 1-day stays were compared between these services. To ameliorate confounders, the ALOS was recalculated (ALOS revised) after excluding patients with length of stay of more than 20 days and those originally admitted to the intensive care unit. Six thousand ninety-nine patients were discharged by the teaching service (group 1), 14 348 by the corporate hospitalist (group 2), and 2634 by the community-based practitioner group (group 3). The mean ALOS revised was significantly lower for the teaching service (3.64 +/- 2.22 days) compared with the other 2 services (4.53 +/- 1.48 and 4.73 +/- 1.02, respectively [P < .001]), although the mean case-mix index was significantly higher for the teaching service compared with the other services. The mean percentage of readmissions within 30 days of discharge and 1-day stays were not significantly different between group 1 and groups 2 and 3. Hospital bed utilization in the teaching service was superior to the nonteaching hospitalist services. Further research should explore the reasons for the differences between these models of care. PMID- 23111481 TI - An analysis of restructuring orientation to enhance nurse retention. AB - The nursing shortage has received much media attention; however, something that contributes to it-nurse turnover-has not received the same attention. Facilities spend time and money to train new employees only to have them leave within a few months. Staff morale, money, time, and quality of care are all affected by nurse turnover. The fact that it often occurs so soon after one takes a position makes it pertinent to look at the process of transition into the new position, namely, the orientation program. This article examines the turnover statistics, costs, rationale, and orientation programs that have proven positive results. It is hoped that the findings can assist health care facilities to replicate successful orientation programs and reduce nurse turnover. PMID- 23111482 TI - Covariation in community- and individual-based community capacity and health behavior: a multilevel analysis of populations in Seoul, South Korea. AB - Community capacity is defined as the degree to which the human, physical, and potential resources of a neighborhood are organized based on mutual solidarity among the residents. The aim of this study was to elucidate the relationship between community capacity and health behaviors in Seoul, South Korea. Multilevel models controlling for socioeconomic variables were used to measure the association between community capacity and health behaviors in 25 districts and 404 subdistricts (n = 14 228). Community capacity was determined to be significant at the more local community level, as it was a significant variable in the subdistrict analysis for explaining health behaviors such as smoking, drinking, and exercising. Community capacity exists not only at the individual level but also at the community level. High community capacity further enhanced the positive effects of individual capacity on health behavior and further weakened the negative effects. PMID- 23111484 TI - How to set up an international classification of diseases, 10th revision training workshop: case study. AB - On September 30, 2014, the US health care system is to assign the last International Classification of Diseases, Ninth Revision, Clinical Modification code. The new system, International Classification of Diseases, 10th Revision (ICD-10), Clinical Modification/Procedure Coding System, will become effective on October 1, 2014. We are embracing one of the largest health care changes in the past 30 years. This article describes the steps in setting up and implementing an efficient and effective ICD-10 training workshop. A 2-day North Carolina ICD-10 workshop is used as a case study. Following the initial workshop, 11 additional workshops were conducted throughout North Carolina. PMID- 23111485 TI - The development and initial assessment of the strategy and leadership systems capability evaluation survey. AB - Hospital management and leadership systems are associated with organizational success and quality care. The Strategy and Leadership Systems Capability Evaluation (CE) survey was developed by GE Healthcare to assess management and leadership systems at health care institutions, serve as a benchmark for improvement, and measure progress. To assess the psychometric properties of the 29-item CE survey, including the factor structure, scoring algorithm, reliability, and discriminant validity, an online survey was completed by 3450 employees at 15 US hospitals. Of these employees, 609 worked at a hospital where a leadership and management intervention occurred after the initial survey administration. Data were also collected on job level, number of hospital beds, hospital ownership, location, community type, and the implementation of hospital interventions. Item response frequencies showed no floor or ceiling effects and limited missing data. Interitem correlations were strong without obvious redundancies, and factor analysis suggested a unidimensional scale. The resulting scale had strong internal consistency and was able to discriminate among known groups. The CE survey was developed to evaluate management and leadership systems at health care institutions. This study provides psychometric evidence in support of the reliability, validity, and scoring structure of this survey. PMID- 23111486 TI - The US Organization for Economic Cooperation and Development Health Care spending chasm: better understanding some of the reasons for the gap and some suggestions as to how it might be narrowed. AB - Comparisons of health care spending between the United States and the rest of the world are frequently made. This article examines macrolevel secondary data comparing health care spending in the United States and other OECD countries, but this comparison does not necessarily present a complete picture. This article puts the US OECD health care spending gap into better context by examining the implications of population differences, quality-of-life spending, obesity trends, and defensive medicine and their contribution to US health care costs. PMID- 23111487 TI - Factors impacting career satisfaction of hospitalists. AB - A study was undertaken to examine various factors that impact career satisfaction of hospitality. This study used data collected by the Center for Studying Health System Change's 2008 Health Tracking Physician survey. The 2008 HTP data set consisted of 4720 physicians belonging to the American Medical Association, of which 206 identified themselves as hospitalists. Results suggested that 41% of hospitalists were very satisfied with their careers in medicine. More than 26% of the hospitalists were 53 years or older. Seven of 10 hospitalists were men, whereas more than 55% were white. In addition, an average respondent earned between $150 000 and $200 000. Nearly 36% of the hospitalists in the study specialized in internal medicine. Regression analysis indicates that high-quality care had a highly significant impact on career satisfaction of hospitalists (P <= .00). In addition, formal written guidelines (P <= .07), gender (P <= .06), and white race (P <= .07) also had a significant impact on career satisfaction of hospitalists. It was concluded that perceived quality of care, presence of formal written guidelines, gender, and race were major predictors of career satisfaction of hospitalists. PMID- 23111488 TI - Managing mechanistic and organic structure in health care organizations. AB - Managers at all levels in a health care organization must organize work to achieve the organization's mission and goals. This requires managers to decide the organization structure, which involves dividing the work among jobs and departments and then coordinating them all toward the common purpose. Organization structure, which is reflected in an organization chart, may range on a continuum from very mechanistic to very organic. Managers must decide how mechanistic versus how organic to make the entire organization and each of its departments. To do this, managers should carefully consider 5 factors for the organization and for each individual department: external environment, goals, work production, size, and culture. Some factors may push toward more mechanistic structure, whereas others may push in the opposite direction toward more organic structure. Practical advice can help managers at all levels design appropriate structure for their departments and organization. PMID- 23111489 TI - Stakeholder analysis: theAndalusian Agency For Healthcare Quality case. AB - The aim of this study was to identify the different groups that can affect or be affected by an agency charged with the promoting and guaranteeing of health care quality in Andalusian region (Spain) and to provide a framework with the stakeholders included in different categories. The study adopted a cross sectional research design. A case study with structured interviews among Andalusian Agency for Healthcare Quality Steering Committee members was carried out in 2010 to define stakeholders' categories and map the interest groups using 5 attributes: influence, importance, legitimacy, power, and urgency. After identification and categorization, stakeholders were weighted qualitatively according to the attributes of importance and influence using 4 possible levels. A matrix was made with the collected data relating both attributes. Furthermore, 8 different types of stakeholders were identified according to attributes power, legitimacy, and urgency. The study concludes that identifying and classifying stakeholders are fundamental to ensuring the success of an organization that must respond to needs and expectations, especially those of its clients. Moreover, knowing stakeholder linkages can contribute to increase organizational worth. This is essential for organizations basically directed to the provision of services in the scope of health care. PMID- 23111491 TI - Employing NeuGen 2.0 to automatically generate realistic morphologies of hippocampal neurons and neural networks in 3D. AB - Detailed cell and network morphologies are becoming increasingly important in Computational Neuroscience. Great efforts have been undertaken to systematically record and store the anatomical data of cells. This effort is visible in databases, such as NeuroMorpho.org. In order to make use of these fast growing data within computational models of networks, it is vital to include detailed data of morphologies when generating those cell and network geometries. For this purpose we developed the Neuron Network Generator NeuGen 2.0, that is designed to include known and published anatomical data of cells and to automatically generate large networks of neurons. It offers export functionality to classic simulators, such as the NEURON Simulator by Hines and Carnevale (2003). NeuGen 2.0 is designed in a modular way, so any new and available data can be included into NeuGen 2.0. Also, new brain areas and cell types can be defined with the possibility of constructing user-defined cell types and networks. Therefore, NeuGen 2.0 is a software package that grows with each new piece of anatomical data, which subsequently will continue to increase the morphological detail of automatically generated networks. In this paper we introduce NeuGen 2.0 and apply its functionalities to the CA1 hippocampus. Runtime and memory benchmarks show that NeuGen 2.0 is applicable to generating very large networks, with high morphological detail. PMID- 23111490 TI - Chromosome-wide regulation of euchromatin-specific 5mC to 5hmC conversion in mouse ES cells and female human somatic cells. AB - DNA cytosine methylation (5mC) is indispensable for a number of cellular processes, including retrotransposon silencing, genomic imprinting, and X chromosome inactivation in mammalian development. Recent studies have focused on 5-hydroxymethylcytosine (5hmC), a new epigenetic mark or intermediate in the DNA demethylation pathway. However, 5hmC itself has no role in pluripotency maintenance in mouse embryonic stem cells (ESCs) lacking Dnmt1, 3a, and 3b. Here, we demonstrated that 5hmC accumulated on euchromatic chromosomal bands that were marked with di- and tri-methylated histone H3 at lysine 4 (H3K4me2/3) in mouse ESCs. By contrast, heterochromatin enriched with H3K9me3, including mouse chromosomal G-bands, pericentric repeats, human satellite 2 and 3, and inactive X chromosomes, was not enriched with 5hmC. Therefore, enzymes that hydroxylate the methyl group of 5mC belonging to the Tet family might be excluded from inactive chromatin, which may restrict 5mC to 5hmC conversion in euchromatin to prevent nonselective de novo DNA methylation. PMID- 23111492 TI - Physiological properties of milk ingredients released by fermentation. AB - The demand for health-promoting food ingredients rises within an increasing market worldwide. Different milks fermented with bacteria, yeasts, moulds or enzymes from animal, plant and microbial sources offer a broad range of possibilities to cover different health aspects with new bioactive components. By the fermentation process interesting ingredients are enriched and released from the matrix, like lactoferrin, micro-nutrients, CLA and sphingolipids or synthesized, such as exo-polysaccharides and bioactive peptides. In particular, milk derived bioactive peptides exert several important health-promoting activities, such as anti-hypertensive, anti-microbial, anti-oxidative, immune modulatory, opioid and mineral-binding properties. Milk-fermentation processes with probiotic bacteria synergistically combine health supporting bacterial and milk ingredient aspects which include new therapeutic solutions concerning hypercholesterolemia, carcinogenic intoxications, treatment of diarrhea, reduction of intestine pathogens, and supporting natural immune defense. Especially, milk-proteins and associated bioactive peptides released during microbial or enzymatic fermentation of milk offer a broad spectrum of new functional properties, for instance anti-hypertensive, anti-microbial, anti oxidative, immuno-modulatory, opioid and mineral-binding properties. This review aimed at discussing recent research activities on physiological purposes and technical process aspects of functional components from fermented milk with a specific focus on biofunctional peptides released from fermented milk proteins. PMID- 23111494 TI - Variations in the degree of epiblepharon with changes in position and induction of general anesthesia. AB - BACKGROUND: To investigate the changes of epiblepharon by evaluating the severity of epiblepharon before and after induction of general anesthesia. METHODS: Sixty three pediatric patients (126 eyes) underwent surgery for epiblepharon between April 2008 and September 2008 (35 females, 28 males; average age: 4.74 years). The severity of epiblepharon in each eye was scored according to skin-fold height (scored 1-4) and area of ciliocorneal touch (scored 1-3) while the patient was in upright and supine positions before induction of general anesthesia and in supine position after induction of anesthesia. RESULTS: The severity of epiblepharon was significantly reduced by a positional change to supine position and induction of general anesthesia. Skin-fold height scores decreased when patients were moved from upright (estimated mean +/- standard error [SE]; 2.98 +/- 0.08) to supine position (2.63 +/- 0.09) (P < 0.001) prior to induction of anesthesia, and decreased further after induction of general anesthesia (2.12 +/- 0.08) (P < 0.001). Ciliocorneal touch scores also decreased after patients were moved to supine position and after induction of general anesthesia (upright: 2.17 +/- 0.05; supine: 1.95 +/- 0.06; general anesthesia: 1.64 +/- 0.07, P < 0.001). CONCLUSIONS: Our study demonstrates that positional changes and general anesthesia using muscle relaxants affect the degree of epiblepharon. Surgeons should be aware of these variations for operative planning of epiblepharon. PMID- 23111495 TI - Contribution of cell walls, nonprotein thiols, and organic acids to cadmium resistance in two cabbage varieties. AB - To study possible cadmium (Cd) resistance mechanisms in cabbage (Brassica oleracea L.), several parameters of metal uptake, distribution, and complexation were compared between two varieties Chunfeng [CF (Cd-tolerant)] and Lvfeng [LF (Cd-sensitive)]. Results showed that CF contained significantly lower Cd concentrations in leaves and higher Cd concentrations in roots than LF. Approximately 70 to 74 % and 66 to 68 % of Cd taken up by LF and CF, respectively, was transported to shoots. More Cd was bound to the cell walls of leaves, stems, and roots in CF than in LF. The higher capacity of CF to limit Cd uptake into shoots could be explained by immobilization of Cd in root cell walls. Compared with control groups, Cd treatment also significantly increased concentrations of nonprotein thiols, phytochelatins (PCs), and citric acid in the leaves and roots of the two varieties; the increases were more pronounced in CF than in LF. Taken together, the results suggest that the greater Cd resistance in CF than in LF may be attributable to the greater capacity of CF to limit Cd uptake into shoots and complex Cd in cell walls and metal binding ligands, such as PCs and citric acid. However, the contributions of PCs and citric acid to Cd detoxification might be smaller than those in cell walls. PMID- 23111496 TI - Effects of HLA-matched blood transfusion for patients awaiting renal transplantation. AB - BACKGROUND: HLA sensitization in potential renal transplant recipients hinders opportunities of receiving suitable organs. To alleviate this, we sought to determine if supplying closely HLA Class I matched leukodepleted blood would minimize sensitization. METHODS: Patients received HLA selected or random units of packed red cells. Selected units were sourced from blood donors included in the British Bone Marrow Registry and had no HLA-A and HLA-B mismatches where available, or alternatively, no HLA antigens with more than five immunogenic triplet mismatches as determined by the HLA-Matchmaker algorithm. Posttransfusion antibody screening confirmed development of de novo Class I and Class II HLA specific IgG antibody(s) or increases in preexisting antibody levels of at least 20%. RESULTS: Thirty-seven and 31 patients received HLA selected (mean, 2.5 units) and random (mean, 3.4 units) blood, respectively. A total of 20 of 37 (54.1%) patients receiving selected units and 10 of 31 (32.3%) patients receiving random units were previously sensitized. No patient receiving HLA selected units demonstrated any change in antibody levels. In patients who received random units, 7 of 31 demonstrated changes in antibody levels with three developing de novo HLA-specific antibodies and four an increase in panel reactive antibody (PRA) of at least 20% (P=0.002). CONCLUSIONS: The risk of developing HLA-specific antibody is significantly reduced in renal patients awaiting transplantation when transfused with HLA selected units of blood compared with random units. With planning, access to HLA typed blood is achievable as many blood transfusion centers recruit donors for stem cell donor registries. PMID- 23111497 TI - HLA-matched blood transfusions? PMID- 23111498 TI - Decompressive craniectomy for acute subdural hematomas: time for a randomized trial. PMID- 23111499 TI - DSM-5 field trials in the United States and Canada, Part III: development and reliability testing of a cross-cutting symptom assessment for DSM-5. AB - OBJECTIVE: The authors sought to document, in adult and pediatric patient populations, the development, descriptive statistics,and test-retest reliability of cross-cutting symptom measures proposed for inclusion in DSM-5. METHOD: Data were collected as part of the multisite DSM-5 Field Trials in large academic settings. There were seven sites focusing on adult patients and four sites focusing on child and adolescent patients.Cross-cutting symptom measures were self-completed by the patient or an informant before the test and the retest interviews, which were conducted from 4 hours to 2 weeks apart. Clinician-report measures were completed during or after the clinical diagnostic interviews. Informants included adult patients, child patients age 11 and older, parents of all child patients age 6 and older, and legal guardians for adult patients unable to self-complete the measures. Study patients were sampled in a stratified design,and sampling weights were used in data analyses. The mean scores and standard deviations were computed and pooled across adult and child sites. Reliabilities were reported as pooled intraclass correlation coefficients (ICCs) with 95% confidence intervals. RESULTS: In adults, test-retest reliabilities of the cross-cutting symptom items generally were good to excellent. At the child and adolescent sites, parents were also reliablereporters of their children's symptoms,with few exceptions. Reliabilities were not as uniformly good for child respondents, and ICCs for several items fell into the questionable range in this age group. Clinicians rated psychosis with good reliability in adult patients but were less reliable in assessing clinical domains related to psychosis in children and to suicide in all age groups. CONCLUSIONS: These results show promising test retest reliability results for this group of assessments, many of which are newly developed or have not been previously tested in psychiatric populations PMID- 23111502 TI - Cell-free biosystems for biomanufacturing. AB - Although cell-free biosystems have been used as a tool for investigating fundamental aspects of biological systems for more than 100 years, they are becoming an emerging biomanufacturing platform in the production of low-value biocommodities (e.g., H(2), ethanol, and isobutanol), fine chemicals, and high value protein and carbohydrate drugs and their precursors. Here we would like to define the cell-free biosystems containing more than three catalytic components in a single reaction vessel, which although different from one-, two-, or three enzyme biocatalysis can be regarded as a straightforward extension of multienzymatic biocatalysis. In this chapter, we compare the advantages and disadvantages of cell-free biosystems versus living organisms, briefly review the history of cell-free biosystems, highlight a few examples, analyze any remaining obstacles to the scale-up of cell-free biosystems, and suggest potential solutions. Cell-free biosystems could become a disruptive technology to microbial fermentation, especially in the production of high-impact low-value biocommodities mainly due to the very high product yields and potentially low production costs. PMID- 23111501 TI - Functional analysis of splice variant expression of MADS AFFECTING FLOWERING 2 of Arabidopsis thaliana. AB - The MADS-AFFECTING FLOWERING 2 (MAF2) gene of Arabidopsis thaliana has been characterized as a repressor of flowering. The molecular basis of MAF2 gene function and role of alternative MAF2 transcripts in flowering time modulation is not understood. MAF2 splice variant expression was quantified in cold-acclimated plants by quantitative RT-PCR. Cold influenced the abundance of splice variants and prompted a functional study of splice forms. Individual variants were overexpressed in the Col background and were assayed for their ability to delay flowering. Overexpression of MAF2 variants 2 and 4 had limited effect on flowering time. Overexpression of MAF2 splice variant 1 resulted in early flowering and affected the expression of the endogenous MAF2 gene and its paralogues, confounding functional assessment. In the Ll-2 Arabidopsis accession, a MAF2, MAF3, MAF4 and FLC null line, MAF2 var1 was consistent in its effect on reproductive delay under ambient and reduced temperatures, indicating that it acts as a repressor of flowering. PMID- 23111503 TI - PNA-based microRNA inhibitors elicit anti-inflammatory effects in microglia cells. AB - Peptide nucleic acid (PNA) inhibitors of miR-221-3p (CU-PNA-221) and miR-466l-3p (CU-PNA-466) demonstrated changes in inflammatory responses. Suppression of inflammatory signalling was unexpected and further investigation led to the identification of calmodulin as a novel target of miRNA-466l-3p. These studies demonstrate that exogenous agents may suppress neuroinflammation mediated by microglial cells. PMID- 23111504 TI - Prevalence of emotional and behavioral symptoms and their impact on daily life activities in a community sample of 3 to 5-year-old children. AB - The aim of the study was to evaluate prevalence and impact of behavioral/emotional symptoms in preschoolers. The sample comprised 1,738 preschoolers with an age range between 37 and 63 months. Parents rated children's symptoms using the Strengths and Difficulties Questionnaire (SDQ) and the impact of perceived difficulties using the impact supplement of the SDQ. The prevalence of a total difficulties score in an abnormal/borderline range was 16.0 % that means lower than rates in schoolchildren. 8.6 % of the preschoolers were rated as symptomatic (borderline/abnormal) and their symptoms were rated as having some or considerable impact on their lives. Parents mostly reported problems of hyperactivity/inattention and their interference with learning abilities. All symptoms scales of the SDQ, except prosocial behavior, significantly explained impact of perceived difficulties. Parents of boys rated significantly higher levels of symptoms and impact. Low parental education was associated with more symptoms and higher impact. PMID- 23111520 TI - Methodology for estimating cancer risks of diagnostic medical exposure: with an example of the risks associated with computed tomography. AB - Because of fast growing medical radiation use, estimating possible late health effects of radiation, including potential cancer risk, is an issue of substantial interest. Since physicians make the decision to order or perform a radiological procedure, it is very important to provide them with objective information about possible radiation-associated risks. Methodology for estimating cancer risks based on recommendations of ICRP Publication 103 is presented in the paper. Organ doses, age, and gender are used as basic parameters. An example of the evaluation of radiation-associated risks from computed tomography examination is presented. PMID- 23111521 TI - Comparative measurements of the external radiation exposure in a 137Cs contaminated village in Belarus based on optically stimulated luminescence in NaCl and thermoluminescence in LiF. AB - Laboratory studies have shown that ordinary household salt (NaCl) exhibits several promising properties for retrospective dosimetry; e.g., a linear dose response and a low detection limit, down to a few mGy or even less. In an attempt to test NaCl as a dosimeter outside the laboratory, the first results from the use of NaCl as a dosimeter under normal environmental conditions are reported here. For this purpose, special dosimeter kits with NaCl and lithium fluoride (LiF) chips were designed. The dosimeter kits were positioned at different locations in a Chernobyl Cs-contaminated village in Belarus during the summers of 2008, 2009, and 2010. The results from the two luminescent detectors were also compared with those of measurements carried out with a handheld 75 cm NaI(Tl) detector and with a 8 dm high pressure ionization chamber. The radiation level in the village was inhomogeneous, and depending on the type of house and countermeasures carried out, the ambient dose rate inside and around the houses varied between 0.05 MUSv h and 0.50 MUSv h. Based on the different measurements, the annual external effective dose to a hypothetical adult population in the village was estimated as 1-1.5 mSv y. Detector readings from the two luminescent materials correlated relatively strongly to that of the ambient survey NaI(Tl) detector. After three repeated surveys using similar dosimeter kits for prospective dosimetry, the potential use of ordinary household salt as a complement to other techniques for retrospective dose estimations is more evident, and shortcomings of the technique have been identified. PMID- 23111522 TI - Occupational and public field exposure from communication, navigation, and radar systems used for air traffic control. AB - Electromagnetic exposure (occupational and general public) to 14 types of air traffic control (ATC) systems is assessed. Measurement methods are proposed for in situ exposure assessment of these ATC systems. In total, 50 sites are investigated at 1,073 locations in the frequency range of 255 kHz to 24 GHz. For all installations, typical and maximal exposure values for workers and the general public are provided. Two of the 14 types of systems, Non-Directional Beacons (NDB) (up to 881.6 V m) and Doppler Very High Frequency (VHF) Omni directional Range (DVOR) (up to 92.3 V m), exhibited levels requiring recommended minimum distances such that the ICNIRP reference levels are not exceeded. Cumulative exposure of all present radiofrequency (RF) sources is investigated, and it is concluded that the ATC source dominates the total exposure in its neighborhood. PMID- 23111523 TI - Validation of the photon dose calculation model in the VARSKIN 4 skin dose computer code. AB - An updated version of the skin dose computer code VARSKIN, namely VARSKIN 4, was examined to determine the accuracy of the photon model in calculating dose rates with different combinations of source geometry and radionuclides. The reference data for this validation were obtained by means of Monte Carlo transport calculations using MCNP5. The geometries tested included the zero volume sources point and disc, as well as the volume sources sphere and cylinder. Three geometries were tested using source directly on the skin, source off the skin with an absorber material between source and skin, and source off the skin with only an air gap between source and skin. The results of these calculations showed that the non-volume sources produced dose rates that were in very good agreement with the Monte Carlo calculations, but the volume sources resulted in overestimates of the dose rates compared with the Monte Carlo results by factors that ranged up to about 2.5. The results for the air gap showed poor agreement with Monte Carlo for all source geometries, with the dose rates overestimated in all cases. The conclusion was that, for situations where the beta dose is dominant, these results are of little significance because the photon dose in such cases is generally a very small fraction of the total dose. For situations in which the photon dose is dominant, use of the point or disc geometries should be adequate in most cases except those in which the dose approaches or exceeds an applicable limit. Such situations will often require a more accurate dose assessment and may require the use of methods such as Monte Carlo transport calculations. PMID- 23111524 TI - Multichannel statistical analysis of low-level radioactivity in the presence of background counts. AB - This paper presents a multichannel extension to the Poisson-based Bayesian statistical analysis of the net count rate in a sample. The derivation gives the net count rate probability density distribution in analytical form. In addition, it presents a Normal approximation that is appropriate when the number of counts is large. The new analysis can exhibit a lower false positive probability than methods that consider the counts for each peak separately or sum the counts for all the expected peaks associated with a radioactive substance. PMID- 23111525 TI - Monte Carlo modeling of ion chamber performance using MCNP. AB - Ion Chambers have a generally flat energy response with some deviations at very low (<100 keV) and very high (>2 MeV) energies. Some improvements in the low energy response can be achieved through use of high atomic number gases, such as argon and xenon, and higher chamber pressures. This work looks at the energy response of high pressure xenon-filled ion chambers using the MCNP Monte Carlo package to develop geometric models of a commercially available high pressure ion chamber (HPIC). The use of the F6 tally as an estimator of the energy deposited in a region of interest per unit mass, and the underlying assumptions associated with its use are described. The effect of gas composition, chamber gas pressure, chamber wall thickness, and chamber holder wall thicknesses on energy response are investigated and reported. The predicted energy response curve for the HPIC was found to be similar to that reported by other investigators. These investigations indicate that improvements to flatten the overall energy response of the HPIC down to 70 keV could be achieved through use of 3 mm-thick stainless steel walls for the ion chamber. PMID- 23111526 TI - Comparative analysis of the dynamics of thrombocytopoietic, granulocytopoietic, and erythropoietic systems in irradiated humans: a modeling approach. AB - Biologically motivated mathematical models, which describe the dynamics of the thrombocytopoietic, granulocytopoietic, and erythropoietic systems in irradiated humans, are thoroughly investigated. These models are the systems of nonlinear ordinary differential equations, whose variables and constant parameters have clear biological meaning. The modeling studies reveal general regularities and peculiarities of the dynamics of the aforementioned hematopoietic lines in acutely and chronically irradiated humans. It is shown that the predictions of the models qualitatively and quantitatively agree with the respective clinical data for humans exposed to acute and chronic irradiation in wide ranges of doses and dose rates. Moreover, the "lethal" dose rate of chronic irradiation, which is evaluated in the framework of the granulocytopoiesis model, coincides with the real minimal dose rate of lethal chronic irradiation for humans. As for the thrombocytopoiesis and erythropoiesis models, the respective "lethal" dose rates of chronic irradiation are very close to the real one for humans. All this bears witness to the validity of employment of the developed models in the investigation and prediction of radiation effects on human hematopoiesis. PMID- 23111527 TI - The HML's new voxel phantoms: two human males, one human female, and two male canines. AB - The Human Monitoring Laboratory (HML) has created five new voxel phantoms that can be used for Monte Carlo simulations. Three phantoms were created from computer tomography image sets that were obtained from facilities in Italy and the USA: a human male and the male canines. Two other phantoms were constructed from commercially available software that is used to demonstrate human anatomical features: a human male and a human female. All the voxel phantoms created by the HML that are described in this note are available at no cost to interested researchers. PMID- 23111528 TI - High risk from background radiation in yangjiang, china. PMID- 23111534 TI - Solvent-tuned hierarchical porosity in nitrocellulose aerogels. AB - We describe the simple preparation of nitrocellulose gels and high surface area (300 + m(2) g(-1)) aerogels and their hierarchical pore structures. The solvent in which the gels form greatly influences the pore geometry and size distribution of the gels in both the macro- and mesopore domains. PMID- 23111535 TI - Sick leave due to back pain in a cohort of young workers. AB - PURPOSE: Evidence on risk factors for sick leave from prospective studies in work settings is limited. Furthermore, most available studies focused on workers with substantial low back disorders. These studies consistently report that physical work factors constitute a hindrance to work. However, it remains unclear whether the same risk factors are relevant in workers with less severe conditions or in early phases of the development of back pain. Therefore, this article aims to study risk factors for the occurrence of sick leave due to low back pain (LBP) among young workers with no or a modest history of back pain. METHODS: Participants were 716 young healthcare or distribution workers with no or minimal antecedents of LBP in the year before inclusion. We investigated the role of potential physical, psychosocial and individual risk factors at baseline on the occurrence of sick leave due to LBP 1 year later. To this purpose, we used Cox regression with a constant risk period. RESULTS: Six per cent (95 % CI 4.1-7.6) of the workers reported sick leave 1 year later; they accounted for 12 % of the sick-leave days independent of cause. A non-stimulating psychosocial work environment turned out to be the strongest risk factor for sick leave due to LBP (RR 6.08; 95 % CI 1.42-26.07). Physical factors were not predictive. CONCLUSIONS: In the early phases of back pain and in less severe conditions, the main benefit of interventions lies in targeting the organisation and design of jobs to create a challenging professional environment. PMID- 23111533 TI - Idiopathic giant cell myocarditis and cardiac sarcoidosis. AB - Idiopathic giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are rare disorders that cause cardiomyopathy, often with ventricular arrhythmias or heart block. Infection, autoimmune processes, and genetics have all been implicated in the pathogenesis of these diseases, but the etiology for both diseases is likely a complex multifactorial process. Both GCM and CS are generally progressive despite treatment with standard heart failure and arrhythmia therapies. Making the diagnosis of GCM or CS on initial clinical presentation is possible in only a small percentage of patients, so myocardial tissue diagnosis is required. The use of multiple noninvasive imaging modalities may aid in diagnosis and assessment of response to treatment. Establishing the diagnosis of GCM or CS early is crucial, as tailored immunosuppressive treatment may significantly alter the clinical course of these patients. The prognosis of patients with GCM is poor, while the prognosis for patients with CS varies according to degree of left ventricular dysfunction. PMID- 23111536 TI - Efficacy of a long-term secondary prevention programme following inpatient cardiovascular rehabilitation on risk and health-related quality of life in a low education cohort: a randomized controlled study. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy of a long-term secondary prevention programme following inpatient cardiovascular rehabilitation on cardiovascular risk and health-related quality of life in a cohort of middle aged (<=58 years) coronary artery disease (CAD) patients of low educational level compared to usual care. DESIGN AND METHODS: The study included 600 patients with CAD, with 271 in the intervention group (IG) and 329 in the control group (CG). The average age was nearly 50 years in both groups, nearly 90% were male, and 77% had less than 10 years of school education. No significant differences existed between the groups at baseline. Both groups had a 3-week comprehensive cardiovascular inpatient rehabilitation programme at the beginning, the intervention consisted of one further rehabilitation session in hospital after 6 months and regular telephone reminders over a period of 36 months. Analyses were conducted on an intention-to-treat basis. To evaluate the individual risk level, we used the PROCAM score and intima-media thickness (IMT) was measured at the common carotid artery on both sides following international standards. Health related quality of life was assessed with the EUROQOL and HADS. RESULTS: Patients in the IG showed better 3-year risk profile outcomes. The PROCAM score increased by 3.0 (IG) and by 3.7 (CG) from the beginning to after 3 years (p > 0.05 intention-to-treat). The average IMT increased by 0.04 mm in the CG and was reduced by 0.03 mm in the IG (p = 0.014 for the difference). The IG had a significant improvement in health-related quality of life. Mortality, myocardial infarction, and stroke were not different although 'other cardiac events' (cardiac surgery or intervention) were significantly lower in the IG than the CG patients (p < 0.05). CONCLUSION: This long-term secondary prevention programme with inpatient rehabilitation at the beginning and telephone reminder for a 3 year period was successful. There were significant differences in health-related quality of life between the IG and CG, despite the relatively positive outcomes in the CG. In this low-education (predominantly male), middle-aged cohort, the positive impact on cardiovascular risk was pronounced in the high-risk subgroup (PROCAM 10-year risk 10-40%). PMID- 23111538 TI - Smoking uptake is associated with increased psychological distress: results of a national longitudinal study. AB - BACKGROUND: There is evidence that smoking is associated with poorer mental health. However, the underlying mechanisms for this remain unclear. We used longitudinal data to assess whether smoking uptake, or failed quit attempts, are associated with increased psychological distress. METHODS: Data were used from Waves 3 (2004/05), 5 (2006/07) and 7 (2008/09) of the longitudinal New Zealand Survey of Family, Income and Employment. Fixed-effects linear regression analyses were performed to model the impact of changes in smoking status and quit status (exposure variables) on changes in psychological distress (Kessler 10 (K10)). RESULTS: After adjusting for time-varying demographic and socioeconomic covariates, smoking uptake was associated with an increase in psychological distress (K10: 0.22, 95% CI 0.01 to 0.43). The associations around quitting and distress were in the expected directions, but were not statistically significant. That is, smokers who successfully quit between waves had no meaningful change in psychological distress (K10: -0.05, 95% CI -0.34 to 0.23), whereas those who tried but failed to quit, experienced an increase in psychological distress (K10: 0.18, 95% CI -0.05 to 0.40). CONCLUSIONS: The findings provide some support for a modest association between smoking uptake and a subsequent increase in psychological distress, but more research is needed before such information is considered for inclusion in public health messages. PMID- 23111539 TI - Epidemiology and treatment outcome of invasive fungal infections in patients with hematological malignancies. AB - Invasive fungal infection (IFI) causes morbidity and mortality among patients with hematological malignancies who receive cytotoxic chemotherapy or hematopoietic stem cell transplantation (HSCT). We evaluated the incidence and treatment outcomes of proven and probable IFI in 22 institutions between 2006 and 2008 following the recent European Organization for Research and Treatment of Cancer/Mycosis Study Group (EORTC/MSG) consensus criteria. We analyzed 2,821 patients with hematological malignancies, including 597 who had undergone HSCT; these included patients with acute leukemia (n = 697), myelodysplastic syndrome (n = 284), lymphoma (n = 1465), or multiple myeloma (n = 375). IFIs were diagnosed in 38 (1.3%) patients (18 proven and 20 probable), including 20 patients who underwent HSCT and 18 who received chemotherapy alone; these included patients with aspergillosis (n = 23), candidiasis (n = 6), mucormycosis (n = 6), trichosporonosis (n = 2), and geotrichosis (n = 1). The incidence of IFI was 5.4 % in allogeneic HSCT patients, 0.4 % in autologous HSCT patients, and 0.8 % in patients receiving chemotherapy alone. Eighteen patients with aspergillosis were diagnosed with probable pulmonary IFI as determined by computed tomography scan and positive galactomannan assay. Overall, antifungal targeted therapies resulted in successful outcomes in 60.0 % of patients. IFI-attributable mortality rate was higher in HSCT patients than in those receiving chemotherapy alone, but the difference was not statistically significant. PMID- 23111541 TI - Managing for efficiency in health care: the case of Greek public hospitals. AB - This paper evaluates the efficiency of public hospitals with two alternative conceptual models. One model targets resource usage directly to assess production efficiency, while the other model incorporates financial results to assess economic efficiency. Performance analysis of these models was conducted in two stages. In stage one, we utilized data envelopment analysis to obtain the efficiency score of each hospital, while in stage two we took into account the influence of the operational environment on efficiency by regressing those scores on explanatory variables that concern the performance of hospital services. We applied these methods to evaluate 96 general hospitals in the Greek national health system. The results indicate that, although the average efficiency scores in both models have remained relatively stable compared to past assessments, internal changes in hospital performances do exist. This study provides a clear framework for policy implications to increase the overall efficiency of general hospitals. PMID- 23111540 TI - Combined effect of dehydroxymethylepoxyquinomicin and gemcitabine in a mouse model of liver metastasis of pancreatic cancer. AB - Activation of nuclear factor-kappaB (NF-kappaB) has been implicated in metastasis of pancreatic cancer. We investigated the effects of the novel NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) on the inhibition of liver metastasis of pancreatic cancer in a mouse model of clinical liver metastasis. Nude mice were xenografted by intra-portal-vein injection with the human pancreatic adenocarcinomas cell line AsPC-1 via small laparotomy. Mice were treated with DHMEQ and gemcitabine (GEM), alone or in combination. The combination of GEM + DHMEQ showed a stronger antitumor effect than either monotherapy. Apoptosis induction in the metastatic foci was greatest in the DHMEQ + GEM group. Significant reductions in the numbers of neovessels were also seen in the DHMEQ and/or GEM groups. Cell growth inhibition assays revealed no synergistic effect of combination therapy, although each monotherapy had an individual cytotoxic effect. Combination therapy produced the greatest inhibition of tumor cell invasiveness in chemoinvasion assay. In addition, combination therapy significantly down-regulated the expression level of matrix metalloproteinase (MMP)-9 mRNA in AsPC-1 cells. DHMEQ also markedly down regulated interleukin-8 and MMP-9, while GEM caused moderate down-regulation of vascular endothelial growth factor in metastatic foci, demonstrated by quantitative reverse transcription-polymerase chain reaction. These results demonstrate that DHMEQ can exert anti-tumor effects by inhibiting angiogenesis and tumor cell invasion, and by inducing apoptosis. Combination therapy with DHMEQ and GEM also showed potential efficacy. DHMEQ is a promising drug for the treatment of advanced pancreatic cancer. PMID- 23111542 TI - [Operations for hemorrhoids: indications and techniques]. AB - Haemorrhoidal disease is one of the most common diseases in general and will in most cases progress without therapy. In the therapeutic context the means of choice are conservative therapies and in the advanced stage of the disease operative measures are necessary. In Germany 40,000-50,000 operations are performed each year. Our aim with the currently available various operation techniques is individualized therapy and indications. Thus a high healing rate, low complication rate and high patient satisfaction can be achieved. PMID- 23111543 TI - [Transanal endoscopic operation: indications and technique]. AB - Transanal endoscopic operation (TEO) is a minimally invasive treatment option for certain rectal tumors. The TEO procedure has evolved as a new technique from transanal endoscopic microsurgery (TEM) which was developed by G. Buess. Apart from the excision of benign lesions this method can also be applied in patients with low-risk T1 carcinoma if size and localization permit complete resection (R0). Using these strict criteria for patient selection one can expect an excellent oncological outcome. However, it must to be stressed that local excision is always part of the diagnostic work-up and that the definitive histology needs to be appreciated. In cases of unfavorable histology (i.e. high risk or higher T stage) radical salvage resection should be performed. Functional results and quality of life are very good following TEO or TEM procedures, especially when comparing the outcome with that of radical rectal resection or abdominoperineal excision. PMID- 23111544 TI - Newer antidepressants and panic disorder: a meta-analysis. AB - Selective serotonin reuptake inhibitors and venlafaxine are currently considered as first-line agents for patients with panic disorder (PD). However, a systematic comparison of newer antidepressants for the treatment of PD is lacking thus far. Eligible studies focusing on PD patients treated with newer antidepressants were entered in the Cochrane Collaboration Review Manager. Our primary outcome measure was the mean change in panic symptoms from the baseline to the endpoint in patients treated with antidepressants as compared with those treated with placebo. Secondary outcome measures included the mean change in the overall anxiety scores and dropout rates. Sensitivity analyses were also carried out. Fifty studies focusing on 5236 patients were included. The following antidepressants were significantly superior to placebo for PD patients with the following increasing order of effectiveness: citalopram, sertraline, paroxetine, fluoxetine, and venlafaxine for panic symptoms and paroxetine, fluoxetine, fluvoxamine, citalopram, venlafaxine, and mirtazapine for overall anxiety symptoms. Aside from reboxetine and fluvoxamine, all drugs were associated with significantly lower dropout rates as compared with placebo. Several clinical variables moderated clinical outcomes. However, because of some inconsistencies across the studies and limited evidence for some drugs under investigation, further head-to-head comparisons are required. PMID- 23111545 TI - A highly selective turn-on near-infrared fluorescent probe for hydrogen sulfide detection and imaging in living cells. AB - We have described a turn-on near-infrared fluorescent probe Cy-NO(2) based on nitro group reduction for intracellular H(2)S detection. The probe employs cyanine dye as a fluorophore, and is equipped with a nitro group as a fluorescent modulator. It is readily employed for assessing intracellular H(2)S level changes, and confocal imaging is achieved successfully. PMID- 23111546 TI - DSM-5 field trials in the United States and Canada, Part I: study design, sampling strategy, implementation, and analytic approaches. AB - OBJECTIVE: This article discusses the design,sampling strategy, implementation,and data analytic processes of the DSM-5 Field Trials. METHOD: The DSM-5 Field Trials were conducted by using a test-retest reliability design with a stratified sampling approach across six adult and four pediatric sites in the United States and one adult site in Canada. A stratified random sampling approach was used to enhance precision in the estimation of the reliability coefficients. A web-based research electronic data capture system was used for simultaneous data collection from patients and clinicians across sites and for centralized data management.Weighted descriptive analyses, intraclass kappa and intraclass correlation coefficients for stratified samples, and receiver operating curves were computed. The DSM-5 Field Trials capitalized on advances since DSM-III and DSM-IV in statistical measures of reliability (i.e., intraclass kappa for stratified samples) and other recently developed measures to determine confidence intervals around kappa estimates. RESULTS: Diagnostic interviews using DSM-5 criteria were conducted by 279 clinicians of varied disciplines who received training comparable to what would be available to any clinician after publication of DSM-5.Overall, 2,246 patients with various diagnoses and levels of comorbidity were enrolled,of which over 86% were seen for two diagnostic interviews. A range of reliability coefficients were observed for the categorical diagnoses and dimensional measures. CONCLUSIONS: Multisite field trials and training comparable to what would be available to any clinician after publication of DSM-5 provided "real-world" testing of DSM-5 proposed diagnoses. PMID- 23111547 TI - The application of meta-analysis within a matched-pair randomized control trial: an illustration testing the effects of communities that care on delinquent behavior. AB - Use of meta-analytic strategies to test intervention effects is an important complement to traditional design-based analyses of intervention effects in randomized control trials. In the present paper, we suggest that meta-analyses within the context of matched-pair designs can provide useful insight into intervention effects. We illustrate the advantages to this analytic strategy by examining the effectiveness of the Communities That Care (CTC) prevention system on 8th-grade delinquent behavior in a randomized matched-pair trial. We estimate the intervention effect within each of the matched-pair communities, aggregate the effect sizes across matched pairs to derive an overall intervention effect, and test for heterogeneity in the effect of CTC on delinquency across matched pairs of communities. The meta-analysis finds that CTC reduces delinquent behavior and that the effect of CTC on delinquent behavior varies significantly across communities. The use of meta-analysis in randomized matched-pair studies can provide a useful accompaniment to other analytic approaches because it opens the possibility of identifying factors associated with differential effects across units or matched pairs in the context of a randomized control trial. PMID- 23111548 TI - A systematic review of behavioral interventions to prevent HIV infection and transmission among heterosexual, adult men in low-and middle-income countries. AB - Prevention of new HIV infections needs to move to the forefront in the fight against HIV and AIDS. In the current economic crisis, low- and middle-income countries (LMICs) should invest limited resources to amass reliable evidence based information about behavioral prevention efforts, and on behaviors that are driving the epidemic among people who are engaging in those behaviors. This paper aims to provide a systematic review and synthesis of behavioral interventions among a group of people in high HIV-burden countries: heterosexual men in LMICs. The review includes articles published between January 2001 and May 2010 that evaluated behavioral prevention interventions among heterosexual males aged 18+ years in LMICs. The studies were evaluated using the quality assessment tool for quantitative studies developed by the Effective Public Health Practice Project. The review identified 19 articles that met the review's inclusion criteria. Most studies were conducted in South Africa (n=6); two each in Uganda and Thailand; and one in each of Angola, Brazil, Bulgaria, India, Nigeria, the Philippines, Russia, Ukraine and Zimbabwe. Eight of 19 interventions increased condom use among their respective populations. Those interventions that sought to reduce the number of sexual partners had little effect, and those that addressed alcohol consumption and intimate partner violence had mixed effects. There was no evidence for any specific format of intervention that impacted best on any of the targeted risk behaviors. The paucity of evaluated interventions for heterosexual men in LMICs suggests that adult men in these countries remain underrepresented in HIV prevention efforts. PMID- 23111551 TI - Time-resolved photoluminescence spectroscopy for the detection of cysteine and other thiol containing amino acids in complex strongly autofluorescent media. AB - A thiol probe based on an iridium complex with long-lived photoluminescence was synthesized, which can be used for the detection of thiols even in the presence of strong background fluorescence. This system provides an easy and fast methodology for detecting thiol containing amino acids, which has potential applications in clinical diagnostics. PMID- 23111552 TI - Gemfibrozil and its combination with metformin on pleiotropic effect on IL-10 and adiponectin and anti-atherogenic treatment in insulin resistant type 2 diabetes mellitus rats. AB - AIM: Gemfibrozil is a PPAR-alpha ligand that inhibits the progression of atherosclerosis in insulin resistance type 2 diabetes mellitus (IR type 2 DM). Gemfibrozil, poor anti-hyperglycemic combined with metformin, evaluated for MMP 9, IL-10 and adiponectin beyond glycemic control. ESSENTIAL METHODS: IR type 2 DM induced by administering streptozotocin (90 mg/kg, i.p.) in neonatal rat model. IR type 2 DM rats at 6-week age treated for 8 weeks with (1) gemfibrozil (140 mg/kg od) and (2) gemfibrozil (70 mg/kg bid) + metformin (60 mg/kg bid). At the end, risk parameters like MMP-9, IL-10 and adiponectin were evaluated by ELISA kits. MAIN RESULTS: Gemfibrozil reduced the MMP-9 levels (-25.740 %) (106.772 +/- 7.201 ng/ml vs. 80.231 +/- 7.023 ng/ml, P < 0.01); increased adiponectin (68.321 %) (8.781 +/- 1.111 MUg/ml vs. 14.782 +/- 1.055 MUg/ml) and IL-10 (155.687 %) (334.208 +/- 26.307 pg/ml vs. 853.472 +/- 23.172 pg/ml, P < 0.001), but poor glycemic control (-6.169 %) (167.5 +/- 16.037 vs. 157.167 +/- 3.911, P = ns), hence combined with metformin showed synergistic activity, reduced the MMP-9 levels (-16.992 %) (106.772 +/- 7.201 ng/ml vs. 89.941 +/- 8.636 ng/ml, P < 0.05) and increased adiponectin (39.870 %) (8.781 +/- 1.111 MUg/ml vs. 12.282 +/- 0.782 MUg/ml) and, IL-10 (80.136 %) (334.208 +/- 26.307 pg/ml vs. 602.029 +/- 39.668 pg/ml, P < 0.01) had good glycemic control (-28.856 %) (167.5 +/- 16.037 mg/dl vs. 129.167 +/- 4.214 mg/dl, P < 0.05). OVERALL CONCLUSIONS: Gemfibrozil plus metformin decrease MMP-9, increase IL-10 and adiponectin acting as anti atherogenic, anti-inflammatory and immunomodulatory in IR type 2 DM. PMID- 23111554 TI - The genome organization of lucerne transient streak and turnip rosette sobemoviruses revisited. AB - Unlike other sobemoviruses, lucerne transient streak virus (LTSV) and turnip rosette virus (TRoV) have been reported to contain two successive ORF1s (denoted as ORF1a and ORF1b) instead of a single ORF1. Also, their next ORF (ORF2a/2a2b) has been mapped to a region ca. 200 nucleotides downstream from that of other sobemoviruses, leading to the lack of transmembrane segments at the N-termini of P2a/2a2b. In the current study, we resequenced this region for TRoV and LTSV. The hypothetical beginning of ORF1b was mapped as the beginning of ORF2a/2a2b for both TRoV and LTSV. Computional analysis revealed transmembrane segments at the N termini of the TRoV and LTSV polyproteins. PMID- 23111555 TI - Incremental effects of restless legs syndrome on nocturnal blood pressure in hypertensive patients and normotensive individuals. AB - BACKGROUND: Few studies have evaluated the role of restless legs syndrome (RLS) in the development of nondipping 24 h blood pressure (BP) patterning/sleep-time hypertension, which has been shown to be an independent predictor of cardiovascular risk. These were indirect studies that had reported the relation between BP and RLS attacks during polysomnographic investigations in the lab. The aim of the present study was to assess the relationship between RLS, which was diagnosed clinically, and night-time BP patterns in a relatively large young cohort who had not been treated before. PATIENTS AND METHODS: After applying the exclusion criteria, this cross-sectional study included 230 consecutive patients with never-treated hypertension who presented to our institution for initial evaluation of hypertension. RLS was assessed using a self-administered questionnaire based on the International Restless Legs Study Group criteria. The questions on RLS were completed by 214 patients and ambulatory BP monitoring was carried out for all patients. RESULTS: In the study group, 133 patients were diagnosed as hypertensive (53.4% nondippings) and 81 patients as normotensives (54.3% nondippings). RLS was present in 61 patients (28.5%) in the total sample. The prevalence of RLS, overall, was significantly higher in nondippings compared with dippings (34.7 vs. 21.2%, respectively; P=0.028). Logistic regression analysis showed that the RLS is an independent determinant for both hypertension (odds ratio=0.43, 95% confidence interval=0.21-0.83; P=0.013) and the nondipping BP patterns (odds ratio=1.96, 95% confidence interval=1.05-3.67; P=0.035). CONCLUSION: We have shown that clinically diagnosed RLS was associated with the nondipping pattern, which has been shown to be an independent predictor of cardiovascular risk. PMID- 23111553 TI - Lyme disease: aetiopathogenesis, factors for disease development and control. AB - Lyme disease is caused by infection with several genospecies from the Borrelia burgdorferi sensu lato (s.l.) complex, and is transmitted by ixodid ticks. Human disease is an infrequent sequel to infection, which suggests that multiple factors underlie disease development. Several innate immune defects modulating disease development are observed in both natural and experimental infections, and significant heterogeneity exists between B. burgdorferi s.l. spirochaetes. These factors create a panel of presentations from asymptomatic carriage to overt and variable disease. In this short review we summarise the host immune responses associated with Lyme disease in humans, domestic species and laboratory mouse strains, and discuss B. burgdorferi s.l. pathogenicity. We also describe briefly the epidemiology of Lyme disease, and current options for the treatment and prevention. PMID- 23111556 TI - B-N bond formation at stanna-closo-dodecaborate. AB - The heteroborate stanna-closo-dodecaborate shows double substitution in the reaction with alkylated acetonitrile. The reaction product, the charge compensated E,E-isomer, was isomerized into the Z,Z-isomer and hydrogenated at the double bonds. Furthermore the methylated cluster shows less reactivity and the monosubstituted cluster was isolated. The reaction products were characterized by elemental analysis and NMR spectroscopy. Three of the substitution products were also characterized by single crystal structure analysis. PMID- 23111557 TI - Biomarkers of primary dysmenorrhea and herbal formula intervention: an exploratory metabonomics study of blood plasma and urine. AB - Primary dysmenorrhea (PDM), a common clinical endocrine disorder affecting young women, is associated with endocrinopathy and metabolic abnormalities. Although some physiological and pathological function parameters have been investigated, little information about the changes of small metabolites in biofluids has been reported, which may cause poor diagnosis and treatment for PDM. The Xiang-Fu-Si Wu Formula (XFSWF) is a Chinese herbal formula used to treat PDM for hundreds of years. The aim of this study was to establish the metabolic profile of PDM and investigate the action mechanism of XFSWF effect. In this cross-sectional study of 25 patients with PDM and 12 healthy controls, contents of small molecular endogenous metabolites in blood plasma and urine samples were measured by ultra performance liquid chromatography (UPLC) coupled with quadrupole-time-of-flight mass spectrometry (QTOF/MS) and triple quadrupole mass spectrometry (QqQ/MS) based techniques and analyzed by multivariate statistical methods. The levels of LPCs including lypso (16 : 1), lysoPC(20 : 4), lysoPC(18 : 2), lysoPC(16 : 0), lysoPC(18 : 1), lysoPC(10 : 1), estrone, 17-hydroxyprogesterone, myristoylglycine and palmitoylglycine increased significantly (p < 0.05) in PDM, while the levels of phytosphingosine, dihydrocortisol and sphingosine decreased significantly (p < 0.05) compared with the healthy controls. These significant perturbations are involved in glycerophospholipid metabolism and sphingolipid metabolism, as well as steroid hormone biosynthesis. The metabolic deviations recovered to the normal level after XFSWF intervention. The results demonstrated that biofluids metabonomics was a powerful tool in clinical diagnosis and treatment of PDM for providing information on changes in metabolites and neural, endocrinal and immune pathways. XFSWF can be used for the treatment of PDM cases, especially for those adolescents who do not desire a contraceptive method, to reduce the risk of secondary dysmenorrhea. PMID- 23111558 TI - Usefulness of three-dimensional computed tomographic angiography with bronchography for the planning of minimally invasive video-assisted thoracic surgery for intralobar pulmonary sequestration. PMID- 23111559 TI - Reply to Collins and Altman. PMID- 23111560 TI - Improved early postoperative outcome for extracardiac Fontan operation without cardiopulmonary bypass: a single-centre experience. AB - OBJECTIVES: The use of modified extracardiac Fontan operation (ECFO) for total cavo-pulmonary connection allows cardiopulmonary bypass (CPB) to be avoided and seems to improve early postoperative results. We evaluated our experience with the off-pump technique for ECFO. METHODS: Since 2009, the last 17 consecutive patients of 137 (median age 3.2 years, median weight 14.5 kg) in whom no intracardiac surgery was necessary underwent ECFO without CPB. The non fenestrated graft was connected end-to-side to the pulmonary artery without bypass; subsequently temporary passive inferior vena cava (IVC)-to-atrial bypass was used for the anastomosis between IVC and graft. The perioperative and postoperative course was compared between consecutive paediatric patients operated on using the CPB vs off-pump technique. RESULTS: There was no mortality in the off-pump group, with a total early mortality of 3.0%. Overall operation time for the Fontan operation using the off-pump technique was significantly reduced (160 vs 200 min, P < 0.001). The median Fontan pressure 24 and 48 h postoperatively was significantly lower in the off-pump group (P = 0.002/0.042). Duration of mechanical ventilation (9 vs 14 h, P = 0.016), pleural effusions (4 vs 8 days, P < 0.001) as well as the median intensive care unit (2 vs 4 days, P = 0.013) and hospital stay (median 10 vs 15 days, P < 0.001) was significantly shorter in patients who underwent the off-pump Fontan operation. The necessity of blood transfusions was significantly reduced with the off-pump in comparison with the on-pump technique (14 of 17 vs 34 of 84 patients, P = 0.003). CONCLUSIONS: The ECFO without CPB is an established low-risk surgical procedure that improves the early postoperative course and significantly reduces the use of blood products and the duration of pleural effusions in selected patients. PMID- 23111561 TI - Anatomical basis of minimally invasive epicardial ablation of atrial fibrillation. AB - Minimally invasive atrial fibrillation surgery (MIAFS) has become a well established and increasingly used option for managing patients with stand-alone arrhythmia. Pulmonary veins (PVs) isolation continues to be the cornerstone of ablation strategies. Indeed, in most cases, atrial fibrillation (AF) is triggered in or near the PVs. Nevertheless, ectopic beats initiating AF may occasionally arise from non-PV foci. The knowledge of the anatomy and underlying morphology of PVs and non-PV foci is essential for cardiac surgeons treating AF patients with epicardial minimally invasive procedures. The anatomical structures relevant to the pathogenesis and the epicardial treatment of AF include the PVs, the pericardial space, the pericardial sinuses, the phrenic nerve, the left atrium, the retro-atrial and caval ganglionated plexuses, the ligament of Marshall, the caval veins and the left atrial appendage. In this review, we briefly describe the basic anatomy of these structures and discuss their specific correlations for cardiac surgeons interested in performing MIAFS. PMID- 23111562 TI - Positron emission tomography-computed tomography scan helps decision making in cardiac surgery. PMID- 23111563 TI - Stress-induced effects, which inhibit host defenses, alter leukocyte trafficking. AB - Acute cold restraint stress (ACRS) has been reported to suppress host defenses against Listeria monocytogenes, and this suppression was mediated by beta1 adrenoceptors (beta1-ARs). Although ACRS appears to inhibit mainly early innate immune defenses, interference with leukocyte chemotaxis and the involvement of beta1-AR (or beta2-AR) signaling had not been assessed. Thus, the link between sympathetic nerve stimulation, release of neurotransmitters, and changes in blood leukocyte profiles, including oxidative changes, following ACRS was evaluated. The numbers of leukocyte subsets in the blood were differentially affected by beta1-ARs and beta2-ARs following ACRS; CD3(+) (CD4 and CD8) T-cells were shown to be decreased following ACRS, and the T cell lymphopenia was mediated mainly through a beta2-AR mechanism, while the decrease in CD19(+) B-cells was influenced through both beta1- and beta2-ARs, as assessed by pharmacological and genetic manipulations. In contrast to the ACRS-induced loss of circulating lymphocytes, the number of circulating neutrophils was increased (i.e., neutrophilia), and this neutrophilia was mediated through beta1-ARs. The increase in circulating neutrophils was not due to an increase in serum chemokines promoting neutrophil emigration from the bone marrow; rather it was due to neutrophil release from the bone marrow through activation of a beta1-AR pathway. There was no loss of glutathione in any of the leukocyte subsets suggesting that there was minimal oxidative stress; however, there was early production of nitric oxide and generation of some protein radicals. Premature egress of neutrophils from bone marrow is suggested to be due to norepinephrine induction of nitric oxide, which affects the early release of neutrophils from bone marrow and lessens host defenses. PMID- 23111564 TI - Appetite, gut hormone and energy intake responses to low volume sprint interval and traditional endurance exercise. AB - Sprint interval exercise improves several health markers but the appetite and energy balance response is unknown. This study compared the effects of sprint interval and endurance exercise on appetite, energy intake and gut hormone responses. Twelve healthy males [mean (SD): age 23 (3) years, body mass index 24.2 (2.9) kg m(-2), maximum oxygen uptake 46.3 (10.2) mL kg(-1) min(-1)] completed three 8 h trials [control (CON), endurance exercise (END), sprint interval exercise (SIE)] separated by 1 week. Trials commenced upon completion of a standardised breakfast. Sixty minutes of cycling at 68.1 (4.3) % of maximum oxygen uptake was performed from 1.75-2.75 h in END. Six 30-s Wingate tests were performed from 2.25-2.75 h in SIE. Appetite ratings, acylated ghrelin and peptide YY (PYY) concentrations were measured throughout each trial. Food intake was monitored from buffet meals at 3.5 and 7 h and an overnight food bag. Appetite (P < 0.0005) and acylated ghrelin (P < 0.002) were suppressed during exercise but more so during SIE. Peptide YY increased during exercise but most consistently during END (P < 0.05). Acylated ghrelin was lowest in the afternoon of SIE (P = 0.018) despite elevated appetite (P = 0.052). Exercise energy expenditure was higher in END than that in SIE (P < 0.0005). Energy intake was not different between trials (P > 0.05). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in END than that in CON (15.7 %; P = 0.006) and SIE (11.5 %; P = 0.082). An acute bout of endurance exercise resulted in lower appetite perceptions in the hours after exercise than sprint interval exercise and induced a greater 24 h energy deficit due to higher energy expenditure during exercise. PMID- 23111565 TI - Three-year survival of patients with chronic systolic heart failure due to hypertension: analysis of prognostic factors. AB - INTRODUCTION: Despite advances in medicine, chronic systolic heart failure (CHF) due to hypertension still constitutes a serious clinical challenge. OBJECTIVES: The aim of the study was to determine risk mortality factors in a 3-year follow up of patients with CHF due to hypertension. PATIENTS AND METHODS: The study involved 140 consecutive stable inpatients with CHF (left ventricular end diastolic diameter >57 mm; left ventricular ejection fraction [LVEF] <40%), without epicardial artery stenosis (>30% vessel lumen), significant heart defect, diabetes, neoplastic, disease, or chronic kidney disease, with a minimum 5-year history of hypertension, and administration of angiotensin-converting enzyme inhibitors (or angiotensin II receptor antagonists), beta-adrenolytics, spironolactone and furosemide for 3 or more months. The follow-up began on admission to the hospital after laboratory tests, resting electrocardiogram and echocardiogram, six-minute walk test, coronarography, and endomyocardial biopsy. Late follow-up data was obtained from the follow-up visits or by telephone. RESULTS: The analysis involved 130 of 140 patients aged 47.8 +/-7.9 years. The 3 year mortality rate was 18.5%. Independent risk factors for death were LVEF (hazard ratio [HR], 0.881; 95% confidence interval [CI], 0.797-0.975, P <0.05), serum glucose (HR, 1.266; 95% CI, 1.085-1.627; P <0.05), N-terminal pro-B-type natriuretic peptide (NT-proBNP; HR, 1.369; 95% CI, 1.166-1.671; P <0.001), and bilirubin levels (HR, 1.057; 95% CI, 1.021-1.094; P <0.01). CONCLUSIONS: Beside LVEF and serum NT-proBNP, other independent risk factors for death in patients with CHF due to hypertension are glucose and bilirubin levels. PMID- 23111566 TI - Matrix-dependent modulation of anisotropic effects on NMR spectra from 7Li+ and 23Na+ encapsulated in cryptands. AB - (7)Li and (23)Na NMR spectra of the respective cations in gelatin and iota carrageenan gels containing cryptand-[2.1.1] (for Li(+)) or cryptand-[2.2.2] (for Na(+)) displayed two transitions: the one at higher frequency corresponded to the cation surrounded by gel, the other to cation inside its appropriately sized cryptand. While binding to cryptands yielded much broader lines and shorter T (1) relaxation times, anisotropic splitting in first order (7)Li or (23)Na NMR spectra was not detected. Stretching the gels resulted in increasing the anisotropic electric field gradient tensor; thus, the NMR transitions of the cation in the gel were split (removal of degeneracy) to display its characteristic 3:4:3 triplet for spin = 3/2 nuclei. The transitions of the cryptand-bound cations (Li(+)-cryptand-[2.1.1] and Na(+)-cryptand-[2.2.2]) showed different extents of interaction with the electric field gradient tensor depending on the composition of the gel matrix. The NMR signal for (7)Li(+) cryptand-[2.1.1] in stretched gelatin gel showed a five-fold increased splitting as compared to the (7)Li(+) signal in the reference gel. In stretched iota carrageenan gels, no anisotropic splitting from the cryptand-bound Li(+) was recorded. Steady-state irradiation envelopes or z-spectra showed evidence of Li(+) exchange between isotropic (cryptand) and anisotropic (gel) sites only at higher temperatures (55 degrees C). For Na(+) bound to the cryptand-[2.2.2], anisotropic splitting (three-fold smaller compared with the (23)Na signal in the reference gel) was only recorded in stretched iota-carrageenan gels, whereas gelatin gels showed only anisotropic splitting for the (23)Na signal in the reference gel. PMID- 23111567 TI - [Mycosis fungoides palmaris et plantaris]. AB - Mycosis fungoides (MF) is a low-grade cutaneous T-cell lymphoma characterized by skin-homing CD4- positive helper T cells. Mycosis fungoides palmaris et plantaris is an uncommon variant primarily involving the palms and soles. An 80-year old man presented with hyperkeratotic erythematous palmoplantar changes. Clinical and histopathologic criteria led to the diagnosis mycosis fungoides palmaris et plantaris. Tumor staging using sonography of the abdomen and lymph nodes, chest x ray and blood examination is recommended, because extracutaneous manifestations may be present. PMID- 23111568 TI - [Protein contact dermatitis in a butcher]. AB - Protein contact dermatitis is a disease primarily seen in food handlers. The usual presenting finding is hand dermatitis. It is triggered by an IgE-mediated food sensitization, so that after local exposure T cells are recruited and cause the dermatitis. The diagnosis is based on history, clinical features and demonstration of IgE-dependent sensitization, which can also cause contact urticaria and even contact anaphylaxis. We report a case of PCD in a butcher, who could continue his work due to adequate diagnosis and management. PMID- 23111569 TI - Bilateral microphthalmos with unilateral superior cyst in a child with autism and CHARGE syndrome. AB - A case of autism with CHARGE syndrome with microphthalmos and a superior colobomatous cyst arising from the optic disc is reported. A 7-year-old boy presented with a gradually increasing mass, involving the superior orbit and upper eyelid of right eye of 3 years' duration. Clinical examination revealed bilateral microphthalmos with typical iris coloboma, posterior synechiae, and cataractous lens. Imaging revealed bilateral optic disc colobomas with a superior cyst in the right orbit. Intraoperatively, a single cystic lesion was seen in the superior orbit arising from the optic disc region. Histopathology was suggestive of a colobomatous cyst, positive for glial tissue [glial fibrillary acidic protein (GFAP) positive] and neuroretinal elements (synaptophysin positive) on immunohistochemistry. Genetic analysis revealed a normal karyotype (46, XY). PMID- 23111570 TI - The inner diameter of the optic disc pit decreases with pars plana vitrectomy. AB - To report a patient with optic disc pit who showed decreased inner diameter of the optic disc pit along with resolution of recurrent macular detachment after pars plana vitrectomy. Pneumatic retinopexy and peripapillary laser photocoagulation was performed in a 28-year-old female with optic disc pit and serous macular detachment. Two months after the initial therapy, serous macular detachment recurred. Then, pars plana vitrectomy with removal of the posterior hyaloid was performed, and intraocular perfluoro-octane (C3F8) tamponade was used. Fundus photography and ocular coherence tomography were obtained at each visit. The patient was followed up for 1 year. Visual acuity was 20/400 (Snellen) at first presentation, improved to 20/40 at 2 weeks after pneumatic retinopexy and peripapillary laser treatment. Then, 2 months later visual acuity decreased to 20/200, improved to 20/40 at 2 weeks after the vitreoretinal surgery, and stayed stable during the 1-year follow-up. It was also noticed on clinical examinations as well as fundus photographs that the inner diameter of the optic disc pit had decreased significantly. Vitreous traction plays an important role in the formation of serous macular detachments with optic disc pits. In these patients, pars plana vitrectomy and posterior hyaloid removal may be an effective treatment for reduction of the inner diameter of the optic pit and resolution of the serous macular detachments. PMID- 23111571 TI - A systematic review of outcomes of chronic disease self-management interventions. AB - PURPOSE: To carry out a systematic review of program outcomes used in the evaluation of group-based self-management interventions aimed at people with arthritis and other chronic conditions. METHODS: The systematic search was performed across databases MEDLINE, EMBASE, CINAHL, and PsycINFO. Both between group and within-group effect sizes (ES) were calculated. Results were interpreted as small (ES ~ 0.2), medium (ES ~ 0.5), or large (ES ~ 0.8) effects. RESULTS: The majority of 18 included trials investigated the effectiveness of arthritis-specific interventions. Across most outcomes, small effects on course participants were shown. While effects on knowledge were large (between-group ES = 0.78), effects on clinical outcomes such as pain (ES = 0.10) were negligible to small. CONCLUSIONS: This paper is consistent with other reviews in this area, suggesting that people with arthritis receive only marginal benefits from participating in chronic disease self-management interventions. When looking at the types of outcomes that trials are based on, however, alternative explanations for these results seem probable. As evaluations heavily rely on patient self report, current approaches to program evaluation may not be sufficient to assess the intended impact of self-management education. An in-depth investigation of the types of outcomes assessed is provided in a separate paper. PMID- 23111572 TI - Risk factors for hospitalization and medical intensive care unit (MICU) admission among HIV-infected Veterans. AB - OBJECTIVE: With improved survival of HIV-infected persons on antiretroviral therapy and growing prevalence of non-AIDS diseases, we asked whether the VACS Index, a composite measure of HIV-associated and general organ dysfunction predictive of all-cause mortality, predicts hospitalization and medical intensive care unit (MICU) admission. We also asked whether AIDS and non-AIDS conditions increased risk after accounting for VACS Index score. METHODS: We analyzed data from the Veterans Aging Cohort Study (VACS), a prospective study of HIV-infected Veterans receiving care between 2002 and 2008. Data were obtained from the electronic medical record, VA administrative databases, and patient questionnaires and were used to identify comorbidities and calculate baseline VACS Index scores. The primary outcome was first hospitalization within 2 years of VACS enrollment. We used multivariable Cox regression to determine risk factors associated with hospitalization and logistic regression to determine risk factors for MICU admission, given hospitalization. RESULTS: Of 3410 patients, 1141 were hospitalized within 2 years; 203 (17.8%)/1141 patients included an MICU admission. Median VACS Index scores were 25 (no hospitalization), 34 (hospitalization only), and 51 (MICU). In adjusted analyses, a 5-point increment in VACS Index score was associated with 10% higher risk of hospitalization and MICU admission. In addition to VACS Index score, Hispanic ethnicity, current smoking, hazardous alcohol use, chronic obstructive pulmonary disease, hypertension, diabetes, and prior AIDS-defining event predicted hospitalization. Among those hospitalized, VACS Index score, cardiac disease, and prior cancer predicted MICU admission. CONCLUSIONS: The VACS Index predicted hospitalization and MICU admission as did current smoking, hazardous alcohol use, and AIDS and certain non-AIDS diagnoses. PMID- 23111574 TI - HIV postexposure prophylaxis in an urban population of female sex workers in Nairobi, Kenya. AB - OBJECTIVES: To assess biological and behavioral factors in HIV-uninfected female sex workers (FSWs) accessing postexposure prophylaxis (PEP) and to characterize the circumstances preceding PEP, time to access, and adherence. METHODS: Participants were HIV-uninfected FSWs enrolled in an HIV care and prevention program in Nairobi, Kenya. Those accessing PEP between 2009 and 2010 were enrolled and compared with controls. Multiple logistic regression models were used to compare PEP-related biological and behavioral parameters. RESULTS: PEP users (n = 326) had been involved in sex work for a shorter duration than nonusers [n = 2570; 3.3 vs. 5.1 yrs, AOR: 0.92, 95% confidence interval (CI): 0.89 to 0.95] and were less likely to report a regular partner (54.9% vs. 72.5%, AOR: 0.52, 0.39 to 0.68). PEP use was associated with gonorrhea infection (6.9% vs. 2.6%, AOR: 2.37, 95% CI: 1.34 to 4.21) and alcohol use (84.3% vs. 76.1%, AOR: 1.58, 95% CI: 1.09 to 2.31), but with increased condom use (85.1% vs. 68.2%, AOR 1.80, 95% CI: 1.38-2.35) and a history of prior HIV testing (89.2 vs. 76.2%, AOR: 2.22, 95% CI: 1.45 to 3.40). Reasons for PEP access centered on issues of client mistrust. The median time from exposure to PEP was 18 hours, with an estimated adherence of 49%. Precise PEP efficacy could not be calculated, but HIV incidence was 0.6% in users (2/326) compared with 2.1% (30/1417) in nonusers (Cox regression P = 0.35). CONCLUSIONS: "PEP services were accessed by 10% of FSWs during the study period and were not implicated in any incident HIV cases." Users had indicators of increased sexual risk and higher health care literacy. Increasing PEP access and compliance in FSWs may be an important HIV prevention strategy. PMID- 23111573 TI - Concurrent classification accuracy of the HIV dementia scale for HIV-associated neurocognitive disorders in the CHARTER Cohort. AB - BACKGROUND: The HIV Dementia Scale (HDS) was developed to screen for HIV associated neurocognitive disorders (HAND), but concerns have persisted regarding its substandard sensitivity. This study aimed to examine the classification accuracy of the HDS using raw and norm-based cut points and to evaluate the contribution of the HDS subtests to predicting HAND. METHODS: A total of 1580 HIV infected participants from 6 US sites completed the HDS, and a gold standard neuropsychological battery, on which 51% of participants were impaired. RESULTS: Sensitivity and specificity to HAND using the standard raw HDS cut point were 24% and 92%, respectively. The raw HDS subtests of attention, recall, and psychomotor speed significantly contributed to classification of HAND, whereas visuomotor construction contributed the least. A modified raw cut point of 14 yielded sensitivity of 66% and specificity of 61%, with cross-validation. Using norms also significantly improved sensitivity to 69% with a concomitant reduction of specificity to 56%, whereas the positive predictive value declined from 75% to 62% and negative predictive value improved from 54% to 64%. The HDS showed similarly modest rates of sensitivity and specificity among subpopulations of individuals with minimal comorbidity and successful viral suppression. CONCLUSIONS: Findings indicate that while the HDS is a statistically significant predictor of HAND, particularly when adjusted for demographic factors, its relatively low diagnostic classification accuracy continues to hinder its clinical utility. A raw cut point of 14 greatly improved the sensitivity of the previously established raw cut score, but may be subject to ceiling effects, particularly on repeat assessments. PMID- 23111576 TI - Population-level impact of Avahan in Karnataka state, south India using multilevel statistical modelling techniques. AB - OBJECTIVE: To assess the population-level impact of "Avahan," the India AIDS Initiative of the Bill & Melinda Gates Foundation, between 2003 and 2008 in Karnataka state, India. DESIGN: Secondary data analysis using all consistent data collection sites from antenatal clinic (ANC) sentinel surveillance data from 2003 to 2008 in Karnataka. METHODS: A multilevel logistic regression model considering individual- and district-level variables was developed to compare time trends in HIV prevalence among young ANC women (younger than 25 years of age) between Avahan (18) and non-Avahan (9) districts. District-level random effects were considered for the intercept and time. The impact was assessed using interaction terms between district type (Avahan vs. non-Avahan) and time. The number of cases averted was estimated, comparing predicted ANC HIV prevalence in the presence versus the absence of Avahan. Data from the National Family Health Survey Round 3 (2006) were used to extrapolate these numbers to the general population. RESULTS: HIV prevalence among young ANC women declined from 1.46% (2003) to 0.83% (2008). The HIV prevalence trend was significantly different between Avahan and non Avahan districts (P = 0.046). Overall, 87,035 cases of HIV infection were estimated to have been averted in the Karnataka general population because of Avahan during the 2003-2008 period (range under varying assumptions: 55,160 150,784). CONCLUSIONS: Our results suggest that Avahan has had a significant impact on the HIV epidemic in the general population of Karnataka. These results suggest that targeted interventions similar to Avahan should be implemented and scaled up in all concentrated and mixed HIV epidemics. PMID- 23111575 TI - Retention of HIV-infected children on antiretroviral treatment in HIV care and treatment programs in Kenya, Mozambique, Rwanda, and Tanzania. AB - BACKGROUND: Retention of children in HIV care is essential for prevention of disease progression and mortality. METHODS: Retrospective cohort of children (aged 0 to <15 years) initiating antiretroviral treatment (ART) at health facilities in Kenya, Mozambique, Rwanda, and Tanzania, from January 2005 to June 2011. Retention was defined as the proportion of children known to be alive and attending care at their initiation facility; lost to follow-up (LTF) was defined as no clinic visit for more than 6 months. Cumulative incidence of ascertained survival and retention after ART initiation was estimated through 24 months using Kaplan-Meier methods. Factors associated with LTF and death were assessed using Cox proportional hazard modeling. RESULTS: A total of 17,712 children initiated ART at 192 facilities: median age was 4.6 years [interquartile ratio (IQR), 1.9 8.3], median CD4 percent was 15% (IQR, 10-20) for children younger than 5 years and 265 cells per microliter (IQR, 111-461) for children aged 5 years or older. At 12 and 24 months, 80% and 72% of children were retained with 16% and 22% LTF and 5% and 7% known deaths, respectively. Retention ranged from 71% to 95% at 12 months and from 62% to 93% at 24 months across countries, respectively, and was lowest for children younger than 1 year (51% at 24 months). LTF and death were highest in children younger than 1 year and children with advanced disease. CONCLUSIONS: Retention was lowest in young children and differed across country programs. Young children and those with advanced disease are at highest risk for LTF and death. Further evaluation of patient- and program-level factors is needed to improve health outcomes. PMID- 23111577 TI - The feasibility of using screening criteria to reduce clinic visits for stable patients on antiretroviral therapy in South Africa. AB - OBJECTIVES: South African HIV care providers are exploring ways to reduce the intensity of patient visits while maintaining high quality of care. We used routinely collected data to model whether a simple screening tool could identify stable patients who would not need to see a doctor during a scheduled medical visit. DESIGN: We identified stable and nonstable visits from January 2007 to September 2011 at a large HIV clinic in Johannesburg, SA. Stable medical visits were defined as having all of the following: stable CD4 count, undetectable viral load, stable weight, not pregnant, no comorbidity, no regimen change within three months, and normal laboratory results for hemoglobin, alanine aminotransferase, and creatinine clearance. METHODS: We assessed the sensitivity and specificity of nonstable visits at predicting indicators of disease progression or needing additional care: (1) ART regimen change and (2) follow-up visits in <2 and <4 weeks from previous visit. RESULTS: Stable visits had a sensitivity of 88.9% (95% confidence interval: 88.2 to 89.7) and a specificity of 44.8% (44.5 to 44.1) at predicting ART therapy changes, and a sensitivity of 72.6% (71.8 to 73.4) and specificity of 45.1% (44.8 to 45.4) for predicting a follow-up visit interval of <2 weeks and similar results for predicting a follow-up visit interval of <4 weeks. CONCLUSIONS: Our retrospective analysis suggests an approach to potentially reduce the number of medical visits while missing few visits in which changes in regimen or additional care would be needed. Evaluation of our criteria in a primary care setting is needed to determine whether they could safely reduce visits. PMID- 23111578 TI - Tenofovir diphosphate and emtricitabine triphosphate concentrations in blood cells compared with isolated peripheral blood mononuclear cells: a new measure of antiretroviral adherence? AB - BACKGROUND: The active metabolites of tenofovir (TFV) and emtricitabine (FTC) in peripheral blood mononuclear cells (PBMCs) have been used as markers of long-term antiretroviral (ARV) adherence. However, the process of isolating PBMCs is expensive, complex, and not feasible in many settings. We compared concentrations of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in the upper layer packed cells (ULPCs) obtained after whole blood centrifugation to isolated PBMCs as a possible alternative marker of adherence. METHODS: Ten HIV+ adults with HIV RNA <50 copies/mL on a TDF/FTC-containing regimen provided 5 paired PBMC and ULPC samples over 6 hours. TFV-DP and FTC-TP concentrations were analyzed by liquid chromatography/mass spectrometry. Partial areas under the curve were calculated using noncompartmental methods and Spearman Rank Correlations (rho) between PBMC and ULPC were determined. RESULTS: The median (25th-75th percentile) concentration of TFV-DP in PBMCs was 143 (103-248) fmol/10(6) cells and in ULPC was 227 (160-394) fmol/10(6) cells (rho = 0.65; P < 0.0001). The concentration of FTC-TP in PBMCs was 6660 (5650-10,000) fmol/10(6) cells and in ULPC was 19.0 (12.0-27.8) fmol/10(6) cells (rho = 0.55; P < 0.0001). Compared to PBMCs, ULPC TFV-DP was 64% higher and FTC-TP was 99.7% lower. ULPC concentrations of TFV-DP and FTC-TP in one additional subject receiving a single dose of TDF/FTC were only 0.05% and 25%, of the other 10 subjects, respectively. CONCLUSIONS: ULPC concentrations significantly correlated with PBMC concentrations. Preliminary single-dose data suggest some discrimination between intermittent versus consistent dosing. ULPC concentrations of TFV-DP and FTC-TP should be further investigated as a simply collected surrogate measure of ARV adherence. PMID- 23111579 TI - Steady state trials: another valid substitution of counterfactual ideal to measure causal effects. AB - OBJECTIVES: Many traditionally established medical interventions are not examined with randomized trials especially in emergency medicine. We researched what is the scientific basis of the measurement of the causal effect in these interventions and proposed another trial to measure causal effects. METHODS: We deduced steady state trials from the counterfactual model and used Bayesian approaches to estimate causal effects statistically. RESULTS: When the state of the observed person is fairly steady before an exposure, the ratio of the after period to the before-period of the exposure is sufficiently small, and changes are obtained in relatively short time, it is possible to postulate that the state of the counterfactual person to be compared is almost equal to the state of the real person before the exposure. Bayesian approaches show that the causal effect of the exposure is estimated even in only one-person steady state trials, when large changes are observed. CONCLUSIONS: Steady state trials are valid methods to measure causal effects and can measure causal effects even in one-person trials. When we can measure the causal effect of interventions with steady state trials, these interventions should be regarded as scientific without use of randomized trials. PMID- 23111582 TI - Bile acids content in brain of common duct ligated rats. AB - INTRODUCTION: Cholestasis leads to liver cell death, fibrosis, cirrhosis, and eventually liver failure. Bile duct ligated rats constitute an interesting model to study the mechanism of cholestasis, and its action on several organs and tissues, including the brain. AIM: To analyze brain bile acids individually in ligated rats to evaluate if its profile is altered towards a more toxic condition in cholestasis. MATERIAL AND METHODS: Male Wistar rats were used and separated in two groups: bile duct ligated rats and sham operated rats (n = 5 in each group). Bile acid profile was assessed in brain homogenates. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase determinations, bilirubin and ammonia plasma concentration were also measured in both groups. RESULTS: Although the total amount of bile acids in control animal brains showed a higher concentration than in bile duct ligated rats, the bile acid profile in this group was found more toxic composition than in controls. Lithocholic acid was present in brain in higher concentration (87.4 % of total brain bile acids) in ligated rats and absent in controls. Alkaline phosphatase, bilirubin and ammonia were significantly higher in bile duct ligated rats than in control group. CONCLUSION: It was found a toxic brain bile acid profile during hepatic cholestasis which could be one of the explanations of hepatic encephalopathy observed in cholestatic diseases. PMID- 23111583 TI - High-density lipoprotein cholesterol and intracoronary thrombosis burden. AB - OBJECTIVE: To carry out a retrospective analysis of the correlation between high density lipoprotein cholesterol (HDL-C) and intracoronary thrombus burden. METHODS AND RESULTS: A total of 270 patients with ST-segment elevation myocardial infarction undergoing primary PCI were analyzed retrospectively. They were divided into two groups: patients with (group A, n=111) and patients without (group B, n=159) angiographic characteristics of thrombus. The results showed that the level of HDL-C was markedly lower in group A than that in group B. The logistic regression analysis of the relationship between multiple factors showed that only the level of HDL-C was correlated negatively with the angiographic characteristics of thrombus. CONCLUSION: HDL-C is correlated with the angiographic presence of thrombus. PMID- 23111584 TI - Increased red blood cell deformability and decreased aggregation as potential adaptive mechanisms in the slow coronary flow phenomenon. AB - OBJECTIVE: At present, the precise pathophysiology of the slow coronary flow phenomenon (SCFP) is still unknown and there is no consensus as to how it should be treated. The rheological factors affect the clinical course of various cardiovascular diseases. We studied the intrinsic properties of blood in the SCFP. MATERIALS AND METHODS: Twenty-six SCFP patients who had angiographically confirmed SCFP, and had otherwise normal epicardial coronary arteries, were included in our study, as were 30 healthy individuals with normal results from arteriography. Red blood cell (RBC) deformability, aggregation, whole-blood viscosity at both native and standard (40%) hematocrit, and plasma viscosity were determined in each individual. The results were analyzed using a Mann-Whitney U test, an unpaired t-test, and a chi-test, where appropriate. RESULTS: The mean thrombolysis in myocardial infarction frame count was significantly higher in SCFP patients than in the controls. RBC deformability measured at five different shear rates was significantly higher in SCFP patients than in the controls. The RBC aggregation index was lower in SCFP patients. There were no statistically significant differences in RBC aggregation half-time (t1/2) and aggregation amplitude, whole-blood viscosity, and plasma viscosity between the two groups. CONCLUSION: The SCFP is associated with increased RBC deformability and decreased RBC aggregation. These hemorheological alterations, possibly also contributing factors in limiting the pathogenesis, can especially serve as beneficial adaptive mechanisms in the SCFP. PMID- 23111581 TI - HTK-N, a modified HTK solution, decreases preservation injury in a model of microsteatotic rat liver transplantation. AB - BACKGROUND: Ischemia/reperfusion injury is an obstacle especially in steatotic livers, including those with steatosis induced by acute toxic stress. Recently, a modified histidine-tryptophan-ketoglutarate (HTK) solution, HTK-N, has been developed. This solution contains N-acetylhistidine, amino acids, and iron chelators. This study was designed to test the effects of HTK-N on preservation injury to rat livers after acute toxic injury. METHODS: Microvesicular steatosis was induced by a single dose of ethanol (8 g/kg BW). Livers were harvested and stored at 4 degrees C for 8 h with HTK or HTK-N before transplantation. Tissue and blood samples were taken at 1, 8, and 24 h after reperfusion to compare serum liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), standard histology, and immunohistochemistry for myeloperoxidase (MPO), caspase-3, and inducible nitric oxide synthase. Survival was compared after 1 week. For statistics, Analysis of Variance and t test were used. RESULTS: HTK-N improved survival from 12.5% in HTK to 87.5% (p < 0.05). Furthermore, liver enzymes were decreased to 2-75% of HTK values (p < 0.05). Necrosis and leukocyte infiltration and MPO, caspase-3, and iNOS expression after transplantation were decreased (p < 0.05). CONCLUSIONS: This study demonstrates that HTK-N protects liver grafts with microvesicular steatosis caused by acute toxic injury from cold ischemic injury better than standard HTK most likely via inhibition of hypoxic injury and oxidative stress and amelioration of the inflammatory reaction occurring upon reperfusion. PMID- 23111585 TI - Young patients hospitalized with an acute coronary syndrome. AB - OBJECTIVES: Limited data are available describing the magnitude, clinical features, treatment practices, and short-term outcomes of younger adults hospitalized with an acute coronary syndrome (ACS). METHODS: The objectives of this large multinational observational study were to describe recent trends in these and related endpoints among adult men and women younger than 55 years of age who were hospitalized with an ACS between 1999 and 2007 as part of the Global Registry of Acute Coronary Events (GRACE) study. RESULTS: The overall proportion of young adults hospitalized with an ACS in our multinational study population was 23% (n=15 052 of 65 119); this proportion remained relatively constant during the years under study. The proportion of comparatively young patients hospitalized with a previous diagnosis of angina pectoris or heart failure decreased over time, whereas the rates of previously diagnosed hypertension in this patient population increased. The proportion of patients developing atrial fibrillation, heart failure, stroke, or an episode of major bleeding during hospitalization for an ACS decreased significantly over time. Both in-hospital (2.1% in 1999; 1.3% in 2007) and 30-day multivariable-adjusted death rates decreased by more than 30% (odds ratio=0.66, 95% confidence interval=0.60-0.74) during the years under study. The hospital use of effective cardiac therapies (e.g. angiotensin-converting enzyme inhibitors, beta-blockers) increased significantly over time. CONCLUSION: The results of this large observational study provide insights into the magnitude, changing characteristics, and short term outcomes of comparatively young adults hospitalized with an ACS. Decreasing rates of short-term mortality and important clinical complications likely reflect enhanced treatment efforts that warrant future monitoring. PMID- 23111587 TI - Adenosine blocks aminopterin-induced suppression of osteoclast differentiation. AB - To search cell surface molecules involved in the regulation of osteoclastogenesis, especially in fusion process, it is one powerful approach to obtain monoclonal antibodies bearing ability to block formation of multinucleated osteoclasts. Ideally, direct bio-assay of hybridoma supernatants is quite convenient to screen monoclonal antibodies of interest from numerous culture wells. However, addition of hybridoma supernatant containing hypoxanthine aminopterin-thymidine (HAT), components of the selection medium, to whole bone marrow cultures strikingly suppressed osteoclastogenesis. Here we clarified aminopterin is the responsible component in HAT medium to inhibit osteoclastogenesis. Methotrexate (MTX), mono-methylated aminopterin, showed similar suppressive effect on osteoclastogenesis. When bone marrow cells were cultured in the presence of all nucleosides, aminopterin and MTX-induced suppression of osteoclastogenesis was abrogated. Among four nucleosides only adenosine canceled aminopterin-induced suppression of osteoclastogenesis. Direct bio-assay of hybridoma supernatant containing HAT selection medium is now available to screen monoclonal antibodies if adenosine-containing culture medium was utilized for evaluating osteoclastogenesis. PMID- 23111588 TI - From natural product to marketed drug: the tiacumicin odyssey. AB - The first members of the tiacumicin family of antibiotics, encompassing more than 40 compounds, were isolated in 1975. Structurally, the core aglycon is an 18 membered macrolactone having two conjugated diene units, one isolated double bond, 5 stereogenic centers and most often, at least one glycosidic linkage. Tiacumicin B, a RNA synthesis inhibitor, is a narrow-spectrum antibiotic against clostridia. For the treatment of Clostridium difficile infection (CDI), it has the same cure rate as vancomycin but with lower relapse rate and was approved by the FDA in May 2011. The aim of this review is to present an overview of the chemistry and biology of tiacumicins since their discovery. PMID- 23111589 TI - Relationship between circulating endothelial progenitor cells and endothelial dysfunction in children with type 1 diabetes: a novel paradigm of early atherosclerosis in high-risk young patients. AB - OBJECTIVE: The low number of circulating endothelial progenitor cells (EPCs) has emerged as a biomarker of cardiovascular (CV) risk in adults. Data regarding EPCs in paediatric populations with CV risk factors are limited. The aim of the study was to estimate the EPC number and its relationship with vascular function and structure in children with type 1 diabetes mellitus (T1DM). DESIGN AND METHODS: We performed a comparative analysis of 52 children with T1DM (mean age 14.5 years; diabetes duration, 6.0 years; HbA1c level, 8.5%) and 36 healthy age- and gender-matched control children. EPCs were identified and analysed by flow cytometry with the use of MABs directed against CD34, CD144 (VE-cadherin) and CD309 (VEGFR-2). sICAM-1, hsCRP, thrombomodulin and adiponectin levels were also assessed. We evaluated vascular function (flow-mediated dilation (FMD)) and structure (carotid intima-media thickness (IMT)) ultrasonographically. RESULTS: Frequencies of CD34+ cells were similar in both groups (P=0.30). In contrast, frequencies of CD34+VE-cadherin+ cells were significantly higher in diabetic children compared with the healthy group (P=0.003). Similarly, diabetic patients tended to present with higher frequencies of CD34+VEGFR+ cells (P=0.06). FMD was lower (6.9 vs 10.5%, P=0.002) and IMT was higher (0.50 vs 0.44 mm, P=0.0006) in diabetic children. We demonstrated a significant relationship between CD34+VEGFR 2+ cells and BMI (r=0.3, P=0.014), HDL (r=-0.27, P=0.04), sICAM-1 (r=0.47, P=0.023) and FMD (r=-0.45, P<0.001). Similarly, frequencies of CD34+VE-cadherin+ cells were significantly correlated with BMI (r=0.32, P=0.02) and FMD (r=-0.31, P=0.03). CONCLUSIONS: We demonstrated here that increased frequencies of EPCs observed in diabetic children are negatively correlated with endothelial function. Further studies are warranted to assess whether this phenomenon might result from effective mobilisation of EPCs in order to repair damaged endothelium in children at increased risk for atherosclerosis. PMID- 23111590 TI - [Ischemic mitral regurgitation : pathomechanisms and current therapeutic options]. AB - Ischemic mitral regurgitation (MR) is a complication of myocardial infarction due to coronary heart disease and may occur during the course of acute ischemia or delayed following adverse left ventricular remodeling. Acute ischemic MR represents a life-threatening condition and requires immediate surgical correction. Chronic ischemic MR develops time-delayed from acute ischemia and is caused by pathological remodeling of the left ventricle or valvular apparatus and mostly affects older patients with severe comorbidities. This common manifestation of ischemic MR contributes to the poor prognosis of such patients. Therapeutic options for the treatment of patients with chronic ischemic MR are limited as current guidelines are based on weak evidence and the optimal treatment is still a matter of controversy. Surgical correction of chronic ischemic MR is only advised in patients with indications for concomitant surgical revascularization and modern interventional or surgical treatment strategies to reduce MR are not included in these guidelines. Modern surgical options and new interventional procedures are available and will influence future treatment strategies of this chronic manifestation of MR. PMID- 23111591 TI - [Chylothorax in an 87-year-old patient]. AB - An 87-year-old woman presented with a left-sided pleural effusion. The milky aspirate fulfilled the criteria of a chylothorax. Thorax computed tomography (CT) showed characteristic multiple cysts and consequently the rare diagnosis of post menopausal pulmonary lymphangioleiomyomatosis was made. In the diagnostic work-up of pleural effusion the determination of triglycerides should be considered to confirm the diagnosis of chylothorax. In the presence of a chylothorax the differential diagnosis of lymphangioleiomyomatosis should be included even in advanced age. PMID- 23111592 TI - [Primary and secondary prevention of stroke]. AB - Despite considerable advances in acute stroke therapy, stroke prevention remains the most promising approach for reducing the burden of stroke. A healthy lifestyle and the treatment of cardiometabolic risk factors are the cornerstones of both primary and secondary stroke prevention. Due to a proportionately higher risk of bleeding complications, platelet inhibitors are not recommended for primary stroke prevention. Platelet inhibitors are effective in the secondary prevention of stroke with acetyl salicylic acid (ASS) and clopidogrel showing the most consistent data. New oral anticoagulants are slightly more effective than coumarin and significantly reduce the risk of intracranial hemorrhage. They offer the opportunity to bring more patients with atrial fibrillation at risk for stroke into anticoagulation particularly those on ASS therapy. Surgery for patients with asymptomatic carotid artery stenosis should be viewed critically with respect to an only marginal benefit and improvement in medical therapies. Carotid endarterectomy remains the gold standard for patients with symptomatic carotid stenosis because of an increased procedural stroke risk with carotid stenting. Patients with symptomatic intracranial stenosis or cryptogenic stroke and a patent foramen ovale should receive only medical treatment. PMID- 23111593 TI - [Pharmaceutical aids in gerontopharmacology]. AB - The administration of drugs is often subject to error when performed by geriatric patients, resulting in reduced therapeutic effects. In particular, the correct administration technique for different dosage forms is a problem in elderly patients with limited audiovisual and ergonomic abilities. In addition to physician and carer intervention, community pharmacists can also contribute to solving outpatient problems of this kind at the time of issuing the drugs. This should preferably be done in collaboration with the respective medical practice. Some of the most common problems in drug administration, as well as the corresponding solutions offered by the pharmacist, are featured in the present paper. Inhalers, injection devices and ophthalmic solutions often cause difficulties for geriatric patients, as do even simple dosage forms such as drops. Pharmacy-based solutions to these problems include for instance: taking over the assembly of complex devices comprising multiple components, instructing patients in the proper use of additional dosing aids or adapting the administration technique to the patient's abilities. PMID- 23111594 TI - [Fever of unknown origin. Infectious causes]. AB - Infectious diseases remain one of the most important causes of fever of unexplained origin (FUO). We review the spectrum of infectious diseases in the different clinical situations of patients with FUO, namely in classical FUO, in patients with HIV infection, in health care-associated or nosocomial FUO, and in immunocompromised patients with FUO. The most important question is which clinical features make a specific disease a candidate to cause FUO. PMID- 23111595 TI - Comparison of solid-state and submerged-state fermentation for the bioprocessing of switchgrass to ethanol and acetate by Clostridium phytofermentans. AB - The conversion of sustainable energy crops using microbiological fermentation to biofuels and bioproducts typically uses submerged-state processes. Alternatively, solid-state fermentation processes have several advantages when compared to the typical submerged-state processes. This study compares the use of solid-state versus submerged-state fermentation using the mesophilic anaerobic bacterium Clostridium phytofermentans in the conversion of switchgrass to the end products of ethanol, acetate, and hydrogen. A shift in the ratio of metabolic products towards more acetate and hydrogen production than ethanol production was observed when C. phytofermentans was grown under solid-state conditions as compared to submerged-state conditions. Results indicated that the end product concentrations (in millimolar) obtained using solid-state fermentation were higher than using submerged-state fermentation. In contrast, the total fermentation products (in weight of product per weight of carbohydrates consumed) and switchgrass conversion were higher for submerged-state fermentation. The conversion of xylan was greater than glucan conversion under both fermentation conditions. An initial pH of 7 and moisture content of 80 % resulted in maximum end products formation. Scanning electron microscopy study showed the presence of biofilm formed by C. phytofermentans growing on switchgrass under submerged-state fermentation whereas bacterial cells attached to surface and no apparent biofilm was observed when grown under solid-state fermentation. To our knowledge, this is the first study reporting consolidated bioprocessing of a lignocellulosic substrate by a mesophilic anaerobic bacterium under solid-state fermentation conditions. PMID- 23111596 TI - Interactions of microorganisms with rare earth ions and their utilization for separation and environmental technology. AB - In recent years, rare earth elements (REEs) have been widely used in various modern technological devices and the global demand for REE has been increasing. The increased demand for REEs has led to environmental exposure or water pollution from rare earth metal mines and various commercial products. Therefore, the development of a safe technology for the separation and adsorption of REEs is very important from the perspective of green chemistry and environmental pollution. In this review, the application and mechanisms of microorganisms for the removal and extraction of REEs from aqueous solutions are described. In addition, the advantages in using microorganisms for REE adsorption and future studies on this topic are discussed. PMID- 23111597 TI - Substrate oxidation by dye-decolorizing peroxidases (DyPs) from wood- and litter degrading agaricomycetes compared to other fungal and plant heme-peroxidases. AB - Catalytic and physicochemical properties of representative fungal dye decolorizing peroxidases (DyPs) of wood- (WRF) and litter-decomposing white-rot fungi (LDF) are summarized and compared, including one recombinant Mycetinis scorodonius DyP (rMscDyP; LDF), the wild-type Auricularia auricula-judae DyP (AauDyP; WRF), and two new DyPs secreted by the jelly fungi Exidia glandulosa (EglDyP; WRF) and Mycena epipterygia (MepDyP; LDF). Homogeneous preparations of these DyPs were obtained after different steps of fast protein liquid chromatography, and they increase the total number of characterized fungal DyP proteins to eight. The peptide sequences of AauDyP, MepDyP, and EglDyP showed highest homologies (52-56%) to the DyPs of M. scorodonius. Five out of the eight characterized fungal DyPs were used to evaluate their catalytic properties compared to classic fungal and plant heme peroxidases, namely lignin peroxidase of Phanerochaete chrysosporium (PchLiP; WRF), versatile peroxidase of Bjerkandera adusta (BadVP; WRF), and generic peroxidases of Coprinopsis cinerea (CiP) and Glycine max (soybean peroxidase=SBP). All DyPs tested possess unique properties regarding the stability at low pH values: 50-90% enzymatic activity remained after 4-h exposition at pH 2.5, and the oxidation of nonphenolic aromatic substrates (lignin model compounds) was optimal below pH 3. Furthermore, all DyPs efficiently oxidized recalcitrant dyes (e.g., Azure B) as well as the phenolic substrate 2,6-dimethoxyphenol. Thus, DyPs combine features of different peroxidases on the functional level and may be part of the biocatalytic system secreted by fungi for the oxidation of lignin and/or toxic aromatic compounds. PMID- 23111598 TI - Genetic analysis of the metabolic pathways responsible for aroma metabolite production by Saccharomyces cerevisiae. AB - During alcoholic fermentation, higher alcohols, esters, and acids are formed from amino acids via the Ehrlich pathway by yeast, but many of the genes encoding the enzymes have not yet been identified. When the BAT1/2 genes, encoding transaminases that deaminate amino acids in the first step of the Ehrlich pathway are deleted, higher metabolite formation is significantly decreased. Screening yeast strains with deletions of genes encoding decarboxylases, dehydrogenases, and reductases revealed nine genes whose absence had the most significant impact on higher alcohol production. The seven most promising genes (AAD6, BAT2, HOM2, PAD1, PRO2, SPE1, and THI3) were further investigated by constructing double- and triple-deletion mutants. All double-deletion strains showed a greater decrease in isobutanol, isoamyl alcohol, isobutyric, and isovaleric acid production than the corresponding single deletion strains with the double-deletion strains in combination with ?bat2 and the ?hom2-?aad6 strain revealing the greatest impact. BAT2 is the dominant gene in these deletion strains and this suggests the initial transaminase step of the Ehrlich pathway is rate-limiting. The triple-deletion strains in combination with BAT2 (?bat2-?thi3-?aad6 and ?bat2-?thi3-?hom2) had the greatest impact on the end metabolite production with the exception of isoamyl alcohol and isovaleric acid. The strain deleted for two dehydrogenases and a reductase (?hom2-?pro2-?aad6) had a greater effect on the levels of these two compounds. This study contributes to the elucidation of the Ehrlich pathway and its significance for aroma production by fermenting yeast cells. PMID- 23111599 TI - Properties and biotechnological applications of halohydrin dehalogenases: current state and future perspectives. AB - Halohydrin dehalogenases (HHDHs) are lyases that catalyze the cleavage of carbon halogen bond of halohydrins. They also can catalyze the reverse reaction in the presence of nucleophiles such as cyanide, azide, and nitrite ions. HHDHs have been recognized as the ideal tools for the degradation of various halogenated environmental pollutants. Moreover, they can be used as biocatalysts for the kinetic resolution of halohydrins and epoxides, and for the preparation of various substituted alcohols. This review is mainly focused on the current status of research on HHDHs, highlighting the production, characterization, structures and mechanism, protein engineering, and biotechnological applications of HHDHs. PMID- 23111600 TI - Growth condition optimization for docosahexaenoic acid (DHA) production by Moritella marina MP-1. AB - The marine organism Moritella marina MP-1 produces the polyunsaturated fatty acid docosahexaenoic acid (DHA). While the basic metabolic pathway for DHA production in this organism has been identified, the impact of growth conditions on DHA production is largely unknown. This study examines the effect of supplemental carbon, nitrogen and salts, growth temperature and media composition and pH on DHA and biomass production and the fatty acid profile. The addition of supplemental nitrogen significantly increased the overall DHA titer via an increase in biomass production. Supplemental glucose or glycerol increased biomass production, but decreased the amount of DHA per biomass, resulting in no net change in the DHA titer. Acidification of the baseline media pH to 6.0 increased DHA per biomass. Changes in growth temperature or provision of supplemental sodium or magnesium chloride did not increase DHA titer. This organism was also shown to grow on defined minimal media. For both media types, glycerol enabled more DHA production per biomass than glucose. Combination of these growth findings into marine broth supplemented with glycerol, yeast extract, and tryptone at pH 6.0 resulted in a final titer of 82+/-5 mg/L, a nearly eightfold increase relative to the titer of 11+/-1 mg/L seen in the unsupplemented marine broth. The relative distribution of other fatty acids was relatively robust to growth condition, but the presence of glycerol resulted in a significant increase in myristic acid (C14:0) and decrease in palmitic acid (C16:0). In summary, DHA production by M. marina MP-1 can be increased more than fivefold by changing the growth media. Metabolic engineering of this organism to increase the amount of DHA produced per biomass could result in additional increases in titer. PMID- 23111601 TI - Noninvasive determination of burn depth in children by digital infrared thermal imaging. AB - Digital infrared thermal imaging is used to assess noninvasively the severity of burn wounds in 13 pediatric patients. A delta-T (DeltaT) parameter obtained by subtracting the temperature of a healthy contralateral region from the temperature of the burn wound is compared with the burn depth measured histopathologically. Thermal imaging results show that superficial dermal burns (IIa) show increased temperature compared with their contralateral healthy region, while deep dermal burns (IIb) show a lower temperature than their contralateral healthy region. This difference in temperature is statistically significant (p<0.0001) and provides a way of distinguishing deep dermal from superficial dermal burns. These results show that digital infrared thermal imaging could be used as a noninvasive procedure to assess burn wounds. An additional advantage of using thermal imaging, which can image a large skin surface area, is that it can be used to identify regions with different burn depths and estimate the size of the grafts needed for deep dermal burns. PMID- 23111602 TI - Noncontact imaging photoplethysmography to effectively access pulse rate variability. AB - Noncontact imaging photoplethysmography (PPG) can provide physiological assessment at various anatomical locations with no discomfort to the patient. However, most previous imaging PPG (iPPG) systems have been limited by a low sample frequency, which restricts their use clinically, for instance, in the assessment of pulse rate variability (PRV). In the present study, plethysmographic signals are remotely captured via an iPPG system at a rate of 200 fps. The physiological parameters (i.e., heart and respiration rate and PRV) derived from the iPPG datasets yield statistically comparable results to those acquired using a contact PPG sensor, the gold standard. More importantly, we present evidence that the negative influence of initial low sample frequency could be compensated via interpolation to improve the time domain resolution. We thereby provide further strong support for the low-cost webcam-based iPPG technique and, importantly, open up a new avenue for effective noncontact assessment of multiple physiological parameters, with potential applications in the evaluation of cardiac autonomic activity and remote sensing of vital physiological signs. PMID- 23111604 TI - E. coli outbreak in a neonate intensive care unit in a general hospital in Mexico City. AB - Nosocomial infections are a major cause of morbidity and mortality among neonates admitted to neonatal intensive care units (NICUs). The aim of this paper was to describe an outbreak of Escherichia coli among infants admitted to the NICU of the General Hospital "Dr. Manuel Gea Gonzalez" in May of 2008. The isolated E. coli strains were identified using standard biochemical methods. The susceptibilities of these strains were analysed by determining their minimal inhibitory concentrations. Following this, their molecular relationships to each other were assessed by pulsed field gel electrophoresis (PFGE) analysis and corroborated by serology. Twelve E. coli strains were isolated from blood, urine, or indwelling catheter samples from five cases of preterm infants within a 3-day period. Patients were admitted to the NICU of the general hospital and, during the outbreak, developed sepsis caused by E. coli. For four of the patients, the average age was 23 days, while one patient was a 3-month-old infant. Prior to sepsis, the infants had received assisted ventilation and hyperalimentation through a central venous catheter. Two profiles were observed by PFGE; profile A was identified as the outbreak's cause and an outcome of cross-infection, while profile B showed genetic differences but serologically it was identified as part of the same serotype. We conclude that E. coli colonised the patients through horizontal transmission. A focal source of the microorganism in this outbreak was not identified, but cross-transmission through handling was the most probable route. PMID- 23111605 TI - Retinal prosthesis safety: alterations in microglia morphology due to thermal damage and retinal implant contact. AB - PURPOSE: In order to develop retinal implants with a large number of electrodes, it is necessary to ensure that they do not cause damage to the neural tissue by the heat that the electrical circuits generate. Knowledge about the threshold of the amount of power that induces damage will assist in developing power budgets for retinal implants. METHODS: Heat-induced retinal damage was evaluated by measuring changes in the morphology of the resident immune cells, the microglia, which are the first cells to respond to retinal trauma. Microglial soma and arbor areas were assessed in rat retinal tissues in vitro to determine the effects of increasing temperatures, implant contact, and heating and implant contact combined. RESULTS: In response to increasing incubation temperatures (no implant), microglial somas enlarged and arbor areas retracted, indicative of retinal stress. Thermal damage thresholds, defined as a significant change in microglial morphology from that observed at the upper limit of normal body temperature, occurred at a temperature of 38.7 degrees C. Implant contact, induced when a passive implant was placed on the retina, also caused similar morphological alterations in microglia, indicating retinal damage. Heated-implant contact exacerbated the effects of temperature alone but still resulted in a thermal damage threshold of 38.7 degrees C, the same as with heating alone. CONCLUSIONS: Our conservative recommendations are that implanted retinal electronics keep power dissipations to less than 19 mW/mm(2) to stay below the microglial thermal damage threshold (2.1 degrees C) and to comply with international standards for implantable devices (2 degrees C). PMID- 23111606 TI - Axonal protection via modulation of the amyloidogenic pathway in tumor necrosis factor-induced optic neuropathy. AB - PURPOSE: To examine the changes in and localization of phosphorylated presenilin1 (p-PS1) and amyloid precursor protein (APP) in the optic nerve after intravitreal injection of TNF and to investigate the role of gamma-secretase in the cleavage of APP in optic nerve degeneration. METHODS: Groups of rats were euthanatized at 1 or 2 weeks after intravitreal injection of TNF. Levels of p-PS1 protein in the optic nerve were determined by immunoblotting and immunohistochemistry. The localization of APP was determined by immunohistochemistry, and its downstream cleavage was determined by immunoprecipitation using 6E10 antibody followed by immunoblotting with an APP intracellular domain (AICD) antibody. The effect of a gamma-secretase inhibitor on TNF-induced optic nerve degeneration was determined by counting the number of axons. RESULTS: p-PS1 was increased in the optic nerve after TNF injection and was found to colocalize with vimentin and glial fibrillary acidic protein, markers of astrocytes. Immunoprecipitation using 6E10 antibody followed by immunoblotting with AICD antibody revealed an increase in gamma-secretase activation in the optic nerve after TNF injection, which was inhibited by treatment with the gamma-secretase inhibitor. Moreover, gamma secretase inhibition significantly prevented the loss of axons in the optic nerve after TNF injection. CONCLUSIONS: The increase in p-PS1 and activation of gamma secretase in the optic nerve may be associated with TNF-induced axonal degeneration. Modulation of gamma-secretase activity may be useful for the treatment of TNF-related optic neuropathy. PMID- 23111607 TI - Quantification of external limiting membrane disruption caused by diabetic macular edema from SD-OCT. AB - PURPOSE: Disruption of external limiting membrane (ELM) integrity on spectral domain optical coherence tomography (SD-OCT) is associated with lower visual acuity outcomes in patients suffering from diabetic macular edema (DME). However, no automated methods to detect ELM and/or determine its integrity from SD-OCT exist. METHODS: Sixteen subjects diagnosed with clinically significant DME (CSME) were included and underwent macula-centered SD-OCT (512 * 19 * 496 voxels). Sixteen subjects without retinal thickening and normal acuity were also scanned (200 * 200 * 1024 voxels). Automated quantification of ELM disruption was achieved as follows. First, 11 surfaces were automatically segmented using our standard 3-D graph-search approach, and the subvolume between surface 6 and 11 containing the ELM region was flattened based on the segmented retinal pigment epithelium (RPE) layer. A second, edge-based graph-search surface-detection method segmented the ELM region in close proximity "above" the RPE, and each ELM A-scan was classified as disrupted or nondisrupted based on six texture features in the vicinity of the ELM surface. The vessel silhouettes were considered in the disruption classification process to avoid false detections of ELM disruption. RESULTS: In subjects with CSME, large areas of disrupted ELM were present. In normal subjects, ELM was largely intact. The mean and 95% confidence interval (CI) of the detected disruption area volume for normal and CSME subjects were mean(normal) = 0.00087 mm(3) and CI(normal) = (0.00074, 0.00100), and mean(CSME) = 0.00461 mm(3) and CI(CSME) = (0.00347, 0.00576) mm(3), respectively. CONCLUSIONS: In this preliminary study, we were able to show that automated quantification of ELM disruption is feasible and can differentiate continuous ELM in normal subjects from disrupted ELM in subjects with CSME. We have started determining the relationships of quantitative ELM disruption markers to visual outcome in patients undergoing treatment for CSME. PMID- 23111608 TI - Relaxin 2 is functional at the ocular surface and promotes corneal wound healing. AB - PURPOSE: We aimed to determine if the insulin-like peptide hormone relaxin 2 (RLN2) is expressed at the ocular surface and in tears and if RLN2 influences wound healing at the ocular surface, which is associated with extracellular matrix (ECM) remodeling. METHODS: We analyzed transcript levels of human RLN2 and its cognate relaxin-like receptors RXFP1 and RXFP2 in tissues of the ocular surface, lacrimal apparatus, and human corneal (HCE), conjunctival (HCjE) and sebaceous (SC) cell lines. We analyzed effects of human RLN2 on cell proliferation and migration and quantified mRNA expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in HCE, HCjE, and SC. Using an alkali-induced corneal wounding model, we analyzed the wound healing rate in C57BL/6 mice eyes after topically applied RLN2. RESULTS: The presence of RLN2, RXFP1, and RXFP2 transcripts was detected in lacrimal gland, eyelid, conjunctiva, cornea, primary corneal fibroblasts, nasolacrimal ducts, and all three cell lines. ELISA revealed RLN2 protein in all ocular surface tissues analyzed and in human tears. Stimulation of HCE, HCjE, and SC with RLN2 significantly increased cell proliferation and migration. Relative mRNA expression levels of MMP2, MMP9, TIMP1, and TIMP2 were significantly influenced by RLN2 in all three cell lines at different time points studied. The local application of RLN2 onto denuded corneal surface resulted in significantly elevated corneal wound healing. CONCLUSIONS: Our data support a novel role for the RLN2 ligand-receptor system at the ocular surface and in the lacrimal apparatus as a potential future therapeutic during wound healing at the ocular surface. PMID- 23111609 TI - Education is positively associated with macular pigment: the Irish Longitudinal Study on Ageing (TILDA). AB - PURPOSE: The three carotenoids lutein, zeaxanthin, and meso-zeaxanthin, are found at the macula and referred to as macular pigment (MP). This study was undertaken to investigate determinants of MP in a large randomly selected sample from the Republic of Ireland (as part of The Irish Longitudinal Study on Ageing [TILDA]). METHODS: MP optical density (MPOD) was measured using customized heterochromatic flicker photometry in 4373 participants. Sociodemographic and self reported health data was obtained using computer assisted personal interview (CAPI). RESULTS: Mean (SD) MPOD for the study group was 0.203 (0.156) with a range of 0 to 1.01. MPOD was higher for participants with secondary education (mean [SD] = 0.205 [0.148]) than for those with only primary education or no education (mean [SD] = 0.183 [0.113]; P < 0.001). MPOD was also higher for those with tertiary education (mean [SD] = 0.232 [0.231]) compared with primary/no education or secondary education (P < 0.001 for both comparisons). CONCLUSIONS: We report that MP is lower amongst those participants of a population-representative study who did not have secondary or third level education when compared with participants who had such education. Given the emerging evidence that MP is important for visual performance and comfort, and given the putative protection that this pigment confers against AMD (especially important in the context of increased risk of AMD in this social group), public health measures aimed at improving diet for this at-risk population need to be considered. PMID- 23111610 TI - Repeatability of Spectralis OCT measurements of macular thickness and volume in diabetic macular edema. AB - PURPOSE: We estimated coefficients of repeatability for Spectralis optical coherence tomography (OCT)-derived automated retinal thickness and volume measurements in subjects with center-involving diabetic macular edema (DME). METHODS: A total of 50 eyes of 50 consecutive patients with center-involving DME underwent four consecutive "fast" volume scans at a single session using one OCT device operated by one of two experienced operators. Bland-Altman coefficients of repeatability (CR) were calculated for automated retinal thickness measurements in the nine Early Treatment of Diabetic Retinopathy Study (ETDRS) subfields, center point thickness, and total macular volume. Scans were evaluated for significant automated retinal boundary detection error and revised estimates for CR calculated with these scans excluded. RESULTS: CR in the central subfield was 8.03 MUm (95% confidence interval [CI] 7.70-8.35 MUm). In other subfields, CR ranged from 6.54 to 18.25 MUm. Scan sets from 13 subjects had significant boundary detection error; reanalysis with these excluded yielded a CR for the central subfield of 7.44 MUm with CR for all other subfields <8 MUm. CONCLUSIONS: Retinal thickness measurements in subjects with DME obtained using Spectralis OCT are considerably less variable than has been reported with other devices. Changes in central subfield thickness >8 MUm can be considered more indicative of true clinical change rather than measurement variability. This finding informs clinical practice and clinical trial design. PMID- 23111612 TI - Long-term decline of central cone function in retinitis pigmentosa evaluated by focal electroretinogram. AB - PURPOSE: We evaluated long-term changes of central cone-mediated function in retinitis pigmentosa (RP) patients by recording focal electroretinograms (fERG). METHODS: A cohort of 43 RP patients was followed from 4 to 16 years (average follow-up 9.3 years, average 10 examinations/patient) by recording the fERG response to a flickering uniform red field overlaying the central 18 degrees of visual field (VF). Statistical censoring led to a reduced dataset of 32 patients (autosomal dominant 9, recessive 5, sporadic 5, x-linked 1, Usher II 12), from which long-term decay rates were estimated by global fitting of individual fERG amplitude time-curves. RESULTS: Long-term follow-up of central cone FERG amplitude showed two main features: short-term variability and long-term decline. fERG short-term variability range was 0.14 to 0.2 log units. Mean yearly decay rate of central fERG was 5.6% (95% confidence interval [CI] 4%-7%). Yearly decline depended on inheritance pattern, being significantly greater in autosomal recessive and sporadic compared to autosomal dominant RP. The degree of central cone fERG decline was unrelated to the size of the residual VF. CONCLUSIONS: The decline of central cone function is significantly slower than global cone function decline in RP. Central cone fERG loss is independent of residual VF. PMID- 23111611 TI - Validating a nonhuman primate model of super-selective intraophthalmic artery chemotherapy: comparing ophthalmic artery diameters. AB - PURPOSE: Superselective intraophthalmic artery chemotherapy (SSIOAC) is being used for treatment of retinoblastoma; however, the hemodynamic consequences and toxicities are not fully known. We developed a nonhuman primate (NHP) model of SSIOAC and reported our clinical observations. For validation, we compared ophthalmic artery (OA) diameters between NHPs and children (<6 years). METHODS: Endovascular cannulation of the right OA was performed three times each in six adult male Rhesus macaques. Angiographic OA images were obtained and measured, and postmortem OAs were histologically sectioned and measured. Retrospectively, computed tomography (CT) and magnetic resonance (MR) angiography images of the head in children and adolescents (as an adult reference) were used to measure the OA luminal diameter at its origin. RESULTS: The median angiographic diameter of treated NHP OA origins (n = 6) was 1.06 mm (range 0.94-1.56). Histologic measurements (8 of 12 NHP OAs) gave a median diameter of 1.09 mm (range 0.95 1.41). In 98 children (from 169 consecutive CT and MR angiography studies; median age 1.01 years, range 0.01-5.74), 186 OAs were measurable at the origin (median luminal diameter 1.28 mm, range 0.82-2.00; P = 0.16 for the angiographic NHP diameters versus pediatric cohort). Angiographic measurements of 34 OAs (of 20 consecutive studies of adolescents; median age 16.55 years, range 14.40-18.18) gave a median luminal diameter of 1.45 mm (origin, range 1.13-1.66; P < 0.0001, adolescent versus pediatric). CONCLUSIONS: Measurements of the OA luminal diameter at its origin were similar between our NHP and pediatric cohort, validating our NHP model for testing both the hemodynamic consequences and toxicities of SSIOAC. PMID- 23111613 TI - Identification and detection of simple 3D objects with severely blurred vision. AB - PURPOSE: Detecting and recognizing three-dimensional (3D) objects is an important component of the visual accessibility of public spaces for people with impaired vision. The present study investigated the impact of environmental factors and object properties on the recognition of objects by subjects who viewed physical objects with severely reduced acuity. METHODS: The experiment was conducted in an indoor testing space. We examined detection and identification of simple convex objects by normally sighted subjects wearing diffusing goggles that reduced effective acuity to 20/900. We used psychophysical methods to examine the effect on performance of important environmental variables: viewing distance (from 10-24 feet, or 3.05-7.32 m) and illumination (overhead fluorescent and artificial window), and object variables: shape (boxes and cylinders), size (heights from 2 6 feet, or 0.61-1.83 m), and color (gray and white). RESULTS: Object identification was significantly affected by distance, color, height, and shape, as well as interactions between illumination, color, and shape. A stepwise regression analysis showed that 64% of the variability in identification could be explained by object contrast values (58%) and object visual angle (6%). CONCLUSIONS: When acuity is severely limited, illumination, distance, color, height, and shape influence the identification and detection of simple 3D objects. These effects can be explained in large part by the impact of these variables on object contrast and visual angle. Basic design principles for improving object visibility are discussed. PMID- 23111614 TI - Primary blast injury to the eye and orbit: finite element modeling. AB - PURPOSE: Primary blast injury (PBI) mostly affects air-filled organs, although it is sporadically reported in fluid-filled organs, including the eye. The purpose of the present paper is to explain orbit blast injury mechanisms through finite element modeling (FEM). METHODS: FEM meshes of the eye, orbit, and skull were generated. Pressure, strain, and strain rates were calculated at the cornea, vitreous base, equator, macula, and orbit apex for pressures known to cause tympanic rupture, lung damage, and 50% chance of mortality. RESULTS: Pressures within the orbit ranged between +0.25 and -1.4 MegaPascal (MPa) for tympanic rupture, +3 and -1 MPa for lung damage, and +20 and -6 MPa for 50% mortality. Higher trinitrotoluene (TNT) quantity and closer explosion caused significantly higher pressures, and the impact angle significantly influenced pressure at all locations. Pressure waves reflected and amplified to create steady waves resonating within the orbit. Strain reached 20% along multiple axes, and strain rates exceeded 30,000 s(-1) at all locations even for the smallest amount of TNT. CONCLUSIONS: The orbit's pyramidlike shape with bony walls and the mechanical impedance mismatch between fluidlike content and anterior air-tissue interface determine pressure wave reflection and amplification. The resulting steady wave resonates within the orbit and can explain both macular holes and optic nerve damage after ocular PBI. PMID- 23111615 TI - Dynamic contrast-enhanced MRI for assessing therapeutic response of choroidal neovascularization in a rat model. AB - PURPOSE: We evaluated the potential of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) as a noninvasive biomarker of choroidal neovascularization (CNV) and its utility as a tool for monitoring therapeutic response in laser-induced rat CNV models. METHODS: CNV was induced in the right eyes of 14 rats using a laser. Rats (n = 7) were treated daily for 14 days with a candidate drug (KR-31831, 50 mg/kg of body weight) having antiangiogenic effects, whereas control rats (n = 7) were treated with the vehicle alone (10% cremophor, 10% absolute ethyl alcohol, and 80% saline). DCE-MRI examinations were performed on the day before surgery (D - 1), and 3, 7, and 14 days after surgery (D + 3, D + 7, and D + 14), from which pharmacokinetic parameters (K(trans), v(e), v(p)) were calculated. Angiography was performed to visualize CNV using FITC-labeled high molecular weight dextran after MRI on D + 14. The paired Wilcoxon test and Mann-Whitney U test were performed for statistical analysis. RESULTS: The K(trans) and v(e) values of the CNV-induced right eyes were significantly higher than those of the intact eyes in control rats at D + 14 (P < 0.05). In the CNV induced eyes, the relative K(trans) and v(e) values of the KR-31831-treated group were significantly lower than those of the nontreated group at D + 14 (P < 0.05). The angiography showed that decreased CNV was observed in rats treated with KR 31831. CONCLUSIONS: Quantitative DCE-MRI produces noninvasive biomarker of CNV, thus allowing monitoring of therapeutic response of antiangiogenic drugs in neovascular age-related macular degeneration (AMD). PMID- 23111616 TI - K2CaV2O7: a pyrovanadate with a new layered type of structure in the A2BV2O7 family. AB - The crystal structure of K(2)CaV(2)O(7) prepared by a conventional solid-state reaction has been solved by a direct method and refined using Rietveld full profile fitting based on X-ray powder diffraction data. This compound crystallises in the triclinic space group (P1, Z = 2) with unit cell constants a = 7.1577(1) A, b = 10.5104(2) A, c = 5.8187(1) A, alpha = 106.3368(9) degrees , beta = 106.235(1) degrees , gamma = 71.1375(9) degrees . The structure can be described as infinite undulating CaV(2)O(7)(2-) layers parallel to the ac plane, which consist of pairs of edge-sharing CaO(6) octahedra connected to each other through V(2)O(7) pyrogroups. The potassium atoms are positioned in two sites between the layers, with a distorted IX-fold coordination of oxygen atoms. The chemical composition obtained from the structural solution was confirmed by energy-dispersive X-ray analysis. The stability of compounds in the family of alkali metal calcium pyrovanadates is discussed based on an analysis of the correlation between anion and cation sizes and theoretical first-principles calculations. PMID- 23111617 TI - Social robots as embedded reinforcers of social behavior in children with autism. AB - In this study we examined the social behaviors of 4- to 12-year-old children with autism spectrum disorders (ASD; N = 24) during three tradic interactions with an adult confederate and an interaction partner, where the interaction partner varied randomly among (1) another adult human, (2) a touchscreen computer game, and (3) a social dinosaur robot. Children spoke more in general, and directed more speech to the adult confederate, when the interaction partner was a robot, as compared to a human or computer game interaction partner. Children spoke as much to the robot as to the adult interaction partner. This study provides the largest demonstration of social human-robot interaction in children with autism to date. Our findings suggest that social robots may be developed into useful tools for social skills and communication therapies, specifically by embedding social interaction into intrinsic reinforcers and motivators. PMID- 23111618 TI - Growth retardation and hair loss in transgenic mice overexpressing human H ferritin gene. AB - H-ferritin (HF) is a core subunit of the iron storage protein ferritin, and plays a central role in the regulation of cellular iron homeostasis. Recent studies revealed that ferritin and HF are involved in a wide variety of iron-independent functions, including regulating biological processes during physiological and pathological conditions, and can be overexpressed in some human diseases. To investigate the in vivo function of HF, we generated transgenic (tg) mice overexpressing the human HF gene (hHF-tg). We established two independent hHF-tg mouse lines. Although both lines of hHF-tg mice were viable, they showed reduced body size compared to wild-type (WT) mice at 4-12 weeks of age. Serum iron concentration and blood parameters of hHF-tg mice such as hemoglobin and red blood cell counts were comparable to those of WT mice. At 3-5 weeks of age, hHF tg mice exhibited temporary loss of coat hair on the trunk, but not on the head or face. Histological analyses revealed that although initial hair development was normal, hHF-tg mice had epidermal hyperplasia with hyperkeratosis, dilated hair follicles, bended hair shafts and keratinous debris during the hairless period. In conclusion, we showed that hHF-tg mice exhibited mild growth retardation and temporary hairless phenotype. Our findings highlight the physiological roles of HF and demonstrate that hHF-tg mice are useful for understanding the in vivo functions of HF. PMID- 23111619 TI - Generation of minipigs with targeted transgene insertion by recombinase-mediated cassette exchange (RMCE) and somatic cell nuclear transfer (SCNT). AB - Targeted transgenesis using site-specific recombinases is an attractive method to create genetically modified animals as it allows for integration of the transgene in a pre-selected transcriptionally active genomic site. Here we describe the application of recombinase-mediated cassette exchange (RMCE) in cells from a Gottingen minipig with four RMCE acceptor loci, each containing a green fluorescence protein (GFP) marker gene driven by a human UbiC promoter. The four RMCE acceptor loci segregated independent of each other, and expression profiles could be determined in various tissues. Using minicircles in RMCE in fibroblasts with all four acceptor loci and followed by SCNT, we produced piglets with a single copy of a transgene incorporated into one of the transcriptionally active acceptor loci. The transgene, consisting of a cDNA of the Alzheimer's disease causing gene PSEN1M146I driven by an enhanced human UbiC promoter, had an expression profile in various tissues similar to that of the GFP marker gene. The results show that RMCE can be done in a pre-selected transcriptionally active acceptor locus for targeted transgenesis in pigs. PMID- 23111620 TI - Lysosomal exoglycosidases and cathepsin D in colon adenocarcinoma. AB - INTRODUCTION: Changes in the structure of membrane glycoconjugates and activity of glycosidases and proteases are important in tumor formation. OBJECTIVES: The aim of the study was to compare the specific activity of lysosomal exoglycosidases: N-acetyl-beta-D-hexosaminidase (HEX), its isoenzymes A (HEX A) and B (HEX B), beta-D-galactosidase (GAL), alpha-fucosidase (FUC), and alpha mannosidase (MAN) with the activity of cathepsin D (CD) in serum, urine, and carcinoma tissue of patients with colon adenocarcinoma. PATIENTS AND METHODS: The specific activity of HEX, HEX A, HEX B, GAL, FUC, MAN, and CD was assayed in serum, urine, and carcinoma tissue of 12 patients with colon adenocarcinoma. RESULTS: Lysosomal exoglycosidases and CD have similar specific activity in colon adenocarcinoma tissue and urine, which is higher than their activity in serum (with the exception of the highest specific activity of CD in urine). A positive correlation was observed between the specific activity of CD and that of HEX, HEX A, FUC, and MAN in the carcinoma tissue and urine as well as between CD and GAL in the urine of patients with colon adenocarcinoma. Negative correlations were observed between protein levels and the specific activity of HEX, HEX A, FUC, MAN, and CD in the carcinoma tissue and urine, and between protein levels and GAL in urine. CONCLUSIONS: Increased degradation and remodeling of glycoconjugates in the colon adenocarcinoma tissue is reflected by increased specific activity of exoglycosidases and CD. The results suggest a strong effect of exoglycosidase action on tissue degradation and a potential role of exoglycosidases in the initiation of proteolysis. PMID- 23111621 TI - Effects of ultraviolet radiation, visible light, and infrared radiation on erythema and pigmentation: a review. AB - The effects of ultraviolet radiation, visible light, and infrared radiation on cutaneous erythema, immediate pigment darkening, persistent pigment darkening, and delayed tanning are affected by a variety of factors. Some of these factors include the depth of cutaneous penetration of the specific wavelength, the individual skin type, and the absorption spectra of the different chromophores in the skin. UVB is an effective spectrum to induce erythema, which is followed by delayed tanning. UVA induces immediate pigment darkening, persistent pigment darkening, and delayed tanning. At high doses, UVA (primarily UVA2) can also induce erythema in individuals with skin types I-II. Visible light has been shown to induce erythema and a tanning response in dark skin, but not in fair skinned individuals. Infrared radiation produces erythema, which is probably a thermal effect. In this article we reviewed the available literature on the effects of ultraviolet radiation, visible light, and infrared radiation on the skin in regards to erythema and pigmentation. Much remains to be learned on the cutaneous effects of visible light and infrared radiation. PMID- 23111622 TI - Greater cardiovascular reactivity to a cold stimulus is due to higher cold pain perception in black Africans: the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study. AB - OBJECTIVE: To evaluate the role of pain perception and pain stimulus components for blood pressure responses to stress in the black and the white African population with hypertension. BASIC METHODS: Cardiovascular regulation in response to a cold pressor stimulus was studied in hypertensive black (n = 110) and white (n = 95) Africans. Perception of stressfulness of the task was assessed on a seven-point Likert scale. Chronic stress levels were evaluated by the General Health Questionnaire and the Coping Strategy Indicator was used to assess individual coping behavior. Autonomic and baroreflex function was evaluated by spectral analysis. MAIN RESULTS: The cold pressor test elicited significant blood pressure elevations with higher relative increases in the black Africans. The higher blood pressure reactivity in black Africans was accompanied by a substantially greater cardiac response and lower parasympathetic outflow as compared with white Africans. Black Africans also reported higher chronic stress levels and rated the stimulus as more painful than their white counterparts. A significant interaction was observed for cardiovascular responses with pain perception but not with chronic stress. Individuals with high pain perception exhibited less dampening of autonomic cardiac exertion than those with low or moderate pain perception. PRINCIPAL CONCLUSION: Black Africans display a more pronounced cold pressor test-induced rise in heart rate and blood pressure, which may be explained by greater pain-related increments in blood pressure. A higher cognitive appraisal of pain and a blunted baroreflex-mediated dampening of autonomic structures may contribute to the exaggerated blood pressure reactivity in black Africans. PMID- 23111623 TI - Sex hormones associated with subclinical kidney damage and atherosclerosis in South African men: the SABPA study. AB - BACKGROUND: Hypertension and increased blood glucose are associated with subclinical kidney damage, atherosclerosis and with low testosterone values. Low testosterone in men is often accompanied by increased levels of estradiol. OBJECTIVES AND METHODS: In this study, the association between estradiol, subclinical kidney damage and atherosclerosis in African and white men in a South African cohort was investigated. Cardiovascular variables were studied by means of B-mode ultrasound and ambulatory blood pressure (BP) monitoring. The sex hormones and other biochemical values were measured from fasting venous blood and overnight urine samples. The ethnic groups were stratified into low and high testosterone groups by means of median split. RESULTS: The low testosterone African group demonstrated a higher cardiovascular risk compared with the low testosterone white men with 91% being hypertensive and having increased albumin to-creatinine ratio (ACR), left carotid intima-media thickness (L-CIMTf) and estradiol-to-testosterone ratio. In the low-testosterone African men, estradiol explained 33% of the variance in ACR, whereas the estradiol-to-testosterone ratio explained 22% of the variance in L-CIMTf, respectively. Estradiol-to-testosterone ratio was positively associated with ACR in the low testosterone whites. CONCLUSION: We conclude that increased levels of estradiol may play a role in the development of subclinical kidney damage in both African and white men as well as atherosclerosis in low-testosterone African men. PMID- 23111624 TI - Gastrointestinal and renal excretion of potassium in African-Americans and White Americans. AB - OBJECTIVE: Several studies have confirmed the remarkable observation that cumulative urinary potassium (K(+)) excretion is less in African-Americans than White Americans even when identical amounts of potassium are provided in the diet. This study was designed to examine whether this decrease in urinary potassium could be compensatory to an increase in gastrointestinal excretion of potassium in African-Americans. METHODS: Twenty-three young, healthy, normotensive participants of both sexes and races were placed on a fixed diet of 100 mEq per day of K(+) and 180 mEq per day of sodium (Na(+)) for 9 days. All urine and stool were collected daily and analyzed for electrolytes. Blood was obtained for determination of electrolytes, blood urea nitrogen (BUN), creatinine, glucose, insulin, renin, and aldosterone at the beginning and at the end of the study period. RESULTS: Cumulative urinary excretion of K(+) was significantly less in African-Americans (609 +/- 31 mEq) compared with White Americans (713 +/- 22 mEq, P = 0.015). There was no significant racial difference, however, in the cumulative gastrointestinal excretion of K (105 +/- 11 versus 95 +/- 9 mEq, P = 0.28) in African-Americans versus White Americans, respectively. CONCLUSION: The racial difference in urinary K(+) handling manifested by decreased excretion of K(+) in African-Americans cannot be attributed to an increase in net gastrointestinal excretion of this cation. PMID- 23111625 TI - Target organ damage assessment in French hypertensive patients without established cardiovascular or renal disease: results of the PREVENT-A study. AB - OBJECTIVES: To evaluate the modalities of subclinical target organ damage (TOD) assessment in France, 2-3 years after publication of the European Society of Hypertension (ESH)/European Society of Cardiology (ESC) 2007 guidelines. METHODS: Two parallel, large, cross-sectional surveys were performed in representative samples of 516 private practice cardiologists, and 943 general practitioners (GPs), in hypertensive patients (952 and 1778, respectively) without established cardiovascular or renal disease. RESULTS: At least one TOD search was performed in 97.6% of cardiologists' patients, performed or ongoing in 96.1% of GPs' patients, with a median number of three TOD searches in both surveys. Only 8.6% of cardiologists' patients and 6.3% of GPs' patients had a full set of TOD analyses [i.e. the five categories investigated: left ventricular hypertrophy (LVH), vascular, renal, retinopathy and cerebrovascular]. When considering the three priority categories of subclinical TOD search recommended by the ESH/ESC guidelines (i.e. LVH, vascular and renal), 63.2% of cardiologists' patients and 49.5% of GPs' patients had this triple assessment completed. The new TOD assessment modalities, namely pulse wave velocity, ankle brachial index and microalbuminuria, were rarely used. Only 3.3% of GPs' patients and 15.4% of cardiologists' patients were reclassified with an upgraded cardiovascular risk. CONCLUSION: Subclinical TOD modalities are commonly assessed in French hypertensive patients without established cardiovascular or renal diseases, although 55% still do not benefit from combined triple LVH, macrovascular and renal assessment. The new modalities of TOD assessment are rarely implemented. Moreover, TOD assessment displayed poor effectiveness in upgrading cardiovascular risk classification. PMID- 23111626 TI - Thermodynamics and molecular dynamics simulations of calcium binding to the regulatory site of human cardiac troponin C: evidence for communication with the structural calcium binding sites. AB - Human cardiac troponin C (HcTnC), a member of the EF hand family of proteins, is a calcium sensor responsible for initiating contraction of the myocardium. Ca(2+) binding to the regulatory domain induces a slight change in HcTnC conformation which modifies subsequent interactions in the troponin-tropomyosin-actin complex. Herein, we report a calorimetric study of Ca(2+) binding to HcTnC. Isotherms obtained at 25 degrees C (10 mM 2-morpholinoethanesulfonic acid, 50 mM KCl, pH 7.0) provided thermodynamic parameters for Ca(2+) binding to both the high affinity and the low-affinity domain of HcTnC. Ca(2+) binding to the N-domain was shown to be endothermic in 2-morpholinoethanesulfonic acid buffer and allowed us to extract the thermodynamics of Ca(2+) binding to the regulatory domain. This pattern stems from changes that occur at the Ca(2+) site rather than structural changes of the protein. Molecular dynamics simulations performed on apo and calcium-bound HcTnC(1-89) support this claim. The values of the Gibbs free energy for Ca(2+) binding to the N-domain in the full-length protein and to the isolated domain (HcTnC(1-89)) are similar; however, differences in the entropic and enthalpic contributions to the free energy provide supporting evidence for the cooperativity of the C-domain and the N-domain. Thermograms obtained at two additional temperatures (10 and 37 degrees C) revealed interesting trends in the enthalpies and entropies of binding for both thermodynamic events. This allowed the determination of the change in heat capacity (?C(p)) from a plot of ?H verses temperature and may provide evidence for positive cooperativity of Ca(2+) binding to the C-domain. PMID- 23111627 TI - Binding properties of Ru(II) polypyridyl complexes with poly(U).poly(A)*poly(U) triplex: the ancillary ligand effect on third-strand stabilization. AB - The binding properties of [RuL(2)(mip)](2+) {where L is 1,10-phenanthroline (phen) or 4,7-dimethyl-1,10-phenanthrollne (4,7-dmp) and mip is 2'-(3",4" methylenedioxyphenyl)imidazo[4',5'-f][1,10]phenanthroline} with regard to the triplex RNA poly(U).poly(A)*poly(U) were investigated using various biophysical techniques and quantum chemistry calculations. In comparison with [Ru(4,7 dmp)(2)(mip)](2+), remarkably higher binding affinity of [Ru(phen)(2)(mip)](2+) for the triplex RNA poly(U).poly(A)*poly(U) was achieved by changing the ancillary ligands. The stabilization of the Hoogsteen-base-paired third strand was improved by about 10.9 degrees C by [Ru(phen)(2)(mip)](2+) against 6.6 degrees C by [Ru(4,7-dmp)(2)(mip)](2+). To the best of our knowledge, [Ru(phen)(2)(mip)](2+) is the first metal complex able to raise the third-strand stabilization of poly(U).poly(A)*poly(U) from 37.5 to 48.4 degrees C. The results reveal that the ancillary ligands have an important effect on third strand stabilization of the triplex RNA poly(U).poly(A)*poly(U) when metal complexes contain the same intercalative ligands. PMID- 23111629 TI - Universal logic gates via liquid-electronic hybrid divider. AB - We demonstrated two-input microdroplet-based universal logic gates using a liquid electronic hybrid divider. All 16 Boolean logic functions have been realized by manipulating the applied voltages. The novel platform consists of a microfluidic chip with integrated microdroplet detectors and external electronic components. The microdroplet detectors act as the communication media for fluidic and electronic information exchange. The presence or absence of microdroplets at the detector translates into the binary signal 1 or 0. The embedded micro-mechanical pneumatically actuated valve (PAV), fabricated using the well-developed multilayer soft lithography technique, offers biocompatibility, flexibility and accuracy for the on-chip realization of different logic functions. The microfluidic chip can be scaled up to construct large-scale microfluidic logic computation. On the other hand, the microfluidic chip with a specific logic function can be applied to droplet-based chemical reactions for on-demand bio or chemical analysis. Our experimental results have presented an autonomously driven, precision-controlled microfluidic chip for chemical reactions based on the IF logic function. PMID- 23111628 TI - Synthesis and structural characterization of soluble neuromelanin analogs provides important clues to its biosynthesis. AB - Elucidating the structure and biosynthesis of neuromelanin (NM) would be an important step towards understanding its putative role in the pathogenesis of Parkinson's disease. A useful complement to studies aimed at unraveling the origin and properties of this essentially insoluble natural substance is the preparation of synthetic derivatives that resemble NM. With this aim in mind, water-soluble conjugates between dopamine-derived melanin and bovine serum albumin (BSA) were synthesized. Melanin-BSA adducts were prepared with both eumelanic oligomers obtained through the oxidative polymerization of dopamine and pheomelanic oligomers obtained under the same conditions from dopamine and cysteine. Iron ions were added during the synthesis to understand the interaction between the pigment and this metal ion, as the NM in neurons in several human brain regions contains significant amounts of iron. The structures of the conjugates were analyzed by (1)H NMR spectroscopy and controlled proteolysis/MS experiments. The binding of iron(III) ions was evaluated by ICP analysis and EPR spectroscopy. The EPR signal from bound iron(III) indicated high-spin octahedral sites and, as also seen for NM, the signal is coupled to a signal from a radical associated with the melanic components of the conjugates. However, the intensity of the EPR signal from iron suggested a reduced fraction of the total iron, indicating that most of the iron is strongly coupled in clusters within the matrix. The amount of paramagnetic, mononuclear iron(III) was greater in the pheomelanin-BSA conjugates, suggesting that iron clustering is reduced in the sulfur-containing pigment. Thus, the melanin-BSA conjugates appear to be good models for the natural pigment. PMID- 23111630 TI - The YidC/Oxa1/Alb3 protein family: common principles and distinct features. AB - The members of the YidC/Oxa1/Alb3 protein family are evolutionary conserved in all three domains of life. They facilitate the insertion of membrane proteins into bacterial, mitochondrial, and thylakoid membranes and have been implicated in membrane protein folding and complex formation. The major classes of substrates are small hydrophobic subunits of large energy-transducing complexes involved in respiration and light capturing. All YidC-like proteins share a conserved membrane region, whereas the N- and C-terminal regions are diverse and fulfill accessory functions in protein targeting. PMID- 23111631 TI - Lewis acid-catalyzed unexpected selective C-C bond cleavage: an efficient and mild construction of cyclopentenes. AB - An intriguing Lewis acid-catalyzed intramolecular ring-opening/cyclization reaction of cyclopropylvinylallenes is developed. This process proceeds at ambient temperature to afford the structurally diverse cyclopentenes exclusively, which demonstrates the unique reactivity of 1,3,4-alkatrien-2-yl cyclopropanes. PMID- 23111632 TI - Quality improvement measures lead to higher surveillance rates for hepatocellular carcinoma in patients with cirrhosis. AB - BACKGROUND: Cirrhosis is a major risk factor associated with the development of hepatocellular carcinoma (HCC). The American Association for the Study of Liver Diseases recommends surveillance for HCC in cirrhosis patients with ultrasound every six months. However, various studies suggest that surveillance rates in actual practice are quite low. AIM: The aims of this study were to evaluate the effectiveness of implementing quality improvement (QI) measures in increasing the rate of HCC surveillance among patients in a tertiary care facility. METHODS: Patients with cirrhosis were prospectively enrolled into a chronic disease management program, which integrates nursing-based protocols with automatic reminders when patients are due for surveillance. Patients enrolled in this program between March 2010 and April 2011 were compared to a prior cohort in 2008 2009. The primary endpoint was the receipt of at least one abdominal imaging study performed for the purposes of surveillance during the study period. RESULTS: Of the 355 patients enrolled, 331 (93 %) had imaging performed for HCC surveillance, compared to 119/160 (74 %) patients in the previous cohort (p < 0.001). Chart review revealed the most common reasons for failure to undergo surveillance were patients' lack of insurance and lack of follow-up on studies ordered at outside institutions. Six patients were diagnosed with HCC during the study period, of which three were at early stage. CONCLUSIONS: Implementation of QI measures incorporating automatic reminders of surveillance status for providers can significantly increase the rate of HCC surveillance among cirrhosis patients. PMID- 23111633 TI - Characterization of a new alginate lyase from newly isolated Flavobacterium sp. S20. AB - Alginate lyase is a promising biocatalyst because of its application in saccharification of alginate for the production of biochemicals and renewable biofuels. This study described the isolation of a new alginate metabolizing bacterium, Flavobacterium sp. S20, from sludge samples and the characterization of its alginate lyase Alg2A. The alginate lyase gene, alg2A, was obtained by constructing and screening the genomic library of the strain S20 and overexpressed in Escherichia coli. Substrate specificity assays indicated Alg2A preferred poly-alpha-L-guluronate as a substrate over poly-beta-D-mannuronate. In the saccharification process of a high content (10 %, w/v) of sodium alginate, the recombinant alginate lyase Alg2A yielded 152 of mM the reducing sugars after 69 h of reaction, and the amounts of oligosaccharides with a different degree of polymerization (DP) generated by Alg2A gradually accumulated without significant variation in the distribution of oligosaccharide compositions. These results indicated that Alg2A possessed high enzymatic capability for saccharifying the alginate, which could be used in saccharifying the alginate biomass prior to the main fermentation process for biofuels. In addition, Alg2A had a different endolytic reaction mode from both the two commercial alginate lyases and other alginate lyases from polysaccharide lyase family 7 owing to high yields of penta , hex-, and hepta-saccharides in the hydrolysis products of Alg2A. Thus, Alg2A could be a good tool for the large-scale preparation of alginate oligosaccharides with high DP. PMID- 23111634 TI - Inhibiting wear particles-induced osteolysis with naringin. AB - PURPOSE: The purpose of this study was to determine the effects of naringin on osteoclastogenesis and osteolysis both in vitro and in vivo. METHODS: In this research osteoclasts were generated from mouse bone marrow monocytes with the receptor activator of NF-KB ligand and the macrophage colony stimulating factor. Naringin, at a concentration of 1, 10, 50, and 100 MUg/mL, was respectively added to the medium. Seven days later, the osteoclasts were determined through tartrate resistant acid phosphatase (TRAP) staining. Mature osteoclasts were isolated from newborn rabbits and cultured for three days on bone slices. Naringin at a concentration of 1, 10, 50, and 100 MUg/mL was respectively added to the medium. The resorption bone slices were quantified, and the area was calculated after toluidine blue and Mayer-hematoxylin staining. Polymethyl methacrylate (PMMA) particles were implanted on the calvariae of C57BL/J6 mice. Naringin, at a dose of 50 MUg/kg and 100 MUg/kg, was respectively given intraperitoneally for seven. Seven days later, the calvariae were removed and processed for pathological analysis. RESULTS: The result indicated that naringin treatment effectively inhibited in vitro osteoclastogenesis and inhibited mature osteoclasts. In vivo data indicated that naringin strongly inhibited PMMA-induced osteolysis. CONCLUSION: Naringin can effectively inhibit osteoclastogenesis and suppress wear particles-induced osteolysis and might be useful in the treatment or prevention of wear particles-induced osteolysis and aseptic loosening for its effect on osteoclast generation and function. PMID- 23111635 TI - Double tension band osteosynthesis in transverse supracondylar distal humerus fractures and nonunions. AB - PURPOSE: The purpose of this study was to evaluate the objective and subjective results achieved after double tension band fixation in transverse extra-articular intracapsular supracondylar distal humerus fractures and nonunions in adults. METHODS: Nine patients presenting six fractures and three nonunions of the distal humerus, treated with double tension band wiring between 1998 and 2011, were retrospectively evaluated. Two fractures were type A2 and four type A3, and the nonunions were oligotrophic; all nine lesions had a supracondylar intracapsular transverse orientation, that passed through the olecranon fossa, in a direction parallel to the joint line, and they compromised both columns of the distal humerus. Patient's age averaged 70 years (range, 56-82). RESULTS: Follow-up averaged 24.6 months (range, 12-53). All fractures and nonunions united; there were no infections, elbow stiffness or heterotopic bone formations. DASH score at final follow-up averaged 14.2 points (range, 4-22). The analog scale of pain averaged 1.1 points (range, 0-3). Elbow range of motion averaged 100 degrees (range, 100-120 degrees ). Flexion averaged 123 degrees (range, 115-130 degrees ) and elbow extension loss averaged 15.5 degrees (range, 10-25 degrees ). CONCLUSIONS: The results achieved with double tension band fixation in transverse extra-articular intracapsular supracondylar distal humerus fractures and nonunions are comparable to the results that can be expected when using other available fixation methods; this technique is faster, less demanding and cheaper, and surgeons should have it in mind when leading with these particular types of distal humerus fractures and nonunions. PMID- 23111636 TI - Seroprevalence of bovine viral diarrhea infection in Yaks (Bos grunniens) on the Qinghai-Tibetan Plateau of China. AB - The seroprevalence of bovine viral diarrhea virus (BVDV) infection in yaks was investigated in Qinghai and Tibet of China during the year 2011. A total of 549 (Tibet 287, Qinghai 262) serum samples was collected from Tibet and Qinghai and were examined for BVDV p80 antibody by ELISA. The results of the experiment showed that 145 (53.65 %) of Tibetan samples and 189 (72.14 %) of Qinghai's samples were positive for BVDV. The observations of the present study suggest that bovine viral diarrhea is common in yaks in Tibet and Qinghai, China. PMID- 23111640 TI - Cooperative formation of silver(I)-mediated base pairs. AB - DNA double helices comprising two neighbouring artificial imidazole-Ag(I) imidazole base pairs incorporate the Ag(I) ions in a cooperative fashion. Isothermal titration calorimetry data confirm the theoretically predicted binding stoichiometry and indicate that Ag(I) binds with association constants >10(6) M( 1) to the metal-free DNA duplex. PMID- 23111639 TI - Direct versus indirect loading of orthodontic miniscrew implants-an FEM analysis. AB - OBJECTIVE: The mesialization of molars in the lower jaw represents a particularly demanding scenario for the quality of orthodontic anchorage. The use of miniscrew implants has proven particularly effective; whereby, these orthodontic implants are either directly loaded (direct anchorage) or employed indirectly to stabilize a dental anchorage block (indirect anchorage). The objective of this study was to analyze the biomechanical differences between direct and indirect anchorage and their effects on the primary stability of the miniscrew implants. MATERIALS AND METHODS: For this purpose, several computer-aided design/computer-aided manufacturing (CAD-CAM)-models were prepared from the CT data of a 21-year-old patient, and these were combined with virtually constructed models of brackets, arches, and miniscrew implants. Based on this, four finite element method (FEM) models were generated by three-dimensional meshing. Material properties, boundary conditions, and the quality of applied forces (direction and magnitude) were defined. After solving the FEM equations, strain values were recorded at predefined measuring points. The calculations made using the FEM models with direct and indirect anchorage were statistically evaluated. RESULTS: The loading of the compact bone in the proximity of the miniscrew was clearly greater with direct than it was with indirect anchorage. The more anchor teeth were integrated into the anchoring block with indirect anchorage, the smaller was the peri implant loading of the bone. CONCLUSIONS: Indirect miniscrew anchorage is a reliable possibility to reduce the peri-implant loading of the bone and to reduce the risk of losing the miniscrew. The more teeth are integrated into the anchoring block, the higher is this protective effect. CLINICAL RELEVANCE: In clinical situations requiring major orthodontic forces, it is better to choose an indirect anchorage in order to minimize the risk of losing the miniscrew. PMID- 23111637 TI - Roles of Wnt signals in bone resorption during physiological and pathological states. AB - Osteoclasts, multinucleated giant cells, are responsible for bone resorption in physiological and pathological conditions such as osteoporosis and rheumatoid arthritis. Osteoclasts develop from the monocyte/macrophage lineage under the strict control of bone-forming osteoblasts. Osteoblast-lineage cells express two cytokines essential for osteoclast differentiation, colony-stimulating factor-1, and receptor activator of nuclear factor kappaB ligand (RANKL) and also express osteoprotegerin, a soluble decoy receptor for RANKL. The signaling molecule Wnt has been shown to be important for the differentiation of osteoblasts through beta-catenin-dependent canonical and beta-catenin-independent noncanonical pathways. Recent studies have established that Wnt-mediated signals are also crucial for bone resorption in both physiological and pathological conditions. In this review, we introduce recent advances in roles of Wnt signaling in bone formation and bone resorption. PMID- 23111641 TI - Pseudolesion in a patient with superior vena cava syndrome. PMID- 23111642 TI - Over-expression of HER2 in Indian patients with gastric cancer. PMID- 23111643 TI - Relevance of cohort studies for the study of transplant infectious diseases. AB - PURPOSE OF REVIEW: The debate on the merits of observational studies as compared with randomized trials is ongoing. We will briefly touch on this subject, and demonstrate the role of cohort studies for the description of infectious disease patterns after transplantation. The potential benefits of cohort studies for the clinical management of patients outside of the expected gain in epidemiological knowledge are reviewed. The newly established Swiss Transplantation Cohort Study and in particular the part focusing on infectious diseases will serve as an illustration. RECENT FINDINGS: A neglected area of research is the indirect value of large, multicenter cohort studies. These benefits can range from a deepened collaboration to the development of common definitions and guidelines. Unfortunately, very few data exist on the role of such indirect effects on improving quality of patient management. SUMMARY: This review postulates an important role for cohort studies, which should not be viewed as inferior but complementary to established research tools, in particular randomized trials. Randomized trials remain the least bias-prone method to establish knowledge regarding the significance of diagnostic or therapeutic measures. Cohort studies have the power to reflect a real-world situation and to pinpoint areas of knowledge as well as of uncertainty. Prerequisite is a prospective design requiring a set of inclusive data coupled with the meticulous insistence on data retrieval and quality. PMID- 23111644 TI - Renal-sparing regimens employing new agents. AB - PURPOSE OF REVIEW: A persistent challenge facing the transplant community is avoiding renal compromise, whether protecting a newly placed kidney allograft or preserving native renal function after another organ has been implanted. One of the principal ways to achieve this is by altering the immunosuppressive regimen. We review some of the more important recent studies in this area. RECENT FINDINGS: Over the past year, two new immunosuppressive agents have received attention. An immunoselective biologic agent, belatacept, continued to demonstrate a sustained benefit in renal function when compared with a cyclosporine-based regimen. In a phase 2 multicenter study, sotrastaurin, a protein kinase C inhibitor, has shown promise in preserving renal graft function but lacks potency as an immunosuppressive agent. A known agent, everolimus, in combination with reduced doses of calcineurin inhibitors or with other agents, continues to be in the forefront as a promising renal-sparing option. Finally, further investigation into mycophenolate mofetil has shown that it has some advantages as a long-term agent when used in monotherapy. SUMMARY: The new therapies investigated show some promise as potential alternative agents. As no drug regimen yet demonstrates an overwhelming benefit over calcineurin inhibitors, particularly regarding overall efficacy, efforts should continue to move forward toward the goal of minimizing chronic kidney disease. PMID- 23111645 TI - Cell transplantation as an initiator of endogenous stem cell-based tissue repair. AB - PURPOSE OF REVIEW: The aim of this review is to summarize recent findings of endogenous cell-based tissue repair triggered by a multitude of approaches, especially stem cell therapy. RECENT FINDINGS: The emerging evidence has demonstrated that an important role of transplanted cells is to act as an initiator to trigger endogenous stem cell-mediated tissue repair after injury. Multiple approaches may orchestrate endogenous regeneration. The low efficacy of endogenous stem cells may be due to deficiency of cytokines to activate and induce endogenous stem cell homing, relatively insufficient endogenous stem cell pool, diseases or aging-related dysfunction of endogenous stem cells, and hostile microenvironments that limit the capacity of endogenous stem cells to repair damaged tissue. In certain situations, external stimulation and/or exogenous stem cells may be required to catalyze the repair. SUMMARY: Endogenous stem cells are playing an important role in tissue repair. An important role of transplanted cells is to act as an initiator to trigger endogenous stem cell-based tissue repair. PMID- 23111646 TI - Hepatitis C and renal transplantation. AB - PURPOSE OF REVIEW: The purpose of this review is to describe the new insights of hepatitis C virus (HCV) infection and renal transplantation. RECENT FINDINGS: HCV is its most frequent cause of liver disease after transplantation. In the long run, HCV infection can lead to cirrhosis, hepatocarcinoma and death in some patients. As interferon is generally contraindicated after transplantation, the best way to treat patients is before transplantation. Long-term patient and graft survival rates are lower in HCV-positive patients than in HCV-negative graft recipients. HCV infection is an independent risk factor for death and graft loss. Mortality is higher, mainly as a result of cardiovascular complications, liver disease and infections but is lower than in HCV-positive patients on the transplant waiting list. New-onset diabetes after transplantation (NODAT), and HCV-related glomerulonephritis, together with chronic rejection and notably transplant glomerulopathy can contribute to graft failure. Despite this factor, transplantation is the best option for the HCV-positive patient on dialysis. Renal transplantation with kidneys from donors with positive anti-HCV antibodies into HCV RNA-positive recipients seems to be safe in the long term. SUMMARY: Renal transplantation is the therapy of choice for dialysis patients with HCV infection. To improve the results, a careful follow-up in the outpatient clinic for early detection of HCV-related complications is mandatory. PMID- 23111647 TI - Allogeneic stem cell transplantation for ischemic myocardial dysfunction. AB - PURPOSE OF REVIEW: Stem cell therapy for the treatment of cardiovascular disease is rapidly moving from bench to bedside. In the settings of acute and chronic myocardial injury, approaches to treatment have explored various cell populations, delivery methods, and times of administration. RECENT FINDINGS: Although initial studies in patients were performed with unfractionated bone marrow cells, further investigations in animal models of myocardial disease have elucidated mechanisms of benefit and opened doors to treatment strategies with stem cells of varied derivation. SUMMARY: Allogeneic stem cell populations have demonstrated therapeutic promise in ischemic heart disease, without a requirement for immunosuppressive drugs, and offer the potential to create large-scale, cryopreserved banks of cells for 'off the shelf' utility. PMID- 23111648 TI - Evaluation of the ENPP1 and PLIN single nucleotide polymorphisms with type 2 diabetes in a Taiwanese population: evidence for replication and gene-gene interaction. AB - BACKGROUND: Addressing gene-gene interactions is essential in defining a trait implicating complex disease-related mechanisms. In this study, we aimed to explore both main effects of single-locus and multi-locus interactions to test the hypothesis that the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) and perilipin (PLIN) genes may contribute to the etiology of type 2 diabetes (T2D) independently and/or through complex interactions in a Taiwanese population. METHODS: There were 416 patients with a diagnosis of T2D and 188 age- and sex-similar control subjects. To investigate gene-gene interactions, we used both the generalized multifactor dimensionality reduction method and logistic regression models. RESULTS: Allelic and genotypic analyses showed significant main effects of ENPP1 rs1044498 (P = 0.000005 and 0.00007, respectively) on the risk of T2D after Bonferroni correction (P < 0.05/2 = 0.025). Compared to the carrier of the AA genotype of the ENPP1 rs1044498 polymorphism, the likelihood of T2D was 2.442 (95% confidence interval, 1.592-3.747) for the carrier of combined AC+CC genotypes after adjustment of sex and body mass index. In addition, the carriers of AA variant in the PLIN rs894160 polymorphism had a higher risk to T2D than those with the combined AG+GG variants (adjusted odds ratio, 1.856; 95% confidence interval, 1.106-3.115) after adjustment of sex and body mass index. Furthermore, the significant 2-locus (P = 0.001) generalized multifactor dimensionality reduction model was identified between ENPP1 and PLIN. Analyses using logistic regression models confirmed the gene-gene interaction. CONCLUSIONS: The results suggest that the ENPP1 and PLIN genes may contribute to the risk of T2D independently and/or in an interactive manner in a Taiwanese population. PMID- 23111649 TI - Echocardiographic evaluation of asymptomatic patients affected by rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) is associated with increased mortality and morbidity because of accelerated atherosclerosis. The study assessed the prevalence of left and right ventricle diastolic and systolic dysfunction in outpatients with RA. METHODS: The study included 93 outpatients with RA. In all patients and control group, echocardiographic conventional and tissue Doppler (TDI) studies were conducted. RESULTS: In the group of RA patients, we found high prevalence of left ventricular systolic and diastolic dysfunction and right diastolic dysfunction compared with controls (13.5% vs 5.5 %, 76.3% vs 48.8% and 41.9% vs 6.6%, respectively; P < 0.001). Rheumatoid arthritis patients and controls showed significant differences about mitral, tricuspid, and pulmonary flow velocity curves; tissue Doppler curves of the lateral and the septal myocardial walls of the left ventricle; and basal myocardial free wall of the right ventricle. There were not any correlations between inflammatory and functional disease parameters and variables of systolic and diastolic function. CONCLUSIONS: Our study shows a high prevalence of left ventricular systolic and diastolic dysfunction in a population of outpatients affected by rheumatoid arthritis. PMID- 23111650 TI - Insulin signaling and insulin resistance. AB - Insulin resistance or its sequelae may be the common etiology of maladies associated with metabolic syndrome (eg, hypertension, type 2 diabetes, atherosclerosis, heart attack, stroke, and kidney failure). It is thus important to understand those factors that affect insulin sensitivity. This review stems from the surprising discovery that interference with angiotensin signaling improves insulin sensitivity, and it provides a general overview of insulin action and factors that control insulin sensitivity. PMID- 23111651 TI - Effect of vitamin D replacement on insulin sensitivity in subjects with vitamin D deficiency. AB - BACKGROUND AND OBJECTIVE: Low vitamin D levels correlate with measures of insulin resistance and prevalence of diabetes mellitus, but there are limited and conflicting data on changes in insulin resistance after vitamin D replacement. The objective of the current study was to examine whether vitamin D replacement improves insulin sensitivity. METHODS: In this randomized double-blind placebo controlled study, 12 healthy subjects with plasma 25-hydroxy vitamin D (25[OH]D) levels of less than 20 ng/mL were treated with ergocalciferol, 50,000 units, orally once a week for 8 weeks or matching placebo. The main outcome measure was insulin-stimulated glucose infusion rate during the last 20 minutes of a hyperinsulinemic-euglycemic glucose clamp study. RESULTS: At baseline, plasma 25(OH)D levels were similar between the ergocalciferol and placebo groups (13.3 +/- 3.8 and 15.7 +/- 2.4 ng/mL, respectively; P = 0.3) but were higher in the ergocalciferol group at 8 weeks (18.8 +/- 5 vs 12.5 +/- 2.2 ng/mL; P = 0.02). Glucose infusion rate was similar between the 2 groups both at baseline and after 8 weeks of treatment. Changes in plasma 25(OH)D levels did not correlate with change in glucose infusion rate. CONCLUSION: Administration of ergocalciferol, 50,000 units, weekly for 8 weeks in subjects with low vitamin D levels improves 25(OH)D levels but does not improve insulin sensitivity. PMID- 23111652 TI - Fasting glucose, obesity, and metabolic syndrome as predictors of type 2 diabetes: the Cooper Center Longitudinal Study. AB - BACKGROUND: To determine risk for type 2 diabetes in subjects with fasting glucose levels in the ranges of normoglycemia, mild hyperglycemia, and intermediate hyperglycemia and to assess the effect of obesity and metabolic syndrome on this risk. SUBJECTS AND METHODS: Incidence of type 2 diabetes mellitus was evaluated in 28,209 relatively healthy subjects participating in the Cooper Center Longitudinal Study. They were included in the study if they had more than 1 fasting plasma glucose measurement, anthropometry, and other parameters of interest. Three subgroups were identified: normoglycemic (<5.6 mmol/L), mild hyperglycemia (5.6-6.0 mmol/L), and intermediate hyperglycemia (6.1 7.0 mmol/L). Diabetes incidence was calculated in categories of sex, age, obesity, and metabolic syndrome status. Incident diabetes was assessed at the earliest clinic visit at which the individual exhibited a blood glucose level of more than 7.0 mmol/L or reported a diagnosis of diabetes. RESULTS: Thirty-one percent of men and 15.9% of women had mild hyperglycemia and 11.9% of men and 3.6% of women had intermediate hyperglycemia. Yearly conversion rates to diabetes were low in individuals with normoglycemia and mild hyperglycemia but were strikingly higher in those with intermediate hyperglycemia. In subjects with intermediate hyperglycemia, presence of obesity and/or metabolic syndrome doubled conversion rates to diabetes. CONCLUSIONS: This study showed a marked difference in outcomes in subjects with mild and intermediate hyperglycemia. Moreover, obesity and metabolic syndrome were associated with strikingly elevated risk for diabetes in subjects with intermediate hyperglycemia. Thus intermediate hyperglycemia plus obesity/metabolic syndrome seemingly justifies intensive clinical intervention for prevention of both diabetes and cardiovascular disease. PMID- 23111654 TI - Anti-livin antibodies in Hashimoto thyroiditis. AB - INTRODUCTION: Livin belongs to the family of apoptosis inhibitors. High livin expression is observed in malignancies of the gastrointestinal tract, lungs, breast, and kidneys, but it is not present in differentiated adult tissues. In some malignant processes, anti-livin antibodies are present. OBJECTIVES: The aim of the study was to evaluate the prevalence of anti-livin antibodies in Hashimoto thyroiditis, a disease characterized by rapid and widespread thyrocyte apoptosis. PATIENTS AND METHODS: The study comprised 65 women with Hashimoto thyroiditis and the control group of 40 healthy women. In the majority of the patients, clinical manifestations of hypothyroidism were observed; all patients had high levels of serum antithyroid peroxidase antibodies. A solid-phase radioimmunoassay in livin coated polyethylene tubes using 125I-labeled protein A was used to determine anti livin antibodies. RESULTS: Significant amounts of anti-livin antibodies were reported in 18 patients (26.8%); 3 patients (4.6%) had borderline antibody levels; while in controls only 1 patient was positive (2.5%, P <0.0001). CONCLUSIONS: In Hashimoto thyroiditis, an autoimmune process is more general and involves numerous autoantibodies including an antibody against apoptosis inhibitor - livin. Anti-livin antibodies cannot serve only as a marker of malignancy because they are also present in autoimmune processes. PMID- 23111653 TI - The Hydra FGFR, Kringelchen, partially replaces the Drosophila Heartless FGFR. AB - Fibroblast growth factor receptors (FGFR) are highly conserved receptor tyrosine kinases, and evolved early in metazoan evolution. In order to investigate their functional conservation, we asked whether the Kringelchen FGFR in the freshwater polyp Hydra vulgaris, is able to functionally replace FGFR in fly embryos. In Drosophila, two endogenous FGFR, Breathless (Btl) and Heartless (Htl), ensure formation of the tracheal system and mesodermal cell migration as well as formation of the heart. Using UAS-kringelchen-5xmyc transgenic flies and targeted expression, we show that Kringelchen is integrated correctly into the cell membrane of mesodermal and tracheal cells in Drosophila. Nevertheless, Kringelchen expression driven in tracheal cells failed to rescue the btl (LG19) mutant. The Hydra FGFR was able to substitute for Heartless in the htl (AB42) null mutant; however, this occurred only during early mesodermal cell migration. Our data provide evidence for functional conservation of this early-diverged FGFR across these distantly related phyla, but also selectivity for the Htl FGFR in the Drosophila system. PMID- 23111655 TI - Healing and expression of growth factors (TGF-beta and PDGF) in canine radial ostectomy gap containing platelet-rich plasma. AB - OBJECTIVES: To evaluate bone healing in an experimental radial ostectomy in dogs treated with autologous platelet-rich plasma (PRP), through histological, densitometric, radiographic studies, as well as expression of growth factors in the ostectomy gap. METHODS: Twenty-one dogs were randomly divided into either a control or a PRP group. All underwent unilateral ostectomy of the radius to generate a gap of 2.0 mm, that was stabilized with external skeletal fixation. The ostectomy gap was either filled with PRP or left empty as a control. The radiographic and densitometric studies were performed after surgery, then at intervals until 60 days during the post-surgery period. Histological and immunohistochemical evaluations were performed at seven or 60 days post-surgery. Analyses were performed using a statistical analysis system, and the level of significance was set at p <0.05. RESULTS: The median radiographic healing score in the PRP group increased significantly between day 0 and day 60. Furthermore, at 60 days, the median healing score and the proportion of healed ostectomies in the control group (score 1; 1/6 healed) and the PRP group (score 5; 4/5 healed) were significantly different. There were differences between groups in radiographic and densitometric values at days 45 and 60. The histological evaluation showed advanced bone healing at 60 days in the PRP group and signs of delayed union in the control group. CLINICAL RELEVANCE: Platelet-rich plasma can be used as an adjuvant therapy because it may promote better bone healing of a radial ostectomy treated with external skeletal fixation in dogs. PMID- 23111656 TI - Coping with job stress by hospital doctors: a comparative study. AB - BACKGROUND: Currently only few studies exists focusing on cross-cultural differences in job stress and stress management. The present study aimed to examine and compare job stress and coping behaviour of Australian and German physicians. METHODS: The present study was designed as a cross-sectional comparison using questionnaire data of 310 German and 256 Australian hospital doctors. The questionnaires contained items on demography and self-rated subjective coping strategies. The Perceived Stress Questionnaire (PSQ) and the Brief COPE Questionnaire were used to analyze national differences in coping behaviour. RESULTS: According to the comparison, German physicians perceived higher values of job stress. Coping behaviour differed significantly between the two doctor samples. CONCLUSIONS: This study demonstrated a number of similarities, but also some unexpected differences in Australian and German doctors' job stress and coping strategies. These findings may help direct further research on cross-cultural investigations and health promotion interventions in both countries. PMID- 23111657 TI - A clinical trial of intravenous peramivir compared with oral oseltamivir for the treatment of seasonal influenza in hospitalized adults. AB - BACKGROUND: Seasonal interpandemic influenza causes >200,000 annual hospitalizations in the United States. Optimal antiviral treatment in hospitalized patients is not established. METHODS: During three interpandemic influenza seasons, 137 patients hospitalized with suspected acute influenza were randomized to 5-day treatment with intravenous peramivir 400 mg or 200 mg once daily or oral oseltamivir 75 mg twice daily. Time to clinical stability and quantitative changes in viral titres from nasopharyngeal specimens were primary and key secondary end points, respectively. RESULTS: Infection was confirmed in 122 patients with influenza A (H1N1), influenza A (H3N2) or influenza B. Median times (95% CI) to clinical stability were 37.0 h (22.0, 48.7) with peramivir 400 mg, 23.7 h (16.0, 38.9) with peramivir 200 mg and 28.1 h (22.0, 37.0) with oseltamivir (P=0.306). Patients (n=97) who were clinically unstable at enrolment had median times (95% CI) to clinical stability of 24.3 h (21.2, 47.5) with peramivir 400 mg, 31.0 h (17.2, 47.7) with peramivir 200 mg and 35.5 h (23.3, 37.9) with oseltamivir (P=0.541). Titres of influenza A viruses in nasopharyngeal specimens decreased similarly across treatments, but more rapid decreases in titres of influenza B occurred with peramivir treatment. There were no deaths among patients with confirmed influenza and the incidence of adverse events was low and generally similar among treatment groups. CONCLUSIONS: Treatment of acute seasonal influenza in hospitalized adults with either peramivir or oseltamivir resulted in generally similar clinical outcomes. Treatment with peramivir was generally safe and well tolerated and could be of benefit in this population. PMID- 23111658 TI - Objective assessment of the human visual attentional state. AB - PRIMARY OBJECTIVE: The purpose of this study was to develop an objective way to assess human visual attention using the alpha-band component of the visual-evoked potential (VEP). DESIGN AND METHODS: Six different attentional conditions were tested: eyes-open, eyes-closed, eyes-closed with backwards number counting, and three rapid-serial visual presentation (RSVP) tasks. Eighteen visually normal, young-adult subjects (ages 21-28 years) were tested binocularly at 1 m for each condition on two separate days. The DiopsysTM NOVA-TR system was used to obtain the visual-evoked potential (VEP) and extracted alpha wave and its related power spectrum. Additionally, the Visual Search and Attention Test (VSAT) was administered as a subjective measure of visual attention. RESULTS: Subjects exhibited significant decreases in power in the alpha band when comparing the eyes-closed with the eyes-open conditions, with power in the eyes-closed condition being, on average, twice as large. The response from the other four conditions did not reflect the differential attentional demands. The ratio of the power in the eyes-closed condition to the eyes-open condition in the lower-alpha frequencies (8-10 Hz) was found to be significantly correlated with the group's performance on the VSAT, especially the 10-Hz component. CONCLUSIONS: An individual's ability to attenuate their alpha component during visual processing may be a predictor of their visual attentional state. These findings solidify the role of the VEP alpha subcomponent as an objective electrophysiological correlate of visual attention, which may be useful in the diagnosis and treatment of human visual attention disorders in the future. PMID- 23111659 TI - Photoinitiated intramolecular diradical cross-linking of polyproline peptides in the gas phase. AB - Polyproline is a fascinating polymer with interesting structural properties that have been studied in both solution and the gas phase. Herein, a method capable of measuring structural dynamics over long timescales is developed and applied to examination of polyproline in the gas phase. This method is based on measuring the probability of two radicals recombining to form a new covalent bond within a single molecule, which provides distance constraint information. To examine polyproline peptides of various lengths, radical precursors were selectively placed at the termini. Photoactivation with 266 nm light can then be used to create a diradical species, and recombination of the two radicals can be used to evaluate end-to-end distances and structural flexibility. The results reveal that interaction of the polyproline termini is more favorable for shorter chain lengths and lower charge states. As charge states increase, Coulombic repulsion favors formation of more extended structures where the termini no longer come in close contact. With increasing chain length, the greater conformational space also appears to decrease the likelihood of the termini being able to recombine. The amount of radical recombination observed for short polyproline peptides in low charge states is not consistent with what would be expected for helical conformations. Rather, molecular mechanics calculations reveal that lower charge state polyproline peptides tends to adopt globular conformations in the gas phase. PMID- 23111660 TI - Leg tendon glands in male bumblebees (Bombus terrestris): structure, secretion chemistry, and possible functions. AB - Among the large number of exocrine glands described in bees, the tarsal glands were thought to be the source of footprint scent marks. However, recent studies showed that the compounds used for marking by stingless bees are secreted by leg tendon instead of tarsal glands. Here, we report on the structure of leg tendon glands in males of Bombus terrestris, together with a description of the chemical composition of their secretions and respective changes of both during the males' lives. The ultrastructure of leg tendon glands shows that the secretory cells are located in three independent regions, separated from each other by unmodified epidermal cells: in the femur, tibia, and basitarsus. Due to the common site of secretion release, the organ is considered a single secretory gland. The secretion of the leg tendon glands of B. terrestris males differs in its composition from those of workers and queens, in particular by (1) having larger proportions of compounds with longer chain lengths, which we identified as wax esters; and (2) by the lack of certain hydrocarbons (especially long chain dienes). Other differences consist in the distribution of double bond positions in the unsaturated hydrocarbons that are predominantly located at position 9 in males but distributed at seven to nine different positions in the female castes. Double bond positions may change chemical and physical properties of a molecule, which can be recognized by the insects and, thus, may serve to convey specific information. The function of male-specific compounds identified from their tendon glands remains elusive, but several possibilities are discussed. PMID- 23111661 TI - Decitabine in patients with relapsed acute myeloid leukemia (AML) after allogeneic stem cell transplantation (allo-SCT). PMID- 23111662 TI - New kinase inhibitor approved for CML. PMID- 23111663 TI - Trauma experts urge cautious use of i.v. fluids. PMID- 23111664 TI - Poor medication adherence remains a problem. PMID- 23111665 TI - Phenylephrine injection may yet become legitimate. PMID- 23111667 TI - Silibinin for cyclopeptide mushroom poisonings. PMID- 23111668 TI - Pilot of a patient-centered pharmacy practice model. PMID- 23111670 TI - Declining susceptibilities of gram-negative bacteria to the fluoroquinolones: effects on pharmacokinetics, pharmacodynamics, and clinical outcomes. AB - PURPOSE: Published evidence of rising gram-negative bacterial resistance to fluoroquinolone therapy is reviewed, with a focus on the potential need for revising pharmacokinetic-pharmacodynamic (PK-PD) targets in order to maintain acceptable clinical outcomes. SUMMARY: With a more than threefold increase in fluoroquinolone use among U.S. adults since the introduction of second- and third generation (i.e., "respiratory") fluoroquinolones 15 years ago, surveillance data indicate a decline in some gram-negative organisms' susceptibility to this antimicrobial class. These trends have raised concerns that the need to attain higher organism-specific minimum inhibitory concentrations (MICs) may lead to worse patient outcomes, even when MIC values are below current established "clinical breakpoints" for fluoroquinolone susceptibility. A growing body of evidence from PK-PD studies suggests that current fluoroquinolone dosing regimens are no longer adequate to achieve validated PK-PD targets. For example, a Monte Carlo simulation using PK data from U.S. hospitals showed decreasing rates of response to standard ciprofloxacin and levofloxacin i.v. dosing regimens among patients treated for infections with Escherichia coli and Klebsiella species. These findings suggest that currently accepted PK-PD targets may need to be revised for certain patient populations, including patients with bloodstream infections (BSIs). More research is needed to confirm the appropriateness of adjusting clinical breakpoints and other strategies to combat rising fluoroquinolone resistance. CONCLUSION: The use of the fluoroquinolones has markedly increased since the introduction of the respiratory fluoroquinolones. Surveillance data and PK-PD studies have raised concerns about suboptimal patient outcomes with the use of fluoroquinolones for some gram-negative infections, particularly BSIs. PK-PD goals and clinical breakpoints may need to be revised for these infections. PMID- 23111671 TI - Antipsychotic treatment response in schizophrenia. AB - PURPOSE: Research supporting the "early-onset" theory of antipsychotic activity is reviewed, with an emphasis on psychometric assessment of early response to antipsychotic agents as a tool for optimizing schizophrenia treatment outcomes. SUMMARY: A growing body of evidence indicates that a poor response to antipsychotic therapy in the first weeks of schizophrenia treatment may justify a prompt switch to alternative medication in some cases. In placebo-controlled trials of both first- and second-generation antipsychotics, nonresponse at week 1 or 2, as determined with assessment instruments such as the Brief Psychiatric Rating Scale (BPRS) and the Positive and Negative Syndrome Scale (PANSS), was found highly predictive of nonresponse at week 4 or later; however, an early favorable response to a particular antipsychotic agent does not appear to be a similarly strong predictor of continued responsiveness. While the available evidence indicates that the BPRS, PANSS, and other scoring tools can be useful in guiding schizophrenia treatment decisions, it also emphasizes the importance of patient-specific factors (e.g., severity of illness at diagnosis, age at symptom onset, premorbid adolescent functioning) as determinants of both initial and longer-term antipsychotic response. CONCLUSION: The current evidence suggests that early nonresponse to antipsychotic treatment may predict subsequent non response, though early response is not necessarily indicative of future response. If patients do not respond to treatment within the first two weeks of an acute exacerbation, clinicians (being cognizant of patient-specific factors) should consider switching antipsychotic agents, except in patients with first-episode psychosis, for whom a longer trial of the initially prescribed therapy appears to be appropriate. PMID- 23111672 TI - Seizure activity during cetuximab infusion in a patient with metastatic colorectal cancer. AB - PURPOSE: The case of a patient with metastatic colorectal cancer who had a seizure during his intial cetuximab infusion is reported. SUMMARY: A 54-year-old Asian man received his first infusion of cetuximab after pretreatment with ondansetron, ranitidine, diphenhydramine, and dexamethasone. Approximately 15 minutes after initiation of the cetuximab infusion, the patient called for help. The nurse found the patient sitting up with a blank stare, and the patient began to have a generalized seizure. The emergency resuscitation team was called and administered lorazepam 2 mg i.v., at which time the seizure ceased. The patient required emergent intubation, but no cardiopulmonary resuscitation was necessary. After intubation, the patient was transferred to the intensive care unit. Computed tomography of the head found no evidence of lesions. The patient remained stable, was extubated, and was transferred out of the intensive care unit the next day. Fourteen days after the seizure, the patient returned for follow-up magnetic resonance imaging of the brain and head with gadolinium contrast. Per the radiologist's report, there were no enhancing lesions to suggest metastases, no abnormalities to suggest infarct or tumor, and no bone abnormalities, and the patient's brain volume was within normal limits for his age. Based on the Naranjo et al. probability scale score, the relationship between the patient's seizure and cetuximab infusion was probable. CONCLUSION: A 54-year-old Asian man developed seizure activity requiring emergent intubation during his initial cetuximab infusion for the treatment of metastatic colorectal cancer. PMID- 23111673 TI - Fall risk associated with inpatient medications. AB - PURPOSE: The association between fall risk and inpatient medications was evaluated. METHODS: A retrospective, case-control study was performed to compare the medication use of patients sustaining at least one fall during hospitalization (case group) with a control group of patients who did not fall. Data were collected from medical records and generated reports. A fall was defined by the hospital as an event in which the patient comes to rest on the floor from a lying, standing, or sitting position. Adult patients (>=18 years of age) admitted between January 1 and December 31, 2006, experiencing a fall at least 48 hours after hospital admission were included in the case group. Each case was matched with one control by age (within five years), sex, admission date (within 30 days), patient care unit, and length of stay. Medications administered within 48 hours before the fall for the case group or designated fall date and time for the control group were documented. RESULTS: Of the 414 documented fall events, 209 patients met the inclusion criteria. Of those patients, 96 matched control patients on all criteria. Significantly more case patients received a greater number of central nervous system (CNS) agents compared with matched control patients (p = 0.017). There was no statistically significant difference in the number of medications from all other drug classes or the total number of medications received by the groups. CONCLUSION: In a sample of hospitalized patients, CNS agents were significantly associated with falls. PMID- 23111674 TI - National survey on continuous and extended infusions of antibiotics. AB - PURPOSE: A national survey was conducted to evaluate the use of continuous and extended infusions for administering beta-lactams and vancomycin. METHODS: The survey was sent to a random sample of 1000 acute care hospital pharmacists in the United States to evaluate the use of continuous and extended infusions of antibiotics. In addition, the same survey was sent to members of the Society of Infectious Diseases Pharmacists (SIDP) to assess the adoption of these infusion strategies. RESULTS: In the random-sample survey, 29 (11.2%) and 15 (5.8%) hospitals reported using continuous and extended infusions, respectively. Common rationales for adopting continuous and extended infusions were greater efficacy, equal or less toxicity, and cost savings. The SIDP survey revealed that 30 (50%) and 21 (35%) of responding pharmacists have initiated continuous and extended infusions, respectively. Common rationales for adopting continuous and extended infusions were greater efficacy, equal or less toxicity, and cost savings. Both surveys found that penicillins were the antibiotics most frequently administered as continuous and extended infusions. CONCLUSION: The results of a survey sent to a random sample of hospital pharmacists and to SIDP members indicated that the majority did not use either continuous or extended infusions of antibiotics. SIDP survey respondents more frequently reported the use of both continuous and extended infusions than the respondents of the random-sample survey, and the percentage of time above the minimum inhibitory concentration was the most frequently assessed pharmacokinetic-pharmacodynamic parameter for both groups. PMID- 23111675 TI - Creating learning opportunities for pharmacy students through an observership program. AB - PURPOSE: The development, implementation, challenges, and future opportunities associated with a pharmacy observership program are described. SUMMARY: In the summer of 2010, the pharmacy observership committee at The Methodist Hospital created a formalized, institution-based pharmacy observership program to introduce first-and second-year pharmacy students to the diverse areas of pharmacy practice. The two-month experience includes opportunities for students to participate in various departmental research projects and to observe the responsibilities of pharmacy staff. Four students have completed the observership program thus far. All observers commented that the program was a valuable introduction to hospital pharmacy. Feedback was obtained from the observers and each preceptor. Limitations of the program include a lack of funding for parking and lodging expenses, a lack of pagers, and a lack of a stipend for the observers. Although there was not an established budget for the program, our perceived costs were approximately $10,000. CONCLUSION: An observership program was established to allow first- and second-year pharmacy students to gain exposure to various aspects of hospital pharmacy outside of a formal internship. PMID- 23111676 TI - Impact of a rapid peptide nucleic acid fluorescence in situ hybridization assay on treatment of Candida infections. AB - PURPOSE: The impact of a rapid peptide nucleic acid fluorescence in situ hybridization (PNA FISH) assay with an antimicrobial stewardship intervention on the treatment of Candida infections was studied. METHODS: The utility of implementing the PNA FISH assay with an antimicrobial stewardship intervention in hospitalized patients with candidemia was evaluated by measuring the median time to Candida species identification, time to targeted therapy, and clinical outcomes, including time to culture clearance, hospital length of stay, and hospital mortality. Secondary objectives included determining the cost effectiveness of the PNA FISH assay by assessing estimated antifungal drug costs (as average wholesale price) before (June 26, 2009-September 19, 2010) and after (September 20, 2010-June 13, 2011) test implementation and confirming test accuracy. For both groups, laboratory personnel notified the physician of the results of Gram's stain from blood culture. RESULTS: Time to targeted therapy significantly decreased after the implementation of the PNA FISH assay (p = 0.0016). The postimplementation group had a higher rate of culture clearance (p = 0.01). Median time to species identification was 0.2 day with the PNA FISH test versus 4 days with routine methods (p < 0.001). Accounting for the cost of the test itself and the cases in which patients were switched to more-expensive therapy on the basis of the test, we estimated that the PNA FISH test resulted in savings of approximately $415 per patient. CONCLUSION: Implementing a PNA FISH test to identify Candida species from yeast-positive blood cultures in conjunction with a pharmacy-driven antimicrobial stewardship protocol decreased the time to targeted antifungal therapy and the time to culture clearance. PMID- 23111677 TI - Leveraging drug-utilization and external benchmarking data to drive change in prescribing behaviors. AB - PURPOSE: Improved outcomes and cost savings achieved at a large hospital through a drug utilization benchmarking and reporting initiative are described. SUMMARY: Using the University HealthSystem Consortium (UHC) Clinical Resource Manager (CRM) database, the University of Kansas Hospital identified nine target areas (based on Medicare Severity Diagnosis-Related Group) in which the hospital's drug utilization practices were deemed suboptimal relative to those of other UHC member facilities with similar caseloads. The pharmacy department developed a CRM template for generating customized reports comparing the hospital's performance on various drug-utilization metrics with that of top-performing peers (i.e., institutions achieving the best patient care outcomes in terms of mortality and length of stay) in the nine target areas. A pre-post comparison of drug utilization data collected before and after implementation of the reporting initiative indicated improved outcomes in all nine initially selected target areas, with estimated cumulative annualized cost savings of about $900,000. The CRM-generated reports are now distributed semiannually to attending physicians and other hospital leaders via electronic and hard-copy means, focusing on variances from UHC top-performer and overall UHC averages in the use of higher cost drugs. The reporting initiative has generally fostered enhanced physician pharmacist collaboration in the investigation of identified drug-utilization variances and implementation of practice changes. CONCLUSION: By evaluating service-specific trends of internal drug utilization against external benchmarks and emulating prescribing practices at top-performing institutions, an academic medical center has achieved improved patient care outcomes and cost savings. PMID- 23111678 TI - Minocycline attenuates mechanical allodynia and expression of spinal NMDA receptor 1 subunit in rat neuropathic pain model. AB - Recent studies have indicated that minocycline, a microglia inhibitor, could potentially be used as an antinociceptive agent in pain management, although the underlying mechanisms remain elusive. In this study, we investigated the extent to which minocycline could influence pain behavior in association with the expression of the N-methyl-D-aspartic acid receptor 1 (NMDAR1) in a rat L5 spinal nerve ligation (SNL) model. We observed that the intrathecal injection of minocycline significantly attenuated mechanical allodynia in a rat SNL model from day 1 postinjection and persisted for at least 18 days. We also observed that the expression of NMDAR1 was increased in the spinal dorsal horn at 8 days after SNL, which could be partly inhibited through the intrathecal injection of minocycline. These findings suggest that the attenuation of allodynia in the SNL model following minocycline administration might be associated with the inhibited expression of NMDAR1 and, therefore, might play an important role in the minocycline-mediated antinociception. PMID- 23111679 TI - Genomic disorders on chromosome 22. AB - PURPOSE OF REVIEW: Chromosome 22, the first human chromosome to be completely sequenced, is prone to genomic alterations. Copy-number variants (CNVs) are common because of an enrichment of low-copy repeat sequences that precipitate a high frequency of nonallelic homologous misalignments and unequal recombination during meiosis. Among these is one of the most common multiple anomaly syndromes in humans and the most common microdeletion syndrome, velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome and DiGeorge syndrome. This review will focus on the recent literature dealing with both the molecular and clinical aspects of chromosome 22 genomic variations. Although the literature covering this area is expansive, the majority is descriptive or analytical of the problems presented by these genomic disorders, and there is little evidence of translational research including treatment outcomes. RECENT FINDINGS: With the increased use of microarray analysis in both research and clinical practice, variations in CNVs are becoming elucidated. Genomic analysis continues to characterize genes and gene effect. Research on the COMT gene continues to yield interesting findings, including a possible sex-mediated effect because of its regulatory role with estrogen. There is a small amount of treatment outcome data relevant to neuropsychiatric disorders in VCFS, but based on small samples and short-term follow-up. SUMMARY: Although hundreds of studies in the past year have focused on genomic disorders of chromosome 22, little progress has been made in the implementation of translational research, even for more common disorders including VCFS. PMID- 23111680 TI - Complementary and alternative therapies for children and adolescents with ADHD. AB - PURPOSE OF REVIEW: To provide a comprehensive review of complementary and alternative medicine (CAM) treatments for children and adolescents with attention deficit hyperactivity disorder (ADHD). RECENT FINDINGS: Many parents of children with ADHD are reluctant to pursue medication options and unable to access behavioral counseling. CAM therapies are often appealing to families and studies show that a large percentage of children with ADHD are treated with one or more CAM therapy. Most research studies evaluating CAM therapies are methodologically flawed, and often times there are inconsistencies across either study design or results. Although the American Academy of Pediatrics does not recommend any CAM therapies for ADHD, essential fatty acid supplementation is likely well tolerated and modestly effective. SUMMARY: Most complementary and alternative treatments do not have adequate research to recommend their use in children with ADHD. Physicians should be aware of the many CAM treatment options and the research surrounding them in order to provide their patients with the most current and accurate information available. PMID- 23111682 TI - Sport-related concussion: time to take notice. PMID- 23111681 TI - Normal neonatal microbiome variation in relation to environmental factors, infection and allergy. AB - PURPOSE OF REVIEW: Bacterial colonization of the infant intestinal tract begins at birth. We are at the forefront of understanding complex relationships between bacteria and multiple parameters of health of the developing infant. Moreover, the establishment of the microbiome in the critical neonatal period is potentially foundational for lifelong health and disease susceptibility. Recent studies utilizing state-of-the-art culture-independent technologies have begun to increase our knowledge about the gut microbiome in infancy, the impact of multiple exposures, and its effects on immune response and clinical outcomes such as allergy and infection. RECENT FINDINGS: Postnatal exposures play a central role in the complex interactions between the nearly blank canvas of the neonatal intestine, whereas genetic factors do not appear to be a major factor. Infant microbial colonization is affected by delivery mode, dietary exposures, antibiotic exposure, and environmental toxicants. Successive microbiome acquisition in infancy is likely a determinant of early immune programming, subsequent infection, and allergy risk. SUMMARY: The novel investigation of the neonatal microbiome is beginning to unearth substantial information, with a focus on immune programming that coevolves with the developing microbiome early in life. Several exposures common to neonatal and infant populations could exert pressure on the development of the microbiome and major diseases including allergy and infection in large populations. PMID- 23111683 TI - Comparison of volatile blends and nucleotide sequences of two Beauveria bassiana isolates of different virulence and repellency towards the termite Macrotermes michealseni. AB - Isolates of the fungus Beauveria bassiana have different levels of virulence and repellency against the termite Macrotermes michaelseni. In the present study, we compared the volatile profiles and gene sequences of two isolates of the fungus with different levels of virulence and repellence to the termite. Gas chromatography-mass spectrometric analyses showed quantitative and qualitative differences in the composition of volatiles of the two isolates. The repellencies of synthetic blends of 10 prominent components that mimicked the volatiles of each of the two isolates were significantly different. Subtractive bioassays showed that the repellency of each isolate was due to synergistic effects of a few constituents. As previously reported for isolates of Metarhizium anisopliae, some differences also were found in the nucleotide sequences of the two isolates of B. bassiana, suggesting a genetic basis for the observed intra-specific differences in their repellency and virulence against the termite. PMID- 23111684 TI - Theoretical investigation of a novel high density cage compound 4,8,11,14,15 pentanitro-2,6,9,13-tetraoxa-4,8,11,14,15 pentaazaheptacyclo[5.5.1.1(3,11).1(5,9)] pentadecane. AB - A novel polynitro cage compound 4,8,11,14,15-pentanitro-2,6,9,13-tetraoxa 4,8,11,14,15-pentaazaheptacyclo [5.5.1.1(3,11).1(5,9)]pentadecane(PNTOPAHP) has been designed and investigated at the DFT-B3LYP/6-31(d) level. Properties, such as electronic structure, IR spectrum, heat of formation, thermodynamic properties and crystal structure have been predicted. This compound is most likely to crystallize in C2/c space group, and the corresponding cell parameters are Z = 8, a = 29.78 A, b = 6.42 A, c = 32.69 A, alpha = 90.00 degrees , beta = 151.05 degrees , gamma = 90.00 degrees and rho = 1.94 g/cm(3). In addition, the detonation velocity and pressure have also been calculated by the empirical Kamlet-Jacobs equation. As a result, the detonation velocity and pressure of this compound are 9.82 km/s, 44.67 GPa, respectively, a little higher than those of 4,10-dinitro-2,6,8,12-tetraoxa-4,10-diazaisowurtzitane(TEX, 9.28 km/s, 40.72 GPa). This compound has a comparable chemical stability to TEX, based on the N NO(2) trigger bond length analysis. The bond dissociation energy ranges from 153.09 kJ mol(-1) to 186.04 kJ mol(-1), which indicates that this compound meets the thermal stability requirement as an exploitable HEDM. PMID- 23111685 TI - Probing mechanism of metal catalyzed hydrolysis of Thymidylyl (3'-O, 5'-S) thymidine phosphodiester derivatives. AB - Hydrolysis of nucleic acids is of fundamental importance in biological sciences. Kinetic and theoretical studies on different substrates wherein the phosphodiester bond combined with alkyl or aryl groups and sugar moiety have been the focus of attention in recent literature. The present work focuses on understanding the mechanism and energetics of alkali metal (Li, Na, and K) catalyzed hydrolysis of phosphodiester bond in modeled substrates including Thymidylyl (3'-O, 5'-S) thymidine phosphodiester (Tp-ST) (1), 3'-Thymidylyl (1 trifluoroethyl) phosphodiester (Tp-OCH(2)CF(3)) (2), 3'-Thymidylyl (o cholorophenyl) phosphodiester (Tp-OPh(o-Cl)) (3) and 3'-Thymidylyl(p-nitrophenyl) phosphodiester (Tp-OPh(p-NO(2))) (4) employing density functional theory. Theoretical calculations reveal that the reaction follows a single-step (A(N)D(N)) mechanism where nucleophile attack and leaving group departure take place simultaneously. Activation barrier for potassium catalyzed Tp-ST hydrolysis (12.0 kcal mol(-1)) has been nearly twice as large compared to that for hydrolysis incorporating lithium or sodium. Effect of solvent (water) on activation energies has further been analyzed by adding a water molecule to each metal ion of the substrate. It has been shown that activation barrier of phosphodiester hydrolysis correlates well with basicity of leaving group. PMID- 23111688 TI - Evaluation of vertical forces in the pads of German Shepherd dogs. AB - OBJECTIVE: To evaluate vertical forces in the pads of German Shepherd dogs by relative percentage among total limb vertical forces using a pressure sensitive walkway. PROCEDURE: A pressure sensitive walkway was used to collect vertical force data for each pad of the limbs of 16 healthy client-owned German Shepherd dogs used for kinetic gait analysis. The vertical force for each pad was evaluated as a percentage of total limb vertical force. Weight distribution among limbs was also recorded. Velocity and acceleration were within a range of 1.3 and 1.6 +/- 0.1 m/s2. The ANOVA test was used to compare data and the paired t-test was used to assess symmetry (p <0.05). RESULTS: The peak vertical force was higher on the metacarpal pad than on the metatarsal pad. Peak vertical force was highest on the metacarpal pad and metatarsal pad followed by the digital pads 3, 4 and 5 of the forelimb, and on the hindlimb by digital pads 3 and 4. Vertical impulse was greatest in the metacarpal pad and digital pads 3 and 4 of the forelimb and hindlimb respectively, followed by digital pads 3, 4, and 5 of the forelimb and the metatarsal pad. CONCLUSION AND CLINICAL RELEVANCE: A vertical force distribution pattern was observed on the pads of the German Shepherd dogs. These data are important for improving the understanding of vertical force distribution during gait and to assess orthopaedic conditions. PMID- 23111686 TI - Aerobic exercise in subacute stroke improves cardiovascular health and physical performance. AB - BACKGROUND AND PURPOSE: Cardiovascular health is often impaired after stroke. Reduced exercise capacity ((Equation is included in full-text article.)VO(2peak)) and changes in the vascular system in the stroke-affected limb may impact performance of physical activities such as walking. There is little information regarding the role of prescribed moderate- to high-intensity exercise in subacute stroke. The purpose of this study was to examine whether an 8-week aerobic exercise intervention would improve cardiovascular health and physical performance in participants with subacute stroke. METHODS: Ten subjects were enrolled in the study and 9 of them completed the intervention. Participants were aged 61.2 +/- 4.7 years old, were 66.7 +/- 41.5 days poststroke, and had minor motor performance deficits (Fugl-Meyer score, 100.3 +/- 29.3). Outcome measures were taken at baseline, postintervention, and at 1-month follow-up. Brachial artery vasomotor reactivity (flow-mediated dilation [FMD]) of both arms was used to assess vascular health, and a peak exercise test was used to assess exercise capacity. The 6-minute walk test (6MWT) was used to assess physical performance. Participants exercised on a recumbent stepper 3 times per week for 8 weeks at a prescribed heart rate intensity. RESULTS: At baseline, we identified between-limb differences in brachial artery FMD and low (Equation is included in full-text article.)VO(2peak) values. After the intervention, significant improvements were observed in the FMD in both arms, resting systolic blood pressure, and the 6MWT. Although we also observed improvements in the resting diastolic blood pressure, heart rate, and (Equation is included in full-text article.)VO(2peak) values, these changes were not significantly different. DISCUSSION AND CONCLUSION: Aerobic exercise in participants with subacute stroke was beneficial for improving cardiovascular health, reducing cardiac risk, and improving physical performance (6MWT). PMID- 23111689 TI - Electric field gradients in Hg compounds: molecular orbital (MO) analysis and comparison of 4-component and 2-component (ZORA) methods. AB - We examine the performance of Density Functional Theory (DFT) approaches based on the Zeroth-Order Regular Approximation (ZORA) Hamiltonian (with and without inclusion of spin-orbit coupling) for predictions of electric field gradients (EFGs) at the heavy atom Hg nucleus. This is achieved by comparing with benchmark DFT and CCSD-T data (Arcisauskaite et al., Phys. Chem. Chem. Phys., 2012, 14, 2651-2657) obtained from 4-component Dirac-Coulomb Hamiltonian calculations. The investigated set of molecules comprises linear HgL(2) (L = Cl, Br, I, CH(3)) and bent HgCl(2) mercury compounds as well as the trigonal planar [HgCl(3)](-) system. In 4-component calculations we used the dyall.cv3z basis set for Hg, Br, I and the cc-pCVTZ basis set for H, C, Cl, whereas in ZORA calculations we used the QZ4P basis set for all the atoms. ZORA-4 reproduces the fully relativistic 4 component DFT reference values within 6% for all studied Hg compounds and employed functionals (BH&H, BP86, PBE0), whereas scalar relativistic (SR)-ZORA-4 results show deviations of up to 15%. Compared to our 4-component CCSD-T benchmark the BH&H functional performs best at both 4-component and ZORA levels. We furthermore observe that changes in the largest component of the diagonalised EFG tensor, V(zz), of linear HgCl(2) show a slightly stronger dependence than the r(-3) scaling upon bond length r(Hg-Cl) alterations. The 4-component/BH&H V(zz) value of -9.26 a.u. for a bent HgCl(2) (?Cl-Hg-Cl = 120 degrees ) is close to 9.60 a.u. obtained for the linear HgCl(2) structure. Thus a point charge model for EFG calculations completely fails in this case. By means of a projection analysis of molecular orbital (MO) contributions to V(zz) in terms of the atomic constituents, we conclude that this is due to the increased importance of the Hg 5d orbitals upon bending HgCl(2) compared to the linear HgCl(2) structure. Changing ligand leads to only minor changes in V(zz) (from -9.60 a.u. (HgCl(2)) to -8.85 a.u. (HgI(2)) at the 4-component/BH&H level). This appears to be due to cancellation of contributions with opposite signs to V(zz) arising from: (i) increasing electron donation from occupied ligand orbitals to the formally empty Hg 6p orbitals and (ii) an increasing bond length and a decreasing negative charge on the ligand along the series. PMID- 23111690 TI - Effect of amide-triazole linkers on the electrochemical and biological properties of ferrocene-carbohydrate conjugates. AB - Amide-triazole linker incorporated ferrocene-carbohydrate conjugates were prepared by adopting a regiospecific copper(II)-catalysed 1,3-cycloaddition of ferrocenoyl propargylamide and isopropylidene/acetyl protected carbohydrate azides. Hydrophilic ferrocene glycoside with an amide-triazole linker was synthesised by deacetylation of the hydroxyl groups. All the new compounds were characterised by UV-visible and electrochemical studies and they were found to be stable in organic solvents as well as in the buffer system under physiological conditions (pH = 7.0). The diffusion coefficient (D(f)) of the conjugates was also calculated by means of cyclic voltammetric studies. It was observed that while the molecular weight of the compounds had no significant effect on the diffusion coefficient, the hydrophobic/hydrophilic nature of the carbohydrate scaffold displayed varied diffusion coefficient values. Stabilization of the compounds in buffer solution under physiological pH led to almost identical diffusion coefficient values. The compounds derived from xylose and ribose exhibited cytotoxicity on hormone-dependent and hormone-independent breast cancer cell lines, whereas the conjugates derived from glucose and galactose were found to be non-toxic in nature. The compounds did not show any antimicrobial activity against Gram-positive and Gram-negative pathogens. PMID- 23111691 TI - [Prospective description of the course of psychopathological symptoms in schizophrenia: evaluation of the short form of the Eppendorf Schizophrenia Inventory]. AB - BACKGROUND: The Eppendorf Schizophrenia Inventory (ESI-K) is a self-assessment procedure which can now be considered as the standard procedure in the diagnostics of schizophrenia. It has been evaluated in many studies and is widely used in research and clinical treatment. In contrast little is known about the psychometric characteristics of the short form of the ESI (ESI-K) which was designed in particular for prospective descriptive courses. MATERIALS AND METHODS: The ESI-K was completed for 40 patients with schizophrenia undergoing complete inpatient psychiatric treatment together with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) form and the Nurses' Observation Scale for Inpatient Evaluation (NOSIE). Of the patients 31 participated in a total of 4 measurements at 1-week intervals. RESULTS: The reliability (Cronbachs alpha) of the ESI-K was high at all measurement time points and was comparable to the reliability of the standard version. The reliability of the PANSS was roughly the same level but that of the NOSIE was poor. The ESI-K correlated in particular with cognitive syndrome and the positive syndrome of the PANSS. All four instruments showed a decrease in scores over the observational time period which indicated a decline in the psychopathological symptoms. CONCLUSIONS: The ESI-K is a valid time-saving procedure for documentation of the course of symptoms in patients with schizophrenia. It reflects clinically relevant aspects from the spectrum of psychotic symptoms. PMID- 23111692 TI - Time-resolved three-dimensional phase contrast MRI evaluation of bicuspid aortic valve and coarctation of the aorta. PMID- 23111693 TI - Comparison of three-dimensional echocardiographic software packages for assessment of left ventricular mechanical dyssynchrony and prediction of response to cardiac resynchronization therapy. AB - AIMS: We directly compared TomTec and QLAB software packages for the three dimensional echocardiographic (3DE) assessment of left ventricular (LV) dyssynchrony including their ability to predict response to cardiac resynchronization therapy (CRT) in patients with ischaemic and non-ischaemic cardiomyopathy. METHODS AND RESULTS: A total of 140 heart failure patients with the LVEF <=35% and 60 healthy volunteers underwent 3DE. A subgroup of 60 patients underwent CRT and were evaluated before and 6-12 months after implantation. The systolic dyssynchrony index (SDI) was derived from the dispersion of time to minimum regional volume for all 16 LV segments and measured with both software packages and compared using Pearson's correlation and Bland-Altman analysis. Measurements of SDI were significantly higher using TomTec compared with QLAB in both patients (10.9 +/- 3.8 vs. 9.7 +/- 3.9, P < 0.001) and healthy volunteers (4.1 +/- 0.8 vs. 2.4 +/- 1, P < 0.001), with large biases and wide limits of agreement. A moderate correlation (r = 0.65, P < 0.001) was observed between both software packages in patients while their inter-observer and intra-observer reliability were good. Of the 60 patients undergoing CRT, reverse remodelling as a measure of response was observed in 41 patients (68%). The optimal SDI cut-off value to predict response to CRT was higher for TomTec than for QLAB (8.8 vs.7.3%, P < 0.001) and demonstrated better sensitivity and specificity (93 and 61%, respectively) compared with QLAB (88 and 33%, respectively). Response prediction in patients with non-ischaemic cardiomyopathy was excellent with a sensitivity and specificity of 95 and 100% for TomTec and 70 and 83% for QLAB using similar cut-off values of 9.1 and 9.2%, respectively. CONCLUSION: Different 3DE software packages for the assessment of mechanical dyssynchrony should not be used interchangeably until better software standardization is achieved. Dyssynchrony assessment with 3DE for the prediction of response to CRT seems particularly useful in patients with non-ischaemic cardiomyopathy. PMID- 23111694 TI - Registry for the Evaluation of the PROgnostic value of a novel integrated imaging approach combining Single Photon Emission Computed Tomography with coronary calcification imaging (REPROSPECT). AB - AIMS: Although an added diagnostic and prognostic value of the global coronary artery calcification (CAC) score as an adjunct to single-photon emission computed tomography (SPECT)-myocardial perfusion image (MPI) has been repeatedly documented, none of the previous studies took advantage of the anatomic information provided by the unenhanced cardiac CT. Therefore, no co-registration has so far been used to match a myocardial perfusion defect with calcifications in the subtending coronary artery. To evaluate the prognostic value of integrating SPECT-MPI with CAC images were obtained from non-enhanced cardiac computed tomography (CT) for attenuation correction to predict major adverse cardiac events (MACE). METHODS AND RESULTS: Follow-up was obtained in 462 patients undergoing a 1-day stress/rest (99m)Tc-teterofosmin SPECT and non enhanced cardiac CT for attenuation correction. Survival free of MACE was determined using the Kaplan-Meier method. After integrating MPI and CT findings, patients were divided into three groups (i) MPI defect matched by calcification (CAC >= 1) in the subtending coronary artery (ii) unmatched MPI and CT finding (iii) normal finding by MPI and CT. At a mean follow-up of 34.5 +/- 13 months, a MACE was observed in 80 patients (33 death, 6 non-fatal myocardial infarction, 9 hospitalizations due to unstable angina, and 32 revascularizations). Survival analysis revealed the most unfavourable outcome (P < 0.001 log-rank test) for patients with a matched finding. CONCLUSION: In the present study, a novel approach using a combined integration of cardiac SPECT-CAC imaging allows for refined risk stratification, as a matched defect emerged as an independent predictor of MACE. PMID- 23111695 TI - Ruthenium-catalyzed C-H/O-H and C-H/N-H bond functionalizations: oxidative annulations of cyclopropyl-substituted alkynes. AB - The chemical behavior of cyclopropyl-substituted alkynes has been probed using the reaction conditions of ruthenium-catalyzed oxidative C-H/O-H and C-H/N-H bond functionalizations. The oxidative annulations proceeded with complete conservation of all cyclopropane fragments and allowed for the one-step preparation of synthetically useful cyclopropyl-substituted isocoumarins and isoquinolones with high regioselectivities and chemical yields. The connectivities of the key heterocyclic products were unambiguously established by X-ray diffraction analysis. PMID- 23111696 TI - New parameters in iron metabolism and functional iron deficiency in patients on maintenance hemodialysis. AB - INTRODUCTION: Iron metabolism has been studied for many years. New substances involved in iron metabolism continue to be described. Functional iron deficiency (FID) is characterized by the presence of adequate iron stores (as defined by standard criteria) but insufficient iron mobilization required for erythropoiesis during administration of erythropoiesis-stimulating agents. OBJECTIVES: The aim of the study was to evaluate new parameters of iron metabolism and the prevalence of FID as well as to assess potential correlations in patients on hemodialysis (HD). PATIENTS AND METHODS: The study included 98 patients on maintenance HD. Standard laboratory methods were used to measure the iron status, complete blood count, creatinine, calcium, phosphorus, albumin, intact parathyroid hormone, and lipids. Commercially available kits were used to measure high-sensitivity C reactive protein (hsCRP), interleukin 6 (IL-6), tumor necrosis factor-alpha, N terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF15), bone morphogeneticprotein (BMP6), hemojuvelin, and hepcidin. RESULTS: FID was present in 23% of the patients on HD and was associated with significantly higher serum ferritin, IL-6, hsCRP, hepcidin, and NT-proBNP levels. There were no significant differences in BMP6 and GDF15 levels between patients with and without FID. Patients on HD had increased prevalence of hypertension, diabetes, and left ventricular hypertrophy and required slightly, but insignificantly, higher erythropoietin doses. Predictors of FID included serum iron levels and residual renal function. CONCLUSIONS: FID is present in a substantial proportion of patients on HD, who thus should be screened for reversible causes of inflammation. New parameters in iron metabolism do not seem to be related to FID in patients on HD. PMID- 23111697 TI - Metastasis of endometrial adenocarcinoma in a primary lung adenocarcinoma. PMID- 23111698 TI - The gamut of host immune responses and immunopathology in parasitic diseases caused by protozoa and helminths: human perspective and experimental models. PMID- 23111701 TI - Statement of clarification. PMID- 23111702 TI - HCV genotype 5: an orphan virus. AB - HCV genotype 5 (HCV-5) is the least known HCV genotype. It is found mainly in South Africa and in restricted areas of Belgium, Spain, France, Syria and Greece. Sporadic cases are reported worldwide. The main modes of transmission are blood transfusion and iatrogenic causes. Little is known about its origin, but various studies have elucidated its spread worldwide. In endemic areas, patients infected with HCV-5 are on average older and have a higher viral load and more advanced fibrosis than those infected with non-HCV-5 genotypes.The current standard of care for HCV-5 chronic infection is 48 weeks of dual therapy with pegylated interferon plus ribavirin. 'Favourable' Il28B polymorphisms are not associated with higher sustained viral response rates. Assessment of shorter duration of therapy is made difficult by the lack of identifiable baseline predictors of response. Whilst there are in vitro data showing good activity of some direct acting antivirals and of host-targeted agents against HCV-5, no clinical trials of these molecules have yet started. PMID- 23111703 TI - Evidence base for multimodal therapy in cachexia. AB - PURPOSE OF REVIEW: The lack of success of unimodal treatment studies in cachexia and the growing awareness that multiple components are responsible for the development of cachexia have led to the view that cachexia intervention should include multimodal treatment. The aim of this article is to examine the evidence for multimodal treatment in the management of cancer cachexia. RECENT FINDINGS: There are some studies involving multimodal treatment that indicate significant effects on cachexia outcomes. There are, however, no randomized controlled trials to date that incorporate fully a structured exercise program, nutrition, good symptom treatment as well as drug treatment, to counteract the effects of altered metabolism. SUMMARY: The effectiveness of any drug intervention for cancer cachexia probably will only be maximized if incorporated into multimodal treatment. Further, cachexia treatment trials should also aim to include patients at an early phase in their cachexia trajectory and use validated outcome measures. PMID- 23111700 TI - Helicobacter pylori infection and gastric carcinogenesis in rodent models. AB - Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis. PMID- 23111704 TI - Self-management in palliative medicine. AB - PURPOSE OF REVIEW: Self-management in the palliative care domain means equipping patients and carers to manage medical aspects of illness, managing life roles and allowing adaptation to the changing dynamics brought on by illness and its progression. As well as dealing with the psychological consequences of living with a life-threatening illness in which the aim is to optimise living. This review will consider the rationale for developing and adopting self-management as a model of care. RECENT FINDINGS: Health policy currently advocates de-investment in traditional approaches to patient management paralleled with a re-engineering of services towards approaches required to underpin self-management care. However, the literature suggests that patients lack a fundamental knowledge and more importantly an understanding of the progression of their illness or what palliative of hospice care is. As a first step, this issue must be addressed in any self-management intervention. In terms of outcomes evidence continues to emerge that when compared with care self-management imparts sustainable understanding in targeted areas and has the potential to create a preventive spend environment. SUMMARY: The role of self-management in palliative care requires further elucidation yet based on the evidence which is predominately gleaned from long-term conditions it would seem sensible if not ethical to educate patients/carers to actively be involved in decision making. PMID- 23111699 TI - Lipids and HCV. AB - Chronic hepatitis C virus (HCV) infection is associated with an increase in hepatic steatosis and a decrease in serum levels of total cholesterol, low density lipoprotein cholesterol (LDL) and apolipoprotein B (apoB), the main protein constituent of LDL and very low-density lipoprotein (VLDL). These changes are more marked in HCV genotype 3 infection, and effective treatment results in their reversal. Low lipid levels in HCV infection correlate not only with steatosis and more advanced liver fibrosis but also with non-response to interferon-based therapy. The clinical relevance of disrupted lipid metabolism reflects the fact that lipids play a crucial role in the life cycle of hepatitis C virus. HCV assembly and maturation in hepatocytes depend on microsomal triglyceride transfer protein and apoB in a manner that parallels the formation of VLDL. VLDL production from the liver occurs throughout the day with an estimated 10(18) particles produced every 24 h whilst the estimated hepatitis C virion production rate is 10(12) virions per day. HCV particles in the serum exist as a mixture of complete low-density infectious lipo-viral particles (LVP) and a vast excess of apoB-associated empty nucleocapsid-free sub-viral particles that are complexed with anti-HCV envelope antibodies. Apolipoprotein E (apoE) is also involved in HCV particle morphogenesis and is an essential apolipoprotein for HCV infectivity. ApoE is a critical ligand for the receptor-mediated removal of triglyceride rich lipoprotein (TRL) remnants by the liver. The dynamics of apoB-associated lipoproteins, including HCV-LVP, change post-prandially with an increase in large TRL remnants and very low density HCV-LVP which are rapidly cleared by the liver (at least three HCV receptors are cellular receptors for uptake of TRL remnants). In summary, HCV utilises triglyceride-rich lipoprotein pathways within the liver and the circulation to its advantage. PMID- 23111705 TI - Can minimally invasive follicular thyroid cancer be approached as a benign lesion?: a population-level analysis of survival among 1,200 patients. AB - BACKGROUND: Minimally invasive follicular thyroid cancer (MIFC) is an encapsulated follicular tumor of low malignant potential. To date, histological criteria are still under debate, and there are no population-level data regarding characteristics and outcomes of patients with MIFC. METHODS: Patients diagnosed with MIFC in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2009 were included. Summary statistics were utilized to analyze patient characteristics; Kaplan-Meier analysis, and one-sample log-rank test were performed. RESULTS: A total of 1,200 patients with MIFC and 4,208 with widely invasive follicular thyroid cancer (WIFC) were identified over 10 years of follow up. MIFC was more common than WIFC in younger patients (mean age 49 vs. 52.3 years; p < 0.001). More patients with MIFC were alive at the end of follow-up (96.8 vs. 86.5% WIFC; p < 0.001). Patients diagnosed with MIFC were less likely than those with WIFC to have lymph nodes involved and distant metastases (0.9 vs. 3.6% and 0.5 vs. 8.9%, respectively; both p < 0.001). Only 2 of 1,200 patients died of disease-specific causes; overall survival was comparable to the general US population (p = 0.16). Total thyroidectomy and RAI ablation were not associated with improvement in patient outcomes (p = 0.2 and 0.443, respectively). CONCLUSIONS: MIFC is associated with survival comparable to that of the normative US general population. Thyroid lobectomy alone may be considered adequate treatment in these patients. PMID- 23111706 TI - Malignant progression in IPMN: a cohort analysis of patients initially selected for resection or observation. AB - BACKGROUND: Intraductal papillary mucinous neoplasms (IPMN) may represent a field defect of pancreatic ductal instability. The relative risk of carcinoma in regions remote from the radiographically identified cyst remains poorly defined. This study describes the natural history of IPMN in patients initially selected for resection or surveillance. METHODS: Patients with IPMN submitted to resection or radiographic surveillance were identified from a prospectively maintained database. Comparisons were made between these two groups. RESULTS: From 1995 to 2010, a total of 356 of 1,425 patients evaluated for pancreatic cysts fulfilled inclusion criteria. Median follow-up for the entire cohort was 36 months. Initial resection was selected for 186 patients (52 %); 114 had noninvasive lesions and 72 had invasive disease. A total of 170 patients underwent initial nonoperative management. Median follow-up for this surveillance group was 40 months. Ninety seven patients (57 % of those under surveillance) ultimately underwent resection, with noninvasive disease in 79 patients and invasive disease in 18. Five of the 18 (28 %) invasive lesions developed in a region remote from the monitored lesion. Ninety invasive carcinomas were identified in the entire population (25 %), ten of which developed the invasive lesion separate from the index cyst, representing 11 % with invasive disease. CONCLUSIONS: Invasive disease was identified in 39 % of patients with IPMN selected for initial resection and 11 % of patients selected for initial surveillance. Ten patients developed carcinoma in a region separate from the radiographically identified IPMN, representing 2.8 % of the study population. Diagnostic, operative, and surveillance strategies for IPMN should consider risk not only to the index cyst but also to the entire gland. PMID- 23111708 TI - From the editor. PMID- 23111707 TI - Molecular staging of surgical margins in oral squamous cell carcinoma using promoter methylation of p16(INK4A), cytoglobin, E-cadherin, and TMEFF2. AB - BACKGROUND: Local recurrence in oral squamous cell carcinoma (OSCC) despite clear surgical margins may indicate the presence of residual, sub-microscopic disease. Molecular assessment of surgical margins may provide a greater prognostic sensitivity compared to histopathology. We aimed to determine whether promoter methylation in deep and mucosal resection margins can predict recurrence in OSCC. METHODS: Forty-eight consecutive OSCC cases were recruited and a 5 mm(3) tumor sample plus 5 deep and 5 mucosal margin samples were snap frozen. Clinical, pathological, adjuvant therapy, and outcome data were recorded. Tumors were informative if >5 % promoter methylation was found for >=1 of 4 genes using qMSP. Margins were declared molecularly positive if >1 % promoter methylation was found in any margin. RESULTS: Thirty (63 %) of 48 cases were methylation informative. Mucosal margin samples were largely positive for methylation (26 of 30, 87 %), indicating the presence of field cancerization. Methylation at >=1 gene promoters in >=1 deep margin correlated with the presence of close/involved mucosal margins (P = 0.027) and increased pT status (P = 0.027) but not the status of deep margins, recurrence, or survival. CONCLUSIONS: The current gene panel did not add prognostic information to histopathological reporting of resection margins. Future efforts should concentrate on improving gene selection, informativity, and assay performance in the patient group with intermediate indications for adjuvant therapy. PMID- 23111709 TI - Goodpasture's syndrome associated with thrombotic thrombocytopenic purpura secondary to an ADAMTS-13 deficit. AB - A 27-year-old man was hospitalized for acute kidney injury associated with antiglomerular basement membrane antibodies (anti-GBM). He underwent immunosuppression and plasma exchange therapy, without recovery of renal function. Later on, he was again admitted to the hospital with seizures. Evidence of microangiopathic hemolytic anemia, with schistocytes in peripheral blood, was present, as well as a persistent low platelet count and activity of von Willebrand factor from adherence to protease (ADAMTS-13) less than 1 %. The presence of IgG antibodies against ADAMTS-13 was documented, leading to a diagnosis of thrombotic thrombocytopenic purpura (TTP) in the context of Goodpasture's syndrome. The TTP was treated with rituximab and plasmapheresis with a good response. We conclude that early measurement of ADAMTS-13 activity dictated the most appropriate therapy and achieved excellent results in this patient. PMID- 23111710 TI - Synovial fluid D-dimer concentration in horses with osteochondritis dissecans and osteoarthritis. AB - OBJECTIVE: To assess the synovial fibrinolytic pathway activation in adult horses with developmental and degenerative arthropathies such as osteochondritis dissecans (OCD) and osteoarthritis (OA) by measuring synovial D-dimer concentrations. METHODS: Prospective observational clinical study of horses admitted for OCD or OA. Synovial fluid was collected during lameness examination or prior to the surgical procedure, and D-dimer concentration and routine synovial fluid analysis were performed. RESULTS: Fifty-eight horses (14 with OCD, 10 with OA and 34 controls) were included in this study. Synovial D-dimer concentrations of horses with OCD and OA were both higher when compared with controls, but were only significantly different in horses with OCD (p = 0.005). However, no statistical differences were observed when comparing synovial D-dimer concentrations from the OCD horses with the OA-affected horses (p = 0.444). CLINICAL SIGNIFICANCE: Activation of coagulation and fibrinolysis play a role in the pathophysiology of equine OCD and OA. PMID- 23111711 TI - From the editors. PMID- 23111712 TI - Reply to "'new-generation' pulse oximeters in extremely low-birth-weight infants". PMID- 23111713 TI - Implementing the electronic medical record: building on success. PMID- 23111714 TI - Invitation to develop targeted interventions to support continued direct breast feeding in the NICU. PMID- 23111715 TI - Elective induction: is it worth the risk? Conclusion of a 3-part series. PMID- 23111716 TI - Development of motor activity and behaviors in the fetus. PMID- 23111717 TI - Relaxation during pregnancy: what are the benefits for mother, fetus, and the newborn? A systematic review of the literature. AB - Previous studies have reported associations between maternal stress during pregnancy and obstetric outcomes as well as fetal development and neonatal adaptation. These findings highlight the importance of identifying pregnant women who experience severe stress and the need for interventions that commence early in pregnancy. The aim of this study was to review studies that investigated the effects of relaxation techniques during pregnancy, including maternal, fetal, and neonatal outcomes. In addition, studies examining maternal endocrine and physiological alterations were reviewed. PubMed was searched using the following key words: maternal well-being, maternal stress, relaxation techniques, pregnancy, fetal neurobehavior, fetal heart rate, neonatal adaptation, and neonatal behavior. (1) Relaxation had a positive impact on women's emotional state. (2) Pregnancy outcomes improved with fewer admissions to the hospital, fewer obstetric complications, longer gestation, reduction of caesarean sections, and fewer postpartum complications. (3) Fetal heart rate and fetal motor activity were reduced as a result of relaxation and therefore interpreted as improved result. (4) Higher-birth-weight and improved performance on the Neonatal Behavioral Assessment Scale was related to relaxation. (5) Relaxation training was associated with reductions in maternal physiological and endocrine measures. Relaxation during pregnancy is associated with salutogenic effects that include regulation of emotional states and physiology. Relaxation is also associated with positive effects both on fetal behavior and on obstetric and neonatal outcomes. Identifying pregnant women at risk and instituting treatment early in pregnancy could improve obstetric and developmental outcomes for both the mother and her fetus. PMID- 23111718 TI - Safe mom, safe baby: a collaborative model of care for pregnant women experiencing intimate partner violence. AB - Violence during pregnancy is a national and global health-related problem. Intimate partner violence significantly increases the risk of maternal and neonatal morbidity and mortality. Abused pregnant women are 1.4 times more likely to deliver a preterm or low-birth-weight infant requiring extended and resource intense care in tertiary settings. Despite the prevalence of intimate partner violence during pregnancy, very little is written about established clinical programs designed to address this problem. This article presents the design, implementation, and evaluation of a nurse-led, evidence-based initiative respected for enhancing the health and safety of abused pregnant women. This interdisciplinary program combines registered nurse case management, the advocacy services of a community-based domestic violence agency, and perinatal care into a seamless continuum of professional services. Program interventions focus on helping clients navigate (1) their perinatal experiences across healthcare settings and (2) the complexities of criminal justice, legal, and social service systems within the community. Program-related data collected and evaluated for performance improvement purposes are discussed, and innovative educational programming is described. PMID- 23111720 TI - The perinatal self-care index: development of an evidence-based assessment tool for use with child sexual abuse survivors. AB - Every ninth woman presenting for prenatal care reports having experienced childhood sexual abuse. Many develop mental health disorders, including posttraumatic stress disorder (PTSD). In response to PTSD, pregnant women survivors of childhood sexual abuse engage in negative perinatal self-care behaviors that can lead to adverse perinatal outcomes. Currently, promotion of perinatal self-care does not consider childhood sexual abuse or PTSD. This study aimed to develop a Perinatal Self-Care Index, determine sensitivity of the index to differences in behaviors of childhood sexual abuse survivors (PTSD-affected and PTSD-resilient), and validate usefulness in relation to birth weight. Secondary analysis was conducted using data from a prospective cohort study of the effects of PTSD on pregnancy outcomes. The index explained 6.5% of variance in birth weight. Prediction improved to 9.4% once PTSD and socioeconomic status were considered. The index is sensitive to differences in PTSD-affected versus PTSD-resilient survivors of childhood sexual abuse and a useful predictor of birth weight in this analysis. PMID- 23111721 TI - Ethical decision making in intrapartum nursing. AB - Nurses are confronted daily with making ethical decisions in practice, in which the "right" or best course of action must be determined. However, for intrapartum nurses, the seemingly ordinary nature of ethical issues means that these concerns may be viewed merely as clinical or logistical problems to be solved, leaving the ethical dimensions obscured. This has consequences not only for women and the provision of safe, family-centered maternity care but also for the quality of nurses' work environments and degree of moral distress experienced. This article explores ethical aspects of intrapartum nursing by applying ethical principles and moral reasoning to an "everyday" situation encountered by intrapartum nurses in practice. Implications for practice and the development of healthy moral communities are considered. PMID- 23111722 TI - Neonatal family care for 24 hours per day: effects on maternal confidence and breast-feeding. AB - In family care (FC) program for neonatal intensive care units (NICUs), parents are encouraged to reside together with their infant for 24 hours a day to actively be involved in the care. The aim of this study was to assess the impact of FC on maternal confidence and breast-feeding. Maternal confidence and rate of breast-feeding were assessed in 31 mothers offered FC that included special family rooms in the NICU, and in 30 mothers from a comparable NICU providing traditional care without such facilities. One week prior to hospital discharge, mothers in the FC group felt better informed regarding nursing issues and had more confidence in interpretation of the infants regarding feeding issues and in caregiving without staff attendance (P < .05). They also reported a higher level of empowerment (P < .05). Three months after discharge, the mothers in the FC group had a higher self-reported skill level for interpretation of the infant's signals and knowledge about breast-feeding (P < .05). Despite similar rate of breast-feeding at discharge, more infants in the FC group were breastfed 3 months after discharge (P < .05). An FC program in the NICU promoted better maternal confidence during the hospital stay and 3 months after discharge compared with traditional care. PMID- 23111723 TI - Coping with the neonatal intensive care unit experience: parents' strategies and views of staff support. AB - It is stressful for parents to have an infant in the neonatal intensive care unit (NICU). To better understand the parents' experience and the role of staff, we examined parental reports of their NICU experiences, coping strategies, and views of the ways NICU staff supported them. Between June and July 2007, we interviewed 29 current and graduate parents from the study institution's NICU. A trained researcher conducted all interviews, which were recorded and transcribed. This was a qualitative analysis of prospectively collected interview data. Parents used the following coping strategies: (1) participating in care of the child; (2) getting away from the NICU; (3) gathering information; (4) involvement of friends and family; and (5) engagement with other NICU parents. Staff can support the parents' coping strategies in the following ways: (1) facilitating participation of the parents with the infant's care; (2) emphasizing documentation of the infant's progress; (3) demonstrating affection for the infant; (4) addressing concerns that make parents hesitant to leave the NICU; (5) providing accurate, consistent clinical information; (6) limiting unscheduled nonemergency phone calls; and (7) arranging voluntarily activities or programs in which parents whose infants have similar medical conditions may interact. PMID- 23111724 TI - The NICU experience: how does it affect the parents' relationship? AB - There is much research about the negative effect of serious and chronic childhood illness on the parent's partner relationship. It is generally assumed that parents of newborns admitted to the neonatal intensive care unit (NICU) also share this risk of relationship strain. However, little research specific to the effects of the NICU on the parent's relationship exists. The focus of most research examining parents of NICU infants is the mother's emotional well-being. The effect on the father is rarely studied. Drawing from studies of other childhood illnesses, it is reasonable to hypothesize that the experience of a NICU hospitalization may also strain the parents' relationship, possibly to the point of dissolution. The implementation of family-centered care in the NICU has had promising outcomes, and it is hypothesized that family-centered care will minimize the emotional stressors that may lead to the dissolution of the parent's partner relationship. PMID- 23111726 TI - On the subject of lawyers... PMID- 23111727 TI - Paracyclophane derivatives in frustrated Lewis pair chemistry. AB - The metal-free activation of hydrogen was achieved using [2.2]paracyclophane derived bisphosphines as Lewis base in frustrated Lewis pair chemistry. The rigid scaffold allows the orientation of functional groups so that steric aspects can be studied without altering the electronic nature. Depending on the geometry, structurally different phosphonium hydridoborates were generated when the frustrated Lewis pairs were exposed to hydrogen. The bisphosphines were applied in the 1,4-hydrosilylation-hydrogenation domino reaction providing access to secondary silyl-protected alcohols from enones in one step. Additionally, the planar-chiral scaffold was applied for the synthesis of novel enantiopure Lewis acids and Lewis bases. PMID- 23111728 TI - New organoboranes in "frustrated Lewis pair" chemistry. AB - The chemistry of "frustrated Lewis pairs" (FLPs) has become a rapidly evolving field since it was introduced 6 years ago. It offers new strategies for small molecule activation and organic synthesis which have long been dominated by transition metals. This chapter focuses on the recent development of organoborane compounds and their applications in FLP chemistry. Modifying the organoboranes along with optimizing the Lewis base partners results in a wide range of reactivities, such as small molecule activation and hydrogenation catalysis. PMID- 23111729 TI - Different efficacy of propranolol in mice with oxygen-induced retinopathy: could differential effects of propranolol be related to differences in mouse strains? PMID- 23111730 TI - Axial length probably does not change with shift in gaze. PMID- 23111731 TI - Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes. AB - AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmo Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmo Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, beta +/- SEM, -3.7 +/- 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, beta +/- SEM, -0.008 +/- 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications. PMID- 23111732 TI - Hypoglycaemia following diabetes remission in patients with 6q24 methylation defects: expanding the clinical phenotype. PMID- 23111733 TI - Comparative kinetic analysis of glycerol 3-phosphate cytidylyltransferase from Enterococcus faecalis and Listeria monocytogenes. AB - BACKGROUND: Glycerol 3-phosphate cytidylyltransferase (GCT) is an enzyme central to the synthesis of teichoic acids, components of the cell wall in gram positive bacteria. Catalysis by GCT from Enterococcus faecalis and Listeria monocytogenes has been investigated and catalytic properties compared. MATERIAL/METHODS: The genes encoding GCT were cloned from genomic DNA and recombinant proteins expressed in E. coli and purified. Enzyme assays were used to determine kinetic constants kcat and Km. Chemical crosslinking provided a means to assess quaternary structure of each GCT. RESULTS: Recombinant Enterococcus faecalis GCT had an apparent kcat value of 1.51 s-1 and apparent Km values of 2.42 mM and 4.03 mM with respect to substrates cytidine 5'-triphosphate (CTP) and glycerol phosphate. Listeria monocytogenes GCT had an apparent kcat value of 4.15 s-1 and apparent Km values of 1.52 mM and 6.56 mM with respect to CTP and glycerol phosphate. This resulted in kcat/Km values of 0.62 s-1mM-1 and 0.37 s-1mM-1 for E. faecalis GCT and 2.73 s-1mM-1 and 0.63 s-1mM-1 for L. monocytogenes GCT with respect to CTP and glycerol phosphate, respectively. CONCLUSIONS: The genome of both Enterococcus faecalis and Listeria monocytogenes contain a gene that encodes a functional GCT. The genes are 67% identical at the nucleotide level and the encoded proteins exhibit a 63% amino acid identity. The purified, recombinant enzymes each appear to be dimeric and display similar kinetic characteristics. Studying the catalytic characteristics of GCT isoforms from pathogenic bacteria provides information important for the future development of potential antibacterial agents. PMID- 23111734 TI - Reconstruction of comminuted long-bone fracture using CF/CPC scaffolds manufactured by rapid prototyping. AB - BACKGROUND: Stabilization and bone healing of fractures in weight-bearing long bones are challenging. This study was conducted to evaluate the effect of a scaffold composed of chitosan fiber and calcium phosphate ceramics (CF/CPC scaffold) on stability and fracture repair in weight-bearing long bones. MATERIAL/METHODS: Comminuted fractures of paired radiuses were created in 36 healthy, mature dogs. The left radius of each dog was classified in the experimental group and treated with CF/CPC scaffold, and the right one was not filled, and was used as a blank control. Of the 12 animals in each group that were killed at week 4, 8, and 12 after the operation, 6 were used for histological analysis, and the other 6 used were for biomechanical studies. Both radiuses from each animal were dissected free and stored for these analyses. All the animals underwent X-ray radiograph pre- and post-operatively. Computer-aided rapid-prototyping technologies were adopted for the fabrication of three dimensional scaffolds with precise geometric control. RESULTS: X-ray showed that the bone fracture area in the experimental group was filled with callus at week 12 after surgery. Histological examination detected slow resorption of the cement and new bone formation since week 4. At week 12, the scaffold material partially degraded and was still present in all specimens. Mechanical testing revealed that the failure strength of the radiuses treated with CF/CPC scaffolds was about 3 times that of the radiuses without implanted scaffolds. CONCLUSIONS: The effect of using CF/CPC scaffold in treating comminuted weight-bearing long bone fractures is satisfactory. PMID- 23111735 TI - A proteomic study of potential VEGF-C-associated proteins in bladder cancer T24 cells. AB - BACKGROUND: Overexpression of vascular endothelial growth factor-C (VEGF-C) has been found to play an important role in malignant progression of various cancer cells, in addition to lymphangiogenesis. However, the mechanisms involved are still largely unknown. Our early research has confirmed that the expression of VEGF-C in bladder cancer was markedly higher than that in normal bladder tissues. VEGF-C can also obviously promote proliferation and invasion of bladder cancer T24 cells. In the present work, we attempted to use proteomic analysis to screen out potential VEGF-C-associated proteins involved in malignant progression of the bladder cancer T24 cells. MATERIAL/METHODS: Lentivirus vector-based RNA interference (RNAi) was employed to diminish VEGF-C expression of bladder cancer T24 cells. Then we performed comparative proteome analysis to explore differentially expressed proteins in T24 cells with and without VEGF-C siRNA, by two-dimensional difference gel electrophoresis (2D-DIGE). RESULTS: Twenty-three proteins were identified. Some proteins (matrix metalloproteinase-9, Keratin 8, Serpin B5, Annexin A8) with significant differences were further confirmed by Western blotting. CONCLUSIONS: The 23 potential VEGF-C-associated proteins identified in our study provide us with further insights into the mechanism of VEGF-C promoting malignant progression of bladder cancer cells. PMID- 23111736 TI - Proteome analysis of human cerebrospinal fluid as a diagnostic biomarker in patients with meningioma. AB - BACKGROUND: To identify meningioma-specific proteins, cerebrospinal fluid (CSF) from 4 patients with a meningioma and 4 patients with a non-brain tumorous lesion were analyzed. MATERIAL/METHODS: Two-dimensional electrophoresis and electrospray quadrupole time-of-flight tandem mass spectrometry analyses revealed 10 unique spots, containing 11 independent proteins (spot #2 and #4 each contained 2 proteins and spot #3 was not identified) were evident in CSF associated with human meningioma: serum albumin precursor (3 different isoforms), Apolipoprotein E (Apo E), Apolipoprotein J precursor (Apo J), Transthyretin precursor (TTR), Prostaglandin D2 synthase 21 kDa (PTGDS), proapolipoprotein, Chain D hemoglobin Ypsilanti, alpha-1-antitrypsin (AAT), and beta-2-microglobulin precursor (beta2M). RESULTS: The contents of Apo E, Apo J and AAT were increased, while PTGDS, TTR and beta2M were decreased. CONCLUSIONS: The results observed by 2 dimensional electrophoresis were verified by Western blot analysis. The unique proteins may represent possible candidate biomarkers of meningioma. PMID- 23111737 TI - Using a novel in vivo model to study the function of nuclear factor kappa B in cerebral ischemic injury. AB - BACKGROUND: Cerebral ischemia is a situation with a deficit blood supply to the brain, which eventually leads to cell death, inflammation, and tissue damage. Nuclear factor kappa B (NF-kappaB) plays an important role in inflammation and immune regulation. The aim of this study was to test the function of the activation of NF-kappaB in vivo in cerebral ischemic injury. MATERIAL/METHODS: We generated an animal model that used the method of occlusion of the middle cerebral artery (MCAO). The 60 traits were equally divided into 5 groups to investigate the role of NAC pretreatment: (1) sham-operation (control), (2) ischemia for 6 hours, (3) ischemia for 6 hours and NAC pretreatment, (4) ischemia for 24 hours, (5) ischemia for 24 hours and NAC pretreatment. The 36 rats were divided randomly into 3 groups: (A) recombinant adenovirus expressing wild-type kappaBalpha(AdIkappaBalphaM) group, (B) recombinant adenovirus expressing wild type IkappaBalpha (AdIkappaBalpha) group, and (C) simple ischemia group. Triphenyltetrazolium chloride (TTC) was used to measure infarct volume. Detection of expression of NF-kappaB was by Immunohistochemistry analysis. RESULTS: The infarct size of the 24-hours ischemia groups were bigger than those of 6-hours ischemia groups (P<0.01). The infarct size of using NAC pretreatment groups was obviously reduced compared with saline control groups (P<0.01).The percentage of cortical p65-positive cells of the group of (A) were significantly less than the groups of (B) and (C). CONCLUSIONS: Our data suggest that N-acetylcysteine (NAC) and Ad-IkappaBalpha-Mut can inhibit the activation of NF-kappaB in vivo, reduce the focal infarct size, and protect the brain tissue in ischemia. PMID- 23111738 TI - Ultrasound elastography as a tool for imaging guidance during prostatectomy: initial experience. AB - BACKGROUND: During laparoscopic or robotic assisted laparoscopic prostatectomy, the surgeon lacks tactile feedback which can help him tailor the size of the excision. Ultrasound elastography (USE) is an emerging imaging technology which maps the stiffness of tissue. In the paper we are evaluating USE as a palpation equivalent tool for intraoperative image guided robotic assisted laparoscopic prostatectomy. MATERIAL/METHODS: Two studies were performed: 1) A laparoscopic ultrasound probe was used in a comparative study of manual palpation versus USE in detecting tumor surrogates in synthetic and ex-vivo tissue phantoms; N=25 participants (students) were asked to provide the presence, size and depth of these simulated lesions, and 2) A standard ultrasound probe was used for the evaluation of USE on ex-vivo human prostate specimens (N=10 lesions in N=6 specimens) to differentiate hard versus soft lesions with pathology correlation. Results were validated by pathology findings, and also by in-vivo and ex-vivo MR imaging correlation. RESULTS: In the comparative study, USE displayed higher accuracy and specificity in tumor detection (sensitivity=84%, specificity=74%). Tumor diameters and depths were better estimated using USE versus with manual palpation. USE also proved consistent in identification of lesions in ex-vivo prostate specimens; hard and soft, malignant and benign, central and peripheral. CONCLUSIONS: USE is a strong candidate for assisting surgeons by providing palpation equivalent evaluation of the tumor location, boundaries and extra capsular extension. The results encourage us to pursue further testing in the robotic laparoscopic environment. PMID- 23111739 TI - Increased dispersion of ventricular repolarization in Emery Dreifuss muscular dystrophy patients. AB - BACKGROUND: Sudden cardiac death (SCD) is common in patients with Emery-Dreifuss muscular dystrophy (EDMD) and is attributed to the development of life threatening arrhythmias that occur in the presence of normal left ventricular systolic function. Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QTc dispersion (QTc-D) and JTc dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with Emery-Dreifuss muscular dystrophy with preserved systolic and diastolic cardiac function. MATERIAL/METHODS: The study involved 36 EDMD patients (age 20 +/- 12, 26 M) and 36 healthy subjects used as controls, matched for age and sex. Heart rate, QRS duration, maximum and minimum QT and JT interval, QTc-D and JTc-D measurements were performed. RESULTS: Compared to the healthy control group, the EDMD group presented increased values of QTc-D (82.7 +/- 44.2 vs. 53.1 +/- 13.7; P=0,003) and JTc-D (73.6 +/- 32.3 vs. 60.4 +/- 11.1 ms; P=0.001). No correlation between QTc dispersion and ejection fraction (R=0.2, P=0.3) was found. CONCLUSIONS: Our study showed a significant increase of QTc-D and JTc-D in Emery Dreifuss muscular dystrophy patients with preserved systolic and diastolic cardiac function. PMID- 23111740 TI - Short-term outcomes of en bloc resection of solitary bone metastases in limbs. AB - BACKGROUND: To evaluate the pain, quality of life (QOL), and limb function of patients after en bloc resection of solitary metastatic bone cancer in the limbs. MATERIAL/METHODS: A total of 27 patients with solitary metastatic bone cancer in the limbs were recruited. All these patients underwent limb-salvage surgery with en bloc resection of the metastatic tumor. Pain and QOL were evaluated before and after surgery. Pain was assessed with a 10-point scale before and 1 month after surgery. The QOL was evaluated with the SF-30 scale before and 3 months after surgery. Limb function was evaluated with the Musculoskeletal Tumor Society scale (MSTS) 3 months after surgery. Follow-up was performed for 6~31 months (mean: 16.15 +/- 7.47 months). RESULTS: All procedures were successfully performed. Post operative complications were found in 6 patients, including incision infection, prosthesis dislocation, deep vein thrombosis, and pulmonary infection. The pain score before and 1 month after surgery was 6.85 +/- 3.11 and 1.26 +/- 0.81, respectively, indicating obvious improvement (t=9.978, P<0.001). The QOL score before and 3 months after surgery was 38.30 +/- 13.05 and 65.78 +/- 10.65, respectively, indicating pronounced improvement (t=-18.550, P<0.001). The mean post-operative MSTS score was 23 +/- 3 (range: 17-30) (t=-1.450, P=0.016). No local recurrence was observed in any patient during the follow-up. CONCLUSIONS: Limb salvage surgery with wide or marginal resection for solitary metastatic bone cancer may significantly improve the pain, QOL, and limb function, but there is no difference in local control between wide and marginal resection. PMID- 23111741 TI - Screening for the markers of kidney damage in men and women on long-term lithium treatment. AB - BACKGROUND: Lithium is the most effective therapeutic modality for the prevention of recurrences in bipolar disorder. An important adverse effect of lithium, especially with long-term treatment, is a possibility of a toxic effect on kidney function. Therefore, the aim of the study was to assess kidney function in a group of long-term lithium-treated patients. MATERIAL/METHODS: The study comprised 80 patients with bipolar mood disorder (26 male, 54 female), aged 60 +/ 11 years. They had been receiving lithium for 5-38 (16 +/- 9) years. Random urine sample was examined for albumin and creatinine excretion, and urinary albumin to creatinine ratio (UACR) was calculated. Specific gravity of the urine sample was recorded. Serum concentration of creatinine was measured and estimated glomerular filtration rate (eGFR) was calculated. Serum concentration of albumin was also measured. RESULTS: Decreased eGFR values <60 ml/min/1.73 m2 were found in 23% of patients, significantly more frequently in men that in women (38% vs. 16%, p=0.04). Elevated UACR values (>30 mg/g) were found in 25% of men and 12% of women, respectively. Serum albumin concentration >52 g/l was detected in 19% of patients (17% of men and 20% of women). Specific gravity of the urine, equal to or below 1.005, was recorded in 21% of men and 14% of women. CONCLUSIONS: The results confirm the opinion that screening for the markers of kidney damage should be performed in long-term lithium-treated patients for identification of persons with impaired kidney function. Male sex seems to be the risk factor for the development of kidney damage during long-term lithium treatment. PMID- 23111742 TI - Vitamin D receptor gene polymorphisms and haplotypes (Apa I, Bsm I, Fok I, Taq I) in Turkish psoriasis patients. AB - BACKGROUND: Psoriasis is an inflammatory disease characterized by increased squamous cell proliferation and impaired differentiation. Vitamin D, Calcitriol, and its analogues are successfully used for psoriasis therapy. However, it is unknown why some psoriasis patients are resistant to Vitamin D therapy. Vitamin D mediates its activity by a nuclear receptor. It is suggested that polymorphisms and haplotypes in the VDR gene may explain the differences in response to vitamin D therapy. MATERIAL/METHODS: In this study, 102 psoriasis patients and 102 healthy controls were studied for VDR gene polymorphisms. The Fok I, Bsm I, Apa I and Taq I polymorphisms were examined by PCR-RFLP, and 50 subjects received vitamin D therapy to evaluate the association between VDR gene polymorphisms and response to vitamin D therapy. Existence of cutting site is shown by capital letters, and lack was shown by lower case. The haplotypes were analysed by CHAPLIN. RESULTS: There was significant difference in allele frequency of T and genotype frequency of Tt between cases and controls (p values 0.038 and 0.04, respectively). The Aa and bb genotypes were significantly higher in early onset than late onset psoriasis (p values 0.008 and 0.04, respectively). The genotypes Ff, ff and TT are significantly different between vitamin D3 therapy responders and non-responders (p values 0.04, 0.0001, 0.009, respectively). To the best of our knowledge, this is the first report showing importance of VDR gene haplotypes in psoriasis, the significance of the Wald and LR (Likelihood Ratio) statistics (p=0,0042) suggest that FfBbAatt is a disease-susceptibility haplotype. CONCLUSIONS: Haplotype analysis is a recent and commonly used method in genetic association studies. Our results reveal a previously unidentified susceptibility haplotype and indicate that certain haplotypes are important in the resistance to vitamin D3 therapy and the onset of psoriasis. The haplotypes can give valuable data where genotypes unable to do. PMID- 23111743 TI - The influence of uremic high cystatin C concentration on neutrophil apoptosis and selected neutrophil functions isolated from healthy subjects. AB - BACKGROUND: Cystatin C (cC) is a cysteine protease inhibitor that may influence immune response. Our aim was to test the effect of a high concentration of cC, characteristic for uremic patients, on neutrophil (PMN) apoptosis and respiratory burst, as well as the cC secretion from PMNs stimulated with proinflammatory cytokines. MATERIAL/METHODS: PMNs from 35 healthy volunteers aged 27-61 years were cultured in presence of cC, IL-1beta or TNF-alpha. The percentage of apoptotic cells based on DNA depletion, Fas, FasL and caspase -3 expression were assessed. CC concentrations were determined by ELISA test. The influence of cC on spontaneous, fMLP-, PMA- or OZ-induced burst response of PMNs was tested using chemiluminescence. RESULTS: PMN cultured in the presence of cC resulted in a significant drop in apoptotic cell percentage (38% [11%; 65%]) compared both to control (70% [29%; 92%], and to the cells cultured with TNF-alpha (58% [24%; 85%]). These differences were not accompanied by Fas, FasL and caspase-3 expression changes. Spontaneous, fMLP- and PMA-stimulated oxidative burst of PMNs preincubated with cC were significantly downregulated. IL-1beta markedly diminished and TNF-alpha significantly increased cC concentration in culture supernatants. CONCLUSIONS: The presented results suggest that antiapoptotic activity of cC results from its inhibitory effect on ROS production. Thus, the higher concentration of cC characteristic for uremic patients may modulate acute inflammation through maintaining PMN longevity and inhibiting their respiratory burst and proinflammatory cytokine-related changes in cC release from PMNs. PMID- 23111744 TI - Antero-medial portal vs. transtibial techniques for drilling femoral tunnel in ACL reconstruction using 4-strand hamstring tendon: a cross-sectional study with 1-year follow-up. AB - BACKGROUND: Antero-medial portal (AMP) and trans-tibial (TT) techniques are the most widely used methods for drilling femoral tunnel in ACL reconstructions; yet, debate continues about the preferred method. This study seeks to compare these 2 techniques in patients with ACL tears. MATERIAL/METHODS: In this comparative study, all cases of isolated ACL reconstruction using 4-strand hamstring tendon in 2006-2010 were evaluated for eligibility. Of 266 patients, 124 cases (60 TT and 64 AMP), with the mean age of 28.48+/-8.3, met the inclusion criteria. Both groups were compared in 8 follow-ups from the point of view of time of: return to post-surgical activities (including walking without crutches, normal life activity, jogging, and exercising), maximum range of passive movements, knee instability (Lachman test), functional condition (subjective IKDC and Lysholm knee scores), therapeutic outcomes, and patient's satisfaction with treatment (VAS). RESULTS: AMP technique significantly accelerates patients' return to activity. AMP patients achieved full range of motion much sooner than TT cases (P<0.0001). After 1-year follow-up, S-IKDC scores were 94.8 +/- 3.9 and 89.2 +/- 4.1 and S-LKS scores were 96.1 +/- 3 and 92.2 +/- 4.1 for AMP and TT groups, respectively (P<0.0001). Knee stability was similar in both groups on Lachman test (P=0.25). AMP group patients (VAS mean score: 9.78 +/- 0.4) had greater satisfaction compared to TT group patients (VAS mean score: 9.53 +/- 0.5) (P=0.003). CONCLUSIONS: AMP technique leads to reduction in time to return to routine activities, better therapeutic outcomes and higher satisfaction rates. PMID- 23111745 TI - Functional Capacity Scale as a new tool for early functional assessment in patients after surgical treatment of intracranial aneurysms: a prospective study involving 128 patients. AB - BACKGROUND: Functional assessment of a patient focuses on the assessment of independence in activities of daily living. The aim of the study was to verify the usefulness of a new tool (Functional Capacity Scale - FCS) for early functional assessment of patients after surgical treatment of an intracranial aneurysm. MATERIAL/METHODS: The study was conducted in the Neurosurgical Department and Clinic, CM in Bydgoszcz, NCU, within a group of 128 patients after surgical treatment of an intracranial aneurysm. Direct observation and measurement were used in the study. In clinical assessment, the Hunt and Hess Scale was applied. For the final functional assessment, the Functional Capacity Scale (FCS), the Glasgow Outcome Scale, the Functional Index "Repty", the Barthel Index, and the Rankin Scale were used. RESULTS: The study shows that on the day of discharge almost 60% of patients are independent or slightly dependent on others for functional capability, and 15% are significantly or totally dependent. FCS significantly correlates with FIR (0.93, p<0.001), GOS (0.89, p<0.01), RS ( 0.88, p<0.01) and BI (0.82, p<0.001). CONCLUSIONS: 1. Fifty percent of patients with intracranial aneurysm assessed at the early postoperative stage leave the ward as functionally capable of performing everyday activities. 2. There are significant correlations between FCS and the other scales used for functional assessment. 3. There is a significant relationship between functional capacity of the patient on the day of discharge and clinical condition before the surgical treatment. PMID- 23111746 TI - Ophthalmic manifestation of skull base metastasis from breast cancer. AB - BACKGROUND: There is a vast discrepancy between the incidence of skull base metastases reported in vivo and at autopsy. Asymptomatic character or unspecific symptoms make the diagnosis difficult, particularly in patients with no history of cancer. Our case illustrates a skull base metastasis from breast cancer, detected in a diagnostic process initiated by ophthalmologic examination. CASE REPORT: We report the case of a 53-year-old woman complaining of ptosis and diplopia, with concomitant loss of skin sensation within the right half of the forehead, and without any other worrisome symptoms or signs. Ophthalmic examination revealed impairment in eye movements, slight proptosis and corneal hypoesthesia on the right side, with normal pupillary light reflexes. The anterior and posterior segments of the eye were normal. Based on CT and MRI, an extensive tumor was detected, infiltrating the right orbit and the frontotemporal region of the skull base, and producing edema of the adjacent aspects of the brain. Aside from partial palsy of the oculomotor nerve and the ophthalmic division of the trigeminal nerve, no abnormalities were found on neurological examination. Explorative craniotomy and histopathological findings revealed a skull base metastasis from breast cancer. CONCLUSIONS: Diplopia, ptosis, proptosis, and ophthalmic nerve sensory loss may be the only manifestation of a skull base metastasis. Careful ophthalmologic examination is crucial in early detection of this life-threatening condition. PMID- 23111747 TI - Recovery of residual curarization after red blood cell transfusion. AB - BACKGROUND: The muscle-relaxing effects of succinylcholine are terminated via hydrolysis by plasma cholinesterase. There are multiple genetic variants of this enzyme and clinical circumstances that might influence the activity of plasma cholinesterase and eventually lead to prolonged neuromuscular blockade following succinylcholine application. CASE REPORT: Here, we report a parturient woman with atonic bleeding who suffered significant blood loss (hemoglobin 6.0 g*dL-1). For surgical curettage, general anesthesia was performed by using short-acting succinylcholine. By the end of the 105-minute procedure, the patient's trachea was extubated. After extubation she showed signs of the prolonged neuromuscular blocking action of succinylcholine. At this time, the patient received an AB0 compatible red blood cell transfusion and recovered instantly from neuromuscular blockade. The plasma cholinesterase (3.200 U*L-1) was below the normal range (4.900-12.000 U*L-1). Patient's blood DNA analysis revealed heterozygously the genetic K variant of plasma cholinesterase. After red blood cell transfusion, serum potassium was elevated (5.7 mmol*L-1; 4.4 mmol*L-1 prior to transfusion). CONCLUSIONS: Pregnancy, blood loss and genetic variation contributed to impairment of plasma cholinesterase. Due to high-speed red blood cell transfusion, hemolytic release of erythrocyte cholinesterase might have terminated the neuromuscular blocking succinylcholine effect. PMID- 23111748 TI - Evaluation of a neurotherapy program for a child with ADHD with Benign Partial Epilepsy with Rolandic Spikes (BPERS) using event-related potentials. AB - BACKGROUND: We hypothesized that there would be a good response to relative beta training, applied to regulate the dynamics of brain function in a patient with benign partial epilepsy with Rolandic Spikes (BPERS), associated with neuropsychiatric deficits resembling the symptoms of attention deficit hyperactivity disorder (ADHD). CASE REPORT: The patient, E.Z., age 9.3, was suffering from neuropsychiatric symptoms, cognitive dysfunction, especially attention deficits, and behavioral changes, rendering him unable to function independently in school and in many situations of everyday life. He was treated for epilepsy, but only slight progress was made. The patient took part in 20 sessions of relative beta training combined with behavioral training. We used standardized neuropsychological testing, as well as ERPs before the experiment and after the completion of the neurotherapy program. Neuropsychological testing at baseline showed multiple cognitive deficits. Over the course of neurotherapy, E.Z.'s verbal and non-verbal IQ increased significantly. His cognitive functions also improved, including immediate and delayed logical and visual recall on the WMS-III, maintaining attention on the WMS-III, and executive functions, but remained below norms. Physiologically, the patient showed substantial changes after neurotherapy, including fewer spikes and an increased P300 NOGO component. CONCLUSIONS: The cognitive deficits characteristic for ADHD in a child with BPERS may be unresponsive to antiepileptic treatment, but are reversible after a carefully selected neurotherapy program, combined with antiepileptic treatment. Event Related Potentials (ERPs) in the GO/NOGO task can be used to assess functional brain changes induced by neurotherapeutical programs. PMID- 23111749 TI - Relationship of systemic blood pressure with ocular perfusion pressure and intraocular pressure of glaucoma patients in telemedical home monitoring. AB - BACKGROUND: We evaluated the relation of systemic blood pressure with intraday variations in ocular perfusion pressure and intraocular pressure in patients with primary open-angle glaucoma in a telemedical home monitoring scenario. MATERIAL/METHODS: In the project Teletonometry Mecklenburg-Vorpommern (TTMV) patients were equipped with a home monitoring system for 24-hour self measurements of intraocular pressure and blood pressure for a period of six months. All measurements were transmitted via telephone modem to an electronic patient record. Ocular perfusion pressure (OPP) was automatically calculated from self-measurements of intraocular pressure (IOP), systolic (SBP) and diastolic blood pressure (DBP) using the equation: OPP=[2/3*(2/3*DBP+1/3*SBP)]-IOP. We present the temporal characteristics of 70 patients with primary open-angle glaucoma based on 3282 self-measurements. RESULTS: The diurnal ocular perfusion pressure trend showed four characteristic phases (7am - 12am, 12am - 6pm, 6pm - 10pm, and 10pm - 7am). Between 7am and 12am ocular perfusion pressure and simultaneously systolic and diastolic blood pressure were significantly depressed compared to all other phases (p<0.05) whereas intraocular pressure showed no significant shifting. Instead intraocular pressure was significantly depressed between 6pm and 10pm (p<0.05) where ocular perfusion pressure reached the highest intraday values. CONCLUSIONS: We found that ocular perfusion pressure in patients with primary open-angle glaucoma showed remarkable circadian fluctuations. A significant decrease in the morning was associated with significantly depressed systolic and diastolic blood pressure levels. In addition we observed normal intraocular pressure values in the morning but a significant decrease in the evening which did not affect ocular perfusion pressure. These conclusions strengthen the evidence that systemic blood pressure fundamentally influences ocular circulation and consequently glaucoma progression. PMID- 23111750 TI - The Na+/Ca2+ exchanger in cardiac ischemia/reperfusion injury. AB - The Na+/Ca2+ exchanger (NCX) is an important electrogenic transporter in maintaining Na+ and Ca2+ homeostasis in a variety of mammalian organs, and is involved in the physiological and pathophysiological regulation of Ca2+ concentration in the myocardium. It can affect cardial structure, electrophysiology and contractile properties. The role of the NCX in heart cells following ischemia/reperfusion (IR) has been investigated using a number of in vitro and in vivo models. During ischemia, ionic disturbances favor Ca2+-influx mode activity as excess Na+ is extruded in exchange for Ca2+, giving rise to increased intracellular Ca2+ levels (Cai). This rise in Cai contributes to reversible cellular dysfunction upon reperfusion, such as myocardial necrosis, arrhythmia, systolic dysfunction and heart failure. We have reviewed the major in vivo and in vitro cardiac IR-related NCX studies in an attempt to clarify the functions of NCX in IR and conclude that recent studies suggest blockage of NCX has potential therapeutic applications. Although the use of different IR models, application of NCX stimulators and inhibitors, and development of NCX transgenic animals do help elucidate the role of this ion exchanger in heart cells, related mechanisms are not completely understood and clinically effective specific NCX inhibitors need further research. PMID- 23111751 TI - Influenza vaccines and vaccinations in Poland - past, present and future. AB - Influenza causes seasonal infections worldwide that can lead to complications and deaths in every age group. The most effective and cheapest way to combat influenza is through vaccination. In many countries, including Poland, for each age group, the rate of vaccination against influenza is still at a very low level, which generates high social costs, not infrequently family tragedies in the case of irreversible complications of influenza, or death of a loved one. Regular vaccination should be part of good medical practice, as well as an individual's engagement in their own health and in that of their family. Based on numerous studies, it is estimated that the effectiveness of current inactivated influenza vaccine in reducing morbidity and mortality in high-risk groups ranges from 50-70%. According to data from the National Institute of Public Health National Institute of Hygiene, the rate of vaccination in children in 2008 in Poland was very low. In the group of children aged from 6 months to 14 years, only 1.1-1.6% were vaccinated. Although influenza vaccination for people aged over 65 years was free of charge in many provinces in this group, only 13.4% of this population was immunized, while in the case of people with chronic diseases, only 11.1% were immunized. The vaccination rate among health care employees is an embarrassing 6.4%. More educational activities addressed to both medical professionals and patients are required in order to increase influenza vaccine coverage in Poland. PMID- 23111753 TI - Benchmarks for 0-0 transitions of aromatic organic molecules: DFT/B3LYP, ADC(2), CC2, SOS-CC2 and SCS-CC2 compared to high-resolution gas-phase data. AB - In the present study a benchmark set of medium-sized and large aromatic organic molecules with 10-78 atoms is presented. For this test set 0-0 transition energies measured in supersonic jets are compared to those calculated with DFT and the B3LYP functional, ADC(2), CC2 and the spin-scaled CC2 variants SOS-CC2 and SCS-CC2. Geometries of the ground and excited states have been optimized with these methods in polarized triple zeta basis sets. Zero-point vibrational corrections have been calculated with the same methods and basis sets. In addition the energies have been corrected by single point calculations with a triple zeta basis augmented with diffuse functions, aug-cc-pVTZ. The deviations of the theoretical results from experimental electronic origins, which have all been measured in the gas phase with high-resolution techniques, were evaluated. The accuracy of SOS-CC2 is comparable to that of unscaled CC2, whereas ADC(2) has slightly larger errors. The lowest errors were found for SCS-CC2. All correlated wave function methods provide significantly better results than DFT with the B3LYP functional. The effects of the energy corrections from the augmented basis set and the method-consistent calculation of the zero-point vibrational corrections are small. With this benchmark set reliable reference data for 0-0 transition energies for larger organic chromophores are available that can be used to benchmark the accuracy of other quantum chemical methods such as new DFT functionals or semi-empirical methods for excitation energies and structures and thereby augments available benchmark sets augments present benchmark sets which include mainly smaller molecules. PMID- 23111752 TI - Vancomycin versus linezolid in the treatment of methicillin-resistant Staphylococcus aureus meningitis in an experimental rabbit model. AB - BACKGROUND: The aim of this study was to compare the antibacterial efficacy of vancomycin and linezolid in a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) meningitis. MATERIAL/METHODS: Meningitis was induced by intracisternal inoculation of ATCC 43300 strain. After 16 h incubation time and development of meningitis, the vancomycin group received vancomycin 20 mg/kg every 12 h. The linezolid-10 and linezolid-20 groups received linezolid in 10 and 20 mg/kg dosages every 12 h, respectively. The control group did not receive any antibiotics. Cerebrospinal fluid bacterial counts were measured at the end of 16 h incubation time and at the end of 24-h treatment. RESULTS: Bacterial counts were similar in all groups at 16 h. At the end of treatment the decrease in bacterial counts in the vancomycin group was approximately 2 logs higher than the linezolid-20 group (p>0.05) and approximately 4 logs higher than in the linezolid 10 group (p: 0.037) (Vancomycin group: -2.860 +/- 4.495 versus Linezolid-20: 0.724 +/- 4.360, versus Linezolid-10: 1.39 +/- 3.37). Full or partial bacteriological response was higher in vancomycin versus linezolid-10 (p: 0.01), but not vancomycin versus linezolid-20 or linezolid-10 versus-linezolid-20 groups. CONCLUSIONS: Our results suggest that linezolid is not statistically inferior to vancomycin in the treatment of MRSA meningitis in an experimental rabbit model in 20 mg/kg q12 h dosage; however, it is inferior in 10 mg/kg q12 h dosage. Additional data should gathered to confirm these findings in advance of clinical trials to assess efficacy in humans. PMID- 23111754 TI - [Heterotopic sebaceous glands in the esophagus: case report with review of the literature]. AB - Heterotopia of sebaceous glands is a very rare endoscopically indistinct benign finding in the esophagus. To date only 30 cases have been reported in the literature. The lesions exhibit a considerable variation in number and size. No malignant transformation has yet been reported. From the pathologists' point of view an inflammatory or neoplastic process has to be excluded as the cause of the non-distinctive endoscopic findings. PMID- 23111755 TI - Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. AB - Cancer-associated fibroblasts (CAFs) play a role in tumour initiation and progression, possibly by inducing epithelial-to-mesenchymal transition (EMT), a series of cellular changes that is known to underlie the process of metastasis. The aim of this study was to determine whether CAFs and surrounding normal breast fibroblasts (NBFs) are able to induce EMT markers and functional changes in breast epithelial cancer cells. Matched pairs of CAFs and NBFs were established from fresh human breast cancer specimens and characterised by assessment of CXCL12 levels, alpha-smooth muscle actin (alpha-SMA) levels and response to doxorubicin. The fibroblasts were then co-cultured with MCF7 cells. Vimentin and E-cadherin expressions were determined in co-cultured MCF7 cells by immunofluorescence and confocal microscopy as well as by western blotting and quantitative PCR. Co-cultured MCF7 cells were also assessed functionally by invasion assay. CAFs secreted higher levels of CXCL12 and expressed higher levels of alpha-SMA compared with NBFs. CAFs were also less sensitive to doxorubicin as evidenced by less H2AX phosphorylation and reduced apoptosis on flow cytometric analysis of Annexin V compared with NBFs. When co-cultured with MCF7 cells, there was greater vimentin and less E-cadherin expression as well as greater invasiveness in MCF7 cells co-cultured with CAFs compared with those co-cultured with NBFs. CAFs have the ability to induce a greater degree of EMT in MCF7 cell lines, indicating that CAFs contribute to a more malignant breast cancer phenotype and their role in influencing therapy resistance should therefore be considered when treating breast cancer. PMID- 23111756 TI - CLEIA CA125 evidences: good analytical performance avoiding "Hook effect". AB - Cancer antigen 125 (CA125) is a coelomic epithelium-related antigen carried by a high molecular weight glycoprotein complex. It is commonly used as a tumor marker for ovarian cancer to monitor disease progression and response to therapy and as an early detection for recurrence after treatment. The aim of this study was to test the reliability of two different assay methods, a radioimmunometric assay (RIA) and an automated chemiluminescent enzyme immunoassay (CLEIA) system, by measuring CA125 serum levels using both methods in 357 patients and comparing the results. Patients were recruited from Oncologic Unit A, Policlinico Umberto I, Roma. Eighty-six were healthy donors, while 271 were oncologic patients representing a variety of diagnoses. Within this group, 76 patients were diagnosed with an ovarian related pathology (28 cancerous and 48 benign). The evaluation of CA125 marker blood levels showed a high agreement in healthy donors group (R (2) = 0.9003). Interesting results emerged when sera collected from oncologic patients were assessed: significant differences between the two assays were found in nine samples. When assayed again with RIA after a dilution, new values agreed with undiluted CLEIA values (R (2) = 0.9847). Our data suggest an overall good comparison between the two methods. However, some artifacts were obtained with RIA and indicate an underlying presence of "hook effect". CLEIA automated assay showed a good reliability and should be preferred to one-step radioimmunoassays in order to minimize errors. PMID- 23111757 TI - Comparative study on the inhibitory effects of antioxidant vitamins and radon on carbon tetrachloride-induced hepatopathy. AB - We have previously reported that radon inhalation activates anti-oxidative functions and inhibits carbon tetrachloride (CCl(4))-induced hepatopathy. It has also been reported that antioxidant vitamins can inhibit CCl(4)-induced hepatopathy. In the current study, we examined the comparative efficacy of treatment with radon, ascorbic acid and alpha-tocopherol on CCl(4)-induced hepatopathy. Mice were subjected to intraperitoneal injection of CCl(4) after inhaling approximately 1000 or 2000 Bq/m(3) radon for 24 h, or immediately after intraperitoneal injection of ascorbic acid (100, 300, or 500 mg/kg bodyweight) or alpha-tocopherol (100, 300, or 500 mg/kg bodyweight). We estimated the inhibitory effects on CCl(4)-induced hepatopathy based on hepatic function-associated parameters, oxidative damage-associated parameters and histological changes. The results revealed that the therapeutic effects of radon inhalation were almost equivalent to treatment with ascorbic acid at a dose of 500 mg/kg or alpha tocopherol at a dose of 300 mg/kg. The activities of superoxide dismutase, catalase, and glutathione peroxidase in the liver were significantly higher in mice exposed to radon than in mice treated with CCl(4) alone. These findings suggest that radon inhalation has an anti-oxidative effect against CCl(4)-induced hepatopathy similar to the anti-oxidative effects of ascorbic acid or alpha tocopherol due to the induction of anti-oxidative functions. PMID- 23111758 TI - Escherichia coli mutants induced by multi-ion irradiation. AB - Wild-type Escherichia coli K12 strain W3110 was irradiated by 10 keV nitrogen ions. Specifically, irradiation was performed six times by N(+) ions, followed by the selection of lac constitutive mutants, and each time a stable S55 mutant was produced. By sequencing the whole genome, the fine map of S55 was completed. Compared with reference sequences, a total of eighteen single nucleotide polymorphisms (SNPs), two insertions and deletions (Indels), and nine structural variations (SVs) were found in the S55 genome. Among the 18 SNPs, 11 are transversional from A, T or C to G, accounting for 55.6% of point mutations. GCCA insertion occurs in the target gene lacI. Four SNPs, including three in rlpB and one in ygbN, are connected with cell envelope and transport. All nine structural variations of S55 are deletions and contain insertion sequence (IS) elements. Six deleted SVs contain disrupted ISs, nonfunctional pseudogenes, and one more 23 252 bp SV in the Rac prophage region. Overall, our results show that deletion bias observed in E. coli K12 genome evolution is generally related to the deletion of some nonfunctional regions. Furthermore, since ISs are unstable factors in a genome, the multi-ion irradiations that caused these deleted fragments in S55 turn out to be beneficial to genome stability, generating a wider mutational spectrum. Thus, it is possible that the mutation of these genes increases the ability of the E. coli genome to resist etch and damage caused by ion irradiation. PMID- 23111759 TI - [Enamel demineralization in orthodontics. Systematic use of fluoride in prevention and treatment]. AB - The development of the white spot demineralization associated with fixed appliance orthodontic treatment is a significant clinical problem. Several studies have reported a significant increase in the prevalence and severity of demineralization after orthodontic therapy. Orthodontists should be proactive and take active responsibility to prevent the development of WSL by educating their patients about the importance of maintaining an excellent dietary compliance and oral hygiene regime. In front of the appearance of the white spots, several preserving palliative treatments can be suggested. PMID- 23111760 TI - Educational Paper: Aspects of clinical pharmacology in children- pharmacovigilance and safety. AB - Adverse drug reactions (ADRs) are a significant problem in children, affecting one in ten children in hospital. Within the community, one in 500 children will experience an adverse drug reaction each year. Pharmacovigilance has been useful in detecting suspected ADRs. However, most ADRs are unreported and often not suspected. Education of health professionals in relation to drug toxicity improves the reporting rate of suspected ADRs. Clinical trials are useful to evaluate the efficacy of drugs. They are, however, not the best way of looking at ADRs where surveillance following the widespread use of a drug is more appropriate. Alongside work by the regulatory agencies, independent investigators have helped collate data. This information has been useful in developing guidelines to prevent further cases of drug toxicity. Greater awareness and understanding of drug toxicity in children should result in more rational prescribing. PMID- 23111761 TI - Educational paper: formulation-related issues in pediatric clinical pharmacology. AB - Developmental physiological changes occur throughout childhood, with important changes observed within the first few weeks and months from birth, potentially affecting drug pharmacokinetics. The impact of confounding factors in relation to the availability of clinically relevant and adequate drug formulations and administration devices is underestimated. Hence, it is important to highlight presently the relevance of formulation issues. Since 2007, the EU Paediatric Regulation enforces paediatric investigation plans in which the applicant has to justify the clinical relevance of each dosage form proposed in relation to age subsets involved and the suitability of administration modalities. Therefore, pediatric drug development has become more relevant, and the importance of using age-appropriate drug formulations has been acknowledged by investigators and other stakeholders. Palatability and acceptability assessment is considered to be important by the regulatory bodies as well as excipient safety and tolerability, as it can be an issue particularly in very young children. However, there remains a lack of research into pediatric biopharmaceutics (methodological input regarding in vitro tools and bridging studies). Clinical pharmacologists with expertise ranging from pharmacodynamics, pharmacokinetics, adverse drug effects, and toxicology should actively contribute in advancing drug formulation issues in children. PMID- 23111762 TI - Disparities in prevalence of key chronic diseases by gender and race/ethnicity among antiretroviral-treated HIV-infected adults in the US. AB - BACKGROUND: Certain sociodemographic subgroups of HIV-infected patients may experience more chronic disease than others due to behavioural risk factors, advanced HIV disease or complications from extended use of combination antiretroviral therapy (cART), but recent comparative data are limited. METHODS: We studied HIV-infected adult patients in care during 2006-2010 who had been prescribed >= 6 months of cART. We analysed the prevalence of selected key chronic conditions and polymorbidity (having 2 or more out of 10 key conditions) by gender and race/ethnicity. RESULTS: Of the 3,166 HIV-infected patients (median age 47 years, CD4+ T-cell count 496 cells/mm3, duration of cART use 6.8 years), 21% were female, 57% were non-Hispanic White and over half were current or former tobacco smokers. The five most frequent conditions among women (median age 45 years) were dyslipidaemia (67.3%), hypertension (57.4%), obesity (31.7%), viral hepatitis B or C coinfection (29.0%) and low high-density lipoprotein cholesterol (HDLc; 27.3%). The five most frequent conditions in men (median age 47 years) were dyslipidaemia (81.2%), hypertension (54.4%), low HDLc (41.1%), elevated triglycerides (32.3%) and elevated non-HDLc (26.8%). In multivariable analyses, Hispanic patients had higher prevalence of obesity and diabetes than White patients; Black patients had higher prevalence of obesity and hypertension but lower rates of lipid abnormalities. Of all patients, 73.7% of women and 66.8% of men had polymorbidity, with no evidence of disparities by race/ethnicity. CONCLUSIONS: Among contemporary cART-treated HIV-infected adults, chronic conditions and polymorbidity were common, underscoring the importance of chronic disease prevention and management among ageing HIV-infected patients. PMID- 23111763 TI - Celiac disease: the new proposed ESPGHAN diagnostic criteria do work well in a selected population. AB - BACKGROUND: The need for an early and accurate diagnosis in celiac disease (CD) has focused attention on new diagnostic approaches, based on the efficiency of serological markers and the high negative predictive value of human leukocyte antigen (HLA) non-DQ2/8. METHODS: We performed a retrospective review of all of the patients suspected of having CD who had undergone a small bowel biopsy in our gastroenterology unit. All symptomatic children with serological marker at time of biopsy (immunoglobulin A-tissue transglutaminase antibody, endomysial antibody, and HLA genotype) were included. The triple test (TT) was positive if immunoglobulin A-tissue transglutaminase antibody was 10 times the upper limit of normal, plus positive endomysial antibody plus human leukocyte antigen-DQ2/DQ8. RESULTS: A total of 150 patients met the inclusion criteria and were enrolled in the study. One hundred sixteen were positive for the TT; 113 of 116 (97.4%) had a Marsh 2/3 histological lesion and had been considered to have CD. Thus, positive predictive value of the TT was 97.4%. The other 3 cases (2.6%) had Marsh 0/1 lesion, so we consider them to be false-positives for the TT; however, on follow up, all 3 children developed histological damage after a gluten challenge. Finally, the positive predictive value of the TT was 100%. Thirty-four patients were negative for the TT: 22 patients are celiac, 3 are celiac but challenge gluten diet is pending, and the 9 patients left have other gastrointestinal disorder. CONCLUSIONS: Our study supports the view that in selected children who are symptomatic and positive for the TT, CD diagnosis could be established independent of histological findings. PMID- 23111764 TI - Gastroparesis in children: the benefit of conducting 4-hour scintigraphic gastric emptying studies. AB - BACKGROUND AND AIM: Scintigraphic gastric emptying study (GES) is the criterion standard for diagnosis of gastroparesis. Adult studies demonstrated that extending GES to 4 hours increases its ability to diagnose delayed gastric emptying. Most pediatric centers assess GES up to 2 hours postmeal. The aim of the present study was to assess the effect of extending GES from 2 to 4 hours in evaluation of children with suspected gastroparesis. METHODS: We conducted a chart review of all children who had a 4-hour GES with standard radiolabeled solid meal in 2009-2010. Results of GES at 1, 2, and 4 hours were compared. Patients were diagnosed as having gastroparesis using adult criteria: if gastric retention of meal was >90%, 60%, and 10% at 1, 2 and 4 hours, respectively. A telephone survey assessed GES time at top 20 pediatric gastroenterology centers in the United States. Cost of evaluation of patients diagnosed as having gastroparesis was estimated. Full-time equivalents of nuclear medicine technicians and number of nuclear medicine studies done at Ann & Robert H. Lurie Children's Hospital of Chicago from 2007 to 2010 were examined. RESULTS: A total of 71 patients (32 boys, average age 10.8 years) were studied. Sixty-two percent (n=44) children had abnormal GES; 23% (8/35) of them who had normal values at 2 hours had abnormal GES at 4 hours (P<0.0001). Twenty-eight percent of patients had delayed GES at 1 hour: all persisted to have abnormal GES at 2 and 4 hours. Cost of evaluation of a child for gastroparesis was $9014. Only 5 of the top 20 pediatric gastroenterology centers in the United States conducted 4-hour GES. Transitioning from 2 hours to 4 hours only required scheduling adjustments and did not result in limitation in the number of scheduled patients. CONCLUSIONS: Extending GES to 4 hours results in a considerable increase in diagnosis of gastroparesis. PMID- 23111766 TI - Gastrointestinal ulceration in celiac disease. PMID- 23111765 TI - Immunophenotype predicts outcome in pediatric acute liver failure. AB - OBJECTIVES: We sought to determine whether markers of T-cell immune activation, including soluble interleukin 2 receptor alpha (sIL2Ralpha) levels predict outcome in pediatric acute liver failure and may target potential candidates for immunomodulatory therapy. METHODS: We analyzed markers of immune activation in 77 patients with pediatric acute liver failure enrolled in a multinational, multicenter study. The outcomes were survival with native liver, liver transplantation (LT), and death without transplantation within 21 days after enrollment. RESULTS: Adjusting for multiple comparisons, only normalized serum sIL2Ralpha level differed significantly among the 3 outcomes, and was significantly higher in patients who died (P=0.02) or underwent LT (P=0.01) compared with those who survived with their native liver. The 37 patients with normal sIL2Ralpha levels all lived, 30 with their native liver. Of the 15 subjects with markedly high sIL2Ralpha (>=5000 IU/mL), 5 survived with their native liver, 2 died, and 8 underwent LT. CONCLUSIONS: Evidence of immune activation is present in some patients who die or undergo LT. Patients with higher sIL2Ralpha levels were more likely to die or undergo LT within 21 days than those with lower levels. Identifying a subset of patients at risk for poor outcome may form the foundation for targeted clinical trials with immunomodulatory drugs. PMID- 23111767 TI - alphaalpha- and alphabeta-zinc-meso-A2B2-tetraarylporphyrins with large optical responses to triethylamine. AB - Synthesis and separation of alphaalpha- and alphabeta-meso-A(2)B(2)-zinc(II) tetraarylporphyrin atropisomers with A = mesityl and B = ortho-phenylethynyl phenyl are reported. Both isomers exhibit large optical responses upon axial NEt(3) coordination which are visible to the human eye and could therefore be beneficial for the design of smart amine sensing materials. The larger spectral changes as compared to Zn(TPP) are attributed to pronounced distortions of the porphyrin pi-system due to steric interactions of the coordinating amine with the porphyrin periphery. This effect as well as the coordination site of NEt(3) at the alphaalpha-isomer have been studied by NMR experiments and were rationalized by DFT calculations and NSD analyses. The solubility in non-polar solvents is greatly enhanced as compared to Zn(TPP), especially of the alphaalpha-isomer. This is explained by analysis of the solid state structures as derived from partial single crystal X-ray diffraction studies. PMID- 23111768 TI - Central giant cell granuloma: treatment with calcitonin, triamcinolone acetonide, and a cystic finding 3 years and 6 months after the primary treatment. AB - BACKGROUND: Central giant cell granuloma is a benign condition of the jaws which may present an aggressive behavior. CASE REPORT: A 9-year-old boy was complaining of swelling in the floor of the mouth. A solid swelling was observed in the area of the lower incisors. From the radiographic exam, we observed a radiolucent image in the mandibular bone with well-defined limits extending from the apical region of tooth 33 to the apical region of tooth 42. DISCUSSION: Due to the diagnosis and the age of the patient, we chose a conservative treatment, administering subcutaneous injections of calcitonin. During this treatment, no reduction to the lesion was observed. Therefore, we chose to treat the lesion with triamcinolone acetonide. Monthly follow-ups demonstrated good lesion reduction and the absence of any clinical symptoms during the first 2 years. After a 3-year follow-up, the patient returned, presenting mobility of the lower incisors. A significant increase in the size of the lesion was observed. After a biopsy, with the removal of tissue which had the appearance of a cyst capsule, microscopic analyses were found to be compatible with a secondarily infected cyst. Two months following this procedure, the patient did not present tooth mobility anymore and the oral mucosa presented a normal aspect. Following a radiographic exam, full lesion repair was observed. These conservative treatments should be the first option in cases of central giant cell granuloma and the patient must be observed for a long period of time, until no further clinical or radiographic signs of lesions are observed. PMID- 23111769 TI - Abuse and other correlates of common mental disorders in youth: a cross-sectional study in Goa, India. AB - PURPOSE: There is a paucity of known correlates of common mental disorders (CMDs) among the youth age group in India. This analysis aims to determine risk factors associated with a probable diagnosis of CMD in a youth sample in India. METHODS: This is a secondary analysis of data collected via a door-to-door (community) survey of 3,662 youth (aged 16-24 years) in selected urban and rural areas in Goa. The urban and rural areas were selected based on their engagement with a Goan-based mental health charity organisation, Sangath. Point prevalence of CMD was estimated using the general health questionnaire-12 (GHQ-12). Multivariate logistic regression analyses determined factors associated with CMD and associations were stratified by gender. RESULTS: In total, 3,649 (1,796 urban; 1,853 rural) youth were assessed for probable diagnosis of CMD. There was an almost equal ratio of males (49 %) to females (51 %) in the sample. During the time of the survey, 91 % of the sample was residing with parents, with 83 % being between the ages of 22 and 24 years living with parents. A small proportion of the sample never attended school (1.1 %) with the rest either educated, employed or unemployed. The point prevalence of probable CMD in the sample was 7.87 %; 95 % CI 7.01-8.80 %. Those living in urban areas had a higher prevalence of CMD (9.12 %; 95 % CI 7.90-10.52 %) compared to those living in rural areas (6.60 %; 95 % CI 5.50-7.82 %). After adjusting for a range of potential confounders, independent risk factors for CMD were being older, i.e., between 22- and 24-years old, (OR 1.60; 95 % CI 1.10-2.24; p = 0.015), residing in urban areas (OR 1.51; 95 % CI 1.12-2.04; p = 0.007), physical abuse (beaten in the last 3 months) by parents, teachers or others (OR 3.10; 95 % CI 2.11-4.51; p < 0.001), sexual harassment (OR 2.01; 95 % CI 1.30-3.20; p = 0.003) and sexual abuse (OR 2.54; 95 % CI 1.94-3.33; p < 0.001). Being able to talk about personal problems (OR 0.52; 95 % CI 0.34-0.80; p = 0.003) was a protective factor. After stratifying by gender, sexual harassment, physical and sexual abuse were associated with a likely CMD diagnosis in females and males. CONCLUSIONS: Sexual and recent physical abuses were independent risk factors for CMD in both genders. In addition, being older and being able to discuss problems were associated with CMD diagnosis in females but not in males. PMID- 23111770 TI - Using variances in hydrocarbon concentration and carbon stable isotope to determine the important influence of irrigated water on petroleum accumulation in surface soil. AB - Hunpu is a wastewater-irrigated area southwest of Shenyang. To evaluate petroleum contamination and identify its sources at the area, the aliphatic hydrocarbons and compound-specific carbon stable isotopes of n-alkanes in the soil, irrigation water, and atmospheric deposition were analyzed. The analyses of hydrocarbon concentrations and geochemical characteristics reveal that the water is moderately contaminated by degraded heavy oil. According to the isotope analysis, inputs of modern C3 plants and degraded petroleum are present in the water, air, and soil. The similarities and dissimilarities among the water, air, and soil samples were determined by concentration, isotope, and multivariate statistical analyses. Hydrocarbons from various sources, as well as the water/atmospheric deposition samples, are more effectively differentiated through principal component analysis of carbon stable isotope ratios (delta(13)C) relative to hydrocarbon concentrations. Redundancy analysis indicates that 57.1 % of the variance in the delta(13)C of the soil can be explained by the delta(13)C of both the water and air, and 35.5 % of the variance in the hydrocarbon concentrations of the soil can be explained by hydrocarbon concentrations of both the water and the air. The delta(13)C in the atmospheric deposition accounts for 28.2 % of the delta(13)C variance in the soil, which is considerably higher than the variance in hydrocarbon concentrations of the soil explained by hydrocarbon concentrations of the atmospheric deposition (7.7 %). In contrast to delta(13)C analysis, the analysis of hydrocarbon concentrations underestimates the effect of petroleum contamination in the irrigated water and air on the surface soil. Overall, the irrigated water exerts a larger effect on the surface soil than does the atmospheric deposition. PMID- 23111771 TI - Ozone levels in the Empty Quarter of Saudi Arabia--application of adaptive neuro fuzzy model. AB - In arid regions, primary pollutants may contribute to the increase of ozone levels and cause negative effects on biotic health. This study investigates the use of adaptive neuro-fuzzy inference system (ANFIS) for ozone prediction. The initial fuzzy inference system is developed by using fuzzy C-means (FCM) and subtractive clustering (SC) algorithms, which determines the important rules, increases generalization capability of the fuzzy inference system, reduces computational needs, and ensures speedy model development. The study area is located in the Empty Quarter of Saudi Arabia, which is considered as a source of huge potential for oil and gas field development. The developed clustering algorithm-based ANFIS model used meteorological data and derived meteorological data, along with NO and NO2 concentrations and their transformations, as inputs. The root mean square error and Willmott's index of agreement of the FCM- and SC based ANFIS models are 3.5 ppbv and 0.99, and 8.9 ppbv and 0.95, respectively. Based on the analysis of the performance measures and regression error characteristic curves, it is concluded that the FCM-based ANFIS model outperforms the SC-based ANFIS model. PMID- 23111772 TI - Epidermal growth factor-induced modulation of cytokeratin expression levels influences the morphological phenotype of head and neck squamous cell carcinoma cells. AB - The migratory ability of tumor cells requires cytoskeletal rearrangement processes. Epidermal growth factor receptor (EGFR)-signaling tightly correlates with tumor progression in head and neck squamous cell carcinomas (HNSCCs), and has previously been implicated in the regulation of cytokeratin (CK) expression. In this study, HNSCC cell lines were treated with EGF, and CK expression levels were monitored by Western blot analysis. Changes in cellular morphology were documented by fluorescence- and atomic force microscopy. Some of the cell lines demonstrated an EGF-dependent modulation of CK expression levels. Interestingly, regression of some CK subtypes or initial up-regulation followed by downregulation at higher EGF-levels could also be observed in the tested cell lines. Overall, the influence of EGF on CK expression levels appeared variable and cell-type-dependent. Real-time cellular analysis of EGF-treated and untreated HNSCC cell lines demonstrated a rise over time in cellular impedance. In three of the EGF-treated HNSCC cell lines, this rise was markedly higher than in untreated controls, whereas in one of the cell lines the gain of cellular impedance was paradoxically reduced after EGF treatment, which was found to correlate with changes in cellular morphology rather than with relevant changes in cellular viability or proliferation. After treating HNSCC cells with EGF, CK filaments frequently appeared diffusely distributed throughout the cytoplasm, and in some cases were found in a perinuclear localization, the latter being reminiscent to observations by other groups. In summary, the data points to a possible role of EGFR in modulating HNSCC cell morphology. PMID- 23111773 TI - Comparative microarray analysis of microRNA expression profiles in primary cutaneous malignant melanoma, cutaneous malignant melanoma metastases, and benign melanocytic nevi. AB - Perturbations in microRNA (miRNA) expression profiles have been reported for cutaneous malignant melanoma (CMM) predominantly when examined in cell lines. Despite the rapidly growing number of newly discovered human miRNA sequences, the availability of up-to-date miRNA expression profiles for clinical samples of primary cutaneous malignant melanoma (PCMM), cutaneous malignant melanoma metastases (CMMM), and benign melanocytic nevi (BMN) is limited. Specimens excised from the center of tumors (lesional) from patients with PCMM (n=9), CMMM (n=4), or BMN (n=8) were obtained during surgery. An exploratory microarray analysis was performed by miRNA expression profiling based on Agilent platform screening for 1205 human miRNAs. The results from the microarray analysis were validated by TaqMan quantitative real-time polymerase chain reaction. In addition to several miRNAs previously known to be associated with CMM, 19 unidentified miRNA candidates were found to be dysregulated in CMM patient samples. Among the 19 novel miRNA candidates, the genes hsa-miR-22, hsa-miR-130b, hsa-miR-146b-5p, hsa-miR-223, hsa-miR-301a, hsa-miR-484, hsa-miR-663, hsa-miR-720, hsa-miR-1260, hsa-miR-1274a, hsa-miR-1274b, hsa-miR-3663-3p, hsa-miR-4281, and hsa-miR-4286 were upregulated, and the genes hsa-miR-24-1*, hsa-miR-26a, hsa-miR-4291, hsa-miR 4317, and hsa-miR-4324 were downregulated. The results of this study partially confirm previous CMM miRNA profiling studies identifying miRNAs that are dysregulated in CMM. However, we report several novel miRNA candidates in CMM tumors; these miRNA sequences require further validation and functional analysis to evaluate whether they play a role in the pathogenesis of CMM. PMID- 23111774 TI - Evaluation of the cognitive functions in patients with chronic renal failure before and after renal transplantation. AB - Chronic renal failure (CRF) and dialysis treatment affect central nervous system and studies have shown that neurocognitive dysfunctions are caused by CRF and dialysis treatment. The aim of this study was to evaluate the changes in cognitive functions of CRF patients after renal transplantation. Neurocognitive functions of 40 renal transplantation patients aged 18-65 years were determined before, 6 and 12 months after transplantation between 2008 and 2010 using neuropsychological tests. Rey Auditory-Verbal Learning Test (RVLT), Rey Complex Figure Test (RCFT), ADAS-cog Test, Stroop Test (ST), Digit Span Test (DST), and Trail Making Test (TMT) were applied. The test results were statistically compared taking into consideration the patients' levels of education, age, gender, donor type, duration of dialysis, dialysis type, and duration of CRF. Neuropsychological test results statistically significantly increased in all the patients after renal transplantation (p < 0.05). The female patients' RVLT test results were statistically higher than the test results of the male patients (p < 0.05). DST, RCFT, RVLT, and (Verbal Fluency Test) VFT results were statistically higher in the patients who were 33 years old or younger (p < 0.05). The patients with high school and college education had statistically significantly higher results in all the tests when compared with the patients that were elementary school graduates (p < 0.05). DST forward task, ST, and RVLT results of the patients, who had received dialysis treatment for 1 year or less, were found to be statistically higher than the results of the patients who had received dialysis for more than 1 year (p < 0.05). The results of RCFT, RVLT, DST backward task, and VFT were statistically higher in the peritoneal dialysis patients than in the hemodialysis patients (p < 0.05). The donor type and the duration of CRF had no significant effects on the results (p > 0.05). The results of this study showed significant improvement in attention, memory, executive functions, pace of data processing and language functions in CRF patients after renal transplantation, as proven with neuropsychological tests. PMID- 23111775 TI - Nicardipine in the treatment of aneurysmal subarachnoid haemorrhage: a meta analysis of published data. AB - Nicardipine is a dihydropyridine-type Ca(2+) channel blocker with a powerful antihypertensive activity and a unique cerebrovascular profile. Recent studies have examined nicardipine for the treatment of patients with aneurysmal subarachnoid haemorrhage (SAH), but have shown inconsistent results. In the current study, a meta-analysis was performed to assess the clinical effectiveness of nicardipine in the prevention of cerebral vasospasm in patients who had suffered from aneurysmal SAH. Medline, EMBASE, and PubMed databases were searched for the controlled trials evaluating nicardipine for treating SAH after a ruptured aneurysm, without language restrictions. Moreover, a manual search of the bibliographies of relevant articles was also conducted. Two researchers of the present study independently performed the literature search and the data extraction. The meta-analyses were performed using the software RevMan 4.2.10 (provided by the Cochrane Collaboration, Oxford, UK). Five published manuscripts involving 1,154 patients were included in this meta-analysis. Nicardipine infusion reduced the risk of poor outcome (death, vegetative state, or dependency) and mortality, with an odds ratio (OR) of 0.58 [95 % confidence interval (CI) 0.37-0.90] and 0.45 (95 % CI 0.15-1.29), respectively. This meta analysis suggests that nicardipine therapy reduces the likelihood of poor outcome and mortality in patients after aneurysmal SAH. PMID- 23111776 TI - Epileptic seizures in multiple sclerosis: a population-based survey in Iran. AB - No large population-based survey has until now been carried out on the linkage of epilepsy (EP) and multiple sclerosis (MS) either in the middle-east or in Asia. In this retrospective population-based study (April 2003 to July 2010) on the total Isfahan cohort of 3,522 Iranian MS patients, we looked for EP/MS patients and compared their features with 1,665 non-EP/MS cases. We identified 105 cases, though, 24 were excluded for an implausible EP/MS link. Among 81 (2.3 %) eligible cases, EP occurred (1) within a mean duration of 5.6 +/- 5.4 years after the development of MS in 64 cases (79 %); (2) at MS onset as the presenting symptom in five cases (6.2 %); and, (3) by a mean duration of 4.3 +/- 4.3 years prior to onset of MS in 12 patients (14.8 %). The overall mean ages at MS onset and at the first seizure episode were 28.5 +/- 11.2 years and 32.5 +/- 14.0 years, respectively. Regarding the age at onset of MS, 12.3 % of EP/MS patients were classified as early-onset; 81.5 % as adult-onset; and 6.2 % as late-onset. Such frequencies were statistically different (P < 0.0001) from those of the 1,665 control non-EP/MS patients (5.9; 93.0 and 1.1 %, respectively). Regarding the pattern of MS, EP/MS patients were classified as relapsing-remitting, secondary progressive, and primary progressive in 60.5, 25.9, and 13.6 %, respectively. This configuration differed (P < 0.0001) from that of non-EP patients (87.9; 6.3 and 5.7 %, respectively). Our results are suggestive of differences between EP/MS and non-EP/MS cases as regards the proportion of MS patterns and age-at-onset classifications. PMID- 23111777 TI - Investigation of the prevalence of essential tremor in individuals aged 18-60 in Erzurum. AB - Essential tremor (ET) is one of the common neurological diseases and it is the most common movement disorder in adults. The main clinical finding in patients with ET is kinetic tremor in the arms. There is no adequate study investigating the prevalence of ET in Turkey. Therefore, this study was planned in the center of the city of Erzurum in order to determine the prevalence of essential tremor in our region. This study was performed door to door in the center of the city of Erzurum. ET screening questionnaires were administered to all participants between the ages of 18-60 at first stage. Those who answer yes to any of the first five questions of the questionnaire were evaluated. Patients without a clear differential diagnosis were called for examination to the neurology department and they were re-evaluated by a faculty member specializing in movement disorders. Patients were classified by using Washington Heights-Inwood Genetic Study of Essential Tremor diagnostic and clinical evaluation scale. The prevalence of ET was calculated as 1.60 % (64 out of 4,024 participants). 30 of the cases were male and 34 were female. First-degree relatives of 30 patients with ET had a history of tremor. While 52 patients had tremor only in their hands, 11 patients had in various organs including hands. There was isolated head tremor in one patient. ET prevalence was increasing with age. The prevalence of ET in people between the ages of 18 and 60 was calculated as 1.60 %. This value is compatible with other measurements of the prevalence of ET. PMID- 23111778 TI - Thalamic laminar necrosis. PMID- 23111779 TI - Ultrasound in free-floating thrombus of the carotid artery: the best diagnostic tool to detect this under estimated condition? PMID- 23111780 TI - Feasibility of transcranial Doppler and single photon emission computed tomography in compound neuroactivation task. AB - The aim of this study was to test feasibility of transcranial Doppler (TCD) and single photon emission computed tomography (SPECT) during compound neuroactivation task. The study was performed in 60 healthy right-handed volunteers. Cerebral blood flow velocity was measured by TCD in both middle cerebral arteries (MCA) at baseline and during computer game. The same stimulus and response pattern was used in 15 subjects that additionally underwent brain SPECT. Percentage differences between measurements were determined through quantitative result assessment. Both methods detected a statistically significant cerebral blood flow increase during neuroactivation. Correlation of TCD and SPECT showed statistically significant correlation only for the increase of cerebral blood flow velocity in the right MCA and for the right-sided cerebral blood flow increase, demonstrating that both methods partially measure similar cerebral blood flow changes that occur during neuroactivation. Comparison of TCD and SPECT showed TCD to be inadequately sensitive method for evaluation of cerebral blood flow during complex activation paradigm. PMID- 23111781 TI - Prevalence of restless legs syndrome in Ankara, Turkey: an analysis of diagnostic criteria and awareness. AB - The aim of this study was threefold: (1) to investigate the prevalence of restless legs syndrome (RLS), in Ankara, Turkey; (2) to determine the predictive values of diagnostic criteria; and (3) to determine the frequency of physician referrals and the frequency of getting the correct diagnosis. A total of 815 individuals, from randomly selected addresses, above the age of 15, were reached using the questionnaire composed of the four diagnostic criteria. Individuals who responded by answering 'yes' for at least one question were interviewed by neurologists for the diagnosis of RLS. Frequency of physician referrals and frequency of getting the correct diagnosis of RLS were also determined for patients getting the final diagnoses of RLS. Prevalence of RLS in Ankara was 5.52 %; 41.0 % of the individuals diagnosed with RLS had replied 'yes' to either one, two or three questions asked by interviewers. However, only 21.3 % of individuals who replied 'yes' to all four questions received the diagnosis of RLS. Among the patients who had the final diagnosis of RLS, 25.7 % had referred to a physician for the symptoms and 22.2 % got the correct diagnosis. The RLS prevalence in Ankara was somewhere between Western and Far East countries compatible with the geographical location. Diagnostic criteria may not be fully predictive when applied by non-physician pollsters. Physician's probability of correctly diagnosing RLS is still low. PMID- 23111782 TI - Cerebral blood flow and metabolic changes in hippocampal regions of a modified rat model with chronic cerebral hypoperfusion. AB - Chronic cerebral hypoperfusion (CCH) causes neurodegeneration which contributes to the cognitive impairment. This study utilized a modified rat model with CCH to investigate cerebral blood flow (CBF) and hippocampal metabolic changes. CBF was measured by laser Doppler flowmetry. Various metabolic ratios were evaluated from selective volumes of interest (VOI) in left hippocampal regions using in vivo proton magnetic resonance spectroscopy ((1)H-MRS). The ultrastructural changes with special respect to ribosomes in rat hippocampal CA1 neurons were studied by electron microscopy. CBF decreased immediately after CCH and remained reduced significantly at 1 day and 3 months postoperatively. (1)H-MRS revealed that CCH led to a significant decrease of N-acetyl aspartate/creatine (NAA/Cr) ratio in the hippocampal VOI in the model rats compared with the sham-operated control rats. However, no changes of myo-inositol/Cr, choline/Cr and glutamate and glutamine/Cr ratios between the model and control groups were observed. Under electron microscopy, most rosette-shaped polyribosomes were relatively evenly distributed in the hippocampal CA1 neuronal cytoplasms of the control rats. After CCH, most ribosomes were clumped into large abnormal aggregates in the model rats. Our data suggests that both permanent decrease of CBF and reduction of NAA/Cr ratio in the hippocampal regions may be related to the cognitive deficits in rats with CCH. PMID- 23111783 TI - Methylobacillus rhizosphaerae sp. nov., a novel plant-associated methylotrophic bacterium isolated from rhizosphere of red pepper. AB - A novel plant-associated obligate methylotrophic bacterium, designated strain Ca 68(T), was isolated from the rhizosphere soil of field-grown red pepper from India. The isolates are strictly aerobic, Gram negative, motile rods multiplying by binary fission and formaldehyde is assimilated via the ribulose monophosphate pathway. A comparative 16S rRNA gene sequence-based phylogenetic analysis placed the strain in a clade with the species Methylobacillus flagellatus, Methylobacillus glycogens and Methylobacillus pratensis, with which it showed pairwise similarity of 97.8, 97.4 and 96.2 %, respectively. The major fatty acids are C(16:0), C(10:0) 3OH and C(16:1) omega7c. The G+C content of the genomic DNA is 59.7 mol%. The major ubiquinone is Q-8. Dominant phospholipids are phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol. Based on 16S rRNA gene sequence analysis and DNA-DNA relatedness (14-19 %) with type strains of the genus Methylobacillus, the novel isolate was classified as a new species of this genus and named Methylobacillus rhizosphaerae Ca-68(T) (=KCTC 22383(T) = NCIMB 14472(T)). PMID- 23111784 TI - Verrucosispora fiedleri sp. nov., an actinomycete isolated from a fjord sediment which synthesizes proximicins. AB - A novel filamentous actinobacterial organism, designated strain MG-37(T), was isolated from a Norwegian fjord sediment and examined using a polyphasic taxonomic approach. The organism was determined to have chemotaxonomic and morphological properties consistent with its classification in the genus Verrucosispora and formed a distinct phyletic line in the Verrucosispora 16S rRNA gene tree. It was most closely related to Verrucosispora maris DSM 45365(T) (99.5 % 16S rRNA gene similarity) and Verrucosispora gifhornensis DSM 44337(T) (99.4 % 16S rRNA gene similarity) but was distinguished from these strains based on low levels of DNA:DNA relatedness (~56 and ~50 %, respectively). It was readily delineated from all of the type strains of Verrucosispora species based on a combination of phenotypic properties. Isolate MG-37(T) (=NCIMB 14794(T) = NRRL-B 24892(T)) should therefore be classified as the type strain of a novel species of Verrucosispora for which the name Verrucosispora fiedleri is proposed. PMID- 23111785 TI - A simple method for simultaneous RP-HPLC determination of indolic compounds related to bacterial biosynthesis of indole-3-acetic acid. AB - In this short technical report, we present a fast and simple procedure for sample preparation and a single-run Reversed Phase High Performance Liquid Chromatography (RP-HPLC) determination of seven indoles (indole-3-acetic acid, indole-3-acetamide, indole-3-acetonitrile, indole-3-ethanol, indole-3-lactic acid, tryptamine and tryptophan) in bacterial culture supernatants. The separation of the analytes, after a single centrifugal filtration clean-up step, was performed using a gradient elution on a symmetry C8 column followed by fluorimetric detection (lambda(ex) = 280/lambda(em) = 350 nm). The calibration curves were linear for all of the studied compounds over the concentration range of 0.0625-125 MUg mL(-1) (r ( 2 ) >= 0.998) and the limits of detection were below 0.015 MUg mL(-1). The applicability of the method was confirmed by analysis of Pseudomonas putida culture supernatants. PMID- 23111786 TI - Plant regeneration and genetic transformation of C. canadensis: a non-model plant appropriate for investigation of flower development in Cornus (Cornaceae). AB - KEY MESSAGE : Efficient Agrobacterium -mediated genetic transformation for investigation of genetic and molecular mechanisms involved in inflorescence architectures in Cornus species. Cornus canadensis is a subshrub species in Cornus, Cornaceae. It has recently become a favored non-model plant species to study genes involved in development and evolution of inflorescence architectures in Cornaceae. Here, we report an effective protocol of plant regeneration and genetic transformation of C. canadensis. We use young inflorescence buds as explants to efficiently induce calli and multiple adventitious shoots on an optimized induction medium consisting of basal MS medium supplemented with 1 mg/l of 6-benzylaminopurine and 0.1 mg/l of 1-naphthaleneacetic acid. On the same medium, primary adventitious shoots can produce a large number of secondary adventitious shoots. Using leaves of 8-week-old secondary shoots as explants, GFP as a reporter gene controlled by 35S promoter and hygromycin B as the selection antibiotic, a standard procedure including pre-culture of explants, infection, co cultivation, resting and selection has been developed to transform C. canadensis via Agrobacterium strain EHA105-mediated transformation. Under a strict selection condition using 14 mg/l hygromycin B, approximately 5 % explants infected by Agrobacterium produce resistant calli, from which clusters of adventitious shoots are induced. On an optimized rooting medium consisting of basal MS medium supplemented with 0.1 mg/l of indole-3-butyric acid and 7 mg/l hygromycin B, most of the resistant shoots develop adventitious roots to form complete transgenic plantlets, which can grow normally in soil. RT-PCR analysis demonstrates the expression of GFP transgene. Green fluorescence emitted by GFP is observed in transgenic calli, roots and cells of transgenic leaves under both stereo fluorescence microscope and confocal microscope. The success of genetic transformation provides an appropriate platform to investigate the molecular mechanisms by which the various inflorescence forms are developed in Cornus plants. PMID- 23111787 TI - Wheat hypersensitive-induced reaction genes TaHIR1 and TaHIR3 are involved in response to stripe rust fungus infection and abiotic stresses. AB - KEY MESSAGE : TaHIR1 and TaHIR3 play positive roles in resistance to the stripe rust fungus via inducing HR and regulating defense-related genes, but are negatively regulated by various abiotic stimuli. Plant hypersensitive-induced reaction (HIR) genes are known to be associated with the hypersensitive response and disease defense. In wheat, two HIR genes, TaHIR1 and TaHIR3, have been identified and found to be up-regulated after infection with the stripe rust fungus. Here, we further determined their roles in defense against abiotic stresses and the stripe rust pathogen, Puccinia striiformis f. sp. tritici. TaHIR1 and TaHIR3 proteins were localized in the plasma membrane of tobacco cells. The expression of TaHIR1 and TaHIR3 was reduced by the environmental stimuli, including low temperature, drought, and high salinity stresses. In addition, the expression of TaHIR1 and TaHIR3 was down-regulated by exogenously applied ethrel and abscisic acid, whereas expression was not affected by treatments with salicylic acid and methyl jasmonate. Furthermore, barley stripe mosaic virus-induced gene silencing of TaHIR1 and TaHIR3 reduced resistance in wheat cultivar Suwon11 against an avirulent stripe rust pathotype CYR23 and area of necrotic cells neighboring the infection sites, and altered the expression levels of defense-related genes. These results suggest that TaHIR1 and TaHIR3 function positively in the incompatible interaction of wheat-stripe rust fungus, but exhibit negative transcriptional response to abiotic stresses. PMID- 23111788 TI - Expression of hsp70, hsp100 and ubiquitin in Aloe barbadensis Miller under direct heat stress and under temperature acclimation conditions. AB - KEY MESSAGE : The study determined the tolerance of Aloe vera to high temperature, focusing on the expression of hsp70 , hsp100 and ubiquitin genes. These were highly expressed in plants acclimated at 35 degrees C prior to a heat shock of 45 degrees C. Aloe barbadensis Miller (Aloe vera), a CAM plant, was introduced into Chile in the semiarid IV and III Regions, which has summer diurnal temperature fluctuations of 25 to 40 degrees C and annual precipitation of 40 mm (dry years) to 170 mm (rainy years). The aim of this study was to investigate how Aloe vera responds to water and heat stress, focusing on the expression of heat shock genes (hsp70, hsp100) and ubiquitin, which not studied before in Aloe vera. The LT(50) of Aloe vera was determined as 53.2 degrees C. To study gene expression by semi-quantitative RT-PCR, primers were designed against conserved regions of these genes. Sequencing the cDNA fragments for hsp70 and ubiquitin showed a high identity, over 95 %, with the genes from cereals. The protein sequence of hsp70 deduced from the sequence of the cDNA encloses partial domains for binding ATP and the substrate. The protein sequence of ubiquitin deduced from the cDNA encloses a domain for interaction with the enzymes E2, UCH and CUE. The expression increased with temperature and water deficit. Hsp70 expression at 40-45 degrees C increased 50 % over the controls, while the expression increased by 150 % over the controls under a water deficit of 50 % FC. The expression of all three genes was also studied under 2 h of acclimation at 35 or 40 degrees C prior to a heat shock at 45 degrees C. Under these conditions, the plants showed greater expression of all genes than when they were subjected to direct heat stress. PMID- 23111789 TI - Microfluidic filtration system to isolate extracellular vesicles from blood. AB - Extracellular vesicles are released by various cell types, particularly tumor cells, and may be potential targets for blood-based cancer diagnosis. However, studies performed on blood-borne vesicles to date have been limited by lack of effective, standardized purification strategies. Using in situ prepared nanoporous membranes, we present a simple strategy employing a microfluidic filtration system to isolate vesicles from whole blood samples. This method can be applied to purify nano-sized particles from blood allowing isolation of intact extracellular vesicles, avoiding the need for laborious and potentially damaging centrifugation steps or overly specific antibody-based affinity purification. Porous polymer monoliths were integrated as membranes into poly(methyl methacrylate) microfluidic chips by benchtop UV photopolymerization through a mask, allowing precise positioning of membrane elements while preserving simplicity of device preparation. Pore size could be manipulated by changing the ratio of porogenic solvent to prepolymer solution, and was tuned to a size proper for extraction of vesicles. Using the membrane as a size exclusion filter, we separated vesicles from cells and large debris by injecting whole blood under pressure through the microfluidic device. To enhance isolation purity, DC electrophoresis was employed as an alternative driving force to propel particles across the filter and increase the separation efficiency of vesicles from proteins. From the whole blood of melanoma-grown mice, we isolated extracellular vesicles and performed RT-PCR to verify their contents of RNA. Melan A mRNA derived from melanoma tumor cells were found enriched in filtered samples, confirming the recovery of vesicles via their cargo. This filtration system can be incorporated into other on-chip processes enabling integrated sample preparation for the downstream analysis of blood-based extracellular vesicles. PMID- 23111790 TI - Experiences using the Fixin locking plate system for the stabilization of appendicular fractures in dogs: a clinical and radiographic retrospective assessment. AB - OBJECTIVES: To retrospectively evaluate the stabilization of appendicular fractures in dogs using the Fixin locking plate system. MATERIALS AND METHODS: Medical records and radiographs of dogs with fractures stabilized with the Fixin system in the period from May 2005 to September 2010 were reviewed. For each patient, data pertaining to signalment, the nature of the fracture, implants used, and evidence of fracture healing were recorded. The outcome and complications were determined from clinical and radiographic follow-up examinations. Limb function was evaluated between 40 days and 90 days postoperatively. Owners of pets with complications were contacted by phone for long-term follow-up. RESULTS: Eighty-two fractures in seventy-five dogs met the inclusion criteria for the study. Radiographic re-examinations were carried out between eight days to two years (median 60 days) following surgery. Seventy-three out of 82 fractures (89%) reached union without complications. Major complications were seen in six dogs (7%). Limb function was graded as 'normal' in 73/75 (97%) dogs and 'mild lameness' in 2/75 (3%) cases. CLINICAL SIGNIFICANCE: Despite a modest complication rate, the Fixin locking bone plating system appears to be an acceptable choice of implant for the stabilization of appendicular fractures in dogs. PMID- 23111791 TI - [Acute myeloic leukemia: evaluation of colony-stimulating factors]. PMID- 23111792 TI - [Does sports help against depression in patients with heart insufficiency?- Fitness training improves depressive mood]. PMID- 23111793 TI - [The German academic degree "Dr. med." is better than its reputation. Results of a questionnaire of doctoral students]. AB - BACKGROUND: Recently there were mostly emotional debates about the scientific background and relevance of the German academic title "Dr. med.", while objective data are scarce. METHODS: When submitting their doctoral thesis at the Medical School of Hannover students were asked anonymously about the type, topic, duration, quality of supervision as well as frequency and type of publication of the results. RESULTS: 180 doctoral candidates (62% women) participated in the study. The supervision was graded as good by the majority of students. The duration working on the thesis was equivalent to 47 weeks of a full time employment. There was some negative influence in participating in lectures and courses. Nearly all participants (98%) would recommend younger students to work on a dissertation as they had done themselves in parallel to the curriculum. The ability of how to interprete scientific data was assumed to be positively influenced. About two thirds stated that the results had been published in original articles at the time of submitting the thesis. CONCLUSIONS: More data from other medical faculties are needed to document the relevance of the medical dissertation to replace the emotional by a more rational debate. PMID- 23111794 TI - [A giant non-parasitic liver cyst as a prominent epigastric mass in an obese patient]. AB - HISTORY AND ADMISSION FINDINGS: A 62-year-old, obese male patient was referred because of an increasing prominent epigastric mass and bloated feeling. An epigastric hernial defect was clinically excluded. INVESTIGATIONS: Abdominal imaging by ultrasound and CT-scan demonstrated a giant liver cyst in the left lobe of 20 cm in diameter with a displacement of the stomach. Endoscopy showed an external compression of the stomach. Cystic echinococcosis was excluded by serology. TREATMENT AND COURSE: Laparoscopic deroofing of the cyst resulted in immediate freedom of symptoms. The further course was uneventful. The patient was discharged one day after the operation. CONCLUSION: Liver cysts may become symptomatic by intestinal compression syndromes or - occasionally - as a prominent abdominal mass. Laparoscopic deroofing is the golden standard of symptomatic non parasitic liver cysts and is associated with a good clinical outcome. PMID- 23111795 TI - [42-year-old woman with pain of wrist after a fall]. PMID- 23111796 TI - [Aortic dissection]. AB - Acute aortic syndrome (AAS) is a modern term to describe interrelated emergency aortic conditions with similar clinical characteristics and challenges. These conditions include aortic dissection, intramural haematoma (IMH), and penetrating atherosclerotic ulcer (PAU and aortic rupture); trauma to the aorta with intimal laceration may also be considered. The common denominator of AAS is disruption of the media layer of the aorta with bleeding within IMH, along the aortic media resulting in separation of the layers of the aorta (dissection), or transmurally through the wall in the case of ruptured PAU or trauma. Population-based studies suggest that the incidence of acute dissection ranges from 2 to 3.5 cases per 100 000 person/year; hypertension and a variety of genetic disorders with altered connective tissues are the most prevalent risk conditions. Patients with AAS often present in a similar fashion, regardless of the underlying condition of dissection, IMH, PAU, or contained aortic rupture. Pain is the most commonly presenting symptom of acute aortic dissection and should prompt immediate attention including diagnostic imaging modalities (such as multislice computed tomography, transoesophageal ultrasound, or magnetic resonance imaging). Prognosis is clearly related to undelayed diagnosis and appropriate surgical repair in the case of proximal involvement of the aorta; affection of distal segments of the aorta may call for individualized therapeutic approaches favouring endovascular in the presence of malperfusion or imminent rupture, or medical management. PMID- 23111797 TI - [The change of pathology in the era of personalized medicine using the example of discordant KRAS mutational status in metastasized colorectal carcinoma]. AB - Modern pathology has developed from "omega" to "alpha" and is vital for therapy and follow-up of tumor treatment today. Pathology has a key role as part of personalized medicine. It is possible to intervene therapeutically into the molecular genetic intricacy of tumors by establishing predictive biomarkers with corresponding tumor therapeutic agents.By identifying the KRAS mutational status at the metastasized colorectal carcinoma, a statement about the benefit of an anti-EGFR-therapy can be given, which is nowadays the basis of diagnostic and therapy of this cancer.For a long period of time a high concordance between primary and metastases inside the KRAS status was taken for granted. Meanwhile, there are many studies demonstrating a possibly underestimated high degree of discordance. The identification of discordances might gather a subcollective, which partially holds a KRAS wild type tissue and thereby might respond with a partial remission. Thus, the survival time of these patients and their quality of living could be successfully improved. PMID- 23111798 TI - [Renal co-morbidity after solid organ transplantation]. PMID- 23111799 TI - [Contrast-enhanced ultrasound]. AB - Contrast enhanced ultrasound (CEUS) is increasingly accepted in the clinical use for diagnostic imaging. The new guidelines and recommendations provide general advice for the use and procedure of CEUS. PMID- 23111800 TI - Complex design of dissipation signals in non-contact atomic force microscopy. AB - Complex interplay between topography and dissipation signals in Non-Contact Atomic Force Microscopy (NC-AFM) is studied by a combination of state-of-the-art theory and experiment applied to the Si(001) surface prone to instabilities. Considering a wide range of tip-sample separations down to the near-contact regime and several tip models, both stiff and more flexible, a sophisticated architecture of hysteresis loops in the simulated tip force-distance curves is revealed. At small tip-surface distances the dissipation was found to be comprised of two related contributions due to both the surface and tip. These are accompanied by the corresponding surface and tip distortion approach-retraction dynamics. Qualitative conclusions drawn from the theoretical simulations such as large dissipation signals (>1.0 eV) and a step-like dissipation dependent on the tip-surface distance are broadly supported by the experimental observations. In view of the obtained results we also discuss the reproducibility of NC-AFM imaging. PMID- 23111801 TI - Valley and subband-selective electronic transport through a line defect embedded carbon nanotube. AB - We theoretically demonstrate the possibility of realizing the valley and subband selective electronic transport properties if line defects are embedded in an armchair carbon nanotube. The physical mechanism for such an interesting transport property is clearly due to the appearance of the special subband spanning two valleys without dispersion, caused by the presence of the line defect. In contrast to a perfect zigzag-edged graphene nanoribbon, which was previously suggested to be a nanodevice prototype to manipulate the valley and subband degrees of freedom, our structure, the line defect embedded carbon nanotube, is less demanding for the current nanotechnique. Therefore, our theoretical investigation provides an alternative and feasible structure to design carbon-based nanoelectronic devices. PMID- 23111802 TI - Familial Mediterranean fever in Japan. AB - Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease that is prevalent in Mediterranean populations. While it is considered a rare disease in the rest of world, a significant number of FMF patients have been reported in East Asia, including Japan. Our aim was to determine the prevalence of FMF in Japan and elucidate the clinical and genetic features of Japanese patients. A primary nationwide survey of FMF was conducted between January and December 2009. Hospitals specializing in pediatrics and hospitals with pediatric, internal medicine, and rheumatology/allergy departments were asked to report all patients with FMF during the survey year. The estimated total number of Japanese FMF patients was 292 (95% confidence interval, 187-398 people). We evaluated the clinical and genetic profiles of Japanese patients from the data obtained in a secondary survey of 134 FMF patients. High-grade fever was observed in 95.5%, chest pain (pleuritis symptoms) in 36.9%, abdominal pain (peritonitis symptoms) in 62.7%, and arthritis in 31.3%. Of the patients profiled, 25.4% of patients experienced their first attack before 10 years of age, 37.3% in their teens, and 37.3% after age 20 years. Colchicine was effective in 91.8% of patients at a relatively low dose (mean dose, 0.89 +/- 0.45 mg/d). AA amyloidosis was confirmed in 5 patients (3.7%). Of the 126 patients studied, 109 (86.5%) were positive for 1 or more genetic mutations and 17 (13.5%) had no mutation detected. Common Mediterranean fever gene (MEFV) mutations were E148Q/M694I (19.8%) and M694I/normal (12.7%). The differences in the prevalence of peritonitis, pleuritis, and a family history of FMF were statistically significant between FMF patients with MEFV exon 10 mutations compared with those without exon 10 mutations.In conclusion, a significant number of patients with FMF exist in Japan. Although Japanese patients with FMF are clinically or genetically different from Mediterranean patients, the delay in diagnosis is an issue that should be resolved. PMID- 23111804 TI - Bedside diagnosis of bilateral diaphragmatic paralysis. PMID- 23111803 TI - Experimental exposure of red-legged partridges (Alectoris rufa) to seeds coated with imidacloprid, thiram and difenoconazole. AB - Pesticide coated seeds are commonly used in agriculture, and may be an important source of food for some birds in times of scarcity, as well as a route of pesticide ingestion. We tested the lethal and sub-lethal effects of treated seed ingestion by the red-legged partridge (Alectoris rufa), a game bird of high socio economic value in Spain. One year-old partridges (n = 42 pairs) were fed for 10 days in spring (prior to breeding) with wheat treated with difenoconazole (fungicide), thiram (fungicide) or imidacloprid (insecticide), using two doses for each pesticide (the one recommended, and its double to represent potential cases of abuse of pesticides). We investigated the direct and indirect effects on the body condition, physiology, immunology, coloration and subsequent reproduction of exposed partridges. For the latter, eggs were collected, measured and incubated and the growth and survival of chicks were monitored. Thiram and imidacloprid at high exposure doses produced mortalities of 41.6 and 58.3 %, respectively. The first death was observed at day 3 for imidacloprid and at day 7 for thiram. Both doses of the three pesticides caused sublethal effects, such as altered biochemical parameters, oxidative stress and reduced carotenoid-based coloration. The high exposure doses of imidacloprid and thiram also produced a decrease in cellular immune response measured by the phytohemagglutinin test in males. Bearing in mind the limitation of the small number of surviving pairs in some treatments, we found that the three pesticides reduced the size of eggs and imidacloprid and difenoconazole also reduced the fertilization rate. In addition, both thiram and imidacloprid reduced chick survival. These experiments highlight that the toxicity of pesticide-treated seeds is a factor to consider in the decline of birds in agricultural environments. PMID- 23111806 TI - Anatomic reconstruction of the medial patellofemoral ligament in children and adolescents with open growth plates: surgical technique and clinical outcome. AB - BACKGROUND: Recurrent lateral patellar dislocation is a common knee injury in the skeletally immature adolescent. Because of the open physis, operative therapy in children is challenging. This study presents the outcomes of a minimally invasive technique for anatomic reconstruction of the medial patellofemoral ligament (MPFL) in children that respects the distal femoral physis. HYPOTHESIS: Anatomic reconstruction of the MPFL in children that maintains the distal femoral physis will prevent redislocation, preserve the distal femoral physis, and improve knee function. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-one consecutive patients with patellofemoral instability and open growth plates underwent anatomic reconstruction of the MPFL that maintained the distal femoral growth plate. Preoperative radiographic examination included AP and lateral views to assess patella alta and limb alignment. Magnetic resonance imaging was performed to evaluate trochlear dysplasia and tibial tubercle-trochlear groove (TT-TG) distance. Evaluation included preoperative and postoperative physical examination, Kujala score, and Tegner activity score. RESULTS: The average age at the time of operation was 12.2 years (range, 10.3-13.9). The average follow-up after operation was 2.8 years after surgery (range, 2.0-3.6). No recurrent dislocation occurred, but 2 patients with high-grade trochlear dysplasia still had a positive apprehension sign. The Kujala score significantly improved from 72.9 (range, 37-87) preoperatively to 92.8 (range, 74-100) postoperatively (P < .01). The Tegner activity score decreased, but not significantly, from 6.0 (range, 3-9) preoperatively to 5.8 (range, 3-9) postoperatively (P = .48). CONCLUSION: Anatomic reconstruction of the MPFL that respects the distal femoral physis in skeletally immature patients is a safe and effective technique for the treatment of patellofemoral instability and allows patients to return to sports without redislocation of the patella. PMID- 23111805 TI - Beneficial effects of stress-dose corticosteroid therapy in canines depend on the severity of staphylococcal pneumonia. AB - PURPOSE: The effects of stress-dose corticosteroid therapy were studied in a canine staphylococcal pneumonia model of septic shock. METHODS: Immediately following intrabronchial bacterial challenge, purpose-bred beagles were treated with stress doses of desoxycorticosterone (DOC), a mineralocorticoid agonist, and dexamethasone (DEX), a glucocorticoid agonist, or with placebo for 96 h. Oxacillin (30 mg/kg every 8 h) was started 4 h after infection onset. Bacterial dose was titrated to achieve 80-90 % lethality (n = 20) using an adaptive design; additional animals (n = 18) were investigated using the highest bacterial dose. RESULTS: Initial analysis of all animals (n = 38) demonstrated that the effects of DOC + DEX were significantly altered by bacterial dose (p = 0.04). The treatment effects of DOC + DEX were different in animals administered high or relatively lower bacterial doses in terms of survival (p = 0.05), shock reversal (p = 0.02), interleukin-6 levels (p = 0.02), and temperature (p = 0.01). DOC + DEX significantly improved the above parameters (p <= 0.03 for all) and lung injury scores (p = 0.02) after high-dose bacterial challenges, but not after lower challenges (p = not significant for all). Oxacillin trough levels were below the minimum inhibitory concentration of the infecting organism, and DOC + DEX increased the frequency of persistent staphylococcal bacteremia (odds ratio 3.09; 95 % confidence interval 1.05-9.11; p = 0.04). CONCLUSIONS: Stress-dose corticosteroids were only beneficial in cases of sepsis with high risk for death and even short courses may interfere with host mechanisms of bacterial clearance. PMID- 23111807 TI - Return to competitive play after hamstring injuries involving disruption of the central tendon. AB - BACKGROUND: The hamstring muscles are the most commonly injured muscle group in many different sports. Recovery time is often unpredictable and prolonged, and recurrent injury is common. HYPOTHESIS: Hamstring injuries that disrupt the central tendon enclosed within the muscle belly require a longer recovery time than do injuries involving only muscle, epimysial fascia, or the musculotendinous junction. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Injury records from professional sports teams were reviewed to determine the length of recovery from each hamstring injury that occurred over a 24-month period. The integrity of the central tendon on magnetic resonance imaging (MRI) was retrospectively reviewed for each case. The association between central tendon disruption on MRI and recovery time was determined. RESULTS: There were 62 hamstring injuries included for analysis; 45 (72%) involved the biceps femoris, 11 (18%) involved the semimembranosus, and 6 (10%) involved the semitendinosus. Central tendon disruption was identified in 12 (45%) of the biceps femoris injuries and in none of the injuries to the other 2 muscles. Three of these injuries were treated surgically, with a median recovery time of 91 days. The median (interquartile range [IQR]) recovery times for those remaining biceps femoris injuries with and without central tendon disruption were 21 days (IQR, 9 28) and 72 days (IQR, 42-109), respectively (P < .01). CONCLUSION: Disruption of the central tendon in injuries to the biceps femoris results in a significantly longer recovery time than injuries that do not disrupt the central tendon. This highlights the distinction between injury to the hamstring muscle and injury to the hamstring tendon, which is underappreciated as being a distinct entity when injury involves the enclosed central portion of the tendon. PMID- 23111808 TI - The life cycle of Haemaphysalis qinghaiensis (Acari: Ixodidae) ticks under laboratory conditions. AB - The developmental stages in the life cycle of Haemaphysalis qinghaiensis were investigated under laboratory conditions. The larval, nymphal and adult ticks were fed on sheep at 25-27 degrees C, 50 % relative humidity (RH) and exposed to daylight. All free-living stages were maintained in an incubator (28 degrees C with 90 % RH and a 12-h photoperiod). The whole life cycle of H. qinghaiensis was completed in an average of 176 days (range 118-247 days). The average developmental periods were 34.44 days for egg incubation; 5.83, 4.20 and 33.70 days for larval pre-feeding, feeding and pre-molting; and 3.88, 5.30 and 46.50 days for nymphal pre-feeding, feeding and pre-molting. The average times for pre feeding, feeding, pre-oviposition and oviposition of female adult ticks were 2.60, 11.40, 8.50, and 19.35 days, respectively. The results confirmed the positive correlation between the weight of the engorged female and the egg mass laid (r = 0.557, P < 0.05). The reproductive efficiency index and reproductive fitness index in females were 5.49 and 4.98, respectively. Engorged nymphs moulting to females (4.53 +/- 0.16 mg) were significantly heavier (P < 0.001) than those moulting to males (3.45 +/- 0.19 mg). The overall sex ratio of the adult ticks was 1:1.1 (M:F). PMID- 23111809 TI - Contrasting resource limitations of marine primary producers: implications for competitive interactions under enriched CO2 and nutrient regimes. AB - Primary producers rarely exist under their ideal conditions, with key processes often limited by resource availability. As human activities modify environmental conditions, and therefore resource availability, some species may be released from these limitations while others are not, potentially disrupting community structure. In order to examine the limitations experienced by algal functional groups that characterise alternate community structures (i.e. turf-forming algae and canopy-forming kelp), we exposed these groups to contemporary and enriched levels of carbon dioxide (CO2) and nutrients. Turfs responded to the individual enrichment of both CO2 and nutrients, with the greatest shift in the biomass and carbon:nitrogen (C:N) ratios observed under their combined enrichment. In contrast, kelp responded to enriched nutrients, but not enriched CO2. We hypothesise that the differing limitations reflect the contrasting physiologies of these functional groups, specifically their methods of C acquisition, such as the possession and/or efficiency of a carbon concentrating mechanism (CCM). Importantly, our results reveal that these functional groups, whose interactions structure entire communities, experience distinct resource limitations, with some potentially limited by a single type of resource (i.e. kelp by nutrients), while others may be co-limited (i.e. turf by CO2 and nutrients). Consequently, the identification of how alternate conditions modify resource availability and limitations may facilitate anticipation of the future sustainability of major ecosystem components and the communities they support. PMID- 23111810 TI - [At the limits of discipline]. AB - According to Foucault, in medicine, the paradigm of discipline has outweighed the paradigm of sovereignty for over a hundred years now. It has become clear, however, that within the field of psychiatry, particularly in psychoanalytic and psychotherapeutic research, an interchangeable corpus of knowledge is not sufficient for the treatment of patients. Moreover, it is often the changing relationship between doctor and patient which seems to be crucial to the process and outcome of the treatment. Every treatment-relationship must be understood as a zone of transference. Psychoanalytic research on transference, its potential and pitfalls, therefore, has to be more integrated into the research of psychic disorders. PMID- 23111811 TI - [Acute effects of a single bout of moderate exercise on psychological well-being in patients with affective disorder during hospital treatment]. AB - OBJECTIVE: To explore the effects of a single bout of exercise on psychological well-being in inpatients with affective disorder. METHODS: Thirty-four participants under hospital treatment because of affective disorder attended a supervised but self-paced 60 min Nordic Walking session. All participants completed a self-report questionnaire on psychological well-being before and after physical activity. RESULTS: A significant increase was found for calmness, activation and mood whereas the scales thoughtfulness, weakness, depression and arousal decreased. CONCLUSIONS: A self-paced but supervised single Nordic Walking session seems to be effective in improving acute psychological well-being in patients with affective disorder. Positive affective components of exercise should be addressed in clinical trials focusing on anti-depressive effects and exercise maintenance in patients with affective disorders. PMID- 23111812 TI - Dual mobility canine total hip prosthesis: implant characteristics and surgical procedure. AB - Prosthetic dislocation is one of the most common complications after canine hip replacement. The use of dual mobility acetabular components has been shown to reduce the rate of dislocation in first intent hip replacement in human patients who are at high risk for dislocation. In such implants, a mobile polyethylene liner articulates on one side with a metallic acetabular component and on the other side with a metallic prosthetic head. A dual mobility cemented acetabular component has been designed for use in dogs, and is available for use in association with a previously designed modular femoral component. This report describes the characteristics and the procedure for implantation of this implant combination. PMID- 23111813 TI - Reply: b-cell frequency in HCV-related mixed cryoglobulinemia. PMID- 23111814 TI - Short-term and mid-term effects of fasting and downset meal pattern on lipid profile in Iranian fasted women. AB - It is not clear that whether the effects of fasting and downset meal pattern on lipid profile are limited only to Ramadan or do they remain after that month. The cohort study was conducted on 49 women aged 20-45 who worked at Shahid Motahari hospital in Isfahan. They put on groups of 23 consuming downset meal and 26 non consuming downset meal persons. Serum triglyceride, cholesterol, LDL, and HDL were measured on the 3 days before the beginning, 3 and 30 days after the end of Ramadan. Repeated measure test was used to determine the changes during times and the interaction effects between times and nocturnal eating pattern. This study showed that fasting causes some short-term and mid-term changes in triglyceride and HDL that is mostly attributable to changes in dietary habits during Ramadan, rather than downset meal pattern. PMID- 23111815 TI - Optimal threshold in CT quantification of emphysema. AB - OBJECTIVES: To determine the optimal threshold by quantitatively assessing the extent of emphysema at the level of the entire lung and at the level of individual lobes using a large, diverse dataset of computed tomography (CT) examinations. METHODS: This study comprises 573 chest CT examinations acquired from subjects with different levels of airway obstruction (222 none, 83 mild, 141 moderate, 63 severe and 64 very severe). The extent of emphysema was quantified using the percentage of the low attenuation area (LAA%) divided by the total lung or lobe volume(s). The correlations between the extent of emphysema, and pulmonary functions and the five-category classification were assessed using Pearson and Spearman's correlation coefficients, respectively. When quantifying emphysema using a density mask, a wide range of thresholds from -850 to -1,000 HU were used. RESULTS: The highest correlations of LAA% with the five-category classification and PFT measures ranged from -925 to -965 HU for each individual lobe and the entire lung. However, the differences between the highest correlations and those obtained at -950 HU are relatively small. CONCLUSION: Although there are variations in the optimal cut-off thresholds for individual lobes, the single threshold of -950 HU is still an acceptable threshold for density-based emphysema quantification. PMID- 23111816 TI - Quantitative analysis of diffusion-weighted magnetic resonance imaging in malignant breast lesions using different b value combinations. AB - OBJECTIVES: To explore how apparent diffusion coefficients (ADCs) in malignant breast lesions are affected by selection of b values in the monoexponential model and to compare ADCs with diffusion coefficients (Ds) obtained from the biexponential model. METHODS: Twenty-four women (mean age 51.3 years) with locally advanced breast cancer were included in this study. Pre-treatment diffusion-weighted magnetic resonance imaging was performed using a 1.5-T system with b values of 0, 50, 100, 250 and 800 s/mm(2). Thirteen different b value combinations were used to derive individual monoexponential ADC maps. All b values were used in the biexponential model. RESULTS: Median ADC (including all b values) and D were 1.04 * 10(-3) mm(2)/s (range 0.82-1.61 * 10(-3) mm(2)/s) and 0.84 * 10(-3) mm(2)/s (range 0.17-1.56 * 10(-3) mm(2)/s), respectively. There was a strong positive correlation between ADCs and Ds. For clinically relevant b value combinations, maximum deviation between ADCs including and excluding low b values (<100 s/mm(2)) was 11.8 %. CONCLUSION: Selection of b values strongly affects ADCs of malignant breast lesions. However, by excluding low b values, ADCs approach biexponential Ds, demonstrating that microperfusion influences the diffusion signal. Thus, care should be taken when ADC calculation includes low b values. PMID- 23111817 TI - Susceptibility-weighted angiography for the detection of high-flow intracranial vascular lesions: preliminary study. AB - OBJECTIVES: Susceptibility-weighted magnetic resonance imaging (MRI) sequences may demonstrate various signal intensities of draining veins in cases of high flow vascular malformation (HFVM), including arteriovenous malformation (AVM) and dural arteriovenous fistula (dAVF). Our objective was to evaluate susceptibility weighted angiography (SWAN) for the detection of HFVM. METHODS: Fifty-eight consecutive patients with a suspected intracranial vascular malformation were explored with SWAN and post-contrast MRI sequences at 3 T. The diagnosis of slow flow vascular malformation (SFVM), including developmental venous anomaly (DVA) or brain capillary telangiectasia (BCT), was based on MRI. Patients with suspected HFVM underwent digital subtraction angiography (DSA). SWAN images were analysed by three blinded readers according to a three-point scale of the venous signal. RESULTS: Thirty-one patients presented 35 SFVM (26 DVA and 9 BCT) that systematically appeared hypointense on SWAN images. In patients with atypical MRI findings, DSA revealed one patient with an atypical DVA and 26 patients with HFVM (22 AVM and 4 dAVF). SWAN revealed at least one venous hyperintensity in all patients with HFVM. Agreement between readers was excellent. CONCLUSIONS: SWAN appears reliable for characterising blood flow dynamics in brain veins. In clinical practice, SWAN can routinely rule out HFVM in patients with atypical brain veins. PMID- 23111818 TI - Added value of FDG-PET imaging in the diagnostic workup for yttrium-90 radioembolisation in patients with colorectal cancer liver metastases. AB - OBJECTIVE: Yttrium-90 radioembolisation (Y90-RE) is recommended for unresectable, chemorefractory liver-dominant disease; however, the incidence of extrahepatic disease (EHD) is high. FDG-PET may have additional value to CT in demonstrating EHD. Our aim was to evaluate the added diagnostic value of FDG-PET to abdominal CT and study the influence of FDG-PET findings on treatment decisions. METHODS: All consecutive patients with colorectal cancer liver metastases (CRCLM) referred for Y90-RE were included. Patients who underwent both CT and FDG-PET in the diagnostic workup were selected. Imaging reports were scrutinised for documented sites of EHD, and changes of management due to FDG-PET findings were determined. RESULTS: A total of 42 patients were included. Findings on CT and FDG-PET matched in 20 patients (no EHD, n = 15; identical EHD, n = 5). In 4 patients, lesions detected on CT were not FDG-avid, and in 18 patients, FDG-PET showed more lesions than CT (P < 0.05). In 7/42 patients (17 %) a change of management was made based on the additional FDG-PET findings, i.e. exclusion from Y90-RE treatment (n = 6) and change in treatment plan (whole liver rather than segmental treatment, n = 1). CONCLUSIONS: In patients with CRCLM referred for Y90-RE, FDG-PET showed significantly more EHD and led to a considerable change of management. PMID- 23111819 TI - Complications and clinical outcome of hepatic artery embolisation in patients with hereditary haemorrhagic telangiectasia. AB - BACKGROUND: Hepatic artery embolisation (HAE) in patients with hereditary haemorrhagic telangiectasia (HHT) is controversial because of the associated complications and unproven long-term benefit. We present our results in 20 such patients over a time span of 17 years. METHODS: Staged HAE was performed using polyvinyl alcohol (PVA) particles and coils. Complications, clinical symptoms and cardiac output were assessed before and after therapy as well as at the end of follow-up (median 92 months, range 26-208 months). RESULTS: Two patients died within 30 days following HAE (10 %). Four further deaths resulted from causes unrelated to HAE. Ischaemic cholangitis, cholecystitis and focal hepatic necrosis with biliary sepsis necessitated re-intervention in four patients. In all but one patient, clinical symptoms resolved with mean cardiac output falling from 11.84 +/- 3.22 l/min pre-treatment to 8.13 +/- 2.67 l/min at the end of follow-up (P < 0.001). One patient required liver transplantation for de novo symptoms of portal hypertension 4 years after primary symptoms had been cured by HAE. CONCLUSION: The 30-day mortality of HAE in patients with HHT is 10 %. The rate of complications requiring re-intervention is 20 %. Clinical response at long-term follow-up is satisfactory. PMID- 23111820 TI - Identification of abuse and dependence cases through a hospital database. AB - Computerized hospital databases are used for clinical and economic research. In France, the hospital administrative database, Programme de medicalisation des systemes d'information (PMSI), could be an interesting means for identifying cases of abuse and dependence in hospitals. PURPOSE: To assess the capability of PMSI to identify cases of abuse and dependence (medicines or illicit drugs; tobacco and alcohol not included). METHODS: Cross-sectional study, from October 1 to December 31, 2008, in teaching hospitals of Bordeaux. All hospitalizations with an ICD-10 code related to possible abuse or dependence were selected. Cases were validated by a committee composed of three pharmacologists using discharge summaries. RESULTS: Among the 34 816 patients registered in the PMSI during the study period, a total of 227 patients were pre-selected as potential cases; 21 patients, hospitalized for abuse or dependence, or complications of which, were included in the analysis. Mean age was 35 years. Substances implicated were buprenorphine (n = 8), benzodiazepines (n = 7), cannabis (n = 6), cocaine (n = 4), heroin (n = 3), amphetamine, ecstasy, morphine, codeine, and tramadol (n = 1, respectively); there was polydrug use in six cases. CONCLUSIONS: The PMSI database can be useful to identify certain cases of abuse and dependence. This pilot study has been conducted at a local level; as the PMSI is available in all hospital settings in France, further analysis could be done at the regional and national levels. Such data could be a valuable indicator to analyze trends and assess the medical consequences of substance abuse. PMID- 23111822 TI - Gold(I)-catalysed direct allylic etherification of unactivated alcohols. AB - Direct allylic etherification of unactivated alcohols occurs regio- and stereoselectively under mild, gold(I)-catalysed conditions. PMID- 23111821 TI - 3D position estimation of flexible instruments: marker-less and marker-based methods. AB - PURPOSE: Endoscopic images can be used to allow accurate flexible endoscopic instrument control. This can be implemented using a pose estimation algorithm, which estimates the actual instrument pose from the endoscopic images. METHODS: In this paper, two pose estimation algorithms are compared: a marker-less and a marker-based method. The marker-based method uses the positions of three markers in the endoscopic image to update the state of a kinematic model of the endoscopic instrument. The marker-less method works similarly, but uses the positions of three feature points instead of the positions of markers. The algorithms are evaluated inside a colon model. The endoscopic instrument is manually operated, while an X-ray imager is used to obtain a ground-truth reference position. RESULTS: The marker-less method achieves an RMS error of 1.5, 1.6, and 1.8 mm in the horizontal, vertical, and away-from-camera directions, respectively. The marker-based method achieves an RMS error of 1.1, 1.7, and 1.5 mm in the horizontal, vertical, and away-from-camera directions, respectively. The differences between the two methods are not found to be statistically significant. CONCLUSIONS: The proposed algorithms are suitable to realize accurate robotic control of flexible endoscopic instruments, enabling the physician to perform advanced procedures in an intuitive way. PMID- 23111823 TI - Synthesis and characterization of reversible chemosensory polymers: modulation of sensitivity through the attachment of novel imidazole pendants. AB - Three novel electron donor-acceptor conjugated polymers (P1-P3) bearing various imidazole pendants have been synthesized. Their excellent photophysical and electrochemical properties make them suitable transduction materials for chemosensing applications. Indeed, polymers P1-P3 have been found to show remarkable sensing capabilities towards H(+) and Fe(2+) in semi-aqueous solutions. Upon titration with H(+), polymers P1 and P2 showed hypsochromic shifts of their absorptions and photoluminescence (PL) maxima with enhanced fluorescence intensities. However, P3 showed diminished absorption and fluorescence intensities under similar conditions due to static quenching. The anomalous behavior of P3 compared with P1 and P2 has been clarified in terms of electronic distributions through computational analysis. Furthermore, P3 (K(SV) = 1.03*10(7)) showed a superior sensing ability towards Fe(2+) compared with P1 (K(SV) = 2.01*10(6)) and P2 (K(SV) = 4.12*10(6)) due to its improved molecular wire effect. Correspondingly, the fluorescence lifetime of P3 was greatly decreased (almost 11-fold) compared to those of polymers P1 (4.6-fold) and P2 (6.2-fold) in the presence of Fe(2+). By means of a fluorescence on-off-on approach, chemosensing reversibilities in protonation-deprotonation and metallation-demetallation have been achieved by employing triethylamine (TEA) and the disodium salt of ethylenediaminetetraacetic acid (Na(2)-EDTA)/phenanthroline, respectively, as suitable counter ligands. (1)H NMR titrations have revealed the unique behavior of P3 compared with P1 and P2. To the best of our knowledge, there have been no previous reports of Fe(2+) sensors based on single imidazole receptors conjugated to a main-chain polymer showing such a diverse sensitivity pattern depending on their attached substituents. PMID- 23111825 TI - Determinations of the high-pressure crystal structures of Sb2Te3. AB - Using the angle-dispersive synchrotron x-ray powder diffraction technique in a diamond anvil cell, the high-pressure behaviors of antimony telluride (Sb(2)Te(3)) are explored up to 52.7 GPa at room temperature. Three high-pressure phases have been observed, at about 8.0 GPa, 13.2 GPa and above 21.6 GPa, respectively. Furthermore, the crystalline structures of these high-pressure phases are determined as monoclinic sevenfold C2/m phase, eightfold C2/c phase and disordered body-centered cubic structure (space group Im - 3m) respectively. The phase-transition sequences and pressures observed are well explained by first principles calculations. The pressure dependence of the volume of all high pressure phases is described by a third-order Birch-Murnaghan equation of state. All the high-pressure phases are metallic and the metallic character for beta-, gamma- and delta-Sb(2)Te(3) increases in turn based on the results of the electronic density of states calculated for each high-pressure phase. PMID- 23111826 TI - Modular augmentation in revision total knee arthroplasty. AB - PURPOSE: Controversy exists about the real effectiveness of modular augmentation to manage bone defects in revision total knee arthroplasty. The purpose of this study was to determine whether use of modular augmentation to reconstruct severe defects (1) significantly increased overall outcomes, (2) caused radiolucency or osteolysis and (3) affected mid-term survivorship of knee revisions. The hypothesis was that modular augmentation provides a good survivorship of knee revisions. METHODS: Thirty-eight consecutive revision knee arthroplasties were followed for a median follow-up period of 7 (4.5-9) years. Type 2 and 3 defects were treated with metal augments, tantalum cones and modular cementless stems. Patients were assessed using the IKS knee and function scores and the HSS score. RESULTS: The median IKS knee and function scores and HSS score were 34 (15-58), 19.5 (13-39) and 30 (24-60) points before the operation, respectively, and 78 (49 97), 76 (58-90) and 80.5 (64-98) points (p < 0.001) at the latest follow-up. The median knee flexion increased from 82 degrees (31 degrees -110 degrees ) to 116 degrees (100 degrees -129 degrees ) (p < 0.01). Tibial radiolucencies were observed in 2 (5.2 %) cases. Re-revision was necessary in three (7.9 %) patients. CONCLUSIONS: Modular augmentation may reduce the need for allografting to treat severe bone defects, providing a well-functioning and durable knee joint reconstruction. PMID- 23111827 TI - Preservation of the posterior cruciate ligament is not helpful in highly conforming mobile-bearing total knee arthroplasty: a randomized controlled study. AB - PURPOSE: The purpose of this study is to investigate whether the preservation of the posterior cruciate ligament (PCL) can be helpful for improving kinematics and clinical outcome in highly conforming mobile-bearing total knee arthroplasty (TKA). METHODS: Ninety osteoarthritic knees were randomly allocated to either the PCL-preserving group or the PCL-sacrificing group. Passive kinematics was recorded with a navigation system immediately after implantation. Three parameters (anterior/posterior translation, varus/valgus rotation, and internal/external rotation) were analysed from 0 degrees to 120 degrees flexion. RESULTS: The PCL-preserving group (42 knees) had more varus rotation over 90 degrees flexion (p < 0.05) and more anterior translation of the femur in all ranges of flexion (p < 0.05) than those in the PCL-sacrificing group (44 knees). There was no difference in the internal/external rotation (p > 0.05). The range of motion, functional scores, and radiographic results did not significantly differ between the two groups at the final follow-up. Three knees in the PCL-preserving group were revised: two presented with instability caused by traumatic attenuation of the PCL and one with subluxation of the insert due to a tight PCL. CONCLUSION: The preservation of the PCL was not helpful for improving kinematics and clinical outcome in highly conforming mobile-bearing TKA. PMID- 23111828 TI - Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro. AB - Supernumerary centrosomes and aneuploidy are associated with a malignant phenotype of tumor cells. Centrosomal clustering is a mechanism used by cancer cells with supernumerary centrosomes to solve the threatening problem of multipolar spindles. Griseofulvin is an antifungal substance that interferes with the microtubule apparatus and inhibits centrosomal clustering. It has also been demonstrated that griseofulvin inhibits the growth of tumor cells in vitro and in vivo. However, it is not yet known whether treatment with griseofulvin inhibits growth of adrenocortical tumor cells. We studied the viability and antiproliferative effects of griseofulvin on cultured NCI-H295R adrenocortical carcinoma cells using Wst-1-, BrdUrd-, and [3H]-thymidine assays. For the detection of apoptosis we used a caspase 3/7 cleavage assay and light microscopy techniques. We observed that incubation with griseofulvin for 24-48 h leads to a decrease in the viability and proliferation of NCI-H295R cells in a dose dependent manner. Significant effects could be observed after incubation with griseofulvin as measured by Wst-1-, BrdUrd-, and [3H]dT- uptake assays. Apoptosis of NCI-H295R cells was increased in a dose-dependent manner up to 4.5-fold after incubation with griseofulvin 40 MUM for 24 h as shown by caspase 3/7 cleavage assay and light microscopy. With regard to new treatment strategies for adrenocortical cancer, griseofulvin, and possibly other agents, which interfere with the microtubule apparatus and inhibit centrosomal clustering, may turn out to be interesting targets for further research. PMID- 23111829 TI - Characterization of NCI-H295R cells as an in vitro model of hyperaldosteronism. AB - In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3betaHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line. PMID- 23111832 TI - Variations in exhaled nitric oxide concentration after three types of dives. AB - INTRODUCTION: An increase in exhaled nitric oxide concentration (FENO) occurs during an exacerbation of chronic obstructive lung disease or other inflammatory processes of the airway. Raised FENO levels are also observed during normobaric, mild hyperoxic exposures, whereas after hyperbaric hyperoxic exposure the FENO level is reduced. This study investigated the variations of FENO after three different types of dives. METHODS: Military divers participated in either a closed circuit rebreather dive (CCR, n = 17, pO2 = 130 kPa), semi-closed circuit rebreather dive (S-CCR, n = 12, pO2 = 180 kPa) or a compressed air dive (scuba, n = 17 pO2 = 126 or attendant, n = 12, pO2 = 118). Before and after each dive, the FENO was measured using a handheld electrochemical analyser (Niox Mino(r)). RESULTS: All values for FENO feel within the normal range (5-25ppb). A small decrease in FENO level was found after all dives. After CCR dives FENO fell from 16.4 (+/- 8.0) pre-dive to13.6 (+/- 7.5) ppb, S-CCR from 16.2 (+/- 7.2) to 13.6 (+/- 6.3) ppb, scuba from 17.1 (+/- 5.6) to 16.1 (+/- 5.2) ppb and attendants from 17.7 (+/- 9.8) to 17.3 (+/- 9.1) ppb. Only after a CCR or S-CCR dive was this decrease statistically significant (P < 0.05). CONCLUSION: In our divers, hyperbaric hyperoxia up to 180 kPa led to a small decrease in FENO in the conductive compartment of the lungs, the biological importance of which is unknown. PMID- 23111830 TI - Burden of skin lesions of arsenicosis at higher exposure through groundwater of taluka Gambat district Khairpur, Pakistan: a cross-sectional survey. AB - Prior surveys conducted have found higher proportion of arsenic-contaminated wells in villages along river Indus in Pakistan. This study aims to determine the prevalence of arsenicosis skin lesions among population exposed to higher exposure in taluka Gambat district Khairpur in Sindh. The cross-sectional survey was conducted from August 2008 to January 2009 among 610 households. A total of 707 water sources (hand pumps/wells) were tested from the villages of union councils of Agra and Jado Wahan for arsenic levels with Quick rapid arsenic field test kits. A total of 110 households exposed to arsenic levels >50 ppb were identified. Case screening for arsenic skin lesions was performed for 610 individuals residing in these 110 high-risk households. Information regarding household and socio-demographic characteristics, height and weight measurements and arsenic exposure assessment were collected. Physical examinations by trained physicians were carried out to diagnose the arsenic skin lesions. After data cleaning, 534 individuals from all age groups were included in the final analysis which had complete exposure and outcome information. Overall prevalence of arsenicosis skin lesions was 13.5 % (72 cases). Of the 534 individuals, 490 (91.8 %) were exposed to arsenic levels of >=100 ppb in drinking water (8.2 % to >50-99 ppb, 58.6 % to 100-299 ppb, 14.6 % to 300-399 ppb and 18 % to >=400 ppb). Prevalence rate (per 100 population) of arsenicosis was highest at arsenic levels of 100-199 ppb (15.2 cases) followed by >=400 ppb (13.5 cases) and 300-399 (12.8 cases). Prevalence rate was higher among females (15.2) compared to males (11.3). Our study reports arsenicosis burden due to exposure to higher arsenic levels in drinking water in Pakistan. Exposure to very high levels of arsenic in drinking water calls for urgent action along river Indus. Prevalence of skin lesions increases with increasing arsenic levels in drinking groundwater. Provision of arsenic-free drinking water is essential to avoid current and future burden of arsenicosis in Pakistan. PMID- 23111833 TI - A subjective evaluation of a drinking system for saturation divers. AB - Studies have shown that divers may lose large volumes of body fluids in hot water suit (HWS) dives lasting for four hours or longer, and that this dehydration is mainly caused by sweating. Body fluid balance may be impaired and the diver's alertness and power of judgement could be influenced by such imbalance. The main objective of the present study was to obtain a subjective judgement of a drinking system for divers (DSFD) and to obtain information related to body fluid loss during long saturation lock-out dives. Via a suction pipe imbedded in the microphone unit in the oronasal mask, the DSFD makes it possible for the diver to drink while in the water. Ten divers tested the drinking system during 12 saturation lock-out dives lasting on average for 5.5 h. A questionnaire was answered after each dive. The divers drank 21 times (range 5-30 times) during the dives, and the average drinking volume was 1.4 litre (range 1.0-1.5 litre) but only drank 0.04 litre (range 0-0.3 litre) in the bell after diving. The system was easy to operate and preparation and clothing did not cause any delay. The suction pipe did not intrude and the microphone performed excellently. The work in water was not hindered by DSFD and all divers were very satisfied with the drinking system. It was obvious that the need for fluid intake after a dive with DSFD was markedly reduced; another good indication of maintained body fluid balance. PMID- 23111824 TI - Age and association of kidney measures with mortality and end-stage renal disease. AB - CONTEXT: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial. OBJECTIVE: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks. DESIGN, SETTING, AND PARTICIPANTS: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years). MAIN OUTCOME MEASURES: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates. RESULTS: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65 74, and >=75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0 12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5 45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories. CONCLUSIONS: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age. PMID- 23111834 TI - Predicting performance in competitive apnea diving, part II: dynamic apnoea. AB - Part I of this series of articles identified the main physiological factors defining the limits of static apnea, while this paper reviews the factors involved when physical work is added in the dynamic distance disciplines, performed in shallow water in a swimming pool. Little scientific work has been done concerning the prerequisites and limitations of swimming with or without fins whilst breath holding to extreme limits. Apneic duration influences all competitive apnea disciplines, and can be prolonged by any means that increase gas storage or tolerance to asphyxia, or reduce metabolic rate, as reviewed in the first article. For horizontal underwater distance swimming, the main challenge is to restrict metabolism despite the work, and to direct blood flow only to areas where demand is greatest, to allow sustained function. Here, work economy, local tissue energy and oxygen stores and the anaerobic capacity of the muscles are key components. Improvements in swimming techniques and, especially in swimming with fins, equipment have already contributed to enhanced performance and may do so further. High lactate levels observed after competition swims suggest a high anaerobic component, and muscle hypoxia could ultimately limit muscle work and swimming distance. However, the frequency of syncope, especially in swimming without fins, suggests that cerebral oxygenation may often be compromised before this occurs. In these pool disciplines, safety is high and the dive can be interrupted by the competitor or safety diver within seconds. The safety routines in place during pool competitions are described. PMID- 23111835 TI - Basic mechanisms of gas transport and past research using perfluorocarbons. AB - Perfluorocarbon compounds have been utilized either in pure (neat) form or as emulsions suspended in aqueous fluids. These man-made chemicals possess a unique physical property allowing them to dissolve much more respiratory gases than any water-based system. Understanding the basic physical chemistry surrounding these emerging medical technologies will assure they are utilized to maximum benefit for mankind. It is clear they should not simply be viewed as 'blood substitutes' but rather as enhanced gas transport pharmaceuticals. PMID- 23111836 TI - The potential role of perfluorocarbon emulsions in decompression illness. AB - Decompression illness (DCI) is an occasional occurrence in sport, professional, and military diving as well as a potential catastrophe in high-altitude flight, space exploration, mining, and caisson bridge construction. DCI theoretically could be a success-limiting problem in escape from a disabled submarine (DISSUB). Perfluorocarbon emulsions (PFCs) have previously been investigated as 'blood substitutes' with one approved by the United States Food and Drug Administration for the treatment of myocardial ischaemia. PFCs possess enhanced (as compared to plasma) respiratory gas solubility characteristics, including oxygen, nitrogen and carbon dioxide. This review examines approximately 30 years of research regarding the utilization of PFCs in gas embolism as well as experimental DCI. To date, no humans have been treated with PFCs for DCI. PMID- 23111837 TI - A novel wearable apnea dive computer for continuous plethysmographic monitoring of oxygen saturation and heart rate. AB - We describe the development of a novel wrist-mounted apnea dive computer. The device is able to measure and display transcutaneous oxygen saturation, heart rate, plethysmographic pulse waveform, depth, time and temperature during breath hold dives. All measurements are stored in an external memory chip. The data processing software reads from the chip and writes the processed data into a comma-separated values file which can be analysed by applications such as Microsoft ExcelTM or Open OfficeTM. The housing is waterproof and pressure resistant to more than 20 bar (2.026 MPa) (breath-hold divers have already exceeded 200 metres' sea water depth). It is compact, lightweight, has low power requirements and is easy to use. PMID- 23111838 TI - Future synergism in diving accident management: The Singapore model. AB - The popularity of diving as a leisure activity has been an increasing trend in recent years. With the rise of this sport inevitably comes increasing numbers and risk of diving-related injuries and demand for professional medical treatment of such injuries. Concurrently, with hyperbaric oxygen therapy (HBOT) being more readily available, new applications for HBOT have been proven for the treatment of various medical conditions. In Singapore, diving and hyperbaric medicine was largely a military medicine specialty and its practice confined to the Singapore Armed Forces for many years. The new Hyperbaric and Diving Medicine Centre set up in Singapore General Hospital (SGH) offers an excellent opportunity for collaboration between the Singapore Navy Medical Service (NMS) and SGH. This combines the expertise in the field of diving and hyperbaric medicine that NMS provides, with the resources and specialized services available at SGH. This collaboration was officially formalized by the recent signing of a Memorandum of Understanding between the two organisations. The partnership will allow both organisations to leverage on each other's strengths and enhance the development of research and training capabilities. This collaboration will also be an important step towards formal recognition and accreditation of diving and hyperbaric medicine as a medical subspecialty in the foreseeable future, thus helping to develop and promote diving and hyperbaric medicine in Singapore. This synergistic approach in diving accident management will also promote and establish Singapore as a leader in the field of diving and hyperbaric medicine in the region. PMID- 23111839 TI - Mechanical testing of a new osteotomy design for tibial tuberosity advancement using the Modified Maquet Technique. AB - OBJECTIVES: To evaluate the mechanical properties of the distal cortical hinge associated with a new osteotomy design for the Modified Maquet Technique (MMT). STUDY DESIGN: Ex vivo mechanical study. METHODS: The osteotomy was started 10 mm caudal to the tibial tuberosity and extended over 150% of the length of the tibial crest; it was slightly curved distally to stay at a distance of 2 to 4 mm from the cranial cortex, according to the body weight. Ninety-six tibiae were tested in advancement, and 60 tibiae were axially loaded perpendicular to the tibial plateau, until failure of the crest. Desired advancement was measured using the common tangent method in 60 tibiae. Angle of opening, thickness, and area of the cortical hinge were recorded. RESULTS: Desired advancement of 6 mm, 9 mm, 12 mm and 15 mm was recorded in 16, 12, 18 and 14 tibiae respectively. Mean maximal advancement in these bones was 15.6 +/- 6.4 mm, 20.8 +/- 5.2 mm, 21.3 +/- 5.2 mm and 22.7 +/- 5.2 mm respectively. The desired advancement was reached in all but one tibia. Advancement was mainly influenced by the angle of opening and the stiffness of the cortical hinge. Mean ultimate load to failure was 6.12 +/- 2.4 times the body weight. It was significantly associated with the body weight, thickness, and area of the cortical hinge. CLINICAL RELEVANCE: Mean maximal advancement was higher than clinically required without occurrence of fissure or fracture. Ultimate load to failure and maximal advancement could be predicted using calculated formulae. PMID- 23111840 TI - Fast separations of intact proteins by liquid chromatography. AB - Scientists working in many fields require fast separations of intact proteins using liquid chromatography. The fast separations here concern not only the separation step alone but also the complete chromatographic process, including column regeneration, system equilibration, and buffer exchange, in one- and two dimensional liquid chromatography in addition to fast purification technologies predominantly on the analytical scale with some unique examples on the preparative and industrial scales. This comprehensive review discusses recent developments in methodologies, packing materials, column techniques, and purification technologies in the field of rapid liquid chromatography of intact proteins. Some typical examples are summarized in the tables. PMID- 23111841 TI - Cultural stressors and mental health symptoms among Mexican Americans: a prospective study examining the impact of the family and neighborhood context. AB - Studies of stress consistently have linked individuals' experiences of stress to maladjustment, but limited attention has been given to cultural stressors commonly experienced by minority individuals. To address this, the current study examined the links between cultural stressors and prospective changes in mental health symptoms in a sample of 710 (49 % female) Mexican American youth. In addition, the moderating role of both family and neighborhood cohesion was examined. In-home interviews were completed with youth, mothers (required) and fathers (optional) to collect data on youth's experiences of cultural stressors (discrimination and language hassles) and internalizing/externalizing behavior, and mothers' report of family cohesion and mothers' and fathers' report of neighborhood cohesion. Analyses revealed that youth's experiences of discrimination and language hassles at 5th grade were related positively to increases in internalizing symptoms at 7th grade. Additionally, youths who reported higher levels of language hassles in 5th grade experienced increases in externalizing symptoms across the 2-year span. Both family and neighborhood cohesion emerged as significant moderating factors but their impact was conditional on youth's gender and nativity. Limitations and future implications are discussed. PMID- 23111842 TI - The role of the school environment in relational aggression and victimization. AB - Research conducted over the last decade has documented both the high rates of and serious consequences associated with both victimization and perpetration of relational aggression. This study examines risk for involvement in relational aggression and victimization among middle school youth, evaluating both individual beliefs about violence, as well as aspects of the school environment, including interpersonal school climate and school responsiveness to violence. A sample of 5,625 primarily urban minority middle school youth (49.2 % female) participating in a violence prevention project completed measures of relational aggression and victimization as well as indicators of individual beliefs about aggression, school norms for aggression, student-teacher and student-student interpersonal climate, and school responsiveness to violence. Unlike results previously found for physical aggression, no school-level indicator of climate was related to relational aggression or victimization. However, individual beliefs about aggression and individual perceptions of the school environment were related strongly to both the perpetration of and victimization by relational aggression. These results suggest not only that individual beliefs and perceptions of the school environment are important in understanding perpetration and victimization of relational aggression, but also that risk for involvement in relational aggression is distinct from that of physical aggression. Implications for school interventions are discussed, as well as suggestions for future research. PMID- 23111844 TI - Racial/Ethnic differences in the educational expectations of adolescents: does pursuing higher education mean something different to latino students compared to white and black students? AB - There are striking disparities in the academic achievement of American youth, with Latino students being a particularly vulnerable population. Adolescents' academic expectations have been shown to predict educational outcomes, and thus are an important factor in understanding educational disparities. This article examines racial/ethnic differences in the future expectations of adolescents, with a particular focus on how expectations about higher education may differ in frequency and meaning for Latino youth. Participants included 375 urban ninth grade students (49 % Latino, 23 % White, 22 % Black, and 6 % other; 51 % female) who gave written descriptions of how they pictured their lives in 5 years. Responses were subsequently coded for content and themes. Results demonstrate that Latino youth were less likely to picture themselves attending college when compared to Black and White youth, and more likely to hold social goals, such as starting their own family. Ethnic/racial differences also were found in the themes present in responses, with Latino and Black students more likely than White students to describe individuation and materialistic goals, and to give more unrealistic responses. For Latino youth only, higher education goals were associated significantly with individuation themes. In addition, for Latino youth, adolescents who wished to pursue higher education reported more depressive symptoms and emotional distress than those who did not picture going to college, whereas the opposite pattern was evident for Black and White youth. These differences may reflect cultural values, such as familismo. Practice implications include the importance of culturally tailoring programs aimed at promoting higher education. PMID- 23111843 TI - Weighing in on the issue: a longitudinal analysis of the influence of selected individual factors and the sports context on the developmental trajectories of eating pathology among adolescents. AB - Eating disorders, and related issues (e.g., body dissatisfaction, weight control behaviors), represent pressing and prevalent health problems that affect American adolescents with alarming frequency and potentially chronic consequences. However, more longitudinal research is needed to elucidate the developmental processes that increase or maintain risk for, and that protect against, eating- and weight-related problems among adolescents. Accordingly, the current study used longitudinal data from 1,050 male and female (68.0 %) adolescents (Grades 9 11)-the majority of whom were European Americans (72.2 %)-who participated in the 4-H Study of Positive Youth Development to (a) describe trajectories of adolescents' eating pathology and body dissatisfaction, (b) identify individual and contextual correlates of these pathways, (c) examine whether trajectories of eating pathology and body dissatisfaction related to adolescents' depressive symptoms, and (d) elucidate whether sports participation moderated associations between specific trajectories of eating pathology and body dissatisfaction and adolescents' depressive symptoms. Results suggest that the diverse pathways of eating pathology and body dissatisfaction that exist across middle adolescence, in combination with adolescents' sports participation, have important implications for the positive and problematic development of our youth. In addition, the findings underscore the need to evaluate the interindividual differences that exist in regard to how sports participation may relate positively and negatively to developmental outcomes. PMID- 23111845 TI - The jingle-jangle fallacy in adolescent autonomy in the family: in search of an underlying structure. AB - The construct of autonomy has a rich, though quite controversial, history in adolescent psychology. The present investigation aimed to clarify the meaning and measurement of adolescent autonomy in the family. Based on theory and previous research, we examined whether two dimensions would underlie a wide range of autonomy-related measures, using data from two adolescent samples (N = 707, 51 % girls, and N = 783, 59 % girls, age range = 14-21 years). Clear evidence was found for a two-dimensional structure, with the first dimension reflecting "volition versus pressure", that is, the degree to which adolescents experience a sense of volition and choice as opposed to feelings of pressure and coercion in the parent-adolescent relationship. The second dimension reflected "distance versus proximity", which involves the degree of interpersonal distance in the parent-adolescent relationship. Whereas volition related to higher well-being, less problem behavior and a secure attachment style, distance was associated mainly with more problem behavior and an avoidant attachment style. These associations were not moderated by age. The discussion focuses on the meaning of adolescent autonomy and on the broader implications of the current findings. PMID- 23111846 TI - Well differentiated fetal adenocarcinoma of the lung in a 38-year-old woman: dynamic computed tomography findings. AB - We report a case of well-differentiated fetal adenocarcinoma (WDFA) of the lung, with emphasis on dynamic CT (computed tomography) findings. The patient was a 38 year-old woman who was found to have a mass in the left upper lung field in chest radiograph screening. Chest radiograph showed a 5.5 cm well-defined mass in the left upper lung field. CT revealed a well-circumscribed mass measuring 5.5 * 5.5 * 5.0 cm with a lobulated margin in the left upper lobe. Intratumoral enhancing vasculature was noted in the early phase of dynamic CT. In the delayed phase, persistent and plateau enhancement was seen. The tumor also had consistently unenhanced areas, suggesting the presence of necrosis. Left upper lobectomy with mediastinal lymph node dissection was performed. The pathology specimen contained tubular glands consisting of non-ciliated columnar cells with areas of solid nests of epithelial cells with weakly eosinophilic cytoplasm (morule) mimicking fetal lung tissue. The tumor was moderately vascularized with areas of comedo necrosis; the stroma was relatively scanty. Final pathological diagnosis was WDFA with left hilar lymph node metastasis (stage T2bN1M0). This is the first report of dynamic CT findings of WDFA, a rare lung tumor. Although these findings are non-specific, they well reflected the pathological characteristics of this tumor. PMID- 23111847 TI - False pancreas divisum: a complication of post-endoscopic retrograde pancreatography pancreatitis. AB - Pancreas divisum (PD) and meandering main pancreatic duct (MMPD) are common developmental variants of the pancreatic ductal system. They always appear in the head of the pancreas and are associated with idiopathic pancreatitis. The condition of these variants is rarely reported to have changed after birth. We present a rare case of false PD that occurred with alteration of loop-type MMPD after endoscopic retrograde pancreatography (ERP) and brush cytology followed by post-procedural pancreatitis. A 76-year-old female underwent pre-surgical ERP and brush cytology for an incidentally detected, expanding branch-type intraductal papillary mucinous neoplasm in the body of pancreas. The guidewire was inserted along the main pancreatic duct (MPD) and had uncoiled the loop-shaped MPD into a linear shape; soon afterwards, the patient developed post-procedural acute pancreatitis. Follow-up magnetic resonance cholangiopancreatography study 1 month later revealed the morphology of PD with an absent ventral duct. We hypothesize that inflammatory synechia had occluded the uncoiled ventral duct. This single case provides evidence that pancreatic ductal anatomy is flexible in some situations. PMID- 23111848 TI - Synthesis and characterization of silver nanoparticles using Cynodon dactylon leaves and assessment of their antibacterial activity. AB - Many methods of synthesizing silver nanoparticles (Ag-NPs) by reducing Ag+ ions using aqueous/organic extracts of various plants have been reported in the past, but the methods are rather slow. In this investigation, silver nanoparticles were quickly synthesized from aqueous silver nitrate through a simple method using leaf extract of a plant--Cynodon dactylon which served as reducing agent, while sunlight acted as a catalyst. The formation of Ag-NPs was indicated by gradual change in colour and pH and confirmed by ultraviolet--visible spectroscopy. The Ag-NPs showed a surface plasmon resonance at 451 nm. Based on the decrease in pH, a possible mechanism of the synthesis of Ag-NPs involving hydroxyl (OH-) ions of polyphenols of the leaf extract is postulated. Ag-NPs having (111) and (200) crystal lattices were confirmed by X-ray diffraction. Scanning electron microscopy revealed the spherical nature of the Ag-NPs, while transmission electron microscopy showed that the nanoparticles were polydispersed with a size range of 8-10 nm. The synthesized Ag-NPs also demonstrated their antibacterial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Salmonella typhimurium. PMID- 23111849 TI - Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques. AB - OBJECTIVES: To investigate the pharmacokinetics (PK) of maraviroc, a CCR5 targeted HIV-1 entry inhibitor, in rhesus macaques following vaginal administration of various maraviroc-loaded aqueous hydroxyethylcellulose (HEC) gels, and to correlate the PK data with efficacy in a single high-dose vaginal SHIV-162P3 challenge model. METHODS: Maraviroc concentrations in vaginal fluid (Weck-Cel((r)) sponge), vaginal tissue (punch biopsy) and plasma were assessed over 72 h following single-dose vaginal application of various maraviroc-loaded HEC gels. The range of maraviroc gel concentrations was sufficiently broad (0.003%-3.3% w/w) that test gels included both fully solubilized and predominantly dispersed formulations. The efficacy of the HEC gels against a single high-dose vaginal SHIV-162P3 challenge was also measured, and correlated with the PK concentrations. RESULTS: Maraviroc concentrations in vaginal fluid (range 10(4)-10(7) ng/mL), vaginal tissue (100-1200 ng/g) and plasma (<10(2) ng/mL) were highly dependent on maraviroc gel loading, irrespective of the form of the maraviroc component within the gel (solubilized versus dispersed). Fluid and plasma concentrations were generally highest 0.5 or 2 h after gel application, before declining steadily through to 72 h. Maraviroc concentrations in the various biological compartments correlated strongly with the extent of protection against vaginal SHIV-162P3 challenge. Complete protection was achieved with a 3.3% w/w maraviroc gel. CONCLUSIONS: A high degree of correlation between PK and efficacy was observed. Based on the data obtained with the 3.3% w/w maraviroc gel, maintenance of vaginal fluid and tissue levels in the order of 10(7) ng/mL and 10(3) ng/g, respectively, are required for complete protection with this compound. PMID- 23111850 TI - Altered antibiotic pharmacokinetics during extracorporeal membrane oxygenation: cause for concern? PMID- 23111851 TI - Prioritizing echocardiography in Staphylococcus aureus bacteraemia. AB - OBJECTIVES: Infective endocarditis (IE) is a severe complication in Staphylococcus aureus bacteraemia (SAB) and recent guidelines from the BSAC recommend all patients undergo echocardiography. We assessed the use of echocardiography at a major tertiary referral centre and sought to identify those patients most likely to have positive findings. METHODS: We retrospectively evaluated all cases of SAB at Oxford University Hospitals NHS Trust between September 2006 and August 2011. RESULTS: Three-hundred-and-six out of 668 patients with SAB underwent cardiac imaging on average 9.8 +/- 1.3 days from the first culture. Thirty-one patients (10.1%) had echocardiographic evidence of IE. Risk factors for observing evidence of IE on scanning included the presence of prosthetic heart valves (32% versus 4%, P < 0.001) or cardiac rhythm management (CRM) devices (16% versus 3%, P < 0.004). On excluding patients with prosthetic valves or CRM devices from the analysis, no patient with a line-related bacteraemia and only one patient (an intravenous drug user) with no/mild regurgitation on transthoracic echocardiography had echo evidence of IE. CONCLUSIONS: We propose that the use of scarce echocardiography resources could be prioritized. Patients with prosthetic heart valves or a CRM device should receive early cardiological input and transoesophageal echocardiography. In patients with a clearly defined line-related bacteraemia who do not have a prosthetic valve or CRM device or clinical features of IE, response to treatment could be closely monitored and imaging deferred. Patients without a line-related infection or prosthetic valve/device could receive a transthoracic echocardiogram as a screening tool. PMID- 23111852 TI - Effect of pravastatin and fosinopril on recurrent urinary tract infections. AB - OBJECTIVES: Recurrent urinary tract infections (UTIs) are a problem affecting both women and men. Animal experiments and in vitro studies indicate that statins might prevent recurrent UTIs. We assessed the effects of pravastatin on UTI antibiotic prescribing among adults. METHODS: A post hoc analysis was conducted with data from PREVEND IT, a trial among participants randomized to receive pravastatin, fosinopril or placebo in a 2 * 2 factorial design over 4 years. Trial data were linked to the pharmacy prescription database IADB.nl. The primary outcome was the number of prescriptions with a nitrofuran derivate, a sulphonamide or trimethoprim as a proxy for UTI antibiotic prescribing. Generalized estimating equations were used to estimate the effect on the number of UTI antibiotic prescriptions. Cox regression was used to determine the effect on first and second (recurrent) UTI antibiotic prescriptions. RESULTS: Of the 864 trial participants, 655 were eligible for analysis. During an average follow-up of 3.8 years, 112 (17%) participants received at least one UTI antibiotic prescription. Intention-to-treat analyses showed that pravastatin was associated with a reduced total number of UTI antibiotic prescriptions (relative risk, 0.43; 95% CI, 0.21-0.88) and occurrence of second UTI antibiotic prescriptions [hazard ratio (HR), 0.25; 95% CI, 0.08-0.77]. No significant effect on occurrence of first UTI antibiotic prescriptions was found (HR, 0.83; 95% CI, 0.57-1.20). Fosinopril was associated with an increased occurrence of first UTI antibiotic prescriptions (HR, 1.82; 95% CI, 1.16-2.88). Combination therapy with fosinopril and pravastatin did not significantly influence the number of UTI antibiotic prescriptions. CONCLUSIONS: This study suggests that pravastatin can reduce the occurrence of recurrent UTIs. Larger studies among patients with recurrent UTIs are warranted. PMID- 23111853 TI - High frequency of fluoroquinolone- and macrolide-resistant streptococci among clinically isolated group B streptococci with reduced penicillin susceptibility. AB - OBJECTIVES: Recently several clinical isolates of Streptococcus agalactiae [also known as group B Streptococcus (GBS)] that have acquired reduced penicillin susceptibility (PRGBS) by amino acid substitutions in the penicillin-binding protein 2X have emerged. The frequency of fluoroquinolone (FQ)- and macrolide resistant streptococci among PRGBS is not yet known. METHODS: Fifty-seven GBS [19 PRGBS and 38 penicillin-susceptible GBS (PSGBS)], isolated from different medical institutions in Japan, were studied. For GBS, the MICs of penicillin G, levofloxacin and erythromycin were determined using the agar dilution method. Nineteen PRGBS were previously confirmed as genetically diverse streptococci by PFGE. Further, the mechanisms underlying penicillin, FQ and macrolide non susceptibility/resistance were analysed. RESULTS: The frequency of non susceptibility to FQs among PSGBS was 18.4% (7/38), whereas that among PRGBS was 100% (19/19). The frequency of resistance to erythromycin among PSGBS was 7.9% (3/38), while that among PRGBS was 47.4% (9/19). Statistical significance was determined using Fisher's exact test between reduced penicillin susceptibility and FQ non-susceptibility (P <= 0.0001) and macrolide resistance (P=0.0012). The resistance/non-susceptibility mechanisms among PRGBS were diverse, suggesting that the PRGBS examined were not clonal. CONCLUSIONS: PRGBS isolates tend to show resistance to FQs and/or macrolides. Because the drug choice for treating these multidrug-resistant GBS is more limited than that for usual GBS, these strains may present future public health challenges. PMID- 23111854 TI - American College of Rheumatology report on reasonable use of musculoskeletal ultrasonography in rheumatology clinical practice. PMID- 23111856 TI - Impaired functional status in primary Sjogren's syndrome. AB - OBJECTIVE: Several studies have demonstrated that primary Sjogren's syndrome (SS) is associated with reduced productivity; however, the impact of primary SS on daily function is not fully understood. This study aims to assess the physical function of primary SS patients and determine the relationship between the functional impairment experienced by primary SS patients and disease activity, patient-reported symptoms, and quality of life. METHODS: Sixty-nine primary SS patients from a specialist clinical service were assessed for their functional ability (Improved Health Assessment Questionnaire [HAQ]), dryness, pain, and overall primary SS-related symptom burden; systemic disease activity; levels of fatigue, daytime somnolence, anxiety, and depression symptoms; quality of life; and systemic inflammation (erythrocyte sedimentation rate, C-reactive protein [CRP] level). Data were compared to 69 healthy volunteers matched for age and sex. RESULTS: Primary SS patients experienced greater functional impairment than controls (Improved HAQ total scores: mean +/- SD 24 +/- 25 for primary SS versus 9 +/- 19 for controls; P = 0.0002) across all domains of activity. In primary SS, functional impairment was significantly associated with physical fatigue (P < 0.0001, R(2) = 0.3), pain (P < 0.0001, R(2) = 0.3), depression (P < 0.0001, R(2) = 0.3), total symptom burden (P < 0.0001, R(2) = 0.3), systemic disease activity (P = 0.002, R(2) = 0.15), quality of life (P < 0.0001, R(2) = 0.3), dryness (P = 0.002, R(2) = 0.12), daytime somnolence (P = 0.02, R(2) = 0.08), anxiety score (P = 0.03, R(2) = 0.07), and CRP level (P = 0.04, R(2) = 0.06). Only CRP level is independently associated with functional impairment (beta = 0.38, P = 0.025). CONCLUSION: Primary SS patients experience significant functional disability compared to age-matched healthy controls. Impaired function is associated with reduced quality of life and symptoms such as pain, fatigue, and depression, as well as disease activity, illustrating the importance of optimal management of all aspects of the disease. PMID- 23111855 TI - Use of disease-modifying antirheumatic drugs during pregnancy and risk of preeclampsia. AB - OBJECTIVE: To describe patterns of disease-modifying antirheumatic drug (DMARD) use during pregnancy in a population-based cohort, and to evaluate the association between autoimmune disease, DMARDs, corticosteroids, and nonsteroidal antiinflammatory drugs (NSAIDs) and preeclampsia. METHODS: Using health care utilization databases from British Columbia (1997-2006), we compared the risk for preeclampsia among 44,786 women with and without autoimmune disease with study drug dispensings before pregnancy (past users) and before and during the first 20 gestational weeks (continuous users). Relative risks (RRs) and 95% confidence intervals (95% CIs) were estimated. RESULTS: Only 414 women (0.1%) had a DMARD dispensing during pregnancy. The incidence of preeclampsia was 2.3% for past DMARD users, 2.7% for past corticosteroid users, and 2.9% for past NSAID users. Compared to past users, the continuous DMARD user RR was 2.29 (95% CI 0.81-6.44), and was 0.89 (95% CI 0.51-1.56) for corticosteroid and 0.84 (95% CI 0.63-1.10) for NSAID users. Compared to women without autoimmune disease, the delivery year adjusted RR was 2.02 (95% CI 1.11-3.64) for women with systemic lupus erythematosus (SLE). The DMARD results were attenuated when antimalarials were excluded, and the delivery year-adjusted RR was 0.95 (95% CI 0.25-3.55) when the DMARD analysis was restricted to women with autoimmune disease. CONCLUSION: Few women were exposed to DMARDs during pregnancy. We observed a 2-fold increased risk of preeclampsia among women with SLE and a nonsignificant increase in risk in DMARD users. The DMARD and preeclampsia association was attenuated when antimalarials were excluded and null when restricted to women with autoimmune disease, which suggests the association is likely due to greater autoimmune disease severity in DMARD users. PMID- 23111858 TI - Chronic kidney disease-a challenge for all ages. PMID- 23111860 TI - The adverse effects of estrogen and selective estrogen receptor modulators on hemostasis and thrombosis. AB - Agonists of the estrogen receptor include estrogens and selective estrogen receptor modulators (SERMs). Both types of compounds increase the risk for thrombosis in the arterial and the venous tree. The magnitude of the effect is influenced by potency, which depends on the type of compound and the dose. The particulars of the process change in each territory. Atherosclerosis, which creates local inflammatory conditions, may favor thrombogenesis in arteries. A direct effect of estrogen agonists is also well endorsed at both arteries, as suggested from data with high-estrogenic contraceptives, and veins. Dose reduction has been proved to be an effective strategy, but there is debate on whether additional benefit may be attained beyond a certain threshold. Hormone therapy and SERMs exhibit a lower potency estrogenic profile, but are mainly used by older women, who have a baseline increased thrombogenic risk. When used as sole agents, estrogens substantially reduce the increased risk (venous thrombosis) or may even be neutral (coronary disease). SERMs exhibit a neutral profile for coronary disease and possibly for stroke but not for venous thrombosis. PMID- 23111859 TI - The magnetite-based receptors in the beak of birds and their role in avian navigation. AB - Iron-rich structures have been described in the beak of homing pigeons, chickens and several species of migratory birds and interpreted as magnetoreceptors. Here, we will briefly review findings associated with these receptors that throw light on their nature, their function and their role in avian navigation. Electrophysiological recordings from the ophthalmic nerve, behavioral studies and a ZENK-study indicate that the trigeminal system, the nerves innervating the beak, mediate information on magnetic changes, with the electrophysiological study suggesting that these are changes in intensity. Behavioral studies support the involvement of magnetite and the trigeminal system in magnetoreception, but clearly show that the inclination compass normally used by birds represents a separate system. However, if this compass is disrupted by certain light conditions, migrating birds show 'fixed direction' responses to the magnetic field, which originate in the receptors in the beak. Together, these findings point out that there are magnetite-based magnetoreceptors located in the upper beak close to the skin. Their natural function appears to be recording magnetic intensity and thus providing one component of the multi-factorial 'navigational map' of birds. PMID- 23111861 TI - A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR). AB - The erythropoiesis-stimulating agents (ESAs) erythropoietin and darbepoetin prevent transfusions among chemotherapy-associated anemia patients. Clinical trials, meta-analyses, and guidelines identify mortality, tumor progression, and venous thromboembolism (VTE) risks with ESA administration in this setting. Product labels advise against administering ESAs with potentially curative chemotherapy (United States) or to conduct risk-benefit assessments (Europe/Canada). Since 2007, fewer chemotherapy-associated anemia patients in the United States and Europe receive ESAs. ESAs and the erythropoietin receptor agonist peginesatide prevent transfusions among chronic kidney disease (CKD) patients; clinical trials, guidelines, and meta-analyses demonstrate myocardial infarction, stroke, VTE, or mortality risks with ESAs targeting high hemoglobin levels. U.S. labels recommend administering ESAs or peginesatide at doses sufficient to prevent transfusions among dialysis CKD patients. For dialysis CKD patients, Canadian and European labels recommend targeting hemoglobin levels of 10 to 12 g/dL and 11 to 12 g/dL, respectively, with ESAs. ESA utilization for dialysis CKD patients has decreased in the United States. PMID- 23111862 TI - Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR). AB - Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ. PMID- 23111864 TI - Drugs that affect platelet function. AB - Drugs represent the most common cause of platelet dysfunction in our overmedicated society. While acetylsalicylic acid (aspirin), adenosine diphosphate receptor antagonists (clopidogrel and prasugrel), and integrin alphaIIbbeta3 (GPIIb-IIIa) receptor blockers (abciximab, eptifibatide, and tirofiban) are well-known prototypes of antiplatelet drugs, other widely used agents such as nonsteroidal anti-inflammatory drugs, antibiotics, cardiovascular and lipid-lowering drugs, selective serotonin reuptake inhibitors, and volume expanders can also impair platelet function and thus cause or aggravate hemorrhages in certain clinical settings. Therefore, induction of a bleeding diathesis remains a significant concern. This is especially relevant in patients with preexisting hemostatic defects of any kind, which may remain compensated as long as platelet function (and/or coagulation) is not inhibited pharmacologically. Identification of individual patients with preexisting hemostatic defects remains crucial (1) to prevent otherwise unexpected bleeding complications, (2) to manage hemorrhagic symptoms adequately, (3) to minimize the risk from invasive procedures, and (4) to avoid unnecessary patient exposure to blood products. This article provides a review of the large variety of agents that have not been designed for antiplatelet therapy but nevertheless interfere with platelet reactivity or induce platelet inhibition. In particular, drug interactions and mechanisms by which these agents can trigger or cause platelet dysfunction are detailed. PMID- 23111863 TI - Thromboprophylaxis guidelines in cancer with a primary focus on ambulatory patients receiving chemotherapy: a review from the Southern Network on Adverse Reactions (SONAR). AB - Patients with cancer are at increased risk for venous thromboembolism (VTE). Factors related to cancer type, site, stage, duration, and extent of disease contribute to the oncology patient's risk of VTE. Patient-specific factors such as history of prior VTE and comorbidity are also contributory. The role of treatment-related factors, including chemotherapy regimen, has been a focus of recent investigation because most cases of VTE in the oncology setting occur in ambulatory patients. Thus, an emerging area of clinical research is primary VTE prophylaxis in the ambulatory cancer setting. Clinical guidelines currently recommend primary thromboprophylaxis in cancer patients who are undergoing surgery, who are hospitalized, and who are in a specific subset of high-risk ambulatory cancer patients. Validated risk stratification tools are essential for identification of patients who are at high risk of thrombosis. Emerging data from recently published clinical trials, as well as ongoing studies, are likely to advance our understanding of the potential utility of antithrombotic agents for primary prophylaxis in ambulatory patients with cancer and may influence future clinical guideline recommendations. PMID- 23111865 TI - Predicting self-perceived antimuscarinic therapy effectiveness on overactive bladder symptoms using the Overactive Bladder 8-Question Awareness Tool. AB - INTRODUCTION AND HYPOTHESIS: This work was designed to explore the ability of the self-administered Overactive Bladder 8-Question Awareness Tool (OAB-V8) to predict patient self-assessed effectiveness of antimuscarinic therapy on OAB symptoms in daily practice. Also, the ability of the tool to predict clinician evaluation of improvement was explored. METHODS: Patients of both genders, >18 years, with symptomatic OAB (score >8 on OAB-V8), and able to understand patient reported outcome instruments were enrolled in this 3-month study. Patients were prescribed treatment with an antimuscarinic drug according to usual practice. Treatment effectiveness was assessed by the clinician and patient using the Clinical Global Impression of Improvement and Treatment Benefit Scale and by improved self-perceived quality of life using the Overactive Bladder Questionnaire Short Form (OAB-q SF) 3 months after initiating or changing an antimuscarinic therapy. Multivariate linear and logistic regression models were applied to explore the predictive validity of OAB-V8 scores at the baseline visit. RESULTS: A total of 246 patients (57.7 years, 67 % women) were analyzed. Based on baseline OAB-V8 scores, logistic regression models were capable of predicting clinical improvement and patient self-perceived treatment benefit in 70 % of cases. OAB-V8 scores significantly correlated with OAB-q SF domains at baseline: 0.790 and - 0.659 for symptom bother and health-related quality of life domains, respectively (p < 0.001 in both cases). Baseline OAB-V8 score was able to predict changes in both domains of the OAB-q SF: R (2) = 0.212 and 0.162 for symptom bother and health-related quality of life, respectively. CONCLUSIONS: The OAB-V8 scale showed evidence of predictive validity for antimuscarinic effectiveness in daily practice based on physician assessment and patient self assessment of improved quality of life and treatment benefit. PMID- 23111866 TI - Ultrasound-guided autologous myoblast injections into the extrinsic urethral sphincter: tissue engineering for the treatment of stress urinary incontinence. AB - INTRODUCTION AND HYPOTHESIS: Limitations of the existing treatment methods for stress urinary incontinence (SUI) have encouraged investigation of new therapeutic approaches in the field of regenerative medicine. Enabled by tissue engineering technology safety, feasibility and efficacy of ultrasound-guided intrasphincteric autologous myoblast implantation to treat SUI presented in the accompanying video were assessed in a pilot study of 38 women. METHODS: Following upper arm muscle biopsy, autologous myoblast suspension was injected into the extrinsic urethral sphincter under transurethral ultrasound visualization. Functional electrical stimulation (FES) was used postoperatively to possibly enhance cell integration. Objective and subjective parameters were compared at 6 weeks, 3 months, and 6 months postoperatively. RESULTS: The tissue harvest, laboratory tissue processing, and myoblast implantation were successful in all 38 patients. No serious adverse events were reported through the course of the study. Objective and subjective measurements collected at baseline were significantly improved at 6 weeks postoperatively. Additional improvement or a plateau was observed at 3 and 6 months postoperatively, not being negatively influenced by discontinuation of FES. Of the patients, 23.7 % considered their SUI cured, and 52.6 % reported improvement at 6 months; 95 % would recommend this treatment to others. CONCLUSIONS: Intrasphincteric ultrasound-guided autologous myoblast injection for SUI is feasible. This simple to perform and well-tolerated minimally invasive procedure safely produced promising initial results. PMID- 23111867 TI - Exposure assessment and associated lung deposition calculations for vehicular exhaust in four metropolitan cities of Pakistan. AB - Ambient aerosol concentrations along the roadside of metropolitan cities of Pakistan were measured using a Grimm 1.109 dust monitor. Considering the high ambient aerosol concentrations, regional lung deposition of aerosol particles in the human respiratory tract was calculated to assess extent of exposure. Lung deposition was computed in terms of mass concentration and the associated surface area for 12 male traffic wardens using the latest version of the stochastic lung deposition code Inhalation, Deposition, and Exhalation of Aerosols in the Lung. The results have revealed 4 to 10 times higher concentrations than recommended by WHO guidelines. The deposition results derived from the model disclose that extrathoracic deposition is in the range of 22 to 28 % with total lung deposition ranging from 40 to 44 % for the scanned particle window of 0.25-10 MUm. Considering an average 8-h shift per day and an average breathing rate of 1.3 m(3) h(-1), it is approximated that in a worker, up to 1.6 mg of inhalable particle mass can deposit per day. PMID- 23111868 TI - The risk of harmful algal blooms (HABs) in the oyster-growing estuaries of New South Wales, Australia. AB - The spatial and temporal variability of potentially harmful phytoplankton was examined in the oyster-growing estuaries of New South Wales. Forty-five taxa from 31 estuaries were identified from 2005 to 2009. Harmful species richness was latitudinally graded for rivers, with increasing number of taxa southward. There were significant differences (within an estuary) in harmful species abundance and richness for 11 of 21 estuaries tested. Where differences were observed, these were predominately due to species belonging to the Pseudo-nitzschia delicatissima group, Dinophysis acuminata, Dictyocha octonaria and Prorocentrum cordatum with a consistent upstream versus downstream pattern emerging. Temporal (seasonal or interannual) patterns in harmful phytoplankton within and among estuaries were highly variable. Examination of harmful phytoplankton in relation to recognised estuary disturbance measures revealed species abundance correlated to estuary modification levels and flushing time, with modified, slow flushing estuaries having higher abundance. Harmful species richness correlated with bioregion, estuary modification levels and estuary class, with southern, unmodified lakes demonstrating greater species density. Predicting how these risk taxa and risk zones may change with further estuary disturbance and projected climate warming will require more focused, smaller scale studies aimed at a deeper understanding of species-specific ecology and bloom mechanisms. Coupled with this consideration, there is an imperative for further taxonomic, ecological and toxicological investigations into poorly understood taxa (e.g. Pseudo-nitzschia). PMID- 23111869 TI - Anaerobic respiration using a complete oxidative TCA cycle drives multicellular swarming in Proteus mirabilis. AB - Proteus mirabilis rapidly migrates across surfaces using a periodic developmental process of differentiation alternating between short swimmer cells and elongated hyperflagellated swarmer cells. To undergo this vigorous flagellum-mediated motility, bacteria must generate a substantial proton gradient across their cytoplasmic membranes by using available energy pathways. We sought to identify the link between energy pathways and swarming differentiation by examining the behavior of defined central metabolism mutants. Mutations in the tricarboxylic acid (TCA) cycle (fumC and sdhB mutants) caused altered patterns of swarming periodicity, suggesting an aerobic pathway. Surprisingly, the wild-type strain swarmed on agar containing sodium azide, which poisons aerobic respiration; the fumC TCA cycle mutant, however, was unable to swarm on azide. To identify other contributing energy pathways, we screened transposon mutants for loss of swarming on sodium azide and found insertions in the following genes that involved fumarate metabolism or respiration: hybB, encoding hydrogenase; fumC, encoding fumarase; argH, encoding argininosuccinate lyase (generates fumarate); and a quinone hydroxylase gene. These findings validated the screen and suggested involvement of anaerobic electron transport chain components. Abnormal swarming periodicity of fumC and sdhB mutants was associated with the excretion of reduced acidic fermentation end products. Bacteria lacking SdhB were rescued to wild-type pH and periodicity by providing fumarate, independent of carbon source but dependent on oxygen, while fumC mutants were rescued by glycerol, independent of fumarate only under anaerobic conditions. These findings link multicellular swarming patterns with fumarate metabolism and membrane electron transport using a previously unappreciated configuration of both aerobic and anaerobic respiratory chain components. Bacterial locomotion and the existence of microbes were the first scientific observations that followed the invention of the microscope. A bacterium can swim through a fluid environment or coordinate motion with a group of bacteria and swarm across a surface. The flagellar motor, which propels the bacterium, is fueled by proton motive force. In contrast to the physiology that governs swimming motility, much less is known about the energy sources required for multicellular swarming on surfaces. In this study, we used Proteus mirabilis as a model organism to study vigorous swarming behavior and genetic and biochemical approaches to define energy pathways and central metabolism that contribute to multicellular motility. We found that swarming bacteria use a complete aerobic tricarboxylic acid (TCA) cycle but do not respire oxygen as the terminal electron acceptor, suggesting that multicellular cooperation during swarming reduces the amount of energy required by individual bacteria to achieve rapid motility. PMID- 23111870 TI - Contrasting life strategies of viruses that infect photo- and heterotrophic bacteria, as revealed by viral tagging. AB - Ocean viruses are ubiquitous and abundant and play important roles in global biogeochemical cycles by means of their mortality, horizontal gene transfer, and manipulation of host metabolism. However, the obstacles involved in linking viruses to their hosts in a high-throughput manner bottlenecks our ability to understand virus-host interactions in complex communities. We have developed a method called viral tagging (VT), which combines mixtures of host cells and fluorescent viruses with flow cytometry. We investigated multiple viruses which infect each of two model marine bacteria that represent the slow-growing, photoautotrophic genus Synechococcus (Cyanobacteria) and the fast-growing, heterotrophic genus Pseudoalteromonas (Gammaproteobacteria). Overall, viral tagging results for viral infection were consistent with plaque and liquid infection assays for cyanobacterial myo-, podo- and siphoviruses and some (myo- and podoviruses) but not all (four siphoviruses) heterotrophic bacterial viruses. Virus-tagged Pseudoalteromonas organisms were proportional to the added viruses under varied infection conditions (virus-bacterium ratios), while no more than 50% of the Synechococcus organisms were virus tagged even at viral abundances that exceeded (5 to 10*) that of their hosts. Further, we found that host growth phase minimally impacts the fraction of virus-tagged Synechococcus organisms while greatly affecting phage adsorption to Pseudoalteromonas. Together these findings suggest that at least two contrasting viral life strategies exist in the oceans and that they likely reflect adaptation to their host microbes. Looking forward to the point at which the virus-tagging signature is well understood (e.g., for Synechococcus), application to natural communities should begin to provide population genomic data at the proper scale for predictively modeling two of the most abundant biological entities on Earth. Viral study suffers from an inability to link viruses to hosts en masse, and yet delineating "who infects whom" is fundamental to viral ecology and predictive modeling. This article describes viral tagging-a high-throughput method to investigate virus-host interactions by combining the fluorescent labeling of viruses for "tagging" host cells that can be analyzed and sorted using flow cytometry. Two cultivated hosts (the cyanobacterium Synechococcus and the gammaproteobacterium Pseudoalteromonas) and their viruses (podo-, myo-, and siphoviruses) were investigated to validate the method. These lab-based experiments indicate that for most virus-host pairings, VT (viral tagging) adsorption is equivalent to traditional infection by liquid and plaque assays, with the exceptions being confined to promiscuous adsorption by Pseudoalteromonas siphoviruses. These experiments also reveal variability in life strategies across these oceanic virus-host systems with respect to infection conditions and host growth status, which highlights the need for further model system characterization to break open this virus-host interaction "black box." PMID- 23111871 TI - Long-term exposure to antibiotics has caused accumulation of resistance determinants in the gut microbiota of honeybees. AB - Antibiotic treatment can impact nontarget microbes, enriching the pool of resistance genes available to pathogens and altering community profiles of microbes beneficial to hosts. The gut microbiota of adult honeybees, a distinctive community dominated by eight bacterial species, provides an opportunity to examine evolutionary responses to long-term treatment with a single antibiotic. For decades, American beekeepers have routinely treated colonies with oxytetracycline for control of larval pathogens. Using a functional metagenomic screen of bacteria from Maryland bees, we detected a high incidence of tetracycline/oxytetracycline resistance. This resistance is attributable to known resistance loci for which nucleotide sequences and flanking mobility genes were nearly identical to those from human pathogens and from bacteria associated with farm animals. Surveys using diagnostic PCR and sequencing revealed that gut bacteria of honeybees from diverse localities in the United States harbor eight tetracycline resistance loci, including efflux pump genes (tetB, tetC, tetD, tetH, tetL, and tetY) and ribosome protection genes (tetM and tetW), often at high frequencies. Isolates of gut bacteria from Connecticut bees display high levels of tetracycline resistance. Resistance genes were ubiquitous in American samples, though rare in colonies unexposed for 25 years. In contrast, only three resistance loci, at low frequencies, occurred in samples from countries not using antibiotics in beekeeping and samples from wild bumblebees. Thus, long-term antibiotic treatment has caused the bee gut microbiota to accumulate resistance genes, drawn from a widespread pool of highly mobile loci characterized from pathogens and agricultural sites. We found that 50 years of using antibiotics in beekeeping in the United States has resulted in extensive tetracycline resistance in the gut microbiota. These bacteria, which form a distinctive community present in healthy honeybees worldwide, may function in protecting bees from disease and in providing nutrition. In countries that do not use antibiotics in beekeeping, bee gut bacteria contained far fewer resistance genes. The tetracycline resistance that we observed in American samples reflects the capture of mobile resistance genes closely related to those known from human pathogens and agricultural sites. Thus, long-term treatment to control a specific pathogen resulted in the accumulation of a stockpile of resistance capabilities in the microbiota of a healthy gut. This stockpile can, in turn, provide a source of resistance genes for pathogens themselves. The use of novel antibiotics in beekeeping may disrupt bee health, adding to the threats faced by these pollinators. PMID- 23111872 TI - Back to the future for dermatophyte genomics. AB - Dermatophytes are a uniquely pathogenic group of fungi that cause most common fungal infections globally. The major cause of athlete's foot is Trichophyton rubrum, a pathogen of human skin. A recent paper in this journal reported the sequencing and analysis of five additional genome sequences, including that of Trichophyton rubrum. These five join the existing two additional genome sequences to bring the total to seven dermatophyte genome sequences, a notable milestone in the study of these fungi. These additional genomes set the stage for future genome-supported studies on the biology, pathogenicity, and host specificity of this important group of pathogens. To predict how this future might play out, we review the history of Aspergillus genomics since the initial publication of the first three Aspergillus genome sequences in 2005, an event that stimulated important studies of the pathogenic Aspergillus species. From these 7 years of Aspergillus history, we offer some speculation on the future of dermatophyte studies supported by the genome sequences given the similarities, differences, and relative levels of support for studies in these two groups of fungi and the diseases they cause. PMID- 23111873 TI - A single native ganglioside GM1-binding site is sufficient for cholera toxin to bind to cells and complete the intoxication pathway. AB - Cholera toxin (CT) from Vibrio cholerae is responsible for the majority of the symptoms of the diarrheal disease cholera. CT is a heterohexameric protein complex with a 240-residue A subunit and a pentameric B subunit of identical 103 residue B polypeptides. The A subunit is proteolytically cleaved within a disulfide-linked loop to generate the A1 and A2 fragments. The B subunit of wild type (wt) CT binds 5 cell surface ganglioside GM(1) (GM(1)) molecules, and the toxin-GM(1) complex traffics from the plasma membrane (PM) retrograde through endosomes and the Golgi apparatus to the endoplasmic reticulum (ER). From the ER, the enzymatic A1 fragment retrotranslocates to the cytosol to cause disease. Clustering of GM(1) by multivalent toxin binding can structurally remodel cell membranes in ways that may assist toxin uptake and retrograde trafficking. We have recently found, however, that CT may traffic from the PM to the ER by exploiting an endogenous glycosphingolipid pathway (A. A. Wolf et al., Infect. Immun. 76:1476-1484, 2008, and D. J. F. Chinnapen et al., Dev. Cell 23:573-586, 2012), suggesting that multivalent binding to GM(1) is dispensable. Here we formally tested this idea by creating homogenous chimeric holotoxins with defined numbers of native GM(1) binding sites from zero (nonbinding) to five (wild type). We found that a single GM(1) binding site is sufficient for activity of the holotoxin. Therefore, remodeling of cell membranes by mechanisms that involve multivalent binding of toxin to GM(1) receptors is not essential for toxicity of CT. Through multivalent binding to its lipid receptor, cholera toxin (CT) can remodel cell membranes in ways that may assist host cell invasion. We recently found that CT variants which bind no more than 2 receptor molecules do exhibit toxicity, suggesting that CT may be able to enter cells by coopting an endogenous lipid sorting pathway without clustering receptors. We tested this idea directly by using purified variants of CT with zero to five functional receptor-binding sites (BS). One BS enabled CT to intoxicate cells, supporting the conclusion that CT can enter cells by coopting an endogenous lipid-sorting pathway. Although multivalent receptor binding is not essential, it does increase CT toxicity. These findings suggest that achieving higher receptor binding avidity or affecting membrane dynamics by lipid clustering and membrane remodeling may be driving forces for evolution of AB(5) subunit toxins that can bind multivalently to cell membrane lipid receptors. PMID- 23111874 TI - Nano-titanium dioxide induces genotoxicity and apoptosis in human lung cancer cell line, A549. AB - The increased inhaled application of titanium dioxide nanoparticles (TiO(2) NPs) increases the potential pulmonary health risks. The present investigations were carried out to study the TiO(2) NPs-induced apoptosis, oxidative stress and genotoxicity in the human lung cancer cell line, A549, a widely used cell system for pulmonary toxicity studies. Tetrazolium bromide salt and lactate dehydrogenase release assays were used to study the cytotoxicity. The genotoxicity studies were carried out using cytokinesis block micronucleus assay. Apoptosis was confirmed by the formation of apoptotic bodies and altered expression (messenger RNA (mRNA) and protein) of markers such as P(53), P(21), Bax, Bcl(2) and cleaved caspase-3. Cells exposed to TiO(2) NPs (10 and 50 MUg/ml) for 6-24 h shows significant induction in oxidative stress, that is, the production of reactive oxygen species and malondialdehyde and decrease in the activity of catalase and glutathione. TiO(2) NPs exposure also induces the formation of apoptotic bodies and micronucleus as marker of genotoxicity. A significant up-regulation in the expression of apoptosis markers such as P(53), P(21) and cleaved caspase-3 was observed, while the levels were down-regulated for Bcl(2) at both mRNA and protein levels. TiO(2) NPs exposure could not pose significant effects on Bax expression. Data indicate that nano-TiO(2) induces oxidative stress, genotoxicity and apoptosis in human lung cancer cell line, A549. Our result also identifies the mechanisms involved in TiO(2) NP-induced changes in A549 cells. Perhaps, reporting for the first time, the association of TiO(2) NPs-induced genotoxicity and apoptosis at transcriptional and translational level in the human lung cancer cell line, A549 cells. PMID- 23111875 TI - Intravascular infusion of PEGylated Au nanoparticles affects cardiovascular function in healthy mice. AB - Recent advances of nanotechnology in clinical settings have spurred the development of various complex engineered nanoparticles (NPs). NPs share characteristics with ultrafine particles (UFPs; <1 MUm) that can cross the pulmonary epithelium and disturb cardiovascular functions. Since these particles are injected directly into the blood stream, it is imperative to clarify whether NPs disrupt cardiovascular functions similar to UFPs. Therefore, we investigated whether engineered polyethylene glycol (PEG)-coated aluminum NPs for biomedical uses disturb cardiovascular functions in healthy mice. Mean arterial blood pressure (MAP) was measured in mice chronically instrumented with telemetric blood pressure transducers, and NPs were administered intravenously (10 mg kg( 1)). The NPs caused a prolonged lowering of MAP 7 days after injection (119.3 +/- 3.3 vs. 97.4 +/- 7.5 min(-1)), with no effect on the endothelial function as revealed by normal endothelial function of small vessels mounted in a myograph. PMID- 23111876 TI - The role of adenosine receptors on amitriptyline-induced electrophysiological changes on rat atrium. AB - We investigated the role of adenosine receptors in amitriptyline-induced cardiac action potential (AP) changes in isolated rat atria. In the first group, APs were recorded after cumulative addition of amitriptyline (1 MUM, 10 MUM and 50 MUM). In other groups, each atrium was incubated with selective adenosine A(1) antagonist (8-cyclopentyl-1,3-dipropylxanthine (DPCPX), 10(-4) M) or selective adenosine A(2a) receptor antagonist (8-(3-chlorostyryl) caffeine, 10(-5) M) before amitriptyline administration. Resting membrane potential, AP amplitude (APA), AP duration at 50% and 80% of repolarization (APD(50) and APD(80), respectively), and the maximum rise and decay slopes of AP were recorded. Amitriptyline (50 MUM) prolonged the APD(50) and APD(80) (p < 0.001) and the maximum rise slope of AP was reduced by amitriptyline (p < 0.0001). Amitriptyline reduced maximum decay slope of AP only at 50 MUM (p < 0.01). DPCPX significantly decreased the 50-MUM amitriptyline-induced APD(50) and APD(80) prolongation (p < 0.001). DPCPX significantly prevented the effects of amitriptyline (1 MUM and 50 MUM) on maximum rise slope of AP (p < 0.05). DPCPX significantly prevented the amitriptyline-induced (50 MUM) reduction in maximum decay slope of AP (p < 0.001). The selective adenosine A(1) receptor antagonist prevented the electrophysiological effects of amitriptyline on atrial AP. A(1) receptor stimulation may be responsible for the cardiovascular toxic effects produced by amitriptyline. PMID- 23111877 TI - Single-agent duloxetine ingestions. AB - Duloxetine is a serotonin and norepinephrine reuptake inhibitor, which is mainly used to treat depression. This retrospective study describes the demographic and clinical effects of duloxetine ingestions reported to the National Poison Data System (NPDS). NPDS data were searched for duloxetine exposures between 2004 and 2010. A total of 11,373 patients were included and exposures were divided into three groups of ages <=6 years old, 7-12 years and >12 years. Neurological clinical effects occurred in 6.1% of the patients aged <=6 years, 13.0% of the patients aged 7-12 years and 24.6% of the patients aged >12 years. Cardiovascular effects occurred in 1.4% of the patients aged <=6 years old, 2.5% of the patients aged 7-12 years and 11.6% of the patients aged >12 years. Gastrointestinal effects occurred in 4.1% of the patients aged <=6 years old, 16.6% of the patients aged 7-12 years and 13.8% of the patients aged >12 years. Tachycardia, nausea, vomiting, agitation/irritability, dizziness/vertigo and drowsiness were among the most common clinical effects in all three groups. Overall, 61.4% of the patients aged <=6 years and 77.5% of the patients aged 7-12 years were managed in a non-health care facility, while 55.8% of the patients aged >12 years were referred to or already in a health care facility. We conclude that the majority of ingestions are benign in both pediatrics and adults. Most symptomatic patients have neurologic, gastrointestinal and cardiovascular effects. Most pediatric patients will be able to be managed in a non-health care facility. PMID- 23111878 TI - Evaluation of paracetamol distribution and stability in case of acute intoxication in rats. AB - Effects of different storing conditions on paracetamol concentration in biological samples of acute intoxicated rats were investigated. The stability and distribution of paracetamol was observed in postmortem serum, liver, kidney and brain tissues. The serum samples were stored for 30 days and daily changes were evaluated for paracetamol. A significant difference (p = 0.05) was noticed on the 30th experimental day. Paracetamol serum levels changed as much as 66.30% and 33.78% for 4 degrees C and -20 degrees C, respectively. The stability of paracetamol in liver stored at -20 degrees C was also evaluated for 30 days. The paracetamol concentration levels taken from liver samples dramatically decreased from 30.36% on the 1st day to 94.97% on the 30th day. The paracetamol distribution in organs was as 2.68 , 1.11 and 0.68 mg/g in liver, kidney and brain samples, respectively. Meaningful difference in paracetamol in serum and liver samples was in observed in 30th day values (p = 0.05). PMID- 23111879 TI - Emergency do not consume/do not use concentrations for ferric chloride in drinking water. AB - The U.S. Congress [PL 107-188] amended the Safe Drinking Water Act and required each community water system serving more than 3,000 people to conduct vulnerability assessments. These assessments address potential circumstances that could compromise the safety and reliability of municipal water. Ferric chloride is used in coagulation and flocculation, and it is used to treat raw water with high viral loads, elevated dissolved solids or high bromide. Iron is an essential nutrient, but elevated concentrations of FeCl3 are corrosive as a result of hydrolysis to HCl. Based on a no-observed-adverse effect level (NOAEL) of 0.5% FeCl3 * 6H2O administered in drinking water to male and female F344 rats for up to 2 years, a do not consume concentration of 200 mg FeCl3 /L can be derived. Since instillation of 0.3 M (48.7 g/L) FeCl3 in saline to rodent vagina failed to elicit damage, a topical do not use concentration of 2000 mg FeCl3/L (600 mg Fe/L) can be assigned. The only FeCl3 data available to quantify ocular toxicity involved a pH 1 solution in rabbit eyes, but HCl instillation (pH 2.5) to rabbit eyes found permanent corneal ulceration after 10 min. The pH of FeCl3 in water at the do not use limit (2.4-2.6) is near the pH (2.0) considered corrosive by regulatory agencies. As direct eye contact with water at pH 4.5 or below increases complaints of ocular discomfort, emergency response plans that address FeCl3 in drinking water must account for Fe levels and the pH of the affected water. PMID- 23111880 TI - Assessment of genotoxicity risk in operation room personnel by the alkaline comet assay. AB - This study was conducted to evaluate the possible genotoxic effects of waste anesthetic gases. Comet assay was performed on peripheral blood lymphocytes of 60 volunteers: 20 healthy unexposed office workers and 40 operation room (OR) personnel at Tanta University Hospital (Egypt). The exposed personnel were anesthetists (6 females and 7 males), surgeons (10 males), nurses (9 females), and technicians (8 males). The study revealed significantly increased comet parameters (mean comet tail length and mean percentage of DNA in the tail) in peripheral blood lymphocytes of OR personnel in comparison with control individuals. The maximum DNA damage was observed in anesthesia technicians, whereas the nurses showed the least DNA damage. Furthermore, significant difference was observed between smoker and nonsmokerOR personnel in relation to mean comet tail length. However, no significant difference was seen due to age, gender, or duration of exposure. Also, significant increase in mean percentage of tail DNA was observed in smoker individuals of both exposed and control groups. As a conclusion, this study points to the risk of DNA damage in personnel who are exposed to waste anesthetic gases. PMID- 23111881 TI - Spectral analysis of thioacetamide-induced electroencephalographic changes in rats. AB - Thioacetamide (TAA) is widely used as a model of hepatic encephalopathy (HE). The aim of our study was to investigate the effects of TAA on electroencephalographic (EEG) changes in rats and to compare them with human HE. Male Wistar rats were divided into groups: (1) saline-treated group and (2) TAA-treated groups: TAA(300) (300 mg/kg), TAA(600) (600 mg/kg), and TAA(900) (900 mg/kg). Daily dose of TAA (300 mg/kg) was administered intraperitoneally once (TAA(300)), twice (TAA(600)), or thrice (TAA(900)) in subsequent days. EEG changes were recorded about 24 h after the last dose of TAA. Absolute and relative power density in alpha bands were significantly higher in TAA(300) versus control group. In TAA(300), absolute beta power density was higher and relative beta power density was lower versus control group. Absolute alpha, theta, delta, and relative theta power were significantly lower, while relative power in delta band was significantly higher in TAA(900) versus control group (p < 0.01). In conclusion, decrease in EEG voltage with an increase in delta relative power, which correspond to the EEG manifestations of severe HE in humans, was observed in TAA(900) group. Electrical activity in TAA(300) group correlates with mild HE in humans. PMID- 23111882 TI - In vitro effects of nitric oxide donors on apoptosis and oxidative/nitrative protein modifications in ADP-activated platelets. AB - Nitric oxide (NO) is an important physiological signaling molecule. However, when produced in excessive amounts, NO can also have toxic effects. The aim of this study is to investigate the effects of exogenous- and endogenous-derived NO on oxidative modifications of proteins and apoptosis in activated platelets. Washed platelets were incubated with L-arginine or nitroso-glutathione (GSNO) in the presence of adenosine diphosphate (ADP). After incubation, caspase-3 activity, phosphatidylserine (PS) externalization and the potential of mitochondrial membrane as markers of apoptosis were measured. In addition, the alterations in protein carbonylation (PCO) and nitrotyrosine (NT) formation as markers of protein oxidation were examined. Platelet activation with ADP (20 uM) significantly increased PCO and NT levels and apoptotic events. After incubation with L-arginine, platelet NO production increased significantly. This L-arginine induced increase caused decreases in formerly increased PCO and NT levels associated with ADP-induced platelet activation. Stimulation of NO production with L-arginine protected platelets from apoptosis. GSNO caused an increase in protein NT levels. Despite this change, GSNO was effective in inhibition of P selectin expression, platelet aggregation, protein carbonylation and apoptosis. The results suggest that L-arginine and GSNO-mediated NO leads to the inhibition of key apoptotic processes including caspase-3 activation, PS exposure and low mitochondrial membrane potential in washed platelets. The inhibitory effect of platelet clearance of L-arginine and GSNO may be a novel useful therapeutic property in clinical application. PMID- 23111883 TI - Toxicity of cadmium and protective effect of bee honey, vitamins C and B complex. AB - The present work aimed to study the toxic effect of cadmium (Cd) on rabbits' blood indices, as well as the therapeutic effect of the antioxidant agents, vitamins C and B complex and bee honey on Cd intoxicated rabbits. Cadmium chloride (CdCl2) was injected subcutaneously at a dose of 3 mg/kg of body weight. The results showed a significant increase in serum glucose, triglycerides, cholesterol, total protein, albumin, globulin, urea and creatinine, compared to the control group. In addition, CdCl2 intoxication increased the levels of uric acid, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase and bilirubin. Concerning haematological parameters, the more obvious changes were an increase in mean corpuscular volume and a decrease in white blood cells count, platelets, lymphocytes, heamatocrit, haemoglobin and red blood cells count. Treatment of CdCl2-intoxicated animals with vitamins C and B complex and bee honey showed a decrease in the harmful effects of Cd by restoring haematological and biochemical changes. Bee honey treatment was the most effective in providing recoveries in the altered blood parameters. PMID- 23111884 TI - Estimation of BDNF gene polymorphism and predisposition to dependence development for selected psychoactive compounds: genetic aspects of addiction with the selected drugs, amphetamine, tetrahydrocannabinol and opiates. AB - The etiology of drug addiction, a central nervous system (CNS) disease, is not fully known. This complex problem is believed to be connected with concurrently affecting genetic, psychological and environmental factors. The development of addiction is connected with CNS reinforcement system and dopaminergic neurotransmission. Molecular processes are postulated to be of universal character and allow to presume a similar mechanism of dependence for both ethanol and other substances. Therefore, elements of dopaminergic transmission become excellent candidates for the examination of genetic influence on the development of addiction. A relationship between alcoholic disease and the presence of TaqIA1 and DRD2 alleles permits to initiate another investigation of gene-coding DRD2 dopamine receptor. The latest results indicate the importance of brain-derived neurotrophic factor (BDNF) in the regulation of dopaminergic route. The purpose of this research was to reveal the relationship between the Val66Met BDNF gene polymorphism and dependence of psychoactive agent. The examinations were performed with the Local Research Ethics Committee approval and patient's consent. The study group consisted of 100 patients (88 men and 12 women) aged 18 52 years, qualified for research program according to the International Classification of Diseases, Tenth Revision (ICD-10) requirements, medical examination and detailed questionnaire. PMID- 23111885 TI - Low cytotoxic elastic niosomes loaded with salmon calcitonin on human skin fibroblasts. AB - A low cytotoxic elastic niosomal formulation loaded with salmon calcitonin was developed. The elastic niosomes were prepared from Tween 61 mixed with cholesterol at various concentrations of the edge activators (sodium cholate (NaC) and sodium deoxycholate (NaDC); 0.25, 0.5, 2.5, 5 and 10% mole) or ethanol (10-30% v/v). The effects of the niosomal concentrations (5, 10 and 20 mM) and phosphate buffer at pH 7.0 (5, 10, 20 and 30 mM) on the physical characteristics of niosomes were investigated. The 5 mM elastic niosomes in 5 mM phosphate buffer containing calcitonin 0.22 mg/mL gave the highest elasticity (deformability index (DI)) at 6.79 +/- 2.03 determined by the extrusion method. The blank elastic niosomes comprised 2.5% mole NaDC, 5% mole NaC or 20% v/v ethanol showed the highest elasticity. The 5% mole NaC elastic niosomes loaded with calcitonin gave the highest DI (21.59 +/- 0.91) and percentages of calcitonin entrapment efficiency (60.11 +/- 4.98). This study has demonstrated that this NaC elastic niosome did not only reduce the cytotoxicity of the loaded calcitonin but also gave superior cell viability to the ethanolic elastic niosome as well. PMID- 23111886 TI - The protective effect of recombinant human erythropoietin against cisplatin induced renal and hepatic dysfunctions in Wistar rats. AB - Cisplatin (Cisp) is one of the most effective chemotherapeutic drugs. However, the dose of Cisp is greatly limited by its toxicity. Recombinant human erythropoietin (rhEPO), a hormone that regulates hematopoiesis, has also been shown to exert tissue-protective effects. The purpose of this study was to explore the protective effect of rhEPO against Cisp-induced renal and liver dysfunctions. Adult male Wistar rats were divided into six groups of six each: control, rhEPO-alone group, Cisp-alone group and rhEPO + Cisp group (pretreatment, cotreatment and posttreatment conditions). Our results showed that Cisp-induced a marked renal and liver failure characterized by a significant decrease in body weight, organ weight and organ ratio and a significant increase in creatinine, blood urea nitrogen, alanine aminotransferase, aspartate aminotransferase, G-glutamyl transferase, alkaline phosphatase, bilirubin conjugated and bilirubin total levels in serum. Histological examination showed that Cisp caused kidney alterations. rhEPO treatments restored body weight, organ weight and organ ratio as well as serum biochemical parameters changed due to Cisp exposure. PMID- 23111887 TI - Two cases of acute dexmedetomidine withdrawal syndrome following prolonged infusion in the intensive care unit: Report of cases and review of the literature. AB - Prolonged infusion of dexmedetomidine, an alpha(2)-adrenoreceptor agonist anesthetic used in the intensive care unit, produces a withdrawal syndrome of sympathetic over-activity, characterized by tachycardia, hypertension and agitation, but there is no recommended standard treatment for this syndrome. We describe two patients with a clinical diagnosis of acute dexmedetomidine withdrawal and its management with oral clonidine. We utilized the principle of managing acute drug withdrawal with longer acting medications. These two cases demonstrated the benefit of using oral, longer acting clonidine to manage acute withdrawal from shorter-acting, intravenous dexmedetomidine. PMID- 23111888 TI - Cytochrome P4501A1 genotypes and smoking- and hypertension-related ischemic stroke risk. AB - This study aimed to determine whether the coding (A4889G) and noncoding region (T6235C) polymorphisms of the gene coding for cytochrome P4501A1 (CYP1A1), a xenobiotic-metabolizing enzyme responsible for the metabolism of carcinogenic polycyclic aromatic hydrocarbons, are involved in the pathogenesis of ischemic stroke in Turkish population. Study group consisted of 226 ischemic stroke patients and 113 controls. Genotypes were attained by allele-specific polymerase chain reaction (PCR) for A4889G and PCR/restriction fragment length polymorphism analysis for T6235C. Frequency of 6235C allele was significantly lower in patients (0.151) compared with controls (0.226, P = 0.015). Prevalence of hypertension and hypertension-associated ischemic stroke risk was lower for 6235C allele carriers. This allele decreased ischemic stroke risk twofold (adjusted odds ratio = 0.48, P = 0.005). There was almost no difference in 4889G allele frequencies in patients (0.445) and controls (0.425). However, prevalence of hypertension was lower in 4889G allele carriers when compared with the wild-type genotypes. In addition, risk of ischemic stroke for smoker and hypertensive individuals was lower when they have at least one 4889G allele. The present study demonstrated that CYP1A1 genetic variants contribute to interindividual variability in smoking- and hypertension-induced ischemic stroke risk. PMID- 23111889 TI - Can we trust in trials stopped early for benefit? PMID- 23111890 TI - Estradiol inhibits vascular endothelial cells pro-inflammatory activation induced by C-reactive protein. AB - In addition of being an important inflammatory biomarker and a risk factor for cardiovascular disease, much evidence indicates that the C-reactive protein (CRP) contributes to the atherosclerosis development process. This plasmatic protein synthesized by hepatocytes in response to inflammation and tissue injury induces pro-inflammatory molecules' expression by endothelial cells (ECs). Previous studies showed that the 17beta-estradiol (E2) has beneficial effects on vascular cells by reducing in vitro pro-inflammatory molecules expressions in EC. Therefore, we hypothesize that E2 blocks or reduces CRP-mediated inflammatory responses by modulating endogenous production of CRP in EC and/or activation mechanisms. Using human aortic ECs (HAECs), we first evaluated CRP production by vascular EC and second demonstrated its self-induction. Indeed, recombinant human CRP stimulation induces a fivefold increase of CRP expression. A 1-h pre treatment of E2 at a physiologic dose (10(-9 )M) leads to an important decrease of CRP production suggesting a partial blockage of its amplification loop mechanism. Furthermore, in HAEC, E2 reduces the secretion of the most potent agonist of CRP induction, the IL-6, by 21 %. E2 pre-treatment also decreased the expression of pro-inflammatory molecules IL-8, VCAM-1, and ICAM-1 induced by CRP and involved in leukocytes recruitment. In addition, we demonstrated that E2 could restore vascular endothelial growth factor-mediated EC migration response impaired by CRP suggesting another pro-angiogenic property of this hormone. These findings suggest that E2 can interfere with CRP pro-inflammatory effects via activation signals using its rapid, non-genomic pathway that may provide a new mechanism to improve vascular repair. PMID- 23111891 TI - Both short intense and prolonged moderate in vitro stimulation reduce the mRNA expression of calcium-regulatory proteins in rat skeletal muscle. AB - Sarcoplasmic and t-tubule membrane proteins regulating sarcoplasmic Ca(2+) concentration exhibit fibre-type-dependent isoform expression, and play central roles in muscle contraction and relaxation. The purpose of this study was to evaluate the effects of in vitro electrical stimulation on the mRNA expression of components involved in Ca(2+) regulation in oxidative and glycolytic skeletal muscle. The mRNA level of Ca(2+)-ATPase (SERCA1, 2), calsequestrin (CASQ1, 2), ryanodine receptor (RyR1), and dihydropyridine receptor (Cacna1) was assessed in rat extensor digitorum longus (EDL) and soleus (SOL) muscles at 4 h of recovery following in vitro stimulations (either short intensive (SHO) 60 Hz, 5 min, or prolonged moderate (PRO) 20 Hz, 40 min). Stimulation induced acute regulation of the mRNA level of Ca(2+)-regulating proteins in a manner that does not follow typical fibre-type-specific transitions. In general, stimulation decreased mRNA content of all proteins studied. Most prominent down-regulation was observed for Cacna1 (26 and 32 % after SHO and PRO, respectively, in SOL; 19 % after SHO in EDL). SERCA1, SERCA2, CASQ1, CASQ2, and RyR1 mRNA content also decreased significantly in both muscles relative to resting control. Of notice is that hexokinase II mRNA content was increased in EDL and unchanged in SOL underlining the specificity of the down-regulation of mRNA of Ca(2+) regulatory proteins. The results demonstrate contraction-induced down-regulation of mRNAs for the main components of Ca(2+)-regulating system in skeletal muscle. The down-regulation of both isoforms of SERCA and CASQ after a single electrical stimulation session suggests that adaptations to repeated stimulation involve further regulatory mechanisms in addition to acute mRNA responses. PMID- 23111892 TI - Sarpogrelate inhibits the expression of ICAM-1 and monocyte-endothelial adhesion induced by high glucose in human endothelial cells. AB - Hyperglycemia is the major cause of diabetic angiopathy. Sarpogrelate hydrochloride is an antiplatelet drug, and expected to be useful in the treatment of chronic arterial occlusive diseases. The aim of our study was to evaluate the possible effects of sarpogrelate hydrochloride on adhesion molecule expression and its underlying mechanism in the prevention and treatment of cardiovascular disorders. Intercellular adhesion molecule-1 (ICAM-1) expression and superoxide dismutase (SOD) activity were determined after endothelial cells were exposed to high glucose in the absence and presence of sarpogrelate hydrochloride. Coincubation of endothelial cells with high glucose for 24 h resulted in a significant increase of monocyte-endothelial cell adhesion and the expression of ICAM-1 (P < 0.01). These effects were abolished by sarpogrelate hydrochloride and sarpogrelate hydrochloride significantly increased SOD activities (40 +/- 8 vs. 47 +/- 7, n = 8, P < 0.01). The low dose sarpogrelate group (0.1 MUM) had significantly higher monocyte-endothelial cell adhesion and the expression of ICAM-1 than medium dose sarpogrelate group (1.0 MUM) and high dose sarpogrelate group (10.0 MUM) (P < 0.05 for comparison among three groups and P < 0.01 for difference between low and high dose sarpogrelate groups). These findings suggested that sarpogrelate hydrochloride was able to protect vascular endothelium from dysfunction induced by high glucose. PMID- 23111893 TI - Intervention of rosiglitazone on myocardium Glut-4 mRNA expression during ischemia-reperfusion injury in cardio-pulmonary bypass in dogs. AB - During cardiac pulmonary bypass (CPB), myocardial ischemia-reperfusion (I/R) induces heart glucose metabolism impairment. Our previous research showed that the decreased glucose utilization is due to decreased glucose transporter-4 (Glut 4) expression and translocation to myocyte surface membranes. This study further examined whether rosiglitazone, a synthetic agonist of peroxisome proliferator activated receptor gamma, could intervene glucose metabolism by regulating Glut-4 mRNA during I/R in dogs. Cardiac ischemia was induced by cardiopulmonary bypass for 30 or 120 min. Plasma insulin and glucose concentrations were measured at pre bypass (control), aortic cross-clamp off (I/R) at 15, 45, and 75 min. The left ventricle biopsies were taken for the expression of Glut-4 mRNA by real-time RT PCR. In dogs receiving 120 min ischemia, coronary arterial, venous glucose concentrations, plasma insulin levels, and insulin resistant index (IRI) were increased, but the expression of Glut-4 mRNA was decreased obviously at 15 min of reperfusion, and recovered gradually. On the other hand, these changes were relatively mild in dogs treated with rosiglitazone in cardioplegic solution and expression of Glut-4 mRNA was increased remarkably. It is concluded that the decrease in total amount of Glut-4 mRNA expression could be one of the important molecular mechanisms, which causes the myocardium insulin resistance. The longer the ischemia period, the decrease in amount of Glut-4 mRNA was more dramatic. Adding rosiglitazone into the cardioplegic solution during I/R can increase the amount of Glut-4 mRNA expression, mitigate the myocardium insulin resistance and improve the myocardium I/R injury during CPB. PMID- 23111895 TI - Buyer beware! doctor be aware!: Questions. PMID- 23111894 TI - Protocol biopsies in pediatric renal transplant recipients on cyclosporine versus tacrolimus-based immunosuppression. AB - BACKGROUND: Protocol biopsies can detect subclinical rejection and early signs of calcineurin inhibitor-induced nephrotoxicity. METHODS: In a prospective study, protocol biopsies 3 and 12 months after transplant in transplanted children from two centers were studied. One center used cyclosporine (CsA)-based immunosuppression and the other center used tacrolimus. Patients were on CsA (n = 26, group 1) or on tacrolimus (n = 10, group 2). Patients received basiliximab induction, mycophenolate mofetil, and prednisone. RESULTS: In patients on CsA, 26 kidney biopsies were performed during the 6 months after transplantation. Eighteen protocol biopsies were performed at 3 months post transplant; 13 were normal and five showed rejection (two borderline and three Banff II rejections). Eight biopsies were motivated by an increase of serum creatinine; four were normal and four revealed signs of acute rejection (two borderline and two Banff II). Twelve protocol biopsies were performed after 12 months; all were normal. For patients on tacrolimus (n = 10), ten protocol transplant biopsies were performed at 3 months post-transplant; none showed signs of rejection. No biopsy was performed for an increase of serum creatinine. There were no differences in patient age, number of human leukocyteantigen (HLA) incompatibilities, or other patient characteristics. CONCLUSIONS: Patients on tacrolimus had less acute rejection episodes detected on protocol biopsies 3 months after transplant. Protocol biopsies seem to play an important role in the detection of subclinical rejection in patients on CsA. PMID- 23111896 TI - Hyperbaric oxygen therapy for acute noise-induced hearing loss: evaluation of different treatment regimens. AB - INTRODUCTION: Impulse noise from firearms is a common cause of acute acoustic trauma (AAT), which is characterized by high-frequency hearing loss and tinnitus. Various treatment modalities have been proposed, some combining medical treatment with hyperbaric oxygen (HBOT) in various ways. We have reviewed the therapeutic effect of primary protocols, with or without HBOT, used in our hospital. METHODS: Sixty-eight soldiers for all of whom pre-AAT audiometry tests were available, were treated with one of three different regimens. Group 1 received oral medication only. Group 2 received HBOT twice a day for 3 days then once a day (7 days), combined with intravenous medication (5 days) followed by oral treatment. Group 3 received HBOT once a day and oral medication for 10 days. Medical treatment consisted of methylprednisolone and piracetam in all groups. Control audiometry was performed after 10 days. Average Hearing Gain (AHG) and Average Residual Hearing Loss (ARHL) were calculated. RESULTS: The mean AHG in Group 1 was +5.58 +/- 3.58 dB (mean +/- SD); in Group 2 it was +20.62 +/- 17.68 dB; and in Group 3 +17.0 +/- 14.0 dB (P = 0.001, Kruskal-Wallis test). The mean ARHL without HBOT was -14.7 +/- 8.27 dB (Group 1), and respectively -2.36 +/- 10.69 dB (Group 2) and -5.0 +/- 8.0 dB (Group 3) in the HBOT groups (P = 0.001, Kruskal Wallis test). CONCLUSION: These results indicate a significant benefit for the combination of HBOT and medical therapy over medical treatment alone. Which of the two HBOT regimens is the more effective, remains to be determined. PMID- 23111897 TI - The two faces of Eve: gaseous anaesthesia and inert gas narcosis. AB - Gaseous anaesthesia has been a great boon for medicine. These drugs form a foundation from which modern surgery has sprung, yet their mechanism(s) of actions remains poorly understood. Inert gas narcosis is a limitation of deep sea diving, and its mechanisms also remain poorly understood. In this review article we summarise what is known about the mechanisms of both gaseous anaesthesia and inert gas narcosis, including both lipid-based biophysical models and protein based biochemical models, as well as explore some striking similarities between the two. These two phenomena may, in reality, be gradations of the same underlying mechanism. Recent findings include biochemical evidence suggesting that both gaseous anaesthesia and inert gas narcosis may be mediated by the occupation of minute spaces within the structure of many biologically important proteins, impairing their ability to undergo conformational changes and biological actions. This is exemplified by exploring the effects of the noble gas xenon, which can behave as either a narcotic gas or gaseous anaesthetic, depending on the partial pressure in which it is present. PMID- 23111898 TI - ANZHMG statement on the administration of mild hyperbaric oxygen therapy. AB - 'Mild' hyperbaric therapy (MHT) and hyperbaric oxygen therapy are easily confused. Essentially the difference lies in the effective oxygen dose. Oxygen is an extremely useful and efficacious drug in a wide range of medical conditions. MHT does not typically provide more available oxygen to the body than is possible with oxygen administration at one atmosphere (sea level), and there is no known therapeutic benefit of mild compression alone. There is, therefore, no documented, biologically plausible evidence for the use of MHT over delivery of oxygen by a simple facemask at one atmosphere of pressure. MHT is advocated for a wide range of clinical conditions, in particular for chronic neurological conditions and as part of a suite of 'wellbeing' therapies. The Australia and New Zealand Hyperbaric Medicine Group, a standing sub-committee of the South Pacific Underwater Medicine Society, is not aware of any reliable clinical evidence for therapeutic benefit from mild hyperbaric therapy and does not recommend the use of this modality for any medical purpose. PMID- 23111899 TI - Health risk management in the Tasmanian abalone diving industry. AB - Risk management is a systematic process applied to all aspects of diving operations. The process aims to reduce accidents and adverse outcomes to a minimum. Risk results from a combination of probability and consequence, and where this combination has major or extreme impact, the risk should not be tolerated. Over the four years 2001-2004, the incidence of decompression illness amongst abalone divers in Tasmania was 1.4 cases per 100 divers per year. Risk management in diving encompasses medical fitness, education and training, dive planning, equipment and maintenance, emergency procedures and equipment, and continual vigilance to remedy new risks as they are identified. There is still much to achieve in the Tasmanian abalone diving industry in all areas of risk management. PMID- 23111900 TI - Eye as a key element of conspecific image eliciting lateralized response in fish. AB - Visual lateralization in different aspects of social behaviour has been found for numerous species of vertebrates ranging from fish to mammals. For inspection of a shoal mate, many fishes show a left eye-right hemisphere preference. Here, we tested the hypothesis that in fish, there is a key cue in the conspecific appearance, which elicits lateralized response to the whole image of the conspecific. In a series of eight experiments, we explored eye preferences in cryptic-coloured Amur sleeper, Perccottus glenii, fry. Fish displayed left-eye preferences at the population level for inspection of a group of conspecifics, their own mirror image, and a motionless flat model of a conspecific. In contrast, no population bias was found for scrutinizing an empty environment or a moving cylinder. When fry were showed a model of a conspecific in a lateral view with the eye displaced from the head to the tail, they again showed a significant preference for left-eye use. On the other hand, 'eyeless' conspecific model elicited no lateralized viewing in fry. Finally, the left-eye preference was revealed for scrutiny of the image of a conspecific eye alone. We argue that in Amur sleeper fry, eye is the element of the conspecific image, which can serve as a 'key' for the initiation of lateralized social response. This key element may serve as a trigger for the rapid recognition of conspecifics in the left eye right hemisphere system. Possible causes and advantages of lateralized perception of social stimuli and their key elements are discussed in the context of current theories of brain lateralization. PMID- 23111901 TI - Learning of an oddity rule by pigeons in a four-choice touch-screen procedure. AB - Six pigeons were trained to peck at a target (odd stimulus) that was presented on a touch-screen together with three identical distractors (non-odd stimuli). The target could be either a square or a circle that was either blue or green, and the distractors in each trial were always of the opposite form and color to the target. Thus, the birds could solve the task by attending to color, form, or both. Transfer tests showed that performance was not disrupted by novel forms, stimulus sizes, distractor numbers, and display configurations, but broke down with novel stimulus types (textured stimuli, clip art images, and photographs). Transfer to novel colors was, for the most part, restricted to trials in which only one component-target or distractors, but not both-had a novel color. This suggested that the pigeons used a couple of if-then rules rather than an oddity concept to solve the task, and that color differences between target and distractors were the only cue upon which responding was based. A control experiment with the order of color and form tests being reversed excluded the possibility of the prevalence of color being an artifact of task order and reinforcement contingencies. PMID- 23111902 TI - A retrospective study of 109 dogs with mandibular fractures. AB - OBJECTIVE: To determine patient factors and fracture morphology of dogs presented with mandibular fractures to a small animal referral centre in South Africa. METHODS: Patient data on age, sex, breed and aetiology of dogs with mandibular fractures were recorded. The fractures were classified according to the anatomical location, displacement, fracture type, fracture line direction, periodontal pathology, and whether there were teeth in the fracture line or not by evaluation of preoperative radiographs. Clinical observations indicated whether these fractures were open or closed. RESULTS: In total, 109 dogs with 135 mandibular fractures were included in the study. Small breed dogs and dogs less than eight months of age predominated (102/109). Dog fights were the most common aetiology in this study (68/109). The molar region was the most commonly affected region (56/135). Evaluation of the radiographs revealed that transverse (73/135), relatively unstable (116/135), and displaced (112/135) fractures were the most common. The majority of fractures involved teeth in the fracture line (100/135), with the first molar frequently involved (54/135). The majority of fractures were open (104/135). CLINICAL SIGNIFICANCE: The results obtained from this study may be used to guide patient and fracture morphology selection in biomechanical studies of mandibular fracture repair techniques. Screening of this patient population may inspire the search for new treatment options for mandibular fracture repair in South Africa. PMID- 23111903 TI - Chirality and template-mediated induction of helical preferences in achiral beta peptides. AB - This study describes chirality- or template-mediated helical induction in achiral beta-peptides for the first time. A strategy of end capping beta-peptides derived from beta-hGly (the smallest achiral beta-amino acid) with a chiral beta-amino acid that possesses a carbohydrate side chain (beta-Caa; C-linked carbo beta amino acid) or a small, robust helical template derived from beta-Caas, was adopted to investigate folding propensity. A single chiral (R)-beta-Caa residue at the C- or N-terminus in these oligomers led to a preponderance of right-handed 12/10-helical folds, which was reiterated more strongly in peptides capped at both the C- and N-terminus. Likewise, the presence of a template (a 12/10-helical trimer) at both the C- and N-terminus resulted in a very robust helix. The propagation of the helical fold and its sustenance was found in a homo-oligomeric sequence with as many as seven beta-hGly residues. In both cases, the induction of helicity was stronger from the N terminus, whereas an anchor at the C terminus resulted in reduced helical propensity. Although these oligomers have been theoretically predicted to favor a 12/10-mixed helix in apolar solvents, this study provides the first experimental evidence for their existence. Diastereotopicity was found in both the methylene groups of the beta-hGly moieties due to chirality. Additionally, the beta-hGly units have shown split behavior in the conformational space to accommodate the 12/10-helix. Thus, end capping to assist chiralty- or template-mediated helical induction and stabilization in achiral beta-peptides is a very attractive strategy. PMID- 23111905 TI - Application of monoliths for bioparticle isolation. AB - Monoliths are today probably the most studied chromatographic supports. There are plethora of publications dealing with different aspects of their preparation, characterization, and applications. The reason for this interest is their inherent properties related to their particular structure, like ease of preparation in various volumes, fast analytics at low pressure and room temperature, and high productivity as a consequence of flow-unaffected properties, especially important for isolation of large biological molecules. Because of that, structure of several monoliths was optimized for analytics and purification of biologic nanoparticles like viruses, virus-like particles (VLPs), cells structures, or even intact cells. In this review, some recent applications of monoliths in the field of bioparticle isolation are described and results are discussed in terms of particular monolith properties. PMID- 23111904 TI - A simple strategy to identify acute hepatitis C virus infection among newly incarcerated injection drug users. AB - Acute hepatitis C virus (HCV) infection is underdiagnosed because most patients are asymptomatic. The majority of new infections occur among people who inject drugs (PWID), many of whom have a history of incarceration. In a previous pilot study, we identified symptomatic HCV cases, mainly among Caucasian inmates. We designed a cross-sectional study to evaluate whether risk factor-based screening of newly incarcerated inmates would enhance identification of asymptomatic acute HCV infection and elucidate any demographic shifts in HCV acquisition. From October 2006 to March 2008, 6,342 inmates underwent health assessments and 3,470 inmates (55%) were screened. The racial distribution was as follows: African American, 24.0%; Caucasian, 49.5%; Hispanic, 22.2%. One hundred seventy-one inmates (4.9%) were classified as high-risk. After further evaluation, 35 (20.5%) inmates were diagnosed with acute HCV with a mean age of 29 years; 62.9% were female and 91% were Caucasian. No African Americans were diagnosed with acute HCV. Our case-finding rate was 1.9 patients/month nearly a three-fold increase compared with our historical control period with a higher proportion of asymptomatic cases. We estimate a prevalence of ~1.0% (95% confidence interval, 0.7%-1.4%) of acute HCV infections among newly incarcerated inmates. CONCLUSION: Within the correctional system, systematic screening based on risk factors successfully identifies acute HCV infection among PWID, including asymptomatic patients. Our data also reflect changing nationwide patterns of injection drug use that vary by age, ethnicity, and race, leading to a marked reduction of acute HCV infections among African Americans compared with non-Hispanic whites. The nationwide implementation of this simple low-cost strategy in prison-based settings could identify more than 7,000 acute HCV infections among PWID, provide insight into changing epidemiologic trends, and facilitate appropriate therapeutic and preventive interventions. PMID- 23111907 TI - Female sexual dysfunction in Iran: study of prevalence and risk factors. AB - PURPOSE: To assess the prevalence of and risk factors for female sexual dysfunction (FSD) among women in Birjand city, Iran. METHODS: This cross sectional population-based survey was conducted in nine areas of Birjand, the provincial center of South Khorasan province and married women aged between 15 and 72 years were included. Data were collected by face-to-face interview and completing a self-administered questionnaire. FSD and related risk factors were assessed. RESULTS: A total of 821 women with mean age of 31.5 +/- 9.1 were studied. Of them, 694 (84.6 %) had active sexual relationship with their husband, 239 (29.1 %) had less than one intercourse per week, 320 (39 %) did not feel pleasure with their sexual activity and intercourse, 86 (10.5 %) had never attained an orgasm, 604 (73.6 %) had a highly satisfactory relationship with their husband. CONCLUSIONS: Dissatisfaction and not feeling pleasure with sexual activity was the most common FSD in our study. Further epidemiologic investigation is clearly warranted. PMID- 23111908 TI - Evaluation of critical flicker fusion frequency and perceived fatigue in divers after air and enriched air nitrox diving. AB - INTRODUCTION: Many divers report less fatigue following dives breathing enriched air nitrox (EANx) compared with breathing air. A reduction of post-dive fatigue with EANx would suggest a pathological origin, possibly the presence of asymptomatic nitrogen bubbles in the body after a dive. METHOD: We studied fatigue in 219 healthy divers performing either an air (n = 121) or EANx32 (oxygen 32%, nitrogen 68%; n = 98) dive to 21.2 +/- 4 metres' sea water for 43.3 +/- 8.6 minutes in tropical open-water conditions. Divers were assessed pre-dive and 30-60 minutes after surfacing using a visual analog scale (VAS) of fatigue and critical flicker fusion frequency (CFFF). RESULTS: The two groups were comparable in sex ratio, age and diving experience. The change in perceived fatigue level after a single dive was significantly lower when EANx was breathed compared to air dives (VAS; P < 0.001). Compared to pre-dive, CFFF decreased by 6% in the air group (P < 0.01) but increased by 4% in the EANx group (P < 0.05). The post-dive difference between the two groups was highly significant (P < 0.001). CONCLUSIONS: Three hypotheses should be considered to explain the difference in post-dive fatigue and alertness between the air and EANx groups: a nitrogen effect, an oxygen effect and a bubble effect. These involve complex phenomena in the functional modifications of the nervous system in hyperbaric environments according to the type of gas used for the dive, and more research will be required to elucidate them. PMID- 23111909 TI - Medical assessment of fitness to dive - comparing a questionnaire and a medical interview-based approach. AB - INTRODUCTION: In Queensland, most entry-level recreational diving students have to complete two diving medical forms (the Recreational Scuba Training Council (RSTC) or similar, and the appendix to Australian Standard 4005.1), as well as undergoing a medical consultation by a medical practitioner experienced in diving medicine. This provides an opportunity to evaluate the performance of the health questionnaire compared to the medical interview. METHODS: We conducted a retrospective analysis of 1,000 consecutive entry-level scuba-diving students assessed by one doctor (CM). Using the medical consultation as the reference standard, we analysed the number of incorrect or inconsistent answers in each of the forms. The main outcome was the number of individuals who were found 'unfit to dive' following the medical, but who appeared fit according to their responses on the RSTC form. RESULTS: Of the 1,000 students, 3.7% failed the medical, 9.4% gave inconsistent answers and 29.9% gave incorrect answers. 63.2% had answered 'no' to all the questions on the RSTC form, and nine of these students (1 in 70) were assessed at the medical as 'unfit' for scuba diving, (0.9% of the total). Logistic regression could not identify factors that reliably predict those at high risk of failing the medical consultation after passing the RSTC questionnaire. Those who gave incorrect responses were more likely to fail (8.4% versus 2.0%, P < 0.0001). CONCLUSIONS: One in 70 candidates failed during the medical consultation after indicating they had no relevant medical problems on a questionnaire. Face-to-face medical interview does identify individuals who are at risk while diving, where two commonly used medical screening forms do not. The practical significance of these conclusions remains unclear. PMID- 23111910 TI - Referral patterns and outcomes of dive medical examinations in a tertiary hyperbaric facility. AB - INTRODUCTION: Scuba diving involves risks, and candidates in Australia usually have a medical evaluation prior to undertaking a diving course. Hyperbaric physicians act as secondary referral practitioners for these assessments. This study aimed to identify reasons for these secondary referrals, and document the assessment process and outcome for potential dive candidates. METHODS: This was a retrospective case-note analysis of candidates for dive medicals presenting to the Department of Diving and Hyperbaric Medicine (DDHM) at the Prince of Wales Hospital, Sydney, over 10 years. RESULTS: We identified a total of 191 candidates aged 12 to 67 years. Most were candidates for recreational diving (n = 148, 77.5%) and 119 (62.3%) were male. Commercial dive candidates had higher median total number of dives (P = 0.005), median maximum depth (P < 0.001) and median years, diving (P = 0.018) than recreational dive candidates. Respiratory problems were the most common referral reason for presentation (35%), followed by CNS (14%), ENT (13%) and cardiovascular conditions (9%). Most candidates were assessed as 'fit to dive' (136 or 71%), 49 (26%) were 'unfit', while six (3%) were subject to restrictions. Forty-three candidates (22%) presented with a diagnosis of asthma, of whom 25 (13%) were considered 'fit to dive'. CONCLUSION: The most common presentation for evaluation was for respiratory conditions, particularly asthma, but a wide range of medical conditions were assessed, and subjects were evaluated on an individual basis. Although current standards in Australia discourage asthmatic subjects from diving, over half of the candidates presenting with a possible diagnosis of asthma were assessed as 'fit to dive'. PMID- 23111911 TI - Provisional report on diving-related fatalities in Australian waters 2005. AB - INTRODUCTION: An individual case review of diving-related deaths reported as occurring in Australia in 2005 was conducted as part of the DAN Asia-Pacific dive fatality reporting project. METHOD: The case studies were compiled using reports from witnesses, the police and coroners. In each case, the particular circumstances of the accident and details from the post-mortem examination, where available, are provided. RESULTS: In total, there were 24 reported fatalities, comprising four females and 20 males. Fourteen deaths occurred while snorkelling and/or breath-hold diving, nine while scuba diving, and one while using surface supply breathing apparatus. Four deaths from large marine animal attacks were recorded. Once again, cardiac-related issues were thought to have contributed to some deaths: five snorkel divers and at least two but possibly up to four scuba divers. Three of the deaths in breath-hold divers were likely to have been associated with apnoeic hypoxia blackout. CONCLUSIONS: Pre-existing medical conditions, trauma from marine creatures and snorkelling or diving alone were features in several deaths in this series. PMID- 23111912 TI - A personal overview of accidents and risk management in the recreational diving industry. AB - Recently the recreational diving industry has experienced an increase in accidents and fatalities (per capita, based on reliable estimates of diver populations). Many of these incidents have resulted from a degradation of training standards for 'performance-based' learning of skills and knowledge, both for students and the instructors, dive masters, and assistants who are responsible for their initial training and subsequent courses aimed at 'advanced' curricula. The industry has also seen a decline in the experience and practical expertise of diving leadership staff responsible for the management of resorts and liveaboard diving operations. The resulting incidents have led to a rise in legal actions and settlement costs or trial verdicts. The important contributing issues in accident causation are discussed. A fundamental lack of understanding of how to effectively use the tools of risk management (waivers and releases, defensive teaching, good record keeping), as well as inadequate pre-training screening that might eliminate some participants based on age, physical condition, or pre-existing medical issues, are contributing to this increase. These factors also complicate the efficient management of litigation through the courts. The costs associated with litigation are now causing increased insurance premiums, reduced scope of coverage for some activities, and outright denial to some seeking insurance. This paper provides a personal perspective based on a 40 year involvement in all aspects of the diving industry and extensive experience in the litigation process as a consultant and expert witness. PMID- 23111906 TI - A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability, and intermediate repeats. AB - We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion. PMID- 23111915 TI - The effect of blood contamination on equine synovial fluid analysis. AB - OBJECTIVE: Based on a systemic complete blood count and a synovial fluid sample, to develop a mathematical model enabling the approximation of corrected values for synovial fluid white blood cell (WBC) count, neutrophil percentage, and total protein concentration in samples of synovial fluid that were contaminated by blood. METHODS: Peripheral venous blood and synovial fluid samples were obtained from ten horses. A pooled synovial fluid sample from each horse was separated into 2 mL aliquots, which were subsequently contaminated with a known percentage of autogenous blood (0 to 50% of the synovial fluid volume). A complete blood count, packed cell volume, total protein (TP) concentration, and differential cytological examination were performed in all the synovial fluid and venous blood samples. Regression analysis was used to generate a model to calculate non contaminated synovial WBC count, TP concentration and synovial neutrophil percentage. Using a further five horses these models were applied in blinded fashion to contaminated synovial fluid samples. Calculated values were compared to non-contaminated measured values. RESULTS: Model results for synovial WBC count and TP concentration were not significantly different from measured values. Calculated neutrophil percentage of synovial fluid WBC was a mean of 6.6% higher than measured values and was significantly different. There was no effect of the severity of contamination (as a percentage of volume) on the ability of the models to predict any of the outcome variables. CLINICAL SIGNIFICANCE: It is possible to calculate non-contaminated synovial fluid WBC and TP values, but not neutrophil percentage, from heavily contaminated samples. Further study would allow for improved prediction, validation and extrapolation to a wider horse population. PMID- 23111916 TI - An accidental fatal intoxication with methoxetamine. AB - This paper reports an unintentional death involving the administration of methoxetamine [2-(3-methoxyphenyl)-2-(ethylamino)-cyclohexanone] and offers some reference values from living drug abusers. Methoxetamine is a new recreational drug with a similar structure to ketamine. The deceased was a 26-year-old male with a history of drug abuse; he was found lying on the floor in his apartment. Several "red-line" plastic bags were found, one of which was labeled "2-(3 methoxyphenyl)-2-(ethylamino)-cyclohexanone" and another labeled "Haze." In four cases from living subjects with unknown doses, concentrations of methoxetamine were found from 0.13 to 0.49 ug/g. In three of the cases, the blood samples also contained natural or synthetic cannabinoids. In the autopsy case, a considerably higher concentration of methoxetamine, 8.6 ug/g, was found in femoral blood. In addition, tetrahydrocannabinol and the three different synthetic cannabinoids AM 694, AM-2201, and JWH-018, were present in femoral blood. The circumstances and the high femoral blood concentration of methoxetamine point toward an unintentional, acute fatal intoxication with methoxetamine, although the presence of the three synthetic cannabinoids may have contributed to the death. PMID- 23111917 TI - Seasonal differences in melatonin concentrations and heart rates during sleep in obese subjects in Japan. AB - During the past several decades, obesity has been increasing globally. In Japan, obesity is defined by a BMI of 25 kg/m2 or over; 28.6 % of men and 20.6 % of women are obese. Obese people have an increased incidence of developing cardiovascular, renal, and hormonal diseases and sleep disorders. Obese people also have shortened sleep durations. We investigated seasonal differences in melatonin concentrations, heart rates, and heart rate variability during sleep in obese subjects in Japan. Five obese (BMI, 32.0 +/- 4.9 kg/m2) and five non-obese (BMI, 23.2 +/- 2.9 kg/m2) men participated in this study in the summer and winter. Electrocardiograms were measured continuously overnight in a climatic chamber at 26 degrees C with a relative humidity of 50 %. Saliva samples for melatonin were collected at 2300 hours, 0200 hours, and 0600 hours. We found that melatonin concentrations during sleep in obese subjects were significantly lower than those in non-obese subjects in the winter. Heart rate during sleep in winter was significantly higher than that in summer in both obese and non-obese subjects. Heart rate variability was not significantly different in the summer and winter in both obese and non-obese subjects. Our results show that decreased nocturnal melatonin concentrations during winter in obese men may be related to higher heart rates, and this may suggest that obese men are at an increased risk of a cardiovascular incident during sleep, especially in the winter. PMID- 23111918 TI - Impairment of short term memory in rats with hepatic encephalopathy due to bile duct ligation. AB - Hepatic encephalopathy (HE) arises from acute or chronic liver diseases and leads to cognitive deficits. Different animal models for the study of HE have demonstrated learning and memory impairment and a number of neurotransmitter systems have been proposed to be involved in this. Recently, it was described that bile duct-ligated (BDL) rats exhibited altered spatio-temporal locomotor and exploratory activities and biosynthesis of neurotransmitter GABA in brain cortices. Therefore, the aim of this study was to evaluate cognition in the same animal model. Male adult Wistar rats underwent common bile duct ligation (BDL rats) or manipulation of common bile duct without ligation (control rats). Six weeks after surgery, control and BDL rats underwent object recognition behavioral task. The BDL rats developed chronic liver failure and exhibited a decreased discrimination index for short term memory (STM) when compared to the control group. There was no difference in long term memory (LTM) as well as in total time of exploration in the training, STM and LTM sessions between the BDL and control rats. Therefore, the BDL rats demonstrated impaired STM for recognition memory, which was not due to decreased exploration. PMID- 23111919 TI - Positive urinary antigen tests for Streptococcus pneumoniae in community-acquired pneumonia: a 7-year retrospective evaluation of health care cost and treatment consequences. AB - A positive pneumococcal urinary antigen test (PUAT) for Streptococcus pneumoniae allows an early switch from empiric to targeted treatment in hospitalised community-acquired pneumonia (CAP) patients. The economic and treatment consequences of this widespread implemented test are, however, unknown. We retrospectively evaluated all tests performed since its introduction in two teaching hospitals. Data on patient characteristics, treatment, admission and outcome were retrieved from the electronic patient files. Test benefits were expressed as the number of days that targeted therapy (i.e. penicillin) was administered to hospitalised CAP patients due to a positive PUAT. This calculation was based on the timing of the PUAT and the initiation of targeted therapy. Subsequently, we performed two direct cost analyses from a hospital perspective, first including tests performed for CAP only, and second including costs of all (excessive) tests. Between 2005 and 2012, 3,479 PUATs were performed, of which 1,907 (55 %) were for CAP. A total of 1,638 PUATs (86 %) were negative and 269 (14 %) were positive. Fifty-two (19 %) positive tests were excluded. In 75 (35 %) of the 217 remaining positive tests, a positive PUAT led to targeted treatment during 293 cumulative admission days. Testing costs for CAP only were ?131 per targeted treatment day. These costs were ?257 if local protocol dictated PUAT use for all CAP cases, as opposed to ?72 if the test was reserved for severe cases only. When including all tests, PUAT costs were ?254 per targeted treatment day. Therefore, improving the selective use of the PUAT in hospitalised CAP patients may lead to increased (cost-)efficiency. PMID- 23111920 TI - Selection of single chain variable fragments specific for the human-inducible costimulator using ribosome display. AB - We applied a ribosome display technique to a mouse single chain variable fragment (scFv) library to select scFvs specific for the inducible costimulator (ICOS). mRNA was isolated from the spleens of BALB/c mice immunized with ICOS protein. Heavy and kappa chain genes (VH and kappa) were amplified separately by reverse transcriptase polymerase chain reaction, and the anti-ICOS VH/kappa chain ribosome display library was constructed with a special flexible linker by overlap extension PCR. The VH/kappa chain library was transcribed and translated in vitro using a rabbit reticulocyte lysate system. Then, antibody-ribosome-mRNA complexes were produced and panned against ICOS protein under appropriate conditions. However, in order to isolate specific scFvs for ICOS, negative selection using CD28 was carried out before three rounds of positive selection on ICOS. After three rounds of panning, the selected scFv DNAs were cloned into pET43.1a and detected by SDS-PAGE. Then, enzyme-linked immunosorbent assay showed that we successfully constructed a native ribosome display library, and among seven clones, clone 5 had the highest affinity for the ICOS and low for the CD28. Anti-ICOS scFvs are assessed for binding specificity and affinity and may provide the potential for development of the humanized and acute and chronic allograft rejection. PMID- 23111921 TI - Novel technology development through thermal drying of encapsulated Kluyveromyces marxianus in micro- and nano-tubular cellulose in lactose fermentation and its evaluation for food production. AB - A novel technology development based on the production of a low-cost starter culture for ripening of cheeses and baking is reported in the present study. The starter culture comprises thermally dried cells of Kluyveromyces marxianus encapsulated in micro- and nano-tubular cellulose. For production of a low-cost and effective biocatalyst, whey was used as raw material for biomass production and thermal drying methods (convective, conventional, and vacuum) were applied and evaluated at drying temperatures ranging from 35 to 60 degrees C. The effect of drying temperature of biocatalysts on fermentability of lactose and whey was evaluated. Storage stability and suitability of biocatalysts as a commercial starter cultures was also assessed and evaluated. All thermally dried biocatalysts were found to be active in lactose and whey fermentation. In all cases, there was sugar conversion ranging from 92 to 100 %, ethanol concentration of up to 1.47 % (v/v), and lactic acid concentrations ranged from 4.1 to 5.5 g/l. However, convective drying of the encapsulated cells of K. marxianus in micro- and nano-tubular cellulose was faster and a more effective drying method while drying at 42 degrees C appear to be the best drying temperature in terms of cell activity, ethanol, and lactic acid formation. Storage of the biocatalysts for 3 months at 4 degrees C proved maintenance of its activity even though fermentation times increased by 50-100 % compared with the fresh dried ones. PMID- 23111922 TI - Binary phenomenon of hope: perceptions of traumatized veterans. AB - This is the second article in a phenomenological study of hope among 10 Israeli reserve soldiers with chronic posttraumatic stress disorder. The aim of the second analysis was to learn about the veterans' conceptualization of hope. The picture of hope that emerges from the analysis of their interviews is of a binary phenomenon in which hope develops but may also be arrested, is conscious but also unconscious, and strengthens the individual but may also weaken one. These findings show the binary phenomenon of hope and how it contributes to coping with traumatic events and therefore can assist professional workers who treat individuals suffering from posttraumatic stress disorder. PMID- 23111924 TI - CPMD simulation of a bimolecular chemical reaction: nucleophilic attack of a disulfide bond under mechanical stress. AB - Previous single-molecule atomic force microscopy (AFM) experiments showed a change in the reactivity of a bimolecular substitution reaction with a definite force acting on a protein containing disulfide bonds. Using Car-Parrinello molecular dynamics (CPMD) simulations, we analyse the relevant reaction pathways for the breaking of a disulfide bond in the presence of nucleophiles. PMID- 23111923 TI - Identification and validation of urinary metabolite biomarkers for major depressive disorder. AB - Major depressive disorder (MDD) is a widespread and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. In this study, a nuclear magnetic resonance spectroscopy-based metabonomic approach was employed to profile urine samples from 82 first-episode drug-naive depressed subjects and 82 healthy controls (the training set) in order to identify urinary metabolite biomarkers for MDD. Then, 44 unselected depressed subjects and 52 healthy controls (the test set) were used to independently validate the diagnostic generalizability of these biomarkers. A panel of five urinary metabolite biomarkers-malonate, formate, N-methylnicotinamide, m hydroxyphenylacetate, and alanine-was identified. This panel was capable of distinguishing depressed subjects from healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.81 in the training set. Moreover, this panel could classify blinded samples from the test set with an AUC of 0.89. These findings demonstrate that this urinary metabolite biomarker panel can aid in the future development of a urine-based diagnostic test for MDD. PMID- 23111925 TI - Donor-derived long-lived intragraft leukocytes are likely generated by hematopoietic stem/progenitor cells in liver. PMID- 23111926 TI - Methods for characterization of biochromatography media. AB - Chromatographic methods represent the most powerful techniques for purification of biopharmaceutical compounds. Quite often, the question arises which chromatographic medium should be chosen for a particular purification task or which technique should be applied to obtain the required information for a process, respectively. The present review aims to guide through these questions by presenting experimental and modeling techniques that allow a detailed characterization and comparison of chromatography media as well provide a guideline of techniques for process development. The first section provides basic information on chromatographic theory, types of chromatographic media, and different types of techniques. The second section governs description of experimental techniques including some advises for laboratory practice. The third section presents and discusses selected references from literature. Within this article, the main focus is on traditional laboratory techniques but also automated high-throughput screening methods will briefly be discussed. PMID- 23111928 TI - Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations. AB - Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity. PMID- 23111929 TI - High rehospitalization rate in alcohol-induced psychotic disorder. AB - Little is known about the prevalence and in particular the outcome of alcohol induced psychotic disorder (AIPD). Data from hospital statistics of the BARMER GEK, one of the major health insurance companies in Germany, show a low overall prevalence of AIPD. An analysis of readmission rates for patients hospitalized for AIPD in 2005 (N = 462) and 2006 (N = 404) for the period up to 2010 revealed very high readmission rates. Only a minority of patients were without relapse [144 (31.2%) of the 2005 sample; 152 (37.6%) of the 2006 sample]. Thus, AIPD appears to be a rare complication of the alcohol use disorder but to have an extremely high rehospitalization rate, probably indicating a more chronic course and worse prognosis than previously thought. More follow-up studies are needed to elucidate this syndrome. PMID- 23111931 TI - Malignant otitis externa: experience with hyperbaric oxygen therapy. AB - With the low incidence of malignant otitis externa (MOE) and its variable manifestations, it is not possible to perform relevant prospective controlled studies in this condition. Therefore, the best evidence on which to base therapeutic decisions is likely to remain retrospective reviews of case series. Even though our knowledge in regard to MOE is not greatly increased by the retrospective case series by Saxby et al in this issue, nevertheless it has value.1 The larger number of cases here confirms that multimodal therapy, with the inclusion of hyperbaric oxygen therapy (HBOT), enables a reduction in mortality compared to earlier case reports without HBOT. This case series is the largest in the literature. The real value of HBOT for MOE remains unclear, in part because in historical reports, patients were probably treated with less efficient antibiotics and surgical procedures than nowadays. It would have been interesting to know whether the fatal cases described here had predominantly intracranial propagation of the infection, because a particularly bad prognosis is expected in these patients even without facial nerve palsy. Cures in this high risk subgroup would have also been worth mentioning. The number of surgical debridements required was noticeably low in this group of patients. One must bear in mind that necrotic tissue cannot be revitalised by HBOT and generally hinders cure. This syndrome of 'necrotizing' infection carries the suffix 'malignant' with good reason, given the high mortality rates reported in the literature. In summary, multimodal therapy is to be recommended for malignant otitis externa. There is no evidence to justify omitting any of the components of the treatment complex, including HBOT; there is currently no high level evidence-based medicine, just sound common sense, for any of the applied measures. PMID- 23111927 TI - General survey of hAT transposon superfamily with highlight on hobo element in Drosophila. AB - The hAT transposons, very abundant in all kingdoms, have a common evolutionary origin probably predating the plant-fungi-animal divergence. In this paper we present their general characteristics. Members of this superfamily belong to Class II transposable elements. hAT elements share transposase, short terminal inverted repeats and eight base-pairs duplication of genomic target. We focus on hAT elements in Drosophila, especially hobo. Its distribution, dynamics and impact on genome restructuring in laboratory strains as well as in natural populations are reported. Finally, the evolutionary history of hAT elements, their domestication and use as transgenic tools are discussed. PMID- 23111932 TI - Acute antioxidant pre-treatment attenuates endothelial microparticle release after decompression. AB - PURPOSE: The hyperbaric and hyperoxic effects of a dive have been demonstrated to elicit changes in oxidative stress, endothelial function and microparticle (MP) release. Endothelial MP, which are small membrane vesicles shed from the endothelium, have been suggested as a valid in vivo marker of endothelial function. Furthermore, recent research has shown an increase in CD105 MP post dive to be associated with a decline in endothelial function. The aim of this study was to ascertain whether antioxidant (AOX) pre-treatment can attenuate increased CD105 MP release post-dive. METHODS: Five healthy, male, pressure-naive subjects completed two simulated dives (control and intervention) breathing compressed air to a depth of 18 metres' sea water for 80 min. For the intervention dive, all subjects received a commercially available AOX pill containing vitamins C and E, selenium and beta-carotene 2 h pre-dive. CD105 MP, total antioxidant capacity (TAC) and thiobarbituric reactive substances assay (TBARS) were determined pre-dive, at depth, immediately and 4 h post-dive. RESULTS: In the control dive, there was a significant increase in CD105 MP immediately post-dive when compared with at depth (P < 0.001) and pre-dive (P = 0.039) values. Antioxidant pre-treatment significantly attenuated this release of CD105 MP post-decompression (P = 0.002). There were no significant changes in TBARS or TAC. CONCLUSION: These results may provide evidence of the potential use of AOX pre-treatment as an effective endothelial pre-conditioner for divers. PMID- 23111930 TI - MAOA and MAOB polymorphisms and anger-related traits in suicidal participants and controls. AB - MAOA and, to a lesser extent, MAOB polymorphisms have been related to aggression traits and suicidality. We aimed to investigate the role of MAOA and MAOB in suicidal versus non-suicidal participants and interactions between genetic variation and suicidal status on aggression and anger-related traits. The sample was composed of three groups: one group of suicide attempters (n = 171, males 35.1 %), one group of suicide completers (n = 90, males 57.8 %) and a healthy control group (n = 317, males 43.8 %). We examined the following markers: MAOA rs909525, rs6323, and rs2064070, and MAOB rs1799836. Anger traits were measured with the state-trait anger expression inventory (STAXI) and aggression traits with the questionnaire for measuring factors of aggression (FAF). Associations were separately examined for males and females. Variation in the three MAOA variants was associated with higher levels of anger expressed outwards (STAXI "anger-out" subscale) in male suicidal patients compared to controls (p < 0.001). In females, the C allele of rs6323 showed higher scores on the same subscale ("anger out") (p = 0.002). Allele frequencies of the MAOA rs909525 were associated with suicidality (p < 0.007). Our findings show an association between genetic variation in three polymorphisms of the MAOA and anger traits in suicidal males and one replication for the functional variant rs6323 in females. This relationship was stronger than a direct genetic association with suicide status. Future studies incorporating endophenotypic measures of anger and aggression in suicidal participants are warranted. PMID- 23111933 TI - 'Sea legs': sharpened Romberg test after three days on a live-aboard dive boat. AB - INTRODUCTION: The sharpened Romberg test (SRT) is commonly used by diving and hyperbaric physicians as an indicator of neurological decompression illness (DCI). People who spend a prolonged time on a boat at sea experience impairment in their balance on returning to shore, a condition known as mal de debarquement ('sea legs'). This conditioning of the vestibular system to the rocking motion of a boat at sea may impact on the utility of the SRT in assessing a diver with potential DCI after a live-aboard dive trip. AIM: To assess the impact 'sea legs' has on the SRT after three days on a live-aboard dive trip. METHODS: Thirty-nine staff and passengers of a three-day, live-aboard dive trip performed a SRT before and after their journey, with assessment of potential variables, including middle ear barotrauma, alcohol consumption, sea-sickness and occult DCI. RESULTS: There was no statistically significant impact on SRT performance, with 100% completion pre-trip and 35 out of 36 divers (97.2%) post-trip. There were trends towards more attempts being required and time needed for successful SRT post-trip, but these were not statistically significant. There was a small, but noteworthy incidence of middle-ear barotrauma, with seven people affected pre-trip, and 13 post-trip. There was a higher incidence in student divers. Middle-ear barotrauma did not appear to have a direct impact on SRT performance. CONCLUSION: There was no significant impact on SRT performance resulting from 'sea legs' after three days at sea. Recreational divers, especially dive students, have a substantial incidence of mild middle ear barotrauma. PMID- 23111934 TI - Malignant otitis externa: experience with hyperbaric oxygen therapy. AB - INTRODUCTION: The treatment of malignant otitis externa (MOE) with hyperbaric oxygen therapy (HBOT) remains controversial. The rarity of MOE, combined with poor access to hyperbaric facilities, explains the paucity of existing data. METHODS: We retrospectively reviewed all patients with a diagnosis of MOE referred to the Prince of Wales Hospital hyperbaric unit over a period of six years, and report one of the largest case series to date. RESULTS: From August 2001 to October 2007, 17 patients with MOE were referred, of whom 15 (88%) completed therapy, one did not tolerate HBOT and one was withdrawn due to pulmonary complications. Length of admission averaged 48 days (range 8-93 days) and three received outpatient care. Five patients had complications attributable to HBOT: acute pulmonary oedema (n = 2), seizure (n = 1), tympanic membrane perforation (n = 1) and claustrophobia (n = 1). Average time to follow up was 47 months (range 1-94 months). Twelve patients (70%) were considered cured of their disease, being disease-free at follow up, including four patients who had died of other causes but were symptom-free at the time of death. Three patients died directly from MOE (18%), one after a recurrence of their disease. Two further patients had recurrent disease, both successfully treated with a second cycle of HBOT and antibiotics. Nine patients (53%) had facial nerve palsy before commencement of HBOT, of whom four died, three from MOE, four had ongoing facial paralysis, and one resolved. CONCLUSIONS: HBOT confers minimal morbidity, but its role in MOE remains uncertain. The high mortality of MOE despite maximal therapeutic intervention highlights the need for more effective treatment protocols. PMID- 23111935 TI - Exceeding the limits - estimated tissue pressures among Western Australian recreational divers. AB - INTRODUCTION: In Western Australia (WA), approximately 40 divers suffer decompression sickness per year, many after exceeding accepted safe time and depth limits. METHODS: Divers on organised recreational scuba dives wore depth/time loggers. Dives ('case' dives) exceeding the Diving Science and Technology gas-content limits (M-values) were matched to control dives made at the same dive site at the same time during which no M-values were exceeded. Potential risk factors for decompression sickness were evaluated using a conditional logistic regression model. RESULTS: A total of 1,032 organised recreational dives were recorded. Case dives (n = 38) were more likely made by females, deeper than other divers in the water at the same time. They were also made by divers less likely to have previously dived as deep. CONCLUSIONS: One in 27 recreational dives studied exceeded an M-value during the dive, but none on surfacing. We recommend that dive organisers in WA continue to encourage recreational dive groups to watch their displayed remaining no-stop time and to dive within the limits of their training and experience. This study successfully utilised periodic depth/time dive profile analysis using freely available software. PMID- 23111936 TI - Analyser position for end-tidal carbon dioxide monitoring in a rebreather circuit. AB - INTRODUCTION: A diving rebreather currently nearing release incorporates an infra red CO2 analyser at the end of the exhale hose and uses the expired gas CO2 measurement made at this position to detect hypercapnia. This configuration may allow exhaled anatomic and mouthpiece dead space gas to mix with alveolar gas in the exhale hose thus falsely lowering the CO2 measurement, especially at low tidal volumes. METHODS: A test circuit was constructed using a typical rebreather mouthpiece and exhale hose connected into an anaesthetic machine breathing loop. True end-tidal PCO2 was measured in gas sampled from the mouth and compared breath-by-breath to the PCO2 measured in gas sampled at the end of the exhale hose. Two subjects each completed 60 breaths at tidal volumes of 500, 750, 1000, 1500 and 2000 ml. RESULTS: There was a small (<= 0.21 kPa) mean difference between true end-tidal CO2 and end-of-hose CO2 at tidal volumes of 1000 ml or more. However, at lower tidal volumes, the mean difference increased and, at 500 ml, it was 1.04 kPa and 0.70 kPa in subjects 1 and 2 respectively. CONCLUSION: Measurement of the peak exhaled PCO2 at the end of a rebreather exhale hose may provide a reasonable estimation of the true end-tidal CO2 at large tidal volumes, but may significantly underestimate the true end-tidal CO2 at low tidal volumes. PMID- 23111937 TI - S100B and its relation to intravascular bubbles following decompression. AB - INTRODUCTION: When neurological damage occurs in divers, it is considered to be caused by gas bubbles. Entrapment of these bubbles may lead to cellular injury and cerebral oedema. S100B is a protein biomarker that is released in CNS injuries and the concentration is related to the amount of brain damage. METHODS: A total of 27 rats were randomly assigned to one of three groups. Group I served as controls (n = 9). Group II (n = 7) underwent a simulated dive to 400 kPa and Group III to 700 kPa (n = 11). In groups II and III, venous gas bubble scores were evaluated by ultrasound during the first hour after surfacing. The amount of S100B in serum after the dives was tested using a commercial ELISA kit. Bubble grades were compared to S100B protein concentrations. RESULTS: The average level of S100B was significantly higher in rats compressed to 700 kPa compared to the control rats, (P = 0.038) and the rats compressed to 400 kPa, (P = 0.003). There was no difference in S100B concentration between groups I and II. Following the dive to 700 kPa, there were significantly higher bubble grades observed than following the dive to 400 kPa (P = 0.001). CONCLUSION: The correlation between bubble grade and an increase in serum protein level of S100B indicates that this protein may be useful as a biomarker for neurological damage caused by decompression. PMID- 23111938 TI - Severe hydrogen sulphide poisoning treated with 4-dimethylaminophenol and hyperbaric oxygen. AB - INTRODUCTION Hydrogen sulphide (H2S) is a highly toxic gas which originates mainly during breakdown of organic matter under anaerobic conditions. After inhalation, H2S binds to mitochondrial respiratory enzymes preventing oxidative phosphorylation, thereby causing reversible inhibition of aerobic metabolism and cellular anoxia. The use of hyperbaric oxygen therapy (HBOT) for H2S poisoning remains controversial, but has a similar underlying rationale to that in carbon monoxide poisoning. METHODS: A retrospective review of patients with severe H2S intoxication who presented during 2006 and 2007 was carried out. Ten victims of severe occupational H2S poisoning were identified, of whom four died at the site of the accident. Two further patients required cardiopulmonary resuscitation at the site of the accident and the remaining four all received 100% oxygen followed by endotracheal intubation and artificial ventilation prior to hospital admission. In these six cases, 4-dimethylaminophenol was administered on admission as an antidote, followed immediately by HBOT using the schedule otherwise used in carbon monoxide intoxication. CLINICAL OUTCOME: The two patients who required cardiopulmonary resuscitation at the site of exposure died of cerebral ischaemia or pulmonary oedema on the first and seventh days after the accident respectively. The remaining four patients recovered without any neurological sequelae and were discharged for outpatient care after a median of nine days (range 8-12 days). No antidote-related adverse effects could be detected. Acid-base status and oxygenation improved and methaemoglobin fell with the first HBOT in all six cases. CONCLUSION: In severe H2S intoxication, supportive HBOT may play a useful role in improving oxygenation and acid-base status quickly and counteracting the decrement in oxygen carriage caused by methaemoglobinaemia due to antidote administration. PMID- 23111939 TI - Hyperbaric oxygen in the treatment of asphyxia in two newborn infants. AB - Hypoxic-ischaemic encephalopathy (HIE) is a common cause of brain damage in the neonatal period. Approximately 10% of births involve some degree of asphyxia, and 1% of these are severe. Current treatment has been limited to supportive measures and the recent use of hypothermia. Beneficial effects of hyperbaric oxygen treatment (HBOT) in neonatal asphyxia have been reported in the Chinese literature. We report the use of HBOT to treat two term neonates with moderate HIE according to Sarnat's classification. Clinical improvement occurred following HBOT. A 50% decrease in the total creatine phosphokinase (CPK) level and a 40% decrease in the CPK myocardial fraction were observed within 24 hours of the first treatment. The decline in CPK levels may be related to a reduction in the overall systemic inflammatory process and cannot be attributed solely to a reduction in brain damage. HBOT may have a role in HIE. PMID- 23111940 TI - Is livestock production prepared for an electrically paralysed world? AB - Politics, insolvency, increased technological complexity and solar flares are factors that currently present uncomfortably real threats to our increasing dependency on electricity. In some scenarios, there may be no warning before electronic and mechanical help will cease to function. Industrial food production appears to be particularly vulnerable. Making preparations for an electrically paralysed period may not only be prudent, and a matter of national security, but might also push scientific efforts in agricultural production past energy reduction and towards more resilient and sustainable options. PMID- 23111941 TI - Phase II study of glucosamine with chondroitin on aromatase inhibitor-associated joint symptoms in women with breast cancer. AB - PURPOSE: Many women with hormone receptor-positive breast cancer discontinue effective aromatase inhibitor (AI) treatment due to joint symptoms. METHODS: We conducted a single-arm, open-label, phase II study evaluating glucosamine-sulfate (1,500 mg/day) + chondroitin-sulfate (1,200 mg/day) for 24 weeks to treat joint pain/stiffness in postmenopausal women with early stage breast cancer who developed moderate-to-severe joint pain after initiating AIs. The primary endpoint was improvement in pain/stiffness at week 24 assessed by the Outcome Measure in Rheumatology Clinical Trials and Osteoarthritis Research Society International (OMERACT-OARSI) criteria. Secondary endpoints assessed changes in pain, stiffness, and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index for hips/knees and the Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands (M SACRAH) for hands/wrists. The Brief Pain Inventory (BPI) assessed pain interference, severity, and worst pain. RESULTS: Of 53 patients enrolled, 39 were evaluable at week 24. From baseline to week 24, 46 % of patients improved according to OMERACT-OARSI criteria. At week 24, there were improvements (all P < 0.05) in pain and function as assessed by WOMAC and M-SACRAH, and in pain interference, severity, and worst pain as assessed by BPI. Estradiol levels did not change from baseline. The most commonly reported side effects were headache (28 %), dyspepsia (15 %), and nausea (17 %). CONCLUSIONS: In this single-arm study, 24 weeks of glucosamine/chondroitin resulted in moderate improvements in AI-induced arthralgias, with minimal side effects, and no changes in estradiol levels. These results suggest a need to evaluate efficacy in a placebo-controlled trial. PMID- 23111942 TI - Validation of the grip test and human activity profile for evaluation of physical performance during the intermediate phase after allogeneic hematopoietic stem cell transplantation. AB - OBJECTIVES: The aims of the presented study were to validate tools evaluating physical functioning (PF) after allogeneic hematopoietic stem cell transplantation (alloHSCT) and to analyze the impact of the clinical course on PF. METHODS: Forty patients undergoing alloHSCT were enrolled in a prospective trial which included evaluation of muscle strength (grip test, CITEC dynamometer), endurance (2-min walk test), anxiety and depression (Hospital Anxiety and Depression Scale), fatigue (Modified Fatigue Impact Scale and Brief Fatigue Inventory), and physical activity (Human Activity Profile--HAP) before (t1) and 1 (t2) and 3 (t3) months after alloHSCT. RESULTS: At t2, all patients showed a 6 % (p = 0.02) loss of muscle strength which was higher in patients with acute graft-versus-host disease (aGVHD) (12 %). While patients without aGVHD recovered at t3, the loss of muscle strength was progressive in patients with aGVHD. The grip test results correlated with the results of detailed measurement of muscle strength by CITEC dynamometer (r = 0.4-0.8, p = 0.05-0.001). Moreover, the HAP scores correlated with physical performance. CONCLUSION: The results demonstrate that loss of PF occurs during the first month followed by a regain during the subsequent 2 months in the absence of aGVHD. The HAP and the grip test may serve as surrogate marker for the strength loss in the course of aGVHD. PMID- 23111943 TI - Bone marrow involvement is predictive of infusion-related reaction during rituximab administration in patients with B cell lymphoma. AB - PURPOSE: The purpose of this study is to evaluate risk factors for infusion related reaction (IRR) following rituximab administration in patients with B cell non-Hodgkin lymphoma. METHODS: A retrospective analysis was conducted of patients with newly diagnosed B cell lymphoma who have received rituximab-included immunochemotherapy with appropriate premedication and commonly used schedule of infusion rate. IRRs were graded by review of the patients' electronic medical record according to the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: One hundred and sixty-nine patients were included in the analysis and most of the patients (150; 88.8 %) had diffuse large B cell lymphoma (DLBCL). Thirty-six patients (21.3 %) had any grade of IRRs: 23 patients were grade (G) 1 (13.6 %), 13 had >=G2 IRRs (7.7 %), and only 4 had >=G3 IRRs (2.4 %). All except one patient had IRR during the first cycle and only two had repetitive IRR thereafter. Bone marrow (BM) involvement was the strongest risk factor for IRR in multivariable analysis (odds ratio 4.06, 95 % confidence interval 1.67-9.89; p = 0.002). A subgroup analysis confined to patients with DLBCL showed very similar results when compared with the entire population, and patients with DLBCL who had >=G2 IRR showed shorter event-free and overall survival when compared to those who did not. CONCLUSIONS: BM involvement is predictive of occurrence of IRR during rituximab administration in patients with B cell lymphoma. More intensive premedication and careful observation for IRR during rituximab administration are required for patients with B cell lymphoma who have BM involvement. PMID- 23111945 TI - Second response to the letter to the editor referencing the manuscript the "use of vitamin E for the prevention of chemotherapy-induced peripheral neuropathy: results of a randomized phase III clinical trial". PMID- 23111944 TI - The relationship between communication and health-related quality of life in survivorship care for Chinese-American and Korean-American breast cancer survivors. AB - OBJECTIVE: The purpose of this study was (1) to compare family communication, decision support (i.e., supporting the patient in making decisions), self efficacy in patient-physician communication (i.e., patients' confidence level in communicating with physicians), and health-related quality of life (HRQOL) between Chinese-American and Korean-American breast cancer survivors (BCS) and (2) to investigate how family communication, decision support, and self-efficacy in patient-physician communication influence HRQOL for Chinese-American and Korean-American BCS. METHODS: A cross-sectional design was used. A total of 157 Chinese-American (n = 86) and Korean-American (n = 71) BCS were recruited from the California Cancer Surveillance Program and area hospitals in Los Angeles County. The chronic care model was utilized. RESULTS: Chinese-Americans and Korean-Americans showed a significant difference in the decision support only. Self-efficacy in patient-physician communication was directly associated with HRQOL for Chinese-Americans, whereas for Korean-Americans, family communication was related to HRQOL. The mediating effects of decision support and self-efficacy in physician-patient communication in the relationship between family communication and HRQOL were observed for Chinese-Americans only. Multiple group analysis demonstrated that the structural paths varied between Chinese-American and Korean-American BCS. CONCLUSIONS: Our results provide insight into the survivorship care of Chinese-American and Korean-American BCS, allowing a better understanding of communication among survivors, family, and healthcare providers. Communication skills to manage conflict and attain consensus among them under the cultural contexts are essential to improve HRQOL for BCS. PMID- 23111946 TI - Mechanism of improved antibody aggregate separation in polyethylene glycol modulated cation exchange chromatography. AB - Ion-exchange chromatography is used in biopharmaceutical downstream processes to reduce product-related impurity levels. Because protein aggregate levels can be considered as a critical quality attribute, the removal of aggregated protein species is of primary importance. The addition of polyethylene glycol (PEG) to the mobile phase in ion-exchange chromatography was found to significantly improve the chromatographic separation of monomers from aggregates. In this work, linear gradient elution experiments with monomeric and aggregated samples of a monoclonal antibody were performed on a strong cation exchange resin at different PEG concentrations to investigate the underlying effects responsible for the observed selectivity improvement. PEG is well known to be excluded from a surface layer volume around the protein and the stationary phase; thus, enhancing adsorption of the preferentially hydrated protein to the hydrated stationary phase. The exclusion volume depends on the accessible surface area of the protein leading to a stronger influence of PEG on larger protein species and thus an improved separation of monomer and aggregates. This hypothesis could be consolidated comparing the distribution equilibrium in PEG solution to that in water by calculating equilibrium constants and transfer free energies using the chromatographic data from the linear gradient elution experiments performed at different pH values. PMID- 23111947 TI - Synthesis, crystal structure and biological activity of novel anthranilic diamide insecticide containing alkyl ether group. AB - In searching for environmentally benign insecticides with high activity, low toxicity and low residue, two series of novel anthranilic diamide containing methyl ether and isopropyl ether group were designed and synthesized. All of the compounds were characterized by (1)H NMR spectroscopy, (13)C NMR spectroscopy and elemental analysis. The single crystal structure of 19j was determined by X-ray diffraction. The insecticidal activities of the new compounds were evaluated. The results showed that some compounds exhibited excellent insecticidal activities against Lepidoptera pests. Among this series, compound, 18l showed 100 % larvicidal activity against Mythimna separate Walker, Plutella xylostella Linnaeus and Laphygma exigua Hubner at the test concentration, which was equal to the available chlorantraniliprole. PMID- 23111948 TI - Evaluation of the impact of a food program on the micronutrient nutritional status of Argentinean lactating mothers. AB - This study was conducted to evaluate the impact of a food aid program (Plan Mas Vida, PMV) on the micronutrient nutritional condition of lactating mothers 1 year after its implementation. The food program provided supplementary diets (wheat- and maize-fortified flour, rice or sugar, and fortified soup) to low-income families from the province of Buenos Aires, Argentina. A prospective, non experimental study was carried out to evaluate the micronutrient nutritional status of lactating mothers (n = 178 at baseline and n = 151 after 1 year). Biochemical tests (hemoglobin, ferritin, zinc, vitamin A, and folic acid), anthropometric assessments (weight and height) and dietary surveys (24-h recall) were performed. We found no significant changes in anthropometric values 1 year after the intervention. The risk for vitamin A (retinol 20-30 MUg/dl) and folate deficiency significantly decreased 1 year after PMV implementation (56.3 vs. 29.9 and 50.3 vs. 3.4 %, respectively; p < 0.001). Anemia was seen in 25.8 % of lactating mothers at baseline, without statistically significant differences 1 year after (p = 0.439). The nutritional data obtained after assessing the early impact of PMV actions may be useful to provincial health authorities to perform periodic evaluations in the future. PMID- 23111949 TI - Mineral composition of and the relationships between them of human basal ganglia in very old age. AB - Trace elements and the relationships among them were investigated by direct chemical analysis in three basal ganglia regions in very old age individuals and age- and gender-related differences were assessed. After ordinary dissections at Nara Medical University were finished, the caudate nucleus, putamen, and globus pallidus belonging to the basal ganglia were removed from the identical cerebra of the subjects who consisted of 22 men and 23 women, ranging in age from 70 to 101 years (average age = 83.3 +/- 7.5 years). After incineration with nitric acid and perchloric acid, the element contents were determined by inductively coupled plasma-atomic emission spectrometry. It was found that the Ca, P, and Mg contents increased significantly in the putamen with aging and the Mg content increased significantly in the globus pallidus with aging, but no elements increased significantly in the caudate nucleus with aging. Regarding the relationships among elements in the basal ganglia, extremely significant direct correlations were found among the Ca, P, and Mg contents in the putamen. These results suggested that slight calcification occurred in the putamen in very old age. With regard to seven elements of Ca, P, S, Mg, Zn, Fe, and Na, it was examined whether there were significant correlations among the caudate nucleus, putamen, and globus pallidus. It was found that there were extremely significant direct correlations among all of the three basal ganglia in the P content. Likewise, with regard to the Fe content, there were extremely or very significant direct correlations among all of the three basal ganglia. Regarding the gender difference in elements, it was found that the Ca content of the caudate nucleus was significantly higher in women than in men. PMID- 23111950 TI - Effects of increasing supplementation of magnesium in diets on productive performance and eggshell quality of aged laying hens. AB - Magnesium (Mg) concentrations in diets have been associated with performance and eggshell quality of laying hens, but the results have been inconclusive. In this experiment, the effects of increasing concentrations of dietary Mg on productive performance and eggshell quality of aged laying hens were evaluated. A total of 640 Hy-Line Brown laying hens of 72 weeks of age were randomly allotted to one of four dietary treatments with four replicates per treatment. A commercial-type basal diet containing 1.6 g/kg Mg was prepared, and three additional diets were prepared to contain 2.3, 2.6, or 3.0 g/kg Mg in diets by adding 1.0, 1.5, or 2.0 g of MgO to the basal diet. The diets were fed to hens ad libitum for 5 weeks. Results indicated that Mg concentrations in eggshells were increased (linear, P < 0.01) with increasing concentrations of Mg in diets. Increasing concentrations of Mg in diets decreased (linear and quadratic, P < 0.01) broken and shell-less egg production, but improved (linear, P < 0.05) eggshell strength. Feed intake was decreased (linear, P < 0.05) with the concentrations of Mg in diets, but hen-day egg production, egg weight, feed conversion ratio, and Haugh unit were not affected by increasing concentrations of Mg in diets. Hunter L* and a* values of eggshell were decreased (linear, P < 0.05) as the concentrations of Mg in diets increased. In conclusion, feeding aged laying hens with diets containing increasing concentrations of Mg up to 3.0 g/kg improves eggshell strength, but has no detrimental effects on laying performance. PMID- 23111951 TI - Visible-light photocatalytic hydrogen generation by using dye-sensitized graphene oxide as a photocatalyst. AB - Dye-sensitized graphene oxide is able to generate hydrogen from water/methanol mixtures (80:20) by using visible or solar light. The most efficient photocatalyst tested contained a tris(2,2-bipyridyl) ruthenium(II) complex incorporated in the interlayer spaces of a few layers of graphene oxide with a moderate degree of oxidation. The graphene oxide-based photocatalyst does not contain noble metals and we have determined that it is two orders of magnitude more active than catalysts based on conventional titania. PMID- 23111955 TI - Microfluidics in the "open space" for performing localized chemistry on biological interfaces. AB - Local interactions between (bio)chemicals and biological interfaces play an important role in fields ranging from surface patterning to cell toxicology. These interactions can be studied using microfluidic systems that operate in the "open space", that is, without the need for the sealed channels and chambers commonly used in microfluidics. This emerging class of techniques localizes chemical reactions on biological interfaces or specimens without imposing significant "constraints" on samples, such as encapsulation, pre-processing steps, or the need for scaffolds. They therefore provide new opportunities for handling, analyzing, and interacting with biological samples. The motivation for performing localized chemistry is discussed, as are the requirements imposed on localization techniques. Three classes of microfluidic systems operating in the open space, based on microelectrochemistry, multiphase transport, and hydrodynamic flow confinement of liquids are presented. PMID- 23111956 TI - Diketopiperazine alkaloids from a mangrove rhizosphere soil derived fungus Aspergillus effuses H1-1. AB - Effusin A (1), a spirobicyclic N,O-acetal derivative with an unprecedented 3',3a',5',6'-tetrahydrospiro[piperazine-2,2'-pyrano[2,3,4-de]chromene] ring system, and a spiro-polyketide-diketopiperazine hybrid dihydrocryptoechinulin D (2) were isolated from a mangrove rhizosphere soil derived fungus, Aspergillus effuses H1-1. Their structures were determined by detailed spectroscopic analysis. Effusin A (1) and dihydrocryptoechinulin D (2) occurred as racemates, the enantiomers of which were separated and characterized by online HPLC-ECD analysis and their absolute configurations were determined by the solution TDDFT ECD calculation approach. The cytotoxic effects of 1 and 2 were preliminarily evaluated and 2 showed potent activity on P388 cells with an IC(50) value of 1.83 MUM. The target of racemic 2 was also investigated and the (12R,28S,31S)-2 enantiomer showed selectivity against topoisomerase I. PMID- 23111952 TI - Natural killer cells in liver disease. AB - Natural killer (NK) cells are enriched in lymphocytes within the liver and have unique phenotypic features and functional properties, including tumor necrosis factor-related apoptosis-inducing ligand-dependent cytotoxicity and specific cytokine profiles. As a key component of innate immunity in the liver, NK cells perform critical roles in host defense against pathogens and tumors through their natural cytotoxicity and cytokine production, and they also act as regulatory cells by engaging in reciprocal interactions with other types of liver cells through cell-to-cell contact and the production of cytokines. Accumulating evidence from the last decade suggests that NK cells play an important role in controlling viral hepatitis, liver fibrosis, and liver tumorigenesis, but also contribute to the pathogenesis of liver injury and inflammation. The characterization of intrahepatic NK cell functions has not only helped us to better understand the pathogenesis of liver disease, but has also revealed new therapeutic targets for managing this disease. PMID- 23111957 TI - Interleukin-2 and autoimmune disease occurrence and therapy. AB - BACKGROUND: Interleukin-2(IL-2), also called T-cell growth factor and primarily produced by antigen-activated T cells, is a kind of lymphoid factor with immunoregulatory effect which can promote T-cell-dependent immune responses. IL-2 was first used as a therapeutic approach to boost immune responses in patients with invasive cancer or advanced HIV disease. OBJECTIVES: The purpose of the review is to refer the mechanism of autoimmune disease caused by IL-2 deletion and the application of IL-2 in curing autoimmune disease. STATE OF THE ART: IL-2 signal plays a key role in promoting the development, homeostasis and the function of the regulatory T cells. The deletion of IL-2 in vivo causes T cell mediated autoimmune diseases. Now it is being considered as a kind of medicine inhibiting immune responses. PERSPECTIVES: Further studies with controlled clinical trials will be needed to prove the potential of IL-2 as a therapeutic strategy for autoimmune diseases. CONCLUSIONS: The decreased production of IL-2 in patients with autoimmune disease leads to immune defects, such as decreased production of Treg cells, decreased AICD and cytotoxicity. Combination therapy based on IL-2 may prove to be beneficial in curing the immunological disorders. PMID- 23111958 TI - High reinfection rate of Helicobacter pylori in young type 1 diabetic patients: a three-year follow-up study. AB - BACKGROUND: Several studies have demonstrated that Helicobacter pylori (H. pylori) eradication does not affect metabolic control in diabetic patients. The prevalence of H. pylori infection and reinfection rate in adult diabetic patients seems to be higher than in controls. AIM OF THE STUDY: To evaluate the reinfection rate of H. pylori three years after a standard eradicating treatment and the late effect of eradication upon metabolic control in young diabetic patients. METHODS: We enrolled 75 diabetic patients and 99 controls, from previous our studies in which we had evaluated H. pylori infection. In all subjects we re-evaluated the presence of H. pylori by means of 13C-Urea Breath Test, metabolic control and the prevalence of gastrointestinal symptoms. The effect of age, sex and socio-economic factors on H. pylori reinfection were also evaluated. RESULTS: The prevalence of H. pylori infection was higher in diabetic patients (17/69, 24%) than in dyspeptic controls of similar age, gender and socio economical status after three years of follow-up. The reinfection rate was higher in diabetic patients than in controls. Multivariate analysis confirmed that age and socio-economical status were independently associated with H. pylori reinfection. CONCLUSIONS: Young patients with diabetes present a higher risk of H. pylori gastric reinfection than controls. In addition, age and mean annual income are associated with reinfection. PMID- 23111959 TI - HIV-HCV co-infection: epidemiology, pathogenesis and therapeutic implications. AB - Hepatitis C virus (HCV) is the cause of more than three-quarters of liver-related deaths in HIV-seropositive individuals and it is remarkable that today approximately one-quarter of HIV-infected individuals in Europe and the USA have a HCV coinfection. HIV/HCV coinfected patients were more likely to develop cirrhosis, had an increased risk of developing AIDS, of HIV-related disease and of overall mortality. How HCV may affect the course of HIV infection is not well known even if it was suggested that HCV co-infection is able to increase immune activation and to sensitize CD4+ T-cells towards apoptosis in the absence of HIV therapy. There are many evidences that the simultaneous presence of HIV infection accelerates the liver damage from HCV favouring the evolution to cirrhosis in co infected patients. HIV increasing of TNF alpha liver production and of HCV replication in peripheral blood lymphomonocytes are the mechanisms at the basis of this phenomenon. HAART had a positive effect on HIV/HCV co-infection, otherwise it does not appear to fully correct the adverse effect of HIV infection on HCV-related outcomes. Traditional treatment with pegilated Interferon plus ribavirin have low rates of sustained virological response in co-infected patients especially if infected with HCV genotype 1, and better results were often obtained in patients in which the use of antiretroviral treatment was avoided to reduce the occurrence of adverse effects. The recent preliminary results on the use of anti-HCV protease inhibitor drugs, boceprevir and telapravir, in co-infected people seems to demonstrate an enhanced antiviral efficacy in the HIV/HCV co-infected population of triple anti-HCV treatment even is some important limitation as interactions with antiretroviral agents and selection of HCV drug resistance, lead to consider the need for further studies designed to assess the best therapeutic strategies. PMID- 23111960 TI - Boswellia serrata and Salvia miltiorrhiza extracts reduce DMN-induced hepatic fibrosis in mice by TGF-beta1 downregulation. AB - BACKGROUND: Hepatic fibrosis is characterised by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins, including collagen that occurs in chronic liver diseases. Transforming growth factor-beta1 (TGF-beta)/Smad3 signalling plays a major role in tissue fibrogenesis acting as a potent stimulus of ECM accumulation. AIM: To evaluate the effects of a combined therapy with anti inflammatory Boswellia and anti-fibrotic Salvia extracts on the course of chronic hepatitis-associated fibrosis induced by dimethylnitrosamine (DMN) in mice, as well as on the hepatic expression of TGF-beta1 and Smad proteins. METHODS: Chronic hepatitis-associated fibrosis was induced in mice by intraperitoneal DMN administration. Mice were assigned to 5 groups: controls; DMN without any treatment; DMN treated orally with Boswellia extracts (50 mg/kg/day); DMN treated orally with Salvia extracts (150 mg/ kg/day); DMN treated orally with both Boswellia (50 mg/kg/day) and Salvia extracts (150 mg/kg/ day). The liver was excised for macroscopic examination and histological, morphometric and immunohistochemical (IHC) analyses. For IHC, alpha-smooth muscle actin (alpha SMA), collagen types I-III, TGF-beta1, connective tissue growth factor (CTGF), Smad3, Smad7, CD3, PCNA and TUNEL antibodies were used. RESULTS: The combined oral administration of Boswellia and Salvia extracts improved the course and macroscopic findings of DMN-induced chronic hepatitis-associated fibrosis. The histological severity of the hepatic fibrosis showed a marked improvement following treatment and was associated with a reduction in the hepatic expression of alpha-SMA, collagen I-III, CTGF, TGF-beta1, Smad3, and Smad7. CONCLUSIONS: These data demonstrate that co-treatment of Boswellia plus Salvia extracts is effective in preventing hepatic fibrosis in DMN-induced chronic hepatitis. The anti-fibrotic properties are mainly related to Salvia extracts and appear to be mediated by the inhibition of the TGF-beta1/Smad3 pathway. PMID- 23111961 TI - Cerebral venous sinus thrombosis: an analyses of 47 patients. AB - OBJECTIVE: Cerebral venous sinus thrombosis (CVST) is an extremely rare disease and its early treatment is important for decreasing the morbidity and mortality. In present study, it was investigated to clinical and etiological factors, localization features, treatment, and prognosis of patients with CVST. PATIENTS AND METHODS: The study group included CVST cases who were followed up between January 2008 and June 2010. Demographical, clinical, radiological, etiological and prognostic characteristics of 47 patients with CVST were retrospectively investigated. RESULTS: Presentation complaints of the patients were as follows in order: acute and/or sub-acute headache (80.8%), impaired consciousness (25.5%), ear complaints (21.3%), paresis (19.1%) and epileptic seizures (14.9%). Chronic daily headache without any signs of neurological deficit was found in 10.6% of cases. Neurologic examinations of 40.4% of the CSVT patients were found to be normal. The most frequently found etiological factors were as follows: MTHFR gene mutation (25.5%), local infections due to chronic otitis complications (21.3%), puerperium (17%), pregnancy (12.8%), lupus anticoagulant positivity (12.8%). The sigmoid sinus was found to be involved in 35 patients (74.5%), the transverse sinus in 29 (61.7%) and superior sagittal sinus in 21 (44.7%). Impaired consciousness (p = 0.046), hemorrhagic infarct (p = 0.017), acute onset (p = 0.026), and presence of hemiparesis (p = 0.019) were found to be associated with increased mortality. CONCLUSIONS: New onset sub-acute or chronic headache may be the only neurologic complaint of CVST patients. Early diagnosis and anticoagulant treatment may decrease mortality and/or morbidity rates related with CVST in these patients. PMID- 23111962 TI - The role of endosomal toll-like receptors in bacterial recognition. AB - BACKGROUND: Infections caused by extracellular Gram positive bacteria are still a major health problems. Better understanding of the mechanisms underlying immune responses to these organisms is key to develop pharmacological agents, including vaccines, to control these infections. OBJECTIVE AND PERSPECTIVES: The objective of this review is to highlight the importance of nucleic acid-sensing, intracellular Toll-like receptors in innate immune recognition and in host defenses against extracellular bacteria. CONCLUSIONS: Toll-like receptors 7 and 9 have a major role in inducing host-protective type I interferon responses in conventional dendritic cells in response to streptococci and other extracellular gram positive bacteria. Moreover an as yet unidentified MyD88-dependent receptor is likely responsible for proinflammatory cytokine induction in response to these pathogens. PMID- 23111963 TI - Anaphylaxis caused by helminths: review of the literature. AB - BACKGROUND: Anaphylaxis is a severe, life-threatening, generalized or systemic hypersensitivity reaction. In many individuals with anaphylaxis a pivotal role is played by IgE and the high-affinity IgE receptor on mast cells or basophils. Less commonly, it is triggered through other immunologic mechanisms, or through nonimmunologic mechanisms. The human immune response to helminth infections is associated with elevated levels of IgE, tissue eosinophilia and mastocytosis, and the presence of CD4+ T cells that preferentially produce IL-4, IL-5, and IL-13. Individuals exposed to helminth infections may have allergic inflammatory responses to parasites and parasite antigens. AIM: To summarize the evidences about the role of helmiths in triggering anaphylaxis. MATERIALS AND METHODS: PubMed search was performed by combining the terms (anaphylaxis, anaphylactic, anaphylactoid) with each one of the etiological agents of human helminthiasis for the period January 1950 to September 2012. RESULTS: < The PubMed search identified 609 papers. Only four genera of helminths were associated with anaphylaxis. (Echinococcus spp, 302 papers; Anisakis spp, 73 papers; Taenia solium cysticercosis, 7 papers; and Ascaris spp., 243 papers). CONCLUSIONS: The risk of anaphylaxis in patients with helminthiasis can vary according to the pathogens, occurring more frequently during echinococcosis of after anisakis infestation and being extremely rare after other helminth infestations. However, physicians, allergist and parasitologist in particular, should be aware of a potential anaphylaxis caused by helminths. PMID- 23111964 TI - Effects of rosiglitazone treatment on insulin resistance and TNF-alpha levels in patients with chronic kidney disease: a prospective study. AB - AIM: The aim of the study was to investigate the effects of rosiglitazone treatment on insulin resistance (IR) and tumor necrosis factor-alpha (TNF-alpha) levels in non-diabetic chronic kidney disease (CKD) patients with IR. PATIENTS AND METHODS: Thirty non-diabetic CKD patients with IR were enrolled in the study. Patients were grouped into two: group 1 (n = 15) received rosiglitazone 4 mg tablet for 3 months and patients who did not receive rosiglitazone treatment constituted the group 2 (n = 15). Baseline and after rosiglitazone treatment, homeostatis model assessment-insulin resistance (HOMA-IR) and TNF-alpha levels were measured. RESULTS: There were no statistical differences in gender, age, HOMA-IR and TNF-alpha levels among group 1 and group 2 (p > 0.05 for all). Compared to baseline in group 1, significant differences were found in HOMA-IR and TNF-alpha levels after 3 months (p = 0.023; p = 0.001, respectively). CONCLUSIONS: Our study indicates that, rosiglitazone treatment improves the IR and decreases TNF-alpha levels in non-diabetic patients CKD with IR. PMID- 23111965 TI - Bladder function after spinal anesthesia for cesarean section: an urodynamic evaluation. AB - BACKGROUND: This study evaluates the effects of spinal anesthesia with hyperbaric bupivacaine plus sufentanil on bladder function in women undergoing cesarean section. SUBJECTS AND METHODS: Thirty caucasian healthy pregnants scheduled for elective Cesarean section under spinal anesthesia performed with hyperbaric bupivacaine plus sufentanil were enrolled. Filling cystometry, proprioceptive bladder sensation during cystometry, rate of spontaneous voiding, post void residual volume, anocutaneous and bulbocavernosus reflex were analyzed at 4, 6 and 8 hours after spinal anesthesia. RESULTS: The proportion of women experiencing first sensation, first desire and strong desire at 4 hours was significantly different from that reported at 6 and 8 hours (p < 0.05 for first sensation and p < 0.01 for first and strong desire). Significant differences were also observed between volumes at which first sensation arose at first measurement (4 hours) and at second and third measurements (p < 0.01). There was a significant difference in rate of spontaneous micturition, with 80% of patients at 8 hours able to spontaneously void versus 40% at 6 hours, (p < 0.01). Moreover, a lower percentage of women had absent and/or light reflexes at 4 hour than at 6 and 8 hours (p < 0.01). CONCLUSIONS: Spinal anesthesia with bupivacaine plus sufentanil causes a clinically significant disturbance on bladder function in women undergoing cesarean section. Even thought recovery of proprioceptive bladder sensation is fast, a full recovery of spontaneous voiding requires a much longer time. A close monitoring of urinary function and of bladder distension is, therefore, advisable. PMID- 23111966 TI - Update on oncoplastic breast surgery. AB - Oncoplastic surgery of the breast (OPS) has generated great excitement over the past years and has become an integrated component of the surgical treatment of breast cancer. Oncoplastic surgical procedures associate the best surgical oncologic principles to achieve wide tumor-free margins with the best principles of plastic surgery to optimize cosmetic outcomes. Thanks to oncoplastic techniques, the role of breast conserving surgery (BCS) has been extended to include a group of patients who would otherwise require mastectomy to achieve adequate tumor clearance. As OPS continues to gain acceptance and diffusion, an optimal and systematic approach to these techniques is becoming increasingly necessary. This article has the aim to review the essential principles and techniques associated with oncoplastic surgery, based on the data acquired through an extensive search of the PUBMED and MEDLINE database for articles published using the key words "breast cancer oncoplastic surgery". This review analyzes possible the advantages", classifications, indications, and the criteria for a proper selection of oncoplastic techniques to facilitate one's ability to master these procedures and make OPS a safe and an effective procedure. PMID- 23111967 TI - A different placement of the stone; rhinolithiasis. AB - INTRODUCTION: Rhinolithiasis is a rare disease and formed by mineralization in the nasal cavity. Precipitated calcareous material on intranasal foreign substances forms the rhinoliths. It is start time could have since childhood. MATERIALS AND METHODS: In this article, we present eight cases of rhinolithiasis who admitted to our Clinic between January 2001 and December 2010 with unilateral chronic nasal discharge, nasal obstruction and oral malodor. CONCLUSIONS: Rhinolithiasis mostly manifests itself with unilateral purulent rhinorrhea, nasal obstruction and facial pain symptoms. We aimed to discuss these entity with similar cases in the literature. PMID- 23111968 TI - The influence of smoking and surgical technique on the accuracy of mucosa supported stereolithographic surgical guide in complete edentulous upper jaws. AB - BACKGROUND: The accuracy of a stereolithographic surgical guide depends on several variables that can affect at any time from the software-planning stage to the surgical field. AIM: The purpose of this study was to evaluate the accuracy of implants inserted using a single mucosa-supported stereolithographic surgical guide determining also the influence of surgical technique (fixed and not-fixed) and smoking on the deviation parameters. MATERIALS AND METHODS: 11 patients, totally edentate in the upper arch and needed an implant-prosthetic rehabilitation, were selected. 95 implants were planned and inserted. The pre- and post-operative CT images were compared using software. RESULTS: Global, coronal (Mean: 1.65; Range: 3.00-0.13; SD:0.56) and apical (Mean: 2.15; Range: 4.23-0.34; SD:0.81), and angular (Mean: 4.62; Range: 15.25-0.28; SD: 2.74) deviation values were determined. The mean values of mucosa thickness in smokers and nonsmokers patients were 4.53 mm and 3.42 mm respectively (p < .05). The accuracy data showed a better result for the angular deviation when the surgical template was fixed (p = .002) and a better global apical deviation in the nonsmokers (p <. 05). CONCLUSIONS: It is essential, especially in smoker patients, to respect a minimum safety distance of 3 mm from limiting anatomic structures. PMID- 23111969 TI - Neonatal molding in deformational auricolar anomalies. AB - INTRODUCTION: Congenital auricular anomalies can be categorized either as malformational or deformational. The first are characterized by a partial absence of the skin or cartilage resulting in a constricted or underdeveloped pinna and require surgical correction. Deformations are characterized by a misshaped but fully developed pinna and are best treated by auricular molding. AIM: Authors want to present their case load in treatment of infants affected by deformational auricolar anomalies and describe their techniques using early splinting for congenital auricular deformities, like prominent ear, lop ear, constricted ear, Stahl's ear. PATIENTS AND METHODS: Between 2009 to 2011, in Maxillo and Oral Surgery Unit, a nonsurgical technique was used to treat 22 ears affected by deformational anomalies in 12 patients soon after birth. Four patients were female. This kind of nonsurgical correction of the deformed auricle was performed on lop ears (n=6), constricted ears (n=8), prominent ears (n= 4), Stahl's ear (n=4). Children more than two months old were also excluded. The mean of treatment time was 5.5 weeks. RESULTS: according to the Authors and the parents 100% of treated auricles improved. Improving at the end of the molding treatment was observed in 18% of the auricles, but recurrence to one year of stopping treatment. There were not complications caused by this procedure. CONCLUSIONS: The nonsurgical molding has the advantage to correct at a very early age a cosmetic abnormality, giving a natural and in the most of the time a satisfactory results, with a prevalence rate of complications of much less than surgical corrections. PMID- 23111970 TI - Etiology and incidence of zygomatic fracture: a retrospective study related to a series of 642 patients. AB - BACKGROUND AND OBJECTIVES: The aim of this paper is to investigate epidemiological data (age, gender), sites, etiology and surgical approach of zygomatic fracture. MATERIALS AND METHODS: A 9 years retrospective clinical and epidemiologic study evaluated 642 patients treated for zygomatic fracture. There were 569 men and 77 women. The age range was 2 to 86 years with 205 (31.9%) in the 21 to 30 years age group. A number of parameters, including age, gender, cause of injury, site of injury, treatment modalities were evaluated. RESULTS: There were 552 (86%) zygoma fractures and 90 (14%) zygomatic arch fractures. The left zygoma was involved in 309 cases (56%); the right zygoma was involved in 243 cases (44%). Concerning the zygomatic arch, the left side was involved in 43 cases (48%) and the right side in 47 cases (52%). 7% of the patients were younger than 9 years old, about 70% between 10 and 39 years, and 18% between 40 and 59 years, while 4% were older than 60 years. Causes of zygoma fracture were traffic accidents in 151 (26%), assault in 117 (20%), accidental falls in 105 (19%), sports injuries in 56 (10%), home injuries in 45 (8%), work accidents in 34 (6%). Causes of zygomatic arch fractures 28 (29.1%) were assaults in 28 (29.1%), traffic accidents in 20 (21.5%), sports injuries in 14 (15.8%), accidental falls in 11 (14%), domestic accidents in 8 (8.8%) and work accidents in 4 (5%). The access to the fronto-zygomatic suture (74.6%) and the maxillary vestibular approaches (66.8%) were the commonest method of reduction of zygomatic fracture. About arch fractures, the Gillies temporal approach was the most used method of reduction (94.4%). CONCLUSIONS: The findings, compared with similar studies reported in the literature, support the view that the highest prevalence is in young male patients and, concerning cause, traffic accidents and assault are the most frequent. PMID- 23111971 TI - Fetomaternal outcome in pregnancy with severe thrombocytopenia. AB - OBJECTIVES: STo study the feto-maternal outcome in pregnancy with severe thrombocytopenia. MATERIALS AND METHODS: It was an observational study involving 1150 pregnant women with term gestation in labour, who were screened for thrombocytopenia. Ninety-four subjects (8.17%) were found to have thrombocytopenia i.e. platelet count < 1,50,/000/mm3, out of which 47 subjects (group A) had platelet count of less than 50.000/mm3 Simultaneously, 47 term pregnant women (group B) having a normal platelet count i.e. > 1.5 lac/mm3 formed the control group. All the subjects were followed during labour and postpartum period for any feto-maternal outcome. RESULTS: Significant history of bleeding tendencies like prolonged bleeding from wound site, easy bruisability and menorrhagia (p = 0.023) was evident in the study population. Abruptio placentae and early onset pregnancy induced hypertension (PIH) in previous gestations was more commonly found in the study population. Anemia and PIH were significantly more in group A. Incision site oozing during cesarean section was significantly more in group A. Moderate thrombocytopenia was more in neonates of study group (p = 0.014), but without any bleeding complications in neonates. CONCLUSIONS: Careful surveillance is required in these high risk patients for earlier detection and treatment of complications so as to decrease the fetomaternal morbidities. PMID- 23111972 TI - Mean platelet volume on admission is associated with further left ventricular functions in primary PTCA patients. AB - AIM: In ST elevation myocardial infarction (STEMI) patients, mean platelet volume (MPV) is associated with infarct related artery patency both before and after reperfusion. In anterior STEMI patients successfully treated with primary percutaneous coronary intervention (PCI), the relationship between left ventricular (LV) function and MPV on admission is unknown. METHODS: 97 anterior STEMI patients successfully revascularizated with PCI between January 2010 and February 2011 are included. MPV on admission is recorded. All patients underwent transthoracic echocardiography within 3 days or before discharge. Patients were divided into two groups according to left ventricular ejection fraction (LVEF), as systolic dysfunction (LVEF < 50%, 1st group) and normal systolic functions (LVEF > 50%, 2nd group). The 1st group included 61 (47 males) patients and the 2nd group included 36 (35 males) patients. RESULTS: MPV was; 9.5+/-1.1 femtoliter (fL) in the 1st and 8.8+/-0.8 fL in the second group. The difference between the groups was significant (p = 0.001). There was a significant difference in the Troponin I levels and white blood cell (WBC) counts on admission between two groups (30+/-29 vs 12.2+/-15.1 ng/mL, p = 0.001 and 12.3+/-3.8 vs 10.6+/-3.4 counts *109/L, p = 0.027, respectively). CONCLUSIONS: In anterior STEMI patients treated with percutaneous coronary intervention, increased MPV on admission is associated with impairment in left ventricular systolic function. PMID- 23111973 TI - Influence of pneumoperitoneum on left ventricular filling pressures and NT-proBNP levels. AB - BACKGROUND: We recently demonstrated that pneumoperitoneum affects diastolic echocardiographic findings in healthy women scheduled for gynaecologic laparoscopy. No reports have been conducted in order to assess the echocardiographic consequences in hypertensive subjects during laparoscopic procedures. AIM: The aim of this study was to evaluate Left Ventricular filling pressures in hypertensive women with and without diastolic dysfunction, combining the tissue Doppler imaging technique and the plasmatic levels of amino terminal proBNP. MATERIALS AND METHODS: Doppler recordings of mitral inflow, tissue Doppler imaging of mitral annulus and N-terminal-proBNP plasmatic levels were obtained in 40 hypertensive women with or without diastolic dysfunction. Measurements were executed in awake patients (T0), after the induction of anesthesia (T1), 10 and 20 minutes after the creation of the pneumoperitoneum (T2 and T3, respectively) and at the end of the surgery (T4). Furthermore, we collected the last blood sample after 12 hours (T5). RESULTS: The E/Ea ratio for the evaluation of left ventricular filling pressures were higher in the diastolic dysfunction group than in the non diastolic dysfunction and significantly increased after pneumoperitoneum. Pneumoperitoneum increased the plasmatic levels of natriuretic peptide in both groups. At the end of the procedure we did not observe any further significant alteration. CONCLUSIONS: Pneumoperitoneum produces a consistent increase of ventricular filling pressures in a population of hypertensive patients with and without diastolic dysfunction. Moreover, there is a significant but transient rise in NT-proBNP after gas insufflation in both groups, most accentuated in the diastolic dysfunction group. PMID- 23111974 TI - Relation of interatrial duration and p wave terminal force as a novel indicator of severe mitral regurgitation. AB - OBJECTIVES: Interatrial duration is defined as prolonged p wave on electrocardiogram. p waves with a negative terminal phase recorded in V1 enclosing an area of one small square on the electrocardiogram is significantly and strongly correlated with interatrial duration. The aim of study was to investigate whether interatrial duration with p terminal force can be used as reflection of echocardiographic severity of mitral regurgitation. MATERIALS AND METHODS: Sixty two consecutive patients with mitral regurgitation. were prospectively studied. Age/gender matched 57 subjects who had normal mitral structure and did not have mitral regurgitation. Patients with mitral regurgitation referred to a single cardiac center for echocardiography and who met the entry criteria documented moderate or severe mitral regurgitation with sinus were included. The interatrial duration was defined on the routine 12-lead electrocardiogram (50 mm/s, 10 mm/mV) using the greatest duration of p waves from D2, D3, AVF and V1. RESULTS: There was a positive correlation between interatrial duration (>/= 110 ms) and effective regurgitant orifice (r = 0.3, p < 0.001). However, left atrial diameter and brain natriuretic peptide were significantly higher in cases with mitral regurgitation. There was also strong correlation between interatrial duration (>/= 110 ms) and p terminal force and left atrial diameter. ROC analysis revealed that interatrial duration of > 110 msec. could predict of severe mitral regurgitation with 88% sensitivity and 100% specificity. CONCLUSIONS: Severe mitral regurgitation, left atrial diameter was correlated with p terminal force and interatrial duration. Significant interatrial duration (>/= 110 ms) and p terminal force might be considered as novel indicators of severe mitral regurgitation. PMID- 23111975 TI - Bioinformatics analysis of two microarray gene-expression data sets to select lung adenocarcinoma marker genes. AB - BACKGROUND: Lung adenocarcinoma (LAC) is the most frequent histologic type of lung cancer and rates of adenocarcinoma are increasing in most countries. Recently, several molecular markers have been identified to predict LAC. However, more prognostic makers and the underlying role of those makers are still imperative. AIM: In this study, our objective was to identify a set of discriminating genes that can be used for characterization and prediction of response to LAC. MATERIALS AND METHODS: Using the bioinformatics analysis method, we merged two LAC datasets-GSE2514 and GSE7670 to find novel target genes and pathways to explain the pathogenicity. RESULTS: The results showed that EDNRB (endothelin receptor type B), ADRB2 (beta-adrenergic receptor), S1PR1 (sphingosine-1-phosphate receptor 1), P2RY14 (PsY purinoceptor 14), LEPR (leptin receptor), GHR (growth hormone receptor), PPM1D (protein phosphatase-1D), and GADD45B (growth arrest and DNA-damage-inducible, beta) have high degrees in response to LAC. Additionally, EDNRB, ADRB2, S1PR1, P2RY14, LEPR, and GHR may be involved in LAC through Neuroactive ligand-receptor interaction, but PPM1D and GADD45B may be through p53 signaling pathway. Some of our prediction had been demonstrated by previous reports, such as ADRB2, S1PR1, GHR, PPM1D, and GADD45B. Therefore, we hope our study could lay a basis for further study of other target genes, such as EDNRB, P2RY14, and LEPR. CONCLUSIONS: It is effective to identify potential molecular marker for LAC and predict their underlying functions by bioinformatics analysis and graph clustering method. However, further experiments are still indispensable to confirm our conclusion. PMID- 23111976 TI - The immunohistochemical detection of P16 and HPV L1 capsid protein on cell block sections from residual PapSpin liquid-based gynecology cytology specimens as a diagnostic and prognostic tool. AB - BACKGROUND: Immunohistochemical staining for p16INK4a (p16) and HPV L1 capsid protein (HPV L1) are a useful ancillary technique for diagnosing preneoplastic lesions of the cervix in histologic specimens. The purpose of the current study was to examine the usefulness of p16 and HPV L1 immunolocalization in PapSpin Liquid-Based Gynecology Cytology Specimens (PapSpin cytology) derived cell block material in the diagnosis and prognosis of preneoplastic lesions of the cervix. METHODS: The cervical cytologic smears of 64 patients who underwent colposcopic biopsy our Center were retrospectively evaluated. The cervical cytologic smears have been previously assessed by the PapSpin cytology and cell blocks were prepared from these samples. Immunohistochemical staining p16 and HPV L1 was performed on paraffin-embedded cell blocks of 64 PapSpin cytology specimens. RESULTS: The positive staining of the cell blocks for P16 was directly proportional to the degree of intraepithelial lesion. In cases with squamous cell carcinoma (SCC) and high grade squamous intraepithelial lesion (HSIL), the positive staining of p16 was found to be statistically significant. In contrast, with the increasing degree of the lesion, a statistically significant decrease was observed in the HPV L1 positivity. CONCLUSIONS: Immunohistochemical p16 and HPV L1 studies on cell block may increase the diagnostic accuracy of cervical cytology. When p16 and HPV L1 are immunohistochemically applied together on the cell blocks, they can provide information about the prognosis of cervical intraepithelial lesions. PMID- 23111977 TI - Acoustic Radial Force Impulse as an effective tool for a prompt and reliable diagnosis of hepatocellular carcinoma - preliminary data. AB - ARFI (Acoustic Radiation Force Impulse) is a novel method based on the use of shear acoustic waves remotely induced by the radiation force of a focused ultrasonic beam. Recently, ARFI has been investigated as a non-invasive method for the assessment of liver fibrosis. The reproducibility of ARFI technology was proved in determining liver fibrosis: in detail, for cirrhosis Fibroscan had its best cut-off at >/= 11 kPa (AUROC of 0.80) whereas ARFI >/= 2.0 m/s (AUROC of 0.89). By pair-wise comparison of AUROC, ARFI was significantly more accurate than TE for a diagnosis of significant and severe fibrosis. Due to the low amount of collagen deposition within hepatocellular carcinoma (HCC) nodules in a context of "hard" cirrhotic parenchyma, ARFI propose itself also as a novel, specific method for an early identification of primitive neoplastic nodules during the follow up of cirrhotic patients. The diagnostic accuracy can be demonstrated either versus the surrounding liver tissue or versus dysplastic or metastatic nodules. Further studies are required to confirm ARFI as a useful tool for HCC follow-up. PMID- 23111978 TI - Radiotherapy and hepatocellular carcinoma: update and review of the literature. AB - Historically radiotherapy has always played a limited role for the treatment of HCC due to the low tolerance of the liver and the subsequent risk of radiation induced liver disease (RILD). Technologist advancements in radiation planning and treatment delivery such as Stereotactic Body Radiotherapy (SBRT) combined with Image Guided Radiotherapy (IGRT) has allowed us to further increase tumor dose while maximally sparing the surrounding not involved liver. Furthermore, together with the growing knowledge of radiobiological models in liver disease, several mono-institutional retrospective and prospective series are reporting very encouraging results. Therefore, radiotherapy might play a significant role for the treatment of unresectable HCC, alone or combined with other locoregional treatment such as transarterial chemoembolisation (TACE). The rationale for studying this technique is really strong and it should be tested in well designed prospective randomized clinical trials. PMID- 23111979 TI - Comorbidity assessment and radiotherapy in elderly cancer patients. AB - More than 60% of all cancer patients in Europe and the USA are older than 65 years at the time of diagnosis. Despite this, elderly patients are generally under-represented in clinical trials. There is a lack of clinical trials to drive evidence-based decision making in the elderly cancer patients. In this review, we address the most important issue surrounding the treatment of older cancer patients: comorbidity assessment. PMID- 23111980 TI - Regional gastrointestinal delivery of remogliflozin etabonate in humans. AB - Remogliflozin etabonate (RE) is the prodrug of remogliflozin (R), an inhibitor of renal glucose transport designed to reduce blood glucose concentrations for the treatment of type 2 diabetes. This open-label, randomized, single-dose, four-way crossover study, (with one add-on arm) in eight healthy men evaluated the regional gastrointestinal absorption of RE, the systemic appearance of the active entity R, and an active metabolite, GSK279782. The InteliSite((r)) Companion Capsule was used to administer a single dose of RE 100 mg to the mid-small intestine or cecum/colon. Oral administration of the IR tablet of RE showed similar bioavailability of R compared with small intestine delivery with both suspension and solution. The lowest bioavailability of remogliflozin was found with large intestine delivery and therefore not a suitable region for prodrug delivery. Although both lower permeability and decreased ester hydrolysis of remogliflozin etabonate in the colon can explain reduced plasma exposures of remogliflozin, the data suggest relatively limited remogliflozin etabonate hydrolysis in the colon and provides evidence for a diminishing gradient of esterase activity from small to large intestine. PMID- 23111981 TI - Unifying protein inference and peptide identification with feedback to update consistency between peptides. AB - We first propose a new method to process peptide identification reports from databases search engines. Then via it we develop a method for unifying protein inference and peptide identification by adding a feedback from protein inference to peptide identification. The feedback information is a list of high-confidence proteins, which is used to update an adjacency matrix between peptides. The adjacency matrix is used in the regularization of peptide scores. Logistic regression (LR) is used to compute the probability of peptide identification with the regularized scores. Protein scores are then calculated with the LR probability of peptides. Instead of selecting the best peptide match for each MS/MS, we select multiple peptides. By testing on two datasets, the results have shown that the proposed method can robustly assign accurate probabilities to peptides, and have a higher discrimination power than PeptideProphet to distinguish correct and incorrect identified peptides. Additionally, not only can our method infer more true positive proteins but also infer less false positive proteins than ProteinProphet at the same false positive rate. The coverage of inferred proteins is also significantly increased due to the selection of multiple peptides for each MS/MS and the improvement of their scores by the feedback from the inferred proteins. PMID- 23111982 TI - A strategy for the molecular diagnosis in hemophilia a in Chinese population. AB - Hemophilia A is an x-linked recessive inherited bleeding disorder. So far, more than 1,885 disease-causing mutations of factor VIII gene have been identified. Clinic confers a great challenge for the molecular diagnosis. We aim to make a better strategy for the molecular diagnosis in Hemophilia A. First, factor VIII intron 22 inversion and intron 1 inversion mutations were detected using Inversion-PCR and double-tube multiple PCRs. And then, non-inversion mutations were analyzed by denaturing high performance liquid chromatography and/or direct sequencing. Novel mutations were further analyzed the conservation and 3D structures by a B domain deleted crystallographic model and bioinformatics. Finally, we can indirectly confirm the diagnosis by linkage analysis for the patients with the confusing diagnosis by the techniques mentioned above. Eleven patients with the factor VIII Inv 22 were found, and the remaining 16 patients were found with 11 different mutations, of which 3 was novel mutations affecting A1, B domains and splicing site. Moreover, the prenatal diagnosis was performed on 14 fetuses. Ten fetuses were successfully confirmed to be normal, 1 fetus to be a heterozygote with factor VIII c.3275-3276 ins A and 3 fetuses to be hemizygotes with factor VIII Inv 22 mutation. PMID- 23111983 TI - Apoptosis induced by benzyl isothiocyanate in gefitinib-resistant lung cancer cells is associated with Akt/MAPK pathways and generation of reactive oxygen species. AB - Gefitinib is the first targeted drug approved for non-small cell lung cancer (NSCLC) treatment. Clinical trails showed that patients with certain clinical and histologic characteristics (such as women, patients of East Asian descent, no history of smoking, and adenocarcinoma) had higher rates of response and overall survival. Despite excellent clinical response to gefitinib in certain NSCLC patients, nearly all patients who respond initially to gefitinib later develop drug resistance. Isothiocyanates have been shown to possess antitumor activity, inhibiting several types of cancer cells growth. However, there are limited studies on their effects on chemoresistance of cancer cells. In this report, we found that benzyl isothiocyanate (BITC) inhibited gefitinib-resistant human NSCLC cells growth by inducing apoptosis in a dose-dependent manner, and activated caspase-3. There were no effects of BITC on epidermal growth factor receptor and multidrug resistant proteins expression. BITC caused cell cycle arrest at G2/M phase, reactive oxygen species generation, and glutathione depletion. Akt activity and NFkappaB transcriptional activation were suppressed; mitogen activated protein kinase and activator protein 1 (AP-1) were activated. Our results demonstrated that BITC overcame gefitinib resistance in lung cancer cells. The further understanding of the anti-resistance mechanism of BITC would contribute to establish it as a potent lead compound for the synthesis of novel anticancer drugs. PMID- 23111984 TI - Experimental versus evaluation unit and multiplicity problem in cell biology study. AB - Yizraeli and Weihs, Cell Biochem Biophys, 61: 605-618, 2011 evaluated the effect of electrical treatment on proliferative metabolic-activity of three experimental cell conditions. They reported, that the "...three independent experiments were done in triplicate (three samples in parallel, O.V.) for each condition...", in three time-points. Therefore, I suggest, that any three samples in parallel (triplicate) in the same experiment shared more similar environmental conditions compared to any three samples (no triplicate) from three different independent experiments. Moreover, the absence of basic statistical information in the manuscript of Yizraeli and Weihs (2011) might be associated with hidden common statistical errors: (a) implicit pseudoreplication due to incorrect determination of the experimental and evaluation units and (b) simultaneous inference without correction of p-values due to ignoring the overall type I error rate. PMID- 23111985 TI - Circulating MicroRNA-122 signature in nonalcoholic fatty liver disease and cardiovascular disease: a new endocrine system in metabolic syndrome. PMID- 23111986 TI - Phosphorylated 3-heteroarylcoumarins and their use in fluorescence microscopy and nanoscopy. AB - Photostable and bright fluorescent dyes with large Stokes shifts are widely used as markers in far-field optical microscopy, but the variety of useful dyes is limited. The present study introduces new 3-heteroaryl coumarins decorated with a primary phosphate group (OP(O)(OH)(2)) attached to C-4 in 2,2,4-trimethyl-1,2 dihydroquinoline fragment fused with the coumarin fluorophore. The general synthetic route is based on the Suzuki reaction of 3-bromocoumarines with hetarylboronic acids followed by oxidation of the methyl group at the C=C bond with SeO(2) (to an aldehyde), reduction with NaBH(4) (to an alcohol), and conversion into a primary phosphate. The 4 position in the coumarin system may be unsubstituted or bear a methyl group. Phosphorylated coumarins were found to have high fluorescence quantum yields in the free state and after conjugation with proteins (in aqueous buffers). In super-resolution light microscopy with stimulated emission depletion (STED), the new coumarin dyes provide an optical resolution of 40-60 nm with a low background signal. Due to their large Stokes shifts and high photostability, phosphorylated coumarins enable to combine multilabel imaging (using one detector and several excitation sources) with diffraction unlimited optical resolution. PMID- 23111987 TI - Risk of cryptorchidism and hypospadias among boys of maternal hairdressers - a Danish population-based cohort study. AB - OBJECTIVES: Pregnant hairdressers may be exposed to a mixture of chemicals in their working environment. The possible relationship between these chemical agents and male reproductive tract malformations has raised concern that the working environment of hairdressers might have adverse effects on fetal development. This study assessed the risk of cryptorchidism and hypospadias among boys of maternal hairdressers. METHODS: National population-based registers were used to determine maternal occupation and identify cases of cryptorchidism and hypospadias. The cohort comprised all children born in Denmark from 1980-2007. Using Cox regression, we estimated hazard ratios (HR) with 95% confidence intervals (95% CI) for hospitalization for cryptorchidism and hypospadias from 1980-2009. RESULTS: Boys of hairdressers were not at increased risk of cryptorchidism (134 cases, HR 0.91; 95% CI 0.77-1.08) or hypospadias (33 cases, HR 1.27; 95% CI 0.90-1.79) compared to children of mothers in other occupations (14 988 and 2556 cases of cryptorchidism and hypospadias, respectively). Additional analyses using children of shop assistants and receptionists as controls and restricted to (i) firstborns, (ii) cryptorchidism cases with corrective surgery, (iii) specific birth years, and (iv) women without social benefit payments in gestational weeks 8-14 produced consistent results of no increased risk. CONCLUSION: Our nationwide cohort study shows that, despite exposure to a complex chemical milieu, hairdressers do not have an increased risk of having boys with cryptorchidism and hypospadias. PMID- 23111989 TI - [Dysfunction of central coherence in schoolchildren with procedural learning disorder]. AB - INTRODUCTION: Children with coordination disorder -non verbal learning disorder, procedural learning disorder (PLD)- have difficulties in understanding complex simultaneous visual information. AIM: Validation of two different visual tasks to measure central coherence function of children with PLD. SUBJECTS AND METHODS: A chimeric image and a complex visual story are showed to 200 schoolchildren: 20 of them have PLD, 60 have PLD plus attention deficit/hyperactivity disorder (PLD + ADHD), 60 have non comorbid ADHD, and 60 subjects are typical control children. A chi square test and a discriminant analysis are used to study the performances of the different groups in verbal description of both images. RESULTS: Performance is lower in children with PLD and PLD + ADHD than in those with non-comorbid ADHD or controls. Moreover 93% and 92% of children with poor performance in, respectively, chimeric and complex images, have PLD or PLD + ADHD. Eighty seven per cent of subjects with PLD + ADHD fail in some of the tasks and, by contrast only 15% of children with ADHD do. CONCLUSIONS: Children with PLD have disability in quick understanding of simultaneous complex information and central coherence. The two tasks used in this research are useful to detect these difficulties, with high sensibility and specificity. PMID- 23111988 TI - Two synthetic antibodies that recognize and neutralize distinct proteolytic forms of the ebola virus envelope glycoprotein. AB - Ebola virus (EBOV) is a highly pathogenic member of the Filoviridae family of viruses that causes severe hemorrhagic fever. Infection proceeds through fusion of the host cell and viral membranes, a process that is mediated by the viral envelope glycoprotein (GP). Following endosomal uptake, a key step in viral entry is the proteolytic cleavage of GP by host endosomal cysteine proteases. Cleavage exposes a binding site for the host cell receptor Niemann-Pick C1 (NPC1) and may induce conformational changes in GP leading to membrane fusion. However, the precise details of the structural changes in GP associated with proteolysis and the role of these changes in viral entry have not been established. Here, we have employed synthetic antibody technology to identify antibodies targeting EBOV GP prior to and following proteolysis (i.e. in the "uncleaved" [GP(UNCL)] and "cleaved" [GP(CL)] forms). We identified antibodies with distinct recognition profiles: Fab(CL) bound preferentially to GP(CL) (EC(50)=1.7 nM), whereas Fab(UNCL) bound specifically to GP(UNCL) (EC(50)=75 nM). Neutralization assays with GP-containing pseudotyped viruses indicated that these antibodies inhibited GP(CL)- or GP(UNCL)-mediated viral entry with specificity matching their recognition profiles (IC(50): 87 nM for IgG(CL); 1 MUM for Fab(UNCL)). Competition ELISAs indicate that Fab(CL) binds an epitope distinct from that of KZ52, a well-characterized EBOV GP antibody, and from that of the luminal domain of NPC1. The binding epitope of Fab(UNCL) was also distinct from that of KZ52, suggesting that Fab(UNCL) binds a novel neutralization epitope on GP(UNCL). Furthermore, the neutralizing ability of Fab(CL) suggests that there are targets on GP(CL) available for neutralization. This work showcases the applicability of synthetic antibody technology to the study of viral membrane fusion, and provides new tools for dissecting intermediates of EBOV entry. PMID- 23111990 TI - [Changes in verbal and nonverbal memory associated with bilateral hippocampal electrode implantation for epilepsy surgery]. AB - INTRODUCTION: An appropriate localization of ictal onset zone in refractory temporal lobe epilepsy favors an adequate outcome associated with surgical treatment. When video-electroencephalogram (video-EEG) and magnetic resonance imaging do not provide accurate data to locate ictal onset zone, the use of subdural or deep intracranial electrodes is indicated. Hippocampal electrode placement could generate functional changes in an unaffected hippocampus. AIM: To describe mnesic changes in patients admitted for epilepsy surgery, with previous bilateral hippocampal implantation using depth electrodes. PATIENTS AND METHODS: We identified eight patients undergoing video-EEG using bilateral hippocampal electrodes. Verbal and nonverbal mnesic performance was evaluated before/after the procedure. The following aspects were considered for the analysis: memory lateralization according to intracarotid amobarbital test (Wada test), invasive ictal onset zone, side of resection and pattern of electrocorticographic dissemination. RESULTS: In patients with memory dominance, contralateral to the ictal onset zone, there was an improvement in verbal and nonverbal memory, suggesting that invasive recordings did not impair mnesic skills of the unaffected hippocampus. In patients with bilateral representation of memory, ipsilateral mnesic impairment was associated with the resection. Contralateral improvement in memory was seen when the right side was resected, as opposed to no changes with resections made on the left side, indicating that electrode implantation of unaffected hippocampus did not generate a functional decline. CONCLUSIONS: Based on the preservation of verbal and nonverbal memory after depth electrode placement, invasive recordings of the hippocampus seem to be safe. PMID- 23111991 TI - [Corpus callosum tumor as the presenting symptom of neurofibromatosis type 1 in a patient and literature review]. AB - INTRODUCTION: Neurofibromatosis type 1 (NF1) is one of the most frequent neurocutaneous syndromes. NF1 can be associated with intracranial tumors in any location, but only rarely in the corpus callosum. AIMS: To describe a case of NF1 presenting as a tumor of the corpus callosum and to carry out a review of the incidence of the tumors of corpus callosum in our series and in the literature. CASE REPORT: We present a child who was studied since 3 years of age because of complete NF1 clinical diagnostic criteria (without genetic study). He was studied by MR and magnetic resonance spectroscopy (MRS). MR study showed neurofibromatosis bright objects distributed over several regions of the cerebral hemispheres and cerebellum, a possible brain stem tumor (bulbar zone) and the splenium of the corpus callosum. The MRS of the brain stem tumor showed changes consistent with a low grade glial tumor. The patient was followed until 19-years of age without demonstrating any changes in the clinical features or the tumor size in both locations Only six cases of corpus callosum tumor in patients with NF1 have been published to date. CONCLUSIONS: We present a new case with tumor of the corpus callosum and NF1. The imaging characteristics and the clinical course were in favour of the benign nature of this type of tumor. PMID- 23111992 TI - [Brain repair after ischemic stroke: role of neurotransmitters in post-ischemic neurogenesis]. AB - INTRODUCTION: Brain ischemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells towards the peri-infarct region occurs. DEVELOPMENT: The success of new neurorestorative treatments for damaged brain implies the need to know, with greater accuracy, the mechanisms in charge of regulating adult neurogenesis, both under physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone, thus being part of the complex signalling network that influences the production of new neurons. CONCLUSION: Neurotransmitters provide a link between brain activity and subventricular zone neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may provide a valuable tool to be used as a neurorestorative therapy in this pathology. PMID- 23111993 TI - [Alzheimer's disease and fragile X syndrome: the Wnt/beta-catenin pathway as a common biological mechanism]. AB - INTRODUCTION: Various disorders affecting the canonical Wnt/beta-catenin signalling pathway have been related to the activation or inactivation of oncogenes and tumour suppressor genes that give rise to a number of well-defined neoplasias, as well as several genes involved in a growing group of complaints, including Alzheimer's disease (AD) and fragile X syndrome (FXS). AIM: To examine the Wnt/beta-catenin signalling pathway as a possible common biological mechanism involved in the origin and development of neurodegenerative conditions and its relationship with cancer. DEVELOPMENT: We review the most recent biomedical literature dealing with the Wnt/beta-catenin signalling pathway and its participation in the genesis of complaints such as AD and FXS. An analysis is also conducted to determine the role that this metabolic pathway might play in explaining the lowered risk of developing cancer displayed by these patients. CONCLUSIONS: The evidence found suggests that the Wnt/beta-catenin pathway could be regulating a set of genes linked with the control of the cell cycle and apoptosis. This would give rise to a metabolic state in which, in conditions such as AD and FXS, the cells would be more likely to undergo apoptosis than initiate mitosis, which would in turn account for the reduced risk of developing cancer. PMID- 23111994 TI - [Cognitive deficit in schizophrenia: MATRICS Consensus Cognitive Battery]. AB - Cognitive deficits constitute a core symptom in schizophrenia, are difficult to treat, and have special relevance regarding prognosis and functional outcome. The search for pharmacological strategies for improving cognition in schizophrenic patients has been hindered by the lack of a consensus regarding instruments for cognitive assessment. The 'Measurement and Treatment Research to Improve Cognition in Schizophrenia' (MATRICS) initiative of the U.S. National Institute of Mental Health (NIMH) set the development of a consensus cognitive battery as one of its objectives. In a first phase, the seven cognitive domains which have been shown to be impaired in schizophrenia and that were to be assessed were identified: Speed of processing, Attention/Vigilance, Working memory, Verbal learning, Visual learning, Reasoning and problem solving, and Social cognition. In a second phase, the MATRICS Consensus Cognitive Battery (MCCB) was developed. This is a cognitive assessment battery composed of ten instruments, which assess the seven domains in a little over one hour. The MCCB has been standardized in U.S. population, and the Spanish standardization has been recently published. PMID- 23111996 TI - [Acute meningitis as the presenting symptom of a pituitary abscess]. PMID- 23111997 TI - [Preferences for oral anticoagulant treatment in the medium and long term prevention of stroke in non valvular atrial fibrillation]. PMID- 23111999 TI - Iron supplementation in the cardiorenal anaemia syndrome: a global metabolic approach. PMID- 23111998 TI - Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study. AB - AIMS: Elevated levels of the mineralocorticoid hormone aldosterone are recognized as a modifiable contributor to the pathophysiology of select cardiovascular diseases due to left heart failure. In pulmonary arterial hypertension (PAH), pulmonary vascular remodelling induces right ventricular dysfunction and heart failure in the absence of left ventricular (LV) dysfunction. Hyperaldosteronism has emerged as a promoter of pulmonary vascular disease in experimental animal models of PAH; however, the extent to which hyperaldosteronism is associated with PAH in patients is unknown. Thus, the central aim of the current study is to determine if hyperaldosteronism is an unrecognized component of the PAH clinical syndrome. METHODS AND RESULTS: Plasma aldosterone levels and invasive cardiopulmonary haemodynamic measurements were obtained for 25 patients referred for evaluation of unexplained dyspnoea or pulmonary hypertension. Compared with controls (n = 5), patients with PAH (n = 18) demonstrated significantly increased plasma aldosterone levels (1200.4 +/- 423.9 vs. 5959.1 +/- 2817.9 pg/mL, P < 0.02), mean pulmonary artery pressure (21.4 +/- 5.0 vs. 45.5 +/- 10.4 mmHg, P < 0.002), and pulmonary vascular resistance (PVR) (1.41 +/- 0.6 vs. 7.3 +/- 3.8 Wood units, P < 0.003) without differences in LV ejection fraction or pulmonary capillary wedge pressure between groups. Among patients not prescribed PAH specific pharmacotherapy prior to cardiac catheterization, a subgroup of the cohort with severe pulmonary hypertension, aldosterone levels correlated positively with PVR (r = 0.72, P < 0.02) and transpulmonary gradient (r = 0.69, P < 0.02), but correlated inversely with cardiac output (r = -0.79, P < 0.005). CONCLUSIONS: These data demonstrate a novel cardiopulmonary haemodynamic profile associated with hyperaldosteronism in patients: diminished cardiac output due to pulmonary vascular disease in the absence of LV heart failure. PMID- 23112000 TI - High prevalence of myocarditis in patients with hypertensive heart disease and cardiac deterioration. AB - AIMS: Structural abnormalities causing cardiac deterioration in hypertensive heart disease (HHD) are poorly understood. The aim of the study was to evaluate left ventricular (LV) myocardial changes in patients with HHD and cardiac failure. METHODS AND RESULTS: Among 1229 patients undergoing an LV or biventricular endomyocardial biopsy because of unexplained LV dysfunction from 2000 to 2010, 45 had HHD. The HHD population had non-invasive assessment of cardiac wall thickness, diameters, and function; endomyocardial samples were processed for histology, immunohistochemistry, and polymerase chain reaction (PCR) for cardiotropic viruses. Mean LV end-diastolic diameter was 63.3 +/- 5.9 mm, LV ejection fraction 29.7 +/- 7.6%, and maximal wall thickness 12.8 +/- 0.9 mm. At histology, hypertrophy with degeneration of cardiomyocytes, increased external/lumen ratio of intramural arterioles, and myocardial fibrosis were observed in 17 patients (38%). In the remaining 28 patients (62%), these histological changes were associated with myocarditis. Myocarditis was present in 40.4% of the cohort without HHD. PCR was negative in HHD without inflammation while it was positive in 10 subjects with myocarditis (enterovirus in 3 cases, adenovirus 4, influenza virus 3). Addition of immunosuppression to supportive therapy in the 18 virus-negative myocarditis subjects was followed at 6 months by significant recovery of LV function in 15 (83%; ejection fraction from 25.3 +/- 9.3% to 49.5 +/- 9.8%) while LV function improved to a minor extent ( ejection fraction from 25 +/- 5.1% to 36 +/- 4.4%) in 12 of 27 patients (44%) on supportive treatment alone. CONCLUSION: Myocarditis is a major cause of cardiac deterioration in patients with HHD; its recognition may improve patient treatment and outcome. PMID- 23112001 TI - Ranolazine for atrial fibrillation: buy one get three beneficial mechanisms! PMID- 23112002 TI - High prevalence of undetected heart failure in long-term care residents: findings from the Heart Failure in Care Homes (HFinCH) study. AB - AIMS: Diagnosis of heart failure in older people in long-term care is challenging because of co-morbidities, cognitive deficit, polypharmacy, immobility, and poor access to services. This study aimed to ascertain heart failure prevalence and clinical management in this population. METHODS AND RESULTS: A total of 405 residents, aged 65-100 years, in 33 UK care facilities were prospectively enrolled between April 2009 and June 2010. The presence of heart failure was determined using European Society of Cardiology guidelines, modified where necessary for immobility. Evaluation of symptoms and signs, functional capacity, and quality of life, portable on-site echocardiography, and medical record review were completed in 399 cases. The point prevalence of heart failure was 22.8% [n = 91, 95% confidence interval (CI) 18.8-27.2%]; of these, 62.7% (n = 57, 95% CI 59.6-66.5%) had heart failure with preserved ejection fraction and 37.3% had left ventricular systolic dysfunction (n = 34, 95% CI 34.8-40.5%). A total of 76% (n = 61) of previous diagnoses of heart failure were not confirmed, and up to 90% (n = 82) of study cases were new. No symptoms or signs were reliable predictors of heart failure. CONCLUSION: Heart failure was diagnosed in almost a quarter of residents: the prevalence was substantially higher than in other populations. The majority of heart failure cases were undiagnosed, while three-quarters of previously recorded cases were misdiagnosed. Common symptoms and signs appear to have little clinical utility in this population. Early, accurate differential diagnosis is key to the effective management of heart failure; this may be failing in long-term care facilities. PMID- 23112003 TI - Validation of Seattle Heart Failure Model for mortality risk prediction in patients treated with cardiac resynchronization therapy. AB - AIMS: Survival prediction by the Seattle Heart Failure Model (SHFM) of patients treated with cardiac resynchronization therapy (CRT) remains ill defined. The performance of the SHFM in this clinical setting was therefore evaluated. METHODS AND RESULTS: Data from 1309 consecutive CRT patients (five centres) were collected retrospectively; 1139 of these patients were considered for analysis. Three-hundred and seven deaths occurred over 40.1 months (interquartile range 25.2-60.0 months; mean event rate 9.7%/year; survival of 89, 81, and 64% at 1, 2, and 5 years). Kaplan-Meier event-free survival analysis stratified according to tertile of SHFM score was significant (log rank test P < 0.001). High-risk tertile (T1) survival was 82, 67, and 46% at 1, 2, and 5 years, respectively. Observed compared with SHFM-predicted survival was 0.11 vs. 0.08, 0.19 vs. 0.16, and 0.36 vs. 0.36, at 1, 2, and 5 years. Model discrimination by c-statistic was 0.64; the logistic models' area under the receiver operating characteristic curve (AUC-ROC) of risk tertiles was 0.66, 0.68, and 0.67, at 1, 2, and 5 years. Compared with the other two groups, T1 was globally more compromised. Within the T1 group, independent predictors of death were male gender, ischaemic heart failure aetiology, lower body weight, and CRT pacemaker. CONCLUSIONS: SHFM performance was found to be modest, tending to overestimate survival. However, SHFM identified a high-risk, globally more compromised patient subgroup, hence supporting a comprehensive approach, which should include nutritional, metabolic, and immunological aspects, as well as defibrillator back-up. PMID- 23112004 TI - B-cell frequency in hepatitis C virus-related mixed cryoglobulinemia. PMID- 23112005 TI - Metabolism of 7-ethoxycoumarin, safrole, flavanone and hydroxyflavanone by cytochrome P450 2A6 variants. AB - CYP 2A6 is a human enzyme that metabolizes many xenobiotics including coumarin, indole, nicotine and carcinogenic nitrosamines. The gene for CYP2A6 is polymorphic. There are few data available to clarify the relationship between P450 genetic variants and the metabolism of materials in food. The CYP 2A6 wild type protein and 13 mutants (CYP2A6.1, CYP2A6.2, CYP2A6.5, CYP2A6.6, CYP2A6.7, CYP2A6.8, CYP2A6.11, CYP2A6.15, CYP2A6.16, CYP2A6.17, CYP2A6.18, CYP2A6.21, CYP2A6.23 and CYP2A6.25) were co-expressed with NADPH-cytochrome P450 reductase in E. coli. The hydroxylase activities toward 7-ethoxycoumarin, coumarin, safrole, flavanone and hydroxyflavanone were examined. Ten types of CYP2A6 variants except for CYP2A6.2, CYP2A6.5 and CYP2A6.6 showed Soret peaks (450 nm) typical of P450 in the reduced CO-difference spectra and had 7-ethoxycoumarin O deethylase activities. CYP2A6.15 and CYP2A6.18 showed higher activities for safrole 1'-hydroxylation than CYP2A6.1. CYP2A6.25 and CYP2A6.7 had lower safrole 1'-hydroxylase activities. CYP2A6.7 had lower flavanone 6- and 2'-hydroxylase activities, whereas CYP2A6.25 had higher 6-hydroxylase activity and lower 2' hydroxylase activity. Hydroxyflavanone was metabolized by CYP2A6.25, but was not metabolized by wild-type CYP2A6.1. These results indicate that CYP2A6.25 possessed new substrate specificity toward flavonoids. PMID- 23112006 TI - Identifying protein complexes in protein-protein interaction networks by using clique seeds and graph entropy. AB - The identification of protein complexes plays a key role in understanding major cellular processes and biological functions. Various computational algorithms have been proposed to identify protein complexes from protein-protein interaction (PPI) networks. In this paper, we first introduce a new seed-selection strategy for seed-growth style algorithms. Cliques rather than individual vertices are employed as initial seeds. After that, a result-modification approach is proposed based on this seed-selection strategy. Predictions generated by higher order clique seeds are employed to modify results that are generated by lower order ones. The performance of this seed-selection strategy and the result-modification approach are tested by using the entropy-based algorithm, which is currently the best seed-growth style algorithm to detect protein complexes from PPI networks. In addition, we investigate four pairs of strategies for this algorithm in order to improve its accuracy. The numerical experiments are conducted on a Saccharomyces cerevisiae PPI network. The group of best predictions consists of 1711 clusters, with the average f-score at 0.68 after removing all similar and redundant clusters. We conclude that higher order clique seeds can generate predictions with higher accuracy and that our improved entropy-based algorithm outputs more reasonable predictions than the original one. PMID- 23112008 TI - Spectroscopic evidence for polymorphic aggregates formed by amyloid-beta fragments. AB - Understanding the structure of amyloid-beta (Abeta) aggregates is a key step towards elucidating the pathology of Alzheimer's disease. In this work, three fragments of the Abeta(1-42) protein, Abeta(1-25) (DAEFRHDSGYEVHHQKLVFFAEDVG), Abeta(25-35) (GSNKGAIIGLM), and Abeta(33-42) (GLMVGGVVIA), were synthesized, and their aggregated structures were examined by linear infrared spectroscopy in the amide-I (mainly the C=O stretching) region. The structures of the formed aggregates were found to be both sequence and pH dependent. The results suggest that instead of forming matured fibrils, as in the case of full-length Abeta(1 42), both Abeta(1-25) and Abeta(33-42) form a mixture of threadlike beta-sheet fibril, soluble beta-sheet oligomer, and random coil structures. The beta-sheet conformations were found to be mainly antiparallel for the former and both parallel and antiparallel for the latter. However, the Abeta(25-35) fragment was found to form assembled fibrils containing predominantly parallel beta-sheets. The conformation and morphology of the aggregates were also confirmed by circular dichroism measurements and transmission electron microscopy. Factors influencing the structures of the aggregates formed by the Abeta fragments were discussed. PMID- 23112007 TI - Cobalt(II)-catalyzed 1,4-addition of organoboronic acids to activated alkenes: an application to highly cis-stereoselective synthesis of aminoindane carboxylic acid derivatives. AB - It all adds up: The 1,4-addition of organoboronic acids to activated alkenes catalyzed by [Co(dppe)Cl(2)] is described. A [3+2]-annulation reaction of ortho iminoarylboronic acids with acrylates to give various aminoindane carboxylic acid derivatives with cis-stereoselectivity is also demonstrated (see scheme; dppe = 1,2-bis(diphenylphosphino)ethane). PMID- 23112009 TI - Evaluation of a LPS-based glycoconjugate vaccine against bovine Escherichia coli mastitis: Formation of LPS Abs in cows after immunization with E. coli core oligosaccharides conjugated to hemocyanine. AB - The immune response of cows against the core oligosaccharide of Escherichia coli rough mutants (core types R1-R4, K-12 and J-5) was investigated after immunization with a synthetic glycoconjugate composed of deacylated LPS conjugated to hemocyanine (22 animals). Ab formation was measured by ELISA using LPS or deacylated LPS conjugated to BSA as an Ag. The glycoconjugate immunogens were used to vaccinate cows (36 animals), which were then challenged intramammarily with E. coli O 157 (K1 negative, R1 core type). Compared with control groups no protection was observed, although high titers against the R1 core type were detected in vaccinated animals. Western blots using the immune sera showed that the Ab response was directed against the core region and not against the O-antigen, which may explain the failure of the vaccine. PMID- 23112010 TI - Effect of antimicrobial peptides from Apis mellifera hemolymph and its optimized version Api88 on biological activities of human monocytes and mast cells. AB - Apidaecin peptides are produced by the honeybee Apis mellifera as a major part of its non-specific defense system against infections. Having verified that the peptides apidaecin 1b and Api88-a designer peptide based on the native apidaecin 1b sequence-are highly active against Gram-negative bacteria, we studied their ability to modulate biological activities of human monocytes and mast cells (MC), two important cell types of the human innate immune system. We could show that both peptides are nontoxic and fairly resistant to degradation in cell culture medium containing 10% FBS. Among the peptides tested we found Api88 to inhibit LPS-induced TNF-alpha production in a concentration-dependent manner. Resting monocytes did not respond to Api88. Whilst Api88 neither induced migration nor affected the phagocytic activity of monocytes it partially inhibited the generation of reactive oxygen intermediates produced in response to LPS. In human MC, however, Api88 triggered degranulation and the mobilization of intracellular Ca(2+)-ions. Taken together these data clearly indicate that Api88 is a multifunctional molecule that can modulate biological responses of human monocytes and MC in addition to its antimicrobial activity. PMID- 23112011 TI - Sexually dimorphic stress and pro-inflammatory cytokine responses to an intravenous corticotropin-releasing hormone challenge of Brahman cattle following transportation. AB - This study was designed to characterize potential sexually dimorphic stress and immunological responses following a corticotropin-releasing hormone (CRH) challenge in beef cattle. Six female (heifers) and six male (bulls) Brahman calves (264 +/- 12 d of age) were administered CRH intravenously (0.5 ug of CRH/kg body mass) after which serum concentrations of cortisol increased from 0.5 h to 4 h. From 1 h to 4 h after CRH administration, serum cortisol concentrations were greater in heifers than in bulls. In all cattle, increased serum concentrations of TNF-alpha, IL-6 and IFN-gamma were observed from 2.5 h to 3 h after CRH, with greater concentrations of IFN-gamma and IL-6 in heifers than bulls. Heifer total leukocyte counts decreased 1 h after CRH administration, while bull leukocyte counts and percent neutrophils decreased 2 h after CRH administration. Heifers had greater rectal temperatures than bulls, yet rectal temperatures did not change following administration of CRH. There was no effect of CRH administration on heart rate. However, bulls tended to have increased heart rate 2 h after CRH administration than before CRH. Heifer heart rate was greater than bulls throughout the study. These data demonstrate that acute CRH administration can elicit a pro-inflammatory response, and cattle exhibit a sexually dimorphic pro-inflammatory cytokine and cortisol response to acute CRH administration. PMID- 23112012 TI - Patients' perception of risk: informed choice in prenatal testing for foetal aneuploidy. AB - Each of us perceives risk differently, and so do our patients. This perception of risk gets even more complex when multiple individuals and interactions are involved: the doctor, the patient-pregnant mother, the spouse-father and the foetus-unborn child. In this review, we address the relationship between different levels of information gathering, from clinical data to experiential knowledge - data, information, knowledge, perception, attitude, wisdom - and how these would impact the perception of risk and informed consent. We discuss how patients might interpret the risks of the same event differently based upon past experiences, and suggest how risk data could be presented more meaningfully for patients and family to assimilate for informed decision making. Finally, we demonstrate how patients' expectations and risk management can impact scientific research and clinical progress by way of the most topical subject of risk screening in pregnancy - non-invasive prenatal testing using cell-free DNA in maternal plasma. PMID- 23112013 TI - Caesarean section scar pregnancy: a case series at a single tertiary centre. AB - We present a case series of four patients with Caesarean scar pregnancies (CSPs) managed at our gynaecological unit between October 2008 and May 2009. Three patients were detected while asymptomatic, and were treated with elective intragestational sac methotrexate injections. The last patient had presented following complications from a termination of pregnancy for a CSP that was misdiagnosed as intrauterine. Following treatment, this patient and another developed arteriovenous malformation, which responded to bilateral uterine artery embolisations and gonadotropin releasing hormone (GnRH)-agonist treatment. PMID- 23112014 TI - Incidence and outcome of prenatally diagnosed, chromosomally normal congenital heart defects in Singapore. AB - INTRODUCTION: Congenital heart defect (CHD) is a significant cause of neonatal and infant mortality. We aimed to evaluate the incidence and pregnancy outcome of foetuses diagnosed with chromosomally normal CHD in KK Women's and Children's Hospital (KKH), Singapore, in 2008-2009. METHODS: We reviewed the medical records of pregnant women who underwent first trimester screening and were diagnosed with foetal CHD at KKH. Additional information was obtained from the Birth Defect Registry for the period 2008-2009. Foetuses with abnormal karyotype or minor lesions not expected to be detected by ultrasonography were excluded. RESULTS: 38 out of 9,834 euploid foetuses were diagnosed with CHD. Major defects were found in 26 (68%) foetuses, while 12 (32%) had minor CHDs. Tetralogy of Fallot, atrioventricular septal defect, hypoplastic left heart syndrome, transposition of the great arteries and ventricular septal defect constituted the five most common major CHDs observed. In 14 (54%) foetuses with prenatally diagnosed major CHD, the outcome was termination of pregnancy, while 12 (46%) pregnancies continued to birth. Among the live-born babies with major CHD, eight (67%) underwent surgery. CONCLUSION: The incidence of non-chromosomal major CHD in Singapore was about 2.6 per 1,000 foetuses. A detection rate of 88.5% was achieved for major CHD during the study period. Advances in CHD management have thrown up new challenges for clinicians in the area of diagnosis, treatment and ethics. Therefore, it may be beneficial to constitute a regulatory entity as a fundamental guide to improve the future management of foetuses diagnosed with CHD. PMID- 23112015 TI - Preimplantation genetic diagnosis of chromosome translocations by analysis of polymorphic short tandem repeats. AB - INTRODUCTION: We aimed to develop and implement a short tandem repeat (STR) polymerase chain reaction alternative to fluorescence in situ hybridisation (FISH) for the preimplantation genetic diagnosis (PGD) of chromosomal translocations. METHODS: Selected informative STRs located on translocated arms of relevant chromosomes were used to discriminate between normal and unbalanced chromosome states in each embryo. RESULTS: PGD cycles were performed on five couples where one spouse carried a balanced translocation. 27 embryos were analysed, of which 12 were normal/balanced, 12 were abnormal/unbalanced and three were indeterminate. Four PGD cycles proceeded to embryo transfer, of which two led to pregnancy. The first pregnancy showed a normal male karyotype, and a healthy baby was delivered at term. A second pregnancy unexpectedly miscarried in the second trimester from unknown causes. CONCLUSION: STR analysis is a simple and suitable alternative to FISH for detecting unbalanced chromosomal states in preimplantation embryos. PMID- 23112016 TI - Maternal and perinatal morbidity after Caesarean delivery at full cervical dilatation. AB - INTRODUCTION: This study aimed to assess maternal and perinatal outcomes following second stage Caesarean sections. METHODS: A retrospective study was conducted in a Singapore-based tertiary referral centre from January 1, 2009 to December 31, 2009. The medical records of all the women who underwent emergency Caesarean sections in the second stage of labour were reviewed. RESULTS: Out of 2,501 emergency Caesarean sections performed, 116 were Caesarean sections in the second stage of labour. Women with non-vertex, twins and preterm deliveries were excluded, and 110 (4.4%, 110/2,501) Caesarean sections were recruited. The majority of the Caesarean sections were determined and performed by registrars or consultants. With regard to maternal outcome, 2.7% (3/110) of patients had primary postpartum haemorrhage and 4.5% (5/110) of patients had vertical or lateral lower uterine segment tears. As for neonatal outcome, although the Apgar scores of newborns were low at birth for 8.2% (9/110) of patients, the Apgar score was > 4 at 5 minutes for all patients. CONCLUSION: Overall, there was no statistically significant adverse maternal or perinatal outcome. PMID- 23112018 TI - Retrospective study of transobturator polypropylene mesh kit for the management of pelvic organ prolapse. AB - INTRODUCTION: This retrospective study assessed the surgical outcomes of patients for whom the transobturator polypropylene mesh kit was used for the management of pelvic organ prolapse (Gynecare Prolift) in a tertiary urogynaecological centre in Singapore from January 1, 2006 to December 31, 2007. METHODS: 169 patients (2006 n = 95; 2007 n = 74) with total (n = 76), anterior (n = 82) and posterior (n = 11) Prolifts were followed up for two years post-surgery. RESULTS: Intraoperatively, the incidence of haematoma, blood loss > 1,000 mL and blood transfusion was lower in 2007 than in 2006, although the difference was not statistically significant. One (1.4%) patient had rectal perforation in 2007. The mesh erosion rates were similar for all Prolift types (total 17.2%; posterior 14.5%; anterior 18.2%). Two patients, who had total Prolift in 2006, required mesh excision under anaesthesia for mesh extrusion. 138 (81.7%) patients were available for review at two years - nine (6.5%) patients had recurrent cystourethrocoeles and two (1.4%) had recurrent vault prolapse. Of the nine patients who had total Prolift with uterine conservation, two (1.4%) had recurrent uterine descent. The subjective cure rates two years after Prolift surgery were 98.7% for patients from 2006 and 100% for patients from 2007. The objective cure rates were 89.6% for patients from 2006 and 91.8% for patients from 2007. CONCLUSION: Prolift mesh surgery appears to have a very high success rate for pelvic reconstructive surgery. The learning curve of the surgeon may, however, be a factor determining surgical outcome in these patients. PMID- 23112017 TI - Does low-molecular-weight heparin improve live birth rates in pregnant women with thrombophilic disorders? A systematic review. AB - INTRODUCTION: Pregnancies in women with thrombophilia are associated with a higher risk of obstetric complications. We systematically reviewed the findings of relevant randomised controlled trials (RCTs) with the aim of investigating the effectiveness of low-molecular-weight heparins (LMWHs) in pregnant women with inherited thrombophilic disorders and its effect on the incidence of live births in these patients. METHODS: The MEDLINE-PubMed and Cochrane CENTRAL databases from 2000 to 2010 were searched using a combination of keywords, including low molecular-weight heparin, enoxaparin, pregnancy, live birth and thrombophilia. Studies were included if they were RCTs assessing the effect of anticoagulant treatment on live birth rates in women with a history of miscarriage without apparent causes other than thrombophilic disorder. Interventions included LMWH, with or without aspirin, aspirin alone or placebo controlled for the prevention of adverse pregnancy outcome. RESULTS: 43 articles with seven RCTs were retrieved following the initial search, of which four studies had to be excluded as they assessed thromboembolic events as the final outcome (n = 1), focused on idiopathic recurrent miscarriages (n = 1), compared efficacy and safety of two doses of enoxaparin (n = 1), and examined patients with or without thrombophilic disorder (n = 1). Pooled data from the remaining three RCTs showed no significant difference in the improvement of live birth rates following LMWH interventions (p = 0.15). CONCLUSION: At present, the use of LMWH in women with inherited thrombophilia with recurrent pregnancy loss is not indicated. Large randomised placebo-controlled trials are further needed to prove the effectiveness of LMWH in these patients. PMID- 23112019 TI - Carpal tunnel syndrome in pregnancy - you need to ask! AB - INTRODUCTION: Carpal tunnel syndrome (CTS) is a common pregnancy complication. However, it is often overlooked by medical practitioners and patients alike. This study aimed to describe CTS in relation to pregnancy and assess how significant the disease was among pregnant women. METHODS: In a prospective cross-sectional study, 333 respondents were randomly selected from among pregnant women attending the primary care maternal health clinic in a university hospital. CTS was diagnosed clinically based on patient history and physical examination. The severity of CTS was assessed using the Boston Carpal Tunnel Questionnaire. Symptomatic respondents were asked whether they had mentioned their problems to doctors and received appropriate treatment. RESULTS: 82 (24.6%) pregnant women presented with symptoms of CTS, a majority of whom were ethnic Malays (Malay 87.8%; non-Malay 12.2%). The risk for developing CTS during the third trimester of pregnancy was found to be two-fold among Malay women compared to patients of other ethnicities (odds ratio 2.262; 95% confidence interval 1.10-4.46; p = 0.024). The commonest complaint was daytime numbness (76.8%). The severity of CTS among patients was predominantly mild (80.5%), and the symptoms were severe enough to affect hand function in approximately one-third (34.1%) of the group. However, only 25.6% of symptomatic patients mentioned their problems to their doctors, and of these, 9.5% received treatment. CONCLUSION: CTS is prevalent in the third trimester of pregnancy, especially among Malay women, in whom the risk of developing the syndrome is two-fold. Yet, this troublesome complication of pregnancy appears to be under-recognised, with most patients not being treated appropriately. PMID- 23112020 TI - Is pregnancy safe with extrahepatic portal vein obstruction? An analysis. AB - INTRODUCTION: We aimed to analyse the pregnancy outcome of women with extrahepatic portal vein obstruction. METHODS: This was a retrospective observational analysis conducted at the Institute of Postgraduate Medical Education and Research, Kolkata, India, between January 2007 and September 2009. A total of 41 pregnancies in 24 women were evaluated. RESULTS: All women conceived spontaneously (maternal age 20-35 years). 17 women had moderate-to severe anaemia, and five women had pancytopenia. Variceal bleeding occurred in ten women during pregnancy, which was managed successfully with endoscopic sclerotherapy in eight women and endoscopic variceal ligation in two women. Preterm labour (14.63%), postpartum haemorrhage (7.31%), abortion (4.87%) and pregnancy-induced hypertension (4.87%) were observed in the 41 pregnancies. There were 39 live births and almost all mothers delivered vaginally, except for four who underwent Caesarean section for obstetric indications. Prematurity (15.38%), low birth weight (10.25%), admission to the neonatal intensive care unit (12.82%), stillbirth (2.56%) and neonatal death (2.56%) were noted in the newborns. CONCLUSION: Variceal bleeding during pregnancy coincided with unfavourable outcomes. Although endoscopic obliteration of varices is a safe and effective method for antenatal management of varices in women, prenatal obliteration results in less morbidity. On rare occasions, obliterated varices can bleed in subsequent pregnancies. Therefore, preconception evaluation of the state of varices prior to each pregnancy and their ligation are important aspects of counselling. A successful foetomaternal outcome is achievable with multidisciplinary backup in a tertiary care centre. PMID- 23112021 TI - Matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 and 2 as potential biomarkers for gestational hypertension. AB - INTRODUCTION: Gestational hypertension (GH) is a common disorder during pregnancy that can progress to preeclampsia and cause various subsequent fatal complications. A cluster of enzymes, called matrix metalloproteinases (MMPs), and its specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), have been reported to be involved in the pathophysiology of GH. The purpose of this study was to examine circulating levels of MMP-9, TIMP-1 and TIMP-2 in pregnant women who had GH and those who were normotensive. METHODS: In a case-control study, the total levels of MMP-9, TIMP-1 and TIMP-2 in the sera of 108 pregnant patients were evaluated using enzyme-linked immunosorbent assays. 54 patients with GH (test group) and 64 normotensive pregnant women (control group) were included in the study. RESULTS: While MMP-9 levels showed a high level of expression in the GH group (p = 0.085), TIMP-1 and TIMP-2 levels showed low levels of expression for the same. Weak positive correlations were found on correlation analysis between maternal age and TIMP-1 in the GH group (r = 0.278, p < 0.05), and between gestational age and TIMP-2 in the control group (r = 0.318, p < 0.05). CONCLUSION: Our findings suggest that MMP-9 may be involved in the pathophysiology of GH. It may be of value to further evaluate MMP-9 as a potential biomarker for predicting preeclampsia in pregnant women. PMID- 23112023 TI - Clinics in diagnostic imaging (142). Cervical oesophagus impacted partial denture. AB - A 58-year-old man presented to the emergency department with sudden pain and odynophagia after drinking water. The patient thought that part of his lower denture may have fallen into his throat. There was moderate tenderness over the lower anterior neck. Radiographs of the neck were normal. Computed tomography showed an impacted partial denture in the upper oesophagus, which was removed by rigid endoscopy. Recheck endoscopy showed a superficial mucosal laceration at 18 cm. Ingestion of dental prostheses is common among the elderly population. The role of imaging in the early detection of ingested foreign bodies, particularly nonradio-opaque ones, is discussed. PMID- 23112022 TI - Exploring maternal mortality in relation to socioeconomic factors in Iran. AB - INTRODUCTION: Maternal mortality is a tragic death, and is perceived as a sensitive indicator of the socioeconomic status and healthcare services in a given country. In this study, the relationship between maternal deaths and factors such as socioeconomic development and the proportion of medical professionals in Iran was examined. METHODS: This was an ecological study, where three main groups of data based on different provinces were applied. Data included maternal mortality ratio, the proportion of medical professionals and socioeconomic variables, such as urban residency, unemployment and literacy. Data were obtained from various sources, including census returns, the Family Unit at the Ministry of Health and Medical Education, Tehran and the Iran Medical Council. Data were analysed using univariate and multivariate methodologies. RESULTS: Multivariate analysis showed a significant inverse relationship between maternal deaths and variables of male literacy (p < 0.001) and unemployment (p = 0.04). A marginally significant association was also found between maternal deaths and the proportion of midwives (p = 0.09). CONCLUSION: Our findings underscore the role of literacy, particularly male literacy, in the prevention of maternal deaths. Iran, as a male-dominated society, could benefit from targeting men for training programmes to enhance the health of their families, and ultimately, that of the society. As economic status does play a role in maternal deaths, there is a need to strengthen the financial situation of families. The number of skilled medical personnel available in a population also plays a key role in reducing maternal deaths. PMID- 23112024 TI - Comment on: Giant omental lipoma. PMID- 23112025 TI - Abuse of lead-contaminated opium in addicts. PMID- 23112026 TI - Comment on: the "broken heart syndrome": you're likely to have it only once! PMID- 23112029 TI - Spontaneous cholecysto-antral-cutaneous fistula: a consequence of neglected calculus cholecystitis. AB - A biliary fistula from the gallbladder can develop as a result of the erosion of stones into the surrounding viscera. An 82-year-old woman with multiple comorbid diseases presented with a persisting discharge from what was thought to be an abscess in the right hypochondrium, which had previously been drained. Sinogram confirmed fistulous communication with the gallbladder and gastric antrum. The fistulous tract was excised together with the gallbladder, and the gastric defect was repaired. The patient made an uneventful recovery. PMID- 23112030 TI - An unusual appearance of renal epithelioid angiomyolipoma. AB - Epithelioid angiomyolipoma is a recently described rare variant of renal angiomyolipoma. It can occur in patients with or without tuberous sclerosis. We report the imaging findings of a case of epithelioid angiomyolipoma that showed the presence of fatty tissue undifferentiated from the typical angiomyolipoma at the beginning. After partial nephrectomy, tumour recurrence occurred two years later, presenting as completely solid tumours with no adipose tissue, and with invasion into the psoas muscle and left adrenal gland. Differentiation of this tumour from renal cell carcinoma is difficult. Both the radiologist and surgeon should be aware of the existence of this tumour and its potentially malignant behaviour. PMID- 23112031 TI - Spontaneous splenic rupture secondary to metastatic malignant spindle cell tumour. AB - We report a case of pathological splenic rupture as a manifestation of malignant metastatic spindle cell tumour. To the best of our knowledge, this is the first case report of an atraumatic-pathological rupture of the spleen secondary to metastatic malignant spindle cell tumour. A 63-year-old man with a previous history of right upper limb amputation for an axillary malignant spindle cell tumour was admitted with an acute abdomen. Computed tomography showed a ruptured spleen. The patient subsequently underwent splenectomy. Histopathology confirmed the presence of malignant metastatic spindle cell tumour. Pathological splenic rupture is a rare manifestation of metastatic malignant spindle cell tumour. Background oncological history and thorough examination of the musculoskeletal system may provide important clues to make a prompt diagnosis. PMID- 23112032 TI - Quadrifurcation of the hepatic artery proper in conjunction with double right gastric arteries. AB - Descriptions of the variant hepatic arterial pattern are common and frequently reported in anatomy archives. We describe a noteworthy deviation from the usual branching pattern in a single cadaver. There was a unique division of the hepatic artery proper into two right gastric arteries (RGAs), apart from the usual branches. Furthermore, an arterial loop was formed by these two RGAs, giving off another RGA, which we termed 'right gastric proper'. This report attempts to evaluate the embryological basis of the anomaly. The significance of this anomalous hepatic arterial pattern is appreciated while performing liver transplantations, hepatic artery infusion of chemotherapeutic drugs and Doppler angiographic procedures. We advocate meticulous familiarisation with the anatomy of the coeliac trunk and its topographic relationship to vital viscera for the operating hepatobiliary surgeon and radiologist. PMID- 23112036 TI - Anterior ischemic optic neuropathy in patient with hereditary spherocytosis and coexisting angioid streaks. AB - Purpose. To describe a rare case of hereditary spherocytosis (HE) with angioid streaks that developed anterior ischemic optic neuropathy (AION).?Method. Case report.?Results. A 53-year-old woman with HE had a 3-day history of blurred vision in the lower hemifield in the left eye. At presentation, her visual acuity was 20/20 OD and 20/200 OS. Perimetric testing showed a relative scotoma in the superior parafoveal region in the right eye and an inferior altitudinal field defect in the left eye. Fundus examination demonstrated angioid streaks in both eyes with swelling of the optic disc in the left eye. Both parvovirus B19 immunoglobulin M and immunoglobulin G were identified in her serum. ?Conclusions. This is the first report of AION in HE and coexisting angioid streaks. The infection by parvovirus itself might be involved in the development of AION. PMID- 23112033 TI - Multicentric osteosarcoma. AB - Multicentric osteosarcoma is a rare type of osteosarcoma with a poor prognosis. It is usually described as the occurrence of tumorous lesions in more than one bone, but without pulmonary metastasis. It may be of a synchronous or metachronous variety. We report the case of a 12-year-old boy with a synchronous variety of multicentric osteosarcoma, although he did not have any risk factors for the disease. We also discuss the current debate on whether multicentric osteosarcoma represents multiple primary tumours or metastatic disease. PMID- 23112034 TI - Spontaneous regression of hepatocellular carcinoma in a cirrhotic patient: possible vascular hypothesis. AB - Spontaneous regression of hepatocellular carcinoma is extremely rare, and the exact pathogenesis leading to this remarkable phenomenon remains unclear. We describe a case of spontaneous regression of an incidentally discovered hepatocellular carcinoma in a 63-year-old man with hepatitis C cirrhosis. The regression followed a series of events, in particular, an upper gastrointestinal haemorrhage. Ischaemic insult may be a major pathway leading to tumour regression. As limited data is available in the literature, knowledge and recognition of this rare event will have implications for patient management and may alter treatment. Further, data may be useful to assess if these patients have an altered prognosis with improved survival. PMID- 23112035 TI - Gitelman's syndrome presenting with hypocalcaemia, basal ganglia calcification and periodic paralysis. AB - Gitelman's syndrome (GS), also referred to as familial hypokalaemia hypomagnesaemia syndrome, is an autosomal recessive renal tubular disorder characterised by hypokalaemic metabolic alkalosis, hypomagnesaemia and hypocalciuria. It is caused by a defect of the thiazide-sensitive sodium chloride co-transporter at the distal tubule. This condition was previously confused with Bartter syndrome. Documentation of hypocalciuria helps to differentiate GS from Bartter syndrome. We report a 44-year-old woman who presented with a history of seizure disorder and periodic paralysis. On investigation, she was found to have hypokalaemic metabolic alkalosis, hypomagnesaemia, hypocalciuria, hypoparathyroidism, hypocalcaemia and basal ganglia calcification, consistent with GS. The atypical features in our case, namely basal ganglia calcification and hypocalcaemia, prompted the writing of this case report. PMID- 23112037 TI - Peripapillary retinal nerve fiber layer thickness in children with iron deficiency anemia. AB - PURPOSE: To evaluate peripapillary retinal nerve fiber layer (RNFL) thickness in children with iron deficiency anemia (IDA) in comparison with healthy controls and to investigate the correlation between peripapillary RNFL thicknesses and the hematologic parameters in these subjects. METHODS: Forty eyes of 40 children with a diagnosis of IDA (anemic group) and 40 eyes of 40 age- and sex-matched healthy children (control group) were enrolled in this study. Peripapillary RNFL thickness measurements were performed using Cirrus HD optical coherence tomography (OCT). RESULTS: Mean age of each group was 11.3+/-2.7 years. Average RNFL and RNFLs of superior and inferior quadrants were significantly thinner in the anemic group than in the control group (p=0.006, p=0.005, and p=0.005, respectively). In addition, average peripapillary RNFL thickness and RNFL thicknesses of superior, inferior, and temporal quadrants were correlated with hemoglobin levels (r1=0.734, p1<0.001, r2=0.456, p2=0.005, r3=0.598, p3<0.001, r4=0.349, p4=0.037, respectively) in anemic group. CONCLUSIONS. We found that children with IDA had different peripapillary RNFL profile measured by Cirrus HD spectral-domain OCT. We caution ophthalmologists when they measure RNFL thickness in children to diagnose glaucoma or other neuro-ophthalmic disorders. PMID- 23112038 TI - Smaller incision size leads to higher predictability in microcoaxial cataract surgery. AB - PURPOSE: The aim of the study was to compare the clinical outcomes of a 1.8 mm, 2.2 mm, and 2.75 mm microcoaxial cataract surgery system. METHODS. In this retrospective study, 129 eyes of 129 patients were included. Patients underwent phacoemulsification using a Stellaris system or an Infiniti system. The incision size was 1.8 mm, 2.2 mm, or 2.75 mm, respectively. Subjects were examined before surgery and 4 weeks after. The surgically induced astigmatism (SIA) was examined. RESULTS: The SIA in the 1.8 mm group was statistically lower compared to the 2.2 mm group (p=0.046) and the 2.75 mm group (p=0.017). There was no significant difference between the 2.2 mm group and the 2.75 mm group. CONCLUSIONS: With the use of appropriate support systems, 1.8 mm incisions appear to result in less SIA than 2.2 mm and 2.75 mm incisions. Advantages may arise from this, especially in the implantation of aspheric, toric, or multifocal lenses. PMID- 23112039 TI - Depth of intrastromal corneal ring segments by OCT. AB - PURPOSE: To compare the depth of intrastromal corneal ring segments (ICRS) with the expected depth value using optical coherence tomography (OCT). METHODS: This was a retrospective comparative study in an ophthalmic unit in a government hospital, the Baruch Padeh Medical Center, Poriya, Israel. Ten eyes of 8 patients with 18 ICRS were reviewed. Eleven segments were Intacs (Addition Technology, Inc.) and 7 Kerarings (Mediphacos). Using anterior segment OCT (OPKO OTI) the shortest distance from the epithelium to the segment at 3 points was measured for each segment. The 3 points are proximal, middle, and distal to the incision. RESULTS: The mean depth of the 18 segments was 360+/-68 um. The mean maximal and minimal depths were 383+/-70 and 336+/-72 um, respectively. The mean depths of the distal, central, and proximal point measurements of all ICRS were 358+/-79, 361+/-77, and 362+/-59 um, respectively; no significant difference was found. No part of the segments tended to be more superficial than others (p=0.98). There was no significant difference between Intacs and Kerarings depths (p=0.43). There was a significant difference between the expected ICRS depth and the OCT measurements (mean 480+/-20) and 360+/-68), respectively. CONCLUSIONS: The ICRS actual depth was less than expected. There was mild variability in segment depth, both between segments and along the same segment. No significant difference was found between the depth of Intacs and Kerarings. PMID- 23112040 TI - Work-related open-globe injuries: demographics and clinical characteristics. AB - PURPOSE: To describe the demographics and clinical characteristics of work related open-globe injuries (OGIs) at a level I trauma center over a 10-year period. METHODS: Retrospective series. RESULTS: A total of 183 eyes with work related OGIs were identified. The majority of injuries occurred in men (96.7%). The anatomic site of the wound was zone 1 in 107 eyes (72.3%). The most common cause was nail gun use (47.0%). The types of OGI included 32 ruptures (17.5%), 112 penetrating injuries (61.2%), 38 intraocular foreign bodies (IOFB) (20.8%), and 1 mixed rupture/IOFB injury (0.5%). Presenting visual acuity (VA) was worse than 20/200 in 112 eyes (65.9%) and no light perception (NLP) in 10 eyes (5.8%). Final VA worse than 20/200 occurred in 64 eyes (37.2%); 11 eyes underwent enucleation. In comparison to non-work-related OGIs (420 eyes), we found significant differences in types and zones of injury, initial and final mean VA, enucleation rate, incidence of cataracts, hyphema, retinal detachment, hemorrhagic choroidals, and afferent pupillary defect (APD). Using multivariate analysis, significant prognostic factors for a final VA of NLP were zone 3 injury, rupture injury, and initial VA of NLP. Risk factors for enucleation included zone 3 injury, APD, and endophthalmitis. CONCLUSIONS: Work-related injuries were noted to have a much higher incidence of IOFBs and cataracts compared to non-work-related OGIs. Zone 3 injuries, rupture injuries, and a presenting VA of NLP were found to be significant predictors for a final VA of NLP. Zone 3 injury, APD, and endophthalmitis were found to be significant predictors for enucleation. PMID- 23112041 TI - Results of phacoemulsification with Malyugin Ring in comparison with manual iris stretching with hooks in eyes with narrow pupil. AB - PURPOSE: To evaluate the results of phacoemulsification in eyes with a narrow pupil dilated with Malyugin Ring, in comparison with manual pupillary stretching with hooks. SETTING: Department of Ophthalmology, Medical University of Lodz, Poland. MATERIALS AND METHODS: The examined group (group 1) consisted of 23 eyes of 23 patients whose pupil was dilated using Malyugin Ring. The reference group (group 2) consisted of 17 eyes of 17 patients whose pupil was dilated manually by stretching with hooks. All patients underwent uneventful standard phacoemulsification. Patients were examined preoperatively, 1 day, and 1 month after the surgery. Best-corrected visual acuity (BCVA), intraocular pressure, anterior and posterior segment of the eye, and corneal endothelial cell density were evaluated. Statistical analysis was done using nonparametric tests. RESULTS: Mean preoperative BCVA in group 1 was 0.31+/-0.27 and in group 2 it was 0.26+/ 0.26 (p>0.05). In both groups there was a significant improvement in BCVA after the surgery (p<0.05). Mean postoperative BCVA in group 1 was 0.75+/-0.30 and in group 2 it was 0.56+/-0.56 (p<0.05). Mean corneal endothelial cell loss measured 30 days postoperatively amounted to 9.35+/-11% in group 1 and 13.77+/-8.0% in group 2 (p<0.05). No serious complications were found. CONCLUSIONS: In eyes with narrow pupil, the use of Malyugin Ring makes the surgery easier and allows for better functional results and smaller corneal endothelial cell loss in comparison with manual pupillary stretching with 2 hooks. PMID- 23112043 TI - Monitoring 'monitoring' and evaluating 'evaluation': an ethical framework for monitoring and evaluation in public health. AB - Monitoring and evaluation (M&E) is an essential part of public health programmes. Since M&E is the backbone of public health programmes, ethical considerations are important in their conduct. Some of the key ethical considerations are avoiding conflicts of interest, maintaining independence of judgement, maintaining fairness, transparency, full disclosure, privacy and confidentiality, respect, responsibility, accountability, empowerment and sustainability. There are several ethical frameworks in public health, but none focusing on the monitoring and evaluation process. There is a need to institutionalise the ethical review of M&E proposals. A theoretical framework for ethical considerations is proposed in this paper. This proposed theoretical framework can act as the blueprint for building the capacity of ethics committees to review M&E proposals. A case study is discussed in this context. After thorough field testing, this practical and field based ethical framework can be widely used by donor agencies, M&E teams, institutional review boards and ethics committees. PMID- 23112042 TI - The active recruitment of health workers: a defence. AB - Many organisations in rich countries actively recruit health workers from poor countries. Critics object to this recruitment on the grounds that it has harmful consequences and that it encourages health workers to violate obligations to their compatriots. Against these critics, I argue that the active recruitment of health workers from low-income countries is morally permissible. The available evidence suggests that the emigration of health workers does not in general have harmful effects on health outcomes. In addition, health workers can immigrate to rich countries and also satisfy their obligations to their compatriots. It is consequently unjustified to blame or sanction organisations that actively recruit health workers. PMID- 23112045 TI - Long-lived intragraft donor leukocytes or relocated donor hematopoietic stem/progenitor cells can cause long-term hematopoietic chimerism after liver transplantation. PMID- 23112044 TI - Great expectations--ethics, avian flu and the value of progress. AB - A recent controversy over the US National Science Advisory Board for Biosecurity's recommendation to censor two publications on genetically modified H5N1 avian influenza has generated concern over the threat to scientific freedom such censorship presents. In this paper, I argue that in the case of these studies, appeals to scientific freedom are not sufficient to motivate a rejection of censorship. I then use this conclusion to draw broader concerns about the ethics of dual-use research. PMID- 23112046 TI - Isolated human/animal stratum corneum as a partial model for 15 steps in percutaneous absorption: emphasizing decontamination, Part I. AB - Since the advent of World War II, governments and laboratories have made a concerted effort to improve prophylactic and therapeutic interventions counteracting cutaneously directed chemical warfare agents (CWA), and by inference, common industrial and consumer dermatotoxicants. In vitro percutaneous penetration assays, first utilized by Tregear in the 1940s and presently in various modifications, have been fundamental to this effort. Percutaneous penetration, often considered a simple one-step diffusion process, consists of at least 15 steps. The first part of this review covers the initial steps related to absorption and excretion kinetics, vehicle characteristics, and tissue disposition. Importantly, the partitioning behavior and stratum corneum (SC) diffusion by a wide physicochemical array of compounds shows that many compounds have similar diffusion coefficients determining their percutaneous absorption in vivo. After accounting for anatomical SC variation, the penetration flux value of a substance depends mainly on its SC/vehicle partition coefficient. Additionally, the SC acts as a 'reservoir' for topically applied molecules and application of tape stripping has been found to quantify the chemical remaining in the SC which can predict total molecular penetration in vivo. Decontamination is of particular concern and even expediting standard washing procedures after dermal chemical exposure often fails to remove chemicals. This overview summarizes knowledge of percutaneous penetration extending insights into the complexities of penetration, decontamination and potential newer assays that may be of practical importance. PMID- 23112049 TI - Identification of N-terminal residues of Sonic Hedgehog important for palmitoylation by Hedgehog acyltransferase. AB - Sonic Hedgehog (Shh) is a secreted morphogen that regulates embryonic development. After removal of the signal peptide, Shh is processed to the mature, active form through autocleavage and a series of lipid modifications, including the attachment of palmitate. Covalent attachment of palmitate to the N-terminal cysteine of Shh is catalyzed by Hedgehog acyltransferase (Hhat) and is critical for proper signaling. The sequences within Shh that are responsible for palmitoylation by Hhat are not known. Here we show that the first six amino acids of mature Shh (CGPGRG) are sufficient for Hhat-mediated palmitoylation. Alanine scanning mutagenesis was used to determine the role of each amino acid and the positional sequence requirement in a cell-based Shh palmitoylation assay. Mutation of residues in the GPGR sequence to Ala had no effect on palmitoylation, provided that a positively charged residue was present within the first seven residues. The N-terminal position exhibited a strong but not exclusive requirement for Cys. Constructs with an N-terminal Ala were not palmitoylated. However, an N-terminal Ser served as a substrate for Hhat, but not the Drosophila melanogaster ortholog Rasp, highlighting a critical difference between the mammalian and fly enzymes. These findings define residues and regions within Shh that are necessary for its recognition as a substrate for Hhat-mediated palmitoylation. Finally, we report the results of a bioinformatics screen to identify other potential Hhat substrates encoded in the human genome. PMID- 23112047 TI - Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. AB - Nonalcoholic steatohepatitis (NASH) is a disorder characterized by simultaneous fat accumulation and chronic inflammation in the liver. In this study, Pin1 expression was revealed to be markedly increased in the livers of mice with methionine choline-deficient (MCD) diet-induced NASH, a rodent model of NASH. In addition, Pin1 KO mice were highly resistant to MCD-induced NASH, based on a series of data showing simultaneous fat accumulation, chronic inflammation, and fibrosis in the liver. In terms of Pin1-induced fat accumulation, it was revealed that the expression levels of peroxisome proliferator-activated receptor alpha and its target genes were higher in the livers of Pin1 KO mice than in controls. Thus, resistance of Pin1 KO mice to hepatic steatosis is partially attributable to the lack of Pin1-induced down-regulation of peroxisome proliferator-activated receptor alpha, although multiple other mechanisms are apparently involved. Another mechanism involves the enhancing effect of hematopoietic Pin1 on the expressions of inflammatory cytokines such as tumor necrosis factor and monocyte chemoattractant protein 1 through NF-kappaB activation, eventually leading to hepatic fibrosis. Finally, to distinguish the roles of hematopoietic or nonhematopoietic Pin1 in NASH development, mice lacking Pin1 in either nonhematopoietic or hematopoietic cells were produced by bone marrow transplantation between wild-type and Pin1 KO mice. The mice having nonhematopoietic Pin1 exhibited fat accumulation without liver fibrosis on the MCD diet. Thus, hepatic Pin1 appears to be directly involved in the fat accumulation in hepatocytes, whereas Pin1 in hematopoietic cells contributes to inflammation and fibrosis. In summary, this is the first study to demonstrate that Pin1 plays critical roles in NASH development. This report also raises the possibility that hepatic Pin1 inhibition to the appropriate level might provide a novel therapeutic strategy for NASH. PMID- 23112048 TI - Ubiquitin-specific protease 9x deubiquitinates and stabilizes the spinal muscular atrophy protein-survival motor neuron. AB - Spinal muscular atrophy (SMA), the leading genetic disorder of infant mortality, is caused by low levels of survival motor neuron (SMN) protein. Currently it is not clear how the SMN protein levels are regulated at the post-transcriptional level. In this report, we find that Usp9x, a deubiquitinating enzyme, stably associates with the SMN complex via directly interacting with SMN. Usp9x deubiquitinates SMN that is mostly mono- and di-ubiquitinated. Knockdown of Usp9x promotes SMN degradation and reduces the protein levels of SMN and the SMN complex in cultured mammalian cells. Interestingly, Usp9x does not deubiquitinate nuclear SMNDelta7, the main protein product of the SMN2 gene, which is polyubiquitinated and rapidly degraded by the proteasome. Together, our results indicate that SMN and SMNDelta7 are differently ubiquitinated; Usp9x plays an important role in stabilizing SMN and the SMN complex, likely via antagonizing Ub dependent SMN degradation. PMID- 23112050 TI - Self-cleavage of human CLCA1 protein by a novel internal metalloprotease domain controls calcium-activated chloride channel activation. AB - The chloride channel calcium-activated (CLCA) family are secreted proteins that regulate both chloride transport and mucin expression, thus controlling the production of mucus in respiratory and other systems. Accordingly, human CLCA1 is a critical mediator of hypersecretory lung diseases, such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis, that manifest mucus obstruction. Despite relevance to homeostasis and disease, the mechanism of CLCA1 function remains largely undefined. We address this void by showing that CLCA proteins contain a consensus proteolytic cleavage site recognized by a novel zincin metalloprotease domain located within the N terminus of CLCA itself. CLCA1 mutations that inhibit self-cleavage prevent activation of calcium-activated chloride channel (CaCC)-mediated chloride transport. CaCC activation requires cleavage to unmask the N-terminal fragment of CLCA1, which can independently gate CaCCs. Gating of CaCCs mediated by CLCA1 does not appear to involve proteolytic cleavage of the channel because a mutant N-terminal fragment deficient in proteolytic activity is able to induce currents comparable with that of the native fragment. These data provide both a mechanistic basis for CLCA1 self cleavage and a novel mechanism for regulation of chloride channel activity specific to the mucosal interface. PMID- 23112051 TI - Mechanistic origin of cross-coupling selectivity in Ni-catalysed Tishchenko reactions. AB - Mechanistic studies have been performed for the recently developed, Ni-catalysed selective cross-coupling reaction between aryl and alkyl aldehydes. A mono carbonyl activation (MCA) mechanism (in which one of the carbonyl groups is activated by oxidative addition) was found to be the most favourable pathway, and the rate-determining step is oxidative addition. Analysing the origin of the observed cross-coupling selectivity, we found the most favourable carbonyl activation step requires both coordination of the aryl aldehyde and oxidative addition of the alkyl aldehyde. Therefore, the stronger pi-accepting ability of the aryl aldehyde (relative to alkyl aldehyde) and the ease of oxidative addition of the alkyl aldehyde (relative to aryl aldehyde) are responsible for the cross coupling selectivity. PMID- 23112053 TI - Excess mortality can be explained by case mix selection. PMID- 23112052 TI - Paper's conclusions will only cause confusion. PMID- 23112054 TI - Caution is needed in interpreting results. PMID- 23112055 TI - Clarification from the National Joint Registry. PMID- 23112056 TI - Evidence for damage control resuscitation is lacking. PMID- 23112057 TI - Recommendations run contrary to current teaching. PMID- 23112058 TI - Check patients for features of spondyloarthritis. PMID- 23112059 TI - Mitochondrial DNA mutations predispose to aminoglycoside induced ototoxicity. PMID- 23112063 TI - More strategies are needed to promote wellbeing among doctors, conference hears. PMID- 23112060 TI - No evidence base for monitoring aminoglycoside levels. PMID- 23112064 TI - FDA raises concerns about ultra-long acting insulins given green light in Europe and Japan. PMID- 23112066 TI - South London trust losing L1m a week should be broken up, says administrator. PMID- 23112065 TI - Breast screening is beneficial, panel concludes, but women need to know about harms. PMID- 23112068 TI - India proposes free primary care to help achieve universal healthcare coverage. PMID- 23112067 TI - Abused patients from closed care home may be at risk in new placements, investigation shows. PMID- 23112069 TI - Ionization-induced solvent migration in acetanilide-methanol clusters inferred from isomer-selective infrared spectroscopy. AB - We present the resonance-enhanced multiphoton ionization, infrared-ultraviolet hole burning (IR-UV HB), and IR dip spectra of the trans-acetanilide-methanol (AA MeOH) cluster in the S(0), S(1), and cationic ground state (D(0)) in a supersonic jet. The IR-UV HB spectra demonstrate the co-existence of two isomers in S(0,1), in which MeOH binds either to the NH or the CO site of the peptide linkage in AA, denoted as AA(NH)-MeOH and AA(CO)-MeOH. When AA(CO)-MeOH is selectively ionized, its IR spectrum in D(0) is the same as that measured for AA(+) (NH)-MeOH. Thus, photoionization of AA(CO)-MeOH induces migration of MeOH from the CO to the NH site with 100% yield. PMID- 23112070 TI - Heterogeneous data integration by tree-augmented naive Bayes for protein-protein interactions prediction. AB - Most proteins execute their functions through interacting with other proteins. Thus, understanding protein-protein interactions (PPIs) is essential to decipher biological functions in a living cell. To predict large-scale PPIs, effective and efficient computational approaches are desirable to integrate heterogeneous data sources provided by advanced technologies. In this paper, we extend our previous work on a Bayesian classifier for human PPI predictions from model organisms, by introducing a tree-augmented naive Bayes (TAN) classifier. TAN maintains the simplicity and robustness of a naive Bayes classifier while allows for the dependence among variables. Our empirical results show that by integrating features extracted from microarray expression measurements, Gene Ontology values, and orthologous scores, TAN achieves higher classification accuracy than the manually constructed Bayesian network classifier and naive Bayes. For human PPI prediction, TAN obtains 88% sensitivity while keeping a reasonable 70% specificity on testing samples. PMID- 23112071 TI - Pregnancy sickness: a biopsychological perspective. AB - Pregnancy sickness is a universal phenomenon, affecting 70% to 85% of all pregnant women. The primary symptoms of pregnancy sickness are nausea, vomiting, and food aversions. In the past, pregnancy sickness was attributed to psychological disturbances of the pregnant woman. However, recent evolutionary psychological and biopsychological studies have reconsidered pregnancy sickness as an embryo-protective mechanism, an evolutionary adaptation to protect the embryo from phytotoxins and other environmental hazards. The biopsychological perspective of pregnancy sickness as an embryo-protective mechanism is presented. PMID- 23112072 TI - Universal cervical length screening for prediction and prevention of preterm birth. AB - Universal transvaginal ultrasound (TVU) cervical length (CL) screening represent a step forward in the campaign against preterm birth (PTB). Transvaginal ultrasound CL is a safe, acceptable, reproducible, and accurate screening test, with potentially widespread availability given its feasibility. For this screening to be effective, the ultrasounds should be done with proper TVU technique and with continuing quality assurance. Clinicians should refrain from screening different populations, at different gestational ages, and from stretching the definition of short CL to include measurements above 25 mm. A single TVU CL measurement at about 18 to 24 6/7 weeks can be offered to all singleton gestations. About 2% to 5% of these women will demonstrate a TVU CL of 20 mm or less and should be offered vaginal progesterone, either 200-mg suppository or 90-mg gel daily, until 36 weeks, being counseled that this intervention has been associated with about 45% decrease in PTB and neonatal benefits. Serial TVU CL measurements, about every 2 weeks and weekly if CL is 25 to 29 mm, can be offered between about 16 and 23 6/7 weeks to singleton gestations with a prior spontaneous PTB. In the 40% of these women who will develop a short TVU CL of less than 25 mm, cerclage should be offered, as it is associated with a significant 30% reduction in the risk of PTB less than 35 weeks and a 36% reduction in composite perinatal mortality and morbidity. Transabdominal CL screening has not been sufficiently studied and cannot be recommended. Results from just 1 trial offer promise for pessary as another effective intervention, which cannot be recommended yet until results are confirmed with another trial. Transvaginal ultrasound CL in multiples cannot be recommended yet, given lack of effective interventions in this population. PMID- 23112074 TI - WITHDRAWN: Chronic intoxication with cobalt following revision total hip arthroplasty. PMID- 23112073 TI - Cervical cancer screening in high- and low-resource countries: implications and new developments. AB - The implementation of cytology-based screening programs for precancerous lesions of the cervix has decreased the incidence of and mortality from cervical cancer in much of the developed world. Countries without the resources to install such frequent and laboratory-dependent screening programs have more and more options at their disposal. A screening program based on cytology analysis requires too much training, infrastructure, and repeated screening to be feasible. Visual inspection with acetic acid, often used throughout the world, is inexpensive and both sensitive and specific, but it lacks reproducibility. Although human papillomavirus (HPV) testing is too expensive for widespread use, its negative predictive value and sensitivity make it a promising method of screening. Utilizing HPV vaccines as a primary mode of prevention may not be financially feasible and does not obviate the need for screening. Cervical cancer has been considered an AIDS-defining illness, with HPV and HIV often coexisting, and screening methods have been shown to be as reliable for women with HIV as those without. Ultimately, the most clinically effective and cost-effective methods for reducing cervical cancer incidence are those that limit the number of visits that women are required to attend. Providing immediate cryotherapy for those with a positive screen, whether by visual inspection or HPV testing, is promising to have quite an impact, although the type of program implemented will depend on the needs and expectations of each country. PMID- 23112075 TI - Cryocompression therapy after elective arthroplasty of the hip. AB - Pneumatic compression and cryotherapy have been successfully being employed in the management of acute tissue damage. The Game Ready System (GRS) combines cyclic compression and cryotherapy. No randomised controlled trial has been performed on the effects of combined cyclic compression and cryotherapy in total hip arthroplasty (THA). We observed postoperative pain, morphine usage, blood loss, wound discharge, patient and medical staff satisfaction, together with the feasibility of a cryocompression machine, total hospital admission time, infection rate, deep vein thrombosis, and short-term prosthesis related problems in this context. Thirty patients, mean age 68 yrs (range 31-83 yrs) undergoing elective hip arthroplasty for end-stage osteoarthritis were included. Control patients (n = 15) received a tricot compression bandage alone, and patients studied received a tricot compression bandage plus intermittent cryocompression therapy 15 times for 30 minutes. Haemoglobin levels on postoperative day (POD) 1 dropped 2.34 mmol/L in the control group and 1,87 mmol/L in the intervention group (p = 0,027). At POD 3 haemoglobin levels were reduced by 2,63 and 2,16 respectively (p = 0,646). A trend occurred towards lower morphine usage, shorter hospital admission time and less wound discharge in the study group. No difference was found in postoperative pain scores. One event of deep venous thrombosis occurred in the control group. Intermittent cryocompression therefore appears to reduce postoperative blood loss. A trend towards less analgesic use, shorter hospital stay, less wound discharge and less pain at 6 weeks postoperatively was also observed. PMID- 23112076 TI - Clinical outcome following surgical intervention for periprosthetic hip fractures at a tertiary referral centre. AB - Complications following surgical intervention for periprosthetic hip fractures are not uncommon. We report the clinical outcome following definitive surgical intervention for this indication at a single tertiary referral centre. All patients admitted between 2003 and 2009 undergoing such treatment were included. Patient demographics, all surgical interventions, complications following definitive fracture treatment, and postoperative mortality were recorded. Radiographs were reviewed to determine the Vancouver classification for each fracture. There were 67 patients (mean age at revision 76.7 years; 61% female). Fractures occurred around primary total hip arthroplasties (43%), revision arthroplasties (34%), and hip hemiarthroplasties (23%). Mean time to fracture from the most recent arthroplasty performed was 7.0 years. Most fractures were Vancouver type B2 (49%). The majority of patients underwent revision total hip arthroplasty (96%), using long-stemmed prostheses or proximal femoral endoprostheses, with cables for fracture fixation. Wound infection and systemic complications were seen in 16% and 13% respectively. One or more further surgical interventions were performed in 12%. There were no deaths in-hospital or at 30 days, with 10 fatalities (15%) at a mean 2-year follow-up. Lower rates of re intervention and mortality were observed when surgery for acute periprosthetic hip fractures was performed at a tertiary centre. Revision hip arthroplasty with or without fracture fixation proved an effective and safe treatment of periprosthetic hip fractures in a high-risk patient population. PMID- 23112077 TI - Serum lactate is a prognostic indicator in patients with hip fracture. AB - BACKGROUND AND PURPOSE: Serum lactate has been shown to be an indicator of adverse clinical outcomes in patients admitted secondary to general trauma or sepsis. We retrospectively investigated whether admission serum venous lactate can predict in-hospital mortality in patients with hip fractures. METHOD AND RESULTS: Over a 38-month period the admission venous lactate of 807 patients with hip fractures was collated. Mean age was 82 years. The overall in-hospital mortality for this cohort was 9.4%. Mortality was not influenced by the fracture pattern or the type of surgery - be it internal fixation or arthroplasty (p = 0.7). A critical threshold of 3 mmol/L with respect to the influence of venous lactate level on mortality was identified. Mortality rate in those with a lactate level of less than 3 mmol/L was 8.6% and 14.2% for those whose level was 3 mmol/L or greater. A 1 mmol/L increase in venous lactate was associated with a 1.2 (1.02 1.41) increased risk of in-hospital mortality. Patients with a venous lactate of 3 mmol/L or higher had twice the odds of death in hospital compared to matched individuals. There was no statistically significant difference in ASA distribution between those with a lactate of less than or greater than 3 mmol/L. CONCLUSIONS: Patients with an elevated venous lactate following hip trauma should be identified as being at increased risk of death and may benefit from targeted medical therapy. PMID- 23112078 TI - p38 (MAPK) stress signalling in replicative senescence in fibroblasts from progeroid and genomic instability syndromes. AB - Werner Syndrome (WS) is a human segmental progeria resulting from mutations in a DNA helicase. WS fibroblasts have a shortened replicative capacity, an aged appearance, and activated p38 MAPK, features that can be modulated by inhibition of the p38 pathway. Loss of the WRNp RecQ helicase has been shown to result in replicative stress, suggesting that a link between faulty DNA repair and stress induced premature cellular senescence may lead to premature ageing in WS. Other progeroid syndromes that share overlapping pathophysiological features with WS also show defects in DNA processing, raising the possibility that faulty DNA repair, leading to replicative stress and premature cellular senescence, might be a more widespread feature of premature ageing syndromes. We therefore analysed replicative capacity, cellular morphology and p38 activation, and the effects of p38 inhibition, in fibroblasts from a range of progeroid syndromes. In general, populations of young fibroblasts from non-WS progeroid syndromes do not have a high level of cells with an enlarged morphology and F-actin stress fibres, unlike young WS cells, although this varies between strains. p38 activation and phosphorylated HSP27 levels generally correlate well with cellular morphology, and treatment with the p38 inhibitor SB203580 effects cellular morphology only in strains with enlarged cells and phosphorylated HSP27. For some syndromes fibroblast replicative capacity was within the normal range, whereas for others it was significantly shorter (e.g. HGPS and DKC). However, although in most cases SB203580 extended replicative capacity, with the exception of WS and DKC the magnitude of the effect was not significantly different from normal dermal fibroblasts. This suggests that stress-induced premature cellular senescence via p38 activation is restricted to a small subset of progeroid syndromes. PMID- 23112080 TI - Ultrafast photodynamics of the indoline dye D149 adsorbed to porous ZnO in dye sensitized solar cells. AB - We investigate the ultrafast dynamics of the photoinduced electron transfer between surface-adsorbed indoline D149 dye and porous ZnO as used in the working electrodes of dye-sensitized solar cells. Transient absorption spectroscopy was conducted on the dye in solution, on solid state samples and for the latter in contact to a I(-)/I(3)(-) redox electrolyte typical for dye-sensitized solar cells to elucidate the effect of each component in the observed dynamics. D149 in a solution of 1:1 acetonitrile and tert-butyl alcohol shows excited-state lifetimes of 300+/-50 ps. This signature is severely quenched when D149 is adsorbed to ZnO, with the fastest component of the decay trace measured at 150+/ 20 fs due to the charge-transfer mechanism. Absorption bands of the oxidized dye molecule were investigated to determine regeneration times which are in excess of 1 ns. The addition of the redox electrolyte to the system results in faster regeneration times, of the order of 1 ns. PMID- 23112079 TI - Establishment of transactivation assay systems using fish, amphibian, reptilian and human thyroid hormone receptors. AB - Thyroid hormones are essential for the regulation of a wide range of biological processes associated with normal development and metabolism in vertebrates. For the screening of chemicals with a potential thyroid hormone and anti-thyroid hormone activities, we have established transient transactivation assay systems using thyroid hormone receptors (TRalpha and TRbeta) from three frog species (Xenopus laevis, Silurana tropicalis and Rana rugosa), a fish (Oryzias latipes), an alligator (Alligator mississippiensis) and a human (Homo sapiens). In all species examined, similar transcriptional activities were found for triiodothyronine (T3 : 10(-11) M in TRalpha and 10(-10) M in TRbeta) and thyroxine (T4 : 10(-9) M in TRalpha and 10(-8) M in TRbeta). Analogs of thyroid hormone (3,5,3',-triiodothyroacetic acid and 3,3',5,5'-tetraiodothyroacetic acid) exhibited weaker activity, requiring 10-fold higher concentrations for induction of activity when compared with T3 and T4 . These results provide support for the usefulness of in vitro screening assay systems as part of an approach to test chemicals for potential thyroid hormone receptor activity. In addition, we observed that T3 -stimulated transcriptional activity of the O. latipes TRalpha was inhibited by 10(-5) M tetrabromobisphenol A (TBBPA). In contrast, TR antagonist activities on TRalpha were not encountered in other species, even with TBBPA concentrations at 10(-5) M. In vitro transactivation assay systems using TRs from various species can be used for the screening of chemicals with thyroid receptor agonist and antagonist activities. They also can be used for studies that examine evolutionary differences among species in the potency of TR activation. PMID- 23112081 TI - Overestimation of hematopoietic stem cell frequencies in human liver grafts. PMID- 23112082 TI - Supramolecular gel-assisted formation of fullerene nanorods. AB - Gel it like it is: Fullerene nanorods (see figure) with a length of several micrometers, can be easily synthesized by a supramolecular gel-assisted self assembly method (SGAS). The results presented here may be useful for the design and construction of new organic nanomaterials by SGAS. PMID- 23112083 TI - A cell-based high-throughput screening assay for posttranscriptional utrophin upregulation. AB - Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease caused by mutations in the dystrophin gene. Utrophin is a homologue of dystrophin that can compensate for its absence when overexpressed in DMD animal models. Utrophin upregulation is therefore a promising therapeutic approach for DMD. Utrophin is regulated at both transcriptional and posttranscriptional levels. Transcriptional regulation has been studied extensively, and assays have been described for the identification of utrophin promoter-targeting molecules. However, despite the profound impact that posttranscriptional regulation has on utrophin expression, screening assays have not yet been described that could be used to discover pharmaceuticals targeting this key phase of regulation. We describe the development and validation of a muscle cell line-based assay in which a stably expressed luciferase coding sequence is flanked by the utrophin 5'- and 3' untranslated regions (UTRs). The assay was validated using the posttranscriptional regulation of utrophin by miR-206. The assay has a Z' of 0.7, indicating robust performance in high-throughput format. This assay can be used to study utrophin regulatory mechanisms or to screen chemical libraries for compounds that upregulate utrophin posttranscriptionally via its UTRs. Compounds identified via this assay, used alone or in a synergistic combination with utrophin promoter-targeting molecules, would be predicted to have therapeutic potential for DMD. PMID- 23112084 TI - Affordable luciferase reporter assay for cell-based high-throughput screening. AB - The firefly luciferase gene is commonly used in cell-based reporter assays. Convenient luciferase assay reagents for use in high-throughput screening (HTS) are commercially available. However, the high cost of these reagents is not within the means of some academic laboratories. Therefore, we set out to develop an affordable luciferase assay reagent applicable in an HTS format using simple liquid-handling steps. The reagent was homemade from individual chemical components and optimized for luminescence intensity and stability. We determined the minimal concentrations of the most expensive components, dithiothreitol (DTT) and D-luciferin, resulting in a total assay reagent cost of less than 1 cent per sample. Signal stability was maximized by omission of coenzyme A and reduction of DTT concentration. The assay was validated in a high-throughput setting using two cancer cell lines carrying a p53-dependent luciferase reporter construct and siRNAs modulating p53 transcriptional activity. Induction of p53 activity by silencing PPM1D or SYVN1 and reduction of p53 activity by silencing p53 remained constant over a 2-h measurement period, with good assay quality (Z' factors mostly above 0.5). Hence, the luciferase assay described herein can be used for affordable reporter readout in cell-based HTS. PMID- 23112086 TI - Nurse accreditation: a better way of working. PMID- 23112087 TI - Removal of a fractured Nexplanon(r). PMID- 23112085 TI - Interactions between artemisinins and other antimalarial drugs in relation to the cofactor model--a unifying proposal for drug action. AB - Artemisinins are proposed to act in the malaria parasite cytosol by oxidizing dihydroflavin cofactors of redox-active flavoenzymes, and under aerobic conditions by inducing their autoxidation. Perturbation of redox homeostasis coupled with the generation of reactive oxygen species (ROS) ensues. Ascorbic acid-methylene blue (MB), N-benzyl-1,4-dihydronicotinamide (BNAH)-MB, BNAH lumiflavine, BNAH-riboflavin (RF), and NADPH-FAD-E. coli flavin reductase (Fre) systems at pH 7.4 generate leucomethylene blue (LMB) and reduced flavins that are rapidly oxidized in situ by artemisinins. These oxidations are inhibited by the 4 aminoquinolines piperaquine (PPQ), chloroquine (CQ), and others. In contrast, the arylmethanols lumefantrine, mefloquine (MFQ), and quinine (QN) have little or no effect. Inhibition correlates with the antagonism exerted by 4-aminoquinolines on the antimalarial activities of MB, RF, and artemisinins. Lack of inhibition correlates with the additivity/synergism between the arylmethanols and artemisinins. We propose association via pi complex formation between the 4 aminoquinolines and LMB or the dihydroflavins; this hinders hydride transfer from the reduced conjugates to the artemisinins. The arylmethanols have a decreased tendency to form pi complexes, and so exert no effect. The parallel between chemical reactivity and antagonism or additivity/synergism draws attention to the mechanism of action of all drugs described herein. CQ and QN inhibit the formation of hemozoin in the parasite digestive vacuole (DV). The buildup of heme Fe(III) results in an enhanced efflux from the DV into the cytosol. In addition, the lipophilic heme-Fe(III) complexes of CQ and QN that form in the DV are proposed to diffuse across the DV membrane. At the higher pH of the cytosol, the complexes decompose to liberate heme-Fe(III) . The quinoline or arylmethanol reenters the DV, and so transfers more heme-Fe(III) out of the DV. In this way, the 4-aminoquinolines and arylmethanols exert antimalarial activities by enhancing heme-Fe(III) and thence free Fe(III) concentrations in the cytosol. The iron species enter into redox cycles through reduction of Fe(III) to Fe(II) largely mediated by reduced flavin cofactors and likely also by NAD(P)H-Fre. Generation of ROS through oxidation of Fe(II) by oxygen will also result. The cytotoxicities of artemisinins are thereby reinforced by the iron. Other aspects of drug action are emphasized. In the cytosol or DV, association by pi complex formation between pairs of lipophilic drugs must adversely influence the pharmacokinetics of each drug. This explains the antagonism between PPQ and MFQ, for example. The basis for the antimalarial activity of RF mirrors that of MB, wherein it participates in redox cycling that involves flavoenzymes or Fre, resulting in attrition of NAD(P)H. The generation of ROS by artemisinins and ensuing Fenton chemistry accommodate the ability of artemisinins to induce membrane damage and to affect the parasite SERCA PfATP6 Ca(2+) transporter. Thus, the effect exerted by artemisinins is more likely a downstream event involving ROS that will also be modulated by mutations in PfATP6. Such mutations attenuate, but cannot abrogate, antimalarial activities of artemisinins. Overall, parasite resistance to artemisinins arises through enhancement of antioxidant defense mechanisms. PMID- 23112090 TI - Sensitivity of translation initiation factor eIF1 as a molecular target of salt toxicity to sodic-alkaline stress in the halophytic grass Leymus chinensis. AB - Eukaryotic translation initiation factors (eIFs) have been shown to be critical in the initiation of protein synthesis. Here, we report the cloning and characterization of a novel gene, LceIF1, from a potentially interesting forage grass, Leymus chinensis (Trin.). The expression results show that LceIF1 is expressed in most organisms under normal conditions, but the transcription patterns differ under sodic-saline and sodic-alkaline stresses. Sodic-saline stress induced a persistent decrease, and sodic-alkaline stress induced overexpression of LceIF1. Potassic-saline and alkaline stresses did not cause any changes in expression of eIF1. These results indicate that not only pH but also Na(+) concentration affects overtranscription of LceIF1. The eIF1 transgenic lines showed relatively high eIF1 expression, resulting in potentially higher stress resistance. Combined with eIF1 transcription in transgenic lines, LceIF1 as a molecular target of salt toxicity is believed to help enhance salt tolerance. PMID- 23112088 TI - The financial costs to patients of diagnosing and excluding ectopic pregnancy. AB - OBJECTIVES: Health care costs are one of the greatest challenges in modern medicine. In gynaecology, diagnosing and excluding ectopic pregnancy (EP) has been shown to be a financial burden to health services because it commonly requires multiple investigations and hospital visits. However, the full economic costs are not captured by an analysis of health care costs alone. This study therefore aimed to assess the indirect costs to patients of diagnosing and excluding EP. METHODS: Patients presenting to a Pregnancy Support Centre in a large UK teaching hospital with abdominal pain and/or bleeding and a positive pregnancy test were recruited during the period June 2010-February 2011. Patients were provided with questionnaires to be completed at home and designed to record and quantify costs that they had incurred until a final diagnosis of their condition was made. A cost-description analysis was performed. RESULTS: 52/203 (26%) recruited patients returned completed questionnaires. The mean cost to patients of diagnosing or excluding EP was L135.13+/-L51.60 (median L20.70). The main cost drivers identified were hospital visits, holiday cancellations, income loss and household help. CONCLUSIONS: Quantification of the indirect costs of diagnosing and excluding EP is challenging because it relies on questionnaire feedback from patients at a time when they have suffered from the emotional impact of pregnancy loss. However, initial estimates suggest that such costs are significant due to diagnostic delays. This further highlights the importance of the development of potential biomarkers of EP to allow prompt diagnosis. PMID- 23112099 TI - Solution-processed optoelectronic properties of functionalized anthradifuran. PMID- 23112095 TI - Isolated human and animal stratum corneum as a partial model for the 15 steps of percutaneous absorption: emphasizing decontamination, part II. AB - Cutaneously directed chemical warfare agents can elicit significant morbidity and mortality. The optimization of prophylactic and therapeutic interventions counteracting these agents is crucial, and the development of decontamination protocols and methodology of post dermal exposure risk assessments would be additionally applicable to common industrial and consumer dermatotoxicants. Percutaneous (PC) penetration is often considered a simple one-step diffusion process but presently consists of at least 15 steps. The systemic exposure to an agent depends on multiple factors and the second part of this review covers absorption and excretion kinetics, wash and rub effects, skin substantivity and transfer, among others. Importantly, the partitioning behavior and diffusion through the stratum corneum (SC) of a wide physicochemical array of compounds shows that many compounds have approximately the same diffusion coefficient which determines their percutaneous absorption in vivo. After accounting for anatomical variation of the SC, the penetration flux value of a substance depends mainly on its SC/vehicle partition coefficient. Additionally, the SC acts as a 'reservoir' for topically applied molecules, and tape stripping methodology can quantify the remaining chemical in the SC which can predict the total molecular penetration in vivo. The determination of ideal decontamination protocols is of utmost importance to reduce morbidity and mortality. However, even expeditious standard washing procedures post dermal chemical exposure often fails to remove chemicals. The second part of this overview continues to review percutaneous penetration extending insights into the complexities of penetration, decontamination and potential newer assays that may be of practical importance. PMID- 23112100 TI - Spatio-temporal regularization in linear distributed source reconstruction from EEG/MEG: a critical evaluation. AB - The high temporal resolution of EEG/MEG data offers a way to improve source reconstruction estimates which provide insight into the spatio-temporal involvement of neuronal sources in the human brain. In this work, we investigated the performance of spatio-temporal regularization (STR) in a current density approach using a systematic comparison to simple ad hoc or post hoc filtering of the data or of the reconstructed current density, respectively. For the used STR approach we implemented a frequency-specific constraint to penalize solutions outside a narrow frequency band of interest. The widely used sLORETA algorithm was adapted for STR and generally used for source reconstruction. STR and filtering approaches were evaluated with respect to spatial localization error and spatial dispersion, as well as to correlation of original and reconstructed source time courses in single source and two source scenarios with fixed source locations and oscillating source waveforms. We used extensive computer simulations and tested all algorithms with different parameter settings (noise levels and regularization parameters) for EEG data. To verify our results, we also used data from MEG phantom measurements. For the investigated scenarios, we did not find any evidence that STR-based methods outperform purely spatial algorithms applied to temporally filtered data. Furthermore, the results show very clearly that the performance of STR depends very much on the choice of regularization parameters. PMID- 23112097 TI - Far-infrared-assisted preparation of a graphene-nickel nanoparticle hybrid for the enrichment of proteins and peptides. AB - A new approach based on far infrared-assisted in situ reduction was developed for the facile one-step preparation of graphene-nickel nanoparticle hybrid by refluxing a mixture solution containing graphene oxide, nickel(II) sulfate, and hydrazine over an far-infrared heater. The reduction time was as short as 20 min. The structure of the material was investigated by transmission electron microscopy, scanning electron microscopy, X-ray diffraction, energy dispersive spectroscopy, vibrating sample magnetometery, and Fourier transform infrared spectroscopy. Magnetic investigations indicate that the grapheme-nickel nanoparticle hybrid exhibits ferromagnetic behavior at room temperature. Meanwhile, the hybrid was successfully employed in the enrichment and identification of proteins and peptides in combination with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry based on its excellent magnetic responsibility, high dispersibility, large surface area, and hydrophobicity, indicating great promise for a wide range of applications. PMID- 23112102 TI - Multilayer films with nanocontainers: redox-controlled reversible encapsulation of guest molecules. AB - Stable multilayer films with cucurbit[8]uril have been fabricated on the basis of the alternating layer-by-layer assembly of a novel side-chain pseudopolyrotaxane and a photoreactive polyanion. The as-prepared multilayer films exhibit good properties as surface-imprinted multilayers, because cucurbit[8]uril molecules that are locked inside the multilayers can act as nanocontainers with specific binding to certain guest molecules, and the loading and release of the guest is redox-controllable and reversible. PMID- 23112098 TI - Synergistic larvicidal effect and morphological alterations induced by ethanolic extracts of Annona muricata and Piper nigrum against the dengue fever vector Aedes aegypti. AB - BACKGROUND: Phytopesticide combinations of different botanical sources are seldom reported. Annona muricata seed and Piper nigrum fruit ethanolic extracts enriched in acetogenins and piperamides, respectively, were synergistically used as larvicides against the dengue fever vector Aedes aegypti. RESULTS: Individual bioassays of A. muricata and P. nigrum indicated respective LC50 values of 93.48 and 1.84 ug mL(-1) against third-instar larvae. Five combinations of different proportions of plant extracts pointed to synergism between the extracts. The best A. muricata:P. nigrum extract combination was 90:10, which showed 5.12 times the amount of synergism, as confirmed by statistical equations and total concentration log versus combination proportions. Concerning the morphology, A. muricata caused larvae body elongation, mainly in the abdomen, along with the appearance of a cervix. Conversely, P. nigrum induced abdomen and whole body shortening. The morphological effects of A. muricata were prevalent in all of the combinations tested, irrespective of its proportion in the combination. CONCLUSION: It is suggested that the different mechanisms of action of the larvicidal actives A. muricata acetogenins and P. nigrum piperamides explain the observed synergism. The combination of inexpensive botanicals and a low-cost organosolvent such as ethanol leads to a simple and efficient phytolarvicidal formulation. PMID- 23112103 TI - Investigating the mode of action of sulfoxaflor: a fourth-generation neonicotinoid. AB - BACKGROUND: The precise mode of action of sulfoxaflor, a new nicotinic acetylcholine receptor-modulating insecticide, is unclear. A detailed understanding of the mode of action, especially in relation to the neonicotinoids, is essential for recommending effective pest management practices. RESULTS: Radiolabel binding experiments using a tritiated analogue of sulfoxaflor ([(3) H]-methyl-SFX) performed on membranes from Myzus persicae demonstrate that sulfoxaflor interacts specifically with the high-affinity imidacloprid binding site present in a subpopulation of the total nAChR pool. In competition studies, imidacloprid-like neonicotinoids displace [(3) H]-methyl-SFX at pM concentrations. The effects of sulfoxaflor on the exposed aphid nervous system in situ are analogous to those of imidacloprid and nitenpyram, and finally the high-affinity sulfoxaflor binding site is absent in a Myzus persicae strain (clone FRC) possessing a single amino acid point mutation (R81T) in the beta nAChR, a region critical for neonicotinoid interaction. CONCLUSION: The nicotinic acetylcholine receptor pharmacological profile of sulfoxaflor in aphids is consistent with that of imidacloprid. Additionally, the insecticidal activity of sulfoxaflor and the current commercialised neonicotinoids is affected by the point mutation in FRC Myzus persicae. Therefore, it is suggested that sulfoxalfor be considered a neonicotinoid, and that this be taken into account when recommending insecticide rotation partnering for effective resistance management programmes. PMID- 23112104 TI - Distinct evolution and predictive value of hepatitis B virus precore and basal core promoter mutations in interferon-induced hepatitis B e antigen seroconversion. AB - Precore (PC) (G1896A) and basal core promoter (BCP) (A1762T/G1764A) mutations of the hepatitis B virus (HBV) genome often emerge in chronic hepatitis B (CHB) patients. Their roles in hepatitis B e antigen (HBeAg) seroconversion induced by interferon (IFN) therapy remain controversial, partly because quantitative analysis for these mutants is lacking. This study aimed to develop a new assay to accurately quantify the PC and BCP mutant percentages and correlate their dynamic changes with IFN-induced HBeAg seroconversion in HBeAg-positive CHB patients. The PC and BCP mutant percentages were analyzed by polymerase chain reaction (PCR) pyrosequencing. Our results showed that this quantitative assay for PC and BCP mutants achieved high accuracy (R(2) > 0.99) within a range between 10% and 90% mutants. We examined dynamic changes of the PC and BCP mutant percentages following IFN treatment in 203 HBeAg-positive CHB patients. By multiple logistic regression analysis, we found that the chance of HBeAg seroconversion increased by 2.2% (odds ratio [OR] = 1.022, 95% confidence interval [CI]: 1.009-1.034, P = 0.001) and 2.3% (OR = 1.023, 95% CI: 1.010-1.037, P = 0.001) per 1% increase of the pretreatment PC and BCP mutant percentages, respectively, after adjustment for other predictors. However, only the pretreatment PC mutation percentage was significantly associated with HBeAg seroconversion with HBV DNA < 2,000 IU/mL (OR = 1.030, 95% CI: 1.014-1.047, P < 0.001). Furthermore, the mutant percentage of PC, but not BCP, in patients achieving HBeAg seroclearance with HBV DNA < 20,000 IU/mL increased significantly during IFN treatment (P = 0.039). Interestingly, patients with HBeAg seroconversion who had a high PC mutant percentage at the end of IFN treatment tended to exhibit high viremia after seroconversion. CONCLUSION: Quantitative analysis of PC and BCP mutants can predict IFN-induced HBeAg seroconversion and demonstrate their distinct evolution patterns during HBeAg seroconversion. (HEPATOLOGY 2013). PMID- 23112105 TI - Asymmetric mixed-valence complexes that consist of cyclometalated ruthenium and ferrocene: synthesis, characterization, and electronic-coupling studies. AB - Three bis-tridentate ferrocene-containing cyclometalated ruthenium complexes, [(Fcdpb)Ru(tpy)](+) (1(+)), [(Fctpy)Ru(dpb)](+) (2(+)), and [(Fcdpb)Ru(Fctpy)](+) (3(+)), have been prepared and characterized, where Fcdpb is the 2-deprotonated form of 1,3-di(2-pyridyl)-5-ferrocenylbenzene, tpy is 2,2':6',2"-terpyridine, dpb is the 2-deprotonated form of 1,3-di(2-pyridyl)benzene, and Fctpy is 4' ferrocenyl-2,2':6',2"-terpyridine. Single crystals of compounds 2(+) and 3(+) have been studied by X-ray analysis. Complexes 1(+) and 2(+) displayed two anodic redox waves, whilst three well-separated redox couples were observed for compound 3(+). A combined experimental and computational study suggested that the ferrocene unit on the Fcdpb moiety in compounds 1(+) and 3(+) was oxidized first. In contrast, the order of the oxidation of ruthenium and ferrocene in complex 2(+) was reversed. Metal-to-metal-charge-transfer transitions (MM'CT) have been observed for the singly oxidized states 1(2+), 2(2+), and 3(2+) in the near infrared region. Hush analysis showed that the metal-metal electronic couplings in compounds 1(2+) and 3(2+) were much stronger than those in compound 2(2+). PMID- 23112094 TI - Enzymatic characterization of germination-specific cysteine protease-1 expressed transiently in cotyledons during the early phase of germination. AB - Papain-like cysteine protease activity that shows a unique transient expression profile in cotyledons of daikon radish during germination was detected. The enzyme showed a distinct elution pattern on DEAE-cellulose compared with cathepsin B-like and Responsive to dessication-21 cysteine protease. Although this activity was not detected in seed prior to imbibition, the activity increased markedly and reached a maximum at 2 days after imbibition and then decreased rapidly and completely disappeared after 5 days. Using cystatin Sepharose, the 26 kDa cysteine protease (DRCP26) was isolated from cotyledons at 2 days after imbibition. The deduced amino acid sequence from the cDNA nucleotide sequence indicated that DRCP26 is an orthologue of Arabidopsis unidentified protein, germination-specific cysteine protease-1, belonging to the C1 family of cysteine protease predicted from genetic information. In an effort to characterize the enzymatic properties of DRCP26, the enzyme was purified to homogeneity from cotyledons at 48 h after imbibition. The best synthetic substrate for the enzyme was carbobenzoxy-Phe-Arg-4-methylcoumaryl-7-amide. All model peptides were digested to small peptides by the enzyme, suggesting that DRCP26 possesses broad cleavage specificity. These results indicated that DRCP26 plays a role in the mobilization of storage proteins in the early phase of seed germination. PMID- 23112101 TI - Inhibitory effects of tert-butylhydroquinone on osteoclast differentiation via up regulation of heme oxygenase-1 and down-regulation of HMGB1 release and NFATc1 expression. AB - Osteoclasts (OCLs) are multinucleated bone-resorbing cells that are differentiated by receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Our recent studies have shown that heme-oxygenase-1 (HO-1), a stress-induced cytoprotective enzyme, plays an important role in OCL differentiation, although the pharmacological significance of this effect remains unknown. In this study, we investigated the effects of tert-butylhydroquinone (tBHQ), a pharmacological HO-1 inducer, on in vitro differentiation of bone marrow-derived macrophages (BMMs) or murine monocytic cell line RAW-D into OCLs. tBHQ inhibited the formation and the bone-resorbing activity of OCLs. Moreover, tBHQ treatment decreased the expression of nuclear factor of activated T cells cytoplasmic-1 (NFATc1), a master regulator of OCL differentiation, and of OCL markers transcriptionally regulated by NFATc1, such as Src and cathepsin K. In addition, tBHQ impaired phosphorylation of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase (MAPK), Jun N-terminal kinase, Akt, and inhibitor of nuclear factor kappa B alpha (IkappaBalpha). Finally, we show that tBHQ inhibited the release of high mobility group box 1 (HMGB1), a recently identified activator of OCL differentiation. Thus, tBHQ inhibits OCL differentiation through the HO-1/HMGB1 pathways. PMID- 23112107 TI - Highly enantio- and diastereoselective generation of two quaternary centers in spirocyclopropanation of oxindole derivatives. AB - Spirocyclopropanes: Only one out of eight possible stereoisomers was obtained in the asymmetric cascade cyclopropanation of alkylidene oxindoles with ethyl 2 chloroacetoacetate. Improved catalyst design ensured that spirocyclopropyl oxindoles featuring two quaternary centers were synthesized in high yield and high enantio- and diastereoselectivity (see scheme). PMID- 23112096 TI - Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies. AB - The presence of cirrhosis increases the potential risk of hemorrhage for patients with hepatocellular carcinoma (HCC). We evaluated the relative risk for hemorrhage in patients with HCC treated with antiangiogenic agents. We performed a systematic review and meta-analysis of antiangiogenic studies in HCC from 1995 to 2011. For nonrandomized studies we compared bleeding risk with other HCC single-arm studies that did not include an antiangiogenic agent. To separate disease-specific factors we also performed a comparison analysis with renal cell cancer (RCC)) studies that evaluated sorafenib. Sorafenib was associated with increased bleeding risk compared to control for all grade bleeding events (odds ratio [OR] 1.77; 95% confidence interval [CI] 1.04, 3.0) but not grade 3-5 events in both HCC and RCC (OR 1.46; 95% CI 0.9, 2.36; P=0.45). When comparing the risk of bleeding in single-arm phase 2 studies evaluating antiangiogenic agents, this risk for all events (OR 4.34; 95% CI 2.16, 8.73) was increased compared to control. CONCLUSION: This analysis of both randomized and nonrandomized studies evaluating an antiangiogenic agent in HCC showed that whereas the use of sorafenib was associated with an increased risk of bleeding in HCC, this was primarily for lower-grade events and similar in magnitude to the risk encountered in RCC. PMID- 23112089 TI - Role of FGFRL1 and other FGF signaling proteins in early kidney development. AB - The mammalian kidney develops from the ureteric bud and the metanephric mesenchyme. In mice, the ureteric bud invades the metanephric mesenchyme at day E10.5 and begins to branch. The tips of the ureteric bud induce the metanephric mesenchyme to condense and form the cap mesenchyme. Some cells of this cap mesenchyme undergo a mesenchymal-to-epithelial transition and differentiate into renal vesicles, which further develop into nephrons. The developing kidney expresses Fibroblast growth factor (Fgf)1, 7, 8, 9, 10, 12 and 20 and Fgf receptors Fgfr1 and Fgfr2. Fgf7 and Fgf10, mainly secreted by the metanephric mesenchyme, bind to Fgfr2b of the ureteric bud and induce branching. Fgfr1 and Fgfr2c are required for formation of the metanephric mesenchyme, however the two receptors can substitute for one another. Fgf8, secreted by renal vesicles, binds to Fgfr1 and supports survival of cells in the nascent nephrons. Fgf9 and Fgf20, expressed in the metanephric mesenchyme, are necessary to maintain survival of progenitor cells in the cortical region of the kidney. FgfrL1 is a novel member of the Fgfr family that lacks the intracellular tyrosine kinase domain. It is expressed in the ureteric bud and all nephrogenic structures. Targeted deletion of FgfrL1 leads to severe kidney dysgenesis due to the lack of renal vesicles. FgfrL1 is known to interact mainly with Fgf8. It is therefore conceivable that FgfrL1 restricts signaling of Fgf8 to the precise location of the nascent nephrons. It might also promote tight adhesion of cells in the condensed metanephric mesenchyme as required for the mesenchymal-to-epithelial transition. PMID- 23112108 TI - Involvement of the p38 MAPK signaling pathway in S-phase cell-cycle arrest induced by Furazolidone in human hepatoma G2 cells. AB - Given the previously described essential role for the p38 mitogen-activation protein kinase (p38 MAPK) signaling pathway in human hepatoma G2 cells (HepG2), we undertook the present study to investigate the role of the p38 MAPK signaling pathway in cell-cycle arrest induced by Furazolidone (FZD). The aim of this study was to determine the effects of FZD on HepG2 cells by activating and inhibiting the p38 MAPK signaling pathway. The cell cycle and proliferation of HepG2 cells treated with FZD were detected by flow cytometry and MTT assay in the presence or absence of p38 MAPK inhibitors (SB203580), respectively. Cyclin D1, cyclin D3 and CDK6 were detected by quantitative real-time PCR and western blot analysis. Our data showed that p38 MAPK became phosphorylated after stimulation with FZD. Activation of p38 MAPK could arise S-phase cell-cycle arrest and suppress cell proliferation. Simultaneously, inhibition of the p38 MAPK signaling pathway significantly prevented S-phase cell-cycle arrest, increased the percentage of cell viability and decreased the expression of cyclin D1, cyclin D3 and CDK6. These results demonstrated that FZD arose S-phase cell-cycle arrest via activating the p38 MAPK signaling pathway in HepG2 cells. Cyclin D1, cyclin D3 and CDK6 are target genes functioning at the downstream of p38 MAPK in HepG2 cells induced by FZD. PMID- 23112112 TI - Simultaneous imaging of mitochondria and lysosomes by using two-photon fluorescent probes. PMID- 23112091 TI - Comparison of autoantibody specificities between traditional and bead-based assays in a large, diverse collection of patients with systemic lupus erythematosus and family members. AB - OBJECTIVE: Replacement of standard immunofluorescence methods with bead-based assays for antinuclear antibody (ANA) testing is a new clinical option. The aim of this study was to evaluate a large, multiethnic cohort of patients with systemic lupus erythematosus (SLE), blood relatives, and unaffected control individuals for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods. METHODS: Serum samples (1,540 SLE patients, 1,154 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead based assay, indirect immunofluorescence (IIF), and immunodiffusion. Autoantibody prevalence, sensitivity for disease detection, clustering of autoantibodies, and associations between newer methods and standard immunodiffusion results were evaluated. RESULTS: The frequencies of ANAs in the sera from African American, Hispanic, and European American patients with SLE were 89%, 73%, and 67%, respectively, by BioPlex 2200 bead-based assay and 94%, 84%, and 86%, respectively, by IIF. When comparing the serum prevalence of 60-kd Ro, La, Sm, nuclear RNP A, and ribosomal P autoantibodies across assays, the sensitivity of detection ranged from 0.92 to 0.83 and the specificity ranged from 0.90 to 0.79. Autoantibody cluster analysis showed associations of autoantibody specificities in 3 subsets: 1) 60 kd Ro, 52-kd Ro, and La, 2) spliceosomal proteins, and 3) double-stranded DNA (dsDNA), chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60-kd Ro in SLE patient sibling pairs was observed (P <= 0.004). Simplex-pedigree SLE patients had a greater prevalence of dsDNA (P = 0.0003) and chromatin (P = 0.005) autoantibodies compared to patients with a multiplex SLE pedigree. CONCLUSION: The frequencies of ANAs detected by a bead based assay are lower than those detected by IIF in European American patients with SLE. These assays have strong positive predictive values across ethnic groups, provide useful information for clinical care, and provide unique insights into familial aggregation and autoantibody clustering. PMID- 23112115 TI - Prostate needle biopsy processing: a survey of laboratory practice across Europe. AB - AIM: To determine the degree of variation in the handling of prostate needle biopsies (PBNx) in laboratories across Europe. METHODS: A web based survey was emailed to members of the European Network of Uropathology and the British Association of Urological Pathologists. RESULTS: Responses were received from 241 laboratories in 15 countries. PNBx were generally taken by urologists (93.8%) or radiologists (23.7%) but in 8.7% were also taken by non-medical personnel such as radiographers, nurses or biomedical assistants. Of the responding laboratories, 40.8% received cores in separate containers, 42.3% processed one core/block, 54.2% examined three levels/block, 49.4% examined one H&E section/level and 56.1% retained spare sections for potential immunohistochemistry. Of the laboratories, 40.9% retained unstained spares for over a year while 36.2% discarded spares within 1 month of reporting. Only two (0.8%) respondents routinely performed immunohistochemistry on all PNBx. There were differences in laboratory practice between the UK and the rest of Europe (RE). Procurement of PNBx by non-medical personnel was more common in the UK. RE laboratories more commonly received each core in a separate container, processed one core/block, examined fewer levels/block and examined more H&E sections/level. RE laboratories also retained spares for potential immunohistochemistry less often and for shorter periods. Use of p63 as the sole basal cell marker was more common in RE. CONCLUSIONS: There are marked differences in procurement, handling and processing of PNBx in laboratories across Europe. This data can help the development of best practice guidelines. PMID- 23112106 TI - Plasma matrix metalloproteinases and postmenopausal breast cancer risk: a nested case-control study in the Multiethnic Cohort study. AB - The survival of malignant breast cells depends upon the remodeling of the extracellular matrix, including complex interactions with matrix metalloproteinases (MMPs). It has been hypothesized that circulating MMPs may serve as early indicators of breast cancer development in hospital-based case control studies. A nested case-control study of the association of pre-diagnostic plasma levels of MMPs with the subsequent risk of postmenopausal breast cancer was conducted within the Multiethnic Cohort. During the follow-up period, 713 women with incident invasive breast cancer were identified and individually (1:1) matched to controls. Four types of MMPs (1, 2, 3, and 7) were analyzed by microsphere immunofluorescence assay. Mean plasma levels of MMPs did not differ significantly between cases and controls; nor were there differences in breast cancer risk by MMP level. No difference in the risk of breast cancer by plasma level of the MMPs was found within strata of age, or ethnicity, although MMP-1 levels were positively associated with breast cancer risk in obese women and women by hormone replacement medications (P values for interaction <0.05). Few significant differences in risk by levels of the MMPs were found by any of the clinical variables. Circulating MMPs were not associated with postmenopausal breast cancer risk. PMID- 23112109 TI - Glycoproteomics using fluid-based specimens in the discovery of lung cancer protein biomarkers: promise and challenge. AB - Lung cancer is the leading cancer in the United States and worldwide. In spite of the rapid progression in personalized treatments, the overall survival rate of lung cancer patients is still suboptimal. Over the past decade, tremendous efforts have been focused on the discovery of protein biomarkers to facilitate the early detection and monitoring of lung cancer progression during treatment. In addition to tumor tissues and cancer cell lines, a variety of biological material has been studied. Particularly in recent years, studies using fluid based specimen or so-called "fluid-biopsy" specimens have progressed rapidly. Fluid specimens are relatively easier to collect than tumor tissue, and they can be repeatedly sampled during the disease progression. Glycoproteins are the major content of fluid specimens and have long been recognized to play fundamental roles in many physiological and pathological processes. In this review, we focus the discussion on recent advances of glycoproteomics, particularly in the identification of potential glyco protein biomarkers using fluid-based specimens in lung cancer. The purpose of this review is to summarize current strategies, achievements, and perspectives in the field. This insight will highlight the discovery of tumor-associated glycoprotein biomarkers in lung cancer and their potential clinical applications. PMID- 23112117 TI - Improved alignment of reticulocyte counts between Sysmex XT-2000i instruments. AB - BACKGROUND: Reticulocytes are the most sensitive index available to authorities who seek to sanction athletes for blood doping based on deviations beyond individual reference ranges. Because such data comprise longitudinal results that are generated by different laboratories, the comparability of reticulocyte counts from different instruments is of crucial importance. AIMS: To enhance between instrument comparability of reticulocyte counts reported by the Sysmex XT-2000i automated haematology analyser. METHODS: We optimised recalibration of instruments towards assigned values of control material (e-CHECK) in tandem with fresh blood verification. RESULTS: In terms of reticulocyte counts reported as a percentage of all cells in a fresh blood sample, it was possible to recalibrate all three test instruments so that the mean of 10 samples was within 0.1% of the comparative instrument's mean value. CONCLUSIONS: This approach provides a straightforward means of reducing between-instrument differences in reticulocyte counts generated by the Sysmex XT-2000i. PMID- 23112119 TI - It is too difficult for ill people to claim benefits. PMID- 23112121 TI - The doctor won't see you now: online consulting and prescribing. PMID- 23112122 TI - The assault on the Liverpool care pathway. PMID- 23112113 TI - Cognitive function, gait, and gait variability in older people: a population based study. AB - BACKGROUND: Gait impairments are associated with falls and loss of independence. The study of factors associated with poorer gait may assist in developing methods to preserve mobility in older people. The aim of this study was to examine the associations between a range of cognitive functions and gait and gait variability in a population-based sample of older people. METHODS: Gait and intra-individual gait variability measures were obtained using the GAITRite walkway in a sample of older people, aged 60-85 years (N = 422), randomly selected from the Tasmanian electoral roll. Raw scores from a cognitive battery were subjected to principal component analyses deriving four summary domains: executive function/attention, processing speed, memory, and visuospatial ability. Multivariable linear regression was used to examine associations between cognitive domains and gait measures adjusting for age, sex, ambulatory activity, medication use, and mood. RESULTS: The mean age of the sample was 72.0 years (SD = 7.0), with 238 men (56%). Poorer executive function was independently associated with poorer performance in most absolute gait measures and with greater variability in double support phase and step time. Processing speed was associated with absolute gait measures and double support phase variability. Visuospatial ability was only associated with greater double support phase variability, independently of executive function and processing speed. Memory was not independently associated with any gait measure. CONCLUSIONS: In community-dwelling older people, executive function/attention and processing speed were associated with many aspects of gait, whereas visuospatial ability may only play a role in double support phase variability. PMID- 23112116 TI - Cancer stem cells markers CD44, CD24 and ALDH1 in breast cancer special histological types. AB - AIMS: CD44, CD24 and ALDH1 are the most consistently used biomarkers to identify and characterise the breast cancer stem cell (CSC) phenotype. However, most studies performed until now analysed samples of invasive ductal carcinomas of no special type (IDC-NST). Therefore, prevalence and clinical significance of these CSC markers in breast carcinomas of special histological types (SHT) is largely unknown. For that reason, this study aims to determine the distribution of the breast CD44, CD24 and ALDH1 CSC markers among a series of invasive breast carcinomas of SHT, in comparison with a series of IDC-NST. METHODS: 117 invasive SHT breast carcinomas were analysed for the expression of CD44, CD24 and ALDH1, by immuhohistochemistry. The distribution of these CSC markers was evaluated among the distinct histological special types, and the results were compared with a series of 466 IDC-NST. RESULTS: The expression prevalence of the breast CSC markers differed between special types and IDC-NST. Medullary, papillary and tubular carcinomas were enriched in the CSC phenotype CD44(+)/CD24(-/low) (80.0%, 100.0% and 100.0%, respectively, vs 45.3% in IDC-NST). Considering the ALDH1 cytoplasmic tumour expression, only medullary and metaplastic carcinomas displayed significant increase in CD44(+)/CD24(-/low)/ALDH1(+) CSC phenotype frequency (36.4% and 28.6%, respectively, vs 4.8% in IDC-NST). CONCLUSIONS: The expression distribution of breast CSC markers is largely dependent on histological type. Interestingly, within the distinct SHT, medullary and metaplastic carcinomas are the two types highly associated with high-grade carcinomas, basal-like and claudin-low molecular subtypes, and to the CSC phenotype CD44(+)/CD24(-/low)/ALDH1(+). PMID- 23112110 TI - Pilot study of a novel patient self-management program for warfarin therapy using venipuncture-acquired international normalized ratio monitoring. AB - STUDY OBJECTIVE: To compare clinical and safety outcomes of warfarin therapy before and after implementation of a novel patient self-management (PSM) program in which patients received their venipuncture-derived international normalized ratio (INR) results through a secure online messaging system and adjusted their warfarin dosages and follow-up visits according to provided support tools. DESIGN: Prospective, open-label, 3-month, pilot study. SETTING: Centralized clinical pharmacy anticoagulation service. PATIENTS: Forty-four patients with atrial fibrillation who were receiving warfarin for more than 6 months were enrolled in the trial between January 1, 2011, and February 28, 2011; 39 patients completed the trial. Patients acted as their own controls. INTERVENTION: Patients received dosing decision support tools during a 2-hour live PSM training class. Those who then demonstrated proficiency in PSM assumed responsibility for their warfarin therapy management. MEASUREMENTS AND MAIN RESULTS: Outcomes of warfarin therapy were measured in each patient before and after implementation of the PSM program. Study variables included time in the therapeutic INR range (TTR), numbers of INR tests performed, and episodes of major bleeding or thrombosis. No significant difference in TTR occurred between the 90 days before PSM program participation and the 90 days of PSM (82.9% vs 81.2%, p=0.65). The mean number of INR tests performed for each patient increased from 2.97 before PSM program participation to 4.38 during PSM (p<0.01). No bleeding or thrombotic events occurred during the PSM phase. CONCLUSION: Patients were trained to engage in PSM using support tools and venipuncture-derived INR results received by an online messaging system to adjust warfarin dosage and frequency of INR testing. No significant difference in TTR occurred in these patients before and during the PSM. This novel PSM model appears to be a feasible method of managing warfarin therapy in carefully selected patients; however, a larger, randomized controlled trial is needed to evaluate the safety and efficacy of the model and its effect on anticoagulation service workload. PMID- 23112120 TI - The role of fatty acids from fish in the prevention of stroke. PMID- 23112123 TI - Application of quantitative proteomics technologies to the biomarker discovery pipeline for multiple sclerosis. AB - Multiple sclerosis is an inflammatory-mediated demyelinating disorder most prevalent in young Caucasian adults. The various clinical manifestations of the disease present several challenges in the clinic in terms of diagnosis, monitoring disease progression and response to treatment. Advances in MS-based proteomic technologies have revolutionized the field of biomarker research and paved the way for the identification and validation of disease-specific markers. This review focuses on the novel candidates discovered by the application of quantitative proteomics to relevant disease-affected tissues in both the human context and within the animal model of the disease known as experimental autoimmune encephalomyelitis. The role of targeted MS approaches for biomarker validation studies, such as multiple reaction monitoring will also be discussed. PMID- 23112114 TI - Aging-related geniohyoid muscle atrophy is related to aspiration status in healthy older adults. AB - BACKGROUND: Age-related muscle weakness due to atrophy and fatty infiltration in orofacial muscles may be related to swallowing deficits in older adults. An important component of safe swallowing is the geniohyoid (GH) muscle, which helps elevate and stabilize the hyoid bone, thus protecting the airway. This study aimed to explore whether aging and aspiration in older adults were related to GH muscle atrophy and fatty infiltration. METHOD: Eighty computed tomography scans of the head and neck from 40 healthy older (average age 78 years) and 40 younger adults (average age 32 years) were analyzed. Twenty aspirators and 20 nonaspirators from the 40 older adults had been identified previously. Two dimensional views in the sagittal and coronal planes were used to measure the GH cross-sectional area and fatty infiltration. RESULTS: GH cross-sectional area was larger in men than in women (p < .05). Decreased cross-sectional area was associated with aging (p < .05), and cross-sectional area was significantly smaller in aspirators compared with nonaspirators, but only among the older men (p < .01). Increasing fatty infiltration was associated with aging in the middle (p < .05) and posterior (p < .01) portions of the GH muscle. There was no significant difference in fatty infiltration of the GH muscle among aspirators and nonaspirators. CONCLUSION: GH muscle atrophy was associated with aging and aspiration. Fatty infiltration in the GH muscle was increased with aging but not related to aspiration status. These findings suggest that GH muscle atrophy may be a component of decreased swallowing safety and aspiration in older adults and warrants further investigation. PMID- 23112127 TI - Rationally designed alpha-helical broad-spectrum antimicrobial peptides with idealized facial amphiphilicity. AB - A series of 12-amino acid peptide analogs is designed using point mutation strategy based on an alpha-helical peptide template. The first mutation in the series, KL12, has an idealized facial amphiphilicity. Subsequent mutations are performed to increase hydrophobic or cationic contents. Idealized facial amphiphilicity show enhanced antimicrobial activity and selectivity against most of the tested microbes. Increasing hydrophobic contents further enhance antimicrobial potency; however, selectivity of the most hydrophobic analog is impaired due to non-specific interactions with mammalian cell membrane. This study demonstrates that facial amphiphilicity and hydrophobic content are strongly correlated with antimicrobial activity and selectivity of antimicrobial peptides. PMID- 23112124 TI - Low dietary folate and methylenetetrahydrofolate reductase deficiency may lead to pregnancy complications through modulation of ApoAI and IFN-gamma in spleen and placenta, and through reduction of methylation potential. AB - SCOPE: Genetic or nutritional disturbances in folate metabolism lead to hyperhomocysteinemia and adverse reproductive outcomes. Folate-dependent homocysteine remethylation is required for methylation reactions and may influence choline/betaine metabolism. Hyperhomocysteinemia has been suggested to play a role in inflammation. The goal of this study was to determine whether folate-related pregnancy complications could be due to altered expression of some inflammatory mediators or due to disturbances in methylation intermediates. METHODS AND RESULTS: Pregnant mice with or without a deficiency of methylenetetrahydrofolate reductase (MTHFR) were fed control diets or folate deficient (FD) diets; tissues were collected at embryonic day 14.5. FD decreased plasma phosphocholine and increased plasma glycerophosphocholine and lysophosphatidylcholine. Liver betaine, phosphocholine, and S adenosylmethionine:S-adenosylhomocysteine ratios were reduced in FD. In liver, spleen, and placenta, the lowest levels of apolipoprotein AI (ApoAI) were observed in Mthfr(+/-) mice fed FD. Increased interferon-gamma (IFN-gamma) was observed in spleen and placentae due to FD or Mthfr genotype. Plasma homocysteine correlated negatively with liver and spleen ApoAI, and positively with IFN-gamma. CONCLUSION: Low dietary folate or Mthfr deficiency during pregnancy may result in adverse pregnancy outcomes by altering expression of the inflammatory mediators ApoAI and IFN-gamma in spleen and placenta. Disturbances in choline metabolism or methylation reactions may also play a role. PMID- 23112118 TI - Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis. AB - OBJECTIVE: To clarify associations of fish consumption and long chain omega 3 fatty acids with risk of cerebrovascular disease for primary and secondary prevention. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Studies published before September 2012 identified through electronic searches using Medline, Embase, BIOSIS, and Science Citation Index databases. ELIGIBILITY CRITERIA: Prospective cohort studies and randomised controlled trials reporting on associations of fish consumption and long chain omega 3 fatty acids (based on dietary self report), omega 3 fatty acids biomarkers, or supplementations with cerebrovascular disease (defined as any fatal or non-fatal ischaemic stroke, haemorrhagic stroke, cerebrovascular accident, or transient ischaemic attack). Both primary and secondary prevention studies (comprising participants with or without cardiovascular disease at baseline) were eligible. RESULTS: 26 prospective cohort studies and 12 randomised controlled trials with aggregate data on 794,000 non-overlapping people and 34,817 cerebrovascular outcomes were included. In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease for 2-4 servings a week versus <= 1 servings a week was 0.94 (95% confidence intervals 0.90 to 0.98) and for >= 5 servings a week versus 1 serving a week was 0.88 (0.81 to 0.96). The relative risk for cerebrovascular disease comparing the top thirds of baseline long chain omega 3 fatty acids with the bottom thirds for circulating biomarkers was 1.04 (0.90 to 1.20) and for dietary exposures was 0.90 (0.80 to 1.01). In the randomised controlled trials the relative risk for cerebrovascular disease in the long chain omega 3 supplement compared with the control group in primary prevention trials was 0.98 (0.89 to 1.08) and in secondary prevention trials was 1.17 (0.99 to 1.38). For fish or omega 3 fatty acids the estimates for ischaemic and haemorrhagic cerebrovascular events were broadly similar. Evidence was lacking of heterogeneity and publication bias across studies or within subgroups. CONCLUSIONS: Available observational data indicate moderate, inverse associations of fish consumption and long chain omega 3 fatty acids with cerebrovascular risk. Long chain omega 3 fatty acids measured as circulating biomarkers in observational studies or supplements in primary and secondary prevention trials were not associated with cerebrovascular disease. The beneficial effect of fish intake on cerebrovascular risk is likely to be mediated through the interplay of a wide range of nutrients abundant in fish. PMID- 23112126 TI - Antioxidant and antiapoptotic effects of proanthocyanidin and ginkgo biloba extract against doxorubicin-induced cardiac injury in rats. AB - Grape seed proanthocyanidins (GSPE) and ginkgo biloba extract (EGb761) are considered to have protective effects against several diseases. The cardiotoxicity of doxorubicin (DOX) has been reported to be associated with oxidative damage. This study was conducted to evaluate the cardioprotective effects of GSPE and EGb761 against DOX-induced heart injury in rats. DOX was administered as a single i.p. dose (20 mg kg(-1)) to adult male rats. DOX intoxicated rats were orally administered GSPE (200 mg kg(-1) day(-1)) or EGb761 (100 mg kg(-1) day(-1)) for 15 consecutive days, starting 10 days prior DOX injection. DOX-induced cardiotoxicity was evidenced by a significant increase in serum aspartate transaminase (AST), creatine phosphokinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), total cholesterol (TC) and triglyceride (TG) activities and levels. Increased oxidative damage was expressed by the depletion of cardiac reduced glutathione (GSH), elevation of cardiac total antioxidant (TAO) level and accumulation of the lipid peroxidation product, malondialdehyde (MDA). Significant rises in cardiac tumour necrosis factor-alpha (TNF-alpha) and caspase-3 levels were noticed in DOX-intoxicated rats. These changes were ameliorated in the GSPE and EGb761-treated groups. Histopathological analysis confirmed the cardioprotective effects of GSPE and EGb761. In conclusion, GSPE and EGb761 mediate their protective effect against DOX-induced cardiac injury through antioxidant, anti-inflammatory and antiapoptotic mechanisms. PMID- 23112125 TI - Lymphotoxin alpha1beta2 expression on B cells is required for follicular dendritic cell activation during the germinal center response. AB - CD19-deficient mice were used as a model to study follicular dendritic cell (FDC) activation because these mice have normal numbers of FDC-containing primary follicles, but lack the ability to activate FDCs or form GCs. It was hypothesized that CD19 expression is necessary for B-cell activation and upregulation of membrane lymphotoxin (mLT) expression, which promotes FDC activation. Using VCAM 1 and FcgammaRII/III as FDC activation markers, it was determined that the adoptive transfer of CD19(+) wild-type B cells into CD19-deficient hosts rescued GC formation and FDC activation, demonstrating that CD19 expression on B cells is required for FDC activation. In contrast, CD19(+) donor B cells lacking mLT were unable to induce VCAM-1 expression on FDCs, furthermore FcgammaRII/III upregulation was impaired in FDCs stimulated with mLT-deficient B cells. VCAM-1 expression on FDCs, but not FcgammaRII/III, was rescued when CD19-deficient B cells expressing transgenic mLT were cotransferred into recipient mice with CD19(+) , mLT-deficient B cells, suggesting that FDC activation requires the CD19 dependent upregulation of mLT on activated B cells. Collectively, these data demonstrate that activated B cells are responsible for the initiation of FDC activation resulting in a microenvironment supportive of GC development and maintenance. PMID- 23112128 TI - Analysis of multicentre trials with continuous outcomes: when and how should we account for centre effects? AB - In multicentre trials, randomisation is often carried out using permuted blocks stratified by centre. It has previously been shown that stratification variables used in the randomisation process should be adjusted for in the analysis to obtain correct inference. For continuous outcomes, the two primary methods of accounting for centres are fixed-effects and random-effects models. We discuss the differences in interpretation between these two models and the implications that each pose for analysis. We then perform a large simulation study comparing the performance of these analysis methods in a variety of situations. In total, we assessed 378 scenarios. We found that random centre effects performed as well or better than fixed-effects models in all scenarios. Random centre effects models led to increases in power and precision when the number of patients per centre was small (e.g. 10 patients or less) and, in some scenarios, when there was an imbalance between treatments within centres, either due to the randomisation method or to the distribution of patients across centres. With small samples sizes, random-effects models maintained nominal coverage rates when a degree-of-freedom (DF) correction was used. We assessed the robustness of random-effects models when assumptions regarding the distribution of the centre effects were incorrect and found this had no impact on results. We conclude that random-effects models offer many advantages over fixed-effects models in certain situations and should be used more often in practice. PMID- 23112132 TI - Current concepts and novel targets in advanced pancreatic cancer. AB - Pancreatic cancer remains one of the most aggressive tumours with a 5-year survival rate of less than 5%. The dismal prognosis of this tumour entity that is associated with a high degree of drug resistance has not changed over the past decades. Since 1997, gemcitabine-based regimens have been the therapy of choice for advanced pancreatic cancer. Recently, however, new combination chemotherapy regimens achieved a significant survival benefit compared to gemcitabine-based therapies. In addition, novel approaches to improve drug delivery are currently being developed, and new drugs targeting signalling pathways both within the tumour cells and the tumour microenvironment are undergoing preclinical and clinical validation. Furthermore, efforts are being made to identify predictive markers for individualised treatment approaches based on molecular tumour characteristics. This review provides an overview on current and emerging concepts as well as novel targets for systemic treatment of advanced pancreatic cancer. Combination therapies incorporating drugs directed against these new targets may open new avenues for improving the efficacy of current treatment approaches and overcoming the devastating prognosis of pancreatic cancer patients. PMID- 23112131 TI - Considerations on selected reaction monitoring experiments: implications for the selectivity and accuracy of measurements. AB - Targeted MS analyses based on selected reaction monitoring (SRM) has enabled significant achievements in proteomic quantification, such that its application to clinical studies has augured great advancements for life sciences. The approach has been challenged by the complexity of clinical samples that affects the selectivity of measurements, in many cases limiting analytical performances to a larger extent than expected. This Personal Perspective discusses some insight to better comprehend the mismatch between the often underestimated sample complexity and the selectivity of SRM measurements performed on a triple quadrupole instrument. The implications for the design and evaluation of SRM assays are discussed and illustrated with selected examples, providing a baseline for a more critical use of the technique in the context of clinical samples and to evaluate alternative methods. PMID- 23112130 TI - Interfacing engineered nanoparticles with biological systems: anticipating adverse nano-bio interactions. AB - The innovative use of engineered nanomaterials in medicine, be it in therapy or diagnosis, is growing dramatically. This is motivated by the current extraordinary control over the synthesis of complex nanomaterials with a variety of biological functions (e.g. contrast agents, drug-delivery systems, transducers, amplifiers, etc.). Engineered nanomaterials are found in the bio context with a variety of applications in fields such as sensing, imaging, therapy or diagnosis. As the degree of control to fabricate customized novel and/or enhanced nanomaterials evolves, often new applications, devices with enhanced performance or unprecedented sensing limits can be achieved. Of course, interfacing any novel material with biological systems has to be critically analyzed as many undesirable adverse effects can be triggered (e.g. toxicity, allergy, genotoxicity, etc.) and/or the performance of the nanomaterial can be compromised due to the unexpected phenomena in physiological environments (e.g. corrosion, aggregation, unspecific absorption of biomolecules, etc.). Despite the need for standard protocols for assessing the toxicity and bio-performance of each new functional nanomaterial, these are still scarce or currently under development. Nonetheless, nanotoxicology and relating adverse effects to the physico-chemical properties of nanomaterials are emerging areas of the utmost importance which have to be continuously revisited as any new material emerges. This review highlights recent progress concerning the interaction of nanomaterials with biological systems and following adverse effects. PMID- 23112133 TI - Digestive cells from Mytilus galloprovincialis show a partial regulatory volume decrease following acute hypotonic stress through mechanisms involving inorganic ions. AB - The response of isolated digestive cells of the digestive gland of Mytilus galloprovincialis to hypotonic shock was studied using videometric methods. The isolated cells exposed to a rapid change (from 1100 to 800 mosmol kg(-1) ) of the bathing solution osmolality swelled but thereafter underwent a regulatory volume decrease (RVD), tending to recover the original size. When the hypotonic stress was applied in the presence of quinine and glibenclamide, known inhibitors of swelling activated ion channels, the cells did not exhibit an RVD response; in addition, they showed a larger increase in size in respect to control cells. These observations suggest that the digestive cells of the digestive gland have the machinery to cope with the hyposmotic shock allowing them to exhibit a small but significant RVD preventing an excessive increase in cell size. The pharmacological treatment of digestive cells during the RVD experiments suggests that cell volume is regulated by K(+) and Cl(-) efflux followed by an obliged water efflux from the cell. The involvement of organic osmolytes such as taurine and betaine seems to be excluded by NMR measurement on digestive cells. PMID- 23112129 TI - The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA. AB - Plasmacytoid dendritic cells (pDCs) produce a vast amount of interferon (IFN) alpha in response to nucleic acids from viruses and damaged self-cells through Toll-like receptor (TLR)7 and TLR9. Pharmaceutical agents that suppress IFN-alpha production by pDCs are instrumental in elucidating the mechanisms behind IFN alpha production, and in developing novel therapies for inflammatory disorders that involve pDCs. Here, we show that a tyrosine kinase inhibitor for chronic myeloid leukemia with multiple targets, dasatinib, strongly suppresses production of IFN-alpha and proinflammatory cytokines by human pDCs stimulated with multimeric CpG oligodeoxynucleotides (CpG-A) without reducing viability. In contrast, other tyrosine kinase inhibitors, imatinib, and nilotinib, did not suppress the cytokine production at clinically relevant concentrations. Inhibitors of SRC family kinases (SFKs), which are prominent targets of dasatinib, also suppressed the cytokine production. Notably, however, dasatinib, but not SFK inhibitors, abrogated prolonged localization of CpG-A in early endosomes, which is a critical step for pDCs to produce a large amount of IFN alpha. This study suggests that dasatinib suppresses IFN-alpha production by pDCs by inhibiting SFK-dependent pathways and SFK-independent endosomal retention of CpG DNA. Kinases controlling the distinctive endosomal trafficking in pDCs may be exploited as targets to develop novel therapies for pDC-related inflammatory disorders. PMID- 23112134 TI - Orientability of the minor director of homeotropically aligned smectic-a elastomers in external mechanical fields. AB - We present studies on bulk smectic-A copolymer networks with end-on attached homeotropically oriented mesogens that show spontaneous optical biaxiality at room temperature. Orthoscopic and conoscopic investigations under uniaxial extension in the layer planes give first evidence of the orientability of the minor director in mechanical fields yielding biaxial monodomains with 3-d orientational long-range order of all three principle axes. This is an important step towards the synthesis of permanently oriented biaxial monodomain elastomers for which highly interesting mechanical and optical properties are expected. PMID- 23112111 TI - Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. AB - PURPOSE: Diabetes is a suspected risk factor for pancreatic cancer, but questions remain about whether it is a risk factor or a result of the disease. This study prospectively examined the association between diabetes and the risk of pancreatic adenocarcinoma in pooled data from the NCI pancreatic cancer cohort consortium (PanScan). METHODS: The pooled data included 1,621 pancreatic adenocarcinoma cases and 1,719 matched controls from twelve cohorts using a nested case-control study design. Subjects who were diagnosed with diabetes near the time (<2 years) of pancreatic cancer diagnosis were excluded from all analyses. All analyses were adjusted for age, race, gender, study, alcohol use, smoking, BMI, and family history of pancreatic cancer. RESULTS: Self-reported diabetes was associated with a forty percent increased risk of pancreatic cancer (OR = 1.40, 95 % CI: 1.07, 1.84). The association differed by duration of diabetes; risk was highest for those with a duration of 2-8 years (OR = 1.79, 95 % CI: 1.25, 2.55); there was no association for those with 9+ years of diabetes (OR = 1.02, 95 % CI: 0.68, 1.52). CONCLUSIONS: These findings provide support for a relationship between diabetes and pancreatic cancer risk. The absence of association in those with the longest duration of diabetes may reflect hypoinsulinemia and warrants further investigation. PMID- 23112135 TI - Considerations on covariates and endpoints in multi-arm multi-stage clinical trials selecting all promising treatments. AB - In early stages of drug development, there is often uncertainty about the most promising among a set of different treatments. To ensure the best use of resources in such situations, it is important to decide which, if any, of the treatments should be taken forward for further testing. In later development, it has been shown that evaluating more than one dose increases the chance of success substantially. In this work, we discuss how multi-arm multi-stage trials can be designed such that all promising treatments are kept in the study at the interim analyses. We first investigate the impact of deviating from the planned design and show how confidence intervals can be constructed before we consider the impact of important covariates. We show that under orthogonality, the inclusion of covariates has no effect on familywise error rate control in the strong sense. We further show that the derived methodology can be used to investigate non normal endpoints. PMID- 23112136 TI - Electrochemical valorisation of glycerol. AB - The worldwide glycerol stocks are increasing; to make the biodiesel industry sustainable economically, this chemical could be used as a secondary primary raw material. Electric energy or hydrogen and added-value-chemical cogeneration becomes more and more an important research topic for increasing economical and industrial interests towards electrochemical technologies. Studies on glycerol electrooxidation for fuel or electrolysis cell applications are scarce. The valorisation of glycerol is generally performed by organic chemistry reactions forming, for example, esters, glycerol carbonates, ethers, acetals or ketals. Glycerol oxidation is made up of complex pathway reactions that can produce a large number of useful intermediates or valuable fine chemicals with presently limited market impact due to expensive production processes. Many of these chemical oxidation routes lead to significant amounts of undesired by-products, and enzymatic processes are limited. Converse to classical heterogeneous processes, electrocatalytic oxidation processes can be tuned by controlling the nature, composition and structure of the electrocatalyts as well as the electrode potential. Such control may lead to very high selectivity and activity, avoiding or limiting product separation steps. The coupling of glycerol oxidation to produce chemicals with the oxygen reduction reaction in a fuel cell or water reduction reaction in an electrolysis cell on Pt-free catalysts results either in coproduction of electrical energy or hydrogen for energy storage. PMID- 23112137 TI - Gold nanoparticles downregulate interleukin-1beta-induced pro-inflammatory responses. AB - Interleukin 1 beta (IL-1beta)-dependent inflammatory disorders, such as rheumatoid arthritis and psoriasis, pose a serious medical burden worldwide, where patients face a lifetime of illness and treatment. Organogold compounds have been used since the 1930s to treat rheumatic and other IL-1beta-dependent diseases and, though their mechanisms of action are still unclear, there is evidence that gold interferes with the transmission of inflammatory signalling. Here we show for the first time that citrate-stabilized gold nanoparticles, in a size dependent manner, specifically downregulate cellular responses induced by IL 1beta both in vitro and in vivo. Our results indicate that the anti-inflammatory activity of gold nanoparticles is associated with an extracellular interaction with IL-1beta, thus opening potentially novel options for further therapeutic applications. PMID- 23112138 TI - High-fat diet feeding induces sex-dependent changes in inflammatory and insulin sensitivity profiles of rat adipose tissue. AB - The aim of the study was to determine, in rats of both sexes, the effect of HF diet feeding on the expression of adipokines involved in inflammatory status and insulin sensitivity and on the levels of proteins involved in lipid handling of retroperitoneal adipose tissue. Eight-week-old Wistar rats of both sexes were fed a control diet (2.9% w/w fat) or an HF diet (30% w/w fat) for 14 weeks. Adiponectin, peroxisome proliferator-activated receptor gamma and inflammatory marker mRNA levels were analyzed by real-time polymerase chain reaction. Levels of insulin receptor, glucose transporter 4, carnitine palmitoyltransferase 1, fatty acid synthase, hormone-sensitive lipase and lipoprotein lipase were determined by Western blot. HF diet feeding did not induce hyperphagia or body weight gain but did promote an increase in adiposity although only in male rats. HF diet impaired glucose tolerance and the expression of inflammatory and insulin sensitivity markers in adipose tissue of male rats, but not in female rats. Male rats seem to be more prone to disorders associated with an unbalanced composition of the diet, even in the absence of hyperphagia. In contrast, female rats counteract excessive fat intake by improving their ability to use lipid fuels, which limits adiposity and maintains insulin sensitivity. PMID- 23112139 TI - The delirium experience: what is the effect on patients, relatives and staff and what can be done to modify this? AB - BACKGROUND: Delirium is a common clinical syndrome with significant associated mortality, morbidity and financial cost. Less is understood about the experience of delirium for the patient, their family and staff involved in their care. OBJECTIVE: This synthesis draws on qualitative and quantitative literature examining different populations (patients, relatives and staff) in different clinical settings (intensive care units, surgery and hospice care) to provide a clinical summary of the delirium experience from the perspective of patients, relatives and staff. DESIGN: A literature search was conducted in Ovid, MEDLINE, Embase, PsychINFO, British Nursing Index and Archive and PubMed between 1980 and 2011 using the terms 'delirium' combined with 'distress', 'recall', 'anxiety', 'depression', 'PTSD', 'experience' and 'patient education'. Articles were restricted to English language only. RESULTS: Evidence suggests that some patients recall delirium and that recollections are generally distressing. Distress may be greater in relatives witnessing delirium and is also reported in professional staff. This distress may result in longer-term psychological sequelae. Remedial action, such as explanatory information to patients and their families, may reduce distress and psychological morbidity. CONCLUSIONS: A better understanding of the experience and psychological consequences of delirium will inform the development of appropriate methods of providing support and information to those at risk of delirium and their families or carers. PMID- 23112140 TI - Multifunctional Au@mSiO2/rhodamine B isothiocyanate nanocomposites: cell imaging, photocontrolled drug release, and photothermal therapy for cancer cells. AB - The synthesis of Au@mesoporous SiO(2)/rhodamine B isothiocyanate (Au@mSiO(2)/RBITC) composite nanoparticles (NPs) is presented and their unique biofunctional properties are studied. The structure and morphology of the NPs are characterized by X-ray powder diffraction, transmission electron microscopy, and Fourier transform infrared spectroscopy. These NPs can not only be functionalized for fluorescence imaging, but also possess well-defined mesopore structures for drug loading and strong infrared surface plasmon absorption for light-controlled drug release and photothermal therapy for cancer cells. In the biological experiments, one 808 nm laser is coupled to a confocal laser scanning microscopy (CLSM) system to monitor the photothermal therapy, drug release, and cell position and viability in real time by using the multichannel function of CLSM for the first time. Such novel nanomaterials offer a new chemotherapeutic route for cancer treatment by combining cell imaging and hyperthermia in a synergistic way. PMID- 23112141 TI - Simple nickel-based catalyst systems combined with graphitic carbon nitride for stable photocatalytic hydrogen production in water. PMID- 23112142 TI - In-vitro permeability of neutral polystyrene particles via buccal mucosa. AB - Drugs can be absorbed well in the oral cavity, which eliminates problems related to intestinal and hepatic first-pass metabolism. Although it is well-established that nanoparticles are small enough to penetrate/permeate epithelial barriers, there is no clear understanding of how they interact with the buccal mucosa. This work provides useful information regarding particle properties with regard to mucosal uptake and can be used for the rational design of nanocarriers. In the buccal mucosa, the uptake of neutral polystyrene nanoparticles (PP) is size dependent. Compared to 25 and 50 nm particles, 200 nm PP particles penetrate into deeper regions of the mucosa. This is attributed to the structure of the buccal mucosa, i.e., mucus layer and microplicae. The particles permeate the mucus layer and deposit in ridge-like folds of superficial buccal cells. Thus, the effects of thermodynamic driving forces and/or interparticle electrostatic repulsion are enhanced and cellular uptake might be reduced for smaller particle sizes. PMID- 23112143 TI - Functionalized graphene for high performance lithium ion capacitors. AB - Lithium ion capacitors (LICs) have recently drawn considerable attention because they utilize the advantages of supercapacitors (high power) and lithium ion batteries (high energy). However, the energy densities of conventional LICs, which consist of a pair of graphite and activated carbon electrodes, are limited by the small capacities of the activated carbon cathodes. To overcome this limitation, we have engaged urea-reduced graphene oxide. The amide functional groups generated during the urea reduction facilitate the enolization processes for reversible Li binding, which improves the specific capacity by 37 % compared to those of conventional systems such as activated carbon and hydrazine-reduced graphene oxide. Utilizing the increased Li binding capability, when evaluated based on the mass of the active materials on both sides, the LICs based on urea reduced graphene oxide deliver a specific energy density of approximately 106 Wh kg(total) (-1) and a specific power density of approximately 4200 W kg(total) ( 1) with perfect capacity retention up to 1000 cycles. These values are far superior to those of previously reported LICs and supercapacitors, which suggests that appropriately treated graphene can be a promising electrode material for LICs. PMID- 23112144 TI - Reply: To PMID 22684891. PMID- 23112145 TI - Auditory abstraction from spectro-temporal features to coding auditory entities. AB - The auditory system extracts behaviorally relevant information from acoustic stimuli. The average activity in auditory cortex is known to be sensitive to spectro-temporal patterns in sounds. However, it is not known whether the auditory cortex also processes more abstract features of sounds, which may be more behaviorally relevant than spectro-temporal patterns. Using recordings from three stations of the auditory pathway, the inferior colliculus (IC), the ventral division of the medial geniculate body (MGB) of the thalamus, and the primary auditory cortex (A1) of the cat in response to natural sounds, we compared the amount of information that spikes contained about two aspects of the stimuli: spectro-temporal patterns, and abstract entities present in the same stimuli such as a bird chirp, its echoes, and the ambient noise. IC spikes conveyed on average approximately the same amount of information about spectro-temporal patterns as they conveyed about abstract auditory entities, but A1 and the MGB neurons conveyed on average three times more information about abstract auditory entities than about spectro-temporal patterns. Thus, the majority of neurons in auditory thalamus and cortex coded well the presence of abstract entities in the sounds without containing much information about their spectro-temporal structure, suggesting that they are sensitive to abstract features in these sounds. PMID- 23112146 TI - MicroRNA-223 is neuroprotective by targeting glutamate receptors. AB - Stroke is a major cause of mortality and morbidity worldwide. Extracellular glutamate accumulation leading to overstimulation of the ionotropic glutamate receptors mediates neuronal injury in stroke and in neurodegenerative disorders. Here we show that miR-223 controls the response to neuronal injury by regulating the functional expression of the glutamate receptor subunits GluR2 and NR2B in brain. Overexpression of miR-223 lowers the levels of GluR2 and NR2B by targeting 3'-UTR target sites (TSs) in GluR2 and NR2B, inhibits NMDA-induced calcium influx in hippocampal neurons, and protects the brain from neuronal cell death following transient global ischemia and excitotoxic injury. MiR-223 deficiency results in higher levels of NR2B and GluR2, enhanced NMDA-induced calcium influx, and increased miniature excitatory postsynaptic currents in hippocampal neurons. In addition, the absence of MiR-223 leads to contextual, but not cued memory deficits and increased neuronal cell death following transient global ischemia and excitotoxicity. These data identify miR-223 as a major regulator of the expression of GluR2 and NR2B, and suggest a therapeutic role for miR-223 in stroke and other excitotoxic neuronal disorders. PMID- 23112147 TI - Synthesis between demic and cultural diffusion in the Neolithic transition in Europe. AB - There is a long-standing controversy between two models of the Neolithic transition. The demic model assumes that the Neolithic range expansion was mainly due to the spread of populations, and the cultural model considers that it was essentially due to the spread of ideas. Here we integrate the demic and cultural models in a unified framework. We show that cultural diffusion explains ~40% of the spread rate of the Neolithic transition in Europe, as implied by archaeological data. Thus, cultural diffusion cannot be neglected, but demic diffusion was the most important mechanism in this major historical process at the continental scale. This quantitative approach can be useful also in regional analysis, the description of Neolithic transitions in other continents, and models of many human spread phenomena. PMID- 23112148 TI - Evidence for chemoreceptors with bimodular ligand-binding regions harboring two signal-binding sites. AB - Chemoreceptor-based signaling is a central mechanism in bacterial signal transduction. Receptors are classified according to the size of their ligand binding region. The well-studied cluster I proteins have a 100- to 150-residue ligand-binding region that contains a single site for chemoattractant recognition. Cluster II receptors, which contain a 220- to 300-residue ligand binding region and which are almost as abundant as cluster I receptors, remain largely uncharacterized. Here, we report high-resolution structures of the ligand binding region of the cluster II McpS chemotaxis receptor (McpS-LBR) of Pseudomonas putida KT2440 in complex with different chemoattractants. The structure of McpS-LBR represents a small-molecule binding domain composed of two modules, each able to bind different signal molecules. Malate and succinate were found to bind to the membrane-proximal module, whereas acetate binds to the membrane-distal module. A structural alignment of the two modules revealed that the ligand-binding sites could be superimposed and that amino acids involved in ligand recognition are conserved in both binding sites. Ligand binding to both modules was shown to trigger chemotactic responses. Further analysis showed that McpS-like receptors were found in different classes of proteobacteria, indicating that this mode of response to different carbon sources may be universally distributed. The physiological relevance of the McpS architecture may lie in its capacity to respond with high sensitivity to the preferred carbon sources malate and succinate and, at the same time, mediate lower sensitivity responses to the less preferred but very abundant carbon source acetate. PMID- 23112149 TI - Late Cretaceous restructuring of terrestrial communities facilitated the end Cretaceous mass extinction in North America. AB - The sudden environmental catastrophe in the wake of the end-Cretaceous asteroid impact had drastic effects that rippled through animal communities. To explore how these effects may have been exacerbated by prior ecological changes, we used a food-web model to simulate the effects of primary productivity disruptions, such as those predicted to result from an asteroid impact, on ten Campanian and seven Maastrichtian terrestrial localities in North America. Our analysis documents that a shift in trophic structure between Campanian and Maastrichtian communities in North America led Maastrichtian communities to experience more secondary extinction at lower levels of primary production shutdown and possess a lower collapse threshold than Campanian communities. Of particular note is the fact that changes in dinosaur richness had a negative impact on the robustness of Maastrichtian ecosystems against environmental perturbations. Therefore, earlier ecological restructuring may have exacerbated the impact and severity of the end Cretaceous extinction, at least in North America. PMID- 23112150 TI - Capturing native long-range contiguity by in situ library construction and optical sequencing. AB - The relatively short read lengths associated with the most cost-effective DNA sequencing technologies have limited their use in de novo genome assembly, structural variation detection, and haplotype-resolved genome sequencing. Consequently, there is a strong need for methods that capture various scales of contiguity information at a throughput commensurate with the current scale of massively parallel sequencing. We propose in situ library construction and optical sequencing on the flow cells of currently available massively parallel sequencing platforms as an efficient means of capturing both contiguity information and primary sequence with a single technology. In this proof-of concept study, we demonstrate basic feasibility by generating >30,000 Escherichia coli paired-end reads separated by 1, 2, or 3 kb using in situ library construction on standard Illumina flow cells. We also show that it is possible to stretch single molecules ranging from 3 to 8 kb on the surface of a flow cell before in situ library construction, thereby enabling the production of clusters whose physical relationship to one another on the flow cell is related to genomic distance. PMID- 23112151 TI - DNA damage and eIF4G1 in breast cancer cells reprogram translation for survival and DNA repair mRNAs. AB - The cellular response to DNA damage is mediated through multiple pathways that regulate and coordinate DNA repair, cell cycle arrest, and cell death. We show that the DNA damage response (DDR) induced by ionizing radiation (IR) is coordinated in breast cancer cells by selective mRNA translation mediated by high levels of translation initiation factor eIF4G1 (eukaryotic initiation factor 4gamma1). Increased expression of eIF4G1, common in breast cancers, was found to selectively increase translation of mRNAs involved in cell survival and the DDR, preventing autophagy and apoptosis [Survivin, hypoxia inducible factor 1alpha (HIF1alpha), X-linked inhibitor of apoptosis (XIAP)], promoting cell cycle arrest [growth arrest and DNA damage protein 45a (GADD45a), protein 53 (p53), ATR interacting protein (ATRIP), Check point kinase 1 (Chk1)] and DNA repair [p53 binding protein 1 (53BP1), breast cancer associated proteins 1, 2 (BRCA1/2), Poly ADP ribose polymerase (PARP), replication factor c2-5 (Rfc2-5), ataxia telangiectasia mutated gene 1 (ATM), meiotic recombination protein 11 (MRE-11), and others]. Reduced expression of eIF4G1, but not its homolog eIF4G2, greatly sensitizes cells to DNA damage by IR, induces cell death by both apoptosis and autophagy, and significantly delays resolution of DNA damage foci with little reduction of overall protein synthesis. Although some mRNAs selectively translated by higher levels of eIF4G1 were found to use internal ribosome entry site (IRES)-mediated alternate translation, most do not. The latter group shows significantly reduced dependence on eIF4E for translation, facilitated by an enhanced requirement for eIF4G1. Increased expression of eIF4G1 therefore promotes specialized translation of survival, growth arrest, and DDR mRNAs that are important in cell survival and DNA repair following genotoxic DNA damage. PMID- 23112152 TI - Metazoan opsin evolution reveals a simple route to animal vision. AB - All known visual pigments in Neuralia (Cnidaria, Ctenophora, and Bilateria) are composed of an opsin (a seven-transmembrane G protein-coupled receptor), and a light-sensitive chromophore, generally retinal. Accordingly, opsins play a key role in vision. There is no agreement on the relationships of the neuralian opsin subfamilies, and clarifying their phylogeny is key to elucidating the origin of this protein family and of vision. We used improved methods and data to resolve the opsin phylogeny and explain the evolution of animal vision. We found that the Placozoa have opsins, and that the opsins share a common ancestor with the melatonin receptors. Further to this, we found that all known neuralian opsins can be classified into the same three subfamilies into which the bilaterian opsins are classified: the ciliary (C), rhabdomeric (R), and go-coupled plus retinochrome, retinal G protein-coupled receptor (Go/RGR) opsins. Our results entail a simple scenario of opsin evolution. The first opsin originated from the duplication of the common ancestor of the melatonin and opsin genes in a eumetazoan (Placozoa plus Neuralia) ancestor, and an inference of its amino acid sequence suggests that this protein might not have been light-sensitive. Two more gene duplications in the ancestral neuralian lineage resulted in the origin of the R, C, and Go/RGR opsins. Accordingly, the first animal with at least a C, an R, and a Go/RGR opsin was a neuralian progenitor. PMID- 23112153 TI - Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability. AB - Large-conductance calcium-activated potassium channels (BK) are potent negative regulators of excitability in neurons and muscle, and increasing BK current is a novel therapeutic strategy for neuro- and cardioprotection, disorders of smooth muscle hyperactivity, and several psychiatric diseases. However, in some neurons, enhanced BK current is linked with seizures and paradoxical increases in excitability, potentially complicating the clinical use of agonists. The mechanisms that switch BK influence from inhibitory to excitatory are not well defined. Here we investigate this dichotomy using a gain-of-function subunit (BK(R207Q)) to enhance BK currents. Heterologous expression of BK(R207Q) generated currents that activated at physiologically relevant voltages in lower intracellular Ca(2+), activated faster, and deactivated slower than wild-type currents. We then used BK(R207Q) expression to broadly augment endogenous BK currents in vivo, generating a transgenic mouse from a circadian clock-controlled Period1 gene fragment (Tg-BK(R207Q)). The specific impact on excitability was assessed in neurons of the suprachiasmatic nucleus (SCN) in the hypothalamus, a cell type where BK currents regulate spontaneous firing under distinct day and night conditions that are defined by different complements of ionic currents. In the SCN, Tg-BK(R207Q) expression converted the endogenous BK current to fast activating, while maintaining similar current-voltage properties between day and night. Alteration of BK currents in Tg-BK(R207Q) SCN neurons increased firing at night but decreased firing during the day, demonstrating that BK currents generate bidirectional effects on neuronal firing under distinct conditions. PMID- 23112154 TI - Immunoglobulin-like transcript receptors on human dermal CD14+ dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming. AB - Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8(+) T cells compared with dermal CD14(+) dendritic cells (DCs). Here we show that dermal CD14(+) DCs instead prime a fraction of naive CD8(+) T cells into cells sharing the properties of type 2 cytokine-secreting CD8(+) T cells (TC2). Differential expression of the CD8-antagonist receptors on dermal CD14(+) DCs, the Ig-like transcript (ILT) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LCs inhibited cytotoxic T lymphocytes (CTLs) and enhanced TC2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14(+) DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and ILT4 receptors inhibited CTL priming by LCs. Thus, ILT receptor expression explains the polarization of CD8(+) T-cell responses by LCs vs. dermal CD14(+) DCs. PMID- 23112156 TI - Stochastic effects are important in intrahost HIV evolution even when viral loads are high. AB - Blood plasma viral loads and the time to progress to AIDS differ widely among untreated HIV-infected humans. Although people with certain HLA (HLA-I) alleles are more likely to control HIV infections without therapy, the majority of such untreated individuals exhibit high viral loads and progress to AIDS. Stochastic effects are considered unimportant for evolutionary dynamics in HIV-infected people when viral load is high or when selective forces strongly drive mutation. We describe a computational study of host-pathogen interaction demonstrating that stochastic effects can have a profound influence on disease dynamics, even in cases of high viral load and strong selective pressure. These stochastic effects are pronounced when the virus must traverse a fitness "barrier" in sequence space to escape the host's cytotoxic T-lymphocyte (CTL) response, as often occurs when a fitness defect imposed by a CTL-driven mutation must be compensated for by other mutations. These "barrier-crossing" events are infrequent and stochastic, resulting in divergent disease outcomes in genetically identical individuals infected by the same viral strain. Our results reveal how genetic determinants of the CTL response control the probability with which an individual is able to control HIV infection indefinitely, and thus provide clues for vaccine design. PMID- 23112155 TI - CDX2 is an amplified lineage-survival oncogene in colorectal cancer. AB - The mutational activation of oncogenes drives cancer development and progression. Classic oncogenes, such as MYC and RAS, are active across many different cancer types. In contrast, "lineage-survival" oncogenes represent a distinct and emerging class typically comprising transcriptional regulators of a specific cell lineage that, when deregulated, support the proliferation and survival of cancers derived from that lineage. Here, in a large collection of colorectal cancer cell lines and tumors, we identify recurrent amplification of chromosome 13, an alteration highly restricted to colorectal-derived cancers. A minimal region of amplification on 13q12.2 pinpoints caudal type homeobox transcription factor 2 (CDX2), a regulator of normal intestinal lineage development and differentiation, as a target of the amplification. In contrast to its described role as a colorectal tumor suppressor, CDX2 when amplified is required for the proliferation and survival of colorectal cancer cells. Further, transcriptional profiling, binding-site analysis, and functional studies link CDX2 to Wnt/beta catenin signaling, itself a key oncogenic pathway in colorectal cancer. These data characterize CDX2 as a lineage-survival oncogene deregulated in colorectal cancer. Our findings challenge a prevailing view that CDX2 is a tumor suppressor in colorectal cancer and uncover an additional piece in the multistep model of colorectal tumorigenesis. PMID- 23112158 TI - Separation of supercritical slab-fluids to form aqueous fluid and melt components in subduction zone magmatism. AB - Subduction-zone magmatism is triggered by the addition of H(2)O-rich slab-derived components: aqueous fluid, hydrous partial melts, or supercritical fluids from the subducting slab. Geochemical analyses of island arc basalts suggest two slab derived signatures of a melt and a fluid. These two liquids unite to a supercritical fluid under pressure and temperature conditions beyond a critical endpoint. We ascertain critical endpoints between aqueous fluids and sediment or high-Mg andesite (HMA) melts located, respectively, at 83-km and 92-km depths by using an in situ observation technique. These depths are within the mantle wedge underlying volcanic fronts, which are formed 90 to 200 km above subducting slabs. These data suggest that sediment-derived supercritical fluids, which are fed to the mantle wedge from the subducting slab, react with mantle peridotite to form HMA supercritical fluids. Such HMA supercritical fluids separate into aqueous fluids and HMA melts at 92 km depth during ascent. The aqueous fluids are fluxed into the asthenospheric mantle to form arc basalts, which are locally associated with HMAs in hot subduction zones. The separated HMA melts retain their composition in limited equilibrium with the surrounding mantle. Alternatively, they equilibrate with the surrounding mantle and change the major element chemistry to basaltic composition. However, trace element signatures of sediment derived supercritical fluids remain more in the melt-derived magma than in the fluid-induced magma, which inherits only fluid-mobile elements from the sediment derived supercritical fluids. Separation of slab-derived supercritical fluids into melts and aqueous fluids can elucidate the two slab-derived components observed in subduction zone magma chemistry. PMID- 23112159 TI - Astronomically calibrated 40Ar/39Ar age for the Toba supereruption and global synchronization of late Quaternary records. AB - The Toba supereruption in Sumatra, ~74 thousand years (ka) ago, was the largest terrestrial volcanic event of the Quaternary. Ash and sulfate aerosols were deposited in both hemispheres, forming a time-marker horizon that can be used to synchronize late Quaternary records globally. A precise numerical age for this event has proved elusive, with dating uncertainties larger than the millennial scale climate cycles that characterized this period. We report an astronomically calibrated (40)Ar/(39)Ar age of 73.88 +/- 0.32 ka (1sigma, full external errors) for sanidine crystals extracted from Toba deposits in the Lenggong Valley, Malaysia, 350 km from the eruption source and 6 km from an archaeological site with stone artifacts buried by ash. If these artifacts were made by Homo sapiens, as has been suggested, then our age indicates that modern humans had reached Southeast Asia by ~74 ka ago. Our (40)Ar/(39)Ar age is an order-of-magnitude more precise than previous estimates, resolving the timing of the eruption to the middle of the cold interval between Dansgaard-Oeschger events 20 and 19, when a peak in sulfate concentration occurred as registered by Greenland ice cores. This peak is followed by a ~10 degrees C drop in the Greenland surface temperature over ~150 y, revealing the possible climatic impact of the eruption. Our (40)Ar/(39)Ar age also provides a high-precision calibration point for other ice, marine, and terrestrial archives containing Toba sulfates and ash, facilitating their global synchronization at unprecedented resolution for a critical period in Earth and human history beyond the range of (14)C dating. PMID- 23112157 TI - Self-monitoring of social facial expressions in the primate amygdala and cingulate cortex. AB - Keeping track of self-executed facial expressions is essential for the ability to correctly interpret and reciprocate social expressions. However, little is known about neural mechanisms that participate in self-monitoring of facial expression. We designed a natural paradigm for social interactions where a monkey is seated in front of a peer monkey that is concealed by an opaque liquid crystal display shutter positioned between them. Opening the shutter for short durations allowed the monkeys to see each other and encouraged facial communication. To explore neural mechanisms that participate in self-monitoring of facial expression, we simultaneously recorded the elicited natural facial interactions and the neural activity of single neurons in the amygdala and the dorsal anterior cingulate cortex (dACC), two regions that are implicated with decoding of others' gestures. Neural activity in both regions was temporally locked to distinctive facial gestures and close inspection of time lags revealed activity that either preceded (production) or lagged (monitor) initiation of facial expressions. This result indicates that single neurons in the dACC and the amygdala hold information about self-executed facial expressions and demonstrates an intimate overlap between the neural networks that participate in decoding and production of socially informative facial information. PMID- 23112160 TI - Ion desolvation as a mechanism for kinetic isotope fractionation in aqueous systems. AB - Molecular dynamics simulations show that the desolvation rates of isotopes of Li(+), K(+), Rb(+), Ca(2+), Sr(2+), and Ba(2+) may have a relatively strong dependence on the metal cation mass. This inference is based on the observation that the exchange rate constant, k(wex), for water molecules in the first hydration shell follows an inverse power-law mass dependence (k(wex) ? m( gamma)), where the coefficient gamma is 0.05 +/- 0.01 on average for all cations studied. Simulated water-exchange rates increase with temperature and decrease with increasing isotopic mass for each element. The magnitude of the water exchange rate is different for simulations run using different water models [i.e., extended simple point charge (SPC/E) vs. four-site transferrable intermolecular potential (TIP4P)]; however, the value of the mass exponent gamma is the same. Reaction rate theory calculations predict mass exponents consistent with those determined via molecular dynamics simulations. The simulation-derived mass dependences imply that solids precipitating from aqueous solution under kinetically controlled conditions should be enriched in the light isotopes of the metal cations relative to the solutions, consistent with measured isotopic signatures in natural materials and laboratory experiments. Desolvation effects are large enough that they may be a primary determinant of the observed isotopic fractionation during precipitation. PMID- 23112161 TI - Ideal, catch, and slip bonds in cadherin adhesion. AB - Classical cadherin cell-cell adhesion proteins play key morphogenetic roles during development and are essential for maintaining tissue integrity in multicellular organisms. Classical cadherins bind in two distinct conformations, X-dimer and strand-swap dimer; during cellular rearrangements, these adhesive states are exposed to mechanical stress. However, the molecular mechanisms by which cadherins resist tensile force and the pathway by which they convert between different conformations are unclear. Here, we use single molecule force measurements with an atomic force microscope (AFM) to show that E-cadherin, a prototypical classical cadherin, forms three types of adhesive bonds: catch bonds, which become longer lived in the presence of tensile force; slip bonds, which become shorter lived when pulled; and ideal bonds that are insensitive to mechanical stress. We show that X-dimers form catch bonds, whereas strand-swap dimers form slip bonds. Our data suggests that ideal bonds are formed as X-dimers convert to strand-swap binding. Catch, slip, and ideal bonds allow cadherins to withstand tensile force and tune the mechanical properties of adhesive junctions. PMID- 23112162 TI - CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. AB - Intestinal metaplasia of the stomach, a mucosal change characterized by the conversion of gastric epithelium into an intestinal phenotype, is a precancerous lesion from which intestinal-type gastric adenocarcinoma arises. Chronic infection with Helicobacter pylori is a major cause of gastric intestinal metaplasia, and aberrant induction by H. pylori of the intestine-specific caudal related homeobox (CDX) transcription factors, CDX1 and CDX2, plays a key role in this metaplastic change. As such, a critical issue arises as to how these factors govern the cell- and tissue-type switching. In this study, we explored genes directly activated by CDX1 in gastric epithelial cells and identified stemness associated reprogramming factors SALL4 and KLF5. Indeed, SALL4 and KLF5 were aberrantly expressed in the CDX1(+) intestinal metaplasia of the stomach in both humans and mice. In cultured gastric epithelial cells, sustained expression of CDX1 gave rise to the induction of early intestinal-stemness markers, followed by the expression of intestinal-differentiation markers. Furthermore, the induction of these markers was suppressed by inhibiting either SALL4 or KLF5 expression, indicating that CDX1-induced SALL4 and KLF5 converted gastric epithelial cells into tissue stem-like progenitor cells, which then transdifferentiated into intestinal epithelial cells. Our study places the stemness-related reprogramming factors as critical components of CDX1-directed transcriptional circuitries that promote intestinal metaplasia. Requirement of a transit through dedifferentiated stem/progenitor-like cells, which share properties in common with cancer stem cells, may underlie predisposition of intestinal metaplasia to neoplastic transformation. PMID- 23112163 TI - Pharyngeal mesoderm regulatory network controls cardiac and head muscle morphogenesis. AB - The search for developmental mechanisms driving vertebrate organogenesis has paved the way toward a deeper understanding of birth defects. During embryogenesis, parts of the heart and craniofacial muscles arise from pharyngeal mesoderm (PM) progenitors. Here, we reveal a hierarchical regulatory network of a set of transcription factors expressed in the PM that initiates heart and craniofacial organogenesis. Genetic perturbation of this network in mice resulted in heart and craniofacial muscle defects, revealing robust cross-regulation between its members. We identified Lhx2 as a previously undescribed player during cardiac and pharyngeal muscle development. Lhx2 and Tcf21 genetically interact with Tbx1, the major determinant in the etiology of DiGeorge/velo-cardio facial/22q11.2 deletion syndrome. Furthermore, knockout of these genes in the mouse recapitulates specific cardiac features of this syndrome. We suggest that PM-derived cardiogenesis and myogenesis are network properties rather than properties specific to individual PM members. These findings shed new light on the developmental underpinnings of congenital defects. PMID- 23112164 TI - NMR structure of a lytic polysaccharide monooxygenase provides insight into copper binding, protein dynamics, and substrate interactions. AB - Lytic polysaccharide monooxygenases currently classified as carbohydrate binding module family 33 (CBM33) and glycoside hydrolase family 61 (GH61) are likely to play important roles in future biorefining. However, the molecular basis of their unprecedented catalytic activity remains largely unknown. We have used NMR techniques and isothermal titration calorimetry to address structural and functional aspects of CBP21, a chitin-active CBM33. NMR structural and relaxation studies showed that CBP21 is a compact and rigid molecule, and the only exception is the catalytic metal binding site. NMR data further showed that His28 and His114 in the catalytic center bind a variety of divalent metal ions with a clear preference for Cu(2+) (K(d) = 55 nM; from isothermal titration calorimetry) and higher preference for Cu(1+) (K(d) ~ 1 nM; from the experimentally determined redox potential for CBP21-Cu(2+) of 275 mV using a thermodynamic cycle). Strong binding of Cu(1+) was also reflected in a reduction in the pK(a) values of the histidines by 3.6 and 2.2 pH units, respectively. Cyanide, a mimic of molecular oxygen, was found to bind to the metal ion only. These data support a model where copper is reduced on the enzyme by an externally provided electron and followed by oxygen binding and activation by internal electron transfer. Interactions of CBP21 with a crystalline substrate were mapped in a (2)H/(1)H exchange experiment, which showed that substrate binding involves an extended planar binding surface, including the metal binding site. Such a planar catalytic surface seems well-suited to interact with crystalline substrates. PMID- 23112165 TI - Structural asymmetry in the magnesium channel CorA points to sequential allosteric regulation. AB - Magnesium ions (Mg(2+)) are essential for life, but the mechanisms regulating their transport into and out of cells remain poorly understood. The CorA-Mrs2 Alr1 superfamily of Mg(2+) channels represents the most prevalent group of proteins enabling Mg(2+) ions to cross membranes. Thermotoga maritima CorA (TmCorA) is the only member of this protein family whose complete 3D fold is known. Here, we report the crystal structure of a mutant in the presence and absence of divalent ions and compare it with previous divalent ion-bound TmCorA structures. With Mg(2+) present, this structure shows binding of a hydrated Mg(2+) ion to the periplasmic Gly-Met-Asn (GMN) motif, revealing clues of ion selectivity in this unique channel family. In the absence of Mg(2+), TmCorA displays an unexpected asymmetric conformation caused by radial and lateral tilts of protomers that leads to bending of the central, pore-lining helix. Molecular dynamics simulations support these movements, including a bell-like deflection. Mass spectrometric analysis confirms that major proteolytic cleavage occurs within a region that is selectively exposed by such a bell-like bending motion. Our results point to a sequential allosteric model of regulation, where intracellular Mg(2+) binding locks TmCorA in a symmetric, transport-incompetent conformation and loss of intracellular Mg(2+) causes an asymmetric, potentially influx-competent conformation of the channel. PMID- 23112167 TI - Bronsted basicity of the air-water interface. AB - Differences in the extent of protonation of functional groups lying on either side of water-hydrophobe interfaces are deemed essential to enzymatic catalysis, molecular recognition, bioenergetic transduction, and atmospheric aerosol-gas exchanges. The sign and range of such differences, however, remain conjectural. Herein we report experiments showing that gaseous carboxylic acids RCOOH(g) begin to deprotonate on the surface of water significantly more acidic than that supporting the dissociation of dissolved acids RCOOH(aq). Thermodynamic analysis indicates that > 6 H(2)O molecules must participate in the deprotonation of RCOOH(g) on water, but quantum mechanical calculations on a model air-water interface predict that such event is hindered by a significant kinetic barrier unless OH(-) ions are present therein. Thus, by detecting RCOO(-) we demonstrate the presence of OH(-) on the aerial side of on pH > 2 water exposed to RCOOH(g). Furthermore, because in similar experiments the base (Me)(3)N(g) is protonated only on pH < 4 water, we infer that the outer surface of water is Bronsted neutral at pH ~3 (rather than at pH 7 as bulk water), a value that matches the isoelectric point of bubbles and oil droplets in independent electrophoretic experiments. The OH(-) densities sensed by RCOOH(g) on the aerial surface of water, however, are considerably smaller than those at the (>1 nm) deeper shear planes probed in electrophoresis, thereby implying the existence of OH(-) gradients in the interfacial region. This fact could account for the weak OH(-) signals detected by surface-specific spectroscopies. PMID- 23112166 TI - Interactions of subunit CCT3 in the yeast chaperonin CCT/TRiC with Q/N-rich proteins revealed by high-throughput microscopy analysis. AB - The eukaryotic chaperonin containing t-complex polypeptide 1 (CCT/TRiC) is an ATP fueled machine that assists protein folding. It consists of two back-to-back stacked rings formed by eight different subunits that are arranged in a fixed permutation. The different subunits of CCT are believed to possess unique substrate binding specificities that are still mostly unknown. Here, we used high throughput microscopy analysis of yeast cells to determine changes in protein levels and localization as a result of a Glu to Asp mutation in the ATP binding site of subunits 3 (CCT3) or 6 (CCT6). The mutation in subunit CCT3 was found to induce cytoplasmic foci termed P-bodies where mRNAs, which are not translated, accumulate and can be degraded. Analysis of the changes in protein levels and structural modeling indicate that P-body formation in cells with the mutation in CCT3 is linked to the specific interaction of this subunit with Gln/Asn-rich segments that are enriched in many P-body proteins. An in vitro gel-shift analysis was used to show that the mutation in subunit CCT3 interferes with the ability of CCT to bind a Gln/Asn-rich protein aggregate. More generally, the strategy used in this work can be used to unravel the substrate specificities of other chaperone systems. PMID- 23112168 TI - General anesthesia selectively disrupts astrocyte calcium signaling in the awake mouse cortex. AB - Calcium signaling represents the principle pathway by which astrocytes respond to neuronal activity. General anesthetics are routinely used in clinical practice to induce a sleep-like state, allowing otherwise painful procedures to be performed. Anesthetic drugs are thought to mainly target neurons in the brain and act by suppressing synaptic activity. However, the direct effect of general anesthesia on astrocyte signaling in awake animals has not previously been addressed. This is a critical issue, because calcium signaling may represent an essential mechanism through which astrocytes can modulate synaptic activity. In our study, we performed calcium imaging in awake head-restrained mice and found that three commonly used anesthetic combinations (ketamine/xylazine, isoflurane, and urethane) markedly suppressed calcium transients in neocortical astrocytes. Additionally, all three anesthetics masked potentially important features of the astrocyte calcium signals, such as synchronized widespread transients that appeared to be associated with arousal in awake animals. Notably, anesthesia affected calcium transients in both processes and soma and depressed spontaneous signals, as well as calcium responses, evoked by whisker stimulation or agonist application. We show that these calcium transients are inositol 1,4,5 triphosphate type 2 receptor (IP(3)R2)-dependent but resistant to a local blockade of glutamatergic or purinergic signaling. Finally, we found that doses of anesthesia insufficient to affect neuronal responses to whisker stimulation selectively suppressed astrocyte calcium signals. Taken together, these data suggest that general anesthesia may suppress astrocyte calcium signals independently of neuronal activity. We propose that these glial effects may constitute a nonneuronal mechanism for sedative action of anesthetic drugs. PMID- 23112169 TI - Alkyltransferase-like protein (Atl1) distinguishes alkylated guanines for DNA repair using cation-pi interactions. AB - Alkyltransferase-like (ATL) proteins in Schizosaccharomyces pombe (Atl1) and Thermus thermophilus (TTHA1564) protect against the adverse effects of DNA alkylation damage by flagging O(6)-alkylguanine lesions for nucleotide excision repair (NER). We show that both ATL proteins bind with high affinity to oligodeoxyribonucleotides containing O(6)-alkylguanines differing in size, polarity, and charge of the alkyl group. However, Atl1 shows a greater ability than TTHA1564 to distinguish between O(6)-alkylguanine and guanine and in an unprecedented mechanism uses Arg69 to probe the electrostatic potential surface of O(6)-alkylguanine, as determined using molecular mechanics calculations. An unexpected consequence of this feature is the recognition of 2,6-diaminopurine and 2-aminopurine, as confirmed in crystal structures of respective Atl1-DNA complexes. O(6)-Alkylguanine and guanine discrimination is diminished for Atl1 R69A and R69F mutants, and S. pombe R69A and R69F mutants are more sensitive toward alkylating agent toxicity, revealing the key role of Arg69 in identifying O(6)-alkylguanines critical for NER recognition. PMID- 23112170 TI - Modification of ghrelin receptor signaling by somatostatin receptor-5 regulates insulin release. AB - Both ghrelin and somatostatin (SST) inhibit glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells, but how these independent actions are regulated has been unclear. The mechanism must accommodate noncanonical ghrelin receptor (GHS-R1a)-G-protein coupling to Galpha(i/o) instead of Galpha(q11) and dependence on energy balance. Here we present evidence for an equilibrium model of receptor heteromerization that fulfills these criteria. We show that GHS-R1a coupling to Galpha(i/o) rather than Galpha(q11) requires interactions between GHS R1a and SST receptor subtype 5 (SST5) and that in the absence of SST5 ghrelin enhances GSIS. At concentrations of GHS-R1a and SST5 expressed in islets, time resolved FRET and bioluminescence resonance energy transfer assays illustrate constitutive formation of GHS-R1a:SST5 heteromers in which ghrelin, but not SST, suppresses GSIS and cAMP accumulation. GHS-R1a-G-protein coupling and the formation of GHS-R1a:SST5 heteromers is dependent on the ratio of ghrelin to SST. A high ratio enhances heteromer formation and Galpha(i/o) coupling, whereas a low ratio destabilizes heteromer conformation, restoring GHS-R1a-Galpha(q11) coupling. The [ghrelin]/[SST] ratio is dependent on energy balance: Ghrelin levels peak during acute fasting, whereas postprandially ghrelin is at a nadir, and islet SST concentrations increase. Hence, under conditions of low energy balance our model predicts that endogenous ghrelin rather than SST establishes inhibitory tone on the beta-cell. Collectively, our data are consistent with physiologically relevant GHS-R1a:SST5 heteromerization that explains differential regulation of islet function by ghrelin and SST. These findings reinforce the concept that signaling by the G-protein receptor is dynamic and dependent on protomer interactions and physiological context. PMID- 23112171 TI - Plasmodium falciparum responds to amino acid starvation by entering into a hibernatory state. AB - The human malaria parasite Plasmodium falciparum is auxotrophic for most amino acids. Its amino acid needs are met largely through the degradation of host erythrocyte hemoglobin; however the parasite must acquire isoleucine exogenously, because this amino acid is not present in adult human hemoglobin. We report that when isoleucine is withdrawn from the culture medium of intraerythrocytic P. falciparum, the parasite slows its metabolism and progresses through its developmental cycle at a reduced rate. Isoleucine-starved parasites remain viable for 72 h and resume rapid growth upon resupplementation. Protein degradation during starvation is important for maintenance of this hibernatory state. Microarray analysis of starved parasites revealed a 60% decrease in the rate of progression through the normal transcriptional program but no other apparent stress response. Plasmodium parasites do not possess a TOR nutrient-sensing pathway and have only a rudimentary amino acid starvation-sensing eukaryotic initiation factor 2alpha (eIF2alpha) stress response. Isoleucine deprivation results in GCN2-mediated phosphorylation of eIF2alpha, but kinase-knockout clones still are able to hibernate and recover, indicating that this pathway does not directly promote survival during isoleucine starvation. We conclude that P. falciparum, in the absence of canonical eukaryotic nutrient stress-response pathways, can cope with an inconsistent bloodstream amino acid supply by hibernating and waiting for more nutrient to be provided. PMID- 23112172 TI - Microfluidics separation reveals the stem-cell-like deformability of tumor initiating cells. AB - Here we report a microfluidics method to enrich physically deformable cells by mechanical manipulation through artificial microbarriers. Driven by hydrodynamic forces, flexible cells or cells with high metastatic propensity change shape to pass through the microbarriers and exit the separation device, whereas stiff cells remain trapped. We demonstrate the separation of (i) a mixture of two breast cancer cell types (MDA-MB-436 and MCF-7) with distinct deformabilities and metastatic potentials, and (ii) a heterogeneous breast cancer cell line (SUM149), into enriched flexible and stiff subpopulations. We show that the flexible phenotype is associated with overexpression of multiple genes involved in cancer cell motility and metastasis, and greater mammosphere formation efficiency. Our observations support the relationship between tumor-initiating capacity and cell deformability, and demonstrate that tumor-initiating cells are less differentiated in terms of cell biomechanics. PMID- 23112174 TI - Indian Ocean warming modulates Pacific climate change. AB - It has been widely believed that the tropical Pacific trade winds weakened in the last century and would further decrease under a warmer climate in the 21st century. Recent high-quality observations, however, suggest that the tropical Pacific winds have actually strengthened in the past two decades. Precise causes of the recent Pacific climate shift are uncertain. Here we explore how the enhanced tropical Indian Ocean warming in recent decades favors stronger trade winds in the western Pacific via the atmosphere and hence is likely to have contributed to the La Nina-like state (with enhanced east-west Walker circulation) through the Pacific ocean-atmosphere interactions. Further analysis, based on 163 climate model simulations with centennial historical and projected external radiative forcing, suggests that the Indian Ocean warming relative to the Pacific's could play an important role in modulating the Pacific climate changes in the 20th and 21st centuries. PMID- 23112173 TI - Vitamin D receptor as a master regulator of the c-MYC/MXD1 network. AB - Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell- and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator beta-catenin. c-MYC levels were widely elevated in vdr(-/-) mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c MYC function, providing a molecular basis for cancer preventive actions of vitamin D. PMID- 23112175 TI - Reduced sensitivity to emotional prosody in congenital amusia rekindles the musical protolanguage hypothesis. AB - A number of evolutionary theories assume that music and language have a common origin as an emotional protolanguage that remains evident in overlapping functions and shared neural circuitry. The most basic prediction of this hypothesis is that sensitivity to emotion in speech prosody derives from the capacity to process music. We examined sensitivity to emotion in speech prosody in a sample of individuals with congenital amusia, a neurodevelopmental disorder characterized by deficits in processing acoustic and structural attributes of music. Twelve individuals with congenital amusia and 12 matched control participants judged the emotional expressions of 96 spoken phrases. Phrases were semantically neutral but prosodic cues (tone of voice) communicated each of six emotional states: happy, tender, afraid, irritated, sad, and no emotion. Congenitally amusic individuals were significantly worse than matched controls at decoding emotional prosody, with decoding rates for some emotions up to 20% lower than that of matched controls. They also reported difficulty understanding emotional prosody in their daily lives, suggesting some awareness of this deficit. The findings support speculations that music and language share mechanisms that trigger emotional responses to acoustic attributes, as predicted by theories that propose a common evolutionary link between these domains. PMID- 23112176 TI - Structural mechanism of RuBisCO activation by carbamylation of the active site lysine. AB - Ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is a crucial enzyme in carbon fixation and the most abundant protein on earth. It has been studied extensively by biochemical and structural methods; however, the most essential activation step has not yet been described. Here, we describe the mechanistic details of Lys carbamylation that leads to RuBisCO activation by atmospheric CO(2). We report two crystal structures of nitrosylated RuBisCO from the red algae Galdieria sulphuraria with O(2) and CO(2) bound at the active site. G. sulphuraria RuBisCO is inhibited by cysteine nitrosylation that results in trapping of these gaseous ligands. The structure with CO(2) defines an elusive, preactivation complex that contains a metal cation Mg(2+) surrounded by three H(2)O/OH molecules. Both structures suggest the mechanism for discriminating gaseous ligands by their quadrupole electric moments. We describe conformational changes that allow for intermittent binding of the metal ion required for activation. On the basis of these structures we propose the individual steps of the activation mechanism. Knowledge of all these elements is indispensable for engineering RuBisCO into a more efficient enzyme for crop enhancement or as a remedy to global warming. PMID- 23112177 TI - Rubisco small-subunit alpha-helices control pyrenoid formation in Chlamydomonas. AB - The pyrenoid is a subcellular microcompartment in which algae sequester the primary carboxylase, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). The pyrenoid is associated with a CO(2)-concentrating mechanism (CCM), which improves the operating efficiency of carbon assimilation and overcomes diffusive limitations in aquatic photosynthesis. Using the model alga Chlamydomonas reinhardtii, we show that pyrenoid formation, Rubisco aggregation, and CCM activity relate to discrete regions of the Rubisco small subunit (SSU). Specifically, pyrenoid occurrence was shown to be conditioned by the amino acid composition of two surface-exposed alpha-helices of the SSU: higher plant-like helices knock out the pyrenoid, whereas native algal helices establish a pyrenoid. We have also established that pyrenoid integrity was essential for the operation of an active CCM. With the algal CCM being functionally analogous to the terrestrial C(4) pathway in higher plants, such insights may offer a route toward transforming algal and higher plant productivity for the future. PMID- 23112178 TI - Transcriptome-wide analyses of CstF64-RNA interactions in global regulation of mRNA alternative polyadenylation. AB - Cleavage stimulation factor 64 kDa (CstF64) is an essential pre-mRNA 3' processing factor and an important regulator of alternative polyadenylation (APA). Here we characterized CstF64-RNA interactions in vivo at the transcriptome level and investigated the role of CstF64 in global APA regulation through individual nucleotide resolution UV crosslinking and immunoprecipitation sequencing and direct RNA sequencing analyses. We observed highly specific CstF64 RNA interactions at poly(A) sites (PASs), and we provide evidence that such interactions are widely variable in affinity and may be differentially required for PAS recognition. Depletion of CstF64 by RNAi has a relatively small effect on the global APA profile, but codepletion of the CstF64 paralog CstF64tau leads to greater APA changes, most of which are characterized by the increased relative use of distal PASs. Finally, we found that CstF64 binds to thousands of dormant intronic PASs that are suppressed, at least in part, by U1 small nuclear ribonucleoproteins. Taken together, our findings provide insight into the mechanisms of PAS recognition and identify CstF64 as an important global regulator of APA. PMID- 23112179 TI - Anatomical evidence for the involvement of medial cerebellar output from the interpositus nuclei in cognitive functions. AB - Although the cerebellar interpositus nuclei are known to be involved in cognitive functions, such as associative motor learning, no anatomical evidence has been available for this issue. Here we used retrograde transneuronal transport of rabies virus to identify neurons in the cerebellar nuclei that project via the thalamus to area 46 of the prefrontal cortex of macaques in comparison with the projections to the primary motor cortex (M1). After rabies injections into area 46, many neurons in the restricted region of the posterior interpositus nucleus (PIN) were labeled disynaptically via the thalamus, whereas no neuron labeling was found in the anterior interpositus nucleus (AIN). The distribution of the labeled neurons was dorsoventrally different from that of PIN neurons labeled from the M1. This defines an anatomical substrate for the contribution of medial cerebellar output to cognitive functions. Like the dentate nucleus, the PIN has dual motor and cognitive channels, whereas the AIN has a motor channel only. PMID- 23112180 TI - Bottom-up construction of in vitro switchable memories. AB - Reaction networks displaying bistability provide a chemical mechanism for long term memory storage in cells, as exemplified by many epigenetic switches. These biological systems are not only bistable but switchable, in the sense that they can be flipped from one state to the other by application of specific molecular stimuli. We have reproduced such functions through the rational assembly of dynamic reaction networks based on basic DNA biochemistry. Rather than rewiring genetic systems as synthetic biology does in vivo, our strategy consists of building simplified dynamic analogs in vitro, in an artificial, well-controlled milieu. We report successively a bistable system, a two-input switchable memory element, and a single-input push-push memory circuit. These results suggest that it is possible to build complex time-responsive molecular circuits by following a modular approach to the design of dynamic in vitro behaviors. Our approach thus provides an unmatched opportunity to study topology/function relationships within dynamic reaction networks. PMID- 23112181 TI - Functional remodeling of RNA processing in replacement chloroplasts by pathways retained from their predecessors. AB - Chloroplasts originate through the endosymbiotic integration of a host and a photosynthetic symbiont, with processes established within the host for the biogenesis and maintenance of the nascent chloroplast. It is thought that several photosynthetic eukaryotes have replaced their original chloroplasts with others derived from different source organisms in a process termed "serial endosymbiosis of chloroplasts." However, it is not known whether replacement chloroplasts are affected by the biogenesis and maintenance pathways established to support their predecessors. Here, we investigate whether pathways established during a previous chloroplast symbiosis function in the replacement chloroplasts of the dinoflagellate alga Karenia mikimotoi. We show that chloroplast transcripts in K. mikimotoi are subject to 3' polyuridylylation and extensive sequence editing. We confirm that these processes do not occur in free-living relatives of the replacement chloroplast lineage, but are otherwise found only in the ancestral, red algal-derived chloroplasts of dinoflagellates and their closest relatives. This indicates that these unusual RNA-processing pathways have been retained from the original symbiont lineage and made use of by the replacement chloroplast. Our results constitute an addition to current theories of chloroplast evolution in which chloroplast biogenesis may be radically remodeled by pathways remaining from previous symbioses. PMID- 23112182 TI - Prediction of economic choice by primate amygdala neurons. AB - The amygdala is a key structure of the brain's reward system. Existing theories view its role in decision-making as restricted to an early valuation stage that provides input to decision mechanisms in downstream brain structures. However, the extent to which the amygdala itself codes information about economic choices is unclear. Here, we report that individual neurons in the primate amygdala predict behavioral choices in an economic decision task. We recorded the activity of amygdala neurons while monkeys chose between saving liquid reward with interest and spending the accumulated reward. In addition to known value-related responses, we found that activity in a group of amygdala neurons predicted the monkeys' upcoming save-spend choices with an average accuracy of 78%. This choice predictive activity occurred early in trials, even before information about specific actions associated with save-spend choices was available. For a substantial number of neurons, choice-differential activity was specific for free, internally generated economic choices and not observed in a control task involving forced imperative choices. A subgroup of choice-predictive neurons did not show relationships to value, movement direction, or visual stimulus features. Choice-predictive activity in some amygdala neurons was preceded by transient periods of value coding, suggesting value-to-choice transitions and resembling decision processes in other brain systems. These findings suggest that the amygdala might play an active role in economic decisions. Current views of amygdala function should be extended to incorporate a role in decision-making beyond valuation. PMID- 23112183 TI - Radiocarbon dates from the Grotte du Renne and Saint-Cesaire support a Neandertal origin for the Chatelperronian. AB - The transition from the Middle Paleolithic (MP) to Upper Paleolithic (UP) is marked by the replacement of late Neandertals by modern humans in Europe between 50,000 and 40,000 y ago. Chatelperronian (CP) artifact assemblages found in central France and northern Spain date to this time period. So far, it is the only such assemblage type that has yielded Neandertal remains directly associated with UP style artifacts. CP assemblages also include body ornaments, otherwise virtually unknown in the Neandertal world. However, it has been argued that instead of the CP being manufactured by Neandertals, site formation processes and layer admixture resulted in the chance association of Neanderthal remains, CP assemblages, and body ornaments. Here, we report a series of accelerator mass spectrometry radiocarbon dates on ultrafiltered bone collagen extracted from 40 well-preserved bone fragments from the late Mousterian, CP, and Protoaurignacian layers at the Grotte du Renne site (at Arcy-sur-Cure, France). Our radiocarbon results are inconsistent with the admixture hypothesis. Further, we report a direct date on the Neandertal CP skeleton from Saint-Cesaire (France). This date corroborates the assignment of CP assemblages to the latest Neandertals of western Europe. Importantly, our results establish that the production of body ornaments in the CP postdates the arrival of modern humans in neighboring regions of Europe. This new behavior could therefore have been the result of cultural diffusion from modern to Neandertal groups. PMID- 23112184 TI - MyD88-deficient Hydra reveal an ancient function of TLR signaling in sensing bacterial colonizers. AB - Toll-like receptor (TLR) signaling is one of the most important signaling cascades of the innate immune system of vertebrates. Studies in invertebrates have focused on the fruit fly Drosophila melanogaster and the nematode Caenorhabditis elegans, and there is little information regarding the evolutionary origin and ancestral function of TLR signaling. In Drosophila, members of the Toll-like receptor family are involved in both embryonic development and innate immunity. In C. elegans, a clear immune function of the TLR homolog TOL-1 is controversial and central components of vertebrate TLR signaling including the key adapter protein myeloid differentiation primary response gene 88 (MyD88) and the transcription factor NF-kappaB are not present. In basal metazoans such as the cnidarians Hydra magnipapillata and Nematostella vectensis, all components of the vertebrate TLR signaling cascade are present, but their role in immunity is unknown. Here, we use a MyD88 loss-of-function approach in Hydra to demonstrate that recognition of bacteria is an ancestral function of TLR signaling and that this process contributes to both host-mediated recolonization by commensal bacteria as well as to defense against bacterial pathogens. PMID- 23112185 TI - Biologically inspired LED lens from cuticular nanostructures of firefly lantern. AB - Cuticular nanostructures found in insects effectively manage light for light polarization, structural color, or optical index matching within an ultrathin natural scale. These nanostructures are mainly dedicated to manage incoming light and recently inspired many imaging and display applications. A bioluminescent organ, such as a firefly lantern, helps to out-couple light from the body in a highly efficient fashion for delivering strong optical signals in sexual communication. However, the cuticular nanostructures, except the light-producing reactions, have not been well investigated for physical principles and engineering biomimetics. Here we report a unique observation of high-transmission nanostructures on a firefly lantern and its biological inspiration for highly efficient LED illumination. Both numerical and experimental results clearly reveal high transmission through the nanostructures inspired from the lantern cuticle. The nanostructures on an LED lens surface were fabricated by using a large-area nanotemplating and reconfigurable nanomolding with heat-induced shear thinning. The biologically inspired LED lens, distinct from a smooth surface lens, substantially increases light transmission over visible ranges, comparable to conventional antireflection coating. This biological inspiration can offer new opportunities for increasing the light extraction efficiency of high-power LED packages. PMID- 23112186 TI - Mutational robustness of 16S ribosomal RNA, shown by experimental horizontal gene transfer in Escherichia coli. AB - The bacterial ribosome consists of three rRNA molecules and 57 proteins and plays a crucial role in translating mRNA-encoded information into proteins. Because of the ribosome's structural and mechanistic complexity, it is believed that each ribosomal component coevolves to maintain its function. Unlike 5S rRNA, 16S and 23S rRNAs appear to lack mutational robustness, because they form the structural core of the ribosome. However, using Escherichia coli Delta7 (null mutant of operons) as a host, we have recently shown that an active hybrid ribosome whose 16S rRNA has been specifically substituted with that from non-E. coli bacteria can be reconstituted in vivo. To investigate the mutational robustness of 16S rRNA and the structural basis for its functionality, we used a metagenomic approach to screen for 16S rRNA genes that complement the growth of E. coli Delta7. Various functional genes were obtained from the Gammaproteobacteria and Betaproteobacteria lineages. Despite the large sequence diversity (80.9-99.0% identity with E. coli 16S rRNA) of the functional 16S rRNA molecules, the doubling times (DTs) of each mutant increased only modestly with decreasing sequence identity (average increase in DT, 4.6 s per mutation). The three dimensional structure of the 30S ribosome showed that at least 40.7% (628/1,542) of the nucleotides were variable, even at ribosomal protein-binding sites, provided that the secondary structures were properly conserved. Our results clearly demonstrate that 16S rRNA functionality largely depends on the secondary structure but not on the sequence itself. PMID- 23112187 TI - Neutrophils orchestrate their own recruitment in murine arthritis through C5aR and FcgammaR signaling. AB - Neutrophil recruitment into the joint is a hallmark of inflammatory arthritides, including rheumatoid arthritis (RA). In a mouse model of autoantibody-induced inflammatory arthritis, neutrophils infiltrate the joint via multiple chemoattractant receptors, including the leukotriene B(4) (LTB(4)) receptor BLT1 and the chemokine receptors CCR1 and CXCR2. Once in the joint, neutrophils perpetuate their own recruitment by releasing LTB(4) and IL-1beta, presumably after activation by immune complexes deposited on joint structures. Two pathways by which immune complexes may activate neutrophils include complement fixation, resulting in the generation of C5a, and direct engagement of Fcgamma receptors (FcgammaRs). Previous investigations showed that this model of autoantibody induced arthritis requires the C5a receptor C5aR and FcgammaRs, but the simultaneous necessity for both pathways was not understood. Here we show that C5aR and FcgammaRs work in sequence to initiate and sustain neutrophil recruitment in vivo. Specifically, C5aR activation of neutrophils is required for LTB(4) release and early neutrophil recruitment into the joint, whereas FcgammaR engagement upon neutrophils induces IL-1beta release and subsequent neutrophil active chemokine production, ensuring continued inflammation. These findings support the concept that immune complex-mediated leukocyte activation is not composed of overlapping and redundant pathways, but that each element serves a distinct and critical function in vivo, culminating in tissue inflammation. PMID- 23112188 TI - MscS-Like10 is a stretch-activated ion channel from Arabidopsis thaliana with a preference for anions. AB - Like many other organisms, plants are capable of sensing and responding to mechanical stimuli such as touch, osmotic pressure, and gravity. One mechanism for the perception of force is the activation of mechanosensitive (or stretch activated) ion channels, and a number of mechanosensitive channel activities have been described in plant membranes. Based on their homology to the bacterial mechanosensitive channel MscS, the 10 MscS-Like (MSL) proteins of Arabidopsis thaliana have been hypothesized to form mechanosensitive channels in plant cell and organelle membranes. However, definitive proof that MSLs form mechanosensitive channels has been lacking. Here we used single-channel patch clamp electrophysiology to show that MSL10 is capable of providing a MS channel activity when heterologously expressed in Xenopus laevis oocytes. This channel had a conductance of ~100 pS, consistent with the hypothesis that it underlies an activity previously observed in the plasma membrane of plant root cells. We found that MSL10 formed a channel with a moderate preference for anions, which was modulated by strongly positive and negative membrane potentials, and was reversibly inhibited by gadolinium, a known inhibitor of mechanosensitive channels. MSL10 demonstrated asymmetric activation/inactivation kinetics, with the channel closing at substantially lower tensions than channel opening. The electrophysiological characterization of MSL10 reported here provides insight into the evolution of structure and function of this important family of proteins. PMID- 23112189 TI - Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A. AB - Chromatin remodeling is essential for controlling the expression of genes during development. The histone-modifying enzyme G9a/KMT1C can act both as a coactivator and a corepressor of transcription. Here, we show that the dual function of G9a as a coactivator vs. a corepressor entails its association within two distinct protein complexes, one containing the coactivator Mediator and one containing the corepressor Jarid1a/KDM5A. Functionally, G9a is important in stabilizing the Mediator complex for gene activation, whereas its repressive function entails a coordinate action with the histone H3 lysine 4 (H3K4) demethylase Jarid1a for the maintenance of gene repression. The essential nature of cross-talk between the histone methyltransferase G9a and the demethylase Jarid1a is demonstrated on the embryonic E(y)-globin gene, where the concurrent introduction of repressive histone marks (dimethylated H3K9 and dimethylated H3K27) and removal of activating histone mark (trimethylated H3K4) is required for maintenance of gene silencing. Taken together with our previous demonstration of cross-talk between UTX and MLL2 to mediate activation of the adult beta(maj)-globin gene, these data suggest a model where "active" and "repressive" cross-talk between histone modifying enzymes coexist on the same multigene locus and play a crucial role in the precise control of developmentally regulated gene expression. PMID- 23112190 TI - Epistasis in tomato color mutations involves regulation of phytoene synthase 1 expression by cis-carotenoids. AB - Tomato (Solanum lycopersicum) fruit accumulate the red carotenoid pigment lycopene. The recessive mutation yellow-flesh (locus r) in tomato eliminates fruit carotenoids by disrupting the activity of the fruit-specific phytoene synthase (PSY1), the first committed step in the carotenoid biosynthesis pathway. Fruits of the recessive mutation tangerine (t) appear orange due to accumulation of 7,9,7',9'-tetra-cis-lycopene (prolycopene) as a result of a mutation in the carotenoid cis-trans isomerase. It was established 60 y ago that tangerine is epistatic to yellow-flesh. This uncharacteristic epistasis interaction defies a paradigm in biochemical genetics arguing that mutations that disrupt enzymes acting early in a biosynthetic pathway are epistatic to other mutations that block downstream steps in the same pathway. To explain this conundrum, we have investigated the interaction between tangerine and yellow-flesh at the molecular level. Results presented here indicate that allele r(2997) of yellow-flesh eliminates transcription of PSY1 in fruits. In a genetic background of tangerine, transcription of PSY1 is partially restored to a level sufficient for producing phytoene and downstream carotenoids. Our results revealed the molecular mechanism underlying the epistasis of t over r and suggest the involvement of cis carotenoid metabolites in a feedback regulation of PSY1 gene expression. PMID- 23112191 TI - Precursor of ether phospholipids is synthesized by a flavoenzyme through covalent catalysis. AB - The precursor of the essential ether phospholipids is synthesized by a peroxisomal enzyme that uses a flavin cofactor to catalyze a reaction that does not alter the redox state of the substrates. The enzyme crystal structure reveals a V-shaped active site with a narrow constriction in front of the prosthetic group. Mutations causing inborn ether phospholipid deficiency, a very severe genetic disease, target residues that are part of the catalytic center. Biochemical analysis using substrate and flavin analogs, absorbance spectroscopy, mutagenesis, and mass spectrometry provide compelling evidence supporting an unusual mechanism of covalent catalysis. The flavin functions as a chemical trap that promotes exchange of an acyl with an alkyl group, generating the characteristic ether bond. Structural comparisons show that the covalent versus noncovalent mechanistic distinction in flavoenzyme catalysis and evolution relies on subtle factors rather than on gross modifications of the cofactor environment. PMID- 23112192 TI - Critical role of calcitonin gene-related peptide receptors in cortical spreading depression. AB - Cortical spreading depression (CSD) is a key pathogenetic step in migraine with aura. Dysfunctions of voltage-dependent and receptor-operated channels have been implicated in the generation of CSD and in the pathophysiology of migraine. Although a known correlation exists between migraine and release of the calcitonin gene-related peptide (CGRP), the possibility that CGRP is involved in CSD has not been examined in detail. We analyzed the pharmacological mechanisms underlying CSD and investigated the possibility that endogenous CGRP contributes to this phenomenon. CSD was analyzed in rat neocortical slices by imaging of the intrinsic optical signal. CSD was measured as the percentage of the maximal surface of a cortical slice covered by the propagation of intrinsic optical signal changes during an induction episode. Reproducible CSD episodes were induced through repetitive elevations of extracellular potassium concentration. AMPA glutamate receptor antagonism did not inhibit CSD, whereas NMDA receptor antagonism did inhibit CSD. Blockade of voltage-dependent sodium channels by TTX also reduced CSD. CSD was also decreased by the antiepileptic drug topiramate, but not by carbamazepine. Interestingly, endogenous CGRP was released in the cortical tissue in a calcium-dependent manner during CSD, and three different CGRP receptor antagonists had a dose-dependent inhibitory effect on CSD, suggesting a critical role of CGRP in this phenomenon. Our findings show that both glutamate NMDA receptors and voltage-dependent sodium channels play roles in CSD. They also demonstrate that CGRP antagonism reduces CSD, supporting the possible use of drugs targeting central CGRP receptors as antimigraine agents. PMID- 23112193 TI - Chemical physics of protein folding. PMID- 23112195 TI - On the two-fluid model of the Kondo lattice. PMID- 23112194 TI - How DNA-repair proteins find their targets. PMID- 23112196 TI - Quick-release medical tape. AB - Medical tape that provides secure fixation of life-sustaining and -monitoring devices with quick, easy, damage-free removal represents a longstanding unmet medical need in neonatal care. During removal of current medical tapes, crack propagation occurs at the adhesive-skin interface, which is also the interface responsible for device fixation. By designing quick-release medical tape to undergo crack propagation between the backing and adhesive layers, we decouple removal and device fixation, enabling dual functionality. We created an ordered adhesive/antiadhesive composite intermediary layer between the medical tape backing and adhesive for which we achieve tunable peel removal force, while maintaining high shear adhesion to secure medical devices. We elucidate the relationship between the spatial ordering of adhesive and antiadhesive regions to create a fully tunable system that achieves strong device fixation and quick, easy, damage-free device removal. We also described ways of neutralizing the residual adhesive on the skin and have observed that thick continuous films of adhesive are easier to remove than the thin islands associated with residual adhesive left by current medical tapes. PMID- 23112197 TI - Reversible online control of habitual behavior by optogenetic perturbation of medial prefrontal cortex. AB - Habits tend to form slowly but, once formed, can have great stability. We probed these temporal characteristics of habitual behaviors by intervening optogenetically in forebrain habit circuits as rats performed well-ingrained habitual runs in a T-maze. We trained rats to perform a maze habit, confirmed the habitual behavior by devaluation tests, and then, during the maze runs (ca. 3 s), we disrupted population activity in a small region in the medial prefrontal cortex, the infralimbic cortex. In accordance with evidence that this region is necessary for the expression of habits, we found that this cortical disruption blocked habitual behavior. Notably, however, this blockade of habitual performance occurred on line, within an average of three trials (ca. 9 s of inhibition), and as soon as during the first trial (<3 s). During subsequent weeks of training, the rats acquired a new behavioral pattern. When we again imposed the same cortical perturbation, the rats regained the suppressed maze running that typified the original habit, and, simultaneously, the more recently acquired habit was blocked. These online changes occurred within an average of two trials (ca. 6 s of infralimbic inhibition). Measured changes in generalized performance ability and motivation to consume reward were unaffected. This immediate toggling between breaking old habits and returning to them demonstrates that even semiautomatic behaviors are under cortical control and that this control occurs online, second by second. These temporal characteristics define a framework for uncovering cellular transitions between fixed and flexible behaviors, and corresponding disturbances in pathologies. PMID- 23112200 TI - Role of an esterase in flavor volatile variation within the tomato clade. AB - Tomato flavor is dependent upon a complex mixture of volatiles including multiple acetate esters. Red-fruited species of the tomato clade accumulate a relatively low content of acetate esters in comparison with the green-fruited species. We show that the difference in volatile ester content between the red- and green fruited species is associated with insertion of a retrotransposon adjacent to the most enzymatically active member of a family of esterases. This insertion causes higher expression of the esterase, resulting in the reduced levels of multiple esters that are negatively correlated with human preferences for tomato. The insertion was evolutionarily fixed in the red-fruited species, suggesting that high expression of the esterase and consequent low ester content may provide an adaptive advantage in the ancestor of the red-fruited species. These results illustrate at a molecular level how closely related species exhibit major differences in volatile production by altering a volatile-associated catabolic activity. PMID- 23112199 TI - Dynamic network structure of interhemispheric coordination. AB - Fifty years ago Gazzaniga and coworkers published a seminal article that discussed the separate roles of the cerebral hemispheres in humans. Today, the study of interhemispheric communication is facilitated by a battery of novel data analysis techniques drawn from across disciplinary boundaries, including dynamic systems theory and network theory. These techniques enable the characterization of dynamic changes in the brain's functional connectivity, thereby providing an unprecedented means of decoding interhemispheric communication. Here, we illustrate the use of these techniques to examine interhemispheric coordination in healthy human participants performing a split visual field experiment in which they process lexical stimuli. We find that interhemispheric coordination is greater when lexical information is introduced to the right hemisphere and must subsequently be transferred to the left hemisphere for language processing than when it is directly introduced to the language-dominant (left) hemisphere. Further, we find that putative functional modules defined by coherent interhemispheric coordination come online in a transient manner, highlighting the underlying dynamic nature of brain communication. Our work illustrates that recently developed dynamic, network-based analysis techniques can provide novel and previously unapproachable insights into the role of interhemispheric coordination in cognition. PMID- 23112201 TI - Assembly of macromolecular complexes by satisfaction of spatial restraints from electron microscopy images. AB - To obtain a structural model of a macromolecular assembly by single-particle EM, a large number of particle images need to be collected, aligned, clustered, averaged, and finally assembled via reconstruction into a 3D density map. This process is limited by the number and quality of the particle images, the accuracy of the initial model, and the compositional and conformational heterogeneity. Here, we describe a structure determination method that avoids the reconstruction procedure. The atomic structures of the individual complex components are assembled by optimizing a match against 2D EM class-average images, an excluded volume criterion, geometric complementarity, and optional restraints from proteomics and chemical cross-linking experiments. The optimization relies on a simulated annealing Monte Carlo search and a divide-and-conquer message-passing algorithm. Using simulated and experimentally determined EM class averages for 12 and 4 protein assemblies, respectively, we show that a few class averages can indeed result in accurate models for complexes of as many as five subunits. Thus, integrative structural biology can now benefit from the relative ease with which the EM class averages are determined. PMID- 23112202 TI - Quantitative field theory of the glass transition. AB - We develop a full microscopic replica field theory of the dynamical transition in glasses. By studying the soft modes that appear at the dynamical temperature, we obtain an effective theory for the critical fluctuations. This analysis leads to several results: we give expressions for the mean field critical exponents, and we analytically study the critical behavior of a set of four-points correlation functions, from which we can extract the dynamical correlation length. Finally, we can obtain a Ginzburg criterion that states the range of validity of our analysis. We compute all these quantities within the hypernetted chain approximation for the Gibbs free energy, and we find results that are consistent with numerical simulations. PMID- 23112203 TI - Internal signal correlates neural populations and biases perceptual decision reports. AB - In perceptual decision-making tasks the activity of neurons in frontal and posterior parietal cortices covaries more with perceptual reports than with the physical properties of stimuli. This relationship is revealed when subjects have to make behavioral choices about weak or uncertain stimuli. If knowledge about stimulus onset time is available, decision making can be based on accumulation of sensory evidence. However, the time of stimulus onset or even its very presence is often ambiguous. By analyzing firing rates and correlated variability of frontal lobe neurons while monkeys perform a vibrotactile detection task, we show that behavioral outcomes are crucially affected by the state of cortical networks before stimulus onset times. The results suggest that sensory detection is partly due to a purely internal signal whereas the stimulus, if finally applied, adds a contribution to this initial processing later on. The probability to detect or miss the stimulus can thus be explained as the combined effect of this variable internal signal and the sensory evidence. PMID- 23112204 TI - Modulation of BK channel voltage gating by different auxiliary beta subunits. AB - Calcium- and voltage-activated potassium channels (BK) are regulated by a multiplicity of signals. The prevailing view is that different BK gating mechanisms converge to determine channel opening and that these gating mechanisms are allosterically coupled. In most instances the pore forming alpha subunit of BK is associated with one of four alternative beta subunits that appear to target specific gating mechanisms to regulate the channel activity. In particular, beta1 stabilizes the active configuration of the BK voltage sensor having a large effect on BK Ca(2+) sensitivity. To determine the extent to which beta subunits regulate the BK voltage sensor, we measured gating currents induced by the pore forming BK alpha subunit alone and with the different beta subunits expressed in Xenopus oocytes (beta1, beta2IR, beta3b, and beta4). We found that beta1, beta2, and beta4 stabilize the BK voltage sensor in the active conformation. beta3 has no effect on voltage sensor equilibrium. In addition, beta4 decreases the apparent number of charges per voltage sensor. The decrease in the charge associated with the voltage sensor in alpha beta4 channels explains most of their biophysical properties. For channels composed of the alpha subunit alone, gating charge increases slowly with pulse duration as expected if a significant fraction of this charge develops with a time course comparable to that of K(+) current activation. In the presence of beta1, beta2, and beta4 this slow component develops in advance of and much more rapidly than ion current activation, suggesting that BK channel opening proceeds in two steps. PMID- 23112205 TI - Viral MHC class I inhibition evades CD8+ T-cell effector responses in vivo but not CD8+ T-cell priming. AB - Although viral MHC class I inhibition is considered a classic immune-evasion strategy, its in vivo role is largely unclear. Mutant cowpox virus lacking its MHC class I inhibitors is markedly attenuated during acute infection because of CD8(+) T-cell-dependent control, but it was not known how CD8(+) T-cell responses are affected. Interestingly, we found no major effect of MHC class I down regulation on priming of functional cowpox virus-specific CD8(+) T cells. Instead, we demonstrate that, during acute infection in vivo, MHC class I down regulation prevents primed virus-specific CD8(+) T cells from recognizing infected cells and exerting effector responses to control the infection. PMID- 23112206 TI - Allard's argument versus Baker's contention for the adaptive significance of selfing in a hermaphroditic fish. AB - Fertilization assurance (Baker's contention) and multilocus coadaptation (Allard's argument) are two distinct hypotheses for the adaptive significance of self-fertilization in hermaphroditic taxa, and both scenarios have been invoked to rationalize isogenicity via incest in various plants and invertebrate animals with predominant selfing. Here we contrast Allard's argument and Baker's contention as applied to the world's only known vertebrate that routinely self fertilizes. We pay special attention to frequencies of locally most common multilocus genotypes in Floridian populations of the Mangrove Rivulus (Kryptolebias marmoratus). Isogenicity patterns in this fish appear inconsistent with Allard's argument, thus leaving Baker's contention as the more plausible scenario (a result also supported by natural history information for this species). These results contrast with the isogenicity patterns and conclusions previously drawn from several self-fertilizing plants and invertebrate animal species. Thus, the adaptive significance of selfing apparently varies across hermaphroditic taxa. PMID- 23112208 TI - Buntaro Adachi (1865-1945): Japanese master of human anatomic variation. AB - Buntaro Adachi (1865-1945) was a Japanese physician, anatomist, and anthropologist and is most remembered for his study on human anatomic variation. At the end of 19th Century, one of the main focuses in anthropology was the comparison between the races. In Japan, anthropological studies of the origin of the modern Japanese race were carried out by Adachi and others. Adachi believed that differences went beyond the bones that were commonly studied in his day and, therefore, investigated soft tissues of the body. Two products of his intense study of variation of human anatomy were Das Arteriensystem der Japaner (The Arterial System of the Japanese) published in 1928 and Das Venensystem der Japaner (The Venous System of the Japanese) published in 1933 and 1940. These books received much attention and were praised by anatomists and anthropologists around the world. Even now, these books are invaluable as references for human anatomic variation. Herein, we provide an overview of the life and achievements of Buntaro Adachi and to our knowledge, this is the first such review in the English language. PMID- 23112209 TI - Retracing the etymology of terms in neuroanatomy. AB - Researching the origin of the terms that we use to identify neuroanatomical structures is a helpful and fascinating exercise. It can provide neuroscientists with a better insight and understanding of the macroscopic anatomy of the cranium and its contents. It can also help the novice to this discipline to become acquainted with structures whose three dimensional anatomy is often difficult to appreciate. The purpose of this article was to investigate the etymology of some of the terms referring to the macroscopic anatomical structures of the skull and the intracranial cavity. We observed how each name unravels an interesting story, sometimes linked to mythological creatures, other times to the shape of animals or objects and tools of everyday life. We conclude that even without a deep knowledge of the Greek, Latin, or Arabic language, learning who described a particular structure and how they decided to name it, makes the study of neuroanatomy more complete and fulfilling. PMID- 23112210 TI - Ralph Ger (1921-2012). PMID- 23112211 TI - Professor R.M.H. McMinn, MBCHB, Phd, MD, FRCS(eng) (20 September 1923-11 July 2012). PMID- 23112213 TI - Fast interpretation of thromboelastometry in non-cardiac surgery: reliability in patients with hypo-, normo-, and hypercoagulability. AB - BACKGROUND: Conventional coagulation test are not useful to guide haemostatic therapy in severe bleeding due to their long turn-around time. In contrast, early variables assessed by point-of-care thromboelastometry (ROTEM((r))) are available within 10-20 min and increasingly used to guide haemostatic therapy in liver transplantation and severe trauma. However, the reliability of early ROTEM((r)) variables to predict maximum clot firmness (MCF) in non-cardiac surgery patients with subnormal, normal, and supranormal MCF has not yet been evaluated. METHODS: Retrospective data of 14,162 ROTEM((r)) assays (3939 EXTEM((r)), 3654 INTEM((r)), 3287 FIBTEM((r)), and 3282 APTEM((r)) assays) of patients undergoing non-cardiac surgery were analysed. ROTEM((r)) variables [clotting time (CT), clot formation time (CFT), alpha-angle, A5, A10, and A15] were related to MCF by linear or non linear regression, as appropriate. The Bland-Altman analyses to assess the bias between early ROTEM((r)) variables and MCF and receiver operating characteristics (ROC) were also performed. RESULTS: Taking the best and worst correlation coefficients for each assay type, CT (r=0.18-0.49) showed the worst correlation to MCF. In contrast, alpha-angle (r=0.85-0.88) and CFT (r=0.89-0.92) demonstrated good but non-linear correlation with MCF. The best and linear correlations were found for A5 (r=0.93-0.95), A10 (r=0.96), and A15 (r=0.97-0.98). ROC analyses provided excellent area under the curve (AUC) values for A5, A10, and A15 (AUC=0.962-0.985). CONCLUSIONS: Early values of clot firmness allow for fast and reliable prediction of ROTEM((r)) MCF in non-cardiac patients with subnormal, normal, and supranormal MCF values and therefore can be used to guide haemostatic therapy in severe bleeding. PMID- 23112214 TI - Balanced crystalloid compared with balanced colloid solution using a goal directed haemodynamic algorithm. AB - BACKGROUND: Controversy exists regarding the optimal i.v. fluids for use with a goal-directed haemodynamic algorithm. METHODS: In a double-blind pilot study, we randomly assigned 50 patients with primary ovarian cancer undergoing cytoreductive surgery to receive either balanced crystalloid or balanced starch (HES, 130/0.4, 6%) solutions up to the dose limit (50 ml kg(-1)). Fluids were administered to optimize stroke volume measured by oesophageal Doppler within a goal-directed haemodynamic algorithm. RESULTS: Baseline subject characteristics were similar in both groups. The balanced HES solution maintained stroke volume (P=0.012) better with administration of less fluid. Subjects in the colloid group reached the dose limits of the study medication less frequently (92% vs 62%, P=0.036) and later (2:26 vs 3:33 h, P=0.006) and also required less transfusion of fresh-frozen plasma units (6.0 vs 3.5 units, P=0.035) compared with the crystalloid group. Intra- and postoperative urine output and perioperative plasma levels of creatinine and neutrophil gelatinase-associated lipocalin as renal injury marker were similar in both groups. No differences in the length of intensive care unit and hospital stay were found. CONCLUSIONS: Using a goal directed haemodynamic algorithm to optimize stroke volume, a balanced HES solution is associated with better haemodynamic stability and reduced need for fresh-frozen plasma. There were no signs of renal impairment by colloid solutions when fluid administration is targeted to optimize cardiac preload. PMID- 23112215 TI - Knowledge, skills and attitudes of doctors towards assessing cognition in older patients in the emergency department. AB - PURPOSE OF THE STUDY: Although cognitive impairment and delirium are highly prevalent in older patients who present to the emergency department, multiple studies have highlighted inadequate detection by doctors. This study investigated potential reasons underlying this. STUDY DESIGN: A 14-item self-administered questionnaire was distributed to all medical, surgical and emergency department physicians involved in the care of older patients in the emergency department of an urban university teaching hospital between January and March 2012. RESULTS: The questionnaire was completed by 76/97 (78%) of eligible respondents. Respondents reported screening an average of one in four older patients that they reviewed. Almost one-third (22/76, 29%) felt they lacked the relevant expertise to perform cognitive screening: those with training in geriatrics were less likely to cite lack of expertise as a factor. While the majority felt screening for cognition in the emergency department-setting was important (59/76, 78%), several limiting factors were identified: lack of a screening tool; lack of privacy; too much noise; and time constraints. There was no consensus on who should perform screening. CONCLUSIONS: Doctors reviewing patients in the emergency department-setting reported several important factors limiting their ability to screen older patients for cognitive impairment. Respondents to this questionnaire did not feel the emergency department environment was conducive towards the assessment of cognition in older patients. Clarification of each discipline's responsibility in the detection, assessment and management of delirium and/or dementia, and the implementation of emergency department cognitive screening instruments more suited to this setting would likely improve detection and management. PMID- 23112218 TI - Prevalence of metabolic syndrome and its selected determinants among urban adult women in South Delhi, India. AB - AIMS: Metabolic syndrome is a clustering of cardiovascular risk factors. Asian Indians, particularly women, have been reported to be at higher risk of developing metabolic syndrome. We aimed to estimate the prevalence of metabolic syndrome and its selected known determinants among adult Asian Indian women of lower socioeconomic status. METHODS: We conducted a cross-sectional study over a period of 1 year from January 2008 to December 2008 in South Delhi, which included 300 women (>20 years) recruited through multistage systematic random sampling. Blood pressure and anthropometric measurements were taken. Biochemical tests were performed on blood samples collected after overnight fasting. Metabolic syndrome was defined using updated National Cholesterol Education Program/Adult Treatment Panel-III (NCEP/ATP-III) guidelines with modified waist circumference for Indians and International Diabetes Federation (IDF) criteria. RESULTS: The overall prevalence of metabolic syndrome was 29.6% (95% CI 23.8 to 36.0) and 20.4% (95% CI 15.3 to 26.1) using NCEP/ATP-III and IDF criteria, respectively. The risk of metabolic syndrome increased with age and calorie intake. Most (203 (90%)) of the study participants were involved in physical activity with a low metabolic equivalent (MET) score but one-fifth (19.5%) had a calorie intake recommended for women involved in vigorous activity. CONCLUSIONS: The high prevalence of metabolic syndrome among women of lower socioeconomic status is a cause of concern, and calls for an effective public health response. PMID- 23112216 TI - Sensory neuromodulators in functional nausea and vomiting: predictors of response. AB - BACKGROUND: Tricyclic antidepressants (TCAs) are known to benefit subjects with functional nausea and vomiting (FNV), but it is not known if alternate neuromodulators are also beneficial. We retrospectively evaluated outcomes and clinical predictors of response in FNV subjects treated with any neuromodulator, including TCAs. METHODS: We identified 94 subjects (43.8+/-1.4 year, 79 F) with FNV (Rome III criteria) over a 12 year period, treated with neuromodulators and followed up for 8.5+/-1.1 months. Clinical presentation, demographics and gastric emptying study (GES) findings (when available) were extracted. Likert scales determined symptom severity at baseline and symptom response or remission at follow-up. Outcomes and predictors of response were evaluated using univariate and multivariate analyses. RESULTS: At least moderate symptom improvement was reported by 72.3%, and 22.3% had symptom remission. Proportions achieving moderate improvement and remission, and mean outcome Likert scores were similar regardless of neuromodulator agent used or GES status. On univariate and multivariate logistic regression analysis, baseline symptom severity affected symptom response, and pain negatively impacted symptom remission to treatment (p<=0.04 for each); GES status failed to predict treatment response or remission. CONCLUSIONS: Symptom improvement with neuromodulators may be seen in over two thirds of subjects with FNV regardless of the specific agent administered. Response may be suboptimal in pain predominant presentations. PMID- 23112217 TI - Predictors of outcome in routine care for Cryptococcal meningitis in Western Kenya: lessons for HIV outpatient care in resource-limited settings. AB - PURPOSE: Cryptococcal meningitis is a leading cause of mortality among HIV infected individuals in sub-Saharan Africa but little is known about its treatment and outcomes in decentralised HIV outpatient settings. We assessed adherence to treatment guidelines and determined predictors of survival. DESIGN: A computerised laboratory database identified HIV-infected adults with cryptococcal meningitis at Family AIDS Care and Education Services in Nyanza Province, Kenya, between 2005-2009. Medical records were reviewed. Kaplan-Meier survival curves were generated. Bivariate and multivariate Cox proportional hazards models were used to determine associations between key clinical characteristics and survival. RESULTS: Medical records were located for 79% (71/90). Mortality was 38% (27/71) over a median follow-up period of 201 days (IQR: 10-705 days). Adherence to local guidelines for treatment of cryptococcal meningitis was 48% (34/71). Higher body mass index was associated with improved survival (HR: 0.82, 95% CI (0.68 to 0.99)) even after controlling for factors such as age, CD4 cell count, receipt of highly active anti-retroviral therapy, and treatment with any anti-fungal therapy. CONCLUSIONS: Cryptococcal meningitis diagnosed in routine HIV outpatient settings is largely treated as an outpatient and adherence to treatment guidelines is poor. Body mass index is a critical independent predictor of outcome. Additional research to determine the most effective strategies to reduce premature mortality is urgently needed. PMID- 23112219 TI - New insights into an old disease: advanced imaging in the diagnosis and management of gout. AB - Advanced imaging modalities including MRI, ultrasound (US), CT and dual energy CT have important applications in gout. While conventional radiography (X-ray) remains the most widely used form of imaging in the clinical setting and is helpful in revealing erosions in chronic gout, these new imaging tools can reveal joint damage and tophi at a much earlier stage. As all are multiplanar techniques, they can define the position and dimensions of tophi, with startling clarity, as well as the size and extent of bone erosions. US and MRI also reveal the severity of inflammation within and adjacent to the joint and can capture information about the composite, vascular nature of many tophaceous deposits. These features can be used as imaging outcome measures, to monitor responses to anti-inflammatory and urate lowering therapies. The new possibility that gout could be diagnosed using imaging, without aspirating the joint, is on the horizon. This review discusses the clinical and research applications of advanced imaging in gout with particular focus on diagnosis and monitoring of joint inflammation and damage. PMID- 23112220 TI - MBoC celebrates its first 20 years. PMID- 23112221 TI - An MBoC favorite: mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA. PMID- 23112222 TI - Building a path in cell biology. AB - Setting up a new lab is an exciting but challenging prospect. We discuss our experiences in finding a path to tackle some of the key current questions in cell biology and the hurdles that we have encountered along the way. PMID- 23112223 TI - Being at the right place at the right time. AB - I am tremendously honored to receive the 2012 Women in Cell Biology Junior Award. In this essay, I recount my career path over the past 15 years. Although many details are specific to my own experiences, I hope that some generalizations can be made to encourage more women to pursue independent scientific careers. Mine is a story of choosing a captivating question, making the most of your opportunities, and finding a balance with life outside the lab. PMID- 23112224 TI - A career at the interface of cell and developmental biology: a view from the crest. AB - Just as neural crest cells migrate great distances through the embryo, my journey has taken me from a childhood in a distant land to a career as a biologist. My mentoring relationships have shaped not only the careers of my trainees, but also the trajectory of my own science. One of the most satisfying aspects of mentoring comes from helping to empower the next generation of scientists to do more tomorrow than is possible today. This, together with a passion for discovery and learning new things, motivates me and makes science such a rewarding career. PMID- 23112225 TI - A passion for the science of the human genome. AB - The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: "How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?" As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives. PMID- 23112226 TI - Membranes, viruses, detergents, and endosomes. AB - The fluid mosaic model for biological membranes was formulated 40 years ago. Ten years later endosomes were discovered as important prelysosomal organelles. At the outset of my research career, I was fortunate to witness both these turning points in biochemistry and cell biology from close up, and to participate in some of the studies. In this short essay, I will describe how this came about, and also try to provide some background as to the general starting situation in those not so distant pioneering years of membrane biology. PMID- 23112227 TI - Why we need more basic biology research, not less. AB - Much of the spectacular progress in biomedical science over the last half-century is the direct consequence of the work of thousands of basic scientists whose primary goal was understanding of the fundamental working of living things. Despite this, many politicians, funders, and even scientists have come to believe that the pace of successful applications to medical diagnosis and therapy is limited by our willingness to focus directly on human health, rather than a continuing deficit of understanding. By this theory, curiosity-driven research, aimed at understanding, is no longer important or even useful. What is advocated instead is "translational" research aimed directly at treating disease. I believe this idea to be deeply mistaken. Recent history suggests instead that what we have learned in the last 50 years is only the beginning. The way forward is to invest more in basic science, not less. PMID- 23112228 TI - An expanding role for cell biologists in drug discovery and pharmacology. AB - The profound challenges facing clinicians, who must prescribe drugs in the face of dramatic variability in response, and the pharmaceutical industry, which must develop new drugs despite ever-rising costs, represent opportunities for cell biologists interested in rethinking the conceptual basis of pharmacology and drug discovery. Much better understanding is required of the quantitative behaviors of networks targeted by drugs in cells, tissues, and organisms. Cell biologists interested in these topics should learn more about the basic structure of drug development campaigns and hone their quantitative and programming skills. A world of conceptual challenges and engaging industry-academic collaborations awaits, all with the promise of delivering real benefit to patients and strained healthcare systems. PMID- 23112229 TI - Living matter--nexus of physics and biology in the 21st century. AB - Cells are made up of complex assemblies of cytoskeletal proteins that facilitate force transmission from the molecular to cellular scale to regulate cell shape and force generation. The "living matter" formed by the cytoskeleton facilitates versatile and robust behaviors of cells, including their migration, adhesion, division, and morphology, that ultimately determine tissue architecture and mechanics. Elucidating the underlying physical principles of such living matter provides great opportunities in both biology and physics. For physicists, the cytoskeleton provides an exceptional toolbox to study materials far from equilibrium. For biologists, these studies will provide new understanding of how molecular-scale processes determine cell morphological changes. PMID- 23112230 TI - Bringing the physical sciences into your cell biology research. AB - Historically, much of biology was studied by physicists and mathematicians. With the advent of modern molecular biology, a wave of researchers became trained in a new scientific discipline filled with the language of genes, mutants, and the central dogma. These new molecular approaches have provided volumes of information on biomolecules and molecular pathways from the cellular to the organismal level. The challenge now is to determine how this seemingly endless list of components works together to promote the healthy function of complex living systems. This effort requires an interdisciplinary approach by investigators from both the biological and the physical sciences. PMID- 23112231 TI - Political advocacy by the American Society for Cell Biology and its partners. AB - I trace how the American Society for Cell Biology became a strong political advocate for the scientific community. I celebrate how good leadership and an effective staff enabled its energetic volunteer organization to have an impact, but I also ask how the effort can be made more successful. PMID- 23112232 TI - ASL/LBD phylogeny suggests that genetic mechanisms of root initiation downstream of auxin are distinct in lycophytes and euphyllophytes. AB - Paleobotanical studies suggest that roots evolved at least twice independently during land plant diversification, once in lycophytes and once in euphyllophytes. Auxin promotes postembryonic root initiation in both groups but from different cell types. In several euphyllophytes, such as Arabidopsis, rice, and maize, AS2/LOB-domain (ASL/LBD) proteins act directly downstream of auxin and are conserved elements necessary for root initiation. It is currently unknown whether similar or different genetic mechanisms act downstream of auxin for root initiation in lycophytes and euphyllophytes. We searched for ASL/LBD proteins in genome sequences spanning the tree of life to retrace their evolutionary history. We performed a phylogenetic analysis of ASL/LBD proteins and mapped the functions of all characterized ASL/LBD onto the phylogenetic trees. We identified a clade specifically associated with root development, which includes no lycophyte sequence. This points toward the existence of distinct genetic mechanisms downstream of auxin for root initiation in lycophytes and euphyllophytes. PMID- 23112234 TI - Modulating the function of human serine racemase and human serine dehydratase by protein engineering. AB - D-Serine is a co-agonist of N-methyl D-aspartate, a glutamate receptor, which is a major excitatory neurotransmitter receptor in the brain. Human serine racemase (hSR) and serine dehydratase (hSDH) are two important pyridoxal-5'-phosphate dependent enzymes that synthesize and degrade D-serine, respectively. hSR and hSDH have significant sequence homology (28% identity) and are similar in their structural folds (root-mean-square deviation, 1.12 A). Sequence alignment and structural comparison between hSR and hSDH reveal that S84 in hSR and A65 in hSDH play important roles in their respective enzyme activities. We surmise that exchange of these two amino acids by introducing S84A hSR and A65S hSDH mutants may result in switching their protein functions. To understand the modulating mechanism of the key residues, mutants S84A in hSR and A65S in hSDH were constructed to monitor the change of activities. The structure of A65S hSDH mutant was determined at 1.3 A resolution (PDB 4H27), elucidating the role of this critical amino acid. Our study demonstrated S84A hSR mutant behaved like hSDH, whereas A65S hSDH mutant acquired an additional function of using D-serine as a substrate. PMID- 23112235 TI - Atypical hereditary sensory and autonomic neuropathy type IV with neither mental retardation nor pain insensitivity. AB - Hereditary sensory and autonomic neuropathy type IV is an autosomal recessive disorder characterized by severe mental retardation and self-mutilation-related complications. Recently, we investigated a 16-year-old Korean boy with normal intelligence. He had preserved pain sensation but was suspected of having hereditary sensory and autonomic neuropathy type IV because of the recurrent bone fractures and painless joint destruction in the absence of any predisposing medical conditions. Genetic analysis of the NTRK1 gene revealed compound heterozygous mutations including c.851-33T>A and c.2303C>T (p.Pro768Leu) in the NTRK1 gene. The p.Pro768Leu mutation has been identified in 2 Japanese patients with a mild phenotype. Therefore, although it is rare, hereditary sensory and autonomic neuropathy type IV should be considered in patients with recurrent bone fractures and painless joint destruction who do not have any predisposing conditions even when they do not have typical clinical features such as mental retardation or pain insensitivity. PMID- 23112236 TI - New Niemann-Pick type C1 gene mutation associated with very severe disease course and marked early cerebellar vermis atrophy. AB - Niemann-Pick type C is an autosomal recessive lipid storage disease caused by mutations in the NPC1 or NPC2 gene. In childhood-onset Niemann-Pick type C, the usual course is slowly progressive, with normal cerebral magnetic resonance at onset. Here the authors present the case of a patient carrying 2 compound heterozygous NPC1 mutations: the known nonsense mutation (p.Trp833X) in exon 16 and a novel missense mutation (p.Ile609Phe) in exon 12. At onset, the patient presented ataxia, cognitive decline, and epilepsy, with early cerebral atrophy and marked cerebellar vermis atrophy. The course of the disease was rapid, and the patient died within 1-2 years of onset. A possible phenotype-genotype correlation is discussed. This case further expands the clinical spectrum and the genetic heterogeneity of Niemann-Pick type C due to NPC1 mutations. PMID- 23112237 TI - Clobazam: a newly approved but well-established drug for the treatment of intractable epilepsy syndromes. AB - Clobazam, a 1,5-benzodiazepine, was introduced in the 1970s as an anxiolytic and antiepileptic drug. Despite worldwide usage, it was only recently approved in the United States (seizures associated with Lennox-Gastaut syndrome). This article reviews historical and recent data to help practitioners better understand clobazam's clinical properties and usage. In many clinical trials, open-label studies, and retrospective reviews, clobazam was generally associated with >=50% seizure reduction for more than half of Lennox-Gastaut syndrome patients, with approximately 10% achieving freedom from drop attacks. Efficacy is persistent, with little evidence for development of tolerance. Clobazam's safety profile appears to be similar to that of other benzodiazepines, but with substantially decreased sedation and increased psychomotor performance. Studies suggest clobazam acts through potentiation of gamma-aminobutyric acid type A receptors in a manner similar to other benzodiazepines. However, clobazam appears to display greater selectivity for receptors responsible for anticonvulsant activity than for those involved in sedation. PMID- 23112238 TI - Gabapentin shows promise in treating refractory insomnia in children. AB - Insomnia is prevalent in pediatrics, particularly in those with neurodevelopmental disorders. Gabapentin has shown promise in treating insomnia in adults. The purpose of our study was to review our experience with using gabapentin to treat insomnia in children. We identified 23 children, seen by the authors in our Pediatric Sleep Clinic from January 2009 to March 2012. The mean age was 7.2 years and 70% were male. The majority (87%) had been given diagnoses of neurodevelopmental or neuropsychiatric disorders. All parents received education in sleep behavioral interventions. The majority of children (70%) had both sleep-onset and sleep maintenance insomnia. The average starting dose of gabapentin was 5 mg/kg every bedtime and the maximal dose was 15 mg/kg every bedtime. At follow-up, improved sleep was noted in 78% of children. Adverse effects were noted in 6 children. PMID- 23112239 TI - Compensated dyslexics have a more efficient error detection system than noncompensated dyslexics. AB - Error/correct-related negativities, response-locked components of the evoked response potential, and N100, a stimulus-locked component, were used to compare error detection monitoring in skilled readers and in compensated and noncompensated dyslexic adolescent readers during a lexical decision task. Results showed a general increase in N100 amplitudes prior to error commission in all groups; a significant decrease in error/correct-related negativity amplitudes in the noncompensated dyslexics compared with the other 2 groups; and smaller error-related negativity correlated with a higher number of decoding errors, lower working memory scores, and lower speed of processing in the neuropsychological battery. Based on the hypothesis in previous studies that the error detection mechanism is a subcomponent of executive functions, the possibility that poor executive ability underlies poor reading skills in the noncompensated dyslexic readers is discussed. These findings can be used as a platform for executive-based diagnosis and training for individuals with reading disabilities. PMID- 23112240 TI - Seizures as a presentation of a pelvic neuroblastoma in a 5-month-old infant. AB - Epilepsy is a very uncommon first manifestation of a neuroblastoma. A 5-month-old healthy infant presented with acute onset seizures and developmental regression. Extensive investigation was remarkable for urinary vanillylmandelic acid and homovanillic acid peaks. Abdominopelvic magnetic resonance imaging (MRI) disclosed a presacral unresectable pelvic neuroblastoma. Chemotherapy and monthly dexamethasone pulses were administrated. Seizures stopped 3 days after the first pulse of dexamethasone. At 3-year follow-up, the patient is asymptomatic and has normal neurologic and developmental examinations. This case illustrates an impressive clinical and electroencephalographic (EEG) improvement on corticosteroid therapy, raising several hypotheses, including the possibility of a nonclassic paraneoplastic neurologic syndrome. PMID- 23112241 TI - Autonomic dysfunction manifesting with asymmetric face flushing and paroxysmal nonconvulsive episodes. AB - Asymmetric face flushing, known as harlequin syndrome, is an autonomic disorder that occurs with other dysfunctions or in isolation. It may be secondary to organic causes or unknown in origin. The latter, which is uncommon in childhood, is considered benign. We report on a boy who first showed this anomaly at 4 years of age, followed up for 6 years. During this time, we saw an increase in the frequency and duration of the episodes of asymmetric face flushing. In the past months, the episodes were associated with a wider involvement of autonomic symptoms, consisting of severe localized headache, lack of coordination, asymmetric sweating, and a loss of strength that lasted about 30 minutes. A review list of young patients affected by this condition is reported. PMID- 23112242 TI - Clobazam for the treatment of intractable epilepsy in children. AB - We describe our experience using clobazam, examining efficacy for individual seizure types and analyzing for factors contributing to initial and sustained response. We retrospectively reviewed medical charts of children treated with clobazam. We collected patient and treatment characteristics and compared response to therapy at 6, 12, and >12 months' duration. One hundred eight patients with a variety of seizure types and etiologies of epilepsy were treated. Response rates for >50% seizure reduction were 59%, 39%, and 30% of patients at 6, 12, and >12 months' therapy, respectively. No seizure type responded more favorably and there were no patient predictors of favorable response. Patients tended to respond early and at low dosing, and half the patients maintained this response for 15 months or more. Clobazam has efficacy against a wide spectrum of seizure types and epilepsy etiologies. An early, low-dose response is a favorable indicator for sustained response. PMID- 23112244 TI - Longitudinal analysis of developmental delays in children with neurofibromatosis type 1. AB - Children with neurofibromatosis type 1 exhibit a variety of developmental delays. However, there is little information about the progression of these deficits over the course of development. Using the Parents' Evaluation of Developmental Status measurement tool, we assessed 124 infants (0-2 years of age), preschool-age children (3-5 years of age), and school-age children (6-8 years of age) with neurofibromatosis type 1 to define the natural history of delays. School-age children exhibited significantly more areas of delay than infants or preschool age children. Delays in math, reading, gross motor, fine motor, and self-help development were observed more frequently in older than younger children. Finally, analysis of 43 subjects for whom longitudinal assessments were available revealed that children often migrated between delayed and nondelayed groups in all areas except gross motor development. Based on these findings, we advocate early developmental screening and intervention for this at-risk pediatric population, especially in the area of gross motor function. PMID- 23112243 TI - Systemic inflammation, intraventricular hemorrhage, and white matter injury. AB - To see if the systemic inflammation profile of 123 infants born before the 28th week of gestation who had intraventricular hemorrhage without white matter injury differed from that of 68 peers who had both lesions, we compared both groups to 677 peers who had neither. Cranial ultrasound scans were read independently by multiple readers until concordance. The concentrations of 25 proteins were measured with multiplex arrays using an electrochemiluminescence system. Infants who had both hemorrhage and white matter injury were more likely than others to have elevated concentrations of C-reactive protein and interleukin 8 on days 1, 7, and 14, and elevated concentrations of serum amyloid A and tumor necrosis factor-alpha on 2 of these days. Intraventricular hemorrhage should probably be viewed as 2 entities: hemorrhage alone and hemorrhage with white matter injury. Each entity is associated with inflammation, but the combination has a stronger inflammatory signal than hemorrhage alone. PMID- 23112245 TI - Importance of utilizing a sensitive free thyroxine assay in Sturge-Weber syndrome. AB - Sturge-Weber syndrome has been found to result in hypothalamic-pituitary dysfunction including central hypothyroidism. Because central hypothyroidism is more prevalent in Sturge-Weber syndrome than in the general population, we routinely evaluated thyroid function. Here we describe 5 children with Sturge Weber syndrome on anticonvulsants and diagnosed with hypothyroidism based on thyroid function testing. All 5 patients were eventually tested utilizing the more accurate free thyroxine equilibrium dialysis assay. Results indicated that only 2 of the 5 patients, who exhibited the most severe symptoms, had true hypothyroidism. This case series demonstrates the benefits of using the free thyroxine by equilibrium dialysis when testing Sturge-Weber syndrome patients on antiepileptic medications. This testing algorithm is more cost-effective and also improves the quality of care by providing an accurate diagnosis more quickly. In addition, we propose consideration of this testing method in any patient taking anticonvulsants, most notably oxcarbazepine. PMID- 23112246 TI - Ictal priapism as an autonomic manifestation of Panayiotopoulos syndrome. AB - Panayiotopoulos syndrome is an idiopathic epilepsy syndrome presenting with a large variety of autonomic symptoms. The mechanism of autonomic symptoms is still not well understood. A neurologically normal 13-month-old boy presented on 2 occasions with complex partial status epilepticus that included significant ictal priapism. Inpatient brain magnetic resonance imaging (MRI) scan showed restricted diffusion-weighted imaging within his left temporal lobe and electroencephalograms (EEGs) left temporal slowing only. An outpatient EEG 6 months later showed abundant multifocal, predominantly posterior, as well as irregular generalized spike-and-slow-wave discharges on normal background consistent with the diagnosis of Panayiotopoulos syndrome. Ictal priapism is a previously undescribed phenomenon that is consistent with parasympathetic manifestations noted in this young boy. Acute postictal MRI and EEG findings suggest that this undeniably fascinating seizure semiological sign may be localized to the left temporal region. PMID- 23112247 TI - Aspirin use in Sturge-Weber syndrome: side effects and clinical outcomes. AB - Sturge-Weber syndrome is a neurocutaneous disorder with skin, eye, and brain involvement. Prior series suggest about 50% of patients have seizures/neurodeterioration. Low-dose (3-5 mg/kg/d) aspirin use in this population is controversial. This study further addresses the side effects and outcomes of low-dose aspirin usage in Sturge-Weber syndrome. Fifty-eight subjects on aspirin with brain involvement were analyzed in a retrospective chart review. Charts were evaluated for brain involvement, age at first seizure, and side effects. Subjects' clinical stability was compared using neurologic scores. The majority of subjects had neurologic scores reflecting reasonable seizure control (91%), none or mild hemiparesis (57%), no vision impairment (71%), and none or mild cognitive impairment (80%). Forty-nine reported no significant side effects, and 9 reported either allergic reaction or minimal to significant bleeding on aspirin. This cohort's clinical experience adds significant support for low-dose aspirin use to optimize neurodevelopmental outcome in Sturge-Weber syndrome with minimal side effects. PMID- 23112248 TI - The relationship between gross motor function and manual ability in cerebral palsy. AB - A retrospective cohort study was conducted to describe the relationship between gross motor function and manual ability in children with cerebral palsy and explore differences between cerebral palsy subtypes and associated comorbidities. Children with cerebral palsy born between 1999 and 2008 were included from the Registre de la Paralyse Cerebrale de Quebec identifying 332 children. The overall agreement between Gross Motor Function Classification System and Manual Ability Classification Scale Levels was moderate (kappa 0.457, standard error 0.034) with a strong positive correlation (Spearman rho of 0.820, standard error 0.023). This agreement was moderate among children with spastic quadriparesis and dysketic cerebral palsy, fair in children with spastic diplegia, and poor in children with spastic hemiplegia. Children with cognitive impairment showed a higher correlation than those without cognitive impairment. The correlation between gross motor function and manual ability in children with CP varies based on neurologic subtype and cognitive level. PMID- 23112249 TI - Two-year follow-up study on neurodevelopmental outcomes after term intrapartum asphyxia using age and stages questionnaire. AB - Birth asphyxia is one of the multiple causes of neonatal encephalopathy. The objective of this study was to evaluate neurodevelopmental outcomes of newborn term infants with definitive asphyxia. Thirty infants met study criteria for asphyxia. The 5-year incidence of asphyxia was estimated to be 5.5 in 1000. According to the Age and Stage Questionnaire, 10.5% of 6-month-old infants, 14.3% of 12- and 18-month-old infants, and 5.3% of 24-month-old infants had neurodevelopmental delay in gross motor function in the absence of cerebral palsy. In 7.3% of 18-month-old infants, neurodevelopmental delay in problem solving ability was observed. Higher values of Apgar score and bicarbonate levels were associated with higher Age and Stage Questionnaire total score. Delivery type, maternal age, gravidity of mother, and existence of mother disease during pregnancy were also associated with lower Age and Stage Questionnaire total score in different stages of life. PMID- 23112250 TI - Simultaneous targeting of COX-2 and AKT using selenocoxib-1-GSH to inhibit melanoma. AB - Melanoma is a highly metastatic and deadly disease. An agent simultaneously targeting the COX-2, PI3K/Akt, and mitogen-activated protein kinase (MAPK) signaling pathways that are deregulated in up to 70% of sporadic melanomas might be an effective treatment, but no agent of this type exists. To develop a single drug inhibiting COX-2 and PI3K/Akt signaling (and increasing MAPK pathway activity to inhibitory levels as a result of Akt inhibition), a selenium containing glutathione (GSH) analogue of celecoxib, called selenocoxib-1-GSH was synthesized. It killed melanoma cells with an average IC(50) of 7.66 MUmol/L compared with control celecoxib at 55.6 MUmol/L. The IC(50) range for normal cells was 36.3 to 41.2 MUmol/L compared with 7.66 MUmol/L for cancer cells. Selenocoxib-1-GSH reduced development of xenografted tumor by approximately 70% with negligible toxicity by targeting COX-2, like celecoxib, and having novel inhibitory properties by acting as a PI3K/Akt inhibitor (and MAPK pathway activator to inhibitory levels due to Akt inhibition). The consequence of this inhibitory activity was an approximately 80% decrease in cultured cell proliferation and an approximately 200% increase in apoptosis following 24-hour treatment with 15.5 MUmol/L of drug. Thus, this study details the development of selenocoxib-1-GSH, which is a nontoxic agent that targets the COX-2 and PI3K/Akt signaling pathways in melanomas to inhibit tumor development. PMID- 23112251 TI - Starting a family: characteristics associated with men's reproductive preferences. AB - Compared with previous generations in the United States, men today are starting families later in life and having fewer children. As a result birthrates in the United States have dropped sharply, and some men never make the transition into parenthood. Using data from the 2006-2010 National Survey of Family Growth, this study examines the characteristics of childless men in the United States between the ages of 15 and 44 (N = 6,168) and whether these men want to have a child sometime in the future. Our main finding is that the majority of childless men want a child someday; however, by the age of 45 more than 1 in 7 still remain childless. PMID- 23112252 TI - Uncovering a role for endocannabinoid signaling in autophagy in preimplantation mouse embryos. AB - Endocannabinoid signaling plays various roles in directing reproductive processes. Mouse embryos are shown to express high levels of CB1 receptor (CB1R). Low concentrations of anandamide stimulate embryo growth and implantation but at higher concentrations it adversely affects implantation. We tested the hypothesis that high levels of endocannabinoids cause autophagic activation and cell death in preimplantation mouse embryos. We used methanandamide (METH), a selective CB1R agonist, to examine the effect of heightened endocannabinoid signaling on autophagy in mouse embryos. Western blotting, immunofluorescence staining, transmission electron microscopy and TUNEL analysis were performed. We observed that METH treatment in vitro or in vivo up-regulated autophagic response in preimplantation mouse embryos. In blastocysts, apoptosis was also increased after METH injections. At 28 nM, which is considered a high physiological dose to embryonic cells, METH up-regulated autophagic activation in trophoblast stem cells. This work demonstrates for the first time that blastocysts respond to higher than normal levels of endocannabinoid by increasing autophagic activation and apoptosis. PMID- 23112253 TI - Causes and predictors of mortality in hospitalized lupus patient in Sarawak General Hospital, Malaysia. AB - Systemic lupus erythematosus (SLE) is a serious autoimmune disease that can be life threatening and fatal if left untreated. Causes and prognostic indicators of death in SLE have been well studied in developed countries but lacking in developing countries. We aimed to investigate the causes of mortality in hospitalized patients with SLE and determine the prognostic indicators of mortality during hospitalization in our center. All SLE patients who were admitted to Sarawak General Hospital from January 1, 2006 to December 31, 2010, were followed up in a prospective study using a standard protocol. Demographic data, clinical features, disease activities and damage indices were collected. Logistic regression and Cox regression analysis were used to determine the prognostic indicators of mortality in our patients. There were a total of 251 patients in our study, with the female to male ratio 10 to 1. Our study patients were of multiethnic origins. They had a mean age of 30.5 +/- 12.2 years and a mean duration of illness of 36.5 +/- 51.6 months. The main involvements were hematologic (73.3%), renal (70.9%) and mucocutaneous (67.3%). There were 26 deaths (10.4%), with the main causes being: infection and flare (50%), infection alone (19%), flare alone (19%) and others (12%). Independent predictors of mortality in our cohort of SLE patients were the presence of both infection and flare of disease (hazard ratio (HR) 5.56) and high damage indices at the time of admission (HR 1.91). Infection and flare were the main causes of death in hospitalized Asian patients with SLE. The presence of infection with flare and high damage indices at the time of admission were independent prognostic indicators of mortality. PMID- 23112255 TI - Severe diet-related iron deficiency anaemia in a 17-month-old child. AB - A 17-month-old girl presented with an upper respiratory tract infections, and was found to have a haemoglobin of 3.3 g/dl. Although noticeably pale, she was largely asymptomatic. Her iron deficiency anaemia was found to be the result of poor diet. With oral iron supplements and improved diet, her haemoglobin increased rapidly, and she is now doing very well. PMID- 23112254 TI - Standard of practice: embolization of spinal arteriovenous fistulae, spinal arteriovenous malformations, and tumors of the spinal axis. PMID- 23112256 TI - Pneumatosis intestinalis in a patient with recurrent Clostridium difficile infection. AB - A 65-year-old man with long-standing diarrhoea, recurrent Clostridium difficile infection (CDI) in the previous 5 months presented to the gastroenterology clinic with recurrent diarrhoea and abdominal cramping. Physical examination was negative for signs of acute abdomen. Stool C difficile PCR was positive. Abdominal imaging demonstrated an extensive pneumatosis intestinalis involving the small bowel and a dilated small bowel loop. He was treated conservatively with oral vancomycin for recurrent CDI with resolution of diarrhoea and abdominal cramping on 1-month follow-up visit. PMID- 23112257 TI - Acute onset of focal seizures, psychiatric features and confusion: a case of autoimmune encephalitis? AB - An elderly woman presented with disorganised thinking, unusual behaviour and clustered episodes of speech arrest accompanied by right-sided face and arm twitching. The following investigations were normal: interictal electroencephalography, brain MRI, cerebrospinal fluid viral PCR and cell count and voltage-gated potassium channel-complex, N-methyl-d-aspartate receptor, gamma aminobutyric acid (B) receptor, alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor, glycine receptor, glutamic acid decarboxylase and paraneoplastic antibodies. The syndrome showed partial spontaneous resolution but 1 year later, typical postencephalopathic features persisted including disinhibition and alteration of sleep-wake cycle. The most likely clinical diagnosis was autoimmune encephalitis and the broader differential diagnoses are discussed within the article. This case demonstrates the need to be aware of this under-recognised and potentially treatable entity. PMID- 23112258 TI - Herpes zoster ophthalmicus in an otherwise healthy 2-year-old child. AB - The following report describes a previously healthy 2-year-old girl with herpes zoster ophthalmicus (HZO). The child presented with a painless vesicular skin eruption covering the left forehead. There was only a history of household exposure to varicella zoster virus (VZV) and the child had not been vaccinated against VZV. PCR assays on vesicular fluid identified VZV DNA. Treatment with acyclovir was started early in the clinical course. In addition, the girl was treated with locally administered ophthalmological acyclovir ointment. Besides some dermal excoriations, a complete resolution of the HZO was achieved without sequelae. PMID- 23112259 TI - Low-voltage EEG activity presenting from psychotic stage in a patient with anti NMDA receptor encephalitis. AB - EEG in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis shows generalised or predominantly frontotemporal delta-theta activity, and epileptiform potentials are less frequent than slowness. The voltage of EEG activity in this disorder is uncertain. We studied the voltage pattern of EEG of two patients. Both patients had psychiatric symptoms, central hypoventilation requiring prolonged ventilatory support, seizures, involuntary movements and autonomic instability. No patient showed abnormal findings on conventional MRI. Mature teratoma was diagnosed in one patient after ovarian tumour resection. Both patients received corticosteroids and intravenous immunoglobulins, and plasmapheresis. One patient recovered completely. In one patient, teratoma was not found, and ventilatory support or sedative drugs were given for about 35 months. The EEG voltages in both patients were decreased in all brain areas as compared with those of the healthy controls. Low-voltage EEG activity in all brain areas was evident from the psychotic stage. PMID- 23112260 TI - Novel mutation of SRD5A2 gene in a patient with 5alpha-reductase 2 deficiency from India. AB - Master N had genital malformation at birth and had bilateral gonads in the labial fold. He was reared as a boy and corrective surgery was done at the age of 4 years and was reassessed at the age of 14 years. His testosterone/dihydrotestosterone (DHT) was 11.8 (reference range <=10). Molecular analysis of SRD5A2 gene indicated the presence of a novel heterozygous missense mutation of p.A52T in exon 1, which was also detected in mother. The father, sister and maternal grandfather were found to have normal SRD5A2 gene sequence. We also detected an intronic (1-2) homozygous T>C transition in patient, whereas both parents were found to have the same transition in heterozygous form. Although 5alpha-steroid reductase 2 deficiency is an autosomal-recessive disorder, in this case, it appears that there may be a dominant inheritance because only one identified mutation was present which was passed from mother to son. PMID- 23112261 TI - A ''not so superficial" skin infection in a patient with diabetes. AB - A woman in her 60s with type 2 diabetes presented with a 4-week history of a rash on her chest wall, flu-like symptoms and a red right eye. On examination, there was a cellulitic rash over the right chest wall, breast and neck and a hypopyon in the right eye. Chest x-ray demonstrated right upper lobe opacification, with subsequent CT and MRI revealing bilateral collections at the lung apices, and a possible permeative bone destruction of the manubrium, respectively. A diagnosis of primary sternal osteomyelitis with associated lung abscesses, chest wall cellulitis and hypopyon due to endogenous endophthalmitis was made, with microbiological assessment identifying group B beta-haemolytic streptococci. The patient underwent surgical debridement of the affected tissue and received 6 weeks of intravenous antibiotics. This case highlights the role of multidisciplinary team involvement in management of infections and the need to consider deep-seated infection in diabetics. PMID- 23112262 TI - Bilateral metastatic melanoma to the extraocular-muscles simulating thyroid eye disease. AB - We report a case of bilateral metastatic melanoma to the extraocular muscles that simulated thyroid eye disease. A 71-year-old man presented with bilateral painless axial proptosis, lid retraction and left gaze restriction. Orbital CT scan demonstrated enlargement of the extraocular muscles with tendon sparing, consistent with thyroid eye disease. However, thyroid function tests and antithyroid antibodies were normal. Systemic review including orbital MRI scan determined the correct diagnosis of metastatic melanoma to the orbit. Metastatic melanoma to the orbit can simulate thyroid eye disease. PMID- 23112263 TI - A rare grade III symptomatic Tsunoda class III left lobe hepatolithiasis in a North American woman. AB - A 44-year-old Caucasian woman without any identified predisposing factors, presented to her local emergency room with multiple episodes of recurrent ascending cholangitis. She underwent a laparoscopic cholecystectomy several years prior to her admission to the hospital for parenteral antibiotic therapy and she had no personal or family history of hypercholesterolaemia. Transferred to a tertiary hospital for surgical therapy, she underwent a left hepatic resection for a chronically infected left lobe hepatolithiasis (HL) conditioning atrophy of the parenchyma due to obstruction of the biliary tree by multiple large cholesterol stones. HL is a very rare condition in Western countries and its aetiology and predisposing factors are still unclear. We present her symptomatology, diagnostic and therapeutic management and discuss the epidemiology and risk factors of HL, that is, a common condition in South East Asia while exceptional in Caucasian patients who have not travelled in high prevalence regions. PMID- 23112264 TI - Illicit ketamine and its bladder consequences: is it irreversible? AB - Ketamine bladder is a new clinical entity that may lead to irreversible damage to the urinary system. We report the severe lower urinary tract symptoms of four young patients referred to our urology unit who were found to have ulcerative cystitis secondary to ketamine abuse. The pathophysiology remains unclear and the treatment is symptomatic. PMID- 23112265 TI - Post-LASIK edema-induced keratopathy (PLEK), a new name based on pathophysiology of the condition. AB - A 33-year-old man who underwent uneventful laser in situ keratomileusis (LASIK) developed pressure-induced stromal edema resulting in an interface haze in both eyes and a pocket of fluid under the flap of the right eye 10 days after surgery, while receiving topical fluorometholone. Intraocular pressure by applanation tonometry was 16 mm Hg in his right eye (erroneous result due to the fluid in the interface) and 34 mm Hg in his left eye. After discontinuation of steroids and addition of ocular hypotensive medication, interface fluid collection disappeared in his right eye. Visual acuity improved and haze diminished in both eyes. This case illustrates that in the same patient a post-LASIK edema induced syndrome may be present with or without fluid in the interface, suggesting that both clinical pictures could be manifestations of a broad spectrum of the same condition. We suggest a new name for this non-inflammatory disorder: post-LASIK edema-induced keratopathy (PLEK). PMID- 23112266 TI - Collaborative care for sick-listed workers with major depressive disorder: a randomised controlled trial from the Netherlands Depression Initiative aimed at return to work and depressive symptoms. AB - OBJECTIVES: Major depressive disorder (MDD) is associated with absenteeism. In this study, the effectiveness of collaborative care, with a focus on return to work (RTW), was evaluated in its effect on depressive symptoms and the duration until RTW in sick-listed workers with MDD in the occupational health setting. METHODS: In this randomised controlled trial, 126 sick-listed workers with MDD were randomised to usual care (N=61) or collaborative care (N=65). Collaborative care was applied by the occupational physician care manager, supported by a web based tracking system and a consultant psychiatrist. Primary outcome measure was time to response. Secondary outcome measures were time to remission, depressive symptoms as continuous measure and the duration until full RTW. RESULTS: Collaborative care participants had a shorter time to response, with a difference of 2.8 months. However, no difference was found on time to remission or depressive symptoms as continuous measure. With a mean of 190 days in the collaborative care group, and 210 days in the usual care group, the groups did not differ significantly from each other in the duration until full RTW. Adherence to the collaborative care intervention was low. CONCLUSIONS: These results do not justify a widespread implementation of collaborative care in occupational healthcare, as it was operationalised in this study. However, since the study might have been underpowered for RTW and because treatment integrity was low, further research, with larger sample sizes, is needed to develop the best fitting (collaborative care) model for addressing RTW in depressed sick listed workers. TRIAL REGISTRATION: : ISRCTN78462860. PMID- 23112267 TI - Occupational solvent exposure during pregnancy and child behaviour at age 2. AB - OBJECTIVES: Many women who work during pregnancy are occupationally exposed to toxicants. The developing central nervous system is highly vulnerable to neurotoxicants such as solvents. Although the neurotoxicity of solvents to adults is well established, very few studies have examined their effects on children's behaviour following prenatal exposure. METHODS: Women from the Perturbateurs endocriniens: Etude Longitudinale sur les Anomalies de la Grossesse, l'Infertilite et l'Enfance (PELAGIE) mother-child cohort (including 3005 working women) were recruited in Brittany (France) between 2002 and 2006, at the beginning of pregnancy, to assess occupational exposure to solvents at that time. Child behaviour was documented at age 2 by mothers (n=1278) assessing components of attention deficit/hyperactivity, aggression, opposition and emotionality. We used a multiple linear regression analysis to evaluate the association between occupational solvent exposure and children's behaviour. Complementary sensitivity analyses allowed us to handle missing data, due mostly to attrition. RESULTS: 20% of women reported occasional exposure and 31% regular exposure to solvents. Children prenatally exposed were more likely to have higher scores of attention deficit/hyperactivity and aggression, and dose-response relations were observed. CONCLUSIONS: The dose-response effect and the high prevalence of children potentially exposed to solvents from their mother's workplace exposure underline the public health relevance of this result. Our results should be replicated in further studies designed to identify which solvents are most deleterious and to assess child behaviour at school age. PMID- 23112269 TI - Validated chromatographic methods for determination of perindopril and amlodipine in pharmaceutical formulation in the presence of their degradation products. AB - Two specific, sensitive, and precise stability-indicating chromatographic methods have been developed, optimized and validated for determination of perindopril arginin (PER) and amlodipine besylate (AML) in their mixtures and in the presence of their degradation products. The first method was based on thin-layer chromatography (TLC) combined with densitometric determination of the separated bands. Adequate separation was achieved using silica gel 60 F254 TLC plates and ethyl acetate-methanol-toluene-ammonia solution, 33% (6.5:2:1:0.5 by volume), as a developing system. The second method was based on high-performance liquid chromatography, by which the proposed components were separated on a reversed phase C18 analytical column using a mobile phase consisting of phosphate buffer (pH 2.5, 0.01 M)-acetonitrile-tetrahydrofuran (60:40:0.1% by volume) with ultraviolet detection at 218 nm. Different parameters affecting the suggested methods were optimized for maximum separation of the cited components. System suitability parameters of the two developed methods were also tested. The suggested methods were validated in compliance with the ICH guidelines and were successfully applied for the quantification of PER and AML in their commercial tablets. Both methods were also statistically compared to each other and to the reference methods with no significant differences in performance. PMID- 23112268 TI - Mental and physical health-related quality of life among U.S. cancer survivors: population estimates from the 2010 National Health Interview Survey. AB - BACKGROUND: Despite extensive data on health-related quality of life (HRQOL) among cancer survivors, we do not yet have an estimate of the percentage of survivors with poor mental and physical HRQOL compared with population norms. HRQOL population means for adult-onset cancer survivors of all ages and across the survivorship trajectory also have not been published. METHODS: Survivors (N = 1,822) and adults with no cancer history (N = 24,804) were identified from the 2010 National Health Interview Survey. The PROMIS(r) Global Health Scale was used to assess HRQOL. Poor HRQOL was defined as 1 SD or more below the PROMIS(r) population norm. RESULTS: Poor physical and mental HRQOL were reported by 24.5% and 10.1% of survivors, respectively, compared with 10.2% and 5.9% of adults without cancer (both P < 0.0001). This represents a population of approximately 3.3 million and 1.4 million U.S. survivors with poor physical and mental HRQOL. Adjusted mean mental and physical HRQOL scores were similar for breast, prostate, and melanoma survivors compared with adults without cancer. Survivors of cervical, colorectal, hematologic, short-survival, and other cancers had worse physical HRQOL; cervical and short-survival cancer survivors reported worse mental HRQOL. CONCLUSION: These data elucidate the burden of cancer diagnosis and treatment among U.S. survivors and can be used to monitor the impact of national efforts to improve survivorship care and outcomes. IMPACT: We present novel data on the number of U.S. survivors with poor HRQOL. Interventions for high-risk groups that can be easily implemented are needed to improve survivor health at a population level. PMID- 23112270 TI - Comparison of clinical data, CT, and bone histopathology in unilateral chronic maxillary sinusitis. AB - OBJECTIVES: To evaluate bone changes demonstrated by computed tomography (CT) as a predictor of the severity of chronic rhinosinusitis. STUDY DESIGN: Cross sectional study. SETTINGS: Tertiary referral university medical center. SUBJECTS AND METHODS: Thirty-eight patients diagnosed with unilateral chronic maxillary sinusitis underwent endoscopic sinus surgery from 2003 to 2009. Preoperative CTs of all patients were reviewed by a single radiologist blinded to the pathologic diagnosis. Bone density was evaluated and expressed in Hounsfield units (HU). Sinus wall thickness (WT) was also measured and compared with the contralateral side. All the histopathologic specimens were reviewed. A database was constructed containing demographic data, clinical symptoms, CT measurements, and histopathologic findings. RESULTS: Average age was 44.07 years, with 22 women (57.9%) and 16 men (42.1%). The average wall density (WD) was 828.7 HU, and no correlation was found between the density of the diseased maxillary sinus bony walls and the severity of the histopathologic inflammatory process of the soft tissue (P = .474). The average wall thickness of the diseased sinuses was 2.6 mm, and a correlation was found between inflammation severity and wall thickness (P = .018). Wall thickening was found in 97.3% of the cases and an increase in density in 78.9% without correlation between WD and WT. CONCLUSION: Wall thickness but not WD obtained from CT scans may be a simple index for evaluation of unilateral chronic rhinosinusitis and its severity. Further studies confirming these results and comparing them with clinical correlates are indicated. PMID- 23112271 TI - Detection of staphylococcal exotoxins in antrochoanal polyps and chronic rhinosinusitis with nasal polyps. AB - OBJECTIVE: Staphylococcal exotoxins have been reported in the pathogenesis of many chronic inflammatory diseases. Recent reports have hypothesized that staphylococcal exotoxins might be related to inflammatory mucosal changes seen in chronic sinusitis with nasal polyps (CRS-NPs). Staphylococcal exotoxins have the capacity to act as superantigens (SAgs), bypassing normal antigen processing and directly stimulating a massive inflammatory response. The objective of this study was to analyze polyp tissue samples from patients with antrochoanal polyps (ACPs) and CRS-NPs for the presence of staphylococcal exotoxins. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Tissue samples were obtained from 29 patients and 16 controls. Thirteen of 29 patients had ACPs, and 16 had CRS-NPs. Specimens were analyzed for the presence of 5 staphylococcal exotoxins (SEA, SEB, SEC, SED, and toxic shock syndrome toxin 1) using enzyme-linked immunosorbent assay (ELISA). RESULTS: At least 1 toxin was detected in 7 of 13 patients with ACPs and in 13 of 16 patients with CRS-NPs, whereas it was detected in only 4 controls. There were no statistically significant differences between ACP and control groups (P = .063). Our results showed a statistically significant association between toxin detection and patients with CRS-NPs (P = .003). CONCLUSION: Inflammatory triggers in ACP remain a subject of debate, and this study does not support the hypothesis that staphylococcal exotoxins may play a role in ACP ethiopathogenesis. Our research is consistent with the possibility of SAgs as etiological agents in the development of bilateral nasal polyposis. PMID- 23112272 TI - Botulinum toxin for the treatment of sialorrhea: a meta-analysis. AB - OBJECTIVES: Botulinum toxin has emerged as an effective approach for the management of sialorrhea. This study presents a critical literature review and meta-analysis to determine the impact of botulinum toxin on drooling severity in patients with sialorrhea. DATA SOURCES: Ovid MEDLINE and the Cochrane databases. REVIEW METHODS: The above sources were searched to identify studies examining botulinum toxin for the treatment of sialorrhea. Included studies were randomized, placebo-controlled trials. Excluded studies failed to report quantifiable outcome measures of drooling severity at 4 weeks postintervention. RESULTS: Eight studies involving 181 patients (83 placebo; 98 active) were included in the analysis. Botulinum toxin was found to significantly decrease the severity of drooling in patients with sialorrhea (standardized mean difference [SMD], -1.54; 95% confidence interval [CI], -2.05 to -1.04; P = .06; I (2) = 48%) when compared with placebo control using random effects models. The effect was significant in both adult (SMD, -1.29; 95% CI, -1.88 to -0.71) and pediatric (SMD, -1.84; 95% CI, -2.67 to -1.00) populations. Both botulinum toxin A (SMD, 1.53; 95% CI, -2.27 to -0.79) and B (SMD, -1.56; 95% CI, -2.32 to -0.79) produced similar effects. Botulinum toxin doses greater than 50 U (SMD, -3.81; 95% CI, 6.19 to -1.43) produced much stronger effects compared with doses less than or equal to 50 U (SMD, -1.32; 95% CI, -2.28 to -0.36). CONCLUSION: Botulinum toxin is a clinically effective therapy that improves drooling severity in patients with sialorrhea. Future studies will need to further evaluate the technique and examine dosages required to achieve optimal outcomes. PMID- 23112273 TI - Sleep endoscopy with midazolam: sedation level evaluation with bispectral analysis. AB - OBJECTIVE: This study examines subjects' level of consciousness with bispectral analysis in sedation endoscopy of the upper airway. STUDY DESIGN: A prospective study. SETTING: University hospital. SUBJECTS AND METHODS: Bispectral analysis levels recorded in natural sleep of 43 patients with obstructive sleep apnea during an overnight polysomnographic sleep study were directly compared with the levels recorded during midazolam sedation sleep endoscopy in the same subjects. The possible muscle relaxation effect of midazolam was examined via surface chin electrodes. Supine Muller maneuver findings in 50 patients with obstructive sleep apnea were also compared with soft tissue dynamics during midazolam sedation sleep endoscopy. RESULTS: In our study of the 43 patients with bispectral analysis during natural sleep and midazolam sedation sleep endoscopy, a predominance of bispectral analysis values indicating N1 and N2 sleep was observed during the sedation study. Midazolam failed to achieve deeper levels of sleep with minimal N3 and no convincing rapid eye movement. As N1 and N2 are the stages during which maximal dynamic activities occur, and they make up an average of 70.5% of total sleep time, from 210 sleep studies at our laboratory, the present technique would be ideal as a surgical assessment tool. No muscle relaxation effect could be detected at our protocol dose of midazolam. The supine Muller maneuver findings were significantly different from those observed during sedation sleep. CONCLUSION: These findings support the value of sleep endoscopy as an efficient and informative technique for the examination of upper airway dynamics relevant to focused surgical planning. PMID- 23112274 TI - Association between anxiety, type A personality, and treatment outcome of dysphonia due to benign causes. AB - OBJECTIVE: Dysphonia has been linked to psychosocial factors such as anxiety and personality type. The aim of this study is to determine whether these factors also affect the treatment outcome of benign dysphonia. STUDY DESIGN: Prospective case series. SETTING: Voice clinic of a tertiary otolaryngology clinic. SUBJECTS AND METHODS: Thirty-seven patients diagnosed with benign dysphonia over a 3-month period were included. Demographic data, the Voice Handicap Index-10 (VHI-10), Reflux Symptom Index (RSI), Clinical Anxiety Scale (CAS), and Bortner Personality Scale were recorded at presentation. After a period of treatment with lifestyle advice, proton pump inhibitors, and/or speech therapy, the VHI-10 and RSI were repeated. RESULTS: After standard dysphonia treatment, 18 patients who reported complete recovery were found to be significantly less anxious (lower CAS scores) than those who did not recover completely (P = .023). However, there was no significant difference in number of complete recoveries between patients of personality types A and B (P > .05). Multivariate regression showed that higher CAS scores had a negative influence on the amount of improvement of VHI-10 (P = .026) but had no impact on RSI (P = .148). Again, personality type had no influence on either RSI or VHI-10 improvement (both P > .05). An additional factor, older age, was found to predict negatively for the amount of RSI improvement (P = .017), but no other predictive variables were identified. CONCLUSION: This is the first study to show that psychosomatic factors may affect treatment outcome in patients with dysphonia due to benign causes. The benefit of adjunctive psycho-cognitive measures warrants further investigation. PMID- 23112275 TI - An evaluation of biodegradable synthetic polyurethane foam in patients following septoplasty: a prospective randomized trial. AB - OBJECTIVE: The purpose of this study is to examine the usability of biodegradable synthetic polyurethane foam (BSPF) after septoplasty by comparing it with Merocel and silicone intranasal splints as packing materials in terms of patient comfort and efficiency. STUDY DESIGN: A prospective, unmasked, randomized trial. SETTING: A tertiary referral center. SUBJECTS AND METHODS: This study was designed to be a prospective, randomized clinical trial. Sixty-eight patients who underwent septoplasty were included in this study. The patients were randomized to receive Merocel, silicone intranasal septal splint (INS), or BSPF after septoplasty. Clinical efficacy on bleeding, pain, and subjective symptoms related to packing materials was evaluated. RESULTS: There was a statistically significant difference between the Merocel group and the other 2 groups in terms of bleeding and adhesion. The average score on the pain scale was 2.47 +/- 1.01 for BSPF, 3.68 +/- 1.27 for INS, and 6 +/- 2.21 for Merocel. Scores on general satisfaction scales were 6.95 +/- 1.42 for Merocel, 8.44 +/- 2.12 for INS, and 8.28 +/- 1.88 for BSPF. CONCLUSION: The efficacy of BSPF was comparable with that of Merocel and INS. Biodegradable synthetic polyurethane foam significantly reduced pain and patient discomfort during packing and removal, followed by INS, compared with Merocel. PMID- 23112276 TI - A parenteral nutrition use survey with gap analysis. AB - BACKGROUND: Parenteral nutrition (PN) is a high-alert medication for which safe practice guidelines are available. Recent adverse events associated with PN have been widely reported. A survey of current practices was indicated as new guidelines are being considered. METHODS: A web-based survey consisting of 70 items was made available for the month of August 2011. Respondents provided answers to questions that addressed all aspects of the PN use process. RESULTS: There were a total of 895 respondents to the survey, including dietitians, nurses, pharmacists, and physicians. They predominantly represented hospital settings (89%), with 44% from academic institutions. Most organizations use a once-daily PN admixture with 21% outsourcing preparation. Electronic PN order entry is available in one-third of organizations, and the use of standardized order sets prevails. Unfortunately, electronic interfaces between computer systems remain infrequent, meaning that at least one transcription step is required by most in the PN use process. There are a wide variety of methods for ordering PN components, many of which are inconsistent with safe practices. Most organizations dedicate a pharmacist to review the PN orders, many of which require clarifications. Documentation at each step of the PN use process with oversight to identify deviations from best practice recommendations is infrequent. A significant proportion (44%) does not track PN-related medication errors. CONCLUSIONS: The survey data are a valuable snapshot of current practices with PN. Poor compliance with some of the safe practice guidelines continues. This will help guide new safety initiatives for the PN use process. PMID- 23112277 TI - Compatibility of intravenous medications with parenteral nutrition: in vitro evaluation. AB - BACKGROUND AND AIM: Hospitalized patients requiring parenteral nutrition (PN) often need to receive intravenous (IV) medications as well. Y-site administration is occasionally necessary, but physicochemical incompatibilities can occur between the medications and PN. The aim of the present study was to assess the physical compatibility between 25 frequently coadministered IV medications and a commercially available ready-to-use total PN. METHODS: PN (NuTRIflex Lipid Special; B. Braun Medical AG, Sempach, Switzerland) and medications were mixed in 1:1 (v/v) proportions, and the stability was assessed at the time of mixing and after 1 and 4 hours. The stability of lipid emulsion was observed by microscopic investigation, visual inspection, dynamic laser light scattering, and laser light obscuration. The binary admixtures of PN (without lipid emulsion) and medications were used to detect discoloration, visibly detectable precipitates, and subvisual particles. RESULTS: Two of 25 medications were incompatible with the lipid emulsion (serum albumin 20% and tropisetron), 2 showed signs of degradation (discoloration) over time (esomeprazole and pantoprazole), and 1 precipitated at high concentrations (5-fluorouracil). The other 20 medications were considered compatible when administered by Y-site. CONCLUSION: The present study validated the compatibility of 1 commercially available PN and 20 medications. These results offer new solutions to support the implementation of complex therapeutic schemes in practice, when coadministration via Y-site cannot be avoided. PMID- 23112278 TI - Kinematics variations after spring-assisted orthosis training in persons with stroke. AB - BACKGROUND: Static wrist splinting after stroke was not effective in facilitating distal movement. However, the purpose of this study is to evaluate the efficacy of training using kinematic parameters after a SaeboFlex orthosis training on chronic stroke patients. CASE DESCRIPTION AND METHODS: Five stroke patients participated in 4 weeks of training using a SaeboFlex orthosis for 1 hour per day, five times per week. Fugl-Meyer Assessment, Box and Block Test, Action Research Arm Test, and Kinematics using a three-dimensional motion analysis system were used for evaluating of training effects. FINDINGS AND OUTCOMES: The upper extremity score of the Fugl-Meyer Assessment and the Box and Block Test score were increased significantly after the intervention. The jerkiness score of the shoulder and elbow joints at the sagittal plane decreased significantly during the reach-to-grasp task at acromion height, and the jerkiness scores of the wrist joint during the reach-to-grasp task decreased significantly at both elbow and acromion heights. CONCLUSION: The results of this study indicate that a SaeboFlex training is effective in recovering the movement of the hemiparetic upper extremity of patients after stroke. CLINICAL RELEVANCE: Using a spring assisted dynamic hand orthosis is considered to be an effective treatment option for providing repetition, task-oriented training, and real-world activities for the hemiparetic upper extremity, which was impaired hand to perform functional training. PMID- 23112279 TI - Environmental oestrogens and breast cancer: long-term low-dose effects of mixtures of various chemical combinations. PMID- 23112281 TI - Immunosuppression increases JC polyomavirus large T antigen DNA load in the brains of patients without progressive multifocal leukoencephalopathy. AB - The relationship between latent JC polyomavirus (JCV) infection and progressive multifocal leukoencephalopathy (PML) remains unclear. In this study, JCV DNA was quantified by real-time polymerase chain reaction (qPCR) in brain and kidney tissue from patients without PML. Immunosuppressed patients had significantly higher JCV DNA levels in brain, compared with immunocompetent patients (P = .001). An inverse relationship was observed between CD4(+) T-cell counts and qPCR determined brain JCV load among patients with HIV infection (r(2) = -0.9; P = .01; n = 7). Higher kidney JCV DNA load was strongly associated with higher brain JCV DNA load (Spearman rho = 0.65; P = .004; n = 18). These findings highlight the importance of latent JVC brain infection to the pathogenesis of PML. PMID- 23112280 TI - A GH3 family member, OsGH3-2, modulates auxin and abscisic acid levels and differentially affects drought and cold tolerance in rice. AB - Plant responses to abiotic stresses are coordinated by arrays of growth and developmental processes. Indole-3-acetic acid (IAA) and abscisic acid (ABA) play critical roles in developmental programmes and environmental responses, respectively, through complex signalling and metabolism networks. However, crosstalk between the two phytohormones in the stress responses remains largely unknown. Here, it is reported that a GH3 family gene, OsGH3-2, encoding an enzyme catalysing IAA conjugation to amino acids, is involved in the modulation of ABA level and stress tolerance. Expression of OsGH3-2 was induced by drought but was suppressed by cold. Overexpression of OsGH3-2 in rice caused significant morphological aberrations related to IAA deficiency, such as dwarfism, smaller leaves, and fewer crown roots and root hairs. The overexpressing line showed significantly reduced carotene, ABA, and free IAA levels, greater stomata aperture, and faster water loss, and was hypersensitive to drought stress. However, the overexpressing line showed increased cold tolerance, which was due to the combined effects of reduced free IAA content, alleviated oxidative damage, and decreased membrane penetrability. Furthermore, expression levels of some ABA synthesis- and stress-related genes were significantly changed in the overexpression line. It was conclude that OsGH3-2 modulates both endogenous free IAA and ABA homeostasis and differentially affects drought and cold tolerance in rice. PMID- 23112284 TI - Handover training: does one size fit all? The merits of mass customisation. AB - BACKGROUND: Experts have recommended training and standardisation as promising approaches to improve handovers and minimise the negative consequences of discontinuity of care. Yet the content and delivery of handover training have been only superficially examined and described in literature. OBJECTIVE: The aim of this study was to formulate recommendations for effective handover training and to examine whether standardisation is a viable approach to training large numbers of healthcare professionals. METHODS: A training needs analysis was conducted by means of a questionnaire, which was filled out by 96 healthcare professionals in primary and secondary care in the Netherlands, Spain, Sweden and Poland. Preferences and recommendations regarding training delivery aspects and training topics that should be included in the handover training were measured. RESULTS: The majority of the participants recommended a short conventional training session with practice assignments, to be completed in small, multidisciplinary groups. Formal examination, e-learning and self-study were not favoured. Recommended training topics were: communication skills, standardised procedures, knowing what to hand over, alertness to vulnerable patient groups and awareness of responsibility. CONCLUSIONS: The idea of completely standardised handover training is not in line with the identified differences in preferences and recommendations between different handover stakeholders. Mass customisation of training, in which generic training is adapted to local or individual needs, presents a promising solution to address general and specific needs, while containing the financial and time costs of designing and delivering handover training. PMID- 23112285 TI - "It's like two worlds apart": an analysis of vulnerable patient handover practices at discharge from hospital. AB - BACKGROUND: Handover practices at hospital discharge are relatively under researched, particularly as regards the specific risks and additional requirements for handovers involving vulnerable patients with limited language, cognitive and social resources. OBJECTIVE: To explore handover practices at discharge and to focus on the patients' role in handovers and on the potential additional risks for vulnerable patients. METHODS: We conducted qualitative interviews with patients, hospital professionals and primary care professionals in two hospitals and their associated primary care centres in Catalonia, Spain. RESULTS: We identified handover practices at discharge that potentially put patients at risk. Patients did not feel empowered in the handover but were expected to transfer information between care providers. Professionals identified lack of medication reconciliation at discharge, loss of discharge information, and absence of plans for follow-up care in the community as quality and safety problems for discharge handovers. These occurred for all patients, but appeared to be more frequent and have a greater negative effect in patients with limited language comprehension and/or lack of family and social support systems. CONCLUSIONS: Discharge handovers are often haphazard. Healthcare professionals do not consider current handover practices safe, with patients expected to transfer information without being empowered to understand and act on it. This can lead to misinformation, omission or duplication of tests or interventions and, potentially, patient harm. Vulnerable patients may be at greater risk given their limited language, cognitive and social resources. Patient safety at discharge could benefit from strategies to enhance patient education and promote empowerment. PMID- 23112286 TI - Comparing the utility of a novel neonatal resuscitation cart with a generic code cart using simulation: a randomised, controlled, crossover trial. AB - OBJECTIVE: To compare a novel neonatal resuscitation cart (NRC) to a generic code cart (GCC). STUDY DESIGN: A prospective, randomised, controlled, crossover trial was performed to compare the utility of the NRC with the GCC during simulated deliveries of extremely low birthweight infants and infants with gastroschisis. Fifteen subjects participated. Mean times and accuracy of equipment and supply retrieval were compared for each scenario using the Wilcoxon test. RESULTS: Mean acquisition times for the NRC were always faster (by 58% to 74%) regardless of scenario (p<0.01). Accuracy of equipment selection did not differ. Ease of use was judged using a Likert scale (1=easiest to use; 5=most difficult), with mean score for NRC 1.1 and GCC 3.7 (p<0.0001). All subjects rated the NRC as easier to use. CONCLUSIONS: The NRC was superior to the GCC in acquisition speed, supply selection and ease of use. PMID- 23112287 TI - Safety climate research: taking stock and looking forward. PMID- 23112288 TI - Perceived causes of prescribing errors by junior doctors in hospital inpatients: a study from the PROTECT programme. AB - INTRODUCTION: Prescribing errors are a major cause of patient safety incidents. Understanding the underlying factors is essential in developing interventions to address this problem. This study aimed to investigate the perceived causes of prescribing errors among foundation (junior) doctors in Scotland. METHODS: In eight Scottish hospitals, data on prescribing errors were collected by ward pharmacists over a 14-month period. Foundation doctors responsible for making a prescribing error were interviewed about the perceived causes. Interview transcripts were analysed using content analysis and categorised into themes previously identified under Reason's Model of Accident Causation and Human Error. RESULTS: 40 prescribers were interviewed about 100 specific errors. Multiple perceived causes for all types of error were identified and were categorised into five categories of error-producing conditions, (environment, team, individual, task and patient factors). Work environment was identified as an important aspect by all doctors, especially workload and time pressures. Team factors included multiple individuals and teams involved with a patient, poor communication, poor medicines reconciliation and documentation and following incorrect instructions from other members of the team. A further team factor was the assumption that another member of the team would identify any errors made. The most frequently noted individual factors were lack of personal knowledge and experience. The main task factor identified was poor availability of drug information at admission and the most frequently stated patient factor was complexity. CONCLUSIONS: This study has emphasised the complex nature of prescribing errors, and the wide range of error-producing conditions within hospitals including the work environment, team, task, individual and patient. Further work is now needed to develop and assess interventions that address these possible causes in order to reduce prescribing error rates. PMID- 23112289 TI - Beliefs and experiences can influence patient participation in handover between primary and secondary care--a qualitative study of patient perspectives. AB - BACKGROUND: Communication between healthcare settings at patient transfers between primary and secondary care, 'handover', is a critical and risky process for patients. Patients' views on their roles in these processes are often lacking despite the knowledge that patient participation contributes to enhanced safety and wellbeing. OBJECTIVE: This study aims to improve the knowledge and understanding of patients' perspectives about their participation in handover. METHODS: Twenty-three Swedish patients with chronic diseases were individually interviewed about their experiences with handovers between three clinical microsystems: emergency room, emergency ward and primary healthcare centres. Data were analysed using inductive qualitative content analysis. RESULTS: Patients participated within the microsystems by exchanging information, and between microsystems by making contact with and conveying information to their next healthcare provider. Enablers for participation included positive encounters with providers, patient empowerment and beliefs about organisational factors. Patients' trust in their providers, and providers' attitudes were important factors in patients' willingness to communicate. Patients who thought medical records access was shared across microsystems volunteered less information to their providers. Patients with experiences of non-effective handovers took more responsibility in the handover to ensure continuity of care. CONCLUSIONS: Patients participate actively in handovers when they feel a need for involvement to ensure continuity of care, and are less active when they perceive that their contribution is unnecessary or not valued. In acute care settings with short hospital stays and less time to establish a trusting relationship between patients and their providers, discharge encounters may be important enablers for patient engagement in handovers. The advantages of a redundant handover process need to be considered. PMID- 23112291 TI - Peer support in hospital--a shared journey. PMID- 23112290 TI - The key actor: a qualitative study of patient participation in the handover process in Europe. AB - BACKGROUND: Patient safety experts have postulated that increasing patient participation in communications during patient handovers will improve the quality of patient transitions, and that this may reduce hospital readmissions. Choosing strategies that enhance patient safety through improved handovers requires better understanding of patient experiences and preferences for participation. OBJECTIVE: The aim of this paper is to explore the patients' experiences and perspectives related to the handovers between their primary care providers and the inpatient hospital. METHODS: A qualitative secondary analysis was performed, based on individual and focus group patient interviews with 90 patients in five European countries. RESULTS: The analysis revealed three themes: patient positioning in the handover process; prerequisites for patient participation and patient preferences for the handover process. Patients' participation ranged from being the key actor, to sharing the responsibility with healthcare professional(s), to being passive participants. For active participation patients required both personal and social resources as well as prerequisites such as information and respect. Some patients preferred to be the key actor in charge; others preferred their healthcare professionals to be the key actors in the handover. CONCLUSIONS: Patients' participation is related to the healthcare system, the activity of healthcare professionals' and patients' capacity for participation. Patients prefer a handover process where the responsibility is clear and unambiguous. Healthcare organisations need a clear and well-considered system of responsibility for handover processes, that takes into account the individual patient's need of clarity, and support in relation to his/hers own recourses. PMID- 23112292 TI - Guideline-concordant antipsychotic use and mortality in schizophrenia. AB - OBJECTIVE: To determine if care concordant with 2009 Schizophrenia Patient Outcomes Research Team (PORT) pharmacological recommendations for schizophrenia is associated with decreased mortality. METHODS: We conducted a retrospective cohort study of adult Maryland Medicaid beneficiaries with schizophrenia and any antipsychotic use from 1994 to 2004 (N = 2132). We used Medicaid pharmacy data to measure annual and average antipsychotic continuity, to calculate chlorpromazine (CPZ) dosing equivalents, and to examine anti-Parkinson medication use. Cox proportional hazards regression models were used to examine the relationship between antipsychotic continuity, antipsychotic dosing, and anti-Parkinson medication use and mortality. RESULTS: Annual antipsychotic continuity was associated with decreased mortality. Among patients with annual continuity greater than or equal to 90%, the hazard ratio [HR] for mortality was 0.75 (95% confidence interval [CI] 0.57-0.99) compared with patients with annual medication possession ratios (MPRs) of less than 10%. The HRs for mortality associated with continuous annual and average antipsychotic continuity were 0.75 (95% CI 0.58 0.98) and 0.84 (95% CI 0.58-1.21), respectively. Among users of first-generation antipsychotics, doses greater than or equal to 1500 CPZ dosing equivalents were associated with increased risk of mortality (HR 1.88, 95% CI 1.10-3.21), and use of anti-Parkinson medication was associated with decreased risk of mortality (HR 0.72, 95% CI 0.55-0.95). Mental health visits were also associated with decreased mortality (HR 0.96, 95% CI 0.93-0.98). CONCLUSIONS: Adherence to PORT pharmacological guidelines is associated with reduced mortality among patients with schizophrenia. Adoption of outcomes monitoring systems and innovative service delivery programs to improve adherence to the PORT guidelines should be considered. PMID- 23112294 TI - A global pattern of thermal adaptation in marine phytoplankton. AB - Rising ocean temperatures will alter the productivity and composition of marine phytoplankton communities, thereby affecting global biogeochemical cycles. Predicting the effects of future ocean warming on biogeochemical cycles depends critically on understanding how existing global temperature variation affects phytoplankton. Here we show that variation in phytoplankton temperature optima over 150 degrees of latitude is well explained by a gradient in mean ocean temperature. An eco-evolutionary model predicts a similar relationship, suggesting that this pattern is the result of evolutionary adaptation. Using mechanistic species distribution models, we find that rising temperatures this century will cause poleward shifts in species' thermal niches and a sharp decline in tropical phytoplankton diversity in the absence of an evolutionary response. PMID- 23112293 TI - The Legionella effector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. AB - Eukaryotic cells can use the autophagy pathway to defend against microbes that gain access to the cytosol or reside in pathogen-modified vacuoles. It remains unclear if pathogens have evolved specific mechanisms to manipulate autophagy. Here, we found that the intracellular pathogen Legionella pneumophila could interfere with autophagy by using the bacterial effector protein RavZ to directly uncouple Atg8 proteins attached to phosphatidylethanolamine on autophagosome membranes. RavZ hydrolyzed the amide bond between the carboxyl-terminal glycine residue and an adjacent aromatic residue in Atg8 proteins, producing an Atg8 protein that could not be reconjugated by Atg7 and Atg3. Thus, intracellular pathogens can inhibit autophagy by irreversibly inactivating Atg8 proteins during infection. PMID- 23112295 TI - A bipolar spindle of antiparallel ParM filaments drives bacterial plasmid segregation. AB - To ensure their stable inheritance by daughter cells during cell division, bacterial low-copy-number plasmids make simple DNA segregating machines that use an elongating protein filament between sister plasmids. In the ParMRC system of the Escherichia coli R1 plasmid, ParM, an actinlike protein, forms the spindle between ParRC complexes on sister plasmids. By using a combination of structural work and total internal reflection fluorescence microscopy, we show that ParRC bound and could accelerate growth at only one end of polar ParM filaments, mechanistically resembling eukaryotic formins. The architecture of ParM filaments enabled two ParRC-bound filaments to associate in an antiparallel orientation, forming a bipolar spindle. The spindle elongated as a bundle of at least two antiparallel filaments, thereby pushing two plasmid clusters toward the poles. PMID- 23112296 TI - Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. AB - Aberrant signaling through the class I phosphatidylinositol 3-kinase (PI3K)-Akt axis is frequent in human cancer. Here, we show that Beclin 1, an essential autophagy and tumor suppressor protein, is a target of the protein kinase Akt. Expression of a Beclin 1 mutant resistant to Akt-mediated phosphorylation increased autophagy, reduced anchorage-independent growth, and inhibited Akt driven tumorigenesis. Akt-mediated phosphorylation of Beclin 1 enhanced its interactions with 14-3-3 and vimentin intermediate filament proteins, and vimentin depletion increased autophagy and inhibited Akt-driven transformation. Thus, Akt-mediated phosphorylation of Beclin 1 functions in autophagy inhibition, oncogenesis, and the formation of an autophagy-inhibitory Beclin 1/14-3 3/vimentin intermediate filament complex. These findings have broad implications for understanding the role of Akt signaling and intermediate filament proteins in autophagy and cancer. PMID- 23112298 TI - Thriving on common ground. PMID- 23112302 TI - Science and the law. Prison terms for L'Aquila experts shock scientists. PMID- 23112303 TI - Scientific integrity. Questions about Japanese researcher go back years. PMID- 23112297 TI - Binary millisecond pulsar discovery via gamma-ray pulsations. AB - Millisecond pulsars, old neutron stars spun up by accreting matter from a companion star, can reach high rotation rates of hundreds of revolutions per second. Until now, all such "recycled" rotation-powered pulsars have been detected by their spin-modulated radio emission. In a computing-intensive blind search of gamma-ray data from the Fermi Large Area Telescope (with partial constraints from optical data), we detected a 2.5-millisecond pulsar, PSR J1311 3430. This unambiguously explains a formerly unidentified gamma-ray source that had been a decade-long enigma, confirming previous conjectures. The pulsar is in a circular orbit with an orbital period of only 93 minutes, the shortest of any spin-powered pulsar binary ever found. PMID- 23112305 TI - 2012 election. Congratulations! Now get to work. PMID- 23112304 TI - Neuroethics. When a brain scan bears bad news. PMID- 23112306 TI - 2012 election. For once, science is an issue in race for a seat in Congress. PMID- 23112307 TI - 2012 election. Food labeling issue tops state ballot questions. PMID- 23112308 TI - 2012 election. Want to tear down your rival? Here's what might work best. PMID- 23112309 TI - A curiosity moment for tropical biology? PMID- 23112310 TI - The real costs of research. PMID- 23112311 TI - Duty of care: protecting researchers abroad. PMID- 23112313 TI - Comment on "Conspecific negative density dependence and forest diversity". AB - Johnson and colleagues (Reports, 18 May 2012, p. 904) claim that conspecific negative density dependence is a pervasive mechanism driving forest diversity, especially for rare tree species. We show that their results are due to a statistical bias in their analysis caused by the exclusion of joint absences. PMID- 23112315 TI - Science and society. Social media and the elections. PMID- 23112316 TI - Oceans. The risks of overfishing. PMID- 23112317 TI - Neuroscience. The mood of a worm. PMID- 23112318 TI - Astronomy. Measuring solar magnetism. PMID- 23112319 TI - Anthropology. Did australopiths climb trees? PMID- 23112320 TI - Chemistry. Lending handedness to the cyclopentadienyl ligand. PMID- 23112321 TI - Ecology. Fishing for answers off Fukushima. PMID- 23112323 TI - Medicine. Can intellectual property save drug development? PMID- 23112322 TI - Neuroscience. Decoding the neuronal Tower of Babel. PMID- 23112324 TI - IBI series winner. Student-directed discovery of the plant microbiome and its products. PMID- 23112325 TI - IBI series winner. A mutant search--Caenorhabditis elegans and gene discovery. PMID- 23112326 TI - Glial progenitor cell-based treatment and modeling of neurological disease. AB - The diseases of myelin are among the most prevalent and disabling conditions in neurology. These diseases include both the vascular and inflammatory demyelinating disorders of adulthood, as well as the childhood leukodystrophies and cerebral palsy. These fundamentally glial disorders may be amenable to treatment by glial progenitor cells (GPCs), which give rise to astroglia and myelin-producing oligodendrocytes. Given the development of new methods for generating and isolating human GPCs, the myelin disorders may now be compelling targets for cell-based therapy. In addition, the efficient engraftment and expansion of human GPCs in murine hosts has led to the development of human glial chimeric mouse brains, which provides new opportunities for studying the species specific roles of human glia in cognition, as well as in disease pathogenesis. PMID- 23112327 TI - Biotinylated Rh(III) complexes in engineered streptavidin for accelerated asymmetric C-H activation. AB - Enzymes provide an exquisitely tailored chiral environment to foster high catalytic activities and selectivities, but their native structures are optimized for very specific biochemical transformations. Designing a protein to accommodate a non-native transition metal complex can broaden the scope of enzymatic transformations while raising the activity and selectivity of small-molecule catalysis. Here, we report the creation of a bifunctional artificial metalloenzyme in which a glutamic acid or aspartic acid residue engineered into streptavidin acts in concert with a docked biotinylated rhodium(III) complex to enable catalytic asymmetric carbon-hydrogen (C-H) activation. The coupling of benzamides and alkenes to access dihydroisoquinolones proceeds with up to nearly a 100-fold rate acceleration compared with the activity of the isolated rhodium complex and enantiomeric ratios as high as 93:7. PMID- 23112328 TI - Chiral cyclopentadienyl ligands as stereocontrolling element in asymmetric C-H functionalization. AB - Metal complexes coordinated by a single cyclopentadienyl (Cp) ligand are widely used, versatile catalysts, but their application to asymmetric reactions has been hindered by the difficulty of designing Cp substituents that effectively bias the coordination sphere. Here, we report on a class of simple C(2)-symmetric Cp derivatives that finely control the spatial arrangement of the transiently coordinated reactants around the central metal atom. Rhodium(III) complexes bearing these ligands proved to be highly enantioselective catalysts for directed carbon-hydrogen (C-H) bond functionalizations of hydroxamic acid derivatives. PMID- 23112330 TI - Feathered non-avian dinosaurs from North America provide insight into wing origins. AB - Previously described feathered dinosaurs reveal a fascinating record of feather evolution, although substantial phylogenetic gaps remain. Here we report the occurrence of feathers in ornithomimosaurs, a clade of non-maniraptoran theropods for which fossilized feathers were previously unknown. The Ornithomimus specimens, recovered from Upper Cretaceous deposits of Alberta, Canada, provide new insights into dinosaur plumage and the origin of the avian wing. Individuals from different growth stages reveal the presence of a filamentous feather covering throughout life and winglike structures on the forelimbs of adults. The appearance of winglike structures in older animals indicates that they may have evolved in association with reproductive behaviors. These specimens show that primordial wings originated earlier than previously thought, among non maniraptoran theropods. PMID- 23112329 TI - Fluorescence enhancement at docking sites of DNA-directed self-assembled nanoantennas. AB - We introduce self-assembled nanoantennas to enhance the fluorescence intensity in a plasmonic hotspot of zeptoliter volume. The nanoantennas are prepared by attaching one or two gold nanoparticles (NPs) to DNA origami structures, which also incorporated docking sites for a single fluorescent dye next to one NP or in the gap between two NPs. We measured the dependence of the fluorescence enhancement on NP size and number and compare it to numerical simulations. A maximum of 117-fold fluorescence enhancement was obtained for a dye molecule positioned in the 23-nanometer gap between 100-nanometer gold NPs. Direct visualization of the binding and unbinding of short DNA strands, as well as the conformational dynamics of a DNA Holliday junction in the hotspot of the nanoantenna, show the compatibility with single-molecule assays. PMID- 23112331 TI - Australopithecus afarensis scapular ontogeny, function, and the role of climbing in human evolution. AB - Scapular morphology is predictive of locomotor adaptations among primates, but this skeletal element is scarce in the hominin fossil record. Notably, both scapulae of the juvenile Australopithecus afarensis skeleton from Dikika, Ethiopia, have been recovered. These scapulae display several traits characteristic of suspensory apes, as do the few known fragmentary adult australopith representatives. Many of these traits change significantly throughout modern human ontogeny, but remain stable in apes. Thus, the similarity of juvenile and adult fossil morphologies implies that A. afarensis development was apelike. Additionally, changes in other scapular traits throughout African ape development are associated with shifts in locomotor behavior. This affirms the functional relevance of those characteristics, and their presence in australopith fossils supports the hypothesis that their locomotor repertoire included a substantial amount of climbing. PMID- 23112332 TI - Maturation-dependent HIV-1 surface protein redistribution revealed by fluorescence nanoscopy. AB - Human immunodeficiency virus type 1 (HIV-1) buds from the cell as an immature particle requiring subsequent proteolysis of the main structural polyprotein Gag for morphological maturation and infectivity. Visualization of the viral envelope (Env) glycoprotein distribution on the surface of individual HIV-1 particles with stimulated emission depletion (STED) superresolution fluorescence microscopy revealed maturation-induced clustering of Env proteins that depended on the Gag interacting Env tail. Correlation of Env surface clustering with the viral entry efficiency revealed coupling between the viral interior and exterior: Rearrangements of the inner protein lattice facilitated the alteration of the virus surface in preparation for productive entry. We propose that Gag proteolysis-dependent clustering of the sparse Env trimers on the viral surface may be an essential aspect of HIV-1 maturation. PMID- 23112333 TI - In vivo architecture and action of bacterial structural maintenance of chromosome proteins. AB - SMC (structural maintenance of chromosome) proteins act ubiquitously in chromosome processing. In Escherichia coli, the SMC complex MukBEF plays roles in chromosome segregation and organization. We used single-molecule millisecond multicolor fluorescence microscopy of live bacteria to reveal that a dimer of dimeric fluorescent MukBEF molecules acts as the minimal functional unit. On average, 8 to 10 of these complexes accumulated as "spots" in one to three discrete chromosome-associated regions of the cell, where they formed higher order structures. Functional MukBEF within spots exchanged with freely diffusing complexes at a rate of one complex about every 50 seconds in reactions requiring adenosine triphosphate (ATP) hydrolysis. Thus, by functioning in pairs, MukBEF complexes may undergo multiple cycles of ATP hydrolysis without being released from DNA, analogous to the behavior of well-characterized molecular motors. PMID- 23112334 TI - Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. AB - Although regulatory T cells (T(regs)) are known to suppress self-reactive autoimmune responses, their role during T cell responses to nonself antigens is not well understood. We show that T(regs) play a critical role during the priming of immune responses in mice. T(reg) depletion induced the activation and expansion of a population of low-avidity CD8(+) T cells because of overproduction of CCL-3/4/5 chemokines, which stabilized the interactions between antigen presenting dendritic cells and low-avidity T cells. In the absence of T(regs), the avidity of the primary immune response was impaired, which resulted in reduced memory to Listeria monocytogenes. These results suggest that T(regs) are important regulators of the homeostasis of CD8(+) T cell priming and play a critical role in the induction of high-avidity primary responses and effective memory. PMID- 23112335 TI - Oxytocin/vasopressin-related peptides have an ancient role in reproductive behavior. AB - Many biological functions are conserved, but the extent to which conservation applies to integrative behaviors is unknown. Vasopressin and oxytocin neuropeptides are strongly implicated in mammalian reproductive and social behaviors, yet rodent loss-of-function mutants have relatively subtle behavioral defects. Here we identify an oxytocin/vasopressin-like signaling system in Caenorhabditis elegans, consisting of a peptide and two receptors that are expressed in sexually dimorphic patterns. Males lacking the peptide or its receptors perform poorly in reproductive behaviors, including mate search, mate recognition, and mating, but other sensorimotor behaviors are intact. Quantitative analysis indicates that mating motor patterns are fragmented and inefficient in mutants, suggesting that oxytocin/vasopressin peptides increase the coherence of mating behaviors. These results indicate that conserved molecules coordinate diverse behavioral motifs in reproductive behavior. PMID- 23112337 TI - Opportunities for earlier diagnosis of HIV in general practice. PMID- 23112336 TI - Vasopressin/oxytocin-related signaling regulates gustatory associative learning in C. elegans. AB - Vasopressin- and oxytocin-related neuropeptides are key regulators of animal physiology, including water balance and reproduction. Although these neuropeptides also modulate social behavior and cognition in mammals, the mechanism for influencing behavioral plasticity and the evolutionary origin of these effects are not well understood. Here, we present a functional vasopressin- and oxytocin-like signaling system in the nematode Caenorhabditis elegans. Through activation of its receptor NTR-1, a vasopressin/oxytocin-related neuropeptide, designated nematocin, facilitates the experience-driven modulation of salt chemotaxis, a type of gustatory associative learning in C. elegans. Our study suggests that vasopressin and oxytocin neuropeptides have ancient roles in modulating sensory processing in neural circuits that underlie behavioral plasticity. PMID- 23112338 TI - Cervical human papillomavirus detection is not affected by menstrual phase. AB - OBJECTIVES: In many settings, human papillomavirus (HPV) DNA testing already plays an important role in cervical cancer screening. It is unclear whether hormonal fluctuations associated with menstrual phase or oral contraceptive (OC) use have any effect on HPV detection. We evaluated the effects of OC use and timing of cervical sampling in relation to women's last menstrual period (LMP) on HPV detection, and viral load in the Brazilian Ludwig-McGill cohort study. METHODS: Women in the cohort were followed every 4-6 months, and at each clinic visit they were asked to complete a questionnaire and to provide a cervical sample for HPV testing. Specimens from 6093 patient visits (n=2209 women) were categorised according to date of LMP into four distinct phases: follicular (days 5-9), midcycle (days 10-15), luteal (days 16-22), or late luteal (days 23-31). RESULTS: Compared with follicular phase (referent group), HPV detection did not differ according to reported LMP for midcycle (OR=1.14, 95% CI 0.95 to 1.37), luteal (OR=1.03, 95% CI 0.85 to 1.25), or late luteal menstrual phase (OR=1.01, 95% CI 0.83 to 1.24), and was also not influenced by OC use. Analyses restricted to high-risk HPV types (grouped) and HPVs 16 and 18 (separately), produced similar non-significant associations. For HPV-positive samples, we found that the menstrual phase did not influence the total viral load. CONCLUSIONS: These results indicate HPV detection is not associated with menstrual phase. Our findings suggest that standardising the timing of specimen collection for HPV testing is not necessary. PMID- 23112339 TI - Systematic review examining differences in HIV, sexually transmitted infections and health-related harms between migrant and non-migrant female sex workers. AB - OBJECTIVES: To assess the evidence of differences in the risk of HIV, sexually transmitted infections (STI) and health-related behaviours between migrant and non-migrant female sex workers (FSWs). METHODS: Systematic review of published peer-reviewed articles that reported data on HIV, STIs or health-related harms among migrant compared with non-migrant FSWs. Studies were mapped to describe their methods and focus, with a narrative synthesis undertaken to describe the differences in outcomes by migration status overall and stratified by country of origin. Unadjusted ORs are presented graphically to describe differences in HIV and acute STIs among FSWs by migration and income of destination country. RESULTS: In general, migrant FSWs working in lower-income countries are more at risk of HIV than non-migrants, but migrants working in higher-income countries are at less risk. HIV prevalence was higher among migrant FSWs from Africa in high-income countries. Migrant FSWs in all countries are at an increased risk of acute STIs. Study designs, definitions of FSWs and recruitment methods are diverse. Behavioural data focussed on sexual risks. DISCUSSION: The lack of consistent differences in risk between migrants and non-migrants highlights the importance of the local context in mediating risk among migrant FSWs. The higher prevalence of HIV among some FSWs originating from African countries is likely to be due to infection at home where HIV prevalence is high. There is a need for ongoing monitoring and research to understand the nature of risk among migrants, how it differs from that of local FSWs and changes over time to inform the delivery of services. PMID- 23112340 TI - A new infectious disease model for estimating and projecting HIV/AIDS epidemics. AB - OBJECTIVES: As the global HIV pandemic enters its fourth decade, countries have collected longer time series of surveillance data, and the AIDS-specific mortality has been substantially reduced by the increasing availability of antiretroviral treatment. A refined model with a greater flexibility to fit longer time series of surveillance data is desired. METHODS: In this article, we present a new epidemiological model that allows the HIV infection rate, r(t), to change over years. The annual change of infection rate is modelled by a linear combination of three key factors: the past prevalence, the past infection rate and a stabilisation condition. We focus on fitting the antenatal clinic (ANC) data and household surveys which are the most commonly available data source for generalised epidemics defined by the overall prevalence being above 1%. A hierarchical model is used to account for the repeated measurement within a clinic. A Bayesian approach is used for the parameter estimation. RESULTS: We evaluate the performance of the newly proposed model on the ANC data collected from urban and rural areas of 31 countries with generalised epidemics in sub Sahara Africa. The three factors in the proposed model all have significant contributions to the reconstruction of r(t) trends. It improves the prevalence fit over the classic Estimation and Projection Package model and provides more realistic projections when the classic model encounters problems. CONCLUSIONS: The proposed model better captures the main pattern of the HIV/AIDS dynamic. It also retains the simplicity of the classic model with a few interpretable parameters that are easy to interpret and estimate. PMID- 23112342 TI - The genitourinary medicine taster: an introduction to GU and HIV medicine for U.K. trainees. PMID- 23112341 TI - Male circumcision reduces penile high-risk human papillomavirus viral load in a randomised clinical trial in Rakai, Uganda. AB - OBJECTIVES: Male circumcision reduces penile high-risk human papillomavirus (HR HPV) prevalence in randomised trials. The goal of this study was to examine the effect of circumcision on HPV viral load among HPV-infected men in a randomised trial of male circumcision. METHODS: In a randomised trial to assess the efficacy of circumcision on HIV acquisition in Rakai, Uganda, HIV-negative men were randomised to immediate (intervention) or delayed (control) circumcision and followed over 24 months. We performed quantitative-PCR HPV viral load assays on penile swabs which tested positive by Linear Array (LA) for six HR-HPV genotypes and estimated viral load in the remaining types by LA signal strength. RESULTS: At 24 months, circumcision intervention arm men infected with one of the six selected HR-HPV genotypes had a lower viral load and significantly reduced HR-HPV high LA band intensity (PRR=0.61, 95% CI 0.43 to 0.86) compared to infected men in the control arm of the trial. The decreased viral load associated with circumcision was seen among HPV infections acquired after enrolment but not among infections that persisted from trial enrolment to 24 months (p=0.80). CONCLUSIONS: The decreased penile HR-HPV shedding observed among HPV-infected circumcised men may help to explain the protective association observed between circumcision and reduced acquisition of HR-HPV in female partners. PMID- 23112343 TI - Stress response and child health. AB - Stress is defined as a state of real or perceived threat to homeostasis. The principal effectors of the stress system are corticotropin-releasing hormone (CRH), arginine vasopressin, the proopiomelanocortin-derived peptides alpha melanocyte-stimulating hormone and beta-endorphin, the glucocorticoids, and the catecholamines norepinephrine and epinephrine. Appropriate responsiveness of the stress system to stressors is a crucial prerequisite for a sense of well-being, adequate performance of tasks, and positive social interactions. By contrast, inappropriate responsiveness of the stress system may impair growth and development and may account for various endocrine, metabolic, autoimmune, and psychiatric disorders. The development and severity of these conditions primarily depend on the genetic vulnerability of the individual, the exposure to adverse environmental factors, and the timing of stressful event(s). Prenatal life, infancy, childhood, and adolescence are critical periods characterized by increased vulnerability to stressors. This review summarizes the topics presented at the fifth New Inroads to Child Health (NICHe) Conference "Stress Response and Child Health" held at Heraklion, Crete, Greece, in May 2012. PMID- 23112344 TI - Prenatal stress, telomere biology, and fetal programming of health and disease risk. AB - A substantial body of epidemiological, clinical, cellular, and molecular evidence converges to suggest that conditions during the intrauterine period of life play a critical role in developmental programming to influence subsequent health and susceptibility for common, complex disorders. Elucidation of the biological mechanisms underlying these effects is an area of considerable interest and investigation, and it is important to determine whether these mechanisms are distinct for different health outcomes or whether there are some common underlying pathways that may account for the effects of disparate prenatal and early postnatal conditions on various health and disease risk phenotypes. We propose that telomere biology may represent a common underlying mechanism connecting fetal programming and subsequent health outcomes. It appears that the initial establishment of telomere length and regulation of telomere homeostasis may be plastic and receptive to the influence of intrauterine and other early life conditions. Moreover, telomere homeostasis in various cell types may serve as a fundamental integrator and regulator of processes underlying cell genomic integrity and function, aging, and senescence over the life span. We advance the hypothesis that context- and time-inappropriate exposures to various forms of physiological stress (maternal-placental-fetal endocrine aberrations and immune, inflammatory, and oxidative stresses) during the intrauterine period of development may alter or program the telomere biology system in a manner that accelerates cellular dysfunction, aging, and disease susceptibility over the life span. PMID- 23112345 TI - Protein complexes and target genes identification by in vivo biotinylation: the STAT5 paradigm. AB - Signal transducers and activators of transcription (STATs) are implicated in physiological cellular processes, stress-related responses, and malignancies. This Presentation provides an overview on STATs, focusing on STAT5, and describes an in vivo biotinylation methodology applied in mammalian cells for identification of STAT5-containing protein complexes and STAT5 target genes. Our results show that in vivo biotinylation can be used efficiently to elucidate the complex STAT5-dependent transcriptional mechanisms. PMID- 23112347 TI - Controllable in vivo hyperthermia effect induced by pulsed high intensity focused ultrasound with low duty cycles. AB - High intensity focused ultrasound (HIFU)-induced hyperthermia is a promising tool for cancer therapy. Three-dimensional nonlinear acoustic-bioheat transfer-blood flow-coupling model simulations and in vivo thermocouple measurements were performed to study hyperthermia effects in rabbit auricular vein exposed to pulsed HIFU (pHIFU) at varied duty cycles (DCs). pHIFU-induced temperature elevations are shown to increase with increasing DC. A critical DC of 6.9% is estimated for temperature at distal vessel wall exceeding 44 degrees C, although different tissue depths and inclusions could affect the DC threshold. The results demonstrate clinic potentials of achieving controllable hyperthermia by adjusting pHIFU DCs, while minimizing perivascular thermal injury. PMID- 23112346 TI - Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet function. AB - Platelets are highly reactive cell fragments that adhere to exposed extracellular matrix (ECM) and prevent excessive blood loss by forming clots. Paradoxically, megakaryocytes, which produce platelets in the bone marrow, remain relatively refractory to the ECM-rich environment of the bone marrow despite having the same repertoire of receptors as platelets. These include the ITAM (immunoreceptor tyrosine-based activation motif)-containing collagen receptor complex, which consists of glycoprotein VI (GPVI) and the Fc receptor gamma-chain, and the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing receptor G6b-B. We showed that mice lacking G6b-B exhibited macrothrombocytopenia (reduced platelet numbers and the presence of enlarged platelets) and a susceptibility to bleeding as a result of aberrant platelet production and function. Platelet numbers were markedly reduced in G6b-B-deficient mice compared to those in wild-type mice because of increased platelet turnover. Furthermore, megakaryocytes in G6b-B deficient mice showed enhanced metalloproteinase production, which led to increased shedding of cell-surface receptors, including GPVI and GPIbalpha. In addition, G6b-B-deficient megakaryocytes exhibited reduced integrin-mediated functions and defective formation of proplatelets, the long filamentous projections from which platelets bud off. Together, these findings establish G6b B as a major inhibitory receptor regulating megakaryocyte activation, function, and platelet production. PMID- 23112348 TI - A single-layer, planar, optofluidic switch powered by acoustically driven, oscillating microbubbles. AB - Merging acoustofluidic mixing with optofluidic integration, we have demonstrated a single-layer, planar, optofluidic switch that is driven by acoustically excited oscillating microbubbles. The device was found to have a switching speed of 5 Hz, an insertion loss of 6.02 dB, and an extinction ratio of 28.48 dB. With its simplicity, low fluid consumption, and compatibility with other microfluidic devices, our design could lead to a line of inexpensive, yet effective optical switches for many lab-on-a-chip applications. PMID- 23112349 TI - Electromechanical instabilities of thermoplastics: Theory and in situ observation. AB - Thermoplastics under voltages are used in diverse applications ranging from insulating cables to organic capacitors. Electromechanical instabilities have been proposed as a mechanism that causes electrical breakdown of thermoplastics. However, existing experiments cannot provide direct observations of the instability process, and existing theories for the instabilities generally assume thermoplastics are mechanically unconstrained. Here, we report in situ observations of electromechanical instabilities in various thermoplastics. A theory is formulated for electromechanical instabilities of thermoplastics under different mechanical constraints. We find that the instabilities generally occur in thermoplastics when temperature is above their glass transition temperatures and electric field reaches a critical value. The critical electric field for the instabilities scales with square root of yield stress of the thermoplastic and depends on its Young's modulus and hardening property. PMID- 23112350 TI - Neuronal alignment on asymmetric textured surfaces. AB - Axonal growth and the formation of synaptic connections are key steps in the development of the nervous system. Here, we present experimental and theoretical results on axonal growth and interconnectivity in order to elucidate some of the basic rules that neuronal cells use for functional connections with one another. We demonstrate that a unidirectional nanotextured surface can bias axonal growth. We perform a systematic investigation of neuronal processes on asymmetric surfaces and quantify the role that biomechanical surface cues play in neuronal growth. These results represent an important step towards engineering directed axonal growth for neuro-regeneration studies. PMID- 23112351 TI - Update on photoprotection. AB - Photoprotection by sunscreens, clothing and glasses are important to protect the skin against the detrimental effects of sun exposure. In order to achieve complete protection, topical strategies must shield against the range of solar wavelengths ultraviolet A, ultraviolet B, infrared radiation that can damage the skin. To provide the necessary broad spectrum coverage, combinations of chemical and physical UV filters along with molecules that are capable of interfering with and/or preventing the deleterious effects of sunlight are discussed in this review. PMID- 23112352 TI - Aging in elderly: chronological versus photoaging. AB - BACKGROUND: Skin is a window to aging changes, a biological reality. There is a dearth of studies regarding the various chronological (intrinsic) aging and photoaging (extrinsic) changes seen in Asians. This study was undertaken to detect the clinical pattern of aging skin changes and dermatoses seen in the elderly. MATERIALS AND METHODS: This was a descriptive study conducted on 500 consecutive elderly individuals attending the Dermatology out-patient department. The severity of photoaging was graded using Glogau scale. RESULTS: Most of the population had skin type IV and V. Majority (415, 83%) of our cases had chronological aging without photoaging and the remaining 85 (17%) individuals had photoaging along with chronological aging. The common skin changes due to chronological aging were thin skin, fine wrinkles, xerosis, and loss of elasticity. Photoaging changes such as dyspigmentation, freckles, thick skin, deep wrinkles, melasma, citrine skin, senile purpura, pseudostellate scar, acrokeratoelastoidosis marginalis, and lentigines were less frequent in our study. Smoking and prolonged sun exposure was the risk factors aggravating photoaging. The most common dermatosis was pruritus in 248 (49.6%) individuals, of which 149 (29.8%) had pruritus associated with xerosis. Contact dermatitis was more common in males. Fungal infections were frequently seen in females. Seborrhoeic keratosis (253, 50.6%) was the most common benign neoplasm more commonly seen in males. Cutaneous malignancies were less common in our study population. CONCLUSION: Photoaging changes were less common than chronological aging changes in skin type IV. Chronological changes were more frequent in females than males, while photoaging was more frequent in males. PMID- 23112353 TI - Prevalence of metabolic syndrome in South Indian patients with psoriasis vulgaris and the relation between disease severity and metabolic syndrome: a hospital based case-control study. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin and joints with an increased cardiovascular risk. Previous studies have shown a higher prevalence of metabolic syndrome (MS) in psoriatic patients. OBJECTIVE: To investigate the prevalence of MS in patients with psoriasis and healthy controls, and to determine the relation between disease severity and the presence of MS. MATERIALS AND METHODS: We performed a hospital-based case-control study on 118 adult patients with psoriasis vulgaris and 120 controls matched for age, sex and body mass index. MS was diagnosed by the presence of three or more of the South Asian Modified National Cholesterol Education Program's Adult Panel III criteria. RESULTS: MS was significantly more common in psoriatic patients than in controls (44.1% vs. 30%, P value = 0.025). Psoriatic patients also had a higher prevalence of triglyceridemia (33.9% vs. 20.8%, P value = 0.011), abdominal obesity (34.7% vs. 32.5%, P value = 0.035) and elevated blood sugar. There was no difference in the high density lipoprotein (HDL) levels and presence of hypertension among patients with psoriasis and normal controls. There was no correlation between the severity and duration of psoriasis with MS. CONCLUSION: MS is frequent in patients with psoriasis. We have found no relationship between disease severity and presence of MS. Hence, we suggest that all patients must be evaluated for the MS, irrespective of the disease severity. PMID- 23112354 TI - Bacteriological study of pyodermas in a tertiary care dermatological center. AB - BACKGROUND: Bacterial skin infection especially Pyoderma, commonly caused by Staphylococcus aureus and group A Streptococci, is quite common in Indian dermatology clinics. Despite a number of new antibiotics, the incidence of bacterial resistance is rising. AIM: To find out causative organisms and their latest antibiotic susceptibility patterns in pyodermas. MATERIALS AND METHODS: All in-patients admitted in the Dermatology wards in Government Medical College, Amritsar were screened over 18 months and those with erosive skin lesions and/or purulent discharge were included in the study and swabs were sent for culture and sensitivity. RESULTS: Majority 49/61 cases (80.33%) comprised of secondary pyodermas while primary pyodermas constituted only 12/61 cases (19.67%). Single organism was isolated in 49 cases (80.33%). More than one type of organism was isolated in 3 cases (4.92%) while none could be isolated from 9 (14.75%) cases. Staphylococcus aureus spp. was the commonest organism isolated in 36 (59.01%) cases and out of these, coagulase positive strains were found to be highly susceptible to amikacin (21cases-100%). Coagulase negative strains were sensitive to amikacin (7 cases-77.7%) and gentamycin (6 cases-66.6%) respectively. CONCLUSION: This study gives an indication of the present pattern of bacteriological profile of pyodermas in a tertiary care hospital in north-west India. In-vitro testing is essential as knowledge of the causative organisms and resistance patterns can help us select appropriate antibiotics without wasting time in using resistant drugs. PMID- 23112355 TI - Dose related efficacy of gabapentin in acute herpetic neuralgia among geriatric patients. AB - BACKGROUND: Herpes zoster is an intractable painful condition, more severe in elderly patients. The pain during the first 30 days of onset is known as Acute Herpetic Neuralgia. Multiple treatments using non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and tricyclic anti-depressants are available, but their side effects limit their use in geriatric patients. Gabapentin is also used in chronic neuropathic pain; however, its role in acute herpetic neuralgia is less explored. AIM: This study was aimed to determine dose related efficacy and safety of gabapentin in reducing pain of acute herpetic neuralgia in geriatric patients. MATERIALS AND METHODS: In this placebo-controlled, four-week trial including 56 subjects, 42 patients received gabapentin in the dosage of 300 mg (n=15), 600 mg (n=14), and 900 mg(n=13) per day in divided doses and 14 patients received placebo within 72 hours of onset of herpes zoster. RESULTS: Subjects receiving gabapentin had a statistically significant reduction (P<0.0001) in visual analog scale (VAS) score as compared to placebo, emphasizing the efficacy of gabapentin in the treatment of acute pain associated with herpes zoster on each assessment (weeks 1, 2, 3, and 4). Gabapentin in doses of 600 mg/day and 900 mg/day was better than 300 mg/day in each visit. However, no difference was observed between gabapentin 600 mg/day and 900 mg/day group at any point of time (P>0.05). CONCLUSION: The results of this study show that gabapentin is effective in acute herpetic neuralgia in different doses with 600 mg/day being the more appropriate dose in terms of safety and efficacy. PMID- 23112356 TI - Polymyositis and dermatomyositis: Disease spectrum and classification. AB - Muscle inflammation and weakness are the key features of idiopathic inflammatory myopathies (IIMs). In addition IIMs are frequently associated with cutaneous and pulmonary involvement. In clinical practice the three common inflammatory myopathies we come across are polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). The Bohan and Peter criteria combine clinical, laboratory, and pathologic features to define PM and DM. They did not recognize inclusion body myositis (IBM) or other inflammatory myopathies, such as granulomatous and eosinophilic myositis. Thus the disease spectrum is wide and IIMs are a heterogeneous group of autoimmune disorders. To address these issues in this article we have discussed the currently developing newer classifications of IIMs. PMID- 23112357 TI - Evaluation and management of polymyositis. AB - Polymyositis (PM) is one of the inflammatory myopathies, disorders characterized pathologically by the presence of inflammatory infiltrates in striated muscle. The principal clinical manifestation of PM is proximal muscle weakness. The cause of PM is unknown, but current evidence suggests that it is an autoimmune disorder. PM can affect people of any age, but most commonly presents between the ages of 50 to 70. PM is rarely seen in people younger than 18 years of age, and is twice as common among females than males. PM is more common in blacks than in whites. The overall prevalence of PM is 1 per 100,000. Muscle weakness may develop suddenly or more insidiously over a period of weeks to months. The classic symptom of PM is proximal weakness, which may manifest as difficulty holding the arms over the head, climbing stairs, or rising from a chair. Weakness of the striated muscle of the upper esophagus may result in dysphagia, dysphonia, and aspiration. The chest wall muscles may be affected, leading to ventilatory compromises. Involvement of cardiac muscle may lead to arrhythmias and congestive heart failure. Dermatomyositis (DM) is closely related to PM, and both are distinguished primarily by the occurrence of characteristic skin abnormalities in the former. PM and DM may be associated with a variety of malignancies. PM may also occur as part of the spectrum of other rheumatic diseases like systemic lupus erythematosus and mixed connective tissue disease. Moreover, inflammatory myopathy may be caused by some drugs (procainamide, D-penicillamine), and viruses, most notably the retroviruses. Corticosteroids and immunosuppressive agents are the mainstays of therapy for PM. The principal goals of therapy are to improve strength and improve physical functioning. Many patients require treatment for several years. The 5-year survival rate for treated patients is in the order of 95%. Up to one-third of PM patients may be left with some degree of residual muscle weakness. PMID- 23112358 TI - Clinical presentation and evaluation of dermatomyositis. AB - Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Evidence supports that DM is an immune-mediated disease and 50-70% of patients have circulating myositis-specific auto-antibodies. Gene expression microarrays have demonstrated upregulation of interferon signaling in the muscle, blood, and skin of DM patients. Patients with classic DM typically present with symmetric, proximal muscle weakness, and skin lesions that demonstrate interface dermatitis on histopathology. Evaluation for muscle inflammation can include muscle enzymes, electromyogram, magnetic resonance imaging, and/or muscle biopsy. Classic skin manifestations of DM include the heliotrope rash, Gottron's papules, Gottron's sign, the V-sign, and shawl sign. Additional cutaneous lesions frequently observed in DM patients include periungual telangiectasias, cuticular overgrowth, "mechanic's hands", palmar papules overlying joint creases, poikiloderma, and calcinosis. Clinically amyopathic DM is a term used to describe patients who have classic cutaneous manifestations for more than 6 months, but no muscle weakness or elevation in muscle enzymes. Interstitial lung disease can affect 35-40% of patients with inflammatory myopathies and is often associated with the presence of an antisynthetase antibody. Other clinical manifestations that can occur in patients with DM include dysphagia, dysphonia, myalgias, Raynaud phenomenon, fevers, weight loss, fatigue, and a nonerosive inflammatory polyarthritis. Patients with DM have a three to eight times increased risk for developing an associated malignancy compared with the general population, and therefore all patients with DM should be evaluated at the time of diagnosis for the presence of an associated malignancy. This review summarizes the immunopathogenesis, clinical manifestations, and evaluation of patients with DM. PMID- 23112359 TI - Basosquamous carcinoma: histopathological features. AB - Basosquamous carcinoma (BSC) is a rare aggressive epithelial neoplasm with features of both basal cell carcinoma and squamous cell carcinoma, with a tendency toward local recurrence and a propensity for lymph node and distant metastases. The aim of the present study was to report the case of a 63-year-old Caucasian male with BSC in the auricular region. PMID- 23112360 TI - Atypical fibroxanthoma: an unusual skin neoplasm in xeroderma pigmentosum. AB - Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder related to defective deoxyribonucleic acid (DNA) repair. Various cutaneous manifestations related to ultraviolet (UV) damage characterize the clinical course. Primary malignant cutaneous neoplasms like squamous cell carcinoma, basal cell carcinoma and malignant melanoma have been reported. Atypical fibroxanthoma is a rare dermal neoplasm occurring in UV-damaged skin. We report an unusual case of atypical fibroxanthoma in a 20-year-old male with XP. PMID- 23112361 TI - Red nodule on the breast. AB - A 63-year-old woman living in the countryside referred to our department with a 2 month history of a red nodule localized on the right breast. Histological examination, immunohistochemical analyses and serologic evaluation conducted with ELISA and Western blot were performed. Clinical diagnosis of borrelial lymphocytoma was not possible solely on the clinical presentation of a classical nodular form without lymphoadenopathy. An absence of a referred prior tick bite and a previous or concomitant erythema migrans at clinical presentation rendered a more challenging diagnosis. The fact that the patient lived in the countryside, the appearance of the breast nodule in September, and serologic, histologic, and immunohistochemical analysis facilitated the diagnosis of borrelial lymphocytoma. We report this case to highlight the importance of an investigation of Lyme borreliosis when a patient living in the countryside presents with a red nodule of the nipple and areola. PMID- 23112362 TI - Mal de meleda with lip involvement: a report of two cases. AB - Mal de Meleda is a rare autosomal recessive transgradient palmoplantar keratoderma characterized by transgradient keratoderma with associated scleroatrophy, nail changes, pseudoainhum around digits and perioral erythema, without a tendency for spontaneous resolution. Involvement of the lip by keratoderma has not been reported in the English literature. Here we present two cases of Mal de Meleda with unusual lip involvement. The first case was a 15-year old girl, born of second-degree consanguineous marriage, who presented with transgradient palmoplantar keratoderma from 6 months of age, with lichenoid papules and plaques on the elbows and knees, conical tapering of the distal digits, flexion deformity of several fingers, digital constriction, knuckle pads and lip involvement. The second case was a 24-year-old male with transgradient palmoplantar keratoderma since birth. He also had scaly plaques on the extensors of bilateral knees and elbows, knuckle pads, pseudosclerodermatous fingers with conical tapering, digital constrictions at various places with mild flexion deformity and lip involvement. Both patients were otherwise normal without any family history. PMID- 23112363 TI - Exogenous ochronosis After Prolonged Use of Topical Hydroquinone (2%) in a 50 Year-Old Indian Female. AB - Ochronosis is a rare disease characterized by speckled and diffuse pigmentation symmetrically over the face, neck, and photo-exposed areas. It is characterized histologically by banana-shaped ochre-colored deposits in the dermis. It can present in exogenous or endogenous form. We report a case of exogenous ochronosis in a 50-year-old Indian woman after prolonged use of topical hydroquinone which is a rare complication with a commonly used drug which is available over the counter. PMID- 23112364 TI - Spectacular skin nodules: cutaneous necrobiotic xanthogranuloma without paraproteinemia. AB - Necrobiotic xanthogranuloma (NXG) is a very rare, progressive variant of non Langerhans cell histiocytosis. It is known to be associated with multisystem involvement and paraproteinemias. A 65-year-old female presented with chronic, slowly growing, asymptomatic periorbital nodules. The lesions had recurred after local excision elsewhere. No systemic involvement or paraproteinemias were detected. A provisional diagnosis of isolated cutaneous NXG was made which was confirmed by histopathology and immunohistochemistry staining. The lesions were surgically excised with excellent cosmetic and functional results. There was no recurrence over a period of 9 months. To our knowledge, this is the second case of NXG reported from India and the first without any systemic manifestations. PMID- 23112365 TI - Prolonged varicella-zoster virus reinfection in an adult after unrelated cord blood transplantation. AB - Most varicella-zoster virus (VZV) infections after cord blood transplantation (CBT) present as localized herpes zoster. Here, we report a case of VZV reinfection in an adult patient after CBT that appeared clinically to be varicella. A 50-year-old Japanese man underwent CBT for the management of acute lymphoblastic leukemia. Seventeen months later, he developed a small number of vesicles with umbilicated centers. A skin biopsy showed an intraepidermal blister containing degenerated balloon cells. Subsequently, the skin eruption developed over his entire body. The patient was treated with intravenous acyclovir for 5 days, followed by oral valacyclovir for 9 days. It took more than 3 weeks for most of the skin lesions to scab. Serum levels of anti-VZV IgG on days 3 and 33 after the onset of the skin eruption were negative and 260 mIU/ml, respectively. Serum anti-VZV IgM on days 3 and 33 was not detected. Our patient was diagnosed with VZV reinfection. PMID- 23112367 TI - Primary cutaneous nocardiosis. AB - A 35-year-old male presented with multiple discharging sinuses and fluctuant swelling on right side of face which started after a vehicular accident three year back. The lesions did not respond to routine antibiotics treatment but went on increasing. Gram smear showed typical acid fast branching filaments suggestive of nocardiosis, which was confirmed by culture. Patient received co-trimoxazole for three and a half month. When seen again after three years, all the lesions had healed with puckered scarring. Patient had received co-trimoxazole for three and a half months with dramatic improvement. PMID- 23112366 TI - Epithelioid hemangioma (angiolymphoid hyperplasia with eosinophilia) in zosteriform distribution. AB - Epithelioid hemangioma (EH) or angiolymphoid hyperplasia with eosinophilia (ALHE) is an uncommon benign disease. We report an unusual case of EH (ALHE) that arose on the lower back in a zosteriform array. The presence of the characteristic histological appearance of plump endothelial cells with hobnail-like protrusions led to the diagnosis of EH (ALHE). Histological examination of the lesion also revealed the existence of arteriovenous shunts, the possible factor contributing to the pathogenesis of EH (ALHE). PMID- 23112368 TI - Menkes kinky hair disease. PMID- 23112369 TI - Occupational allergic contact dermatitis: a clinical study in a tertiary care centre in central kerala. PMID- 23112370 TI - Urticaria meter. PMID- 23112371 TI - Lack of relationship between blood groups and clinical outcome (body surface area affected) in patients with pemphigus vulgaris. PMID- 23112372 TI - Salt-and-pepper Appearance: A Cutaneous Clue for the Diagnosis of Systemic Sclerosis. PMID- 23112373 TI - VDRL Test and its Interpretation. PMID- 23112374 TI - Authors' reply. PMID- 23112375 TI - On the patterns of distribution of segmental nevi of melanocytic origin. PMID- 23112376 TI - Author's Reply. PMID- 23112377 TI - Chronic Bullous Disease Of Childhood with IgG Predominance: What is the locus standi? PMID- 23112378 TI - Authors' reply. PMID- 23112379 TI - Vesalius revised. His annotations to the 1555 Fabrica. AB - The De humani corporis fabrica [The Fabric of the Human Body], Basle, 1543, of Andreas Vesalius is deservedly famous as the first modern book of anatomy. A second edition was published in Basle in 1555, but little is known of Vesalius' activities after that date. This article discusses a recent find: Vesalius' own copy of the 1555 edition, heavily annotated in preparation for a never published third edition. Vesalius made hundreds of changes to the second edition, the great majority being stylistic, altering the Latin words but not the overall meaning. There are also changes to the plates to give greater clarity or to correct mistakes by the original block-cutter. There is little new anatomical material, although Vesalius continued to meditate about what he had earlier discovered. He shows no sign of being acquainted with the findings of others, like Colombo or Falloppia, that were published after he had moved his residence from Brussels to Spain in summer 1559, perhaps leaving this volume behind. The number of annotations shows Vesalius' passionate concern not only for accuracy but also for the most effective way of proclaiming his new anatomical message. PMID- 23112380 TI - The chemistry of famine: nutritional controversies and the Irish Famine, c.1845 7. AB - The activities of Irish medical practitioners in relieving the impact of the Irish Famine (c.1845-52) have been well documented. However, analysis of the function of contemporary medico-scientific ideas relating to food has remained mostly absent from Famine historiography. This is surprising, given the burgeoning influence of Liebigian chemistry and the rising social prominence of nutritional science in the 1840s. Within this article, I argue that the Famine opened up avenues for advocates of the social value of nutritional science to engage with politico-economic discussion regarding Irish dietary, social and economic transformation. Nutritional science was prominent within the activities of the Scientific Commission, the Central Board of Health and in debates regarding soup kitchen schemes. However, the practical inefficacy of many scientific suggestions resulted in public associations being forged between nutritional science and the inefficiencies of state relief policy, whilst emergent tensions between the state, science and the public encouraged scientists in Ireland to gradually distance themselves from state-sponsored relief practices. PMID- 23112381 TI - Debating scientific medicine: homoeopathy and allopathy in late nineteenth century medical print in Bengal. AB - The historiography of medicine in South Asia often assumes the presence of preordained, homogenous, coherent and clearly-bound medical systems. They also tend to take the existence of a medical 'mainstream' for granted. This article argues that the idea of an 'orthodox', 'mainstream' named allopathy and one of its 'alternatives' homoeopathy were co-produced in Bengal. It emphasises the role of the supposed 'fringe', ie. homoeopathy, in identifying and organising the 'orthodoxy' of the time. The shared market for medicine and print provided a crucial platform where such binary identities such as 'homoeopaths' and 'allopaths' were constituted and reinforced. This article focuses on a range of polemical writings by physicians in the Bengali print market since the 1860s. Published mostly in late nineteenth-century popular medical journals, these concerned the nature, definition and scope of 'scientific' medicine. The article highlights these published disputes and critical correspondence among physicians as instrumental in simultaneously shaping the categories 'allopathy' and 'homoeopathy' in Bengali print. It unravels how contemporary understandings of race, culture and nationalism informed these medical discussions. It further explores the status of these medical contestations, often self-consciously termed 'debates', as an essential contemporary trope in discussing 'science' in the vernacular. PMID- 23112382 TI - 'A most protean disease': aligning medical knowledge of modern influenza, 1890 1914. AB - This article reconstructs the process of defining influenza as an infectious disease in the contexts of British medicine between 1890 and 1914. It shows how professional agreement on its nature and identity involved aligning different forms of knowledge produced in the field (public health), in the clinic (metropolitan hospitals) and in the laboratory (bacteriology). Two factors were crucial to this process: increasing trust in bacteriology and the organisation of large-scale collective investigations into influenza by Britain's central public authority, the Medical Department of the Local Government Board. These investigations integrated epidemiological, clinical and bacteriological evidence into a new definition of influenza as a specific infection, in which a germ - Bacillus influenzae - was determined as playing a necessary but not sufficient role in its aetiology, transmission and pathogenesis. In defining 'modern influenza', bacteriological concepts and techniques were adapted to and selectively incorporated into existing clinical, pathological and epidemiological approaches. Mutual alignment thus was crucial to its construction and, more generally, to shaping developing relationships between laboratory, clinical and public health medicine in turn-of-the-century Britain. While these relationships were marked by tension and conflict, they were also characterised by important patterns of convergence, in which the problems, interests and practices of public health professionals, clinicians and laboratory pathologists were made increasingly commensurable. Rather than retrospectively judge the late nineteenth century definition of influenza as being based on the wrong microbe, this article argues for the need to examine how it was established through a particular alignment of medical knowledge, which then underpinned medical approaches to the disease up to and beyond the devastating 1918-19 pandemic. PMID- 23112383 TI - Mrs Killer and Dr Crook: birth attendants and birth outcomes in early twentieth century Derbyshire. AB - After the passing of the 1902 Midwives Act, a growing proportion of women were delivered by trained and supervised midwives. Standards of midwifery should therefore have improved over the first three decades of the twentieth century, yet nationally this was not reflected in the main outcome measures (stillbirths, early neonatal mortality and maternal death). This paper shows that there was a difference in the risks associated with delivery by the different attendants, with qualified midwives having the best outcome, then bona-fide (untrained) midwives and lastly doctors, even when account is taken of the fact that doctors were called in cases of medical need and may have been booked where a problematic delivery was expected. The paper argues that the lack of improvement in outcome measures could be consistent with improving standards of care among both trained and bona-fide midwives, because increased attention to the rules stipulating when midwives called for medical help meant that a doctor was called into an increasing number of deliveries (including less complicated ones), raising the chance of unnecessary and dangerous interventions. PMID- 23112384 TI - Between prevention and therapy: Gio Batta Gori and the National Cancer Institute's Diet, Nutrition and Cancer Programme, 1974-1978. AB - This paper explores the origins of the Diet, Nutrition and Cancer Programme (DNCP) of the National Cancer Institute (NCI) and its fate under its first director, Gio Batta Gori. The DNCP is used to explore the emergence of federal support for research on diet, nutrition and cancer following the 1971 Cancer Act, the complex relations between cancer prevention and therapeutics in the NCI during the 1970s, the broader politics around diet, nutrition and cancer during that decade, and their relations to Senator George McGovern's select committee on Nutrition and Human Needs. It also provides a window onto the debates and struggles over whether NCI research should be funded by contracts or grants, the nature of the patronage system within the federal cancer research agency, how a director, Gio Gori, lost patronage within that system and how a tightening of the budget for cancer research in the mid-to-late 1970s affected the DNCP. PMID- 23112385 TI - 'Fibre body': the concept of fibre in eighteenth-century medicine, c.1700-40. AB - This paper attempts a comprehensive account of 'fibre medicine' elaborated by iatromechanists from c. 1700 to c. 1740. Fibre medicine, a medical theory informed by the notion of the fibre, has been neglected by medical historians despite the pivotal role played by the fibre in animal economy. Referring to a wide range of medical fields such as anatomy, physiology, pathology, therapeutics and life sciences, this paper elucidates the ways that the fibre serves as an indispensable concept for iatromechanists to establish their medical theories. This paper also highlights the metaphorical dimension of the fibre as an integral part of fibre medicine. In re-evaluating the concept of the fibre, this paper seeks to redress the neuro-centric view of eighteenth-century medicine, and attempts to locate the fibre body amidst the fundamental shift from humoralism to solidism. PMID- 23112388 TI - The Mutter Museum, College of Physicians of Philadelphia, 19 South 22nd Street, Philadelphia, PA 19303, USA. PMID- 23112391 TI - Febuxostat: a novel agent for management of hyperuricemia in gout. AB - Gout is a metabolic disorder characterized by elevated uric acid levels in the body, associated with painful arthritis, tophi and nephropathy. The most frequently used pharmacologic urate lowering strategies involve reducing urate production with a xanthine oxidase inhibitor and enhancing urinary excretion of uric acid with a uricosuric agent. Urate lowering agents are limited in number, availability and effectiveness. The emergence of a new medication, febuxostat, to lower serum urate levels is welcome as no new drug have been approved since the introduction of allopurinol, in 1964, and the drugs that are available have limitations owing to inefficacy or toxicity. Febuxostat is a novel, nonpurine selective inhibitor of xanthine oxidase, is a potential alternative to allopurinol for patients with hyperuricemia and gout. PMID- 23112392 TI - Effects of Combination of Thiazolidinediones with Melatonin in Dexamethasone induced Insulin Resistance in Mice. AB - In type 2 Diabetes, oxidative stress plays an important role in development and aggregation of insulin resistance. In the present study, long term administration of the dexamethasone led to the development of insulin resistance in mice. The effect of thiazolidinediones pioglitazone and rosiglitazone, with melatonin on dexamethasone-induced insulin resistance was evaluated in mice. Insulin resistant mice were treated with combination of pioglitazone (10 mg/kg/day, p.o.) or rosiglitazone (5 mg/kg/day, p.o.) with melatonin 10 mg/kg/day p.o. from day 7 to day 22. In the biochemical parameters, the serum glucose, triglyceride levels were significantly lowered (P<0.05) in the combination groups as compared to dexamethasone treated group as well as with individual groups of pioglitazone, rosiglitazone, and melatonin. There was also, significant increased (P<0.05) in the body weight gain in combination treated groups as compared to dexamethasone as well as individual groups. The combination groups proved to be effective in normalizing the levels of superoxide dismutase, catalase, glutathione reductase and lipid peroxidation in liver homogenates may be due to antioxidant effects of melatonin and decreased hyperglycemia induced insulin resistance by thiazolidinediones. The glucose uptake in the isolated hemidiaphragm of mice was significantly increased in combination treated groups (PM and RM) than dexamethasone alone treated mice as well as individual (pioglitazone, rosiglitazone, melatonin) treated groups probably via increased in expression of GLUT-4 by melatonin and thiazolidinediones as well as increased in insulin sensitivity by thiazolidinediones. Hence, it can be concluded that combination of pioglitazone and rosiglitazone, thiazolidinediones, with melatonin may reduces the insulin resistance via decreased in oxidative stress and control on hyperglycemia. PMID- 23112393 TI - Preparation and in vitro characterization of mucoadhesive hydroxypropyl guar microspheres containing amlodipine besylate for nasal administration. AB - Amlodipine besylate microspheres for intranasal administration were prepared with an aim to avoid first-pass metabolism, to achieve controlled blood level profiles and to improve therapeutic efficacy. Hydroxypropyl Guar, a biodegradable polymer, was used in the preparation of microspheres by employing water in oil emulsification solvent evaporation technique. The formulation variables were drug concentration, emulsifier concentration, temperature, agitation speed and polymer concentration. All the formulations were evaluated for particle size, particle shape and surface morphology by scanning electron microscopy, percentage yield, drug entrapment efficiency, in vitro mucoadhesion test, degree of swelling and in vitro drug diffusion through sheep nasal mucosa. The microspheres obtained were free flowing, spherical and the particles ranged in size from 13.4+/-2.38 MUm to 43.4+/-1.92 MUm very much suitable for nasal delivery. Increasing polymer concentration resulted in increased drug entrapment efficiency and increased particle size. Amlodipine besylate was entrapped into the microspheres with an efficiency of 67.2+/-1.18 % to 81.8+/-0.64 %. The prepared microspheres showed good mucoadhesion properties, swellability and sustained the release of the drug over a period of 8 h. The data obtained were analysed by fitment into various kinetic models; it was observed that the drug release was matrix diffusion controlled and the release mechanism was found to be non-Fickian. Stability studies were carried out on selected formulations at 5+/-3 degrees , 25+/-2 degrees /60+/-5% RH and 40+/-2 degrees /75+/-5% RH for 90 days. The drug content was observed to be within permissible limits and there were no significant deviations in the in vitro mucoadhesion and in vitro drug diffusion characteristics. PMID- 23112395 TI - Effect of Fluoxetine on an Experimental Model of Diabetes-induced Neuropathic Pain Perception in the Rat. AB - The aim of the present study was to study the effect of chronic treatment (9 weeks) of fluoxetine (20 mg/kg p.o.) a selective serotonin reuptake inhibitor on blood glucose level and in prevention of diabetic neuropathic pain perception. Evaluation of diabetic neuropathy was performed after 9 weeks of single injection of streptozotocin (70 mg/kg i.v.) in rats. Blood glucose level, glycated haemoglobin, grip strength, pain sensitivity and threshold in diabetic rats were measured at the end of 9 weeks. The results of the present study indicate that the 9 weeks treatment of fluoxetine demonstrates hypoglycemic effect; it marked decreases the blood glucose level in diabetic treated animals. There was also decrease in the grip strength in diabetic rat indicates to induction of neuropathy or nerve damage. Fluoxetine increase the grip strength of diabetic rats. There was also found loss of pain perception in diabetes rats which measured using hot plate and tail flick methods. Fluoxetine increases the licking time and withdrawal latency in hot plate and tail flick test respectively indicates the presence of pain perception and prevention of nerve damage demonstrates its protective effect in diabetic neuropathy. Our study concludes the chronic treatment of fluoxetine significantly decreases the glycemic level as well as it protected from the development of diabetic neuropathy. PMID- 23112394 TI - Ion-activated In Situ Gelling Ophthalmic Delivery Systems of Azithromycin. AB - Gelation of pectin caused by divalent cations especially calcium ions has been applied to develop an ophthalmic formulation of azithromycin in the present study. Rapid elimination of drug on instillation into cul de sac would be minimal with in situ gelling ophthalmic solution leading to increased precorneal contact time and prolonged drug delivery. In the formulation development studies pectin was used in different concentrations (1-5% w/v) and different proportions of the hydrocolloids hydroxypropyl methylcellulose and sodium carboxymethyl cellulose of different grades of viscosity were used. The primary criteria for formulation optimization were gelling capacity and rheological behaviour. In addition, formulations were evaluated for pH, and antimicrobial efficacy and drug release. The clarity, pH, gelation in simulated tear fluid and rheological properties of the optimized formulations were satisfactory. The formulations inhibited the growth of Staphylococcus aureus effectively in cup-plate method and were proved to be safe and non irritant on rabbit eyes. The results indicate that pectin based in situ gels can be successfully used to prolong the duration of action of azithromycin. PMID- 23112396 TI - Ranitidine Hydrochloride-loaded Ethyl Cellulose and Eudragit RS 100 Buoyant Microspheres: Effect of pH Modifiers. AB - A floating type of dosage form of ranitidine hydrochloride in the form of microspheres capable of floating on simulated gastric fluid was prepared by solvent evaporation technique. Microspheres prepared with ethyl cellulose, Eudragit((r)) RS100 alone or in combination were evaluated for percent yield, drug entrapment, percent buoyancy and drug release and the results demonstrated satisfactory performance. Microspheres exhibited ranitidine hydrochloride release influenced by changing ranitidine hydrochloride-polymer and ranitidine hydrochloride-polymer-polymer ratio. Incorporation of a pH modifier has been the usual strategy employed to enhance the dissolution rate of weakly basic drug from floating microspheres. Further citric acid, fumaric acid, tartaric acid were employed as pH modifiers. Microspheres prepared with ethyl cellulose, Eudragit((r)) RS100 and their combination that showed highest release were utilized to study the effect of pH modifiers on ranitidine hydrochloride release from microspheres which is mainly affected due to modulation of microenvironmental pH. In vitro release of ranitidine hydrochloride from microspheres into simulated gastric fluid at 37 degrees showed no significant burst effect. However the amount of release increased with time and significantly enhanced by pH modifiers. 15% w/w concentration of fumaric acid provide significant drug release from ranitidine hydrochloride microspheres prepared with ranitidine hydrochloride:ethyl cellulose (1:3), ranitidine hydrochloride:Eudragit((r)) RS100 (1:2) and ranitidine hydrochloride:ethyl cellulose:Eudragit((r)) RS100 (1:2:1) whereas citric acid, tartaric acid showed significant cumulative release at 20% w/w. In all this study suggest that ethyl celluose, Eudragit((r)) RS100 alone or in combination with added pH modifiers can be useful in floating microspheres which can be proved beneficial to enhance the bioavailability of ranitidine hydrochloride. PMID- 23112397 TI - Synthesis and evaluation of antiinflammatory, analgesic and ulcerogenic potential of NSAIDs bearing 1,3,4-oxadiazole scaffold. AB - Synthesis of 1,3,4-oxadiazole derivatives of diclofenac and mefenamic acid are described. The target compounds 5-[2-(2,6-dichloroanilino)benzyl]-2-aryl-1,3,4 oxadiazole (3a-3e) and 5-[2-(2,3-dimethylanilino)phenyl]-2-(aryl)-1,3,4 oxadiazole (6a-6e) were obtained by treating 2 and 5 with various aromatic acids using POCl(3) as dehydrating agent. They were purified and characterized by IR, (1)H-NMR and elemental analysis. These compounds were further subjected to antiinflammatory, analgesic and acute ulcerogenic activity. Compound 3c and 6d exhibited good antiinflammatory activity and compounds 3c, 3e, 6c, 6d, 6e were found to be non ulcerogenic. PMID- 23112398 TI - Development and evaluation of microbial degradation dependent compression coated secnidazole tablets for colonic delivery. AB - The present paper describes development of a polysaccharide based compression coated tablets of secnidazole for colon delivery. Core tablet containing secnidazole was compression coated with various proportions of guar gum, xanthan gum and chitosan, either alone or in combinations. Drug release studies were performed in simulated gastric fluid (SGF) for 2 h followed by simulated intestinal fluid (SIF, pH 7.4) up to 24 h. Secnidazole release from the prepared formulations was dependent on the type and concentration of polymer used in the formulation. Tablets coating containing either guar gum or xanthan gum showed ~30 40% drug release in 8 h. Further, in vitro dissolution studies of selected formulations performed in the dissolution media with rat caecal contents showed 54.48+/-0.24 - 60.42+/-0.16% of drug release. Formulations with single polymer in coating layer were unsuitable for targeting secnidazole release to colon region. Combination of chitosan with guar gum or xanthan gum exhibited control over secnidazole release. PMID- 23112399 TI - Determination and estimation of pharmacokinetic profile of caffeine in form of extract of green tea leaves and its analogy with synthetic form. AB - The aim of the study was to formulate and investigate the pharmacokinetic parameters for the tablets of herbal extract of caffeine with comparison to synthetic formulation. The tablets of the aqueous herbal extract of leaves of Camellia sinensis and synthetic caffeine were formulated by wet granulation technique. The HPLC and HPTLC were applied as analytical tools for estimation of caffeine. The batches of formulation (B1 to B7) were subjected for various pre and post-formulation studies. The pharmacokinetic of the batch B5 was assessed in rabbits, and the results were compared to synthetic batch B7. With the suitable pre and post-formulation results, the B5 showed in vitro release of 90.54% of caffeine at the end of 60 min. The release followed first order kinetics and the plot of Higuchi and Peppas confirms anomalous diffusion as the basic mechanism behind the release. B5 revealed non-significant mean C(max), t(1/2), and AUC of 1.88 MUg/ml, 5.52 h and 9.67 MUg.h/ml respectively compared to B7. The study highlights; no significant difference in the pharmacological effect of caffeine when administered in the form of extract. The administration of herbal extract can further provide the other health benefits lacked by synthetic caffeine. PMID- 23112400 TI - Inhalational system for Etoposide liposomes: formulation development and in vitro deposition. AB - Etoposide is a semisynthetic compound, widely used in treatment of non small cell lung cancer. However, frequent dosing and adverse effects remain a major concern in the use of etoposide. Liposomal systems for pulmonary drug delivery have been particularly attractive because of their compatibility with lung surfactant components. In the present investigation, pulmonary liposomal delivery system of etoposide was prepared by film hydration method. Various parameters were optimized with respect to entrapment efficiency as well as particle size of etoposide liposomes. For better shelf life of etoposide liposomes, freeze drying using trehalose as cryoprotectant was carried out. The liposomes were characterized for entrapment efficiency, particle size, surface topography, and in vitro drug release was carried out in simulated lung fluid at 37 degrees at pH 7.4. The respirable or fine particle fraction was determined by using twin stage impinger. The stability study of freeze dried as well as aqueous liposomal systems was carried out at 2-8 degrees and at ambient temperature (28+/-4 degrees ). The freeze dried liposomes showed better fine particle fraction and drug content over the period of six months at ambient as well as at 2-8 degrees storage condition compared to aqueous dispersion of liposomes. PMID- 23112401 TI - ATT- A Double Edged Sword? AB - Antitubercular therapy (ATT) induced hepatotoxicity, although well known to clinicians, is often over looked and underrated. Given the low threshold of starting ATT, especially empirically, the adverse manifestations can take a considerable toll. A variety of associated risk factors compound the morbidity. We throw light on one such a case where ATT was detrimental to the patient and review the literature and possible preventive strategies. PMID- 23112402 TI - Estimation of Total Phenols and Flavonoids in Extracts of Actaea spicata Roots and Antioxidant Activity Studies. AB - Actaea spicata Linn. (Ranunculaceae) has been traditionally used for the treatment of various ailments such as rheumatism, inflammation, nerve diseases, lumbago, scrofula and chorea, but no systematic phytochemical and pharmacological work has ever been carried out on this potential plant. Preliminary phytochemical screening showed presence of phenols and flavonoids in A. spicata. Thus, the present investigation was undertaken to estimate total phenols and flavonoids in methanol extract of A. spicata roots, and its ethyl acetate fraction. In vitro antioxidant activity was also evaluated in the methanol extract and ethyl acetate fraction using DPPH method. Ethyl acetate fraction was found to contain twice the content of flavonoids and phenols in comparison to methanolic extract, whereas phenolic content in methanol extract was approximately similar to ethyl acetate fraction. A significant antioxidant activity, i.e., mean percentage inhibition of DPPH radical was observed in methanol extract and ethyl acetate fraction at the concentration of 10 MUg/ml and 5 MUg/ml respectively. Finally, it was suggested that polyphenols are responsible for antioxidant activity of A. spicata. PMID- 23112403 TI - Solubility prediction of satranidazole in propylene glycol-water mixtures using extended hildebrand solubility approach. AB - Extended Hildebrand solubility approach is used to estimate the solubility of satranidazole in binary solvent systems. The solubility of satranidazole in various propylene glycol-water mixtures was analyzed in terms of solute-solvent interactions using a modified version of Hildebrand-Scatchard treatment for regular solutions. The solubility equation employs term interaction energy (W) to replace the geometric mean (delta(1)delta(2)), where delta(1) and delta(2) are the cohesive energy densities for the solvent and solute, respectively. The new equation provides an accurate prediction of solubility once the interaction energy, W, is obtained. In this case, the energy term is regressed against a polynomial in delta(1) of the binary mixture. A quartic expression of W in terms of solvent solubility parameter was found for predicting the solubility of satranidazole in propylene glycol-water mixtures. The expression yields an error in mole fraction solubility of ~3.74%, a value approximating that of the experimentally determined solubility. The method has potential usefulness in preformulation and formulation studies during which solubility prediction is important for drug design. PMID- 23112404 TI - Synthesis and Evaluation of N-substituted Imidazole Derivatives for Antimicrobial Activity. AB - A series of N-substituted imidazole derivatives was synthesized. Imidazole nucleus was reacted with ethylchloroacetate to form imidazole ester. Reaction of the imidazole ester (I) with different amines yields the desired products (1a- 1e). The compounds were characterized by FT-IR, (1)H-NMR and mass spectra. The synthesized compounds were evaluated for the antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger by determination of MIC (minimum inhibitory concentration) using tube dilution method. Compound (1b) was found to be the most active antimicrobial compound amongst others in the series. PMID- 23112405 TI - Evaluation of bioequivalence of two oral formulations of olanzapine. AB - Olanzapine is an atypical antipsychotic drug, used for the management of schizophrenia and for the treatment of moderate to severe mania associated with bipolar disorder. The objective of the present randomised, crossover study was to compare the bioavailability of olanzapine 10 mg/5 ml powder for oral suspension with olanzapine 10 mg orally disintegrating tablet. Eighteen healthy male volunteers were randomly assigned to crossover, single-dose treatment regimens. Serial blood samples were collected, and plasma concentrations of olanzapine were analysed using the LC-MS/MS technique. Pharmacokinetic parameters and bioequivalence limits were calculated using non-compartmental methods. Average C(max) following administration of the single 10 mg disintegrating tablet formulation and 10 mg/5 ml suspension were 14.47+/-4.25 ng/ml and 13.56+/-3.99 ng/ml respectively. Corresponding median T(max) were 5.0 h and 6.0 h, respectively. The average AUC(0-t) values and AUC(0-inf) values were similar following each of the olanzapine preparations. Overall, the 90% Confidence Interval for the intra-individual ratios of the log-transformed C(max) and AUC values of the two formulations were within the bioequivalence interval of 80 125%. The study has demonstrated the bioequivalence of the 10 mg tablet and the 10 mg/5 ml oral suspension of olanzapine. PMID- 23112406 TI - Comparison of Gastroprotective Effects of Triphala Formulations on Stress-induced Ulcer in Rats. AB - Triphala is categorized as rejuvenator and traditionally been used in various gastric disorders including intestinal inflammation. The aim of present study was to examine the comparative gastroprotective effects of Triphala formulations against experimental gastric ulcer in rats to substantiate its traditional claim. Gastric ulcer was induced by water immersion plus stress-induced ulcers in rats. The drug effects were assessed by studying macroscopic gross injury and stomach tissue biochemical parameters. Triphala unequal formulation and Chinnodbhavadi kwath showed significant antiulcer activity and this is evident from reduction of ulcer index, lipid peroxidation and hydroxyl radical levels and concomitantly raised levels of catalase and superoxide dismutase. Though similar kind of activity was observed in Triphala equal formulation the magnitude was much less. Further, Chinnodbhavadi kwath significantly increased the glutathione and ATPase level but Triphala equal formulation significantly increased glutathione level only. Based on the data generated, it is suggested that among the three formulations studied, Chinnodbhavadi kwath and Triphala unequal formulations provides significant protection in gastric ulcer as compared to Triphala equal formulation. PMID- 23112407 TI - Colloidal dispersions for the delivery of acyclovir: a comparative study. AB - This paper describes a comparative study on the performances of ethosomes and solid lipid nanoparticle as delivery systems for acyclovir. Ethosomes were spontaneously produced by dissolution of phosphatidylcholine and acyclovir in ethanol followed by addition of an aqueous buffer while solid lipid nanoparticle were produced by homogenization and ultrasonication. Both colloidal systems were morphologically characterized by cryo-transmission electron microscopy. The encapsulation efficiency was 94.2+/-2.8% for ethosomes and 53.2+/-0.2% for solid lipid nanoparticle. Concerning Z potential, both formulations are close to neutrality. The diffusion coefficients of the drug from ethosomes and solid lipid nanoparticle, determined by a Franz cell method, were 9.4 and 1.2-fold lower as compared to the free acyclovir in solution, thus evidencing the ability of both colloidal systems in enhancing the diffusion of the drug. The antiviral activity against HSV-1 of both systems was tested by plaque reduction assay in monolayer cultures of Vero cells. Data showed that no significant differences in the antiviral activity were observed by acyclovir in the free or loaded forms. Taken together these results, colloidal systems could be interesting to mediate the penetration of acyclovir within Vero cells. PMID- 23112408 TI - Development and Validation of a Stability-indicating UV Spectroscopic Method for Candesartan in Bulk and Formulations. AB - A simple, specific, accurate and stability-indicating UV- Spectrophotometric method was developed for the estimation of candesartan cilexitil, using a Shimadzu, model 1700 spectrophotometer and a mobile phase composed of methanol: water in the ratio of 9:1 at wave length (lambda(max)) 254 nm. Linearity was established for candesartan in the range of 10-90 MUg/ml. The percentage recovery of was found to be in the range of 99.76-100.79%. The drug was subjected to acid, alkali and neutral hydrolysis, oxidation, dry heat, UV light and photolytic degradation. Validation experiments performed to demonstrate system suitability, specificity, precision, linearity, accuracy, interday assay, intraday assay, robustness, ruggedness, LOD, and LOQ. While estimating the commercial formulation there was no interference of excipients and other additives. Hence this method can be used for routine determination of candesartan cilexetil in bulk and their pharmaceutical dosage forms. The proposed method for stability study shows that there was appreciable degradation found in stress condition of candesartan. PMID- 23112409 TI - Development and Validation of RP-HPLC Method for Simultaneous Determination of Granisetron and Dexamethasone. AB - A new simple, selective, rapid, precise and accurate reverse phase HPLC method has been developed for simultaneous estimation of granisetron and dexamethasone. The method was developed using CPS Hypersil CN column (250*4.6 mm I.D.) with a mobile phase consisting of acetonitrile:buffer (100 mM Triethylamine adjusted to pH 3.0 with o-phosphoric acid) in ratio of 25:75 at a flow rate of 2 ml/min. Detection was carried out at 242 nm. The developed method was evaluated for various system suitability parameters and validated for linearity, accuracy, precision, LOD, LOQ as per ICH guidelines. It was also evaluated for bench top stability and freeze/thaw stability. The proposed method can be used for the estimation of these drugs in their combined dosage forms. PMID- 23112410 TI - Ecopharmacovigilance: an issue urgently to be addressed. PMID- 23112412 TI - Protective and curative effects of Cocos nucifera inflorescence on alloxan induced pancreatic cytotoxicity in rats. AB - OBJECTIVES: This study was planned to investigate the effects of pre and post treatment of young inflorescence of Cocos nucifera (CnI) on alloxan-induced diabetic rats. MATERIALS AND METHODS: Male albino Sprague Dawely rats were divided into five groups of six animals each. Group I was normal control, Group II was diabetic control, Cocos nucifera Inflorescence (CnI) was fed along with diet [20% (w/w)] orally (Group III) for a period of 11 days prior to alloxan injection (150 mg/kg i.p.). The curative effect of CnI was evaluated at the same feeding levels in alloxan-induced diabetic rats (Group IV) for a period of 30 days. The effects of both pretreatment and post-treatment (Group V) were also evaluated. Biochemical parameters such serum glucose, hepatic glycogen, and enzymes involving carbohydrate metabolism (hexokinase, phosphoglucomutase, pyruvate kinase, glucose-6-phosphatase, fructose 1, 6-diphosphatase, glucose-6 phosphate dehydrogenase, and glycogen phosphorylase) were assayed along with pancreatic histopathology. Data were analyzed using one-way analysis of variance followed by Duncan's post hoc multiple variance test. P < 0.05 was considered statistical significant. RESULTS: Diabetic control rats showed significant increase in serum glucose (P < 0.05) and decrease in hepatic glycogen levels (P < 0.05) compared to normal rats, which was reversed to near normal in both CnI pretreated and post-treated rats. Treatment with CnI resulted in significant decrease (P < 0.05) in activities of gluconeogenic enzymes in Group III and IV on compared to the diabetic control group, while glycolytic enzyme activities were improved in these groups. The cytotoxicity of pancreatic islets also ameliorated by treatment with CnI on histopathological examination. CONCLUSION: The results obtained in the study indicate the protective and curative effects of CnI on alloxan-induced pancreatic cytotoxicity, which is mediated through the regulation of carbohydrate metabolic enzyme activities and islets cell repair. PMID- 23112411 TI - Comparison of sensory attributes and immediate efficacy of intranasal ciclesonide and fluticasone propionate in allergic rhinitis: a randomized controlled trial. AB - OBJECTIVES: Intranasal corticosteroids (INCs) are the most effective modality for treating allergic rhinitis and their sensory attributes are important in patient compliance. This study aimed to compare the sensory attributes (scent, immediate taste, aftertaste, run down to throat, nose run off, soothing feel, nasal irritation, and urge to sneeze) and immediate response to the new intranasal steroid, ciclesonide (CIC), with fluticasone propionate (FLP) in allergic rhinitis. MATERIALS AND METHODS: A randomized, double blind, single dose, crossover study was done with 74 patients presenting with acute allergic rhinitis. Eligible subjects were randomized in 1:1 ratio to one of the two treatment sequences - CIC followed by FLP or vice versa. Sensory attributes were assessed using a questionnaire to score each item on a seven-point Likert scale, immediately and 2 min after dosing. Total nasal symptom score (TNSS) was calculated to evaluate immediate efficacy 10 min after first drug administration. Overall preference was recorded 10 min after the second drug administration. Patients were queried about treatment emergent adverse events following study drug administration and also 24 h later over the phone. RESULTS: Patients (58% males; pooled median age 32 years [Interquartile range, IQR, 25-41]; pooled median symptom duration 24 months [IQR 12-72]) preferred FLP over CIC nasal spray overall (55.41% vs. 25.68%, P = 0.007) and also with respect to attributes of scent, soothing feel, and nasal irritation. There was no statistically significant difference in immediate efficacy. Two patients reported mild headache following CIC first, while three felt mild headache, one dizziness, and one nasal congestion following FLP first administration. There were no delayed adverse events. CONCLUSIONS: There was no difference in immediate outcome following use of either of the two INCs. FLP was preferred over CIC with respect to scent, soothing feel and nasal irritation, and also overall. There were no significant adverse events. PMID- 23112413 TI - Antidepressant-like activity of (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a), a novel 5-HT(3) receptor antagonist: an investigation in behaviour-based rodent models of depression. AB - AIM: The present study was designed to investigate the antidepressant potential of (4-phenylpiperazin-1-yl) (quinoxalin-3-yl) methanone (4a), a novel 5-HT(3) receptor antagonist, with an optimal log P (2.84) and pA(2) value (7.3) greater than ondansetron (6.9) using rodent behavioural models of depression. MATERIALS AND METHODS: Swiss albino mice were used in actophotometer test, forced swim test (FST) and 5-hydroxytryptophan (5-HTP) induced head twitch response. Reserpine induced hypothermia (RIH) and olfactory bulbectomy were performed in male Wistar rats. Statistical analysis was carried out by using one-way analysis of variance followed by Tukey's test. RESULTS: Acute treatment of 4a (1-4 mg/kg, i.p.) in mice produced antidepressant-like effects in FST without affecting the baseline locomotion in actophotometer test. Further, 4a (2-4 mg/kg, i.p.) potentiated the 5-HTP induced head twitches response in mice and also antagonized RIH in rats. Furthermore, sub-chronic (14 days) treatment with 4a (2-4 mg/ kg, p.o.) significantly attenuated the behavioural anomalies induced by bilateral olfactory bulbectomy in rats in modified open field exploration. CONCLUSIONS: These preliminary investigations confirm that 4a exhibits antidepressant-like activity in behaviour based rodent models of depression. PMID- 23112414 TI - Effect of methanolic fraction of Kalanchoe crenata on metabolic parameters in adriamycin-induced renal impairment in rats. AB - OBJECTIVES: To investigate the effect of Kalanchoe crenata methanolic fraction (MEKC) on proteinuria, glucosuria, and some other biochemical parameters in adriamycin-induced renal impairment in rats. MATERIALS AND METHODS: Ether anesthetized rats received three intravenous injections (days 0, 14, and 28) of 2 mg/kg body weight of adriamycin. Repeated doses of the extract (0, 50, and 68 mg/kg b.w.) and losartan (10 mg/kg b.w.) were administered orally once daily, for 6 weeks, to these rats. Kidney functions were assessed through biochemical parameters. RESULTS: MEKC decreased proteinuria and also the urinary excretion of creatinine, glucose, and urea significantly in diseased rats. A decrease in serum levels of creatinine, urea, potassium, alkaline phosphatase, conjugate bilirubin, and alanine transaminase level was also recorded in nephropathic rats, but plasma levels of uric acid and glucose remained unchanged. Moreover, the plant extract markedly (P < 0.05) increased plasma sodium and decreased (P < 0.01) the urinary sodium and potassium levels. CONCLUSIONS: The results indicated that the treatment with the methanolic fraction of K. crenata may improve proteinuria and all other symptoms due to adriamycin-induced nephropathy and, more than losartan, could ameliorate kidney and liver functions. K. crenata could be a potential source of new oral antinephropathic drug. PMID- 23112415 TI - A simple cold pressure technique for the evaluation of analgesic drugs in healthy subjects. AB - AIM: An experimental pain model which is sensitive and reproducible would be a useful pharmacological tool both for existing and new drugs. The aim of the present study was to establish a simple and reliable method of producing experimental pain which can be used for screening of analgesic agents. MATERIALS AND METHODS: The method was standardized by recording pain threshold and pain tolerance values in 24 healthy volunteers. Reproducibility of the test procedure was evaluated by recording the pain threshold and pain tolerance values by a single observer on two sessions (inter-day reproducibility), and second observer in one session (inter-observer reproducibility), separately. Validity of the model was further tested by evaluating the analgesic effect of tramadol in 12 healthy volunteers. RESULTS: Cold pain model was found to produce low variability with coefficient of variation less than 15%. Inter-observer and inter-day reproducibility was very good as shown by Bland - Altman plot with most of the values within +/- 2SD. Analgesic activity by Tramadol was statistically different from placebo (P < 0.05). CONCLUSION: The newly developed pain model offers a stable and sensitive method for the early assessment of analgesic activity. PMID- 23112416 TI - Study of antiurolithiatic activity of Asparagus racemosus on albino rats. AB - AIMS: The aim of this study was to investigate the effect of ethanolic extract of Asparagus racemosus on urolithiasis in rats. MATERIALS AND METHODS: Thirty-six male Wistar albino rats were randomly divided into six groups (n = 6). Ethylene glycol (EG) 0.75% and ammonium chloride (AC) 2% in drinking water were fed to all groups (Groups II-VI) except normal control (Group I) rats for 10 days to induce urolithiasis. Group III-VI rats were treated with ethanolic extract of Asparagus racemosus at doses 200, 400, 800, and 1600 mg/kg, respectively, for 10 days. Positive control (Group II) rats were treated with EG/AC alone. Group I rats were administered drinking water and distilled water (6 MUl/g) by gavage. After 10 days, blood samples were collected and analyzed for serum concentrations of calcium, phosphorus, urea, and creatinine. The kidneys were removed and sectioned for histopathological examination. The data were presented as mean +/- standard error of mean and analyzed using one-way analysis of variance and Student's "t" test. P < 0.05 was considered statistically significant. Conventional windows software was used for statistical analysis. RESULTS: The rats treated with ethanolic extract of A. racemosus at doses 800 and 1600 mg/ kg significantly (P < 0.05) reduced the serum concentrations of calcium, phosphorus, urea, and creatinine. Histopathology of the kidneys in Groups V and VI revealed less tissue damage and were almost similar to Group I rats. CONCLUSIONS: The ethanolic extract of A. racemosus has protective effect against urolithiasis. PMID- 23112417 TI - Effect of Tinospora cordifolia on experimental diabetic neuropathy. AB - OBJECTIVES: To evaluate the effect of aqueous extract of stem of Tinospora cordifolia (TC) on hyperalgesia in streptozotocin induced diabetic rats and in- vitro aldose reductase inhibition. MATERIALS AND METHODS: Wistar albino rats, rendered diabetic with streptozotocin, were divided into 5 groups, namely the diabetic control treated with vehicle (DC), standard control which received glibenclamide+metformin (SC), test groups treated with 100, 200and 400 mg/kg b.w. of Tinospora cordifolia (TC1, TC2 and TC3 respectively). A group of five normal animals served as normal control (NC). Fasting blood glucose, body weight and reaction time to tail flick were measured one week after induction of diabetes. The animals were then treated orally for two weeks after which the same parameters were repeated. In-vitro aldose reductase inhibition assay was carried out at concentrations of 5, 10, 25, 50, 100 and 200 mcg/ml of Tinospora cordifolia using rat lens from normal rats. The in-vivo results were analysed with Mann Whitney test. RESULTS: The DC group demonstrated a decrease in the reaction time (hyperalgesia) compared to NC while a significant increase in the reaction time was observed with SC, TC2 and TC3 groups (p<0.05) as compared to the DC group. TC1 and TC2 showed a significant reduction in body weight compared to their baseline values (p<0.05). There was no significant change in the fasting blood glucose (FBS) in any of the groups. In-vitro aldose reductase inhibition was observed with TC with an IC(50) of 103 mcg/ml. CONCLUSIONS: Tinospora cordifolia prevents the hyperalgesia in experimental diabetic neuropathy. It has an aldose reductase inhibitory activity in-vitro which may contribute to the beneficial effects. PMID- 23112418 TI - Standardized Clitoria ternatea leaf extract as hyaluronidase, elastase and matrix metalloproteinase-1 inhibitor. AB - AIM: Plant Clitoria ternatea L. is claimed to possess a wide range of activities including antiinflammatory, local anesthetic and antidiabetic effect, etc. The aim of the present study was to evaluate the wound healing potential of standardized C. ternatea leaf extract in terms of different enzymatic models, which are mostly associated with skin wound. MATERIALS AND METHODS: The methanol extract and fractions were screened for its hyaluronidase, elastase, and matrix metalloproteinase-1 (MMP-1) inhibitory activity compared with standard oleanolic acid. The activity was rationalized through reverse phase high performance liquid chromatography (RP-HPLC) standardization of the extract and fractions with respect to its isolated biomarker taraxerol (yield 5.27% w/w). RESULTS: The extract showed significant (P < 0.001) hyaluronidase (IC(50) 18.08 +/- 0.46 MUg/ ml) and MMP-1 (P < 0.05) inhibition, but the elastase inhibition was insignificant (IC(50) 42.68 +/- 0.46 MUg/ml). Among the fractions, ethyl acetate fraction showed significant (P < 0.001) inhibition of hyaluronidase (IC(50) 28.01 +/- 0.48 MUg/ml) and MMP-1 (P < 0.01). The HPLC analysis revealed that the extract and the ethyl acetate fraction are enriched with taraxerol (5.32% w/w and 4.55% w/w, respectively). CONCLUSIONS: The experiment validated the traditional uses of C. ternatea and may be recommended for use in the treatment of different types of skin wounds, where taraxerol may be a responsible biomarker. PMID- 23112419 TI - Betulinic acid inhibits superoxide anion-mediated impairment of endothelium dependent relaxation in rat aortas. AB - OBJECTIVES: To investigate the protective effect of betulinic acid (BA) on endothelium-dependent relaxation (EDR) in rat aortas exposed to pyrogallol produced superoxide anion and its underlying mechanism. MATERIALS AND METHODS: The thoracic aorta of male Sprague-Dawley rats was isolated to mount in the organ bath system and the effect of BA on acetylcholine (ACh)-induced EDR, nitric oxide (NO) level, reactive oxygen species (ROS) level, nitric oxide synthase (NOS) activity, and superoxide dismutase (SOD) activity of aortic rings exposed to pyrogallol (500 MUM) for 15 min were measured. RESULTS: BA evoked a concentration dependent EDR in aortas, and pretreatment with EC(50) (2.0 MUM) concentration of BA markedly enhanced ACh-induced EDR of aortas exposed to pyrogallol-produced superoxide anion (E(max) rose from 23.91 +/- 5.41% to 42.45 +/- 9.99%), which was markedly reversed by both N(w) -nitro-L-arginine methyl ester hydrochloride (L NAME) and methylene blue, but not by indomethacin. Moreover, BA significantly inhibited the increase of ROS level, as well as the decrease of NO level, the endothelial NOS (eNOS) activity, and the SOD activity in aortas induced by pyrogallol-derived superoxide anion. CONCLUSION: These results indicate that BA reduces the impairment of EDR in rat aortas exposed to exogenous superoxide anion, which may closely relate to the reduction of oxidative stress and activation of eNOS-NO pathway. PMID- 23112420 TI - Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and amyloid precursor protein (AbetaPP) expression in rat brain. AB - AIM: Scopolamine is known to produce amnesia due to blockade of the cholinergic neurotransmission. The present study investigated the potential of Convolvulus pluricaulis (CP) to attenuate scopolamine (2 mg/kg, i.p) induced increased protein and mRNA levels of tau, amyloid precursor protein (AbetaPP), amyloid beta (Abeta) levels and histopathological changes in rat cerebral cortex. MATERIALS AND METHODS: The study was conducted on male Wistar rats (250 +/- 20 g) divided into four groups of eight animals each. Groups 1 and 2 served as controls receiving normal saline and scopolamine for 4 weeks, respectively. Group 3 received rivastigmine (standard) and group 4 received aqueous extract of CP simultaneously with scopolamine. Western blot and RT-PCR analysis were used to evaluate the levels of protein and mRNA of amyloid precursor protein (AbetaPP) and tau in rat cortex and ELISA was used to measure the amyloid beta (Abeta) levels. Histopathology was also performed on cortical section of all groups. RESULT: Oral administration of CP extract (150 mg/kg) to scopolamine treated rats reduced the increased protein and mRNA levels of tau and AbetaPP levels followed by reduction in Abeta levels compared with scopolamine treated group. The potential of extract to prevent scopolamine neurotoxicity was reflected at the microscopic level as well, indicative of its neuroprotective effects. CONCLUSION: CP treatment alleviated neurotoxic effect of scopolamine reflects its potential as potent neuroprotective agent. PMID- 23112421 TI - Nimesulide inhibits the proliferation of HepG2 by up-regulation of Smad4. AB - OBJECTIVES: Hepatocellular carcinoma (HCC) is receiving increased attention. This study was designed to investigate the effect of selective Cyclooxygenase-2 (COX 2) inhibitor, nimesulide, on the expression of Smad4 in human hepatocellular carcinoma HepG2. MATERIALS AND METHODS: HepG2 cells were incubated in various concentrations of nimesulide (25, 50, 100, 200, 400 MUmol/L) to detect the effect of proliferation by MTS. The apoptosis of HepG2 was determined by TUNEL; fluorescence microscope was used to observe the expression of Smad4. RESULTS: The result showed that nimesulide inhibited the proliferation of HepG2 cell in a concentrations-dependent manner, and promoted the karyopyknosis and fragmentation of HepG2 cell nucleus, induced its apoptosis, the number of fluorescence labeling of Smad4 in Nimesulide group was higher than control group (P<0.05). CONCLUSIONS: Nimesulide inhibits the proliferation and promotes apoptosis of HepG2 by up regulation of Smad4 in HepG2. PMID- 23112422 TI - Preventive effect of glycosaminoglycans from Amussium pleuronectus (Linne) on biomolecules, lactate dehydrogenase-isoenzyme and electrocardiographic patterns in isoproterenol-induced myocardial infarction in Wistar rats. AB - OBJECTIVES: This study was aimed to assess the cardioprotective role of low molecular weight glycosaminoglycans (LMW-GAG) in isoproterenol (ISO)-induced myocardial infarction (MI) in male Wistar rats. Effect of LMW-GAG on biomolecules, lactate dehydrogenase (LDH)-isoenzyme, and electrocardiographic (ECG)-patterns was studied as evidence of cardioprotection. MATERIALS AND METHODS: Male Wistar rats (140 +/- 10 g) were divided into four groups; untreated control (group I), LMW-GAG treated (300 MUg/day s. c. for 2 weeks-group II), ISO (85 mg s.c. injected on 13(th) and 14(th) days-group III), and LMW-GAG plus ISO (300 MUg/day s. c. for 12 days followed by 85 mg/kg ISO on the end of 13(th) and 14(th) days-group IV). At the end of the experimental period, all animals were terminated. RESULTS: Rats treated with LMW-GAG (300 MUg/kg) for 12 days showed significant increasing levels of triglyceride (TG) (both serum and heart tissue), low density lipoprotein (LDL), very low density lipoprotein (VLDL), total cholesterol, uric acid, creatinine, and glucose. However, it significantly decreased the levels of high density lipoprotein (HDL) (serum), plasma total protein, and albumin/globulin (A/G) ratio. ISO also adversely affected the LDH isoenzymes and caused marked elevation in ST segment. Pretreatment with LMW-GAG (300 MUg/kg) daily for a period of 2 weeks prevented the ISO-treated changes. CONCLUSIONS: The results indicate that LMW-GAG exhibits a cardioprotective effect in ISO-induced MI in rats, by maintaining the biomolecules and LDH-isoenzymes. PMID- 23112423 TI - Evaluation of antiobesity and cardioprotective effect of Gymnema sylvestre extract in murine model. AB - OBJECTIVE: Obesity plays a central role in the insulin resistance syndrome, which is associated with hyperinsulinemia, hypertension, hyperlipidemia, type 2 diabetes mellitus, and an increased risk of atherosclerotic cardiovascular disease. The present study was done to assess the effect of Gymnema sylvestre extract (GSE) in the high fat diet (HFD)-induced cellular obesity and cardiac damage in Wistar rats. MATERIALS AND METHODS: Adult male Wistar rats (150-200 g body weight) were used in this study. HFD was used to induce obesity. Body mass index, hemodynamic parameters, serum leptin, insulin, glucose, lipids, apolipoprotein levels, myocardial apoptosis, and antioxidant enzymes were assessed. Organ and visceral fat pad weights and histopathological studies were also carried out. RESULTS: Oral feeding of HFD (20 g/day) for a period of 28 days resulted in a significant increase in body mass index, organ weights, visceral fat pad weight, cardiac caspase-3, cardiac DNA laddering (indicating apoptotic inter-nucleosomal DNA fragment), and lipid peroxide levels of cardiac tissues of rats. Further, mean arterial blood pressure, heart rate, serum leptin, insulin, LDH, LDL-C, total cholesterol, triglycerides, and apolipoprotein-B levels were enhanced significantly, whereas serum HDL-C, apoliporotein-A1 levels, and cardiac Na(+) K(+) ATPase, antioxidant enzymes levels were significantly decreased. Furthermore, treatment with standardized ethanolic GSE (200 m/kg/p.o.) for a period of 28 days resulted in significant reversal of above mentioned changes in the obese Wistar rats. CONCLUSION: The present study has demonstrated the significant antiobesity potential of GSE in murine model of obesity. PMID- 23112424 TI - Effect of aqueous extract of Aegle marmelos unripe fruit on inflammatory bowel disease. AB - OBJECTIVE: The present study was designed to evaluate the effect of Aegle marmelos unripe fruit extract (AMFE) on inflammatory bowel disease (IBD) in Wistar albino rats. MATERIALS AND METHODS: Effect of AMFE was studied on acetic acid induced ulcerative colitis (1 ml of 4% acetic acid solution, transrectal) and indomethacin-induced enterocolitis (10 mg/kg, single dose, p.o) in Wistar albino rats. The extract was administered orally at different dose of 150, 200 and 250 mg/kg body weight. Disease pathogenesis was assessed by measuring disease activity index (DAI), macroscopic score, microscopic score, mesenteric mast cell protection, superoxide dismutase (SOD), and malonaldehyde (MDA) levels in the above two models. RESULTS: The results showed a dose dependent decrease in intestinal inflammation following treatment with AMFE. Significant protection in mast cell degranulation was observed in acetic acid and indomethacin-induced IBD models. Treatment with AMFE significantly decreased the MDA levels and increased SOD activity. CONCLUSION: In our study, AMFE produced anti-inflammatory, antioxidant, and mast cell stabilizing effects demonstrating protective effect in inflammatory bowel disease. PMID- 23112425 TI - Antidiarrheal efficacy of a quinazolin CFTR inhibitor on human intestinal epithelial cell and in mouse model of cholera. AB - OBJECTIVE: This study aimed to evaluate the antidiarrheal efficacy and pharmacological properties of ethyl 2-(4-oxo-3-o-tolyl-3,4-dihydroquinazolin-2 ylthio)acetate (DQA) as an inhibitor of cystic fibrosis transmembrane conductance regulator protein (CFTR) both in vitro and in vivo. MATERIALS AND METHODS: The effects of DQA on CFTR function and cell viability were investigated in Fisher rat thyroid (FRT) cells expressing human CFTR and human intestinal epithelial T84 cells by short-circuit current measurements and MTT assays, respectively. In vivo antidiarrheal efficacy of DQA was evaluated in a closed loop model of cholera in mice. RESULTS: In permeabilized FRT cells, apical chloride current induced by CFTR agonists (10 MUM forskolin, 100 MUM CPT-cAMP, and 20 MUM apigenin) was inhibited by DQA with IC(50) ~ 20 MUM and complete inhibition at 200 MUM. The inhibitory effect was reversible and not associated with cytotoxicity to FRT cells (5-500 MUM DQA for 24 h). Likewise, DQA effectively inhibited both forskolin and cholera toxin-induced transepithelial chloride secretion in T84 cells. In mice, intraluminal injection of 100 MUM DQA reduced cholera toxin (1 MUg/closed loop)-induced intestinal fluid secretion by 85% without affecting intestinal fluid absorption. CONCLUSIONS: DQA represents a new class of small molecule CFTR inhibitor with potential application in treatment of cholera. PMID- 23112426 TI - Effects of pravastatin on the pharmacokinetic parameters of nimodipine after oral and intravenous administration in rats: possible role of CYP3A4 inhibition by pravastatin. AB - OBJECTIVE: The aim of this study was to investigate the effects of pravastatin on the pharmacokinetics of nimodipine in rats. MATERIALS AND METHODS: The effect of pravastatin on P-glycoprotein (P-gp) and cytochrome P450 (CYP) 3A4 activity was evaluated. Nimodipine was administered to rats intravenously (3 mg/kg) and orally (12 mg/kg) with pravastatin (0.3 and 1 mg/kg). RESULTS: Pravastatin inhibited CYP3A4 enzyme activity in a concentration-dependent manner with a 50% inhibition concentration (IC(50)) of 14 uM. Compared with the oral control group, the area under the plasma concentration-time curve (AUC(0-infinity)) of nimodipine was increased significantly. Consequently, the absolute bioavailability (AB) of nimodipine with pravastatin (1 mg/kg) was 31.1%, which was significantly enhanced compared with the oral control group. Moreover, the relative bioavailability (RB) of nimodipine was 1.12- to 1.31-fold greater than that of the control group. CONCLUSIONS: The enhanced oral bioavailability of nimodipine might be mainly due to inhibition of the CYP3A-mediated metabolism of nimodipine in the small intestine and/or in the liver and due to reduction of the total body clearance rather than both to inhibition of the P-gp efflux transporter in the small intestine and reduction of renal elimination of nimodipine by pravastatin. The increase in the oral bioavailability of nimodipine with pravastatin should be taken into consideration of potential drug interactions between nimodipine and pravastatin. PMID- 23112428 TI - Introduction of case based teaching to impart rational pharmacotherapy skills in undergraduate medical students. AB - OBJECTIVE: The aim of this study is to assess the impact of case based teaching (CBT) on learning rational prescribing and to compare CBT with the traditional method of teaching (TRD). MATERIALS AND METHODS: Second year Bachelor of Medicine and Bachelor of Surgery (MBBS) students (n = 179) were administered a pre-test and randomly divided into groups to receive CBT (n = 96) and TRD (n = 83). CBT group was further sub-divided into CBT1 and CBT2. Both these groups were taught two topics each by CBT and TRD during tutorials; however, the topics were switched with respect to method of teaching. The post-test comprised of three therapeutic problems of which two were related, and one was not related to the tutorial topics. Marks obtained in the post-test were graded and analysed using Fischer's exact test. RESULTS: In the post-test, the therapeutic problems on diabetes mellitus and peptic ulcer were attempted by 85.41% students from CBT and 73.49% from TRD group. CBT group obtained more marks for these problems (4.23 +/- 0.94; P < 0.001) than the TRD (3.32 +/- 0.92) group. Also, more students in the CBT obtained grade 3 (P < 0.001) and fewer obtained grade 1 (P < 0.01), compared to the TRD group. When the grades of the two CBT groups were compared, it was found that fewer students in CBT 2 had obtained grade 1 and those scoring higher grades were comparable between the two groups. For the therapeutic problem on malaria, 7.29% students from CBT and 18.07% from TRD received 0 grade (P < 0.05). More students received >= 2 grade in CBT group (P < 0.05). CONCLUSION: Use of CBT during tutorials is better than TRD and facilitates learning of rational pharmacotherapy. PMID- 23112427 TI - An evaluation of the effects of nonselective and cardioselective beta-blockers on wound healing in Sprague Dawley rats. AB - OBJECTIVES: To investigate the effect of a nonselective beta-blocker (propranolol) and cardioselective beta-blocker (metoprolol) on wound healing in rats using incision and excision wound models and to compare the effect of these drugs on wound healing. MATERIALS AND METHODS: Propranolol and metoprolol were given orally. Sprague Dawley rats of either sex were used. Incision and excision wound models were used to evaluate the wound-healing activity. Effects of metoprolol and propranolol on tensile strength, period of epithelialization, and hydroxyproline content were observed. Histological analysis was done to see collagen deposition and inflammatory infiltrate. STATISTICAL ANALYSIS USED: The data was subjected to analysis of variance (ANOVA) followed by Scheffe's test. P < 0.05 was considered to be statistically significant. Statistical analysis was done using SPSS software version 15.0. RESULTS: Administration of propranolol or metoprolol was shown to decrease tensile strength, delay wound contraction and re epithelialization, increase inflammatory infiltrate, and reduce collagen density and hydroxyproline levels. CONCLUSIONS: The results suggest that nonselective and cardioselective beta-blockers delay wound healing and these effects are mediated by beta1-receptors. PMID- 23112429 TI - Effect of Hygrophila spinosa in ethylene glycol induced nephrolithiasis in rats. AB - OBJECTIVE: Hygrophila spinosa (Acanthaceae) is traditionally used to treat urinary calculi. The present study aimed to evaluate the antiurolithiatic activity of methanolic extract of Hygrophila spinosa (Acanthaceae) in ethylene glycol induced nephrolithiasic rats. MATERIALS AND METHODS: Methanolic extract of Hygrophila spinosa (HSME) (250 and 500 mg/ kg body weight) was administered orally to male Wistar albino rats. Ethylene glycol (EG) was used to induce nephrolithiasis. The parameters studied included water intake, urinary volume, urinary pH, urinary and kidney oxalate and calcium, urinary magnesium and serum uric acid. RESULTS: Ethylene glycol feeding resulted in hyperoxaluria as well as increased renal excretion of calcium and serum uric acid along with decreased excretion of urinary magnesium. Treatment with HSME significantly reduced the elevated urinary oxalate, urinary calcium and serum uric acid with increase in reduced urinary magnesium. Ethylene glycol feeding also resulted in increased levels of calcium and oxalate in kidney which was decreased after the treatment with HSME. The increased deposition of stone forming constituents in the kidneys of ethylene glycol treated rats was significantly lowered by treatment with HSME. CONCLUSION: The results indicate that the aerial parts of Hygrophila spinosa are endowed with antiurolithiatic activity, thereby justifying its traditional claim. PMID- 23112430 TI - Fixed drug eruption to fluconazole: a case report and review of literature. AB - Fixed drug eruption (FDE) is mainly characterized by skin lesions that recur at the same anatomic sites upon repeated exposures to an offending agent. It represents the most common cutaneous adverse drug reaction pattern in Indian patients. Here, we report an FDE to fluconazole. PMID- 23112431 TI - Multiple cutaneous neutropenic ulcers associated with azathioprine. AB - We report a case of neutropenic ulceration in a 42-year-old woman receiving azathioprine for pemphigus vulgaris. She developed multiple indolent ulcers involving the nose, neck, and back, after about 6-8 weeks following commencement of azathioprine 50 mg daily. The ulcers were large, disfiguring, dry, and with basal necrotic slough. They were painless and did not discharge pus. The absolute neutrophil count was severely depressed initially, but normalized following azathioprine withdrawal. Swab culture revealed colonization with Klebsiella pneumoniae and the ulcers healed with local debridement, treatment with imipenem, and topical application of mupirocin. However, nasal disfigurement persisted. Neutropenic ulceration is known to be associated with azathioprine therapy but we report this case because of the unusual presentation-indolent cutaneous ulcers. Early recognition of the problem and drug withdrawal can prevent complications like disfigurement. PMID- 23112432 TI - Olanzapine induced de-novo obsessive compulsive disorder in a patient with schizophrenia. AB - There are reports of de novo development or exacerbation of obsessive-compulsive symptoms in patients with schizophrenia treated with atypical antipsychotics, although this is widely debated. We report one such case where a patient with a primary diagnosis of schizophrenia, treated with olanzapine, developed de novo obsessive-compulsive disorder, with convincing evidence for its causality due to the drug. PMID- 23112433 TI - First reported case of tenofovir-induced photoallergic reaction. AB - A 50-year-old man, a known case of human immunodeficiency virus infection for the past 1 year, was on antiretroviral therapy in the form of stavudine, lamivudine, and nevirapine. Three days after replacing stavudine with tenofovir, he developed redness on the face and neck and within 48 h the rash became generalized. Dermatological examination revealed involvement of photoexposed areas of the face in the form of erythema and ill-defined hyperpigmented plaques, with mild periorbital edema. There was specific involvement of V and nape of the neck. Extensive erythema and scaling were also present on buttocks, thighs, and upper third of legs. A diagnosis of photoallergic dermatitis to tenofovir was considered and confirmed by histopathology and photopatch test. He responded well to the stoppage of the drug and oral corticosteroids. This is the first report of a photoallergic reaction to tenofovir in the literature. PMID- 23112434 TI - Gynecomastia caused by ethionamide. AB - A 43 year old male patient, known case of multidrug resistant tuberculosis, was prescribed antitubercular drugs: kanamycin, levofloxacin, ethionamide, terizidone, Para-Aminosalicylate Sodium (PAS), pyrazinamide and pyridoxine. After 4 months of treatment, the patient developed a lump in the right breast which was approximately around 3 * 3 cm in size, tender on palpation, and not fixed to the underlying tissues. Ultrasonography (USG) revealed a hypoechoic mass of size 2.5 * 0.92 * 2.6 cm in the right breast region behind the nipple without any infiltration to the deeper structures. Gynecomastia due to ethionamide was suspected and the patient was advised anti-inflammatory drugs for 5 days without any change in drug therapy. The pain subsided; however, the nodule remained. Treatment was continued without any change till the patient stopped using the drugs on his own and without doctor's consent. Within a week of stopping of treatment the nodule also disappeared. PMID- 23112435 TI - First case of mirtazepine-induced Stevens-Johnson syndrome from India. AB - A 28-year-old woman, a known case of systemic lupus erythematosus (SLE), was admitted with mucocutaneous ulceroerosive lesions with blisters and thrombocytopenia after taking antidepressant mirtazepine. Exacerbation of SLE and drug-induced eruption was diagnosed. Clinical and laboratory markers were suggestive of Stevens-Johnson syndrome. This is a rare adverse effect of the newer generation antidepressant mirtazepine. PMID- 23112436 TI - Glancing and Stopping Behavior of Motorcyclists and Car Drivers at Intersections. AB - For the past decade, motorcycle fatalities have risen while other motor vehicle fatalities have declined. Many motorcycle fatalities occurred within intersections after a driver failed to see a motorcyclist. However, little is known about the behavior of motorcyclists when they negotiate an intersection. A study was undertaken to compare the behavior at intersections of an experienced group of motorcyclists when they were operating a motorcycle with their behavior when they were driving a car. Each participant navigated a course through low volume, open roads. Participants wore eye-tracking equipment to record eye-glance information, and the motorcycle and car were instrumented with an onboard accelerometer and Global Positioning System apparatus. Results showed that participants were more likely to make last glances toward the direction of the most threatening traffic before they made a turn when they were driving a car than when they were riding a motorcycle. In addition, motorcyclists were less likely to come to a complete stop at a stop sign than car drivers. These results suggested that motorcyclists were exposing themselves to unnecessary risk. Specifically, motorcyclists frequently failed to make proper glances and practice optimal riding techniques. The behavior of the motorcyclists was compared with the current Motorcycle Safety Foundation curriculum. The results suggested that threat-response and delayed-apex techniques should be added to the training curriculum. PMID- 23112437 TI - Sentinel surveillance of blindness: an initiative of the national programme for control of blindness in India. PMID- 23112438 TI - Universal health insurance in India: ensuring equity, efficiency, and quality. AB - Indian health system is characterized by a vast public health infrastructure which lies underutilized, and a largely unregulated private market which caters to greater need for curative treatment. High out-of-pocket (OOP) health expenditures poses barrier to access for healthcare. Among those who get hospitalized, nearly 25% are pushed below poverty line by catastrophic impact of OOP healthcare expenditure. Moreover, healthcare costs are spiraling due to epidemiologic, demographic, and social transition. Hence, the need for risk pooling is imperative. The present article applies economic theories to various possibilities for providing risk pooling mechanism with the objective of ensuring equity, efficiency, and quality care. Asymmetry of information leads to failure of actuarially administered private health insurance (PHI). Large proportion of informal sector labor in India's workforce prevents major upscaling of social health insurance (SHI). Community health insurance schemes are difficult to replicate on a large scale. We strongly recommend institutionalization of tax funded Universal Health Insurance Scheme (UHIS), with complementary role of PHI. The contextual factors for development of UHIS are favorable. SHI schemes should be merged with UHIS. Benefit package of this scheme should include preventive and in-patient curative care to begin with, and gradually include out-patient care. State-specific priorities should be incorporated in benefit package. Application of such an insurance system besides being essential to the goals of an effective health system provides opportunity to regulate private market, negotiate costs, and plan health services efficiently. Purchaser-provider split provides an opportunity to strengthen public sector by allowing providers to compete. PMID- 23112439 TI - Implementing quality process in public sector hospitals in India: the journey begins. PMID- 23112440 TI - The risk factor of domestic violence in India. AB - BACKGROUND: It is over the last decade that research in this field of domestic violence has led to greater recognition of the issue as public health problem. The paper aims to study the prevalence of physical, psychological, and sexual violence and potential risk factors of the women confronting violence within the home in India. MATERIALS AND METHODS: A multicentric study with analytical cross sectional design was applied. It covers 18 states in India with 14,507 women respondents. Multistage sampling and probability proportion to size were done. RESULTS: The result shows that overall 39 per cent of women were abused. Women who have a lower household income, illiterate, belonging to lower caste, and have a partner who drinks/bets, etc. found to be important risk factors and place women in India at a greater risk of experiencing domestic violence. CONCLUSION: As India has already passed a bill against domestic violence, the present results on robustness of the problem will be useful to sensitize the concerned agencies to strictly implement the law. This may lead to more constructive and sustainable response to domestic violence in India for improvement of women health and wellbeing. PMID- 23112441 TI - Profile of presentation of human immunodeficiency virus infection in north India, 2003-2007. AB - BACKGROUND: Clinico-epidemiological profile of the Human immunodeficiency virus (HIV) epidemic in India is varied and depends on multitude of factors including geographic location. We analyzed the characteristics of HIV-infected patients attending our Immunodeficiency Clinic to determine any changes in their profile over five years. SETTINGS AND DESIGN: A retrospective observational study. MATERIALS AND METHODS: The study sample included all patients with HIV infection from January 1, 2003 to December 31, 2007. Diagnosis of HIV was made according to National AIDS Control Organization guidelines. RESULTS: Of 3 067 HIV-infected patients, 1 887 (61.5%) were male and 1 180 (38.5%) were female patients. Mean age of patients was 35.1 +/- 9.0 years. Majority (91.8%) of patients were in the age group of 15 to 49 years. Progressively increasing proportion of female patients was noted from year 2004 onward. Median CD4 count at presentation in year 2003 was 197/MUl (Interquartile range [IQR] = 82.5-373) while in year 2007 it was 186.5/MUl (IQR = 86.3-336.8). Mean CD4 count of male patients was 203.7 +/ 169.4/MUl, significantly lower as compared with female patients, which was 284.8 +/- 223.3/MUl (P value <=0.05). Every year, substantial proportions of patients presenting to clinic had CD4 count<200/MUl indicating advanced disease. Predominant route of transmission was heterosexual in 2 507 (81.7%) patients. Tuberculosis and oropharyngeal candidiasis were the most common opportunistic infections (OIs). Cryptococcal meningitis was the most common central nervous infection. Our patients had comparatively lower median CD4 counts at the time of presentation with various OIs. CONCLUSIONS: Patients had advanced stage of HIV infection at the time of presentation throughout five years. Females presented earlier during the course of HIV infection. There is need for early screening and increasing awareness in healthcare providers to make a diagnosis of HIV much sooner. PMID- 23112442 TI - Assessment of Quality of Life of HIV-Positive People Receiving ART: An Indian Perspective. AB - CONTEXT: HIV/AIDS is known to affect an individual not only physically but also mentally, socially, and financially. It is a syndrome that builds a vacuum in a person affecting his/her life as a whole. AIMS: The purpose of the present study is to evaluate the quality of life (QOL) of people living with HIV/AIDS (PLHIV) receiving ART and its association with Body mass index (BMI) and CD4 count. STUDY DESIGN: An observational study was performed on PLHIV receiving ART in Orissa, India. MATERIALS AND METHODS: Data on sociodemographic profile, BMI, and CD4 were gathered from 153 HIV-positive subjects. QOL was assessed using WHOQOL-HIV BREF scale. RESULTS: The overall QOL score of the subjects was moderate; PLHIV with lower BMI also had poorer QOL (P<0.05). Employment affected only the social health domain of the subjects. Men reported poorer level of independence and physical health while women reported poorer social relationships and environment. All the six domains correlated significantly with the overall QOL indicated by the G-facet. CONCLUSION: Attention toward improving the nutritional status of PLHIV should be accorded high priority to ensure improvement in the overall QOL of PLHIV. PMID- 23112443 TI - Assessment of impact of small group teaching among students in community medicine. AB - BACKGROUND: We conducted a study to assess the impact of small group teaching (SGT) among students by feedback analysis to identify intricacy so that learning can be facilitated. MATERIALS AND METHODS: This cross-sectional study was undertaken among 182 MBBS students studying at a teaching hospital at Gangtok. Students were provided with a questionnaire following an assignment on a scheduled topic. Students were asked to provide feedback on the modes of teaching learning practiced in community medicine with the parameters of evaluation including assessment of presentation by faculty member in reference to relevance, sequencing, depth, interaction, etc., to the overall rating of presentations in different teaching-learning methods. RESULTS: The faculty members were on the positive evaluation by the students in the SGT, which was preferred over lectures as the teaching-learning methods. Among SGTs "tutorials" were graded better than "practical", "seminar" and "field posting" on the basis of longer duration at a stretch. Among the parameters for evaluation, relevance, depth, and interaction in regard to scheduled topic of presentations, the rating was significantly higher in SGT than different other teaching-learning methods. Largely the students noted that the time devoted and number of hours/sessions allotted for each topic was adequate. CONCLUSION: All forms of SGT were on the positive appraisal by the students on their learning experience and were considered as a comprehensive tool for in-depth teacher-student interaction. PMID- 23112444 TI - A Comparative Study of the Management Decisions by IMNCI Algorithm and by Pediatricians of a Teaching Hospital for the Children Between 2 Months to 5 Years. AB - BACKGROUND: Integrated management of neonatal and childhood illness (IMNCI) is already operational in many states of India, but there are very few studies in Indian scenario comparing its validity and reliability with the pediatricians' decisions. OBJECTIVES: 1) To compare the IMNCI decision with the decision of pediatricians; 2) to assess the significance of multiple presenting symptoms in the IMNCI algorithm. MATERIALS AND METHODS: The study was conducted among the sick children between 2 months to 5 years presented in pediatric department from January to March 2009. The IMNCI decision was compared with pediatrician's decisions by percent agreement, Kappa and weighted Kappa with the aids of SPSS version 10. RESULTS: The overall diagnostic agreement between IMNCI algorithm and pediatrician's decisions was 36.64%, (Kappa 0.16 and weighted Kappa 0.29) with 51.15% over diagnosis and 12.21% under diagnosis. The importance given by IMNCI algorithm in cases of multiple presenting symptoms was also reflected as it was evident that 37.50% children presented with three symptoms were categorized as red, whereas it was 28.57% and 11.67% for those presented with two and one symptom, respectively, (P < 0.0001). Pediatricians also gave importance for presence of multiple symptoms by considering 50% as admissible in the group presented with three symptoms, 30.16% in the group presented with two symptoms, and 16.67% in the group presented with only one symptom. The association was also statistically significant (P = 0.018). CONCLUSION: Diagnostic discordance is seen mainly due to over diagnosis of all fever cases as malaria. Importance of presence of comorbidities was also reflected. PMID- 23112445 TI - Emergency Obstetric Care in a Rural Hospital: On-call Specialists Can Manage C sections. AB - BACKGROUND: Institutional birth and Emergency Obstetric Care (EmOC) are important strategies of the National Rural Health Mission (NRHM). While the Community Health Center (CHC) is expected to serve EmOC needs in NRHM, the CHCs are hamstrung due to chronic shortage of specialist doctors. Alternative strategies are therefore needed for ensuring EmOC. OBJECTIVES: This study aims to estimate the EmOC needs in a private rural hospital from case records and find some useful predictors for caesarian section (C-section) and to assess C-section needs in the context of on-call specialist support. MATERIALS AND METHODS: We analyzed a two decade series of 2587 obstetric cases in a private rural hospital for normal deliveries and EmOC including C-section. RESULTS: About 80% of the obstetric cases were normal deliveries. Of the remaining 20% cases that required EmOC, nearly one-third required C-section. In the series, two maternal deaths occurred due to hemorrhage. About 13% case records showed past abortion, which adds to EmOC workload. Primipararous mothers with higher age had a greater incidence (23%) of C-section. The C-section rate shows a steady rise from 3% to above 10% in the series. CONCLUSIONS: This rural hospital required C-section in 6.4% cases. This C-section workload was managed with the help of on-call specialists. The local hospital team could manage 93.6% of the cases and abortions with only two maternal deaths. This strategy of an on-call specialist team can be an option for CHCs till resident specialists are adequately available. PMID- 23112446 TI - Disaster management in flash floods in leh (ladakh): a case study. AB - BACKGROUND: On August 6, 2010, in the dark of the midnight, there were flash floods due to cloud burst in Leh in Ladakh region of North India. It rained 14 inches in 2 hours, causing loss of human life and destruction. The civil hospital of Leh was badly damaged and rendered dysfunctional. Search and rescue operations were launched by the Indian Army immediately after the disaster. The injured and the dead were shifted to Army Hospital, Leh, and mass casualty management was started by the army doctors while relief work was mounted by the army and civil administration. OBJECTIVE: The present study was done to document disaster management strategies and approaches and to assesses the impact of flash floods on human lives, health hazards, and future implications of a natural disaster. MATERIALS AND METHODS: The approach used was both quantitative as well as qualitative. It included data collection from the primary sources of the district collectorate, interviews with the district civil administration, health officials, and army officials who organized rescue operations, restoration of communication and transport, mass casualty management, and informal discussions with local residents. RESULTS: 234 persons died and over 800 were reported missing. Almost half of the people who died were local residents (49.6%) and foreigners (10.2%). Age-wise analysis of the deaths shows that the majority of deaths were reported in the age group of 25-50 years, accounting for 44.4% of deaths, followed by the 11-25-year age group with 22.2% deaths. The gender analysis showed that 61.5% were males and 38.5% were females. A further analysis showed that more females died in the age groups <10 years and >=50 years. CONCLUSIONS: Disaster preparedness is critical, particularly in natural disasters. The Army's immediate search, rescue, and relief operations and mass casualty management effectively and efficiently mitigated the impact of flash floods, and restored normal life. PMID- 23112447 TI - Strategic national pharmaceutical stockpile: a concept for optimization of medical resources during disasters. PMID- 23112448 TI - Overview of publicly funded health insurance: Tamil Nadu model. PMID- 23112449 TI - Child Rearing Practices Amongst Brothel-based Commercial Sex Workers. PMID- 23112450 TI - Tetanus following dog bite. PMID- 23112451 TI - Waste management in dental office. PMID- 23112452 TI - Suicides Versus Attempted Suicides: What is the Truth in the Numbers? PMID- 23112453 TI - Pandemic Influenza A: H1N1 2009 Vaccine: A Concern on Neurological Adverse Effect. PMID- 23112454 TI - Immunocytochemistry versus nucleic acid amplification in fine needle aspirates and tissues of extrapulmonary tuberculosis. AB - BACKGROUND: Immunocytochemistry (ICC) is an established routine diagnostic adjunct to cytology and histology for tumor diagnosis but has received little attention for diagnosis of tuberculosis. AIMS: To have an objective method of direct visualization of mycobacteria or their products in clinical extrapulmonary tuberculosis (EPTB) specimens, immunocytochemical localization of M. tuberculosis antigen by staining with species specific monoclonal antibody to 38-kDa antigen of Mycobacterium tuberculosis complex. MATERIALS AND METHODS: Immunostaining with specific monoclonal antibody to 38-kDa antigen of Mycobacterium tuberculosis complex was done in fresh and archival fine needle aspirates and tissue granulomata of 302 cases of extrapulmonary tuberculosis and was compared with the molecular diagnostic i.e., nucleic amplification and conventional [Cytomorphology, Ziehl Neelsen (ZN) staining and culture] tests and 386 controls. RESULTS: Diagnostic indices by Bayesian analysis for all types of archival and fresh material varied from 64 to 76% in nucleic acid amplification (NAA) and 96 to 98% in ICC. There was no significant difference in the diagnostic indices of ZN staining and/ or ICC in fresh or archival material whereas the sensitivity of NAA differed significantly in fresh versus archival material both in cytology (71.4% vs 52.1%) and histology (51.1% vs 38.8%). ICC can be easily used on archival smears and formalin-fixed paraffin-embedded tissue sections with almost equal sensitivity and specificity as with fresh material, in contrast to NAA which showed significant difference in test results on archival and fresh material. CONCLUSIONS: Low detection sensitivity of MTB DNA in archival material from known tuberculous cases showed the limitation of in-house NAA-based molecular diagnosis. ICC was found to be sensitive, specific and a better technique than NAA and can be used as an adjunct to conventional morphology and ZN staining for the diagnosis of EPTB in tissue granulomas. PMID- 23112455 TI - Utility of concentration method by modified bleach technique for the demonstration of acid-fast bacilli in the diagnosis of tuberculous lymphadenopathy. AB - BACKGROUND: Microscopy detection of acid fast bacilli (AFB) by Ziehl-Neelsen (ZN) method has many advantages when it comes to speed and feasibility though it has a low sensitivity. If the sensitivity could be improved, it has the potential to become an even more valuable tool for detection of AFB. OBJECTIVES: To evaluate the efficacy of bleach concentration method in the cytodiagnosis of tuberculous lymphadenitis in comparison with routine Ziehl-Neelsen method and to compare the positivity in various cytomorphological categories. MATERIALS AND METHODS: A total of 112 cases of tuberculous lymphadenitis diagnosed by fine needle aspiration cytology (FNAC) were categorized into six cytomorphological patterns. The acid-fast bacilli positivity by routine staining was correlated with modified bleach methods of ZN staining. Sensitivity of routine ZN and modified bleach concentration was compared. RESULTS: The classic cytomorphological pattern of tuberculosis of epithelioid granulomas, langhans giant cells and caseous necrosis was seen in 37.5% of cases. Routine ZN staining detected AFB in 12.5% of cases and the modified bleach method in 60.7%. Modified bleach method showed AFB positivity in additional 54 cases where routine AFB staining was negative. The modified bleach method showed AFB positivity in all cases where routine ZN staining was positive. CONCLUSION: The modified bleach method was more sensitive and safer than routine ZN staining. As the background was clear, the bacilli were easily visible and the screening time was shorter. PMID- 23112456 TI - Epidermal inclusion cyst in breast: Is it so rare? AB - BACKGROUND: Epidermal inclusion cyst in the breast (EICB) is very rare. It presents as breast lump mainly in peri-areolar region and needs to be differentiated from other breast lesions with predominance of squamous cells. AIM: To analyze the role of fine needle aspiration cytology (FNAC) in patients presenting with breast lump. MATERIALS AND METHODS: The present study is a retrospective study over the period of past 2 years, where the patients presented with firm breast lumps. Six of these cases were diagnosed as EICB on FNAC. Smears from these cases were reviewed for cytomorphological findings and correlated with clinico-radiological details. RESULTS: Patients ranged in age from 25 to 60 years, and female to male sex ratio was 2:1 (female 4, male 2). Mammography was done in women (4), which showed solid, well-defined mass lesions in peri-areolar region and were suggestive of benign breast lesions (3) and infective lesion (1). FNA was performed; Giemsa-stained smears showed predominantly mature benign squamous cell and anucleated squames in all cases, thus one of the cytological diagnoses was EICB. Five of these cases had histological confirmation. CONCLUSION: EIC of breast is not that rare lesion as considered. The patients may not seek medical attention because of small painless swelling; unless the lump increases in size or becomes painful. FNAC is confirmatory in the presence of a typical pultaceous aspirate and cytomorphological features of EIC. Thus, FNAC plays a crucial role in its diagnosis and management. Symptomatic cases should be readily excised and need histological correlation to rule out any potential complications that can arise in these cysts. PMID- 23112457 TI - Touch imprint cytology of prostate core needle biopsy specimens: A useful method for immediate reporting of prostate cancer. AB - BACKGROUND: Cytology plays an important role in the preoperative assessment of many cancers. It is used as a first-line pathological investigation in both screening and diagnostic purposes. AIMS: To determine the diagnostic value and accuracy of touch imprint cytology (TIC) smear of prostate core needle biopsy (CNB) specimens in the diagnosis of prostate carcinoma. MATERIALS AND METHODS: One hundred and twenty-one patients had ultrasound-guided transrectal prostate CNB. A total of 1210 TIC smears were prepared from all CNB specimens. RESULTS: Diagnoses of 1210 TIC smears were compared with the histopathological findings of the CNB specimens. One hundred and seventy (14%) TIC smears were found positive for malignancy, 35 (2.9%) were diagnosed as suspicious for malignancy and 1005 (83.1%) were found negative for malignancy. Twenty-five of 35 suspicious imprints and 150 of 170 malignant smears were confirmed to be malignant on histopathological evaluation. Although 20 malignant TIC smears were defined as benign in standard histological preparations, 10 of them had definitive diagnosis of malignancy following extensive serial sectioning. Last of all, there were 10 false-positive cytology results. Moreover, 10 of the 35 suspected TIC smears were false negative when compared with the histopathological diagnosis. The sensitivity, specificity, positive predictive value and negative predictive value of touch imprint smear results were 100%, 98%, 90.2% and 100%, respectively. CONCLUSIONS: TIC smears can provide an immediate and reliable cytological diagnosis of prostate carcinoma. It may clearly help the rapid detection of carcinoma, particularly in highly suspected cases that had negative routine biopsy results for malignancy with abnormal serum prostate specific antigen (PSA) levels and atypical digital rectal examination. PMID- 23112458 TI - Effectiveness of the cell block technique in diagnostic cytopathology. AB - BACKGROUND: One of the constraints of the conventional FNA smear is the limited material available for adjuvant diagnostic investigations including immunocytochemistry. The cell block technique employs the retrieval of small tissue fragments from a FNA specimen which are processed to form a paraffin block. It is widely accepted that cell block technique increases the cellular yield and improves diagnostic accuracy. The ability to obtain numerous tissue sections allows for multiple immunostains and other studies to be performed akin to paraffin sections produced in histopathology. AIMS: To determine the effectiveness of the cell block technique by comparing cytomorphological preservation and immunocytochemistry (ICC) stains on paired cell block and conventional fine needle aspiration (FNA) samples. MATERIALS AND METHODS: In this prospective study, material for both glass slides and cell blocks were collected simultaneously during fine needle aspirates from 47 samples comprising lung and liver masses. Grading of cellularity, morphological preservation, architectural preservation, immunocytochemical staining intensity and presence of background staining on paired FNA smears and cell block samples were compared. Each arm of the paired analysis was performed blindly without knowledge of the grading outcome of the other. The Kappa statistic (kappa) was used to measure inter-rater agreement. RESULTS: The 47 samples evaluated included FNAs from the lung, 24/47 (51%) and liver, 23/47 (49%). The immunocytochemistry stains consisted of 44/47 (94%) CK7; 44/47 (94%) CK20; 18/47 (38%) TTF1; 10/47 (21%) synaptophysin; 10/47 (21%) Hepar-1 and 7/47 (15%) AE1/3. There was no overall agreement in preservation of cytomorphological detail and ICC staining between the two methods. The Papanicolaou-stained conventional FNA smears fared better than the cell block for the evaluation of nuclear and morphologic characteristics. The ICC stains worked better on the cell block samples due to lack of background and aberrant staining. CONCLUSION: Direct FNA smears and cell blocks complement each other and our results indicate that both are needed in the diagnostic work-up of patients. The cost implications of performing both techniques on all FNA material warrants further evaluation. PMID- 23112460 TI - Nasal osteogenic chondrosarcoma. PMID- 23112459 TI - Breast fine needle aspiration cytology practices and commonly perceived diagnostic significance of cytological features: A pan- India survey. AB - BACKGROUND: Methodical and meticulous understanding of clinico-pathological procedures and decision making process of cancer diagnosis and identification of aspects that are well-suited for computer-aided analysis are first steps toward development of assistive computational tool for analysis of breast fine needle aspiration cytology (FNAC) slides. AIMS: To identify variables in practice of FNAC as used for diagnosis of breast lesions and commonly perceived diagnostic significance of cytological features for diagnosis of benign or malignant condition of breast lesions. MATERIALS AND METHODS: An India-wide questionnaire based survey of cytopathologists/pathologists' breast FNAC reporting practices and their opinion on diagnostic significance of cytological features in diagnosis of benign or malignant nature of breast lesion were conducted. RESULTS: Fifty-one experts working with various medical education institutes (~52% of participants), oncological tertiary care centers (~28%) and primary care centers/private diagnostic pathology laboratories (~20%) spread over 13 states of India have participated in the survey. Constants and variables observed in clinico cytopathological practices and combined opinion of the participants on diagnostic significance of cytological features are presented here. CONCLUSIONS: There exist analogous as well as varied components in clinico-pathological procedures and diagnostic interpretation by individuals. These constants and variables in the practice of breast FNAC should be considered, when drawing up specifications for an assistive computational tool for analysis of breast FNAC slides. The estimate for commonly perceived significance of cytological features obtained through this study will help in their selection for computer-aided analysis of breast FNAC slides and further in selection of corresponding feature quantification techniques. PMID- 23112461 TI - Metastatic malignant melanoma intraoperative imprint cytology of brain tumor. PMID- 23112462 TI - Invasive maxillary aspergillosis masquerading as malignancy in two cases: Utility of cytology as a rapid diagnostic tool. AB - Fungi have emerged as important etiological agents for chronic sinusitis. Invasive aspergillosis has been reported in immunocompromised individuals or diabetics; however, it is uncommonly seen in immunocompetent patients. Definitive diagnosis of these lesions is based on histological examination and fungal culture. We report two cases of invasive maxillary lesions in immunocompetent patients, clinically suspected of malignancy; however, fine needle aspiration cytology showed fungal hyphae, morphologically suggestive of Aspergillus, which was later confirmed on histopathology. Aspiration cytology thus plays a crucial role in the early and definitive diagnosis of fungal sinusitis in cases clinico radiologically suspected of malignancy. An early diagnosis will help the clinician for early and appropriate management and follow-up in order to decrease the high morbidity and mortality associated with it. PMID- 23112463 TI - Primary breast actinomyces simulating malignancy: A case diagnosed by fine-needle aspiration cytology. AB - We report a case of primary actinomycosis of breast diagnosed by fine needle aspiration cytology (FNAC) in a postmenopausal lady who presented with a clinical impression of malignancy. Resolution of infection while conserving the breast was achieved by timely diagnosis and effective antibiotic therapy. The literature reports that primary actinomycosis of the breast is very rare after menopause, with only very few cases found after extensive search. It is imperative that this condition should be considered in the differential diagnosis of malignancy. The effectiveness of cell block sections in the final diagnosis is also highlighted. PMID- 23112464 TI - Disseminated cryptococcosis presenting with generalized lymphadenopathy. AB - Cryptococcosis is a common opportunistic infection among immunocompromised individuals. Some of the commonly affected sites are respiratory and central nervous system. Lymph node is an unusual site of involvement which could mimic tuberculosis, as seen in our case. We report a 32-year-old male immunocompromised patient presenting with generalized lymphadenopathy who was clinically suspected to have tuberculous lymphadenitis. He was diagnosed to have disseminated cryptococcosis on fine needle aspiration cytology and fungal isolation on culture. PMID- 23112465 TI - Cytological diagnosis of lepromatous leprosy: A report of two cases with review of literature. AB - The "gold standard" for the diagnosis and classification of leprosy to date, is histological examination of skin biopsy in correlation with the bacteriological indices. These are, however, time-consuming. An attempt was made to diagnose leprosy using fine needle aspiration cytology (FNAC) which is a simple, safe, cost-effective and time-saving procedure with minimal trauma and complications. This case report highlights the role of FNAC in rapid diagnosis and early management, in patients of leprosy. PMID- 23112466 TI - Cytological features of ossifying fibromyxoid tumor of soft parts. AB - A case of ossifying fibromyxoid tumor (OFMT) evaluated during an intraoperative pathological consultation is presented. The patient, a 70-year-old woman was being followed because of a tumor in the left buttock. Cytological smears were obtained after scrapping the tumoral cut surface and revealed a myxoid background with fragments composed of a denser, fibrillar metachromatic stroma with accompanying round to oval tumoral nuclei and no vessels. Single cells were predominantly monomorphic with a round to oval morphology and scarce cytoplasm. The most relevant feature of the tumor was its peripheral, plaque-like, calcified consistency. The review of the cytological descriptions of four cases revealed similar findings that can be presumed as those of a low-grade myxoid tumor of round to oval cells. A specific recognition of OFMT based solely on cytological features seems difficult. However, when such features are coupled with characteristic radiological findings (peripheral calcification) this entity must be considered. PMID- 23112467 TI - Cytodiagnosis of mucosal malignant melanoma of nasal cavity: A case report with review of literature. AB - Sinonasal malignant melanoma is of unusual occurrence. Common sites for melanomas are head, neck region, and the lower extremities as they are exposed to sunlight, which is one of the predisposing factors. We report a case of primary mucosal malignant melanoma of the nasal cavity in a 68-year-old male for its rare occurrence. The primary knowledge of its existence and evaluation of its cytological features are important for a correct preoperative cytological diagnosis and thereby clinical implications for appropriate therapeutic intervention. The cytological features when evaluated along with clinical, histopathological and immunohistochemical features are sufficiently diagnostic. The rarity of its occurrence warrants its mention. PMID- 23112468 TI - Germ cell tumor of ovary with plenty of sarcoid like granulomas: A diagnosis on fine needle aspiration cytology. AB - Germ cell tumors of ovary with elements of two or more subtypes are relatively uncommon. Sarcoid-like granulomas are seen in rare association with dysgerminomas, a subgroup of germ cell tumors of ovary, which are again less common. Fine-needle aspiration cytology (FNAC) of the gonadal germ cell tumor, though not performed frequently, is of help when a gonadal mass does not require resection as in lymphoma which can be treated by chemotherapy. FNAC helps to diagnose this tumor and to rule out other lesions, including germ cell tumors. It is also an effective, rapid and reliable procedure for the diagnosis of germ cell tumors. PMID- 23112469 TI - Lymphoma of the cervix: A diagnostic pitfall on cervicovaginal smear. AB - Malignant lymphoma that secondarily involves the cervix is a rare condition and may be difficult to distinguish from follicular cervicitis and small cell carcinoma. Cervical lymphoma is sometimes misdiagnosed on cervicovaginal cytology due to its rarity. We report a case of a cervical lymphoma in a 65-year-old woman, which was diagnosed as a squamous cell carcinoma on cervicovaginal cytology. PMID- 23112470 TI - Cytomorphological features of lymphoepithelial carcinoma of submandibular gland in an adolescent male. AB - A case of lymphoepithelial carcinoma (LEC) occurring in right submandibular gland of a 13-year-old Indian male is presented, wherein the lesion unveiled itself only after multiple fine needle aspiration (FNA) procedures. This unusual neoplasm has high frequency of occurrence in Eskimos and a predilection for the parotid gland. The aspirates obtained were highly cellular comprising tight clusters of atypical epithelial cells with admixture of lymphocytes. Histopathological examination of the resected submandibular gland and lymph node chain was consistent with the diagnosis of LEC. Immunohistochemistry (IHC) revealed cytokeratin (CK)-positive and S-100-negative tumor cells lying admixed with CD45-positive lymphoid cells. A detailed otorhinolaryngological examination with inclusion of multiple biopsies was found negative for any primary tumor. Although histopathological features of this entity are well established, only a handful of case reports describing cytological features of this entity are present in medical literature. We conclude that the cytomorphological features of LEC are sufficiently distinctive to at least, suggest a possibility of this lesion. PMID- 23112471 TI - Role of syringe holder in reducing needle stick injuries. PMID- 23112472 TI - Author's response. PMID- 23112473 TI - J Conserv Dent: BI-MONTHLY from 2013. PMID- 23112474 TI - The efficacy of pre-operative oral medication of paracetamol, ibuprofen, and aceclofenac on the success of maxillary infiltration anesthesia in patients with irreversible pulpitis: A double-blind, randomized controlled clinical trial. AB - AIM: To determine the effect of preoperative administration of paracetamol (PARA), ibuprofen (IBUP), or aceclofenac (ACEC) on the success of maxillary infiltration anesthesia in patients with irreversible pulpitis in a double blinded randomized controlled trial. MATERIALS AND METHODS: One hundred and twenty patients with irreversible pulpitis of a maxillary first molar participated. Patients indicated their pain scores on a Heft Parker visual analog scale, after which they were randomly divided into four groups (n = 30). The subjects received identical capsules containing 1000 mg PARA, 800 mg IBUP, 100 mg ACEC or cellulose powder (placebo, PLAC), 1 h before administration of maxillary infiltration anesthesia with 2% lidocaine containing 1:200,000 epinephrine. Access cavities were then prepared and success of anesthesia was defined as the absence of pain during access preparation and root canal instrumentation. The data were analyzed using chi-squared tests. RESULTS: The success rates in descending order were 93.3% (IBUP), 90% (ACEC), 73.3% (PARA), and 26.5 % (PLAC). A significant (P < 0.001) difference was found between the drug groups and the PLAC group. CONCLUSIONS: Pre-operative administration of PARA, IBUP, and ACEC significantly improved the efficacy of maxillary infiltration anesthesia in patients with irreversible pulpitis. PMID- 23112475 TI - Dentinal hypersensitivity: A comparative clinical evaluation of CPP-ACP F, sodium fluoride, propolis, and placebo. AB - BACKGROUND: Dentine hypersensitivity is a transient condition that often resolves with the natural sclerotic obturation of dentinal tubules. A potent topically applied in-office desensitizing treatment is indicated as the choice of treatment when dentine hypersensitivity is localized to one or two teeth. AIM: The present study aimed to evaluate and compare the clinical efficiency of CPP-ACP F, sodium fluoride, propolis, and distilled water that was used as placebo in treating dentinal hypersensitivity. MATERIALS AND METHODS: 120 patients aged 20-40 years reporting with dentinal hypersensitivity in relation to canine, premolar and molars with erosion, abrasion, and gingival recession were randomly assigned to four groups of 30 patients each. Response to air jet and tactile stimuli were measured using visual analogue scale initially on 1st, 7th, 15th, 28th, 60(th), and final assessment was done on the 90th day. STATISTICAL ANALYSIS: A statistical analysis was done using Anova test (Fischer's test) and Tukey HSD test for multicomparison. RESULTS: The teeth treated with the test group showed decrease in the mean hypersensitivity values compared to control group, over a period of three months. The results showed propolis to be most efficient in treating dentinal hypersensitivity and CPP- ACPF showed to be the least efficient. CONCLUSION: All test groups were effective in reducing dentinal hypersensitivity, although they differed in rapidity of action over the period of 3 months. Further studies can be done using advanced materials and techniques. Multiple therapeutic modalities have been developed to treat dentinal hypersensitivity including products that impede nerve conduction of pain stimulus, products that mechanically occlude dentinal tubules, and calcium containing products designed to create plugs in the tubules utilizing a demineralization mechanism. PMID- 23112476 TI - Molecular identification of an Enterococcus faecalis endocarditis antigen efaA in root canals of therapy-resistant endodontic infections. AB - INTRODUCTION: Enterococcus faecalis has long been implicated in persistent root canal infections and therapy-resistant endodontic infections. It has also been associated with bacteremia, that is, infective endocarditis arising from certain invasive dental procedures. E. faecalis endocarditis antigen (efaA) has been identified as one of the principal virulence factors associated with infective endocarditis. AIM: To detect the presence of putative E. faecalis virulence factor, efaA in root canals of therapy-resistant endodontic infections using polymerase chain reaction (PCR) amplification. MATERIALS AND METHODS: Samples were obtained from 32 patients (20-70 years) undergoing endodontic retreatment, which were incubated in prereduced thioglycollate broth and subcultured onto ethyl violet azide broth (EVA; selective medium for E. faecalis). Deoxyribonucleic acid (DNA) was extracted from the samples and analyzed for the endocarditis virulence factor efaA using PCR. RESULTS: Among the positive E. faecalis samples, efaA gene was identified in 11 out of 15 samples. CONCLUSION: Our findings indicate that efaA, a potent E. faecalis virulence gene can be found in E. faecalis strains detected in root canals of therapy-resistant endodontic infections similar to reports for 'medical' strains. PMID- 23112477 TI - Incidence of post-operative pain after single visit and multiple visit root canal treatment: A randomized controlled trial. AB - AIM: To compare the incidence and intensity of post-obturation pain after single or multi visit root canal treatment on single rooted teeth in a randomized controlled trial. MATERIALS AND METHODS: Two hundred patients requiring root canal treatment on permanent single rooted teeth (both vital and non vital) were included. The patients were assigned randomly into two groups of 100 patients each. The teeth in Group1 (n = 100) were obturated at the first visit, whilst those in Group 2 (n = 100) were obturated in a second visit 7 days later. A modified Heft Parker visual analog scale was used to measure pre-operative pain and post-obturation pain at 6, 12, 24 and 48 hours after obturation. Independent sample T-tests was used for statistical analysis. RESULTS: Twelve patients were excluded from the study as they failed to follow the scheduled revisit. Data were obtained from the remaining 188 patients. There was no statistically significant difference in the incidence and intensity of post-obturation pain experienced by two groups. CONCLUSIONS: The incidence and intensity of post-obturation pain experience following one- or two-visit root canal treatment on teeth with a single canal were not significantly different. PMID- 23112478 TI - SealBio: A novel, non-obturation endodontic treatment based on concept of regeneration. AB - INTRODUCTION: "SealBio", an innovative, non-surgical endodontic treatment protocol, based on "regenerative concept" has been developed to manage pulp and periapically involved teeth. MATERIALS AND METHODS: Subsequent to Institute's ethical clearance, 18 patients presenting with signs and symptoms of pulp and periapical disease were included in the study. (11/M, 7/F; Mean age - 44.7 years; range 15-76 years). The protocol included a modified cleaning and shaping technique involving apical clearing and foramen widening, combined with inducing bleeding and clot formation in the apical region. Calcium-sulphate based cement was condensed with hand pluggers into the canal orifices. An appropriate permanent restoration was given. The patients were followed-up clinically and radiographically at regular interval of 6 months. Six teeth in 3 patients were also evaluated pre and post treatment CBCT at 6-months. RESULTS: The novel treatment protocol was found to be favourable in resolving periapical infection, both clinically and radiographically. CONCLUSIONS: This innovative endodontic treatment protocol highlights and reiterates the importance of cleaning and shaping and puts forth the possible role of stem cells and growth factors in healing after non-surgical endodontic therapy. PMID- 23112479 TI - Flexural strength of a composite resin light cured with different exposure modes and immersed in ethanol or distilled water media. AB - AIM: The aim of this in vitro study was to evaluate the flexural strength of a composite resin polymerized with three different modes of light exposure. MATERIALS AND METHODS: The three different modes of light exposure were conventional, 600 mW/cm2/40s; soft start, 300 mW/cm2/10s + 600 mW/cm2/30s; pulse delay, 600 mW/cm2/1s + 60 s of waiting time + 600 mW/cm2/39s). Twenty samples were prepared for each polymerization method. Flexural strength (FS) tests were carried out with a 2 kN load at a speed of 0.5 mm/ min. All tested groups were submitted to analysis of variance (one-way-ANOVA) and Tukey's test (P < 0.05). RESULTS: When stored in water, conventional and pulse delay groups presented higher FS values which were statistically different from the soft start group. When stored in 100% ethanol, conventional and soft start groups presented higher FS values which were statistically different from the pulse delay group. CONCLUSION: Different polymerization modes and immersion media can affect the physical properties (flexural strength) of composite resin. PMID- 23112480 TI - Counteraction of reactive oxygen species and determination of antibacterial efficacy of proanthocyanidin and lycopene when mixed with calcium hydroxide and chlorhexidine mixture: An in vitro comparative study. AB - AIM: The objective of the study was to determine the neutralizing effect of proanthocyanidin (grape seed extract) and lycopene (tomato extract) on reactive oxygen species (ROS) generated by the mixture when used as an intracanal medicament. The study also evaluated the effect of proanthocyanidin and lycopene on the antibacterial efficacy of a mixture of chlorhexidine (CHX) and calcium hydroxide [Ca(OH)(2)] against Enterococcus feacalis. MATERIALS AND METHODS: Four sample groups were prepared as follows. Group I: 2% CHX gluconate (control group) and group II: a mixture of 125 mg of Ca(OH)(2) with 2% CHX gluconate solution. Group III was a mixture of 125 mg of Ca(OH)(2) with 1 mL of 2% CHX gluconate solution and 1 mL of 5% proanthocyanidin solution and group IV, a mixture of 125 mg of Ca(OH)(2) with 1 mL of 2% CHX gluconate solution and 1 mL of 5% lycopene solution. The groups were analyzed for ROS formation using the mass spectrometer (JEOL GC MATE II) immediately after preparation. The antibacterial property was evaluated by using agar diffusion method and the results were statistically analyzed using one-way analysis of variance (ANOVA) and Tukey-Kramer multiple comparison tests. RESULTS: The peak value of 196.96 denotes ROS formation. Group II shows a higher peak value than other groups. Group IV shows a drastic reduction in the peak value. Group IV shows a drastic reduction in ROS formation when compared with group II, group III, and the control group. Antibacterial efficacy was higher in group IV, followed by group III, group II, and group I. CONCLUSION: Lycopene and proanthocyanidin reduce the ROS significantly by virtue of their antioxidant property. Lycopene shows more antioxidant property when compared with proanthocyanidin. PMID- 23112481 TI - System B, Endo-Twinn and E-Fill. True temperatures inside the canal. AB - BACKGROUND: The aim of this study is to verify the variations of the temperature inside the root canal with three different gutta-percha heating systems. MATERIALS AND METHODS: A split-tooth model was built with a lateral groove at 3.5 mm from working length (WL) in order to insert a Chromel-Alumel K-type thermocouple placed in contact with gutta-percha. The thermocouple was connected to a digital thermometer. Sixty obturations were made with medium gutta-percha points. For 20 specimens the System B was used with the Buchanan fine plugger and the temperature was set at 200 degrees C; for other 20 specimens the Endo-Twinn with a fine plugger was used and for the last 20 specimens we used the E-Fill with a 40.04 plugger. All pluggers were pushed to 3.5 mm from WL so that the tips were in contact to the probe. RESULTS: The analysis of 60 samples showed the highest temperature average using the System B after 10 seconds (86.85 degrees C), after 15 seconds (94.9 degrees C), after 20 seconds (100.4 degrees C) and after 25 seconds (104.5 degrees C). The Endo-Twinn average values are similar to System-B ones. The E-Fill average values are lower (69.9 degrees C) than the other two systems evaluated only after 10 seconds due to limited working time. The temperatures average obtained using different systems of warm vertical compaction are lower than what was declared by the producing companies. CONCLUSION: Time is one the most important parameters to consider using these systems. Temperatures reached from the System B and Endo-Twinn after 25 seconds; however, seem to be sufficient to ensure an optimal adaptation of the gutta percha in the anatomical complexity of root canals. The temperatures obtained from the E-Fill, only after 10 seconds, instead seems to be insufficient to assure the rheological characteristics of gutta-percha. PMID- 23112482 TI - The effect of retreatment procedure on the pH changes at the surface of root dentin using two different calcium hydroxide pastes. AB - AIM: To compare pH changes at the cervical, middle and apical surfaces of root dentin in retreated and non- retreated teeth, after canal obturation with two different calcium hydroxide pastes. MATERIALS AND METHODS: After instrumentation of 55 extracted teeth, three cavities with 0.75 mm depth and 1.5 mm in diameter were drilled at buccal root surface. The teeth were randomly divided into five groups. Canals in the first two groups were filled with either mixture of calcium hydroxide and saline solution and calcium hydroxide and 2% chlorhexidine (CHX). In the third and fourth groups canals were first obturated with gutta-percha and AH26 sealer, and then materials were removed. After 2 days canals were filled with two different calcium hydroxide pastes similar to the first and the second groups. The pH was measured in the prepared cavities at 1, 3, 7 and 14 days. RESULTS: In the non-retreated groups, pH at the surface of the roots was significantly higher in comparison to the retreated ones (P value < 0.001). pH values were significantly higher in the non-retreated teeth filling with calcium hydroxide and saline solution (P value < 0.001). CONCLUSION: Regarding to the little pH changes at the surface of dentin in retreated teeth, the hydroxyl ions cannot penetrate into the dentinal tubules. Thus, to achieve higher pH at the root surface in retreated teeth, it is clinically advisable to remove more dentin from the inner walls and to use normal saline as a vehicle for calcium hydroxide rather than acidic pH materials. PMID- 23112483 TI - Comparative evaluation of effect of acidic beverage on enamel surface pre-treated with various remineralizing agents: An In vitro study. AB - AIM: This study aimed at quantitatively evaluating the effect of colabased beverage on the calcium loss of enamel surface pre-treated with fluorideenriched casein phosphopeptideamorphous calcium phosphate (CPP-ACPF) and betaeta-ricalcium phosphate (beta-TCP) using energy dispersive X-ray analysis (EDX). MATERIALS AND METHODS: 24 enamel specimens were prepared from the buccal and palatal surfaces of extracted intact human premolars and were randomly assigned to study groups and control group. Specimens of Group II were pre-treated with CPP-ACPF and Group III treated with beta-TCP twice daily for 4 for 28 days, followed by storage in artificial saliva. All specimens were evaluated for mineral (calcium and phosphorus) content (wt%) after pre-treatment using SEM-EDAX. The specimens were then placed in the acidic beverages for 4 days for 10 Mineral content was again measured using SEM-EDAX. RESULTS: Statistical analysis using one-way ANOVA followed by Tukey's HSD test was applied to compare the re-mineralization and de mineralization of the samples. CONCLUSION: The present study concluded that both the remineralizing agents tested were found to be effective in inhibiting the de mineralization caused by colabased beverage. Among the remineralizing agents tested, beta-TCP was found to be more effective than CPP-ACPF. PMID- 23112484 TI - Comparative evaluation of the effect of different bonding agents on the ultramorphology of primary tooth dentin and the resin dentin interface. AB - AIM: To analyze and compare the changes in the ultramorphology of dentin in primary teeth using different bonding agents and to study the resin/dentin interface produced by them. MATERIALS AND METHODS: Occlusal surfaces of 50 extracted human deciduous teeth were grounded to expose the dentin. The teeth were divided into two groups (A) For viewing surface morphology- 18 teeth divided into four groups: (a) for viewing dentinal morphology (3 teeth), (b) Scotchbond multi-purpose (5 teeth), (c) Adhe SE (5 teeth), (d) Futurabond (5 teeth). (B) For viewing interfacial morphology- 32 teeth divided into four groups with 8 teeth each: (a) Scotch Bond Multipurpose (3M, ESPE),), (b) Adhe Se (Vivadent), (c) Optibond All-in-One (Kerr), (d) Futurabond NR (VOCO, Cuxhaven, Germany). The adhesives were applied to each group following the manufacturer's instruction. All the samples were then prepared for viewing under SEM. RESULTS: The photographs were graded using a four-step (0-3) scale method proposed by Ferrari et al. For Scotchbond, 12 (75%) were graded as 2 Grade 3 was observed in only 1 observation in the entire lot of materials. The results obtained for Adhe SE and Optibond AIO were similar, i.e. in 5 (31.25%) observations each the scores were 0 and in 11 (68.75%) observations each the scores were 1. In case of Futurabond, 3 (18.75%) observations were graded as 0 and 13 (81.25%) were graded as 1, thus showing a mean score of 0.81+/-0.40. CONCLUSION: Three- step bonding agent results in the complete removal of smear layer. While the self- etch approach is not efficient in removing the smear layer and opening of the dentinal tubules. The longest resin tags with lateral branches were seen in two groups- Scotch bond multipurpose and Optibond FL. PMID- 23112485 TI - To determine whether the first file to bind at the working length corresponds to the apical diameter in roots with apical curvatures both before and after preflaring. AB - AIM: To evaluate the discrepancies between the diameter of the canal and the first file to bind at the working length, before and after preflaring in teeth with apical curvatures. MATERIALS AND METHODS: Twenty teeth with apical curvatures were selected for the study. Following access, the patency file was fixed at the working length, and the apices were ground perpendicular to the canal at this level. Diameters of canal and the first file to bind at the working length were observed for each tooth, both before and after preflaring, under stereomicroscope at 30X magnification. RESULTS: ANOVA and post hoc Bonferroni tests showed significant differences in both groups regarding anatomical diameter at working length and the first file to bind. The area of contact of the file at apical region remained the same in both groups. CONCLUSION: Using the first file to bind for gauging the diameter of the apical canal was found to be an unreliable method in teeth with apical curvatures, even after preflaring. PMID- 23112486 TI - Effectiveness of a new canal brushing technique in removing calcium hydroxide from the root canal system: A scanning electron microscope study. AB - AIM: To evaluate the effectiveness of Canal Brush technique removal Ca(OH)(2) from the root canal system using Scanning Electron Microscope (SEM). MATERIALS AND METHODS: Eighteen teeth were instrumented up to #40 and dressed with Ca(OH)(2). Ca(OH)(2) was removed with master apical file (MAF) (Group 1, n:6) and CanalBrush technique (Group 2, n:6). Six teeth served as positive and negative controls. The roots were splited in the buccolingual direction and prepared for SEM examination. Two examiners evaluated the wall cleanliness then statistical analysis was performed by Mann-Whitney U and Friedman tests. RESULTS: Differences in cleanliness were observed between Group 1 and Group 2 in the apical thirds (P=0.002). In the coronal and middle thirds, there were no differences between the two groups. CONCLUSIONS: It is essential to re-instrument the root canal walls using instrumentation techniques while irrigating with NaOCl and EDTA combination. The Canal Brush technique results in the packing effect of the Ca(OH)(2) through to the apex. PMID- 23112487 TI - The reinforcement effect of polyethylene fibre and composite impregnated glass fibre on fracture resistance of endodontically treated teeth: An in vitro study. AB - AIM: The aim of this study was to evaluate the fracture resistance of endodontically treated maxillary premolars with wide mesio-occluso-distal (MOD) cavities restored with either composite resin, or composite resin reinforced with different types of fibres. MATERIALS AND METHODS: Fifty human maxillary premolars were selected. Five intact teeth served as positive controls. Endodontic therapy was carried out in the remaining forty-five teeth. Standardized MOD cavities were prepared in all the teeth. The teeth were restored with a nanocomposite using an incremental technique. These forty five teeth were randomly divided into three experimental groups (Group A, B and C) (n = 15). The teeth in Group A did not undergo any further procedures. The teeth in Group B and C were reinforced with composite impregnated glass fibre and polyethylene fibre, respectively. Fracture resistance was measured in Newtons (N). RESULTS: The positive controls showed the highest mean fracture resistance (811.90 N), followed by Group B (600.49N), Group A (516.96N) and Group C (514.64N), respectively. One Way analysis of variance (ANOVA) test revealed a statistically significant difference between all the groups (P = 0.001). Post-hoc Tukey test revealed a moderately significant difference (P = 0.034) between Control and Group B, and a strongly significant difference between Control and Group A (P = 0.002), and Control and Group C (P = 0.001). CONCLUSIONS: Endodontic therapy and MOD cavity preparation significantly reduced the fracture resistance of endodontically treated maxillary premolars (P = 0.001). No statistically significant difference was found between the experimental groups (Group A, B and C) (P > 0.1). However, the fracture resistance of the composite impregnated glass fibre reinforced group was much higher than the others. PMID- 23112488 TI - Effect of different root canal irrigants on the sealing ability of two all-in-one self-etch adhesives: An in vitro study. AB - AIM: To evaluate the effect of different root canal irrigants on the sealing ability of two self-etch adhesives, using dye penetration method, within the pulp chamber. MATERIALS AND METHODS: 72 extracted human molars were divided into six groups, according to the irrigant and self-etch adhesives used. After de-roofing the pulp chamber with a carborundum disc, the pulp was extirpated using excavator and broaches. In 36 samples, pulp chambers were bonded with Xeno V after irrigation with either 2% CHX (Group1: Xe-CHX) ; 17% EDTA + 5.25% NaOCl (Group2: Xe- EDTA + NaOCl) or normal saline (Group3: Xe-NS) and in other half samples, pulp chambers were bonded with Adper Easy One after irrigation with either 2% CHX (Group 4: Ad-CHX); 17%EDTA + 5.25% NaOCl (Group5: Ad-EDTA+NaOCl) or normal saline (Group 6: Ad-NS). All the samples were restored with Filtek Z350. Ten teeth from each group were assessed for dye penetration. Two samples in each group were viewed under scanning electron microscope to observe resin-dentin interfacial adaptation. Data was statistically analyzed using Mann-Whitney and Kruskal Wallis tests at a significance level of P < 0.05. RESULTS: MEAN MICROLEAKAGE SCORES AND STANDARD DEVIATION OBSERVED WERE: Group 1 (Xe-CHX): 2.8 +/- 0.42, Group 2 (Xe EDTA + NaOCl): 2.3 +/- 0.82, Group 3 (Xe-NS): 2.9 +/- 0.31, Group 4 (Ad-CHX): 1.2 +/- 0.91, Group 5 (Ad-EDTA + NaOCl): 0.8 +/- 0.63, Group 6 (Ad-NS): 1.9 +/- 0.99. CONCLUSIONS: Adper Easy One showed significantly less leakage than Xeno V when normal saline was used as an irrigant. EDTA treatment followed by NaOCl application significantly reduced microleakage and improved the interfacial adaptation with Adper Easy One. CHX did not significantly affect the sealing ability of both one-step self-etch adhesives tested. PMID- 23112489 TI - The effect of surface treatments and bonding regimens on microtensile bond strengths of repaired composite: An in vitro study. AB - AIM: To assess the microtensile bond strength of repaired composite resin that was surface treated by diamond point or silicon carbide followed by bonding using either only total- etch bonding regimen or silane coupling agent with adhesive resin. MATERIALS AND METHODS: Fourteen composite blocks were aged under deionized water for 14 days. The bonding surface was prepared with coarse diamond point or silicon carbide. Two blocks with no surface treatment were used as control groups. The bonding regimen was either total-etch bonding regimen or silane coupling agent and bonding agent. The aged samples were then bonded to new composite. Five sections per block (each 1mm thick) were prepared; cut to obtain an adhesive zone of approximately 1mm(2) and subjected to microtensile bond strength testing. RESULTS: The highest bond strength was obtained by surface treatment by coarse diamond point and total etch bonding regimen and least by silicon carbide and silane. A statistically significant difference was seen in all the four groups. CONCLUSIONS: Surface treatment by a coarse diamond point and total-etch bonding regimen provides highest bond strength. Thus, a simpler treatment regimen can contribute to a better bond strength in repaired composites. PMID- 23112490 TI - Surgical intervention for treating an extensive internal resorption with unfavorable crown-to-root ratio. AB - Internal resorption is a rare lesion in permanent teeth. Managing perforating internal resorption is a great challenge for dentists. This report presents a successful surgical treatment of a maxillary central incisor that had extensive root perforation due to internal resorption. After unsuccessful nonsurgical approach, during surgical intervention apical part of the resorption defect was removed and the coronal part was filled with mineral trioxide aggregate. Three years later the tooth was symptom free with normal mobility and pocket depth despite unfavorable crown-to-root ratio. This case report have shown that surgical intervention and using mineral trioxide aggregate as root canal filling material in a tooth with extensive internal resorption and unfavorable crown-to root ratio can be considered as a treatment option. PMID- 23112491 TI - Root canal treatment of a mandibular second premolar with atypical canal pattern. AB - To present a unique case of mandibular second premolar with an atypical canal pattern. Thorough knowledge of root canal morphology, appropriate assessment of the pulp chamber floor, and critical interpretation of radiographs are a prerequisite for successful root canal treatment. Mandibular premolars frequently exhibit variable and complex root canal morphology and are one of the most difficult cases to treat endodontically. These teeth may require skillful and special root canal preparation and obturation techniques. This article reports an unusual case of a mandibular second premolar with atypical canal pattern that was successfully treated endodontically. PMID- 23112492 TI - Platelet Rich Fibrin in the revitalization of tooth with necrotic pulp and open apex. AB - Regeneration of pulp-dentin complex in an infected necrotic tooth with an open apex is possible if the canal is effectively disinfected. The purpose of this case report is to add a regenerative endodontic case to the existing literature about using Platelet Rich Fibrin (PRF). A nine year old boy who accidently broke his immature maxillary central incisor tooth, developed pulpal necrosis with apical periodontitis. After the access cavity preparation, the canal was effectively irrigated with 20 ml of 5.25% sodium hypochlorite solution and 10ml of 0.2% chlorhexidine solution and dried with paper points. Triple antibiotic paste was placed inside the canal and left for 21 days. 12 ml of whole blood was drawn from the patient's right antecubital vein and centrifuged for 10 minutes to obtain the Choukroun's PRF. After the removal of the triple antibiotic paste, the PRF was placed into the canal till the level of cementoenamel junction and 3mm of grey MTA was placed directly over the PRF clot. The setting of MTA was confirmed 3 days later and the tooth was double sealed with GIC and Composite restoration. After 1 year the clinical examination revealed negative responses to percussion and palpation tests. The tooth responded positively to cold and electric pulp tests. Radiographic examination revealed continued thickening of the dentinal walls, root lengthening, regression of the periapical lesion and apical closure. On the basis of the results obtained in our case report we conclude that revitalization of necrotic infected immature tooth is possible under conditions of total canal disinfection and PRF is an ideal biomaterial for pulp-dentin complex regeneration. PMID- 23112493 TI - Electronic apex locators in the presence of various irrigants. PMID- 23112494 TI - A clinical trial of cold lateral compaction with Obtura II technique in root canal obturation. PMID- 23112495 TI - Analyzing association and repeated measures data. PMID- 23112496 TI - 13(th) IACDE & IES Post Graduate Convention. PMID- 23112497 TI - 1(st) National Convention on Endodontic and Conservative Dentistry Clinical Research. PMID- 23112498 TI - First-aid at workplace-past, current and future. PMID- 23112499 TI - Identification of awkward postures that cause discomfort to Liquid Petroleum Gas workers in Mumbai, India. AB - BACKGROUND: Awkward, extreme and repetitive postures have been associated with work related musculoskeletal discomfort and injury to the lower back. Liquid Petroleum Gas (LPG) workers in India; that is the delivery men carry heavy cylinders on their shoulders and back. The cylinders come in commercial and residential form which range in weight from 14.2kgs, 16.2kgs, 19.2kgs, 32kgs, 40 kgs etc. They have a tedious schedule of 8 h/day and mostly associated with loading and unloading of the cylinders. Their job demands a high intensity of strength and power. They are exposed to high level of physical demands and relatively lesser amount of rest which makes them vulnerable to various injuries over a period of time. MATERIALS AND METHODS: 100 LPG workers (delivery men) were interviewed using the Ovako work assessment system OWAS posture code and action category system developed by ISMAIL et al.[10] was used. A battery of questions with specific stress was constructed and validated in the Department of Physiotherapy, Padmashree Dr D.Y Patil University, Nerul, Navi Mumbai, India. RESULTS: This study presented an ergonomic assessment of LPG workers. The results show that the workers work in awkward postures. They transfer the cylinders in poor postures with high velocity and motion repetitiveness thus subjecting their spine to greater amounts of compressive forces. Regarding to work discomfort survey questionnaire, the postures cause ill effects on their various body segments. Among them 90% fall in category 4 while loading the cylinder, that is the load by those postures have a very harmful effect on musculoskeletal, system corrective action for improvement required immediately. And while unloading 70% fall in category 3, which are postures that have harmful effect on musculoskeletal system. Corrective actions should be done as soon as possible. Majority of workers also complained of severe injury to back-34%, shoulder-20%, knee-20%, neck-16%, and toes-10%. CONCLUSION: These findings provide a prima facie evidence of higher occupational stresses among the LPG workers because of identified specific stressors prevalent in their jobs and explore the possible intervention strategies for its reduction. PMID- 23112500 TI - Serum total immunoglobin-E and health hazards in workers involved in land fill and compost areas of hazardous waste management plants. AB - BACKGROUND: The exposures of bio-aerosols have reported higher occupational health hazards, the association between serum total IgE levels and job categories and occupational health hazards of waste disposal area was limited. The present study was undertaken to assess the relationship between occupational health hazards and Serum total IgE in waste disposal area. MATERIALS AND METHODS: One hundred eighty subjects working in waste disposal areas in different parts of Bangalore at Karnataka, India were enrolled into the study in 2009. Using questionnaire the respiratory morbidity and other work related problems in HWW was carried. The levels of serum total IgE in study subjects were determined by using Enzyme-linked -immunosorbent assay kits (DRG International Inc, USA). The differences of serum total IgE levels between the groups were computed by using non-parametric Mann-Whitney U test. SPSS 10.0 for windows version of statistical software was used in the analysis. RESULTS: The levels of serum total IgE was significantly increased in landfill area (P=0.027) compose plant workers (P=0.020). The morbidity conditions such as respiratory and musculoskeletal found significantly higher in waste disposal workers as compared to controls. CONCLUSION: The levels of serum total IgE was significantly increased in land fill area and compose plant workers but no significant relationship was found between the levels of serum total IgE and occurrence of health related symptoms or past respiratory disease. PMID- 23112501 TI - Shipbuilding and mesothelioma in Monfalcone, Italy. AB - The Monfalcone area, northeastern Italy, a small industrial district with large shipyards, shows a high incidence of asbestos-related mesothelioma. In order to reconstruct some features of the Monfalcone shipbuilding activity during World War II and its health effects, the shipyard roll were examined, and people hired in 1942 were identified. The list of 2,776 persons hired in 1942 was coupled with the Pathological Anatomy Units archives of the Monfalcone and the Trieste Hospitals. Eighteen of the above persons had been diagnosed with pleural mesothelioma in the period 1981-2005. Eight patients had their first exposure in 1942, and the others had histories of previous exposures. Of 557 persons aged 14 15 years in 1942, six had a diagnosis of pleural mesothelioma. Necropsy findings were available in 14 cases. The burdens of lung asbestos bodies, isolated in 11 cases, showed wide variation (from 150 to 600,000 bodies per gram of dried tissue). While probably underestimated, the present data indicate a high incidence of mesothelioma among the shipyard workers of Monfalcone. PMID- 23112502 TI - Occupational hearing loss of the workmen of an open cast chromite mines. AB - BACKGROUND: The present work aimed at to describe hearing threshold based on audiometry data of the mine workers based on their age, work station and years of working of an open cast chromite mine in Odisha, India at high fence. MATERIALS AND METHODS: A cross-sectional study of hearing threshold of the subjects of the chromite mine was carried out. Audiometric data of 500 subjects were taken from the hospital of the mines of Sukinda Valley, Jajpur, Odisha, India. The latest audiometry data available during the period 2002 to 2008 was used in the statistical analysis. RESULTS: The age group 50-60 years is found to be the most influential age group suffering significant hearing loss on both the ears. Also, the Work Zone area is found to be most significant area affecting hearing loss on both the ears. However, the subjects having experience of 30-35 and 25-30 years have the most significant hearing loss on the left and right ears, respectively. CONCLUSION: The hearing loss is found to be at 6 kHz, thus the working areas of the subjects working at work zone should be regularly rotated in less noisy areas to reduce the exposure duration. High frequency noise protective device should be advocated among all the subjects in general and HEMMs operators in particulars. Regular audiometry test of all the subjects should be performed to identify the hearing loss of the subjects occurring at 6 kHz. It is essential to perform periodic maintenance of all the HEMMs to keep all the vehicles in good condition those are generating noise at dominating frequency of 4 and 6 kHz. PMID- 23112503 TI - Occupational stress, mental health and coping among information technology professionals. AB - BACKGROUND: Experience of occupational stress is inevitably involved in the execution of any type of work. Stress has an adaptive value. It motivates the individual to attend to the task and get rid of the tension or demand the unattended task produced. MATERIALS AND METHODS: The study was planned to investigate the differences between executives and shop floor workers on occupational stress, mental health, job satisfaction and coping. A random sample of 200 executives and shop floor employees collected from Nuclear Fuel Complex of Hyderabad City. A well developed sub-scales of Occupational Stress indicator like Mental Health, and Coping behavior were used in the present study. RESULTS AND CONCLUSION: The shop floor workers experiencing more job stress and lower mental health. But these two groups did not differ in their coping behaviour. The executives are better with work home balance. PMID- 23112504 TI - Establishing pre-employment vision standards for goldsmiths. AB - BACKGROUND: The process of jewellery making involves the goldsmiths working with tiny visual tasks at closer working distances, which demands high visual ability. AIM: To establish vision standards for Goldsmiths. MATERIALS AND METHODS: Visual task analysis was carried out in different Goldsmith workstations. The minimal visual demands of the jobs were determined based on Grundy's nomogram. Depending on the importance of certain visual functions to perform the job, criteria for visual competency was laid down. Visual abilities of goldsmiths were evaluated in order to determine their visual capability status, based on the previously laid criteria. Job competency status of goldsmiths was determined based on the supervisors' grading with respect to the quality and quantity of work. Visual competency and job competency of goldsmiths were then compared in order to establish vision standards. RESULTS: Visual task analysis was carried out in 91 workstations. The median of working distance, work area, critical size of the task, and illuminance were 23 cm (IQR: 20- 29), 514.5 Sq Cm (IQR: 183-746.5), and 536.5 lux (IQR: 170-536.5), respectively. Visual abilities of 113 goldsmiths were evaluated. 44.7% of goldsmiths were found to be visually competent. Job competency status of 30 goldsmiths was obtained, in which 18 (60%) were found to be highly job competent. Based on the visual demands, vision standard for jewellery makers was developed. CONCLUSION: The vision standards so obtained could be used as minimum visual requirements for the entry level Goldsmiths. PMID- 23112505 TI - Increase in DNA damage in lymphocytes and micronucleus frequency in buccal cells in silica-exposed workers. AB - The alkaline single cell gel electrophoresis (comet assay) was applied to study the genotoxic properties of silica in human peripheral blood lymphocytes (PBL). The study was designed to evaluate the DNA damage of lymphocytes and the end points like micronuclei from buccal smears in a group of 45 workers, occupationally exposed to silica, from small mines and stone quarries. The results were compared to 20 sex and age matched normal individuals. There was a statistically significant difference in the damage levels between the exposed group and the control groups. The types of damages (type I -type 1V) were used to measure the DNA damage. The numbers of micronuclei were higher in the silica exposed population. The present study suggests that the silica exposure can induce lymphocyte DNA damage and produces significant variation of micronuclei in buccal smear. PMID- 23112506 TI - Neuropsychiatric manifestations of methyl iodide. AB - Methyl iodide is a monohalomethane and with a chemical formula CH(3)I. Acute exposures to methyl iodide have frequently occurred in the workplace. Predominantly, neuropsychiatric symptoms of acute exposure to monohalomethanes consist of headache, nausea, vomiting, drowsiness, dizziness, giddiness, diarrhea, confusion, ataxia, slurred speech, paralysis, convulsions, delirium, coma, and death. We report two cases who presented to our emergency services after accidental exposure to methyl iodide for a short duration. These case reports highlighted concurrence of frankly psychotic features and acute confusional state in workers vulnerable to industrial exposure to toxic chemicals. Understanding the mechanism of neuro-toxicity will perhaps throw some light on co-existence of both psychiatric and neurological symptoms. Awareness of these toxic effects at vulnerable work places will lead to timely and appropriate interventions. Importance of safety precautions and education of both workers and supervisors cannot be overemphasized here. PMID- 23112507 TI - A review of permissible limits of drinking water. AB - Water is one of the prime necessities of life. We can hardly live for a few days without water. In a man's body, 70-80% is water. Cell, blood, and bones contain 90%, 75%, and 22% water, respectively. The general survey reveals that the total surface area of earth is 51 crore km(2) out of which 36.1 crore km(2) is covered sea. In addition to this, we get water from rivers, lakes, tanks, and now on hills. In spite of such abundance, there is a shortage of soft water in the world. Physicochemical parameter of any water body plays a very important role in maintaining the fragile ecosystem that maintains various life forms. Present research paper deals with various water quality parameter, chlorides, dissolved oxygen, total iron, nitrate, water temperature, pH, total phosphorous, fecal coli form bacteria, and adverse effect of these parameters on human being. PMID- 23112508 TI - Occupational health practice: Training and accreditation. PMID- 23112509 TI - Skin tumours. PMID- 23112511 TI - Safe practice of cosmetic dermatology: avoiding legal tangles. AB - The present day dermatologists, in addition to conventional skin physicians, are also dermatologic-surgeons and cosmetologists in their practice. The cosmetic procedures have the inherent risk of malpractice litigations leaving an unsatisfied patient and a troublesome lawsuit against the doctor. A MEDLINE search was conducted for article with words such as legal issues and dermatology, malpractice in dermatology, safe practice of cosmetology etc. The selected articles are scrutinized and compiled so as to help the young dermatologists to have a comprehensive overview of safe cosmetology practice. This article aims at sensitizing the young dermatologists for the possible complications and provides an overview of safe practice. It also provides a list of simple routine precautions which helps the dermatologist to avoid unnecessary trips to the courthouse. PMID- 23112510 TI - Treatment of the ageing hand with dermal fillers. AB - Following the trend in facial cosmetic procedures, patients are now increasingly requesting hand rejuvenation treatments. Intrinsic ageing of the hands is characterized by loss of dermal elasticity and atrophy of the subcutaneous tissue. Thus, veins, tendons and bony structures become apparent. Among the available procedures, intrinsic ageing of the hands is best improved by restoring the volume of soft tissue. Volume restoration can be achieved with a number of long-lasting dermal fillers with varying degrees of improvement and treatment longevity. The dermal fillers used in hand rejuvenation include autologous fat, collagen, hyaluronic acid, calcium hydroxylapatite and poly-L-lactic acid. Here, we describe our preferred injection method for hand rejuvenation using calcium hydroxylapatite and a single-bolus injection. PMID- 23112512 TI - Determination of Melanin and Haemoglobin in the Skin of Idiopathic Cutaneous Hyperchromia of the Orbital region (ICHOR): A Study of Indian Patients. AB - BACKGROUND: Idiopathic cutaneous hyperchromia at the orbital region (ICHOR) is a cutaneous hyperchromia characterised by bilateral darkening of the eyelid and orbital skin that contrasts with the adjoining facial skin. ICHOR is frequent in dark skin. It interferes with the face appearance which often causes difficulties in societal acceptance and may impact quality of life. OBJECTIVE: The aim of this investigation was to study the epidemiology, clinical features and risk factors associated with ICHOR in Indian patients and also to study the distribution of melanin and haemoglobin in ICHOR patients. This study also assessed the relevance of SIAscopy technique (spectrophotometric intracutaneous analysis (SIA)), a new objective non-invasive method to measure melanin and haemoglobin concentration in vivo. MATERIALS AND METHODS: Thirty-three patients diagnosed with ICHOR at the All India Institute of Medical Sciences, New Dehli, India, were included in the study. Epidemiological data were collected through a self-administrated questionnaire. Standard photographs were taken from each patient and SIAscopy measurements were done on dark circles and normal skin. RESULTS: Surprisingly our study showed no significant correlation between ICHOR prevalence and family history, atopic and contact dermatitis, contemporaneous melasma and hormonal factors. The study confirms that sun exposure is a risk factor of dark circles aggravation. Indeed patients tend to reduce sun exposure after the onset of dark circles. SIAscopy analysis reveals significant differences in the concentration of total melanin, of dermal melanin and of haemoglobin between ICHOR skin and normal skin of the same patient. CONCLUSION: This study confirms that melanin deposits and blood stasis in dark circles may play a role in ICHOR pathogenesis and cause the darkening of skin under eyes. SIAscopy provides objective diagnostic information about ICHOR. PMID- 23112513 TI - Idiopathic cutaneous hyperchromia at the orbital region or periorbital hyperpigmentation. PMID- 23112514 TI - Cryotherapy in treatment of keloids: evaluation of factors affecting treatment outcome. AB - BACKGROUND: Keloids are cosmetically disfiguring benign fibrous outgrowths, which present as a major therapeutic dilemma due to their frequent recurrence. Despite a wide therapeutic armamentarium available for these scars, none has been found to be completely effective and satisfactory. Cryosurgery has offered some promise in the treatment of keloids.We conducted this study to evaluate the effect of cryotherapy in treatment of keloids and to relate the treatment outcome with the clinico-etiological factors. MATERIALS AND METHODS: A hospital-based interventional study was conducted in 30 patients of keloids. Patients received two freeze thaw cycles of 15 seconds each at four weekly intervals for six sessions or flattening greater than 75%; whichever occurred earlier. Patients were assessed after three treatment sessions and at treatment completion regarding thickness and firmness of lesions. Patient satisfaction scale was used to evaluate the treatment outcome at completion of six treatment sessions. Paired Students t-test and Analysis of variance (ANOVA) were used for statistical analysis. RESULTS: Average flattening noted after 3 and 6 sessions of cryotherapy was 30.76% and 58.13%, respectively. The duration of lesions and thickness of keloids correlated significantly with the result of treatment. The site and aetiology did not influence the outcome of cryosurgical treatment. CONCLUSION: Cryotherapy seems to be an effective treatment modality for keloids of recent onset, particularly smaller lesions. Duration and thickness of the keloids were found to be the most important factors in determining treatment outcome with cryotherapy in our study. Larger studies are, however, required to confirm the efficacy of this treatment modality and to validate our findings of the factors affecting treatment outcome. PMID- 23112515 TI - Use of lasers for the management of refractory cases of hidradenitis suppurativa and pilonidal sinus. AB - BACKGROUND: Hidradinitis suppurativa (HS) and pilonidal sinus (PNS) are chronic inflamatory skin diseases, often refractory to treatment and search for a new treatment is on. We tried deroofing with the help of carbon dioxide laser in patients of HS and PNS, however there was recurrence. AIM: To evaluate a technique combining the use of CO(2) laser and long pulse 1064 nm Neodymium-doped Yttrium Aluminium Garnet (Nd:YAG) laser for the treatment of HS and PNS. MATERIALS AND METHODS: In 4 patients with HS and 5 patients with PNS, we performed procedure in two steps: first destroying the hair follicles with long pulse Nd yag 1064 laserfollowed by deroofing with carbon di oxide laser. Follow up was done upto 3 years. RESULTS: All patients with HS were females in the age group of 30-40 years. In PNS, 2 male patients were of age less than 20, two male patients of age more than 20 and one females of age less than 20. None of the HS or PNS patients showed recurrence. CONCLUSION: The deroofing with CO(2) laser along with hair follicle removal with long pulse Nd:YAG laser is an effective minimally invasive tissue saving surgical intervention for the treatment of refractory HS and PNS lesions. PMID- 23112516 TI - Evaluation and treatment of surgical management of silicone mastitis. AB - Injected liquid silicone continues to be employed by unscrupulous practitioners in many parts of the world for the purpose of breast augmentation. Complications vary; however, inflammation, foreign body reaction, and granuloma formation often lead to painful and disfigured breasts. Furthermore, migrations of silicone to remote tissues cause additional problems. We present a review of cases and propose an updated algorithm for the diagnosis and management silicone mastitis. We describe two representative cases of mastitis cause by injected liquid silicone. Patients uniformly developed inflammation and granuloma formation causing painful and disfigured breasts. Each patient required bilateral mastectomy and breast reconstruction. Although injection of liquid silicone has been condemned by the legitimate medical community for the purpose of breast augmentation, it continues to be illicitly performed and there exists a sizable patient population suffering from the complications of this procedure. Accurate identification requires a high index of suspicion in patients presenting with firm and painful breasts. An aggressive management strategy is recommended in the setting of silicone mastitis due to the risk of obscuring malignancy. PMID- 23112517 TI - Silicone injections. PMID- 23112518 TI - Desire for penile girth enhancement and the effects of the self-injection of hyaluronic Acid gel. AB - Penile girth enhancement is a controversial subject but demands for enhancement are increasing steadily. Although various fillers have been widely used for soft tissue augmentation, there is no reliable material for this particular situation. Here we report a case of an acute hypersensitivity reaction in a man after his first self-injection of a filler material, which, he claimed, was hyaluronic acid gel for penile girth enhancement and glans penis augmentation. PMID- 23112519 TI - Sclerotherapy for the treatment of infantile hemangiomas. AB - Sclerotherapy is a simple, technically easy and effective mode of treatment for infantile hemangiomas (IH). It acts by blocking the growth of actively proliferating lesions, by targeting their vascularity accelerating their regression. Polidocanol is a commonly used sclerosant. We report two interesting cases of IH treated solely with polidocanol sclerotherapy and discuss the unique place this modality has in the armamentarium against IH. Sclerotherapy was found to be especially useful for large, exuberant and pedunculated lesions, producing rapid regression and preventing the disfiguring sequelae which are likely if large or pedunculated lesions are left to involute on their own. PMID- 23112520 TI - Giant Tuberous Xanthomas in a Case of Type IIA Hypercholesterolemia. AB - Tuberous xanthomas are papulonodular skin lesions present in lipoprotein metabolism disorders. A patient presented with multiple large swellings (up to 20 cm in size) all over the body, which on excision were found to be tuberous xanthomas. Investigations revealed the diagnosis of familial hypercholesterolemia. This case is reported to document the unusual presentation of giant tuberous xanthomas. PMID- 23112521 TI - Giant occipitocervical lipomas: evaluation with two cases. AB - Lipomas are capsulated benign tumours that are commonly found in all body parts. A lipoma is a well-defined mesenchymal tumour that arises from the adipose tissue. Although giant lipomas are rare in the head and neck regions, when they are located here, they are most commonly found in the subcutaneous posterior neck area. Recurrence as well as invasion is very rare after total surgical excision. In this article, we present two rare cases of giant lipomas in the posterior occipitocervical region, which is an exceptional location. PMID- 23112522 TI - Phenolisation as a mode of treatment of mucosal cysts. AB - Mucous cysts are one of the common cystic lesions of minor salivary glands seen mostly on mucous surface of lower lip and buccal mucosa. Many modalities of treatment for mucosal cysts exist including excision and suturing, deroofing, marsupialization, radiosurgery and cryotherapy. We have used 88% phenol as a mode of treatment of mucosal cysts. PMID- 23112523 TI - Surgical correction of pseudoxanthoma elasticum. PMID- 23112524 TI - Proliferating trichilemmal tumor of scalp: benign or malignant, a dilemma. PMID- 23112525 TI - Atypical leiomyoma of scrotum. PMID- 23112526 TI - Scald burn mimicking genitalia amputation. PMID- 23112527 TI - Rare Case of Giant Plunging Ranula without Intraoral Component Presenting as a Subcutaneous Swelling in the Neck: A Diagnostic Dilemma. PMID- 23112528 TI - Effective and inexpensive dressing for mammaplasties. PMID- 23112529 TI - Chondroid syringoma: a diagnosis by fine needle aspiration cytology. PMID- 23112530 TI - My vision: j young pharm. PMID- 23112531 TI - Preparation and evaluation of montelukast sodium loaded solid lipid nanoparticles. AB - Solid lipid nanoparticles (SLNs) are an alternative carrier system used to load the drug for targeting, to improve the bioavailability by increasing its solubility, and protecting the drug from presystemic metabolism. The avoidance of presystemic metabolism is due to the nano-metric size range, so that the liver cannot uptake the drug from the delivery system and is not metabolized by the liver. Montelukast sodium is an anti-asthmatic drug, because of its poor oral bioavailability, presystemic metabolism, and decreased half-life; it was chosen to formulate as the solid lipid nanoparticle (SLN) system by hot homogenization followed by an ultrasonication method, to overcome the above. Compritol ATO 888, stearic acid, and glyceryl monostearate were used as a lipid matrix and polyvinyl alcohol as a surfactant. The prepared formulations have been evaluated for entrapment efficiency, drug content, in vitro drug release, particle size analysis, scanning electron microscopy, Fourier transform-infrared studies (FT IR), differential scanning calorimetry (DSC), and stability. Particle size analysis revealed that the SLN prepared from the higher melting point lipid showed a larger particle size and with increased carbon chain length of the fatty acids. Entrapment efficiency (EE) was ranging from 42% to 92%. In vitro release studies showed maximum cumulative drug release was obtained for F 1 (59.1%) containing stearic acid, and the lowest was observed for F 18 (28.1%) containing compritol ATO 888 after 12 h and all the formulations followed first-order release kinetics. FT-IR and DSC studies revealed no interaction between drug and lipids. Studies showed that increase in lipid concentration, increased particle size, EE, and maintained the sustained release of drug. Among all, compritol ATO 888 was chosen as the best lipid for formulating SLN because it had high EE and sustained the drug release. PMID- 23112532 TI - FTIR and Raman Spectroscopic Investigations of a Norfloxacin/Carbopol934 Polymeric Suspension. AB - Till now very few formulations are available from which the drug is uniformly absorbed, so that the safe and effective blood level of norfloxacin could be maintained for a prolonged period. To fulfill this requirement, a controlled release mucoadhesive suspension was prepared by using a mucoadhesive carbopol934 polymer. The chemical interaction between norfloxacin and the polymer in formulation (prepared by an ultrasonication method) has been studied by FTIR and Raman spectroscopy. From the spectral interpretation, it has been found that in formulation, the carboxylic groups of norfloxacin and hydroxyl groups of carbopol934 undergo chemical interaction, leading to esterification and hydrogen bonding. The formation of micellies due to esterification and hydrogen bonding causes more drug entrapment and a stable formulation. From this it can be concluded that the formulation of norfloxacin may give a better controlled release and mucoadhesive action in the gastrointestinal tract. Hence, carbopol934 could be considered as an effective carrier for norfloxacin. PMID- 23112533 TI - Optimization of pellets containing solid dispersion prepared by extrusion/spheronization using central composite design and desirability function. AB - Furosemide is a class IV biopharmaceutical classification system drug having poor water solubility and low bioavailability due to the hepatic first-pass metabolism and has a short half-life of 2 h. To overcome the above drawback, this study was carried to prepare and evaluate the pellets containing furosemide solid dispersion (SD) for oral administration prepared by extrusion/spheronization. SD of furosemide was prepared with Eudragit L-100 at a drug-to-polymer ratio of 1:2 by employing a solvent evaporation method and characterized. Further, microcrystalline cellulose pellets containing SD were consequently prepared using a lab scale extrusion/ spheronizer and evaluated for in vitro drug release studies. The influence of process parameters used during extrusion/spheronization on the pellet properties was also studied using 2-factor, 3-level central composite design in order to improve the product quality. Additionally, the desirability function approach was applied to acquire the preeminent compromise between the multiple responses. Pellets containing solid dispersion (PSD) were prepared using optimal parameter settings demonstrated 88.52 +/- 0.69% of the drug was released in a sustained release manner till 12 h. In vitro drug release data were fitted to various release kinetics models to study the mechanism of drug release. Drug release from the PSD was found to follow zero-order and Higuchi's model. Both studied parameters had great influence on the responses. PSD showed augmentation in the drug release profile till 12 h. The final optimized formulation was obtained by encapsulating best SD formulation within the pellet core to release the drug in the most soluble form in stomach and a sustained fashion in intestine. PMID- 23112534 TI - Effect of a disintegration mechanism on wetting, water absorption, and disintegration time of orodispersible tablets. AB - The aim of this study was to evaluate the influence of disintegration mechanism of various types of disintegrants on the absorption ratio (AR), wetting time (WT), and disintegration time (DT) of orodispersible tablets (ODTs). ODTs were prepared by direct compression using mannitol as filler and disintegrants selected from a range of swellable, osmotic, and porous disintegrants. Tablets formed were characterized for their water AR, WT, and DT. The porosity and mechanical strength of the tablets were also measured. Results show that the DT of formulated ODTs was directly related to the WT and was a function of the disintegration mechanism of the disintegrant used. The lowest WT and DT were observed for tablets formulated using the osmotic disintegrant sodium citrate and these tablets also showed the lowest AR and porosity. The wetting and disintegration of tablets containing the highly swellable disintegrant, sodium starch glycollate, was slowest despite their high water AR and high tablet porosity. Rapid wetting and disintegration of ODTs were therefore not necessarily related to the porosity of the tablets. PMID- 23112535 TI - Antiurolithiatic Effects of Solanum xanthocarpum Fruit Extract on Ethylene-Glycol Induced Nephrolithiasis in Rats. AB - This study was designed to evaluate the effects of Solanum xanthocarpum fruit extract in ethylene-glycol-induced urolithiasis in the male Wistar rats. Nephrolithiasis was induced in male Wistar rats by adding ethylene glycol (0.75%) in drinking water for 28 days. Animals were divided into six groups, each containing six viz. Vehicle control, model control, S. xanthocarpum methanol extract in different doses of 100, 200, and 400 mg/kg p.o., Cystone (750 mg/kg, p.o.) served as a standard. Hyperoxaluria as well as an increase in the excretion of calcium, phosphate, uric acid and decrease in citrate and magnesium in urine, impairment of renal function and oxidative imbalance in kidney were observed in the calculi-induced group. Treatment with S. xanthocarpum decreases hyperoxaluria, calcium, and uric acid, improves renal function, and also produces antioxidant effects. Crystalluria was characterized by excretion calcium oxalate (CaOX) crystals, which were enormous in the lithogenic group but smaller in the drug-treated group. The histology showed that the calculi-induced group had a large deposition of CaOX crystals in kidney while the treated group had trivial and fewer deposits. The result indicates the antiurolithiatic activity of S. xanthocarpum mediated possibly by CaOX crystal inhibition, diuretic, antioxidant and maintaining balance between stone promoter and inhibitor constituents, and this study rationalized its medicinal use in urolithiasis. PMID- 23112536 TI - Anti-hyperglycemic and Anti-hyperlipidemic Effects of Bryonia Laciniosa Seed Extract and its Saponin Fraction in Streptozotocin-induced Diabetes in Rats. AB - Bryonia laciniosa Linn. (Cucurbitaceae) seed is used in traditional medicine for a number of ailments including metabolic disorders. This investigation was carried out to investigate the anti-hyperglycemic and anti-hyperlipidemic potential of the ethanolic extract of seeds of B. laciniosa Linn. and its saponin fraction in streptozotocin-induced diabetic rats. The ethanolic extract (250 and 500 mg/kg; p.o.) and saponin fraction (100 and 200 mg/kg; p.o.) were administered to diabetic rats and standard drug insulin (5 IU/kg; i.p.) to the group serving as a positive control. Effects of the ethanolic extract and saponin fraction on various biochemical parameters were studied in diabetic rats. Data were statistically analysed by one-way ANOVA followed by Dunnett's t-test. Oral administration of the ethanolic extract and saponin fraction for 28 days to streptozotocin-induced diabetes rats significantly (P < 0.05) decreased the levels of blood glucose and improved the levels of plasma insulin. The levels of triglycerides, cholesterol, high density lipoprotein, low density lipoprotein, very low density lipoprotein, aspartate amino transferase and alanine amino transferase, urea, and creatinine were markedly altered in streptozotocin-induced diabetic rats. Oral administration of the ethanolic extract and saponin fraction restored all these biochemical parameters to near control levels. This study reveals the efficacy of B. laciniosa seed extract and its saponin fraction in the amelioration of diabetes and its associated complications. PMID- 23112537 TI - Pharmacological and biochemical interventions of cigarette smoke, alcohol, and sexual mating frequency on idiopathic rat model of Parkinson's disease. AB - Parkinson's Disease (PD) is a neurodegenerative disorder in the nigrostriatal pathway of animals and humans and is responsible for most of the movement disorders, including rigidity. The present study aimed to determine the effect of chronic cigarette smoke, alcohol intake, and frequent sexual mating on 1-Methyl-4 phenyl-1,2,3,6-tertahydro pyridine (MPTP)-induced rat model of PD. After treatment, the effect of these factors was determined by biochemical and molecular evaluation. Dopamine (DA) concentration, antioxidant enzymes, and mitochondrial activity decreased after treatment with cigarette smoke, alcohol, and frequent sexual mating when compared to the values in the control group. Excessive exposure of these factors may lead to neurodegeneration, dopaminergic toxicities, and, ultimately, clinical parkinsonism. Earlier literature from different publisher suggested that nicotine and cigarette smoke can protect the dopaminergic neurons in the substantia nigra against MPTP toxicity. In this study, we assessed the effect of the above three factors on an MPTP-treated rat model and concluded that they have a neurodegenerative effect and were found to be toxic to dopaminergic neurons in the substantia nigra. Further investigation is required to understand the exact etiology of clinical parkinsonism. PMID- 23112538 TI - Molecular Docking and Prediction of Pharmacokinetic Properties of Dual Mechanism Drugs that Block MAO-B and Adenosine A(2A) Receptors for the Treatment of Parkinson's Disease. AB - Monoamine oxidase B (MAO-B) inhibitory potential of adenosine A(2A) receptor (AA(2A)R) antagonists has raised the possibility of designing dual-target directed drugs that may provide enhanced symptomatic relief and that may also slow the progression of Parkinson's disease (PD) by protecting against further neurodegeneration. To explain the dual inhibition of MAO-B and AA(2A)R at the molecular level, molecular docking technique was employed. Lamarckian genetic algorithm methodology was used for flexible ligand docking studies. A good correlation (R(2)= 0.524 and 0.627 for MAO-B and AA(2A)R, respectively) was established between docking predicted and experimental K(i) values, which confirms that the molecular docking approach is reliable to study the mechanism of dual interaction of caffeinyl analogs with MAO-B and AA(2A)R. Parameters for Lipinski's "Rule-of-Five" were also calculated to estimate the pharmacokinetic properties of dual-target-directed drugs where both MAO-B inhibition and AA(2A)R antagonism exhibited a positive correlation with calculated LogP having a correlation coefficient R(2) of 0.535 and 0.607, respectively. These results provide some beneficial clues in structural modification for designing new inhibitors as dual-target-directed drugs with desired pharmacokinetic properties for the treatment of PD. PMID- 23112539 TI - General Public Expectation from the Communication Process with their Healthcare Providers. AB - The current study aimed to explore the public views and expectation about a successful communication process between the healthcare providers/physicians and patients in Penang Island, Malaysia. A cross-sectional study was conducted in Penang Island using a 14-item questionnaire. Statistical Package for Social Sciences (SPSS) software version 15.0((r)) were used to analyze the collected data. A nonparametric statistics was applied; the Chi-square test was applied to measure the association among the variables. P-values less than 0.05 were considered statistically significant. A total of N (500) respondents have shown willingness to participate in the study with a response rate of 83.3%. The majority 319 (63.9%) have disclosed to communicate with their healthcare providers in the Malay language and about 401 (80.4%) of the respondents were found satisfied with the information provided by the physician. It was a common expectation by the most of the sample to focus more on the patient history before prescribing any medicine. Moreover, about 60.0% of the respondents expected that the healthcare providers must show patience to the patient's queries. The level of satisfaction with the information shared by the healthcare providers was higher among the respondents with a higher education level. Furthermore, patients with higher level of education expect that physician shouldwell understand their views and medical history to prescribe a better therapeutic regimen. PMID- 23112540 TI - Peritoneal carcinomatosis of colorectal origin: Incidence, prognosis and treatment options. AB - Peritoneal carcinomatosis (PC) is one manifestation of metastatic colorectal cancer (CRC). Tumor growth on intestinal surfaces and associated fluid accumulation eventually result in bowel obstruction and incapacitating levels of ascites, which profoundly affect the quality of life for affected patients. PC appears resistant to traditional 5-fluorouracil-based chemotherapy, and surgery was formerly reserved for palliative purposes only. In the absence of effective treatment, the historical prognosis for these patients was extremely poor, with an invariably fatal outcome. These poor outcomes likely explain why PC secondary to CRC has received little attention from oncologic researchers. Thus, data are lacking regarding incidence, clinical disease course, and accurate treatment evaluation for patients with PC. Recently, population-based studies have revealed that PC occurs relatively frequently among patients with CRC. Risk factors for developing PC have been identified: right-sided tumor, advanced T-stage, advanced N-stage, poor differentiation grade, and younger age at diagnosis. During the past decade, both chemotherapeutical and surgical treatments have achieved promising results in these patients. A chance for long-term survival or even cure may now be offered to selected patients by combining radical surgical resection with intraperitoneal instillation of heated chemotherapy. This combined procedure has become known as hyperthermic intraperitoneal chemotherapy. This editorial outlines recent advancements in the medical and surgical treatment of PC and reviews the most recent information on incidence and prognosis of this disease. Given recent progress, treatment should now be considered in every patient presenting with PC. PMID- 23112541 TI - Diagnosis of Zollinger-Ellison syndrome: increasingly difficult. AB - In the present paper the increasing difficulty of diagnosis of Zollinger-Ellison syndrome (ZES) due to issues raised in two recent papers is discussed. These issues involve the difficulty and need to withdraw patients suspected of ZES from treatment with Proton Pump Inhibitors (omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole) and the unreliability of many gastrin radioimmunoassays. The clinical context of each of these important issues is reviewed and the conclusions in these articles commented from the perspective of clinical management. PMID- 23112542 TI - Molecular targets in the treatment of alcoholic hepatitis. AB - Alcohol related costs to health and society are high. One of the most serious complications of alcohol misuse to the individual is the development of alcoholic hepatitis (AH), a clinical syndrome of jaundice and progressive inflammatory liver injury in patients with a history of recent heavy alcohol use. It has a poor outcome and few existing successful therapies. The use of glucocorticoids in patients with severe AH is still controversial and there remains a group of patients with glucocorticoid-resistant disease. However, as our understanding of the pathogenesis of the condition improves there are opportunities to develop new targeted therapies with specific actions to control liver inflammation without having a detrimental effect on the immune system as a whole. In this article we review the molecular mechanisms of AH concentrating on the activation of the innate and adaptive immune response. We consider existing treatments including glucocorticoids, anti-tumor necrosis factor therapy and pentoxifylline and their limitations. Using our knowledge of the disease pathogenesis we discuss possible novel therapeutic approaches. New targets include pro-inflammatory cytokines such as interleukin (IL)-17, chemokines and their receptors (for example IL-8, CXCL9 and CXCR3) and augmentation of anti-inflammatory molecules such as IL-10 and IL 22. And there is also future potential to consider combination therapy to selectively modulate the immune response and gain control of disease. PMID- 23112543 TI - Checkmate to liver biopsy in chronic hepatitis C? AB - Liver biopsy (LB) has traditionally been considered the gold standard for pretreatment evaluation of liver fibrosis in patients with chronic hepatitis C (CHC). However, LB is an invasive procedure with several shortcomings (intra- and interobserver variability of histopathological interpretation, sampling errors, high cost) and the risk of rare but potentially life-threatening complications. In addition, LB is poorly accepted by patients and it is not suitable for repeated evaluation. Furthermore, the prevalence of CHC makes LB unrealistic to be performed in all patients with this disease who are candidates for antiviral therapy. The above-mentioned drawbacks of LB have led to the development of noninvasive methods for the assessment of liver fibrosis. Several noninvasive methods, ranging from serum marker assays to advanced imaging techniques, have proved to be excellent tools for the evaluation of liver fibrosis in patients with CHC, whereas the value of LB as a gold standard for staging fibrosis prior to antiviral therapy has become questionable for clinicians. Despite significant resistance from those in favor of LB, noninvasive methods for pretreatment assessment of liver fibrosis in patients with CHC have become part of routine clinical practice. With protease inhibitors-based triple therapy already available and substantial improvement in sustained virological response, the time has come to move forward to noninvasiveness, with no risks for the patient and, thus, no need for LB in the assessment of liver fibrosis in the decision making for antiviral therapy in CHC. PMID- 23112544 TI - Treatment of locally advanced rectal cancer: controversies and questions. AB - Rectal cancers extending through the rectal wall, or involving locoregional lymph nodes (T3/4 or N1/2), have been more difficult to cure. The confines of the bony pelvis and the necessity of preserving the autonomic nerves makes surgical extirpation challenging, which accounts for the high rates of local and distant relapse in this setting. Combined multimodality treatment for rectal cancer stage II and III was recommended from National Institute of Health consensus. Neoadjuvant chemoradiation using fluoropyrimidine-based regimen prior to surgical resection has emerged as the standard of care in the United States. Optimal time of surgery after neoadjuvant treatment remained unclear and prospective randomized controlled trial is ongoing. Traditionally, 6-8 wk waiting period was commonly used. The accuracy of studies attempting to determine tumor complete response remains problematic. Currently, surgery remains the standard of care for rectal cancer patients following neoadjuvant chemoradiation, whereas observational management is still investigational. In this article, we outline trends and controversies associated with optimal pre-treatment staging, neoadjuvant therapies, surgery, and adjuvant therapy. PMID- 23112545 TI - Experimental and clinical evidence of antioxidant therapy in acute pancreatitis. AB - Oxidative stress has been shown to play an important role in the pathogenesis of acute pancreatitis (AP). Antioxidants, alone or in combination with conventional therapy, should improve oxidative-stress-induced organ damage and therefore accelerate the rate of recovery. In recent years, substantial amounts of data about the efficiency of antioxidants against oxidative damage have been obtained from experiments with rodents. Some of these antioxidants have been found beneficial in the treatment of AP in humans; however, at present there is insufficient clinical data to support the benefits of antioxidants, alone or in combination with conventional therapy, in the management of AP in humans. Conflicting results obtained from experimental animals and humans may represent distinct pathophysiological mechanisms mediating tissue injury in different species. Further detailed studies should be done to clarify the exact mechanisms of tissue injury in human AP. Herein I tried to review the existing experimental and clinical studies on AP in order to determine the efficiency of antioxidants. The use of antioxidant enriched nutrition is a potential direction of clinical research in AP given the lack of clues about the efficiency and safety of antioxidant usage in patients with AP. PMID- 23112546 TI - Dietary copper triggers onset of fulminant hepatitis in the Long-Evans cinnamon rat model. AB - AIM: To investigate the impact of dietary copper given at different time points on the onset of fulminant hepatitis. METHODS: The Long-Evans cinnamon (LEC) rat model of Wilson's disease (WD) was used to study the impact of high dietary copper (hCu) on the induction of fulminant hepatitis at early or late time points of life. High Cu diet was started in rat pups or in adults (month 5) for three months. Animals that received reduced dietary copper (rCu) throughout their lifetime served as a control. Hepatitis-associated serum markers (alanine aminotransferase, aspartate transaminase, bilirubin) were analyzed in animal groups receiving hCu or rCu. Liver copper content and liver histology were revealed at sacrifice. A set of 5 marker genes previously found to be affected in injured liver and which are related to angiogenesis (Vegfa), fat metabolism (Srebf1), extracellular matrix (Timp1), oxidative stress (Hmox1), and the cell cycle (Cdkn1a) were analyzed by real-time polymerase chain reaction. RESULTS: Regardless of the time point when hCu was started, LEC rats (35/36) developed fulminant hepatitis and died. Animals receiving rCu (36/36) remained healthy, did not develop hepatitis, and survived long term without symptoms of overt disease, although liver copper accumulated in adult animals (477 +/- 75 MUg/g). With regard to start of hCu, onset of fulminant hepatitis was significantly (P < 0.001) earlier in adults (35 +/- 9 d) that showed pre-accumulation of liver copper as compared to the pup group (77 +/- 15 d). Hepatitis-associated serum markers, liver copper and liver histology, as well as gene expression, were affected in LEC rats receiving hCu. However, except for early and rapid onset of hepatitis, biochemical and molecular markers were similar at the early and late time points of disease. CONCLUSION: Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper suggests that there is a critical threshold of liver copper which is important to trigger the course of WD. PMID- 23112547 TI - MUC5AC/beta-catenin expression and KRAS gene alteration in laterally spreading colorectal tumors. AB - AIM: To clarify differences in mucin phenotype, proliferative activity and oncogenetic alteration among subtypes of colorectal laterally spreading tumor (LST). METHODS: LSTs, defined as superficial elevated lesions greater than 10 mm in diameter with a low vertical axis, were macroscopically classified into two subtypes: (1) a granular type (Gr-LST) composed of superficially spreading aggregates of nodules forming a flat-based lesion with a granulonodular and uneven surface; and (2) a non-granular type (NGr-LST) with a flat smooth surface and an absence of granulonodular formation. A total of 69 LSTs, comprising 36 Gr LSTs and 33 NGr-LSTs, were immunohistochemically stained with MUC2, MUC5AC, MUC6, CD10 (markers of gastrointestinal cell lineage), p53, beta-catenin and Ki-67 antibodies, and examined for alteration in exon 1 of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and exon 15 of v-raf murine sarcoma viral oncogene homologue B1 (BRAF) by polymerase chain reaction followed by direct sequencing. RESULTS: Histologically, 15 Gr-LST samples were adenomas with low grade dysplasia (LGD), 12 were high-grade dysplasia (HGD) and 9 were adenocarcinomas invading the submucosa (INV), while 12 NGr-LSTs demonstrated LGD, 14 HGD and 7 INV. In the proximal colon, MUC5AC expression was significantly higher in the Gr-type than the NGr-type. MUC6 was expressed only in NGr-LST. MUC2 or CD10 did not differ. P53 expression demonstrated a significant stepwise increment in progression through LGD-HGD-INV with both types of LST. Nuclear beta catenin expression was significantly higher in the NGr-type. Ki-67 expression was significantly higher in the Gr-type in the lower one third zone of the tumor. In proximal, but not distal colon tumors, the incidence of KRAS provided mutation was significantly higher in the Gr-type harboring a specific mutational pattern (G12V). BRAF mutations (V600E) were detected only in two Gr-LSTs. CONCLUSION: The two subtypes of LST, especially in the proximal colon, have differing phenotypes of gastrointestinal cell lineage, proliferation and activation of Wnt/beta catenin or RAS/RAF/extracellular signal-regulated kinase signaling. PMID- 23112548 TI - Software for automated classification of probe-based confocal laser endomicroscopy videos of colorectal polyps. AB - AIM: To support probe-based confocal laser endomicroscopy (pCLE) diagnosis by designing software for the automated classification of colonic polyps. METHODS: Intravenous fluorescein pCLE imaging of colorectal lesions was performed on patients undergoing screening and surveillance colonoscopies, followed by polypectomies. All resected specimens were reviewed by a reference gastrointestinal pathologist blinded to pCLE information. Histopathology was used as the criterion standard for the differentiation between neoplastic and non neoplastic lesions. The pCLE video sequences, recorded for each polyp, were analyzed off-line by 2 expert endoscopists who were blinded to the endoscopic characteristics and histopathology. These pCLE videos, along with their histopathology diagnosis, were used to train the automated classification software which is a content-based image retrieval technique followed by k-nearest neighbor classification. The performance of the off-line diagnosis of pCLE videos established by the 2 expert endoscopists was compared with that of automated pCLE software classification. All evaluations were performed using leave-one-patient out cross-validation to avoid bias. RESULTS: Colorectal lesions (135) were imaged in 71 patients. Based on histopathology, 93 of these 135 lesions were neoplastic and 42 were non-neoplastic. The study found no statistical significance for the difference between the performance of automated pCLE software classification (accuracy 89.6%, sensitivity 92.5%, specificity 83.3%, using leave-one-patient out cross-validation) and the performance of the off-line diagnosis of pCLE videos established by the 2 expert endoscopists (accuracy 89.6%, sensitivity 91.4%, specificity 85.7%). There was very low power (< 6%) to detect the observed differences. The 95% confidence intervals for equivalence testing were: -0.073 to 0.073 for accuracy, -0.068 to 0.089 for sensitivity and -0.18 to 0.13 for specificity. The classification software proposed in this study is not a "black box" but an informative tool based on the query by example model that produces, as intermediate results, visually similar annotated videos that are directly interpretable by the endoscopist. CONCLUSION: The proposed software for automated classification of pCLE videos of colonic polyps achieves high performance, comparable to that of off-line diagnosis of pCLE videos established by expert endoscopists. PMID- 23112549 TI - Quantitation of HBsAg predicts response to entecavir therapy in HBV genotype C patients. AB - AIM: To analysis the factors that predict the response to entecavir therapy in chronic hepatitis patients with hepatitis B virus (HBV) genotype C. METHODS: Fifty patients [hepatitis B e antigen (HBeAg)-negative:HBeAg-positive = 26:24] with HBV genotype C, who received naive entecavir therapy for > 2 years, were analyzed. Patients who showed HBV DNA levels >= 3.0 log viral copies/mL after 2 years of entecavir therapy were designated as slow-responders, while those that showed < 3.0 log copies/mL were termed rapid-responders. Quantitative hepatitis B surface antigen (HBsAg) levels (qHBsAg) were determined by the Architect HBsAg QT immunoassay. Hepatitis B core-related antigen was detected by enzyme immunoassay. Pre-C and Core promoter mutations were determined using by polymerase chain reaction (PCR). Drug-resistance mutations were detected by the PCR-Invader method. RESULTS: At year 2, HBV DNA levels in all patients in the HBeAg-negative group were < 3.0 log copies/mL. In contrast, in the HBeAg-positive group, 41.7% were slow-responders, while 58.3% were rapid-responders. No entecavir-resistant mutants were detected in the slow-responders. When the pretreatment factors were compared between the slow- and rapid-responders; the median qHBsAg in the slow responders was 4.57 log IU/mL, compared with 3.63 log IU/mL in the rapid responders (P < 0.01). When the pretreatment factors predictive of HBV DNA negative status at year 2 in all 50 patients were analyzed, HBeAg-negative status, low HBV DNA levels, and low qHBsAg levels were significant (P < 0.01). Multivariate analysis revealed that the low qHBsAg level was the most significant predictive factor (P = 0.03). CONCLUSION: Quantitation of HBsAg could be a useful indicator to predict response to entecavir therapy. PMID- 23112550 TI - Inhibition of gastric perception of mild distention by omeprazole in volunteers. AB - AIM: To evaluate the effects of omeprazole on gastric mechanosensitivity in humans. METHODS: A double lumen polyvinyl tube with a plastic bag was introduced into the stomach of healthy volunteers under fluorography and connected to a barostat device. Subjects were then positioned so they were sitting comfortably, and the minimal distending pressure (MDP) was determined after a 30-min adaptation period. Isobaric distensions were performed in stepwise increments of 2 mmHg (2 min each) starting from the MDP. Subjects were instructed to score feelings at the end of every step using a graphic rating scale: 0, no perception; 1, weak/vague; 2, weak but significant; 3, moderate/vague; 4, moderate but significant; 5, severe discomfort; and 6, unbearable pain. After this first test, subjects received omeprazole (20 mg, after dinner) once daily for 1 wk. A second test was performed on the last day of treatment. RESULTS: No adverse effects were observed. Mean MDP before and after treatment was 6.3 +/- 0.3 mmHg and 6.2 +/- 0.5 mmHg, respectively. One subject before and 2 after treatment did not reach a score of 6 at the maximum bag volume of 750 mL. After omeprazole, there was a significant increase in the distension pressure required to reach scores of 1 (P = 0.019) and 2 (P = 0.017) as compared to baseline. There were no changes in pressure required to reach the other scores after treatment. Two subjects before and one after omeprazole rated their abdominal feeling < 1 at MDP, and mean (+/- SE) abdominal discomfort scores at MDP were 0.13 +/- 0.09 and 0.04 +/- 0.04, respectively. Mean scores induced by each MDP + 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 (mmHg) were 1.1 +/- 0.3, 2.0 +/- 0.4, 2.9 +/- 0.5, 3.3 +/- 0.4, 4.6 +/- 0.3, 5.2 +/- 0.3, 5.5 +/- 0.2, 5.5 +/- 0.3, 5.7 +/- 0.3, and 5.4, respectively. After omeprazole, abdominal feeling scores for the same incremental pressures over MDP were 0.3 +/- 0.1, 0.8 +/- 0.1, 2.0 +/- 0.4, 2.8 +/- 0.4, 3.8 +/- 0.4, 4.6 +/- 0.4, 4.9 +/- 0.3, 5.4 +/- 0.4, 5.2 +/- 0.6, and 5.0 +/- 1.0, respectively. A significant decrease in feeling score was observed at intrabag pressures of MDP + 2 mmHg (P = 0.028) and + 4 mmHg (P = 0.013), respectively, after omeprazole. No significant score changes were observed at pressures >= MDP + 6 mmHg. CONCLUSION: Although the precise mechanisms are undetermined, the present study demonstrated that omeprazole decreases mechanosensitivity to mild gastric distension. PMID- 23112551 TI - Thioredoxin and thioredoxin-interacting protein as prognostic markers for gastric cancer recurrence. AB - AIM: To evaluate the potential of thioredoxin (TXN) and thioredoxin-interacting protein (TXNIP) expression as biomarkers for predicting gastric cancer recurrence. METHODS: TXN and TXNIP expression levels were acquired from gene expression microarray data for 65 human gastric cancer tissues. We determined whether each gene expression level was associated with cancer recurrence and investigated the relationship between the two genes. For validation, the expression levels of TXN and TXNIP were measured by quantitative real-time reverse transcription polymerase chain reaction in 68 independent stage III gastric cancer patients. The correlation between gene expression and cancer prognosis was evaluated. Immunohistochemical staining was performed to investigate the protein expression levels of TXN and TXNIP and to characterize the expression patterns of each protein. RESULTS: TXN was a prognosis-related gene (P = 0.009), whereas TXNIP, a TXN inhibitor, demonstrated a negative correlation with TXN in the gene expression microarray data. In the 68 stage III patients, the expression levels of both TXN and TXNIP had a statistically significant effect on recurrence-free survival (RFS, P = 0.008 and P = 0.036, respectively). The low TXN and high TXNIP expression group exhibited a better prognosis than the other groups, and the high TXN and low TXNIP expression group exhibited a poorer prognosis (P < 0.001 for RFS and P = 0.001 for overall survival). More than half of the patients in the simultaneously high TXN and low TXNIP expression group experienced a recurrence within 1 year after curative surgery, and the 5-year survival rate of the patients in this group was 29%, compared with 89% in the low TXN and high TXNIP expression group. The TXN protein was overexpressed in 65% of the gastric cancer tissues, whereas the TXNIP protein was underexpressed in 85% of the cancer cells. In a correlation analysis, TXN and TXNIP were highly correlated with many oncogenes and tumor suppressors as well as with genes related to energy, protein synthesis and autophagy. CONCLUSION: TXN and TXNIP are promising prognostic markers for gastric cancer, and performing personalized adjuvant treatment based on TXN and TXNIP expression levels would be an effective practice in the treatment of gastric cancer. PMID- 23112552 TI - Photodynamic therapy prolongs metal stent patency in patients with unresectable hilar cholangiocarcinoma. AB - AIM: To evaluate the effect of photodynamic therapy (PDT) on metal stent patency in patients with unresectable hilar cholangiocarcinoma (CC). METHODS: This was a retrospective analysis of patients with hilar CC referred to our institution from December, 1999 to January, 2011. Out of 232 patients, thirty-three patients with unresectable hilar CC were treated. Eighteen patients in the PDT group were treated with uncovered metal stents after one session of PDT. Fifteen patients in the control group were treated with metal stents alone. Porfimer sodium (2 mg/kg) was administered intravenously to PDT patients. Forty-eight hours later, PDT was administered using a diffusing fiber that was advanced across the tumor by either endoscopic retrograde cholangiopancreatography or percutaneous cholangiography. After performance of PDT, uncovered metal stents were inserted to ensure adequate decompression and bile drainage. Patient survival rates and cumulative stent patency were calculated using Kaplan-Meier analysis with the log-rank test. RESULTS: The PDT and control patients were comparable with respect to age, gender, health status, pre-treatment bilirubin, and hilar CC stage. When compared to control, the PDT group was associated with significantly prolonged stent patency (median 244 +/- 66 and 177 +/- 45 d, respectively, P = 0.002) and longer patient survival (median 356 +/- 213 and 230 +/- 73 d, respectively, P = 0.006). Early complication rates were similar between the groups (PDT group 17%, control group 13%) and all patients were treated conservatively. Stent malfunctions occurred in 14 PDT patients (78%) and 12 control patients (80%). Of these 26 patients, twenty-two were treated endoscopically and four were treated with external drainage. CONCLUSION: Metal stenting after one session of PDT may be safe with acceptable complication rates. The PDT group was associated with a significantly longer stent patency than the control group in patients with unresectable hilar CC. PMID- 23112553 TI - Surgical outcome of pancreatic cancer using radical antegrade modular pancreatosplenectomy procedure. AB - AIM: To evaluate the surgical outcomes following radical antegrade modular pancreatosplenectomy (RAMPS) for pancreatic cancer. METHODS: Twenty-four patients underwent RAMPS with curative intent between January 2005 and June 2009 at the National Cancer Center, South Korea. Clinicopathologic data, including age, sex, operative findings, pathologic results, adjuvant therapy, postoperative clinical course and follow-up data were retrospectively collected and analyzed for this study. RESULTS: Twenty-one patients (87.5%) underwent distal pancreatectomy and 3 patients (12.5%) underwent total pancreatectomy using RAMPS. Nine patients (37.5%) underwent combined vessel resection, including 8 superior mesenteric portal vein resections and 1 celiac axis resection. Two patients (8.3%) underwent combined resection of other organs, including the colon, stomach or duodenum. Negative tangential margins were achieved in 22 patients (91.7%). The mean tumor diameter for all patients was 4.09 +/- 2.15 cm. The 2 patients with positive margins had a mean diameter of 7.25 cm. The mean number of retrieved lymph nodes was 20.92 +/- 11.24 and the node positivity rate was 70.8%. The median survival of the 24 patients was 18.23 +/- 6.02 mo. Patients with negative margins had a median survival of 21.80 +/- 5.30 mo and those with positive margins had a median survival of 6.47 mo (P = 0.021). Nine patients (37.5%) had postoperative complications, but there were no postoperative mortalities. Pancreatic fistula occurred in 4 patients (16.7%): 2 patients had a grade A fistula and 2 had a grade B fistula. On univariate analysis, histologic grade, positive tangential margin, pancreatic fistula and adjuvant therapy were significant prognostic factors for survival. CONCLUSION: RAMPS is a feasible procedure for achieving negative tangential margins in patients with carcinoma of the body and tail of the pancreas. PMID- 23112554 TI - Biochemical characteristics of neonatal cholestasis induced by citrin deficiency. AB - AIM: To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies. METHODS: Patients under 6 mo of age who were referred for investigation of conjugated hyperbilirubinaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homozygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a comprehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared. RESULTS: Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range): 178.0 (111.2 236.4) MUmol/L in NICCD vs 112.0 (84.9-153.9) MUmol/L in BA and 103.0 (70.9 135.3) MUmol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) MUmol/L in NICCD vs 134.0 (115.9-151.2) MUmol/L in BA and 87.3 (63.0-123.6) MUmol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0 223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in NICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range): 0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94 1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72 1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4 26.9) in INC patients, P = 0.0001] compared to the BA and INC groups. CONCLUSION: NICCD has significantly different biochemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol. PMID- 23112555 TI - Colonic stenting vs emergent surgery for acute left-sided malignant colonic obstruction: a systematic review and meta-analysis. AB - AIM: To investigate the effects of emergent preoperative self-expandable metallic stent (SEMS) vs emergent surgery for acute left-sided malignant colonic obstruction. METHODS: Two investigators independently searched the MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, as well as references of included studies to identify randomized controlled trials (RCTs) that compared two or more surgical approaches for acute colonic obstruction. Summary risk ratios (RR) and 95% CI for colonic stenting and emergent surgery were calculated. RESULTS: Eight studies met the selection criteria, involving 444 patients, of whom 219 underwent SEMS and 225 underwent emergent surgery. Seven studies reported difference of the one-stage stoma rates between the two groups (RR, 0.60; 95% CI: 0.48-0.76; P < 0.0001). Only three RCTs described the follow-up stoma rates, which showed no significant difference between the two groups (RR, 0.80; 95% CI: 0.59-1.08; P = 0.14). Difference was not significant in the mortality between the two groups (RR, 0.91; 95% CI: 0.50-1.66; P = 0.77), but there was significant difference (RR, 0.57; 95% CI: 0.44-0.74; P < 0.0001) in the overall morbidity. There were no significant differences between the two groups in the anastomotic leak rate (RR, 0.60; 95% CI: 0.28-1.28; P = 0.19), occurrence of abscesses, including peristomal abscess, intraperitoneal abscess and parietal abscess (RR, 0.83; 95% CI: 0.36-1.95; P = 0.68), and other abdominal complications (RR: 0.67; 95% CI: 0.40-1.12; P = 0.13). CONCLUSION: SEMS is not obviously more advantageous than emergent surgery for patients with acute left sided malignant colonic obstruction. PMID- 23112556 TI - Comparison between different reconstruction routes in esophageal squamous cell carcinoma. AB - AIM: To compare postoperative complications and prognosis of esophageal squamous cell carcinoma patients treated with different routes of reconstruction. METHODS: After obtaining approval from the Medical Ethics Committee of the Sun Yat-Sen University Cancer Center, we retrospectively reviewed data from 306 consecutive patients with histologically diagnosed esophageal squamous cell carcinoma who were treated between 2001 and 2011. All patients underwent radical McKeown-type esophagectomy with at least two-field lymphadenectomy. Regular follow-up was performed in our outpatient department. Postoperative complications and long-term survival were analyzed by treatment modality, baseline patient characteristics, and operative procedure. Data from patients treated via the retrosternal and posterior mediastinal routes were compared. RESULTS: The posterior mediastinal and retrosternal reconstruction routes were employed in 120 and 186 patients, respectively. Pulmonary complications were the most common complications experienced during the postoperative period (46.1% of all patients; 141/306). Compared to the retrosternal route, the posterior mediastinal reconstruction route was associated with a lower incidence of anastomotic stricture (15.8% vs 27.4%, P = 0.018) and less surgical bleeding (242.8 +/- 114.2 mL vs 308.2 +/- 168.4 mL, P < 0.001). The median survival time was 26.8 mo (range: 1.6-116.1 mo). Upon uni/multivariate analysis, a lower preoperative albumin level (P = 0.009) and a more advanced pathological stage (pT; P = 0.006; pN; P < 0.001) were identified as independent factors predicting poor prognosis. The reconstruction route did not influence prognosis (P = 0.477). CONCLUSION: The posterior mediastinal route of reconstruction reduces incidence of postoperative complications but does not affect survival. This route is recommended for resectable esophageal squamous cell carcinoma. PMID- 23112557 TI - Carbon dioxide insufflation for endoscopic retrograde cholangiopancreatography: A meta-analysis and systematic review. AB - AIM: To assess the safety and efficacy of carbon dioxide (CO(2)) insufflation during endoscopic retrograde cholangiopancreatography (ERCP). METHODS: The Cochrane Library, Medical Literature Analysis and Retrieval System Online, Excerpta Medica Database, Science Citation Index Expanded, Chinese Biomedical Literature Database, and references in relevant publications were searched up to December 2011 to identify randomized controlled trials (RCTs) comparing CO(2) insufflation with air insufflation during ERCP. The trials were included in the review irrespective of sample size, publication status, or language. Study selection and data extraction were performed by two independent authors. The meta analysis was performed using Review Manager 5.1.6. A random-effects model was used to analyze various outcomes. Sensitivity and subgroup analyses were performed if necessary. RESULTS: Seven double-blind RCTs involving a total of 818 patients were identified that compared CO(2) insufflation (n = 404) with air insufflation (n = 401) during ERCP. There were a total of 13 post-randomization dropouts in four RCTs. Six RCTs had a high risk of bias and one had a low risk of bias. None of the RCTs reported any severe gas-related adverse events in either group. A meta-analysis of 5 RCTs (n = 459) indicated that patients in the CO(2) insufflation group had less post-ERCP abdominal pain and distension for at least 1 h compared with patients in the air insufflation group. There were no significant differences in mild cardiopulmonary complications [risk ratio (RR) = 0.43, 95% CI: 0.07-2.66, P = 0.36], cardiopulmonary (e.g., blood CO(2) level) changes [standardized mean difference (SMD) = -0.97, 95% CI: -2.58-0.63, P = 0.23], cost analysis (mean difference = 3.14, 95% CI: -14.57-20.85, P = 0.73), and total procedure time (SMD = -0.05, 95% CI: -0.26-0.17, P = 0.67) between the two groups. CONCLUSION: CO(2) insufflation during ERCP appears to be safe and reduces post-ERCP abdominal pain and discomfort. PMID- 23112558 TI - Clostridium perfringens bacteremia caused by choledocholithiasis in the absence of gallbladder stones. AB - A 67-years-old male presented with periumbilical abdominal pain, fever and jaundice. His anaerobic blood culture was positive for clostridium perfringens. Computed tomogram scan of the abdomen and abdominal ultrasound showed normal gallbladder and common bile duct (CBD). Subsequently magnetic resonance cholangiopancreaticogram showed choledocholithiasis. Endoscopic retrograde cholangiopancreaticogramwith sphincterotomy and CBD stone extraction was performed. The patient progressively improved with antibiotic therapy Choledocholithiasis should be considered as a source of clostridium perfringens bacteremia especially in the setting of elevated liver enzymes with cholestatic pattern. PMID- 23112559 TI - A de novo germline MLH1 mutation in a Lynch syndrome patient with discordant immunohistochemical and molecular biology test results. AB - We describe a patient with a Homo sapiens mutL homolog 1 (MLH1)-associated Lynch syndrome with previous diagnoses of two distinct primary cancers: a sigmoid colon cancer at the age of 39 years, and a right colon cancer at the age of 50 years. The mutation identified in his blood and buccal cells, c.1771delG, p.Asp591Ilefs*25, appears to be a de novo event, as it was not transmitted by either of his parents. This type of de novo event is rare in MLH1 as only three cases have been reported in the literature so far. Furthermore, the discordant results observed between replication error phenotyping and immunohistochemistry highlight the importance of the systematic use of both pre-screening tests in the molecular diagnosis of Lynch syndrome. PMID- 23112560 TI - Ischemic colitis and large bowel infarction: a case report. AB - Ischemic bowel disease results from an acute or chronic drop in the blood supply to the bowel and may have various clinical presentations, such as intestinal angina, ischemic colitis or intestinal infarction. Elderly patients with systemic atherosclerosis who are symptomatic for the disease in two or more vascular beds have multiple comorbidities and are particularly at risk. The clinical evolution and outcome of this disease are difficult to predict because of its pleomorphic aspects and the general lack of statistical data. In this paper, we present the case of a patient who was monitored in our unit for six years. For this patient, we encountered iterative changes in the clinical pattern, beginning with chronic "intestinal angina" and finishing with signs of acute mesenteric ischemia after an episode of ischemic colitis. This evolution is particularly rare in clinical practice, and the case is instructive because it raises discussions about the natural history of the condition and the therapeutic decisions that should be made at every stage of the disease. An important lesson is that ischemic bowel disease should always be considered in patients who have multiple risk factors for atherosclerosis and have experienced recurrent "indistinct" abdominal symptoms. In these cases, aggressive investigation and therapeutic decisions must be taken whenever possible. Despite an absence of standardized protocols, angiographic evaluation and revascularization procedures have beneficial outcomes. Current advances in endovascular therapy, such as percutaneous transluminal angioplasty with stenting, should be increasingly used in patients with chronic mesenteric ischemia. Such therapy can avoid the risks that are associated with open repair. However, technical difficulties, especially in severe stenotic lesions, frequently occur. PMID- 23112561 TI - Gastrointestinal stromal tumor presenting with prominent calcification. AB - We present a rare case of a gastrointestinal stromal tumor (GIST) in the stomach with prominent calcification at presentation. A 61-year-old woman visited our hospital because of epigastric discomfort. A spherical calcified lesion with a diameter of about 30 mm was incidentally shown in the left upper quadrant on an abdominal X-ray. Computed tomography demonstrated that the tumor was growing from the upper gastric body, with calcification in the peripheral ring area. A laparoscopic partial gastrectomy was performed, and the resected specimen revealed a well-circumscribed tumor with exophytic growth from the gastric muscularis propria. Microscopic examination revealed spindle-shaped tumor cells with calcification and hemorrhage. Additionally, positive immunoreactivity of the tumor to KIT and CD34 and a low mitotic index resulted in the diagnosis of very low risk GIST. There are a few case reports of heavily calcified GIST, although solitary or punctate calcification of primary GIST has been reported in several case series. Dystrophic calcification of necrotic or degenerative tissue is the supposed cause of primary calcified GISTs. In contrast, appearance of calcification after administration of imatinib mesylate, which may be one indicator of disease response, is possibly caused by a different mechanism. PMID- 23112562 TI - Hepatothorax due to a right diaphragmatic rupture related to duodenal ulcer perforation. AB - Here, we present the case of a 53-year-old man with a hepatothorax due to a right diaphragmatic rupture related to duodenal ulcer perforation. On admission, the patient complained of severe acute abdominal pain, with physical examination findings suspicious for a perforated peptic ulcer. Of note, the patient had no history of other medical conditions or recent trauma, and the initial chest radiography and laboratory findings were not specific. A subsequent abdominal computed tomography revealed intrathoracic displacement of the liver, gallbladder, transverse colon and omentum through a right diaphragmatic defect. The patient then underwent an explorative laparotomy that confirmed duodenal ulcer perforation. A primary repair of the duodenal perforation was performed, and the diaphragmatic defect was repaired using a polytetrafluoroethylene patch after the organs were reduced and the cavity irrigated. This particular case proves interesting as right-sided spontaneous diaphragmatic ruptures are very rare and difficult to diagnose. Additionally, the best treatment for such large diaphragmatic defects is still controversial, especially in cases of intrathoracic or intra-abdominal contamination. PMID- 23112563 TI - Tracheobronchial nodules and pulmonary infiltrates in a patient with Crohn's disease. AB - Crohn's disease is a granulomatous systemic disorder of unknown etiology. Obvious pulmonary involvement is exceptional. Tracheal involvement in Crohn's disease is even more unusual, only a few cases have been reported to date. We herein report a rare case of tracheobronchial nodules and pulmonary infiltrates in both lungs as a complication of Crohn's disease. A 42-year-old man underwent pancolectomy for multiple broken colon caused by Crohn's disease. Forty days later pulmonary symptoms and radiologic abnormalities were noted. A search for bacterial (including mycobacteria) and fungal in the repeated sputum proved negative. The treatment consisted of intravenous antimicrobials for one month, but there was no improvement in pyrexia or cough and radiologic abnormalities. Fibreoptic bronchoscopy (FOB) was performed and revealed nodes in the trachea and the right upper lobe opening. Histopathology of tracheobronchial nodules and bronchial mucosa biopsy specimen both showed granulomatous inflammation with proliferation of capillaries and inflammatory cells. Oral steroid and salicylazosulfapyridine were commenced and led to marked improvement in symptoms and an almost complete resolution of his chest radiograph. Repeated FOB showed that nodes in the trachea disappeared and the ones in the right upper lobe opening diminished obviously. Crohn's disease can be associated with several respiratory manifestations. The form of tracheal and bronchopulmonary involvement in Crohn's disease is rare and responded well to steroids. PMID- 23112565 TI - Vortex formation and instability in the left ventricle. PMID- 23112564 TI - Severe acute cholangitis after endoscopic sphincterotomy induced by barium examination: A case report. AB - Endoscopic sphincterotomy (EST) is considered as a possible etiological factor for severe cholangitis. We herein report a case of severe cholangitis after endoscopic sphincterotomy induced by barium examination. An adult male patient presented with epigastric pain was diagnosed as having choledocholithiasis by ultrasonography. EST was performed and the stone was completely cleaned. Barium examination was done 3 d after EST and severe cholangitis appeared 4 h later. The patient was recovered after treated with tienam for 4 d. Barium examination may induce severe cholangitis in patients after EST, although rare, barium examination should be chosen cautiously. Cautions should be also used when EST is performed in patients younger than 50 years to avoid the damage to the sphincter of Oddi. PMID- 23112566 TI - Vascular endothelial growth factor-C secretion is increased by advanced glycation end-products: possible implication in ocular neovascularization. AB - PURPOSE: Neovascularization is a common complication of many degenerative and vascular diseases of the retina. Advanced glycation end-products (AGEs) have a pathologic role in the development of retinal neovascularization, mainly for their ability in upregulating vascular endothelial growth factor-A (VEGF-A) secretion. The aim of this study was to investigate whether AGEs are able to modulate the secretion of VEGF-C, another angiogenic factor that increases the effect of VEGF-A. METHODS: A human retinal pigment epithelial cell line (ARPE-19) and human endothelial vascular cell line (HECV) cells were cultured for 24 h in presence of AGEs, and then mRNA expression of VEGF-C was analyzed with reverse transcription-polymerase chain reaction (RT-PCR). To verify whether AGEs-induced VEGF secretion is mediated by RAGE (Receptor for AGEs), RAGE expression was depleted using the small interfering RNA method. To investigate whether VEGF-A is involved in upregulating VEGF-C secretion, the cells were cultured for 24 h in the presence of bevacizumab, a monoclonal antibody against VEGF-A, alone or in combination with AGEs. VEGF-A and VEGF-C levels in the supernatants of the treated cells were evaluated with enzyme-linked immunosorbent assay. RESULTS: Exposure to AGEs significantly increased VEGF-C gene expression in ARPE-19 cells. AGEs-induced VEGF-C secretion was upregulated in retinal pigment epithelium (RPE) and endothelial cells. Downregulation of RAGE expression decreased VEGF-A secretion in cell models, and increased VEGF-C secretion in ARPE-19 cells. Adding bevacizumab to the culture medium upregulated constitutive VEGF-C secretion but did not affect AGEs-induced VEGF-C secretion. CONCLUSIONS: These findings suggest that AGEs take part in the onset of retinal neovascularization, not only by modulating VEGF-A but also by increasing VEGF-C secretion. In addition, our results suggest that VEGF-C may compensate for treatments that reduce VEGF-A. PMID- 23112567 TI - Susceptibility to advanced age-related macular degeneration and alleles of complement factor H, complement factor B, complement component 2, complement component 3, and age-related maculopathy susceptibility 2 genes in a Mexican population. AB - PURPOSE: To investigate the association of age-related macular degeneration (AMD) high risk alleles of the complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), complement component 3 (C3), and age-related maculopathy susceptibility 2 (ARMS2) genes in a Mexican population for the first time. METHODS: Genotyping was performed for the Y402H variant of CFH, for the L9H, R32Q, and K565E variants of CFB, the E318D variant of C2, the A69S variant of ARMS2, and the R102G variant of C3 in 159 Mexican mestizo patients at advanced stages of AMD, i.e., CARMS (Clinical Age-Related Maculopathy Staging System) grade 4 or 5. The frequency of these variants was also investigated in a group of 152 control subjects without AMD. Genomic DNA was extracted from blood leukocytes, and genotyping was performed using PCR followed by direct sequencing. Allele-specific restriction enzyme digestion was used to detect the R102G polymorphism in C3. RESULTS: There were significant differences in the allelic distribution between the two groups for CFH Y402H (p=1*10(-5)), ARMS A69S (p=4*10(-7)), and CFB R32Q (p=0.01). The odds ratios (95% confidence interval) obtained for the risk alleles of these three variants were 3.8 (2.4-5.9), 3.04 (2.2-4.3), and 2.5 (1.1-5.7), respectively. Haplotype analysis including the two most significantly associated alleles (CFH Y402H and ARMS A69S) indicated that the C-T combination conferred an odds ratio (95% confidence interval) of 6.9 (3.2 14.8). The exposed attributable risk for this particular haplotype was 85.5%. CONCLUSIONS: This is the first case-control investigation of AMD-high risk alleles in a Latino population. Our results support that CFH, ARMS2, and CFB AMD risk alleles are consistently associated with the disease, even in ethnic groups with a complex admixture of ancestral populations such as Mexican mestizos. PMID- 23112568 TI - A rapid standardized quantitative microfluidic system approach for evaluating human tear proteins. AB - PURPOSE: To explore the potential of a chip-based miniaturized capillary gel electrophoresis device in a quantitative evaluation of the human tear protein profile and to validate the method. METHODS: A total of 5 MUl of tears were collected from 25 patients diagnosed as having mild to moderate dry eye according to Dry Eye Workshop guidelines and from 20 matched normal volunteers. Protein analysis was performed with the 2100 Bioanalyzer; different protein kit assays were evaluated (Protein 80 kit, Protein 230 kit, High Sensitivity Protein 250 kit) for sizing and quantifying protein samples from 5 to 80 kDa, 14 to 230 kDa, and 5 to 250 kDa, respectively. A standard protein ladder was loaded on each chip to allow an estimation of the appropriate molecular weight of the separated proteins; a sample buffer containing a lower and an upper marker was used to check the correct alignment of each lane. Virtual bands generated by the Bioanalyzer were identified and validated as follows: tear samples were run in parallel and proteins separated by one-dimensional and two-dimensional sodium dodecyl sulfate-PAGE and characterized by immunoblotting, enzymatic digestion, and analysis with liquid chromatography-mass spectrometry followed by a search of the SProt human protein database. RESULTS: Analyses were successfully performed by using as small as a 2 MUl tear sample. The Protein 230 kit was selected as the best chip kit, able to differentiate all the proteins of interest. The measurement noise parameters were low, and reproducibility and repeatability exhibited high accuracy (0.998 and 0.995, respectively) and precision (0.974 and 0.977, respectively). The coefficient of variability was slightly higher than that declared by the manufacturer (6.2% versus 5.0%). Total protein content and the following proteins were recognized in all samples: lipophilin A lysozyme C, tear lipocalin-1, zinc-alpha-2-glycoprotein, serotransferrin, lactotransferrin, and exudated serum albumin. CONCLUSIONS: Our data demonstrate that this chip based tear protein analysis is a reliable method of instrumental diagnosis in daily clinical activity and may provide supporting evaluation parameters for diagnosing and managing tear-based disorders. PMID- 23112569 TI - Review: magnetic resonance imaging techniques in ophthalmology. AB - Imaging the eye with magnetic resonance imaging (MRI) has proved difficult due to the eye's propensity to move involuntarily over typical imaging timescales, obscuring the fine structure in the eye due to the resulting motion artifacts. However, advances in MRI technology help to mitigate such drawbacks, enabling the acquisition of high spatiotemporal resolution images with a variety of contrast mechanisms. This review aims to classify the MRI techniques used to date in clinical and preclinical ophthalmologic studies, describing the qualitative and quantitative information that may be extracted and how this may inform on ocular pathophysiology. PMID- 23112570 TI - Suggestive association between PLA2G12A single nucleotide polymorphism rs2285714 and response to anti-vascular endothelial growth factor therapy in patients with exudative age-related macular degeneration. AB - PURPOSE: The use of anti-vascular endothelial growth factor (anti-VEGF) therapy, with drugs such as ranibizumab and bevacizumab, to treat neovascular age-related macular degeneration (nAMD) produces an effective but widely variable response. Identifying markers that predict differentiated response could serve as a valuable assay in developing more personalized medicine. This study aimed to identify single nucleotide polymorphisms (SNPs) that influence the outcome of treatment with anti-VEGF therapy for AMD. METHODS: One hundred six patients with nAMD were treated with either ranibizumab or bevacizumab as needed over a period of 12 months. Visual acuity and the presence of macular fluid were measured with optical coherence tomography at baseline, six months, and 12 months. Patients were then classified as good or poor responders based on change in visual acuity and macular fluid on follow-up visits. DNA extracted from blood was genotyped with a TaqMan-based allelic discrimination SNP assay for 21 SNPs in six candidate genes (PLAG12A, IL23R, STAT3, VEGFA, KDR, and HIF1A). The SNPs were primarily selected based on previously reported associations with AMD and functional involvement in angiogenesis pathways. SNPs shown to be promising for association with anti-VEGF therapy were then assessed in an independent AMD case-control cohort. RESULTS: Of the 106 patients with nAMD, 77 were classified as good responders and 29 as poor responders. For rs2285714 (PLA2G12A), the frequency of minor allele T was 40.1% for good responders compared to 51.7% for poor responders (odds ratio: 1.60, 95% confidence interval of odds ratio: 0.87-2.94, p=0.13). Genetic model analysis of rs2285714 (PLA2G12A) demonstrated an association between rs2285714 (PLA2G12A) and therapy response in a dominant genotypic model. Patients carrying at least one T allele of rs2285714 were 2.79 times (95% confidence interval=1.02-7.69, p<0.05) more likely to be poor responders (79.3% of poor responders) than good responders (57.3% of good responders). However, after adjusting for multiple testing by the false discovery rate or Bonferroni correction, the initially observed association was no longer statistically significant. No association was identified between the remaining SNPs and response status. The SNP rs2285714 of PLA2G12A was not significantly associated with AMD in an independent AMD case-control cohort. CONCLUSIONS: Data suggest a possible weak association between rs2285714 (PLA2G12A) and response to anti-VEGF therapy, but the association must be confirmed in additional cohorts with larger patient samples. Identifying factors that predict the differentiated response could provide a valuable assay for developing approaches in personalized medicine. PMID- 23112571 TI - Amelioration of endotoxin-induced uveitis treated with an IkappaB kinase beta inhibitor in rats. AB - PURPOSE: Endotoxin-induced uveitis (EIU) is an animal model for acute ocular inflammation. Several substances play major roles in the development of inflammatory changes in EIU, including tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6. These inflammatory cytokines trigger the degradation of IkappaB by activating IkappaB kinases (IKKs). Released nuclear factor kappaB (NFkappaB) subsequently translocates to the nucleus, where NFkappaB expresses its proinflammatory function. IMD-0354, N-(3,5-Bis trifluoromethylphenyl)-5-chloro-2-hydroxybenzamide, selectively inhibits IKKbeta, particularly when induced by proinflammatory cytokines, such as TNF-alpha and IL 1beta. In the present study, we examined whether IKKbeta inhibition has therapeutic effects on EIU by using IMD-0354 and its prodrug IMD-1041. METHODS: Six-week-old male Lewis rats were used. EIU was induced with subcutaneous injections of 200 MUg of lipopolysaccharide (LPS) from Escherichia coli that had been diluted in 0.1 ml of phosphate-buffered saline. IMD-0354 was administered intraperitoneally at 30, 10, 3, or 0 mg/kg, suspended in 1.0 ml of 0.5% carboxymethyl cellulose sodium. The prodrug IMD-1041 (100 mg/kg) was also administered orally. The rats were euthanized 24 h after LPS injection, and EIU severity was evaluated histologically. The number of infiltrating cells and the protein, TNF-alpha, and monocyte chemoattractant protein-1 (MCP-1) concentrations in the aqueous humor were determined. TNF-alpha and MCP-1 concentrations were quantified with enzyme-linked immunosorbent assay. Eye sections were also stained with anti-NFkappaB and phosphorylated I-kappaBalpha antibodies. RESULTS: The number of infiltrating cells in aqueous humor was 53.6+/-9.8*10(5), 72.5+/ 17.0*10(5), 127.25+/-32.0*10(5), and 132.0+/-25.0*10(5) cells/ml in rats treated with 30, 10, 3, or 0 mg/kg of IMD-0354, respectively. The total protein concentrations of aqueous humor were 92.6+/-3.1 mg/ml, 101.5+/-6.8 mg/ml, 112.6+/ 1.9 mg/ml, and 117.33+/-1.8 mg/ml in rats treated with 30, 10, 3, and 0 mg/kg of IMD-0354, respectively. Infiltrating cells and protein concentrations were significantly decreased by treatment with IMD-0354 (p<0.01). IMD-0354 treatment significantly reduced the concentration of TNF-alpha (p<0.05) and MCP-1 (p<0.01) in aqueous humor. The number of NFkappaB positive nuclei was reduced when treated with IMD-0354. Furthermore, IMD-0354-treated EIU rats showed only background levels of phosphorylated I-kappaBalpha; however, it was strongly expressed in the iris-ciliary body cell cytoplasm of the IMD-0354 untreated EIU rats. Oral administration of IMD-1041 also decreased the cell number (p<0.01) and protein concentration (p<0.05) of aqueous humor in EIU. CONCLUSIONS: Acute uveitis was ameliorated by inhibition of IKKbeta in rats. IMD-0354 and its prodrug IMD-1041 seem to be promising candidates for treating intraocular inflammation/uveitis. PMID- 23112572 TI - Attenuation of corneal myofibroblast development through nanoparticle-mediated soluble transforming growth factor-beta type II receptor (sTGFbetaRII) gene transfer. AB - PURPOSE: To explore (i) the potential of polyethylenimine (PEI)-DNA nanoparticles as a vector for delivering genes into human corneal fibroblasts, and (ii) whether the nanoparticle-mediated soluble extracellular domain of the transforming growth factor-beta type II receptor (sTGFbetaRII) gene therapy could be used to reduce myofibroblasts and fibrosis in the cornea using an in vitro model. METHODS: PEI DNA nanoparticles were prepared at a nitrogen-to-phosphate ratio of 30 by mixing linear PEI and a plasmid encoding sTGFbetaRII conjugated to the fragment crystallizable (Fc) portion of human immunoglobulin. The PEI-DNA polyplex formation was confirmed through gel retardation assay. Human corneal fibroblasts (HCFs) were generated from donor corneas; myofibroblasts and fibrosis were induced with TGFbeta1 (1 ng/ml) stimulation employing serum-free conditions. The sTGFbetaRII conjugated to the Fc portion of human immunoglobulin gene was introduced into HCF using either PEI-DNA nanoparticles or Lipofectamine. Suitable negative and positive controls to compare selected nanoparticle and therapeutic gene efficiency were included. Delivered gene copies and mRNA (mRNA) expression were quantified with real-time quantitative PCR (qPCR) and protein with enzyme linked immunosorbent assay (ELISA). The changes in fibrosis parameters were quantified by measuring fibrosis marker alpha-smooth muscle actin (SMA) mRNA and protein levels with qPCR, immunostaining, and immunoblotting. Cytotoxicity was determined using cellular viability, proliferation, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. RESULTS: PEI readily bound to plasmids to form nanoparticular polyplexes and exhibited much greater transfection efficiency (p<0.01) than the commercial reagent Lipofectamine. The PEI-DNA-treated cultures showed 4.5*10(4) plasmid copies/ug DNA in real-time qPCR and 7,030+/-87 pg/ml sTGFbetaRII protein in ELISA analyses, whereas Lipofectamine transfected cultures demonstrated 1.9*10(3) gene copies/ug DNA and 1,640+/-100 pg/ml sTGFbetaRII protein during these assays. The PEI-mediated sTGFbetaRII delivery remarkably attenuated TGFbeta1-induced transdifferentiation of corneal fibroblasts to myofibroblasts in cultures, as indicated by threefold lower levels of SMA mRNA (p<0.01) and significant inhibition of SMA protein (up to 96+/-3%; p<0.001 compared to no-gene-delivered cultures) in immunocytochemical staining and immunoblotting. The nanoparticle-mediated delivery of sTGFbetaRII showed significantly better antifibrotic effects than the Lipofectamine under similar experimental conditions. However, the inhibition of myofibroblast in HCF cultures by sTGFbetaRII overexpression by either method was significantly higher than the naked vector transfection. Furthermore, PEI- or Lipofectamine-mediated sTGFbetaRII delivery into HCF did not alter cellular proliferation or phenotype at 12 and 24 h post-treatment. Nanoparticles treated with HCF showed more than 90% cellular viability and very low cell death (2-6 TUNEL+ cells), suggesting that the tested doses of PEI-nanoparticles do not induce significant cell death. CONCLUSIONS: This study demonstrated that PEI-DNA nanoparticles are an attractive vector for the development of nonviral corneal gene therapy approaches and that the sTGFbetaRII gene delivery into keratocytes could be used to control corneal fibrosis in vivo. PMID- 23112574 TI - Membrane frizzled-related protein gene-related ophthalmological syndrome: 30 month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature. AB - PURPOSE: To report a new sporadic case of membrane frizzled-related protein gene (MFRP)-related syndrome with a 30-month follow-up, and to review the literature for genotype-phenotype correlation in MFRP mutations. METHODS: A complete ophthalmological evaluation was performed at presentation and 30 months later, including best-corrected visual acuity test, slit lamp examination, fundoscopy, kinetic perimetry, electroretinography, fundus imaging (color, red-free, and autofluorescence), and morphologic-biometric analysis of the eye structures with an optical biometer, anterior-segment optical coherence tomography, retinal optical coherence tomography, and a confocal scanning laser for optic nerve head study. Polymerase chain reaction amplification of DNA obtained from peripheral blood lymphocytes and nucleotide sequencing of the complete MFRP gene were performed. The literature on cases of posterior microphthalmos and retinitis pigmentosa associated with MFRP mutations was reviewed. RESULTS: A 33-year-old female patient presented with posterior microphthalmos, retinitis pigmentosa with patches of retinal pigmented epithelium atrophy and scarce pigment mobilization, foveoschisis, and optic nerve drusen. After 30 months, progression of rod-cone retinal degeneration was detected. One obligate carrier showed a normal eye phenotype. A homozygote mutation in the MFRP gene (c.492delC), predicting a truncated protein (P166fsX190), was identified with genetic analysis. To our knowledge, 17 cases of MFRP-related syndrome have been reported in the literature, including the patient described herein. The phenotype of the syndrome, expressivity, and age of onset varied among and within the affected families. However, all patients sharing homozygous mutation c.492delC (alternatively named c.498delC) showed a complete phenotype (including foveoschisis and optic nerve head drusen), and similar fundus characteristics. CONCLUSIONS: A new sporadic case of MFRP-related syndrome is reported. Review of the literature showed variability in the phenotype, but initial elements of genotype-phenotype correlation have been identified in patients sharing the mutation of the present case. PMID- 23112573 TI - Effects of intravitreal insulin and insulin signaling cascade inhibitors on emmetropization in the chick. AB - PURPOSE: Intravitreal insulin has been shown to be a powerful stimulator of myopia in chickens, in particular if the retinal image is degraded or defocused. In most tissues, the insulin receptor activates two main signaling pathways: a) the mitogen-activated protein kinase (MAPK) cascade (e.g., mitogen-activated protein kinasem kinase [MEK] and extracellular regulated kinase [ERK]) and b) the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway. In the current study, insulin was injected, and these pathways were separately inhibited to determine which is activated when the retinal image is defocused by spectacle lenses. METHODS: Chicks were treated with either +7 D, -7 D, or no lenses. They were intravitreally injected with insulin, the MEK inhibitor U0126, the PI3K inhibitor Ly294002, or a combination of insulin and one of the inhibitors. Refractions and ocular dimension were measured at the beginning and after four days of treatment. The retinal proteins of the chicks were measured with western blots after 2 h and four days of treatment. Incubation occurred with anti-Akt1, anti-Erk1/2, anti-phospho-Akt(Thr308), and anti-phospho-Erk1/2((Thr202/Tyr204)) antibodies, and the ratio between the relative intensity of the phospho-form and the total-form was calculated. RESULTS: Chicks wearing positive lenses and injected with saline and with PI3K inhibitor compensated for the imposed defocus and became hyperopic. Insulin injections and insulin plus PI3K inhibitor injections prevented lens-induced hyperopia, whereas the MEK inhibitor alone and insulin plus MEK inhibitor had no effect. Obviously, the MEK inhibitor suppressed the effect of insulin on eye growth in the plus lens-treated animals. Chicks treated with negative lenses and injected with insulin, or with insulin plus MEK inhibitor, overcompensated for the imposed defocus. This effect of insulin was not detected in eyes injected with PI3K inhibitor plus insulin, suggesting that the PI3K inhibitor suppressed the effects of insulin in minus lens-treated animals. Insulin increased the ratio of phospho-Akt/total-Akt in animals with normal visual exposure but even more so in chicks wearing plus or minus lenses. The increase was blocked by simultaneous PI3K inhibitor injections in control eyes but not in lens-treated eyes. Insulin also increased the ratio of phospho ERK/total-ERK in animals with normal visual exposure and in animals wearing positive lenses, compared to U0126- and Ly294002-injected eyes. In contrast, no significant activation of the MEK/ERK pathway was observed in the negative lens treated animals. CONCLUSIONS: Intravitreal insulin promoted axial eye growth and stimulated both signaling pathways. The PI3K/Akt pathway was activated in control and plus and minus lens-treated eyes, but the MEK/ERK pathway was activated only with positive lenses or no lenses. With negative lenses, insulin did not stimulate the MEK/ERK signaling cascade. Independent of the pathway stimulated after insulin binding, the effect on insulin was always the same: an increase in eye growth. PMID- 23112575 TI - Design of near-infrared fluorescent bioactive conjugated functional iron oxide nanoparticles for optical detection of colon cancer. AB - BACKGROUND: Colon cancer is one of the major causes of death in the Western world. Early detection significantly improves long-term survival for patients with the disease. Near- infrared (NIR) fluorescent nanoparticles hold great promise as contrast agents for tumor detection. NIR offers several advantages for bioimaging compared with fluorescence in the visible spectrum, ie, lower autofluorescence of biological tissues, lower absorbance, and consequently deeper penetration into biomatrices. METHODS AND RESULTS: NIR fluorescent iron oxide nanoparticles with a narrow size distribution were prepared by nucleation, followed by controlled growth of thin iron oxide films onto cyanine NIR dye conjugated gelatin-iron oxide nuclei. For functionalization, and in order to increase the NIR fluorescence intensity, the NIR fluorescent iron oxide nanoparticles obtained were coated with human serum albumin containing cyanine NIR dye. Leakage of the NIR dye from these nanoparticles into phosphate-buffered saline solution containing 4% albumin was not detected. The work presented here is a feasibility study to test the suitability of iron oxide-human serum albumin NIR fluorescent nanoparticles for optical detection of colon cancer. It demonstrates that encapsulation of NIR fluorescent dye within these nanoparticles significantly reduces photobleaching of the dye. Tumor-targeting ligands, peanut agglutinin and anticarcinoembryonic antigen antibodies (alphaCEA), were covalently conjugated with the NIR fluorescent iron oxide-human serum albumin nanoparticles via a poly(ethylene glycol) spacer. Specific colon tumor detection was demonstrated in chicken embryo and mouse models for both nonconjugated and the peanut agglutinin-conjugated or alphaCEA-conjugated NIR fluorescent iron oxide-human serum albumin nanoparticles. CONCLUSION: Conjugation of peanut agglutinin or alphaCEA to the nanoparticles significantly increased the fluorescence intensity of the tagged colon tumor tissues relative to the nonconjugated nanoparticles. PMID- 23112577 TI - Consequences of neurologic lesions assessed by Barthel Index after Botox((r)) injection may be underestimated. AB - PURPOSE: The aim of this study was to investigate whether the consequences of neurologic lesions are underestimated when the Barthel Index (BI) is used to assess the clinical outcome of botulinum toxin injection. PATIENTS AND METHODS: The records for all in- and outpatients with various neurologic lesions (stroke, multiple sclerosis, spinal cord injury, traumatic brain injury, and so forth) who had been referred to the authors' departments and who had received botulinum toxin type A (Botox((r))) for spasticity within a 4-year period (2008-2011) were examined retrospectively. BI data were collected and analyzed. RESULTS: The BI score was found to have increased in follow-up assessments (P = 0.048). No correlation was found between the degree of spasticity and the BI score. CONCLUSION: The specific injection of Botox in patients with neurologic lesions was not strongly correlated with a significant functional outcome according to the BI. The results of this study suggest that clinicians need to look at other measurement scales for the assessment of significant outcomes of Botox in the rehabilitation process after neurologic lesions. PMID- 23112576 TI - Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients. AB - S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM((r)). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S CKD602 and monocytes. PMID- 23112578 TI - Prevalence and risk factors associated with peripheral artery disease in elderly patients undergoing peritoneal dialysis. AB - BACKGROUND: Rapid growth of the elderly peritoneal dialysis (PD) population is posing a special challenge for renal teams. Peripheral artery disease (PAD) has been reported to be an independent predictor of cardiovascular and all-cause mortality in hemodialysis patients. However, the prevalence and associated risk factors for PAD in elderly PD patients have not yet been fully investigated. METHODS: A total of 69 elderly PD patients were included in the present study. PAD was defined as either an ankle-brachial index < 0.9 or a history of intermittent claudication, lower-limb amputation, foot ulcers, or gangrene. On enrollment, clinical and biochemical characteristics were collected. RESULTS: The overall prevalence of PAD was 31.9%. Compared with non-PAD patients, PAD patients were significantly older and more likely to be female and have longer PD duration and lower diastolic blood pressure (P < 0.001, = 0.002, 0.018, and 0.007, respectively). Serum albumin level (P < 0.001) and residual renal Kt/V value (P < 0.001) were significantly lower, but the serum C-reactive protein level (P = 0.005) was significantly higher, in PAD patients compared with non-PAD patients. Logistic regression analysis showed that serum albumin level (odds ratio = 1.485, P = 0.040) and residual renal Kt/V value (odds ratio = 1.725, P = 0.016) were independently associated with PAD. CONCLUSION: A high prevalence of PAD appeared among elderly PD patients in Macao. Serum albumin level and residual renal Kt/V value were independently related to PAD. PMID- 23112579 TI - Patterns of warfarin use and subsequent outcomes in atrial fibrillation in primary care practices. AB - BACKGROUND: Warfarin is recommended for stroke prevention in high-risk patients with atrial fibrillation. However, it is often underutilized and inadequately managed in actual clinical practice. OBJECTIVES: To examine the patterns of warfarin use and their relationship with stroke and bleeding in atrial fibrillation patients in community-based primary care practices. DESIGN: Retrospective longitudinal cohort study. PARTICIPANTS: A total of 1141 atrial fibrillation patients were selected from 17 primary care practices with a shared electronic medical record and characterized by stroke risk, potential barriers to anticoagulation, and comorbid conditions. MAIN MEASURES: Duration and number of warfarin exposures, interruptions in warfarin exposure > 45 days, stroke, and bleeding events. RESULTS: Among 1141 patients with a mean age of 70 years (standard deviation 13.3) and mean follow-up of 3.4 years (standard deviation 3.0), 764 (67%) were treated with warfarin. Warfarin was discontinued within 1 year in 194 (25.4%), and 349 (45.7%) remained on warfarin at the end of follow up. Interruptions in warfarin use were common, occurring in 32.6% (249 of 764) of patients. Those with two or more interruptions were younger and at lower baseline stroke risk when compared to those with no interruptions. There were 76 first strokes and 73 first-bleeding events in the follow-up period. When adjusted for baseline stroke risk, time to warfarin start, and total exposure time, two or more interruptions in warfarin use was associated with an increased risk of stroke (relative risk, 2.29; 95% confidence interval: 1.29-4.07). There was no significant association between warfarin interruptions and bleeding events. CONCLUSION: Warfarin was underutilized in a substantial portion of eligible atrial fibrillation patients in these community-based practices. In addition, prolonged interruptions in anticoagulation were common in this population, and multiple interruptions were associated with over twice the risk of stroke when compared to those treated continuously. PMID- 23112581 TI - Vehicle unpaved road response spectrum acquisition based on accelerometer and GPS data. AB - This paper describes a response acquisition system composed of some spindle accelerometers and a time synchronized on-board GPS receiver developed in order to collect the dynamic response of vehicle riding on an unpaved road. A method of time-space conversion for calculating the response spectrum is proposed to eliminate the adverse effect of time-varying speed, based on the transform from the equitime sampled spindle acceleration responses to equidistance sampling. By using two groups of independent distance histories acquired from GPS, a method called long-range error correction is proposed to improve the accuracy of the vehicle's distance information, which is critical for the time-space conversion. The accuracy and limitations of the system have been analyzed, and its validity has been verified by implementing the system on a wheel loader for road response spectrum measuring. This paper offers a practical approach to obtaining unpaved road response spectra for durability road simulation. PMID- 23112580 TI - Treating thalassemia major-related iron overload: the role of deferiprone. AB - Over the last 20 years, management for thalassemia major has improved to the point where we predict that patients' life expectancy will approach that of the normal population. These outcomes result from safer blood transfusions, the availability of three iron chelators, new imaging techniques that allow specific organ assessment of the degree of iron overload, and improvement in the treatment of hepatitis. In October 2011, the Food and Drug Administration licensed deferiprone, further increasing the available choices for iron chelation in the US. The ability to prescribe any of the three chelators as well as their combinations has led to more effective reduction of total body iron. The ability to determine the amount of iron in the liver and heart by magnetic resonance imaging allows the prescription of the most appropriate chelation regime for patients and to reconsider what our aims with respect to total body iron should be. Recent evidence from Europe has shown that by normalizing iron stores not only are new morbidities prevented but also reversal of many complications such as cardiac failure, hypothyroidism, hypogonadism, impaired glucose tolerance, and type 2 diabetes can occur, improving survival and patients' quality of life. The most effective way to achieve normal iron stores seems to be with the combination of deferoxamine and deferiprone. Furthermore, outcomes should continue to improve in the future. Starting relative intensive chelation in younger children may prevent short stature and abnormal pubertal maturation as well as other iron related morbidities. Also, further information should become available on the use of other combinations in chelation treatment, some of which have been used only in a very limited fashion to date. All these advances in management require absolute cooperation and understanding of parents, children, and, subsequently, the patients themselves. Only with such cooperation can normal long-term survival be achieved, as adherence to treatment is now likely the primary barrier to longevity. PMID- 23112582 TI - Validation of SMOS soil moisture products over the Maqu and Twente regions. AB - The validation of Soil Moisture and Ocean Salinity (SMOS) soil moisture products is a crucial step in the investigation of their inaccuracies and limitations, before planning further refinements of the retrieval algorithm. Therefore, this study intended to contribute to the validation of the SMOS soil moisture products, by comparing them with the data collected in situ in the Maqu (China) and Twente (The Netherlands) regions in 2010. The seasonal behavior of the SMOS soil moisture products is generally in agreement with the in situ measurements for both regions. However, the validation analysis resulted in determination coefficients of 0.55 and 0.51 over the Maqu and Twente region, respectively, for the ascending pass data, and of 0.24 and 0.41, respectively, for the descending pass data. Moreover, a systematic dry bias of the SMOS soil moisture was found of approximately 0.13 m(3)/m(3) for the Maqu region and 0.17 m(3)/m(3) for the Twente region for ascending pass data. Several factors might have affected the retrieval accuracy, such as the presence of Radio Frequency Interference (RFI), the use of inaccurate land cover information and the presence of frozen soils not correctly detected in winter. Improving the RFI filtering method and the quality of the retrieval algorithm inputs, such as land surface temperature and land cover, would certainly improve the accuracy of the retrieved soil moisture. PMID- 23112583 TI - Experimental estimating deflection of a simple beam bridge model using grating eddy current sensors. AB - A novel three-point method using a grating eddy current absolute position sensor (GECS) for bridge deflection estimation is proposed in this paper. Real spatial positions of the measuring points along the span axis are directly used as relative reference points of each other rather than using any other auxiliary static reference points for measuring devices in a conventional method. Every three adjacent measuring points are defined as a measuring unit and a straight connecting bar with a GECS fixed on the center section of it links the two endpoints. In each measuring unit, the displacement of the mid-measuring point relative to the connecting bar measured by the GECS is defined as the relative deflection. Absolute deflections of each measuring point can be calculated from the relative deflections of all the measuring units directly without any correcting approaches. Principles of the three-point method and displacement measurement of the GECS are introduced in detail. Both static and dynamic experiments have been carried out on a simple beam bridge model, which demonstrate that the three-point deflection estimation method using the GECS is effective and offers a reliable way for bridge deflection estimation, especially for long-term monitoring. PMID- 23112584 TI - Research on a novel low modulus OFBG strain sensor for pavement monitoring. AB - Because of the fatigue and deflection damage of asphalt pavement, it is very important for researchers to monitor the strain response of asphalt layers in service under vehicle loads, so in this paper a novel polypropylene based OFBG (Optical Fiber Bragg Gratings) strain sensor with low modulus and large strain sensing scale was designed and fabricated. PP with MA-G-PP is used to package OFBG. The fabrication techniques, the physical properties and the sensing properties were tested. The experimental results show that this kind of new OFBG strain sensor is a wonderful sensor with low modulus (about 1 GPa) and good sensitivity, which would meet the needs for monitoring some low modulus materials or structures. PMID- 23112586 TI - Fabrication of high sensitivity carbon microcoil pressure sensors. AB - This work demonstrates a highly sensitive pressure sensor that was fabricated using carbon microcoils (CMCs) and polydimethylsiloxane (PDMS). CMCs were grown by chemical vapor deposition using various ratios of Fe-Sn catalytic solution. The pressure sensor has a sandwiched structure, in which the as-grown CMCs were inserted between two PDMS layers. The pressure sensor exhibits piezo-resistivity changes in response to mechanical loading using a load cell system. The yields of the growth of CMCs at a catalyst proportion of Fe:Sn = 95:5 reach 95%. Experimental results show that the sensor achieves a high sensitivity of 0.93%/kPa from the CMC yield of 95%. The sensitivity of the pressure sensor increases with increasing yield of CMCs. The demonstrated pressure sensor shows the advantage of high sensitivity and is suitable for mass production. PMID- 23112585 TI - A wireless interface for replacing the cables in bridge-sensor applications. AB - This paper presents a solution in which a wireless interface is employed to replace the cables in bridge-sensor measurement applications. The most noticeable feature of the presented approach is the fact that the wireless interface simply replaces the cables without any additional hardware modification to the existing system. In this approach, the concept of reciprocal topology is employed, where the transmitter side acquires signals with its own transfer function and the receiver side reconstructs them with the transfer function reciprocal to the transmitter transfer function. In this paper the principle of data acquisition and reconstruction is described together with the implementation details of the signal transfer from the sensor to the signal-monitoring equipment. The wireless data communication was investigated and proprietary data-reduction methods were developed. The proposed methods and algorithms were implemented using two different wireless technologies. The performance was evaluated with a dedicated data-acquisition system and finally, the test results were analyzed. The two different sets of results indicated the high level of amplitude and the temporal accuracy of the wirelessly transferred sensor signals. PMID- 23112588 TI - Low-voltage 96 dB snapshot CMOS image sensor with 4.5 nW power dissipation per pixel. AB - Modern "smart" CMOS sensors have penetrated into various applications, such as surveillance systems, bio-medical applications, digital cameras, cellular phones and many others. Reducing the power of these sensors continuously challenges designers. In this paper, a low power global shutter CMOS image sensor with Wide Dynamic Range (WDR) ability is presented. This sensor features several power reduction techniques, including a dual voltage supply, a selective power down, transistors with different threshold voltages, a non-rationed logic, and a low voltage static memory. A combination of all these approaches has enabled the design of the low voltage "smart" image sensor, which is capable of reaching a remarkable dynamic range, while consuming very low power. The proposed power saving solutions have allowed the maintenance of the standard architecture of the sensor, reducing both the time and the cost of the design. In order to maintain the image quality, a relation between the sensor performance and power has been analyzed and a mathematical model, describing the sensor Signal to Noise Ratio (SNR) and Dynamic Range (DR) as a function of the power supplies, is proposed. The described sensor was implemented in a 0.18 um CMOS process and successfully tested in the laboratory. An SNR of 48 dB and DR of 96 dB were achieved with a power dissipation of 4.5 nW per pixel. PMID- 23112587 TI - CMOS cell sensors for point-of-care diagnostics. AB - The burden of health-care related services in a global era with continuously increasing population and inefficient dissipation of the resources requires effective solutions. From this perspective, point-of-care diagnostics is a demanded field in clinics. It is also necessary both for prompt diagnosis and for providing health services evenly throughout the population, including the rural districts. The requirements can only be fulfilled by technologies whose productivity has already been proven, such as complementary metal-oxide semiconductors (CMOS). CMOS-based products can enable clinical tests in a fast, simple, safe, and reliable manner, with improved sensitivities. Portability due to diminished sensor dimensions and compactness of the test set-ups, along with low sample and power consumption, is another vital feature. CMOS-based sensors for cell studies have the potential to become essential counterparts of point-of care diagnostics technologies. Hence, this review attempts to inform on the sensors fabricated with CMOS technology for point-of-care diagnostic studies, with a focus on CMOS image sensors and capacitance sensors for cell studies. PMID- 23112589 TI - Magnetic properties of liquid-phase sintered CoFe2O4 for application in magnetoelastic and magnetoelectric transducers. AB - Cobalt ferrite is a ferrimagnetic magnetostrictive ceramic that has potential application in magnetoelastic and magnetoelectric transducers. In this work, CoFe(2)O(4) was obtained using a conventional ceramic method and Bi(2)O(3) was used as additive in order to obtain liquid-phase sintered samples. Bi(2)O(3) was added to the ferrite in amounts ranging from 0.25 mol% to 0.45 mol% and samples were sintered at 900 degrees C and 950 degrees C. It was observed the presence of Bi-containing particles in the microstructure of the sintered samples and the magnetostriction results indicated microstructural anisotropy. It was verified that it is possible to get dense cobalt ferrites, liquid-phase sintered, with relative densities higher than 90% and with magnetostriction values very close to samples sintered without additives. PMID- 23112590 TI - Label-free electrochemical diagnosis of viral antigens with genetically engineered fusion protein. AB - We have developed a simple electrochemical biosensing strategy for the label-free diagnosis of hepatitis B virus (HBV) on a gold electrode surface. Gold-binding polypeptide (GBP) fused with single-chain antibody (ScFv) against HBV surface antigen (HBsAg), in forms of genetically engineered protein, was utilized. This GBP-ScFv fusion protein can directly bind onto the gold substrate with the strong binding affinity between the GBP and the gold surface, while the recognition site orients toward the sample for target binding at the same time. Furthermore, this one-step immobilization strategy greatly simplifies a fabrication process without any chemical modification as well as maintaining activity of biological recognition elements. This system allows specific immobilization of proteins and sensitive detection of targets, which were verified by surface plasmon resonance analysis and successfully applied to electrochemical cyclic voltammetry and impedance spectroscopy upto 0.14 ng/mL HBsAg. PMID- 23112591 TI - A monotonic degradation assessment index of rolling bearings using fuzzy support vector data description and running time. AB - Performance degradation assessment based on condition monitoring plays an important role in ensuring reliable operation of equipment, reducing production downtime and saving maintenance costs, yet performance degradation has strong fuzziness, and the dynamic information is random and fuzzy, making it a challenge how to assess the fuzzy bearing performance degradation. This study proposes a monotonic degradation assessment index of rolling bearings using fuzzy support vector data description (FSVDD) and running time. FSVDD constructs the fuzzy monitoring coefficient epsilon- which is sensitive to the initial defect and stably increases as faults develop. Moreover, the parameter epsilon- describes the accelerating relationships between the damage development and running time. However, the index epsilon- with an oscillating trend disagrees with the irreversible damage development. The running time is introduced to form a monotonic index, namely damage severity index (DSI). DSI inherits all advantages of epsilon- and overcomes its disadvantage. A run-to-failure test is carried out to validate the performance of the proposed method. The results show that DSI reflects the growth of the damages with running time perfectly. PMID- 23112592 TI - Synthesis of bioactive microcapsules using a microfluidic device. AB - Bioactive microcapsules containing Bacillus thuringiensis (BT) spores were generated by a combination of a hydro gel, microfluidic device and chemical polymerization method. As a proof-of-principle, we used BT spores displaying enhanced green fluorescent protein (EGFP) on the spore surface to spatially direct the EGFP-presenting spores within microcapsules. BT spore-encapsulated microdroplets of uniform size and shape are prepared through a flow-focusing method in a microfluidic device and converted into microcapsules through hydrogel polymerization. The size of microdroplets can be controlled by changing both the dispersion and continuous flow rate. Poly(N-isoproplyacrylamide) (PNIPAM), known as a hydrogel material, was employed as a biocompatible material for the encapsulation of BT spores and long-term storage and outstanding stability. Due to these unique properties of PNIPAM, the nutrients from Luria-Bertani complex medium diffused into the microcapsules and the microencapsulated spores germinated into vegetative cells under adequate environmental conditions. These results suggest that there is no limitation of transferring low-molecular-weight substrates through the PNIPAM structures, and the viability of microencapsulated spores was confirmed by the culture of vegetative cells after the germinations. This microfluidic-based microencapsulation methodology provides a unique way of synthesizing bioactive microcapsules in a one-step process. This microfluidic based strategy would be potentially suitable to produce microcapsules of various microbial spores for on-site biosensor analysis. PMID- 23112593 TI - On-line estimation of laser-drilled hole depth using a machine vision method. AB - The paper presents a novel method for monitoring and estimating the depth of a laser-drilled hole using machine vision. Through on-line image acquisition and analysis in laser machining processes, we could simultaneously obtain correlations between the machining processes and analyzed images. Based on the machine vision method, the depths of laser-machined holes could be estimated in real time. Therefore, a low cost on-line inspection system is developed to increase productivity. All of the processing work was performed in air under standard atmospheric conditions and gas assist was used. A correlation between the cumulative size of the laser-induced plasma region and the depth of the hole is presented. The result indicates that the estimated depths of the laser-drilled holes were a linear function of the cumulative plasma size, with a high degree of confidence. This research provides a novel machine vision-based method for estimating the depths of laser-drilled holes in real time. PMID- 23112594 TI - A search strategy of Level-Based Flooding for the Internet of Things. AB - This paper deals with the query problem in the Internet of Things (IoT). Flooding is an important query strategy. However, original flooding is prone to cause heavy network loads. To address this problem, we propose a variant of flooding, called Level-Based Flooding (LBF). With LBF, the whole network is divided into several levels according to the distances (i.e., hops) between the sensor nodes and the sink node. The sink node knows the level information of each node. Query packets are broadcast in the network according to the levels of nodes. Upon receiving a query packet, sensor nodes decide how to process it according to the percentage of neighbors that have processed it. When the target node receives the query packet, it sends its data back to the sink node via random walk. We show by extensive simulations that the performance of LBF in terms of cost and latency is much better than that of original flooding, and LBF can be used in IoT of different scales. PMID- 23112596 TI - A distributed reasoning engine ecosystem for semantic context-management in smart environments. AB - To be able to react adequately a smart environment must be aware of the context and its changes. Modeling the context allows applications to better understand it and to adapt to its changes. In order to do this an appropriate formal representation method is needed. Ontologies have proven themselves to be one of the best tools to do it. Semantic inference provides a powerful framework to reason over the context data. But there are some problems with this approach. The inference over semantic context information can be cumbersome when working with a large amount of data. This situation has become more common in modern smart environments where there are a lot sensors and devices available. In order to tackle this problem we have developed a mechanism to distribute the context reasoning problem into smaller parts in order to reduce the inference time. In this paper we describe a distributed peer-to-peer agent architecture of context consumers and context providers. We explain how this inference sharing process works, partitioning the context information according to the interests of the agents, location and a certainty factor. We also discuss the system architecture, analyzing the negotiation process between the agents. Finally we compare the distributed reasoning with the centralized one, analyzing in which situations is more suitable each approach. PMID- 23112595 TI - Behavior-based cleaning for unreliable RFID data sets. AB - Radio Frequency IDentification (RFID) technology promises to revolutionize the way we track items and assets, but in RFID systems, missreading is a common phenomenon and it poses an enormous challenge to RFID data management, so accurate data cleaning becomes an essential task for the successful deployment of systems. In this paper, we present the design and development of a RFID data cleaning system, the first declarative, behavior-based unreliable RFID data smoothing system. We take advantage of kinematic characteristics of tags to assist in RFID data cleaning. In order to establish the conversion relationship between RFID data and kinematic parameters of the tags, we propose a movement behavior detection model. Moreover, a Reverse Order Filling Mechanism is proposed to ensure a more complete access to get the movement behavior characteristics of tag. Finally, we validate our solution with a common RFID application and demonstrate the advantages of our approach through extensive simulations. PMID- 23112597 TI - Mosaicing of hyperspectral images: the application of a spectrograph imaging device. AB - Hyperspectral monitoring of large areas (more than 10 km(2)) can be achieved via the use of a system employing spectrometers and CMOS cameras. A robust and efficient algorithm for automatically combining multiple, overlapping images of a scene to form a single composition (i.e., for the estimation of the point-to point mapping between views), which uses only the information contained within the images themselves is described here. The algorithm, together with the 2D fast Fourier transform, provides an estimate of the displacement between pairs of images by accounting for rotations and changes of scale. The resulting mosaic was successively georeferenced within the WGS-84 geographic coordinate system. This paper also addresses how this information can be transferred to a push broom type spectral imaging device to build the hyperspectral cube of the area prior to land classification. The performances of the algorithm were evaluated using sample images and image sequences acquired during a proximal sensing field campaign conducted in San Teodoro (Olbia-Tempio-Sardinia). The hyperspectral cube closely corresponds to the mosaic. Mapping allows for the identification of objects within the image and agrees well with ground-truth measurements. PMID- 23112598 TI - Harvesting energy from the counterbalancing (weaving) movement in bicycle riding. AB - Bicycles are known to be rich source of kinetic energy, some of which is available for harvesting during speedy and balanced maneuvers by the user. A conventional dynamo attached to the rim can generate a large amount of output power at an expense of extra energy input from the user. However, when applying energy conversion technology to human powered equipments, it is important to minimize the increase in extra muscular activity and to maximize the efficiency of human movements. This study proposes a novel energy harvesting methodology that utilizes lateral oscillation of bicycle frame (weaving) caused by user weight shifting movements in order to increase the pedaling force in uphill riding or during quick speed-up. Based on the 3D motion analysis, we designed and implemented the prototype of an electro-dynamic energy harvester that can be mounted on the bicycle's handlebar to collect energy from the side-to-side movement. The harvester was found to generate substantial electric output power of 6.6 mW from normal road riding. It was able to generate power even during uphill riding which has never been shown with other approaches. Moreover, harvesting of energy from weaving motion seems to increase the economy of cycling by helping efficient usage of human power. PMID- 23112599 TI - FunBlocks. A modular framework for AmI system development. AB - The last decade has seen explosive growth in the technologies required to implement Ambient Intelligence (AmI) systems. Technologies such as facial and speech recognition, home networks, household cleaning robots, to name a few, have become commonplace. However, due to the multidisciplinary nature of AmI systems and the distinct requirements of different user groups, integrating these developments into full-scale systems is not an easy task. In this paper we propose FunBlocks, a minimalist modular framework for the development of AmI systems based on the function module abstraction used in the IEC 61499 standard for distributed control systems. FunBlocks provides a framework for the development of AmI systems through the integration of modules loosely joined by means of an event-driven middleware and a module and sensor/actuator catalog. The modular design of the FunBlocks framework allows the development of AmI systems which can be customized to a wide variety of usage scenarios. PMID- 23112600 TI - A wireless magnetic resonance energy transfer system for micro implantable medical sensors. AB - Based on the magnetic resonance coupling principle, in this paper a wireless energy transfer system is designed and implemented for the power supply of micro implantable medical sensors. The entire system is composed of the in vitro part, including the energy transmitting circuit and resonant transmitter coils, and in vivo part, including the micro resonant receiver coils and signal shaping chip which includes the rectifier module and LDO voltage regulator module. Transmitter and receiver coils are wound by Litz wire, and the diameter of the receiver coils is just 1.9 cm. The energy transfer efficiency of the four-coil system is greatly improved compared to the conventional two-coil system. When the distance between the transmitter coils and the receiver coils is 1.5 cm, the transfer efficiency is 85% at the frequency of 742 kHz. The power transfer efficiency can be optimized by adding magnetic enhanced resonators. The receiving voltage signal is converted to a stable output voltage of 3.3 V and a current of 10 mA at the distance of 2 cm. In addition, the output current varies with changes in the distance. The whole implanted part is packaged with PDMS of excellent biocompatibility and the volume of it is about 1 cm(3). PMID- 23112601 TI - Detection of formaldehyde in water: a shape-effect on the plasmonic sensing properties of the gold nanoparticles. AB - The effect of morphology on the plasmonic sensing of the presence of formaldehyde in water by gold nanostructures has been investigated. The gold nanostructures with two different morphologies, namely spherical and rod, were prepared using a seed-mediated method. In typical results, it was found that the plasmonic properties of gold nanostructures were very sensitive to the presence of formaldehyde in their surrounding medium by showing the change in both the plasmonic peaks position and the intensity. Spherical nanoparticles (GNS), for example, indicated an increase in the sensitivity when the size was increased from 25 to 35 nm and dramatically decreased when the size was further increased. An m value, the ratio between plasmonic peak shift and refractive index change, as high as 36.5 nm/RIU (refractive index unit) was obtained so far. An expanded sensing mode to FD was obtained when gold nanostructures with nanorods morphology (GNR) were used because of the presence of two plasmonic modes for response probing. However, in the present study, effective plasmonic peak shift was not observed due to the intense plasmonic coupling of closely packed nanorod structures on the surface. Nevertheless, the present results at least provide a potential strategy for response enhancement via shape-effects. High performance plasmonic sensors could be obtained if controlled arrays of nanorods can be prepared on the surface. PMID- 23112602 TI - Multi-sensor fusion of infrared and electro-optic signals for high resolution night images. AB - Electro-optic (EO) image sensors exhibit the properties of high resolution and low noise level at daytime, but they do not work in dark environments. Infrared (IR) image sensors exhibit poor resolution and cannot separate objects with similar temperature. Therefore, we propose a novel framework of IR image enhancement based on the information (e.g., edge) from EO images, which improves the resolution of IR images and helps us distinguish objects at night. Our framework superimposing/blending the edges of the EO image onto the corresponding transformed IR image improves their resolution. In this framework, we adopt the theoretical point spread function (PSF) proposed by Hardie et al. for the IR image, which has the modulation transfer function (MTF) of a uniform detector array and the incoherent optical transfer function (OTF) of diffraction-limited optics. In addition, we design an inverse filter for the proposed PSF and use it for the IR image transformation. The framework requires four main steps: (1) inverse filter-based IR image transformation; (2) EO image edge detection; (3) registration; and (4) blending/superimposing of the obtained image pair. Simulation results show both blended and superimposed IR images, and demonstrate that blended IR images have better quality over the superimposed images. Additionally, based on the same steps, simulation result shows a blended IR image of better quality when only the original IR image is available. PMID- 23112603 TI - Grey level and noise evaluation of a Foveon X3 image sensor: a statistical and experimental approach. AB - Radiometric values on digital imagery are affected by several sources of uncertainty. A practical, comprehensive and flexible procedure to analyze the radiometric values and the uncertainty effects due to the camera sensor system is described in this paper. The procedure is performed on the grey level output signal using image raw units with digital numbers ranging from 0 to 2(12)-1. The procedure is entirely based on statistical and experimental techniques. Design of Experiments (DoE) for Linear Models (LM) are derived to analyze the radiometric values and estimate the uncertainty. The presented linear model integrates all the individual sensor noise sources in one global component and characterizes the radiometric values and the uncertainty effects according to the influential factors such as the scene reflectance, wavelength range and time. The experiments are carried out under laboratory conditions to minimize the rest of uncertainty sources that might affect the radiometric values. It is confirmed the flexibility of the procedure to model and characterize the radiometric values, as well as to determine the behaviour of two phenomena when dealing with image sensors: the noise of a single image and the stability (trend and noise) of a sequence of images. PMID- 23112604 TI - A multi-parameter decoupling method with a Lamb wave sensor for improving the selectivity of label-free liquid detection. AB - In this paper, a liquid multi-parameter decoupling method with only one Lamb wave sensor is presented. In a Lamb wave sensor, antisymmetric modes (A(01) mode for low frequency, A(03) mode for high frequency) and symmetric modes (S(0) mode) are used to detect multiple parameters of a liquid, such as its density, sound velocity, and viscosity. We found they can play very different roles in the detections. For example, the A(01) mode is very sensitive to the liquid's density but the A(03) mode is sensitive to the sound velocity. Here, the A(0) mode is used to identify the density of the detected liquid and with this density value we obtained the viscosity by the amplitude shifts of the S(0) mode. This could be a way to distinguish an unknown liquid with high sensitivity or to solve the problem of selectivity of label-free detection on biosensors. PMID- 23112605 TI - A synchronous multi-body sensor platform in a Wireless Body Sensor Network: design and implementation. AB - BACKGROUND: Human life can be further improved if diseases and disorders can be predicted before they become dangerous, by correctly recognizing signals from the human body, so in order to make disease detection more precise, various body signals need to be measured simultaneously in a synchronized manner. OBJECT: This research aims at developing an integrated system for measuring four signals (EEG, ECG, respiration, and PPG) and simultaneously producing synchronous signals on a Wireless Body Sensor Network. DESIGN: We designed and implemented a platform for multiple bio-signals using Bluetooth communication. RESULTS: First, we developed a prototype board and verified the signals from the sensor platform using frequency responses and quantities. Next, we designed and implemented a lightweight, ultra-compact, low cost, low power-consumption Printed Circuit Board. CONCLUSION: A synchronous multi-body sensor platform is expected to be very useful in telemedicine and emergency rescue scenarios. Furthermore, this system is expected to be able to analyze the mutual effects among body signals. PMID- 23112606 TI - Non-destructive inspection methods for LEDs using real-time displaying Optical Coherence Tomography. AB - In this study, we report the applicability of two different Optical Coherence Tomography (OCT) technologies for inspecting Light Emitting Diode (LED) structures. Sectional images of a LED were captured using a Spectral Domain OCT (SD-OCT) system and a Swept Source OCT (SS-OCT) system. Their center wavelengths are 850 and 1,310 nm, respectively. We acquired cross-sectional two dimensional (2D) images of a normal LED and extracted sectional profiles to inspect possible wire disconnection that may be present in the LED manufacturing process. The SD OCT and SS-OCT images were compared with each other in the same sample to study their advantages. The distribution of fluorescence material was observed more clearly with the SD-OCT of 850 nm wavelength, whereas the status of wire connection was clearer in the SS-OCT images with 1,310 nm wavelength. In addition, the volume of the fluorophore space was calculated from the OCT images. This is the first report that a nondestructive optical imaging modality such as OCT can be applied to finding screen defects in LED. We expect this method can improve the inspection efficacy over traditional inspection methods such as Charged Coupled Device (CCD) camera or X-ray instruments. PMID- 23112607 TI - A semantic autonomous video surveillance system for dense camera networks in Smart Cities. AB - This paper presents a proposal of an intelligent video surveillance system able to detect and identify abnormal and alarming situations by analyzing object movement. The system is designed to minimize video processing and transmission, thus allowing a large number of cameras to be deployed on the system, and therefore making it suitable for its usage as an integrated safety and security solution in Smart Cities. Alarm detection is performed on the basis of parameters of the moving objects and their trajectories, and is performed using semantic reasoning and ontologies. This means that the system employs a high-level conceptual language easy to understand for human operators, capable of raising enriched alarms with descriptions of what is happening on the image, and to automate reactions to them such as alerting the appropriate emergency services using the Smart City safety network. PMID- 23112608 TI - In-line fiber optic interferometric sensors in single-mode fibers. AB - In-line fiber optic interferometers have attracted intensive attention for their potential sensing applications in refractive index, temperature, pressure and strain measurement, etc. Typical in-line fiber-optic interferometers are of two types: Fabry-Perot interferometers and core-cladding-mode interferometers. It's known that the in-line fiber optic interferometers based on single-mode fibers can exhibit compact structures, easy fabrication and low cost. In this paper, we review two kinds of typical in-line fiber optic interferometers formed in single mode fibers fabricated with different post-processing techniques. Also, some recently reported specific technologies for fabricating such fiber optic interferometers are presented. PMID- 23112609 TI - Mechanisms for the direct electron transfer of cytochrome c induced by multi walled carbon nanotubes. AB - Multi-walled carbon nanotube (MWCNT)-modified electrodes can promote the direct electron transfer (DET) of cytochrome c (Cyt c). There are several possible mechanisms that explain the DET of Cyt c. In this study, several experimental methods, including Fourier transform infrared spectroscopy, circular dichroism, ultraviolet-visible absorption spectroscopy, and electron paramagnetic resonance spectroscopy were utilized to investigate the conformational changes of Cyt c induced by MWCNTs. The DET mechanism was demonstrated at various nano-levels: secondary structure, spatial orientation, and spin state. In the presence of MWCNTs, the secondary structure of Cyt c changes, which exposes the active site, then, the orientation of the heme is optimized, revolving the exposed active center to the optimum spatial orientation for DET; and finally, a transition of spin states is induced, providing relatively high energy and a more open microenvironment for electron transfer. These changes at different nano-levels are closely connected and form a complex process that promotes the electron transfer of Cyt c. PMID- 23112610 TI - Cognitive LF-Ant: a novel protocol for healthcare wireless sensor networks. AB - In this paper, the authors present the Cognitive LF-Ant protocol for emergency reporting in healthcare wireless sensor networks. The protocol is inspired by the natural behaviour of ants and a cognitive component provides the capabilities to dynamically allocate resources, in accordance with the emergency degree of each patient. The intra-cluster emergency reporting is inspired by the different capabilities of leg-manipulated ants. The inter-cluster reporting is aided by the cooperative modulation diversity with spectrum sensing, which can detect new emergency reporting requests and forward them. Simulations results show the decrease of average delay time as the probability of opportunistic access increases, which privileges the emergency reporting related to the patients with higher priority of resources' usage. Furthermore, the packet loss rate is decreased by the use of cooperative modulation diversity with spectrum sensing. PMID- 23112611 TI - Detection of non-PCR amplified S. enteritidis genomic DNA from food matrices using a gold-nanoparticle DNA biosensor: a proof-of-concept study. AB - Bacterial pathogens pose an increasing food safety and bioterrorism concern. Current DNA detection methods utilizing sensitive nanotechnology and biosensors have shown excellent detection, but require expensive and time-consuming polymerase chain reaction (PCR) to amplify DNA targets; thus, a faster, more economical method is still essential. In this proof-of-concept study, we investigated the ability of a gold nanoparticle-DNA (AuNP-DNA) biosensor to detect non-PCR amplified genomic Salmonella enterica serovar Enteritidis (S. enteritidis) DNA, from pure or mixed bacterial culture and spiked liquid matrices. Non-PCR amplified DNA was hybridized into sandwich-like structures (magnetic nanoparticles/DNA/AuNPs) and analyzed through detection of gold voltammetric peaks using differential pulse voltammetry. Our preliminary data indicate that non-PCR amplified genomic DNA can be detected at a concentration as low as 100 ng/mL from bacterial cultures and spiked liquid matrices, similar to reported PCR amplified detection levels. These findings also suggest that AuNP DNA biosensors are a first step towards a viable detection method of bacterial pathogens, in particular, for resource-limited settings, such as field-based or economically limited conditions. Future efforts will focus on further optimization of the DNA extraction method and AuNP-biosensors, to increase sensitivity at lower DNA target concentrations from food matrices comparable to PCR amplified DNA detection strategies. PMID- 23112612 TI - A four-quadrant PVDF transducer for surface acoustic wave detection. AB - In this paper, a polyvinylidene fluoride (PVDF) piezoelectric transducer was developed to detect laser-induced surface acoustic waves in a SiO(2)-thin film-Si substrate structure. In order to solve the problems related to, firstly, the position of the probe, and secondly, the fact that signals at different points cannot be detected simultaneously during the detection process, a four-quadrant surface acoustic wave PVDF transducer was designed and constructed for the purpose of detecting surface acoustic waves excited by a pulse laser line source. The experimental results of the four-quadrant piezoelectric detection in comparison with the commercial nanoindentation technology were consistent, the relative error is 0.56%, and the system eliminates the piezoelectric surface wave detection direction deviation errors, improves the accuracy of the testing system by 1.30%, achieving the acquisition at the same time at different testing positions of the sample. PMID- 23112613 TI - Cross Layer Adaptation of Check intervals in low power listening MAC protocols for lifetime improvement in Wireless Sensor Networks. AB - Preamble sampling-based MAC protocols designed for Wireless Sensor Networks (WSN) are aimed at prolonging the lifetime of the nodes by scheduling their times of activity. This scheduling exploits node synchronization to find the right trade off between energy consumption and delay. In this paper we consider the problem of node synchronization in preamble sampling protocols. We propose Cross Layer Adaptation of Check intervals (CLAC), a novel protocol intended to reduce the energy consumption of the nodes without significantly increasing the delay. Our protocol modifies the scheduling of the nodes based on estimating the delay experienced by a packet that travels along a multi-hop path. CLAC uses routing and MAC layer information to compute a delay that matches the packet arrival time. We have implemented CLAC on top of well-known routing and MAC protocols for WSN, and we have evaluated our implementation using the Avrora simulator. The simulation results confirm that CLAC improves the network lifetime at no additional packet loss and without affecting the end-to-end delay. PMID- 23112614 TI - Pedestrian navigation based on a waist-worn inertial sensor. AB - We present a waist-worn personal navigation system based on inertial measurement units. The device makes use of the human bipedal pattern to reduce position errors. We describe improved algorithms, based on detailed description of the heel strike biomechanics and its translation to accelerations of the body waist to estimate the periods of zero velocity, the step length, and the heading estimation. The experimental results show that we are able to support pedestrian navigation with the high-resolution positioning required for most applications. PMID- 23112615 TI - Numerical investigations on electric field characteristics with respect to capacitive detection of free-flying droplets. AB - In this paper a multi-disciplinary simulation of a capacitive droplet sensor based on an open plate capacitor as transducing element is presented. The numerical simulations are based on the finite volume method (FVM), including calculations of an electric field which changes according to the presence of a liquid droplet. The volume of fluid (VOF) method is applied for the simulation of the ejection process of a liquid droplet out of a dispenser nozzle. The simulations were realised using the computational fluid dynamic (CFD) software CFD ACE+. The investigated capacitive sensing principle enables to determine the volume of a micro droplet passing the sensor capacitor due to the induced change in capacity. It could be found that single droplets in the considered volume range of 5 nL < V(drop) < 100 nL lead to a linear change of the capacity up to DeltaQ < 30 fC. The sensitivity of the focused capacitor geometry was evaluated to be S(i) = 0.3 fC/nL. The simulation results are validated by experiments which exhibit good agreement. PMID- 23112616 TI - Numerical and experimental study on the development of electric sensor as for measurement of red blood cell deformability in microchannels. AB - A microsensor that can continuously measure the deformability of a single red blood cell (RBC) in its microchannels using microelectrodes is described in this paper. The time series of the electric resistance is measured using an AC current vs. voltage method as the RBC passes between counter-electrode-type micro membrane sensors attached to the bottom wall of the microchannel. The RBC is deformed by the shear flow created in the microchannel; the degree of deformation depends on the elastic modulus of the RBC. The resistance distribution, which is unique to the shape of the RBC, is analyzed to obtain the deformability of each cell. First, a numerical simulation of the electric field around the electrodes and RBC is carried out to evaluate the influences of the RBC height position, channel height, distance between the electrodes, electrode width, and RBC shape on the sensor sensitivity. Then, a microsensor was designed and fabricated on the basis of the numerical results. Resistance measurement was carried out using samples of normal RBCs and rigidified (Ca(2+)-A23186 treated) RBCs. Visualization measurement of the cells' behavior was carried out using a high-speed camera, and the results were compared with those obtained above to evaluate the performance of the sensor. PMID- 23112617 TI - Binaural sound localizer for azimuthal movement detection based on diffraction. AB - Sound localization can be realized by utilizing the physics of acoustics in various methods. This paper investigates a novel detection architecture for the azimuthal movement of sound source based on the interaural level difference (ILD) between two receivers. One of the microphones in the system is surrounded by barriers of various heights in order to cast the direction dependent diffraction of the incoming signal. The gradient analysis of the ILD between the structured and unstructured microphone demonstrates the rotation directions as clockwise, counter clockwise, and no rotation of the sound source. Acoustic experiments with different types of sound source over a wide range of target movements show that the average true positive and false positive rates are 67% and 16%, respectively. Spectral analysis demonstrates that the low frequency delivers decreased true and false positive rates and the high frequency presents increases of both rates, overall. PMID- 23112618 TI - Resolution in QCM sensors for the viscosity and density of liquids: application to lead acid batteries. AB - In battery applications, particularly in automobiles, submarines and remote communications, the state of charge (SoC) is needed in order to manage batteries efficiently. The most widely used physical parameter for this is electrolyte density. However, there is greater dependency between electrolyte viscosity and SoC than that seen for density and SoC. This paper presents a Quartz Crystal Microbalance (QCM) sensor for electrolyte density-viscosity product measurements in lead acid batteries. The sensor is calibrated in H(2)SO(4) solutions in the battery electrolyte range to obtain sensitivity, noise and resolution. Also, real time tests of charge and discharge are conducted placing the quartz crystal inside the battery. At the same time, the present theoretical "resolution limit" to measure the square root of the density-viscosity product [Formula: see text] of a liquid medium or best resolution achievable with a QCM oscillator is determined. Findings show that the resolution limit only depends on the characteristics of the liquid to be studied and not on frequency. The QCM resolution limit for [Formula: see text] measurements worsens when the density viscosity product of the liquid is increased, but it cannot be improved by elevating the work frequency. PMID- 23112619 TI - Optimal design of the absolute positioning sensor for a high-speed maglev train and research on its fault diagnosis. AB - This paper studies an absolute positioning sensor for a high-speed maglev train and its fault diagnosis method. The absolute positioning sensor is an important sensor for the high-speed maglev train to accomplish its synchronous traction. It is used to calibrate the error of the relative positioning sensor which is used to provide the magnetic phase signal. On the basis of the analysis for the principle of the absolute positioning sensor, the paper describes the design of the sending and receiving coils and realizes the hardware and the software for the sensor. In order to enhance the reliability of the sensor, a support vector machine is used to recognize the fault characters, and the signal flow method is used to locate the faulty parts. The diagnosis information not only can be sent to an upper center control computer to evaluate the reliability of the sensors, but also can realize on-line diagnosis for debugging and the quick detection when the maglev train is off-line. The absolute positioning sensor we study has been used in the actual project. PMID- 23112620 TI - Hyperspectral analysis of soil nitrogen, carbon, carbonate, and organic matter using regression trees. AB - The characterization of soil attributes using hyperspectral sensors has revealed patterns in soil spectra that are known to respond to mineral composition, organic matter, soil moisture and particle size distribution. Soil samples from different soil horizons of replicated soil series from sites located within Washington and Oregon were analyzed with the FieldSpec Spectroradiometer to measure their spectral signatures across the electromagnetic range of 400 to 1,000 nm. Similarity rankings of individual soil samples reveal differences between replicate series as well as samples within the same replicate series. Using classification and regression tree statistical methods, regression trees were fitted to each spectral response using concentrations of nitrogen, carbon, carbonate and organic matter as the response variables. Statistics resulting from fitted trees were: nitrogen R(2) 0.91 (p < 0.01) at 403, 470, 687, and 846 nm spectral band widths, carbonate R(2) 0.95 (p < 0.01) at 531 and 898 nm band widths, total carbon R(2) 0.93 (p < 0.01) at 400, 409, 441 and 907 nm band widths, and organic matter R(2) 0.98 (p < 0.01) at 300, 400, 441, 832 and 907 nm band widths. Use of the 400 to 1,000 nm electromagnetic range utilizing regression trees provided a powerful, rapid and inexpensive method for assessing nitrogen, carbon, carbonate and organic matter for upper soil horizons in a nondestructive method. PMID- 23112621 TI - Ubiquitous green computing techniques for high demand applications in Smart environments. AB - Ubiquitous sensor network deployments, such as the ones found in Smart cities and Ambient intelligence applications, require constantly increasing high computational demands in order to process data and offer services to users. The nature of these applications imply the usage of data centers. Research has paid much attention to the energy consumption of the sensor nodes in WSNs infrastructures. However, supercomputing facilities are the ones presenting a higher economic and environmental impact due to their very high power consumption. The latter problem, however, has been disregarded in the field of smart environment services. This paper proposes an energy-minimization workload assignment technique, based on heterogeneity and application-awareness, that redistributes low-demand computational tasks from high-performance facilities to idle nodes with low and medium resources in the WSN infrastructure. These non optimal allocation policies reduce the energy consumed by the whole infrastructure and the total execution time. PMID- 23112622 TI - Intelligent urban public transportation for accessibility dedicated to people with disabilities. AB - The traditional urban public transport system generally cannot provide an effective access service for people with disabilities, especially for disabled, wheelchair and blind (DWB) passengers. In this paper, based on advanced information & communication technologies (ICT) and green technologies (GT) concepts, a dedicated public urban transportation service access system named Mobi+ has been introduced, which facilitates the mobility of DWB passengers. The Mobi+ project consists of three subsystems: a wireless communication subsystem, which provides the data exchange and network connection services between buses and stations in the complex urban environments; the bus subsystem, which provides the DWB class detection & bus arrival notification services; and the station subsystem, which implements the urban environmental surveillance & bus auxiliary access services. The Mobi+ card that supports multi-microcontroller multi transceiver adopts the fault-tolerant component-based hardware architecture, in which the dedicated embedded system software, i.e., operating system micro-kernel and wireless protocol, has been integrated. The dedicated Mobi+ embedded system provides the fault-tolerant resource awareness communication and scheduling mechanism to ensure the reliability in data exchange and service provision. At present, the Mobi+ system has been implemented on the buses and stations of line '2' in the city of Clermont-Ferrand (France). The experiential results show that, on one hand the Mobi+ prototype system reaches the design expectations and provides an effective urban bus access service for people with disabilities; on the other hand the Mobi+ system is easily to deploy in the buses and at bus stations thanks to its low energy consumption and small form factor. PMID- 23112623 TI - A wide linear range Eddy Current Displacement Sensor equipped with dual-coil probe applied in the Magnetic Suspension Flywheel. AB - The Eddy Current Displacement Sensor (ECDS) is widely used in the Magnetic Suspension Flywheel (MSFW) to measure the tiny clearance between the rotor and the magnetic bearings. The linear range of the ECDS is determined by the diameter of its probe coil. Wide clearances must be measured in some new MSFWs recently designed for the different space missions, but the coil diameter is limited by some restrictions. In this paper, a multi-channel ECDS equipped with dual-coil probes is proposed to extend the linear range to satisfy the demands of such MSFWs. In order to determine the best configuration of the dual-coil probe, the quality factors of the potential types of the dual-coil probes, the induced eddy current and the magnetic intensity on the surface of the measuring object are compared with those of the conventional single-coil probe. The linear range of the ECDS equipped with the selected dual-coil probe is extended from 1.1 mm to 2.4 mm under the restrictions without adding any cost for additional compensation circuits or expensive coil materials. The effectiveness of the linear range extension ability and the dynamic response of the designed ECDS are confirmed by the testing and the applications in the MSFW. PMID- 23112624 TI - Sensorial systems applied to Intelligent Spaces. PMID- 23112626 TI - Automatic carbon dioxide-methane gas sensor based on the solubility of gases in water. AB - Biogas methane content is a relevant variable in anaerobic digestion processing where knowledge of process kinetics or an early indicator of digester failure is needed. The contribution of this work is the development of a novel, simple and low cost automatic carbon dioxide-methane gas sensor based on the solubility of gases in water as the precursor of a sensor for biogas quality monitoring. The device described in this work was used for determining the composition of binary mixtures, such as carbon dioxide-methane, in the range of 0-100%. The design and implementation of a digital signal processor and control system into a low-cost Field Programmable Gate Array (FPGA) platform has permitted the successful application of data acquisition, data distribution and digital data processing, making the construction of a standalone carbon dioxide-methane gas sensor possible. PMID- 23112625 TI - Lab-on-a-chip pathogen sensors for food safety. AB - There have been a number of cases of foodborne illness among humans that are caused by pathogens such as Escherichia coli O157:H7, Salmonella typhimurium, etc. The current practices to detect such pathogenic agents are cell culturing, immunoassays, or polymerase chain reactions (PCRs). These methods are essentially laboratory-based methods that are not at all real-time and thus unavailable for early-monitoring of such pathogens. They are also very difficult to implement in the field. Lab-on-a-chip biosensors, however, have a strong potential to be used in the field since they can be miniaturized and automated; they are also potentially fast and very sensitive. These lab-on-a-chip biosensors can detect pathogens in farms, packaging/processing facilities, delivery/distribution systems, and at the consumer level. There are still several issues to be resolved before applying these lab-on-a-chip sensors to field applications, including the pre-treatment of a sample, proper storage of reagents, full integration into a battery-powered system, and demonstration of very high sensitivity, which are addressed in this review article. Several different types of lab-on-a-chip biosensors, including immunoassay- and PCR-based, have been developed and tested for detecting foodborne pathogens. Their assay performance, including detection limit and assay time, are also summarized. Finally, the use of optical fibers or optical waveguide is discussed as a means to improve the portability and sensitivity of lab-on-a-chip pathogen sensors. PMID- 23112627 TI - Sensing free sulfur dioxide in wine. AB - Sulfur dioxide (SO(2)) is important in the winemaking process as it aids in preventing microbial growth and the oxidation of wine. These processes and others consume the SO(2) over time, resulting in wines with little SO(2) protection. Furthermore, SO(2) and sulfiting agents are known to be allergens to many individuals and for that reason their levels need to be monitored and regulated in final wine products. Many of the current techniques for monitoring SO(2) in wine require the SO(2) to be separated from the wine prior to analysis. This investigation demonstrates a technique capable of measuring free sulfite concentrations in low volume liquid samples in white wine. This approach adapts a known colorimetric reaction to a suspended core optical fiber sensing platform, and exploits the interaction between guided light located within the fiber voids and a mixture of the wine sample and a colorimetric analyte. We have shown that this technique enables measurements to be made without dilution of the wine samples, thus paving the way towards real time in situ wine monitoring. PMID- 23112628 TI - An integrative architecture for a sensor-supported trust management system. AB - Trust plays a key role not only in e-worlds and emerging pervasive computing environments, but also already for millennia in human societies. Trust management solutions that have being around now for some fifteen years were primarily developed for the above mentioned cyber environments and they are typically focused on artificial agents, sensors, etc. However, this paper presents extensions of a new methodology together with architecture for trust management support that is focused on humans and human-like agents. With this methodology and architecture sensors play a crucial role. The architecture presents an already deployable tool for multi and interdisciplinary research in various areas where humans are involved. It provides new ways to obtain an insight into dynamics and evolution of such structures, not only in pervasive computing environments, but also in other important areas like management and decision making support. PMID- 23112629 TI - Vision-based sensor for early detection of periodical defects in web materials. AB - During the production of web materials such as plastic, textiles or metal, where there are rolls involved in the production process, periodically generated defects may occur. If one of these rolls has some kind of flaw, it can generate a defect on the material surface each time it completes a full turn. This can cause the generation of a large number of surface defects, greatly degrading the product quality. For this reason, it is necessary to have a system that can detect these situations as soon as possible. This paper presents a vision-based sensor for the early detection of this kind of defects. It can be adapted to be used in the inspection of any web material, even when the input data are very noisy. To assess its performance, the sensor system was used to detect periodical defects in hot steel strips. A total of 36 strips produced in ArcelorMittal Aviles factory were used for this purpose, 18 to determine the optimal configuration of the proposed sensor using a full-factorial experimental design and the other 18 to verify the validity of the results. Next, they were compared with those provided by a commercial system used worldwide, showing a clear improvement. PMID- 23112630 TI - Development of a plastic-based microfluidic immunosensor chip for detection of H1N1 influenza. AB - Lab-on-a-chip can provide convenient and accurate diagnosis tools. In this paper, a plastic-based microfluidic immunosensor chip for the diagnosis of swine flu (H1N1) was developed by immobilizing hemagglutinin antigen on a gold surface using a genetically engineered polypeptide. A fluorescent dye-labeled antibody (Ab) was used for quantifying the concentration of Ab in the immunosensor chip using a fluorescent technique. For increasing the detection efficiency and reducing the errors, three chambers and three microchannels were designed in one microfluidic chip. This protocol could be applied to the diagnosis of other infectious diseases in a microfluidic device. PMID- 23112631 TI - A linear, millimetre displacement-to-frequency transducer. AB - The paper presents a novel linear, high-fidelity millimetre displacement-to frequency transducer, based on the resistive conversion of displacement into a proportional voltage, and then frequency. The derivation of the nonlinearity, fidelity and sensitivity of the transducer is presented. Experimental results confirm that a displacement of 0-100 mm is converted into a frequency range of 0 100 kHz, with a normalised fidelity factor of 99.91%, and a worst-case nonlinearity of less than 0.08%. Tests using laboratory standards show that a displacement of 10 mm is transduced with an accuracy of +/- 0.6%, and a standard deviation of 530 Hz. Estimates included in the paper show that the transducer could cost less than 1% of existing systems for millimeter displacement measurement. PMID- 23112632 TI - Detecting unknown attacks in wireless sensor networks that contain mobile nodes. AB - As wireless sensor networks are usually deployed in unattended areas, security policies cannot be updated in a timely fashion upon identification of new attacks. This gives enough time for attackers to cause significant damage. Thus, it is of great importance to provide protection from unknown attacks. However, existing solutions are mostly concentrated on known attacks. On the other hand, mobility can make the sensor network more resilient to failures, reactive to events, and able to support disparate missions with a common set of sensors, yet the problem of security becomes more complicated. In order to address the issue of security in networks with mobile nodes, we propose a machine learning solution for anomaly detection along with the feature extraction process that tries to detect temporal and spatial inconsistencies in the sequences of sensed values and the routing paths used to forward these values to the base station. We also propose a special way to treat mobile nodes, which is the main novelty of this work. The data produced in the presence of an attacker are treated as outliers, and detected using clustering techniques. These techniques are further coupled with a reputation system, in this way isolating compromised nodes in timely fashion. The proposal exhibits good performances at detecting and confining previously unseen attacks, including the cases when mobile nodes are compromised. PMID- 23112633 TI - A low-cost, portable, high-throughput wireless sensor system for phonocardiography applications. AB - This paper presents the design and testing of a wireless sensor system developed using a Microchip PICDEM developer kit to acquire and monitor human heart sounds for phonocardiography applications. This system can serve as a cost-effective option to the recent developments in wireless phonocardiography sensors that have primarily focused on Bluetooth technology. This wireless sensor system has been designed and developed in-house using off-the-shelf components and open source software for remote and mobile applications. The small form factor (3.75 cm * 5 cm * 1 cm), high throughput (6,000 Hz data streaming rate), and low cost ($13 per unit for a 1,000 unit batch) of this wireless sensor system make it particularly attractive for phonocardiography and other sensing applications. The experimental results of sensor signal analysis using several signal characterization techniques suggest that this wireless sensor system can capture both fundamental heart sounds (S1 and S2), and is also capable of capturing abnormal heart sounds (S3 and S4) and heart murmurs without aliasing. The results of a denoising application using Wavelet Transform show that the undesirable noises of sensor signals in the surrounding environment can be reduced dramatically. The exercising experiment results also show that this proposed wireless PCG system can capture heart sounds over different heart conditions simulated by varying heart rates of six subjects over a range of 60-180 Hz through exercise testing. PMID- 23112634 TI - Fast analysis of superoxide dismutase (SOD) activity in barley leaves using visible and near infrared spectroscopy. AB - Visible and near infrared (Vis/NIR) spectroscopy was investigated for the fast analysis of superoxide dismutase (SOD) activity in barley (Hordeum vulgare L.) leaves. Seven different spectra preprocessing methods were compared. Four regression methods were used for comparison of prediction performance, including partial least squares (PLS), multiple linear regression (MLR), least squares support vector machine (LS-SVM) and Gaussian process regress (GPR). Successive projections algorithm (SPA) and regression coefficients (RC) were applied to select effective wavelengths (EWs) to develop more parsimonious models. The results indicated that Savitzky-Golay smoothing (SG) and multiplicative scatter correction (MSC) should be selected as the optimum preprocessing methods. The best prediction performance was achieved by the LV-LS-SVM model on SG spectra, and the correlation coefficients (r) and root mean square error of prediction (RMSEP) were 0.9064 and 0.5336, respectively. The conclusion was that Vis/NIR spectroscopy combined with multivariate analysis could be successfully applied for the fast estimation of SOD activity in barley leaves. PMID- 23112635 TI - A comb-drive actuator driven by capacitively-coupled-power. AB - This paper presents a new actuation mechanism to drive comb-drive actuators. An asymmetric configuration of the finger overlap was used to generate capacitive coupling for the actuation mechanism. When the driving voltages were applied on the stators, a voltage would be induced at the rotor due to the capacitive coupling. Then, an electrostatic force would be exerted onto the rotor due to the voltage differences between the stators and the rotor. The actuator's static displacement and resonant frequency were theoretically analyzed. To verify the design, a comb-drive actuator with different initial finger overlaps, i.e., 159.3 MUm and 48.9 MUm on each side, was fabricated and tested. The results show that the actuator worked well using the proposed actuation mechanism. A static displacement of 41.7 MUm and a resonant frequency of 577 Hz were achieved. Using the actuation mechanism, no electrical connection is required between the rotor and the outside power supply. This makes some comb-drive actuators containing heterogeneous structures easy to design and actuate. PMID- 23112636 TI - Determination of soil pore water salinity using an FDR sensor working at various frequencies up to 500 MHz. AB - This paper presents the application of a frequency-domain reflectometry (FDR) sensor designed for soil salinity assessment of sandy mineral soils in a wide range of soil moisture and bulk electrical conductivity, through the determination of soil complex dielectric permittivity spectra in the frequency range 10-500 MHz. The real part of dielectric permittivity was assessed from the 380-440 MHz, while the bulk electrical conductivity was calculated from the 165 325 MHz range. The FDR technique allows determination of bulk electrical conductivity from the imaginary part of the complex dielectric permittivity, without disregarding the dielectric losses. The soil salinity status was determined using the salinity index, defined as a partial derivative of the soil bulk electrical conductivity with respect to the real part of the soil complex dielectric permittivity. The salinity index method enables determining the soil water electrical conductivity value. For the five sandy mineral soils that have been tested, the relationship between bulk electrical conductivity and the real part of dielectric permittivity is essentially linear. As a result, the salinity index method applied for FDR measurements may be adapted to field use after examination of loam and clayey soils. PMID- 23112637 TI - Novel fiber optic sensor probe with a pair of highly reflected connectors and a vessel of water absorption material for water leak detection. AB - The use of a fiber optic quasi-distributed sensing technique for detecting the location and severity of water leakage is suggested. A novel fiber optic sensor probe is devised with a vessel of water absorption material called as water combination soil (WCS) located between two highly reflected connectors: one is a reference connector and the other is a sensing connector. In this study, the sensing output is calculated from the reflected light signals of the two connectors. The first reflected light signal is a reference and the second is a sensing signal which is attenuated by the optical fiber bending loss due to the WCS expansion absorbing water. Also, the bending loss of each sensor probe is determined by referring to the total number of sensor probes and the total power budget of an entire system. We have investigated several probe characteristics to show the design feasibility of the novel fiber sensor probe. The effects of vessel sizes of the probes on the water detection sensitivity are studied. The largest vessel probe provides the highest sensitivity of 0.267 dB/mL, while the smallest shows relatively low sensitivity of 0.067 dB/mL, and unstable response. The sensor probe with a high output value provides a high sensitivity with various detection levels while the number of total installable sensor probes decreases. PMID- 23112638 TI - Aircraft aerodynamic parameter detection using micro hot-film flow sensor array and BP neural network identification. AB - Air speed, angle of sideslip and angle of attack are fundamental aerodynamic parameters for controlling most aircraft. For small aircraft for which conventional detecting devices are too bulky and heavy to be utilized, a novel and practical methodology by which the aerodynamic parameters are inferred using a micro hot-film flow sensor array mounted on the surface of the wing is proposed. A back-propagation neural network is used to model the coupling relationship between readings of the sensor array and aerodynamic parameters. Two different sensor arrangements are tested in wind tunnel experiments and dependence of the system performance on the sensor arrangement is analyzed. PMID- 23112639 TI - A beacon interval shifting scheme for interference mitigation in body area networks. AB - This paper investigates the issue of interference avoidance in body area networks (BANs). IEEE 802.15 Task Group 6 presented several schemes to reduce such interference, but these schemes are still not proper solutions for BANs. We present a novel distributed TDMA-based beacon interval shifting scheme that reduces interference in the BANs. A design goal of the scheme is to avoid the wakeup period of each BAN coinciding with other networks by employing carrier sensing before a beacon transmission. We analyze the beacon interval shifting scheme and investigate the proper back-off length when the channel is busy. We compare the performance of the proposed scheme with the schemes presented in IEEE 802.15 Task Group 6 using an OMNeT++ simulation. The simulation results show that the proposed scheme has a lower packet loss, energy consumption, and delivery latency than the schemes of IEEE 802.15 Task Group 6. PMID- 23112640 TI - Adaptive color calibration based one-shot structured light system. AB - In one-shot color structured light systems, the color of stripe patterns are typically distorted with respect to color crosstalk, ambient light and the albedo of the scanned objects, leading to mismatch in the correspondence of color stripes between the projected and captured images. In this paper, an adaptive color calibration and Discrete Trend Transform algorithm are presented to achieve high-resolution 3D reconstructions. The adaptive color calibration, according to the relative albedo in RGB channels, can improve the accuracy of labeling stripe by alleviating the effect of albedo and ambient light while decoding the color. Furthermore, the Discrete Trend Transform in the M channel makes the color calibration an effective method for detecting weak stripes due to the uneven surfaces or reflectance characteristics of the scanned objects. With this approach, the presented system is suitable for scanning moving objects and generating high-resolution 3D reconstructions without the need of dark laboratory environments. PMID- 23112641 TI - The combined application of impinger system and permeation tube for the generation of volatile organic compound standard gas mixtures at varying diluent flow rates. AB - Commercial standard gas generators are often complex and expensive devices. The objective of this research was to assess the performance of a simplified glass impinger system for standard gas generation from a permeation tube (PT) device. The performance of the impinger standard gas generation system was assessed for four aromatic VOCs (benzene, toluene, ethylbenzene, and m-xylene; BTEX) at varying flow rates (FR) of 50 to 800 mL.min(-1). Because actual permeation rate (APR) values deviated from those computed by the manufacturer's formula (MPR), new empirical relationships were developed to derive the predicted PR (PPR) of the target components. Experimental results corrected by such a formula indicate that the compatibility between the APR and MPR generally increased with low FR, while the reproducibility was generally reduced with decreasing flow rate. Although compatibility between different PRs is at a relatively small and narrow FR range, the use of correction formula is recommendable for the accurate use of PT. PMID- 23112642 TI - Use of a combined SpO2/PtcCO2 sensor in the delivery room. AB - Arterial oxygen saturation (SaO(2)) and partial arterial pressure of carbon dioxide (PaCO(2)) are important respiratory parameters in critically ill neonates. A sensor combining a pulse oximeter with the Stow-Severinghaus electrode, required for the measurement of peripheral oxygen saturation (SpO(2)) and transcutaneous partial pressure of carbon dioxide (PtcCO(2)), respectively, has been recently used in neonatal clinical practice (TOSCA(500O)Radiometer). We evaluated TOSCA usability and reliability in the delivery room (DR), throughout three different periods, on term, late-preterm, and preterm neonates. During the first period (period A), 30 healthy term neonates were simultaneously monitored with both TOSCA and a MASIMO pulse oximeter. During the second period (period B), 10 healthy late-preterm neonates were monitored with both TOSCA and a transcutaneous device measuring PtcCO(2) (TINA(O) TCM3, Radiometer). During the third period (period C), 15 preterm neonates were monitored with TOSCA and MASIMO after birth, during stabilization, and during transport to the neonatal intensive care unit (NICU). Blood gas analyses were performed to compare transcutaneous and blood gas values. TOSCA resulted easily and safely usable in the DR, allowing reliable noninvasive SaO(2) estimation. Since PtcCO(2) measurements with TOSCA required at least 10 min to be stable and reliable, this parameter was not useful during the early resuscitation immediately after birth. Moreover, PtcCO(2) levels were less precise if compared to the conventional transcutaneous monitoring. However, PtcCO(2) measurement by TOSCA was useful as trend-monitoring after stabilization and during transport to NICU. PMID- 23112643 TI - A comparison between metaheuristics as strategies for minimizing cyclic instability in Ambient Intelligence. AB - In this paper we present a comparison between six novel approaches to the fundamental problem of cyclic instability in Ambient Intelligence. These approaches are based on different optimization algorithms, Particle Swarm Optimization (PSO), Bee Swarm Optimization (BSO), micro Particle Swarm Optimization (MU-PSO), Artificial Immune System (AIS), Genetic Algorithm (GA) and Mutual Information Maximization for Input Clustering (MIMIC). In order to be able to use these algorithms, we introduced the concept of Average Cumulative Oscillation (ACO), which enabled us to measure the average behavior of the system. This approach has the advantage that it does not need to analyze the topological properties of the system, in particular the loops, which can be computationally expensive. In order to test these algorithms we used the well known discrete system called the Game of Life for 9, 25, 49 and 289 agents. It was found that PSO and MU-PSO have the best performance in terms of the number of agents locked. These results were confirmed using the Wilcoxon Signed Rank Test. This novel and successful approach is very promising and can be used to remove instabilities in real scenarios with a large number of agents (including nomadic agents) and complex interactions and dependencies among them. PMID- 23112645 TI - Fault diagnostics for turbo-shaft engine sensors based on a simplified on-board model. AB - Combining a simplified on-board turbo-shaft model with sensor fault diagnostic logic, a model-based sensor fault diagnosis method is proposed. The existing fault diagnosis method for turbo-shaft engine key sensors is mainly based on a double redundancies technique, and this can't be satisfied in some occasions as lack of judgment. The simplified on-board model provides the analytical third channel against which the dual channel measurements are compared, while the hardware redundancy will increase the structure complexity and weight. The simplified turbo-shaft model contains the gas generator model and the power turbine model with loads, this is built up via dynamic parameters method. Sensor fault detection, diagnosis (FDD) logic is designed, and two types of sensor failures, such as the step faults and the drift faults, are simulated. When the discrepancy among the triplex channels exceeds a tolerance level, the fault diagnosis logic determines the cause of the difference. Through this approach, the sensor fault diagnosis system achieves the objectives of anomaly detection, sensor fault diagnosis and redundancy recovery. Finally, experiments on this method are carried out on a turbo-shaft engine, and two types of faults under different channel combinations are presented. The experimental results show that the proposed method for sensor fault diagnostics is efficient. PMID- 23112646 TI - Closed loop control of penetration depth during CO2 laser lap welding processes. AB - In this paper we describe a novel spectroscopic closed loop control system capable of stabilizing the penetration depth during laser welding processes by controlling the laser power. Our novel approach is to analyze the optical emission from the laser generated plasma plume above the keyhole, to calculate its electron temperature as a process-monitoring signal. Laser power has been controlled by using a quantitative relationship between the penetration depth and the plasma electron temperature. The sensor is able to correlate in real time the difference between the measured electron temperature and its reference value for the requested penetration depth. Accordingly the closed loop system adjusts the power, thus maintaining the penetration depth. PMID- 23112644 TI - Fully integrated biochip platforms for advanced healthcare. AB - Recent advances in microelectronics and biosensors are enabling developments of innovative biochips for advanced healthcare by providing fully integrated platforms for continuous monitoring of a large set of human disease biomarkers. Continuous monitoring of several human metabolites can be addressed by using fully integrated and minimally invasive devices located in the sub-cutis, typically in the peritoneal region. This extends the techniques of continuous monitoring of glucose currently being pursued with diabetic patients. However, several issues have to be considered in order to succeed in developing fully integrated and minimally invasive implantable devices. These innovative devices require a high-degree of integration, minimal invasive surgery, long-term biocompatibility, security and privacy in data transmission, high reliability, high reproducibility, high specificity, low detection limit and high sensitivity. Recent advances in the field have already proposed possible solutions for several of these issues. The aim of the present paper is to present a broad spectrum of recent results and to propose future directions of development in order to obtain fully implantable systems for the continuous monitoring of the human metabolism in advanced healthcare applications. PMID- 23112647 TI - Long-term stability of the SGA-WZ strapdown airborne gravimeter. AB - Accelerometers are one of the most important sensors in a strapdown airborne gravimeter. The accelerometer's drift determines the long-term accuracy of the strapdown inertial navigation system (SINS), which is the primary and most critical component of the strapdown airborne gravimeter. A long-term stability test lasting 104 days was conducted to determine the characteristics of the strapdown airborne gravimeter's long-term drift. This stability test was based on the first set of strapdown airborne gravimeters built in China, the SGA-WZ. The test results reveal a quadratic drift in the strapdown airborne gravimeter data. A drift model was developed using the static data in the two end sections, and then this model was used to correct the test data. After compensating for the drift, the drift effect improved from 70 mGal to 3.46 mGal with a standard deviation of 0.63 mGal. The quadratic curve better reflects the drift's real characteristics. In comparison with other methodologies, modelling the drift as a quadratic curve was shown to be more appropriate. Furthermore, this method allows the drift to be adjusted throughout the course of the entire campaign. PMID- 23112648 TI - Design and fabrication of a large-stroke deformable mirror using a gear-shape ionic-conductive polymer metal composite. AB - Conventional camera modules with image sensors manipulate the focus or zoom by moving lenses. Although motors, such as voice-coil motors, can move the lens sets precisely, large volume, high power consumption, and long moving time are critical issues for motor-type camera modules. A deformable mirror (DM) provides a good opportunity to improve these issues. The DM is a reflective type optical component which can alter the optical power to focus the lights on the two dimensional optical image sensors. It can make the camera system operate rapidly. Ionic polymer metal composite (IPMC) is a promising electro-actuated polymer material that can be used in micromachining devices because of its large deformation with low actuation voltage. We developed a convenient simulation model based on Young's modulus and Poisson's ratio. We divided an ion exchange polymer, also known as Nafion((r)), into two virtual layers in the simulation model: one was expansive and the other was contractive, caused by opposite constant surface forces on each surface of the elements. Therefore, the deformation for different IPMC shapes can be described more easily. A standard experiment of voltage vs. tip displacement was used to verify the proposed modeling. Finally, a gear shaped IPMC actuator was designed and tested. Optical power of the IPMC deformable mirror is experimentally demonstrated to be 17 diopters with two volts. The needed voltage was about two orders lower than conventional silicon deformable mirrors and about one order lower than the liquid lens. PMID- 23112649 TI - A survey on clustering routing protocols in wireless sensor networks. AB - The past few years have witnessed increased interest in the potential use of wireless sensor networks (WSNs) in a wide range of applications and it has become a hot research area. Based on network structure, routing protocols in WSNs can be divided into two categories: flat routing and hierarchical or clustering routing. Owing to a variety of advantages, clustering is becoming an active branch of routing technology in WSNs. In this paper, we present a comprehensive and fine grained survey on clustering routing protocols proposed in the literature for WSNs. We outline the advantages and objectives of clustering for WSNs, and develop a novel taxonomy of WSN clustering routing methods based on complete and detailed clustering attributes. In particular, we systematically analyze a few prominent WSN clustering routing protocols and compare these different approaches according to our taxonomy and several significant metrics. Finally, we summarize and conclude the paper with some future directions. PMID- 23112650 TI - An intelligent knowledge-based and customizable home care system framework with ubiquitous patient monitoring and alerting techniques. AB - This study develops and integrates an efficient knowledge-based system and a component-based framework to design an intelligent and flexible home health care system. The proposed knowledge-based system integrates an efficient rule-based reasoning model and flexible knowledge rules for determining efficiently and rapidly the necessary physiological and medication treatment procedures based on software modules, video camera sensors, communication devices, and physiological sensor information. This knowledge-based system offers high flexibility for improving and extending the system further to meet the monitoring demands of new patient and caregiver health care by updating the knowledge rules in the inference mechanism. All of the proposed functional components in this study are reusable, configurable, and extensible for system developers. Based on the experimental results, the proposed intelligent homecare system demonstrates that it can accomplish the extensible, customizable, and configurable demands of the ubiquitous healthcare systems to meet the different demands of patients and caregivers under various rehabilitation and nursing conditions. PMID- 23112651 TI - A hybrid TOA-fingerprinting based localization of mobile nodes using UWB signaling for Non-line-of-sight conditions. AB - Recently, Impulse Radio Ultra Wideband (IR-UWB) signaling has become popular for providing precise location accuracy for mobile and wireless sensor node localization in the indoor environment due to its large bandwidth and high time resolution while providing ultra-high transmission capacity. However, the Non line-of-sight (NLOS) error mitigation has considerable importance in localization of wireless nodes. In order to mitigate NLOS errors in indoor localization this paper proposes and investigates a novel approach which creates a hybrid combination of channel impulse response (CIR)-based fingerprinting (FP) positioning and an iterative Time of Arrival (TOA) real time positioning method using Ultra Wideband (UWB) signaling. Besides, to reduce the calculation complexities in FP method, this paper also introduces a unique idea for the arrangement of reference nodes (or tags) to create a fingerprinting database. The simulation results confirm that the proposed hybrid method yields better positioning accuracies and is much more robust in NLOS error mitigation than TOA only and FP only and a conventional iterative positioning method. PMID- 23112652 TI - Noise smoothing for structural vibration test signals using an improved wavelet thresholding technique. AB - In structural vibration tests, one of the main factors which disturb the reliability and accuracy of the results are the noise signals encountered. To overcome this deficiency, this paper presents a discrete wavelet transform (DWT) approach to denoise the measured signals. The denoising performance of DWT is discussed by several processing parameters, including the type of wavelet, decomposition level, thresholding method, and threshold selection rules. To overcome the disadvantages of the traditional hard- and soft-thresholding methods, an improved thresholding technique called the sigmoid function-based thresholding scheme is presented. The procedure is validated by using four benchmarks signals with three degrees of degradation as well as a real measured signal obtained from a three-story reinforced concrete scale model shaking table experiment. The performance of the proposed method is evaluated by computing the signal-to-noise ratio (SNR) and the root-mean-square error (RMSE) after denoising. Results reveal that the proposed method offers superior performance than the traditional methods no matter whether the signals have heavy or light noises embedded. PMID- 23112653 TI - Complete scene recovery and terrain classification in textured terrain meshes. AB - Terrain classification allows a mobile robot to create an annotated map of its local environment from the three-dimensional (3D) and two-dimensional (2D) datasets collected by its array of sensors, including a GPS receiver, gyroscope, video camera, and range sensor. However, parts of objects that are outside the measurement range of the range sensor will not be detected. To overcome this problem, this paper describes an edge estimation method for complete scene recovery and complete terrain reconstruction. Here, the Gibbs-Markov random field is used to segment the ground from 2D videos and 3D point clouds. Further, a masking method is proposed to classify buildings and trees in a terrain mesh. PMID- 23112654 TI - Biotin-functionalized semiconducting polymer in an organic field effect transistor and application as a biosensor. AB - This report presents biotin-functionalized semiconducting polymers that are based on fluorene and bithiophene co-polymers (F8T2). Also presented is the application of these polymers to an organic thin film transistor used as a biosensor. The side chains of fluorene were partially biotinylated after the esterification of the biotin with corresponding alcohol-groups at the side chain in F8T2. Their properties as an organic semiconductor were tested using an organic thin film transistor (OTFT) and were found to show typical p-type semiconductor curves. The functionality of this biosensor in the sensing of biologically active molecules such as avidin in comparison with bovine serum albumin (BSA) was established through a selective decrease in the conductivity of the transistor, as measured with a device that was developed by the authors. Changes to the optical properties of this polymer were also measured through the change in the color of the UV-fluorescence before and after a reaction with avidin or BSA. PMID- 23112655 TI - Three-dimensional laser scanning for geometry documentation and construction management of highway tunnels during excavation. AB - Driven by progress in sensor technology, computer software and data processing capabilities, terrestrial laser scanning has recently proved a revolutionary technique for high accuracy, 3D mapping and documentation of physical scenarios and man-made structures. Particularly, this is of great importance in the underground space and tunnel construction environment as surveying engineering operations have a great impact on both technical and economic aspects of a project. This paper discusses the use and explores the potential of laser scanning technology to accurately track excavation and construction activities of highway tunnels. It provides a detailed overview of the static laser scanning method, its principles of operation and applications for tunnel construction operations. Also, it discusses the planning, execution, data processing and analysis phases of laser scanning activities, with emphasis given on geo referencing, mesh model generation and cross-section extraction. Specific case studies are considered based on two construction sites in Greece. Particularly, the potential of the method is examined for checking the tunnel profile, producing volume computations and validating the smoothness/thickness of shotcrete layers at an excavation stage and during the completion of excavation support and primary lining. An additional example of the use of the method in the geometric documentation of the concrete lining formwork is examined and comparisons against dimensional tolerances are examined. Experimental comparisons and analyses of the laser scanning method against conventional surveying techniques are also considered. PMID- 23112656 TI - A semi-automatic image-based close range 3D modeling pipeline using a multi camera configuration. AB - The generation of photo-realistic 3D models is an important task for digital recording of cultural heritage objects. This study proposes an image-based 3D modeling pipeline which takes advantage of a multi-camera configuration and multi image matching technique that does not require any markers on or around the object. Multiple digital single lens reflex (DSLR) cameras are adopted and fixed with invariant relative orientations. Instead of photo-triangulation after image acquisition, calibration is performed to estimate the exterior orientation parameters of the multi-camera configuration which can be processed fully automatically using coded targets. The calibrated orientation parameters of all cameras are applied to images taken using the same camera configuration. This means that when performing multi-image matching for surface point cloud generation, the orientation parameters will remain the same as the calibrated results, even when the target has changed. Base on this invariant character, the whole 3D modeling pipeline can be performed completely automatically, once the whole system has been calibrated and the software was seamlessly integrated. Several experiments were conducted to prove the feasibility of the proposed system. Images observed include that of a human being, eight Buddhist statues, and a stone sculpture. The results for the stone sculpture, obtained with several multi-camera configurations were compared with a reference model acquired by an ATOS-I 2M active scanner. The best result has an absolute accuracy of 0.26 mm and a relative accuracy of 1:17,333. It demonstrates the feasibility of the proposed low-cost image-based 3D modeling pipeline and its applicability to a large quantity of antiques stored in a museum. PMID- 23112657 TI - Switching algorithm for maglev train double-modular redundant positioning sensors. AB - High-resolution positioning for maglev trains is implemented by detecting the tooth-slot structure of the long stator installed along the rail, but there are large joint gaps between long stator sections. When a positioning sensor is below a large joint gap, its positioning signal is invalidated, thus double-modular redundant positioning sensors are introduced into the system. This paper studies switching algorithms for these redundant positioning sensors. At first, adaptive prediction is applied to the sensor signals. The prediction errors are used to trigger sensor switching. In order to enhance the reliability of the switching algorithm, wavelet analysis is introduced to suppress measuring disturbances without weakening the signal characteristics reflecting the stator joint gap based on the correlation between the wavelet coefficients of adjacent scales. The time delay characteristics of the method are analyzed to guide the algorithm simplification. Finally, the effectiveness of the simplified switching algorithm is verified through experiments. PMID- 23112658 TI - A self-optimizing scheme for energy balanced routing in Wireless Sensor Networks using SensorAnt. AB - Planning of energy-efficient protocols is critical for Wireless Sensor Networks (WSNs) because of the constraints on the sensor nodes' energy. The routing protocol should be able to provide uniform power dissipation during transmission to the sink node. In this paper, we present a self-optimization scheme for WSNs which is able to utilize and optimize the sensor nodes' resources, especially the batteries, to achieve balanced energy consumption across all sensor nodes. This method is based on the Ant Colony Optimization (ACO) metaheuristic which is adopted to enhance the paths with the best quality function. The assessment of this function depends on multi-criteria metrics such as the minimum residual battery power, hop count and average energy of both route and network. This method also distributes the traffic load of sensor nodes throughout the WSN leading to reduced energy usage, extended network life time and reduced packet loss. Simulation results show that our scheme performs much better than the Energy Efficient Ant-Based Routing (EEABR) in terms of energy consumption, balancing and efficiency. PMID- 23112659 TI - Energy-efficient scheduling for hybrid tasks in control devices for the Internet of Things. AB - In control devices for the Internet of Things (IoT), energy is one of the critical restriction factors. Dynamic voltage scaling (DVS) has been proved to be an effective method for reducing the energy consumption of processors. This paper proposes an energy-efficient scheduling algorithm for IoT control devices with hard real-time control tasks (HRCTs) and soft real-time tasks (SRTs). The main contribution of this paper includes two parts. First, it builds the Hybrid tasks with multi-subtasks of different function Weight (HoW) task model for IoT control devices. HoW describes the structure of HRCTs and SRTs, and their properties, e.g., deadlines, execution time, preemption properties, and energy-saving goals, etc. Second, it presents the Hybrid Tasks' Dynamic Voltage Scaling (HTDVS) algorithm. HTDVS first sets the slowdown factors of subtasks while meeting the different real-time requirements of HRCTs and SRTs, and then dynamically reclaims, reserves, and reuses the slack time of the subtasks to meet their ideal energy-saving goals. Experimental results show HTDVS can reduce energy consumption about 10%-80% while meeting the real-time requirements of HRCTs, HRCTs help to reduce the deadline miss ratio (DMR) of systems, and HTDVS has comparable performance with the greedy algorithm and is more favorable to keep the subtasks' ideal speeds. PMID- 23112660 TI - An improved force feedback control algorithm for active tendons. AB - An active tendon, consisting of a displacement actuator and a co-located force sensor, has been adopted by many studies to suppress the vibration of large space flexible structures. The damping, provided by the force feedback control algorithm in these studies, is small and can increase, especially for tendons with low axial stiffness. This study introduces an improved force feedback algorithm, which is based on the idea of velocity feedback. The algorithm provides a large damping ratio for space flexible structures and does not require a structure model. The effectiveness of the algorithm is demonstrated on a structure similar to JPL-MPI. The results show that large damping can be achieved for the vibration control of large space structures. PMID- 23112661 TI - Miniaturized integrated platform for electrical and optical monitoring of cell cultures. AB - The following paper describes the design and functions of a miniaturized integrated platform for optical and electrical monitoring of cell cultures and the necessary steps in the fabrication and testing of a silicon microchip Micro ElectroMechanical Systems (MEMS)-based technology for cell data recording, monitoring and stimulation. The silicon microchip consists of a MEMS machined device containing a shank of 240 MUm width, 3 mm long and 50 MUm thick and an enlarged area of 5 mm * 5 mm hosting the pads for electrical connections. Ten platinum electrodes and five sensors are placed on the shank and are connected with the external electronics through the pads. The sensors aim to monitor the pH, the temperature and the impedance of the cell culture. The electrodes are bidirectional and can be used both for electrical potential recording and stimulation of cells. The fabrication steps are presented, along with the electrical and optical characterization of the system. The target of the research is to develop a new and reconfigurable platform according to the particular applications needs, as a tool for the biologist, chemists and medical doctors working is the field of cell culture monitoring in terms of growth, maintenance conditions, reaction to electrical or chemical stimulation (drugs, toxicants, etc.). HaCaT (Immortalised Human Keratinocyte) cell culture has been used for demonstration purposes in order to provide information on the platform electrical and optical functions. PMID- 23112662 TI - Real time voltage and current phase shift analyzer for power saving applications. AB - Nowadays, high importance is given to low energy devices (such as refrigerators, deep-freezers, washing machines, pumps, etc.) that are able to produce reactive power in power lines which can be optimized (reduced). Reactive power is the main component which overloads power lines and brings excessive thermal stress to conductors. If the reactive power is optimized, it can significantly lower the electricity consumption (from 10 to 30%-varies between countries). This paper will examine and discuss the development of a measuring device for analyzing reactive power. However, the main problem is the precise real time measurement of the input and output voltage and current. Such quality measurement is needed to allow adequate action intervention (feedback which reduces or fully compensates reactive power). Several other issues, such as the accuracy and measurement speed, must be examined while designing this device. The price and the size of the final product need to remain low as they are the two important parameters of this solution. PMID- 23112663 TI - Development and application of integrated optical sensors for intense E-field measurement. AB - The measurement of intense E-fields is a fundamental need in various research areas. Integrated optical E-field sensors (IOESs) have important advantages and are potentially suitable for intense E-field detection. This paper comprehensively reviews the development and applications of several types of IOESs over the last 30 years, including the Mach-Zehnder interferometer (MZI), coupler interferometer (CI) and common path interferometer (CPI). The features of the different types of IOESs are compared, showing that the MZI has higher sensitivity, the CI has a controllable optical bias, and the CPI has better temperature stability. More specifically, the improvement work of applying IOESs to intense E-field measurement is illustrated. Finally, typical uses of IOESs in the measurement of intense E-fields are demonstrated, including application areas such as E-fields with different frequency ranges in high-voltage engineering, simulated nuclear electromagnetic pulse in high-power electromagnetic pulses, and ion-accelerating field in high-energy physics. PMID- 23112664 TI - Enhancing health care delivery through ambient intelligence applications. AB - This paper presents the implementation of a smart environment that employs Ambient Intelligence technologies in order to augment a typical hospital room with smart features that assist both patients and medical staff. In this environment various wireless and wired sensor technologies have been integrated, allowing the patient to control the environment and interact with the hospital facilities, while a clinically oriented interface allows for vital sign monitoring. The developed applications are presented both from a patient's and a doctor's perspective, offering different services depending on the user's role. The results of the evaluation process illustrate the need for such a service, leading to important conclusions about the usefulness and crucial role of AmI in health care. PMID- 23112666 TI - CANoE: a context-aware notification model to support the care of older adults in a nursing home. AB - Taking care of elders in a nursing home is not an easy task. Caregivers face two major problems: a lack of awareness of the situations surrounding the elderly care and the lack of information regarding the availability and the activities of other caregivers to support their coordination process. Various efforts have proposed solutions to cope with these problems, but they do it without considering all the requirements imposed by the criticality of this type of environment. In this paper we propose CANoE, a model for the design of context aware notifications in critical environments, such as a nursing home. The main feature of this model is that it considers three sources of context (the environment, and the issuer and the receiver of the notification) for adapting the content, the terms of delivery and the presentation of the notification message. Based on the CANoE model we developed the CANoE-Aw and CU-IDA systems, which were evaluated through two case studies in a nursing home. The results of these evaluations provide evidence that caregivers achieved an increased awareness of the situations of care of the elderly and perceived the systems as adequate tools to support their coordination while attending a situation of care. PMID- 23112667 TI - Recent advances in paper-based sensors. AB - Paper-based sensors are a new alternative technology for fabricating simple, low cost, portable and disposable analytical devices for many application areas including clinical diagnosis, food quality control and environmental monitoring. The unique properties of paper which allow passive liquid transport and compatibility with chemicals/biochemicals are the main advantages of using paper as a sensing platform. Depending on the main goal to be achieved in paper-based sensors, the fabrication methods and the analysis techniques can be tuned to fulfill the needs of the end-user. Current paper-based sensors are focused on microfluidic delivery of solution to the detection site whereas more advanced designs involve complex 3-D geometries based on the same microfluidic principles. Although paper-based sensors are very promising, they still suffer from certain limitations such as accuracy and sensitivity. However, it is anticipated that in the future, with advances in fabrication and analytical techniques, that there will be more new and innovative developments in paper-based sensors. These sensors could better meet the current objectives of a viable low-cost and portable device in addition to offering high sensitivity and selectivity, and multiple analyte discrimination. This paper is a review of recent advances in paper-based sensors and covers the following topics: existing fabrication techniques, analytical methods and application areas. Finally, the present challenges and future outlooks are discussed. PMID- 23112669 TI - Novel system for bite-force sensing and monitoring based on magnetic near field communication. AB - Intraoral devices for bite-force sensing have several applications in odontology and maxillofacial surgery, as bite-force measurements provide additional information to help understand the characteristics of bruxism disorders and can also be of help for the evaluation of post-surgical evolution and for comparison of alternative treatments. A new system for measuring human bite forces is proposed in this work. This system has future applications for the monitoring of bruxism events and as a complement for its conventional diagnosis. Bruxism is a pathology consisting of grinding or tight clenching of the upper and lower teeth, which leads to several problems such as lesions to the teeth, headaches, orofacial pain and important disorders of the temporomandibular joint. The prototype uses a magnetic field communication scheme similar to low-frequency radio frequency identification (RFID) technology (NFC). The reader generates a low-frequency magnetic field that is used as the information carrier and powers the sensor. The system is notable because it uses an intra-mouth passive sensor and an external interrogator, which remotely records and processes information regarding a patient's dental activity. This permits a quantitative assessment of bite-force, without requiring intra-mouth batteries, and can provide supplementary information to polysomnographic recordings, current most adequate early diagnostic method, so as to initiate corrective actions before irreversible dental wear appears. In addition to describing the system's operational principles and the manufacture of personalized prototypes, this report will also demonstrate the feasibility of the system and results from the first in vitro and in vivo trials. PMID- 23112677 TI - A fast and sensitive quantitative lateral flow immunoassay for Cry1Ab based on a novel signal amplification conjugate. AB - A novel lateral flow immunoassay (LFIA) signal amplification strategy for the detection of Cry1Ab based on amplification via a polylysine (PL) chain and biotin streptavidin system (BSAS) is described. In this system, multiple fluorescence dyes (FL) were directly coated on the surface of PL and conjugated with antibody via the BSAS for construction of novel signal amplification (FLPL-BSAS-mAb1) conjugates, in which FL, PL and BSAS were employed to improve the sensitivity of LFIA. Compared with conventional LFIA, the sensitivity of FLPL-BSAS-mAb1-based LFIA was increased by approximately 100-fold. Quantified linearity was achieved in the value range of 0-1,000 pg/mL. The limit of detection (LOD) was reached 10 pg/mL after optimization of reaction conditions. To our knowledge, this represents one of the most sensitive LFIA for Cry1Ab yet reported. Furthermore, the detection time for this method was about 10 min. Therefore, it should be an attractive alternative compared to conventional immunoassays in routine control for Cry1Ab. PMID- 23112678 TI - A novel method for measuring in-shoe navicular drop during gait. AB - Analysis of foot movement is essential in the treatment and prevention of foot related disorders. Measuring the in-shoe foot movement during everyday activities, such as sports, has the potential to become an important diagnostic tool in clinical practice. The current paper describes the development of a thin, flexible and robust capacitive strain sensor for the in-shoe measurement of the navicular drop. The navicular drop is a well-recognized measure of foot movement. The position of the strain sensor on the foot was analyzed to determine the optimal points of attachment. The sensor was evaluated against a state-of-the-art video-based system that tracks reflective markers on the bare foot. Preliminary experimental results show that the developed strain sensor is able to measure navicular drop on the bare foot with an accuracy on par with the video-based system and with a high reproducibility. Temporal comparison of video-based, barefoot and in-shoe measurements indicate that the developed sensor measures the navicular drop accurately in shoes and can be used without any discomfort for the user. PMID- 23112686 TI - Instrumentation in developing chlorophyll fluorescence biosensing: a review. AB - Chlorophyll fluorescence can be defined as the red and far-red light emitted by photosynthetic tissue when it is excited by a light source. This is an important phenomenon which permits investigators to obtain important information about the state of health of a photosynthetic sample. This article reviews the current state of the art knowledge regarding the design of new chlorophyll fluorescence sensing systems, providing appropriate information about processes, instrumentation and electronic devices. These types of systems and applications can be created to determine both comfort conditions and current problems within a given subject. The procedure to measure chlorophyll fluorescence is commonly split into two main parts; the first involves chlorophyll excitation, for which there are passive or active methods. The second part of the procedure is to closely measure the chlorophyll fluorescence response with specialized instrumentation systems. Such systems utilize several methods, each with different characteristics regarding to cost, resolution, ease of processing or portability. These methods for the most part include cameras, photodiodes and satellite images. PMID- 23112689 TI - Slope estimation during normal walking using a shank-mounted inertial sensor. AB - In this paper we propose an approach for the estimation of the slope of the walking surface during normal walking using a body-worn sensor composed of a biaxial accelerometer and a uniaxial gyroscope attached to the shank. It builds upon a state of the art technique that was successfully used to estimate the walking velocity from walking stride data, but did not work when used to estimate the slope of the walking surface. As claimed by the authors, the reason was that it did not take into account the actual inclination of the shank of the stance leg at the beginning of the stride (mid stance). In this paper, inspired by the biomechanical characteristics of human walking, we propose to solve this issue by using the accelerometer as a tilt sensor, assuming that at mid stance it is only measuring the gravity acceleration. Results from a set of experiments involving several users walking at different inclinations on a treadmill confirm the feasibility of our approach. A statistical analysis of slope estimations shows in first instance that the technique is capable of distinguishing the different slopes of the walking surface for every subject. It reports a global RMS error (per-unit difference between actual and estimated inclination of the walking surface for each stride identified in the experiments) of 0.05 and this can be reduced to 0.03 with subject-specific calibration and post processing procedures by means of averaging techniques. PMID- 23112690 TI - In vivo histamine optical nanosensors. AB - In this communication we discuss the development of ionophore based nanosensors for the detection and monitoring of histamine levels in vivo. This approach is based on the use of an amine-reactive, broad spectrum ionophore which is capable of recognizing and binding to histamine. We pair this ionophore with our already established nanosensor platform, and demonstrate in vitro and in vivo monitoring of histamine levels. This approach enables capturing rapid kinetics of histamine after injection, which are more difficult to measure with standard approaches such as blood sampling, especially on small research models. The coupling together of in vivo nanosensors with ionophores such as nonactin provide a way to generate nanosensors for novel targets without the difficult process of designing and synthesizing novel ionophores. PMID- 23112693 TI - Force monitoring in a maxilla model and dentition using optical fiber Bragg gratings. AB - The aim of this work is to show the possibility of using fiber optic sensors to instrument inside parts of an artificial maxilla and measure internal tension transmitted by the orthodontic and orthopedic appliances to the dentition and the adjacent bone. Bragg gratings written in a standard optical fiber were used to monitor the maxillary teeth and a multiplexed fiber was used to monitor the surface of the maxillary bone, transversally to the longest axis of the teeth. A Universal Test Machine was used to evaluate the sensitivity of the sensor to the vertical and lateral forces applied on the teeth. A wavelength shift of approximately 0.30 nm was detected when applying loads ranging from 0 to 20 N. By applying forces using the standard orthodontic appliances installed on the dentition it was possible to detect a range of forces between 0.025 N to 0.035 N during the activation of the arch wire and extra-oral forces. The use of the internal sensors in an artificial model made possible the monitoring of the resulting forces on the internal parts of the teeth and at the position where the strain takes place within the maxilla. The sensors detected that the orthodontic forces were not transmitted to the surface of the maxilla. This information is important to elucidate and to correlate undesirable effects as tooth root absorption and local pain during the orthodontic treatment. PMID- 23112697 TI - Grapefruit fiber filled with silver nanowires surface plasmon resonance sensor in aqueous environments. AB - A kind of surface plasmon resonance sensor based on grapefruit photonic crystal fiber (PCF) filled with different numbers of silver nanowires has been studied in this paper. The surface plasmon resonance modes and the sensing properties are investigated comprehensively using the finite element method (FEM). The simulation results show that the intensity sensitivity is related to nanowire numbers and the distance between two nanowires. The optimum value obtained is 2,400 nm/RIU, corresponding to a resolution of 4.51 * 10(-5) RIU with a maximum distance of 2 MUm. To a certain extent, the PCF filled with more nanowires is better than with just one. Furthermore, the air holes of grapefruit PCF are large enough to operate in practice. Moreover, the irregularity of the filled nanowires has no effect on sensitivity, which will be very convenient for the implementation of experiments. PMID- 23112707 TI - Optical sensors based on plastic fibers. AB - The recent advances of polymer technology allowed the introduction of plastic optical fiber in sensor design. The advantages of optical metrology with plastic optical fiber have attracted the attention of the scientific community, as they allow the development of low-cost or cost competitive systems compared with conventional technologies. In this paper, the current state of the art of plastic optical fiber technology will be reviewed, namely its main characteristics and sensing advantages. Several measurement techniques will be described, with a strong focus on interrogation approaches based on intensity variation in transmission and reflection. The potential applications involving structural health monitoring, medicine, environment and the biological and chemical area are also presented.